iron(iii) chloride hexahydrate catalyzed one-pot...

IRON(III) CHLORIDE HEXAHYDRATE CATALYZED ONE-POT THREE-

COMPONENT AZA-FRIEDEL-CRAFTS REACTION OF ACTIVATED

ARENES WITH A COMBINATION OF N-BOC CARBAMATE AND

ALDEHYDES AND ITS APPLICATION FOR THE SYNTHESIS OF

UNSYMMETRICAL TRIARYLMETHANES

SUREEPORN RUENGSANGTONGKUL

A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF

THE REQUIREMENTS FOR THE MASTER DEGREE OF SCIENCE

IN CHEMISTRY

FACULTY OF SCIENCE

BURAPHA UNIVERSITY

JUNE 2015

COPYRIGHT OF BURAPHA UNIVERSITY

iii

ACKNOWLEDGEMENT

I am indebted to the Department of Chemistry, Faculty of Science, Burapha

University, Thailand, where I performed my experiments and study. This thesis was

completed with the help of many people. Firstly, I would like to express my sincere

gratitude and deep appreciation to Assistant Professor Dr. Jaray Jaratjaroonphong, my

principal advisor, for teaching me scientific reasoning, valuable instructions, expert

guidance, excellent suggestions and kindness.

I am also grateful to Dr. Tinnagon Keawin, from Department of Chemistry,

Ubon Ratchathani University and Dr. Anan Athipornchai, who accepted the request to

participate in the jury of my thesis.

I would to express my sincere gratitude and deep appreciation to Dr.

Prapapan Techasauvapak, Assistant Professor Dr. Jongkolnee Jongaramruong,

Assistant Professor Dr. Rungnapha Saeeng, Assistant Professor Dr. Ekaruth Srisook,

Dr. Uthaiwan Sirion and Dr. Anan Athipornchai, my organic chemistry lecturers for

teaching me basic knowledge and scientific reasoning and expert guidance.

I thank the Thailand Research Fund for financial support to J.J. Financial

support from the Center for Innovation in Chemistry (PERCH-CIC), Commission on

Higher Education, Ministry of Education and a Grant from the Faculty of Science,

Burapha University, Thailand are also gratefully acknowledged.

Finally, my success will not be happened if without great support from my

family. Therefore, I would like to take this opportunity to appreciate all of them. For

their great support and help full to success education for my Master degree.

Sureeporn Ruengsangtongkul

iv

55910079: MAJOR: CHEMISTRY; M.Sc. (CHEMISTRY)

KEYWORD: FeCl3∙6H2O/ Bi(OTf)3/ ΑLPHA-BRANCHED AMINES /

UNSYMMETRICAL TRIARYLMETHANES/ AZA-FRIEDEL-

CRAFTS REACTION/ FRIEDEL-CRAFTS REACTION

SUREEPORN RUENGSANGTONGKUL: IRON(III) CHLORIDE

HEXAHYDRATE CATALYZED ONE-POT THREE-COMPONENT AZA-

FRIEDEL-CRAFTS REACTION OF ACTIVATED ARENES WITH A

COMBINATION OF N-BOC CARBAMATE AND ALDEHYDES AND ITS

APPLICATION FOR THE SYNTHESIS OF UNSYMMETRICAL TRIARYL-

METHANES. ADVISORY COMMITTEE: JARAY JARATJAROONPHONG, Ph.D.

194 P. 2015.

Iron(III) chloride hexahydrate (FeCl3∙6H2O) is found to be an efficient

catalyst for a one-pot synthesis of α-branched amines via aza-Friedel-Crafts reaction

of electron-rich arenes or heteroarenes with a combination of aldehydes and tert-butyl

carbamate for in dichloroethane or toluene under "open flask" and mild conditions.

In the presence of 5 mol% of FeCl3∙6H2O in toluene or dichloroethane (ClCH2CH2Cl)

at room temperature the reaction give the corresponding N-Boc protected α-branched

amines in moderate to high yields. These N-Boc protected α-branched amines can be

transformed to unsymmetrical triarylmethanes through sequential reactions with the

different arenes.

Ar1 Ar2/R2

HN O

O

H2N O

O

Ar2/R2CHO

FeCl3 6H2O

solvent, 0-rt

Ar1 H

Het H

or

Ar2 = aryl or heteroaryl

R2 = alkyl

Ar1

Ar3

Ar2

solvent, rt

Ar3 H

-Branched amines UnsymmetricalTriarylmethanes

FeCl3 6H2O

CONTENTS

Page

ABSTRACT......................................................................................................... iv

CONTENTS......................................................................................................... v

LIST OF TABLES................................................................................................ viii

LIST OF FIGURES.............................................................................................. ix

LIST OF ABBREVIATIONS............................................................................... xx

THE RELEVANCE OF THE RESEARCH WORK TO THAILAND................ xxiii

CHAPTER

1. INTRODUCTION..................................................................................... 1

Objectives............................................................................................. 5

Contribution to knowledge................................................................... 6

Scope of the study................................................................................ 6

2. LITERATURE REVIEWS........................................................................ 7

3. RESEARCH METHODOLOGY.............................................................. 43

1. The aza-Friedel-Crafts reaction of electron-rich arenes with

aldehyde and tert-butyl carbamate in the presence of FeCl3∙6H2O:

Synthesis of the corresponding α-branched amines........................

44

1.1 Optimization of the reaction condition for aza-Friedel-Crafts

alkylation of 1,3,5-trimethoxybenzene with tert-butyl

carbamate and benzaldehyde.....................................................

44

1.1.1 Reaction of 1,3,5-trimethoxybenzene with tert-butyl

carbamate and benzaldehyde in various of solvent

using FeCl3∙6H2O as catalyst..........................................

45


carbamate and benzaldehyde in various catalyst

loading of FeCl3∙6H2O using toluene as solvent............

47


carbamate and benzaldehyde in various catalyst loading

of FeCl3∙6H2O using ClCH2CH2Cl as solvent.................

48

vi

CONTENTS (CONTINUED)

Chapter Page

1.2 The aza-Friedel-Crafts alkylation of 1,3,5-trimethoxybenzene

with tert-butyl carbamate and various aldehydes in the

presence of FeCl3∙6H2O under optimized reaction condition....

49

1.2.1 The reaction of 1,3,5-trimethoxybenzene with tert-butyl

carbamate and various aromatic aldehydes in the

presence of FeCl3∙6H2O as catalyst: The synthesis of

α-branched amines III-4…..………………….………...

49

1.2.2 The reaction of 1,3,5-trimethoxybenzene, tert-butyl

carbamate with various heteroaromatic aldehydes in

the presence of FeCl3∙6H2O as catalyst: The synthesis

of α-branched amines III-6..............................................

58

1.2.3 The reaction of 1,3,5-trimethoxybenzene, tert-butyl

carbamate with various aliphatic aldehydes in the

presence of FeCl3∙6H2O as catalyst: The synthesis of

α-branched amines III-7..................................................

60

1.3 FeCl3∙6H2O catalyzed aza-Friedel-Crafts reaction of various

electron-rich arenes, tert-butyl carbamate with aromatic and

aliphatic aldehydes under optimized reaction condition...........

67

1.3.1 Reaction of electron-rich arenes with tert-butyl

carbamate and aromatic aldehydes using FeCl3∙6H2O as

catalyst …………..…………………………....………...

68

1.3.2 Reaction of electron-rich arenes, tert-butyl carbamate

with aliphatic aldehydes using FeCl3∙6H2O as catalyst...

75

2. The Friedel-Crafts reaction of electron-rich arenes with N-Boc

diarylmethylcarbamate: Synthesis of the corresponding

unsymmetrical triarylmethanes........................................................

81

2.1 Reaction of 2-methylfuran with N-Boc diarylmethylcarbamate

in various catalyst……………………………………………..

81

vii

CONTENTS (CONTINUED)

Chapter Page

2.2 FeCl3∙6H2O catalyzed Friedel-Crafts alkylation of various

N-Boc diarylmethylcarbamate as alkylating agent with

different arene under optimized reaction condition...................

86

2.2.1 Reaction of tert-butyl phenyl(2,4,6-trimethoxyphenyl)-

methylcarbamate III-4a with different arene...................

86

2.2.2 Reaction of tert-butyl phenyl(2,4,5-trimethoxyphenyl)-

methylcarbamate III-8a with different arene...................

87

2.2.3 Reaction of tert-butyl (5-methylfuran-2-yl)(phenyl)

methylcarbamate III-8b or tert-butyl (5-methylfuran-2-

yl)(4-nitrophenyl)methylcarbamate III-8c with different

arene.................................................................................

93

2.3 FeCl3∙6H2O catalyzed Friedel-Crafts alkylation of various

N-Boc diarylmethylcarbamate as alkylating agent with indole

under optimized reaction condition...........................................

104

4. RESULTS DISSCUSSION AND CONCLUSION................................... 107

CONCLUSION.................................................................................... 142

Compound characterization.................................................................. 143

REFERENCES..................................................................................................... 187

BIOGRAPHY.......................................................................................................

.

194

LIST OF TABLES

Tables Page

4-1 Reaction of 1,3,5-trimethoxybenzene with benzaldehyde and tert-butyl

carbamate in various of solvent...............................................................

109

4-2 Reaction of 1,3,5-trimethoxybenzene with benzaldehyde and tert-butyl

carbamate in various catalyst loading …….............................................

111

4-3 Reaction of 1,3,5-trimethoxybenzene, tert-butyl carbamate with

various aromatic aldehydes.....................................................................

113


disubstituted aromatic aldehydes.............................................................

115


heteroaromatic aldehydes........................................................................

116


aliphatic aldehydes..................................................................................

118

4-7 Reaction of various arenes, tert-butyl carbamate with benzaldehyde,

2-methylpropanal under the optimized reaction condition......................

122

4-8 Reaction of N-Boc diarylmethylcarbamates and 2-methylfuran in

various catalysts loading..........................................................................

129

4-9 Reaction of tert-butyl phenyl(2,4,6-trimethoxyphenyl)methyl

carbamate III-4a with different arene....................................................

133

4-10 Reaction of tert-butyl phenyl(2,4,5-trimethoxyphenyl)methyl

carbamate III-8a with different arene.....................................................

135

4-11 Reaction of tert-butyl (5-methylfuran-2-yl)(phenyl)methylcarbamate

III-8b or tert-butyl (5-methylfuran-2-yl)(4-nitrophenyl)methyl-

carbamate III-8c with different arene....................................................

138

4-12 Reaction of various N-Boc diarylmethylcarbamate as alkylating agent

with indole...............................................................................................

141

LIST OF FIGURES

Figures Page

1-1 Examples of bioactive α-branched amine derivatives............................ 2

1-2 Examples of bioactive unsymmetrical triarymethane derivatives.......... 3

1-3 Main current synthetic approaches of unsymmetrical triarylmethanes.. 4

1-4 FeCl3·6H2O-catalyzed formation of α-branched amines and

unsymmetrical triarylmethanes...............................................................

5

2-1 The enantioselective Friedel-Crafts reaction of indoles with imines

II-2 using chiral organic catalysts...........................................................

8

2-2 The reaction of 1,3,5-trimethoxybenzene with imines II-7 under the

Iron(III) chloride catalyst.......................................................................

9

2-3 The reaction of 1,2-dimethoxybenzene with imines II-10 under the

Iron(III) chloride catalyst........................................................................

9

2-4 The reactions of arenes with aziridines under the Iron(III) chloride

catalyst....................................................................................................

9

2-5 Ir(III)-SnCl3 catalyzed aza-Friedel-Crafts reaction................................. 10

2-6 The synthesis of triarylmethanes by Ir(III)-SnCl3 catalyst..................... 10

2-7 The three component reaction of aromatic compounds, carbamates

and aldehydes using H2SO4 as catalyst...................................................

11

2-8 The three-component aza Friedel-Craft reaction of 2-naphthaldehyde,

o-anisidine and 1-methylindole using C9H19COOH in water.................

12

2-9 The synthesis of triarylmethanes II-32................................................... 13

2-10 Transformations of aza-Friedel-Crafts Products..................................... 13

2-11 I2-catalyzed three-component aza-Friedel–Crafts reaction..................... 14

2-12 Fe(III)-catalyzed three-component aza-Friedel–Crafts reaction............. 14

2-13 Bi(OTf)3-catalyzed three-component aza-Friedel–Crafts reaction......... 15

2-14 The synthesis of α-branched amines using Bi(OTf)3 as catalyst............ 15

2-15 Transformations of aza-Friedel-Crafts Products..................................... 16

x

LIST OF FIGURES (CONTINUED)

Figures Page

2-16 The synthesis of aminoalkyl naphthols using sulfamic acid as

catalyst....................................................................................................

16

2-17 The synthesis of aminoalkyl naphthols using I2 as catalyst.................... 17

2-18 The synthesis of aminoalkyl naphthols using SiO2-NaHSO4 as catalyst 17

2-19 The synthesis of aminoalkyl naphthols using Brønsted acidic ionic

liquid ([TEBSA][HSO4]) as catalyst...................

18

2-20 The synthesis of aminoalkyl naphthols using VB1 as catalyst................ 19

2-21 The synthesis of aminoalkyl naphthols using P2O5 as catalyst............... 19

2-22 The synthesis of aminoalkyl naphthols/phenols using EAN as catalyst. 20

2-23 [RuCl2(p-cymene)]2 catalyzed arylation of benzylic amines witharyl

bromides and aryl iodides.......................................................................

20

2-24 The possible mechanism for the ruthenium(II) catalyzed arylation of

benzylic amines with aryl halides...........................................................

21

2-25 The Synthesis of (p-Nitroaryl)diarylmethane......................................... 22

2-26 The Synthesis of unsymmetrical triarylmethane derivatives using

Brønsted acid or Lewis acid as catalyst..........................................................

23

2-27 The Synthesis of unsymmetrical bis(indolyl)alkanes............................. 24

2-28 The Synthesis of unsymmetrical triarylmethane derivatives using

FeCl3 as catalyst......................................................................................

24

2-29 Reaction of carbinol with 1- and 2-naphthol.......................................... 25

2-30 The synthesis of thiophene containing triarylmethanes.......................... 26

2-31 The synthesis of unsymmetrical tri-, tetraarylmethanes....................... 26

2-32

The synthesis of unsymmetrical triarylmethanes using AuCl4Na∙2H2O

as catalyst................................................................................................

27

2-33 The chemoselective synthesis for Friedel-Crafts reaction of

diarylmethanols and nucleophiles...........................................................

27

xi


Figures Page

2-34 The chemoselective synthesis of unprotected anilines and mono-, di-

arylmethanol using Re2O7 as catalyst...................................................

28

2-35 The mechanism for the benzylation of anilines.................................... 28

2-36 The synthesis of di-, triarylmethanes using o-benzenedisulfonimide

as catalyst..............................................................................................

29

2-37 FeCl3 catalyzed symmetrical triarylmethanes formations..................... 29

2-38 FeCl3 catalyzed the mono-aromatic substitution product..................... 30

2-39 FeCl3 catalyzed unsymmetrical triarylmethanes formations................. 30

2-40 The synthesis of unsymmetrical triarylmethane derivatives using

Cu(OTf)2/(±)-binap as catalyst..............................................................

31

2-41 Sc(OTf)3 catalyzed aza-Friedel-Crafts alkylation of sulfonamide

adducts and electron-rich aromatic and heteroaromatic compounds....

31

2-42 The synthesis of unsymmetrical 3,3'-bis(indolyl)methanes using

achiral Brønsted acid II-159 as catalyst................................................

32

2-43 The synthesis of unsymmetrical 3,3'-bis(indolyl)methanes using

chiral Brønsted acid II-156 as catalyst.................................................

33

2-44 The synthesis of N-arylsufoylamido sulfones using FeCl3·6H2O as

catalyst..................................................................................................

33

2-45 Transformation of α-amido sulfones into unsymmetrical

triarylmethane derivatives with FeCl3·6H2O........................................

34

2-46 The mechanism for the iron(III) catalyzed Friedel-Crafts reaction..... 35

2-47 Transformation of α-amido sulfones into unsymmetrical

triarylmethane derivatives with [B(C6F5)3]...........................................

35

2-48 Reaction of benzylation and silylation.................................................. 36

2-49 Reaction of [3+3]-cyclocondensation follow by cyclization and

aromatization.........................................................................................

36

xii


Figures Page

2-50 The synthesis of Friedel-Crafts alkylation of diketone and arenes

using SiO2-NaHSO4 as catalyst.............................................................

37

2-51 FeCl3 catalyzed one-pot three-component Friedel-Crafts reactions..... 37

2-52 Binuclear complex catalyzed one-pot three-component Friedel-Crafts

reactions................................................................................................

38

2-53 ZnCl2 catalyzed one-pot three-component Friedel-Crafts reactions..... 39

2-54 Transformation of bis(indolyl)methane into 3-diarylmethylindoles or

3-arylmethylindoles..............................................................................

39

2-55 The cationic Pd(II)/bpy-catalyzed one-pot synthesis of

unsymmetrical triarylmethane derivatives............................................

40

2-56 The synthesis of triarylmethanes via deprotonative-cross-coupling..... 40

2-57 The stereospecific synthesis for Suzuki-Miyaura cross-coupling of

enantio enrich triarylmethanes..............................................................

41

2-58 Palladium-catalyzed arylation of diarylmethanol derivatives and

oxazoles.................................................................................................

42

4-1 A model reaction for the synthesis of α-branched amine derivatives

and unsymmetrical triarylmethanes......................................................

107

4-2 A model reaction for the synthesis of α-branched amines.................... 108

4-3 The synthesis of α-branched amine derivatives using FeCl3∙6H2O as

catalyst..................................................................................................

112

4-4 The one-pot three-component aza-Friedel-Crafts reactionof arenes or

heteroarenes with aldehydes and tert-butyl carbamates........................

120

4-5 Plausible reaction mechanism............................................................... 126

4-6 A model reaction for the synthesis of unsymmetrical triarylmethanes

using FeCl3∙6H2O as the catalyst..........................................................

127

xiii


Figures Page

4-7 A model reaction for the synthesis of unsymmetrical triarylmethanes

of N-Boc diarylmethylcarbamate III-4a or III-8a and

2-methylfuran........................................................................................

128

4-8 Plausible reaction mechanism............................................................... 131

4-9 The synthesis of unsymmetrical triarylmethane derivatives using

FeCl3∙6H2O as the catalyst....................................................................

132

4-10 The synthesis of α-branched amine derivatives using FeCl3∙6H2O as

catalyst..................................................................................................

142

4-11 The synthesis of unsymmetrical triaylmethane derivatives using

FeCl3∙6H2O as catalyst..........................................................................

143

4-12 Structure of tert-butyl[(2,4,6-trimethoxyphenyl)phenylmethyl]-

carbamate III-4a.................................................................................

143

4-13 Structure of tert-butyl (2-fluorophenyl)(2,4,6-trimethoxyphenyl)-

methylcarbamate III-4b........................................................................

144

4-14 Structure of tert-butyl (4-fluorophenyl)(2,4,6-trimethoxyphenyl)-

methylcarbamate III-4c........................................................................

144

4-15 Structure of tert-butyl (4-chlorophenyl)(2,4,6-trimethoxyphenyl)-

methylcarbamate III-4d........................................................................

145

4-16 Structure of tert-butyl (4-bromophenyl)(2,4,6-trimethoxyphenyl)-

methylcarbamate III-4e........................................................................

145

4-17 Structure of tert-butyl (4-nitrophenyl)(2,4,6-trimethoxyphenyl)-

methylcarbamate III-4f........................................................................

146

4-18 Structure of tert-butyl (4-methoxyphenyl)(2,4,6-trimethoxyphenyl)-

methylcarbamate III-4g........................................................................

147

xiv


Figures Page

4-19 Structure of methyl 4-((tert-butoxycarbonylamino)(2,4,6-trimethoxy-

phenyl)methyl)benzoate III-4h............................................................

147

4-20 Structure of tert-butyl (4-formylphenyl)(2,4,6-trimethoxyphenyl)-

methylcarbamate III-4j.........................................................................

148

4-21 Structure of tert-butyl 1,4-phenylenebis((2,4,6-trimethoxyphenyl)-

methylene)dicarbamatee III-5a............................................................

148

4-22 Structure of tert-butyl furan-2-yl(2,4,6-trimethoxyphenyl)methyl-

carbamate III-6a...................................................................................

149

4-23 Structure of tert-butyl pyridin-2-yl(2,4,6-trimethoxyphenyl)methyl-

carbamate III-6b..................................................................................

150

4-24 Structure of tert-butyl 1-(2,4,6-trimethoxyphenyl)propylcarbamate

III-7a.....................................................................................................

150

4-25 Structure of tert-butyl 1-(2,4,6-trimethoxyphenyl)pentylcarbamate

III-7b....................................................................................................

151

4-26 Structure of tert-butyl 3-phenyl-1-(2,4,6-trimethoxyphenyl)propyl-

carbamate III-7c...................................................................................

151

4-27 Structure of tert-butyl 2-methyl-1-(2,4,6-trimethoxyphenyl)propyl-

carbamate III-7d...................................................................................

152

4-28 Structure of tert-butyl 2-ethyl-1-(2,4,6-trimethoxyphenyl)butyl-

carbamate III-7e...................................................................................

153

4-29 Structure of tert-butyl 3-methyl-1-(2,4,6-trimethoxyphenyl)butyl-

carbamate III-7f....................................................................................

153

4-30 Structure of tert-butyl cyclopropyl(2,4,6-trimethoxyphenyl)methyl-

carbamate III-7g...................................................................................

154

4-31 Structure of tert-butyl cyclopentyl(2,4,6-trimethoxyphenyl)methyl-

carbamate III-7h...................................................................................

154

xv


Figures Page

4-32 Structure of tert-butyl cyclohexyl(2,4,6-trimethoxyphenyl)methyl-

carbamate III-7i...................................................................................

155

4-33 Structure of tert-butyl phenyl(2,4,5-trimethoxyphenyl)methyl-

carbamate III-8a...................................................................................

156

4-34 Structure of 5,5'-(phenylmethylene)bis(1,2,4-trimethoxybenzene)

III-9a.....................................................................................................

156

4-35 Structure of tert-butyl (5-methylfuran-2-yl)(phenyl)methylcarbamate

III-8b....................................................................................................

157

4-36 Structure of 5,5'-(phenylmethylene)bis(2-methylfuran) III-9b............ 157

4-37 Structure of tert-butyl (5-methylfuran-2-yl)(4-nitrophenyl)methyl-

carbamate III-8c..................................................................................

158

4-38 Structure of 5,5'-((4-nitrophenyl)methylene)bis(2-methylfuran)

III-9c....................................................................................................

158

4-39 Structure of tert-butyl (5-ethylfuran-2-yl)(phenyl)methylcarbamate

III-8d...................................................................................................

159

4-40 Structure of 5,5'-(phenylmethylene)bis(2-ethylfuran) III-9d.............. 159

4-41 Structure of tert-butyl (5-methylthiophen-2-yl)(phenyl)methyl-

carbamate III-8e...................................................................................

160

4-42 Structure of 5,5'-(phenylmethylene)bis(2-methylthiophene) III-9e.... 160

4-43 Structure of tert-butyl (5-ethylthiophen-2-yl)(phenyl)methyl-

carbamate III-8f....................................................................................

161

4-44 Structure of tert-butyl 2-((tert-butoxycarbonylamino)(phenyl)-

methyl)- 1H-pyrrole-1-carboxylate III-8g............................................

161

4-45 Structure of tert-butyl (1H-indol-3-yl)(phenyl)methylcarbamate

III-8h....................................................................................................

162

4-46 Structure of 3,3'-(phenylmethylene)bis(1H-indole) III-9h................... 162

xvi


Figures Page

4-47 Structure of tert-butyl 2-methyl-1-(2,4,5-trimethoxyphenyl)propyl-

carbamate III-10a.................................................................................

163

4-48 Structure of 5,5'-(2-methylpropane-1,1-diyl)bis(1,2,4-trimethoxy-

benzene) III-11a...................................................................................

163

4-49 Structure of tert-butyl 2-methyl-1-(5-methylfuran-2-yl)propyl-

carbamate III-10b.................................................................................

164

4-50 Structure of tert-butyl 1-(5-ethylfuran-2-yl)-2-methylpropyl-

carbamate III-10c.................................................................................

165

4-51 Structure of 5,5'-(2-methylpropane-1,1-diyl)bis(2-ethylfuran) III-11c 165

4-52 Structure of tert-butyl 2-methyl-1-(5-methylthiophen-2-yl)propyl-

carbamate III-10d................................................................................

166

4-53 Structure of tert-butyl 1-(5-ethylthiophen-2-yl)-2-methylpropyl-

carbamate III-10e................................................................................

166

4-54 Structure of tert-butyl 2-(1-(tert-butoxycarbonylamino)-2-

methylpropyl)-1H-pyrrole-1-carboxylate III-10f................................

167

4-55 Structure of (syn/anti)-tert-butyl 2,5-bis(1-(tert-butoxycarbonyl-

amino)-2-methylpropyl)-1H-pyrrole-1-carboxylate III-12a................

167

4-56 Structure of (syn/anti)-tert-butyl 2,5-bis(1-(tert-butoxycarbonyl-

amino)- 2-methylpropyl)-1H-pyrrole-1-carboxylate III-12a..............

168

4-57 Structure of 2-methyl-5-(phenyl(2,4,6-trimethoxyphenyl)methyl)-

furan III-13a.........................................................................................

169

4-58 Structure of 1,3,5-trimethoxybenzene III-1a........................................ 169


furan III-13b........................................................................................

170

xvii


Figures Page

4-60 Structure of 2-ethyl-5-(phenyl(2,4,5-trimethoxyphenyl)methyl)furan

III-13c...................................................................................................

170


thiophene III-13d..................................................................................

171

4-62 Structure of 2-ethyl-5-(phenyl(2,4,5-trimethoxyphenyl)methyl)-

thiophene III-13e..................................................................................

172

4-63 Structure of tert-butyl 2-(phenyl(2,4,5-trimethoxyphenyl)methyl)-

1H-pyrrole-1-carboxylate III-13f.........................................................

172

4-64 Structure of 2-ethyl-5-(phenyl(2,4,5-trimethoxyphenyl)methyl)-1H-

pyrrole III-13g.....................................................................................

173

4-65 Structure of 3-(phenyl(2,4,5-trimethoxyphenyl)methyl)-1H-indole

III-13h..................................................................................................

173

4-66 Structure of 5-methoxy-3-(phenyl(2,4,5-trimethoxyphenyl)methyl)-

1H-indole III-13i.................................................................................

174

4-67 Structure of 6-fluoro-3-(phenyl(2,4,5-trimethoxyphenyl)methyl)-1H-

indole III-13j........................................................................................

175

4-68 Structure of 2-ethyl-5-((5-methylfuran-2-yl)(phenyl)methyl)furan

III-13k..................................................................................................

175

4-69 Structure of 2-ethyl-5-((5-methylfuran-2-yl)(4-nitrophenyl)methyl)-

furan III-13l..........................................................................................

176

4-70 Structure of (5-((5-methylfuran-2-yl)(phenyl)methyl)furan-2-yl)-

methanol III-13m................................................................................

177

4-71 Structure of 2-methyl-5-((5-methylthiophen-2-yl)(phenyl)methyl)-

furanIII-13o..........................................................................................

177

xviii


Figures Page

4-72 Structure of 2-methyl-5-((5-methylthiophen-2-yl)(4-nitrophenyl)-

methyl)furan III-13p.............................................................................

178

4-73 Structure of 2-((5-ethylthiophen-2-yl)(phenyl)methyl)-5-methylfuran

III-13q..................................................................................................

178

4-74 Structure of 2-((5-ethylthiophen-2-yl)(4-nitrophenyl)methyl)-5-

methylfuran III-13r..............................................................................

179

4-75 Structure of tert-butyl 2-((5-methylfuran-2-yl)(phenyl)methyl)-1H-

pyrrole-1-carboxylate III-13s..............................................................

180

4-76 Structure of tert-butyl 2-((5-methylfuran-2-yl)(4-nitrophenyl)-

methyl)-1H-pyrrole-1-carboxylate III-13t............................................

180

4-77 Structure of 2-ethyl-5-((5-methylfuran-2-yl)(phenyl)methyl)-1H-

pyrrole III-13u......................................................................................

181

4-78 Structure of 2-ethyl-5-((5-methylfuran-2-yl)(4-nitrophenyl)methyl)-

1H-pyrrole III-13v................................................................................

181

4-79 Structure of 3-((5-methylfuran-2-yl)(phenyl)methyl)-1H-indole

III-13w..................................................................................................

182

4-80 Structure of 3-((5-methylfuran-2-yl)(4-nitrophenyl)methyl)-1H-

indole III-13x........................................................................................

182

4-81 Structure of 5-methoxy-3-((5-methylfuran-2-yl)(phenyl)methyl)-1H-

indole III-13y......................................................................................

183

4-82 Structure of 5-methoxy-3-((5-methylfuran-2-yl)(4-nitrophenyl)-

methyl)-1H-indole III-13z...................................................................

183

4-83 Structure of 6-fluoro-3-((5-methylfuran-2-yl)(phenyl)methyl)-1H-

indole III-13aa......................................................................................

184

4-84 Structure of 6-fluoro-3-((5-methylfuran-2-yl)(4-nitrophenyl)methyl)-

xix

1H-indole III-13ab............................................................................... 184


Figures Page

4-85 Structure of 3-((5-methylthiophen-2-yl)(phenyl)methyl)-1H-indole

III-13ac.................................................................................................

185

4-86 Structure of tert-butyl 2-((1H-indol-3-yl)(phenyl)methyl)-1H-

pyrrole-1-carboxylate III-13ad.............................................................

185

LIST OF ABBREVIATIONS

Ar aryl

br s broad singlet (spectral)

br t broad triplet (spectral)

Calcd calculated

chemical shift relative of TMS (spectra)

J coupling constant

oC degree celsius

ClCH2CH2Cl dichloroethane

CH2Cl2 dichloromethane

d doublet (spectral)

dd doublet of doublets (spectral)

ddd doublet of doublet of doublets (spectral)

ESI electrospray ionization

equiv equivalent

EtOAc ethyl acetate

HRMS High Resolution Mass Spectrometry

h or hr hour

IR infrared

max maximum absorption frequencies

MHz megahertz

m.p. melting point

MeOH methanol

xxi

LIST OF ABBREVIATIONS (CONTINUED)

Me methyl

mm millimetre

mL millilitre

mg milligram

min minute

mmol millimole

m multiplet (spectral)

NaCl sodium chloride

NaHCO3 sodium hydrogen carbonate

Na2S2O3 sodium thiosulfate

Na2SO4 sodium sulfate

NMR Nuclear Magnetic Resonance

ppm parts per million (in NMR)

% percentage

Ph phenyl

q quartet (spectral)

cm-1

reciprocal centimeter (wave number in IR spectra)

Rf retardation factor

RT or rt room temperature

s singlet (spectral)

SiO2 silicon dioxide

t triplet (spectral)

xxii

LIST OF ABBREVIATIONS (CONTINUED)

td triplet of doublets (spectral)

TMS tetramethylsilane

THF tetrahydrofuran

TLC Thin Layer Chromatography

m/z value of mass divided by charge

CHAPTER 1

INTRODUCTION

1. Alpha-branched amines

Synthetic and biological interest in highly functionalized acyclic and cyclic

of α-branched amines (Gall, Haurena, Sengmany, Martens, & Troupel, 2009;

Shirakawa & Kobayashi, 2006, Kogen et al., 2002) have contributed to the wealth of

the experimental methodology developed (Figure 1-1). In particular, the addition of

nucleophiles to the carbon-nitrogen double bond of imines and its derivertives. Imines

are highly desirable, owing to their versatile applications as electrophilic reagents in

many organic reactions. However, many of these methods entail important practical

enhancement of the reactivity of imino derivative such as N-sulfinyl imines (Weix,

Shi, & Ellman, 2005; Brak & Ellman, 2010; Guijarro, Pablo, & Yus, 2010; Chen,

Wang, & Lin, 2010; Reddy, Gupta, Villhauer, & Liu, 2012; Zhang, Yang, Wang,

Lin, & Wang, 2012; Fernández-Salas, Maestro, Rodríguez-Fernández, García-Ruano,

& Alonso, 2013) and N-sulfonyl imines (Esquivias, Arrayás, & Cerretero, 2006;

Kang, Zhao, & You, 2007; Arrayás et al., 2008; Wang, Sun, & Wu, 2008; Marques &

Burke, 2010; Mei, Ji, Han, & Pan, 2011; Wang et al., 2011; Hesp, Bergman, &

Ellman, 2012; Tauchert, Incarvito, Rheingold, Bergman, & Ellman, 2012) have

important for use in asymmetric synthesis. However, the cleavage of

N-protective sulfinyl and sulfonyl groups required harsh conditions and multistep

process for prepared imine precursors. Recently, interesting approach have been

reported which use N-acyl imines (Schneider & Manolikakes, 2013; Muskawar,

Kumar, & Bhagat, 2013) and N-Boc imines (Jaratjaroonphong, Tuengpanya, &

Ruengsangtongkul, 2015; Jaratjaroonphong, Krajangsri, & Reutrakul, 2012) as imine

acceptors. These classes of imines can prepared in single step and without isolating

the imines intermediate. Moreover, N-protective Boc group is also easily removed

under mild acidic conditions. Therefore, the development of processes that allow

the formation of carbon-nitrogen bond in a single operation is highly desirable for

reducing the number of reaction steps, inexpensive starting materials and mild

conditions.

