DEVELOPMENT OF ORGANIC REACTION METHODOLOGY USING …
Transcript of DEVELOPMENT OF ORGANIC REACTION METHODOLOGY USING …
DEVELOPMENT OF ORGANIC REACTION METHODOLOGY
USING POLYMER-SUPPORTED REAGENTS, FOCUSED
MICROWAVES AND ON-WATER CHEMISTRY
A Thesis submitted to the University of North Bengal
For the Award of
Doctor of Philosophy
in
Chemistry
By
Kinkar Biswas
GUIDE
Prof. Basudeb Basu
Department of Chemistry
University of North Bengal
April-2016
Dedicated
TO
My Parents
&
Family members
ACKNOWLEDGEMENT
This thesis is the outcome of a long rigorous journey in which I have been encouraged and
supported by many peoples who actually make my dream possible. It is really pleasure moment
for me to express my full gratitude for them.
Primarily, I would like to express my deep and sincere gratitude to my supervisor Dr. Basudeb
Basu, Professor, Department of Chemistry, University of North Bengal, Darjeeling, for his
invaluable ideas, guidance and constant support during the entire period of my research work.
I wish to express my warm and sincere thanks to Prof. Dongyuan Zhao, Department of
Chemistry, Fudan University, Shanghai, P. R. China, for his assistance and support during my
research work.
I also would like to thank to Dr. Goutam De, Chief Scientist & Head, Nano-Structured Materials
Division, CSIR-CGCRI, Kolkata, for his valuable suggestion on metal nanocomposites of my
thesis work.
I express my full gratitude to Prof. Ashutosh Ghosh, University of Calcutta, Kolkata, India for
carrying out the single crystal XRD.
I gratefully acknowledge to Dr. A.K. Nanda, Prof. P. Ghosh and Dr. S. Das for recording and
interpreting NMR spectra.
I offer my special thanks to Yunke Jing, China and Shreyasi Chattopadhyay, Kolkata for their
valuable contribution in my scientific work.
I would like to thank my labmates, Sekhar Da, Bablee di, Susmita Di, Sujit, Babli Di, Debasish,
Samir, Sankar, Suchandra and Prasun for their help and active co-oparation throughout my
research period.
I convey my special thanks to Bhaskar, Joyanta, Antara, Sumanta, Kausik Da, Prasenjit and
Mossaraf for their constant support.
I am really lucky that I have spent some memorable moments with Sujit in my Ph.D. work.
I would like to express my thanks to CSIR, New Delhi, for awarding me Junior Research
Fellowship, University of North Bengal for providing the infrastructural facilities and DST, New
Delhi.
I express my full gratitude to Head and all respected teachers of Department of Chemistry,
University of North Bengal.
It’s my fortune to gratefully acknowledge my Teacher‒in‒Charge (TIC), Uttam Roy of Raiganj
College (University College, now Raiganj University) for giving me a chance for persuing my
Ph.D. programme.
I am really grateful to UGC, Kolkata for giving me the Teacher Fellowship under UGC‒FDP
programme.
I really acknowledge my elder brother for his constant inspiration throughout my life.
I would like to thank my wife Esha and my daughter Aishiki for their constant selflessness, love
and support.
I also acknowledge my all relatives and family members.
Last but not the least I like to acknowledge my Parents for their constant love and support.
Without them, I would not be half the person that I am today.
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ABSTRACT
The research work embodied in this thesis entitled “DEVELOPMENT OF ORGANIC
REACTION METHODOLOGY USING POLYMER-SUPPORTED REAGENTS,
FOCUSED MICROWAVES AND ON-WATER CHEMISTRY” is primarily focused on
polymer‒supported heterogeneous catalysis, „on‒water‟ and microwave‒assisted organic
reactions. The entire works essentially follow some principles of Green Chemistry. The work
was initiated in July 2008 as a CSIR‒NET‒JRF and completed with the support from UGC
under faculty development program. Based on different facets and contents of the work, the
thesis has been divided into five chapters.
As a prelude to present work, the Chapter I covers a brief review on the recent development and
trends towards polymer‒supported reagents and metal nanoparticle composites as heterogeneous
catalysts in organic reactions. Among diverse polymeric supports or assembly, the inorganic
polymers mainly utilized as suitable solid supports and metal encapsulating agents and
inorganic‒organic hybrid materials like Coordination Clusters, Metal Organic Frameworks are
used as metal embedding supports and further applications in diverse fields including catalysis.
Besides, the organic polymeric materials are discussed quite elaborately since the present work
in the next chapter is directed towards the use of organic polymeric resins as the suitable support
for the immobilization of mono‒ and bimetallic species and subsequent applications of the
resulting nanocomposites as heterogeneous catalysts. Illuminating examples along with merits
and demerits are discussed in this chapter with updated references.
Chapter II describes our works on the preparation of poly‒ionic resin embedded with bimetallic
(Pd & Fe) nanocomposites, their characterization by FT‒IR, powder XRD, AAS, SEM and TEM
analyses and subsequent use as catalyst in hydrodehalogenation of aromatic halides in the
presence of NaBH4 in aqueous THF. The new bimetallic nanocomposite consisting of palladium,
iron oxide and Amberlite resin formate has been found to be as an efficient, chemoselective and
recyclable heterogeneous catalyst. Enhanced catalytic activity has been explained in the light of
synergism between two metallic species and a plausible mechanism is proposed accordingly.
ii
The Chapter III is divided in three sections: Section A, B & C
Section A gives a concise background of „On‒water‟ chemistry in the field of organic synthesis.
The primitive reaction developed by Paul Anastus opened a new epoch in the field of organic
synthetic methodology. Though organic compounds are insoluble in aqueous medium but in
some cases, the reaction rates were found to be increased tremendously. This phenomenon has
been explained by two effects. Finally, these section ensembles some metal‒catalyzed and
without metal catalyzed organic reactions with interesting examples of recent work.
Section B details on Suzuki‒Miyaura coupling reaction at room temperature and „on‒water‟
conditions. In the present work, sodium salt of aryl trihydroxy borate was used as an efficient
water soluble organoboron species, which couple with aryl halides under Pd‒catalyzed
„on‒water‟ conditions. Other methods using aryl boronic acid/esters under „on‒water‟ conditions
often proceed very slow and/or incomplete conversions along with the difficulty to isolate the
products from the reaction mixture. The protocol was established as a general and practical
strategy with applications to wide variety of aryl halides. Further extension of this 'on water'
protocol was extended towards the preparation of some pharmaceutically important
benzimidazole‒ and benzotriazole‒based biphenyl scaffolds with appreciable conversions. A
comparison of the reactivity of using homogeneous Pd(OAc)2 and heterogeneous ARF‒Pd
catalyst has also been examined and excellent conversions of biaryls were obtained using both
types of catalysts.
Section C delineates our studies towards the 'click' thiol addition to alkynes leading to the
formation of (E/Z)‒vinyl sulfides, carried out under 'on‒water' conditions in the presence of a
range of additives. In general, the (E)‒isomer is formed preferentially. However, the
stereochemical outcome has been found to be dependent of the additives, which could be used as
'stereoselective switch' to E‒ or Z‒vinyl sulfides, though succinct reasons for the selectivity are
not understood. While a combination of Amberlite resin Chloride‒FeCl3 leads to maximum
Z‒stereoselectivity for reaction with aromatic thiols, the presence of D(+)‒glucose affords
iii
maximum Z‒stereoselectivity for reaction with aliphatic thiols. Other additives favor usual
formation E‒vinyl sulfides.
The Chapter IV describes an efficient and rapid protocol for the synthesis of libraries of
carbodithioate esters from organyl thiocyanates by reacting with cyclic amine‒based
dithiocarbamic acid salts in water. Alkyl thiocyanates, often considered as psuedohalides, are
reluctant to undergo substitution reaction with dithiocarbamate nucleophile and usually give rise
to the formation of disulfides under basic medium. The protocol is found to be applicable in
general to various thiocyanates like benzyl/aroyl methyl/cinnamyl etc. Other notable features
include no by‒products like disulfides, metal‒ and alkali‒free, aqueous conditions and finally
easy and near‒quantitative formation of cyclic amine‒based dithiocarbamic acid salt as stable
alternative reagent.
Chapter V depicts preparation of new CuI‒1,3‒dithioether coordination polymer complex,
characterization by NMR and single crystal X‒ray structure determination, and finally its
efficient role as catalyst in azide‒alkyne cycloaddition (AAC) reaction. Although few examples
of other dithioether‒based Cu(I) complexes are known in the literature, the present
1,3‒dithioether ligand‒based Cu(I) complex is not known, and there is no example of such
complexes used as the catalyst for the AAC reaction. The present study therefore establishes a
iv
new and convenient catalytic process for the one‒pot AAC in multi‒component manner, and the
catalytic system has been found to be recyclable. The yields of the cycloadducts are excellent in
diverse array of reactants. While trying the AAC under microwave irradiation however did not
give satisfactory results.
v
PREFACE
The ever increasing demand for efficient syntheses of novel organic compounds remains the
major driving force for the development of new and efficient greener methodologies.
Heterogeneous catalysis becomes important from both economic and environmental point of
view. The development of suitable polymer support to immobilize the reagents/catalysts
followed by its applications to various organic transformations is well accepted. Besides this,
„On‒water‟ reaction methodology and microwave assisted organic syntheses (MAOS) could
overcome the fulfillment of the preliminary requirements of Green chemistry.
The present research work describes the multidisciplinary approaches towards solid‒supported
organic synthesis, nanocatalysis and „on‒water‟ organic reaction methodologies. This thesis
begins with Chapter I, which introduces a brief review of different types of polymer supported
reagents/polymeric materials with special emphasis on ion‒exchange resin. Chapter II deals
with the synthesis and characterization of novel Pd/Fe2O3 bimetallic NPs soaked on Amberlite
Resin Formate (ARF) and application towards hydrodehalogenation reaction. Chapter III
contains three sectional parts; Section A gives a brief assessment of „On‒water‟ chemistry with
metal‒ or without metal‒catalyzed organic reactions. Section B deals with on‒water
Suzuki‒Miyaura coupling reaction using aryl trihydroxy borate salts as alternating boron partner
and Section C represents a general outline for the stereoselective switch of hydrothiolation
reaction with the aid of various additives in water at ambient conditions. A new methodology for
the synthesis of carbodithioate esters using dithiocarbamate salts of sec. amine and alkyl
thiocyanates has been described in Chapter IV. Finally, the Chapter V is to focus on the
synthesis and characterization of a novel polymeric catalyst involving CuI and 1,3‒dithioether
ligand and find application towards one‒pot azide‒alkyne cycloaddition reaction for the
regioselective synthesis of 1,4‒disubstituted 1,2,3‒triazoles isomers.
vi
TABLE OF CONTENTS
Abstract i‒iv
Preface v
List of Tables xi
List of Schemes xiii
List of Figures xvi
List of Appendices xviii
Appendix A: List of Publications xix
Appendix B: Oral Presentation & Poster Presentation xx
Abbreviation xxi
CHAPTER I Brief review on polymer‒supported metal NPs /reagent 1‒14
I.1. Polymer supports 2
I.2. Types of Polymer supports 3
I.2.1. Inorganic supports 3
I.2.1.1. Metal Oxides 4
I.2.1.2. KF/Al2O3 5
I.2.1.3. Clay Minerals
5
I.2.1.4. Silica 5
I.2.1.5. Zeolites 5
I.2.2. Hybrid polymeric assembly 6
I.2.2.1. Coordination clusters 6
I.2.2.2. Coordination polymers or Metal Organic
Framework (MOF)
7
I.2.3. Organic polymer supports 8
I.2.3.1. PVP and PPO 8
I.2.3.2. Dendrimers 9
I.2.3.3. Polysachharides 9
I.2.3.4. Polypeptides 10
I.2.3.5. Polystyrene Resins 10
I.2.3.6. Ion‒exchange resins 11
I.2.3.6.1. Types of ion‒exchange resins 11
I.2.3.6.2. Ion‒exchange resins as polymeric
supports for reagents
12
I.2.3.6.3. Ion‒exchange resins for
immobilization of metal NPs
12
I.3. References 14
CHAPTER II
Amberlite Resin Formate (ARF) and Pd/Fe2O3 Bimetallic
Nanocomposites (Pd/Fe–ARF): Enhanced and Chemoselective
Catalytic Activity in Hydrodehalogenation of Haloaromatics
15‒39
vii
II.1. Introduction 16
II.2. Background and Objectives 16
II.3. Present work: Results and Discussion 21
II.3.1. Preparation of (Pd/Fe‒ARF) 21
II.3.2. Characterization of the composites (Pd/Fe‒ARF) 22
II.3.2.1. FT‒IR Spectroscopy 23
II.3.2.2. Powder X‒ray diffraction patterns 24
II.3.2.3. Scanning electron microscopy (SEM) of ARF,
Fe‒ARF‒110 and Pd/Fe‒ARF nanocomposites
25
II.3.2.4. Transmission electron microscopy (TEM) of
ARF, Fe‒ARF and Pd/Fe‒ARF
nanocomposites
27
II.3.3. Catalytic activity of Pd/Fe–ARF–110
nanocomposites
30
II.3.4. Recycling Experiment 32
II.3.5. Comparison of turnover frequency of various
catalytic systems
33
II.3.6. Plausible Mechanism towards enhanced
catalytic activity
34
II.4. Conclusion 35
II.5. Experimental section 35
II.5.1. General information 35
II.5.2. Preparation Fe–ARF 36
II.5.3. Preparation of Pd/Fe–ARF–110 36
II.5.4. Preparation of Pd/Fe–ARF–110–OA 36
II.5.5. Preparation of Pd/Fe–ARF–110–NaOA 37
II.5.6. Typical procedure for hydrodehalogenation of
haloarenes in the presence of Pd/Fe‒ARF‒110
37
II.5.7. Physical properties and spectral data of compounds 38
II.6. References 39
CHAPTER III
SECTION A
“On‒water” organic reactions: A brief review 40‒46
III.A.1. On‒water Chemistry 41
III.A.2. Water Effects on Organic Reactions 41
III.A.2.1. Breslow Hydrophobic Effect 41
III.A.2.2. Marcus trans‒Phase H‒Bonding 42
III.A.3. Some examples of „on‒water‟ organic reactions 42
III.A.4. Metal–catalyzed Sp2 C–H bond activation and catalytic cross–coupling
reactions
45
viii
III.A.5. Disadvantages of water in organic reactions 45
III.A.6. References 46
CHAPTER III
SECTION B
„On‒water‟ Suzuki‒Miyaura reaction at ambient condition using
aryl trihydroxy borate salt as an alternative boron partner
47‒69
III.B.1. Introduction 48
III.B.2. Background and Objectives 50
III.B.3. Present work: Results and discussion 54
III.B.4. Conclusion 59
III.B.5. Experimental section 60
III.B.5.1. General information 60
III.B.5.2. General procedure for the preparation of aryl
trihydroxyboronate salts from boronic acids
60
III.B.5.3. General procedure for Suzuki‒Miyaura coupling reactions 60
III.B.5.4. Representative procedures for the synthesis of 7 and 8 60
III.B.5.5. Physical properties and Spectral data of compounds 61
III.B.6 References 69
CHAPTER III
SECTION C
In quest of “stereoselective‒switch” for on‒water hydrothiolation of
terminal alkynes using different additives and green synthesis of
vicinal dithioethers
70‒90
III.C.1. Introduction 71
III.C.2. Background and Objectives 72
III.C.3. Present Work: Results and Discussion 79
III.C.4. Conclusions 83
III.C.5. Experimental section 84
III.C.5.1. General information 84
III.C.5.2. General procedure for mono‒hydrothiolation of alkynes 84
III.C.5.3. General procedure for di‒hydrothiolation of alkynes 84
III.C.5.4. Physical properties and spectral data of compounds 85
III.C.6. References 90
CHAPTER IV
Cyclic ammonium salts of dithiocarbamic acid: Stable alternative
reagents for the synthesis of S‒alkyl carbodithioates from organyl
thiocyanates in water
91‒116
IV.1. Introduction 92
IV.2. Background and objectives 93
IV.3. Present Work: Results and Discussion 97
IV.4 Mechanism 104
ix
IV.5. Conclusion 104
IV.6. Experimental section 105
IV.6.1. General information 105
IV.6.2. General Procedure for the synthesis of cyclic ammonium
salts of dithiocarbamic acid (2b‒2e)
105
IV.6.2.1. Physical properties and spectral data of cyclic
ammonium salts of dithiocarbamic acid (2b‒2e) 105
IV.6.3. General procedure for the synthesis of S‒alkyl carbodithioate
esters 106
IV.6.3.1. Physical properties and spectral data of
carbodithioate esters 107
IV.7. References 116
CHAPTER V
Synthesis of new 1,3‒dithioether‒Cu(I) complex and its catalytic
action in one‒pot azide‒alkyne "click" reaction 117‒139
V.1. Introduction 118
V.1.1. Azide–Alkyne Cycloaddition (AAC) reactions 118
V.2. Background and Objectives 119
V.3. Present work: Results and Discussion 121
V.3.1. Preparation of 1,3‒bis(4‒fluorophenylthio)‒propane ligand
(L1)
121
V.3.2. Synthesis of CuI‒1, 3‒bis(4‒fluorophenylthio)‒propane (L1)
coordination complex (complex 1)
122
V.3.3. Characterization of complex 1 122
V.3.3.1. NMR spectroscopy 122
V.3.3.2. UV‒Visible and fluorescence spectroscopy 124
V.3.3.3. Single crystal X‒ray diffraction 126
V.3.4. Catalytic application 128
V.3.5. One‒pot two‒step process for the synthesis of sulfur
functionalized 1,2,3‒triazole derivative
131
V.3.6. Mechanism 131
V.4. Conclusion 132
V.5. Experimental section 132
V.5.1. General information 132
V.5.2. Procedure for the synthesis of 1,3‒bis(4‒fluorophenylthio)
‒propane (L 1)
133
V.5.3. Procedure for the synthesis of Complex 1 133
V.5.4. General procedures for Cu(I)‒catalyzed AAC reaction 133
V.5.5. Physical properties and spectral data of compounds 134
V.6. References 138
x
Bibliography
References for Chapter I 139‒142
References for Chapter II 142‒145
References for Chapter III, Section A 145‒146
References for Chapter III, Section B 146‒148
References for Chapter III, Section C 149‒150
References for Chapter IV 150‒153
References for Chapter V 153‒154
Index 155‒157
xi
LIST OF TABLES
Table No. Title Page No.
Table I.1. Description of Coordination clusters (CCs) for the general formula
of Mx(μ‒L)yL/z]
n
7
Table II.1. Symmetric and anti‒symmetric stretching vibrational data of ARF,
Fe‒ARF and Pd/Fe–ARF obtained at different temperatures
23
Table II.2. Optimization of reaction conditions for the hydrodebromination of
9,10 dibromoanthracene
30
Table II.3. Hydrodehalogenation of haloarenes in the presence of the
nanocomposite catalyst Pd/Fe–ARF‒110
31
Table II.4. Comparison of TOF of various catalytic systems tested in the
hydrodehalogenation of haloarenes
33
Table III.B.1. Optimization of Reaction Conditions of SM Coupling reaction 55
Table III.B.2. Suzuki‒Miyaura coupling reactions of aryl iodides with sodium
aryltrihydroxyborates in water
55
Table III.B.3. Suzuki‒Miyaura coupling reactions of aryl bromides with
sodium aryltrihydroxyborates in water
56
Table III.B.4. Suzuki‒Miyaura coupling reactions of aryl chlorides with
sodium aryltrihydroxyborates in water
57
Table III.B.5. SM coupling reactions with aryl trihydroxyborates in water
using heterogeneous Pd‒catalyst (ARF–Pd) 58
Table III.C.1. Role of additives in the addition of PhSH to phenylacetylene
under on‒water and at room temperature conditions
80
Table III.C.2. Hydrothiolation of aryl acetylene [A] with aromatic thiols [B] in
(1:1.1) molar ratios in water at room temperature
81
Table III.C.3. Hydrothiolation aromatic terminal alkynes with aliphatic thiols 82
Table III.C.4. Dihydrothiolation of aliphatic alkyne with thiols in water at room
temperature
83
Table IV.1. Optimization of the reaction conditions for the conversion of
benzyl thiocyanate to S‒alkyl cabodithioates
98
Table IV.2.
Synthesis of diverse S‒alkyl carbodithioates by varying organyl
thiocyanates and dithiocarbamate salts
100
Table IV.3. Further functionalizations in the synthesis of S‒alkyl
carbodithioates
103
Table V.1. Crystal Data, Data Collection and Structure Refinement for
complex 1
126
Table V.2. Selected bond length 127
Table V.3. Selected bond angle 128
Table V.4. Optimization of reaction conditions for the one‒pot azide‒alkyne
click reaction
129
xii
Table V.5. Catalytic activity of complex 1 in the AAC reaction
130
xiii
LIST OF SCHEMES
Scheme No.
Title
Page No.
Scheme I.1. Classification of polymer supports 3
Scheme I.2. Examples of some commonly used metal oxides 4
Scheme I.3. Organic reactions on KF‒Al2O3 and metal‒doped KF‒Al2O3
surface
5
Scheme I.4. Encapsulation of Pd/Rh bimetallic nanoparticles on PAMAM
dendrimer
9
Scheme I.5. Synthesis and Derivatization of PS‒Based Solid Supports
11
Scheme I.6. Immobilization of metal ions onto ion‒exchange resin 13
Scheme I.7. Amberlite resin formate in catalytic hydrogenation reactions 13
Scheme I.8. Preparation of ARF‒Pd 14
Scheme I.9. Preparation of bimetallic pd/Cu supported on ARF. 14
Scheme II.1. Oxygen reduction reaction using Pd/Fe catalyst 17
Scheme II.2. Hydrodehalogenation of haloaromatics using PdO in basic
condition and high temperature
17
Scheme II.3. Pd‒phosphite catalyst for the dehalogenation of aryl chlorides
and bromides
17
Scheme II.4. Study of hydrodebromination of 4,4/‒dibromobiphenyl using
PdCl2 and dppf ligand
18
Scheme II.5. Nanoscale zerovalent iron (nZVI) for the reduction of
Tetrabromobisphenol A (TBBPA)
18
Scheme II.6. Nickel catalyzed hydrodehalogenation of aryl halides with
iso‒propyl zinc bromide
18
Scheme II.7. A simple Pd(OAc)2 catalyzed hydrodehalogenation reaction
using 2‒butanol as hydrogen source
19
Scheme II.8. Zirconia‒supported Cu/Ni bimetallic catalyst for
hydrodehalogenation reaction
19
Scheme II.9. Polychlorinated biphenyls are dechlorinated by granular
activated carbon (GAC) composites
20
Scheme II.10. Polychlorobiphenyl reduced by Pd/Fe bimetallic nanotubes 20
Scheme II.11. Hydrodehalogenation method using Pt/Pd/Fe (1:1:2)
trimetallic nanoparticle and ammonium formate
20
Scheme II.12. Plausible mechanism for enhanced catalytic activity in
hydrodehalogenation using NaBH4 in water.
35
Scheme III.A.1. Demonstrative example of cycloaddition of quadricyclane
with azodicarboxylate
43
Scheme III.A.2. Rate acceleration of cycloaddition reaction in presence of
water
43
Scheme III.A.3. Various examples of on‒water organic reactions 44
xiv
Scheme III.A.4. Some examples of metal–catalyzed Sp2 C–H bond activation
and catalytic cross–coupling reactions
45
Scheme III.B.1. SM coupling reaction in aqueous microdrplets with
catalytically active fluoruos interfaces 50
Scheme III.B.2. Ligand‒free palladium catalyzed SM coupling reaction using
Microwave heating in water
51
Scheme III.B.3. Polyaniline (PANI) supported palladium nanoparticles as
semi‒heterogeneous catalyst for SM coupling reactions
51
Scheme III.B.4. Nonoionic amphiphiles mediated SM coupling in water. 52
Scheme III.B.5. A mild and efficient method for the synthesis of biaryls in
water and surfactants
52
Scheme III.B.6. Pd(OAc)2‒catalyzed SM reaction between alkyl
trifluoroborates and aryl halides
53
Scheme III.B.7. Pd/C‒catalyzed cross‒coupling of various aryl bromides with
sodium tetraphenylborate
53
Scheme III.B.8. Synthesis of aryl trihydroxy borate salts for the
Suzuki‒Miyaura coupling reaction 53
Scheme III.B.9. Pd(OAc)2‒catalyzed SM reaction in the presence of aryl
trihydroxy borate salts and aryl halides
54
Scheme III.B.10. Synthesis of 6a and 6b 59
Scheme III.B.11. Synthesis of benzimidazole– and benzotriazole–based
biphenyl scafolds 59
Scheme III.C.1. Substituted 2‒pyrimidyl vinyl sulfide used in materials
science
72
Scheme III.C.2. 1‒Alkenyl sulphides from hydrothiolation of terminal alkynes 72
Scheme III.C.3. Synthesis of 1,1‒Disubstituted alkyl vinyl sulfides by
rhodium catalyst 73
Scheme III.C.4. Preparation of MCM‒41‒2P‒RhCl(PPh3) 73
Scheme III.C.5. Hydrothiolation reaction in presence of heterogeneous
MCM‒41‒2P‒RhCl(PPh3) catalyst 73
Scheme III.C.6. Stereoslective synthesis of vinyl sulfides by Pd‒catalyzed
reaction
74
Scheme III.C.7. Polymer‒supported palladium catalyst for stereoselective S‒S
bond addition to terminal alkynes
74
Scheme III.C.8. Palladium catalyzed synthesis of cis‒configured vinyl
thioethers
75
Scheme III.C.9. Organoactinide‒mediated hydroyhiolation of terminal alkynes
with aliphatic, aromatic and benzylic thiols
75
Scheme III.C.10. Ni(acac)2 catalyzed regioselective synthesis of β‒vinyl
sulfides by hydrothiolation reaction
76
Scheme III.C.11. Mechanism of Ni‒NHC catalyzed hydrothiolation reaction. 77
xv
Scheme III.C.12. In(III)‒catalyzed substrate selective hydrothiolation of
terminal alkynes
77
Scheme III.C.13. Cu(I)‒catalyzed hydrothiolation under CO2 and argon
atmosphere
77
Scheme III.C.14. Hydrothiolation of alkynes with thiophenols in presence of
β‒Cyclodextrin in Water
78
Scheme III.C.15. Water‒promoted regioselective hydrothiolation reaction 78
Scheme III.C.16. Green synthesis of vicinal dithioethers and alkenyl thioethers 79
Scheme IV.1. One‒pot preparation of dithiocarbamate in water without
using any catalyst
93
Scheme IV.2. One‒pot clean method for the synthesis of carbodithioates 93
Scheme IV.3. One‒pot synthesis of 2‒hydroxydithiocarbamates in DES and
PEG
94
Scheme IV.4. Basic resin (Amberlite IRA 400) supported one‒pot synthesis
of dithiocarbamate
94
Scheme IV.5. Michael addition of aryl amines towards electron deficient
alkenes
94
Scheme IV.6. Synthesis of dithiocarbamates using [pmIm]Br ionic liquid. 95
Scheme IV.7. Markovnikov addition reaction of dithiocarbamate to ethyl
vinyl ether
95
Scheme IV.8. Ru(acac)3 catalyzed synthesis of allyl/cinnamyl
dithiocarbamates
96
Scheme IV.9. Metal free three‒component reaction of N‒tosylhydrazones,
carbon disulfide and amines
96
Scheme IV.10. Synthesis of sec. cyclic aliphatic amine‒based
dithiocarbamate salts 99
Scheme IV.11. Proposed reaction mechanism 104
Scheme V.1. The primitive Huisgen‟s 1,3‒dipolar cycloaddition reaction 118
Scheme V.2. CuBr.PhSMe‒catalyzed cycloaddition reaction of alkyl azide
and phenyl acetylene
119
Scheme V.3. Preparation of CuX2(SNS) catalysts and application towards
azide‒alkyne click reaction
120
Scheme V.4. Cu‒SNS catalyst for one‒pot azide‒alkyne cycloaddition
reaction
120
Scheme V.5. “Click‒and‒click” – hybridised 1,2,3‒triazoles supported
Cu(I) coordination polymers for azide–alkyne cycloaddition
121
Scheme V.6. One‒pot two‒step synthesis of sulfur functionalized
1,2,3‒triazole derivative
131
Scheme V.7. A plausible mechanistic path for the multicomponent AAC
reaction
132
xvi
LIST OF FIGURES
Figure I.1. Structure of Merrifield Resin 2
Figure I.2. A schematic diagram of the apoferritin 6
Figure I.3. A schematic presentation for the synthesis of metal–organic
framework (MOF)
8
Figure I.4. Structures of poly(N‒vinyl‒2‒pyrrolidone) (PVP) and
poly(2,5‒dimethylphenylene oxide) (PPO)
8
Figure I.5. Structure of Chitin and Chitosane 10
Figure I.6. Structures of various ion‒exchange resins 12
Figure II.1. Schematic preparative steps of Pd/Fe‒ARF–110
nanocomposites
22
Figure II.2. Photographic images of six nanocomposites 22
Figure II.3. FT‒IR spectra of ARF, Fe‒ARF and Pd/Fe‒ARF bimetallic
nanocomposites
23
Figure II.4. The powder XRD patterns of six nanocomposites prepared
under different conditions
25
Figure II.5. The SEM images of (a) ARF; (b) Fe–ARF–110; (c) Pd/Fe–
ARF–80; (d) Pd/Fe–ARF–110; (e) Pd/Fe–ARF–140; (f)
Pd/Fe–ARF–110–OA and (g) Pd/Fe–ARF–110–NaOA
nanocomposites, respectively
27
Figure II.6. TEM images: (a) of Fe–ARF–110 and (b) its average particle
size distribution histogram from (a); (c) of Pd/Fe‒ARF‒110
and (d) its average particle size distribution histogram from
(c); (e) of Pd/Fe–ARF–110–OA and (f) its average particle
size distribution histogram from (e); (g) of Pd/Fe–ARF–110–
NaOA and (h) its average particle size distribution histogram
from (g)
28
Figure II.7. (a) TEM‒EDX spectrum of Pd/Fe–ARF‒110
nanocomposites; (b) EDX elemental mapping image of
Pd/Fe2O3 bimetallic nanocomposites, green dots, Pd; red dots,
Fe
29
Figure II.8. Recycling experiments using Pd/Fe‒ARF‒110 catalyst in
hydrodebromination of 9, 10‒dibromoanthracene 33
Figure III.A.1. (a) Hydrated small hydrophobic aggregates, (b) hydrated
large hydrophobic aggregates
42
Figure III.B.1. The chemical structure of trityl losertan 48
Figure III.B.2. Structures of some drugs and pharmaceuticals containing
biphenyl moiety
49
Figure III.B.3. Structures of some analgesic drugs synthesized by SM
coupling reaction
49
xvii
Figure III.B.4. Biphenyls used in materials science 50
Figure III.C.1. Vinyl sulfides used as synthetic intermediates. 71
Figure III.C.2. Vinyl sulfides used as biologically active molecules 71
Figure III.C.3. Structures of Ni‒NHC complex and some NHCs 76
Figure IV.1 Structures of carbamic acid, thiocarbamic acid and
dithiocarbamic acid and their esters
92
Figure IV.2. Examples of compounds of potential therapeutic value
bearing S‒alkyl carbodithioate esters function
93
Figure IV.3. HRMS of compound 4b 102
Figure V.1. 1H‒NMR spectra of L1 [1,3‒bis(4‒fluorophenylthio)
‒propane] in d6‒DMSO
123
Figure V.2. 1H‒NMR spectra of complex 1 in d6‒DMSO 124
Figure V.3. UV‒Visible spectra of CuI, L1 and complex 1 were taken in
MeCN
125
Figure V.4. Fluorescence spectrum of complex 1(5 μM solution) in
MeCN solvent
125
Figure V.5. View of (a) the monomeric unit of the coordination polymer,
(b) ORTEP picture of the complex 1 and (c) infinite 1‒D
chain of complex 1 incorporating dinuclear Cu(μ2‒I)2Cu
motifs along „b‟ axis
127
xviii
LIST OF APPENDICES
APPENDIX A:
List of Publications
APPENDIX B:
Oral Presentation & Poster Presentation
xix
APPENDIX A
List of Publications
1. “Highly effective alternative aryl trihydroxyborate salts for a ligand‒free, on‒water
Suzuki–Miyaura coupling reaction” Basudeb Basu, Kinkar Biswas, Sekhar Kundu and
Sujit Ghosh, Green Chem., 2010, 12, 1734–1738.
2. “In Quest of „„Stereoselective Switch‟‟ for On‒Water Hydrothiolation of Terminal
Alkynes Using Different Additives and Green Synthesis of Vicinal Dithioethers”
Basudeb Basu, Kinkar Biswas, Samir Kundu, and Debasish Sengupta, Organic
Chemistry International, 2014, Article ID 358932.
3. “Cyclic ammonium salts of dithiocarbamic acid: Stable alternative reagents for the
synthesis of S‒alkyl carbodithioates from organyl thiocyanates in water”, Kinkar
Biswas, Sujit Ghosh, Pranab Ghosh and Basudeb Basu, accepted in J. Sulfur Chem., 2016
(DOI ‒ 10.1080/17415993.2016.1166225).
4. “Amberlite Resin Formate (ARF) and Pd/Fe2O3 Bimetallic Nanocomposites: Enhanced
and Chemoselective Catalytic Activity in Hydrodehalogenation of Haloaromatics”,
Kinkar Biswas, Shreyasi Chattopadhyay,
Goutam De,
Basudeb Basu, Yunke Jing and
Dongyuan Zhao (manuscript under preparation).
Review article
1. “Additives in Organic and Biochemical Reactions”, Kinkar Biswas and Basudeb Basu,
SMU Medical Journal, 2014, Vol. 1, No. 1, 29–40.
xx
APPENDIX B
Oral Presentation
“Synthesis, characterization and application of new heterogeneous Pd/Fe bimetallic
nanocomposites”, in the National Seminar “Frontier in Chemistry ‒2015” organized by
the Department of Chemistry, NBU and funded by UGC and SAP (DRS‒III), held at
University of North Bengal, Darjeeling, India, February 17‒18, 2015.
Poster Presentation
“Graphene oxide (GO) – an efficient carbocatalyst for the one‒pot tandem reduction and
cyclization for quinoxaline synthesis”, Babli Roy, Kinkar Biswas, Sujit Ghosh and
Basudeb Basu, National Symposium on Recent Trends and Perspectives in Chemistry
(RTPC‒2015), held at National Institute of Technology, Sikkim, India, January 23‒24,
2015.
“Role of additives in triggering stereoselective switch in alkyne hydrothiolation”, Sujit
Ghosh, Kinkar Biswas, Babli Roy, Susmita Paul, Bablee Mandal, Basudeb Basu, 12th
CRSI National Symposium in Chemistry & 4th
CRSI‒RSC Symposium in Chemistry, held
at Indian Institute of Chemical Technology (IICT), Hyderabad, India, February 4‒7,
2010.
“Highly effective alternative aryl trihydroxyborate salts for a ligand‒free, on‒water
Suzuki–Miyaura coupling reaction”, Sujit Ghosh, Kinkar Biswas, Sekhar Kundu and
Basudeb Basu, International Symposium (ISOC‒2009) on “Organic Chemistry: Trends
in 21st Century held at Indian Association for the Cultivation of Science (IACS), Kolkata,
India, December 10‒12, 2009.
“Catechol violet as new, efficient, and versatile ligand for Cu(I)‒catalyzed C–S coupling
reactions”, Kinkar Biswas, Bablee Mandal, Sajal Das, Susmita Paul, Sekhar Kundu,
Sujit Ghosh and Basudeb Basu, 11th
CRSI National Symposium in Chemistry (NSC‒11)
held at National Chemical Laboratory (NCL), Pune (India), February 6‒8, 2009.
xxi
ABBREVIATION
AAC Azide‒alkyne cycloaddition mol% Mole percent
ARF Amberlite resin formate MW Microwave oC Degree Celsius NHC N‒heterocyclic carbene
CCs Coordination clusters NMR Nuclear magnetic resonance
d doublet NPs Nanoparticles
dd doublet of a doublet nZVI Nanoscale zerovalent iron
DMF Dimethyl formamide OWCF On‒water catalyst‒free
DTCE Dithiocarbamate esters p‒XRD Powder X‒ray diffraction
DVB Divinyl benzene ROP Ring opening polymerization
EDX Energy‒dispersive X‒ray s singlet
GAC Granular activated carbon SEM Scanning electron microscope
h hour/hours SDS Sodium dodecyl sulfate
HOCs Halogenated organic compounds t triplet
HRMS High resolution mass spectrometry TBAB n‒tetrabutyl ammonium bromide
MAOS Microwave‒assisted
organic synthesis
TEM Transmission electron microscope
MHz Mega hertz THF Tetrahydrofuran
min minute TMEDA N,N,N/,N
/‒tetramethylethylenediamine
MOF Metal organic framework TOF Turnover frequency
1
CHAPTER I
Brief review on polymer‒supported metal NPs
/reagents
2
I.1. Polymer supports
Heterogeneous catalysis, performed over a solid surface is the heart of the modern energy
and chemical industries. Most of the recognized and emerging chemical processes are
performed using functional nanomaterials. Solid‒supported organic synthesis now become
promising over toxic and hazardous organic solvent‒based syntheses.1 Additionally the
Solid‒supported organic synthesis is important because it reduces pollution to the
environment, lowers the cost of the method and it is easy for handling.
Since the revolutionary work by Robert Bruce Merrifield (Nobel laureate in Chemistry on
1984) in polymer supports, it became the interesting topic in organic synthesis.2
This solid
phase procedure revolutionized polypeptide and polynucleotide synthesis, which is important
for pharmaceutical and combinatorial chemistry. The structure of Merrifield resin is actually
the copolymer of styrene and chloromethylstyrene. Additionally this polymer is also cross–
linked with divinylbenzene. The structure of the Merrifield resin is depicted in Figure I.1.
Cl
Cl Cl
Cl ClCl
Figure I.1. Structure of Merrifield Resin
After successful invention of Merrifield resin, solid‒supported organic synthesis became
hot topic in synthetic methodology. Polymer‒assisted solution‒phase synthesis,3a
has various
advantages over conventional solution‒phase chemistry in following aspects:
1) the supported species can be separated easily by filtration and washing,
2) workup procedures are simple,
3) reuse of supported reagent after reaction,
4) the ease of adaptation to continuous‒flow processes and hence use in automated
synthesis,
5) toxicity and odour of the species become reduced and
3
6) chemical differences, such as prolonged activity or altered selectivity of a catalyst in
supported form compared with its soluble analogue.
Now a days‟ scientists focus mainly on two factors associated with green chemistry namely
E‒factor and atom economy. The polymer‒supported organic synthesis must be one of the
ways to reduce the chemical and economical wastes. There are three important parameters
that impact on both the commercial viability and the inherent greenness of a particular
catalyst:3b
1) Selectivity – the amount of substrate converted to the desired product as a percentage
of total consumed substrate (a catalyst will be of limited benefit if it also enhances the
rate of by‒product formation).
2) Turnover frequency – the number of moles of product produced per mole of catalyst
per second (low turn over frequencies will mean large amounts of catalyst are
required, resulting in higher cost and potentially more waste).
3) Turnover number – the amount of product per mole of catalyst (this is related to
catalyst lifetime and hence to cost and waste).
I.2. Types of Polymer supports
Based on the requirement of different reaction conditions various types of polymer
supports are used.1b
They are classified mainly in three categories as (a) Inorganic supports,
(b) Inorganic‒organic hybrid polymeric matrices and (c) Organic supports (Scheme I.1).
Inorganic OrganicHybrid
1. Metal Oxides2. KF/Al2O3
3. Clay minerals4. Silica5. Zeolites.
1. PVP and PPO2. Dendimers3. Polysachharides4. Polypeptides5. Polystyrene Resin6. Ion-exchange Resin
1. Coordination clusters2. Coordination polymers or Metal Organic Framework (MOF)
Polymer supports
Scheme I.1. Classification of polymer supports
I.2.1. Inorganic supports
There is a variety of heterogeneous catalysts, but the most common types consist of an
inorganic or polymeric support, which may be inert or have acid or basic functionality,
4
together with a bound metal, Pd, Pt, Ni or Co. Due to inertness of the supports the reactants
are in a different phase to the catalyst. Therefore, both diffusion and adsorption influence the
overall rate of the catalytic reaction.
Surface area is one of the most important factors in determining throughput (amount of
reactant converted per unit time per unit mass of catalyst). Many modern inorganic supports
have surface areas of 100 to >1000 m2g
‒1. The vast majority of this area arises due to the
presence of internal pores; these pores may be of very fine size distribution to allow specific
molecular sized species to enter or leave. Materials with an average pore size of less than
1.5‒2 nm are named as microporous, whilst those with pore sizes above this are called
mesoporous materials. Materials with very large pore sizes (>50 nm) are named as
macroporous materials.3b
I.2.1.1. Metal Oxides
Metal oxides are generally used as inorganic polymeric supports. Some examples of the metal
oxide supports are given below (Scheme I.2).
Metal Oxides
MgO Al2O3 MnO TiO2 Fe2O3 ZnO ZrO2 CeO2
Scheme I.2. Examples of some commonly used metal oxides
A huge number of literature reports focus on the catalytic properties of NPs supported on
metal oxides, including oxides of Al,4 Ti,
5 Zr,
6 Mg,
7 Zn,
8 Ce,
9 Fe,
10 Mn,
11 some of the recent
examples are cited. The metal supports can stabilize one or more metal nanoparticles on to
their surface. Basic nanocrystalline magnesium oxide (MgO)‒stabilized palladium NPs was
found to be very active in the Suzuki‒Miyaura cross‒coupling of aryl bromides and iodides
with several arylboronic acids in pure water at room temperature.12
ZnO‒supported Pd,
Pd‒Ag, Pd‒Cu and Pd‒Ni catalysts (Pd‒M/ZnO) were also studied in Suzuki‒Miyaura cross‒
coupling reactions.13
Recently, cerium oxide (CeO2) has been extensively used as
photocatalyst and heterogeneous catalysts for organic reactions.14
Alumina is probably the
most common inorganic oxide that is used as the solid surface to catalyze or mediate a large
variety of organic reactions. Alumina surface can act as a base, as an acid or neutral medium
5
for catalyzing the organic reactions. Metal‒doped alumina composites were successfully
applied in C−S, C−N, C−O and C‒C cross‒coupling reactions.15
The catalyst stability
depends on the nature of the metal(s) and the support. For example, hydrogenation reaction
can be effectively achieved by CuNPs in the presence of calcined ZrO2 surface.16
I.2.1.2. KF/Al2O3
Alumina doped with potassium fluoride (KF/alumina) has been extensively used as solid
basic surface in vast range of organic transformations,17
since it was introduced by Ando and
Clark.18
KF/Al2O3 or metal‒doped KF/Al2O3 were used in various solvent‒free C−S, C−N,
C−O and C‒C bond formation reactions (Scheme I.3).19
KF-Al2O3
Metal-doped KF-Al2O3
N- or S- alkylation reaction
Ether synthesis
Epoxidation
Amide bond synthesis
Michael/Aza-Michael addition
Alkene synthesis
Heterocycles
Pd or Ni deposition
Pd/KF-Al2O3
Suzuki-Miyaura coupling
Ni/KF-Al2O3
Sonogashira coupling
Scheme I.3. Organic reactions on KF‒Al2O3 and metal‒doped KF‒Al2O3 surface
I.2.1.3. Clay Minerals
Finely grained crystalline sheet silicates form a large family of clay minerals, which act as
inert support for highly dispersed metals, metal complexes and enzymes etc.20
I.2.1.4. Silica
Polymorphic forms of silica, hydrated or anhydrous SiO2.xH2O is most often used as
catalyst‒support due to high surface area and large pore volumes. Common support material
consists of refractory oxides such as SiO2. This material exhibits high specific surface areas,
high porosities, and high thermal and mechanical stability and comes in a variety of pore
sizes, while they are mostly chemically inert.21
Silica surface, modified silica surfaces or
metal doped silica surfaces are also efficient for the various organic transformations.19
I.2.1.5. Zeolites
Zeolites are crystalline microporous aluminosilicates consisting of molecular‒sized
intracrystalline channels and cages used as highly selective adsorbents. These insoluble
6
supports have high surface area.22
Zeolites have a crystal structure, which is constructed from
TO4 tetrahedra, where T is either Si or Al. Each structure type is given a unique framework
code e.g. sodalite is SOD (no. of tetrahedral in ring = 4), zeolite‒A is LTA (no. of tetrahedral
in ring = 8) and ZSM‒5 is MFI (no. of tetrahedral in ring = 10).
