new ring transformations of 1,2,3-dithiazoles

DEPARTMENT OF CHEMISTRY

NEW RING TRANSFORMATIONS OF

1,2,3-DITHIAZOLES

MARIA KOYIONI

A Dissertation Submitted to the University of Cyprus in Partial

Fulfillment of the Requirements for the Degree of Doctor of

Philosophy

November 2016

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© Maria Koyioni, 2016

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VALIDATION PAGE

Doctoral Candidate: Maria Koyioni

Doctoral Thesis Title: New Ring Transformations of 1,2,3-Dithiazoles

The present Doctoral Dissertation was submitted in partial fulfillment of the requirements

for the degree of Doctor of Philosophy at the Department of Chemistry and was approved

on the 20th of December 2016 by the members of the Examination Committee.

Examination Committee:

1. Dr. Savvas N. Georgiades, University of Cyprus (Committee Chairman)

..…….…………..……………..

2. Prof. Donald Craig, Imperial College London, UK (External Examiner)

..…….…………..……………..

3. Dr. Sławomir Szafert, University of Wrocław, Poland (External Examiner)

..…….…………..……………..

4. Dr. Athanassios Nicolaides, University of Cyprus (Internal Examiner)

..…….…………..……………..

5. Prof. Panayiotis A. Koutentis, University of Cyprus (Research Supervisor)

..…….…………..……………..

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DECLARATION OF DOCTORAL CANDIDATE

The present doctoral dissertation was submitted in partial fulfillment of the requirements

for the degree of Doctor of Philosophy of the University of Cyprus. The work described

within this Thesis has been carried out exclusively by Maria Koyioni at the Organic

Chemistry Research Laboratory, Department of Chemistry, University of Cyprus under the

supervision of Professor Panayiotis A. Koutentis (September 2010 - October 2016).

The exceptions include: the initial optimization study on the ring transformation of

N-azinyldithiazolimines to azino-fused thiazoles in Chapter 2 performed by Dr. Sophia S.

Michaelidou, the elemental analysis of all compounds performed by Stephen Boyer at

London Metropolitan University and the single crystal X-ray crystallographic studies

performed by Dr. Maria Manoli and Dr. Manolis J. Manos.

Date

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Signature

……………………….

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ΠΕΡΙΛΗΨΗ

Η παρούσα Διδακτορική Διατριβή αρχίζει με μία σύντομη εισαγωγή στην ετεροκυκλική

χημεία, η οποία στη συνέχεια επικεντρώνεται σε S,N-ετεροκυκλικές ενώσεις πλούσιες σε

θείο, και συγκεκριμένα στη χρήση των 1,2,3-διθειαζολών στην οργανική σύνθεση, με

έμφαση στον τύπο μηχανισμού της αντίδρασης που λαμβάνει χώρα.

Στο Κεφάλαιο 2, ο μετασχηματισμός δακτυλίου τύπου ANRORC Ν-αζινυλ-4-χλωρο-5Η-

1,2,3-διθειαζολ-5-ιμινών 61a-b και 62a-l σε αζινο-θειαζόλες 55a-b και 63a-l, του οποίου η

ανακάλυψη έγινε από προηγούμενο μέλος της ομάδας, τη Δρ. Σοφία Σ. Μιχαηλίδου,

μελετήθηκε ως προς το εύρος εφαρμογής και τους περιορισμούς του.

Στο Κεφάλαιο 3, μελετήθηκε η αντίδραση του 4,5-διχλωρο-1,2,3-διθειαζολικού χλωριδίου

1 με 5-αμινοπυραζόλες, η οποία δίνει ως κύρια προϊόντα τα 6Η-πυραζολο[3,4-c]-

ισοθειαζολο-3-καρβονιτρίλια 70 και τις 4-χλωρο-Ν-(πυραζολ-5-υλ)-5Η-1,2,3-διθειαζολ-5-

ιμίνες 68. Η αναλογία 70:68 μπορεί να μεταβληθεί με αλλαγή του pΗ του μέσου της

αντίδρασης. Κρυσταλλογραφία ακτίνων Χ υποστήριξε τη προτεινόμενη δομή του

4,6-διμεθυλο-6Η-πυραζολο[3,4-c]ισοθειαζολο-3-καρβονιτριλίου 70a, το οποίο είχε

προσδιοριστεί στο παρελθόν από άλλους ερευνητές, εσφαλμένα, ως το 4,6-διμεθυλο-1Η-

πυραζολο[3,4-d]θειαζολο-5-καρβονιτρίλιο 69a. Επιπρόσθετα, θερμόλυση των 4-χλωρο-Ν-

(πυραζολ-5-υλ)-5Η-1,2,3-διθειαζολ-5-ιμινών 68 έδωσε τα σωστά 1Η-πυραζολο[3,4-d]-

θειαζολο-5-καρβονιτρίλια 69.

Στην αντίδραση θερμόλυσης της 4-χλωρο-Ν-(πυραζολ-5-υλ)-5Η-1,2,3-διθειαζολ-5-ιμίνης

68a, εκτός από το κύριο προϊόν, 1Η-πυραζολο[3,4-d]θειαζολο-5-καρβονιτρίλιο 69a,

παρατηρήθηκε και ο σχηματισμός ενός παραπροϊόντος σε πολύ χαμηλή απόδοση, το οποίο

ταυτοποιήθηκε ως το 5,7-διμεθυλο-5-πυραζολο[3,4-e][1,2,4]διθειαζιν-3-καρβονιτρίλιο

91a. Στο Κεφάλαιο 4, παρουσιάζεται η ανάπτυξη μιας συνθετικής μεθοδολόγιας η οποία

προσφέρει πρόσβαση στα 5Η-πυραζολο[3,4-e][1,2,4]διθειαζιν-3-καρβονιτρίλια 91, σε

καλές αποδόσεις (74-85%) μέσω της αντίδρασης των 4-χλωρο-Ν-(πυραζολ-5-υλ)-5Η-

1,2,3-διθειαζολ-5-ιμινών 68 με Εt2ΝΗ και μετέπειτα προσθήκη π. H2SO4. Από αυτή την

αντίδραση, σχηματίζονται επίσης τα 6Η-πυραζολο[3,4-f][1,2,3,5]τριθειαζεπιν-4-καρβο-

νιτρίλια 94 σε χαμηλή απόδοση (0-6%). Η αντίδραση προχωρά μέσω του ενδιαμέσου

(Z)-2-[(διαιθυλαμινο)δισουλφανυλ-2-[(1H-πυραζολ-5-υλ)ιμινο]ακετονιτριλίου 93, το

οποίο όπως έχει δειχθεί, στην περίπτωση του 1,3-διμέθυλο αναλόγου 93a, στην απουσία

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οξέος μετατρέπεται στο 4,6,10,12-τετραμεθυλο-6Η-πυραζολο[3,4-f]πυραζολο[3',4':4,5]-

πυριμιδο[6,1-d][1,2,3,5]τριθειαζεπιν-8,12b(10H)-δικαρβονιτρίλιο 104 (67%).

Στο Κεφάλαιο 5, γίνεται διερεύνηση και βελτιστοποίηση της αντίδρασης μιας σειράς

4-χλωρο-1,2,3-διθειαζολών 2 με το DABCO η οποία δίνει 4-[Ν-(2-χλωροαιθυλ)πιπεραζιν-

1-υλ]-5Η-1,2,3-διθειαζόλες 143-165. Τα προϊόντα λαμβάνονται σε πολύ καλές αποδόσεις,

και μπορούν να τροποποιηθούν περαιτέρω στη χλωροαίθυλο ομάδα μέσω αντίδρασης με

διάφορα πυρηνόφιλα, αφήνοντας άθικτο το διθειαζολικό δακτύλιο.

Στο Κεφάλαιο 6, περιγράφεται η βελτιστοποίηση της αντίδρασης διπλής C-N σύξευξης

καταλυόμενης με Pd(0) των 5,5'-διβρωμο-2,2'-διθειαζολών 180 με αρυλαμίνες και στη

συνέχεια in situ οξείδωση με οξείδιο του αργύρου προς σχηματισμό κινοειδών

5,5'-διαρυλιμινο-2,2'-διθειαζολών 182 σε μέτριες εώς καλές αποδόσεις (22 παραδείγματα,

28-92%). Οι 5,5'-διαρυλιμινο-2,2'-διθειαζόλες 182 μελετήθηκαν με φασματοσκοπία

UV/vis, κυκλική βολταμετρία και υπολογιστικές μεθόδους. Με αλλαγή των

περιφερειακών υποκαταστατών τα ενεργειακά επίπεδα HOMO και LUMO μεταβάλλονται

και το οπτικό χάσμα μπορεί να ρυθμιστεί μέχρι και το εγγύς υπέρυθρο. Ηλεκτροχημικός

χαρακτηρισμός έδειξε ότι οι κινοειδείς 2,2'-διθειαζόλες 182 παρουσιάζουν αμφοτερική

οξειδοαναγωγική συμπεριφορά.

Η διατριβή τελειώνει με το Πειραματικό Μέρος.

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ABSTRACT

The Thesis begins with a brief introduction on heterocyclic chemistry, which then focuses

on sulfur rich S,N-heterocycles, and especially on the use of 1,2,3-dithiazoles in organic

synthesis ,with emphasis on the type of reaction mechanism taking place.

In Chapter 2, an ANRORC-type ring transformation of N-azinyl-4-chloro-5H-1,2,3-

dithiazol-5-imines 61a-b and 62a-l to azino-fused thiazoles 55a-b and 63a-l, previously

discovered by a former member of the group, Dr. Sophia S. Michaelidou, was explored

regarding both its scope and limitations.

In Chapter 3, the reaction of Appel salt 1 with 5-aminopyrazoles is investigated, which

gives as main products 6H-pyrazolo[3,4-c]isothiazole-3-carbonitriles 70 and 4-chloro-

N-(pyrazol-5-yl)-5H-1,2,3-dithiazol-5-imines 68. The product ratio 70:68 can be modified

by adjusting the pH of the reaction medium. Single crystal X-ray crystallography

supported the structure of 4,6-dimethyl-6H-pyrazolo[3,4-c]isothiazole-3-carbonitrile 70a

which was previously misassigned, by other researchers, as the 4,6-dimethyl-1H-

pyrazolo[3,4-d]thiazole-5-carbonitrile 69a. Furthermore, thermolysis of 4-chloro-

N-(pyrazol-5-yl)-5H-1,2,3-dithiazol-5-imines 68 gives the correct 1H-pyrazolo[3,4-d]-

thiazole-5-carbonitriles 69.

From the thermolysis of 4-chloro-N-(pyrazol-5-yl)-5H-1,2,3-dithiazol-5-imine 68a, the

formation of a very minor side product was also observed, which was identified as the

5,7-dimethyl-5H-pyrazolo[3,4-e][1,2,4]dithiazine-3-carbonitrile 91a. In Chapter 4, the

development of a synthetic method which enables access to these 5H-pyrazolo[3,4-e]-

[1,2,4]dithiazine-3-carbonitriles 91, in good yields (74-85%), by treatment of 4-chloro-

N-(pyrazol-5-yl)-5H-1,2,3-dithiazol-5-imines 68 with Et2NH and then concd H2SO4, is

described. 6H-Pyrazolo[3,4-f][1,2,3,5]trithiazepine-4-carbonitriles 94 are also formed as

minor products (0-6%). The reaction proceeds via the intermediate formation of

(Z)-2-[(diethylamino)disulfanyl]-2-[(1H-pyrazol-5-yl)imino]acetonitrile 93, which, in the

case of the 1,3-dimethyl analogue 93a, is shown that in the absence of acid transforms to

the 4,6,10,12-tetramethyl-6H-pyrazolo[3,4-f]pyrazolo[3',4':4,5]pyrimido[6,1-d][1,2,3,5]tri-

thiazepine-8,12b(10H)-dicarbonitrile 104 (67%).

In Chapter 5, the reaction of a series of 4-chloro-5H-1,2,3-dithiazoles 2 with DABCO

which gives 4-[N-(2-chloroethyl)piperazin-1-yl]-5H-1,2,3-dithiazoles 143-165 is inve-

stigated and optimized reaction conditions are developed. The products are obtained in

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very good yields and can be further manipulated on the 2-chloroethyl moiety by reaction

with various nucleophiles, leaving the dithiazole ring intact.

In Chapter 6, the development of a Pd(0)-catalyzed double C-N coupling reaction of 5,5'-

dibromo-2,2'-bithiazoles 180 with (het)arylamines and subsequent in situ silver(I) oxide

mediated oxidation to give cross-conjugated quinoidal 5,5'-diarylimino-2,2'-bithiazoles in

moderate to high yields (22 examples, 28-92%), is described. The highly colored

5,5'-diarylimino-2,2'-bithiazoles 182 were studied by UV/vis spectroscopy, cyclic

voltammetry and computational methods. By manipulating the peripheral substituents, the

HOMO and LUMO energy levels are altered and the optical band gap can be tuned up to

the NIR region. Electrochemical characterization revealed that quinoidal 2,2'-bithiazoles

182 display amphoteric redox behavior.

The Τhesis finishes with the Experimental Section.

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“Strength does not come from winning. Your struggles develop your strengths. When you

go through hardships and decide not to surrender, that is strength.”

Arnold Schwarzenegger

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ACKNOWLEDGEMENTS

Coming to the end of this long journey, I would like to sincerely thank my supervisor

Professor Panayiotis A. Koutentis for the opportunity he gave me to work on the projects

described herein as well as for his guidance, patience and support all of these years.

Furthermore, acknowledgments go to the Cyprus Research Promotion Foundation (CRPF)

(Grant No ΕΠΙΧΕΙΡΗΣΕΙΣ/ΕΦΑΡΜ/0308/19 and NΕΑ ΥΠΟΔΟΜΗ/ΝΕΚΥΠ/0308/02)

and University of Cyprus (YPOTROFIES UCY/09-2015 - 09-2016) for financial support.

I also thank Stephen Boyer for elemental analysis (London Metropolitan University), the

laboratory technicians Savvas Savva and Panicos Andreou for their technical support

(University of Cyprus) and Dr. Maria Manoli and Dr. Manolis J. Manos for X-ray

crystallographic studies (University of Cyprus).

Big thanks also go to the KRG members, past and present, especially to Andreas, Styliana

and Georgia (with which we were together through almost all of my PhD years) for their

friendship, support, help and knowledge exchange all these years, and Herakleidia for her

help and support when I first joined the group as a diploma student and during the first

year of my PhD. I also thank the new diploma students, Eleni and Natasa for their

friendship.

Outside the lab, I deeply thank my very best friends Rodoulla, Elli and Andria for their

love, patience and support during the years of my PhD and not only!

Last but not least, I heartily thank my family: My Mom (Photini) for her relentless caring,

love and support. My Dad (George) and my big brothers, Andreas and Stauros, as well as

my nephews George and Marios, for all their love.

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To my yiayia Andriani

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CONTENTS

Sections Page

Validation Page i

Declaration of Doctoral Candidate iii

Abstract in Greek v

Abstract in English ix

Acknowledgements xv

Contents xix

Abbreviations xxv

Brief Contents

Chapter 1 Introduction 1

Chapter 2 The Conversion of N-Azinyl-4-chloro-5H-1,2,3-dithiazol-5-imines into

Azino-fused Thiazole-2-carbonitriles 25

Chapter 3 The Reaction of 1H-Pyrazol-5-amines with 4,5-Dichloro-1,2,3-dithiazolium

Chloride: A Route to Pyrazolo[3,4-c]isothiazoles and

Pyrazolo[3,4-d]thiazoles 33

Chapter 4 Synthesis of Fused 1,2,4-Dithiazines and 1,2,3,5-Trithiazepines 51

Chapter 5 4-[N-(2-Chloroethyl)piperazin-1-yl]-5H-1,2,3-dithiazoles:

The Reaction of DABCO with 4-Chloro-5H-1,2,3-dithiazoles 71

Chapter 6 Synthesis and Characterization of Cross-conjugated 5,5'-Diarylimino

Quinoidal 2,2'-Bithiazoles 93

Chapter 7 Experimental Section 127

List of Compounds Prepared 227

Appendices 239

References 267

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Detailed Contents

Chapter 1 Introduction 1

1.1 Heterocyclic Chemistry 2

1.1.1 Definition 2

1.1.2 Importance of Heterocycles 2

1.1.3 Classification of Heterocycles: Non-aromatic and Aromatic 4

1.2 Nitrogen Heterocycles 6

1.3 Sulfur-nitrogen Heterocycles 7

1.3.1 Thiazoles 7

1.4 Sulfur-nitrogen Rich Heterocycles 10

1.5 1,2,3-Dithiazoles 12

1.5.1 1,2,3-Dithiazoliums 12

1.5.2 Neutral 1,2,3-Dithiazoles 15

1.5.3 Application in Synthesis: Reaction Mechanisms 15

1.5.3.1 Intramolecular Attack at S1 16

1.5.3.2 Intramolecular Attack at C5 17

1.5.3.3 Intermolecular Attack at S2 18

1.5.3.4 Intermolecular Attack at C5 21

1.6 Origin of Thesis 23

Chapter 2 The Conversion of N-Azinyl-4-chloro-5H-1,2,3-dithiazol-5-imines into

Azino-fused Thiazole-2-carbonitriles 25

2.1 Introduction 26

2.2 Optimization of the ANRORC Transformation of N-Azinyl-4-chloro-5H-

1,2,3-dithiazol-5-imines 27

2.3 Scope and Limitations of the ANRORC Transformation of N-Azinyl-4-

chloro-5H-1,2,3-dithiazol-5-imines 29

2.4 Comparison with Other Methods 31

2.5 Conclusions 32

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Chapter 3 The Reaction of 1H-Pyrazol-5-amines with 4,5-Dichloro-1,2,3-dithiazolium

Chloride: A Route to Pyrazolo[3,4-c]isothiazoles and

Pyrazolo[3,4-d]thiazoles 33

3.1 Introduction 34

3.2 Reaction of Appel Salt 1 with 1H-Pyrazol-5-amines 67 36

3.3 Optimization of the Reaction 40

3.4 Mechanistic Rationale 43

3.5 Synthesis of 1H-Pyrazolo[3,4-d]thiazole-5-carbonitriles 69 via Thermolysis

of 4-Chloro-N-(pyrazol-5-yl)-5H-1,2,3-dithiazol-5-imines 68 45

3.6 Routes to N-Unsubstituted Pyrazolo[3,4-c]isothiazole-3-carbonitriles and

Pyrazolo[3,4-d]thiazole-5-carbonitriles 46

3.7 Conclusions 49

Chapter 4 Synthesis of Fused 1,2,4-Dithiazines and 1,2,3,5-Trithiazepines 51

4.1 Introduction 52

4.2 Thermolysis of 4-Chloro-N-(1,3-dimethyl-1H-pyrazol-5-yl)-5H-1,2,3-

dithiazol-5-imine 68a 53

4.3 Optimization of the Transformation of 4-Chloro-N-(1,3-dimethyl-1H-pyra-

zol-5-yl)-5H-1,2,3-dithiazol-5-imine 68a to 5,7-Dimethyl-5H-pyrazolo-

[3,4-e][1,2,4]dithiazine-3-carbonitrile 91 54

4.3.1 Conversion of N-Pyrazolyldithiazolimine 68a to the Disulfide 93a 55

4.3.2 Conversion of the Disulfide 93a into the 1,2,4-Dithiazine 91a 58

4.3.3 One-pot Conversion of N-Pyrazolyldithiazolimine 68a into the

1,2,4-Dithiazine 91a 60

4.4 Scope and Limitations of the One-pot Reaction 62

4.5 Transformation of 5,7-Dimethyl-5H-pyrazolo[3,4-e][1,2,4]dithiazine-3-

carbonitrile 91a to 6,8-Dimethyl-6H-pyrazolo[3,4-f][1,2,3,5]trithiazepine-4-

carbonitrile 94a 63

4.6 Thermolysis of 5H-Pyrazolo[3,4-e][1,2,4]dithiazine-3-carbonitriles 91 66

4.7 Unexpected Chemistry of Disulfide 93a 67

4.8 Conclusions 69

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Chapter 5 4-[N-(2-Chloroethyl)piperazin-1-yl]-5H-1,2,3-dithiazoles:

Τhe Reaction of DABCO with 4-Chloro-5H-1,2,3-dithiazoles 71

5.1 Introduction 72

5.2 Optimization of the Reaction of 4-Chloro-N-phenyl-5H-1,2,3-dithiazol-

5-imine 95a with DABCO to give 4-[N-(2-Chloroethyl)piperazin-1-yl]-

N-phenyl-5H-1,2,3-dithiazol-5-imine 119 75

5.3 Structure Elucidation of Compounds 119, 120h, 121a and 122 77

5.4 Scope and Limitations of the Reaction of 1,2,3-Dithiazoles with DABCO 80

5.5 Rationale for the Relative Reactivity of 1,2,3-Dithiazoles with DABCO 82


5.7 Chemistry of 4-[N-(2-Chloroethyl)piperazin-1-yl]-5H-1,2,3-dithiazoles 88

5.7.1 Manipulations on the 2-Chloroethyl Moiety 88

5.7.2 Manipulations at the Dithiazole C5 Position 89

5.8 Conclusions 90

Chapter 6 Synthesis and Characterization of Cross-Conjugated 5,5'-Diarylimino

Quinoidal 2,2' Bithiazoles 93

6.1 Introduction 94

6.2 Optimization of the Pd(0)-Mediated Double C-N Coupling Reaction of

5,5'-Dibromo-4,4'-diphenyl-2,2'-bithiazole 180a with 4-n-Butoxyaniline 96

6.2.1 Part I: Solvent, Base, Catalyst and Ligand Screen 98

6.2.2 Part II: Fine Tuning 99

6.2.3 Ligand Bite Angle Study 101

6.3 Structure Elucidation of Compounds 184, 185 and 186 102

6.4 Scope and Limitations of the Pd(0)-Mediated Double C-N Coupling

Reaction of 5,5'-Dibromo-4,4'-disubstituted-2,2'-bithiazoles 180 with

Anilines 104

6.5 Stereoisomers of Quinoidal 2,2'-Bithiazole 182a: A Computational Study 107

6.6 Experimental UV/vis Absorption of Quinoidal 2,2'-Bithiazoles 182 107

6.7 TD-DFT Computational Studies on Quinoidal 2,2'-Bithiazoles 182 109

6.8 Cyclic Voltammetry of Quinoidal 2,2'-Bithiazoles 182 120

6.9 Conclusions 125

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Chapter 7 Experimental Section 127

7.1 General Procedures and Methods 128

7.2 Compounds Related to Chapter 2 130





7.7 X-Ray Crystallographic Studies 221

7.8 Computational Studies Methods 225

7.9 Cyclic Voltammetry Studies Methods 225

List of Compounds Prepared 227

Appendices 239

Appendix I Atomic Cartesian Coordinates of Compounds:

118, 137, 139, 140, 182 and 189-192 239

Appendix II Cyclic Voltammograms of Compounds 182 263

References 267

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ABBREVIATIONS

Å Ångström unit

Ac acetyl

acetone-d6 deuterated acetone

AIBN 2,2′-azobisisobutyronitrile

aka also known as

Alk alkyl

ANRORC addition of nucleophile ring opening ring closure

APT attached proton test

aq. aqueous

Ar aryl

ASCT2 amino-acid transporter 2

BINAP (±)-2,2′-bis(diphenylphosphino)-1,1′-binaphthalene

BDE bond dissociation energy

Bn benzyl

bp boiling point

br broad

Bu butyl

t-Bu tert-butyl

n-Bu normal butyl

t-BuXPhos 2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl

Bz benzoyl

ca. approximately (Latin: circa)

CAN cerium ammonium nitrate

cat. catalytic

°C Celsius degrees

cf. compare (Latin: confer)

cm-1 wavelength unit

concd concentrated

CT charge transfer

CV cyclic voltammetry

d doublet (NMR) or days

d distance

2D two-dimensional

Da Dalton unit (mass spectrometry)

DABCO 1,4-diazabicyclo[2.2.2]octane

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dba trans,trans-dibenzylideneacetone

DBU 1,8-diazabicyclo[5.4.0]undec-7-ene

DCE 1,2-dichloroethane

DCM dichloromethane

dd double doublet

ddd doublet of double doublets

decomp. decomposition

DEPT distortionless enhancement by polarization transfer

DFT density functional theory

DHB 2,5-dihydroxybenzoic acid

DMA N,N-dimethylacetamide

DMF N,N-dimethylformamide

DMSO dimethylsulfoxide

DMSO-d6 deuterated dimethylsulfoxide

DNA deoxyribonucleic acid

DPEPhos (oxydi-2,1-phenylene)bis(diphenylphosphine)

dppe ethylenebis(diphenylphosphine)

dppf 1,1′-ferrocenediyl-bis(diphenylphosphine)

DSC differential scanning calorimetry

DTDAF dithiadiazafulvalenes

E electrophile

E energy or opposite (German: entgegen)

E1/2 potential at which half the peak current is observed (measured in V)

EDG electron donating group

e.g. for example (Latin: exempli gratia)

Eg energy gap or bandgap

Eg,opt optical band gap

Eg,TD-DFT computationally obtained band gap

EI electron ionization

equiv equivalent(s)

Epa anodic peak potential (measured in V)

Epc cathodic peak potential (measured in V)

Et ethyl

et al. and others (Latin: et alia)

etc. and other things or and so forth (Latin: et cetera)

eV electron volt

EWG electron withdrawing group

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f oscillator strength

Fc ferrocene

Fc+ ferrocenium

FDA Food and Drug Administration

FIV feline immunodeficiency virus

FMO frontier molecular orbital

FTIR fourier transform infrared

g gas

GCMS gas chromatography mass spectrometry

h hour(s)

Hal halogen

HAr heteroaromatic

HCCA α-cyano-4-hydroxycinnamic acid

c-hexane cyclohexane

n-hexane normal hexane

HIV human immunodeficiency virus

HOMO highest occupied molecular orbital

hv photolysis

Hz Hertz

i.e. that is (Latin: id est)

inf inflection

io incomplete oxidation

IR infrared

ir incomplete reaction

J coupling constant (measured in Hz)

JohnPhos 2-(di-tert-butylphosphino)biphenyl

kJ kilojoules

l liquid

LG leaving group

lit. literature

m multiplet (NMR) or medium (IR)

m meta

M+ molecular ion

MALDI matrix-assisted laser desorption/ionization

max maximum

MBT 2-mercaptobenzothiazole

Me methyl

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MHz megahertz

min minutes

mL milliliter

mM millimolar

MO molecular obital

mp melting point

MP2 second order Møller-Plesset perturbation theory

MS mass spectrometry

m/z mass to charge ratio

MW molecular weight

NBS N-bromosuccinimide

nm nanometers

NMR nuclear magnetic resonance

Nu nucleophile

o ortho

OAc acetate

OFET organic field-effect transistor

OPV organic photovoltaic

osc. oscillator

ox oxidation

p para

PAC prespotted AnchorChip

PEPPSI™-IPr [1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene](3-chloro-

pyridyl)palladium(II) dichloride

Ph phenyl

PhCl chlorobenzene

PhH benzene

Phth phthalimide

pKa negative log of the acid dissociation constant, -logKa

ppm parts per million

i-Pr2NEt N,N-diisopropylethylamine (aka Hünig’s base)

py pyridine

q quartet

qt quartet of triplets

RB3LYP restricted Becke, 3-parameter, Lee-Yang-Parr

red reduction

Rf retention factor

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s singlet (NMR) or strong (IR)

sat. saturated

SCE saturated calomel electrode

sec seconds

t triplet

TCNEO tetracyanoethylene oxide

TD time dependent

temp temperature

TFA trifluoroacetic acid

TFA-d deuterated trifluoroacetic acid

THF tetrahydrofuran

TLC thin layer chromatography

TMS trimethylsilyl

TOF time of flight

TsOH 4-toluenesulfonic acid

tt triplet of triplets

UV ultraviolet

V Volt

vis visible

vs versus

w weak (IR)

WHO World Health Organization

Xantphos 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene

Z together (German: zusammen)

δ chemical shift

Δ heat

ΔE energy difference

ε extinction coefficient

λmax maximum wavelength

μΑ microampere

μL microliter

μmol micromoles

μW microwave irradiation

ν frequency

σ Hammett substituent constant

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CHAPTER 1

Introduction

Contents

1.1 Heterocyclic Chemistry 2

1.1.1 Definition 2

1.1.2 Importance of Heterocycles 2

1.1.3 Classification of Heterocycles: Non-aromatic and Aromatic 4

1.2 Nitrogen Heterocycles 6

1.3 Sulfur-Nitrogen Heterocycles 7

1.3.1 Thiazoles 7

1.4 Sulfur-Nitrogen Rich Heterocycles 10

1.5 1,2,3-Dithiazoles 12

1.5.1 1,2,3-Dithiazoliums 12

1.5.2 Neutral 1,2,3-Dithiazoles 15

1.5.3 Application in Synthesis: Reaction Mechanisms 15

1.5.3.1 Intramolecular Attack at S1 16

1.5.3.2 Intramolecular Attack at C5 17

1.5.3.3 Intermolecular Attack at S2 18

1.5.3.4 Intermolecular Attack at C5 21

1.6 Origin of Thesis 23

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1.1 Heterocyclic Chemistry

1.1.1 Definition

Heterocycles, as defined by IUPAC, are “cyclic compounds having as ring members atoms

of at least two different elements”.1 More commonly, heterocycles are described as cyclic

compounds whose ring atoms contain at least one element from the periodic table other

than carbon.

Heterocyclic chemistry deals with the synthesis, chemistry and properties of these

compounds and is one of the largest branches of organic chemistry since about 85-90% of

organic chemistry publications involve heterocycles.2

1.1.2 Importance of Heterocycles

Within our bodies, many of the molecules that are involved in biochemical processes, e.g.,

provision of energy, transmission of nerve impulses, sight, metabolism and the transfer of

hereditary information, are heterocyclic. These heterocycles are either biosynthesized by

the body or obtained directly from food sources.

Deoxyribonucleic acid (DNA), the carrier of all genetic information in nearly all living

systems, is a polymer composed of monomers called nucleotides. Each nucleotide consists

of: a pentose sugar, a phosphate group, and a nucleobase. More importantly, the four

nucleobases of DNA i.e. cytosine (C), guanine (G), adenine (A) and thymine (T), are all

nitrogen heterocycles (Figure 1).

Figure 1. The four nucleobases present in DNA

Vitamins, which come from the Latin “vita” meaning life, are another family of

compounds that are important in biochemical processes. 70% of the vitamins contain

heterocycles in their structures, varying from the simplest vitamin B3 (nicotinic acid),

which helps keep the digestive system healthy and assists in processing carbohydrates, to

the more complex vitamin B12 (cobalamin) which has a key role in the normal functioning

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of the brain and nervous system, for making red blood cells and helping in the production

of DNA and RNA (Figure 2).

Figure 2. Structures of the vitamins B3 and B12

This list can be expanded to a wide range of biomolecules: amino acids, hormones,

enzymes and co-enzymes and many others where heterocycles are present and play a

significant role for their function.

Aside from the human body, heterocycles are widespread in Nature; in terrestrial and

marine living organisms and microorganisms. In many cases, natural heterocycles display

interesting biological activities and pharmaceutical research is frequently inspired from

these. For example, Ecteinascidin-743 (ET-743), a marine tetrahydroisoquinoline alkaloid

isolated from the mangrove tunicate Ecteinascidia turbinata,3a is an anti-tumor drug (aka

Yondelis®) approved by the European Medicines Agency in 20074 and the U. S. Food and

Drug Administration (FDA) in 2015,5 for advanced soft tissue sarcoma (Figure 3).

Figure 3. Photograph of a mangrove tunicate in Nassau, Bahamas3b and structure of ET-743

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In fact, naturally occurring or lab synthesized heterocycles predominate in pharmaceutical

products. In 2015, 70% of the top 20 best-selling drugs (by revenue),6 and 65% of the

compounds on the World Health Organization’s (WHO’s) essential medicines list7 were

heterocyclic.

Furthermore, heterocycles find applications in many other sectors, such as agrochemicals

(e.g., pesticides, insecticides and rodenticides), preservatives in food, ingredients in

cosmetic products (e.g., shampoos, face creams etc.), detergents and dyes in textile

industry, information storage, photographic sensitizers and developers, imaging agents,

markers and tracers, liquid crystals, plastics, rubber stabilizers, vulcanization accelerators,

energetic compounds (e.g., explosives), as heat resistant fibers in aerospace technology and

so on.8

1.1.3 Classification of Heterocycles: Non-aromatic and Aromatic

Heterocycles, can be classified into two main categories: Non-aromatic and aromatic

heterocycles. Non-aromatic heterocycles include saturated and partially unsaturated

heterocyclic compounds. The majority of heterocycles are comprised of three-, four-, five-

and six-membered rings. In general, they can have properties similar to their non-cyclic

counterparts but frequently heterocycles exhibit significant differences, particularly in the

smaller rings where strain is a determining factor on reactivity.

Aromatic heterocycles (heteroarenes or hetarenes), are planar or nearly planar cyclic

conjugated heterocycles with (4n + 2) delocalized π electrons (Hückel aromaticity). They

are the most important heterocyclic subgroup, possess highly specific features and are

frequently found in Nature and in many man-made applications. In contrast, planar

conjugated heterocycles that contain only 4n delocalized π electrons can be considered to

be antiaromatic (Möbius aromaticity) but these are comparatively rare.9

The majority of hetarenes are composed of five- and six-membered ring size compounds,

and formally these are derived by replacing the CH group on their carbocyclic aromatic

counterparts, cyclopentadienyl anion and benzene by NH, O and S or N, O+ and S+,

respectively.10 This gives the simplest heteroaromatic systems namely: pyrrole, furan and

thiophene for the five-membered analogues, and pyridine, pyrylium and thiopyrylium

cation for the six-membered rings (Figure 4). Heteroatom rich aromatic compounds are

possible by further multiple replacements of CH groups in the five- and six-membered ring

systems with retention of the aromatic character.

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Figure 4. Structures of the simplest six- and five-membered heterocycles

The introduction of heteroatoms to carbocycles imparts distinctive and often striking

properties. The simplest way to observe the varying effects on the properties of aromatic

compounds by introducing the heteroatoms is by looking at their resonance energies.

Benzene, the prototype of aromatic compounds, has a resonance energy of 150 kJ/mol, the

heterocyclic analogues follow the order: pyridine (117 kJ/mol), thiophene (122 kJ/mol),

pyrrole (90 kJ/mol), and furan (68 kJ/mol).11

The lower resonance energies of hetarenes vs their carbocyclic analogues and the intrinsic

properties of the heteroatom itself, enables their involvement in a wide range of reactions.

Furthermore, heterocycles, depending on the pH can: Exist as one tautomeric form or

another; act as acids or bases; form or destroy hydrogen bonds and metal complexes; and

show a wide variety of redox behaviors depending on the substituents and the heteroatoms

present.

This diverse behavior of heterocycles is nicely demonstrated by the amino acid L-histidine,

which contains the hetarene imidazole. L-Histidine, is present in the active site of many

proteins/enzymes and plays a central role for their function. In chymotrypsin, a proteolytic

enzyme of the digestive system, the histidine residue acts both as a base and an acid

catalyst to help shuttle protons from serine hydroxyl to amide carbonyl groups

(Scheme 1).12 MARIA KOYIO

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Scheme 1. Structure of the amino acid L-histidine and its role in the active center of chymotrypsin

1.2 Nitrogen Heterocycles

N-Heterocycles are the most widespread heterocycles in Nature and industry. The most

common five-membered N-hetarene systems are pyrrole and imidazole and their benzo-

fused analogues indole and benzimidazole, while pyridine and pyrimidine, and benzo-

fused analogues (iso)quinoline and quinazoline are the most common six-membered

systems (Figure 5).

Figure 5. Structures of the most commonly encountered N-hetarenes

From the five-membered N-heterocycles, indole is probably the most widely distributed in

Nature having medicinal importance.13 Indole is also found in the essential amino acid

tryptophan which, apart from being a protein constituent, serves as a biosynthetic precursor

to important metabolites, indole containing or not, such as serotonin (neurotransmitter) and

melatonin (hormone) or kynurenine (vitamin B3 precursor), respectively (Figure 6).14

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Figure 6. Structure of the amino acid tryptophan and three of its most important metabolites

From the six-membered N-heterocycles, considerable attention is focused on quinazolines

which are widely found in many pharmaceuticals e.g., gefitinib (Iressa®), erlotinib

(Tarceva®) and lapatinib (Tyverb®)15 (Figure 7), all of which are FDA approved anti-

cancer drugs.16

Figure 7. Examples of FDA approved quinazoline-containing anti-cancer drugs

1.3 Sulfur-Nitrogen Heterocycles

S,N-Heterocycles constitute another important class of heterocycles, and although they are

not as widespread as their nitrogen analogues, they play a significant role both in

biological and material sciences.

1.3.1 Thiazoles

The simplest and most common S,N-heterocycle is thiazole (1,3-thiazole). It is not difficult

to see the importance of thiazole in Nature as it is a component of thiamine (vitamin B1), a

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water soluble vitamin that helps the body to release energy from carbohydrates during

metabolism and assists in the normal functioning of the nervous system by playing a role

in the synthesis of neurotransmitters, such as acetylcholine.17 A reduced form of thiazole is

also present in firefly luciferin, the light-emitting compound of fireflies18 (Figure 8).

Figure 8. Examples of naturally occurring compounds containing the thiazole moiety

The thiazole unit also frequently occurs in many compounds with important biological

activities, and is present in many approved drugs e.g., Sprycel® (dasatinib, anticancer),20

Norvir® (ritonavir, anti-HIV drug)21 and Mobic® (meloxicam, anti-inflammatory agent),22

and in agrochemicals such as thiamethoxam (insecticide)23 (Figure 9). Thiazoles also find

applications in synthesis as synthetic auxiliaries e.g., as a masked formyl group,24 or as

chiral auxiliaries (1,3-thiazolidine-2-thiones) for aldol type reactions.25

Figure 9. Structures of biologically active compounds containing the thiazole moiety

Thiazole can formally be derived from thiophene by the replacement of one β-CH group

with an sp2 nitrogen. Interestingly, replacing the α-CH by sp2 nitrogen formally provides

access to the less common isomer isothiazole (1,2-thiazole) (Figure 10).

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Figure 10. The simplest S,N-heterocycles isothiazole and thiazole

Thiazole is a 6π aromatic system, since the sulfur lone pair participates via delocalization

to the π system, and helps satisfy the Hückel 4n + 2 rule. The resonance forms of thiazole

are shown in Figure 11.

Figure 11. Selected resonance forms of thiazole

The aromatic character of thiazole is supported by 1H NMR spectroscopy. The chemical

shift of the ring hydrogens is between 7.27 and 8.77 ppm, indicating a strong diamagnetic

effect. Calculated π electron density indicates that the C5 position is electron rich and is the

primary site for electrophilic substitution, while the C2 position is electron poor and thus

the site for nucleophilic substitution; this is confirmed by the experimental observations.19

The reduced forms of thiazole: 2,3-, 2,5- and 4,5-dihydrothiazoles (thiazolines) and

2,3,4,5-tetrahydrothiazole (thiazolidine) are also known (Figure 12).

Figure 12. Structures of dihydrothiazoles (thiazolines) and tetrahydrothiazole (thiazolidine)

The most common and oldest synthesis of monocyclic thiazoles is Hantzsch thiazole

synthesis, which involves the reaction of α-haloketones with thioamides (Scheme 2).26

Scheme 2. Hantzsch synthesis of thiazoles

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The Hantzsch thiazole synthesis was first reported in 1887 by Hantzsch and Weber,27 and

since then many variations of the acyclic starting materials have been used for the

construction of the thiazole ring, involving all the possible ring constructions.

Comprehensive reviews for the preparation of the thiazole ring system have appeared in

both Science of Synthesis28 and Comprehensive Heterocyclic Chemistry.29

1.4 Sulfur-Nitrogen Rich Heterocycles

The sequential replacement of cyclopentadienyl and benzene CHs by NH/N+ and/or S/S+,

can lead to heteroatom-rich five- and six-membered ring systems, respectively. The

presence of many nitrogen and sulfur atoms in a ring is often associated with instability

and difficulties in the synthesis. In reality, stable S,N-rich heterocycles with unusual and

interesting properties can often be obtained. For example, the sequential replacement of

thiazole CHs with N and/or S gives 18 possible S,N-rich heterocycles six of which are

inorganic (Figure 13). A feature of increasing both the number and variety of heteroatoms

within a cyclic system is that the amount of published work decreases. Dramatic decreases

in the number of publications are noticeable as the number of sulfur atoms in a ring system

increase. For example, thiazole has 66781 citations (from a Reaxys® general structure

search including both aromatic and non-aromatic, monocyclic and fused thiazoles on

September 21, 2016). Replacing just one CH with N gives three possible isomers: the

1,2,3-, 1,3,4- and 1,3,5-thiadiazoles with 2661, 11075 and 2877 citations, respectively,

while replacement with S gives the three possible isomers: 1,2,3-, 1,2,4- and 1,4,2-

dithiazoles with even lower number of citations: 283, 499 and 48, respectively. The work

of our research group focuses on this niche area of heterocycles and specifically on 1,2,3-

dithiazoles.

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Figure 13. All possible S,N-heterocycles by sequential replacement of thiazole CHs with S and/or

N atoms and their citations appeared in Reaxys® (general search including both aromatic and non-

aromatic, monocyclic and fused structures on September 21, 2016)

Organic Inorganic

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1.5 1,2,3-Dithiazoles

1.5.1 1,2,3-Dithiazoliums

Dithiazoles are five-membered ring compounds which contain two carbon, one nitrogen

and two sulfur atoms. Dithiazoliums are the fully aromatic cations of dithiazoles and can

formally be derived from thiazoles or isothiazoles by replacing a CH group with the

isoelectronic S+ (Figure 14). All four possible isomers: 1,2,3-,30 1,2,4-,31 1,3,2-32 and 1,4,2-

dithiazoliums33 are known, and the most well studied are 1,2,3- and 1,2,4-dithiazoliums.

Figure 14. The four possible dithiazolium isomers

The most common monocyclic 1,2,3-dithiazolium compound is 4,5-dichloro-1,2,3-

dithiazolium chloride (Appel salt) 1, which was first reported in 1985 by Appel et al.28

Appel salt 1 is readily prepared from chloroacetonitrile and disulfur dichloride (sulfur

monochloride) and reacts easily with nucleophiles e.g., active methylenes, primary

arylamines, hydrogen sulfide and water, at the C5 position to give neutral 4-chloro-5H-

1,2,3-dithiazoles 2 (Scheme 3).28

Scheme 3. Synthesis of 4,5-dichloro-1,2,3-dithiazolium chloride salt (Appel salt) 1 and its reaction

with various nucleophiles

Appel salt 1 is formally aromatic (6π e-) and resonance structures can be drawn where the

positive charge is delocalized onto either sulfur atoms (Figure 15). X-Ray crystallography

reveals that the S-S bond (dS-S 2.034 Å) is shorter than a normal single S-S bond (dS-S

2.06 Å) and slightly longer than that reported for the corresponding separation in a fully

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delocalized 1,2-dithiolium ring (dS-S 2.023 Å).34 Furthermore, the chloride adopts an

almost equidistant in-plane geometry with respect to both S1 and S2 dithiazolium atoms

which suggests a nearly equal interaction of the anion with both sulfur atoms.35

Figure 15. Major resonance forms of Appel salt 1

Other derivatives of acetonitrile can also react with disulfur dichloride to give 4-chloro-5-

substituted-1,2,3-dithiazolium salts 3 (Scheme 4).36

Scheme 4. Synthesis of 4-substituted-5-chloro-1,2,3-dithiazolium salts 3

An interesting example, is the 4-chloro-5-pentafluorophenyl-1,2,3-dithiazolium chloride

3h which on reduction with Ph3Sb gives the stable dithiazolyl radical 4 (Scheme 5).37

Scheme 5. The synthesis of 4-chloro-5-pentafluoro-1,2,3-dithiazolyl radical 4

5-Chloro-4-substituted-1,2,3-dithiazolium chlorides 6 can be prepared by the reaction of

acetoximes 5 with disulfur dichloride. Nevertheless, these salts are not very stable and are

converted in situ to the neutral 5-chloro-4-substituted-5H-1,2,3-dithiazoles 7 by reaction

with nucleophiles (Scheme 6).38

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Scheme 6. Preparation of 5-chloro-4-substituted-5H-1,2,3-dithiazoles 7 via the in situ formation of

5-chloro-4-substituted-1,2,3-dithiazolium chlorides 6 from acetoximes 5

A very important subclass of 1,2,3-dithiazolium salts are (het)areno-fused 1,2,3-dithi-

azolium chlorides 8 known as Herz salts, which can be prepared via the reaction of

aromatic amines with disulfur dichloride.39 Mild hydrolysis e.g., with aq. NaOAc40 or

aq. NaHCO3,41 gives 3H-1,2,3-benzodithiazole 2-oxides 9, alkaline hydrolysis of which

leads to the formation of 2-aminobenzenethiols 1039 that are useful intermediates for the

synthesis of benzothiazoles40,42 (Scheme 7).

Scheme 7. Synthesis of Herz salts 8 and their hydrolysis to 2-aminobenzenethiols 10

A modified Herz synthesis was used by Oakley et al.43 to prepare Herz salts 13 and 14,

from pyridine or pyrazine bis(aminothiols) 11 and 12, respectively. The former after

further modification gave the dithiazolyl radicals 15 and 16, respectively (Scheme 8).

Scheme 8. Synthesis of bis(dithiazolyl) radicals 15 and 16 via double modified Herz reaction of

pyridine or pyrazine bis(aminothiols) 11 and 12, respectively

The dithiazolyl radical 16 (X = N) at ambient temperatures displays interesting

semiconducting properties.43b Other dithiazolyl radicals, 17 and 18, with interesting

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properties were also prepared via similar methods; the dithiazolyl radical 17 behaves as a

metamagnet below 5 K44 while the semiquinone-bridged bis(dithiazolyl) 18 orders as a

spin-canted antiferromagnet at 4.5 K45 (Figure 16).

Figure 16. Examples of 1,2,3-dithiazolyl radicals with interesting magnetic properties

1.5.2 Neutral 1,2,3-Dithiazoles

Neutral 1,2,3-dithiazoles display interesting biological activities such as antitumor,38

antibacterial,46 antifungal,47 and herbicidal.48 Recently, 1,2,3-dithiazoles showed activities

as inhibitors of the glutamine/amino acid transporter ASCT2,49 and the feline

immunodeficiency virus (FIV) nucleocapsid protein.50 Furthermore, several analogues

elicited pigment loss on developing Xenopus embryos.51

1.5.3 Application in Synthesis: Reaction Mechanisms

Apart from their interesting biological properties, 1,2,3-dithiazoles are versatile

intermediates in organic synthesis giving access to many otherwise difficult to access

heterocycles. The 1,2,3-dithiazole ring has two particularly weak bonds: the S1-S2 and

S2-N3 with bond dissociation energies (BDE) 429 and 464 kJ/mol, respectively.52 The

weakness of these bonds can lead to their cleavage in the presence of thiophiles and

subsequent transformation of the dithiazole into new ring systems or functionalities. These

frequently contain a nitrile group, which originates from the N3-C4 ring atoms. The

thermodynamic stability of nitriles (BDE C≡N 927 kJ/mol)53 probably assists in driving

these dithiazole fragmentations.

The main 1,2,3-dithiazole ring cleavage pathways can be classified into two main

categories: Those that initiate by an intramolecular attack at S1 or C5, followed by

fragmentation of the dithiazole ring and the formation of a new heterocycle, and those that

initiate by attack of an external nucleophile at S2 or C5.

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1.5.3.1 Intramolecular Attack at S1

Intramolecular attack of an appended nucleophilic moiety at the dithiazole S1 results in the

fragmentation of the dithiazole, generation of elemental sulfur (S8) and HCl, and formation

of a thermodynamically stable nitrile group (Scheme 9).

Scheme 9. General reaction mechanism initiated by intramolecular attack at S1

The most illustrative example of this type of reaction is the thermolysis of N-aryl-4-chloro-

5H-1,2,3-dithiazol-5-imines 19 which gives benzothiazole-2-carbonitriles 21. The

mechanism is proposed to proceed via nucleophilic attack of the N-aryl moiety onto the

dithiazole S1 position (Scheme 10).54

Scheme 10. Mechanism for the transformation of N-aryldithiazolimines 19 to benzothiazole-2-

carbonitriles 21

Benzothiazole is a privileged scaffold with many applications in medicinal chemistry. The

latent cyano group in benzothiazole-2-carbonitriles can also be used for further

manipulation. Worthy of note, is the recent use of the dithiazole to benzothiazole ring

transformation to access specifically substituted benzothiazole-2-carbonitriles for the

synthesis of luciferin analogues.55

Another example of intramolecular attack at S1 is the transformation of (dithiazolylidene)-

acetonitriles 22 to isothiazoles 24 via the in situ formation of the imine 23 that acts as the

internal nucleophile that attacks the S1 atom (Scheme 11).56

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Scheme 11. Transformation of (dithiazolylidene)acetonitriles 22 to isothiazoles 24

Isothiazoles are also formed by the reaction of enamines with Appel salt 1. In this case the

enamine reacts via its C3 carbon with Appel salt 1 giving an imine 25, similar to that

formed in the reaction of (dithiazolylidene)acetonitriles 22 with nucleophiles, which then

cyclises in situ onto S1 leading to the observed product 26 (Scheme 12).57

Scheme 12. Reaction of enamines with Appel salt 1

1.5.3.2 Intramolecular Attack at C5

In this type of mechanism an appended nucleophilic moiety attacks the C5 position leading

to the fragmentation of the dithiazole ring with loss of both sulfurs, elimination of HCl and

formation of the thermodynamically stable nitrile group (Scheme 13). There are many

examples where the dithiazole is transformed via this type of mechanism to (het)areno-

fused pyrimidines,58 oxazoles,54,59 imidazoles60 and other heterocycles.61

Scheme 13. General reaction mechanism initiated by intramolecular attack at C5

One characteristic example is the transformation of dithiazolimines 27 into benzimid-

azoles 31.60a In this case, the adjacent amino group serves as the nucleophile which attacks

the C5 atom to give the spirocyclic intermediate 28 that then ring fragments to the

observed product 31. The ring fragmentation can occur either in one step by the loss of

diatomic sulfur (S2) (Path A) or in two steps via initial aromatization of intermediate 28

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with loss of HC1 to give the intermediate nitrile disulfide 29 which can then lose elemental

sulfur (S8) via sulfur chain extension (intermediate 30) (Scheme 14).62

Scheme 14. Plausible mechanisms for the transformation of dithiazolimines 27 to benzimidazoles

31

1.5.3.3 Intermolecular Attack at S2

This reaction pathway proceeds via initial attack at S2 to form an intermediate disulfide 33

(Scheme 16), which is sometimes isolable,63 as in the case of Kim’s reaction of

N-aryldithiazolimines 19 with dialkylamines which gives disulfide 32 (Scheme 15).63a

Scheme 15. Formation of stable disulfide 32

In most of the cases, the intermediate disulfide 33 spontaneously collapses in the presence

of the external nucleophile (Paths A & C, Scheme 16) with formation of cyclic or acyclic

structures or by attack of a neighboring nucleophilic group (Paths B & D-F, Scheme 16);

worthy of note is that the neighboring nucleophile can be generated in situ by addition of a

nucleophile to a reactive site of the molecule (Scheme 16).

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Scheme 16. Possible reaction pathways proceeding via the intermediate formation of disulfide 33

An interesting example, which involves the formation of a cyclic structure, is the synthesis

of 1,3,4-thiadiazole-2,5-dicarbonitrile 36 from the bis(dithiazole) 34 and polymer bound

Ph3P. Initial attack of the thiophilic Ph3P at the dithiazole S2 position leads to the

formation of the intermediate disulfide 35. A second thiophile can then attack this

intermediate at S2 generating a nucleophilic S1 which can cyclize onto the electrophilic C5

position of the adjacent dithiazole moiety. Ring fragmentation of the dithiazole (Section

1.5.3.2) gives the observed 1,3,4-thiadiazole structure (Scheme 17).64

Scheme 17. Plausible reaction mechanism for the formation of 1,3,4-thiadiazole-2,5-dicarbonitrile

36

Interestingly, in the reported literature there is only one example were both sulfurs of the

intermediate disulfide are retained in the final product (Path B, Scheme 16). This is the

reaction of 1,2,3-dithiazoles with dialkylamines which gives 4-(dialkylamino)-5H-1,2,3-

dithiazoles 38.65 Initially, the reaction was assumed to proceed via direct nucleophilic

substitution of the C4 chlorine, however, UV/vis studies revealed that the reaction

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proceeds via ring opening of the dithiazole to form an intermediate disulfide 37. Addition

of dialkylamine at the formed cyano group generates an amidine moiety that cyclizes onto

the S2 of the disulfide to reform the initial dithiazole ring (Scheme 18). This is an example

of a degenerate ANRORC66 (Addition of the Nucleophile, Ring Opening and Ring Closure)

mechanism.

Scheme 18. Proposed mechanism for the formation of 4-(dialkylamino)-5H-1,2,3-dithiazoles 38

Nevertheless, no examples exist where a new heterocyclic system is formed retaining the

two sulfur atoms of the intermediate disulfide (Path F, Scheme 16). Such an example was

discovered during this Thesis and is presented in Chapter 4.

An example demonstrating the formation of acyclic structures (Path A, Scheme 16) is the

treatment of dithiazolimines 39 with DBU to give cyanothioformamides 40 (Scheme 19).

Scheme 19. An example of the formation of acyclic cyanothioformamides 40 from 1,2,3-dithiazoles

39

A tentative mechanistic rationale for the reaction was proposed as follows: Nucleophilic

attack via the DBU amidine nitrogen at the dithiazole S2 ring sulfur and subsequent ring-

opening affords the disulfide 41. A second equivalent of DBU can then abstract HCl to

give the neutral disulfide 42. Further nucleophilic attack by a third equivalent of DBU

cleaves the disulfide S–S bond to give the cyanothioformamide 40 and the sulfane 45

(Scheme 20).67

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Scheme 20. Plausible mechanism for the DBU-mediated transformation of 1,2,3-dithiazoles 39 to

cyanothioformamides 40

1.5.3.4 Intermolecular Attack at C5

In this category of reactions, the mechanism is proposed to proceed via initial attack of an

external nucleophile at the dithiazole C5 position to give the tetrahedral intermediate 46.

Subsequent cleavage of the dithiazole and concomitant loss of sulfur (S2 or S8) and HCl

affords the cyano compound 47 (Scheme 21), the fate of which depends on the functional

groups present.

Scheme 21. General reaction mechanism initiated by intermolecular attack at C5

For example, if a bisnucleophile is used, and depending on number of bonds separating the

two nucleophiles, a second addition at the carbon, previously C5 of the dithiazole ring

(Path C), or addition to the formed CN group (Path D), or addition to an adjacent

electrophilic group (Paths A-B) can occur. In this way, a variety of polycyclic structures

can be obtained (Scheme 22).65b,68

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Scheme 22. Possible cyclisations that can occur after formation of intermediate 47 depending on

the peripheral reactive sites

A characteristic example of this type of mechanism is illustrated by the reaction of the

N-(4-chloro-5H-1,2,3-dithiazol-5-ylidene)anthranilate 48 with primary alkylamines.

Nucleophilic attack of the primary alkylamine at the dithiazole C5 position gives the

intermediate 49, which extrudes HCl and sulfur to give the cyanoamidine 50.

Intramolecular nucleophilic attack of the amino group to the adjacent ester carbonyl carbon

takes place rapidly to yield quinazolinones 51 (Scheme 23).68a

Scheme 23. Reaction mechanism for the transformation of 4-chloro-N-(4-chloro-5H-1,2,3-dithiazol-

5-ylidene)anthranilate 48 to quinazolinones 51

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Interestingly, this reaction was used for the synthesis of alkaloids rutaecarpine 53a,

hortiacine 53b, euxylophoricine A 53c and euxylophoricine D 53d (Scheme 24).69

Scheme 24. Use of 1,2,3-dithiazoles in the synthesis of natural products proceeding via initial

attack of a bisnucleophile leading to formation of quinazolinone 52 (like Scheme 23) following

cyclisation at the previously C5 of the dithiazole ring (Scheme 22, Path E)

1.6. Origin of Thesis

From the above mentioned examples on 1,2,3-dithiazole chemistry, it is evident that Appel

salt 1 is a versatile starting material for the synthesis of other useful heterocycles. While

scientists have worked on Appel salt 1 for over 30 years, reports on new aspects of its

chemistry regularly appear, which indicates that the full scope of this heterocycle has yet to

be fully understood. As such, this Thesis focuses on the exploration of Appel salt

chemistry with two broad aims: i) To develop new synthetic methods for the synthesis of

useful heterocycles, and ii) to discover new and unusual reactions of mechanistic interest.

One of the most well known and most exploited reactions of Appel salt 1 is its conversion

to N-aryl-4-chloro-5H-1,2,3-dithiazol-5-imines 19 and subsequent thermolysis to afford

benzothiazole-2-carbonitriles 21 (Section 1.5.3.1, Scheme 10). Surprisingly, until recently,

there were no examples of this ring transformation that led to hetareno-fused thiazoles.

Since these are privileged scaffolds and their preparation often requires multistep syntheses,

the discovery of new, simple and cheap methods for their synthesis is desirable.

Prior work from our team indicated that the thermolysis of the simplest azine analogues

N-(4-chloro-5H-1,2,3-dithiazol-5-ylidene)pyridin-n-amines 54 (where n = 2, 3 and 4,

respectively) did afford thiazolopyridines 55 but only in low to moderate yields (Scheme

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25).70 Nevertheless, the product yields were dramatically improved to near quantitative

yields by taking advantage of an alternative thiophile-assisted ANRORC strategy

(Chapter 2). The initial aim of this Thesis was to investigate the scope and breadth of this

high yielding ANRORC strategy to access a wide range of azino-fused thiazole-2-

carbonitriles and then to extend the study by examining the possibility of using 1,2,3-

dithiazole chemistry to access azolo-fused thiazoles.

Scheme 25. General scheme for the thermolysis of the simplest N-(4-chloro-5H-1,2,3-dithiazol-5-

ylidene)pyridin-n-amines 54 to give thiazolopyridines 55

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CHAPTER 2

The Conversion of N-Azinyl-4-chloro-5H-1,2,3-dithiazol-5-imines into Azino-fused

Thiazole-2-carbonitriles

Contents

2.1 Introduction 26


1,2,3-dithiazol-5-imines 27

2.3 Scope and Limitations of the ANRORC Transformation of N-Azinyl-4-

chloro-5H-1,2,3-dithiazol-5-imines 29

2.4 Comparison with Other Methods 31

2.5 Conclusions 32

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2.1 Introduction

The thermolysis of N-aryl-4-chloro-5H-1,2,3-dithiazol-5-imines 19 to give areno-fused

thiazole-2-carbonitriles has been, in most part, limited to the preparation of benzothiazole-

2-carbonitriles 21 (Scheme 26). The reactions are accompanied by the formation of

elemental sulfur (S8) and, when the aniline is electron poor, arylcarbonocyanidimidic

chlorides 56.71 Mechanistic rationale for the formation of products 21 and 56 has been

proposed by Rees.54,71

Scheme 26. Thermolysis products of N-aryl-4-chloro-5H-1,2,3-dithiazol-5-imines 19

Many benzothiazole-2-carboxamides, which can be readily derived from benzothiazole-2-

carbonitriles, possess useful physical and biological properties.72 Interesting biological

activities are also shown by isosteric azino-fused thiazole-2-carboxamides, including

anticoagulant (e.g., the thiazole[5,4-b]pyridines 57)73 or antiviral behavior (e.g., the

thiazolo[5,4-c]pyridines 58),74 and inhibition of kinases (e.g., the thiazolo[5,4-d]-

pyrimidines 5975 and thiazolo[4,5-d]pyrimidines 6076) (Figure 17).

Figure 17. Representative structures of some biologically active azino-fused thiazoles

Unlike benzothiazoles,72,77,78 routes to azino-fused thiazoles are less well developed.79 By

analogy with the formation of benzothiazole-2-carbonitriles 21 (Scheme 26) the

thermolysis of N-azinyl-4-chloro-5H-1,2,3-dithiazol-5-imines could provide a facile route

to azino-fused thiazole-2-carbonitriles.

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Preliminary work from our team showed that thermolysis of the simplest azinyl analogues

4-chloro-N-pyrid-n-yl-5H-1,2,3-dithiazol-5-imines 54 (where n = 2, 3 and 4, respectively)

gives thiazolopyridines 55 in low to moderate yields.70 Nevertheless, the product yields

were dramatically improved by taking advantage of an alternative thiophile-assisted

ANRORC strategy, to obtain the pyrido-fused thiazole-2-carbonitriles in high to near

quantitative yields.70

Initially, the most critical experiments of the prior study were repeated and verified for

their reproducibility. In continuation, we examined the scope of this chemistry by applying

the ANRORC strategy to an expanded family of N-azinyl-4-chloro-5H-1,2,3-dithiazol-5-

imines which led to a broad array of azino-fused thiazole-2-carbonitriles.


1,2,3-dithiazol-5-imines

Attempts to prepare thiazolopyridines via the thermolysis of various 4-chloro-N-pyridyl-

5H-1,2,3-dithiazol-5-imines gave only low to moderate yields of the desired products

together with several minor side products.70 In light of the π electron deficiency of pyridine

we then considered the thiophile-assisted ANRORC66 style ring transformation of

dithiazoles which we and others have previously demonstrated with success.47c,54,58,67,80,81

Tentatively, we postulated that the generation of a nucleophilic S1 atom could be trapped

at the pyridyl’s more electrophilic sites i.e. C2, C4 and C6. Furthermore, by introducing a

suitable nucleofuge at these positions such as a halogen, the cyclisation step could occur

via a facile intramolecular nucleophilic aromatic substitution thus avoiding the need for

oxidative rearomatisation (Scheme 27).

Scheme 27. Representative mechanism for the proposed thiophile-assisted ANRORC-style ring

transformation

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Gratifyingly, the thiophile-assisted ANRORC-style ring transformation of 4-chloro-N-(2-

chloropyrid-3-yl)-5H-1,2,3-dithiazol-5-imine 61a with BnEt3NHal (Hal = Cl, Br, I) gave as

only product the thiazolo[5,4-b]pyridine 55a in moderate to quantitative yields. The

reaction was optimized with respect to solvent, equivalents of reagents and atmosphere

(Table 1).82

Under atmospheric air or in non-dried and deaerated solvents the reaction mixture was

complex providing the desired product in low to moderate yields. When the reaction took

place in anhydrous conditions and in dry and deaerated chlorobenzene the product was

obtained in high yields. The reactions with chloride or bromide (Table 1, entries 1 and 2,

respectively) took significantly longer to consume the starting dithiazole than with iodide

(Table 1, entry 3). Furthermore, BnEt3NI could be used in catalytic amounts (5 mol %),

although this led to longer reaction times (20 h vs 2 h with 100 mol % of BnEt3NI) (cf

entries 3 to 6, Table 1). While only the results in chlorobenzene are shown in Table 1 we

note that dry deaerated benzene, toluene and xylene can also be used without significant

changes in the product yield.

Table 1. Reaction of 4-chloro-N-(2-chloropyrid-3-yl)-5H-1,2,3-dithiazol-5-imine 61a (0.19 mmol) with R4NHal in dry PhCl (2 mL) at ca. 131 °C under argon atmosphere

entry R4NHal time yields (%)

(equiv) (h) S8 55a

1 BnEt3NCl (1) 9 94 89 2 Et4NBr (1) 11 84 99 3 BnEt3NI (1) 0.33 84 66 4 BnEt3NI (0.50) 1.25 99 92 5 BnEt3NI (0.25) 2 100 92 6 BnEt3NI (0.05) 24 83 98

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2.3 Scope and Limitations of the ANRORC Transformation of N-Azinyl-

4-chloro-5H-1,2,3-dithiazol-5-imines

In light of this success, the scope and limitations of the reaction were investigated further.

For that reason, 4-chloro-N-(2-chloroazinyl)-5H-1,2,3-dithiazol-5-imines 62a-l were

prepared using the standard method for the condensation of Appel salt 1 with aminoazines

(Table 2).83

Table 2. Reaction of Appel salt 1 (0.48 mmol) with aminoazines (1 equiv) in DCM (4 mL) at ca. 20 °C

entry A B C D yield (%)

62

1 N CH CH CMe 62a (60) 2 N CH CMe CH 62b (82) 3 N CH CCl CH 62c (82) 4 N CH CBr CH 62d (81)

5 N CH CI CH 62e (81)

6 N COMe CH CH 62f (90) 7 N CCl CH CH 62g (85) 8 N CH N CH 62h (78) 9 N CH N CCl 62i (50) 10 N CMe N CCl 62j (71) 11 N CCl N CH 62k (77) 12 N CH CH N 62l (90)a

Then, the dithiazolimines 62 were treated under the optimized conditions and in nearly all

cases, the desired azino-fused thiazole-2-carbonitriles 63 were obtained in excellent yields

(Table 3). A selection of 4-chloro-N-(2-chloropyrid-3-yl)-5H-1,2,3-dithiazol-5-imines

bearing substituents at the pyridyl C4 and C5 positions reacted with BnEt3NI to give near

quantitative yields of the corresponding thiazolopyridines (Table 3, entries 3-7). Similarly,

the reaction with 4-chloro-N-(4-chloropyrid-3-yl)-5H-1,2,3-dithiazol-5-imine 61b gave the

thiazolo[4,5-c]pyridine 55b in 99% yield (Table 3, entry 2). The exceptions, however,

were the pyridine analogues bearing a substituent at the pyridyl C6 position (Table 3,

entries 8 & 9), where the desired thiazolopyridines 63e and 63f were obtained in low to

moderate yields, 36 and 43%, respectively together with isothiocyanates 64a and 64b

isolated as minor side products, 12 and 13% yields, respectively. Furthermore, diazines

such as the pyrimidinyl analogues 62h-k gave thiazolopyrimidines in good to excellent

yields (Table 3, entries 10-13), but the reaction of the pyrazinyl analogue 62l (Table 3,

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entry 14) could not be brought to completion even after 5 days; repeating the reaction with

1 equivalent of BnEt3NI also led to incomplete consumption of starting dithiazole after 12

h and a complex reaction mixture. At the time that this research was going on we did not

have an explanation for this anomalous result, however, similar anomalous behavior was

observed in a later reaction (Chapter 5) and can now be attributed to decrease on the

electrophilicity of the S2 atom, caused by an increase of its electronic population as a result

of an N…S non-bonding interaction between the ortho to the imine pyrazinyl N and the S1

in the dithiazole 62l (for extensive discussion see Chapter 5, Section 5.6).

Table 3. Reaction of N-azinyl-1,2,3-dithiazolimines 61, 62 (0.19 mmol) with BnEt3NI (5 mol %) in dry PhCl (2 mL) at ca. 131 °C under argon atmosphere

entry dithiazole A B C D time yields (%) (h) 64 55, 63

1 61a N CH CH CH 24 - 55a (98) 2 61b CH CH N CH 20 - 55b (99) 3 62a N CH CH CMe 31 - 63a (98) 4 62b N CH CMe CH 51 - 63b (98) 5 62c N CH CCl CH 41 - 63c (97) 6 62d N CH CBr CH 36 - 63d (92)

7 62e N CH CI CH 51 - 63e (93)

8 62f N COMe CH CH 43 64a (12) 63f (36) 9 62g N CCl CH CH 48 64b (13) 63g (43)

10 62h N CH N CH 31 - 63h (97) 11 62i N CH N CCl 26 - 63i (80) 12 62j N CMe N CCl 27 - 63j (89) 13 62k N CCl N CH 35 - 63k (93) 14 62l N CH CH N 132 - 63l (42)a

a Yield based on 10% recovered starting dithiazolimine 62l

To the best of our knowledge, with the exception of compound 55a, the above azino-fused

thiazole-2-carbonitriles are all new and the compounds all bear a potentially useful C2

nitrile, which can readily be further modified, adding value to the method.

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2.4 Comparison with Other Methods

After this work was published,84 the synthesis of the parent thiazolo[5,4-b]pyridine-2-

carbonitrile 55a was also reported via a Cu(I)-mediated cyclisation of N-(2-bromopyrid-3-

yl)-4-chloro-5H-1,2,3-dithiazol-5-imine 66a.85 As can be seen from Table 4 (entry 1), the

reaction of 4-chloro-N-(2-chloropyrid-3-yl)-5H-1,2,3-dithiazol-5-imine 65a via the Cu(I)-

mediated cyclisation gave a low (31%) yield of the desired product similar to that obtained

from a typical thermolysis reaction of 4-chloro-N-(pyrid-3-yl)-5H-1,2,3-dithiazol-5-imine

54b (Table 5, entry 2).

Table 4. Literature Cu(I)-mediated cyclisation of 4-chloro-N-halopyridyl-5H-1,2,3-dithiazol-5-imines

entry dithiazole Hal X Y CuI temp time yields

(equiv) (°C) (h) (%)

1 65a Cl N CH 1 115 0.5 55a (31) 2 66a Br N CH 1 115 0.5 55a (72) 3 66b Br CH N 1 130 1 55d (45)

On switching to N-(2-bromopyrid-3-yl)-4-chloro-5H-1,2,3-dithiazol-5-imine 66a, the

Cu(I)-mediated ring transformation affords the product 55a in a much improved 72% yield

(Table 4, entry 2), however, this is still lower than the above presented ANRORC method

which provides access to this thiazole 55a in almost quantitative yield (Table 3, entry 1).

The Cu(I)-mediated cyclisation was also applied to N-(3-bromopyrid-2-yl)-4-chloro-5H-

1,2,3-dithiazol-5-imine 66b (Table 4, entry 3) which gave thiazolo[4,5-b]pyridine-2-

carbonitrile 55d in moderate (45%) yield. A direct comparison for this example with the

presented method is not possible since the analogous reaction of 4-chloro-N-(3-

chloropyrid-2-yl)-5H-1,2,3-dithiazol-5-imine 65b (Hal = Cl, X = CH, Y = N) with

BnEt3NI was not performed. Nevertheless, worthy of note is that in the analogous

thermolysis of 4-chloro-N-(pyrid-2-yl)-5H-1,2,3-dithiazol-5-imine 54a no formation of the

desired product was observed (Table 5, entry 1).

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Table 5. Thermolysis of 4-chloro-N-pyridyl-5H-1,2,3-dithiazol-5-imines 54a-c under argon for 10

min

entry dithiazole decomp.

onset/peak temp reaction temp yields

(°C)a (°C) (%)

1 pyrid-2-yl (54a) 209.7/211.3 210 55d (0)

2 pyrid-3-yl (54b) 145.3/157.7 155 55a (31),b 55c (35),c 54b (32)

3 pyrid-4-yl (54c) 184.0/185.5 190 55b (30),b 54c (8) a Onset/peak decomposition temperatures determined using DSC in hermetically sealed

aluminum pans under argon atmosphere with a heating rate of 5 °C/min b Yields based on recovered dithiazolimines 54

2.5. Conclusions

The thermolysis of readily prepared 4-chloro-N-pyridyl-5H-1,2,3-dithiazol-5-imines

affords elemental sulfur and thiazolopyridines in low to moderate yields. However, by

taking advantage of an ANRORC-style ring transformation, 4-chloro-N-(2-chloropyrid-3-

yl)-5H-1,2,3-dithiazol-5-imine 61a treated with a catalytic amount of BnEt3NI (5 mol %)

as thiophile gave thiazolo[5,4-b]pyridine-2-carbonitrile 55a in near quantitative yield. In

this way, fourteen azino-fused thiazole-2-carbonitriles were prepared in two steps and in

high overall yield via readily available Appel salt 1.

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CHAPTER 3

The Reaction of 1H-Pyrazol-5-amines with 4,5-Dichloro-1,2,3-dithiazolium Chloride:

A Route to Pyrazolo[3,4-c]isothiazoles and Pyrazolo[3,4-d]thiazoles

Contents

3.1 Introduction 34

3.2 Reaction of Appel Salt 1 with 1H-Pyrazol-5-amines 67 36

3.3 Optimization of the Reaction 40



of 4-Chloro-N-(pyrazol-5-yl)-5H-1,2,3-dithiazol-5-imines 68 45

3.6 Routes to N-Unsubstituted Pyrazolo[3,4-c]isothiazole-3-carbonitriles

and Pyrazolo[3,4-d]thiazole-5-carbonitriles 46

3.7 Conclusions 49

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3.1 Introduction

In light of the successful synthesis of azino-fused thiazole-2-carbonitriles (Chapter 2) we

considered the possibility for accessing azolo-fused thiazole-2-carbonitriles via Appel salt

chemistry.

Azolo-fused thiazoles,86 are less well studied than benzo- and azino-fused thiazoles,

nevertheless, several analogues show diverse bioactivity while others are useful in the

material sciences. For example, 4H-pyrrolo[2,3-d]thiazoles, 4H-pyrrolo[3,2-d]thiazoles,

1H-pyrazolo[3,4-d]thiazoles and/or 1H-pyrazolo[4,3-d]thiazoles modulate and/or inhibit

various protein kinases, which are important in cancer therapy.87 Furthermore, azolo-fused

thiazoles can influence the progress of neurological diseases such as schizophrenia or

Alzheimer’s disease: 4H-Pyrrolo[2,3-d]thiazoles and/or 4H-pyrrolo[3,2-d]thiazoles can

inhibit D-amino acid oxidase,88 while 1H-pyrazolo[3,4-d]thiazoles and/or 1H-pyrazolo-

[4,3-d]thiazoles can modulate the mGluR4 receptor activity.89 4H-Pyrrolo[2,3-d]thiazoles

and/or 4H-pyrrolo[3,2-d]thiazoles can also act as anti-inflammatory agents e.g., as

cannabinoid hCB2 receptor agonists90a and as inhibitors of MCP-1,90b or show anti-allergic

activity e.g., as modulators of CRTH291

(Figure 18).

Figure 18. Representative structures of some biologically active azolo-fused thiazoles

In the materials sciences, thiazolo[5,4-d]thiazoles have been incorporated into

donor/acceptor polymers or oligomers for use in organic semiconductors92 and also are

components of silver halide photographic materials.93 Despite their broad applications and

unlike the 6-5 fused thiazolohetarenes,72,77-79 the synthesis of condensed 5-5 thiazoles via

construction of the thiazole ring has not been extensively explored.86

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Interestingly, while several N-hetaryldithiazolimines are known,47d,94 only one report of

their transformation into fused 5-5 thiazoles exists: L’abbe et al.,95 claimed the reaction of

Appel salt 1 with 1H-pyrazol-5-amines 67 gave 1H-pyrazolo[3,4-d]thiazole-5-carbonitriles

69 via the in situ formation of the N-pyrazolyldithiazolimines 68 (Scheme 28).

Scheme 28. Reaction of Appel salt 1 with 1,3-disubstituted 1H-pyrazol-5-amines 67 to give

1H-pyrazolo[3,4-d]thiazoles 69 (R1, R2 = Me, Ph)95

While the structure assignment for the 1H-pyrazolo[3,4-d]thiazoles 69 was presumably

influenced by the known transformation of N-aryldithiazolimines into benzo-

thiazoles,54,71,96,97 we considered the spectral data provided to be inconclusive. In addition,

the typical ring transformation of N-aryldithiazolimines into thiazoles requires thermolytic

temperatures and, to the best of our knowledge, there are no reports of room temperature

transformations. As such, the reported in situ transformation to give 1H-pyrazolo[3,4-d]-

thiazoles 69 was unique.

Furthermore, 1H-pyrazol-5-amines 67 are ambident nucleophiles,98,99 which can react with

electrophiles via the C4 ring carbon (enaminic attack) as well as via the exocyclic amino

group (normal attack). As such, we hypothesized that 6H-pyrazolo[3,4-c]isothiazoles 70

may have been formed as well as, or instead of, the proposed 1H-pyrazolo[3,4-d]thiazoles

69 (Figure 19). These two bicyclic hetarenes would have similar spectroscopic properties

making a conclusive structural assignment difficult.

Figure 19. The two possible isomeric products from the reaction of 5-aminopyrazoles 67 with

Appel salt 1

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Reactions reported by Rees57a and Kim57b where primary enamines such as methyl

3-aminocrotonate 71 and 6-amino-1,3-dialkyluracils 72 react with Appel salt 1 to give the

5-cyano-3-methylisothiazole-4-carboxylate 73 and 5,7-dialkyl-4,6-dioxo-4,5,6,7-tetrahy-

droisothiazolo[3,4-d]pyrimidine-3-carbonitriles 74, respectively (Scheme 29), supported

our hypothesis.

Scheme 29. Reactions of enamines 71 and 72 with Appel salt 1 to give isothiazole-5-

carbonitriles 73 and 74, respectively

In this Chapter, we describe our reinvestigation on the reaction of Appel salt 1 with

1H-pyrazol-5-amines 67, which gives the 6H-pyrazolo[3,4-c]isothiazoles 70, previously

misassigned as the 1H-pyrazolo[3,4-d]thiazoles 69,95 and the N-pyrazolyldithiazolimines

68 that on thermolysis give the 1H-pyrazolo[3,4-d]thiazoles 69.

3.2 Reaction of Appel Salt 1 with 1H-Pyrazol-5-amines 67

Adding a solution of 1,3-dimethyl-1H-pyrazol-5-amine 67a (1 equiv) and 2,6-lutidine

(2 equiv) in DCM (20 mL) to a stirred suspension of Appel salt 1 (1.0 g, 1 equiv) in DCM

(20 mL) under argon at ca. 20 °C followed by 1 h stirring was reported to give 1,3-di-

methyl-1H-pyrazolo[3,4-d]thiazole-5-carbonitrile 69a in 81% yield.95 In our hands,

however, the reaction gave a complex mixture from which we isolated five products:

4,6-Dimethyl-6H-pyrazolo[3,4-c]isothiazole-3-carbonitrile 70a, 4-chloro-N-(1,3-dimethyl-

1H-pyrazol-5-yl)-5H-1,2,3-dithiazol-5-imine 68a, 5-amino-1,3-dimethyl-1H-pyrazole-4-

carbothioyl cyanide 75, (3Z,3'Z)-N',N''-trisulfanediylbis(4,6-dimethyl-6H-pyrazolo[3,4-c]-

isothiazole-3-carbimidoyl chloride) 76, and (Z)-N-{[(Z)-1-(5-amino-1,3-dimethyl-1H-pyra-

zol-4-yl)-2-chloro-2-[(Z)-(4-chloro-5H-1,2,3-dithiazol-5-ylidene)amino]vinyl]disulfanyl}-

4,6-dimethyl-6H-pyrazolo[3,4-c]isothiazole-3-carbimidoyl chloride 77 in 12, 5, 4, 12 and

13% yields, respectively (Scheme 30).

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Scheme 30. Reaction of Appel salt 1 with 1,3-dimethyl-1H-pyrazol-5-amine 67a

4,6-Dimethyl-6H-pyrazolo[3,4-c]isothiazole-3-carbonitrile 70a was isolated as colorless

needles, mp 102-106 °C (from c-hexane). Elemental analysis and mass spectrometry

supported the formula C7H6N4S. The NMR and IR spectroscopic data matched that reported

for the isomeric 1,3-dimethyl-1H-pyrazolo[3,4-d]thiazole-5-carbonitrile 69a,95 however,

single crystal X-ray diffraction studies (Figure 20) identified the structure to be the fused

isothiazole 70a and not as previously reported the fused thiazole 69a.

Figure 20. Ellipsoid (probability level of 50%) representation of the crystal structure of 4,6-dimethyl-

6H-pyrazolo[3,4-c]isothiazole-3-carbonitrile 70a with crystallographic atom labelling, The H atoms

are omitted for clarity

The N-pyrazolyldithiazolimine 68a was obtained as yellow prisms, mp 154-156 C (from

c-hexane) and was stable at room temperature; no decomposition was observed during a hot

recrystallization. Differential scanning calorimetry (DSC) of the N-pyrazolyldithiazolimine

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68a gave a decomposition with an onset point at 158.2 C and its thermolysis on a

quantitative scale (0.1 mmol) under argon atmosphere at ca. 170 C gave S8 (78%), traces

(by TLC) of an, at that time, unidentified side product (see Chapter 4), and 1,3-dimethyl-

1H-pyrazolo[3,4-d]thiazole-5-carbonitrile 69a (77%) (Table 7, entry 1). The spectroscopic

data collected for the pyrazolo[3,4-d]thiazole-5-carbonitrile 69a prepared in this manner

differed significantly from that reported in the literature.95 With the single crystal X-ray

diffraction study of the above fused isothiazole 70a, we therefore, concluded that the earlier

structural assignment for the fused thiazole 69a was incorrect.

The 5-amino-1,3-dimethyl-1H-pyrazole-4-carbothioyl cyanide 75 was obtained as orange

plates, mp 212-213 C (from CHCl3). Elemental analysis and mass spectrometry supported

the formula C7H8N4S. The 1H NMR spectrum showed the presence of two methyl groups,

the absence of the pyrazole H4 resonance and the presence of a D2O exchangeable NH2

resonance at δH 7.23 ppm which was further supported by IR spectroscopy ν(N-H)

3339 cm-1. In addition to the two Me resonances, the 13C NMR data showed the presence of

five quaternary carbon resonances one of which fitted for a nitrile at δC 116.2 ppm as

supported also by the IR stretching frequency at ν(C≡N) 2226 cm-1. The structural

assignment of compound 75 is tentative.

(3Z,3'Z)-N',N''-3-Trisulfanediylbis(4,6-dimethyl-6H-pyrazolo[3,4-c]isothiazole-3-carbimi-

doyl chloride) 76 was obtained as yellow needles, mp 201-208 °C (from DCE). Elemental

analysis and mass spectrometry tentatively supported the formula C14H12Cl2N8S5, which

fitted for two molecules of either fused pyrazoles 69a or 70a and S3Cl2. Interestingly, IR

spectroscopy showed an absence of amino or cyano stretching frequencies. 1H and 13C

NMR spectroscopy also supported the presence of four high field quaternary signals

corresponding to at least two dimethylpyrazoles. The absence of the H4 pyrazole

resonance in the 1H NMR suggested the pyrazoles units have undergone substitution at the

C4 position and this was also supported by the 13C NMR data. No resonances were visible

in either the 13C NMR data that corresponded to the presence of sp hybridized carbons

further supporting the absence of nitrile groups. Based on the above data we suspected that

a symmetrical trisulfur dichloride adduct of either fused pyrazole 69a or 70a had formed.

(Z)-N-{[(Z)-1-(5-Amino-1,3-dimethyl-1H-pyrazol-4-yl)-2-chloro-2-[(Z)-(4-chloro-5H-

1,2,3-dithiazol-5-ylidene)amino]vinyl]disulfanyl}-4,6-dimethyl-6H-pyrazolo[3,4-c]isothia-

zole-3-carbimidoyl chloride 77 was obtained as red needles, mp 143–145 C (from

n-pentane/DCM). Elemental analysis and mass spectrometry tentatively supported the

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formula C16H14Cl3N9S5. IR spectroscopy showed the presence of amino stretching

frequencies v(N-H) 3327w and 3196w cm-1, which was also supported by a broad signal in

the 1H NMR spectrum at δH 3.77 ppm that integrated for two H’s and was D2O

exchangeable. The 1H and 13C NMR spectra also indicated the presence of four methyl

groups suggesting the presence of at least two dimethylpyrazole units.

Based on the above spectroscopic data we were unable to confidently assign structures for

side products 76 and 77. As such, we attempted to elucidate further information on these

by investigating their stability towards heat or acid: Heating a pure sample of the side

products 76 or 77 gave the 6H-pyrazolo[3,4-c]isothiazole 70a (89 and 48%, respectively)

while treating them with concd H2SO4 at ca. 20 °C gave the carboxamide 78 (99 and 34%,

respectively), dehydration of which using POCl3 gave the carbonitrile 70a in 98% (Scheme

31).

Scheme 31. Behavior of trisulfide 76 and disulfide 77 under thermal or acidic conditions

The data from these studies confirmed that the side products were comprised of

pyrazolo[2,3-c]isothiazoles or their possible intermediates. To resolve their structures

conclusively, single crystals of both side-products 76 and 77 were grown and the structures

solved by single crystal X-ray crystallography (Figures 21 & 22, respectively).

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Figure 21. Ellipsoid (probability level of 50%) representation of the crystal structure of

(3Z,3'Z)-N',N''-trisulfanediylbis(4,6-dimethyl-6H-pyrazolo[3,4-c]isothiazole-3-carbimidoyl chloride)

76 with crystallographic atom labelling. The H atoms are omitted for clarity


(Z)-N-{[(Z)-1-(5-amino-1,3-dimethyl-1H-pyrazol-4-yl)-2-chloro-2-[(Z)-(4-chloro-5H-1,2,3-dithiazol-5-

ylidene)amino]vinyl]disulfanyl}-4,6-dimethyl-6H-pyrazolo[3,4-c]isothiazole-3-carbimidoyl chloride 77

with crystallographic atom labelling. The H atoms are omitted for clarity

3.3 Optimization of the Reaction

Having identified the major products from the reaction of 1,3-dimethyl-1H-pyrazol-5-amine

67a with Appel salt 1, the influence of time and mode of reagent addition on the reaction

was investigated. As shown above (Section 3.2), when a solution of the pyrazol-5-amine

67a in DCM was mixed with 2,6-lutidine before the addition of Appel salt 1 and then stirred

for 1 to 3 h the reaction mixture was complex. Nevertheless, allowing the reaction to stir for

longer (6-15 h) provided a significantly simpler reaction mixture (by TLC) and only the

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6H-pyrazolo[3,4-c]isothiazole 70a could be isolated, although in a moderate 52% yield

(Scheme 32, Conditions A). Alternatively, if the pyrazol-5-amine 67a was left stirring with

Appel salt 1 for 12 h before the addition of base then the N-pyrazolyldithiazolimine 68a was

isolated as the major product in 44% yield, together with a small quantity of the

pyrazoloisothiazole 70a (14%). This result alerted us to the effect the amine base had on the

yield of the N-pyrazolyldithiazolimine 68a. Since the pyrazol-5-amine 67a itself can act as

base (e.g., 1-methyl-1H-pyrazol-5-amine has a pKa of 9.77),100 we carried out the reaction

under non-basic conditions by preparing the HCl salt of the pyrazolamine: Adding Appel

salt 1 to a suspension of the pyrazolamine hydrochloride 67a·HCl in DCM or to a solution

of the pyrazolamine 67a in DCM purged with HCl (g), led to the formation of the

N-pyrazolyldithiazolimine 68a in 68 and 69% yields, respectively (Scheme 32, Conditions B).

Scheme 32. Reaction of Appel salt 1 with pyrazol-5-amine 67a under basic and acidic conditions

With these partially optimized conditions in hand, we screened the reaction of Appel salt 1

with a series of pyrazol-5-amines 67a-i (Table 6). With 1-unsubstituted 1H-pyrazolamines

67b and 67c, regardless of which conditions were used, the major products were the

N-pyrazolyldithiazolimines 68b and 68c while the isothiazoles 70b and 70c were observed

in very low yields (Table 6, entries 2 & 3). The reactions of Appel salt 1 with 1-methyl-3-

phenyl-1H-pyrazol-5-amine 67d and 1-benzyl-3-phenyl-1H-pyrazol-5-amine 67f were

similar to those with 1,3-dimethyl-1H-pyrazol-5-amine 67a described above; i.e., under

basic conditions the major products were the 6H-pyrazolo[3,4-c]isothiazoles 70d and 70f

(45 and 41%, respectively) (Table 6, entries 4 and 6, cond. A), while under acidic

conditions the major products were the N-pyrazolyldithiazolimines 68d and 68f (73 and

55%, respectively) (Table 6, entries 4 & 6, cond. B).

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Unexpectedly, using conditions B the 1-benzyl-3-methyl-1H-pyrazol-5-amine 67e reacted

with Appel salt 1 to give as major product the pyrazolo[3,4-c]isothiazole 70e (26%) and

the desired N-pyrazolyldithiazolimine 68e in only trace amounts. The 1-benzyl-N-pyra-

zolyldithiazolimine 68e was formed in somewhat higher yield (17%) when the free base of

1-benzyl-3-methyl-1H-pyrazol-5-amine 67e was used (Table 6, entry 5, cond. B).

