Heterobimetallic and Monometallic Catalysts for … · Heterobimetallic and Monometallic Catalysts...

Heterobimetallic and Monometallic Catalysts for

Asymmetric Hydroamination and Tandem Reaction

vorgelegt von Master Chemiker Nibadita Purkait

aus Haldia (Indien)

Von der Fakultät II - Mathematik und Naturwissenschaften der Technischen Universität Berlin

zur Erlangung des akademischen Grades Doktor der Naturwissenschaften

Dr. rer. nat.

genehmigte Dissertation

Promotionsausschuss: Vorsitzender: Prof. Dr.-Ing. Matthias Bickermann Erster Berichter: Prof. Dr. rer. nat. Siegfried Blechert Zweiter Berichter: Prof. Dr. rer. nat. Bernd Schmidt Tag der wissenschaftlichen Aussprache: 20. September 2012

Berlin 2012

D 83

Heterobimetallic and Monometallic Catalysts for

Asymmetric Hydroamination and Tandem Reaction

Thesis submitted by M.Sc. Nibadita Purkait

from Haldia (India)

From the Faculty II - Mathematics and Natural Sciences the Technical University of Berlin

to obtain the academic degree Doctor of Science (PhD)

Dr. rer. nat.

approved thesis

Examination committee: Chairman: Prof. Dr.-Ing. Matthias Bickermann First examiner: Prof. Dr. rer. nat. Siegfried Blechert Second examiner: Prof. Dr. rer. nat. Bernd Schmidt Date of the examination: 20th September 2012

Berlin 2012

D 83

This work in my PhD has been done under the supervision of Prof. Dr. Siegfried Blechert and

second supervisor Prof. Dr. Thomas Braun from January 2010 to September 2012 at the

Institute of Chemistry, Faculty II of Mathematics and Natural Sciences, Technical University

of Berlin.

iii

Abstract

The hydroamination reaction is among the most versatile means of forming nitrogen-

containing heterocycles, compounds of interest in a variety of chemical disciplines. While the

reaction has been intensely studied, concerns still exist over its amenability to organic

synthesis. This thesis details the development of various zinc based chiral and achiral

catalysts for inter and intramolecular hydroamination reactions of alkenes and alkynes and

mechanistic studies.

The first chapter consists of importance of the amines and the methods of preparation have

been described. Different metal catalysts according to their position in periodic table which

are been used for hydroamination, their advantages and disadvantages are been highlighted

including the mechanism of the processes. Finally why zinc has been chosen as the most

suitable metal for the hydroamination reaction has been explained.

The second chapter contains a consecutive or domino hydroamination reaction between

amine and alkyne to produce bicyclic and tricyclic- 1,2-dihydroquinoline derivatives

catalysed by a zinc complex. This consecutive reaction gives us the possibility to diminish

the number of step to obtain the resulted products. At the end of this chapter, the results and

observations of this reaction prone us to propose a possible mechanism.

In third chapter, intramolecular asymmetric hydroamination has been described. Starting

from the chiral ligand synthesis and modification of electronic, steric factors on ligand has

been described micro analytically. Then ligands are been used for enantioselective

intramolecular hydroamination. Metal centre has also been varied by different transition and

also late transition metals. The combination of zinc and zirconium shows the best results. At

the end of the chapter, some kinetic study and NMR study has been carried out to understand

the mechanism of the reaction and with the observed results the mechanism has been

established.

Forth chapter describes the development of new and very efficient catalyst TMP-ZnCl for

hydroamination. Using this TMP-ZnCl as a catalyst, primary amino-alkene, secondary

amino-alkene and also amino-alkynes showed hydroamination reaction to form pyrrolidine

systems efficiently. This chapter also contains a separate project which involved the

development of Di-butyl magnesium as an efficient catalyst for hydroamination. This catalyst

has already shown to be an efficient catalyst for hydroamination to form pyrrolidine systems

in our laboratory. Here we tested the efficiency of this catalyst for hydroamination to obtain

piperidine derivatives.

v

Acknowledgements

I am thankful to many people during my PhD work for their overwhelmed support. Firstly, I

would like to give my profound and sincere gratitude to my thesis supervisor Prof. Dr.

Siegfried Blechert for giving me the chance to work in his very high level working group and

for his careful guidance, patience, motivation, enthusiasm, and immense knowledge. Without

his meticulous planning, incisive thinking and cogent advice, my work throughout PhD

would not have taken this form how it is in today. Discussions with him have aided a long

way in structuring and cohering the thoughts lay random and unfocussed. His suggestions,

criticism and constant encouragement helped me immensely to achieve this target. His true

scientific spirit has helped me a lot during my research work.

I would like to say my thanks to Prof. Dr. Thomas Braun as my second supervisor for his

very interesting and valuable discussion.

I would like to thank Prof. Dr. Bernd Schmidt for taking the position of second examiner and

Prof. Dr. Matthias Bickermann for taking the position of chairman in the examination

committee.

I also wish to thank Mrs Roswitha Hentschel and Mrs Marianne Lehmann for their all

inestimable help concerning the official work.

My hearty thanks to all of my lab colleagues, students worked with me for their help and co-

operation inside the lab and to all the stuff members involved in the instrumental section for

their continuous help for the measurement in the chemistry department in TU berlin.

I acknowledge to BIG-NSE for giving me the chance to come to Germany and to do my

doctoral study here. My acknowledge goes to all the PhD students and all the members in

BIG-NSE, especially Dr. J. P. Lonjaret for his continuous help from the beginning to the end

of my stay in Germany and also I would like to thank Unicat for the financial support during

the three years period in Germany.

And last but never the least no words will be enough to express my love and regards to my

family – my parents Kalpana Purkait and Atal Purkait, Dada, Didi, Suri and friends specially

Mamta Suri who is always my inner strength even being far away from me. I would like to

dedicate this thesis to my mother Mrs Kalpana Purkait, who is always my support during my

study and to Dr. Suribabu Jammi, who was and is my continuous support and for his endless

love – this would be a small contribution to their dream for me and hope and patience on me.

- Nibadita Purkait

vii

‘‘The sweetness of the southern breeze,

The sacred charm and strength that dwell

On Aryan altars, flaming, free;

All these be yours and many more

No ancient soul could dream before’’-

by Swami Vivekananda

ix

To Maa and Mr

xi

Table of Contents

Abstract……………………………………………………………………………………….iii

Acknowledgment……………………………………………………………..………………..v

Abbreviations………………………………………………………………………..…........xiv

Chapter 1 Introduction

1.1 Amines and their importance………………………………………………………….3

1.2 General approaches to prepare amines………………………………………………...5

1.3 Hydroamination………………………………………………………………………..8

1.4 Challenge in hydroamination ………………………………………………………....9

1.4.1 Regioselectivity -Markovnikov product vs. Anti Markovnikov product……………...9

1.4.2 Activation energy…………………………………………………………………….10

1.4.3 Thermodynamics and kinetics of hydroamination…………………………………...10

1.5 Activation …………………………………………………………………………....11

1.5.1 Activation of carbon-carbon multiple bond………………………………………….11

1.5.2 Activation of N-H bond………………………………………………………………12

1.5.3 Activation of amine by oxidative addition………………………………………...…13

1.6 Metal catalyzed hydroamination…………………………………………………..…14

1.6.1 Alkali and alkaline earth metal catalyzed hydroamination………………………..…14

1.6.2 Early transition metal and lanthanides catalyzed hydroamination…………………...16

1.6.3 Late transition metal catalyzed hydroamination……………………………………..18

1.7 Zinc and organo-zinc compounds in organic synthesis……………………………...20

1.8 Objective of this thesis……………………………………………………………….22

1.9 References……………………………………………………………………………23

Chapter 2 Synthesis of 1,2-Dihydroquinolines and Tricyclic Quinolines from Simple

Amines and Alkynes – A Consecutive Zn Catalysed Process

2.1 Introduction ………………………………………………………………………….33

2.1.1 Consecutive reaction…………………………………………………………………33

2.1.2 Motivation……………………………………………………………………………33

2.2 β-diiminates ……………………………………………………………………….…35

2.3 Preparation of the catalyst …………………………………………………………...36

2.4 Substrate synthesis ……………………………………………………………..……37

2.5 Optimization …………………………………………………………………………38

xii

2.6 Results and discussion ……………………………………………………………….40

2.7 Mechanism study…………………………………………………………………..…45

2.8 Further transformation and application………………………………………………46

2.8.1 Metathesis ……………………………………………………………………………47

2.8.2 Metathesis catalysts………………………………………………………………..…47

2.8.3 Metathesis mechanism……………………………………………………………….48

2.8.4 Present study on metathesis- application of the tandem reaction……………......…..49

2.8.4.1 Substrate synthesis………………………………………………………………..….50

2.9 Side reaction………………………………………………………………………….51

2.10 Summary …………………………………………………………………………….53

2.11 References…………………………………………………………………...……….53

Chapter 3 Synthesis of Chiral Salen-type Ligands and Application in Highly

Enantioselective Hydroamination

3.1 Introduction …………………………………………………………….……………59

3.1.1 Asymmetric synthesis……………………………………………………………..…59

3.1.2 Salen ligands in asymmetric synthesis……………………………………………….61

3.1.3 Motivation ……………………………………………………………………..…….62

3.2 Synthesis of ligand systems …………………………………………………….……65

3.2.1 Synthesis of bromine containing salen ligands……………………………………....65

3.2.2 Synthesis of bromine free salen ligands………………………………………..…….67

3.3 Optimization …………………………………………………………………………70

3.3.1 Optimization of metal combination…………………………………………..………70

3.3.2 Optimization of reaction condition…………………………………………..……….72

3.3.3 Optimization of catalytically active salen ligands……………………………...…….73

3.3.3.1 Reaction with bromine containing salen ligands………………………………….….73

3.3.3.2 Reaction with bromine free salen ligands……………………………………...…….74

3.4 Substrate synthesis……………………………………………………………..…….75

3.5 Result and discussion………………………………………………………...………78

3.6 Mechanism study…………………………………………………………………..…84

3.7 Summary and outlook………………………………………………………………..86

3.8 References …………………………………………………………………...………87

Chapter 4 Development of Easily Accessible Catalysts for Hydroamination

4.1 Introduction and motivation …………………………………………………………91

xiii

4.2 n-Bu2Mg as the catalyst for hydroamination ………………………………...………93

4.2.1 Optimization ………………………………………………………………………....94

4.2.2 Results and discussion …………………………………………………………...…..94

4.3 Mechanism of the reaction ………………………………………………………..…95

4.4 TMPZnCl as the reagent for hydroamination ………………………………..………96

4.5 Mechanism of the reaction ……………………………………………………….….98

4.6 References ……………………………………………………………...……………99

Chapter 5 Experimental

5.1 General experimental part…………………………………………………..………103

5.2 Experimental part for chapter 2 .……………………………………………...…….106

5.3 Experimental part for chapter 3 ……………………...………………………..……123

5.4 Experimental part for chapter 4 ………………………………………………...…..149

5.5 References…………………………………………………………………………..151

xiv

Abbreviations

AcOEt Ethylacetate

AcOH Acetic acid

Ar Aromatic

AT Aminotroponato

ATI Aminotroponiminato

ATR Attenuated Total Reflectance

BDI β-Diketimine, β-Diketiminato

Bim Bisimidazole

BINAM 1,1´-binaphthyl 2,2´-diamine

BINAP 1,1´-binaphthyl 2,2´-bis(diphenylphosphine)

Bn Benzyl

Box Bisoxazoline

br.s Broad Signal

BTSA Bistrimethylsilylamide, Bistrimethylsilylamine

Bu Butyl

c Concentration, Cyclo

cat. Catalyst

cat. Catalytic

CI Chemical Ionisation

cm Centimeter

Cokat. Cocatalyst

COSY Correlation Spectroscopy

Cy Cyclohexyl

d Doublet, day

dba Dibenzylidenacetone

DBU 1,8-Diazabicyclo[5.4.0]undec-7-en

DCM Dichlormethane

DEPT Distortionless Enhancement by Polarization Transfer

DIA Diisopropylamine

DIAD Diisopropylazodicarboxylate

DIBAL-H Diisobutylaluminiumhydride

DMF Dimethylformamide

DMSO Dimethylsulfoxide

DNA Deoxyribonucleic acid

xv

DPPF 1,1´-Bis(diphenylphosphino)ferrocene

EDA Ethylendiamine

ee Enantiomeric excess

EE Ethylacetate

EI Electronimpact-Ionisation

EN Electronegativity

eq Equivalent

ESI Electrospray Ionisation

Et Ethyl

Et2O Diethylether

EWG Electron Withdrawing Group

FAB Fast Atom Bombardment

fkt. Functional

g Gramm

h Hour

HMG 3-hydroxy-3-methyl-glutaryl

HMQC Heteronuclear Multiple Quantum Coherence

HOMO Highest occupied molecular orbital

HPLC High Performance Liquid Chromatography

HR high-resolution

HV High vacuum

Hz Hertz

i Iso

IOx Imine-Oxazoline

IR Infrared

J Coupling Constant

LAH Lithiumaluminiumhydride

Lig. Ligand

LUMO Lowest unoccupied molecular orbital

M Metall, Molmasse, Molarity

m Multiplet

mbar Millibar

MDI 4,4'-methylene diphenyl diisocyanate

Me Methyl

mg Milligramm

xvi

MHz Megahertz

min Minute

mL Milliliter

MOM Methoxy Methyl

MS Mass-spectrometry

Ms Mesyl

MTBE tert-Butylmethylether

m/z Mass to Charge Ratio

NBS N-Brom-succinimide

nm Nanometer

NMR Nuclear Magnetic Resonance

Nt Turn Over Number

Nu Nucleophile

OAc Acetate

OTf Triflate

org. Organic

p Para

PCC Pyridiniumchlorochromate

PG Protecting Group

Ph Phenyl

pH Potential of Hydrogen

PMB para-Methoxybenzyl

ppm Parts Per Million

Pr Propyl

PTSA para-Toluene sulfonic acid

q Quartet

quant. Quantitative

RCM Ring closing metathesis

Rf Retentions factor

RNA Ribonucleic acid

ROCM Ring opening cross metathesis

ROM Ring opening metathesis

ROMP Ring opening metathesis polymerization

RT Room Temperature

s Singlet, stark

xvii

sept Septet

SHOP Shell higher olefin process

mp. Melting point

t, tert Tertiary

t Triplet

TBAF Tetrabutylammoniumfluoride

TDI Toluene-2,4-diisocyanate

TEA Triethylamine

Temp. Temperature

TFA Trifluoroacetic acid

THF Tetrahydrofuran

TMS Trimethylsilyl

TMP 2,2,6,6-tetramethylpiperidine

TOF Turn Over Frequency

Ts para-Toluenesulfonyl

UV Ultraviolet

VIS Visible

w Weak

Chapter 1

Introduction

2

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3

-------------------------------------------------------------------------------------------------------------------------------------- Introduction

1.1 Amines and their importance

Amines are the substituent products of ammonia and their relevant classes of compounds such

as imines, enamines and amides are widely distributed in nature and are essential to life

because their structural subunits exist in many natural products such as vitamins, hormones,

antibiotics, as well as alkaloids. They also show important and extensive practical

applications in pharmaceuticals, herbicides, dyes, as building blocks in organic synthesis, in

biological systems, as ligands for catalysis, in materials science, medicinal chemistry and also

are highly ubiquitous and valuable both as final products and as versatile intermediates in

many chemical reactions.1 Although much of the chemistry of amines was discovered in the

nineteenth century, the implementation of the Haber-Bosch process at Leuna in Germany in

1917 marks the beginning of modern age of amine chemistry.2 Naturally occurring amines are

often biologically highly effective and essential for certain biological processes connections.

Amino acids and the nucleobases of DNA & RNA have amino groups in their molecular

structures.3 The breakdown of amino acids releases amines, famously in the case of decaying

fish which smells of tri-methylamine. Many neurotransmitters are amines, including

dopamine, epinephrine, histamine, norepinephrine and serotonin.4 Protonated amino groups (-

NH3+) are the most common positively charged moieties in proteins, specifically in the amino

acid lysine. Additionally, the terminal charged primary ammonium group on lysine forms salt

bridges with carboxylate groups of other amino acids in polypeptides, which is one of the

primary influences on the three-dimensional structures of proteins.5

Lower aliphatic amines with chain lengths up to C7 are mainly used as organic intermediates

and used in the synthesis of solvents, detergents, medicines, insecticides, herbicides, corrosion

inhibitors, surfactants, dyes, plastics, etc.6 In 1988, worldwide approximately 690000 tones of

these classes of compounds were produced by industry.7

Aliphatic amines having at least one C8-chain length belong to the group of fatty amines.8

Due to the surface-active properties of the corresponding ammonium salts are used as fabric

softeners, detergents, lubricants and anti-foam and flotation aids.9

Aromatic amines and nitrogen-containing heterocyclic compounds have very complex and

diverse uses. Aniline and its derivatives are useful in rubber processing chemicals, herbicides,

pigments and dyestuff chemistry specifically as a precursor to indigo.10

Due to this high importance of amines in many areas, the amine synthesis has an important

locus in the pharmaceutical industry and the production of agrochemicals. The outstanding

4

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characteristic of amines is its (mostly weak) basic character. In Figure 1 some

pharmaceutically important amines are shown.

HO

OH

(R)

HN

Me

OH

(R)-(–)-L-adrenaline

(Cardiac arrest, Anaphylaxis,

Asthma deseases)

HO

OH

NH2

Dopamine

(neurotransmitter)

NH

HO

NH2

Serotonin

(vasoconstrictor)

N

NH

NH2

Histamine

(Schizophrenia desease)

NH

HO NMe

Me

Bufotenin

(endogenous metabolite)

N

N

Me

H

Nicotine

(antiherbivore chemical)

NHNH

NO

O

NMe

Me

O

Me

OO Me MeH

Voacamine

(antimalarial drug)

N

O

O

Me

MeMe

OH

O

N

OMe

OMeH

MeH

Dauricine

(calcium channel blocker)

NMe Me

O

OH

OMe

NMe Me

OMe

O

OH

Tubocurarine

(skeletal muscle relaxant)

HN

Me

O

O

O

O

NH

Me

Carpaine

(cardiovascular effect)

Figure 1. Pharmaceutically important amines.

Application of amines ranges from products such as corrosion inhibitors, wetting and surface-

active agents, dyes, dispersing agents, emulsifiers or petroleum additives to highly value-

added intermediates for drugs and crops protection agents. Due to their high importance with

respect to pharmaceuticals and dyes, several million tons of amines are produced in industry

worldwide per year. Hence, the development of practical and convenient methods for

constructing nitrogen-containing compounds is highly desirable.

5

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1.2 General approaches to prepare amines

The classical well developed methods for the synthesis of amines are reduction of nitrogen-

containing functionalities in higher oxidation states (e.g. reduction of nitriles, imines, azides,

nitroso and nitro compounds), nucleophilic substitution of halogens or other potential leaving

groups at sp3 hybridized carbons by ammonia and amines, aminoalkylation, reductive

amination of carbonyl compounds.11 A schematic overview of possible methods for the

formation of amines is shown in Scheme 1.

Scheme 1. Different methods to prepare amines.

Substitution reactions are quantitatively the most common amination. They mostly originate

from halides or alcohols. But multiple alkylations due to the multiple nucleophilic

substitutions of the halogen or the hydroxyl group are always a problem. Moreover, it is

obtained as a waste product as halogen compound or contaminated with water.12 The reaction

of a carbonyl compounds with ammonia, followed by catalytic reduction or reduction by any

Scheme 2. Preparation of amines from carbonyl compounds.

6

-------------------------------------------------------------------------------------------------------------------------------------- Introduction

reducing reagents, produces amines. N-substituted, N,N-disubstituted amines can be obtained

by reacting carbonyl compounds with primary amines and secondary amines respectively

(Scheme 2). In indirect methods, the amino group is formed by reaction of a relatively highly

refined precursor that already contains a C-N bond (reduction of imines, nitriles, azides,

amides and nitro compounds) (Scheme 3).

Scheme 3. Preparation of amines from azide compounds.

Primary amines can also be prepared by the Gabriel synthesis (Scheme 4). In this method, the

sodium or potassium salt of phthalimide is N-alkylated with a primary alkyl halide to give the

corresponding N-alkylphthalimide. Upon workup by acidic hydrolysis the primary amine is

liberated as the amine salt. The reaction fails with most secondary alkyl halides.

Scheme 4. Preparation of amines by Gabriel synthesis.

Nitriles and amides can be reduced with lithium aluminum hydride (LiAIH4) to prepare

amines. As amides are easily prepared from acid and amines, their reduction is a preferred

method for making all classes of amines (Scheme 5). Despite numerous opportunities for

manufacturing amines, only a few are suitable for industrial applications. Industrial practices

on amine production largely based on the alkylation of ammonia or primary or secondary

amines with alcohols13 and also by hydration or hydroformylation-hydrogenation from

nitriles.14

Scheme 5. Preparation of amines from nitriles and amides using lithium aluminium hydride.

7

-------------------------------------------------------------------------------------------------------------------------------------- Introduction

The main products of this reaction are the methyl amines (1994: 600000 tons). Methyl amines

are important intermediates for the production of solvents, insecticides, herbicides,

pharmaceuticals and detergents. It is produced in large scale by stepwise methylation of

ammonia with methanol under very drastic conditions; at 350 - 500 °C, 15 - 30 bar pressure

followed by heterogeneous dehydration (eg, aluminum silicates, acid zeolites).15

Technical amines, such as α, ω-alkane diamines [e.g. hexamethylene diamine (HMDA in

1991: 1.14 million tons per year) for nylon 6,6- or resin production] are now almost

exclusively produced by hydrogenation of the dinitrile precursors. Fatty amines are also

obtained by hydrogenation from the corresponding cyanides, which are prepared by

dehydration of the fatty acid amides.16 Following the principle of the hydroamination, in

BASF chemical company, tert-butylamine is been produced from isobutene.17 Isobutene

reacts directly with ammonia over heterogeneous zeolite catalysts to form tert-butylamine.

In addition to the short-chain aliphatic amines and fatty amines, then comes the aromatic

amine such as aniline which plays a key role in large-scale chemical industry. In 1993 its

production capacity was estimated at about 2 million tons per year,16 where it was produced

by using the most traditional production method that is from nitrobenzene (Scheme 6).18

Scheme 6. Preparation of aromatic amines from nitro compounds.

Aniline is a very important intermediate for the synthesis of a variety of aromatic compounds

such as isocyanates (TDI, MDI), rubber chemicals, dyes and pharmaceuticals. In recent years

a series of elegant catalytic processes have been described for the formation of aromatic C-N

bond via nucleophilic substitution reactions of aryl-halide compounds. The work of Hartwig

and Buchwald is one of the important methods, in which the palladium-catalyzed reactions of

amines with halogenated aromatic compounds are described for the C-N bond formation

reaction (Scheme 7).19

Scheme 7. Hartwig and Buchwald coupling to prepare amines.

8

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These above described methods suffer from drawbacks such as by product formation as well

as poor selectivity. Many cases the method needs highly specified starting material.

1.3 Hydroamination

Hydroamination , the addition of an N-H bond across carbon-carbon unsaturation, offers an

efficient, atom-economical route to primary, secondary and tertiary amines, imines and

enamines, by converting readily accessible alkenes and alkynes into desirable, more highly

substituted nitrogen-containing products in a single step (Scheme 8).

Scheme 8. Intermolecular and intramolecular hydroamination of alkenes and alkynes with

amine.

Hydroamination of alkenes directly provides a convenient access to stable saturated amines,

while hydroamination of alkynes affords relatively reactive amines and imines, which can be

used for further synthetic manipulations. However, since alkenes are less reactive and more

readily available than alkynes, the hydroamination of alkenes is the more attractive

transformation for industrial application.

In hydroamination non-activated olefins and alkynes are used, which can only be activated

with the aid of catalysts and induce the addition of the amine to the multiple bonds. This

outlined the significance of an appropriate catalyst to reduce the activation barrier of the

hydroamination. With regard to these factors, hydroamination is one of the challenges for

modern research of catalysis. Since the discovery of the hydroamination, the potential of this

method was detected, this is reflected in the rapidly growing number of research reports in the

last few decades (Figure 2). Although lots of research has been done on hydroamination still

many more to come to find out a general solution and to overcome the drawbacks and

challenges.

9

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Figure 2. Number of publications on Hydroamination (data collected from Sci-finder)

1.4 Challenge in hydroamination

1.4.1 Regioselectivity – Markownikov product vs. Anti Markownikov

product

Regioselectivity is one of the main challenges in organic chemistry for the application of

catalysis. The hydroamination of substituted alkenes with amines can give Markovnikov- or

anti-Markovnikov regioisomers (Scheme 9).20 In 1993, according to the chemical engineering

news anti-Markovnikov reaction was one of the top ten challenges in catalysis.21 Markovnikov

product is usually favoured as a consequence of the higher stability of the intermediate

carbenium ion. However, the highly challenging anti-Markovnikov product is of great interest

for large scale production of industrial amines. Particularly, the use of amine derivatives as

detergents is necessary using the linear, branched product to ensure biodegradability.

NHR

NR

R HNR'R''R

NR'R''H R

HNR'R''+

NR

Markovnikov Anti-Markovnikov

Scheme 9. Markovnikov and anti-Markovnikov product in hydroamination reaction.

10

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1.4.2 Activation energy

Olefins with non-activated double bonds are inert to amines. Even higher temperatures do not

lead to the formation of adducts, since the necessary amount of activation energy is too high

and the reaction is characterized by a negative reaction enthalpy. The use of catalysts opened

pathways which is energetically more favourable as it decreases the required activation

energy and thus provide the reaction between non-activated olefin and amines. This fact is

illustrated in Figure 3 by the addition of ammonia to ethylene.22

Figure 3. Energy diagram for the hydroamination reaction between ethylene and ammonia.

1.4.3 Thermodynamics and kinetics of hydroamination

From a thermodynamical point of view, the noncatalyzed direct addition of ammonia or

simple amines to alkenes is feasible since corresponding reactions are slightly exothermic or

approximately thermoneutral but the reaction entropy is highly negative. To illustrate this

fact, three representative sets of thermodynamical data for the reactions of ethylene with

ammonia and ethylamines are presented in Table 1.23

Table 1. Thermodynamical data for the reactions of ammonia and ethylene.

Reaction ∆RGθ (kJ/mol) ∆RHθ (kJ/mol) ∆RSθ (kJ/mol K)

- 14.7 - 52.7 - 127.3

- 33.4 - 78.7 - 152.6

- 30.0 - 79.5 - 166.3

Activation energy for catalyzed reaction

Activation energy for non-catalyzed reaction

Overall energy released during reaction

Catalyzed reaction

Non-catalyzed reaction

11

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In general, the high activation barrier exists for the direct addition of amines across C-C

multiple bonds comes from electrostatic repulsion between the electron lone pair at the

nitrogen nucleophile and the electron rich π-bond of the alkene or alkyne. However, it is not

pretty easy to carry out the hydroamination reaction at elevated temperature to overcome the

high activation barrier, as at higher temperature, caused by the general negative reaction

entropy ∆RSθ of the amine addition, the reversible reaction undergoes backward to give the

reactant back. Additionally, in the case of concerted mechanism, during the addition of the N-

H bond to C-C double bond there is not a strong interaction between the reactants because of

the symmetry forbidden HOMO-LUMO overlapping. Also high energy difference between

the orbitals involved, π(C=C)/σ*(N-H) or σ(N-H)/π∗(C=C) makes the process unfavourable.

Therefore, it is very important to identify alternative catalytic procedures for the

hydroamination reactions. Catalysis is obligatory for this conversion and hence either amines

or olefins are been activated by metal sources.

1.5 Activation

As discussed above metal is essential for hydroamination reaction. The addition of amines to

non-activated multiple bonds can be activated by alkali metals, early transition metals (groups

3-5, as well as lanthanides and actinides) or late transition metals (groups 8-10). In principle,

these metals allow three different strategies for the catalytic activation in hydroamination

reaction. First, olefins can be activated by π-coordination to a metal making the olefin more

inclined toward nucleophilic attack by the amine. Secondly, the N-H bond can be activated by

deprotonation to the more nucleophilic amide of electropositive metals and thirdly, N-H bond

is oxidatively added to a transition metal when intermediate amide is formed which allows

insertion of the alkenes either into the M-N or M-H bond.

1.5.1 Activation of carbon-carbon multiple bond

Double or triple bond can be activated by the coordination to a Lewis acidic metal centre.

Alkene activation is generally accomplished with the late transition-metal catalysts, which

reduce the electron density and thus make susceptible to attack by amine nucleophiles. The

mechanism of activation of olefin by metal in hydroamination reaction has shown in Scheme

10. 2-Amino ethyl complex (A) is formed when an amine attacks on a coordinated alkene.

Alkynes are also activated in the same way for a nucleophilic attack, it yields the

corresponding α-ammonio ethenyl complex.24 β-Hydride elimination from resulting 2-

aminoalkyl intermediate leads to the oxidative amination products (C) and protonolysis of the

M-C bond releases the hydroamination product (B).

12

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Scheme 10. Activation of olefin by metal in hydroamination reaction.

During the nucleophilic attack, an electron pair is transferred from the lone pair of the amine

to the carbon atom coordinated to the metal. This charge transfer is favoured for a positive

metal centre as compared to a neutral one. A disadvantage of the activation of double and

triple bonds with known catalysts such as palladium25, platinum26, gold27, iridium28,

rhodium29 and ruthenium30 is primarily their high prices. In addition, the β-hydride

elimination as a side reaction is a common problem; again substrate range for the reaction is

very much limited.31 Amines are nucleophiles and therefore it also can coordinate to the Lewis

acid with the olefin together and thus the catalytic activity of the catalyst drastically reduces

by the coordinative saturation. Therefore, in such cases electron-deficient amines, amides and

carbamates are used as nucleophiles.

1.5.2 Activation of N-H bond

Another approach could be by the activation of amine using alkali/alkaline earth metals or

lanthanides to deprotonate the amine to the corresponding amide (A) which is now highly

nucleophilic and directly attacks alkenes (Scheme 11). Nowadays, besides the alkali/alkaline

earth metals, early transition metals and in particular the lanthanide metals are used in the

hydroamination reaction by the activation of the amino group. Due to their high catalytic

activity, these catalysts react under very mild conditions. Especially in the asymmetric

hydroamination the lanthanide catalysts have established very strong position, as reflected in

the growing multitude of research articles.32 The activation of the amines is carried out by

deprotonating the amine group, wherein a metal-amide bond A is generated (Scheme 11).

Now the metal amide complex which is highly nucleophilic directly attacks the olefin to form

the complex B. Then protonation of the complex B is carried out with another molecule of the

substrate to give the hydroamination product C.

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Scheme 11. Activation of amines by metal in hydroamination reaction.

1.5.3 Activation of amine by oxidative addition

Another method of amine activation route is by oxidative addition of an N-H bond to an

electron rich, coordinatively unsaturated, metal centre (MLn). A hydrido amido complex

[MH(NR2)] (A) is formed by the reaction which enables the subsequent insertion of the

alkene into M-N bond generating a hydrido-2-aminoalkyl (B) complex (Scheme 12).

Scheme 12. Activation of amines by oxidative addition in hydroamination reaction.

14

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After the reductive elimination of the alkylamine product, metal centre in the low oxidation

state is regenerated again for the catalytic cycle. In the oxidative addition, an electron pair of

the metal should be available for the formation of one of the two new metal-ligand bonds.

1.6 Metal catalyzed hydroamination

Figure 4. Periodic table containing metals which are used for hydroamination reaction.

Several catalysts have been synthesized and used successfully for hydroamination of olefin

and alkynes with amines. In this section catalyst systems according to their position in

periodic table have been described. Also their advantages and disadvantages of the most

important catalyst systems are highlighted. These discussions include the alkali/alkaline earth

metals, early transition metals, late transition metals and some examples of organo-zinc

compound which are useful in organic chemistry (Figure 4).