2

Cl

N

NO

OH

O

N

CNNC

N

N

N

H

N

HN

ON

O

CetirizingAnti-histamine agent

Selegiline Rasagiline

Treatment for Parkinson's disease

RivastigmineAnti-hyperparathyroidism agent

LetrozoleAnti-cancer agent

N

N

NF

Br

Et

Nonsteroidal aromatase inhibitoragainst breast cancer

F3C

HN

Cl

N

CO2Me

S

ClopidogrelAntiplatelet agent

CinacalcetTreatment for Alzheimer's disease

O

Me2N O

O

NO2

NHMe HCl

O

Me2N O

O

NO2

NHMe HCl

Acetylcholinesterase (AChE) and serotonin transporter (SERT) dual inhibitor

Figure 1-1 Examples of bioactive α-branched amine derivatives.

2. Unsymmetrical triarylmethanes

Triarylmethanes (TRAMs) have attracted considerable attention of chemists

due to their varied biological activities such as anti-cancer (Zhuo et al., 2014; Yin,

Hu, & Hartmann, 2013; Taylor, Harris, & Jarvo, 2012; Shirakawa & Kobayashi,

2006), anti-tubercular (Parai, Panda, Chaturvedi, Manju, & Sinha, 2008; Das et al.,

2007), anti-implantation (Srivastava, Sangita, Ray, Singh, Dwivedi, & Kumar, 2004)

and inhibition of PDE-4 leads to a reduction in inflammatory cell activity (O’Shea

et al., 2005) (Figure 1-2).

3

O

OMe

R O

OMe

R

OH

Diaryloxy methanophenanthrene derivertives

R = 2o or 3o amines, NMe2, NEt2, , and

Antitubercular activity

N N N

OMe

NMe2

Anti-breast cancer agent

N

N

NF

Br

Et

Anti-breast cancer agent

S

OMe

OH

Anti-tuberculosis agent

NN

N

Cl NN

NH

VorozoleAnti-cancer agent

N

S

N

O

HF2CO

O

F3C

CF3

OH

Anti-inflammatory activity

R2R1

R3

Anti-implantation

R1 = OCH3, R2 = OH, R3 = OCH3/OH

NNO

Anti-cancer agent

Figure 1-2 Examples of bioactive unsymmetrical triarymethane derivatives.

Numerous available methods for the construction of triarylmethanes and

their heterocyclic analogous have been developed. However, the method for

the synthesis of unsymmetric triarylmethane is far less explored. To the best of

our knowledge, there are six approaches for construction of unsymmetrical triaryl-

methanes: (1) Friedel-Crafts type arylation of diaryl methanols (Katritzky & Toader,

1997; Das, Panda, & Panda, 2005; Zeng, Ji, & Wang, 2005; Jana, Maiti, & Biswas,

2007; Das et al., 2007; Parai et al., 2008; McCubbin & Krokhin, 2010; Hikawa,

Suzuki, & Azumaya, 2013; Yokoyama et al., 2013; Nallagonda, Rehan, & Ghorai,

2014; Barbero et al., 2014), (2) arylation of diarylmethyl acetate (Li, Daun, Kang,

4

Wang, Yu, & Wu, 2008), (3) Friedel-Crafts type arylation of diarylmethyl amines

(Esquivias, Arrayás, & Carretero, 2006; He, Sun, Zheng, & You, 2009; Gu et al.,

2010; Thirupathi & Kim, 2010; Neupane et al., 2011), (4) arylation of diarylmethyl

diketone (Ahmad, Riahi, & Langer, 2009; Aoyama et al., 2014), (5) one-pot three-

component Friedel-Crafts-type reaction of arene, aldehyde and tertiary amines or o-

methoxyaniline (Liu, He, & Wang, 2011; Zhang et al., 2014; Ganesan & Ganesan,

2014) and (6) cross-coupling reaction (Lin & Lu, 2007; Zhang, Bellomo, Creamer,

Dreher, & Walsh, 2012; Harris, Hanna, Greene, Moore, & Jarvo, 2013; Hirano, Satoh,

& Miura, 2014). However, some of the reported methods suffer from disadvantages

such as the use of expensive and corrosive reagents, multistep process, and low yields

of products. As a results, there still exists a need for development of new approaches

to the synthesis of unsymmetrical triarylmethanes in more simple, efficient, catalytic

and environmental unfriendliness way.

Ar1 Ar2

Ar3

Ar1 Ar2

OR1

Ar3-H Ar1 Ar2

OAc

Ar3-H

Ar1 Ar2

NR2Ar3-HUnsymmetricalTriarymethanes

Ar1 Ar2

R3

O

R3

O

Ar1-CHO

Ar3-H

Ar2-H

Ar1 Ar2

[M] Ar3

Diarylmethyl diketones

One-pot three-componentFriedel-Crafts reaction

Diarylmethyl amines

Diarylmethyl acetates

Diaryl methanols

Cross-coupling reaction

1)

2)

3)

4) Ar3-H

5)

6)

X

or Ar3-H

X = H, Br Cl, OTf

Ar2 = N,N-dimethylaniline

Figure 1-3 Main current synthetic approaches of unsymmetrical triarylmethanes.

Iron salts as effective, alternative, and promising transition-metal catalysts

have received much more attention because of their less expensive, readily available,

5

and environmentally benign properties. These iron salts were found to have promising

catalytic abilities in many organic transformations including iron-catalyzed oxidation,

hydrogenation, hydrosilylation rearrangement, Michael addition, C-C bond and

C-heteroatom bond forming reactions and tandem reactions (Liu, He, & Wang, 2011).

Iron(III) chloride hexahydrate (ferric chloride hexahydrate, FeCl3·6H2O) is one type

of the iron salts were found to have promising catalytic abilities in Friedel-Crafts

reactions (Thirupathi & Kim, 2010).

In this research, we have interested to study a simple, mild and efficient

method for the synthesis of α-branched amines via FeCl3·6H2O catalyzed aza-Friedel-

Crafts reaction of electron-rich arenes and a combination of aldehyde and carbamate,

which diverse unsymmetrical triarylmethanes through sequential reactions with the

different arenes as shown in Figure 1-4.

Ar1 Ar2/R2

HN O

O

H2N O

O

Ar2/R2CHO

FeCl3 6H2O

solvent, 0-rt

Ar1 H

Het H

or


R2 = alkyl

Ar1

Ar3

Ar2

solvent, rt

Ar3 H


FeCl3 6H2O

Figure 1-4 FeCl3·6H2O-catalyzed formation of α-branched amines and

unsymmetrical triarylmethanes.

Objectives

1. To study the synthesis of corresponding α-branched amines via a novel

aza-Friedel-Crafts reactions of electron-rich arenes with combination of aldehyde and

tert-butylcarbamate in the presence of FeCl3·6H2O as catalyst.

2. To study the synthesis of corresponding unsymmetrical triarylmethanes

via a novel Friedel-Crafts alkylation of different arenes with α-branched amines as

alkylating agent in the presence of FeCl3·6H2O as catalyst.

6

Contribution to Knowledge

1. This new exploratory study will provided a simple, mild and efficient

method for the synthesis of the corresponding α-branched amines and unsymmetrical

triarylmethanes via aza-Friedel-Crafts and Friedel-Crafts reaction of electron-rich

arenes using FeCl3·6H2O which is an inexpensive, nontoxic and environmental

friendly catalyst.

2. The application of these new methodologies to the synthesis of

α-branched amine and unsymmetrical triarylmethane derivatives are ubiquitous

in medicals, materials and dyes.

Scope of the study

1. Optimizing the reaction conditions of 1,3,5-trimethoxybenzene,

benzaldehyde and tert-butyl carbamate for the synthesis of the corresponding

α-branched amines in term of chemical yield by varying the catalyst loading of

FeCl3·6H2O, quantity of solvents, and type of solvents.

2. Synthesis of α-branched amines by using a variety of electron-rich arenes

or heteroarenes, and tert-butyl carbamate with a series of aldehydes including

aromatic and aliphatic aldehydes under optimized reaction condition.

3. Synthesis of unsymmetrical triarylmethanes via Friedel-Crafts reaction

using α-branced amines as an alkylating agent under optimized reaction condition.

4. Elucidating the structures of the resulting α-branched amines and

unsymmetrical triarylmethanes by using spectroscopic techniques.

CHAPTER 2

LITERATURE REVIEWS

α-Branched amines

Synthetic and biological interests in highly functionalized N-protected

α-branched amine derivatives have contributed to the wealth of experimental

methodology developed by numerous strategies. Among these methods, the Friedel-

Crafts reaction of imine derivatives known as aza-Friedel-Crafts reaction (AFCR) is

one of the most widely utilized chemical transformations for the construction of

the functionalized N-protected α-branched amine derivatives. Only recently, several

groups have reported a one-pot three-component aza-Friedel-Crafts reaction without

preparation of imine substrates. The selected examples for the synthesis of

N-protected α-branched amine derivatives using aza-Friedel-Crafts reaction are shown

below.

Selected examples of α-branched amines formations by aza-Friedel-Crafts

alkylation of electron-rich arenes with imine derivatives

Aza-Friedel-Crafts reaction (AFCR) is one of the most powerful tools in

organic synthesis for a synthetically outstanding C-C bond-forming process leading to

functionalized amine derivatives.

Wang, Song, Hong, Li, and Deng (2006) developed the first highly

enantioselective Friedel-Crafts reaction of indoles II-1 with imines II-2 using chiral

organic catalysts II-3 or II-4. With unprecedented scope for both indoles and imines

as well as utilizing practical chiral catalysts, this reaction provided a direct and

broadly useful catalytic enantioselective approach toward 3-indolyl alkylamines,

which should facilitate the asymmetric synthesis of biologically interesting indole

compounds (Figure 2-1). Its unique applicability to alkyl imines, in particular, should

open new possibilities in the total synthesis of indole alkaloids and their analogues.

8

+

N

H R2

P

10 mol% II-3 or II-4

EtOAc, 50 oC

8-72 h

P = SO2Ph, Ts

N

II-5 (53-98 % yield, 86-96 %ee)

H

R1

N

MeO

N

H

HN

S

HN

CF3

CF3

II-3

HNR2*

P

II-1 II-2

N

MeO

N

H

HN

S

HN

CF3

CF3

II-4

R2 = H, 4-ClC6H4, 3-MeOC6H4, 2-BrC6H4,

4-F3CC6H4, 4-MeC6H4, furyl, cyclohexyl,

(CH3)2CH, (CH3)2CHCH2, CH3(CH2)2CH2,

BnOCH2

NH

R1

R1 = H, 6-Cl, 6-Br,

6-OMe, 5-Me,

4-OMe

Figure 2-1 The enantioselective Friedel-Crafts reaction of indoles with imines II-2

using chiral organic catalysts.

Later on, Wang, Sun, and Wu (2008) used Iron(III) chloride as catalyst in

the Friedel-Crafts reaction of electron-rich arenes with imines or aziridines. It was

found that reactions of imines were highly substrate dependent, which generated

mono- or double-addition products. The FeCl3-catalyzed Friedel-Crafts reactions of

electron-rich arenes with imines was examined using 1,3,5-trimethoxybenzene and

imines II-7 to give the desired products II-8 in moderate to good yields (Figure 2-2).

Whereas, when 1,2-dimethoxybenzene reacted with imines II-7 under the same

conditions, triarylmethanes II-10 was obtained via a double Friedel-Crafts reaction in

low yields (Figure 2-3). Furthermore, the reactions of arenes with aziridines were also

studied and the reactions proceed smoothly to afford β-branched amines II-13 with

excellent regioselectivity (Figure 2-4). The advantages of this method include high

efficiency and excellent regioselectivity (less than 2 min), experimentally operational

ease, and mild conditions.

9

R1

NTs

H+FeCl3 (5 mol%)

CH3NO2rt, 12 h

OMe

MeO OMe

NHTs

R1

II-8 (52-72 %)

(R1 = H, 4-F)

OMe

OMeMeO

II-6 II-7

Figure 2-2 The reaction of 1,3,5-trimethoxybenzene with imines II-7 under the

Iron(III) chloride catalyst.

R1

NTs

H+FeCl3 (5 mol%)

CH3NO2rt, 12 h

OMeR1

II-10 (20-21 %)

(R1 = H, 4-F)

MeO

OMeMeO

OMe

OMe

II-9 II-7

Figure 2-3 The reaction of 1,2-dimethoxybenzene with imines II-10 under the

Iron(III) chloride catalyst.

R1R2+

FeCl3 (5 mol%)

CH3NO2

rt, < 2 min

R2

II-13(0-90%)

NHTsN

Ts

R1

II-11 II-12

R2 = H, 4-Cl, 4-Me, 4-FR1 = 1,3,5-trimethoxybenzene,

1,2-dimethoxybenzene,


anisole

1,2-dimethylbenzene,

chlorobenzene,

trifluoromethylbenzene

N,N-dimethylaniline,

furan,

benzo[d][1,3]dioxole

Figure 2-4 The reactions of arenes with aziridines under the Iron(III) chloride

catalyst.

10

Very recently, Chatterjee, Maity, Mohapatra, and Roy (2013) reported

a heterobimetallic catalyst aza-Friedel-Crafts reaction of N-sulfonyl adimines and

highly electron-rich arenes as well as heteroarenes (1,3,5-trimethoxybenzene and

indole derivatives, respectively) (Figure 2-5). This methodology afforded α-branced

amines in good yields and structurally diverse symmetrical and unsymmetrical

triarylmethanes via cleavage of sp3 carbon-nitrogen bond in good to high yields

(Figure 2-6).

NTs

Ar2-H/Het2-HAr1

Ar2 = 1,3,5-trimethoxybenzene,

indole

+

1 mol% IrIII-SnCl3 cat.

ClCH2CH2Cl,

0-rt oC

Ar2/Het2

HN Ar2/Het2

Ar2/Het2

+

II-14 II-15 II-16 (77-88%) II-17 (0-10%)

Ar1 = C6H5

4-ClC6H4

4-BrC6H4

4-NO2C6H4

4-OMeC6H4

3-MeC6H4

4-MeC6H4

Ts

Ar1

Figure 2-5 Ir(III)-SnCl3 catalyzed aza-Friedel-Crafts reaction.

Ar2/Het2 = 1,3,5-trimethoxybenzene,

indole

1 mol% IrIII-SnCl3 cat.

ClCH2CH2Cl,

rt-80 oC

Ar2/Het2

HN

Ar1 = C6H5,

4-ClC6H4,

4-BrC6H4,

4-MeC6H4

+ Ar-H3/Het-H3

Ar3/Het3 = anisole,

indole,

2-methylfuran,

2,5-dimethylfuran,

2-methylthiophene

Ar2/Het2

Ar3/Het3

Ar1

II-16 II-15 II-18 (70-89%)

Ts

Ar1

Figure 2-6 The synthesis of triarylmethanes by Ir(III)-SnCl3 catalyst.

11

Selected examples of α-branched amines formations by one-pot theree component

aza-Friedel-Crafts alkylation of electron-rich arenes, aldehydes and amines or

carbamate

In recent years, multi-component aza-Friedel-Crafts reactions have gained

much importance in organic synthesis to furnish the desired products in a single

operation without isolating the imine intermediates. Thus, the reaction times are

reduced and both the energy and raw materials are also saved. On the best of our

knowledge, only few examples of this strategy were reported.

In 1999, Bensel, Pevere, Desmurs, Wagner, and Mioskowski synthesized

a wide range of alkoxycarbonyl protected benzylic amines using a three-component

reaction involving carbamates, aromatic aldehydes and aromatic substrates (Figure

2-7). This reaction proceeds through electrophilic substitution of the aromatic

compound by a N-carbamoyl iminium which is generated in situ by condensation of

the carbamate with the aromatic aldehyde. Unfortunately, using aliphatic aldehydes

in this case was unsuccessful.

R3 = Et,

iPr,

CH2CCI3,

Bn

R1+

H2SO4, AcOH

rt, 12 h

HN

R2

R1

O

R2 H

O

H2N OR3

O

OR3

II-19 II-21II-20 II-22 (0-85%)

R1 = 2,5-dimethylanisole,

benzodioxole,

ter t-butylbenzene,

bromobenzene,

1,2-dichlorobenzene

R2 = benzaldehyde,

4-trifluoromethylbenzaldehyde

2,5-dichlorobenzaldehyde

+

Figure 2-7 The three-component reaction of aromatic compounds, carbamates and

aldehydes using H2SO4 as catalyst.

Later, Shirakawa, and Kobayashi (2006) developed a novel protocol for

three-component aza-Friedel-Crafts reactions of aldehydes, primary amines, and

indoles in water catalyzed by carboxylic acids. The aza-Friedel-Crafts reactions

(AFCR) have been known to be difficult to control, but the present reaction system

12

enabled the desired products to be obtained in high yields. It is noted that the reaction

proceeded under nonmetallic conditions in water and that various 3-substituted

indoles including biologically active compounds were prepared by utilizing

the reactive C-N bond. This simple system offers a novel efficient method for

the synthesis of various 3-substituted indoles (Figure 2-8).

NH2

OMeH

O

N+ +

C9H19COOH

(5 mol%)

H2O, rt, 24 h

HN

N

MeO

II-26 (91%)II-25II-23 II-24

Figure 2-8 The three-component aza-Friedel-Craft reaction of 2-naphthaldehyde, o-

anisidine and 1-methylindole using C9H19COOH in water.

After the AFCR, the crude products were treated with 1,1'-carbonyldi-

imidazole (CDI) in the presence of Sc(OTf)3 as a catalyst. The reactions of various

3-substituted indole derivatives, aldehydes bearing aromatic, heteroaromatic, and

alkyl groups gave the corresponding products II-32 in moderate to high yields in two

steps (Figure 2-9).

Further examples of the synthetic utility of the present method are

demonstrated by the transformation of the AFCR products. As a result of the high

reactivity of the C-N bond, AFCR product was readily converted to various

nucleophiles in the presence of C9H19COOH as a catalyst. Substitution using thiol,

allyltin, and silyl enol ether nucleophiles also proceeded smoothly and gave

the valuable compounds in good yields (Figure 2-10).

13

R1

+

C9H19COOH(10 mol%)

N

R4

R3

R2

HN

NR3

R2

R4

O

N NNN

Sc(OTf)3(10 mol%)

toluene, 70 oC, 3 h

R1

N

NR3

R2

R4N

II-32 (53-90%, 2 steps)

nonsteroidal aromatase inhibitor againstbreast cancer

II-27 II-29II-28 II-30

II-31 (CDI)

+H2O, rt, 24 h

R1 = 2-naphthyl,

Ph,

4-MeO-C6H4,

4-Cl-C6H4,

4-F-C6H4,

3-thienyl,

(CH3)2CHCH2,

c-C6H11

R1-CHO

R2 = Me, R3, R4 = H,

R2, R3, R4 = H,

R2, R3 = Me, R4 = H,

R2 = Me, R3 = H, R4 = OMe,

R2 = Et, R3 = H, R4 = Br

NH2

OMe

MeO

Figure 2-9 The synthesis of triarylmethanes II-32.

+

C9H19COOH(10 mol%)

N

Me

HN

N

Me

N

N

N

S

N

Me

N

Me

O

II-23

II-24

II-25 II-26

+

II-34

II-36

OMe

NH2

H

O

H2O, rt, 24 h

MeO

Me

II-38

CDI

Sc(OTf)3, toluene

70 oC, 3 h

II-33

SH

Sc(OTf)3, toluene

70 oC, 24 h

II-35

Sc(OTf)3, toluene

70 oC, 24 h

Me3SiO(Ph)C CH2 II-37

Figure 2-10 Transformations of aza-Friedel-Crafts Products.

14

In 2012, Jaratjaroonphong, Krajangsri, and Reutrakul demonstrated

an efficient iodine-catalyzed one-pot three-component aza-Friedel-Crafts reaction of

arenes/heteroarenes, benzyl/tert-butyl carbamate and a wide variety of aldehydes in

toluene under ‘open-flask’ and mild conditions. Typically, the reaction proceed

smoothly to provide, selectively the corresponding N-Cbz or N-Boc protected

α-branched amines in good to excellent yields (Figure 2-11). It should be noted that

small amount of triarylmethane derivatines were obtained in some cases.

Ar-H

NH2CO2R

H R1

O I2 (5 mol%)

toluene, rt Ar R1

NHCO2R

R = benzyl, tert -butyl

+Ar Ar

R1

+

Ar = 1,2,4-trimethoxybenzene2-naphthol2-methylfuran2-ethylfuran2-methylthiophene

II-39 II-40

II-41

II-42 II-43

(major products) (minor products)

R1 = C6H5, 4-ClC6H4, (CH3)2CH

Figure 2-11 I2-catalyzed three-component aza-Friedel-Crafts reaction.

Late on, Halli and Manolikakes (2013) reported an eco-friendly and efficient

catalyst of Fe(III) chloride hexahydrate for catalyzed three-component aza-Friedel-

Crafts reaction of amides, glyoxalates and arenes or heteroarenes in nitromethane

under thermal conditions to give the corresponding arylglycines in moderate to high

yields (Figure 2-12).

R2 NH2

O

H CO2R1

O

Ar/Het-H

FeCl3.6H2O (2-5mol%)

or Fe(ClO4)3.xH2O (2-5 mol%)

MeNO2, 80-100 oC, 24 h Het/Ar CO2R1

HN R2

O

II-44 II-45 II-46 II-47 (32-94 %)

Ar = 1,2-dimethylbenzene, 1,3-dimrthylbenzene,1,4-dimethylbenzene, 1,3,5-trimethylbenzene,anisole, 2-Cl-anisole, 2-Br-anisole,2-I-anisole, 2-Me-anisole, 2-PivHN-anisole,4-PivHN-anisole, pyrene, anthracene

Het = 2-Br-thiophene, 2-Cl-thiophene, 2-Me-thiophene,benzofuran, 1-tosylindole, 1-tosylpyrrole

R1 = H, Et, iPr

R2 = Me, tBu, Ph, OEt, OBn, Fmoc,

4-MeO-C6H4, 4-Br-C6H4,

4-O2N-C6H4, CH2CHCH2O,

1-(2-nitrophenyl)ethyl carbamate,

Figure 2-12 Fe(III)-catalyzed three-component aza-Friedel-Crafts reaction.

15

In the same year, Schneider and Manolikakes (2013) found that treatment of

a combination of amides, formaldehyde and arenes or heteroarenes with Bi(OTf)3

gave their respective amidomethylarenes and heteroarenes in moderate to high yields

(Figure 2-13).

R NH2

O

H H

O

Ar/Het-H

Bi(OTf)3 (5 mol%)

MeNO2, rt-100 oC, 18 h Het/Ar H

HN R

O

II-48 II-49 II-50 II-51 (45-96 %)

Ar = 1,3-dimethylbenzene, 1,3,5-trimethylbenzene,anisole, 2-Cl-anisole, 2-Br-anisole,2-I-anisole, N -o-tolylpivalamide, 4-Br-phenol,ethyl 4-methoxybenzoate

Het = 2-Br-thiophene, 2-Cl-thiophene, 2-Me-thiophene,benzofuran, 1-tosylindole

R = Me, tBu, Ph, OBz, OEt, Cl-CH2, NCCH2, CH2CH,4-MeO-C6H4, 4-MeO-C6H4, oxazolidin-2-one,

2-(1,3-dioxoisoindolin-2-yl)-3-methylbutanamide

Figure 2-13 Bi(OTf)3-catalyzed three-component aza-Friedel-Crafts reaction.

Recently, Jaratjaroonphong, Tuengpanya, and Ruengsangtongkul reported

a catalyst behavior of Bi(OTf)3 for catalyzed one-pot three-component aza-Friedel-

Crafts reaction of arenes/heteroarenes, benzyl/tert-butyl carbamates and a wide

variety of aldehydes to provide N-Cbz or N-Boc protected α-branched amines in good

to excellent yields (Figure 2-14). Furthermore, these conditions can also be

transformed N-Cbz or N-Boc protected α-branched amines into the unsymmetrical

triarylmethanes with good to high yields (Figure 2-15).

Ar-H

NH2CO2R2

H R1

OBi(OTf)3 (5 mol%)

toluene, rt Ar R1

NHCO2R

R2 = benzyl, ter t-butyl

+Ar Ar

R1

+

Ar = 1,3,5-trimethoxybenzene1,2,4-trimethoxybenzene2-methylfuran, 2-ethylfuran2-methylthiophene, 2-ethylthiophene2-ethylpyrrole, indole

II-52 II-53

II-41

II-54 II-55

(major) (minor)

R1 = C6H5, 2-FC6H4, 4-FC6H4,

4-ClC6H4, 4-BrC6H4, 4-O2NC6H4,

4-MeOC6H4, CH3CH2, CH3(CH2)2CH2,

PhCH2CH2, (CH3)2CHCH2, (CH3)2CH,

cyclopropyl, cyclopentyl, cyclohexyl

Figure 2-14 The synthesis of α-branched amines using Bi(OTf)3 as catalyst.

16

R = benzyl, ter t-butyl

NHCO2R

II-54

Bi(OTf)3 (10 mol%)

toluene, rtO

OMe

MeO

OMe

II-57

OMe

MeO

OMe

II-56

O

Figure 2-15 Transformations of aza-Friedel-Crafts Products.

Selected examples of amidoalkyl naphthol formations by one-pot, theree component

aza-Friedel-Crafts alkylation of β-naphthol, aldehydes and carbamates or urea

Patil, Singh, Surpur, and Samant (2007) reported a method for the synthesis

of 1-amidoalkyl-2-naphthols by a one-pot three-component condensation of

2-naphthol, ureas/amides and aldehydes in the presence of sulfamic acid as a catalyst

under ultrasonic irradiation and ambient conditions giving 1-amidoalkyl-2-naphthols

in excellent yields and in short reaction time (Figure 2-16).

R1 = C6H5, 4-CH3C6H4, 2-CH3C6H4,

3-O2NC6H4, 2-ClC6H4, 4-ClC6H4,

4-FC6H4, 2-BrC6H4, 3-BrC6H4,

4-BrC6H4, Furyl

OH

+ + R2CONH2

H3N+SO3-

)))) 28-30 oC

neat or ClCH2CH2Cl

10-120 min.

OH

NHCOR2R1

II-58 II-59 II-60 II-61 (55-94%)

R2 = CH3, CH3NH, Ph, NH2

R1CHO

Figure 2-16 The synthesis of aminoalkyl naphthols using sulfamic acid as catalyst.

Later on, Das, Laxminarayana, Ravikanth, and Rao (2007) developed a very

simple and efficient method for the high-yielding synthesis of amidoalkyl naphthols

by one-pot three-component coupling reaction of 2-naphthol, aromatic aldehydes and

urea or amides. In the presence of iodine as a catalyst in dichloethane at room

temperature or under solvent-free conditions at higher temperature, the reaction

17

proceed smoothly to afford common the corresponding amidoalkyl naphthols in high


+ R1CHO + R2CONH2

I2 (5 mol%)

ClCH2CH2Cl, rt

or

neat, 125 oC

OH

Ar NHCOR

II-62 II-63 II-64 (20-93 %)II-58

R2 = NH2, CH3, Ph, CH2=CH

OH

R1 = C6H5, 4-CH3C6H4,

3-O2NC6H4, 2,4-Cl2C6H3,

4-ClC6H4, 2-BrC6H4,

naphthal, CH3CH2

Figure 2-17 The synthesis of aminoalkyl naphthols using I2 as catalyst.

Shaterian, Hosseinian, and Ghashang (2008) reported a highly efficient

synthesis of 1-carbamatoalkyl-2-naphthol derivatives via a new one-pot three-

component condensation reaction between aryl aldehydes, 2-naphthol and

methyl/benzyl carbamates in the presence of silica supported sodium hydrogen sulfate

(SiO2-NaHSO4) as an effective heterogeneous catalyst under thermal and solvent-free

conditions. The reactions were successful to provide the desired products in moderate

to high yields (Figure 2-18). Moreover, the products can be deprotected and used to

prepare potentially biologically active 1-aminomethyl-2-naphthol derivatives.

R1 = C6H5, 4-O2NC6H4,

4-FC6H3, 2-ClC6H3,

4-ClC6H4, 2,4-Cl2C6H3,

3-ClC6H4, 3-O2NC6H4,

2,5-(OMe)2C6H3, 3-OMeC6H3,

C5H4N, CH3CH2

CH3(CH2)4CH2

+

OH

+ R2O NH2

O

R2 = Me, CH2Ph

SiO2-NaHSO4

Solvent-free

100 oCII-65II-58 II-66 II-67 (0-95 %)

R1CHO

OH

R1 NHCOOR2

Figure 2-18 The synthesis of aminoalkyl naphthols using SiO2-NaHSO4 as catalyst.

18

Hajipour, Ghayeb, Sheikhan, and Ruoho (2009) developed a facile,

convenient and solvent-free method for the one-pot synthesis of amidoalkyl naphthols

derivatives. Condensation of aldehydes with amides or urea and 2-naphthol in

the presence of a catalytic amount of Brønsted acidic ionic liquid ([TEBSA][HSO4])

under thermal solvent-free conditions to afford the products in good yields.

Gratifyingly, high yields, short reaction time, easy work-up and reusability of

the catalyst are advantages of this procedure (Figure 2-19).

R1 = C6H5, 2-ClC6H4, 4-ClC6H4, 2,6-Cl2C6H3,

4-BrC6H4, 3-O2NC6H4, 4-O2NC6H4,

4-MeC6H4, 3-MeOC6H4, 2,5-(MeO)2C6H3

4-NCC6H4, 4-CH3OCOC6H4

OH

R2 = CH3, C6H5, NH2

+ + R2CONH2

OH

R1 NHCOR2

5 mol% IL

120 oC, solvent-free, 10 min

IL = (CH3CH2)3NCH2(CH2)2CH2SO3H HSO4

II-68 II-69 II-70 (73-91%)II-58

R1CHO

Figure 2-19 The synthesis of aminoalkyl naphthols using Brønsted acidic ionic liquid

([TEBSA][HSO4]) as catalyst.

Later, Lei, Ma, and Hu (2009) reported a facile, efficient, and practical

method for the preparation of amidoalkyl naphthol derivatives. The reaction was

carried out by treatment of β-naphthol with aromatic aldehyde and different amide

including benzamide, acetamide, acrylamide, and N-substituted amides in

the presence of VB1 in ethanol at 80 oC to give the aminoalkyl naphthol derivatives in

good yields (Figure 2-20).

19

N

N

NS

H3C

OH

H3C

NH3Cl Cl

OH

+ R1-CHO + R2CONH2

10 mol% VB1

80 oC, EtOH

OH

R1 NHCOR2

II-58 II-71 II-72 II-73 (0-93%)

R2 = Ph, CH3, NH2, CH2=CH2

VB1

R1 = C6H5, 4-MeC6H4,

3-O2NC6H4, 4-MeOC6H4,

CH3CH2, CH3CH2CH2

PhCH=CH

Figure 2-20 The synthesis of aminoalkyl naphthols using VB1 as catalyst.