Table 6. Reaction of Appel salt 1 with pyrazol-5-amines 67 (1 equiv) in DCM at ca. 20 °C

entry pyrazole R1 R2 yields (%)

Cond. Aa Cond. Bb

1 67a Me Me 70a (51) 68a (0) 70a (1) 68a (70)

2 67b H Me 70b (4) 68b (65) 70b (0) 68b (74)

3 67c H Ph 70c (7) 68c (58) 70c (0) 68c (92)

4 67d Me Ph 70d (45) 68d (0) 70d (5) 68d (73)

5 67e Bn Me 70e (47) 68e (0) 70e (29)c 68e (17)c

6 67f Bn Ph 70f (41) 68f (0) 70f (9) 68f (55)

7 67g t-Bu Me 70g (39) 68g (0) 70g (21) 68g (0)

8 67h t-Bu Ph 70h (38) 68h (0) 70h (37) 68h (0)

9 67i Ph Me 70i (36) 68i (0) 70i (6) 68i (22)

10 67j Ph Ph 70j (34) 68j (0) 70j (19) 68j (9) a Cond. A: i) DCM, 2,6-lutidine (2 equiv), ca. 20 °C, 15 h b Cond. B: i) DCM, HCl (g), ca. 20 °C, 12 h ii) 2,6-lutidine (2 equiv), ca. 20 °C, 3 h c No HCl (g) was used

Reaction of Appel salt 1 with the 1-(tert-butyl)-3-methyl- and 1-(tert-butyl)-3-phenyl-1H-

pyrazol-5-amines 67g and 67h using either conditions A or B gave only the 6-(tert-butyl)-

4-methyl- and 6-(tert-butyl)-4-phenyl-6H-pyrazolo[3,4-c]isothiazole-3-carbonitriles 70g

and 70h, respectively, and none of the corresponding 1-(tert-butyl)-N-

pyrazolyldithiazolimines (Table 6, entry 7 & 8). Presumably the bulky tert-butyl group at

N1 shielded the neighboring C5 amine promoting attack at the enaminic C4 position. For

the 1-phenyl-1H-pyrazol-5-amines 67i and 67j, using both sets of reaction conditions, the

reaction mixtures were more complex and the products 68i, 68j, 70i and 70j were obtained

in low to moderate yields (Table 6, entries 9 & 10).

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3.4 Mechanistic Rationale

The formation of the N-pyrazolyldithiazolimine 68 was a result of the expected normal

attack of the exocyclic primary amine at the highly electrophilic C5 position of Appel salt

1. The formation of the 6H-pyrazolo[3,4-c]isothiazole 70, however, can result from the

ambident activity of 1H-pyrazol-5-amines 67 i.e. their ability to also react via the C4

position (enaminic attack) (Scheme 33).

Scheme 33. Proposed reaction mechanism for the formation of the 6H-pyrazolo[3,4-c]-

isothiazoles 70

While the proposed ylidene 80 was not observed in the reaction mixture, similar

intermediates have been invoked for the reaction of Appel salt 1 with the primary enamines

(E)-methyl 3-aminobut-2-enoate 7157a and 6-amino-1,3-dialkyluracils 7257b (Scheme 29).

The exocyclic imine of intermediate 80, assisted by the pyrazole N1 ring nitrogen, can

cyclize onto the dithiazole S1 atom, leading to formation of the isothiazole with

concomitant cleavage of the dithiazole that gives an N-mercaptocarbimidoyl chloride

intermediate 81. From this intermediate the dithiazole S2 atom can extrude as S8 via a

bimolecular sulfur chain extension process62b,101 and the isolation of the trisulfide 76

tentatively supports this. Interestingly, chloride mediated thiophilic ring opening of the

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proposed dithiazolium intermediate 79 can lead to the isomeric sulfenyl chloride 82 that

can lose sulfur dichloride to afford the carbothioyl cyanide 75 (Scheme 34). The isolation

of the carbothioyl cyanide 75 adds tentative support for the above mechanistic rationale.

Scheme 34. Possible route to 5-amino-1,3-dimethyl-1H-pyrazole-4-carbothioyl cyanide 75

The structure of the disulfide 77 provides further evidence that the pyrazolamine 67a

reacted with Appel salt 1 via the enaminic C4 carbon, a necessary criterion for the

formation of the pyrazoloisothiazoles 70. A tentative but plausible mechanism for the

formation of the disulfide 77 can involve the condensation of three components: The

proposed N-mercaptocarbimidoyl chloride intermediate 81 could add to the carbothioyl

cyanide 75 to give a disulfide intermediate that then captures a molecule of Appel salt 1 to

give the ketenimine 83. The thiophilic addition of thiols to thiones to give disulfides is well

documented.102 The highly electrophilic ketenimine 83, now activated by the dithiazolium

cation, can rapidly capture chloride to give the neutral species 77 (Scheme 35).

Scheme 35. Tentative mechanism for the formation of the disulfide 77

It is not possible at this stage to predict the order of events leading to the final product,

nevertheless, the structures of the disulfide 77, the carbothioyl cyanide 75 and the

pyrazoloisothiazoles 70 clearly support that in these cases Appel salt 1 reacted at the

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pyrazole’s enaminic C4 position. Interestingly, on extending the reaction time the minor

side products 75-77 disappeared from the reaction mixture (by TLC) suggesting that they

could be possible intermediates to the final products.

1H-Pyrazol-5-amines are widely used in synthesis,98,99 however, predicting their selectivity

towards electrophiles (i.e. 5-NH2 vs C4 attack) is not trivial as many factors can influence

the course of the reaction. In our case, where Appel salt 1 is used as the electrophile and

1-alkylpyrazol-5-amines as the nucleophile, the results described above indicate that the

determining factor is the pH of the reaction medium. Under basic conditions (cond. A)

reaction at the C4 pyrazole position (enaminic attack) was favored while under acidic

conditions (cond. B), the expected direct (normal) attack of the pyrazole exocylic primary

amine was observed. This could be explained in terms of the initial protonation of

5-aminopyrazoles which occurs on the ring nitrogens,100 thus reducing the electron density

of the pyrazole ring and deactivating enaminic like behavior. The results become more

complex, however, when the N1 substituent is changed. In the case of bulky tert-butyl

groups at N1 (e.g., pyrazol-5-amines 70g and 70h) only the formation of isothiazole is

observed in reasonable quantities. The reactions of 1-phenylpyrazolamines 67i and 67j

were also complex affording the desired products in only low to moderate yields.

Presumably this was owed to a combination of both steric and electronic effects; the N1

phenyl group being both considerably bulkier and also inductively less electron releasing

than the methyl group, simultaneously shielding the 5-amino group and deactivating

enaminic C4 position from reaction with the Appel salt 1. Lastly, the 1-unsubstituted

pyrazolamines 67b and 67c, regardless the reaction conditions, reacted mainly via the

exocyclic amino group possibly owing to the 1H-pyrazol-3-amine prototautomeric form

being more favorable than the 1H-pyrazol-5-amine form.103


of 4-Chloro-N-(pyrazol-5-yl)-5H-1,2,3-dithiazol-5-imines 68

With a series of 4-chloro-N-(pyrazol-5-yl)-5H-1,2,3-dithiazol-5-imines 68 in hand, we then

investigated their thermal behavior. Using differential scanning calorimetry (DSC) the

thermal decomposition points of each compound were determined, and then neat samples

(0.1 mmol) were thermolyzed at temperatures slightly above their decomposition onset

points under an argon atmosphere (Table 7).

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Table 7. Thermolysis of N-pyrazolyldithiazolimines 68

entry dithiazole R1 R2 decomp. onset temp time yields 69

(°C) (°C) (min) (%)

1 68a Me Me 158.2 170 15 69a (77)

2 68b H Me 158.4 170 10 69b (-a)

3 68c H Ph 196.3 210 10 69c (-a)

4 68d Me Ph 149.0 170 15 69d (83)

5 68e Bn Me 142.1 180 15 69e (69)

6 68f Bn Ph 161.6 200 15 69f (85)

7 68i Ph Me 126.8 150 15 69g (83)

8 68j Ph Ph 160.6 180 15 69h (78) a Intractable black solids

In general, thermolysis of the 1,3-disubstituted N-pyrazolyldithiazolimines 68 gave the

desired 1H-pyrazolo[3,4-d]thiazole-5-carbonitriles 69, respectively in 69-85% yields

(Table 7, entries 1 & 4-8). The reactions were accompanied by the formation of S8, traces

of unreacted N-pyrazolyldithiazolimines 68 and in some cases minor unidentified side

products, which could be avoided by raising the thermolysis temperature. In the case of the

1-unsubstituted analogues N-pyrazolyldithiazolimines 68b and 68c, thermolysis gave

mainly S8 and intractable black solids (Table 7, entries 2 & 3).

3.6 Routes to N-Unsubstituted Pyrazolo[3,4-c]isothiazole-3-carbonitriles and

Pyrazolo[3,4-d]thiazole-5-carbonitriles

The above syntheses worked particularly well for 1-alkyl or aryl-substituted 1H-pyrazol-5-

amines but not for 1-unsubstituted pyrazolamines: The reaction of 1-unsubstituted pyrazol-

amines 67b and 67c with Appel salt 1 gave the 6-unsubstituted pyrazolo[3,4-c]isothiazole-

3-carbonitriles 70b and 70c in low yields [Table 7, entries 2 (4%) & 3 (7%), respectively],

while the thermolysis of the readily obtained 1-unsubstituted N-pyrazolyldithiazolimines

68b and 68c, gave mainly S8 and intractable black solids (Table 7, entries 2 & 3). As such,

we proposed alternative syntheses via either protodebenzylation of the

6-benzylpyrazolo[3,4-c]isothiazoles 70e and 70f, and the 1-benzylpyrazolo[3,4-d]thiazole-

5-carbonitriles 69e and 69f, or protodebutylation of the 6-(tert-butyl)pyrazolo[3,4-c]-

isothiazoles 70g and 70h.

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Initial efforts to debenzylate the pyrazolothiazole 69f or the pyrazoloisothiazole 70f using

typical debenzylation methods [Pd/C (5 mol %), H2 (2 atm); BBr3 (10 equiv) in DCM;104

cerium ammonium nitrate (CAN) (6 equiv) in MeCN/H2O;105 Na, NH3 (l)] failed.

Nevertheless, by using Br2 and AIBN106 followed by an alkali work-up, needed to

hydrolyze any N-benzoylated side products, we were able to obtain both 3-phenyl-1H-

pyrazolo[3,4-d]thiazole-5-carbonitrile 69c and 4-phenyl-6H-pyrazolo[3,4-c]isothiazole-3-

carbonitrile 70c in good yields (76 and 92%, respectively). Unfortunately, for the methyl

analogues 69e and 70e the Br2/AIBN debenzylation conditions worked less well affording

complex mixtures (by TLC) and only a low yield (19%) of the N-unsubstituted

pyrazoloisothiazole 70b was obtained from the latter (Scheme 36).

An alternative route to 6-unsubstituted pyrazolo[3,4-c]isothiazoles 70b and 70c involved

treating the available N-benzyl and N-(tert-butyl) analogues 70e-h with acid. Initially the

4-phenyl-6H-pyrazolo[3,4-c]isothiazoles 70f and 70h were treated with neat AcOH (pKa

4.76)107 heated to ca. 118 °C for 3 d but only the corresponding carboxamides 84a and 84b

were obtained both in 83% yield. Fortunately, by using concd H2SO4 and raising the

reaction temperature to ca. 60 °C for 1-5 h, the pyrazolo[3,4-c]isothiazoles 70e-70h were

fully converted into the corresponding 6H-pyrazolo[3,4-c]isothiazole-3-carboxamides 85a

and 85b in 59-98% yields. For the 6-(tert-butyl)-6H-pyrazolo[3,4-c]isothiazoles 70g and

70h the debutylation was also effective when the reaction was performed at ca. 20 °C for

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1 d. In the case of the 6-benzyl-6H-pyrazolo[3,4-c]isothiazoles 70e and 70f, however, the

reaction at ca. 20 °C was not very successful and degradation was observed with time.

Subsequent dehydration of the carboxamides 85a and 85b with neat POCl3 at ca. 60 °C

gave the desired carbonitriles 70b and 70c, respectively, in good overall yields (50-90%).

Nevertheless, similar treatment of the 1-benzyl-1H-pyrazolo[3,4-d]thiazoles 69e and 69f

with neat concd H2SO4 at ca. 60 °C led to degradation while selective hydration of the

nitriles could be achieved by carrying out the reaction at ca. 20 °C for 2 h to give the

carboxamides 86a (85%) and 86b (88%) (Scheme 37). Extended reaction times at

ca. 20 °C also led to degradation.

Scheme 37. Preparation of 6-unsubstituted pyrazoloisothiazoles 70b and 70c and 1-benzyl-1H-

pyrazolo[3,4-d]thiazole-5-carboxamides 86

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3.7 Conclusions

1H-Pyrazol-5-amines 67 react with Appel salt 1 either via ‘normal’ or ‘enaminic’ attack

depending on the pH of the medium. Basic conditions favor formation of the 6H-pyrazolo-

[3,4-c]isothiazole-3-carbonitriles 70 (enaminic attack) while acidic conditions favor the

formation of (Z)-N-(4-chloro-5H-1,2,3-dithiazol-5-ylidene)-1H-pyrazol-5-amines 68

(normal attack). Exceptions were the 1-(tert-butyl)-3-phenylpyrazol-5-amines 67g and 67h

and the 1-unsubstituted pyrazol-5-amines 67b and 67c which independent of the reaction

conditions gave as major products the pyrazoloisothiazoles 70g and 70h and the

dithiazolylidene-1H-pyrazol-5-amines 68b and 68c, respectively. The 4-chloro-N-(pyrazol-

5-yl)-5H-1,2,3-dithiazol-5-imines 68 gave on thermolysis the 1H-pyrazolo[3,4-d]thiazoles

69 in good yields. Furthermore, single crystal X-ray crystallography supported the

structure of 4,6-dimethyl-6H-pyrazolo[3,4-c]isothiazole-3-carbonitrile 70a which was

previously mistaken to be 1,3-dimethyl-1H-pyrazolo[3,4-d]thiazole-3-carbonitrile 69a.

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CHAPTER 4

Synthesis of Fused 1,2,4-Dithiazines and 1,2,3,5-Trithiazepines

Contents

4.1 Introduction 52

4.2 Thermolysis of 4-Chloro-N-(1,3-dimethyl-1H-pyrazol-5-yl)-5H-1,2,3-

dithiazol-5-imine 68a 53

4.3 Optimization of the Transformation of 4-Chloro-N-(1,3-dimethyl-1H-

pyrazol-5-yl)-5H-1,2,3-dithiazol-5-imine 68a to 5,7-Dimethyl-5H-pyrazolo-

[3,4-e][1,2,4]dithiazine-3-carbonitrile 91a 54

4.3.1 Conversion of N-Pyrazolyldithiazolimine 68a to the Disulfide 93a 55

4.3.2 Conversion of the Disulfide 93a into the 1,2,4-Dithiazine 91a 58

4.3.3 One-pot Conversion of N-Pyrazolyldithiazolimine 68a into the

1,2,4-Dithiazine 91a 60

4.4 Scope and Limitations of the One-pot Reaction 62


carbonitrile 91a to 6,8-Dimethyl-6H-pyrazolo[3,4-f][1,2,3,5]trithiazepine-

4-carbonitrile 94a 63

4.6 Thermolysis of 5H-Pyrazolo[3,4-e][1,2,4]dithiazine-3-carbonitriles 91 66

4.7 Unexpected Chemistry of Disulfide 93a 67

4.8 Conclusions 69

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4.1 Introduction

1,2-Dithiines,108 which are six-membered heterocycles with two adjacent sulfur atoms,

have attracted considerable attention because of their unusual red color,109 questions about

their structure and their potential antiaromaticity,109a,110 their occurrence in plants111 and

their interesting biological activities112 such as antibiotic,113 antiviral,114 nematicidal,115

insecticidal,116 antifungal activity,117 and DNA cleaving properties.118

Figure 23. General structures of 1,2-dithiine and its aza analogues 1,2,3- and 1,2,4-dithiazines

Aza analogues of 1,2-dithiines are less well known. The two isomeric mono-aza dithiines,

the 1,2,3- and the 1,2,4-dithiazines (Figure 23), are both rare systems with few reports on

their synthesis and chemistry. To the best of our knowledge, there are three reports

describing the synthesis of monocyclic 8π 1,2,3-dithiazines119 while for 8π 1,2,4-dithia-

zines there are only two reports on the synthesis of benzo-fused analogues.120

Scheme 38. Known syntheses of 1,2,4-dithiazines

The first, and more general synthesis of 3-anilino-1,2,4-benzodithiazines 88 involved the

condensation of N-ethylaniline or 4-bromo-N-ethylaniline with substituted o-thiocyanato-

phenylisothiocyanates 87,120a while more recently, another benzo-fused analogue 90 was

isolated from the reaction of 2,2'-diaminodiphenyl disulfide 89 with N-benzoyl

thiocyanate120b (Scheme 38).

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Interestingly, di- and tetrahydro-1,2,4-dithiazines are more common.121 Bridged analogues

of 3,6-dihydro-1,2,4-dithiazin-5-ones are also present in natural products and possess

interesting biological activities such as antibacterial (e.g., hyalodendrin),122 antiviral (e.g.,

aranotin)123 and antitumor (e.g., gliotoxin)124 (Figure 24).

Figure 24. Examples of natural products, with interesting biological activities, containing a bridged

3,6-dihydro-1,2,4-dithiazin-5-one moiety

During the thermolysis of 4-chloro-N-(pyrazol-5-yl)-5H-1,2,3-dithiazol-5-imines 68,125

which gives S8 and pyrazolo[3,4-d]thiazoles 69 (Chapter 3), we obtained an unidentified

minor side product. In this Chapter, we report the structure elucidation of this product,

which is a rare example of a fused 1,2,4-dithiazine. Furthermore, we describe an optimized

synthesis of this heterocycle and studies related to its chemistry.

4.2 Thermolysis of 4-Chloro-N-(1,3-dimethyl-1H-pyrazol-5-yl)-5H-1,2,3-dithi-

azol-5-imine 68a

Thermolysis of 4-chloro-N-(1,3-dimethyl-1H-pyrazol-5-yl)-5H-1,2,3-dithiazol-5-imine 68a

at ca. 170 °C for 15 min gave S8, 1,3-dimethyl-1H-pyrazolo[3,4-d]thiazole-5-carbonitrile

69a and a minor red colored side product 91a (2%) (Scheme 39).

Scheme 39. Thermolysis of 4-chloro-N-(1,3-dimethyl-1H-pyrazol-5-yl)-5H-1,2,3-dithiazol-5-imine

68a

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The compound was isolated as red needles, mp (DSC) onset: 98.2 °C, peak max: 98.6 °C

(from n-pentane at ca. -20 °C). Mass spectrometry and elemental analysis supported the

molecular formula C7H6N4S2. UV/vis data showed a lowest energy absorption at λmax

(DCM) 521 nm (log ε 2.81) which accounted for the deep red color. 1H NMR data showed

the presence of two methyl resonances and the absence of the pyrazole H4 resonance

indicating that substitution had occurred at the pyrazole C4 position. 13C NMR data

showed, in addition to the two methyl resonances, the presence of five C (s) resonances,

from which one fitted for C≡N (δC 113.0 ppm). The presence of the nitrile was further

supported by IR spectroscopy [ν(C≡N) 2218 cm-1]. Based on the data the compound was

tentatively identified as 5,7-dimethyl-5H-pyrazolo[3,4-e][1,2,4]dithiazine-3-carbonitrile

91a and this was further supported by single crystal X-ray crystallography (Figure 25).


5H-pyrazolo[3,4-e][1,2,4]dithiazine-3-carbonitrile 91a with crystallographic atom labeling. The H

atoms were omitted for clarity. Worthy of note, is that atoms N1, C2, N2, N3, C3, C4 and S1 are

effectively in a plane from which atoms C1 and S2 deviate by 0.453 and 1.269 Å, respectively

4.3 Optimization of the Transformation of 4-Chloro-N-(1,3-dimethyl-1H-

pyrazol-5-yl)-5H-1,2,3-dithiazol-5-imine 68a to 5,7-Dimethyl-5H-pyrazolo-

[3,4-e][1,2,4]dithiazine-3-carbonitrile 91a

A plausible ANRORC66 mechanism can be proposed for the formation of the pyrazolo-

[3,4-e][1,2,4]dithiazine 91a: Thiophilic attack on the S2 sulfur atom of the dithiazolimine

68 by chloride or an equivalent nucleophile released during the thermolysis can give the

intermediate disulfide 92. In the presence of the electron rich enaminic C4 position of the

pyrazole ring, the disulfide 92 could undergo an intramolecular cyclization to give the

observed product 91 (Scheme 40).

Intermediates analogous to the disulfide 92 are frequently proposed in reactions involving

thiophile mediated ring transformations of 1,2,3-dithiazolimines. Typical thiophiles that

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induce ring transformation of 1,2,3-dithiazolimines include triphenylphosphine

(Ph3P),127b,128 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU),67 tetraalkylammonium halides

(R4NHal),84 and dialkylamines,63a,65a,68a while other less common reagents include

Grignard reagents,127a phosphoranes,63b and sodium hydride.60b Reaction of the dithiazole

68a with common thiophiles (R4NHal, Ph3P, DBU), however, gave either mixtures of the

thiazole 69a and the dithiazine 91a in low to moderate yields, or no formation of the

desired product.

Scheme 40. Proposed disulfide intermediate 92 involved in the transformation of dithiazole 68 into

dithiazine 91

Nevertheless, Kim et al., have described the synthesis of stable disulfides from

1,2,3-dithiazolimines on treatment with either phosphoranes63b or dialkylamines.63a As

such, a two-step route to the dithiazine 91a was developed via the synthesis and isolation

of the postulated disulfide intermediate.

4.3.1 Conversion of N-Pyrazolyldithiazolimine 68a to the Disulfide 93a

In theory, two equivalents of dialkylamine are needed to ring open the dithiazole 68 and

give the disulfide 93: One equivalent of dialkylamine to act as base to trap the HCl

released during the reaction and one equivalent to act as thiophile which is retained in the

product (Scheme 41).

Scheme 41. Proposed mechanism for the dialkylamine mediated ring opening of

N-pyrazolyldithiazolimine 68 to disulfide 93

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Four dialkylamines (diethylamine, piperidine, morpholine and pyrrolidine) were

investigated in five different solvent systems (MeCN, DCM, THF, EtOAc and EtOH). The

reaction rates followed the trend pyrrolidine > piperidine > Et2NH >> morpholine.

Furthermore, of the solvents examined MeCN was by far the best for this transformation:

In THF, EtOAc and EtOH the reactions proceeded very slowly and could not be driven to

completion, while in DCM the reaction was slower than in MeCN. While the reaction rate

was dependent on the concentration and nucleophilicity of the dialkylamines, the desired

disulfide was also unstable under the reaction conditions, especially with the more

nucleophilic pyrrolidine. Extended reaction times led to a complex TLC and a build-up of

intractable polar material that was baseline on TLC. As such, it was necessary to balance

the equivalents and nucleophilicity of the dialkylamine so that the starting dithiazole was

consumed rapidly and converted to the desired disulfide in high yield. To facilitate this at

least one equivalent of dialkylamine was replaced by a sterically hindered trialkylamine;

Hünig’s base was suitable for this purpose. Interestingly, the concentration of Hünig’s base

also influenced the rate of reaction, since higher concentrations of Hünig’s base led to

faster consumption of the starting dithiazole. Owing to this, the reaction rates were

modified by adjusting the concentration of both dialkylamine and Hünig’s base. With

Hünig’s base (1 equiv) and pyrrolidine (3 equiv) the reaction was rapid (15 min) and gave

the desired disulfide in 79-82% yields. Nevertheless, if the reaction was left for longer

before being worked up the yield of disulfide dropped which was expected owing to the

presence of excess thiophilic pyrrolidine. To overcome this problem, the pyrrolidine was

replaced with the less nucleophilic diethylamine. As such, treating a suspension of the

dithiazole in MeCN at ca. 20 °C with Hünig’s base (1 equiv) and diethylamine (3 equiv)

gave in 25 min the disulfide in 89% (Table 8, entry 6). By increasing the equivalents of

Hünig’s base (up to 2 equiv) and decreasing the equivalents of diethylamine (down to 2

equiv) the reaction time was extended (up to 1.5 h) without a drop in yield and the desired

disulfide was isolable in yields ranging between 88-89% (Table 8, entries 3-5). Using only

1 equivalent of Hünig’s base and 2 equivalents of diethylamine led to extended reaction

time and after 3 h the disulfide was isolated in 80% yield (Table 8, entry 2). A good

compromise was to use Hünig’s base (1.5 equiv) and diethylamine (2.5 equiv) in MeCN at

ca. 20 °C for 1 h which consistently gave the disulfide in 88-89% yields.

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Table 8. Transformation of 4-chloro-N-(1,3-dimethyl-1H-pyrazol-5-yl)-5H-1,2,3-dithiazol-5-imine 68a to 2-[(diethylamino)disulfanyl]-2-[(1,3-dimethyl-1H-pyrazol-5-yl)imino]acetonitrile 93a

entry Et2NH i-Pr2NEt time yield 93a

(equiv) (equiv) (h) (%)

1 1 1.25 11 60a

2 2 1 3 80

3 2 2 1.42 89

4 2.5 1 1.67 87

5 2.5 1.5 1 89

6 3 1 0.42 89

7 4 0 0.25 73 a The reaction mixture contained unidentified side products and unreacted starting material 68a

The disulfide 93a was obtained as beige needles, mp (DSC) onset: 64.4 °C, peak max:

65.0 °C (from n-pentane at ca. -20 °C). Elemental analysis and mass spectrometry

supported the formula C11H17N5S2. UV/vis spectroscopy showed a lowest energy

absorption at λmax(DCM) 353 nm (log ε 4.16) supporting the presence of the pyrazole ring.

1H and 13C NMR data showed two similar sets of resonances, possibly belonging to major

and minor isomers (ratio 4:1 by 1H NMR); the ratio was independent of the deuterated

solvent used or whether the sample was recrystallized or measured directly after

chromatography. The 1H NMR data indicated the presence of a C4 unsubstituted

dimethylpyrazole (δH 6.27 ppm, H4) and one diethylamino group. Furthermore, the 13C

NMR data showed the presence of four C (s), one of which fitted for C≡N (δC 113.2 ppm),

and one C (d) resonance (δC 100.8 ppm) for the pyrazole CH. The presence of the nitrile

was also supported by the IR data [ν(C≡N) 2214 cm-1]. The structure was determined by

single crystal X-ray crystallography (Figure 26). Tentatively, the two sets of resonance

signals could be attributed to E,Z-isomerization in solution.

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2-[(diethylamino)disulfanyl]-2-[(1,3-dimethyl-1H-pyrazol-5-yl)imino]acetonitrile 93a with

crystallographic atom labeling. The H atoms were omitted for clarity

4.3.2 Conversion of the Disulfide 93a into the 1,2,4-Dithiazine 91a

Attempts to convert the disulfide 93a into the desired dithiazine 91a under non acidic

reaction conditions failed to give the expected dithiazine, presumably owing to the poor

nucleofugality of the diethylamide, but did lead to interesting new chemistry (see Section

4.7). As such, acid was used to improve the nucleofugality of diethylamide (Scheme 42).

Scheme 42. Proposed mechanism for the acid mediated ring closure of the disulfide 93 to give

dithiazine 91a

Use of acids like HClO4 [pKa(MeCN) 1.57],129 H2SO4 [pKa(MeCN) 7.20],129 TsOH

[pKa(MeCN) 8.45]129 and MeSO3H [pKa(MeCN) 9.97]129 led to the formation of the

desired product in low to moderate yields while the use of concd HCl [1 equiv,

pKa(MeCN) 8.90]129 led to the spontaneous formation of the desired product in high yield

(75%). The use of HBr [pKa(MeCN) 5.50]129 also led to the spontaneous formation of the

dithiazine 91a in comparable yield with HCl (79%) but traces of thiazole 69a were also

observed (by TLC) while the use of HI (1 equiv) led to degradation (a control reaction

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showed that the dithiazine 91a was not stable in the presence of HI). Interestingly, use of

concd H2SO4 (2 equiv) in combination with BnEt3NCl (1 equiv) also led to product

formation in high yield (86%), suggesting the need for the presence of a halide counterion.

Screening the equivalents of HCl needed we found that slight excess (1.25 equiv) from the

stoichiometric 1 equivalent was needed for optimum results (entries 1-3, Table 9). Use of

more than 1.25 equiv did not influence the reaction negatively (Table 9, entries 4-6).

Table 9. Acid catalyzed transformation of 2-[(diethylamino)disulfanyl]-2-[(1,3-dimeth-yl-1H-pyrazol-5-yl)imino]acetonitrile 93a to 5,7-dimethyl-5H-pyrazolo[3,4-e][1,2,4]di-thiazine-3-carbonitrile 91a

entry concd HCl yields (%)

(x equiv) 94a 91a

1 1 5 75

2 1.1 4 78

3 1.25 5 82

4 1.5 5 82

5 2 4 86

6 3 2 86

Under these conditions a yellow colored minor side product was also observed. The

compound was obtained as yellow prisms, mp (DSC) onset: 66.7 °C, peak max: 71.7 °C

(from n-pentane at ca. -20 °C). Mass spectrometry and elemental analysis gave the

molecular formula C7H6N4S3. UV/vis data showed a lowest energy absorption that was

structured with one shoulder [λmax(DCM)/nm 373 (log ε 3.65), 414 inf (3.26)], supporting

the presence of the pyrazole ring. 1H NMR data revealed the presence of two methyl

resonances and the absence of the pyrazole H4 indicating that substitution had occurred at

this position. In addition, 13C NMR data showed the presence of five C (s) resonances, one

of which fitted for C≡N (δC 114.6 ppm). The presence of the nitrile was also supported by

the IR data [ν(C≡N) 2218 cm-1]. Based on these spectroscopic data the compound was

tentatively assigned as the 6,8-dimethyl-6H-pyrazolo[3,4-f][1,2,3,5]trithiazepine-4-carbo-

nitrile 94a and further supported by X-ray crystallography (Figure 27).

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6H-pyrazolo[3,4-f][1,2,3,5]trithiazepine-4-carbonitrile 94a with crystallographic atom labeling. The H

atoms were omitted for clarity. Worthy of note, is that atoms S1, C1, C5, N3, N2, C2, and N1

effectively define a plane from which atoms S3 and S2 sit above and below the plane by 0.175 and

1.134 Å, respectively; the trithiazepine ring, essentially has an envelope conformation

4.3.3 One-pot Conversion of N-Pyrazolyldithiazolimine 68a into the 1,2,4-Dithiazine

91a

With a two-step procedure successfully developed, we then developed a one-pot two-step

process. A solution of dithiazole 68a in MeCN at ca. 20 °C was treated with i-Pr2NEt and

Et2NH using a variety of reagent stoichiometries that had yielded the best yields for the

formation of the disulfide 93a (see Table 8) (i.e. Et2NH/i-Pr2NEt of 2:2, 2.5:1.5 and 3:1).

On consumption of the starting material (by TLC) and formation of the desired disulfide

93a concd HCl (3-5 equiv) or concd H2SO4 (3-6 equiv) was added and after 5 min stirring

the reaction was worked-up.

Initially the Et2NH/i-Pr2NEt ratio of 2.5:1.5 was investigated. When concd HCl (4 or 5

equiv) was added, the desired dithiazine 91a was formed in 60 and 59% yields,

respectively, together with trithiazepine 94a as minor side product (Table 10, entries 5 &

6). Use of less than 3 equivalents of concd HCl led to a significant drop of the dithiazine

yield (35%; Table 10, entry 4). Interestingly, addition of concd H2SO4 (4 or 5 equiv) led to

the formation of the dithiazine 91a in higher yields; 70 and 74%, respectively (Table 10,

entries 7 & 8) while use of more than 5 equivalents led to no significant improvement in

yield (72%, Table 10, entry 9). Fortunately, a similar trend was also observed when we

used concd H2SO4 (4 to 6 equiv) for Et2NH/i-Pr2NEt stoichiometries 2:2 (Table 10, entries

1-3) and 3:1 (Table 10, entries 10-12) that also led to equally good dithiazine yields (up to

74-75%).

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We concluded that the best conditions for the one-pot two-step transformation of dithiazole

68a into dithiazine 91a involved treating the dithiazole 68a with either 1 or 1.5 equivalents

of Hünig’s base followed by 3 or 2.5 equivalents of diethylamine, respectively until the

dithiazole was consumed (by TLC) after which time 5 equivalents of concd H2SO4 were

added for 5 min. These two sets of conditions consistently gave yields of 74% for the

dithiazine 91a together with a small quantity of trithiazepine 94a (5-7%) (Table 10, entries

6 & 9).

Table 10. One-pot transformation of 4-chloro-N-(1,3-dimethyl-1H-pyrazol-5-yl)-5H-1,2,3-dithiazol-5-imine 68a to 6,8-dimethyl-6H-pyrazolo[3,4-f][1,2,3,5]trithiazepine-4-carbonitrile 94a and 5,7-dimethyl-5H-pyrazolo[3,4-e][1,2,4]dithiazine-3-carbonitrile 91a

entry Et2NH i-Pr2NEt concd acid yields (%)

(equiv) (equiv) (equiv) 94a 91a

1a 2 2 H2SO4 (4) 4 71

2a 2 2 H2SO4 (5) 4 75

3a 2 2 H2SO4 (6) 4 71

4b 2.5 1.5 HCl (3) 8 35

5b 2.5 1.5 HCl (4) 5 60

6b 2.5 1.5 HCl (5) 6 59

7b 2.5 1.5 H2SO4 (4) 5 70

8b 2.5 1.5 H2SO4 (5) 5 74

9b 2.5 1.5 H2SO4 (6) 4 72

10c 3 1 H2SO4 (4) 7 70

11c 3 1 H2SO4 (5) 5 74

12c 3 1 H2SO4 (6) 4 74 a Consumption of dithiazole 68a (by TLC) took 1.42 h. b Consumption of dithiazole 68a (by TLC) took 1 h. c Consumption of dithiazole 68a (by TLC) took 25 min

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4.4 Scope and Limitations of the One-pot Reaction

This one-pot two-step reaction protocol was successfully applied to a range of

N-(1,3-disubstituted-1H-pyrazol-5-yl)dithiazolimines 68 (Table 11).

Table 11. One-pot transformation of 4-chloro-N-(pyrazol-5-yl)-5H-1,2,3-dithiazol-5-imines 68 into 5H-pyrazolo[3,4-e][1,2,4]dithiazine-3-carbonitriles 91a

entry dithiazole R1 R2 yields

(%)

1 68a Me Me 94a (5) 91a (74)

2 68d Me Ph 94b (5) 91b (75)

3 68e Bn Me 94c (6) 91c (78)

4 68f Bn Ph 94d (-)b 91d (85)b

5 68i Ph Me 94e (0) 91e (85)

6c 68j Ph Ph 94f (0) 91f (80) a Reagents and conditions: i) Et2NH (3 equiv), i-Pr2NEt (1 equiv), MeCN, ca. 20 °C, 25 min; ii) concd H2SO4 (5 equiv), ca. 20 °C, 5 min. b Compounds 91d and 94d (ratio 91d/94d, 14:1 by 1H NMR) were inseparable by chromatography, however, a microanalytically pure sample of dithiazine 91d was obtained after recrystallization. c A trace of the pyrazolothiazole 69h was observed (by TLC)

With these results in hand, we envisioned that the transformation of N-(pyrazol-5-

yl)dithiazolimines 68 to 5H-pyrazolo[3,4-e][1,2,4]dithiazine-3-carbonitriles 91 could also

be applied to other electron rich arenes. As such, a series of N-aryldithiazolimines 95 were

subjected to the optimized one-pot conditions (Scheme 43).

Scheme 43. Conversion of N-aryldithiazolimines 95 into benzo[e][1,2,4]dithiazine-3-carbonitriles 96

Treatment of the least activated N-phenyldithiazolimine 95a with Et2NH and then concd

H2SO4 led only to a complex reaction mixture and no traces of either the 1,2,4-benzo-

dithiazine 96a or benzothiazole 97a were detected. Nevertheless, the introduction of

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electron releasing groups such as methoxy and hydroxy groups 95b-d did lead to formation

of the 1,2,4-benzodithiazines 96. In particular, the most activated dithiazolimine 95d (R1 =

HO, R2 = MeO) led to the formation of the 1,2,4-benzodithiazine 96d in a 70% yield

together with a small quantity of the benzothiazole 97d (13%). Interestingly, the isolated

reaction products indicated the cyclization occurred regioselectively para to the more

dominant electron releasing substituent. The structure of the 1,2,4-benzodithiazines was

confirmed by X-ray crystallography for the hydroxy analogue 96c (Figure 28).

Figure 28. Ellipsoid (probability level of 50%) representation of the crystal structure of 6-hydroxy-

benzo[e][1,2,4]dithiazine-3-carbonitrile 96c with crystallographic atom labeling. The H atoms were

omitted for clarity



4-carbonitrile 94a

The formation of the 5H-pyrazolo[3,4-e][1,2,4]dithiazine-3-carbonitriles 91 was in most

cases accompanied by a small quantity of the 1,2,3,5-trithiazepines 94 which were

relatively unstable and on silica (2D-TLC) converted back into the 1,2,4-dithiazines 91.

The formation and instability of trithiazepines 94 suggested that an equilibrium may exist

between the dithiazine, the trithiazepine and an active form of sulfur, similar to that

observed between 1,2,3-trithioles and 1,2,3,4,5-pentathiepins.130 Related transformations

also included the conversion of bridged 3,6-dihydro-1,2,4-dithiazin-5-ones to bridged

4,7-dihydro-1,2,3,5-trithiazepin-6-ones and vice versa131 and an interesting quantitative

conversion of (1R,1'R)-diborn-2-eno[2,3-c;3',2'-e][1,2]dithiine to (1R,1'R)-diborn-2-eno-

[2,3-d;3',2'-f][1,2,3]trithiepine, which was facilitated by the release of ring strain on going

from a six- to a seven-membered ring.132

Initially, we investigated the transformation of 5,7-dimethyl-5H-pyrazolo[3,4-e][1,2,4]-

dithiazine-3-carbonitrile 91a into 6,8-dimethyl-6H-pyrazolo[3,4-f][1,2,3,5]trithiazepine-4-

carbonitrile 94a by heating to reflux a mixture of the dithiazine 91a and S8 (10 equiv) in

various solvents (MeCN, DMF, acetone, DCM, CHCl3, THF, PhCl, 1,4-dioxane, CS2,

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n-heptane and c-hexane). Degradation was observed (by TLC) in either DMF or acetone,

while a small amount of the trithiazepine 94a was observed in MeCN, THF and 1,4-diox-

ane. A significant formation of the trithiazepine 94a was noted only in PhCl, however, at

the reflux temperature of PhCl (bp 131 °C) the formation of thiazole 69a (15%) was also

observed (Table 12, entry 1). Repeating the reaction in PhCl at a lower temperature

(ca. 100 °C) led after 16 h only to a small quantity of trithiazepine 94a (6%) (Table 12,

entry 2). Gratifyingly, when either catalytic (0.1 equiv) or stoichiometric (1.0 equiv)

quantities of DABCO were added to the reaction mixture (Table 12, entries 3 & 4), after

only 20 and 6 min, respectively, the trithiazepine 94a could be isolated in 43 and 47%

yields, based on recovered unreacted dithiazine 91a. This conversion could also be

achieved more slowly (ca. 5 h) at lower reaction temperatures ca. 40 °C but the overall

yields of the trithiazepine 94a and recovered dithiazine 91a were poor (Table 12, entry 5).

Table 12. Transformation of 5,7-dimethyl-5H-pyrazolo[3,4-e][1,2,4]dithiazine-3-carbo-nitrile 91a to 6,8-dimethyl-6H-pyrazolo[3,4-f][1,2,3,5]trithiazepine-4-carbonitrile 94a

entry temp DABCO time yields (%)a

(°C) (equiv) (h) 91ab 94a 69a 98

1 131 0 16 33 18 22 0

2 100 0 16 69 19 0 0

3 100 0.1 0.33 44 43 0 trace

4 100 1.0 0.10 45 47 0 trace

5 40 1.0 5 31 20 0 trace

6 100 1.0 16 trace trace 17 23

7 60 1.0 27 12 7 15 27 a Yields based on recovered dithiazine 91a. b Recovered dithiazine 91a

Interestingly, under these conditions a trace of a new orange colored side product was

observed. The compound was obtained as orange needles, mp (DSC) onset: 186.6 °C, peak

max: 187.6 °C (from c-hexane). Mass spectrometry and elemental analysis gave the

molecular formula C7H6N4S3. UV/vis data showed a lowest energy absorption that was

structured with at least two shoulders [λmax(DCM)/nm 457 inf (log ε 3.77), 480 (3.84), 505

inf (3.70)], indicating a relatively rigid structure with extensive π-conjugation. 1H NMR

data showed the presence of two methyl resonances typical of a dimethylpyrazole unit,

however, no pyrazole H4 resonance was observed suggesting substitution had occurred at

this position. In addition to the two methyl resonances, 13C NMR data showed five C (s)

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resonances. IR data showed the absence of any nitrile functionality. Based on these

spectroscopic data the compound was tentatively identified as the 5,7-dimethyl-5H-[1,2,3]-

dithiazolo[4,5-b]pyrazolo[3,4-e][1,4]thiazine 98 and this was supported by X-ray crystallo-

graphy (Figure 29).

Figure 29. Ellipsoid (probability level of 50%) representation of the crystal structure of 5,7-dimeth-

yl-5H-[1,2,3]dithiazolo[4,5-b]pyrazolo[3,4-e][1,4]thiazine 98 with crystallographic atom labeling. The

H atoms were omitted for clarity

When 1 equivalent of DABCO and longer reaction times (16 h) were used the pyrazolo-

[3,4-e][1,4]thiazine 98 was isolated in 23%, accompanied by the formation of thiazole 69a

(17%) (Table 12, entry 6). Decreasing the reaction temperature to ca. 60 °C did not improve

the yield of the thiazine 98 nor avoid the formation of thiazole 69a (Table 12, entry 7).

Presumably, ring opening of the dithiazine 91a or even the trithiazepine 94a mediated by

the postulated thiophilic DABCO/S8 adduct 99133 afforded a species such as compound 100.

Rotation of the imine bond can bring the nitrile group close to the pyrazole C4 thiolate

(species 101) and a cascade cyclization and concomitant loss of S8 via a chain extension

mechanism62b,101 could lead to the formation of the tricyclic 1,4-thiazine 98 (Scheme 44).

Scheme 44. Tentative mechanistic rationale for the formation of 5,7-dimethyl-5H-[1,2,3]dithiazolo-

[4,5-b]pyrazolo[3,4-e][1,4]thiazine 98

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4.6 Thermolysis of 5H-Pyrazolo[3,4-e][1,2,4]dithiazine-3-carbonitriles 91

1,2,4-Dithiazines are structurally similar to 1,2-dithiines and therefore could readily

extrude sulfur thermally132,134 or photochemically135 to give the more aromatic and

thermally stable thiazoles. In our hands, a DCM solution of dithiazine 91a exposed to

intense sunlight or to irradiation at 365 nm from a hand held UV/vis lamp appeared to be

stable. Nevertheless, DSC studies indicated that the dithiazines 91 were thermally labile

and the subsequent thermolysis of the dithiazines 91 in diphenyl ether at ca. 250 C gave

the corresponding thiazoles 69 in near quantitative yields (Table 13).

Table 13. Thermolysis of 5H-pyrazolo[3,4-e][1,2,4]dithiazine-3-carbonitriles 91 to give 1H-pyrazolo[3,4-d]thiazole-5-carbonitriles 69

entry dithiazine R1 R2 decomp. onseta time yields 69 (°C) (min) (%)

1 91a Me Me -b 30 69a (100) 2 91b Me Ph 175.9 30 69d (95) 3 91c Bn Me 171.8 25 69e (95) 4 91d Bn Ph 187.3 35 69f (94) 5 91e Ph Me 157.2 20 69g (100) 6 91f Ph Ph 149.2 25 69h (100)

a Decomp. onset temperatures determined via DSC using a heating rate of 5 °C/min under an argon atmosphere. b No decomp. onset was determined as compound 91a had a low bp (onset 189.6 °C, peak max 198.3 °C) and escaped from the DSC pan

The reaction mechanism for this ring contraction is probably similar to that for the ring

contraction of the analogous 1,2-dithiins into thiophenes.132,134c,136 A thermally mediated

6π electrocyclic ring opening of the dithiazine can lead to the formation of a [4-thioxo-1H-

pyrazol-5(4H)-ylidene]carbamothioyl cyanide 102, which, aided by the electron releasing

pyrazole N1 atom, can then recyclize to the thiazolo intermediate 103. This can then lose

S8 via a sulfur chain extension mechanism101 to afford the fully aromatic pyrazolo[3,4-d]-

thiazole 69 (Scheme 45).

Scheme 45. Tentative mechanism for the ring contraction of 1,2,4-dithiazines 91 into thiazoles 69

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4.7 Unexpected Chemistry of Disulfide 93a

TLC analysis of a solution of the disulfide 93a in MeCN that had been left to stand at

ca. 20 °C, over 3 days, indicated the gradual disappearance of the disulfide and formation

of some S8, Et2NSnNEt2 (n = 1-3) (by TLC) and a colorless product isolated in 40% yield.

The compound was obtained as colorless prisms, mp (DSC) onset: 209.7 °C, peak max:

211.4 °C (from c-hexane). Elemental analysis and mass spectrometry gave the formula

C14H12N8S3. UV/vis data showed a lowest energy absorption at λmax(DCM) 336 nm (log ε

3.82) supporting the presence of the pyrazole ring. 1H NMR data showed the presence of

four methyl groups typical for two dimethylpyrazole units, however, no pyrazole H4

resonances were observed suggesting substitution had occurred at the pyrazole C4

positions. 13C NMR data showed, in addition to the four methyl resonances, the presence

of ten C (s) resonances. IR supported the presence of C≡N functionality [ν(C≡N)

2245 cm-1]. Based on these spectroscopic data, however, the structure elucidation was

inconclusive. Fortunately, single crystal X-ray crystallography supported the structure to

be 4,6,10,12-tetramethyl-6H-pyrazolo[3,4-f]pyrazolo[3',4':4,5]pyrimido[6,1-d][1,2,3,5]tri-

thiazepine-8,12b(10H)-dicarbonitrile 104 (Figure 30).

Figure 30. Ellipsoid (probability level of 50%) representation of the crystal structure of 4,6,10,12-

tetramethyl-6H-pyrazolo[3,4-f]pyrazolo[3',4':4,5]pyrimido[6,1-d][1,2,3,5]trithiazepine-8,12b(10H)-

dicarbonitrile 104 with crystallographic atom labeling. The H atoms were omitted for clarity

MARIA KOYIONI

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When a solution of the disulfide 93a (0.2 mmol) in MeCN (4 mL) was heated at ca. 82 °C

for ca. 1 h the tetracycle 104 was obtained in a surprisingly good yield of 67% (Scheme

46). Interestingly, at ca. 82 °C, a trace of the expected dithiazine 91a was observed (by

TLC) at the beginning of the reaction but this was quickly consumed. Furthermore, a pure

sample of the tetracycle 104 in PhCl heated to ca. 131 °C for 12 h was stable (by TLC).

Scheme 46. Formation of 4,6,10,12-tetramethyl-6H-pyrazolo[3,4-f]pyrazolo[3',4':4,5]pyrimido-

[6,1-d][1,2,3,5]trithiazepine-8,12b(10H)-dicarbonitrile 104 from the disulfide 93a

Formally, this tetracyclic product 104 can form from the Diels-Alder cycloaddition of one

dithiazine 91a and one trithiazepine 94a followed by loss of diatomic sulfur (S2), however,

preliminary studies suggest this cycloaddition/retrocycloaddition pathway was not valid:

A 1:1 equimolar mixture of the dithiazine 91a and the trithiazepine 94a in MeCN heated to

reflux gave none of the tetracycle 104. As such, we tentatively proposed a stepwise

mechanism that invoked the enaminic character of one pyrazole and the highly

electrophilic carbon of the exocyclic imine of a second pyrazole 93a (Scheme 47).

Electrophilic substitution at the pyrazole C4 carbon by the imine of a second pyrazole 93a

can give a coupled species 105 that can undergo an intramolecular cyclization to provide

the pyrazolo[3,4-d]pyrimidine intermediate 106 and a species akin to N,N-diethyl-

disulfanamine. The latter small molecule can act as an active form of sulfur to extend the

disulfide chain of 106 to give a species similar to 107 that undergoes a final cyclization to

the observed tetracyclic 104.

To the best of our knowledge, monocyclic or fused 1,2,3,5-trithiazepines have not been

reported. Bridged 4,7-dihydro-1,2,3,5-trithiazepin-6-ones, however, appear in several

fungal metabolites and like their analogous 3,6-dihydro-1,2,4-dithiazin-5-ones possess

interesting biological activities.137 The scope of this transformation, details regarding its

mechanism and the biological properties of the tetracycle 104 are now under investigation.

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Scheme 47. Tentative mechanism for the formation of 4,6,10,12-tetramethyl-6H-pyrazolo[3,4-f]-

pyrazolo[3',4':4,5]pyrimido[6,1-d][1,2,3,5]trithiazepine-8,12b(10H)-dicarbonitrile 104 from the

disulfide 93a

4.8 Conclusions

An efficient one-pot two-step route to pyrazole fused 1,2,4-dithiazine-3-carbonitriles 91

has been developed starting from 4-chloro-N-(pyrazol-5-yl)-5H-1,2,3-dithiazol-5-imines

68. The reaction requires the use of a dialkylamine to ring open the dithiazole to afford an

isolable disulfide intermediate 93, which on treatment with acid cyclizes to give mainly the

desired dithiazines 91 (74-85%) accompanied by small quantities of 1,2,3,5-trithiazepines

94 (0-6%). In the presence of “active” sulfur 1,3-dimethyl-5H-pyrazolo[3,4-e][1,2,4]-

dithiazine-3-carbonitrile 91a can be converted into the trithiazepine 94a in yields as high

as 47%. Interestingly, extending the reaction times (>16 h) serendipitously afforded the

pyrazolo[3,4-e][1,4]thiazine 98. Other unexpected chemistry occurred when the disulfide

93a was heated in neat acetonitrile affording the unusual tetracyclic 6H-pyrazolo[3,4-f]-

pyrazolo[3',4':4,5]pyrimido[6,1-d][1,2,3,5]trithiazepine 104. The reactions described above

demonstrate that 4-chloro-1,2,3-dithiazoles can be used to provide facile access to fused

1,2,4-dithiazines, a difficult-to-access and potentially interesting ring system.

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MARIA KOYIONI

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CHAPTER 5

4-[N-(2-Chloroethyl)piperazin-1-yl]-5H-1,2,3-dithiazoles:

The Reaction of DABCO with 4-Chloro-5H-1,2,3-dithiazoles

Contents

5.1 Introduction 72

5.2 Optimization of the Reaction of 4-Chloro-N-phenyl-5H-1,2,3-dithiazol-

5-imine 95a with DABCO to give 4-[N-(2-Chloroethyl)piperazin-1-yl]-

N-phenyl-5H-1,2,3-dithiazol-5-imine 119 75

5.3 Structure Elucidation of Compounds 119, 120h, 121a and 122 77

5.4 Scope and Limitations of the Reaction of 1,2,3-Dithiazoles with DABCO 80

5.5 Rationale for the Relative Reactivity of 1,2,3-Dithiazoles with DABCO 82


5.7 Chemistry of 4-[N-(2-Chloroethyl)piperazin-1-yl]-5H-1,2,3-dithiazoles 88

5.7.1 Manipulations on the 2-Chloroethyl Moiety 88

5.7.2 Manipulations at the Dithiazole C5 Position 89

5.8 Conclusions 90 MARIA KOYIONI

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5.1 Introduction

During our investigations on the conversion of 4-chloro-N-(1,3-dimethyl-1H-pyrazol-5-yl)-

5H-1,2,3-dithiazol-5-imine 68a to the 5,7-dimethyl-5H-pyrazolo[3,4-e][1,2,4]dithiazine-3-

carbonitrile 91a (Chapter 4) we considered the use of DABCO for the formation of the

quaternized intermediate disulfide 108 which could cyclize in situ to the desired

1,2,4-dithiazine 91a in the absence of acid (Scheme 48).

Scheme 48. Postulated formation of intermediate disulfide 108

Treatment of the pyrazolodithiazolimine 68a with DABCO in DCM at ca. 20 °C gave

predominately unreacted starting material. At higher temperatures (PhMe, ca. 110 °C) the

reaction proceeded to give not the desired 1,2,4-dithiazine but rather unexpectedly

4-[N-(2-chloroethyl)piperazin-1-yl]-N-(1,3-dimethyl-1H-pyrazol-5-yl)-5H-1,2,3-dithiazol-

5-imine 109 in 78% yield (Scheme 49).

Scheme 49. The reaction of 4-chloro-N-(1,3-dimethyl-1H-pyrazol-5-yl)-5H-1,2,3-dithiazol-5-imine

68a with DABCO

During this transformation the dithiazole C4 position was substituted with an N-(2-chloro-

ethyl)piperazinyl group. Presumably, this originated from ring opening of quaternized

DABCO by chloride. This result was interesting as there are only four reports on the

functionalization of the dithiazole C4 position that maintain the integrity of the dithiazole

ring,54,59a,65 the most general of which, is the reaction of N-aryl-4-chloro-5H-1,2,3-dithiazol-

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5-imines 19 with dialkylamines which gives N-aryl-4-dialkylamino-5H-1,2,3-dithiazol-5-imines

110.65a This reaction, however, suffers from variable yields, the formation of unknown side

products, and lacks generality. The transformation proceeds via an ANRORC66 style mechanism

where dialkylamine attacks the S2 ring sulfur cleaving the 1,2,3-dithiazole to form an

intermediate disulfide 32 that adds a second dialkylamine to the nitrile to give an amidine

which then cyclizes onto the disulfide to release the initial dialkylamine (Scheme 50).

Scheme 50. Reaction and mechanism for the transformation of N-aryl-4-chloro-5H-1,2,3-dithiazol-

5-imines 19 to N-aryl-4-dialkylamino-5H-1,2,3-dithiazol-5-imines 110

Rarer examples of C4 substitution reactions include: The intramolecular cyclisation of

4-chloro-N-(2-hydroxyphenyl)-5H-1,2,3-dithiazol-5-imine 111a to benzo[b][1,2,3]dithia-

zole[5,4-e][1,4]oxazine 112a,54 which recently was extended to include a pyrido-fused

analogue 112b,59a and the reaction of 5-(4-chloro-5H-1,2,3-dithiazol-5-ylidene)-2,2-dime-

thyl-1,3-dioxane-4,6-dione 113 with secondary dialkylamines to give 5-(4-dialkylamino-

5H-1,2,3-dithiazol-5-ylidene)-2,2-dimethyl-1,3-dioxane-4,6-diones 114 and 6-dialkylami-

nocarbamoyl-5-oxo-5H-furo[2,3-d][1,2,3]dithiazoles 11565b (Scheme 51).

Scheme 51. Rare examples for the functionalization of the C4 position of 1,2,3-dithiazoles

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Ring opening of quaternized DABCO in the presence of an external nucleophile was first

invoked in 1963 when its acid catalyzed polymerization was reported.138 That same year,

the reaction of DABCO with p-chloronitrobenzenes gave N-(2-chloroethyl)-N'-(4-nitro-

phenyl)piperazines 116 and/or N-{2-[N-(4-nitrophenyl)piperazin-1-yl]ethyl}-1,4-diazabi-

cyclo[2.2.2]octan-1-ium chlorides 117 and 118139 (Scheme 52).

Scheme 52. Reaction of p-chloronitrobenzenes with DABCO

Despite these early observations and some sporadic reports,140 only recently has the

quaternization and subsequent ring opening of DABCO been used as a strategy for the

synthesis of compound libraries bearing a 2-substituted ethylpiperazine group.141 Other

bicyclic (e.g., quinuclidine)142 and non-bicyclic143 tertiary amines behave similarly under

appropriate conditions.

Since the piperazine group frequently appears in biologically active compounds144 and, in

particular, the N-heteroaryl-N'-ethylpiperazine fragment is part of several approved drugs

such as Sprycel® (dasatinib) and Geodon® (ziprasidone) (Figure 31), we chose to develop

this reaction further.

Figure 31. Examples of biologically active compounds containing the N-heteroaryl-

N'-ethylpiperazine fragment

In this Chapter, we report an investigation on the reaction of 4-chloro-5H-1,2,3-dithiazoles

with DABCO, which examines the scope and limitations of the reaction. Furthermore,

MARIA KOYIONI

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facile functionalization of the obtained N-(2-chloroethyl)piperazinyl dithiazole products is

demonstrated.

5.2 Optimization of the Reaction of 4-Chloro-N-phenyl-5H-1,2,3-dithiazol-5-

imine 95a with DABCO to give 4-[N-(2-Chloroethyl)piperazin-1-yl]-N-

phenyl-5H-1,2,3-dithiazol-5-imine 119

Initial investigations showed that the reaction of 4-chloro-N-(1,3-dimethyl-1H-pyrazol-5-

yl)-5H-1,2,3-dithiazol-5-imine 68a with DABCO to give the 4-[N-(2-chloroethyl)pipera-

zin-1-yl]-5H-1,2,3-dithiazole 109 was also applicable to other 1,2,3-dithiazoles. As such,

for the optimization of the reaction, with respect to the reaction solvent, reagent

concentrations, reaction time and temperature, the structurally simpler 4-chloro-N-phenyl-

5H-1,2,3-dithiazol-5-imine 95a was chosen. Initial studies showed that in polar solvents

(DCM, THF, 1,4-dioxane or MeCN) the dithiazolimine 95a reacted with DABCO even at

ca. 20 °C to give S8 and multiple unidentified colorless products while no formation of the

desired product was observed. In less polar solvents (c-hexane, PhMe, xylene or PhCl)

predominately unreacted starting material was observed at ca. 20 °C but on heating these

reactions at reflux the formation of the desired product, 4-[N-(2-chloroethyl)piperazin-1-

yl]-N-phenyl-5H-1,2,3-dithiazol-5-imine 119, was observed (by TLC). The reactions

performed in PhCl at ca. 131 °C were the cleanest and fastest. Nevertheless, even in hot

PhCl three side products were also formed. Based on spectroscopic data (see Section 5.3)

these side products were identified as: N-phenyl-4-[N-(2-thiocyanatoethyl)piperazin-1-yl]-

5H-1,2,3-dithiazol-5-imine 120h, N-(2-chloroethyl)-N-phenylpiperazine-1-carbimidoyl

cyanide 121a and N-(2-{N-[5-(phenylimino)-5H-1,2,3-dithiazol-4-yl]piperazin-1-yl}ethyl)-

1,4-diazabicyclo[2.2.2]octan-1-ium chloride 122.

The concentration of the reaction mixtrure was critical: Irrespective of the equivalents of

DABCO used, when the concentration of the dithiazolimine 95a was high (0.2 mmol in

2 mL PhCl) the desired product 119 was obtained in moderate 53-63% yields (Table 14,

entries 1-3). In these reactions, the carbimidoyl cyanide 121a was also formed in

significant quantities (10-16%) together with brown intractable polar materials (baseline on

TLC). By diluting the reaction (0.2 mmol of 95a in 4, 8 and 12 mL of PhCl) the yield of

the desired product 119 increased (65-79%), reaching a plateau in 8 mL of PhCl. Under

these conditions the formation of the side products 120h and 121a was minimized and the

reactions were less complex. Under these “dilute” conditions it was also necessary to

increase the quantity of DABCO to achieve a good reaction rate and limit side reactions.

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With less than 2 equivalents of DABCO the reactions needed prolonged heating (>8 h) and

led to lower product yields (65-70%) (Table 14, entries 4 & 7).

Table 14. The reaction of 4-chloro-N-phenyl-5H-1,2,3-dithiazol-5-imine 95a (0.2 mmol) with DABCO (x equiv) in PhCl (y mL) at ca. 131 °C

entry PhCl (mL)

DABCO (equiv)

time (h)

yields (%)

95ab 119 120h 121a 1 2 1 24 traces 53 4 10 2 2 1.2 3 traces 63 8 16

3 2 2 1.5 traces 54 3 16

4 4 1.2 6 4 65 5 8 5 4 2 2.2 4 74 2 4 6 4 2 4 traces 69 6 5 7 8 1.2 23 5 65 5 5 8 8 1.5 8 traces 70 2 7 9 8 2 4 5 79 2 2

10 8 2 7 2 71 4 5 11 8 3 2.2 3 81 2 3 12 12 2 7 3 79 3 3

a Product 122 in most cases was not isolated sufficiently pure to calculate a yield b Recovered starting material

The best yields were obtained with 2 or 3 equivalents of DABCO (79-81%) but even in

these cases 3-5% starting material remained unreacted (Table 14, entries 9 & 11).

Extending the reaction time to consume all the starting material had a detrimental effect on

product yield without complete consumption of the starting material (Table 14, entry 10).

As such, we selected as our optimized reaction conditions the use of DABCO (2 equiv) in

PhCl (8 mL) heated at ca. 131 °C for 4 h (Table 14, entry 9). MARIA KOYIO

NI

77

5.3 Structure Elucidation of Compounds 119, 120h, 121a and 122

4-[N-(2-Chloroethyl)piperazin-1-yl]-N-phenyl-5H-1,2,3-dithiazol-5-imine 119 was obtained

as yellow plates, mp 73-74 °C (from n-hexane/t-BuOMe at ca. -20 °C). Mass spectrometry

gave a parent ion of m/z 343 with an isotope pattern typical for the presence of one

chlorine atom. Combined with elemental analysis data this supported a molecular formula

of C14H17ClN4S2. UV/vis data showed a lowest energy absorption at 379 nm

[λmax(EtOH)/nm 379 (log ε 3.83); λmax(DCM)/nm 382 (log ε 3.90)] which was similar to

that of the starting 4-chloro-N-phenyl-5H-1,2,3-dithiazol-5-imine 95a [λmax(EtOH)/nm 373

(log ε 3.77)]96 suggesting the presence of the dithiazole ring. 1H NMR spectroscopy

revealed the presence of three aromatic sp2 CH resonances integrating for 5 H with a

splitting pattern typical for a mono-substituted phenyl. In addition, four aliphatic sp3 CH2

resonances, were observed, two of which were triplets, with a J coupling of 7.0 Hz, each

integrating for 2 H [δH 3.62 (2H, t, J 7.0) & 2.79 (2H, t, J 7.0) ppm] and two were doublet

of doublets, with J couplings of 5.0 and 5.0 Hz, each integrating for 4 H [δH 3.79 (4H, dd, J

5.0, 5.0) & 2.67 (4H, dd, J 5.0, 5.0) ppm]; these data were characteristic for an

N-[(2-substituted)ethyl]piperazine group.145 In addition to the three sp2 CH and the four

aliphatic sp3 CH2 resonances, 13C NMR spectroscopy showed the presence of three C (s)

resonances in the range 153-161 ppm [δC 160.6 (s), 158.3 (s), 152.5 (s) ppm]. These are in

the range typical for the C (s) resonances of 1,2,3-dithiazolimines.96 Based on these

spectroscopic data the compound was tentatively identified as 4-[N-(2-chloro-ethyl)-

piperazin-1-yl]-N-phenyl-5H-1,2,3-dithiazol-5-imine 119.

N-Phenyl-4-[N-(2-thiocyanatoethyl)piperazin-1-yl]-5H-1,2,3-dithiazol-5-imine 120h was

obtained as yellow plates, mp 86-87 °C (from n-hexane/t-BuOMe at ca. -20 °C). Mass

spectrometry gave a parent ion of m/z 364 which in combination with elemental analysis

supported a molecular formula of C15H17N5S3. UV/vis data showed a lowest energy

absorption at 382 nm [λmax(DCM)/nm 382 (3.74)] which was identical with

4-[N-(2-chloroethyl)piperazin-1-yl]-N-phenyl-5H-1,2,3-dithiazol-5-imine 119. 1H NMR

spectroscopy revealed the presence of three aromatic sp2 CH resonances integrating for

5 H with a splitting pattern typical for a mono-substituted phenyl, and also four aliphatic

sp3 CH2 resonances two of which were triplets, with J coupling of 7.0 Hz, each integrating

for 2 H [δH 3.22 (2H, t, J 6.5) & 2.80 (2H, t, J 6.5) ppm] and two were doublet of doublets,

with J couplings of 4.8-5.0 Hz, each integrating for 4 H [δH 3.78 (4H, dd, J 4.8, 4.8) &

2.64 (4H, dd, J 5.0, 5.0) ppm]. These data were very similar with 4-[N-(2-chloroethyl)-

piperazin-1-yl]-N-phenyl-5H-1,2,3-dithiazol-5-imine 119; the only difference observed

MARIA KOYIONI

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was the upfield shift of one of the sp3 CH2 resonances (3.22 ppm for 120h vs 3.62 ppm for

119), which for dithiazolimine 119 must correspond to the CH2 next to the chlorine atom.

The upfield shift, tentatively indicated the substitution of the chlorine atom with a less

electron withdrawing substituent. In addition to these resonances, 13C NMR spectroscopy

showed the presence of four C (s) resonances [δC 160.5 (s), 158.2 (s), 152.5 (s), 113.0 (s)

ppm], three of which were identical with 119, further supporting the presence of the

dithiazole ring, while the fourth fitted for X-C≡N (δC 113 ppm). IR spectroscopy gave a

stretching frequency characteristic for thiocyanates [ν(C≡N) 2145 cm-1]. Based on these

spectroscopic data the compound was tentatively identified as N-phenyl-4-[N-(2-

thiocyanatoethyl)piperazin-1-yl]-5H-1,2,3-dithiazol-5-imine 120h. This compound was

also independently synthesized by reaction of 4-[N-(2-chloroethyl)piperazin-1-yl]-N-

phenyl-5H-1,2,3-dithiazol-5-imine 119 with KSCN (see Section 5.7.1).

N-(2-Chloroethyl)-N-phenylpiperazine-1-carbimidoyl cyanide 121a was obtained as

colorless plates, mp 45-46.5 °C (from n-hexane/Et2O at ca. -40 °C). Mass spectrometry

gave a parent ion of m/z 277 with an isotope pattern typical for the presence of one

chlorine. In combination with elemental analysis data, this supported a molecular formula

of C14H17ClN4. UV/vis data showed a lowest energy absorption at 311 nm [λmax(DCM)/nm

311 (log ε 3.79)] which suggested the presence of conjugation but owing to the absence of

any significant color we tentatively dismissed the presence of a dithiazole ring. 1H NMR

spectroscopy showed three aromatic sp2 CH resonances integrating for 5 H typical for the

presence of a mono-substituted phenyl, and also four aliphatic sp3 CH2 resonances [δH 3.73

(4H, br s), 3.63 (2H, t, J 6.5), 2.83 (2H, t, J 6.0), 2.65 (4H, br s) ppm] for which integrals,

chemical shifts and splitting patterns were very similar with 4-[N-(2-chloroethyl)piperazin-

1-yl]-N-phenyl-5H-1,2,3-dithiazol-5-imine 119, suggesting that both the phenylimine and

the N-[(2-chloro)ethyl]piperazinyl moieties were intact. In addition to these resonances,

13C NMR spectroscopy revealed the presence of three C (s) resonances which differed

significantly from those of dithiazolimine 119 further supporting the absence of the

dithiazole ring. In addition, one of the C (s) resonances fitted for C≡N (δC 108.2 ppm). The

presence of the C≡N was further supported by IR spectroscopy [ν(C≡N) 2228 cm-1]. Based

on these spectroscopic data the compound was tentatively identified as N-(2-chloroethyl)-

N-phenylpiperazine-1-carbimidoyl cyanide 121a. This compound was also independently

synthesized by reaction of 4-chloro-N-phenyl-5H-1,2,3-dithiazol-5-imine 95a with

N-[(2-chloro)ethyl]piperazine 168a (see Section 5.6, Table 17).

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N-(2-{N-[5-(Phenylimino)-5H-1,2,3-dithiazol-4-yl]piperazin-1-yl}ethyl)-1,4-diazabicyclo-

[2.2.2]octan-1-ium chloride 122 was obtained as yellow glassy plates, decomp. (DSC)

onset: 184.4 °C, peak max: 194.2 °C (precipitated from DCM with n-pentane/Et2O).

MALDI-TOF analysis on a ground steel plate with 2,5-dihydroxybenzoic acid (DHB) as

matrix gave a parent ion of m/z 417 which on MS/MS showed the loss of m/z 112;

equivalent to one molecule of DABCO. When the same sample was analyzed on a PAC II

384/96 HCCA plate a parent ion of m/z 453 (5%) with a chlorine isotope pattern was

observed, together with fragments that corresponded to the loss of a chlorine atom [m/z

417 (60%), M+-Cl] and subsequent loss of a DABCO molecule [m/z 305 (100%), M+-Cl-

DABCO]. Furthermore, on the spectrum, peaks corresponding to an N-ethylpiperazine

fragment (m/z 175) and a DABCO molecule (m/z 112) were observed. UV/vis data showed

a lowest energy absorption at 380 nm [λmax(DCM)/nm 380 (log ε 3.75)] similar to

4-[N-(2-chloroethyl)piperazin-1-yl]-N-phenyl-5H-1,2,3-dithiazol-5-imine 119 indicating

the presence of the dithiazole ring. 1H NMR spectroscopy showed the presence of three

aromatic sp2 CH resonances, supporting the presence of a mono-substituted phenyl, and six

aliphatic sp3 CH2 resonances. Two of the sp3 CH2 resonances were doublet of doublets,

with J couplings of 7.2 Hz, each integrated for 6 H and with chemical shifts in the range of

3-4 ppm [δH 3.83 (6H, dd, J 7.2, 7.2) & 3.19 (6H, dd, J 7.2, 7.2) ppm]; these data were

typical for the presence of a quaternized DABCO moiety.146 The remaining four sp3 CH2

resonances [δH 3.90 (2H, dd, J 5.1, 5.1), 3.71 (4H, br s), 2.89 (2H, dd, J 4.8, 4.8), 2.68 (4H,

dd, J 4.5, 4.5) ppm] were very similar with those of 4-[N-(2-chloroethyl)piperazin-1-yl]-N-

phenyl-5H-1,2,3-dithiazol-5-imine 119 except from the downfield movement for one of the

sp3 CH2 resonances (3.90 ppm for 122 vs 3.62 for 119). As mentioned above, this signal

for dithiazolimine 119 must correspond to the CH2 next to the chlorine atom, and the

downfield shift, tentatively, indicates the substitution of the chlorine atom with a more

electron withdrawing substituent, this probably can be attributed to the quaternized

DABCO. In addition to these resonances, 13C NMR spectroscopy showed the presence of

three C (s) resonances [δC 160.4 (s), 158.1 (s), 152.4 (s) ppm] which were identical with

the dithiazolimine 119. Furthermore, the compound was highly hygroscopic and water

soluble which further supported the presence of a quaternized moiety. Based on these

spectroscopic data and observations, the compound was tentatively identified as

N-(2-{N-[5-(phenylimino)-5H-1,2,3-dithiazol-4-yl]piperazin-1-yl}ethyl)-1,4-diazabicyclo-

[2.2.2]octan-1-ium chloride 122. This compound was also obtained by the reaction of clean

and recrystallized N-(2-chloroethyl)piperazin-1-yl]-N-phenyl-5H-1,2,3-dithiazol-5-imine

119 with DABCO in PhCl (see Section 5.6).

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5.4 Scope and Limitations of the Reaction of 1,2,3-Dithiazoles with DABCO

The partially optimized reaction conditions were applied to a diverse library of 4-chloro-

5H-1,2,3-dithiazoles to investigate the scope and limitations of the reaction (Table 15).

N-Aryl-4-chloro-5H-1,2,3-dithiazol-5-imines bearing ortho-substituents 122-126 reacted

faster than those containing only meta- or para-substituents, 127-129 and 130-134,

respectively (Table 15, entries 2-6 vs entries 7-14). Furthermore, within an ortho-, meta- or

para-substituted series, the reaction was faster in the presence of electron withdrawing

substituents. For example, within the ortho-substituted series the reaction rate followed the

trend Me < MeO < Br ≈ Cl < O2N. 4-Chloro-N-hetaryl-5H-1,2,3-dithiazol-5-imines also

worked well (Table 15, entries 18 & 20). The reactions of dithiazolimines 137, 139 and

140, however, were slow, especially, in the case of the pyrid-2-yl analogue 137 which,

even after 12 h gave the product in 46% yield together with 40% recovered starting

material; longer reaction times or increasing the equivalents of DABCO did not improve

product yield: In the first case, increasing the consumption of starting material failed to

improve the product yield, and in the second case a lower yield of the desired product was

obtained.

The optimized reaction conditions from the reaction of DABCO (2 equiv) with

dithiazolimine 95a (Table 14, entry 9) also worked well with 4-chloro-5H-1,2,3-dithiazol-

5-one 2c and 4-chloro-5H-1,2,3-dithiazole-5-thione 2d to give the analogous 2-chloro-

ethylpiperazinyl products 162 and 163 in high yields, 85 and 76%, respectively.

Nevertheless, these reactions were also partially re-optimized and, interestingly, alternative

reaction conditions were identified that gave comparable product yields. These were: For

4-chloro-5H-1,2,3-dithiazol-5-one 2c the use of PhCl (6 mL) and DABCO (1.2 equiv) for

1.25 h which gave the product 162 in 85% yield and for the 4-chloro-5H-1,2,3-dithiazole-

5-thione 2d the use of PhCl (8 mL) and DABCO (1.5 equiv) for 4 h which gave the

product 163 in 71% yield. In the latter case, only a subtle decrease on product yield was

observed in comparison with the best conditions from the dithiazolimine 95a study. As

demonstrated for those two dithiazoles, the reaction was scalable (up to 1.6 mmol) without

significant loss on product yield. To the best of our knowledge, this is the first report for

the modification at the C4 position of these dithiazoles; the structure of the thione 163 was

supported by single crystal X-ray crystallography (Figure 32).

Disappointingly, with the 4-chloro-5H-1,2,3-dithiazol-5-ylidenes 141 and 142 the desired

products were not observed and predominantly intractable baseline material was obtained.

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Table 15. Reaction of 4-chloro-5H-1,2,3-dithiazoles with DABCO

entry dithiazole time yield

(X) (h) (%)

1 95a (PhN) 4 119 (79) 2 122 (2-MeC6H4N) 4.5 143 (83) 3 123 (2-MeOC6H4N) 2.5 144 (91) 4 124 (2-ClC6H4N) 1.25 145 (90) 5 125 (2-BrC6H4N) 1.25 146 (92) 6 126 (2-O2NC6H4N) 0.42 147 (88) 7 127 (3-MeC6H4N) 5.5 148 (82) 8 128 (3-MeOC6H4N) 5.5 149 (78) 9 129 (3-BrC6H4N) 4.4 150 (83) 10 130 (4-MeC6H4N) 7.3 151 (76) 11 131 (4-MeOC6H4N) 7 152 (70) 12 132 (4-BrC6H4N) 5 153 (80) 13 133 (4-O2NC6H4N) 3 154 (74) 14 134 (4-NCC6H4N) 3.42 155 (82) 15 135 (naphth-1-ylN) 3 156 (76) 16 136 (naphth-2-ylN) 5 157 (77) 17 137 (pyrid-2-ylN) 12 158 (46)a 18 138 (pyrid-3-ylN) 4 159 (85) 19 139 (pyrazin-2-ylN) 12 160 (74)b 20 68a (pyrazol-5-ylN) 8.7 109 (79) 21 140 (thiazol-2-ylN) 12 161 (71)c 22 2c (O) 0.33 162 (85) 23 2d (S) 3 163 (76) 24 141 [(CN)2C] 3 164 (-)d 25 142 [(CO2Et)2C] 5 165 (-)d

a 40% recovered starting material. b 15% recovered starting material. c 8% recovered starting material. d Predominantly baseline material

observed

Figure 32. Ellipsoid (probability level of 50%) representation of the crystal structure

4-[N-(2-chloroethyl)piperazin-1-yl]-5H-1,2,3-dithiazole-5-thione 163 with crystallographic atom

labeling. The H atoms were omitted for clarity

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5.5 Rationale for the Relative Reactivity of 1,2,3-Dithiazoles with DABCO

The relative reactivities of the dithiazoles towards DABCO suggested that the substituent

at C5 affected the electrophilicity of the dithiazole ring. In the case of the N-aryl-

dithiazolimines 95a, 122-134 both steric and electronic factors, were discernible. Owing to

steric hinderance, ortho-substituted N-aryl-4-chloro-5H-1,2,3-dithiazol-5-imines 122-126

were expected to have a greater torsion angle between the dithiazole and the N-aryl ring

compared with their meta- and para-substituted analogues, 127-129 and 130-134,

respectively. As the torsion angle increases, the conjugation between the N-aryl and the

dithiazole decreases147 leading to an increase in the electrophilicity of the latter.

The reactivity of the N-azin-2-yl- 137 and 139 and N-azol-2-yl- 140 substituted dithiazol-

imines was more intriguing, as their reactions were considerably slower than all the other

dithiazolimines. Especially, in the case of the N-azin-2-yl- analogues 137 and 139, intro-

ducing the pyridyl (or pyrazinyl) ring was expected to increase the electrophilicity of the

dithiazole compared to the N-phenyl analogue 95a owing to the electron withdrawing

character of the pyridyl (or pyrazinyl) ring. Nevertheless, these dithiazoles appeared more

resistant to nucleophilic attack by DABCO than the corresponding N-phenyl dithiazolimine

95a. The relative order of reactivity decreased accordingly: Phenyl > thiazol-2-yl >

pyrazin-2-yl > pyrid-2-yl. A common feature in these N-hetaryl analogues was the ortho

nitrogen atom to the dithiazole ring that can participate in an N…S interaction with the

dithiazole S-1 atom. For comparison, the reactivity of the pyrid-3-yl analogue 138, which

is isomeric to the pyrid-2-yl 137 but has no possible intramolecular N…S interaction, was

comparable with the N-phenyl dithiazolimine 95a.

Non-bonded X…E-Y interactions (where X = N, O or S and E = S, Se or Te) attracted

considerable interest,148 and their nature as well as the factors influencing their strength

have been studied experimentally,149 and computationally.150 From computational studies,

it has been suggested that two major factors influence these X…E-Y interactions: (a) An

electrostatic interaction and b) a molecular orbital interaction which involves electron

donation from the lone pair heteroatom X (nX orbital) to the antibonding orbital of the E-Y

bond (in our case the S-S bond) (σ*E-Y

orbital).

The major characteristics of X…E-Y interactions are that: (a) The molecules adopt a planar

conformation where the X…E-Y atoms essentially align (150-180°); (b) the distance of

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X…E is longer than a typical covalent X-E bond but smaller than the sum of the van der

Waals radii of the two atoms; and (c) the E-Y bond is lengthened. The strength of the

interaction depends both on the electronegativity of Y and X: More electronegative Ys

and/or less electronegative Xs lead to stronger X…E interactions and vice versa.

To investigate the strength of the N…S interaction in dithiazoles 137, 139 and 140 and the

effect on their reactivity, the structures of the dithiazoles 95a, 137, 139 and 140 were

optimized at the DFT RB3LYP/6-31G+(d,p) level of theory and their geometric parameters

and Mulliken atomic charges, calculated at the MP2/6-31G(d) level of theory for the

optimized structures, were analyzed.

As can be observed from Figure 33 and Table 16 the N…S distance decreases in the order

thiazol-2-yl (2.656 Å) > pyrazin-2-yl (2.574 Å) > pyrid-2-yl (2.519 Å) with concomitant

lengthening of the S-S bond, thiazol-2-yl (2.147 Å) < pyrazin-2-yl (2.154 Å) < pyrid-2-yl

(2.163 Å). Compared with the N-phenyl dithiazolimine 95a, where there is no N…S

interaction, the lengthening of the S-S bond in the N-hetaryl dithiazolimines 140, 139 and

137 is in the order of 0.15-0.3 Å. The above geometric data supported that the strength of

the N…S interaction increased in the order thiazol-2-yl < pyrazin-2-yl < pyrid-2-yl, which

can be explained in terms of both steric and electronic effects. The weakened N…S

interaction in the pyrazin-2-yl 139 compared to the pyrid-2-yl analogue 137 can be

attributed to the presence of the additional sp2 nitrogen of the pyrazin-2-yl which makes

this azine more electronegative than the pyrid-2-yl analogue leading to a weaker orbital

interaction.149a While the thiazol-2-yl moiety is more electron rich than the pyrid-2-yl and

pyrazin-2-yl moieties which could lead to stronger N…S interaction, this was not observed

for steric reasons since the geometry of the five membered thiazol-2-yl ring prevented the

sp2 nitrogen atom from attaining an optimum alignment of its lone pair (nN) with the

antibonding orbital σ*S-S. This decrease on the strength of the X…E interaction imposed by

the exchange of a six- for a five-membered ring was also observed on a recent study on

N…Se interactions.150e

By comparing the experimentally observed order of reactivity with the N…S interaction

strength, as measured by the N…S distance, it was evident that as the N…S interaction

increased the dithiazole became less reactive towards DABCO. This can now be attributed

to a decrease on the electrophilicity of the S2 atom caused by an increase of its electronic

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population as a result of the nN σ*

S-S interaction. Furthermore, this was supported by

Mulliken population analysis151 (Table 16) which showed an increase on the electronic

population of S2 and a decrease in the electronic population of S1 on dithiazoles 140, 139

and 137 in comparison with the “parent” dithiazole 95a.

Table 16. Geometric parameters of optimized dithiazoles at the DFT RB3LYP/6-31G+(d,p) level of theory and Mulliken atomic charges computed at the MP2/6-31G(d) level of theory

Distance (Å) phenyl 95a

thiazol-2-yl 140

pyrazin-2-yl 139

pyrid-2-yl 137

S-S 2.133 2.147 2.154 2.163

N…S - 2.656 2.574 2.519

Angle (°)

S1-C5-N6 128.17 126.14 126.58 126.33

C5-N6-C7 127.39 119.83 120.52 120.07

N6-C7-X8 124.48 126.03 120.36 118.89

Mulliken charge

S1 0.074 0.196 0.193 0.190

S2 0.301 0.279 0.272 0.252

C4 0.078 0.087 0.081 0.083

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5.6 Mechanistic Rationale

A plausible mechanism for the formation of the 4-[N-(2-chloroethyl)piperazin-1-yl]-5H-

1,2,3-dithiazoles involves an ANRORC-style66 ring opening of the 1,2,3-dithiazole by the

nucleophilic DABCO to give a disulfide 166, analogous to the reaction of secondary

dialkylamines with 1,2,3-dithiazoles.54,59a,65 Unlike the reactions of primary or secondary

amines, the steric bulk of DABCO, presumably prevents a second attack at S2 by another

DABCO which limits the formation of side products that arise from cleavage of the

disulfide chain.63a,68a As such, a second molecule of DABCO can competitively add to the

more accessible nitrile to afford an amidine that then intramolecularly adds to S2, which now

hosts a quaternized DABCO as a nucleofuge. The reaction sequence leads to the construction

of a new 1,2,3-dithiazole 167 that now contains a quaternized DABCO at C4. Subsequent

ring opening of the quaternized DABCO by chloride gives the final product (Scheme 53).

Scheme 53. Plausible mechanism for the formation of 4-[N-(2-chloroethyl)piperazin-1-yl]-5H-1,2,3-

dithiazoles

The possibility that free N-(2-chloroethyl)piperazine 168a, which can form in the reaction

mixture, reacted with the 4-chloro-5H-1,2,3-dithiazoles to give the observed products was

also considered. Treating the dithiazolimine 95a (0.2 mmol) with pure N-(2-chloroethyl)-

piperazine 168a (2 equiv) in PhCl (8 mL) heated at reflux, however, gave a complex

reaction mixture which at 2 h contained unreacted starting material 95a (37%),

4-[N-(2-chloroethyl)piperazin-1-yl]-N-phenyl-5H-1,2,3-dithiazol-5-ylidene}aniline 119 (6%),

carbimidoyl cyanide 121a (9%) and multiple unidentified colorless side products.

Tentatively, this suggested that the reaction of the 1,2,3-dithiazoles with free

N-(2-chloroethyl)-piperazine 168a was not a major pathway leading to the formation of the

N-{4-[N-(2-chloroethyl)piperazin-1-yl]-5H-1,2,3-dithiazoles. Furthermore, when the

dithiazoles 95a, 2c-d were treated with pure N-(2-chloroethyl)piperazine 168a or

N-(2-cyanoethyl)piperazine 168b under Kim’s conditions,63a the carbimidoyl cyanides 121

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were obtained in moderate to excellent yields, while no traces of the ANRORC products

119, 162-163 were observed (Table 17).

Table 17. Reaction of 1,2,3-dithiazoles 95a, 2c-d with N-[(2-substituted)ethyl]piperazines 168 in DCM

entry dithiazole piperazine time X Y yields

(equiv) (h) (%)

1 95a 168a (5) 2.0 PhN Cl 121a (67)a 2 95a 168b (3) 4.5 PhN NC 121b (98) 3 2c 168a (3) 0.33 O Cl 121c (64)a 4 2c 168b (3) 0.33 O NC 121d (75) 5 2d 168a (3) 0.17 S Cl 121e (98) 6 2d 168b (3) 0.17 S NC 121f (98)

a Complex reaction mixture

The possibility of a direct displacement of the C4 chlorine by DABCO cannot be

eliminated but seems less probable since, to date, direct intermolecular nucleophilic attack

at the 1,2,3-dithiazole C4 position has not been documented. Furthermore, Mulliken

population analysis (Table 16) shows significantly more positive character on S2 (0.301)

than on C4 (0.078).

N-Phenyl-4-[N-(2-thiocyanatoethyl)piperazin-1-yl]-5H-1,2,3-dithiazol-5-imine 120h was

obtained from nucleophilic displacement of the chloride by thiocyanate. Presumably minor

decomposition of the dithiazoles released cyanide, a typical thiophile (anthio anion), which

in the presence of sulfur can generate thiocyanate.152

Carbimidoyl cyanides, analogous to 121, were observed previously by Kim et al.63a,153 in

the reaction of 1,2,3-dithiazoles with dialkylamines, and mechanistic rationale was

provided. A similar mechanism could take place in this case, however, the attacking

nucleophile can either be DABCO or free N-(2-chloroethyl)piperazine 168a, which as

mentioned above could be present in minor quantities in the reaction mixture.

N-(2-{N-[5-(Phenylimino)-5H-1,2,3-dithiazol-4-yl]piperazin-1-yl}ethyl)-1,4-diazabicyclo-

[2.2.2]octan-1-ium chloride 122 presumably formed via nucleophilic attack of DABCO on

the 2-chloroethyl moiety of the 4-[N-(2-chloroethyl)piperazin-1-yl]-N-phenyl-5H-1,2,3-

dithiazol-5-imine 119. To support this, the dithiazolimine 119 was treated with DABCO

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(1 equiv) in PhCl (2 mL) at ca. 131 °C for 12 h and not surprisingly, N-(2-{N-[5-(phenyl-

imino)-5H-1,2,3-dithiazol-4-yl]piperazin-1-yl}ethyl)-1,4-diazabicyclo[2.2.2]octan-1-ium

chloride 122 was isolated in 64% yield, together with 36% recovered starting material.

5.7 Chemistry of 4-[N-(2-Chloroethyl)piperazin-1-yl]-5H-1,2,3-dithiazoles

5.7.1 Manipulations on the 2-Chloroethyl Moiety

The 4-[N-(2-chloroethyl)piperazin-1-yl]-5H-1,2,3-dithiazoles contain a 2-chloroethyl

group that can be modified by reaction with various nucleophiles. Nevertheless, in the

presence of the 1,2,3-dithiazole, which hosts weak S-S and S-N bonds that are susceptible

to thiophilic attack,63b,64,65a,67,68a,85,126,127b,128 it was important to identify both nucleophiles

and conditions that would not cleave the ring system.