1.6.1 Alkali and alkaline earth metal catalyzed hydroamination

After first publication of alkali metal catalyzed hydroamination33 in 1948, alkali and alkaline

earth metals are been used widely for hydroamination reaction. Most frequently lithium,

sodium and potassium-based organometallic compounds are been used for this reaction. In

organic synthesis, especially organolithiums such as methyllithium, butyllithium and tert-

butyllithium shows application in the hydroamination of unactivated olefins even at very low

temperatures.34 It shows high catalytic activity in the presence of chiral ligands in the

enantioselective addition of amines to olefins (Scheme 13).34c In addition to alkali metal

15

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compounds, metal amides35, metal hydrides36 and elemental metals which react in situ to the

metal amides37 are also important to mention.

Scheme 13. Alkali metal catalyzed asymmetric hydroamination reaction.

The reaction is believed to proceed according to the mechanism shown in Scheme 14. The

alkyl metal compound (MR') reacts with the amine (HNR2) to form a metal amide A, which

has a considerably higher nucleophilicity than the amine and is now capable to react with an

unactivated olefin B. The result gives a new highly reactive alkyl-metal compound C, which

is protonated by another amine molecule. This will form the hydroamination product D and

the metal amide species A, which again goes back in the catalytic cycle.

Scheme 14. Mechanism of alkali and alkaline earth metal catalyzed hydroamination.

A disadvantage of this type of catalysis is sometimes high temperatures and pressures

necessary to achieve high conversions with alkyl-substituted olefins.36 This affects the

substrates containing electrophilic centers such as carbonyl, ester or nitro groups. Only the

addition of styrene proceeds under much milder conditions, making them synthetically

useful.38 Another adverse reaction that occurs due to the high basicity of the catalyst used is

16

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the double bond isomerization, wherein a terminal double bond is converted via an

intermediate of an allyl anion to an internal E-substituted double bond. This side reaction

occurs especially with alkyllithiums.39 With use of novel, calcium-based catalysts it is not

observed.40

1.6.2 Early transition metal and lanthanides catalyzed hydroamination

Before 1989 organolathanides were mainly used for ethylene polymerization. In 1989, Marks

et al. reported the first intramolecular hydroamination/cyclization of amino-alkenes and

amino-alkynes by using organolanthanide catalysts.41 They showed that organometallic rare

earth metal complexes e.g. (Me5Cp)2LnE, Me2Si[(η5- C5Me4)(tBuN)]Ln; E = H, N(SiMe3)2,

CH(SiMe3)2, Ln = La, Nd, Sm, Y, Lu and homoleptic Ln[N(SiMe3)2]3 are suitable for the

hydroamination/cyclization of terminal alkenes, 1,3-dienes, allenes and alkynes to the

corresponding cyclic amines, enamines or imines and also regiospecific five- and six-

membered nitrogen heterocycles. Most reactions have very high turnover frequencies (TOF)

and were achieved at room temperature; however the formation of six and seven membered

rings required elevated temperature. The highest TOF occurred in the five membered ring

syntheses and it can be enhanced by the insertion of alkyl substituent at internal carbon atom

at the β-position from amine in the substrate (Thorpe-Ingold effect).42

There are now a variety of organolanthanide catalysts of lanthanum, neodymium, samarium,

erbium, ytterbium and lutetium exist, which are used for their high catalytic activity in the

hydroamination of unactivated olefins.43

Figure 5. Chiral lanthanides complexes for hydroamination.

Chiral lanthanocene complexes were also prepared by substituting the cyclopentadienyl

ligands by (+)-neomenthyl, (-)-phenylmenthyl, (-)-menthyl substituents as chiral center.44 A

17

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comparison in olefin hydroamination reaction shows that the lanthanides-catalyzed

intermolecular reaction runs significantly slower than the intramolecular.45 The

hydroamination of alkynes has been carried out both intra-and intermolecularly. Despite the

epimerization of lanthanocene complexes, these catalyst systems give enantioselectivities up

to 74% in the intramolecular hydroamination of olefins to five-membered cyclic amines.46 In

the case of homologous six-membered heterocycles, the enantioselectivity was only 16% due

to the epimerization. There are now numerous lanthanocene catalysts available which are

bidentate, tetradentate and non-epimerisable, which are used for the asymmetric

hydroamination reaction.32d,47 They showed high activity, which was the starting point for

research on catalysts of this type. Reactions of aminoalkenes with lanthanide and other early

transition metals were also performed via the activation of the nitrogen. Here, the precatalyst

A reacts with a substrate molecule with the elimination of hydrogen (or one alkane) to form

metal amide species B which is also the resting state of the catalyst. The rate-determining step

takes place via the cyclic transition state C, the insertion of the olefin into the Ln-N bond. The

hydroamination product D is formed after the protonation by a substrate and this substrate

again form the metal amide complex B and completes the catalytic cycle (Scheme 15).

Scheme 15. Mechanism of lanthanides catalyzed hydroamination reaction

A major disadvantage is the extreme sensitivity of the catalysts with respect to oxygen and

water due to the high oxophilicity of the metals. And polar functional groups such as esters,

amides, ethers coordinate with the metal atom thus it deactivates the metal. These

disadvantages are the main reason why even though they are very active catalysts, until now

only they are used very rarely in natural product synthesis. Examples are shown in Figure 6.48

18

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Figure 6. Natural products obtained by lanthanides catalyzed hydroamination.

From the group of early transition metal catalysts of scandium49, titanium50, yttrium51,

zirconium52, hafnium53 and tantalum54 are used in the hydroamination of which the complexes

of titanium and zirconium show higher reactivity.

1.6.3 Late transition metal catalyzed hydroamination

The transition metal-mediated hydroamination with stoichiometric amounts of late transition

metals has been around for more than 40 years. The most used metals are palladium55,

platinum56, copper57, thallium58, silver59, gold60, ruthenium61, rhodium62 and mercury63. The

mechanism of the hydroamination with late transition metals corresponds to that of the

Wacker-oxidation (Scheme 16).31 Reaction between amine and metal complex A forms

alkylmetallo-complex B. This complex now follow two pathways – 1) complex B can

undergo protonolysis of the M-C bond to give the desired product and the metal salt A for the

further catalytic cycle (path 1), and another pathway is 2) β- hydride elimination produce an

enamine C and halogen metal hydride species, which is responsible for the reductive

elimination of elemental metal (path 2).

Simple metal salts undergo the only one adverse reaction path 2. Therefore it gives the

enamines and the catalyst must also be used stoichiometrically. And it is quite obvious that

nowadays stoichiometric use of the catalyst is not desirable for academic as well as industrial

purpose. Again metals such as palladium, platinum, gold, silver, rhodium, ruthenium or

iridium due to their high acquisition costs are rarely used in the hydroamination. In addition to

the high prices, the transition metals such as mercury and nickel are environmentally harmful

and unhealthy. In particular, nickel is a frequent cause of contact allergy and is therefore less

and less frequently used in alloys. By the addition of stoichiometric amounts of co-oxidant

such as quinones or CuCl2/O2, it was possible to carry out the reaction with the catalytic

amounts of these metals.64

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Scheme 16. Mechanism of hydroamination with late transition metal.

Another solution of the problem lies in the suppression of unwanted β-hydride elimination,

which means that the further reaction i.e. the protonolysis of metal-carbon bond occurs. This

could be achieved by using bulky, bidentate phosphine ligands such as BINAP, Biphemp,

Xantphos or DPPF instead of simple metal salts complexes. The addition of strong acids such

as trifluoromethanesulfonic acid also helps to accelerate the protonolysis of the M-C bond. At

this point, the work of Hartwig, who carried out intermolecular additions to styrenes, either

the Markovnikov or the anti-Markovnikov selective products are formed depending on the

choice of the metal and the phosphine ligands (Scheme 17).65

Scheme 17. Regeioselective addition of morpholin to styrene by Hartwig.

By using chiral phosphine ligands the reactions were carried out asymmetrically and the

obtained enantioselectivities were 70%.66 Catalysts with late transition metals have the

advantage of high selectivity and a wide tolerance toward polar functional groups. The

20

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disadvantage is that these catalysts generally have a lower activity and therefore often higher

temperatures and high catalyst loadings are needed.

All these three groups are characterized by a series of metal catalysts for hydroamination with

preliminary advantages and disadvantages. This also means that there are no ideal catalysts

for the hydroamination and this fact justifies studies of catalyst systems with other metals and

to find out a general solution. The catalyst should be good in activity and a high tolerance

power toward functional groups. Furthermore, the metals used should be non-toxic and

inexpensive. Metals which exhibit this character are copper, iron and zinc. Out of them zinc

shows particular interest for organometallic chemistry.

1.7 Zinc and organo-zinc compounds in organic synthesis

Zinc is in addition to iron and copper, one of the most widely used metals. Because of its low

capital price, its non-toxicity and tolerance toward functional group there is various

applications in organic and organometallic chemistry. Zinc has its application in roofs, gutters

and dry battery. Furthermore, zinc dust is used as a reducing agent for the recovery of

precious metals such as silver and gold. Zinc is also used for the coatings on iron parts (which

is called "galvanizing") to protect against corrosion.67 Zinc has been used from long back

onwards, about 2500 years ago, as the ornaments (almost 80-90% were zinc in the alloy of

lead, iron, antimony, and other metals), but they were first isolated by Flemish metallurgist

P.M. de Respour in 1668, he reported that he extracted metallic zinc from zinc oxide for the

first time.68 Today, compounds with zinc-carbon bond in organic synthesis cannot be

ignored.69 Zinc has a higher electronegativity compared to lithium or magnesium, so the

carbon-zinc bond has higher covalent bonding ability. Alkylzinc reagents are therefore much

less reactive than lithium or Grignard reagents and comparable with tin and boron-organic

reagents. Although it has decreased reactivity compare to other organometallic compounds

but has a higher selectivity and higher tolerance towards functional groups (Figure 7).70

Figure 7. Comparison of reactivity and selectivity of organometallic compounds.

21

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In organic synthesis organozinc compounds have very diverse and outstanding applications.

Thus, elemental zinc, zinc salts or zinc-organic compounds all are useful in synthesis. In most

cases zinc is used in stoichiometric amounts; catalytic reactions are not yet widespread. A

well-known exception is the zinc catalyzed addition of acetylenes to aldehydes by Carreira.71

A large number of important reactions as well as asymmetric C-C bond formation are carried

out with the zinc-nucleophiles such as the asymmetric 1,2-additions to aldehydes,72 the 1,4-

addition to enones73 and the Reformatsky reaction74. Elemental zinc is mainly used in

combination with acids for mild reduction of heteroatom-heteroatom bonds.75 Thus, peroxides

and disulfides are reduced to the corresponding alcohols and thiols, nitro compounds are

reduced to amines and hydroxylamines to amines and alcohols. Also in Clemmensen

reduction, aldehydes or ketones are converted to the respective alkanes.76 The Simmons-Smith

reaction is one of the most important reactions for the preparation of cyclopropanes.77

Another important reaction is the Negishi reaction of aryl or acyl halides with organozinc

reagents, which is one of the most important cross-coupling reactions for the preparation of

functionalized building blocks.78 The use of zinc as a catalyst for the hydroamination been

limited largely to heterogeneous catalyst systems, in which zinc salts were intercalated into

zeolites or clays.79 These catalysts showed a relatively low activity in the intramolecular

hydroamination of alkynes. In another study, the hydroamination of alkynes has been studied

with zinc triflate.80 Zinc has already established itself in the hydroamination of unactivated

olefins and alkynes. Recently in Blechert and Roesky group, β-diketiminate zinc complexes

have been prepared for the hydroamination of alkynes81 and also aminotroponiminate zinc

complexes with different leaving groups as catalysts for the intramolecular hydroamination of

alkenes (Scheme 18).82

Scheme 18. Zinc catalyzed hydroamination by P. W. Roesky and S. Blechert et al.

22

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1.8 Objective of this thesis

Although a series of catalyst for hydroamination reaction are been developed by different

groups, but those catalyst systems are limited either in substrate scope or storage. Again the

high sensitivity of the early transition metal and lanthanides, high expenses and toxicity for

the late transition metals (e.g. Ag, Au, Rd, Ir catalysts) and also for the alkali metal and

alkaline earth metals require drastic reaction condition – which gives limitation for their uses

in industrial purpose. For the mechanistic studies on structure-activity relationships and the

development of the scope of known catalysts for the practical applications in hydroamination

reaction it is important to search for new active catalyst systems.

In this present work hydroamination of alkenes and alkynes are investigated using cheap

metal source with homogeneous catalyst. As homogeneous catalysts are useful for the

mechanistic studies, optimization studies and allows us to know the influence of ligands

systems; we have developed a homogeneous chiral hetero bimetallic salen-type ligand system

which shows high reactivity and selectivity for enantioselective intramolecular

hydroamination reaction. Another important aspect of chemistry is to minimize the number of

steps in organic synthesis. In this context, we have developed a zinc catalyzed consecutive

process which allows us to perform multistep synthesis in a single step to obtain the amines.

In addition, the structures of ligands systems, also the product stereochemistry are determined

by various spectroscopic methods as well as by X-ray crystallography method. Finally

mechanism also established based on some experimental evidences.

The main theme of this work contains:

• Tandem reaction with the BDI-Zn complexes – this can reduces the number of steps

and gives easy synthesis of small building block for various natural products.

• Ligand synthesis – for the asymmetric (heterobimetallic salen-type complexes)

hydroamination reaction.

• Asymmetric hydroamination using heterobimetallic salen-type complexes to get

highly enantio-enriched cyclic amines.

• Mechanism has been established based on NMR experimental evidences.

• Easily handled and cheap catalysts are prepared for the hydroamination reaction.

23

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26

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3892; b) I. Aillaud, J. Collin, J. Hannedouche, E. Schulz, Dalton Trans. 2007, 5105-5118; c)

K. C. Hultzsch, Adv. Synth. Catal. 2005, 347, 367-391; d) J. F. Hartwig, Pure Appl. Chem.

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S. Doye, Eur. J. Org. Chem. 2003, 935-946; g) P. W. Roesky, T. E. Müller, Angew. Chem.

2003, 115, 2812-2814; h) Müller, T. E. in Encyclopedia of Catalysis (Ed.: J. T. Horváth),

Wiley, New York 2002; i) J. Seayad, A. Tillack, C. G. Hartung, M. Beller, Adv. Synth. Catal.

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29

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Inorg. Chem. 2009, 1369–1375.

Chapter 2

Synthesis of 1,2-Dihydroquinolines and Tricyclic

Quinolines from Simple Amines and Alkynes – a

Consecutive Zn Catalyzed Process

32

-------------------------------------------------------------------------------------------------------------------------------------- Synthesis of 1,2-Dihydroquinolines and Tricyclic Quinolines from Simple Amines and Alkynes – a Consecutive Zn Catalyzed Process

33


2.1 Introduction

2.1.1. Consecutive Reaction

The search for cleaner, safer and environmentally friendly technologies to reduce the wastes

together with the use of reusable systems, environmentally friendly reagents and catalysts are

important parameters to achieve more sustainable processes and is one of the priorities in

chemistry. A domino reaction1 is a consecutive series of organic reactions which often

progress via highly reactive intermediates involving multiple catalytic events which allows

the decrease of energy consuming steps such as separation and purification of intermediates.

It allows the organic synthesis of complex multinuclear molecules from very simple acyclic

precursor. The foremost advantages of a cascade reaction in organic synthesis are that the

reaction is clean, displays high atom economy and does not involve workup and isolation of

many intermediates.

2.1.2 Motivation

Transition metal catalyzed consecutive addition of amines to C-C multiple bonds and C-C

bond formation method is a highly attractive, challenging and demanding topic for the

construction of nitrogen containing multi-ring organic compounds because it can give the

products directly from readily and commercially available starting materials without any by-

products with high atom economy and selectivity. Domino reactions are highly attractive

because several individual reactions are coupled yielding a product in a single process.1

Figure 8. Biologically active dihydroquinoline derivatives.

34


Another advantage of such cascade reactions in organic synthesis is often a high atom

economy.2 Substituted hydroquinoline derivatives are important structure units in various

natural products and pharmaceuticals.3 Many heterocycles containing such units show

biological activity and potential therapeutics such as antibacterial,4 anti-inflammatory,5

inhibitors for lipid peroxidation,6 HMG-CoA reductase,7 and progesterone agonists,8

antagonists.9 Few of the biologically important compounds are shown in Figure 8 which

contains dihydroquinoline as the main building block.

Many synthesis of hydroquinolines are starting with aniline derivatives has been reported10

such as Brønsted acid catalyzed tandem reaction,11 modified Skraup reactions,12 Michael-

aldol reaction,13 metathesis14 and tandem reactions of aromatic amines with alkynes.15

Hydroaminations of alkynes with aromatic amines followed by metal catalyzed formation of

the heterocycles have also been described.

In 2005, Li and co-workers reported a domino route using 5 mol% AgBF4 in diethyl ether at

temperature between 140 °C – 190 °C.15a The study was based on both the Lewis acidity and

the transition metal character of the silver catalyst. The process has been carried out under

solvent free conditions (Scheme 19).

Scheme 19. Preparation of dihydroquinoline using silver by Li et al.

At the same time Yi and his co-workers used 5 mol% of a catalytically active cationic

ruthenium-acetylide complex combining hydroamination and C-H bond activation in benzene

at 95 °C (Scheme 20).10d The reaction undergoes with trace amounts of the isomerization

products (<5%).

Scheme 20. Preparation of dihydroquinoline using ruthenium by Yi et al.

35


Later Che et al. prepared 1,2-dihydroquinolines and quinolines by a tandem hydroamination -

hydroarylation with 5 mol% of a Au(I) NHC-complex under microwave conditions at 150 °C

(Scheme 21).10a,15b

Scheme 21. Preparation of dihydroquinoline using gold and silver combination by Che et al.

The above literature methods are consisting of gold, silver or ruthenium type of expensive

metals. Herein we present a new domino process using a consecutive catalysis with 5 mol%

of a Zn-complex (8) as a cheap metal together with 15 mol% of an anilinium salt (10) as

proton source. In context of our work on Zn-catalyzed hydroamination, our group has

reported recently a new domino hydroamination-alkyne addition reaction giving access to

functionalized propargylamines.16 The regioselective hydroamination of an alkyne with a

cationic Zn-complex lead to an iminium salt followed by the Zn-catalyzed addition of

monosubstituted acetylenes. In continuation of this work we observed in case of aryl amines,

like N-methylaniline, at elevated temperatures the hydroquinoline derivative 21 as byproduct.

The importance of such type of heterocycles motivated us to do further studies on this

reaction.

2.2 β-Diiminates

β-Diiminates17 are versatile ligands because they are easy to prepare and tune, they allow

precise architecture of steric properties. Even though β-diiminates do not show high affinity to

nitrogen donors, still they bind strongly to the transition metals due to their negative charge.

They stabilize low coordination numbers, thus allowing the synthesis of species that - with

other ligands - would be highly reactive transient intermediates. Formally, the β-diiminate

anion is a 4-electron σ-donor, but much of its chemistry can be rationalized more easily by

36


assuming that the ligand is also a strong π-donor. Thus, it shows definite analogies with Cp*

in its chemistry with Rh and other metals. Some examples of the use of β-diimine in organic

reaction – in radical cyclization of haloacetals18 (Scheme 22) and in the polymerization of

propylene19 (Scheme 23) are shown below.

O O

BrR

R' cat. Cr(III)-X

2 equiv Mn

4 equiv terpinen

PbX2O O

RR'

N

Me

Cr

Me Me

NXyl

XMe

Scheme 22. Chromium β-diiminate complex for the catalytic radical cyclization of

haloacetals.

Scheme 23. Propylene polymerization with α-keto-β-diimine initiators.

2.3 Preparation of the catalyst

The BDI-Zinc catalyst has been prepared according to the literature procedure20 and also

following Mustafa Biyikal’s doctoral thesis (2009) procedure starting from acetyl acetone 1

and 2,6-diisopropylaniline 2 (Scheme 24). It could be prepared by two ways - i) without

deprotecting the keto group, after the first amination, activatation of the second keto group

with Meerwein’s salt is required and ii) first protecting one of the keto group with ethylene

diol to get 6. According to the first method, the reaction of 1 and 2 in benzene gives mono-

aminated product 3. 3 is then treated with Meerwein’s salt at – 78 °C to give activated product

4. Another equivalent of 2,6-diisopropylaniline is then added in ether to give 5 as the product.

Then 5 is treated with sodium methoxide in methanol, it gives the β-diimine (BDI) 7 as grey

solid. It can be synthesized directly from mono-protected acetyl acetone, by treating 6 with

excess of 2,6-diisopropylaniline in benzene. The BDI ligand 7 is then treated with dimethyl

zinc which gives white crystals of the zinc-catalyst 8. Co-catalyst 10 has been prepared by

reacting N,N-dimethylaniline and CF3OTf in hexane at room temperature. The BDI-Zn

37


complex 8 is then treated with the co-catalyst 10 in toluene to give the active catalyst 9. In our

reaction the active catalyst 9 is been formed in situ by adding the BDI-Zn complex 8 and co-

catalyst 10 in toluene.

Scheme 24. Preparation of the BDI-Zn catalyst.

2.4 Substrates synthesis

Most of the substrates are commercially available and were used directly after buying from

commercial source. N-allyl aniline 12 was prepared by alkylating aniline with allyl bromide in

presence of Na2CO3 in DMF (Scheme 25) following the literature procedure.21

Scheme 25. Synthesis of the substrate 12.

Substrate 15 was prepared following the literature procedure22 and Marta Porta’s doctoral

thesis (2010). Treating p-methoxy aniline 13 with 1-pentenoic acid in presence oxalylchloride

and pyridine in DCM at 0 °C gives the corresponding amide 14 with 92% yield. Amide 14

38


was then reduced with lithium aluminium hydride in ether at 0 °C to give the corresponding

secondary amine 15 with 68% yield (Scheme 26).


Alkyne 18 was synthesized following the literature procedure.23 Reaction of but-3-yn-1-ol 16

treated with molecular sieves and trityl chloride 17 at 0 °C in pyridine and dichloromethane

gives the product 18 with 93% yield as an amorphous solid (Scheme 27).


2.5 Optimization

Reaction condition was optimized taking a mixture of N-methyl aniline 19 with 2.5 eq. of 1-

hexyne 20. Different salts and Lewis acids are been used for the reaction, the results are

shown in the table 2. We found that NH4PF6 and HBF4 does not show any reaction with or

without [PhNMe2H][OTf] (table 2, entry 1, 2, 5, 6). Although AlMe3 alone gives trace amount

of product (table 2, entry 3, 4) but with [PhNMe2H][OTf] gives 15% isolated product at 130

°C (table 2, entry 4). Alone [PhNMe2H][OTf] gives 20% product (table 2, entry 7). Increasing

temperature leads to the decomposition of the product.

39


Table 2. Optimization of additive and co-catalyst.a

Entry Additive Activator Temp (oC) Yields (%)b

1 NH4PF6 ---- 130 no reaction

2 NH4PF6 [PhNMe2H][SO3CF3] 130 no reaction

3 AlMe3 ---- 130 trace

4 AlMe3 [PhNMe2H][SO3CF3] 130 15

5 HBF4 ----- 130 no reaction

6 HBF4 [PhNMe2H][SO3CF3] 130 no reaction

7 ---- [PhNMe2H][SO3CF3] 130 20

8 ---- [PhNMe2H][SO3CF3] 150 16

NH

MeC4H9+

19 20

additive/activator

toluene

D

NMe

C4H9

Me

C4H9

21

aReaction condition: all reactions were carried out with 0.25 mmol amine and 0.75 mmol alkyne in 0.5 ml toluene at 130 °C in closed reaction vial. bIsolated yields are mentioned.

When 19 and 20 were heated in toluene together with 5 mol% of a 1:1 mixture of precatalyst

8 and activator 10 for 24 h at 70 °C yielding 99% of the expected propargylamine 22 (table 3,

entry 2). The same reaction at 130 °C gave under decomposition as only product which could

be isolated by chromatography on silica gel the wanted 1,2-dihydroquinoline 21 in a yield of

28% (table 3, entry 3). Similar results were obtained by heating the isolated 22 with 5 mol%

of the 1:1 mixture of Zn-complex and activator at 130 °C, thus indicating 22 as a precursor for

the formation of 21. However, the pure thermal reaction of 22 led only to decomposition,

which demonstrates a catalytic reaction. The C-C bond formation between the arene and triple

bond could go via direct metal catalyzed cyclization. In literature a similar copper-promoted

reaction has been described.24 Another pathway is the aromatic Aza-Claisen rearrangement

followed by cyclization of the resulting allene.25 The thermal rearrangement of N-propargyl

anilines require high temperatures which lead to decomposition of products.26 The Lewis acid

or proton catalyzed process is significantly milder.11 Consequently we tested the influence of

40


the anilinium salt 10 on the reaction 22 → 21. We were pleased to see a complete conversion

of 22 after 6 h at 130 °C yielding 98% of the wanted dihydroquinoline 21. We supposed that

the low yield formation of 21 during the first attempt was caused by a small excess of the

activator 10. Thus heating N-methyl aniline and 2.5 eq. of 1-hexyne with 5 mol% Zn-complex

and 15 mol% 10 at 130 °C gave a clean formation of the wanted 1,2-dihydroquinoline with an

excellent yield of 97% (table 3, entry 6). It also shows that the activator has more roles in

spite of activating the precatalyst.

Table 3. Optimization of reaction condition.a

entry catalyst (8) activator (10) temperature Time Yield 22b Yield 21b

(mol%) (mol%) (oC) (h) (%) (%)

1 5 0 130 48 56c 44c

2 5 5 70 24 99 0

3 5 5 130 24 0 28

4 5 15 80 24 80 5

5 5 15 110 24 50 40

6 5 15 130 24 0 97

7 0 15 130 24 0 0

NH

Me NMe

C4H9

Me

C4H9

NMe

C4H9

Me

C4H9

2.5 eq. C4H9 [20]

19

X mol% 8

X mol% 10

toluene, X oC 22 21

+

aReaction condition: all reactions were carried out with 0.25 mmol amine and 0.625 mmol alkyne in 0.5 ml toluene at 130 °C in closed reaction vial. bIsolated yields are mentioned. cConversion measured from proton NMR.

2.6 Result and discussion

With these conditions in hand we tested the scope of this method. We synthesized first a

series of substituted 1,2-dihydroquinolines starting from N-methyl aniline and aliphatic

alkynes. The results are presented in table 4. Besides 1-hexyne 20, 1-pentyne 23 and 1-

heptyne 25 were also used giving similar yields. Dihydroquinoline 24 forms with 93% and 26

with 98% yield (table 4, entry 2, 3). Not surprisingly olefins 28 are also tolerated (table 4,

41


entry 5). Due to the weak Brønsted acid 10 the method tolerates the trityl protected 4-pentinol

18, yielding 27 with an excellent overall yield of 92% (table 4, entry 4). In this case, the

isolation of the product by chromatography on silica failed due to the liability of the trityl

groups under such slightly acidic condition. Using neutral alumina we could purify 27 without

problems. 6-Chloro-1-hexyne 30 reacts with amine giving a mixture of products (table 4,

entry 6). The mixture of products is due to the possibility of chlorine as leaving group during

the reaction. Alkynes 31 and 32 do not show any reaction towards N-methyl aniline.

Table 4. Synthesis of bicyclic 1,2-dihydroquinoline derivatives from N-methyl aniline and

aliphatic alkynes. a

OPh

PhPh

Entry Amine Alkyne Time [h] Product Yield [%] b

NMe

Me

Me

NMe

MeO

33OPh

Ph

PhPh

Ph

Ph

Me

1

2

6

Me24 98

24 92

3

26

27

4

5 24 NMe

Me

7

NH

Me

Me

24 NMe

Me

MeMe

19

23

25

18

28

24

29

93

89

Me

20

NMe

MeMeMe

21

9724

Cl

MeO

Me

HN

no reaction

no reaction

mixture of compounds --

--

--8

30

31

32

24

24

24


42


Aryl acetylenes 33, 35, 37 were also used to prepare dihydroquinolines (table 5). The reaction

of phenyl acetylene 33 with 19 gave the dihydroquinoline 34 with only moderate yields of

55% whereas the donor substituted arenes gives yields 86% of 36 and 88% of 38.

Table 5. Synthesis of bicyclic 1,2-dihydroquinoline derivatives from N-methyl aniline and

aromatic alkynes. a


We also tested N-allylaniline 12. This substrate would give an N,N-allyl-propargylaniline as

an intermediate which could undergo two different N-aryl Claisen rearrangements. The sole

product which could be isolated with 64% yield was again a quinoline derivative 39,

indicating the propargylic rearrangement at least as the predominant pathway. A byproduct

resulting from an allyl rearrangement could not be found, but such a reaction cannot be

excluded, in particular in view of the different yields of 39 and 21. Electron donating group

(OMe) containing compound 15 also shows excellent reaction with the alkyne 28 giving 96%

yield of 40. Ortho substituted aniline derivatives 41 and 42 do not show any reaction (table 6,

entry 3, 4). Due to the steric hindrance diphenyl amine 43 does not undergo reaction with

aliphatic as well as aromatic alkynes (table 6, entry 5, 6).

43


Table 6. Synthesis of bicyclic 1,2-dihydroquinoline derivatives from other anilines and

substituted aniline derivatives. a


In order to extend the methodology also for the synthesis of tricyclic 1,2-dihydroquinoline

derivatives we tested 1,2,3,4-tetrahydroquinoline 44 and 2,3-dihydroindole 55. The results are

presented in table 6 and table 7. The reactivity of the tetrahydroquinoline 44 is comparable

with N-methyl aniline 19. The overall yields using alkyl and aryl substituted acetylenes are

mostly excellent. With phenylacetylene it gave 45 with a moderate yield of 53% (table 7,

entry 1), like in the case of 34 (table 5, entry 1). Similar to the previous results with aliphatic

alkyne it also gives high yield of 46. Methyl substituted phenylacetylene 47 gives 48 with

90% yield (table 7, entry 3). Methoxy substituted phenylacetylenes also works well in this

condition (table 7, entry 4, 5). Here also alkyne 28 gives high yield of the dihydroquinoline 51

(table 7, entry 6). Free amine containing alkyne 52 does not give corresponding

dihydroquinoline but it gives the propargylamine 53 with 62% yield (table 7, entry 7). The

pyridine containing alkyne 54 does not show any reaction in this condition (table 7, entry 8).

44


Table 7. Synthesis of tricyclic 1,2-dihydroquinoline derivatives from tetra-hydroquinoline. a

Entry Amine Alkyne Time [h] Product Yield [%] b

NH

N

Ph

Me

Ph

1 24 53

45

NMe

MeMe

2 24 96

46

Me

NMe

MeMe

24 903

48

NMe

OMeMeO

24 86

49

4

NMe

MeO OMe24 93

50

5

6

51

44

33

35

37

20

47

NMe28 94

NMe

NH2

H2N

N no reaction

7

8

52 53

54

NH2

62

24

24

24


Dihydroindole 55 is also a suitable substrate and forms tri-cyclic dihydroquinolines with good

yields (table 8). The yields for the fused heterocycles 56, 57, 59 are in the range for 53% -

45


60% (table 8, entry 1 – 3). This means an average of 85% - 88% for each step of the domino

process consisting of hydroamination, alkyne addition, rearrangement and cyclization. The

primary amine does not undergo any reaction at 130 °C but it gives trace amount of product

60 at 150 °C (table 8, entry 4).

