DEVELOPMENT OF ORGANIC REACTION METHODOLOGY

USING POLYMER-SUPPORTED REAGENTS, FOCUSED

MICROWAVES AND ON-WATER CHEMISTRY

A Thesis submitted to the University of North Bengal

For the Award of

Doctor of Philosophy

in

Chemistry

By

Kinkar Biswas

GUIDE

Prof. Basudeb Basu

Department of Chemistry

University of North Bengal

April-2016

Dedicated

TO

My Parents

&

Family members

ACKNOWLEDGEMENT

This thesis is the outcome of a long rigorous journey in which I have been encouraged and

supported by many peoples who actually make my dream possible. It is really pleasure moment

for me to express my full gratitude for them.

Primarily, I would like to express my deep and sincere gratitude to my supervisor Dr. Basudeb

Basu, Professor, Department of Chemistry, University of North Bengal, Darjeeling, for his

invaluable ideas, guidance and constant support during the entire period of my research work.

I wish to express my warm and sincere thanks to Prof. Dongyuan Zhao, Department of

Chemistry, Fudan University, Shanghai, P. R. China, for his assistance and support during my

research work.

I also would like to thank to Dr. Goutam De, Chief Scientist & Head, Nano-Structured Materials

Division, CSIR-CGCRI, Kolkata, for his valuable suggestion on metal nanocomposites of my

thesis work.

I express my full gratitude to Prof. Ashutosh Ghosh, University of Calcutta, Kolkata, India for

carrying out the single crystal XRD.

I gratefully acknowledge to Dr. A.K. Nanda, Prof. P. Ghosh and Dr. S. Das for recording and

interpreting NMR spectra.

I offer my special thanks to Yunke Jing, China and Shreyasi Chattopadhyay, Kolkata for their

valuable contribution in my scientific work.

I would like to thank my labmates, Sekhar Da, Bablee di, Susmita Di, Sujit, Babli Di, Debasish,

Samir, Sankar, Suchandra and Prasun for their help and active co-oparation throughout my

research period.

I convey my special thanks to Bhaskar, Joyanta, Antara, Sumanta, Kausik Da, Prasenjit and

Mossaraf for their constant support.

I am really lucky that I have spent some memorable moments with Sujit in my Ph.D. work.

I would like to express my thanks to CSIR, New Delhi, for awarding me Junior Research

Fellowship, University of North Bengal for providing the infrastructural facilities and DST, New

Delhi.

I express my full gratitude to Head and all respected teachers of Department of Chemistry,

University of North Bengal.

It’s my fortune to gratefully acknowledge my Teacher‒in‒Charge (TIC), Uttam Roy of Raiganj

College (University College, now Raiganj University) for giving me a chance for persuing my

Ph.D. programme.

I am really grateful to UGC, Kolkata for giving me the Teacher Fellowship under UGC‒FDP

programme.

I really acknowledge my elder brother for his constant inspiration throughout my life.

I would like to thank my wife Esha and my daughter Aishiki for their constant selflessness, love

and support.

I also acknowledge my all relatives and family members.

Last but not the least I like to acknowledge my Parents for their constant love and support.

Without them, I would not be half the person that I am today.

i

ABSTRACT

The research work embodied in this thesis entitled “DEVELOPMENT OF ORGANIC

REACTION METHODOLOGY USING POLYMER-SUPPORTED REAGENTS,

FOCUSED MICROWAVES AND ON-WATER CHEMISTRY” is primarily focused on

polymer‒supported heterogeneous catalysis, „on‒water‟ and microwave‒assisted organic

reactions. The entire works essentially follow some principles of Green Chemistry. The work

was initiated in July 2008 as a CSIR‒NET‒JRF and completed with the support from UGC

under faculty development program. Based on different facets and contents of the work, the

thesis has been divided into five chapters.

As a prelude to present work, the Chapter I covers a brief review on the recent development and

trends towards polymer‒supported reagents and metal nanoparticle composites as heterogeneous

catalysts in organic reactions. Among diverse polymeric supports or assembly, the inorganic

polymers mainly utilized as suitable solid supports and metal encapsulating agents and

inorganic‒organic hybrid materials like Coordination Clusters, Metal Organic Frameworks are

used as metal embedding supports and further applications in diverse fields including catalysis.

Besides, the organic polymeric materials are discussed quite elaborately since the present work

in the next chapter is directed towards the use of organic polymeric resins as the suitable support

for the immobilization of mono‒ and bimetallic species and subsequent applications of the

resulting nanocomposites as heterogeneous catalysts. Illuminating examples along with merits

and demerits are discussed in this chapter with updated references.

Chapter II describes our works on the preparation of poly‒ionic resin embedded with bimetallic

(Pd & Fe) nanocomposites, their characterization by FT‒IR, powder XRD, AAS, SEM and TEM

analyses and subsequent use as catalyst in hydrodehalogenation of aromatic halides in the

presence of NaBH4 in aqueous THF. The new bimetallic nanocomposite consisting of palladium,

iron oxide and Amberlite resin formate has been found to be as an efficient, chemoselective and

recyclable heterogeneous catalyst. Enhanced catalytic activity has been explained in the light of

synergism between two metallic species and a plausible mechanism is proposed accordingly.

ii

The Chapter III is divided in three sections: Section A, B & C

Section A gives a concise background of „On‒water‟ chemistry in the field of organic synthesis.

The primitive reaction developed by Paul Anastus opened a new epoch in the field of organic

synthetic methodology. Though organic compounds are insoluble in aqueous medium but in

some cases, the reaction rates were found to be increased tremendously. This phenomenon has

been explained by two effects. Finally, these section ensembles some metal‒catalyzed and

without metal catalyzed organic reactions with interesting examples of recent work.

Section B details on Suzuki‒Miyaura coupling reaction at room temperature and „on‒water‟

conditions. In the present work, sodium salt of aryl trihydroxy borate was used as an efficient

water soluble organoboron species, which couple with aryl halides under Pd‒catalyzed

„on‒water‟ conditions. Other methods using aryl boronic acid/esters under „on‒water‟ conditions

often proceed very slow and/or incomplete conversions along with the difficulty to isolate the

products from the reaction mixture. The protocol was established as a general and practical

strategy with applications to wide variety of aryl halides. Further extension of this 'on water'

protocol was extended towards the preparation of some pharmaceutically important

benzimidazole‒ and benzotriazole‒based biphenyl scaffolds with appreciable conversions. A

comparison of the reactivity of using homogeneous Pd(OAc)2 and heterogeneous ARF‒Pd

catalyst has also been examined and excellent conversions of biaryls were obtained using both

types of catalysts.

Section C delineates our studies towards the 'click' thiol addition to alkynes leading to the

formation of (E/Z)‒vinyl sulfides, carried out under 'on‒water' conditions in the presence of a

range of additives. In general, the (E)‒isomer is formed preferentially. However, the

stereochemical outcome has been found to be dependent of the additives, which could be used as

'stereoselective switch' to E‒ or Z‒vinyl sulfides, though succinct reasons for the selectivity are

not understood. While a combination of Amberlite resin Chloride‒FeCl3 leads to maximum

Z‒stereoselectivity for reaction with aromatic thiols, the presence of D(+)‒glucose affords

iii

maximum Z‒stereoselectivity for reaction with aliphatic thiols. Other additives favor usual

formation E‒vinyl sulfides.

The Chapter IV describes an efficient and rapid protocol for the synthesis of libraries of

carbodithioate esters from organyl thiocyanates by reacting with cyclic amine‒based

dithiocarbamic acid salts in water. Alkyl thiocyanates, often considered as psuedohalides, are

reluctant to undergo substitution reaction with dithiocarbamate nucleophile and usually give rise

to the formation of disulfides under basic medium. The protocol is found to be applicable in

general to various thiocyanates like benzyl/aroyl methyl/cinnamyl etc. Other notable features

include no by‒products like disulfides, metal‒ and alkali‒free, aqueous conditions and finally

easy and near‒quantitative formation of cyclic amine‒based dithiocarbamic acid salt as stable

alternative reagent.

Chapter V depicts preparation of new CuI‒1,3‒dithioether coordination polymer complex,

characterization by NMR and single crystal X‒ray structure determination, and finally its

efficient role as catalyst in azide‒alkyne cycloaddition (AAC) reaction. Although few examples

of other dithioether‒based Cu(I) complexes are known in the literature, the present

1,3‒dithioether ligand‒based Cu(I) complex is not known, and there is no example of such

complexes used as the catalyst for the AAC reaction. The present study therefore establishes a

iv

new and convenient catalytic process for the one‒pot AAC in multi‒component manner, and the

catalytic system has been found to be recyclable. The yields of the cycloadducts are excellent in

diverse array of reactants. While trying the AAC under microwave irradiation however did not

give satisfactory results.

v

PREFACE

The ever increasing demand for efficient syntheses of novel organic compounds remains the

major driving force for the development of new and efficient greener methodologies.

Heterogeneous catalysis becomes important from both economic and environmental point of

view. The development of suitable polymer support to immobilize the reagents/catalysts

followed by its applications to various organic transformations is well accepted. Besides this,

„On‒water‟ reaction methodology and microwave assisted organic syntheses (MAOS) could

overcome the fulfillment of the preliminary requirements of Green chemistry.

The present research work describes the multidisciplinary approaches towards solid‒supported

organic synthesis, nanocatalysis and „on‒water‟ organic reaction methodologies. This thesis

begins with Chapter I, which introduces a brief review of different types of polymer supported

reagents/polymeric materials with special emphasis on ion‒exchange resin. Chapter II deals

with the synthesis and characterization of novel Pd/Fe2O3 bimetallic NPs soaked on Amberlite

Resin Formate (ARF) and application towards hydrodehalogenation reaction. Chapter III

contains three sectional parts; Section A gives a brief assessment of „On‒water‟ chemistry with

metal‒ or without metal‒catalyzed organic reactions. Section B deals with on‒water

Suzuki‒Miyaura coupling reaction using aryl trihydroxy borate salts as alternating boron partner

and Section C represents a general outline for the stereoselective switch of hydrothiolation

reaction with the aid of various additives in water at ambient conditions. A new methodology for

the synthesis of carbodithioate esters using dithiocarbamate salts of sec. amine and alkyl

thiocyanates has been described in Chapter IV. Finally, the Chapter V is to focus on the

synthesis and characterization of a novel polymeric catalyst involving CuI and 1,3‒dithioether

ligand and find application towards one‒pot azide‒alkyne cycloaddition reaction for the

regioselective synthesis of 1,4‒disubstituted 1,2,3‒triazoles isomers.

vi

TABLE OF CONTENTS

Abstract i‒iv

Preface v

List of Tables xi

List of Schemes xiii

List of Figures xvi

List of Appendices xviii

Appendix A: List of Publications xix

Appendix B: Oral Presentation & Poster Presentation xx

Abbreviation xxi

CHAPTER I Brief review on polymer‒supported metal NPs /reagent 1‒14

I.1. Polymer supports 2

I.2. Types of Polymer supports 3

I.2.1. Inorganic supports 3

I.2.1.1. Metal Oxides 4

I.2.1.2. KF/Al2O3 5

I.2.1.3. Clay Minerals

5

I.2.1.4. Silica 5

I.2.1.5. Zeolites 5

I.2.2. Hybrid polymeric assembly 6

I.2.2.1. Coordination clusters 6

I.2.2.2. Coordination polymers or Metal Organic

Framework (MOF)

7

I.2.3. Organic polymer supports 8

I.2.3.1. PVP and PPO 8

I.2.3.2. Dendrimers 9

I.2.3.3. Polysachharides 9

I.2.3.4. Polypeptides 10

I.2.3.5. Polystyrene Resins 10

I.2.3.6. Ion‒exchange resins 11

I.2.3.6.1. Types of ion‒exchange resins 11

I.2.3.6.2. Ion‒exchange resins as polymeric

supports for reagents

12

I.2.3.6.3. Ion‒exchange resins for

immobilization of metal NPs

12

I.3. References 14

CHAPTER II

Amberlite Resin Formate (ARF) and Pd/Fe2O3 Bimetallic

Nanocomposites (Pd/Fe–ARF): Enhanced and Chemoselective

Catalytic Activity in Hydrodehalogenation of Haloaromatics

15‒39

vii

II.1. Introduction 16

II.2. Background and Objectives 16

II.3. Present work: Results and Discussion 21

II.3.1. Preparation of (Pd/Fe‒ARF) 21

II.3.2. Characterization of the composites (Pd/Fe‒ARF) 22

II.3.2.1. FT‒IR Spectroscopy 23

II.3.2.2. Powder X‒ray diffraction patterns 24

II.3.2.3. Scanning electron microscopy (SEM) of ARF,

Fe‒ARF‒110 and Pd/Fe‒ARF nanocomposites

25

II.3.2.4. Transmission electron microscopy (TEM) of

ARF, Fe‒ARF and Pd/Fe‒ARF

nanocomposites

27

II.3.3. Catalytic activity of Pd/Fe–ARF–110

nanocomposites

30

II.3.4. Recycling Experiment 32

II.3.5. Comparison of turnover frequency of various

catalytic systems

33

II.3.6. Plausible Mechanism towards enhanced

catalytic activity

34

II.4. Conclusion 35

II.5. Experimental section 35

II.5.1. General information 35

II.5.2. Preparation Fe–ARF 36

II.5.3. Preparation of Pd/Fe–ARF–110 36

II.5.4. Preparation of Pd/Fe–ARF–110–OA 36

II.5.5. Preparation of Pd/Fe–ARF–110–NaOA 37

II.5.6. Typical procedure for hydrodehalogenation of

haloarenes in the presence of Pd/Fe‒ARF‒110

37

II.5.7. Physical properties and spectral data of compounds 38

II.6. References 39

CHAPTER III

SECTION A

“On‒water” organic reactions: A brief review 40‒46

III.A.1. On‒water Chemistry 41

III.A.2. Water Effects on Organic Reactions 41

III.A.2.1. Breslow Hydrophobic Effect 41

III.A.2.2. Marcus trans‒Phase H‒Bonding 42

III.A.3. Some examples of „on‒water‟ organic reactions 42

III.A.4. Metal–catalyzed Sp2 C–H bond activation and catalytic cross–coupling

reactions

45

viii

III.A.5. Disadvantages of water in organic reactions 45

III.A.6. References 46

CHAPTER III

SECTION B

„On‒water‟ Suzuki‒Miyaura reaction at ambient condition using

aryl trihydroxy borate salt as an alternative boron partner

47‒69

III.B.1. Introduction 48

III.B.2. Background and Objectives 50

III.B.3. Present work: Results and discussion 54

III.B.4. Conclusion 59

III.B.5. Experimental section 60

III.B.5.1. General information 60

III.B.5.2. General procedure for the preparation of aryl

trihydroxyboronate salts from boronic acids

60

III.B.5.3. General procedure for Suzuki‒Miyaura coupling reactions 60

III.B.5.4. Representative procedures for the synthesis of 7 and 8 60

III.B.5.5. Physical properties and Spectral data of compounds 61

III.B.6 References 69

CHAPTER III

SECTION C

In quest of “stereoselective‒switch” for on‒water hydrothiolation of

terminal alkynes using different additives and green synthesis of

vicinal dithioethers

70‒90

III.C.1. Introduction 71

III.C.2. Background and Objectives 72

III.C.3. Present Work: Results and Discussion 79

III.C.4. Conclusions 83

III.C.5. Experimental section 84

III.C.5.1. General information 84

III.C.5.2. General procedure for mono‒hydrothiolation of alkynes 84

III.C.5.3. General procedure for di‒hydrothiolation of alkynes 84

III.C.5.4. Physical properties and spectral data of compounds 85

III.C.6. References 90

CHAPTER IV

Cyclic ammonium salts of dithiocarbamic acid: Stable alternative

reagents for the synthesis of S‒alkyl carbodithioates from organyl

thiocyanates in water

91‒116

IV.1. Introduction 92

IV.2. Background and objectives 93

IV.3. Present Work: Results and Discussion 97

IV.4 Mechanism 104

ix

IV.5. Conclusion 104

IV.6. Experimental section 105

IV.6.1. General information 105

IV.6.2. General Procedure for the synthesis of cyclic ammonium

salts of dithiocarbamic acid (2b‒2e)

105

IV.6.2.1. Physical properties and spectral data of cyclic

ammonium salts of dithiocarbamic acid (2b‒2e) 105

IV.6.3. General procedure for the synthesis of S‒alkyl carbodithioate

esters 106

IV.6.3.1. Physical properties and spectral data of

carbodithioate esters 107

IV.7. References 116

CHAPTER V

Synthesis of new 1,3‒dithioether‒Cu(I) complex and its catalytic

action in one‒pot azide‒alkyne "click" reaction 117‒139

V.1. Introduction 118

V.1.1. Azide–Alkyne Cycloaddition (AAC) reactions 118

V.2. Background and Objectives 119

V.3. Present work: Results and Discussion 121

V.3.1. Preparation of 1,3‒bis(4‒fluorophenylthio)‒propane ligand

(L1)

121

V.3.2. Synthesis of CuI‒1, 3‒bis(4‒fluorophenylthio)‒propane (L1)

coordination complex (complex 1)

122

V.3.3. Characterization of complex 1 122

V.3.3.1. NMR spectroscopy 122

V.3.3.2. UV‒Visible and fluorescence spectroscopy 124

V.3.3.3. Single crystal X‒ray diffraction 126

V.3.4. Catalytic application 128

V.3.5. One‒pot two‒step process for the synthesis of sulfur

functionalized 1,2,3‒triazole derivative

131

V.3.6. Mechanism 131

V.4. Conclusion 132

V.5. Experimental section 132

V.5.1. General information 132

V.5.2. Procedure for the synthesis of 1,3‒bis(4‒fluorophenylthio)

‒propane (L 1)

133

V.5.3. Procedure for the synthesis of Complex 1 133

V.5.4. General procedures for Cu(I)‒catalyzed AAC reaction 133

V.5.5. Physical properties and spectral data of compounds 134

V.6. References 138

x

Bibliography

References for Chapter I 139‒142

References for Chapter II 142‒145

References for Chapter III, Section A 145‒146

References for Chapter III, Section B 146‒148

References for Chapter III, Section C 149‒150

References for Chapter IV 150‒153

References for Chapter V 153‒154

Index 155‒157

xi

LIST OF TABLES

Table No. Title Page No.

Table I.1. Description of Coordination clusters (CCs) for the general formula

of Mx(μ‒L)yL/z]

n

7

Table II.1. Symmetric and anti‒symmetric stretching vibrational data of ARF,

Fe‒ARF and Pd/Fe–ARF obtained at different temperatures

23

Table II.2. Optimization of reaction conditions for the hydrodebromination of

9,10 dibromoanthracene

30

Table II.3. Hydrodehalogenation of haloarenes in the presence of the

nanocomposite catalyst Pd/Fe–ARF‒110

31

Table II.4. Comparison of TOF of various catalytic systems tested in the

hydrodehalogenation of haloarenes

33

Table III.B.1. Optimization of Reaction Conditions of SM Coupling reaction 55

Table III.B.2. Suzuki‒Miyaura coupling reactions of aryl iodides with sodium

aryltrihydroxyborates in water

55

Table III.B.3. Suzuki‒Miyaura coupling reactions of aryl bromides with

sodium aryltrihydroxyborates in water

56

Table III.B.4. Suzuki‒Miyaura coupling reactions of aryl chlorides with

sodium aryltrihydroxyborates in water

57

Table III.B.5. SM coupling reactions with aryl trihydroxyborates in water

using heterogeneous Pd‒catalyst (ARF–Pd) 58

Table III.C.1. Role of additives in the addition of PhSH to phenylacetylene

under on‒water and at room temperature conditions

80

Table III.C.2. Hydrothiolation of aryl acetylene [A] with aromatic thiols [B] in

(1:1.1) molar ratios in water at room temperature

81

Table III.C.3. Hydrothiolation aromatic terminal alkynes with aliphatic thiols 82

Table III.C.4. Dihydrothiolation of aliphatic alkyne with thiols in water at room

temperature

83

Table IV.1. Optimization of the reaction conditions for the conversion of

benzyl thiocyanate to S‒alkyl cabodithioates

98

Table IV.2.

Synthesis of diverse S‒alkyl carbodithioates by varying organyl

thiocyanates and dithiocarbamate salts

100

Table IV.3. Further functionalizations in the synthesis of S‒alkyl

carbodithioates

103

Table V.1. Crystal Data, Data Collection and Structure Refinement for

complex 1

126

Table V.2. Selected bond length 127

Table V.3. Selected bond angle 128

Table V.4. Optimization of reaction conditions for the one‒pot azide‒alkyne

click reaction

129

xii

Table V.5. Catalytic activity of complex 1 in the AAC reaction

130

xiii

LIST OF SCHEMES

Scheme No.

Title

Page No.

Scheme I.1. Classification of polymer supports 3

Scheme I.2. Examples of some commonly used metal oxides 4

Scheme I.3. Organic reactions on KF‒Al2O3 and metal‒doped KF‒Al2O3

surface

5

Scheme I.4. Encapsulation of Pd/Rh bimetallic nanoparticles on PAMAM

dendrimer

9

Scheme I.5. Synthesis and Derivatization of PS‒Based Solid Supports

11

Scheme I.6. Immobilization of metal ions onto ion‒exchange resin 13

Scheme I.7. Amberlite resin formate in catalytic hydrogenation reactions 13

Scheme I.8. Preparation of ARF‒Pd 14

Scheme I.9. Preparation of bimetallic pd/Cu supported on ARF. 14

Scheme II.1. Oxygen reduction reaction using Pd/Fe catalyst 17

Scheme II.2. Hydrodehalogenation of haloaromatics using PdO in basic

condition and high temperature

17

Scheme II.3. Pd‒phosphite catalyst for the dehalogenation of aryl chlorides

and bromides

17

Scheme II.4. Study of hydrodebromination of 4,4/‒dibromobiphenyl using

PdCl2 and dppf ligand

18

Scheme II.5. Nanoscale zerovalent iron (nZVI) for the reduction of

Tetrabromobisphenol A (TBBPA)

18

Scheme II.6. Nickel catalyzed hydrodehalogenation of aryl halides with

iso‒propyl zinc bromide

18

Scheme II.7. A simple Pd(OAc)2 catalyzed hydrodehalogenation reaction

using 2‒butanol as hydrogen source

19

Scheme II.8. Zirconia‒supported Cu/Ni bimetallic catalyst for

hydrodehalogenation reaction

19

Scheme II.9. Polychlorinated biphenyls are dechlorinated by granular

activated carbon (GAC) composites

20

Scheme II.10. Polychlorobiphenyl reduced by Pd/Fe bimetallic nanotubes 20

Scheme II.11. Hydrodehalogenation method using Pt/Pd/Fe (1:1:2)

trimetallic nanoparticle and ammonium formate

20

Scheme II.12. Plausible mechanism for enhanced catalytic activity in

hydrodehalogenation using NaBH4 in water.

35

Scheme III.A.1. Demonstrative example of cycloaddition of quadricyclane

with azodicarboxylate

43

Scheme III.A.2. Rate acceleration of cycloaddition reaction in presence of

water

43

Scheme III.A.3. Various examples of on‒water organic reactions 44

xiv

Scheme III.A.4. Some examples of metal–catalyzed Sp2 C–H bond activation

and catalytic cross–coupling reactions

45

Scheme III.B.1. SM coupling reaction in aqueous microdrplets with

catalytically active fluoruos interfaces 50

Scheme III.B.2. Ligand‒free palladium catalyzed SM coupling reaction using

Microwave heating in water

51

Scheme III.B.3. Polyaniline (PANI) supported palladium nanoparticles as

semi‒heterogeneous catalyst for SM coupling reactions

51

Scheme III.B.4. Nonoionic amphiphiles mediated SM coupling in water. 52

Scheme III.B.5. A mild and efficient method for the synthesis of biaryls in

water and surfactants

52

Scheme III.B.6. Pd(OAc)2‒catalyzed SM reaction between alkyl

trifluoroborates and aryl halides

53

Scheme III.B.7. Pd/C‒catalyzed cross‒coupling of various aryl bromides with

sodium tetraphenylborate

53

Scheme III.B.8. Synthesis of aryl trihydroxy borate salts for the

Suzuki‒Miyaura coupling reaction 53

Scheme III.B.9. Pd(OAc)2‒catalyzed SM reaction in the presence of aryl

trihydroxy borate salts and aryl halides

54

Scheme III.B.10. Synthesis of 6a and 6b 59

Scheme III.B.11. Synthesis of benzimidazole– and benzotriazole–based

biphenyl scafolds 59

Scheme III.C.1. Substituted 2‒pyrimidyl vinyl sulfide used in materials

science

72

Scheme III.C.2. 1‒Alkenyl sulphides from hydrothiolation of terminal alkynes 72

Scheme III.C.3. Synthesis of 1,1‒Disubstituted alkyl vinyl sulfides by

rhodium catalyst 73

Scheme III.C.4. Preparation of MCM‒41‒2P‒RhCl(PPh3) 73

Scheme III.C.5. Hydrothiolation reaction in presence of heterogeneous

MCM‒41‒2P‒RhCl(PPh3) catalyst 73

Scheme III.C.6. Stereoslective synthesis of vinyl sulfides by Pd‒catalyzed

reaction

74

Scheme III.C.7. Polymer‒supported palladium catalyst for stereoselective S‒S

bond addition to terminal alkynes

74

Scheme III.C.8. Palladium catalyzed synthesis of cis‒configured vinyl

thioethers

75

Scheme III.C.9. Organoactinide‒mediated hydroyhiolation of terminal alkynes

with aliphatic, aromatic and benzylic thiols

75

Scheme III.C.10. Ni(acac)2 catalyzed regioselective synthesis of β‒vinyl

sulfides by hydrothiolation reaction

76

Scheme III.C.11. Mechanism of Ni‒NHC catalyzed hydrothiolation reaction. 77

xv

Scheme III.C.12. In(III)‒catalyzed substrate selective hydrothiolation of

terminal alkynes

77

Scheme III.C.13. Cu(I)‒catalyzed hydrothiolation under CO2 and argon

atmosphere

77

Scheme III.C.14. Hydrothiolation of alkynes with thiophenols in presence of

β‒Cyclodextrin in Water

78

Scheme III.C.15. Water‒promoted regioselective hydrothiolation reaction 78

Scheme III.C.16. Green synthesis of vicinal dithioethers and alkenyl thioethers 79

Scheme IV.1. One‒pot preparation of dithiocarbamate in water without

using any catalyst

93

Scheme IV.2. One‒pot clean method for the synthesis of carbodithioates 93

Scheme IV.3. One‒pot synthesis of 2‒hydroxydithiocarbamates in DES and

PEG

94

Scheme IV.4. Basic resin (Amberlite IRA 400) supported one‒pot synthesis

of dithiocarbamate

94

Scheme IV.5. Michael addition of aryl amines towards electron deficient

alkenes

94

Scheme IV.6. Synthesis of dithiocarbamates using [pmIm]Br ionic liquid. 95

Scheme IV.7. Markovnikov addition reaction of dithiocarbamate to ethyl

vinyl ether

95

Scheme IV.8. Ru(acac)3 catalyzed synthesis of allyl/cinnamyl

dithiocarbamates

96

Scheme IV.9. Metal free three‒component reaction of N‒tosylhydrazones,

carbon disulfide and amines

96

Scheme IV.10. Synthesis of sec. cyclic aliphatic amine‒based

dithiocarbamate salts 99

Scheme IV.11. Proposed reaction mechanism 104

Scheme V.1. The primitive Huisgen‟s 1,3‒dipolar cycloaddition reaction 118

Scheme V.2. CuBr.PhSMe‒catalyzed cycloaddition reaction of alkyl azide

and phenyl acetylene

119

Scheme V.3. Preparation of CuX2(SNS) catalysts and application towards

azide‒alkyne click reaction

120

Scheme V.4. Cu‒SNS catalyst for one‒pot azide‒alkyne cycloaddition

reaction

120

Scheme V.5. “Click‒and‒click” – hybridised 1,2,3‒triazoles supported

Cu(I) coordination polymers for azide–alkyne cycloaddition

121

Scheme V.6. One‒pot two‒step synthesis of sulfur functionalized

1,2,3‒triazole derivative

131

Scheme V.7. A plausible mechanistic path for the multicomponent AAC

reaction

132

xvi

LIST OF FIGURES

Figure I.1. Structure of Merrifield Resin 2

Figure I.2. A schematic diagram of the apoferritin 6

Figure I.3. A schematic presentation for the synthesis of metal–organic

framework (MOF)

8

Figure I.4. Structures of poly(N‒vinyl‒2‒pyrrolidone) (PVP) and

poly(2,5‒dimethylphenylene oxide) (PPO)

8

Figure I.5. Structure of Chitin and Chitosane 10

Figure I.6. Structures of various ion‒exchange resins 12

Figure II.1. Schematic preparative steps of Pd/Fe‒ARF–110

nanocomposites

22

Figure II.2. Photographic images of six nanocomposites 22

Figure II.3. FT‒IR spectra of ARF, Fe‒ARF and Pd/Fe‒ARF bimetallic

nanocomposites

23

Figure II.4. The powder XRD patterns of six nanocomposites prepared

under different conditions

25

Figure II.5. The SEM images of (a) ARF; (b) Fe–ARF–110; (c) Pd/Fe–

ARF–80; (d) Pd/Fe–ARF–110; (e) Pd/Fe–ARF–140; (f)

Pd/Fe–ARF–110–OA and (g) Pd/Fe–ARF–110–NaOA

nanocomposites, respectively

27

Figure II.6. TEM images: (a) of Fe–ARF–110 and (b) its average particle

size distribution histogram from (a); (c) of Pd/Fe‒ARF‒110

and (d) its average particle size distribution histogram from

(c); (e) of Pd/Fe–ARF–110–OA and (f) its average particle

size distribution histogram from (e); (g) of Pd/Fe–ARF–110–

NaOA and (h) its average particle size distribution histogram

from (g)

28

Figure II.7. (a) TEM‒EDX spectrum of Pd/Fe–ARF‒110

nanocomposites; (b) EDX elemental mapping image of

Pd/Fe2O3 bimetallic nanocomposites, green dots, Pd; red dots,

Fe

29

Figure II.8. Recycling experiments using Pd/Fe‒ARF‒110 catalyst in

hydrodebromination of 9, 10‒dibromoanthracene 33

Figure III.A.1. (a) Hydrated small hydrophobic aggregates, (b) hydrated

large hydrophobic aggregates

42

Figure III.B.1. The chemical structure of trityl losertan 48

Figure III.B.2. Structures of some drugs and pharmaceuticals containing

biphenyl moiety

49

Figure III.B.3. Structures of some analgesic drugs synthesized by SM

coupling reaction

49

xvii

Figure III.B.4. Biphenyls used in materials science 50

Figure III.C.1. Vinyl sulfides used as synthetic intermediates. 71

Figure III.C.2. Vinyl sulfides used as biologically active molecules 71

Figure III.C.3. Structures of Ni‒NHC complex and some NHCs 76

Figure IV.1 Structures of carbamic acid, thiocarbamic acid and

dithiocarbamic acid and their esters

92

Figure IV.2. Examples of compounds of potential therapeutic value

bearing S‒alkyl carbodithioate esters function

93

Figure IV.3. HRMS of compound 4b 102

Figure V.1. 1H‒NMR spectra of L1 [1,3‒bis(4‒fluorophenylthio)

‒propane] in d6‒DMSO

123

Figure V.2. 1H‒NMR spectra of complex 1 in d6‒DMSO 124

Figure V.3. UV‒Visible spectra of CuI, L1 and complex 1 were taken in

MeCN

125

Figure V.4. Fluorescence spectrum of complex 1(5 μM solution) in

MeCN solvent

125

Figure V.5. View of (a) the monomeric unit of the coordination polymer,

(b) ORTEP picture of the complex 1 and (c) infinite 1‒D

chain of complex 1 incorporating dinuclear Cu(μ2‒I)2Cu

motifs along „b‟ axis

127

xviii

LIST OF APPENDICES

APPENDIX A:

List of Publications

APPENDIX B:

Oral Presentation & Poster Presentation

xix

APPENDIX A

List of Publications

1. “Highly effective alternative aryl trihydroxyborate salts for a ligand‒free, on‒water

Suzuki–Miyaura coupling reaction” Basudeb Basu, Kinkar Biswas, Sekhar Kundu and

Sujit Ghosh, Green Chem., 2010, 12, 1734–1738.

2. “In Quest of „„Stereoselective Switch‟‟ for On‒Water Hydrothiolation of Terminal

Alkynes Using Different Additives and Green Synthesis of Vicinal Dithioethers”

Basudeb Basu, Kinkar Biswas, Samir Kundu, and Debasish Sengupta, Organic

Chemistry International, 2014, Article ID 358932.

3. “Cyclic ammonium salts of dithiocarbamic acid: Stable alternative reagents for the

synthesis of S‒alkyl carbodithioates from organyl thiocyanates in water”, Kinkar

Biswas, Sujit Ghosh, Pranab Ghosh and Basudeb Basu, accepted in J. Sulfur Chem., 2016

(DOI ‒ 10.1080/17415993.2016.1166225).

4. “Amberlite Resin Formate (ARF) and Pd/Fe2O3 Bimetallic Nanocomposites: Enhanced

and Chemoselective Catalytic Activity in Hydrodehalogenation of Haloaromatics”,

Kinkar Biswas, Shreyasi Chattopadhyay,

Goutam De,

Basudeb Basu, Yunke Jing and

Dongyuan Zhao (manuscript under preparation).

Review article

1. “Additives in Organic and Biochemical Reactions”, Kinkar Biswas and Basudeb Basu,

SMU Medical Journal, 2014, Vol. 1, No. 1, 29–40.

xx

APPENDIX B

Oral Presentation

“Synthesis, characterization and application of new heterogeneous Pd/Fe bimetallic

nanocomposites”, in the National Seminar “Frontier in Chemistry ‒2015” organized by

the Department of Chemistry, NBU and funded by UGC and SAP (DRS‒III), held at

University of North Bengal, Darjeeling, India, February 17‒18, 2015.

Poster Presentation

“Graphene oxide (GO) – an efficient carbocatalyst for the one‒pot tandem reduction and

cyclization for quinoxaline synthesis”, Babli Roy, Kinkar Biswas, Sujit Ghosh and

Basudeb Basu, National Symposium on Recent Trends and Perspectives in Chemistry

(RTPC‒2015), held at National Institute of Technology, Sikkim, India, January 23‒24,

2015.

“Role of additives in triggering stereoselective switch in alkyne hydrothiolation”, Sujit

Ghosh, Kinkar Biswas, Babli Roy, Susmita Paul, Bablee Mandal, Basudeb Basu, 12th

CRSI National Symposium in Chemistry & 4th

CRSI‒RSC Symposium in Chemistry, held

at Indian Institute of Chemical Technology (IICT), Hyderabad, India, February 4‒7,

2010.

“Highly effective alternative aryl trihydroxyborate salts for a ligand‒free, on‒water

Suzuki–Miyaura coupling reaction”, Sujit Ghosh, Kinkar Biswas, Sekhar Kundu and

Basudeb Basu, International Symposium (ISOC‒2009) on “Organic Chemistry: Trends

in 21st Century held at Indian Association for the Cultivation of Science (IACS), Kolkata,

India, December 10‒12, 2009.

“Catechol violet as new, efficient, and versatile ligand for Cu(I)‒catalyzed C–S coupling

reactions”, Kinkar Biswas, Bablee Mandal, Sajal Das, Susmita Paul, Sekhar Kundu,

Sujit Ghosh and Basudeb Basu, 11th

CRSI National Symposium in Chemistry (NSC‒11)

held at National Chemical Laboratory (NCL), Pune (India), February 6‒8, 2009.

xxi

ABBREVIATION

AAC Azide‒alkyne cycloaddition mol% Mole percent

ARF Amberlite resin formate MW Microwave oC Degree Celsius NHC N‒heterocyclic carbene

CCs Coordination clusters NMR Nuclear magnetic resonance

d doublet NPs Nanoparticles

dd doublet of a doublet nZVI Nanoscale zerovalent iron

DMF Dimethyl formamide OWCF On‒water catalyst‒free

DTCE Dithiocarbamate esters p‒XRD Powder X‒ray diffraction

DVB Divinyl benzene ROP Ring opening polymerization

EDX Energy‒dispersive X‒ray s singlet

GAC Granular activated carbon SEM Scanning electron microscope

h hour/hours SDS Sodium dodecyl sulfate

HOCs Halogenated organic compounds t triplet

HRMS High resolution mass spectrometry TBAB n‒tetrabutyl ammonium bromide

MAOS Microwave‒assisted

organic synthesis

TEM Transmission electron microscope

MHz Mega hertz THF Tetrahydrofuran

min minute TMEDA N,N,N/,N

/‒tetramethylethylenediamine

MOF Metal organic framework TOF Turnover frequency

1

CHAPTER I

Brief review on polymer‒supported metal NPs

/reagents

2

I.1. Polymer supports

Heterogeneous catalysis, performed over a solid surface is the heart of the modern energy

and chemical industries. Most of the recognized and emerging chemical processes are

performed using functional nanomaterials. Solid‒supported organic synthesis now become

promising over toxic and hazardous organic solvent‒based syntheses.1 Additionally the

Solid‒supported organic synthesis is important because it reduces pollution to the

environment, lowers the cost of the method and it is easy for handling.

Since the revolutionary work by Robert Bruce Merrifield (Nobel laureate in Chemistry on

1984) in polymer supports, it became the interesting topic in organic synthesis.2

This solid

phase procedure revolutionized polypeptide and polynucleotide synthesis, which is important

for pharmaceutical and combinatorial chemistry. The structure of Merrifield resin is actually

the copolymer of styrene and chloromethylstyrene. Additionally this polymer is also cross–

linked with divinylbenzene. The structure of the Merrifield resin is depicted in Figure I.1.

Cl

Cl Cl

Cl ClCl

Figure I.1. Structure of Merrifield Resin

After successful invention of Merrifield resin, solid‒supported organic synthesis became

hot topic in synthetic methodology. Polymer‒assisted solution‒phase synthesis,3a

has various

advantages over conventional solution‒phase chemistry in following aspects:

1) the supported species can be separated easily by filtration and washing,

2) workup procedures are simple,

3) reuse of supported reagent after reaction,

4) the ease of adaptation to continuous‒flow processes and hence use in automated

synthesis,

5) toxicity and odour of the species become reduced and

3

6) chemical differences, such as prolonged activity or altered selectivity of a catalyst in

supported form compared with its soluble analogue.

Now a days‟ scientists focus mainly on two factors associated with green chemistry namely

E‒factor and atom economy. The polymer‒supported organic synthesis must be one of the

ways to reduce the chemical and economical wastes. There are three important parameters

that impact on both the commercial viability and the inherent greenness of a particular

catalyst:3b

1) Selectivity – the amount of substrate converted to the desired product as a percentage

of total consumed substrate (a catalyst will be of limited benefit if it also enhances the

rate of by‒product formation).

2) Turnover frequency – the number of moles of product produced per mole of catalyst

per second (low turn over frequencies will mean large amounts of catalyst are

required, resulting in higher cost and potentially more waste).

3) Turnover number – the amount of product per mole of catalyst (this is related to

catalyst lifetime and hence to cost and waste).

I.2. Types of Polymer supports

Based on the requirement of different reaction conditions various types of polymer

supports are used.1b

They are classified mainly in three categories as (a) Inorganic supports,

(b) Inorganic‒organic hybrid polymeric matrices and (c) Organic supports (Scheme I.1).

Inorganic OrganicHybrid

1. Metal Oxides2. KF/Al2O3

3. Clay minerals4. Silica5. Zeolites.

1. PVP and PPO2. Dendimers3. Polysachharides4. Polypeptides5. Polystyrene Resin6. Ion-exchange Resin

1. Coordination clusters2. Coordination polymers or Metal Organic Framework (MOF)

Polymer supports

Scheme I.1. Classification of polymer supports

I.2.1. Inorganic supports

There is a variety of heterogeneous catalysts, but the most common types consist of an

inorganic or polymeric support, which may be inert or have acid or basic functionality,

4

together with a bound metal, Pd, Pt, Ni or Co. Due to inertness of the supports the reactants

are in a different phase to the catalyst. Therefore, both diffusion and adsorption influence the

overall rate of the catalytic reaction.

Surface area is one of the most important factors in determining throughput (amount of

reactant converted per unit time per unit mass of catalyst). Many modern inorganic supports

have surface areas of 100 to >1000 m2g

‒1. The vast majority of this area arises due to the

presence of internal pores; these pores may be of very fine size distribution to allow specific

molecular sized species to enter or leave. Materials with an average pore size of less than

1.5‒2 nm are named as microporous, whilst those with pore sizes above this are called

mesoporous materials. Materials with very large pore sizes (>50 nm) are named as

macroporous materials.3b

I.2.1.1. Metal Oxides

Metal oxides are generally used as inorganic polymeric supports. Some examples of the metal

oxide supports are given below (Scheme I.2).

Metal Oxides

MgO Al2O3 MnO TiO2 Fe2O3 ZnO ZrO2 CeO2

Scheme I.2. Examples of some commonly used metal oxides

A huge number of literature reports focus on the catalytic properties of NPs supported on

metal oxides, including oxides of Al,4 Ti,

5 Zr,

6 Mg,

7 Zn,

8 Ce,

9 Fe,

10 Mn,

11 some of the recent

examples are cited. The metal supports can stabilize one or more metal nanoparticles on to

their surface. Basic nanocrystalline magnesium oxide (MgO)‒stabilized palladium NPs was

found to be very active in the Suzuki‒Miyaura cross‒coupling of aryl bromides and iodides

with several arylboronic acids in pure water at room temperature.12

ZnO‒supported Pd,

Pd‒Ag, Pd‒Cu and Pd‒Ni catalysts (Pd‒M/ZnO) were also studied in Suzuki‒Miyaura cross‒

coupling reactions.13

Recently, cerium oxide (CeO2) has been extensively used as

photocatalyst and heterogeneous catalysts for organic reactions.14

Alumina is probably the

most common inorganic oxide that is used as the solid surface to catalyze or mediate a large

variety of organic reactions. Alumina surface can act as a base, as an acid or neutral medium

5

for catalyzing the organic reactions. Metal‒doped alumina composites were successfully

applied in C−S, C−N, C−O and C‒C cross‒coupling reactions.15

The catalyst stability

depends on the nature of the metal(s) and the support. For example, hydrogenation reaction

can be effectively achieved by CuNPs in the presence of calcined ZrO2 surface.16

I.2.1.2. KF/Al2O3

Alumina doped with potassium fluoride (KF/alumina) has been extensively used as solid

basic surface in vast range of organic transformations,17

since it was introduced by Ando and

Clark.18

KF/Al2O3 or metal‒doped KF/Al2O3 were used in various solvent‒free C−S, C−N,

C−O and C‒C bond formation reactions (Scheme I.3).19

KF-Al2O3

Metal-doped KF-Al2O3

N- or S- alkylation reaction

Ether synthesis

Epoxidation

Amide bond synthesis

Michael/Aza-Michael addition

Alkene synthesis

Heterocycles

Pd or Ni deposition

Pd/KF-Al2O3

Suzuki-Miyaura coupling

Ni/KF-Al2O3

Sonogashira coupling

Scheme I.3. Organic reactions on KF‒Al2O3 and metal‒doped KF‒Al2O3 surface

I.2.1.3. Clay Minerals

Finely grained crystalline sheet silicates form a large family of clay minerals, which act as

inert support for highly dispersed metals, metal complexes and enzymes etc.20

I.2.1.4. Silica

Polymorphic forms of silica, hydrated or anhydrous SiO2.xH2O is most often used as

catalyst‒support due to high surface area and large pore volumes. Common support material

consists of refractory oxides such as SiO2. This material exhibits high specific surface areas,

high porosities, and high thermal and mechanical stability and comes in a variety of pore

sizes, while they are mostly chemically inert.21

Silica surface, modified silica surfaces or

metal doped silica surfaces are also efficient for the various organic transformations.19

I.2.1.5. Zeolites

Zeolites are crystalline microporous aluminosilicates consisting of molecular‒sized

intracrystalline channels and cages used as highly selective adsorbents. These insoluble

6

supports have high surface area.22

Zeolites have a crystal structure, which is constructed from

TO4 tetrahedra, where T is either Si or Al. Each structure type is given a unique framework

code e.g. sodalite is SOD (no. of tetrahedral in ring = 4), zeolite‒A is LTA (no. of tetrahedral

in ring = 8) and ZSM‒5 is MFI (no. of tetrahedral in ring = 10).