In the same year, Nandi, Samai, Kumar, and Singh (2009) studied

multicomponent, one-pot reaction of 2-naphthol with aromatic aldehydes and amides

using P2O5 as catalyst at 60 oC. The results provided the corresponding amidoalkyl

naphthol derivatives in excellent yields (Figure 2-21). The present approach offers

several advantages such as reduced reaction times, moderate temperature, higher

yields, eco-friendly reaction condition, easy purification and economic availability of

the catalyst.

R1 = C6H5, 4-NO2C6H4, 3-NO2C6H4, 2- NO2C6H4,

4-ClC6H4, 2-ClC6H4, 4-OMeC6H4, 2-OMeC6H4,

4-MeC6H4, 2,4-Cl2C6H3, 4-NMe2C6H4

OH

+

CHO

+ H2N R2

O P2O5 (10 mol%)

solvent-free

60 oC

NH

O

R2

OH

II-58 II-74 II-75 II-76 (80-97%)

R2 = CH3, Ph, CH3Cl

R1

R1

Figure 2-21 The synthesis of aminoalkyl naphthols using P2O5 as catalyst.

In recently, Mulla, Salama, Pathan, Inamdar, and Chavan (2013) found that

ionic liquids, ethylammonium nitrate (EAN) can catalyzed one-pot three-component

20

reaction of various aldehydes, amides/carbamates/urea, and naphthols/phenols under

the absence of solvent to give 1-amido and 1-carbamatoalkyl naphthols/phenols

in high yields (Figure 2-22).

R1 = 2-naphthol, 2,5-Me-phenol

OH

+ + H2N R3

OEAN

solvent-free, rt, 1 hNH

O

R3

OH

II-77 II-78 II-79 II-80 (85-96%)

R2-CHO

R1

R2

R1

R2 = C6H5, 4-ClC6H4, 4-MeOC6H4,

4-MeC6H4, 2-furyl, 2-thienyl,

3-formyl chromone

R3 = CH3, C6H5, C6H5CH2,

CH3CH2O, C6H5CH2O, NH2

Figure 2-22 The synthesis of aminoalkyl naphthols/phenols using EAN as catalyst.

Selected examples of α-branched amines formations with other reaction

Dastbaravardeh, Schnürch, and Mihovilovic (2013) developed

a regioselective direct arylation of benzylic amines with aryl bromides and aryl

chlorides in the presence of [RuCl2(p-cymene)]2 in a o-xylene. The uses of K2CO3

as a base, PPh3 and cyclohexanol as an additives play a key role in the reaction

to afford the corresponding α-branched amine derivatives in moderate to high yields

(Figure 2-23). The proposed mechanism for the ruthenium(II) catalyzed reaction

are also illustrated as shown in Figure 2-24.

N

R

NH

Ph

Ar X

[RuCl2(p-cymene)]2

PPh3, cyclohexanol

K2CO3, o-xylene

160 oC, 30 h

N

R

NH

PhAr

R = Me, C6H5

X = Br, I

II-81 II-82 II-84 (39-79 %)

II-83

Ar = C6H5, 2-Me-C6H4, 3-Me-C6H4,3-MeO-C6H4, 3-Cl-C6H4, 4-Me-C6H4,4-tBu-C6H4, 4-nBu-C6H4, 4-MeO-C6H4,4-Me2NC6H4, 4-F-C6H4, 4-Cl-C6H4,4-EtO2C-C6H4, 4-MeOC-C6H4, 4-O2N-C6H4,4-NC-C6H4, 1-naphthyl, 2-thienyl, 3-pyridyl

Figure 2-23 [RuCl2(p-cymene)]2 catalyzed arylation of benzylic amines with

aryl bromides and aryl iodides.

21

Ru

Cl

ClCl

Ru

Cl

iPr

Me

Me

iPr

+II

+II

2 KOPiv

2 KCl

1/2

Me iPr

Ru

PivO

O

OtBu

Me iPr

RuPivO

OPiv

N

N

R

NH

H Ph

NH

H

Ph

R

Me iPr

RuO OPiv

N

NH

H

R

Ph

O

tBu

Me iPr

Ru OPiv

N

NH

R

Ph

Ar

Me iPr

Ru OPiv

N

NH

R

Ph

tBu

OH

O

K2CO3KHCO3

KOPivKX

N

R

NH

Ar Ph

Ar X

KOPiv

oxidativeaddition

reductiveelimination

CMDconcer ted metalation deprotonat ion

II-81

II-84

II-82

II-83

II-85

II-86

II-87

II-88

II-89

+II

+II

+II

+II

+IV

Figure 2-24 The possible mechanism for the ruthenium(II) catalyzed arylation of

benzylic amines with aryl halides.

22

Unsymmetrical triarylmethanes

The synthesis of unsymmetrical triarylmethane has attracted much attention

from the synthetic community because of their versatile applications such biological

activity, photochromic agents, dyes, protective groups, building blocks for dendrimers

and applications in material science. Despite, this broad range of applications, only

a few methodology of this compound have been reported. Moreover, the most of

development of synthetic methods for the preparation of unsymmetrical

triarylmethanes are limited to the preparation of starting material in two steps

leading to the corresponding unsymmetrical triarylmethanes.

Selected examples of unsymmetrical triarylmethane formations by Friedel-Crafts-

type arylations of diarylmethanols

Katritzky and Toader (1997) developed a regiospecific Friedel-Crafts

alkylation method for the synthesis of unsymmetrical triarylmethane derivatives,

(p-nitroaryl)diarylmethane. Condensation of benzotiazole with diaylmethanols

in the presence of p-toluenesulfonic acid gave the corresponding (diarylmethyl)-

benzotiazole II-91 as an alkylating agent. Then, the carefully temperature controlled

for Friedel-Crafts reaction of alkylated product with 2- or 3-methoxy nitrobenzenes

II-92 in the presence of potassium tert-butoxide in dry THF at -20 oC provided

expected products in low to excellent yields (Figure 2-25).

OH

R1 R2

Bt

R1 R2

BtH

p-TsOH, reflux,PFCLs, 24 h

R1 R2

t -BuOK

dry THF, -20 oC, 4 h

NO2

OMeNO2

OMe

R1 = H, 4-Me, 4-MeO, 4-(N,N-dimethylamino)

R2 = H, 2-Me, 4-Cl, 2-MeO, 4-MeO, 3,4,5-MeO,

4-biphenyl, 4-n-hexyloxy, 5-methylthien-2-yl

II-90 II-91 II-93

II-92

Figure 2-25 The Synthesis of (p-Nitroaryl)diarylmethanes

23

In 2005, Das, Panda, and Panda used the addition of aromatic aldehydes

with Grignard reagent for preparation of heteroarylcarbinol such as thienyl, pyridyl

and (5-methyl)-furyl cabinols II-96 which were used as electrophilic partner of

Frieldel-Crafts alkylation. The carbinol II-96 were treated with various nucleophiles

in the presence of Brønsted acid or Lewis acid under heat condition to give

unsymmetrical triarylmethanes in low to high yields (Figure 2-26).

Het

OHHet

X

II-94

II-96 (65-68 %)

II-99 (5-76 %)

Het CHO

II-95

OMe

Het = 2-Thienyl, 3-pyridyl, (5-mrthyl)-2-furyl

THF

rt, 1-2 h

X Y

or R1

II-97 II-98 OMe

Het

II-100 (60-80 %)

OMe

Y

R1

or

conc. H2SO4 or anh. AlCl3

benzene, 60-70 oC,

0.5-2 h

X = OH, OCH3, NHC2H5, N(CH3)2, NH2, Y = SH

R = H, 2-CH3, 3-CH3

MgBrMeO

Figure 2-26 The Synthesis of unsymmetrical triarylmethane derivatives using

Brønsted acid or Lewis acid as catalyst.

In the same year, Zeng, Ji, and Wang (2005) reported an efficient synthesis

of unsymmetrical bis(indolyl)alkanes II-103 at ambient temperature using

inexpensive ceric ammonium nitrate (CAN) catalyzed Friedel-Crafts alkylation of

(indolyl)alkyl methanols II-101 with various substituted indole derivatives under

ultrasonic irradiation in Figure 2-27.

24

R2

OH

N

R1

NH

R3CAN

))), EtOH, rt2-5 h

R2

N

R1

NHR3

II-101 II-102 II-103 (75-96 %)

R1 = H, Ts

R2 = Ph, n-nonanyl, n-octanyl, n-hexanyl, n-butanyl,

R3 = H, CH3, BnO, Ts

Figure 2-27 The Synthesis of unsymmetrical bis(indolyl)alkanes.

Jana, Maiti, and Biswas (2007) developed a practical reaction system

involving mild, environmentally benign and atom economic of C-C bond formation,

which was using inexpensive FeCl3 activated varieties of carbinols such as allylic,

benzylic and propargylic alcohols and follow by nucleophilic addition of electron rich

indole and pyrrole in nitromethane as solvent, the reaction proceeded efficiently

to afford the unsymmetrical triarylmethanes in moderate to excellent yields (Figure

2-28).

Het-H

Ar1

OH

Ar2/ R Ar1

Het

Ar2/ RFeCl3 (10 mol%),

CH3NO2, rt-55 oC, 1-4 hII-104 II-106 (56-98 %)

II-105

Ar1 = allylic phenyl,

4-MeO-allylic phenyl,

4-Cl-allylic phenyl

phenyl,

4-MeO-phenyl,

2-thienyl

propargyl

Ar2 = phenyl, R = methyl

Het = indole,1-methylindole1-tosylindole,2-methylindole,pyrrole

Figure 2-28 The Synthesis of unsymmetrical triarylmethane derivatives using FeCl3

as catalyst.

Des et al. (2007) reported a simple and practical method for the synthesis of

unsymmetrical triarylmethanes for enhanced anti-tubercular activity via reduction of

commercially available benzophenone derivatives leading to benzohydrol derivatives.

Next, the carbinols were used as alkylating agents in the Friedel-Crafts alkylation of

25

1- and 2-naphthols. The reaction was performed by refluxing a mixture of 1- or 2-

naphthols and carbinols in dry benzene to provide unsymmetrical triarylmethane

II-109 and II-110, respectively in moderate to high yields as shown in Figure 2-29.

II-109 (84-89 %)

O

XNaBH4, methanol

0 oC-rt, 2 h

OH

X

X

X

HO

OH

1-naphthol

ref lux, 2 h

2-naphthol

X = H, Cl, F

II-110 (68-73 %)

II-107 II-108

dry benzene

ref lux, 2 h

dry benzene

Figure 2-29 Reaction of carbinol with 1- and 2-naphthols.

One year later, Parai et al. (2008) developed methodology for the synthesis

of unsymmetrical triarymethane via replace one of the aryl rings with thiophene

in the triarylmethane nucleus for enhanced anti-tubercular activity. Nucleophilic

addition of Grignard reagents onto thiophene-2-carbaldehyde and p-chloro-

benzaldehyde in THF furnished the carbinol derivatives. Then Friedel-Crafts

alkylation of carbinols with phenol led to the mixtures of unsymmetrical

triarylmethane II-115 and II-116 in 6-12 % and 58-61 %, respectively (Figure 2-30).

26

R1

X SY

Mg, THF

0 oC, rt, 2 h

R1

OH

S

R1 = m-OCH3, X = Br

= p-OCH3, X = Br

= p-SCH3, X = Br

= p-Cl, X = CHO

Y = CHO= Br

II-111 II-112 II-113

conc. H2SO4 (cat.)

dry benzene,ref lux, 2 h

R1

S

HO

R1

S

OH

II-114

II-115 (6-12 %) II-116 (58-61 %)

OH

Figure 2-30 The synthesis of thiophene containing triarylmethanes.

McCubbin and Krokhin (2010) demonstrated that arylboronic acid

catalyzing Friedel-Crafts reaction of mono-, di-, and triarylmethanols as well as

electron-rich arenes in refluxing dichloroethane or toluene to provide the

corresponding unsymmetrical tri-, tetraarylmethanes in excellent yields. Excepted

diarylmethane was not observed or shown in low to high yields (Figure 2-31).

Ar1-H Ar2

OH

R2

R1

C6F5B(OH)2 (10 mol%)

ClCH2CH2Cl or toluene,

4 A M.S., ref lux, 16 ho

II-117 II-118

Ar2

Ar1

R2

R1

II-119 (0-99%)

Ar1 = indole, pyrrole, 2-naphthol

2-methylfurane,


1,3,5-trimethoxybenzene,

2-methoxynaphthalene

Ar2 = 4-MeO-C6H4, 4-HO-C6H4,

4-NH2-C6H4, 2-MeO-4-HO-C6H3

3,4-Cl-C6H3, 2-HO-5-Br-C6H3

3-Br-4-MeO-5-HO-C6H2, naphthyl

R1 = H, Me, (CH2)5, R2 = H, Me, (CH2)5,

Figure 2-31 The synthesis of unsymmetrical tri-, and tetraarylmethanes.

In 2013, Hikawa, Suzuki, and Azumaya (2013) reported the direct

substitution reaction of benzhydryl and benzylic alcohols with strong π-nucleophile

indoles using a water soluble gold(III)/TPPMS catalyst system in water at 80 oC.

They found that reaction of benzhydryl alcohol were highly substitutents on the aryl

27

ring dependent, which enhance the stability of the carbocations into the corresponding

triarylmethane as shown in Figure 2-32.

NHO

R4

R2 R3

R1AuCl4Na 2H2O (0.5-2 mol%)

TPPM (0.5-2 mol%)

H2O, 80 oC, 16 hN

R2

R1

R4 R3

H2O

R1 = H, CN, Cl, CO2Me, Me, CO2H

R2 = H, Me

R3 = OMe, Me, Cl, Br, F

R4 = Ph, Me, H

II-120 II-121 II-122 (0-95 %) II-123

Figure 2-32 The synthesis of unsymmetrical triarylmethanes using AuCl4Na∙2H2O

as catalyst.

Later on, Yokoyama et al. (2013) employed a similar reaction condition

to convert diarylmethanol into N-benzylation or C-benzylation by using chemo-

selective behavior of substituted on diarylmethanol and on nucleophiles controlled

the Friedel-Crafts reaction. However, according to the above mentioned method,

the reaction did not occur without water and water-soluble phosphine ligand, TPPMS

(Figure 2-33).

OH

R1 R2

NH

R3

CO2HR4

R1 R2

N

CO2HR4

R1 R2

HNR3

HO2C

C-benzylation N-benzylation

Conditions : AuCl4Na.2H2O (5 mol%),

TPPM (5 mol%), H2O,

80-120 oC, 16-24 h

R1 or R2 = H, OMe, Me, F

R3 = H, Me

R4 = H

R4

R1 or R2 = H, Cl, Me

R3 = H

R4 = H, Br, I, F, CF3, Me

R3

II-124

II-125 II-127 (22-94 %)II-126 (74-86 %)

Figure 2-33 The chemoselective synthesis for Friedel-Crafts reaction of

diarylmethanols and nucleophiles.

28

Recently, Nallagonda, Rehan, and Ghorai (2014) reported the chemo-

selective synthesis of unprotected anilines and mono- as well as diarylmethanols

in acetonitrile at elevated temperature (60-80 oC) using Re2O7 as catalyst, leading to

excellent chemoselective formation of C-alkylated over N-alkylated products (Figure

2-34). Furthermore, they proposed the mechanism for the current benzylation of

anilines as shown in Figure 2-35.

H/R

OH

Ar/Het

NH2

FG

C-benzylation

NH2

H/R

NH

Ar/Het

FG

II-128

II-129

II-131 (41-88 %)II-130

Re2O7 (5 mol%)

CH3CN, 60-80 oC

4-72 h

R = Me, iPr, allyl, propargyl, Et

Ar = phenyl, 2-methoxybenzene,4-methoxybenzene,3,4-methoxybenzene, naphthyl

Het = thiophene, 2-bromothiophene,N-Boc pyrrole, 2,3-dihydrobenzo[b][1,4]dioxine,9H -xanthene, 9H -thioxanthene, benzofuran,benzo[b]thiophene, indole

FG

R/H

Ar/Het

Figure 2-34 The chemoselective synthesis of unprotected anilines and mono-, di-

arylmethanols using Re2O7 as catalyst.

Ar

OH

R

H/R Ar/HetH/R

NH

Ar/Het

Re2O7

Ar

O

R

ReO3

Ar R ReO4

NH2

FG

NH2FG

HOReO3

II-133 II-134

thermodynamicallycontrolled

kineticallycontrolled

HOReO3

NH

ReO4

FG

FG

II-134

II-129 II-132 II-133

II-128

II-130 II-131

Figure 2-35 The mechanism for the benzylation of anilines.

29

More recently, Barbero et al. (2014) found that strong Brønsted acid,

o-benzenedisulfonimide, can catalyzed diarylmethanols/styrenes and variety of arenes

into their corresponding di- and tri-arylmethanes in absence of solvents (Figure 2-36).

Ar1 R1

OH

II-135

or

R2

II-136

Ar2/Het-Hneat conditions

II-138 (10 mol%)

II-137

II-139

Ar R1

Ar/Het

or

R2

Ar/Het

II-140

O

Ar

R1Ar

R1

R1 = H, Me, C6H5,

4-MeO-C6H5,

4-F-C6H5,

4-(CH3)2N-C6H5

Ar1 = C6H5,

4-MeO-C6H5,

4-F-C6H5,

4-O2N-C6H5

4-(CH3)2N-C6H5

Ar2 = 1,3-dimethoxybenzene,

1,2,4-ttimethoxybenzene,

2-methylfuran, pyrrole,

indole,1-methylindole,

2-methylindole,

7-isopropyl-1,4-dimethylazulene

R2 = 4-MeO-C6H5

S

NHS

O

O

II-141

II-138

Figure 2-36 The synthesis of di-, triarylmethanes using o-benzenedisulfonimide as

catalyst.


type arylations of diarylmethyl acetate

Li et al. (2008) demonstrated that FeCl3 in the presence of acetic anhydride

can serve as an effective catalyzed for the reaction of various arenes with aromatic

aldehyde to proceed the corresponding triarylmethanes (Figure 2-37). However, the

reaction required high temperature (80 ºC) and acetic anhydride as an activating agent.

Ar1

ArAr+

FeCl3 (10 mol%)

Ac2O, 80 oC, 22 hAr1-CHO Ar-H

Ar1 = 4-BrC6H4, 3-BrC6H4, 2-BrC6H4, 2-ClC6H4

Ar-H = p-xylene, 4-bromoanisole, 4-chloroanisole, 1,3,5-trimethoxybenzene

II-139 II-140 II-141 (59-90 %)

Figure 2-37 FeCl3 catalyzed symmetrical triarylmethanes formations.

30

Interestingly, when the reaction between benzaldehyde and 1,3,5-trimethyl-

benzene was carried out at room temperature, the mono-aromatic substitution product

was isolated in 92% yield (Figure 2-38).

CHO FeCl3 (10 mol%)

Ac2O (2 equiv)

CH2Cl2, rt, 2h

OAc

II-142 II-143 II-144 (92 %)

Figure 2-38 FeCl3 catalyzed the mono-aromatic substitution product.

Furthermore, the mono-aromatic substitution procedure leading to

diarylmethyl acetate could be applied for a convenient one-pot synthesis of

unsymmetrical triarylmethanes starting from aromatic aldehydes and two type of

arenes (Figure 2-39). However, this sequential one-pot procedure proceeded very well

using bulky arenes (1,3,5-trimethylbenzene and 1,2,4,5-tetramethylbenzene) as first

arene.

Ar2

Ar1Ph+

II-148 (47-89 %)

Ar1-HPh H

O

FeCl3

Ac2OPh Ar1

OAc

Ar2-H

II-142 II-145 II-146

II-147

Ar1 = 1,3,5-trimethylbenzene,

1,2,4,5-tetramethylbenzene

Ar2 = 1,3,5-trimethylbenzene,

1-bromo-4-methoxybenzene

indole, 2,5-dimethylthiophene

Figure 2-39 FeCl3 catalyzed unsymmetrical triarylmethanes formations.


type arylations of diarylmethylamines

Esquivias et al. (2006) demonstrated that Cu(OTf)2/(±)-binap can serve as

an effective catalyst for aza-Friedel-Crafts alkylation of N-sulfonyl imines with

electron-rich aromatic and heteroaromatic compounds base on the use of the

2-pyridylsulfonyl moiety as the key controlled double electrophilic aromatic

31

substitution, which provided unsymmetrical triarylmethanes in moderate to high

yields as shown in Figure 2-40.

Ar1 H

NSO2(2-Py)

Ar2 H

10 mol% Cu(OTf)2

10 mol% ( )-binap

CH2Cl2, rt Ar1 Ar2

HNSO2(2-Py)

Ar3 H

40 oC, 20-120 minAr1 Ar2

Ar3

II-149 II-150 II-151

II-152

II-153 (43-73 %)

Ar1 = C6H5,

3-Me-C6H4,

4-F-C6H4,

naphthyl

Ar2 = 1-methylindole,

2-methylindole,

5-methoxy-1-methylindole

Ar3 = 1,3,5-trimethoxybenzene,

N ,N-dimethylaniline,

3-methoxy-N,N-dimethylaniline

2-methoxyfuran, 2-methoxythiophene

2-methylindole,

5-methoxy-1-methylindole

Figure 2-40 The synthesis of unsymmetrical triarylmethane derivatives using

Cu(OTf)2/(±)-binap as catalyst.

To further extend this methodology to the case of triarylmethanes that do not

necessarily contain an indole moiety, the second electrophilic aromatic substitution

was investigated with isolated sulfonamide adducts. They found that this reaction

occured cleanly using Sc(OTf)3 as catalyst in CH3CN at 60 oC and this methodology

provided access to unsymmetrical triarylmethanes containing both electron-rich and

electron-poor aromatic rings. (Figure 2-41)

Ar1 Ar2

HNSO2(2-Py)

Ar3 HCH3CN, 60 oC, 12 h

Ar1 Ar2

Ar310 mol% Sc(OTf)3

II-154 II-155 II-156 (44-65 %)

Ar1 = C6H5, 4-O2NC6H4

3,4-FC6H3, 2-naphthyl

Ar2 = 3-MeO-4-(CH3)2NC6H3,

1-MeO-naphthyl

Ar3 = 2-methoxythiophene,

3-methylindole,

1,3,5-trimethoxybenzene

Figure 2-41 Sc(OTf)3 catalyzed aza-Friedel-Crafts alkylation of sulfonamide adducts

and electron-rich aromatic and heteroaromatic compounds.

32

He, Sun, Zheng, and You (2009) developed an efficient method for

the synthesis of unsymmetrical 3,3'-bis(indolyl)methanes II-160 via Friedel-Crafts

alkylation of N-methylindole and variety of α-(3-indolyl)benzylamines using achiral

Brønsted acid II-159 as catalyst in toluene at room temperature to provide

the corresponding unsymmetrical triarylmethane derivatives in good to excellent


NHTs

Ar

HN

R

N

Ar

HN

R

N

NP

N O

OH

Ts

Ts

R = H, 2-Me, 4-Me,5-F, 5-Br, 5-Me,5-MeO, 6-Br,6-BnO

Ar = Ph, 2-BrC6H4, 4-BrC6H4,3-O2NC6H4, 4-O2NC6H4,4-MeC6H4, 4-MeOC6H4

II-157 II-158 II-160 (61-98 %)

II-159

II-159 (5 mol%)

toluene, rt

Figure 2-42 The synthesis of unsymmetrical 3,3'-bis(indolyl)methanes using achiral

Brønsted acid II-159 as catalyst.

Later on, Gu et al. (2010) carried out the synthesis of unsymmetrical

3,3'-bis(indolyl)methane from N-methylindole and variety of α-(3-indolyl)benzyl-

amines in the presence of chiral Brønsted acid. The reaction proceeded in toluene

at room temperature and the products were obtained in good to excellent yields and

moderate enantioselectivities (45-68% ee).

33

NHTs

Ar

HN

R

N

Ar

HN

R

N

R = H,5-F,5-Br,5-Me,5-MeO,6-Br,6-BnO

Ar = Ph,4-BrC6H4,4-MeC6H4,4-MeOC6H4

II-160 II-158 II-162 (61-96 % yields, 45-68% ee)

II-161-(S) (5 mol%)

toluene, rt

R

R

O

O

POH

O

CF3

CF3

R2 =

II-161-(S)

Figure 2-43 The synthesis of unsymmetrical 3,3'-bis(indolyl)methanes using chiral

Brønsted acid II-161 as catalyst.

In the same year, Thirupathi and Kim (2010) used FeCl3·6H2O as Lewis

acid catalyst for the condensation of arenes with N-arylsufoylamido sulfones. Under

these conditions, not only α-amido sulfones II-165 was found but also bis-arene II-

166

was observed by TLC during the course of the reaction and had completely

disappeared at end of the reaction, which was applied to preparation of triarylmethane

derivatives (Figure 2-44).

CbzHN

R

SO2Ar

OMe

MeO

OMe

R

SO2Ar

OMe

OMe

MeO

FeCl3.6H2O (10 mol%)

CH2Cl2, rt

ROMe

OMe

MeO

OMe

OMe

OMe

R = C6H5, 2-ClC6H4,3-ClC6H4, 4-ClC6H4,4-MeC6H4, 4-MeOC6H4,4-O2NC6H4, 4-CNC6H4,3-Me-4-MeOC6H3, 3-F-4-MeOC6H3,3,4-MeOC6H3, 3,4,5-MeOC6H2, PhCH2CH2,(CH3)2CH, CH3CH2CH2, cyclohexyl,cyclohex-2-enyl, (5-methyl)-2-furyl,(5-methyl)-2-thienyl, 2-naphthyl

Ar = C6H5, 4-MeC6H4

II-163 II-164 II-165

II-166

Figure 2-44 The synthesis of N-arylsufoylamido sulfones using FeCl3·6H2O as

catalyst.

34

Later, they were carried out for the assumptions by using Lewis acid

to promoted Friedel-Crafts alkylation of α-amido sulfones reacted with arenes and

or difference arenes to afford the corresponding addition products (Figure 2-45) and

they proposed the mechanism for the iron(III) catalyzed reaction as shown in Figure

2-46.

R1OMe

OMe

MeO

FeCl3.6H2O (10-30 mol%)

CH2Cl2, rt

R1 = C6H5, 3-MeC6H4, 3-FC6H4,

4-MeOC6H4, 3,4-MeOC6H3

Ar = C6H5, 4-MeC6H4

II-166 II-167 II-168 (38-60 %)

R1

SO2Ar

OMe

OMe

MeONH

R2

NH

R2

R2 = H, MeO

Figure 2-45 Transformation of α-amido sulfones into unsymmetrical triarylmethane

derivatives with FeCl3·6H2O.

35

NH

R2

R1

SO2Ar

OMe

OMe

MeO

R1

S

OMe

OMe

MeOO

O

Ar

FeIII

FeIII

R1OMe

OMe

MeO

ArSO2FeIII

R1

S

OMe

OMe

MeOO

O

Ar

FeIII

R1OMe

OMe

MeO NH

R2

ROMe

OMe

MeO

OMe

OMe

OMe

OMe

OMe

MeO

or

or

II-165

II-169

II-170

II-171

II-163II-167

II-166 II-168

Figure 2-46 The mechanism for the iron(III) catalyzed Friedel-Crafts reaction.

One year later, Neupane et al. (2011) found that treatment of hetero-

aromatic or electron-rich arenes and α-amido sulfones with [B(C6F5)3] gave

respective unsymmetrical triarylmethanes in moderate yields (Figure 2-47).

R1OMe

OMe

MeO

B(C6F5)3 (5 mol%)

CH2Cl2, ref lux

II-165 II-167 II-168 (0-58 %)

R1

SO2Ar

OMe

OMe

MeONH

R2

NH

R2

Figure 2-47 Transformation of α-amido sulfones into unsymmetrical triarylmethane

derivatives with [B(C6F5)3].

36


type arylations of diarylmethyldiketones

Ahmad, Riahi, and Langer (2011) reported the combination methods of

benzylation and [3+3]-cyclocondensation for the synthesis of triarylmethane

derivatives. FeCl3 catalyzed benzylation of acetylacetone and diarylmethanol gave

benzylate product, which was treated with trimethylsilyl chloride proceed to provide

silyl enol ether (Figure 2-48). Then, TiCl4 mediate [3+3]-cyclocondensation of

silyl enol ether precursor reacted with 1,3-bis(silyl enol ether), follow by cyclization

and aromatization to give triarylmethane derivatives in moderate yields (Figure 2-49).

R1 R2

OH

Me

O

Me

O

Me

O

Me

O

R1 R2

Me

Me3SiO

Me

O

R1 R2

FeCl3.6H2O (5 mol%)

CH3NO2, 50 oC, 4 h

Me3SiCl, NEt3

C6H6, 20 oC, 72 h

II-169

II-170

R1 = Ph, 4-MeOC6H4,

4-FC6H4, 4-ClC6H4,

Me

R2 = Ph, 4-MeOC6H4,

4-FC6H4, 4-ClC6H4

II-171 (81-92 %)II-170 (85-94 %)

Figure 2-48 Reaction of benzylation and silylation.

R1 = Ph, 4-MeOC6H4,

4-FC6H4, 4-ClC6H4,

Me

R2 = Ph, 4-MeOC6H4,

4-FC6H4, 4-ClC6H4

R3 = H, Me, Et

R4 = Me, Et

Me

Me3SiO

Me

O

R1 R2

II-170

Me3SiO OSiMe3

R3

OR4

TiCl4, CH2Cl2

-78 20 oC, 20 h

R1 R2

O

OR4

OH

R3

Me Me

II-171 II-172 (31-55 %)

Figure 2-49 Reaction of [3+3]-cyclocondensation follow by cyclization and

aromatization.

Recently, Aoyama et al. (2014) employed an efficient silica gel supported

sodium hydrogen sulfate (SiO2-NaHSO4) as catalyst to catalyzed Friedel-Crafts

37

alkylation of diketone and arenes in nitromethane under thermal condition leading to

triarylmethane derivatives in low to excellent yields (Figure 2-50).

R1 R2

OO

Ar/Het-H

NaHSO4/SiO2 (2.1 mmol)

chlorobenzene, 110 oC, 6 hR1 R2

Ar/Het

II-176 II-177 II-178 (4-99 %)

R1 = Ph,

4-ClC6H4,

4-MeOC6H4

R2 = Me,

4-ClC6H4,

4-MeOC6H4

Ar = 1,2-dimethoxybenzene,1,3-dimethoxybenzene,1,4-dimethoxybenzene,1,3,5-trimethoxybenzene,1,3,5-trimethylbenzene,4-Me-phenol,4-MeO-phenol,4-O2N-phenol,phenol,anisole

Het = benzo[b]thiophene,2-bromo-thiophene,2methylfuran

or ZnCl2/SiO2 (1.5 mmol)

Figure 2-50 The synthesis of Friedel-Crafts alkylation of diketone and arenes using

SiO2-NaHSO4 as catalyst.

Selected examples of unsymmetrical triarylmethane formations by one-pot three

component Friedel-Crafst-type reactions

Liu, He, and Wang (2011) reported the first and highly efficient FeCl3

as Lewis acid catalyzed one-pot three-component Friedel-Crafts reactions of indoles,

aldehydes, and tertiary aromatic amines. The reactions generated the corresponding

unsymmetrical triarylmethanes in moderate to good yields under mild reaction

condition as shown in Figure 2-51.

N

R1 R2 CHON

R3

10 mol% FeCl3

ClCH2CH2Cl, N2

100 oC, 24 h

R2

NNR1

R3

II-179 II-180 II-181 II-182 (48-72 %)

R1 = H, 3-MeO R2 = H, C6H5, 3-MeO-C6H4,

4-MeO-C6H4, 2-Cl-C6H4,

4-Cl-C6H4, CH3CH2CH2,

2-naphthyl

R3 = H, Me

Figure 2-51 FeCl3 catalyzed one-pot three-component Friedel-Crafts reactions.

38

A closely related approach to above mentioned method was reported by

Zhang et al. (2014). They found that aza-Friedel-Crafts alkylation can also use

binuclear complex of bis(ethylcyclopentadienyl)zirconium perfluorooctanesulfonate

as catalyst for condensation of indoles, aldehydes and N,N-dimethylaniline to give

the corresponding 3-diarylmethylindoles in moderate to high yields (Figure 2-52).