I.2.2. Hybrid polymeric assembly
I.2.2.1. Coordination clusters
Supramolecular chemistry is often called molecular information science, dictates the
spontaneous assembly of non‒covalently linked molecular clusters of unique shape and
composition. This requires both a driving force and a dynamic system so that all possible
molecular structures can be explored to generate the formation of the thermodynamically
favored structures. An example of such a structure in nature is the iron storage protein
apoferritin (Figure I.2).23
L-Ferritin
H-Ferritin
Fe3+
Fe2+
Apoferritin Holoferritin
Figure I.2. A schematic diagram of the apoferritin
In the last two decades the synthesis and study of coordination clusters (CCs) of
paramagnetic metals in moderate oxidation states attract much attention in the field of
material chemistry.24
Some CCs have been characterized as a narrow‒waisted cylinder of
dimensions 2.8–3.1nm (Ag‒S) and the sizes were determined (the Mo species in the form of
anion having approximately the size of haemoglobin).25
The simplest general formula of CCs of 3d metals in moderate oxidation states is
[Mx(μ‒L)yL/z]
n, where μ‒L is a bridging organic or inorganic ligand, L
/ is a terminate ligand,
x is an integer number larger than 2, y and z are integer numbers and n can be zero
(molecule), positive (cationic CC) or a negative (anionic CC) integer number. The
classification of the CCs is divided in tabular form (Table I.1).
7
Table I.1. Description of Coordination clusters (CCs) for the general formula of
Mx(μ‒L)yL/z]
n.
Mx(μ‒L)yL/z]
n Designation
M x μ‒L L/ y z n
Metal integer>
2
bridging organic
or inorganic
ligand
terminate
ligand,
integer integer 0 Molecule
Metal integer>
2
bridging organic
or inorganic
ligand
terminate
ligand,
integer integer „+‟
integer
cationic CC
Metal integer>
2
bridging organic
or inorganic
ligand
terminate
ligand,
integer integer „‒‟
integer
Anionic CC
In many cases, two or more bridging ligands, often a combination of organic and inorganic
ones and more than one type of terminal (monodentate or chelating) ligands including solvent
molecules were used. This class of compounds is found in the literature with several names
such as oligomeric, polynuclear, highnuclearity or polymetallic complexes, cages, clusters
and CCs; but scientists generally prefer the later term.26
I.2.2.2. Coordination polymers or Metal Organic Framework (MOF)
In the recent years, the designs and constructions of oligo‒ and poly (nuclear) coordination
architectures attract much attention because of their new structural topologies and fascinating
architectures. It has been used in optoelectronic devices,27
microporous materials,28
and
catalysis.29
The smart combination of organic ligand “spacers” and metal ion “nodes” has been
considered as one of the most common synthetic methods to produce coordination polymers
with predictable networks (Figure I.3).30
8
0-D (Dot) 1-D (Chain)
2-D (Layer) 3-D (Network)
+
Metal ions Organic linkers
SolutionSelf assembly
Solid Phase
Figure I.3. A schematic presentation for the synthesis of metal–organic framework (MOF)
The advantage of constructing these metal–organic framework (MOF) architectures is to
allow a wide choice in various parameters, including diverse electronic properties and
coordination geometry of the metal ions, as well as versatile functions and structures of
organic ligands. That is also the aspiration for achieving the ultimate aim of crystal
engineering: gaining control of the topology and geometry of the networks formed through
sensible choice of ligand, metal precursor geometry and synthesis conditions.31
I.2.3. Organic polymer supports
I.2.3.1. PVP and PPO
Poly(N‒vinyl‒2‒pyrrolidone), PVP and poly(2,5‒dimethylphenylene oxide), PPO are the
most used polymer for NP stabilization and catalysis, because they fulfill both steric and
ligand requirements (Figure I.4). The metal NPs are stabilized through the steric bulk of
Polymeric framework. A very efficient olefin and benzene hydrogenation has been
effectively done by PVP stabilized Pt‒, Pd‒ and Rh NPs.22
NO
CH
CH2
n
PVP
Poly(vinylpyrrolidone)
O
n
PPOPoly(2,5-dimethylphenylene oxide)
Figure I.4. Structures of poly(N‒vinyl‒2‒pyrrolidone) (PVP) and poly(2,5‒dimethylphenylene oxide)
(PPO)
9
Toshima‟s group developed a very important concept of catalysis using two different
metals such as Au and Pd in the same NPs in the 1970.32
This idea has been beautifully
developed by Toshima‟s group who used PVP to stabilize core–shell bimetallic Au–PdNPs,
that is, NPs in which the core is Au and the shell is Pd.33
I.2.3.2. Dendrimers
Dendrimers are one of the classes of organic polymers but unlike polymers, there are
perfectly defined on the molecular level with a polydispersity of 1.0.34
They have shapes
resemblance to molecular trees or cauliflowers and become globular after a few generations.
They can entrap and stabilize metal NPs especially if there are heteroatoms in the
dendrimer‟s interiors.35
The dendritic branches and termini bind the small substrates into the
dendrimer and stabilize the NPs. The formation of NPs stabilized by dendrimers for catalysis
has been anticipated in 1998 by the three research groups of Crooks,35
Tomalia,36
and
Esumi.37
Metal NPs were introduced inside the dendrimers or at the dendrimer periphery.37
Poly(amidoamine), PAMAM is one of the common dendrimer, which is generally used to
entrap the metal ions. A schematic diagram of bimetallic nanocomposites on PAMAM
dendrimer has been established by Crook where two metals were simultaneously entrapped in
the polymeric matrix (Scheme I.4).
RhCl3, K2PdCl4
Complexation
NaBH4
reduction
Reactant
ProductPd2+
Rh3+Pd/Rh bimetallic
PAMAM dendrimer
(Agglomeration)
Scheme I.4. Encapsulation of Pd/Rh bimetallic nanoparticles on PAMAM dendrimer
PAMAM dendrimer PdNP catalysts can be effectively used as oxidation, reduction, Heck
coupling reaction and Suzuki‒Miyaura C‒C coupling reactions.38
I.2.3.3. Polysachharides
Starch, cellulose and other polysaccharides are used as greener renewable sources and
found applications to the field of catalysis. Starch is the second largest biomass on the planet
and as such represents one of the most important renewable resources for the future needs of
a sustainable society. Starch is an inexpensive polysaccharide extracted from renewable
agricultural resources (rice, potatoes, wheat and corn etc). It has wide applications due to its
10
biodegradability and biocompatibility properties. Trimethylene Carbonate (TMC)
ring‒opening polymerization (ROP) was performed in the presence of native starch
particles.39
Cellulose nanofibers are inherently low cost and are easily available and treated as
eco‒friendly material as they are easily recyclable.40
Chitosan (CS), the N‒deacetylated
derivative of chitin (chitin is a long chain polysaccharides of N‒acetyl glucosamine, a
derivative of glucose), that is widely used as suitable solid supports for the immobilization of
a metal catalyst (Figure I.5).41
O
OH
NHO
CH3OH
NHO
CH3
HO
HO*O
*
nChitin
OH
HOHO O
OH
O
OH
NH2
OHHO
NH2 NH2
n
Chitosane
Figure I.5. Structure of Chitin and Chitosane
Cyclodextrines are also bio‒polymers used in various organic transformations.42
I.2.3.4. Polypeptides
Micellar amphiphilic block copolymers containing a hydrophobic polypeptide block have
received much attention, mainly due to the possible applications in drug delivery.43
Elias et al
reported first example of an amphiphilic block polypeptide based Pd‒catalyst for
hydrogenation of acetopheneone in water medium.43
Marcelo et al described the synthesis of
magnetite polypeptide solid support and used it as a recoverable catalyst for the reduction
reaction. They modified the magnetite−polypeptide nanoparticles introducing new molecules
of dopamine via aminolysis, which can act as support of gold NPs.44
I.2.3.5. Polystyrene Resins
The polymeric supports used by Merrifield for his early work in solid‒phase peptide
synthesis were based on 2% divinylbenzene (DVB) cross–linked polystyrenes (PS). PS has
been found to be one of the most accepted polymeric materials used in various syntheses
because it is inexpensive, readily available, mechanically robust, chemically inert and
smoothly functionalizable. Various percentages and types of cross–linking agents have been
incorporated into the PS resins, the most common being DVB, but other examples include
ethylene glycol dimethylacrylate (EGDMA) and tetraethylene glycol diacrylate (TEGDA) to
11
give different solvation properties. A schematic representation of polymerization of styrene
with functionalized monomers is shown in Scheme I.4.45
RadicalInitiatorO
O
O
O
DVBEGDMA
or
Cl
ClPS
XPS
Macroporous orGel based resin
Cross-Linkers
X = NH2 aminomethyl-PSX = OH hydroxymethyl-PS
Derivatization
PS = polystyrene
+
Scheme I.5. Synthesis and derivatization of PS‒based solid supports
TentaGel,46
and ArgoGel,47
are two commercially available polymeric resins where the
incorporation of the PEG chains dramatically increases resin compatibility with polar
solvents.
PS‒based phosphine catalysts have been found to be synthesized and used for palladium
entrapment. The PS‒supported Pd catalysts were used for various C−C cross–coupling
reactions.48
Similarly, PS‒supported Rh and Ru catalyst were also prepared and used for
various organic transformations.45
I.2.3.6. Ion‒exchange resins
Various techniques were introduced over the last few decades relating the immobilization
procedure onto insoluble polymer support material so that the catalyst can be quantitatively
separated by filtration and recycled.
Ion‒exchange materials are those insoluble substances, which can able to immobilize the
metals onto it. Ion‒exchange materials are insoluble substances containing loosely held ions,
which are able to be exchanged with other ions in solutions.
Most ion‒exchange resins are comprised on cross–linked polystyrene‒divinylbenzene
copolymers containing ion‒exchanging functional groups.49
I.2.3.6.1. Types of ion‒exchange resins
The ion‒exchange resins are classified into two major groups: They are mainly,
Cation exchanger (containing anionic functionalities and positively charged mobile
ions): Cation exchangers are further divided into two groups such as,
12
Strong acid exchange (e.g., containing sulfonic acid groups or the
corresponding salts) and
Weak acid exchange (e.g., containing carboxylic acid groups or the
corresponding salts) resins.
Anion exchanger (with cationic functionalities) Similarly anion exchangers are
divided into two groups such as,
Strong base exchange (e.g., containing quaternary ammonium groups) and
Weak base exchange (e.g., containing ammonium groups) resins.
Other ion‒exchanging materials include homopolystyrene and acrylic based resins and
Nafion, a perfluorinated polymer containing sulfonic acid.50
I.2.3.6.2. Ion‒exchange resins as polymeric supports for reagents
Amberlyst‒15 is routinely used in organic synthesis as heterogeneous reusable acid
catalysts for various selective transformations of simple and complex molecules.51
Structures
of some polymer‒supported reagents, generally used in oxidation reactions, reduction
reactions are given below in the Figure I.6.3 The selective reduction of functional groups is a
common need in organic synthesis. Borohydride exchange resin (BER),52
was introduced in
the 1970s and has since proven to be of considerable value in the reduction of organic
compounds. This reagent reduces both ketones and aldehydes readily to corresponding
alcohol. Halogenation is one of the important steps for the synthesis of various important
intermediates and molecules. Polymer‒supported halogenization reagents are also used for
the halogenations of alkenes or alkynes (Figure I.6).3 C−C bond formation reactions and
substitution reactions have also been achieved with polymer‒supported reagents.53
NMe3 IO4 NMe3 OOH
= PS(cross-linked)
NMe3 BH4
BER = Borohydride exchange resin
= Amberlyte A-26
NMe3 Br3
Reducing agentOxidizing agent Halogenation agent
Figure I.6. Structures of various ion‒exchange resins
I.2.3.6.3. Ion‒exchange resins for immobilization of metal NPs
13
Immobilization of metal ions and charged metal complexes onto ion‒exchange resin is an
equilibrium process driven by noncovalent electrostatic interactions (Scheme I.5, strong
cation exchanger example). The affinity and selectivity of resins varies with the ionic size
and charge of the ions. Generally, the affinity is greatest for large ions with high valence.54
SO3YPS (MLk)x+Zx
-
x
(MLk)x+ xY+Z-Solvent
Y = H, Na, Li M = metal L = ligand Z = PF6, BF4
SO3PS
Scheme I.6. Immobilization of metal ions onto cation‒exchange resin
Anion exchange resin‒supported metal catalysts are very influential for various organic
transformations. Many different metals were found to immobilize on these metal surfaces
with tremendous catalytic efficiencies.55,56
It was found that Amberlite IRA‒900 anion (chloride form) exchange resins,
commercially available and inexpensive poly‒ ionic resin, could be able to exchange the
anion with formate anion (HCOO¯) easily and quantitatively. The resulting Amberlite Resin
Formate (anion), designated as ARF, could be utilized as a solid‒phase version of the
H‒donor in Pd‒catalyzed catalytic transfer hydrogenation. The ARF was air stable and
recovered from a reaction easily. Several alkenes, imine
and nitroarenes
were thus
hydrogenated using the ARF and catalytic amount of palladium acetate under mild conditions
and C‒C and C‒Hetero atom bonds can also be generated by this catalyst.57
NR3
Aq. HCOOH
Cl
(10%; v/v) NR3
HCOO
Amberlite IRA Chloride form
Amberlite IRA Formate form
X
R3
R2
R1
R4
NR3
HCOO
Pd(OAc)275 oC, DMF
X
R3
R2
R1
R4
R1 = R2 = PH, Ar, HR3 = R4 = COOEt, COOMe, CN, NHBoc, Ph, HX = C, N
NO2
R5
NR3
HCOO
Pd(OAc)2100-120 oC, DMF
NH2
R5
R5 = Cl, COMe, Me, COOMe, OH
14
Scheme I.7. Amberlite resin formate (ARF) in catalytic hydrogenation reactions
The ARF bound Pd was synthesized in our laboratory by the following technique (Scheme
I.8).57a,b
ARF-Pd
NR3
HCOO
Pd(OAc)2
Na2PdCl4
DMF
Stirring at RTNR3
HCOO Pd
Scheme I.8. Preparation of ARF‒Pd
By applying this technique, a new and efficient catalytic system was developed in our
laboratory, which was successfully applied in catalytic reduction and C‒C cross‒coupling
reactions.18,58
Bimetallic NPs supported on ARF was also synthesized and characterized. The
Pd/Cu‒ARF bimetallic nanocomposites was prepared and used successfully for Sonogashira
coupling reaction.59
ARF-Pd/CuNR3
HCOO
Pd(OAc)2
Cu(OAc)2
DMF
60 oC, 1h
Scheme I.9. Preparation of bimetallic Pd/Cu supported on ARF
I.3. References
References are given in BIBLIOGRAPHY under Chapter I (pp. 139−142).
15
CHAPTER II
Amberlite Resin Formate (ARF) and Pd/Fe2O3
Bimetallic Nanocomposites (Pd/Fe–ARF):
Enhanced and Chemoselective Catalytic Activity
in Hydrodehalogenation of Haloaromatics
16
II.1. Introduction
Bimetallic heterogeneous catalysis offers attractive opportunities to the perspectives of
„Green Chemistry‟ due to some common features viz. simplicity of work‒up, recyclability,
and minimization of metallic ravage.1
Carbon‒carbon,2,3
carbon‒heteroatom bond‒forming
reactions,1
click reactions,1
hydrogenation,4
and hydrodehalogenation reactions,5
are
efficiently done by using bimetallic nanoparticles (NPs). Incorporation of one metal to
another metal on solid surface can modify the catalytic properties on the surface and it can
alter/tune an organic reaction effectively. For example, palladium pervoskite‒oxide lattice
was used as an alternative electrocatalyst for oxygen reduction reaction (ORR). By doping of
a Pd ion to pervoskite lattice gave LaFe0.95Pd0.05O3‒δ and LaFe0.9Pd0.1O3‒δ and these catalysts
exhibited mass activity, durability than commercial Pt/C catalysts (Scheme II.1).6
O2 Oxygen Reduction Reaction OH
ORR activity: (Pi)Pd3/4+> Pd2+> Pd0
Scheme II.1. Oxygen reduction reaction using Pd/Fe catalyst
Hydrogenation reactions can be done by Ru/Sn, Ni/Pd or Co/Si nanoclusters supported
with silica or other polymeric materials have been successfully used.4
Similarly,
carbon‒carbon cross‒coupling reactions are often carried out by using bimetallic catalysts
involving Pd/Rh,7 Pd/Ni,
3b Pd/Cu nanoparticles (NPs),
2 etc with high efficiency and
selectivity. Indirect functionalization of alcohols with 1,3‒dimethylbarbituric acid followed
by spiro‒cyclization by Ir/Pd bimetallic catalyst.8 R. Grigg et al. reported a novel sequential
palladium/ruthenium‒catalyzed three‒component process where allene insertion followed by
olefin metathesis led to the formation of heterocycles.9
II.2. Background and Objectives
Halogenated aromatics, like polyhalogenated biphenyls, polychlorinated
dibenzo‒p‒dioxins (PCDDs), dibenzofurans (PCDFs) etc. are often highly toxic to the human
and animals and it becomes a serious threat to environmental pollution.9 Several
hydrodehalogenation methods have been developed by using many monometal‒based
systems namely Pd, Fe and Ni catalysts.
10‒13 But some of these methods have been carried out
at a high temperature by using inorganic bases and toxic ligands, and requiring long reaction
time.10, 14
Some methods for hydrodehalogenation reaction are discussed below:
17
PdO bound on polystyrene beads was effective for hydrodehalogenation of haloaromatics.
This catalytic system showed good catalytic acitivities for the hydrohalogenation and
required 10 mol% PdO and 1.5 equivalent of K3PO4 as base and high temperature, 110 oC
(Scheme II.2).10b
X
R
10 mol% PdOK3PO4 (1.5 eqiv)
DMF/ Cyclohexanol
110 oC, 12 h
H
R
R = 4-Me, 2-MeO, 4-MeO, 3-MeO, 4-t-Bu, 4-OH, 4-Ph, 1-Naphthyl, 2-Pyridyl, X = I, Br and Cl
Scheme II.2. Hydrodehalogenation of haloaromatics using PdO in basic condition and high
temperature
The catalytic system based on Pd–phosphite for the dehalogenation reactions of aryl
chlorides and bromides has been described by S. Lee et al. In this case the Pd–phosphite
catalyst effectively promoted the dehalogenation of aryl halides to give dehalogenated
products in moderate to excellent yields in the presence of a strong base and required high
temperature (Scheme II.3).10c
Cl
R
Pd2(dba)3
Ligand
NaOtBu, i-PrOH
80 oC, 3 h
H
R
Br
R
Pd2(dba)3
Ligand
Cs2CO3, Cyclohexanol
120 oC, 10 h
O
tBu
Me
tBu
P
O
O
O
P
O
O
But
But
Me O
tBu
Me P
O
O
O
P
O
O
But
Me
Phosphite ligands
Scheme II.3. Pd‒phosphite catalyst for the dehalogenation of aryl chlorides and bromides
Hydrodebromination of 4,4/‒dibromobiphenyl has been demonstrated by T. S. A. Hor and
his group. In this methodology 4,4/‒dibromobiphenyl was reduced to biphenyl by PdCl2 and
1,1/‒bis(diphenylphosphino)ferrocene (dppf). NaBH4 used as reductant (Scheme II.4.).
11b
18
PdCl2, dppf
NaBH4, TMEDATHF
BrBr
Scheme II.4. Study of hydrodebromination of 4,4/‒dibromobiphenyl using PdCl2 and dppf ligand
Tetrabromobisphenol A (TBBPA), one of the most widely used brominated flame
retardants were debromoinated by nanoscale zerovalent iron (nZVI) in methanol/water
(50/50, v/v) solutions. Zerovalent iron nanoparticles debrominated the TBBPA to
tribromobisphenol A, dibromobisphenol A, bromobisphenol A and bisphenol A. More than
86% of TBBPA was debrominated within 16 h in a pH of 7.5 and the reaction solution
initially containing 3.0 g/L of nZVI. A higher dosage of nZVI in addition to acidic conditions
facilitated the debromination process (Scheme II.5).12
HO
Br
BrCH3
CH3
Br
OH
Br
HO
CH3
CH3
OH HO
CH3
CH3
OH
Br
HO
Br
BrCH3
CH3
OH
Br
HO
BrCH3
CH3
OH
Br
+
+
BPA BBPA
Di-BBPA Tri-BBPA
Debromination
n-ZVI
Scheme II.5. Nanoscale zerovalent iron (nZVI) for the reduction of Tetrabromobisphenol A
(TBBPA)
A nickel‒catalyzed hydrodehalogenation of aryl halides with iso‒propyl zinc bromide or
tert‒butylmagnesium chloride has been developed by S. Enthaler et al. (Scheme II.6).13
N ONi
ON
F3CC tBu
Ph
PPh3
X
R
5 mol% Ni-cat.
1.5 eqiv.-iPrZnBr
THF
70 oC, 24 h
H
R
Nickel catalystX = I, Br, Cl
Scheme II.6. Nickel–catalyzed hydrodehalogenation of aryl halides with iso‒propyl zinc bromide
A practical and high‒yielding protocol for the dehalogenation of aromatic halides in the
presence of palladium acetate, triphenylphosphine and potassium carbonate was developed
by H. Zhang et al. A number of highly functionalized aromatic halides and α‒haloketones
were dehalogenated with 2‒butanol as hydrogen donors at 100 oC (Scheme II.7).
14b
19
X
R
Pd(OAc)2, Ph3P, K2CO3
2-butanol, 100 oC, 12 h
H
R
X = I, Br, Cl
Scheme II.7. A simple Pd(OAc)2–catalyzed hydrodehalogenation reaction using 2‒butanol as
hydrogen source
Like monometal based systems, various bimetallic NPs have been developed for
hydrodehalogenation of halogenated compounds. K. Parida et al. found that mesoporous
zirconia supported copper and nickel bimetallic catalysts was employed for
hydrodehalogenation reaction of chlorobenzenes and substituted chlorobenzenes in the
presence of H2 gas at room temperature (Scheme II.8).10c
ClnR
mmol of substrate/mmol of metal= 10
H2 flow rate = 10 mL/min Methanol = 10 mL, RT, 2 h
Hn
R
R = 4-Me, 4-MeO, 4-OH, 4-NO2
Cu-Ni/ZrO2
5-9 nm size of metal nano particlesRecycle for 3rd run
Scheme II.8. Zirconia‒supported Cu/Ni bimetallic catalyst for hydrodehalogenation reaction
A few reports on various Pd/Fe‒based bimetallic nanocatalysts are also known to catalyze
hydrodehalogenation reactions. However, in most cases, the catalyst preparative methods are
tedious, expensive, found to be limited with specific chloro‒or bromo‒ compounds. In other
words, their catalytic efficiency was not investigated with general applicability to diverse
aromatic/aliphatic halides. For example, poly(vinylidene fluoride)‒alumina
membrane‒supported Pd/Fe nanocatalyst has been prepared and used in the dechlorination of
only monochloroacetic acid.15
S. R. Al‒Abed et al. developed an effective strategy, employing a series of innovative
granular activated carbon (GAC) composites incorporated with iron/palladium (Fe/Pd)
bimetallic nanoparticles. In this methodology the polychlorinated biphenyls were first
adsorbed on the GAC surface and their electrochemical dechlorination by Fe/Pd bimetal on
the same surface could be simultaneously achieved (Scheme II.9).16
20
Granulated activated charcoal (GAC)
Pd (2-3 nm)
Zero valent iron (ZVI)Cl
2-Chloro biphenyl Biphenyl
Scheme II.9. Polychlorinated biphenyls are dechlorinated by granular activated carbon (GAC)
composites
Pd/Fe bimetallic nanotubes have been prepared and employed for hydrodehalogenation of
only polychlorobiphenyls (Scheme II.10).17
Cl
Cl
Cl
Cl
Polychloro biphenyl BiphenylPd/Fe nanotubes
Scheme II.10. Polychlorobiphenyl reduced by Pd/Fe bimetallic nanotubes
Huang et al. prepared Pd/Fe bimetallic catalysts with micron sizes and employed
specifically for the hydrodehalogenation of tetrabromo‒ or tetrachlorobisphenol A.5e,f
S. Balalaie et al. synthesized the homogeneous Pt/Pd/Fe trimetallic nanoparticle using a
water‒in‒oil microemulsion system of water/AOT/isooctane at room temperature. This
nanopaticle was characterized by various physical techniques and used as
hydrodehalogenation of halogenated organic compounds (HOCs). It was found that the
Pt/Pd/Fe (1:1:2) trimetallic combination was superior to other bimetallic combinations (Pt/Pd,
Pt/Fe or Pd/Fe). The trimetallic catalyst was effective even after fifth catalytic run whereas
the bimetallic combination Pd/Fe (1:1) losses its catalytic activity after first run (Scheme
II.11)5d
Aliphatic halides or aromatic halides
Pt/Pd/Fe+ Dehalogenated ProductNH4OCOHiso-propanol
Scheme II.11. Hydrodehalogenation method using Pt/Pd/Fe (1:1:2) trimetallic nanoparticle and
ammonium formate
21
Surprisingly, there is no example of Pd/Fe‒based heterogeneous nanocatalyst, which could
perform in general hydrodehalogenation of various haloaromatic compounds. It is therefore
imperative to develop new material‒based bimetallic nanocatalysts, which should be broadly
applicable to all types of haloaromatics with high efficiency and recyclability.
In connection with our interest in developing efficient and environment‒friendly catalysts,
we have been able to develop a new heterogeneous catalyst involving palladium and iron
species embedded with macroporous amberlite resins formate (ARF) and designated as
Pd/Fe–ARF. The ARF has been prepared from poly‒ionic amberlite resins chloride by our
previously reported conditions.18
Pd/Fe–ARF was prepared by co‒immobilization of
palladium and iron on the poly‒ionic resin surface. The nanocatalysts were characterized by
spectroscopy (FT‒IR), scanning electron microscopy (SEM), transmission electron
microscopy (TEM), TEM with energy dispersive X‒ray (EDX) analysis and powder X‒ray
diffraction (XRD) patterns. Furthermore, the nanocomposite (Pd/Fe–ARF) has been used as
recyclable and general catalyst with enhanced and chemoselective activity in the
hydrodehalogenation reactions of potentially hazardous and all kinds of haloaromatics except
fluoroarenes.
II.3. Present work: Results and Discussion
II.3.1. Preparation of (Pd/Fe‒ARF)
The Amberlite resin formate (ARF) was prepared according to our previously reported
procedure,18
the Fe–ARF–110 was synthesized from FeCl3 (162 mg, 1 mmol) in ARF (500
mg) and bimetallic nanocomposites (Pd/Fe–ARF) were prepared through co‒impregnation
mode from ARF (500 mg) and palladium chloride (0.473 mmol) and anhydrous ferric
chloride (0.493 mmol) at varying temperatures (80, 110 & 140 oC) which have been denoted
as Pd/Fe‒ARF–80, Pd/Fe‒ARF–110 and Pd/Fe‒ARF–140. Since fatty acid salts are known to
be used as stabilizer in controlling size and shape of nanoparticles,19
we prepared two other
varieties of Pd/Fe‒ARF in the presence of capping agents like oleic acid and sodium oleate at
110 oC and corresponding nanocomposites were designated as Pd/Fe‒ARF‒110‒OA (with
oleic acid) and Pd/Fe‒ARF‒110‒NaOA (with sodium oleate) respectively. All five
as‒synthesized bimetallic nanocomposite materials were characterized by spectroscopic,
p‒XRD and microscopic techniques and compared with the orginal support ARF. Images for
the preparative steps of Pd/Fe‒ARF–110 are given in the Figure II.1 below as demonstration.
22
Figure II.1. Schematic preparative steps of Pd/Fe‒ARF–110 nanocomposites
The photos of all six nanocomposites are shown in the Figure II.2.
Figure II.2. Photographic images of six nanocomposites
Characterization of the nanocomposites was performed using various techniques and
discussed below.
II.3.2. Characterization of the composites (Pd/Fe–ARF)
The morphology and microstructure of the samples were examined by FT‒IR
spectroscopy, X‒ray diffraction patterns (powder XRD), scanning electron microscopy
(SEM) and transmission electron microscopy (TEM) and TEM equipped with energy
dispersive X‒ray (EDX) analysis.
23
II.3.2.1. FT‒IR Spectroscopy
The FT–IR spectra of bimetallic composites were recorded in the range 4000–400 cm−1
and compared with that of ARF. Figure II.3 shows the comparative FT–IR spectra in the
range of 2000–400 cm−1
. The carboxylate anion (HCOO−) of the ARF exhibits both
symmetric and anti‒symmetric stretching vibrationsat 1349 and 1590 cm−1
respectively, while
those of Pd/Fe‒ARF‒110 display similar absorptions at 1420 and 1611 cm−1
. Such significant
shifting of absorption bands (71–21cm−1
) might be attributed to metal–oxygen attachment in
the composites.18
Similar spectra and shifting of stretching vibrations for the carboxylate
anion (HCOO−) were also observed for other five nanocomposites Fe‒ARF, Pd/Fe‒ARF‒80,
Pd/Fe‒ARF‒140, Pd/Fe‒ARF‒OA and Pd/Fe‒ARF‒NaOA.
Figure II.3. FT‒IR spectra of ARF, Fe‒ARF and Pd/Fe‒ARF bimetallic nanocomposites
Table II.1. Symmetric and anti‒symmetric stretching vibrational data of ARF, Fe‒ARF and Pd/Fe–
ARF obtained at different temperatures
2000 1750 1500 1250 1000
16301611
1572
ARF
1380
1349
1590
Fe-ARF
Pd/Fe-ARF-110
Pd/Fe-ARF-140
Pd/Fe-ARF-80
1480
1664
Pd/Fe-ARF-NaOA
1420
Pd/Fe-ARF-OA
Tra
ns
mit
tan
ce
(%
)
Wavenumber (cm-1
)
24
Sl.
No.
ARF and Nanocomposites Symmetric stretching
of (HCOO−) (in cm
‒1)
Anti‒Symmetric
stretching of
(HCOO−) (in cm
‒1)
1. ARF 1349 1590
2. Fe–ARF 1420 1611
2. Pd/Fe–ARF–80 1420 1630
3. Pd/Fe–ARF–110 1420 1611
4. Pd/Fe–ARF–140 1420 1611
5. Pd/Fe–ARF–110–OA 1420 1611
6. Pd/Fe–ARF–110–NaOA 1420 1611
II.3.2.2. Powder X‒ray diffraction patterns
The Bragg diffraction patterns obtained by powder XRD of all six different
nanocomposites are shown in Figure II.4. The XRD patterns of the samples confirmed the
presence of α‒Fe2O3, small amount of Fe3O4 and Pd,20
along with amorphous characteristics
of the organic polymeric resins in the range 2θ of 20o.2
XRD pattern of Fe‒ARF‒110 showed
presence of peaks at 2θ of 25, 33, 35, 42, 50, 54, 63 and 65o
corresponding to the (012),
(104), (110), (113), (024), (116), (214) and (300) planes, respectivelyof α‒Fe2O3
(JCPDS#01‒087‒1166).21
Whereas, in the case of Pd/Fe‒ARF‒80 the peaks related to only
cubic Pd were observed at 2θ values of 40o and 46° correspond to (111) and (200) planes
(JCPDS#01‒087‒0643), and no peaks of α‒Fe2O3 can be detected. On the other hand, XRD
patterns of both Pd/Fe‒ARF‒110 and Pd/Fe‒ARF‒140 exhibited co‒existence of α‒Fe2O3
and cubic Pd. In this case a trace of Fe3O4 was also found (JCPDS #01–075–0449). Presence
of both Fe3O4 and α‒Fe2O3 along with cubic Pd was also observed for both the composites
Pd/Fe‒ARF‒110‒OA and Pd/Fe‒ARF‒110‒NaOA. Furthermore, the approximate particle
size of the metal nanoparticles in the composites (Pd/Fe–ARF–80, Pd/Fe–ARF–110, Pd/Fe–
ARF–140 and Pd/Fe–ARF–110–OA) were calculated using Scherer equation from the
respective Pd (111) peak and found to be ~4–5 nm in all cases. However, signature of any
metallic Fe(0) nanoparticles were not observed in such bimetallic nanocomposites.22
25
Figure II.4. The powder XRD patterns of six nanocomposites prepared under different conditions
II.3.2.3. Scanning electron microscopy (SEM) of ARF, Fe‒ARF and Pd/Fe‒ARF
nanocomposites
The preparation conditions (mainly temperature) affect the structure, shape (or
morphology), and size distribution of the metal nanoparticles incorporated in the resins.23
The
surface morphology of Fe–ARF and Pd/Fe–ARF nanocomposites, prepared at different
temperatures and conditions were examined by scanning electron microscopy (SEM) and
compared with that of ARF and presented in Figure II.5. Distinct variations of the surface
morphologies are observed, presumably because of the deposition of metal NPs on the
surface of poly‒ionic resinous materials. Several dots are seen in the images of the
composites at same magnification, which could be due to the NPs deposited on to the surface.
In Figure II.5.a, some pores are clearly seen (marked by red circles) on the macroporous ARF
resin surface while for the Fe‒ARF or Pd/Fe‒ARF nanocomposites (Figure II.5.b‒g), these
pores are diminished due metal nanoparticles deposition.
10 20 30 40 50 60 70 80
(21
7)
(11
9)
(12
5)
(30
0)
Fe-ARF
(220)
(20
0)
Fe3O
4
Pd/Fe-ARF-110
Fe2O
3Pd (Cubic)
(11
1)
(21
4)
(11
6)
(02
4)
(11
3)(1
10
)
(10
4)
Pd/Fe-ARF-110-NaOA
(01
2)
Pd/Fe-ARF-110-OA
Pd/Fe-ARF-140
Unidentified
Inte
ns
ity
Pd/Fe-ARF-80
2 (degree)
26
27
Figure II.5. The SEM images of (a) ARF; (b) Fe–ARF–110; (c) Pd/Fe–ARF–80; (d) Pd/Fe–ARF–
110; (e) Pd/Fe–ARF–140; (f) Pd/Fe–ARF–110–OA and (g) Pd/Fe–ARF–110–NaOA nanocomposites,
respectively
II.3.2.4. Transmission electron microscopy (TEM) of ARF, Fe‒ARF and bimetallic
Pd/Fe‒ARF nanocomposites
Further analysis of the TEM image for Fe–ARF–110 indicates the presence of α‒Fe2O3
nanoparticles on ARF surface (Figure II.6). Similarly the TEM images of Pd/Fe–ARF
nanocomposites prepared at different conditions presented in Figures II.6.(c)‒(h). The
presence of metal/metal oxide nanoclusters with a fairly regular size is clearly evident from
the Figure II.6 (a, c, e and g). The average particle size distribution histogram for the Fe–
ARF–110, Pd/Fe–ARF–110, Pd/Fe–ARF–110–OA and Pd/Fe–ARF–110–NaOA were also
estimated (from Figure II.6 (b, d, f and h)). The mean diameter of Fe2O3 and Pd/Fe2O3
nanoparticles are given in the respectives histogram pictures. It is clearly seen from the
figures that most of the Pd/Fe2O3 nanoparticles were found in fairly regular size of 4.78 nm in
Pd/Fe–ARF–110 nanocomposites (Figure II.6, d).
0 1 2 3 4 5 6 7 8 9
0
5
10
15
20
25
30 (b)
4.24 nm
%
Average diameter (nm)
0 1 2 3 4 5 6 7 8 9
0
10
20
30
40(d)
4.78 nm
%
Average diameter (nm)
28
0 2 4 6 8 10 12 140
5
10
15
20
25
30(f)
3.13 nm
4.17 nm
%
Average diameter (nm)
2 3 4 5 6 7 8 9
0
5
10
15
20
25
(h)
5.0 nm
4.28 nm
%
Average diameter(nm)
Figure II.6. TEM images: (a) of Fe–ARF–110 and (b) its average particle size distribution histogram
from (a); (c) of Pd/Fe‒ARF‒110 and (d) its average particle size distribution histogram from (c); (e)
of Pd/Fe–ARF–110–OA and (f) its average particle size distribution histogram from (e); (g) of Pd/Fe–
ARF–110–NaOA and (h) its average particle size distribution histogram from (g)
Energy‒dispersive X‒ray spectroscopy (EDX) of TEM images was performed to obtain
elemental composition of the bimetallic composite. The EDX spectrum taken from one of the
bimetallic nanoparticles of Pd/Fe–ARF–110, revealed the presence of both Pd and Fe. This is
further confirmed by EDX elemental mapping of the same region, which is shown in Figure
II.7.(b). Pd (green) and Fe (red) particles are found with carbon particles (white) of resin
materials.
29
(b)
Figure II.7. (a) TEM‒EDX spectrum of Pd/Fe–ARF‒110 nanocomposites; (b) EDX elemental
mapping image of Pd/Fe2O3 bimetallic nanocomposites, green dots, Pd; red dots, Fe
30
II.3.3. Catalytic activity of Pd/Fe–ARF–110 nanocomposites
After the synthesis and charaterization of the ARF‒supported bimetallic composite, the
catalytic activity of the Pd/Fe‒ARF‒110 was evaluated in hydrodehalogenation reaction. As
discussed above, haloaromatic compounds are known to be toxic pollutants in the
environment. Initially, as the model case, we studied the catalytic activity and reaction
conditions in the hydrodebromination of 9,10‒dibromoanthracene using the reductant
NaBH4. The results are presented in Table II.2. At room temperature, the reaction did not
proceed smoothly even after 16 hours and the isolated yield of the desired product was only
10% (entry 1). Further increase in temperature did show minor increase in yield (entry 2).
However, carrying out the reaction in a mixture of THF:H2O (2:1) resulted in profound
change in the course of the reaction, and the hydrodebrominated product was obtained in high
yield (96%) (entry 3). While decreasing the quantity of the catalyst from 100 to 50 mg
mmol‒1
gave rise to similar conversion (entry 4), further lowering of the catalyst to 25 mg
mmol‒1
could not afford excellent conversion (entry 5). The reaction did not proceed in the
absence of NaBH4 and the catalyst, respectively, keeping other conditions unchanged (entries
7 & 8). Among different conditions were attempted, best conversion was achieved in the
presence of the catalyst (50 mg mmol‒1
; 0.0474 mmol of Pd and 0.0493 mmol of Fe) and
N,N,N/,N
/‒tetramethylethylenediamine (TMEDA) in THF:H2O (2:1) mixture at 70
oC under
aerobic condition (entry 4).
Table II.2. Optimization of reaction conditions for the hydrodebromination of 9,10
dibromoanthracene.
Br
Br
Pd/Fe-ARF-110, NaBH4
Base, Solvent, Temp.
Entry Solvent Base Catalyst
(mg)
Temperature
(oC)
Time (h) Yielda (%)
1 THF TMEDA 100 RT 16 10
2 THF TMEDA 100 70 16 25
3 THF:H2O (2:1) TMEDA 100 70 4 96
4 THF:H2O (2:1) TMEDA 50 70 5 96
5 THF:H2O (2:1) TMEDA 25 70 10 60
6 THF:H2O (2:1) Et3N 50 70 7 80
7b THF:H2O (2:1) TMEDA 50 70 22 Nil
31
8c THF:H2O (2:1) TMEDA 00 70 16 Nil
Reaction conditions: 9, 10‒dibromoanthracene (1 mmol), NaBH4 (4 mmol), TMEDA (4 mmol),
THF:H2O (2:1, (v/v), 2 mL), Pd/Fe–ARF‒110 catalyst (50 mg). aIsolated yield after purification by column chromatography by silica.
bNo NaBH4 was added.
cNo catalyst was used.
With the optimized reactions at our hand (Table II.2, entry 4), we attempted similar
hydrodehalogenation reaction of a range of mono‒ and poly‒substituted haloarenes.
Gratifyingly, in each case, near‒quantitative conversion was achieved under the optimal
reactions conditions. The results are shown in Table II.3. Different aromatic halides (Cl,
Br and I) are smoothly reduced under the catalytic conditions. In the case of
poly‒substituted bromoaromatic such as 2,4,6‒tribromophenol or tetrabromobisphenol A
(TBBPA), the reaction, however, took longer reaction time (9‒12 h) (Table II.3, entries 4 and
5). Mixed aromatic halide, 3‒bromochlorobenzene also underwent easy reaction with
near‒quantitative conversion (entry 9). However, sp2CF bond could not be removed with
this catalyst under the condition (entry 11). Since conjugated CC double bonds are also
reducible, we tested one example bearing both double bond and bromide groups.
Gratifyingly, the double bond remained unchanged, while complete hydrodebromination
occurred indicating chemoselective nature of the catalyst (entry 12).
Table II.3. Hydrodehalogenation of haloarenes in the presence of the nanocomposite catalyst
Pd/Fe–ARF‒110a
Entry Haloarenes Time
(h)
Product Yield
(%)
1 Br NHCOCH3
4.5 NHCOCH3
95
2
Br
Br
5
96
3 BrBr
5
97
4 OHBr
Br
Br
9
OH
96
32
5 OH C
CH3
CH3
OH
Br
BrBr
Br
12
OH C
CH3
CH3
OH
90
6
NBr Br
4.5
N
90
7 NH2Cl
5 NH2
96
8 OHCl
Cl
5 OH
91
9
Br Cl
5
96
10 I
4
94
11 F NH2
12 NH2
Nilb
12 O
Bun
Br
5 O
Bun
87
a Haloarene (1 mmol), NaBH4 (4 mmol), TMEDA (4 mmol), THF:H2O (2:1, (v/v), 2 mL), Pd/Fe–
ARF–110 (50 mg), heating the reaction mixture at 70 oC under aerobic condition.
bNot detected in HPLC analysis.
II.3.4. Recycling Experiment
Catalytic efficiency of a catalyst is often measured by its life cycle i.e. stability,
selectivity, turn over number (TON) and turn over frequency (TOF). In order to check the
recycling potentiality, we isolated the catalyst (Pd/Fe‒ARF‒110) by simple filtration
followed by washing with water, acetone and then drying under vacuum. The recovered
catalyst was used in the hydrodebromination of 9,10‒dibromoanthracene. The catalyst was
found to be effective for consecutive five runs tested without any significant drop in respect
of conversion (Figure II.8).
33
1 2 3 4 5
0
20
40
60
80
100
Isola
ted y
ield
(%
)
No. of runs
Figure II.8. Recycling experiments using Pd/Fe‒ARF‒110 catalyst in hydrodebromination of
9,10‒dibromoanthracene
II.3.5. Comparison of turnover frequency of reported similar catalytic systems
It is noteworthy to mention that previous studies involving Pd/Fe bimetallic catalysts in
hydrodehalogenation reaction have not used aqueous NaBH4 as the hydrogen source, though
monometallic Pd or Ni complexes have been used as the catalysts in the presence of aqueous
NaBH4. A comparative catalytic efficiency, as presented in Table II.4, revealed that
monometallic complexes did show better TOF, possibly due to their function as
homogeneous catalysts. However, they are not recoverable and reusable. On the other hand,
the reported bimetallic catalysts did show relatively poor TOF as compared to our catalytic
system.
Table II.4. Comparison of TOF of various catalytic systems tested in the
hydrodehalogenation of haloarenes.
Entry Catalyst Hydrogen Source TOF (hr‒1
)a References
1 Pd/Fe bimetallic
nanotubes
Ethanol/water 0.0262 [17]
2 Vermiculite supported
nanoscale ZVI dopped
with Pd (Pd/Fe‒VMT)
Acidic solution 0.00595 [5c]
3 Micron sized Pd/Fe
bimetallic catalyst
KHPO4, dil. HCl in
methanol
0.5137 [5e]
34
4 PdCl2(dppf)2 NaBH4 0.472 to 38 [24a]
5 Tetraazabicyclo based
Nickel (II) complex
NaBH4 19.51 [24b]
6 Pd/Fe‒ARF‒110 NaBH4 4.05 This study aTOF was calculated based on experimental data. TOF = mmol of product/ mmol of catalyst per hour.