I.2.2. Hybrid polymeric assembly

I.2.2.1. Coordination clusters

Supramolecular chemistry is often called molecular information science, dictates the

spontaneous assembly of non‒covalently linked molecular clusters of unique shape and

composition. This requires both a driving force and a dynamic system so that all possible

molecular structures can be explored to generate the formation of the thermodynamically

favored structures. An example of such a structure in nature is the iron storage protein

apoferritin (Figure I.2).23

L-Ferritin

H-Ferritin

Fe3+

Fe2+

Apoferritin Holoferritin

Figure I.2. A schematic diagram of the apoferritin

In the last two decades the synthesis and study of coordination clusters (CCs) of

paramagnetic metals in moderate oxidation states attract much attention in the field of

material chemistry.24

Some CCs have been characterized as a narrow‒waisted cylinder of

dimensions 2.8–3.1nm (Ag‒S) and the sizes were determined (the Mo species in the form of

anion having approximately the size of haemoglobin).25

The simplest general formula of CCs of 3d metals in moderate oxidation states is

[Mx(μ‒L)yL/z]

n, where μ‒L is a bridging organic or inorganic ligand, L

/ is a terminate ligand,

x is an integer number larger than 2, y and z are integer numbers and n can be zero

(molecule), positive (cationic CC) or a negative (anionic CC) integer number. The

classification of the CCs is divided in tabular form (Table I.1).

7

Table I.1. Description of Coordination clusters (CCs) for the general formula of

Mx(μ‒L)yL/z]

n.

Mx(μ‒L)yL/z]

n Designation

M x μ‒L L/ y z n

Metal integer>

2

bridging organic

or inorganic

ligand

terminate

ligand,

integer integer 0 Molecule

Metal integer>

2

bridging organic

or inorganic

ligand

terminate

ligand,

integer integer „+‟

integer

cationic CC

Metal integer>

2

bridging organic

or inorganic

ligand

terminate

ligand,

integer integer „‒‟

integer

Anionic CC

In many cases, two or more bridging ligands, often a combination of organic and inorganic

ones and more than one type of terminal (monodentate or chelating) ligands including solvent

molecules were used. This class of compounds is found in the literature with several names

such as oligomeric, polynuclear, highnuclearity or polymetallic complexes, cages, clusters

and CCs; but scientists generally prefer the later term.26

I.2.2.2. Coordination polymers or Metal Organic Framework (MOF)

In the recent years, the designs and constructions of oligo‒ and poly (nuclear) coordination

architectures attract much attention because of their new structural topologies and fascinating

architectures. It has been used in optoelectronic devices,27

microporous materials,28

and

catalysis.29

The smart combination of organic ligand “spacers” and metal ion “nodes” has been

considered as one of the most common synthetic methods to produce coordination polymers

with predictable networks (Figure I.3).30

8

0-D (Dot) 1-D (Chain)

2-D (Layer) 3-D (Network)

+

Metal ions Organic linkers

SolutionSelf assembly

Solid Phase

Figure I.3. A schematic presentation for the synthesis of metal–organic framework (MOF)

The advantage of constructing these metal–organic framework (MOF) architectures is to

allow a wide choice in various parameters, including diverse electronic properties and

coordination geometry of the metal ions, as well as versatile functions and structures of

organic ligands. That is also the aspiration for achieving the ultimate aim of crystal

engineering: gaining control of the topology and geometry of the networks formed through

sensible choice of ligand, metal precursor geometry and synthesis conditions.31

I.2.3. Organic polymer supports

I.2.3.1. PVP and PPO

Poly(N‒vinyl‒2‒pyrrolidone), PVP and poly(2,5‒dimethylphenylene oxide), PPO are the

most used polymer for NP stabilization and catalysis, because they fulfill both steric and

ligand requirements (Figure I.4). The metal NPs are stabilized through the steric bulk of

Polymeric framework. A very efficient olefin and benzene hydrogenation has been

effectively done by PVP stabilized Pt‒, Pd‒ and Rh NPs.22

NO

CH

CH2

n

PVP

Poly(vinylpyrrolidone)

O

n

PPOPoly(2,5-dimethylphenylene oxide)

Figure I.4. Structures of poly(N‒vinyl‒2‒pyrrolidone) (PVP) and poly(2,5‒dimethylphenylene oxide)

(PPO)

9

Toshima‟s group developed a very important concept of catalysis using two different

metals such as Au and Pd in the same NPs in the 1970.32

This idea has been beautifully

developed by Toshima‟s group who used PVP to stabilize core–shell bimetallic Au–PdNPs,

that is, NPs in which the core is Au and the shell is Pd.33

I.2.3.2. Dendrimers

Dendrimers are one of the classes of organic polymers but unlike polymers, there are

perfectly defined on the molecular level with a polydispersity of 1.0.34

They have shapes

resemblance to molecular trees or cauliflowers and become globular after a few generations.

They can entrap and stabilize metal NPs especially if there are heteroatoms in the

dendrimer‟s interiors.35

The dendritic branches and termini bind the small substrates into the

dendrimer and stabilize the NPs. The formation of NPs stabilized by dendrimers for catalysis

has been anticipated in 1998 by the three research groups of Crooks,35

Tomalia,36

and

Esumi.37

Metal NPs were introduced inside the dendrimers or at the dendrimer periphery.37

Poly(amidoamine), PAMAM is one of the common dendrimer, which is generally used to

entrap the metal ions. A schematic diagram of bimetallic nanocomposites on PAMAM

dendrimer has been established by Crook where two metals were simultaneously entrapped in

the polymeric matrix (Scheme I.4).

RhCl3, K2PdCl4

Complexation

NaBH4

reduction

Reactant

ProductPd2+

Rh3+Pd/Rh bimetallic

PAMAM dendrimer

(Agglomeration)

Scheme I.4. Encapsulation of Pd/Rh bimetallic nanoparticles on PAMAM dendrimer

PAMAM dendrimer PdNP catalysts can be effectively used as oxidation, reduction, Heck

coupling reaction and Suzuki‒Miyaura C‒C coupling reactions.38

I.2.3.3. Polysachharides

Starch, cellulose and other polysaccharides are used as greener renewable sources and

found applications to the field of catalysis. Starch is the second largest biomass on the planet

and as such represents one of the most important renewable resources for the future needs of

a sustainable society. Starch is an inexpensive polysaccharide extracted from renewable

agricultural resources (rice, potatoes, wheat and corn etc). It has wide applications due to its

10

biodegradability and biocompatibility properties. Trimethylene Carbonate (TMC)

ring‒opening polymerization (ROP) was performed in the presence of native starch

particles.39

Cellulose nanofibers are inherently low cost and are easily available and treated as

eco‒friendly material as they are easily recyclable.40

Chitosan (CS), the N‒deacetylated

derivative of chitin (chitin is a long chain polysaccharides of N‒acetyl glucosamine, a

derivative of glucose), that is widely used as suitable solid supports for the immobilization of

a metal catalyst (Figure I.5).41

O

OH

NHO

CH3OH

NHO

CH3

HO

HO*O

*

nChitin

OH

HOHO O

OH

O

OH

NH2

OHHO

NH2 NH2

n

Chitosane

Figure I.5. Structure of Chitin and Chitosane

Cyclodextrines are also bio‒polymers used in various organic transformations.42

I.2.3.4. Polypeptides

Micellar amphiphilic block copolymers containing a hydrophobic polypeptide block have

received much attention, mainly due to the possible applications in drug delivery.43

Elias et al

reported first example of an amphiphilic block polypeptide based Pd‒catalyst for

hydrogenation of acetopheneone in water medium.43

Marcelo et al described the synthesis of

magnetite polypeptide solid support and used it as a recoverable catalyst for the reduction

reaction. They modified the magnetite−polypeptide nanoparticles introducing new molecules

of dopamine via aminolysis, which can act as support of gold NPs.44

I.2.3.5. Polystyrene Resins

The polymeric supports used by Merrifield for his early work in solid‒phase peptide

synthesis were based on 2% divinylbenzene (DVB) cross–linked polystyrenes (PS). PS has

been found to be one of the most accepted polymeric materials used in various syntheses

because it is inexpensive, readily available, mechanically robust, chemically inert and

smoothly functionalizable. Various percentages and types of cross–linking agents have been

incorporated into the PS resins, the most common being DVB, but other examples include

ethylene glycol dimethylacrylate (EGDMA) and tetraethylene glycol diacrylate (TEGDA) to

11

give different solvation properties. A schematic representation of polymerization of styrene

with functionalized monomers is shown in Scheme I.4.45

RadicalInitiatorO

O

O

O

DVBEGDMA

or

Cl

ClPS

XPS

Macroporous orGel based resin

Cross-Linkers

X = NH2 aminomethyl-PSX = OH hydroxymethyl-PS

Derivatization

PS = polystyrene

+

Scheme I.5. Synthesis and derivatization of PS‒based solid supports

TentaGel,46

and ArgoGel,47

are two commercially available polymeric resins where the

incorporation of the PEG chains dramatically increases resin compatibility with polar

solvents.

PS‒based phosphine catalysts have been found to be synthesized and used for palladium

entrapment. The PS‒supported Pd catalysts were used for various C−C cross–coupling

reactions.48

Similarly, PS‒supported Rh and Ru catalyst were also prepared and used for

various organic transformations.45

I.2.3.6. Ion‒exchange resins

Various techniques were introduced over the last few decades relating the immobilization

procedure onto insoluble polymer support material so that the catalyst can be quantitatively

separated by filtration and recycled.

Ion‒exchange materials are those insoluble substances, which can able to immobilize the

metals onto it. Ion‒exchange materials are insoluble substances containing loosely held ions,

which are able to be exchanged with other ions in solutions.

Most ion‒exchange resins are comprised on cross–linked polystyrene‒divinylbenzene

copolymers containing ion‒exchanging functional groups.49

I.2.3.6.1. Types of ion‒exchange resins

The ion‒exchange resins are classified into two major groups: They are mainly,

Cation exchanger (containing anionic functionalities and positively charged mobile

ions): Cation exchangers are further divided into two groups such as,

12

Strong acid exchange (e.g., containing sulfonic acid groups or the

corresponding salts) and

Weak acid exchange (e.g., containing carboxylic acid groups or the

corresponding salts) resins.

Anion exchanger (with cationic functionalities) Similarly anion exchangers are

divided into two groups such as,

Strong base exchange (e.g., containing quaternary ammonium groups) and

Weak base exchange (e.g., containing ammonium groups) resins.

Other ion‒exchanging materials include homopolystyrene and acrylic based resins and

Nafion, a perfluorinated polymer containing sulfonic acid.50

I.2.3.6.2. Ion‒exchange resins as polymeric supports for reagents

Amberlyst‒15 is routinely used in organic synthesis as heterogeneous reusable acid

catalysts for various selective transformations of simple and complex molecules.51

Structures

of some polymer‒supported reagents, generally used in oxidation reactions, reduction

reactions are given below in the Figure I.6.3 The selective reduction of functional groups is a

common need in organic synthesis. Borohydride exchange resin (BER),52

was introduced in

the 1970s and has since proven to be of considerable value in the reduction of organic

compounds. This reagent reduces both ketones and aldehydes readily to corresponding

alcohol. Halogenation is one of the important steps for the synthesis of various important

intermediates and molecules. Polymer‒supported halogenization reagents are also used for

the halogenations of alkenes or alkynes (Figure I.6).3 C−C bond formation reactions and

substitution reactions have also been achieved with polymer‒supported reagents.53

NMe3 IO4 NMe3 OOH

= PS(cross-linked)

NMe3 BH4

BER = Borohydride exchange resin

= Amberlyte A-26

NMe3 Br3

Reducing agentOxidizing agent Halogenation agent

Figure I.6. Structures of various ion‒exchange resins

I.2.3.6.3. Ion‒exchange resins for immobilization of metal NPs

13

Immobilization of metal ions and charged metal complexes onto ion‒exchange resin is an

equilibrium process driven by noncovalent electrostatic interactions (Scheme I.5, strong

cation exchanger example). The affinity and selectivity of resins varies with the ionic size

and charge of the ions. Generally, the affinity is greatest for large ions with high valence.54

SO3YPS (MLk)x+Zx

-

x

(MLk)x+ xY+Z-Solvent

Y = H, Na, Li M = metal L = ligand Z = PF6, BF4

SO3PS

Scheme I.6. Immobilization of metal ions onto cation‒exchange resin

Anion exchange resin‒supported metal catalysts are very influential for various organic

transformations. Many different metals were found to immobilize on these metal surfaces

with tremendous catalytic efficiencies.55,56

It was found that Amberlite IRA‒900 anion (chloride form) exchange resins,

commercially available and inexpensive poly‒ ionic resin, could be able to exchange the

anion with formate anion (HCOO¯) easily and quantitatively. The resulting Amberlite Resin

Formate (anion), designated as ARF, could be utilized as a solid‒phase version of the

H‒donor in Pd‒catalyzed catalytic transfer hydrogenation. The ARF was air stable and

recovered from a reaction easily. Several alkenes, imine

and nitroarenes

were thus

hydrogenated using the ARF and catalytic amount of palladium acetate under mild conditions

and C‒C and C‒Hetero atom bonds can also be generated by this catalyst.57

NR3

Aq. HCOOH

Cl

(10%; v/v) NR3

HCOO

Amberlite IRA Chloride form

Amberlite IRA Formate form

X

R3

R2

R1

R4

NR3

HCOO

Pd(OAc)275 oC, DMF

X

R3

R2

R1

R4

R1 = R2 = PH, Ar, HR3 = R4 = COOEt, COOMe, CN, NHBoc, Ph, HX = C, N

NO2

R5

NR3

HCOO

Pd(OAc)2100-120 oC, DMF

NH2

R5

R5 = Cl, COMe, Me, COOMe, OH

14

Scheme I.7. Amberlite resin formate (ARF) in catalytic hydrogenation reactions

The ARF bound Pd was synthesized in our laboratory by the following technique (Scheme

I.8).57a,b

ARF-Pd

NR3

HCOO

Pd(OAc)2

Na2PdCl4

DMF

Stirring at RTNR3

HCOO Pd

Scheme I.8. Preparation of ARF‒Pd

By applying this technique, a new and efficient catalytic system was developed in our

laboratory, which was successfully applied in catalytic reduction and C‒C cross‒coupling

reactions.18,58

Bimetallic NPs supported on ARF was also synthesized and characterized. The

Pd/Cu‒ARF bimetallic nanocomposites was prepared and used successfully for Sonogashira

coupling reaction.59

ARF-Pd/CuNR3

HCOO

Pd(OAc)2

Cu(OAc)2

DMF

60 oC, 1h

Scheme I.9. Preparation of bimetallic Pd/Cu supported on ARF

I.3. References

References are given in BIBLIOGRAPHY under Chapter I (pp. 139−142).

15

CHAPTER II

Amberlite Resin Formate (ARF) and Pd/Fe2O3

Bimetallic Nanocomposites (Pd/Fe–ARF):

Enhanced and Chemoselective Catalytic Activity

in Hydrodehalogenation of Haloaromatics

16

II.1. Introduction

Bimetallic heterogeneous catalysis offers attractive opportunities to the perspectives of

„Green Chemistry‟ due to some common features viz. simplicity of work‒up, recyclability,

and minimization of metallic ravage.1

Carbon‒carbon,2,3

carbon‒heteroatom bond‒forming

reactions,1

click reactions,1

hydrogenation,4

and hydrodehalogenation reactions,5

are

efficiently done by using bimetallic nanoparticles (NPs). Incorporation of one metal to

another metal on solid surface can modify the catalytic properties on the surface and it can

alter/tune an organic reaction effectively. For example, palladium pervoskite‒oxide lattice

was used as an alternative electrocatalyst for oxygen reduction reaction (ORR). By doping of

a Pd ion to pervoskite lattice gave LaFe0.95Pd0.05O3‒δ and LaFe0.9Pd0.1O3‒δ and these catalysts

exhibited mass activity, durability than commercial Pt/C catalysts (Scheme II.1).6

O2 Oxygen Reduction Reaction OH

ORR activity: (Pi)Pd3/4+> Pd2+> Pd0

Scheme II.1. Oxygen reduction reaction using Pd/Fe catalyst

Hydrogenation reactions can be done by Ru/Sn, Ni/Pd or Co/Si nanoclusters supported

with silica or other polymeric materials have been successfully used.4

Similarly,

carbon‒carbon cross‒coupling reactions are often carried out by using bimetallic catalysts

involving Pd/Rh,7 Pd/Ni,

3b Pd/Cu nanoparticles (NPs),

2 etc with high efficiency and

selectivity. Indirect functionalization of alcohols with 1,3‒dimethylbarbituric acid followed

by spiro‒cyclization by Ir/Pd bimetallic catalyst.8 R. Grigg et al. reported a novel sequential

palladium/ruthenium‒catalyzed three‒component process where allene insertion followed by

olefin metathesis led to the formation of heterocycles.9

II.2. Background and Objectives

Halogenated aromatics, like polyhalogenated biphenyls, polychlorinated

dibenzo‒p‒dioxins (PCDDs), dibenzofurans (PCDFs) etc. are often highly toxic to the human

and animals and it becomes a serious threat to environmental pollution.9 Several

hydrodehalogenation methods have been developed by using many monometal‒based

systems namely Pd, Fe and Ni catalysts.

10‒13 But some of these methods have been carried out

at a high temperature by using inorganic bases and toxic ligands, and requiring long reaction

time.10, 14

Some methods for hydrodehalogenation reaction are discussed below:

17

PdO bound on polystyrene beads was effective for hydrodehalogenation of haloaromatics.

This catalytic system showed good catalytic acitivities for the hydrohalogenation and

required 10 mol% PdO and 1.5 equivalent of K3PO4 as base and high temperature, 110 oC

(Scheme II.2).10b

X

R

10 mol% PdOK3PO4 (1.5 eqiv)

DMF/ Cyclohexanol

110 oC, 12 h

H

R

R = 4-Me, 2-MeO, 4-MeO, 3-MeO, 4-t-Bu, 4-OH, 4-Ph, 1-Naphthyl, 2-Pyridyl, X = I, Br and Cl

Scheme II.2. Hydrodehalogenation of haloaromatics using PdO in basic condition and high

temperature

The catalytic system based on Pd–phosphite for the dehalogenation reactions of aryl

chlorides and bromides has been described by S. Lee et al. In this case the Pd–phosphite

catalyst effectively promoted the dehalogenation of aryl halides to give dehalogenated

products in moderate to excellent yields in the presence of a strong base and required high

temperature (Scheme II.3).10c

Cl

R

Pd2(dba)3

Ligand

NaOtBu, i-PrOH

80 oC, 3 h

H

R

Br

R

Pd2(dba)3

Ligand

Cs2CO3, Cyclohexanol

120 oC, 10 h

O

tBu

Me

tBu

P

O

O

O

P

O

O

But

But

Me O

tBu

Me P

O

O

O

P

O

O

But

Me

Phosphite ligands

Scheme II.3. Pd‒phosphite catalyst for the dehalogenation of aryl chlorides and bromides

Hydrodebromination of 4,4/‒dibromobiphenyl has been demonstrated by T. S. A. Hor and

his group. In this methodology 4,4/‒dibromobiphenyl was reduced to biphenyl by PdCl2 and

1,1/‒bis(diphenylphosphino)ferrocene (dppf). NaBH4 used as reductant (Scheme II.4.).

11b

18

PdCl2, dppf

NaBH4, TMEDATHF

BrBr

Scheme II.4. Study of hydrodebromination of 4,4/‒dibromobiphenyl using PdCl2 and dppf ligand

Tetrabromobisphenol A (TBBPA), one of the most widely used brominated flame

retardants were debromoinated by nanoscale zerovalent iron (nZVI) in methanol/water

(50/50, v/v) solutions. Zerovalent iron nanoparticles debrominated the TBBPA to

tribromobisphenol A, dibromobisphenol A, bromobisphenol A and bisphenol A. More than

86% of TBBPA was debrominated within 16 h in a pH of 7.5 and the reaction solution

initially containing 3.0 g/L of nZVI. A higher dosage of nZVI in addition to acidic conditions

facilitated the debromination process (Scheme II.5).12

HO

Br

BrCH3

CH3

Br

OH

Br

HO

CH3

CH3

OH HO

CH3

CH3

OH

Br

HO

Br

BrCH3

CH3

OH

Br

HO

BrCH3

CH3

OH

Br

+

+

BPA BBPA

Di-BBPA Tri-BBPA

Debromination

n-ZVI

Scheme II.5. Nanoscale zerovalent iron (nZVI) for the reduction of Tetrabromobisphenol A

(TBBPA)

A nickel‒catalyzed hydrodehalogenation of aryl halides with iso‒propyl zinc bromide or

tert‒butylmagnesium chloride has been developed by S. Enthaler et al. (Scheme II.6).13

N ONi

ON

F3CC tBu

Ph

PPh3

X

R

5 mol% Ni-cat.

1.5 eqiv.-iPrZnBr

THF

70 oC, 24 h

H

R

Nickel catalystX = I, Br, Cl

Scheme II.6. Nickel–catalyzed hydrodehalogenation of aryl halides with iso‒propyl zinc bromide

A practical and high‒yielding protocol for the dehalogenation of aromatic halides in the

presence of palladium acetate, triphenylphosphine and potassium carbonate was developed

by H. Zhang et al. A number of highly functionalized aromatic halides and α‒haloketones

were dehalogenated with 2‒butanol as hydrogen donors at 100 oC (Scheme II.7).

14b

19

X

R

Pd(OAc)2, Ph3P, K2CO3

2-butanol, 100 oC, 12 h

H

R

X = I, Br, Cl

Scheme II.7. A simple Pd(OAc)2–catalyzed hydrodehalogenation reaction using 2‒butanol as

hydrogen source

Like monometal based systems, various bimetallic NPs have been developed for

hydrodehalogenation of halogenated compounds. K. Parida et al. found that mesoporous

zirconia supported copper and nickel bimetallic catalysts was employed for

hydrodehalogenation reaction of chlorobenzenes and substituted chlorobenzenes in the

presence of H2 gas at room temperature (Scheme II.8).10c

ClnR

mmol of substrate/mmol of metal= 10

H2 flow rate = 10 mL/min Methanol = 10 mL, RT, 2 h

Hn

R

R = 4-Me, 4-MeO, 4-OH, 4-NO2

Cu-Ni/ZrO2

5-9 nm size of metal nano particlesRecycle for 3rd run

Scheme II.8. Zirconia‒supported Cu/Ni bimetallic catalyst for hydrodehalogenation reaction

A few reports on various Pd/Fe‒based bimetallic nanocatalysts are also known to catalyze

hydrodehalogenation reactions. However, in most cases, the catalyst preparative methods are

tedious, expensive, found to be limited with specific chloro‒or bromo‒ compounds. In other

words, their catalytic efficiency was not investigated with general applicability to diverse

aromatic/aliphatic halides. For example, poly(vinylidene fluoride)‒alumina

membrane‒supported Pd/Fe nanocatalyst has been prepared and used in the dechlorination of

only monochloroacetic acid.15

S. R. Al‒Abed et al. developed an effective strategy, employing a series of innovative

granular activated carbon (GAC) composites incorporated with iron/palladium (Fe/Pd)

bimetallic nanoparticles. In this methodology the polychlorinated biphenyls were first

adsorbed on the GAC surface and their electrochemical dechlorination by Fe/Pd bimetal on

the same surface could be simultaneously achieved (Scheme II.9).16

20

Granulated activated charcoal (GAC)

Pd (2-3 nm)

Zero valent iron (ZVI)Cl

2-Chloro biphenyl Biphenyl

Scheme II.9. Polychlorinated biphenyls are dechlorinated by granular activated carbon (GAC)

composites

Pd/Fe bimetallic nanotubes have been prepared and employed for hydrodehalogenation of

only polychlorobiphenyls (Scheme II.10).17

Cl

Cl

Cl

Cl

Polychloro biphenyl BiphenylPd/Fe nanotubes

Scheme II.10. Polychlorobiphenyl reduced by Pd/Fe bimetallic nanotubes

Huang et al. prepared Pd/Fe bimetallic catalysts with micron sizes and employed

specifically for the hydrodehalogenation of tetrabromo‒ or tetrachlorobisphenol A.5e,f

S. Balalaie et al. synthesized the homogeneous Pt/Pd/Fe trimetallic nanoparticle using a

water‒in‒oil microemulsion system of water/AOT/isooctane at room temperature. This

nanopaticle was characterized by various physical techniques and used as

hydrodehalogenation of halogenated organic compounds (HOCs). It was found that the

Pt/Pd/Fe (1:1:2) trimetallic combination was superior to other bimetallic combinations (Pt/Pd,

Pt/Fe or Pd/Fe). The trimetallic catalyst was effective even after fifth catalytic run whereas

the bimetallic combination Pd/Fe (1:1) losses its catalytic activity after first run (Scheme

II.11)5d

Aliphatic halides or aromatic halides

Pt/Pd/Fe+ Dehalogenated ProductNH4OCOHiso-propanol

Scheme II.11. Hydrodehalogenation method using Pt/Pd/Fe (1:1:2) trimetallic nanoparticle and

ammonium formate

21

Surprisingly, there is no example of Pd/Fe‒based heterogeneous nanocatalyst, which could

perform in general hydrodehalogenation of various haloaromatic compounds. It is therefore

imperative to develop new material‒based bimetallic nanocatalysts, which should be broadly

applicable to all types of haloaromatics with high efficiency and recyclability.

In connection with our interest in developing efficient and environment‒friendly catalysts,

we have been able to develop a new heterogeneous catalyst involving palladium and iron

species embedded with macroporous amberlite resins formate (ARF) and designated as

Pd/Fe–ARF. The ARF has been prepared from poly‒ionic amberlite resins chloride by our

previously reported conditions.18

Pd/Fe–ARF was prepared by co‒immobilization of

palladium and iron on the poly‒ionic resin surface. The nanocatalysts were characterized by

spectroscopy (FT‒IR), scanning electron microscopy (SEM), transmission electron

microscopy (TEM), TEM with energy dispersive X‒ray (EDX) analysis and powder X‒ray

diffraction (XRD) patterns. Furthermore, the nanocomposite (Pd/Fe–ARF) has been used as

recyclable and general catalyst with enhanced and chemoselective activity in the

hydrodehalogenation reactions of potentially hazardous and all kinds of haloaromatics except

fluoroarenes.

II.3. Present work: Results and Discussion

II.3.1. Preparation of (Pd/Fe‒ARF)

The Amberlite resin formate (ARF) was prepared according to our previously reported

procedure,18

the Fe–ARF–110 was synthesized from FeCl3 (162 mg, 1 mmol) in ARF (500

mg) and bimetallic nanocomposites (Pd/Fe–ARF) were prepared through co‒impregnation

mode from ARF (500 mg) and palladium chloride (0.473 mmol) and anhydrous ferric

chloride (0.493 mmol) at varying temperatures (80, 110 & 140 oC) which have been denoted

as Pd/Fe‒ARF–80, Pd/Fe‒ARF–110 and Pd/Fe‒ARF–140. Since fatty acid salts are known to

be used as stabilizer in controlling size and shape of nanoparticles,19

we prepared two other

varieties of Pd/Fe‒ARF in the presence of capping agents like oleic acid and sodium oleate at

110 oC and corresponding nanocomposites were designated as Pd/Fe‒ARF‒110‒OA (with

oleic acid) and Pd/Fe‒ARF‒110‒NaOA (with sodium oleate) respectively. All five

as‒synthesized bimetallic nanocomposite materials were characterized by spectroscopic,

p‒XRD and microscopic techniques and compared with the orginal support ARF. Images for

the preparative steps of Pd/Fe‒ARF–110 are given in the Figure II.1 below as demonstration.

22

Figure II.1. Schematic preparative steps of Pd/Fe‒ARF–110 nanocomposites

The photos of all six nanocomposites are shown in the Figure II.2.

Figure II.2. Photographic images of six nanocomposites

Characterization of the nanocomposites was performed using various techniques and

discussed below.

II.3.2. Characterization of the composites (Pd/Fe–ARF)

The morphology and microstructure of the samples were examined by FT‒IR

spectroscopy, X‒ray diffraction patterns (powder XRD), scanning electron microscopy

(SEM) and transmission electron microscopy (TEM) and TEM equipped with energy

dispersive X‒ray (EDX) analysis.

23

II.3.2.1. FT‒IR Spectroscopy

The FT–IR spectra of bimetallic composites were recorded in the range 4000–400 cm−1

and compared with that of ARF. Figure II.3 shows the comparative FT–IR spectra in the

range of 2000–400 cm−1

. The carboxylate anion (HCOO−) of the ARF exhibits both

symmetric and anti‒symmetric stretching vibrationsat 1349 and 1590 cm−1

respectively, while

those of Pd/Fe‒ARF‒110 display similar absorptions at 1420 and 1611 cm−1

. Such significant

shifting of absorption bands (71–21cm−1

) might be attributed to metal–oxygen attachment in

the composites.18

Similar spectra and shifting of stretching vibrations for the carboxylate

anion (HCOO−) were also observed for other five nanocomposites Fe‒ARF, Pd/Fe‒ARF‒80,

Pd/Fe‒ARF‒140, Pd/Fe‒ARF‒OA and Pd/Fe‒ARF‒NaOA.

Figure II.3. FT‒IR spectra of ARF, Fe‒ARF and Pd/Fe‒ARF bimetallic nanocomposites

Table II.1. Symmetric and anti‒symmetric stretching vibrational data of ARF, Fe‒ARF and Pd/Fe–

ARF obtained at different temperatures

2000 1750 1500 1250 1000

16301611

1572

ARF

1380

1349

1590

Fe-ARF

Pd/Fe-ARF-110

Pd/Fe-ARF-140

Pd/Fe-ARF-80

1480

1664

Pd/Fe-ARF-NaOA

1420

Pd/Fe-ARF-OA

Tra

ns

mit

tan

ce

(%

)

Wavenumber (cm-1

)

24

Sl.

No.

ARF and Nanocomposites Symmetric stretching

of (HCOO−) (in cm

‒1)

Anti‒Symmetric

stretching of

(HCOO−) (in cm

‒1)

1. ARF 1349 1590

2. Fe–ARF 1420 1611

2. Pd/Fe–ARF–80 1420 1630

3. Pd/Fe–ARF–110 1420 1611

4. Pd/Fe–ARF–140 1420 1611

5. Pd/Fe–ARF–110–OA 1420 1611

6. Pd/Fe–ARF–110–NaOA 1420 1611

II.3.2.2. Powder X‒ray diffraction patterns

The Bragg diffraction patterns obtained by powder XRD of all six different

nanocomposites are shown in Figure II.4. The XRD patterns of the samples confirmed the

presence of α‒Fe2O3, small amount of Fe3O4 and Pd,20

along with amorphous characteristics

of the organic polymeric resins in the range 2θ of 20o.2

XRD pattern of Fe‒ARF‒110 showed

presence of peaks at 2θ of 25, 33, 35, 42, 50, 54, 63 and 65o

corresponding to the (012),

(104), (110), (113), (024), (116), (214) and (300) planes, respectivelyof α‒Fe2O3

(JCPDS#01‒087‒1166).21

Whereas, in the case of Pd/Fe‒ARF‒80 the peaks related to only

cubic Pd were observed at 2θ values of 40o and 46° correspond to (111) and (200) planes

(JCPDS#01‒087‒0643), and no peaks of α‒Fe2O3 can be detected. On the other hand, XRD

patterns of both Pd/Fe‒ARF‒110 and Pd/Fe‒ARF‒140 exhibited co‒existence of α‒Fe2O3

and cubic Pd. In this case a trace of Fe3O4 was also found (JCPDS #01–075–0449). Presence

of both Fe3O4 and α‒Fe2O3 along with cubic Pd was also observed for both the composites

Pd/Fe‒ARF‒110‒OA and Pd/Fe‒ARF‒110‒NaOA. Furthermore, the approximate particle

size of the metal nanoparticles in the composites (Pd/Fe–ARF–80, Pd/Fe–ARF–110, Pd/Fe–

ARF–140 and Pd/Fe–ARF–110–OA) were calculated using Scherer equation from the

respective Pd (111) peak and found to be ~4–5 nm in all cases. However, signature of any

metallic Fe(0) nanoparticles were not observed in such bimetallic nanocomposites.22

25

Figure II.4. The powder XRD patterns of six nanocomposites prepared under different conditions

II.3.2.3. Scanning electron microscopy (SEM) of ARF, Fe‒ARF and Pd/Fe‒ARF

nanocomposites

The preparation conditions (mainly temperature) affect the structure, shape (or

morphology), and size distribution of the metal nanoparticles incorporated in the resins.23

The

surface morphology of Fe–ARF and Pd/Fe–ARF nanocomposites, prepared at different

temperatures and conditions were examined by scanning electron microscopy (SEM) and

compared with that of ARF and presented in Figure II.5. Distinct variations of the surface

morphologies are observed, presumably because of the deposition of metal NPs on the

surface of poly‒ionic resinous materials. Several dots are seen in the images of the

composites at same magnification, which could be due to the NPs deposited on to the surface.

In Figure II.5.a, some pores are clearly seen (marked by red circles) on the macroporous ARF

resin surface while for the Fe‒ARF or Pd/Fe‒ARF nanocomposites (Figure II.5.b‒g), these

pores are diminished due metal nanoparticles deposition.

10 20 30 40 50 60 70 80

(21

7)

(11

9)

(12

5)

(30

0)

Fe-ARF

(220)

(20

0)

Fe3O

4

Pd/Fe-ARF-110

Fe2O

3Pd (Cubic)

(11

1)

(21

4)

(11

6)

(02

4)

(11

3)(1

10

)

(10

4)

Pd/Fe-ARF-110-NaOA

(01

2)

Pd/Fe-ARF-110-OA

Pd/Fe-ARF-140

Unidentified

Inte

ns

ity

Pd/Fe-ARF-80

2 (degree)

26

27

Figure II.5. The SEM images of (a) ARF; (b) Fe–ARF–110; (c) Pd/Fe–ARF–80; (d) Pd/Fe–ARF–

110; (e) Pd/Fe–ARF–140; (f) Pd/Fe–ARF–110–OA and (g) Pd/Fe–ARF–110–NaOA nanocomposites,

respectively

II.3.2.4. Transmission electron microscopy (TEM) of ARF, Fe‒ARF and bimetallic

Pd/Fe‒ARF nanocomposites

Further analysis of the TEM image for Fe–ARF–110 indicates the presence of α‒Fe2O3

nanoparticles on ARF surface (Figure II.6). Similarly the TEM images of Pd/Fe–ARF

nanocomposites prepared at different conditions presented in Figures II.6.(c)‒(h). The

presence of metal/metal oxide nanoclusters with a fairly regular size is clearly evident from

the Figure II.6 (a, c, e and g). The average particle size distribution histogram for the Fe–

ARF–110, Pd/Fe–ARF–110, Pd/Fe–ARF–110–OA and Pd/Fe–ARF–110–NaOA were also

estimated (from Figure II.6 (b, d, f and h)). The mean diameter of Fe2O3 and Pd/Fe2O3

nanoparticles are given in the respectives histogram pictures. It is clearly seen from the

figures that most of the Pd/Fe2O3 nanoparticles were found in fairly regular size of 4.78 nm in

Pd/Fe–ARF–110 nanocomposites (Figure II.6, d).

0 1 2 3 4 5 6 7 8 9

0

5

10

15

20

25

30 (b)

4.24 nm

%

Average diameter (nm)

0 1 2 3 4 5 6 7 8 9

0

10

20

30

40(d)

4.78 nm

%

Average diameter (nm)

28

0 2 4 6 8 10 12 140

5

10

15

20

25

30(f)

3.13 nm

4.17 nm

%

Average diameter (nm)

2 3 4 5 6 7 8 9

0

5

10

15

20

25

(h)

5.0 nm

4.28 nm

%

Average diameter(nm)

Figure II.6. TEM images: (a) of Fe–ARF–110 and (b) its average particle size distribution histogram

from (a); (c) of Pd/Fe‒ARF‒110 and (d) its average particle size distribution histogram from (c); (e)

of Pd/Fe–ARF–110–OA and (f) its average particle size distribution histogram from (e); (g) of Pd/Fe–

ARF–110–NaOA and (h) its average particle size distribution histogram from (g)

Energy‒dispersive X‒ray spectroscopy (EDX) of TEM images was performed to obtain

elemental composition of the bimetallic composite. The EDX spectrum taken from one of the

bimetallic nanoparticles of Pd/Fe–ARF–110, revealed the presence of both Pd and Fe. This is

further confirmed by EDX elemental mapping of the same region, which is shown in Figure

II.7.(b). Pd (green) and Fe (red) particles are found with carbon particles (white) of resin

materials.

29

(b)

Figure II.7. (a) TEM‒EDX spectrum of Pd/Fe–ARF‒110 nanocomposites; (b) EDX elemental

mapping image of Pd/Fe2O3 bimetallic nanocomposites, green dots, Pd; red dots, Fe

30

II.3.3. Catalytic activity of Pd/Fe–ARF–110 nanocomposites

After the synthesis and charaterization of the ARF‒supported bimetallic composite, the

catalytic activity of the Pd/Fe‒ARF‒110 was evaluated in hydrodehalogenation reaction. As

discussed above, haloaromatic compounds are known to be toxic pollutants in the

environment. Initially, as the model case, we studied the catalytic activity and reaction

conditions in the hydrodebromination of 9,10‒dibromoanthracene using the reductant

NaBH4. The results are presented in Table II.2. At room temperature, the reaction did not

proceed smoothly even after 16 hours and the isolated yield of the desired product was only

10% (entry 1). Further increase in temperature did show minor increase in yield (entry 2).

However, carrying out the reaction in a mixture of THF:H2O (2:1) resulted in profound

change in the course of the reaction, and the hydrodebrominated product was obtained in high

yield (96%) (entry 3). While decreasing the quantity of the catalyst from 100 to 50 mg

mmol‒1

gave rise to similar conversion (entry 4), further lowering of the catalyst to 25 mg

mmol‒1

could not afford excellent conversion (entry 5). The reaction did not proceed in the

absence of NaBH4 and the catalyst, respectively, keeping other conditions unchanged (entries

7 & 8). Among different conditions were attempted, best conversion was achieved in the

presence of the catalyst (50 mg mmol‒1

; 0.0474 mmol of Pd and 0.0493 mmol of Fe) and

N,N,N/,N

/‒tetramethylethylenediamine (TMEDA) in THF:H2O (2:1) mixture at 70

oC under

aerobic condition (entry 4).

Table II.2. Optimization of reaction conditions for the hydrodebromination of 9,10

dibromoanthracene.

Br

Br

Pd/Fe-ARF-110, NaBH4

Base, Solvent, Temp.

Entry Solvent Base Catalyst

(mg)

Temperature

(oC)

Time (h) Yielda (%)

1 THF TMEDA 100 RT 16 10

2 THF TMEDA 100 70 16 25

3 THF:H2O (2:1) TMEDA 100 70 4 96

4 THF:H2O (2:1) TMEDA 50 70 5 96

5 THF:H2O (2:1) TMEDA 25 70 10 60

6 THF:H2O (2:1) Et3N 50 70 7 80

7b THF:H2O (2:1) TMEDA 50 70 22 Nil

31

8c THF:H2O (2:1) TMEDA 00 70 16 Nil

Reaction conditions: 9, 10‒dibromoanthracene (1 mmol), NaBH4 (4 mmol), TMEDA (4 mmol),

THF:H2O (2:1, (v/v), 2 mL), Pd/Fe–ARF‒110 catalyst (50 mg). aIsolated yield after purification by column chromatography by silica.

bNo NaBH4 was added.

cNo catalyst was used.

With the optimized reactions at our hand (Table II.2, entry 4), we attempted similar

hydrodehalogenation reaction of a range of mono‒ and poly‒substituted haloarenes.

Gratifyingly, in each case, near‒quantitative conversion was achieved under the optimal

reactions conditions. The results are shown in Table II.3. Different aromatic halides (Cl,

Br and I) are smoothly reduced under the catalytic conditions. In the case of

poly‒substituted bromoaromatic such as 2,4,6‒tribromophenol or tetrabromobisphenol A

(TBBPA), the reaction, however, took longer reaction time (9‒12 h) (Table II.3, entries 4 and

5). Mixed aromatic halide, 3‒bromochlorobenzene also underwent easy reaction with

near‒quantitative conversion (entry 9). However, sp2CF bond could not be removed with

this catalyst under the condition (entry 11). Since conjugated CC double bonds are also

reducible, we tested one example bearing both double bond and bromide groups.

Gratifyingly, the double bond remained unchanged, while complete hydrodebromination

occurred indicating chemoselective nature of the catalyst (entry 12).

Table II.3. Hydrodehalogenation of haloarenes in the presence of the nanocomposite catalyst

Pd/Fe–ARF‒110a

Entry Haloarenes Time

(h)

Product Yield

(%)

1 Br NHCOCH3

4.5 NHCOCH3

95

2

Br

Br

5

96

3 BrBr

5

97

4 OHBr

Br

Br

9

OH

96

32

5 OH C

CH3

CH3

OH

Br

BrBr

Br

12

OH C

CH3

CH3

OH

90

6

NBr Br

4.5

N

90

7 NH2Cl

5 NH2

96

8 OHCl

Cl

5 OH

91

9

Br Cl

5

96

10 I

4

94

11 F NH2

12 NH2

Nilb

12 O

Bun

Br

5 O

Bun

87

a Haloarene (1 mmol), NaBH4 (4 mmol), TMEDA (4 mmol), THF:H2O (2:1, (v/v), 2 mL), Pd/Fe–

ARF–110 (50 mg), heating the reaction mixture at 70 oC under aerobic condition.

bNot detected in HPLC analysis.

II.3.4. Recycling Experiment

Catalytic efficiency of a catalyst is often measured by its life cycle i.e. stability,

selectivity, turn over number (TON) and turn over frequency (TOF). In order to check the

recycling potentiality, we isolated the catalyst (Pd/Fe‒ARF‒110) by simple filtration

followed by washing with water, acetone and then drying under vacuum. The recovered

catalyst was used in the hydrodebromination of 9,10‒dibromoanthracene. The catalyst was

found to be effective for consecutive five runs tested without any significant drop in respect

of conversion (Figure II.8).

33

1 2 3 4 5

0

20

40

60

80

100

Isola

ted y

ield

(%

)

No. of runs

Figure II.8. Recycling experiments using Pd/Fe‒ARF‒110 catalyst in hydrodebromination of

9,10‒dibromoanthracene

II.3.5. Comparison of turnover frequency of reported similar catalytic systems

It is noteworthy to mention that previous studies involving Pd/Fe bimetallic catalysts in

hydrodehalogenation reaction have not used aqueous NaBH4 as the hydrogen source, though

monometallic Pd or Ni complexes have been used as the catalysts in the presence of aqueous

NaBH4. A comparative catalytic efficiency, as presented in Table II.4, revealed that

monometallic complexes did show better TOF, possibly due to their function as

homogeneous catalysts. However, they are not recoverable and reusable. On the other hand,

the reported bimetallic catalysts did show relatively poor TOF as compared to our catalytic

system.

Table II.4. Comparison of TOF of various catalytic systems tested in the

hydrodehalogenation of haloarenes.

Entry Catalyst Hydrogen Source TOF (hr‒1

)a References

1 Pd/Fe bimetallic

nanotubes

Ethanol/water 0.0262 [17]

2 Vermiculite supported

nanoscale ZVI dopped

with Pd (Pd/Fe‒VMT)

Acidic solution 0.00595 [5c]

3 Micron sized Pd/Fe

bimetallic catalyst

KHPO4, dil. HCl in

methanol

0.5137 [5e]

34

4 PdCl2(dppf)2 NaBH4 0.472 to 38 [24a]

5 Tetraazabicyclo based

Nickel (II) complex

NaBH4 19.51 [24b]

6 Pd/Fe‒ARF‒110 NaBH4 4.05 This study aTOF was calculated based on experimental data. TOF = mmol of product/ mmol of catalyst per hour.