Table 8. Synthesis of tricyclic 1,2-dihydroquinoline derivatives from dihydroindole and

primary amine. a


2.7 Mechanism study

Our hypothesis for the mechanism is summarized in scheme 28. The reaction of the Zn-

complex 8 with the anilinium salt 10 gives the catalytic active cationic Zn-species 9, which

leads via Markovnikov hydroamination, protonation of the enamine, addition of the Zn-

acetylide B and protonation to the propargylic ammonium salt D. This should undergo a

proton catalyzed 3,3-sigmatropic rearrangement. The resulting allene E can be trapped by

protonation to an allyl cation F which cyclizes to the final product G. A direct proton

catalyzed cyclization of this type of propargylamines seems less likely to us, because such a

synthesis of 2,2-disubstituted 1,2-dihydroquinolines has to the best of our knowledge not been

described. However, a clear proof of our proposal was not possible, since we could not obtain

our propargylamines with a quaternary carbon in an enantio enriched form. The yields of the

46


sequence D → G are remarkable, since many described propargylic aromatic N-Claisen

rearrangements process less efficient. Our studies clearly indicated the importance of the

suitable proton source. The use of the co-catalyst 10 is not only crucial for the activation of

the Zn-catalyst, but also for the last proton catalyzed steps. The reaction of propargylamines

with stronger acids like HCl gave no quinoline derivatives. Instead we observed elimination

of the aniline substituent. A weak acid like binol-derived phosphoric acid, (R)-3,3’-bis(9-

anthracenyl)-1,1’-binaphthyl-2,2’-diylhydrogenphosphate is also working, but it cannot be

used in combination with 8.27

Scheme 28. Proposed mechanism.

2.8 Further transformation/Application

The dihydroquinoline product obtained from this consecutive method can further be used for

several purpose such as metathesis or cycloisomerization, which will lead further to increase

in number of rings in the systems.

Figure 9. Different possible transformation of the dihydroquinoline product obtained by the

above described consecutive process.

47


2.8.1 Metathesis

Carbon-carbon bond formation is one of the main interests in organic synthesis. In this

context olefin metathesis28 i.e. the exchange of alkylidene allows the redistribution of

fragments of different olefins and generates new carbon-carbon double bond (Scheme 29).

Last few decades this reaction has taken a major role in organic synthesis and has matured

from a “black box” laboratory curiosity to a useful synthetic methodology for the synthesis of

carbon-carbon double bonds.29 Olefin metathesis, one of the most efficient transition metal-

mediated C–C bond forming reactions, has emerged during the last few years as a powerful

synthetic strategy for obtaining fine chemicals, biologically active compounds, architecturally

complex assemblies, new materials and functionalised polymers tailored for specific uses,

including sensors, semiconductors and microelectronic devices. This has resulted in a broad

diversification towards sustainable technologies, and immense impact on the academic and

industrial chemical community, from production of smart, nanostructured materials to the

manufacture of new pharmaceuticals.30 Metathesis is highly important because it is often

creates fewer undesired by-products and hazardous wastes than alternate organic reactions.

The high importance of this reaction, elucidation of the reaction mechanism and discovery of

a variety of highly efficient and selective catalysts brought Noble Prize in 2005 collectively to

Yves Chauvin for postulating the new generally accepted olefin metathesis mechanism and to

Robert H. Grubbs’ and Richard R. Schrock for availing a significant number of efficient and

easy-to-handle early transition-metal and ruthenium olefin metathesis catalysts.

Scheme 29. General reaction mechanism of metathesis.

2.8.2 Metathesis catalysts

Metathesis is one metal catalyzed reaction. The catalyst systems are mainly categorized into

two types: Schrock catalyst and Grubbs’ catalyst. Schrock catalysts are generally

molybdenum(VI)- and tungsten(VI)-based (Figure 10). And Grubbs’ catalysts are on the hand

ruthenium(II) carbenoid complexes. Again Grubbs’ catalysts are of two types – generation I

and generation II, and also Grubbs' catalysts are often modified with a chelating

isopropoxystyrene ligand to form the related Hoveyda-Grubbs catalyst (Figure 11).

48


N

MoMe

Ph

Me

iPriPr

OO

Me

MeMe

Me

tBu

tBuN

iPriPr

Mo

O

OMe

F3CCF3

N

iPriPr

Mo

O

OtBu

tBuMeMePh

MeMePh

MeF3C CF3

Figure 10. Schrock catalysts for metathesis.

PCy3

RuCl

PhCl

PCy3

RuCl

PhCl

PCy3

NN

MeMeMe Me

Me Me

RuCl

ClO

NN

MeMeMe Me

Me Me

Me

Me

Grubbs' I catalyst Grubbs' II catalyst Grubbs'-Hoveyda catalyst

Figure 11. Grubbs’ and Hoveyda catalyst for metathesis.

Metathesis reaction was first commercialized in petroleum reformation for the synthesis of

higher olefins (Shell Higher Olefin Process - SHOP), with nickel catalysts under high

pressure and high temperatures. Modern applications include the synthesis of pharmaceutical

drugs31, the manufacturing of high-strength materials, the preparation of cancer-targeting

nanoparticles32, and the conversion of renewable plant-based feedstocks into hair and skin

care products.33

2.8.3 Metathesis mechanism

Initially in 1971, the mechanism for metathesis was believed to proceed through pairwise

mechanism in which two olefins enter the metal’s coordination sphere.34 Later Hérisson and

Chauvin postulated a nonpairwise mechanism in which metal carbenes and

metallacyclobutanes represent key intermediates, the overall mechanism undergoes via a

[2+2] cycloaddition/cycloreversion sequence between an olefin and metal carbene species

(Scheme 30).35 Further experimental support for this proposed mechanism was later provided

by Katz36 and Grubbs37.

49


Scheme 30. Mechanism for metathesis proposed by Hérisson and Chauvin.

The outcome from olefin metathesis completely depends on the olefin structure. Highly

strained cyclic olefins undergo ring opening metathesis polymerization (ROMP)38, again α,ω-

dienes will undergo ring closing metathesis (RCM) to form five-, six-, or higher membered

hetero39 or carbocyclic olefins in presence of suitable olefin metathesis catalysts.40 Under

ethylene atmosphere or in presence of acyclic olefins, cyclic olefins form acyclic dienes via

ring-opening metathesis (ROM)41 or ring-opening cross metathesis (ROCM)42.

2.8.4 Present study on metathesis- application of the tandem reaction

The product obtained from the tandem hydroamination reaction can be used for metathesis

reaction. First we have carried metathesis using compound 40. There was no reaction found

when 40 was treated with Grubbs’I. Although 40 reacts with Grubbs’II and Hoveyda II, but it

end up with polymerization (Scheme 31).

Scheme 31. Initial experiment for metathesis reaction.

50


The polymerization may be due to the higher ring size. To avoid the polymerization, reaction

was carried out at lower concentration but it does not show any reactivity. Then substrates

which can give smaller ring size products were prepared. To prepare 6-membered product 61

substrate 62 is required, for 5-membered 63, substrate 64 is needed (Scheme 32).

Scheme 32. Retro synthesis of 6, 5-membered ring size product.

2.8.4.1 Substrate synthesis

The aniline derivatives are prepared from their corresponding anilines. Compound 65 was

prepared from p-methoxy aniline and allyl bromide as described in the scheme 25. Alkyne 68

is synthesized starting from allyl bromide 67 and ethynyl magnesium bromide 66 treating in

THF at -78 °C (Scheme 33).

MgBr Br+

6866 67

THF

- 78 oC

Scheme 33. Synthesis of alkynes 68.

N

MeO

Me

OMe

HN

+ N

MeO

Me

65

68 62 61

Xcat 8+10

toluene

130 oC

Scheme 34. Schematic approach of the compound 61.

51


We tried to prepare compound 62 from 65 and 68 using the tandem reaction developed in this

chapter above. But the reaction between methoxy substituted N-allyl aniline and 4-pent-1-yne

gives a mixture of several compounds, this is due to the isomerisation of 4-pent-1-yne at

higher temperature (above 100 °C) (Scheme 34). We also tried with other substrate but we

could not succeed to get wanted product (table 9). So reaction requires further optimization

for getting best results.

Table 9. Reaction of anime and alkyne to prepare the substrate for metathesis. a

Me

OMe

HN

entry amine alkyne time(h) temp(oC) product

24 130 mixture of products



65

15

69

68

69

1

2

3

aReaction condition: all reactions were carried out with 0.25 mmol amine, 0.625 mmol alkyne, 5 mol% 8 and 15 mol% 10 in 0.5 ml toluene at 130 °C in closed reaction vial.

2.9 Side reaction

During the reaction when we take 1:1 ratio of the precatalyst 9 and anilinium salt 10, we

found one side reaction between the precatalyst 9 and alkynes to get a C-C coupling product

(Scheme 35). But increasing the concentration of anilinium salt 10 the problem has been

overcome.

Scheme 35. Side reaction between the BDI-Zn catalyst and alkyne.

52


The reaction also found to be working as well as with other zinc salt (table 10). With diethyl

zinc it gives very less conversion of the C-C coupling product 70. Zinc acetate gives 50%

yield of the product whereas catalyst 8 at 130 °C gives full conversion (table 10, entry 5).

Table 10. Reaction with different zinc salt to prepare the compound 70. a

aReaction condition: all reactions were carried out with 0.5 mmol β-diimines, 0.5 mmol alkyne 5 mol% zinc catalyst and 5 mol% 10 in 0.5 ml toluene at 130 °C in closed reaction vial. bConversion in NMR.

β-Diimines 7 gives similar type of C-C coupling product with different alkynes under this

reaction condition using 5 mol% of the BDI-Zn catalyst 9 (table 11). With the alkyne 58 it

gives the coupling product 71 with 98% yield whereas alkyne 25 gives 71% coupling product

72. Reaction with phenyl acetylene gives the terminal double bond containing product 70 as

there is no possibility of isomerization (scheme 35), but with the alkyne 58 and 25 the

products undergoes isomerization to the more substituted double bond product 71 and 72.

Table 11. C-C coupling reaction with β-Diimines 7 and alkynes with BDI-Zn catalyst 9. a

aReaction condition: all reactions were carried out with 0.5 mmol β-diimines, 0.5 mmol alkyne, 5 mol% 8 and 5 mol% 10 in 0.5 ml toluene at 130 °C in closed reaction vial. bIsolated yields are reported.

53


2.10 Summary

In this chapter, the use of the zinc complex [{(i-Pr)}2BDI-ZnMe] 8 and the co-

catalyst [PhNMe2H] [SO3CF3] 10 in consecutive reaction was presented. It was the first time

to prepare 1,2-dihydroquinolines from amine and alkyne by using zinc catalyst via a

consecutive hydroamination-alkyne addition-cyclization reactions. Special ammonium salts

are necessary which act as proton source. The activator has more roles inspite of activating

the zinc catalyst, it also donates proton for the cyclization in one of the final step. For the

reaction, the first step that is the propargylamine forming step is zinc catalyzed and the second

step that is the cyclization is proton catalyzed. The mechanism of the consecutive

reaction could not completely be elucidated by experiment so one hypothesis has been given

as the mechanism. In summary, a zinc catalyst was developed, which form complex with

amines and alkynes in a consecutive reaction to form 1,2-dihydroquinoline derivatives. In

addition we showed the precatalyst has two roles for this reaction.

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Fogg, Curr. Org. Chem. 2006, 10, 185; e) S. Monfette, D. E. Fogg, Chem. Rev. 2009, 109,

3783. 41 J. A. Tallarico, M. L. Randall, M. L. Snapper, Tetrahedron, 1997, 53, 16511. 42 a) A. K. Chatterjee, R. H. Grubbs, Org. Lett. 1999, 1, 1751; b) A. K. Chatterjee, D. P.

Sanders, R. H. Grubbs, Org. Lett. 2002, 4, 1939; c) S. J. Connon, S. Blechert, Angew. Chem.

Int. Ed. 2003, 42, 1900; d) A. K. Chatterjee, T. L. Choi, D. P. Sanders, R. H. Grubbs, J. Am.

Chem. Soc. 2003, 125, 11360.

Chapter 3

Synthesis of Chiral Salen-type Ligands and

Application in Highly Enantioselective

Hydroamination

58

-------------------------------------------------------------------------------------------------------------------------------------- Synthesis of Chiral Salen-type Ligands and Application in Highly Enantioselective Hydroamination

59


3.1 Introduction

3.1.1 Asymmetric synthesis

The universe is dissymmetrical; for if the whole of the bodies which compose the solar system

were placed before a glass moving with their individual movements, the image in the glass

could not be superimposed on reality……Life is dominated by dissymmetrical actions. I can

foresee that all living species are primordially, in their structure, in their external forms,

functions of cosmic dissymmetry.

- Louis Pasteur.

This visionary written more than 100 years ago by Louis Pasteur, has profoundly influenced

the development of asymmetric synthesis in organic chemistry known as chirality. Chirality is

of fundamental significance, as most of the biologically important molecules found in nature

are optically active. A biologically active chiral compound interacts with its receptor site in a

chiral manner and enantiomers may be discriminated by the receptor in very different ways.

Thus it is pretty obvious that the two enantiomers of a drug may interact differently with the

receptor, leading to different effects.

Biological activities of different enantiomers of the chiral compounds can vary very widely. It

could be possible that only one enantiomer has the desired biological activity and the other

does not show significant activity, again sometimes both the enantiomers have identical or

almost identical bioactivity, even it is possible that both the isomers have completely different

kinds of biological activity. Enantiomers often smell and taste different. Some of the diverse

properties of enantiomers are shown in Figure 12.

The sad history of thalidomide1 reminds us the high importance of preparation of highly

enantio-enriched chiral compounds. So it is the responsibility of synthetic chemists to provide

highly efficient and reliable methods for the synthesis of chiral compounds with 100%

enantiomeric excess form, so that the tragedy of thalidomide does not repeat again. Even in

the early 1990s, about 90 % of synthetic chiral drugs were still racemic–that is, equimolar

mixtures of both enantiomers, which reflects the difficulty in the practical synthesis of single-

enantiomeric compounds.2 In asymmetric synthesis the most important, desirable and the

challenging topic is catalytic asymmetric synthesis because one chiral catalyst molecule can

create millions of chiral products just like enzymes does in the biological systems.

60


HO

Me

NMe

H

Me

(-)-Benzomorphia

(eases pain, unhabituational)

(+)-Benzomorphia

(faintly pain-easing, habituational)

O

HO

OH

(-)-Benzopyryldiol

(strong carcinogenicity)

(+)-Benzopyryldiol

(no carcinogenicity)

OH

O

H2N

O H NH2

L-asparagine(bitter)

D-asparagine(sweet)

N

S

NMe

Me

HCl

HHOAc

O

OMe

(S,S)-form is effective

in relieving myocardial infarction

O

Me

Me

(R)-carvone(spearmint odor)

(S)-carvone(caraway odor)

NSN

N

O

O

NH

tBuHO

(R)-timolol (adrenergic blocker)

(S)-timolol (ineffective)

O NH

Me

Me

HOH

(S)-propranolol

(98 times active than (R) isomer)

Me OOH

Sex pheromone of the Japanese beetle

(its isomer is inactive)

Figure 12. Example of pharmaceuticals and natural products with diverse properties of the

enantiomers.

In the twentieth century, homogeneous chiral catalysts have been developed with which a

large breakthrough was obtained in the asymmetrical synthesis. Since the first report in the

1960’s, a wide variety of organometallic complexes have developed for the asymmetric

catalysis.3 The high importance of this topic brought Noble Prize in 2001 to William S.

Knowles and Ryoji Noyori for their work on chiral catalyzed hydrogenation reactions (Scheme

36) and K. Barry Sharpless for his work on chiral catalyzed oxidation reactions (Scheme 37).4

Scheme 36. Noyori asymmetric hydrogenation.

61


Scheme 37. Sharpless epoxidation.

These catalyst systems show high enantioselectivity in the reactions, but their use is limited to

specific classes of substrates. For example, the Sharpless epoxidation failed in the asymmetric

epoxidation of olefins, in which there is no alcohol functional group in the allylic position.

The Jacobsen and Katsuki epoxidation allows the enantioselective formation of epoxides from

various cis-substituted olefins using a chiral salen-manganese catalyst and a stoichiometric

oxidant. Also for hydroamination reactions, the asymmetric approach to the synthesis is

particularly attractive, because chiral amines are valuable for industry and drugs.5 Currently,

catalysts that allow the formation of enantiomerically pure amines are limited.

3.1.2 Salen ligands in asymmetric synthesis

Numerous chiral metal complexes have been synthesized for various highly enantioselective

reaction.6 Salen ligands have attracted considerable attention due to their easily tuneable

stereochemical properties, including coordination geometries and conformations, which

readily create effective chiral environments around the metal centres, resulting in exquisite

selectivity in asymmetric catalysis. Salen ligands are generally the Schiff bases, prepared by

the condensation of salicylaldehyde and amine. SalenH2 is commercially available. It was first

prepared by P. Pfeiffer in 1933 (Scheme 38).7

Scheme 38. Synthesis of salen ligands.

In 1938, Tsumaki reported that the cobalt(II) complex, Co(salen) reversibly bound O2, which

led to intensive research on cobalt complexes of salen and related ligands for their capacity

for oxygen storage and transport, looking for potential synthetic oxygen carriers.8 Although

salen ligands are reported long back but its application in asymmetric catalysis was unknown

until 1990. In 1990, Jacobsen and Katsuki applied independently salen ligands in

enansioselective epoxidation of un-functionalized olefins.9 Compare to the Sharpless

epoxidation, the Jacobsen epoxidation has a broad range of starting materials10 (Scheme 39)

62


also opened up the broad application in enantioselective ring opening of epoxides, conjugate

addition, hetero Diels Alder reaction, cyclopropanation and other reactions.

Scheme 39. Jacobsen-Katsuki enantioselective epoxidation.

Since the synthesis of first salen metal complex, the application of salen complexes has grown

rapidly and a broad range of asymmetric catalysis has now been described including

oxidations, additions and reductions. Nowadays salen metal complexes are among the most

enantioselective catalysts and find applications in different reactions as heterogeneous and

homogeneous catalysts,10a such as cyanosilylation11, cycloaddition12, hydrocyanation13 and

many more. The salen metal catalysts have applications in many asymmetric

organic reactions. Some examples are shown in the table 12.

Table 12. Reaction of salen metal complexes in asymmetric synthesis.

3.1.3 Motivation

Intramolcular asymmetric hydroamination of aminoalkenes generally gives either pyrrolidine

or piperidine systems (Scheme 40). For last few decades there is a lot of progress in high

efficient ligand synthesis for asymmetric hydroamination. Those catalyst systems are mainly

63


efficient for pyrrolidine systems. But for piperidine systems there are very few catalysts

which are moderately efficient. Again ligand preparation and storage is another problem for

those catalyst systems. So it is a highly important target for organic chemist to find out ligand

systems which are very easily synthesizable and easy for storage and more importantly very

efficient for piperidine systems.

Scheme 40. General scheme of intramolecular hydroamination reaction of primary amino

alkenes.

Although there are lots of investigation over this topic but there is still no general solution in

respect to both reactivity and selectivity. Although piperidine moiety is an important building

block for several natural products and pharmaceuticals (Figure 13),14 mostly the study on

enantioselective hydroamination is concentrated on pyrolidine systems, but for piperidine

systems there are limited reports with moderate results.15 Here main focus has given to the

development of a methodology to synthesise highly enantioenriched piperidine systems.

OO

O

HN

F

(+)-Paroxetine

(antidepressant )

MeO

O

N

F

(+)-Femoxetine

(selective serotonin

reuptake inhibitor)

Me

NH

NH

Me

H

X

X = O (+)-Dasycarpidone

X = CH2 (+)-Ulein

(Antimalarial activity)

NH

O

N

H

HMe

Me

(-)-16-Episilicine

NH

N

O

HO

Ph

HH

Ervitsine

N

N

O

O

O

Mbs

H

route to madangamines

N

Monomorine

(trail pheromone)

N

NHAcH

(+)-epiquinamide

Figure 13. Example of pharmaceuticals and natural products containing piperidine systems.

64


Despite the fact that the salen complexes show high activity and selectivity, their application

in asymmetric hydroamination reaction was not reported yet. During our investigations on

asymmetric catalytic intramolecular hydroamination, Mustafa Biyikal (doctoral thesis 2009)

found that heterobimetallic salen type ligand system provides very high reactivity and

enantioselectivity. Herein, we report first asymmetric hydroamination to prepare highly

enantioriched piperidine systems from nonactivated amino-alkenes using heterobimetallic

salen complexes. A series of monometallic complexes have been developed for asymmetric

hydroamination (Figure 14). To date, the highest activity and selectivity is shown by the rare

earth metal catalysts, but their sensitivity towards air, moisture, and functional group limit

their use in organic synthesis.16 For this reason the preparation and storage of these rare earth

metal complexes is possible only under absolute conditions. Again cost of these metal-ligand

systems limits its application in industry. However, zinc tolerates numerous functional groups

and found applications as cheap catalyst and reagent for many reactions.

Figure 14. Monometallic catalyst systems for asymmetric hydroamination by different

groups.

Recently, we reported the first hydroamination reaction of nonactivated olefins at room

temperature by using dimeric tetra-nuclear zinc complexes derived from new generation of

Schiff base ligands having two centres for metal coordination (Scheme 18, chapter 1).17 The

high activity of these complexes prompted us to develop novel air and water resistant chiral

salen zinc complexes for intramolecular asymmetric hydroamination of nonactivated amino-

olefins. During the investigation on asymmetric hydroamination our group has developed a

65


novel hetero bi-metallic chiral salen-type catalyst consisting four chiral centres, which shows

high reactivity as well as selectivity for piperidine systems.

3.2 Synthesis of Ligand systems

The design of an appropriate ligand sphere is the most important part in catalysis. The activity

and selectivity of catalysts depend to a large extent on the nature of the ligands. Fine tuning of

steric and electronic requirements in the ligand is essential to accomplish high activity and

selectivity. The nature of ligand (type, size, basicity, capabilities of hard/soft ligand

functionalities) promptly affects the properties such as mononuclearity, cation size, Lewis

acidity; from these the reactivity of the complexes can be determined. The synthesis and

characterization of the ligands is the subject of this chapter. The intention is to design and

prepare new ligands which are able to stabilize the complexes primarily with cheap metal

such as zinc. The second goal is applying these ligand systems for enantioselective

hydroamination of primary amino-olefins, which will be the subject in this chapter.

3.2.1 Synthesis of bromine containing ligand systems

While developing new ligand systems for hydroamination in our group, Mustafa Biyikal

found an unexpected rearrangement step to get the compounds 76, 77. In our previous report

we have demonstrated a novel synthetic route for the synthesis of dimeric tetranuclear zinc

complexes.19 Following the same route herein we synthesised bromine containing salen

ligands from methylated 3,5,7-tribromo tropolone 74 involving a rearrangement step as the

major step giving the product having two different amines 76, 77. Tropolone 73 is first

brominated with bromine in methanol at room temperature to get the 3,5,7-tribromotropolone

74 with over 98% yield. Under Mitsunobu reaction condition 74 is treated with

triphenylphosphine, DIAD and methanol in ether to get methyl protected 3,5,7-

tribromotropolone 75 with 79% yield (Scheme 41).

OOHBr

Br

Br

PPh3/DIADMeOHEt2O79%

OOMeBr

Br

Br

OOH Br2

MeOHRT98%73 74 75

Scheme 41. Synthesis of methylated 3,5,7-tribromotropolone 75.

Methyl protected 3,5,7-tribromotropolone 75 is then treated with first arylethylamine in

hexane at room temperature for overnight and then isopropylamine was added into the

solution at -78 °C, a rearrangement product salicylaldimine ligand (76, 77) is formed in which

66


both the amines are present. This step gives very low yield due to the formation of other

possible side products containing two isopropyl anime and also containing two

arylethylamine. Condensation of salicylaldimine ligand (76, 77) with chiral (S,S)-

cyclohexanediamine 78 gives the bromine containing Salen-type ligands (79, 80) as orange

crystals with over 90% yield. The NMR spectra of bromine containing salen type ligands are

identical with the Mustafa Biyikal thesis (Scheme 42).

OOMeBr

Br

Br

1.NH2R

/hexane, RT

2. MeMe

NH2-78 oC to RT

OH HN R

Me

H2N NH2

EtOH, 80 oC

N N

OH

NH

Br

Br

Br

Br

HO

HN

R RMeMe

BrBr

75 76 R = Cyclohexyl (52%)

77 R = 1-Napthyl (50%)

79 R = Cyclohexyl (96%)

80 R = 1-Napthyl (91%)

78

(S)(S)(S)

(S)

N

Me

Me

Scheme 42. Synthesis of bromine containing salen ligands.

The salicylaldimines 76, 77 forms from 75 via a rearrangement step. It is believed that

isopropylamine is reacting at the 6 position of 75 to form the compound 81 (Scheme 43).

Then it forms a bicyclic compound 82 through isomerisation. Bicyclic compound 82 then

rearrange to more stable salicylaldimine product 76, 77.

Scheme 43. Mechanism of rearrangement step from 75 to 76, 77.

The ligand systems (79, 80) contain four stereo centres. A series of bromine containing ligand

systems are been synthesized changing the stereo-centres by taking different aryl amine in the

67


rearrangement step following the above procedure. The (S,S,R,R) salen-ligand 79 and

(S,S,S,S) salen-ligand 83 are diastereomers, where the chiral centre in the N-1-Phenyethyl

group was changed. Also changing the substituent over the N-aryl/alkyl group with N-1-

naphthylethyl group ligand 80 is been prepared. Ligands are air and moisture stable for

months. The precatalyst 84 is prepared simply by heating ligand 79 with Zn(OAc)2·2H2O in

ethanol for 5 h. Precatalyst is stable to air and moisture like the ligands for months.

Figure 15. Bromine containing salen-ligands and precatalyst.

3.2.2 Synthesis of bromine free ligand systems

Other salen ligands are also prepared modifying different substituent over the ligand.

Together with Grzegorz Dolega and Lenard Hussein, we have varied the bromine and we

prepared the ligands 92. These bromine free ligands are synthesized following a different

route starting from commercially available 2,6-dibromo phenol 85. 2,6-Dibromo phenol 85 is

first protected with MOMCl at 0 °C to get MOM protected 2,6-dibromophenolate 86 as

yellow oil with 97% yield. The MOM protected 2,6-dibromo phenol 86 reacted with chiral

amine 87 by Buchwald-Hartwig cross coupling reaction with Pd2(dba)3, racemic BINAP and

t-BuONa in toluene heated at 75 °C for 5 hours which leads to the compound 88 as yellow oil

with 76% yield. Then 88 is formylated in the presence of the base PhLi/BuLi and DMF as the

formylating agent in THF. It gives 89% of the formylated product 89 as colourless crystals.

The conversion of 88 from 89 requires two bases, because the first base takes the proton from

the amine and the second one reacts with the C-Br bond. MOM deprotection of 89 by

hydrolysis in acid medium gives 95% of the free alcohol 90 as yellow crystals and finally

condensation of 90 with chiral diamine 91 in toluene via an azeotropic distillation method

leads to bromine free ligand systems 92 with 85% yield as orange crystals. During the ligand

preparation most of the solid compounds are been purified by crystallization to get the best

enantiopure product.

68


Scheme 44. Synthesis of bromine free salen ligands.

Similar to the bromine containing ligands here also we have prepared a series of bromine free

ligands varying the four stereo centres in 92 to check the influence of each stereo centres over

the reactivity and selectivity. Ligands 93, 94 and 96 are diastereomers. Ligands 93 and 94 are

prepared by taking different enantiomers of aryl amine 87. For ligand 96 we have changed the

chiral centre over the cyclohexane diamine. Not only the stereo-centre we have changed but

Figure 16. Bromine free salen ligand systems.

69


also we have synthesized ligands varying the substituents in 91. Ligand 95 has been

synthesized by taking chiral 1-naphthylethyl amine as 87. The diamine part was also modified

with chiral binaphthyl diamine group to get the ligand 97. Taking 87 as (S)-

tetrahydronaphthalene-1-amine and 91 as (S)-binaphthyl diamine ligand 98 has been prepared.

Precatalysts 99 and 100 have been prepared by direct condensation and metal insertion in the

final step of the ligands 93 and 98 respectively. The ligands are orange crystals and the

precatalysts are yellow powder and both are air and moisture stable. The crystal structure of

the precatalyst 100 has been shown in the Figure 17. The zinc complex 100 crystallizes in the

orthorhombic system having space group P212121 with four asymmetric molecules in the unit

cell. The crystal packing has been shown in the Figure 18.

Figure 17. Crystal structure of 100. For better clarity, the H atoms are omitted. Selected bond

lengths [Å]: Zn1-O2 1.920(2), Zn1-O1 1.940(2), Zn1-N1 2.025(3), Zn1-N2

2.130(2), Zn1-O3 2.318(2). Selected bond angles [°]: O2-Zn1-O1 118.08(10), O2-Zn1-N1

146.56(10), O1-Zn1-N1 92.68(10), O2-Zn1-N2 89.74(9), O1-Zn1-N2 107.88(9), N1-Zn1-

N2 93.01(10), O2-Zn1-O3 83.72(9), O1-Zn1-O3 94.54(9), N1-Zn1-O3 80.90(9), N2-Zn1-

O3 157.06(9).

70


Figure 18. Crystal molecular packing of the compound 100.

3.3 Optimization

3.3.1 Optimization of metal combination

In these ligand systems there are two pockets: N1,N2,O1,O2 and O1,O2,N3,N4 for metal co-

ordination. Precatalyst (99, 100) alone does not show reactivity towards asymmetric

hydroamination. Precatalyst with the combination of excess Me2Zn also does not show any

reactivity (table 13, entry 1). So further studies went for searching the best metal combination

for these kinds of ligand systems. Different transition metals and also late transition metals

were been taken in combination with zinc precatalyst and tested for the intramolecular

hydroamination reaction to convert the amino alkene 101 to the piperidine 102. (The crystal

structure of the naphthoyl protected product of the piperidine 102 is shown in Figure 19). The

results are shown in table 13. The combinations of zinc with Sm, La (table 13, entry 2- 3) with

Figure 19. Crystal structure of the naphthoyl protected product of the piperidine 101 after the

reaction with the ligand 96. This crystal crystalizes as triclinic system having space group P-1

with two asymmetric molecules in the unit cell.

71


or without the presence of base KBTSA are inert for this reaction. Combination of zinc and

zirconium shows reactivity as well as selectivity (table 13, entry 4 and 7). Zr(NMe2)4 shows

(96% ee) higher reactivity and selectivity over ZrCl4 (22% ee). Among titanium salts although

Cp2TiCl2 does not show reactivity (table 13, entry 10) but Ti(NMe2)4 shows high reactivity

(table 13, entry 5). Ti(NMe2)4 gave almost racemic mixture. Reaction with In, Ga and Cu do

not show any reaction (table 13, entry 8, 9, 11). Reaction has been tried also with Lewis acid

like Et3B.THF, but no reaction has been found (table 13, entry 6).

Table 13. Standardisation of metal combination.a

entry metal sourcea

M1 M2

KBTSA

(mol %)

temp

(°C)

time

(h)

conversionb

(%)

eec

(%)

1

2

Me2Zn Me2Zn

Me2Zn La(OTf)3

0

15

120

120

24

24

0

0

--

--

3 Me2Zn SmCl3 15 120 24 0 --

4 Me2Zn Zr(NMe2)4 -- 80 24 >99 96

5 Me2Zn Ti(NMe2)4 -- 80 72 >99 2

6 Me2Zn Et3B.THF -- 120 36 0 --

7 Me2Zn ZrCl4 -- 80 4 d >99 22

8 Me2Zn InCl3 15 120 24 0 --

9 Me2Zn GaCl3 15 120 24 0 --

10 Me2Zn Cp2TiCl2 15 120 24 0 --

11 Me2Zn CuBr2 25 120 24 0 --

aReaction conditions: amino-alkene 101 (0.25 mmol) in toluene (0.5 ml) at 80 ° C, 15 mol% of each metal has been used. bThe conversion was determined by 1H NMR spectroscopy. cThe enantiomeric purity was determined by chiral HPLC column (R,R) Beta-Gem 1 with 25:75 mixture of isopropanol and hexane, flow rate 0.75 ml/min.