II.3.6. Plausible Mechanism towards enhanced catalytic activity
In quest of the enhanced catalytic activity exhibited by this newly prepared heterogeneous
bimetallic system, we attempted to explore on its mechanistic function in the
hydrodehalogenation reaction. Literature survey towards the mechanism of the
hydrodehalogenation reaction with bimetallic catalysts revealed that the reaction goes
through the reductive catalytic pathway where one metal (particularly iron or zinc) generates
hydrogen through corrosion with water and the second metal is used as a dopant to form
metal hydride. Nanosized bimetallic particles with zero valent iron such Ni/Fe or Pd/Fe with
large surface area has profound effect on the degradation of haloaromatics due to the increase
of the availability of surface reaction sites.25
On the other hand, it is known that the reaction
of NaBH4 with water liberates hydrogen slowly at room temperature, and can be accelerated
with the aid of metal NPs coated on metal oxides or on carbon. For example, Pt NP coated on
LiCoO2, Pt/C or Pd/C, due to their (Pt or Pd) higher d‒band center, were found to be
excellent catalysts to generate hydrogen from aqueous NaBH4 solution.26,27
Using our
catalyst, the reaction slowly proceeds without adding water (Table II.2, entry 3) and does not
proceed at all in the absence of NaBH4 (Table II.2, entry 7). We therefore tend to believe that
the origin of the active reducing source is NaBH4. Since our catalytic system consists of
Pd/Fe(III), where iron oxide itself cannot produce hydrogen from the reaction of NaBH4 and
water effectively,26
we presume that a synergism between Pd(0) and Fe(III) NPs in the
bimetallic system might exist, which makes faster BH bond‒breaking and H* formation.27
Subsequently hydride transfer to oxidative addition species [ArPdX] results in the
formation of dehydrohalogenated product, as proposed in Scheme II.12.
The high activity of Pd on iron oxide at low temperature may also be attributed due to the
redox properties and oxygen storage capabilities of iron oxides. It is seen that the partially
reduced iron oxide (i.e. Fe3O4) provides sorption sites for O2 in form of Fe2+
ions and thereby
acts as oxygen sink. Electron transfer effect between metal oxide and Pd makes the
composites to be active one.28
35
Scheme II.12. Plausible mechanism for the enhanced catalytic activity in the hydrodehalogenation of
haloaromatics using NaBH4 in water
II.4. Conclusion
In summary, we have developed a new heterogeneous bimetallic nanocomposite material
based on amberlite resin formate, palladium and iron oxides that exhibits enhanced catalytic
performance for the hydrodehalogenation of haloaromatic compounds. A synergism between
the two metal species dispersed on the polymeric surface in combination with aqueous
NaBH4 as the reducing source could be responsible for excellent catalytic activity. This is
unique since no such combination has ever been explored. Furthermore, the heterogeneous
catalyst has been found to be recyclable with nearly equal efficiency tested for five
consecutive runs. The newly developed catalytic system is found to be better as compared to
other similar catalysts used for this reaction in terms of easy method of preparation, cheap
starting materials, avoiding any precious ancillary ligands, mild reaction conditions, and
applicability to diverse aromatic halides, high TOF and recyclability.
II.5. Experimental section
II.5.1. General information
Amberlite IRA 900 (chloride form) was purchased from Acros Organics, Belgium and
used after washing with water and acetone followed by drying under vacuum. Other
chemicals were purchased and used directly. FT‒IR spectra were recorded with a
FT‒IR‒8300 SHIMADZU spectrophotometer using a KBr pellet method. NMR spectra were
taken in CDCl3 using a Bruker Avance AV‒300 spectrometer operating for 1H at 300 MHz
36
and for 13
C at 75 MHz. The spectral data were measured using TMS as the internal standard.
The X‒ray diffraction (XRD) studies of the powder samples were done using the Rigaku
SmartLab (9 kW) diffractometer using CuKa radiation.
The amberlite resin formate (ARF) was prepared from commercially available amberlite
IRA 900 (chloride form) (source: Acros Organics, Belgium) by rinsing with 10% aqueous
sodium formate solution until free from chloride ions. The resin beads were then washed with
water followed by acetone, dried under vacuum, and used for the preparation of
heterogeneous bimetallic nanocomposites.
II.5.2. Preparation Fe–ARF
To a homogenize solution of FeCl3 (162 mg, 1 mmol) in DMF (8 mL), 500 mg of ARF
(the globular beads were pulverized to dust particles) was added, and the mixture was stirred
for 5 mins at room temperature. Then the mixture was taken in a screw‒capped sealed tube
and heated at 110 oC for 8 h with occasional shaking. The yellow supernatant liquid after
filtration gives red coloured composite materials. The material was washed with dry and
distilled DMF (3×5 mL) followed by distilled water (2×5 mL) and acetone (2×5 mL). The
resulting dust composites were dried under vacuum.
II.5.3. Preparation of Pd/Fe–ARF–110
To a solution of PdCl2 (84 mg, 0.473 mmol) and FeCl3 (80 mg, 0.493 mmol) in DMF (8
mL), 500 mg of ARF (the globular beads were pulverized to dust particles) was added, and
the mixture taken in a screw‒capped sealed tube was heated at 110 oC for 8 h with occasional
shaking. The supernatant liquid appeared completely colourless by this time and ARF powder
turned black. The mixture was cooled to room temperature and the powdered composite
materials were filtered off, washed thoroughly with dry and distilled DMF (3×5 mL)
followed by distilled water (2×5 mL) and acetone (2×5 mL). The resulting shining black
dusty materials were dried under vacuum and used for analysis and catalytic reactions.
Pd/Fe–ARF–80 and Pd/Fe–ARF–140 were also prepared according to the above procedure at
80 and 140 oC respectively.
II.5.4. Preparation of Pd/Fe–ARF–110–OA
To a solution of oleic acid (282 mg, 1mmol) in DMF (5 mL), 500 mg of dust ARF was
added and heated at 110 oC in a screw‒capped sealed tube for 1 h. Then a solution of PdCl2
(42 mg, 0.237 mmol) and FeCl3 (154 mg, 0.947 mmol) in DMF (3 mL) was added to the
37
mixture of oleic acid and ARF. The overall reaction mixture was heated for 8 h at 110 oC
gives a fairly black colour nanocomposite of Pd/Fe2O3. The clear supernatant liquid was
filtered‒off and the black residue was washed with dry and distilled DMF (3×5 mL) followed
by acetone (4×5 mL). The black materials were dried under vacuum and characterized.
II.5.5. Preparation of Pd/Fe–ARF–110–NaOA
Sodium oleate was first prepared by titration of the ethanolic solution of oleic acid with
ethanolic solution of sodium ethoxide in pH‒meter. The white solid appeared was filtered‒off
by rotary evaporator under azeotrope distillation. To a solution of sodium oleate (304 mg,
1mmol) in DMF (5 mL), 500 mg of dust ARF was added and heated at 110 oC in a
screw‒capped sealed tube for 2 h. Then a solution of PdCl2 (42 mg, 0.237 mmol) and FeCl3
(154 mg, 0.947 mmol) in DMF (3 mL) was added to the mixture of sodium oleate and ARF.
The overall reaction mixture was heated for 8 h at 110 oC gives a brownish‒black coloured
nanocomposite of Pd/Fe2O3. The supernatant liquid was filtered‒off and the brownish‒black
residue was washed with dry and distilled DMF (3×5 mL) followed by distilled water (2×5
mL) and acetone (3×5 mL). The black materials were dried under vacuum and characterized.
II.5.6. Typical procedure for hydrodehalogenation of haloarenes in the presence of
Pd/Fe‒ARF‒110
To a suspension of Pd/Fe–ARF‒110 (50 mg) in THF:H2O (2:1, v/v, 2 mL), haloarene (1
mmol), TMEDA (4 mmol), NaBH4 (4 mmol) were added. The reaction mixture was then
heated in a round‒bottomed flask fitted with condenser and maintaining gentle magnetic
stirring for hours, as noted in Table II.3. The progress of the reaction was monitored by tlc.
After completion of the reaction, the mixture was diluted by water (5 mL), and filtered off the
catalyst. The filtrate was extracted with DCM (4×10 mL) and the combined organic extracts
were washed with brine (1×5 mL), dried over anhydrous Na2SO4 and concentrated under
vacuum. The residue was purified by passing through a short silica gel column
chromatography and eluted with light petroleum or mixture of ethyl acetate–light petroleum
to afford the desired hydrodehalogenated product. All products were characterized by 1H,
13C
NMR and FT‒IR spectral data, and also compared with the reported melting points (for
known solid compounds). The conversion to benzene, pyridine, aniline or phenol was
checked and compared by HPLC analysis.
38
II.5.7. Physical properties and spectral data of compounds
Table II.4, Entry 1
N‒phenylacetamide29
HN
O
CH3
White solid, mp 112‒113 oC (Lit.
29 109‒114
oC)
1H NMR (CDCl3, 300 MHz): δ/ppm 2.05 (s, 3H, ‒CH3), 6.98‒7.03 (m, 1H), 7.17‒7.22 (m,
2H), 7.41‒7.43 (m, 2H), 7.78 (s, 1H, ‒NHCOCH3).
13C NMR (CDCl3, 75 MHz): δ/ppm 24.4, 120.1, 124.3, 128.9, 138.0, 169.0.
Table II.4, Entry 2
Anthracene30
White solid, mp 112‒113 oC (Lit.
30 109‒114
oC)
1H‒ and
13C‒NMR spectra of this compound could not determine in CDCl3 or d6‒DMSO
solvent due to solubility problem.
Table II.4, Entry 3
Biphenyl31
White crystalline solid, mp 67‒68 oC (Lit.
31 68‒70
oC)
1H NMR (CDCl3, 300 MHz): δ/ppm 7.47‒7.52 (m, 2H), 7.56‒7.61 (m, 4H), 7.74‒7.77 (m,
4H).
13C NMR (CDCl3, 75 MHz): δ/ppm 127.3, 127.4, 128.9, 141.4.
Table II.4, Entry 5
Bisphenol‒A32
CH3
CH3
OHHO
39
White solid, mp 218‒219 oC (Lit.
32 220
oC)
1H NMR (d6‒Acetone, 300 MHz): δ/ppm 1.58 (s, 6H), 6.69‒6.75 (m, 4H), 7.02‒7.37 (m,
4H); 8.16 (s, 2H, ‒OH).
13C NMR (d6‒Acetone, 75 MHz): δ/ppm 30.6, 41.1, 114.5, 127.5, 141.9, 155.0.
Table II.4, Entry 10
Naphthalene30
White crystalline solid, mp 79‒81oC (Lit.
30 80‒82
oC)
1H NMR (CDCl3, 300 MHz): δ/ppm 7.55‒7.58 (m, 4H), 7.91‒7.96 (m, 4H).
13C NMR (CDCl3, 75 MHz): δ/ppm 125.9, 127.9, 133.5.
Table II.4, Entry 12
(E)‒Butyl cinnamate33
O
O
Colourless liquid
IR (KBr): νmax = 2358, 2330, 2959, 2932, 1713, 1638 cm
‒1.
1H NMR (CDCl3, 300 MHz): δ/ppm 0.92 (d, J = 2.1 Hz, 3H, ‒CH2CH2CH2CH3), 1.30‒1.43
(m, 2H, ‒CH2CH2CH2CH3), 1.58‒1.67 (m, 2H, ‒CH2CH2CH2CH3), 4.08‒4.17 (m, 2H,
‒CH2CH2CH2CH3); 6.37 (d, J = 16.2 Hz, 1H), 7.29‒7.34 (m, 3H), 7.43‒7.46 (m, 2H), 7.60
(d, 1H, J = 15.9 Hz).
13C NMR (CDCl3, 75 MHz): δ/ppm 13.7, 19.2, 30.8, 64.4, 118.3, 128.0, 128.8, 130.2, 134.5,
144.5, 167.1.
II.6. References
References are given in BIBLIOGRAPHY under Chapter II (pp. 142−145).
40
CHAPTER III
SECTION A
“On‒water” organic reactions: A brief review
41
III.A.1. On‒water Chemistry
Organic solvents have played a key role in the development of useful products. One of the
key roles of the organic solvents is to homogenize the reactants and speeding up reactions
through improved mixing. But, volatile organic solvents (VOCs) have adverse effects on the
environment, which includes conjunctivital irritation, nose and throat discomfort, headache,
allergic skin reaction, dyspnea, nausea, fatigue and dizziness. Because of these adverse health
effects, benign non‒volatile solvents are introduced in the organic reactions. Supercritical
carbon dioxide (scCO2) and supercritical water (scH2O) have tremendous synthetic utility in
organic reactions. But due to the corrosive properties of the supercritical fluids, the uses of
these solvents are limited as reaction media.1
So, water plays an important role in organic
synthesis regarding environmental aspects. Water is unique due to its some unusual
properties like a large temperature window in which it remains liquid, exclusive hydrogen
bonding, high heat capacity and large dielectric constant. It is not treated as popular choice of
solvent in organic synthetic chemistry because functional groups of organic molecule may
themselves react with water and most of the organic molecules are highly insoluble in it due
to their hydrophobic nature. So, it is assumed that a mixture of water and nonpolar organic
reactants will usually give low yields of the desired products. But, recent findings told that
both the rates and selectivity of organic reactions can be increased by addition of water.2
Water has ability to form weak non‒covalent bonds with other compounds and to connect in
electron transport reactions as exemplified by many biological and synthetic reactions.3 So
water has a tremendous demand as a solvent or additive to carry out organic reactions.
The reactions in aqueous medium are mainly divided into two categories namely
„in‒water‟ and „on‒water‟ reactions. In both of these cases, the reactions are classified
according to the solubility of the reactants and products. In the case of „in‒water‟ reactions
both the substrates are soluble in water but the product is insoluble on the same medium
whereas for „on‒water‟ reactions the substrates and the products are completely insoluble in
water. After reaction, the water is free from organic materials in both of these cases. This is
sometimes called „ideal green reactions‟.4 In general water is considered as „„green solvent‟‟
for organic reactions; though, chemical reactions performed „in‒ or on‒water‟ are not
generally considered as greener reactions and often do not satisfy the requirements of ideal
green processes.3
III.A.2. Water Effects on Organic Reactions
III.A.2.1. Breslow Hydrophobic Effect
42
The Breslow hydrophobic effect is observed in „in‒water‟ reactions. Small covalent
organic molecules repel water molecules. When present in water, they are forced to form
aggregates in order to decrease the organic surface area exposed to water.5 The hydrophobic
effect has a major influence on the stereochemical outcome of reactions. The
Hydrogen‒Bonding effect and the polarity effect have also been shown in this case.4
III.A.2.2. Marcus trans‒phase H‒bonding
In 2007 Marcus and Jung proposed that the key to understanding the on‒water
phenomenon was the unique chemistry that occurs at the water‒oil phase boundary.6 At large
hydrophobic surfaces about 1 in 4 of the water molecules in the final layer has an OH free
group directed at the boundary in contrast to small hydrophobic aggregates, which can be
fully enclosed by hydration water clusters with lateral H‒bonds along the boundary (Figure
III.A.1).4
Figure III.A.1. (a) Hydrated small hydrophobic aggregates and (b) hydrated large hydrophobic
aggregates
III.A.3. Some examples of ‘on‒water’ organic reactions
Sharpless et al. defined „on‒water‟ conditions using water as solvent for the reaction of
water insoluble reactants. His group reported a very affectionate example of the acceleration
of the reaction rate on water with cycloaddition reaction of quadricyclane and dimethyl
azodicarboxylate (Scheme III.A.1). The time for completion of the reaction was measured for
a wide variety of solvents and it was found that the water required only 10 min.7
43
N
NCOOMe
MeOOC
+'On-water'
N
N COOMe
COOMe
10 min, 82%
Scheme III.A.1. Demonstrative example of “on‒water”cycloaddition of quadricyclane with
azodicarboxylate
Another impressive result on cycloaddition rate acceleration was reported by the group of
Engberts in their study of the Diels–Alder reaction of cyclopentadiene and
3‒aryl‒1‒(2‒pyridyl) 2‒propen‒1‒ones.8
They showed that the reaction carried out in water
as solvent was 287‒times faster than the same reaction in acetonitrile. In addition, they found
that the reaction in water, combined with the use of Lewis acid and micellar catalysis, was
accelerated by a factor of 1 800 000 compared to the reaction in acetonitrile.
It was found that the cycloaddition of trans,trans‒2,4‒hexadienyl acetate and
N‒propylmaleimide in water medium showed considerable rate acceleration as compared to
other organic solvents (Scheme III.A.2).9
OO N
O
O
'On-water'
8 h, 81%
N
O
OAcO
H
H
Other organic solvents requires more time than water
Scheme III.A.2. Rate acceleration of cycloaddition reaction in presence of water
Carbon–carbon bond formation reactions are fundamental in organic chemistry and a large
number of catalysts have been used for the C–C coupling reactions (Scheme III.A.3).10
The
direct C–C coupling of indole with 1,4‒benzoquinones has been widely studied. This
coupling reaction is generally catalyzed by Brønsted (HCl, H2SO4 and CH3CO2H),11
and
Lewis acids [InBr3 and Bi(OTf)3],12
in organic solvents.
Under the on‒water catalyst‒free (OWCF) C–C coupling reactions of indole with
1,4‒benzoquinones has also been reported by C. J. Li et al. A tremendous increase in rates of
reaction was found to efficiently give a range of bis(indolyl)‒1,4‒quinones in good yields
(Scheme III.A.3).13
On‒water nucleophilic substitution reaction of 2,3‒dichloro‒1,4‒naphthoquinone with
aniline was effectively done at 50 oC to give the corresponding product in quantitative yield.
44
The reaction was compared with the other solvents like benzene, MeOH or EtOH and it was
found that water is more efficient compared to other conditions (Scheme III.A.3).14
The increase of rate and selectivity of these on‒water reactions obtained via the interaction
of nonpolar or hydrophobic regions of reactants (Scheme III.A.3).15
The Wittig reaction is one of the important tools to generate the olefinic double bonds. M.
Bergdahl and his groups reported Wittig reaction by various aromatic aldehydes and
stabilized ylides in water and other solvents (Scheme III.A.3).16
In this case water was found
to be the most efficient medium in terms of yield and stereoselectivity of products compared
to other polar or non‒polar medium. Tiwari and Kumar reported the on‒water Wittig reaction
of insoluble aromatic and aliphatic aldehydes with phosphorus ylides at 25 oC (Scheme
III.A.3).17
They found that alkali metal salts (LiCl and NaCl) decreased the rate of reaction.
Chakraborti and co‒workers reported the on‒water synthesis of 2‒aryl/heteroaryl/styryl
benzothiazoles and 2‒alkyl/aryl alkyl benzothiazolines. A variety of aldehydes such as alkyl,
aryl, and heteroaryl reacted with 2‒amino thiophenol under on‒water conditions to give the
condensation products. The reaction was found to be chemoselective without giving
thia‒Michael addition product (Scheme III.A.3).18
R3
R4
R2
R1
Cl
Cl
O
O
R3
R4
R2
R1
Cl
Cl
O
OCl
Cl
O
O
NH2HN
Cl
O
O
H2O, 50 oC
CHO
R1Ph3P COR2
water
COR2
R1
R1 = H, 4-NO2, 4-Br;
R2 = Ph, -Me, -OMe
R1 CHO
SH
NH2
R2
N
SR1
Few examples of On-water reactions
Water, RT
Wittig Reaction
Substitution
Condensation
Catalyst-free C-C coupling reactions
Scheme III.A.3. Various examples of of on‒water organic reactions
45
III.A.4. Metal–catalyzed Sp2 C–H bond activation and catalytic cross–coupling reactions
After catalytic successes for C–H bond transformations in water involving the palladium
and ruthenium catalysts and with the help of a carboxylate partner, water is found to be
beneficial for the direct catalytic arylation with (hetero)aryl halides of functional arene and
ortho C–H bonds with pyridine, pyrazole, oxazoline etc. In most of the cases the C–H bond
activation and the deprotonation are compatible with water. However, water is a poor solvent
for organic molecules and most of the catalytic cross–coupling reactions of C–H bonds in
water are consistent with „on‒water‟ reactions. In those cases, the catalyst is soluble in water
or the surfactants modify the reaction.5,19
Some recent examples of metal catalyzed sp2 C–H
bond activation followed by C–C bond formation in aqueous medium are illustrated below
(Scheme III.A.4).20
Microwave assisted „on‒water‟ ligand‒free palladium‒catalyzed
Suzuki‒Miyaura coupling reaction has been reported by Leadbeater et al. Chloro‒, bromo‒
and iodo‒ arenes are well participated in this reaction.21
R
R R
C-C homocoupling
N
SPh
H
H
Ar-IPd-Cat., Ag(I)
Water, 60 oC
N
SPh
Ar
H
Pd-Cat., K2CO3, H2O
N
sp2 C–H bond activation in water and
catalytic C-C crosscoupling reactions
+ArX, Het-X
Ru-cat., K2CO3,
H20, 80 oC
N
Het/Ar
Selective monoarylation of arenes
F
F
F
F
F
Ar-I
F
F
F
F
F
Ar
Arylation of C-H bonds of electron-poor fluorinated arenes in water
Pd-Cat., Ag(I)
K2CO3, H20
NH
O
R2
R1
R4R3
N
O
R3
R4
R1
R2
Ru-and Cu-Cat.
t-AmOH, H2O
+
+
C-C coupling of heterocycles
and aryl halides
Annulation
Pd, Ru or Fe cat.
X
B(OH)2R
+
R
Suzuki reaction
2
X= Cl, Br & I
Scheme III.A.4. Some examples of metal–catalyzed Sp2 C–H bond activation and catalytic cross–
coupling reactions
III.A.5. Disadvantages of water in organic reactions
The main drawback of organic reactions performed in water is the solubility of organic
reactants. Organic reactants generally give immiscible or biphasic mixture with water. The
problem may overcome by using phase transfer catalyst, co‒solvents and heating the reaction
46
mixture. When heating the reaction mixture, some of the reactants and products can
decompose in aqueous reaction mixture. Formation of unwanted side products is also a major
drawback of the utilization of water in organic synthesis. However, some greener approaches
have been developed and solved by designing protocols based on the use of microwaves,
ultrasound or pressure reactors and using other benign co‒solvents.
III.A.6. References
References are given in BIBLIOGRAPHY under Chapter III, Section A (pp. 145−146).
47
CHAPTER III
SECTION B
„On‒water‟ Suzuki‒Miyaura reaction at
ambient condition using aryl trihydroxy borate
salt as an alternative boron partner
48
III.B.1. Introduction
The seminal paper of Miyaura, Yamada and Suzuki,1 built the foundation of one of the
most important and useful methods for the construction of carbon–carbon bonds, in particular
for the formation of biaryls. In spite of the other approaches (e.g. Kharash coupling,2
Negishi
coupling,3 Stille coupling,
4 Hiyama coupling,
5 and Kumuda coupling
6) for C–C bond
formation, Suzuki–Miyaura (SM) coupling reaction has received much more popularity due
to stability, functional group tolerance, commercial accessibility and also ease of handling the
organoboron species. During last few decades the Suzuki–Miyaura coupling has found
widespread applications in academic laboratories, fine chemical industries, pharmaceutical,
natural product synthesis,7 and in materials sciences.
8
For example, Losartan, an antihypertensive drug or CI–1034, a potent endothelian receptor
antagonist have been synthesized in large scale. The key step in the synthesis of the Losertan
was a Pd‒catalyzed Suzuki‒Miyaura cross–coupling reaction.9
N
N
NN
N
Tr
n-Bu
Cl
HOH2C
Trityl losertan: Angiotensin II receptor antagonist
Figure III.B.1. The chemical structure of trityl losertan
Similarly, benzimidazole derivatives bearing substituted biphenyls, a potential inhibitors
of hepatitis C virus, have been prepared using the SM coupling reaction.10
Stereoselctive
synthesis of axially chiral natural products, (‒)‒Steganone has been synthesized by K.
Kamikawa and his group. (‒)‒Steganone is an antileukemic bisbenzocyclooctadiene lignin
lactone.11
Similarly a CB1 antagonist for the treatment of obesity has also been prepared by
SM coupling reaction12
Nicolaou et al. have prepared an anti‒HIV alkaloid natural product,
Michellamine B by SM coupling reaction.13
49
O
O
O
O
OMe
MeO
MeO
(-)-Steganone
N
N
N
N
N
Cl
Cl
Me
NH
O
NH2
Me
CE-178, 253
NN
Me
ONH
N
Cl
Cl
Cl
SR141716A, (Rimonabant)
N
NO
HOOC
Anti-Hepatitis C Virus drug
NH
HN
Me
Me
Me OH
OH
OH Me
MeOHOMe
Me
HO
OH Me
Michellamine B alkaloid natural product: anti-HIV activity
Important biphenyl scaffolds
Figure III.B.2. Structures of some drugs and pharmaceuticals containing biphenyl moiety
Xenbucin, a non‒steroidal antihypercholesterolemic, analgesic drugs and Flurbiprofen 1, a
nonsteroidal antiinflammatory and analgesic drug have also been developed.14
OXenbucin
non-steroidal antihypercholesterolem-ic and analgesic drug
F
Me
O
OH
Flurbiprofen 1
nonsteroidal antiinflammatory and analgesicdrug
Figure III.B.3. Structures of some analgesic drugs synthesized by SM coupling reaction
Biaryls precursors have attracted considerable attention in materials science. For example,
fluorinated biphenyl derivatives are fundamental building blocks for synthesis of fluorinated
liquid crystals, which are generally used in thin‒film transistor displays.15
Highly
50
photosensitive organic phototransistors used as light‒emitting diodes also contain biphenyl
moieties (Figure III.B.4).16
S
S
Bithiophene oligimer, Organic phototransistor
RFn
Fluorinated biphenyl: used as TFT-LCDs
Figure III.B.4. Biphenyls used in materials science
III.B.2. Background and Objectives
In recent years, improvement of the SM coupling reaction has been directed towards the
more efficient, economic and greener techniques, especially with reference to the Pd‒catalyst,
requirement of base and carrying out the reaction without any solvent or in water.17
Pd
complexes with various phosphorus ligands are invariably used as the catalyst for this
reaction. The recent trends in organic synthesis involve reactions in solvent‒free conditions
or in water (readily available non toxic solvent as reaction medium) to obtain the target
molecule in cleaner and environmentally benign way.18
Some methodologies for SM coupling reaction using water as reaction medium and phenyl
boronic acids as one of the coupling partner have been developed. A few examples are
illustrated here. The SM coupling reaction in aqueous microdroplets with catalytically active
fluorous interfaces has been developed by T.S. Huck et al. They have used the microfluidic
techniques and novel fluorous‒tagged Pd‒catalyst for SM coupling reaction. The generation
of the droplet reactors with catalytically active walls was effective for small molecules
synthesis. K2CO3 was used a base in this reaction (Scheme III.B.1).19
Br (HO)2B+K2CO3, H2O
Novel fluorous-tagged-Pd-cat.
R R
R = 4-OH, 4-COOH, 3-COOH
Scheme III.B.1. SM coupling reaction in aqueous microdroplets with catalytically active fluoruos
interfaces
Ligand‒free palladium acetate‒catalyzed SM coupling in water under microwave
irradiation has been developed by N. E. Leadbeater et al. 60 W of microwave irradiation was
used and the temperature ramped to 150 oC. Chloro, bromo and iodo arenes were participated
51
in this reaction. Na2CO3 was used as base and TBAB as phase transfer catalyst (Scheme
III.B.2).20
Br (HO)2B+
R R
R = H, 4-NO2, 4-COMe, 4-CH3, 2-CH3, 4-OMe, 3-OMe, 2-OMe, 4-NH2, 4-CHO, 4-OH,
4-COOH, 4-COOMe
R1 = 2-Me, 4-COOH
R1
Pd(OAc)2
Na2CO3, H2O
W = 60 WR1
Scheme III.B.2. Ligand‒free palladium‒catalyzed SM coupling reaction using Microwave heating in
water
P. L. Diaconescu and his coworkers have found that poly aniline (PANI) was able to
reduce and stabilize the palladium nanoparticles. This semi‒heterogeneous catalyst was
effective for chloro and fluoro arenes for undergoing the SM coupling reaction (Scheme
III.B.3).21
Cl (HO)2B+NaOH, H2O
80-100 oC, 2-6 h
5 mol% Pd/PANI
R R
R = 4-OH, 4-COOH, 4-OEt, 4-OMe, 2-OMe
F (HO)2B+F
1 eqv. 1 eqv.
1 eqv. 2 eqv.
NaOH, H2O
100 oC, 24 h
0.1 mol% Pd/PANI
Scheme III.B.3. Polyaniline (PANI) supported palladium nanoparticles as semi‒heterogeneous
catalyst for SM coupling reactions
Similarly phosphine‒free palladium‒catalyzed Suzuki‒Miyaura coupling reaction was
developed by Y. Wang and his group.22
Although many organic reactions are facilitated in
aqueous media, some reactions proceed very slowly because of poor solubility of the
substrate/reagents in water. Efforts have been made to overcome the problems by introducing
phase transfer catalysts.23
An efficient biphasic SM coupling reactions catalyzed by Pd‒complexes with water
soluble phosphine ligands and detergents as phase transfer agents have been well
documented. G. Oehme and his group developed a new method using CTAB as phase
transfer reagents water soluble palladium complex. The biphasic medium was the mixture of
toluene/ethanol/water in 1:1:1 ratio.23d
52
A convenient method for the SM coupling reaction was developed by B. H. Lipshutz et al.
using nonionic amphiphiles as phase transfer catalysts (Scheme III.B.4).23e
O
OO
OH
O
O
nm
PTS: m = 4 and n = 14- 15TPGS: m =1 and n = 23-24
OO
H
10
TritonR X-100
XR
Pd-Cat. 0.02 mmol, Et3N, amphiphile solun.= 2 mL
RB(OH)2
ArSO3RF
Pd-Cat. 0.01 mmol, Et3N, amphiphile solun.= 2 mL
Ar
Scheme III.B.4. Nonoionic amphiphiles mediated SM coupling in water
A heterogeneous Pd/C mediated biaryl formation from SM coupling reaction has been
carried out by phase transfer catalysts. CTAB, a surfactant was used in this protocol. Steric
hindrance was not the major factor for the formation of o‒substituted biphenyls. In these
cases the reactions were performed at 60 oC for 24 hours. Maximum conversion of activated
aryl chlorides were achieved at 100 oC (Scheme III.B.5).
24
B(OH)2 XR1
R H2O/CTAB
Pd/C, K2CO3
R
R1+
X = I, Br and Cl
CTAB = Cetyltrimethyl ammonium bromide
Scheme III.B.5. A mild and efficient method for the synthesis of biaryls in water and surfactants
In the case of SM couplings, hydrophobic aryl boronic acids often show very slow and/or
incomplete conversions along with the difficulty to isolate the products from the reaction
mixture.19‒22
In order to overcome such drawbacks, potassium aryltrifluoroborates being
endowed for its easy preparation and it can be stored and handled easily than arylboronic
acids or esters.25
G. A. Molander et al. reported the SM coupling reaction using alkyl trifluoroborates and
aryl or heteroaryl chlorides, which are less expensive than aryl bromides and aryl iodides.
This method was found to be amenable to coupling with aryl bromides, iodides and triflates
as well (Scheme III.B.6).26
53
BF3K
N
Cl Ror
Pd(OAc)2 (10 mol%)ligands (20 mol%)
K2CO3, 10:1 toluene/H2O
N
R
R1
or
+ Cl
R1
i-Pr-O O-i-Pr
PCy2
RuPhos
Ligand
R = 2-OMe, 4-Me, 2,6-dimethyl, 4-COCH3, 4-NO2, 4-CF3, 4-CN, 4-CHO, 3,5-dimethoxy
R1 = 2-OMe, 2-F, 4-CHO
Scheme III.B.6. Pd(OAc)2‒catalyzed SM reaction between alkyl trifluoroborates and aryl halides
Ligand‒free water mediated palladium charcoal‒catalyzed SM coupling reaction of
tetraarylborates with aryl bromides was developed by Y. Xu et al. The reactions were
performed with the aryl bromo carboxylic acids. Pd/C (5 mol%) used as palladium source
and Na2CO3 as base. This mild and environmental friendly reaction was suitable for the
preparation of various biaryl carboxylic acids (Scheme III.B.7).27
Br
HOOC
R
+5 mol% Pd/C
NaOH or Na2CO3
H2O
HOOC
RPh4BNa
R = -Cl, -F, -OMe, -OH
Scheme III.B.7. Pd/C‒catalyzed cross‒coupling of various aryl bromides with sodium
tetraphenylborate
Moreover, Cammidge et al. reported a different approach to the use of organoboron
species in SM coupling reactions whereby aryl trihydroxyborate salts have been prepared,
isolated and employed in Pd–catalyzed coupling with aryl bromides in refluxing toluene for
24 h without the need for additional base. Subsequently, phenyltrihydroxyborate has also
been used in the SM coupling with bromostilbene (vinyl bromide) in presence of KOH. In
quest of greener approaches the aryl trihydroxy borate salts attract much attention than aryl
boronic acids (Scheme III.B.8).28
Br
R1. Mg
2. B(OMe)3
3. Normal workup
B(OH)2
RNaOH
B(OH)3Na
RToluene
Ar Br
PdCl2(dppf)Biaryls
Aryl trihydroxy borate salt
R = 2-Me, 3-Me, 4-Me, 2-OMe, 3-OMe, 4-OMe, 4-Me3C, 4-C6H13
Scheme III.B.8. Synthesis of aryl trihydroxy borate salts for the Suzuki‒Miyaura coupling reaction
54
In connection with our interest in the development of the SM coupling reaction, we
investigated the coupling reaction of a wide range of aryl halides (I, Br, Cl) including
heteroaryl halides with different sodium aryltrihydroxyborates.
III.B.3. Present work: Results and Discussion
Here we describe our investigations, which practically constitute an efficient, mild,
ligand‒ and base‒free protocol for the SM coupling reactions in water at ambient temperature
by using aryl trihydroxyborate salt as an alternating bornating agent (Scheme III.B.9). We
further extended our work to construct a protocol for the synthesis of pharmaceutically
important analogues and efficient use of heterogeneous polymer–supported Pd catalyst
covering the essential aspects of green chemistry.
G
X B(OH)3
Na
+
R1 GR1R2 R2
G = C, N, S (Thiophene when G = S)
R1 = Me, OMe, Br, F, NO2, COMe, NH2, OH
X = I, Br, Cl
R2 = H, Me, OMe
Pd catalyst (0.5 mol%)
TBAB / H2O at RT
Pd Catalyst = Pd(OAc)2 or ARF-Pd
(62 - 97%)
Scheme III.B.9. Pd(OAc)2‒catalyzed SM reaction in the presence of aryl trihydroxy borate salts
and aryl halides
Primarily, the SM coupling reaction was optimized by a model reaction between 3–
iodoanisole and phenyl trihydroxyboarte with the aid of 0.5 mol% Pd(OAc)2 (Table
III.B.1). The phenyltrihydroxyborate salt was prepared according to the reported
procedure,28
and used directly without further purification. Although the reaction was not
successful in toluene at 100 oC (Table III.B.1, entry 1) but it worked well in DMF at room
temperature to afford the desired product in 96% yield. (Table III.B.1, entry 2). Similar
reactions were performed in dioxane or acetone–water and it worked efficiently within
8–24 h under similar conditions (Table III.B.1, entries 3 and 4). Due to poor solubilty of
the aryl iodide in water, the reaction did not give excellent formation of biphenyl
derivative (38% yield). To overcome this limitation, the use of n‒tetrabutylammonium
bromide (TBAB) in equimolar amount can lead to the formation of the desired product
within 4 h at room temperaure in 92% yield. It was revealed that both polar protic or
aprotic solvents were good enough to effect the SM coupling without requiring any bases
and high temperature. Hence, the optimized reaction condition utilized 0.5 mol % of
55
Pd(OAc)2 and 1 equiv. of TBAB in water at room temperature.
Table III.B.1. Optimization of Reaction Conditions of SM Coupling reaction.
I
MeO
B(OH)3
Na MeO
+Pd(OAc)2 (0.5 mol%)
Solvent / Temp.
1 2 3a
Entry Solvent Temperature (oC) Time (h) Yield
a (%)
1 Toluene 100 8 00
2 DMF RT 4 96
3 Dioxane RT 24 45
4 Acetone:water
(1:1)
RT 8 93
5 Water RT 4 38
6 Waterb RT 4 91
7 Waterc RT 8 50
a Isolated yields after purification by column chromatography on silica.
b 1 equiv. of TBAB was added.
c 0.5 equiv. of TBAB was added.
All reactions were carried out using 0.5 mol% Pd(OAc)2.
After achieving the optimal conditions, the scope and limitations of both substrates and
aryl trihydroxy borate salts were examined. Initially, we applied these reaction conditions
to the coupling of various functionalized aryl iodides with sodium salt of phenyl
trihydroxyborate in water (Table III.B.2, 3a‒3g). Aryl iodides bearing different
substituent such as OMe, Me, NH2, F, I, etc. at different positions underwent smooth SM
coupling affording coresponding biphenyls in 41–97% yields. The other aryl
trihydroxyborate salts were effective as phenyl trihydroxy borate salt and they underwent
the smooth coupling with aryl iodides (Table III.B.2, 3h‒3l). The reaction of 2–iodo
thiophene with p–methoxy boronates (Table III.B.2, 3k) efficiently proceeded to give
resulting biphenyl in 92% yield under optimized conditions.
Table III.B.2. Suzuki‒Miyaura coupling reactions of aryl iodides with sodium
aryltrihydroxyborates in water.a,b
3a-3l
G
I B(OH)3
Na
+
R1 R1R2 R2
G = C, N, S (Thiophene when G = S)
R1 = Me, OMe, F, NH2, I
R2 = H, Me, OMe
Pd(OAc)2 (0.5 mol%)
TBAB / H2O at RT
1 2
56
3h8 h, 79%
3i8 h, 86%
3j3.5 h, 74%
3l7 h, 97%
3a4h, 92%
3b4 h, 86%
3c2.5 h, 84%
3d4 h, 81%
3f5 h, 41%
MeO
MeO
OMe
Me
3e4 h, 94%
F
3g6 h, 81%
NH2
MeO Me
Me Me
MeMeO
Me OMeS
OMe
3k3 h, 92%
aAryl iodides and arylboronic acid salt used in 1:1.1 molar ratios.
bIsolated yields after purification by column chromatography on silica.
Mechanistically, the oxidative addition of palladium to the C–halogen bond depends on
the nature of halogens and occurs in the descending order of I>Br>Cl. We therefore
examined the couplings of aryl bromides. Several aryl bromides including di–and
tribromoarenes and heteroaryl bromides were found to give the corresponding unsymmetrical
biaryls in good to excellent yields (Table III.B.3, 3m and 3o and 3p). While
p‒bromoacetophenone showed faster rate (2 h) of reaction possibly due to the presence of
electron withdrawing group (3n) and 2,4,6‒trihydroxyphenol required long time (24 h) for
the coupling reaction, which may be attributed to steric and multi‒couplings factors (3q).
Thus, aryl bromides like iodides underwent easy coupling with phenyl trihydroxyborate.
Table III.B.3. Suzuki‒Miyaura coupling reactions of aryl bromides with sodium
aryltrihydroxyborates in water.a,b
G
Br B(OH)3
Na
+
R1 R1R2 R2
G = C, N
R1 = Me, OMe, COMe, OH, Br
R2 = H, Me
Pd(OAc)2 (0.5 mol%)
TBAB / H2O at RT
3m-3t4 2
57
3m8 h, 72%
Me
MeOO
3n2 h, 95%
3o4 h, 66%(with 22% mono product)
3p6 h, 67%
OH
3q24 h, 82%
3r3.5 h, 74%
MeO Me
N
Me
3s3.5 h, 66%
N
3t8 h, 83%
aAryl bromides and arylboronic acid salt used in 1:1.1 molar ratios.
bIsolated yields after purification by column chromatography on silica.
Similar reaction with aryl chloride did not occur at all at room temperature. Leadbeater
et al reported the microwave–assisted SM coupling of aryl chlorides at 150–175 oC in
aqueous medium. Thus, aryl chlorides are very sluggish towards coupling reaction and
needed relatively higher temperature, longer reaction time and/or the presence of
activating group.29
We therefore performed these reactions at 100 oC. It was found that,
reactions with activated aryl chlorides successfully gave the desired products in excellent
yields (Table III.B.4, 3n and 3u) while the unactivated aryl chlorides remained unchanged
even after 24 h under refluxing conditions (Table III.B.4, 3v and 3w).
Table III.B.4. Suzuki‒Miyaura coupling reactions of aryl chlorides with sodium
aryltrihydroxyborates in water.a,b
3n, 3u-3w
Cl B(OH)3
Na
+
R1 = NO2, COMe, OH, NH2
Pd(OAc)2 (0.5 mol%)
TBAB / H2O at RT
5 2
R1 R1
3v
100 oC, 24h, Not formed
HO
3w
100 oC, 24h, Not formed
H2N
3u
100 oC, 5 h, 96%
O2N3n
100 oC, 4 h, 85%
aAryl chlorides and arylboronic acid salt used in 1 : 1.1 molar ratios.
bIsolated yields after purification by column chromatography on silica.
58
With the success to establish the use of aryl trihydroxyborate salts as an alternative to
aryl boronic acid or ester and to carry out the reaction in water under ambient conditions,
we extended our study to conduct similar reactions using a polymer‒supported
heterogeneous Pd‒catalyst. Since the reactions on heterogeneous surface is one of the
essential condition for Green chemistry. Recently, we developed a new Pd‒catalyst
immobilized onto ion‒exchange resins, designated as ARF‒Pd and was successfully used
in Heck, Suzuki‒Miyaura and Sonogashira coupling reactions.30
The trihydroxyborate salt
was found to be equally active towards SM‒copling reactions in presence of catalytic
amount of ARF‒Pd. These results are given in the table below (Table III.B.5, entries
1‒5).
Table III.B.5. SM coupling reactions with aryl trihydroxyborates in water using
heterogeneous Pd‒catalyst (ARF–Pd).a,b
Entry Aryl halides Aryl trihydroxy
borate
Temp.
(oC)
Time
(h)
Product Yield
(%)
1 MeO I
PhB(OH)3Na
RT 5 PhMeO
78
2
MeO I
PhB(OH)3Na
RT 5
MeO Ph
81
3 Br
O
Me
PhB(OH)3Na
100 4 Ph
O
Me
89
4 Me I
PhB(OH)3Na
100 3 Me Ph
93
5
MeO I
Me B(OH)3Na
100 5
MeO Me
72
a300 mg ARF‒Pd (0.94 mol% Pd) was used.
b Isolated yields after purification by column chromatography on silica.
As stated above, water soluble sodium salts aryltrihydroxyborates have proven highly
effective in SM coupling reactions in water at ambient temperatures. Having established a
general mild protocol for SM coupling reactions using aryltrihydroxyborate salts in water,
we probed the utility of this protocol in a modular synthesis of some phamaceutically
important benzimidazole– and benzotriazole–based biphenyls.9 At first we prepared 6a
and 6b compounds according to the following Scheme III.B.10. Initially 4‒iodo toluene
was reacted with NBS in CCl4 medium in the presence of light and a radical intiator,
59
benzoyl peroxide. 4‒iodo benzyl bromide was obtained from this reaction. Afterthat the
benzimidazole and benzotriazole were reacted with 4‒iodo benzyl bromide separately
under refluxing condition in acetonitrile solvent with the aid of potassium hydroxide
(KOH) yielded compounds 6a and 6b to near‒quantitative yield.
I CH3
NBS
Benzoyl peroxideCCl4
I
Br
NH
N
NH
NN
KOH, MeCN, reflux
N
N
I
NN
N
I
6a
6b
Scheme III.B.10. Synthesis of 6a and 6b
Thus, compounds 7 and 8 were synthesized from compounds 6a and 6b respectively,
where the SM couplings were effciently performed using sodium phenyltrihydroxyborate
in a mixture of DMF‒H2O (2:1, v/v). These compounds were characterized by 1H‒NMR,
13C‒ NMR spectroscopic techniques and by HRMS data.
6a, G = CH6b, G = N
7 8
N
N
NG
N
I
NN
N
Scheme III.B.11. Synthesis of benzimidazole– and benzotriazole–based biphenyl scafolds
III.B.4. Conclusion
In summary, we have shown that the the sodium aryltrihydroxyborate salts can be used
as an alternative coupling partner instead of less stable boron compounds in SM coupling
reaction in water at ambient condition in presence of TBAB or in a mixture of an organic
solvent–water. The significant improvement of the existing Suzuki–Miyaura cross–
coupling has been seen throughout the reaction. A large varieties of aryl halides were
used without any disturbance.
60
III.B.5. Experimental section
III.B.5.1. General information
All the reactions were carried out in open vessel under aerobic conditions. All aryl boronic
acids and aryl iodides were purchased from Sigma‒Aldrich, India. Aryl bromides and
chlorides were purchased from SRL, India. For column chromatography: silica (60‒120
mesh) (SRL, India), and for tlc, Merck plates coated with silica gel 60, F254 were used.
Melting point of the solid compounds was determined in concentrated H2SO4 bath. FT‒IR
spectra were recorded with a FT‒IR‒8300 SHIMADZU spectrophotometer using a KBr
pellet method for solid compounds and in neat for liquid compounds. NMR spectra of almost
all biaryls were recorded in CDCl3 on Bruker AV 300 spectrometer using TMS as the internal
standard. HRMS data were obtained in Micromass Q‒TOF micro Mass Spectrometer under
ESI (positive mode).