N

R1 CHONH

II-186 (2.5 mol%)

ClCH2CH2Cl,

100 oC, 24 h

R1

NHN

II-183 II-184 II-185 II-187 (0-82 %)

R2 = H, 2-CH3, 5-OCH3, 5-F,

5-Cl, 5-Br, 5-NO2, 6-F,7-CH3

R2

R2

R1 = C6H5, 4-Me-C6H4,

4-MeO-C6H4, 4-NC-C6H4,

4-O2N-C6H4, 2,4-Cl-C6H3,

2-naphthylZr

OH

Zr

HO

H2O OH2

H2OOH2

OH2

H2O

O S C8F17

O

O 4

4H2O.

2THF

II-186 binuclear complex

Figure 2-52 Binuclear complex catalyzed one-pot three-component Friedel-Crafts

reactions.

Recently, Ganesan and Ganesan (2014) reported the synthesis of

unsymmetrical triarylmethanes via three-component Friedel-Crafts alkylation of

indole, aldehydes, and tertiary aromatic amines using anhydrous ZnCl2 as catalyst.

Condensation of indole, aldehydes and tertiary aromatic amines in the presence of

anhydrous ZnCl2 (1 eq) in toluene or methanol at room temperature to 100 oC

gave 3-diarylmethylindoles or 3-arylmethylindoles as a major products. Moreover,

bis(indolyl)methane was obtained as a minor product (Figure 2-53).

39

NR1R1

R2 CHONH

anh. ZnCl2 (1 eq)

toluene or methanol

rt-100 oC, 5-12 h

R2

NHN

R1

R1

II-185 II-186 II-187

II-188 (51-68 %)

R2 = H, C6H5, 2-Cl-C6H4,

4-Cl-C6H4, 4-MeO-C6H4,

R1 = Me, Et

R2

NHHN

II-189

Figure 2-53 ZnCl2 catalyzed one-pot three-component Friedel-Crafts reactions.

Further research was carried out to clarify the mechanism for the

transformation of bis(indolyl)methane into 3-diarylmethylindoles or 3-arylmethyl-

indoles. Interestingly, the reaction of bis(indolyl)methane with tertiary aromatic

amines in the presence of ZnCl2 (1 eq) in toluene at 140 oC for 5 h gave the resulting

3-diarylmethylindole II-193 in 54% yield (Figure 2-54).

HN NH

anh. ZnCl2 (1 eq)

toluene, 140 oC, 5 h,

in pressure tube

N

NHN

II-193 (54 %)II-188II-192

Figure 2-54 Transformation of bis(indolyl)methane into 3-diarylmethylindoles or 3-

arylmethylindoles.

Selected examples of unsymmetrical triarylmethane formations by Palladium

catalyzed cross coupling reaction

Lin and Lu (2007) reported the cationic Pd(II)/bpy-catalyzed one-pot

synthesis of unsymmetrical triarylmethanes from arylboronic acids, aryl aldehydes

and electron-rich arenes with low catalyst loading in moderate to high yields. (Figure

2-55)

40

Ar1 B(OH)2 Ar2 CHOcationic PdII

CH3NO2, 80 oC, 24 hAr3 H

Ar3

Ar1 Ar2

II-197 (cationic PdII)

II-194 II-195 II-196

II-197

II-198 (57-99 %)

N

N

Pd

HO

OH

PdN

N

2+

2 BF4

Ar1 = C6H5,

4-Me-C6H4,

4-MeO-C6H4,

4-F-C6H4

Ar2 = 3-O2N-C6H4,

4-O2N-C6H4

Ar3 = 1,2-dimethoxybenzene,

1,3,5-trimethoxybenzene

Figure 2-55 The cationic Pd(II)/bpy-catalyzed one-pot synthesis of unsymmetrical

triarylmethane derivatives.

In 2012, Zhang et al. developed method for the palladium-catalyzed

C(sp3)-H arylation of diarylmethanes at room temperature for synthesis of

triarylmethanes via deprotonative-cross-coupling process in high yields (Figure 2-56).

Ar1

H

5 mol% Pd(OAc)2

7.5 mol% NiXantphos

KN(SiMe3)2 (3 equiv)

cyclopentyl methyl ether

rt, 12 h

Ar1

Ar2Ar2 Br

II-199 II-200 II-201 (66-99 %)

Ar1 = C6H5, 2-Me-C6H4,

4-Me-C6H4, 4-MeO-C6H4,

4-Cl-C6H4, 4-F-C6H4,

indolyl, thienyl

Ar2 = 4-tBu-C6H4,

4-(CH3)2N-C6H4

HN

O

PPh2 PPh2

NiXantphos

Figure 2-56 The synthesis of triarylmethanes via deprotonative-cross-coupling.

Later on, Harris, Hanna, Greene, Moore, and Jarvo (2013) demonstrated

the nikel can serve as efficient catalyst for Suzuki-Miyaura cross-coupling of enantio-

enrich triarylmethanes from benzylic carbamates and pivalates with aryl- and

heteroarylboronic esters which used bulky SIMes and PCy3 ligand of nikel

41

to controlled the setereospecific to give the desire products in excellent specificity and

moderate to high yields.

O O

N

OB

O

Ar

MeMe Ni(cod)2 (10 mol%),

ligand

t-BuOK, n-BuOH,THF:PhMe, rt, 24 h

Ar

Ar

ligand: PCy3

ligand: SIMes

orII-202 II-203

II-204 (67-90 % yields, 57-94 % ee)

II-205 (0-98 % yields, ND-97 % ee)

Ar = 4-FC6H4, 4-MeOC6H4,4-F3CC6H4, 4-(CH3)2NC6H4,4-HOH2CC6H4, 4-MeOCC6H4,4-(CH2)(Boc)HNC6H4,(2-N,N-dimethylamine)-5-pyrimidine,3-furane, (1-methyl)-5-indole

Figure 2-57 The stereospecific synthesis for Suzuki-Miyaura cross-coupling of

enantio enrich triarylmethanes

Recently, Tabuchi, Hirano, Satoh, and Miura (2014) developed method for

the palladium-catalyzed arylation of diarylmethanol derivatives and oxazoles under

thermal conditions for synthesis of triarylmethanes via cross-coupling process

in moderate to high yields (Figure 2-58).

42

Ar1

OR1

Ar2

PdCl2(MeCN)2 (10 mol%),PPhCy2 (20 mol%)

LiO-t -Bu, 1,4-dioxane

120 oC, 6h

O

N

Ar1 Ar2

NO

R2 O

N

Ar1 Ar2

NO

R2

R1 = Boc, Piv, CO2Me

R2 = C6H5, 4-Me-C6H4,


4-F3C-C6H4, 3,4-MeO-C6H3,

PhCHCH, 1-naphthyl

Ar1 = Me, Ph, 2-MeO-C6H4,


4-NC-C6H4, 2-thienyl, 2-furyl

Ar2 = phenyl, biphenyl, 1-naphthyl, 2-naphthyl,

2-benzofuryl, 3-benzo[b]thienyl

II-206

II-207

II-209

II-208 (7-82 %)

II-210 (31-80 %)

Figure 2-58 Palladium-catalyzed arylation of diarylmethanol derivatives and

oxazoles.

CHAPTER 3

RESEARCH METHODOLOGY

General Methods

The high resolution 400 MHz 1H NMR and 100 MHz

13C NMR spectra

were performed on BRUKER AVANCE 400 spectrometer at Department of

Chemistry, Faculty of Science, Burapha University. Spectra were recorded using

deutero chloroform, tetradeuteromethanol, and hexadeuterobenzene solutions and

recorded as δ value in ppm down field from TMS (internal standard δ 0.00) or with

residue non-deuterated solvent peak as the internal standard. The IR spectra were

recorded on a Perkin Elmer System 2000 FT-IR. Mass spectrometric analyses were

recorded on a Finnigan MAT mass spectrometer. High resolution mass spectra were

recorded on Finnigan MAT 95. Melting points were recorded using GALLENKAMP

Melting point apparatus Griffin. All reagents and solvents were commercially

available in high purity. Solvent extracts were dried over anhydrous magnesium

sulfate or sodium sulfate. Solvents were removed by using rotary evaporator at water

aspirator pressure. A trace amount of solvent was removed under vacuum (ca. 0.1

mmHg). Radial chromatography on a Chromatotron was performe using Merck silica

gel 60 PF254 with CaSO4 1/2 H2O and was activated by heating in an oven at 80 oC for

45 min. For column chromatography, 70-230 mesh Merck silica gel 60 [E. Merck,

Darmstadt, Germany] was employed. Thin layer chromatography (TLC) was

performed with Merck silica gel 60 PF254 aluminium plate. Flash chromatography was

performed using 230-400 mesh Merck silica gel 60.

44

1. The aza-Friedel-Crafts reaction of electron-rich arenes with

aldehyde and tert-butyl carbamate in the presence of FeCl3∙6H2O:

Synthesis of the corresponding α-branched amines

1.1 Optimization of the reaction condition for aza-Friedel-Crafts

alkylation of 1,3,5-trimethoxybenzene with tert-butyl carbamate

and benzaldehyde

III-1a III-2a

H2N O

O

solvent, rt

FeCl3.6H2O (x mol%)

HN O

O

OMe

OMeMeO

MeO

MeO OMe

III-3

III-4a

H

O

General procedure A

To a sovent (THF, DMF, CH3NO2, CH3OH, H2O/CH3OH, ClCH2CH2Cl,

toluene; 1 mL) of 1,3,5-trimethoxybenzeneIII-1a (0.1682 g, 1.0 mmol), tert-butyl

carbamate III-3 (0.1172 g, 1.0 mmol) and benzaldehyde III-2a (0.11 mL, 1.1 mmol)

in a test-tube open to air at room temperature was added FeCl3∙6H2O (x mol%).

After the reaction was stirred until completion (TLC analysis), the reaction mixture

was quenched with saturated aqueous NaHCO3 (10 mL) and extracted with CH2Cl2

(2 x 10 mL). The combined organic layer was washed with water (10 mL),

saturated aqueous NaCl dried over anhydrous Na2SO4 and filtered. The filtrate was

evaporated (aspirator then vacuo) to give a crude product, which was purified by

radial chromatography (SiO2, 100% hexane to 20% EtOAc/hexane as eluent) to give

α-branched amine III-4a.

45

1.1.1 Reaction of 1,3,5-trimethoxybenzene with tert-butyl carbamate

and benzaldehyde in various of solvent using FeCl3∙6H2O as

catalyst

III-1a

H2N O

O

solvent, rt


HN O

O

OMe

OMeMeO

MeO

MeO OMe

III-2a

III-3

III-4a

H

O

1.1.1.1 Reaction in the presence of tetrahydrofuran (THF)

Following the general procedure A, FeCl3∙6H2O (0.0270 g, 10 mol%)

and THF (1 mL) were employed. The reaction was stirred at room temperature for

24 h. The crude product was purified by radial chromatography (SiO2, 100% hexane

to 20% EtOAc/hexane as eluent) to give α-branched amine III-4a (0.1663 g, 44%).

1.1.1.2 Reaction in the presence of dimethylformamide (DMF)


and DMF (1 mL) were employed. The reaction was stirred at room temperature for



1.1.1.3 Reaction in the presence of nitromethane (CH3NO2)


and CH3NO2 (1 mL) were employed. The reaction was stirred at room temperature for



1.1.1.4 Reaction in the presence of methanol (CH3OH)


and CH3OH (1 mL) were employed. The reaction was stirred at room temperature for



1.1.1.5 Reaction in the presence of water (H2O)

Following the general procedure A, FeCl3∙6H2O (0.0270 g, 10 mol%),

H2O (1 mL) and CH3OH (0.25 mL) were employed. The reaction was stirred at room

46

temperature for 24 h. The crude product was purified by radial chromatography (SiO2,

100% hexane to 20% EtOAc/hexane as eluent) to give α-branched amine III-4a

(0.1311 g, 35%).

1.1.1.6 Reaction in the presence of dichloroethane (ClCH2CH2Cl)

Reaction in the presence of dichloroethane (ClCH2CH2Cl) for 24 h


and ClCH2CH2Cl (1 mL) were employed. The reaction was stirred at room



(0.3197 g, 86%).






(0.3295 g, 88%).






(0.3383 g, 90%).

1.1.1.7 Reaction in the presence of toluene

Reaction in the presence of toluene for 24 h


and toluene (1 mL) were employed. The reaction was stirred at room temperature for






47









and benzaldehyde in various catalyst loading of FeCl3∙6H2O

using toluene as solvent

III-1a III-2a

H2N O

O

toluene, rt

FeCl3.6H2O (x mol%)

HN O

O

OMe

OMeMeO

MeO

MeO OMe

III-3

III-4a

H

O

1.1.2.1 Reaction in the presence of 10 mol% of FeCl3∙6H2O



2 h. The crude product was purified by radial chromatography (SiO2, 100% hexane to

20% EtOAc/hexane as eluent) to α-branched amine III-4a (0.3421 g, 91%).





20% EtOAc/hexane as eluent) to give α-branched amine III-4a (0.3201 g, 86%).

1.1.2.3 Reaction in the presence of 2.5 mol% of FeCl3∙6H2O

Following the general procedure A, FeCl3∙6H2O (0.0068 g, 2.5 mol%)



20% EtOAc/hexane as eluent) to give α-branched amine III-4a (0.2222 g, 59%).

48


and benzaldehyde in various catalyst loading of FeCl3∙6H2O

using ClCH2CH2Cl as solvent

III-1a III-2a

H2N O

O

ClCH2CH2Cl, rt

FeCl3.6H2O (x mol%)

HN O

O

OMe

OMeMeO

MeO

MeO OMe

III-3

III-4a

H

O





100% hexane to 20% EtOAc/hexane as eluent) to α-branched amine III-4a (0.3383 g,

90%).






(0.3371 g, 89%).

1.1.3.3 Reaction in the presence of 2.5 mol% of FeCl3∙6H2O

Following the general procedure A, FeCl3∙6H2O (0.0068 g, 2.5 mol%)




(0.2990 g, 80%).

49

1.2 The aza-Friedel-Crafts alkylation of 1,3,5-trimethoxybenzene with

tert-butyl carbamate and various aldehydes in the presence of

FeCl3∙6H2O under optimized reaction condition

III-1a III-2

HNOMe

OMeMeO

MeO

MeO OMe

RR-CHO

H2N O

O

toluene or ClCH2CH2Cl, rt

5 mol% FeCl3.6H2O

III-3

III-4

O

O

General procedure B

To a toluene or dichloroethane solution (1 mL) of 1,3,5-trimethoxybenzene

III-1a (0.1682 g, 1.0 mmol), tert-butyl carbamate III-3 (0.1172 g, 1.0 mmol) and

benzaldehyde III-2a (0.11 mL, 1.1 mmol) in a test-tube open to air at room

temperature was added FeCl3∙6H2O (5 mol%, 0.0135 g). After the reaction was

stirred until completion (TLC analysis), the reaction mixture was quenched with

saturated aqueous NaHCO3 (10 mL) and extracted with CH2Cl2 (2 x 10 mL).

The combined organic layer was washed with water (10 mL), saturated aqueous NaCl

dried over anhydrous Na2SO4 and filtered. The filtrate was evaporated (aspirator then

vacuo) to give a crude product, which was purified by radial chromatography (SiO2,

100% hexane to 20% EtOAc/hexane as eluent) to give α-branched amine III-4a.


carbamate and various aromatic aldehydes in the presence of

FeCl3∙6H2O as catalyst: The synthesis of α-branched amines

III-4

1.2.1.1 Reaction of 1,3,5-trimethoxybenzene with tert-butyl

carbamate and benzaldehyde.

III-1atoluene or ClCH2CH2Cl, rt

III-2a

III-3

III-4a

H2N O

O

FeCl3.6H2O (5 mol%)

HN O

O

OMe

OMeMeO

MeO

MeO OMe

H

O

50

1.2.1.1.1 Reaction of 1,3,5-trimethoxybenzene with tert-butyl

carbamate and benzaldehyde using toluene as solvent

Following the general procedure B, benzaldehyde (0.11 mL,

1.1 mmol) was employed. The reaction was stirred at room temperature for 2 h. The

crude product was purified by radial chromatography (SiO2, 100% hexane to 20%

EtOAc/ hexane as eluent) to give α-branched amine III-4a (0.3201 g, 86%).


carbamate and benzaldehyde using ClCH2CH2Cl as

solvent

Following the general procedure B, benzaldehyde (0.11 mL,



EtOAc/ hexane as eluent) to give α-branched amine III-4a (0.3371 g, 89%).


carbamate and 2-fluorobenzaldehyde

III-1a III-2b III-4b

HN O

O

OMe

OMeMeO

MeO

MeOOMe

H

O

FF


III-3H2N O

O

FeCl3.6H2O (5 mol%)


carbamate and 2-fluorobenzaldehyde using toluene

as solvent

Following the general procedure B, 2-fluorobenzaldehyde (0.12

mL, 1.1 mmol) was employed. The reaction was stirred at room temperature for 2 h.

The crude product was purified by radial chromatography (SiO2, 100% hexane to

20% EtOAc/hexane as eluent) to give α-branched amine III-4b (0.3336 g, 85%).

51


carbamate and 2-fluorobenzaldehyde using

ClCH2CH2Cl as solvent

Following the general procedure B, 2-fluorobenzaldehyde

(0.12 mL, 1.1 mmol) was employed. The reaction was stirred at room temperature for


20% EtOAc/hexane as eluent) to give α-branched amine III-4b (0.3715 g, 95%).


carbamate and 4-fluorobenzaldehyde

III-1a III-2c III-4c

HN O

O

OMe

OMeMeO

MeO

MeO OMe

H

O

F Ftoluene or ClCH2CH2Cl, rt

III-3H2N O

O

FeCl3.6H2O (5 mol%)


carbamate and 4-fluorobenzaldehyde using toluene

as solvent




20% EtOAc/hexane as eluent) to give α-branched amine III-4c (0.3264 g, 83%).


carbamate and 4-fluorobenzaldehyde using






52


carbamate and 4-chlorobenzaldehyde

III-1a III-2d III-4d

HN O

O

OMe

OMeMeO

MeO

MeO OMe

H

O

Cl Cltoluene or ClCH2CH2Cl, rt

III-3H2N O

O

FeCl3.6H2O (5 mol%)


carbamate and 4-chlorobenzaldehyde using toluene

as solvent

Following the general procedure B, 4-chlorobenzaldehyde

(0.1546 g, 1.1 mmol) was employed. The reaction was stirred at room temperature for


20% EtOAc/hexane as eluent) to give α-branched amine III-4d (0.2781 g, 68%).


carbamate and 4-chlorobenzaldehyde using


Following the general procedure B, 4-chlorobenzaldehyde



20% EtOAc/hexane as eluent) to give α-branched amine III-4d (0.3297 g, 81%).


carbamate and 4-bromobenzaldehyde

III-1a III-2e III-4e

HN O

O

OMe

OMeMeO

MeO

MeO OMe

H

O

Br Brtoluene or ClCH2CH2Cl, rt

III-3H2N O

O

FeCl3.6H2O (5 mol%)

53


carbamate and 4-bromobenzaldehyde using toluene

as solvent

Following the general procedure B, 4-bromobenzaldehyde



20% EtOAc/hexane as eluent) to give α-branched amine III-4e (0.2897 g, 64%).


carbamate and 4-bromobenzaldehyde using


Following the general procedure B, 4-bromobenzaldehyde



20% EtOAc/hexane as eluent) to give α-branched amine III-4e (0.3939 g, 87%).


carbamate and 4-nitrobenzaldehyde

III-1a III-2f III-4f

HN O

O

OMe

OMeMeO

MeO

MeO OMe

H

O

O2N NO2toluene or ClCH2CH2Cl, rt

III-3H2N O

O

FeCl3.6H2O (5 mol%)


carbamate and 4-nitrobenzaldehyde using toluene

as solvent

Following the general procedure B, 4-nitorbenzaldehyde (0.1662 g,



EtOAc/hexane as eluent) to give α-branched amine III-4f (0.2780 g, 66%).

54


carbamate and 4-nitrobenzaldehyde using


Following the general procedure B, 4-nitorbenzaldehyde (0.1662 g,



EtOAc/hexane as eluent) to give α-branched amine III-4f (0.3730 g, 89%).


carbamate and 4-methoxybenzaldehyde

III-1a III-2g III-4g

HN O

O

OMe

OMeMeO

MeO

MeO OMe

H

O

MeO OMetoluene or ClCH2CH2Cl, rt

III-3H2N O

O

FeCl3.6H2O (5 mol%)


carbamate and 4-methoxybenzaldehyde using toluene

as solvent

Following the general procedure B, 4-methoxybenzaldehyde



20% EtOAc/hexane as eluent) to give α-branched amine III-4g (0.3367 g, 83%).


carbamate and 4-methoxybenzaldehyde using


Following the general procedure B, 4-methoxybenzaldehyde




55


carbamate and methyl 4-formylbenzoate

III-1a III-2h III-4h

HN O

O

OMe

OMeMeO

MeO

MeO OMe

H

O

MeO

O O

OMetoluene, ClCH2CH2Cl, rt

III-3H2N O

O

FeCl3.6H2O (5 mol%)


carbamate and methyl 4-formylbenzoate using toluene

as solvent

Following the general procedure B, methyl 4-formylbenzoate



20% EtOAc/hexane as eluent) to give α-branched amine III-4h (0.3479 g, 81%).


carbamate and methyl 4-formylbenzoate using


Following the general procedure B, methyl 4-formylbenzoate



20% EtOAc/hexane as eluent) to give α-branched amine III-4h (0.3550 g, 82%).

56


carbamate and phthalaldehyde

III-1a III-2i

III-4i

OMe

OMeMeO

H

O

toluene orClCH2CH2Cl, rt

III-3H2N O

O

FeCl3.6H2O (5 mol%)

III-5a

H

O

HN O

O

MeO

MeOOMe

H O

HN O

O

MeO

MeO

HN

OO

OMe OMe

OMeOMe


carbamate and phthalaldehyde using toluene as

solvent

Following the general procedure B, phthalaldehyde (0.1475 g,

1.1 mmol) was employed. After stirring the reaction at room temperature for 24 h,

the complex mixture was observed.


carbamate and phthalaldehyde using


Following the general procedure B, phthalaldehyde (0.1475 g,

1.1 mmol) was employed. After stirring the reaction at room temperature for 24 h,

the complex mixture was observed.

57


carbamate and terephthalaldehyde

III-1a III-2j

III-4j

HN O

O

OMe

OMeMeO

MeO

MeO OMe

H

O

H

O

O

H

toluene or ClCH2CH2Cl,rt

III-3H2N O

O

FeCl3.6H2O (5 mol%)

III-5b

HN O

O

MeO

MeO OMe

MeO OMe

OMeNH

O

O


carbamate and terephthalaldehyde using toluene as

solvent

Following the general procedure B, terephthalaldehyde (0.1475 g,



EtOAc/hexane as eluent) to give α-branched amine III-4j (0.2081 g, 52%) and

α-branched amine III-5b (0.1281 g, 38%).


carbamate and terephthalaldehyde using


Following the general procedure B, terephthalaldehyde (0.1475 g,



EtOAc/hexane as eluent) to give α-branched amine III-4j (0.2129 g, 53%) and

α-branched amine III-5b (0.0861 g, 26%).

58

1.2.2 The reaction of 1,3,5-trimethoxybenzene, tert-butyl carbamate

with various heteroaromatic aldehydes in the presence of

FeCl3∙6H2O as catalyst: The synthesis of α-branched amines

III-6


carbamate and furfural

III-1a III-2k III-6a

HN O

O

OMe

OMeMeO

MeO

MeO OMe

H

O

OOtoluene or ClCH2CH2Cl, rt

III-3H2N O

O

FeCl3.6H2O (5 mol%)


carbamate and furfural using toluene as solvent

Following the general procedure B, furfural (0.09 mL, 1.1 mmol)

was employed. The reaction was stirred at room temperature for 24 h. The crude

product was purified by radial chromatography (SiO2, 100% hexane to 20%

EtOAc/hexane as eluent) to give α-branched amine III-6a (0.1204 g, 33%).


carbamate and furfural using ClCH2CH2Cl as

solvent

Following the general procedure B, furfural (0.09 mL, 1.1 mmol)




59


carbamate and 2-pyridinecarboxaldehyde


III-3H2N O

O

FeCl3.6H2O (5 mol%)

III-1a III-2l

HN O

O

OMe

OMeMeO

MeO

MeO OMe

III-6b

N

H

O

N


carbamate and 2-pyridinecarboxaldehyde using

toluene as solvent

Following the general procedure B, 2-pyridinecarboxaldehyde (0.11

mL, 1.1 mmol) in toluene (1.5 mL) was employed. The reaction was stirred at 80 oC

for 3 h. The crude product was purified by radial chromatography (SiO2, 100%

hexane to 30% EtOAc/hexane as eluent) to give α-branched amine III-6b (0.2495 g,

67%).


carbamate and 2-pyridinecarboxaldehyde using


Following the general procedure B, 2-pyridinecarboxaldehyde (0.11

mL, 1.1 mmol) was employed. The reaction was stirred at 80 oC for 3 h. The crude


EtOAc/hexane as eluent) to give α-branched amine III-6b (0.3244 g, 87%).

60

1.2.3 The reaction of 1,3,5-trimethoxybenzene, tert-butyl carbamate

with various aliphatic aldehydes in the presence of FeCl3∙6H2O

as catalyst: The synthesis of α-branched amines III-7


carbamate and propanal

III-1a III-2m III-7a

HN O

O

OMe

OMeMeO

MeO

MeO OMe

H

O


III-3H2N O

O

FeCl3.6H2O (5 mol%)


carbamate and propanal using toluene as solvent

Following the general procedure B, propanal (0.08 mL, 1.1 mmol)





carbamate and propanal using ClCH2CH2Cl as

solvent

Following the general procedure B, propanal (0.08 mL, 1.1 mmol)





carbamate and pentanal

III-1a III-2n III-7b

HN O

O

OMe

OMeMeO

MeO

MeO OMe

H

O


III-3H2N O

O

FeCl3.6H2O (5 mol%)

61


carbamate and pentanal using toluene as solvent

Following the general procedure B, pentanal (0.12 mL, 1.1 mmol)


product was purified by radial chromatography (SiO2, 100% hexane to 30% EtOAc/

hexane as eluent) to give α-branched amine III-7b (0.3389 g, 96%).


carbamate and pentanal using ClCH2CH2Cl as

solvent

Following the general procedure B, pentanal (0.12 mL, 1.1 mmol)



hexane as eluent) to give α-branched amine III-7b (0.3315 g, 94%).


carbamate and 3-phenylpropanal

III-1a III-2o III-7c

HN O

O

OMe

OMeMeO

MeO

MeO OMe

H

O


III-3H2N O

O

FeCl3.6H2O (5 mol%)


carbamate and 3-phenylpropanal using toluene as

solvent

Following the general procedure B, 3-phenylpropanal (0.14 mL,

1.1 mmol) was employed. The reaction was stirred at room temperature for 1 h.



62


carbamate and 3-phenylpropanal using ClCH2CH2Cl

as solvent

Following the general procedure D, 3-phenylpropanal (0.14 mL,





carbamate and 2-methylpropanal

III-1a III-2p III-7d

HN O

O

OMe

OMeMeO

MeO

MeO OMe

H

O


III-3H2N O

O

FeCl3.6H2O (5 mol%)


carbamate and 2-methylpropanal using toluene as

solvent

Following the general procedure B, 2-methylpropanal (0.10 mL,



20% EtOAc/ hexane as eluent) to give α-branched amine III-7d (0.3320 g, 98%).


carbamate and 2-methylpropanal using ClCH2CH2Cl

as solvent

Following the general procedure B, 2-methylpropanal (0.10 mL, 1.1

mmol) was employed. The reaction was stirred at room temperature for 1 h. The crude


hexane as eluent) to give α-branched amine III-7d (0.3256 g, 99%).

63


carbamate and 2-ethylbutanal

III-1a III-2q III-7e

HN O

O

OMe

OMeMeO

MeO

MeO OMe

H

O


III-3H2N O

O

FeCl3.6H2O (5 mol%)


carbamate and 2-ethylbutanal using toluene as

solvent

Following the general procedure B, 2-ethylbutanal (0.14 mL,

1.1 mmol) in toluene (1.5 mL) was employed. The reaction was stirred at room


100% hexane to 20% EtOAc/ hexane as eluent) to give α-branched amine III-7e

(0.2976 g, 81%).


carbamate and 2-ethylbutanal using ClCH2CH2Cl

as solvent

Following the general procedure B, 2-ethylbutanal (0.14 mL,



20% EtOAc/ hexane as eluent) to give α-branched amine III-7e (0.2958 g, 80%).


carbamate and 3-methylbutanal

III-1a III-2r III-7f

HN O

O

OMe

OMeMeO

MeO

MeO OMe

H

O


III-3H2N O

O

FeCl3.6H2O (5 mol%)

64


carbamate and 3-methylbutanal using toluene as

solvent

Following the general procedure B, 3-methylbutanal (0.12 mL,



EtOAc/ hexane as eluent) to give α-branched amine III-7f (0.3467 g, 98%).


carbamate and 3-methylbutanal using ClCH2CH2Cl

as solvent

Following the general procedure B, 3-methylbutanal (0.12 mL,



EtOAc/ hexane as eluent) to give α-branched amine III-7f (0.2272 g, 64%).


carbamate and cyclopropane carboxaldehyde

III-1a III-2s III-7g

HN O

O

OMe

OMeMeO

MeO

MeO OMe

H

O


III-3H2N O

O

FeCl3.6H2O (5 mol%)


carbamate and cyclopropane carboxaldehyde using

toluene as solvent

Following the general procedure B, cyclopropanecarbaldehyde




65


carbamate and cyclopropane carboxaldehyde using







carbamate and cyclopentane carboxaldehyde

III-1a III-2t III-7h

HN O

O

OMe

OMeMeO

MeO

MeO OMe

H

O


III-3H2N O

O

FeCl3.6H2O (5 mol%)


carbamate and cyclopropanecarbaldehyde using

toluene as solvent



90 min The crude product was purified by radial chromatography (SiO2, 100% hexane

to 20% EtOAc/hexane as eluent) to give α-branched amine III-7h (0.3310 g, 90%).


carbamate and cyclopropanecarbaldehyde using





20% EtOAc/hexane as eluent) to give α-branched amine III-7h (0.2500 g, 68 %).

66


carbamate and cyclohexanecarboxaldehyde

III-1a III-2u III-7i

HN O

O

OMe

OMeMeO

MeO

MeO OMe

H

O


III-3H2N O

O

FeCl3.6H2O (5 mol%)

1.2.3.9.1 Reaction of 1,3,5-trimethoxybenzene with tert-

butyl carbamate and cyclohexanecarbaldehyde

using toluene as solvent

Following the general procedure B, cyclohexanecarbaldehyde (0.13



20% EtOAc/hexane as eluent) to give α-branched amine III-7i (0.3647 g, 96%).

1.2.3.9.2 Reaction of 1,3,5-trimethoxybenzene with tert-

butyl carbamate and 3-methylbutanal using


Following the general procedure B, cyclohexanecarbaldehyde (0.13



20% EtOAc/hexane as eluent) to give α-branched amine III-7i (0.2381 g, 63%).

67

1.3 FeCl3∙6H2O catalyzed aza-Friedel-Crafts reaction of various

electron-rich arenes, tert-butyl carbamate with aromatic

and aliphatic aldehydes under optimized reaction condition

Ar-H

III-8 R = arylIII-10 R = alkyl

III-2III-1

R-CHOArAr

R+


+

Het-H

R = aryl or alkyl

+HN O

O

Ar H


III-3H2N O

O

FeCl3.6H2O (5 mol%)

General procedure C

A mixture of tert-butyl carbamate (0.1172 g, 1.0 mmol), freshly distilled

aldehydes (0.11 mL, 1.1 mmol) and FeCl3∙6H2O (5 mol%) in a round-bottomed flask

was added toluene (5 mL) or ClCH2CH2Cl (5 mL). A solution of arenes (0.10 mL, 1.0

mmol) in solvent (10 mL) was added dropwise to the reaction mixture at 0 oC. After

the reaction was stirred until completion (TLC analysis), the reaction mixture was

quenched with aqueous NaHCO3 (10 mL) and extracted with CH2Cl2 (2 x 10 mL).