II.3.6. Plausible Mechanism towards enhanced catalytic activity

In quest of the enhanced catalytic activity exhibited by this newly prepared heterogeneous

bimetallic system, we attempted to explore on its mechanistic function in the

hydrodehalogenation reaction. Literature survey towards the mechanism of the

hydrodehalogenation reaction with bimetallic catalysts revealed that the reaction goes

through the reductive catalytic pathway where one metal (particularly iron or zinc) generates

hydrogen through corrosion with water and the second metal is used as a dopant to form

metal hydride. Nanosized bimetallic particles with zero valent iron such Ni/Fe or Pd/Fe with

large surface area has profound effect on the degradation of haloaromatics due to the increase

of the availability of surface reaction sites.25

On the other hand, it is known that the reaction

of NaBH4 with water liberates hydrogen slowly at room temperature, and can be accelerated

with the aid of metal NPs coated on metal oxides or on carbon. For example, Pt NP coated on

LiCoO2, Pt/C or Pd/C, due to their (Pt or Pd) higher d‒band center, were found to be

excellent catalysts to generate hydrogen from aqueous NaBH4 solution.26,27

Using our

catalyst, the reaction slowly proceeds without adding water (Table II.2, entry 3) and does not

proceed at all in the absence of NaBH4 (Table II.2, entry 7). We therefore tend to believe that

the origin of the active reducing source is NaBH4. Since our catalytic system consists of

Pd/Fe(III), where iron oxide itself cannot produce hydrogen from the reaction of NaBH4 and

water effectively,26

we presume that a synergism between Pd(0) and Fe(III) NPs in the

bimetallic system might exist, which makes faster BH bond‒breaking and H* formation.27

Subsequently hydride transfer to oxidative addition species [ArPdX] results in the

formation of dehydrohalogenated product, as proposed in Scheme II.12.

The high activity of Pd on iron oxide at low temperature may also be attributed due to the

redox properties and oxygen storage capabilities of iron oxides. It is seen that the partially

reduced iron oxide (i.e. Fe3O4) provides sorption sites for O2 in form of Fe2+

ions and thereby

acts as oxygen sink. Electron transfer effect between metal oxide and Pd makes the

composites to be active one.28

35

Scheme II.12. Plausible mechanism for the enhanced catalytic activity in the hydrodehalogenation of

haloaromatics using NaBH4 in water

II.4. Conclusion

In summary, we have developed a new heterogeneous bimetallic nanocomposite material

based on amberlite resin formate, palladium and iron oxides that exhibits enhanced catalytic

performance for the hydrodehalogenation of haloaromatic compounds. A synergism between

the two metal species dispersed on the polymeric surface in combination with aqueous

NaBH4 as the reducing source could be responsible for excellent catalytic activity. This is

unique since no such combination has ever been explored. Furthermore, the heterogeneous

catalyst has been found to be recyclable with nearly equal efficiency tested for five

consecutive runs. The newly developed catalytic system is found to be better as compared to

other similar catalysts used for this reaction in terms of easy method of preparation, cheap

starting materials, avoiding any precious ancillary ligands, mild reaction conditions, and

applicability to diverse aromatic halides, high TOF and recyclability.

II.5. Experimental section

II.5.1. General information

Amberlite IRA 900 (chloride form) was purchased from Acros Organics, Belgium and

used after washing with water and acetone followed by drying under vacuum. Other

chemicals were purchased and used directly. FT‒IR spectra were recorded with a

FT‒IR‒8300 SHIMADZU spectrophotometer using a KBr pellet method. NMR spectra were

taken in CDCl3 using a Bruker Avance AV‒300 spectrometer operating for 1H at 300 MHz

36

and for 13

C at 75 MHz. The spectral data were measured using TMS as the internal standard.

The X‒ray diffraction (XRD) studies of the powder samples were done using the Rigaku

SmartLab (9 kW) diffractometer using CuKa radiation.

The amberlite resin formate (ARF) was prepared from commercially available amberlite

IRA 900 (chloride form) (source: Acros Organics, Belgium) by rinsing with 10% aqueous

sodium formate solution until free from chloride ions. The resin beads were then washed with

water followed by acetone, dried under vacuum, and used for the preparation of

heterogeneous bimetallic nanocomposites.

II.5.2. Preparation Fe–ARF

To a homogenize solution of FeCl3 (162 mg, 1 mmol) in DMF (8 mL), 500 mg of ARF

(the globular beads were pulverized to dust particles) was added, and the mixture was stirred

for 5 mins at room temperature. Then the mixture was taken in a screw‒capped sealed tube

and heated at 110 oC for 8 h with occasional shaking. The yellow supernatant liquid after

filtration gives red coloured composite materials. The material was washed with dry and

distilled DMF (3×5 mL) followed by distilled water (2×5 mL) and acetone (2×5 mL). The

resulting dust composites were dried under vacuum.

II.5.3. Preparation of Pd/Fe–ARF–110

To a solution of PdCl2 (84 mg, 0.473 mmol) and FeCl3 (80 mg, 0.493 mmol) in DMF (8

mL), 500 mg of ARF (the globular beads were pulverized to dust particles) was added, and

the mixture taken in a screw‒capped sealed tube was heated at 110 oC for 8 h with occasional

shaking. The supernatant liquid appeared completely colourless by this time and ARF powder

turned black. The mixture was cooled to room temperature and the powdered composite

materials were filtered off, washed thoroughly with dry and distilled DMF (3×5 mL)

followed by distilled water (2×5 mL) and acetone (2×5 mL). The resulting shining black

dusty materials were dried under vacuum and used for analysis and catalytic reactions.

Pd/Fe–ARF–80 and Pd/Fe–ARF–140 were also prepared according to the above procedure at

80 and 140 oC respectively.

II.5.4. Preparation of Pd/Fe–ARF–110–OA

To a solution of oleic acid (282 mg, 1mmol) in DMF (5 mL), 500 mg of dust ARF was

added and heated at 110 oC in a screw‒capped sealed tube for 1 h. Then a solution of PdCl2

(42 mg, 0.237 mmol) and FeCl3 (154 mg, 0.947 mmol) in DMF (3 mL) was added to the

37

mixture of oleic acid and ARF. The overall reaction mixture was heated for 8 h at 110 oC

gives a fairly black colour nanocomposite of Pd/Fe2O3. The clear supernatant liquid was

filtered‒off and the black residue was washed with dry and distilled DMF (3×5 mL) followed

by acetone (4×5 mL). The black materials were dried under vacuum and characterized.

II.5.5. Preparation of Pd/Fe–ARF–110–NaOA

Sodium oleate was first prepared by titration of the ethanolic solution of oleic acid with

ethanolic solution of sodium ethoxide in pH‒meter. The white solid appeared was filtered‒off

by rotary evaporator under azeotrope distillation. To a solution of sodium oleate (304 mg,

1mmol) in DMF (5 mL), 500 mg of dust ARF was added and heated at 110 oC in a

screw‒capped sealed tube for 2 h. Then a solution of PdCl2 (42 mg, 0.237 mmol) and FeCl3

(154 mg, 0.947 mmol) in DMF (3 mL) was added to the mixture of sodium oleate and ARF.

The overall reaction mixture was heated for 8 h at 110 oC gives a brownish‒black coloured

nanocomposite of Pd/Fe2O3. The supernatant liquid was filtered‒off and the brownish‒black

residue was washed with dry and distilled DMF (3×5 mL) followed by distilled water (2×5

mL) and acetone (3×5 mL). The black materials were dried under vacuum and characterized.

II.5.6. Typical procedure for hydrodehalogenation of haloarenes in the presence of

Pd/Fe‒ARF‒110

To a suspension of Pd/Fe–ARF‒110 (50 mg) in THF:H2O (2:1, v/v, 2 mL), haloarene (1

mmol), TMEDA (4 mmol), NaBH4 (4 mmol) were added. The reaction mixture was then

heated in a round‒bottomed flask fitted with condenser and maintaining gentle magnetic

stirring for hours, as noted in Table II.3. The progress of the reaction was monitored by tlc.

After completion of the reaction, the mixture was diluted by water (5 mL), and filtered off the

catalyst. The filtrate was extracted with DCM (4×10 mL) and the combined organic extracts

were washed with brine (1×5 mL), dried over anhydrous Na2SO4 and concentrated under

vacuum. The residue was purified by passing through a short silica gel column

chromatography and eluted with light petroleum or mixture of ethyl acetate–light petroleum

to afford the desired hydrodehalogenated product. All products were characterized by 1H,

13C

NMR and FT‒IR spectral data, and also compared with the reported melting points (for

known solid compounds). The conversion to benzene, pyridine, aniline or phenol was

checked and compared by HPLC analysis.

38

II.5.7. Physical properties and spectral data of compounds

Table II.4, Entry 1

N‒phenylacetamide29

HN

O

CH3

White solid, mp 112‒113 oC (Lit.

29 109‒114

oC)

1H NMR (CDCl3, 300 MHz): δ/ppm 2.05 (s, 3H, ‒CH3), 6.98‒7.03 (m, 1H), 7.17‒7.22 (m,

2H), 7.41‒7.43 (m, 2H), 7.78 (s, 1H, ‒NHCOCH3).

13C NMR (CDCl3, 75 MHz): δ/ppm 24.4, 120.1, 124.3, 128.9, 138.0, 169.0.

Table II.4, Entry 2

Anthracene30

White solid, mp 112‒113 oC (Lit.

30 109‒114

oC)

1H‒ and

13C‒NMR spectra of this compound could not determine in CDCl3 or d6‒DMSO

solvent due to solubility problem.

Table II.4, Entry 3

Biphenyl31

White crystalline solid, mp 67‒68 oC (Lit.

31 68‒70

oC)

1H NMR (CDCl3, 300 MHz): δ/ppm 7.47‒7.52 (m, 2H), 7.56‒7.61 (m, 4H), 7.74‒7.77 (m,

4H).

13C NMR (CDCl3, 75 MHz): δ/ppm 127.3, 127.4, 128.9, 141.4.

Table II.4, Entry 5

Bisphenol‒A32

CH3

CH3

OHHO

39

White solid, mp 218‒219 oC (Lit.

32 220

oC)

1H NMR (d6‒Acetone, 300 MHz): δ/ppm 1.58 (s, 6H), 6.69‒6.75 (m, 4H), 7.02‒7.37 (m,

4H); 8.16 (s, 2H, ‒OH).

13C NMR (d6‒Acetone, 75 MHz): δ/ppm 30.6, 41.1, 114.5, 127.5, 141.9, 155.0.

Table II.4, Entry 10

Naphthalene30

White crystalline solid, mp 79‒81oC (Lit.

30 80‒82

oC)

1H NMR (CDCl3, 300 MHz): δ/ppm 7.55‒7.58 (m, 4H), 7.91‒7.96 (m, 4H).

13C NMR (CDCl3, 75 MHz): δ/ppm 125.9, 127.9, 133.5.

Table II.4, Entry 12

(E)‒Butyl cinnamate33

O

O

Colourless liquid

IR (KBr): νmax = 2358, 2330, 2959, 2932, 1713, 1638 cm

‒1.

1H NMR (CDCl3, 300 MHz): δ/ppm 0.92 (d, J = 2.1 Hz, 3H, ‒CH2CH2CH2CH3), 1.30‒1.43

(m, 2H, ‒CH2CH2CH2CH3), 1.58‒1.67 (m, 2H, ‒CH2CH2CH2CH3), 4.08‒4.17 (m, 2H,

‒CH2CH2CH2CH3); 6.37 (d, J = 16.2 Hz, 1H), 7.29‒7.34 (m, 3H), 7.43‒7.46 (m, 2H), 7.60

(d, 1H, J = 15.9 Hz).

13C NMR (CDCl3, 75 MHz): δ/ppm 13.7, 19.2, 30.8, 64.4, 118.3, 128.0, 128.8, 130.2, 134.5,

144.5, 167.1.

II.6. References

References are given in BIBLIOGRAPHY under Chapter II (pp. 142−145).

40

CHAPTER III

SECTION A

“On‒water” organic reactions: A brief review

41

III.A.1. On‒water Chemistry

Organic solvents have played a key role in the development of useful products. One of the

key roles of the organic solvents is to homogenize the reactants and speeding up reactions

through improved mixing. But, volatile organic solvents (VOCs) have adverse effects on the

environment, which includes conjunctivital irritation, nose and throat discomfort, headache,

allergic skin reaction, dyspnea, nausea, fatigue and dizziness. Because of these adverse health

effects, benign non‒volatile solvents are introduced in the organic reactions. Supercritical

carbon dioxide (scCO2) and supercritical water (scH2O) have tremendous synthetic utility in

organic reactions. But due to the corrosive properties of the supercritical fluids, the uses of

these solvents are limited as reaction media.1

So, water plays an important role in organic

synthesis regarding environmental aspects. Water is unique due to its some unusual

properties like a large temperature window in which it remains liquid, exclusive hydrogen

bonding, high heat capacity and large dielectric constant. It is not treated as popular choice of

solvent in organic synthetic chemistry because functional groups of organic molecule may

themselves react with water and most of the organic molecules are highly insoluble in it due

to their hydrophobic nature. So, it is assumed that a mixture of water and nonpolar organic

reactants will usually give low yields of the desired products. But, recent findings told that

both the rates and selectivity of organic reactions can be increased by addition of water.2

Water has ability to form weak non‒covalent bonds with other compounds and to connect in

electron transport reactions as exemplified by many biological and synthetic reactions.3 So

water has a tremendous demand as a solvent or additive to carry out organic reactions.

The reactions in aqueous medium are mainly divided into two categories namely

„in‒water‟ and „on‒water‟ reactions. In both of these cases, the reactions are classified

according to the solubility of the reactants and products. In the case of „in‒water‟ reactions

both the substrates are soluble in water but the product is insoluble on the same medium

whereas for „on‒water‟ reactions the substrates and the products are completely insoluble in

water. After reaction, the water is free from organic materials in both of these cases. This is

sometimes called „ideal green reactions‟.4 In general water is considered as „„green solvent‟‟

for organic reactions; though, chemical reactions performed „in‒ or on‒water‟ are not

generally considered as greener reactions and often do not satisfy the requirements of ideal

green processes.3

III.A.2. Water Effects on Organic Reactions

III.A.2.1. Breslow Hydrophobic Effect

42

The Breslow hydrophobic effect is observed in „in‒water‟ reactions. Small covalent

organic molecules repel water molecules. When present in water, they are forced to form

aggregates in order to decrease the organic surface area exposed to water.5 The hydrophobic

effect has a major influence on the stereochemical outcome of reactions. The

Hydrogen‒Bonding effect and the polarity effect have also been shown in this case.4

III.A.2.2. Marcus trans‒phase H‒bonding

In 2007 Marcus and Jung proposed that the key to understanding the on‒water

phenomenon was the unique chemistry that occurs at the water‒oil phase boundary.6 At large

hydrophobic surfaces about 1 in 4 of the water molecules in the final layer has an OH free

group directed at the boundary in contrast to small hydrophobic aggregates, which can be

fully enclosed by hydration water clusters with lateral H‒bonds along the boundary (Figure

III.A.1).4

Figure III.A.1. (a) Hydrated small hydrophobic aggregates and (b) hydrated large hydrophobic

aggregates

III.A.3. Some examples of ‘on‒water’ organic reactions

Sharpless et al. defined „on‒water‟ conditions using water as solvent for the reaction of

water insoluble reactants. His group reported a very affectionate example of the acceleration

of the reaction rate on water with cycloaddition reaction of quadricyclane and dimethyl

azodicarboxylate (Scheme III.A.1). The time for completion of the reaction was measured for

a wide variety of solvents and it was found that the water required only 10 min.7

43

N

NCOOMe

MeOOC

+'On-water'

N

N COOMe

COOMe

10 min, 82%

Scheme III.A.1. Demonstrative example of “on‒water”cycloaddition of quadricyclane with

azodicarboxylate

Another impressive result on cycloaddition rate acceleration was reported by the group of

Engberts in their study of the Diels–Alder reaction of cyclopentadiene and

3‒aryl‒1‒(2‒pyridyl) 2‒propen‒1‒ones.8

They showed that the reaction carried out in water

as solvent was 287‒times faster than the same reaction in acetonitrile. In addition, they found

that the reaction in water, combined with the use of Lewis acid and micellar catalysis, was

accelerated by a factor of 1 800 000 compared to the reaction in acetonitrile.

It was found that the cycloaddition of trans,trans‒2,4‒hexadienyl acetate and

N‒propylmaleimide in water medium showed considerable rate acceleration as compared to

other organic solvents (Scheme III.A.2).9

OO N

O

O

'On-water'

8 h, 81%

N

O

OAcO

H

H

Other organic solvents requires more time than water

Scheme III.A.2. Rate acceleration of cycloaddition reaction in presence of water

Carbon–carbon bond formation reactions are fundamental in organic chemistry and a large

number of catalysts have been used for the C–C coupling reactions (Scheme III.A.3).10

The

direct C–C coupling of indole with 1,4‒benzoquinones has been widely studied. This

coupling reaction is generally catalyzed by Brønsted (HCl, H2SO4 and CH3CO2H),11

and

Lewis acids [InBr3 and Bi(OTf)3],12

in organic solvents.

Under the on‒water catalyst‒free (OWCF) C–C coupling reactions of indole with

1,4‒benzoquinones has also been reported by C. J. Li et al. A tremendous increase in rates of

reaction was found to efficiently give a range of bis(indolyl)‒1,4‒quinones in good yields

(Scheme III.A.3).13

On‒water nucleophilic substitution reaction of 2,3‒dichloro‒1,4‒naphthoquinone with

aniline was effectively done at 50 oC to give the corresponding product in quantitative yield.

44

The reaction was compared with the other solvents like benzene, MeOH or EtOH and it was

found that water is more efficient compared to other conditions (Scheme III.A.3).14

The increase of rate and selectivity of these on‒water reactions obtained via the interaction

of nonpolar or hydrophobic regions of reactants (Scheme III.A.3).15

The Wittig reaction is one of the important tools to generate the olefinic double bonds. M.

Bergdahl and his groups reported Wittig reaction by various aromatic aldehydes and

stabilized ylides in water and other solvents (Scheme III.A.3).16

In this case water was found

to be the most efficient medium in terms of yield and stereoselectivity of products compared

to other polar or non‒polar medium. Tiwari and Kumar reported the on‒water Wittig reaction

of insoluble aromatic and aliphatic aldehydes with phosphorus ylides at 25 oC (Scheme

III.A.3).17

They found that alkali metal salts (LiCl and NaCl) decreased the rate of reaction.

Chakraborti and co‒workers reported the on‒water synthesis of 2‒aryl/heteroaryl/styryl

benzothiazoles and 2‒alkyl/aryl alkyl benzothiazolines. A variety of aldehydes such as alkyl,

aryl, and heteroaryl reacted with 2‒amino thiophenol under on‒water conditions to give the

condensation products. The reaction was found to be chemoselective without giving

thia‒Michael addition product (Scheme III.A.3).18

R3

R4

R2

R1

Cl

Cl

O

O

R3

R4

R2

R1

Cl

Cl

O

OCl

Cl

O

O

NH2HN

Cl

O

O

H2O, 50 oC

CHO

R1Ph3P COR2

water

COR2

R1

R1 = H, 4-NO2, 4-Br;

R2 = Ph, -Me, -OMe

R1 CHO

SH

NH2

R2

N

SR1

Few examples of On-water reactions

Water, RT

Wittig Reaction

Substitution

Condensation

Catalyst-free C-C coupling reactions

Scheme III.A.3. Various examples of of on‒water organic reactions

45

III.A.4. Metal–catalyzed Sp2 C–H bond activation and catalytic cross–coupling reactions

After catalytic successes for C–H bond transformations in water involving the palladium

and ruthenium catalysts and with the help of a carboxylate partner, water is found to be

beneficial for the direct catalytic arylation with (hetero)aryl halides of functional arene and

ortho C–H bonds with pyridine, pyrazole, oxazoline etc. In most of the cases the C–H bond

activation and the deprotonation are compatible with water. However, water is a poor solvent

for organic molecules and most of the catalytic cross–coupling reactions of C–H bonds in

water are consistent with „on‒water‟ reactions. In those cases, the catalyst is soluble in water

or the surfactants modify the reaction.5,19

Some recent examples of metal catalyzed sp2 C–H

bond activation followed by C–C bond formation in aqueous medium are illustrated below

(Scheme III.A.4).20

Microwave assisted „on‒water‟ ligand‒free palladium‒catalyzed

Suzuki‒Miyaura coupling reaction has been reported by Leadbeater et al. Chloro‒, bromo‒

and iodo‒ arenes are well participated in this reaction.21

R

R R

C-C homocoupling

N

SPh

H

H

Ar-IPd-Cat., Ag(I)

Water, 60 oC

N

SPh

Ar

H

Pd-Cat., K2CO3, H2O

N

sp2 C–H bond activation in water and

catalytic C-C crosscoupling reactions

+ArX, Het-X

Ru-cat., K2CO3,

H20, 80 oC

N

Het/Ar

Selective monoarylation of arenes

F

F

F

F

F

Ar-I

F

F

F

F

F

Ar

Arylation of C-H bonds of electron-poor fluorinated arenes in water

Pd-Cat., Ag(I)

K2CO3, H20

NH

O

R2

R1

R4R3

N

O

R3

R4

R1

R2

Ru-and Cu-Cat.

t-AmOH, H2O

+

+

C-C coupling of heterocycles

and aryl halides

Annulation

Pd, Ru or Fe cat.

X

B(OH)2R

+

R

Suzuki reaction

2

X= Cl, Br & I

Scheme III.A.4. Some examples of metal–catalyzed Sp2 C–H bond activation and catalytic cross–

coupling reactions

III.A.5. Disadvantages of water in organic reactions

The main drawback of organic reactions performed in water is the solubility of organic

reactants. Organic reactants generally give immiscible or biphasic mixture with water. The

problem may overcome by using phase transfer catalyst, co‒solvents and heating the reaction

46

mixture. When heating the reaction mixture, some of the reactants and products can

decompose in aqueous reaction mixture. Formation of unwanted side products is also a major

drawback of the utilization of water in organic synthesis. However, some greener approaches

have been developed and solved by designing protocols based on the use of microwaves,

ultrasound or pressure reactors and using other benign co‒solvents.

III.A.6. References

References are given in BIBLIOGRAPHY under Chapter III, Section A (pp. 145−146).

47

CHAPTER III

SECTION B

„On‒water‟ Suzuki‒Miyaura reaction at

ambient condition using aryl trihydroxy borate

salt as an alternative boron partner

48

III.B.1. Introduction

The seminal paper of Miyaura, Yamada and Suzuki,1 built the foundation of one of the

most important and useful methods for the construction of carbon–carbon bonds, in particular

for the formation of biaryls. In spite of the other approaches (e.g. Kharash coupling,2

Negishi

coupling,3 Stille coupling,

4 Hiyama coupling,

5 and Kumuda coupling

6) for C–C bond

formation, Suzuki–Miyaura (SM) coupling reaction has received much more popularity due

to stability, functional group tolerance, commercial accessibility and also ease of handling the

organoboron species. During last few decades the Suzuki–Miyaura coupling has found

widespread applications in academic laboratories, fine chemical industries, pharmaceutical,

natural product synthesis,7 and in materials sciences.

8

For example, Losartan, an antihypertensive drug or CI–1034, a potent endothelian receptor

antagonist have been synthesized in large scale. The key step in the synthesis of the Losertan

was a Pd‒catalyzed Suzuki‒Miyaura cross–coupling reaction.9

N

N

NN

N

Tr

n-Bu

Cl

HOH2C

Trityl losertan: Angiotensin II receptor antagonist

Figure III.B.1. The chemical structure of trityl losertan

Similarly, benzimidazole derivatives bearing substituted biphenyls, a potential inhibitors

of hepatitis C virus, have been prepared using the SM coupling reaction.10

Stereoselctive

synthesis of axially chiral natural products, (‒)‒Steganone has been synthesized by K.

Kamikawa and his group. (‒)‒Steganone is an antileukemic bisbenzocyclooctadiene lignin

lactone.11

Similarly a CB1 antagonist for the treatment of obesity has also been prepared by

SM coupling reaction12

Nicolaou et al. have prepared an anti‒HIV alkaloid natural product,

Michellamine B by SM coupling reaction.13

49

O

O

O

O

OMe

MeO

MeO

(-)-Steganone

N

N

N

N

N

Cl

Cl

Me

NH

O

NH2

Me

CE-178, 253

NN

Me

ONH

N

Cl

Cl

Cl

SR141716A, (Rimonabant)

N

NO

HOOC

Anti-Hepatitis C Virus drug

NH

HN

Me

Me

Me OH

OH

OH Me

MeOHOMe

Me

HO

OH Me

Michellamine B alkaloid natural product: anti-HIV activity

Important biphenyl scaffolds

Figure III.B.2. Structures of some drugs and pharmaceuticals containing biphenyl moiety

Xenbucin, a non‒steroidal antihypercholesterolemic, analgesic drugs and Flurbiprofen 1, a

nonsteroidal antiinflammatory and analgesic drug have also been developed.14

OXenbucin

non-steroidal antihypercholesterolem-ic and analgesic drug

F

Me

O

OH

Flurbiprofen 1

nonsteroidal antiinflammatory and analgesicdrug

Figure III.B.3. Structures of some analgesic drugs synthesized by SM coupling reaction

Biaryls precursors have attracted considerable attention in materials science. For example,

fluorinated biphenyl derivatives are fundamental building blocks for synthesis of fluorinated

liquid crystals, which are generally used in thin‒film transistor displays.15

Highly

50

photosensitive organic phototransistors used as light‒emitting diodes also contain biphenyl

moieties (Figure III.B.4).16

S

S

Bithiophene oligimer, Organic phototransistor

RFn

Fluorinated biphenyl: used as TFT-LCDs

Figure III.B.4. Biphenyls used in materials science

III.B.2. Background and Objectives

In recent years, improvement of the SM coupling reaction has been directed towards the

more efficient, economic and greener techniques, especially with reference to the Pd‒catalyst,

requirement of base and carrying out the reaction without any solvent or in water.17

Pd

complexes with various phosphorus ligands are invariably used as the catalyst for this

reaction. The recent trends in organic synthesis involve reactions in solvent‒free conditions

or in water (readily available non toxic solvent as reaction medium) to obtain the target

molecule in cleaner and environmentally benign way.18

Some methodologies for SM coupling reaction using water as reaction medium and phenyl

boronic acids as one of the coupling partner have been developed. A few examples are

illustrated here. The SM coupling reaction in aqueous microdroplets with catalytically active

fluorous interfaces has been developed by T.S. Huck et al. They have used the microfluidic

techniques and novel fluorous‒tagged Pd‒catalyst for SM coupling reaction. The generation

of the droplet reactors with catalytically active walls was effective for small molecules

synthesis. K2CO3 was used a base in this reaction (Scheme III.B.1).19

Br (HO)2B+K2CO3, H2O

Novel fluorous-tagged-Pd-cat.

R R

R = 4-OH, 4-COOH, 3-COOH

Scheme III.B.1. SM coupling reaction in aqueous microdroplets with catalytically active fluoruos

interfaces

Ligand‒free palladium acetate‒catalyzed SM coupling in water under microwave

irradiation has been developed by N. E. Leadbeater et al. 60 W of microwave irradiation was

used and the temperature ramped to 150 oC. Chloro, bromo and iodo arenes were participated

51

in this reaction. Na2CO3 was used as base and TBAB as phase transfer catalyst (Scheme

III.B.2).20

Br (HO)2B+

R R

R = H, 4-NO2, 4-COMe, 4-CH3, 2-CH3, 4-OMe, 3-OMe, 2-OMe, 4-NH2, 4-CHO, 4-OH,

4-COOH, 4-COOMe

R1 = 2-Me, 4-COOH

R1

Pd(OAc)2

Na2CO3, H2O

W = 60 WR1

Scheme III.B.2. Ligand‒free palladium‒catalyzed SM coupling reaction using Microwave heating in

water

P. L. Diaconescu and his coworkers have found that poly aniline (PANI) was able to

reduce and stabilize the palladium nanoparticles. This semi‒heterogeneous catalyst was

effective for chloro and fluoro arenes for undergoing the SM coupling reaction (Scheme

III.B.3).21

Cl (HO)2B+NaOH, H2O

80-100 oC, 2-6 h

5 mol% Pd/PANI

R R

R = 4-OH, 4-COOH, 4-OEt, 4-OMe, 2-OMe

F (HO)2B+F

1 eqv. 1 eqv.

1 eqv. 2 eqv.

NaOH, H2O

100 oC, 24 h

0.1 mol% Pd/PANI

Scheme III.B.3. Polyaniline (PANI) supported palladium nanoparticles as semi‒heterogeneous

catalyst for SM coupling reactions

Similarly phosphine‒free palladium‒catalyzed Suzuki‒Miyaura coupling reaction was

developed by Y. Wang and his group.22

Although many organic reactions are facilitated in

aqueous media, some reactions proceed very slowly because of poor solubility of the

substrate/reagents in water. Efforts have been made to overcome the problems by introducing

phase transfer catalysts.23

An efficient biphasic SM coupling reactions catalyzed by Pd‒complexes with water

soluble phosphine ligands and detergents as phase transfer agents have been well

documented. G. Oehme and his group developed a new method using CTAB as phase

transfer reagents water soluble palladium complex. The biphasic medium was the mixture of

toluene/ethanol/water in 1:1:1 ratio.23d

52

A convenient method for the SM coupling reaction was developed by B. H. Lipshutz et al.

using nonionic amphiphiles as phase transfer catalysts (Scheme III.B.4).23e

O

OO

OH

O

O

nm

PTS: m = 4 and n = 14- 15TPGS: m =1 and n = 23-24

OO

H

10

TritonR X-100

XR

Pd-Cat. 0.02 mmol, Et3N, amphiphile solun.= 2 mL

RB(OH)2

ArSO3RF

Pd-Cat. 0.01 mmol, Et3N, amphiphile solun.= 2 mL

Ar

Scheme III.B.4. Nonoionic amphiphiles mediated SM coupling in water

A heterogeneous Pd/C mediated biaryl formation from SM coupling reaction has been

carried out by phase transfer catalysts. CTAB, a surfactant was used in this protocol. Steric

hindrance was not the major factor for the formation of o‒substituted biphenyls. In these

cases the reactions were performed at 60 oC for 24 hours. Maximum conversion of activated

aryl chlorides were achieved at 100 oC (Scheme III.B.5).

24

B(OH)2 XR1

R H2O/CTAB

Pd/C, K2CO3

R

R1+

X = I, Br and Cl

CTAB = Cetyltrimethyl ammonium bromide

Scheme III.B.5. A mild and efficient method for the synthesis of biaryls in water and surfactants

In the case of SM couplings, hydrophobic aryl boronic acids often show very slow and/or

incomplete conversions along with the difficulty to isolate the products from the reaction

mixture.19‒22

In order to overcome such drawbacks, potassium aryltrifluoroborates being

endowed for its easy preparation and it can be stored and handled easily than arylboronic

acids or esters.25

G. A. Molander et al. reported the SM coupling reaction using alkyl trifluoroborates and

aryl or heteroaryl chlorides, which are less expensive than aryl bromides and aryl iodides.

This method was found to be amenable to coupling with aryl bromides, iodides and triflates

as well (Scheme III.B.6).26

53

BF3K

N

Cl Ror

Pd(OAc)2 (10 mol%)ligands (20 mol%)

K2CO3, 10:1 toluene/H2O

N

R

R1

or

+ Cl

R1

i-Pr-O O-i-Pr

PCy2

RuPhos

Ligand

R = 2-OMe, 4-Me, 2,6-dimethyl, 4-COCH3, 4-NO2, 4-CF3, 4-CN, 4-CHO, 3,5-dimethoxy

R1 = 2-OMe, 2-F, 4-CHO

Scheme III.B.6. Pd(OAc)2‒catalyzed SM reaction between alkyl trifluoroborates and aryl halides

Ligand‒free water mediated palladium charcoal‒catalyzed SM coupling reaction of

tetraarylborates with aryl bromides was developed by Y. Xu et al. The reactions were

performed with the aryl bromo carboxylic acids. Pd/C (5 mol%) used as palladium source

and Na2CO3 as base. This mild and environmental friendly reaction was suitable for the

preparation of various biaryl carboxylic acids (Scheme III.B.7).27

Br

HOOC

R

+5 mol% Pd/C

NaOH or Na2CO3

H2O

HOOC

RPh4BNa

R = -Cl, -F, -OMe, -OH

Scheme III.B.7. Pd/C‒catalyzed cross‒coupling of various aryl bromides with sodium

tetraphenylborate

Moreover, Cammidge et al. reported a different approach to the use of organoboron

species in SM coupling reactions whereby aryl trihydroxyborate salts have been prepared,

isolated and employed in Pd–catalyzed coupling with aryl bromides in refluxing toluene for

24 h without the need for additional base. Subsequently, phenyltrihydroxyborate has also

been used in the SM coupling with bromostilbene (vinyl bromide) in presence of KOH. In

quest of greener approaches the aryl trihydroxy borate salts attract much attention than aryl

boronic acids (Scheme III.B.8).28

Br

R1. Mg

2. B(OMe)3

3. Normal workup

B(OH)2

RNaOH

B(OH)3Na

RToluene

Ar Br

PdCl2(dppf)Biaryls

Aryl trihydroxy borate salt

R = 2-Me, 3-Me, 4-Me, 2-OMe, 3-OMe, 4-OMe, 4-Me3C, 4-C6H13

Scheme III.B.8. Synthesis of aryl trihydroxy borate salts for the Suzuki‒Miyaura coupling reaction

54

In connection with our interest in the development of the SM coupling reaction, we

investigated the coupling reaction of a wide range of aryl halides (I, Br, Cl) including

heteroaryl halides with different sodium aryltrihydroxyborates.

III.B.3. Present work: Results and Discussion

Here we describe our investigations, which practically constitute an efficient, mild,

ligand‒ and base‒free protocol for the SM coupling reactions in water at ambient temperature

by using aryl trihydroxyborate salt as an alternating bornating agent (Scheme III.B.9). We

further extended our work to construct a protocol for the synthesis of pharmaceutically

important analogues and efficient use of heterogeneous polymer–supported Pd catalyst

covering the essential aspects of green chemistry.

G

X B(OH)3

Na

+

R1 GR1R2 R2

G = C, N, S (Thiophene when G = S)

R1 = Me, OMe, Br, F, NO2, COMe, NH2, OH

X = I, Br, Cl

R2 = H, Me, OMe

Pd catalyst (0.5 mol%)

TBAB / H2O at RT

Pd Catalyst = Pd(OAc)2 or ARF-Pd

(62 - 97%)

Scheme III.B.9. Pd(OAc)2‒catalyzed SM reaction in the presence of aryl trihydroxy borate salts

and aryl halides

Primarily, the SM coupling reaction was optimized by a model reaction between 3–

iodoanisole and phenyl trihydroxyboarte with the aid of 0.5 mol% Pd(OAc)2 (Table

III.B.1). The phenyltrihydroxyborate salt was prepared according to the reported

procedure,28

and used directly without further purification. Although the reaction was not

successful in toluene at 100 oC (Table III.B.1, entry 1) but it worked well in DMF at room

temperature to afford the desired product in 96% yield. (Table III.B.1, entry 2). Similar

reactions were performed in dioxane or acetone–water and it worked efficiently within

8–24 h under similar conditions (Table III.B.1, entries 3 and 4). Due to poor solubilty of

the aryl iodide in water, the reaction did not give excellent formation of biphenyl

derivative (38% yield). To overcome this limitation, the use of n‒tetrabutylammonium

bromide (TBAB) in equimolar amount can lead to the formation of the desired product

within 4 h at room temperaure in 92% yield. It was revealed that both polar protic or

aprotic solvents were good enough to effect the SM coupling without requiring any bases

and high temperature. Hence, the optimized reaction condition utilized 0.5 mol % of

55

Pd(OAc)2 and 1 equiv. of TBAB in water at room temperature.

Table III.B.1. Optimization of Reaction Conditions of SM Coupling reaction.

I

MeO

B(OH)3

Na MeO

+Pd(OAc)2 (0.5 mol%)

Solvent / Temp.

1 2 3a

Entry Solvent Temperature (oC) Time (h) Yield

a (%)

1 Toluene 100 8 00

2 DMF RT 4 96

3 Dioxane RT 24 45

4 Acetone:water

(1:1)

RT 8 93

5 Water RT 4 38

6 Waterb RT 4 91

7 Waterc RT 8 50

a Isolated yields after purification by column chromatography on silica.

b 1 equiv. of TBAB was added.

c 0.5 equiv. of TBAB was added.

All reactions were carried out using 0.5 mol% Pd(OAc)2.

After achieving the optimal conditions, the scope and limitations of both substrates and

aryl trihydroxy borate salts were examined. Initially, we applied these reaction conditions

to the coupling of various functionalized aryl iodides with sodium salt of phenyl

trihydroxyborate in water (Table III.B.2, 3a‒3g). Aryl iodides bearing different

substituent such as OMe, Me, NH2, F, I, etc. at different positions underwent smooth SM

coupling affording coresponding biphenyls in 41–97% yields. The other aryl

trihydroxyborate salts were effective as phenyl trihydroxy borate salt and they underwent

the smooth coupling with aryl iodides (Table III.B.2, 3h‒3l). The reaction of 2–iodo

thiophene with p–methoxy boronates (Table III.B.2, 3k) efficiently proceeded to give

resulting biphenyl in 92% yield under optimized conditions.

Table III.B.2. Suzuki‒Miyaura coupling reactions of aryl iodides with sodium

aryltrihydroxyborates in water.a,b

3a-3l

G

I B(OH)3

Na

+

R1 R1R2 R2

G = C, N, S (Thiophene when G = S)

R1 = Me, OMe, F, NH2, I

R2 = H, Me, OMe

Pd(OAc)2 (0.5 mol%)

TBAB / H2O at RT

1 2

56

3h8 h, 79%

3i8 h, 86%

3j3.5 h, 74%

3l7 h, 97%

3a4h, 92%

3b4 h, 86%

3c2.5 h, 84%

3d4 h, 81%

3f5 h, 41%

MeO

MeO

OMe

Me

3e4 h, 94%

F

3g6 h, 81%

NH2

MeO Me

Me Me

MeMeO

Me OMeS

OMe

3k3 h, 92%

aAryl iodides and arylboronic acid salt used in 1:1.1 molar ratios.

bIsolated yields after purification by column chromatography on silica.

Mechanistically, the oxidative addition of palladium to the C–halogen bond depends on

the nature of halogens and occurs in the descending order of I>Br>Cl. We therefore

examined the couplings of aryl bromides. Several aryl bromides including di–and

tribromoarenes and heteroaryl bromides were found to give the corresponding unsymmetrical

biaryls in good to excellent yields (Table III.B.3, 3m and 3o and 3p). While

p‒bromoacetophenone showed faster rate (2 h) of reaction possibly due to the presence of

electron withdrawing group (3n) and 2,4,6‒trihydroxyphenol required long time (24 h) for

the coupling reaction, which may be attributed to steric and multi‒couplings factors (3q).

Thus, aryl bromides like iodides underwent easy coupling with phenyl trihydroxyborate.

Table III.B.3. Suzuki‒Miyaura coupling reactions of aryl bromides with sodium

aryltrihydroxyborates in water.a,b

G

Br B(OH)3

Na

+

R1 R1R2 R2

G = C, N

R1 = Me, OMe, COMe, OH, Br

R2 = H, Me

Pd(OAc)2 (0.5 mol%)

TBAB / H2O at RT

3m-3t4 2

57

3m8 h, 72%

Me

MeOO

3n2 h, 95%

3o4 h, 66%(with 22% mono product)

3p6 h, 67%

OH

3q24 h, 82%

3r3.5 h, 74%

MeO Me

N

Me

3s3.5 h, 66%

N

3t8 h, 83%

aAryl bromides and arylboronic acid salt used in 1:1.1 molar ratios.

bIsolated yields after purification by column chromatography on silica.

Similar reaction with aryl chloride did not occur at all at room temperature. Leadbeater

et al reported the microwave–assisted SM coupling of aryl chlorides at 150–175 oC in

aqueous medium. Thus, aryl chlorides are very sluggish towards coupling reaction and

needed relatively higher temperature, longer reaction time and/or the presence of

activating group.29

We therefore performed these reactions at 100 oC. It was found that,

reactions with activated aryl chlorides successfully gave the desired products in excellent

yields (Table III.B.4, 3n and 3u) while the unactivated aryl chlorides remained unchanged

even after 24 h under refluxing conditions (Table III.B.4, 3v and 3w).

Table III.B.4. Suzuki‒Miyaura coupling reactions of aryl chlorides with sodium

aryltrihydroxyborates in water.a,b

3n, 3u-3w

Cl B(OH)3

Na

+

R1 = NO2, COMe, OH, NH2

Pd(OAc)2 (0.5 mol%)

TBAB / H2O at RT

5 2

R1 R1

3v

100 oC, 24h, Not formed

HO

3w

100 oC, 24h, Not formed

H2N

3u

100 oC, 5 h, 96%

O2N3n

100 oC, 4 h, 85%

aAryl chlorides and arylboronic acid salt used in 1 : 1.1 molar ratios.

bIsolated yields after purification by column chromatography on silica.

58

With the success to establish the use of aryl trihydroxyborate salts as an alternative to

aryl boronic acid or ester and to carry out the reaction in water under ambient conditions,

we extended our study to conduct similar reactions using a polymer‒supported

heterogeneous Pd‒catalyst. Since the reactions on heterogeneous surface is one of the

essential condition for Green chemistry. Recently, we developed a new Pd‒catalyst

immobilized onto ion‒exchange resins, designated as ARF‒Pd and was successfully used

in Heck, Suzuki‒Miyaura and Sonogashira coupling reactions.30

The trihydroxyborate salt

was found to be equally active towards SM‒copling reactions in presence of catalytic

amount of ARF‒Pd. These results are given in the table below (Table III.B.5, entries

1‒5).

Table III.B.5. SM coupling reactions with aryl trihydroxyborates in water using

heterogeneous Pd‒catalyst (ARF–Pd).a,b

Entry Aryl halides Aryl trihydroxy

borate

Temp.

(oC)

Time

(h)

Product Yield

(%)

1 MeO I

PhB(OH)3Na

RT 5 PhMeO

78

2

MeO I

PhB(OH)3Na

RT 5

MeO Ph

81

3 Br

O

Me

PhB(OH)3Na

100 4 Ph

O

Me

89

4 Me I

PhB(OH)3Na

100 3 Me Ph

93

5

MeO I

Me B(OH)3Na

100 5

MeO Me

72

a300 mg ARF‒Pd (0.94 mol% Pd) was used.

b Isolated yields after purification by column chromatography on silica.

As stated above, water soluble sodium salts aryltrihydroxyborates have proven highly

effective in SM coupling reactions in water at ambient temperatures. Having established a

general mild protocol for SM coupling reactions using aryltrihydroxyborate salts in water,

we probed the utility of this protocol in a modular synthesis of some phamaceutically

important benzimidazole– and benzotriazole–based biphenyls.9 At first we prepared 6a

and 6b compounds according to the following Scheme III.B.10. Initially 4‒iodo toluene

was reacted with NBS in CCl4 medium in the presence of light and a radical intiator,

59

benzoyl peroxide. 4‒iodo benzyl bromide was obtained from this reaction. Afterthat the

benzimidazole and benzotriazole were reacted with 4‒iodo benzyl bromide separately

under refluxing condition in acetonitrile solvent with the aid of potassium hydroxide

(KOH) yielded compounds 6a and 6b to near‒quantitative yield.

I CH3

NBS

Benzoyl peroxideCCl4

I

Br

NH

N

NH

NN

KOH, MeCN, reflux

N

N

I

NN

N

I

6a

6b

Scheme III.B.10. Synthesis of 6a and 6b

Thus, compounds 7 and 8 were synthesized from compounds 6a and 6b respectively,

where the SM couplings were effciently performed using sodium phenyltrihydroxyborate

in a mixture of DMF‒H2O (2:1, v/v). These compounds were characterized by 1H‒NMR,

13C‒ NMR spectroscopic techniques and by HRMS data.

6a, G = CH6b, G = N

7 8

N

N

NG

N

I

NN

N

Scheme III.B.11. Synthesis of benzimidazole– and benzotriazole–based biphenyl scafolds

III.B.4. Conclusion

In summary, we have shown that the the sodium aryltrihydroxyborate salts can be used

as an alternative coupling partner instead of less stable boron compounds in SM coupling

reaction in water at ambient condition in presence of TBAB or in a mixture of an organic

solvent–water. The significant improvement of the existing Suzuki–Miyaura cross–

coupling has been seen throughout the reaction. A large varieties of aryl halides were

used without any disturbance.

60

III.B.5. Experimental section

III.B.5.1. General information

All the reactions were carried out in open vessel under aerobic conditions. All aryl boronic

acids and aryl iodides were purchased from Sigma‒Aldrich, India. Aryl bromides and

chlorides were purchased from SRL, India. For column chromatography: silica (60‒120

mesh) (SRL, India), and for tlc, Merck plates coated with silica gel 60, F254 were used.

Melting point of the solid compounds was determined in concentrated H2SO4 bath. FT‒IR

spectra were recorded with a FT‒IR‒8300 SHIMADZU spectrophotometer using a KBr

pellet method for solid compounds and in neat for liquid compounds. NMR spectra of almost

all biaryls were recorded in CDCl3 on Bruker AV 300 spectrometer using TMS as the internal

standard. HRMS data were obtained in Micromass Q‒TOF micro Mass Spectrometer under

ESI (positive mode).