A selection of N-, O- and S-nucleophiles reacted cleanly with the N-(2-chloroethyl)pipera-

zinyl dithiazoles 119, 162 and 163 in hot MeCN (ca. 81 °C) to give, predominantly, the

desired N-[(2-(substituted)ethyl]piperazinyl products in good to excellent yields (Table 18).

An exception was sodium azide (Table 18, entry 1) which reacted with the thione 163 to

give after 3 h a complex mixture, including unreacted starting material, which was not

pursued further. Also, in the reactions with N-methylbenzylamine (Table 18, entry 2)

significant quantities (10-20% by TLC) of starting material remained after 4-7 h;

increasing the equivalents of both N-methylbenzylamine and K2CO3 (up to 2 equiv) led to

the completion of the reaction, however, no improvement on the product yields was

observed. The reactions with aniline and N-methylaniline took significantly longer than the

other nucleophiles (Table 18, entries 3 & 4), as such, these arylamines were used in excess

(10 equiv); in these two cases the desired products were precipitated out of the reaction as

the hydrochloride salts. Furthermore, potassium cyanide was tested as C-nucleophile but

instead of the desired products 120j, 169j and 170j (Y = CN) the thiocyanato adducts 120h,

169h and 170h were obtained in low to moderate yields (Table 18, entry 10). Cyanide,

which is thiophilic,152 presumably preferentially attacked the dithiazoles S2 atom to cleave

the ring and eventually expel thiocyanate that then reacted with intact dithiazoles at the

2-chloroethyl moiety to give the observed products.

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Table 18. Reaction of 4-[N-(2-chloroethyl)piperazin-1-yl]-5H-1,2,3-dithiazoles 119, 162 and 163 (0.1 mmol) with various nucleophiles in MeCN (2 mL) at ca. 81 °C

from 119 from 162 from 163

entry reagent

(equiv)

Y time

(h)

yield

(%)

time

(h)

yield

(%)

time

(h)

yield

(%)

1 NaN3 (1.1) N3 2.5 120a (94) 5 169a (97) 3 170a (-)a,g

2 Bn(Me)NH (1.1)b N(Me)Bn 7 120b (63) 6 169b (40) 8 170b (53)

3 PhNH2 (10)c N(H)Ph 24 120c (72)e 24 169c (83)e 24 170c (64)e

4 Ph(Me)NH (10)d N(Me)Ph 24 120d (54)e 24 169d (78)e 38 170d (84)e

5 PhthNK (2) NPhth 2.3 120e (97) 1.5 169e (90) 3 170e (91)

6 NaOAc (2) OAc 10 120f (95) 8.5 169f (93) 12 170f (94)

7 NaOBz (1.1) OBz 11 120g (98) 5.5 169g (97) 13 170g (95)

8 KSCN (1.1) SCN 1.6 120h (91) 2.5 169h (94) 4 170h (90)

9 MBTf (1.1)b S(benzothiazol-2-yl) 1.4 120i (90) 2.5 169i (81) 6 170i (75)

10 KCN (1.1) SCN 3 120h (18)a 1.3 169h (41)g 4 170h (49)g

a Complex reaction mixture. b Used in combination with K2CO3 (1.1 equiv). c Reaction performed at 0.4 mmol scale. d Reaction performed at 0.8 mmol scale. e Yield for the HCl salt, isolated by filtration. f MBT = 2-Mercaptobenzothiazole. g A significant amount of intractable polar material (baseline on TLC) was observed

5.7.2 Manipulations at the Dithiazole C5 Position

Having introduced the N-(2-chloroethyl)piperazinyl group at the dithiazole C4 position we

then considered whether in its presence we could also modify the C5 position. Since the

reaction of (4-chloro-5H-1,2,3-dithiazol-5-ylidene)methanes 141 and 142 with DABCO

failed to give the desired 4-[N-(2-chloroethyl)piperazinyl]substituted dithiazoles 164 and

165, respectively (Table 15, entries 24 & 25), we attempted to access these dithiazol-

ylidenes from the dithiazolethione 163. Gratifyingly, treatment of thione 163 with

tetracyanoethylene oxide (TCNEO) or diazomalonate, under the conditions specified in

Scheme 54, gave the {4-[N-(2-chloroethyl)piperazin-1-yl]-5H-1,2,3-dithiazol-5-ylidene}-

methanes 164 and 165 in 33 and 36% yields, respectively. Furthermore, treatment of thione

163 with diphenydiazomethane gave the ylidene 171 in 50% yield (Scheme 54).

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Scheme 54. Manipulation of the dithiazole C5 position of 4-[N-(2-chloroethyl)piperazin-1-yl]-5H-

1,2,3-dithiazole-5-thione 163

Worthy of note, was that pure and recrystallized ylidene 171 was stable at ca. 20 °C for at

least one month, in contrast to the analogous (4-chloro-5H-1,2,3-dithiazol-5-ylidene)-

diphenylmethane 172, which when left standing overnight decomposes to S8 and

3-phenylbenzo[b]thiophene-2-carbonitrile 173 (Scheme 55).56b Presumably, the piperazine

at C5, which (a) releases electron density into the dithiazole making it less electrophilic,

and (b) is a poorer nucleofuge than chloride, makes the fragmentation of the dithiazole less

facile.

Scheme 55. Transformation of (4-chloro-5H-1,2,3-dithiazol-5-ylidene)diphenylmethane 172 to

3-phenylbenzo[b]thiophene-2-carbonitrile 173

5.8 Conclusions

A general and high yielding method for the C4 functionalization of 4-chloro-1,2,3-

dithiazoles with a 2-(chloroethyl)piperazinyl group has been developed. The reaction

worked well with 4-chloro-N-aryl-5H-1,2,3-dithiazol-5-imines 122-140, the 4-chloro-5H-

1,2,3-dithiazol-5-one 2c and –thione 2d but with (4-chloro-5H-1,2,3-dithiazol-5-ylidene)-

methanes 141 and 142 intractable baseline material was obtained. Nevertheless, several

{4-[2-(chloroethyl)piperazinyl]-5H-1,2,3-dithiazol-5-ylidene}methanes were prepared in

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modest yields via the C5 post functionalization of the 4-(2-chloroethyl)piperizinyl

dithiazolothione 163. The N-(2-chloroethyl)piperazinyl group can also be further modified

by reaction with various nucleophiles without degrading the dithiazole system. As such,

the above synthetic protocols provide a general route for modifying the C4 position of

1,2,3-dithiazoles, giving access to products that can be further functionalized either at the

2-chloroethyl side chain or the C5 position. The compounds synthesized are currently

under biological evaluation.

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CHAPTER 6

Synthesis and Characterization of Cross-Conjugated 5,5'-Diarylimino Quinoidal

2,2'-Bithiazoles

Contents

6.1 Introduction 94


5,5'-Dibromo-4,4'-diphenyl-2,2'-bithiazole 180a with 4-n-Butoxyaniline 96

6.2.1 Part I: Solvent, Base, Catalyst and Ligand Screen 98

6.2.2 Part II: Fine Tuning 99

6.2.3 Ligand Bite Angle Study 101

6.3 Structure Elucidation of Compounds 184, 185 and 186 102



Anilines 104

6.5 Stereoisomers of Quinoidal 2,2'-Bithiazole 182a: A Computational Study 107

6.6 Experimental UV/vis Absorption of Quinoidal 2,2'-Bithiazoles 182 107

6.7 TD-DFT Computational Studies on Quinoidal 2,2'-Bithiazoles 182 109

6.8 Cyclic Voltammetry of Quinoidal 2,2'-Bithiazoles 182 120

6.9 Conclusions 125

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6.1 Introduction

The work herein was inspired by the serendipitous discovery of a very minor side product

by prior group member working on the chemistry of 1,2,3-dithiazoles.154 Reaction of

(Z)-2-[(4-chloro-5H-1,2,3-dithiazol-5-ylidene)amino]-6-ethoxy-4-phenylpyridine-3,5-dicar-

bonitrile 174 with Et2NH gives as major product 4-(diethylamino)-7-ethoxy-5-phenyl-

pyrido[2,3-d]pyrimidine-2,6-dicarbonitrile 175 (84%) (Scheme 56). From the reaction

several minor side products were isolated, among which was and the unusual quinoidal

2,2'-bithiazole 6,6'-{[(2E,5Z,5'Z)-4,4'-bis(diethylamino)-5H,5'H-(2,2'-bithiazolylidene)-5,5'-

diylidene]bis(azanylylidene)}bis(2-ethoxy-4-phenylpyridine-3,5-dicarbonitrile) 178 (2%).

Scheme 56. The reaction of (Z)-2-[(4-chloro-5H-1,2,3-dithiazol-5-ylidene)amino]-6-ethoxy-4-

phenylpyridine-3,5-dicarbonitrile 174 with Et2NH

2,2'-Bithiazoles, an important thiazole subclass, can exist at three oxidation levels:

Dithiadiazafulvalenes (DTDAFs), aromatic 2,2'-bithiazoles and quinoidal 2,2'-bithiazoles

(Figure 34). Aromatic 2,2'-bithiazoles are the most well studied, and several analogues

display interesting biological properties such as antiviral activity against hepatitis B155 or

HIV,156 while others inhibit histone deacetylase.157 Many aromatic 2,2'-bithiazoles also

appear in small molecules, oligomers and polymers, with diverse applications e.g., as

components in fluorescent chemosensors,158 organic photovoltaics (OPV),159 and organic

field-effect transistors (OFET),160 as liquid crystals,161 macrocycles,162 and ligands for

metal coordination.163

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Figure 34. Structures of 2,2'-bithiazoles at three possible oxidation levels

DTDAFs and quinoidal 2,2'-bithiazoles are cross-conjugated, i.e. they possess at least

“three unsaturated groups, two of which although conjugated to a third unsaturated center

are not conjugated to each other”.164 Cross-conjugation can be used to modify both the

optical and electronic properties of a molecule.165 Furthermore, cross-conjugation can

make molecules susceptible to quantum interference phenomena.166 These features make

cross-conjugated systems interesting for applications in organic electronics.

DTDAFs167 are similar to tetrathiafulvalene168 (Figure 35) and exhibit good electron

donating properties, making them useful components of conducting charge transfer salts.

In contrast, quinoidal 2,2'-bithiazoles are electronically similar to quinones i.e. the addition

of 1e- completes the π sextet required for Hückel aromaticity, potentially making them

good redox reversible electron acceptors.169 To the best of our knowledge, there are only

two reports on quinoidal 2,2'-bithiazoles: The above mentioned quinoidal 2,2'-bithiazole

178154 and (E)-2,2'-[5H,5'H-(2,2'-bithiazolylidene)-5,5'-diylidene]dimalononitriles 179170

(Figure 35).

Figure 35. General structures of tetrathiafulvalene and quinoidal 2,2'-bithiophenes and the

structures of known quinoidal 2,2'-bithiazoles 179

Quinoidal compounds have been used to design low band gap materials,171 and quinoidal

2,2'-bithiophenes, which are structurally similar to the quinoidal 2,2'-bithiazoles reported

herein, show n-type and/or ambipolar semiconductor properties.172 The scarcity of studies

on the aza analogues, quinoidal 2,2'-bithiazoles, can be attributed to the absence of a

general and high yielding synthesis to these systems.

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In light of the above, we became interested in studying the quinoidal 2,2'-bithiazole 178

further. To facilitate the study of this compound, we needed a higher yielding synthesis but

our efforts to optimize its formation via 1,2,3-dithiazoles chemistry failed. Nevertheless, a

one-pot, two-step, chromatography-free route was developed that involved a Pd(0)-

mediated double C-N coupling of readily available 5,5'-dibromo-2,2'-bithiazoles 180 with

(het)arylamines to give 5,5'-diarylamino-2,2'-bithiazoles 181 that were then oxidized in

situ to analogous 5,5'-diarylimino quinoidal 2,2'-bithiazoles 182.

Scheme 57. Pd(0)-mediated double C-N coupling route to quinoidal 2,2'-bithiazoles 182


5,5'-Dibromo-4,4'-diphenyl-2,2'-bithiazole 180a with 4-n-Butoxyaniline

For the optimization of the double Pd(0)-mediated double C-N coupling route to the

quinoidal 2,2'-bithiazoles 182, the readily available 5,5'-dibromo-4,4'-diphenyl-2,2'-

bithiazole 180a and 4-n-butoxyaniline were used as starting materials, as this combination

gave products with good solubility that assisted with the work-up. Our starting point was

the use of Pd(OAc)2 (20 mol %), BINAP (20 mol %) and K2CO3 (2.4 equiv) which in

1,4-dioxane at ca. 101 °C under argon atmosphere after 9 h led to the direct formation of

the desired product (2E,5Z,5'Z)-5,5'-di(4-n-butoxyphenylimino)-4,4'-diphenyl-5H,5'H-2,2'-

bithiazolylidene 182d in 39% yield. While the intermediate 5,5'-di(4-n-butoxyanilino)-4,4'-

diphenyl-2,2'-bithiazole 181d was not observed (by TLC), three side products were

isolated and based on their spectroscopic data were identified as: 5-(4-n-Butoxyanilino)-

4,4'-diphenyl-2,2'-bithiazole 184, 5-(4-n-butoxyanilino)-4,4',4'',4'''-tetraphenyl-

[2,2':5',5'':2'',2''']quaterthiazole 185 and 5,5'''-bis(4-n-butoxyanilino)-4,4',4'',4'''-tetraphenyl-

[2,2':5',5'':2'',2''']quaterthiazole 186 obtained in 13%, 3% and 10% yields, respectively

(Scheme 58). Initial attempts to optimize the reaction included lowering the catalyst and

the ligand loadings to 10 mol % but this led to incomplete reactions even after 4 days. As

such, the optimization was continued with 20 mol % loadings.

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Scheme 58. Reaction of 5,5'-dibromo-4,4'-diphenyl-2,2'-bithiazole 180a with 4-n-butoxyaniline;

a combined product yield from chromatography free procedure (33%) and chromatography of the

filtrate (6%)

A chromatography-free procedure was developed for the reaction work-up. The mixture

after completion of the reaction (by TLC) was left to cool at ca. 20 °C, dissolved in DCM

and passed through a short pad of silica. The solvent was evaporated in vacuo and the

residue was suspended in acetone and filtered. All the side products were soluble in

acetone, leaving behind the clean product as an acetone insoluble solid.

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6.2.1 Part I: Solvent, Base, Catalyst and Ligand Screen

Solvent screening. With Pd(OAc)2 (20 mol %), BINAP (20 mol %), K2CO3 (2.4 equiv) and

4-n-butoxyaniline the use of either dry THF (bp 66 °C) or dry PhH (bp 80 °C), heated at

reflux, led to incomplete reactions or long reaction times. Performing the same reactions in

a sealed tube at ca. 120 °C gave faster reaction times and moderate product yields: 34%

yield after 19 h (4-n-BuOC6H4NH2 2.7 equiv used) for THF and 38% yield after 14.5 h for

PhH (4-n-BuOC6H4NH2 2 equiv used). In either MeCN or DMSO, predominately

intractable polar brown baseline material (by TLC) was obtained and formation of

unknown side products, while in dry PhMe or xylene protodebromination led to the

formation of side products. When the reactions were repeated in the absence of

4-n-butoxyaniline some debromination of the 2,2'-bithiazole was observed and oxidized

products of PhMe and xylene (benzaldehydes) were isolated. As such, we chose to retain

1,4-dioxane as the reaction solvent.

Base screening. The use of different bases (Cs2CO3, K3PO4, NaOH) did not lead to any

improvement. With 4-n-BuOC6H4NH2 (2 equiv), Pd(OAc)2 (20 mol %) and BINAP

(20 mol %) in 1,4-dioxane, Cs2CO3 (2.4 equiv) gave a faster reaction time (6 h) than

K2CO3 and marginally lower product yield (27%, chromatography-free). The use of K3PO4

(2.4 equiv) gave a longer reaction time (33 h) and only a marginally lower product yield

(28%). With NaOH (2.4 equiv) the reaction could not be driven to completion (48 h).

Ligand screening. With 4-n-BuOC6H4NH2 (2 equiv), Pd(OAc)2 (20 mol %), BINAP

(20 mol %) and K2CO3 (2.4 equiv) in 1,4-dioxane, monophosphino ligands [JohnPhos,

t-BuXPhos, (MeO)3P] failed to give the desired product. The diphosphino ligands, dppf

and dppe, gave very little product, but in the case of DPEPhos an improved reaction time

was observed compared to BINAP (7 h vs 9 h) although the product yield was reduced also

(27% vs 39%).

Catalyst screening. Based on the above, a series of catalysts (20 mol %), Pd(Ph3P)2Cl2,

Pd(Ph3P)4, [Pd(dppf)Cl2]·DCM, (MeCN)2PdCl2, PEPPSI™-IPr catalyst, Pd2dba3,

(PhCN)2PdCl2, PdCl2, Pd{[3,5-(F3C)2C6H3]3P}3 aka Superstable Pd(0)®, were screened

with both BINAP and DPEPhos as ligands (20 mol %), and K2CO3 (2.4 equiv) as base in

1,4-dioxane. In most cases the use of DPEPhos (Table 19, even # entries) led to improved

product yields and/or reaction times compared to the use of BINAP (Table 19, odd #

entries). Gratifyingly, with Superstable Pd(0)® and DPEPhos the desired product was

obtained in a significantly improved yield (68%).

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Table 19. Part I: Ligand and catalyst screening for the C-N coupling of 5,5'-dibromo-4,4'-diphenyl-2,2'-bithiazole 180a (0.1 mmol) with 4-n-butoxyaniline

entry catalyst ligand time

(h) yield (%)

1 Pd(Ph3P)2Cl2 BINAP 3 d ira 2 Pd(Ph3P)2Cl2 DPEPhos 2 d ira 3 Pd(Ph3P)4 BINAP 4 d ira 4 Pd(Ph3P)4 DPEPhos 27 49 5 (PhCN)2PdCl2 BINAP (>30 h) 44 hb 33 6 (PhCN)2PdCl2 DPEPhos 27 h 48 7 [Pd(dppf)Cl2]2·DCM BINAP (>28 h) 44 hb 33 8 [Pd(dppf)Cl2]·DCM DPEPhos 1.5 d 53 9 Superstable Pd(0)® BINAP 2 d ira 10 Superstable Pd(0)® DPEPhos 1 d 68 11 Pd2dba3 BINAP (>30 h) 44 hb 13 12 Pd2dba3 DPEPhos 17 h 47 13 (MeCN)2PdCl2 BINAP (>20 h) 28 hb 35 14 (MeCN)2PdCl2 DPEPhos 27 h 57

a Incomplete reaction. b Time that the reaction was stopped; reaction time longer than the time indicated in parenthesis

6.2.2 Part II: Fine Tuning

After identifying the best catalytic system i.e. Superstable Pd(0)® as catalyst, DPEPhos as

ligand, K2CO3 as base and 1,4-dioxane as solvent, the reaction was further optimized.

Worthy of note, was that under these reaction conditions, the intermediates: 5'-Bromo-5-

(4-n-butoxyanilino)-4,4'-diphenyl-2,2'-bithiazole 183 and 5,5'-di(4-n-butoxyanilino)-4,4'-

diphenyl-2,2'-bithiazole 181d were clearly observable in the reaction mixture (by TLC). As

such, the completion of the reaction was monitored both by the consumption of the starting

material as well as the complete consumption of the observed intermediates.

By combining the use of Superstable Pd(0)® and DPEPhos we were able to decrease the

loadings from 20 to 10 mol % and obtain complete consumption of the starting material

and after 36 h isolate the product 182d in a 70% yield. Reducing the loadings to 5 mol %,

however, gave after 72 h a mixture of the reduced and oxidized 2,2'-bithiazoles, 181d and

182d, respectively. Longer reaction times did not improve the reaction further. To facilitate

the oxidation step after complete consumption of the starting material 180a and of the

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monoaminated intermediate 183 the reaction was left refluxing under atmospheric air, but

even after 20 h the diaminated intermediate 181d was still present without significant

decrease of its intensity (by TLC).

The addition of oxidants was then investigated (Table 20). Addition of metal oxides after

the complete consumption of 180a and 183 led to the quick and complete oxidation of

181d to the desired quinoidal 2,2'-bithiazole 182d. From the oxidants screened (MnO2,

Ag2O, PbO2 and HgO) the most efficient were Ag2O and HgO which could be used in

equimolar quantities. For MnO2 and PbO2 2 equivalents were necessary for complete

consumption of the diaminated intermediate. As such, Ag2O was used for further

experiments to avoid the use of the more toxic HgO.

Table 20. Part II: Fine tuning on the C-N coupling of 5,5'-dibromo-4,4'-diphenyl-2,2'-bithiazole 180a (0.1 mmol) with 4-n-butoxyaniline

entry Superstable Pd(0)®

(mol %) DPEPhos

(mol%) time T1

(h) oxidant (equiv)

time T2 (min)

yield (%)

1 20 20 24 - 68 2 10 10 36 - 70 3 5 5 72 - ioa 4 5 5 11b air 20 ioa 5 5 5 11b MnO2 (1) - ioa 6 5 5 11b MnO2 (2) 0.25 84 7 5 10 8b MnO2 (2) 0.25 85 8 5 20 7.5b MnO2 (2) 0.25 87 9 5 10 8b PbO2 (2) 0.45 85 10 5 10 8b HgO (2) 0.27 87 11 5 10 8b Ag2O (2) 0.20 84 12 5 10 8b Ag2O (1) 0.20 85 13 5 10 8b Ag2O (0.5) - ioa 14 2.5 5 15b Ag2O (1) 0.50 88 15 1.25 5 16b Ag2O (1) 0.67 86

a Incomplete oxidation. b Time at which all the monominated intermediate 183 was consumed

With the best oxidant and base selected, we reinvestigated lowering the catalyst and ligand

loadings and were able to decrease the catalyst to as low as 1.25 mol % and the ligand to

5 mol % without affecting the product yield, but this did lead to longer reaction times (16

h). Further increasing the ligand to catalyst ratio (4:1) did no significantly improve the

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reaction time (7.5 h) or the product yield (87%); both were very similar to the 2:1 ratio

reaction (Table 20, entry 8 vs 7).

The optimum equivalents for K2CO3 were also investigated. The use of an equimolar

quantity led to a slightly longer reaction time and marginally lower product yield. No

advantage in yield or reaction time was observed on increasing the K2CO3 to 4 equivalents.

With the best oxidant and base selected, we reinvestigated decreasing the catalyst and

ligand loadings: The catalyst could be decreased to as low as 1.25 mol % and the ligand to

5 mol % without affecting the product yield, but this did lead to longer reaction times (16 h)

(Table 20, entry 15). Lower loadings were not investigated for practical reasons (weighing

accuracy). As such, taking into account all three factors: Yield, reaction time and reagent

cost, the best conditions were concluded to be: Superstable Pd(0)® (1.25 mol %), DPEPhos

(5 mol %) and K2CO3 (2.4 equiv) in 1,4-dioxane. Under these optimized reaction

conditions only the side product 184 was observed in negligible amounts (by TLC).

6.2.3 Ligand Bite Angle Study

As mentioned above, during the ligand screen, we observed that most of the reactions gave

consistently better product yields (by ca. 15-30%) when DPEPhos was used in place of

BINAP. This was tentatively attributed to the effect of the natural bite angle.173 To

investigate this further, we screened side by side three different phosphine ligands BINAP,

DPEPhos and Xantphos with natural bite angles 92°, 102° and 107°, respectively, under

the optimized conditions [Superstable Pd(0)® (1.25 mol %), ligand (5 mol %), K2CO3

(2.4 equiv), 1,4-dioxane]. With BINAP, which has the smallest bite angle, the reaction

could not be driven to completion even after 72 h. In the case of Xantphos a longer

reaction time (29 h vs 16 h for BINAP) and decreased product yield (63% vs 86% for

BINAP) was obtained. Tentatively, this indicated that a wider bite angle of 102° was

indeed beneficial for the reaction, but it was detrimental to increase this further to 107°.

Similar behavior was also observed in a cross-coupling reaction of 2-butylmagnesium

chloride with bromobenzene, where catalysts with larger bite angles than DPEPhos led to

decreased activity and selectivity. This was attributed to the stabilization of trigonal

bipyramidal Pd intermediates by ligands with larger bite angles which led to formation of

homocoupled products.174

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6.3 Structure Elucidation of Compounds 184, 185 and 186

5-(4-n-Butoxyanilino)-4,4'-diphenyl-2,2'-bithiazole 184 was obtained as yellow

microcrystals, mp 109.5–110.5 °C (from n-hexane/Et2O at ca. -20 °C). Mass spectrometry

gave a parent ion of m/z 484 (MH+, 100%), which was ca. one 4-n-butoxyaniline molecule

less than the quinoidal bithiazole 182d. No bromine isotopes were observed. In

combination with elemental analysis, the data tentatively supported a molecular formula of

C28H25N3OS2. UV/vis absorption spectroscopy showed a λmax(DCM) at 413 nm (log ε 4.16)

supporting the presence of extensive conjugation. 1H NMR spectroscopy revealed the

presence of nine (two of which were overlapping) aromatic CH resonances integrating in

total for 15 H, one D2O exchangeable resonance integrating for 1 H and four alkyl, three

CH2 and one CH3 resonances. From the aromatic signals, two were characteristic for one

para-disubstituted benzene [δH 7.06 (2H, d, J 9.0), 6.88 (2H, d, J 8.5) ppm] and were

significantly upfield in comparison with the other aromatic signals tentatively indicating

that an EDG was attached on the ring, suggesting the presence of one 4-n-butoxyanilino

moiety. From the remaining seven signals, six were characteristic for two different mono-

substituted benzenes [δH 7.94 (2H, d, J 7.5), 7.89 (2H, d, J 7.0), 7.48-7.42 (4H, m), 7.36-

7.33 (2H, m) ppm] suggesting the presence of an unsymmetrical substituted 4,4'-diphenyl-

2,2'-bithiazole. The remaining signal [δH 7.50 (1H, s) ppm] was characteristic for the C5

hydrogen of the 4,4'-diphenyl-2,2'-bithiazole. The D2O exchangeable resonance [δH 5.90

(1H, br s) ppm] indicated the presence of an NH group which was further supported by IR

spectroscopy [ν(N-H) 3366 and 3304 cm-1]. 13C NMR data showed eight C (s) and nine

C (d) resonances further supporting the presence of an unsymmetrical substituted

4,4'-diphenyl-2,2'-bithiazole. Based on the above the compound was tentatively assigned as

the 5-(4-n-butoxyanilino)-4,4'-diphenyl-2,2'-bithiazole 184.

5-(4-n-Butoxyanilino)-4,4',4'',4'''-tetraphenyl[2,2':5',5'':2'',2''']quaterthiazole 185 was

obtained as yellow-orange microcrystals, mp 179-180 °C (from n-hexane/Et2O at

ca. -20 °C. MALDI-TOF MS analysis gave a parent ion with m/z 802 (MH+, 53%), without

a bromine isotope pattern, which in combination with elemental analysis tentatively

supported the molecular formula C46H35N5OS4. 1H NMR spectroscopy revealed the

presence of multiple aromatic CH resonances, many of which were overlapping,

integrating in total for 25 H, one D2O exchangeable resonance integrating for 1 H, and four

alkyl, three CH2 and one CH3, resonances. Two of the resolved aromatic resonances,

integrating for 2 H each, were characteristic for a para-disubstituted benzene, and were

considerably upfield in comparison with the other aromatic resonances, supporting the

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presence of one 4-n-butoxyanilino substituent. One singlet aromatic resonance at 7.62 ppm

which overlapped with the other aromatic resonances tentatively supported the presence of

one free bithiazole C5 position. The remaining aromatic resonances integrating for 20 H

tentatively supported the presence of two 4,4'-diphenyl-2,2'-bithiazole moieties. The D2O

exchangeable resonance [δH 6.01 (1H, br s) ppm] indicated the presence of an NH group,

which was further supported by IR spectroscopy [ν(N-H) 3344 cm-1]. 13C NMR data

revealed the presence of seventeen C (s), at least twelve C (d), three C (t) and one C (q)

resonances further supporting the presence of two unsymmetrical 4,4'-diphenyl-2,2'-

bithiazole moieties. Based on these data the compound was tentatively assigned as

5-(4-n-butoxyanilino)-4,4',4'',4'''-tetraphenyl[2,2':5',5'':2'',2''']quarterthiazole 185.

5,5'''-Bis(4-n-butoxyanilino)-4,4',4'',4'''-tetraphenyl[2,2':5',5'':2'',2''']quaterthiazole 186 was

obtained as orange microcrystals, mp 205-210 °C (from n-hexane/Et2O at ca. -20 °C.

MALDI-TOF MS analysis gave a parent ion with m/z 966 (MH++1, 60%), without a

bromine isotope pattern, which was twice the MW of 5-(4-n-butoxyanilino)-4,4'-diphenyl-

2,2'-bithiazole 184 tentatively indicating a dimer of 5-(4-n-butoxyanilino)-4,4'-diphenyl-

2,2'-bithiazole 184. In combination with elemental analysis the data tentatively supported

the molecular formula C46H35N5OS4. UV/vis spectroscopy gave a λmax(DCM) at 449 nm

(log ε 4.78) indicating the presence of extensive conjugation. 1H NMR spectroscopy

revealed the presence of eight aromatic CH resonances (two of which overlapped), one

D2O exchangeable resonance, and four alkyl, three CH2 and one CH3, resonances. The

bithiazole C5 H signal was absent indicating that substitution occurred at this position. The

1H NMR resonances in combination with the mass spectrum further supported a

symmetrical C5 dimer of 5-(4-n-butoxyanilino)-4,4'-diphenyl-2,2'-bithiazole 184. 13C

NMR data revealed the presence of ten C (s), seven C (d), three C (t) and one C (q)

resonances, further supporting a symmetrical molecule. The 1H D2O exchangeable

resonance [δH 5.99 (2H, br s) ppm] indicated the presence of NH group which was further

supported by IR spectroscopy [ν(N-H) 3379 cm-1]. Based on these data the compound was

tentatively assigned as 5,5'''-bis(4-n-butoxyanilino)-4,4',4'',4'''-tetraphenyl[2,2':5',5'':2'',2''']-

quaterthiazole 186.

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Anilines

The optimized reaction conditions (Section 6.2.2) were applied to a series of 5,5'-dibromo-

2,2'-bithiazoles 180 with various anilines as coupling partners. The reaction worked well

with both electron donating and withdrawing groups (EDG and EWG, respectively) on

either the arylamine (Table 21, entries 2-5 & 6-11, respectively) or the 4,4'-diaryl rings of

the 2,2'-bithiazole (Table 21, entries 13-17 & 18-23, respectively).

Table 21. C-N coupling of 5,5'-dibromo-4,4'-disubstituted-2,2'-bithiazoles 180 (0.1 mmol) with anilinesa

entry bithiazole (R) Ar time T1

(h) time T2

(min) yield 182

(%)

1 180a (Ph) Ph 25 25 182a (83) 2 180a (Ph) 4-n-BuC6H4 19 20 182b (75) 3 180a (Ph) 4-MeOC6H4 22 28 182c (85) 4 180a (Ph) 4-n-BuOC6H4 16 10 182d (86) 5 180a (Ph) 4-Et2NC6H4 24 10 182e (68) 6 180a (Ph) 4-F3CC6H4 24 20 182f (87) 7 180a (Ph) 4-NCC6H4 22 10 182g (92) 8 180a (Ph) 4-O2NC6H4 16 10 182h (-)b 9 180a (Ph) pyrid-2-yl 36 - 182i (ir)c 10 180a (Ph) pyrid-3-yl 21 20 182j (57)c 11 180a (Ph) pyrid-4-yl 21 15 182k (35)c 12 180a (Ph) carbazol-3-ylg 17.5 30 182l (91) 13 180b (4-t-BuC6H4) 4-n-BuOC6H4 18 10 182m (66) 14 180b (4-t-BuC6H4) 4-O2NC6H4 14 11 182n (83) 15 180b (4-t-BuC6H4) pyrid-2-yl 21 10 182o (28)b 16 180c (4-MeOC6H5) Ph 21 10 182p (76) 17 180c (4-MeOC6H5) 4-n-BuOC6H4 16 10 182q (55) 18 180d (4-FC6H4) 4-n-BuOC6H4 16 20 182r (76) 19 180e (4-F3CC6H4) Ph 16 25 182s (87) 20 180e (4-F3CC6H4) 4-n-BuOC6H4 19 20 182t (84) 21 180e (4-F3CC6H4) 4-Et2NC6H4 17 10 182u (78) 22 180f (4-O2NC6H4) 4-n-BuOC6H4 16 10 182v (74)d 23 180f (4-O2NC6H4) 4-Et2NC6H4 16 15 182w (69)d 24 180g (pyrid-2-yl) 4-n-BuOC6H4 12 - 182x (nr)e 25 180h (2'-n-hexylthien-2-yl) 4-n-BuOC6H4 20 10 182y (65) 26 180i (H) 4-n-BuOC6H4 72 - 182z (-)f 27 180j (Me) 4-n-BuOC6H4 72 - 182aa (-)f

a Reaction conditions: (i) ArNH2 (2 equiv), Superstable Pd(0)® (1.25 mol %), DPEPhos

(5 mol %), K2CO3 (2.4 equiv), 1,4-dioxane (2.5 mL), argon, ca. 101 °C, T1 h; (ii) Ag2O

(1.2 equiv), ca. 101 °C, T2 min. b Very insoluble product. c Incomplete reaction. d Minor side

products (187 and 188) also obtained (see Figure 36). e No reaction. f Mainly unreacted starting

material and brown baseline material. g N-(2-Ethylhexyl)

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Worthy of note was that the reaction of 4,4'-dibromo-5,5'-diphenyl-2,2'-bithiazole 180a

with 4-nitroaniline (Table 21, entry 8), led to an insoluble product 182h making its

isolation and characterization difficult. As such, 4-nitroaniline was reacted with

5,5'-dibromo-4,4'-bis(4-tert-butylphenyl)-2,2'-bithiazole 180b which gave a more soluble

product 182n (Table 21, entry 14).

The reaction of 4-n-butoxyaniline with 4,4'-dibromo-5,5'-di(pyrid-2-yl)-2,2'-bithiazole

180g (Table 21, entry 24) led to no product formation. This is not surprising, since

pyridines can coordinate to palladium175 and poison the catalytic cycle.176 The reaction of

2-, 3- and 4-pyridinamines with 4,4'-dibromo-5,5'-diphenyl-2,2'-bithiazole 180a proceeded

slowly (Table 21, entries 9-11) and could not be pushed to completion. In the reaction of

2-aminopyridine (Table 21, entry 9) all attempts to isolate a pure sample of the desired

product failed: After work-up and recrystallization, a mixture was obtained of the desired

product and an unidentified side product in about equimolar quantities (as judged by 1H

NMR). Repeating the reaction with 5,5'-dibromo-4,4'-bis[4-(tert-butyl)phenyl]-2,2'-

bithiazole 180b as coupling partner, gave a more soluble product which could be purified

by column chromatography, although, also in this case the reaction did not reach

completion. The reactions with 3- and 4-pyridinamines (Table 21, entries 10 & 11) worked

better since only significant quantities of the mono-aminated intermediate (akin 183) (by

TLC) remained unreacted and pure samples of the products were isolated (with work-up

procedure B, see Section 7.6.4). When 5,5'-dibromo-4,4'-bis(4-nitrophenyl)-2,2'-bithiazole

180f reacted with either 4-n-butoxyaniline or N,N-diethyl-p-phenylenediamine the minor

side products 187 and 188 were also observed that came from reduction of one of the nitro

groups (Figure 36).

.

Figure 36. Side products from the C-N coupling of 5,5'-dibromo-4,4'-bis(4-nitrophenyl)-2,2'-

bithiazole 180f with arylamines

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Electron rich hetarenes were well tolerated: The reaction of 4-n-butoxyaniline with

5,5'-dibromo-4,4'-bis(5-n-hexylthien-2-yl)-2,2'-bithiazole 180h gave the desired product

182y in 65% yield (Table 21, entry 25), while the reaction of 3-amino-9-(2-ethylhexyl)-

9H-carbazole with 5,5'-dibromo-4,4'-phenyl-2,2'-bithiazole 180a gave the desired product

182l in a high (91%) yield (Table 21, entry 12). Both thienyl and carbazole moieties are

frequently used as components in organic electronics owing their ease of structural

modification, optical properties, electrochemical behavior and environmental stability.177

Disappointingly, the reactions of 4-n-butoxyaniline with the 4,4'-unsubstituted and

4,4'-dimethylsubstituted 5,5'-dibromo-2,2'-bithiazoles, 180i (Table 21, entry 26) and 180j

(Table 21, entry 27), respectively, gave after 72 h predominately unreacted starting

material and intractable brown baseline material (by TLC). Identifying reaction conditions

to enable these reactions will broaden the scope of this route and remains under

investigation.

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6.5 Stereoisomers of Quinoidal 2,2'-Bithiazole 182a: A Computational Study

The geometry of the 5,5'-diarylimino quinoidal 2,2'-bithiazoles 182 is defined by: (a) The

geometry of the central double bond linking the two thiazole units [S-trans (2E) or S-cis

(2Z) isomer] and (b) the geometry of the 5-arylimine moieties (5Z,5'Z, 5E,5'Z or 5E,5'E).

The X-ray structure of the quinoidal 2,2'-bithiazole 178 revealed the compound to have a

2E,5Z,5'Z geometry.154 We questioned whether this geometry also applied to the analogues

synthesized herein. Significant steric crowding between the phenyl group of the

5-arylimine moieties and the C4 phenyl groups in the 5E,5'E-isomers led to compounds of

much higher energy e.g., isomer 2E,5E,5'E- 182a''' was less stable than the 5Z,5'Z isomer

182a'' by 81.6 kJ/mol. As such, the geometry optimization study focused on the least

sterically crowded 5Z,5'Z isomers 182a' and 182a'' which showed that the 2E,5Z,5'Z-

isomer 182a'' (S-trans) was 16.9 kJ/mol more stable than the 2Z,5Z,5'Z-isomer 182a'

(S-cis) (Figure 37). Interestingly, reports on fully aromatic and quinoidal 2,2'-bithiophenes

also suggest a preference for the S-trans isomer which is in most cases energetically more

stable than the S-cis.172b,178

Figure 37. Structures of geometric isomers 182a', 182a'' and 182a'''

Based on the above computational study we tentatively assumed all the quinoidal

bithiazoles reported herein adopt a 2E,5Z,5'Z-geometry, as seen with the X-ray structure of

compound 178.154

6.6 Experimental UV/vis Absorption of Quinoidal 2,2'-Bithiazoles 182

Examination of the HOMO and LUMO frontier molecular orbitals of compound 182a

(Figure 38) revealed delocalization of the electron density across the whole molecule (for a

more detailed discussion see Section 6.7). As such, modifications at both the 5,5'-diaryl-

imino and the 4,4'-diaryl groups could potentially strongly influence the absorption profile

of these molecules.

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HOMO (-5.28 eV) LUMO (-3.20 eV)

Figure 38. Frontier molecular orbital (HOMO and LUMO) representations of compound 182a

Indeed, from the experimental UV/vis spectra we observed that the peripheral substitution

influenced significantly the longest wavelength absorption maxima (Figure 39).

Figure 39. UV/vis absorption of quinoidal 2,2’-bithiazoles 182

Arbitrarily taking compound 182a as a reference point, we observed that addition of EDGs

at either the 5,5'-diarylimino or the 4,4'-diaryl moieties led to red shifts of the longest

wavelength (lowest energy) absorption maxima (λmax). The red shifts of the λmax were more

pronounced when the EDG was attached at the 5,5'-diarylimino rather than the 4,4'-diaryl

moieties: e.g., when a MeO substituent (Table 22, entry 3) was attached at the para

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position of the 5,5'-diarylimino groups a 38 nm red shift was observed, but only a 15 nm

red shift was observed when it was attached at the para position of the 4,4'-diaryl groups

(Table 22, entry 16). In contrast, the effect of EWGs was less significant and the direction

of the shift was opposite on each side e.g., introducing a F3C group at the 5,5'-diarylimino

moieties led to a 6 nm blue shift (Table 22, entry 6), but a 13 nm red shift was observed

when a F3C group was attached at the 4,4'-diaryl groups (Table 22, entry 21).

The λmax shifts were broadly proportional to the electron releasing and withdrawing

abilities of the substituents as determined by their Hammett values (σpara); e.g., for EDGs

on the 5,5'-diarylimino groups the red shifts were in the order 4-n-Bu (14 nm) < 4-MeO

(38 nm) < 4-n-BuO (45 nm) < 4-Et2N (200 nm) in line with their increasing (absolute)

Hammett values (σpara) which are -0.16, -0.28, -0.32 and -0.53, respectively.179

Interestingly, when strongly EDGs (Et2N-) were introduced at the 5,5'-diarylimino groups

and strongly EWGs (F3C- or O2N-) at the 4,4'-diaryl groups the λmax was further shifted to

lower energies in the NIR region (Table 22, compounds 182u and 182w with 242 and 302

nm red shifts, respectively).

6.7 TD-DFT Computational Studies on Quinoidal 2,2'-Bithiazoles 182

To obtain more information regarding the influence of substituents, the structures were

optimized at the DFT RB3LYP/6-31G(d,p) level of theory and computational optical band

gaps were obtained from TD-DFT calculations at the same level of theory.

The TD-DFT data of all the studied compounds indicated that the longest wavelength

absorptions corresponded to the excitation from HOMO to LUMO; representative

transitions for compound 182a and molecular orbitals associated with them are shown in

Table 23 & Figure 40, respectively.

In general, the TD-DFT computationally determined band gaps were in good agreement

with the experimentally obtained optical band gaps (error 0.04-0.27 eV) with a nearly

linear correlation (Figure 41). The bigger deviations (0.20-0.27 eV) were observed for

compounds 182e, 182u and 182w. Interestingly, examination of the HOMO and LUMO

orbitals of these compounds revealed a significant charge transfer (CT) character

associated with the first excitation. Based on this, the bigger errors observed in these

cases are not surprising since it is known that TD-DFT gives substantial errors on the

excitation energies of CT excited states.180

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Table 23. Singlet excited states for 182a from TD-DFT data at the RB3LYP/6-31G(d,p) level of theory

excited state transition energy (eV) λ (nm) osc. strength

S1 HOMO → LUMO (66%) 2.0835 595 0.9774

S2 HOMO-1 → LUMO (89%)

HOMO-9 → LUMO (3%) HOMO-9 → LUMO (3%)

2.5719 482 0.0001

S3 HOMO-2 → LUMO (79%) 2.8031 442 0.3225

S4 HOMO-3 → LUMO (82%)

HOMO-2 → LUMO (6%) HOMO-6 → LUMO (3%)

3.0520 406 0.1504

S5

HOMO-4 → LUMO (82%) HOMO-9 → LUMO (6%) HOMO → LUMO+1 (2%) HOMO → LUMO+1 (2%)

3.1252 397 0.0003

S6 HOMO-5 → LUMO (84%) HOMO → LUMO+1 (12%)

3.1971 388 0.0003

Figure 40. Molecular orbitals associated with the major transitions of compound 182a

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Figure 41. Graph showing the correlation of the calculated optical band gaps Eg,TD-DFT with the

experimentally obtained optical band gaps Eg,opt; dashed line shows the ideal situation where

Eg,TD-DFT = Eg,opt

From the analysis of the computed HOMO and LUMO energy levels the following

were observed:

a) When EDGs are introduced at the 5,5'-diarylimino groups (Table 22, entries 2-5), the

energies of the HOMO and the LUMO become less negative, but the change of the

HOMO energy was greater than that of the LUMO (almost 50% more), which led to an

overall lowering of the HOMO-LUMO gap (ΔEHOMO-LUMO).

b) When EDGs are introduced at the 4,4'-diaryl groups (Table 22, entries 16 & 19),

again, the energies of the HOMO and the LUMO become less negative, but the change

in energy of the HOMO is only marginally more than that for LUMO. Consequently,

ΔEHOMO-LUMO is lowered but to a lesser extent than when EDGs are introduced at the

5,5'-diarylimino moieties.

c) As expected, the introduction of EWGs at the 5,5'-diarylimino groups lowers the HOMO

and LUMO energy levels (Table 22, entries 6-11), but the relative lowering of their

energies is similar with only very subtle differences i.e. the HOMO level lowers by only

~0.02 eV more than the LUMO, which leads to a very small increase of the ΔEHOMO-LUMO.

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d) When EWGs are introduced to the 4,4'-diaryl groups (Table 22, entries 21, 24 & 25) the

effect was reversed i.e. the LUMO level decreases slightly more than the HOMO level, and

relatively more than the decrease of the HOMO in the case of the 5,5'-diarylimino groups,

which leads to a decrease of the ΔEHOMO-LUMO.

e) When both EDG and EWGs are attached, the effects appear to be additive (Table 22,

e.g., entries 20, 22, 23, 26 & 27).

Apart from these general trends some anomalies were also observed. In the case of pyrid-

2-ylamino substituent (Table 22, entries 9 & 15), which was expected to act as an EWG

similar to the 3- and 4-pyridyls (Table 22, entries 10 & 11), appeared to act as a very mild

EDG (see also Figure 45). Examination of the DFT optimized structure of bithiazole 182i

revealed the presence of an N…S non-bonding interaction: The molecule adopts a planar

conformation with the distance N'2···S1 (d(N'2…S1) 2.736 Å) being smaller than the sum of

the van der Waals’ radii of N and S (3.35 Å) and the atoms N'2…S1-C2 nearly in line

(angle of 160°).

N…S non-bonding interactions148 originate from electron donation of the lone pair of the

nitrogen (nN orbital) to the anti-bonding orbital of an S-X bond (σ*

S-X orbital) (see also

Chapter 5, Section 5.5), in this case the S1-C2 bond (Figure 42). This interaction

contributes to electron release towards the thiazole core which counterbalances the electron

accepting ability of the pyrid-2-yl ring.

Figure 42. The N…S non-bonding interaction in the pyrid-2-yl analogue 182i

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HOMO and LUMO molecular orbitals representations. Additional information was

obtained from the representations of the frontier molecular orbitals HOMO and LUMO,

which are the major contributors for the transition to the first excited state. In general, both

the HOMO and the LUMO molecular orbitals are delocalized across the whole molecule,

with larger molecular coefficients on the 2,2'-bithiazole core and smaller on the peripheral

aryl groups. The major difference between the HOMO and LUMO, is that the HOMO has

zero orbital density at the C5/C5' positions of the bithiazole while the LUMO has zero

orbital density at the sulfur atoms S1/S1'. The latter observation was apparent across all the

compounds studied, irrespective of substitution on the peripheral aryl groups. Nevertheless,

the electron distribution of the HOMO and LUMO molecular orbitals was susceptible to

the electron donating or electron withdrawing ability of the attached substituents. When

strong EDGs were attached either at the 4,4'-diaryl or 5,5'-diarylimino moieties the HOMO

remained localized on the moiety that hosted the EDG, leaving the other moiety with very

little orbital density. This effect was more intense when the attachment was on the

5,5'-diarylimino moiety (Figure 43 vs 46). When EWGs were attached either at the

4,4'-diaryl or 5,5'-diarylimino moieties, the orbital density remained localized on the other

opposing moiety leaving the moiety hosting the EWG with very little orbital density

(Figures 44, 45 & 46). In this case, the effect was much more intense when the EWG was

attached at the 4,4'-diaryl moiety, which was the opposite to that observed for the EDGs.

The effect was additive and when the strong EDG Et2N- was attached at the

5,5'-diarylimino moieties and the strong EWG O2N- at the 4,4'-diaryl moieties this led to

the complete localization of the HOMO orbital on the bithiazole core and diarylimino

moieties (~zero orbital density on the 4,4'-diaryl moieties), while the LUMO was mainly

delocalized on the opposite moiety (decreased electron density on the 5,5'-diarylimino

moieties) (Figure 47). This was reminiscent to the spatial separation of HOMO and LUMO

molecular orbitals which is frequently observed in related cruciforms.181

The difference on the extent of localization of the HOMO orbital depending on whether the

substituents were attached to the 5,5'-diarylimino or the 4,4'-diaryl moieties was analogous

to the extent of bathochromic or ipsochromic shift discussed above. As such, the two are

closely correlated, but, the reason why EDGs affect greater when attached at the

5,5'-diarylimino moieties and EWGs affect greater when attached at the 4,4'-diaryl

moieties, remains unclear.

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Nevertheless, it was also apparent that in the case of the compounds 182e, 182u and 182w,

the transition to the first excited state was accompanied by a significant CT: The HOMO

and the LUMO localized predominately on the 5,5'-diarylimino and 4,4'-diaryl moieties,

respectively. Compounds with CT transitions possess very small band gaps,182,183 and in

fact, compounds 182e, 182u and 182w, have the smallest optical band gaps, 1.48, 1.38 and

1.27 eV, respectively, in the series of the quinoidal bithiazoles 182 synthesized herein.

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Figure 44. HOMO (below) and LUMO (above) molecular orbital representations for compounds

182g-h showing the effect of EWGs attached on the 5,5'-diarylimino moieties. As can be seen no

dramatic changes are observed on the electronic distribution by increasing the electron accepting

abilities of the EWG at these positions (with dashed green line are the energy levels of 182a)

Figure 45. HOMO (below) and LUMO (above) molecular orbital representations for compounds

182i-k showing the effect of pyridyl substituents at the 5,5'-diarylimino moiety. As can be seen no

dramatic changes are observed on the electronic distribution. For 182i is apparent the slight

increase on the HOMO energy level relative to 182a due to the electron donation originating from

the N···S interaction (with dashed green line are the energy levels of 182a)

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6.8 Cyclic Voltammetry of Quinoidal 2,2'-Bithiazoles 182

In general, the quinoidal 2,2'-bithiazoles 182 displayed amphoteric redox behavior. Many

showed two reversible or quasi-reversible oxidation waves, with onset values for the first

oxidation in a range of 0.47 to 1.46 V (vs SCE), and two reversible reduction waves, with

onset values for the first reduction in a range of -0.29 to -0.68 V (vs SCE) (Table 24).

Compared to Yamashita’s quinoidal bithiazole 179a (E1/2red1 0.34 V and E1/2

red2 0.01 eV vs

SCE; Table 25, entry 1),170 compounds 182 are weaker electron acceptors, which was

expected since the former possess a dicyanomethylidene moiety, a strong electron

accepting group. Nevertheless, their electron accepting ability is comparable to

dithiaquaterphenoquinone 193 (-0.43 V vs SCE; Table 25, entry 2) (Figure 48), which was

studied by Takahashi et al.,184 and preliminary studies on this and similar compounds

showed a potential for application in a wide range of material’s applications. Yamashita’s

bithiazole 179a displayed no oxidations in the electrochemical window studied, but the

dihiaquaterphenoquinone 193 displayed an oxidation at 0.91 V which lies in the range

observed for the quinoidal bithiazoles 182.

Table 25. Electrochemical data vs SCE for representative literature compounds for comparison with quinoidal bithiazoles 182

entry compound Epaox1 Epa

ox2 Epcred1 E1/2

red1 E1/2red2

1 179a170 - - - 0.34 0.01 2 193184 0.91 1.4 -0.43 - -

Figure 48. Structure of dihiaquaterphenoquinone 193

For compounds 182c, 182d, 182m, 182q, 182r, and 182t, which have in common the

presence of alkoxy substituents, a small cathodic peak was observed after the reversed

cathodic wave of the first oxidation. Compounds 182e, 182u and 182w, which have in

common the strong EDG Et2N group, displayed a very strong cathodic peak in positive

potentials. Compound 182v gave a rather complex CV (see Appendix II). At this point of

time we cannot explain these results and this will be the subject of further studies.

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From the electrochemical data the EHOMO, ELUMO and Eg,EChem energies185 (Table 26) where

calculated via two methods: In the first method the EHOMO and ELUMO energies were

calculated based on the onset potential of the first oxidation (Eonsetox1) and the onset

potential of the first reduction (Eonsetred1), respectively, while in the second method, the

anodic peak max for the first oxidation Epaox1 and the cathodic peak max for the first

reduction Epcred1, respectively, were used. The use of the onset potentials is the preferred

and most widely used method for the determination of the frontier orbitals energy levels

and consequently for the determination of the electrochemical band gap Eg,EChem.185 In our

case, a better agreement with the optical band gaps was observed when the peak maxima

were used (Figures 49 & 50). Nevertheless, a direct comparison of the electrochemical and

optical band gaps is not always feasible owing to the fundamental differences of the

processes involved.186 Usually, the band gaps obtained from the electrochemically data are

larger than the optical band gaps. Interestingly this was not observed in our case, with the

Eg,EChem energies obtained from the onset potentials been smaller than the optical band gaps.

Figure 49. Graph showing the correlation of the electrochemically obtained band gaps from the

onsets of the first oxidation and reduction, Eg,EChemonset, with the experimentally obtained optical

band gaps Eg,opt; dashed line shows the ideal situation where Eg,EChemonset = Eg,opt

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Figure 50. Graph showing the correlation of the electrochemically obtained band gaps from the

peak maxima of the first oxidation and reduction, Eg,EChempa,pc, with the experimentally obtained

optical band gaps Eg,opt; dashed line shows the ideal situation where Eg,EChempa,pc = Eg,opt

Interestingly, the electrochemically determined EHOMO and ELUMO values were very close

to those obtained for the recently reported quinoidal 2,2'-bithiophene 194 (Figure 51;

EHOMO = -5.25 eV and ELUMO = -3.76 eV) that displayed ambipolar behavior in OFET

devices.172b

Figure 51. Structure of recently reported quinoidal 2,2'-bithiophene 194172b

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6.9 Conclusions

In conclusion, 22 new cross-conjugated quinoidal 5,5'-diarylimino 2,2'-bithiazoles were

prepared via a double Pd(0)-catalyzed C-N coupling protocol and subsequent in situ

oxidation in moderate to high yields. By manipulating the peripheral substituents, the

HOMO & LUMO energy levels can be altered and the optical band gap can be tuned up to

the NIR region. Electrochemical studies revealed that quinoidal 2,2'-bithiazoles 182

display amphoteric redox behavior in contrast to 2,2'-bithiazole 179a which showed only

reductions in the electrochemical window studied.

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CHAPTER 7

Experimental Section

Contents

7.1 General Procedures and Methods 128






7.7 X-ray Crystallographic Studies 221

7.8 Computational Studies Methods 225

7.9 Cyclic Voltammetry Studies Methods 225

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7.1 General Procedures and Methods

All chemicals were commercially available except those whose synthesis is described.

Where dry solvents used were freshly distilled from CaH2 under argon. Dry THF and dry

1,4-dioxane were further dried by refluxing over potassium and then distilled. K2CO3 was

powdered and dried in vacuo at ca. 400 °C. Reactions were protected from atmospheric

moisture by CaCl2 drying tubes. Anhydrous Na2SO4 was used for drying organic extracts,

and all volatiles were removed under reduced pressure. All reaction mixtures and column

eluents were monitored by TLC using commercial aluminum backed thin layer

chromatography (TLC) plates (Merck Kieselgel 60 F254). The plates were observed under

UV light at 254 and 365 nm. The technique of dry flash chromatography was used

throughout for all non-TLC scale chromatographic separations using Merck Silica Gel 60

(less than 0.063 mm).187 Melting points were determined using a PolyTherm-A, Wagner &

Munz, Koefler-Hotstage Microscope apparatus or via a TA Instruments DSC Q1000 with

samples hermetically sealed in aluminum pans under an argon atmosphere, using heating

rates of 5 °C/min (DSC mp and decomp. points listed by onset and peak max values).

Solvents used for recrystallization are indicated after the melting point. UV/vis spectra

were obtained using a Perkin-Elmer Lambda-25 or a Shimadzu UV-1601 UV/vis

spectrophotometer and inflections are identified by the abbreviation “inf”. IR spectra were

recorded on a Shimadzu FTIR-NIR Prestige-21 spectrometer with a Pike Miracle Ge ATR

accessory and strong, medium and weak peaks are represented by s, m and w respectively.

1H and 13C NMR spectra were recorded on a Bruker Avance 500 machine (at 500 and 125

MHz, respectively). Deuterated solvents were used for homonuclear lock and the signals

are referenced to the deuterated solvent peaks. DEPT or APT NMR studies were used to

identify quaternary, tertiary, secondary and primary carbons, which are indicated by (s), (d),

(t) and (q) notations, respectively. Low resolution (EI) mass spectra were recorded on a

Shimadzu Q2010 GCMS with direct inlet probe or on an Agilent 6890/5973N GCMS.

MALDI-TOF MS were conducted on a Bruker Autoflex III time-of-flight (TOF) mass

spectrometer. 4,5-Dichloro-1,2,3-dithiazolium chloride 1,30 (Z)-2-chloro-N-(4-chloro-5H-

1,2,3-dithiazol-5-ylidene)pyridin-3-amine 61a,83 (Z)-4-chloro-N-(4-chloro-5H-1,2,3-dithi-

azol-5-ylidene)pyridin-3-amine 61b,83 1,3-dimethyl-1H-pyrazol-5-amine 67a,188 3-methyl-

1H-pyrazol-5-amine 67b,189 3-phenyl-1H-pyrazol-5-amine 67c,190 1-methyl-3-phenyl-1H-

pyrazol-5-amine 67d,190 1-benzyl-3-methyl-1H-pyrazol-5-amine 67e,191 1-benzyl-3-

phenyl-1H-pyrazol-5-amine 67f,192 1-(tert-butyl)-3-methyl-1H-pyrazol-5-amine 67g,193

1-(tert-butyl)-3-phenyl-1H-pyrazol-5-amine 67h,194 3-methyl-1-phenyl-1H-pyrazol-5-

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amine 67i,195 1,3-diphenyl-1H-pyrazol-5-amine 67j,190 (Z)-N-(4-chloro-5H-1,2,3-dithiazol-

5-ylidene)aniline 95a,196 (Z)-N-(4-chloro-5H-1,2,3-dithiazol-5-ylidene)-3-methoxyaniline

95b,196 (Z)-5-[(4-chloro-5H-1,2,3-dithiazol-5-ylidene)amino]-2-methoxyphenol 95d,49

N-(4-chloro-5H-1,2,3-dithiazol-5-ylidene)-2-methylaniline 122,196 N-(4-chloro-5H-1,2,3-

dithiazol-5-ylidene)-2-methoxyaniline 123,46c 2-chloro-N-(4-chloro-5H-1,2,3-dithiazol-5-

ylidene)aniline 124,30 2-bromo-N-(4-chloro-5H-1,2,3-dithiazol-5-ylidene)aniline 125,96

N-(4-chloro-5H-1,2,3-dithiazol-5-ylidene)-2-nitroaniline 126,96 N-(4-chloro-5H-1,2,3-

dithiazol-5-ylidene)-3-methoxyaniline 128,96 3-bromo-N-(4-chloro-5H-1,2,3-dithiazol-5-

ylidene)aniline 129,196 N-(4-chloro-5H-1,2,3-dithiazol-5-ylidene)-4-methylaniline 130,196

N-(4-chloro-5H-1,2,3-dithiazol-5-ylidene)-4-methoxyaniline 131,30 4-bromo-N-(4-chloro-

5H-1,2,3-dithiazol-5-ylidene)aniline 132,65a N-(4-chloro-5H-1,2,3-dithiazol-5-ylidene)-4-

nitroaniline 133,30 N-(4-chloro-5H-1,2,3-dithiazol-5-ylidene)-4-cyanoaniline 134,127a

N-(4-chloro-5H-1,2,3-dithiazol-5-ylidene)naphth-1-ylamine 135,46c N-(4-chloro-5H-1,2,3-

dithiazol-5-ylidene)naphth-2-ylamine 136,196 N-(4-chloro-5H-1,2,3-dithiazol-5-ylidene)-

pyrid-2-ylamine 137,96 N-(4-chloro-5H-1,2,3-dithiazol-5-ylidene)pyrid-3-ylamine 138,83

N-(4-chloro-5H-1,2,3-dithiazol-5-ylidene)pyrazin-2-ylamine 139,83 N-(4-chloro-5H-1,2,3-

dithiazol-5-ylidene)thiazol-2-ylamine 140,47d 4-chloro-5H-1,2,3-dithiazol-5-one 2c,197

4-chloro-5H-1,2,3-dithiazole-5-thione 2d,30 2-(4-chloro-5H-1,2,3-dithiazol-5-ylidene)-

malononitrile 141,198 2-(4-chloro-5H-1,2,3-dithiazol-5-ylidene)malonate 142,56b N-(2-chlo-

roethyl)piperazine dihydrochloride 168a·2HCl,199 N-(2-cyanoethyl)piperazine 168b,200

TCNEO,201 diazomalonate,202 diphenyldiazomethane,203 4,4'-diphenyl-2,2'-bithiazole,204

4,4'-bis(4-methoxyphenyl)-2,2'-bithiazole,205 4,4'-bis(4-nitrophenyl)-2,2'-bithiazole,206

4,4'-bis(5-hexylthien-2-yl)-2,2'-bithiazole,207 5,5'-dibromo-4,4'-bis(5-hexylthien-2-yl)-2,2'-

bithiazole,207 5,5'-dibromo-2,2'-bithiazole,170 5,5'-dibromo-4,4'-dimethyl-2,2'-bithiazole208

and 9-(2-ethylhexyl)-9H-carbazol-3-amine209 were prepared according to literature

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7.2 Compounds Related to Chapter 2

7.2.1 Synthesis of [(4-Chloro-5H-1,2,3-dithiazol-5-ylidene)amino]azines 62

7.2.1.1 (Z)-2-Chloro-N-(4-chloro-5H-1,2,3-dithiazol-5-ylidene)-4-methylpyridin-3-

amine 62a (Typical Procedure)

To a stirred suspension of 4,5-dichloro-1,2,3-dithiazolium chloride 1 (100 mg, 0.48 mmol)

in DCM (4 mL) at ca. 20 °C and protected with CaCl2 drying tube, was added 2-chloro-4-

methylpyridin-3-amine (68.4 mg, 0.48 mmol). The reaction mixture was left to stir at

ca. 20 °C for 1 h and then to this was added 2,6-lutidine (112 μL, 0.96 mmol) and the

mixture was stirred at ca. 20 °C for an additional 2 h. The reaction mixture was then

adsorbed onto silica and chromatographed to afford the title compound 62a (80.1 mg,

60%), as yellow needles, mp (DSC) onset: 156.2 oC peak max: 158.6 oC (from c-hexane);

Rf 0.58 (DCM); (found: C, 34.39; H, 1.80; N, 15.02. C8H5Cl2N3S2 requires: C, 34.54;

H, 1.81; N, 15.11%); λmax(DCM)/nm 234 (log ε 3.05), 278 (2.70), 352 (2.90); vmax/cm-1

3057w (aryl C-H), 2974w and 2918w (alkyl C-H), 1599s, 1574m, 1555m, 1514m, 1454w,

1437w, 1364s, 1281w, 1261w, 1240w, 1211s, 1182m, 1150m, 1088w, 1030w, 1007w,

883s, 858s, 814s, 779s; δH(500 MHz; CDCl3) 8.13 (1H, d, J 5.0), 7.16 (1H, dd, J 5.0, 0.5),

2.21 (3H, s); δC(125 MHz; CDCl3) 163.3 (s), 146.6 (s), 145.6 (d), 144.5 (s), 140.1 (s),

139.2 (s), 125.1 (d), 17.5 (q); MALDI-TOF MS (m/z): 282 (MH++4, 10%), 280 (MH++2,

70), 278 (MH+, 100).

7.2.1.2 (Z)-2-Chloro-N-(4-chloro-5H-1,2,3-dithiazol-5-ylidene)-5-methylpyridin-3-

amine 62b

Similar treatment of 2-chloro-5-methylpyridin-3-amine (68.4 mg, 0.48 mmol) with

4,5-dichloro-1,2,3-dithiazolium chloride 1 (100 mg, 0.48 mmol) and 2,6-lutidine (112 μL,

0.96 mmol) gave the title compound 62b (109.5 mg, 82%), as yellow needles, mp

130-131 °C (from c-hexane); Rf 0.42 (n-hexane/DCM, 30:70); (found: C, 34.71; H, 1.81;

N, 14.98. C8H5Cl2N3S2 requires: C, 34.54; H, 1.81; N, 15.11%); λmax(DCM)/nm 232 (log ε

3.50), 287 (3.10), 363 (3.25); vmax/cm-1 3042w (aryl C-H), 2922w (alkyl C-H), 1576s,

1545m, 1503m, 1493m, 1414m, 1393m, 1379m, 1290w 1250w, 1221w, 1204s, 1142m,

1082s, 1038w, 976w, 907w, 864s, 854m, 800m, 750s; δH(500 MHz; acetone-d6) 8.10 (1H,

dd, J 2.0, 0.5), 7.48 (1H, dd, J 2.0, 1.0), 2.36 (3H, s); δC(125 MHz; CDCl3) 162.6 (s), 147.4

(s), 146.8 (d), 144.5 (s), 139.4 (s), 133.8 (s), 127.8 (d), 17.8 (q); MALDI-TOF MS (m/z):

282 (MH++4, 7%), 280 (MH++2, 75), 278 (MH+, 100).

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7.2.1.3 (Z)-2,5-Dichloro-N-(4-chloro-5H-1,2,3-dithiazol-5-ylidene)pyridin-3-amine

62c

Similar treatment of 2,5-dichloropyridin-3-amine (78.2 mg, 0.48 mmol) with 4,5-dichloro-

1,2,3-dithiazolium chloride 1 (100 mg, 0.48 mmol) and 2,6-lutidine (112 μL, 0.96 mmol)

gave the title compound 62c (117.5 mg, 82%), as orange needles, mp 152.5-153 °C (from

c-hexane); Rf 0.70 (n-hexane/DCM, 30:70); (found: C, 28.05; H, 0.68; N, 14.00.

C7H2Cl3N3S2 requires: C, 28.16; H, 0.68; N, 14.07%); λmax(DCM)/nm 233 (log ε 3.11), 293

(2.72), 364 (2.88); vmax/cm-1 3080w, 3053w and 3040w (aryl C-H), 1574s, 1545m, 1535m,

1493s, 1402s, 1383m, 1263w, 1234w, 1217w, 1200m, 1161w, 1146m, 1126s, 1090m,

1080m, 930s, 897w, 866m, 856m, 795m; δH(500 MHz; CDCl3) 8.23 (1H, d, J 2.5), 7.46

(1H, d, J 2.5); δC(125 MHz; CDCl3) 163.6 (s), 147.4 (s), 145.3 (s), 144.8 (d), 140.5 (s),

131.3 (s), 127.1 (d); MALDI-TOF MS (m/z): 302 (MH++4, 24%), 300 (MH++2, 100), 298

(MH+, 71).

7.2.1.4 (Z)-5-Bromo-2-chloro-N-(4-chloro-5H-1,2,3-dithiazol-5-ylidene)pyridin-3-

amine 62d

Similar treatment of 5-bromo-2-chloropyridin-3-amine (99.6 mg, 0.48 mmol) with

4,5-dichloro-1,2,3-dithiazolium chloride (1) (100 mg, 0.48 mmol) and 2,6-lutidine (112 μL,

0.96 mmol) gave the title compound 62d (133.4 mg, 81%), as orange needles, mp (DSC)

onset: 172.6 °C, peak max: 173.9 °C (from c-hexane/DCE); Rf 0.70 (n-hexane/DCM,

30:70); (found; C, 24.36; H, 0.67; N, 12.18. C7H2BrCl2N3S2 requires: C, 24.51; H, 0.59;

N, 12.25%); λmax(DCM)/nm 231 (log ε 3.31), 294 (2.91), 361 (3.03); vmax/cm-1 3075w (aryl

C-H), 1570s, 1541m, 1530m, 1518m, 1491s, 1400s, 1375m, 1263w, 1233w, 1215w,

1198m, 1159w, 1142m, 1119m, 1082s, 905s, 868s, 854s, 791m; δH(500 MHz; DMSO-d6)

8.43 (1H, d, J 2.0), 8.08 (1H, d, J 2.5); δC(125 MHz; DMSO-d6) 165.1 (s), 146.3 (d), 145.9

(s), 145.8 (s), 140.2 (s), 130.4 (d), 119.4 (s); MALDI-TOF MS (m/z): 346 (MH++4, 44%).

344 (MH++2, 100), 342 (MH+, 54).

7.2.1.5 (Z)-2-Chloro-N-(4-chloro-5H-1,2,3-dithiazol-5-ylidene)-5-iodopyridin-3-

amine 62e

Similar treatment of 2-chloro-5-iodopyridin-3-amine (122.1 mg, 0.48 mmol) with


0.96 mmol) gave the title compound 62e (151.7 mg, 81%), as yellow needles, mp

177.1-179.1 °C (from c-hexane/DCE); Rf 0.70 (n-hexane/DCM, 30:70); (found: C, 21.63;

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H, 0.54; N, 10.84. C7H2Cl2IN3S2 requires: C, 21.55; H, 0.52; N, 10.77%); λmax(DCM)/nm

232 (log ε 3.34), 299 (2.82), 365 (2.98); vmax/cm-1 3069w (aryl C-H), 1564s, 1535w,

1520m, 1508m, 1487s, 1400s, 1375m, 1265w, 1229w, 1198m, 1142m, 1117m, 1076s,

889s, 868s, 851m, 789m; δH(500 MHz; DMSO-d6) 8.51 (1H, d, J 2.0), 8.14 (1H, d, J 2.0);

δC(125 MHz; DMSO-d6) 164.9 (s), 151.3 (d), 146.0 (s), 145.8 (s), 140.9 (s), 135.5 (d), 93.2

(s); MALDI-TOF MS (m/z): 394 (MH++4, 6%), 392 (MH++2, 65), 390 (MH+, 100).

7.2.1.6 (Z)-2-Chloro-N-(4-chloro-5H-1,2,3-dithiazol-5-ylidene)-6-methoxypyridin-3-

amine 62f

Similar treatment of 2-chloro-6-methoxypyridin-3-amine (76.1 mg, 0.48 mmol) with


0.96 mmol) gave the title compound 62f (127.1 mg, 90%), as orange plates, mp

139.6-140.8 °C (from c-hexane); Rf 0.75 (n-hexane/DCM, 30:70); (found: C, 32.70;

H, 1.62; N, 14.16. C8H5Cl2N3OS2 requires: C, 32.66; H, 1.71; N, 14.28%); λmax(DCM)/nm

244 (log ε 3.09), 295 (2.90), 381 (2.82), 420 inf (2.62); vmax/cm-1 2997w and 2959w (alkyl

C-H), 1582s, 1547w, 1470s, 1441w, 1416m, 1364s, 1308s, 1258m, 1171w, 1155w, 1132m,

1070m, 1018s, 903m, 858s, 826s, 770s; δH(500 MHz; CDCl3) 7.46 (1H, d, J 8.5), 6.77 (1H,

d, J 8.5), 3.97 (3H, s); δC(125 MHz; CDCl3) 161.2 (s), 161.1 (s), 147.7 (s), 139.8 (s), 137.8

(s), 130.4 (d), 110.3 (d), 54.4 (q); MALDI-TOF MS (m/z): 298 (MH++4, 8%), 296 (MH++2,

53), 294 (MH+, 100).

7.2.1.7 (Z)-2,6-Dichloro-N-(4-chloro-5H-1,2,3-dithiazol-5-ylidene)pyridin-3-amine

62g

Similar treatment of 2,6-dichloropyridin-3-amine (78.2 mg, 0.48 mmol) with 4,5-dichloro-


gave the title compound 62g (121.8 mg, 85%), as yellow plates, mp 109.8-110.8 °C (from



(3.02), 368 (2.96); vmax/cm-1 3042w (aryl C-H), 1574s, 1557m, 1547m, 1504m, 1491m,

1412s, 1350m, 1248m, 1234s, 1150m, 1136s, 1076m, 1007w, 935w, 866s, 814s, 797s;

δH(500 MHz; CDCl3) 7.44 (1H, d, J 8.0), 7.36 (1H, d, J 8.0); δC(125 MHz; CDCl3) 163.2

(s), 147.4 (s), 146.3 (s), 143.9 (s), 141.6 (s), 129.9 (d), 124.1 (d); MALDI-TOF MS (m/z):

302 (MH++4, 34%), 300 (MH++2, 91), 298 (MH+, 100).

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7.2.1.8 (Z)-4-Chloro-N-(4-chloro-5H-1,2,3-dithiazol-5-ylidene)pyrimidin-5-amine 62h

Similar treatment of 4-chloropyrimidin-5-amine (62.2 mg, 0.48 mmol) with 4,5-dichloro-


gave the title compound 62h (99.3 mg, 78%), as orange plates, mp (DSC) onset: 124.8 °C,

peak max: 126.8 °C (from c-hexane); Rf 0.47 (DCM); (found: C, 27.13; H, 0.83; N, 21.09.


(2.73), 365 (2.88); vmax/cm-1 1593s, 1578m, 1551m, 1524m, 1416m, 1391s, 1290m, 1211m,

1179w, 1161m, 1123m, 1103m, 916m, 895w, 860s, 791m; δH(500 MHz; CDCl3) 8.86 (1H,

s), 8.52 (1H, s); δC(125 MHz; CDCl3) 164.2 (s), 155.4 (d), 152.0 (s), 147.6 (d), 147.4 (s),

143.5 (s); MALDI-TOF MS (m/z): 269 (MH++4, 9%), 267 (MH++2, 74), 265 (MH+, 100).

7.2.1.9 (Z)-4,6-Dichloro-N-(4-chloro-5H-1,2,3-dithiazol-5-ylidene)pyrimidin-5-amine

62i

Similar treatment of 4,6-dichloropyrimidin-5-amine (78.7 mg, 0.48 mmol) with


0.96 mmol) gave the title compound 62i (132.3 mg, 50%), as colorless prisms, mp (DSC)

onset: 195.7 °C, peak max: 197.3 °C (from c-hexane); Rf 0.53 (n-hexane/DCM, 30:70);

(found: C, 23.97; H, 0.35; N, 18.65. C6HCl3N4S2 requires: C, 24.05; H, 0.34; N, 18.70%);

λmax(DCM)/nm 236 (log ε 3.13), 278 (2.92), 357 (3.03); vmax/cm-1 3076w (aryl C-H), 1591s,

1580m, 1560w, 1528m, 1506s, 1404m, 1375w, 1356s, 1323w, 1294w, 1236w, 1227w,

1179m, 1165m, 1144w, 968w, 878m, 858w, 816s, 793s, 770m; δH(500 MHz; CDCl3) 8.63

(1H, s); δC(125 MHz; CDCl3) 165.3 (s), 153.7 (d), 151.2 (s), 146.8 (s), 140.8 (s); MALDI-

TOF MS (m/z): 303 (MH++4, 35%), 301 (MH++2, 100), 299 (MH+, 93).

7.2.1.10 (Z)-4,6-Dichloro-N-(4-chloro-5H-1,2,3-dithiazol-5-ylidene)-2-methylpyri-

midin-5-amine 62j

Similar treatment of 4,6-dichloro-2-methylpyrimidin-5-amine (85.4 mg, 0.48 mmol) with


0.96 mmol) gave the title compound 62j (106.9 mg, 71%), as yellow prisms, mp (DSC)

onset: 178.1 °C, peak max: 179.7 °C (from c-hexane); Rf 0.50 (n-hexane/DCM, 20:80);

(found: C, 26.73; H, 0.94; N, 17.84. C7H3Cl3N4S2 requires: C, 26.81; H, 0.96; N, 17.86%);

λmax(DCM)/nm 235 (log ε 3.19), 281 (2.92), 358 (3.00); vmax/cm-1 1605m, 1589s, 1543m,

1487m, 1410m, 1362w, 1304m, 1290m, 1177w, 1163m, 1140w, 1034w, 1007w, 918w,

908w, 887w, 872s, 816s, 773s, 764m; δH(500 MHz; CDCl3) 2.72 (3H, s); δC(125 MHz;

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CDCl3) 165.3 (s), 164.6 (s), 150.8 (s), 146.8 (s), 138.0 (s), 25.1 (q); MALDI-TOF MS

(m/z): 317 (MH++4, 18%), 315 (MH++2, 100), 313 (MH+, 82).

7.2.1.11 (Z)-2,4-Dichloro-N-(4-chloro-5H-1,2,3-dithiazol-5-ylidene)pyrimidin-5-amine

62k

Similar treatment of 5-amino-2,4-dichloropyrimidine (78.7 mg, 0.48 mmol) with


0.96 mmol) gave the title compound 62k (98.0 mg, 77%), as red prisms, mp 117.2-

118.2 °C (from c-hexane); Rf 0.60 (n-hexane/DCM, 30:70); (found: C, 24.16; H, 0.36;

N, 18.77. C6HCl3N4S2 requires: C, 24.05; H, 0.34; N, 18.70%); λmax(DCM)/nm 235 (log ε

3.14), 289 (2.74), 367 (2.95); vmax/cm-1 1572m, 1553s, 1514w, 1495m, 1481m, 1408w,

1385s, 1315m, 1271m, 1258m, 1204m, 1188m, 1155w, 1096w, 872s, 806s, 756s; δH(500

MHz; CDCl3) 8.43 (1H, s); δC(125 MHz; CDCl3) 164.6 (s), 156.1 (s), 153.6 (s), 149.6 (d),

147.4 (s), 142.1 (s); MALDI-TOF MS (m/z): 303 (MH++4, 9%), 301 (MH++2, 74), 299

(MH+, 100).

7.2.1.12 (Z)-3-Chloro-N-(4-chloro-5H-1,2,3-dithiazol-5-ylidene)pyrazin-2-amine 62l

Similar treatment of 3-chloropyrazin-2-amine (62.2 mg, 0.48 mmol) with 4,5-dichloro-


gave the title compound 62l (114.5 mg, 90%), as orange needles, mp (DSC) onset:

247.6 °C, peak max: 249.6 °C (from c-hexane/DCE); Rf 0.50 (n-hexane/DCM, 50:50);

(found: C, 27.14; H, 0.79; N, 21.12. C6H2Cl2N4S2 requires: C, 27.18; H, 0.76; N, 21.13%);

λmax(DCM)/nm 230 (log ε 3.62), 247 (3.66), 255 inf (3.62), 314 (3.47), 328 inf (3.38), 384

inf (3.55), 398 (3.84), 417 (3.97), 439 (3.80); vmax/cm-1 1516m, 1501m, 1464s, 1423m,

1387s, 1354w, 1323w, 1277w, 1215w, 1192m, 1163w, 1094m, 1078w, 1069m, 1001w,

951w, 908m, 874s, 837m, 800m, 777w; δH(500 MHz; DMSO-d6) 8.74 (1H, d, J 3.0), 8.43

(1H, d, J 2.5); δC(125 MHz; DMSO-d6) 162.3 (s), 148.9 (s), 148.6 (s), 145.4 (s), 139.9 (d),

138.3 (d); MALDI-TOF MS (m/z): 269 (MH++4, 6%), 267 (MH++2, 65), 265 (MH+, 100). MARIA KOYIONI

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7.2.2 Treatment of [N-(4-Chloro-5H-1,2,3-dithiazol-5-ylidene)amino]azines 55

anf 62 with BnEt3NI

7.2.2.1 Thiazolo[5,4-b]pyridine-2-carbonitrile 55a (Typical Procedure)

To a mixture of (Z)-2-chloro-N-(4-chloro-5H-1,2,3-dithiazol-5-ylidene)pyridin-3-amine

61a (50.2 mg, 0.19 mmol) and BnEt3NI (3.0 mg, 9.5 μmol) under argon atmosphere was

added dry and deaerated PhCl (2 mL). The reaction mixture was immersed into a preheated

Wood’s metal bath at ca. 150 °C and left to stir at reflux until all the starting material

consumed (controlled by TLC). After, the reaction mixture was removed from the Wood’s

metal bath and allowed to cool to ca. 20 °C, dissolved with DCM (10 mL) and adsorbed

onto silica. Chromatography (n-hexane) gave S8 (5.0 mg, 83%), further elution (DCM)

gave the title compound 55a (30.0 mg, 98%) as colorless cotton fibers, mp (DSC) onset:

133.6 °C, peak max: 134.3 °C (lit.,210 135 °C) (from c-hexane); Rf 0.50 (n-hexane/DCM,

20:80); (found: C, 52.07; H, 2.00; N, 25.92. C7H3N3S requires: C, 52.16; H, 1.88;

N, 26.07%); λmax(DCM)/nm 243 inf (log ε 2.72), 247 (2.74), 274 (2.92), 303 (2.82);

vmax/cm-1 3107w and 3065w (aryl C-H), 2236w (C≡N), 1574w, 1551m, 1466m, 1441s,

1377m, 1279m, 1248m, 1223w, 1204w, 1167m, 1155m, 1119w, 1090w, 1042w, 880w,

810s; δH(500 MHz; CDCl3) 8.82 (1H, dd, J 4.5, 1.5), 8.49 (1H, dd, J 8.5, 1.5), 7.63 (1H, dd,

J 8.5, 4.5); δC(125 MHz; CDCl3) 157.5 (s), 150.9 (d), 145.2 (s), 137.7 (s), 132.6 (d), 122.9

(d), 112.5 (s); m/z (EI) 161 (M+, 100%), 109 (26), 103 (12), 82 (24), 70 (18), 64 (6), 51 (6).

7.2.2.2 Thiazolo[4,5-c]pyridine-2-carbonitrile 55b

Similar treatment of (Z)-4-chloro-N-(4-chloro-5H-1,2,3-dithiazol-5-ylidene)pyridin-3-

amine 61b (50.2 mg, 0.19 mmol) gave S8, and the title compound 55b (30.3 mg, 99%) as

colorless needles, mp (DSC) onset: 187.2 °C, peak max: 187.8 °C (from c-hexane); Rf 0.61

(DCM/t-BuOMe, 90:10); (found: C, 52.19; H, 1.77; N, 25.95. C7H3N3S requires: C, 52.16;

H, 1.88; N, 26.07%); λmax(DCM)/nm 241 (log ε 3.51), 279 (3.35), 298 inf (3.01); vmax/cm-1

3094w and 3065w (aryl C-H), 2232w (C≡N), 1576m, 1526w, 1458m, 1437s, 1416m,

1387w, 1275m, 1231m, 1196s, 1157s, 1123w, 1084m, 1036m, 922m, 881m, 822s; δH(500

MHz; CDCl3) 9.56 (1H, s), 8.75 (1H, d, J 5.5), 7.97 (1H, dd, J 5.5, 0.5); δC(125 MHz;

CDCl3) 148.5 (s), 147.8 (d), 146.5 (d), 142.8 (s), 137.9 (s), 116.4 (d), 112.2 (s); m/z (EI)

161 (M+, 100%), 134 (7), 109 (25), 82 (61), 69 (16), 64 (8), 52 (5).

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7.2.2.3 7-Methylthiazolo[5,4-b]pyridine-2-carbonitrile 63a

Similar treatment of (Z)-2-chloro-N-(4-chloro-5H-1,2,3-dithiazol-5-ylidene)-4-methyl-

pyridin-3-amine 62a (52.9 mg, 0.19 mmol) gave S8, and the title compound 63a (32.6 mg,

98%) as colorless needles, mp (DSC) onset: 176.9 °C, peak max: 177.5 °C (from c-hexane);

Rf 0.50 (n-hexane/DCM, 20:80); (found: C, 54.76; H, 2.79; N, 23.92. C8H5N3S requires:

C, 54.84; H, 2.88; N, 23.98%); λmax(DCM)/nm 229 (log ε 2.80), 241 (2.82), 245 (2.82), 280

(3.17), 296 inf (3.03), 311 inf (2.83); vmax/cm-1 3071w (aryl C-H), 2922w and 2866w (alkyl

C-H), 2234m (CN), 1566s, 1466m, 1441s, 1373m, 1344m, 1273m, 1242m, 1219w,

1207w, 1165m, 1142s, 1103w, 1034w, 1003w, 901w, 891w, 872m, 841s; δH(500 MHz;

CDCl3) 8.64 (1H, d, J 4.5), 7.40 (1H, dd, J 4.8, 0.8), 2.81 (3H, d, J 0.5); δC(125 MHz;

CDCl3) 157.5 (s), 150.7 (d), 145.5 (s), 144.9 (s), 136.1 (s), 123.5 (d), 112.7 (s), 17.8 (q);

MALDI-TOF MS (m/z): 176 (MH+, 100%).

7.2.2.4 6-Methylthiazolo[5,4-b]pyridine-2-carbonitrile 63b

Similar treatment of (Z)-2-chloro-N-(4-chloro-5H-1,2,3-dithiazol-5-ylidene)-5-methyl-

pyridin-3-amine 62b (52.9 mg, 0.19 mmol) gave S8, and the title compound 63b (32.6 mg,



C, 54.84; H, 2.88; N, 23.98%); λmax(DCM)/nm 228 (log ε 3.26), 246 inf (3.29), 250 (3.33),

272 (3.44), 314 (3.33); vmax/cm-1 3057w (aryl C-H), 2928w and 2859w (alkyl C-H), 2236m

(CN), 1539m, 1466m, 1439s, 1383w, 1360m, 1307w, 1265s, 1240w, 1188w, 1171m,

1155s, 1134m, 1086w, 1047w, 1013w, 978m, 889s, 762w; δH(500 MHz; CDCl3) 8.66 (1H,

d, J 2.0), 8.27 (1H, dd, J 1.8, 0.8), 2.57 (3H, s); δC(125 MHz; CDCl3) 154.7 (s); 152.4 (d),

145.4 (s), 137.5 (s), 133.4 (s), 132.2 (d), 112.7 (s), 18.5 (q); MALDI-TOF MS (m/z): 176

(MH+, 100%).

7.2.2.5 6-Chlorothiazolo[5,4-b]pyridine-2-carbonitrile 63c

Similar treatment of (Z)-2,5-dichloro-N-(4-chloro-5H-1,2,3-dithiazol-5-ylidene)pyridin-3-

amine 62c (56.4 mg, 0.19 mmol) gave S8, and the title compound 63c (36.1 mg, 97%) as


(n-hexane/DCM, 20:80); (found: C, 42.83; H, 1.02; N, 21.39. C7H2ClN3S requires:


270 (3.00), 275 inf (2.97), 318 (2.90), 325 inf (2.84); vmax/cm-1 3073w (aryl C-H), 2239w

(CN), 1528m, 1445s, 1360m, 1281m, 1252s, 1229m, 1211w, 1157s, 1146s, 1094s, 1078w,

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941s, 893s; δH(500 MHz; CDCl3) 8.78 (1H, d, J 2.5), 8.47 (1H, d, J 2.5); δC(125 MHz;

CDCl3) 155.0 (s), 150.1 (d), 145.6 (s), 139.5 (s), 131.8 (s), 131.7 (d), 112.2 (s); MALDI-

TOF MS (m/z): 198 (MH++2, 30%), 196 (MH+, 100).

7.2.2.6 6-Bromothiazolo[5,4-b]pyridine-2-carbonitrile 63d

Similar treatment of (Z)-5-bromo-2-chloro-N-(4-chloro-5H-1,2,3-dithiazol-5-ylidene)-

pyridin-3-amine 62d (65.2 mg, 0.19 mmol) gave S8, and the title compound 63d (42.0 mg,


Rf 0.70 (n-hexane/DCM, 20:80); (found: C, 34.97; H, 0.84; N, 17.45. C7H2BrN3S requires:


271 (3.10), 276 inf (3.07), 319 (2.98), 325 inf (2.94); vmax/cm-1 3046m (aryl C-H), 2236w

(CN), 1526m, 1443s, 1431m, 1360m, 1283w, 1254s, 1227w, 1155s, 1138m, 1096m,

1069w, 918s, 910s; δH(500 MHz; CDCl3) 8.86 (1H, d, J 2.0), 8.64 (1H, d, J 2.5); δC(125

MHz; CDCl3) 155.5 (s), 152.0 (d), 146.1 (s), 139.2 (s), 134.7 (d), 119.8 (s), 112.1 (s);

MALDI-TOF MS (m/z): 242 (MH++2, 100%), 240 (MH+, 81).