The combined organic layer was washed with brine (10 mL), dried over anhydrous

Na2SO4 and filtered. The filtrate was evaporated (aspirator then vacuo) to give a crude

product, which was purified by radial chromatography (SiO2, 100% hexane to 20%

EtOAc/hexane as eluent) to give the corresponding α-branched amines.

68

1.3.1 Reaction of electron-rich arenes with tert-butyl carbamate and

aromatic aldehydes using FeCl3∙6H2O as catalyst


carbamate and benzaldehyde

III-1b III-2a III-8a

HN O

O

MeO

H

O

OMe OMe

MeO

OMe

MeO

OMe OMe

OMe

OMe

+

MeO

OMe

III-9a


III-3H2N O

O

FeCl3.6H2O (5 mol%)



Following the general procedure B, 1,2,4-trimethoxybenzene

(0.15 mL, 1.0 mmol), benzaldehyde (0.11 mL, 1.1 mmol), tert-butyl carbamate

(0.1172 g, 1.0 mmol) and toluene (1 mL) were employed. The reaction was stirred at

room temperature for 24 h. The crude product was purified by radial chromatography

(SiO2, 100% hexane to 30% EtOAc/hexane as eluent) to give α-branched amine

III-8a (0.2508 g, 67%) and the corresponding triarylmethane III-9a (0.0679 g, 32%).



solvent


(0.15 mL, 1.0 mmol), benzaldehyde (0.22 mL, 2.2 mmol), tert-butyl carbamate

(0.1172 g, 1.0 mmol) and ClCH2CH2Cl (1 mL) were employed. The reaction was

stirred at room temperature for 24 h. The crude product was purified by radial

chromatography (SiO2, 100% hexane to 30% EtOAc/hexane as eluent) to give

α-branched amine III-8a (0.2090 g, 56%) and the corresponding triarylmethane

III-9a (0.0933 g, 44%).

69

1.3.1.2 Reaction of 2-methylfuran with tert-butyl carbamate and

benzaldehyde

III-2a

H

O

+

O OHN O

O

OO

III-1c III-8b III-9b


III-3H2N O

O

FeCl3.6H2O (5 mol%)

1.3.1.2.1 Reaction of 2-methylfuran with tert-butyl carbamate

and benzaldehyde using toluene as solvent

Following the general procedure B, 2-methylfuran (0.09 mL,

1.0 mmol), benzaldehyde (0.11 mL, 1.1 mmol), tert-butyl carbamate (0.1172 g,

1.0 mmol) and toluene (1 mL) were employed. The reaction was stirred at room


100% hexane to 10% EtOAc/hexane as eluent) to give α-branched amine III-8b

(0.2063 g, 72%) and the corresponding bis(furyl)methane III-9b (0.0049 g, 4%).


and benzaldehyde using ClCH2CH2Cl as solvent



1.0 mmol) and ClCH2CH2Cl (1 mL) were employed. The reaction was stirred at room



(0.1838 g, 64%) and the corresponding bis(furyl)methane III-9b (0.0454 g, 36%).


4-nitrobenzaldehyde

III-2f

H

O

+

O OHN O

O

OO

III-1c III-8c III-9c


III-3H2N O

O

FeCl3.6H2O (5 mol%)

O2N NO2NO2

70



Following the general procedure B, 2-methylfuran (0.09 mL, 1.0

mmol), 4-nitrobenzaldehyde (0.1664 g, 1.1 mmol), tert-butyl carbamate (0.1172 g, 1.0

mmol) and toluene (1 mL) were employed. The reaction was stirred at room


100% hexane to 10% EtOAc/hexane as eluent) to give α-branched amine III-8c

(0.2234 g, 66%) and the corresponding bis(furyl)methane III-9c (0.0065 g, 4%).

1.3.1.4 Reaction of 2-ethylfuran with tert-butyl carbamate and

benzaldehyde

III-2a

H

O

+

O OHN O

O

OO

III-1d III-8d III-9d


III-3H2N O

O

FeCl3.6H2O (5 mol%)

1.3.1.4.1 Reaction of 2-ethylfuran with tert-butyl carbamate


Following the general procedure B, 2-ethylfuran (0.11 mL,

1.0 mmol), benzaldehyde (0.11 mL, 1.1 mmol) and tert-butyl carbamate (0.1172 g,

1.0 mmol) and toluene (1.5 mL) were employed. The reaction was stirred at room


100% hexane to 10% EtOAc/hexane as eluent) to give α-branched amine III-8d

(0.1959 g, 65%) and the corresponding bis(furyl)methane III-9d (0.0240 g, 17%).







71


(0.0885 g, 29%) and the corresponding bis(furyl)methane III-9d (0.0981 g, 70%).

1.3.1.5 Reaction of 2-methylthiophene with tert-butyl carbamate

and benzaldehyde

III-2a

H

O

+

S SHN O

O

SS

III-1e III-8e III-9e


III-3H2N O

O

FeCl3.6H2O (5 mol%)

1.3.1.5.1 Reaction of 2-methylthiophene with tert-butyl


Following the general procedure B, 2-methylthiophene (0.10 mL,




100% hexane to 10% EtOAc/hexane as eluent) to give α-branched amine III-8e

(0.0675 g, 22%) as a sole product.



solvent






(0.1716 g, 57%) and the corresponding bis(thienyl)methane III-9e (0.0055 g, 4%).

72

1.3.1.6 Reaction of 2-ethylthiophene with tert-butyl carbamate and

benzaldehyde


III-3H2N O

O

FeCl3.6H2O (5 mol%)

III-2a

H

O

+

S SHN O

O

SS

III-1f III-8f III-9f

1.3.1.6.1 Reaction of 2-ethylthiophene with tert-butyl carbamate


Following the general procedure B, 2-ethylthiophene (0.11 mL,




100% hexane to 5% EtOAc/hexane as eluent) to give α-branched amine III-8f




solvent







73

1.3.1.7 Reaction of N-Boc-pyrrole with tert-butyl carbamate and

benzaldehyde

III-2a

H

O

+

N N

HN O

O

NN

III-1g III-8g III-9g

Boc Boc

Boc Boc


III-3H2N O

O

FeCl3.6H2O (5 mol%)

1.3.1.7.1 Reaction of N-Boc-pyrrole with tert-butyl carbamate


Following the general procedure B, N-Boc-pyrrole (1.0 mL,




100% hexane to 10% EtOAc/hexane as eluent) to give α-branched amine III-8g

(0.0904 g, 24%) as a sole product







100% hexane to 10% EtOAc/hexane as eluent) to give α-branched amine III-8g


1.3.1.8 Reaction of indole with tert-butyl carbamate and

benzaldehyde

III-2a

H

O

+

HN NHHN O

O

HN

III-1h

NH

III-8h III-9h

III-3H2N O

O

FeCl3.6H2O (5 mol%)


74

1.3.1.8.1 Reaction of indole with tert-butyl carbamate and

benzaldehyde using toluene as solvent

Reaction of indole with tert-butyl carbamate and benzaldehyde

using 5 mol% of FeCl3∙6H2O for 30 min

Following the general procedure C, FeCl3∙6H2O (0.0135 g,

0.05 mmol) was added to a solution mixture of tert-butyl carbamate (0.1172 g,

1.0 mmol) and benzaldehyde (0.11 mL, 1.1 mmol) in toluene (5 mL). A solution of

indole (0.1172 g, 1.0 mmol) in toluene (10 mL) was added dropwise to the reaction

mixture at 0 oC for 30 min. The crude product was purified by radial chromatography

(SiO2, 100% hexane and 70:30:1 CH2Cl2:hexane:MeOH as eluent) to give α-branched

amine III-8h (0.0118 g, 4%) and the corresponding bis(indolyl)methane III-9h

(0.0665 g, 41%).


using 5 mol% of FeCl3∙6H2O for 2 h





mixture at 0 oC for 2 h. The crude product was purified by radial chromatography

(SiO2, 100% hexane and 70:30:1 CH2Cl2:hexane:MeOH as eluent) to give α-branched


(0.1165 g, 72%).


using 10 mol% of FeCl3∙6H2O





mixture at -40 oC to room temperature for 7 h. The crude product was purified by

radial chromatography (SiO2, 100% hexane and 70:30:1 CH2Cl2:hexane:MeOH as

eluent) to give α-branched amine III-8h (0.0114 g, 3%) and the corresponding

bis(indolyl)-methane III-9h (0.0429 g, 27%).

75

1.3.1.8.2 Reaction of indole with tert-butyl carbamate and

benzaldehyde using ClCH2CH2Cl as solvent

Following the general procedure C, FeCl3∙6H2O (0.0135 g, 0.05

mmol) was added to a solution mixture of tert-butyl carbamate (0.1172 g, 1.0 mmol)

and benzaldehyde (0.11 mL, 1.1 mmol) in ClCH2CH2Cl (5 mL). A solution of indole

(0.1172 g, 1.0 mmol) in ClCH2CH2Cl (10 mL) was added dropwise to the reaction

mixture at 0 oC for 17 min. The crude product was purified by radial chromatography

(SiO2, 100% hexane and 70:30:1 CH2Cl2:hexane:MeOH as eluent)to give α-branched


(0.0609 g, 42%).

1.3.2 Reaction of electron-rich arenes, tert-butyl carbamate with

aliphatic aldehydes using FeCl3∙6H2O as catalyst


carbamate and 2-methylpropanal

III-1b III-2p III-10a

HN O

O

MeO

H

O

OMe OMe

MeO

OMe

MeO

OMe OMe

OMe

OMe

+

MeO

OMe

III-11a

III-3H2N O

O

FeCl3.6H2O (5 mol%)




solvent


(1.0 mL, 1.0 mmol), 2-methylpropanal (0.11 mL, 1.1 mmol), tert-butyl carbamate

(0.1172 g, 1.0 mmol) and toluene (1 mL) were employed. The reaction was stirred at

room temperature for 24 h. The crude product was purified by radial chromatography

(SiO2, 100% hexane to 10% EtOAc/hexane as eluent) to give α-branched amine

III-10a (0.2215 g, 63%) and the corresponding bis(aryl)alkane III-11a (0.0165 g,

9%).

76



as solvent


(1.0 mL, 1.0 mmol), 2-methylpropanal (0.11 mL, 1.1 mmol), tert-butyl carbamate

(0.1172 g, 1.0 mmol) and ClCH2CH2Cl (1 mL) were employed. The reaction was

stirred at room temperature for 24 h. The crude product was purified by radial


α-branched amine III-12a (0.2172 g, 64%) and the corresponding bis(aryl)alkane

III-13a (0.0478 g, 25%).


2-methylpropanal

III-2p

H

O

+ O O

HN O

O

OO


III-3H2N O

O

FeCl3.6H2O (5 mol%)



and 2-methylpropanal using toluene as solvent


1.0 mmol), 2-methylpropanal (0.11 mL, 1.1 mmol), tert-butyl carbamate (0.1172 g,






and 2-methylpropanal using ClCH2CH2Cl as solvent





77



1.3.2.3 Reaction of 2-ethylfuran with tert-butyl carbamate and

2-methylpropanal

III-2p

H

O

+ O O

HN O

O

OO

III-1d III-10c III-11c

III-3H2N O

O

FeCl3.6H2O (5 mol%)









(0.2561 g, 96%) and the corresponding bis(furyl)alkane III-11c (0.0042 g, 3%).








(0.2609 g, 98%) and the corresponding bis(aryl)alkane III-11c (0.0012 g, 1%).

78

1.3.2.4 Reaction of 2-methylthiophene with tert-butyl carbamate

and 2-methylpropanal

III-2p

H

O

+ S S

HN O

O

SS

III-1e III-10d III-11d

III-3H2N O

O

FeCl3.6H2O (5 mol%)




solvent








carbamate and 2-methylpropanal using








79

1.3.2.5 Reaction of 2-ethylthiophene with tert-butyl carbamate and

2-methylpropanal

III-2p

H

O

+ S S

HN O

O

SS

III-1f III-10e III-11e

III-3H2N O

O

FeCl3.6H2O (5 mol%)


1.3.2.5.1 Reaction of 2-ethylthiophene with tert-butyl


solvent







1.3.2.5.2 Reaction of 2-ethylthiophene with tert-butyl


as solvent







80

1.3.2.6 Reaction of N-Boc-pyrrole with tert-butyl carbamate and

2-methylpropanal

III-2p

H

O

+

HN O

O

NN

III-1g III-10f

III-12a

III-3H2N O

O

FeCl3.6H2O (5 mol%)

Boc Boctoluene or ClCH2CH2Cl, rt

N

Boc

HN

HN

O

O O

O

N N

III-11f

Boc Boc








(0.0497 g, 15%) and (syn/anti)-α-branched amine III-12a (0.0123 g, 5%).








(0.1435 g, 42%) and (syn/anti)-α-branched amine III-12a (0.0868 g, 34%).

81



unsymmetrical triarylmethanes

2.1 Optimization of the reaction condition for Friedel-Crafts reaction of

2-methylfuran with N-Boc diarylmethylcarbamate

HN O

O

MeO

MeO OMe

O

catalyst (x mol%)

ClCH2CH2Cl, rt

MeO

MeO OMe

III-4a III-1c III-13a

O

General procedure D

To a dichloroethane solution (2 mL) of N-Boc diaylmethylcarbamate III-4a

(0.1867 g, 0.5 mmol) and 2-methylfuran III-1c (0.04 mL, 0.5 mmol) in a test-tube

open to air at room was added catalyst (I2, Montmorillonite K10 clay, Bi(OTf)3,

In(OTf)3, NbCl5, AlCl3∙6H2O, FeCl3 or FeCl3∙6H2O; x mmol). After the reaction was

stirred until completion (TLC analysis), the reaction mixture was quenched with

distilled water (10 mL) and extracted with EtOAc (2 x 10 mL). The combined organic

layer were washed with water (10 mL) and saturated aqueous NH4Cl (10 mL), dried

over anhydrous Na2SO4 and filtered. The filtrate was evaporated (aspirator then

vacuo) to give a crude product, which was purified by radial chromatography (SiO2,

100% hexane to 50% EtOAc/hexane as eluent) to give the corresponding

unsymmetrical triarylmethanes III-13.

82

2.1.1 Reaction of 2-methylfuran with N-Boc diarylmethylcarbamate

in various catalyst

Ar

HN O

O

O

catalyst (x mol%)

ClCH2CH2Cl, rt

Ar

III-4a or III-8a III-1c III-13

OO

III-9b III-1

OAr-H

Ar = 1,3,5-trimethoxybenzene, III-4a= 1,2,4-trimethoxybenzene, III-10a

III-13a, Ar = 1,3,5-trimethoxybenzeneIII-13b, Ar = 1,2,4-trimethoxybenzene

2.1.1.1 Reaction of 2-methylfuran with tert-butyl phenyl(2,4,6-

trimethoxyphenyl)methylcarbamate III-4a in various

catalyst

2.1.1.1.1 Reaction in the presence of 10 mol% of I2

Following the general procedure D, I2 (0.0127 g, 0.05 mmol) was

employed as catalyst. The reaction was stirred at room temperature for 24 h.


20% EtOAc/ hexane as eluent) to give unsymmetrical triarylmethane III-13a

(0.0701 g, 41%), triarylmethane III-9b (0.0141 g, 22%) and 1,3,5-trimethoxybenzene

III-1a (0.0027 g, 3%).







III-1a (0.0252 g, 30%).






83


III-1a (0.0244 g, 29%).

2.1.1.1.4 Reaction in the presence of 50 mg of montmorillonite

K10 clay

Following the general procedure D, montmorillonite K10 clay

(50 mg) was employed as catalyst. The reaction was stirred at room temperature for


to 20% EtOAc/ hexane as eluent) to give unsymmetrical triarylmethane III-13a


III-1a (0.0090 g, 14%).

2.1.1.1.5 Reaction in the presence of 100 mg of montmorillo-

nite K10 clay

Following the general procedure D, montmorillonite K10 clay

(100 mg) was employed as catalyst. The reaction was stirred at room temperature for




III-1a (0.0087 g, 10%).

2.1.1.1.6 Reaction in the presence of 10 mol% of Bi(OTf)3

Following the general procedure D, Bi(OTf)3 (0.0328 g,

0.1 mmol) was employed as catalyst. The reaction was stirred at room temperature for




III-1a (0.0087 g, 10%).

2.1.1.1.7 Reaction in the presence of 10 mol% of In(OTf)3

Following the general procedure D, In(OTf)3 (0.0281 g,

0.05 mmol) was employed as catalyst. The reaction was stirred at room temperature


hexane to 20% EtOAc/ hexane as eluent) to give unsymmetrical triarylmethane

III-13a (0.0332 g, 20%), triarylmethane III-9b (0.0075 g, 12%) and 1,3,5-

trimethoxybenzene III-1a (0.0078 g, 9%).

84















2.1.1.1.10 Reaction in the presence of 1.1 equivalent of

AlCl3∙6H2O

Following the general procedure D, AlCl3∙6H2O (0.1328 g,




III-13a (0.0043 g, 2%), in a small amount of triarylmethane III-9b and 1,3,5-


2.1.1.1.11 Reaction in the presence of 10 mol% of FeCl3

Following the general procedure D, FeCl3 (0.0081 g, 0.05 mmol)

was employed as catalyst. The reaction was stirred at room temperature for 24 h.



(0.0195 g, 12%), in a small amount of triarylmethane III-9b and 1,3,5-


2.1.1.1.12 Reaction in the presence of 10 mol% of FeCl3∙6H2O

Following the general procedure D, FeCl3∙6H2O (0.0135 g,


85





2.1.1.2 Reaction of 2-methylfuran with tert-butyl phenyl(2,4,5-

trimethoxyphenyl)methylcarbamate III-8a in the presence

of 10 mol% of FeCl3∙6H2O

Following the general procedure D, FeCl3∙6H2O (0.0135 g,



hexane to 20% EtOAc/ hexane as eluent) to give unsymmetrical triarylmethane III-

13b (0.1288 g, 76%) as a sole product.

86

2.2 FeCl3∙6H2O catalyzed Friedel-Crafts alkylation of various N-Boc

diarylmethylcarbamate as alkylating agent with different arene

under optimized reaction condition

Ar1/Het

HN O

O

Ar2

Ar1/Het

III-4 = Ar1

III-8 = Het

III-13

Ar2 Ar2

III-9 or III-15 III-1

Ar1/Het H10 mol% FeCl3

.6H2O

ClCH2CH2Cl, rt

III-1

R R R

R = H, NO2

Ar2 H

2.2.1 Reaction of tert-butyl phenyl(2,4,6-trimethoxyphenyl)methyl-

carbamate III-4a with different arene

2.2.1.1 Reaction of tert-butyl phenyl(2,4,6-trimethoxyphenyl)-

methylcarbamate III-4a with 2-methylfuran

HN O

O

MeO

MeO OMe

O

ClCH2CH2Cl, rt

MeO

MeO OMe


OO

OMe

OMeMeO

III-9b

III-1a

10 mol% FeCl3.6H2O

O

Following the general procedure D, tert-butyl phenyl(2,4,6-trimethoxy

phenyl)methylcarbamate III-4a (0.1866 g, 0.5 mmol), 2-methylfuran (0.05 mL,

0.5 mmol) and FeCl3∙6H2O (0.0135 g, 0.05 mmol) in ClCH2CH2Cl (2 mL) were

employed. The reaction was stirred at room temperature for 24 h. The crude product

was purified by radial chromatography (SiO2, 100% hexane to 20% EtOAc/hexane as

eluent) to give unsymmetrical triarylmethane III-13a (0.0895 g, 53%), triarylmethane

III-9b (0.0139 g, 22%) and 1,3,5-trimethoxybenzene III-1a (0.0278 g, 33%).

87




methylcarbamate III-8a with 2-methylfuran

HN O

O

MeO

MeO

O

ClCH2CH2Cl, rt

MeO

MeO

III-8a III-1c III-13b

OO

OMe

MeO

III-9b

III-1b

10 mol% FeCl3.6H2O

O

OMe OMe

OMe


phenyl)methylcarbamate III-8a (0.1866 g, 0.5 mmol), 2-methylfuran (0.05 mL,




eluent) to give unsymmetrical triarylmethane III-13b (0.1288 g, 76%) as a sole

product.


methylcarbamate III-8a with 2-ethylfuran

HN O

O

MeO

MeO

OMeO

MeO

III-8a III-1d III-13c

10 mol% FeCl3.6H2O

ClCH2CH2Cl, rt

OMe OMe

O

OO

OMe

MeO

III-9d

III-1b

OMe

88


phenyl)methylcarbamate III-8a (0.1491 g, 0.4 mmol), 2-ethylfuran (0.04 mL,




eluent) to give unsymmetrical triarylmethane III-13c (0.1267 g, 95%) as a sole

product.


methylcarbamate III-8a with 2-methylthiophene

HN O

O

MeO

MeO

SMeO

MeO

III-8a III-1e III-13d

10 mol% FeCl3.6H2O

ClCH2CH2Cl, rt

OMe OMe

S

SS

OMe

MeO

III-9e

III-1b

OMe


phenyl)methylcarbamate III-8a (0.0933 g, 0.25 mmol), 2-methylthiophene (0.03 mL,




eluent) to give unsymmetrical triarylmethane III-13d (0.0533 g, 60%) as a sole

product.

89


methylcarbamate III-8a with 2-ethylthiophene

HN O

O

MeO

MeO

SMeO

MeO

III-8a III-1f III-13e

10 mol% FeCl3.6H2O

ClCH2CH2Cl, rt

OMe OMe

S

SS

OMe

MeO

III-9f

III-1b

OMe


phenyl)methylcarbamate III-8a (0.1495 g, 0.4 mmol), 2-ethylthiophene (0.05 mL,




eluent) to give unsymmetrical triarylmethane III-13e (0.0983 g, 66%) as a sole

product.


methylcarbamate III-8a with N-Boc pyrrole

HN O

O

MeO

MeO

NMeO

MeO

III-8a III-1g

III-13f

10 mol% FeCl3.6H2O

ClCH2CH2Cl, rt

OMe

OMe

N

Boc

Boc

N

BocOMe

OMeMeO

MeO

MeOOMe

III-14aIII-9g

N N

BocBoc

OMe

MeO

III-1b

OMe

90


phenyl)methylcarbamate III-8a (0.1495 g, 0.4 mmol), N-Boc pyrrole (0.07 mL,




eluent) to give unsymmetrical triarylmethane III-13f (0.0571 g, 33%) and

unsymmetrical triarylmethane III-14a (0.0612 g, 36%).


methylcarbamate III-8a with 2-ethylpyrrole

HN O

O

MeO

MeO

NHMeO

MeO

III-8a III-1i III-13g

10 mol% FeCl3.6H2O

ClCH2CH2Cl, rt

OMe OMe

NH

NH

NH

OMe

MeO

III-15a

III-1b

OMe


phenyl)methylcarbamate III-8a (0.0933 g, 0.25 mmol), 2-ethylpyrrole (0.03 mL,




eluent) to give unsymmetrical triarylmethane III-13g (0.0417 g, 49%) as a sole

product.

91


methylcarbamate III-8a with indole

HN O

O

MeO

MeO


10 mol% FeCl3.6H2O

ClCH2CH2Cl, rt

OMe

OMe

MeO

III-9h

III-1b

OMe

HN NH

NH

MeO

OMe

MeO

NH


phenyl)methylcarbamate III-8a (0.1868 g, 0.5 mmol), indole (0.0598 g, 0.5 mmol)

and FeCl3∙6H2O (0.0135 g, 0.05 mmol) in ClCH2CH2Cl (2 mL) were employed.

The reaction was stirred at room temperature for 12 h. The crude product was purified

by radial chromatography (SiO2, 100% hexane to 30% EtOAc/hexane as eluent)

to give unsymmetrical triarylmethane III-13h (0.1337 g, 93%) as a sole product.


methylcarbamate III-8a with 5-methoxyindole

HN O

O

MeO

MeO

III-8a III-1j III-13i

10 mol% FeCl3.6H2O

ClCH2CH2Cl, rt

OMe

OMe

MeO

III-15b

III-1b

OMe

HN NH

NH

MeO

OMe

MeO

NH

MeO

MeO

MeO OMe

92


phenyl)methylcarbamate III-8a (0.0933 g, 0.25 mmol), 5-methoxyindole (0.0383 g,




eluent) to give unsymmetrical triarylmethane III-13i (0.0969 g, 96%) as a sole

product.


methylcarbamate III-8a with 6-fluoroindole

HN O

O

MeO

MeO

III-8a III-1k III-13j

10 mol% FeCl3.6H2O

ClCH2CH2Cl, rt

OMe

OMe

MeO

III-15c

III-1b

OMe

HN NH

NH

MeO

OMe

MeO

NH

F

F F F


phenyl)methylcarbamate III-8a (0.1495 g, 0.4 mmol), 6-fluoroindole (0.0556 g,




eluent) to give unsymmetrical triarylmethane III-13j (0.1272 g, 80%) as a sole

product.

93

2.2.3 Reaction of tert-butyl (5-methylfuran-2-yl)(phenyl)methyl-

carbamate III-8b or tert-butyl (5-methylfuran-2-yl)(4-nitro-

phenyl)methylcarbamate III 8c with different arene

2.2.3.1 Reaction of tert-butyl (5-methylfuran-2-yl)(phenyl)methyl-

carbamate III-8b with 2-ethylfuran

III-8b III-1d III-13k

10 mol% FeCl3.6H2O

ClCH2CH2Cl, rtO

OO

III-9d

III-1c

HN O

O

O

O

O

O

Following the general procedure D, tert-butyl (5-methylfuran-2-yl)-

(phenyl)methylcarbamate III-8b (0.0718 g, 0.25 mmol), 2-ethylfuran (0.03 mL,




eluent) to give unsymmetrical triarylmethane III-13k (0.0640 g, 96%) as a sole

product.

2.2.3.2 Reaction of tert-butyl (5-methylfuran-2-yl)(4-nitrophenyl)-

methylcarbamate III-8c with 2-ethylfuran

III-8c III-1d III-13l

10 mol% FeCl3.6H2O

ClCH2CH2Cl, rtO

OO

III-15d

III-1c

HN O

O

O

O

O

O

NO2NO2 NO2

94


(4-nitrophenyl)methylcarbamate III-8c (0.0827 g, 0.25 mmol), 2-ethylfuran (0.03 mL,




eluent) to give unsymmetrical triarylmethane III-13l (0.0349 g, 59%) as a sole

product.


carbamate III-8b with furfuryl alcohol

III-8b III-1l III-13m

10 mol% FeCl3.6H2O

ClCH2CH2Cl, rtO

OO

III-15e

III-1c

OH

HO OH

HN O

O

O

O

O

HO

O


(4-nitrophenyl)methylcarbamate III-8b (0.0718 g, 0.25 mmol), furfuryl alcohol

(0.02 mL, 0.25 mmol) and FeCl3∙6H2O (0.0068 g, 0.025 mmol) in ClCH2CH2Cl

(2 mL) were employed. The reaction was stirred at room temperature for 24 h.


20% EtOAc/hexane as eluent) to give unsymmetrical triarylmethane III-13m (0.0279

g, 45%) as a sole product.

95


methylcarbamate III-8c with furfuryl alcohol

III-8c III-1l III-13n

10 mol% FeCl3.6H2O

ClCH2CH2Cl, rtO

OO

III-15f

III-1c

OH

HO OH

HN O

O

O

O

O

HO

O

NO2NO2 NO2


(4-nitrophenyl)methylcarbamate III-8c (0.0664 g, 0.2 mmol), furfuryl alcohol (0.02

mL, 0.2 mmol) and FeCl3∙6H2O (0.0054 g, 0.02 mmol) in ClCH2CH2Cl (1 mL) were

employed. The reaction was stirred at room temperature for 24 h. No reaction was

observed and both starting materials were recovered in quantitative yields.


carbamate III-8b with 2-methylthiophene

III-8b III-1e III-13o

10 mol% FeCl3.6H2O

ClCH2CH2Cl, rtS

SS

III-9e

III-1c

HN O

O

O

S

O

O


(phenyl)methylcarbamate III-8b (0.0718 g, 0.25 mmol), 2-methylthiophene (0.03 mL,




96

eluent) to give unsymmetrical triarylmethane III-13o (0.0576 g, 86%) as a sole

product.


methylcarbamate III-8c with 2-methylthiophene

III-8c III-1e III-13p

10 mol% FeCl3.6H2O

ClCH2CH2Cl, rtS

SS

III-15g

III-1c

HN O

O

O

S

O

O

NO2NO2 NO2


(4-nitrophenyl)methylcarbamate III-8c (0.0830 g, 0.25 mmol), 2-methylthiophene

(0.03 mL, 0.25 mmol) and FeCl3∙6H2O (0.0135 g, 0.05 mmol) in ClCH2CH2Cl (2 mL)

were employed. The reaction was stirred at room temperature for 24 h. The crude

product was purified by radial chromatography (SiO2, 100% hexane to

20% EtOAc/hexane as eluent) to give unsymmetrical triarylmethane III-13p (0.0570



carbamate III-8b with 2-ethylthiophene

III-8b III-1f III-13q

10 mol% FeCl3.6H2O

ClCH2CH2Cl, rtS

SS

III-9f

III-1c

HN O

O

O

S

O

O

97


(phenyl)methylcarbamate III-8b (0.0718 g, 0.25 mmol), 2-ethylthiophene (0.03 mL,




eluent) to give unsymmetrical triarylmethane III-13q (0.0628 g, 90%) as a sole

product.


methylcarbamate III-8c with 2-ethylthiophene

III-8c III-1f III-13r

10 mol% FeCl3.6H2O

ClCH2CH2Cl, rtS

SS

III-15h

III-1c

HN O

O

O

S

O

O

NO2NO2 NO2


(4-nitrophenyl)methylcarbamate III-8c (0.0830 g, 0.25 mmol), 2-ethylthiophene


(1 mL) were employed. The reaction was stirred at room temperature for 24 h. The

crude product was purified by radial chromatography (SiO2, 100% hexane to

20% EtOAc/hexane as eluent) to give unsymmetrical triarylmethane III-13r (0.0428


98


carbamate III-8b with N-Boc pyrrole

III-8b III-1g

III-13s

10 mol% FeCl3.6H2O

ClCH2CH2Cl, rtN

Boc

N

Boc

III-14bIII-9g

N N

BocBoc

III-1c

HN O

O

O

NBoc

O

O

O O


(phenyl)methylcarbamate III-8b (0.0718 g, 0.25 mmol), N-Boc pyrrole (0.04 mL,




eluent) to give unsymmetrical triarylmethane III-13s (0.0472 g, 58%) as a sole

product.

2.2.3.10 Reaction of tert-butyl (5-methylfuran-2-yl)(4-nitrophe-

nyl)methylcarbamate III-8c with N-Boc pyrrole

III-8c III-1g

III-13t

10 mol% FeCl3.6H2O

ClCH2CH2Cl, rtN

Boc

N

Boc

III-14cIII-15i

N N

BocBoc

III-1c

HN O

O

O

NBoc

O

O

O O

NO2

NO2NO2 O2N NO2

99


(4-nitrophenyl)methylcarbamate III-8c (0.0665 g, 0.2 mmol), N-Boc pyrrole

(0.04 mL, 0.2 mmol) and FeCl3∙6H2O (0.0054 g, 0.02 mmol) in ClCH2CH2Cl (1 mL)

were employed. The reaction was stirred at room temperature for 24 h. The crude

product was purified by radial chromatography (SiO2, 100% hexane to

20% EtOAc/hexane as eluent) to give unsymmetrical triarylmethane III-13t (0.0431


2.2.3.11 Reaction of tert-butyl (5-methylfuran-2-yl)(phenyl)-

methylcarbamate III-8b with 2-ethylpyrrole

III-8b III-1i III-13u

10 mol% FeCl3.6H2O

ClCH2CH2Cl, rtNH

NH

NH

III-15a

III-1c

HN O

O

O

O

NH

O


(phenyl)methylcarbamate III-8b (0.0718 g, 0.25 mmol), 2-ethylthiophene (0.03 mL,




eluent) to give unsymmetrical triarylmethane III-13u (0.0063 g, 12%) as a sole

product.