III.B.5.2. General procedure for the preparation of aryl trihydroxyboronate salts from

boronic acids

Arylboronic acids were dissolved in a minimum amount of warm toluene with stirring and

the solution was allowed cool to room temperature. Once saturated, aqueous sodium

hydroxide solution was added dropwise until no further precipitate formed. The mixture was

allowed to stir for 30 minutes and the colourless precipitate was filtered off and washed

several times with toluene to give the corresponding salt.

III.B.5.3. General procedure for Suzuki‒Miyaura coupling reactions

A mixture of aryl iodides/bromides/chlorides (2 mmol), sodium aryltrihydroxyborate (2.2

mmol), Pd(OAc)2 (0.5 mol%) and TBAB (2 mmol, 1 equiv) was taken in distilled water (5

mL). The mixture was stirred by magnetic bar at room temperature for several hours (see

Table III.B.2, Table III.B.3 and Table III.B.4). After the reaction was completed (monitored

by tlc), the mixture was extracted with diethyl ether (3 × 20 mL). The combined organic layer

was then washed with brine (10 mL), dried (anhydrous Na2SO4), and evaporated. The residue

was purified on a short column of silica using light petroleum as the eluent to afford the

desired unsymmetrical biphenyl as liquid or solid. For the cases of di‒iodo, di‒bromo and

tribromo compounds, two and three equivalents of sodium aryltrihydroxyborate salts were

used respectively.

III.B.5.4. Representative procedures for the synthesis of 7 and 8

61

A mixture of 1‒(4‒iodobenzyl)‒1H‒benzo[d]imidazole 6a (334 mg, 1 mmol) or

1‒(4‒iodobenzyl)‒1H‒benzo[d][1,2,3]triazole 6b (335 mg, 1 mmol), sodium salt of

phenyltrihydroxyborate (177 mg, 1.1 mmol), Pd(OAc)2 (1.1 mg, 0.5 mol%) or ARF–Pd (300

mg, 0.94 mol% of Pd) and TBAB (322 mg, 1 mmol) was taken in a DMF–water mixture (2: 1

(v/v), 3 mL). The reaction mixture was heated at 100 oC for 24 h. After completion of the

reaction in both cases (monitored by tlc), the mixture was diluted with water and extracted

with ethyl acetate (2×20 mL). The combined organic layer was then washed with brine (NaCl

solution, 10 mL), poured over anhydrous Na2SO4 and evaporated. Finally the residue was

purified over a short column of silica with 1: 9 (EA:light petroleum) eluent afforded

N‒(4‒phenyl benzyl) benzimidazole 7 (236 mg, 83%); m.p. 163 oC or N‒(4‒phenyl benzyl)

benzotriazole 8 (227 mg, 80%); m.p. 180 oC.

III.B.5.5. Physical properties and Spectral data of compounds

Table III.B.2, 3a

3‒Methoxy biphenyl31

3aMeO

Colourless liquid

IR (Neat): νmax = 3031 (=C‒H aromatic str.), 3001, 2939, 2835 (C‒H str. in CH3 of OCH3),

1610 (C=C str.), 1574, 1481, 1037 cm‒1

.

1H NMR (CDCl3, 300 MHz): δ/ppm 3.75 (s, 3H, ‒OCH3), 6.77‒6.81 (m, 1H), 7.03‒7.10 (m,

2H, ArH), 7.21‒7.36 (m, 4H, ArH), 7.47‒7.51 (m, 2H, ArH).

13C NMR (CDCl3, 75 MHz): δ/ppm 55.2 (‒OCH3), 112.6, 112.8, 119.6, 127.1, 127.4, 128.7,

129.7, 141.0, 142.7, 159.9.

Table III.B.2, 3b

4‒Methoxy biphenyl32

3b

MeO

62

White solid, mp 88‒90 oC (Lit.

32 91‒92

oC)

IR (KBr): νmax = 2923 (=C‒H str.), 2854 (C‒H str. in CH3 of OCH3), 1608 (C=C str.), 1519,

1458, 1034 (C‒O‒C sym. str.) cm‒1

.

1H NMR (CDCl3, 300 MHz): δ/ppm 3.83 (s, 3H, ‒OCH3), 6.96 (d, J = 8.7 Hz, 2H, ArH),

7.22‒7.55 (m, 7H, ArH).

13C NMR (CDCl3, 75 MHz): δ/ppm 55.3 (‒OCH3), 114.2, 126.6, 126.7, 128.2, 128.7, 133.8,

140.8, 159.2.

Table III.B.2, 3c

2‒Methoxy biphenyl33

3c

OMe

Colourless liquid

(Reported as low melting solid of Mp 29‒30 oC)

33

IR (Neat): νmax = 3028 (=C‒H str.), 2935, 2835 (C‒H str. in CH3 of OCH3), 1597 (C=C str.),

1504, 1462, 1431, 1026 (C‒O‒C sym. str.) cm‒1

.

1H NMR (CDCl3, 300 MHz): δ/ppm 3.79 (s, 3H, ‒OCH3), 6.96‒7.05 (m, 2H, ArH),

7.29‒7.42 (m, 5H, ArH), 7.51‒7.54 (m, 2H, ArH).

13C NMR (CDCl3, 75 MHz): δ/ppm 55.5 (‒OCH3), 111.2, 120.8, 126.9, 127.9, 128.6, 129.5,

130.7, 130.8, 138.5, 156.5.

Table III.B.2, 3d

4‒Methyl biphenyl33

3d

Me

White solid, mp 46‒48 oC (Lit.

33 49‒50

oC)

IR (KBr): νmax = 3030 (=C‒H str.), 2923 (C‒H str. in CH3), 2858, 1620 (C=C str.), 1525,

1485, 1458 cm‒1

.

1H NMR (CDCl3, 300 MHz): δ/ppm 2.29 (s, 3H, ‒CH3), 7.10‒7.52 (m, 9H, ArH).

63

13C NMR (CDCl3, 75 MHz): δ/ppm 21.2 (‒CH3), 126.8, 126.9, 127.1, 128.7, 129.4, 137.0,

138.3, 141.1.

Table III.B.2, 3f

1, 3‒Di phenyl benzene32

3f

White solid, mp 87‒88 oC (Lit.

22 89

oC)

IR (KBr): νmax = 3062 (=C‒H str.), 3028, 1593 (C=C str.), 1570, 1493, 1470 cm

‒1.

1H NMR (CDCl3, 300 MHz): δ/ppm 7.28‒7.62 (m, 13H, ArH), 7.78 (s, 1H, ArH).

13C NMR (CDCl3, 75 MHz): δ/ppm 126.1, 127.2, 127.3, 128.7, 129.1, 141.1, 141.7.

Table III.B.2, 3g

2‒Amino biphenyl34

3g

NH2

Pink crystalline solid, mp 48‒50 oC (Lit.

34 44‒46

oC)

IR (KBr): νmax = 3480 (assym. N‒H str. primary aromatic amine), 3390 (sym. N‒H str. for

primary aromatic amine), 3030 (=C‒H str.), 1614 (C=C str.), 1579, 1500, 1481, 1313 (C‒N

str. of primary aromatic amine), 1284 cm‒1

.

1H NMR (CDCl3, 300 MHz): δ/ppm 3.33 (br s, 2H, ‒NH2); 6.75‒6.85 (m, 2H, ArH),

7.11‒7.23 (m, 2H, ArH), 7.30‒7.36 (m, 1H, ArH), 7.40‒7.49 (m, 4H, ArH).

13C NMR (CDCl3, 75 MHz): δ/ppm 115.6, 118.6, 127.1, 127.6, 128.4, 128.8, 129.8, 130.4,

139.5, 143.4.

Table III.B.2, 3h

4‒Methoxy 3‒methyl biphenyl35

64

3h

MeO

Me

White solid, mp 55 oC (Lit.

35 48‒49

oC)

IR (KBr): νmax = 3035 (=C‒H str.), 2977, 2912 (C‒H str. in CH3), 2835 (C‒H str. in CH3 of

OCH3), 1604 (C=C str.), 1512, 1489, 1466, 1026 (C‒O‒C sym. str.) cm‒1

.

1H NMR (CDCl3, 300 MHz): δ/ppm 2.28 (s, 3H, ‒CH3), 3.86 (s, 3H, ‒OCH3), 6.87‒7.56 (m,

8H, ArH).

13C NMR (CDCl3, 75 MHz): δ/ppm 16.4 (CH3), 55.4 (OCH3), 110.2, 125.4, 126.5, 126.7,

126.9, 128.6, 129.5, 133.4, 141.1, 157.4.

Table III.B.2, 3i

3, 4/‒dimethyl biphenyl

3i

Me

Me

Colouless liquid

IR (Neat): νmax = 3023 (=C‒H str.), 2919 (C‒H str. in CH3), 1606, 1588, 1516, 1500 (C=C

str.) cm‒1

.

1H NMR (CDCl3, 300 MHz): δ/ppm 2.39 (s, 6H, ‒CH3) 7.13‒7.50 (m, 8H, ArH).

13C NMR (CDCl3, 75 MHz): δ/ppm 21.3 (CH3), 124.1, 127.0, 127.7, 127.8, 128.6, 129.4,

136.9, 138.2, 138.5, 141.1.

Table III.B.2, 3j

3‒Methoxy 3/‒methyl biphenyl

36

3jMeMeO

Colourless liquid

IR (Neat): νmax = 3028 (=C‒H str.), 2999, 2920 (C‒H str. in CH3), 2834 (C‒H str. in CH3 of

OCH3), 1593 (C=C str.), 1466, 1042 (C‒O‒C sym. str.) cm‒1

.

65

1H NMR (CDCl3, 300 MHz): δ/ppm 2.41 (s, 3H, ‒CH3), 3.86 (s, 3H, ‒OCH3), 7.11‒7.39 (m,

8H, ArH).

13C NMR (CDCl3, 75 MHz): δ/ppm 21.5 (CH3), 55.3 (‒OCH3), 112.6, 112.9, 119.7, 124.3,

128.0, 128.1, 128.6, 129.6, 138.3, 141.1, 142.9, 159.9.

Table III.B.2, 3k

2‒(4‒methoxy phenyl) thiophene37

S

OMe

3k

Pale yellow solid, mp 106 oC (Lit.

37 103‒104

oC)

IR (KBr): νmax = 3100 (=C‒H str.), 3080, 3000, 2960 (C‒H str. in CH3 of OCH3), 2820, 1606

(C=C str.), 1533, 1500, 1465, 1031 (C‒O‒C sym. str.) cm‒1

.

1H NMR (CDCl3, 300 MHz): δ/ppm 3.81 (s, 3H, ‒OCH3), 6.91 (d, J = 9 Hz, 2H, ArH),

7.03‒7.25 (m, 3H, ArH), 7.53 (d, J = 8.7 Hz, 2H, ArH).

13C NMR (CDCl3, 75 MHz): δ/ppm 55.3 (‒OCH3), 114.3, 122.1, 123.8, 127.2, 127.3, 127.9,

144.3, 159.2.

Table III.B.3, 3m

4‒Methoxy 3‒methyl biphenyl30

3mMe

MeO

White solid, mp 74‒75 oC (Lit.

30 75

oC)

IR (KBr): νmax = 3035 (=C‒H str.), 2977, 2912 (C‒H str. in CH3), 2835, (C‒H str. in CH3 of

OCH3), 1604 (C=C str.), 1512, 1489, 1466, 1026 cm‒1

(C‒O‒C sym. str.) cm‒1

.

1H NMR (CDCl3, 300 MHz): δ/ppm 2.28 (s, 3H, ‒CH3), 3.86 (s, 3H, ‒OCH3), 6.87‒7.56 (m,

8H, ArH).

13C NMR (CDCl3, 75 MHz): δ/ppm 16.4 (CH3), 55.4 (OCH3), 110.2, 125.4, 126.5, 126.7,

126.9, 128.6, 129.5, 133.4, 141.1, 157.4.

Table III.B.3, 3n

66

4‒Acetyl biphenyl32

O

3n

White solid, mp 120‒121 oC (Lit.

32 120‒121

oC)

IR (KBr): νmax = 2923 (=C‒H str.), 1681 (C=O str.), 1610 (C=C str.), 1458 cm

‒1.

1H NMR (CDCl3, 300 MHz): δ/ppm 2.63 (S, 3H, ‒COCH3), 7.40‒7.47 (m, 3H, ArH),

7.62‒7.70 (m, 4H, ArH), 8.03 (d, J = 8.4 Hz, 2H).

13C NMR (CDCl3, 75 MHz): δ/ppm 26.9 (COCH3), 127.2, 128.2, 128.9, 129.8, 131.8, 135.8,

139.8, 145.8, 197.7 (C=O).

Table III.B.3, 3o

1, 4‒Diphenyl benzene32

3o

White solid, mp. 214‒216 oC ( Lit.

32 215‒217

oC)

IR (KBr): νmax = 3035 (=C‒H str.), 2970, 2935, 1597 (C=C str.), 1574, 1477, 1454 cm

‒1.

1H NMR (CDCl3, 300 MHz): δ/ppm 7.23‒7.67 (m, 14H, ArH).

13C NMR (CDCl3, 75 MHz): δ/ppm 127.0, 127.3, 127.4, 128.8, 140.1, 140.6.

Table III.B.3, 3p

1, 2‒Diphenyl benzene38

3p

White solid, mp 56‒57 oC (Lit.

38 58

oC)

IR (KBr): νmax = 3024 (=C‒H str.), 1597 (C=C str.), 1574, 1473 cm

‒1.

1H NMR (CDCl3, 300 MHz): δ/ppm 7.10‒7.18 (m, 10H, ArH), 7.37‒7.43 (m, 4H, ArH).

13C NMR (CDCl3, 75 MHz): δ/ppm 126.4, 127.4, 127.8, 129.8, 130.6, 140.5, 141.5.

67

Table III.B.3, 3q

2, 4, 6‒tri phenyl phenol (solid)39

OH

3q

White solid, mp 139‒140 oC (Lit.

39 142‒144

oC)

IR (KBr): νmax = 3514 (free phenolic ‒OH), 3062 (=C‒H str.), 3035, 1600 (C=C str.), 1574,

1493, 1462 cm‒1

.

1H NMR (CDCl3, 300 MHz): δ/ppm 5.46 (s, 1H, ‒OH); 7.31‒7.66 (m, 17H, ArH).

13C NMR (CDCl3, 75 MHz): δ/ppm 126.7, 126.8, 127.8, 128.6, 128.8, 129.1, 129.4, 133.8,

134.2, 137.5, 140.5, 148.9.

Table III.B.3, 3s

3‒(3‒methyl phenyl) quinoline

N

Me

3s

Pale yellow viscous liquid

IR (Neat): νmax = 3030 (=C‒H str.), 2922, 1606 (C=C, C=N str.), 1580, 1492 cm

‒1.

1H NMR (CDCl3, 300 MHz): δ/ppm 1.59 (s, 3H, ‒CH3), 6.36‒6.87 (m, 6H, ArH), 7.00 (d, J =

8.1 Hz, 1H, ArH), 7.28 (d, J = 8.4 Hz, 1H, ArH), 7.43 (s, 1H, ArH), 8.3 (s, 1H, ArH).

13C NMR (CDCl3, 75 MHz): δ/ppm 21.6 (CH3), 124.5, 127.1, 128.0, 128.1, 128.2, 128.9,

129.0, 129.1, 129.4, 133.4, 134.0, 137.7, 138.9, 147.1, 149.8.

Table III.B.3, 3t

2, 6‒Di phenyl pyridine40

68

N

3t

White solid, mp 80‒81 oC (Lit.

40 80‒81

oC)

IR (KBr): νmax = 3055 (=C‒H str.), 3035, 2923, 1586 (C=C, C=N str.), 1566, 1489, 1458

cm‒1

.

1H NMR (CDCl3, 300 MHz): δ/ppm 7.39‒7.51 (m, 6H, ArH), 7.65‒7.80 (m, 3H, ArH), 8.15

(d, J = 7.5 Hz, 4H, ArH).

13C NMR (CDCl3, 75 MHz): δ/ppm 118.7, 126.9, 128.7, 128.9, 137.5, 139.4, 156.3.

Table III.B.4, 3u

4‒Nitro biphenyl20

3u

O2N

Pale yellow crystalline solid

Mp 114‒115 oC (Lit.

20 114‒115

oC)

IR (KBr): νmax = 2923

(=C‒H str.), 2854, 1597 (C=C str.), 1512 (aromatic nitro asym. str.),

1458, 1346 (aromatic nitro sym. str.) cm‒1

.

1H NMR (CDCl3, 300 MHz): δ/ppm 7.46‒7.53 (m, 3H, ArH), 7.61‒7.64 (m, 2H, ArH), 7.73

(d, J = 8.7 Hz, 2H, ArH), 8.29 (d, J = 9 Hz, 2H).

13C NMR (CDCl3, 75 MHz): δ/ppm 124.1, 127.3, 127.8, 128.9, 129.1, 138.7, 147.0, 147.6.

Entry 7

N‒(4‒phenyl benzyl) benzimidazole

7N

N

White solid, mp 163 oC

IR (KBr): νmax = 3030 (=C‒H str.), 2924, 1653 (C=N str.), 1610, 1541 (C=C str.), 1496, 1452,

1371 (C‒N str. of aromatic tertiary amine), 1354, 1330 cm‒1

.

69

1H NMR (CDCl3, 300 MHz): δ/ppm 5.41 (s, 2H, ‒CH2), 7.25‒7.83 (m, 13H, ArH), 8.07 (s, 1H,

ArH).

13C NMR (CDCl3, 75 MHz): δ/ppm 48.73 (‒CH2, aliphatic), 110.2, 120.2, 122.6, 123.3, 127.1,

127.6, 127.8, 128.8, 129.1, 133.8, 134.2, 140.3, 141.4, 143.1, 143.3.

HRMS: Calcd for C20H16N2H: [M+H]+ 285.1392; found: 285.1387.

Entry 8

N‒(4‒phenyl benzyl) benzotriazole

8N

NN

White solid, mp 180 oC

IR (KBr): νmax = 3028 (=C‒H str.), 2923, 1616 (C=C str.), 1590, 1560, 1541, 1516, 1497, 1483,

1456, 1442 cm‒1

.

1H NMR (CDCl3, 300 MHz): δ/ppm 5.88 (s, 2H, ‒CH2); 7.25‒8.09 (m, 13H, ArH).

13C NMR (CDCl3, 75 MHz): δ/ppm 51.9 (CH2 aliphatic), 109.7, 120.1, 124.0, 127.0, 127.5,

127.6, 127.7, 128.0, 128.8, 132.8, 133.6, 140.2, 141.4, 146.3.

HRMS: Calcd for C19H15N3Na: [M+Na]+ 308.1164; found: 308.1163.

III.B.6. References

References are given in BIBLIOGRAPHY under Chapter III, Section B (pp. 146−148).

70

CHAPTER III

SECTION C

In quest of “stereoselective‒switch” for

on‒water hydrothiolation of terminal alkynes

using various additives and green synthesis of

vicinal dithioethers

71

III.C.1. Introduction

Organosulfur compounds play a key role in convenient intermediates for chemical

synthesis, materials chemistry and important biological intermediates.1 1‒Alkenyl sulfides

are important synthetic intermediates in total synthesis of many naturally occurring and

biologically active compounds as well as versatile building blocks for many functionalized

molecules.2 The synthetic utility of alkenyl sulfides has been established by different research

groups.3

A few examples of the vinyl sulfides as key synthetic intermediate of many potent

compounds are shown in the Figure III.C.1 below:

N O

SOH

SOH

O

HO

OAc

O

O

O

NH

O

O

Ph

OH

NHPh

O

BzO HAcO

OS

O

VT-labeled TaxolBioorthogonal ligations using oQMS

Vinyl sulfide

Figure III.C.1. Vinyl sulfides used as synthetic intermediates

Q. Li et al developed a bioorthogonal ligation using o‒quinolinone quinone methide and

vinyl thioether.4 VT‒labeled taxol was prepared by N. Muraoka and his group smoothly.

5

Similarly, some biological molecules containing vinyl sulfide moiety have been synthesized.

The vinyl sulfide analogues of Angiotensin II with high affinity and full agonist activity at

the AT1 receptor have also been synthesized.6 The streptogramin antibiotics, Griseoviridin

also contained vinyl sulfide with nine‒membered macrocycle moiety (Figure III.C.2).7

HN

NH

HN

NH

O

O

O

O

S S

Vinyl sulfide cyclized analogous of Angiotensin II

O

NH

O

S

O

ONH

OHHO

O

Griseoviridin (the steptogramin antibiotics)

Figure III.C.2. Vinyl sulfides used as biologically active molecules

Multisubstituted olefins, which are important for materials science and pharmaceutical

chemistry and these can be synthesized by the Mizoroki‒Heck reaction of 2‒pyrimidyl vinyl

72

sulfide.8

N

NS

Ar I (1 eqiv)

Pd[P(t-Bu)3]2Et3N

toluene, 60 oC

N

NSAr

Ar1 I (1 eqiv)

90 oC

N

NSAr

Ar1

Scheme III.C.1. Substituted 2‒pyrimidyl vinyl sulfide used in materials science

III.C.2. Background and Objectives

Increasing demand for alkenyl sulfides in material science, organic and bio‒organic

chemistry has furthered the development of new synthetic methods.2e,9

The addition of thiols

to alkynes is considered as one of the straightforward methods to obtain vinyl sulphides either

catalyzed by transition metal complexes,10‒16

or base‒promoted17

and/or through free

radicals.18

This reaction is often judged as a part of “click chemistry” and a process of high

atom‒economy.19

Mechanistically, addition of thiols to alkynes is believed to occur (i) via

radical pathway producing unselective mixture of (E/Z)‒anti‒Markovnikov vinyl sulphides;

(ii) base‒mediated nucleophilic addition giving all types of adducts or (iii) transition‒metal

complex catalyzed processes yielding Markovnikov vinyl sulphides and anti‒Markovnikov

vinyl sulphides (Scheme III.C.2). Varying degrees of stereo‒ and regioselectivity selectivity

and turnover are reported in the literature.

Scheme III.C.2. 1‒Alkenyl sulphides from hydrothiolation of terminal alkynes

C6H5 HC6H5 SH

Additives [A]1a

C6H5

H

H

SC6H5H

C6H5

H

SC6H5C6H5

SC6H5

H

H+ +

2b 2cWater / Rt 2a

(Markovnikov) (Anti-Markovnikov)

(E)-isomer (Z)-isomer

Most reports in the literature described the formation of thermodynamically more stable

(E)‒vinyl sulfide in considerable excess over the (Z)‒isomer. On the other hand,

hydrothiolation, particularly of aryl and benzyl thiols and catalyzed by transition‒metal

complexes, often produces a mixture of anti‒Markovnikov (E)‒alkenyl sulfide (syn addition)

and Markovnikov adduct and thus suffers from poor regioselectivity. 1,1‒Disubstituted alkyl

vinyl sulfides were synthesized via rhodium‒catalyzed hydrothiolation reaction. The reaction

goes through predominantly via Merkovnikov addition by thiols to alkynes. J. A. Love et al

73

invented such Merkovnikov addition in the presence of 3,5‒dimethyl

pyrazolylborate‒rhodium complex (Scheme III.C.3).11a

N

N

H

N

N

N

N

RhPPh3

PPh3

Tp*Rh(PPh3)2

Tp* = 3, 5-dimethyl pyrazolylborate

SH3 mol% cat.

DCE: PhCH3 (1:1) = 4 mL

RT, 2 h

SR

R = -H, 4-NMe2, 4-OCH3, 4-CH3, 4-Br, 4-CF3, 3-OCH3, 2-OCH3,and

2-pyridyl

R+

Scheme III.C.3. Synthesis of 1,1‒Disubstituted alkyl vinyl sulfides by rhodium catalyst

Similarly diphosphino‒functionalized MCM‒41 anchored Rh‒complex

[MCM‒41‒2P‒RhCl(PPh3)] have exhibited high catalytic activity. This is an example of

heterogeneous Rh‒catalyzed hydrothiolation of alkynes with thiols.20

OSiMe3

Si(CH2)3N

OEt

PPh2

PPh2

RhCl(PPh3)3

Benzene, RT, 48 h

OSiMe3

Si(CH2)3N

OEt PPh2

PPh2

RhCl

PPh3

MCM-41-2P MCM-41-2P-RhCl(PPh3)

Scheme III.C.4. Preparation of MCM‒41‒2P‒RhCl(PPh3)

The reaction went through complete anti‒Merkovnikov fashion and (E)‒vinyl sulfides

formed as major product. The stereochemistry of the addition products were determined by

1H‒NMR spectra (Scheme III.C.5).

20

Ar SH+

3mol% MCM-41-2P-RhCl(PPh3)

EtOH, 40 oC, 24 h

H

H

SAr

R R

R = -H, 4-OCH3, 4-CH3, 4-Cl, 4-F, andn-C6H13, i-C5H11 1-cyclohexylAr = Ph, 4-CH3C6H4, 4-ClC6H4

(E)-vinyl sulfide

Scheme III.C.5. Hydrothiolation reaction in presence of heterogeneous MCM‒41‒2P‒RhCl(PPh3)

catalyst

74

Highly stereo‒ and regio‒controlled synthesis of vinyl sulfides via Pd‒catalyzed

hydrothiolation of alkynes with thiols has been effectively done by A. Ogawa and his group.

They had shown the regio‒isomer i.e. Merkovnikov product was formed exclusively in

presence of Pd(OAc)2 whereas the anti‒Merkovnikov adduct was obtained in presence of

radical initiator (Scheme III.C.6).21

R Ph SH+ RSPh

SPh

R radical initiatorPd(OAc)2

Scheme III.C.6. Stereoslective synthesis of vinyl sulfides by Pd‒catalyzed reaction

The first example of polymer‒supported palladium catalysts for stereoselective S‒S bond

addition to terminal alkynes has been established by I. Beletskaya et al. The exclusive

(Z)‒selectivity has been achieved by this methodology. Diselenides did not undergo the

reaction under this condition (Scheme III.C.7).22

R Ph S+ S PhPPh3

Pd2dba3

140 oC, 2h, tolueneArS

R

SAr

94-99% yield

Z/E> 99:1

Scheme III.C.7. Polymer‒supported palladium catalyst for stereoselective S‒S bond addition to

terminal alkynes

The Stereoselective (Z)‒vinyl sulfides can be effectively synthesized by C. M. Frech and

his group in presence of dichloro(amine phosphine) complex of palladium. Selective

formation of cis‒configured vinyl thioethers have been achieved by this methodology. The

addition followed anti‒Merkovnikov fashion. A large number of alkynes and thiols were

participated in this reaction (Scheme III.C.8).12a

75

PCy

Cy

N

PCy

Cy

N

PdCl

Cl

Pd-cat.(0.05 mol%)

NaOH, NMP, 120 oCH

S

H

R1

R1 = -H, 4-F, 4-Br and

R2 = -H, 4-OMe, 4-NH2, 2-Me, 4-

Br, 3-Br

(Z)-vinyl sulfide

SH

R1 R2

+R2

Dichlorobis[1-(dicyclohexylphosphanyl)piperidine]

palladium

Scheme III.C.8. Palladium‒catalyzed synthesis of cis‒configured vinyl thioethers

Organoactinide complexes can also use as hydrothiolation of alkynes with various thiols.

A large number of aliphatic, aromatic and benzylic thiols were participated in this

methodology. This was the first report of the use of f‒element catalysts to affect the efficient

hydrothiolation with high degree of Markovnikov selectivity (Scheme III.C.9).23

SH+

S

SH +

S

SH +

S

Aliphatic thiols and alkynes Aromatic thiols and alkynes Aliphatic thiols and aromatic alkynes

Cat. Cat. Cat.

Cat. = Me2SiCp''2Th[CH2TMS]2

Scheme III.C.9. Organoactinide‒mediated hydroyhiolation of terminal alkynes with aliphatic,

aromatic and benzylic thiols

Efficient and convenient synthesis of β‒vinyl sulfides by Ni‒catalyzed regioselective

addition of thiols to alkynes has been achieved. I. P. Beletskaya and his group developed this

methodology using Ni(acac)2 as the catalyst. 2 mol% of the catalyst was sufficient for this

conversion. Only 15 min to 3.5 h was required for complete conversion of products (Scheme

III.C.10).24

76

R SH

R1

+

R

SR1

S

R

S R

R1R1

+ +

Yield: 99% 1%

Stereoselectivity: 89% 5% 5%

Ni(acac)2, 2 mol%

40 oC, 15 min to

3.5 h

R = -C5H11, -CH2CH2OH, -C(Me2)OH, -C(Me2)OMe, -C(Me2)OCOMe, Ph

R1 = -H, 4-CH3, 4-Cl

Scheme III.C.10. Ni(acac)2‒catalyzed regioselective synthesis of β‒vinyl sulfides by hydrothiolation

reaction

NHC‒based Nickel catalysts have been found for the selective transfer of a single arylthio

group in the catalytic hydrothiolation reaction. Some structures of NHC are depicted in the

Figure III.C.3 below:

N N

IMesN, N'-bis(2,4, 6-trimethylphenyl)-imidazole-2-ylidine

NHC = IMes, SIMes and IPr

N N

SIMesN, N'-bis(2,4, 6-trimethylphenyl)-imidazolin-2-ylidine

N N

IPrN, N'-bis(2, 6-diisopropylphenyl)-imidazole-2-ylidine

NiNHCCl

Figure III.C.3. Structures of Ni‒NHC complex and some NHCs

The reaction was performed at 80 oC with triethyl amine as base and toluene as solvent.

Reaction required 5 hours for desired conversion of the products. The exact mechanism was

described by the authors and this is presented below (Scheme III.C.11).10

NiNHCCl

PhSH+ Et3N

Toluene, 2 h, 80 oCNi

SCHN

RNi

R

S

NHC

PhSH R

SPh

NiSCHN

+

[Et3NH] Cl

77

Scheme III.C.11. Mechanism of Ni‒NHC‒catalyzed hydrothiolation reaction

Recently it has been shown that In(OTf)3 selectively catalyzes both Markovnikov and

anti‒Markovnikov hydrothiolation of terminal alkynes. When 2‒mercapto benzothiazole,

2‒mercapto benzoxazole or 2‒mercapto oxazole reacted with terminal alkynes Merkovnikov

adduct has been found to form. In the case of aliphatic or aromatic thiols, anti‒Merkovnikov

adduct was formed (Scheme III.C.12).16

S

NSH

In(OTf)3

Toluene, reflux

In(OTf)3

Toluene, refluxS

NS

R SHS

R

Merkovnikov additionAnti-Merkovnikov addition

R = Cyclohexyl, cyclopentyl, n-propyl, iso-propyl, p-tolyl

Scheme III.C.12. In(III)‒catalyzed substrate selective hydrothiolation of terminal alkynes

The (E)‒ and (Z)‒ selectivity of the vinyl sulfide can be achieved by tuning the reaction

environment under Cu(I)‒catalyzed hydrothiolation reaction. Under argon and CO2

atmospheres E‒isomer and Z‒isomer was formed respectively with major amounts (Scheme

III.C.13).25

Ar SH+Cu(I)

R1

R1S

Ar

Ar

Cu(I)

CO2 Ar SR1

E-vinyl sulfide Z-vinyl sulfide

R1 = aryl, alkyl, heterocyclic

Scheme III.C.13. Cu(I)‒catalyzed hydrothiolation under CO2 and argon atmosphere

However, transition metal complexes are generally expensive, their uses are not

eco‒friendly and the course of the reaction might suffer deactivation due to the formation of

strong metal–sulphur bonds.26

Moreover regioselective (anti‒Markovnikov) on‒water hydrothiolation processes have

been reported in the absence or presence of some additives.18

Although the development of

new methodologies using metal catalysts attract much interest in hydrothiolation reaction, the

78

use of greener solvent media seek importance to the aspect of Green Chemistry.

β‒Cyclodextrine promoted stereoselective hydrothiolation reaction was performed by K. R.

Rao and his group. They have shown that the complete formation (E)‒vinyl sulfides can be

achieved in water medium. In this protocol only aromatic terminal alkynes and aromatic

thiols were participated. The addition pattern in this case was totally anti‒Merkovnikov

fashion and the product was absolutely (E)‒vinyl sulfide (Scheme III.C.14).27

R1HS

R2+

-CD, H2O

RT

H S

H

R1

R2

R1 = H, Me, Br, Cl

R2 = H, Me, OMe, Cl, Br

-CD = Cyclodextrin

Scheme III.C.14. Hydrothiolation of alkynes with thiophenols in presence of β‒Cyclodextrin in

Water

Water‒promoted regioselective hydrothiolation of alkynes was performed by B. C. Ranu

et al. They have shown that an internal alkyne adds thiols to give both (E)‒ and (Z)‒ products

at room temperature. When dithio compounds were used and reacted with terminal alkynes, a

cylic dithio compound was formed. It is to be noted that no uniformity of the E:Z ratio of the

products have been achieved in this methodology. The reaction was found to be retarded

down in absence of water (Scheme III.C.15).28

R2R1

H

R2R1

SR H

SRR1

R2

RSH

H2O, RT+

S

SR1n

n = 2,3 R2 = H

SH

SHn

H2O, 80 oC

R, R1 = alkyl, aryl

R2 = H, alkyl

Scheme III.C.15. Water‒promoted regioselective hydrothiolation reaction

Similarly water mediated hydrothiolation of aromatic and aliphatic alkynes have been

performed by G. B. Hammond and his group. This methodology did not require any metal

catalysts and hazardous solvent. Vicinal dithioethers were formed by the reaction of one

equivalent of aliphatic alkynes and two equivalents of aromatic or aliphatic thiols. Aryl thiols

were more reactive than aliphatic thiols. In this case the radical initiator could be the

dioxygen in the air. The specific role of the solvent was not clear at this case but it seemed

79

water has some ability to stabilize the radical intermediate and therefore facilitate the radical

mediated reaction. When aromatic thiols reacted with the aliphatic alkynes, dihydrothiolated

products have been achieved. But in the case of propergyl alcohols, monohydrothiolation

product has been achieved (Scheme III.C.16).18

R1

SHR3

R3S SR3

R2 R1 R2R4

R6

OH

R5

R4

S

R3

R5OH

R6

H2O, RT H2O, RT-60 oC

dihydrothiolationmonohydrothiolation

Scheme III.C.16. Green synthesis of vicinal dithioethers and alkenyl thioethers

So it is clearly envisaged from the above schemes that a large variety of reagents/catalysts

that are used in the hydrothiolation of terminal alkynes with varying degrees of success in

controlling stereo‒ and regioselectivity. However, many reports include expensive metal

catalysts, non‒aqueous solvents and high temperature and moreover lacks from

(E/Z)‒stereoselectivity. In practice, there is no general guideline by which one can proceed to

prepare a specific stereoisomer of a vinylic sulfide using this straightforward and

atom‒economic reaction under mild and environment‒friendly conditions. Moreover, there

are conditions that give rise to selective formation of the thermodynamically favoured

(E)‒alkenyl sulfide, it remains a challenge to develop such optimum conditions that

selectively produce (Z)‒alkenyl sulfides under complete metal‒free, base‒free and on‒water

conditions. Here, we examined a systematic investigation on the stereo‒ and regioselective

addition of aliphatic and aromatic thiols to terminal alkynes in the presence of different

additives in catalytic or stoichiometric quantities under on‒water conditions.

III.C.3. Present work: Results and Discussion

Preliminary studies on the influence of catalyst and/or promoter in hydrothiolation were

studied with a model reaction of phenyl acetylene (1a) and benzenethiol in the presence of

various metal salts, homogeneous and heterogeneous additives/promoters under on‒water

conditions at room temperature. The reaction was optimized using various

additives/promoters included inorganic salts, water‒soluble organic molecules, amino acids,

surfactants or heterogeneous ion‒exchange resins, and the results are summarized in Table

III.C.1. Since the hydrothiolated adducts were formed in varying ratios (E/Z ratios), the

results in the Table III.C.1 have been arranged showing gradual change in the formation of

(E)‒vinyl sulfide (2b) to the (Z)‒isomer (2c). The neat condition and the reaction with water

80

yielded the (E/Z) ratio as 83:17 and 80:20 respectively (Table III.C.1, entry 1 and 2). The

screening shows that the E/Z ratio in favor of (E)‒vinyl sulfide (87:13) is formed in the

presence of NaCl (Table III.C.1., entry 3). The gradual diminish in E stereoselectivity has

been observed from sucrose to starch in Table III.C.1. (entries 4 to 10). Bronstead acid

(trifluoro acetic acid) and Lewis acid (BF3‒Et2O) also increase the Z stereoselectivity (entries

of 5 and 6). Similarly, amino acids enhanced the Z stereoselectivity (entries 8 and 9). But, the

stereochemical outcome favouring the (E)‒isomer was also seen when the reaction was

carried out at higher temperature (65 oC) and continued for longer reaction time (10 h) (entry

11; E/Z ratio 88:12). On the other side the Z stereoselectivity has been found to gradually

increase from entry 13 to entry 23 in Table III.C.1. The major (Z)‒vinyl sulfide was obtained

in the presence of a combination of Amberlite resins (Cl) and FeCl3.6H2O (entry 23; E/Z ratio

22:78). However, a specific observation has to be noted from this study that the on‒water

additions did not give rise to the formation of any Markovnikov adduct, i.e. other regioisomer

(2a) was not obtained. The NMR spectral data of the crude products indicated only a mixture

of 2b and 2c and indeed there was no existance of 2a.

Table III.C.1. Role of additives in the addition of PhSH to phenylacetylene under on‒water

and at room temperature conditions.a

C6H5 HC6H5 SH

Additives [A]1a

C6H5

H

H

SC6H5H

C6H5

H

SC6H5C6H5

SC6H5

H

H+ +

2b 2cWater / RT 2a

(Markovnikov) (Anti-Markovnikov)

(E)-isomer (Z)-isomer

Entry Additive [A]b

(E/Z) ratioc,d

Entry Additive [A]b

(E/Z) ratioc,d

1 Nil (Neat) 83:17 13 CuI‒Catechol Violet 60:40

2 Nil (Water) 80:20 14 Amberlite Resins (Cl) 58:42

3 NaCl 87:13 15 n‒Bu4Br 57:43

4 Sucrose 85:15 16 D‒Glucose 56:44

5 CF3COOH 78:22 17 CuI 52:48

6 BF3.Et2O 76:24 18 Cholesterol 51:49

7 Catechol Violet 75:25 19 CTAB 49:51

8 L‒Proline 70:30 20 FeCl3.6H2O 44:56

9 Glycin 69:31 21 Amberlite Resins (OH) 40:60

10 Starch 64:36 22 D‒Glucose & FeCl3.6H2O 35:65

11e

Water (65 oC) 88:12 23 Amberlite Resins (Cl) & 22:78

81

12 Water (65 oC) 64:36 FeCl3

.6H2O

aReaction conditions: Phenyl acetylene (0.5 mmol), PhSH (0.55 mmol), water (1 mL), 2 h.

bAdditive [A] (2 mol %).

cE/Z ratio was determined by

1H NMR of the crude mixture.

dYield of the mixture of stereoisomers after chromatographic purification varies in the range 80‒90%.

eThe reaction was continued for 10 h; all other reactions were carried at room temperature unless

mentioned.

At this point, effect of functional groups in the aromatic moiety in either of the addition

partners could be worth investigating. Since a combination of ion‒exchange resins and ferric

chloride showed a better selectivity towards the formation of (Z)‒vinyl sulfide, this study was

performed under similar conditions. The results are presented in Table III.C.2. It is seen that

both electron‒donating and electron‒withdrawing functional groups present on the aryl ring

can give rise to the anti‒Markovnikov hydrothiolation products in excellent yields (85‒94%).

Highest (Z)‒selectivity was found in the reaction between phenyl acetylene and

p‒methoxybenzenethiol (Table III.C.2, entry 4; E/Z 12:88), possibly due to easy

emulsification of the alkyne in water upon stirring, which might be supportive in addition to

the presence of the additive. On the other hand, presence of electron‒withdrawing group

(fluorine) on the thiol part did not show any appreciable influence towards stereoselective

addition yielding the (E)‒ isomer in major (entries 6‒7). It seems that there is not much

electronic influence of the functional groups in the aryl ring of either of the addition partners;

rather their stability in water in the presence of the additive might have some control towards

anti‒Markovnikov stereoselectivity.

Table III.C.2. Hydrothiolation of aryl acetylene [A] with aromatic thiols [B] in (1:1.1) molar

ratios in water at room temperature.

R1 H SHR2

H

H

S

R1

R2

Amberlite resins (Cl) - FeCl3

+

[A] [B] [C]Water, RT

Entry [A] [B] Time (h) Yielda (%) [C] E / Z [C]

b

1 R1 = H R

2 = H 2.0 85 22 : 78

2 R1 = CH3 R

2 = H 3.5 91 40 : 60

3 R1 = CH3 R

1 = CH3 2.5 88 29 : 71

4 R1 = H R

1 = OCH3 3.0 93 12 : 88

5 R1 = CH3 R

1 = OCH3 2.0 90 22 : 78

82

6 R1 = H R

2 = F 2.0 88 80: 20

7 R1 = CH3 R

2 = F 2.0 94 39: 61

aYield represents the product [C] after purification by column chromatography.

bE/Z ratio was determined by

1H NMR of the crude mixture.

In cases of aryl acetylenes and aliphatic thiols combination, D(+)‒glucose plays a vital

role for achieving (Z)‒stereoselectivity. Hydrothiolation of aryl acetylenes (terminal) with

aliphatic thiols in the presence of one equivalent of D(+)‒glucose showed a general trend in

favour of the formation of (Z)‒vinyl sulphides. For example, phenyl acetylene undergoes

hydrothiolation in the presence of n‒alkyl thiols afforded the corresponding 1‒alkenyl

sulphides with (E/Z) ratios (14:86). The results are listed below in Table III.C.3.

Table III.C.3. Hydrothiolation aromatic terminal alkynes with aliphatic thiols.

R1 H

H

H

S

R1D (+)-Glucose

+

[A] [D] [E]

SH

n nWater, RT

Entry [A] [D] Time (h) Yielda (%) [E] E / Z [C]

b

1 R1 = H n = 3 3.0 75 20 : 80

2 R1 = H n = 5 3.0 64 14 : 86

3 R1 = CH3 n = 3 4.5 79 14 : 86

4 R1 = CH3 n = 5 5.0 51 21 : 79

aYield represents the product [E] after purification by column chromatography.

bE/Z ratio was determined by

1H NMR of the crude product mixture.

Since there is significant reactivity difference between aliphatic and aromatic thiols,29

we

ought to investigate the stereochemical outcome in two other cases: hydrothiolation of (i)

aliphatic terminal alkynes and aliphatic thiols and (ii) aliphatic terminal alkynes and aromatic

thiols. It has been seen from previous reports that aliphatic alkynes undergo dihydrothiolation

yielding vicinal disulfides only irrespective of nature of the thiol.18a,28

Thus, aliphatic

terminal alkynes were subjected to hydrothiolation with aromatic and aliphatic thiols under

on‒water conditions. Apparently, there was influence of additives in this double‒addition

reaction. The results are presented in Table III.C.4, which show that aliphatic terminal

alkynes undergo double‒ additions yielding finally 1, 2‒disulfides only in the presence or

absence of D (+)‒Glucose.

83

Table III.C.4. Dihydrothiolation of aliphatic alkyne with thiols in water at room temperature.

Water/ RT

[A] [B]/[D] [F]

HR1 + R2 SHR1

R2S SR2

Entry [A] [B]/[D]a

Time (h) Yieldb (%) [F]

1c

R1 = CH3‒CH2‒CH2 R

2 = Ph 5 88

2 R1 = CH3‒CH2‒CH2 R

2 = Ph 5 76

3 R1 = CH2OAc R

2 = Ph 6 79

4 R1 = CH3‒CH2‒CH2 R

2 = CH3(CH2)6SH 9 58

a[A]:[B] is 1:2.2 molar ratios.

bYield represents the product [F] after purification by column chromatography.

cD (+) Glucose (1 equiv) was added.

As regards to the mechanism of hydrothiolation of terminal alkynes in water, the literature

reports are of different views. For example, Ranu et al,28

found that the water‒promoted

regioselective hydrothiolation excluded the radical pathway because the reaction proceeds in

the presence of dissolved oxygen whereas Hammond et al,7a

hinted that the reaction probably

proceeds through a radical mechanism under similar conditions. The latter group further

observed that the reaction did not occur in the presence of galvinoxyl free radical. But this

was not only the proof for radical mechanism.30

Our studies demonstrated a role of additives

in governing the stereoselectivity but the specific function of the additive, particularly in

aqueous medium and the mechanistic routes are not cleared. Furthermore, carrying out the

reaction in the presence of radical initiator (AIBN) or light did not make the process faster

appreciably. Several transition metal complexes are known to catalyze the process of

hydrothiolation via radical intermediates leading to major anti‒Markovnikov 1‒alkenyl

sulfides. In the absence of such metal complexes, the stabilization of the reactive species has

been achieved by water as well as by the additive might alter the course of the reaction

pathway.