7.2.2.7 6-Iodothiazolo[5,4-b]pyridine-2-carbonitrile 63e

Similar treatment of (Z)-2-chloro-N-(4-chloro-5H-1,2,3-dithiazol-5-ylidene)-5-iodo-

pyridin-3-amine 62e (74.1 mg, 0.19 mmol) gave S8, and the title compound 63e (50.7 mg,

93%) as colorless needles, mp 153.3-154.3 ºC (from c-hexane); Rf 0.70 (n-hexane/DCM,

20:80); (found: C, 29.38; H, 0.76; N, 14.58. C7H2IN3S requires: C, 29.29; H, 0.70;

N, 14.64%); λmax(DCM)/nm 235 (log ε 3.46), 255 (3.29), 267 inf (3.16), 278 inf (3.07), 327

(2.91); vmax/cm-1 3061w and 3042m (aryl C-H), 2236w (CN), 1522m, 1449s, 1433m,

1356m, 1287m, 1250s, 1223w, 1182w, 1150s, 1128m, 1098m, 1090m, 1070w, 905s;

δH(500 MHz; CDCl3) 8.98 (1H, d, J 2.0), 8.83 (1H, d, J 2.0); δC(125 MHz; CDCl3) 156.5

(d), 156.1 (s), 146.6 (s), 140.6 (d), 138.6 (s), 112.1 (s), 91.2 (s); MALDI-TOF MS (m/z):

288 (MH+, 100%).

7.2.2.8 2-Chloro-3-isothiocyanato-6-methoxypyridine 64a and

5-Methoxythiazolo[5,4-b]pyridine-2-carbonitrile 63f

Similar treatment of (Z)-2-chloro-N-(4-chloro-5H-1,2,3-dithiazol-5-ylidene)-6-methoxy-

pyridin-3-amine 62f (55.9 mg, 0.19 mmol) gave after chromatography (n-hexane) S8,

followed by (n-hexane/DCM, 50:50) 2-chloro-3-isothiocyanato-6-methoxypyridine 64a

(4.6 mg, 12%) as colorless plates, mp 86.1-86.6 °C (from n-pentane); Rf 0.71

MARIA KOYIONI

138

(n-hexane/DCM, 50:50); (found: C, 42.03; H, 2.64; N, 14. 00. C7H2IN3S requires: C, 41.90;

H, 2.51; N, 13.96%); λmax(DCM)/nm 233 (log ε 3.17), 269 inf (2.98), 280 (3.15), 292

(3.14); vmax/cm-1 2959w, 2924m and 2853w (alkyl C-H), 2204w, 2135m and 2075m

(N=C=S), 1593m, 1549m, 1477s, 1441w, 1416m, 1371m, 1358s, 1315s, 1271m, 1261m,

1180m, 1130w, 1074s, 1016s, 962w, 935m, 881m, 826s, 804w; δH(500 MHz; CDCl3) 7.42

(1H, d, J 8.5), 6.66 (1H, d, J 8.5), 3.94 (3H, s); δC(125 MHz; CDCl3) 161.2 (s), 145.6 (s),

140.0 (s), 136.7 (d), 120.2 (s), 110.2 (d), 54.6 (q); m/z (EI) 202 (M++2, 36%), 200 (M+,

100), 173 (16), 171 (43), 165 (9), 159 (6), 157 (13), 150 (6), 143 (4), 137 (3), 135 (16), 96

(42), 76 (4), 70 (11), 64 (15), 52 (3). Further elution (n-hexane/DCM, 20:80) gave

5-methoxythiazolo[5,4-b]pyridine-2-carbonitrile 63f (13.1 mg, 36%) as colorless plates,

mp (DSC) onset: 128.2 °C, peak max: 128.6 °C (from c-hexane); Rf 0.63 (n-hexane/DCM,

20:80); (found: C, 50.29; H, 2.67; N, 21.91. C8H5N3OS requires: C, 50.25; H, 2.64;

N, 21.98%); λmax(DCM)/nm 250 (log ε 3.97), 257 (3.46), 290 inf (3.40), 314 (3.80), 322

(3.80); vmax/cm-1 3067w (aryl C-H), 2970w and 2945w (alkyl C-H) 2236m (CN), 1585s,

1545m, 1479s, 1439s, 1425w, 1410w, 1366s, 1329m, 1296s, 1277s, 1186w, 1153s, 1120m,

1080m, 1009s, 974w, 903w, 847m, 837s, 760w; δH(500 MHz; CDCl3) 8.26 (1H, d, J 9.0),

7.02 (1H, d, J 9.0), 4.05 (3H, s); δC(125 MHz; CDCl3) 164.6 (s), 155.7 (s), 141.2 (s), 134.4

(d), 132.7 (s), 113.1 (d) 113.0 (s), 54.7 (q); MALDI-TOF MS (m/z): 192 (MH+, 100%).

7.2.2.9 2,6-Dichloro-3-isothiocyanatopyridine 64b and 5-Chlorothiazolo[5,4-b]-

pyridine-2-carbonitrile 63g

Similar treatment of (Z)-2,6-dichloro-N-(4-chloro-5H-1,2,3-dithiazol-5-ylidene)pyridin-3-

amine 62g (56.7 mg, 0.19 mmol) gave after chromatography (n-hexane) S8, followed by

(n-hexane/DCM, 50:50) 2,6-dichloro-3-isothiocyanatopyridine 64b as colorless plates

(4.2 mg, 13%), mp (DSC) onset: 64.3 °C, peak max: 66.0 °C (from n-pentane); Rf 0.44

(n-hexane/DCM, 70:30); (found: C, 35.28; H, 1.07; N, 13.58. C6H2Cl2N2S requires:

C, 35.14; H, 0.98; N, 13.66%); λmax(DCM)/nm 232 (log ε 2.95), 282 (2.78), 297 (2.85);

vmax/cm-1 3084w and 3049w (aryl C-H), 2224w, 2054s (N=C=S), 1537m, 1423s, 1348s,

1323m, 1238m, 1188m, 1152s, 1132s, 1088m, 968w, 939s, 876s, 810m; δH(500 MHz;

acetone-d6) 7.95 (1H, d, J 8.0), 7.59 (1H, d, J 8.5); δC(125 MHz; CDCl3) 147.7 (s), 147.1

(s), 142.7 (s), 135.9 (d), 127.1 (s), 123.7 (d); m/z (EI) 208 (M++4, 14%), 206 (M++2, 37),

204 (M+, 100), 171 (11), 169 (30), 110 (10), 98 (3), 85 (3), 76 (6), 64 (5). Further elution

(n-hexane/DCM, 20:80) gave 5-chlorothiazolo[5,4-b]pyridine-2-carbonitrile 63g as

colorless needles (13.3 mg, 43%), mp (DSC) onset: 153.7 °C, peak max: 154.6 °C (from


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C7H2ClN3S requires: C, 42.98; H, 1.03; N, 21.48%); λmax(DCM)/nm 247 inf (log ε 2.77),

253 (2.87), 281 (3.05), 305 (3.21), 314 (3.16); vmax/cm-1 3090w and 3051w (aryl C-H),

2232w (CN), 1572s, 1539m, 1452s, 1422m, 1375w, 1354s, 1337m, 1288m, 1271m,

1244w, 1177m, 1152s, 1125m, 1082m, 881m, 843s, 783w, 766m; δH(500 MHz; CDCl3)

8.42 (1H, d, J 9.0), 7.62 (1H, d, J 8.5); δC(125 MHz; CDCl3) 156.7 (s), 152.4 (s), 144.3 (s),

137.8 (s), 134.5 (d), 124.2 (d), 112.2 (s); MALDI-TOF MS (m/z): 198 (MH++2, 27%), 196

(MH+, 100).

7.2.2.10 Thiazolo[5,4-d]pyrimidine-2-carbonitrile 63h

Similar treatment of (Z)-4-chloro-N-(4-chloro-5H-1,2,3-dithiazol-5-ylidene)pyrimidin-5-

amine 62h (50.4 mg, 0.19 mmol) gave S8, and the title compound 63h (29.9 mg, 97%) as

colorless plates, mp (DSC) onset: 160.8 °C, peak max: 161.9 °C (from c-hexane); Rf 0.50

(DCM); (found: C, 44.26; H, 1.28; N, 34.50. C6H2N4S requires: C, 44.44; H, 1.24;

N, 34.55%); λmax(DCM)/nm 236 (log ε 2.99), 239 (3.00), 271 (3.16), 277 (3.16), 285 (3.09);

vmax/cm-1 3036w (aryl C-H), 2237w (CN), 1562m, 1514m, 1445m, 1431m, 1371s, 1306m,

1242w, 1211m, 1157s, 1099m, 1084m, 928m, 880w, 858w, 831w, 762m; δH(500 MHz;

CDCl3) 9.59 (1H, s), 9.33 (1H, s); δC(125 MHz; CDCl3) 164.7 (s), 156.7 (d), 153.8 (d),

143.3 (s), 138.7 (s), 111.9 (s); MALDI-TOF MS (m/z): 163 (MH+, 100%).

7.2.2.11 7-Chlorothiazolo[5,4-d]pyrimidine-2-carbonitrile 63i

Similar treatment of (Z)-4,6-dichloro-N-(4-chloro-5H-1,2,3-dithiazol-5-ylidene)pyrimidin-

5-amine 62i (56.9 mg, 0.19 mmol) gave S8, and the title compound 63i (29.9 mg, 80%) as

colorless plates, mp (DSC) onset: 117.4 °C, peak max: 118.1 °C (from c-hexane); Rf 0.47

(n-hexane/DCM, 20:80); (found: C, 36.75; H, 0.56; N, 28.53. C6HClN4S requires: C, 36.65;

H, 0.51; N, 28.50%); λmax(DCM)/nm 239 inf (log ε 3.08), 242 (3.08), 278 (3.19), 285 inf

(3.15); vmax/cm-1 2234w (CN), 1545s, 1499s, 1443m, 1429m, 1422s, 1364w, 1341s,

1254w, 1229m, 1206w, 1165m, 1142w, 1119s, 997w, 970w, 951w, 899w, 870m, 839s,

775m; δH(500 MHz; CDCl3) 9.09 (1H, s); δC(125 MHz; CDCl3) 165.1 (s), 157.2 (s), 156.0

(d), 141.4 (s), 138.7 (s), 111.6 (s); m/z (EI) 198 (M++2, 39%), 196 (M+, 100), 161 (80), 134

(16), 117 (2), 111 (4), 82 (27), 76 (4), 70 (14).

7.2.2.12 7-Chloro-5-methylthiazolo[5,4-d]pyrimidine-2-carbonitrile 63j

Similar treatment of (Z)-4,6-dichloro-N-(4-chloro-5H-1,2,3-dithiazol-5-ylidene)-2-methyl-

pyrimidin-5-amine 62j (59.6 mg, 0.19 mmol) gave S8, and the title compound 63j (35.6 mg,

89%) as colorless needles, mp (DSC) onset: 94.9 °C, peak max: 96.3 °C (from n-pentane);

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Rf 0.50 (n-hexane/DCM, 20:80); (found: C, 39.96; H, 1.48; N, 26.49. C7H3ClN4S requires:

C, 39.91; H, 1.44; N, 26.60%); λmax(DCM)/nm 244 (log ε 3.14), 286 (3.25); vmax/cm-1

2237w (CN), 1557s, 1493m, 1450m, 1420m, 1406m, 1356w, 1321w, 1296w, 1227m,

1215m, 1179m, 1126s, 1103w, 1065w, 1030w, 910m, 853m, 837m, 791w, 772w; δH(500

MHz; CDCl3) 2.89 (3H, s); δC(125 MHz; CDCl3) 167.7 (s), 165.5 (s), 156.4 (s), 139.3 (s),

137.2 (s), 111.7 (s), 26.0 (q); m/z (EI) 212 (M++2, 25%), 210 (M+, 61), 175 (100), 134 (32),

117 (3), 111 (3), 82 (26), 70 (12).

7.2.2.13 5-Chlorothiazolo[5,4-d]pyrimidine-2-carbonitrile 63k

Similar treatment of (Z)-2,4-dichloro-N-(4-chloro-5H-1,2,3-dithiazol-5-ylidene)pyrimidin-

5-amine 62k (56.9 mg, 0.19 mmol) gave S8, and the title compound 63k (34.7 mg, 93%) as


(n-hexane/DCM, 20:80); (found: C, 36.57; H, 0.54; N, 28.41. C6HClN4S requires: C, 36.55;

H, 0.51; N, 28.50%); λmax(DCM)/nm 229 (log ε 3.17), 242 (3.21), 272 inf (3.10), 280

(3.32), 284 (3.35), 294 (3.33); vmax/cm-1 2243w (CN), 1556s, 1512s, 1447m, 1358s,

1248w, 1227m, 1200s, 1182s, 1177s, 1138m, 1126w, 1094m, 939m, 883m, 799w, 772;

δH(500 MHz; CDCl3) 9.44 (1H, s); δC(125 MHz; CDCl3) 166.5 (s), 159.5 (s), 155.5 (d),

142.3 (s), 138.9 (s), 111.6 (s); MALDI-TOF MS (m/z): 198 (M++2, 27%), 196 (M+, 100).

7.2.2.14 Thiazolo[4,5-b]pyrazine-2-carbonitrile 63l

Similar treatment of (Z)-3-chloro-N-(4-chloro-5H-1,2,3-dithiazol-5-ylidene)pyrazin-2-

amine 62l (50.4 mg, 0.19 mmol) gave after chromatography (n-hexane) S8, then (DCM)

recovered (Z)-3-chloro-N-(4-chloro-5H-1,2,3-dithiazol-5-ylidene)pyrazin-2-amine 62l

(5.0 mg, 10%) as orange needles, mp (DSC) onset: 247.6 °C, peak max: 249.6 °C (from

c-hexane/DCE); identical to that described above. Further elution (DCM/t-BuOMe, 90:10)

gave the title compound 63l (11.7 mg, 38%) as colorless needles, mp (DSC) onset: 119.8

°C, peak max: 120.4 °C (from c-hexane); Rf 0.73 (DCM/t-BuOMe, 90:10); (found:

C, 44.35; H, 1.25; N, 34.47. C6H2N4S requires: C, 44.44; H, 1.24; N, 34.55%);

λmax(DCM)/nm 258 inf (log ε 2.90), 268 (2.99), 278 (2.99), 306 (3.30), 312 (3.31);

vmax/cm-1 3073w and 3040w (aryl C-H), 2234 (CN), 1524m, 1464m, 1443m, 1352m,

1333m, 1310m, 1248w, 1229m, 1207s, 1150s, 1123w, 1094m, 1036m, 903m, 874m, 845m,

785w, 764w; δH(500 MHz; CDCl3) 8.96 (1H, d, J 2.0), 8.80 (1H, d, J 2.5); δC(125 MHz;

CDCl3) 155.8 (s), 151.5 (s), 145.1 (d), 144.6 (d), 141.7 (s), 112.0 (s); MALDI-TOF MS

(m/z): 163 (MH+, 100%).

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7.3.1 Reaction of 1,3-Dimethyl-1H-pyrazol-5-amine 67a with 4,5-Dichloro-1,2,3-

dithiazolium chloride 1

To a stirred suspension of 4,5-dichloro-1,2,3-dithiazolium chloride 1 (1.00 g, 4.8 mmol) in

DCM (20 mL) at ca. 20 °C under argon atmosphere, was added in one portion a solution of

1,3-dimethyl-1H-pyrazol-5-amine 67a (0.53 g, 4.8 mmol) and 2,6-lutidine (1.12 mL,

9.6 mmol) in DCM (20 mL). The mixture was stirred for 1 h and then adsorbed on silica

and chromatographed (DCM) to give 4,6-dimethyl-6H-pyrazolo[3,4-c]isothiazole-3-carbo-

nitrile 70a (99 mg, 12%) as colorless needles, mp 102-106 °C (from c-hexane), Rf 0.45

(DCM); (found: C, 47.31; H, 3.38; N, 31.30. C7H6N4S requires: C, 47.18; H, 3.39;

N, 31.44%); λmax(DCM)/nm 291 (log ε 2.73), 369 (2.39); vmax/cm-1 2992w, 2928w and

2851w (alkyl C-H), 2218s (CN), 1582s, 1514m, 1441m, 1410m, 1383m, 1331m, 1246m,

1229m, 1034m, 986m, 934w, 899s, 841m, 745m; δH(500 MHz; CDCl3) 3.90 (3H, s), 2.53

(3H, s); δC(125 MHz; CDCl3) 165.7 (s), 135.4 (s), 130.3 (s), 120.4 (s), 110.3 (s), 34.8 (q),

13.1 (q); m/z (EI) 178 (M+, 100%), 163 (22), 150 (7), 135 (5), 123 (5), 108 (9), 91 (10), 70

(24), 64 (7), 46 (8), 43 (41). Further elution (DCM/t-BuOMe, 98:2) gave (Z)-N-(4-chloro-

5H-1,2,3-dithiazol-5-ylidene)-1,3-dimethyl-1H-pyrazol-5-amine 68a (58 mg, 5%) as

yellow prisms, mp (DSC) onset: 146.3 °C, peak max: 156.6 C, decomp. onset: 158.2 C,

peak max: 158.9 C (from c-hexane/DCE); Rf 0.67 (DCM/t-BuOMe, 90:10); (found:

C, 34.13; H, 2.76; N, 22.81. C7H7ClN4S2 requires: C, 34.07; H, 2.86; N, 22.71%);

λmax(DCM)/nm 250 (log ε 2.83), 270 (2.58), 382 inf (2.86), 389 inf (2.85), 401 (2.91), 418

inf (2.79); vmax/cm-1 2932w (alkyl C-H), 1578s, 1555w, 1514m, 1443m, 1410w, 1373w,

1360w, 1292m, 1192m, 1148m, 1049w, 1013m, 878s, 856m, 777s; δH(500 MHz; CDCl3)

6.23 (1H, s), 3.90 (3H, s), 2.34 (3H, s); δC(125 MHz; CDCl3) 153.9 (s), 149.0 (s), 147.6 (s),

145.9 (s), 94.5 (d), 34.9 (q), 14.2 (q); m/z (EI) 248 (M++2, 40%), 246 (M+, 92), 211 (M+-Cl,

73), 182 (6), 179 (22), 170 (8), 152 (31), 147 (20), 137 (8), 127 (14), 125 (18), 120 (100),

110 (8), 106 (20), 102 (31), 95 (20), 93 (23), 80 (21), 70 (46), 64 (64), 52 (25), 42 (38).

Further elution (DCM/t-BuOMe, 98:2) gave 5-amino-1,3-dimethyl-1H-pyrazole-4-

carbothioyl cyanide 75 (33.5 mg, 4%) as orange plates, mp 212-213 °C (from CHCl3); Rf

0.23 (DCM/t-BuOMe, 90:10); (found: C, 46.53; H, 4.33; N, 30.95. C7H8N4S requires:


vmax/cm-1 3339m (NH2), 3211w, 3165w, 3011w, 2988w, 2965w and 2930w (alkyl C-H),

2226w (CN), 1632s, 1562m, 1557m, 1526m, 1493s, 1452m, 1435m, 1389m, 1339m,

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1238w, 1215w, 1128w, 1024m, 989m, 972m, 955m, 862w, 739w; δH(500 MHz; CDCl3)

7.23 (2H, br s), 3.59 (3H, s), 2.57 (3H, s); δC(125 MHz; DMSO-d6) 165.2 (s), 154.0 (s),

145.7 (s), 122.6 (s), 116.2 (s), 33.9 (q), 14.0 (q); MALDI-TOF MS (m/z): 181 (MH++1,

39%), 181 (MH+, 100), 154 (79), 111 (29). Further elution (DCM/t-BuOMe, 95:5) gave

(3Z,3'Z)-N',N''-3-trisulfanediylbis(4,6-dimethyl-6H-pyrazolo[3,4-c]isothiazole-3-carbimi-

doyl chloride) 76 (125 mg, 12%) as yellow needles, mp (DSC) onset: 178.7 C, peak max:

184.0 C, decomp. onset: 191.4 C, peak max: 198.6 C (from DCE); Rf 0.67

(DCM/t-BuOMe, 80:20); (found: C, 32.22; H, 2.11; N, 21.50. C14H12Cl2N8S5 requires:


2990w, 2959w and 2913w (alkyl C-H), 1578m, 1557m, 1510m, 1454m, 1435m, 1406m,

1377m, 1335m, 1244m, 1219m, 1190m, 1040m, 989m, 966m, 935w, 845m, 800s; δH(500

MHz; CD2Cl2) 3.81 (3H, s), 2.56 (3H, s); δC(125 MHz; CD2Cl2) 167.3 (s), 150.9 (s), 137.1

(s), 132.3 (s), 124.9 (s), 34.6 (q), 15.9 (q); MALDI-TOF MS (m/z): 525 (M++3, 27%), 523

(M++1, 78), 521 (M+-1, 65), 485 (12), 460 (7), 458 (9), 425 (15), 389 (4), 309 (14), 307

(23), 276 (12), 249 (56), 247 (100), 244 (74), 227 (9), 213 (40). Further elution

(DCM/t-BuOMe, 60:40) gave (Z)-N-{[(Z)-1-(5-amino-1,3-dimethyl-1H-pyrazol-4-yl)-2-

chloro-2-[(Z)-(4-chloro-5H-1,2,3-dithiazol-5-ylidene)amino]vinyl]disulfanyl}-4,6-dime-

thyl-6H-pyrazolo[3,4-c]isothiazole-3-carbimidoyl chloride 77 (154 mg, 13%) as red

needles, mp 143–145 C (from n-pentane/DCM); Rf 0.27 (DCM/t-BuOMe, 40:60); (found:

C, 32.13; H, 2.21; N, 20.94. C16H14Cl3N9S5 requires C, 32.12; H, 2.31; N, 21.04%);

λmax(DCM)/nm 313 (log ε 4.18), 417 (4.28), 465 inf (4.16); vmax/cm-1 3327w and 3196w

(NH2), 2934w (alkyl C-H), 1649m, 1557s, 1512m, 1485m, 1423m, 1404m, 1383m, 1339m,

1298m, 1227m, 1161s, 1107w, 1043w, 993w, 968m, 897w, 859s, 845m, 799s, 785s, 735m;

δH(500 MHz; CDCl3) 3.83 (3H, s), 3.77 (2H, br s), 3.57 (3H, s), 2.58 (3H, s), 2.03 (3H, s);

δC(125 MHz; CDCl3) 166.7 (s), 152.8 (s), 151.1 (s), 149.3 (s), 147.2 (s), 143.6 (s), 136.9

(s), 130.0 (s), 129.3 (s), 128.9 (s), 124.2 (s), 99.3 (s), 34.3 (q), 34.2 (q), 15.7 (q), 13.7 (q);

MALDI-TOF MS (m/z): 603 (M++6, 18%), 601 (M++4, 51), 599 (M++2, 96), 597 (M+,

100), 530 (19), 499 (14), 385 (32), 383 (33), 351 (19), 349 (34), 347 (67), 285 (28), 283

(97), 247 (12), 212 (9), 176 (6).

7.3.2 Thermolysis of Side-products 76 and 77 (Scheme 31)

7.3.2.1 Thermolysis of the Trisulfide 76 (Typical Procedure)

A stirred neat sample of (3Z,3'Z)-N',N''-trisulfanediylbis(4,6-dimethyl-6H-pyrazolo[3,4-c]-

isothiazole-3-carbimidoyl chloride) 76 (20.0 mg, 0.04 mmol) under an argon atmosphere

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was immersed into a preheated Wood’s metal bath at ca. 250 C. After 4 min the mixture

was allowed to cool to ca. 20 C and extracted with DCM (3 × 1 mL). The combined

extracts were adsorbed onto silica and chromatographed (n-hexane) to give S8. Further

elution (DCM/t-BuOMe, 99:1) gave 4,6-dimethyl-6H-pyrazolo[3,4-c]isothiazole-3-

carbonitrile 70a (12.1 mg, 89%) as colorless needles, mp 102-106 °C (from c-hexane),

Rf 0.45 (DCM), identical to that described above.

7.3.2.2 Thermolysis of Disulfide 77

Similar treatment of (Z)-N-{[(Z)-1-(5-amino-1,3-dimethyl-1H-pyrazol-4-yl)-2-chloro-2-

[(Z)-(4-chloro-5H-1,2,3-dithiazol-5-ylidene)-amino]vinyl]disulfanyl}-4,6-dimethyl-6H-

pyrazolo[3,4-c]isothiazole-3-carbimidoyl chloride 77 (20.0 mg, 0.03 mmol) at ca. 200 C

for 2 min gave 4,6-dimethyl-6H-pyrazolo[3,4-c]isothiazole-3-carbonitrile 70a (5.8 mg,

49%) as colorless needles, mp 102-106 °C (from c-hexane), Rf 0.45 (DCM), identical to

that described above.

7.3.4 Reaction of Trisulfide 76 and Disulfide 77 with concd H2SO4 (Scheme 30)

To concd H2SO4 (1 mL) at ca. 20 C was added either (3Z,3'Z)-N',N''-trisulfanediyl-

bis(4,6-dimethyl-6H-pyrazolo[3,4-c]isothiazole-3-carbimidoyl chloride) 76 (20.0 mg,

0.04 mmol) or (Z)-N-{[(Z)-1-(5-amino-1,3-dimethyl-1H-pyrazol-4-yl)-2-chloro-2-[(Z)-(4-

chloro-5H-1,2,3-dithiazol-5-ylidene)amino]vinyl]disulfanyl}-4,6-dimethyl-6H-pyrazolo-

[3,4-c]isothiazole-3-carbimidoyl chloride 77 (20.0 mg, 0.03 mmol). On consumption of

either compound 76 or 77 (by TLC) the reaction mixture was then poured onto crushed ice,

left to warm to ca. 20 C, neutralized (sat. NaHCO3) and extracted with t-BuOMe (4 × 10 mL).

The combined extracts were then dried (Na2SO4), filtered and evaporated to dryness. The

residue was dissolved in THF (5 mL), adsorbed onto silica and chromatographed

(t-BuOMe) to give 4,6-dimethyl-6H-pyrazolo[3,4-c]isothiazole-3-carboxamide 78

(14.8 mg, 99% from 76 and 4.0 mg, 34% from 77) as colorless needles, mp 181-182 C

(from c-hexane/EtOH); Rf 0.33 (t-BuOMe); (found: C, 42.79; H, 4.13; N, 28.40.

C7H8N4OS requires: C, 42.85; H, 4.11; N, 28.55%); λmax(EtOH)/nm 224 (log ε 2.87), 282

(2.94), 351 (2.64); vmax/cm-1 3356m and 3163m (NH2), 1692s (C=O), 1626m, 1589m,

1516m, 1443m, 1389s, 1377s, 1317m, 1215m, 1123m, 1032m, 989w, 934m, 920w, 827m,

781m; δH(300 MHz; DMSO-d6) 8.09 (1H, br s), 7.96 (1H, br s), 3.75 (3H, s), 2.44 (3H, s);

δC(75 MHz; DMSO-d6) 166.0 (s), 160.3 (s), 150.9 (s), 135.8 (s), 126.1 (s), 34.1 (q), 14.2

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(q); m/z (EI) 196 (M+, 100%), 180 (21), 151 (33), 138 (3), 125 (4), 108 (10), 98 (4), 94 (4),

90 (7), 82 (13), 69 (8), 64 (7).

7.3.5 Dehydration of 4,6-Dimethyl-6H-pyrazolo[3,4-c]isothiazole-3-carboxamide

78

To a stirred solution of 4,6-dimethyl-6H-pyrazolo[3,4-c]isothiazole-3-carboxamide 78

(19.6 mg, 0.1 mmol) in toluene (1 mL), was added in one portion POCl3 (100 μL, 1 mmol).

The reaction mixture was then heated to ca. 110 C for 3 h, then left to cool to ca. 20 C,

adsorbed onto silica and chromatographed (DCM/t-BuOMe, 99:1) to give 4,6-dimethyl-

6H-pyrazolo[3,4-c]isothiazole-3-carbonitrile 70a (17.5 mg, 98%) as colorless needles, mp

102-106 °C (from c-hexane), Rf 0.45 (DCM), identical to that described above.

7.3.6. Reaction of 1H-Pyrazol-5-amines 67 with 4,5-Dichloro-1,2,3-dithiazolium

chloride 1 (see Table 6 for yields)

General Procedure A: To a stirred solution of the appropriate 1H-pyrazol-5-amine 67

(0.48 mmol) in DCM (4 mL) at ca. 20 °C and protected with CaCl2 drying tube, was added

in one portion 2,6-lutidine (112 μL, 0.96 mmol). The reaction mixture was then stirred for

5 min and then 4,5-dichloro-1,2,3-dithiazolium chloride 1 (100 mg, 0.48 mmol) was added.

After an additional 15 h stirring at ca. 20 C the reaction mixture was adsorbed onto silica

and chromatographed.

General Procedure B: A stirred solution of the appropriate 1H-pyrazol-5-amine 67

(0.48 mmol) in dry DCM (4 mL) at ca. 20 °C was purged for 30 sec with HCl (g). After

the purge was complete, to the reaction mixture was added in one portion 4,5-dichloro-

1,2,3-dithiazolium chloride 1 (100 mg, 0.48 mmol). The reaction mixture was then stirred

for 12 h and then in one portion 2,6 lutidine (112 μL, 0.96 mmol) was added. The reaction

mixture was stirred for an additional 3 h, then adsorbed onto silica and chromatographed.

7.3.6.1 (Z)-N-(4-Chloro-5H-1,2,3-dithiazol-5-ylidene)-3-methyl-1H-pyrazol-5-amine

68b

Procedure A: 72.5 mg, 65%. Procedure B: 83 mg, 74%. Chromatography eluent:

DCM/t-BuOMe, 95:5. Orange prisms, mp (DSC) onset: 150.8 C, peak max: 154.8 ºC,

decomp. onset: 158.4 C, peak max: 161.1 C (from c-hexane/DCE); Rf 0.48

(DCM/t-BuOMe, 98:2); (found: C, 31.06; H, 2.19; N, 23.92. C6H5ClN4S2 requires:

C, 30.97; H, 2.17; N, 24.08%); λmax(DCM)/nm 250 (log ε 3.98), 255 inf (3.93), 274 inf

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(3.41), 375 inf (3.93), 389 (4.02), 406 inf (3.90); vmax/cm-1 3208m (N-H), 3150w, 2928w

and 2862w (alkyl C-H), 1578m, 1543s, 1533m, 1491m, 1449w, 1396m, 1375m, 1281m,

1175m, 1136m, 1026w, 1003m, 876s, 868s, 826w, 779m, 768s; δH(500 MHz; DMSO-d6)

12.93 (1H, s), 6.24 (1H, s), 2.30 (3H, s); δC(125 MHz; DMSO-d6) 154.5 (s), 154.2 (s),

148.2 (s), 141.5 (s), 101.4 (d), 11.4 (q); MALDI-TOF MS (m/z): 235 (MH++2, 56%), 233

(MH+, 100), 197 (91), 140 (67).

7.3.6.2 (Z)-N-(4-Chloro-5H-1,2,3-dithiazol-5-ylidene)-3-phenyl-1H-pyrazol-5-amine

68c

Procedure A: 82 mg, 58%. Procedure B: 130 mg, 92%. Chromatography eluent: DCM.

Orange needles, mp (DSC) onset: 190.9 C, peak max: 193.8 ºC, decomp. onset: 196.3 C,

peak max: 199.9 C (from c-hexane/DCE); Rf 0.44 (DCM); (found: C, 44.80; H, 2.32;

N, 18.94. C11H7ClN4S2 requires: C, 44.82; H, 2.39; N, 19.01%); λmax(DCM)/nm 258 (log ε

4.50), 378 inf (4.05), 391 (4.14), 408 inf (4.00); vmax/cm-1 3341m (N-H), 3154w, 3065w

and 3017w (aryl C-H), 1549m, 1522w, 1501w, 1487m, 1472m, 1456m, 1396w, 1314w,

1296w, 1273w, 1204m, 1159m, 1009m, 957w, 914w, 868m, 816w, 795w, 727s; δH(500

MHz; DMSO-d6) 13.72 (1H, s), 7.83 (2H, d, J 7.5), 7.50 (2H, dd, J 7.8, 7.8), 7.40 (1H, dd,

J 7.3, 7.3), 6.98 (1H, d, J 2.0); δC(125 MHz; DMSO-d6) 154.8 (s), 154.3 (s), 147.6 (s),

144.2 (s), 129.0 (d), 128.8 (s), 128.6 (d), 125.2 (d), 99.4 (d); MALDI-TOF MS (m/z): 297

(MH++2, 28%), 295 (MH+, 100), 205 (13).

7.3.6.3 (Z)-N-(4-Chloro-5H-1,2,3-dithiazol-5-ylidene)-1-methyl-3-phenyl-1H-pyrazol-

5-amine 68d

Procedure A: 0%. Procedure B: 108 mg, 73%. Chromatography eluent: n-hexane/DCM,

40:60. Yellow needles, mp (DSC) onset: 140.0 °C, peak max: 140.6 C, decomp. onset:

149.0 C, peak max: 150.6 C (from c-hexane); Rf 0.52 (n-hexane/DCM, 30:70); (found:


λmax(DCM)/nm 251 (log ε 4.36), 300 inf (3.59), 376 inf (3.92), 392 inf (4.03), 409 (4.09),

428 inf (3.94); vmax/cm-1 3065w (aryl C-H), 2930w and 2847w (alkyl C-H), 1585m, 1547w,

1531w, 1512w, 1491m, 1460m, 1427w, 1352w, 1300m, 1188m, 1144m, 1107w, 1072w,

1034w, 955m, 918w, 870m, 845m, 773s, 748s; δH(500 MHz; CDCl3) 7.83 (2H, d, J 7.0),

7.43 (2H, dd, J 7.8, 7.8), 7.34 (1H, dd, J 7.3, 7.3), 6.73 (1H, s), 4.03 (3H, s); δC(125 MHz;

CDCl3) 154.5 (s), 150.2 (s), 149.0 (s), 146.5 (s), 133.1 (s), 128.7 (d), 128.0 (d), 125.4 (d),

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91.8 (d), 35.4 (q); MALDI-TOF MS (m/z): 311 (MH++2, 53%), 309 (MH+, 100), 289 (57),

205 (90).

7.3.6.4 (Z)-1-Benzyl-N-(4-chloro-5H-1,2,3-dithiazol-5-ylidene)-3-methyl-1H-pyrazol-

5-amine 68e

Procedure A: 0%. Procedure B: 26.5 mg, 17%. Chromatography eluent: DCM. Yellow

plates, mp (DSC) onset: 138.0 C, peak max: 140.8 C, decomp. onset: 142.1 C, peak

max: 142.6 C (from c-hexane); Rf 0.26 (DCM); found: C, 48.32; H, 3.52; N, 17.23.

C13H11ClN4S2 requires: C, 48.36; H, 3.43; N, 17.35%); λmax(DCM)/nm 252 (log ε 4.04),

303 (3.58), 388 inf (4.17), 405 (4.23), 425 inf (4.09); vmax/cm-1 3061w and 3042w (aryl

C-H), 2940w (alkyl C-H), 1560m, 1551m, 1518m, 1495m, 1456w, 1447w, 1437m, 1369m,

1346w, 1331w, 1306w, 1288w, 1209m, 1204w, 1177w, 1152m, 1121w, 1032w, 1016m,

1001w, 935w, 926w, 880m, 849m, 820m, 791m, 762s, 741m; δH(500 MHz; acetone-d6)

7.37 (2H, d, J 7.0), 7.30 (2H, dd, J 7.3, 7.3), 7.24 (1H, dd, J 7.3, 7.3), 6.35 (1H, s), 5.44

(2H, s), 2.26 (3H, s); δC(125 MHz; CDCl3) 154.0 (s), 149.1 (s), 148.1 (s), 145.5 (s), 137.3

(s), 94.9 (d), 51.8 (t), 14.4 (q); MALDI-TOF MS (m/z): 325 (MH++2, 56%), 323 (MH+,

100), 91 (59).

7.3.6.5 (Z)-1-Benzyl-N-(4-chloro-5H-1,2,3-dithiazol-5-ylidene)-3-phenyl-1H-pyrazol-

5-amine 68f

Procedure A: 0%. Procedure B: 101.5 mg, 55%. Chromatography eluent: n-hexane/DCM,

60:40. Yellow needles, mp (DSC) onset: 158.9 C, peak max: 160.0 C, decomp. onset:



λmax(DCM)/nm 258 (log ε 4.44), 394 inf (4.09), 411 (4.14), 434 inf (3.98); vmax/cm-1 3065w

and 3024w (aryl C-H), 2947w (alkyl C-H), 1564m, 1549m, 1526w, 1501m, 1493m, 1487m,

1462m, 1454m, 1441m, 1423w, 1354w, 1327w, 1308m, 1292w, 1206m, 1200m, 1177w,

1163m, 1155m, 1136m, 1088m, 1072w, 1028w, 970w, 955m, 922w, 910m, 878m, 849m,

837w, 822w, 791m, 777m, 762s; δH(500 MHz; DMSO-d6) 7.86 (2H, d, J 7.0), 7.42 (2H, dd,

J 7.5, 7.5), 7.34-7.25 (6H, m), 6.90 (1H, s), 5.49 (2H, s); δC(125 MHz; DMSO-d6) 157.1

(s), 149.6 (s), 147.7 (s), 146.6 (s), 137.4 (s), 132.8 (s), 128.8 (d), 128.6 (d), 128.1 (d), 127.9

(d), 127.7 (d), 125.2 (d), 91.9 (d), 51.3 (t); MALDI-TOF MS (m/z): 387 (MH++2, 29%),

385 (MH+, 76%), 90 (100).

MARIA KOYIONI

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7.3.6.6 (Z)-N-(4-Chloro-5H-1,2,3-dithiazol-5-ylidene)-3-methyl-1-phenyl-1H-pyrazol-

5-amine 68i

Procedure A: 0%. Procedure B: 32.5 mg, 22%. Chromatography eluent: n-hexane/DCM,

80:20. Yellow needles, mp (DSC) onset: 121.8 °C, peak max: 122.7 C, decomp. onset:



λmax(DCM)/nm 243 (log ε 4.27), 263 (4.22), 280 inf (4.09), 397 inf (4.08), 412 (4.11), 432

inf (3.97); vmax/cm-1 3127w (aryl C-H), 2928w (alkyl C-H), 1578m, 1520m, 1497m, 1462m,

1431m, 1418m, 1371m, 1317w, 1269w, 1179m, 1148m, 1074m, 1026m, 1011w, 1001w,

982w, 905m, 870m, 837m, 773s, 746m; δH(500 MHz; CDCl3) 7.85 (2H, d, J 8.0), 7.44 (2H,

dd, J 7.8, 7.8), 7.31 (1H, dd, J 7.5, 7.5), 6.44 (1H, s), 2.44 (3H, s); δC(125 MHz; CDCl3)

154.8 (s), 149.3 (s), 149.2 (s), 146.0 (s), 139.2 (s), 128.5 (d), 126.7 (d), 124.0 (d), 96.1 (d),

14.4 (q); MALDI-TOF MS (m/z): 311 (MH++2, 94%), 309 (MH+, 100), 275 (42), 273 (57),

216 (94), 209 (100).

7.3.6.7 (Z)-N-(4-Chloro-5H-1,2,3-dithiazol-5-ylidene)-1,3-diphenyl-1H-pyrazol-5-

amine 68j

Procedure A: 0%. Procedure B: 16 mg, 9%. Chromatography eluent: n-hexane/DCM,

90:10. Yellow needles, mp 92-94 °C (from c-hexane); Rf 0.39 (n-hexane/DCM, 50:50);

(found: C, 55.20; H, 2.86; N, 14.98. C17H11ClN4S2 requires: C, 55.05; H, 2.99; N, 15.11%);

λmax(DCM)/nm 256 (log ε 3.48), 271 inf (3.39), 395 (3.05), 413 (3.06), 431 inf (2.92);

vmax/cm-1 3071w (aryl C-H), 1578m, 1531m, 1497s, 1456m, 1410w, 1368w, 1304w,

1261w, 1209w, 1186w, 1146m, 1088w, 1074w, 1026w, 1016w, 950m, 916w, 868s, 845w,

829w, 770s, 760m, 745m; δH(500 MHz; CDCl3) 7.97 (2H, dd, J 8.5, 1.0), 7.94 (2H, dd, J

8.5, 1.0), 7.49 (2H, dd, J 8.0, 8.0), 7.46 (2H, dd, J 7.5, 7.5), 7.39-7.34 (2H, m), 6.92 (1H, s);


(d), 128.6 (d), 128.4 (d), 127.0 (d), 125.7 (d), 124.2 (d), 93.2 (d); MALDI-TOF MS (m/z):

373 (MH++2, 49%), 371 (MH+, 75), 335 (14), 278 (100), 271 (19).

7.3.6.8 4-Methyl-6H-pyrazolo[3,4-c]isothiazole-3-carbonitrile 70b

Procedure A: 3 mg, 4%. Procedure B: 0%. Chromatography eluent: DCM/t-BuOMe, 90:10.

Colorless needles, 182-183.5 C (from c-hexane/CHCl3), Rf 0.33 (DCM/t-BuOMe, 97:3);

(found: C, 43.79; H, 2.37; N, 34.21. C6H4N4S requires: C, 43.89; H, 2.46; N, 34.12%);

λmax(EtOH)/nm 235 (log ε 3.79), 291 (4.61), 351 (3.83); vmax/cm-1 3292s (N-H), 2245m and

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2226m (CN), 1585s, 1506m, 1477w, 1439m, 1383m, 1368m, 1302m, 1215w, 1159w,

1082s, 986m, 897s, 841m, 791s; δH(500 MHz; DMSO-d6) NH resonance missing, 2.44 (3H,

s); δC(125 MHz; DMSO-d6) 166.5 (s), 135.8 (s), 130.4 (s), 119.2 (s), 111.0 (s), 12.8 (q);

MALDI-TOF MS (m/z): 165 (MH+, 100%).

7.3.6.9 4-Phenyl-6H-pyrazolo[3,4-c]isothiazole-3-carbonitrile 70c

Procedure A: 7.5 mg, 7%; Procedure B: 0%. Chromatography eluent: DCM/t-BuOMe,

90:10. Pale yellow needles, mp 196-197 C (from c-hexane/CHCl3); Rf 0.68

(DCM/t-BuOMe, 96:4); (found: C, 58.53; H, 2.56; N, 24.67. C11H6N4S requires: C, 58.39;


3226m (N-H), 3051w (aryl C-H), 2224m (CN), 1584m, 1512m, 1464m, 1437w, 1385m,

1327m, 1317m, 1298m, 1281m, 1190w, 1101w, 1084m, 1070w, 1013w, 916w, 891s,

856m, 835w, 791s, 777s, 745s; δH(500 MHz; CDCl3) 10.04 (1H, s), 8.04 (2H, dd, J 8.5,

1.5), 7.55 (2H, dd, J 7.5, 7.5), 7.47 (1H, dd, J 7.5, 7.5); δC(125 MHz; CDCl3) 166.5 (s),

140.9 (s), 130.7 (s), 129.6 (d), 129.2 (d), 127.6 (s), 126.9 (d), 121.9 (s), 111.0 (s); MALDI-

TOF MS (m/z): 229 (MH++1, 34%), 227 (MH+, 100), 202 (16), 77 (18).

7.3.6.10 6-Methyl-4-phenyl-6H-pyrazolo[3,4-c]isothiazole-3-carbonitrile 70d

Procedure A: 52 mg, 45%. Procedure B: 6 mg, 5%. Chromatography eluent:

n-hexane/DCM, 60:40. Yellow needles, mp (DSC) onset: 155.9 ºC, peak max: 156.5 C

(from c-hexane); Rf 0.54 (n-hexane/DCM, 40:60); (found: C, 59.85; H, 3.32; N, 23.23.

C12H8N4S requires: C, 59.98; H, 3.36; N, 23.32%); λmax(DCM)/nm 265 (log ε 3.34), 291

(3.30), 391 (2.83); vmax/cm-1 3061w (aryl C-H), 2941w (alkyl C-H), 2216w (CN), 1574m,

1518m, 1491m, 1456m, 1435m, 1406w, 1346m, 1319w, 1298w, 1287m, 1260m, 1231m,

1182w, 1171w, 1157m, 1074w, 1034m, 1024m, 920w, 907w, 881m, 841m, 772m, 739s;

δH(500 MHz; CDCl3) 8.00 (2H, dd, J 8.5, 1.5), 7.52 (2H, dd, J 7.5, 7.5), 7.43 (1H, dd, J 7.4,

7.4), 4.05 (3H, s); δC(125 MHz; CDCl3) 166.2 (s), 138.0 (s), 130.9 (s), 129.2 (d), 129.1 (d),

127.2 (s), 126.6 (d), 121.6 (s), 111.3 (s), 35.2 (q); MALDI-TOF MS (m/z): 241 (MH+,

60%), 240 (M+, 100), 229 (14).

7.3.6.11 6-Benzyl-4-methyl-6H-pyrazolo[3,4-c]isothiazole-3-carbonitrile 70e

Procedure A: 57.5 mg, 47%. Procedure B: 35.5 mg, 29%. Chromatography eluent: DCM.

Beige needles, mp 101.5-102 C (from n-hexane at ca. 20 C); Rf 0.47 (DCM); (found:

C, 61.37; H, 3.87; N, 21.93. C13H10N4S requires: C, 61.40; H, 3.96; N, 22.03%);

MARIA KOYIONI

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λmax(DCM)/nm 295 (log ε 4.00), 371 (3.68); vmax/cm-1 3030w (aryl C-H), 2976w and

2938w (alkyl C-H), 2220m (C≡N), 1582s, 1510m, 1495m, 1472w, 1454m, 1443m, 1416m,

1387m, 1346m, 1333m, 1298m, 1267s, 1234m, 1204m, 1157w, 1111m, 1107m, 1098m,

1069m, 1069m, 1026w, 903s, 833s, 818m, 770m, 745m; δH(500 MHz; CDCl3) 7.36-7.27

(5H, m), 5.37 (2H, s), 2.53 (3H, s); δC(125 MHz; CDCl3) 165.3 (s), 136.0 (s), 135.9 (s),

130.7 (s), 128.8 (d), 128.2 (d), 128.0 (d), 120.5 (s), 110.3 (s), 52.3 (t), 13.2 (q); MALDI-

TOF MS (m/z): 255 (MH+, 100%), 106 (49), 91 (87).

7.3.6.12 6-Benzyl-4-phenyl-6H-pyrazolo[3,4-c]isothiazole-3-carbonitrile 70f

Procedure A: 62.5 mg, 41%. Procedure B: 13.5 mg, 9%. Chromatography eluent:

n-hexane/DCM, 70:30. Yellow needles, mp (DSC) 109-110.5 C (from n-pentane at

ca. -20 °C); Rf 0.36 (n-hexane/DCM, 60:40); (found: C, 68.28; H, 3.71; N, 17.64.

C18H12N4S requires: C, 68.33; H, 3.82; N, 17.71%); λmax(DCM)/nm 266 (log ε 4.21), 289

(4.09), 392 (3.81); vmax/cm-1 3065w and 3030w (aryl C-H), 2976w and 2941w (alkyl C-H),

2220m (CN), 1568m, 1516m, 1497w, 1483m, 1458m, 1435m, 1416m, 1352w, 1342m,

1300w, 1263s, 1244w, 1206w, 1163m, 1117m, 1074m, 1047w, 1024w, 1003w, 974w,

939w, 914m, 878m, 839m, 820m, 777m, 772m, 741s; δH(500 MHz; CDCl3) 8.03 (2H, dd,

J 8.5, 1.5), 7.52 (2H, dd, J 7.8, 7.8), 7.45-7.41 (3H, m), 7.36-7.29 (3H, m), 5.52 (2H, d);

δC(125 MHz; CDCl3) 165.8 (s), 138.5 (s), 135.6 (s), 130.9 (s), 129.3 (d), 129.1 (d), 128.8

(d), 128.3 (d), 128.1 (d), 127.6 (s), 126.8 (d), 121.6 (s), 111.2 (s), 52.7 (t); MALDI-TOF

MS (m/z): 317 (MH+, 70%), 316 (M+, 100), 315 (87), 90 (65).

7.3.6.13 6-(tert-Butyl)-4-methyl-6H-pyrazolo[3,4-c]isothiazole-3-carbonitrile 70g

Procedure A: 41 mg, 39%. Procedure B: 22 mg, 21%. Chromatography eluent:

n-hexane/DCM, 60:40. Colorless needles, mp 63-64 °C (from n-pentane at ca. -20 °C); Rf

0.38 (n-hexane/DCM, 50:50); (found: C, 54.42; H, 5.55; N, 25.34. C10H12N4S requires:


vmax/cm-1 2982m, 2940w and 2876w (alkyl C-H), 2222m (CN), 1574m, 1493m, 1470m,

1456m, 1435w, 1412m, 1398s, 1373m, 1366m, 1329m, 1269m, 1240s, 1167m, 1123s,

1032m, 1001w, 939w, 905s, 843m, 802m, 746m; δH(500 MHz; CDCl3) 2.52 (3H, s), 1.69

(9H, s); δC(125 MHz; CDCl3) 164.9 (s), 134.1 (s), 131.8 (s), 118.8 (s), 110.6 (s), 59.5 (s),

28.8 (q), 13.1 (q); MALDI-TOF MS (m/z): 220 (M+, 100%), 218 (35), 204 (15), 175 (8),

164 (9), 149 (8), 72 (46).

MARIA KOYIONI

150

7.3.6.14 6-(tert-Butyl)-4-phenyl-6H-pyrazolo[3,4-c]isothiazole-3-carbonitrile 70h


n-hexane/DCM, 70:30. Yellow needles, mp 120-121.5 °C (from n-pentane at ca. -20 °C);



vmax/cm-1 2990w, 2978w and 2938w (alkyl C-H), 2214m (CN), 1560m, 1508m, 1481m,

1464m, 1404m, 1395m, 1368m, 1344m, 1325w, 1298w, 1283m, 1271w, 1246m, 1231m,

1196w, 1179w, 1159m, 1128m, 1105w, 1098w, 1074w, 1030m, 1022m, 937w, 914m,

878w, 849m, 799m, 770m, 739s; δH(500 MHz; CDCl3) 8.03 (2H, d, J 7.5), 7.51 (2H, dd, J

7.8, 7.8), 7.41 (1H, dd, J 7.5, 7.5), 1.79 (9H, s); δC(125 MHz; CDCl3) 165.4 (s), 136.5 (s),

131.4 (s), 129.0 (d), 128.8 (d), 128.6 (s), 126.7 (d), 119.9 (s), 111.6 (s), 60.3 (s), 28.8 (q);

MALDI-TOF MS (m/z): 283 (MH+, 96%), 282 (M+, 49), 227 (100).

7.3.6.15 4-Methyl-6-phenyl-6H-pyrazolo[3,4-c]isothiazole-3-carbonitrile 70i


n-hexane/DCM, 80:20. Yellow needles, mp 145-145.5 C (from c-hexane); Rf 0.48

(n-hexane/DCM, 60:40); (found: C, 60.04; H, 3.45; N, 23.12. C12H8N4S requires: C, 59.98;

H, 3.36; N, 23.32%); λmax(DCM)/nm 257 (log ε 3.80), 290 (3.36), 295 inf (3.34), 396

(2.98); vmax/cm-1 3071w (aryl C-H), 2924w (alkyl C-H), 2218 (CN), 1591m, 1578m,

1514s, 1501m, 1487m, 1474w, 1445m, 1425m, 1387m, 1341m, 1283m, 1152w, 1117m,

1101m, 1070m, 1059w, 1030w, 1016w, 997w, 903m, 870w, 831w, 752s; δH(500 MHz;

acetone-d6) 8.13 (2H, d, J 8.0), 7.54 (2H, dd, J 8.0, 8.0), 7.28 (1H, dd, J 7.5, 7.5), 2.62 (3H,

s); δC(125 MHz; CDCl3) 163.2 (s), 138.4 (s), 137.4 (s), 132.3 (s), 129.3 (d), 125.3 (d),

120.8 (s), 117.1 (d), 110.0 (s), 13.2 (q); m/z (EI) 240 (M+, 100%), 225 (6), 214 (5), 199 (8),

129 (5), 118 (28), 91 (20), 77 (49), 64 (9), 51 (40).

7.3.6.16 4,6-Diphenyl-6H-pyrazolo[3,4-c]isothiazole-3-carbonitrile 70j

Procedure A: 49.5 mg, 34%. Procedure B: 27.5 mg, 19%. Chromatography eluent:

n-hexane/DCM, 90:10. Yellow needles, mp 152.5-154 °C (from c-hexane); Rf 0.60

(n-hexane/DCM, 60:40); (found: C, 67.65; H, 3.25; N, 18.46. C17H10N4S requires: C, 67.53;


3067w (aryl C-H), 2218m (CN), 1597m, 1566m, 1514m, 1501s, 1464m, 1450w, 1420m,

1348m, 1306w, 1281m, 1186w, 1163w, 1136s, 1126m, 1101w, 1072m, 1028w, 1013m,

968w, 918w, 901m, 833m, 773m; δH(500 MHz; CDCl3) 8.26 (2H, d, J 8.0), 8.14 (2H, d, J

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7.5), 7.58-7.48 (5H, m), 7.30 (1H, dd, J 7.5, 7.5); δC(125 MHz; CDCl3) one C (s)

resonance missing, 163.8 (s), 139.4 (s), 138.4 (s), 130.4 (s), 129.8 (d), 129.4 (d), 129.1 (d),

127.1 (d), 125.8 (d), 121.9 (s), 117.7 (d), 111.0 (s); m/z (EI) 302 (M+, 100%), 276 (4), 225

(4), 180 (5), 153 (9), 151 (5), 103 (5), 91 (4), 77 (77), 70 (8), 51 (32).

7.3.7 1H-Pyrazolo[3,4-d]thiazole-5-carbonitriles 69 (General Procedure)

A stirred sample of the appropriate neat N-(dithiazolylidene)pyrazolamine 68 (0.1 mmol)

under an argon atmosphere was immersed into a preheated Wood’s metal bath at

temperatures specified in Table 7. After 10-15 min the reaction mixture was allowed to

cool to ca. 20 C and extracted with DCM (3 × 1 mL). The combined extracts were

adsorbed onto silica and chromatographed.

7.3.7.1 1,3-Dimethyl-1H-pyrazolo[3,4-d]thiazole-5-carbonitrile 69a

Chromatography eluent: DCM/t-BuOMe, 90:10. Colorless needles (13.7 mg, 77%), mp

99-100.5 °C (from c-hexane); Rf 0.20 (DCM); (found: C, 47.29; H, 3.26; N, 31.34.

C7H6N4S requires: C, 47.18; H, 3.39; N, 31.44%); λmax(DCM)/nm 293 (log ε 2.80), 316 inf

(2.32); vmax/cm-1 2941w (alkyl C-H), 2224m (CN), 1551m, 1497m, 1452m, 1420m, 1389s,

1356m, 1271w, 1233m, 1165m, 1144m, 1099m, 1047m, 993w, 926w, 837w, 810w, 781w;

δH(500 MHz; CDCl3) 4.07 (3H, s), 2.47 (3H, s); δC(125 MHz; CDCl3) 159.0 (s), 139.2 (s),

137.9 (s), 114.6 (s), 113.0 (s), 36.1 (q), 13.9 (q); m/z (EI) 178 (M+, 100%), 163 (15), 85

(94), 70 (86), 58 (8).

7.3.7.2 1-Methyl-3-phenyl-1H-pyrazolo[3,4-d]thiazole-5-carbonitrile 69d

Chromatography eluent: DCM. Colorless needles (19.9 mg, 83%), mp (DSC) onset:

170.5 C, peak max: 171.3 C (from c-hexane); Rf 0.53 (DCM); (found: C, 59.90; H, 3.42;

N, 23.29. C12H8N4S requires: C, 59.98; H, 3.36; N, 23.32%); λmax(DCM)/nm 260 inf (log ε

3.33), 264 (3.35), 281 inf (3.24), 295 (3.34), 348 (2.67); vmax/cm-1 3065w, 3042w and

3007w (aryl C-H), 2945w (alkyl C-H), 2224m (CN), 1545m, 1472s, 1462m, 1452m,

1395m, 1364m, 1356m, 1327w, 1304w, 1292m, 1238m, 1206m, 1182w, 1169w, 1155w,

1121m, 1076w, 1045w, 1030m, 1011m, 912w, 893w, 758s, 731m; δH(500 MHz; CDCl3)

7.73 (2H, d, J 7.0), 7.43 (2H, dd, J 7.5, 7.5), 7.34 (1H, dd, J 7.3, 7.3), 4.14 (3H, s); δC(125

MHz; CDCl3) 159.4 (s), 141.1 (s), 139.7 (s), 130.8 (s), 129.1 (d), 128.9 (d), 125.6 (d),

112.9 (s), 112.5 (s), 36.6 (q); MALDI-TOF MS (m/z): 240 (M+, 100).

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7.3.7.3 1-Benzyl-3-methyl-1H-pyrazolo[3,4-d]thiazole-5-carbonitrile 69e

Chromatography eluent: DCM. Colorless prisms (17.5 mg, 69%), mp 91-93 °C (from

n-pentane at ca. -20 C); Rf 0.56 (DCM); (found: C, 61.39; H, 3.87; N, 21.84. C13H10N4S

requires: C, 61.40; H, 3.96; N, 22.03%); λmax(DCM)/nm 293 (log ε 4.20), 328 (3.75);

vmax/cm-1 3069w, 3034w, 2957w, 2926w, 2230m (CN), 1653m, 1533m, 1500m, 1491m,

1456s, 1445m, 1433m, 1389s, 1358m, 1346w, 1331w, 1325w, 1296m, 1273s, 1206m,

1159m, 1148m, 1117m, 1098m, 1076m, 1026w, 1003m, 930m, 910m, 854w, 824m, 772m,

760w, 748w, 741w, 737w, 731w; δH(500 MHz; DMSO-d6) 7.34-7.25 (5H, m), 5.54 (2H, s),

2.42 (3H, s); δC(125 MHz; DMSO-d6) 158.1 (s), 139.6 (s), 138.4 (s), 136.5 (s), 128.8 (d),

128.0 (d), 127.7 (d), 115.3 (s), 113.4 (s), 52.7 (d), 13.6 (q). MALDI-TOF MS (m/z): 255

(MH+, 100), 242 (15), 91 (55).

7.3.7.4 1-Benzyl-3-phenyl-1H-pyrazolo[3,4-d]thiazole-5-carbonitrile 69f

Chromatography eluent: n-hexane/DCM, 50:50. Beige needles (26.9 mg, 85%), mp 113.5-



4.27), 268 (4.28), 297 (4.21), 350 (3.59); vmax/cm-1 3059w, 3032w and 3009w (aryl C-H),

2983w and 2938w (alkyl C-H), 2226m (CN), 1530m, 1497m, 1472s, 1460m, 1456m,

1447m, 1427m, 1395m, 1354m, 1344w, 1323w, 1290m, 1279m, 1200m, 1163w, 1153w,

1119s, 1076m, 1032w, 1011m, 993w, 972w, 937w, 922w, 891w, 820w, 773s; δH(500 MHz;

CDCl3) 7.82 (2H, d, J 7.0), 7.49 (2H, dd, J 7.8, 7.8), 7.44-7.38 (3H, m), 7.37-7.29 (3H, m),

5.66 (2H, s); δC(125 MHz; CDCl3) 158.9 (s), 141.4 (s), 139.9 (s), 135.5 (s), 130.8 (s),

129.1 (d), 128.9 (d), 128.8 (d), 128.4 (d), 128.1 (d), 125.7 (d), 112.9 (s), 54.0 (t); MALDI-

TOF MS (m/z): 317 (MH+, 100%), 91 (90).

7.3.7.5 3-Methyl-1-phenyl-1H-pyrazolo[3,4-d]thiazole-5-carbonitrile 69g

Chromatography eluent: n-hexane/DCM, 50:50. Beige plates (19.9 mg, 83%), mp 127-


N, 23.29. C12H8N4S requires: C, 59.98; H, 3.36; N, 23.32%); λmax(DCM)/nm 247 (log ε

3.41), 294 (3.33), 354 (2.88); vmax/cm-1 2926w (alkyl C-H), 2224m (CN), 1593m, 1518s,

1495m, 1464m, 1443m, 1391m, 1381m, 1362m, 1335w, 1317w, 1246w, 1167m, 1144s,

1101m, 1074m, 1043w, 1026w, 1005w, 903m, 868w, 760s, 754s; δH(500 MHz; CDCl3)

8.12 (2H, d, J 8.0), 7.51 (2H, dd, J 8.0, 8.0), 7.31 (1H, dd, J 7.3, 7.3), 2.59 (3H, s); δC(125

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MHz; CDCl3) 157.1 (s), 139.6 (s), 139.5 (s), 138.5 (s), 129.4 (d), 126.4 (d), 118.7 (d),

117.5 (s), 112.9 (s), 14.1 (q); MALDI-TOF MS (m/z): 241 (MH+, 100%), 205 (18).

7.3.7.6 1,3-Diphenyl-1H-pyrazolo[3,4-d]thiazole-5-carbonitrile 69h

Chromatography eluent: n-hexane/DCM, 60:40. Yellow needles (23.6 mg, 78%), mp (DSC)

onset: 185.2 C, peak max: 185.6 C (from c-hexane); Rf 0.46 (n-hexane/DCM, 70:30);

(found: C, 67.44; H, 3.18; N, 18.40. C17H10N4S requires: C, 67.53; H, 3.33; N, 18.53%);

λmax(DCM)/nm 239 (log ε 3.37), 278 (3.64), 288 inf (3.61), 371 (3.00); vmax/cm-1 3061w

(aryl C-H), 2226m (CN), 1595m, 1514s, 1487m, 1476m, 1460m, 1445w, 1393w, 1362s,

1331w, 1321m, 1287m, 1213w, 1163w, 1150m, 1128w, 1098w, 1076m, 1024w, 1001m,

989m, 916w, 908w, 772m, 758s, 729m; δH(500 MHz; CDCl3) 8.26 (2H, dd, J 8.5, 1.0),

7.93 (2H, dd, J 8.0, 1.0), 7.58-7.53 (4H, m), 7.46 (1H, dd, J 7.3, 7.3), 7.36 (1H, dd, J 7.5,

7.5); δC(125 MHz; CDCl3) one C (s) resonance missing, 142.0 (s), 140.1 (s), 138.6 (s),

130.3 (s), 129.5 (d), 129.4 (d), 129.2 (d), 126.8 (d), 126.0 (d), 119.0 (d), 115.3 (s), 112.8

(s); MALDI-TOF MS (m/z): 303 (MH+, 92%), 302 (M+, 100).

7.3.8 Debenzylation Reactions with Br2/AIBN

7.3.8.1 3-Phenyl-1H-pyrazolo[3,4-d]thiazole-5-carbonitrile 69c (Typical Procedure)

A stirred mixture of 1-benzyl-3-phenyl-1H-pyrazolo[3,4-d]thiazole-5-carbonitrile 69f

(31.6 mg, 0.1 mmol), dibromine (7.7 μL, 0.15 mmol), AIBN (3.3 mg, 0.02 mmol) and

PhH/H2O (2:1, 1.5 mL) was heated at ca. 80 C for 2 h. The reaction mixture was then

allowed to cool to ca. 20 C and additional dibromine (7.7 μL, 0.15 mmol) and AIBN

(3.3 mg, 0.02 mmol) were added and the mixture was then heated again at ca. 80 C for a

further 5 h. The reaction mixture was then allowed to cool to ca. 20 C and the volatiles

removed in vacuo. To the remaining residue, a solution of NaOH in EtOH (2 mL, 0.05 M)

was added and the mixture heated to ca. 78 C for 12 h. The reaction mixture was then

allowed to cool to ca. 20 oC, adsorbed onto silica and chromatographed (DCM/t-BuOMe,

90:10) to give the title compound 69c (17.2 mg, 76%) as colorless cotton fibers, mp 191-

193 C (from c-hexane/CHCl3), Rf 0.57 (DCM/t-BuOMe, 90:10); (found: C, 58.51; H, 2.73;


4.30), 262 (4.31), 290 (4.34), 325 inf (3.75); vmax/cm-1 3105w, 3024w and 2895w (N-H),

2234w (C≡N), 1501m, 1474m, 1437s, 1387w, 1314m, 1298m, 1184m, 1125s, 1096w,

1001w, 986m, 901w, 818m, 756s; δH(500 MHz; acetone-d6) NH resonance missing, 7.91

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(2H, d, J 7.0), 7.57 (2H, dd, J 7.8, 7.8), 7.46 (1H, dd, J 7.5, 7.5); δC(125 MHz; TFA-d)

160.7 (s), 149.5 (s), 144.2 (s), 134.4 (d), 131.8 (d), 128.4 (d), 126.1 (s), 115.6 (s), 111.7 (s);

MALDI-TOF MS (m/z): 227 (MH+, 100%)

7.3.8.2 4-Methyl-6H-pyrazolo[3,4-c]isothiazole-3-carbonitrile 70b

Similar treatment of 6-benzyl-4-methyl-6H-pyrazolo[3,4-c]isothiazole-3-carbonitrile 70e

(25.4 mg, 0.1 mmol) gave the title compound 70b (3.1 mg, 19%) as colorless needles,

182-183.5 C (from c-hexane/CHCl3), Rf 0.33 (DCM/t-BuOMe, 97:3), identical to that

described above.


Similar treatment of 6-benzyl-4-phenyl-6H-pyrazolo[3,4-c]isothiazole-3-carbonitrile 70f

(31.6 mg, 0.1 mmol) gave the title compound 70c (20.8 mg, 92%) as pale yellow needles,

mp 196-197 C (from c-hexane/CHCl3); Rf 0.68 (DCM/t-BuOMe, 96:4), identical to that

described above.

7.3.9 Hydration of 1H-Pyrazolo[3,4-d]thiazole-5-carbonitriles 69e and 69f and

6H-Pyrazolo[3,4-c]isothiazole-3-carbonitriles 70f and 70h

7.3.9.1 6-Benzyl-4-phenyl-6H-pyrazolo[3,4-c]isothiazole-3-carboxamide 84a

(Typical Procedure)

A stirred solution of 6-benzyl-4-phenyl-6H-pyrazolo[3,4-c]isothiazole-3-carbonitrile 70f

(31.6 mg, 0.1 mmol) in AcOH (2 mL) was heated at ca. 118 C for 3 d. The reaction

mixture was allowed to cool to ca. 20 C, poured onto crushed ice, neutralized (sat.

NaHCO3) and extracted with t-BuOMe (3 20 mL). The combined organic extracts were

dried (Na2SO4), filtered and evaporated to dryness. The residue obtained was dissolved in

DCM (10 mL), adsorbed onto silica and chromatographed to give the title compound 84a

(27.8 mg, 83%), as pale yellow needles, mp 181-183 C (from c-hexane/CHCl3); Rf 0.50

(DCM/t-BuOMe, 90:10); (found: C, 64.56; H, 4.21; N, 16.62. C18H14N4OS requires:


vmax/cm-1 3451m, 3439m, 3331w, 3273w and 3130m (N-H), 2931w (alkyl C-H), 1670s

(C=O), 1659m, 1607m, 1572m, 1514w, 1495w, 1477m, 1454m, 1435m, 1412m, 1391m,

1358w, 1352w, 1327m, 1308m, 1273m, 1206w, 1182w, 1157w, 1134m, 1109m, 1076m,

1070m, 1042w, 1022m, 934m, 924m, 887m, 845m, 839m, 791m, 779m, 770m, 758m;

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δH(500 MHz; CDCl3) 7.71 (2H, d, J 8.0), 7.52-7.46 (3H, m), 7.43 (2H, d, J 7.5), 7.33 (2H,

dd, J 7.5, 7.5), 7.29 (1H, dd, J 7.3, 7.3), 5.75 (2H, br s), 5.50 (2H, s); δC(125 MHz; CDCl3)

one C (d) resonance missing, 166.6 (s), 161.0 (s), 150.9 (s), 138.2 (s), 136.1 (s), 131.8 (s),

129.5 (d), 129.0 (d), 128.7 (d), 128.13 (d), 128.06 (d), 121.8 (s), 52.3 (t); MALDI-TOF MS

(m/z): 335 (MH+, 100%), 333 (M+-1, 27), 324 (31), 318 (28), 292 (15), 281 (13), 257 (10),

90 (67).

7.3.9.2 6-(tert-Butyl)-4-phenyl-6H-pyrazolo[3,4-c]isothiazole-3-carboxamide 84b

Similar treatment of 6-(tert-butyl)-4-phenyl-6H-pyrazolo[3,4-c]isothiazole-3-carbonitrile

70h (28.2 mg, 0.1 mmol) gave the title compound 84b (23.7 mg, 83%), as pale yellow

needles, mp 197.5-198.5 C (from c-hexane/CHCl3); Rf 0.43 (DCM/Et2O, 90:10); (found:

C, 59.86; H, 5.26; N, 18.74. C15H16N4OS requires: C, 59.98; H, 5.37; N, 18.65%);

λmax(DCM)/nm 260 (log ε 4.13), 290 (4.10), 373 (3.89); vmax/cm-1 3462m, 3269m and

3173m (N-H), 2980m and 2932w (alkyl C-H), 1665m, 1639s (C=O), 1611m, 1568m,

1510w, 1466m, 1439w, 1383s, 1329m, 1300w, 1283w, 1263m, 1242m, 1182m, 1134s,

1094m, 1074w, 1020m, 986w, 926m, 914m, 872m, 845m, 804m, 773s, 748s; δH(500 MHz;

CDCl3) 7.71 (2H, d, J 7.0), 7.50 (2H, dd, J 7.3, 7.3), 7.45 (1H, dd, J 7.3, 7.3), 6.15 (1H, br

s), 5.66 (1H, br s), 1.78 (9H, s); δC(125 MHz; CDCl3) 166.3 (s), 161.5 (s), 149.1 (s), 136.3

(s), 132.3 (s), 129.2 (d), 128.9 (d), 128.8 (d), 122.9 (s), 59.8 (s), 28.9 (q); MALDI-TOF MS

(m/z): 301 (MH+, 100%), 245 (80).

7.3.9.3 1-Benzyl-3-methyl-1H-pyrazolo[3,4-d]thiazole-5-carboxamide 86a

Similar treatment of 1-benzyl-3-methyl-1H-pyrazolo[3,4-d]thiazole-5-carbonitrile 69e

(25.4 mg, 0.1 mmol) with concd H2SO4 (1 mL) at ca. 20 C for 2 h gave the title

compound 86a as colorless needles (23.1 mg, 85%), mp 159-161 C (from

c-hexane/CHCl3); Rf 0.29 (DCM/Et2O, 90:10); (found: C, 57.29; H, 4.31; N, 20.46.


(4.02), 316 (3.71); vmax/cm-1 3470m, 3347w, 3275w and 3196m (N-H), 1688s (C=O),

1585m, 1531m, 1501m, 1485m, 1460m, 1402m, 1377m, 1356w, 1333w, 1319w, 1288w,

1271m, 1204w, 1153m, 1119m, 1070m, 1034w, 1007w, 941w, 924w, 908w, 818w, 766m,

731m; δH(500 MHz; DMSO-d6) 8.32 (1H, s), 8.04 (1H, s), 7.33 (2H, dd, J 7.3, 7.3), 7.29-

7.26 (3H, m), 5.52 (2H, s), 2.39 (3H, s); δC(125 MHz; DMSO-d6) 169.0 (s), 161.2 (s),

158.5 (s), 138.1 (s), 136.9 (s), 128.5 (d), 127.6 (d), 127.3 (d), 114.1 (s), 52.1 (t), 13.5 (q);

MALDI-TOF MS (m/z): 273 (MH+, 82%), 257 (22), 229 (7), 91 (100).

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7.3.9.4 1-Benzyl-3-phenyl-1H-pyrazolo[3,4-d]thiazole-5-carboxamide 86b

Similar treatment of 1-benzyl-3-methyl-1H-pyrazolo[3,4-d]thiazole-5-carbonitrile 69f

(25.4 mg, 0.1 mmol) with concd H2SO4 (1 mL) at ca. 20 C for 2 h gave the title

compound 86b as colorless cotton fibers (29.4 mg, 88%), mp 204-205 C (from

c-hexane/CHCl3); Rf 0.48 (DCM/Et2O, 90:10); (found: C, 64.57; H, 4.16; N, 16.66.

C18H14N4OS requires: C, 64.65; H, 4.22; N, 16.75%); λmax(DCM)/nm 265 (log ε 4.35), 295

(4.19), 334 inf (3.77); vmax/cm-1 3447m and 3150m (N-H), 1690s (C=O), 1595m, 1533m,

1489m, 1452m, 1412m, 1383m, 1360m, 1331m, 1296m, 1281m, 1202w, 1175w, 1155w,

1123m, 1074m, 1013m, 991w, 945m, 920w, 908w, 889w, 835w, 772m, 766m, 733s;

δH(500 MHz; DMSO-d6) 8.44 (1H, s), 8.13 (1H, s), 7.83 (2H, d, J 7.5), 7.52 (2H, dd, J 7.8,

7.8), 7.41 (1H, dd, J 7.3, 7.3), 7.36-7.34 (4H, m), 7.32-7.28 (1H, m), 5.69 (2H, s); δC(125

MHz; DMSO-d6) one C (s) resonance missing, 169.9 (s), 161.0 (s), 159.1 (s), 140.5 (s),

136.5 (s), 131.0 (s), 129.1 (d), 128.6 (d), 128.4 (d), 127.8 (d), 127.4 (d), 125.1 (d), 112.0

(s), 52.7 (t); MALDI-TOF MS (m/z): 335 (MH+, 100%), 318 (7), 292 (6), 91 (72).

7.3.10 N-Debenzylation/Debutylation Reactions Using concd H2SO4

General Procedure (see Scheme 37 for yields and reaction times): To stirred concd H2SO4

(1 mL) at ca. 20 oC the appropriate 6H-pyrazolo[3,4-c]isothiazole-3-carbonitrile 70e-70h

(0.1 mmol) was added in one portion. The reaction mixture was then placed in a preheated

oil bath at ca. 60 C and stirred at this temperature until completion of the reaction (by

TLC). After which time, the reaction mixture was allowed to cool to ca. 20 C, poured

onto crushed ice and neutralized (sat. NaHCO3). The aqueous phase was extracted with

t-BuOMe (3 × 20 mL), and the combined organic phase, dried (Na2SO4) and the volatiles

removed in vacuo. The residue was dissolved in THF/EtOH 1:1 (10 mL) adsorbed onto

silica and chromatographed.

7.3.10.1 4-Methyl-6H-pyrazolo[3,4-c]isothiazole-3-carboxamide 85a

Beige plates, mp (DSC) onset: 239.5 C, peak max: 248.4 C, decomp. onset: 250.2 C,

peak max: 251.2 C (from EtOH); Rf 0.35 (Et2O); (found: C, 39.56; H, 3.23; N, 30.69.


(3.74), 341 (3.60); vmax/cm-1 3455m, 3261m and 3183m (N-H), 1651s (C=O), 1585m,

1572m, 1510w, 1493m, 1431m, 1381m, 1294m, 1132w, 1078m, 1042m, 991m, 928m,

841w, 795m, 768m, 752w; δH(500 MHz; DMSO-d6) 12.55 (1H, s), 8.09 (1H, br s), 7.89

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(1H, br s), 2.44 (3H, s); δC(125 MHz; DMSO-d6) 167.5 (s), 160.8 (s), 149.8 (s), 137.1 (s),

126.5 (s), 14.4 (q); MALDI-TOF MS (m/z): 181 (M+-1, 100%), 138 (3).

7.3.10.2 4-Phenyl-6H-pyrazolo[3,4-c]isothiazole-3-carboxamide 85b

Pale yellow plates, mp 261-262 C (from EtOH); Rf 0.62 (DCM/t-BuOMe, 70:30); (found:

C, 54.20; H, 3.17; N, 22.86. C11H8N4OS requires: C, 54.09; H, 3.30; N, 22.94%);

λmax(EtOH)/nm 206 (log ε 4.17), 254 (4.12), 278 (4.13), 346 (3.90); vmax/cm-1 3464w,

3343w, 3287w (N-H), 2833w, 1655m, 1651m, 1589m, 1497w, 1464w, 1437m, 1371m,

1323m, 1302m, 1277m, 1169w, 1105m, 1072m, 1034m, 1015m, 914m, 858m, 783s, 739m;

δH(500 MHz; DMSO-d6) 13.24 (1H, br s), 8.19 (1H, br s), 8.09 (1H, br s), 7.83 (2H, dd, J

8.5, 1.5), 7.45 (2H, dd, J 7.5, 7.5), 7.39 (1H, dd, J 7.3, 1.3); δC(125 MHz; DMSO-d6) 167.5

(s), 161.7 (s), 151.2 (s), 139.1 (s), 132.2 (s), 128.52 (d), 128.47 (d), 127.4 (d), 122.7 (s);

MALDI-TOF MS (m/z): 246 (MH++1, 42%), 245 (MH+, 100), 228 (54).

7.3.11 Dehydration Reactions with POCl3

7.3.11.1 Methyl-6H-pyrazolo[3,4-c]isothiazole-3-carbonitrile 70b (Typical Procedure)

To stirred POCl3 (3 mL) at ca. 20 °C was added in one portion 4-methyl-6H-

pyrazolo[3,4-c]isothiazole-3-carboxamide 85a (18.2 mg, 0.1 mmol). The reaction mixture

was then placed in a preheated oil bath at ca. 60 C for 4.5 h. The reaction mixture was

then allowed to cool to ca. 20 C, poured onto crushed ice, neutralized (sat. NaHCO3) and

extracted with CHCl3 (3 × 100 mL). The combined organic extracts were dried (Na2SO4),

filtered and evaporated to dryness. The residue obtained was dissolved in DCM, adsorbed

onto silica and chromatographed (DCM/t-BuOMe, 90:10) to give the title compound 70b

(13.9 mg, 85%) as colorless needles, 182-183.5 C (from c-hexane/CHCl3), Rf 0.33

(DCM/t-BuOMe, 97:3), identical to that described above.


Similar treatment of 4-phenyl-6H-pyrazolo[3,4-c]isothiazole-3-carboxamide 85b (24.4 mg,

0.1 mmol) gave the title compound 70c (20.7 mg, 92%) as pale yellow needles, mp 196-

197 C (from c-hexane/CHCl3); Rf 0.68 (DCM/t-BuOMe, 96:4), identical to that described

above.

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7.4.1 Stepwise Synthesis of 5,7-Dimethyl-5H-pyrazolo[3,4-e][1,2,4]dithiazine-3-

carbonitrile 91a

7.4.1.1 (Z)-2-[(Diethylamino)disulfanyl-2-(1,3-dimethyl-1H-pyrazol-5-yl)imino]-

acetonitrile 93a

To a stirred suspension of (Z)-N-(4-chloro-5H-1,2,3-dithiazol-5-ylidene)-1,3-dimethyl-1H-

pyrazol-5-amine 68a (49.3 mg, 0.2 mmol) in MeCN (4 mL) at ca. 20 °C was added

Hünig’s base (34.5 μL, 0.2 mmol) followed by diethylamine (63.0 μL, 0.6 mmol). After 25

min stirring the reaction mixture was diluted with n-hexane and poured onto a packed

silica column. Elution with DCM/t-BuOMe (90:10) afforded a mixture from which the

volatiles were removed under vacuum. The remaining residue was diluted with DCM,

adsorbed onto silica and chromatographed (DCM/t-BuOMe, 95:5) to give the title

compound 93a (50 mg, 89%) as beige needles, mp (DSC) onset: 64.4 °C, peak max:

65.0 °C, decomp. onset: 91.5 °C, peak max: 99.4 °C (from n-pentane at ca. -20 °C), Rf 0.43

(DCM); (found: C, 46.53; H, 5.99; N, 24.66. C11H17N5S2 requires: C, 46.62; H, 6.05;

N, 24.71%); λmax(DCM)/nm 246 (log ε 3.96), 352 (4.16); vmax/cm-1 3138w (aryl C-H),

2972m, 2934m and 2870w (alkyl C-H), 2214m (C≡N), 1557m, 1512m, 1470m, 1445m,

1375m, 1368m, 1348m, 1302m, 1173m, 1163m, 1098w, 1065s, 1043s, 1011s, 920m, 914m,

847m, 795m; δH(500 MHz; CDCl3) major 6.27 (1H, s), 3.86 (3H, s), 3.09 (4H, q, J 7.3),

2.28 (3H, s), 1.21 (6H, t, J 7.0); minor 6.63 (1H, s), 3.85 (3H, s), 3.03 (4H, q, J 7.2), 2.28

(3H, s), 1.20 (6H, t, J 7.3) (major/minor, 5:1); δC(125 MHz; CDCl3) major 147.8 (s), 143.5

(s), 138.8 (s), 113.2 (s), 100.8 (d), 52.3 (t), 35.3 (q), 13.93 (q), 13.1 (q); minor 148.2 (s),

144.4 (s), 137.3 (s), 109.8 (s), 95.1 (d), 52.2 (t), 35.0 (q), 13.94 (q), 13.2 (q); MALDI-TOF

MS (m/z): 285 (M++2, 57%), 284 (M++1, 99), 213 (100), 181 (69), 104 (47), 71 (52).

7.4.1.2 Treatment of (Z)-2-[(Diethylamino)disulfanyl-2-(1,3-dimethyl-1H-pyrazol-5-

yl)imino]acetonitrile 93a with concd HCl

To a stirred solution of (Z)-2-[(diethylamino)disulfanyl-2-(1,3-dimethyl-1H-pyrazol-5-

yl)imino]acetonitrile 93a (28.3 mg, 0.1 mmol) in MeCN (2 mL) at ca. 20 °C was added in

one portion concd HCl (11 μL, 0.125 mmol). After 5 min stirring, the mixture was

adsorbed onto silica and chromatographed (n-hexane/t-BuOMe, 90:10) to give

6,8-dimethyl-6H-pyrazolo[3,4-f][1,2,3,5]trithiazepine-4-carbonitrile 94a (1.3 mg, 5%) as

yellow needles, mp (DSC) onset: 66.7 °C, peak max: 71.7 °C, decomp. onset: 166.8 °C,

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peak max: 185.7 °C (from n-pentane at ca. -20 °C), Rf 0.40 (n-hexane/t-BuOMe, 80:20);

(found: C, 34.57; H, 2.41; N, 23.24. C7H6N4S3 requires: C, 34.69; H, 2.50; N, 23.12%);

λmax(DCM)/nm 301 (log ε 3.58), 373 (3.65), 414 inf (3.26); vmax/cm-1 2949w and 2922w

(alkyl C-H), 2218w (C≡N), 1584m, 1481m, 1427m, 1422s, 1387m, 1342m, 1306m, 1198w,

1121w, 1080m, 1042s, 1018m, 995m, 901m, 754s; δH(500 MHz; CDCl3) 3.96 (3H, s), 2.28

(3H, s); δC(125 MHz; CDCl3) 146.1 (s), 140.7 (s), 127.8 (s), 121.0 (s), 114.6 (s), 36.7 (q),

12.5 (q); MALDI-TOF MS (m/z): 243 (M++1, 28%), 242 (M+, 65), 241 (M+-1, 100), 178

(32), 177 (75). Further elution (n-hexane/t-BuOMe, 90:10) gave 5,7-dimethyl-5H-

pyrazolo[3,4-e][1,2,4]dithiazine-3-carbonitrile 91a as red needles (17.2 mg, 82%), mp

(DSC) onset: 98.2 °C, peak max: 98.6 °C, bp onset: 189.6 °C, peak max: 198.3 °C (from

n-hexane), Rf 0.32 (n-hexane/t-BuOMe, 80:20); (found: C, 40.10; H, 2.69; N, 26.54.

C7H6N4S2 requires: C, 39.98; H, 2.88; N, 26.65%); λmax(DCM)/nm 288 (log ε 3.82), 357

inf (3.60), 377 (3.64), 521 (2.81); vmax/cm-1 2943w (alkyl C-H), 2218m (C≡N), 1504s,

1495m, 1452m, 1377m, 1337w, 1292m, 1209w, 1177w, 1103m, 1065s, 1045m, 1038m,

988w, 912m, 764w, 746m; δH(500 MHz; CDCl3) 3.78 (3H, s), 2.19 (3H, s); δC(125 MHz;

CDCl3) 146.3 (s), 143.2 (s), 126.2 (s), 113.0 (s), 94.5 (s), 35.4 (q), 12.1 (q); MALDI-TOF

MS (m/z): 212 (M++2, 26%), 211 (M++1, 81), 210 (M+, 100), 195 (56).

7.4.2 One-pot Transformation of (Z)-N-(4-Chloro-5H-1,2,3-dithiazol-5-ylidene)-

1H-pyrazol-5-amines 68 to 5H-Pyrazolo[3,4-e][1,2,4]dithiazine-3-carboni-

triles 91

General Procedure: To a stirred suspension of the appropriate (Z)-N-(4-chloro-5H-1,2,3-

dithiazol-5-ylidene)-1H-pyrazol-5-amine 5 (0.2 mmol) in MeCN (4 mL) at ca. 20 °C was

added Hünig’s base (34.5 μL, 0.2 mmol) followed by diethylamine (63.0 μL, 0.6 mmol).

After 25 min stirring, to the mixture was added in one portion concd H2SO4 (55 μL,

1 mmol). The mixture was stirred for 5 min and then adsorbed onto silica and

chromatographed to give the corresponding 6H-pyrazolo[3,4-f][1,2,3,5]trithiazepine-4-

carbonitriles 94 and 5H-pyrazolo[3,4-e][1,2,4]dithiazine-3-carbonitriles 91.

7.4.2.1 5,7-Dimethyl-5H-pyrazolo[3,4-e][1,2,4]dithiazine-3-carbonitrile 91a

Chromatography eluent: n-hexane/t-BuOMe, 90:10. Obtained as red needles (31 mg, 74%),

mp (DSC) onset: 98.2 °C, peak max: 98.6 °C, bp onset: 189.6 °C, peak max: 198.3 °C

(from n-hexane), Rf 0.32 (n-hexane/t-BuOMe, 80:20); identical to that described above.

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7.4.2.2 5-Methyl-7-phenyl-5H-pyrazolo[3,4-e][1,2,4]dithiazine-3-carbonitrile 91b

Chromatography eluent: n-hexane/t-BuOMe, 98:2. Obtained as red needles (41 mg, 75%),

mp (DSC) onset: 106.8 ºC, peak max: 108.5 C, decomp. onset: 175.9 C, peak max:

211.4 C (from n-hexane); Rf 0.38 (n-hexane/t-BuOMe, 90:10); (found: C, 52.86; H, 2.89;

N, 20.58. C12H8N4S2 requires: C, 52.92; H, 2.96; N, 20.57%); λmax(DCM)/nm 255 (log ε

4.31), 325 inf (3.51), 409 (3.59), 508 (2.77); vmax/cm-1 2945w (alkyl C-H), 2222w (C≡N),

1522m, 1481m, 1454m, 1431m, 1308m, 1204w, 1180w, 1169w, 1074m, 1045m, 1009m,

916w, 868w, 772s, 746m; δH(500 MHz; CDCl3) 7.68 (2H, d, J 8.0), 7.45 (2H, dd, J 7.3,

7.3), 7.38 (1H, dd, J 7.5, 7.5), 3.91 (3H, s); δC(125 MHz; CDCl3) 146.9 (s), 145.6 (s),

130.8 (s), 128.9 (d), 128.8 (d), 126.7 (d), 126.3 (d), 113.0 (s), 93.8 (s), 35.9 (q); MALDI-

TOF MS (m/z): 274 (M++2, 15%), 273 (M++1, 59), 272 (M+, 100), 257 (69), 168 (7).