III.B.5.2. General procedure for the preparation of aryl trihydroxyboronate salts from
boronic acids
Arylboronic acids were dissolved in a minimum amount of warm toluene with stirring and
the solution was allowed cool to room temperature. Once saturated, aqueous sodium
hydroxide solution was added dropwise until no further precipitate formed. The mixture was
allowed to stir for 30 minutes and the colourless precipitate was filtered off and washed
several times with toluene to give the corresponding salt.
III.B.5.3. General procedure for Suzuki‒Miyaura coupling reactions
A mixture of aryl iodides/bromides/chlorides (2 mmol), sodium aryltrihydroxyborate (2.2
mmol), Pd(OAc)2 (0.5 mol%) and TBAB (2 mmol, 1 equiv) was taken in distilled water (5
mL). The mixture was stirred by magnetic bar at room temperature for several hours (see
Table III.B.2, Table III.B.3 and Table III.B.4). After the reaction was completed (monitored
by tlc), the mixture was extracted with diethyl ether (3 × 20 mL). The combined organic layer
was then washed with brine (10 mL), dried (anhydrous Na2SO4), and evaporated. The residue
was purified on a short column of silica using light petroleum as the eluent to afford the
desired unsymmetrical biphenyl as liquid or solid. For the cases of di‒iodo, di‒bromo and
tribromo compounds, two and three equivalents of sodium aryltrihydroxyborate salts were
used respectively.
III.B.5.4. Representative procedures for the synthesis of 7 and 8
61
A mixture of 1‒(4‒iodobenzyl)‒1H‒benzo[d]imidazole 6a (334 mg, 1 mmol) or
1‒(4‒iodobenzyl)‒1H‒benzo[d][1,2,3]triazole 6b (335 mg, 1 mmol), sodium salt of
phenyltrihydroxyborate (177 mg, 1.1 mmol), Pd(OAc)2 (1.1 mg, 0.5 mol%) or ARF–Pd (300
mg, 0.94 mol% of Pd) and TBAB (322 mg, 1 mmol) was taken in a DMF–water mixture (2: 1
(v/v), 3 mL). The reaction mixture was heated at 100 oC for 24 h. After completion of the
reaction in both cases (monitored by tlc), the mixture was diluted with water and extracted
with ethyl acetate (2×20 mL). The combined organic layer was then washed with brine (NaCl
solution, 10 mL), poured over anhydrous Na2SO4 and evaporated. Finally the residue was
purified over a short column of silica with 1: 9 (EA:light petroleum) eluent afforded
N‒(4‒phenyl benzyl) benzimidazole 7 (236 mg, 83%); m.p. 163 oC or N‒(4‒phenyl benzyl)
benzotriazole 8 (227 mg, 80%); m.p. 180 oC.
III.B.5.5. Physical properties and Spectral data of compounds
Table III.B.2, 3a
3‒Methoxy biphenyl31
3aMeO
Colourless liquid
IR (Neat): νmax = 3031 (=C‒H aromatic str.), 3001, 2939, 2835 (C‒H str. in CH3 of OCH3),
1610 (C=C str.), 1574, 1481, 1037 cm‒1
.
1H NMR (CDCl3, 300 MHz): δ/ppm 3.75 (s, 3H, ‒OCH3), 6.77‒6.81 (m, 1H), 7.03‒7.10 (m,
2H, ArH), 7.21‒7.36 (m, 4H, ArH), 7.47‒7.51 (m, 2H, ArH).
13C NMR (CDCl3, 75 MHz): δ/ppm 55.2 (‒OCH3), 112.6, 112.8, 119.6, 127.1, 127.4, 128.7,
129.7, 141.0, 142.7, 159.9.
Table III.B.2, 3b
4‒Methoxy biphenyl32
3b
MeO
62
White solid, mp 88‒90 oC (Lit.
32 91‒92
oC)
IR (KBr): νmax = 2923 (=C‒H str.), 2854 (C‒H str. in CH3 of OCH3), 1608 (C=C str.), 1519,
1458, 1034 (C‒O‒C sym. str.) cm‒1
.
1H NMR (CDCl3, 300 MHz): δ/ppm 3.83 (s, 3H, ‒OCH3), 6.96 (d, J = 8.7 Hz, 2H, ArH),
7.22‒7.55 (m, 7H, ArH).
13C NMR (CDCl3, 75 MHz): δ/ppm 55.3 (‒OCH3), 114.2, 126.6, 126.7, 128.2, 128.7, 133.8,
140.8, 159.2.
Table III.B.2, 3c
2‒Methoxy biphenyl33
3c
OMe
Colourless liquid
(Reported as low melting solid of Mp 29‒30 oC)
33
IR (Neat): νmax = 3028 (=C‒H str.), 2935, 2835 (C‒H str. in CH3 of OCH3), 1597 (C=C str.),
1504, 1462, 1431, 1026 (C‒O‒C sym. str.) cm‒1
.
1H NMR (CDCl3, 300 MHz): δ/ppm 3.79 (s, 3H, ‒OCH3), 6.96‒7.05 (m, 2H, ArH),
7.29‒7.42 (m, 5H, ArH), 7.51‒7.54 (m, 2H, ArH).
13C NMR (CDCl3, 75 MHz): δ/ppm 55.5 (‒OCH3), 111.2, 120.8, 126.9, 127.9, 128.6, 129.5,
130.7, 130.8, 138.5, 156.5.
Table III.B.2, 3d
4‒Methyl biphenyl33
3d
Me
White solid, mp 46‒48 oC (Lit.
33 49‒50
oC)
IR (KBr): νmax = 3030 (=C‒H str.), 2923 (C‒H str. in CH3), 2858, 1620 (C=C str.), 1525,
1485, 1458 cm‒1
.
1H NMR (CDCl3, 300 MHz): δ/ppm 2.29 (s, 3H, ‒CH3), 7.10‒7.52 (m, 9H, ArH).
63
13C NMR (CDCl3, 75 MHz): δ/ppm 21.2 (‒CH3), 126.8, 126.9, 127.1, 128.7, 129.4, 137.0,
138.3, 141.1.
Table III.B.2, 3f
1, 3‒Di phenyl benzene32
3f
White solid, mp 87‒88 oC (Lit.
22 89
oC)
IR (KBr): νmax = 3062 (=C‒H str.), 3028, 1593 (C=C str.), 1570, 1493, 1470 cm
‒1.
1H NMR (CDCl3, 300 MHz): δ/ppm 7.28‒7.62 (m, 13H, ArH), 7.78 (s, 1H, ArH).
13C NMR (CDCl3, 75 MHz): δ/ppm 126.1, 127.2, 127.3, 128.7, 129.1, 141.1, 141.7.
Table III.B.2, 3g
2‒Amino biphenyl34
3g
NH2
Pink crystalline solid, mp 48‒50 oC (Lit.
34 44‒46
oC)
IR (KBr): νmax = 3480 (assym. N‒H str. primary aromatic amine), 3390 (sym. N‒H str. for
primary aromatic amine), 3030 (=C‒H str.), 1614 (C=C str.), 1579, 1500, 1481, 1313 (C‒N
str. of primary aromatic amine), 1284 cm‒1
.
1H NMR (CDCl3, 300 MHz): δ/ppm 3.33 (br s, 2H, ‒NH2); 6.75‒6.85 (m, 2H, ArH),
7.11‒7.23 (m, 2H, ArH), 7.30‒7.36 (m, 1H, ArH), 7.40‒7.49 (m, 4H, ArH).
13C NMR (CDCl3, 75 MHz): δ/ppm 115.6, 118.6, 127.1, 127.6, 128.4, 128.8, 129.8, 130.4,
139.5, 143.4.
Table III.B.2, 3h
4‒Methoxy 3‒methyl biphenyl35
64
3h
MeO
Me
White solid, mp 55 oC (Lit.
35 48‒49
oC)
IR (KBr): νmax = 3035 (=C‒H str.), 2977, 2912 (C‒H str. in CH3), 2835 (C‒H str. in CH3 of
OCH3), 1604 (C=C str.), 1512, 1489, 1466, 1026 (C‒O‒C sym. str.) cm‒1
.
1H NMR (CDCl3, 300 MHz): δ/ppm 2.28 (s, 3H, ‒CH3), 3.86 (s, 3H, ‒OCH3), 6.87‒7.56 (m,
8H, ArH).
13C NMR (CDCl3, 75 MHz): δ/ppm 16.4 (CH3), 55.4 (OCH3), 110.2, 125.4, 126.5, 126.7,
126.9, 128.6, 129.5, 133.4, 141.1, 157.4.
Table III.B.2, 3i
3, 4/‒dimethyl biphenyl
3i
Me
Me
Colouless liquid
IR (Neat): νmax = 3023 (=C‒H str.), 2919 (C‒H str. in CH3), 1606, 1588, 1516, 1500 (C=C
str.) cm‒1
.
1H NMR (CDCl3, 300 MHz): δ/ppm 2.39 (s, 6H, ‒CH3) 7.13‒7.50 (m, 8H, ArH).
13C NMR (CDCl3, 75 MHz): δ/ppm 21.3 (CH3), 124.1, 127.0, 127.7, 127.8, 128.6, 129.4,
136.9, 138.2, 138.5, 141.1.
Table III.B.2, 3j
3‒Methoxy 3/‒methyl biphenyl
36
3jMeMeO
Colourless liquid
IR (Neat): νmax = 3028 (=C‒H str.), 2999, 2920 (C‒H str. in CH3), 2834 (C‒H str. in CH3 of
OCH3), 1593 (C=C str.), 1466, 1042 (C‒O‒C sym. str.) cm‒1
.
65
1H NMR (CDCl3, 300 MHz): δ/ppm 2.41 (s, 3H, ‒CH3), 3.86 (s, 3H, ‒OCH3), 7.11‒7.39 (m,
8H, ArH).
13C NMR (CDCl3, 75 MHz): δ/ppm 21.5 (CH3), 55.3 (‒OCH3), 112.6, 112.9, 119.7, 124.3,
128.0, 128.1, 128.6, 129.6, 138.3, 141.1, 142.9, 159.9.
Table III.B.2, 3k
2‒(4‒methoxy phenyl) thiophene37
S
OMe
3k
Pale yellow solid, mp 106 oC (Lit.
37 103‒104
oC)
IR (KBr): νmax = 3100 (=C‒H str.), 3080, 3000, 2960 (C‒H str. in CH3 of OCH3), 2820, 1606
(C=C str.), 1533, 1500, 1465, 1031 (C‒O‒C sym. str.) cm‒1
.
1H NMR (CDCl3, 300 MHz): δ/ppm 3.81 (s, 3H, ‒OCH3), 6.91 (d, J = 9 Hz, 2H, ArH),
7.03‒7.25 (m, 3H, ArH), 7.53 (d, J = 8.7 Hz, 2H, ArH).
13C NMR (CDCl3, 75 MHz): δ/ppm 55.3 (‒OCH3), 114.3, 122.1, 123.8, 127.2, 127.3, 127.9,
144.3, 159.2.
Table III.B.3, 3m
4‒Methoxy 3‒methyl biphenyl30
3mMe
MeO
White solid, mp 74‒75 oC (Lit.
30 75
oC)
IR (KBr): νmax = 3035 (=C‒H str.), 2977, 2912 (C‒H str. in CH3), 2835, (C‒H str. in CH3 of
OCH3), 1604 (C=C str.), 1512, 1489, 1466, 1026 cm‒1
(C‒O‒C sym. str.) cm‒1
.
1H NMR (CDCl3, 300 MHz): δ/ppm 2.28 (s, 3H, ‒CH3), 3.86 (s, 3H, ‒OCH3), 6.87‒7.56 (m,
8H, ArH).
13C NMR (CDCl3, 75 MHz): δ/ppm 16.4 (CH3), 55.4 (OCH3), 110.2, 125.4, 126.5, 126.7,
126.9, 128.6, 129.5, 133.4, 141.1, 157.4.
Table III.B.3, 3n
66
4‒Acetyl biphenyl32
O
3n
White solid, mp 120‒121 oC (Lit.
32 120‒121
oC)
IR (KBr): νmax = 2923 (=C‒H str.), 1681 (C=O str.), 1610 (C=C str.), 1458 cm
‒1.
1H NMR (CDCl3, 300 MHz): δ/ppm 2.63 (S, 3H, ‒COCH3), 7.40‒7.47 (m, 3H, ArH),
7.62‒7.70 (m, 4H, ArH), 8.03 (d, J = 8.4 Hz, 2H).
13C NMR (CDCl3, 75 MHz): δ/ppm 26.9 (COCH3), 127.2, 128.2, 128.9, 129.8, 131.8, 135.8,
139.8, 145.8, 197.7 (C=O).
Table III.B.3, 3o
1, 4‒Diphenyl benzene32
3o
White solid, mp. 214‒216 oC ( Lit.
32 215‒217
oC)
IR (KBr): νmax = 3035 (=C‒H str.), 2970, 2935, 1597 (C=C str.), 1574, 1477, 1454 cm
‒1.
1H NMR (CDCl3, 300 MHz): δ/ppm 7.23‒7.67 (m, 14H, ArH).
13C NMR (CDCl3, 75 MHz): δ/ppm 127.0, 127.3, 127.4, 128.8, 140.1, 140.6.
Table III.B.3, 3p
1, 2‒Diphenyl benzene38
3p
White solid, mp 56‒57 oC (Lit.
38 58
oC)
IR (KBr): νmax = 3024 (=C‒H str.), 1597 (C=C str.), 1574, 1473 cm
‒1.
1H NMR (CDCl3, 300 MHz): δ/ppm 7.10‒7.18 (m, 10H, ArH), 7.37‒7.43 (m, 4H, ArH).
13C NMR (CDCl3, 75 MHz): δ/ppm 126.4, 127.4, 127.8, 129.8, 130.6, 140.5, 141.5.
67
Table III.B.3, 3q
2, 4, 6‒tri phenyl phenol (solid)39
OH
3q
White solid, mp 139‒140 oC (Lit.
39 142‒144
oC)
IR (KBr): νmax = 3514 (free phenolic ‒OH), 3062 (=C‒H str.), 3035, 1600 (C=C str.), 1574,
1493, 1462 cm‒1
.
1H NMR (CDCl3, 300 MHz): δ/ppm 5.46 (s, 1H, ‒OH); 7.31‒7.66 (m, 17H, ArH).
13C NMR (CDCl3, 75 MHz): δ/ppm 126.7, 126.8, 127.8, 128.6, 128.8, 129.1, 129.4, 133.8,
134.2, 137.5, 140.5, 148.9.
Table III.B.3, 3s
3‒(3‒methyl phenyl) quinoline
N
Me
3s
Pale yellow viscous liquid
IR (Neat): νmax = 3030 (=C‒H str.), 2922, 1606 (C=C, C=N str.), 1580, 1492 cm
‒1.
1H NMR (CDCl3, 300 MHz): δ/ppm 1.59 (s, 3H, ‒CH3), 6.36‒6.87 (m, 6H, ArH), 7.00 (d, J =
8.1 Hz, 1H, ArH), 7.28 (d, J = 8.4 Hz, 1H, ArH), 7.43 (s, 1H, ArH), 8.3 (s, 1H, ArH).
13C NMR (CDCl3, 75 MHz): δ/ppm 21.6 (CH3), 124.5, 127.1, 128.0, 128.1, 128.2, 128.9,
129.0, 129.1, 129.4, 133.4, 134.0, 137.7, 138.9, 147.1, 149.8.
Table III.B.3, 3t
2, 6‒Di phenyl pyridine40
68
N
3t
White solid, mp 80‒81 oC (Lit.
40 80‒81
oC)
IR (KBr): νmax = 3055 (=C‒H str.), 3035, 2923, 1586 (C=C, C=N str.), 1566, 1489, 1458
cm‒1
.
1H NMR (CDCl3, 300 MHz): δ/ppm 7.39‒7.51 (m, 6H, ArH), 7.65‒7.80 (m, 3H, ArH), 8.15
(d, J = 7.5 Hz, 4H, ArH).
13C NMR (CDCl3, 75 MHz): δ/ppm 118.7, 126.9, 128.7, 128.9, 137.5, 139.4, 156.3.
Table III.B.4, 3u
4‒Nitro biphenyl20
3u
O2N
Pale yellow crystalline solid
Mp 114‒115 oC (Lit.
20 114‒115
oC)
IR (KBr): νmax = 2923
(=C‒H str.), 2854, 1597 (C=C str.), 1512 (aromatic nitro asym. str.),
1458, 1346 (aromatic nitro sym. str.) cm‒1
.
1H NMR (CDCl3, 300 MHz): δ/ppm 7.46‒7.53 (m, 3H, ArH), 7.61‒7.64 (m, 2H, ArH), 7.73
(d, J = 8.7 Hz, 2H, ArH), 8.29 (d, J = 9 Hz, 2H).
13C NMR (CDCl3, 75 MHz): δ/ppm 124.1, 127.3, 127.8, 128.9, 129.1, 138.7, 147.0, 147.6.
Entry 7
N‒(4‒phenyl benzyl) benzimidazole
7N
N
White solid, mp 163 oC
IR (KBr): νmax = 3030 (=C‒H str.), 2924, 1653 (C=N str.), 1610, 1541 (C=C str.), 1496, 1452,
1371 (C‒N str. of aromatic tertiary amine), 1354, 1330 cm‒1
.
69
1H NMR (CDCl3, 300 MHz): δ/ppm 5.41 (s, 2H, ‒CH2), 7.25‒7.83 (m, 13H, ArH), 8.07 (s, 1H,
ArH).
13C NMR (CDCl3, 75 MHz): δ/ppm 48.73 (‒CH2, aliphatic), 110.2, 120.2, 122.6, 123.3, 127.1,
127.6, 127.8, 128.8, 129.1, 133.8, 134.2, 140.3, 141.4, 143.1, 143.3.
HRMS: Calcd for C20H16N2H: [M+H]+ 285.1392; found: 285.1387.
Entry 8
N‒(4‒phenyl benzyl) benzotriazole
8N
NN
White solid, mp 180 oC
IR (KBr): νmax = 3028 (=C‒H str.), 2923, 1616 (C=C str.), 1590, 1560, 1541, 1516, 1497, 1483,
1456, 1442 cm‒1
.
1H NMR (CDCl3, 300 MHz): δ/ppm 5.88 (s, 2H, ‒CH2); 7.25‒8.09 (m, 13H, ArH).
13C NMR (CDCl3, 75 MHz): δ/ppm 51.9 (CH2 aliphatic), 109.7, 120.1, 124.0, 127.0, 127.5,
127.6, 127.7, 128.0, 128.8, 132.8, 133.6, 140.2, 141.4, 146.3.
HRMS: Calcd for C19H15N3Na: [M+Na]+ 308.1164; found: 308.1163.
III.B.6. References
References are given in BIBLIOGRAPHY under Chapter III, Section B (pp. 146−148).
70
CHAPTER III
SECTION C
In quest of “stereoselective‒switch” for
on‒water hydrothiolation of terminal alkynes
using various additives and green synthesis of
vicinal dithioethers
71
III.C.1. Introduction
Organosulfur compounds play a key role in convenient intermediates for chemical
synthesis, materials chemistry and important biological intermediates.1 1‒Alkenyl sulfides
are important synthetic intermediates in total synthesis of many naturally occurring and
biologically active compounds as well as versatile building blocks for many functionalized
molecules.2 The synthetic utility of alkenyl sulfides has been established by different research
groups.3
A few examples of the vinyl sulfides as key synthetic intermediate of many potent
compounds are shown in the Figure III.C.1 below:
N O
SOH
SOH
O
HO
OAc
O
O
O
NH
O
O
Ph
OH
NHPh
O
BzO HAcO
OS
O
VT-labeled TaxolBioorthogonal ligations using oQMS
Vinyl sulfide
Figure III.C.1. Vinyl sulfides used as synthetic intermediates
Q. Li et al developed a bioorthogonal ligation using o‒quinolinone quinone methide and
vinyl thioether.4 VT‒labeled taxol was prepared by N. Muraoka and his group smoothly.
5
Similarly, some biological molecules containing vinyl sulfide moiety have been synthesized.
The vinyl sulfide analogues of Angiotensin II with high affinity and full agonist activity at
the AT1 receptor have also been synthesized.6 The streptogramin antibiotics, Griseoviridin
also contained vinyl sulfide with nine‒membered macrocycle moiety (Figure III.C.2).7
HN
NH
HN
NH
O
O
O
O
S S
Vinyl sulfide cyclized analogous of Angiotensin II
O
NH
O
S
O
ONH
OHHO
O
Griseoviridin (the steptogramin antibiotics)
Figure III.C.2. Vinyl sulfides used as biologically active molecules
Multisubstituted olefins, which are important for materials science and pharmaceutical
chemistry and these can be synthesized by the Mizoroki‒Heck reaction of 2‒pyrimidyl vinyl
72
sulfide.8
N
NS
Ar I (1 eqiv)
Pd[P(t-Bu)3]2Et3N
toluene, 60 oC
N
NSAr
Ar1 I (1 eqiv)
90 oC
N
NSAr
Ar1
Scheme III.C.1. Substituted 2‒pyrimidyl vinyl sulfide used in materials science
III.C.2. Background and Objectives
Increasing demand for alkenyl sulfides in material science, organic and bio‒organic
chemistry has furthered the development of new synthetic methods.2e,9
The addition of thiols
to alkynes is considered as one of the straightforward methods to obtain vinyl sulphides either
catalyzed by transition metal complexes,10‒16
or base‒promoted17
and/or through free
radicals.18
This reaction is often judged as a part of “click chemistry” and a process of high
atom‒economy.19
Mechanistically, addition of thiols to alkynes is believed to occur (i) via
radical pathway producing unselective mixture of (E/Z)‒anti‒Markovnikov vinyl sulphides;
(ii) base‒mediated nucleophilic addition giving all types of adducts or (iii) transition‒metal
complex catalyzed processes yielding Markovnikov vinyl sulphides and anti‒Markovnikov
vinyl sulphides (Scheme III.C.2). Varying degrees of stereo‒ and regioselectivity selectivity
and turnover are reported in the literature.
Scheme III.C.2. 1‒Alkenyl sulphides from hydrothiolation of terminal alkynes
C6H5 HC6H5 SH
Additives [A]1a
C6H5
H
H
SC6H5H
C6H5
H
SC6H5C6H5
SC6H5
H
H+ +
2b 2cWater / Rt 2a
(Markovnikov) (Anti-Markovnikov)
(E)-isomer (Z)-isomer
Most reports in the literature described the formation of thermodynamically more stable
(E)‒vinyl sulfide in considerable excess over the (Z)‒isomer. On the other hand,
hydrothiolation, particularly of aryl and benzyl thiols and catalyzed by transition‒metal
complexes, often produces a mixture of anti‒Markovnikov (E)‒alkenyl sulfide (syn addition)
and Markovnikov adduct and thus suffers from poor regioselectivity. 1,1‒Disubstituted alkyl
vinyl sulfides were synthesized via rhodium‒catalyzed hydrothiolation reaction. The reaction
goes through predominantly via Merkovnikov addition by thiols to alkynes. J. A. Love et al
73
invented such Merkovnikov addition in the presence of 3,5‒dimethyl
pyrazolylborate‒rhodium complex (Scheme III.C.3).11a
N
N
H
N
N
N
N
RhPPh3
PPh3
Tp*Rh(PPh3)2
Tp* = 3, 5-dimethyl pyrazolylborate
SH3 mol% cat.
DCE: PhCH3 (1:1) = 4 mL
RT, 2 h
SR
R = -H, 4-NMe2, 4-OCH3, 4-CH3, 4-Br, 4-CF3, 3-OCH3, 2-OCH3,and
2-pyridyl
R+
Scheme III.C.3. Synthesis of 1,1‒Disubstituted alkyl vinyl sulfides by rhodium catalyst
Similarly diphosphino‒functionalized MCM‒41 anchored Rh‒complex
[MCM‒41‒2P‒RhCl(PPh3)] have exhibited high catalytic activity. This is an example of
heterogeneous Rh‒catalyzed hydrothiolation of alkynes with thiols.20
OSiMe3
Si(CH2)3N
OEt
PPh2
PPh2
RhCl(PPh3)3
Benzene, RT, 48 h
OSiMe3
Si(CH2)3N
OEt PPh2
PPh2
RhCl
PPh3
MCM-41-2P MCM-41-2P-RhCl(PPh3)
Scheme III.C.4. Preparation of MCM‒41‒2P‒RhCl(PPh3)
The reaction went through complete anti‒Merkovnikov fashion and (E)‒vinyl sulfides
formed as major product. The stereochemistry of the addition products were determined by
1H‒NMR spectra (Scheme III.C.5).
20
Ar SH+
3mol% MCM-41-2P-RhCl(PPh3)
EtOH, 40 oC, 24 h
H
H
SAr
R R
R = -H, 4-OCH3, 4-CH3, 4-Cl, 4-F, andn-C6H13, i-C5H11 1-cyclohexylAr = Ph, 4-CH3C6H4, 4-ClC6H4
(E)-vinyl sulfide
Scheme III.C.5. Hydrothiolation reaction in presence of heterogeneous MCM‒41‒2P‒RhCl(PPh3)
catalyst
74
Highly stereo‒ and regio‒controlled synthesis of vinyl sulfides via Pd‒catalyzed
hydrothiolation of alkynes with thiols has been effectively done by A. Ogawa and his group.
They had shown the regio‒isomer i.e. Merkovnikov product was formed exclusively in
presence of Pd(OAc)2 whereas the anti‒Merkovnikov adduct was obtained in presence of
radical initiator (Scheme III.C.6).21
R Ph SH+ RSPh
SPh
R radical initiatorPd(OAc)2
Scheme III.C.6. Stereoslective synthesis of vinyl sulfides by Pd‒catalyzed reaction
The first example of polymer‒supported palladium catalysts for stereoselective S‒S bond
addition to terminal alkynes has been established by I. Beletskaya et al. The exclusive
(Z)‒selectivity has been achieved by this methodology. Diselenides did not undergo the
reaction under this condition (Scheme III.C.7).22
R Ph S+ S PhPPh3
Pd2dba3
140 oC, 2h, tolueneArS
R
SAr
94-99% yield
Z/E> 99:1
Scheme III.C.7. Polymer‒supported palladium catalyst for stereoselective S‒S bond addition to
terminal alkynes
The Stereoselective (Z)‒vinyl sulfides can be effectively synthesized by C. M. Frech and
his group in presence of dichloro(amine phosphine) complex of palladium. Selective
formation of cis‒configured vinyl thioethers have been achieved by this methodology. The
addition followed anti‒Merkovnikov fashion. A large number of alkynes and thiols were
participated in this reaction (Scheme III.C.8).12a
75
PCy
Cy
N
PCy
Cy
N
PdCl
Cl
Pd-cat.(0.05 mol%)
NaOH, NMP, 120 oCH
S
H
R1
R1 = -H, 4-F, 4-Br and
R2 = -H, 4-OMe, 4-NH2, 2-Me, 4-
Br, 3-Br
(Z)-vinyl sulfide
SH
R1 R2
+R2
Dichlorobis[1-(dicyclohexylphosphanyl)piperidine]
palladium
Scheme III.C.8. Palladium‒catalyzed synthesis of cis‒configured vinyl thioethers
Organoactinide complexes can also use as hydrothiolation of alkynes with various thiols.
A large number of aliphatic, aromatic and benzylic thiols were participated in this
methodology. This was the first report of the use of f‒element catalysts to affect the efficient
hydrothiolation with high degree of Markovnikov selectivity (Scheme III.C.9).23
SH+
S
SH +
S
SH +
S
Aliphatic thiols and alkynes Aromatic thiols and alkynes Aliphatic thiols and aromatic alkynes
Cat. Cat. Cat.
Cat. = Me2SiCp''2Th[CH2TMS]2
Scheme III.C.9. Organoactinide‒mediated hydroyhiolation of terminal alkynes with aliphatic,
aromatic and benzylic thiols
Efficient and convenient synthesis of β‒vinyl sulfides by Ni‒catalyzed regioselective
addition of thiols to alkynes has been achieved. I. P. Beletskaya and his group developed this
methodology using Ni(acac)2 as the catalyst. 2 mol% of the catalyst was sufficient for this
conversion. Only 15 min to 3.5 h was required for complete conversion of products (Scheme
III.C.10).24
76
R SH
R1
+
R
SR1
S
R
S R
R1R1
+ +
Yield: 99% 1%
Stereoselectivity: 89% 5% 5%
Ni(acac)2, 2 mol%
40 oC, 15 min to
3.5 h
R = -C5H11, -CH2CH2OH, -C(Me2)OH, -C(Me2)OMe, -C(Me2)OCOMe, Ph
R1 = -H, 4-CH3, 4-Cl
Scheme III.C.10. Ni(acac)2‒catalyzed regioselective synthesis of β‒vinyl sulfides by hydrothiolation
reaction
NHC‒based Nickel catalysts have been found for the selective transfer of a single arylthio
group in the catalytic hydrothiolation reaction. Some structures of NHC are depicted in the
Figure III.C.3 below:
N N
IMesN, N'-bis(2,4, 6-trimethylphenyl)-imidazole-2-ylidine
NHC = IMes, SIMes and IPr
N N
SIMesN, N'-bis(2,4, 6-trimethylphenyl)-imidazolin-2-ylidine
N N
IPrN, N'-bis(2, 6-diisopropylphenyl)-imidazole-2-ylidine
NiNHCCl
Figure III.C.3. Structures of Ni‒NHC complex and some NHCs
The reaction was performed at 80 oC with triethyl amine as base and toluene as solvent.
Reaction required 5 hours for desired conversion of the products. The exact mechanism was
described by the authors and this is presented below (Scheme III.C.11).10
NiNHCCl
PhSH+ Et3N
Toluene, 2 h, 80 oCNi
SCHN
RNi
R
S
NHC
PhSH R
SPh
NiSCHN
+
[Et3NH] Cl
77
Scheme III.C.11. Mechanism of Ni‒NHC‒catalyzed hydrothiolation reaction
Recently it has been shown that In(OTf)3 selectively catalyzes both Markovnikov and
anti‒Markovnikov hydrothiolation of terminal alkynes. When 2‒mercapto benzothiazole,
2‒mercapto benzoxazole or 2‒mercapto oxazole reacted with terminal alkynes Merkovnikov
adduct has been found to form. In the case of aliphatic or aromatic thiols, anti‒Merkovnikov
adduct was formed (Scheme III.C.12).16
S
NSH
In(OTf)3
Toluene, reflux
In(OTf)3
Toluene, refluxS
NS
R SHS
R
Merkovnikov additionAnti-Merkovnikov addition
R = Cyclohexyl, cyclopentyl, n-propyl, iso-propyl, p-tolyl
Scheme III.C.12. In(III)‒catalyzed substrate selective hydrothiolation of terminal alkynes
The (E)‒ and (Z)‒ selectivity of the vinyl sulfide can be achieved by tuning the reaction
environment under Cu(I)‒catalyzed hydrothiolation reaction. Under argon and CO2
atmospheres E‒isomer and Z‒isomer was formed respectively with major amounts (Scheme
III.C.13).25
Ar SH+Cu(I)
R1
R1S
Ar
Ar
Cu(I)
CO2 Ar SR1
E-vinyl sulfide Z-vinyl sulfide
R1 = aryl, alkyl, heterocyclic
Scheme III.C.13. Cu(I)‒catalyzed hydrothiolation under CO2 and argon atmosphere
However, transition metal complexes are generally expensive, their uses are not
eco‒friendly and the course of the reaction might suffer deactivation due to the formation of
strong metal–sulphur bonds.26
Moreover regioselective (anti‒Markovnikov) on‒water hydrothiolation processes have
been reported in the absence or presence of some additives.18
Although the development of
new methodologies using metal catalysts attract much interest in hydrothiolation reaction, the
78
use of greener solvent media seek importance to the aspect of Green Chemistry.
β‒Cyclodextrine promoted stereoselective hydrothiolation reaction was performed by K. R.
Rao and his group. They have shown that the complete formation (E)‒vinyl sulfides can be
achieved in water medium. In this protocol only aromatic terminal alkynes and aromatic
thiols were participated. The addition pattern in this case was totally anti‒Merkovnikov
fashion and the product was absolutely (E)‒vinyl sulfide (Scheme III.C.14).27
R1HS
R2+
-CD, H2O
RT
H S
H
R1
R2
R1 = H, Me, Br, Cl
R2 = H, Me, OMe, Cl, Br
-CD = Cyclodextrin
Scheme III.C.14. Hydrothiolation of alkynes with thiophenols in presence of β‒Cyclodextrin in
Water
Water‒promoted regioselective hydrothiolation of alkynes was performed by B. C. Ranu
et al. They have shown that an internal alkyne adds thiols to give both (E)‒ and (Z)‒ products
at room temperature. When dithio compounds were used and reacted with terminal alkynes, a
cylic dithio compound was formed. It is to be noted that no uniformity of the E:Z ratio of the
products have been achieved in this methodology. The reaction was found to be retarded
down in absence of water (Scheme III.C.15).28
R2R1
H
R2R1
SR H
SRR1
R2
RSH
H2O, RT+
S
SR1n
n = 2,3 R2 = H
SH
SHn
H2O, 80 oC
R, R1 = alkyl, aryl
R2 = H, alkyl
Scheme III.C.15. Water‒promoted regioselective hydrothiolation reaction
Similarly water mediated hydrothiolation of aromatic and aliphatic alkynes have been
performed by G. B. Hammond and his group. This methodology did not require any metal
catalysts and hazardous solvent. Vicinal dithioethers were formed by the reaction of one
equivalent of aliphatic alkynes and two equivalents of aromatic or aliphatic thiols. Aryl thiols
were more reactive than aliphatic thiols. In this case the radical initiator could be the
dioxygen in the air. The specific role of the solvent was not clear at this case but it seemed
79
water has some ability to stabilize the radical intermediate and therefore facilitate the radical
mediated reaction. When aromatic thiols reacted with the aliphatic alkynes, dihydrothiolated
products have been achieved. But in the case of propergyl alcohols, monohydrothiolation
product has been achieved (Scheme III.C.16).18
R1
SHR3
R3S SR3
R2 R1 R2R4
R6
OH
R5
R4
S
R3
R5OH
R6
H2O, RT H2O, RT-60 oC
dihydrothiolationmonohydrothiolation
Scheme III.C.16. Green synthesis of vicinal dithioethers and alkenyl thioethers
So it is clearly envisaged from the above schemes that a large variety of reagents/catalysts
that are used in the hydrothiolation of terminal alkynes with varying degrees of success in
controlling stereo‒ and regioselectivity. However, many reports include expensive metal
catalysts, non‒aqueous solvents and high temperature and moreover lacks from
(E/Z)‒stereoselectivity. In practice, there is no general guideline by which one can proceed to
prepare a specific stereoisomer of a vinylic sulfide using this straightforward and
atom‒economic reaction under mild and environment‒friendly conditions. Moreover, there
are conditions that give rise to selective formation of the thermodynamically favoured
(E)‒alkenyl sulfide, it remains a challenge to develop such optimum conditions that
selectively produce (Z)‒alkenyl sulfides under complete metal‒free, base‒free and on‒water
conditions. Here, we examined a systematic investigation on the stereo‒ and regioselective
addition of aliphatic and aromatic thiols to terminal alkynes in the presence of different
additives in catalytic or stoichiometric quantities under on‒water conditions.
III.C.3. Present work: Results and Discussion
Preliminary studies on the influence of catalyst and/or promoter in hydrothiolation were
studied with a model reaction of phenyl acetylene (1a) and benzenethiol in the presence of
various metal salts, homogeneous and heterogeneous additives/promoters under on‒water
conditions at room temperature. The reaction was optimized using various
additives/promoters included inorganic salts, water‒soluble organic molecules, amino acids,
surfactants or heterogeneous ion‒exchange resins, and the results are summarized in Table
III.C.1. Since the hydrothiolated adducts were formed in varying ratios (E/Z ratios), the
results in the Table III.C.1 have been arranged showing gradual change in the formation of
(E)‒vinyl sulfide (2b) to the (Z)‒isomer (2c). The neat condition and the reaction with water
80
yielded the (E/Z) ratio as 83:17 and 80:20 respectively (Table III.C.1, entry 1 and 2). The
screening shows that the E/Z ratio in favor of (E)‒vinyl sulfide (87:13) is formed in the
presence of NaCl (Table III.C.1., entry 3). The gradual diminish in E stereoselectivity has
been observed from sucrose to starch in Table III.C.1. (entries 4 to 10). Bronstead acid
(trifluoro acetic acid) and Lewis acid (BF3‒Et2O) also increase the Z stereoselectivity (entries
of 5 and 6). Similarly, amino acids enhanced the Z stereoselectivity (entries 8 and 9). But, the
stereochemical outcome favouring the (E)‒isomer was also seen when the reaction was
carried out at higher temperature (65 oC) and continued for longer reaction time (10 h) (entry
11; E/Z ratio 88:12). On the other side the Z stereoselectivity has been found to gradually
increase from entry 13 to entry 23 in Table III.C.1. The major (Z)‒vinyl sulfide was obtained
in the presence of a combination of Amberlite resins (Cl) and FeCl3.6H2O (entry 23; E/Z ratio
22:78). However, a specific observation has to be noted from this study that the on‒water
additions did not give rise to the formation of any Markovnikov adduct, i.e. other regioisomer
(2a) was not obtained. The NMR spectral data of the crude products indicated only a mixture
of 2b and 2c and indeed there was no existance of 2a.
Table III.C.1. Role of additives in the addition of PhSH to phenylacetylene under on‒water
and at room temperature conditions.a
C6H5 HC6H5 SH
Additives [A]1a
C6H5
H
H
SC6H5H
C6H5
H
SC6H5C6H5
SC6H5
H
H+ +
2b 2cWater / RT 2a
(Markovnikov) (Anti-Markovnikov)
(E)-isomer (Z)-isomer
Entry Additive [A]b
(E/Z) ratioc,d
Entry Additive [A]b
(E/Z) ratioc,d
1 Nil (Neat) 83:17 13 CuI‒Catechol Violet 60:40
2 Nil (Water) 80:20 14 Amberlite Resins (Cl) 58:42
3 NaCl 87:13 15 n‒Bu4Br 57:43
4 Sucrose 85:15 16 D‒Glucose 56:44
5 CF3COOH 78:22 17 CuI 52:48
6 BF3.Et2O 76:24 18 Cholesterol 51:49
7 Catechol Violet 75:25 19 CTAB 49:51
8 L‒Proline 70:30 20 FeCl3.6H2O 44:56
9 Glycin 69:31 21 Amberlite Resins (OH) 40:60
10 Starch 64:36 22 D‒Glucose & FeCl3.6H2O 35:65
11e
Water (65 oC) 88:12 23 Amberlite Resins (Cl) & 22:78
81
12 Water (65 oC) 64:36 FeCl3
.6H2O
aReaction conditions: Phenyl acetylene (0.5 mmol), PhSH (0.55 mmol), water (1 mL), 2 h.
bAdditive [A] (2 mol %).
cE/Z ratio was determined by
1H NMR of the crude mixture.
dYield of the mixture of stereoisomers after chromatographic purification varies in the range 80‒90%.
eThe reaction was continued for 10 h; all other reactions were carried at room temperature unless
mentioned.
At this point, effect of functional groups in the aromatic moiety in either of the addition
partners could be worth investigating. Since a combination of ion‒exchange resins and ferric
chloride showed a better selectivity towards the formation of (Z)‒vinyl sulfide, this study was
performed under similar conditions. The results are presented in Table III.C.2. It is seen that
both electron‒donating and electron‒withdrawing functional groups present on the aryl ring
can give rise to the anti‒Markovnikov hydrothiolation products in excellent yields (85‒94%).
Highest (Z)‒selectivity was found in the reaction between phenyl acetylene and
p‒methoxybenzenethiol (Table III.C.2, entry 4; E/Z 12:88), possibly due to easy
emulsification of the alkyne in water upon stirring, which might be supportive in addition to
the presence of the additive. On the other hand, presence of electron‒withdrawing group
(fluorine) on the thiol part did not show any appreciable influence towards stereoselective
addition yielding the (E)‒ isomer in major (entries 6‒7). It seems that there is not much
electronic influence of the functional groups in the aryl ring of either of the addition partners;
rather their stability in water in the presence of the additive might have some control towards
anti‒Markovnikov stereoselectivity.
Table III.C.2. Hydrothiolation of aryl acetylene [A] with aromatic thiols [B] in (1:1.1) molar
ratios in water at room temperature.
R1 H SHR2
H
H
S
R1
R2
Amberlite resins (Cl) - FeCl3
+
[A] [B] [C]Water, RT
Entry [A] [B] Time (h) Yielda (%) [C] E / Z [C]
b
1 R1 = H R
2 = H 2.0 85 22 : 78
2 R1 = CH3 R
2 = H 3.5 91 40 : 60
3 R1 = CH3 R
1 = CH3 2.5 88 29 : 71
4 R1 = H R
1 = OCH3 3.0 93 12 : 88
5 R1 = CH3 R
1 = OCH3 2.0 90 22 : 78
82
6 R1 = H R
2 = F 2.0 88 80: 20
7 R1 = CH3 R
2 = F 2.0 94 39: 61
aYield represents the product [C] after purification by column chromatography.
bE/Z ratio was determined by
1H NMR of the crude mixture.
In cases of aryl acetylenes and aliphatic thiols combination, D(+)‒glucose plays a vital
role for achieving (Z)‒stereoselectivity. Hydrothiolation of aryl acetylenes (terminal) with
aliphatic thiols in the presence of one equivalent of D(+)‒glucose showed a general trend in
favour of the formation of (Z)‒vinyl sulphides. For example, phenyl acetylene undergoes
hydrothiolation in the presence of n‒alkyl thiols afforded the corresponding 1‒alkenyl
sulphides with (E/Z) ratios (14:86). The results are listed below in Table III.C.3.
Table III.C.3. Hydrothiolation aromatic terminal alkynes with aliphatic thiols.
R1 H
H
H
S
R1D (+)-Glucose
+
[A] [D] [E]
SH
n nWater, RT
Entry [A] [D] Time (h) Yielda (%) [E] E / Z [C]
b
1 R1 = H n = 3 3.0 75 20 : 80
2 R1 = H n = 5 3.0 64 14 : 86
3 R1 = CH3 n = 3 4.5 79 14 : 86
4 R1 = CH3 n = 5 5.0 51 21 : 79
aYield represents the product [E] after purification by column chromatography.
bE/Z ratio was determined by
1H NMR of the crude product mixture.
Since there is significant reactivity difference between aliphatic and aromatic thiols,29
we
ought to investigate the stereochemical outcome in two other cases: hydrothiolation of (i)
aliphatic terminal alkynes and aliphatic thiols and (ii) aliphatic terminal alkynes and aromatic
thiols. It has been seen from previous reports that aliphatic alkynes undergo dihydrothiolation
yielding vicinal disulfides only irrespective of nature of the thiol.18a,28
Thus, aliphatic
terminal alkynes were subjected to hydrothiolation with aromatic and aliphatic thiols under
on‒water conditions. Apparently, there was influence of additives in this double‒addition
reaction. The results are presented in Table III.C.4, which show that aliphatic terminal
alkynes undergo double‒ additions yielding finally 1, 2‒disulfides only in the presence or
absence of D (+)‒Glucose.
83
Table III.C.4. Dihydrothiolation of aliphatic alkyne with thiols in water at room temperature.
Water/ RT
[A] [B]/[D] [F]
HR1 + R2 SHR1
R2S SR2
Entry [A] [B]/[D]a
Time (h) Yieldb (%) [F]
1c
R1 = CH3‒CH2‒CH2 R
2 = Ph 5 88
2 R1 = CH3‒CH2‒CH2 R
2 = Ph 5 76
3 R1 = CH2OAc R
2 = Ph 6 79
4 R1 = CH3‒CH2‒CH2 R
2 = CH3(CH2)6SH 9 58
a[A]:[B] is 1:2.2 molar ratios.
bYield represents the product [F] after purification by column chromatography.
cD (+) Glucose (1 equiv) was added.
As regards to the mechanism of hydrothiolation of terminal alkynes in water, the literature
reports are of different views. For example, Ranu et al,28
found that the water‒promoted
regioselective hydrothiolation excluded the radical pathway because the reaction proceeds in
the presence of dissolved oxygen whereas Hammond et al,7a
hinted that the reaction probably
proceeds through a radical mechanism under similar conditions. The latter group further
observed that the reaction did not occur in the presence of galvinoxyl free radical. But this
was not only the proof for radical mechanism.30
Our studies demonstrated a role of additives
in governing the stereoselectivity but the specific function of the additive, particularly in
aqueous medium and the mechanistic routes are not cleared. Furthermore, carrying out the
reaction in the presence of radical initiator (AIBN) or light did not make the process faster
appreciably. Several transition metal complexes are known to catalyze the process of
hydrothiolation via radical intermediates leading to major anti‒Markovnikov 1‒alkenyl
sulfides. In the absence of such metal complexes, the stabilization of the reactive species has
been achieved by water as well as by the additive might alter the course of the reaction
pathway.