III.C.4. Conclusions

In search of finding „stereoselective‒switch‟ for the hydrothiolation of terminal alkynes

under on‒water conditions, we have found two types of additives that could lead to the

stereoselective formation of the (Z)‒1‒alkenyl sulfides in substantial quantities depending on

84

the nature of both reacting partners. Here we are able to give a direction for the formation of

(Z)‒isomer by mild and green reaction conditions.

III.C.5. Experimental section

III.C.5.1. General information

All the reactions were carried out in closed vessel under ambient conditions. Amberlyst®

IRA‒900, Cl form was purchased from ACROS Organics, India. FeCl3.6H2O and

D(+)‒glucose were purchased from Sd‒fine Chem. Ltd. and Glaxo Laboratories (India) Ltd.

respectively. For column chromatography: silica (60‒120 mesh) (SRL, India), and for tlc,

Merck plates coated with silica gel 60, F254 were used. All compounds were identified by 1H‒

and 13

C‒NMR spectra, recorded on a Bruker AV300 spectrometer operating at 300 and 75

MHz respectively and supported by FT‒IR spectra. All NMR spectra were measured in

CDCl3. Chemical shifts are given in δ (ppm) downfield from TMS. Characterization of

sulfanes (Table III.C.2, Table III.C.3 and Table III.C.4) has been made from melting point

and 1H‒ and

13C‒NMR spectral data.

III.C.5.2. General procedure for mono‒hydrothiolation of alkynes

To a mixture of alkyne (1 mmol), thiol (1.1 mmol) in water (0.5 mL) was added the

additive (1 mmol) and stirred at room temperature (25‒30 oC) for 2‒5 h (tlc). The reaction

mixture was extracted with diethyl ether (3×10 mL), and the combined organic layer was

washed with brine and then dried over Na2SO4. Evaporation of solvent under vacuo afforded

an oily residue, which was passed through a short bed of silica gel and NMR spectrum was

recorded to evaluate the percent of (E/Z) isomers. NMR spectral data and scanned copies of

selected NMR spectra are given in the supporting information and found to be in good

agreement with those reported.

III.C.5.3. General procedure for di‒hydrothiolation of alkynes

A mixture of alkyne (1 mmol), thiol (2.2 mmol) in water (0.5 mL) was stirred for 5‒9 h at

room temperature (tlc). The reaction mixture was then extracted with diethyl ether (3×10

mL), and the combined organic layer was washed with brine and then dried over Na2SO4.

Evaporation of solvent under vacuo afforded an oily residue, which was passed through a

short bed of silica gel to afford 1, 2‒disufides in good to excellent yields. The products were

identified on the basis of 1H‒,

13C‒NMR spectral data, and/or by comparison with the data

85

reported in the literature. NMR spectral data and scanned copies of selected NMR spectra

(1H‒ &

13C‒) are given in the supporting information.

III.C.5.4. Physical properties and spectral data of compounds

Table III.C.2, Entry 1

Mixture of (E/Z)‒phenyl(styryl)sulfane31

S

Pale yellow oil, E/Z ratio = 28:72 (from 1H‒NMR spectral data)

1H NMR (CDCl3, 300 MHz): δ/ppm 6.49 (d, J = 10.8 Hz), 6.58 (d, J = 10.8 Hz), 6.72 (d, J =

15.6 Hz), 6.88 (d, J = 15.6 Hz), 7.19–7.52 (m, Ar‒H).

13C NMR (CDCl3, 75 MHz): δ/ppm 123.3, 126.0, 126.9, 127.1, 127.2, 127.2, 127.6, 128.3,

128.7, 128.7, 129.1, 129.8, 130.0, 131.8, 135.2, 136.2, 136.4, 136.5.

Table III.C.2, Entry 2

Mixture of (E/Z)‒phenyl(4‒methylstyryl)sulfane

H3C

S

Pale yellow crystalline solid, mp 39–40 oC; E/Z ratio = 40:60 (from

1H‒NMR spectral data)

1H NMR (CDCl3, 300 MHz): δ/ppm 2.32, 2.34 (s, ‒CH3), 6.42 (d, J = 10.5 Hz), 6.56 (d, J =

10.8 Hz), 6.72 (d, J = 15.3 Hz), 6.81 (d, J = 15.6 Hz), 7.09–7.45 (m, Ar‒H).

13C NMR (CDCl3, 75 MHz): δ/ppm 21.2, 21.3 (CH3), 121.7, 124.7, 125.9, 126.7, 127.0,

127.3, 128.9, 129.0, 129.3, 129.4, 129.7, 129.9, 132.3, 133.6, 133.7, 134.1, 135.5, 136.3,

136.9, 137.5.

Table III.C.2, Entry 3

Mixture of (E/Z)‒(4‒methylphenyl)(4‒methylstyryl)sulfane

H3C

S

CH3

White crystalline solid, mp 48–49 oC; E/Z ratio = 29:71 (from

1H‒NMR spectral data)

86

1H NMR (CDCl3, 300 MHz): δ/ppm 2.31, 2.32 (s, ‒CH3), 6.38 (d, J = 10.8 Hz), 6.50 (d, J =

10.8 Hz), 6.64 (d, J = 15.3 Hz), 6.79 (d, J = 15.3 Hz), 7.07–7.43 (m, Ar‒H).

13C NMR (CDCl3, 75 MHz): δ/ppm 21.0, 21.1, 21.2 (CH3), 122.9, 125.8, 125.9, 126.6, 128.7,

128.9, 129.3, 129.7, 129.9, 130.3, 130.4, 131.0, 137.0, 137.2, 137.3.

Table III.C.2, Entry 4

Mixture of (E/Z)‒(4‒methoxyphenyl)(styryl)sulfane32

S

OCH3

White crystalline solid, mp 61 oC (Lit. mp 58‒60

oC); E/Z ratio = 12:88 (from

1H‒NMR

spectral data)

1H NMR (CDCl3, 300 MHz): δ/ppm 3.74, 3.76 (s, ‒OCH3), 6.38 (d, J = 11.1 Hz), 6.46 (d, J =

10.8 Hz), 6.49 (d, J = 15.6 Hz), 6.81 (d, J = 15.6 Hz), 6.84–7.52 (m, Ar‒H).

13C NMR (CDCl3, 75 MHz): δ/ppm 55.0, 55.3, 55.5, 55.8 (OCH3), 114.8, 114.9, 125.7, 126.8,

127.1, 127.9, 128.2, 128.3, 128.4, 128.6, 128.8, 128.9, 128.9, 129.1, 132.5, 132.8, 132.9,

133.1, 133.4, 136.6, 136.7, 159.5.

Table III.C.2, Entry 5

Mixture of (E/Z)‒(4‒methoxyphenyl)(4‒methylstyryl)sulfane

H3C

S

OCH3

White crystalline solid, mp 68 oC; E/Z ratio = 22:78 (from

1H‒NMR spectral data)

1H NMR (CDCl3, 300 MHz): δ/ppm 2.30, 2.34 (s, ‒CH3), 3.77 (s, ‒OCH3), 6.32 (d, J = 10.8

Hz), 6.45 (d, J = 10.8 Hz), 6.75 (d, J = 15.3 Hz), 6.84–7.41 (m, Ar‒H and olefinic H).

13C NMR (CDCl3, 75 MHz): δ/ppm 21.3, 21.4 (CH3), 55.0, 55.3, 55.5, 55.8 (OCH3), 113.9,

114.7, 114.8, 124.2, 124.8, 125.3, 125.8, 126.7, 127.0, 127.2, 127.7, 127.8, 128.2, 128.3,

128.5, 128.6, 128.7, 128.8, 129.0, 129.0, 129.1, 129.3, 129.4, 129.5, 130.0, 131.9, 132.4,

132.7, 132.8, 133.0, 133.1, 133.3, 133.9, 134.0, 136.8, 137.1.

Table III.C.2, Entry 6

Mixture of (E/Z)‒(4‒fluorophenyl)(styryl)sulfane

87

S

F

Pale yellow oil, E/Z ratio = 80:20 (from 1H‒NMR spectral data)

1H NMR (CDCl3, 300 MHz): δ/ppm 6.41 (d, J = 10.5 Hz), 6.58 (d, J = 10.5 Hz), 6.65 (d, J =

15.3 Hz), 6.83 (d, J = 15.6 Hz), 7.01–7.43 (m, Ar‒H).

13C NMR (CDCl3, 75 MHz): δ/ppm 116.2, 116.53, 123.8, 123.9, 125.9, 126.0, 126.1, 126.5,

127.0, 127.7, 128.6, 128.8, 129.8, 129.9, 131.1, 132.5, 132.6, 132.7, 136.4, 160.6, 163.9.

Table III.C.2, Entry 7

Mixture of (E/Z)‒(4‒fluorophenyl)(4‒methylstyryl)sulfane

S

FH3C

White crystalline solid, mp 60–61 oC; E/Z ratio = 39:61(from

1H‒NMR spectral data)

1H NMR (CDCl3, 300 MHz): δ/ppm 2.35 (s, ‒CH3), 6.32 (d, J = 10.5 Hz), 6.53 (d, J = 10.5

Hz), 6.64 (d, J = 15.6 Hz), 6.74 (d, J = 15.0 Hz), 7.00–7.37 (m, Ar‒H).

13C NMR (CDCl3, 75 MHz): δ/ppm 21.2, 21.3, 21.4 (‒CH3), 116.1, 116.4, 122.3, 125.3,

125.9, 126.0, 126.8, 127.2, 127.6, 128.2, 128.5, 128.8, 129.0, 129.0, 129.1, 129.4, 130.2,

130.2, 131.5, 131.6, 131.8, 132.1, 132.3, 132.4, 132.5, 132.6, 133.5, 133.6, 137.1, 137.6,

160.6, 163.8, 163.9.

Table III.C.3, Entry 1

Mixture of (E/Z)‒pentyl(styryl)sulfane

S

Pale yellow oil, E/Z ratio = 20:80 (from 1H‒NMR spectral data)

1H NMR (CDCl3, 300 MHz): δ/ppm 0.90 (t), 1.20–1.58 (m), 1.63–1.73 (m), 2.76 (t), 6.23 (d,

J = 11.1 Hz), 6.42 (d, J =10.8 Hz), 6.45 (d, J = 15.3 Hz), 6.72 (d, J = 15.6 Hz), 7.16–7.49 (m,

Ar‒H).

13C NMR (CDCl3, 75 MHz): δ/ppm 14.0, 22.3, 29.1, 29.9, 30.7, 31.0, 35.9, 125.2, 126.5,

127.7, 127.8, 128.1, 128.4, 128.7, 129.0, 137.0.

88

Table III.C.3, Entry 2

Mixture of (E/Z)‒heptyl(styryl)sulfane

S

Pale yellow oil, E/Z ratio = 14:86 (from 1H‒NMR spectral data)

1H NMR (CDCl3, 300 MHz): δ/ppm 0.88 (t), 1.28–1.78 (m), 2.78 (t), 6.24 (d, J = 10.8 Hz),

6.43 (d, J = 11.1 Hz), 6.45 (d, J = 15.3 Hz), 6.72 (d, J = 15.6 Hz), 7.20–7.49 (m, Ar–H).

13C NMR (CDCl3, 75 MHz): δ/ppm 14.0, 22.6, 28.6, 30.3, 31.7, 35.9, 125.2, 126.5, 127.7,

128.2, 128.6, 137.0.

Table III.C.3, Entry 3

Mixture of (E/Z)‒pentyl(4‒methylstyryl)sulfane

H3C

S

Colourless oil, E/Z ratio = 14:86 (from 1H‒NMR spectral data)

1H NMR (CDCl3, 300 MHz): δ/ppm 0.90 (t), 1.29–1.43 (m), 1.68 (m), 2.33 (s), 2.77 (t), 6.17

(d, J = 10.8 Hz), 6.40 (d, J = 10.8 Hz), 6.65 (d, J = 15.3 Hz), 7.08–7.39 (m, Ar–H and

olefinic H).

13C NMR (CDCl3, 75 MHz): δ/ppm 13.9, 21.2, 22.3, 29.1, 29.9, 30.7, 30.9, 32.6, 35.8, 125.2,

125.3, 126.5, 128.5, 129.3, 134.2, 134.3, 136.3.

Table III.C.3, Entry 4

Mixture of (E/Z)‒heptyl(4‒methylstyryl)sulfane

H3C

S

Yellow oil

E/Z ratio = 21:79 (from 1H–NMR spectral data)

1H NMR (CDCl3, 300 MHz): δ/ppm 0.90 (t), 1.20–1.39 (m), 1.52–1.72 (m), 2.31 (s), 2.65–

2.79 (t), 6.16 (d, J = 10.8 Hz), 6.39 (d, J = 10.8 Hz), 6.65(d, J = 16.8 Hz), 7.07–7.93 (m,

Ar‒H and olefinic H).

89

13C NMR (CDCl3, 75 MHz): δ/ppm 14.1, 21.2, 21.3, 22.6, 28.6, 28.9, 30.2, 31.7, 35.8, 122.2,

126.5, 128.1, 128.4, 128.6, 128.9, 129.3, 134.2, 136.3.

Table III.C.4, Entry 1

1‒(1‒(Phenylthio)pentan‒2‒ylthio)benzene

S

S

Colourless oil

1H NMR (CDCl3, 300 MHz): δ/ppm 0.93 (t, J = 3.6 Hz, 3H), 1.49–1.60 (m, 4H), 2.84–2.92

(m, 1H), 3.10–3.27 (m, 2H), 7.16–7.33 (m, Ar‒H).

13C NMR (CDCl3, 75 MHz): δ/ppm 13.8, 20.0, 34.8, 39.5, 48.1, 126.2, 127.2, 128.9, 128.9,

128.9, 129.8, 132.5, 134.4, 135.9.

Table III.C.4, Entry 2

2,3‒Bis(Phenylthio)propyl acetate

OS

S

O

Pale yellow oil

1H NMR (CDCl3, 300 MHz): δ/ppm 2.10 (s, 3H), 3.13–3.24 (m, 2H), 3.34–3.37 (m, 1H),

4.29–4.42 (m, 2H), 7.21–7.39 (m, Ar‒H).

13C NMR (CDCl3, 75 MHz): δ/ppm 20.7, 35.8, 47.1, 64.5, 126.6, 127.8, 129.0, 129.2, 129.9,

132.9, 135.2, 170.7.

Table III.C.4, Entry 3

1‒(1‒(Heptylthio)pentan‒2‒ylthio)heptane

S

S

90

Colourless oil

1H NMR (CDCl3, 300 MHz): δ/ppm 0.86–0.95 (m, 9H), 1.28–1.80 (m, 24H), 2.50–2.75 (m,

6H), 2.82–2.87 (dd, J = 4.2 and 12 Hz, 1H).

13C NMR (CDCl3, 75 MHz): δ/ppm 13.2, 13.9, 14.0, 14.8, 19.9, 22.6, 28.4, 28.8, 28.9, 29.4,

29.8, 29.9, 30.3, 30.8, 31.7, 33.1, 35.7, 38.4, 45.5.

III.C.6. References

References are given in BIBLIOGRAPHY under Chapter III, Section C (pp. 149‒150).

91

CHAPTER IV

Cyclic ammonium salts of dithiocarbamic acid:

Stable alternative reagents for the synthesis

of S‒alkyl carbodithioates from organyl

thiocyanates in water

92

IV.1. Introduction

S‒Alkyl carbodithioate esters are esters of dithiocarbamic acids. These are also known as

dithiocarbamate esters (DTCE), are functional organosulfur compounds that were first

utilized as fungicides during Second World War.1 The structures of esters of carbamic acid,

thiocarbamic acid and dithiocarbamic acid are given in the Figure IV.1.

Figure IV.1. Structures of carbamic acid, thiocarbamic acid and dithiocarbamic acid and their esters

Dithiocarbamates are also mainly used as important fungicides of vegetables, crops and

plants.2‒4

S‒alkyl carbodithioate esters and its derivatives show antibacterial,5‒7

anthelmintic,8

anticandidal activity and cytotoxicity,9 antihistaminic,

10 as well as anticancer properties.

8,11‒13

They can also be helpful for the treatment of cardiovascular disorders and inflammatory

diseases,14

human myelogenous leukemia K562 cells,15

and can be used as HIV‒I NCp7

inhibitors,16

or non‒vanilloid TRPV1 antagonists.17

A few structures of S‒alkyl

carbodithioate esters with potential therapeutic value are shown in Figure IV.2. Further utility

of carbodithioate ester as linkers in solid‒phase organic synthesis is also well

documented.18,19

Carbodithioate esters are widely used as suitable ligands to assemble on

metal nanoparticles in surface science and nanomaterial chemistry.20,21

They are also

well‒known in rubber industry as sulfur vulcanization acceptors,22

and radical chain transfer

agents in the reversible addition fragmentation chain transfer (RAFT) polymerizations.23‒25

Many useful synthetic intermediates contain the carbodithioate ester moiety.26,27

As a result,

several methods for the synthesis of carbodithioate esters have been developed.28

93

NH

NH

SCH3

SS

NH

H3C

O S

SCH3

N N

ClS

S

NMe2N N S

S NC

Brassinin, cancer chemopreventive activity

Sulforamatecancer chemopreventive agent

RWJ-025856attenuating effects on tumor

necrosis factor a (TNFa)-induced apoptosis in murinefibrosarcoma WEHI 164 cells

990207inhibiting the tumor growth of sarcoma

180 (S180), hepatocyte carcinoma 22 (H22)

Figure IV.2. Examples of compounds of potential therapeutic value bearing S‒alkyl carbodithioate

esters function

IV.2. Background and objectives

Synthesis of S‒alkyl/aryl carbodithioate esters is generally achieved by either nucleophilic

substitution reactions under basic medium or transition metal‒catalyzed cross–coupling

reactions. M. R. Saidi reported a highly efficient one‒pot amines and carbon disulfide with

α,β‒unsaturated compounds in water. This simple protocol avoids the use of basic and highly

toxic organic solvents and catalysts. The catalyst‒free, cleaner reaction and simple

experimental procedure have been highly acclaimed (Scheme IV.1).29

HN

CS2 COOMeWater

RTN S

S

COOMe+ +

Scheme IV.1. One‒pot preparation of dithiocarbamate in water without using any catalyst

The same group also developed a clean and catalyst‒free simple one‒pot methodology for

the synthesis of S‒alkyl dithiocarbamate (Scheme IV.2).30

RR1NH R2XCS2, RT

3-12 h

S

R1RN SR2+

Scheme IV.2. One‒pot clean method for the synthesis of carbodithioates

A deep eutectic solvent (DES) and polyethylene glycol (PEG) promoted the

environmentally friendly and fast synthesis of dithiocarbamate derivatives via a one‒pot,

94

three‒component condensation of an amine, carbon disulfide and an epoxide has been

developed by N. Azizi et al. The main advantages of the protocol included simple

experimental procedures, short reaction times, low cost, efficient yields and use of greener

solvent, which made this method as attractive strategy (Scheme IV.3).31

O

PhO

HNCS2 N S

S

OPh

OH

+ +PEG or DES

RT, 60 min

PEG = Polyethylene glycolDES = Deep eutectic solvent

Scheme IV.3. One‒pot synthesis of 2‒hydroxydithiocarbamates in DES and PEG

Basic resin (Amberlite IRA 400) supported a highly efficient and one‒pot synthesis of

dithiocarbamates was done by the Michael addition of dithiocarbamate anion to α,

β‒unsaturated compounds. Dimethyl sulfoxide was used as solvent and the reaction took 2 to

4 hours for completion (Scheme IV.4).32

CS2 EWG

Amberlite IRA 400

Dry DMSO, RT, 2-4h

N S

S

EWG+ +R1R2NH

R1

R2

R3R3

EWG = -COCH3, -COOCH3, -CONH2, -CN

Scheme IV.4. Basic resin (Amberlite IRA 400) supported one‒pot synthesis of dithiocarbamate

Alkaline Al2O3 mediated Michael addition of electron deficient alkenes with aryl amines

and carbondisulfide has been reported by X. Wang et al. A wide range of amines were used

and the reaction was clean and reused without complex workup (Scheme IV.5).33

CS2

Alkaline Al2O3

RT, 20 h

N S

S

+ +R1R2NH

O

OMe

R1

R2

O

OMe

R1 = Ph, R2 = H

Scheme IV.5. Michael addition of aryl amines towards electron deficient alkenes

Ranu et al developed a new methodology for the synthesis of dithiocarbamate by one‒pot

three component condensation of an amine, carbon disulfide and an activated

95

alkene/dichloromethane/epoxide using a room‒temperature ionic liquid (RTIL). The

reactions were found to be very fast and symmetrical dithiocarbamates have been synthesized

by this methodology (Scheme IV.6).34

NH CS2+[pmIm]]Br

0 oC, 2 minN

S

S

OR

RT, 15 min

Y

RT, 10-30 min

CH2X2

RT, 10-20 min

N

S

SR

OH

N

S

S S

S

N

N

S

SY

R = Alkyl, Ph

Y = CO2Me, CN,COPh, CO2NH2, CO2H

X = Cl, Br, I

Scheme IV.6. Synthesis of dithiocarbamates using [pmIm]Br ionic liquid

A very common methodology of one‒pot three component reactions has been established

by A. Z. Halimehjani et al. In this protocol the ethyl vinyl ether was used as an electrophile.

This reaction was complete regioselective towards Markovnikov addition (Scheme IV.7).35

RR1NH CS2+ OH2O

RT+

R1RN S

S

O

RR1NH = Piperidine, pyrrolidine, morpholine,

diisopropyl amine, n-butyl amine, allyl amine,

diallyl amine, benzyl amine

Scheme IV.7. Markovnikov addition reaction of dithiocarbamate to ethyl vinyl ether

Allyl and cinnamyl acetates are rarely used as electrophiles in dithiocarbamates

preparation. A convenient and efficient one‒pot three component condensation of

nonactivated allyl/cinnamyl acetate, carbon disulfide and an amine in presence of Ru(acac)3

in water has been demonstrated by B. C. Ranu et al. The reaction underwent via a catalytic

Ru(II) species, generated in situ during the reaction. The methodology was found to be

attractive due its operational simplicity, use of low catalyst loading, excellent

stereoselectivity in the reactions of trans‒cinnamyl acetate and use of water as solvent

(Scheme IV.8).36

96

R OAc + CS2 + HNRu(acac)3, H2O

RefluxR S N

S

R = H, alkyl, aryl, heteroaryl

Scheme IV.8. Ru(acac)3 catalyzed synthesis of allyl/cinnamyl dithiocarbamates

Like allyl or cinnamyl acetates tosyl hydrazones were rarely used for the formation of

carbodithioates. A new, convenient and efficient transition metal‒free synthesis of S‒alkyl

dithiocarbamates through one‒pot reaction of N‒tosylhydrazones, carbon disulfide and

amines was reported by Y.‒Y. Wei et al. The reaction required a base, high temperature and

an organic solvent, dioxane (Scheme IV.9).37

NNHTs

R2R1+ CS2 + HN

K2CO3

Dioxane, 110 oC, 4 h

S

R2R1

N

S

Tosyl hydrazone

Scheme IV.9. Metal free three‒component reaction of N‒tosylhydrazones, carbon disulfide and

amines

Anilines can also be used for the preparation of carbodithioate ester bearing sec. NH group

in the presence of DMSO and strong base like NaOH.38

Most of the procedures involve harsh

reaction conditions, long reaction time, hazardous organic solvents, metal catalysts and bases.

Organyl thiocyanates, often considered as psuedohalides and are easily available, were not

used as the starting materials, presumably because of the fact that the thiocyanate may

undergo disulfide (‒S‒S‒) bond formation under basic medium.39,40

We found that the

reaction of a sec. amine with CS2 produces a stable salt, which can be isolated easily in

almost quantitative yield and stored for several weeks in the air. The salt can efficiently react

with alkyl/aroyl methyl/cinnamyl thiocyanates in water medium at room temperature to

afford corresponding carbodithioate esters in good to excellent yields without formation of

any other by‒products such as organyl disulfide. Here we describe an efficient, base‒ and

metal‒free protocol for the synthesis of various S‒substituted carbodithioate esters by using

variety of cyclic sec. amine‒based dithiocarbamate salts from diverse organyl thiocyanates.

To the best of our knowledge organyl thiocyantes have not been used previously as the

precursor for preparation of carbodithioate esters. The other main advantages of this protocol

97

are metal‒ and alkali‒free, which possibly leads to avoid the disulfide bond formation, clean

reaction affording excellent yields and can be carried out in water medium at ambient

condition.

IV.3. Present work: Results and Discussion

As a part of preliminary study, as presented in Table IV.1, we had conducted the reaction

of a neat mixture of benzyl thiocyanate, CS2 and morpholine in one‒pot manner, which led to

the pure desired benzyl morpholine‒4‒carbodithioate ester 4a in only 72% isolated yield

(Table IV.1, entry 1). Moreover, the reaction showed partial formation of dibenzyl disulfide

on tlc monitoring of the experiment, although it was not isolated in considerable quantity

after column chromatography. Considering that the intermediate salt derived from the amine

and CS2 could be the actual nucleophile, the sodium salt of morpholinodithioformate 2a was

used to react with benzyl thiocyanate 3a (Table IV.1, entry 2). However, we obtained the

desired carbodithioate ester 4a again with the formation of dibenzyl disulfide, presumably

attributable to the basic reaction medium that facilitates the disulfide from benzyl thiocyanate

3a.39,40

In order to avoid the basic reaction medium, we considered that the dithiocarbamate

salt consisting of both organyl cationic and anionic part might be suitable and accordingly,

we prepared the salt 2b from a mixture of morpholine and CS2 in diethyl ether following the

reported procedure.41

The salt 2b now contains morpholino‒based cationic and anionic part

and stirring a mixture of benzyl thiocyanate 3a with the salt 2b (in equimolar quantity) in

water at room temperature gave rise to clean reaction without any trace of disulfide

formation, producing 4a in 76% isolated yield (Table IV.1, entry 3). Heating the reaction

mixture of 2b and 3a in water or ethanol at 60 oC resulted in rather better yield of 4a

(78‒82%; Table IV.1, entries 4 and 5). On the other hand, use of water‒ethanol (1:1) as the

solvent and conducting the reaction at room temperature gave 4a in 80% yield (Table IV.1,

entry 6). It is likely that organyl thiocyanates are poorly soluble in water, and we employed

two different phase transfer agents, n‒tetrabutyl ammonium bromide (TBAB) and sodium

dodecyl sulfate (SDS). While the use of TBAB was found to improve marginal increase in

the yield of 4a (Table IV.1, entry 7), the presence of SDS (either in stoichiometric or in 10

mol%) afforded 4a in excellent yield (96%) (Table IV.1, entries 8 and 9). Thus, excellent

conversion of benzyl thiocyanate to benzyl morpholine‒4‒carbodithioate ester 4a is

practically possible if we use separately‒prepared amine‒based salt and perform the reaction

under conditions as in entry 9 of Table IV.1. In aqueous medium reactions, anionic phase

98

transfer agents as additive are usually more effective than cationic agents.42

Here, we used

both TBAB (cationic) and SDS (anionic) additives and the results are in conformity with

previous reports. The better functioning of the anionic phase transfer agents like SDS might

be explained in the light of considering the whole system as a microreactor, where organyl

thiocyanate having resided in the hydrophobic dodecyl core may come in contact with the

reactant (here the dithocarbamate salt) being present in water through the formation of

hydrogen bond with anionic sulfate ion.

Table IV.1. Optimization of the reaction conditions for the conversion of benzyl thiocyanate

to S‒alkyl cabodithioates.

SCN

NO

H

H

N O

S

S

S

S

N

O

3a

2b

4a

Solvent

Temperature, Additive

N O

S

S

2aNa

or+

Entry Solvent (2 mL) T (°C) Additive Time(h) Yielda (%)

1b Neat RT No 1 72

2c Water RT No 1 60

d

3e Water RT No 1 76

4 Water 60 No 1 78

5 EtOH 60 No 1 82

6 Water: EtOH RT No 1 80

7f Water RT TBAB 1 84

8g Water RT SDS 1 96

9h Water RT SDS 1 96

aYield represents pure isolated product after purification by column chromatography.

bMixture of benzyl thiocyanate (1 mmol), morpholine (2 mmol) and CS2 (1 mmol) was stirred at room

temperature. cSalt 2a was used.

d20% dibenzyl disulphide was isolated.

eSalt 2b was used.

fTetrabutyl ammonium bromide (TBAB; stoichiometric) was used.

gSodium dodecyl sulfate (SDS; stoichiometric) was used.

h10 mol% SDS was used.

99

Being encouraged by this observation, we wanted to develop a general and practical

procedure for the conversion of organyl thiocyanate into carbodithioate ester. We prepared

other dithiocarbamate salts (2c‒2e) from three different cyclic sec. amines such as piperidine,

pyrrolidine and piperazine (Scheme IV.10).

NO

H

H

N O

S

SN

H

H

N

S

S

N

S

S

NH

HN N

S

SS

SN NH

H

HNHN

H

H

2b 2c

2d 2e

(Morpholinium morpholinodithioformate)

(Piperidinium piperidinodithioformate)

(Pyrrolidinium pyrrolidinodithioformate)

Bis(piperazinium)piperazine-1,4-dicarbodithioate

N O

S

S

2a

Na

(Sodium morpholinodithioformate)

XN

H

HX

N

S

S

n = 2, X = O (2b)n = 2, X = CH2 (2c)n = 1, X = CH2 (2d)

XNH

n

CS2 in diethyl ether

Stir at RTn n

simple preparation

crystalline solid

easy separation

stored for longer time under air

1

2b-2d

XN

H

Hn 2

N N

S

SS

S

n = 2, X = NH (2e)

Na

NaOH, CS2

or

EtOH:H2O (1:1)

Stir at 0-5 oC

XN

S

S

n

n = 2, X = O (2a)

Scheme IV.10. Synthesis of sec. cyclic aliphatic amine‒based dithiocarbamate salts

Being encouraged by this observation, we wanted to develop a general and practical

procedure for the conversion of organyl thiocyanate into carbodithioate ester. We prepared

other dithiocarbamate salts (2c‒2e) from three different cyclic sec. amines such as piperidine,

pyrrolidine and piperazine (Scheme IV.10), and employed our optimized conditions (as in

entry 9) for reaction with various functionalized organyl thiocyanates. The results are

presented in Table IV.2. It is clearly evident that different substituted benzyl thiocyanates and

naphthyl methyl thiocyanate underwent smooth conversion to the corresponding

dithiocarboate esters with all types of dithiocarbamate salts. While 2‒ and 4‒chloro benzyl

100

thiocyanates worked equally efficiently without any steric encumbrance, the

piperazine‒based dithiocarbamate salt 2e reacted with benzyl or 2‒chlorobenzyl thiocyanates

to produce bis‒carbodithioate esters in 82‒83% yields within 3h (4l and 4m).

Table IV.2. Synthesis of diverse S‒alkyl carbodithioates by varying organyl thiocyanates and

dithiocarbamate salts.a,b

XN

H

HX

N

S

S

n n

XN

H

Hn 2

N N

S

SS

S

or +SCN

R

S N

S

Xn

RSDS (10 mol%)

Water, RT

3

4l, 4m

N N

S

SS

S

orR

R

2b, X = O, n = 22c, X = CH2, n = 22d, X = CH2, n = 12e, X = NH, n = 2

R = H, 2-Cl, 4-Cl

4a-4k

Entry R1─SCN

(3)

Salt

(2)

Time (h) T (oC) Product

(4)

Yield (%)

1

SCN

2b

1.0

RT S N

S

O4a

96

2

SCN

Cl

2b

1.0

RT S N

S

OCl 4b

98

3 SCN

Cl

2b

1.0

RT

4c

S N

S

OCl

97

4 SCN

2b

1.5

RT S N

S

O

4d

87

5 SCN

2c

1.0

RT S N

S

4e

95

101

6 SCN

Cl

2c

1.0

RT S N

S

Cl 4f

98

7

SCN

2c

1.5

RT S N

S

4g

89

8 SCN

Cl

2c

1.0

RT S N

S

Cl

4h

97

9 SCN

2d

2.0

RT S N

S

4i

94

10 SCN

Cl

2d

2.5

RT S N

S

Cl 4j

96

11

SCN

2d

2.5

RT S N

S

4k

86

12 SCN

2e

3.0

RT

N N

S

SS

S

4l

82

13 SCN

Cl

2e

3.0

RT

N N

S

SS

SCl

Cl

4m

83

aA mixture of 2 (1.0 mmol), 3 (1.0 mmol), SDS (10 mol%) in water (2 mL) was stirred at RT in open

air. For 4l and 4m, 2 mmol of 3 was used. bYield represents pure product isolated by column chromatography.

102

The carbodithioate esters are identified by melting point and compared with literature

report (for solid compounds) and hence characterized by 1H‒NMR,

13C‒NMR spectroscopy.

High resolution mass spectrometry was performed in some cases to identify the

carbodithioate esters. The HRMS spectra of compound 4b are given in Figure IV.3 below:

Figure IV.3. HRMS of compound 4b

To broaden the scope of the reaction further, alkyl thiocyanates bearing β‒carbonyl

function, 5 (e.g. aroyl methyl thiocyanates) or β‒alkenyl function, 6 (e.g. styrenyl methyl

thiocyanates) were subjected to similar reaction. Corresponding organic carbodithioate esters

containing carbonyl or styrenyl methyl group could be easily synthesized in aqueous medium

at ambient temperature. Three different dithiocarbamate salts of sec. amine (2b‒2d) were

used and the results are presented in Table IV.3 (7a‒7e, 8a and 8b). In all cases,

corresponding benzoyl methyl carbodithioates bearing Cl, Br or NO2 groups attached with

the aromatic ring were prepared in excellent isolated yields (7a‒7e). All the compounds were

characterized by spectral data and compared with melting points wherever known and

reported. Facile preparation of these functionalized carbodithioate esters via easy

103

nucleophilic substitution reaction from alkyl thiocyanates in aqueous medium at ambient

temperature is notable and not reported previously via one‒pot three‒component reaction.

Table IV.3. Further functionalizations in the synthesis of S‒alkyl carbodithioates.a,b

XN

H

HX

N

S

S

n n +

R/R/

SDS (10 mol%)

Water, RT

6

7a-7e

or

SCN

SCN

O

Ph

O

S

S

NX

n

or

SPh

S

N

Xn

5

R/ = 4-Cl, 4-Br, 3-NO2

2b, X = O, n = 22c, X = CH2, n = 22d, X = CH2, n = 1 8a, 8b

Entry R2─SCN

(5 and 6)

Salt

(2)

Time(h)

)

T(oC) Product

(7 and 8)

Yield (%)

1

Br

O

SCN

2b

3.0

RT

Br

O

S

S

N

O

7a

95

2

Br

O

SCN

2c

3.0

RT

Br

O

S

S

N

7b

94

3

Cl

O

SCN

2c

4.0

RT

Cl

O

S

S

N

7c

95

4

O

SCN

NO2

2c

3.5

RT

O

S

S

N

NO2

7d

86

5

Cl

O

SCN

2d

3.0

RT

Cl

O

S

S

N

7e

96

6 SCN

2b

1.5

RT

8a

S

S

N

O

92

7 SCN

2c

1.5

RT S

S

N

8b

93

104

a A mixture of 2 (1.0 mmol), 5 or 6 (1.0 mmol), SDS (10 mol%) in water (2 mL) was stirred at RT in

open air. b Yield represents pure product isolated by column chromatography.

IV.4. Mechanism

The reaction presumably occurs via simple nucleophilic substitution reaction. Organyl

thiocyanates are considered as psuedohalides that might not produce the corresponding

carbocation easily and hence the reaction is expected to proceed via SN2 pathway (Scheme

IV.11). The dithiocarbamate salt consisting of both organyl cationic and anionic system

seems to be more active than using in situ mixture of sec. amine and CS2. Use of additives

like SDS might help organic reactants to become rather homogeneous affording excellent

conversions. The possibility of formation of thiyl radical via β‒bond cleavage of the alkyl

thiocyanate can be excluded as reaction conditions neither support radical formation nor the

corresponding disulfide is formed in the reaction.43,44

On the other hand, aqueous ferric

chloride solution produces blood‒red coloration suggesting the formation of thiocyanate

anion.

+

SDS / H2O

R S

S

N

FeCl3 solution gives blood red

colouration

R SS R

NH

H

N

S

S

R

S

C

N

+

Not formed through homolytic fission of -bond of

alkyl thiocyanate

SCN

NH

HRT

Scheme IV.11. Proposed reaction mechanism

IV.5. Conclusion

In conclusion, we have shown that easily accessible and air‒stable cyclic sec.

amine‒based dithiocarbamate salts could serve as an efficient reagent for the preparation of a

large variety of S‒substituted carbodithioate esters from rarely used organyl thiocyanates as a

common strategy. The use of this type salt not only shows superior activity to the existing

one‒pot three‒component procedure but also establishes as alternative reagent, obtained

easily in quantitative conversion, for the preparation of carbodithioate esters. The simple

procedure can be carried out at room temperature, in water medium and afforded with

excellent yields.

105

IV.6. Experimental section

IV.6.1. General information

Morpholine, piperidine and pyrrolidine were purchased from Lancaster and used after

distillation. Piperazine was purchased from Loba Chemie. Carbon disulfide (CS2) and sodium

dodecyl sulfate (SDS) were purchased from SDFCL and used directly. Benzyl, naphthyl

methyl, cinnamyl and aroyl methyl thiocyanates were prepared from reported procedure and

purified by column chromatography before use. Melting point of the solid compounds was

determined in concentrated H2SO4 bath. FT‒IR spectra were recorded with a FT‒IR‒8300

SHIMADZU spectrophotometer using a KBr pellet method for solid compounds and in neat

for liquid compounds. NMR spectra were taken in CDCl3 using a Bruker AV‒300

spectrometer operating for 1H at 300 MHz and for

13C at 75 MHz. The spectral data were

measured using TMS as the internal standard. HRMS was performed by Micromass Q‒TOF

Spectrometer under ESI (positive mode).

IV.6.2. General Procedure for the synthesis of cyclic ammonium salts of dithiocarbamic

acid (2b‒2e)41

A solution of CS2 (5 mmol) in diethyl ether (5 mL) was slowly added to a solution of

morpholine (10 mmol) or piperidine (10 mmol) or pyrrolidine (10 mmol) in diethyl ether (5

mL). The reaction mixtures were stirred for 30 min at room temperature. Solid salts were

precipitated during this time and were filtered off through Buchner funnel, washed with

diethyl ether and dried under vacuum to obtain the desired salts 2b–2d. In the case of 2e, a

solution of CS2 (6 mmol) in diethyl ether (5 mL) was slowly added to a solution of piperazine

(9 mmol) in diethyl ether (6 mL). The reaction mixture was stirred for 45 min at room

temperature. The grey solids were filtered off, washed with diethyl ether and dried under

vacuum to get the desired salt 2e.

IV.6.2.1. Physical properties and spectral data of cyclic ammonium salts of

dithiocarbamic acid (2b‒2e)

Morpholinium morpholinodithioformate (Salt 2b)41

NO

H

H

N O

S

S

White solid; yield: 1.23 g (98%); mp 197200 oC (Lit.

41 Mp 195197

oC)

106

IR (KBr): νmax = 2854, 2711, 2475, 1583, 1420, 1255, 1215, 1112, 978, 876 cm‒1

.

Piperidinium piperidinodithioformate (Salt 2c)

N

H

H

N

S

S

White solid; yield: 1.20 g (98%); mp 164166 oC (Lit.

41 Mp

160

oC)

IR (KBr): νmax = 2936, 2843, 2731, 2497, 1583, 1409, 1215, 1122, 958 cm‒1

.

Pyrrolidinium pyrrolidinodithioformate (Salt 2d)

N

S

S

NH

H

Off‒white solid; yield: 1.05 g (96%); mp 149151 oC

IR (KBr): νmax = 2946, 2864, 2516, 2393, 1390, 1318, 1164, 999, 938 cm‒1

.

Bis(piperazinium)piperazine‒1,4‒dicarbodithioate (Salt 2e)

N N

S

SS

SN NH

H

HNHN

H

H

Grey solid; yield: 1.19 g (97%); mp 238242 oC

IR (KBr): νmax = 3162, 2915, 2434, 2331, 1634, 1390, 1225, 1123, 958, 855 cm‒1

.

IV.6.3. General procedure for the synthesis of S‒alkyl carbodithioate esters

A mixture of organyl thiocyanate (1 mmol), dithiocarbamate salt (1 mmol) and sodium

dodecyl sulfate (SDS, 0.1 mmol) in water (2 mL) was stirred vigorously with a magnetic bar

at room temperature. The progress of the reaction was monitored by tlc. After the reaction

was continued for specified time, as mentioned in Table IV.2 & IV.3, the reaction mixture

was extracted with ethyl acetate (3×5 mL) and the combined organic extracts were collected

over anhydrous Na2SO4. Evaporation of the volatiles afforded the crude product, which was

further purified by column chromatography over silica gel. Elution with a mixture of

EtOAc−PE furnished the desired product. Yields of the products are shown in Table IV.2 &

IV.3.

107

All products were identified and characterized by spectral data (FT‒IR, 1H‒ &,

13C‒NMR), by melting point for solid compounds (compared wherever known). Unknown

carbodithioate esters were further analyzed either by HRMS or by elemental analysis.

IV.6.3.1. Physical properties and spectral data of carbodithioate esters

Table IV.2, 4a

Benzyl morpholine‒4‒carbodithioate37

S N

S

O

Light yellow solid, mp 6465 oC (Lit.

32 5960

oC)

IR (KBr): νmax = 3038, 2976, 2869, 1920, 1635, 1617, 1559, 1489, 1456, 1304, 1271, 1235,

924, 825, 725, 543 cm‒1

.

1H NMR (CDCl3, 300 MHz): δ/ppm 3.73 (s, 4H, 2 × OCH2), 4.014.33 (m, 4H, 2 × NCH2),

4.57 (s, 2H, SCH2), 7.227.39 (m, 5H).

13C NMR (CDCl3, 75 MHz): δ/ppm 42.0 (SCH2), 50.8 (NCH2), 66.3 (OCH2), 127.6, 128.7,

129.4, 135.8, 197.1 (C=S).

Table IV.2, 4b

2‒Chlorobenzyl morpholine‒4‒carbodithioate

S N

S

OCl

White crystalline solid, mp 9496 oC

IR (KBr): νmax = 3053, 2992, 2931, 2855, 1918, 1654, 1635, 1617, 1542, 1444, 1347, 1310,

1271, 1053, 1028, 868, 731, 582 cm‒1

.

1H NMR (CDCl3, 300 MHz): δ/ppm 3.77 (s, 4H, 2 × OCH2), 4.17 (s, br, 4H, 2 × NCH2), 4.76

(s, 2H, SCH2), 7.217.64 (m, 4H).

13C NMR (CDCl3, 75 MHz): δ/ppm 39.5 (SCH2), 50.9 (NCH2), 66.2 (OCH2), 126.9, 129.1,

129.6, 131.6, 134.1, 134.6, 196.9 (C=S).

HRMS (ESI): m/z [M+Na]+ calcd for C12H14ClNONaS2: 310.0103; found 310.0105.

108

Table IV.2, 4c

4‒Chlorobenzyl morpholine‒4‒carbodithioate

S N

S

OCl

White crystalline solid, mp 7981 oC

IR (KBr): νmax = 3007, 2977, 2916, 2870, 1833, 1656, 1620, 1542, 1423, 1268, 1217, 1034,

998, 837, 643 cm‒1

.

1H NMR (CDCl3, 300 MHz): δ/ppm 3.66 (s, 4H, 2 × OCH2), 3.90 (s, 2H, NCH2), 4.17 (s, 2H,

NCH2), 4.47 (s, 2H, SCH2), 7.177.25 (m, 4H).

13C NMR (CDCl3, 75 MHz): δ/ppm 40.83 (SCH2), 50.83 (NCH2), 66.10 (OCH2), 128.60,

130.57, 133.26, 134.59, 196.50 (C=S).

Table IV.2, 4d

(Naphthalen‒1‒yl) methyl morpholine‒4‒carbodithioate

S N

S

O

Light brown solid, mp 115117 oC

IR (KBr): νmax = 3053, 2976, 2900, 2869, 1699, 1578, 1538, 1420, 1356, 1301, 1271, 1189,

998, 786, 630 cm‒1

.