7.4.2.3 5-Benzyl-7-methyl-5H-pyrazolo[3,4-e][1,2,4]dithiazine-3-carbonitrile 91c

Chromatography eluent: n-hexane/t-BuOMe, 95:5. Obtained as red oil (45 mg, 78%),

(DSC) decomp. onset: 171.8 C, peak max: 204.1 C; Rf 0.31 (n-hexane/t-BuOMe, 90:10);


λmax(DCM)/nm 295 (log ε 3.68), 357 inf (3.59), 377 (3.63), 522 (2.77); vmax/cm-1 3065w

and 3032w (aryl C-H), 2928w and 2853w (alkyl C-H), 2220w (C≡N), 1514m, 1497m,

1460m, 1454m, 1441m, 1375w, 1358w, 1314m, 1294m, 1279m, 1227w, 1204w, 1182w,

1144m, 1094m, 1061m, 1030m, 1003w, 918m, 907m, 820w, 758m, 735s; δH(500 MHz;

CDCl3) 7.35-7.29 (3H, m), 7.24 (2H, d, J 7.3), 5.25 (2H, s), 2.20 (3H, s); δC(125 MHz;

CDCl3) 146.1 (s), 143.8 (s), 135.5 (s), 128.8 (d), 128.2 (d), 127.9 (d), 126.2 (s), 113.1 (s),

95.0 (s), 52.3 (t), 12.3 (q); MALDI-TOF MS (m/z): 288 (M++2, 63%), 287 (M++1, 93), 286

(M+, 100), 253 (36), 245 (12), 195 (12), 182 (22), 104 (7), 91 (98).

7.4.2.4 5-Benzyl-7-phenyl-5H-pyrazolo[3,4-e][1,2,4]dithiazine-3-carbonitrile 91d

Chromatography eluent: n-hexane/t-BuOMe, 95:5. Obtained as brown needles (59 mg,

85%), mp (DSC) onset: 130.3 °C, peak max: 134.3 °C, decomp. onset: 187.3 C, peak max:

208.5 C (from c-hexane); Rf 0.52 (n-hexane/t-BuOMe, 90:10); (found: C, 61.92; H, 3.62;


4.32), 305 inf (3.62), 407 (3.62), 520 (2.77); vmax/cm-1 3063w and 3032w (aryl C-H),

2976w and 2940w (alkyl C-H), 2222w (C≡N), 1530m, 1495m, 1481m, 1464w, 1452m,

1427m, 1354m, 1331m, 1317m, 1294m, 1283m, 1180m, 1132m, 1067m, 1026w, 1009m,

916w, 907w, 872w, 772s, 731s; δH(500 MHz; CDCl3) 7.71 (2H, d, J 7.0 Hz), 7.44 (2H, dd,

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J 7.5, 7.5), 7.39-7.30 (6H, m), 5.39 (2H, s); δC(125 MHz; CDCl3) one C (d) resonance

missing, 146.6 (s), 146.0 (s), 135.3 (s), 130.8 (s), 128.87 (d), 128.85 (d), 128.3 (d), 127.9

(d), 126.8 (d), 126.2 (s), 113.1 (s), 94.2 (s), 52.8 (t); MALDI-TOF MS (m/z): 350 (M++2,

36%), 349 (M++1, 80), 348 (M+, 100), 315 (11), 257 (14), 245 (30), 90 (80). The dithiazine

91d co-eluted on chromatography with the trithiazepine 94d, nevertheless, a

microanalytically pure sample of compound 91d was obtained by recrystallization.

7.4.2.5 7-Methyl-5-phenyl-5H-pyrazolo[3,4-e][1,2,4]dithiazine-3-carbonitrile 91e

Chromatography eluent: n-hexane/t-BuOMe, 95:5. Obtained as brown needles (46 mg,


179.8 C (from n-pentane at ca. -20 °C); Rf 0.44 (n-hexane/t-BuOMe, 90:10); (found:

C, 53.01; H, 2.87; N, 20.56. C12H8N4S2 requires: C, 52.92; H, 2.96; N, 20.57%);

λmax(DCM)/nm 239 (log ε 4.24), 307 (3.63), 359 inf (3.60), 401 (3.76), 520 (2.87);

vmax/cm-1 3105w, 3082w and 3049w (aryl C-H), 2924 (alkyl C-H), 2216w (C≡N), 1591m,

1504s, 1464m, 1435m, 1418m, 1368w, 1352m, 1319w, 1163m, 1107m, 1074m, 1057m,

1024m, 1001w, 964w, 932w, 907m, 854m, 760s, 733s; δH(500 MHz; CDCl3) 7.59 (2H, d,

J 8.0), 7.47 (2H, dd, J 8.0, 8.0), 7.37 (1H, dd, J 7.5, 7.5), 2.32 (3H, s); δC(125 MHz; CDCl3)

146.0 (s), 144.6 (s), 137.6 (s), 129.2 (d), 128.0 (d), 125.4 (s), 122.7 (d), 113.1 (s), 98.1 (s),

12.4 (q); MALDI-TOF MS (m/z): 274 (M++2, 25%), 273 (M++1, 100), 272 (M+, 44), 246

(5), 239 (19), 240 (22), 231 (13), 220 (35), 209 (22), 198 (3), 155 (5).

7.4.2.6 5,7-Diphenyl-5H-pyrazolo[3,4-e][1,2,4]dithiazine-3-carbonitrile 91f

Chromatography eluent: n-hexane/t-BuOMe, 95:5. Obtained as orange/brown cotton fibers

(54 mg, 80%), mp (DSC) onset: 144.7 °C, peak max: 147.0 °C, decomp. onset: 149.2 C,

peak max: 164.2 C (from n-hexane at ca. -20 °C); Rf 0.56 (n-hexane/t-BuOMe, 90:10);


λmax(DCM)/nm 239 (log ε 4.25), 267 (4.33), 332 inf (3.53), 422 (3.67), 509 inf (2.93);

vmax/cm-1 3061w (aryl C-H), 2218w (C≡N), 1595m, 1518m, 1499s, 1477m, 1460m, 1454m,

1427m, 1344m, 1319m, 1300m, 1236w, 1202m, 1152m, 1090m, 1072m, 1055m, 1026m,

1003m, 982m, 903m, 835m, 764s, 758s, 731m; δH(500 MHz; CDCl3) 7.81 (2H, d, J 7.0),

7.71 (2H, d, J 8.0), 7.53-7.48 (4H, m), 7.45-7.41 (2H, m); δC(125 MHz; CDCl3) 146.7 (s),

146.6 (s), 137.7 (s), 130.6 (s), 129.23 (d), 129.20 (d), 129.0 (d), 128.3 (d), 127.0 (d), 125.4

(s), 123.1 (d), 113.1 (s), 97.3 (s); MALDI-TOF MS (m/z): 336 (M++2, 22%), 335 (M++1,

63), 334 (M+, 100), 301 (12), 282 (13), 271 (3), 231 (36), 198 (3), 155 (4).

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7.4.2.7 6,8-Dimethyl-6H-pyrazolo[3,4-f][1,2,3,5]trithiazepine-4-carbonitrile 94a

Chromatography eluent: n-hexane/t-BuOMe (90:10). Obtained as yellow needles (2.4 mg,

5%), mp (DSC) onset: 66.7 °C, peak max: 71.7 °C, decomp. onset: 166.8 °C, peak max:

185.7 °C (from n-pentane at ca. -20 °C), Rf 0.40 (n-hexane/t-BuOMe, 80:20), identical to

that described above.

7.4.2.8 6-Methyl-8-phenyl-6H-pyrazolo[3,4-f][1,2,3,5]trithiazepine-4-carbonitrile 94b

Chromatography eluent: n-hexane/t-BuOMe, 90:10. Obtained as pale yellow needles

(3.0 mg, 5%), mp 104-106 °C (from n-pentane at ca. -20 °C); Rf 0.40 (n-hexane/t-BuOMe,

90:10); (found: C, 47.30; H, 2.54; N, 18.32. C12H8N4S3 requires: C, 47.35; H, 2.65;

N, 18.41%); λmax(DCM) 250 (log ε 4.32), 295 inf (3.79), 385 (3.95); vmax/cm-1 3059w (aryl

C-H), 2947w (alkyl C-H), 2218w (C≡N), 1589m, 1558m, 1506m, 1456m, 1448m, 1433m,

1414m, 1387w, 1341w, 1317m, 1306m, 1200w, 1182w, 1157w, 1146w, 1076m, 1020m,

1003m, 914m, 853w, 770s, 758m; δH(500 MHz; CDCl3) 7.68 (2H, d, J 8.0), 7.47 (2H, dd,

J 7.5, 7.5), 7.42 (1H, dd, J 7.5, 7.5), 4.08 (3H, s); δC(125 MHz; CDCl3) 148.9 (s), 141.1 (s),

131.2 (s), 128.9 (d), 128.7 (d), 128.3 (s), 127.8 (d), 120.5 (s), 114.5 (s), 37.2 (q); MALDI-

TOF MS (m/z): 306 (M++2, 48%), 305 (M++1, 100), 304 (M+, 86), 242 (18), 241 (70), 240

(33). Although the compound was obtained microanalytically pure by recrystallization, it

was not very stable in solution and afforded a trace of dithiazine 91b which was visible in

the NMR.

7.4.2.9 6-Benzyl-8-methyl-6H-pyrazolo[3,4-f][1,2,3,5]trithiazepine-4-carbonitrile 94c

Chromatography eluent: n-hexane/t-BuOMe, 90:10. Obtained as yellow needles (3.8 mg,


193.3 C (from n-pentane at ca. -20 °C); Rf 0.52 (n-hexane/t-BuOMe, 90:10); (found:


λmax(DCM)/nm 303 (log ε 3.76), 370 (3.88), 407 inf (3.57); vmax/cm-1 2212w (C≡N),

1582m, 1558w, 1539w, 1522w, 1506w, 1497m, 1477m, 1454m, 1422m, 1402m, 1360w,

1346w, 1323m, 1296m, 1279w, 1204w, 1152w, 1076m, 1055s, 1028m, 1003m, 947w,

905m, 818w, 795w, 768s, 735s; δH(500 MHz; CDCl3) 7.36-7.28 (5H, m), 5.47 (2H, s),

2.29 (3H, s); δC(125 MHz; CDCl3) 146.6 (s), 140.2 (s), 136.0 (s), 128.8 (d), 128.13 (d),

128.12 (d), 128.0 (s), 121.4 (s), 114.5 (s), 53.3 (t), 12.7 (q); MALDI-TOF MS (m/z): 320

(M++2, 78%), 319 (M++1, 80), 318 (M+, 28), 310 (7), 286 (18), 278 (6), 256 (40), 255

(100), 91 (86).

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7.4.3 Synthesis of (Z)-3-[(4-Chloro-5H-1,2,3-dithiazol-5-ylidene)amino]phenol 95c


in DCM (10 mL) protected by CaCl2 drying tube at ca. 20 °C was added 3-aminophenol

(262 mg, 2.4 mmol) in one portion. After 2 h, to the reaction mixture was added Hünig’s

base (835 μL, 4.8 mmol). After an additional 1 h the mixture was adsorbed on silica and

chromatographed (DCM) to give unidentified minor red side products. Further elution

(DCM/t-BuOMe, 95:5) gave (Z)-3-[(4-chloro-5H-1,2,3-dithiazol-5-ylidene)amino]phenol

95c as yellow plates (245 mg, 42%), mp 102-104 °C (from c-hexane/DCE), Rf 0.45

(DCM/t-BuOMe, 96:4); (found: C, 39.19; H, 1.93; N, 11.36. C8H5ClN2OS2 requires:

C, 39.27; H, 2.06; N, 11.45%); λmax(DCM)/nm 377 (log ε 3.74); vmax/cm-1 3242m (O-H),

1585s, 1574s, 1518w, 1503w, 1476m, 1462m, 1314m, 1300m, 1281m, 1227m, 1173s,

1136m, 1078m, 997m, 959m, 897s, 866m, 808m, 787m, 754m; δH(500 MHz; DMSO-d6)

9.73 (1H, br s), 7.27 (1H, dd, J 8.0, 8.0), 6.65 (1H, dd, J 8.0, 1.5), 6.62 (1H, dd, J 8.0, 1.5),

6.59 (1H, dd, J 2.0, 2.0); δC(125 MHz; DMSO-d6) 159.0 (s), 158.6 (s), 152.1 (s), 146.7 (s),

130.7 (d), 113.2 (d), 109.7 (d), 105.8 (d); m/z (EI) 246 (M++2, 21%), 244 (M+, 51), 209

(19), 183 (16), 151 (8), 145 (13), 119 (100), 93 (21), 91 (14), 64 (37).

7.4.4 One-pot Transformation of N-(4-Chloro-5H-1,2,3-dithiazol-5-ylidene)-

anilines 95 to Benzo[e][1,2,4]dithiazine-3-carbonitriles 96

General Procedure: To a stirred suspension of the appropriate N-(4-chloro-5H-1,2,3-

dithiazol-5-ylidene)aniline 95 (0.2 mmol) in MeCN (4 mL) at ca. 20 °C was added

Hünig’s base (34.5 μL, 0.2 mmol) followed by diethylamine (63.0 μL, 0.6 mmol). After 25

min stirring, to the mixture was added in one portion concd H2SO4 (55 μL, 1 mmol). The

mixture was stirred for 5 min and then adsorbed on silica and chromatographed to give the

corresponding benzo[e][1,2,4]dithiazine-3-carbonitriles 96 and benzo[d]thiazole-2-carbo-

nitriles 97.

7.4.4.1 6-Methoxybenzo[e][1,2,4]dithiazine-3-carbonitrile 96b

Chromatography eluent: n-hexane/t-BuOMe, 90:10. Obtained as red plates (7.6 mg, 17%),

mp (DSC) onset: 129.1 °C, peak max: 129.5 °C, decomp. onset: 130.5 °C, peak max:


N, 12.50. C9H6N2OS2 requires: C, 48.63; H, 2.72; N, 12.60%); λmax(DCM)/nm 258 (log ε

4.13), 279 inf (3.88), 350 (3.56), 481 (2.67); vmax/cm-1 2972w, 2848w, 2228w (C≡N),

1595m, 1557m, 1530m, 1468m, 1437m, 1398w, 1310m, 1277m, 1236s, 1196w, 1165m,

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1128m, 1069m, 1057s, 1024m, 951m, 851m, 816s, 754m; δH(500 MHz; CDCl3) 7.24-7.22

(1H, m), 6.94-6.92 (2H, m), 3.84 (3H, s); δC(125 MHz; CDCl3) 161.0 (s), 145.5 (s), 133.6

(s), 129.7 (d), 117.7 (d), 112.9 (s), 112.5 (d), 109.9 (s), 55.8 (q); MALDI-TOF MS (m/z):

224 (M++2, 19%), 223 (M++1, 64), 222 (M+, 96), 204 (100).

7.4.4.2 6-Hydroxybenzo[e][1,2,4]dithiazine-3-carbonitrile 96c

Chromatography eluent: DCM. Obtained as red prisms (23 mg, 55%), mp (DSC) onset:

148.2 °C, peak max: 150.6 °C, decomp. onset: 152.9 °C, peak max: 156.7 °C (from

CHCl3); Rf 0.60 (DCM/t-BuOMe, 96:4); (found: C, 46.25; H, 1.86; N, 13.33. C8H4N2OS2

requires: C, 46.14; H, 1.94; N, 13.45%); λmax(DCM)/nm 256 (log ε 3.94), 277 inf (3.69),

346 (3.38), 482 (2.41); vmax/cm-1 3379m (O-H), 2241m (C≡N), 1609w, 1560m, 1541m,

1506w, 1470m, 1431m, 1333m, 1290s, 1250m, 1227m, 1217m, 1152s, 1136w, 1126m,

1067m, 1051m, 963m, 878m, 822s, 766m; δH(500 MHz; CDCl3) 7.21-7.20 (1H, m), 6.89-

6.87 (2H, m), 5.57 (1H, br s); δC(125 MHz; CDCl3) 157.2 (s), 145.4 (s), 133.9 (s), 130.0

(d), 118.4 (d), 114.6 (d), 112.8 (s), 110.2 (s); MALDI-TOF MS (m/z): 210 (M++2, 17%),

209 (M++1, 100), 208 (M+, 22).

7.4.4.3 6-Hydroxy-7-methoxybenzo[e][1,2,4]dithiazine-3-carbonitrile 96d

Chromatography eluent: DCM. Obtained as red needles (33 mg, 70%), mp (DSC) onset:

172.8 °C, peak max: 174.6 °C, decomp. onset: 175.4 C, peak max: 177.8 C (from

c-hexane/DCM); Rf 0.40 (DCM); (found: C, 45.34; H, 2.46; N, 11.58. C9H6N2O2S2

requires: C, 45.37; H, 2.54; N, 11.76%); λmax(DCM)/nm 271 (log ε 4.35), 359 (3.76), 485

(3.20); vmax/cm-1 3372m (O-H), 3005w (aryl C-H), 2990w, 2945w and 2837w (alkyl C-H),

2239m (C≡N), 1609m, 1562m, 1522m, 1497s, 1462m, 1449m, 1433m, 1342m, 1283s,

1260s, 1225m, 1207m, 1179m, 1171m, 1157m, 1061m, 1051m, 1040m, 1009m, 874s,

812m, 766m; δH(500 MHz; CDCl3) 6.98 (1H, s), 6.74 (1H, s), 5.72 (1H, s), 3.96 (3H, s);

δC(125 MHz; CDCl3) 148.5 (s), 147.0 (s), 139.9 (s), 128.5 (s), 114.5 (d), 113.1 (s), 110.3

(d), 109.7 (s), 56.5 (q). MALDI-TOF MS (m/z): 240 (M++2, 26%), 239 (M++1, 100), 238

(M+, 63), 220 (30), 212 (10), 206 (22), 205 (12).

7.4.4.4 5-Methoxybenzo[d]thiazole-2-carbonitrile 97b

Chromatography eluent: n-hexane/t-BuOMe, 90:10. Obtained as colorless needles (3.0 mg,

8%), mp 94-96 °C, lit.,96 99-100 °C (from c-hexane); Rf 0.68 (DCM); λmax(DCM)/nm 287

(log ε 4.05), 295 inf (4.05), 349 (3.62); δH(500 MHz; CDCl3) 7.82 (1H, d, J 9.0), 7.63 (1H,

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d, J 2.5), 7.28 (1H, dd, J 9.0, 2.5), 3.92 (3H, s); δC(125 MHz; CDCl3) 160.2 (s), 153.9 (s),

137.1 (s), 127.4 (s), 121.9 (d), 120.1 (d), 113.1 (s), 106.1 (d), 55.8 (q); MALDI-TOF MS

(m/z): 192 (M++2, 91%), 191 (M++1, 100).

7.4.4.5 5-Hydroxybenzo[d]thiazole-2-carbonitrile 97c

Chromatography eluent: DCM/t-BuOMe, 95:5. Obtained as colorless needles (4.2 mg,

12%), mp (DSC) onset: 192.1 °C, peak max: 193.2 °C, lit.,211 193.5-194 °C (from

c-hexane/CHCl3); Rf 0.40 (DCM/t-BuOMe, 92:8); λmax(DCM)/nm 285 (log ε 4.06), 295 inf

(3.99), 341 (3.61); δH(500 MHz; CDCl3) 7.82 (1H, d, J 9.0), 7.62 (1H, d, J 2.5), 7.23 (1H,

dd, J 9.0, 2.5), 5.69 (1H, s); δC(125 MHz; DMSO-d6) 158.0 (s), 153.3 (s), 137.1 (s), 125.8

(s), 123.4 (d) 119.7 (d), 113.5 (s), 108.2 (d); MALDI-TOF MS (m/z): 178 (M++2, 44%),

177 (M++1, 100), 164 (11), 159 (38), 151 (53).

7.4.4.6 5-Hydroxy-6-methoxybenzo[d]thiazole-2-carbonitrile 97d

Chromatography eluent: DCM/t-BuOMe, 95:5). Obtained as colorless plates (5.4 mg,

13%), mp 173-175 °C (from c-hexane/CHCl3); Rf 0.69 (DCM/t-BuOMe, 90:10); (found:

C, 52.50; H, 3.01; N, 13.58. C9H6N2O2S requires: C, 52.42; H, 2.93; N, 13.58%);

λmax(DCM)/nm 266 (log ε 3.76), 312 (4.03), 335 (3.75); vmax/cm-1 3292w (O-H), 2226m

(C≡N), 1551m, 1485m, 1466w, 1452m, 1423m, 1354w, 1288s, 1234m, 1204m, 1182m,

1128m, 1047m, 1007m, 907w, 856m, 835m, 827m, 777m; δH(500 MHz; CDCl3) 7.68 (1H,

s), 7.31 (1H, s), 6.01 (1H, br s), 4.04 (3H, s); δC(125 MHz; CDCl3) 149.3 (s), 147.5 (s),

147.3 (s), 133.8 (s), 128.0 (s), 113.3 (s), 108.6 (d), 100.9 (d), 56.5 (q); MALDI-TOF MS

(m/z): 208 (M++2, 8%), 207 (M++1, 54), 193 (26), 192 (100), 191 (6), 181 (20), 175 (7).

7.4.5 Transformation of 5,7-Dimethyl-5H-pyrazolo[3,4-e][1,2,4]dithiazine-3-


4-carbonitrile 94a

A mixture of 5,7-dimethyl-5H-pyrazolo[3,4-e][1,2,4]dithiazine-3-carbonitrile 91a (21 mg,

0.1 mmol), S8 (256 mg, 1 mmol) and DABCO (11.2 mg, 0.1 mmol) in PhCl (2 mL) was

heated in a preheated Wood’s metal bath at ca. 100 °C. After 6 min the reaction was

cooled to ca. 0 °C, filtered and washed with n-hexane to remove excess sulfur. The filtrate

was poured onto packed silica and chromatographed (n-hexane/t-BuOMe, 90:10) to give

6,8-dimethyl-6H-pyrazolo[3,4-f][1,2,3,5]trithiazepine-4-carbonitrile 94a (6.3 mg, 26%) as

yellow needles, mp (DSC) onset: 66.7 °C, peak max: 71.7 °C, decomp. onset: 166.8 °C,

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peak max: 185.7 °C (from n-pentane at ca. -20 °C), Rf 0.40 (n-hexane/t-BuOMe, 80:20);

identical to that described above. Further elution (n-hexane/t-BuOMe, 90:10) gave

unreacted 5,7-dimethyl-5H-pyrazolo[3,4-e][1,2,4]dithiazine-3-carbonitrile 91a as red

needles (9.5 mg, 45%), mp (DSC) onset: 98.2 °C, peak max: 98.6 °C, bp onset: 189.6 °C,

peak max: 198.3 °C (from n-hexane), Rf 0.32 (n-hexane/t-BuOMe, 80:20); identical to that

described above.

7.4.6 Transformation of 5,7-Dimethyl-5H-pyrazolo[3,4-e][1,2,4]dithiazine-3-

carbonitrile 91a to 5,7-Dimethyl-5H-[1,2,3]dithiazolo[4,5-b]pyrazolo-

[3,4-e][1,4]thiazine 98

A mixture of 5,7-dimethyl-5H-pyrazolo[3,4-e][1,2,4]dithiazine-3-carbonitrile 91a (21 mg,

0.1 mmol), S8 (256 mg, 1.0 mmol) and DABCO (11.2 mg, 0.1 mmol) in PhCl (2 mL) was

heated at ca. 100 °C. After 16 h the reaction was cooled to ca. 0 °C, filtered and washed

with DCM to remove excess sulfur. The filtrate was adsorbed onto silica and

chromatographed (n-hexane) to give sulfur. Further elution (DCM) gave traces of

6,8-dimethyl-6H-pyrazolo[3,4-f][1,2,3,5]trithiazepine-4-carbonitrile 94a and 5,7-dimethyl-

5H-pyrazolo[3,4-e][1,2,4]dithiazine-3-carbonitrile 91a. Further elution (DCM) gave

1,3-dimethyl-1H-pyrazolo[3,4-d]thiazole-5-carbonitrile 69a as colorless needles (3.0 mg,

17%), mp 99-100.5 °C, (from c-hexane); Rf 0.20 (DCM); δH(500 MHz; CDCl3) 4.07 (3H,

s), 2.47 (3H, s); m/z (EI) 178 (M+, 100%), 163 (15), 85 (94), 70 (86), 58 (8); identical that

described above. Further elution (DCM) gave 5,7-dimethyl-5H-[1,2,3]dithiazolo-

[4,5-b]pyrazolo[3,4-e][1,4]thiazine 98 (5.5 mg, 23%) as orange needles, mp (DSC) onset:

186.6 °C, peak max: 187.6 °C (from c-hexane); Rf 0.24 (n-hexane/t-BuOMe, 80:20);


λmax(DCM)/nm 275 (log ε 4.19), 347 (3.20), 359 inf (3.17), 436 inf (3.62), 457 inf (3.77),

480 (3.84), 505 inf (3.70); vmax/cm-1 2947w and 2918w (alkyl C-H), 1508m, 1504m,

1474m, 1454m, 1369m, 1358m, 1288m, 1101m, 1057m, 989w, 945m, 854m, 735s; δH(500

MHz; CDCl3) 3.71 (3H, s), 2.08 (3H, s); δC(125 MHz; CDCl3) 171.0 (s), 148.9 (s), 141.1

(s), 140.9 (s), 91.0 (s), 34.2 (q), 12.0 (q). MALDI-TOF MS (m/z): 244 (M++2, 15%), 243

(M++1, 40), 242 (M+, 100).

7.4.7 Thermolysis of 5H-Pyrazolo[3,4-e][1,2,4]dithiazine-3-carbonitriles 91

General Procedure: A stirred solution of the appropriate 5H-pyrazolo[3,4-e][1,2,4]-

dithiazine-3-carbonitrile 91 (0.1 mmol) in Ph2O (1 mL) was heated at ca. 250 °C. After

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consumption of the starting material (by TLC) the mixture was adsorbed onto silica and

chromatographed.

7.4.7.1 1,3-Dimethyl-1H-pyrazolo[3,4-d]thiazole-5-carbonitrile 68a

Chromatography eluent: DCM/t-BuOMe, 90:10. Obtained as colorless needles (17.8 mg,

100%), mp 99-100.5 ºC, lit.,18 99-100.5 ºC (from c-hexane); Rf 0.20 (DCM); δH(500 MHz;

CDCl3) 4.07 (3H, s), 2.47 (3H, s); m/z (EI) 178 (M+, 100%), 163 (15), 85 (94), 70 (86), 58

(8); identical to that described above.

7.4.7.2 1-Methyl-3-phenyl-1H-pyrazolo[3,4-d]thiazole-5-carbonitrile 68b

Chromatography eluent: DCM. Obtained as colorless needles (22.8 mg, 95%), mp (DSC)

onset: 170.5 C, peak max: 171.3 C (from c-hexane); Rf 0.53 (DCM) δH(500 MHz; CDCl3)

7.80 (2H, d, J 7.0), 7.50 (2H, dd, J 7.5, 7.5), 7.40 (1H, dd, J 7.3, 7.3), 4.21 (3H, s);

MALDI-TOF MS (m/z): 240 (M+, 100); identical to that described above.

7.4.7.3 1-Benzyl-3-methyl-1H-pyrazolo[3,4-d]thiazole-5-carbonitrile 68c

Chromatography eluent: DCM. Obtained as colorless prisms (24.1 mg, 95%), mp 91-93 °C

(from n-pentane at ca. -20 C); Rf 0.56 (DCM); δH(500 MHz; DMSO-d6) 7.34-7.25 (5H,

m), 5.54 (2H, s), 2.42 (3H, s); MALDI-TOF MS (m/z): 255 (M++1, 100), 242 (15), 91 (55);

identical to that described above.

7.4.7.4 1-Benzyl-3-phenyl-1H-pyrazolo[3,4-d]thiazole-5-carbonitrile 68d

Chromatography eluent: n-hexane/DCM, 50:50. Obtained as beige needles (29.7, 94%),

mp 113.5-114.5 °C (from c-hexane); Rf 0.50 (n-hexane/DCM, 50:50); δH(500 MHz; CDCl3)

7.82 (2H, d, J 7.0), 7.49 (2H, dd, J 7.8, 7.8), 7.44-7.38 (3H, m), 7.37-7.29 (3H, m), 5.66

(2H, s); MALDI-TOF MS (m/z): 317 (M++1, 100%), 91 (90); identical to that described

above.

7.4.7.5 3-Methyl-1-phenyl-1H-pyrazolo[3,4-d]thiazole-5-carbonitrile 68e

Chromatography eluent: n-hexane/DCM, 50:50. Obtained as beige plates (24 mg, 100%),

mp 127-128.5 °C (from c-hexane); Rf 0.50 (n-hexane/DCM, 50:50); δH(500 MHz; CDCl3)

8.12 (2H, d, J = 8.0 Hz), 7.51 (2H, dd, J = 8.0, 8.0 Hz), 7.31 (1H, dd, J 7.3, 7.3), 2.59

(3H, s); MALDI-TOF MS (m/z): 241 (M++1, 100%), 205 (18); identical to that described

above.

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7.4.7.6 1,3-Diphenyl-1H-pyrazolo[3,4-d]thiazole-5-carbonitrile 68f

Chromatography eluent: n-hexane/DCM, 60:40. Obtained as yellow needles (30 mg,

100%), mp (DSC) onset: 185.2 C, peak max: 185.6 C (from c-hexane); Rf 0.46

(n-hexane/DCM, 70:30); δH(500 MHz; CDCl3) 8.26 (2H, dd, J 8.5, 1.0), 7.93 (2H, dd, J

8.0, 1.0), 7.58-7.53 (4H, m), 7.46 (1H, dd, J 7.3, 7.3), 7.36 (1H, dd, J 7.5, 7.5); MALDI-

TOF MS (m/z): 303 (M++1, 92%), 302 (M+, 100); identical to that described above.

7.4.8 Transformation of (E)-2-[(Diethylamino)disulfanyl-2-(1,3-dimethyl-1H-

pyrazol-5-yl)imino]acetonitrile 93a to 4,6,10,12-Tetramethyl-6H-pyrazolo-

[3,4-f]pyrazolo[3',4':4,5]pyrimido[6,1-d][1,2,3,5]trithiazepine-8,12b(10H)-

dicarbonitrile 104

A stirred solution of (Z)-2-[(diethylamino)disulfanyl-2-(1,3-dimethyl-1H-pyrazol-5-

yl)imino]acetonitrile 93a (56.7 mg, 0.2 mmol) in MeCN (4 mL) was heated at ca. 82 °C

for 1.25 h. The mixture left to cool at ca. 20 °C, diluted with n-hexane and poured onto a

packed silica column. Chromatography (n-hexane) gave sulfur and Et2NSxEt2N. Further

elution (n-hexane/acetone, 90:10) gave 4,6,10,12-tetramethyl-6H-pyrazolo[3,4-f]pyrazolo-

[3',4':4,5]pyrimido[6,1-d][1,2,3,5]trithiazepine-8,12b(10H)-dicarbonitrile 104 (26.0 mg,

67%) as colorless prisms, mp (DSC) onset: 209.7 °C, peak max: 211.4 °C, decomp. onset:

213.5 °C, peak max: 215.2 °C (from c-hexane); Rf 0.60 (DCM/t-BuOMe, 96:4); (found:


λmax(DCM)/nm 236 (log ε 4.14), 336 (3.82); vmax/cm-1 2995w, 2949w and 2926w (alkyl

C-H), 2245w (C≡N), 1578s, 1555m, 1522m, 1493m, 1452m, 1437m, 1412m, 1377m,

1364m, 1287s, 1242m 1186m, 1113m, 1096m, 1063w, 1040m, 1009w, 989m, 955m, 912m,

847m, 799m, 752s; δH(500 MHz; CDCl3) 3.89 (3H, s), 3.80 (3H, s), 2.37 (3H, s), 2.35 (3H,

s); δC(125 MHz; CDCl3) 149.5 (s), 143.6 (s), 140.5 (s), 138.5 (s), 128.6 (s), 119.4 (s),

111.1 (s), 110.3 (s), 94.5 (s), 63.8 (s), 36.2 (q), 34.6 (q), 12.6 (q), 12.0 (q); MALDI-TOF

MS (m/z): 390 (M++2, 15%), 389 (M++1, 22), 388 (M+, 86%), 377 (11), 368 (27), 323

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7.5 Compounds related to Chapter 5

7.5.1 Synthesis of Non-literature N-(4-Chloro-5H-1,2,3-dithiazol-5-ylidene)-

anilines

7.5.1.1 N-(4-Chloro-5H-1,2,3-dithiazol-5-ylidene)-3-methylaniline 127

(Typical Procedure)


in DCM (4 mL) was added m-toluidine (52 μL, 0.24 mmol) in one portion. The mixture

was stirred at ca. 20 °C for 2 h and then was added Hünig’s base (164 μL, 0.48 mmol) and

stirred for additional 1 h. The mixture was then adsorbed onto silica and chromatographed

(n-hexane/DCM, 90:10) to give the title compound 127 as yellow fibers (100.8 mg, 87%),

mp 36-37 °C (n-pentane at ca. -40 °C); Rf 0.50 (n-hexane/DCM, 70:30); (found: C, 44.55;

H, 2.91; N, 11.43. C9H7ClN2S2 requires: C, 44.53; H, 2.91; N, 11.54%); λmax(DCM)/nm

308 inf (log ε 3.32), 377 (3.76), 386 inf (3.75), 408 inf (3.62); vmax/cm-1 3017w (aryl C-H),

2916w (alkyl C-H), 1589m, 1570s, 1531m, 1508w, 1481m, 1375w, 1329w, 1254m, 1169m,

1140m, 1086w, 1047w, 997m, 970w, 934m, 912m, 874s, 856s, 785m, 748s; δH(300 MHz;

acetone-d6) 7.39 (1H, dd, J 8.1, 8.1), 7.09 (1H, d, J 7.8), 7.05-7.03 (2H, m), 2.38 (3H, s);

δC(125 MHz; acetone-d6) 159.4 (s), 152.5 (s), 148.6 (s), 140.8 (s), 130.7 (d), 128.0 (d),

121.0 (d), 116.9 (d), 21.5 (q); MALDI-TOF MS (m/z): 245 (MH++2, 44%), 243 (MH+,

100), 227 (9), 207 (90), 198 (7), 150 (3).

7.5.2 Synthesis of 4-[N-(2-Chloroethyl)piperazin-1-yl]-5H-1,2,3-dithiazoles

7.5.2.1 N-{4-[N-(2-Chloroethyl)piperazin-1-yl]-5H-1,2,3-dithiazol-5-ylidene}aniline

119 (Typical Procedure)

To a stirred solution of N-(4-chloro-5H-1,2,3-dithiazol-5-ylidene)aniline 95a (45.7 mg,

0.20 mmol) in PhCl (8 mL) at ca. 20 °C was added in one portion DABCO (44.8 mg,

0.40 mmol). The mixture was then heated at ca. 131 °C for 4 h and then left to cool to

ca. 20 °C. The mixture was poured onto a packed column of silica and eluted with

n-hexane. Subsequent elution (n-hexane/Et2O, 90:10) gave unreacted N-(4-chloro-5H-

1,2,3-dithiazol-5-ylidene)aniline 95a (2.4 mg, 5%). Further elution (n-hexane/Et2O, 80:20)

gave the title compound 119 as yellow plates (53.6 mg, 79%), mp 73-74 °C (from

n-hexane/t-BuOMe at ca. -20 oC); Rf 0.21 (n-hexane/Et2O, 70:30); (found: C, 49.30;


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237 inf (log ε 4.11), 281 inf (3.60), 379 (3.83); vmax/cm-1 3013w (aryl C-H), 2961w, 2845m

and 2826m (alkyl C-H), 1593m, 1578s, 1518m, 1481m, 1464m, 1447m, 1385m, 1306m,

1294m, 1269m, 1250s, 1219m, 1202m, 1169m, 1138m, 1126m, 1080m, 1051m, 1034w,

993s, 953m, 907m, 858m, 829m, 793m, 764m, 727m; δH(500 MHz; CDCl3) 7.43 (2H, dd,

J 8.0, 8.0), 7.20 (1H, dd, J 7.5, 7.5), 7.12 (2H, dd, J 8.5, 1.0), 3.79 (4H, dd, J 5.0, 5.0), 3.62

(2H, t, J 7.0), 2.79 (2H, t, J 7.0), 2.67 (4H, dd, J 5.0, 5.0); δC(125 MHz; CDCl3) 160.6 (s),

158.3 (s), 152.5 (s), 129.7 (d), 125.6 (d), 119.4 (d), 59.8 (t), 52.8 (t), 48.3 (t), 40.8 (t);

MALDI-TOF MS (m/z): 343 (MH++2, 28%), 341 (MH+, 100), 305 (63), 291 (27), 147 (9).

Further elution (n-hexane/Et2O, 60:40) gave N-{4-[N-(2-thiocyanatoethyl)piperazin-1-yl]-

5H-1,2,3-dithiazol-5-ylidene}aniline 120h as yellow plates (1.3 mg, 2%); mp 86-87 °C

(from n-hexane/t-BuOMe at ca. -20 °C); Rf 0.38 (n-hexane/t-BuOMe, 40:60); (found:

C, 49.60; H, 4.73; N 19.19. C15H17N5S3 requires: C, 49.56; H, 4.71; N, 19.27%);

λmax(DCM)/nm 244 inf (log ε 4.03), 279 (log ε 3.60), 381 (3.76); vmax/cm-1 3001w (aryl

C-H), 2936w and 2820w (alkyl C-H), 2145m (C≡N), 1595m, 1578s, 1526m, 1481m,

1449m, 1431m, 1383m, 1377m, 1350m, 1310m, 1285m, 1269m, 1252s, 1215m, 1163m,

1140m, 1121m, 1082m, 1001m, 995m, 955m, 907m, 887m, 858m, 820m, 791m, 760s;

δH(500 MHz; CDCl3) 7.43 (2H, dd, J 7.8, 7.8), 7.21 (1H, dd, J 7.5, 7.5), 7.12 (2H, d, J 7.5),

3.78 (4H, dd, J 4.8, 4.8), 3.22 (2H, t, J 6.5), 2.80 (2H, t, J 6.5), 2.64 (4H, dd, J 5.0, 5.0);

δC(125 MHz; CDCl3) 160.5 (s), 158.2 (s), 152.5 (s), 129.7 (d), 125.7 (d), 119.4 (d), 113.0

(s), 56.3 (t), 52.4 (t), 48.2 (t), 32.4 (t); MALDI-TOF MS (m/z): 364 (MH+, 100%), 337 (6),

321 (50), 305 (4), 236 (56), 170 (4), 129 (7). Further elution (n-hexane/Et2O, 40:60) gave

N-(2-chloroethyl)-N-phenylpiperazine-1-carbimidoyl cyanide 121a as colorless plates

(1.8 mg, 3%), mp 45-46.5 °C (from n-hexane/Et2O at ca. -40 °C); Rf 0.39 (DCM/t-BuOMe,

98:2); (found: C, 60.61; H, 6.12; N, 20.36. C14H17ClN4 requires: C, 60.76; H, 6.19;

N, 20.24%); λmax(DCM)/nm 272 (log ε 3.96), 311 (3.79); vmax/cm-1 3055w (aryl C-H),

2947w and 2818w (alkyl C-H), 2228w (C≡N), 1612s, 1587s, 1449m, 1435m, 1368m,

1312m, 1290m, 1252m, 1204m, 1167m, 1132m, 1103w, 1072w, 1049w, 1030w, 1001m,

970m, 947w, 903w, 820m, 777m, 718m; δH(500 MHz; CDCl3) 7.34 (2H, dd, J 7.8, 7.8),

7.14 (1H, dd, J 7.5, 7.5), 6.93 (2H, dd, J 8.2, 0.8), 3.73 (4H, br s), 3.63 (2H, t, J 6.5), 2.83

(2H, t, J 6.0), 2.65 (4H, br s); δC(125 MHz; CDCl3) 148.1 (s), 133.9 (s), 129.1 (d), 124.6

(d), 121.4 (d), 108.2 (s), 59.4 (t), 52.3 (t), 40.6 (t), 29.7 (t); MALDI-TOF MS (m/z): 279

(MH++2, 42%), 277 (MH+, 100), 250 (24), 241 (79), 227 (10), 224 (6), 188 (4), 147 (5),

129 (3), 118 (13).

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7.5.2.2 N-{[N-(2-Chloroethyl)piperazin-1-yl]-5H-1,2,3-dithiazol-5-ylidene}-2-methyl-

aniline 143

Similar treatment of N-(4-chloro-5H-1,2,3-dithiazol-5-ylidene)-2-methylaniline 122

(48.6 mg, 0.2 mmol) gave the title compound 143 as yellow plates (58.8 mg, 83%),

chromatography eluent: n-hexane/Et2O, 70:30; mp 97-99 °C (from n-hexane at ca. -40 °C);

Rf 0.53 (n-hexane/Et2O, 60:40); (found: C, 50.62; H, 5.51; N, 15.87. C15H19ClN4S2

requires: C, 50.76; H, 5.40; N, 15.79%); λmax(DCM)/nm 279 inf (log ε 3.58), 371 (3.81);

vmax/cm-1 3015w (aryl C-H), 2955w and 2824m (alkyl C-H), 1601m, 1593m, 1572m,

1530m, 1479m, 1456m, 1441m, 1387m, 1375m, 1352w, 1337w, 1310m, 1296m, 1271m,

1252m, 1221m, 1169m, 1130m, 1115m, 1078m, 1065m, 1055w, 1034m, 997s, 864m,

858m, 835m, 814m, 795m, 760m, 721s; δH(500 MHz; acetone-d6) 7.32 (1H, d, J 7.5), 7.28

(1H, dd, J 7.8, 7.8), 7.12 (1H, ddd, J 7.5, 7.5, 1.0), 7.03 (1H, dd, J 8.0, 1.0), 3.79 (4H, dd, J

4.8, 4.8), 3.69 (2H, t, J 7.0), 2.76 (2H, t, J 6.8), 2.67 (4H, dd, J 5.0, 5.0); δC(125 MHz;

CDCl3) 160.6 (s), 157.6 (s), 151.7 (s), 131.0 (d), 128.8 (s), 127.2 (d), 125.5 (d), 116.7 (d),

59.8 (t), 52.8 (t), 48.1 (t), 40.8 (t), 17.8 (q); MALDI-TOF MS (m/z): 357 (MH++2, 29%),

355 (MH+, 64), 321 (4), 250 (100).

7.5.2.3 N-{[N-(2-Chloroethyl)piperazin-1-yl]-5H-1,2,3-dithiazol-5-ylidene}-2-

methoxyaniline 144

Similar treatment of N-(4-chloro-5H-1,2,3-dithiazol-5-ylidene)-2-methoxyaniline 123

(51.7 mg, 0.2 mmol) gave the title compound 144 as yellow needles (68.2 mg, 91%),

chromatography eluent: n-hexane/Et2O, 60:40; mp 101-102 °C (from n-hexane); Rf 0.30

(n-hexane/Et2O, 60:40); (found: C, 48.74; H, 4.99; N, 15.09. C15H19ClN4OS2 requires:


3007w (aryl C-H), 2940w and 2835m (alkyl C-H), 1601m, 1584m, 1530m, 1489m, 1464m,

1454m, 1437m, 1387m, 1379m, 1329w, 1310m, 1292m, 1277m, 1269m, 1256s, 1246m,

1227w, 1219m, 1209m, 1186m, 1161m, 1148w, 1123m, 1115m, 1078m, 1065w, 1047m,

1026m, 995s, 947w, 928w, 860m, 831m, 824m, 812m, 802m, 793m, 758s, 746m, 737m,

729m; δH(500 MHz; CDCl3) 7.17 (1H, ddd, J 7.8, 7.8, 1.8), 7.06 (1H, dd, J 7.8, 1.8), 7.02-

6.98 (2H, m), 3.84 (3H, s), 3.81 (4H, dd, J 4.8, 4.8), 3.62 (2H, t, J 7.0), 2.78 (2H, t, J 7.0),

2.67 (4H, dd, J 5.0, 5.0); δC(75 MHz; CDCl3) 161.4 (s), 158.1 (s), 149.7 (s), 141.6 (s),

126.4 (d), 121.3 (d), 119.0 (d), 112.2 (d), 59.9 (t), 55.8 (q), 52.8 (t), 48.3 (t), 40.8 (t);

MALDI-TOF MS (m/z): 373 (MH++2, 25%), 371 (MH+, 50), 338 (3), 306 (2), 266 (100).

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7.5.2.4 2-Chloro-N-{[N-(2-chloroethyl)piperazin-1-yl]-5H-1,2,3-dithiazol-5-ylidene}-

aniline 145

Similar treatment of 2-chloro-N-(4-chloro-5H-1,2,3-dithiazol-5-ylidene)aniline 124


chromatography eluent: n-hexane/Et2O, 70:30; mp 95.5-96 °C (from n-hexane at

ca. -20 °C); Rf 0.52 (n-hexane/Et2O, 60:40); (found: C, 44.93; H, 4.42; N, 14.88.

C14H16Cl2N4S2 requires: C, 44.80; H, 4.30; N, 14.93%); λmax(DCM)/nm 281 inf (log ε 3.73),

374 (3.87); vmax/cm-1 3065w and 3015w (aryl C-H), 2957m and 2826m (alkyl C-H), 1603s,

1580m, 1530m, 1464m, 1439m, 1389m, 1375m, 1352w, 1337w, 1310m, 1294m, 1271m,

1263m, 1252m, 1221m, 1204w, 1171m, 1130m, 1107m, 1078m, 1057m, 1034m, 999s,

951w, 935w, 866m, 856m, 833m, 808m, 793m, 754m, 748m, 725s, 700m; δH(500 MHz;

CDCl3) 7.48 (1H, dd, J 8.0, 1.5), 7.32 (1H, ddd, J 7.6, 7.6, 1.3), 7.16-7.11 (2H, m), 3.84

(4H, dd, J 4.8, 4.8), 3.62 (2H, t, J 7.0), 2.78 (2H, t, J 7.0), 2.68 (4H, dd, J 5.0, 5.0); δC(125

MHz; CDCl3) 162.6 (s), 157.9 (s), 149.6 (s), 130.5 (d), 128.1 (d), 126.2 (d), 125.7 (s),

118.8 (d), 59.8 (t), 52.8 (t), 48.4 (t), 40.8 (t); MALDI-TOF MS (m/z): 377 (MH++2, 66%),

375 (MH+, 79), 339 (4), 272 (37), 270 (100).

7.5.2.5 2-Bromo-N-{[N-(2-chloroethyl)piperazin-1-yl]-5H-1,2,3-dithiazol-5-ylidene}-

aniline 146

Similar treatment of 2-bromo-N-(4-chloro-5H-1,2,3-dithiazol-5-ylidene)aniline 125


chromatography eluent: n-hexane/Et2O, 70:30; mp 63-65 °C (from n-hexane/Et2O at

ca. -40 oC); Rf 0.26 (n-hexane/Et2O, 70:30); (found: C, 40.21; H, 3.87; N, 13.33.

C14H16BrClN4S2 requires: C, 40.06; H, 3.84; N, 13.35%); λmax(DCM)/nm 352 inf (log ε

4.05), 269 inf (4.01), 377 (3.78); vmax/cm-1 3051w and 3005w (aryl C-H), 2941w and

2814m (alkyl C-H), 1589s, 1574s, 1522m, 1462m, 1449m, 1435m, 1385m, 1352w, 1337w,

1310m, 1290m, 1250m, 1217m, 1130m, 1080m, 1063w, 1043m, 1028m, 997s, 955w,

864m, 831m, 822w, 799m, 754s, 719m; δH(500 MHz; CDCl3) 7.66 (1H, dd, J 8.0, 1.5),

7.36 (1H, ddd, J 7.6, 7.6, 1.3), 7.14 (1H, dd, J 8.0, 1.5), 7.05 (1H, ddd, J 7.8, 7.8, 1.3), 3.85


MHz; CDCl3) 162.5 (s), 157.8 (s), 151.1 (s), 133.5 (d), 128.9 (d), 126.5 (d), 118.6 (d),

115.7 (s), 59.8 (t), 52.8 (t), 48.4 (t), 40.8 (t); MALDI-TOF MS (m/z): 423 (MH++4, 18%),

421 (MH++2, 80), 419 (MH+, 71), 417 (M+, 18), 387 (6), 316 (100), 314 (75).

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7.5.2.6 N-{[N-(2-Chloroethyl)piperazin-1-yl]-5H-1,2,3-dithiazol-5-ylidene}-2-nitro-

aniline 147

Similar treatment of N-(4-chloro-5H-1,2,3-dithiazol-5-ylidene)-2-nitroaniline 126 (54.7 mg,

0.2 mmol) gave the title compound 147 as yellow microcrystalline powder (68.4 mg, 88%),

chromatography eluent: n-hexane/Et2O, 60:40; mp 120.5-122 °C (from n-hexane/Et2O at


C14H16ClN5O2S2 requires: C, 43.58; H, 4.18; N, 18.15%); λmax(DCM)/nm 255 inf (log ε

3.98), 364 (3.84); vmax/cm-1 3028w (aryl C-H), 2936w and 2820w (alkyl C-H), 1614m,

1599m, 1568m, 1518s (NO2), 1464m, 1454m, 1445m, 1387m, 1335s (NO2), 1304m,

1267m, 1256m, 1219m, 1163m, 1128m, 1103w, 1080m, 1061w, 1038w, 997m, 955m,

874m, 851m, 841m, 806w, 793m, 779m, 752m, 735m; δH(300 MHz; CDCl3) 8.08 (1H, dd,

J 8.3, 1.4), 7.66 (1H, ddd, J 7.8, 7.8 , 1.3), 7.30 (1H, ddd, J 8.6, 7.4, 1.2), 7.17 (1H, dd, J

8.1, 1.2), 3.79 (4H, dd, J 5.0, 5.0), 3.61 (2H, t, J 6.9), 2.77 (2H, t, J 6.9), 2.65 (4H, dd, J

5.0, 5.0); δC(75 MHz; CDCl3) 163.5 (s), 157.6 (s), 147.0 (s), 140.1 (s), 135.2 (d), 125.6 (d),

125.3 (d), 120.3 (d), 59.8 (t), 52.7 (t), 48.5 (t), 40.8 (t); MALDI-TOF MS (m/z): 388

(MH++2, 30%), 386 (MH+, 68), 349 (20), 281 (100), 105 (14).


aniline 148



chromatography eluent: n-hexane/Et2O, 80:20; mp 110-112 °C (from n-hexane at


C15H19ClN4S2 requires: C, 50.76; H, 5.40; N, 15.79%); λmax(DCM)/nm 278 inf (log ε 3.73),

372 (3.78); vmax/cm-1 3015w (aryl C-H), 2943w and 2847w (alkyl C-H), 1564s, 1516m,

1479m, 1460m, 1456m, 1450m, 1385m, 1371m, 1354w, 1335w, 1304m, 1294m, 1269m,

1254m, 1244m, 1219m, 1206m, 1169m, 1136m, 1126m, 1103w, 1092w, 1078m, 1061w,

1049w, 1034w, 999m, 991m, 953m, 930w, 901m, 876m, 851m, 833m, 826m, 797m, 781m,

745m, 733m, 704s; δH(500 MHz; CDCl3) 7.32 (1H, dd, J 8.3, 8.3), 7.02 (1H, d, J 7.5),

6.94-6.93 (2H, m), 3.78 (4H, dd, J 4.8, 4.8), 3.62 (2H, t, J 7.0), 2.79 (2H, t, J 6.8), 2.66 (4H,

dd, J 5.0, 5.0), 2.38 (3H, s); δC(75 MHz; CDCl3) 160.3 (s), 158.2 (s), 152.5 (s), 139.6 (s),

129.5 (d), 126.4 (d), 120.1 (d), 116.0 (d), 59.8 (t), 52.7 (t), 48.2 (t), 40.8 (t), 21.5 (q);

MALDI-TOF MS (m/z): 357 (MH++2, 34%), 355 (MH+, 76), 321 (3), 250 (100).

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methoxyaniline 149


(51.7 mg, 0.2 mmol) gave the title compound 149 as a yellow oil (57.9 mg, 78%),

chromatography eluent: n-hexane/Et2O, 70:30; Rf 0.30 (n-hexane/Et2O, 60:40); (found:

C, 48.62; H, 5.16; N, 15.23. C15H19ClN4OS2 requires: C, 48.57; H, 5.16; N, 15.11%);

λmax(DCM)/nm 273 (log ε 4.31), 385 (3.82); vmax/cm-1 3000w (aryl C-H), 2940w and

2832m (alkyl C-H), 1578s, 1522m, 1479m, 1464m, 1447m, 1433m, 1377m, 1310m,

1283m, 1248m, 1192m, 1163m, 1146s, 1080m, 1043m, 999m, 991m, 955m, 943m, 853m,

822m, 777m, 743m; δH(500 MHz; CDCl3) 7.33 (1H, dd, J 8.0, 8.0), 6.75 (1H, ddd, J 8.3,

2.5, 0.7), 6.72 (1H, ddd, J 7.8, 2.0, 0.7), 6.66 (1H, dd, J 2.3, 2.3), 3.82 (3H, s), 3.78 (4H, dd,

J 4.8, 4.8), 3.62 (2H, t, J 6.8), 2.79 (2H, t, J 7.0), 2.67 (4H, dd, J 5.0, 5.0); δC(125 MHz;

CDCl3) 160.83 (s), 160.80 (s), 158.3 (s), 153.9 (s), 130.6 (d), 111.6 (d), 111.3 (d), 105.0

(d), 59.8 (t), 55.4 (q), 52.8 (t), 48.3 (t), 40.8 (t); MALDI-TOF MS (m/z): 373 (MH++2,

39%), 371 (MH+, 77), 337 (3), 266 (100).


aniline 150


(61.5 mg, 0.2 mmol) gave the title compound 150 as a yellow microcrystalline powder

(69.7 mg, 83%), chromatography eluent: n-hexane/Et2O, 80:20; mp 52-53.5 °C (from

n-hexane at ca. -40 °C); Rf 0.57 (n-hexane/Et2O, 60:40); (found: C, 40.15; H, 3.76;

N, 13.49. C14H16BrClN4S2 requires: C, 40.06; H, 3.84; N, 13.35%); λmax(DCM)/nm 286

(log ε 3.56), 378 (3.81); vmax/cm-1 3022w (aryl C-H), 2953w and 2849m (alkyl C-H), 1605s,

1584m, 1562m, 1526m, 1464m, 1437m, 1414m, 1389m, 1375m, 1352w, 1337m, 1312m,

1294m, 1279m, 1258m, 1240m, 1207m, 1165m, 1150m, 1134m, 1105w, 1082m, 1061m,

999s, 991m, 945m, 889m, 878m, 866m, 822m, 804m, 773m, 760m, 733w; δH(500 MHz;

acetone-d6) 7.44 (1H, dd, J 8.0, 8.0), 7.40 (1H, ddd, J 8.0, 1.5, 1.5), 7.31 (1H, dd, J 2.0,

2.0), 7.14 (1H, ddd, J 7.7, 2.0, 1.3), 3.74 (4H, dd, J 5.0, 5.0), 3.68 (2H, t, J 7.0), 2.75 (2H, t,

J 6.8), 2.66 (4H, dd, J 5.0, 5.0); δC(75 MHz; CDCl3) 161.9 (s), 158.1 (s), 153.8 (s), 131.1

(d), 128.4 (d), 123.2 (s), 122.7 (d), 117.9 (d), 59.8 (t), 52.7 (t), 48.3 (t), 40.8 (t); MALDI-

TOF MS (m/z): 423 (MH++4, 17%), 421 (MH++2, 64), 419 (MH+, 47), 417 (M+, 11), 387

(12), 356 (2), 316 (100), 314 (78).

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aniline 151



chromatography eluent: n-hexane/Et2O, 80:20; mp 64.5-66 °C (from n-hexane at



386 (3.81); vmax/cm-1 3022w (aryl C-H), 2965w and 2830w (alkyl C-H), 1609m, 1578s,

1566s, 1522m, 1501m, 1460m, 1456m, 1443m, 1387m, 1371m, 1354w, 1335w, 1308m,

1292m, 1271m, 1250s, 1215m, 1171m, 1136m, 1126m, 1111m, 1078m, 1061m, 1051w,

1032w, 997s, 966w, 951w, 864m, 839m, 818m, 797m, 756m, 725m, 718m; δH(300 MHz;

acetone-d6) 7.28 (2H, d, J 7.8), 7.05 (2H, d, J 8.1), 3.73 (4H, dd, J 5.0, 5.0), 3.67 (2H, t, J

6.9), 2.74 (2H, t, J 6.9), 2.64 (4H, dd, J 5.0, 5.0), 2.34 (3H, s); δC(75 MHz; acetone-d6)

160.7 (s), 159.3 (s), 151.1 (s), 136.2 (s), 131.1 (d), 120.3 (d), 60.6 (t), 53.6 (t), 49.2 (t),

42.0 (t), 21.1 (q); MALDI-TOF MS (m/z): 357 (MH++2, 41%), 355 (MH+, 100), 321 (3),

290 (2), 250 (74).


methoxyaniline 152



chromatography eluent: n-hexane/Et2O, 70:30; mp 41-45 °C (from n-pentane/DCM at


C15H19ClN4OS2 requires: C, 48.57; H, 5.16; N, 15.11%); λmax(DCM)/nm 293 (log ε 3.74),

389 (3.86), 403 inf (3.82); vmax/cm-1 3019w (aryl C-H), 2961w and 2847w (alkyl C-H),

1603m, 1564m, 1518m, 1501s, 1460m, 1452m, 1443m, 1387m, 1354w, 1337w, 1304m,

1294m, 1246s, 1219m, 1163m, 1136m, 1126m, 1109m, 1078m, 1061w, 1034m, 995m,

953m, 864m, 841m, 827m, 814m, 797m, 750m, 729m; δH(500 MHz; CDCl3) 7.16 (2H, d,

J 9.0), 6.96 (2H, d, J 9.0), 3.83 (3H, s), 3.77 (4H, dd, J 4.5, 4.5), 3.62 (2H, t, J 7.0), 2.78

(2H, t, J 7.0), 2.67 (4H, dd, J 5.0, 5.0); δC(125 MHz; CDCl3) 158.7 (s), 158.4 (s), 157.5 (s),

144.9 (s), 121.3 (d), 114.6 (d), 59.8 (t), 55.5 (q), 52.8 (t), 48.3 (t), 40.8 (t); MALDI-TOF

MS (m/z): 373 (MH++2, 29%), 371 (MH+, 100), 339 (11), 306 (8), 266 (89).

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aniline 153



chromatography eluent: n-hexane/Et2O, 80:20; mp 55-56 °C (n-hexane/Et2O); Rf 0.47

(n-hexane/t-BuOMe, 60:40); (found: C, 40.14; H, 3.93; N, 13.34. C14H16BrClN4S2 requires:

C, 40.06; H, 3.84; N, 13.35%); λmax(DCM)/nm 247 inf (log ε 4.32), 278 inf (4.08), 387

(3.94); vmax/cm-1 2940w and 2814m (alkyl C-H), 1587s, 1574s, 1518m, 1477s, 1449m,

1395m, 1377m, 1352m, 1310m, 1290m, 1250s, 1211m, 1167m, 1130m, 1099m, 1069m,

1005s, 995s, 955m, 860m, 835m, 824m, 797m, 733m, 712m; δH(500 MHz; CDCl3) 7.53

(2H, d, J 9.0), 7.00 (2H, d, J 8.5), 3.76 (4H, dd, J 5.0, 5.0), 3.61 (2H, t, J 7.0), 2.78 (2H, t,

J 7.0), 2.65 (4H, dd, J 5.0, 5.0); δC(125 MHz; CDCl3) 161.1 (s), 158.2 (s), 151.3 (s), 132.8

(d), 121.3 (d), 118.5 (s), 59.8 (t), 52.7 (t), 48.3 (t), 40.8 (t); MALDI-TOF MS (m/z): 423

(MH++4, 24%), 421 (MH++2, 72), 419 (MH+, 51), 387 (6), 316 (100), 314 (65), 145 (3),

105 (4).

7.5.2.13 N-{[N-(2-Chloroethyl)piperazin-1-yl]-5H-1,2,3-dithiazol-5-ylidene}-4-nitro-

aniline 154

Similar treatment of N-(4-chloro-5H-1,2,3-dithiazol-5-ylidene)-4-nitroaniline 133

(0.2 mmol, 54.7 mg) gave the title compound 154 as yellow plates/prisms (57.1 mg, 74%),


ca. -40 °C); Rf 0.43 (n-hexane/t-BuOMe, 40:60); (found: C, 43.67; H, 4.07; N, 18.20.

C14H16ClN5O2S2 requires: C, 43.58; H, 4.18; N, 18.15%); λmax(DCM)/nm 284 (log ε 3.97),

323 (3.90), 411 (3.67); vmax/cm-1 3069w and 3030w (aryl C-H), 2946w and 2832w (alkyl

C-H), 1593m, 1582m, 1514s, 1483m, 1454m, 1389m, 1375m, 1339s, 1310m, 1294m,

1273w, 1256m, 1219m, 1209m, 1169m, 1128m, 1111m, 1078w, 1067w, 999m, 951w,

870m, 860m, 841w, 827m, 802m, 789m, 754m, 737m; δH(500 MHz; CDCl3) 8.31 (2H, d,

J 9.0), 7.20 (2H, d, J 9.0), 3.79 (4H, br s), 3.63 (2H, t, J 7.0), 2.81 (2H, t, J 6.8), 2.69 (4H,

br s); δC(125 MHz; CDCl3) 162.8 (s), 157.87 (s), 157.84 (s), 144.8 (s), 125.9 (d), 120.0 (d),

59.7 (t), 52.7 (t), 48.3 (t), 40.7 (t); MALDI-TOF MS (m/z): 388 (MH++2, 55%), 386 (MH+,

99), 384 (38), 352 (6), 281 (100), 217 (5), 145 (11), 105 (16).

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cyanoaniline 155

Similar treatment of N-(4-chloro-5H-1,2,3-dithiazol-5-ylidene)-4-cyanoaniline 134



ca. 40 °C); Rf 0.25 (n-hexane/Et2O, 60:40); (found: C, 49.33; H, 4.37; N, 19.20.


391 (3.88); vmax/cm-1 2938w and 2816w (alkyl C-H), 2224m (C≡N), 1603m, 1572s, 1508m,

1495m, 1462m, 1447m, 1410w, 1383m, 1373m, 1335w, 1310m, 1288m, 1275m, 1260m,

1252m, 1219m, 1202m, 1169m, 1144m, 1132m, 1111m, 1078w, 1053w, 993m, 955w,

864m, 847s, 833m, 824m, 808m, 797m, 735m; δH(300 MHz; CDCl3) 7.72 (2H, d, J 8.4),

7.17 (2H, d, J 8.4), 3.77 (4H, dd, J 5.0, 5.0), 3.61 (2H, t, J 6.9), 2.79 (2H, t, J 6.9), 2.66

(4H, dd, J 5.0, 5.0); δC(75 MHz; CDCl3) 162.5 (s), 158.0 (s), 156.1 (s), 134.1 (d), 120.2 (d),

118.8 (s), 108.6 (s), 59.8 (t), 52.7 (t), 48.4 (t), 40.8 (t); MALDI-TOF MS (m/z): 368

(MH++2, 72%), 366 (MH+, 100), 364 (25), 334 (7), 332 (11), 301 (3), 270 (3), 261 (97),

197 (3), 145 (3), 106 (12).

7.5.2.15 N-{[N-(2-Chloroethyl)piperazin-1-yl]-5H-1,2,3-dithiazol-5-ylidene}naphth-1-

ylamine 156

Similar treatment of N-(4-chloro-5H-1,2,3-dithiazol-5-ylidene)naphth-1-ylamine 135

(55.8 mg, 0.2 mmol) gave the title compound 156 as yellow/orange plates (59.4 mg, 76%),

chromatography eluent: n-hexane/Et2O, 80:20; mp 121-122 °C (from n-hexane at



391 (3.78); vmax/cm-1 3013w (aryl C-H), 2941w and 2806w (alkyl C-H), 1591m, 1578m,

1518m, 1503m, 1466m, 1439m, 1393m, 1385m, 1371m, 1367w, 1337w, 1308m, 1290m,

1261m, 1250m, 1213m, 1204m, 1173w, 1128m, 1105m, 1076m, 1016m, 993s, 970m,

953w, 881m, 853m, 833m, 818m, 802m, 789m, 772s, 729m; δH(500 MHz; CDCl3) 8.02

(1H, d, J 8.5), 7.88 (1H, d, J 7.5), 7.72 (1H, d, J 8.0), 7.56-7.48 (3H, m), 7.28 (1H, d, J 7.0),

3.90 (4H, dd, J 5.0, 5.0), 3.64 (2H, t, J 7.0), 2.82 (2H, t, J 6.8), 2.72 (4H, dd, J 5.0, 5.0);

δC(75 MHz; CDCl3) 160.8 (s), 158.3 (s), 149.1 (s), 134.4 (s), 128.0 (d), 126.7 (d), 126.5 (s),

126.00 (d), 125.96 (d), 125.8 (d), 123.2 (d), 112.4 (d), 59.8 (t), 53.0 (t), 48.3 (t), 40.9 (t);

MALDI-TOF MS (m/z): 393 (MH++2, 33%), 391 (MH+, 77), 286 (100).

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7.5.2.16 N-{[N-(2-Chloroethyl)piperazin-1-yl]-5H-1,2,3-dithiazol-5-ylidene}naphth-2-

ylamine 157

Similar treatment of N-(4-chloro-5H-1,2,3-dithiazol-5-ylidene)naphth-2-ylamine 136


chromatography eluent: n-hexane/Et2O, 80:20; mp 75-76 °C (from n-hexane at ca. -40 °C);

Rf 0.43 (n-hexane/Et2O, 60:40); (found: C, 55.47; H, 4.84; N, 14.47. C18H19ClN4S2

requires: C, 55.30; H, 4.90; N, 14.33%); λmax(DCM)/nm 274 inf (log ε 4.11), 338 (3.70),

388 (3.80); vmax/cm-1 3017w (aryl C-H), 2961w and 2847w (alkyl C-H), 1562s, 1518m,

1503m, 1462m, 1450m, 1441w, 1433w, 1389m, 1371m, 1354w, 1335w, 1306m, 1296m,

1269m, 1250m, 1221m, 1206m, 1169m, 1157w, 1126m, 1101w, 1076m, 1059w, 1032w,

997m, 959m, 949m, 905m, 889m, 856m, 833m, 826m, 816m, 743s, 727m; δH(500 MHz;

CDCl3) 7.91 (1H, d, J 8.5), 7.84 (1H, d, J 8.0), 7.81 (1H, d, J 7.5), 7.56 (1H, d, J 2.0), 7.49

(1H, ddd, J 7.3, 7.3, 1.0), 7.46 (1H, ddd, J 7.5, 7.5, 1.5), 7.29 (1H, dd, J 8.5, 2.0), 3.83 (4H,

dd, J 4.8, 4.8), 3.63 (2H, t, J 7.0), 2.81 (2H, t, J 7.0), 2.70 (4H, dd, J 5.0, 5.0); δC(125 MHz;

CDCl3) 160.8 (s), 158.5 (s), 150.2 (s), 134.1 (s), 131.6 (s), 129.8 (d), 127.84 (d), 127.82 (d),

126.6 (d), 125.5 (d), 120.5 (d), 115.4 (d), 59.9 (t), 52.8 (t), 48.4 (t), 40.8 (t); MALDI-TOF

MS (m/z): 393 (MH++2, 23%), 391 (MH+, 56), 356 (3), 286 (100).

7.5.2.17 N-{[N-(2-Chloroethyl)piperazin-1-yl]-5H-1,2,3-dithiazol-5-ylidene}pyrid-2-yl-

amine 158

Similar treatment of N-(4-chloro-5H-1,2,3-dithiazol-5-ylidene)pyrid-2-ylamine 137





299 (3.84), 408 (4.03), 423 (4.07); vmax/cm-1 2955w and 2837w (alkyl C-H), 1589m,

1564m, 1514m, 1485m, 1447m, 1433s, 1375m, 1356m, 1339w, 1308m, 1292m, 1261m,

1246m, 1144m, 1128m, 1101m, 1090w, 1070m, 1036w, 1015w, 999m, 961w, 851m, 891m,

876w, 835m, 816m, 799m, 785s, 739s, 719m; δH(300 MHz; CDCl3) 8.61 (1H, ddd, J 8.5,

3.0, 1.0), 7.82 (1H, ddd, J 7.7, 7.7, 1.8), 7.49 (1H, d, J 8.1), 7.21 (1H, ddd, J 7.1, 5.0, 1.1),

3.86 (4H, br s), 3.68 (2H, t, J 6.9), 2.86 (2H, t, J 6.9), 2.79 (4H, dd, J 4.5, 4.5); δC(75 MHz;

CDCl3) 162.0 (s), 157.5 (s), 154.9 (s), 144.2 (d), 137.8 (d), 122.3 (d), 120.8 (d), 59.8 (t),

52.8 (t), 48.7 (t), 40.6 (t); MALDI-TOF MS (m/z): 344 (MH++2, 62%), 342 (MH+, 100),

306 (6), 250 (12), 248 (30), 237 (72).

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7.5.2.18 N-{[N-(2-Chloroethyl)piperazin-1-yl]-5H-1,2,3-dithiazol-5-ylidene}pyrid-3-yl-

amine 159

Similar treatment of N-(4-chloro-5H-1,2,3-dithiazol-5-ylidene)pyrid-3-ylamine 138


chromatography eluent: n-hexane/Et2O, 50:50; mp 83-84 °C (from n-hexane/DCM at

ca. -40 °C); Rf 0.39 (DCM/Et2O, 70:30); (found: C, 45.79; H, 4.63; N, 20.55.


384 (3.74); vmax/cm-1 3075w and 3013w (pyridyl C-H), 2926w and 2832m (alkyl C-H),

1584m, 1564s, 1558s, 1506s, 1474m, 1458m, 1447m, 1410m, 1375m, 1360m, 1339w,

1325w, 1308m, 1290m, 1275m, 1252s, 1223m, 1209m, 1190m, 1148m, 1130m, 1113m,

1094m, 1084m, 1074m, 1045m, 1011m, 999m, 974m, 955m, 934m, 868m, 833m, 810s,

793m, 739m, 708m; δH(500 MHz; CDCl3) 8.46-8.44 (2H, m), 7.46 (1H, ddd, J 8.5, 2.5,

1.5), 7.36 (1H, dd, J 8.0, 5.0), 3.78 (4H, dd, J 4.8, 4.8), 3.62 (2H, t, J 6.8), 2.79 (2H, t, J

6.8), 2.67 (4H, dd, J 5.0, 5.0); δC(125 MHz; CDCl3) 162.8 (s), 158.1 (s), 148.4 (s), 146.7

(d), 142.0 (d), 126.4 (d), 124.1 (d), 59.8 (t), 52.7 (t), 48.4 (t), 40.8 (t); MALDI-TOF MS

(m/z): 343 (M++2, 33%), 341 (M+, 100), 304 (87).

7.5.2.19 N-{[N-(2-Chloroethyl)piperazin-1-yl]-5H-1,2,3-dithiazol-5-ylidene}pyrazin-2-

ylamine 160

Similar treatment of N-(4-chloro-5H-1,2,3-dithiazol-5-ylidene)pyrazin-2-ylamine 139


chromatography eluent: DCM/Et2O, 80:20; mp 140-141 °C (from c-hexane); Rf 0.35

(DCM/Et2O, 60:40); (found: C, 42.19; H, 4.37; N, 24.34. C12H15ClN6S2 requires: C, 42.04;

H, 4.41; N, 24.51%); λmax(DCM)/nm 247 (log ε 4.17), 270 inf (3.93), 321 (3.87), 418 inf

(4.08), 432 (4.14); vmax/cm-1 3057w and 3009w (pyrazinyl C-H), 2938w and 2837m (alkyl

C-H), 1533m, 1514m, 1479s, 1456s, 1441m, 1408s, 1375m, 1358m, 1339m, 1314m,

1292m, 1275m, 1252s, 1196m, 1179m, 1157m, 1146m, 1128m, 1090m, 1070w, 1059w,

1013m, 999s, 955m, 928w, 895m, 845m, 837m, 816m, 797m, 754m, 733m, 716m, 706m;

δH(300 MHz; CDCl3) 3.84 (1H, d, J 1.5), 8.54 (1H, dd, J 2.7, 1.5), 8.41 (1H, d, J 2.7), 3.85


MHz; CDCl3) 162.3 (s), 159.8 (s), 151.6 (s), 145.5 (d), 139.9 (d), 138.9 (d), 59.9 (t), 52.8

(t), 49.0 (t), 40.9 (t); MALDI-TOF MS (m/z): 345 (MH++2, 55%), 343 (MH+, 100), 250 (6),

248 (16), 238 (79).

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7.5.2.20 N-{[N-(2-Chloroethyl)piperazin-1-yl]-5H-1,2,3-dithiazol-5-ylidene}-1,3-

dimethyl-1H-pyrazol-5-amine 109

Similar treatment of N-(4-chloro-5H-1,2,3-dithiazol-5-ylidene)-1,3-dimethyl-1H-pyrazol-

5-amine 68a (49.3 mg, 0.2 mmol) gave the title compound 109 as yellow needles (56.7 mg,

79%), chromatography eluent: n-hexane/Et2O, 50:50; mp 112-113 °C (from c-hexane); Rf

0.45 (DCM/Et2O, 70:30); (found: C, 43.32; H, 5.27; N, 23.31. C13H19ClN6S2 requires:


345 inf (3.69), 360 inf (3.75), 377 inf (3.87), 395 (3.98), 414 (3.97); vmax/cm-1 2940w and

2820w (alkyl C-H), 1574m, 1514m, 1445m, 1400m, 1369m, 1306m, 1288m, 1248m,

1213w, 1173m, 1144m, 1128m, 1107w, 1082m, 1009m, 999m, 957w, 876m, 831m, 806m,

754m, 727s; δH(500 MHz; CDCl3) 6.27 (1H, s), 3.82 (3H, s), 3.77 (4H, dd, J 4.8, 4.8), 3.63

(2H, t, J 7.0), 2.80 (2H, t, J 7.0), 2.70 (4H, dd, J 4.8, 4.8), 2.33 (3H, s); δC(125 MHz;

CDCl3) 159.6 (s), 155.7 (s), 147.4 (s), 146.7 (s), 94.8 (d), 59.8 (t), 52.8 (t), 48.7 (t), 40.8 (t),

34.9 (q), 14.2 (q); MALDI-TOF MS (m/z): 361 (MH++2, 39%), 359 (MH+, 100), 327 (15),

325 (22), 254 (70), 190 (11), 154 (7), 105 (11).

7.5.2.21 N-{[N-(2-Chloroethyl)piperazin-1-yl]-5H-1,2,3-dithiazol-5-ylidene}thiazol-2-

amine 161

Similar treatment of N-(4-chloro-5H-1,2,3-dithiazol-5-ylidene)thiazol-2-ylamine 140

(47.1 mg, 0.2 mmol) gave the title compound 161 as yellow/orange plates (44.5 mg, 64%),

chromatography eluent: n-hexane/Et2O, 80:20; mp 142-143 °C (from c-hexane); Rf 0.43

(n-hexane/Et2O, 60:40); (found: C, 38.06; H, 4.12; N, 20.05. C11H14ClN5S3 requires:


402 inf (3.94), 419 (4.10), 438 (4.08); vmax/cm-1 3078w and 3065w (thiazolyl C-H), 2947w

and 2826w (alkyl C-H), 1522m, 1481s, 1462m, 1447m, 1410m, 1381m, 1373m, 1335m,

1321m, 1308m, 1292m, 1271m, 1250m, 1215m, 1155s, 1136m, 1125m, 1105w, 1084m,

1074m, 1053w, 1032w, 997s, 866m, 847m, 829m, 802m, 773s, 760m, 735m, 704m;

δH(500 MHz; CDCl3) 7.75 (1H, d, J 4.0), 7.25 (1H, d, J 3.5), 3.79 (4H, dd, J 4.5, 4.5), 3.64

(2H, t, J 7.0), 2.81 (2H, t, J 7.0), 2.72 (4H, dd, J 5.0, 5.0); δC(125 MHz; CDCl3) 170.1 (s),

161.2 (s), 159.3 (s), 138.7 (d), 118.6 (d), 59.9 (t), 52.8 (t), 49.0 (t), 40.9 (t); MALDI-TOF

MS (m/z): 350 (MH++2, 30%), 348 (MH+, 58), 312 (5), 248 (8), 243 (100).

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7.5.2.22 4-[N-(2-Chloroethyl)piperazin-1-yl]-5H-1,2,3-dithiazol-5-one 162

Similar treatment of 4-chloro-5H-1,2,3-dithiazol-5-one 2c (30.7 mg, 0.2 mmol) gave the

title compound 162 as yellow plates (45.3 mg, 85%), chromatography eluent:

n-hexane/Et2O, 70:30; mp (DSC) onset: 83.9 °C, peak max: 84.9 °C, decomp. onset:

191.6 °C, peak max: 193.4 °C (from n-hexane/t-BuOMe at ca. -20 °C); Rf 0.36 (n-hexane/

t-BuOMe, 70:30); (found: C, 36.04; H, 4.59; N, 15.72. C8H12ClN3OS2 requires: C, 36.15;

H, 4.55; N, 15.81%); λmax(DCM)/nm 272 (log ε 2.96), 376 (3.82); vmax/cm-1 2940w and

2816m (alkyl C-H), 1667m, 1649m, 1632s, 1530m, 1452m, 1443m, 1387m, 1337m,

1327m, 1308m, 1294m, 1248s, 1231m, 1217m, 1146m, 1140m, 1128m, 1072m, 989s,

949m, 853m, 822m, 791m, 766m, 746m; δH(500 MHz; CDCl3) 3.66 (4H, dd, J 4.8, 4.8),

3.60 (2H, t, J 6.8), 2.77 (2H, t, J 6.8), 2.62 (4H, dd, J 4.3, 4.3); δC(125 MHz; CDCl3) 186.1

(s), 155.1 (s), 59.7 (t), 52.6 (t), 47.2 (t), 40.7 (t); MALDI-TOF MS (m/z): 268 (MH++2,

45%), 266 (MH+, 100), 249 (29), 235 (39), 155 (53), 138 (5), 129 (5), 113 (7).

7.5.2.23 4-[N-(2-Chloroethyl)piperazin-1-yl]-5H-1,2,3-dithiazole-5-thione 163

Similar treatment of 4-chloro-5H-1,2,3-dithiazole-5-thione 2d (33.9 mg, 0.2 mmol) gave

the title compound 163 as red plates (43.0 mg, 76%), chromatography eluent:

n-hexane/Et2O, 70:30; mp 68-69 °C (from n-hexane/t-BuOMe at ca. -20 °C); Rf 0.33

(n-hexane/t-BuOMe, 70:30); (found: C, 34.23; H, 4.27; N, 14.82. C8H12ClN3S3 requires:

C, 34.09; H, 4.29; N, 14.91%); λmax(DCM)/nm 254 inf (log ε 3.80), 327 (3.45), 457 (3.96),

536 inf (2.68); vmax/cm-1 2949w and 2820m (alkyl C-H), 1474m, 1447m, 1371m, 1354m,

1333m, 1300m, 1283m, 1260m, 1246s, 1209m, 1200m, 1123s, 1051s, 1003m, 982s, 853m,

829m, 818s, 799m, 745m; δH(500 MHz; CDCl3) 3.69 (4H, br s), 3.62 (2H, t, J 6.8), 2.80

(2H, t, J 7.0), 2.68 (4H, dd, J 4.3, 4.3); δC(125 MHz; CDCl3) 202.0 (s), 165.8 (s), 59.7 (t),

52.6 (t), 48.7 (t), 40.6 (t); MALDI-TOF MS (m/z): 283 (M++2, 34%), 281 (M+, 100), 279

(41), 247 (20), 216 (14), 176 (32), 105 (12).

7.5.3 Synthesis of N-(2-Chloroethyl)piperazine 168a

To a stirred suspension of N-(2-chloroethyl)piperazine dihydrochloride 168a·2HCl

(500 mg, 2.26 mmol) in DCM (10 mL) was added DBU (675 μL, 4.51 mmol). The mixture

was stirred at ca. 20 °C until all the solids dissolved. Then the solvent was evaporated

under reduced pressure at ca. 20 oC and the remaining residue was triturated with Et2O

(10 mL) and the solution was separated from the resulting gummy precipitation. The

solvent was evaporated under reduced pressure to give N-(2-chloroethyl)piperazine 168a

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as a colorless oil (218.5 mg, 65%), vmax/cm-1 3273m (N-H), 2941m and 2814m (alkyl C-H),

1645m, 1454m, 1371m, 1341m, 1321m, 1310m, 1269m, 1184m, 1142s, 1123s, 1061m,

1011m, 914m, 802s, 733s; δH(500 MHz; CDCl3) NH resonance missing (deuterium

exchanged), 3.58 (2H, t, J 7.2), 2.89 (4H, dd, J 4.8, 4.8), 2.70 (2H, t, J 7.0), 2.47 (4H, br s);

δC(125 MHz; CDCl3) 60.4 (t), 54.5 (t), 46.0 (t), 40.8 (t). Worthy of note, was that the

compound was stable at ca. 20 oC and suitable for subsequent chemistry for several hours

but decomposed when left standing overnight.

7.5.4 Reaction of 4-Chloro-1,2,3-dithiazoles 95a, 2c-d with N-[2-(Substituted)-

ethyl]piperazines 168

General Procedure: A mixture of the appropriate 4-chloro-1,2,3-dithiazole 95a, 2c or 2d

(0.2 mmol) and N-(2-chloroethyl)piperazine 168a or N-(2-cyanoethyl)piperazine 168b

(0.6 mmol) in DCM (4 mL) was stirred at ca. 20 °C for the time specified in Table 17.

Then the mixture was poured onto a packed column of silica and chromatographed to give

the corresponding amidine 121a-f.

7.5.4.1 N-(2-Chloroethyl)-N-phenylpiperazine-1-carbimidoyl cyanide 121a

In this case 148.6 mg (1 mmol) of N-(2-chloroethyl)piperazine 168a was used. Chromato-

graphy eluent: n-hexane/Et2O, 70:30. Obtained as colorless plates (37.1 mg, 67%), mp

45-46.5 °C (from n-hexane/Et2O at ca. -40 °C), identical to that described above.

7.5.4.2 N-(2-Cyanoethyl)-N-phenylpiperazine-1-carbimidoyl cyanide 121b

Chromatography eluent: n-hexane/Et2O, 20:80. Obtained as colorless prisms (52.4 mg,

98%), mp 41-43 °C (from n-hexane/Et2O at ca. -40 °C); Rf 0.31 (DCM/Et2O, 90:10);

(found: C, 67.53; H, 6.55; N, 26.03. C15H17N5 requires: C, 67.39; H, 6.41; N, 26.20%);

λmax(MeCN)/nm 270 (log ε 4.07), 301 inf (3.89); vmax/cm-1 3057w (aryl C-H), 2949w and

2824w (alkyl C-H), 2249w and 2228w (C≡N), 1612s, 1589s, 1485w, 1449m, 1425m,

1368m, 1331w, 1290m, 1252m, 1215m, 1179m, 1169m, 1142m, 1107w, 1072w, 1001m,


7.14 (1H, dd, J 7.3, 7.3), 6.93 (2H, dd, J 8.5, 1.0), 3.72 (4H, dd, J 5.0, 5.0), 2.76 (2H, t,

J 6.8), 2.62 (4H, dd, J 5.0, 5.0), 2.55 (2H, t, J 7.0); δC(125 MHz; CDCl3) 148.1 (s), 133.9

(s), 129.1 (d), 124.6 (d), 121.4 (d), 118.4 (s), 108.2 (s), 53.1 (t), 52.0 (t), 45.6 (t), 16.1 (t);

MALDI-TOF MS (m/z): 268 (MH+, 100%), 241 (68), 227 (65), 198 (5), 172 (48), 129 (9),

124 (33), 97 (5), 77 (2), 55 (2).

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7.5.4.3 N-(2-Chloroethyl)piperazine-1-carbonyl cyanide 121c

Chromatography eluent: n-hexane/Et2O: 30:70. Obtained as colorless needles (25.9 mg,

64%), mp 39.5-41 °C (from n-hexane/Et2O at ca. -20 °C); Rf 0.42 (DCM/Et2O, 90:10);

(found: C, 47.47; H, 6.13; N, 20.67. C8H12ClN3O requires: C, 47.65; H, 6.00; N, 20.84%);

λmax(MeCN)/nm 231 (log ε 3.89); vmax/cm-1 2932w, 2820w and 2778w (alkyl C-H), 2230w

(C≡N), 1672s (C=O), 1578w, 1522w, 1441m, 1379w, 1366m, 1354m, 1314m, 1285m,

1267m, 1250m, 1227m, 1180w, 1144m, 1130m, 1038m, 997m, 945m, 885w, 858w, 808w,

758m, 719m; δH(500 MHz; CDCl3) 3.78 (2H, dd, J 5.0, 5.0), 3.67 (2H, dd, J 5.0, 5.0), 3.58

(2H, t, J 6.8), 2.79 (2H, t, J 6.5), 2.64 (2H, dd, J 5.0, 5.0), 2.56 (2H, dd, J 5.3, 5.3);

δC(125 MHz; CDCl3) 143.1 (s), 110.1 (s), 59.1 (t), 52.9 (t), 51.8 (t), 46.9 (t), 42.2 (t), 40.7

(t); MALDI-TOF MS (m/z): 204 (MH++2, 29%), 202 (MH+, 85), 166 (100), 113 (13).

7.5.4.4 N-(2-Cyanoethyl)piperazine-1-carbonyl cyanide 121d

Chromatography eluent: n-hexane/Et2O, 10:90. Obtained as colorless needles (28.9 mg,

75%), mp 61.5-63.5 °C (from n-pentane/Et2O at ca. -20 °C); Rf 0.30 (DCM/Et2O, 90:10);

(found: C, 56.15; H, 6.37; N, 29.02. C9H12N4O requires: C, 56.24; H, 6.29; N, 29.15%);

λmax(MeCN)/nm 231 (log ε 3.80); vmax/cm-1 2955w, 2814w and 2772w (alkyl C-H), 2255w

and 2226w (C≡N), 1667s (C=O), 1460m, 1452m, 1435m, 1423m, 1375m, 1360m, 1350m,

1329m, 1298m, 1285m, 1254m, 1229m, 1142m, 1109m, 1045m, 1016m, 993m, 962w,

934m, 891m, 760m; δH(500 MHz; CDCl3) 3.79 (2H, dd, J 5.3, 5.3), 3.67 (2H, dd, J 5.3,

5.3), 2.74 (2H, t, J 6.8), 2.63 (2H, dd, J 5.0, 5.0), 2.55 (2H, dd, J 5.3, 5.3), 2.53 (2H, t, J

6.8); δC(125 MHz; CDCl3) 143.1 (s), 118.2 (s), 110.1 (s), 52.8 (t), 52.5 (t), 51.5 (t), 46.8 (t),

42.1 (t), 16.2 (t); MALDI-TOF MS (m/z): 193 (MH+, 40%), 192 (M+, 100), 152 (6), 100

(60), 91 (42).

7.5.4.5 N-(2-Chloroethyl)piperazine-1-carbothioyl cyanide 121e

Chromatography eluent: n-hexane/Et2O, 50:50. Obtained as yellow plates (42.7 mg, 98%),

mp 108-109 °C (from c-hexane); Rf 0.63 (DCM/Et2O, 90:10); (found: C, 44.25; H, 5.45;

N, 19.41. C8H12ClN3S requires: C, 44.13; H, 5.56; N, 19.30%); λmax(DCM)/nm 320 (log ε

4.16); vmax/cm-1 2934w, 2801w and 2778w (alkyl C-H), 2224w (C≡N), 1508s (C=O),

1462m, 1437m, 1375m, 1350m, 1312m, 1283m, 1265m, 1238m, 1166m, 1140m, 1128m,

1101m, 1076m, 1045m, 1030m, 1007m, 943m, 910w, 872w, 758m; δH(300 MHz; CDCl3)

4.17 (2H, dd, J 5.3, 5.3), 4.09 (2H, dd, J 5.1, 5.1), 3.60 (2H, t, J 6.5), 2.82 (2H, t, J 6.6),

2.72 (2H, dd, J 5.3, 5.3), 2.67 (2H, dd, J 5.3, 5.3); δC(75 MHz; CDCl3) 163.9 (s), 111.6 (s),

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58.7 (t), 53.4 (t), 52.7 (t), 51.5 (t), 46.8 (t), 40.7 (t); MALDI-TOF MS (m/z): 220 (MH++2,

31%), 218 (MH+, 74), 216 (100), 184 (25), 175 (7), 139 (7), 113 (12), 106 (27).