III.C.4. Conclusions
In search of finding „stereoselective‒switch‟ for the hydrothiolation of terminal alkynes
under on‒water conditions, we have found two types of additives that could lead to the
stereoselective formation of the (Z)‒1‒alkenyl sulfides in substantial quantities depending on
84
the nature of both reacting partners. Here we are able to give a direction for the formation of
(Z)‒isomer by mild and green reaction conditions.
III.C.5. Experimental section
III.C.5.1. General information
All the reactions were carried out in closed vessel under ambient conditions. Amberlyst®
IRA‒900, Cl form was purchased from ACROS Organics, India. FeCl3.6H2O and
D(+)‒glucose were purchased from Sd‒fine Chem. Ltd. and Glaxo Laboratories (India) Ltd.
respectively. For column chromatography: silica (60‒120 mesh) (SRL, India), and for tlc,
Merck plates coated with silica gel 60, F254 were used. All compounds were identified by 1H‒
and 13
C‒NMR spectra, recorded on a Bruker AV300 spectrometer operating at 300 and 75
MHz respectively and supported by FT‒IR spectra. All NMR spectra were measured in
CDCl3. Chemical shifts are given in δ (ppm) downfield from TMS. Characterization of
sulfanes (Table III.C.2, Table III.C.3 and Table III.C.4) has been made from melting point
and 1H‒ and
13C‒NMR spectral data.
III.C.5.2. General procedure for mono‒hydrothiolation of alkynes
To a mixture of alkyne (1 mmol), thiol (1.1 mmol) in water (0.5 mL) was added the
additive (1 mmol) and stirred at room temperature (25‒30 oC) for 2‒5 h (tlc). The reaction
mixture was extracted with diethyl ether (3×10 mL), and the combined organic layer was
washed with brine and then dried over Na2SO4. Evaporation of solvent under vacuo afforded
an oily residue, which was passed through a short bed of silica gel and NMR spectrum was
recorded to evaluate the percent of (E/Z) isomers. NMR spectral data and scanned copies of
selected NMR spectra are given in the supporting information and found to be in good
agreement with those reported.
III.C.5.3. General procedure for di‒hydrothiolation of alkynes
A mixture of alkyne (1 mmol), thiol (2.2 mmol) in water (0.5 mL) was stirred for 5‒9 h at
room temperature (tlc). The reaction mixture was then extracted with diethyl ether (3×10
mL), and the combined organic layer was washed with brine and then dried over Na2SO4.
Evaporation of solvent under vacuo afforded an oily residue, which was passed through a
short bed of silica gel to afford 1, 2‒disufides in good to excellent yields. The products were
identified on the basis of 1H‒,
13C‒NMR spectral data, and/or by comparison with the data
85
reported in the literature. NMR spectral data and scanned copies of selected NMR spectra
(1H‒ &
13C‒) are given in the supporting information.
III.C.5.4. Physical properties and spectral data of compounds
Table III.C.2, Entry 1
Mixture of (E/Z)‒phenyl(styryl)sulfane31
S
Pale yellow oil, E/Z ratio = 28:72 (from 1H‒NMR spectral data)
1H NMR (CDCl3, 300 MHz): δ/ppm 6.49 (d, J = 10.8 Hz), 6.58 (d, J = 10.8 Hz), 6.72 (d, J =
15.6 Hz), 6.88 (d, J = 15.6 Hz), 7.19–7.52 (m, Ar‒H).
13C NMR (CDCl3, 75 MHz): δ/ppm 123.3, 126.0, 126.9, 127.1, 127.2, 127.2, 127.6, 128.3,
128.7, 128.7, 129.1, 129.8, 130.0, 131.8, 135.2, 136.2, 136.4, 136.5.
Table III.C.2, Entry 2
Mixture of (E/Z)‒phenyl(4‒methylstyryl)sulfane
H3C
S
Pale yellow crystalline solid, mp 39–40 oC; E/Z ratio = 40:60 (from
1H‒NMR spectral data)
1H NMR (CDCl3, 300 MHz): δ/ppm 2.32, 2.34 (s, ‒CH3), 6.42 (d, J = 10.5 Hz), 6.56 (d, J =
10.8 Hz), 6.72 (d, J = 15.3 Hz), 6.81 (d, J = 15.6 Hz), 7.09–7.45 (m, Ar‒H).
13C NMR (CDCl3, 75 MHz): δ/ppm 21.2, 21.3 (CH3), 121.7, 124.7, 125.9, 126.7, 127.0,
127.3, 128.9, 129.0, 129.3, 129.4, 129.7, 129.9, 132.3, 133.6, 133.7, 134.1, 135.5, 136.3,
136.9, 137.5.
Table III.C.2, Entry 3
Mixture of (E/Z)‒(4‒methylphenyl)(4‒methylstyryl)sulfane
H3C
S
CH3
White crystalline solid, mp 48–49 oC; E/Z ratio = 29:71 (from
1H‒NMR spectral data)
86
1H NMR (CDCl3, 300 MHz): δ/ppm 2.31, 2.32 (s, ‒CH3), 6.38 (d, J = 10.8 Hz), 6.50 (d, J =
10.8 Hz), 6.64 (d, J = 15.3 Hz), 6.79 (d, J = 15.3 Hz), 7.07–7.43 (m, Ar‒H).
13C NMR (CDCl3, 75 MHz): δ/ppm 21.0, 21.1, 21.2 (CH3), 122.9, 125.8, 125.9, 126.6, 128.7,
128.9, 129.3, 129.7, 129.9, 130.3, 130.4, 131.0, 137.0, 137.2, 137.3.
Table III.C.2, Entry 4
Mixture of (E/Z)‒(4‒methoxyphenyl)(styryl)sulfane32
S
OCH3
White crystalline solid, mp 61 oC (Lit. mp 58‒60
oC); E/Z ratio = 12:88 (from
1H‒NMR
spectral data)
1H NMR (CDCl3, 300 MHz): δ/ppm 3.74, 3.76 (s, ‒OCH3), 6.38 (d, J = 11.1 Hz), 6.46 (d, J =
10.8 Hz), 6.49 (d, J = 15.6 Hz), 6.81 (d, J = 15.6 Hz), 6.84–7.52 (m, Ar‒H).
13C NMR (CDCl3, 75 MHz): δ/ppm 55.0, 55.3, 55.5, 55.8 (OCH3), 114.8, 114.9, 125.7, 126.8,
127.1, 127.9, 128.2, 128.3, 128.4, 128.6, 128.8, 128.9, 128.9, 129.1, 132.5, 132.8, 132.9,
133.1, 133.4, 136.6, 136.7, 159.5.
Table III.C.2, Entry 5
Mixture of (E/Z)‒(4‒methoxyphenyl)(4‒methylstyryl)sulfane
H3C
S
OCH3
White crystalline solid, mp 68 oC; E/Z ratio = 22:78 (from
1H‒NMR spectral data)
1H NMR (CDCl3, 300 MHz): δ/ppm 2.30, 2.34 (s, ‒CH3), 3.77 (s, ‒OCH3), 6.32 (d, J = 10.8
Hz), 6.45 (d, J = 10.8 Hz), 6.75 (d, J = 15.3 Hz), 6.84–7.41 (m, Ar‒H and olefinic H).
13C NMR (CDCl3, 75 MHz): δ/ppm 21.3, 21.4 (CH3), 55.0, 55.3, 55.5, 55.8 (OCH3), 113.9,
114.7, 114.8, 124.2, 124.8, 125.3, 125.8, 126.7, 127.0, 127.2, 127.7, 127.8, 128.2, 128.3,
128.5, 128.6, 128.7, 128.8, 129.0, 129.0, 129.1, 129.3, 129.4, 129.5, 130.0, 131.9, 132.4,
132.7, 132.8, 133.0, 133.1, 133.3, 133.9, 134.0, 136.8, 137.1.
Table III.C.2, Entry 6
Mixture of (E/Z)‒(4‒fluorophenyl)(styryl)sulfane
87
S
F
Pale yellow oil, E/Z ratio = 80:20 (from 1H‒NMR spectral data)
1H NMR (CDCl3, 300 MHz): δ/ppm 6.41 (d, J = 10.5 Hz), 6.58 (d, J = 10.5 Hz), 6.65 (d, J =
15.3 Hz), 6.83 (d, J = 15.6 Hz), 7.01–7.43 (m, Ar‒H).
13C NMR (CDCl3, 75 MHz): δ/ppm 116.2, 116.53, 123.8, 123.9, 125.9, 126.0, 126.1, 126.5,
127.0, 127.7, 128.6, 128.8, 129.8, 129.9, 131.1, 132.5, 132.6, 132.7, 136.4, 160.6, 163.9.
Table III.C.2, Entry 7
Mixture of (E/Z)‒(4‒fluorophenyl)(4‒methylstyryl)sulfane
S
FH3C
White crystalline solid, mp 60–61 oC; E/Z ratio = 39:61(from
1H‒NMR spectral data)
1H NMR (CDCl3, 300 MHz): δ/ppm 2.35 (s, ‒CH3), 6.32 (d, J = 10.5 Hz), 6.53 (d, J = 10.5
Hz), 6.64 (d, J = 15.6 Hz), 6.74 (d, J = 15.0 Hz), 7.00–7.37 (m, Ar‒H).
13C NMR (CDCl3, 75 MHz): δ/ppm 21.2, 21.3, 21.4 (‒CH3), 116.1, 116.4, 122.3, 125.3,
125.9, 126.0, 126.8, 127.2, 127.6, 128.2, 128.5, 128.8, 129.0, 129.0, 129.1, 129.4, 130.2,
130.2, 131.5, 131.6, 131.8, 132.1, 132.3, 132.4, 132.5, 132.6, 133.5, 133.6, 137.1, 137.6,
160.6, 163.8, 163.9.
Table III.C.3, Entry 1
Mixture of (E/Z)‒pentyl(styryl)sulfane
S
Pale yellow oil, E/Z ratio = 20:80 (from 1H‒NMR spectral data)
1H NMR (CDCl3, 300 MHz): δ/ppm 0.90 (t), 1.20–1.58 (m), 1.63–1.73 (m), 2.76 (t), 6.23 (d,
J = 11.1 Hz), 6.42 (d, J =10.8 Hz), 6.45 (d, J = 15.3 Hz), 6.72 (d, J = 15.6 Hz), 7.16–7.49 (m,
Ar‒H).
13C NMR (CDCl3, 75 MHz): δ/ppm 14.0, 22.3, 29.1, 29.9, 30.7, 31.0, 35.9, 125.2, 126.5,
127.7, 127.8, 128.1, 128.4, 128.7, 129.0, 137.0.
88
Table III.C.3, Entry 2
Mixture of (E/Z)‒heptyl(styryl)sulfane
S
Pale yellow oil, E/Z ratio = 14:86 (from 1H‒NMR spectral data)
1H NMR (CDCl3, 300 MHz): δ/ppm 0.88 (t), 1.28–1.78 (m), 2.78 (t), 6.24 (d, J = 10.8 Hz),
6.43 (d, J = 11.1 Hz), 6.45 (d, J = 15.3 Hz), 6.72 (d, J = 15.6 Hz), 7.20–7.49 (m, Ar–H).
13C NMR (CDCl3, 75 MHz): δ/ppm 14.0, 22.6, 28.6, 30.3, 31.7, 35.9, 125.2, 126.5, 127.7,
128.2, 128.6, 137.0.
Table III.C.3, Entry 3
Mixture of (E/Z)‒pentyl(4‒methylstyryl)sulfane
H3C
S
Colourless oil, E/Z ratio = 14:86 (from 1H‒NMR spectral data)
1H NMR (CDCl3, 300 MHz): δ/ppm 0.90 (t), 1.29–1.43 (m), 1.68 (m), 2.33 (s), 2.77 (t), 6.17
(d, J = 10.8 Hz), 6.40 (d, J = 10.8 Hz), 6.65 (d, J = 15.3 Hz), 7.08–7.39 (m, Ar–H and
olefinic H).
13C NMR (CDCl3, 75 MHz): δ/ppm 13.9, 21.2, 22.3, 29.1, 29.9, 30.7, 30.9, 32.6, 35.8, 125.2,
125.3, 126.5, 128.5, 129.3, 134.2, 134.3, 136.3.
Table III.C.3, Entry 4
Mixture of (E/Z)‒heptyl(4‒methylstyryl)sulfane
H3C
S
Yellow oil
E/Z ratio = 21:79 (from 1H–NMR spectral data)
1H NMR (CDCl3, 300 MHz): δ/ppm 0.90 (t), 1.20–1.39 (m), 1.52–1.72 (m), 2.31 (s), 2.65–
2.79 (t), 6.16 (d, J = 10.8 Hz), 6.39 (d, J = 10.8 Hz), 6.65(d, J = 16.8 Hz), 7.07–7.93 (m,
Ar‒H and olefinic H).
89
13C NMR (CDCl3, 75 MHz): δ/ppm 14.1, 21.2, 21.3, 22.6, 28.6, 28.9, 30.2, 31.7, 35.8, 122.2,
126.5, 128.1, 128.4, 128.6, 128.9, 129.3, 134.2, 136.3.
Table III.C.4, Entry 1
1‒(1‒(Phenylthio)pentan‒2‒ylthio)benzene
S
S
Colourless oil
1H NMR (CDCl3, 300 MHz): δ/ppm 0.93 (t, J = 3.6 Hz, 3H), 1.49–1.60 (m, 4H), 2.84–2.92
(m, 1H), 3.10–3.27 (m, 2H), 7.16–7.33 (m, Ar‒H).
13C NMR (CDCl3, 75 MHz): δ/ppm 13.8, 20.0, 34.8, 39.5, 48.1, 126.2, 127.2, 128.9, 128.9,
128.9, 129.8, 132.5, 134.4, 135.9.
Table III.C.4, Entry 2
2,3‒Bis(Phenylthio)propyl acetate
OS
S
O
Pale yellow oil
1H NMR (CDCl3, 300 MHz): δ/ppm 2.10 (s, 3H), 3.13–3.24 (m, 2H), 3.34–3.37 (m, 1H),
4.29–4.42 (m, 2H), 7.21–7.39 (m, Ar‒H).
13C NMR (CDCl3, 75 MHz): δ/ppm 20.7, 35.8, 47.1, 64.5, 126.6, 127.8, 129.0, 129.2, 129.9,
132.9, 135.2, 170.7.
Table III.C.4, Entry 3
1‒(1‒(Heptylthio)pentan‒2‒ylthio)heptane
S
S
90
Colourless oil
1H NMR (CDCl3, 300 MHz): δ/ppm 0.86–0.95 (m, 9H), 1.28–1.80 (m, 24H), 2.50–2.75 (m,
6H), 2.82–2.87 (dd, J = 4.2 and 12 Hz, 1H).
13C NMR (CDCl3, 75 MHz): δ/ppm 13.2, 13.9, 14.0, 14.8, 19.9, 22.6, 28.4, 28.8, 28.9, 29.4,
29.8, 29.9, 30.3, 30.8, 31.7, 33.1, 35.7, 38.4, 45.5.
III.C.6. References
References are given in BIBLIOGRAPHY under Chapter III, Section C (pp. 149‒150).
91
CHAPTER IV
Cyclic ammonium salts of dithiocarbamic acid:
Stable alternative reagents for the synthesis
of S‒alkyl carbodithioates from organyl
thiocyanates in water
92
IV.1. Introduction
S‒Alkyl carbodithioate esters are esters of dithiocarbamic acids. These are also known as
dithiocarbamate esters (DTCE), are functional organosulfur compounds that were first
utilized as fungicides during Second World War.1 The structures of esters of carbamic acid,
thiocarbamic acid and dithiocarbamic acid are given in the Figure IV.1.
Figure IV.1. Structures of carbamic acid, thiocarbamic acid and dithiocarbamic acid and their esters
Dithiocarbamates are also mainly used as important fungicides of vegetables, crops and
plants.2‒4
S‒alkyl carbodithioate esters and its derivatives show antibacterial,5‒7
anthelmintic,8
anticandidal activity and cytotoxicity,9 antihistaminic,
10 as well as anticancer properties.
8,11‒13
They can also be helpful for the treatment of cardiovascular disorders and inflammatory
diseases,14
human myelogenous leukemia K562 cells,15
and can be used as HIV‒I NCp7
inhibitors,16
or non‒vanilloid TRPV1 antagonists.17
A few structures of S‒alkyl
carbodithioate esters with potential therapeutic value are shown in Figure IV.2. Further utility
of carbodithioate ester as linkers in solid‒phase organic synthesis is also well
documented.18,19
Carbodithioate esters are widely used as suitable ligands to assemble on
metal nanoparticles in surface science and nanomaterial chemistry.20,21
They are also
well‒known in rubber industry as sulfur vulcanization acceptors,22
and radical chain transfer
agents in the reversible addition fragmentation chain transfer (RAFT) polymerizations.23‒25
Many useful synthetic intermediates contain the carbodithioate ester moiety.26,27
As a result,
several methods for the synthesis of carbodithioate esters have been developed.28
93
NH
NH
SCH3
SS
NH
H3C
O S
SCH3
N N
ClS
S
NMe2N N S
S NC
Brassinin, cancer chemopreventive activity
Sulforamatecancer chemopreventive agent
RWJ-025856attenuating effects on tumor
necrosis factor a (TNFa)-induced apoptosis in murinefibrosarcoma WEHI 164 cells
990207inhibiting the tumor growth of sarcoma
180 (S180), hepatocyte carcinoma 22 (H22)
Figure IV.2. Examples of compounds of potential therapeutic value bearing S‒alkyl carbodithioate
esters function
IV.2. Background and objectives
Synthesis of S‒alkyl/aryl carbodithioate esters is generally achieved by either nucleophilic
substitution reactions under basic medium or transition metal‒catalyzed cross–coupling
reactions. M. R. Saidi reported a highly efficient one‒pot amines and carbon disulfide with
α,β‒unsaturated compounds in water. This simple protocol avoids the use of basic and highly
toxic organic solvents and catalysts. The catalyst‒free, cleaner reaction and simple
experimental procedure have been highly acclaimed (Scheme IV.1).29
HN
CS2 COOMeWater
RTN S
S
COOMe+ +
Scheme IV.1. One‒pot preparation of dithiocarbamate in water without using any catalyst
The same group also developed a clean and catalyst‒free simple one‒pot methodology for
the synthesis of S‒alkyl dithiocarbamate (Scheme IV.2).30
RR1NH R2XCS2, RT
3-12 h
S
R1RN SR2+
Scheme IV.2. One‒pot clean method for the synthesis of carbodithioates
A deep eutectic solvent (DES) and polyethylene glycol (PEG) promoted the
environmentally friendly and fast synthesis of dithiocarbamate derivatives via a one‒pot,
94
three‒component condensation of an amine, carbon disulfide and an epoxide has been
developed by N. Azizi et al. The main advantages of the protocol included simple
experimental procedures, short reaction times, low cost, efficient yields and use of greener
solvent, which made this method as attractive strategy (Scheme IV.3).31
O
PhO
HNCS2 N S
S
OPh
OH
+ +PEG or DES
RT, 60 min
PEG = Polyethylene glycolDES = Deep eutectic solvent
Scheme IV.3. One‒pot synthesis of 2‒hydroxydithiocarbamates in DES and PEG
Basic resin (Amberlite IRA 400) supported a highly efficient and one‒pot synthesis of
dithiocarbamates was done by the Michael addition of dithiocarbamate anion to α,
β‒unsaturated compounds. Dimethyl sulfoxide was used as solvent and the reaction took 2 to
4 hours for completion (Scheme IV.4).32
CS2 EWG
Amberlite IRA 400
Dry DMSO, RT, 2-4h
N S
S
EWG+ +R1R2NH
R1
R2
R3R3
EWG = -COCH3, -COOCH3, -CONH2, -CN
Scheme IV.4. Basic resin (Amberlite IRA 400) supported one‒pot synthesis of dithiocarbamate
Alkaline Al2O3 mediated Michael addition of electron deficient alkenes with aryl amines
and carbondisulfide has been reported by X. Wang et al. A wide range of amines were used
and the reaction was clean and reused without complex workup (Scheme IV.5).33
CS2
Alkaline Al2O3
RT, 20 h
N S
S
+ +R1R2NH
O
OMe
R1
R2
O
OMe
R1 = Ph, R2 = H
Scheme IV.5. Michael addition of aryl amines towards electron deficient alkenes
Ranu et al developed a new methodology for the synthesis of dithiocarbamate by one‒pot
three component condensation of an amine, carbon disulfide and an activated
95
alkene/dichloromethane/epoxide using a room‒temperature ionic liquid (RTIL). The
reactions were found to be very fast and symmetrical dithiocarbamates have been synthesized
by this methodology (Scheme IV.6).34
NH CS2+[pmIm]]Br
0 oC, 2 minN
S
S
OR
RT, 15 min
Y
RT, 10-30 min
CH2X2
RT, 10-20 min
N
S
SR
OH
N
S
S S
S
N
N
S
SY
R = Alkyl, Ph
Y = CO2Me, CN,COPh, CO2NH2, CO2H
X = Cl, Br, I
Scheme IV.6. Synthesis of dithiocarbamates using [pmIm]Br ionic liquid
A very common methodology of one‒pot three component reactions has been established
by A. Z. Halimehjani et al. In this protocol the ethyl vinyl ether was used as an electrophile.
This reaction was complete regioselective towards Markovnikov addition (Scheme IV.7).35
RR1NH CS2+ OH2O
RT+
R1RN S
S
O
RR1NH = Piperidine, pyrrolidine, morpholine,
diisopropyl amine, n-butyl amine, allyl amine,
diallyl amine, benzyl amine
Scheme IV.7. Markovnikov addition reaction of dithiocarbamate to ethyl vinyl ether
Allyl and cinnamyl acetates are rarely used as electrophiles in dithiocarbamates
preparation. A convenient and efficient one‒pot three component condensation of
nonactivated allyl/cinnamyl acetate, carbon disulfide and an amine in presence of Ru(acac)3
in water has been demonstrated by B. C. Ranu et al. The reaction underwent via a catalytic
Ru(II) species, generated in situ during the reaction. The methodology was found to be
attractive due its operational simplicity, use of low catalyst loading, excellent
stereoselectivity in the reactions of trans‒cinnamyl acetate and use of water as solvent
(Scheme IV.8).36
96
R OAc + CS2 + HNRu(acac)3, H2O
RefluxR S N
S
R = H, alkyl, aryl, heteroaryl
Scheme IV.8. Ru(acac)3 catalyzed synthesis of allyl/cinnamyl dithiocarbamates
Like allyl or cinnamyl acetates tosyl hydrazones were rarely used for the formation of
carbodithioates. A new, convenient and efficient transition metal‒free synthesis of S‒alkyl
dithiocarbamates through one‒pot reaction of N‒tosylhydrazones, carbon disulfide and
amines was reported by Y.‒Y. Wei et al. The reaction required a base, high temperature and
an organic solvent, dioxane (Scheme IV.9).37
NNHTs
R2R1+ CS2 + HN
K2CO3
Dioxane, 110 oC, 4 h
S
R2R1
N
S
Tosyl hydrazone
Scheme IV.9. Metal free three‒component reaction of N‒tosylhydrazones, carbon disulfide and
amines
Anilines can also be used for the preparation of carbodithioate ester bearing sec. NH group
in the presence of DMSO and strong base like NaOH.38
Most of the procedures involve harsh
reaction conditions, long reaction time, hazardous organic solvents, metal catalysts and bases.
Organyl thiocyanates, often considered as psuedohalides and are easily available, were not
used as the starting materials, presumably because of the fact that the thiocyanate may
undergo disulfide (‒S‒S‒) bond formation under basic medium.39,40
We found that the
reaction of a sec. amine with CS2 produces a stable salt, which can be isolated easily in
almost quantitative yield and stored for several weeks in the air. The salt can efficiently react
with alkyl/aroyl methyl/cinnamyl thiocyanates in water medium at room temperature to
afford corresponding carbodithioate esters in good to excellent yields without formation of
any other by‒products such as organyl disulfide. Here we describe an efficient, base‒ and
metal‒free protocol for the synthesis of various S‒substituted carbodithioate esters by using
variety of cyclic sec. amine‒based dithiocarbamate salts from diverse organyl thiocyanates.
To the best of our knowledge organyl thiocyantes have not been used previously as the
precursor for preparation of carbodithioate esters. The other main advantages of this protocol
97
are metal‒ and alkali‒free, which possibly leads to avoid the disulfide bond formation, clean
reaction affording excellent yields and can be carried out in water medium at ambient
condition.
IV.3. Present work: Results and Discussion
As a part of preliminary study, as presented in Table IV.1, we had conducted the reaction
of a neat mixture of benzyl thiocyanate, CS2 and morpholine in one‒pot manner, which led to
the pure desired benzyl morpholine‒4‒carbodithioate ester 4a in only 72% isolated yield
(Table IV.1, entry 1). Moreover, the reaction showed partial formation of dibenzyl disulfide
on tlc monitoring of the experiment, although it was not isolated in considerable quantity
after column chromatography. Considering that the intermediate salt derived from the amine
and CS2 could be the actual nucleophile, the sodium salt of morpholinodithioformate 2a was
used to react with benzyl thiocyanate 3a (Table IV.1, entry 2). However, we obtained the
desired carbodithioate ester 4a again with the formation of dibenzyl disulfide, presumably
attributable to the basic reaction medium that facilitates the disulfide from benzyl thiocyanate
3a.39,40
In order to avoid the basic reaction medium, we considered that the dithiocarbamate
salt consisting of both organyl cationic and anionic part might be suitable and accordingly,
we prepared the salt 2b from a mixture of morpholine and CS2 in diethyl ether following the
reported procedure.41
The salt 2b now contains morpholino‒based cationic and anionic part
and stirring a mixture of benzyl thiocyanate 3a with the salt 2b (in equimolar quantity) in
water at room temperature gave rise to clean reaction without any trace of disulfide
formation, producing 4a in 76% isolated yield (Table IV.1, entry 3). Heating the reaction
mixture of 2b and 3a in water or ethanol at 60 oC resulted in rather better yield of 4a
(78‒82%; Table IV.1, entries 4 and 5). On the other hand, use of water‒ethanol (1:1) as the
solvent and conducting the reaction at room temperature gave 4a in 80% yield (Table IV.1,
entry 6). It is likely that organyl thiocyanates are poorly soluble in water, and we employed
two different phase transfer agents, n‒tetrabutyl ammonium bromide (TBAB) and sodium
dodecyl sulfate (SDS). While the use of TBAB was found to improve marginal increase in
the yield of 4a (Table IV.1, entry 7), the presence of SDS (either in stoichiometric or in 10
mol%) afforded 4a in excellent yield (96%) (Table IV.1, entries 8 and 9). Thus, excellent
conversion of benzyl thiocyanate to benzyl morpholine‒4‒carbodithioate ester 4a is
practically possible if we use separately‒prepared amine‒based salt and perform the reaction
under conditions as in entry 9 of Table IV.1. In aqueous medium reactions, anionic phase
98
transfer agents as additive are usually more effective than cationic agents.42
Here, we used
both TBAB (cationic) and SDS (anionic) additives and the results are in conformity with
previous reports. The better functioning of the anionic phase transfer agents like SDS might
be explained in the light of considering the whole system as a microreactor, where organyl
thiocyanate having resided in the hydrophobic dodecyl core may come in contact with the
reactant (here the dithocarbamate salt) being present in water through the formation of
hydrogen bond with anionic sulfate ion.
Table IV.1. Optimization of the reaction conditions for the conversion of benzyl thiocyanate
to S‒alkyl cabodithioates.
SCN
NO
H
H
N O
S
S
S
S
N
O
3a
2b
4a
Solvent
Temperature, Additive
N O
S
S
2aNa
or+
Entry Solvent (2 mL) T (°C) Additive Time(h) Yielda (%)
1b Neat RT No 1 72
2c Water RT No 1 60
d
3e Water RT No 1 76
4 Water 60 No 1 78
5 EtOH 60 No 1 82
6 Water: EtOH RT No 1 80
7f Water RT TBAB 1 84
8g Water RT SDS 1 96
9h Water RT SDS 1 96
aYield represents pure isolated product after purification by column chromatography.
bMixture of benzyl thiocyanate (1 mmol), morpholine (2 mmol) and CS2 (1 mmol) was stirred at room
temperature. cSalt 2a was used.
d20% dibenzyl disulphide was isolated.
eSalt 2b was used.
fTetrabutyl ammonium bromide (TBAB; stoichiometric) was used.
gSodium dodecyl sulfate (SDS; stoichiometric) was used.
h10 mol% SDS was used.
99
Being encouraged by this observation, we wanted to develop a general and practical
procedure for the conversion of organyl thiocyanate into carbodithioate ester. We prepared
other dithiocarbamate salts (2c‒2e) from three different cyclic sec. amines such as piperidine,
pyrrolidine and piperazine (Scheme IV.10).
NO
H
H
N O
S
SN
H
H
N
S
S
N
S
S
NH
HN N
S
SS
SN NH
H
HNHN
H
H
2b 2c
2d 2e
(Morpholinium morpholinodithioformate)
(Piperidinium piperidinodithioformate)
(Pyrrolidinium pyrrolidinodithioformate)
Bis(piperazinium)piperazine-1,4-dicarbodithioate
N O
S
S
2a
Na
(Sodium morpholinodithioformate)
XN
H
HX
N
S
S
n = 2, X = O (2b)n = 2, X = CH2 (2c)n = 1, X = CH2 (2d)
XNH
n
CS2 in diethyl ether
Stir at RTn n
simple preparation
crystalline solid
easy separation
stored for longer time under air
1
2b-2d
XN
H
Hn 2
N N
S
SS
S
n = 2, X = NH (2e)
Na
NaOH, CS2
or
EtOH:H2O (1:1)
Stir at 0-5 oC
XN
S
S
n
n = 2, X = O (2a)
Scheme IV.10. Synthesis of sec. cyclic aliphatic amine‒based dithiocarbamate salts
Being encouraged by this observation, we wanted to develop a general and practical
procedure for the conversion of organyl thiocyanate into carbodithioate ester. We prepared
other dithiocarbamate salts (2c‒2e) from three different cyclic sec. amines such as piperidine,
pyrrolidine and piperazine (Scheme IV.10), and employed our optimized conditions (as in
entry 9) for reaction with various functionalized organyl thiocyanates. The results are
presented in Table IV.2. It is clearly evident that different substituted benzyl thiocyanates and
naphthyl methyl thiocyanate underwent smooth conversion to the corresponding
dithiocarboate esters with all types of dithiocarbamate salts. While 2‒ and 4‒chloro benzyl
100
thiocyanates worked equally efficiently without any steric encumbrance, the
piperazine‒based dithiocarbamate salt 2e reacted with benzyl or 2‒chlorobenzyl thiocyanates
to produce bis‒carbodithioate esters in 82‒83% yields within 3h (4l and 4m).
Table IV.2. Synthesis of diverse S‒alkyl carbodithioates by varying organyl thiocyanates and
dithiocarbamate salts.a,b
XN
H
HX
N
S
S
n n
XN
H
Hn 2
N N
S
SS
S
or +SCN
R
S N
S
Xn
RSDS (10 mol%)
Water, RT
3
4l, 4m
N N
S
SS
S
orR
R
2b, X = O, n = 22c, X = CH2, n = 22d, X = CH2, n = 12e, X = NH, n = 2
R = H, 2-Cl, 4-Cl
4a-4k
Entry R1─SCN
(3)
Salt
(2)
Time (h) T (oC) Product
(4)
Yield (%)
1
SCN
2b
1.0
RT S N
S
O4a
96
2
SCN
Cl
2b
1.0
RT S N
S
OCl 4b
98
3 SCN
Cl
2b
1.0
RT
4c
S N
S
OCl
97
4 SCN
2b
1.5
RT S N
S
O
4d
87
5 SCN
2c
1.0
RT S N
S
4e
95
101
6 SCN
Cl
2c
1.0
RT S N
S
Cl 4f
98
7
SCN
2c
1.5
RT S N
S
4g
89
8 SCN
Cl
2c
1.0
RT S N
S
Cl
4h
97
9 SCN
2d
2.0
RT S N
S
4i
94
10 SCN
Cl
2d
2.5
RT S N
S
Cl 4j
96
11
SCN
2d
2.5
RT S N
S
4k
86
12 SCN
2e
3.0
RT
N N
S
SS
S
4l
82
13 SCN
Cl
2e
3.0
RT
N N
S
SS
SCl
Cl
4m
83
aA mixture of 2 (1.0 mmol), 3 (1.0 mmol), SDS (10 mol%) in water (2 mL) was stirred at RT in open
air. For 4l and 4m, 2 mmol of 3 was used. bYield represents pure product isolated by column chromatography.
102
The carbodithioate esters are identified by melting point and compared with literature
report (for solid compounds) and hence characterized by 1H‒NMR,
13C‒NMR spectroscopy.
High resolution mass spectrometry was performed in some cases to identify the
carbodithioate esters. The HRMS spectra of compound 4b are given in Figure IV.3 below:
Figure IV.3. HRMS of compound 4b
To broaden the scope of the reaction further, alkyl thiocyanates bearing β‒carbonyl
function, 5 (e.g. aroyl methyl thiocyanates) or β‒alkenyl function, 6 (e.g. styrenyl methyl
thiocyanates) were subjected to similar reaction. Corresponding organic carbodithioate esters
containing carbonyl or styrenyl methyl group could be easily synthesized in aqueous medium
at ambient temperature. Three different dithiocarbamate salts of sec. amine (2b‒2d) were
used and the results are presented in Table IV.3 (7a‒7e, 8a and 8b). In all cases,
corresponding benzoyl methyl carbodithioates bearing Cl, Br or NO2 groups attached with
the aromatic ring were prepared in excellent isolated yields (7a‒7e). All the compounds were
characterized by spectral data and compared with melting points wherever known and
reported. Facile preparation of these functionalized carbodithioate esters via easy
103
nucleophilic substitution reaction from alkyl thiocyanates in aqueous medium at ambient
temperature is notable and not reported previously via one‒pot three‒component reaction.
Table IV.3. Further functionalizations in the synthesis of S‒alkyl carbodithioates.a,b
XN
H
HX
N
S
S
n n +
R/R/
SDS (10 mol%)
Water, RT
6
7a-7e
or
SCN
SCN
O
Ph
O
S
S
NX
n
or
SPh
S
N
Xn
5
R/ = 4-Cl, 4-Br, 3-NO2
2b, X = O, n = 22c, X = CH2, n = 22d, X = CH2, n = 1 8a, 8b
Entry R2─SCN
(5 and 6)
Salt
(2)
Time(h)
)
T(oC) Product
(7 and 8)
Yield (%)
1
Br
O
SCN
2b
3.0
RT
Br
O
S
S
N
O
7a
95
2
Br
O
SCN
2c
3.0
RT
Br
O
S
S
N
7b
94
3
Cl
O
SCN
2c
4.0
RT
Cl
O
S
S
N
7c
95
4
O
SCN
NO2
2c
3.5
RT
O
S
S
N
NO2
7d
86
5
Cl
O
SCN
2d
3.0
RT
Cl
O
S
S
N
7e
96
6 SCN
2b
1.5
RT
8a
S
S
N
O
92
7 SCN
2c
1.5
RT S
S
N
8b
93
104
a A mixture of 2 (1.0 mmol), 5 or 6 (1.0 mmol), SDS (10 mol%) in water (2 mL) was stirred at RT in
open air. b Yield represents pure product isolated by column chromatography.
IV.4. Mechanism
The reaction presumably occurs via simple nucleophilic substitution reaction. Organyl
thiocyanates are considered as psuedohalides that might not produce the corresponding
carbocation easily and hence the reaction is expected to proceed via SN2 pathway (Scheme
IV.11). The dithiocarbamate salt consisting of both organyl cationic and anionic system
seems to be more active than using in situ mixture of sec. amine and CS2. Use of additives
like SDS might help organic reactants to become rather homogeneous affording excellent
conversions. The possibility of formation of thiyl radical via β‒bond cleavage of the alkyl
thiocyanate can be excluded as reaction conditions neither support radical formation nor the
corresponding disulfide is formed in the reaction.43,44
On the other hand, aqueous ferric
chloride solution produces blood‒red coloration suggesting the formation of thiocyanate
anion.
+
SDS / H2O
R S
S
N
FeCl3 solution gives blood red
colouration
R SS R
NH
H
N
S
S
R
S
C
N
+
Not formed through homolytic fission of -bond of
alkyl thiocyanate
SCN
NH
HRT
Scheme IV.11. Proposed reaction mechanism
IV.5. Conclusion
In conclusion, we have shown that easily accessible and air‒stable cyclic sec.
amine‒based dithiocarbamate salts could serve as an efficient reagent for the preparation of a
large variety of S‒substituted carbodithioate esters from rarely used organyl thiocyanates as a
common strategy. The use of this type salt not only shows superior activity to the existing
one‒pot three‒component procedure but also establishes as alternative reagent, obtained
easily in quantitative conversion, for the preparation of carbodithioate esters. The simple
procedure can be carried out at room temperature, in water medium and afforded with
excellent yields.
105
IV.6. Experimental section
IV.6.1. General information
Morpholine, piperidine and pyrrolidine were purchased from Lancaster and used after
distillation. Piperazine was purchased from Loba Chemie. Carbon disulfide (CS2) and sodium
dodecyl sulfate (SDS) were purchased from SDFCL and used directly. Benzyl, naphthyl
methyl, cinnamyl and aroyl methyl thiocyanates were prepared from reported procedure and
purified by column chromatography before use. Melting point of the solid compounds was
determined in concentrated H2SO4 bath. FT‒IR spectra were recorded with a FT‒IR‒8300
SHIMADZU spectrophotometer using a KBr pellet method for solid compounds and in neat
for liquid compounds. NMR spectra were taken in CDCl3 using a Bruker AV‒300
spectrometer operating for 1H at 300 MHz and for
13C at 75 MHz. The spectral data were
measured using TMS as the internal standard. HRMS was performed by Micromass Q‒TOF
Spectrometer under ESI (positive mode).
IV.6.2. General Procedure for the synthesis of cyclic ammonium salts of dithiocarbamic
acid (2b‒2e)41
A solution of CS2 (5 mmol) in diethyl ether (5 mL) was slowly added to a solution of
morpholine (10 mmol) or piperidine (10 mmol) or pyrrolidine (10 mmol) in diethyl ether (5
mL). The reaction mixtures were stirred for 30 min at room temperature. Solid salts were
precipitated during this time and were filtered off through Buchner funnel, washed with
diethyl ether and dried under vacuum to obtain the desired salts 2b–2d. In the case of 2e, a
solution of CS2 (6 mmol) in diethyl ether (5 mL) was slowly added to a solution of piperazine
(9 mmol) in diethyl ether (6 mL). The reaction mixture was stirred for 45 min at room
temperature. The grey solids were filtered off, washed with diethyl ether and dried under
vacuum to get the desired salt 2e.
IV.6.2.1. Physical properties and spectral data of cyclic ammonium salts of
dithiocarbamic acid (2b‒2e)
Morpholinium morpholinodithioformate (Salt 2b)41
NO
H
H
N O
S
S
White solid; yield: 1.23 g (98%); mp 197200 oC (Lit.
41 Mp 195197
oC)
106
IR (KBr): νmax = 2854, 2711, 2475, 1583, 1420, 1255, 1215, 1112, 978, 876 cm‒1
.
Piperidinium piperidinodithioformate (Salt 2c)
N
H
H
N
S
S
White solid; yield: 1.20 g (98%); mp 164166 oC (Lit.
41 Mp
160
oC)
IR (KBr): νmax = 2936, 2843, 2731, 2497, 1583, 1409, 1215, 1122, 958 cm‒1
.
Pyrrolidinium pyrrolidinodithioformate (Salt 2d)
N
S
S
NH
H
Off‒white solid; yield: 1.05 g (96%); mp 149151 oC
IR (KBr): νmax = 2946, 2864, 2516, 2393, 1390, 1318, 1164, 999, 938 cm‒1
.
Bis(piperazinium)piperazine‒1,4‒dicarbodithioate (Salt 2e)
N N
S
SS
SN NH
H
HNHN
H
H
Grey solid; yield: 1.19 g (97%); mp 238242 oC
IR (KBr): νmax = 3162, 2915, 2434, 2331, 1634, 1390, 1225, 1123, 958, 855 cm‒1
.
IV.6.3. General procedure for the synthesis of S‒alkyl carbodithioate esters
A mixture of organyl thiocyanate (1 mmol), dithiocarbamate salt (1 mmol) and sodium
dodecyl sulfate (SDS, 0.1 mmol) in water (2 mL) was stirred vigorously with a magnetic bar
at room temperature. The progress of the reaction was monitored by tlc. After the reaction
was continued for specified time, as mentioned in Table IV.2 & IV.3, the reaction mixture
was extracted with ethyl acetate (3×5 mL) and the combined organic extracts were collected
over anhydrous Na2SO4. Evaporation of the volatiles afforded the crude product, which was
further purified by column chromatography over silica gel. Elution with a mixture of
EtOAc−PE furnished the desired product. Yields of the products are shown in Table IV.2 &
IV.3.
107
All products were identified and characterized by spectral data (FT‒IR, 1H‒ &,
13C‒NMR), by melting point for solid compounds (compared wherever known). Unknown
carbodithioate esters were further analyzed either by HRMS or by elemental analysis.
IV.6.3.1. Physical properties and spectral data of carbodithioate esters
Table IV.2, 4a
Benzyl morpholine‒4‒carbodithioate37
S N
S
O
Light yellow solid, mp 6465 oC (Lit.
32 5960
oC)
IR (KBr): νmax = 3038, 2976, 2869, 1920, 1635, 1617, 1559, 1489, 1456, 1304, 1271, 1235,
924, 825, 725, 543 cm‒1
.
1H NMR (CDCl3, 300 MHz): δ/ppm 3.73 (s, 4H, 2 × OCH2), 4.014.33 (m, 4H, 2 × NCH2),
4.57 (s, 2H, SCH2), 7.227.39 (m, 5H).
13C NMR (CDCl3, 75 MHz): δ/ppm 42.0 (SCH2), 50.8 (NCH2), 66.3 (OCH2), 127.6, 128.7,
129.4, 135.8, 197.1 (C=S).
Table IV.2, 4b
2‒Chlorobenzyl morpholine‒4‒carbodithioate
S N
S
OCl
White crystalline solid, mp 9496 oC
IR (KBr): νmax = 3053, 2992, 2931, 2855, 1918, 1654, 1635, 1617, 1542, 1444, 1347, 1310,
1271, 1053, 1028, 868, 731, 582 cm‒1
.
1H NMR (CDCl3, 300 MHz): δ/ppm 3.77 (s, 4H, 2 × OCH2), 4.17 (s, br, 4H, 2 × NCH2), 4.76
(s, 2H, SCH2), 7.217.64 (m, 4H).
13C NMR (CDCl3, 75 MHz): δ/ppm 39.5 (SCH2), 50.9 (NCH2), 66.2 (OCH2), 126.9, 129.1,
129.6, 131.6, 134.1, 134.6, 196.9 (C=S).
HRMS (ESI): m/z [M+Na]+ calcd for C12H14ClNONaS2: 310.0103; found 310.0105.
108
Table IV.2, 4c
4‒Chlorobenzyl morpholine‒4‒carbodithioate
S N
S
OCl
White crystalline solid, mp 7981 oC
IR (KBr): νmax = 3007, 2977, 2916, 2870, 1833, 1656, 1620, 1542, 1423, 1268, 1217, 1034,
998, 837, 643 cm‒1
.
1H NMR (CDCl3, 300 MHz): δ/ppm 3.66 (s, 4H, 2 × OCH2), 3.90 (s, 2H, NCH2), 4.17 (s, 2H,
NCH2), 4.47 (s, 2H, SCH2), 7.177.25 (m, 4H).
13C NMR (CDCl3, 75 MHz): δ/ppm 40.83 (SCH2), 50.83 (NCH2), 66.10 (OCH2), 128.60,
130.57, 133.26, 134.59, 196.50 (C=S).
Table IV.2, 4d
(Naphthalen‒1‒yl) methyl morpholine‒4‒carbodithioate
S N
S
O
Light brown solid, mp 115117 oC
IR (KBr): νmax = 3053, 2976, 2900, 2869, 1699, 1578, 1538, 1420, 1356, 1301, 1271, 1189,
998, 786, 630 cm‒1
.