1H NMR (CDCl3, 300 MHz): δ/ppm 3.66 (s, 4H, 2 × OCH2), 3.914.06 (m, 4H, 2 × NCH2),

4.95 (s, 2H, SCH2), 7.317.52 (m, 4H), 7.717.98 (m, 2H), 8.008.01 (m, 1H).

13C NMR (CDCl3, 75 MHz): δ/ppm 40.3 (SCH2), 50.5 (NCH2), 66.2 (OCH2), 123.9, 125.4,

126.0, 126.5, 128.3, 128.8, 128.8, 131.0, 131.8, 133.9, 197.2 (C=S).

Table IV.2, 4e

Benzyl piperidine‒1‒carbodithioate45

S N

S

109

Pale yellow viscous liquid

IR (neat): νmax = 3040, 2974, 2864, 1945, 1620, 1590, 1545, 1495, 1358, 1340, 1291, 1279,

1222, 1016, 980, 840, 742 cm‒1

.

1H NMR (CDCl3, 300 MHz): δ/ppm 1.62 (s, 6H, NCH2(CH2)3), 3.80 (s, br, 2H, NCH2), 4.21

(s, br, 2H, NCH2), 4.49 (s, 2H, SCH2), 7.157.33 (m, 5H).

13C NMR (CDCl3, 75 MHz): δ/ppm 24.3 (NCH2CH2CH2), 25.8 (NCH2CH2), 42.2 (SCH2),

52.7 (NCH2), 127.4, 128.6, 129.4, 136.1, 195.3 (C=S).

Table IV.2, 4f

2‒Chlorobenzyl piperidine‒1‒carbodithioate

S N

S

Cl

Yellow viscous liquid

IR (neat): νmax = 3010, 2970, 2860, 1996, 1580, 1546, 1493, 1357, 1340, 1280, 1224, 1074,

946, 840, 746, 650 cm‒1

.

1H NMR (CDCl3, 300 MHz): δ/ppm 1.69 (s, 6H, NCH2(CH2)3), 3.87 (s, br, 2H, NCH2), 4.29

(s, br, 2H, NCH2), 4.72 (s, 2H, SCH2), 7.187.23 (m, 2H), 7.347.38 (m, 1H), 7.547.58 (m,

1H).

13C NMR (CDCl3, 75 MHz): δ/ppm 24.3 (NCH2CH2CH2), 25.6 (NCH2CH2), 39.7 (SCH2),

51.4 (NCH2), 53.1 (NCH2), 126.9, 128.9, 129.5, 131.6, 134.4, 134.5, 194.9 (C=S).

Table IV.2, 4g

(Naphthalen‒1‒yl) methyl piperidine‒1‒carbodithioate

S N

S

White solid, mp 9395 oC

IR (KBr): νmax = 3038, 2947, 2870, 1620, 1596, 1563, 1542, 1474, 1435, 1399, 1365, 1281,

1235, 1210, 1113, 980, 870, 776, 670, 588 cm‒1

.

110

1H NMR (CDCl3, 300 MHz): δ/ppm 1.63 (s, 6H, NCH2(CH2)3), 3.75 (s, br, 2H, NCH2), 4.27

(s, br, 2H, NCH2), 4.93 (s, 2H, SCH2), 7.317.58 (m, 4H), 7.717.85 (m, 2H), 8.08.01 (m,

1H).

13C NMR (CDCl3, 75 MHz): δ/ppm 24.3 (NCH2CH2CH2), 25.9 (NCH2CH2), 40.6 (SCH2),

52.8 (NCH2), 124.1, 125.5, 125.9, 126.4, 128.3, 128.6, 128.8, 131.4, 131.9, 133.9, 195.3

(C=S).

HRMS (ESI): m/z [M+Na]+ calcd for C17H19NNaS2: 324.0857; found 324.0855.

Table IV.2, 4h

4‒Chlorobenzyl piperidine‒1‒carbodithioate

S N

S

Cl

White solid, mp 8385 oC

IR (KBr): νmax = 3007, 1961, 2855, 1632, 1617, 1577, 1542, 1508, 1481, 1429, 1378, 1281,

1225, 1110, 1080, 974, 843, 746, 652 cm‒1

.

1H NMR (CDCl3, 300 MHz): δ/ppm 1.62 (s, 6H, NCH2(CH2)3), 3.79 (s, br, 2H, NCH2), 4.22

(s, br, 2H, NCH2 ), 4.44 (s, 2H, SCH2), 7.157.27 (m, 4H).

13C NMR (CDCl3, 75 MHz): δ/ppm 24.3 (NCH2CH2CH2), 25.5 (NCH2CH2), 41.2 (SCH2),

53.1 (NCH2), 128.7, 130.7, 133.2, 135.0, 194.7 (C=S).

Table IV.2, 4i

Benzyl pyrrolidine‒1‒carbodithioate45

S N

S

Yellow liquid

IR (neat): νmax = 3048, 2970, 2865, 1903, 1590, 1440, 1365, 1308, 1216, 1070, 1012, 944,

826, 780, 503 cm‒1

.

1H NMR (CDCl3, 300 MHz): ppmm, 4H, NCH2(CH2)2) 3.62 (t, J = 6.3 Hz, 2H,

NCH2), 3.93 (t, J = 6.9 Hz, 2H, NCH2), 4.58 (s, 2H, SCH2), 7.227.33 (m, 3H), 7.387.41

(m, 2H).

111

13C NMR (CDCl3, 75 MHz): ppm 24.3 (NCH2CH2), 26.1 (NCH2CH2), 41.3 (SCH2), 50.5

(NCH2), 55.0 (NCH2), 127.4, 128.6, 129.3, 136.5, 192.4 (C=S).

Table IV.2, 4j

4‒Chlorobenzyl pyrrolidine‒1‒carbodithioate

S N

S

Cl

Pale yellow solid, mp 6062 oC

IR (KBr): νmax = 2966, 2864, 1903, 1595, 1441, 1328, 1092, 1009, 948, 825, 744, 507 cm

‒1.

1H NMR (CDCl3, 300 MHz): ppmm, 4H, NCH2(CH2)2) 3.62 (t, J = 6.3 Hz,

2H, NCH2), 3.93 (t, J = 6.9 Hz, 2H, NCH2), 7.247.27 (m, 2H), 7.327.35 (m, 2H).

13C NMR (CDCl3, 75 MHz): ppm 24.2 (NCH2CH2), 26.0 (NCH2CH2), 40.2 (SCH2), 50.6

(NCH2), 55.1 (NCH2), 128.6, 130.6, 133.1, 135.4, 191.8 (C=S).

Table IV.2, 4k

(Naphthalen‒1‒yl) methyl pyrrolidine‒1‒carbodithioate

S N

S

White solid, mp 116118 oC

IR (KBr): νmax = 3040, 2950, 2880, 1542, 1450, 1400, 1364, 1342, 1280, 1210, 1134, 1072,

980, 808, 770, 672, 540 cm‒1

.

1H NMR (CDCl3, 300 MHz): /ppm 1.871.97 (m, 4H, NCH2(CH2)2), 3.51 (t, J = 6.9 Hz,

2H, NCH2), 3.94 (t, J = 6.6 Hz, 2H, NCH2), 5.01 (s, 2H, SCH2), 7.347.40 (m, 1H),

7.437.54 (m, 2H), 7.58 (d, J = 6.9 Hz, 1H), 7.76 (d, J = 8.1 Hz, 1H), 7.817.84 (m, 1H),

8.08 (d, J = 8.1 Hz, 1H).

13C NMR (CDCl3, 75 MHz): /ppm 24.3 (NCH2CH2), 26.1 (NCH2CH2), 39.6 (SCH2), 50.5

(NCH2), 55.0 (NCH2), 124.1, 125.5, 125.9, 126.4, 128.2, 128.6, 128.8, 131.8, 131.8, 133.9,

192.3 (C=S).

112

Table IV.2, 4l

Dibenzyl piperazine‒1,4‒dicarbodithioate46

N N

S

SS

S

White solid, mp 124126 oC (Lit.

46 122123

oC)

IR (KBr): νmax = 3068, 3038, 2931, 1538, 1505, 1474, 1435, 1413, 1277, 1210, 1159, 1043,

924, 849, 694 cm‒1

.

1H NMR (CDCl3, 300 MHz): /ppm 4.18 (s, br, 8H, 4 × NCH2), 4.51 (s, 4H, 2 × SCH2)

7.197.32 (m, 10H).

13C NMR (CDCl3, 75 MHz): /ppm 42.2 (SCH2), 48.7 (NCH2), 127.7, 128.7, 129.4, 135.5,

197.5 (C=S).

Table IV.2, 4m

Bis‒(2‒chlorobenzyl) piperazine‒1,4‒dicarbodithioate

N N

S

SS

SCl

Cl

Grey solid, mp 148150 oC

IR (KBr): νmax = 2916, 1640, 1420, 1276, 1041, 990, 928, 846, 744 cm

‒1.

1H NMR (CDCl3, 300 MHz): ppm 4.28 (s, br, 8H, 4 × NCH2), 4.72 (s, 4H, 2 × SCH2)

7.187.26 (m, 4H), 7.357.39 (m, 2H), 7.537.56 (m, 2H).

13C NMR (CDCl3, 75 MHz): ppm 39.6 (SCH2), 48.9 (NCH2), 126.9, 129.2, 129.6, 131.5,

133.8, 134.6, 197.2 (C=S).

Table IV.3, 7a

113

4‒Bromo phenacyl morpholine‒4‒carbodithioate

Br

O

S

S

N

O

White solid, mp 164166 oC

IR (KBr): νmax = 2967, 2906, 2855, 1686, 1583, 1430, 1276, 1125, 1112, 990, 816, 539 cm

‒1.

1H NMR (CDCl3, 300 MHz): δ/ppm 3.71 (t, J = 4.8 Hz, 4H, 2 × OCH2), 3.97 (s, br, 2H,

NCH2), 4.2 (s, br, 2H, NCH2), 4.77 (s, 2H, SCH2), 7.547.59 (m, 2H), 7.847.88 (m, 2H).

13C NMR (CDCl3, 75 MHz): δ/ppm 44.3 (SCH2), 51.5 (NCH2), 66.2 (OCH2), 128.8, 130.1,

132.1, 134.9, 192.3 (C=O), 195.65 (C=S).

Table IV.3, 7b

4‒Bromo phenacyl piperidine‒1‒carbodithioate

Br

O

S

S

N

White solid, mp 116118 oC

IR (KBr): νmax = 3007, 2947, 2869, 1687, 1584, 1438, 1362, 1286, 1253, 973, 858, 666 cm

‒1.

1H NMR (CDCl3, 300 MHz): /ppm1.65 (s, 6H, NCH2(CH2)3), 3.89 (s, br, 2H, NCH2), 4.18

(s, br, 2H, NCH2), 4.77 (s, 2H, SCH2), 7.547.57 (m, 2H), 7.867.89 (m, 2H).

13C NMR (CDCl3, 75 MHz): ppm24.2 (NCH2CH2CH2), 25.9 (NCH2CH2), 44.5 (SCH2),

51.7 (NCH2), 53.6 (NCH2), 128.6, 130.1, 131.9, 135.0, 192.7 (C=O), 193.7 (C=S).

Table IV.3, 7c

4‒Chloro phenacyl piperidine‒1‒carbodithioate

Cl

O

S

S

N

Yellowish white solid, mp 110112 oC

114

IR (KBr): νmax = 3007, 2961, 2855, 1690, 1587, 1438, 1347, 1244, 1113, 971, 858, 682, 548

cm‒1

.

1H NMR (CDCl3, 300 MHz): /ppm (s, 6H, NCH2(CH2)3), 3.89 (s, br, 2H, NCH2), 4.19

(s, br, 2H, NCH2), 4.77 (s, 2H, SCH2), 7.547.58 (m, 2H), 7.857.90 (m, 2H).

13C NMR (CDCl3, 75 MHz): ppm 24.2 (NCH2CH2CH2), 25.4 (NCH2CH2), 26.1

(NCH2CH2), 44.5 (SCH2), 51.8 (NCH2), 53.7 (NCH2), 128.7, 130.1, 132.0, 135.0, 192.7

(C=O), 193.6 (C=S).

Table IV.3, 7d

3‒Nitro phenacyl piperidine‒1‒carbodithioate

O

S

S

N

NO2

Pale yellow solid, mp 109111 oC

IR (KBr): νmax = 2926, 2854, 1697, 1613, 1532, 1430, 1337, 1204, 1112, 1072, 979, 804, 733,

672 cm‒1

.

1H NMR (CDCl3, 300 MHz): ppm 1.73 (s, 6H, NCH2(CH2)3), 3.97 (s, br, 2H, NCH2), 4.25

(s, br, 2H, NCH2), 4.86 (s, 2H, SCH2), 7.697.74 (m, 1H), 8.408.46 (m, 2H), 8.908.91 (m,

1H).

13C NMR (CDCl3, 75 MHz): /ppm 24.16 (NCH2CH2CH2), 26.02 (NCH2CH2), 44.09

(SCH2), 52.09 (NCH2), 53.79 (NCH2), 123.45, 127.49, 129.95, 134.13, 137.87, 148.58,

191.84 (C=O), 193.39 (C=S).

Table IV.3, 7e

4‒Chloro phenacyl pyrrolidine‒1‒carbodithioate

Cl

O

S

S

N

Pale yellow solid, mp 102104 oC

IR (KBr): νmax = 2957, 2876, 1676, 1583, 1430, 1286, 1184, 1080, 990, 958, 825, 528 cm

‒1.

115

1H NMR (CDCl3, 300 MHz): ppm 1.942.03 (m, 2H, NCH2CH2), 2.062.14 (m, 2H,

NCH2CH2), 3.74 (t, J = 6.9 Hz, 2H, NCH2), 3.9 (t, J = 6.9 Hz, 2H, NCH2), 4.85 (s, 2H,

SCH2), 7.447.47 (m, 2H), 8.018.04 (m, 2H).

13C NMR (CDCl3, 75 MHz): ppm 24.3 (NCH2CH2), 26.1 (NCH2CH2), 44.0 (SCH2), 50.8

(NCH2), 55.5 (NCH2), 128.9, 130.0, 134.4, 139.8, 190.7 (C=O), 192.4 (C=S).

Table IV.3, 8a

(E)‒Cinnamyl morpholine‒4‒carbodithioate36

S

S

N

O

White crystalline solid, mp 8082 oC (Lit.

36 reported as yellowish viscous liquid)

IR (KBr): νmax = 3038, 2961, 2869, 1720, 1620, 1577, 1469, 1304, 1268, 1220, 1113, 992,

755 cm‒1

.

1H NMR (CDCl3, 300 MHz): δ/ppm 3.78 (t, J = 4.5 Hz, 4H, 2 × OCH2), 4.174.24 (m, 6H, 2

× NCH2, SCH2), 6.286.38 (m, 1H, PhCH=CHCH2), 6.67 (d, J = 15.6 Hz, 1H, PhCH),

7.237.41 (m, 5H).

13C NMR (CDCl3, 75 MHz): δ/ppm 39.97 (SCH2), 50.90 (NCH2), 66.26 (OCH2), 123.68,

126.45, 127.76, 128.56, 133.95, 136.60, 197.03 (C=S).

Table 3, 8b

(E)‒Cinnamyl piperidine‒1‒carbodithioate36

S

S

N

White crystalline solid, mp 7375 oC (Lit.

36 reported as yellowish viscous liquid)

IR (KBr): νmax = 3048, 2947, 2869, 1617, 1566, 1472, 1435, 1265, 1235, 1135, 1116, 1110,

973, 743 cm‒1

.

1H NMR (CDCl3, 300 MHz): δ/ppm 1.63 (s, 6H, NCH2(CH2)3), 3.82 (s, br, 2H, NCH2),

4.014.13 (m, 2H, SCH2 ), 4.23 (s, br, 2H, NCH2), 6.206.31 (m, 1H, PhCH=CHCH2), 6.56

(d, J = 15.9 Hz, 1H, PhCH), 7.127.31 (m, 5H).

116

13C NMR (CDCl3, 75 MHz): δ/ppm 24.3 (NCH2CH2CH2), 26.0 (NCH2CH2), 40.2 (SCH2),

51.4 (NCH2), 124.2, 126.4, 127.7, 128.5, 133.6, 136.7, 195.0 (C=S).

IV.7. References

References are given in BIBLIOGRAPHY under Chapter IV (pp. 150‒153).

117

CHAPTER V

Synthesis of new 1,3‒dithioether‒Cu(I) complex

and its catalytic action in one‒pot

azide‒alkyne "click" reaction

118

V.1. Introduction

V.1.1. Azide–Alkyne Cycloaddition (AAC) reactions

1,2,3‒Triazoles are important heterocyclic scaffold in biological and pharmaceutical

viewpoint, such as H1‒antihistamine,1 anti‒bacterial,

2 and anti‒HIV activity,

3 and selective

β3‒adrenergic receptor agonism.4

The model reaction for the synthesis of 1,2,3‒triazole is the Huisgen [3+2] cycloaddition

reaction which was developed in 1984 by Rolf Huisgen (Scheme V.1).5 But the drawbacks in

this method is high reaction temperature and lack of regioselectivity both 1,4 as well as 1,5

substituted 1,2,3 triazoles are obtained by this method. Later on Sharpless and Meldal

independently revealed that Cu(I) could assist regiospecific formation of 1,4‒substituted

1,2,3‒triazole under milder condition.6

R1 N3 R2 H+Heating Slow

100 oC

N

N

N

R1

R2

N

N

N

R1

R2+

1, 5-isomer 1,4-isomer

Huisgen's 1, 3-dipolar cycloaddition

Scheme V.1. The primitive Huisgen‟s 1,3‒dipolar cycloaddition reaction

To make the reaction regioselective, various metal catalysts were introduced from last few

decades. Among all metal salts/catalysts, copper salts or catalysts were found to be superior

choice for this cycloaddition reaction. Various methodologies are reported where Cu(OAc)2,

CuCl2 or simple salts of Cu(I) or Cu(II) were used as main catalyst source. The simplest Cu(I)

catalyzed click triazole synthesis is effectively achieved by excess of CuSO4 and sodium

ascorbate where sodium ascorbate reduces the Cu(II) to Cu(I) and inhibit the aerobic

oxidation of Cu(II) species.7

Alternatively, preformed stable Cu(I) complexes with

phosphines or nitrogen ligands could be employed by small proportion. Polydentate nitrogen

donor and triphenyl phosphine are also used as ligands. But main problem of using phosphine

ligand gives unwanted Staudinger reaction.7

Many homogeneous and heterogeneous

Cu‒catalysts are also well known for azide‒alkyne cycloaddition reactions. In last decade,

polymeric Cu catalysts (coordination polymer of Cu) attract much interest for the synthesis of

triazole molecules.

The use of multicomponent approach is more convenient over two component Huisgen

[3+2] cycloaddition method as it avoids direct use of organic azides which are not only

119

difficult to handle because of their toxicity and explosive nature but also of its tedious

isolation and purification process.8

It should be noted that the noncatalyzed Huisgen reaction occurs at elevated temperature

and in the case of reactive substrates even at ambient temperature with significantly

prolonged reaction times. However, the microwave heating may help the reaction with a rate

enhancement to produce 1,4 substituted triazoles. The use of microwave irradiation has

significantly shortened reaction times, to minutes, with excellent yields and purities and

exclusive formation of the 1,4 isomer.9

Using polymer supported Cu(I) composite, Cu(I)‒pPDA (pPDA: polyphenylene diamine)

Mallick and his co‒workers showed azide alkyne cycloaddition (AAC) reaction by

microwave irradiation technique under solvent free condition. Both domestic as well as

laboratory microwave worked well to afford 1,2,3‒triazole derivatives. The reaction was

believed to proceed through the formation of Cu(0) acetylide complex intermediate. To avoid

the toxic and hazardous nature of the organic azide the reaction could also be achieved by

multicomponet approach using sodium azide and alkyl halide.10

V.2. Background and Objectives

For well‒defined catalyst system, PPh3, NHC, imidazole, sulfur and nitrogen based

molecules are among the most used ligands. The sulfur‒based ligands attract much attention

in the vicinity of copper complex formation and subsequently on click reaction.11

Cu‒thioamide catalyzed click reaction has been explored recently.12

Quick and highly efficient copper (I)‒catalyzed on‒water cycloaddition of water‒insoluble

aliphatic and aryl azides was excellently done by H. Fu and his group. The catalytic system in

this case was CuBr and thioanisole. They tried with various sulfur ligands in this protocol but

thioanisole was found to be the best one under this catalytic condition.13

N3 CuBr.PhSMe

Water, RT

NN

N

+

Scheme V.2. CuBr.PhSMe‒catalyzed cycloaddition reaction of alkyl azide and phenyl acetylene

A hybrid SNS ligand with an amine moiety and two sulfur moieties can effectively form

an one‒dimentional mononuclear polymer with copper [CuX2(SNS)]. T. S. A. Hor et al

synthesized SNS ligand based copper catalysts, which have been found to be efficient for

120

azide‒alkyne click reaction.The have synthesized a four different copper complexes with

SNS ligands and the complexes were characterized by various techniques. They studied the

effectiveness of these catalysts by monitoring an azide‒alkyne cycloaddition reaction in a

multicomponent approach between benzyl chloride, phenyl acetylene and sodium azide. The

substrates scope is limited here.14

SNH

S S

NH

SCu

BrBr

S

NH

SCu

ClCl

CuBr

MeOH

CuCl

MeOH

bis(2-(benzylthio)ethyl)amine (SNS)

NN

N

Cl

Cu-SNS catalysts

MeCN/H2O, RT

+ NaN3 +

Scheme V.3. Preparation of CuX2(SNS) catalysts and application towards azide‒alkyne click reaction

S.‒Q. Bai and T. S. A. Hor et al reported a new class of SNS ligands and found application

in copper complex formation. Hybrid nitrogen‒sulfur (SNS) ligands are promising in

catalytic reactions because of the assembling of hard and soft donors and hemilabile

functions in the corresponding ligands. These ligands were able to coordinate with CuI, CuBr

and CuCl salts. The copper complexes appeared as polymeric units and one‒pot azide‒alkyne

cycloaddition reactions were effectively done by these complexes.15

S

N

S

N

S

Cu N S N

Cu

Cu

Cu

H

Cu

RBr

NaN3+ +

R1

Cu cat. 2 mol%

CH3OH:H2O (1:1)

35 oC, 15 hN N

NR

R1

Cu-SNS ligands

1, 2, 3-triazole

Scheme V.4. Cu‒SNS catalyst for one‒pot azide‒alkyne cycloaddition reaction

A novel pyridyl and thioether hybridized 1, 2, 3‒triazole ligands have been synthesized by

T. S. A. Hor and his group from CuAAC click reactions. These compounds were further

121

utilized for making of new type of dithioether based CuI coordination complex. The resultant

complexes were again used in one‒pot azide‒alkyne click reactions. In this protocol the

reactions took long time for completion. This methodology opened a new dimension for the

polymeric coordination complex catalyzed click reactions.16

N SNCl

HClN S N

NN

N+

2-pyridyl or 4-pyridyl

NaN3, CuSO4

Na ascorbate

K2CO3, RTt-BuOH: H2O

CuICu-complex

Step 1.

Step 2.

R NaN3+ + R1 Br

Cu-complex, 0.5 mol%

MeOH: H2O = 1:1, 2 mL

50 oC, 24 h

N NN

R

R1

Click

Click

Click-and-click

Scheme V.5. “Click‒and‒click” – hybridised 1,2,3‒triazoles supported Cu(I) coordination polymers

for azide–alkyne cycloaddition

1,3‒Dithioether ligands play a vital role for the preparation of coordination clusters.17

They have wide applications in the field of phtophysical phenomena,17a,c

and in bio‒inorganic

chemistry.18

But, 1,3‒dithioether based CuI polymeric complexes have never been used for

1,3‒dipolar cycloaddition reaction. Here, we describe a clean methodology for the synthesis

of 1,2,3‒triazole molecules in presence of 1,3‒dithioether based CuI complex. Our

1,3‒bis(4‒fluorophenylthio)‒propane ligand based CuI coordination complex was first

synthesized and characterized by NMR, fluorescence spectroscopy and single crystal X‒ray

diffraction pattern. The catalyst undergoes a smooth azide‒alkyne cycloaddition reaction in

water‒acetonitrile (1:1, v/v) solvent mixture at 50 oC. Only 0.5 mg of the catalyst is required

for the complete conversion of the product.

V.3. Present work: Results and Discussion

V.3.1. Preparation of 1,3–bis(4–fluorophenylthio) –propane ligand (L1)

The 1,3–bis(4–fluorophenylthio)–propane ligand (L1) was synthesized according to our

previously reported procedure.19

This ligand was characterized by 1H– and

13C–NMR

spectroscopy. The synthetic procedure of L1 is given in experimental section.

V.3.2. Synthesis of CuI–1,3–bis(4–fluorophenylthio)–propane (L1) coordination

complex (complex 1)

122

The preparation procedure of the complex 1 is given in experimental section in details.

V.3.3. Characterization of complex 1

V.3.3.1. NMR spectroscopy

The as–synthesized complex 1 was characterized by several techniques such as 1H– and

13C– NMR, UV–Visible, fluorescence spectroscopy and by single crystal XRD techniques.

1H– and

13C–NMR spectra of complex 1 and the ligand 1,3–bis(4–fluorophenylthio)–

propane, L1 were taken separately in d6–DMSO solvent. Some changes were observed in 1H–

NMR spectra between L1 and complex 1, and this indicates the complex formation between

ligand L1 and CuI. The 1H–NMR spectra of L1 and the complex 1 are given in Figure V.1

and Figure V.2. In 1H–NMR spectrum of L1, a clear splitting into triplet and quintet are

observed but in 1H–NMR spectrum of complex 1 these pattern are absent. This indicates the

coordination may happen between CuI and sulfur donor atoms of the ligand L1. The spectra

also indicate the presence of the Cu(I) in the complex 1 rather than Cu(II).

123

Figure V.1. 1H–NMR spectra of L1 [1, 3–bis(4–fluorophenylthio)–propane] in d6–DMSO

124

Figure V.2. 1H–NMR spectra of complex 1 in d6–DMSO

V.3.3.2. UV–Visible and fluorescence spectroscopy

The λmax of the ligand L1 and complex 1 were determined by UV–Visible spectroscopy.

CuI, L1 and the complex 1 gave maximum absorption at λ = 240 nm, 252 nm and 246 nm

respectively (Figure V.3).

125

200 250 300 350 400

-0.2

0.0

0.2

0.4

0.6

0.8

1.0

1.2

240 nm

252 nm

246 nm

Complex 1

Ligand (L1)

CuI

AU

Wavelength (nm)

Figure V.3. UV–Visible spectra of CuI, L1 and complex 1 were taken in MeCN

The 1–D polymers, [(Cu2X2)(μ–RS(CH2)5SR)2]n exhibited the maxima at 450 nm.20

It was

found that the change of halogen atom form iodine to bromine caused the emission band at

lower wavelength.20

The spacer size might be one of the key factor for decreasing the

emission wavelength. In our study, the complex 1 in liquid–state shows broad

photoluminescent emissions at room temperature (Figure V.4). The maximum emission is

341 nm under the excitation wavelengths of 246 nm for complex 1. Since our complex 1

contains fluorine atoms and two CH2 groups less than the reported coordination polymers so

the spacer effect might be the key factor in this particular case. As a result, a much lower

emission band is observed. Additionally, the fluorine atoms attached with the phenyl rings

may affect photoluminescent properties of the as–synthesized Cu(I) complex.

250 300 350 400 450 500 550 600 650

0

10000

20000

30000

40000

50000

60000

70000

325 nm

341 nm

Inte

nsi

ty (

AU

)

Wavelength (nm)

Emission scan with excitation of 246 nm

Figure V.4. Fluorescence spectrum of complex 1 (5 μM solution) in MeCN solvent

126

V.3.3.3. Single crystal X–ray diffraction

Complex 1 crystallizes in the monoclinic space group P 21/c, and shows a polymeric

propagation in the form of [(CuI)2{ArS(CH2)3SAr}2]n metallopolymer (Figure V.5). The 1D–

network is built up upon dimeric Cu2I2 units, which are interconnected via dithioether

ligands. The framework consists of Cu2(μ–I)2 prismatic part connected with the dithioether

ligands. Within the cluster core, the Cu‒I bond lengths range between 2.5867 (5) and 2.6443

(12) Å. The Cu…Cu distance between the two Cu (I) centers, 2.7812 (10) Å falls

significantly below the sum of the vander Waals radius (2.8 Å). The mean Cu‒S bond length

of range between 2.3339 (11) to 2.3551 (12) Å similar to [{Cu(μ–I)2Cu}2{μ–

PhS(CH2)3SPh}2]n (2.3465 Å). The angle between Cu…I…Cu is 64.23° and I…Cu…I

115.77° in the metallocluster. The crystal data, data collection and structure refinement for

complex 1 is given in the Table V.1.

Table V.1. Crystal Data, Data Collection and Structure Refinement for complex 1

Formula C15H14CuF2IS2 Cell volume/Å3 1684.06 (12)

Formula weight 486.83 Cell formula units Z, Z/ 4, 0

Temperature/K 293 (2) density (calculated) g/cm3 1.920

Description Prismatic θ range for data collection/deg 1.43–25.07

Colour White F(000) 944.0

Crystal system Monoclinic crystal size/mm 0.08, 0.12,

0.24

Space group P 21/C Absorption co–efficient (μ) 3.387

a/Å 16.2003(7) index ranges –19 ≤ h ≤ 15

–8 ≤ k ≤ 8

–18 ≤ l ≤ 18

b/Å 7.4990(3) reflections collected 20413

c/Å 15.7177(7) independent reflections 2989

Cell angle (α) 90o refinement method full–matrix

least–squares

on F2

Cell angle (β) 118.12o (2) R–equivalents 0.0424

Cell angle (γ) 90 o Sigma I/net I 0.0265

127

(a) (b)

(c)

Figure V.5. View of (a) the monomeric unit of the coordination polymer, (b) ORTEP picture of the

complex 1 and (c) infinite 1–D chain of complex 1 incorporating dinuclear Cu(μ2–I)2Cu motifs along

„b‟ axis

Selected bond lengths and bond angles are also given in the Tables below.

Table V.2. Selected bond length

Bond Length Bond Length

I1–Cu1 2.5867 (5) C10–C11 1.362 (7)

I1–Cu1 2.6443 (6) C13–C12 1.377 (6)

Cu1–S1 2.339 (11) C13–C14 1.384 (6)

Cu1–S2 2.3551 (12) C14–C15 1.395 (6)

Cu1–I1 2.6443 (6) C20–C19 1.373 (6)

S2–C19 1.782 (4) C20–C21 1.394 (7)

S2–C22 1.813 (4) C24–C23 1.524 (6)

S1–C13 1.775 (4) C24–S1 1.813 (4)

128

S1–C24 1.813 (4) C19–C18 1.399 (6)

F1–C10 1.366 (5) C18–C17 1.363 (7)

F2–C16 1.355 (6) C11–C12 1.389 (7)

C22–C23 1.507 (7) C17–C16 1.381 (9)

C10–C15 1.348 (7) C16–C21 1.345 (9)

Table V.3. Selected bond angle

Bond Angle Bond Angle

Cu1–I1–Cu1 64.23 (2) C11–C10–F1 117.9 (4)

S1–Cu1–S2 108.26 (4) C12–C13–C14 119.9 (4)

S1–Cu1–I1 113.87 (3) C12–C13–S1 124.3 (3)

S2–Cu1–I1 111.66 (3) C14–C13–S1 115.9 (3)

S1–Cu1–I1 105.37 (3) C13–C14–C15 119.8 (4)

S2–Cu1–I1 100.87 (3) C19–C20–C21 119.9 (5)

I1–Cu1–I1 115.77 (2) C23–C24–S1 110.9 (3)

S1–Cu1–Cu1 128.93 (4) C20–C19–C18 120.5 (4)

S2–Cu1–Cu1 121.50 (4) C20–C19–S2 117.4 (3)

I1–Cu1–Cu1 58.89 (18) C18–C19–S2 122.1 (3)

I1–Cu1–Cu1 56.88 (18) C17–C18–C19 119.3 (5)

C19–S2–C22 101.3 (2) C22–C23–C24 116.1 (4)

C19–S2–Cu1 109.32 (14) C10–C11–C12 118.3 (4)

C22–S2–Cu1 103.62 (15) C18–C17–C16 118.8 (5)

C13–S1–C24 102.8 (2) C13–C12–C11 120.1 (4)

C13–S1–Cu1 104.03 (13) C10–C15–C14 118.5 (4)

C24–S1–Cu1 110.61 (15) C21–C16–F2 118.6 (6)

C23–C22–S2 114.7 (3) C21–C16–C17 123.4 (5)

C15–C10–C11 123.3 (4) F2–C16–C17 117.9 (6)

C15–C10–F1 118.8 (4) C16–C21–C20 118.1 (5)

V.3.4. Catalytic application

The catalytic activity of complex 1 towards the one–pot AAC reaction under base–free

conditions was optimized by the model reaction of benzyl bromide, NaN3 and

phenylacetylene with varying catalyst loading under different temperature and solvents

conditions. The reaction was first studied at neat condition and higher temperature (60 °C)

with 5 mg of the complex 1. After 5 hours, 84% of the product was isolated under this

condition (entry 1). When methanol was used as solvent relatively less conversion was

achieved compare to neat condition (70%) (entry 2). Similarly the reactions on acetonitrile

and water gave 87% and 80% yield of the product respectively (entry 3 & 4). A binary

solvent mixture of MeCN and water (1:1) resulted excellent yield of the desired product with

129

lesser time (entry 5). The reaction was also carried out in μW reactor and to check the

enhancement of the yield and rate of the model reaction. But unfortunately the yield of the

reaction could not increase tremendously than conventional thermal heating (entry 6). The

drop of product conversion was found when we studied the reaction at room temperature

(entry 7). The catalyst loading was also performed from entry 8 to entry 10 and the catalytic

activity was effective for 0.5 mg (0.00088 mmol of Cu was present in 0.5 mg of the complex

1, which was confirmed by Atomic absorption spectroscopy (AAS) study) of the complex 1

for this reaction (Table V.4, entry 11).

Table V.4. Optimization of reaction conditions for the one–pot azide–alkyne click reaction.

NaN3

Br

+ +

Complex 1x mg

Solvent, TemperatureN

NN

Entry Solvent Complex 1 (mg) Temperature

(oC)

Time (h) Yielda (%)

1 Neat 5 60 5 84

2 Methanol 5 60 5 70

3 Acetonitrile 5 60 5 87

4 Water 5 60 8 80

5 Acetonitrile: water 5 60 3 97

6 Acetonitrile: water 5 60 0.5 92b

7 Acetonitrile: water 5 50 3 97

8 Acetonitrile: water 5 RT 5 85

9 Acetonitrile: water 3 50 3 97

10 Acetonitrile: water 1 50 3 96

11 Acetonitrile: water 0.5 50 3 96

Reaction conditions: Phenyl acetylene (1 mmol), NaN3 (1.2 mmol) and benzyl bromide (1.1 mmol),

complex 1 (0.5 mg, 0.00088 mmol of Cu), MeCN:H2O (1:1 (v/v), 2 mL). aIsolated yield after purification through column chromatography by silica gel.

bReaction tried on focused microwave reactor.

The complex 1 is air stable and can tolerate a range of alkyl, allyl and cinnamyl halides

under mild reaction conditions (Table V.5). The terminal alkynes have participated in this

reaction very smoothly. Phenyl acetylene, 4–ethanyl toluene and 2–bromo phenyl acetylene

gave excellent yield (entry 1 to 3). 4–nitro–phenyl acetylene also gave excellent yield but

slightly lesser than the previous one (entry 4). Apart from aromatic alkyne, alphatic alkyne

gave excellent yield (entry 5) also. Allyl bromide was found to be very active as a coupling

130

partner in this AAC reaction (entry 6 and 7). Benzyl chlorides are also reactive as benzyl

bromides (entry 8 and 9). But the same reaction when carried out with diphenyl acetylene, an

internal alkyne no reaction occurred even after 12 hours (entry 10). This methodology has

been also applied for cinnamyl chlorides (entry 11 and 12). All the reactions proceeded

without difficulty and the products were isolated in good to excellent yields in high purity in

column chromatography.

Table V.5. Catalytic activity of complex 1 in the AAC reaction.a

NaN3+ +

Complex 10.5 mg

MeCN:H2O(2:1), 50 oC

R1

N

NN R2

R1 X R2 H

Entry R1CH2X R2 H Time

(h)

Product Yield

(%)

1 PhCH2Br Ph 3 Ph N

N N

Ph

97

2 PhCH2Br p-Tol 3 Ph N

N N

p-Tol

96

3 PhCH2Br o-Br-Ph 5 Ph N

N N

o-Br-Ph

96

4 PhCH2Br p-O2N-Ph 4 Ph N

N N

p-NO2-Ph

91

5 PhCH2Br Ph

OH

4 Ph N

N N OHPh

90

6 Br Ph 4 N

N N

Ph

81

7 Br p-Tol 4 N

N N

p-Tol

83

8 PhCH2Cl Ph 3.5 Ph N

N N

Ph

95

9 PhCH2Cl p-Tol 3.5 Ph N

N N

p-Tol

94

10 PhCH2Br Ph Ph 12

Ph N

N N

Ph

Ph

Not

isolated

11 Ph Cl Ph 4 N

N N

PhPh

84

131

12 Ph Cl p-Tol 4 N

N N

p-TolPh

85

Reaction conditions: Teminal alkynes (1 mmol), NaN3 (1.2 mmol) and benzyl/allyl/cinnamyl halide

(1.1 mmol), complex 1 (0.5 mg, 0.00088 mmol of Cu), MeCN: H2O (1:1 (v/v), 2 mL). aIsolated yield after purification through column chromatography by silica gel.

V.3.5. One–pot two–step process for the synthesis of sulfur functionalized 1,2,3–triazole

derivative

1,2,3–triazoles containing diverse functional groups have strong potential as steel

corrosion inhibitors or suitable ligands for transition–metal chemistry. We have prepared

sulfur functionalized pendant arms of 1,2,3–triazole compounds in a multicomponent

approach via one–pot two–step reaction using our catalyst. Benzenethiol (1.1 mmol, 121 mg)

was first reacted with propergyl bromide (1 mmol, 119 mg) in presence of triethyl amine (2

mmol, 202 mg) in water at room temperature. After 2 h, benzyl bromide (1.1 mmol, 188 mg)

and sodium azide (1.2 mmol, 78 mg) and complex 1 (0.5 mg, 0.00088 mmol of Cu) were

added to the reaction mixture. The progress of the reaction was monitored by tlc and finally

the desired product was isolated in column chromatography. The preparation methodology is

depicted in the Scheme V.6 below.

SH

BrWater

Et3N

RT, 2 h, Stirring+

SBr

NaN3

Complex 1, MeCN

50 oC

SN

NN

Scheme V.6. One–pot two–step synthesis of sulfur functionalized 1,2,3–triazole derivative

V.3.6. Mechanism

A possible mechanism for this multicomponent azide–alkyne coupling reaction was

proposed in Scheme V.7. The reaction was initiated by the metalation of phenylacetylene in

the presence of complex 1 giving copper acetylide. In next step alkyl azide was formed in–

situ by the substitution reaction between alkyl halide and sodium azide. The polymeric

copper acetylide moiety reacted with alkyl azide in cycloaddition fashion followed by

elimination of complex 1 give rise to 1,4–disubstituted triazole as the main product.21

132

Scheme V.7. A plausible mechanistic path for the multicomponent AAC reaction

V.4. Conclusion

In summary, we have prepared a highly efficient CuI–1, 3–bis(4–fluorophenylthio)–

propane catalyst for one–pot multicomponent cycloaddition reaction among aliphatic/aryl

alkynes, allyl/benzyl halides and sodium azide at 50 oC. The multicomponent approach of

this method can avoid the direct use of toxic and explosive organic azides. The method uses

commercially available and inexpensive combination CuI and easily prepared 1, 3–bis(4–

fluorophenylthio)–propane ligand as the catalyst system. Excellent regioselectivity was

observed for the synthesis of 1,2,3–triazole compounds.

V.5. Experimental section

V.5.1. General information

CuI was purchased from Sd–fine chemicals ltd., India. Allyl bromide and 4–

flurothiophenol were purchased from Sd–fine chemicals and Sigma–Aldrich, India

respectively. Allyl bromide was purified by simple distillation before use and other chemicals

were purchased and used directly. UV–Visible spectra were recorded by Jasco V–530

UV/VIS Spectrophotometer in acetonitrile solvent. Photoluminescences were measured using

Photon Technologies International Quantamaster–40 spectrofluorimeter. Single crystal X–ray

133

diffraction data were measured by using the Oxford Diffraction X–Calibur CCD System and

data were collected independent data were collected with MoKα radiation at 150 K. CEM

Discover microwave reactor was used for microwave heating. AAS was measured by Varian

Spectr AA 50B Atomic Absorption Spectrometer. NMR spectra were taken in CDCl3 or d6–

DMSO using a Bruker Avance AV–300 spectrometer operating for 1H at 300 MHz and for

13C at 75 MHz. The spectral data were measured using TMS as the internal standard.

V.5.2. Procedure for the synthesis of 1,3–bis(4–fluorophenylthio)–propane (L1)

A mixture of allyl bromide (2.0 mmol, 240 mg) and 4–fluorobenzenethiol (5.0 mmol, 640

mg) was mixed with silica gel (mesh size 60–120, 1.0 g), moistened with few drops of water

and stirred magnetically by using a spin magnetic bar for 16 h. The reaction was monitored

by tlc. After completion of the reaction, the product was purified by column chromatography

over silica gel. The product was eluted with light petroleum and we get the 1,3–bis(4–

fluorophenylthio)–propane. 1,3–bis(4–fluorophenylthio)–propane was characterized by 1H–

and 13

C–NMR and compared with literature data.19

V.5.3. Procedure for the synthesis of Complex 1

CuI (1 mmol, 190 mg) was first stirred in dry and distilled acetonitrile (5 mL) at room

temperature for 1 hour. Then a solution of 1,3–bis(4–fluorophenylthio)–propane ligand L1 (2

mmol, 592 mg) in acetonitrile was added to the solution of CuI and stir the reaction mixture

for 1 h at room temeperature. The reaction mixture was then stirred under refluxing condition

for 20 hours and kept this at room temperature to see if any crystal separates from the

reaction mixture. But no crystals came out from the reaction mixture at room temperature

even after 2 days. After that distilled petroleum ether was added drop wise to the

concentrated reaction mixture and poured it for cooling in refrigerator. A pale yellow

coloured crystal was found on the light petroleum part and separated by simple filtration and

washed it with light petroleum (4×5 mL). Finally the crystals were dried under vacuum. This

catalyst is named as complex 1.

V.5.4. General procedures for Cu(I)–catalyzed AAC reaction

To a solution of 0.5 mg complex 1 in MeCN: H2O (1:1 v/v), add benzyl/allyl/cinnamyl

halide (1.1 mmol) and NaN3 (1.2 mmol). The reaction mixture was stirred for few minutes at

room temperature. Then terminal alkyne (1.0 mmol) was added to the reaction mixture. A

colour change was found from colorless to brown of the reaction mixture. The reaction

134

mixture was then heated at 50 oC in a round–bottomed flask fitted with condenser and

maintaining gentle magnetic stirring for hours, as noted in Table V.5. The progress of the

reaction was monitored by tlc. After completion of the reaction, the mixture was diluted by

water (2 mL) and the filtrate was extracted with ethyl acetate (4×10 mL) and the combined

organic parts were washed with brine (1×5 mL), dried over anhydrous Na2SO4 and

concentrated under vacuum. The residue was purified by passing through a short silica gel

column chromatography and eluted with mixture of ethyl acetate–light petroleum to afford

the desired triazole product. All products were characterized by 1H–,

13C–NMR spectral data,

and also compared with the reported melting points (for known solid compounds).

V.5.5. Physical properties and spectral data of compounds

1–(3–(4–fluorophenylthio)propylthio)–4–fluorobenzene, Ligand 1 (L1)19

F

S S

F

Colourless liquid

1H–NMR (d6–DMSO, 300 MHz): /ppm 1.77 (quintet, J = 6.9 Hz, 2H, CH2), 3.02 (t, J = 6.9

Hz, 4H, 2CH2, 7.11‒7.18 (m, 4H, ArH), 7.34‒7.39 (m, 4H, ArH).