7.5.4.6 N-(2-Cyanoethyl)piperazine-1-carbothioyl cyanide 121f

Chromatography eluent: n-hexane/Et2O, 20:80. Obtained as yellow plates (41.0 mg, 98%),

mp 125-126 °C (from c-hexane/DCE); Rf 0.45 (DCM/Et2O, 90:10); (found: C, 51.95;

H, 5.87; N, 26.79. C9H12N4S requires: C, 51.90; H, 5.81; N, 26.90%); λmax(DCM)/nm 320

(log ε 4.11); vmax/cm-1 2965w and 2830m (alkyl C-H), 2249w and 2224w (C≡N), 1510s,

1466m, 1449m, 1437m, 1381m, 1350m, 1333m, 1300m, 1283m, 1269m, 1242m, 1211w,

1196m, 1140m, 1101m, 1076w, 1032m, 1015m, 993m, 941m, 910w, 874w, 824w, 758m;

δH(300 MHz; CDCl3) 4.17 (2H, dd, J 5.3, 5.3), 4.09 (2H, dd, J 5.1, 5.1), 2.76 (2H, t, J 6.8),

2.71 (2H, dd, J 5.1, 5.1), 2.65 (2H, dd, J 5.1, 5.1), 2.55 (2H, t, J 6.6); δC(75 MHz; CDCl3)

163.9 (s), 118.1 (s), 111.5 (s), 53.3 (t), 52.4 (t), 52.3 (t), 51.1 (t), 46.7 (t), 16.2 (t); MALDI-

TOF MS (m/z): 209 (MH+, 100%), 192 (5), 182 (16), 175 (50), 168 (77), 141 (3), 113 (19),

97 (63).

7.5.5 Reaction of N-{4-[N-(2-Chloroethyl)piperazin-1-yl]-5H-1,2,3-dithiazol-5-

ylidene}aniline 119 with DABCO

To a stirred solution of N-{4-[N-(2-chloroethyl)piperazin-1-yl]-5H-1,2,3-dithiazol-5-

ylidene}aniline 119 (68.2 mg, 0.2 mmol) in PhCl (2 mL) at ca. 20 °C was added in one

portion DABCO (22.4 mg, 0.2 mmol) and the mixture was then heated at ca. 131 °C for

12 h. Then the mixture was allowed to cool to ca. 20 °C, filtered and the collected solid

was washed with n-hexane to give N-(2-{N-[5-(phenylimino)-5H-1,2,3-dithiazol-4-

yl]piperazin-1-yl}ethyl)-1,4-diazabicyclo[2.2.2]octan-1-ium chloride 122 as yellow glassy

plates (58.2 mg, 64%), decomp. (DSC) onset: 198.5 °C, peak max: 201.7 °C (precipitated

from DCM with n-pentane/Et2O followed by sonication in MeCN); (found: C, 52.96;


241 inf (log ε 4.01), 274 inf (3.84), 380 (3.75); vmax/cm-1 3005w (aryl C-H), 2965w, 2886w

and 2832m (alkyl C-H), 1597s, 1584s, 1533m, 1483m, 1445m, 1393m, 1339w, 1312m,

1277w, 1267w, 1244s, 1213w, 1200w, 1182w, 1150m, 1101m, 1078m, 1061m, 1003m,

995m, 949m, 905m, 899m, 858m, 849m,843m, 822m, 795m, 762m; δH(300 MHz; CDCl3)

7.40 (2H, dd, J 7.8, 7.8), 7.17 (1H, dd, J 7.5, 7.5), 7.08 (2H, dd, J 8.7, 1.2), 3.90 (2H, dd, J

5.1, 5.1), 3.83 (6H, dd, J 7.2, 7.2), 3.71 (4H, br s), 3.19 (6H, dd, J 7.2, 7.2), 2.89 (2H, dd, J

4.8, 4.8), 2.68 (4H, dd, J 4.5, 4.5); δC(75 MHz; CDCl3) 160.4 (s), 158.1 (s), 152.4 (s),

129.7 (d), 125.6 (d), 119.3 (d), 59.7 (t), 52.8 (t), 52.6 (t), 52.0 (t), 48.1 (t), 45.4 (t);

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MALDI-TOF MS (m/z): 417 (M+, 22%), 327 (30), 305 (100), 250 (7), 138 (10), 113 (3),

70 (3). The filtrate was adsorbed onto silica and chromatographed (n-hexane/Et2O, 80:20)

to give unreacted N-{4-[N-(2-chloroethyl)piperazin-1-yl]-5H-1,2,3-dithiazol-5-ylidene}-

aniline 119 (24.4 mg, 36%).

7.5.6 Reactions of 4-[N-(2-Chloroethyl)piperazin-1-yl]-5H-1,2,3-dithiazoles

with Nucleophiles.

7.5.6.1 Reaction with Sodium Azide (General Procedure)

To a stirred solution of the appropriate 4-[N-(2-chloroethyl)piperazin-1-yl]-5H-1,2,3-

dithiazole (0.10 mmol) in MeCN (2 mL) at ca. 20 °C was added in one portion NaN3

(7.2 mg, 0.11 mmol). The mixture was then heated at ca. 81 °C for the time specified in

Table 18 (entry 1) and then left to cool to ca. 20 °C. The mixture was adsorbed onto silica

and chromatography (n-hexane/Et2O, 90:10) gave in some cases traces of unreacted

starting material. Further elution gave the corresponding 4-[N-(2-azidoethyl)piperazin-1-

yl]-5H-1,2,3-dithiazole.

7.5.6.1.1 N-{4-[N-(2-Azidoethyl)piperazin-1-yl]-5H-1,2,3-dithiazol-5-ylidene}aniline

120a

Chromatography eluent: n-hexane/Et2O, 70:30. Obtained as yellow needles (32.8 mg,

94%); mp 42.5-44.5 °C (n-hexane/Et2O at ca. -40 °C); Rf 0.48 (n-hexane/Et2O, 60:40);

(found: C 48.48; H, 5.02; N, 28.13. C14H17N7S2 requires: C, 48.40; H, 4.93; N, 28.22%);

λmax(DCM)/nm 283 (log ε 3.61), 382 (3.83); vmax/cm-1 2938m and 2814m (alkyl C-H),

2099s (N≡N), 1582s, 1574s, 1522m, 1483m, 1449m, 1379m, 1350m, 1304m, 1285m,

1250s, 1144m, 1072m, 1051m, 1001m, 993s, 955m, 907m, 858m, 831m, 818m, 793m,

762s; δH(300 MHz; CDCl3) 7.43 (2H, dd, J 8.0, 8.0), 7.20 (1H, dd, J 7.5, 7.5), 7.12 (2H, d,

J 8.1), 3.79 (4H, dd, J 5.0, 5.0), 3.38 (2H, t, J 6.0), 2.67-2.63 (6H, m); δC(75 MHz; CDCl3)

160.6 (s), 158.3 (s), 152.5 (s), 129.7 (d), 125.6 (d), 119.3 (d), 57.2 (t), 52.8 (t), 48.3 (t),

48.1 (t); MALDI-TOF MS (m/z): 348 (MH+, 100%), 314 (19), 291 (23), 283 (6), 275 (5),

236 (82), 172 (8), 111 (5), 67 (11).

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7.5.6.1.2 4-[N-(2-Azidoethyl)piperazin-1-yl]-5H-1,2,3-dithiazol-5-one 169a

Chromatography eluent: n-hexane/Et2O, 70:30. Obtained as a yellow oil (26.4 mg, 97%),

Rf 0.68 (DCM/t-BuOMe, 90:10); (found: C, 35.19; H, 4.26; N, 30.71. C8H12N6OS2 requires:


2941w and 2816m (alkyl C-H), 2099m (N≡N), 1659s, 1651s, 1530m, 1449m, 1383m,

1348m, 1304m, 1285m, 1246m, 1144m, 1067m, 988m, 953m, 816m, 800m, 768m; δH(500

MHz; CDCl3) 3.65 (4H, dd, J 4.8, 4.8), 3.36 (2H, t, J 5.8), 2.63 (2H, t, J 6.0), 2.60 (4H, dd,

J 5.0, 5.0); δC(125 MHz; CDCl3) 186.1 (s), 155.1 (s), 57.1 (t), 52.6 (t), 48.0 (t), 47.2 (t);

MALDI-TOF MS (m/z): 272 (M+, 100%), 270 (59), 228 (13), 215 (21), 213 (18), 199 (8).

7.5.6.2 Reaction with N-Benzylmethylamine (General Procedure)


dithiazole (0.10 mmol) in MeCN (2 mL) at ca. 20 °C was added in one portion

N-benzylmethylamine (14.2 μL, 0.11 mmol) and then powdered K2CO3 (15.2 mg,

0.11 mmol). The mixture was then heated at ca. 81 °C for the time specified in Table 18

(entry 2) and then left to cool to ca. 20 °C. The mixture was filtered, washed with DCM

and the filtrate adsorbed onto silica and chromatographed (n-hexane/Et2O, 70:30) to give

unreacted starting material. Further elution gave the corresponding 4-(N-{2-[benzyl-

(methyl)amino]ethyl}piperazin-1-yl)-5H-1,2,3-dithiazole.

7.5.6.2.1 N-[4-(N-{2-[Benzyl(methyl)amino]ethyl}piperazin-1-yl)-5H-1,2,3-dithiazol-5-

ylidene]aniline 120b

Chromatography eluent: Et2O. Obtained as yellow plates (22.5 mg, 63%); mp 89.5-91 °C

(MeCN at ca. -40 °C); Rf 0.38 (Et2O); (found: C, 62.18; H, 6.33; N, 16.59. C22H27N5S2

requires: C, 62.09; H, 6.39; N, 16.46%); λmax(DCM)/nm 290 (log ε 3.56), 383 (3.79);

vmax/cm-1 2922m, 2851m and 2806m (alkyl C-H), 1595m, 1585m, 1522m, 1483m, 1460m,

1447m, 1379m, 1323w, 1308w, 1292m, 1271m, 1252m, 1213w, 1177m, 1130m, 1121m,

1080m, 1018m, 993m, 957m, 914w, 858m, 831m, 787m, 766m, 746m; δH(500 MHz;

acetone-d6) 7.47 (2H, dd, J 8.0, 8.0), 7.36-7.34 (2H, m), 7.30 (2H, dd, J 7.5, 7.5), 7.22 (2H,

dd, J 7.5, 7.5), 7.13 (2H, dd, J 8.5, 1.0), 3.72 (4H, dd, J 4.8, 4.8), 3.52 (2H, s), 2.58 (4H, dd,

J 5.3, 5.3), 2.55 (4H, s), 2.20 (3H, s); δC(500 MHz; acetone-d6) 161.8 (s), 159.3 (s), 154.0

(s), 140.8 (s), 130.8 (d), 129.7 (d), 129.0 (d), 127.7 (d), 126.4 (d), 120.2 (d), 63.3 (t), 57.3

(t), 55.7 (t), 54.1 (t), 49.4 (t), 43.0 (q); MALDI-TOF MS (m/z): 426 (MH+, 100%), 424

(62), 392 (6), 333 (29), 305 (77), 275 (3), 148 (82), 134 (5).

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7.5.6.2.2 4-(N-{2-[Benzyl(methyl)amino]ethyl}piperazin-1-yl)-5H-1,2,3-dithiazol-5-one

dihydrochloride 169b

Chromatography eluent: Et2O/acetone (95:5). Obtained as an unstable yellow oil (14.0 mg,

40%) which was fully characterized as the dihydrochloride salt.

4-N-{2-[Benzyl(methyl)amino]ethyl}piperazin-1-yl)-5H-1,2,3-dithiazol-5-one 169b was

dissolved in DCM and purged with HCl (g) for 5 seconds. The precipitated salt was filtered

and washed with DCM to give 4-(N-{2-[benzyl(methyl)amino]ethyl}piperazin-1-yl)-5H-

1,2,3-dithiazol-5-one dihydrochloride 169b·2HCl as a microcrystalline pale yellow

powder, decomp. (DSC) onset: 222.6 °C, peak max: 223.4 °C; (found: C, 45.28; H, 5.79;

N, 13.09. C16H24Cl2N4OS2 requires: C, 45.39; H, 5.71; N, 13.23%); λmax(H2O)/nm 262

(3.21), 369 (3.79); vmax/cm-1 2359brm (N+-H), 1649s, 1520m, 1495m, 1479w, 1460m,

1449m, 1398m, 1389m, 1362w, 1315m, 1279m, 1261m, 1211w, 1196m, 1177w, 1144w,

1119m, 1061m, 1043m, 966m, 947m, 924m, 837m, 822m, 797m, 752s, 706s; δH(500 MHz;

D2O) 7.61-7.55 (5H, m), 4.49 (2H, s), 3.87 (4H, br s), 3.75-3.63 (4H, m), 3.47 (4H, br s),

2.92 (3H, s); δC[125 MHz; D2O (0.5 mL) + DMSO-d6 (0.1 mL)] 189.1 (s), 156.7 (s), 132.6

(d), 132.2 (d), 131.1 (d), 129.9 (s), 62.3 (t), 53.4 (t), 51.7 (t), 50.3 (t), 45.9 (t), 41.1 (q);

MALDI-TOF MS (m/z): 351 (MH+, 100%), 258 (5), 230 (77), 148 (69), 90 (5).

7.5.6.2.3 4-(N-{2-[Benzyl(methyl)amino]ethyl}piperazin-1-yl)-5H-1,2,3-dithiazol-5-

thione dihydrochloride 170b

Chromatography eluent: Et2O/acetone (95:5). Obtained as an unstable red oil (19.5 mg,

53%) which was fully characterized as the dihydrochloride salt.

4-(N-{2-[Benzyl(methyl)amino]ethyl}piperazin-1-yl)-5H-1,2,3-dithiazole-5-thione 170b

was dissolved in DCM and purged with HCl (g) for 5 seconds. The precipitated salt was

filtered and washed with DCM to give 4-(N-{2-[benzyl(methyl)amino]ethyl}piperazin-1-

yl)-5H-1,2,3-dithiazol-5-thione dihydrochloride 170b·2HCl as microcrystalline red

powder, decomp. (DSC) onset: 209.4 °C, peak max: 214.0 °C; (found: C, 43.80; H, 5.41;

N, 12.67. C16H24Cl2N4S3 requires: C, 43.73; H, 5.50; N, 12.75%); λmax(H2O)/nm 235 (log ε

3.91), 315 (3.25), 441 (3.88); vmax/cm-1 2984w and 2916w (alkyl C-H), 2419m (N+-H),

1609w, 1493m, 1477m, 1452m, 1396m, 1337m, 1279m, 1261s, 1213w, 1182w, 1167m,

1152m, 1123s, 1076m, 1049m, 1043m, 1030m, 991m, 964s, 922m, 856w, 849m, 839m,

824m, 804m, 785m, 741m, 708m; δH(500 MHz; D2O) 7.61-7.57 (5H, m), 4.49 (2H, s),

3.90 (4H, br s), 3.74-3.69 (4H, m), 3.52 (4H, br s), 2.93 (3H, s); δC[125 MHz; D2O +

DMSO-d6 (1 drop)] 203.7 (s), 167.1 (s), 132.6 (d), 132.2 (d), 131.1 (d), 129.8 (s), 62.4 (t),

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53.6 (t), 51.8 (t), 50.2 (t), 47.5 (t), 41.3 (q); MALDI-TOF MS (m/z): 367 (MH+, 85%), 365

(100), 335 (6), 274 (3), 246 (92), 148 (75), 134 (4).

7.5.6.3 Reaction with Aniline (General Procedure)

To a stirred suspension of the appropriate 4-[N-(2-chloroethyl)piperazin-1-yl]-5H-1,2,3-

dithiazole (0.40 mmol) in dry and deaerated MeCN (2 mL) at ca. 20 °C under an argon

atmosphere was added dropwise aniline (365 μL, 4.0 mmol). The mixture was then heated

at ca. 81 °C under argon for the time specified in Table 18 (entry 3) and then left to cool to

ca. 20 °C. The mixture was then cooled to ca. -20 °C for 12 h and the resulting precipitate

was collected by filtration and washed with cold MeCN to give the corresponding

4-{N-[2-(phenylamino)ethyl]piperazin-1-yl}-5H-1,2,3-dithiazole hydrochloride.

7.5.6.3.1 N-(4-{N-[2-(Phenylamino)ethyl]piperazin-1-yl}-5H-1,2,3-dithiazol-5-ylidene)-

aniline hydrochloride 120c

Obtained as yellow needles (124.3 mg, 72%); mp (DSC) onset: 195.6 °C, peak max:

198.6 °C, decomp. onset: 200.5 °C, peak max: 201.4 °C (from EtOH); (found: C, 55.23;

H, 5.65; N, 16.04. C20H24ClN5S2 requires: C, 55.35; H, 5.57; N, 16.14%); λmax(MeOH)/nm

244 (log ε 4.35), 285 (3.76), 379 (3.79); vmax/cm-1 3250m (N-H), 3113w and 3024w (aryl

C-H), 2585m and 2475m (N+-H), 1603m, 1562s, 1526m, 1501m, 1483m, 1466m, 1441m,

1381m, 1310m, 1277m, 1258m, 1229m, 1182m, 1128m, 1086m, 1053m, 1026m, 1007m,

970s, 941m, 864m, 822m, 785m, 756s; δH(500 MHz; DMSO-d6 at ca. 80 oC) two NH

resonances missing (deuterium exchanged), 7.48 (2H, dd, J 7.8, 7.8), 7.24 (1H, dd, J 7.3,

7.3), 7.15-7.10 (4H, m), 6.68 (2H, d, J 7.5), 6.62 (1H, dd, J 7.3, 7.3), 4.08 (4H, br s), 3.53

(2H, t, J 6.3), 3.42 (4H, br s), 3.30 (2H, t, J 6.3); δC(125 MHz; DMSO-d6) 160.6 (s), 157.1

(s), 152.2 (s), 147.7 (s), 129.8 (d), 128.9 (d), 125.5 (d), 119.1 (d), 116.4 (d), 112.3 (d), 54.3

(t), 50.4 (t), 44.6 (t), 37.1 (t); MALDI-TOF MS (m/z): 398 (MH+, 100%), 363 (12), 305

(87), 279 (42), 236 (5).

7.5.6.3.2 4-{N-[2-(Phenylamino)ethyl]piperazin-1-yl}-5H-1,2,3-dithiazol-5-one

hydrochloride 169c

Obtained as yellow needles (118.6 mg, 83%), mp 179-181 °C (from EtOH); (found:

C, 47.00; H, 5.27; N, 15.72. C14H19ClN4OS2 requires: C, 46.85; H, 5.34; N, 15.61%);

λmax(MeOH)/nm 245 (log ε 4.23), 293 (3.46), 373 (3.87); vmax/cm-1 3258m (N-H), 3026w

(aryl C-H), 2848w (alkyl C-H), 2569m (N+-H), 1663s (C=O), 1605s, 1530m, 1499m,

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1474m, 1443m, 1435m, 1387m, 1360m, 1310m, 1271m, 1248s, 1225m, 1182m, 1130m,

1086m, 1051m, 1032m, 970s, 945m, 891m, 814m, 758s; δH(500 MHz; DMSO-d6 at

ca. 80 oC) two NH resonances missing (deuterium exchanged), 7.11 (2H, dd, J 8.5, 7.5),

6.68 (2H, dd, J 8.5, 1.0), 6.61 (1H, ddd, J 7.3, 7.3, 1.0), 3.92 (4H, br s), 3.52 (2H, t, J 6.3),

3.37 (4H, br s), 3.26 (2H, t, J 6.3); δC(125 MHz; DMSO-d6) 186.3 (s), 154.7 (s), 147.7 (s),

128.9 (d), 116.4 (d), 112.3 (d), 54.3 (t), 50.2 (t), 43.7 (t), 37.1 (t); MALDI-TOF MS (m/z):

323 (MH+, 100%), 262 (2), 230 (71), 206 (2), 119 (9).

7.5.6.3.3 4-{N-[2-(Phenylamino)ethyl]piperazin-1-yl}-5H-1,2,3-dithiazole-5-thione

hydrochloride 170c

Obtained as red plates (96.0 mg, 64%), decomp. (DSC) onset: 190.1 °C, peak max:

194.5 °C (from CHCl3/EtOH); (found: C, 44.80; H, 5.09; N, 14.81. C14H19ClN4S3 requires:

C, 44.85; H, 5.11; N, 14.94%); λmax(MeOH)/nm 243 (log ε 4.28), 273 inf (3.75), 320 inf

(3.35), 450 (3.92); vmax/cm-1 3246m (N-H), 2571m (N+-H), 1603m (C=S), 1526m, 1497m,

1481m, 1433m, 1385m, 1350m, 1308m, 1250s, 1225m, 1179m, 1146m, 1121m, 1080m,

1047m, 993m, 968s, 885m, 841m, 824m, 806m, 748s; δH(500 MHz; DMSO-d6 at ca. 80 oC)

two NH resonances missing (deuterium exchanged), 7.11 (2H, dd, J 8.5, 7.0), 6.68 (2H, d,

J 7.5), 6.61 (1H, dd, J 7.3, 7.3), 3.96 (4H, br s), 3.52 (2H, t, J 6.3), 3.40 (4H, br s), 3.29

(2H, t, J 6.5); δC(125 MHz; DMSO-d6) 202.1 (s), 165.0 (s), 147.7 (s), 128.9 (d), 116.4 (d),

112.3 (d), 54.2 (t), 50.4 (t), 45.2 (t), 37.1 (t); MALDI-TOF MS (m/z): 339 (MH+, 100%),

246 (59), 120 (3).

7.5.6.4 Reaction with N-Methylaniline (General Procedure)

To a stirred suspension of the appropriate 4-[N-(2-chloroethyl)piperazin-1-yl]-5H-1,2,3-

dithiazole (0.80 mmol) in dry and deaerated MeCN (2 mL) at ca. 20 °C under an argon

atmosphere was added dropwise N-methylaniline (867 μL, 8.0 mmol). The mixture was

then heated at ca. 81 °C under argon for the time specified in Table 18 (entry 4) and then

left to cool to ca. 20 °C. The mixture was then cooled to ca. -20 °C for 12 h and the

resulting precipitate was collected by filtration and washed with cold MeCN to give the

corresponding 4-{N-[2-(phenylamino)ethyl]piperazin-1-yl}-5H-1,2,3-dithiazole hydro-

chloride.

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7.5.6.4.1 N-[4-(N-{2-[Methyl(phenyl)amino]ethyl}piperazin-1-yl)-5H-1,2,3-dithiazol-5-

ylidene]aniline hydrochloride 120d

In this case the mixture was cooled to ca. -40 °C for 24 h. Obtained as yellow prisms

(194.2 mg, 54%); mp (DSC) onset: 186.2°C, peak max: 191.8 °C, decomp. onset: 194.2 °C,

peak max: 196.6 °C (from EtOH); (found: C, 56.28; H, 5.96; N, 15.58. C21H26ClN5S2

requires: C, 56.30; H, 5.85; N, 15.63%); λmax(MeOH)/nm 253 (log ε 4.45), 277 inf (4.05),

379 (3.83); vmax/cm-1 3053w and 3028w (aryl C-H), 2951w and 2932w (alkyl C-H), 2365m

(N+-H), 1595s, 1585s, 1531m, 1510m, 1479m, 1454m, 1443m, 1398m, 1381m, 1369m,

1283m, 1250m, 1219m, 1159m, 1123m, 1086m, 1072m, 1036m, 1020m, 989m, 970s,

928m, 858m, 849m, 839m, 793m, 781m, 772m, 752s, 748s, 706s; δH(500 MHz; DMSO-d6

at ca. 80 oC) one NH resonance missing (deuterium exchanged), 7.48 (2H, dd, J 8.0, 7.5),

7.25-7.18 (3H, m), 7.14 (2H, dd, J 8.5, 1.0), 6.86 (2H, d, J 8.0), 6.70 (1H, dd, J 7.3, 7.3),

4.06 (4H, br s), 3.82 (2H, t, J 7.5), 3.41 (4H, br s), 3.26 (2H, t, J 7.3), 2.95 (3H, s); δC(75

MHz; DMSO-d6) 160.6 (s), 157.1 (s), 152.2 (s), 148.3 (s), 129.8 (d), 129.0 (d), 125.5 (d),

119.1 (d), 116.5 (d), 112.3 (d), 51.0 (t), 50.4 (t), 45.9 (t), 44.7 (t), 37.8 (q); MALDI-TOF

MS (m/z): 412 (MH+, 100%), 377 (2), 305 (65), 134 (37).

7.5.6.4.2 4-(N-{2-[Methyl(phenyl)amino]ethyl}piperazin-1-yl)-5H-1,2,3-dithiazol-5-one

hydrochloride 169d

Obtained as yellow plates (232.5 mg, 78%), mp (DSC) onset: 178.8 °C, peak max:

182.8 °C, decomp. onset 186.2 °C, peak max: 191.9 °C (from EtOH); (found: C, 48.20;

H, 5.52; N, 15.00. C15H21ClN4OS2 requires: C, 48.31; H, 5.68; N, 15.02%);

λmax(MeOH)/nm 254 (log ε 4.25), 301 (3.48), 372 (3.82); vmax/cm-1 3024w (aryl C-H),

2911w (alkyl C-H); 2409m (N+-H), 1638s (C=O), 1507m, 1526m, 1508s, 1462m, 1445m,

1383m, 1360m, 1281m, 1271m, 1236m, 1211m, 1194m, 1184m, 1161w, 1111m, 1094m,

1076m, 1049w, 1038m, 991m, 959s, 862m, 845m, 822m, 789m, 745s; δH(500 MHz;

DMSO-d6 at ca. 80 oC) one NH resonance missing (deuterium exchanged), 7.20 (2H, dd, J

8.5, 7.5), 6.85 (2H, d, J 8.0), 6.70 (1H, dd, J 7.3, 7.3), 3.91 (4H, br s), 3.81 (2H, t, J 7.5),

3.36 (4H, br s), 3.22 (2H, t, J 7.5), 2.93 (3H, s); δC(125 MHz; DMSO-d6) 186.3 (s), 154.7

(s), 148.2 (s), 129.0 (d), 116.6 (d), 112.3 (d), 51.0 (t), 50.1 (t), 45.8 (t), 43.8 (t), 37.8 (q);

MALDI-TOF MS (m/z): 337 (MH+, 100%), 274 (4), 246 (5), 230 (59), 134 (18), 132 (15).

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7.5.6.4.3 4-(N-{2-[Methyl(phenyl)amino]ethyl}piperazin-1-yl)-5H-1,2,3-dithiazole-5-

thione hydrochloride 170d

Obtained as red plates (237.2 mg, 84%), decomp. (DSC) onset: 186.7 °C, peak max:

191.3 °C (from CHCl3/EtOH); (found: C, 46.35; H, 5.53; N, 14.38. C15H21ClN4S3 requires:

C, 46.32; H, 5.44; N, 14.40%); λmax(MeOH)/nm 241 inf (log ε 4.30), 253 (4.40), 284 inf

(3.82), 320 inf (3.52), 450 (4.02); vmax/cm-1 3051w (aryl C-H), 2936w (alkyl C-H), 2401m

(N+-H), 1597m (C=S), 1508m, 1485m, 1435m, 1422m, 1383m, 1377m, 1366m, 1275m,

1252m, 1229m, 1215m, 1198m, 1159m, 1121m, 1105m, 1076m, 1028m, 1015m, 988m,

970m, 918w, 866w, 829m, 820m, 800m, 743s; δH(500 MHz; DMSO-d6 at ca. 80 oC) one

NH resonance missing (deuterium exchanged), 7.20 (2H, dd, J 8.8, 7.3), 6.85 (2H, d, J 8.0),

6.70 (1H, dd, J 7.3, 7.3), 3.95 (4H, br s), 3.81 (2H, t, J 7.5), 3.40 (4H, br s), 3.25 (2H, t, J

7.3), 3.11 (2H, br s), 2.93 (3H, s); δC(125 MHz; DMSO-d6) 202.1 (s), 165.0 (s), 148.2 (s),

129.0 (d), 116.5 (d), 112.3 (d), 51.0 (t), 50.4 (t), 45.9 (t), 45.2 (t), 37.8 (q); MALDI-TOF

MS (m/z): 353 (MH+, 60%), 351 (100), 319 (4), 246 (67), 244 (34), 220 (3), 134 (61), 132

(27).

7.5.6.5 Reaction with Potassium Phthalimide (General Procedure)


dithiazole (0.10 mmol) in MeCN (2 mL) at ca. 20 °C was added in one portion potassium

phthalimide (37 mg, 0.20 mmol). The mixture was then heated at ca. 81 °C for the time

specified in Table 18 (entry 5) and then left to cool to ca. 20 °C. The mixture was adsorbed

onto silica and chromatography (n-hexane/Et2O, 90:10) gave in some cases traces of

unreacted starting material. Further elution gave the corresponding

4-[N-(2-phthalimidoethyl)piperazin-1-yl]-5H-1,2,3-dithiazole.

7.5.6.5.1 N-{4-[N-(2-Phthalimidoethyl)piperazin-1-yl]-5H-1,2,3-dithiazol-5-ylidene}-

aniline 120e


97%); mp 115-116 °C (from n-hexane/t-BuOMe at ca. -40 °C); Rf 0.29 (n-hexane/Et2O,

60:40); (found: C, 58.57; H, 4.61; N, 15.59. C22H21N5O2S2 requires: C, 58.52; H, 4.69;

N, 15.51%); λmax(DCM)/nm 243 (log ε 4.38), 281 (4.01), 382 (3.77); vmax/cm-1 2941w and

2828w (alkyl C-H), 1767m, 1705s (C=O), 1591m, 1578m, 1522m, 1481m, 1452m, 1437m,

1395m, 1387m, 1360m, 1325m, 1281m, 1271m, 1244m, 1209m, 1144m, 1115m, 1105m,

1078m, 1013m, 993m, 918m, 860m, 814m, 797m, 766m, 760m, 714s, 706m; δH(300 MHz;

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CDCl3) 7.88-7.82 (2H, m), 7.75-7.68 (2H, m), 7.42 (2H, dd, J 7.8, 7.8), 7.19 (1H, dd, J 7.5,

7.5), 7.11 (2H, d, J 8.1), 3.85 (2H, t, J 6.5), 3.70 (4H, dd, J 4.8, 4.8), 2.71-2.65 (6H, m);

δC(75 MHz; CDCl3); 168.3 (s), 160.6 (s), 158.4 (s), 152.5 (s), 133.9 (d), 132.2 (s), 129.7


(m/z): 452 (MH+, 100%), 418 (2), 236 (58), 217 (4).

7.5.6.5.2 4-[N-(2-Phthalimidoethyl)piperazin-1-yl]-5H-1,2,3-dithiazol-5-one 169e

Chromatography eluent: n-hexane/Et2O, 40:60. Obtained as pale yellow cotton fibers

(33.7 mg, 90%), mp 136-138 °C (from c-hexane); Rf 0.36 (n-hexane/t-BuOMe, 50:50);

(found: C, 51.13; H, 4.36; N, 14.73. C16H16N4O3S2 requires: C, 51.05; H, 4.28; N, 14.88%);

λmax(DCM)/nm 242 (log ε 4.17), 276 (4.17), 377 (3.70); vmax/cm-1 2941w and 2845w (alkyl

C-H), 1767m, 1705s (C=O), 1667s (C=O), 1530m, 1464m, 1452m, 1441m, 1396m, 1387m,

1341m, 1335m, 1300m, 1269m, 1246m, 1207m, 1202m, 1144m, 1128m, 1099m, 1074m,

1026m, 1009m, 991m, 874m, 820m, 808m, 791m; δH(500 MHz; CDCl3) 7.81-7.79 (2H, m),

7.72-7.67 (2H, m), 3.81 (2H, t, J 6.3), 3.53 (4H, dd, J 4.5, 4.5), 2.64 (2H, t, J 6.5), 2.59 (4H,

dd, J 4.8, 4.8); δC(125 MHz; CDCl3) 186.0 (s), 168.2 (s), 155.1 (s), 133.8 (d), 132.0 (s),

123.1 (d), 55.5 (t), 52.4 (t), 47.3 (t), 35.0 (t); MALDI-TOF MS (m/z): 377 (MH+, 100%),

375 (64), 345 (30), 316 (72), 285 (75), 214 (9), 174 (35), 124 (4).

7.5.6.5.3 4-[N-(2-Phthalimidoethyl)piperazin-1-yl]-5H-1,2,3-dithiazol-5-thione 170e

Chromatography eluent: n-hexane/Et2O, 40:60. Obtained as red plates (35.6 mg, 91%),

mp 165.5-167.5 °C (from c-hexane/DCE); Rf 0.55 (DCM/Et2O, 80:20); (found: C, 49.11;

H, 4.04; N, 14.18. C16H16N4O2S3 requires: C, 48.96; H, 4.11; N, 14.27%); λmax(DCM)/nm

242 (log ε 4.41), 267 (4.12), 331 inf (2.49), 458 (4.00); vmax/cm-1 2830w and 2810w (alkyl

C-H), 1761m, 1701s (C=O), 1479m, 1474m, 1441m, 1402m, 1379m, 1358m, 1325m,

1277m, 1271m, 1242s, 1200m, 1190m, 1173m, 1146m, 1123s, 1103m, 1055m, 1040m,

1015m, 984m, 920m, 891m, 858m, 826m, 812m, 764m, 721s; δH(500 MHz; CDCl3) 7.86-

7.83 (2H, m), 7.73-7.70 (2H, m), 3.87 (2H, br s), 3.64 (4H, br s), 2.72 (6H, br s); δC(125

MHz; CDCl3) 202.0 (s), 168.3 (s), 165.9 (s), 133.9 (d), 132.2 (s), 123.2 (d), 55.6 (t), 52.5

(t), 48.7 (t), 35.0 (t); MALDI-TOF MS (m/z): 393 (MH+, 100%), 358 (42), 328 (13), 288

(7), 217 (47), 203 (9), 177 (37), 174 (48).

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7.5.6.6 Reaction with Sodium Acetate (General Procedure)


dithiazole (0.10 mmol) in MeCN (2 mL) at ca. 20 °C was added in one portion NaOAc



and chromatography (n-hexane/Et2O, 90:10) gave traces of unreacted starting material.

Further elution gave the corresponding 4-[N-(2-acetoxyethyl)piperazin-1-yl]-5H-1,2,3-

dithiazole.

7.5.6.6.1 N-{4-[N-(2-Acetoxyethyl)piperazin-1-yl]-5H-1,2,3-dithiazol-5-ylidene}aniline

120f

Chromatography eluent: n-hexane/Et2O, 20:80. Obtained as a yellow oil (34.6 mg, 95%);

Rf 0.35 (t-BuOMe); (found: C, 53.01; H, 5.43; N, 15.21. C16H20N4O2S2 requires: C, 52.73;

H, 5.53; N, 15.37%); λmax(DCM)/nm 243 inf (log ε 3.98), 280 (3.59), 382 (3.71); vmax/cm-1

2940w and 2826w (alkyl C-H), 1738s (C=O), 1595m, 1582m, 1574m, 1522m, 1485m,

1449m, 1379m, 1306m, 1233s, 1150m, 1078m, 1043m, 993m, 905w, 858m, 826m, 795m,

762m; δH(500 MHz; CDCl3) 7.43 (2H, dd, J 7.8, 7.8), 7.20 (1H, dd, J 7.3, 7.3), 7.13 (2H, d,

J 8.0), 4.25 (2H, t, J 5.8), 3.80 (4H, br s), 2.72-2.69 (6H, m), 2.08 (3H, s); δC(125 MHz;

CDCl3) 170.9 (s), 160.6 (s), 158.3 (s), 152.5 (s), 129.7 (d), 125.6 (d), 119.3 (d), 61.6 (t),

56.7 (t), 53.0 (t), 48.2 (t), 21.0 (q); MALDI-TOF MS (m/z): 365 (MH+, 100%), 331 (4),

236 (76), 86 (21).

7.5.6.6.2 4-[N-(2-Acetoxyethyl)piperazin-1-yl]-5H-1,2,3-dithiazol-5-one 169f

Chromatography eluent: n-hexane/Et2O, 20:80. Obtained as yellow prisms (26.8 mg, 93%);

mp 32.5-34 °C (n-hexane/Et2O at ca. -40 °C); Rf 0.20 (n-hexane/t-BuOMe, 50:50); (found:

C, 41.50; H, 5.28; N, 14.36. C10H15N3O3S2 requires: C, 41.51; H, 5.23; N, 14.52%);

λmax(DCM)/nm 276 (log ε 3.81), 376 (3.71); vmax/cm-1 2941w and 2822w (alkyl C-H),

1736m, 1659s, 1651m, 1530m, 1449m, 1383m, 1306m, 1236s, 1150m, 1043m, 988m,

816m; δH(500 MHz; CDCl3) 4.20 (2H, t, J 5.8), 3.64 (4H, dd, J 4.8, 4.8), 2.66 (2H, t, J 5.8),

2.60 (4H, dd, J 4.8, 4.8), 2.06 (3H, s); δC(125 MHz; CDCl3) 186.1 (s), 170.9 (s), 155.1 (s),

61.5 (t), 56.6 (t), 52.8 (t), 47.2 (t), 21.0 (q); MALDI-TOF MS (m/z): 290 (MH+, 100), 288

(56), 230 (38), 229 (41), 87 (23).

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7.5.6.6.3 4-[N-(2-Acetoxyethyl)piperazin-1-yl]-5H-1,2,3-dithiazole-5-thione 170f

Chromatography eluent: n-hexane/Et2O, 20:80. Obtained as a red oil (29.0 mg, 94%); Rf

0.21 (DCM/t-BuOMe, 90:10); (found: C, 39.42; H, 4.82; N, 13.63. C10H15N3O2S3 requires:


538 inf (2.75); vmax/cm-1 2940w and 2822w (alkyl C-H), 1736m, 1732m, 1485m, 1445m,

1375m, 1306m, 1236s, 1125s, 1051m, 1007w, 980m, 812m; δH(500 MHz; CDCl3) 4.21

(2H, t, J 5.8), 3.67 (4H, dd, J 4.3, 4.3), 2.68 (2H, t, J 6.0), 2.65 (4H, dd, J 4.8, 4.8), 2.06

(3H, s); δC(125 MHz; CDCl3) 202.0 (s), 170.9 (s), 165.9 (s), 61.6 (t), 56.6 (t), 52.9 (t), 48.8

(t), 21.0 (q); MALDI-TOF MS (m/z): 306 (MH+, 100%), 304 (32), 246 (17), 86 (10).

7.5.6.7 Reaction with Sodium Benzoate (General Procedure)


dithiazole (0.10 mmol) in MeCN (2 mL) at ca. 20 °C was added in one portion NaOBz



and chromatography (n-hexane/Et2O, 90:10) gave traces of unreacted starting material.

Further elution gave the corresponding 4-[N-(2-benzoyloxyethyl)piperazin-1-yl]-5H-1,2,3-

dithiazole.

7.5.6.7.1 N-{4-[N-(2-Benzoyloxyethyl)piperazin-1-yl]-5H-1,2,3-dithiazol-5-ylidene}-

aniline 120g

Chromatography eluent: n-hexane/Et2O, 80:20. Obtained as a yellow microcrystalline

powder (41.6 mg, 98%); mp 55-56.5 °C (from n-hexane/t-BuOMe at ca. -40 oC); Rf 0.43

(n-hexane/t-BuOMe, 40:60); (found: C, 59.35; H, 5.01; N, 13.33. C21H22N4O2S2 requires:

C, 59.13; H, 5.20; N, 13.14%); λmax(DCM)/nm 272 inf (log ε 3.74), 281 (3.71), 294 inf

(3.61), 382 (3.80); vmax/cm-1 3063w and 3009w (aryl C-H), 2806w and 2754w (alkyl C-H),

1713s (C=O), 1574s, 1524m, 1487m, 1450m, 1400m, 1362m, 1314m, 1275s, 1246m,

1234m, 1173m, 1148m, 1107m, 1069m, 1030m, 1016m, 991m, 949m, 934m, 856m, 826m,

804m, 791m, 766m, 708s; δH(500 MHz; CDCl3) 8.04 (2H, d, J 7.0), 7.57 (1H, dd, J 7.5,

7.5), 7.47-7.42 (4H, m), 7.20 (1H, dd, J 7.5, 7.5), 7.12 (2H, d, J 7.5), 4.53 (2H, br s), 3.83

(4H, br s), 2.90 (2H, br s), 2.79 (4H, br s); δC(125 MHz; CDCl3) 166.4 (s), 160.6 (s), 158.2

(s), 152.5 (s), 133.0 (d), 130.1 (s), 129.7 (d), 129.6 (d), 128.4 (d), 125.6 (d), 119.4 (d), 62.3

(t), 56.7 (t), 53.0 (t), 48.2 (t); MALDI-TOF MS (m/z): 427 (MH+, 100%), 393 (6), 305 (19),

276 (2), 236 (83), 192 (4), 149 (49), 104 (4).

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7.5.6.7.2. 4-[N-(2-Benzoyloxyethyl)piperazin-1-yl]-5H-1,2,3-dithiazol-5-one 169g


97%), mp 59-61.5 °C (from n-hexane/Et2O at ca. -20 °C); Rf 0.43 (DCM/Et2O, 90:10);


λmax(DCM)/nm 274 (log ε 3.93), 281 inf (3.90), 377 (3.73); vmax/cm-1 3067w and 3030w

(aryl C-H), 2833w and 2851w (alkyl C-H), 1722s (C=O), 1659s, 1601m, 1526m, 1450m,

1445m, 1414m, 1383m, 1331m, 1312m, 1279s, 1267s, 1250m, 1225m, 1194m, 1177m,

1152m, 1119m, 1070m, 1026m, 989m, 955m, 816m; δH(500 MHz; CDCl3) 8.03 (2H, d, J

7.0), 7.56 (1H, dd, J 7.5, 7.5), 7.44 (2H, dd, J 7.8, 7.8), 4.47 (2H, t, J 5.8), 3.65 (4H, dd, J

4.8, 4.8), 2.82 (2H, t, J 5.8), 2.68 (4H, dd, J 5.0, 5.0); δC(125 MHz; CDCl3) 186.1 (s),

166.4 (s), 155.1 (s), 133.0 (d), 130.0 (s), 129.5 (d), 128.4 (d), 62.4 (t), 56.6 (t), 52.9 (t),

47.3 (t); MALDI-TOF MS (m/z): 352 (MH+, 100%), 350 (61), 291 (47), 260 (14), 230 (37),

149 (19), 104 (7).

7.5.6.7.3 4-[N-(2-Benzoyloxyethyl)piperazin-1-yl]-5H-1,2,3-dithiazole-5-thione 170g

Chromatography eluent: n-hexane/Et2O, 80:20. Obtained as a red oil (34.8 mg, 95%),

Rf 0.54 (DCM/t-BuOMe, 90:10); (found: C, 49.15; H, 4.73; N, 11.32. C15H17N3O2S3

requires: C, 49.02; H, 4.66; N, 11.43%); λmax(DCM)/nm 256 inf (log ε 3.95), 268 inf (3.92),

280 inf (3.82), 289 inf (3.70), 327 (3.45), 457 (3.97); vmax/cm-1 2932w and 2826w (alkyl

C-H), 1717m (C=S), 1601w, 1485m, 1445m, 1379m, 1314m, 1271s, 1246m, 1175m,

1125m, 1070m, 1051m, 1026m, 980m, 810m; δH(500 MHz; CDCl3) 8.04 (2H, d, J 7.0),

7.57 (1H, dd, J 7.5, 7.5), 7.45 (2H, dd, J 7.8, 7.8), 4.50 (2H, br s), 3.70 (4H, br s), 2.87 (2H,

br s), 2.76 (4H, br s); δC(125 MHz; CDCl3) 202.0 (s), 166.4 (s), 165.8 (s), 133.1 (d), 130.1

(s), 129.6 (d), 128.4 (d), 62.3 (t), 56.6 (t), 52.9 (t), 48.8 (t); MALDI-TOF MS (m/z): 368

(MH+, 100%), 335 (12), 305 (4), 246 (61), 149 (30), 105 (8).

7.5.6.8 Reaction with Potassium Thiocyanate (General Procedure)


dithiazole (0.10 mmol) in MeCN (2 mL) at ca. 20 °C was added in one portion KSCN



and chromatography (n-hexane/Et2O, 90:10) gave in some cases traces of unreacted

starting material. Further elution gave the corresponding 4-[N-(2-thiocyanatoethyl)-

piperazin-1-yl]-5H-1,2,3-dithiazole.

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7.5.6.8.1 N-{4-[N-(2-Thiocyanatoethyl)piperazin-1-yl]-5H-1,2,3-dithiazol-5-ylidene}-

aniline 120h


91%); mp 86-87 °C (from n-hexane/t-BuOMe at ca. -20 °C); Rf 0.38 (n-hexane/t-BuOMe,

40:60); identical to that described above.

7.5.6.8.2 4-[N-(2-Thiocyanatoethyl)piperazin-1-yl]-5H-1,2,3-dithiazol-5-one 169h

Chromatography eluent: n-hexane/Et2O, 50:50. Obtained as pale yellow prisms (27.3 mg,

94%), mp 92-93 °C (from c-hexane); Rf 0.32 (n-hexane/t-BuOMe, 50:50); (found: C, 37.33;

H, 4.04; N, 19.32. C9H12N4OS3 requires: C, 37.48; H, 4.19; N, 19.43%); λmax(DCM)/nm

276 (log ε 3.61), 377 (3.80); vmax/cm-1 3015w (aryl C-H), 2954w and 2824m (alkyl C-H),

2156m (C≡N), 1643s (C=O), 1618m, 1522m, 1450m, 1387m, 1368m, 1335m, 1308m,

1277m, 1252s, 1225s, 1163m, 1144m, 1125m, 1103m, 1072m, 1059m, 1007m, 989s,


3.20 (2H, t, J 6.5), 2.78 (2H, t, J 6.5), 2.59 (4H, dd, J 4.8, 4.8); δC(125 MHz; CDCl3) 186.0

(s), 155.0 (s), 112.9 (s), 56.1 (t), 52.2 (t), 47.0 (t), 32.1 (t); MALDI-TOF MS (m/z): 289

(MH+, 100%), 287 (78), 262 (49), 228 (49), 216 (5).

7.5.6.8.3 4-[N-(2-Thiocyanatoethyl)piperazin-1-yl]-5H-1,2,3-dithiazole-5-thione 170h

Chromatography eluent: n-hexane/Et2O, 50:50. Obtained as red plates (27.5 mg, 90%), mp

104.5-105.5 °C (from n-hexane/t-BuOMe at ca. -20 °C); Rf 0.55 (DCM/Et2O, 90:10);


λmax(DCM)/nm 252 inf (log ε 3.87), 330 (3.40), 456 (3.93), 540 inf (2.48); vmax/cm-1 2943w

and 2824m (alkyl C-H), 2151m (C≡N), 1479m, 1441m, 1381m, 1369m, 1356m, 1312m,

1288m, 1265m, 1250s, 1211m, 1202m, 1136m, 1121s, 1101m, 1065m, 1053m, 1042m,

1001m, 982s, 853m, 827m, 795m, 762m; δH(500 MHz; CDCl3) 3.67 (4H, br s), 3.21 (2H, t,

J 6.5), 2.80 (2H, t, J 6.5), 2.65 (4H, dd, J 5.0, 5.0); δC(125 MHz; CDCl3) 202.0 (s), 165.8

(s), 112.9 (s), 56.2 (t), 52.2 (t), 48.7 (t), 32.3 (t); MALDI-TOF MS (m/z): 305 (MH+, 61%),

303 (100), 278 (58), 271 (10), 246 (21), 177 (3), 129 (6).

7.5.6.9 Reaction with 2-Mercaptobenzothiazole (General Procedure)


dithiazole (0.10 mmol) in MeCN (2 mL) at ca. 20 °C was added in one portion

2-mercaptobenzothiazole (18.4 μL, 0.11 mmol) and then powdered K2CO3 (0.11 mmol,

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15.2 mg). The mixture was then heated at ca. 81 °C for the time specified in Table 18

(entry 9) and then left to cool to ca. 20 °C. The mixture was filtered, washed with DCM

and the filtrate adsorbed onto silica and chromatographed to give the corresponding

4-{N-[2-(benzo[d]thiazol-2-ylthio)ethyl]piperazin-1-yl}-5H-1,2,3-dithiazole.

7.5.6.9.1 N-(4-{N-[2-(Benzo[d]thiazol-2-ylthio)ethyl]piperazin-1-yl}-5H-1,2,3-

dithiazol-5-ylidene)aniline 120i

Chromatography eluent: n-hexane/Et2O, 40:60. Obtained as yellow plates (42.8 mg, 90%);

mp 118-119 °C (from n-hexane/Et2O at ca. -40 °C); Rf 0.35 (n-hexane/Et2O, 50:50);


λmax(DCM)/nm 243 (log ε 4.31), 282 (4.23), 290 (4.19), 301 (4.11), 381 (3.77); vmax/cm-1

3067w and 3024w (aryl C-H), 2841m and 2826m (alkyl C-H), 1591m, 1572s, 1516m,

1485m, 1462m, 1454m, 1447m, 1427m, 1377m, 1371m, 1360m, 1312m, 1292m, 1269m,

1254m, 1242m, 1211m, 1206m, 1132m, 1080m, 1016m, 993s, 953m, 858m, 845m, 829m,

793m, 754s, 723m; δH(300 MHz; CDCl3) 7.86 (1H, d, J 8.1), 7.76 (1H, d, J 7.8), 7.46-7.38

(3H, m), 7.29 (1H, dd, J 7.5, 7.5), 7.20 (1H, dd, J 7.4, 7.4), 7.13 (2H, d, J 8.1), 3.79 (4H,

dd, J 4.8, 4.8), 3.56 (2H, t, J 7.1), 2.87 (2H, t, J 7.1), 2.71 (4H, dd, J 5.0, 5.0); δC(75 MHz;

CDCl3) 166.9 (s), 160.7 (s), 158.3 (s), 153.2 (s), 152.5 (s), 135.3 (s), 129.7 (d), 126.0 (d),

125.6 (d), 124.2 (d), 121.5 (d), 121.0 (d), 119.4 (d), 57.1 (t), 52.6 (t), 48.3 (t), 30.8 (t);

MALDI-TOF MS (m/z): 471 (M+, 52%), 437 (7), 304 (100), 235 (8), 193 (30).

7.5.6.9.2 4-{N-[2-(Benzo[d]thiazol-2-ylthio)ethyl]piperazin-1-yl}-5H-1,2,3-dithiazol-5-

one 169i

Chromatography eluent: n-hexane/Et2O, 30:70. Obtained as a yellow needles (32.4 mg,

81%), mp 69-70 °C (n-hexane/Et2O at ca. -40 °C); Rf 0.67 (DCM/Et2O, 90:10); (found:

C, 45.51; H, 4.13; N, 14.12. C15H16N4OS4 requires: C, 45.43; H, 4.07; N, 14.13%);

λmax(DCM)/nm 245 inf (log ε 4.12), 281 (4.26), 289 inf (4.21), 302 (4.10), 377 (3.84);

vmax/cm-1 3057w (aryl C-H), 2934m and 2812m (alkyl C-H), 1659s (C=O), 1530m, 1454m,

1427s, 1385m, 1308m, 1273m, 1248m, 1128m, 1074m, 989s, 816m, 756s, 725m;

δH(500 MHz; CDCl3) 7.85 (1H, d, J 8.0), 7.74 (1H, d, J 8.0), 7.41 (1H, dd, J 7.8, 7.8), 7.29

(1H, dd, J 7.5, 7.5), 3.66 (4H, dd, J 4.5, 4.5), 3.54 (1H, t, J 7.3), 2.85 (2H, t, J 6.0), 2.66

(4H, br s); δC(125 MHz; CDCl3) 186.1 (s), 166.7 (s), 155.1 (s), 153.1 (s), 135.2 (s), 126.0


(m/z) 397 (MH+, 100%), 305 (7), 230 (62), 194 (5), 138 (3).

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7.5.6.9.3 4-{N-[2-(Benzo[d]thiazol-2-ylthio)ethyl]piperazin-1-yl}-5H-1,2,3-dithiazole-5-

thione hydrochloride 170i·HCl

Chromatography eluent: n-hexane/Et2O, 30:70. Obtained as an unstable red oil (33.7 mg,

75%), which was characterized as the hydrochloride salt. 4-{N-[2-(Benzo[d]thiazol-2-

ylthio)ethyl]piperazin-1-yl}-5H-1,2,3-dithiazole-5-thione 170i dissolved in MeCN/DCM

(2:1, 5 mL) and purged with HCl (g) for 5-10 sec. To the mixture was added n-pentane and

the resulting precipitate was collected by filtration and washed with n-pentane to give

4-{N-[2-(benzo[d]thiazol-2-ylthio)ethyl]piperazin-1-yl}-5H-1,2,3-dithiazole-5-thione

hydrochloride 170i·HCl as a red microcrystalline powder, decomp. (DSC) onset: 182.2 °C,

peak max: 186.6 °C; (found: C, 39.97; H, 3.70; N, 12.37. C15H17ClN4S5 requires: C, 40.12;

H, 3.82; N, 12.48%); λmax(MeOH)/nm 225 (log ε 4.39), 234 inf (4.29), 243 inf (4.20), 278

(4.23), 288 inf (4.17), 301 (4.06), 330 inf (3.34), 450 (3.87); vmax/cm-1 3063w (aryl C-H),

2884w and 2938w (alkyl C-H), 2556m (N+-H), 1481m, 1456m, 1427m, 1402m, 1391m,

1342m, 1333m, 1265m, 1190m, 1132m, 1123m, 1086m, 1061m, 1032m, 1001m, 974m,

957m, 932m 868m, 826m, 810m, 750s, 721m, 706m; δH(500 MHz; DMSO-d6) 11.44 (1H,

br s), 8.04 (1H, d, J 7.5), 7.90 (1H, d, J 8.0), 7.50 (1H, dd, J 7.5, 7.5), 7.40 (1H, dd, J 7.5,

7.5), 4.40 (2H, d, J 13.0), 3.83 (2H, t, J 7.5), 3.70 (2H, d, J 11.0), 3.59 (2H, t, J 7.8), 3.40

(2H, dd, J 12.5, 12.5), 3.33-3.22 (2H, m); δC(125 MHz; CDCl3) 202.1 (s), 165.0 (s), 164.8

(s), 152.4 (s), 134.7 (s), 126.4 (d), 124.7 (d), 121.8 (d), 121.3 (d), 54.3 (t), 50.4 (t), 45.2 (t),

26.1 (t); MALDI-TOF MS (m/z): 413 (MH+, 100%), 379 (6), 246 (77).

7.5.7 Chemistry of 4-[N-(2-chloroethyl)piperazin-1-yl]-5H-1,2,3-dithiazole-5-

thione 163

7.5.7.1 Reaction with TCNEO

To a stirred solution of 4-[N-(2-chloroethyl)piperazin-1-yl]-5H-1,2,3-dithiazole-5-thione

163 (28.2 mg, 0.1 mmol) in toluene (0.5 mL) at ca. 20 °C was added TCNEO (28.8 mg,

0.2 mmol) in one portion and the mixture left to stir at this temperature for 2 h. Then the

reaction mixture was diluted with n-hexane/DCM and poured onto a packed column of

silica and chromatography (DCM/Et2O, 30:70) gave the desired product together with

unidentified side products. A second chromatography (Et2O) gave pure

2-{4-[N-(2-chloroethyl)piperazin-1-yl]-5H-1,2,3-dithiazol-5-ylidene}malononitrile 164 as

orange needles (10.5 mg, 33%), decomp. (DSC) onset: 160.1 °C, peak max: 161.1 °C

(from Et2O at ca. -20 oC); Rf 0.76 (Et2O); (found: C, 42.13; H, 3.75; N, 22.19.

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270 inf (3.57), 380 inf (3.65), 445 (4.10); vmax/cm-1 2941w, 2843w and 2818w (alkyl C-H),

2208m (C≡N), 1487m, 1468s, 1464s, 1454m, 1371m, 1356m, 1339m, 1312m, 1294w,

1275m, 1260m, 1211m, 1159m, 1148m, 1125m, 1084m, 1001m, 939m, 895m, 851m,

837m, 826m, 814s, 737w, 710m; δH(500 MHz; CDCl3) 3.60 (2H, t, J 6.8), 3.25 (4H, br s),

2.80 (2H, t, J 7.0), 2.77 (4H, dd, J 4.5, 4.5); δC(125 MHz; CDCl3) 167.9 (s), 162.1 (s),

116.3 (s), 112.6 (s), 65.4 (s), 59.4 (t), 51.9 (t), 51.3 (t), 40.9 (t); MALDI-TOF MS (m/z):

316 (MH++2, 25%), 314 (MH+, 67), 278 (100), 264 (8), 242 (2), 226 (3), 147 (7).

7.5.7.2 Reaction with Diazomalonate

To a stirred solution of diazomalonate (56.0 mg, 0.3 mmol) in PhCl (2 mL) at ca. 20 °C

was added 4-[N-(2-chloroethyl)piperazin-1-yl]-5H-1,2,3-dithiazole-5-thione 163 (28.2 mg,

0.1 mmol) and CuBr (43.2 mg, 0.3 mmol) and the mixture was heated under vigorous

reflux (external temperature ca. 170 °C) for 3 h. Then the mixture left to cool to ca. 20 °C

and then poured onto a packed column of silica. Chromatography (n-hexane/Et2O, 90:10)

gave unreacted diazomalonate and thione 163. Further elution (n-hexane/Et2O, 60:40) gave

an unidentified yellow side product (2.7 mg). A last elution (n-hexane/Et2O, 60:40) gave

diethyl 2-{4-[N-(2-chloroethyl)piperazin-1-yl]-5H-1,2,3-dithiazol-5-ylidene}malonate 165

as yellow plates (14.0 mg, 37%), mp 74-75 °C (from n-hexane/Et2O at ca. -20 oC); Rf 0.33

(n-hexane/Et2O, 60:40); (found: C, 44.03; H, 5.31; N, 10.36. C15H22ClN3O4S2 requires:

C, 44.17; H, 5.44; N, 10.30%); λmax(DCM)/nm 269 inf (log ε 3.24), 421 (3.96); vmax/cm-1

2984w, 2961w, 2938w, 2839w and 2803w (alkyl C-H), 1697m, 1651m, 1518m, 1479m,

1456m, 1366m, 1321m, 1281m, 1254m, 1238s, 1171m, 1138w, 1121m, 1099m, 1065w,

1034m, 1015m, 1007m, 991m, 935m, 862m, 839m, 810m, 785m, 772m, 748m, 727m;

δH(500 MHz; CDCl3) 4.32 (2H, q, J 7.0), 4.30 (2H, q, J 7.2), 3.59 (2H, t, J 7.0), 3.11 (2H,

br s), 2.96 (2H, br s), 2.83 (2H, br s), 2.76 (2H, t, J 7.0), 2.32 (2H, br s), 1.32 (3H, t, J 7.3),

1.31 (3H, t, J 7.0); δC(125 MHz; CDCl3) 167.0 (s), 165.6 (s), 164.7 (s), 154.9 (s), 112.5 (s),

62.1 (t), 61.7 (t), 59.8 (t), 52.2 (t), 51.7 (t), 40.8 (t), 14.2 (q), 14.0 (q); MALDI-TOF MS

(m/z): 409 (M++2, 48%), 407 (M+, 72), 369 (44), 361 (100), 331 (12), 145 (22).

7.5.7.3 Reaction with Diphenyldiazomethane

To a stirred solution of diphenyldiazomethane (77.7 mg, 0.4 mmol) in DCM (1 mL) was

added 4-N-(2-chloroethyl)piperazin-1-yl]-5H-1,2,3-dithiazole-5-thione 163 (28.2 mg,

0.1 mmol) and the mixture left stirring at ca. 20 °C for 20 h. Then the mixture was diluted

with n-hexane and poured onto a packed column of silica and chromatography (DCM)

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gave the desired product as a mixture with multiple colorless side products. A second

chromatography (n-hexane/Et2O, 60:40) gave pure 4-[N-(2-chloroethyl)piperazin-1-yl]-5-

(diphenylmethylene)-5H-1,2,3-dithiazole 171 as orange needles (20.7 mg, 50%), mp 122-

124 °C (from n-hexane/Et2O at ca. -20 oC); Rf 0.48 (n-hexane/Et2O, 60:40); (found:


λmax(DCM)/nm 264 (log ε 4.19), 286 inf (4.26), 432 (3.76); vmax/cm-1 3063w and 3026w

(aryl C-H), 2951w, 2882w, 2841m and 2822m (alkyl C-H), 1520m, 1503m, 1491m,

1464m, 1445m, 1381m, 1368m, 1360m, 1306m, 1288m, 1267m, 1254m, 1209m, 1159m,

1138m, 1126m, 1103w, 1086m, 1074m, 1034w, 999m, 974w, 951w, 926w, 905w, 853m,

824m, 802m, 785m, 770s, 754m, 733m, 708s; δH(500 MHz; CD3CN at ca. 65 °C) 7.42-

7.39 (3H, m), 7.37-7.31 (3H, m), 7.24-7.21 (2H, m), 7.11-7.09 (2H, m), 3.47 (2H, t, J 6.5),

2.98 (4H, dd, J 4.5, 4.5), 2.47 (2H, t, J 6.8), 1.89 (4H, br s); δC(125 MHz; CDCl3) 162.1 (s),

144.8 (s), 141.6 (s), 140.4 (s), 133.2 (s), 131.6 (d), 129.3 (d), 129.0 (d), 128.17 (d), 128.15

(d), 127.3 (d), 59.6 (t), 51.2 (t), 48.8 (t), 40.5 (t); MALDI-TOF MS (m/z): 417 (M++2,

14%), 415 (M+, 25), 380 (8), 348 (14), 320 (29), 177 (2), 147 (100), 118 (37).

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7.6.1 Synthesis of 4,4'-Disubstituted-2,2'-bithiazoles 195

General Procedure: A stirred mixture of the appropriate 1-aryl-2-bromoethan-1-one

(4 mmol) and rubeanic acid (240 mg, 2 mmol) in dry EtOH (20 mL) was heated at

ca. 78 °C for 12-14 h. The reaction mixture was then left to cool to ca. 20 °C and the

precipitate present was collected by filtration, washed (MeOH), dried under vacuum and

recrystallized to afford the desired 4,4'-disubstituted-2,2'-bithiazole 195.

7.6.1.1 4,4'-Bis[4-(tert-butyl)phenyl]-2,2'-bithiazole 195a

Colorless plates (640 mg, 74%), mp (DSC) onset: 301.4 °C, peak max: 303.4 °C

(c-hexane/CHCl3); Rf 0.50 (n-hexane/DCM, 60:40); (found: C, 72.02; H, 6.38; N, 6.56.

C26H28N2S2 requires: C, 72.18; H, 6.52; N, 6.48%); λmax(DCM)/nm 257 (log ε 4.65), 267

inf (4.61), 278 inf (4.47), 287 inf (4.28), 358 (4.10), 365 inf (4.06); vmax/cm-1 3119m (aryl

C-H), 2961m, 2903w and 2862w (alkyl C-H), 1474m, 1412m, 1362m, 1296w, 1267m,

1202w, 1119m, 1111m, 1053m, 1016m, 943m, 895m, 887m, 839s, 760s, 729s; δH(500

MHz; CDCl3) 7.91 (4H, d, J 6.5), 7.54 (2H, s), 7.49 (4H, d, J 6.5), 1.37 (18H, s); δC(125

MHz; CDCl3) 161.2 (s), 156.6 (s), 151.6 (s), 131.3 (s), 126.2 (d), 125.7 (d), 114.1 (d), 34.7

(s), 31.3 (q); MALDI-TOF MS (m/z): 433 (MH+, 73%), 418 (43), 402 (5), 378 (100), 55

(51).

7.6.1.2 4,4'-Bis(4-fluorophenyl)-2,2'-bithiazole 195b

Beige cotton fibers (563 mg, 79%), mp (DSC) onset: 237.5 °C, peak max: 238.4 °C (from

CHCl3); Rf 0.39 (n-hexane/DCM, 60:40); (found: C, 60.43; H, 2.71; N, 7.82. C18H10F2N2S2

requires: C, 60.66; H, 2.83; N, 7.86%); λmax(DCM)/nm 249 (log ε 4.76), 262 inf (4.58), 279

inf (4.36), 353 (4.26), 365 inf (4.19); vmax/cm-1 3109w (aryl C-H), 1605m, 1530m, 1476m,

1414m, 1294m, 1271w, 1227m, 1161m, 1101m, 1051m, 1015m, 955m, 941m, 889m, 841s,

835s, 808m, 802m, 750m, 745s, 706m; δH(500 MHz; CDCl3) 7.96 (4H, dd, JHH 8.5, 4JHF

5.5), 7.54 (2H, s), 7.15 (4H, dd, JHH 8.5, 3JHF 8.5); δC(125 MHz; CDCl3) 163.0 (d, 1JCF

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247.5), 161.3 (s), 155.6 (s), 130.2 (d, 4JCF 3.8), 128.2 (d, 4JCF 7.5), 115.8 (d, 3JCF 21.3),

114.4 (d); MALDI-TOF MS (m/z): 356 (M+, 73%), 323 (7), 235 (20), 205 (19), 152 (100),

120 (5), 109 (12).

7.6.1.3 4,4'-Bis[4-(trifluoromethyl)phenyl]-2,2'-bithiazole 195c

Colorless plates (664 mg, 73%), mp (DSC) onset: 223.1 °C, peak max: 224.6 °C (from

CHCl3); Rf 0.57 (n-hexane/DCM, 60:40); (found: C, 52.29; H, 2.04; N, 6.17. C20H10F6N2S2


(4.22), 358 inf (4.13); vmax/cm-1 3115w (aryl C-H), 1614m, 1582w, 1476m, 1414m, 1319s,

1306m, 1192m, 1144m, 1173m, 1144s, 1128m, 1109s, 1069s, 1051m, 1015m, 941m,

887m, 860m, 856m, 847m, 835m, 773m, 764m, 733m; δH(500 MHz; CDCl3) 8.10 (4H, d, J

8.0), 7.73 (2H, s), 7.72 (4H, d, J 8.0); δC(125 MHz; CDCl3) 161.4 (s), 155.1 (s), 137.0 (s),

130.4 (q, 2JCF 32.5), 126.7 (d), 125.8 (q, 4JCF 3.8), 124.1 (q, 1JCF 270.5, CF3), 116.7 (d);

MALDI-TOF MS (m/z): 456 (M+, 100%), 423 (8), 285 (21), 255 (14), 202 (93), 183 (10).

7.6.1.4 4,4'-Di(pyrid-2-yl)-2,2'-bithiazole 195d

Beige needles (643 mg, 100%), mp (DSC) onset: 296.3 °C, peak max: 297.4 °C (from

DMA); Rf 0.42 (DCM/Et2O, 80:20); λmax(DCM)/nm 242 (log ε 4.75), 288 (4.65), 296 inf

(4.58), 345 (4.35), 356 inf (4.29); vmax/cm-1 3123m and 3007w (hetaryl C-H), 1587s,

1570m, 1504m, 1470s, 1427s, 1408m, 1329m, 1269m, 1250m, 1207m, 1196w, 1153w,

1088m, 1055m, 1040m, 995m, 947m, 883m, 833m, 806m, 799m, 772s, 760s, 741m;

δH(500 MHz; TFA-d) 8.82 (2H, d, J 5.5), 8.74 (2H, s), 8.70 (2H, dd, J 8.0, 8.0), 8.58 (2H,

d, J 8.0), 8.04 (2H, dd, J 6.5, 6.5); δC(125 MHz; TFA-d) one C (s) resonance missing,

150.0 (d), 147.2 (s), 146.4 (s), 142.8 (d), 129.4 (d), 128.3 (d), 125.9 (d); MALDI-TOF MS

(m/z): 323 (MH+, 100%), 291 (7), 188 (6), 135 (30).

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7.6.2 Synthesis of 5,5'-Dibromo-4,4'-disubstituted-2,2'-bithiazoles 180

7.6.2.1 5,5'-Dibromo-4,4'-diphenyl-2,2'-bithiazole 180a

A stirred mixture of 4,4'-diphenyl-2,2'-bithiazole (6 mmol) and NBS (4.28 mg, 24 mmol)

in DMF (60 mL) was heated at ca. 70 °C for 4 d. The reaction mixture was then left to cool

to ca. 20 °C, and the precipitate that formed was collected by filtration, washed (MeOH),

dried under vacuum and recrystallized to afford the title compound 180a (2.1 g, 73%) as

pale yellow needles, mp (DSC) onset: 265.8 °C, peak max: 267.5 °C (from CHCl3); Rf 0.45

(n-hexane/DCM, 60:40); (found: C, 45.22; H, 2.02; N, 5.97. C18H10Br2N2S2 requires:


(4.24), 362 (4.30), 374 inf (4.22); vmax/cm-1 3059w and 3022w (aryl C-H), 1580w, 1514m,

1470s, 1445m, 1410m, 1335w, 1290m, 1265m, 1182m, 1128m, 1105w, 1072m, 1030m,

997m, 964w, 932s, 912m, 843w, 833w, 762s; δH(500 MHz; CDCl3) 7.99 (4H, d, J 7.8),

7.50 (4H, dd, J 7.3, 7.3), 7.44 (2H, dd, J 7.5, 7.5); δC(125 MHz; CDCl3) 159.9 (s), 153.6

(s), 132.7 (s), 128.9 (d), 128.6 (d), 128.4 (d), 106.8 (s); MALDI-TOF MS (m/z): 481

(MH++4, 64%), 479 (MH++2, 100), 477 (MH+, 41), 399 (46), 267 (11), 215 (19), 133 (80).

7.6.2.2 5,5'-Dibromo-4,4'-bis[4-(tert-butyl)phenyl]-2,2'-bithiazole 180b

A stirred mixture of 4,4'-bis[4-(tert-butyl)phenyl]2,2'-bithiazole 195a (216.3 mg, 0.5 mmol)

with NBS (356 mg, 2 mmol) in CHCl3 (10 mL) was heated at ca. 61 °C for 6 h and then

left to cool to ca. 20 °C. The solvent was evaporated in vacuo and the resulting solid was

suspended in MeOH, filtered, dried and recrystallized to give the title compound 180b (244

mg, 83%) as pale yellow microcrystals, mp (DSC) onset: 290.6 °C, peak max: 290.9 °C

(from CHCl3/Et2O); Rf 0.64 (n-hexane/DCM, 60:40); (found: C, 52.68; H, 4.47; N, 4.79.

C26H26Br2N2S2 requires: C, 52.89; H, 4.44; N, 4.74%); λmax(DCM)/nm 240 inf (log ε 4.32),

261 (4.50), 367 (4.16), 377 inf (4.12); vmax/cm-1 2963m, 2901w and 2866w (alkyl C-H),

1472m, 1408m, 1362m, 1317w, 1294w, 1260m, 1198m, 1136m, 1121m, 1101m, 1024m,

1018m, 993m, 926s, 893w, 853m, 841m, 831m, 756m, 723m; δH(500 MHz; CDCl3) 7.92

(4H, d, J 8.5), 7.51 (4H, d, J 8.5), 1.37 (18H, s); δC(125 MHz; CDCl3) 159.9 (s), 153.6 (s),

152.0 (s), 129.9 (s), 128.3 (d), 125.4 (d), 106.2 (s), 34.8 (s), 31.3 (q); MALDI-TOF MS

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(m/z): 593 (MH++4, 37%), 591 (MH++2, 100), 589 (MH+, 41), 575 (14), 513 (66), 511 (46),

189 (13), 174 (9).

7.6.2.3 5,5'-Dibromo-4,4'-bis(4-methoxyphenyl)-2,2'-bithiazole 180c

A stirred mixture of 4,4'-bis-(4-methoxyphenyl)-2,2'-bithiazole (380.5 mg, 1 mmol) with

NBS (712 mg, 4 mmol) in CHCl3 (20 mL) was heated at ca. 61 °C for 1 h and then left to

cool to ca. 20 °C. The solvent was evaporated in vacuo and the resulting solid was

suspended in MeOH, filtered, dried and recrystallized to give the title compound 180c (397

mg, 74%) as beige plates, mp (DSC) onset: 237.3 °C, peak max: 240.6 °C, decomp. onset:

265.7 °C, peak max: 269.0 °C (from CHCl3); Rf 0.14 (n-hexane/DCM, 60:40); (found:

C, 44.51; H, 2.54; N, 5.33. C20H14Br2N2O2S2 requires: C, 44.63; H, 2.62; N, 5.20%);

λmax(DCM)/nm 245 inf (log ε 4.30), 274 (4.57), 375 (4.18), 386 inf (4.14); vmax/cm-1 3007w

(aryl C-H), 2938w and 2839w (alkyl C-H), 1609m, 1526m, 1472s, 1441m, 1418m, 1304m,

1250m, 1179m, 1128w, 1115m, 1055m, 1030m, 995m, 928s, 853w, 833s, 812m, 785m,

729m; δH(500 MHz; CDCl3) 7.95 (4H, d, J 9.0), 7.01 (4H, d, J 8.5), 3.88 (6H, s); δC(125

MHz; CDCl3) 160.0 (s), 159.8 (s), 153.3 (s), 130.0 (d), 125.4 (s), 113.8 (d), 105.3 (s), 55.4

(q); MALDI-TOF MS (m/z): 540 (M++4, 45%), 538 (M++2, 74), 536 (M+, 30), 506 (12),

504 (10), 458 (13), 414 (14), 242 (6), 162 (100).

7.6.2.4 5,5'-Dibromo-4,4'-bis(4-fluorophenyl)-2,2'-bithiazole 180d

A stirred mixture of 4,4'-bis-(4-fluorophenyl)-2,2'-bithiazole 195b (178.2 mg, 0.5 mmol)

and NBS (356 mg, 2 mmol) in DMF (5 mL) was heated at ca. 90 °C for 4 d. The reaction

mixture was then left to cool to ca. 20 °C, and the precipitated that formed was collected

by filtration, washed (MeOH), dried and recrystallized to afford the title compound 180d

(216 mg, 84%) as pale yellow needles, mp (DSC) onset: 287.5 °C, peak max: 288.1 °C

(from CHCl3); Rf 0.50 (n-hexane/DCM, 60:40); (found: C, 41.90; H, 1.49; N, 5.53.

C18H8Br2F2N2S2 requires: C, 42.05; H, 1.57; N, 5.45%); λmax(DCM)/nm 237 inf (log ε

4.24), 252 (4.38), 269 inf (4.11), 352 inf (4.07), 363 (4.13), 376 inf (4.06); vmax/cm-1

1603m, 1522m, 1472s, 1406m, 1292m, 1267m, 1233m, 1159m, 1126m, 1094m, 1016m,

1001m, 937m, 856m, 833s, 812m, 800m, 723m; δH(500 MHz; CDCl3) 7.99 (4Η, dd, JHH

8.5, 4JCF 5.5), 7.18 (4H, dd, JHH 8.5, 3JCF 8.5); δC(125 MHz; CDCl3 at ca. 55 °C) 164.2 (s),

161.1 (d, 1JCF 271.3), 152.9 (s), 130.6 (d, 3JCF 8.8), 129.0 (d, 4JCF 3.8), 115.4 (d, 2JCF 21.3),

106.6 (s); MALDI-TOF MS (m/z): 517 (MH++4, 70%), 515 (MH++2, 100), 513 (MH+, 73),

435 (17), 381 (10), 183 (9), 151 (50).

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7.6.2.5 5,5'-Dibromo-4,4'-bis[4-(trifluoromethyl)phenyl]-2,2'-bithiazole 180e

A stirred mixture of 4,4'-bis[4-(trifluoromethyl)phenyl]-2,2'-bithiazole 195c (228.2 mg, 0.5

mmol) and NBS (356 mg, 2 mmol) in DMF (5 mL) was heated at ca. 70 °C for 4 d. The

reaction mixture was then left to cool to ca. 20 °C, and the precipitated that formed was

collected by filtration, washed (MeOH), dried and recrystallized to afford the title

compound 180e (226.0 mg, 74%) as colorless cotton fibers, mp (DSC) onset: 233.1 °C,

peak max: 233.3 °C (from c-hexane); Rf 0.66 (n-hexane/DCM, 60:40); (found: C, 39.22;

H, 1.24; N, 4.67. C20H8Br2F6N2S2 requires: C, 39.11; H, 1.31; N, 4.56%); λmax(DCM)/nm

247 (log ε 4.56), 276 (4.28), 345 inf (4.25), 358 (4.33), 367 inf (4.25); vmax/cm-1 3197w

(aryl C-H), 1620m, 1472w, 1410m, 1325s, 1321s, 1240m, 1200w, 1163m, 1111s, 1072m,

1016m, 993m, 934m, 843m, 827m, 772m; δH(500 MHz; CDCl3) 8.13 (2H, d, J 8.0), 7.75

(2H, d, J 8.5); δC(125 MHz; CDCl3) 160.1 (s), 152.1 (s), 136.0 (s), 130.7 (q, 2JCF 32.5),

128.9 (d), 125.4 (q, 3JCF 3.8), 124.0 (q, 1JCF 270.8), 108.4 (s); MALDI-TOF MS (m/z): 617

(MH++4, 62%), 615 (MH++2, 100), 613 (MH+, 86), 583 (7), 581 (9), 579 (5), 537 (29), 535

(39), 201 (41).

7.6.2.6 5,5'-Dibromo-4,4'-bis(4-nitrophenyl)-2,2'-bithiazole 180f

A mixture of 4,4'-bis(4-nitrophenyl)-2,2'-bithiazole (205.2 mg, 0.5 mmol) and NBS (356

mg, 2 mmol) in DMF (5 mL) was heated at ca. 90 °C for 4 d. The reaction mixture was

then left to cool to ca. 20 °C, and the precipitated that formed was collected by filtration,

washed (MeOH), dried and recrystallized to afford the title compound 180f (189 mg, 67%)

as beige cotton fibers, mp (DSC) onset: 318.4 °C, peak max: 319.7 °C (from pyridine); Rf

0.69 (n-hexane/DCM, 60:40); (found: C, 38.29; H, 1.30; N, 9.97. C18H8Br2N4O4S2 requires:

C, 38.05; H, 1.42; N, 9.86%); λmax(DCM)/nm 265 (log ε 4.71), 342 (4.88), 348 inf (4.88),

367 inf (4.76); vmax/cm-1 3082w (aryl C-H), 1599m, 1520m, 1470m, 1346s, 1319m, 1307m,

1256w, 1182w, 1107m, 1016w, 995m, 928m, 860m, 831m, 758m, 746m, 702m; δH(500

MHz; pyridine-d5) 8.39 (4H, d, J 9.0), 8.29 (4H, d, J 8.5); δC(125 MHz; pyridine-d5) 160.3

(s), 151.4 (s), 148.0 (s), 138.8 (s), 129.7 (d), 124.0 (d), 111.1 (s); MALDI-TOF MS (m/z):

571 (MH++4, 68%), 569 (MH++2, 100), 567 (MH+, 42), 525 (44), 523 (56), 521 (15).

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7.6.2.7 5,5'-Dibromo-4,4'-di(pyrid-2-yl)-2,2'-bithiazole 180g

A stirred mixture of 4,4'-di(pyrid-2-yl)-2,2'-bithiazole 195d (161.2 mg, 0.5 mmol) and

NBS (356 mg, 2 m mol) in DMF (5 mL) was heated at ca. 90 °C for 4 d. The reaction

mixture was then left to cool to ca. 20 °C, and the precipitated that formed was collected

by filtration, washed (MeOH), dried and recrystallized to afford the title compound 180g

(155 mg, 65%) as beige needles, mp (DSC) onset: 296.0 °C, peak max: 298.7 °C (from

DMA); Rf 0.51 (DCM/Et2O, 90:10); (found: C, 40.14; H, 1.59; N, 11.70. C16H8Br2N4S2

requires: C, 40.02; H, 1.68; N, 11.67%); λmax(DCM)/nm 241 inf (log ε 4.65), 285 (4.53),

348 inf (4.40), 356 (4.48), 369 inf (4.34); vmax/cm-1 3044w and 3015w (pyridyl C-H),

1585m, 1568m, 1504w, 1472m, 1466m, 1427m, 1408m, 1317w, 1308m, 1263m, 1242w,

1159m, 1088m, 1047m, 999m, 935s, 845w, 785s, 737s; δH(500 MHz; TFA-d) 9.10 (2H, d,

J 8.5), 8.84 (2H, d, J 5.5), 8.70 (2H, dd, J 8.0, 8.0), 8.05 (2H, dd, J 6.8, 6.8); δC(125 MHz;

TFA-d) 162.1 (s), 149.2 (d), 144.4 (s), 143.3 (s), 143.2 (d), 127.9 (d), 125.9 (d), 120.2 (s);

MALDI-TOF MS (m/z): 483 (MH++4, 65%), 481 (MH++2, 96), 479 (MH+, 52), 403 (40),

401 (93), 399 (100), 321 (57), 319 (27), 236 (20), 186 (40), 134 (55).

7.6.3 Reaction of 5,5'-Dibromo-4,4'-diphenyl-2,2'-bithiazole 180a with

4-n-Butoxyaniline Using Pd(OAc)2, BINAP, and K2CO3 in 1,4-Dioxane

A mixture of 5,5'-dibromo-4,4'-diphenyl-2,2'-bithiazole 180a (0.1 mmol), Pd(OAc)2

(4.5 mg, 20 mol %), BINAP (12.5 mg, 20 mol %) and powdered dry K2CO3 (33.2 mg,

0.24 mmol) was deaerated and filled with argon. To this was added dry 1,4-dioxane

(2.5 mL) and the resulting mixture was stirred at ca. 20 °C for 30 sec, after which was

added under argon 4-n-butoxyaniline (0.2 mmol). The mixture was then immersed into a

preheated (ca. 115 °C) Wood’s metal bath. After complete consumption of both the

starting bithiazole 180a and of the monoaminated intermediate 183 (by TLC) the mixture

was removed from the Wood’s metal bath and allowed to air cool to ca. 20 °C. The

reaction mixture was dissolved in DCM (ca. 70 mL) and passed through a short pad of

silica and washed thoroughly with DCM until all the material was collected. The solvent

was removed under reduced pressure and the resulting solid was suspended in acetone and

filtered. The collected solid was dried and recrystallized to afford pure

(2E,5Z,5'Z)-N5,N5'-bis(4-n-butoxyphenyl)-4,4'-diphenyl-5H,5'H-(2,2'-bithiazolylidene)-

5,5'-diimine 182d as lustrous green needles (21.4 mg, 33%), mp (DSC) onset: 266.8 °C,

peak max: 267.6 °C, decomp. onset: 302.2 °C, peak max: 312.2 °C (from c-hexane/DCE);

Rf 0.72 (n-hexane/DCM, 40:60); (found: C, 70.66; H, 5.71; N, 8.78. C38H36N4O2S2 requires:

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440 inf (4.12), 538 inf (4.52), 580 (4.67), 600 inf (4.65); vmax/cm-1 3063w (aryl C-H),


1393w, 1379w, 1339w, 1321m, 1304m, 1290m, 1246s, 1231s, 1182m, 1167m, 1113m,

1069m, 1038m, 1011m, 916m, 862m, 841m, 833m, 808m, 799m, 775m; δH(500 MHz;

CDCl3) 8.57 (4H, d, J 7.0), 7.54-7.47 (6H, m), 7.35 (4H, d, J 9.0), 7.01 (4H, d, J 9.0), 4.03

(4H, t, J 6.5), 1.81 (4H, tt, J 7.0, 7.0), 1.53 (4H, qt, J 7.5, 7.5), 1.01 (6H, t, J 7.5); δC(125

MHz; CDCl3) 165.2 (s), 158.8 (s), 158.2 (s), 145.7 (s), 143.5 (s), 132.5 (s), 131.5 (d), 130.8

(d), 128.3 (d), 123.0 (d), 115.2 (d), 68.0 (t), 31.3 (t), 19.3 (t), 13.9 (q); MALDI-TOF MS

(m/z): 644 (M+, 55%), 587 (6), 366 (100), 348 (23), 296 (35), 292 (25), 240 (34). The

filtrate was adsorbed onto silica and chromatographed (n-hexane/Et2O, 70:30) to give a

small quantity of (2E,5Z,5'Z)-N5,N5'-bis(4-n-butoxyphenyl)-4,4'-diphenyl-5H,5'H-(2,2'-

bithiazolylidene)-5,5'-diimine 182d that was dissolved in acetone (4 mg, 6%). Further

elution (n-hexane/Et2O, 70:30) gave 5-(4-n-butoxyanilino)-4,4'-diphenyl-2,2'-bithiazole

184 as yellow microcrystals (6.5 mg, 13%) mp (hot-stage) 109.5–110.5 °C (from

n-hexane/Et2O at ca. -20 °C); Rf 0.62 (n-hexane/Et2O, 60:40) (found: C, 69.66; H, 5.34;

N,-8.57. C28H25N3OS2 requires: C, 69.54; H, 5.21; N, 8.69%); λmax(DCM)/nm 245 (log ε

4.59), 282 inf (4.18), 320 (4.10), 413 (4.16); vmax/cm-1 3366w and 3304w (N-H), 3119w

(aryl C-H), 2955m and 2870w (alkyl C-H), 1597m, 1578w, 1537m, 1508s, 1472m, 1445m,

1422m, 1393w, 1360m, 1315m, 1283m, 1236m, 1171m, 1123w, 1109w, 1072m, 1061m,

1026m, 1013m, 980w, 961w, 937m, 897m, 881w, 851m, 829m, 820m, 779m, 772m, 745m;

δH(500 MHz; CDCl3) 7.94 (2H, d, J 7.5), 7.89 (2H, d, J 7.0), 7.50 (1H, s), 7.48-7.42 (4H,

m), 7.36-7.33 (2H, m), 7.06 (2H, d, J 9.0), 6.88 (2H, d, J 8.5), 5.90 (1H, br s), 3.95 (2H, t,

J 6.5), 1.80-1.74 (2H, m), 1.52-1.47 (2H, m), 0.99 (3H, t, J 7.3); δC(125 MHz; CDCl3) one

C (s) resonance missing, 162.0 (s), 156.0 (s), 155.0 (s), 148.9 (s), 142.6 (s), 140.8 (s),

137.0 (s), 134.0 (s), 128.9 (d), 128.7 (d), 128.3 (d), 127.7 (d), 127.6 (d), 126.4 (d), 119.0

(d), 115.6 (d), 113.6 (d), 68.2 (t), 31.4 (t), 19.2 (t), 13.9 (q); MALDI-TOF MS (m/z): 484

(MH+, 100%), 427 (87), 309 (19), 277 (8), 204 (77), 187 (18), 148 (24), 123 (32), 108 (18).

Further elution (n-hexane/E2O, 60:40) gave 5-(4-n-butoxyanilino)-4,4',4'',4'''-

tetraphenyl[2,2':5',5'':2'',2''']quaterthiazole 185 as yellow-orange microcrystals (2.3 mg,

3%), mp 179-180 °C (from n-hexane/Et2O at ca. -20 °C); Rf 0.50 (n-hexane/Et2O, 60:40);

(found: C, 68.74; H, 4.21; N, 8.82. C46H35N5OS4 requires: C, 68.89; H, 4.40; N, 8.73%);

λmax(DCM)/nm 251 (log ε 4.88), 285 inf (4.52), 315 (4.38), 361 (4.33), 436 (4.44);

vmax/cm-1 3344w (N-H), 3051w (aryl C-H), 2955w (alkyl C-H), 1599w, 1508m, 1487w,

1470m, 1460m, 1441m, 1414m, 1344w, 1310w, 1240m, 1175w, 1128w, 1070m, 1059w,

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1030m, 1009m, 941s, 918m, 893m, 822m, 773m, 737m, 702m; δH(500 MHz; CDCl3) 7.95

(2H, d, J 7.5), 7.84 (2H, d, J 7.0), 7.66-7.60 (5H, m), 7.47-7.43 (4H, m), 7.38-7.32 (2H, m),

7.30-7.26 (6H, m), 7.08 (2H, d, J 9.0), 6.88 (2H, d, J 9.0), 6.01 (1H, br s), 3.96 (2H, t, J

6.5), 1.80-1.74 (2H, m), 1.53-1.47 (2H, m), 0.99 (3H, t, J 7.5); δC(125 MHz; CDCl3) three

C (d) resonances missing, 162.4 (s), 161.4 (s), 160.8 (s), 156.8 (s), 155.3 (s), 154.8 (s),

154.4 (s), 147.3 (s), 143.7 (s), 140.4 (s), 136.6 (s), 133.9 (s), 133.7 (s), 133.4 (s), 133.3 (s),

129.0 (d), 128.8 (d), 128.6 (d), 128.52 (d), 128.47 (br d), 128.4 (d), 127.8 (d), 127.5 (d),

126.4 (d), 123.7 (s), 121.7 (s), 119.4 (d), 115.7 (d), 115.1 (d), 68.2 (t), 31.4 (t), 19.2 (t),

13.9 (q); MALDI-TOF MS (m/z): 802 (MH+, 53%), 745 (100), 522 (25), 296 (5), 148 (4).