72


3.3.2 Optimization of reaction condition

Next the ratio of the metal combination of zinc and zirconium were optimized (see table 14).

Reaction of ligand with only zinc results no reaction. The combination of ligand with only

Zr(NMe2)4 in 10:15 ratio provides product with full conversion with 77% ee (table 14, entry

2). Decreasing the ratio of ligand and Zr(NMe2)4 to 10:9 gives better ee (90%) but takes

longer reaction time (table 14, entry 3). The ratio of ligand, Zn, Zr in 10:15:15 showed full

conversion with 97% ee (table 14, entry 4). This result leads us to propose the in-situ forming

catalyst is a hetero-bimetallic complex. Decreasing the ratio of ligand and metals to 10:10:10

the ee has increased to 98% with less conversion (table 14, entry 5). We observed the

dropping of enansioselectivity by decreasing the ligand loading (table 14, entry 6). Precatalyst

99 shows better result but with longer reaction time (table 14, entry 7).

Table 14. Standardization of ligand metal ratio.a

Entry ligand (93) Me2Zn Zr(NMe2)4 time conversionb eec

(mol%) (X mol%) (Y mol%) (h) (%) (%)

1 10 30 0 24 0 --

2 10 0 15 18 >99 77

3 10 0 9 36 99 90

4 10 15 15 18 >99 97

5 10 10 10 84 81 98

6 5 7.5 7.5 24 >99 89

7 Precatalyst 99

10 -- 10 5 d 90 96

ligand 93

X%Me2Zn

Y% Zr(NMe2)4toluene

D

NH2

Ph Ph

101

HN

*

PhPh

Me

102

aReaction conditions: amino-alkene 101 (0.25 mmol) in toluene (0.5 ml) at 80 ° C. bThe conversion was determined by 1H NMR spectroscopy. cThe enantiomeric purity was determined by chiral HPLC column (R,R) Beta-Gem 1 with 25:75 mixture of isopropanol and hexane, flow rate 0.75 ml/min.

73


3.3.3 Optimization of the catalytically active salen-ligands

Now all the synthesized ligands are tested for the asymmetric hydroamination reaction taking

amino-alkene 101 as the standard substrate under the optimized condition, that is, in presence

of 10 mol% of the ligand, 15 mol% of each dimethyl zinc and tetrakis(dimethylamino)

zinconium in toluene at 80 °C.

3.3.3.1 Reaction with bromine containing salen ligands

First, all the bromine containing ligands are tested for the asymmetric intramolecular

hydroamination reaction taking 101 as the standard substrate to prepare piperidine 102 under

the optimized condition. The results are summarized in table 15. We observed ligand 79 with

(S,S,R,R) configuration gives 96% ee of piperidine 102 with full conversion in 24 h at 80 °C.

Table 15. Reaction of 102 with bromine containing ligands and precatalyst.a


Ligand 83 with (S,S,S,S) configuration which is the diasteroisomer of the ligand 79 gives 87%

ee (table 15, entry 3). It shows that although the diamine stereocentres are responsible for the

enantioselectivity but the stereocentres of aryl/alkyl amines have role over the

enantioselectivity of the product. Ligand 80 which contain the naphthyl group was also tested

for the reaction and it shows low reactivity as well as selectivity (after 5 days 80% conversion

with 78% ee). It could be the steric bulkiness is the problem for reactivity and selectivity. The

precatalyst 84 with 15 mol% of Zr(NMe2)4 gives 88% of piperidine 102 after 5 days with 95%

74


ee. So it shows that among the bromine containing ligands and precatalysts the ligand 79 with

(S,S,R,R) configuration is giving the best result.

3.3.3.2 Reaction with bromine free salen ligands

To understand the role of bromine in the ligand systems, bromine free ligand systems were

synthesized. Ligand 93 is the bromine free ligand corresponding to 79. Ligand 93 shows

better enantioselectivity (98% ee) than the bromine containing one 79 (table 16, entry 1). Also

different substituents in the ligand system have been modified to understand the role of them.

Table 16. Reaction of 102 with bromine free ligands and precatalyst.a


Here the four stereocentres are also been changed and different ligands are prepared (Figure

16). Reaction has been carried out taking ligand 94 which is the diastereo isomer of the ligand

93 (table 16, entry 2). Decrease of enantioselectivity observed in this case which shows

similar trend as it was for the bromine containing ligand (table 15, entry 3). Increasing the

steric bulk over the aryl amine chiral centre with 1-naphthylethylamine, does not affect much

75


on enantioselectivity, with ligand 95 it gives 94.5% ee. Later cyclohexadiamine part also been

modified with chiral binaphthyldiamine group. But this ligands show very poor

enantioselectivity. Ligands 97 gives almost racemic mixture and ligand 98 gives 16.5% ee

(table 16, entry 4, 5). One interesting result has been found when reaction was done with the

ligand 96 which is another diastereo isomer of the ligand 93 and 94, where the stereocentre

over chiral diamine has been changed to (R,R). Interestingly the opposite isomer of the

piperidine 102 was obtained in this case (table 16, entry 6). Ligand 96 is slightly less reactive

and less selective compare to the corresponding (S,S,R,R) ligand 93 (table 16, entry 6).

Similar to the bromine containing precatalysts 84 (table 15, entry 4), here also precatalyst 99

takes longer time and gives almost similar enantioselectivity (table 16, entry 7). Precatalyst

100 gives equal ratio of the enantiomers (table 16, entry 8).

From this it can be concluded that although the aryl/alkyl amine stereocentre has role in the

stereoselectivity, but the chiral diamine centres determine the stereochemistry of the product.

Among all the synthesized ligands, ligand 93 is the best ligand for the enantioselective

hydroamination reaction to prepare the piperidine systems. So further reactions with different

other substrates were carried out using ligand 93 as the standard ligand.

3.4 Substrate synthesis

A series of substrates were synthesized to check the applicability of the ligand systems.

Substrates 101, 106 - 111 (Figure 20) are been synthesized starting from the corresponding

alkyl or arylnitrile following the literature procedure (Scheme 45).18 The alkyl or arylnitriles

103 are treated with 4-bromo-1-butene in the presence of 1.5 - 2 equivalents of NaH at ice

cold temperature in THF to get the nitrile derivative products 104. This nitrile is then further

reduced with lithium aluminium hydride to obtain the corresponding aminoalkenes 105

(Scheme 45).

Scheme 45. Preparation of the starting materials for hydroamination reaction.

76


Figure 20. Substrates 101, 106 – 111 for hydroamination reaction.

Compound 119 was synthesized starting form 2,2-diphenylpent-4-enal 113. It is treated with

Wittig reagent 114 in presence of the base potassium tert-butoxide, which gives the product

vinyl ether 115 with 69% yield. Hydrolysis of 115 gave aldehyde 116 in 84% yields, which is

the elongation of one carbon of the starting material 113. Now reduction with NaBH4 in

methanol gives 74% of the alcohol 117. Finally Mitsunobu reaction of 117 with PPh3/DIAD

and (PhO)2P(O)N3 gives 66% of the corresponding azide 118, which on treatment with PPh3

in water gives the aminoalkene 119 with 68% yield (Scheme 46).

Scheme 46. Preparation of the starting material 119.

The substituted di-arylaminoalkenes 124 have also been prepared following the literature

procedure.19 First potassium cyanoacetate 120 was synthesized by treating cyanoacetic acid

and potassium tert-butoxide in ethanol, which gives white solid of the product 120 with 98%

yield.

Scheme 47. Preparation of potassium cyanoacetate 120.

77


When 2 equivalents of substituted aryl halide 121 treated with little excess of potassium

cyanoacetate 120 in the presence of Pd(dba)3 at 140 °C in xylene, it undergoes a oxidative

decarboxylation reaction to give the nitrile 122. This step is although yielding well in small

scale but for large scale it gives very poor yield (from 40 to 55%) (Scheme 48).

Scheme 48. Preparation of substituted di-arylnitrile 122.

Then di-arylnitrile 122 is converted to the corresponding aminoalkenes (Scheme 49)

following the same procedure as described in Scheme 45. In these steps moderate to very

good yields were obtained. Using this above described method, a series of substrates 125 –

130 have been prepared (Figure 21).

Scheme 49. Preparation of substituted di-arylaminoalkenes 124.

NH2

MeMe

NH2NH2 NH2

Me

NH2

Me

NH2

OMe OMe

125 126 127

128 129 130

Figure 21. Substituted di-arylaminoalkenes substrates 125 – 130 for hydroamination reaction.

78


3.5 Results and discussion

Our prior observation is that this hetero bimetallic salen types of catalyst catalyzed the

intramolecular hydroamination/cyclization reaction allows access to the derivatives of

piperidines in nearly quantitative yield using 10 mol% of the catalyst loading. To monitor the

reaction, it has been done in sealed NMR tube using deuterated solvent. As shown in Figure

22, conversions were determined from the integration of substrate a, b protons and product c

protons.

Figure 22. NMR study of intramolecular hydroamination with ligand 93 to prepare the

piperidine 102.

c

a

b

Zr(NMe2)4

79


Reactions were done with all the synthesized substrate taking 10 mol% of ligand 93 and 10

mol% of Me2Zn and 15 mol% of Zr(NMe2)4 in toluene. Table 17 shows the substrates scope

for the primary amines containing geminal disubstitution on the alkyl linker. Results show

that geminal diphenyl substituted amino-alkene 101 gives highest reactivity as well as

selectivity (table 17, entry 4); it forms the piperidine 102; within 19 h gives full conversion

and 98% enantioselectivity at 80 °C. Cyclohexyl substituted amino-alkene 108 undergoes

cyclization at 80 °C to the piperidine 133 in 41h and gives 78% ee (table 17, entry 3).

Dimethyl substituted piperidine 131 is formed at 120 °C and takes longer time and 46%

enantioselectivity was obtained (table 17, entry 1). No reaction was observed for cyclopentane

substituted amino-alkene 107 even at higher temperature (table 17, entry 2). Reaction was

also done by changing the position of geminal disubstituted phenyl groups (table 17, entry 5).

Compound 119 shows less reactivity but moderate selectivity; it gives 134 with 64% ee in

48 h. Racemic mixture of the compound 110 was also reacted for cyclization and it gives the

diastereomer 135 full conversion with 56% ee and 67% dr. Amino-alkene 111 undergoes

reaction with full conversation but during HPLC we could not separate the peaks to measure

the ee value of the piperidine 136. Mono-substituted amino alkene 109 does not show any

reaction (table 17, entry 8).

In table 18, hydroamination/cyclization of substituted aryl amino alkenes are been listed.

Although the reaction from 101 to 102 (table 17, entry 4) shows highest selectivity, but the

substitution over the phenyl ring diminishes the selectivity. This can be due to the too much

steric crowding or may be due to the electronic effect. Di(p-methyl)phenyl substituted amino

alkene 125 undergoes complete cyclization with 80% ee of the product 138 (table 18, entry 1).

Here also mono substituted amino alkenes 126 and 129 do not undergo reaction (table 18,

entry 2, 5). Diastereomer 140 was also prepared with 44.7% ee (table 18, entry 3). Increasing

the steric hindrance over the di-substitution decreases the enantioselectivity (table18, entry 4);

compound 128 gives the piperidine product 141 with only 45% ee. Again substitutions with

electron donation group decreases further the enantioselectivity for the piperidine systems.

Amino alkene 130 cyclizes to the piperidine 143 with 31% ee.

Reactions were also done with amino alkenes derived from aniline and benzyl amine (table

19). But for this case no reaction was found (table 19, entry 1 - 4).

These results show that the intramolecular hydroamination reaction was influenced greatly by

the substitution pattern on the aminoalkene. Geminally di-substituted substrates are more

reactive for the hydroamination reaction.

80


Table 17. Asymmetric hydroamination with di-alkyl or di-aryl substituted aminoalkenes. a

NH2

R R

10 mol% Ligand 93

15 mol% Me2Zn

15 mol% Zr(NMe2)4

toluene

80 oC

HN

*

RR

Me

entry substrate product time (h) conversion(%) b ee (%)c

72 >99 46

48 0 --

41 >99 78

19 >99 98

48 55 64

24 >99 56(dr: 67)

22 >99 --d

48 0 --

1 106

2 107

3 108

4 101

5 119

6 110

7 111

8 109

NH131

NH

Me

Me

Me

Me

NH

Me

NH

Me

Ph

Ph

PhPh

NH

Me

NH

Me

Ph

132

133

102

134

135

NH

Me

Ph

137

NH

Me

Ph

136

Ph

aReaction conditions: amino-alkene 101 (0.25 mmol) in toluene (0.5 ml) at 80 ° C. bThe conversion was determined by 1H NMR spectroscopy. cThe ee was determined by chiral HPLC column (R,R) Beta-Gem 1. dpeaks could not be separable in HPLC.

81


Table 18. Asymmetric hydroamination with substituted aryl amino alkenes. a

entry substrate product time (hr) conversion (%)b ee(%)c

24 >99 80

24 0 --

24 >99 44.7

24 >99 45

48 -- --

24 >99 31

1 125

2 126

3 127

4 128

5 129

6 130

HN

MeMe

MeMe

NH

Me

HN

Me

Me

HN

Me

HN

Me

HN

OMeOMe

Me

138

139

140

141

142

143

aReaction conditions: amino-alkene 101 (0.25 mmol) in toluene (0.5 ml) at 80 ° C. bThe conversion was determined by 1H NMR spectroscopy. cThe enantiomeric purity was determined by chiral HPLC column (R,R) Beta-Gem 1.

82


Table 19. Asymmetric hydroamination with amino alkenes derived from aniline and benzyl

amine. a

NH2m

n

10 mol% Ligand 93

15 mol% Me2Zn

15 mol% Zr(NMe2)4

toluene

80 oC

NH

m

n

Me

m = 0, 1, -O-CH2n = 0, 1

NH2NH

Me

entry substrate product time conversionb ee

(h) (%) (%)

NH2NH

Me

NH2 NH

Me

O

NH2 NH

O

Me

72 0 --

72 0 --

72 0 --

72 0 --

1

2

3

4

144 148

145

146

147

149

150

151

aReaction conditions: amino-alkene 101 (0.25 mmol) in toluene (0.5 ml) at 80 ° C. bThe conversion was determined by 1H NMR spectroscopy.

Reactions were also done with the substrates to form pyrrolidine (156 - 158) as well as

azepane (159) systems (table 20). Geminal di-methyl substituted amino alkene 152 does not

react at 80 °C (table 20, entry 1). At higher temperature (120 °C) it isomerizes to the internal

double bond. Cyclopentane substituted compound 153 shows slow reactivity with 57% ee

(table 20, entry 2). Di-phenyl substituted compound 154 is highly reactive, but gave very less

selectivity (table 20, entry 4). No reaction was found for the preparation of azepane from the

amino alkene 155 (table 20, entry 5).

83


Table 20. Asymmetric hydroamination with primary amino-alkene to form pyrrolidine and azepane. a

aReaction conditions: amino-alkene 101 (0.25 mmol) in toluene (0.5 ml) at 80 ° C. bThe conversion was determined by 1H NMR spectroscopy. cThe enantiomeric purity was determined by chiral HPLC column (R,R) Beta-Gem 1.

The substrates get more benefit for kinetic favour due to the fact that the geminal di-

substitution decreases the conformational freedom of the aminoalkene, favouring reactive

conformations (Thorpe-Ingold effect20) (Figure 23). Again more electron rich and also more

steric congested groups also decrease the selectivity. It can be seen from the data in Figure 23

that for a given catalyst, reaction time decreased with increasing steric demand of the geminal

substituents. But it is upto a certain limit, over steric crowdedness again decreases the

selectivity (table 18, entry 4).

84


NH

131

Me

Me

Me

NH

MeNH

Me

Ph

Ph

133134

NH

Me

Ph

137

>99% conversion, >99% conversion >99% conversion 0% conversion

98% ee 78% ee 46% ee --

19 h 41 h 72 h 48 h

> > >

Figure 23. Thorpe-Ingold effect in intramolecular hydroamination catalyzed by ligand 94 and

zinc and zirconium as the metals.

3.6 Mechanism study

To understand the reaction mechanism, first we have to get information about the active

centre in the catalyst. As there two pockets N1,N2,O1,O2 and O1,O2,N3,N4 are available for

metal to coordinate, so first we carried out reaction taking the ligand systems where there is

the possibility of having only one pocket, i.e. the well-known Jacobsen ligand 160. As we

know ligand or precatalyst with only zinc does not show any reactivity for our reaction, so we

treated the Jacobsen ligand 160 with Zr(NMe2)4 in the ratio of 1:1. And we found although

amino-alkene 154 shows high reactivity to form pyrolidine 158 with very low selectivity but

amino-alkene 101 stays inert. Which shows that the first pocket N1,N2,O1,O2 is not fit

enough for the piperidine systems at our particular condition and it is the second pocket

O1,O2,N3,N4, where reaction is taking place.

Scheme 50. Reaction of amino alkene 154 and 101 to prepare pyrrolidine 158 and piperidine

102 with Jacobsen ligand 160.

85


Pocket N1,N2,O1,O2 is co-ordinating with zinc to prevent flexibility of the ligand. The

crystal structure shows that N3-O2 bond distance is almost double than the distance N1-O2,

so it is quite impossible to fix one metal in the pocket O1,O2,N3,N4. Zirconium can either

bind with N3 and O1 or with N4 and O2 to form the complex catalyst 161. The evidence of

forming the complex catalyst 161 is obtained from NMR study (Figure 24). As after the

formation of the complex with zirconium salt, the precatalyst 99 lost its C2 symmetry, so

each signal of the precatalyst splitted in to two different signals. Excess addition of the

zirconium salt (Ligand: Zr = 10:20), vanishes the old signal and completely transform into

trimetallic complex (one zinc and two zirconium). Trimetallic complexes also have been tried

for intramolecular hydroamination reaction, although it is highly reactive but selectivity went

down.

Figure 24. Evidence of formation of the complex catalyst 161 from NMR study.

Based on the evidences found in NMR, the following mechanism has been proposed (Scheme

51). As precatalyst 99 does not show any reaction, so it is to be assumed that the reaction is

taking place in the zirconium centre. Due to the polarization between zirconium and substrate

amine, the NHMe2 group which is co-ordinately bonded with metal is replaced by the amino-

alkene B to form the complex C. Consequently another substrate B replaces one of the NMe2

86


group to give D. Then D undergoes hydroamination reaction forming a six membered

transition state E. When another substrate B approaches to the metal centre it leads to the

product piperidine F and giving back D for the catalytic cycle.

Scheme 51. Mechanism of the intramolecular hydroamination reaction of primary amino-

alkene by heterobimatallic complex 161.

3.7 Summary and outlook

In conclusion we have developed one highly catalytically active, user friendly catalyst system

92 for enantioselective hydroamination with the very well-known salen type of ligands. The

87


ligand and precatalyst are air stable and can be stored on bench for months. We found the

combination of ligand 93, ZnMe2 and Zr(NMe2)4 is the best for achieving high

enantioselectivity of piperidine system up to 98% ee. Ligands are easily prepared from

commercially available materials and can be synthesized in gram scale. The results show that

zinc centre is necessary for getting higher selectivity. From NMR study we have showed that

zirconium is situating in one of the co-ordination centres and reaction is taking place in the

zirconium centre.

3.8 References

1 G. Blaschke, H. P. Kraft, K. Fickentscher, F. Köhler, Arzneim. Forsch. 1979, 29, 1640. 2 a) Chem. Eng. News, 1990, 68(12), 26; b) S. Borman, Chem. Eng. News, 1990, 68(28), 9. 3 a) Asymmetric Syntheis; R. A. Aitken, S. N. Kilenyi, Eds; Chapman and Hall: London, 1992.

b) A. Koskinen, Asymmetric Syntheis of Natural prducts; John Wiley and Sons: Chichester,

1993. c) Catalytic Asymmetric Syntheis; I. Ojima, Ed.; VCH: NewYork, 1993. d) R. Noyori,

Asymmetric Catalysis in Organic Synthesis; Wiley-Interscience: New York, 1994. e) M.

Nόgrádi, Stereoselective Synthesis; VCH: Weinheim, 1995. f) R. E. Gawley, J. Aube,

Principles of Asymmetric Synthesis; Pergamon: Oxford, 1996, Vol. 14. g) Comprehensive

Asymmetric Catalysis; E. N. Jacobsen, A. Pfaltz, H. Yamamoto, Eds.; Springer Verlag: New

York, 1999, Vol. 1-3. 4 a) T. Katsuki, K. B. Sharpless, J. Am. Chem. Soc. 1980, 102, 5974; b) L. Kürti, B. Czakó,

Strategic Applications of Named Reactions in Organic Chemistry, ELSEVIER Academic

Press, 2005; c) R. Noyori, Angew. Chem. Int. Ed. 2002, 41, 2008-2022; d) R. Noyori, T.

Ohkuma, Angew. Chem. 2001, 113, 40-75. 5 A. Seayad, M. Ahmed, H. Klein, R. Jackstell, T. Gross, M. Beller, Science, 2002, 297, 1676. 6 For review, see: H. U. Blaser, M. Studer, Acc. Chem. Res. 2007, 40, 1348-1356. 7 P. Pfeiffer, E. Breith, E. Lübbe, T. Tsumaki, Justus Liebig's Annalen der Chemie, 1933, 503,

84–130. 8 T. Tsumaki, Bull. Chem. Soc. Jap. 1938, 13 (2), 252–260. 9 Jacobsen, E. N. Asymmetric Catalytic Epoxidation of Unfunctionalized Olefins. In

Catalytic Asymmetric Synthesis; Ojima, I., Ed.; VCH Publishers: New York, 1993; pp 159-

202. For reviews, see: a) H. C. Kolb, M. S. Vannieuwenhze, K. B. Sharpless, Chem. Rev.

1994, 94, 2483-2547; b) M. C. Noe, M. A. Letavic, S. L. Snow, S. W. McCombie, Org.

React. 1994, 66, 109-625.

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10 a) C. Baleizão, H Garcia, Chem. Rev. 2006, 106, 3987-4043; b) P. G. Cozzi, Chem. Soc.

Rev. 2004, 33, 410-421; c) L. Canali, D. C. Sherrington, Chem. Soc. Rev. 1999, 28, 85-93; d)

N. E. Jacobsen, W. Zhang, A. R. Muci, J. R. Ecker, L. Deng, J. Am. Chem. Soc. 1991, 113,

7063-7064. 11 Q. Y. Wen, W. M. Ren, X. B. Lu, Org. Biomol. Chem. 2011, 9 (18), 6323-6330; L.

Chengwei, C. Qigan, X. Daqian, W. Shoufeng, X. Chungu, S. Wei, Eur. J. Org. Chem. 2011,

19, 3407-3411. 12 A. Decortes, A. M. Castilla, A. W. Kleij, Angew. Chem. Int. Ed. 2010, 49(51), 9822-9837. 13 Z. Zhang, Z. Wang, R. Zhang, K. Ding, Angew. Chem. Int. Ed. 2010, 49(38), 6746-6. 14 a) M. Amat, M. Pérez, J. Bosch, Chem. Eur. J. 2011, 17, 7724 – 7732; b) C. Escolano, M.

Amat, J. Bosch, Chem. Eur. J. 2006, 12, 8198 – 8207; c) B. I. Morinaka, T. F. Molinski, J.

Nat. Prod. 2011, 74 (3), 430–440; d) M. A. Capron, D. F. Wiemer, J. Nat. Prod. 1996, 59 (8),

794–795; e) K. Wei, W. Li, K. Koike, Y. Pei, Y. Chen, T. Nikaido, J. Nat. Prod. 2004, 67 (6),

1005–1009; f) A. M. Belostotskii, Z. Goren, H. E. Gottlieb, J. Nat. Prod. 2004, 67 (11),

1842–1849; g) S. J. Tan, Y. Y. Low, Y. M. Choo, Z. Abdullah, T. Etoh, M. Hayashi, K.

Komiyama, T. S. Kam, J. Nat. Prod. 2010, 73 (11), 1891–1897. 15 a) P. W. Roesky, T. E. Müller, Angew. Chem. Int. Ed. 2003, 42, 2708 – 2710; b) K. Manna,

S. Xu, A. D. Sadow, Angew. Chem. Int. Ed. 2011, 50, 1865 –1868; c) D. C. Leitch, R. H.

Platel, L. L. Schafer, J. Am. Chem. Soc. 2011, 133 (39), 15453–15463; d) F. Zhang, H. Songb,

G. Zi, Dalton Trans. 2011, 40, 1547–1566; e) S. Hong, S. Tian, M. V. Metz, T. J. Marks, J.

Am. Chem. Soc. 2003, 125, 14768-14783. 16 a) M. R. Gagné, T. J. Marks, J. Am. Chem. Soc. 1989, 111, 4108; b) M. R. Gagné, S. P.

Nolan, T. J. Marks, Organometallics, 1990, 9, 1716, c) K.C. Hultzsch, Adv. Synth. Catal.

2005, 347, 367; d) S. Hong, T. J. Marks, Acc. Chem. Res. 2004, 37, 673. 17 M. Biyikal, K. Löhnwitz, P. W. Roesky, S. Blechert, Synlett, 2008, 20, 3106–3110. 18 a) C. F. Bender, A. R. Widenhoefer, J. Am. Chem. Soc. 2005, 127, 1070-1071; b) A. J. M.

Burrell, I. Coldham, L. Watson, N. Oram, D. Pilgram, G. N. Martin, J. Org. Chem. 2009, 74,

2290; c) J. Y. Kim, T. Livinghouse, Org. Chem. 2005, 7, 1737; d) Z. Liu, J. F. Hartwig, J.

Am. Chem. Soc. 2008, 130, 1570-1571. 19 a) R. Shang, D. S. Ji, L. Chu, Y. Fu, L. Liu, Angew. Chem. Int. Ed. 2011, 50, 4470 –4474;

b) J. Plaček, F. Szőcs, D. Braun, T. Skrzek, Macromol. Chem. Phys. 1994. 195, 463 – 473; c)

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Chapter 4

Development of Easily Accessible Catalysts for Hydroamination

90

-------------------------------------------------------------------------------------------------------------------------------------- Development of Easily Accessible Catalysts for Hydroamination

91


4.1 Introduction and motivation

The high importance of nitrogen containing compounds leads us to find out efficient synthesis

method. Among other methods hydroamination is one of the most efficient methods, as it

gives waste free, highly atom economical and green pathway to prepare nitrogen containing

compounds. Last few decades research on alkene and alkyne hydroamination has been

developed mostly on transition metal based catalyzed – early transition metal, lanthanides;

actinides and late transition metal catalyzed hydroamination. In spite of having low cost,

alkali metal based reaction has rarely been focused for hydroamination reaction. There are

some literature reports which describe the uses of alkaline based metal catalyzed

intramolecular hydroamination.

In 2005, Hill et al. has described one calcium catalyzed hydroamination for pyrolidine as well

as for piperidine at room temperature.1 In 2009, Procopiou et al. found same type of ligand

environment also useful with the combination of magnesium for hydroamination reaction.2 It

is reactive at room temperature to prepare pyrolidines, at 60 °C it is reactive for piperidines

systems and even it is reactive for 7- membered nitrogen containing systems at 80 °C. They

have proposed a bi-metallic complex as the active intermediate for this reaction.

Scheme 52. Intramolecular hydroamination using β-diketiminate-stabilized magnesium

methyl complex by Procopiou et al.

In 2007, Roesky and Blechert group have synthesized aminotroponate and

aminotroponiminate calcium amides as catalysts for the hydroamination/cyclization catalysis.

Pyrrolidines are synthesized easily at room temperature and piperidines at 60 °C.3 In 2008, the

same group they have shown the same ligand environment can be useful with the combination

of other alkaline and alkaline earth metal such as K, Sr, Ba for hydroamination reaction.4

92


Scheme 53. Intramolecular hydroamination using Aminotroponate and Aminotroponiminate

Calcium Amides as Catalysts by Roesky and Blechert et al.

In 2010, group from Sadow have carried out hydroamination with magnesium containing

tris(4,4-dimethyl-2-oxazolinyl)phenylborate catalyst system which is highly reactive for

primary amino alkenes as well as secondary amino alkenes.5

Scheme 54. Intramolecular hydroamination using co-ordinatively saturated RMgMe (R =

tris(4,4- dimethyl-2-oxazolinyl)phenylborate) as precatalysts by Sadow et al.

In 2011, M. S. Hill et al. have described ligand systems with bis(imino)acenapthene, which

show unprecedented stability toward Schlenk-type redistribution and exceptional catalytic

activity toward the hydroamination of amino-alkenes.6 In the same year, Barrett, Hill,

Procopiou have described magnesium methyl and the calcium and strontium silylamide β-

diketiminate derivatives which show high reactivity for intramolecular hydroamination

irrespective of ring size.7

93


Scheme 55. Intramolecular hydroamination using β-diketiminate-stabilized magnesium

silylamides complex by Hill et al.

Again for most of the alkali metal based catalyzed reactions have their limitation in its highly

sensitive and sophisticated ligand synthesis, which makes it more costly than the metal itself.

So it is very important to find out new catalyst for hydroamination which can be easily

synthesizable as well as with low cost. During our work on hydroamination we find out that

the commercially available Bu2Mg has successfully used as a catalyst or precatalyst in the

hydroamination of olefins in our group. In our lab D. Kittler (2007) and D. A. Schlesiger

(2008) have already shown in their diploma thesis that di-butyl magnesium is a highly

efficient reagent for pyrrolidine systems and it has high catalytic activity at room temperature

for the hydroamination of allylated norbornene system with high chemoselectivity (Scheme

56). While working on piperidine compounds we found out that for pyridine systems also it is

equally efficient.

Scheme 56. Intramolecular hydroamination using n-butyl magnesium to prepare pyrrolidines

by S. Blechert et al.

4.2 n-Bu2Mg as the catalyst for hydroamination

The present work deals with the investigation and optimization of hydroamination with

magnesium base: di-butyl magnesium 162. Di-n-butyl magnesium is one of the cheap

reagents for hydroamination reaction. Di-n-butylmagnesium is highly soluble, basic

magnesium organometallic compound. In addition, they are in contrast to the compounds of

late transition metals, non-toxic and inexpensive material. It can also be easily synthesized by

the addition of one equivalent of n-BuLi in toluene to one equivalent of n-BuMgCI in ether.

94


We have used the commercially available di-butyl magnesium directly after receiving for our

hydroamination reaction.

4.2.1 Optimization

Compound 101 has taken as the standard substrate for optimization. Reactions were done in

different temperature and different catalyst loading (table 21) and it was found that at higher

temperature and higher catalyst loading it takes few minutes to complete the reaction (table

21, entry 1). With 10 mol% of catalyst loading and at 40 °C it takes 4 h for full conversion.

Catalyst loading can be decreased to 2.5 mol%, but it takes longer reaction time. 5 mol% of n-

di-butyl magnesium at 60 °C gives full conversion within 1 h. At room temperature no

reaction was found.

Table 21. Optimization of reaction condition. a

aReaction conditions: amino-alkene 101 (0.25 mmol) in toluene (0.5 mL). bThe conversion

was determined by 1H NMR spectroscopy.