13C–NMR (d6–DMSO, 75 MHz): /ppm 28.4, 32.3, 116.4, 116.7, 131.3, 131.4, 131.7, 131.9,

159.7, 162.9.

Complex 1

Pale yellow coloured crystalline solid

1H–NMR (d6–DMSO, 300 MHz): /ppm 1.76 (s, 2H, CH2), 3.02 (d, J = 6.0 Hz, 4H, 2CH2),

7.13 (d, J = 7.2 Hz, 4H, ArH), 7.37 (d, J = 4.5 Hz, 4H, ArH).

13C–NMR (d6–DMSO, 75 MHz): /ppm 28.1, 32.9, 116.4, 116.7, 131.0, 132.1, 161.4, 163.1.

Table V.6, entry 1

1–Benzyl–4–phenyl–1H–1,2,3–triazole22

NN

N

135

White crystalline needle, mp126‒128 oC (Lit.

22 128‒130

oC)

1H NMR (CDCl3, 300 MHz): /ppm 5.47 (s, 2H), 7.19‒7.33 (m, 8H), 7.58 (s, 1H), 7.70‒7.72

(m, 2H).

13C NMR (CDCl3, 75 MHz): /ppm 54.1, 119.5, 125.6, 127.9, 128.1, 128.7, 128.8, 129.1,

130.5, 134.6, 148.1.

Table V.6, entry 2

1‒Benzyl‒4‒(p‒tolyl)‒1H‒1,2,3‒triazole22

NN

N

Me

White crystalline solid, mp152‒154 oC (Lit.

22 150

oC)

1H NMR (CDCl3, 300 MHz): /ppm 2.26 (s, 3H), 5.44 (s, 2H), 7.10 (d, J = 7.8 Hz, 2H),

7.18‒7.28 (m, 5H), 7.53 (s, 1H), 7.6 (d, J = 8.1 Hz, 2H).

13C NMR (CDCl3, 75 MHz): /ppm 21.2, 54.1, 119.1, 125.5, 127.6, 127.9, 128.6, 129.0,

129.4, 134.7, 137.9, 148.2.

Table V.6, entry 3

1‒Benzyl‒4‒(2‒bromo phenyl)‒1H‒1,2,3‒triazole23

NN

N

Br

Light pink solid, mp 80‒82 oC

1H NMR (CDCl3, 300 MHz): /ppm 5.58 (s, 2H), 7.12‒7.18 (m, 1H), 7.25‒7.39 (m, 6H), 7.6

(d, J = 7.8, 1H), 8.07‒8.15 (m, 2H).

13C NMR (CDCl3, 75 MHz): /ppm 54.2, 121.2, 123.1, 127.7, 127.9 128.7, 129.1, 129.4,

130.6, 131.3, 133.5, 134.7, 145.7.

Table V.6, entry 4

1‒benzyl‒4‒(4‒nitrophenyl)‒1H‒1,2,3‒triazole24

136

N

N N

NO2

Yellow crystalline solid, mp 171‒172 oC

1H NMR (d6‒DMSO, 300 MHz): /ppm 5.69 (s, 2H), 7.34‒7.38 (m, 5H), 8.11‒8.14 (m, 2H),

8.28‒8.31 (m, 2H), 8.91 (s, 1H).

13C NMR (d6–DMSO, 75 MHz): /ppm 53.7, 124.1, 124.8, 126.4, 128.5, 128.7, 129.3, 136.2,

137.5, 145.2, 147.1.

Table V.6, entry 5

1‒(1‒benzyl‒1H‒1,2,3‒triazol‒4‒yl)‒1‒phenylethanol25

N

N N OH

White solid, mp 133‒135 oC

1H NMR (d6–DMSO, 300 MHz): /ppm 1.81 (s, 3H), 5.54 (s, 2H), 5.85 (s, 1H), 7.18‒7.21

(m, 1H), 7.26‒7.37 (m, 7H), 7.45‒7.48 (m, 2H), 7.89 (s, 1H).

13C NMR (d6–DMSO, 75 MHz): /ppm 31.3, 53.1, 71.4, 122.1, 125.6, 126.8, 128.2, 128.5,

128.6, 129.2, 136.6, 148.8, 155.9.

Table V.6, entry 6

1‒Allyl‒4‒phenyl‒1H‒1,2,3‒triazole26

NN

N

White crystalline solid, mp 62‒64 oC (Lit.

26 56‒58

oC)

1H NMR (CDCl3, 300 MHz): /ppm 4.96 (d, 2H), 5.26‒5.34 (m, 2H), 5.95‒6.08 (m, 1H),

7.28‒7.42 (m, 3H), 7.76‒7.83 (m, 3H).

13C NMR (CDCl3, 75 MHz): /ppm 52.7, 119.7, 120.1, 125.7, 128.1, 128.8, 130.6, 131.3,

147.9.

Table V.6, entry 7

1‒Allyl‒4‒(p‒tolyl)‒1H‒1,2,3‒triazole26

137

NN

N

Me

White crystalline solid, mp 88‒90 oC

1H NMR (CDCl3, 300 MHz): /ppm 2.36 (s, 3H), 4.97‒5.01 (m, 2H), 5.29‒5.38 (m, 2H),

5.98‒6.11 (m, 1H), 7.02‒7.26 (m, 2H), 7.69‒7.72 (m, 3H).

13C NMR (CDCl3, 75 MHz):/ppm 21.3, 52.7, 119.1, 120.1, 125.6, 127.8, 129.5, 131.4,

138.0, 148.1.

Table V.6, entry 8

1‒(E‒cinnamyl)‒4‒phenyl‒1H‒1,2,3‒triazole27

NN

N

White solid, mp 136‒137 oC (Lit.

27 132‒134

oC)

1H NMR (CDCl3, 300 MHz): /ppm 5.11‒5.13 (m, 2H), 6.29‒6.41 (m, 1H), 6.66 (d, J = 15.9

Hz, 1H), 7.24‒7.47 (m, 8H), 7.79‒7.83 (m, 3H).

13C NMR (CDCl3, 75 MHz): /ppm 52.4, 119.5, 121.9, 125.7, 126.8, 128.2, 128.6, 128.8,

128.9, 130.6, 135.4, 135.5, 148.1.

Table V.6, entry 9

1‒(E‒cinnamyl)‒4‒(p‒tolyl)‒1H‒1,2,3‒triazole

NN

N

Me

White solid, mp 145‒147 oC

138

1H NMR (CDCl3, 300 MHz): /ppm 2.35 (s, 3H), 5.11‒5.14 (m, 2H), 6.30‒6.4 (m, 1H),

6.67(d, J = 15.6 Hz, 1H), 7.19‒7.36 (m, 7H), 7.69‒7.75 (m, 3H).

13C NMR (CDCl3, 75 MHz): /ppm 21.3, 52.4, 119.1, 122.0, 125.6, 126.7, 127.8, 128.5,

128.7, 129.5, 135.3, 135.5, 137.9, 148.1.

1‒benzyl‒4‒((phenylthio)methyl)‒1H‒1,2,3‒triazole28

SN

NN

White crystalline solid, mp 75‒76 oC (Lit.

28 71‒73

oC)

1H NMR (CDCl3, 300 MHz): /ppm 4.19 (s, 2H), 5.44 (s, 2H), 7.13‒7.35 (m, 11H).

13C NMR (CDCl3, 75 MHz): /ppm 29.04, 29.08 (‒SCH2), 54.1 (‒NCH2), 122.0, 126.5,

127.9, 128.7, 128.93, 128.95, 129.1, 129.8, 129.9, 134.7, 135.4, 145.3.

V.6. References

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155

INDEX

A

Acetonitrile 43, 59, 124, 130, 131, 135

Allyl bromide 131, 134, 135

Ambient 47, 54, 58, 59, 84, 97, 102, 103, 119

Anhydrous 5, 21, 37, 60, 61, 106, 134

Aryl bromides 4, 52, 53, 56, 57, 60

Aryl iodides 52, 55, 56, 60

Aryl trihydroxy borate 47, 53‒55, 58

B

Benzimidazole 48, 58, 59, 61, 68

Benzoyl peroxide 59

Biaryls 48, 49, 52, 56, 60

Bimetallic 9, 14‒16, 19‒21, 23, 24, 27‒29, 33‒35,

141, 142, 144

Biphasic 45, 51

Bragg diffraction pattern 24

C

Carbon disulfide 93‒96, 104

Characterization 22, 84, 122, 144

Chromatography 31, 37, 55‒60, 82‒84, 97, 98, 101, 104,

105, 106, 129‒134

Click 16, 72, 117‒121, 129

Clusters 6, 7, 16, 27, 42, 121

Coordination clusters 6, 7, 121

Cycloaddition 42, 43, 118‒121, 131, 132, 153

Cyclodextrine 10, 78

D

D(+)‒glucose 82, 84

9,10‒dibromoanthracene 30, 32, 33

Diethyl ether 60, 84, 97, 105

Disulfide 82, 96, 97, 104

Dithiocarbamate 92‒96, 99, 102, 104, 106

Dithioether 70, 78, 79, 117, 121, 127

E

EDX elemental mapping 28, 29

Eluent 60, 61

Energy dispersive X‒ray 21, 22

Epoxide 94, 95

H

Heterocyclic 118

Heterogeneous catalyst 3, 4, 21, 35, 51

156

Histogram 27, 28

Hydrodehalogenation 15‒21, 30‒37, 143

Hydrothiolation 70, 72‒79, 81‒84

I

Iron oxide (Fe2O3) 34

L

Luminescence 132

M

Macroporous 4, 21, 25

Merkovnikov 72‒74, 77, 78

Merrifield 2, 10, 139

Metallopolymer 126

Methodology 2, 17, 19, 74, 75, 78, 93‒95, 121, 130

Microwave 45, 46, 50, 51, 57, 119, 129, 133, 155

Monoclinic 126

Monometallic 33

Morpholine 97, 98, 105‒108, 113, 115

Morphology 22, 25

Multicomponent 118, 120, 131, 132

N

NBS 58

Nanocatalysts 19, 21

Nanocomposites 9, 14, 15, 21‒25, 27, 29, 30, 36

Nanotubes 20, 33

nZVI 18

O

Optimization 30, 55, 98, 129

P

Palladium 4, 11, 13, 16, 18, 19, 21, 35, 45, 50, 51,

53, 56, 74, 75, 149

Palladium chloride 21

Phase transfer catalyst 46, 51, 52

Photoluminescent 125

Piperidine 99, 105, 108‒110, 113‒115

Polymerization 10, 11, 92

Polystyrene 10, 11, 12, 17

Polymer‒supported reagents 12

PVP 8, 9

Pyrrolidine 99, 105, 110, 111, 114

Q

Quintet 122, 134

R

Radical 58, 72, 74, 78, 79, 83, 92, 104, 150

157

Recycling 32, 33

Regioisomer 80

Regioselective 75‒79, 83, 95, 118

Resin 2, 10‒15, 21, 24 25, 28, 35, 36, 58,

79‒81, 94

S

Solvent‒free 5, 50

Spacer 7, 125

Stereoselectivity 44, 79‒83, 95

Surfactant 45, 52, 79

T

Thiocyanate 91, 96‒100, 102, 104, 105, 106

Thioether 71, 74, 75, 78, 79, 121

Thiols 72‒75, 77‒79, 81‒83

Triazole 118, 119, 131, 132‒136

Triplet 122

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PAPERS

PAPER www.rsc.org/greenchem | Green Chemistry

Highly effective alternative aryl trihydroxyborate salts for a ligand-free,on-water Suzuki–Miyaura coupling reaction

Basudeb Basu,* Kinkar Biswas, Sekhar Kundu and Sujit Ghosh

Received 18th May 2010, Accepted 9th July 2010DOI: 10.1039/c0gc00122h

Aryl trihydroxyborate salts of sodium, an easily accessible and stable alternative source oforganoboron species, can efficiently promote Pd-catalyzed ligand-free, on-water Suzuki–Miyaura(SM) coupling reactions at ambient temperature.

Introduction

The seminal paper of Miyaura, Yamada and Suzuki1 laidthe foundation of one of the most important and usefulmethods for the construction of carbon–carbon bonds, inparticular for the formation of unsymmetrical biaryls. Despiteother alternative approaches for C–C bond formation suchas Kharash coupling,2 Negishi coupling,3 Stille coupling,4

Hiyama coupling,5 and Kumuda coupling,6 the Suzuki–Miyaura(SM) coupling reaction has arguably received much morepopularity due to stability, commercial availability and ease ofhandling of the organoboron compounds. The Suzuki–Miyauracoupling has found widespread applications in academic lab-oratories, fine chemical industries, synthesis of biologicallyactive pharmaceuticals, as well as in the burgeoning area ofnanotechnology, as reflected from contributions from myriadresearch groups.7 For example, Losartan, an antihypertensivedrug,8a CI-1034, a potent endothelian receptor antagonist,8b CE-178,253 benzenesulfonate, a CB1 antagonist for the treatment ofobesity8c or apoptolidin A, a potent antitumor agent8d have beensynthesised on a large scale employing the SM coupling as a keystep. Similarly, benzimidazole derivatives bearing substitutedbiphenyl moieties, potential inhibitors of hepatitis C virus, havebeen prepared using the SM coupling reaction.9 Review articlesby Danishefsky et al.10 and Nicolaou et al.11 amply demonstratevarious applications of the SM coupling reaction in the synthesisof natural products.

In recent years, amelioration of the SM coupling reaction hasbeen directed towards the more efficient, economic and greenertechniques, especially in respect of Pd-catalyst, requirementof base and carrying out the reaction in water or in theabsence of any solvent.12 Recent trends in organic synthesisinvolve reactions under solvent-free or on-water conditions toobtain the target molecule in a cleaner and environmentallybenign way.13 Although many organic reactions are facilitatedin aqueous media, some reactions proceed very slowly becauseof poor solubility of the substrate/reagents in water. In thecase of SM couplings, hydrophobic aryl boronic acids oftenshow very slow and/or incomplete conversions along with thedifficulty to isolate the products from the reaction mixture.14

Department of Chemistry, North Bengal University, Darjeeling, 734 013,India. E-mail: basu_nbu@hotmail.com; Fax: 91 353 2699001; Tel: 91353 2776381

Efforts have been made to overcome the problem by introducingphase transfer catalysts,15 water soluble salts of reagents16 orcatalysts17 or carrying out the reaction in aqueous buffer.18

Two types of water-soluble organoborate salts viz. potassiumaryl trifluoroborates16a–d and sodium aryl trihydroxyborates,16e,f

which are easy to prepare, store and handle, have been employedin Pd-catalyzed cross-couplings with aryl halides. Yet, despitesome positive features of using aryl trihydroxyborate salts, aque-ous SM coupling usually requires elevated temperatures, organicco-solvents, ligand-based Pd-catalysts, high catalyst loadingsand/or tedious work-up. In this paper we present an ambienton-water protocol for the SM coupling reaction of a widerange of aryl halides (I, Br or Cl) including heteroaryl halideswith different sodium aryl trihydroxyborates. Our observationspractically constitute an efficient, mild, ligand-free method forthe SM coupling reactions in water at ambient temperatureby using aryl trihydroxyborate salt as one of the couplingpartners (Scheme 1). This paper also reports successful extensionof the procedure through the use of polymer-supported Pd-catalyst (ARF–Pd), a heterogeneous Pd-catalyst developed byour group,19 covering the essential aspects of green chemistry.Furthermore, we have demonstrated modular synthesis ofpharmaceutically important benzimidazole- and benzotriazole-based biphenyl scaffolds using an alternative water-solublesodium organoborate salt.

Results and discussion

Preliminary optimization of the SM coupling reactions was car-ried out using 3-iodoanisole and phenyltrihydroxyborate withthe aid of 0.5 mol% Pd(OAc)2 (Table 1). The phenyl trihydroxyb-orate salt was prepared following the reported procedure,16e andused directly without further purification. Investigations usingdifferent solvents revealed that the coupling is unsuccessful intoluene (Table 1 entry 1), partly successful in dioxane (Table 1,entry 2) but worked efficiently in DMF (Table 1, entry 3). Onswitching over to aqueous media, it was found that a mixtureof acetone–water also worked efficiently within 8 h under mildconditions (Table 1, entry 4). However, carrying out the reactionin only water resulted in the formation of the biphenyl derivativein 38% yield (Table 1, entry 5), which may be attributed tothe poor solubility of aryl iodide in water. To overcome thisshortcoming, we decided to use tetrabutylammonium bromide(TBAB), a phase transfer reagent, in an equimolar amount.

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Scheme 1

Table 1 Optimization of reaction conditions for the SM coupling using3-iodoanisole and phenyltrihydroxyborate

Entry Solvent Temperature Time % of Yielda

1 Toluene 100 ◦C 8 h 002 Dioxane RT 24 h 453 DMF RT 4 h 964 Acetone : water RT 8 h 935 Water RT 4 h 386 Waterb RT 4 h 927 Waterc RT 8 h 50

a Isolated yields after purification by column chromatography on silica.b 1 equiv. of TBAB was added. c 0.5 equiv. of TBAB was added. Allreactions were carried out using 0.5 mol% Pd(OAc)2.

This led to the formation of the desired unsymmetrical biphenylwithin 4 h at room temperature in 92% yield (Table 1, entry 6). Anexperiment with 0.5 equivalents of TBAB, however, afforded thedesired product only in 50% yield, even after 8 h (Table 1, entry7). It was revealed that polar protic or aprotic solvents are goodenough to effect the SM coupling at room temperature. Thus,the optimized reaction conditions are: 0.5 mol% of Pd(OAc)2

and 1 equivalent of TBAB in water at room temperature.After identification of the optimal conditions, the scope and

limitations of the reaction were examined. Initially, we appliedthese reaction conditions to the coupling of various functional-ized aryl iodides with the sodium salt of phenyltrihydroxyboratein water. The results are presented in Table 1. Aryl iodidesbearing different substituents such as OMe, Me, NH2, F andI underwent smooth SM coupling affording the correspondingunsymmetrical biphenyls in 84–94% yields (Table 2, entries 1–7). Mechanistically, the oxidative addition of aryl halides topalladium(0) depends on the nature of halogens and occurs inthe descending order of I > Br > Cl.20 We therefore examinedthe couplings of other aryl electrophiles bearing bromide andchloride. Several aryl bromides including di- and tribromoareneswere found to give the corresponding unsymmetrical biarylsin good to excellent yields (Table 2, entries 8–13). While p-bromoacetophenone showed a faster rate of reaction (2 h)(Table 2, entry 9), 2,4,6-tribromophenol required a longer time(24 h) (Table 2, entry 13) for the coupling reaction, which may bedue to the presence of the electron-withdrawing acetyl group inthe former example. Thus, aryl iodides and bromides underwenteasy coupling with phenyl trihydroxyborate. A similar reactionwith aryl chloride was not successful even after heating thereaction mixture at 100 ◦C for 24 h (Table 2, entries 14–15). Lead-beater et al.18a reported the microwave-assisted SM coupling of

aryl chlorides at 150–175 ◦C in aqueous media indicating thataryl chlorides are very sluggish towards the SM coupling reac-tion and require relatively higher temperature, longer reactiontime and/or the presence of electron-withdrawing groups. Weexamined aryl chlorides bearing nitro or acetyl groups, whichhowever afforded the desired coupled products in excellentyields at refluxing temperatures (100 ◦C) (Table 2, entries 16–17). Changing the coupling partner phenyltrihydroxyborate withm-tolyltrihydroxyborate and p-anisyltrihydroxyborate did workefficiently with bromo and iodoarenes (Table 2, entries 18–22and 24). The SM coupling reaction with heteroaryl halideswas also successful. For example, 3-bromoquinoline or 2,6-dibromopyridine gave the desired coupled products in 66% and83% yields respectively (entries 22–23), while similar couplingof 2-iodothiophene with p-anisyltrihydroxyborate afforded thecorresponding unsymmetrical biphenyl in 92% yield within 3 h(Table 2, entry 24).

Recently, we developed a new Pd-catalyst (where Pd wasimmobilized onto ion-exchange resins), designated as ARF–Pd, which was successfully applied to Heck, Suzuki–Miyaura

† Spectral data of selected biphenyls: 3-Methoxy biphenyl (liquid);Table-2, Entry-1: IR (film): nmax 1574, 1610 cm-1. 1H NMR (CDCl3,d ppm-1 relative to TMS): 3.75 (3H, s, –OCH3); 6.77–6.81 (1H, m,aromatic proton); 7.03–7.10 (2H, m, 2 aromatic protons); 7.21–7.36(4H, m, all aromatic protons); 7.47–7.51 (2H, m, 2 aromatic protons).13C NMR (CDCl3, d ppm-1): 55.2 (OCH3); 112.6; 112.8; 119.6; 127.1;127.4; 128.7; 129.7; 141.0; 142.7; 159.9 (aromatic carbons). 2-Methoxybiphenyl (liquid); Table-2, Entry-3: IR (film): nmax 1504, 1597 cm-1. 1HNMR (CDCl3, d ppm-1 relative to TMS): 3.79 (3H, s, –OCH3); 6.96–7.05(2H, m, 2 aromatic protons); 7.29–7.42 (5H, m, all aromatic protons);7.51–7.54 (2H, m, 2 aromatic protons). 13C NMR (CDCl3, dPpm-1):55.54 (OCH3); 111.2; 120.8; 126.9; 127.9; 128.6; 129.5; 130.7; 130.8;138.5; 156.5 (aromatic carbons). 3,4¢-Dimethyl biphenyl (liquid); Table-2, Entry-19: IR (film): nmax 1588, 1606 cm-1. 1H NMR (CDCl3, d ppm-1

relative to TMS) 2.390 (6H, s, CH3); 7.13–7.50 (8H, m, 8, all aromaticprotons). 13C NMR (CDCl3, d ppm-1): 21.3 (CH3); 124.1; 127.0; 127.7;127.8; 128.6; 129.4; 136.9; 138.2; 138.5; 141.1 (aromatic carbons). 3-Methoxy 3¢-methyl biphenyl (liquid); Table-2, Entry-20: IR (neat): nmax

1593 cm-1. 1H NMR (CDCl3, d ppm-1 relative to TMS): 2.41 (3H, s,CH3); 3.86 (3H, s, –OCH3); 7.11–7.39 (8H, m, all aromatic protons).13CNMR (CDCl3, d ppm-1): 21.5 (CH3); 55.3 (OCH3); 112.6; 112.9; 119.7;124.3; 128.0; 128.1; 128.6; 129.6; 138.3; 141.1; 142.9; 159.9 (aromaticcarbons). 3-(3-Methyl phenyl) quinoline (liquid); Table-2, Entry-22: IR(film): nmax 1580, 1606 cm-1. 1H NMR (CDCl3, d ppm-1 relative to TMS):1.59 (3H, s, CH3); 6.36–6.87 (6H, m, 6 aromatic protons); 7.00 (1H, d,J = 8.1 Hz, aromatic proton); 7.28 (1H, d, J = 8.4 Hz, aromatic proton);7.43 (1H, s); 8.3 (1H, s). 13C NMR (CDCl3, d ppm-1): 21.6 (CH3); 124.5;127.1; 128.0; 128.1; 128.2; 128.9; 129.0; 129.1; 129.4; 133.4; 134.0; 137.7;138.9; 147.1; 149.8 (aromatic carbons). 2-(4-Methoxy phenyl) thiophene;Table-2, Entry-24: mp 106 ◦C; IR (KBr): nmax 1500, 1533, 1606 cm-1. 1HNMR (CDCl3, d ppm-1 relative to TMS): 3.81 (3H, s, –OCH3); 6.91(2H, d, J = 9 Hz, 2 aromatic protons); 7.03–7.25 (3H, m, all aromaticprotons); 7.53 (2H, d, J = 8.7 Hz, 2 aromatic protons). 13C NMR (CDCl3,d ppm-1): 55.3 (OCH3); 114.3; 122.1; 123.8; 127.2; 127.3; 127.9; 144.3;159.2 (aromatic carbons).

This journal is © The Royal Society of Chemistry 2010 Green Chem., 2010, 12, 1734–1738 | 1735

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Table 2 On-water SM coupling reactions with sodium aryl trihydrox-yborates using 0.5 mol% of Pd(OAc)2

a Aryl halide and arylboronic acid salt used in 1 : 1.1 ratios formono-coupling. b Isolated yields after purification by columnchromatography on silica.†

and Sonogashira coupling reactions.19 To extend further, weemployed the heterogeneous Pd-catalyst (ARF–Pd) replacingPd(OAc)2. Indeed, trihydroxyborate salts were found to beequally active in SM coupling reactions in the presence ofa catalytic amount of ARF–Pd. The results are presented inTable 3. In all the cases, the ARF–Pd was separated by filtrationand the desired products were obtained after chromatographicpurification in excellent yields (85–93%) (Table 3, entries 1–5).

As shown above, water-soluble sodium salts of aryl trihy-droxyborates have proven to be highly effective in SM couplingreactions in water at ambient temperatures. Low loading ofthe Pd-catalyst (direct use of Pd(OAc)2 or polymer-bound Pd)and absence of any phosphine ligands are notable features tomention. Having established a general, mild, aerobic and on-water protocol for the SM coupling reactions using aryl trihy-droxyborate salts, we probed the utility of this protocol in mod-ular synthesis of pharmaceutically important benzimidazole-and benzotriazole-based biphenyl scaffolds. Thus, compounds 2and 3 were synthesized from compounds 1a and 1b respectively(Scheme 2), where the SM couplings were efficiently performedusing sodium phenyltrihydroxyborate in a mixture of DMF–H2O (2 : 1).

Conclusions

In summary, our studies have established that easily accessibleand air-stable sodium aryl trihydroxyborates can be effectivelyused as an alternative source of organoboron species in ligand-free Pd-catalyzed SM cross-coupling reactions in water underan aerobic atmosphere and at room temperature. The protocolhas been found to be broadly applicable to a variety of arylhalides (X = Br, I) and also to aryl chlorides bearing electron-withdrawing groups. It is further shown to be effective withheterogeneous Pd-catalysts and also extended to the modularsynthesis of some pharmaceutically important benzimidazole-and benzotriazole-based biphenyl scaffolds.

Experimental

General procedure for Suzuki–Miyaura coupling

A mixture of 3-iodoanisole (468 mg, 2 mmol), sodium phenyltri-hydroxyborate (354 mg, 2.2 mmol), Pd(OAc)2 (2.2 mg, 0.5 mol%)and TBAB (644 mg, 2 mmol; 1 equiv) was taken in water (5 mL).The mixture was magnetically stirred at room temperature forseveral hours (see Table 2). After the reaction was complete(monitored by tlc), the mixture was extracted with ether (3¥ 20 mL). The combined organic layer was then washed withbrine (10 mL), dried (anhydrous Na2SO4), and evaporated. Theresidue was purified on a short column of silica using lightpetroleum as the eluent to afford the desired unsymmetricalbiphenyl (338 mg, 92%); liquid.

Synthesis of compounds 2 and 3

A mixture of 1-(4-iodobenzyl)-1H-benzo[d]imidazole (334 mg,1 mmol) or 1-(4-iodobenzyl)-1H-benzo[d][1,2,3]triazole(335 mg, 1 mmol) and sodium salt of phenyltrihydroxyborate(177 mg, 1.1 mmol), ARF–Pd (300 mg, 0.94 mol% of Pd)and TBAB (322 mg, 1 mmol) was taken in a DMF–water

1736 | Green Chem., 2010, 12, 1734–1738 This journal is © The Royal Society of Chemistry 2010

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Table 3 SM coupling reactions with aryl trihydroxyborates in water using heterogeneous Pd-catalyst (ARF–Pd)

Entry Aryl halidesa Sodium trihydroxyborate Temp. Time/h Product Yieldb (%)

1 RT 5 85

2 RT 5 88

3 100 ◦C 4 92

4 100 ◦C 3 93

5 100 ◦C 5 87

a 300 mg ARF-Pd (0.94 mol% Pd) was used. b Isolated yields after purification by column chromatography on silica.

Scheme 2 Conditions: a1a or 1b (1 mmol), PhB(OH)3Na (1.1 mmol) in DMF–H2O (2 : 1; 3 mL), Pd(OAc)2 (1.1 mg, 0.5 mol%), 100 ◦C for 24 h.

mixture (2 : 1; 3 mL). The mixture was heated at 100 ◦C for24 h. After completion of the reaction (monitored by tlc), themixture was extracted with ethyl acetate (2 ¥ 20 mL). Thecombined organic layer was then washed with brine (10 mL),dried over anhydrous Na2SO4, and evaporated. Finally theresidue was purified over a short column of silica and elutionwith 1 : 9 (EA : light petroleum) afforded N-(4-phenyl benzyl)benzimidazole 2 (236 mg, 83%); m.p. 163 ◦C or N-(4-phenylbenzyl) benzotriazole 3 (227 mg, 80%); m.p. 180 ◦C.

Spectral data for 2. 1H NMR (CDCl3): d 5.41 (2H, s, (CH2);7.25–7.83 (13H, m, all aromatic protons); 8.07 (1H, s, aromaticproton). 13C NMR (CDCl3): d 48.7 (CH2 aliphatic carbon);110.2; 120.2; 122.6; 123.3; 127.1; 127.6; 127.8; 128.8; 129.1;133.8; 134.2; 140.3; 141.4; 143.1; 143.3 (aromatic carbons). IR(KBr): nmax 1610, 1653 cm-1. HRMS: Calculated for C20H16N2H:[M+H]+, 285.1392; found: 285.1387.

Spectral data for 3. 1H NMR (CDCl3): d 5.88 (2H, s,(CH2); 7.25–8.09 (13H, m, all aromatic protons). 13C NMRNMR (CDCl3): d 51.9 (CH2 aliphatic carbon); 109.7; 120.1;124.0; 127.0; 127.5; 127.6; 127.7; 128; 128.8; 132.8; 133.6; 140.2;141.4; 146.3 (aromatic carbons). IR (KBr): nmax 1590, 1616 cm-1.HRMS: Calculated for C19H15N3Na: [M+Na]+ 308.1164; found:308.1163.

Acknowledgements

We are grateful to the Department of Science & Technology, NewDelhi for financial support (Grant No. SR/S1/OC–49/2006).KB and SG thank CSIR, New Delhi for awarding juniorresearch fellowships.

References1 N. Miyaura, K. Yamada and A. Suzuki, Tetrahedron Lett., 1979, 20,

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Research ArticleIn Quest of ‘‘Stereoselective Switch’’ for On-WaterHydrothiolation of Terminal Alkynes Using Different Additivesand Green Synthesis of Vicinal Dithioethers

Basudeb Basu, Kinkar Biswas, Samir Kundu, and Debasish Sengupta

Department of Chemistry, North Bengal University, Darjeeling 734 013, India

Correspondence should be addressed to Basudeb Basu; basu nbu@hotmail.com

Received 30 October 2013; Accepted 18 December 2013; Published 13 February 2014

Academic Editor: Ralph Nicholas Salvatore

Copyright © 2014 Basudeb Basu et al. This is an open access article distributed under the Creative Commons Attribution License,which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

On-water hydrothiolation reaction between terminal alkyne and thiol has been probed in the presence of various additives.Aromatic alkynes yield corresponding 1-alkenyl sulfides, whereas aliphatic alkynes undergo double-addition yielding vicinaldisulfides in good to excellent yields. Formation of 1-alkenyl sulfides proceeds with a high degree of regioselectivity (via anti-Markovnikov addition), and switching the stereoselectivity between E/Z isomers has been noticeably realized in the presence ofdifferent additives/promoters.

1. Introduction

Organosulfur compounds play a key role in biologicalprocesses, new materials, and chemical synthesis [1, 2]. 1-Alkenyl sulfides are important synthetic intermediates intotal synthesis of many naturally occurring and biologicallyactive compounds as well as versatile building blocks formany functionalized molecules [3–9]. The synthetic utilityof alkenyl sulfides has been demonstrated in several reportsby different research groups [10–17]. Increasing demand foralkenyl sulfides in material science, organic, and bioorganicchemistry has furthered the development of new syntheticmethods [6, 18–21]. The addition of thiols to alkynes isconsidered as one of the straightforward methods to obtainvinyl sulphides either catalyzed by transitionmetal complexes[22–39], or base-promoted [40–44] and/or through freeradicals [21, 45–48]. This reaction is often judged as a partof “click chemistry” and a process of high atom economy [49,50]. Mechanistically, addition of thiols to alkynes is believedto occur (i) via radical pathway producing unselective mix-ture of (E/Z)-anti-Markovnikov vinyl sulphides, (ii) base-mediated nucleophilic addition giving all types of adducts,or (iii) transition-metal complex catalyzed processes yieldingMarkovnikov vinyl sulphides and (E) anti-Markovnikov vinyl

sulphides (Scheme 1). Varying degrees of stereo- and regios-electivity and turnover are reported in the literature [22–48].

Additives are a kind of reagents whose effects are verymuch similar to catalysts. They have often shown a profoundrole in variety of organic reactions in terms of the rate ofthe reaction, yield of the product, or change in the courseof the reaction [51, 52]. In hydrothiolation, most reports inthe literature described the formation of thermodynamicallymore stable E-vinyl sulfide in considerable excess over theZ-isomer. On the other hand, hydrothiolation, particularlyof aryl and benzyl thiols and catalyzed by transition-metalcomplexes, often produces a mixture of anti-Markovnikov E-alkenyl sulfide (syn addition) and Markovnikov adduct andthus suffers from poor regioselectivity. Among the transitionmetal catalysts, rhodium complexes, both in homogeneousand heterogeneous forms, have exhibited high catalyticactivity [51, 52]. Recently, In(OTf)

3has been shown to

selectively catalyze bothMarkovnikov and anti-Markovnikovhydrothiolation of terminal alkynes [38]. However, transi-tion metal complexes are generally expensive, their usesare not ecofriendly, and the course of the reaction mightsuffer deactivation due to the formation of strong metal-sulphur bonds [53]. More regioselective (anti-Markovnikov)on-water hydrothiolation processes have been reported in

Hindawi Publishing CorporationOrganic Chemistry InternationalVolume 2014, Article ID 358932, 6 pageshttp://dx.doi.org/10.1155/2014/358932

2 Organic Chemistry International

HSH

Additives [A]1a

H

H

H

H

H

H+ +

2b 2cWater/Rt

2a

(Markovnikov)(Anti-Markovnikov)

(E)-isomer (Z)-isomer

C6H5

C6H5

C6H5

C6H5 C6H5

SC6H5

SC6H5 SC6H5

Scheme 1: 1-Alkenyl sulphides from hydrothiolation of terminal alkynes.

the absence [45–48, 54] or presence of some additives like𝛽-cyclodextrine [55]. Indeed, there are large varieties ofreagents/catalysts that are used in the hydrothiolation ofterminal alkynes with varying degrees of success in con-trolling stereo- and regioselectivity. However, many reportsinclude expensive metal catalysts, nonaqueous solvents, andhigh temperature and moreover lack (E/Z)-stereoselectivity.In practice, there is no general guideline by which one canproceed to prepare a specific stereoisomer of a vinylic sul-fide using this straightforward and atom-economic reactionunder mild and environment-friendly conditions. Moreover,there are conditions that give rise to selective formationof the thermodynamically favoured (E)-alkenyl sulfide, itremains an unmet and elusive goal to develop optimumconditions that selectively produce (Z)-alkenyl sulfides undercomplete metal-free, base-free and on-water conditions.Since hydrothiolation of alkynes is a robust, atom-economicand highly useful synthetic method in C–S bond formation[6], we undertook a systematic investigation on the stereo-and regioselective addition of aliphatic and aromatic thiolsto terminal alkynes in the presence of different additives incatalytic quantities under on-water conditions. We reportherein our studies that constitute a rather broad guideline of“stereoselective switch” for the preparation of stereoselective(E/Z)-1-alkenyl sulfides.

2. Materials and Methods

All compounds were identified by 1H- and 13C-NMR spectra,recorded on a Bruker AV300 spectrometer operating at 300and 75MHz, respectively, and supported by FT-IR spectra.All NMR spectra were measured in chloroform-d. Chemicalshifts are given in 𝛿 (ppm) downfield from TMS. Analyticalthin-layer chromatography (tlc) was performed on precoatedaluminum plates from Merck silica gel 60 F

254as the adsor-

bent (layer thickness 0.25mm). The developed plates wereair-dried and exposed to UV light. Column chromatographywas performed on silica gel (source: SRL India; 60–120mesh).

2.1. General Procedure for Monohydrothiolation of Alkynes.To a mixture of alkyne (1mmol), thiol (1.1mmol) in water(0.5mL) was added to the additive (1mmol) and stirred atroom temperature (25–30∘C) for 2–5 h (TLC). The reactionmixture was extracted with diethyl ether (3 × 10mL), and thecombined organic layerwaswashedwith brine and then driedover Na

2SO4. Evaporation of solvent under vacuo afforded an

oily residue, which was passed through a short bed of silica

gel, and NMR spectrum was recorded to evaluate the percentof (E/Z) isomers. NMR spectral data and scanned copies ofselected NMR spectra are given in the Supplementary Mate-rial available online at http://dx.doi.org/10.1155/2014/358932and are found to be in good agreement with those reported.

2.2. General Procedure for Dihydrothiolation of Alkynes. Ina mixture of alkyne (1mmol), thiol (2.2mmol) in water(0.5mL) was stirred for 5–9 h at room temperature (TLC).The reactionmixture was then extracted with diethyl ether (3× 10mL), and the combined organic layer was washed withbrine and then dried over Na

2SO4. Evaporation of solvent

under vacuo afforded an oily residue, which was passedthrough a short bed of silica gel to afford 1, 2-disulfides ingood to excellent yields. The products were identified on thebasis of 1H, 13C NMR spectral data, and/or by comparisonwith the data reported in the literature. NMR spectral dataand scanned copies of selected NMR spectra (1H- and 13C)are given in the Supplementary Material.

3. Results and Discussion

Preliminary studies on the influence of catalyst and/orpromoter on hydrothiolation were studied with a modelreaction of phenyl acetylene (1a) and benzenethiol in thepresence of various homogeneous and heterogeneous addi-tives/promoters under on-water conditions at room tem-perature. Screening of additives/promoters included inor-ganic salts, water-soluble organic molecules, amino acids,surfactants, or heterogeneous ion-exchange resins, and theresults are summarized in Table 1. Since the hydrothiolatedadducts are formed in varying ratios (E/Z ratios), the resultsin Table 1 have been arranged showing a gradual change inthe formation of (E)-vinyl sulfide (2b) to the (Z)-isomer (2c).The screening shows that the E/Z ratio in favor of (E)-vinylsulfide (87 : 13) is formed in the presence of NaCl (Table 1,entry 3), while the major (Z)-vinyl sulfide is obtained inthe presence of a combination of amberlite resins (Cl) andFeCl3⋅6H2O (entry 23; E/Z ratio 22 : 78). The stereochemical

outcome favouring the (E)-isomer is also seen when thereaction is carried out at higher temperature (65∘C) andcontinued for longer reaction time (10 h) (entry 11; E/Z ratio88 : 12). However, a specific observation may be noted fromthis study that the on-water additions do not give rise to theformation of any Markovnikov adduct; that is, in no case wasthe other regioisomer (2a) obtained. The NMR spectral data

Organic Chemistry International 3

Table 1: Role of additives in the addition of PhSH to phenylacetylene under on-water conditions at room temperature producing selectivelyanti-Markovnikov adductsa.

HAdditives [A]

H

HH

H

+

Water/Rt

C6H5

C6H5

C6H5

SC6H5 SC6H5

(E) (Z)

C6H5–SH

Entry Additive [A]b (E/Z) ratioc, d Entry Additive [A]b (E/Z) ratioc, d

1 Nil (neat) 83 : 17 13 CuI-Catechol violet 60 : 402 Nil (water) 80 : 20 14 Amberlite resins (Cl) 58 : 423 NaCl 87 : 13 15 n-Bu4NBr 57 : 434 Sucrose 85 : 15 16 D-Glucose 56 : 445 CF3COOH 78 : 22 17 CuI 52 : 486 BF3⋅Et2O 76 : 24 18 Cholesterol 51 : 497 Catechol violet 75 : 25 19 CTAB 49 : 518 L-Proline 70 : 30 20 FeCl3⋅6H2O 44 : 569 Glycin 69 : 31 21 Amberlyst resins (OH) 40 : 6010 Starch 64 : 36 22 D-Glucose and FeCl3⋅6H2O 35 : 6511e Water (65∘C) 88 : 12 23 Amberlite resins (Cl) and FeCl3⋅6H2O 22 : 7812 Water (65∘C) 64 : 36aReaction conditions: phenyl acetylene (0.5mmol), PhSH (0.55mmol), water (1mL), 2 h. bAdditive [A] (2mol %). cE/Z ratio was determined by 1HNMR ofthe crude mixture. dYield of the mixture of stereoisomers after chromatographic purification varies in the range 80–90%. eThe reaction was continued for 10 h;all other reactions were carried out at room temperature unless otherwise mentioned.

of the unpurified products indicated only amixture of 2b and2c, and indeed there was no trace of 2a.

At this point, effect of functional groups in the aromaticmoiety in either of the addition partners could be worthinvestigating. Since a combination of ion-exchange resinsand ferric chloride showed a better selectivity towards theformation of (Z)-vinyl sulfide, this study was performedunder similar conditions. The results are presented inTable 2. It is seen that both electron-donating and electron-withdrawing functional groups present on the aryl ring cangive rise to the anti-Markovnikov hydrothiolation productsin excellent yields (85–94%). The highest (Z)-selectivity wasfound in the reaction between phenyl acetylene and p-methoxybenzenethiol (Table 2, entry 4; E/Z 12 : 88), possiblydue to the easy emulsification of the alkyne in water uponstirring, which might be supportive, in addition to thepresence of the additive. On the other hand, presence of theelectron-withdrawing group (fluorine) on the thiol part didnot show any appreciable influence towards stereoselectiveaddition yielding the (E)-isomer in major quantity (entries6-7). It seems that there is not much electronic influence ofthe functional groups in the aryl ring of either of the additionpartners; rather their stability in water in the presence of theadditive might have some control towards anti-Markovnikovstereoselectivity.

Further studies of aryl acetylenes (terminal) withaliphatic thiols in the presence of one equivalent of D (+)-glucose showed a general trend in favour of the formationof (Z)-vinyl sulphides. For example, phenyl acetyleneor p-tolyl acetylene undergoes hydrothiolation in thepresence of n-alkyl thiols that afforded the corresponding1-alkenyl sulphides with (E/Z) ratios (14 : 86). The results aresummarized in Table 3.

Since there is significant reactivity difference betweenaliphatic and aromatic thiols [56, 57], we ought to investigatethe stereochemical outcome in two other cases: hydrothiola-tion of (i) aliphatic terminal alkynes and aliphatic thiols and(ii) aliphatic terminal alkynes and aromatic thiols. It has beenseen from previous reports that aliphatic alkynes undergodihydrothiolation yielding vicinal disulfides only irrespectiveof the nature of the thiol [45, 54]. Thus, aliphatic terminalalkynes were subjected to hydrothiolation with aromaticand aliphatic thiols under on-water conditions. Seemingly,there was an influence of additives on this double-additionreaction. The results are presented in Table 4, which showthat aliphatic terminal alkynes undergo double- additionsyielding finally 1, 2-disulfides only in the presence or absenceof D (+)-glucose.

With regard to the mechanism of hydrothiolation of ter-minal alkynes in water, the literature reports are of differentviews. For example, Bhadra and Ranu [54], in their studieson water-promoted regioselective hydrothiolation, ruled outthe likeliness of a radical pathway as the reaction proceedsin the presence of dissolved oxygen. On the other hand,Jin et al. [45], hinted that the reaction probably proceedsthrough a radical mechanism under similar conditions. Thelatter group further observed that the reaction does notoccur in the presence of galvinoxyl-free radical, althoughuse of such radical quencher does not always prove radicalmechanism [54, 55]. Our studies indeed demonstrated arole of additives in governing the stereoselectivity but thespecific function of the additive, particularly in aqueousmedium, and themechanistic routes are not clear at this time.Furthermore, carrying out the reaction in the presence ofradical initiator (AIBN) or light did not make the processfaster appreciably. Several transition metal complexes are

4 Organic Chemistry International

Table 2: Hydrothiolation of aryl thiol [B] to aryl acetylene [A] in (1.1 : 1) in water at room temperature.

H SHH

H

S

Amberlite resins (Cl)

+

[A] [B] [C]

-FeCl3/water/r.t.R1

R1

R2

R2

Entry [A] [B] Time (h) Yielda (%) [C] E/Z [C]b

1 R1 = H R2 = H 2.0 85 22 : 782 R1 = CH3 R2 = H 3.5 91 40 : 603 R1 = CH3 R1 = CH3 2.5 88 29 : 714 R1 = H R1 = OCH3 3.0 93 12 : 885 R1 = CH3 R1 = OCH3 2.0 90 22 : 786 R1 = H R2 = F 2.0 88 80 : 207 R1 = CH3 R2 = F 2.0 94 39 : 61aYield represents the product [C] after purification by column chromatography. bE/Z ratio was determined by 1HNMR of the crude mixture.