Further elution (n-hexane/Et2O, 30:70) gave 5,5'''-bis(4-n-butoxyanilino)-4,4',4'',4'''-

tetraphenyl[2,2':5',5'':2'',2''']quaterthiazole 186 as orange microcrystals (9.3 mg, 10%) mp

205-210 °C (from n-hexane/Et2O at ca. -20 °C); Rf 0.42 (n-hexane/Et2O, 60:40); (found:

C, 69.68; H, 4.90; N, 8.82. C56H48N6O2S4 requires: C, 69.68; H, 5.01; N, 8.71%);

λmax(DCM)/nm 245 (log ε 5.10), 298 inf (4.77), 350 inf (4.57), 449 (4.78); vmax/cm-1 3379w

(N-H), 3061w (aryl C-H), 2953w and 2870w (alkyl C-H), 1599m, 1530m, 1508s, 1489m,

1460m, 1435w, 1418m, 1369m, 1288w, 1240s, 1200w, 1169w, 1119m, 1107m, 1072m,

1028m, 1009m, 974w, 939m, 920w, 835m, 802w, 791w, 766m, 745w, 735m, 725m;

δH(500 MHz; CDCl3) 7.83 (4H, d, J 8.0), 7.62-7.60 (4H, m), 7.45 (4H, dd, J 7.5, 7.5), 7.33

(2H, dd, J 7.5, 7.5), 7.27-7.24 (6H, m), 7.08 (4H, d, J 9.0), 6.88 (4H, d, J 8.5), 5.99 (2H, br

s), 3.95 (4H, t, J 6.5), 1.80-1.74 (4H, m), 1.55-1.46 (4H, m), 0.99 (6H, t, J 7.4); δC(125

MHz; CDCl3) one C (d) resonance missing, 162.2 (s), 155.3 (s), 154.3 (s), 147.5 (s), 143.5

(s), 140.4 (s), 136.7 (s), 133.9 (s), 133.5 (s), 129.0 (d), 128.44 (d), 128.39 (d), 127.8 (d),

127.5 (d), 122.1 (s), 119.4 (d), 115.7 (d), 68.2 (t), 31.4 (t), 19.2 (t), 13.9 (q); MALDI-TOF

MS (m/z): 966 (MH++1, 60%), 909 (100), 853 (11), 686 (33).

7.6.4 Synthesis of Quinoidal 2,2'-Bithiazoles 182

General Procedure: A mixture of the appropriate 5,5'-dibromo-4,4'-disubstituted-2,2'-

bithiazole 180 (0.1 mmol), Superstable Pd(0)® (2.7 mg, 1.25 mol %), DPEPhos (2.7 mg,

5 mol %) and powdered dry K2CO3 (33.2 mg, 0.24 mmol) was deaerated and filled with

argon. To this was added dry 1,4-dioxane (2.5 mL) and the resulting mixture was stirred at

ca. 20 °C for 30 sec, after which was added under argon the appropriate aniline (0.2 mmol).

The mixture was then immersed into a preheated (ca. 115 °C) Wood’s metal bath. After

complete consumption of both the starting bithiazole 180 and of the monoaminated

intermediate (akin 183) (by TLC) the mixture was removed from the Wood’s metal bath

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and allowed to air cool to ca. 20 °C. Ag2O (0.12 mmol) was then added and the mixture

was immersed back into the preheated (ca. 115 °C) Wood’s metal bath until complete

consumption of the diaminated intermediate 181d. The work up procedure was dependent

on the solubility of the final product.

Work up procedure A: The reaction mixture was dissolved in DCM, passed through a short

pad of silica and washed thoroughly with DCM until all the material was collected. The

solvent was removed under reduced pressure and the resulting solid was suspended in

acetone and filtered. The collected solid was recrystallized from the appropriate solvent to

give pure quinoidal 2,2'-bithiazole 182.

Work up procedure B: The solvent was removed under reduced pressure and the resulting

solid was suspended in water, sonicated and filtered. The solid was collected, suspended in

acetone, sonicated and filtered. The collected solid was recrystallized from the appropriate

solvent to give pure quinoidal 2,2'-bithiazole 182.

Work up procedure C: The reaction mixture was dissolved in hot DCE, passed through a

short pad of silica and washed thoroughly with hot DCE until all the material was collected.

The solvent was removed under reduced pressure and the resulting solid was suspended in

acetone and filtered. The collected solid was recrystallized from the appropriate solvent to

give pure quinoidal 2,2'-bithiazole 182.

7.6.4.1 (2E,5Z,5'Z)-N5,N5'-4,4'-Tetraphenyl-5H,5'H-(2,2'-bithiazolylidene)-5,5'-

diimine 182a

Work up procedure C. Red needles (41.4 mg, 83%), mp (DSC) onset: 326.4 °C, peak max:

330.0 °C, decomp. onset: 331.6 °C, peak max: 333.1 °C (from CHCl3); Rf 0.29

(n-hexane/DCM, 70:30); (found: C, 71.86; H, 3.97; N, 10.98. C30H20N4S2 requires:


(4.12), 376 (4.05), 541 (4.61); vmax/cm-1 3063w (aryl C-H), 1603m, 1585s, 1481m, 1441m,

1325m, 1302m, 1219m, 1206m, 1177m, 1070m, 1024m, 999m, 924m, 897m, 847m, 810m,

777m, 760m, 702s; δH(500 MHz; TFA-d) 8.06 (4H, d, J 7.5), 7.76 (2H, dd, J 7.5, 7.5),

7.65-7.60 (14H, m); δC(125 MHz; TFA-d) 173.7 (s), 170.2 (s), 154.4 (s), 140.4 (s), 136.7

(d), 133.6 (d), 132.1 (d), 131.5 (d), 131.4 (d), 129.3 (s), 123.4 (d); MALDI-TOF MS (m/z):

500 (M+, 30%), 294 (7), 224 (100).

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7.6.4.2 (2E,5Z,5'Z)-N5,N5'-Bis(4-n-butylphenyl)-4,4'-diphenyl-5H,5'H-(2,2'-bithiazol-

ylidene)-5,5'-diimine 182b

Work up procedure A. Red needles (46.1 mg, 75%), mp (DSC) onset: 230.8 °C, peak max:

231.5 °C (from CHCl3); Rf 0.38 (n-hexane/DCM, 70:30); (found: C, 74.31; H, 6.07;


4.26), 282 inf (4.22), 315 (4.23), 378 (4.06), 555 (4.62), 583 inf (4.56); vmax/cm-1 2955m,

2926m and 2855m (alkyl C-H), 1597m, 1589m, 1503m, 1485m, 1441m, 1410w, 1375w,

1325m, 1300m, 1221m, 1206m, 1179m, 1111m, 1080m, 1070m, 1016m, 920m, 883m,

854s, 841m, 818m, 777m, 700s; δH(500 MHz; CDCl3) 8.57 (4H, dd, J 8.5, 1.5), 7.53 (2H,

dd, J 7.3, 7.3), 7.48 (4H, dd, J 7.3, 7.3), 7.29 (4H, d, J 8.5), 7.22 (4H, d, J 8.5), 2.67 (4H, t,

J 7.8), 1.65 (4H, tt, J 7.6, 7.6), 1.40 (4H, qt, J 7.4, 7.4), 0.96 (6H, t, J 7.5); δC(125 MHz;

CDCl3) 165.0 (s), 161.0 (s), 148.9 (s), 145.8 (s), 141.7 (s), 132.3 (s), 131.7 (d), 130.8 (d),

129.5 (d), 128.4 (d), 120.6 (d), 35.4 (t), 33.6 (t), 22.4 (t), 14.0 (q); MALDI-TOF MS (m/z):

613 (MH+, 28%), 350 (39), 332 (15), 280 (100), 223 (34).

7.6.4.3 (2E,5Z,5'Z)-N5,N5'-Bis(4-methoxyphenyl)-4,4'-diphenyl-5H,5'H-(2,2'-bithiazol-

ylidene)-5,5'-diimine 182c

Work up procedure C. Lustrous green needles (66.3 mg, 85%), mp (DSC) onset: 324.9 °C,

peak max: 327.4 °C, decomp. onset: 329.2 °C, peak max: 332.1 °C (from DCE); Rf 0.51

(n-hexane/DCM, 40:60); (found: C, 68.62; H, 4.35; N, 10.08. C32H24N4O2S2 requires:


434 inf (4.03), 576 (4.59), 599 inf (4.57); vmax/cm-1 2963w, 2928w and 2833w (alkyl C-H),

1603m, 1585m, 1578m, 1574m, 1501s, 1483m, 1441m, 1325m, 1294m, 1244s, 1223m,

1177m, 1165m, 1109m, 1078m, 1069m, 1032m, 916m, 860m, 837s, 826m, 814m, 806m,

773m, 763m, 700m; δH(500 MHz; CDCl3 at ca. 55 °C) 8.59 (4H, d, J 8.0), 7.53-7.47 (6H,

m), 7.35 (4H, d, J 9.0), 7.02 (4H, d, J 8.5), 3.88 (6H, s); δC(125 MHz; TFA-d) 170.2 (s),

169.8 (s), 164.8 (s), 154.2 (s), 136.7 (d), 132.2 (s), 131.7 (d), 131.5 (d), 129.3 (s), 126.2 (d),

118.0 (d), 56.8 (q); MALDI-TOF MS (m/z): 560 (M+, 47%), 503 (12), 324 (88), 306 (85),

280 (8), 254 (100), 226 (9), 223 (17).

7.6.4.4 (2E,5Z,5'Z)-N5,N5'-Bis(4-n-butoxyphenyl)-4,4'-diphenyl-5H,5'H-(2,2'-bithia-

zolylidene)-5,5'-diimine 182d

Lustrous green needles (54.8 mg, 86%), mp (DSC) onset: 266.8 °C, peak max: 267.6 °C,

decomp. onset: 302.2 °C, peak max: 312.2 °C (from c-hexane/DCE); Rf 0.72

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(n-hexane/DCM, 40:60); δH(500 MHz; CDCl3) 8.57 (4H, d, J 7.0), 7.54-7.47 (6H, m), 7.35

(4H, d, J 9.0), 7.01 (4H, d, J 9.0), 4.03 (4H, t, J 6.5), 1.81 (4H, tt, J 7.0, 7.0), 1.53 (4H, qt,

J 7.5, 7.5), 1.01 (6H, t, J 7.5); identical to that described above.

7.6.4.5 4,4'-{[(2E,5Z,5'Z)-4,4'-Diphenyl-5H,5'H-(2,2'-bithiazolylidene)-5,5'-diylid-

ene]bis(azanylylidene)}bis(N,N-diethylaniline) 182e

Work up procedure A. Lustrous olive green plates (44.0 mg, 68%), mp (DSC) onset:

254.4 °C, peak max: 256.6 °C, decomp. onset: 258.2 °C, peak max: 260.3 °C (from DCE);

Rf 0.40 (n-hexane/DCM, 40:60); (found: C, 71.06; H, 6.13; N, 13.01. C38H38N6S2 requires:


inf (4.78), 745 (4.84); vmax/cm-1 3069w (aryl C-H), 2972m and 2889w (alkyl C-H), 1601s,

1512s, 1468m, 1441m, 1402m, 1375m, 1350m, 1335m, 1323m, 1306m, 1267m, 1221m,

1196m, 1175s, 1150s, 1126m, 1076m, 1067m, 1015m, 914m, 854m, 812m, 800m, 785m,

721m; δH(500 MHz; CD2Cl2) 8.54 (4H, dd, J 7.5, 2.0), 7.54-7.50 (6H, m), 7.46 (4H, d, J

9.5), 6.80 (4H, d, J 9.0), 3.45 (8H, q, J 7.3), 1.23 (12H, t, J 7.3); δC(125 MHz; CDCl3)

164.8 (s), 152.7 (s), 147.2 (s), 145.6 (s), 137.4 (s), 133.2 (s), 130.82 (d), 130.80 (d), 128.1

(d), 125.2 (d), 111.7 (d), 44.6 (t), 12.7 (q); MALDI-TOF MS (m/z): 643 (MH+, 78%), 585

(8), 366 (100), 347 (28), 295 (8).

7.6.4.6 (2E,5Z,5'Z)-4,4'-Diphenyl-N5,N5'-bis[4-(trifluoromethyl)phenyl]-5H,5'H-(2,2'-

bithiazolylidene)-5,5'-diimine 182f

Work up procedure C. Red needles (55.2 mg, 87%), mp (DSC) onset: 344.5 °C, peak max:

347.4 °C, decomp. onset: 348.2 °C, peak max: 349.7 °C (from DCE); Rf 0.71

(n-hexane/DCM, 50:50); (found: C, 60.24; H, 2.74; N, 8.92. C32H18F6N4S2 requires:


(4.22), 310 inf (4.12), 383 (4.17), 533 (4.77); vmax/cm-1 3069w (aryl C-H), 1599m, 1591m,

1501w, 1487m, 1443m, 1408m, 1319s, 1225m, 1204m, 1180s, 1171m, 1128m, 1121m,

1103s, 1080m, 1065s, 1013m, 951w, 920m, 856s, 847s, 799m, 777m, 762m, 743m, 702m;

δH(500 MHz; TFA-d) 8.31 (4H, d, J 7.5), 7.91 (4H, d, J 8.5), 7.76 (2H, dd, J 7.5, 7.5),

7.66-7.62 (8H, m); δC(125 MHz; TFA-d) 170.4 (s), 170.0 (s), 156.4 (s), 148.4 (s), 136.9 (d),

134.6 (q, 2JCF 33.8), 132.8 (d), 131.8 (d), 131.3 (s), 129.7 (q, 3JCF 3.8), 125.2 (q, 1JCF

269.4), 123.6 (d); MALDI-TOF MS (m/z): 637 (MH+, 39%), 363 (10), 293 (100), 224 (5).

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7.6.4.7 4,4'-{[(2E,5Z,5'Z)-4,4'-Diphenyl-5H,5'H-(2,2'-bithiazolylidene)-5,5'-diylid-

ene]bis(azanylylidene)}dibenzonitrile 182g

Work up procedure C. Lustrous green needles (50.3 mg, 92%), mp (DSC) decomp. onset:

354.8 °C, peak max: 355.7 °C (from DMA); Rf 0.61 (DCM); (found: C, 70.02; H, 3.18;


4.49), 280 inf (4.31), 308 inf (4.23), 383 (4.09), 536 (4.70); vmax/cm-1 3069w (aryl C-H),

2230m and 2224m (C≡N), 1611m, 1585s, 1495m, 1485m, 1441m, 1323m, 1304m, 1229m,

1204m, 1179m, 1171m, 1134w, 1107m, 1076m, 1028w, 1015w, 1003w, 918s, 856s, 826m,

802m, 775m, 746m, 727m, 700s; δH(500 MHz; TFA-d) 8.31 (4H, d, J 7.0), 7.99 (4H, d, J

7.5), 7.74 (2H, dd, J 7.3), 7.66-7.60 (8H, m); δC(125 MHz; TFA-d) one C (s) resonance

missing, 169.5 (s), 169.3 (s), 155.8 (s), 149.5 (s), 136.3 (d), 136.0 (d), 132.1 (d), 131.0 (d),

130.4 (s), 123.2 (d), 112.5 (s); MALDI-TOF MS (m/z): 551 (MH+, 28%), 321 (18), 249

(100).

7.6.4.8 (2E,5Z,5'Z)-4,4'-Diphenyl-N5,N5'-di(pyrid-3-yl)-5H,5'H-(2,2'-bithiazolylidene)-

5,5'-diimine 182j

Work up procedure B. Lustrous green needles (28.5 mg, 57%), mp (DSC) onset: 294.3 °C,

peak max: 300.8 °C, decomp. onset: 305.0 °C, peak max: 305.7 °C (from DMA); Rf 0.52

(DCM/Et2O, 60:40); λmax(DCM)/nm 269 (log ε 4.42), 280 inf (439), 381 (4.14), 536 (4.73);

vmax/cm-1 3038w (aryl C-H), 1584m, 1557s, 1472m, 1443m, 1414m, 1323m, 1302m,

1229m, 1209m, 1180m, 1119w, 1099m, 1072m, 1020m, 922m, 854m, 816m, 797m, 772m,

708s; δH(500 MHz; TFA-d) 8.74 (2H, d, J 2.5), 8.69 (2H, d, J 6.0), 8.46 (2H, ddd, J 8.5,

2.5, 1.0), 8.38 (4H, d, J 7.5), 8.17 (2H, dd, J 8.5, 5.5), 7.58 (2H, dd, J 7.5, 7.5), 7.46 (4H,

dd, J 8.0, 8.0); δC(125 MHz; TFA-d) 172.5 (s), 169.1 (s), 151.9 (s), 148.9 (s), 140.3 (d),

140.0 (d), 136.2 (d), 135.7 (d), 132.5 (d), 131.7 (s), 130.65 (d), 130.61 (d); MALDI-TOF

MS (m/z): 503 (MH +, 48%), 446 (6), 400 (5), 296 (84), 225 (100).

7.6.4.9 (2E,5Z,5'Z)-4,4'-Diphenyl-N5,N5'-di(pyrid-4-yl)-5H,5'H-(2,2'-bithiazolylidene)-

5,5'-diimine 182k

Work up procedure B. Red cotton fibers (17.6 mg, 35%), mp (DSC) decomp. onset:

318.6 °C, peak max: 320.5 °C (from DMA); Rf 0.35 (DCM/Et2O, 60:40); (found: C, 66.76;

H, 3.48; N, 16.69. C28H18N6S2 requires: C, 66.91; H, 3.61; N, 16.72%); λmax(DCM)/nm 255

(log ε 4.25), 275 inf (4.17), 293 inf (4.08), 381 (4.08), 530 (4.70); vmax/cm-1 3071w (aryl

C-H), 1607m, 1580m, 1574m, 1549m, 1481m, 1443m, 1410m, 1325m, 1304m, 1244m,

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1209m, 1180m, 1076m, 1057w, 1030w, 1003w, 989m, 918m, 858m, 835m, 797m, 777m,

739m, 700s; δH(500 MHz; TFA-d) 8.76 (4H, d, J 6.5), 8.47 (4H, d, J 8.0), 7.69 (4H, d, J

6.0), 7.60 (2H, dd, J 7.5, 7.5), 7.48 (4H, dd, J 7.8, 7.8); δC(125 MHz; TFA-d) one C (d)

resonance missing, 170.0 (s), 168.4 (s), 168.2 (s), 148.6 (s), 144.6 (d), 135.6 (d), 132.3 (d),

131.8 (s), 130.6 (d); MALDI-TOF MS (m/z): 503 (MH +, 46%), 445 (8), 296 (100), 278

(36), 225 (60).

7.6.4.10 (2E,5Z,5'Z)-N5,N5'-Bis[9-(2-ethylhexyl)-9H-carbazol-3-yl]-4,4'-diphenyl-

5H,5'H-(2,2'-bithiazolylidene)-5,5'-diimine 182l

Work up procedure C. Blue microcrystals (82.5 mg, 91%), mp (DSC) onset: 255.2 °C,

peak max: 256.4 °C; decomp. onset: 301.4 °C, peak max: 312.1 °C (from c-hexane/CHCl3);

Rf 0.50 (n-hexane/DCM, 60:40); (found: C, 75.08; H, 6.12; N, 9.61. C58H58N6S2 requires:


295 inf (4.76), 339 inf (4.53), 464 (4.30), 594 inf (4.61), 633 (4.73), 662 inf (4.72);

vmax/cm-1 3064w (aryl C-H), 2951m, 2926m, 2870w and 2851w (alkyl C-H), 1622m,

1597m, 1574m, 1557m, 1487m, 1474m, 1460m, 1441m, 1346m, 1325m, 1306m, 1283m,

1209m, 1180m, 1153m, 1138m, 1125m, 1074m, 1022m, 1001w, 920m, 899w, 870m,

851m, 845m, 818s, 799m, 777m, 746s, 729m, 704s; δH(500 MHz; CDCl3 at ca. 55 °C)

8.68-8.66 (4H, m), 8.18-8.16 (4H, m), 7.58 (2H, dd, J 8.5, 2.0), 7.53-7.47 (10H, m), 7.43

(2H, d, J 8.5), 7.29-7.27 (2H, m), 4.23-4.20 (4H, m), 2.16-2.12 (2H, m), 1.44-1.28 (16H,

m), 0.97 (6H, t, J 7.5), 0.89 (6H, t, J 7.0); δC(125 MHz; CDCl3) 165.1 (s), 158.0 (s), 145.9

(s), 142.4 (s), 141.6 (s), 139.9 (s), 132.7 (s), 131.4 (d), 130.9 (d), 128.3 (d), 126.1 (d),

123.5 (s), 122.9 (s), 120.9 (d), 120.7 (d), 119.2 (d), 113.3 (d), 109.6 (d), 109.4 (d), 47.7 (t),

39.5 (d), 31.0 (t), 28.8 (t), 24.4 (t), 23.0 (t), 14.0 (q), 10.9 (q); MALDI-TOF MS (m/z): 903

(MH+, 55%), 846 (64), 804 (67), 496 (100), 478 (80), 426 (72), 396 (65), 295 (12).

7.6.4.11 (2E,5Z,5'Z)-N5,N5'-Bis(4-n-butoxyphenyl)-4,4'-bis[4-(tert-butyl)phenyl]-

5H,5'H-(2,2'-bithiazolylidene)-5,5'-diimine 182m

Work up procedure A. Lustrous green cotton fibers (50.1 mg, 66%), mp (DSC) onset:

258.8 °C, peak max: 259.3 °C (from c-hexane/DCE); Rf 0.63 (n-hexane/DCM, 50:50);


λmax(DCM)/nm 256 inf (log ε 4.35), 271 inf (4.30), 327 (4.37), 396 inf (4.21), 416 (4.23),

440 (4.24), 539 inf (4.57), 577 (4.71), 598 inf (4.68); vmax/cm-1 3071w (aryl C-H), 2957m

and 2870w (alkyl C-H), 1607m, 1566m, 1549m, 1501m, 1474m, 1464m, 1408w, 1395w,

1364w, 1319m, 1308m, 1290m, 1267m, 1252s, 1234m, 1200m, 1161m, 1115m, 1070w,

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1040m, 1007m, 914m, 860m, 841m, 826m, 800m, 746w, 716m; δH(500 MHz; CDCl3) 8.49

(4H, d, J 8.5), 7.51 (4H, d, J 8.5), 7.35 (4H, d, J 9.0), 7.00 (4H, d, J 9.0), 4.03 (4H, t, J 6.5),

1.84-1.78 (4H, m), 1.57-1.50 (4H, m), 1.37 (18H, s), 1.01 (6H, t, J 7.5); δC(125 MHz;

CDCl3) 165.0 (s), 159.1 (s), 158.1 (s), 155.1 (s), 145.5 (s), 143.6 (s), 130.6 (d), 129.8 (s),

125.4 (d), 123.0 (d), 115.2 (d), 68.0 (t), 35.0 (s), 31.3 (t), 31.1 (q), 19.3 (t), 13.9 (q);

MALDI-TOF MS (m/z): 757 (MH +, 18%), 700 (100), 644 (58), 423 (67), 365 (25), 352

(55), 348 (16), 296 (24).

7.6.4.12 (2E,5Z,5'Z)-4,4'-Bis[4-(tert-butyl)phenyl]-N5,N5'-bis(4-nitrophenyl)-5H,5'H-

(2,2'-bithiazolylidene)-5,5'-diimine 182n

Work up procedure A. Lustrous green needles (58.5 mg, 83%), mp (DSC) decomp. onset:

369.0 °C, peak max: 372.0 °C (from DCE); Rf 0.61 (n-hexane/DCM, 40:60);

λmax(DCM)/nm 274 inf (log ε 4.44), 304 (4.53), 374 (4.41), 547 (4.88); vmax/cm-1 3098w

and 3071w (aryl C-H), 2968w (alkyl C-H), 1593m, 1566m, 1520m, 1481m, 1410m, 1339s,

1323m, 1310m, 1269m, 1223m, 1196m, 1126w, 1111m, 1072m, 1013m, 916m, 858m,

845m, 829m, 800m, 756m, 716m, 710m; δH(500 MHz; CDCl3) 8.47 (4H, d, J 8.5), 8.37

(4H, d, J 9.0), 7.52 (4H, d, J 9.0), 7.30 (4H, d, J 9.0), 1.36 [18H, s, C(CH3)3]; δC(125 MHz;

CDCl3) 165.2 (s), 164.8 (s), 157.2 (s), 156.5 (s), 145.6 (s), 145.3 (s), 130.6 (d), 128.7 (s),

125.8 (d), 125.7 (d), 120.4 (d), 68.1 (s), 31.0 (q); MALDI-TOF MS (m/z): 704 (MH++1,

37%), 648 (100), 631 (10), 590 (8), 396 (12), 325 (6), 57 (8).

7.6.4.13 (2E,5Z,5'Z)-4,4'-Bis[4-(tert-butyl)phenyl]-N5,N5'-di(pyrid-2-yl)-5H,5'H-(2,2'-

bithiazolylidene)-5,5'-diimine 182o

Work up procedure A was followed however the solid obtained was chromatographed

(n-hexane/DCM, 60:40) prior to recrystallization. Lustrous green plates (17.3 mg, 28%),

mp (DSC) onset: 339.6 °C, peak max: 344.7 °C, decomp. onset: 345.8 °C, peak max:

346.2 °C (from DCE); Rf 0.63 (n-hexane/DCM, 40:60); λmax(DCM)/nm 277 inf (log ε 4.34),

297 inf (4.36), 313 (4.38), 320 inf (4.38), 413 (4.14), 524 inf (4.54), 554 (4.79), 591 (4.87);

vmax/cm-1 3069w (aryl C-H), 2965m, 2903w and 2864w (alkyl C-H), 1607m, 1566m, 1526s,

1458m, 1429s, 1362m, 1321m, 1308m, 1292m, 1260m, 1238m, 1211m, 1204m, 1198m,

1146m, 1125m, 1098m, 1080w, 1018m, 966m, 926m, 878m, 841m, 804m, 791s, 737m,

716m, 700m; δH(500 MHz; TFA-d) 8.67-8.62 (4H, m), 8.39 (4H, d, J 8.5), 8.03 (2H, d, J

8.5), 7.78 (2H, dd, J 6.8, 6.8), 7.57 (4H, d, J 8.5), 1.33 (18H, s); δC(125 MHz; TFA-d)

175.0 (s), 170.4 (s), 162.3 (s), 157.6 (s), 151.7 (d), 150.2 (s), 143.0 (d), 133.3 (d), 129.6 (s),

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128.5 (d), 125.6 (d), 119.1 (d), 37.3 (s), 31.8 (q); MALDI-TOF MS (m/z): 615 (MH+, 44%),

600 (10), 560 (100), 501 (14), 350 (6), 281 (77), 225 (19).

7.6.4.14 (2E,5Z,5'Z)-4,4'-Bis(4-methoxyphenyl)-N5,N5'-diphenyl-5H,5'H-(2,2'-bithiazol-

ylidene)-5,5'-diimine 182p

Work up procedure A. Lustrous green needles (42.6 mg, 76%), mp (DSC) onset: 320.3 °C,


(n-hexane/DCM, 40:60); (found: C, 68.52; H, 4.49; N, 9.86. C32H24N4O2S2 requires:


(4.32), 557 (4.85); vmax/cm-1 3080w (aryl C-H), 2959w, 2922w and 2832w (alkyl C-H),

1595m, 1580m, 1514w, 1481m, 1447w, 1418w, 1323m, 1302m, 1261m, 1221m, 1169s,

1115w, 1080m, 1034m, 924m, 897m, 849m, 837m, 816m, 799m, 779m, 750m, 737m;

δH(500 MHz; CDCl3) 8.63 (4H, d, J 9.0), 7.48 (4H, dd, J 7.8), 7.28-7.23 (6H, m), 6.98 (4H,

d, J 9.0), 3.89 (6H, s); δC(125 MHz; TFA-d) 175.8 (s), 168.3 (s), 168.1 (s), 153.4 (s), 140.2

(s), 134.6 (d), 134.2 (d), 132.7 (d), 124.0 (d), 123.1 (s), 118.0 (d), 57.0 (q); MALDI-TOF

MS (m/z): 560 (M+, 39%), 529 (11), 324 (42), 254 (100).

7.6.4.15 (2E,5Z,5'Z)-N5,N5'-Bis(4-n-butoxyphenyl)-4,4'-bis(4-methoxyphenyl)-5H,5'H-

(2,2'-bithiazolylidene)-5,5'-diimine 182q

Work up procedure A. Lustrous blue needles (38.6 mg, 55%), mp (DSC) onset: 244.1 °C,

peak max: 245.5 °C, decomp. onset: 311.8 °C, peak max: 318.8 °C (from c-hexane/CHCl3);

Rf 0.42 (n-hexane/DCM, 40:60); (found: C, 67.99; H, 5.57; N, 8.09. C40H40N4O4S2 requires:


580 (4.85), 604 inf (4.82); vmax/cm-1 3084w (aryl C-H), 2961w, 2934w and 2870w (alkyl

C-H), 1601m, 1580m, 1566m, 1501m, 1474m, 1418m, 1319m, 1302m, 1261m, 1254m,

1242m, 1221m, 1171s, 1105m, 1078m, 1030m, 916m, 860m, 835s, 772m, 739m, 721w;

δH(500 MHz; CDCl3) 8.63 (4H, d, J 9.0), 7.32 (4H, d, J 9.0), 7.01-6.98 (8H, m), 4.03 (4H, t,

J 6.5), 3.89 (6H, s, OCH3), 1.84-1.78 (4H, m), 1.57-1.49 (4H, m), 1.01 (6H, t, J 7.5);


(d), 125.5 (s), 122.8 (d), 115.2 (d), 113.8 (d), 68.0 (t), 55.4 (q), 31.3 (t), 19.3 (t), 13.9 (q);

MALDI-TOF MS (m/z): 705 (MH+, 62%), 674 (5), 647 (13), 396 (100), 326 (37), 270 (5).

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7.6.4.16 (2E,5Z,5'Z)-N5,N5'-Bis(4-n-butoxyphenyl)-4,4'-bis(4-fluorophenyl)-5H,5'H-

(2,2'-bithiazolylidene)-5,5'-diimine 182r

Work up procedure B. Lustrous green needles (52.0 mg, 76%), mp (DSC) onset: 264.6 °C,


(n-hexane/DCM, 40:60); (found: C, 66.92; H, 4.90; N, 8.38. C38H34F2N4O2S2 requires:


(4.15), 443 (4.18), 538 inf (4.56), 581 (4.72), 603 inf (4.70); vmax/cm-1 3084w (aryl C-H),


1395w, 1317m, 1306m, 1292m, 1248m, 1233m, 1221m, 1169m, 1161s, 1113m, 1072m,

1038m, 1016m, 1009m, 1003m, 918m, 908w, 862m, 849m, 837s, 816m, 799m, 777m,

729m; δH(500 MHz; TFA-d) 8.15 (4H, dd, JHH 9.0, 4JHF 5.0), 7.69 (4H, d, J 9.5), 7.37 (4H,

dd, JHH 8.5, 3JHF 8.5), 7.24 (4H, d, J 9.0), 4.22 (4H, t, J 6.8), 1.87 (4H, tt, J 7.0, 7.0), 1.54

(4H, qt, J 7.5, 7.5), 1.01 (6H, t, J 7.5); δC(125 MHz; TFA-d) 168.6 (d, 1JCF 260.0), 168.3

(s), 167.8 (s), 164.2 (s), 154.0 (s), 134.1 (d, 3JCF 10), 132.8 (s), 125.9 (d), 125.8 (d, 4JCF

2.5), 118.8 (d, 2JCF 22.5), 118.5 (d), 70.9 (t), 31.7 (t), 19.7 (t), 13.2 (q); MALDI-TOF MS

(m/z): 681 (MH+, 51%), 624 (21), 384 (100), 366 (8), 314 (13), 310 (10), 258 (18).

7.6.4.17 (2E,5Z,5'Z)-N5,N5'-Diphenyl-4,4'-bis[4-(trifluoromethyl)phenyl]-5H,5'H-(2,2'-

bithiazolylidene)-5,5'-diimine 182s

Work up procedure A. Lustrous green needles (55.7 mg, 87%), mp (DSC) onset: 314.8 °C,

peak max: 315.6 °C, decomp. onset: 334.0 °C, peak max: 341.4 °C (from c-hexane/CHCl3);

Rf 0.83 (n-hexane/DCM, 40:60); (found: C, 60.19; H, 2.77; N, 8.93. C32H18F6N4S2 requires:

C, 60.37; H, 2.85; N, 8.80%); λmax(DCM)/nm 261 (log ε 4.24), 318 (4.26), 350 inf (4.10),

392 inf (3.95), 553 (4.61); vmax/cm-1 3059w and 3032w (aryl C-H), 1614w, 1568m, 1516w,

1483m, 1449w, 1408m, 1327m, 1315s, 1306m, 1219m, 1192m, 1161m, 1111s, 1063m,

1018m, 1001w, 964w, 924m, 905m, 851m, 816m, 772m, 758m, 750m, 702m; δH(500 MHz;

CDCl3) 8.70 (4H, d, J 8.5), 7.74 (4H, d, J 8.5), 7.51 (4H, dd, J 7.8, 7.8), 7.31 (2H, dd, J 7.5,

7.5), 7.27 (4H, d, J 8.0); δC(125 MHz; TFA-d) 169.1 (s), 168.9 (s), 156.8 (s), 144.6 (s),

138.4 (q, 2JCF 32.5), 134.4 (s), 133.3 (d), 133.1 (d), 132.6 (d), 128.5 (q, 3JCF 2.5), 125.4 (q,

1JCF 270.4), 123.8 (d); MALDI-TOF MS (m/z): 636 (M+, 42%), 566 (34), 362 (39), 343 (5),

317 (6), 291 (100).

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7.6.4.18 (2E,5Z,5'Z)-N5,N5'-Bis(4-n-butoxyphenyl)-4,4'-bis[4-(trifluoromethyl)phenyl]-

5H,5'H-(2,2'-bithiazolylidene)-5,5'-diimine 182t

Work up procedure A. Green needles (65.9 mg, 84%), mp (DSC) onset: 240.4 °C, peak

max: 241.0 °C (from DCE); Rf 0.78 (n-hexane/DCM, 40:60); (found: C, 61.44; H, 4.38;

N, 7.26. C40H34F6N4O2S2 requires: C, 61.53; H, 4.39; N, 7.18%); λmax(DCM)/nm 268 (log ε

4.43), 330 (4.52), 442 (4.10), 602 (4.69), 618 inf (4.68); vmax/cm-1 2953w, 2934w and

2870w (alkyl C-H), 1605m, 1558w, 1543m, 1503m, 1468m, 1408m, 1393m, 1329m,

1319m, 1308m, 1296m, 1246m, 1231m, 1169s, 1123m, 1111m, 1084m, 1061m, 1016m,

970m, 918m, 847m, 833s, 814m, 802m, 789m, 764m, 702m; δH(500 MHz; TFA-d) 8.23

(4H, d, J 8.5), 7.87 (4H, d, J 8.0), 7.61 (4H, d, J 8.5), 7.18 (4H, d, J 9.0), 4.16 (4H, t, J 6.5),

1.81 (4H, tt, J 7.0, 7.0), 1.48 (4H, qt, J 7.4, 7.4), 0.95 (6H, t, J 7.5); δC(125 MHz; TFA-d)

one C (s) missing, 168.7 (s), 166.0 (s), 155.8 (s), 138.2 (q, 2JCF 33.3), 135.0 (s), 133.7 (s),

132.6 (d), 128.4 (d), 126.7 (d), 125.0 (q, 1JCF 269.5), 119.0 (d), 71.6 (t), 32.3 (t), 20.2 (t),

13.8 (q); MALDI-TOF MS (m/z): 781 (MH +, 68%), 724 (68), 712 (71), 434 (100), 416

(21), 366 (35), 360 (59), 308 (57).

7.6.4.19 4,4'-[{(2E,5Z,5'Z)-4,4'-Bis[4-(trifluoromethyl)phenyl]-5H,5'H-(2,2'-bithia-

zolylidene)-5,5'-diylidene}bis(azanylylidene)]bis(N,N-diethylaniline) 182u

Work up procedure A. Dark purple needles (60.8 mg, 78%), mp (DSC) onset: 271.8 °C,


(n-hexane/DCM, 40:60); (found: C, 61.58; H, 4.74; N, 10.72. C40H36F6N6S2 requires:


473 (4.13), 744 inf (4.71), 787 (4.78); vmax/cm-1 3063w (aryl C-H), 2970w and 2930w

(alkyl C-H), 1605m, 1510m, 1460m, 1400m, 1348m, 1317s, 1269m, 1225m, 1175s, 1152s,

1117m, 1107m, 1076m, 1061m, 1016m, 951w, 918m, 851m, 814m, 791m, 762m, 723m;

δH(500 MHz; CDCl3) 8.69 (4H, d, J 8.0), 7.74 (4H, d, J 8.5), 7.48 (4H, d, J 9.0), 6.84 (4H,

br d, J 7.5), 3.47 (8H, q, J 7.0, NCH2), 1.24 (12H, t, J 7.0); δC(125 MHz; TFA-d) one C (s)

missing, 170.8 (s), 169.4 (s), 157.0 (s), 148.4 (s), 138.6 (q, 2JCF 32.5), 134.3 (s), 133.5 (d),

128.6 (d), 126.5 (d), 126.3 (d), 125.5 (q, 1JCF 270.0), 57.7 (t), 11.5 (q); MALDI-TOF MS

(m/z): 778 (M+, 81%), 763 (16), 734 (11), 720 (38), 709 (21), 433 (100), 418 (26), 415 (27),

375 (5), 363 (9).

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7.6.4.20 (2E,5Z,5'Z)-N5,N5'-Bis(4-n-butoxyphenyl)-4,4'-bis(4-nitrophenyl)-5H,5'H-

(2,2'-bithiazolylidene)-5,5'-diimine 182v

Work up procedure: the reaction mixture was left to cool at ca. 20 °C, dissolved in DCM

adsorbed onto silica and chromatographed (n-hexane/DCM, 50:50). Obtained as maroon

needles (54.1 mg, 74%), mp (DSC) onset: 272.2 °C, peak max: 272.7 °C, decomp. onset:

279.7 °C, peak max: 290.2 °C (from c-hexane/CHCl3); Rf 0.33 (n-hexane/DCM, 40:60);


λmax(DCM)/nm 268 (log ε 4.60), 360 (4.58), 439 inf (4.24), 641 (4.73); vmax/cm-1 3109w

and 3051w (aryl C-H), 2959w, 2932w and 2872w (alkyl C-H), 1605m, 1566m, 1518m,

1501m, 1472m, 1404w, 1341s, 1310m, 1258m, 1238m, 1161s, 1105m, 1069m, 1026m,

1015m, 972w, 920m, 853m, 831m, 799m, 760m, 704m; δH(500 MHz; CDCl3) 8.79 (4H, d,

J 9.0), 8.33 (4H, d, J 9.0), 7.39 (4H, d, J 9.0), 7.03 (4H, d, J 9.0), 4.05 (4H, t, J 6.5), 1.85-

1.80 (4H, m), 1.58-1.50 (4H, m), 1.02 (6H, t, J 7.3); δC(125 MHz; CDCl3) 163.4 (s), 159.0

(s), 156.6 (s), 149.2 (s), 147.5 (s), 142.3 (s), 137.9 (s), 131.8 (d), 123.7 (d), 123.3 (d), 115.4

(d), 68.1 (t), 31.3 (t), 19.3 (t), 13.9 (q); MALDI-TOF MS (m/z): 735 (MH +, 71%), 678 (64),

411 (100), 355 (7), 291 (5), 285 (9).

Further elution (n-hexane/DCM, 40:60) gave 4-{(2E,5Z,5'Z)-5,5'-bis[(4-n-butoxy-

phenyl)imino]-4'-(4-nitrophenyl)-5H,5'H-(2,2'-bithiazolylidene)-4-yl}aniline 187 as blue

needles (13.4 mg, 19%), mp (DSC) decomp. onset: 267.8 °C, peak max: 269.5 °C (from

c-hexane/CHCl3); Rf 0.55 (DCM); (found: C, 64.73; H, 4.99; N, 12.00. C38H36N6O4S2

requires: C, 64.75; H, 5.15; N, 11.92%); λmax(DCM)/nm 266 inf (log ε 4.54), 284 inf (4.51),

328 inf (4.36), 503 inf (4.47), 543 inf (4.56), 624 (4.79); vmax/cm-1 3387w (N-H), 3073w

(aryl C-H), 2957w, 2930w and 2870w (alkyl C-H), 1618m, 1597m, 1559m, 1520m, 1499m,

1470m, 1414m, 1377m, 1341m, 1325s, 1290m, 1244m, 1233m, 1206m, 1179s, 1169m,

1107m, 1074m, 1028m, 1013m, 970m, 918m, 862m, 837s, 799m, 783m, 760m, 741m,

704m; δH(500 MHz; CDCl3) 8.77 (2H, d, J 9.0), 8.58 (2H, d, J 9.0), 8.27 (2H, d, J 9.0),

7.34 (2H, d, J 8.5), 7.30 (2H, d, J 9.0), 7.01 (2H, d, J 9.0), 7.00 (2H, d, J 9.0), 6.71 (2H, d,

J 9.0), 4.20 (2H, br s), 4.03 (2H, t, J 6.5), 4.02 (2H, t, J 6.5), 1.84-1.79 (4H, m), 1.57-1.49

(4H, m), 1.01 (6H, t, J 7.3); δC(125 MHz; CDCl3) four C resonances belonging to one n-

BuO group are missing or overlapping with the signals of the other n-BuO group, 165.0 (s),

160.7 (s), 159.3 (s), 158.3 (s), 158.23 (s), 158.20 (s), 150.6 (s), 148.7 (s), 148.4 (s), 143.7

(s), 143.22 (s), 143.16 (s), 138.5 (s), 133.5 (d), 131.3 (d), 123.2 (d), 123.1 (d), 122.8 (d),

122.6 (s), 115.24 (d), 115.22 (d), 114.3 (d), 68.1 (t), 31.3 (t), 19.3 (t), 13.9 (q); MALDI-

TOF MS (m/z): 705 (MH+, 58%), 647 (20), 411 (62), 382 (29), 311 (100).

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7.6.4.21 4,4'-{[(2E,5Z,5'Z)-4,4'-Bis(4-nitrophenyl)-5H,5'H-(2,2'-bithiazolylidene)-5,5'-

diylidene]bis(azanylylidene)}bis(N,N-diethylaniline) 182w

Work up procedure B. Brown microcrystals (50.6 mg, 69%), mp (DSC) decomp. onset:

276.8 °C, peak max: 280.5 °C (from DCE); Rf 0.80 (n-hexane/NH3 sat. DCM, 20:80);


λmax(DCM)/nm 277 (4.20), 360 (4.29), 474 (4.23), 785 inf (4.54), 843 (4.63); vmax/cm-1

3075w (aryl C-H), 2976w and 2924w (alkyl C-H), 1601s, 1514m, 1503m, 1406m, 1358m,

1337m, 1319m, 1269m, 1227m, 1173s, 1150s, 1107m, 1070m, 1013m, 920w, 868m, 853m,

818m, 799m, 762m, 723m, 700m; δH(500 MHz; CDCl3 at ca. 55 °C) 8.78 (4H, d, J 9.0),

8.30 (4H, d, J 9.0), 7.45 (4H, d, J 9.0), 7.12 (4H, d, J 8.5), 3.53 (8H, q, J 7.2), 1.26 (12H, t,

J 7.3); δC(125 MHz; CDCl3 at ca. 55 °C) one C (s) resonance missing, 162.6 (s), 149.2 (s),

147.5 (s), 143.8 (s), 142.2 (s), 138.4 (s), 131.7 (d), 124.9 (d), 123.3 (d), 116.5 (d), 48.0 (t),

11.9 (q); MALDI-TOF MS (m/z): 732 (M+, 75%), 717 (24), 702 (5), 687 (17), 674 (16),

410 (100), 395 (12).

Chromatography of the filtrate (n-hexane/NH3 sat. DCM, 50:50) gave 4,4'-{[(2E,5Z,5'Z)-

4-(4-aminophenyl)-4'-(4-nitrophenyl)-5H,5'H-(2,2'-bithiazolylidene)-5,5'-diylidene]bis-

(azanylylidene)}bis(N,N-diethylaniline) 188 as lustrous green needles (9.3 mg, 13%) mp

(DSC) decomp. onset: 252.1 °C, peak max: 255.9 °C (from c-hexane/DCM); Rf 0.62

(n-hexane/NH3 sat. DCM, 20:80); (found: C, 64.82; H, 5.39; N, 16.22. C38H38N8O2S2


(4.40), 341 inf (4.35), 379 (4.35), 514 (4.59), 775 (4.84); vmax/cm-1 3360w (N-H), 3069w

(aryl C-H), 2968m and 2920w (alkyl C-H), 1601s, 1512s, 1402m, 1356m, 1333m, 1267m,

1219m, 1196m, 1173s, 1152s, 1107m, 1070m, 1013m, 916m, 858m, 843m, 816m, 789m,

760m, 739m, 721m, 706m; δH(500 MHz; CDCl3) two H resonances belonging to one Et2N

group are missing or overlapping with the signals of the other Et2N group, 8.80 (2H, d, J

9.0), 8.58 (2H, d, J 8.5), 8.29 (2H, d, J 9.0), 7.452 (2H, d, J 9.0), 7.448 (2H, d, J 9.0),

6.773 (2H, d, J 9.0), 6.768 (2H, d, J 9.5), 6.74 (2H, d, J 8.5), 4.12 (2H, br s), 3.45 (8H, q, J

7.0), 1.23 (12H, t, J 7.0); δC(125 MHz; CDCl3) two C resonances belonging to one Et2N

group are missing or overlapping with the signals of the other Et2N group, 164.9 (s), 160.4

(s), 152.9 (s), 152.3 (s), 149.8 (s), 148.3 (s), 148.0 (s), 147.3 (s), 147.1 (s), 143.5 (s), 139.4

(s), 137.5 (s), 137.1 (s), 133.2 (d), 131.2 (d), 125.14 (d), 125.09 (d), 123.4 (s), 123.1 (d),

114.3 (d), 111.77 (d), 111.72 (d), 44.7 (q), 12.7 (t); MALDI-TOF MS (m/z): 702 (M+,

74%), 644 (33), 410 (100), 381 (27), 310 (64).

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7.6.4.22 (2E,5Z,5'Z)-N5,N5'-Bis(4-n-butoxyphenyl)-4,4'-bis(5-n-hexylthien-2-yl)-

5H,5'H-(2,2'-bithiazolylidene)-5,5'-diimine 182y

Work up procedure A. Green needles (54.0 mg, 65%), mp (DSC) onset: 155.1 °C, peak

max: 155.6 °C (from c-hexane); Rf 0.66 (n-hexane/DCM, 60:40); (found: C, 66.87; H, 6.74;

N, 6.90. C46H56N4O2S4 requires: C, 66.95; H, 6.84; N, 6.79%); λmax(DCM)/nm 264 (log ε

4.29), 288 inf (4.18), 345 (4.24), 354 inf (4.21), 469 inf (4.28), 506 inf (4.34), 563 inf

(4.54), 601 (4.73), 642 (4.74); vmax/cm-1 3067w (aryl C-H), 2957m, 2930m, 2872w and

2855w (alkyl C-H), 1605m, 1566m, 1537m, 1530m, 1501s, 1481m, 1447m, 1393w,

1371m, 1327w, 1287m, 1246s, 1219m, 1163m, 1107m, 1070m, 1024m, 1007m, 972m,

908m, 878w, 841m, 833m, 810m, 799m, 781m, 706m; δH(500 MHz; CDCl3) 8.35 (2H, d, J

4.0), 7.39 (4H, d, J 9.0), 7.01 (4H, d, J 9.0), 6.88 (2H, d, J 3.5), 4.03 (4H, t, J 6.5), 2.89

(4H, t, J 7.5), 1.84-1.78 (4H, m), 1.76-1.71 (4H, m), 1.56-1.51 (4H, m), 1.43-1.36 (4H, m),

1.34-1.30 (8H, m), 1.01 (6H, t, J 7.3), 0.90 (6H, t, J 7.0); δC(125 MHz; CDCl3) 159.4 (s),

158.1 (s), 156.8 (s), 155.8 (s), 145.0 (s), 142.7 (s), 133.8 (d), 133.0 (s), 125.9 (d), 123.3 (d),

115.2 (d), 68.0 (t), 31.54 (t), 31.48 (t), 31.3 (t), 30.7 (t), 28.8 (t), 22.6 (t), 19.3 (t), 14.1 (q),

13.9 (q); MALDI-TOF MS (m/z): 825 (MH+, 54%), 768 (93), 457 (100).

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7.7 X-ray Crystallographic Studies

7.7.1 General Procedure and Instrumentation

Data were collected on an Oxford-Diffraction Supernova diffractometer, equipped with a

CCD area detector utilizing Mo-Kα radiation (λ = 0.71073 Å). A suitable crystal was

attached to glass fibers using paratone-N oil and transferred to a goniostat where they was

cooled for data collection. Unit cell dimensions were determined and refined by using 6074

(3.02 θ 28.90º) reflections for 70a and 76, 5674 (3.40 θ 26.97º) reflections for 77,

1396 (3.83 θ 29.44º) reflections for 91a, 1925 (3.61 θ 28.38º) reflections for 93a,

1339 (3.99 θ 28.13º) reflections for 94a, 1061 (3.73 θ 27.93º) reflections for 98 and

2589 (3.90 θ 28.84º) reflections for 104. For compound 96c and 163 data were

collected utilizing Cu-Kα radiation (λ = 1.5418 Å). Unit cell dimensions were determined

and refined by using 1375 (4.58 θ 72.39) reflections for 96c and 2064 (3.29 θ

72.43) reflections for 163. Empirical absorption corrections (multi-scan based on

symmetry-related measurements) were applied using CrysAlis RED software.212 The

structure was solved by direct methods using SIR92213 and refined on F2 using full-matrix

least squares using SHELXL97.214 Software packages used: CrysAlis CCD212 for data

collection, CrysAlis RED212 for cell refinement and data reduction, WINGX for geometric

calculations,215 and DIAMOND216 for molecular graphics. The non-H atoms were treated

anisotropically. For compounds 70a, 76, 77 the hydrogen atom attached to N3 was located

on a difference Fourier map, whereas all other hydrogen atoms were placed in calculated,

ideal positions and refined as riding on their respective carbon atoms.

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7.7.2 Crystal Refinement Data

7.7.2.1 4,6-Dimethyl-6H-pyrazolo[3,4-c]isothiazole-3-carbonitrile 70a

C7H6N4S, M = 178.18, triclinic, space group P 1̄ , a = 3.8592(3) Å, b = 8.404(2) Å,

c = 12.541(2) Å, α = 87.52(2)°, β = 85.342(9)°, γ = 81.578(9)°, V = 400.83(8) Å3, Z = 2,

T = 100(2) K, ρcalcd = 1.477 g cm-3, 2θmax = 24.99, μ(MoKα) = 0.347 mm-1. 2255

reflections measured, 1417 independent reflections (Rint = 0.0381). The final R1 and wR(F2)

values were 0.0508 and 0.1434 [I > 2σ(I)], respectively. The goodness of fit on F2 was

0.903.

7.7.2.2 Crystal refinement data for compound 76

C14H12Cl2N8S5, M = 523.57, monoclinic, space group C2/c, a = 34.721(5) Å, b = 4.0036(5)

Å, c = 14.975(2) Å, β = 100.148(13)°, V = 2049.1(5) Å3, Z = 4, T = 100(2) K, ρcalcd = 1.697

g cm-3, 2θmax = 26.5, μ(MoKα) = 0.847 mm-1. 4564 reflections measured, 2101

independent reflections (Rint = 0.0575). The final R1 and wR(F2) values were 0.0623 and

0.1812 [I > 2σ(I)], respectively. The goodness of fit on F2 was 1.035.


C16H14Cl3N9S5, M = 599.06, triclinic, space group P-1, a = 10.4490(4) Å, b = 12.6255(8) Å,

c = 21.3511(9) Å, α = 97.143(4)o, β = 92.352(3)o, γ = 93.441(4)o, V = 2786.5(2) Å3, Z = 4,

T = 100(2) K, ρcalcd = 1.428 g cm-3, 2θmax = 25, μ(MoKα) = 0.727 mm-1. 20504 reflections

measured, 9786 independent reflections (Rint = 0.0575). The final R1 and wR(F2) values

were 0.0824 and 0.2523 [I > 2σ(I)], respectively. The goodness of fit on F2 was 1.000.

7.7.2.4 Crystal refinement data for compound 91a

C7H6N4S2, M = 210.30, monoclinic, space group P-21/c, a = 3.9220(3) Å, b = 16.8520(14)

Å, c = 13.4334(11) Å, α = 90(3)o, β = 94.338(8)o, γ = 90o, V = 885.32(12) Å3, Z = 4,

T = 100(2) K, ρcalcd = 1.578 g cm-3, 2θmax = 25. Refinement of 118 parameters on 1565

independent reflections out of 2092 measured reflections (Rint = 0.0440) led to R1 = 0.0392

[I>2s(I)], wR2 = 0.1006 (all data), and S = 1.052 with the largest difference peak and hole

of 0.403 and -0.371 e-3, respectively.

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C11H17N5S2, M = 283.44, triclinic, space group P-1, a = 7.9239(7) Å, b = 8.1833(6) Å,

c = 11.9333(11) Å, α = 86.140(7)o, β = 78.319(8)o, γ = 65.964(8)o, V = 691.97(11) Å3,

Z = 2, T = 100(3) K, ρcalcd = 1.360 g cm-3, 2θmax = 25. Refinement of 163 parameters on

2445 independent reflections out of 4661 measured reflections (Rint = 0.0540) led to

R1 = 0.0503 [I>2s(I)], wR2 = 0.1466 (all data), and S = 1.076 with the largest difference

peak and hole of 0.493 and -0.566 e-3, respectively.


C7H6N4S3, M = 242.32, triclinic, space group P-1, a = 7.8861(6) Å, b = 8.2893(10) Å,

c = 8.3398(9) Å, α = 113.381(11)o, β = 99.470(8)o, γ = 97.678(8)o, V = 481.53(10) Å3,

Z = 2, T = 100(2) K, ρcalcd = 1.671 g cm-3, 2θmax = 25. Refinement of 128 parameters on

1697 independent reflections out of 2833 measured reflections (Rint = 0.0343) led to

R1 = 0.0442 [I>2s(I)], wR2 = 0.1059 (all data), and S = 1.036 with the largest difference

peak and hole of 0.418 and -0.395 e-3, respectively.

7.7.2.7 Crystal refinement data for compound 96c

C8H4N2OS2, M = 208.25, Monoclinic, space group P 2/n, a = 6.5307(2)Å, b = 6.6741(2)Å,

c = 19.4614(7)Å, α = 900, β = 97.118(3)0, γ = 900, V = 841.72(5)Å3, Z = 4, T = 100(2) K,

ρcalcd= 1.643 g cm-3, 2θmax=67. Refinement of 121 parameters on 1497 independent

reflections out of 4627 measured reflections (Rint=0.0235) led to R1= 0.0635 (I>2s(I)),

wR2= 0.1595 (all data), and S = 1.072 with the largest difference peak and hole of 0.771

and -0.265 e-3 respectively


C7H6N4S3, M = 242.32, monoclinic, space group P21, a = 3.8380(4) Å, b = 7.3609(8) Å,

c = 16.2830(17) Å, α = 90o, β = 92.324(10)o, γ = 90o, V = 459.64(8) Å3, Z = 2, T = 100(2)

K, ρcalcd = 1.751 g cm-3, 2θmax = 25. Refinement of 127 parameters on 1131 independent

reflections out of 1598 measured reflections (Rint = 0.0304) led to R1 = 0.0432 [I>2s(I)],

wR2 = 0.1051 (all data), and S = 1.062 with the largest difference peak and hole of 0.433

and -0.353 e-3, respectively.

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C14H12N8S3, M = 388.53, monoclinic, space group P 21/c, a = 9.7319(4) Å, b = 18.6419(9)

Å, c = 9.2096(5) Å, α = 90o, β = 94.930(4)o, γ = 90o, V = 1664.64(14) Å3, Z = 4, T = 100(2)

K, ρcalcd = 1.550 g cm-3, 2θmax = 25. Refinement of 226 parameters on 2928 independent

reflections out of 3538 measured reflections (Rint = 0.0322) led to R1 = 0.0438 [I>2s(I)],

wR2 = 0.1222 (all data), and S = 1.062 with the largest difference peak and hole of 0.644

and -0.624 e-3, respectively.

7.7.2.10 Crystal Refinement Data for Compound 163

C8H12ClN3S3, M = 281.84, Monoclinic, space group P 21/n, a = 11.0496(4) Å, b =

7.8673(2) Å, c = 13.8104(5) Å, α = 90o, β = 103.673(4)o, γ = 90o, V = 1166.52(7) Å3, Z = 4,

T = 100(2) K, ρcalcd = 1.605 g cm-3, 2θmax = 67. Refinement of 136 parameters on 2075

independent reflections out of 5856 measured reflections (Rint = 0.0323) led to R1 = 0.0348

[I > 2s(I)], wR2 = 0.4198 (all data), and S = 1.092 with the largest difference peak and hole

of 0.385 and -0.510 e-3, respectively.

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7.8 Computational Studies Methods

The geometries of the dithiazoles 95a, 137, 139 and 140 were optimized at the DFT

RB3LYP/6-31G+(d,p) level of theory and analytical second derivatives were computed

using vibrational analysis to confirm each stationary point to be a minimum by yielding

zero imaginary frequencies. For the Mulliken population analyses,151 single-point

calculations were performed on the optimized structures of 95a, 137, 139 and 140 by

employing the MP2/6-31G(d) level of theory with additional keyword “Density = MP2”.

The geometries of the quinoidal bithiazoles 182 and 189-192 were optimized at the DFT

RB3LYP/6-31G(d,p) level of theory and analytical second derivatives were computed

using vibrational analysis to confirm each stationary point to be a minimum by yielding

zero imaginary frequencies. For the lowest band gap compound 182w the wavefunction

was checked for stability and found to be stable. TD-DFT calculations were performed also

at the RB3LYP/6-31G(d,p) level of theory to obtain the vertical excitation energies. All the

computations were performed using the Gaussian 03217 or the Gaussian 09218 suite of

programs.

7.9 Cyclic Voltammetry Studies Methods

Cyclic voltammetry studies were performed on a Princeton Applied Research Potentiostat-

Galvanostat 263A. The concentrations of bithiazoles 182 used were 0.5 mM in DCM

(5 mL) containing n-Bu4NPF6 (0.1 M) as an electrolyte. A three electrode electrochemical

cell was used with glassy carbon disk as working electrode, Pt wire as counter electron and

Ag/AgCl (1 M KCl) as reference electrode. Scan rate 50 mV/s. Temperature = 20 °C.

Ferrocene (Fc) (EFc/Fc+ 0.475 V vs SCE) was used as an external reference.219

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LIST OF COMPOUNDS PREPARED

Compound number in bold followed by page number where compound appears in

Chapter 7 (Experimental Section).

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APPENDIX I

Atomic Cartesian Coordinates

N-(4-Chloro-5H-1,2,3-dithiazol-5-ylidene)aniline 95a

atom coordinates (Angstroms) x y z

C1 -3.535635 -1.163999 0.595456 C2 -2.181624 -0.826330 0.641126 C3 -1.733055 0.373415 0.055827 C4 -2.672262 1.232221 -0.546904 C5 -4.016425 0.874989 -0.609904 C6 -4.455266 -0.325308 -0.038929 H7 -3.870931 -2.086049 1.061403 H8 -1.489687 -1.472281 1.171393

H9 -2.319100 2.168755 -0.965881 H10 -4.726413 1.539114 -1.093998 H11 -5.505608 -0.597657 -0.077952 N12 -0.408378 0.818460 0.079359 C13 0.645706 0.107972 0.045964 C14 2.001989 0.720571 0.070611 S15 0.778259 -1.695386 -0.108222 Cl16 2.118724 2.437193 0.274952 N17 3.074378 0.036429 -0.079953 S18 2.903670 -1.612712 -0.269559

N-(4-Chloro-5H-1,2,3-dithiazol-5-ylidene)pyrid-2-ylamine 137


C1 -3.126947 -1.283799 0.000320 C2 -1.678179 0.524145 -0.000015 C3 -2.752438 1.436427 -0.000178 C4 -4.045943 0.933946 -0.000105 C5 -4.246129 -0.454763 0.000138 H6 -3.227812 -2.366596 0.000531 H7 -2.540608 2.499549 -0.000362 H8 -4.895236 1.610703 -0.000235

H9 -5.243283 -0.881842 0.000202 N10 -0.381974 1.006746 -0.000043 C11 0.613166 0.186138 -0.000068 C12 2.008725 0.664026 -0.000010 S13 0.514009 -1.598702 -0.000409 Cl14 2.294131 2.377371 0.000080 N15 3.017422 -0.132018 0.000111 S16 2.670885 -1.763893 0.000142 N17 -1.876177 -0.805063 0.000255

N-(4-Chloro-5H-1,2,3-dithiazol-5-ylidene)pyrazin-2-ylamine 139


C1 3.178777 -1.262173 0.000254 C2 1.688490 0.481911 -0.000219 C3 2.775061 1.388802 -0.000151 C4 4.238453 -0.357851 0.000226 H5 3.347760 -2.336071 0.000411 H6 2.582384 2.457996 -0.000313 H7 5.268597 -0.702329 0.000388

N8 0.401523 0.974711 -0.000348 C9 -0.608284 0.170794 -0.000292 C10 -1.995038 0.675944 0.000084 S11 -0.547818 -1.613828 -0.000139 Cl12 -2.248919 2.391444 0.000105 N13 -3.015681 -0.105341 0.000398 S14 -2.697999 -1.740286 -0.000033 N15 1.907652 -0.841457 0.000043 N16 4.035250 0.973103 0.000059

N-(4-Chloro-5H-1,2,3-dithiazol-5-ylidene)thiazol-2-amine 140


N1 -0.459868 0.820522 0.000258 C2 0.623553 0.113416 0.000373 C3 1.956457 0.740242 0.000285 S4 0.717073 -1.666788 -0.000061 Cl5 2.057994 2.471248 0.000052 N6 3.041797 0.050900 -0.000102

S7 2.863034 -1.605474 -0.000259 C8 -1.671371 0.201973 0.000174 S9 -3.145413 1.161400 -0.000369 C10 -3.216430 -1.392908 0.000311 C11 -4.058986 -0.313176 -0.000162 H12 -3.533799 -2.428556 0.000574 H13 -5.139842 -0.309039 -0.000333 N14 -1.877172 -1.099584 0.000416

MARIA KOYIONI

240

(2Z,5Z,5'Z)-N5,N5',4,4'-Τetraphenyl-5H,5'H-(2,2'-bithiazolylidene)-5,5'-diimine 182a'


C1 3.155876 -0.252198 -0.030311 C2 2.721526 1.175650 -0.033091 C3 0.690395 0.223927 -0.036340 N4 1.426698 1.365161 -0.022280 S5 1.655900 -1.270060 -0.077382 C6 -0.690528 0.223898 -0.036318 C7 -2.721682 1.175574 -0.033010 S8 -1.656012 -1.270119 -0.077248 N9 -1.426866 1.365117 -0.022223 C10 -3.155977 -0.252291 -0.030297 N11 4.363473 -0.650754 0.068750 N12 -4.363569 -0.650881 0.068521 C13 4.791376 -1.982911 0.058689 C14 5.844314 -2.324079 0.926859 C15 4.281238 -2.960453 -0.815414 C16 6.336607 -3.624409 0.958185 H17 6.247761 -1.554931 1.577221 C18 4.799807 -4.254257 -0.794076 H19 3.511604 -2.697661 -1.532927 C20 5.817635 -4.596050 0.097399 H21 7.136345 -3.878982 1.647386 H22 4.406571 -4.997180 -1.481804 H23 6.212383 -5.607269 0.113596 C24 -4.791259 -1.983115 0.058599 C25 -4.280633 -2.960737 -0.815110 C26 -5.844365 -2.324295 0.926560 C27 -4.798957 -4.254637 -0.793643

H28 -3.510777 -2.697960 -1.532397 C29 -6.336426 -3.624714 0.958008 H30 -6.248142 -1.555087 1.576644 C31 -5.817010 -4.596431 0.097579 H32 -4.405337 -4.997645 -1.481061 H33 -7.136319 -3.879289 1.647030 H34 -6.211556 -5.607727 0.113864 C35 -3.622956 2.341640 -0.030444 C36 -3.051000 3.619379 0.149273 C37 -5.014616 2.246454 -0.216930 C38 -3.845621 4.758382 0.148293 H39 -1.978661 3.692247 0.287775 C40 -5.803778 3.395392 -0.218703 H41 -5.466932 1.274058 -0.353971 C42 -5.227797 4.652348 -0.035872 H43 -3.388033 5.732843 0.291493 H44 -6.875918 3.304720 -0.366308 H45 -5.848483 5.543748 -0.037450 C46 3.622749 2.341761 -0.030460 C47 3.050708 3.619502 0.148991 C48 5.014462 2.246630 -0.216662 C49 3.845269 4.758541 0.148077 H50 1.978329 3.692307 0.287233 C51 5.803565 3.395607 -0.218381 H52 5.466860 1.274263 -0.353596 C53 5.227489 4.652550 -0.035785 H54 3.387615 5.732999 0.291080 H55 6.875742 3.304982 -0.365749 H56 5.848133 5.543980 -0.037341

(2E,5Z,5'Z)-N5,N5',4,4'-Tetraphenyl-5H,5'H-(2,2'-bithiazolylidene)-5,5'-diimine 182a''

atom coordinates (Angstroms)

x y z

C1 -3.176512 -0.071204 -0.044944 C2 -2.511739 -1.406405 -0.082150 C3 -0.677387 -0.119761 -0.073244 C4 3.176558 0.071183 -0.045023 C5 2.511727 1.406333 -0.082165 C6 0.677425 0.119593 -0.073268 N7 -4.437205 0.100582 0.078257 N8 4.437242 -0.100599 0.078187 C9 -5.097299 1.332909 0.114107 C10 -6.210603 1.432047 0.969319 C11 -4.760019 2.433026 -0.696600 C12 -6.932453 2.617678 1.052196 H13 -6.477660 0.568481 1.569582 C14 -5.506386 3.608098 -0.625321 H15 -3.943589 2.354725 -1.406080 C16 -6.584589 3.712017 0.254797 H17 -7.777108 2.685782 1.731463 H18 -5.243205 4.445712 -1.264644 H19 -7.156943 4.632889 0.310765 C20 -3.204970 -2.705038 -0.094757 C21 -4.579672 -2.842172 -0.364527 C22 -2.444893 -3.868441 0.150587 C23 -5.169075 -4.104853 -0.384683

H24 -5.174826 -1.959048 -0.550826 C25 -3.041567 -5.122523 0.132819 H6 -1.385967 -3.764601 0.356044 C27 -4.408179 -5.247124 -0.135667 H28 -6.230046 -4.194258 -0.598538 H29 -2.441667 -6.006122 0.329548 H30 -4.874195 -6.228151 -0.150648 C31 3.204873 2.705021 -0.094766 C32 4.579645 2.842220 -0.364113 C33 2.444629 3.868400 0.150176 C34 5.168960 4.104946 -0.384269 H35 5.174933 1.959122 -0.550116 C36 3.041210 5.122526 0.132409 H37 1.385647 3.764512 0.355313 C38 4.407900 5.247196 -0.135662 H39 6.229992 4.194394 -0.597799 H40 2.441182 6.006109 0.328820 H41 4.873839 6.228259 -0.150634 N42 -1.201130 -1.372269 -0.080759 N43 1.201112 1.372135 -0.080738 S44 -1.878300 1.187900 -0.083645 S45 1.878313 -1.187988 -0.083792 C46 5.097401 -1.332885 0.114025 C47 6.210763 -1.431908 0.969186 C48 4.760128 -2.433078 -0.696574 C49 6.932692 -2.617484 1.052096

MARIA KOYIONI

241

H50 6.477796 -0.568281 1.569373 C51 5.506567 -3.608106 -0.625255 H52 3.943643 -2.354894 -1.406002 C53 6.584834 -3.711899 0.254793

H54 7.777395 -2.685507 1.731311 H55 5.243384 -4.445779 -1.264497 H56 7.157248 -4.632732 0.310797

(2E,5E,5'E)-N5,N5',4,4'-Τetraphenyl-5H,5'H-(2,2'-bithiazolylidene)-5,5'-diimine 182a'''


C1 2.991613 1.046404 -0.284270 C2 2.841353 -0.438040 -0.116890 C3 0.672504 0.129980 -0.060446 C4 -2.991526 -1.046537 0.283929 C5 -2.841234 0.437906 0.116343 C6 -0.672394 -0.130180 0.060008 N7 1.610866 -0.855780 0.035482 N8 -1.610750 0.855606 -0.036008 S9 1.333457 1.734845 -0.394850 S10 -1.333365 -1.734985 0.394590 N11 3.975288 1.859552 -0.330496 N12 -3.975211 -1.859621 0.330323 C13 3.922443 -1.437687 -0.196305 C14 3.827023 -2.611210 0.572320 C15 4.995862 -1.293045 -1.090130 C16 4.798936 -3.601588 0.468505 H17 2.984990 -2.730701 1.245226 C18 5.957219 -2.294253 -1.201676 H19 5.070860 -0.406143 -1.708228 C20 5.867085 -3.446403 -0.418558 H21 4.720836 -4.497962 1.076407 H22 6.777870 -2.173257 -1.901982 H23 6.623223 -4.221505 -0.501378 C24 -3.922323 1.437558 0.195724 C25 -3.826993 2.610943 -0.573111 C26 -4.995667 1.293022 1.089661 C27 -4.798933 3.601313 -0.469382

H28 -2.985017 2.730338 -1.246103 C29 -5.957036 2.294222 1.201129 H30 -5.070590 0.406209 1.707897 C31 -5.866990 3.446246 0.417807 H32 -4.720930 4.497585 -1.077444 H33 -6.777627 2.173328 1.901521 H34 -6.623151 4.221334 0.500541 C35 -5.306612 -1.634869 -0.018972 C36 -6.308930 -2.185873 0.800184 C37 -5.677988 -1.000806 -1.219650 C38 -7.650712 -2.046086 0.458002 H39 -6.012401 -2.709179 1.703462 C40 -7.021882 -0.893475 -1.566648 H41 -4.907754 -0.616091 -1.880057 C42 -8.015582 -1.401200 -0.726894 H43 -8.414940 -2.458721 1.110385 H44 -7.293894 -0.408341 -2.499655 H45 -9.062137 -1.309818 -1.000592 C46 5.306525 1.634965 0.019452 C47 5.677548 1.000165 1.219860 C48 6.309077 2.186908 -0.798811 C49 7.021306 0.893056 1.567433 H50 4.907147 0.614727 1.879650 C51 7.650738 2.047328 -0.456098 H52 6.012775 2.710754 -1.701851 C53 8.015242 1.401710 0.728515 H54 7.293041 0.407358 2.500226 H55 8.415144 2.460689 -1.107811 H56 9.061692 1.310494 1.002674

(2E,5Z,5'Z)-N5,N5'-Βis(4-n-butylphenyl)-4,4'-diphenyl-5H,5'H-(2,2'-bithiazolylidene)-5,5'-

diimine 182b


C1 -2.695426 -1.356565 -0.017049 C2 -1.502578 -2.232768 -0.196932 C3 -0.455066 -0.252316 -0.147415 C4 2.883872 1.683701 -0.255511 C5 1.685235 2.562403 -0.144905 C6 0.639683 0.581176 -0.178921 N7 -3.884182 -1.790572 0.167902 N8 4.089509 2.107386 -0.199910 C9 -5.033610 -1.015171 0.335127 C10 -6.029786 -1.533754 1.183478 C11 -5.285576 0.199446 -0.330085 C12 -7.210165 -0.834679 1.399679 H13 -5.841851 -2.480664 1.679206 C14 -6.486035 0.874480 -0.124280 H15 -4.563387 0.595549 -1.035312 C16 -7.464852 0.383017 0.749477

H17 -7.954573 -1.242717 2.079046 H18 -6.665355 1.806572 -0.654683 C19 -1.526650 -3.701939 -0.298431 C20 -2.706898 -4.443000 -0.496196 C21 -0.300051 -4.395062 -0.216537 C22 -2.655453 -5.831479 -0.605019 H23 -3.653692 -3.924778 -0.557051 C24 -0.258549 -5.779284 -0.322682 H25 0.609948 -3.826043 -0.067053 C26 -1.437397 -6.505504 -0.517971 H27 -3.574974 -6.387969 -0.760816 H28 0.694382 -6.295415 -0.252132 H29 -1.404207 -7.587983 -0.601716 C30 1.708511 4.032784 -0.066447 C31 2.838337 4.804789 -0.395810 C32 0.529477 4.697034 0.333050 C33 2.784877 6.195500 -0.322770 H24 3.749074 4.308819 -0.701140

MARIA KOYIONI

242

C35 0.486458 6.083394 0.407462 H36 -0.342207 4.103970 0.583710 C37 1.615212 6.840516 0.079263 H38 3.664025 6.776984 -0.584416 H39 -0.428219 6.576676 0.722816 H40 1.580875 7.924679 0.136507 N41 -0.353635 -1.602010 -0.245087 N42 0.536448 1.931820 -0.094319 S43 -2.115100 0.357616 0.005086 S44 2.298571 -0.026140 -0.354431 C25 5.248050 1.335027 -0.299591 C46 6.372113 1.787804 0.417183 C47 5.387871 0.194490 -1.112695 C48 7.572862 1.092347 0.365786 H49 6.270872 2.685668 1.018170 C50 6.606419 -0.476938 -1.174177 H51 4.562672 -0.139747 -1.731656 C52 7.716095 -0.055276 -0.430050 H53 8.423106 1.452933 0.939581 H54 6.698470 -1.345771 -1.821315 C55 -9.876539 0.648422 -0.034250 H56 -10.028640 -0.433086 0.081868 H57 -9.526055 0.795841 -1.064558 C58 -11.208620 1.380150 0.167025

H59 -11.550443 1.231680 1.200427 H60 -11.048891 2.461090 0.053567 C61 9.133600 -1.866665 0.667923 H62 8.290413 -2.566714 0.597437 H63 9.026443 -1.360608 1.636729 C64 10.454122 -2.645056 0.637163 H65 10.555957 -3.146717 -0.334816 H66 11.292639 -1.938274 0.702113 C67 9.017932 -0.823253 -0.461886 H68 9.121631 -1.331023 -1.428900 H69 9.859700 -0.122866 -0.386611 C70 -8.776333 1.110271 0.942930 H71 -8.620112 2.189324 0.819676 H72 -9.129362 0.962866 1.971477 C73 10.568495 -3.679255 1.761020 H74 11.519815 -4.218803 1.712439 H75 10.506146 -3.202924 2.745923 H76 9.762722 -4.419507 1.701761 C77 -12.300165 0.919874 -0.803788 H78 -13.238180 1.458667 -0.635454 H79 -12.001898 1.088690 -1.844632 H80 -12.506188 -0.150356 -0.689772

(2E,5Z,5'Z)-N5,N5'-Βis(4-methoxyphenyl)-4,4'-diphenyl-5H,5'H-(2,2'-bithiazolylidene)-

5,5'-diimine 182c


C1 3.050189 0.900455 -0.111208 C2 2.060756 2.010294 -0.068672 C3 0.622548 0.293345 -0.020751 C4 -3.050149 -0.900404 0.111214 C5 -2.060715 -2.010242 0.068659 C6 -0.622504 -0.293298 0.020732 N7 4.318317 1.073608 -0.059396 N8 -4.318276 -1.073571 0.059394 C9 5.310475 0.098095 -0.090351 C10 6.539347 0.442607 0.500794 C11 7.609951 -0.444565 0.532225 H12 6.629115 1.424273 0.954301 C13 6.277563 -2.047473 -0.704847 C14 7.483166 -1.702733 -0.073845 H15 8.532835 -0.146905 1.015085 H16 6.207632 -3.014987 -1.190675 N17 0.803895 1.637335 -0.008003 N18 -0.803854 -1.637288 0.007983 S19 2.120817 -0.653546 -0.119396 S20 -2.120773 0.653594 0.119377 C21 -5.310466 -0.098089 0.090363 C22 -6.539303 -0.442610 -0.500844 C23 -7.609941 0.444523 -0.532258 H24 -6.629024 -1.424251 -0.954415 C25 -6.277656 2.047406 0.704956 C26 -7.483226 1.702653 0.073895 H27 -8.532791 0.146864 -1.015187 H28 -6.207786 3.014897 1.190840 C29 -2.387674 -3.447133 0.065514 C30 -3.649435 -3.951933 0.431229

C31 -1.374162 -4.360222 -0.293832 C32 -3.884284 -5.325729 0.431422 H33 -4.435291 -3.263280 0.708245 C34 -1.618014 -5.727848 -0.295498 H35 -0.400466 -3.973510 -0.570630 C36 -2.875921 -6.218238 0.067646 H37 -4.862164 -5.699162 0.721183 H38 -0.826506 -6.414657 -0.580651 C39 2.387706 3.447188 -0.065554 C40 3.649483 3.951987 -0.431215 C41 1.374168 4.360282 0.293710 C42 3.884323 5.325785 -0.431432 H43 4.435359 3.263332 -0.708170 C44 1.618010 5.727909 0.295351 H45 0.400459 3.973571 0.570467 C46 2.875933 6.218298 -0.067738 H47 4.862217 5.699217 -0.721149 H48 0.826481 6.414721 0.580440 C49 5.206199 -1.168295 -0.708909 H50 4.300768 -1.449628 -1.233756 C51 -5.206260 1.168272 0.709001 H52 -4.300858 1.449610 1.233894 H53 3.066008 7.287777 -0.067769 H54 -3.066003 -7.287716 0.067657 O55 -8.464360 2.646033 0.117201 O56 8.464255 -2.646166 -0.117114 C57 -9.711130 2.352124 -0.496119 H58 -10.335066 3.233885 -0.345161 H59 -9.598805 2.169049 -1.572113 H60 -10.194975 1.483618 -0.031906 C61 9.711013 -2.352358 0.496278 H62 9.598644 -2.169330 1.572277

MARIA KOYIONI

243

H63 10.334911 -3.234144 0.345310 H64 10.194925 -1.483854 0.032133

(2E,5Z,5'Z)-N5,N5'-Βis(4-n-butoxyphenyl)-4,4'-diphenyl-5H,5'H-(2,2'-bithiazolylidene)-

5,5'-diimine 182d


C1 -2.820396 -1.473061 -0.326486 C2 -1.634825 -2.369999 -0.362892 C3 -0.554247 -0.407954 -0.358979 C4 2.820626 1.473674 -0.326564 C5 1.635070 2.370647 -0.362754 C6 0.554456 0.408619 -0.358980 N7 -4.025210 -1.889852 -0.201905 N8 4.025466 1.890394 -0.201997 C9 -5.187739 -1.126372 -0.154863 C10 -6.287322 -1.709562 0.500461 C11 -5.370029 0.142486 -0.749885 C12 -7.505081 -1.048254 0.616577 H13 -6.156292 -2.694678 0.936163 C14 -6.589011 0.795877 -0.661583 H15 -4.571646 0.600517 -1.322045 C16 -7.663643 0.217601 0.033049 H17 -8.320468 -1.524562 1.147074 H18 -6.738328 1.763574 -1.128852 C19 -1.678675 -3.842827 -0.370872 C20 -2.834800 -4.577726 -0.692758 C21 -0.493817 -4.546287 -0.069290 C22 -2.801056 -5.970978 -0.707398 H23 -3.749967 -4.050870 -0.924307 C24 -0.470116 -5.935344 -0.081134 H25 0.398287 -3.981310 0.174557 C26 -1.624954 -6.655579 -0.400843 H27 -3.700692 -6.523276 -0.962931 H28 0.450103 -6.459344 0.160030 H29 -1.605845 -7.741613 -0.411318 C30 1.678954 3.843473 -0.370592 C31 2.835132 4.578371 -0.692294 C32 0.494087 4.546939 -0.069050 C33 2.801429 5.971626 -0.706798 H34 3.750308 4.051511 -0.923800 C35 0.470427 5.935997 -0.080764 H36 -0.398055 3.981963 0.174659 C37 1.625316 6.656231 -0.400293 H38 3.701107 6.523922 -0.962187 H39 -0.449801 6.460000 0.160361 H40 1.606238 7.742266 -0.410666

N41 -0.471880 -1.761880 -0.364771 N42 0.472113 1.762546 -0.364604 S43 -2.210405 0.231463 -0.366003 S44 2.210600 -0.230834 -0.366220 C45 5.187919 1.126757 -0.155149 C46 6.287460 1.709419 0.500703 C47 5.370138 -0.141761 -0.750905 C48 7.505096 1.047849 0.616669 H49 6.156504 2.694304 0.936950 C50 6.589008 -0.795385 -0.662766 H51 4.571787 -0.599316 -1.323492 C52 7.663581 -0.217688 0.032435 H53 8.320459 1.523720 1.147596 H54 6.738273 -1.762822 -1.130591 O55 8.807685 -0.952849 0.069850 O56 -8.807870 0.952556 0.070665 C57 9.943641 -0.431809 0.762111 H58 9.686684 -0.245180 1.814879 H59 10.247355 0.526035 0.315489 C60 11.063483 -1.456526 0.654229 H61 10.708043 -2.408210 1.067958 H62 11.275292 -1.635353 -0.407052 C63 12.339860 -1.011627 1.378559 H64 12.113710 -0.826735 2.437341 H65 12.678702 -0.051136 0.967261 C66 13.471176 -2.038365 1.271492 H67 14.369115 -1.696781 1.795672 H68 13.175827 -2.999307 1.706987 H69 13.743701 -2.219142 0.225874 C70 -9.943993 0.430754 0.762081 H71 -9.687467 0.243551 1.814853 H72 -10.247208 -0.526903 0.314723 C73 -11.064099 1.455193 0.654316 H74 -10.709195 2.406708 1.068891 H75 -11.275408 1.634679 -0.406953 C76 -12.340713 1.009366 1.377665 H77 -12.115058 0.823810 2.436436 H78 -12.679010 0.049050 0.965514 C79 -13.472315 2.035800 1.270714 H80 -14.370400 1.693575 1.794225 H81 -13.177497 2.996552 1.706988 H82 -13.744383 2.217177 0.225081

MARIA KOYIONI

244

4,4'-{[(2E,5Z,5'Z)-4,4'-Diphenyl-5H,5'H-(2,2'-bithiazolylidene)-5,5'-diylidene]bis(azanyl-

ylidene)}bis(N,N-diethylaniline) 182e


C1 2.819680 -1.450707 0.102473 C2 1.644465 -2.351778 0.043474 C3 0.545224 -0.401011 -0.015487 C4 -2.843041 1.460570 -0.151884 C5 -1.667447 2.361758 -0.094837 C6 -0.569230 0.409575 -0.059799 N7 4.035510 -1.862905 0.085485 N8 -4.059205 1.867978 -0.105648 C9 5.204691 -1.121889 0.124535 C10 6.382113 -1.803617 -0.247035 C11 5.351569 0.221637 0.533272 C12 7.620572 -1.186732 -0.261425 H13 6.293603 -2.847983 -0.529200 C14 6.590698 0.843055 0.532891 H15 4.498486 0.788322 0.886362 C16 7.767099 0.171603 0.116244 H17 8.482967 -1.781365 -0.533938 H18 6.638411 1.879697 0.842070 N19 0.476168 -1.753883 -0.029401 N20 -0.499228 1.762384 -0.036323 S21 2.193411 0.248989 0.089762 S22 -2.217409 -0.240063 -0.169364 C23 -5.219933 1.111906 -0.151941 C24 -6.386306 1.721357 0.350798 C25 -5.360999 -0.187220 -0.685345 C26 -7.608479 1.071075 0.369047 H27 -6.299455 2.722855 0.760240 C28 -6.586977 -0.833470 -0.697415 H29 -4.514938 -0.689463 -1.139542 C30 -7.757882 -0.232117 -0.170743 H31 -8.450693 1.586433 0.810472 H32 -6.628532 -1.822588 -1.134761 N33 8.991399 0.830051 0.090679 N34 -8.993157 -0.873578 -0.211948 C35 -1.718799 3.835475 -0.074556 C36 -2.857487 4.573206 -0.447468 C37 -0.557952 4.537740 0.310877 C38 -2.830888 5.966743 -0.428960 H39 -3.754183 4.047109 -0.743797 C40 -0.541032 5.926992 0.331056 H41 0.321616 3.970857 0.592877

C42 -1.678886 6.649875 -0.039193 H43 -3.717398 6.520564 -0.724415 H44 0.361064 6.449182 0.636614 C45 1.694887 -3.825946 0.036424 C46 2.822804 -4.561820 0.443777 C47 0.542761 -4.529993 -0.370854 C48 2.794510 -5.955414 0.437252 H49 3.712197 -4.033934 0.758119 C50 0.524242 -5.919439 -0.379458 H51 -0.328937 -3.964486 -0.678911 C52 1.651493 -6.640483 0.024972 H53 3.672431 -6.507843 0.759774 H54 -0.370821 -6.443091 -0.702678 C55 -10.134934 -0.214102 0.434336 H56 -10.162987 0.817998 0.071799 H57 -9.990602 -0.156863 1.526353 C58 -11.498381 -0.837217 0.139241 H59 -12.273110 -0.190373 0.561798 H60 -11.678972 -0.915833 -0.937217 H61 -11.623537 -1.826875 0.587216 C62 -9.043416 -2.323728 -0.408833 H63 -8.420878 -2.582721 -1.269163 H64 -10.059329 -2.589057 -0.703932 C65 -8.625068 -3.147045 0.816853 H66 -8.678529 -4.218073 0.594141 H67 -7.600831 -2.911951 1.119417 H68 -9.282644 -2.947237 1.669264 C69 10.188486 0.163135 -0.422248 H70 9.872278 -0.578415 -1.156414 H71 10.707659 -0.384161 0.383160 C72 9.203569 1.996684 0.954947 H73 8.546833 1.912468 1.827336 H74 10.226197 1.943817 1.346059 C75 11.175398 1.103285 -1.119371 H76 11.588928 1.858619 -0.445261 H77 12.015306 0.518068 -1.507061 H78 10.698562 1.615790 -1.959851 C79 8.987998 3.351691 0.269142 H80 9.686553 3.493562 -0.559301 H81 7.975182 3.437002 -0.133974 H82 9.139530 4.165688 0.986701 H83 1.636628 -7.726706 0.019342 H84 -1.665217 7.736028 -0.024530

(2E,5Z,5'Z)-4,4'-Diphenyl-N5,N5'-bis[4-(trifluoromethyl)phenyl]-5H,5'H-(2,2'-bithiazol-

ylidene)-5,5'-diimine 182f


C1 2.840014 1.415204 -0.067594 C2 1.670318 2.344359 -0.058155 C3 0.561260 0.397348 -0.014096 C4 -2.840011 -1.415199 0.067594 C5 -1.670315 -2.344354 0.058150 C6 -0.561256 -0.397343 0.014094