100


nyl)methylcarbamate III-8c with ethylpyrrole

III-8c III-1i III-13v

10 mol% FeCl3.6H2O

ClCH2CH2Cl, rtNH

NH

NH

III-15j

III-1c

HN O

O

O

O

NH

ONO2 NO2 NO2


(4-nitrophenyl)methylcarbamate III-8c (0.0830 g, 0.25 mmol), 2-ethylpyrrole


(2 mL) were employed. After stirring the reaction at room temperature for 24 h,

the 20 mol% of FeCl3∙6H2O (0.0135 g, 0.025 mmol) was added to the reaction

mixture at room temperature to 70 oC for 33 h. The crude product was purified by

radial chromatography (SiO2, 100% hexane to 30% EtOAc/hexane as eluent) to give

unsymmetrical triarylmethane III-13v (0.0081 g, 11%) as a sole product.


methylcarbamate III-8b with indole

III-1h III-13w

10 mol% FeCl3.6H2O

ClCH2CH2Cl, rt

III-9h

III-1c

HN NH

NH

HN O

O

O

O

NH

O

III-8b


(phenyl)methylcarbamate III-8b (0.0733 g, 0.25 mmol), indole (0.0302 g, 0.25 mmol)


101



to give unsymmetrical triarylmethane III-15r (0.0627 g, 85%) as a sole product.


nyl)methylcarbamate III-8c with indole

III-1h III-13x

10 mol% FeCl3.6H2O

ClCH2CH2Cl, rt

III-15k

III-1c

HN NH

NH

HN O

O

O

O

NH

O

III-8c

NO2NO2 NO2


(4-nitrophenyl)methylcarbamate III-8c (0.1329 g, 0.4 mmol), indole (0.0480 g,




eluent) to give unsymmetrical triarylmethane III-13x (0.0692 g, 52%) as a sole

product.


methylcarbamate III-8b with 5-methoxyindoleindole

III-1j III-13y

10 mol% FeCl3.6H2O

ClCH2CH2Cl, rt

III-15b

III-1c

HN NH

NH

HN O

O

O

O

NH

O

III-8b

MeO

MeO OMe

MeO

102


(phenyl)methylcarbamate III-8b (0.0718 g, 0.25 mmol), 5-methoxyindole (0.0385 g,




eluent) to give unsymmetrical triarylmethane III-13y (0.0416 g, 87%) as a sole

product.


nyl)methylcarbamate III-8c with 5-methoxyindole

III-1j III-13z

10 mol% FeCl3.6H2O

ClCH2CH2Cl, rt

III-15l

III-1c

HN NH

NH

HN O

O

O

O

NH

O

III-8c

MeO

MeO OMe

MeO

NO2

NO2

NO2


(4-nitrophenyl)methylcarbamate III-8c (0.0830 g, 0.25 mmol), 5-methoxyindole

(0.0384 g, 0.25 mmol) and FeCl3∙6H2O (0.0068 g, 0.025 mmol) in ClCH2CH2Cl

(2 mL) were employed. After stirring the reaction at room temperature for 24 h,

the 10 mol% of FeCl3∙6H2O (0.0068 g, 0.025 mmol) was added to the reaction

mixture at room temperature for 3 h. The crude product was purified by radial


unsymmetrical triarylmethane III-13z (0.0216 g, 24%) as a sole product.

103


methylcarbamate III-8b with 6-fluoroindole

III-1k III-13aa

10 mol% FeCl3.6H2O

ClCH2CH2Cl, rt

III-15c

III-1c

HN NH

NH

HN O

O

O

O

NH

O

III-8b

F

F

F F


(phenyl)methylcarbamate III-8b (0.0863 g, 0.3 mmol), 6-fluoroindole (0.0419 g, 0.3

mmol) and FeCl3∙6H2O (0.0083 g, 0.03 mmol) in ClCH2CH2Cl (2 mL) were



eluent) to give unsymmetrical triarylmethane III-15t (0.0789 g, 86%) as a sole

product.


nyl)methylcarbamate III-8c with 6-fluoroindole

III-1k III-13ab

10 mol% FeCl3.6H2O

ClCH2CH2Cl, rt

III-15m

III-1c

HN NH

NH

HN O

O

O

O

NH

O

III-8c

F

F

F F

NO2

NO2

NO2

104


(4-nitrophenyl)methylcarbamate III-8c (0.1661 g, 0.5 mmol), 6-fluoroindole (0.0689

g, 0.5 mmol) and FeCl3∙6H2O (0.0135 g, 0.05 mmol) in ClCH2CH2Cl (2 mL) were



eluent) to give unsymmetrical triarylmethane III-13ab (0.0417 g, 24%) as a sole

product.


diarylmethylcarbamate as alkylating agent with indole under

optimized reaction condition

III-10 III-1j III-13

10 mol% FeCl3.6H2O

ClCH2CH2Cl, rtAr

HN O

O

ArNH

NH

III-9g

HN NH

Ar-H

III-1


carbamate III-8a with indole

HN O

O

MeO

MeO


10 mol% FeCl3.6H2O

ClCH2CH2Cl, rt

OMe

OMe

MeO

III-9h

III-1b

OMe

HN NH

NH

MeO

OMe

MeO

NH

Following the general procedure D, tert-butyl phenyl(2,4,5-trimethoxy-

phenyl)methylcarbamate III-8a (0.1868 g, 0.5 mmol), indole (0.0598 g, 0.5 mmol)



105


to give unsymmetrical triarylmethane III-13h (0.1337 g, 93%) as a sole product.

2.3.2 Reaction of tert-butyl (5-methylfuran-2-yl)(phenyl)methyl-

carbamate III-8b with indole

III-1h III-13w

10 mol% FeCl3.6H2O

ClCH2CH2Cl, rt

III-9h

III-1c

HN NH

NH

HN O

O

O

O

NH

O

III-8b


(phenyl)methylcarbamate III-8b (0.0733 g, 0.25 mmol), indole (0.0302 g, 0.25 mmol)




to give unsymmetrical triarylmethane III-13w (0.0627 g, 85%) as a sole product.

2.3.3 Reaction of tert-butyl (5-methylthiophen-2-yl)(phenyl)methyl-

carbamate III-8e with indole

III-1h III-13ac

10 mol% FeCl3.6H2O

ClCH2CH2Cl, rt

III-9h

III-1e

HN NH

NH

HN O

O

S

S

NH

S

III-8e


(4-nitrophenyl)methylcarbamate III-8e (0.1516 g, 0.5 mmol), indole (0.0597 g,


106



eluent) to give unsymmetrical triarylmethane III-13ac (0.1418 g, 94%) as a sole

product.

2.3.4 Reaction of tert-butyl 2-((tert-butoxycarbonylamino)(phenyl)-

methyl)-1H-pyrrole-1-carboxylate III-8g with indole

III-1h III-13ad

10 mol% FeCl3.6H2O

ClCH2CH2Cl, rt

III-9h

III-1g

HN NH

NH

HN O

O

N

N

NH

N

III-8g

Boc Boc

Boc


(4-nitrophenyl)methylcarbamate III-8g (0.1862 g, 0.5 mmol), indole (0.0597 g,




eluent) to give unsymmetrical triarylmethane III-13ad (0.1116 g, 60%) as a sole

product.

CHAPTER 4

RESULTS DISCUSSION & CONCLUSION

Results & Discussion

α-Branched amine derivatives and unsymmetrical triarylmethanes are

attractive target molecules because of their applications in medicinal and meterials

chemistry. Method for the synthesis of α-branched amine derivatives have been

developed which mainly centered on Friedel-Crafts alkylation of electron-rich arenes

with aldehydes in the presence of Lewis acids as catalyst. However, most methods

reported to date are multi-step processes, require harsh reaction conditions.

In recently, FeCl3∙6H2O has received considerable attention in organic synthesis

due to their less expensive, readily available, and environmentally benign properties.

These factors led the chemists to pay more attention towards the iron-based catalysis

for mild and green reactions. Moreover, FeCl3∙6H2O has a high tolerance to air

as well as moisture and can be easily removed from reaction systems. Therefore,

we will investigated the possibility of performing FeCl3∙6H2O catalyzed aza-Friedel-

Crafts reaction for the synthesis of α-branched amine derivatives via one-pot three-

component aza-Friedel-Crafts reaction of electron-rich arenes with a series of

aldehydes and tert-butyl carbamate. Furthermore, we will studied a novel efficient

aza-Friedel-Crafts reaction of the resulting α-branched amine products with difference

heteroaromatic or electron-rich arenes, leading to unsymmetrical triarylmethanes.

Ar1 Ar2/R2

HN O

O

H2N O

O

Ar2/R2CHO

FeCl3 6H2O

solvent, 0-rt

Ar1 H

Het H

or


R2 = alkyl

Ar1

Ar3

Ar2

solvent, rt

Ar3 H


FeCl3 6H2O

Figure 4-1 A model reaction for the synthesis of α-branched amine derivatives and

unsymmetrical triarylmethanes.

108

1. The aza-Friedel-Crafts reaction of arenes with aldehyde and tert-

butyl carbamate in the present of FeCl3∙6H2O: Synthesis of

the corresponding α-branched amine.

In a preliminary study, we developed a simple and efficient synthesis of

N-Boc protected α-branched amine via one-pot three-component aza-Friedel-Crafts

reaction of electron-rich arenes and a combination of aldehydes and tert-butyl

carbamate using FeCl3∙6H2O as catalyst.

1.1 Optimization studies on the reaction of 1,3,5-trimethoxybenzene

with benzaldehyde and tert-butyl carbamate.

Initially, the reaction of 1,3,5-trimethoxybenzene, benzaldehyde and tert-

butyl carbamate in the presence of FeCl3∙6H2O were employed as a model reaction for

the synthesis of α-branched amines (Figure 4-1).

III-1a III-2a

H2N O

O

solvent, rt

FeCl3.6H2O (x mol%)

HN O

O

OMe

OMeMeO

MeO

MeO OMe

III-3

III-4a

H

O

Figure 4-2 A model reaction for the synthesis of α-branched amines

1.1.1 Reaction of 1,3,5-trimethoxybenzene with benzaldehyde and

tert-butyl carbamate in various solvent using FeCl3∙6H2O as

catalyst.

The effect of solvent on FeCl3∙6H2O catalyzed coupling reaction of

1,3,5-trimethoxybenzene with benzaldehyde and tert-butyl carbamate was first

studied. The reaction was carried out employing 10 mol% FeCl3∙6H2O as catalysts

in various solvents such as THF, DMF, CH3NO2, CH3OH, H2O, ClCH2CH2Cl,

toluene and the results are summarized in Table 4-1. In all solvents employed,

the desired product III-4a was obtained in moderate to high yields (35-91%).

From the results, it should be noted that the non-polar and weakly polar solvents

such as toluene and ClCH2CH2Cl, respectively, gave the desired product III-4a

109

in high yields. Decreasing the reaction time was not affect for the chemical yield of

products (86-91%, entries 6-11). When the reaction was carried out in polar solvent

such as CH3NO2 and CH3OH which can be occured the solvation with the catalyst,

the reaction gave the desired product in slightly lower yields (72-81%, entries 3-4).

Moreover, in the case of the highly coordinative solvent with the vacant coordinating

site of Fe(III) such as THF and DMF afforded the desired product in lower yields and

required longer reaction time (36-44%, entries 1-2). Additionally, the reaction

was also performed in water as a reaction medium due to its many advantages from

economic, environmental, and safety standpoints. However, the desired product was

obtained in moderate yield (35%, entry 5). The homogeneity of the reaction media

might be the cause of the lower yield and the longer reaction time when water was

employed as the solvent.

Table 4-1 Reaction of 1,3,5-trimethoxybenzene with benzaldehyde and tert-butyl

carbamate in various of solvent.a

III-1a

H2N O

O

solvent, rt


HN O

O

OMe

OMeMeO

MeO

MeO OMe

III-2a

III-3

III-4a

H

O

Entry FeCl3∙6H2O

(mol %)

Solvent Time (h) Yield III-4ab

(%)

1 10 THF 24 44

2 10 DMF 48 36

3 10 CH3NO2 24 81

4 10 CH3OH 24 72

5 10 H2O/CH3OH 24 35c

6 10 ClCH2CH2Cl 24 86

7 10 ClCH2CH2Cl 12 88

110

Table 4-1 (continued).a

Entry FeCl3∙6H2O

(mol %)


(%)

8 10 ClCH2CH2Cl 2 90

9 10 toluene 24 88

10 10 toluene 12 89

11 10 toluene 2 91

a Reaction conditions: III-1a (1.0 mmol), III-2a (1.1 mmol), III-3 (1.0 mmol),

FeCl3∙6H2O (10 mol%) in toluene (1 mL) at room temperature. b Isolated yields.

c The reaction was carried out using 4:1 H2O/CH3OH as solvent.

1.1.2 Reaction of 1,3,5-trimethoxybenzene with benzaldehyde and

tert-butyl carbamate in various catalyst loading of FeCl3∙6H2O.

To optimize the amount of catalyst, the reactions of 1,3,5-trimethoxy-

benzene, benzaldehyde and tert-butyl carbamate in toluene or ClCH2CH2Cl at room

temperature were selected as a model reaction condition because FeCl3∙6H2O showed

comparable catalytic activity in both solvents. We found that the reaction

in the presence of 5 mol% of FeCl3∙6H2O gave the desired product III-4a in 86% and

89% yields, respectively (entries 2 and 5). When catalytic loading was raised to

10 mol%, the reaction gave the product in comparable yields (entries 1 and 4).

Interestingly, decreasing the catalyst loading to 2.5 mol% and stirring the reaction in

toluene decreased the chemical yield of the product (entry 3). Therefore, 5 mol% of

catalyst loading was found to be the optimal quantity and sufficient to push

the reaction forward.

111

Table 4-2 Reaction of 1,3,5-trimethoxybenzene with benzaldehyde and tert-butyl

carbamate in various catalyst loading.a

III-1a III-2a

H2N O

O


FeCl3.6H2O (x mol%)

HN O

O

OMe

OMeMeO

MeO

MeO OMe

III-3

III-4a

H

O

Entry FeCl3∙6H2O

(mol %)


(%)

1 10 Toluene 2 91

2 5 Toluene 2 86

3 2.5 Toluene 2 59

4 10 ClCH2CH2Cl 2 90

5 5 ClCH2CH2Cl 2 89

6 2.5 ClCH2CH2Cl 2 80


FeCl3∙6H2O (10 mol%) in solvent (1 mL) at room temperature. b Isolated yields.

1.2 The aza-Friedel-Crafts reaction of 1,3,5-trimethoxybenzene, tert-

butyl carbamate in the presence of FeCl3∙6H2O with various

aldehydes under optimized reaction condition.

On the basis of the previously optimized reaction conditions, the scope of

this transformation in the direct three-component aza-Friedel-Crafts reaction of

1,3,5-trimethoxybenzene with a combination of tert-butyl carbamate and a number of

aromatic aldehydes was evaluated (Figure 4-2, Table 4-3 to Table 4-6).

112

III-1a III-2

HNOMe

OMeMeO

MeO

MeO OMe

RR-CHO

H2N O

O


5 mol% FeCl3.6H2O

III-3

III-4, R = arylIII-6, R = heteroarylIII-7, R = alkyl

O

O

Figure 4-3 The synthesis of α-branched amine derivatives using FeCl3∙6H2O as

catalyst.


carbamate and aromatic aldehydes using FeCl3∙6H2O as

catalyst

At the beginning of exploratory studies for the scope of these reaction,

a variety of aromatic aldehydes containing electron-rich, electron-neutral, and

electron-deficient on the aromatic ring underwent one-pot three-component

aza-Friedel-Crafts reaction with 1,3,5-trimethoxybenzene and tert-butyl carbamate

using toluene and ClCH2CH2Cl as solvent were employed (Table 4-3). In the presence

of 5 mol% of FeCl3∙6H2O, 1,3,5-trimethoxybenzene reacted efficiently with tert-

butyl carbamate and a number of aromatic aldehydes possessing either electron-

withdrawing (F, Cl, Br and NO2) or electron-donating (OMe) substituents gave

the corresponding N-protected diarylmethylamines III-4a to III-4h in moderate to

high yields (64-95%). Not only monosubstituted aromatic carbaldehydes were

successful, but the reaction of disubstituted aromatic carbaldehyde under the same

condition also gave the α-branched amine III-4i as a major product in moderate yield.

Furthermore, α,α'-branched amine III-5a was obtained as minor product (Table 4-4).

In comparison to the reaction in toluene and ClCH2CH2Cl, the product yields

in the case of toluene were obtained slightly lower than those in ClCH2CH2Cl, but

the longer reaction time was required. From these results, the method for the synthesis

of α-branched amines was designed to test the effects of substitution on the aromatic

ring of aldehydes in terms of yields and reaction times which using different solvent.

It is observed that substituents on the aromatic ring of aldehydes have a delicate effect

on the reaction process in different solvent. The reaction using toluene as solvent was

113

found to be highly sensitive to the substituted of aromatic aldehyde. The reaction of

electron-rich aromatic aldehydes gave better chemical yield than the reaction of

electron poor aromatic aldehydes. On the other hand, the reaction in the presence of

ClCH2CH2Cl afforded the desired products with comparable yields. The homogeneity

of the reaction media might be the cause of the higher yields and shorter reaction time

when ClCH2CH2Cl was employed as the solvent.

Table 4-3 Reaction of 1,3,5-trimethoxybenzene, tert-butyl carbamate with various

aromatic aldehydes.a

III-1a III-2

HNOMe

OMeMeO

MeO

MeO OMe

RR-CHO

H2N O

O


5 mol% FeCl3.6H2O

III-3

III-4

O

O

Entry R-CHO Products Toluene ClCH2CH2Cl

Time

(h)

Yieldb

(%)

Time

(h)

Yieldb

(%)

1 H

O

HN O

O

OMeMeO

MeO

2 86

2 90

III-2a III-4a

2 H

O

F

HN O

O

OMeMeO

MeO

F

2 85

3 95

III-2b III-4b

3

F

H

O

HN O

O

OMeMeO

MeO

F

2 83

2 95

III-2c III-4c

114





Time

(h)

Yieldb

(%)

Time

(h)

Yieldb

(%)

4

Cl

H

O

HN O

O

OMeMeO

MeO

Cl

2 68

2 81

III-2d III-4d

5 H

O

Br

HN O

O

OMeMeO

MeO

Br

2 64

2 87

III-2e III-4e

6

O2N

H

O

HN O

O

OMeMeO

MeO

NO2

2 66

2 89

III-2f III-4f

7

MeO

H

O

HN O

O

OMeMeO

MeO

OMe

2 83

2 80

III-2g III-4g

8 MeO2C

H

O

HN O

O

MeO

MeO OMe CO2Me

4 81

2 82

III-2h III-4h

115

Table 4-4 Reaction of 1,3,5-trimethoxybenzene, tert-butyl carbamate with di

substituted aromatic aldehydes.a

III-1a III-2

HNOMe

OMeMeO

MeO

MeO OMe

RH2N O

O


5 mol% FeCl3.6H2O

III-3

III-4

O

O

H

O

OHC

R-CHO Time

(h)

Products Yields (%)b

H

O

O

H

III-2i

24

HN O

O

MeO

MeOOMe

H O

HN O

O

MeO

MeO

HN

OO

OMe OMe

OMeOMe

III-4i (NR) III-5a (NR)

III-4i (NR)c III-5a (NR)

c

H

O

H

O III-2j

1

HN O

O

MeO

MeO OMe

O

H

HN O

O

MeO

MeO OMe

MeO OMe

OMeNH

O

O

III-4j (52) III-5b (38)

III-4j (53)c III-5b (26)

c



c The

reaction was carried out using FeCl3∙6H2O (5 mol%) in ClCH2CH2Cl (1 mL).

116


carbamate and heteroaromatic aldehydes using FeCl3∙6H2O as

catalyst

After that, the synthesis of α-branched heteroarylamines have been

developed by the reaction of heteroaromatic aldehydes with 1,3,5-trimethoxybenzene

and tert-butyl carbamate (Table 4-5). The reaction of 1,3,5-trimethoxybenzene and

tert-butyl carbamate with furfural gave the N-Boc protected diarylmethylamine

III-6a in low yields (entries 1). While, the reaction of 2-pyridinecarbaldehyde with

1,3,5-trimethoxybenzene and tert-butyl carbamate at room temperature was

unsuccessful. Only starting material were recovered from the reaction mixture

(entry 2). However, heating the reaction mixture of 1,3,5-trimethoxybenzene with

2-pyridinecarbaldehyde and tert-butyl carbamate at 80 oC for 3 h afforded

the expected α-branched amine III-6b in moderate to good yield.

Table 4-5 Reaction of 1,3,5-trimethoxybenzene, tert-butyl carbamate with

heteroaromatic aldehydes.a

III-1a III-2

HNOMe

OMeMeO

MeO

MeO OMe

HetHet-CHO

H2N O

O


5 mol% FeCl3.6H2O

III-3

III-6

O

O


Time

(h)

Yieldb

(%)

Time

(h)

Yieldb

(%)

1 H

O

O

HN O

O

MeO

MeO OMeO

24 33

24 11

III-2k III-6a

117




c The

reaction was carried out in toluene (1.5 mL) at 80 oC.

d The reaction was carried out in

at 80 oC.


carbamate and aliphatic aldehydes using FeCl3∙6H2O as

catalyst.

The reaction of 1,3,5-trimethoxybenzene with aliphatic aldehydes and

tert-butyl carbamate was then studied and the results are summarized in Table 4-6.

The reaction of 1,3,5-trimethoxybenzene and tert-butyl carbamate with long chain

aliphatic aldehydes gave the diarylalkanes III-7a to III-7c in moderate to high yields

(entries 1-3). The α-substituted aliphatic aldehydes, isobutyraldehyde and

2-ethylbutanal also proceed smoothly to afford the product III-7d to III-7e in high

yields (entry 4-5). For the β-substituted aliphatic aldehydes (entries 6), the product

III-7f was obtained in moderate to high yields. The reaction of 1,3,5-trimethoxy-

benzene and tert-butyl carbamate with cyclic carbaldehydes such as cyclopropane,

cyclopentane and cyclohexane carboxaldehydes led to the corresponding diaryl-

alkanes III-7g-i in moderate to high yields (entries 7-9). As the results, it should be

noted that the product yields in the case of aliphatic aldehydes depended on

the solvent effect. The reaction of aliphatic aldehyde in toluene gave the products in

excellent yields. Compared to aromatic aldehydes in ClCH2CH2Cl, the aliphatic


Time

(h)

Yieldb

(%)

Time

(h)

Yieldb

(%)

2 N

H

O

HN O

O

MeO

MeO OMeN

3 67c

3 87d

III-2l III-6b

118

aldehydes in ClCH2CH2Cl afforded lower yields of the corresponding α-branched

amines, probably due to the enol formation at the α-hydrogen of carbonyl group.

Table 4-6 Reaction of 1,3,5-trimethoxybenzene, tert-butyl carbamate with aliphatic

aldehydes.a

III-1a III-2

HNOMe

OMeMeO

MeO

MeO OMe

RR-CHO

H2N O

O


5 mol% FeCl3.6H2O

III-3

III-7 R = alkyl

O

O


Time

(h)

Yieldb

(%)

Time

(h)

Yieldb

(%)

1 O

H

HN O

O

MeO

MeO OMe

2 96

2 69

III-2m III-7a

2 O

H

HN O

O

MeO

MeO OMe

4 96

4 94

III-2n III-7b

3

O

H

HN O

O

MeO

MeO OMe

1 91

1 95

III-2o III-7c

4

O

H

HN O

O

MeO

MeO OMe

1 98

1 99

III-2p III-7d

119





Time

(h)

Yieldb

(%)

Time

(h)

Yieldb

(%)

5 H

O

HN O

O

MeO

MeO OMe

4 81

4 80

III-2q III-7e

6 O

H

HN

O

OMeO

MeO OMe

4 98

4 64

III-2r III-7f

7

O

H

HN O

O

MeO

MeO OMe

2 83

2 64

III-2s III-7g

8 H

O

HN O

O

MeO

MeO OMe

1.5 90

2 68

III-2t III-7h

9 H

O

HN O

O

MeO OMe

MeO

2 96

2 63

III-2u III-7i

120

1.3 The aza-Friedel-Crafts reaction of various arenes, tert-butyl

carbamate with aromatic and aliphatic aldehydes in the presence of

FeCl3∙6H2O under optimized reaction condition.

The one-pot three-component aza-Friedel-Crafts reaction of an array of

arenes or heteroarenes with aldehydes, and tert-butyl carbamates was subsequently

investigated (Figure 4-4 and Table 4-7). The results presented in Table 4-7 showed

that the reactions led to selective formation of α-branched amines in low to high

yields depending on the arenes or heteroarenes substrates.

Ar-H


III-2III-1

R-CHOArAr

R+


+

Het-H

R = aryl or alkyl

+HN O

O

Ar H


III-3H2N O

O

FeCl3.6H2O (5 mol%)

Figure 4-4 The one-pot three-component aza-Friedel-Crafts reaction of arenes or

heteroarenes with aldehydes and tert-butyl carbamates.

1.3.1 The aza-Friedel-Crafts reaction of various electron-rich arenes,

tert-butyl carbamate with aromatic and aliphatic aldehydes

under optimized reaction condition.

Under optimized reaction conditions, the scope of the aza-Friedel-Crafts

alkylation of arenes with tert-butyl carbamate and aldehydes in both toluene and

dichloroethane as solvent were also studied and the results are outlined in Table 4-7.

The one-pot three-component aza-Friedel-Crafts reaction in toluene and

dichloroethane were successfully applied to other aromatic and heteroaromatic

compounds with benzaldehyde and tert-butyl carbamate to afford the functionalized

α-branched amines in low to good yields (2-72%, entries 1-17). From the results,

we can conclude that the reaction of the highest electron-rich arene, 1,2,4-trimethoxy-

benzene, gave the corresponding diarylmethylamine III-8a and triarylmethane III-9a

with comparable yield (entries 1-2). The formation of triarylmethane III-9a might be

obtained by addition of a second molecule of 1,2,4-trimethoxybenzene to the resulting

diarylmethyl amine III-8a. While the reaction of oxygen heteroaromatic arene

121

derivatives, 2-methylfuran with benzaldehyde and tert-butyl carbamates in toluene as

solvent gave the compound III-8b in good yields and a trace amount of

triarylmethane III-9b (entry 3). On the other hand, the reaction of 2-ethylfuran in

dichloroethane as solvent proceeded smoothly to afford triarylmethane III-10k in

70%. Gratifyingly, the less reactive nucleophile such as 2-methylthiophene and

2-ethylthiophene, also reactive with benzaldehyde and tert-butyl carbamate in

dichloroethane to provide diarylmethylamines III-8e to III-8f in good yields (entries

8-11). Under the same conditions, N-Boc pyrrole was also tested in the raction and

the desired α-branched amine adduct was observed in low yields (24-29%, entries

12-13). These might be explaned by the N-Boc protective group of pyrrole had steric

interactive and electronic effects which results in lower yields of the product.

It should be noted that no side product was obtained in these case. Notably, when

unprotected indole was employed as reactive nucleophile in the reaction mixture

under low reaction concentration and low temperature, the side product which derived

from bisarylation of aldehyde, was observed as a major product (entries 14-17).

Subsequently, the scope of arenes with tert-butyl carbamate and aliphatic

aldehyde were examined and the results are shown in entries 18 to 29. Under the same

aromatic aldehyde condition, all the case of arenes with a combination of tert-butyl

carbamate and aliphatic aldehyde, isobutyraldehyde, gave α-branched amine adducts

III-10a to III-10f in low to excellent yields. Interestingly, the chemical yields of

α-branched amines in the case of aliphatic aldehyde were higher than those of

aromatic aldehyde except in the case of thiophene (entries 24-27). These could be

due to the rate of keto-tautomerism of isobutyraldehyde was lower than the rate of

imine formation in the reaction media. Therefore, the electrophilicity aliphatic imines

derived from aliphatic aldehydes were reacted with a collection of arenes rather than

the less electrophilicity aromatic imines derived from aromatic aldehydes to afford the

desired α-branched amines in higher yields and trace amount of triarylmethane as a

side product. Moreover, the reaction of N-Boc protected pyrrole was occured

compound III-12a as a side product (entries 27-28).

122

Table 4-7 Reaction of various arenes, tert-butyl carbamate with benzaldehyde,

2-methylpropanal under the optimized reaction condition.a

Ar-H


III-2III-1

R-CHOArAr

R+


+

Het-H

R = aryl or alkyl

+HN O

O

Ar H


III-3H2N O

O

FeCl3.6H2O (5 mol%)

Entry Ar-H Time

(h)

Products Yieldsb

(%)

1 OMe

MeO

OMe

24 HN O

O

MeO

OMe

MeO

67

OMe

MeO

OMe OMe

OMe

OMe

32

2 24 56c 44

c


3

O

III-1c

2 HN O

O

O

72 O O

4

4 2 64c 36

c

III-8b III-9b

5 24 HN O

O

ONO2

66d

O O

NO2

4d

III-8c III-9c

6

O

2 HN O

O

O

65d

O O

17d

7 2 29c 70

c

III-1d III-8d III-9d

123


Entry Ar-H Time

(h)

Products Yieldsb

(%)

8

S

3 HN O

O

S

22d S S

-d,e

9 3 57c 4

c

III-1e III-8e III-9e

10

S

2 HN O

O

S

9 S S

-e

11 2 27c -

c,e

III-1f III-8f III-9f

12 N

Boc

3 HN O

O

N

Boc

24d N N

Boc Boc

12

13 24 29c 13

III-1g III-8g III-9g

14

NH

0.5

HN O

O

HN

4f

HN NH

41f

15 2 5f 72

f

16 7 3g 27

g

17 0.28 2h 42

h

III-1h III-8h III-9h

18

OMe

MeO

OMe

24 HN O

O

MeO

OMe

MeO

63

OMe

MeO

OMe OMe

OMe

OMe

9

19 24 64c 25

c


124


Entry Ar-H Time

(h)

Products Yieldsb

(%)

20

O

24 HN O

O

O

80 OO

-e

21 24 89c -

c,e


22 O

2 HN O

O

O

96 O O

3

23 2 98c 1

c

III-1d III-10c III-11c

24

S

1 HN O

O

S

6

S S

-e

25 4 37 -c,e

III-1e III-10d III-11d

26 S

2 HN O

O

S

12 S S

-e

27 2 13 -c,e

III-1f III-10e III-11e

28

N

Boc

24 HN O

O

N

Boc

15i

N N

Boc Boc

-e,i

29 24 42

-c,e,j

III-1g III-10f III-11f



c The

reaction was carried out using FeCl3∙6H2O (5 mol%) in ClCH2CH2Cl (1 mL).d The

reaction was carried out in toluene (1.5 mL). e No reaction based on TLC analysis.

f The reaction was carried out in toluene (15 mL) at 0

oC.

g The reaction was carried

125

out using FeCl3∙6H2O (10 mol%) in toluene (15 mL) at -40 oC to room temperature.

h The reaction was carried out in ClCH2CH2Cl (15 mL) at 0

oC.

i The reaction was

carried out in toluene (1.5 mL) and gave (syn or anti)-III-12a as minor product in 5%

(0.0123 g). j The reaction gave (syn or anti)-III-12a as minor product in 34% (0.0868 g).

On the basis of the literature information (Li et al., 2008; Thirupathi & Kim,

2010; Thirupathi, Neupane, & Lee, 2011; Jaratjaroonphong, Tuengpanya, &

Ruengsangtongkul, 2015) and our experimental results, a plausible explanation of

the mechanism is depicted in Figure 4-4. The first step is the formation of I, which is

formed by coordination of the aldehyde to FeCl3∙6H2O. Condensation of I with tert-

butyl carbamate gives the resulting activated N-Boc imine II. The nucleophilic

addition of 1,2,4-trimethoxybenzene III-1b attacks the resulting imine II, leading to

the formation of the desired amine III-8a. Further, the formation of triarylmethane

III-9a could be explained by addition of a second 1,2,4-trimethoxybenzene to

the reactive intermediate IV, which is generated by Fe(III) ion catalyzed carbamate

elimination of III-8a.

126

H R

OFeIII

H2N O

O

H R

N O

OFeIII

FeIII

R

MeO

OMe

MeOH

N O

OFeIII

HN

R

MeO

OMe

MeO

O

O

FeIII +

R

MeO

OMe

MeO

NHBocFeIII

OMe

OMe

MeO

H R

O

OMe

OMe

MeOR

MeO

OMe

MeO

OMe

OMe

MeO

I

II

IIIIII-8a

IV

III-3

III-1b

III-9aIII-1b

FeIII

Figure 4-5 Plausible reaction mechanism.