4.2.2 Results and discussion

The substrates which have been synthesized in chapter 3, are used here for hydroamination

reaction in presence of n-dibutyl magnesium (table 22). With 5 mol% of catalyst at 60 °C

cyclohexane substituted amino-alkene 108 gives 21% conversion within 21 h, with increasing

the catalyst loading to 10 mol% and increasing the temperature to 80 °C it gives 70% isolated

yield (table 22, entry 3, 4). Cyclopentane substituted amino alkene 107 does not show any

reactivity even in higher catalyst loading as well as at higher temperature (table 22, entry 5,

6). Although 106 does not show reactivity at 80 °C but it gives product with full conversion

95


and 64% as isolated yield at 120 °C (table 22, entry 7, 8). Using n-Bu2Mg, azepane 167 also

can be prepared at 120 °C with 60% conversion (table 22, entry 9, 10).

Table 22. Hydroamination of primary amino-alkene to prepare piperidine using n-Bu2Mg as

catalyst.a

aReaction conditions: amino-alkene 101 (0.25 mmol) in toluene (0.5 mL). bIsolated yields are

reported.

4.3 Mechanism of the reaction

A possible mechanism of the reaction is as shown in the Scheme 57. Catalyst n-dibutyl

magnesium reacts with two equivalents of substrate B either by stepwise mechanism or by

direct substitution to form the substrate-metal complex C. Now the intramolecular

hydroamination takes place via a six-membered transition state D. When another molecule of

substrate approaches towards the metal, it gives the hydroamination product E through the

regeneration of intermediate C for completing the catalytic cycle.

96


Scheme 57. Possible mechanism of the intramolecular hydroamination reaction by n-dibutyl

magnesium.

4.4 TMP-ZnCl as the catalyst for hydroamination

The use of magnesium bases for the direct metalation of arenes and heteroarenes has been

pioneered by Eaton et al.8 Lithium bases have been used extensively to ortho-metalated

various unsaturated systems.9 There are a number of useful synthetic applications of mixed

Mg/Li bases of the type R2NMgCl·LiCl such as (2,2,6,6-tetramethylpiperidide)magnesium

chloride–lithium chloride, (TMP)MgCl·LiCl.10 Later from Knochel group, they have

developed kinetically highly active LiCl-solubilized TMP base (TMP = 2,2,6,6-

tetramethylpiperidyl): TMPZnCl·LiCl (169) displays high chemoselectivity in various

directed zincations of arenes and heterocycles. TMP-ZnCl was prepared by the treatment of

2,2,6,6- tetramethylpiperidine (168; TMP-H) with n-BuLi (1.0 equiv, -40 to -10 °C, 1 h)

followed by the addition of ZnCl2 (1.1 equiv, -10 °C, 30 min) provides a ca. 1.3 M solution of

TMPZnCl·LiCl (169), stable at room temperature (Scheme 58)

97


Scheme 58. Preparation of (TMP)ZnCl.LiCl.

The resulting solution of the complex base 169 allows chemoselective zincation at room

temperature that tolerates sensitive functions such as an aldehyde or a nitro group. In our

group we found that it is also useful for hydroamination.

NCl

N Cl

TMPZn.LiCl (171)

(1.1 equiv)

THF, 25 oC, 30-45 min

NCl

N ClLiCl.ClZn

NCl

N Cl

E

E

Scheme 59. Chemoselective zincation of arenes and heteroarenes by Knochel et al.

First time we have used TMPZnCl·LiCl (169) for hydroamination reaction and we found that

it is effective for primary amino-alkenes, secondary amino-alkenes as well primary amino-

alkynes (table 23). For primary amino-alkene, 1.0 equivalent of TMPZnCl·LiCl (169) at 80

°C gives full conversion within 24 h. Going down to catalyst loading needs higher

temperature – with 5 mol% of catalyst loading gives full conversion with 24 h at 120 °C

(table 23, entry 4). Further lower catalyst loading shows slower reaction (table 23, entry 5).

Secondary amine compound 171 needs minimum 80 °C for full conversion to 172 (table 23,

entry 8). Amino alkyne 173 gives stable inamine 174 at 120 °C with 5 mol% of 169 (table 23,

entry 11).

98


Table 23. Hydroamination reaction with primary amino-alkene, secondary amino-alkene as

well primary amino-alkyne. a

entry substrate product catalyst loading temp time conversionb

(mol%) (oC) (h) (%)

NH2

PhPh

NH

PhPh

Me

1 eq 80 24 >99

50 80 24 48

10 120 24 >99

5 120 24 >99

2.5 120 24 48.4

5 RT 24 1.3

5 120 12 >99

5 80 24 >99

5 60 24 16.2

5 120 24 >99

170

1

2

3

4

5

6

7

8

9

10

11

154

HN

Ph Ph

N

PhPh

Me

Ph

Ph

172

171

S

NH2

S N

Me

173

174

HN

R R

N

RR

R'

R'

toluene

0.5(M) TMPZnCl.LiCl (169)

toluene

aReaction conditions: amino-alkene 101 (0.25 mmol) in toluene (0.5 mL). bThe conversion

was determined by 1H NMR spectroscopy.

4.5 Mechanism of the reaction

The possible mechanism of the reaction has shown in Scheme 60. Here possibility of forming

metal-nitrogen double bond is ruled out as the secondary amines also show reactivity (table

23, entry 6-10). It suggests that TMP-ZnCl A reacts with the amino-alkene B to form the

99


complex C. Complex C is then reacts with another substrate to give the intermediate D.

Intermediate D reacts with another substrate to give the hydroamination product E and the

complex C is regenerated for the completion of catalytic cycle.

R RNH2

N

Zn

R R

R RNH2

A

B

B

Zn

HNTMP

R R

NH

RR

Me

C

D

E

N

Me

Me

Me

Me

ZnCl

TMP

Scheme 60. Possible mechanism of intramolecular hydroamination of primary and secondary

amino-alkene and amino-alkynes with TMP-ZnCl.

4.6 References

1 M. R. Crimmin, I. J. Casely, M. S. Hill, J. Am. Chem. Soc. 2005, 127, 2042-2043. 2 M. R. Crimmin, M. Arrowsmith, A. G. M. Barrett, I. J. Casely, M. S. Hill, P. A. Procopiou,

J. Am. Chem. Soc. 2009, 131, 9670–9685. 3 S. Datta, P. W. Roesky, S. Blechert, Organometallics, 2007, 26, 4392-4394. 4 S. Datta, M. T. Gamer, P. W. Roesky, Organometallics, 2008, 27, 1207–1213. 5 J. F. Dunne, D. B. Fulton, A. Ellern, A. D. Sadow, J. Am. Chem. Soc. 2010, 132, 17680–

17683. 6 M. Arrowsmith, M. S. Hill, G. Kociok-Köhn, Organometallics, 2011, 30, 1291–1294.

100


7 M. Arrowsmith, M. R. Crimmin, A. G. M. Barrett, M. S. Hill, G. Kociok-Köhn, P. A.

Procopiou, Organometallics, 2011, 30, 1493–1506. 8 a) P. E. Eaton, R. M. Martin, J. Org. Chem. 1988, 53, 2728; b) P. E. Eaton, C.-H. Lee, Y.

Xiong, J. Am. Chem. Soc. 1989, 111, 8016; c) P. E. Eaton, K. A. Lukin, J. Am. Chem. Soc.

1993, 115, 11370; d) M.-X. Zhang, P. E. Eaton, Angew. Chem. Int. Ed. 2002, 41, 2169. 9 a) V. Snieckus, Chem. Rev. 1990, 90, 879; b) J. Clayden, C. C. Stimson, M. Keenan, Chem.

Commun. 2006, 1393; c) M. Schlosser, Angew. Chem. Int. Ed. 2005, 44, 376; d) K.W.

Henderson, W. J. Kerr, Chem. Eur. J. 2001, 7, 3431; e) A. Turck, N. PlK, F. Mongin, G.

QuKguiner, Tetrahedron, 2001, 57, 4489; f) F. Mongin, G. QuKguiner, Tetrahedron, 2001,

57, 4059; g) F. Levoux, P. Jeschke, M. Schlosser, Chem. Rev. 2005, 105, 827; h) M. Kauch,

D. Hoppe, Synthesis, 2006, 1578; i)W. Clegg, S. H. Dale, E. Hevia, G. W. Honeyman, R. E.

Mulvey, Angew. Chem. Int. Ed. 2006, 45, 2371; j) D. M. Hodgson, S. M. Miles, Angew.

Chem. Int. Ed. 2006, 45, 93; k) M. Yus, F. Foubelo, Handbook of Functionalized

Organometallics, Vol. 1 (Ed.: P. Knochel), Wiley-VCH, Weinheim, 2005, p. 7. 10 a) A. Krasovskiy, V. Krasovskaya, P. Knochel, Angew. Chem. Int. Ed. 2006, 45, 2958; b)

W. Lin, O. Baron, P. Knochel, Org. Lett. 2006, 8, 5673.

Chapter 5

Experimental

102

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103

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5.1 General experimental part

Methods: All moisture sensitive reactions were - where necessary – performed in flame-

dried glassware using the Schlenk tube, septum and cannula techniques. The weighing and

transferring oxygen and / or water-sensitive compounds was carried out in the glovebox Lab

master 130 from M. Braun Inc. The inert gas was nitrogen, which was used without further

purification. The determinations of oxygen and moisture values were controlled by PLC

control lab COMBI analyzer. The term ‘concentrated under reduced pressure’ refers to the

removal of solvents and other volatile materials using a rotary evaporator with the water bath

keeping temperature at 40 °C, followed by removal of residual solvent at high vacuum (< 0.2

mbar).

Materials. Unless otherwise indicated, all substances were purchased from commercial

sources and used without further purification. β-diiminate zinc complex 8 and precatalyst 10

were prepared according to the literature procedure1. Ruthenium catalyst GI was bought from

Aldrich. GII , HII were taken from lab colleagues. n-Dibutylmagnesium was bought from

Aldrich in a 1M solution in heptane.

Solvents were distilled prior to use, where appropriate, dried and used directly. THF, diethyl

ether, d6-benzene and toluene dried over sodium, DCM and hexane over calcium hydride and

methanol over magnesium and kept over 4Å molecular sieves. All other solvents were dried

over molecular sieves (4Å).

Thin-layer chromatograms were performed with TLC-foils from Merck which contain

silica gel 60 F254, layer thickness 0.2 mm and also aluminum oxide 150 F254, wherein for the

detection, UV light of wavelength 254 nm and potassium permanganate (1.0 g KMnO4, 5.0 g

Na2CO3 in 200 ml of water), vanillin (1 M H2SO4 ethanolic solution of vanillin), ninhydrin

(0.2g/100 ml EtOH), cerium molybdate solution (40g of ammonium pentamolybdate + 1.6 g

of cerium (IV) sulfate + 800 ml of diluted sulfuric acid (1:9) with water) were used.

Preparative thin layer chromatography was carried out on silica plates (F254, 20 x 20cm,

60 A) from ICN Biomedicals or on aluminum oxide plates (F254, 20 x 20 cm, 150 T) from

Merck.

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Column chromatography was performed with flash silica gel from Merck (particle size 0.03

to 0.06 mm) and with Alumina (activated, basic, Brockmann 1 from Sigma Aldrich)

1H-NMR spectra were recorded with the device DRX 500 (500 MHz) and AM 400 (400

MHz) spectrometer from Brucker at RT. The chemical shifts are reported as dimensionless

values in ppm and refer to the residual proton content of the used deuterated solvent as an

internal reference. Noted in parentheses are the multiplicities and the coupling constants J

[Hz] are determined by the magnitude of the splitting (difference in frequency between

peaks). The multiplicities are as follows: s (singlet), d (doublet), t (triplet), q (quartet), sept

(septet), m (multiplet), brs (broad signal). The invisible chemical shifts were not specified.

13C-NMR spectra were recorded using the device DRX 500 (500 MHz) and AM 400 (400

MHz) manufactured by Brucker at RT. The chemical shifts are taken from the proton-

decoupled spectra and broadband in non-dimensional values (ppm) relative to internal solvent

specified peak. The number of directly bound protons was determined by DEPT.

2D NMR spectra (COSY, HMQC) were recorded with DRX 500 (500 MHz) and AM 400

(400 MHz) instrument from Brucker at RT.

IR spectra were recorded with an infrared spectrophotometer from Perkin-Elmer 881 as ATR

(Attenuated Total Reflectance). Insoluble solids were recorded as KBr pellets with a FT-IR

spectrometer Bruker Equinox 55. The absorption bands are given in wavenumbers [cm-1].

GC-MS spectra were recorded on a GC HP 6890 with a glass capillary column HP-1 (25 m,

ID 0.25 mm, film thikness 0.3 mm) and MSD HP 5971 A detector from Hewlett-Packard.

MS and HRMS spectra were recorded on a Finnigan MAT 95 SQ or Varian MAT 711. The

samples were measured via a direct inlet and ionized with an ionization potential of 70 eV by

electron impact (EI), as well as by chemical ionization (CI) with isobutane or by atom

bombardment (FAB) of glycerol. The evaporation temperatures are indicated and the relative

signal intensity of the fragments is given in percent relative to the strongest signal.

ESI-MS and HR-ESI-MS spectra were recorded with a Finnigan MAT 95 SQ or Varian

MAT 711 with an ESI LTQ Orbitrap XL adapter from Thermo Scientific at RT. Acetonitrile

105

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was purchased from Fisher Scientific. The relative signal intensity of the fragments is given

in percent relative to the strongest signal.

Optical rotations were measured with a polarimeter Perkin-Elmer 341 at 20°C and the

wavelength is 589 nm (sodium D line). The respective solvent and the concentration [g/100

ml] are given in parentheses.

[α]20D = (α . 100)/(c . d)

α = measured optical rotation

c = concentration in g/100ml

d = length of the cuvette (1 dm)

HPLC analysis were performed on a Varian ProStar system performed (autosampler model

410, UV-VIS detector model 320; Solvent Delivery Module Model 210 Fraction Collector

Model 701). As the column models which were used: Chiralcel OD-H (0.46 cm ø x 25 cm)

from Daicel Chemical Industries, (R, R) Beta-Gem 1 (0.46 cm ø x 25 cm) manufactured by

Regis Technologies Inc. HPLC-grade eluents were purchased from Fisher Scientific. The

separation conditions were specified as follows: column used, mobile phase mixture, flow

rate, detector wavelength. The enantiomeric excesses were determined by the respective

integrals of the signal rates are as follows:

Melting points were determined with a Leica Galen III hot stage microscope with a control

unit of the Wagner-Munz and the air-and water-sensitive substances with a Melting Point

Büchi B-540 of the company and are uncorrected.

Chemical names were taken from the Cambridge Soft ChemDraw Ultra 12.0 version, which

is in accordance with Beilstein nomenclature.

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5.2 Experimental part for chapter 2

Experimental details. All reactions with air/or water-sensitive compounds were performed

under a dry nitrogen atmosphere with either standard Schlenk vacuum-line techniques or

inside glove box. Dry, oxygen-free solvents were used throughout. Toluene was distilled over

CaH2 dried over molecular sieves and degassed by sparging with nitrogen and stored over Na

under N2. Prior to use, all substrates were purified by bulk to bulk distillation and kept inside

glove box. The amines and alkynes were purchased from Acros Organics, Aldrich and Fluka

and used freshly as soon as reached. Catalyst 8 and activator 10 were synthesized according

to literature procedure.2

Preparation of the substrate 15, 18.

4-methoxy-N-(pent-4-en-1-yl)aniline (15). Oxalylchloride

(0.23 ml, 2.68 mmol) was slowly added under nitrogen atmosphere to a solution of pentenoic

acid (0.28 g, 2.24 mmol) in 2 ml of anhydrous DCM at rt. After 2 h the solvent was removed

under reduced pressure. The crude material was dissolved in 3 ml anhydrous DCM and a

solution of aniline (0.25 g, 2.68 mmol) in 1 ml anhydrous DCM followed by pyridine (0.45

ml, 5.38 mmol) were added at 0 °C. The reaction mixture was allowed to warm up to rt and

stirred overnight. After addition of 20 ml of DCM the organic phase was washed

subsequently with an aqueous sat. solution of NaHCO3 (1 x 20 ml) and a 5% HCl aqueous

solution (1 x 20 ml) , dried over MgSO4 and concentrated under reduced pressure. After

purification by column chromatography (SiO2, hexane/EtOAc 7:1), N-phenyl-4-pentenamide

was obtained in 68% yield (0.32 g, 1.83 mmol) as a white solid. The spectroscopic data are in

the agreement with those reported in the literature.3 A solution of N-phenyl-4-pentenamide

(0.32 g, 1.84 mmol) in 20 ml anhydrous Et2O was added dropwise to a suspension of LiAlH4

(0.21 g, 5.48 mmol) in 30 ml anhydrous ether at 0 °C under nitrogen atmosphere. After 3 h,

complete conversion was achieved and then the reaction mixture was quenched with 10 ml of

wet EtOAc and 10 ml of wet methanol. After filtration through celite and purification by

column chromatography (SiO2, CH2Cl2/MeOH 20:1), the title compound was isolated as

clear oil in 63% yield (0.47 g, 2.92 mmol).4 1H NMR (500 MHz, CDCl3) δ 6.84 – 6.74 (m,

2H), 6.62 (d, J = 8.8 Hz, 2H), 5.87 (ddt, J = 16.9, 10.2, 6.7 Hz, 1H), 5.12 – 4.96 (m, 2H),

3.77 (s, 3H), 3.52 (s, 1H), 3.12 (t, J = 7.1 Hz, 2H), 2.20 (q, J = 7.1 Hz, 2H), 1.80 – 1.66 (m,

107

-------------------------------------------------------------------------------------------------------------------------------------- Experimental

2H). 13C NMR (126 MHz, CDCl3) δ 152.07 (C), 142.64 (C), 138.13 (CH), 115.04 (CH2),

114.93 (CH), 114.12 (CH), 55.85 (CH3), 44.48 (CH2), 31.34 (CH2), 28.76 (CH2).

1-trityloxybut-3-yne 5 (18)

But-3-yn-1-ol (2.0 g, 28.5 mmol) in pyridine (2 ml) and dichloromethane (70 ml) was treated

with molecular sieves (20 g) and tritylchloride (8.3 g, 30 mmol) at 0°C. The mixture was

stirred at room temperature for 12 h. Filtration and chromatography (hexanes /EtOAc 5: 1)

furnished 1-trityloxy-but-3-yne (8.27 g, 93%) as an amorphous solid. 1H NMR (benzene-d6, 400 MHz, CDCl3) δ 7.42 - 7.48 (m, 6H), 7.20-7.33 (m, 9H), 3.25 (t, J

= 6.7 Hz, 2H), 2.52 (dt, J = 6.7, 2.5 Hz, 2H), 2.04 (t, J = 3.1 Hz, 1H). 13C NMR (101 MHz,

CDCl3) δ 144.0, 128.7, 127.8, 127.0, 86.7, 81.6, 69.2, 62.0, 20.0. MS: (EI, 70eV, 50 °C) m/z

= 312 [M] (19), OTr - S14 - 284 (4), 243 (100), 236 (58), 165 (46), 105 (63), 83 (29). IR

(ATR): ν (cm-1) = 3289, 2928, 2880, 1594, 1488, 1446, 1209, 1155, 1082, 1029, 999, 740,

705.

Typical Procedure for the Synthesis of 1,2-dihydroquinoline derivative.

Reactions were typically performed in reaction vials and prepared in an inert atmosphere. The

precatalyst 8 (24.90 mg, 0.05 mmol) and the cocatalyst 10 [PhNMe2H][OTf] (40.20 mg, 0.15

mmol) were dissolved in toluene (2 ml). The substrate N-methyl aniline (107 mg, 1 mmol)

and n-hexyne (246.42 mg, 3 mmol) were added in the mixture. Subsequently, the mixture

was injected into the reaction vial. The reaction mixture was then heated in an oil bath at 130

°C for 24 h. The reaction is cooled to room temperature and solvent was removed by

evaporation. The crude mixture was purified by column chromatography using cyclohexane -

DCM giving 21 with 97% as isolated yield.

2,4-dibutyl-1,2-dihydro-1,2-dimethylquinoline. (21) (Rf

0.61, 20% cyclohexane, DCM) was prepared according to the procedure described in General

procedure, purified by column chromatography (SiO2, 100% cyclohexane to 20%

cyclohexane, DCM). (Yield 97%). Liquid, colorless. 1H NMR (benzene-d6, 400 MHz,

CDCl3) δ 7.10 – 6.96 (m, 2H), 6.58 (t, J = 7.4 Hz, 1H), 6.46 (d, J = 8.5 Hz, 1H), 5.09 (s, 1H),

2.72 (s, 2H), 2.34 (tq, J = 13.7, 7.0 Hz, 1H), 1.81 (dd, J = 19.8, 11.2 Hz, 1H), 1.57 – 1.48 (m,

108

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2H), 1.40 (dt, J = 15.0, 6.4 Hz, 3H), 1.31 – 1.24 (m, 6H), 1.23 (s, 1H), 1.13 (t, J = 6.1 Hz,

2H), 0.93 (dd, J = 8.9, 5.6 Hz, 3H), 0.90 – 0.84 (m, 3H). 13C NMR (benzene-d6, 101 MHz,

CDCl3) δ 145.93 (C), 132.89 (C), 128.49 (CH), 127.61 (CH), 124.69 (C), 122.96 (C), 122.89

(CH), 121.49 (C), 115.37 (CH), 109.72 (CH), 59.37 (C), 41.16 (CH2), 31.73 (CH2), 30.58

(CH2), 30.33 (CH), 27.08 (CH2), 26.96 (CH), 23.05 (CH2), 22.69 (CH2), 14.12 (CH3), 13.99

(CH3). IR (ATR): ν (cm-1) = 3059, 2956, 2929, 2860, 1663, 1595, 1494, 1480, 1454, 1357,

1308, 1086, 1052, 741. HRMS-ESI (MH+, C19H30N): calculated 272.2378, experimental:

272.2370.

1,2-dihydro-1,2-dimethyl-2,4-dipropylquinoline. (24) (Rf 0.64,

20% cyclohexane, DCM) was prepared according to the procedure described in General


cyclohexane, DCM). (Yield 93%). Liquid, colorless. 1H NMR (400 MHz, CDCl3) δ 7.10 –

7.01 (m, 2H), 6.58 (td, J = 7.4, 1.1 Hz, 1H), 6.46 (dd, J = 8.7, 0.8 Hz, 1H), 5.11 (s, 1H), 2.74

(s, 3H), 2.40 – 2.25 (m, 2H), 1.85 – 1.77 (m, 1H), 1.63 – 1.53 (m, 2H), 1.47 – 1.33 (m, 1H),

1.29 – 1.20 (m, 5H), 0.97 (t, J = 7.3 Hz, 3H), 0.91 – 0.85 (m, 3H). 13C NMR (101 MHz,

CDCl3) δ 145.97 (C), 132.64 (C), 128.52 (CH), 127.75 (CH), 122.90 (CH), 121.49 (C),

115.38 (CH), 109.69 (CH), 59.42 (C), 43.91 (CH2), 34.14 (CH2), 30.39 (CH3), 27.14 (CH3),

21.47 (CH2), 18.24 (CH2), 14.50 (CH3), 14.10 (CH3). IR (ATR): ν (cm-1) = 3060, 3015, 2956,

2930, 2813, 1663, 1596, 1569, 1494, 1480, 1453, 1422, 1376, 1356, 1344, 1308, 1262, 1210,

1191, 1167, 1157, 1120, 1085, 1053, 827, 740. HRMS-ESI (MH+, C19H30N): calculated

244.2065, experimental: 244.2060.

1,2-dihydro-1,2-dimethyl-2,4-dipentylquinoline. (26)

(Rf 0.63, 20% cyclohexane, DCM) was prepared according to the procedure described in

General procedure, purified by column chromatography (SiO2, 100% cyclohexane to 20%


CDCl3) δ 7.09 (dtd, J = 7.3, 4.1, 1.6 Hz, 2H), 6.61 (td, J = 7.5, 1.1 Hz, 1H), 6.52 – 6.46 (m,

1H), 5.13 (s, 1H), 2.76 (s, 1H), 2.47 – 2.29 (m, 2H), 1.90 – 1.82 (m, 1H), 1.63 – 1.56 (m, 2H),

109

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1.43 – 1.37 (m, 6H), 1.32 – 1.29 (m, 4H), 1.27 (s, 3H), 1.19 – 1.16 (m, 1H), 0.97 – 0.92 (m,

3H), 0.90 (dd, J = 9.4, 4.3 Hz, 3H). 13C NMR (benzene-d6, 101 MHz, CDCl3) δ 145.98 (C),

132.97 (C), 128.52 (CH), 127.67 (CH), 122.92 (CH), 121.56 (C), 115.44 (CH), 109.79 (CH),

59.42 (C), 41.47 (CH2), 32.29 (CH2), 32.03 (CH2), 31.92 (CH2), 30.34 (CH3), 28.10 (CH2),

26.88 (CH3), 24.60 (CH2), 22.64 (CH2), 22.60 (CH2), 14.13 (CH3), 14.08 (CH3). IR (ATR): ν

(cm-1) = 3062, 2956, 2929, 2859, 1662, 1595, 1494, 1480, 1454, 1356, 1308, 1197, 1053,

741. HRMS-ESI (MH+, C21H34N): calculated 300.2691, experimental: 300.2686.

1,2-dihydro-1,2-dimethyl-2,4-di(pent-4-enyl)quinolone.

(29) (Rf 0.64, 20% cyclohexane, DCM) was prepared according to the procedure described in


cyclohexane, DCM). (Yield 89%). Liquid, colorless. 1H NMR (400 MHz, CDCl3) δ 7.10 –

7.02 (m, 2H), 6.58 (t, J = 7.4 Hz, 1H), 6.47 (d, J = 8.0 Hz, 1H), 5.81 (dddt, J = 34.1, 16.9,

10.2, 6.7 Hz, 2H), 5.10 (s, 1H), 5.07 – 4.89 (m, 4H), 2.73 (s, 3H), 2.45 – 2.29 (m, 2H), 2.14

(dd, J = 14.6, 6.9 Hz, 2H), 2.04 (q, J = 7.0 Hz, 2H), 1.89 – 1.78 (m, 1H), 1.71 – 1.60 (m, 2H),

1.48 (ddd, J = 11.3, 10.0, 6.3 Hz, 1H), 1.36 (tdd, J = 12.8, 7.0, 3.9 Hz, 1H), 1.29 – 1.20 (m,

4H). 13C NMR (101 MHz, CDCl3) δ 145.91 (C), 138.85 (CH), 138.74 (CH), 132.75 (C),

128.63 (CH), 127.66 (CH), 122.92 (CH), 121.28 (C), 115.47 (CH), 114.71 (CH2), 114.58

(CH2), 109.76 (CH), 59.39 (C), 40.83 (CH2), 33.97 (CH2), 33.63 (CH2), 31.40 (CH2), 30.37

(CH3), 27.59 (CH2), 27.07 (CH3), 24.21 (CH2). IR (ATR): ν (cm-1) = 3074, 2974, 2932, 2862,

1737, 1663, 1640, 1595, 1570, 1495, 1481, 1450, 1423, 1355, 1348, 1308, 1252, 1195, 1166,

1161, 1128, 1088, 1054, 992, 910, 742. HRMS-ESI (MH+, C25H26NO2): calculated:

296.2378, experimental: 296.2373.

1,2-dihydro-1,2-dimethyl-2,4-bis(3-

(trityloxy)propyl)quinolone. (27) (Rf 0.37, 20% cyclohexane, DCM) was prepared

according to the procedure described in General procedure, purified by column

chromatography (Al2O3, 100% cyclohexane to 20% cyclohexane, DCM). (Yield 92%). Semi-

110

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liquid, colorless. 1H NMR (400 MHz, CDCl3) δ 7.47 – 7.40 (m, 7H), 7.37 (dd, J = 8.1, 1.5

Hz, 3H), 7.29 (d, J = 7.2 Hz, 5H), 7.24 – 7.14 (m, 16H), 7.13 – 7.09 (m, 2H), 6.82 (dd, J =

27.7, 5.4 Hz, 1H), 6.39 (dd, J = 49.0, 8.7 Hz, 1H), 4.99 (d, J = 18.8 Hz, 1H), 3.15 (t, J = 6.4

Hz, 1H), 3.08 – 2.95 (m, 2H), 2.91 (t, J = 6.3 Hz, 1H), 2.71 (d, J = 10.9 Hz, 3H), 2.48 – 2.37

(m, 1H), 2.19 – 2.06 (m, 1H), 1.87 (m, 2H), 1.63 – 1.52 (m, 3H), 1.24 (m, 1H), 1.17 (d, J =

12.0 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 147.37, 144.48, 144.46, 143.80, 133.65,

133.15, 131.16, 131.09, 128.70, 128.68, 127.72, 127.66, 127.30, 127.25, 126.84, 126.76,

126.51, 125.64, 122.96, 119.95, 115.51, 108.73, 86.43, 86.41, 86.38, 86.23, 64.19, 63.94,

63.85, 63.38, 63.23, 59.29, 59.21, 38.04, 37.88, 30.31, 30.23, 28.90, 28.56, 26.66, 25.67. IR

(ATR): ν (cm-1) = 3085, 3056, 3029, 2940, 2869, 1703, 1596, 1491, 1448, 1361, 1182, 1073,

1033, 762, 745, 704. HRMS-ESI (MH+, C55H54NO2): calculated 760.4155, experimental:

760.4149.

1,2-dihydro-1,2-dimethyl-2,4-diphenylquinoline. (34) (Rf 0.45, 20%

cyclohexane, DCM) was prepared according to the procedure described in General


cyclohexane, DCM). (yield 55%). Liquid, colorless. 1H NMR (benzene-d6, 400 MHz,

CDCl3) δ 7.76 (d, J = 7.6 Hz, 1H,), 7.64 (d, J = 7.6 Hz, 2H), 7.52 (d, J = 7.8 Hz, 1H), 7.48 –

7.42 (m, 2H), 7.37 – 7.34 (m, 2H), 7.29 (d, J = 15.5 Hz, 2H), 7.21 (d, J = 15.5 Hz, 1H), 6.99

(dd, J = 7.8, 1.6 Hz, 1H), 6.68 – 6.59 (m, 2H), 5.38 (s, 1H, H-9), 2.65 (s, 3H), 1.84 (s, 3H). 13C NMR (benzene-d6, 101 MHz, CDCl3) δ 147.56, 145.11 (C), 139.52 (C), 133.84 (C),

130.41 (CH), 129.34 (CH), 129.05 (CH), 128.31 (CH), 128.14 (CH), 127.23 (CH), 126.87

(CH), 126.82 (CH), 125.92 (CH), 120.99, 115.94 (CH), 110.18 (CH), 63.38 (C), 32.86 (CH3),

23.17 (CH3). IR (ATR): ν (cm-1) = 3057, 3028, 2967, 2814, 1595, 1488, 1443, 1330, 1026,

750, 699. HRMS-ESI (MH+, C23H22N): calculated 312.1752, experimental: 312.1746.

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1,2-dihydro-2,4-bis(4-methoxyphenyl)-1,2-

dimethylquinoline. (36) (Rf 0.32, 5% cyclohexane, ethylacetate) was prepared according to

the procedure described in General procedure, purified by column chromatography (SiO2,

100% cyclohexane to 3% cyclohexane, ehylacetate). (Yield 86%). Liquid, colorless. 1H

NMR (400 MHz, CDCl3) δ 7.33 – 7.26 (m, 4H), 7.20 – 7.14 (m, 1H), 6.97 – 6.91 (m, 2H),

6.90 – 6.84 (m, 3H), 6.83 – 6.79 (m, 2H), 4.67 (s, 1H), 3.83 (s, 3H), 3.77 (s, 3H), 3.08 (s,

3H), 1.73 (s, 3H). 13C NMR (benzene-d6, 101 MHz, CDCl3) δ 159.33 (C), 157.35 (C),

143.94 (C), 142.19 (C), 140.16 (C), 131.93 (C), 130.41 (C), 129.77 (CH), 128.29 (CH),

127.83 (CH), 126.48 (CH), 120.64 (CH), 113.49 (CH), 113.16 (CH), 112.84 (CH), 110.54

(CH), 55.33 (CH3), 55.22 (CH3), 41.26 (C), 36.56 (CH3), 30.68 (CH3). IR (ATR): ν (cm-1) =

3061, 2998, 2958, 2931, 2834, 1717, 1648, 1607, 1575, 1510, 1476, 1464, 1376, 1301, 1287,

1247, 1178, 1091, 1033, 1004, 830, 793, 752. HRMS-ESI (MH+, C25H26NO2): calculated:

372.1964, experimental: 372.1958.