Table 3: Hydrothiolation aromatic terminal alkynes with aliphatic thiols.

HH

H

S

D (+)-glucose /water/r.t.+

[A] [B] [C]

SH

n nR1

R1

Entry [A] [B] Time (h) Yielda (%) [C] E/Z [C]b

1 R1 = H 𝑛 = 3 3.0 75 20 : 802 R1 = H 𝑛 = 5 3.0 64 14 : 863 R1 = CH3 𝑛 = 3 4.5 79 14 : 864 R1 = CH3 𝑛 = 5 5.0 51 21 : 79aYield represents the product [C] after purification by column chromatography. bE/Z ratio was determined by 1HNMR of the crude product mixture.

Table 4: Dihydrothiolation of aliphatic alkyne with thiols in water at room temperature.

Water/r.t.

[A] [C][B]

H +R1

R1R2–SH

R2S SR2

Entry [A] [B]a Time (h) Yieldb (%) [C]1c R1 = CH3-CH2-CH2 R2 = Ph 5 882 R1 = CH3-CH2-CH2 R2 = Ph 5 763 R1 = CH2OAc R2 = Ph 6 794 R1 = CH3-CH2-CH2 R2 = CH3(CH2)6 9 58a[A] : [B] is 1 : 2.2. bYield represents the product [C] after purification by column chromatography. cD (+)-Glucose (1 equiv) was added.

known to catalyze the process of hydrothiolation via radicalintermediates leading to major anti-Markovnikov 1-alkenylsulfides. In the absence of suchmetal complexes, it seems thatstabilization of the reactive species by water as well as by theadditive might govern the course of the reaction as well as thestereoselectivity.

4. Conclusions

In quest of finding “stereoselective switch” for the hydroth-iolation of terminal alkynes under on-water conditions, ourstudies apparently revealed two types of additives that could

lead to the stereoselective formation of the (Z)-1-alkenylsulfides in substantial quantities depending on the nature ofboth reacting partners. Since most of the metal-free methodsdescribe formation of the (E)-1-alkenyl sulfides in majoramount, the present findings could steer in designing mildand green reaction conditions for stereoselective preparationof (E/Z) alkenyl sulphides under on-water conditions.

Conflict of Interests

The authors declare that there is no conflict of interestsregarding the publication of this paper.

Organic Chemistry International 5

Acknowledgments

The authors are grateful to the Department of Science andTechnology, New Delhi, for financial support (Grant no.SR/S1/OC-86/2010 (G)). Samir Kundu and Debasish Sen-gupta respectively thank the UGC and CSIR, New Delhi, forawarding research fellowships.

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JOURNAL OF SULFUR CHEMISTRY, 2016http://dx.doi.org/10.1080/17415993.2016.1166225

SHORT COMMUNICATION

Cyclic ammonium salts of dithiocarbamic acid: stablealternative reagents for the synthesis of S-alkylcarbodithioates from organyl thiocyanates in water

Kinkar Biswas, Sujit Ghosh, Pranab Ghosh and Basudeb Basu

Department of Chemistry, North Bengal University, Darjeeling, India

ABSTRACTCarbodithioate esters are important functional organosulfur com-pounds widely used in diverse fields such as pharmaceuticals, agro-chemicals and material sciences. Common preparative methodsinclude reaction of alkyl halides, carbon disulfide and bases underboth metal-free and metal-catalyzed conditions. However, organylthiocyanates have not been previously explored, possibly because oftheir conversion to organyl disulfides under basic conditions. Here,we report an efficient and practical method for the preparation oflibraries of carbodithioate esters from organyl thiocyanates by react-ing with cyclic amine-based dithiocarbamic acid salts in water. Theprotocol is found to be applicable in general to various thiocyanatessuch as benzyl/aroyl methyl/cinnamyl and so on. Other notable fea-tures includenoby-products suchasdisulfides,metal- andalkali-free,aqueous conditions, and finally easy andnear-quantitative formationof cyclic amine-based dithiocarbamic acid salt as a stable alternativereagent.

ARTICLE HISTORYReceived 5 January 2016Accepted 9 March 2016

KEYWORDSAlkyl thiocyanate; aqueousmedium; carbodithioateester; cyclic sec. amine;dithiocarbamate salt

1. Introduction

S-alkyl carbodithioate esters, also known as dithiocarbamate esters, are functionalorganosulfur compounds that were first utilized as fungicides during the Second WorldWar.[1] These are also largely used as important fungicides of crops, vegetables and

CONTACT Basudeb Basu basu_nbu@hotmail.com Department of Chemistry, North Bengal University,Darjeeling, India

Supplemental data for this article can be accessed here. http://dx.doi.org/10.1080/17415993.2016.1166225

© 2016 Informa UK Limited, trading as Taylor & Francis Group

47484950515253545556575859606162636465666768697071727374757677787980818283848586878889909192

2 K. BISWAS ET AL.

NH

NHSCH3

S SNH

H3C

O S

SCH3

N N S

S NCN N

ClS

S

NMe2

Brassinin,cancer chemopreventive activity

Sulforamatecancer chemopreventive agent

RWJ-025856attenuating effects on tumor

necrosis factor a (TNFa)-induced apoptosis in murinefibrosarcoma WEHI 164 cells

990207inhibiting the tumor growth of sarcoma

180 (S180), hepatocyte carcinoma 22 (H22)

Figure 1. Examples of compounds of potential therapeutic value bearing the S-alkyl carbodithioateester function.

plants.[2–4] Many literature reports demonstrate that the S-alkyl carbodithioate estersand its derivatives exhibit antibacterial,[5–7] anthelmintic,[8] anticandidal activity andcytotoxicity,[9] antihistaminic,[10] aswell as anticancer properties.[8,11–13] They can alsobe helpful for the treatment of cardiovascular disorders and inflammatory diseases.[14]They show in vitro antitumor activity against human myelogenous leukemia K562cells,[15] and can be used as HIV-I NCp7 inhibitors,[16] or non-vanilloid TRPV1antagonists.[17] A few structures of S-alkyl carbodithioate esters with potential thera-peutic value are shown in Figure 1. Further utility of carbodithioate esters as linkersin solid-phase organic synthesis is also well documented.[18,19] In surface science andnanomaterial chemistry, carbodithioate esters arewidely used as suitable ligands for assem-bly on metal nanoparticles.[20,21] They are familiar in the rubber industry as sulfurvulcanization acceptors,[22] and radical chain transfer agents in the reversible additionfragmentation chain transfer polymerizations.[23–25] They also represent useful syntheticintermediates.[26,27] As a result, several methods for the synthesis of carbodithioate estershave been developed.[28]

Commonly, synthesis of S-alkyl/aryl carbodithioate esters is achieved by either nucle-ophilic substitution reactions under basic medium or transition metal-catalyzed cross-coupling reactions (Scheme 1). The reaction of sec. amine with carbon disulfide (CS2)produces an intermediate nucleophile that reacts with various substrates, such as alkylhalide,[29] allyl acetate,[30] epoxide,[31] tosyl hydrazone [32]and α,β-unsaturated car-bonyl compounds,[33–35] in one-pot metal-free or under metal-catalyzed reaction con-ditions to afford the corresponding carbodithioate esters (Scheme 1). Anilines can also beused for the preparation of carbodithioate esters bearing sec. NH group in the presence ofDMSO and a strong base such as NaOH.[36] Most of the procedures involve harsh reac-Q1tion conditions, long reaction time, hazardous organic solvents, metal catalyzts and bases.Organyl thiocyanates, often considered as psuedohalides and are easily available, were not

93949596979899100101102103104105106107108109110111112113114115116117118119120121122123124125126127128129130131132133134135136137138

JOURNAL OF SULFUR CHEMISTRY 3

Xia et al.Tetrahedron, 2009

Alkaline Al2O330 h

OPhO

Azizi et al.RSC Adv., 2012

PEG, RT, 1 h

R1R2NH

+ CS2

R3-X

RT, 3-12 h, neat

Saidi et al.Org. Lett., 2006

Cinnamyl / Allyl acetate

Ranu et al.RSC Adv., 2012

Ru(II) Catalyst, 100 oC, water

Base, dioxane110 ºC, 4 h

Sha et al.Org. Biomol. Chem., 2013

''Our protocol''

R-SCN

(X = Cl, Br, I)

Ref. 29

Ref. 31

Ref. 30

Ref. 32

Ref. 34

S-Alkyl carbodithioate

O

OMe

RS

S

N

+

XN

H

HX

NS

S

n nSDS/H2O

RT

n = 1,2X = O, CH2

NNHTs

R'R

Scheme 1. Methods for the synthesis of S-alkyl carbodithioate esters.

used as the starting materials, presumably because of the fact that the thiocyanate mayundergo disulfide (–S–S–) bond formation under basic medium.[37,38]

We found that the reaction of a sec. amine with CS2 produces a stable salt, which canbe isolated easily in almost quantitative yield and stored for several weeks in the air. Thesalt can efficiently react with alkyl/aroyl methyl/cinnamyl thiocyanates in water mediumat room temperature to afford corresponding carbodithioate esters in the presence of thecationic phase transfer agent (sodiumdodecyl sulfate (SDS)) in excellent yieldswithout for-mation of other by-products such as organyl disulfide. We report herein an efficient, base-and metal-free protocol for the synthesis of various S-substituted carbodithioate esters byusing variety of cyclic sec. amine-based dithiocarbamate salts from diverse organyl thio-cyanates. While organyl thiocyantes have not been used previously as the precursor forpreparation of carbodithioate esters, other notable advantages of this protocol are metal-and alkali-free conditions, which possibly lead to the avoidance of disulfide bond forma-tion and clean reactions affording excellent yields, and can be carried out in water mediumat room temperature (Scheme 1).

2. Results and discussion

As a part of preliminary study, as presented in Table 1, we have conducted the reactionof a neat mixture of benzyl thiocyanate, CS2 and morpholine in a one-pot manner, whichled to the pure desired benzyl morpholine-4-carbodithioate ester 4a in 72% isolated yield(Table 1, entry 1). The reaction showed partial formation of dibenzyl disulfide on TLC Q2monitoring of the experiment, although it was not isolated in appreciable quantity aftercolumn chromatography. Considering that the intermediate salt derived from the amineand CS2 could be the actual nucleophile, the sodium salt of morpholinodithioformate 2awas used to react with benzyl thiocyanate 3a (Table 1, entry 2). However, we obtained thedesired carbodithioate ester 4a again with the formation of dibenzyl disulfide, presumablyattributable to the basic reaction medium that facilitates disulfide formation from benzyl

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4 K. BISWAS ET AL.

Table 1. Optimization of the reaction conditions for the conversion of benzyl thiocyanate to S-alkylcabodithioates.

SCN

NOH

HN O

S

S

S

S

N

O

3a

2b

4a

SolventTemperature,

Additive

N OS

S

2aNa

or +

Entry Solvent T (°C) Additive Time (h) Yielda (%)

1b Neat RT No 1 722c Water RT No 1 60d

3e Water RT No 1 764 Water 60 No 1 785 EtOH 60 No 1 826 Water: EtOH RT No 1 807f Water RT TBAB 1 848g Water RT SDS 1 969h Water RT SDS 1 96aYield represents pure isolated product after purification by column chromatography.bMixture of benzyl thiocyanate (1mmol), morpholine (2mmol) and CS2 (1mmol) in 2mL solvent was stirred at roomtemperature.

cSalt 2awas used.d20% dibenzyl disulphide was isolated.eSalt 2bwas used.fTetrabutyl ammonium bromide (TBAB; stoichiometric) was used.gSodium dodecyl sulfate (SDS; stoichiometric) was used.hSDS (10mol%) was used.

thiocyanate 3a.[37,38] In order to avoid the basic reactionmedium, we considered that thedithiocarbamate salt consisting of both organyl cationic and anionic part might be a betteralternative and accordingly, we prepared the salt 2b from amixture of morpholine and CS2in diethyl ether following the reported procedure.[39]

The salt 2b contains themorpholino-based cationic and anionic part and stirring amix-ture of benzyl thiocyanate 3a and 2b (in equimolar quantity) in water at room temperaturegave rise to a clean reaction without any trace of disulfide formation, producing 4a in 76%isolated yield (Table 1, entry 3). Heating the reaction mixture of 2b and 3a in water orethanol at 60°C resulted in a better yield of 4a (78–82%; Table 1, entries 4 and 5). On theother hand, use of water–ethanol (1:1) as the solvent and conducting the reaction at roomtemperature gave 4a in 80% yield (Table 1, entry 6).

It is likely that organyl thiocyanates are poorly soluble in water, and we employed twodifferent phase transfer agents, n-tetrabutyl ammonium bromide (TBAB) and SDS. Whilethe use of TBAB was found to lead to a marginal increase in the yield of 4a (Table 1, entry7), the presence of SDS (either in stoichiometric or in 10mol%) afforded 4a in excellentyield (96%) (Table 1, entries 8 and 9). Thus, excellent conversion of benzyl thiocyanate tobenzyl morpholine-4-carbodithioate ester 4a is indeed possible if we use separately pre-pared amine-based salt, and perform the reaction under conditions as described in entry9 of Table 1. In aqueous medium reactions, anionic phase transfer agents as additive areusually more effective than cationic agents.[40] Here, we used both TBAB (cationic) and

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JOURNAL OF SULFUR CHEMISTRY 5

NOH

HN O

S

SN

H

HN

S

S

NS

SN

H

HN N

S

SS

SN NH

H

HNHN

H

H

2c2b

e22d

(Morpholiniummorpholinodithioformate)

(Piperidiniumpiperidinodithioformate)

(Pyrrolidiniumpyrrolidinodithioformate)

Bis(piperazinium)piperazine-1,4-dicarbodithioate

XN

H

HX

NS

S

n = 2, X = O (2b)n = 2, X = CH2 (2c)n = 1, X = CH2(2d)

XNH

n

CS2 in diethyl ether

Stir at RTn n

simple preparationcrystalline solideasy separationstored for longer time under air

1

2b-2d

XN

H

Hn 2

N NS

SS

S

n = 2, X = NH (2e)

N OS

S

2a

Na

(Sodiummorpholinodithioformate)

Na

NaOH, CS2

or

EtOH:H2O (1:1)Stir at 0-5 ºC

XN

S

S

n

n = 2, X = O (2a)

Scheme 2. Synthesis of sec. cyclic aliphatic amine-based dithiocarbamate salts (2b–2e).

SDS (anionic) additives and the results are in conformity with previous reports. The bet-ter functioning of the anionic phase transfer agents such as SDS might be explained in thelight of considering the whole system as a microreactor, where organyl thiocyanate havingresided in the hydrophobic dodecyl core may come in contact with the reactant (here thedithocarbamate salt) being present in water through the formation of hydrogen bond withanionic sulfate ion.

Encouraged by this observation, we wanted to develop a general and practical proce-dure for the conversion of organyl thiocyanates into carbodithioate esters. We preparedother dithiocarbamate salts (2c–2e) from three different cyclic sec. amines such as piperi-dine, pyrrolidine and piperazine (Scheme 2), and employed our optimized conditions (asin Table 1, entry 9) for reaction with various functionalized organyl thiocyanates. Theresults are presented in Table 2. It is clearly evident that different chloro-substituted ben-zyl thiocyanates and naphthyl methyl thiocyanate underwent smooth conversion to thecorresponding carbodithioate esters with all types of dithiocarbamate salts (4a–4m ofTable 2).While 2- and 4-chloro benzyl thiocyanates worked equally efficiently without anysteric encumbrance, the piperazine-based dithiocarbamate salt 2e reacted with benzyl or2-chlorobenzyl thiocyanates to produce bis-carbodithioate esters in 82–83% yields within3 h (4l and 4m).

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6 K. BISWAS ET AL.

Table 2. Synthesis of diverse S-alkyl carbodithioates from organyl thiocyanates and dithiocarbamatesalts.a,b

XN

H

HX

NS

S

n n

XN

H

Hn 2

N NS

SS

S

or +SCN

R

S N

S

Xn

RSDS (10 mol%)

Water, RT

3

4l, 4m

N NS

SS

S

orR

R

2b, X = O, n = 22c, X = CH2, n = 22d, X = CH2, n = 12e, X = NH, n = 2

R = H, 2-Cl, 4-Cl

4a-4k

Entry R1−SCN (3) Salt (2) Time (h) T (°C) Product (4) Yield (%)

SCN S N

S

O

1 2b 1.0 RT 96

SCN

Cl

S N

S

OCl

2 2b 1.0 RT 98

SCN

Cl

S N

S

OCl

3 2b 1.0 RT 97

SCN S N

S

O

4 2b 1.5 RT 87

SCN S N

S5 2c 1.0 RT 95

SCN

Cl

S N

S

Cl

6 2c 1.0 RT 98

SCN S N

S7 2c 1.5 RT 89

(continued).

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JOURNAL OF SULFUR CHEMISTRY 7

Table 2. Continued.

Entry R1−SCN (3) Salt (2) Time (h) T (°C) Product (4) Yield (%)

SCN

Cl

S N

S

Cl

8 2c 1.0 RT 97

SCN S N

S9 2d 2.0 RT 94

SCN

Cl

S N

S

Cl

10 2d 2.5 RT 96

SCN S N

S11 2d 2.5 RT 86

SCN

N NS

SS

S

12 2e 3.0 RT 82

SCN

Cl

N NS

SS

SCl

C

13 2e 3.0 RT 83

aA mixture of 2 (1.0mmol), 3 (1.0mmol), SDS (10mol%) in water (2mL) was stirred at RT in open air. For 4l and 4m,compound 3 (2mmol) was used.

bYield represents pure product isolated by column chromatography.

To broaden the scope of the reaction further, alkyl thiocyanates bearing β-carbonylfunction (e.g. aroylmethyl, 5) or β-alkenyl function (e.g. styrenylmethyl, 6) were subjectedto similar reaction conditions. Corresponding functionalized organic carbodithioate estersbearing carbonyl or styrenyl methyl group could be easily synthesized in aqueous mediumat ambient temperature. Three different sec. amine-based dithiocarbamate salts (2b–2d)were used and corresponding carbodithioates bearing Cl, Br or NO2 groups attached withthe aromatic ring (7a–7e, 8a and 8b) were obtained in high yields (Table 3). All the com-pounds were characterized by spectral data and compared with melting points whereverknown and reported.

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8 K. BISWAS ET AL.

Table 3. Synthesis of functionalized S-alkyl carbodithioates.a,b

XN

H

HX

NS

S

n n +

R/R/

SDS (10 mol%)

Water, RT

6

7a-7e

or

SCN

SCN

O

Ph

OS

S

N X

n

or

SPh

S

N

Xn

5R/ = 4-Cl, 4-Br, 3-NO2

2b, X = O, n = 22c, X = CH2, n = 22d, X = CH2, n = 1 8a, 8b

Entry R2−SCN (5 and 6) Salt (2) Time (h) T (°C) Product (7 and 8) Yield (%)

Br

O

SCN

Br

O

S

S

N

O1 2b 3.0 RT 95

Br

O

SCN

Br

O

S

S

N

2 2c 3.0 RT 94

Cl

O

SCN

Cl

O

S

S

N

3 2c 4.0 RT 95

O

SCN

NO2

O

S

S

N

NO2

4 2c 3.5 RT 86

Cl

O

SCN

Cl

O

S

S

N

5 2d 3.0 RT 96

SCN S

S

N

O

6 2b 1.5 RT 92

SCN S

S

N

7 2c 1.5 RT 93

aA mixture of 2 (1.0mmol), 5 or 6 (1.0mmol), SDS (10mol%) in water (2mL) was stirred at RT in open air.bYield represents pure product isolated by column chromatography.

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JOURNAL OF SULFUR CHEMISTRY 9

+

SDS/H2OR S

S

N

2

R SS R

3

NH

H

N

S

S

R

S

C

N

+ Not formedthrough

homolytic fissionof –bond of

alkyl thiocyanate

4 SCNFeCl3 solutiongives blood red

colouration

NH

HRT

Scheme 3. Proposed reaction mechanism.

3. Mechanism

The reaction presumably occurs via a simple nucleophilic substitution reaction. Organylthiocyanates are considered as psuedohalides that might not produce the correspondingcarbocation easily and hence the reaction is expected to proceed via the SN2 pathway Q3(Scheme 3). The dithiocarbamate salt consisting of both organyl cationic and anionic sys-tem seems to render better results than using an in situmixture of sec. amine andCS2 or thecorresponding sodium salt. Use of additives such as SDS likely help the organic reactantsbecome more homogeneous affording excellent conversions. The possibility of the forma-tion of thiyl radical via β-bond cleavage of the alkyl thiocyanate can be excluded sincethe reaction conditions do not support radical formation nor is the corresponding disul-fide formed in the reaction.[41,42] On the other hand, aqueous ferric chloride solutionproduces blood-red coloration indicating elimination of the thiocyanate anion.

4. Conclusion

In conclusion, we have shown that easily accessible and air-stable cyclic sec. amine-baseddithiocarbamate salts can serve as efficient reagents for the preparation of a large varietyof S-substituted carbodithioate esters from rarely used organyl thiocyanates as a commonstrategy. The use of this type of salt not only shows superior activity to the existing one-potthree-component procedure but also establishes it as alternative reagent, obtained easily inquantitative conversion, for the preparation of carbodithioate esters. The simple procedurecan be carried out at room temperature, in water medium and affords excellent yields.Further applications of these easily accessible salts are currently under active pursuit fromthis laboratory. This method also establishes that the sec. amine-based dithiocarbamatesalts can serve as a stable more reactive alternative than in situ use of volatile CS2 and sec.amine reagent, not only for this reaction, but also for other purposes, which are currentlybeing pursued in this laboratory.

5. Experimental

5.1. General information

Morpholine, piperidine and pyrrolidine were purchased from Lancaster and used afterdistillation. Piperazine was purchased from Loba Chemie. CS2 and SDS were purchasedfrom SDFCL and used directly. Benzyl, naphthyl methyl, cinnamyl and aroyl methyl thio- Q4cyanates were prepared from reported procedure and purified by column chromatographybefore use.Melting point of the solid compounds was determined in a concentratedH2SO4

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10 K. BISWAS ET AL.

bath. FT-IR spectra were recorded with a FT-IR-8300 SHIMADZU spectrophotometerQ5using a KBr pellet method for solid compounds and in neat for liquid compounds. NMRQ6spectra were taken in CDCl3 using a Bruker AV-300 spectrometer operating for 1H at300MHz and for 13C at 75MHz.

5.2. General procedure for the synthesis cyclic ammonium salts of dithiocarbamicacid (2b–2e) [39]

A solution of CS2 (5mmol) in diethyl ether (5mL) was slowly added to a solution ofmorpholine (10mmol) or piperidine (10mmol) or pyrrolidine (10mmol) in diethyl ether(5mL). The reactionmixtures were stirred for 30min at room temperature. Solid salts wereprecipitated during this time and were filtered off through a Buchner funnel, washed withdiethyl ether and dried under vacuum to obtain the desired salts 2b–2d. In the case of2e, a solution of CS2 (6mmol) in diethyl ether (5mL) was slowly added to a solution ofpiperazine (9mmol) in diethyl ether (6mL). The reaction mixture was stirred for 45minat room temperature. The grey solids were filtered off, washed with diethyl ether and driedunder vacuum to obtain the desired salt 2e.

5.2.1. Morpholiniummorpholinodithioformate (salt 2b) [39]White solid; yield: 1.23 g (98%); Mp: 197–200°C, Lit. Mp 195–197°C.[39] IR (KBr):Q7νmax = 2854, 2711, 2475, 1583, 1420, 1255, 1215, 1112, 978, 876 cm−1.

5.2.2. Piperidinium piperidinodithioformate (salt 2c) [39]White solid; yield: 1.20 g (98%); Mp: 164–166°C, Lit. Mp 160°C.[39] IR (KBr):νmax = 2936, 2843, 2731, 2497, 1583, 1409, 1215, 1122, 958 cm−1.

5.2.3. Pyrrolidinium pyrrolidinodithioformate (salt 2d)Off-white solid; yield: 1.05 g (96%); Mp: 149–151°C. IR (KBr): νmax = 2946, 2864, 2516,2393, 1390, 1318, 1164, 999, 938 cm−1.

5.2.4. Bis(piperazinium)piperazine-1,4-dicarbodithioate (salt 2e)Grey solid; yield: 1.19 g (97%); Mp: 238–242°C. IR (KBr): νmax = 3162, 2915, 2434, 2331,1634, 1390, 1225, 1123, 958, 855 cm−1.

5.3. General procedure for the synthesis of S-alkyl carbodithioate esters

A mixture of organyl thiocyanate (1mmol), dithiocarbamate salt (1mmol) and SDS(0.1mmol) in water (2mL) was stirred vigorously using a magnetic bar at room tempera-ture. The progress of the reaction wasmonitored by TLC. After the reaction was continuedfor specified time, as mentioned in Tables 2 and 3, the reaction mixture was extractedwith ethyl acetate (3× 5mL) and the combined organic extracts were collected over anhy-drous Na2SO4. Evaporation of the volatiles afforded the crude product, which was furtherpurified by column chromatography over silica gel. Elution with a mixture of EtOAc−PEQ8furnished the desired product. Yields of the products are shown in Tables 2 and 3.

All the products were identified and characterized by spectral data (FT-IR, 1H and 13CNMR), by melting point for solid compounds (compared wherever known).

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JOURNAL OF SULFUR CHEMISTRY 11

5.3.1. Benzyl morpholine-4-carbodithioate (Table 2, 4a) [32]Light yellow solid; yield: 0.243 g (96%); Mp: 64–65°C, Lit. Mp 59–60°C.[32] IR (KBr):νmax = 3038, 2976, 2869, 1920, 1635, 1617, 1559, 1489, 1456, 1304, 1271, 1235, 924, 825,725, 543 cm−1. 1H NMR (CDCl3, 300MHz): δ 3.73 (s, 4H, 2×OCH2), 4.01–4.33 (m, 4H,2×NCH2), 4.57 (s, 2H, SCH2), 7.22–7.39 (m, 5H). 13C NMR (CDCl3, 75MHz): δ 42.02(SCH2), 50.81 (NCH2), 66.27 (OCH2), 127.65, 128.67, 129.42, 135.78, 197.11 (C=S).

5.3.2. 2-Chlorobenzyl morpholine-4-carbodithioate (Table 2, 4b)White crystalline solid; yield: 0.281 g (98%); Mp: 94–96°C. IR (KBr): νmax = 3053, 2992,2931, 2855, 1918, 1654, 1635, 1617, 1542, 1444, 1347, 1310, 1271, 1053, 1028, 868,731, 582 cm−1. 1H NMR (CDCl3, 300MHz): δ 3.77 (s, 4H, 2×OCH2), 4.17 (s, br, 4H,2×NCH2), 4.76 (s, 2H, SCH2), 7.21–7.64 (m, 4H). 13C NMR (CDCl3, 75MHz): δ 39.48(SCH2), 50.91 (NCH2), 66.25 (OCH2), 126.98, 129.10, 129.61, 131.56, 134.12, 134.58,196.91 (C=S).

5.3.3. 4-Chlorobenzyl morpholine-4-carbodithioate (Table 2, 4c)White solid; yield: 0.278 g (97%); Mp: 79–81°C. IR (KBr): νmax = 3007, 2977, 2916, 2870,1833, 1656, 1620, 1542, 1423, 1268, 1217, 1034, 998, 837, 643 cm−1. 1H NMR (CDCl3,300MHz): δ 3.66 (s, 4H, 2×OCH2), 3.90 (s, 2H, NCH2), 4.17 (s, 2H, NCH2), 4.47 (s, 2H,SCH2), 7.17–7.25 (m, 4H). 13C NMR (CDCl3, 75MHz): δ 40.83 (SCH2), 50.83 (NCH2),66.10 (OCH2), 128.60, 130.57, 133.26, 134.59, 196.50 (C=S).

5.3.4. (Naphthalen-1-yl) methyl morpholine-4-carbodithioate (Table 2, 4d)Light brown solid; yield: 0.263 g (87%); Mp: 115–117°C. IR (KBr): νmax = 3053, 2976,2900, 2869, 1699, 1578, 1538, 1420, 1356, 1301, 1271, 1189, 998, 786, 630 cm−1. 1H NMR(CDCl3, 300MHz): δ 3.66 (s, 4H, 2×OCH2), 3.91–4.06 (m, 4H, 2×NCH2), 4.95 (s, 2H,SCH2), 7.31–7.52 (m, 4H), 7.71–7.98 (m, 2H), 8.00–8.01 (m, 1H). 13C NMR (CDCl3,75MHz): δ 40.34 (SCH2), 50.47 (NCH2), 66.23 (OCH2), 123.93, 125.46, 126.01, 126.50,128.34, 128.80, 128.83, 131.06, 131.84, 133.90, 197.25 (C=S).

5.3.5. Benzyl piperidine-1-carbodithioate (Table 2, 4e) [43]Pale yellow viscous liquid; yield: 0.238 g (95%). IR (neat): νmax = 3040, 2974, 2864, 1945,1620, 1590, 1545, 1495, 1358, 1340, 1291, 1279, 1222, 1016, 980, 840, 742 cm−1. 1HNMR (CDCl3, 300MHz): δ 1.62 (s, 6H, NCH2(CH2)3), 3.80 (s, br, 2H, NCH2), 4.21 (s,br, 2H, NCH2), 4.49 (s, 2H, SCH2), 7.15–7.33 (m, 5H). 13C NMR (CDCl3, 75MHz): δ

24.29 (NCH2CH2CH2), 25.79 (NCH2CH2), 42.25 (SCH2), 52.67 (NCH2), 127.45, 128.56,129.38, 136.12, 195.31 (C=S).

5.3.6. 2-Chlorobbenzyl piperidine-1-carbodithioate (Table 2, 4f)Yellow viscous liquid; yield: 0.280 g (98%). IR (neat): νmax = 3010, 2970, 2860, 1996, 1580,1546, 1493, 1357, 1340, 1280, 1224, 1074, 946, 840, 746, 650 cm−1. 1H NMR (CDCl3,300MHz): δ 1.69 (s, 6H, NCH2(CH2)3), 3.87 (s, br, 2H, NCH2), 4.29 (s, br, 2H, NCH2),4.72 (s, 2H, SCH2), 7.18–7.23 (m, 2H), 7.34–7.38 (m, 1H), 7.54–7.58 (m, 1H). 13C NMR(CDCl3, 75MHz): δ 24.29 (NCH2CH2CH2), 25.62 (NCH2CH2), 39.66 (SCH2), 51.42(NCH2), 53.10 (NCH2), 126.96, 128.95, 129.55, 131.56, 134.45, 134.54, 194.91 (C=S).

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12 K. BISWAS ET AL.

5.3.7. (Naphthalen-1-yl) methyl piperidine-1-carbodithioate (Table 2, 4g)White solid; yield: 0.268 g (89%); Mp: 93–95°C. IR (KBr): νmax = 3038, 2947, 2870, 1620,1596, 1563, 1542, 1474, 1435, 1399, 1365, 1281, 1235, 1210, 1113, 980, 870, 776, 670,588 cm−1. 1H NMR (CDCl3, 300MHz): δ 1.63 (s, 6H, NCH2(CH2)3), 3.75 (s, br, 2H,NCH2), 4.27 (s, br, 2H, NCH2), 4.93 (s, 2H, SCH2), 7.31–7.58 (m, 4H), 7.71–7.85 (m,2H), 8.0–8.01 (m, 1H). 13C NMR (CDCl3, 75MHz): δ 24.29 (NCH2CH2CH2), 25.90(NCH2CH2), 40.56 (SCH2), 52.83 (NCH2), 124.11, 125.49, 125.96, 126.43, 128.30, 128.66,128.78, 131.42, 131.90, 133.88, 195.26 (C=S).

5.3.8. 4-Chlorobenzyl piperidine-1-carbodithioate (Table 2, 4h)White solid; yield: 0.277 g (97%); Mp: 83–85°C. IR (KBr): νmax = 3007, 1961, 2855, 1632,1617, 1577, 1542, 1508, 1481, 1429, 1378, 1281, 1225, 1110, 1080, 974, 843, 746, 652 cm−1.1H NMR (CDCl3, 300MHz): δ 1.62 (s, 6H, NCH2(CH2)3), 3.79 (s, br, 2H, NCH2), 4.22(s, br, 2H, NCH2), 4.44 (s, 2H, SCH2), 7.15–7.27 (m, 4H). 13C NMR (CDCl3, 75MHz): δ24.27 (NCH2CH2CH2), 25.54 (NCH2CH2), 41.20 (SCH2), 53.08 (NCH2), 128.67, 130.70,133.21, 135.04, 194.70 (C=S).

5.3.9. Benzyl pyrrolidine-1-carbodithioate (Table 2, 4i) [43]Yellow liquid; yield: 0.223 g (94%). IR (neat): νmax = 3048, 2970, 2865, 1903, 1590, 1440,1365, 1308, 1216, 1070, 1012, 944, 826, 780, 503 cm−1. 1H NMR (CDCl3, 300MHz): δ

1.92−2.10 (m, 4H, NCH2(CH2)2), 3.62 (t, J = 6.3Hz, 2H, NCH2), 3.93 (t, J = 6.9Hz,2H, NCH2), 4.58 (s, 2H, SCH2), 7.22–7.33 (m, 3H), 7.38–7.41 (m, 2H). 13C NMR (CDCl3,75MHz): 24.29 (NCH2CH2), 26.08 (NCH2CH2), 41.30 (SCH2), 50.52 (NCH2), 55.03(NCH2), 127.39, 128.56, 129.27, 136.55, 192.46 (C=S).

5.3.10. 4-Chloro benzyl pyrrolidine-1-carbodithioate (Table 2, 4j)Pale yellow solid; yield: 0.261 g (96%); Mp: 60–62°C. IR (KBr): νmax = 2966, 2864, 1903,1595, 1441, 1328, 1092, 1009, 948, 825, 744, 507 cm−1. 1H NMR (CDCl3, 300MHz): δ

1.92−2.10 (m, 4H, NCH2(CH2)2), 3.62 (t, J = 6.3Hz, 2H, NCH2), 3.93 (t, J = 6.9Hz,2H, NCH2), 7.24–7.27 (m, 2H), 7.32–7.35 (m, 2H). 13C NMR (CDCl3, 75MHz): 24.25(NCH2CH2), 26.05(NCH2CH2), 40.21 (SCH2), 50.56 (NCH2), 55.15 (NCH2), 128.61,130.56, 133.10, 135.42, 191.81 (C=S).

5.3.11. (Naphthalen-1-yl) methyl pyrrolidine-1-carbodithioate (Table 2, 4k)White solid; yield: 0.247 g (86%); Mp: 116–118°C. IR (KBr): νmax = 3040, 2950, 2880,1542, 1450, 1400, 1364, 1342, 1280, 1210, 1134, 1072, 980, 808, 770, 672, 540 cm−1. 1HNMR (CDCl3, 300MHz): δ 1.87–1.97 (m, 4H, NCH2(CH2)2), 3.51 (t, J = 6.9Hz, 2H,NCH2), 3.94 (t, J = 6.6Hz, 2H, NCH2), 5.01 (s, 2H, SCH2), 7.34–7.40 (m, 1H), 7.43–7.54(m, 2H), 7.58 (d, J = 6.9Hz, 1H), 7.76 (d, J = 8.1Hz, 1H), 7.81–7.84 (m, 1H), 8.08 (d,J = 8.1Hz, 1H). 13C NMR (CDCl3, 75MHz): δ 24.29 (NCH2CH2), 26.06 (NCH2CH2),39.64 (SCH2), 50.51 (NCH2), 55.02 (NCH2), 124.08, 125.50, 125.98, 126.44, 128.17, 128.61,128.81, 131.77, 131.85, 133.92, 192.33 (C=S).

5.3.12. Dibenzyl piperazine-1,4-dicarbodithioate (Table 2, 4l) [44]White solid; yield: 0.343 g (82%); Mp: 124–126°C, Lit. Mp 122–123°C.[45] IR (KBr):Q9νmax = 3068, 3038, 2931, 1538, 1505, 1474, 1435, 1413, 1277, 1210, 1159, 1043, 924,

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JOURNAL OF SULFUR CHEMISTRY 13

849, 694 cm−1. 1H NMR (CDCl3, 300MHz): δ 4.18 (s, br, 8H, 4×NCH2), 4.51 (s, 4H,2× SCH2), 7.19–7.32 (m, 10H). 13C NMR (CDCl3, 75MHz): δ 42.16 (SCH2), 48.71(NCH2), 127.74, 128.69, 129.39, 135.51, 197.53 (C=S).

5.3.13. Bis-(2-chlorobenzyl) piperazine-1,4-dicarbodithioate (Table 2, 4m)Grey solid; yield: 0.404 g (83%); Mp: 148–150°C. IR (KBr): νmax = 2916, 1640, 1420, 1276,1041, 990, 928, 846, 744 cm−1. 1H NMR (CDCl3, 300MHz): δ 4.28 (s, br, 8H, 4×NCH2),4.72 (s, 4H, 2× SCH2), 7.18–7.26 (m, 4H), 7.35–7.39 (m, 2H), 7.53–7.56 (m, 2H). 13CNMR (CDCl3, 75MHz): δ 39.64 (SCH2), 48.99 (NCH2), 126.98, 129.21, 129.63, 131.54,133.81, 134.56, 197.19 (C=S).

5.3.14. 4-Bromo phenacyl morpholine-4-carbodithioate (Table 3, 7a)White solid; yield: 0.342 g (95%); Mp: 164–166°C. IR (KBr): νmax = 2967, 2906, 2855,1686, 1583, 1430, 1276, 1125, 1112, 990, 816, 539 cm−1. 1H NMR (CDCl3, 300MHz): δ3.71 (t, J = 4.8Hz, 4H, 2×OCH2), 3.97 (s, br, 2H, NCH2), 4.2 (s, br, 2H, NCH2), 4.77 (s,2H, SCH2), 7.54–7.59 (m, 2H), 7.84–7.88 (m, 2H).13C NMR (CDCl3, 75MHz): δ 44.28(SCH2), 51.55 (NCH2), 66.21 (OCH2), 128.85, 130.06, 132.08, 134.88, 192.28 (C=O),195.65 (C=S).

5.3.15. 4-Bromo phenacyl piperidine-1-carbodithioate (Table 3, 7b)White solid; yield: 0.336 g (94%); Mp: 116–118°C. IR (KBr): νmax = 3007, 2947, 2869,1687, 1584, 1438, 1362, 1286, 1253, 973, 858, 666 cm−1. 1H NMR (CDCl3, 300MHz):δ 1.65 (s, 6H, NCH2(CH2)3), 3.89 (s, br, 2H, NCH2), 4.18 (s, br, 2H, NCH2), 4.77 (s,2H, SCH2), 7.54–7.57 (m, 2H), 7.86–7.89 (m, 2H). 13C NMR (CDCl3, 75MHz): δ 24.16(NCH2CH2CH2), 25.95 (NCH2CH2), 44.50 (SCH2), 51.76 (NCH2), 53.66 (NCH2), 128.62,130.09, 131.99, 135.04, 192.71 (C=O), 193.70 (C=S).

5.3.16. 4-Chloro phenacyl piperidine-1-carbodithioate (Table 3, 7c)Yellowish white solid; yield: 0.298 g (95%); Mp: 110–112°C. IR (KBr): νmax = 3007, 2961,2855, 1690, 1587, 1438, 1347, 1244, 1113, 971, 858, 682, 548 cm−1. 1H NMR (CDCl3,300MHz): δ 1.65 (s, 6H,NCH2(CH2)3), 3.89 (s, br, 2H,NCH2), 4.19 (s, br, 2H,NCH2), 4.77(s, 2H, SCH2), 7.54–7.58 (m, 2H), 7.85–7.90 (m, 2H). 13C NMR (CDCl3, 75MHz): δ 24.18(NCH2CH2CH2), 25.42 (NCH2CH2), 26.09 (NCH2CH2), 44.49 (SCH2), 51.78 (NCH2),53.72 (NCH2), 128.67, 130.11, 132.01, 135.00, 192.75 (C=O), 193.63 (C=S).

5.3.17. 3-Nitro phenacyl piperidine-1-carbodithioate (Table 3, 7d)Pale yellow solid; yield: 0.279 g (86%);Mp: 109–111°C. IR (KBr): νmax = 2926, 2854, 1697,1613, 1532, 1430, 1337, 1204, 1112, 1072, 979, 804, 733, 672 cm−1. 1H NMR (CDCl3,300MHz): δ 1.73 (s, 6H, NCH2(CH2)3), 3.97 (s, br, 2H, NCH2), 4.25 (s, br, 2H, NCH2),4.86 (s, 2H, SCH2), 7.69–7.74 (m, 1H), 8.40–8.46 (m, 2H), 8.90–8.91 (m, 1H). 13C NMR(CDCl3, 75MHz): δ 24.16 (NCH2CH2CH2), 26.02 (NCH2CH2), 44.09 (SCH2), 52.09(NCH2), 53.79 (NCH2), 123.45, 127.49, 129.95, 134.13, 137.87, 148.58, 191.84 (C=O),193.39 (C=S).

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14 K. BISWAS ET AL.

5.3.18. 4-Chloro phenacyl pyrrolidine-1-carbodithioate (Table 3, 7e)Pale yellow solid; yield: 0.287 g (96%);Mp: 102–104°C. IR (KBr): νmax = 2957, 2876, 1676,1583, 1430, 1286, 1184, 1080, 990, 958, 825, 528 cm−1. 1H NMR (CDCl3, 300MHz): δ

1.94–2.03 (m, 2H, NCH2CH2), 2.06–2.14 (m, 2H, NCH2CH2), 3.74 (t, J = 6.9Hz, 2H,NCH2), 3.9 (t, J = 6.9Hz, 2H, NCH2), 4.85 (s, 2H, SCH2), 7.44–7.47 (m, 2H), 8.01–8.04(m, 2H). 13C NMR (CDCl3, 75MHz): δ 24.33 (NCH2CH2), 26.12 (NCH2CH2), 44.04(SCH2), 50.80 (NCH2), 55.53 (NCH2), 128.99, 130.01, 134.43, 139.88, 190.68 (C=O),192.43 (C=S).

5.3.19. (E)-Cinnamylmorpholine-4-carbodithioate, (Table 3, 8a) [30]White crystalline solid, yield: 0.257 g (92%); Mp: 80–82°C (Lit. reported as yellowish vis-cous liquid). IR (KBr): νmax = 3038, 2961, 2869, 1720, 1620, 1577, 1469, 1304, 1268,1220, 1113, 992, 755 cm−1. 1H NMR (CDCl3, 300MHz): δ 3.78 (t, J = 4.5Hz, 4H,2×OCH2), 4.17–4.24 (m, 6H, 2×NCH2, SCH2), 6.28–6.38 (m, 1H, PhCH=CHCH2),6.67 (d, J = 15.6Hz, 1H, PhCH), 7.23–7.41 (m, 5H). 13C NMR (CDCl3, 75MHz): δ 39.97(SCH2), 50.90 (NCH2), 66.26 (OCH2), 123.68, 126.45, 127.76, 128.56, 133.95, 136.60,197.03 (C=S).

5.3.20. (E)-Cinnamyl piperidine-1-carbodithioate (Table 3, 8b) [30]White crystalline solid; yield: 0.258 g (93%); Mp: 73–75°C (Lit. reported as yellowish vis-cous liquid). IR (KBr): νmax = 3048, 2947, 2869, 1617, 1566, 1472, 1435, 1265, 1235, 1135,1116, 1110, 973, 743 cm−1. 1H NMR (CDCl3, 300MHz): δ 1.63 (s, 6H, NCH2(CH2)3),3.82 (s, br, 2H, NCH2), 4.01–4.13 (m, 2H, SCH2), 4.23 (s, br, 2H, NCH2), 6.20–6.31(m, 1H, PhCH=CHCH2), 6.56 (d, J = 15.9Hz, 1H, PhCH), 7.12–7.31 (m, 5H). 13CNMR (CDCl3, 75MHz): 24.32 (NCH2CH2CH2), 26.00 (NCH2CH2), 40.23 (SCH2), 51.37(NCH2), 124.17, 126.44, 127.67, 128.54, 133.59, 136.72, 195.04 (C=S).

Disclosure statement

No potential conflict of interest was reported by the authors.

Funding

KB and SG thank the UGC, New Delhi, for award of their fellowships under UGC-FDP program.

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