127



unsymmetrical triarylmethanes

In previous work, the reaction of electron-rich arenes with a combination of

aldehydes and tert-butyl carbamate using FeCl3∙6H2O as catalyst leading to N-Boc

diarylmethylcarbamate or α-branched amine derivatives was successful. We then

studied the Friedel-Crafts reaction by using N-Boc diarylmethylcarbamates as an

alkylating agent for the efficient synthesis of unsymmetrical triarylmethanes (Figure

4-4).

Ar1 Ar2

HN O

O

Ar1

Ar3

Ar2

FeCl3.6H2O

solvent, rt

Ar3 H

-Branched amines UnsymmetricalTriarylmethanesor

N-Boc diarylmethylcarbamates

Figure 4-6 A model reaction for the synthesis of unsymmetrical triarylmethanes using

FeCl3∙6H2O as the catalyst.

2.1 Optimization of the reaction condition for Friedel-Crafts reaction of

2-methylfuran with N-Boc diarylmethylcarbamates

For initial optimization of the reaction conditions, tert-butyl phenyl(2,4,6-

trimethoxyphenyl)methylcarbamate (III-4a) or tert-butyl phenyl(2,4,5-trimethoxy-

phenyl)methylcarbamate (III-8a) with 2-methylfuran (III-1c) using FeCl3∙6H2O as

the catalyst at room temperature were chosen as model reaction for the synthesis of

unsymmetrical triarylmethanes III-13 (Figure 4-5).

128

Ar

HN O

O

O

catalyst (x mol%)

ClCH2CH2Cl, rt

Ar


OO

III-9b III-1

OAr-H



Figure 4-7 A model reaction for the synthesis of unsymmetrical triarylmethanes of

N-Boc diarylmethylcarbamate III-4a or III-8a and 2-methylfuran.

2.1.1 Reaction of 2-methylfuran with N-Boc diarylmethylcarbamate

in various catalyst

Preliminary investigation revealed that the species of catalyst had a

significant influence on the reaction of N-Boc diarylmethylcarbamate with 2-methyl-

furan. The results for the reaction of tert-butyl phenyl(2,4,6-trimethoxyphenyl)-

methylcarbamate (III-4a) with 2-methylfuran in the presence of various Lewis acid

using dichloroethane as solvent at room temperature are summarized in Table 4-8.

One of the most efficient catalysts was FeCl3∙6H2O which can be catalyzed

the reaction to afford the desired unsymmetrical triarylmethane III-13a in moderate

yield (entry 12). Moreover, the undesired product III-9b and 1,3,5-trimethoxybenzene

which might be obtained via retro aza-Friedel-Crafts reaction of the starting material

III-4a were isolated in 22% and 33%, respectively. Meanwhile, I2 gives the desired

product in moderate yield. Again, the compounds III-9b and 1,3,5-trimethoxybenzene

were also found. When the less sterically N-Boc diarylmethyl carbamate, tert-butyl-

phenyl(2,4,5-trimethoxyphenyl)methylcarbamate (III-8a) was used as alkylating

agent to react with 2-methylfuran in the presence of FeCl3∙6H2O (10 mol%),

the reaction proceed smoothly to afford the desired product III-13a in high yield

(88%). Furthermore, no side product was obtained. Base on these results, FeCl3∙6H2O

was chosen as the Lewis acid catalyst for the synthesis of unsymmetrical

triarylmethanes III-13.

129

Table 4-8 Reaction of N-Boc diarylmethylcarbamates and 2-methylfuran in various

catalysts loading.a

Ar

HN O

O

O

catalyst (x mol%)

ClCH2CH2Cl, rt

Ar


OO

III-9b III-1

OAr-H



Entry Catalyst Mol % Time

(h)


III-13 III-9b III-1

1 I2 10 24 III-13a (41) 22 III-1a (3)

2 I2 20 24 III-13a (33) 34 III-1a (30)

3 I2 40 24 III-13a (25) 36 III-1a (29)

4 Montmorillonite 50 mg 24 III-13a (18) 8 III-1a (14)

5 Montmorillonite 100 mg 24 III-13a (28) 10 III-1a (10)

6 Bi(OTf)3 10 24 III-13a (34) 27 III-1a (10)

7 In(OTf)3 10 24 III-13a (20) 12 III-1a (9)

8 In(OTf)3 20 24 III-13a (27) 9 III-1a (14)

9 In(OTf)3 40 24 III-13a (37) 39 III-1a (35)

10 AlCl3∙6H2O 1.1 eq 24 III-13a (2) trace III-1a (3)

11 FeCl3 10 24 III-13a (12) trace III-1a (11)

12 FeCl3∙6H2O 10 24 III-13a (53) 22 III-1a (33)

13 FeCl3∙6H2O 10 1 III-13b (76) - III-1b (-)

a Reaction conditions: III-4a or III-8a (0.5 mmol), III-1c (0.5 mmol) in ClCH2CH2Cl

(2 mL) at room temperature. b Isolated yields.

130

On the basis of the literature information (Jaratjaroonphong, Tuengpanya, &

Ruengsangtongkul, 2015) and our experimental results, a plausible explanation of

the mechanism is depicted in Figure 4-8. The first step is the formation of I, which is

formed by coordination of carbonyl group of N-Boc protected diarylmethyl amine to

FeCl3∙6H2O. Then, elimination of carbamate group and generated benzylic

carbocation II. The nucleophilic addition of 2-methylfuran III-1c to the resulting

carbocation II, gave the formation of the desired unsymmetrical triarylmethane

III-13a. Further, the formation of side products III-9b and III-1a could be explained

by ortho-directing, methoxy group of 2,4,6-trimethoxyphenyl ring donated ion pair to

the aromatic system in the intermediate I and follow by replacement of hydrogen at

N-H position gave the oxonium ion III. Then, Fe(III) catalyzed retro aza-Friedel-

Crafts reaction of III gave 1,3,5-trimethoxybenzene and reactive imine IV which

could then reacted with 2-methylfuran gave α-branched amine intermediate V and

followed by the formation of triarylmethane III-9b via nucleophilic addition of

2-methylfuran to intermediate VII as showed in Figure 4-5.

131

HN O

O

MeO OMe

MeO

FeCl3 6H2O

HN O

O

MeO OMe

MeO

FeIII

MeO OMe

MeO

MeO OMe

MeOO

N O

O

MeO OMe

MeO

FeIII

H

OMe

MeO OMeH

N O

O

HN O

O

O

FeIII HN O

O

FeIII

O

O

O

O

III-4a

I II

III-13a

III

III-1a

III-9b

IV

V VI VII

OIII-1c

OIII-1c

OIII-1c

Figure 4-8 Plausible reaction mechanism.

132


diarylmethylcarbamates as alkylating agent with different arene

under optimized reaction condition

Following the optimization of the reaction conditions, the aza-Friedel-Crafts

alkylation of different arenes, including five-membered heteroaromatic system such

derivatives of furan, thiophene, pyrrole and indole with various N-Boc diarylmethyl-

carbamates in the presence of FeCl3∙6H2O (10 mol%) at room temperature were

carried out to extend the scope of the reaction and the results are shown in Figure 4-9

and Table 4-9 to 4-11.

Ar1/Het

HN O

O

Ar2

Ar1/Het

III-4 = ArIII-8 = Het

III-13

Ar2 Ar2

III-9 or III-15 III-1

Ar1/Het H10 mol% FeCl3

.6H2O

ClCH2CH2Cl, rt

III-1

R R R

R = H, NO2

Ar2 H

Figure 4-9 The synthesis of unsymmetrical triarylmethane derivatives using

FeCl3∙6H2O as the catalyst.


carbamate III-4a with 2-methylfuran

From our methodology for the synthesis of α-branched amines,

the reaction of 1,3,5-trimethoxybenzene and a combination of benzaldehyde and

tert-butyl carbamate as starting material for in situ N-Boc imine preparation

in the presence of 5 mol% of FeCl3∙6H2O as catalyst, gave the formation of only

corresponding α-branched amine adduct III-4a. Therefore, we interested in the use of

these products as alkylating substrate for the C-C bond-forming reaction by reacting

with 2-methylfuran in dichloroethane using FeCl3∙6H2O (10 mol%) as catalyst.

The results presented in Table 4-9 showed that the reaction gave unsymmetrical

triarylmethane III-13a in 53% yield. However, compounds III-9b and III-1a were

also isolated as side products in 22% and 33% yields, respectively.

133

Table 4-9 Reaction of tert-butyl phenyl(2,4,6-trimethoxyphenyl)methyl carbamate

III-4a with different arene.a

HN O

O

MeO

MeO OMe

O

ClCH2CH2Cl, rt

MeO

MeO OMe


OO

OMe

OMeMeO

III-9b

III-1a

10 mol% FeCl3.6H2O

O

Arene Time

(h)


III-13a III-9b III-1a

O

1c

24 O

MeO

MeO OMe

OO

OMe

OMeMeO

53 22 33

a Reaction conditions: III-4a (0.5 mmol), III-1c (0.5 mmol) in ClCH2CH2Cl (2 mL)

at room temperature. b Isolated yields.



The scope of the reaction under the optimized conditions (Table 4-8, entry

12) was investigated by tert-butyl phenyl(2,4,5-trimethoxyphenyl)methylcarbamate

III-8a with other activated arenes in the presence of 10 mol% FeCl3∙6H2O in

dichloroethane at room temperature and the results are outlined in Table 4-10.

The reaction of tert-butyl phenyl(2,4,5-trimethoxyphenyl)methylcarbamate III-8a

with 2-methylfuran or 2-ethylfuran in dichloroethane at room temperature gave

the product III-13b and III-13c in high yields (76% and 95% yields, respectively)

(entries 1 and 2). The less reactive heteroaromatic areane, 2-methylthiophene reacted

with tert-butyl phenyl(2,4,5-trimethoxyphenyl)methylcarbamate III-8a under

134

the optimized condition at room temperature for 24 h to afford the corresponding

unsymmetrical triarylmethane III-13d in moderate yield (entry 3). Similarly, when

using 2-ethylthiophene as nucleophile was occurred unsymmetrical triarylmethane

adduct III-13e in comparable yield (entry 4). Under the same condition, when N-Boc

pyrrole was used as a nucleophile, the reaction showed steric and electronic effect that

was responsible in low yield of the desired product III-13f (33%, entry 5). As we

expected that unsymmetrical triarylmethane adduct III-14a derived from double

nucleophilic addition at C-2 and C-5 position of N-Boc pyrrole was obtaine as the side

product in 36% yield. While the reaction of N-H unprotected pyrrole, 2-ethylpyrrole,

gave unsymmetrical triarylmethane III-13g in 49% yield (entry 6). Interestingly,

the reaction of tert-butyl phenyl(2,4,5-trimethoxyphenyl)methylcarbamate III-8a with

reactive indole derivatives such as indole, 5-methoxy and 6-fluoroindole led to

selective formation of unsymmetrical triarylmethane in 93%, 96% and 80% yields,

respectively (entries 7-9).

To comparing the reactivity of heteroaromatic arenes such as furan,

thiophene, pyrrole and indole derivatives, we found that the nucleophilicity of indole

derivatives were higher reactivity than the other heteroarenes which could be reacted

with N-Boc protected diarylmethyl amines to give the resulting unsymmetrical

triarylmethanes in high to excellent yields. Moreover, indole containing fluoro and

methoxy substitutent on the 6 and 5 position, respectively, showed only slightly effect

on the yields of products. Considering the five-membered heteroaromatic arenes,

furan derivatives were more reactive than thiophene and pyrrole to give the desired

product in higher than yields another. Interestingly, the less reactive arenes such as

thiophene derivatives gave the yield of the desired unsymmetrical triarylmethanes

more than pyrrole derivatives. Therefore, indole derivatives are the most reactive

arenes, follow by furan, thiophene and pyrrole derivatives, respectively.

135

Table 4-10 Reaction of tert-butyl phenyl(2,4,5-trimethoxyphenyl)methylcarbamate

III-8a with different arene.a

HN O

O

MeO

MeO ClCH2CH2Cl, rt

III-10a III-1

10 mol% FeCl3.6H2O

OMe

Het-H

MeO

MeO

OMe

Het

III-13

Entry Het-H Time

(h)

Products Yields

(%)b

1 O

III-1c 1

OMeO

MeO

OMe

III-13b 76

2 O

III-1d 4 O

MeO

MeO

OMe

III-13c 95c

3 S

III-1e 24

SMeO

MeO

OMe

III-13d 60d

4 S

III-1f 24 S

MeO

MeO

OMe

III-13e 66c

136


Entry Het-H Time

(h)

Products Yields

(%)b

5 N

Boc

III-1g 24

NMeO

MeO

OMe

Boc

III-13f 33c,e

6 NH

III-1i 1 NH

MeO

MeO

OMe

III-13g 49d

7 NH

III-1h 12

NH

MeO

OMe

MeO

III-13h 93

8 NH

MeO

III-1j 12

NH

MeO

OMe

MeO

MeO

III-13i 96d

9 NH

F III-1k 12

NH

MeO

OMe

MeO

F

III-13j 80c

a Reaction conditions: III-8a (0.5 mmol), III-1 (0.5 mmol), FeCl3∙6H2O (10 mol%) in

ClCH2CH2Cl (2 mL) at room temperature. b Isolated yields.

c The reaction was carried

out using III-8a (0.4 mmol), III-1 (0.4 mmol), FeCl3∙6H2O (10 mol%) in

ClCH2CH2Cl (2 mL) at room temperature. d The reaction was carried out using III-8a

(0.25 mmol), III-1 (0.25 mmol), FeCl3∙6H2O (10 mol%) in ClCH2CH2Cl (2 mL) at

room temperature. e The reaction gave the mixture of syn-III-14a and anti-III-14a as

minor product which can not be separated.

137

2.2.3 Reaction of tert-butyl (5-methylfuran-2-yl)(phenyl)methylcarba-

mate III-10b or tert-butyl (5-methylfuran-2-yl)(4-nitrophenyl)-

methylcarbamate III-10k with different arenes

We then explored the synthesis of unsymmetrical triarylmethanes

containing a biological active furan ring by Friedel-Crafts reaction of N-Boc

diarylmethylcarbamate III-8b and III-8c with a collection of heteroarenes in the

presence of FeCl3∙6H2O as catalyst and investigated the effect of nitro group as

substituent on the aromatic ring at the para position. The results are summarized in

Table 4-11. The results presented in Table 4-11 showed that all the reactions gave

selective formation of unsymmetrical triarylmethane derivatives III-13k-ab. Initially,

N-Boc diarylmethylcarbamate III-8b was treated with 2-ethylfuran to provide

the product III-13k in excellent yield (entry 1). Under the same condition, when

N-Boc diarylmethylcarbamate III-8c was used, the desired product III-13l was

isolated in lower yield (59%, entry 2). The reaction of furfuryl alcohol with N-Boc

diarylmethyl-carbamate III-8b also gave the desired product III-13m in 45% yield.

On the other hand, no reaction was observed, when N-Boc diarylmethylcarbamate III-

8c was used as alkylating agent. The reaction of less reactive nucleophile such as

2-methylthiophene and 2-ethylthiophene with N-Boc diarylmethylcarbamates III-8b

or III-8c in the presence of FeCl3∙6H2O (10 mol%) gave compounds III-8b and

III-8c in moderate to high yields (entries 5-8). Both the reaction of N-Boc pyrrole

with N-Boc diarylmethylcarbamate III-8b and III-8c provided the compounds

III-13s-t in moderate yields (entries 9-10). Meanwhile, 2-ethylpyrrole reacted with

N-Boc diarylmethylcarbamates III-8b or III-8c in similar conditions gave

the corresponding unsymmetrical triarylmethanes with 12% and 11% yields,

respectively (entries 11-12). In the case of indole derivatives such as indole,

5-methoxy and 6-fluoroindole reacted with with N-Boc diarylmethylcarbamate III-8b

smoothly to afford the desired products in 85%, 87% and 86% yields, respectively

(entries 13, 15 and 17). Futhermore, changing the N-Boc diarylmethylcarbamate

III-8b to N-Boc diarylmethylcarbamate III-8c to react with indole provided

the product III-13x in moderate yield (52%, entry 13). However, the reaction of

5-methoxyindole with N-Boc diarylmethylcarbamate III-8c in the presence of

FeCl3∙6H2O (20 mol%) under dichloroethane solution gave the desired product

138

III-13z in low yield (entry 16). Similarly, the reaction of 6-fluoroindole with N-Boc

diarylmethylcarbamate III-8c provided the desired product III-13ab in 24% yield

(entry 18).

Table 4-11 Reaction of tert-butyl (5-methylfuran-2-yl)(phenyl)methylcarbamate

III-8b or tert-butyl (5-methylfuran-2-yl)(4-nitrophenyl)methylcarba-

mate III-8c with different arene.a

III-8 III-1 III-13

10 mol% FeCl3.6H2O

ClCH2CH2Cl, rt

HN O

O

O

Het

O

Het-H

R RR = H, III-10b

= NO2, III-10k

Entry Het-H

Products R Time

(h)

Yields (%)b

1

O III-1d

O

OR

H 1 III-13k (96)

2 NO2 24 III-13l (59)c

3

O

OH

III-1l

O

O

HO

R

H 24 III-13m (45)

4 NO2 24 III-13n (NR)d

5

S III-1e

S

OR

H 4 III-13o (86)

6 NO2 24 III-13p (71)

7

S III-1f

S

OR

H 4 III-13q (90)c

8 NO2 24 III-13r (74)c

139


Entry Het-H

Products R Time

(h)

Yields (%)b

9 N

Boc

III-1g

NBoc

OR

H 24 III-13s (58)c

10 NO2 24 III-13t (56)d

11

NH

III-1i NH

OR

H 24 III-13u (12)

12 NO2 57 III-13v (11) e

13 NH

III-1h

NH

OR

H 24 III-13w (85)

14 NO2 24 III-13x (52)f

15

NH

MeO

III-1j

NH

O

MeO

R

H 1 III-13y (87)

16 NO2 27 III-13z (24)g

17

NH

F III-1k

NH

O

F

R

H 24 III-13aa (86)h

18 NO2 24 III-13ab (24)i

a Reaction conditions: III-8 (0.25 mmol), III-1 (0.25 mmol), FeCl3∙6H2O (10 mol%)

in ClCH2CH2Cl (2 mL) at room temperature. b Isolated yields.

c The reaction was

carried out using III-8 (0.25 mmol), III-1 (0.25 mmol), FeCl3∙6H2O (10 mol%) in

ClCH2CH2Cl (1 mL) at room temperature. d

The reaction was carried out using III-8

(0.2 mmol), III-1 (0.2 mmol), FeCl3∙6H2O (10 mol%) in ClCH2CH2Cl (1 mL) at

room temperature. e

The reaction was carried out using FeCl3∙6H2O (30 mol%) at

room temperature to 70 oC.

f The reaction was carried out using III-8 (0.4 mmol), III-

140

1 (0.4 mmol), FeCl3∙6H2O (10 mol%) in ClCH2CH2Cl (2 mL) at room temperature. g

The reaction was carried out using FeCl3∙6H2O (20 mol%). h The reaction was carried

out using III-8 (0.3 mmol), III-1 (0.3 mmol), FeCl3∙6H2O (10 mol%) in ClCH2CH2Cl

(2 mL) at room temperature. i The reaction was carried out using III-8 (0.5 mmol),

III-1 (0.5 mmol), FeCl3∙6H2O (10 mol%) in ClCH2CH2Cl (2 mL) at room

temperature.


diarylmethylcarbamate as alkylating agent with indole under

optimized reaction condition

Base on the optimization conditions, the Friedel-Crafts reaction of wide

range a biologically active indole with various N-Boc diarylmethylcarbamate in the

presence of FeCl3∙6H2O (10 mol%) leading to the unsymmetrical triarylmethane

containing indole ring was then carried out. The results are shown in Table 4-12.

As the results, the reaction of tert-butyl phenyl(2,4,5-trimethoxyphenyl)-

methylcarbamate III-8a with indole in dichloroethane at room temperature for 12 h

proceeded smoothly to provide the product III-13h in excellent yield (93%, entry 1).

Under the same condition, when tert-butyl (5-methylfuran-2-yl)(phenyl)methyl-

carbamate III-8b was used as an alkylating agent, the desired product III-13w was

obtained in 85% (entry 2). Gratifyingly, the less reactive alkylating agent of

tert-butyl-(5-methyl-thiophen-2-yl)(phenyl)methylcarbamate also gave expected

product in excellent yield (94%, entry 3). The reaction of sterically alkylating agent,

tert-butyl 2-((tert-butoxycarbonyl-amino)(phenyl)methyl)-1H-pyrrole-1-carboxylate

with indole also afforded the corresponding unsymmetrical triarylmethane III-13ad in

moderate yield (60%, entry 4).

141

Table 4-12 Reaction of various N-Boc diarylmethylcarbamate as alkylating agent

with indole.a

III-8 III-1h III-13

10 mol% FeCl3.6H2O

ClCH2CH2Cl, rtAr

HN O

O

ArNH

NH

Entry III-8 Time

(h)

Products Yields

(%)b

1

HN

MeO

OMe

MeO

O

O

III-8a 12

NH

MeO

OMe

MeO

III-13h 93

2 HN

O

O

O

III-8b 24

NH

O

III-13w 85c

3 HN

O

O

S

III-8e 24

NH

S

III-13ac 94

4 HN

O

O

N

Boc

III-8g 24

NH

N

Boc

III-13ad 60

a Reaction conditions: III-8 (0.5 mmol), III-1h (0.5 mmol), FeCl3∙6H2O (10 mol%) in

ClCH2CH2Cl (2 mL) at room temperature. b Isolated yields.

c The reaction was carried

out using III-8 (0.25 mmol), III-h (0.25 mmol), FeCl3∙6H2O (10 mol%) in

ClCH2CH2Cl (2 mL) at room temperature.

142

Conclusions

1. The synthesis of α-branched amine derivatives using FeCl3∙6H2O as catalyst.

We have developed a simple, and efficient procedure for the preparation of

N-Boc protected α-branched amine derivatives through one-pot three-components

aza-Friedel-Crafts reactions of arenes with a combination of aldehydes, and tert-butyl

carbamate using FeCl3∙6H2O (5 mol%) as catalyst in toluene and dichloroethane at

room temperature. Mild reactions conditions low, catalyst loading, and one-step

synthesis are advantages of the present procedure.

III-1

Ar1-HHN

Ar1 Ar2/ Het/ R2or

Het-H

Ar2/ Het/ R2CHO

III-4 Ar = arylIII-6 Het = heteroylIII-7 R = alkyl

+

III-2

H2N O

O



III-3

O

O

Figure 4-10 The synthesis of α-branched amine derivatives using FeCl3∙6H2O as

catalyst

2. The synthesis of unsymmetrical triarylmethane derivatives.

We have developed a simple and practical method for the synthesis of

unsymmetrical triarylmethanes via Friedel-Crafts reaction of electron-rich hetero-

aromatic arenes with various N-Boc diarylmethylcarbamates as alkylating agent using

FeCl3∙6H2O (10 mol%) as catalyst in dichloroethane at room temperature. Typically,

the corresponding unsymmetrical triarylmethanes were obtained in low to high yields.

The use of mild reaction conditions, low catalytic loading, less expensive, readily

available, and environmentally benign iron catalyst and high selective synthesis are

advantages of the present procedure.

143

Ar1 Ar2

HN O

O

Ar1

Ar3

Ar2FeCl3

.6H2O (10 mol%)

ClCH2CH2Cl, rt

Ar3 H

III-4 or III-8 III-1 III-13

Figure 4-11 The synthesis of unsymmetrical triaylmethane derivatives using

FeCl3∙6H2O as catalyst

Compound characterizations

All products were characterized by spectroscopic methods (NMR, IR, and HRMS)

Spectral data of α-branched amine derivatives

HN

O

OMeO

MeO OMe

Figure 4-12 Structure of tert-butyl[(2,4,6-trimethoxyphenyl)phenylmethyl]carbamate

III-4a

Compound III-4a: A white solid; m.p. 132-133 oC; Rf = 0.27 (2:8 EtOAc/

hexane); 1

H NMR (400 MHz, CDCl3): δ 7.26-7.24 (m, 4H, ArH), 7.17-7.16 (m, 1H,

ArH), 6.60 (d, J = 10.2 Hz, 1H, NH), 6.27 (d, J = 10.2 Hz, 1H, CHPh), 6.17 (s, 2H,

ArH), 3.83 (s, 3H, OCH3), 3.79 (s, 6H, 2xOCH3), 1.48 (s, 9H, 3xCH3); 13

C NMR (100

MHz, CDCl3): δ 160.6 (C), 158.6 (C), 155.7 (C), 143.6 (C), 127.9 (CH), 126.1 (CH),

125.9 (CH), 111.2 (C), 91.2 (CH), 79.0 (C), 55.9 (OCH3), 55.4 (OCH3), 48.2 (CHPh),

28.6 (CH3); IR (film): νmax 3456 (N-H), 2975, 2939, 2840, 1713, 1593, 1494, 1455,

1419, 1365, 1234, 1205, 1154, 1127, 1042, 1017, 951 cm-1

; HRMS (ESI-TOF) calcd

for C21H27NO5Na [M+Na]+ 396.1787, found 396.1782.

144

HN

O

OMeO

MeOOMe F

Figure 4-13 Structure of tert-butyl (2-fluorophenyl)(2,4,6-trimethoxyphenyl)methyl-

carbamate III-4b

Compound III-4b: A white solid; m.p. 128-129 oC; Rf = 0.28 (2:8 EtOAc/

hexane); 1

H NMR (400 MHz, CDCl3):δ 7.33 (t, J = 7.7 Hz, 1H, ArH), 7.15 (q,

J = 6.1 Hz, 1H, ArH), 7.03 (t, J = 7.4 Hz, 1H, ArH), 6.93 (t, J = 9.4 Hz, 1H, ArH),

6.77 (d, J = 9.9 Hz, 1H, NH), 6.14 (s, 2H, ArH), 6.07 (d, J = 9.9 Hz, 1H, CHPh), 3.81

(s, 3H, OCH3), 3.79 (s, 6H, 2xOCH3), 1.46 (s, 9H, 3xCH3); 13

C NMR (100 MHz,

CDCl3): δ 160.7 (C), 160.5 (1J = 247.0 Hz, C-F), 158.7 (C), 155.1 (C), 130.0

(2J

= 14.0Hz, C-F), 128.2, (

3J

= 4.0 Hz, C-F), 127.9 (

3J

= 8.0 Hz, CH-F), 123.1

(4J

= 2.0 Hz, CH-F), 115.4 (

2J

= 22.0 Hz, C-F), 110.0 (C), 91.2 (CH), 79.2 (C), 55.9

(OCH3), 55.3 (OCH3), 44.0 (CHPh), 28.5 (CH3); IR (film): νmax 3457 (N-H), 2975,

2939, 1717, 1609, 1593, 1492, 1457, 1229, 1205, 1154, 1130, 1041, 757 cm-1

; HRMS

(ESI-TOF) calcd for C21H26FNO5 Na [M+Na]+ 414.1693, found 414.1687.

HN

O

OMeO

MeO OMe F

Figure 4-14 Structure of tert-butyl (4-fluorophenyl)(2,4,6-trimethoxyphenyl)methyl-

carbamate III-4c

Compound III-4c: A white solid; m.p. 119-121 oC; Rf = 0.31 (2:8 EtOAc/

hexane); 1

H NMR (400 MHz, CDCl3): δ 7.21 (dd, J = 8.1, 5.7 Hz, 2H, ArH), 6.92

(t, J = 8.7 Hz, 2H, ArH), 6.55 (d, J = 10.0 Hz, 1H, NH), 6.25 (d, J = 10.0 Hz, 1H,

CHPh), 6.17 (s, 2H, ArH), 3.83 (s, 3H, OCH3), 3.79 (s, 6H, 2xOCH3), 1.48 (s, 9H,

3xCH3); 13

C NMR (100 MHz, CDCl3): δ 161.7 (1J = 242.0 Hz, C-F), 161.0 (C), 158.7

145

(C), 155.9 (C), 139.6 (4J = 2.0 Hz, C-F), 127.8 (

3J = 8.0 Hz, CH-F), 114.8

(2J = 21.0 Hz, CH-F), 111.2 (C), 91.5 (CH), 79.4 (C), 56.2 (OCH3), 55.6 (OCH3),

48.0 (CHPh), 28.8 (CH3); IR (film): νmax 3455 (N-H), 2975, 2939, 2841, 1712, 1609,

1493, 1457, 1366, 1221, 1205, 1155, 1126, 1042, 1016, 952, 814 cm-1

; HRMS (ESI-

TOF) calcd for C21H26FNO5Na [M+Na]+ 414.1693, found 414.1687.

HN

O

OMeO

MeO OMe Cl

Figure 4-15 Structure of tert-butyl (4-chlorophenyl)(2,4,6-trimethoxyphenyl)methyl-

carbamate III-4d

Compound III-4d: A white solid; m.p. 114-115 oC; Rf = 0.36 (2:8 EtOAc/

hexane); 1

H NMR (400 MHz, CDCl3): δ 7.22-7.17 (m, 4H, ArH), 6.55 (d,

J = 10.0 Hz, 1H, NH), 6.22 (d, J = 10.0 Hz, 1H, CHPh), 6.16 (s, 2H, ArH), 3.82 (s,

3H, OCH3), 3.79 (s, 6H, 2xOCH3), 1.48 (s, 9H, 3xCH3); 13

C NMR (100 MHz,

CDCl3): δ 160.7 (C), 158.4 (C), 155.5 (C), 142.2 (C), 131.7 (C), 127.9 (CH), 127.4

(CH), 110.5 (C), 91.1 (2xCH), 79.2 (C), 55.8 (OCH3), 55.3 (OCH3), 47.7 (CHPh),

28.5 (CH3); IR (film): νmax 3455 (N-H), 2975, 2939, 2840, 1713, 1609, 1594, 1491,

1456, 1205, 1154, 1128, 1014, 750 cm-1

; HRMS (ESI-TOF) calcd for C21H27ClNO5

[M+H]+ 408.1578, found 408.1572.

HN

O

OMeO

MeO OMe Br

Figure 4-16 Structure of tert-butyl (4-bromophenyl)(2,4,6-trimethoxyphenyl)methyl-

carbamate III-4e

146

Compound III-4e: A white solid; m.p. 133-135 oC; Rf = 0.33 (2:8 EtOAc/

hexane); 1

H NMR (400 MHz, CDCl3): δ 7.35 (d, J = 8.4 Hz, 2H, ArH), 7.13

(d, J = 8.4 Hz, 2H, ArH), 6.53 (d, J = 9.9 Hz, 1H, NH), 6.21 (d, J = 9.9 Hz, 1H,


3xCH3); 13

C NMR (100 MHz, CDCl3): δ 160.7 (C), 158.4 (C), 155.6 (C), 142.8 (C),

130.9 (CH), 127.9 (CH), 119.9 (C), 110.5 (C), 91.1 (CH), 79.3 (C), 55.9 (OCH3), 55.4

(OCH3), 47.8 (CHPh), 28.5 (CH3); IR (film): νmax 3453 (N-H), 2973, 2839, 1713,

1610, 1493, 1205, 1154, 1128, 1010, 952, 814 cm-1

; HRMS (ESI-TOF) calcd for

C21H26BrNO5Na [M+Na]+ 474.0892, found 474.0887.

HN

O

OMeO

MeO OMe NO2

Figure 4-17 Structure of tert-butyl (4-nitrophenyl)(2,4,6-trimethoxyphenyl)methyl-

carbamate III-4f

Compound III-4f: A yellow solid; m.p. 161-163 oC; Rf = 0.21 (2:8 EtOAc/

hexane, 2 eluent); 1



CHPh), 6.16 (s, 2H, ArH), 3.83 (s, 6H, 2xOCH3), 3.80 (s, 3H, OCH3), 1.49 (s, 9H,

3xCH3); 13


146.4 (C), 126.6 (CH), 123.1 (CH), 109.7 (C), 91.1 (CH), 79.6 (C), 55.8 (OCH3), 55.3

(OCH3), 48.0 (CHPh), 28.4 (CH3); IR (film): νmax 3450 (N-H), 2975, 2940, 2841,

1712, 1607, 1492, 1347, 1205, 1154, 1120, 1043 cm-1


C21H27N2O7 [M+H]+ 419.1818, found 419.1815.