1,2-dihydro-2,4-bis(3-methoxyphenyl)-1,2-

dimethylquinoline. (38) (Rf 0.32, 5% cyclohexane, ethylacetate) was prepared according to

the procedure described in General procedure, purified by column chromatography (SiO2,

100% cyclohexane to 3% cyclohexane, ehylacetate). (Yield 88%). Liquid, colorless. 1H

NMR (400 MHz, CDCl3) δ 7.30 – 7.26 (m, 1H), 7.24 (m, 1H), 7.14 (dd, J = 10.8, 4.4 Hz,

3H), 6.94 (dd, J = 7.8, 1.5 Hz, 1H), 6.91 (d, J = 7.6 Hz, 1H), 6.88 – 6.83 (m, 2H), 6.81 – 6.77

(m, 1H), 6.57 (t, J = 7.1 Hz, 2H), 5.32 (s, 1H), 3.79 (d, J = 1.5 Hz, 6H), 2.61 (s, 3H), 1.75 (s,

3H). 13C NMR (101 MHz, CDCl3) δ 159.68 (C), 159.41 (C), 142.67 (C), 140.90 (C), 133.74

(C), 130.23 (CH), 129.37 (CH), 129.34 (CH), 129.26 (CH), 129.16 (CH), 125.93 (C), 121.53

(CH), 120.97 (C), 119.26 (CH), 116.06 (CH), 114.55 (CH), 113.19 (CH), 112.91 (CH),

111.95 (CH), 110.38 (CH), 63.41 (C), 55.29 (CH3), 55.28 (CH3), 33.00 (CH3), 22.91 (CH3).

IR (ATR): ν (cm-1) = 3063, 2960, 2935, 2833, 1597, 1484, 1464, 1431, 1314, 1286, 1256,

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1231, 1216, 1176, 1045, 874, 820, 782, 747, 720, 700. HRMS-ESI (MH+, C25H26NO2):

calculated: 372.1964, experimental: 372.1958.

1-allyl-2,4-dibutyl-1,2-dihydro-2-methylquinoline. (39) (Rf

0.63, 20% cyclohexane, DCM) was prepared according to the procedure described in General


cyclohexane, DCM). (Yield 64%). Liquid, colorless. 1H NMR (400 MHz, CDCl3) δ 7.05

(dd, J = 7.5, 1.6 Hz, 1H), 7.02 – 6.95 (m, 1H), 6.54 (td, J = 7.4, 1.1 Hz, 1H), 6.41 (d, J = 8.2

Hz, 1H), 5.95 – 5.79 (m, 1H), 5.24 (dd, J = 17.3, 1.6 Hz, 1H), 5.17 – 5.09 (m, 1H), 5.06 (s,

1H), 3.85 (dd, J = 4.3, 2.2 Hz, 2H), 2.42 – 2.27 (m, 2H), 1.80 (dd, J = 11.5, 9.2 Hz, 1H), 1.57

– 1.52 (m, 3H), 1.45 – 1.35 (m, 3H), 1.29 (s, 3H), 1.25 (dd, J = 8.2, 4.4 Hz, 3H), 0.94 (dd, J =

8.8, 5.7 Hz, 3H), 0.84 (t, J = 7.0 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 144.89 (C), 136.11

(CH), 132.54 (C), 128.21 (CH), 126.87 (CH), 123.12 (CH), 121.20 (C), 115.65 (CH2), 115.12

(CH), 110.62 (CH), 60.13 (C), 46.10 (CH2), 41.79 (CH2), 31.77 (CH2), 30.59 (CH2), 29.13

(CH3), 26.72 (CH2), 23.00 (CH2), 22.71 (CH2), 14.07 (CH3), 14.01 (CH3). IR (ATR): ν (cm-1)

= 3301, 3034, 2956, 2929, 2870, 2860, 1665, 1596, 1493, 1454, 1377, 1309, 1253, 1240,

1159, 918, 841, 741. HRMS-ESI (MH+, C21H32N): calculated 298.2535, experimental:

298.2529.

5,7-dibutyl-5-methyl-1,2,3,5-tetrahydropyrido[3,2,1-

ij]quinolone. (46) (Rf 0.54, 20% cyclohexane, DCM) was prepared according to the

procedure described in General procedure, purified by column chromatography (SiO2, 100%

cyclohexane to 20% cyclohexane, DCM). (Yield 96%). Liquid, colorless. 1H NMR (benzene-

d6, 400 MHz, CDCl3) δ 6.91 (dd, J = 7.6, 1.3 Hz, 1H), 6.82 – 6.74 (m, 1H), 6.51 – 6.40 (m,

1H), 5.05 (s, 1H), 3.28 – 3.15 (m, 2H), 2.81 – 2.65 (m, 2H), 2.42 – 2.25 (m, 2H), 1.98 – 1.81

(m, 3H), 1.61 – 1.50 (m, 2H), 1.46 – 1.37 (m, 3H), 1.32 (tdd, J = 13.2, 8.9, 4.5 Hz, 3H), 1.26

(s, 3H), 1.21 (ddd, J = 19.6, 10.5, 6.0 Hz, 1H), 0.98 – 0.87 (m, 6H). 13C NMR (benzene-d6,

101 MHz, CDCl3) δ 142.01 (C), 132.95 (C), 128.81 (CH), 127.03 (CH), 121.48 (CH), 120.86

(C), 120.82 (C), 114.81 (CH), 59.04 (C), 41.65 (CH2), 40.39 (CH2), 32.01 (CH2), 30.66

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(CH2), 28.49 (CH2), 27.17 (CH2), 26.48 (CH), 23.14 (CH2), 22.74 (CH2), 21.81 (CH2), 14.17

(CH3), 14.02 (CH3). IR (ATR): ν (cm-1) = 3029, 2954, 2928, 2859, 1663, 1592, 1478, 1454,

1431, 1325, 1305, 1255, 1115, 1053, 842, 778, 741. HRMS-ESI (MH+, C21H32N):

calculated: 298.2535, experimental: 298.2528.

5-methyl-5,7-di(pent-4-enyl)-1,2,3,5-

tetrahydropyrido[3,2,1-ij]quinolone. (51) (Rf 0.48, 20% cyclohexane, DCM) was prepared


chromatography (SiO2, 100% cyclohexane to 20% cyclohexane, DCM). (Yield 94%). Liquid,

colorless. 1H NMR (400 MHz, CDCl3) δ 6.88 (dt, J = 13.8, 6.9 Hz, 1H), 6.81 – 6.74 (m, 1H),

6.49 – 6.41 (m, 1H), 5.81 (dddt, J = 26.0, 16.9, 10.2, 6.7 Hz, 2H), 5.08 – 4.88 (m, 5H), 3.27 –

3.10 (m, 2H), 2.79 – 2.61 (m, 2H), 2.43 – 2.24 (m, 2H), 2.18 – 2.09 (m, 2H), 2.09 – 1.99 (m,

2H), 1.95 – 1.81 (m, 3H), 1.69 – 1.59 (m, 2H), 1.59 – 1.36 (m, 3H), 1.26 (s, 3H). 13C NMR

(101 MHz, CDCl3) δ 142.04 (C), 138.94 (CH), 138.81 (CH), 132.76 (C), 128.91 (CH),

127.10 (CH), 121.46 (CH), 120.85 (C), 120.54 (C), 114.83 (CH), 114.65 (CH2), 114.56

(CH2), 59.02 (C), 41.63 (CH2), 40.07 (CH2), 34.06 (CH2), 33.67 (CH2), 31.67 (CH2), 28.46

(CH2), 27.64 (CH2), 26.59 (CH3), 24.29 (CH2), 21.77 (CH2). IR (ATR): ν (cm-1) = 3074,

3029, 2975, 2932, 2861, 2841, 2760, 1662, 1640, 1592, 1578, 1478, 1454, 1444, 1432, 1414,

1356, 1325, 1305, 1253, 1248, 1201, 1177, 1156, 1146, 1105, 1029, 992, 909, 781, 729.

HRMS-ESI (MH+, C25H26NO2): calculated: 322.2535, experimental: 322.2529.

5-methyl-5,7-diphenyl-1,2,3,5-tetrahydropyrido[3,2,1-ij]quinolone.




CDCl3) δ 7.66 – 7.61 (m, 2H), 7.40 – 7.28 (m, 8H), 7.28 – 7.23 (m, 2H), 6.87 (dd, J = 7.4, 1.5

Hz, 1H), 6.73 (dd, J = 7.7, 1.5 Hz, 1H), 6.43 (t, J = 7.5 Hz, 1H), 5.24 (s, 1H), 3.16 – 3.09 (m,

1H), 2.87 (dtd, J = 8.0, 4.6, 2.5 Hz, 1H), 2.82 – 2.67 (m, 2H), 1.84 (s, 3H). 13C NMR

(benzene-d6, 101 MHz, CDCl3) δ 147.64 (C), 141.26 (C), 139.87 (C), 133.87 (C), 129.77

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(CH), 129.55 (CH), 129.09 (CH), 128.26 (CH), 128.08 (CH), 127.14 (CH), 126.84 (CH),

126.79 (CH), 124.48 (CH), 121.00 (C), 119.95 (C), 115.10 (CH), 62.92 (C), 43.91 (CH2),

28.36 (CH2), 23.35 (CH3), 21.58 (CH2). IR (ATR): ν (cm-1) = 3057, 3027, 2923, 2852, 1598,

1577, 1489, 1474, 1442, 1389, 1074, 1028, 1008, 841, 756, 698. HRMS-ESI (MH+,

C25H24N): calculated: 338.1909, experimental: 338.1902.

NMe

MeMe 5-methyl-5,7-di-p-tolyl-1,2,3,5-tetrahydropyrido[3,2,1-



cyclohexane to 20% cyclohexane, DCM). (Yield 90%). Liquid, colorless. 1H NMR (400

MHz, CDCl3) δ 7.53 – 7.46 (m, 2H), 7.21 – 7.17 (m, 2H), 7.14 (ddd, J = 8.5, 4.8, 0.6 Hz,

4H), 6.85 (d, J = 7.3 Hz, 1H), 6.74 (dd, J = 7.7, 1.5 Hz, 1H), 6.42 (td, J = 7.5, 3.8 Hz, 1H),

5.21 (s, 1H), 3.10 (ddd, J = 7.4, 6.7, 5.0 Hz, 1H), 2.86 (ddd, J = 10.4, 4.5, 3.0 Hz, 1H), 2.82 –

2.64 (m, 2H), 2.34 (d, J = 5.4 Hz, 6H), 2.33 – 2.23 (m, 2H), 1.79 (s, 3H). 13C NMR (101

MHz, CDCl3) δ 144.69 (C), 141.20 (C), 136.93 (C), 136.72 (C), 136.37 (C), 133.59 (C),

129.75 (CH), 129.41 (CH), 128.95 (CH), 128.90 (CH), 128.73 (CH), 126.78 (CH), 124.44

(CH), 120.99 (C), 120.15 (C), 115.05 (CH), 62.63 (C), 43.83 (CH2), 28.36 (CH2), 23.42

(CH3), 21.57 (CH2), 21.17 (CH3), 20.99 (CH3). IR (ATR): ν (cm-1) = 3047, 3024, 2969, 2923,

2858, 1904, 1652, 1591, 1510, 1475, 1453, 1432, 1317, 1183, 1019, 814, 744. HRMS-ESI

(MH+, C27H28N): calculated 366.2222, experimental: 366.2216.

5,7-bis(4-methoxyphenyl)-5-methyl-1,2,3,5-




colorless. 1H NMR (400 MHz, CDCl3) δ 7.57 – 7.46 (m, 2H), 7.24 – 7.21 (m, 1H), 6.94 (d, J

= 7.6 Hz, 1H), 6.90 – 6.81 (m, 4H), 6.74 (d, J = 7.7 Hz, 1H), 6.60 (t, J = 7.3 Hz, 1H), 6.51 –

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6.36 (m, 1H), 5.20 (s, 1H), 3.84 – 3.77 (m, 6H), 3.33 – 3.26 (m, 1H), 3.11 (ddd, J = 15.1,

12.2, 10.6 Hz, 1H), 2.90 – 2.65 (m, 3H), 2.00 – 1.85 (m, 1H), 1.79 (s, J = 7.6 Hz, 3H). 13C

NMR (101 MHz, CDCl3) δ 158.78 (C), 158.36 (C), 141.28 (C), 140.01 (C), 133.20 (C),

132.29 (C), 130.16 (CH), 129.70 (CH), 129.39 (CH), 127.98 (CH), 124.39 (CH), 120.97 (C),

120.22 (C), 114.99 (CH), 113.48 (CH), 113.45 (CH), 62.28 (C), 55.29 (CH3), 55.27 (CH3),

43.70 (CH2), 41.99 (CH2), 28.38 (CH2), 23.45 (CH3). IR (ATR): ν (cm-1) = 3063, 2961, 2930,

2835, 1607, 1509, 1456, 1303, 1247, 1175, 1106, 1032, 829, 745. HRMS-ESI (MH+,

C27H28NO2): calculated 398.2120, experimental: 398.2115.

5,7-bis(3-methoxyphenyl)-5-methyl-1,2,3,5-




colorless. 1H NMR (400 MHz, CDCl3) δ 7.32 – 7.27 (m, 1H), 7.25 (d, J = 5.4 Hz, 1H), 7.21

(dt, J = 5.8, 2.6 Hz, 2H), 6.93 – 6.90 (m, 1H), 6.90 – 6.84 (m, 3H), 6.82 – 6.76 (m, 2H), 6.46

(t, J = 7.5 Hz, 1H), 5.27 (s, 1H), 3.81 (d, J = 2.6 Hz, 6H), 3.27 – 3.02 (m, 2H), 2.97 (s, 1H),

2.95 – 2.86 (m, 1H), 2.86 – 2.66 (m, 2H), 1.82 (s, 3H). 13C NMR (101 MHz, CDCl3) δ

159.70 (C), 159.39 (C), 149.40 (C), 141.30 (C), 141.26 (C), 133.84 (C), 129.57 (CH), 129.57

(CH), 129.22 (CH), 129.09 (CH), 124.50 (CH), 121.61 (CH), 121.15 (C), 119.95 (C), 119.29

(CH), 115.25 (CH), 114.58 (CH), 113.11 (CH), 112.87 (CH), 111.90 (CH), 62.95 (C), 55.29

(CH3), 55.27 (CH3), 43.94 (CH2), 28.38 (CH2), 23.17 (CH3), 21.64 (CH2). IR (ATR): ν (cm-1)

= 3066, 3028, 2997, 2959, 2935, 2834, 1598, 1583, 1535, 1486, 1451, 1431, 1362, 1316,

1286, 1255, 1212, 1193, 1040, 875, 782, 744, 718, 700. HRMS-ESI (MH+, C27H28NO2):

calculated 398.2120, experimental: 398.2115.

4,6-dibutyl-2,4-dihydro-4-methyl-1H-pyrrolo[3,2,1-



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cyclohexane to 20% cyclohexane, DCM). (Yield 59%). Liquid, colorless. 1H NMR (benzene-

d6, 400 MHz, CDCl3) δ 6.85 (dd, J = 10.6, 4.3 Hz, 2H), 6.45 (t, J = 7.4 Hz, 1H), 4.99 (s, 1H),

3.60 – 3.32 (m, 2H), 3.07 – 2.88 (m, 2H), 2.43 – 2.21 (m, 2H), 1.81 – 1.65 (m, 1H), 1.59 –

1.49 (m, 2H), 1.46 – 1.27 (m, 7H), 1.20 (s, 3H), 0.98 – 0.87 (m, 6H). 13C NMR (benzene-d6,

101 MHz, CDCl3) δ 149.10 (C), 133.26 (C), 126.37 (CH), 125.81 (C), 123.53 (CH), 120.34

(CH), 117.17 (C), 115.88 (CH), 58.27 (C), 45.29 (CH2), 40.40 (CH2), 30.97 (CH2), 30.71

(CH2), 28.22 (CH2), 27.46 (CH2), 25.19 (CH3), 23.18 (CH2), 22.62 (CH2), 14.17 (CH3), 14.00

(CH3). IR (ATR): ν (cm-1) = 3054, 2955, 2928, 2859, 1640, 1589, 1484, 1457, 1377, 1366,

1283, 1056, 741. HRMS-ESI (MH+, C20H30N): calculated: 284.2378, experimental:

284.2374.

4,6-dibenzyl-2,4-dihydro-4-methyl-1H-pyrrolo[3,2,1-




MHz, CDCl3) δ 7.39 (dd, J = 9.4, 6.4 Hz, 2H), 7.26 (d, J = 2.9 Hz, 2H), 7.22 (d, J = 7.2 Hz,

2H), 7.19 (d, J = 6.9 Hz, 1H), 7.12 – 7.08 (m, 1H), 7.05 (t, J = 7.2 Hz, 3H), 6.86 – 6.80 (m,

1H), 6.73 (dd, J = 15.6, 7.5 Hz, 2H), 6.56 (d, J = 3.1 Hz, 1H), 5.27 (s, 1H), 3.75 (dd, J = 36.5,

16.1 Hz, 2H), 3.23 (d, J = 13.5 Hz, 1H), 2.95 (d, J = 13.5 Hz, 1H), 1.68 (s, 3H), 1.54 (m, 4H). 13C NMR (benzene-d6, 101 MHz, CDCl3) δ 139.07 (C), 136.29 (C), 132.05 (C), 130.15

(CH), 129.21 (CH), 128.83 (CH), 128.33 (CH), 127.79 (CH), 126.49 (CH), 126.09 (CH),

124.54 (C), 123.39 (CH), 122.72 (CH), 120.45 (CH), 119.45 (CH), 119.14 (C), 115.00 (CH),

102.49 (CH), 60.42 (C), 51.30 (CH2), 37.45 (CH2), 30.85 (CH3), 29.71 (CH2). IR (ATR): ν

(cm-1) = 3059, 3028, 2925, 2854, 1797, 1684, 1601, 1495, 1453, 1379, 1241, 1185, 1147,

1048, 916, 807, 770, 748, 702. HRMS-ESI (MH+, C26H26N): calculated: 352.2065,

experimental: 352.2374.

2,4-dihydro-4-methyl-4,6-diphenyl-1H-pyrrolo[3,2,1-ij]quinolone.


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CDCl3) δ 7.64 – 7.59 (m, 2H), 7.38 (m, 7H), 7.31 – 7.24 (m, 1H), 6.95 (dd, J = 7.2, 0.9 Hz,

1H), 6.82 (d, J = 7.6 Hz, 1H), 6.49 (t, J = 7.5 Hz, 1H), 5.35 (s, 1H), 3.51 (dd, J = 17.6, 8.9

Hz, 1H), 3.13 (ddd, J = 10.2, 8.9, 6.4 Hz, 1H), 3.01 (qd, J = 9.6, 5.6 Hz, 2H), 1.85 (s, 3H). 13C NMR (benzene-d6, 101 MHz, CDCl3) δ 147.90 (C), 145.13 (C), 138.52 (C), 134.15 (C),

130.12 (CH), 128.62 (CH), 128.36 (CH), 128.24 (CH), 127.47 (CH), 127.11 (CH), 126.82

(CH), 126.60 (C), 124.51 (CH), 122.57 (CH), 116.91 (CH), 116.44 (C), 61.24 (CH), 46.47

(CH2), 28.10 (CH2), 23.56 (CH3). IR (ATR): ν (cm-1) = 3055, 3028, 2972, 2851, 1627, 1599,

1492, 1457, 1444, 1335, 1281, 1208, 1154, 1073, 1027, 1003, 776, 757, 699. HRMS-ESI

(MH+, C24H22N): calculated: 324.1752, experimental: 324.1746.

6-methoxy-2-methyl-1,2,4-tri(pent-4-en-1-yl)-1,2-

dihydroquinoline. (40) (Rf 0.3, 20% cyclohexane, DCM) was prepared according to the



MHz, CDCl3) δ 6.72 (d, J = 2.7 Hz, 1H), 6.66 (dd, J = 8.8, 2.8 Hz, 1H), 6.32 (d, J = 8.8 Hz,

1H), 5.96 – 5.82 (m, 2H), 5.76 (ddt, J = 16.9, 10.1, 6.7 Hz, 1H), 5.14 (s, 1H), 5.13 – 4.91 (m,

6H), 3.78 (s, 3H), 3.20 – 3.04 (m, 2H), 2.39 – 2.31 (m, 2H), 2.20 – 2.09 (m, 4H), 2.02 (q, J =

7.0 Hz, 2H), 1.83 – 1.72 (m, 2H), 1.68 (m, 2H), 1.51 – 1.36 (m, 2H), 1.29 (s, 3H), 1.27 – 1.12

(m, 2H). 13C NMR (126 MHz, CDCl3) δ 150.22 (C), 139.34 (C), 138.86 (CH), 138.69 (CH),

138.06 (CH), 132.12 (C), 128.54 (CH), 122.73 (C), 115.05 (CH2), 114.75 (CH2), 114.51

(CH2), 112.64 (CH), 110.74 (CH), 110.15 (CH), 59.62 (C), 55.88 (CH3), 43.51 (CH2), 40.94

(CH2), 34.07 (CH2), 33.63 (CH2), 31.42 (CH2), 31.39 (CH2), 28.68 (CH3), 27.56 (CH2), 27.12

(CH2), 23.93 (CH2). IR (ATR): ν (cm-1) = 3075, 2976, 2933, 1640, 1491, 1430, 1298, 1206,

1051, 992, 910, 797. HRMS-ESI (MH+, C26H37NO): calculated: 379.2875, experimental:

379.2899.

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(E)-N-((Z)-4-((2,6-diisopropylphenyl)amino)-3-(1-phenylvinyl)pent-

3-en-2-ylidene)-2,6-diisopropylaniline. (70) 1H NMR (400 MHz, CDCl3) δ 13.15 (s, 1H),

7.64 (dd, J = 8.5, 1.1 Hz, 2H), 7.40 – 7.33 (m, 2H), 7.32 – 7.26 (m, 1H), 7.14 (s, 6H), 6.01 (d,

J = 1.9 Hz, 1H), 5.35 (d, J = 1.9 Hz, 1H), 3.29 – 3.14 (m, 4H), 1.65 (s, 6H), 1.20 (d, J = 6.7

Hz, 24H). 13C NMR (101 MHz, CDCl3) δ 161.41 (C), 147.54 (C), 142.36 (C), 141.70 (C),

140.90 (C), 128.44 (CH), 127.48 (CH), 125.87 (CH), 124.99 (CH), 123.06 (CH), 117.42

(CH2), 104.93 (C), 28.35 (CH), 24.10 (CH3), 23.26 (CH3), 19.15 (CH3). IR (ATR): ν (cm-1) =

3060, 2961, 2926, 2868, 1602, 1535, 1464, 1443, 1363, 1236, 1193, 782, 764, 710. HRMS-

ESI (MH+, C37H49N2): calculated: 521.3896, experimental: 521.3883.

(E)-N-((3Z,4Z)-3-(1-((2,6-

diisopropylphenyl)amino)ethylidene)-4-methylnon-4-en-2-ylidene)-2,6-

diisopropylaniline. (72) 1H NMR (400 MHz, CDCl3) δ 13.15 (s, 1H), 7.12 (s, 6H), 5.50 (td,

J = 7.0, 1.4 Hz, 1H), 3.14 (dt, J = 13.7, 6.9 Hz, 4H), 2.07 – 1.96 (m, 2H), 1.91 (dd, J = 2.5,

1.2 Hz, 3H), 1.66 (d, J = 2.9 Hz, 6H), 1.38 – 1.30 (m, 4H), 1.19 (dd, J = 7.9, 7.0 Hz, 12H),

1.14 (dd, J = 6.9, 1.9 Hz, 12H), 0.95 – 0.87 (m, 3H). 13C NMR (101 MHz, CDCl3) δ 159.85,

142.49, 142.35, 141.11, 135.91, 130.97, 124.81, 123.02, 31.45, 29.24, 28.29, 28.23, 26.07,

24.15, 24.10, 23.28, 23.22, 22.99, 18.07, 13.93. IR (ATR): ν (cm-1) = 3059, 2961, 2926,

2867, 1601, 1528, 1465, 1457, 1363, 1267, 1240, 1191, 1102, 1058, 804, 772. HRMS-ESI

(MH+, C36H55N2): calculated: 515.4365, experimental: 515.4356.

(E)-N-((Z)-4-((2,6-diisopropylphenyl)amino)-3-((Z)-1-phenylprop-

1-en-2-yl)pent-3-en-2-ylidene)-2,6-diisopropylaniline. (71) 1H NMR (400 MHz, CDCl3) δ

13.27 (s, 1H), 7.53 (d, J = 7.2 Hz, 2H), 7.29 (dd, J = 10.1, 4.7 Hz, 2H), 7.20 (t, J = 7.3 Hz,

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1H), 7.10 (dt, J = 6.6, 4.9 Hz, 6H), 6.51 (s, 1H), 3.13 (dtd, J = 13.7, 6.9, 3.8 Hz, 4H), 2.12 (d,

J = 1.3 Hz, 3H), 1.65 (s, 6H), 1.23 – 1.14 (m, 18H), 1.02 (d, J = 6.9 Hz, 6H). 13C NMR (101

MHz, CDCl3) δ 159.54, 142.36, 142.28, 140.75, 138.94, 129.88, 128.02, 127.92, 126.37,

124.96, 123.05, 123.03, 28.38, 28.32, 28.13, 26.93, 24.29, 24.02, 23.35, 23.23, 17.94. IR

(ATR): ν (cm-1) = 3332, 2960, 2925, 2854, 1731, 1602, 1532, 1459, 1363, 1266, 1241, 772.

HRMS-ESI (MH+, C38H51N2): calculated: 535.4052, experimental: 535.4042.

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1,2-dihydro-1,2-dimethyl-2,4-dipropylquinoline(24).

121

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5,7-dibutyl-5-methyl-1,2,3,5-tetrahydropyrido[3,2,1-ij]quinoline (15)

122

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4,6-dibutyl-2,4-dihydro-4-methyl-1H-pyrrolo[3,2,1-ij]quinoline (21)

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Experiment details.

For ligands synthesis most of the reaction were done using normal Schlenk techniques until

mentioned. (R)-phenylethylamine was obtained from BASF AG, optical purity: ee 99.9 %.

(1S, 2S)-cyclohexane-1,2-diamine was obtained from Aldrich, Cat. Number: 346713, optical

purity ee 99%

Preparation of Ligand 93:

(R)-3-bromo-2-(methoxymethoxy)-N-(1-phenylethyl)aniline. (88)

To a mixture of 1,3-dibromo-2-(methoxymethoxy)benzene (10.0 mmol, 2.970 g), (R)-

phenylethylamine (Note 1) (10.20 mmol, 1.30 ml), t-BuONa (13.30 mmol, 1.280 g), racemic

BINAP (0.386 mmol, 0.240 g) and Pd2(dba)3 (0.193 mmol, 0.177 g) was added toluene (20

ml). The resulting red suspension was stirred for 5 h at 70 °C. The mixture was cooled to r.t.

and diluted with diethyl ether (5 ml). Insoluble solids formed were removed by filtration and

filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography

(toluene: c-Hexane, 7:3) to afford (R)-3-bromo-2-(methoxymethoxy)-N-(1-

phenylethyl)aniline; yield 2.555 g (76%); Oil; [α]D20 = -122.2 (c= 0.5, CH2Cl2);

1H NMR

(400 MHz, CDCl3): δ 7.14-7.41 (m, 5H), 6.77 (dd, J = 8.0, J= 1.4 Hz, 1H), 6.69 (t, J = 8.0

Hz, 1H), 6.30 (dd, J = 8.0, J= 1.4 Hz, 1H), 5.13 and 5.16 (two d, J = 5.8 Hz, 2H), 5.11 (bs,

1H, exchangeable with D2O), 4.45 (m, 1H), 3.68 (s, 3H), 1.55 (d, J = 6.7 Hz, 3H); 13C NMR

(100 MHz, CDCl3): δ 144.90 (C), 142.58 (C), 141.82 (C), 128.72, 127.01, 126.16, 125.76,

120.17, 116.69 (C), 111.38, 100.01 (CH2), 57.88, 53.28, 25.07 (CH3); IR (ATR): 3405, 2924

cm-1; HRMS (ESI) m/z: (M+H+) calcd for C16H19O2NBr: 336.059. Found: 336.0592.

Lit: Synthesis 2003, 8, 1181-1186.

(R)-2-(methoxymethoxy)-3-(phenylethylamino)benzaldehyde. (89)

To a -78 °C cooled solution of (R)-3-bromo-2-(methoxymethoxy)-N-(1-phenylethyl)aniline

(5.57 mmol, 1.873 g) in THF (20 ml) were added PhLi (7.241 mmol, 4.6 ml, 1.58M in

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dibutyl ether) and next after 15 min., n-BuLi (7.241 mmol, 3.0 ml, 2.4M in hexane). The

reaction mixture was stirred at -78 °C for 30 min and DMF (3 ml) was added dropwise at -78

°C. When the substrate was consumed (30 min, TLC control), the reaction mixture was

warmed to 0°C and sat. aqueous NH4Cl (20 ml) and water (20 ml) were added. The mixture

was extracted with diethyl ether (3×20 ml) and combined organic layers were washed with

brine, dried (MgSO4) and concentrated in vacuo. The residue was chromatographed on a

silica gel column (t-BuOMe: c-hexane, 1:4) to give (R)-2-(methoxymethoxy)-3-

(phenylethylamino)benzaldehyde (1.420 g, 89%). Colorless crystals mp 83-84 °C (t-

BuOMe/hexane); [α]D20 = -211.2 (c= 0.5, CH2Cl2);

1H NMR (400 MHz, CDCl3): δ 10.27 (s,

1H), 7.20-7.30 (m, 5H), 7.07 (dd, 1H, J = 7.8, J = 1.5 Hz), 6.94 (t, 1H, J = 7.8 Hz), 6.61 (dd,

1H, J = 7.8, J = 1.5 Hz), 5.13 and 5.16 (two d, 2H, J = 6.0 Hz), 5.05 (bs, 1H), 4.48 (m, 1H),

3.65 (s, 3H), 1.57 (d, 3H, J = 6.7 Hz); 13C NMR (100 MHz, CDCl3): δ 191.25, 147.45 (C),

144.28 (C), 141.18 (C), 128.97 (C), 128.80, 127.13, 125.72, 125.32, 117.69, 116.55, 101.38

(CH2), 58.13, 53.48, 25.39; IR (ATR): 3418, 2966, 1647 cm-1; HRMS (ESI) m/z: (M+Na+)

calcd for C17H19NO3Na: 308.1262. Found: 308.1255.