1H NMR (CDCl3, 300 MHz): δ/ppm 3.66 (s, 4H, 2 × OCH2), 3.914.06 (m, 4H, 2 × NCH2),
4.95 (s, 2H, SCH2), 7.317.52 (m, 4H), 7.717.98 (m, 2H), 8.008.01 (m, 1H).
13C NMR (CDCl3, 75 MHz): δ/ppm 40.3 (SCH2), 50.5 (NCH2), 66.2 (OCH2), 123.9, 125.4,
126.0, 126.5, 128.3, 128.8, 128.8, 131.0, 131.8, 133.9, 197.2 (C=S).
Table IV.2, 4e
Benzyl piperidine‒1‒carbodithioate45
S N
S
109
Pale yellow viscous liquid
IR (neat): νmax = 3040, 2974, 2864, 1945, 1620, 1590, 1545, 1495, 1358, 1340, 1291, 1279,
1222, 1016, 980, 840, 742 cm‒1
.
1H NMR (CDCl3, 300 MHz): δ/ppm 1.62 (s, 6H, NCH2(CH2)3), 3.80 (s, br, 2H, NCH2), 4.21
(s, br, 2H, NCH2), 4.49 (s, 2H, SCH2), 7.157.33 (m, 5H).
13C NMR (CDCl3, 75 MHz): δ/ppm 24.3 (NCH2CH2CH2), 25.8 (NCH2CH2), 42.2 (SCH2),
52.7 (NCH2), 127.4, 128.6, 129.4, 136.1, 195.3 (C=S).
Table IV.2, 4f
2‒Chlorobenzyl piperidine‒1‒carbodithioate
S N
S
Cl
Yellow viscous liquid
IR (neat): νmax = 3010, 2970, 2860, 1996, 1580, 1546, 1493, 1357, 1340, 1280, 1224, 1074,
946, 840, 746, 650 cm‒1
.
1H NMR (CDCl3, 300 MHz): δ/ppm 1.69 (s, 6H, NCH2(CH2)3), 3.87 (s, br, 2H, NCH2), 4.29
(s, br, 2H, NCH2), 4.72 (s, 2H, SCH2), 7.187.23 (m, 2H), 7.347.38 (m, 1H), 7.547.58 (m,
1H).
13C NMR (CDCl3, 75 MHz): δ/ppm 24.3 (NCH2CH2CH2), 25.6 (NCH2CH2), 39.7 (SCH2),
51.4 (NCH2), 53.1 (NCH2), 126.9, 128.9, 129.5, 131.6, 134.4, 134.5, 194.9 (C=S).
Table IV.2, 4g
(Naphthalen‒1‒yl) methyl piperidine‒1‒carbodithioate
S N
S
White solid, mp 9395 oC
IR (KBr): νmax = 3038, 2947, 2870, 1620, 1596, 1563, 1542, 1474, 1435, 1399, 1365, 1281,
1235, 1210, 1113, 980, 870, 776, 670, 588 cm‒1
.
110
1H NMR (CDCl3, 300 MHz): δ/ppm 1.63 (s, 6H, NCH2(CH2)3), 3.75 (s, br, 2H, NCH2), 4.27
(s, br, 2H, NCH2), 4.93 (s, 2H, SCH2), 7.317.58 (m, 4H), 7.717.85 (m, 2H), 8.08.01 (m,
1H).
13C NMR (CDCl3, 75 MHz): δ/ppm 24.3 (NCH2CH2CH2), 25.9 (NCH2CH2), 40.6 (SCH2),
52.8 (NCH2), 124.1, 125.5, 125.9, 126.4, 128.3, 128.6, 128.8, 131.4, 131.9, 133.9, 195.3
(C=S).
HRMS (ESI): m/z [M+Na]+ calcd for C17H19NNaS2: 324.0857; found 324.0855.
Table IV.2, 4h
4‒Chlorobenzyl piperidine‒1‒carbodithioate
S N
S
Cl
White solid, mp 8385 oC
IR (KBr): νmax = 3007, 1961, 2855, 1632, 1617, 1577, 1542, 1508, 1481, 1429, 1378, 1281,
1225, 1110, 1080, 974, 843, 746, 652 cm‒1
.
1H NMR (CDCl3, 300 MHz): δ/ppm 1.62 (s, 6H, NCH2(CH2)3), 3.79 (s, br, 2H, NCH2), 4.22
(s, br, 2H, NCH2 ), 4.44 (s, 2H, SCH2), 7.157.27 (m, 4H).
13C NMR (CDCl3, 75 MHz): δ/ppm 24.3 (NCH2CH2CH2), 25.5 (NCH2CH2), 41.2 (SCH2),
53.1 (NCH2), 128.7, 130.7, 133.2, 135.0, 194.7 (C=S).
Table IV.2, 4i
Benzyl pyrrolidine‒1‒carbodithioate45
S N
S
Yellow liquid
IR (neat): νmax = 3048, 2970, 2865, 1903, 1590, 1440, 1365, 1308, 1216, 1070, 1012, 944,
826, 780, 503 cm‒1
.
1H NMR (CDCl3, 300 MHz): ppmm, 4H, NCH2(CH2)2) 3.62 (t, J = 6.3 Hz, 2H,
NCH2), 3.93 (t, J = 6.9 Hz, 2H, NCH2), 4.58 (s, 2H, SCH2), 7.227.33 (m, 3H), 7.387.41
(m, 2H).
111
13C NMR (CDCl3, 75 MHz): ppm 24.3 (NCH2CH2), 26.1 (NCH2CH2), 41.3 (SCH2), 50.5
(NCH2), 55.0 (NCH2), 127.4, 128.6, 129.3, 136.5, 192.4 (C=S).
Table IV.2, 4j
4‒Chlorobenzyl pyrrolidine‒1‒carbodithioate
S N
S
Cl
Pale yellow solid, mp 6062 oC
IR (KBr): νmax = 2966, 2864, 1903, 1595, 1441, 1328, 1092, 1009, 948, 825, 744, 507 cm
‒1.
1H NMR (CDCl3, 300 MHz): ppmm, 4H, NCH2(CH2)2) 3.62 (t, J = 6.3 Hz,
2H, NCH2), 3.93 (t, J = 6.9 Hz, 2H, NCH2), 7.247.27 (m, 2H), 7.327.35 (m, 2H).
13C NMR (CDCl3, 75 MHz): ppm 24.2 (NCH2CH2), 26.0 (NCH2CH2), 40.2 (SCH2), 50.6
(NCH2), 55.1 (NCH2), 128.6, 130.6, 133.1, 135.4, 191.8 (C=S).
Table IV.2, 4k
(Naphthalen‒1‒yl) methyl pyrrolidine‒1‒carbodithioate
S N
S
White solid, mp 116118 oC
IR (KBr): νmax = 3040, 2950, 2880, 1542, 1450, 1400, 1364, 1342, 1280, 1210, 1134, 1072,
980, 808, 770, 672, 540 cm‒1
.
1H NMR (CDCl3, 300 MHz): /ppm 1.871.97 (m, 4H, NCH2(CH2)2), 3.51 (t, J = 6.9 Hz,
2H, NCH2), 3.94 (t, J = 6.6 Hz, 2H, NCH2), 5.01 (s, 2H, SCH2), 7.347.40 (m, 1H),
7.437.54 (m, 2H), 7.58 (d, J = 6.9 Hz, 1H), 7.76 (d, J = 8.1 Hz, 1H), 7.817.84 (m, 1H),
8.08 (d, J = 8.1 Hz, 1H).
13C NMR (CDCl3, 75 MHz): /ppm 24.3 (NCH2CH2), 26.1 (NCH2CH2), 39.6 (SCH2), 50.5
(NCH2), 55.0 (NCH2), 124.1, 125.5, 125.9, 126.4, 128.2, 128.6, 128.8, 131.8, 131.8, 133.9,
192.3 (C=S).
112
Table IV.2, 4l
Dibenzyl piperazine‒1,4‒dicarbodithioate46
N N
S
SS
S
White solid, mp 124126 oC (Lit.
46 122123
oC)
IR (KBr): νmax = 3068, 3038, 2931, 1538, 1505, 1474, 1435, 1413, 1277, 1210, 1159, 1043,
924, 849, 694 cm‒1
.
1H NMR (CDCl3, 300 MHz): /ppm 4.18 (s, br, 8H, 4 × NCH2), 4.51 (s, 4H, 2 × SCH2)
7.197.32 (m, 10H).
13C NMR (CDCl3, 75 MHz): /ppm 42.2 (SCH2), 48.7 (NCH2), 127.7, 128.7, 129.4, 135.5,
197.5 (C=S).
Table IV.2, 4m
Bis‒(2‒chlorobenzyl) piperazine‒1,4‒dicarbodithioate
N N
S
SS
SCl
Cl
Grey solid, mp 148150 oC
IR (KBr): νmax = 2916, 1640, 1420, 1276, 1041, 990, 928, 846, 744 cm
‒1.
1H NMR (CDCl3, 300 MHz): ppm 4.28 (s, br, 8H, 4 × NCH2), 4.72 (s, 4H, 2 × SCH2)
7.187.26 (m, 4H), 7.357.39 (m, 2H), 7.537.56 (m, 2H).
13C NMR (CDCl3, 75 MHz): ppm 39.6 (SCH2), 48.9 (NCH2), 126.9, 129.2, 129.6, 131.5,
133.8, 134.6, 197.2 (C=S).
Table IV.3, 7a
113
4‒Bromo phenacyl morpholine‒4‒carbodithioate
Br
O
S
S
N
O
White solid, mp 164166 oC
IR (KBr): νmax = 2967, 2906, 2855, 1686, 1583, 1430, 1276, 1125, 1112, 990, 816, 539 cm
‒1.
1H NMR (CDCl3, 300 MHz): δ/ppm 3.71 (t, J = 4.8 Hz, 4H, 2 × OCH2), 3.97 (s, br, 2H,
NCH2), 4.2 (s, br, 2H, NCH2), 4.77 (s, 2H, SCH2), 7.547.59 (m, 2H), 7.847.88 (m, 2H).
13C NMR (CDCl3, 75 MHz): δ/ppm 44.3 (SCH2), 51.5 (NCH2), 66.2 (OCH2), 128.8, 130.1,
132.1, 134.9, 192.3 (C=O), 195.65 (C=S).
Table IV.3, 7b
4‒Bromo phenacyl piperidine‒1‒carbodithioate
Br
O
S
S
N
White solid, mp 116118 oC
IR (KBr): νmax = 3007, 2947, 2869, 1687, 1584, 1438, 1362, 1286, 1253, 973, 858, 666 cm
‒1.
1H NMR (CDCl3, 300 MHz): /ppm1.65 (s, 6H, NCH2(CH2)3), 3.89 (s, br, 2H, NCH2), 4.18
(s, br, 2H, NCH2), 4.77 (s, 2H, SCH2), 7.547.57 (m, 2H), 7.867.89 (m, 2H).
13C NMR (CDCl3, 75 MHz): ppm24.2 (NCH2CH2CH2), 25.9 (NCH2CH2), 44.5 (SCH2),
51.7 (NCH2), 53.6 (NCH2), 128.6, 130.1, 131.9, 135.0, 192.7 (C=O), 193.7 (C=S).
Table IV.3, 7c
4‒Chloro phenacyl piperidine‒1‒carbodithioate
Cl
O
S
S
N
Yellowish white solid, mp 110112 oC
114
IR (KBr): νmax = 3007, 2961, 2855, 1690, 1587, 1438, 1347, 1244, 1113, 971, 858, 682, 548
cm‒1
.
1H NMR (CDCl3, 300 MHz): /ppm (s, 6H, NCH2(CH2)3), 3.89 (s, br, 2H, NCH2), 4.19
(s, br, 2H, NCH2), 4.77 (s, 2H, SCH2), 7.547.58 (m, 2H), 7.857.90 (m, 2H).
13C NMR (CDCl3, 75 MHz): ppm 24.2 (NCH2CH2CH2), 25.4 (NCH2CH2), 26.1
(NCH2CH2), 44.5 (SCH2), 51.8 (NCH2), 53.7 (NCH2), 128.7, 130.1, 132.0, 135.0, 192.7
(C=O), 193.6 (C=S).
Table IV.3, 7d
3‒Nitro phenacyl piperidine‒1‒carbodithioate
O
S
S
N
NO2
Pale yellow solid, mp 109111 oC
IR (KBr): νmax = 2926, 2854, 1697, 1613, 1532, 1430, 1337, 1204, 1112, 1072, 979, 804, 733,
672 cm‒1
.
1H NMR (CDCl3, 300 MHz): ppm 1.73 (s, 6H, NCH2(CH2)3), 3.97 (s, br, 2H, NCH2), 4.25
(s, br, 2H, NCH2), 4.86 (s, 2H, SCH2), 7.697.74 (m, 1H), 8.408.46 (m, 2H), 8.908.91 (m,
1H).
13C NMR (CDCl3, 75 MHz): /ppm 24.16 (NCH2CH2CH2), 26.02 (NCH2CH2), 44.09
(SCH2), 52.09 (NCH2), 53.79 (NCH2), 123.45, 127.49, 129.95, 134.13, 137.87, 148.58,
191.84 (C=O), 193.39 (C=S).
Table IV.3, 7e
4‒Chloro phenacyl pyrrolidine‒1‒carbodithioate
Cl
O
S
S
N
Pale yellow solid, mp 102104 oC
IR (KBr): νmax = 2957, 2876, 1676, 1583, 1430, 1286, 1184, 1080, 990, 958, 825, 528 cm
‒1.
115
1H NMR (CDCl3, 300 MHz): ppm 1.942.03 (m, 2H, NCH2CH2), 2.062.14 (m, 2H,
NCH2CH2), 3.74 (t, J = 6.9 Hz, 2H, NCH2), 3.9 (t, J = 6.9 Hz, 2H, NCH2), 4.85 (s, 2H,
SCH2), 7.447.47 (m, 2H), 8.018.04 (m, 2H).
13C NMR (CDCl3, 75 MHz): ppm 24.3 (NCH2CH2), 26.1 (NCH2CH2), 44.0 (SCH2), 50.8
(NCH2), 55.5 (NCH2), 128.9, 130.0, 134.4, 139.8, 190.7 (C=O), 192.4 (C=S).
Table IV.3, 8a
(E)‒Cinnamyl morpholine‒4‒carbodithioate36
S
S
N
O
White crystalline solid, mp 8082 oC (Lit.
36 reported as yellowish viscous liquid)
IR (KBr): νmax = 3038, 2961, 2869, 1720, 1620, 1577, 1469, 1304, 1268, 1220, 1113, 992,
755 cm‒1
.
1H NMR (CDCl3, 300 MHz): δ/ppm 3.78 (t, J = 4.5 Hz, 4H, 2 × OCH2), 4.174.24 (m, 6H, 2
× NCH2, SCH2), 6.286.38 (m, 1H, PhCH=CHCH2), 6.67 (d, J = 15.6 Hz, 1H, PhCH),
7.237.41 (m, 5H).
13C NMR (CDCl3, 75 MHz): δ/ppm 39.97 (SCH2), 50.90 (NCH2), 66.26 (OCH2), 123.68,
126.45, 127.76, 128.56, 133.95, 136.60, 197.03 (C=S).
Table 3, 8b
(E)‒Cinnamyl piperidine‒1‒carbodithioate36
S
S
N
White crystalline solid, mp 7375 oC (Lit.
36 reported as yellowish viscous liquid)
IR (KBr): νmax = 3048, 2947, 2869, 1617, 1566, 1472, 1435, 1265, 1235, 1135, 1116, 1110,
973, 743 cm‒1
.
1H NMR (CDCl3, 300 MHz): δ/ppm 1.63 (s, 6H, NCH2(CH2)3), 3.82 (s, br, 2H, NCH2),
4.014.13 (m, 2H, SCH2 ), 4.23 (s, br, 2H, NCH2), 6.206.31 (m, 1H, PhCH=CHCH2), 6.56
(d, J = 15.9 Hz, 1H, PhCH), 7.127.31 (m, 5H).
116
13C NMR (CDCl3, 75 MHz): δ/ppm 24.3 (NCH2CH2CH2), 26.0 (NCH2CH2), 40.2 (SCH2),
51.4 (NCH2), 124.2, 126.4, 127.7, 128.5, 133.6, 136.7, 195.0 (C=S).
IV.7. References
References are given in BIBLIOGRAPHY under Chapter IV (pp. 150‒153).
117
CHAPTER V
Synthesis of new 1,3‒dithioether‒Cu(I) complex
and its catalytic action in one‒pot
azide‒alkyne "click" reaction
118
V.1. Introduction
V.1.1. Azide–Alkyne Cycloaddition (AAC) reactions
1,2,3‒Triazoles are important heterocyclic scaffold in biological and pharmaceutical
viewpoint, such as H1‒antihistamine,1 anti‒bacterial,
2 and anti‒HIV activity,
3 and selective
β3‒adrenergic receptor agonism.4
The model reaction for the synthesis of 1,2,3‒triazole is the Huisgen [3+2] cycloaddition
reaction which was developed in 1984 by Rolf Huisgen (Scheme V.1).5 But the drawbacks in
this method is high reaction temperature and lack of regioselectivity both 1,4 as well as 1,5
substituted 1,2,3 triazoles are obtained by this method. Later on Sharpless and Meldal
independently revealed that Cu(I) could assist regiospecific formation of 1,4‒substituted
1,2,3‒triazole under milder condition.6
R1 N3 R2 H+Heating Slow
100 oC
N
N
N
R1
R2
N
N
N
R1
R2+
1, 5-isomer 1,4-isomer
Huisgen's 1, 3-dipolar cycloaddition
Scheme V.1. The primitive Huisgen‟s 1,3‒dipolar cycloaddition reaction
To make the reaction regioselective, various metal catalysts were introduced from last few
decades. Among all metal salts/catalysts, copper salts or catalysts were found to be superior
choice for this cycloaddition reaction. Various methodologies are reported where Cu(OAc)2,
CuCl2 or simple salts of Cu(I) or Cu(II) were used as main catalyst source. The simplest Cu(I)
catalyzed click triazole synthesis is effectively achieved by excess of CuSO4 and sodium
ascorbate where sodium ascorbate reduces the Cu(II) to Cu(I) and inhibit the aerobic
oxidation of Cu(II) species.7
Alternatively, preformed stable Cu(I) complexes with
phosphines or nitrogen ligands could be employed by small proportion. Polydentate nitrogen
donor and triphenyl phosphine are also used as ligands. But main problem of using phosphine
ligand gives unwanted Staudinger reaction.7
Many homogeneous and heterogeneous
Cu‒catalysts are also well known for azide‒alkyne cycloaddition reactions. In last decade,
polymeric Cu catalysts (coordination polymer of Cu) attract much interest for the synthesis of
triazole molecules.
The use of multicomponent approach is more convenient over two component Huisgen
[3+2] cycloaddition method as it avoids direct use of organic azides which are not only
119
difficult to handle because of their toxicity and explosive nature but also of its tedious
isolation and purification process.8
It should be noted that the noncatalyzed Huisgen reaction occurs at elevated temperature
and in the case of reactive substrates even at ambient temperature with significantly
prolonged reaction times. However, the microwave heating may help the reaction with a rate
enhancement to produce 1,4 substituted triazoles. The use of microwave irradiation has
significantly shortened reaction times, to minutes, with excellent yields and purities and
exclusive formation of the 1,4 isomer.9
Using polymer supported Cu(I) composite, Cu(I)‒pPDA (pPDA: polyphenylene diamine)
Mallick and his co‒workers showed azide alkyne cycloaddition (AAC) reaction by
microwave irradiation technique under solvent free condition. Both domestic as well as
laboratory microwave worked well to afford 1,2,3‒triazole derivatives. The reaction was
believed to proceed through the formation of Cu(0) acetylide complex intermediate. To avoid
the toxic and hazardous nature of the organic azide the reaction could also be achieved by
multicomponet approach using sodium azide and alkyl halide.10
V.2. Background and Objectives
For well‒defined catalyst system, PPh3, NHC, imidazole, sulfur and nitrogen based
molecules are among the most used ligands. The sulfur‒based ligands attract much attention
in the vicinity of copper complex formation and subsequently on click reaction.11
Cu‒thioamide catalyzed click reaction has been explored recently.12
Quick and highly efficient copper (I)‒catalyzed on‒water cycloaddition of water‒insoluble
aliphatic and aryl azides was excellently done by H. Fu and his group. The catalytic system in
this case was CuBr and thioanisole. They tried with various sulfur ligands in this protocol but
thioanisole was found to be the best one under this catalytic condition.13
N3 CuBr.PhSMe
Water, RT
NN
N
+
Scheme V.2. CuBr.PhSMe‒catalyzed cycloaddition reaction of alkyl azide and phenyl acetylene
A hybrid SNS ligand with an amine moiety and two sulfur moieties can effectively form
an one‒dimentional mononuclear polymer with copper [CuX2(SNS)]. T. S. A. Hor et al
synthesized SNS ligand based copper catalysts, which have been found to be efficient for
120
azide‒alkyne click reaction.The have synthesized a four different copper complexes with
SNS ligands and the complexes were characterized by various techniques. They studied the
effectiveness of these catalysts by monitoring an azide‒alkyne cycloaddition reaction in a
multicomponent approach between benzyl chloride, phenyl acetylene and sodium azide. The
substrates scope is limited here.14
SNH
S S
NH
SCu
BrBr
S
NH
SCu
ClCl
CuBr
MeOH
CuCl
MeOH
bis(2-(benzylthio)ethyl)amine (SNS)
NN
N
Cl
Cu-SNS catalysts
MeCN/H2O, RT
+ NaN3 +
Scheme V.3. Preparation of CuX2(SNS) catalysts and application towards azide‒alkyne click reaction
S.‒Q. Bai and T. S. A. Hor et al reported a new class of SNS ligands and found application
in copper complex formation. Hybrid nitrogen‒sulfur (SNS) ligands are promising in
catalytic reactions because of the assembling of hard and soft donors and hemilabile
functions in the corresponding ligands. These ligands were able to coordinate with CuI, CuBr
and CuCl salts. The copper complexes appeared as polymeric units and one‒pot azide‒alkyne
cycloaddition reactions were effectively done by these complexes.15
S
N
S
N
S
Cu N S N
Cu
Cu
Cu
H
Cu
RBr
NaN3+ +
R1
Cu cat. 2 mol%
CH3OH:H2O (1:1)
35 oC, 15 hN N
NR
R1
Cu-SNS ligands
1, 2, 3-triazole
Scheme V.4. Cu‒SNS catalyst for one‒pot azide‒alkyne cycloaddition reaction
A novel pyridyl and thioether hybridized 1, 2, 3‒triazole ligands have been synthesized by
T. S. A. Hor and his group from CuAAC click reactions. These compounds were further
121
utilized for making of new type of dithioether based CuI coordination complex. The resultant
complexes were again used in one‒pot azide‒alkyne click reactions. In this protocol the
reactions took long time for completion. This methodology opened a new dimension for the
polymeric coordination complex catalyzed click reactions.16
N SNCl
HClN S N
NN
N+
2-pyridyl or 4-pyridyl
NaN3, CuSO4
Na ascorbate
K2CO3, RTt-BuOH: H2O
CuICu-complex
Step 1.
Step 2.
R NaN3+ + R1 Br
Cu-complex, 0.5 mol%
MeOH: H2O = 1:1, 2 mL
50 oC, 24 h
N NN
R
R1
Click
Click
Click-and-click
Scheme V.5. “Click‒and‒click” – hybridised 1,2,3‒triazoles supported Cu(I) coordination polymers
for azide–alkyne cycloaddition
1,3‒Dithioether ligands play a vital role for the preparation of coordination clusters.17
They have wide applications in the field of phtophysical phenomena,17a,c
and in bio‒inorganic
chemistry.18
But, 1,3‒dithioether based CuI polymeric complexes have never been used for
1,3‒dipolar cycloaddition reaction. Here, we describe a clean methodology for the synthesis
of 1,2,3‒triazole molecules in presence of 1,3‒dithioether based CuI complex. Our
1,3‒bis(4‒fluorophenylthio)‒propane ligand based CuI coordination complex was first
synthesized and characterized by NMR, fluorescence spectroscopy and single crystal X‒ray
diffraction pattern. The catalyst undergoes a smooth azide‒alkyne cycloaddition reaction in
water‒acetonitrile (1:1, v/v) solvent mixture at 50 oC. Only 0.5 mg of the catalyst is required
for the complete conversion of the product.
V.3. Present work: Results and Discussion
V.3.1. Preparation of 1,3–bis(4–fluorophenylthio) –propane ligand (L1)
The 1,3–bis(4–fluorophenylthio)–propane ligand (L1) was synthesized according to our
previously reported procedure.19
This ligand was characterized by 1H– and
13C–NMR
spectroscopy. The synthetic procedure of L1 is given in experimental section.
V.3.2. Synthesis of CuI–1,3–bis(4–fluorophenylthio)–propane (L1) coordination
complex (complex 1)
122
The preparation procedure of the complex 1 is given in experimental section in details.
V.3.3. Characterization of complex 1
V.3.3.1. NMR spectroscopy
The as–synthesized complex 1 was characterized by several techniques such as 1H– and
13C– NMR, UV–Visible, fluorescence spectroscopy and by single crystal XRD techniques.
1H– and
13C–NMR spectra of complex 1 and the ligand 1,3–bis(4–fluorophenylthio)–
propane, L1 were taken separately in d6–DMSO solvent. Some changes were observed in 1H–
NMR spectra between L1 and complex 1, and this indicates the complex formation between
ligand L1 and CuI. The 1H–NMR spectra of L1 and the complex 1 are given in Figure V.1
and Figure V.2. In 1H–NMR spectrum of L1, a clear splitting into triplet and quintet are
observed but in 1H–NMR spectrum of complex 1 these pattern are absent. This indicates the
coordination may happen between CuI and sulfur donor atoms of the ligand L1. The spectra
also indicate the presence of the Cu(I) in the complex 1 rather than Cu(II).
123
Figure V.1. 1H–NMR spectra of L1 [1, 3–bis(4–fluorophenylthio)–propane] in d6–DMSO
124
Figure V.2. 1H–NMR spectra of complex 1 in d6–DMSO
V.3.3.2. UV–Visible and fluorescence spectroscopy
The λmax of the ligand L1 and complex 1 were determined by UV–Visible spectroscopy.
CuI, L1 and the complex 1 gave maximum absorption at λ = 240 nm, 252 nm and 246 nm
respectively (Figure V.3).
125
200 250 300 350 400
-0.2
0.0
0.2
0.4
0.6
0.8
1.0
1.2
240 nm
252 nm
246 nm
Complex 1
Ligand (L1)
CuI
AU
Wavelength (nm)
Figure V.3. UV–Visible spectra of CuI, L1 and complex 1 were taken in MeCN
The 1–D polymers, [(Cu2X2)(μ–RS(CH2)5SR)2]n exhibited the maxima at 450 nm.20
It was
found that the change of halogen atom form iodine to bromine caused the emission band at
lower wavelength.20
The spacer size might be one of the key factor for decreasing the
emission wavelength. In our study, the complex 1 in liquid–state shows broad
photoluminescent emissions at room temperature (Figure V.4). The maximum emission is
341 nm under the excitation wavelengths of 246 nm for complex 1. Since our complex 1
contains fluorine atoms and two CH2 groups less than the reported coordination polymers so
the spacer effect might be the key factor in this particular case. As a result, a much lower
emission band is observed. Additionally, the fluorine atoms attached with the phenyl rings
may affect photoluminescent properties of the as–synthesized Cu(I) complex.
250 300 350 400 450 500 550 600 650
0
10000
20000
30000
40000
50000
60000
70000
325 nm
341 nm
Inte
nsi
ty (
AU
)
Wavelength (nm)
Emission scan with excitation of 246 nm
Figure V.4. Fluorescence spectrum of complex 1 (5 μM solution) in MeCN solvent
126
V.3.3.3. Single crystal X–ray diffraction
Complex 1 crystallizes in the monoclinic space group P 21/c, and shows a polymeric
propagation in the form of [(CuI)2{ArS(CH2)3SAr}2]n metallopolymer (Figure V.5). The 1D–
network is built up upon dimeric Cu2I2 units, which are interconnected via dithioether
ligands. The framework consists of Cu2(μ–I)2 prismatic part connected with the dithioether
ligands. Within the cluster core, the Cu‒I bond lengths range between 2.5867 (5) and 2.6443
(12) Å. The Cu…Cu distance between the two Cu (I) centers, 2.7812 (10) Å falls
significantly below the sum of the vander Waals radius (2.8 Å). The mean Cu‒S bond length
of range between 2.3339 (11) to 2.3551 (12) Å similar to [{Cu(μ–I)2Cu}2{μ–
PhS(CH2)3SPh}2]n (2.3465 Å). The angle between Cu…I…Cu is 64.23° and I…Cu…I
115.77° in the metallocluster. The crystal data, data collection and structure refinement for
complex 1 is given in the Table V.1.
Table V.1. Crystal Data, Data Collection and Structure Refinement for complex 1
Formula C15H14CuF2IS2 Cell volume/Å3 1684.06 (12)
Formula weight 486.83 Cell formula units Z, Z/ 4, 0
Temperature/K 293 (2) density (calculated) g/cm3 1.920
Description Prismatic θ range for data collection/deg 1.43–25.07
Colour White F(000) 944.0
Crystal system Monoclinic crystal size/mm 0.08, 0.12,
0.24
Space group P 21/C Absorption co–efficient (μ) 3.387
a/Å 16.2003(7) index ranges –19 ≤ h ≤ 15
–8 ≤ k ≤ 8
–18 ≤ l ≤ 18
b/Å 7.4990(3) reflections collected 20413
c/Å 15.7177(7) independent reflections 2989
Cell angle (α) 90o refinement method full–matrix
least–squares
on F2
Cell angle (β) 118.12o (2) R–equivalents 0.0424
Cell angle (γ) 90 o Sigma I/net I 0.0265
127
(a) (b)
(c)
Figure V.5. View of (a) the monomeric unit of the coordination polymer, (b) ORTEP picture of the
complex 1 and (c) infinite 1–D chain of complex 1 incorporating dinuclear Cu(μ2–I)2Cu motifs along
„b‟ axis
Selected bond lengths and bond angles are also given in the Tables below.
Table V.2. Selected bond length
Bond Length Bond Length
I1–Cu1 2.5867 (5) C10–C11 1.362 (7)
I1–Cu1 2.6443 (6) C13–C12 1.377 (6)
Cu1–S1 2.339 (11) C13–C14 1.384 (6)
Cu1–S2 2.3551 (12) C14–C15 1.395 (6)
Cu1–I1 2.6443 (6) C20–C19 1.373 (6)
S2–C19 1.782 (4) C20–C21 1.394 (7)
S2–C22 1.813 (4) C24–C23 1.524 (6)
S1–C13 1.775 (4) C24–S1 1.813 (4)
128
S1–C24 1.813 (4) C19–C18 1.399 (6)
F1–C10 1.366 (5) C18–C17 1.363 (7)
F2–C16 1.355 (6) C11–C12 1.389 (7)
C22–C23 1.507 (7) C17–C16 1.381 (9)
C10–C15 1.348 (7) C16–C21 1.345 (9)
Table V.3. Selected bond angle
Bond Angle Bond Angle
Cu1–I1–Cu1 64.23 (2) C11–C10–F1 117.9 (4)
S1–Cu1–S2 108.26 (4) C12–C13–C14 119.9 (4)
S1–Cu1–I1 113.87 (3) C12–C13–S1 124.3 (3)
S2–Cu1–I1 111.66 (3) C14–C13–S1 115.9 (3)
S1–Cu1–I1 105.37 (3) C13–C14–C15 119.8 (4)
S2–Cu1–I1 100.87 (3) C19–C20–C21 119.9 (5)
I1–Cu1–I1 115.77 (2) C23–C24–S1 110.9 (3)
S1–Cu1–Cu1 128.93 (4) C20–C19–C18 120.5 (4)
S2–Cu1–Cu1 121.50 (4) C20–C19–S2 117.4 (3)
I1–Cu1–Cu1 58.89 (18) C18–C19–S2 122.1 (3)
I1–Cu1–Cu1 56.88 (18) C17–C18–C19 119.3 (5)
C19–S2–C22 101.3 (2) C22–C23–C24 116.1 (4)
C19–S2–Cu1 109.32 (14) C10–C11–C12 118.3 (4)
C22–S2–Cu1 103.62 (15) C18–C17–C16 118.8 (5)
C13–S1–C24 102.8 (2) C13–C12–C11 120.1 (4)
C13–S1–Cu1 104.03 (13) C10–C15–C14 118.5 (4)
C24–S1–Cu1 110.61 (15) C21–C16–F2 118.6 (6)
C23–C22–S2 114.7 (3) C21–C16–C17 123.4 (5)
C15–C10–C11 123.3 (4) F2–C16–C17 117.9 (6)
C15–C10–F1 118.8 (4) C16–C21–C20 118.1 (5)
V.3.4. Catalytic application
The catalytic activity of complex 1 towards the one–pot AAC reaction under base–free
conditions was optimized by the model reaction of benzyl bromide, NaN3 and
phenylacetylene with varying catalyst loading under different temperature and solvents
conditions. The reaction was first studied at neat condition and higher temperature (60 °C)
with 5 mg of the complex 1. After 5 hours, 84% of the product was isolated under this
condition (entry 1). When methanol was used as solvent relatively less conversion was
achieved compare to neat condition (70%) (entry 2). Similarly the reactions on acetonitrile
and water gave 87% and 80% yield of the product respectively (entry 3 & 4). A binary
solvent mixture of MeCN and water (1:1) resulted excellent yield of the desired product with
129
lesser time (entry 5). The reaction was also carried out in μW reactor and to check the
enhancement of the yield and rate of the model reaction. But unfortunately the yield of the
reaction could not increase tremendously than conventional thermal heating (entry 6). The
drop of product conversion was found when we studied the reaction at room temperature
(entry 7). The catalyst loading was also performed from entry 8 to entry 10 and the catalytic
activity was effective for 0.5 mg (0.00088 mmol of Cu was present in 0.5 mg of the complex
1, which was confirmed by Atomic absorption spectroscopy (AAS) study) of the complex 1
for this reaction (Table V.4, entry 11).
Table V.4. Optimization of reaction conditions for the one–pot azide–alkyne click reaction.
NaN3
Br
+ +
Complex 1x mg
Solvent, TemperatureN
NN
Entry Solvent Complex 1 (mg) Temperature
(oC)
Time (h) Yielda (%)
1 Neat 5 60 5 84
2 Methanol 5 60 5 70
3 Acetonitrile 5 60 5 87
4 Water 5 60 8 80
5 Acetonitrile: water 5 60 3 97
6 Acetonitrile: water 5 60 0.5 92b
7 Acetonitrile: water 5 50 3 97
8 Acetonitrile: water 5 RT 5 85
9 Acetonitrile: water 3 50 3 97
10 Acetonitrile: water 1 50 3 96
11 Acetonitrile: water 0.5 50 3 96
Reaction conditions: Phenyl acetylene (1 mmol), NaN3 (1.2 mmol) and benzyl bromide (1.1 mmol),
complex 1 (0.5 mg, 0.00088 mmol of Cu), MeCN:H2O (1:1 (v/v), 2 mL). aIsolated yield after purification through column chromatography by silica gel.
bReaction tried on focused microwave reactor.
The complex 1 is air stable and can tolerate a range of alkyl, allyl and cinnamyl halides
under mild reaction conditions (Table V.5). The terminal alkynes have participated in this
reaction very smoothly. Phenyl acetylene, 4–ethanyl toluene and 2–bromo phenyl acetylene
gave excellent yield (entry 1 to 3). 4–nitro–phenyl acetylene also gave excellent yield but
slightly lesser than the previous one (entry 4). Apart from aromatic alkyne, alphatic alkyne
gave excellent yield (entry 5) also. Allyl bromide was found to be very active as a coupling
130
partner in this AAC reaction (entry 6 and 7). Benzyl chlorides are also reactive as benzyl
bromides (entry 8 and 9). But the same reaction when carried out with diphenyl acetylene, an
internal alkyne no reaction occurred even after 12 hours (entry 10). This methodology has
been also applied for cinnamyl chlorides (entry 11 and 12). All the reactions proceeded
without difficulty and the products were isolated in good to excellent yields in high purity in
column chromatography.
Table V.5. Catalytic activity of complex 1 in the AAC reaction.a
NaN3+ +
Complex 10.5 mg
MeCN:H2O(2:1), 50 oC
R1
N
NN R2
R1 X R2 H
Entry R1CH2X R2 H Time
(h)
Product Yield
(%)
1 PhCH2Br Ph 3 Ph N
N N
Ph
97
2 PhCH2Br p-Tol 3 Ph N
N N
p-Tol
96
3 PhCH2Br o-Br-Ph 5 Ph N
N N
o-Br-Ph
96
4 PhCH2Br p-O2N-Ph 4 Ph N
N N
p-NO2-Ph
91
5 PhCH2Br Ph
OH
4 Ph N
N N OHPh
90
6 Br Ph 4 N
N N
Ph
81
7 Br p-Tol 4 N
N N
p-Tol
83
8 PhCH2Cl Ph 3.5 Ph N
N N
Ph
95
9 PhCH2Cl p-Tol 3.5 Ph N
N N
p-Tol
94
10 PhCH2Br Ph Ph 12
Ph N
N N
Ph
Ph
Not
isolated
11 Ph Cl Ph 4 N
N N
PhPh
84
131
12 Ph Cl p-Tol 4 N
N N
p-TolPh
85
Reaction conditions: Teminal alkynes (1 mmol), NaN3 (1.2 mmol) and benzyl/allyl/cinnamyl halide
(1.1 mmol), complex 1 (0.5 mg, 0.00088 mmol of Cu), MeCN: H2O (1:1 (v/v), 2 mL). aIsolated yield after purification through column chromatography by silica gel.
V.3.5. One–pot two–step process for the synthesis of sulfur functionalized 1,2,3–triazole
derivative
1,2,3–triazoles containing diverse functional groups have strong potential as steel
corrosion inhibitors or suitable ligands for transition–metal chemistry. We have prepared
sulfur functionalized pendant arms of 1,2,3–triazole compounds in a multicomponent
approach via one–pot two–step reaction using our catalyst. Benzenethiol (1.1 mmol, 121 mg)
was first reacted with propergyl bromide (1 mmol, 119 mg) in presence of triethyl amine (2
mmol, 202 mg) in water at room temperature. After 2 h, benzyl bromide (1.1 mmol, 188 mg)
and sodium azide (1.2 mmol, 78 mg) and complex 1 (0.5 mg, 0.00088 mmol of Cu) were
added to the reaction mixture. The progress of the reaction was monitored by tlc and finally
the desired product was isolated in column chromatography. The preparation methodology is
depicted in the Scheme V.6 below.
SH
BrWater
Et3N
RT, 2 h, Stirring+
SBr
NaN3
Complex 1, MeCN
50 oC
SN
NN
Scheme V.6. One–pot two–step synthesis of sulfur functionalized 1,2,3–triazole derivative
V.3.6. Mechanism
A possible mechanism for this multicomponent azide–alkyne coupling reaction was
proposed in Scheme V.7. The reaction was initiated by the metalation of phenylacetylene in
the presence of complex 1 giving copper acetylide. In next step alkyl azide was formed in–
situ by the substitution reaction between alkyl halide and sodium azide. The polymeric
copper acetylide moiety reacted with alkyl azide in cycloaddition fashion followed by
elimination of complex 1 give rise to 1,4–disubstituted triazole as the main product.21
132
Scheme V.7. A plausible mechanistic path for the multicomponent AAC reaction
V.4. Conclusion
In summary, we have prepared a highly efficient CuI–1, 3–bis(4–fluorophenylthio)–
propane catalyst for one–pot multicomponent cycloaddition reaction among aliphatic/aryl
alkynes, allyl/benzyl halides and sodium azide at 50 oC. The multicomponent approach of
this method can avoid the direct use of toxic and explosive organic azides. The method uses
commercially available and inexpensive combination CuI and easily prepared 1, 3–bis(4–
fluorophenylthio)–propane ligand as the catalyst system. Excellent regioselectivity was
observed for the synthesis of 1,2,3–triazole compounds.
V.5. Experimental section
V.5.1. General information
CuI was purchased from Sd–fine chemicals ltd., India. Allyl bromide and 4–
flurothiophenol were purchased from Sd–fine chemicals and Sigma–Aldrich, India
respectively. Allyl bromide was purified by simple distillation before use and other chemicals
were purchased and used directly. UV–Visible spectra were recorded by Jasco V–530
UV/VIS Spectrophotometer in acetonitrile solvent. Photoluminescences were measured using
Photon Technologies International Quantamaster–40 spectrofluorimeter. Single crystal X–ray
133
diffraction data were measured by using the Oxford Diffraction X–Calibur CCD System and
data were collected independent data were collected with MoKα radiation at 150 K. CEM
Discover microwave reactor was used for microwave heating. AAS was measured by Varian
Spectr AA 50B Atomic Absorption Spectrometer. NMR spectra were taken in CDCl3 or d6–
DMSO using a Bruker Avance AV–300 spectrometer operating for 1H at 300 MHz and for
13C at 75 MHz. The spectral data were measured using TMS as the internal standard.
V.5.2. Procedure for the synthesis of 1,3–bis(4–fluorophenylthio)–propane (L1)
A mixture of allyl bromide (2.0 mmol, 240 mg) and 4–fluorobenzenethiol (5.0 mmol, 640
mg) was mixed with silica gel (mesh size 60–120, 1.0 g), moistened with few drops of water
and stirred magnetically by using a spin magnetic bar for 16 h. The reaction was monitored
by tlc. After completion of the reaction, the product was purified by column chromatography
over silica gel. The product was eluted with light petroleum and we get the 1,3–bis(4–
fluorophenylthio)–propane. 1,3–bis(4–fluorophenylthio)–propane was characterized by 1H–
and 13
C–NMR and compared with literature data.19
V.5.3. Procedure for the synthesis of Complex 1
CuI (1 mmol, 190 mg) was first stirred in dry and distilled acetonitrile (5 mL) at room
temperature for 1 hour. Then a solution of 1,3–bis(4–fluorophenylthio)–propane ligand L1 (2
mmol, 592 mg) in acetonitrile was added to the solution of CuI and stir the reaction mixture
for 1 h at room temeperature. The reaction mixture was then stirred under refluxing condition
for 20 hours and kept this at room temperature to see if any crystal separates from the
reaction mixture. But no crystals came out from the reaction mixture at room temperature
even after 2 days. After that distilled petroleum ether was added drop wise to the
concentrated reaction mixture and poured it for cooling in refrigerator. A pale yellow
coloured crystal was found on the light petroleum part and separated by simple filtration and
washed it with light petroleum (4×5 mL). Finally the crystals were dried under vacuum. This
catalyst is named as complex 1.
V.5.4. General procedures for Cu(I)–catalyzed AAC reaction
To a solution of 0.5 mg complex 1 in MeCN: H2O (1:1 v/v), add benzyl/allyl/cinnamyl
halide (1.1 mmol) and NaN3 (1.2 mmol). The reaction mixture was stirred for few minutes at
room temperature. Then terminal alkyne (1.0 mmol) was added to the reaction mixture. A
colour change was found from colorless to brown of the reaction mixture. The reaction
134
mixture was then heated at 50 oC in a round–bottomed flask fitted with condenser and
maintaining gentle magnetic stirring for hours, as noted in Table V.5. The progress of the
reaction was monitored by tlc. After completion of the reaction, the mixture was diluted by
water (2 mL) and the filtrate was extracted with ethyl acetate (4×10 mL) and the combined
organic parts were washed with brine (1×5 mL), dried over anhydrous Na2SO4 and
concentrated under vacuum. The residue was purified by passing through a short silica gel
column chromatography and eluted with mixture of ethyl acetate–light petroleum to afford
the desired triazole product. All products were characterized by 1H–,
13C–NMR spectral data,
and also compared with the reported melting points (for known solid compounds).
V.5.5. Physical properties and spectral data of compounds
1–(3–(4–fluorophenylthio)propylthio)–4–fluorobenzene, Ligand 1 (L1)19
F
S S
F
Colourless liquid
1H–NMR (d6–DMSO, 300 MHz): /ppm 1.77 (quintet, J = 6.9 Hz, 2H, CH2), 3.02 (t, J = 6.9
Hz, 4H, 2CH2, 7.11‒7.18 (m, 4H, ArH), 7.34‒7.39 (m, 4H, ArH).
13C–NMR (d6–DMSO, 75 MHz): /ppm 28.4, 32.3, 116.4, 116.7, 131.3, 131.4, 131.7, 131.9,
159.7, 162.9.