N7 4.060616 1.789109 0.001201 N8 -4.060614 -1.789104 -0.001201 C9 5.168809 0.938645 -0.020248 C10 6.230815 1.241067 0.852042 C11 7.376455 0.457435 0.866074 H12 6.129133 2.091264 1.517768 C13 6.468598 -0.904352 -0.915443 C14 7.500795 -0.619575 -0.018965

MARIA KOYIONI

245

H15 8.186258 0.690547 1.548806 H16 6.577527 -1.721975 -1.619390 N17 0.500838 1.752909 -0.016176 N18 -0.500834 -1.752905 0.016171 S19 2.203370 -0.274510 -0.074256 S20 -2.203366 0.274515 0.074253 C21 -5.168809 -0.938642 0.020251 C22 -6.230817 -1.241069 -0.852034 C23 -7.376459 -0.457441 -0.866063 H24 -6.129135 -2.091268 -1.517759 C25 -6.468600 0.904353 0.915447 C26 -7.500799 0.619571 0.018973 H27 -8.186264 -0.690557 -1.548792 H28 -6.577529 1.721977 1.619393 C29 -1.744397 -3.813442 0.068185 C30 -2.929587 -4.524649 0.336248 C31 -0.560727 -4.540993 -0.181694 C32 -2.924762 -5.917963 0.349289 H33 -3.844237 -3.981012 0.527528 C34 -0.566363 -5.929468 -0.170395 H35 0.353162 -3.995330 -0.384671 C36 -1.749722 -6.625559 0.095586 H37 -3.846197 -6.451964 0.561237 H38 0.352701 -6.472460 -0.369262 C39 1.744401 3.813446 -0.068194

C40 2.929590 4.524651 -0.336260 C41 0.560732 4.540998 0.181686 C42 2.924767 5.917965 -0.349306 H43 3.844239 3.981013 -0.527541 C44 0.566369 5.929473 0.170383 H45 -0.353157 3.995337 0.384666 C46 1.749728 6.625562 -0.095602 H47 3.846203 6.451964 -0.561257 H48 -0.352694 6.472467 0.369251 C49 5.307929 -0.136553 -0.917421 H50 4.525018 -0.347123 -1.637419 C51 -5.307928 0.136558 0.917422 H52 -4.525015 0.347132 1.637417 H53 1.753189 7.711574 -0.105314 H54 -1.753182 -7.711571 0.105295 C55 -8.723800 1.492064 -0.029989 C56 8.723792 -1.492073 0.030000 F57 -8.595388 2.484637 -0.942534 F58 -9.827864 0.790059 -0.372064 F59 8.970332 -2.084681 -1.159896 F60 9.827857 -0.790075 0.372085 F61 8.595371 -2.484650 0.942540 F62 -8.970336 2.084676 1.159906

4,4'-{[(2E,5Z,5'Z)-4,4'-Diphenyl-5H,5'H-(2,2'-bithiazolylidene)-5,5'-diylidene]bis(azanyl-

ylidene)}dibenzonitrile 182g


C1 3.023138 0.958895 -0.055992 C2 2.012944 2.058287 -0.093972 C3 0.615637 0.306611 -0.091573 C4 -3.023135 -0.958885 -0.056166 C5 -2.012950 -2.058283 -0.094101 C6 -0.615629 -0.306618 -0.091615 N7 4.283390 1.139490 0.068243 N8 -4.283387 -1.139491 0.068120 C9 5.245041 0.129747 0.086511 C10 6.288993 0.247667 1.024208 C11 5.265610 -0.940068 -0.829633 C12 7.296305 -0.702690 1.083085 H13 6.279328 1.089734 1.707581 C14 6.287952 -1.879604 -0.788043 H15 4.497927 -1.014807 -1.591676 C16 7.305672 -1.777748 0.175041 H17 8.087433 -0.617587 1.820146 H18 6.305493 -2.696663 -1.501283 C19 2.316380 3.496660 -0.102112 C20 3.601576 4.011834 -0.358117 C21 1.258804 4.401398 0.133922 C22 3.815628 5.388416 -0.373898 H23 4.422121 3.331737 -0.539401 C24 1.482535 5.771691 0.120717 H25 0.268753 4.006790 0.329361 C26 2.763254 6.272240 -0.134026 H27 4.811330 5.770839 -0.577139 H28 0.658600 6.452989 0.310159

H29 2.937280 7.344184 -0.145411 C30 -2.316384 -3.496657 -0.102160 C31 -3.601592 -4.011845 -0.358083 C32 -1.258799 -4.401384 0.133883 C33 -3.815643 -5.388427 -0.373794 H34 -4.422141 -3.331754 -0.539371 C35 -1.482530 -5.771678 0.120748 H36 -0.268741 -4.006768 0.329263 C37 -2.763259 -6.272240 -0.133922 H38 -4.811352 -5.770859 -0.576981 H39 -0.658587 -6.452965 0.310187 H40 -2.937285 -7.344185 -0.145252 N41 0.765098 1.654805 -0.097749 N42 -0.765099 -1.654806 -0.097786 S43 2.135897 -0.610973 -0.097517 S44 -2.135892 0.610971 -0.097637 C45 -5.245052 -0.129753 0.086399 C46 -6.288963 -0.247674 1.024150 C47 -5.265637 0.940083 -0.829711 C48 -7.296279 0.702667 1.083068 H49 -6.279242 -1.089735 1.707531 C50 -6.287985 1.879618 -0.788073 H51 -4.497969 1.014859 -1.591764 C52 -7.305677 1.777738 0.175028 H53 -8.087392 0.617561 1.820144 H54 -6.305509 2.696724 -1.501260 C55 8.352323 -2.754120 0.223207 C56 -8.352333 2.754101 0.223267 N57 -9.202401 3.547928 0.263157 N58 9.202429 -3.547916 0.262897

MARIA KOYIONI

246

(2E,5Z,5'Z)-N5,N5'-Bis(4-nitrophenyl)-4,4'-diphenyl-5H,5'H-(2,2'-bithiazolylidene)-5,5'-di-

imine 182h


C1 2.918641 1.237106 -0.054679 C2 1.810258 2.238518 -0.089071 C3 0.583936 0.363368 -0.083914 C4 -2.918638 -1.237102 -0.054667 C5 -1.810255 -2.238514 -0.089059 C6 -0.583933 -0.363364 -0.083908 N7 4.157817 1.532080 0.060940 N8 -4.157815 -1.532079 0.060941 C9 5.205181 0.612602 0.068399 C10 6.222036 0.792725 1.027215 C11 5.329418 -0.420763 -0.882508 C12 7.309963 -0.065815 1.071465 H13 6.128911 1.607675 1.736451 C14 6.429134 -1.269334 -0.856219 H15 4.578642 -0.537105 -1.656031 C16 7.400963 -1.089611 0.126705 H17 8.092520 0.045008 1.811276 H18 6.547751 -2.064646 -1.581231 C19 1.979280 3.698214 -0.096131 C20 3.211200 4.329746 -0.353785 C21 0.843155 4.501203 0.143908 C22 3.297747 5.720102 -0.366825 H23 4.090621 3.728811 -0.538758 C24 0.940082 5.886236 0.133459 H25 -0.106038 4.016787 0.340474 C26 2.168987 6.502735 -0.122478 H27 4.253504 6.192964 -0.571323 H28 0.057499 6.488598 0.325936 H29 2.243723 7.586139 -0.131564

C30 -1.979278 -3.698210 -0.096126 C31 -3.211193 -4.329739 -0.353813 C32 -0.843160 -4.501200 0.143939 C33 -3.297741 -5.720094 -0.366861 H34 -4.090608 -3.728802 -0.538806 C35 -0.940089 -5.886233 0.133483 H36 0.106028 -4.016785 0.340531 C37 -2.168988 -6.502730 -0.122489 H38 -4.253492 -6.192955 -0.571386 H39 -0.057512 -6.488597 0.325980 H40 -2.243725 -7.586134 -0.131580 N41 0.605802 1.719633 -0.090588 N42 -0.605800 -1.719630 -0.090583 S43 2.183410 -0.407827 -0.090598 S44 -2.183407 0.407831 -0.090571 C45 -5.205179 -0.612604 0.068399 C46 -6.222055 -0.792753 1.027190 C47 -5.329399 0.420786 -0.882483 C48 -7.309983 0.065785 1.071441 H49 -6.128942 -1.607721 1.736406 C50 -6.429117 1.269354 -0.856194 H51 -4.578609 0.537149 -1.655989 C52 -7.400965 1.089605 0.126706 H53 -8.092555 -0.045058 1.811233 H54 -6.547720 2.064686 -1.581188 N55 8.556183 -1.992344 0.161146 N56 -8.556187 1.992337 0.161147 O57 -9.403954 1.803749 1.034658 O58 -8.610198 2.886380 -0.684618 O59 8.610211 -2.886365 -0.684641 O60 9.403928 -1.803785 1.034685

(2E,5Z,5'Z)-4,4'-Diphenyl-N5,N5'-di(pyrid-2-yl)-5H,5'H-(2,2'-bithiazolylidene)-5,5'-diimine

182i


C1 -3.161993 0.017382 0.025295 C2 -2.527473 1.364620 0.044786 C3 -0.681086 0.108060 0.039466 C4 3.161942 -0.017369 0.025261 C5 2.527422 -1.364605 0.044763 C6 0.681035 -0.108048 0.039448 N7 -4.438474 -0.163967 -0.020235 N8 4.438430 0.163960 -0.020220 C9 -5.026561 -1.421112 -0.054718 C10 -6.431144 -1.478737 -0.148198 C11 -7.047196 -2.721485 -0.185518 H12 -6.994207 -0.553521 -0.191720 H13 -8.128131 -2.796368 -0.258229 C14 -3.236478 2.656918 0.047584 C15 -4.614268 2.786302 0.304975 C16 -2.483827 3.825802 -0.195704 C17 -5.212858 4.044773 0.316489 H18 -5.201226 1.897887 0.489727

C19 -3.089576 5.075765 -0.187456 H20 -1.422362 3.729041 -0.390646 C21 -4.458935 5.192075 0.069585 H22 -6.276295 4.127231 0.521471 H23 -2.494025 5.962802 -0.382273 H24 -4.932250 6.169752 0.077162 C25 3.236444 -2.656891 0.047569 C26 4.614253 -2.786230 0.304877 C27 2.483806 -3.825803 -0.195631 C28 5.212875 -4.044686 0.316407 H29 5.201202 -1.897792 0.489552 C30 3.089586 -5.075750 -0.187368 H31 1.422327 -3.729076 -0.390513 C32 4.458964 -5.192016 0.069597 H33 6.276326 -4.127109 0.521326 H34 2.494045 -5.962810 -0.382112 H35 4.932303 -6.169682 0.077186 N36 -1.214292 1.356655 0.044125 N37 1.214241 -1.356643 0.044112 S38 -1.866856 -1.217298 0.039677

MARIA KOYIONI

247

S39 1.866804 1.217312 0.039616 C40 5.026565 1.421084 -0.054706 C41 6.431154 1.478650 -0.148135 H42 6.994179 0.553409 -0.191623 C43 4.873443 3.718320 -0.036097 H44 4.221363 4.588238 0.011169 C45 7.047260 2.721372 -0.185453 H46 8.128201 2.796207 -0.258129 C47 -4.873341 -3.718340 -0.036076

H48 -4.221227 -4.588229 0.011223 C49 -6.256143 -3.873102 -0.127980 H50 -6.696407 -4.864198 -0.153283 C51 6.256255 3.873023 -0.127956 H52 6.696561 4.864100 -0.153257 N53 -4.267821 -2.528502 -0.000045 N54 4.267873 2.528507 -0.000074


182j


C1 -3.175774 -0.044685 -0.052673 C2 -2.523509 -1.386503 -0.085485 C3 -0.678081 -0.115676 -0.077604 C4 3.175775 0.044686 -0.052673 C5 2.523510 1.386504 -0.085485 C6 0.678082 0.115677 -0.077604 N7 -4.436837 0.137320 0.062751 N8 4.436838 -0.137319 0.062751 C9 -5.091780 1.366775 0.096324 C10 -6.253204 1.445985 0.893389 H11 -6.557887 0.564845 1.454307 C12 -6.635070 3.623694 0.317634 C13 -3.227736 -2.678339 -0.094074 C14 -4.602033 -2.805932 -0.371405 C15 -2.478468 -3.846270 0.163874 C16 -5.201565 -4.063675 -0.386628 H17 -5.189664 -1.920197 -0.568032 C18 -3.085357 -5.095310 0.151221 H19 -1.420186 -3.750088 0.376057 C20 -4.451347 -5.210209 -0.124841 H21 -6.261853 -4.145911 -0.606055 H22 -2.494370 -5.982429 0.358364 H23 -4.925461 -6.187316 -0.135407 C24 3.227737 2.678340 -0.094074 C25 4.602034 2.805932 -0.371404 C26 2.478469 3.846271 0.163873

C27 5.201567 4.063676 -0.386627 H28 5.189666 1.920197 -0.568030 C29 3.085359 5.095311 0.151220 H30 1.420187 3.750089 0.376054 C31 4.451348 5.210209 -0.124841 H32 6.261855 4.145911 -0.606053 H33 2.494372 5.982430 0.358361 H34 4.925463 6.187316 -0.135407 N35 -1.212185 -1.362544 -0.083828 N36 1.212186 1.362545 -0.083828 S37 -1.868300 1.201650 -0.089171 S38 1.868301 -1.201649 -0.089173 C39 5.091780 -1.366776 0.096324 C40 6.253200 -1.445990 0.893394 H41 6.557882 -0.564852 1.454316 C42 6.635065 -3.623698 0.317633 H43 7.265626 -4.503261 0.428216 H44 -7.265633 4.503257 0.428216 C45 4.738101 -2.507446 -0.644243 H46 3.889845 -2.491202 -1.319868 C47 -4.738100 2.507448 -0.644238 H48 -3.889841 2.491208 -1.319859 C49 5.527094 -3.648632 -0.529151 H50 5.289434 -4.544474 -1.094139 C51 -5.527095 3.648633 -0.529146 H52 -5.289434 4.544477 -1.094129 N53 6.999730 -2.540698 1.020398 N54 -6.999736 2.540692 1.020393


182k


C1 -3.169567 -0.086391 -0.020375 C2 -2.501796 -1.423727 -0.053819 C3 -0.676210 -0.123747 -0.045877 C4 3.169611 0.086410 -0.020118 C5 2.501798 1.423746 -0.053381 C6 0.676234 0.123716 -0.045756 N7 -4.429803 0.094952 0.084657 N8 4.429849 -0.094973 0.084719 C9 -5.049191 1.347375 0.095615 C10 -6.009297 1.615745 1.083489

C11 -6.655971 2.847453 1.070432 H12 -6.225792 0.873190 1.843645 H13 -7.389906 3.080507 1.839620 C14 -3.190659 -2.722585 -0.065097 C15 -4.573750 -2.859374 -0.291070 C16 -2.419300 -3.887294 0.138741 C17 -5.160018 -4.123223 -0.310291 H18 -5.178166 -1.976360 -0.445570 C19 -3.013176 -5.142264 0.121935 H20 -1.354563 -3.784012 0.311491 C21 -4.387796 -5.266420 -0.103513 H22 -6.227200 -4.212905 -0.489545

MARIA KOYIONI

248

H23 -2.405292 -6.026964 0.285574 H24 -4.851483 -6.248446 -0.117648 C25 3.190626 2.722620 -0.064868 C26 4.573826 2.859364 -0.290214 C27 2.419132 3.887395 0.138105 C28 5.160070 4.123221 -0.309635 H29 5.178341 1.976302 -0.444057 C30 3.012980 5.142373 0.121087 H31 1.354311 3.784156 0.310363 C32 4.387713 5.266479 -0.103712 H33 6.227342 4.212858 -0.488373 H34 2.404985 6.027121 0.284048 H35 4.851377 6.248514 -0.118016 N36 -1.191832 -1.379636 -0.053594 N37 1.191839 1.379611 -0.053335 S38 -1.884224 1.177979 -0.051713 S39 1.884247 -1.178000 -0.051288

C40 5.049186 -1.347450 0.095490 C41 6.009187 -1.615989 1.083516 H42 6.225478 -0.873520 1.843814 C43 5.550821 -3.519905 -0.806444 H44 5.398016 -4.290482 -1.560000 C45 4.826270 -2.331222 -0.881632 H46 4.128178 -2.163229 -1.694320 C47 -4.826103 2.331415 -0.881328 H48 -4.127875 2.163477 -1.693909 C49 6.655878 -2.847599 1.070333 H50 7.389629 -3.080939 1.839599 C51 -5.550610 3.520000 -0.806080 H52 -5.397636 4.290855 -1.559305 N53 6.447364 -3.798404 0.147688 N54 -6.447335 3.798373 0.148066

(2E,5Z,5'Z)-N5,N5'-Bis[9-(2-ethylhexyl)-9H-carbazol-3-yl]-4,4'-diphenyl-5H,5'H-(2,2'-

bithiazolylidene)-5,5'-diimine 182l


C1 -2.997276 -0.689002 -0.898545 C2 -2.123455 -1.893657 -0.874750 C3 -0.522034 -0.328277 -0.902634 C4 3.249936 0.497860 -0.852388 C5 2.375228 1.698803 -0.941237 C6 0.776206 0.131057 -0.900918 N7 -4.272748 -0.729806 -0.792595 N8 4.521645 0.549322 -0.713472 C9 -5.148843 0.354691 -0.812149 C10 -6.324053 0.201118 -0.055361 C11 -4.945579 1.529667 -1.580753 C12 -7.241855 1.247233 -0.026985 H13 -6.463754 -0.719782 0.497677 C14 -5.881810 2.554300 -1.568478 H15 -4.075814 1.609321 -2.221680 C16 -7.031671 2.437670 -0.779009 C17 -2.594123 -3.288942 -0.835328 C18 -3.914129 -3.666041 -1.145153 C19 -1.666526 -4.295827 -0.494606 C20 -4.288890 -5.007943 -1.109061 H21 -4.635365 -2.904347 -1.406613 C22 -2.049719 -5.630604 -0.456532 H23 -0.648669 -4.007349 -0.259714 C24 -3.364415 -5.993863 -0.763778 H25 -5.310324 -5.282807 -1.355535 H26 -1.323011 -6.390905 -0.185786 H27 -3.663335 -7.037767 -0.734951 C28 2.843953 3.094270 -0.994791 C29 4.172621 3.449595 -1.293229 C30 1.905904 4.122167 -0.762804 C31 4.545301 4.791246 -1.352756 H32 4.901768 2.671576 -1.471603 C33 2.287031 5.456903 -0.819435 H34 0.881482 3.850220 -0.536810 C35 3.610095 5.798635 -1.115272 H36 5.573438 5.048817 -1.589935 H37 1.551999 6.234140 -0.632062

H38 3.907139 6.842472 -1.161095 N39 -0.834507 -1.648011 -0.865041 N40 1.086850 1.450868 -0.950261 S41 -1.920180 0.763065 -0.972851 S42 2.176534 -0.958951 -0.853188 C43 5.399587 -0.531381 -0.638805 C44 6.549765 -0.332033 0.145062 C45 5.225841 -1.746484 -1.350713 C46 7.469803 -1.371443 0.250383 H47 6.675584 0.616504 0.653924 C48 6.166986 -2.763380 -1.261455 H49 4.375171 -1.863811 -2.011357 C50 7.293857 -2.598080 -0.447866 H51 6.025356 -3.681163 -1.824751 C52 8.423218 -3.431959 -0.109482 C53 9.234460 -2.675712 0.781644 N54 8.649305 -1.428158 0.983936 C55 9.134084 -0.371022 1.858209 H56 9.832959 -0.824893 2.568184 H57 8.282215 -0.012373 2.449116 C58 9.814663 0.836151 1.171079 H59 9.068070 1.316801 0.522660 C60 10.206629 1.848843 2.270827 H61 11.101610 1.479600 2.793191 H62 9.411668 1.888693 3.028880 C63 10.459464 3.276328 1.768221 H64 11.233520 3.273201 0.989416 H65 9.546573 3.653796 1.286206 C66 10.879914 4.243364 2.882679 H67 11.794880 3.867400 3.360265 H68 10.110112 4.249741 3.666181 C69 11.113839 5.672401 2.384042 H70 11.413981 6.337239 3.200304 H71 11.902521 5.702540 1.623664 H72 10.205741 6.088499 1.933289 C73 11.029057 0.439653 0.296536 H74 11.575166 -0.376389 0.788629 H75 11.727151 1.284430 0.267242 C76 10.699771 0.046627 -1.148784

MARIA KOYIONI

249

H77 10.065923 -0.840848 -1.205011 H78 10.178885 0.861542 -1.664048 H79 11.616483 -0.165486 -1.708937 C80 10.413943 -3.206654 1.314174 C81 10.771029 -4.501653 0.945532 H82 11.682798 -4.932331 1.348860 C83 9.980691 -5.259250 0.063907 H84 10.290205 -6.264613 -0.203949 C85 8.808083 -4.730509 -0.465363 H86 11.039647 -2.636670 1.992706 H87 8.196130 -5.316891 -1.144793 C88 -8.158298 3.300863 -0.514897 C89 -8.516399 4.586167 -0.939306 C90 -9.001755 2.598910 0.388557 C91 -10.182085 3.170021 0.875513 H92 -10.823993 2.641277 1.572007 C93 -10.512311 4.451469 0.439408 H94 -11.424080 4.915167 0.804315 C95 -9.693156 5.154144 -0.461160 H96 -9.982087 6.149926 -0.782588 H97 -7.881055 5.133533 -1.629741 H98 -5.718453 3.442657 -2.171666 N99 -8.443257 1.355245 0.668307 C100 -9.021032 0.371137 1.573362 H101 -8.228023 -0.324859 1.860273

H102 -9.321028 0.892332 2.491012 C103 -10.239223 -0.392172 1.000375 H104 -10.943009 0.370917 0.639941 C105 -10.941448 -1.161753 2.137373 H106 -10.262623 -1.922604 2.546803 H107 -11.134876 -0.462470 2.963239 C108 -12.267845 -1.824076 1.741928 H109 -12.096289 -2.573417 0.958240 H110 -12.932254 -1.068495 1.298586 C111 -12.982039 -2.493555 2.923302 H112 -12.316207 -3.244931 3.369161 H113 -13.161990 -1.745768 3.707620 C114 -14.307840 -3.153319 2.533084 H115 -14.156563 -3.933136 1.778099 H116 -14.792764 -3.618199 3.397474 H117 -15.007048 -2.420801 2.114161 C118 -9.872474 -1.265085 -0.221664 H119 -10.796738 -1.536659 -0.744867 H120 -9.306524 -0.645894 -0.927191 C121 -9.082474 -2.545580 0.077580 H122 -9.665996 -3.258617 0.668619 H123 -8.802300 -3.045572 -0.854736 H124 -8.155904 -2.346766 0.625986

(2E,5Z,5'Z)-N5,N5'-Bis(4-n-butoxyphenyl)-4,4'-bis(4-(tert-butyl)phenyl)-5H,5'H-(2,2'-

bithiazolylidene)-5,5'-diimine 182m


C1 -2.964535 -1.157268 -0.226681 C2 -1.883668 -2.179319 -0.256484 C3 -0.595200 -0.346231 -0.247633 C4 2.964541 1.157269 -0.226665 C5 1.883674 2.179319 -0.256507 C6 0.595208 0.346231 -0.247641 N7 -4.209370 -1.437603 -0.114581 N8 4.209374 1.437603 -0.114534 C9 -5.278500 -0.546392 -0.082243 C10 -6.440138 -0.989903 0.574947 C11 -5.312691 0.725175 -0.697678 C12 -7.575316 -0.192154 0.672828 H13 -6.424859 -1.976337 1.026848 C14 -6.449803 1.514611 -0.627544 H15 -4.464352 1.080081 -1.271229 C16 -7.586358 1.073725 0.068765 H17 -8.441993 -0.563860 1.205679 H18 -6.485533 2.485228 -1.111011 C19 -2.086327 -3.636149 -0.267717 C20 -3.316980 -4.251151 -0.548113 C21 -0.978849 -4.471934 -0.011349 C22 -3.430896 -5.641048 -0.567362 H23 -4.183976 -3.636730 -0.747606 C24 -1.107899 -5.851211 -0.029321 H25 -0.019773 -4.014934 0.203301 C26 -2.337962 -6.477840 -0.308770 H27 -4.400819 -6.068015 -0.794410 H28 -0.229606 -6.454787 0.179177 C29 2.086328 3.636152 -0.267734

C30 3.316993 4.251162 -0.548060 C31 0.978827 4.471926 -0.011437 C32 3.430898 5.641061 -0.567305 H33 4.184006 3.636749 -0.747500 C34 1.107865 5.851206 -0.029416 H35 0.019743 4.014919 0.203159 C36 2.337938 6.477843 -0.308795 H37 4.400829 6.068036 -0.794301 H38 0.229553 6.454772 0.179031 N39 -0.660949 -1.700320 -0.253582 N40 0.660955 1.700322 -0.253607 S41 -2.172006 0.470319 -0.259258 S42 2.172014 -0.470316 -0.259285 C43 5.278501 0.546385 -0.082187 C44 6.440116 0.989864 0.575064 C45 5.312708 -0.725153 -0.697680 C46 7.575291 0.192110 0.672941 H47 6.424823 1.976276 1.027013 C48 6.449819 -1.514591 -0.627551 H49 4.464384 -1.080031 -1.271270 C50 7.586354 -1.073737 0.068812 H51 8.441949 0.563787 1.205842 H52 6.485565 -2.485184 -1.111066 O53 8.640435 -1.934606 0.087790 O54 -8.640438 1.934594 0.087758 C55 -9.834092 1.552161 0.772653 H56 -9.610851 1.353508 1.830893 H57 -10.237044 0.627213 0.335217 C58 -10.832813 2.692122 0.635406 H59 -10.383963 3.603783 1.048312 H60 -11.003297 2.881730 -0.431462

MARIA KOYIONI

250

C61 -12.164447 2.396800 1.336584 H62 -11.981836 2.201370 2.401867 H63 -12.596629 1.473732 0.927202 C64 -13.175151 3.538641 1.194437 H65 -14.116350 3.301901 1.700294 H66 -12.787516 4.466762 1.628664 H67 -13.402940 3.736408 0.141209 C68 9.834084 -1.552190 0.772702 H69 9.610845 -1.353607 1.830956 H70 10.237014 -0.627206 0.335322 C71 10.832828 -2.692121 0.635376 H72 10.384013 -3.603810 1.048257 H73 11.003280 -2.881679 -0.431506 C74 12.164478 -2.396799 1.336522 H75 11.981897 -2.201403 2.401817 H76 12.596633 -1.473712 0.927155 C77 13.175195 -3.538620 1.194311 H78 14.116403 -3.301883 1.700154 H79 12.787585 -4.466762 1.628515 H80 13.402962 -3.736347 0.141070 C81 -2.433417 -8.012518 -0.319846 C82 -1.455338 -8.580281 -1.376241 H83 -0.420067 -8.294626 -1.169074 H84 -1.503128 -9.674921 -1.387806

H85 -1.707468 -8.218225 -2.378186 C86 -2.051780 -8.559301 1.076765 H87 -2.734700 -8.182191 1.844879 H88 -2.103691 -9.653846 1.083189 H89 -1.035916 -8.272439 1.363413 C90 -3.850667 -8.510456 -0.660039 H91 -4.589801 -8.167655 0.071281 H92 -4.172118 -8.179251 -1.652859 H93 -3.867169 -9.605042 -0.656637 C94 2.433395 8.012526 -0.319855 C95 3.850562 8.510461 -0.660405 H96 4.589873 8.167678 0.070743 H97 4.171765 8.179239 -1.653298 H98 3.867058 9.605048 -0.657020 C99 2.052139 8.559276 1.076868 H100 2.103504 9.653848 1.083137 H101 1.036560 8.271926 1.364036 H102 2.735615 8.182597 1.844698 C103 1.455048 8.580331 -1.375981 H104 1.706945 8.218338 -2.378007 H105 0.419828 8.294656 -1.168592 H106 1.502819 9.674972 -1.387495

(2E,5Z,5'Z)-4,4'-Bis[4-(tert-butyl)phenyl]-N5,N5'-bis(4-nitrophenyl)-5H,5'H-(2,2'-bithiazol-

ylidene)-5,5'-diimine 182n


C1 3.085569 0.730110 0.015873 C2 2.785880 -0.734489 0.018507 C3 0.686365 0.051611 0.003490 C4 -3.085108 -0.730296 -0.016346 C5 -2.785407 0.734282 -0.019117 C6 -0.685886 -0.051789 -0.004304 N7 4.258607 1.234266 -0.062341 N8 -4.258194 -1.234317 0.062428 C9 4.546359 2.597640 -0.027313 C10 5.456755 3.100680 -0.977895 C11 5.813179 4.440761 -0.972872 H12 5.862298 2.421956 -1.720029 C13 4.408881 4.799754 0.986110 C14 5.283987 5.277139 0.011679 H15 6.497001 4.849942 -1.705656 H16 4.035110 5.478342 1.742424 N17 1.506053 -1.027113 0.000903 N18 -1.505575 1.026921 -0.001642 S19 1.518927 1.620042 0.037269 S20 -1.518455 -1.620215 -0.038131 C21 -4.546368 -2.597576 0.027743 C22 -5.459150 -3.099348 0.976729 C23 -5.816113 -4.439280 0.972218 H24 -5.866089 -2.419710 1.717261 C25 -4.407522 -4.800745 -0.983240 C26 -5.285036 -5.276822 -0.010335 H27 -6.501766 -4.847475 1.703838 H28 -4.032328 -5.480217 -1.738055 C29 -3.780685 1.811206 -0.026184 C30 -5.159982 1.599892 -0.193065

C31 -3.332828 3.142482 0.123804 C32 -6.047295 2.674568 -0.208060 H33 -5.535336 0.592456 -0.308366 C34 -4.227050 4.199055 0.110070 H35 -2.272504 3.326165 0.251607 C36 -5.611878 3.997805 -0.057897 H37 -7.100895 2.461166 -0.343274 H38 -3.839404 5.205584 0.232502 C39 3.781169 -1.811393 0.025568 C40 5.160462 -1.600053 0.192463 C41 3.333341 -3.142672 -0.124480 C42 6.047796 -2.674711 0.207423 H43 5.535801 -0.592615 0.307806 C44 4.227585 -4.199226 -0.110779 H45 2.273021 -3.326371 -0.252303 C46 5.612409 -3.997952 0.057206 H47 7.101392 -2.461291 0.342644 H48 3.839963 -5.205759 -0.233250 C49 6.567270 -5.202070 0.071747 C50 -6.566712 5.201944 -0.072466 C51 6.173147 -6.151650 1.228832 H52 5.149640 -6.522355 1.123299 H53 6.841055 -7.019756 1.249504 H54 6.247226 -5.643423 2.195626 C55 8.036228 -4.784125 0.270150 H56 8.387799 -4.131610 -0.535650 H57 8.187884 -4.265645 1.222415 H58 8.673758 -5.673692 0.274961 C59 6.455545 -5.958402 -1.274177 H60 6.732303 -5.310554 -2.112156 H61 7.126669 -6.824241 -1.278331 H62 5.440659 -6.324014 -1.454891

MARIA KOYIONI

251

C63 -6.454770 5.958448 1.273344 H64 -5.439833 6.324005 1.453885 H65 -7.125829 6.824338 1.277466 H66 -6.731473 5.310731 2.111442 C67 -6.172737 6.151362 -1.229733 H68 -6.840665 7.019451 -1.250456 H69 -5.149227 6.522104 -1.124371 H70 -6.246917 5.642992 -2.196444 C71 -8.035710 4.784008 -0.270600 H72 -8.187486 4.265266 -1.222703 H73 -8.387229 4.131738 0.535420 H74 -8.673201 5.673603 -0.275596

C75 4.037359 3.461417 0.963755 H76 3.373773 3.073480 1.728379 C77 -4.035471 -3.462551 -0.961309 H78 -3.369915 -3.075656 -1.724743 N79 5.667341 6.691998 0.028463 N80 -5.668942 -6.691542 -0.026633 O81 6.449541 7.084014 -0.838851 O82 5.184155 7.406586 0.908159 O83 -5.184175 -7.407140 -0.904639 O84 -6.453184 -7.082427 0.839346

(2E,5Z,5'Z)-4,4'-Bis(4-(tert-butyl)phenyl)-N5,N5'-di(pyrid-2-yl)-5H,5'H-(2,2'-bithiazol-

ylidene)-5,5'-diimine 182o


C1 -2.485227 1.956429 -0.003363 C2 -2.829416 0.506376 -0.002698 C3 -0.600942 0.339206 -0.000635 C4 2.485145 -1.956344 0.003313 C5 2.829360 -0.506294 0.002554 C6 0.600892 -0.339085 0.000460 N7 -3.367698 2.898136 0.002516 N8 3.367615 -2.898060 -0.002325 C9 -3.039500 4.247011 0.005399 C10 -4.099898 5.174922 0.020386 C11 -3.801832 6.529980 0.023837 H12 -5.120204 4.809010 0.029597 C13 -1.479737 5.941361 -0.002254 C14 -2.462105 6.930657 0.012200 H15 -4.599188 7.267171 0.035443 H16 -0.424953 6.209034 -0.011598 N17 -1.794351 -0.304256 0.000261 N18 1.794309 0.304358 -0.000439 S19 -0.702327 2.114240 -0.005627 S20 0.702244 -2.114122 0.005480 C21 3.039463 -4.246951 -0.005067 C22 4.099903 -5.174822 -0.019582 C23 3.801897 -6.529894 -0.022887 H24 5.120197 -4.808869 -0.028538 C25 1.479771 -5.941373 0.002410 C26 2.462184 -6.930628 -0.011580 H27 4.599289 -7.267051 -0.034127 H28 0.424995 -6.209090 0.011484 C29 4.184598 0.067495 0.001063 C30 5.363741 -0.693699 0.057200 C31 4.316104 1.472456 -0.054531 C32 6.613453 -0.074854 0.057496 H33 5.292702 -1.771327 0.099403 C34 5.564177 2.072857 -0.054623 H35 3.418799 2.078192 -0.097749 C36 6.751963 1.317570 0.001617 H37 7.492301 -0.707351 0.103070 H38 5.615467 3.156579 -0.099395

C39 -4.184636 -0.067453 -0.001189 C40 -5.363787 0.693636 -0.058598 C41 -4.316100 -1.472367 0.055604 C42 -6.613470 0.074729 -0.058943 H43 -5.292782 1.771230 -0.101719 C44 -5.564143 -2.072829 0.055666 H45 -3.418785 -2.078020 0.099770 C46 -6.751938 -1.317650 -0.001809 H47 -7.492330 0.707137 -0.105558 H48 -5.615393 -3.156514 0.101372 C49 -8.115233 -2.028334 -0.000878 C50 8.115294 2.028184 0.000617 C51 -8.203696 -2.966922 -1.228313 H52 -7.412734 -3.722174 -1.220570 H53 -9.166045 -3.490849 -1.237158 H54 -8.116133 -2.400918 -2.161343 C55 -9.293312 -1.038133 -0.065614 H56 -9.304518 -0.361298 0.794849 H57 -9.267355 -0.432589 -0.977364 H58 -10.238734 -1.590028 -0.063374 C59 -8.257001 -2.864366 1.293796 H60 -8.202455 -2.225301 2.181023 H61 -9.222369 -3.382591 1.306718 H62 -7.471682 -3.620964 1.378815 C63 8.256332 2.865596 -1.293240 H64 7.470817 3.622115 -1.377109 H65 9.221599 3.384009 -1.306056 H66 8.201502 2.227440 -2.181105 C67 8.204563 2.965435 1.229020 H68 9.167070 3.489066 1.238006 H69 7.413823 3.720934 1.222431 H70 8.117244 2.398465 2.161486 C71 9.293358 1.037843 0.063564 H72 9.267850 0.431213 0.974608 H73 9.304092 0.362037 -0.797709 H74 10.238805 1.589698 0.061483 H75 -2.184650 7.979370 0.014286 H76 2.184775 -7.979354 -0.013572 N77 -1.753085 4.634081 -0.005739 N78 1.753063 -4.634080 0.005752

MARIA KOYIONI

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(2E,5Z,5'Z)-4,4'-Bis(4-methoxyphenyl)-N5,N5'-diphenyl-5H,5'H-(2,2'-bithiazolylidene)-

5,5'-diimine 182p

atom coordinates (Angstroms)

x y z

C1 -2.939515 1.206750 -0.033667

C2 -2.868029 -0.285447 -0.020869

C3 -0.669805 0.159210 -0.007428

C4 2.939160 -1.206800 0.033683

C5 2.867715 0.285389 0.020753

C6 0.669475 -0.159138 0.007153

N7 -4.022327 1.882893 0.041004

N8 4.022051 -1.882873 -0.040874

C9 -4.108096 3.279859 0.010257

C10 -5.033258 3.888078 0.877981

C11 -5.191887 5.269974 0.882251

H12 -5.604475 3.255781 1.549943

C13 -3.570218 5.466731 -0.894435

C14 -4.462112 6.066885 -0.004588

H15 -5.895884 5.727123 1.571521

H16 -3.014243 6.075810 -1.601309

N17 -1.649494 -0.776282 0.005258

N18 1.649207 0.776298 -0.005533

S19 -1.246185 1.838667 -0.065325

S20 1.245788 -1.838612 0.065254

C21 4.108265 -3.279785 -0.010176

C22 5.036236 -3.887240 -0.875452

C23 5.195503 -5.269058 -0.879876

H24 5.609127 -3.254377 -1.545451

C25 3.568700 -5.467316 0.891965

C26 4.463482 -6.066676 0.004476

H27 5.901717 -5.725596 -1.567280

H28 3.010927 -6.076964 1.596927

C29 4.015762 1.196005 0.024292

C30 5.350798 0.770006 0.138496

C31 3.773198 2.587558 -0.078216

C32 6.403139 1.683071 0.147008

H33 5.560946 -0.287903 0.216277

C34 4.810456 3.498316 -0.071808

H35 2.749228 2.931402 -0.162814

C36 6.140589 3.054355 0.041107

H37 7.417944 1.315126 0.238170

H38 4.625396 4.564227 -0.152255

C39 -4.016045 -1.196091 -0.024387

C40 -5.351143 -0.770056 -0.137714

C41 -3.773403 -2.587692 0.077291

C42 -6.403471 -1.683139 -0.146184

H43 -5.561350 0.287890 -0.214849

C44 -4.810644 -3.498468 0.070905

H45 -2.749385 -2.931557 0.161222

C46 -6.140842 -3.054475 -0.041136

H47 -7.418327 -1.315163 -0.236642

H48 -4.625524 -4.564417 0.150695

C49 -3.384956 4.085062 -0.889013

H50 -2.708957 3.626078 -1.602154

C51 3.382843 -4.085737 0.886601

H52 2.704494 -3.627388 1.597907

O53 7.088257 4.028039 0.038406

O54 -7.088486 -4.028185 -0.038500

C55 -8.453432 -3.646915 -0.150316

H56 -8.648934 -3.123766 -1.094283

H57 -9.026207 -4.574658 -0.126999

H58 -8.762718 -3.008746 0.686409

C59 8.453136 3.646790 0.151085

H60 9.025948 4.574505 0.127559

H61 8.648164 3.124130 1.095420

H62 8.762816 3.008175 -0.685154

H63 -4.596528 7.144232 -0.008911

H64 4.598357 -7.143967 0.008719

(2E,5Z,5'Z)-N5,N5'-Bis(4-n-butoxyphenyl)-4,4'-bis(4-methoxyphenyl)-5H,5'H-(2,2'-bithi-

azolylidene)-5,5'-diimine 182q


C1 -2.868624 1.369552 0.153355 C2 -1.720055 2.313011 0.053519 C3 -0.567270 0.389966 0.026913 C4 2.868571 -1.369487 -0.153376 C5 1.720018 -2.312951 -0.053456 C6 0.567211 -0.389925 -0.026827 N7 -4.098209 1.728813 0.129423 N8 4.098153 -1.728766 -0.129460 C9 -5.217424 0.903590 0.222723 C10 -6.392840 1.368190 -0.392917 C11 -5.281122 -0.316505 0.931595 C12 -7.574066 0.633658 -0.362554 H13 -6.354080 2.317617 -0.917084 C14 -6.461998 -1.040552 0.989347

H15 -4.416627 -0.679347 1.475422 C16 -7.615035 -0.583985 0.332007 H17 -8.451832 1.017983 -0.867644 H18 -6.518793 -1.971373 1.543885 N19 -0.537811 1.742582 -0.023046 N20 0.537768 -1.742541 0.023144 S21 -2.191974 -0.308495 0.190610 S22 2.191918 0.308554 -0.190507 C23 5.217378 -0.903555 -0.222729 C24 6.392802 -1.368230 0.392843 C25 5.281083 0.316599 -0.931500 C26 7.574041 -0.633719 0.362511 H27 6.354030 -2.317699 0.916932 C28 6.461972 1.040627 -0.989220 H29 4.416584 0.679507 -1.475276 C30 7.615017 0.583980 -0.331951 H31 8.451810 -1.018101 0.867552

MARIA KOYIONI

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H32 6.518772 1.971494 -1.543682 C33 1.815417 -3.776689 -0.019883 C34 3.002401 -4.488648 -0.263275 C35 0.643078 -4.522529 0.250934 C36 3.029803 -5.881843 -0.235229 H37 3.911000 -3.940612 -0.471020 C38 0.662365 -5.902967 0.283476 H39 -0.280913 -3.987542 0.435741 C40 1.859666 -6.599127 0.039903 H41 3.964191 -6.393449 -0.432088 H42 -0.235281 -6.474361 0.495058 C43 -1.815418 3.776753 0.019956 C44 -3.002513 4.488730 0.262770 C45 -0.642942 4.522584 -0.250300 C46 -3.029889 5.881922 0.234691 H47 -3.911211 3.940697 0.470089 C48 -0.662200 5.903022 -0.282858 H49 0.281135 3.987592 -0.434655 C50 -1.859613 6.599195 -0.039883 H51 -3.964366 6.393541 0.431095 H52 0.235562 6.474401 -0.493991 O53 -8.713497 -1.381783 0.438658 O54 8.713491 1.381767 -0.438557 O55 1.774104 -7.955511 0.093154 O56 -1.774016 7.955575 -0.093120 C57 2.950220 -8.717850 -0.139948 H58 2.653560 -9.763170 -0.045634 H59 3.350308 -8.544656 -1.146613 H60 3.728739 -8.494173 0.599816 C61 -2.950231 8.717927 0.139417

H62 -3.350753 8.544812 1.145922 H63 -2.653531 9.763240 0.045148 H64 -3.728434 8.494193 -0.600665 C65 -9.920187 -0.987920 -0.215084 H66 -9.741126 -0.874260 -1.294099 H67 -10.257800 -0.015953 0.173379 C68 -10.962762 -2.064837 0.048294 H69 -10.577318 -3.023123 -0.320926 H70 -11.087865 -2.174103 1.132572 C71 -12.312811 -1.752536 -0.608419 H72 -12.173844 -1.631626 -1.691240 H73 -12.684854 -0.787099 -0.239527 C74 -13.363748 -2.835770 -0.348202 H75 -14.316726 -2.588187 -0.826093 H76 -13.037121 -3.805954 -0.738469 H77 -13.550160 -2.956842 0.724591 C78 9.920211 0.987789 0.215062 H79 9.741224 0.874043 1.294080 H80 10.257746 0.015839 -0.173511 C81 10.962818 2.064678 -0.048301 H82 10.577437 3.022954 0.321009 H83 11.087864 2.174016 -1.132578 C84 12.312892 1.752272 0.608313 H85 12.173976 1.631277 1.691131 H86 12.684880 0.786854 0.239321 C87 13.363853 2.835491 0.348131 H88 13.037280 3.805654 0.738493 H89 14.316846 2.587836 0.825954 H90 13.550215 2.956644 -0.724661

(2E,5Z,5'Z)-4,4'-Bis(4-methoxyphenyl)-N5,N5'-bis(4-nitrophenyl)-5H,5'H-(2,2'-bithiazol-

ylidene)-5,5'-diimine 189


C1 -3.118348 -0.574975 -0.007599 C2 -2.255238 -1.795782 -0.018955 C3 -0.648454 -0.231468 -0.003532 C4 3.118362 0.574989 0.007543 C5 2.255255 1.795798 0.018877 C6 0.648469 0.231485 0.003450 N7 -4.395983 -0.583851 0.070322 N8 4.396000 0.583857 -0.070328 C9 -5.207576 0.548398 0.034948 C10 -6.242834 0.645168 0.986175 C11 -7.112285 1.725283 0.976038 H12 -6.337873 -0.135746 1.732586 C13 -5.973701 2.613905 -0.986639 C14 -6.968126 2.699714 -0.013278 H15 -7.903083 1.825188 1.708631 H16 -5.906819 3.383039 -1.745717 N17 -0.963765 -1.546576 -0.006514 N18 0.963782 1.546593 0.006430 S19 -2.043334 0.869223 -0.025865 S20 2.043349 -0.869207 0.025780 C21 5.207578 -0.548400 -0.034930 C22 6.242895 -0.645164 -0.986094 C23 7.112329 -1.725291 -0.975927 H24 6.337997 0.135769 -1.732477

C25 5.973609 -2.613940 0.986659 C26 6.968094 -2.699740 0.013360 H27 7.903165 -1.825194 -1.708480 H28 5.906671 -3.383084 1.745722 C29 2.731035 3.177994 0.033233 C30 4.088174 3.537502 0.126828 C31 1.774089 4.220955 -0.038764 C32 4.482401 4.872520 0.145019 H33 4.838795 2.761171 0.182221 C34 2.156871 5.546018 -0.022817 H35 0.724772 3.960283 -0.108173 C36 3.519516 5.887803 0.069459 H37 5.536744 5.109010 0.220316 H38 1.425705 6.345225 -0.079763 C39 -2.731017 -3.177978 -0.033297 C40 -4.088157 -3.537487 -0.126855 C41 -1.774068 -4.220939 0.038681 C42 -4.482384 -4.872505 -0.145034 H43 -4.838780 -2.761158 -0.182232 C44 -2.156850 -5.546002 0.022746 H45 -0.724749 -3.960265 0.108064 C46 -3.519496 -5.887788 -0.069494 H47 -5.536728 -5.108997 -0.220303 H48 -1.425682 -6.345208 0.079677 C49 -5.091978 1.540905 -0.959749 H50 -4.327597 1.452214 -1.723548

MARIA KOYIONI

254

C51 5.091899 -1.540930 0.959735 H52 4.327459 -1.452255 1.723476 O53 3.791907 7.215408 0.078907 O54 -3.791887 -7.215393 -0.078932 C55 -5.149032 -7.633752 -0.174283 H56 -5.609787 -7.288752 -1.107481 H57 -5.126210 -8.723708 -0.163991 H58 -5.739892 -7.274665 0.676686 C59 5.149050 7.633766 0.174291 H60 5.126230 8.723721 0.164001

H61 5.609782 7.288763 1.107500 H62 5.739931 7.274679 -0.676664 N63 -7.893038 3.836266 -0.036562 N64 7.892985 -3.836310 0.036685 O65 7.741363 -4.681338 0.920531 O66 8.768277 -3.881036 -0.829441 O67 -8.768290 3.880967 0.829605 O68 -7.741450 4.681329 -0.920384

4,4'-[(2E,5Z,5'Z)-5,5'-Bis(phenylimino)-5H,5'H-(2,2'-bithiazolylidene)-4,4'-diyl]bis(N,N-

diethylaniline) 190


C1 2.387936 2.098285 0.022518 C2 2.806991 0.665024 0.062314 C3 0.583675 0.366213 0.010001 C4 -2.387936 -2.098251 -0.022554 C5 -2.806995 -0.664992 -0.062351 C6 -0.583679 -0.366179 -0.010065 N7 3.191085 3.090881 -0.058894 N8 -3.191082 -3.090849 0.058850 C9 2.807762 4.437242 -0.069403 C10 3.468007 5.293104 -0.969554 C11 3.159203 6.648982 -1.008903 H12 4.209710 4.867487 -1.637724 C13 1.583421 6.347776 0.793186 C14 2.216174 7.184618 -0.127029 H15 3.664309 7.293488 -1.722661 H16 0.863370 6.757552 1.495820 N17 1.811495 -0.197558 0.041672 N18 -1.811499 0.197592 -0.041727 S19 0.581713 2.144812 0.012910 S20 -0.581716 -2.144780 -0.012972 C21 -2.807729 -4.437202 0.069358 C22 -3.467915 -5.293078 0.969537 C23 -3.159072 -6.648948 1.008875 H24 -4.209603 -4.867480 1.637736 C25 -1.583366 -6.347701 -0.793275 C26 -2.216064 -7.184559 0.126963 H27 -3.664132 -7.293467 1.722653 H28 -0.863329 -6.757457 -1.495934 C29 -4.183204 -0.183369 -0.115658 C30 -5.317433 -1.016733 -0.161451 C31 -4.418313 1.210549 -0.122728 C32 -6.601188 -0.494772 -0.214852 H33 -5.182411 -2.089717 -0.142303 C34 -5.692528 1.738205 -0.175729 H35 -3.565953 1.878973 -0.083146 C36 -6.839832 0.901730 -0.239897 H37 -7.426056 -1.194229 -0.226415 H38 -5.795216 2.815566 -0.171614 C39 4.183196 0.183387 0.115663 C40 5.317447 1.016732 0.161229 C41 4.418274 -1.210535 0.122996

C42 6.601194 0.494751 0.214656 H43 5.182449 2.089715 0.141887 C44 5.692481 -1.738209 0.176032 H45 3.565896 -1.878948 0.083604 C46 6.839810 -0.901750 0.239960 H47 7.426076 1.194194 0.226025 H48 5.795143 -2.815573 0.172147 C49 1.867725 4.983270 0.823937 H50 1.388296 4.345067 1.558244 C51 -1.867709 -4.983202 -0.824015 H52 -1.388318 -4.344982 -1.558333 H53 -1.985529 -8.245330 0.150383 H54 1.985668 8.245395 -0.150457 N55 8.121422 -1.425253 0.340629 N56 -8.121448 1.425208 -0.340538 C57 8.356881 -2.834188 0.018251 H58 9.315742 -3.123911 0.449238 H59 7.613540 -3.441949 0.540130 C60 9.257021 -0.492939 0.308977 H61 9.049488 0.299205 1.034859 H62 9.330707 -0.001893 -0.675200 C63 -8.356947 2.834122 -0.018108 H64 -9.315787 3.123858 -0.449130 H65 -7.613582 3.441915 -0.539918 C66 -9.257018 0.492852 -0.309050 H67 -9.049470 -0.299157 -1.035078 H68 -9.330664 0.001623 0.675037 C69 -10.611243 1.100772 -0.669618 H70 -11.347415 0.293285 -0.725317 H71 -10.971154 1.816509 0.074747 H72 -10.584210 1.595204 -1.645480 C73 -8.344098 3.149723 1.483551 H74 -7.382909 2.885878 1.933342 H75 -8.519021 4.217837 1.651021 H76 -9.126597 2.593135 2.009632 C77 8.343950 -3.149859 -1.483392 H78 8.518602 -4.218026 -1.650811 H79 7.382825 -2.885795 -1.933192 H80 9.126588 -2.593497 -2.009505 C81 10.611210 -1.100854 0.669692 H82 10.971073 -1.816806 -0.074490 H83 11.347438 -0.293404 0.725183 H84 10.584139 -1.595036 1.645680

MARIA KOYIONI

255

(2E,5Z,5'Z)-N5,N5'-Bis(4-n-butoxyphenyl)-4,4'-bis(4-fluorophenyl)-5H,5'H-(2,2'-bithiazol-

ylidene)-5,5'-diimine 182r


C1 -2.846272 -1.416022 0.159250 C2 -1.681783 -2.336859 0.074052 C3 -0.561713 -0.397226 0.028115 S4 -2.198236 0.274365 0.173145 C5 0.561878 0.397598 -0.028206 S6 2.198395 -0.274013 -0.173248 C7 1.681963 2.337235 -0.074144 C8 2.846446 1.416375 -0.159328 N9 0.509270 1.751681 0.004858 N10 -0.509090 -1.751315 -0.004956 N11 4.067116 1.805537 -0.137894 N12 -4.066922 -1.805251 0.137825 C13 1.753437 3.807218 -0.050094 C14 0.588487 4.525402 0.296652 C15 2.914577 4.532578 -0.379952 C16 0.580406 5.912904 0.323154 H17 -0.308735 3.971496 0.545645 C18 2.914511 5.924700 -0.359593 H19 3.814674 3.996271 -0.645581 C20 1.749271 6.593912 -0.006980 H21 -0.308640 6.471816 0.593689 H22 3.801664 6.493247 -0.615997 C23 -1.753293 -3.806839 0.049957 C24 -0.588544 -4.525026 -0.297438 C25 -2.914263 -4.532178 0.380440 C26 -0.580504 -5.912531 -0.323980 H27 0.308552 -3.971130 -0.546901 C28 -2.914234 -5.924298 0.360056 H29 -3.814209 -3.995868 0.646573 C30 -1.749199 -6.593522 0.006782 H31 0.308382 -6.471452 -0.595026 H32 -3.801248 -6.492839 0.616948 F33 -1.747831 -7.940811 -0.016281 F34 1.747859 7.941200 0.016051 C35 5.213556 1.020089 -0.209299 C36 6.384581 1.580749 0.332538 C37 5.311778 -0.250767 -0.820219 C38 7.595639 0.897719 0.323039 H39 6.317196 2.566230 0.781720 C40 6.520964 -0.926654 -0.855982

H41 4.452013 -0.693359 -1.309313 C42 7.671262 -0.369580 -0.274030 H43 8.469270 1.357903 0.768041 H44 6.604226 -1.895809 -1.336419 C45 -5.213433 -1.019926 0.209220 C46 -6.384471 -1.580910 -0.332259 C47 -5.311736 0.251121 0.819747 C48 -7.595625 -0.898053 -0.322780 H49 -6.317010 -2.566523 -0.781140 C50 -6.521006 0.926848 0.855482 H51 -4.451961 0.693991 1.308568 C52 -7.671326 0.369425 0.273895 H53 -8.469262 -1.358505 -0.767489 H54 -6.604332 1.896149 1.335614 O55 8.799316 -1.124999 -0.352141 O56 -8.799470 1.124715 0.351967 C57 10.013512 -0.616759 0.204534 H58 10.279176 0.332134 -0.283378 H59 9.877704 -0.416982 1.277152 C60 11.098751 -1.660002 -0.017658 H61 10.788189 -2.597382 0.459699 C62 -10.013725 0.616103 -0.204240 H63 -10.279116 -0.332676 0.284046 H64 -9.878157 0.416000 -1.276827 C65 -11.099083 1.659236 0.017894 H66 -10.788868 2.596485 -0.459944 H67 -11.173094 1.864164 1.092916 C68 -12.461834 1.215498 -0.528203 H69 -12.757048 0.271394 -0.050941 H70 -12.373740 1.000110 -1.601625 C71 -13.557832 2.262249 -0.307531 H72 -13.306677 3.207800 -0.800579 H73 -14.518320 1.922686 -0.707355 H74 -13.695704 2.471974 0.758885 H75 11.173088 -1.864517 -1.092737 C76 12.461402 -1.216748 0.529079 H77 12.372990 -1.001795 1.602562 H78 12.756952 -0.272499 0.052313 C79 13.557277 -2.263611 0.308331 H80 14.517686 -1.924417 0.708658 H81 13.305759 -3.209336 0.800859 H82 13.695497 -2.472881 -0.758129

(2E,5Z,5'Z)-N5,N5'-Diphenyl-4,4'-bis[4-(trifluoromethyl)phenyl]-5H,5'H-(2,2'-bithiazol-

ylidene)-5,5'-diimine 182s


C1 -2.570887 -1.868104 0.052420 C2 -2.848535 -0.403782 0.028996 C3 -0.610912 -0.317123 0.009820 C4 2.570896 1.868108 -0.052415 C5 2.848544 0.403787 -0.028990 C6 0.610921 0.317128 -0.009817 N7 -3.471466 -2.771782 -0.024125

N8 3.471473 2.771789 0.024123 C9 -3.255787 -4.153250 -0.006653 C10 -4.106345 -4.936455 -0.809154 C11 -3.968519 -6.319648 -0.840651 H12 -4.855395 -4.432974 -1.411442 C13 -2.190586 -6.183342 0.787971 C14 -3.010211 -6.950255 -0.041690 H15 -4.618202 -6.909826 -1.480007 H16 -1.460128 -6.667725 1.429184

MARIA KOYIONI

256

N17 -1.786036 0.362675 -0.006953 N18 1.786044 -0.362670 0.006958 S19 -0.773744 -2.081914 0.082118 S20 0.773753 2.081919 -0.082113 C21 3.255783 4.153255 0.006650 C22 4.106347 4.936471 0.809135 C23 3.968509 6.319662 0.840629 H24 4.855410 4.432998 1.411414 C25 2.190550 6.183334 -0.787964 C26 3.010182 6.950257 0.041680 H27 4.618196 6.909849 1.479973 H28 1.460077 6.667707 -1.429167 C29 4.185764 -0.216329 -0.021139 C30 5.370741 0.503015 -0.260250 C31 4.275479 -1.603201 0.222322 C32 6.602639 -0.145632 -0.254026 H33 5.318744 1.567625 -0.439649 C34 5.504582 -2.245451 0.230872 H35 3.365611 -2.160939 0.407610 C36 6.675424 -1.517074 -0.008142 H37 7.510993 0.418150 -0.434858 H38 5.561837 -3.309716 0.431385 C39 -4.185755 0.216331 0.021142

C40 -5.370731 -0.503016 0.260247 C41 -4.275473 1.603203 -0.222315 C42 -6.602631 0.145627 0.254022 H43 -5.318733 -1.567627 0.439642 C44 -5.504578 2.245451 -0.230867 H45 -3.365606 2.160944 -0.407599 C46 -6.675419 1.517071 0.008142 H47 -7.510985 -0.418157 0.434848 H48 -5.561835 3.309717 -0.431376 C49 -2.302015 -4.794195 0.806449 H50 -1.682083 -4.212623 1.479801 C51 2.301992 4.794187 -0.806438 H52 1.682052 4.212606 -1.479776 H53 2.912439 8.031354 0.056506 H54 -2.912477 -8.031352 -0.056519 C55 8.001818 -2.227093 -0.054395 C56 -8.001816 2.227084 0.054395 F57 -8.043457 3.266418 -0.808847 F58 -9.027100 1.402427 -0.251593 F59 9.027110 -1.402432 0.251555 F60 8.253674 -2.730199 -1.285654 F61 8.043467 -3.266403 0.808876 F62 -8.253692 2.730154 1.285665

(2E,5Z,5'Z)-N5,N5'-Bis(4-n-butoxyphenyl)-4,4'-bis[4-(trifluoromethyl)phenyl]-5H,5'H-

(2,2'-bithiazolylidene)-5,5'-diimine 182t


C1 -2.969215 1.137440 0.157291 C2 -1.898796 2.161953 0.065036 C3 -0.598729 0.340343 0.026780 C4 2.968998 -1.137410 -0.157496 C5 1.898568 -2.161897 -0.065399 C6 0.598516 -0.340294 -0.027212 N7 -4.220879 1.411070 0.135042 N8 4.220639 -1.411114 -0.135172 C9 -5.290127 0.525838 0.212709 C10 -6.510319 0.979585 -0.321785 C11 -7.653728 0.189307 -0.308954 H12 -6.534489 1.968104 -0.768621 C13 -6.411218 -1.532329 0.862167 C14 -7.610570 -1.080878 0.286246 H15 -8.567592 0.568682 -0.749272 H16 -6.404398 -2.505769 1.340984 N17 -0.675367 1.693736 -0.014165 N18 0.675133 -1.693696 0.013717 S19 -2.162205 -0.483988 0.177225 S20 2.161998 0.484020 -0.177712 C21 5.289933 -0.525939 -0.212811 C22 6.510078 -0.979726 0.321748 C23 7.653515 -0.189486 0.308964 H24 6.534187 -1.968242 0.768592 C25 6.411126 1.532176 -0.862248 C26 7.610433 1.080691 -0.286258 H27 8.567346 -0.568889 0.749329 H28 6.404363 2.505611 -1.341075 C29 2.109370 -3.621553 -0.035695 C30 3.320695 -4.232892 -0.405244 C31 1.032969 -4.442585 0.359870

C32 3.448514 -5.619088 -0.378004 H33 4.156463 -3.616296 -0.704179 C34 1.164774 -5.823084 0.390811 H35 0.098010 -3.975246 0.644486 C36 2.376185 -6.417783 0.020469 H37 4.386948 -6.081356 -0.663317 H38 0.333692 -6.442773 0.709698 C39 -2.109471 3.621640 0.035454 C40 -3.320787 4.233125 0.404808 C41 -1.032856 4.442580 -0.359741 C42 -3.448400 5.619346 0.377688 H43 -4.156701 3.616620 0.703511 C44 -1.164452 5.823097 -0.390551 H45 -0.097892 3.975141 -0.644179 C46 -2.375867 6.417933 -0.020436 H47 -4.386832 6.081717 0.662841 H48 -0.333197 6.442702 -0.709153 C49 -5.268801 -0.750047 0.821628 H50 -4.370196 -1.113634 1.305960 C51 5.268678 0.749937 -0.821748 H52 4.370102 1.113551 -1.306115 C53 2.496071 -7.917304 -0.002328 C54 -2.495507 7.917472 0.002500 F55 -1.779918 8.493251 -0.989886 F56 -3.776760 8.325713 -0.131084 F57 3.777386 -8.325309 0.131396 F58 2.036951 -8.435906 -1.165985 F59 1.780501 -8.493121 0.990048 F60 -2.036191 8.435898 1.166158 O61 8.663393 1.934819 -0.368480 O62 -8.663498 -1.935041 0.368510 C63 -9.917396 -1.549952 -0.201113 H64 -9.791939 -1.348559 -1.274548

MARIA KOYIONI

257

H65 -10.276129 -0.626584 0.275691 C66 -10.898979 -2.690423 0.024390 H67 -10.487998 -3.601319 -0.427758 H68 -10.974027 -2.881141 1.101955 C69 -12.287507 -2.394932 -0.556008 H70 -12.199257 -2.197102 -1.632787 H71 -12.683083 -1.473195 -0.108348 C72 -13.280858 -3.538090 -0.328272 H73 -12.930796 -4.465559 -0.794513 H74 -13.418138 -3.736327 0.740367 C75 9.917204 1.549776 0.201364 H76 9.791570 1.348405 1.274782 H77 10.276046 0.626408 -0.275357

C78 10.898792 2.690271 -0.023995 H79 10.487751 3.601151 0.428132 H80 10.973952 2.881016 -1.101547 C81 12.287262 2.394787 0.556547 H82 12.198889 2.196839 1.633295 H83 12.682938 1.473118 0.108839 C84 13.280585 3.538019 0.329059 H85 12.930430 4.465416 0.795373 H86 14.261512 3.301769 0.752850 H87 13.417970 3.736391 -0.739541 H88 -14.261820 -3.301845 -0.751986

4,4'-{[(2E,5Z,5'Z)-4,4'-Bis[4-(trifluoromethyl)phenyl]-5H,5'H-(2,2'-bithiazolylidene)-5,5'-

diylidene]bis(azanylylidene)}bis(N,N-diethylaniline) 182u


C1 -3.051458 0.956280 0.058676 C2 -2.054160 2.047417 0.002338 C3 -0.627505 0.322143 -0.014819 C4 3.039001 -0.916082 -0.111867 C5 2.039806 -2.005480 -0.059750 C6 0.615586 -0.278164 -0.041876 N7 -4.321931 1.141754 0.018072 N8 4.308574 -1.105652 -0.066170 C9 -5.332788 0.197757 0.074683 C10 -6.601376 0.612379 -0.381947 C11 -5.239118 -1.113336 0.590469 C12 -7.698296 -0.230411 -0.378077 H13 -6.701506 1.629501 -0.747472 C14 -6.337807 -1.956968 0.615266 H15 -4.309066 -1.474097 1.013473 C16 -7.602472 -1.557017 0.113953 H17 -8.645138 0.164155 -0.723328 H18 -6.202965 -2.954801 1.013199 N19 -0.796783 1.664555 -0.044744 N20 0.783060 -1.620944 -0.013076 S21 -2.134940 -0.607062 0.081226 S22 2.124461 0.648902 -0.135360 C23 5.326022 -0.169163 -0.113087 C24 6.590869 -0.597599 0.339499 C25 5.240214 1.154548 -0.598406 C26 7.692699 0.238709 0.350626 H27 6.678562 -1.612389 0.714539 C28 6.344427 1.990403 -0.614698 H29 4.311992 1.530852 -1.011600 C30 7.614300 1.567062 -0.143615 H31 8.620029 -0.148537 0.750038 H32 6.212173 2.988808 -1.010590 N33 -8.679123 -2.433597 0.121890 N34 8.726660 2.397093 -0.190791 C35 2.339986 -3.450912 -0.043318 C36 3.606911 -3.981208 -0.347729 C37 1.295346 -4.344823 0.269954 C38 3.817829 -5.357057 -0.337185 H39 4.418650 -3.307685 -0.583222 C40 1.508681 -5.715792 0.281529 H41 0.317869 -3.941131 0.504189

C42 2.774000 -6.228751 -0.023028 H43 4.799599 -5.754782 -0.570293 H44 0.698716 -6.391367 0.533804 C45 -2.356389 3.492350 -0.016585 C46 -3.625906 4.021034 0.279832 C47 -1.311439 4.387674 -0.325015 C48 -3.838948 5.396546 0.266572 H49 -4.437844 3.346298 0.511216 C50 -1.526850 5.758259 -0.339084 H51 -0.332117 3.985256 -0.553635 C52 -2.794678 6.269597 -0.042237 H53 -4.822754 5.792934 0.493304 H54 -0.716550 6.434870 -0.587494 C55 9.983859 1.907877 0.391657 H56 10.164946 0.907905 -0.014582 H57 9.887244 1.788502 1.483385 C58 11.218511 2.754240 0.086294 H59 12.099019 2.227633 0.466292 H60 11.353827 2.895854 -0.990305 H61 11.195744 3.735724 0.567885 C62 8.548875 3.838393 -0.377837 H63 7.870898 4.002298 -1.219432 H64 9.503688 4.256906 -0.697203 C65 8.044046 4.582062 0.865692 H66 7.926935 5.649385 0.650167 H67 7.076708 4.192216 1.194752 H68 8.748322 4.481813 1.697956 C69 -9.958765 -2.055223 -0.480204 H70 -9.758028 -1.333206 -1.272157 H71 -10.603659 -1.550393 0.258920 C72 -8.701424 -3.544725 1.080909 H73 -8.107678 -3.263540 1.957116 H74 -9.730363 -3.654628 1.441667 C75 -10.721201 -3.223978 -1.110400 H76 -11.012071 -3.982755 -0.379032 H77 -11.639705 -2.845668 -1.570054 H78 -10.122955 -3.706457 -1.888662 C79 -8.208011 -4.886072 0.524687 H80 -8.835293 -5.229847 -0.301498 H81 -7.182713 -4.810506 0.152421 H82 -8.230246 -5.649461 1.310136 C83 2.992747 -7.715539 -0.074142 C84 -3.015856 7.756080 0.006410

MARIA KOYIONI

258

F85 2.755075 -8.213173 -1.311541 F86 4.263716 -8.050964 0.243100 F87 2.174808 -8.376905 0.775659 F88 -4.285463 8.089506 -0.318199

F89 -2.194027 8.417963 -0.839229 F90 -2.785821 8.255056 1.244783

4,4'-[(2E,5Z,5'Z)-5,5'-Bis(phenylimino)-5H,5'H-(2,2'-bithiazolylidene)-4,4'-diyl]dibenzo-

nitrile 191


C1 -3.003894 1.039457 -0.061825 C2 -2.841980 -0.440811 -0.048516 C3 -0.677137 0.125958 -0.011618 C4 3.003885 -1.039457 0.061835 C5 2.841971 0.440810 0.048522 C6 0.677128 -0.125958 0.011621 N7 -4.131470 1.637129 0.012124 N8 4.131463 -1.637127 -0.012119 C9 -4.338147 3.019466 0.006076 C10 -5.415121 3.498344 0.775815 C11 -5.699901 4.858392 0.820010 H12 -6.001210 2.783159 1.343513 C13 -3.900436 5.289003 -0.732579 C14 -4.944037 5.760597 0.065546 H15 -6.521014 5.215899 1.433999 H16 -3.324811 5.981079 -1.339959 N17 -1.602663 -0.866669 -0.007434 N18 1.602653 0.866668 0.007438 S19 -1.346492 1.767241 -0.073383 S20 1.346483 -1.767241 0.073388 C21 4.338151 -3.019463 -0.006071 C22 5.415117 -3.498332 -0.775828 C23 5.699908 -4.858377 -0.820024 H24 6.001189 -2.783143 -1.343537 C25 3.900476 -5.289002 0.732598 C26 4.944066 -5.760588 -0.065545 H27 6.521014 -5.215878 -1.434027 H28 3.324870 -5.981083 1.339991

C29 3.940325 1.422495 0.052710 C30 5.275996 1.082451 0.338924 C31 3.629052 2.771457 -0.221683 C32 6.266615 2.057347 0.347128 H33 5.528793 0.052216 0.546392 C34 4.613903 3.745430 -0.218315 H35 2.601294 3.036009 -0.438421 C36 5.946254 3.394872 0.067363 H37 7.292876 1.788223 0.572127 H38 4.365265 4.778495 -0.435492 C39 -3.940334 -1.422497 -0.052709 C40 -5.276005 -1.082454 -0.338924 C41 -3.629058 -2.771459 0.221678 C42 -6.266622 -2.057351 -0.347132 H43 -5.528803 -0.052219 -0.546388 C44 -4.613908 -3.745435 0.218305 H45 -2.601301 -3.036010 0.438416 C46 -5.946259 -3.394878 -0.067372 H47 -7.292884 -1.788228 -0.572131 H48 -4.365268 -4.778500 0.435478 C49 -3.589510 3.930917 -0.762935 H50 -2.799214 3.574633 -1.414295 C51 3.589538 -3.930920 0.762957 H52 2.799252 -3.574642 1.414332 H53 5.175495 -6.820928 -0.089952 H54 -5.175455 6.820938 0.089951 C55 6.969478 4.398286 0.072731 C56 -6.969482 -4.398293 -0.072744 N57 7.799572 5.213682 0.076666 N58 -7.799575 -5.213690 -0.076683

(2E,5Z,5'Z)-4,4'-Bis(4-nitrophenyl)-N5,N5'-diphenyl-5H,5'H-(2,2'-bithiazolylidene)-5,5'-

diimine 192


C1 2.777031 -1.546617 -0.051818 C2 2.875551 -0.060715 -0.038101 C3 0.644792 -0.243012 -0.010447 C4 -2.777057 1.546634 0.051765 C5 -2.875579 0.060729 0.038018 C6 -0.644819 0.243030 0.010327 N7 3.780301 -2.334522 0.024528 N8 -3.780322 2.334552 -0.024520 C9 3.735141 -3.731922 0.012696 C10 4.686411 -4.401720 0.804808 C11 4.717864 -5.791189 0.842382 H12 5.377301 -3.808256 1.394479 C13 2.913885 -5.879470 -0.761580

C14 3.832150 -6.536912 0.058802 H15 5.443174 -6.295270 1.473871 H16 2.239724 -6.452131 -1.391449 N17 1.728750 0.573587 -0.002688 N18 -1.728774 -0.573566 0.002573 S19 1.017836 -1.974911 -0.071594 S20 -1.017862 1.974930 0.071481 C21 -3.735147 3.731953 -0.012636 C22 -4.686367 4.401797 -0.804767 C23 -4.717803 5.791268 -0.842281 H24 -5.377233 3.808369 -1.394502 C25 -2.913909 5.879458 0.761781 C26 -3.832123 6.536947 -0.058620 H27 -5.443074 6.295384 -1.473785 H28 -2.239776 6.452083 1.391712

MARIA KOYIONI

259

C29 -4.126751 -0.718952 0.041124 C30 -5.391527 -0.142943 0.269109 C31 -4.042108 -2.111847 -0.176204 C32 -6.536693 -0.932636 0.275589 H33 -5.468023 0.922651 0.432650 C34 -5.179077 -2.904733 -0.173052 H35 -3.069264 -2.555780 -0.347569 C36 -6.416324 -2.301180 0.053495 H37 -7.515739 -0.505669 0.451637 H38 -5.129048 -3.972776 -0.341756 C39 4.126735 0.718948 -0.041175 C40 5.391467 0.142962 -0.269449 C41 4.042143 2.111795 0.176461 C42 6.536646 0.932637 -0.275918 H43 5.467925 -0.922600 -0.433214 C44 5.179128 2.904660 0.173348 H45 3.069324 2.555705 0.348030

C46 6.416335 2.301138 -0.053508 H47 7.515660 0.505697 -0.452213 H48 5.129149 3.972664 0.342317 C49 2.854945 -4.487398 -0.785197 H50 2.160815 -3.989249 -1.453027 C51 -2.854985 4.487384 0.785337 H52 -2.160896 3.989197 1.453181 H53 -3.866917 7.621767 -0.077732 H54 3.866956 -7.621730 0.077961 N55 7.628083 3.136566 -0.058633 N56 -7.628053 -3.136625 0.058654 O57 8.706318 2.578133 -0.259307 O58 7.489187 4.343664 0.138234 O59 -8.706337 -2.578112 0.258847 O60 -7.489075 -4.343793 -0.137763

(2E,5Z,5'Z)-N5,N5'-Bis(4-n-butoxyphenyl)-4,4'-bis(4-nitrophenyl)-5H,5'H-(2,2'-bithiazol-

ylidene)-5,5'-diimine 182v


C1 -2.671559 1.732889 -0.013880 C2 -1.408629 2.509124 -0.034500 C3 -0.516502 0.457856 -0.029430 S4 -2.222956 -0.022496 -0.044391 C5 0.516303 -0.457557 -0.029415 S6 2.222763 0.022792 -0.044313 C7 1.408440 -2.508807 -0.034492 C8 2.671367 -1.732588 -0.013816 N9 0.305400 -1.796063 -0.030348 N10 -0.305599 1.796358 -0.030331 N11 3.833231 -2.263844 0.087594 N12 -3.833449 2.264080 0.087546 C13 1.305426 -3.980020 -0.037443 C14 0.052361 -4.559642 0.256977 C15 2.388861 -4.825717 -0.343688 C16 -0.116098 -5.935768 0.254362 H17 -0.781692 -3.908906 0.489054 C18 2.227377 -6.207162 -0.351577 H19 3.353169 -4.392348 -0.567272 C20 0.978873 -6.744569 -0.051065 H21 -1.069962 -6.393128 0.483900 H22 3.049228 -6.870542 -0.588908 C23 -1.305563 3.980338 -0.037475 C24 -0.052289 4.559897 0.256208 C25 -2.389147 4.826110 -0.342990 C26 0.116229 5.936012 0.253573 H27 0.781878 3.909113 0.487736 C28 -2.227607 6.207549 -0.350885 H29 -3.353610 4.392792 -0.566008 C30 -0.978895 6.744885 -0.051120 H31 1.070260 6.393313 0.482537 H32 -3.049582 6.870978 -0.587652 N33 -0.807933 8.205570 -0.057423 N34 0.807979 -8.205263 -0.057349 O35 -0.309138 -8.651001 0.206615 O36 0.309368 8.651238 0.205880 O37 1.791233 -8.895557 -0.326523

O38 -1.791321 8.895931 -0.325936 C39 5.067593 -1.627221 0.112900 C40 6.128207 -2.352511 0.703394 C41 5.359138 -0.365058 -0.439061 C42 7.401402 -1.823146 0.785191 H43 5.911203 -3.334720 1.110007 C44 6.646517 0.163941 -0.384037 H45 4.594173 0.195976 -0.962921 C46 7.675590 -0.554480 0.241939 H47 8.211692 -2.371048 1.253956 H48 6.837837 1.130251 -0.834008 C49 -5.067744 1.627306 0.112874 C50 -6.128335 2.352225 0.703851 C51 -5.359223 0.365337 -0.439555 C52 -7.401439 1.822641 0.785702 H53 -5.911398 3.334308 1.110805 C54 -6.646519 -0.163863 -0.384488 H55 -4.594274 -0.195354 -0.963807 C56 -7.675560 0.554153 0.242004 H57 -8.211709 2.370242 1.254851 H58 -6.837803 -1.130004 -0.834839 O59 8.956958 -0.125769 0.361886 O60 -8.956838 0.125194 0.362066 C61 9.318182 1.151751 -0.173055 H62 9.120077 1.170765 -1.254131 H63 8.708485 1.936621 0.296363 C64 10.796550 1.373648 0.109593 H65 11.367419 0.551778 -0.339446 H66 10.959875 1.315109 1.192563 C67 11.299734 2.719455 -0.427248 H68 11.121108 2.771631 -1.509641 H69 10.712672 3.533739 0.018300 C70 12.787151 2.950831 -0.145230 H71 13.119866 3.917035 -0.536689 H72 12.992585 2.938179 0.930800 H73 13.403512 2.172874 -0.608970 C74 -9.317987 -1.152140 -0.173365 H75 -9.120155 -1.170630 -1.254499 H76 -8.708040 -1.937124 0.295542

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C77 -10.796249 -1.374408 0.109553 H78 -11.367416 -0.552680 -0.339366 H79 -10.959371 -1.315918 1.192556 C80 -11.299196 -2.720337 -0.427202 H81 -10.712178 -3.534502 0.018622 H82 -11.120304 -2.772676 -1.509543

C83 -12.786664 -2.951788 -0.145508 H84 -13.119168 -3.918150 -0.536752 H85 -12.992383 -2.938821 0.930464 H86 -13.402987 -2.174042 -0.609655

4,4'-{[(2E,5Z,5'Z)-4,4'-Bis(4-nitrophenyl)-5H,5'H-(2,2'-bithiazolylidene)-5,5'-diylidene]-

bis(azanylylidene)}bis(N,N-diethylaniline) 182w


C1 -2.968208 -1.135156 -0.098119 C2 -1.897929 -2.149959 -0.042451 C3 -0.594964 -0.332211 0.003162 C4 2.981397 1.148871 0.127579 C5 1.913879 2.167149 0.070439 C6 0.606517 0.352290 0.040620 N7 -4.222431 -1.417912 -0.084134 N8 4.236777 1.423217 0.092716 C9 -5.312276 -0.571562 -0.123747 C10 -6.560771 -1.157214 0.181972 C11 -5.324075 0.799296 -0.467918 C12 -7.736763 -0.432461 0.188655 H13 -6.577940 -2.216145 0.419341 C14 -6.499818 1.530400 -0.474841 H15 -4.413124 1.304487 -0.764774 C16 -7.749437 0.951119 -0.129498 H17 -8.655661 -0.959358 0.409172 H18 -6.440770 2.579099 -0.735671 N19 -0.668852 -1.681674 0.020266 N20 0.683305 1.701468 0.016343 S21 -2.163175 0.488653 -0.088526 S22 2.172097 -0.473033 0.138119 O23 5.313636 0.558634 0.143057 O24 6.553708 1.078817 -0.284165 O25 5.310768 -0.776925 0.605364 C26 7.708119 0.318051 -0.295634 H27 6.578527 2.104121 -0.639410 C28 6.466763 -1.537945 0.620945 H29 4.405514 -1.221862 1.000696 C30 7.711442 -1.023407 0.171197 H31 8.613417 0.773200 -0.673081 H32 6.396239 -2.550045 0.997007 N33 -8.905740 1.713228 -0.118441 N34 8.872605 -1.779223 0.210253 C35 2.116312 3.628416 0.050749 C36 3.341221 4.241328 0.378874 C37 1.018515 4.448055 -0.290778 C38 3.467603 5.626127 0.360770 H39 4.187965 3.622617 0.639591 C40 1.136749 5.829050 -0.313987 H41 0.074859 3.977224 -0.537288 C42 2.365853 6.403241 0.012906 H43 4.401628 6.111116 0.614344

H44 0.303621 6.467245 -0.579210 C45 -2.094784 -3.612427 -0.033004 C46 -3.309872 -4.229257 -0.388680 C47 -1.000150 -4.428723 0.325772 C48 -3.430048 -5.614679 -0.380807 H49 -4.153646 -3.612738 -0.663468 C50 -1.112327 -5.810434 0.339572 H51 -0.063670 -3.954933 0.593113 C52 -2.331851 -6.388541 -0.014846 H53 -4.356318 -6.102719 -0.656058 H54 -0.281673 -6.446153 0.618155 N55 -2.458810 -7.851968 -0.003337 N56 2.499394 7.865959 -0.009167 O57 3.595385 8.346869 0.282121 O58 1.506870 8.527229 -0.317902 O59 -1.469672 -8.510261 0.322098 O60 -3.546255 -8.336409 -0.319774 C61 10.099322 -1.199277 -0.356654 H62 10.228224 -0.205877 0.085284 H63 9.986272 -1.045576 -1.442028 C64 11.380241 -1.987956 -0.093130 H65 12.225064 -1.406628 -0.474134 H66 11.543861 -2.149885 0.976558 H67 11.397665 -2.956344 -0.600575 C68 8.792528 -3.228368 0.406918 H69 8.126697 -3.430810 1.249875 H70 9.773085 -3.580046 0.728238 C71 8.339060 -4.011505 -0.832039 H72 8.290316 -5.082412 -0.608498 H73 7.349569 -3.687174 -1.166205 H74 9.037588 -3.872118 -1.663388 C75 -10.194102 1.150086 0.291773 H76 -10.004670 0.275099 0.911873 H77 -10.757152 0.802647 -0.589826 C78 -8.953197 2.983201 -0.852965 H79 -8.290894 2.912578 -1.722376 H80 -9.965229 3.092435 -1.257714 C81 -11.061950 2.111854 1.108720 H82 -11.353091 3.001461 0.543492 H83 -11.982185 1.599412 1.406436 H84 -10.540851 2.433857 2.014883 C85 -8.598386 4.222228 -0.021190 H86 -9.296297 4.356549 0.808815 H87 -7.592765 4.146461 0.400904 H88 -8.637642 5.119005 -0.648933

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(2E,5Z,5'Z)-N5,N5'-Bis(4-n-butoxyphenyl)-4,4'-bis(5-n-hexylthiophen-2-yl)-5H,5'H-(2,2'-

bithiazolylidene)-5,5'-diimine 182y


C1 -2.124024 -2.548134 0.035068 C2 -2.778892 -1.216975 -0.053143 C3 -0.657102 -0.515948 -0.075382 S4 -0.338059 -2.264974 -0.000276 C5 0.359342 0.414574 -0.113466 S6 0.038497 2.162347 -0.204490 C7 2.479967 1.118263 -0.136014 C8 1.823415 2.450823 -0.176499 N9 1.670637 0.080990 -0.093918 N10 -1.967869 -0.181196 -0.100229 N11 2.467442 3.556709 -0.129072 N12 -2.769268 -3.645703 0.170068 C13 3.907671 0.917037 -0.130356 C14 4.944578 1.825851 -0.217959 S15 4.537218 -0.721863 -0.004951 C16 6.225147 1.218215 -0.181611 H17 4.764009 2.887989 -0.302938 C18 6.184901 -0.152808 -0.066704 H19 7.149564 1.780200 -0.239769 C20 -4.205881 -1.014759 -0.083909 C21 -5.244525 -1.925989 -0.068809 S22 -4.832246 0.628435 -0.159590 C23 -6.523579 -1.316340 -0.115125 H24 -5.066144 -2.990948 -0.023815 C25 -6.480532 0.058524 -0.168712 H26 -7.448983 -1.879694 -0.110096 C27 7.325891 -1.132383 0.013047 H28 7.268645 -1.673345 0.968335 H29 7.199627 -1.898621 -0.764453 C30 -7.619301 1.041260 -0.240917 H31 -7.502860 1.788575 0.556131 H32 -7.548273 1.604691 -1.182267 C33 8.717174 -0.500132 -0.124056 H34 8.851946 0.257828 0.658450 H35 8.783716 0.028891 -1.083596 C36 9.846933 -1.532648 -0.029576 H37 9.776975 -2.060324 0.932197 H38 9.707012 -2.298042 -0.806066 C39 11.245028 -0.918837 -0.170041 H40 11.383206 -0.148627 0.602231 H41 11.317244 -0.396018 -1.134459 C42 12.378804 -1.946329 -0.066777 H43 12.239655 -2.716845 -0.837304 H44 12.307775 -2.467041 0.897834 C45 13.771601 -1.325973 -0.210903 H46 13.954620 -0.577002 0.567934 H47 13.885017 -0.827316 -1.180215 H48 14.557660 -2.084039 -0.133672 C49 -9.012815 0.407362 -0.138140 H50 -9.091680 -0.146269 0.806448 H51 -9.138450 -0.329925 -0.941650 C52 -10.140574 1.443038 -0.220762 H53 -10.009077 2.189530 0.575340 H54 -10.059234 1.993474 -1.168787 C55 -11.540520 0.827194 -0.110910

H56 -11.624436 0.283061 0.840683 H57 -11.669765 0.074441 -0.901745 C58 -12.672599 1.857418 -0.204772 H59 -12.541801 2.611177 0.583593 H60 -12.590555 2.398635 -1.157142 C61 -14.067185 1.235055 -0.089519 H62 -14.191618 0.715870 0.867590 H63 -14.851998 1.995147 -0.159257 H64 -14.241905 0.503008 -0.886161 C65 1.933251 4.843224 -0.169177 C66 2.695241 5.856353 0.438596 C67 0.730825 5.216233 -0.810129 C68 2.265914 7.179346 0.465062 H69 3.630973 5.577348 0.912106 C70 0.309818 6.536959 -0.811360 H71 0.143667 4.479353 -1.345737 C72 1.061884 7.529261 -0.163089 H73 2.873537 7.925313 0.962593 H74 -0.606267 6.829666 -1.313569 C75 -2.236413 -4.931747 0.238183 C76 -1.042003 -5.356512 -0.370163 C77 -3.005635 -5.895200 0.926979 C78 -0.617530 -6.681975 -0.278387 H79 -0.453329 -4.664510 -0.961301 C80 -2.578219 -7.205060 1.044783 H81 -3.939134 -5.577274 1.379747 C82 -1.376070 -7.613378 0.441757 H83 0.300516 -6.974957 -0.773084 H84 -3.160342 -7.941374 1.588791 O85 0.547865 8.789243 -0.211376 O86 -1.047763 -8.924688 0.604368 C87 1.254431 9.848841 0.434453 H88 1.367458 9.624895 1.505142 H89 2.261661 9.945452 0.003658 C90 0.458072 11.129895 0.232954 H91 -0.550305 10.983716 0.639079 H92 0.340490 11.304595 -0.843560 C93 1.120837 12.344517 0.894316 H94 1.241570 12.154885 1.969423 H95 2.134871 12.472266 0.491940 C96 0.326402 13.638077 0.691944 H97 -0.681039 13.554015 1.114226 H98 0.820041 14.487452 1.174347 H99 0.219828 13.874783 -0.372414 C100 0.155247 -9.414667 0.010748 H101 0.121367 -9.268813 -1.078685 H102 1.018805 -8.854594 0.397619 C103 0.273208 -10.892894 0.352814 H104 -0.620742 -11.410627 -0.015992 H105 0.271176 -11.001996 1.444274 C106 1.534403 -11.535115 -0.237970 H107 2.422186 -11.001962 0.127995 H108 1.532022 -11.409747 -1.329141 C109 1.657398 -13.023068 0.103359 H110 2.564421 -13.456862 -0.329068 H111 1.697452 -13.178250 1.187123 H112 0.801361 -13.589099 -0.280190

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APPENDIX II

Cyclic Voltammograms of Compounds 182

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MARIA KOYIONI

new ring transformations of 1,2,3-dithiazoles

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