(R)-2-hydroxy-3-(1-phenylethylamino)benzaldehyde. (90) To a

suspension of (R)-2-(methoxymethoxy)-3-(1-phenylethylamino)benzaldehyde (3.5 mmol, 1.0

g) in MeOH (15 ml) was added dropwise aqueous solution of 6M HCl (7 ml) at room

temperature. After 4h, saturated aqueous NaHCO3 was added slowly until neutral pH was

attained. The reaction mixture was extracted with diethyl ether (3×50 ml). The combined

ether layers were washed with brine, dried (MgSO4) and concentrated in vacuo. The residue

was chromatographed on a silica gel column (t-BuOMe: c-hexane, 3:97) to give (R)-2-

hydroxy-3-(1-phenylethylamino)benzaldehyde (0.8 g, 95%). Yellow crystals mp 81-82 °C

(Hexane); [α]D20 = -211.2 (c = 0.5, CH2Cl2);

1H NMR (400 MHz, CDCl3): δ 11.39 (s, 1H,

exchangeable with D2O), 9.82 (s, 1H), 7.30-7.38 (m, 4H), 7.21-7.27 (m, 1H), 6.84 (dd, 1H, J

= 7.8, J = 1.5), 6.73 (t, 1H, J = 7.8 Hz), 6.52 (dd, 1H, J = 7.8 Hz, J = 1.3 Hz), 4.74 (bs, 1H,

exchangeable with D2O), 4.50 (m, 1H), 1.59 (d, 3H, J = 6.7 Hz); 13C NMR (100 MHz,

CDCl3): δ 197.44 (HC=O), 148.94 (C), 144.65 (C), 136.63 (C), 128.75, 127.06, 125.75,

120.11, 119.98, 119.02 (C), 116.80, 53.18, 25.37; IR (ATR): 3418, 2840, 1647 cm-1; HRMS

(ESI) m/z: (M+H+) calcd for C15H16O2N: 242.1181. Found: 242.1175.

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(R) -6,6`- ((1E, 1 E)-(1S, 2S) -cyclohexane- 1,2-diylbis (azan-1-

yl-1 -ylidene)bis(methan-1-yl-1-ylidene))bis(2-((R)-1-phenylethylamino)phenol. (93) (R)-

2-hydroxy-3-(1-phenylethylamino)benzaldehyde (2.91 mmol, 702 mg) and (1S, 2S)-

cyclohexane-1,2-diamine (Note 2) (1.45 mmol, 166 mg) were heated in toluene in the

presence of catalytic amounts of p-TsOH. Water was removed by azeotropic distillation.

After cooling to room temperature, solvent was evaporated in vacuo. The product was

purified by fast filtration on silica gel (t-BuOMe: c-Hexane, 3:17) and crystallization. Yield

85%, 698 mg; orange crystals mp 166-168 °C (Hexane); [α]D20 = +300.4 (c= 0.5, CH2Cl2);

1H NMR (400 MHz, CDCl3): δ 13.95 (s, 2H, exchangeable with D2O), 8.22 (s, 2H), 7.13-

7.39 (m, 10H), 6.50 (m, 4H), 6.27 (dd, 2H, J = 6.9, J = 2.4 Hz), 4.68 (bs, 2H, exchangeable

with D2O), 4.45 (m, 2H), 3.34 (m, 2H), 1.83-2.03 (m, 4H), 1.70 (m, 2H), 1.55 (d, 6H, J = 6.7

Hz), 1.49 (m, 2H); 13C NMR (100 MHz, CDCl3): δ 165.17, 150.43 (C), 145.22 (C), 136.84

(C), 128.61, 126.81, 125.82, 118.68, 118.31, 116.14 (C), 112.84, 71.75, 53.46, 33.23 (CH2),

25.25, 24.16 (CH2); IR (ATR): 3422, 2926, 1623 cm-1; HRMS (ESI) m/z: (M+H+) calcd for

C36H41N4O2: 561.3229. Found: 561.3219.

(R)-6,6'-((1E,1'E)-(1S,2S)-cyclohexane-1,2-diylbis(azan-1-yl-

1-ylidene)bis(methan-1-yl-1-ylidene))bis(3,5-dibromo-2-((R)-1-

phenylethylamino)phenol). (79) Prepared following the same procedure like ligand B.

orange crystals mp 59-61 °C (Hexane); [α]D20 = +551.9 (c= 0.5, CH2Cl2);

1H NMR (400

MHz, CDCl3) δ 14.86 (s, 2H, exchangeable with D2O), 8.43 (s, 2H), 7.28 (d, J = 7.3 Hz, 5H),

7.23 – 7.09 (m, 5H), 6.91 (s, 2H), 5.22 (m, 2H), 4.60 (s, 2H, exchangeable with D2O), 3.43

(m, 2H), 2.14 (d, J = 12.0 Hz, 2H), 1.95 (m, 2H), 1.76 (m, 2H), 1.52 (m, 2H), 1.46 (d, J = 6.3

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Hz, 6H); 13C NMR (101 MHz, CDCl3) δ 165.21 (C), 165.18 (CH), 128.30 (CH), 126.97

(CH), 126.93 (C), 126.90 (CH), 126.22 (C), 126.19 (CH), 124.53 (CH), 112.61 (C), 112.60

(C), 69.24 (CH), 54.57 (C), 32.42 (CH2), 24.02 (CH2), 23.77 (CH3); IR (ATR): 3336, 2929,

2859, 1621, 1583, 1476, 1447, 1429, 1228, 922, 759, 699 cm-1; HRMS (ESI) m/z: (M+H+)

calcd for C36H37Br4N4O2 : 872.9645. Found: 872.9642.

(S)-6,6'-((1E,1'E)-(1S,2S)-cyclohexane-1,2-diylbis(azan-1-yl-

1-ylidene)bis(methan-1-yl-1-ylidene))bis(3,5-dibromo-2-((S)-1-

phenylethylamino)phenol). (83) Prepared following the same procedure like ligand B.

orange crystals mp 57-60 °C (Hexane); [α]D20 = +726.0 (c= 0.5, CH2Cl2);

1H NMR (400

MHz, CDCl3) δ 14.90 (s, 2H), 8.45 (s, 2H), 7.29 – 7.24 (m, 20H), 7.22 – 7.11 (m, 17H), 6.92

(s, 5H), 5.20 (q, J = 6.8 Hz, 6H), 4.50 (s, 6H), 3.43 (d, J = 8.7 Hz, 6H), 2.13 (d, J = 13.7 Hz,

6H), 1.94 (d, J = 8.7 Hz, 6H), 1.74 (d, J = 8.2 Hz, 7H), 1.51 (dd, J = 8.4, 6.1 Hz, 4H), 1.48 (d,

J = 6.2 Hz, 18H), 1.42 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 165.18 (CH), 161.14 (C),

145.05 (C), 136.72 (C), 128.29 (CH), 126.86 (CH), 126.19 (CH), 124.57 (CH), 116.70 (C),

114.62 (C), 112.73 (C), 69.47 (CH), 54.56 (CH), 32.49 (CH2), 24.03 (CH2), 23.66 (CH3); IR

(ATR): 3345, 2935, 2861, 1620, 1476, 1447, 1428, 1229, 922, 759, 699 cm-1; HRMS (ESI)

m/z: (M+H+) calcd for C36H37Br4N4O2 : 872.9645. Found: 872.9642.

(S)-6,6'-((1E,1'E)-(1S,2S)-cyclohexane-1,2-diylbis(azan-1-yl-

1-ylidene)bis(methan-1-yl-1-ylidene))bis(3,5-dibromo-2-((S)-1-(naphthalen-1-

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yl)ethylamino)phenol). (80) Prepared following the same procedure like ligand B. orange

crystals. [α]D20 = +368.0 (c= 0.5, CH2Cl2);

1H NMR (400 MHz, CDCl3) δ 14.90 (s, 2H), 8.49

(s, 2H), 8.34 (d, J = 8.4 Hz, 2H), 7.81 (dd, J = 8.0, 1.4 Hz, 2H), 7.65 (d, J = 8.2 Hz, 2H), 7.51

(ddd, J = 8.5, 6.8, 1.5 Hz, 2H), 7.45 (ddd, J = 8.1, 6.8, 1.1 Hz, 4H), 7.28 (dd, J = 12.4, 5.1

Hz, 2H), 6.91 (d, J = 2.9 Hz, 2H), 6.21 (q, J = 6.6 Hz, 2H), 4.77 (s, 2H), 3.54 – 3.39 (m, 2H),

2.20 – 2.03 (m, 2H), 1.93 (d, J = 9.0 Hz, 2H), 1.74 (d, J = 10.4 Hz, 2H), 1.56 (d, J = 6.6 Hz,

6H), 1.49 (t, J = 9.8 Hz, 2H); 13C NMR (101 MHz, CDCl3) δ 165.12 (CH), 161.50 (C),

141.00 (C), 136.82 (C), 133.90 (C), 131.15 (C), 128.72 (CH), 127.42 (CH), 125.87 (CH),

125.51 (CH), 125.36 (CH), 124.68 (CH), 123.75 (CH), 122.19 (CH), 115.37 (C), 113.69 (C),

112.48 (C), 69.27 (CH), 49.97 (CH), 32.46 (CH2), 24.01 (CH2), 23.24 (CH3); IR (ATR):

3351, 3047, 3047, 2936, 2862, 1703, 1621, 1476, 1446, 1429, 1371, 1233, 923, 798, 777 cm-

1; HRMS (ESI) m/z: (M+H+) calcd for C44H41Br4N4O2: 972.9958. Found: 972.9947.

(S) (S)

N N

OH

NH

HO

HN

(S) (S) MeMe

(S)-6,6'-((1E,1'E)-(1S,2S)-cyclohexane-1,2-diylbis(azan-1-yl-1-

ylidene)bis(methan-1-yl-1-ylidene))bis(2-((S)-1-phenylethylamino)phenol). (94) Prepared

following the same procedure like ligand B. orange crystals mp 166-168 °C (Hexane); [α]D20

= +803.2 (c= 0.5, CH2Cl2); 1H NMR (400 MHz, CDCl3) δ 13.95 (s, 2H, exchangeable with

D2O), 8.20 (s, 2H), 7.36 (dd, J = 8.0, 1.0 Hz, 4H), 7.30 (dd, J = 10.3, 4.9 Hz, 4H), 7.24 – 7.17

(m, 2H), 6.57 – 6.41 (m, 4H), 6.27 (dd, J = 7.2, 2.1 Hz, 2H), 4.70 (s, 2H), 4.45 (q, J = 6.5 Hz,

2H), 3.40 – 3.26 (m, 2H), 1.97 (d, J = 14.2 Hz, 2H), 1.89 (d, J = 8.8 Hz, 2H), 1.69 (t, J = 20.4

Hz, 2H), 1.55 (d, J = 6.7 Hz, 6H), 1.49 (dd, J = 12.9, 6.7 Hz, 2H); 13C NMR (101 MHz,

CDCl3) δ 165.14 (CH), 150.36 (C), 145.33 (C), 136.76 (C), 128.59 (CH), 126.78 (CH),

125.83 (CH), 118.65 (CH), 118.26 (CH), 116.09 (C), 112.83 (CH), 71.80 (CH), 53.33 (CH),

33.22 (CH2), 25.24 (CH3), 24.18 (CH2); IR (ATR): 3416, 3058, 3025, 2930, 2859, 1701,

1624, 1505, 1448, 1354, 1274, 1250, 1142, 1027, 842, 760, 732, 700 cm-1; HRMS (ESI) m/z:

(M+H+) calcd for C36H41N4O2: 561.3224. Found: 561.3219.

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(R)-6,6'-((1E,1'E)-(1R,2R)-cyclohexane-1,2-diylbis(azan-1-yl-1-

ylidene)bis(methan-1-yl-1-ylidene))bis(2-((R)-1-phenylethylamino)phenol). (96) Prepared

following the same procedure like ligand B. orange crystals mp 166-168 °C (Hexane); [α]D20

could not be measure due to bright colour (c= 0.5, CH2Cl2); 1H NMR (400 MHz, CDCl3) δ

13.94 (s, 2H), 8.20 (s, 2H), 7.38 – 7.33 (m, 4H), 7.32 – 7.26 (m, 4H), 7.23 – 7.17 (m, 2H),

6.57 – 6.40 (m, 4H), 6.27 (dd, J = 7.1, 2.0 Hz, 2H), 4.70 (s, 2H), 4.45 (q, J = 6.4 Hz, 2H),

3.33 (dd, J = 11.0, 7.0 Hz, 2H), 1.93 (dd, J = 31.9, 11.7 Hz, 4H), 1.72 (d, J = 10.3 Hz, 2H),

1.55 (t, J = 6.9 Hz, 6H), 1.48 (t, J = 9.8 Hz, 2H); 13C NMR (101 MHz, CDCl3) δ 165.13

(CH), 150.37 (C), 145.29 (C), 136.72 (C), 128.58 (CH), 126.78 (CH), 125.83 (CH), 118.67

(CH), 118.25 (CH), 116.08 (C), 112.87 (C), 71.80 (CH), 53.35 (CH), 33.21 (CH2), 25.21

(CH3), 24.18 (CH2); IR (ATR): 3417, 3059, 3026, 2927, 2856, 1728, 1625, 1505, 1448,

1354, 1274, 1251, 1213, 1027, 732, 700 cm-1; HRMS (ESI) m/z: (M+H+) calcd for

C36H41N4O2: 561.3224. Found: 561.3220.

(S)-6,6'-((1E,1'E)-(1,1'-binaphthyl-2,2'-diylbis(azan-

1-yl-1-ylidene))bis(methan-1-yl-1-ylidene))bis(2-((R)-1-phenylethylamino)phenol). (97)

Prepared following the same procedure like ligand B. orange crystals. [α]D20 could not be

measure due to bright color (c= 0.5, CH2Cl2); 1H NMR (400 MHz, CDCl3) δ 13.94 (s, 2H),

8.57 (s, 2H), 8.09 (d, J = 8.7 Hz, 2H), 7.97 (d, J = 8.1 Hz, 2H), 7.61 (d, J = 8.8 Hz, 2H), 7.45

(ddd, J = 8.1, 6.7, 1.3 Hz, 2H), 7.31 – 7.26 (m, 8H), 7.26 – 7.21 (m, 4H), 7.19 (ddd, J = 8.6,

5.4, 2.7 Hz, 2H), 6.53 – 6.47 (m, 4H), 6.26 – 6.21 (m, 2H), 4.43 (d, J = 5.3 Hz, 2H), 4.40 –

4.32 (m, 2H), 1.47 (d, J = 6.7 Hz, 6H); 13C NMR (101 MHz, CDCl3) δ 163.10 (CH), 148.55

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(C), 145.28 (C), 144.30 (C), 136.47 (C), 133.36 (C), 132.38 (C), 129.92 (CH), 128.69 (C),

128.57 (CH), 128.23 (CH), 126.89 (CH), 126.75 (CH), 126.43 (CH), 125.80 (CH), 125.63

(CH), 119.33 (CH), 118.70 (CH), 117.81 (CH), 117.24 (C), 113.53 (CH), 53.43 (CH3), 25.14

(CH3); IR (ATR): 3416, 3056, 2964, 1715, 1605, 1590, 1501, 1480, 1348, 1275, 1201, 821,

749, 732, 701 cm-1; HRMS (ESI) m/z: (M+H+) calcd for C50H43N4O2: 731.3381. Found:

731.3379.

(S)-6,6'-((1E,1'E)-(1,1'-binaphthyl-2,2'-diylbis(azan-

1-yl-1-ylidene))bis(methan-1-yl-1-ylidene))bis(2-((S)-1,2,3,4-tetrahydronaphthalen-1-

ylamino)phenol). (98) Prepared following the same procedure like ligand B. orange crystals.

[α]D20 could not be measured due to bright colour (c= 0.5, CH2Cl2);

1H NMR (400 MHz,

CDCl3) δ 14.90 (s, 2H), 8.58 (s, 2H), 8.01 (d, J = 8.7 Hz, 2H), 7.91 (d, J = 8.2 Hz, 2H), 7.53

(t, J = 6.8 Hz, 2H), 7.40 (ddd, J = 8.1, 6.7, 1.3 Hz, 2H), 7.30 (d, J = 7.1 Hz, 2H), 7.26 – 7.20

(m, 2H), 7.20 – 7.15 (m, 4H), 7.13 (t, J = 6.7 Hz, 4H), 6.74 – 6.65 (m, 4H), 6.58 (dd, J = 7.3,

1.9 Hz, 2H), 4.51 (s, 2H), 4.33 (d, J = 8.1 Hz, 2H), 2.91 – 2.68 (m, 4H), 2.02 – 1.79 (m, 6H),

1.75 (dt, J = 9.7, 6.4 Hz, 2H); 13C NMR (101 MHz, CDCl3) δ 162.94 (CH), 148.70 (C),

144.18 (C), 138.29 (C), 137.67 (C), 136.81 (C), 133.25 (C), 132.32 (C), 129.92 (CH), 129.21

(CH), 128.90 (CH), 128.73 (C), 128.25 (CH), 126.95 (CH), 126.83 (CH), 126.37 (CH),

126.06 (CH), 125.62 (CH), 119.16 (CH), 118.76 (CH), 117.66 (CH), 117.55 (C), 112.22

(CH), 51.05 (CH), 29.41 (CH2), 28.83 (CH2), 19.72 (CH2); IR (ATR): 3426, 3056, 2933,

2861, 1605, 1589, 1578, 1499, 1480, 1275, 1202, 971, 818, 746, 731 cm-1; HRMS (ESI) m/z:

(M+H+) calcd for C54H47N4O2: 783.3694. Found: 783.3681.

Preparation of starting material of the type 105.

A solution of n-BuLi (40 ml, 100 mmol; 2.5 M in hexane) in THF is added dropwise to the

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solution of freshly distilled diisopropylamine in THF (20 ml) at -78 °C. The reaction mixture

then warmed to 0 °C again cooled to -78 °C. Then alkyl- or arylnitrile (100 mmol) in THF

(20 ml) was added dropwise and stir for 2 h. Then allyl- or homoallylbromide is added

dropwise at this temperature. After finishing the addition the reaction mixture is warmed to

room temperature and stirred for 3 h. Reaction mixture is then washed with 10% NH4Cl

aqueous solution (50 ml) and extracted with Et2O (2 x 50 ml). The organic layer were

combined and dried over MgSO4, filtered and the solvent was removed under reduced

pressure and purified with column chromatography to give the nitrile product. A solution of

obtained nitrile in Et2O was added dropwise to the suspension of LiAlH4 (2 eq) in Et2O at 0

°C. The suspension was stirred at room temperature overnight and then treated with ice water

and 15% NaOH aqueous solution. Filtered over celite, dried, evaporated and purified with

column chromatography.

2,2-diphenylhex-5-en-1-amine. (101) Yield 97%. Liquid; 1H NMR

(400 MHz, CDCl3) δ 7.35 – 7.25 (m, 4H), 7.24 – 7.15 (m, 6H), 5.77 (ddt, J = 16.8, 10.2, 6.5

Hz, 1H), 5.09 – 4.83 (m, 2H), 3.33 (s, 2H), 2.32 – 2.11 (m, 2H), 1.84 – 1.68 (m, 2H), 1.13 (d,

J = 47.8 Hz, 2H). 13C NMR (101 MHz, CDCl3) δ 146.32 (C), 138.83 (CH), 128.29 (CH),

128.10 (CH), 126.06 (CH), 114.37 (CH2), 51.82 (C), 49.13 (CH2), 35.81 (CH2), 28.63 (CH2).

HRMS (ESI) m/z: (M+H+) calcd for C18H22N: 252.1747. Found: 252.1745. IR (ATR): 3058,

2926, 1666, 1640, 1495, 1444, 910, 756, 699.

2,2-dimethylhex-5-en-1-amine. (106) Yield 79%. Liquid; 1H NMR

(400 MHz, CDCl3) δ 5.81 (ddt, J = 16.8, 10.2, 6.6 Hz, 1H), 5.03 – 4.88 (m, 2H), 2.43 (s, 2H),

2.04 – 1.90 (m, 2H), 1.35 – 1.23 (m, 4H), 0.84 (s, 6H). 13C NMR (101 MHz, CDCl3) δ

139.53 (CH), 113.95 (CH2), 52.80 (CH2), 38.60 (CH2), 34.46 (C), 28.41 (CH2), 24.60 (CH3).


3076, 2958, 2927, 2869, 1666, 1468, 1367, 908.

(1-(but-3-enyl)cyclopentyl)methanamine. (107) Yield 95%. Liquid; 1H NMR (400 MHz, CDCl3) δ 5.82 (ddt, J = 16.8, 10.2, 6.6 Hz, 1H), 5.12 – 4.84 (m, 2H),

2.51 (s, 2H), 2.03 – 1.93 (m, 2H), 1.57 (m, 4H), 1.45 – 1.39 (m, 2H), 1.38 – 1.32 (m, 4H),

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1.20 (s, 2H). 13C NMR (101 MHz, CDCl3) δ 139.45 (CH), 114.00 (CH2), 49.02 (CH2), 46.67

(C), 36.40 (CH2), 35.45 (CH2), 29.17 (CH2), 25.15(CH2). HRMS (ESI) m/z: (M+H+) calcd

for C10H20N: 154.1591. Found: 154.1583. IR (ATR): 3308, 3075, 2946, 2864, 1666, 1640,

1451, 1369, 1126, 993, 907.

2-phenylhex-5-en-1-amine. (109) Yield 74%. Liquid; 1H NMR (400

MHz, CDCl3) δ 7.34 – 7.28 (m, 2H), 7.24 – 7.19 (m, 1H), 7.19 – 7.15 (m, 2H), 5.83 – 5.67

(m, 1H), 5.02 – 4.86 (m, 2H), 2.88 (ddd, J = 21.3, 12.6, 7.1 Hz, 2H), 2.60 (ddd, J = 14.4, 9.2,

5.3 Hz, 1H), 2.00 – 1.84 (m, 2H), 1.81 – 1.55 (m, 2H), 1.03 (s, 2H). 13C NMR (101 MHz,

CDCl3) δ 143.31 (C), 138.53 (CH), 128.56 (CH), 128.03 (CH), 126.48 (CH), 114.63 (CH2),

49.24 (CH), 48.20 (CH2), 33.01 (CH2), 31.54 (CH2). HRMS (ESI) m/z: (M+H+) calcd for

C12H18N: 176.1434. Found: 176.1429. IR (ATR): 3369, 3062, 3027, 2921, 2856, 1665, 1640,

1494, 1452, 1368, 995, 910, 760, 701.

2-(but-3-enyl)-2-phenylhex-5-en-1-amine. (110) Prepared following

the same procedure as described above taking 2-phenyl acetonitrile and 2 equivalent of 4-

bromo-1butene as the starting material. Yield 50%, liquid. 1H NMR (400 MHz, CDCl3) δ

7.41 – 7.28 (m, 4H), 7.25 – 7.17 (m, 1H), 5.89 – 5.73 (m, 2H), 5.09 – 4.89 (m, 4H), 2.92 (s,

2H), 1.99 – 1.84 (m, 4H), 1.83 – 1.75 (m, 4H), 0.88 (s, 2H). 13C NMR (101 MHz, CDCl3) δ

145.10 (C), 138.93 (CH), 128.37 (CH), 126.70 (CH), 125.90 (CH), 114.26 (CH2), 48.70

(CH2), 45.24 (C), 34.10 (CH2), 27.93 (CH2). HRMS (ESI) m/z: (M+H+) calcd for C16H24N:

230.1904. Found: 230.1902. IR (ATR): 3075, 2974, 2934, 2858, 1666, 1640, 1601, 1498,

1445, 1369, 1237, 995, 908, 758, 699.

2-benzyl-2-phenylhex-5-en-1-amine (111). A solution of n-BuLi (40

ml, 100 mmol; 2.5 M in hexane) in THF is added dropwise to the solution of freshly distilled

diisopropylamine in THF (20 ml) at -78 oC. The reaction mixture then warmed to 0 oC again

cooled to -78 oC. Then 2-phenylacetonitrile (100 mmol) in THF (20 ml) was added dropwise

and stir for 2 h. Then homoallylbromide (100 mmol) is added dropwise at this temperature.

After finishing the addition the reaction mixture is warmed to room temperature and stirred

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for 3 h. The reaction mixture is again cooled to -78 oC and benzyl bromide (100 mmol) is

added dropwise. And the reaction mixture is stirred overnight at room temperature. Reaction

mixture is then washed with 10% NH4Cl aqueous solution (50 ml) and extracted with Et2O (2

x 50 ml). The organic layer were combined and dried over MgSO4, filtered and the solvent

was removed under reduced pressure to give the nitrile product. The nitrile compound then

reduced with LiAlH4 and purified with column chromatography to give the amine. (163c) 1H

NMR (400 MHz, CDCl3) δ 7.40 – 7.30 (m, 2H), 7.30 – 7.19 (m, 3H), 7.19 – 7.12 (m, 3H),

6.90 – 6.77 (m, 2H), 5.77 (dtt, J = 17.0, 10.5, 6.5 Hz, 1H), 4.97 (dddd, J = 20.8, 10.2, 3.2, 1.7

Hz, 2H), 3.71 – 3.55 (m) and 3.10 – 2.87 (m) (4H), 2.04 – 1.88 (m, 2H), 1.77 – 1.65 (m, 2H),

1.25 (s, 2H). 13C NMR (101 MHz, CDCl3) δ 144.57 (C – E1), 143.51 (C – E2), 138.68 (CH

– E1), 138.37 (CH – E2), 138.04 (C – E1), 137.03 (C – E2), 130.32 (CH – E1), 130.27 (CH –

E2), 128.66 (CH – E1), 128.37 (CH – E2), 127.98 (CH – E1), 127.77 (CH – E2), 127.05 (CH

– E1), 126.93 (CH – E2), 126.64 (CH – E1), 126.48 (CH – E2), 126.09 (CH – E1), 126.04

(CH – E2), 114.57 (CH2 – E1), 114.32 (CH2 – E1), 47.21 (CH2 – E1), 46.64 (C – E1), 45.21

(C – E2), 44.98 (CH2 – E2), 43.31 (CH2 – E1), 41.60 (CH2 – E2), 34.60 (CH2 – E1), 33.79

(CH2 – E2), 28.18 (CH2 – E1), 28.13 (CH2 – E2). HRMS (ESI) m/z: (M+H+) calcd for

C19H24N: 266.1904. Found: 266.1900. IR (ATR): 3317, 3061, 3028, 2933, 1663, 1640, 1602,

1544, 1497, 1453, 1445, 1372, 1078, 1032, 995, 910, 763, 749, 700.

Synthesis of 3,3-diphenylhex-5-en-1-amine.

3,3-diphenylhex-5-en-1-amine. (118) To an ice cold suspension of

phosphoric acid (3.94 g, 11.5 mmol) salt (113) and THF (30 ml) was added to a solution of

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KOtBu (1.29 g, 11.5 mmol) in THF (20 ml) dropwise and then this mixture was stirred for 1 h

at 0°C. After that at 0 °C was added solution of the aldehyde starting material 112 (907 mg,

3.84 mmol) and reaction was stirred for 14 h (overnight) at room temperature. Water was

added (30 ml) and extracted with MTBE (3 x 100 ml). Dried with sodium sulphate and

evaporated to dryness. Purified with column chromatography using 5% MTBE in

cyclohexane to get the ether 114 with 69% isolated yield. Hydrolysis of the ether 114 gives

the alcohol and which isomerizes to the corresponding aldehyde 115 with 84% of isolated

yield. In Sodium borohydride (205mg, 5.4 mmol) add 10 mL of 95% methanol and stir until

the solid is dissolved. Aldehyde 115 (671mg, 2.68 mmol) is added dropwise to the

borohydride solution while stirring the mixture continuously at 0 °C. The addition should

take about 45 minutes. After the addition is complete, allow the reaction mixture to stand at

room temperature for 15 minutes with occasional stirring. Then 20-40 ml of water was added.

The reaction mixture is the extracted with 20 ml of diethyl ether. Combine the ether extracts;

wash them with an equal volume of water; and dry them with anhydrous magnesium sulfate

or sodium sulfate. Evaporated to dryness and purified with column chromatography (10%

ethyl acetate in cyclohexane) to get the alcohol 116 with 74% yield. Then alcohol 116

(815mg, 3.23 mmol) is treated with PPh3 (1.02 g, 3.88 mmol), DIAD (762 µl, 3.88 mmol),

azide (834 µl, 3.88 mmol) in 30 ml THF at 0 °C to give the azide 117 with 66% yield. Azide

117 (710 mg, 2.56 mmol) was diluted in THF (15 ml) and PPh3 (739 mg, 2.82 mmol) was

then added. After 1 h water (10 ml) was added and mixture was stirred for 24 h at rt. Solvent

was removed by evaporation and purified with column chromatography (5 to 20% methanol

in DCM) to get the amine 118 with 68% yield. Liquid; 1H NMR (400 MHz, CDCl3) δ 7.29 –

7.23 (m, 4H), 7.20 – 7.14 (m, 6H), 5.36 (ddt, J = 17.1, 10.1, 7.0 Hz, 1H), 4.99 (dddt, J = 18.3,

10.1, 2.1, 1.2 Hz, 2H), 2.90 – 2.83 (m, 2H), 2.45 (s, 2H), 2.29 – 2.20 (m, 2H), 1.29 (s, 2H).

13C NMR (101 MHz, CDCl3) δ 148.00 (C), 134.57 (CH), 127.95 (CH), 127.74 (CH), 125.82

(CH), 117.58 (CH2), 48.33 (C), 42.72 (CH2), 41.52 (CH2), 37.70 (CH2). HRMS (ESI) m/z:

(M+H+) calcd for C18H22N: 252.1747. Found: 252.1751.

Preparation of substituted di-aryl aminoalkene of the type 124:

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Preparation of potassium cyanoacetate (120)

A 200 mL two-necked round-bottomed flask was charged with 2-cyanoacetic acid (3.40 g,

40.0 mmol) and ethanol (40 ml). To this, a solution of potassium tert-butoxide (4.48 g, 40

mmol) in ethanol (40 ml) was added dropwise over 30 min. After completion of addition, the

reaction mixture was stirred for another 1 hour at room temperature. After removing

approximately 4/5 of the ethanol solvent by slow evaporation on rotary evaporator, diethyl

ether (50 ml) was added. The resulting solid was collected by filtration, washed sequentially

with ethanol (5 ml × 2) and diethyl ether (10 ml × 2). The resultant solids were transferred to

a round-bottom flask and dried under vacuum at 30 °C for 2 hours to afford potassium

cyanoacetate in 94% yields. Characterization data accorded with literature reports.

General procedures for the synthesis of α-diaryl nitriles: 6

Pd2(dba)3 (0.075 mmol), XPhos (0.6 mmol), and potassium cyanoacetate (5.0 mmol) were

added into a Schlenk tube in the presence of Teflon-coated magnetic stir bar. The tube was

evacuated and re-filled with nitrogen for 3 cycles. ArBr (5.0 mmol) and xylene (10.0 ml)

were then added. The tube was stirred for 1 min at room temperature and then immersed into

a 140 °C preheated oil bath for overnight. The reaction was quenched by cooling to ambient

temperature and EtOAc (~50 ml) and water (~50 ml) were added. The organic supernatant

was analyzed by GC. The organic layer was isolated and the remained aqua was further

extracted with EtOAc (~50 ml × 3). The combined organic phase was concentrated under

reduced pressure. The crude product was purified by flash column chromatography on silica

gel. The pure fraction was collected and dried under vacuum and followed proton (1H) and

carbon (13C) NMR characterization to get the corresponding nitrile 122. The nitrile 122 then

transformed to the corresponding amino-alkenes following the same procedure as described

for the preparation of 105.

NH2

MeMe

2,2-di-p-tolylhex-5-en-1-amine. (125) 1H NMR (400 MHz,

CDCl3) δ 7.11 – 7.04 (m, 8H), 5.83 – 5.69 (m, 1H), 5.01 – 4.85 (m, 2H), 3.28 (s, 2H), 2.33 (s,

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6H), 2.18 – 2.10 (m, 2H), 1.75 (ddd, J = 11.9, 8.5, 5.8 Hz, 2H), 1.08 – 0.92 (s, 2H). 13C NMR

(101 MHz, CDCl3) δ 143.16 (C), 138.91 (CH), 135.51 (C), 128.81 (CH), 128.09 (CH),

114.30 (CH2), 51.05 (CH), 49.03 (CH2), 35.88 (CH2), 28.63 (CH2), 20.93 (CH3). HRMS

(ESI) m/z: (M+H+) calcd for C20H26N: 280.2060. Found: 280.2051. IR (ATR): 3390, 3052,

3021, 2921, 2865, 2731, 1901, 1667, 1640, 1511, 1450, 1367, 1236, 1191, 1117, 1020, 994,

908, 810, 734.