Complex 1
Pale yellow coloured crystalline solid
1H–NMR (d6–DMSO, 300 MHz): /ppm 1.76 (s, 2H, CH2), 3.02 (d, J = 6.0 Hz, 4H, 2CH2),
7.13 (d, J = 7.2 Hz, 4H, ArH), 7.37 (d, J = 4.5 Hz, 4H, ArH).
13C–NMR (d6–DMSO, 75 MHz): /ppm 28.1, 32.9, 116.4, 116.7, 131.0, 132.1, 161.4, 163.1.
Table V.6, entry 1
1–Benzyl–4–phenyl–1H–1,2,3–triazole22
NN
N
135
White crystalline needle, mp126‒128 oC (Lit.
22 128‒130
oC)
1H NMR (CDCl3, 300 MHz): /ppm 5.47 (s, 2H), 7.19‒7.33 (m, 8H), 7.58 (s, 1H), 7.70‒7.72
(m, 2H).
13C NMR (CDCl3, 75 MHz): /ppm 54.1, 119.5, 125.6, 127.9, 128.1, 128.7, 128.8, 129.1,
130.5, 134.6, 148.1.
Table V.6, entry 2
1‒Benzyl‒4‒(p‒tolyl)‒1H‒1,2,3‒triazole22
NN
N
Me
White crystalline solid, mp152‒154 oC (Lit.
22 150
oC)
1H NMR (CDCl3, 300 MHz): /ppm 2.26 (s, 3H), 5.44 (s, 2H), 7.10 (d, J = 7.8 Hz, 2H),
7.18‒7.28 (m, 5H), 7.53 (s, 1H), 7.6 (d, J = 8.1 Hz, 2H).
13C NMR (CDCl3, 75 MHz): /ppm 21.2, 54.1, 119.1, 125.5, 127.6, 127.9, 128.6, 129.0,
129.4, 134.7, 137.9, 148.2.
Table V.6, entry 3
1‒Benzyl‒4‒(2‒bromo phenyl)‒1H‒1,2,3‒triazole23
NN
N
Br
Light pink solid, mp 80‒82 oC
1H NMR (CDCl3, 300 MHz): /ppm 5.58 (s, 2H), 7.12‒7.18 (m, 1H), 7.25‒7.39 (m, 6H), 7.6
(d, J = 7.8, 1H), 8.07‒8.15 (m, 2H).
13C NMR (CDCl3, 75 MHz): /ppm 54.2, 121.2, 123.1, 127.7, 127.9 128.7, 129.1, 129.4,
130.6, 131.3, 133.5, 134.7, 145.7.
Table V.6, entry 4
1‒benzyl‒4‒(4‒nitrophenyl)‒1H‒1,2,3‒triazole24
136
N
N N
NO2
Yellow crystalline solid, mp 171‒172 oC
1H NMR (d6‒DMSO, 300 MHz): /ppm 5.69 (s, 2H), 7.34‒7.38 (m, 5H), 8.11‒8.14 (m, 2H),
8.28‒8.31 (m, 2H), 8.91 (s, 1H).
13C NMR (d6–DMSO, 75 MHz): /ppm 53.7, 124.1, 124.8, 126.4, 128.5, 128.7, 129.3, 136.2,
137.5, 145.2, 147.1.
Table V.6, entry 5
1‒(1‒benzyl‒1H‒1,2,3‒triazol‒4‒yl)‒1‒phenylethanol25
N
N N OH
White solid, mp 133‒135 oC
1H NMR (d6–DMSO, 300 MHz): /ppm 1.81 (s, 3H), 5.54 (s, 2H), 5.85 (s, 1H), 7.18‒7.21
(m, 1H), 7.26‒7.37 (m, 7H), 7.45‒7.48 (m, 2H), 7.89 (s, 1H).
13C NMR (d6–DMSO, 75 MHz): /ppm 31.3, 53.1, 71.4, 122.1, 125.6, 126.8, 128.2, 128.5,
128.6, 129.2, 136.6, 148.8, 155.9.
Table V.6, entry 6
1‒Allyl‒4‒phenyl‒1H‒1,2,3‒triazole26
NN
N
White crystalline solid, mp 62‒64 oC (Lit.
26 56‒58
oC)
1H NMR (CDCl3, 300 MHz): /ppm 4.96 (d, 2H), 5.26‒5.34 (m, 2H), 5.95‒6.08 (m, 1H),
7.28‒7.42 (m, 3H), 7.76‒7.83 (m, 3H).
13C NMR (CDCl3, 75 MHz): /ppm 52.7, 119.7, 120.1, 125.7, 128.1, 128.8, 130.6, 131.3,
147.9.
Table V.6, entry 7
1‒Allyl‒4‒(p‒tolyl)‒1H‒1,2,3‒triazole26
137
NN
N
Me
White crystalline solid, mp 88‒90 oC
1H NMR (CDCl3, 300 MHz): /ppm 2.36 (s, 3H), 4.97‒5.01 (m, 2H), 5.29‒5.38 (m, 2H),
5.98‒6.11 (m, 1H), 7.02‒7.26 (m, 2H), 7.69‒7.72 (m, 3H).
13C NMR (CDCl3, 75 MHz):/ppm 21.3, 52.7, 119.1, 120.1, 125.6, 127.8, 129.5, 131.4,
138.0, 148.1.
Table V.6, entry 8
1‒(E‒cinnamyl)‒4‒phenyl‒1H‒1,2,3‒triazole27
NN
N
White solid, mp 136‒137 oC (Lit.
27 132‒134
oC)
1H NMR (CDCl3, 300 MHz): /ppm 5.11‒5.13 (m, 2H), 6.29‒6.41 (m, 1H), 6.66 (d, J = 15.9
Hz, 1H), 7.24‒7.47 (m, 8H), 7.79‒7.83 (m, 3H).
13C NMR (CDCl3, 75 MHz): /ppm 52.4, 119.5, 121.9, 125.7, 126.8, 128.2, 128.6, 128.8,
128.9, 130.6, 135.4, 135.5, 148.1.
Table V.6, entry 9
1‒(E‒cinnamyl)‒4‒(p‒tolyl)‒1H‒1,2,3‒triazole
NN
N
Me
White solid, mp 145‒147 oC
138
1H NMR (CDCl3, 300 MHz): /ppm 2.35 (s, 3H), 5.11‒5.14 (m, 2H), 6.30‒6.4 (m, 1H),
6.67(d, J = 15.6 Hz, 1H), 7.19‒7.36 (m, 7H), 7.69‒7.75 (m, 3H).
13C NMR (CDCl3, 75 MHz): /ppm 21.3, 52.4, 119.1, 122.0, 125.6, 126.7, 127.8, 128.5,
128.7, 129.5, 135.3, 135.5, 137.9, 148.1.
1‒benzyl‒4‒((phenylthio)methyl)‒1H‒1,2,3‒triazole28
SN
NN
White crystalline solid, mp 75‒76 oC (Lit.
28 71‒73
oC)
1H NMR (CDCl3, 300 MHz): /ppm 4.19 (s, 2H), 5.44 (s, 2H), 7.13‒7.35 (m, 11H).
13C NMR (CDCl3, 75 MHz): /ppm 29.04, 29.08 (‒SCH2), 54.1 (‒NCH2), 122.0, 126.5,
127.9, 128.7, 128.93, 128.95, 129.1, 129.8, 129.9, 134.7, 135.4, 145.3.
V.6. References
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139
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155
INDEX
A
Acetonitrile 43, 59, 124, 130, 131, 135
Allyl bromide 131, 134, 135
Ambient 47, 54, 58, 59, 84, 97, 102, 103, 119
Anhydrous 5, 21, 37, 60, 61, 106, 134
Aryl bromides 4, 52, 53, 56, 57, 60
Aryl iodides 52, 55, 56, 60
Aryl trihydroxy borate 47, 53‒55, 58
B
Benzimidazole 48, 58, 59, 61, 68
Benzoyl peroxide 59
Biaryls 48, 49, 52, 56, 60
Bimetallic 9, 14‒16, 19‒21, 23, 24, 27‒29, 33‒35,
141, 142, 144
Biphasic 45, 51
Bragg diffraction pattern 24
C
Carbon disulfide 93‒96, 104
Characterization 22, 84, 122, 144
Chromatography 31, 37, 55‒60, 82‒84, 97, 98, 101, 104,
105, 106, 129‒134
Click 16, 72, 117‒121, 129
Clusters 6, 7, 16, 27, 42, 121
Coordination clusters 6, 7, 121
Cycloaddition 42, 43, 118‒121, 131, 132, 153
Cyclodextrine 10, 78
D
D(+)‒glucose 82, 84
9,10‒dibromoanthracene 30, 32, 33
Diethyl ether 60, 84, 97, 105
Disulfide 82, 96, 97, 104
Dithiocarbamate 92‒96, 99, 102, 104, 106
Dithioether 70, 78, 79, 117, 121, 127
E
EDX elemental mapping 28, 29
Eluent 60, 61
Energy dispersive X‒ray 21, 22
Epoxide 94, 95
H
Heterocyclic 118
Heterogeneous catalyst 3, 4, 21, 35, 51
156
Histogram 27, 28
Hydrodehalogenation 15‒21, 30‒37, 143
Hydrothiolation 70, 72‒79, 81‒84
I
Iron oxide (Fe2O3) 34
L
Luminescence 132
M
Macroporous 4, 21, 25
Merkovnikov 72‒74, 77, 78
Merrifield 2, 10, 139
Metallopolymer 126
Methodology 2, 17, 19, 74, 75, 78, 93‒95, 121, 130
Microwave 45, 46, 50, 51, 57, 119, 129, 133, 155
Monoclinic 126
Monometallic 33
Morpholine 97, 98, 105‒108, 113, 115
Morphology 22, 25
Multicomponent 118, 120, 131, 132
N
NBS 58
Nanocatalysts 19, 21
Nanocomposites 9, 14, 15, 21‒25, 27, 29, 30, 36
Nanotubes 20, 33
nZVI 18
O
Optimization 30, 55, 98, 129
P
Palladium 4, 11, 13, 16, 18, 19, 21, 35, 45, 50, 51,
53, 56, 74, 75, 149
Palladium chloride 21
Phase transfer catalyst 46, 51, 52
Photoluminescent 125
Piperidine 99, 105, 108‒110, 113‒115
Polymerization 10, 11, 92
Polystyrene 10, 11, 12, 17
Polymer‒supported reagents 12
PVP 8, 9
Pyrrolidine 99, 105, 110, 111, 114
Q
Quintet 122, 134
R
Radical 58, 72, 74, 78, 79, 83, 92, 104, 150
157
Recycling 32, 33
Regioisomer 80
Regioselective 75‒79, 83, 95, 118
Resin 2, 10‒15, 21, 24 25, 28, 35, 36, 58,
79‒81, 94
S
Solvent‒free 5, 50
Spacer 7, 125
Stereoselectivity 44, 79‒83, 95
Surfactant 45, 52, 79
T
Thiocyanate 91, 96‒100, 102, 104, 105, 106
Thioether 71, 74, 75, 78, 79, 121
Thiols 72‒75, 77‒79, 81‒83
Triazole 118, 119, 131, 132‒136
Triplet 122
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PAPERS
PAPER www.rsc.org/greenchem | Green Chemistry
Highly effective alternative aryl trihydroxyborate salts for a ligand-free,on-water Suzuki–Miyaura coupling reaction
Basudeb Basu,* Kinkar Biswas, Sekhar Kundu and Sujit Ghosh
Received 18th May 2010, Accepted 9th July 2010DOI: 10.1039/c0gc00122h
Aryl trihydroxyborate salts of sodium, an easily accessible and stable alternative source oforganoboron species, can efficiently promote Pd-catalyzed ligand-free, on-water Suzuki–Miyaura(SM) coupling reactions at ambient temperature.
Introduction
The seminal paper of Miyaura, Yamada and Suzuki1 laidthe foundation of one of the most important and usefulmethods for the construction of carbon–carbon bonds, inparticular for the formation of unsymmetrical biaryls. Despiteother alternative approaches for C–C bond formation suchas Kharash coupling,2 Negishi coupling,3 Stille coupling,4
Hiyama coupling,5 and Kumuda coupling,6 the Suzuki–Miyaura(SM) coupling reaction has arguably received much morepopularity due to stability, commercial availability and ease ofhandling of the organoboron compounds. The Suzuki–Miyauracoupling has found widespread applications in academic lab-oratories, fine chemical industries, synthesis of biologicallyactive pharmaceuticals, as well as in the burgeoning area ofnanotechnology, as reflected from contributions from myriadresearch groups.7 For example, Losartan, an antihypertensivedrug,8a CI-1034, a potent endothelian receptor antagonist,8b CE-178,253 benzenesulfonate, a CB1 antagonist for the treatment ofobesity8c or apoptolidin A, a potent antitumor agent8d have beensynthesised on a large scale employing the SM coupling as a keystep. Similarly, benzimidazole derivatives bearing substitutedbiphenyl moieties, potential inhibitors of hepatitis C virus, havebeen prepared using the SM coupling reaction.9 Review articlesby Danishefsky et al.10 and Nicolaou et al.11 amply demonstratevarious applications of the SM coupling reaction in the synthesisof natural products.
In recent years, amelioration of the SM coupling reaction hasbeen directed towards the more efficient, economic and greenertechniques, especially in respect of Pd-catalyst, requirementof base and carrying out the reaction in water or in theabsence of any solvent.12 Recent trends in organic synthesisinvolve reactions under solvent-free or on-water conditions toobtain the target molecule in a cleaner and environmentallybenign way.13 Although many organic reactions are facilitatedin aqueous media, some reactions proceed very slowly becauseof poor solubility of the substrate/reagents in water. In thecase of SM couplings, hydrophobic aryl boronic acids oftenshow very slow and/or incomplete conversions along with thedifficulty to isolate the products from the reaction mixture.14
Department of Chemistry, North Bengal University, Darjeeling, 734 013,India. E-mail: [email protected]; Fax: 91 353 2699001; Tel: 91353 2776381
Efforts have been made to overcome the problem by introducingphase transfer catalysts,15 water soluble salts of reagents16 orcatalysts17 or carrying out the reaction in aqueous buffer.18
Two types of water-soluble organoborate salts viz. potassiumaryl trifluoroborates16a–d and sodium aryl trihydroxyborates,16e,f
which are easy to prepare, store and handle, have been employedin Pd-catalyzed cross-couplings with aryl halides. Yet, despitesome positive features of using aryl trihydroxyborate salts, aque-ous SM coupling usually requires elevated temperatures, organicco-solvents, ligand-based Pd-catalysts, high catalyst loadingsand/or tedious work-up. In this paper we present an ambienton-water protocol for the SM coupling reaction of a widerange of aryl halides (I, Br or Cl) including heteroaryl halideswith different sodium aryl trihydroxyborates. Our observationspractically constitute an efficient, mild, ligand-free method forthe SM coupling reactions in water at ambient temperatureby using aryl trihydroxyborate salt as one of the couplingpartners (Scheme 1). This paper also reports successful extensionof the procedure through the use of polymer-supported Pd-catalyst (ARF–Pd), a heterogeneous Pd-catalyst developed byour group,19 covering the essential aspects of green chemistry.Furthermore, we have demonstrated modular synthesis ofpharmaceutically important benzimidazole- and benzotriazole-based biphenyl scaffolds using an alternative water-solublesodium organoborate salt.
Results and discussion
Preliminary optimization of the SM coupling reactions was car-ried out using 3-iodoanisole and phenyltrihydroxyborate withthe aid of 0.5 mol% Pd(OAc)2 (Table 1). The phenyl trihydroxyb-orate salt was prepared following the reported procedure,16e andused directly without further purification. Investigations usingdifferent solvents revealed that the coupling is unsuccessful intoluene (Table 1 entry 1), partly successful in dioxane (Table 1,entry 2) but worked efficiently in DMF (Table 1, entry 3). Onswitching over to aqueous media, it was found that a mixtureof acetone–water also worked efficiently within 8 h under mildconditions (Table 1, entry 4). However, carrying out the reactionin only water resulted in the formation of the biphenyl derivativein 38% yield (Table 1, entry 5), which may be attributed tothe poor solubility of aryl iodide in water. To overcome thisshortcoming, we decided to use tetrabutylammonium bromide(TBAB), a phase transfer reagent, in an equimolar amount.
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Scheme 1
Table 1 Optimization of reaction conditions for the SM coupling using3-iodoanisole and phenyltrihydroxyborate
Entry Solvent Temperature Time % of Yielda
1 Toluene 100 ◦C 8 h 002 Dioxane RT 24 h 453 DMF RT 4 h 964 Acetone : water RT 8 h 935 Water RT 4 h 386 Waterb RT 4 h 927 Waterc RT 8 h 50
a Isolated yields after purification by column chromatography on silica.b 1 equiv. of TBAB was added. c 0.5 equiv. of TBAB was added. Allreactions were carried out using 0.5 mol% Pd(OAc)2.
This led to the formation of the desired unsymmetrical biphenylwithin 4 h at room temperature in 92% yield (Table 1, entry 6). Anexperiment with 0.5 equivalents of TBAB, however, afforded thedesired product only in 50% yield, even after 8 h (Table 1, entry7). It was revealed that polar protic or aprotic solvents are goodenough to effect the SM coupling at room temperature. Thus,the optimized reaction conditions are: 0.5 mol% of Pd(OAc)2
and 1 equivalent of TBAB in water at room temperature.After identification of the optimal conditions, the scope and
limitations of the reaction were examined. Initially, we appliedthese reaction conditions to the coupling of various functional-ized aryl iodides with the sodium salt of phenyltrihydroxyboratein water. The results are presented in Table 1. Aryl iodidesbearing different substituents such as OMe, Me, NH2, F andI underwent smooth SM coupling affording the correspondingunsymmetrical biphenyls in 84–94% yields (Table 2, entries 1–7). Mechanistically, the oxidative addition of aryl halides topalladium(0) depends on the nature of halogens and occurs inthe descending order of I > Br > Cl.20 We therefore examinedthe couplings of other aryl electrophiles bearing bromide andchloride. Several aryl bromides including di- and tribromoareneswere found to give the corresponding unsymmetrical biarylsin good to excellent yields (Table 2, entries 8–13). While p-bromoacetophenone showed a faster rate of reaction (2 h)(Table 2, entry 9), 2,4,6-tribromophenol required a longer time(24 h) (Table 2, entry 13) for the coupling reaction, which may bedue to the presence of the electron-withdrawing acetyl group inthe former example. Thus, aryl iodides and bromides underwenteasy coupling with phenyl trihydroxyborate. A similar reactionwith aryl chloride was not successful even after heating thereaction mixture at 100 ◦C for 24 h (Table 2, entries 14–15). Lead-beater et al.18a reported the microwave-assisted SM coupling of
aryl chlorides at 150–175 ◦C in aqueous media indicating thataryl chlorides are very sluggish towards the SM coupling reac-tion and require relatively higher temperature, longer reactiontime and/or the presence of electron-withdrawing groups. Weexamined aryl chlorides bearing nitro or acetyl groups, whichhowever afforded the desired coupled products in excellentyields at refluxing temperatures (100 ◦C) (Table 2, entries 16–17). Changing the coupling partner phenyltrihydroxyborate withm-tolyltrihydroxyborate and p-anisyltrihydroxyborate did workefficiently with bromo and iodoarenes (Table 2, entries 18–22and 24). The SM coupling reaction with heteroaryl halideswas also successful. For example, 3-bromoquinoline or 2,6-dibromopyridine gave the desired coupled products in 66% and83% yields respectively (entries 22–23), while similar couplingof 2-iodothiophene with p-anisyltrihydroxyborate afforded thecorresponding unsymmetrical biphenyl in 92% yield within 3 h(Table 2, entry 24).
Recently, we developed a new Pd-catalyst (where Pd wasimmobilized onto ion-exchange resins), designated as ARF–Pd, which was successfully applied to Heck, Suzuki–Miyaura
† Spectral data of selected biphenyls: 3-Methoxy biphenyl (liquid);Table-2, Entry-1: IR (film): nmax 1574, 1610 cm-1. 1H NMR (CDCl3,d ppm-1 relative to TMS): 3.75 (3H, s, –OCH3); 6.77–6.81 (1H, m,aromatic proton); 7.03–7.10 (2H, m, 2 aromatic protons); 7.21–7.36(4H, m, all aromatic protons); 7.47–7.51 (2H, m, 2 aromatic protons).13C NMR (CDCl3, d ppm-1): 55.2 (OCH3); 112.6; 112.8; 119.6; 127.1;127.4; 128.7; 129.7; 141.0; 142.7; 159.9 (aromatic carbons). 2-Methoxybiphenyl (liquid); Table-2, Entry-3: IR (film): nmax 1504, 1597 cm-1. 1HNMR (CDCl3, d ppm-1 relative to TMS): 3.79 (3H, s, –OCH3); 6.96–7.05(2H, m, 2 aromatic protons); 7.29–7.42 (5H, m, all aromatic protons);7.51–7.54 (2H, m, 2 aromatic protons). 13C NMR (CDCl3, dPpm-1):55.54 (OCH3); 111.2; 120.8; 126.9; 127.9; 128.6; 129.5; 130.7; 130.8;138.5; 156.5 (aromatic carbons). 3,4¢-Dimethyl biphenyl (liquid); Table-2, Entry-19: IR (film): nmax 1588, 1606 cm-1. 1H NMR (CDCl3, d ppm-1
relative to TMS) 2.390 (6H, s, CH3); 7.13–7.50 (8H, m, 8, all aromaticprotons). 13C NMR (CDCl3, d ppm-1): 21.3 (CH3); 124.1; 127.0; 127.7;127.8; 128.6; 129.4; 136.9; 138.2; 138.5; 141.1 (aromatic carbons). 3-Methoxy 3¢-methyl biphenyl (liquid); Table-2, Entry-20: IR (neat): nmax
1593 cm-1. 1H NMR (CDCl3, d ppm-1 relative to TMS): 2.41 (3H, s,CH3); 3.86 (3H, s, –OCH3); 7.11–7.39 (8H, m, all aromatic protons).13CNMR (CDCl3, d ppm-1): 21.5 (CH3); 55.3 (OCH3); 112.6; 112.9; 119.7;124.3; 128.0; 128.1; 128.6; 129.6; 138.3; 141.1; 142.9; 159.9 (aromaticcarbons). 3-(3-Methyl phenyl) quinoline (liquid); Table-2, Entry-22: IR(film): nmax 1580, 1606 cm-1. 1H NMR (CDCl3, d ppm-1 relative to TMS):1.59 (3H, s, CH3); 6.36–6.87 (6H, m, 6 aromatic protons); 7.00 (1H, d,J = 8.1 Hz, aromatic proton); 7.28 (1H, d, J = 8.4 Hz, aromatic proton);7.43 (1H, s); 8.3 (1H, s). 13C NMR (CDCl3, d ppm-1): 21.6 (CH3); 124.5;127.1; 128.0; 128.1; 128.2; 128.9; 129.0; 129.1; 129.4; 133.4; 134.0; 137.7;138.9; 147.1; 149.8 (aromatic carbons). 2-(4-Methoxy phenyl) thiophene;Table-2, Entry-24: mp 106 ◦C; IR (KBr): nmax 1500, 1533, 1606 cm-1. 1HNMR (CDCl3, d ppm-1 relative to TMS): 3.81 (3H, s, –OCH3); 6.91(2H, d, J = 9 Hz, 2 aromatic protons); 7.03–7.25 (3H, m, all aromaticprotons); 7.53 (2H, d, J = 8.7 Hz, 2 aromatic protons). 13C NMR (CDCl3,d ppm-1): 55.3 (OCH3); 114.3; 122.1; 123.8; 127.2; 127.3; 127.9; 144.3;159.2 (aromatic carbons).
This journal is © The Royal Society of Chemistry 2010 Green Chem., 2010, 12, 1734–1738 | 1735
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Table 2 On-water SM coupling reactions with sodium aryl trihydrox-yborates using 0.5 mol% of Pd(OAc)2
a Aryl halide and arylboronic acid salt used in 1 : 1.1 ratios formono-coupling. b Isolated yields after purification by columnchromatography on silica.†
and Sonogashira coupling reactions.19 To extend further, weemployed the heterogeneous Pd-catalyst (ARF–Pd) replacingPd(OAc)2. Indeed, trihydroxyborate salts were found to beequally active in SM coupling reactions in the presence ofa catalytic amount of ARF–Pd. The results are presented inTable 3. In all the cases, the ARF–Pd was separated by filtrationand the desired products were obtained after chromatographicpurification in excellent yields (85–93%) (Table 3, entries 1–5).
As shown above, water-soluble sodium salts of aryl trihy-droxyborates have proven to be highly effective in SM couplingreactions in water at ambient temperatures. Low loading ofthe Pd-catalyst (direct use of Pd(OAc)2 or polymer-bound Pd)and absence of any phosphine ligands are notable features tomention. Having established a general, mild, aerobic and on-water protocol for the SM coupling reactions using aryl trihy-droxyborate salts, we probed the utility of this protocol in mod-ular synthesis of pharmaceutically important benzimidazole-and benzotriazole-based biphenyl scaffolds. Thus, compounds 2and 3 were synthesized from compounds 1a and 1b respectively(Scheme 2), where the SM couplings were efficiently performedusing sodium phenyltrihydroxyborate in a mixture of DMF–H2O (2 : 1).
Conclusions
In summary, our studies have established that easily accessibleand air-stable sodium aryl trihydroxyborates can be effectivelyused as an alternative source of organoboron species in ligand-free Pd-catalyzed SM cross-coupling reactions in water underan aerobic atmosphere and at room temperature. The protocolhas been found to be broadly applicable to a variety of arylhalides (X = Br, I) and also to aryl chlorides bearing electron-withdrawing groups. It is further shown to be effective withheterogeneous Pd-catalysts and also extended to the modularsynthesis of some pharmaceutically important benzimidazole-and benzotriazole-based biphenyl scaffolds.
Experimental
General procedure for Suzuki–Miyaura coupling
A mixture of 3-iodoanisole (468 mg, 2 mmol), sodium phenyltri-hydroxyborate (354 mg, 2.2 mmol), Pd(OAc)2 (2.2 mg, 0.5 mol%)and TBAB (644 mg, 2 mmol; 1 equiv) was taken in water (5 mL).The mixture was magnetically stirred at room temperature forseveral hours (see Table 2). After the reaction was complete(monitored by tlc), the mixture was extracted with ether (3¥ 20 mL). The combined organic layer was then washed withbrine (10 mL), dried (anhydrous Na2SO4), and evaporated. Theresidue was purified on a short column of silica using lightpetroleum as the eluent to afford the desired unsymmetricalbiphenyl (338 mg, 92%); liquid.
Synthesis of compounds 2 and 3
A mixture of 1-(4-iodobenzyl)-1H-benzo[d]imidazole (334 mg,1 mmol) or 1-(4-iodobenzyl)-1H-benzo[d][1,2,3]triazole(335 mg, 1 mmol) and sodium salt of phenyltrihydroxyborate(177 mg, 1.1 mmol), ARF–Pd (300 mg, 0.94 mol% of Pd)and TBAB (322 mg, 1 mmol) was taken in a DMF–water
1736 | Green Chem., 2010, 12, 1734–1738 This journal is © The Royal Society of Chemistry 2010
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Table 3 SM coupling reactions with aryl trihydroxyborates in water using heterogeneous Pd-catalyst (ARF–Pd)
Entry Aryl halidesa Sodium trihydroxyborate Temp. Time/h Product Yieldb (%)
1 RT 5 85
2 RT 5 88
3 100 ◦C 4 92
4 100 ◦C 3 93
5 100 ◦C 5 87
a 300 mg ARF-Pd (0.94 mol% Pd) was used. b Isolated yields after purification by column chromatography on silica.
Scheme 2 Conditions: a1a or 1b (1 mmol), PhB(OH)3Na (1.1 mmol) in DMF–H2O (2 : 1; 3 mL), Pd(OAc)2 (1.1 mg, 0.5 mol%), 100 ◦C for 24 h.
mixture (2 : 1; 3 mL). The mixture was heated at 100 ◦C for24 h. After completion of the reaction (monitored by tlc), themixture was extracted with ethyl acetate (2 ¥ 20 mL). Thecombined organic layer was then washed with brine (10 mL),dried over anhydrous Na2SO4, and evaporated. Finally theresidue was purified over a short column of silica and elutionwith 1 : 9 (EA : light petroleum) afforded N-(4-phenyl benzyl)benzimidazole 2 (236 mg, 83%); m.p. 163 ◦C or N-(4-phenylbenzyl) benzotriazole 3 (227 mg, 80%); m.p. 180 ◦C.
Spectral data for 2. 1H NMR (CDCl3): d 5.41 (2H, s, (CH2);7.25–7.83 (13H, m, all aromatic protons); 8.07 (1H, s, aromaticproton). 13C NMR (CDCl3): d 48.7 (CH2 aliphatic carbon);110.2; 120.2; 122.6; 123.3; 127.1; 127.6; 127.8; 128.8; 129.1;133.8; 134.2; 140.3; 141.4; 143.1; 143.3 (aromatic carbons). IR(KBr): nmax 1610, 1653 cm-1. HRMS: Calculated for C20H16N2H:[M+H]+, 285.1392; found: 285.1387.
Spectral data for 3. 1H NMR (CDCl3): d 5.88 (2H, s,(CH2); 7.25–8.09 (13H, m, all aromatic protons). 13C NMRNMR (CDCl3): d 51.9 (CH2 aliphatic carbon); 109.7; 120.1;124.0; 127.0; 127.5; 127.6; 127.7; 128; 128.8; 132.8; 133.6; 140.2;141.4; 146.3 (aromatic carbons). IR (KBr): nmax 1590, 1616 cm-1.HRMS: Calculated for C19H15N3Na: [M+Na]+ 308.1164; found:308.1163.
Acknowledgements
We are grateful to the Department of Science & Technology, NewDelhi for financial support (Grant No. SR/S1/OC–49/2006).KB and SG thank CSIR, New Delhi for awarding juniorresearch fellowships.
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Research ArticleIn Quest of ‘‘Stereoselective Switch’’ for On-WaterHydrothiolation of Terminal Alkynes Using Different Additivesand Green Synthesis of Vicinal Dithioethers
Basudeb Basu, Kinkar Biswas, Samir Kundu, and Debasish Sengupta
Department of Chemistry, North Bengal University, Darjeeling 734 013, India
Correspondence should be addressed to Basudeb Basu; basu [email protected]
Received 30 October 2013; Accepted 18 December 2013; Published 13 February 2014
Academic Editor: Ralph Nicholas Salvatore
Copyright © 2014 Basudeb Basu et al. This is an open access article distributed under the Creative Commons Attribution License,which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
On-water hydrothiolation reaction between terminal alkyne and thiol has been probed in the presence of various additives.Aromatic alkynes yield corresponding 1-alkenyl sulfides, whereas aliphatic alkynes undergo double-addition yielding vicinaldisulfides in good to excellent yields. Formation of 1-alkenyl sulfides proceeds with a high degree of regioselectivity (via anti-Markovnikov addition), and switching the stereoselectivity between E/Z isomers has been noticeably realized in the presence ofdifferent additives/promoters.
1. Introduction
Organosulfur compounds play a key role in biologicalprocesses, new materials, and chemical synthesis [1, 2]. 1-Alkenyl sulfides are important synthetic intermediates intotal synthesis of many naturally occurring and biologicallyactive compounds as well as versatile building blocks formany functionalized molecules [3–9]. The synthetic utilityof alkenyl sulfides has been demonstrated in several reportsby different research groups [10–17]. Increasing demand foralkenyl sulfides in material science, organic, and bioorganicchemistry has furthered the development of new syntheticmethods [6, 18–21]. The addition of thiols to alkynes isconsidered as one of the straightforward methods to obtainvinyl sulphides either catalyzed by transitionmetal complexes[22–39], or base-promoted [40–44] and/or through freeradicals [21, 45–48]. This reaction is often judged as a partof “click chemistry” and a process of high atom economy [49,50]. Mechanistically, addition of thiols to alkynes is believedto occur (i) via radical pathway producing unselective mix-ture of (E/Z)-anti-Markovnikov vinyl sulphides, (ii) base-mediated nucleophilic addition giving all types of adducts,or (iii) transition-metal complex catalyzed processes yieldingMarkovnikov vinyl sulphides and (E) anti-Markovnikov vinyl
sulphides (Scheme 1). Varying degrees of stereo- and regios-electivity and turnover are reported in the literature [22–48].
Additives are a kind of reagents whose effects are verymuch similar to catalysts. They have often shown a profoundrole in variety of organic reactions in terms of the rate ofthe reaction, yield of the product, or change in the courseof the reaction [51, 52]. In hydrothiolation, most reports inthe literature described the formation of thermodynamicallymore stable E-vinyl sulfide in considerable excess over theZ-isomer. On the other hand, hydrothiolation, particularlyof aryl and benzyl thiols and catalyzed by transition-metalcomplexes, often produces a mixture of anti-Markovnikov E-alkenyl sulfide (syn addition) and Markovnikov adduct andthus suffers from poor regioselectivity. Among the transitionmetal catalysts, rhodium complexes, both in homogeneousand heterogeneous forms, have exhibited high catalyticactivity [51, 52]. Recently, In(OTf)
3has been shown to
selectively catalyze bothMarkovnikov and anti-Markovnikovhydrothiolation of terminal alkynes [38]. However, transi-tion metal complexes are generally expensive, their usesare not ecofriendly, and the course of the reaction mightsuffer deactivation due to the formation of strong metal-sulphur bonds [53]. More regioselective (anti-Markovnikov)on-water hydrothiolation processes have been reported in
Hindawi Publishing CorporationOrganic Chemistry InternationalVolume 2014, Article ID 358932, 6 pageshttp://dx.doi.org/10.1155/2014/358932
2 Organic Chemistry International
HSH
Additives [A]1a
H
H
H
H
H
H+ +
2b 2cWater/Rt
2a
(Markovnikov)(Anti-Markovnikov)
(E)-isomer (Z)-isomer
C6H5
C6H5
C6H5
C6H5 C6H5
SC6H5
SC6H5 SC6H5
Scheme 1: 1-Alkenyl sulphides from hydrothiolation of terminal alkynes.
the absence [45–48, 54] or presence of some additives like𝛽-cyclodextrine [55]. Indeed, there are large varieties ofreagents/catalysts that are used in the hydrothiolation ofterminal alkynes with varying degrees of success in con-trolling stereo- and regioselectivity. However, many reportsinclude expensive metal catalysts, nonaqueous solvents, andhigh temperature and moreover lack (E/Z)-stereoselectivity.In practice, there is no general guideline by which one canproceed to prepare a specific stereoisomer of a vinylic sul-fide using this straightforward and atom-economic reactionunder mild and environment-friendly conditions. Moreover,there are conditions that give rise to selective formationof the thermodynamically favoured (E)-alkenyl sulfide, itremains an unmet and elusive goal to develop optimumconditions that selectively produce (Z)-alkenyl sulfides undercomplete metal-free, base-free and on-water conditions.Since hydrothiolation of alkynes is a robust, atom-economicand highly useful synthetic method in C–S bond formation[6], we undertook a systematic investigation on the stereo-and regioselective addition of aliphatic and aromatic thiolsto terminal alkynes in the presence of different additives incatalytic quantities under on-water conditions. We reportherein our studies that constitute a rather broad guideline of“stereoselective switch” for the preparation of stereoselective(E/Z)-1-alkenyl sulfides.
2. Materials and Methods
All compounds were identified by 1H- and 13C-NMR spectra,recorded on a Bruker AV300 spectrometer operating at 300and 75MHz, respectively, and supported by FT-IR spectra.All NMR spectra were measured in chloroform-d. Chemicalshifts are given in 𝛿 (ppm) downfield from TMS. Analyticalthin-layer chromatography (tlc) was performed on precoatedaluminum plates from Merck silica gel 60 F
254as the adsor-
bent (layer thickness 0.25mm). The developed plates wereair-dried and exposed to UV light. Column chromatographywas performed on silica gel (source: SRL India; 60–120mesh).
2.1. General Procedure for Monohydrothiolation of Alkynes.To a mixture of alkyne (1mmol), thiol (1.1mmol) in water(0.5mL) was added to the additive (1mmol) and stirred atroom temperature (25–30∘C) for 2–5 h (TLC). The reactionmixture was extracted with diethyl ether (3 × 10mL), and thecombined organic layerwaswashedwith brine and then driedover Na
2SO4. Evaporation of solvent under vacuo afforded an
oily residue, which was passed through a short bed of silica
gel, and NMR spectrum was recorded to evaluate the percentof (E/Z) isomers. NMR spectral data and scanned copies ofselected NMR spectra are given in the Supplementary Mate-rial available online at http://dx.doi.org/10.1155/2014/358932and are found to be in good agreement with those reported.
2.2. General Procedure for Dihydrothiolation of Alkynes. Ina mixture of alkyne (1mmol), thiol (2.2mmol) in water(0.5mL) was stirred for 5–9 h at room temperature (TLC).The reactionmixture was then extracted with diethyl ether (3× 10mL), and the combined organic layer was washed withbrine and then dried over Na
2SO4. Evaporation of solvent
under vacuo afforded an oily residue, which was passedthrough a short bed of silica gel to afford 1, 2-disulfides ingood to excellent yields. The products were identified on thebasis of 1H, 13C NMR spectral data, and/or by comparisonwith the data reported in the literature. NMR spectral dataand scanned copies of selected NMR spectra (1H- and 13C)are given in the Supplementary Material.
3. Results and Discussion
Preliminary studies on the influence of catalyst and/orpromoter on hydrothiolation were studied with a modelreaction of phenyl acetylene (1a) and benzenethiol in thepresence of various homogeneous and heterogeneous addi-tives/promoters under on-water conditions at room tem-perature. Screening of additives/promoters included inor-ganic salts, water-soluble organic molecules, amino acids,surfactants, or heterogeneous ion-exchange resins, and theresults are summarized in Table 1. Since the hydrothiolatedadducts are formed in varying ratios (E/Z ratios), the resultsin Table 1 have been arranged showing a gradual change inthe formation of (E)-vinyl sulfide (2b) to the (Z)-isomer (2c).The screening shows that the E/Z ratio in favor of (E)-vinylsulfide (87 : 13) is formed in the presence of NaCl (Table 1,entry 3), while the major (Z)-vinyl sulfide is obtained inthe presence of a combination of amberlite resins (Cl) andFeCl3⋅6H2O (entry 23; E/Z ratio 22 : 78). The stereochemical
outcome favouring the (E)-isomer is also seen when thereaction is carried out at higher temperature (65∘C) andcontinued for longer reaction time (10 h) (entry 11; E/Z ratio88 : 12). However, a specific observation may be noted fromthis study that the on-water additions do not give rise to theformation of any Markovnikov adduct; that is, in no case wasthe other regioisomer (2a) obtained. The NMR spectral data
Organic Chemistry International 3
Table 1: Role of additives in the addition of PhSH to phenylacetylene under on-water conditions at room temperature producing selectivelyanti-Markovnikov adductsa.
HAdditives [A]
H
HH
H
+
Water/Rt
C6H5
C6H5
C6H5
SC6H5 SC6H5
(E) (Z)
C6H5–SH
Entry Additive [A]b (E/Z) ratioc, d Entry Additive [A]b (E/Z) ratioc, d
1 Nil (neat) 83 : 17 13 CuI-Catechol violet 60 : 402 Nil (water) 80 : 20 14 Amberlite resins (Cl) 58 : 423 NaCl 87 : 13 15 n-Bu4NBr 57 : 434 Sucrose 85 : 15 16 D-Glucose 56 : 445 CF3COOH 78 : 22 17 CuI 52 : 486 BF3⋅Et2O 76 : 24 18 Cholesterol 51 : 497 Catechol violet 75 : 25 19 CTAB 49 : 518 L-Proline 70 : 30 20 FeCl3⋅6H2O 44 : 569 Glycin 69 : 31 21 Amberlyst resins (OH) 40 : 6010 Starch 64 : 36 22 D-Glucose and FeCl3⋅6H2O 35 : 6511e Water (65∘C) 88 : 12 23 Amberlite resins (Cl) and FeCl3⋅6H2O 22 : 7812 Water (65∘C) 64 : 36aReaction conditions: phenyl acetylene (0.5mmol), PhSH (0.55mmol), water (1mL), 2 h. bAdditive [A] (2mol %). cE/Z ratio was determined by 1HNMR ofthe crude mixture. dYield of the mixture of stereoisomers after chromatographic purification varies in the range 80–90%. eThe reaction was continued for 10 h;all other reactions were carried out at room temperature unless otherwise mentioned.
of the unpurified products indicated only amixture of 2b and2c, and indeed there was no trace of 2a.
At this point, effect of functional groups in the aromaticmoiety in either of the addition partners could be worthinvestigating. Since a combination of ion-exchange resinsand ferric chloride showed a better selectivity towards theformation of (Z)-vinyl sulfide, this study was performedunder similar conditions. The results are presented inTable 2. It is seen that both electron-donating and electron-withdrawing functional groups present on the aryl ring cangive rise to the anti-Markovnikov hydrothiolation productsin excellent yields (85–94%). The highest (Z)-selectivity wasfound in the reaction between phenyl acetylene and p-methoxybenzenethiol (Table 2, entry 4; E/Z 12 : 88), possiblydue to the easy emulsification of the alkyne in water uponstirring, which might be supportive, in addition to thepresence of the additive. On the other hand, presence of theelectron-withdrawing group (fluorine) on the thiol part didnot show any appreciable influence towards stereoselectiveaddition yielding the (E)-isomer in major quantity (entries6-7). It seems that there is not much electronic influence ofthe functional groups in the aryl ring of either of the additionpartners; rather their stability in water in the presence of theadditive might have some control towards anti-Markovnikovstereoselectivity.
Further studies of aryl acetylenes (terminal) withaliphatic thiols in the presence of one equivalent of D (+)-glucose showed a general trend in favour of the formationof (Z)-vinyl sulphides. For example, phenyl acetyleneor p-tolyl acetylene undergoes hydrothiolation in thepresence of n-alkyl thiols that afforded the corresponding1-alkenyl sulphides with (E/Z) ratios (14 : 86). The results aresummarized in Table 3.
Since there is significant reactivity difference betweenaliphatic and aromatic thiols [56, 57], we ought to investigatethe stereochemical outcome in two other cases: hydrothiola-tion of (i) aliphatic terminal alkynes and aliphatic thiols and(ii) aliphatic terminal alkynes and aromatic thiols. It has beenseen from previous reports that aliphatic alkynes undergodihydrothiolation yielding vicinal disulfides only irrespectiveof the nature of the thiol [45, 54]. Thus, aliphatic terminalalkynes were subjected to hydrothiolation with aromaticand aliphatic thiols under on-water conditions. Seemingly,there was an influence of additives on this double-additionreaction. The results are presented in Table 4, which showthat aliphatic terminal alkynes undergo double- additionsyielding finally 1, 2-disulfides only in the presence or absenceof D (+)-glucose.
With regard to the mechanism of hydrothiolation of ter-minal alkynes in water, the literature reports are of differentviews. For example, Bhadra and Ranu [54], in their studieson water-promoted regioselective hydrothiolation, ruled outthe likeliness of a radical pathway as the reaction proceedsin the presence of dissolved oxygen. On the other hand,Jin et al. [45], hinted that the reaction probably proceedsthrough a radical mechanism under similar conditions. Thelatter group further observed that the reaction does notoccur in the presence of galvinoxyl-free radical, althoughuse of such radical quencher does not always prove radicalmechanism [54, 55]. Our studies indeed demonstrated arole of additives in governing the stereoselectivity but thespecific function of the additive, particularly in aqueousmedium, and themechanistic routes are not clear at this time.Furthermore, carrying out the reaction in the presence ofradical initiator (AIBN) or light did not make the processfaster appreciably. Several transition metal complexes are
4 Organic Chemistry International
Table 2: Hydrothiolation of aryl thiol [B] to aryl acetylene [A] in (1.1 : 1) in water at room temperature.
H SHH
H
S
Amberlite resins (Cl)
+
[A] [B] [C]
-FeCl3/water/r.t.R1
R1
R2
R2
Entry [A] [B] Time (h) Yielda (%) [C] E/Z [C]b
1 R1 = H R2 = H 2.0 85 22 : 782 R1 = CH3 R2 = H 3.5 91 40 : 603 R1 = CH3 R1 = CH3 2.5 88 29 : 714 R1 = H R1 = OCH3 3.0 93 12 : 885 R1 = CH3 R1 = OCH3 2.0 90 22 : 786 R1 = H R2 = F 2.0 88 80 : 207 R1 = CH3 R2 = F 2.0 94 39 : 61aYield represents the product [C] after purification by column chromatography. bE/Z ratio was determined by 1HNMR of the crude mixture.
Table 3: Hydrothiolation aromatic terminal alkynes with aliphatic thiols.