2-(p-tolyl)hex-5-en-1-amine. (126) 1H NMR (400 MHz, CDCl3) δ 7.17

– 7.08 (m, 2H), 7.08 – 7.03 (m, 2H), 5.91 – 5.62 (m, 1H), 5.07 – 4.78 (m, 2H), 2.98 – 2.86

(m, 1H), 2.86 – 2.76 (m, 1H), 2.57 (ddd, J = 14.4, 9.5, 5.3 Hz, 1H), 2.33 (s, 3H), 2.01 – 1.84

(m, 2H), 1.80 – 1.55 (m, 2H), 1.47 – 1.17 (s, 2H). 13C NMR (101 MHz, CDCl3) δ 140.05 (C),

138.59 (CH), 135.97 (C), 129.28 (CH), 127.90 (CH), 114.59 (CH2), 48.66 (CH), 48.14 (CH2),

33.05 (CH2), 31.54 (CH2), 21.04 (CH3). HRMS (ESI) m/z: (M+H+) calcd for C13H20N:

190.1591. Found: 190.1586. IR (ATR): 3302, 3075, 2974, 2922, 2857, 1896, 1665, 1640,

1514, 1453, 1367, 995, 909, 816, 723.

2-(but-3-en-1-yl)-2-(p-tolyl)hex-5-en-1-amine. (127) 1H NMR (400

MHz, CDCl3) δ 7.23 – 7.17 (m, 2H), 7.14 (d, J = 8.1 Hz, 2H), 5.87 – 5.72 (m, 2H), 5.05 –

4.85 (m, 4H), 2.89 (s, 2H), 2.31 (s, 3H), 1.96 – 1.80 (m, 4H), 1.79 – 1.70 (m, 4H), 1.03 – 0.79

(s, 2H). 13C NMR (101 MHz, CDCl3) δ 141.92 (C), 139.01 (CH), 135.32 (C), 129.11 (CH),

126.57 (CH), 114.24 (CH2), 48.76 (CH2), 44.89 (C), 34.02 (CH2), 27.93 (CH2), 20.87 (CH3).


2996, 2974, 2922, 1897, 1821, 1666, 1640, 1514, 1454, 1369, 1236, 994, 908, 814, 724.

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NH2

2,2-di(naphthalen-1-yl)hex-5-en-1-amine. (128) 1H NMR (400 MHz,

CDCl3) δ 7.98 (dd, J = 18.2, 7.3 Hz, 1H), 7.84 – 7.74 (m, 3H), 7.71 (t, J = 9.1 Hz, 4H), 7.65 –

7.56 (m, 2H), 7.19 (t, J = 7.5 Hz, 2H), 6.90 (dd, J = 13.5, 6.6 Hz, 2H), 5.72 (ddt, J = 16.9,

10.2, 6.6 Hz, 1H), 4.86 (dd, J = 31.4, 23.1 Hz, 2H), 3.91 – 3.62 (m, 2H), 2.79 (td, J = 12.4,

4.2 Hz, 1H), 2.58 (td, J = 12.4, 4.5 Hz, 1H), 1.96 (d, J = 12.5 Hz, 1H), 1.32 – 1.16 (m, 1H),

0.82 (s, 2H). HRMS (ESI) m/z: (M+H+) calcd for C26H26N: 252.2060. Found: 252.2061. IR

(ATR): 3387, 3047, 2970, 2933, 1666, 1598, 1509, 1396, 1366, 912, 792, 777, 734.

2-(naphthalen-1-yl)hex-5-en-1-amine. (129) 1H NMR (400 MHz, CDCl3)

δ 8.17 (dd, J = 7.6, 6.9 Hz, 1H), 7.92 – 7.85 (m, 1H), 7.75 (d, J = 8.1 Hz, 1H), 7.58 – 7.44

(m, 3H), 7.40 (dd, J = 7.2, 1.2 Hz, 1H), 5.90 – 5.69 (m, 1H), 5.04 – 4.86 (m, 2H), 3.62 (t, J =

15.7 Hz, 1H), 3.07 (s, 2H), 2.08 – 1.76 (m, 4H), 1.42 – 0.95 (s, 2H). 13C NMR (101 MHz,

CDCl3) δ 139.59, 139.40, 138.55, 134.08, 132.92, 129.03, 126.85, 125.92, 125.62, 125.49,

123.27, 114.81, 77.50, 77.18, 76.86, 47.77, 41.79, 33.06, 31.60. HRMS (ESI) m/z: (M+H+)

calcd for C16H20N: 226.1591. Found: 226.1594. IR (ATR): 3296, 3061, 2931, 1664, 1640,

1511, 1396, 995, 911, 843, 798, 778.

2,2-bis(3-methoxyphenyl)hex-5-en-1-amine. (130) 1H NMR (400 MHz,

CDCl3) δ 7.20 (ddd, J = 10.2, 6.5, 2.7 Hz, 2H), 6.74 (dqd, J = 3.4, 2.5, 1.2 Hz, 6H), 5.77 (ddt,

J = 16.7, 10.2, 6.5 Hz, 1H), 5.01 – 4.86 (m, 2H), 3.76 (s, 6H), 3.30 (s, 2H), 2.24 – 2.10 (m,

2H), 1.83 – 1.70 (m, 2H), 1.00 (s, 2H). 13C NMR (101 MHz, CDCl3) δ 159.34 (C), 147.91

(C), 138.80 (CH), 128.98 (CH), 120.76 (CH), 114.85 (CH), 114.37 (CH2), 110.58 (CH),

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55.16 (CH3), 48.95 (C), 35.59 (CH2), 28.61 (CH2). HRMS (ESI) m/z: (M+H+) calcd for

C20H26NO2: 312.1959. Found: 312.1962. IR (ATR): 3309, 3075, 2937, 2834, 1666, 1640,

1598, 1581, 1489, 1464, 1432, 1291, 1248, 1049, 910, 777, 721, 701.

All the aminoalkenes were distilled from CaH2, degassed and stored inside a glovebox prior

to use. All other chemicals used here are commercially available. [Zr(NMe2)4] was obtained

from Acros. 1H and 13C{1H} NMR spectra were collected on a Bruker DRX-400

spectrometer. [α]D20 values were measured on a 341 Perkin Elmer polarimeter.

General procedure for catalytic hydroamination/cyclization

Inside the glovebox in reaction vial ligand (10 mol%) is disolved in toluene and Me2Zn (10

mol%) solution (1.2 M in toluene) is added. Then Zr(NMe2)4 (15 mol%) in toluene is added.

Then the amine (in toluene) is added. The vial is closed and taken out from glovebox and

heated at specified temperature.

Procedure for determination of enantiomeric excess of pyrrolidine products.

HPLC analysis. The enantiomeric excess of chiral pyrrolidines were also determined by

HPLC analysis of the naphthoyl derivatized product (mobile phase = Hexane/Isopropanol:

75/25, flow rate = 0.75 ml/min, back pressure = 50 bar, wavelength = 254 nm) using (R,R)

beta gem 1 column (Regis Technologies Inc. column dimensions = 25 cm x 4.6 mm I.D.).

Typical procedure of derivatization: After finishing the reaction solvent is evaporated by

vaccum. Then the reaction mixture is diluted with dichloromethane, 1-naphthyol chloride

(1.05 equiv.) was added to the solution of pyrrolidine (1.0 equiv.) and triethylamine (1.5

equiv.) in dichloromethane at room temperature. The resultant mixture was stirred for 2 h,

and then the volatile materials were removed by rotary evaporation giving a white solid. The

product was extracted 1M HCl and pentane and organic layer is dried over MgSO4 and

solvent removed in vacuo. The crude product was purified by short silica column with the

eluent: cyclohexane/MTBE (from 10% to 50%).

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NH

Me

Me

Me

2,5,5-trimethylpiperidine. (131) HRMS (ESI) m/z: (M+H+) calcd for

C19H24NO: 282.1858. Found: 282.1850 (mass of the corresponding naphthoyl derivative). IR

(ATR): 3055, 2936, 2864, 1631, 1508, 1465, 1429, 1297, 1142, 804, 781. [α]D20 = - 2.4 (c=

0.985, CH2Cl2). HPLC : (R,R)-Beta Gem 1, Hexane:iPrOH 75:25, 0.75 ml/min, 254 nm.

NH

Me 3-methyl-2-azaspiro[5.5]undecane. (133). 1H NMR (400 MHz, CDCl3) δ

2.87 (dd, J = 12.3, 2.5 Hz, 1H), 2.60 – 2.46 (m, 1H), 2.33 (d, J = 12.3 Hz, 1H), 1.66 (ddd, J =

14.1, 8.5, 5.5 Hz, 1H), 1.48 (d, J = 13.0 Hz, 1H), 1.46 – 1.35 (m, 8H), 1.26 – 1.07 (m, 5H),

1.04 (d, J = 6.3 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 56.65 (CH2), 52.92 (CH), 38.91

(CH2), 35.54 (CH2), 31.51 (CH2), 31.44 (CH2), 30.37 (CH2), 27.00 (CH2), 22.79 (CH3), 21.63

(CH2). HRMS (ESI) m/z: (M+H+) calcd for C22H28NO: 322.2166. Found: 322.2163 (mass of

the corresponding naphthoyl derivative). IR (ATR): 3055, 2928, 2855, 1631, 1429, 1213,

1023, 802, 780. [α]D20 = - 3.3 (c= 0.385, CH2Cl2). HPLC : (R,R)-Beta Gem 1, Hexane:iPrOH

75:25, 0.75 ml/min, 254 nm.

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NH

Me

PhPh

2-methyl-5,5-diphenylpiperidine.(102) 1H NMR (400 MHz, CDCl3) δ 7.50

– 7.41 (m, 2H), 7.41 – 7.33 (m, 2H), 7.29 – 7.21 (m, 3H), 7.21 – 7.10 (m, 3H), 3.95 (dd, J =

13.7, 3.1 Hz, 1H), 3.15 (d, J = 13.7 Hz, 1H), 2.90 – 2.77 (m, 1H), 2.73 (dq, J = 13.6, 3.4 Hz,

1H), 2.33 – 2.16 (m, 1H), 2.01 (s, 1H), 1.75 – 1.58 (m, 1H), 1.30 – 1.11 (m, 1H), 1.05 (d, J =

6.4 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 148.73 (C), 144.64 (C), 128.71 (CH), 128.28

(CH), 128.26 (CH), 126.48 (CH), 125.90 (CH), 125.88 (CH), 55.66 (CH2), 52.39 (CH), 45.27

(C), 35.39 (CH2), 31.28 (CH2), 22.37 (CH3). HRMS (ESI) m/z: (M+H+) calcd for C18H22N:

252.1747. Found: 252.1792. IR (ATR): 3433, 3057, 2970, 1701, 1628, 1431, 1362, 1296,

1216, 1046, 803, 781, 748, 702. [α]D20 = -14.0 (c= 0.5, CH2Cl2). HPLC: (R,R)-Beta Gem 1,

Hexane:iPrOH 75:25, 0.75 ml/min, 254 nm.

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PhPh

NH

Me 2-methyl-4,4-diphenylpiperidine. (134) 1H NMR (400 MHz, C6D6) δ 7.27 –

7.10 (m, 8H), 7.10 – 6.98 (m, 2H), 2.78 (dd, J = 10.9, 2.5 Hz, 3H), 2.55 – 2.40 (m, 2H), 1.97

(ddd, J = 13.5, 11.5, 5.2 Hz, 1H), 1.64 (dd, J = 13.3, 11.2 Hz, 1H), 0.98 (d, J = 6.2 Hz, 3H),

0.63 (s, 1H). 13C NMR (101 MHz, C6D6) δ 151.71 (C), 145.93 (C), 128.65 (CH), 128.62

(CH), 128.41 (CH), 126.48 (CH), 125.74 (CH), 125.73 (CH), 48.16 (CH), 46.15 (C), 45.96

(CH2), 43.62 (CH2), 37.38 (CH2), 23.36 (CH3). HRMS (ESI) m/z: (M+H+) calcd for


(ATR): 3056, 2966, 2931, 1630, 1495, 1431, 1371, 1235, 1022, 791, 781, 702. HPLC: (R,R)-

Beta Gem 1, Hexane:iPrOH 75:25, 0.75 ml/min, 254 nm.

NH

Me

Ph

5-(but-3-enyl)-2-methyl-5-phenylpiperidine (135). 1H NMR (400 MHz,

CDCl3) δ 7.40 – 7.34 (m, 3H), 7.33 – 7.24 (m, 1H), 7.24 – 7.15 (m, 1H), 5.67 (dddt, J = 32.2,

16.8, 10.2, 6.5 Hz, 1H), 4.94 – 4.76 (m, 2H), 3.65 (dd, J = 13.6, 3.1 Hz) and 3.26 (dd, J =

12.3, 2.7 Hz) (1H), 2.80 (dd, J = 12.3, 6.9 Hz) and 2.75 – 2.56 (m) (2H), 2.50 – 2.41 (m) and

2.18 – 2.09 (m) (1H), 2.09 – 1.94 (m) and 1.84 (dtd, J = 18.1, 11.9, 6.0 Hz) (1H), 1.77 – 1.57

(m, 3H), 1.56 – 1.37 (m, 3H), 1.32 (s, 1H), 1.13 (d, J = 6.3 Hz) and 0.94 (d, J = 6.4 Hz) (3H),

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1.11 – 0.98 (m, 1H). 13C NMR (101 MHz, CDCl3) δ 147.56 (C – E1), 143.83 (C – E2),

139.21 (CH – E1), 139.08 (CH – E2), 128.54 (CH – E1), 128.18 (CH – E2), 127.49 (CH –

E1), 125.81 (CH – E2), 125.77 (CH – E1), 125.63 (CH – E2), 113.95 (CH2 – E1), 113.92

(CH2 – E2), 55.92 (CH2 – E1), 55.85 (CH2 – E2), 52.95 (CH – E1), 52.08 (CH – E2), 43.50

(CH2 – E1), 40.66 (C – E1), 38.98 (C – E2), 35.04 (CH2 – E1), 34.57 (CH2 – E1), 32.93 (CH2

– E2), 31.41 (CH2 – E1), 30.58 (CH2 – E2), 28.11 (CH2 – E1), 27.79 (CH2 – E2), 22.56 (CH3

– E2), 22.52 (CH3 – E2). HRMS (ESI) m/z: (M+H+) calcd for C16H24N: 230.1904. Found:

230.1919. [α]D20 = +16.4 (c= 0.085, CH2Cl2). HPLC : (R,R)-Beta Gem 1, Hexane:iPrOH

85:15, 0.55 ml/min, 254 nm.

HN

PhPh

Me 5-benzyl-2-methyl-5-phenylpiperidine (136). 1H NMR (400 MHz, CDCl3) δ 7.32

– 7.26 (m, 1H), 7.21 (ddq, J = 7.8, 4.0, 1.5 Hz, 1H), 7.17 – 7.13 (m, 1H), 7.11 – 7.04 (m, 3H),

6.60 (tdd, J = 8.2, 4.0, 2.2 Hz, 2H), 3.64 (dd, J = 13.7, 3.3 Hz,) and 3.37 (dd, J = 12.2, 2.6

Hz) (1H), 3.14 (dd, J = 38.7, 13.2 Hz, 1H), 2.87 – 2.79 (m, 1H), 2.72 – 2.61 (m, 2H), 2.37

(dq, J = 13.8, 3.3 Hz) and 2.11 – 2.04 (m) (1H), 1.72 – 1.59 (m, 2H), 1.57 – 1.47 (m, 1H),

142

-------------------------------------------------------------------------------------------------------------------------------------- Experimental

1.31 (s, 1H), 1.19 (d, J = 6.3 Hz) and 0.92 (d, J = 6.4 Hz) (3H), 1.11 – 0.96 (m, 1H). 13C

NMR (101 MHz, CDCl3) δ 147.14 (C – E1), 143.17 (C – E2), 138.51 (C – E1), 137.18 (C –

E2), 130.39 (CH – E1), 130.35 (CH – E2), 128.37 (CH – E1), 127.88 (CH – E2), 127.77 (CH

– E1), 127.32 (CH – E1), 127.31 (CH – E2), 126.24 (CH – E2), 125.91 (CH – E1), 125.89

(CH – E2), 125.78(CH – E1), 125.70 (CH – E2), 55.54 (CH2 – E1), 55.20 (CH2 – E2), 52.84

(CH – E1), 52.15 (CH – E2), 50.73 (CH2 – E1), 42.40 (CH2 – E2), 42.11 (C – E1), 40.33 (C –

E2), 34.57 (CH2 – E1), 32.54 (CH2 – E2), 31.36 (CH2 – E1), 30.93 (CH2 – E2), 22.62 (CH3 –

E1), 22.49 (CH3 – E2). IR (ATR): 3058, 2931, 2857, 1632, 1430, 1288, 1258, 1209, 1130,

1045, 802, 780, 702. HRMS (ESI) m/z: (M+H+) calcd for C30H30NO: 420.2322. Found:

420.2318 (mass of the corresponding naphthoyl derivative). IR (ATR): 3058, 2931, 2857,

1632, 1496, 1465, 1430, 1288, 1258, 1209, 1130, 1025, 802, 780, 702. [α]D20 = +3.5 (c= 0.85,

CH2Cl2). HPLC: (R,R)-Beta Gem 1, Hexane:iPrOH 85:15, 0.55 ml/min, 254 nm.

HN

MeMe

Me 2-methyl-5,5-di-p-tolylpiperidine (138). 1H NMR (400 MHz,

CDCl3) δ 7.31 – 7.26 (m, 2H), 7.16 (d, J = 8.0 Hz, 2H), 7.03 (s, 4H), 3.91 (dd, J = 13.7, 3.0

Hz, 1H), 3.12 (d, J = 13.7 Hz, 1H), 2.84 (dqd, J = 12.8, 6.4, 3.1 Hz, 1H), 2.75 (s, 1H), 2.68

(ddd, J = 13.7, 6.7, 3.3 Hz, 1H), 2.35 – 2.29 (m, 3H), 2.26 (s, 3H), 2.18 (td, J = 13.4, 3.6 Hz,

1H), 1.66 (dq, J = 13.4, 3.5 Hz, 1H), 1.27 – 1.14 (m, 1H), 1.06 (d, J = 6.4 Hz, 3H). 13C NMR

143

-------------------------------------------------------------------------------------------------------------------------------------- Experimental

(101 MHz, CDCl3) δ 145.73 (C), 141.20 (C), 135.42 (C), 135.40 (C), 129.54 (CH), 128.99

(CH), 127.89 (CH), 126.24 (CH), 55.37 (CH2), 52.46 (CH), 44.52 (C), 35.21 (CH2), 31.09

(CH2), 22.11 (CH3), 20.95 (CH3), 20.85 (CH3). HRMS (ESI) m/z: (M+H+) calcd for


(ATR): 2947, 2942, 1703, 1629, 1509, 1431, 1362, 1298, 1193, 1044, 808, 780, 728. [α]D20 =

+2.5 (c= 0.85, CH2Cl2). HPLC: (R,R)-Beta Gem 1, Hexane:iPrOH 75:25, 0.75 ml/min, 254

nm.

HN

Me

Me

5-(but-3-en-1-yl)-2-methyl-5-(p-tolyl)piperidine (140). 1H NMR

(400 MHz, CDCl3) δ 7.25 – 7.20 (m, 1H), 7.14 (dd, J = 13.9, 8.1 Hz, 3H), 5.78 – 5.58 (m,

1H), 4.96 – 4.76 (m, 2H), 3.62 (dd, J = 13.6, 3.1 Hz) and 3.25 (dd, J = 12.4, 2.7 Hz) (1H),

2.78 (t, J = 9.0 Hz) and 2.74 – 2.58 (m) (2H), 2.49 – 2.38 (m, 1H), 2.33 (d, J = 5.5 Hz, 3H),

2.16 – 2.07 (m) and 2.06 – 1.95 (m) (1H), 1.82 (ddd, J = 15.1, 10.7, 4.8 Hz, 1H), 1.77 – 1.58

(m, 3H), 1.52 (ddt, J = 8.3, 6.0, 4.1 Hz, 1H), 1.43 (td, J = 9.3, 6.3 Hz, 1H), 1.15 (d, J = 6.3

Hz) and 0.95 (d, J = 6.4 Hz) (3H), 1.12 – 0.99 (m, 1H). 13C NMR (101 MHz, CDCl3) δ

144

-------------------------------------------------------------------------------------------------------------------------------------- Experimental

140.54, 139.22, 139.15, 135.30, 135.05, 129.30, 128.91, 127.33, 125.62, 113.91, 55.83,

52.97, 52.13, 43.48, 40.28, 38.61, 34.89, 34.51, 32.87, 31.34, 30.40, 28.11, 27.78, 22.47,

20.91. HRMS (ESI) m/z: (M+H+) calcd for C28H32NO: 398.2479. Found: 398.2475 (mass of

the corresponding naphthoyl derivative). IR (ATR): 3420, 3048, 2929, 2707, 1629, 1510,

1436, 1294, 1140, 802, 780. [α]D20 = -3.5 (c= 0.94, CH2Cl2). HPLC : (R,R)-Beta Gem 1,

Hexane:iPrOH 75:25, 0.75 ml/min, 254 nm.

HN

OMeOMe

Me 5,5-bis(3-methoxyphenyl)-2-methylpiperidine (143). 1H NMR (400

MHz, CDCl3) δ 7.29 – 7.23 (m, 1H), 7.15 (t, J = 8.0 Hz, 1H), 7.02 – 6.96 (m, 2H), 6.79 –

6.71 (m, 3H), 6.66 (ddd, J = 8.1, 2.5, 0.7 Hz, 1H), 3.88 (dd, J = 13.7, 3.1 Hz, 1H), 3.79 (s,

3H), 3.73 (s, 3H), 3.09 (d, J = 13.8 Hz, 1H), 2.81 – 2.71 (m, 1H), 2.67 (ddd, J = 13.6, 6.7, 3.3

145

-------------------------------------------------------------------------------------------------------------------------------------- Experimental

Hz, 1H), 2.17 (td, J = 13.4, 3.6 Hz, 1H), 1.64 (ddd, J = 13.3, 6.7, 3.5 Hz, 1H), 1.47 (d, J =

32.4 Hz, 1H), 1.24 – 1.10 (m, 1H), 1.01 (d, J = 6.4 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ

159.89 (C), 159.41 (C), 150.35 (C), 146.29 (C), 129.61 (CH), 129.13 (CH), 120.55 (CH),

118.90 (CH), 114.93 (CH), 113.26 (CH), 110.34 (CH), 110.21 (CH), 55.74 (CH2), 55.14

(CH3), 55.11 (CH3), 52.32 (CH), 45.24 (C), 35.41 (CH2), 31.45 (CH2), 22.43 (CH3). HRMS

(ESI) m/z: (M+H+) calcd for C31H32NO3: 466.2377. Found: 466.2372 (mass of the

corresponding naphthoyl derivative). IR (ATR): 3428, 3052, 2952, 2834, 1701, 1628, 1582,

1487, 1464, 1432, 1362, 1333, 1289, 1256, 1052, 868, 804, 781, 710. [α]D20 = -1.3 (c= 3.755,

CH2Cl2). HPLC: (R,R)-Beta Gem 1, Hexane:iPrOH 75:25, 0.75 ml/min, 254 nm.

146

-------------------------------------------------------------------------------------------------------------------------------------- Experimental

(S)-6,6'-((1E,1'E)-((1S,2S)-cyclohexane-1,2-

diylbis(azanylylidene))bis(methanylylidene))bis(2-(((S)-1-phenylethyl)amino)phenol):

(93)

N N

OH

NH

HO

HN

MeMe

N N

OH

NH

HO

HN

MeMe

147

-------------------------------------------------------------------------------------------------------------------------------------- Experimental

2,2-diphenylhex-5-en-1-amine: (101)

148

-------------------------------------------------------------------------------------------------------------------------------------- Experimental

2-methyl-5,5-diphenylpiperidine(102):

149

-------------------------------------------------------------------------------------------------------------------------------------- Experimental


Development of new reagents for hydroamination:

General procedure for the preparation of TMP-ZnCl:

Reagent i-Pr-MgCl·LiCl

Mg turnings (110 mmol) and anhyd LiCl (100 mmol) were placed in a dried argon-flushed

flask, and THF (50 ml) was added. A solution of i-PrCl (100 mmol) in THF (50 ml) was

slowly added at RT. The reaction starts within few minutes. After the addition was complete,

the reaction mixture was stirred for 12 h at RT. The grey solution of i-PrMgCl·LiCl was

cannulated from the excess of magnesium to a different flask under argon. A yield of ca. 95–

98% of i- PrMgCl·LiCl was obtained. The reagent was titrated prior to use by the method of

Paquette.

Reagent TMP-MgCl·LiCl

A dry and N2-flushed 250 ml Schlenk flask, equipped with a magnetic stirring bar and a

septum, was charged with freshly titrated i-PrMgCl·LiCl (1.2 M in THF) (100 ml, 120

mmol). 2,2,6,6-Tetramethylpiperidine (TMPH) (19.8 g, 126 mmol, 1.05 equiv) was added

dropwise at RT. The reaction mixture was stirred at r.t. until gas evolution was completed

(ca. 24 h). The reagent was titrated with benzoic acid prior to use [4-

(phenylazo)diphenylamine as indicator].

Reagent TMP-ZnCl·LiCl

In an N2-flushed Schlenk flask, ZnCl2 (53.0 mmol, 7.22 g) was dried in vacuo at 140 °C for 4

h. After cooling to room temperature, freshly titrated TMP-MgCl (100 mmol, 1.00 M, 100

ml) was added dropwise. The resulting mixture was stirred for 15 h at 25 °C. The freshly

prepared solution of TMP-ZnCl was titrated prior to use at 0 °C with benzoic acid using 4-

(phenylazo)diphenylamine as indicator. A concentration of 0.5 M in THF was obtained.

The products 163, 164, 166 are having the spectra similar to the 102, 133, 131 respectively.

150

-------------------------------------------------------------------------------------------------------------------------------------- Experimental

2-methyl-6,6-diphenylazepane (167). 1H NMR (400 MHz, CDCl3) δ 7.33 – 7.22

(m, 6H), 7.21 – 7.12 (m, 4H), 3.90 (d, J = 14.6 Hz, 1H), 3.09 (d, J = 14.6 Hz, 1H), 2.88 –

2.75 (m, 1H), 2.57 (dd, J = 14.7, 8.2 Hz, 1H), 2.12 (ddd, J = 13.7, 10.9, 9.6 Hz, 1H), 1.92 –

1.77 (m, 2H), 1.77 – 1.64 (m, 1H), 1.44 (s, 1H), 1.38 – 1.23 (m, 1H), 1.09 (d, J = 6.4 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 150.26 (C), 148.34 (C), 128.19 (CH), 128.16 (CH), 127.56

(CH), 127.41 (CH), 125.77 (CH), 125.58 (CH), 57.56 (CH2), 56.70 (CH), 52.36 (C), 40.17

(CH2), 40.13 (CH2), 23.49 (CH3), 23.00 (CH2).

N-benzyl-2,2-diphenylpent-4-en-1-amine. (171) N-Benzyl-2,2-

diphenylpent-4-en-1-amine. The indicated compound was obtained in a 98% yield as

colorless oil according to literature procedures.7 1H NMR (400 MHz, CDCl3) δ 7.19-7.35

(m, 15H), 5.34-5.45 (m, 1H), 5.04 (dt, J = 16.0, 1.2 Hz, 1H), 4.95 (dt, J = 10.0, .12 Hz, 1H),

3.25 (s, 2H), 3.77 (s, 2H), 3.09 (d, J = 7.2 Hz, 2H), 1.00 (s, 1H); 13C NMR (100 MHz,

CDCl3) δ 147.1, 140.9, 135.1, 128.5, 128.4, 128.3, 128.2, 127.0, 126.2, 117.9, 55.5, 54.4,

50.4, 41.9.

2-(prop-2-yn-1-yl)-2-(thiophen-2-yl)pent-4-yn-1-amine. (173) 1H NMR

(400 MHz, CDCl3) δ 7.26 - 7.22 (m, 1H), 6.99 - 6.96 (m, 2H), 3.07 (s, 2H), 2.82 - 2.72 (d,

4H), 2.06 - 2.01 (m, 2H), 1.06 (s, 2H). 13C NMR (101 MHz, CDCl3) δ 147.48, 126.65,

124.48, 124.11, 80.33, 71.36, 50.39, 45.46, 27.25.

1-benzyl-2-methyl-4,4-diphenylpyrrolidine. (172) 1H NMR (400 MHz,

CDCl3) δ 7.48 (d, J = 7.2 Hz, 2H), 7.44 – 7.39 (m, 2H), 7.38 – 7.31 (m, 6H), 7.31 – 7.27 (m,

4H), 7.23 – 7.18 (m, 1H), 4.19 (d, J = 13.3 Hz, 1H), 3.75 (d, J = 9.8 Hz, 1H), 3.35 (d, J =

151

-------------------------------------------------------------------------------------------------------------------------------------- Experimental

13.3 Hz, 1H), 3.01 (dt, J = 16.4, 8.2 Hz, 1H), 2.97 – 2.84 (m, 2H), 2.32 (dd, J = 12.6, 7.7 Hz,

1H), 1.27 (d, J = 6.0 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 150.78, 148.84, 140.23,

128.71, 128.34, 128.26, 127.95, 127.56, 127.37, 126.91, 125.92, 125.53, 66.59, 59.78, 58.14,

52.65, 48.13, 19.67.

5-methyl-3-(prop-2-yn-1-yl)-3-(thiophen-2-yl)-3,4-dihydro-2H-pyrrole .

(174) 1H NMR (400 MHz, CDCl3) δ 7.18 – 7.14 (m, 1H), 6.95 – 6.91 (m, 1H), 6.90 – 6.87

(m, 1H), 4.20 – 4.02 (m, 2H), 2.97 (q, J = 17.3 Hz, 2H), 2.63 – 2.61 (m, 2H), 2.06 (s, 3H),

1.99 (t, J = 2.6 Hz, 1H). 13C NMR (101 MHz, CDCl3) δ 173.76, 150.47, 126.78, 123.48,

123.41, 80.93, 73.28, 71.02, 52.49, 48.12, 31.55, 19.97.

5.5 References

1 M. Biyikal, K. Löhnwitz, N. Meyer, M. Dochnahl, P. W. Roesky, S. Blechert, Eur. J. Inorg.

Chem. 2010, 1070–1081. 2 M. Biyikal, M. Porta, P. W. Roesky, S. Blechert, Adv. Synth. Catal. 2010, 352, 1870 –

1875. 3 I. Tellitu, A. Urrejola, S. Serna, I. Moreno, M. T. Herrero, E. Dominguez, R. SanMartin, A.

Correa, Eur. J. Org. Chem. 2007, 437 – 444. 4 B. Gaspar, E. M. Carreira, Angew. Chem. 2008, 120, 5842 – 5844. 5 J. Mulzer, M. Berger, J. Org. Chem. 2004, 69, 891-898. 6 a) R. Shang, D.-S. Ji, L. Chu, Y. Fu, L. Liu, Angew. Chem. Int. Ed. 2011, 50, 4470 –4474;

b) P. Y. Yeung, K. H. Chung, F. Y. Kwong, Org. lett. 2011, 13, 2912–2915. 7 C. F. Bender, R. A. Widenhoefer, J. Am. Chem. Soc. 2005, 127, 1070.

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