HH
H
S
D (+)-glucose /water/r.t.+
[A] [B] [C]
SH
n nR1
R1
Entry [A] [B] Time (h) Yielda (%) [C] E/Z [C]b
1 R1 = H 𝑛 = 3 3.0 75 20 : 802 R1 = H 𝑛 = 5 3.0 64 14 : 863 R1 = CH3 𝑛 = 3 4.5 79 14 : 864 R1 = CH3 𝑛 = 5 5.0 51 21 : 79aYield represents the product [C] after purification by column chromatography. bE/Z ratio was determined by 1HNMR of the crude product mixture.
Table 4: Dihydrothiolation of aliphatic alkyne with thiols in water at room temperature.
Water/r.t.
[A] [C][B]
H +R1
R1R2–SH
R2S SR2
Entry [A] [B]a Time (h) Yieldb (%) [C]1c R1 = CH3-CH2-CH2 R2 = Ph 5 882 R1 = CH3-CH2-CH2 R2 = Ph 5 763 R1 = CH2OAc R2 = Ph 6 794 R1 = CH3-CH2-CH2 R2 = CH3(CH2)6 9 58a[A] : [B] is 1 : 2.2. bYield represents the product [C] after purification by column chromatography. cD (+)-Glucose (1 equiv) was added.
known to catalyze the process of hydrothiolation via radicalintermediates leading to major anti-Markovnikov 1-alkenylsulfides. In the absence of suchmetal complexes, it seems thatstabilization of the reactive species by water as well as by theadditive might govern the course of the reaction as well as thestereoselectivity.
4. Conclusions
In quest of finding “stereoselective switch” for the hydroth-iolation of terminal alkynes under on-water conditions, ourstudies apparently revealed two types of additives that could
lead to the stereoselective formation of the (Z)-1-alkenylsulfides in substantial quantities depending on the nature ofboth reacting partners. Since most of the metal-free methodsdescribe formation of the (E)-1-alkenyl sulfides in majoramount, the present findings could steer in designing mildand green reaction conditions for stereoselective preparationof (E/Z) alkenyl sulphides under on-water conditions.
Conflict of Interests
The authors declare that there is no conflict of interestsregarding the publication of this paper.
Organic Chemistry International 5
Acknowledgments
The authors are grateful to the Department of Science andTechnology, New Delhi, for financial support (Grant no.SR/S1/OC-86/2010 (G)). Samir Kundu and Debasish Sen-gupta respectively thank the UGC and CSIR, New Delhi, forawarding research fellowships.
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JOURNAL OF SULFUR CHEMISTRY, 2016http://dx.doi.org/10.1080/17415993.2016.1166225
SHORT COMMUNICATION
Cyclic ammonium salts of dithiocarbamic acid: stablealternative reagents for the synthesis of S-alkylcarbodithioates from organyl thiocyanates in water
Kinkar Biswas, Sujit Ghosh, Pranab Ghosh and Basudeb Basu
Department of Chemistry, North Bengal University, Darjeeling, India
ABSTRACTCarbodithioate esters are important functional organosulfur com-pounds widely used in diverse fields such as pharmaceuticals, agro-chemicals and material sciences. Common preparative methodsinclude reaction of alkyl halides, carbon disulfide and bases underboth metal-free and metal-catalyzed conditions. However, organylthiocyanates have not been previously explored, possibly because oftheir conversion to organyl disulfides under basic conditions. Here,we report an efficient and practical method for the preparation oflibraries of carbodithioate esters from organyl thiocyanates by react-ing with cyclic amine-based dithiocarbamic acid salts in water. Theprotocol is found to be applicable in general to various thiocyanatessuch as benzyl/aroyl methyl/cinnamyl and so on. Other notable fea-tures includenoby-products suchasdisulfides,metal- andalkali-free,aqueous conditions, and finally easy andnear-quantitative formationof cyclic amine-based dithiocarbamic acid salt as a stable alternativereagent.
ARTICLE HISTORYReceived 5 January 2016Accepted 9 March 2016
KEYWORDSAlkyl thiocyanate; aqueousmedium; carbodithioateester; cyclic sec. amine;dithiocarbamate salt
1. Introduction
S-alkyl carbodithioate esters, also known as dithiocarbamate esters, are functionalorganosulfur compounds that were first utilized as fungicides during the Second WorldWar.[1] These are also largely used as important fungicides of crops, vegetables and
CONTACT Basudeb Basu [email protected] Department of Chemistry, North Bengal University,Darjeeling, India
Supplemental data for this article can be accessed here. http://dx.doi.org/10.1080/17415993.2016.1166225
© 2016 Informa UK Limited, trading as Taylor & Francis Group
47484950515253545556575859606162636465666768697071727374757677787980818283848586878889909192
2 K. BISWAS ET AL.
NH
NHSCH3
S SNH
H3C
O S
SCH3
N N S
S NCN N
ClS
S
NMe2
Brassinin,cancer chemopreventive activity
Sulforamatecancer chemopreventive agent
RWJ-025856attenuating effects on tumor
necrosis factor a (TNFa)-induced apoptosis in murinefibrosarcoma WEHI 164 cells
990207inhibiting the tumor growth of sarcoma
180 (S180), hepatocyte carcinoma 22 (H22)
Figure 1. Examples of compounds of potential therapeutic value bearing the S-alkyl carbodithioateester function.
plants.[2–4] Many literature reports demonstrate that the S-alkyl carbodithioate estersand its derivatives exhibit antibacterial,[5–7] anthelmintic,[8] anticandidal activity andcytotoxicity,[9] antihistaminic,[10] aswell as anticancer properties.[8,11–13] They can alsobe helpful for the treatment of cardiovascular disorders and inflammatory diseases.[14]They show in vitro antitumor activity against human myelogenous leukemia K562cells,[15] and can be used as HIV-I NCp7 inhibitors,[16] or non-vanilloid TRPV1antagonists.[17] A few structures of S-alkyl carbodithioate esters with potential thera-peutic value are shown in Figure 1. Further utility of carbodithioate esters as linkersin solid-phase organic synthesis is also well documented.[18,19] In surface science andnanomaterial chemistry, carbodithioate esters arewidely used as suitable ligands for assem-bly on metal nanoparticles.[20,21] They are familiar in the rubber industry as sulfurvulcanization acceptors,[22] and radical chain transfer agents in the reversible additionfragmentation chain transfer polymerizations.[23–25] They also represent useful syntheticintermediates.[26,27] As a result, several methods for the synthesis of carbodithioate estershave been developed.[28]
Commonly, synthesis of S-alkyl/aryl carbodithioate esters is achieved by either nucle-ophilic substitution reactions under basic medium or transition metal-catalyzed cross-coupling reactions (Scheme 1). The reaction of sec. amine with carbon disulfide (CS2)produces an intermediate nucleophile that reacts with various substrates, such as alkylhalide,[29] allyl acetate,[30] epoxide,[31] tosyl hydrazone [32]and α,β-unsaturated car-bonyl compounds,[33–35] in one-pot metal-free or under metal-catalyzed reaction con-ditions to afford the corresponding carbodithioate esters (Scheme 1). Anilines can also beused for the preparation of carbodithioate esters bearing sec. NH group in the presence ofDMSO and a strong base such as NaOH.[36] Most of the procedures involve harsh reac-Q1tion conditions, long reaction time, hazardous organic solvents, metal catalyzts and bases.Organyl thiocyanates, often considered as psuedohalides and are easily available, were not
93949596979899100101102103104105106107108109110111112113114115116117118119120121122123124125126127128129130131132133134135136137138
JOURNAL OF SULFUR CHEMISTRY 3
Xia et al.Tetrahedron, 2009
Alkaline Al2O330 h
OPhO
Azizi et al.RSC Adv., 2012
PEG, RT, 1 h
R1R2NH
+ CS2
R3-X
RT, 3-12 h, neat
Saidi et al.Org. Lett., 2006
Cinnamyl / Allyl acetate
Ranu et al.RSC Adv., 2012
Ru(II) Catalyst, 100 oC, water
Base, dioxane110 ºC, 4 h
Sha et al.Org. Biomol. Chem., 2013
''Our protocol''
R-SCN
(X = Cl, Br, I)
Ref. 29
Ref. 31
Ref. 30
Ref. 32
Ref. 34
S-Alkyl carbodithioate
O
OMe
RS
S
N
+
XN
H
HX
NS
S
n nSDS/H2O
RT
n = 1,2X = O, CH2
NNHTs
R'R
Scheme 1. Methods for the synthesis of S-alkyl carbodithioate esters.
used as the starting materials, presumably because of the fact that the thiocyanate mayundergo disulfide (–S–S–) bond formation under basic medium.[37,38]
We found that the reaction of a sec. amine with CS2 produces a stable salt, which canbe isolated easily in almost quantitative yield and stored for several weeks in the air. Thesalt can efficiently react with alkyl/aroyl methyl/cinnamyl thiocyanates in water mediumat room temperature to afford corresponding carbodithioate esters in the presence of thecationic phase transfer agent (sodiumdodecyl sulfate (SDS)) in excellent yieldswithout for-mation of other by-products such as organyl disulfide. We report herein an efficient, base-and metal-free protocol for the synthesis of various S-substituted carbodithioate esters byusing variety of cyclic sec. amine-based dithiocarbamate salts from diverse organyl thio-cyanates. While organyl thiocyantes have not been used previously as the precursor forpreparation of carbodithioate esters, other notable advantages of this protocol are metal-and alkali-free conditions, which possibly lead to the avoidance of disulfide bond forma-tion and clean reactions affording excellent yields, and can be carried out in water mediumat room temperature (Scheme 1).
2. Results and discussion
As a part of preliminary study, as presented in Table 1, we have conducted the reactionof a neat mixture of benzyl thiocyanate, CS2 and morpholine in a one-pot manner, whichled to the pure desired benzyl morpholine-4-carbodithioate ester 4a in 72% isolated yield(Table 1, entry 1). The reaction showed partial formation of dibenzyl disulfide on TLC Q2monitoring of the experiment, although it was not isolated in appreciable quantity aftercolumn chromatography. Considering that the intermediate salt derived from the amineand CS2 could be the actual nucleophile, the sodium salt of morpholinodithioformate 2awas used to react with benzyl thiocyanate 3a (Table 1, entry 2). However, we obtained thedesired carbodithioate ester 4a again with the formation of dibenzyl disulfide, presumablyattributable to the basic reaction medium that facilitates disulfide formation from benzyl
139140141142143144145146147148149150151152153154155156157158159160161162163164165166167168169170171172173174175176177178179180181182183184
4 K. BISWAS ET AL.
Table 1. Optimization of the reaction conditions for the conversion of benzyl thiocyanate to S-alkylcabodithioates.
SCN
NOH
HN O
S
S
S
S
N
O
3a
2b
4a
SolventTemperature,
Additive
N OS
S
2aNa
or +
Entry Solvent T (°C) Additive Time (h) Yielda (%)
1b Neat RT No 1 722c Water RT No 1 60d
3e Water RT No 1 764 Water 60 No 1 785 EtOH 60 No 1 826 Water: EtOH RT No 1 807f Water RT TBAB 1 848g Water RT SDS 1 969h Water RT SDS 1 96aYield represents pure isolated product after purification by column chromatography.bMixture of benzyl thiocyanate (1mmol), morpholine (2mmol) and CS2 (1mmol) in 2mL solvent was stirred at roomtemperature.
cSalt 2awas used.d20% dibenzyl disulphide was isolated.eSalt 2bwas used.fTetrabutyl ammonium bromide (TBAB; stoichiometric) was used.gSodium dodecyl sulfate (SDS; stoichiometric) was used.hSDS (10mol%) was used.
thiocyanate 3a.[37,38] In order to avoid the basic reactionmedium, we considered that thedithiocarbamate salt consisting of both organyl cationic and anionic part might be a betteralternative and accordingly, we prepared the salt 2b from amixture of morpholine and CS2in diethyl ether following the reported procedure.[39]
The salt 2b contains themorpholino-based cationic and anionic part and stirring amix-ture of benzyl thiocyanate 3a and 2b (in equimolar quantity) in water at room temperaturegave rise to a clean reaction without any trace of disulfide formation, producing 4a in 76%isolated yield (Table 1, entry 3). Heating the reaction mixture of 2b and 3a in water orethanol at 60°C resulted in a better yield of 4a (78–82%; Table 1, entries 4 and 5). On theother hand, use of water–ethanol (1:1) as the solvent and conducting the reaction at roomtemperature gave 4a in 80% yield (Table 1, entry 6).
It is likely that organyl thiocyanates are poorly soluble in water, and we employed twodifferent phase transfer agents, n-tetrabutyl ammonium bromide (TBAB) and SDS. Whilethe use of TBAB was found to lead to a marginal increase in the yield of 4a (Table 1, entry7), the presence of SDS (either in stoichiometric or in 10mol%) afforded 4a in excellentyield (96%) (Table 1, entries 8 and 9). Thus, excellent conversion of benzyl thiocyanate tobenzyl morpholine-4-carbodithioate ester 4a is indeed possible if we use separately pre-pared amine-based salt, and perform the reaction under conditions as described in entry9 of Table 1. In aqueous medium reactions, anionic phase transfer agents as additive areusually more effective than cationic agents.[40] Here, we used both TBAB (cationic) and
185186187188189190191192193194195196197198199200201202203204205206207208209210211212213214215216217218219220221222223224225226227228229230
JOURNAL OF SULFUR CHEMISTRY 5
NOH
HN O
S
SN
H
HN
S
S
NS
SN
H
HN N
S
SS
SN NH
H
HNHN
H
H
2c2b
e22d
(Morpholiniummorpholinodithioformate)
(Piperidiniumpiperidinodithioformate)
(Pyrrolidiniumpyrrolidinodithioformate)
Bis(piperazinium)piperazine-1,4-dicarbodithioate
XN
H
HX
NS
S
n = 2, X = O (2b)n = 2, X = CH2 (2c)n = 1, X = CH2(2d)
XNH
n
CS2 in diethyl ether
Stir at RTn n
simple preparationcrystalline solideasy separationstored for longer time under air
1
2b-2d
XN
H
Hn 2
N NS
SS
S
n = 2, X = NH (2e)
N OS
S
2a
Na
(Sodiummorpholinodithioformate)
Na
NaOH, CS2
or
EtOH:H2O (1:1)Stir at 0-5 ºC
XN
S
S
n
n = 2, X = O (2a)
Scheme 2. Synthesis of sec. cyclic aliphatic amine-based dithiocarbamate salts (2b–2e).
SDS (anionic) additives and the results are in conformity with previous reports. The bet-ter functioning of the anionic phase transfer agents such as SDS might be explained in thelight of considering the whole system as a microreactor, where organyl thiocyanate havingresided in the hydrophobic dodecyl core may come in contact with the reactant (here thedithocarbamate salt) being present in water through the formation of hydrogen bond withanionic sulfate ion.
Encouraged by this observation, we wanted to develop a general and practical proce-dure for the conversion of organyl thiocyanates into carbodithioate esters. We preparedother dithiocarbamate salts (2c–2e) from three different cyclic sec. amines such as piperi-dine, pyrrolidine and piperazine (Scheme 2), and employed our optimized conditions (asin Table 1, entry 9) for reaction with various functionalized organyl thiocyanates. Theresults are presented in Table 2. It is clearly evident that different chloro-substituted ben-zyl thiocyanates and naphthyl methyl thiocyanate underwent smooth conversion to thecorresponding carbodithioate esters with all types of dithiocarbamate salts (4a–4m ofTable 2).While 2- and 4-chloro benzyl thiocyanates worked equally efficiently without anysteric encumbrance, the piperazine-based dithiocarbamate salt 2e reacted with benzyl or2-chlorobenzyl thiocyanates to produce bis-carbodithioate esters in 82–83% yields within3 h (4l and 4m).
231232233234235236237238239240241242243244245246247248249250251252253254255256257258259260261262263264265266267268269270271272273274275276
6 K. BISWAS ET AL.
Table 2. Synthesis of diverse S-alkyl carbodithioates from organyl thiocyanates and dithiocarbamatesalts.a,b
XN
H
HX
NS
S
n n
XN
H
Hn 2
N NS
SS
S
or +SCN
R
S N
S
Xn
RSDS (10 mol%)
Water, RT
3
4l, 4m
N NS
SS
S
orR
R
2b, X = O, n = 22c, X = CH2, n = 22d, X = CH2, n = 12e, X = NH, n = 2
R = H, 2-Cl, 4-Cl
4a-4k
Entry R1−SCN (3) Salt (2) Time (h) T (°C) Product (4) Yield (%)
SCN S N
S
O
1 2b 1.0 RT 96
SCN
Cl
S N
S
OCl
2 2b 1.0 RT 98
SCN
Cl
S N
S
OCl
3 2b 1.0 RT 97
SCN S N
S
O
4 2b 1.5 RT 87
SCN S N
S5 2c 1.0 RT 95
SCN
Cl
S N
S
Cl
6 2c 1.0 RT 98
SCN S N
S7 2c 1.5 RT 89
(continued).
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JOURNAL OF SULFUR CHEMISTRY 7
Table 2. Continued.
Entry R1−SCN (3) Salt (2) Time (h) T (°C) Product (4) Yield (%)
SCN
Cl
S N
S
Cl
8 2c 1.0 RT 97
SCN S N
S9 2d 2.0 RT 94
SCN
Cl
S N
S
Cl
10 2d 2.5 RT 96
SCN S N
S11 2d 2.5 RT 86
SCN
N NS
SS
S
12 2e 3.0 RT 82
SCN
Cl
N NS
SS
SCl
C
13 2e 3.0 RT 83
aA mixture of 2 (1.0mmol), 3 (1.0mmol), SDS (10mol%) in water (2mL) was stirred at RT in open air. For 4l and 4m,compound 3 (2mmol) was used.
bYield represents pure product isolated by column chromatography.
To broaden the scope of the reaction further, alkyl thiocyanates bearing β-carbonylfunction (e.g. aroylmethyl, 5) or β-alkenyl function (e.g. styrenylmethyl, 6) were subjectedto similar reaction conditions. Corresponding functionalized organic carbodithioate estersbearing carbonyl or styrenyl methyl group could be easily synthesized in aqueous mediumat ambient temperature. Three different sec. amine-based dithiocarbamate salts (2b–2d)were used and corresponding carbodithioates bearing Cl, Br or NO2 groups attached withthe aromatic ring (7a–7e, 8a and 8b) were obtained in high yields (Table 3). All the com-pounds were characterized by spectral data and compared with melting points whereverknown and reported.
323324325326327328329330331332333334335336337338339340341342343344345346347348349350351352353354355356357358359360361362363364365366367368
8 K. BISWAS ET AL.
Table 3. Synthesis of functionalized S-alkyl carbodithioates.a,b
XN
H
HX
NS
S
n n +
R/R/
SDS (10 mol%)
Water, RT
6
7a-7e
or
SCN
SCN
O
Ph
OS
S
N X
n
or
SPh
S
N
Xn
5R/ = 4-Cl, 4-Br, 3-NO2
2b, X = O, n = 22c, X = CH2, n = 22d, X = CH2, n = 1 8a, 8b
Entry R2−SCN (5 and 6) Salt (2) Time (h) T (°C) Product (7 and 8) Yield (%)
Br
O
SCN
Br
O
S
S
N
O1 2b 3.0 RT 95
Br
O
SCN
Br
O
S
S
N
2 2c 3.0 RT 94
Cl
O
SCN
Cl
O
S
S
N
3 2c 4.0 RT 95
O
SCN
NO2
O
S
S
N
NO2
4 2c 3.5 RT 86
Cl
O
SCN
Cl
O
S
S
N
5 2d 3.0 RT 96
SCN S
S
N
O
6 2b 1.5 RT 92
SCN S
S
N
7 2c 1.5 RT 93
aA mixture of 2 (1.0mmol), 5 or 6 (1.0mmol), SDS (10mol%) in water (2mL) was stirred at RT in open air.bYield represents pure product isolated by column chromatography.
369370371372373374375376377378379380381382383384385386387388389390391392393394395396397398399400401402403404405406407408409410411412413414
JOURNAL OF SULFUR CHEMISTRY 9
+
SDS/H2OR S
S
N
2
R SS R
3
NH
H
N
S
S
R
S
C
N
+ Not formedthrough
homolytic fissionof –bond of
alkyl thiocyanate
4 SCNFeCl3 solutiongives blood red
colouration
NH
HRT
Scheme 3. Proposed reaction mechanism.
3. Mechanism
The reaction presumably occurs via a simple nucleophilic substitution reaction. Organylthiocyanates are considered as psuedohalides that might not produce the correspondingcarbocation easily and hence the reaction is expected to proceed via the SN2 pathway Q3(Scheme 3). The dithiocarbamate salt consisting of both organyl cationic and anionic sys-tem seems to render better results than using an in situmixture of sec. amine andCS2 or thecorresponding sodium salt. Use of additives such as SDS likely help the organic reactantsbecome more homogeneous affording excellent conversions. The possibility of the forma-tion of thiyl radical via β-bond cleavage of the alkyl thiocyanate can be excluded sincethe reaction conditions do not support radical formation nor is the corresponding disul-fide formed in the reaction.[41,42] On the other hand, aqueous ferric chloride solutionproduces blood-red coloration indicating elimination of the thiocyanate anion.
4. Conclusion
In conclusion, we have shown that easily accessible and air-stable cyclic sec. amine-baseddithiocarbamate salts can serve as efficient reagents for the preparation of a large varietyof S-substituted carbodithioate esters from rarely used organyl thiocyanates as a commonstrategy. The use of this type of salt not only shows superior activity to the existing one-potthree-component procedure but also establishes it as alternative reagent, obtained easily inquantitative conversion, for the preparation of carbodithioate esters. The simple procedurecan be carried out at room temperature, in water medium and affords excellent yields.Further applications of these easily accessible salts are currently under active pursuit fromthis laboratory. This method also establishes that the sec. amine-based dithiocarbamatesalts can serve as a stable more reactive alternative than in situ use of volatile CS2 and sec.amine reagent, not only for this reaction, but also for other purposes, which are currentlybeing pursued in this laboratory.
5. Experimental
5.1. General information
Morpholine, piperidine and pyrrolidine were purchased from Lancaster and used afterdistillation. Piperazine was purchased from Loba Chemie. CS2 and SDS were purchasedfrom SDFCL and used directly. Benzyl, naphthyl methyl, cinnamyl and aroyl methyl thio- Q4cyanates were prepared from reported procedure and purified by column chromatographybefore use.Melting point of the solid compounds was determined in a concentratedH2SO4
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10 K. BISWAS ET AL.
bath. FT-IR spectra were recorded with a FT-IR-8300 SHIMADZU spectrophotometerQ5using a KBr pellet method for solid compounds and in neat for liquid compounds. NMRQ6spectra were taken in CDCl3 using a Bruker AV-300 spectrometer operating for 1H at300MHz and for 13C at 75MHz.
5.2. General procedure for the synthesis cyclic ammonium salts of dithiocarbamicacid (2b–2e) [39]
A solution of CS2 (5mmol) in diethyl ether (5mL) was slowly added to a solution ofmorpholine (10mmol) or piperidine (10mmol) or pyrrolidine (10mmol) in diethyl ether(5mL). The reactionmixtures were stirred for 30min at room temperature. Solid salts wereprecipitated during this time and were filtered off through a Buchner funnel, washed withdiethyl ether and dried under vacuum to obtain the desired salts 2b–2d. In the case of2e, a solution of CS2 (6mmol) in diethyl ether (5mL) was slowly added to a solution ofpiperazine (9mmol) in diethyl ether (6mL). The reaction mixture was stirred for 45minat room temperature. The grey solids were filtered off, washed with diethyl ether and driedunder vacuum to obtain the desired salt 2e.
5.2.1. Morpholiniummorpholinodithioformate (salt 2b) [39]White solid; yield: 1.23 g (98%); Mp: 197–200°C, Lit. Mp 195–197°C.[39] IR (KBr):Q7νmax = 2854, 2711, 2475, 1583, 1420, 1255, 1215, 1112, 978, 876 cm−1.
5.2.2. Piperidinium piperidinodithioformate (salt 2c) [39]White solid; yield: 1.20 g (98%); Mp: 164–166°C, Lit. Mp 160°C.[39] IR (KBr):νmax = 2936, 2843, 2731, 2497, 1583, 1409, 1215, 1122, 958 cm−1.
5.2.3. Pyrrolidinium pyrrolidinodithioformate (salt 2d)Off-white solid; yield: 1.05 g (96%); Mp: 149–151°C. IR (KBr): νmax = 2946, 2864, 2516,2393, 1390, 1318, 1164, 999, 938 cm−1.
5.2.4. Bis(piperazinium)piperazine-1,4-dicarbodithioate (salt 2e)Grey solid; yield: 1.19 g (97%); Mp: 238–242°C. IR (KBr): νmax = 3162, 2915, 2434, 2331,1634, 1390, 1225, 1123, 958, 855 cm−1.
5.3. General procedure for the synthesis of S-alkyl carbodithioate esters
A mixture of organyl thiocyanate (1mmol), dithiocarbamate salt (1mmol) and SDS(0.1mmol) in water (2mL) was stirred vigorously using a magnetic bar at room tempera-ture. The progress of the reaction wasmonitored by TLC. After the reaction was continuedfor specified time, as mentioned in Tables 2 and 3, the reaction mixture was extractedwith ethyl acetate (3× 5mL) and the combined organic extracts were collected over anhy-drous Na2SO4. Evaporation of the volatiles afforded the crude product, which was furtherpurified by column chromatography over silica gel. Elution with a mixture of EtOAc−PEQ8furnished the desired product. Yields of the products are shown in Tables 2 and 3.
All the products were identified and characterized by spectral data (FT-IR, 1H and 13CNMR), by melting point for solid compounds (compared wherever known).
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JOURNAL OF SULFUR CHEMISTRY 11
5.3.1. Benzyl morpholine-4-carbodithioate (Table 2, 4a) [32]Light yellow solid; yield: 0.243 g (96%); Mp: 64–65°C, Lit. Mp 59–60°C.[32] IR (KBr):νmax = 3038, 2976, 2869, 1920, 1635, 1617, 1559, 1489, 1456, 1304, 1271, 1235, 924, 825,725, 543 cm−1. 1H NMR (CDCl3, 300MHz): δ 3.73 (s, 4H, 2×OCH2), 4.01–4.33 (m, 4H,2×NCH2), 4.57 (s, 2H, SCH2), 7.22–7.39 (m, 5H). 13C NMR (CDCl3, 75MHz): δ 42.02(SCH2), 50.81 (NCH2), 66.27 (OCH2), 127.65, 128.67, 129.42, 135.78, 197.11 (C=S).
5.3.2. 2-Chlorobenzyl morpholine-4-carbodithioate (Table 2, 4b)White crystalline solid; yield: 0.281 g (98%); Mp: 94–96°C. IR (KBr): νmax = 3053, 2992,2931, 2855, 1918, 1654, 1635, 1617, 1542, 1444, 1347, 1310, 1271, 1053, 1028, 868,731, 582 cm−1. 1H NMR (CDCl3, 300MHz): δ 3.77 (s, 4H, 2×OCH2), 4.17 (s, br, 4H,2×NCH2), 4.76 (s, 2H, SCH2), 7.21–7.64 (m, 4H). 13C NMR (CDCl3, 75MHz): δ 39.48(SCH2), 50.91 (NCH2), 66.25 (OCH2), 126.98, 129.10, 129.61, 131.56, 134.12, 134.58,196.91 (C=S).
5.3.3. 4-Chlorobenzyl morpholine-4-carbodithioate (Table 2, 4c)White solid; yield: 0.278 g (97%); Mp: 79–81°C. IR (KBr): νmax = 3007, 2977, 2916, 2870,1833, 1656, 1620, 1542, 1423, 1268, 1217, 1034, 998, 837, 643 cm−1. 1H NMR (CDCl3,300MHz): δ 3.66 (s, 4H, 2×OCH2), 3.90 (s, 2H, NCH2), 4.17 (s, 2H, NCH2), 4.47 (s, 2H,SCH2), 7.17–7.25 (m, 4H). 13C NMR (CDCl3, 75MHz): δ 40.83 (SCH2), 50.83 (NCH2),66.10 (OCH2), 128.60, 130.57, 133.26, 134.59, 196.50 (C=S).
5.3.4. (Naphthalen-1-yl) methyl morpholine-4-carbodithioate (Table 2, 4d)Light brown solid; yield: 0.263 g (87%); Mp: 115–117°C. IR (KBr): νmax = 3053, 2976,2900, 2869, 1699, 1578, 1538, 1420, 1356, 1301, 1271, 1189, 998, 786, 630 cm−1. 1H NMR(CDCl3, 300MHz): δ 3.66 (s, 4H, 2×OCH2), 3.91–4.06 (m, 4H, 2×NCH2), 4.95 (s, 2H,SCH2), 7.31–7.52 (m, 4H), 7.71–7.98 (m, 2H), 8.00–8.01 (m, 1H). 13C NMR (CDCl3,75MHz): δ 40.34 (SCH2), 50.47 (NCH2), 66.23 (OCH2), 123.93, 125.46, 126.01, 126.50,128.34, 128.80, 128.83, 131.06, 131.84, 133.90, 197.25 (C=S).
5.3.5. Benzyl piperidine-1-carbodithioate (Table 2, 4e) [43]Pale yellow viscous liquid; yield: 0.238 g (95%). IR (neat): νmax = 3040, 2974, 2864, 1945,1620, 1590, 1545, 1495, 1358, 1340, 1291, 1279, 1222, 1016, 980, 840, 742 cm−1. 1HNMR (CDCl3, 300MHz): δ 1.62 (s, 6H, NCH2(CH2)3), 3.80 (s, br, 2H, NCH2), 4.21 (s,br, 2H, NCH2), 4.49 (s, 2H, SCH2), 7.15–7.33 (m, 5H). 13C NMR (CDCl3, 75MHz): δ
24.29 (NCH2CH2CH2), 25.79 (NCH2CH2), 42.25 (SCH2), 52.67 (NCH2), 127.45, 128.56,129.38, 136.12, 195.31 (C=S).
5.3.6. 2-Chlorobbenzyl piperidine-1-carbodithioate (Table 2, 4f)Yellow viscous liquid; yield: 0.280 g (98%). IR (neat): νmax = 3010, 2970, 2860, 1996, 1580,1546, 1493, 1357, 1340, 1280, 1224, 1074, 946, 840, 746, 650 cm−1. 1H NMR (CDCl3,300MHz): δ 1.69 (s, 6H, NCH2(CH2)3), 3.87 (s, br, 2H, NCH2), 4.29 (s, br, 2H, NCH2),4.72 (s, 2H, SCH2), 7.18–7.23 (m, 2H), 7.34–7.38 (m, 1H), 7.54–7.58 (m, 1H). 13C NMR(CDCl3, 75MHz): δ 24.29 (NCH2CH2CH2), 25.62 (NCH2CH2), 39.66 (SCH2), 51.42(NCH2), 53.10 (NCH2), 126.96, 128.95, 129.55, 131.56, 134.45, 134.54, 194.91 (C=S).
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12 K. BISWAS ET AL.
5.3.7. (Naphthalen-1-yl) methyl piperidine-1-carbodithioate (Table 2, 4g)White solid; yield: 0.268 g (89%); Mp: 93–95°C. IR (KBr): νmax = 3038, 2947, 2870, 1620,1596, 1563, 1542, 1474, 1435, 1399, 1365, 1281, 1235, 1210, 1113, 980, 870, 776, 670,588 cm−1. 1H NMR (CDCl3, 300MHz): δ 1.63 (s, 6H, NCH2(CH2)3), 3.75 (s, br, 2H,NCH2), 4.27 (s, br, 2H, NCH2), 4.93 (s, 2H, SCH2), 7.31–7.58 (m, 4H), 7.71–7.85 (m,2H), 8.0–8.01 (m, 1H). 13C NMR (CDCl3, 75MHz): δ 24.29 (NCH2CH2CH2), 25.90(NCH2CH2), 40.56 (SCH2), 52.83 (NCH2), 124.11, 125.49, 125.96, 126.43, 128.30, 128.66,128.78, 131.42, 131.90, 133.88, 195.26 (C=S).
5.3.8. 4-Chlorobenzyl piperidine-1-carbodithioate (Table 2, 4h)White solid; yield: 0.277 g (97%); Mp: 83–85°C. IR (KBr): νmax = 3007, 1961, 2855, 1632,1617, 1577, 1542, 1508, 1481, 1429, 1378, 1281, 1225, 1110, 1080, 974, 843, 746, 652 cm−1.1H NMR (CDCl3, 300MHz): δ 1.62 (s, 6H, NCH2(CH2)3), 3.79 (s, br, 2H, NCH2), 4.22(s, br, 2H, NCH2), 4.44 (s, 2H, SCH2), 7.15–7.27 (m, 4H). 13C NMR (CDCl3, 75MHz): δ24.27 (NCH2CH2CH2), 25.54 (NCH2CH2), 41.20 (SCH2), 53.08 (NCH2), 128.67, 130.70,133.21, 135.04, 194.70 (C=S).
5.3.9. Benzyl pyrrolidine-1-carbodithioate (Table 2, 4i) [43]Yellow liquid; yield: 0.223 g (94%). IR (neat): νmax = 3048, 2970, 2865, 1903, 1590, 1440,1365, 1308, 1216, 1070, 1012, 944, 826, 780, 503 cm−1. 1H NMR (CDCl3, 300MHz): δ
1.92−2.10 (m, 4H, NCH2(CH2)2), 3.62 (t, J = 6.3Hz, 2H, NCH2), 3.93 (t, J = 6.9Hz,2H, NCH2), 4.58 (s, 2H, SCH2), 7.22–7.33 (m, 3H), 7.38–7.41 (m, 2H). 13C NMR (CDCl3,75MHz): 24.29 (NCH2CH2), 26.08 (NCH2CH2), 41.30 (SCH2), 50.52 (NCH2), 55.03(NCH2), 127.39, 128.56, 129.27, 136.55, 192.46 (C=S).
5.3.10. 4-Chloro benzyl pyrrolidine-1-carbodithioate (Table 2, 4j)Pale yellow solid; yield: 0.261 g (96%); Mp: 60–62°C. IR (KBr): νmax = 2966, 2864, 1903,1595, 1441, 1328, 1092, 1009, 948, 825, 744, 507 cm−1. 1H NMR (CDCl3, 300MHz): δ
1.92−2.10 (m, 4H, NCH2(CH2)2), 3.62 (t, J = 6.3Hz, 2H, NCH2), 3.93 (t, J = 6.9Hz,2H, NCH2), 7.24–7.27 (m, 2H), 7.32–7.35 (m, 2H). 13C NMR (CDCl3, 75MHz): 24.25(NCH2CH2), 26.05(NCH2CH2), 40.21 (SCH2), 50.56 (NCH2), 55.15 (NCH2), 128.61,130.56, 133.10, 135.42, 191.81 (C=S).
5.3.11. (Naphthalen-1-yl) methyl pyrrolidine-1-carbodithioate (Table 2, 4k)White solid; yield: 0.247 g (86%); Mp: 116–118°C. IR (KBr): νmax = 3040, 2950, 2880,1542, 1450, 1400, 1364, 1342, 1280, 1210, 1134, 1072, 980, 808, 770, 672, 540 cm−1. 1HNMR (CDCl3, 300MHz): δ 1.87–1.97 (m, 4H, NCH2(CH2)2), 3.51 (t, J = 6.9Hz, 2H,NCH2), 3.94 (t, J = 6.6Hz, 2H, NCH2), 5.01 (s, 2H, SCH2), 7.34–7.40 (m, 1H), 7.43–7.54(m, 2H), 7.58 (d, J = 6.9Hz, 1H), 7.76 (d, J = 8.1Hz, 1H), 7.81–7.84 (m, 1H), 8.08 (d,J = 8.1Hz, 1H). 13C NMR (CDCl3, 75MHz): δ 24.29 (NCH2CH2), 26.06 (NCH2CH2),39.64 (SCH2), 50.51 (NCH2), 55.02 (NCH2), 124.08, 125.50, 125.98, 126.44, 128.17, 128.61,128.81, 131.77, 131.85, 133.92, 192.33 (C=S).
5.3.12. Dibenzyl piperazine-1,4-dicarbodithioate (Table 2, 4l) [44]White solid; yield: 0.343 g (82%); Mp: 124–126°C, Lit. Mp 122–123°C.[45] IR (KBr):Q9νmax = 3068, 3038, 2931, 1538, 1505, 1474, 1435, 1413, 1277, 1210, 1159, 1043, 924,
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JOURNAL OF SULFUR CHEMISTRY 13
849, 694 cm−1. 1H NMR (CDCl3, 300MHz): δ 4.18 (s, br, 8H, 4×NCH2), 4.51 (s, 4H,2× SCH2), 7.19–7.32 (m, 10H). 13C NMR (CDCl3, 75MHz): δ 42.16 (SCH2), 48.71(NCH2), 127.74, 128.69, 129.39, 135.51, 197.53 (C=S).
5.3.13. Bis-(2-chlorobenzyl) piperazine-1,4-dicarbodithioate (Table 2, 4m)Grey solid; yield: 0.404 g (83%); Mp: 148–150°C. IR (KBr): νmax = 2916, 1640, 1420, 1276,1041, 990, 928, 846, 744 cm−1. 1H NMR (CDCl3, 300MHz): δ 4.28 (s, br, 8H, 4×NCH2),4.72 (s, 4H, 2× SCH2), 7.18–7.26 (m, 4H), 7.35–7.39 (m, 2H), 7.53–7.56 (m, 2H). 13CNMR (CDCl3, 75MHz): δ 39.64 (SCH2), 48.99 (NCH2), 126.98, 129.21, 129.63, 131.54,133.81, 134.56, 197.19 (C=S).
5.3.14. 4-Bromo phenacyl morpholine-4-carbodithioate (Table 3, 7a)White solid; yield: 0.342 g (95%); Mp: 164–166°C. IR (KBr): νmax = 2967, 2906, 2855,1686, 1583, 1430, 1276, 1125, 1112, 990, 816, 539 cm−1. 1H NMR (CDCl3, 300MHz): δ3.71 (t, J = 4.8Hz, 4H, 2×OCH2), 3.97 (s, br, 2H, NCH2), 4.2 (s, br, 2H, NCH2), 4.77 (s,2H, SCH2), 7.54–7.59 (m, 2H), 7.84–7.88 (m, 2H).13C NMR (CDCl3, 75MHz): δ 44.28(SCH2), 51.55 (NCH2), 66.21 (OCH2), 128.85, 130.06, 132.08, 134.88, 192.28 (C=O),195.65 (C=S).
5.3.15. 4-Bromo phenacyl piperidine-1-carbodithioate (Table 3, 7b)White solid; yield: 0.336 g (94%); Mp: 116–118°C. IR (KBr): νmax = 3007, 2947, 2869,1687, 1584, 1438, 1362, 1286, 1253, 973, 858, 666 cm−1. 1H NMR (CDCl3, 300MHz):δ 1.65 (s, 6H, NCH2(CH2)3), 3.89 (s, br, 2H, NCH2), 4.18 (s, br, 2H, NCH2), 4.77 (s,2H, SCH2), 7.54–7.57 (m, 2H), 7.86–7.89 (m, 2H). 13C NMR (CDCl3, 75MHz): δ 24.16(NCH2CH2CH2), 25.95 (NCH2CH2), 44.50 (SCH2), 51.76 (NCH2), 53.66 (NCH2), 128.62,130.09, 131.99, 135.04, 192.71 (C=O), 193.70 (C=S).
5.3.16. 4-Chloro phenacyl piperidine-1-carbodithioate (Table 3, 7c)Yellowish white solid; yield: 0.298 g (95%); Mp: 110–112°C. IR (KBr): νmax = 3007, 2961,2855, 1690, 1587, 1438, 1347, 1244, 1113, 971, 858, 682, 548 cm−1. 1H NMR (CDCl3,300MHz): δ 1.65 (s, 6H,NCH2(CH2)3), 3.89 (s, br, 2H,NCH2), 4.19 (s, br, 2H,NCH2), 4.77(s, 2H, SCH2), 7.54–7.58 (m, 2H), 7.85–7.90 (m, 2H). 13C NMR (CDCl3, 75MHz): δ 24.18(NCH2CH2CH2), 25.42 (NCH2CH2), 26.09 (NCH2CH2), 44.49 (SCH2), 51.78 (NCH2),53.72 (NCH2), 128.67, 130.11, 132.01, 135.00, 192.75 (C=O), 193.63 (C=S).
5.3.17. 3-Nitro phenacyl piperidine-1-carbodithioate (Table 3, 7d)Pale yellow solid; yield: 0.279 g (86%);Mp: 109–111°C. IR (KBr): νmax = 2926, 2854, 1697,1613, 1532, 1430, 1337, 1204, 1112, 1072, 979, 804, 733, 672 cm−1. 1H NMR (CDCl3,300MHz): δ 1.73 (s, 6H, NCH2(CH2)3), 3.97 (s, br, 2H, NCH2), 4.25 (s, br, 2H, NCH2),4.86 (s, 2H, SCH2), 7.69–7.74 (m, 1H), 8.40–8.46 (m, 2H), 8.90–8.91 (m, 1H). 13C NMR(CDCl3, 75MHz): δ 24.16 (NCH2CH2CH2), 26.02 (NCH2CH2), 44.09 (SCH2), 52.09(NCH2), 53.79 (NCH2), 123.45, 127.49, 129.95, 134.13, 137.87, 148.58, 191.84 (C=O),193.39 (C=S).
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14 K. BISWAS ET AL.
5.3.18. 4-Chloro phenacyl pyrrolidine-1-carbodithioate (Table 3, 7e)Pale yellow solid; yield: 0.287 g (96%);Mp: 102–104°C. IR (KBr): νmax = 2957, 2876, 1676,1583, 1430, 1286, 1184, 1080, 990, 958, 825, 528 cm−1. 1H NMR (CDCl3, 300MHz): δ
1.94–2.03 (m, 2H, NCH2CH2), 2.06–2.14 (m, 2H, NCH2CH2), 3.74 (t, J = 6.9Hz, 2H,NCH2), 3.9 (t, J = 6.9Hz, 2H, NCH2), 4.85 (s, 2H, SCH2), 7.44–7.47 (m, 2H), 8.01–8.04(m, 2H). 13C NMR (CDCl3, 75MHz): δ 24.33 (NCH2CH2), 26.12 (NCH2CH2), 44.04(SCH2), 50.80 (NCH2), 55.53 (NCH2), 128.99, 130.01, 134.43, 139.88, 190.68 (C=O),192.43 (C=S).
5.3.19. (E)-Cinnamylmorpholine-4-carbodithioate, (Table 3, 8a) [30]White crystalline solid, yield: 0.257 g (92%); Mp: 80–82°C (Lit. reported as yellowish vis-cous liquid). IR (KBr): νmax = 3038, 2961, 2869, 1720, 1620, 1577, 1469, 1304, 1268,1220, 1113, 992, 755 cm−1. 1H NMR (CDCl3, 300MHz): δ 3.78 (t, J = 4.5Hz, 4H,2×OCH2), 4.17–4.24 (m, 6H, 2×NCH2, SCH2), 6.28–6.38 (m, 1H, PhCH=CHCH2),6.67 (d, J = 15.6Hz, 1H, PhCH), 7.23–7.41 (m, 5H). 13C NMR (CDCl3, 75MHz): δ 39.97(SCH2), 50.90 (NCH2), 66.26 (OCH2), 123.68, 126.45, 127.76, 128.56, 133.95, 136.60,197.03 (C=S).
5.3.20. (E)-Cinnamyl piperidine-1-carbodithioate (Table 3, 8b) [30]White crystalline solid; yield: 0.258 g (93%); Mp: 73–75°C (Lit. reported as yellowish vis-cous liquid). IR (KBr): νmax = 3048, 2947, 2869, 1617, 1566, 1472, 1435, 1265, 1235, 1135,1116, 1110, 973, 743 cm−1. 1H NMR (CDCl3, 300MHz): δ 1.63 (s, 6H, NCH2(CH2)3),3.82 (s, br, 2H, NCH2), 4.01–4.13 (m, 2H, SCH2), 4.23 (s, br, 2H, NCH2), 6.20–6.31(m, 1H, PhCH=CHCH2), 6.56 (d, J = 15.9Hz, 1H, PhCH), 7.12–7.31 (m, 5H). 13CNMR (CDCl3, 75MHz): 24.32 (NCH2CH2CH2), 26.00 (NCH2CH2), 40.23 (SCH2), 51.37(NCH2), 124.17, 126.44, 127.67, 128.54, 133.59, 136.72, 195.04 (C=S).
Disclosure statement
No potential conflict of interest was reported by the authors.
Funding
KB and SG thank the UGC, New Delhi, for award of their fellowships under UGC-FDP program.
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