147

HN

O

OMeO

MeO OMe OMe

Figure 4-18 Structure of tert-butyl (4-methoxyphenyl)(2,4,6-trimethoxyphenyl)-

methylcarbamate III-4g

Compound III-4g: A white solid; m.p. 112-113 oC; Rf = 0.30 (2:8 EtOAc/



(d, J = 8.6 Hz, 2H, ArH), 6.55 (d, J = 10.2 Hz, 1H, NH), 6.27 (d, J =10.2 Hz, 1H,


OCH3), 1.48 (s, 9H, 3xCH3); 13

C NMR (100 MHz, CDCl3): δ 160.4 (C), 158.5 (C),

158.0 (C), 155.6 (C), 135.7 (C), 127.1 (CH), 113.3 (CH), 111.1 (C), 91.2 (CH), 78.9

(C), 55.9 (OCH3), 55.3 (OCH3), 55.1 (OCH3), 47.8 (CHPh), 28.5 (CH3); IR (film):

νmax 3456 (N-H), 2973, 2938, 2838, 1712, 1609, 1593, 1510, 1495, 1465, 1365, 1246,

1205, 1154, 1126, 1038, 952, 813 cm-1

; HRMS (ESI-TOF) calcd for C22H29NO6Na

[M+Na]+ 426.1893, found 426.1887.

MeO

MeO OMe

HN O

O

CO2Me

Figure 4-19 Structure of methyl 4-((tert-butoxycarbonylamino)(2,4,6-trimethoxy-

phenyl)methyl)benzoateIII-4h

Compound III-4h: A white solid; m.p. 118-120 oC; Rf = 0.20 (2:8

EtOAc/hexane); 1H NMR (400 MHz, CDCl3): δ 7.91 (d, J = 8.1 Hz, 2H, ArH), 7.31


CHPh), 6.16 (s, 2H, ArH), 3.89 (s, 3H, OCH3), 3.82 (s, 3H, OCH3), 3.77 (s, 6H,

2xOCH3), 1.48 (s, 9H, 3xCH3); 13

C NMR (100 MHz, CDCl3): δ 166.9 (C), 160.7 (C),

158.2 (C), 155.4 (C), 149.0 (C), 129.1 (CH), 127.8 (C), 125.7 (CH), 110.2 (C), 91.0

148

(CH), 79.1 (C), 55.7 (OCH3), 55.1 (OCH3), 51.7 (OCH3), 48.0 (CHPh), 28.3 (CH3);

IR (film): νmax 3453 (N-H), 2970, 2840, 1717, 1610, 1493, 1456, 1350, 1279, 1205,

1154, 1119, 1018, 951, 764 cm-1


[M+Na]+ 454.1842, found 454.1841.

MeO

MeO OMe

HN O

O

H

O

Figure 4-20 Structure of tert-butyl (4-formylphenyl)(2,4,6-trimethoxyphenyl)methyl-

carbamate III-4j

Compound III-4j: A pale yellow oil; Rf = 0.38 (4:6 EtOAc/hexane);

1H NMR (400 MHz, CDCl3): δ 9.56 (s, 1H, CHO), 7.77 (d, J = 8.0 Hz, 2H, ArH),

7.41 (d, J = 8.0 Hz, 2H, ArH), 6.64 (d, J = 9.8 Hz, 1H, NH), 6.22 (d, J = 9.8 Hz, 1H,


3xCH3); 13


151.1 (C), 134.6, (C), 129.5 (CH), 126.5 (CH), 110.2 (C), 91.1 (CH), 79.4 (C), 55.8

(OCH3), 55.3 (OCH3), 48.2 (CHPh), 28.4 (CH3); IR (film): νmax 3454 (N-H), 2974,

2939, 2840, 2735, 1715, 1704, 1607, 1495, 1456, 1206, 1043, 951, 819, 736 cm-1

;

HRMS (ESI-TOF) calcd for C22H27NO6Na [M+Na]+ 424.1736, found 424.1740.

HN

O

OMeO

MeO OMe

NHO

O

OMe

OMeMeO

Figure 4-21 Structure of tert-butyl 1,4-phenylenebis((2,4,6-trimethoxyphenyl)-

methylene)dicarbamatee III-5a

149


hexane): 1H NMR (400 MHz, CDCl3): δ 7.10 (s, 4H, ArH), 6.54 (d, J = 8.2 Hz, 2H,

2xNH), 6.25 (dd, J = 10.2, 2.2 Hz, 2H, 2xCHPh), 3.80 (s, 6H, 2xOCH3), 3.76 (s, 6H,

2xOCH3), 3.75 (s, 6H, 2xOCH3), 1.47 (s, 9H, 3xCH3), 1.46 (s, 9H, 3xCH3); 13

C NMR

(100 MHz, CDCl3): δ 160.4 (C), 158.5 (C), 155.6 (C), 141.2 (C), 125.6, (CH), 111.1

(C), 91.1 (CH), 78.9 (C), 55.9 (OCH3), 55.3 (OCH3), 48.0 (CHPh), 28.6 (CH3); IR

(film): νmax 3457 (N-H), 2974, 2938, 2840, 1713, 1609, 1593, 1495, 1456, 1365,

1233, 1205, 1154, 1124, 1042, 951, 814 cm-1


C36H48N2O10Na [M+Na]+ 691.3207, found 691.3203.

HN O

O

MeO

MeO OMeO

Figure 4-22 Structure of tert-butyl furan-2-yl(2,4,6-trimethoxyphenyl)methyl-

carbamate III-6a


hexane): 1H NMR (400 MHz, CDCl3): δ 7.29 (d, J = 5.6 Hz, 1H, CH), 6.59

(d, J = 10.2 Hz, 1H, NH), 6.24 (br s, 1H, CH), 6.17 (s, 2H, ArH), 6.12 (br d,

J = 8.2 Hz, 1H, CHPh), 5.94 (br s, 1H, CH), 3.83 (s, 3H, OCH3), 3.81 (s, 6H,

2xOCH3), 1.48 (s, 9H, 3xCH3); 13

C NMR (100 MHz, CDCl3): δ 160.8 (C), 158.8 (C),

155.8 (C), 155.3 (C), 141.2 (CH), 110.0 (CH), 108.4 (C), 105.0 (CH), 91.1 (CH), 79.2

(C), 55.9 (OCH3), 55.2 (OCH3), 43.5 (CHPh), 28.4 (CH3); IR (film): νmax 3456 (N-H),

2975, 2938, 2841, 1716, 1610, 1594, 1494, 1466, 1366, 1233, 1205, 1153, 1122,

1042, 1009, 952, 820 cm-1

; HRMS (ESI-TOF) calcd for C19H25NO6Na [M+Na]+

386.1580, found 386.1585.

150

HN O

O

MeO

MeO OMeN

Figure 4-23 Structure of tert-butyl pyridin-2-yl(2,4,6-trimethoxyphenyl)methyl-

carbamate III-6b


hexane): 1H NMR (400 MHz, CDCl3): δ 8.50 (d, J = 4.6 Hz, 1H, CH), 7.54

(t, J = 7.6 Hz, 1H, CH), 7.22 (d, J = 7.9 Hz, 1H, CH), 7.06 (br t, J = 5.9 Hz, 1H, CH),

6.63 (d, J = 9.7 Hz, 1H, NH), 6.30 (d, J = 9.7 Hz, 1H, CHPh), 6.15 (s, 2H, ArH), 3.81

(s, 3H, OCH3), 3.75 (s, 6H, 2xOCH3), 1.48 (s, 9H, 3xCH3); 13

C NMR (100 MHz,

CDCl3): δ 161.8 (C), 160.6 (C), 158.7 (C), 155.8 (C), 148.4 (CH), 135.8 (CH), 121.0

(CH), 120.7 (CH), 111.2 (C), 91.3 (CH), 78.9 (C), 55.9 (OCH3), 55.2 (OCH3), 49.6

(CHPh), 28.5 (CH3); IR (film): νmax 3455 (N-H), 2974, 2937, 2840, 1715, 1608, 1592,

1496, 1456, 1333, 1226, 1205, 1171, 1155, 1119, 1043, 1020, 951, 814, 770 cm-1

;

HRMS (ESI-TOF) calcd for C20H27N2O5 [M+H]+ 375.1920, found 375.1921.

HN

O

OMeO

MeO OMe

Figure 4-24 Structure of tert-butyl 1-(2,4,6-trimethoxyphenyl)propylcarbamate

III-7a



NH), 5.23 (q, J = 7.7 Hz, 1H, CHPh), 3.83 (s, 6H, 2xOCH3), 3.81 (s, 3H, OCH3),

1.82-1.68 (m, 2H, CH2CH3), 1.45 (s, 9H, 3xCH3), 0.83 (t, J = 7.4 Hz, 3H, CH2CH3);

13C NMR (100 MHz, CDCl3): δ 160.0 (C), 158.7 (C), 155.6 (C), 111.2 (C), 91.0

(CH), 78.5 (C), 55.8 (OCH3), 55.3 (OCH3), 47.2 (CHPh), 28.7 (CH2), 28.5 (CH3),

151

11.0 (CH3); IR (Film): νmax 3458 (N-H), 1713, 1610, 1592, 1497, 1456, 1364, 1230,

1205, 1171, 1155, 1138, 1060, 1042, 951, 814 cm-1


C17H28NO5 [M+H]+ 326.1967, found 326.1971.

HN

O

OMeO

MeO OMe

Figure 4-25 Structure of tert-butyl 1-(2,4,6-trimethoxyphenyl)pentylcarbamate

III-7b


hexane): 1H- NMR (400 MHz, CDCl3): δ 6.13 (2H, s, ArH), 5.79 (d, J = 10.2 Hz, 1H,

NH), 5.30 (1H, q, J = 8.5 Hz, CHPh), 3.83 (s, 6H, 2xOCH3), 3.81 (s, 3H, OCH3),

1.76-1.64 (m, 2H,CH2), 1.44 (s, 9H, 3xCH3), 1.30-1.25 (m, 3H, CH2CH-H), 1.15-1.13

(1H, m, CH-H), 0.85 (t, J = 7.0 Hz, 3H, CH2CH3); 13

C NMR (100 MHz, CDCl3):

δ 159.9 (C), 158.5 (C), 155.4 (C), 111.4 (C), 90.9 (CH), 78.4 (C), 55.7 (OCH3), 55.2

(OCH3), 45.7 (CHPh), 35.5 (CH2), 28.5 (CH2), 28.4 (CH3), 22.5 (CH2), 14.0 (CH3);

IR (Film): νmax 3458 (N-H), 2958, 2935, 2860, 1713, 1610, 1593, 1496, 1456, 1365,

1205, 1172, 1154, 1138, 1041, 953, 814 cm-1

; HRMS (ESI-TOF) calcd for C19H32NO5

[M+H]+ 354.2280, found 354.2275.

HN

O

OMeO

MeO OMe

Figure 4-26 Structure of tert-butyl 3-phenyl-1-(2,4,6-trimethoxyphenyl)propyl-

carbamate III-7c

Compound III-7c: A colorless oil; Rf = 0.18 (1:9 EtOAc/hexane, 2 eluent);

1H NMR (400 MHz, CDCl3): δ 7.28-7.13 (m, 2H, ArH), 7.17-7.13 (m, 3H, ArH), 6.14

152

(s, 2H, ArH), 5.86 (d, J = 10.2 Hz, 1H, NH), 5.42 (q, J = 7.6 Hz, 1H, CHPh), 3.83 (s,

6H, 2xOCH3), 3.82 (s, 3H, OCH3), 2.73-2.65 (m, 1H, CH-H), 2.51-2.43 (m, 1H,

CH-H), 2.14-2.07 (m, 1H, CH-H), 2.02-1.94 (m, 1H, CH-H), 1.46 (s, 9H, 3xCH3);


(CH), 128.6 (CH), 128.4 (CH), 125.7 (CH), 111.2 (C), 91.2 (CH), 79.0 (C), 56.1

(OCH3), 55.6 (OCH3), 46.2 (CH2), 37.8 (CHPh), 33.2 (CH2), 28.8 (CH3); IR (film):

νmax 3454 (N-H), 2969, 2939, 2835, 1172, 1609, 1592, 1495, 1455, 1365, 1260, 1204,

1151, 1119, 1043, 951, 814, 750 cm-1

; HRMS (ESI-TOF) calcd for C23H32NO5

[M+H]+ 402.2280, found 402.2275.

HN

O

OMeO

MeO OMe

Figure 4-27 Structure of tert-butyl 2-methyl-1-(2,4,6-trimethoxyphenyl)propyl-

carbamate III-7d



NH), 4.97 (t, J = 10.2 Hz, 1H, CHPh), 3.81 (s, 6H, 2xOCH3), 3.80 (s, 3H, OCH3),

2.05-1.98 (m, 1H, CHCH3), 1.42 (s, 9H, 3xCH3), 1.00 (d, J = 6.6 Hz, 3H, CHCH3),

0.69 (d, J = 6.6 Hz, 3H, CHCH3); 13

C NMR (100 MHz, CDCl3): δ 159.9 (C), 158.7

(C), 155.8 (C), 111.3 (C), 91.0 (CH), 78.4 (C), 55.8 (OCH3), 55.3 (OCH3), 51.8

(CHPh), 33.3 (CHCH3), 28.5 (CH3), 19.8 (CH3); IR (film): νmax 3458 (N-H), 2965,

2839, 1714, 1609, 1592, 1497, 1456, 1365, 1230, 1205, 1154, 1101, 1040, 1009 cm-1

;

HRMS (ESI-TOF) calcd for C18H30NO5 [M+H]+ 340.2124, found 340.2118.

153

HN O

O

MeO

MeO OMe

Figure 4-28 Structure of tert-butyl 2-ethyl-1-(2,4,6-trimethoxyphenyl)butylcarbamate

III-7e




1.88-1.66 (m, 2H, CH2CH3), 1.63-1.49 (m, 1H, CHCH3), 1.43 (s, 9H, 3xCH3),

1.17-1.13 (m, 2H, CH2CH3), 0.90 (t, J = 7.2 Hz, 3H, CH2CH3), 0.73 (d, J = 7.4 Hz,

3H, CH2CH3); 13

C NMR (100 MHz, CDCl3): δ 159.8 (C), 158.8 (C), 155.6 (C), 111.6

(C), 91.0 (CH), 78.3 (C), 55.8 (OCH3), 55.2 (OCH3), 48.2 (CHPh), 44.6 (CHCH3),

28.5 (CH3), 21.5 (CH2CH3), 21.2 (CH2CH3), 10.4 (CH2CH3), 10.3 21.5 (CH2CH3); IR

(film): νmax 3458 (N-H), 2964, 2938, 2876, 2839, 1715, 1610, 1497, 1457, 1365,

1220, 1205, 1155, 1040, 1009, 951, 876, 814 cm-1

.

HN

O

OMeO

MeO OMe

Figure 4-29 Structure of tert-butyl 3-methyl-1-(2,4,6-trimethoxyphenyl)butyl-

carbamate III-7f

Compound III-7f: A white solid; m.p. 91-93 oC; Rf = 0.30 (2:8 EtOAc/


NH), 5.41 (q, J = 7.7 Hz, 1H, CHPh), 3.83 (s, 6H, 2xOCH3), 3.80 (s, 3H, OCH3),

1.70-1.63 (m, 1H, CH-H), 1.57-1.48 (m, 1H, CH-H), 1.44 (m, 10H, CHCH3 and

3xCH3), 0.95 (d, J = 6.5 Hz, 3H, CH3), 0.90 (d, J = 6.5 Hz, 3H, CH3); 13

C NMR

(100 MHz, CDCl3): δ 159.9 (C), 158.4 (C), 155.3 (C), 111.8 (C), 90.9 (CH), 78.4 (C),

154

55.7 (OCH3), 55.2 (OCH3), 45.0 (CH2), 44.1 (CHPh), 28.5 (CH3), 25.3 (CH), 22.7

(CH3); IR (film): νmax 3458 (N-H), 2957, 2840, 1712, 1610, 1593, 1496, 1456, 1365,

1219, 1205, 1155, 1110, 1042, 951, 814, 764, 750 cm-1


C19H32NO5 [M+H]+ 354.2280, found 354.2275.

MeO

MeO OMe

HN O

O

Figure 4-30 Structure of tert-butyl cyclopropyl(2,4,6-trimethoxyphenyl)methyl-

carbamate III-7g

Compound III-7g: A white solid; m.p. 105-107 oC; Rf = 0.28 (2:8 EtOAc/


NH), 4.68 (t, J = 9.7 Hz, 1H, CHPh), 3.83 (s, 3H, OCH3), 3.81 (s, 6H, 2xOCH3), 1.44

(s, 9H, 3xCH3), 1.37-1.33 (m ,1H, CH-H), 0.56-0.52 (m, 1H, CH-H), 0.44-0.41 (m,

1H, CH-H), 0.35-0.33 (m, 1H, CH-H); 13

C NMR (100 MHz, CDCl3): δ 160.0 (C),

158.3 (C), 155.6 (C), 111.6 (C), 91.0 (CH), 78.5 (C), 55.8 (OCH3), 55.3 (OCH3), 49.9

(CHPh), 28.5 (CH3), 17.0 (CHCH2), 3.7 (CH2), 3.1 (CH2); IR (film): νmax 3460

(N-H), 1712, 1610, 1593, 1495, 1456, 1205, 1154, 1111, 1041, 1017, 957, 814 cm-1

;


MeO

MeO OMe

HN O

O

Figure 4-31 Structure of tert-butyl cyclopentyl(2,4,6-trimethoxyphenyl)methyl-

carbamate III-7h

Compound III-7h: A white solid; m.p. 116-118 oC; Rf = 0.36 (2:8 EtOAc/


155

NH), 5.12 (t, J = 10.4 Hz, 1H, CHPh), 3.83 (s, 3H, OCH3), 3.81 (s, 6H, 2xOCH3),

2.38-2.32 (m, 1H, CHCH2), 1.76-1.68 (m, 2H, CH2), 1.61-1.56 (m, 1H, CH-H),

1.54-1.43 (m, 12H, 3xCH-H, 3xCH3), 1.27-1.20 (m, 1H, CH-H), 1.17-1.12 (m, 1H,

CH-H); 13


91.3 (CH), 78.6 (C), 56.0 (OCH3), 55.5 (OCH3), 50.0 (CHPh), 45.8 (CHCH2), 30.4

(CH2), 29.8 (CH2), 28.8 (CH3), 25.4 (2xCH2); IR (Film): νmax 3458 (N-H), 2954,

2868, 2839, 1712, 1609, 1592, 1497, 1455, 1365, 1230, 1204, 1163, 1152, 1117,

1040, 1011, 952, 814, 752 cm-1

; HRMS (ESI) calcd for C20H32NO5 [M+H]+

366.2280, found 366.2275.

HN

O

OMeO

MeO OMe

Figure 4-32 Structure of tert-butyl cyclohexyl(2,4,6-trimethoxyphenyl)methyl-

carbamate III-7i

Compound III-7i: A white solid; m.p. 138-140 oC; Rf = 0.39 (2:8 EtOAc/



1.94-1.91 (br m, 1H, CHCH2), 1.75-1.59 (br m, 4H, 2xCH2), 1.43 (s, 9H, 3xCH3),

1.26-1.04 (br m, 5H, CH-H), 0.97-0.91 (br m, 1H, CH-H); 13

C NMR (100 MHz,

CDCl3): δ 159.8 (C), 158.6 (C), 155.7 (C), 110.7 (C), 90.8 (CH), 78.3 (C), 55.7

(OCH3), 55.2 (OCH3), 50.6 (CHPh), 42.5 (CHCH2), 30.0 (CH2), 29.8 (CH2), 28.5

(CH3), 26.4 (CH2), 26.2 (2xCH2); IR (film): νmax 3458 (N-H), 2929, 2850, 1713, 1609,

1592, 1496, 1454, 1364, 1204, 1172, 1143, 1112, 1039, 1009, 951, 814, 750 cm-1

;

HRMS (ESI-TOF) calcd for C21H34NO5 [M+H]+

380.2437, found 380.2431.

156

HN

O

OMeO

MeO

OMe

Figure 4-33 Structure of tert-butyl phenyl(2,4,5-trimethoxyphenyl)methylcarbamate

III-8a


hexane); 1H NMR (400 MHz, CDCl3): δ 7.29-7.18 (m, 5H, ArH), 6.82 (s, 1H, ArH),

6.53 (s, 1H, ArH), 6.00 (br d, J = 8.0 Hz, 1H, NH), 5.67 (br d, J = 5.8 Hz, 1H, CHPh),

3.88 (s, 3H, OCH3), 3.83 (s, 3H, OCH3), 3.70 (s, 3H, OCH3), 1.46 (s, 9H, 3xCH3);

13C NMR (100 MHz, CDCl3): δ 155.7 (C), 151.6 (C), 149.3 (C), 143.3 (C), 142.8 (C),

128.5 (CH), 127.0 (CH), 126.8 (CH), 122.0 (C), 113.4 (CH), 98.8 (CH), 79.8 (C),

57.0 (OCH3), 56.7 (OCH3), 56.5 (OCH3), 55.3 (CHPh), 28.5 (CH3); IR (film): νmax

3368 (N-H), 2976, 2934, 2829, 1710, 1510, 1455, 1366, 1275, 1260, 1206, 1168,

1034, 863, 764, 750 cm-1


396.1787, found 396.1781.

OMe

MeO

OMe

OMe

MeO OMe

Figure 4-34 Structure of 5,5'-(phenylmethylene)bis(1,2,4-trimethoxybenzene) III-9a


hexane); 1

H NMR (400 MHz, CDCl3): δ 7.28-7.24 (m, 2H, ArH), 7.18 (m, 1H, ArH),

7.07 (d, J = 7.6 Hz, 2H, ArH), 6.56 (s, 2H, ArH), 6.44 (s, 2H, ArH), 6.10 (s, 1H,

CHPh), 3.90 (s, 6H, 2xOCH3), 3.68 (s, 6H, 2xOCH3), 3.65 (s, 6H, 2xOCH3);


(CH), 128.3 (CH), 126.1 (CH), 124.9 (C), 115.0 (CH), 98.8 (CH), 57.4 (OCH3), 57.0

157

(OCH3), 56.4 (OCH3), 42.9 (CHPh); IR (Film): νmax 2928, 2846, 1729, 1509, 1464,

1394, 1317, 1275, 1259, 1206, 1178, 1035, 764, 750 cm-1

; HRMS (ESI) calcd for

C25H28O6Na [M+Na]+ 447.1784, found: 447.1760.

HN

O

O

O

Figure 4-35 Structure of tert-butyl (5-methylfuran-2-yl)(phenyl)methylcarbamate

III-8b



H NMR (400 MHz, CDCl3): 7.38-7.28 (m ,5H, ArH), 5.99 (br s,

1H, NH), 5.90 (br s, 2H, 2xCH), 5.30 (br s, 1H, CHPh), 2.27 (s, 3H, CH3), 1.46 (br s,

9H, 3xCH3); 13


(C), 128.8 (CH), 127.2 (CH), 108.4 (CH), 106.4 (CH), 80.2 (C), 53.0 (CHPh), 28.7

(3xCH3), 13.9 (CH3); IR (film): νmax 3338 (N-H), 2978, 2925, 1706, 1496, 1455,

1367, 1243, 1168, 1046, 1021, 964, 879, 784, 700 cm-1


C17H21NO3Na [M+Na]+ 310.1419, found 310.1418.

O O

Figure 4-36 Structure of 5,5'-(phenylmethylene)bis(2-methylfuran) III-9b

Compound III-9b: A yellow oil; Rf = 0.56 (1:9 EtOAc/hexane); 1

H NMR

(400 MHz, CDCl3): δ 7.35-7.28 (br m, 5H, ArH), 5.91 (br d, J = 4.3 Hz, 4H, 4xCH),

5.37 (s, 1H, CHPh), 2.28 (s, 6H, 2xCH3); 13

C NMR (100 MHz, CDCl3): δ 152.8 (C),

151.4 (C), 140.0 (C), 128.39 (CH), 128.36 (CH), 126.9 (CH), 108.1 (CH), 106.0

158

(CH), 45.1 (CHPh), 13.6 (CH3); IR (film): νmax 1603, 1561, 1494, 1452, 1218, 1022,

778 cm-1

; HRMS (ESI-TOF) calcd for C17H17O2 [M+H]+ 253.1229, found 253.1223.

HN

ONO2

O

O

Figure 4-37 Structure of tert-butyl (5-methylfuran-2-yl)(4-nitrophenyl)methyl-

carbamate III-8c

Compound III-8c: A yellow oil; Rf = 0.41 (1:9 EtOAc/ hexane); 1H NMR

(400 MHz, CDCl3): δ 8.22 (d, J = 8.5 Hz, 2H, 2xArH), 7.52 (d, J = 8.5 Hz, 1H,

2xArH), 6.01 (br s, 1H, NH), 5.93 (d, J = 10.0 Hz, 2xfuryl-H), 5.41 (br s, 1H, CHPh),

2.26 (s, 3H, CH3), 1.46 (s, 9H, 3xCH3); 13

C NMR (100 MHz, CDCl3): δ 154.9 (C),

153.0 (2xC), 150.5 (C), 147.9 (C), 127.8 (2xCH), 123.8 (2xCH), 109.0 (CH), 106.5

(CH), 80.6 (C), 52.9 (CHPh), 28.4 (3xCH3), 13.5 (CH3); IR (film): νmax 3406 (N-H),

1715, 1521, 1349, 1244, 1166, 1022, 857, 788 cm-1

.

OO

NO2

Figure 4-38 Structure of 5,5'-((4-nitrophenyl)methylene)bis(2-methylfuran) III-9c

Compound III-9c: A yellow solid; m.p. 87-91 oC; Rf = 0.48 (1:9 EtOAc/

hexane); 1


(d, J = 8.7 Hz, 2H, ArH), 5.96 (br d, J = 3.0 Hz, 2H, 2xCH), 5.94 (br d, J = 3.0 Hz,

2H, 2xCH), 5.45 (s, 1H, CHPh), 2.27 (s, 6H, 2xCH3); 13


δ 152.5 (C), 151.4 (C), 147.9 (C), 147.5 (C), 129.7 (CH), 124.2 (CH), 109.3 (CH),

106.7 (CH), 45.3 (CHPh), 14.0 (CH3); IR (Film): max 2923, 1606, 1560, 1519, 1348,

159

1218, 1110, 1022, 950, 827, 781, 735 cm-1

; Compound is literature known, see:

[Chandrasekhar, S., Khatun, S., Rajesh, G. & Reddy, C. R. (2009). Tetrahedron Lett.,

50, 6693-6697].

HN

O

O

O

Figure 4-39 Structure of tert-butyl (5-ethylfuran-2-yl)(phenyl)methylcarbamate

III-8d

Compound III-8d: A yellow solid; m.p. 75-77 oC; Rf = 0.30 (1:9 EtOAc/

hexane); 1H NMR (400 MHz, CDCl3): δ 7.36-7.26 (m, 5H, ArH), 5.98 (br s, 1H, NH),

5.89 (br d, J = 3.1 Hz, 2H, 2xCH), 5.28 (br s, 1H, CHPh). 2.61 (q, J = 7.6 Hz, 2H,

CH2CH3), 1.45 (br s, 9H, 3xCH3), 1.20 (t, J = 7.6 Hz, 3H, CH2CH3); 13

C NMR

(100 MHz, CDCl3): δ 157.8 (C), 154.9 (C), 152.0 (C), 140.4 (C), 128.5 (CH), 127.5

(CH), 126.9 (CH), 107.9 (CH), 104.4 (CH), 79.9 (C), 52.8 (C), 28.4 (3xCH3), 21.4

(CH2), 12.0 (CH3): IR (film): νmax 3338 (N-H), 2976, 2935, 1705, 1496, 1455, 1367,

1246, 1168, 1046, 1013, 880, 751 cm-1

: HRMS (ESI-TOF) calcd for C18H23NO3Na

[M+Na]+ 324.1576, found 324.1579.

O O

Figure 4-40 Structure of 5,5'-(phenylmethylene)bis(2-ethylfuran) III-9d

Compound III-9d: A yellow oil; Rf = 0.58 (1:9 EtOAc/hexane); 1H NMR

(400 MHz, CDCl3): δ 7.37-7.28 (br m, 5H, ArH), 5.93 (br d, J = 2.7 Hz, 2H, 2xCH),

5.90 (br d, J = 2.7 Hz, 2H, 2xCH), 5.39 (s, 1H, CHPh), 2.64 (q, J = 7.6 Hz, 4H,

2xCH2), 1.23 (t, J = 7.6 Hz, 6H, 2xCH3); 13

C NMR (100 MHz, CDCl3): δ 157.4 (C),

160

153.0 (C), 140.4 (C), 128.6 (CH), 127.1 (CH), 108.2 (CH), 104.7 (CH), 45.4 (CHPh),

21.6 (CH2), 12.4 (CH3); IR (Film): νmax 2973, 2938, 1603, 1559, 1496, 1453, 1404,

1183, 1058, 1013, 975, 777, 731, 699 cm-1

: HRMS (ESI-TOF) calcd for C19H20O2Na

[M+Na]+ 303.1361, found 303.1292.

HN

S

O

O

Figure 4-41 Structure of tert-butyl (5-methylthiophen-2-yl)(phenyl)methylcarbamate

III-8e

Compound III-8d: A pale yellow solid; m.p. 105-109 oC; Rf = 0.39 (1:9

EtOAc/ hexane); 1

H NMR (400 MHz, CDCl3): δ 7.37-7.27 (m, 5H, ArH), 6.57-6.55

(m, 2H, 2xCH), 6.02 (br s, 1H, NH), 5.21 (br s, 1H, CHPh), 2.42 (s, 3H, CH3), 1.44

(br s, 9H, 3xCH3); 13

C NMR (100 MHz, CDCl3): δ 154.7 (C), 143.8 (C), 141.9 (C),

139.7 (C), 128.6 (CH), 127.6 (CH), 126.8 (CH), 125.3 (CH), 124.7 (CH), 80.0 (C),

54.6 (CH), 28.4 (3xCH3), 15.3 (CH3): IR (film): νmax 3357 (N-H), 2978, 2919, 1691,

1515, 1367, 1173, 1019, cm-1

; HRMS (ESI-TOF) calcd for C17H21NO2SNa [M+Na]+

326.1191, found 326.1190.

S S

Figure 4-42 Structure of 5,5'-(phenylmethylene)bis(2-methylthiophene) III-9e

Compound III-9e: A pale yellow oil; Rf = 0.59 (1:9 EtOAc/hexane);

1H NMR (400 MHz, CDCl3): δ 7.36-7.27 (m, 5H, ArH), 6.64 (br d, J = 3.4 Hz, 2H,

2xCH), 6.61 (br d, J = 3.4 Hz, 2H, 2xCH), 5.72 (s, 1H, CHPh), 2.46 (s, 3H, CH3);

13C NMR (100 MHz, CDCl3): δ 145.3 (C), 143.9 (C), 139.1 (C), 128.5 (CH), 128.4

(CH), 127.0 (CH), 125.7 (CH), 124.6 (CH), 47.9 (CHPh), 15.4 (CH3); IR (film): νmax

161

1600, 1493, 1451, 1404, 1228, 1167, 1029, 796 cm-1

; Compound is literature known,

see: [Nair, V., Abhilash, K. G., & Vidya, N. (2005). Org. Lett., 7, 5857-5859].

HN

S

O

O

Figure 4-43 Structure of tert-butyl (5-ethylthiophen-2-yl)(phenyl)methylcarbamate

III-8f

Compound III-8f: A white solid; m.p. 77-81 oC; Rf = 0.42 (1:9 EtOAc/

hexane, 2 eluent); 1H NMR (400 MHz, CDCl3): δ 7.40-7.30 (m, 5H, ArH), 6.60

(s, 2H, CH), 6.05 (br s, 1H, NH), 5.26 (br s, 1H, CHPh), 2.80 (q, J = 7.5 Hz, 2H,

CH2CH3), 1.46 (br s, 9H, 3xCH3), 1.29 (t, J = 7.5 Hz, 3H, CH2CH3); 13

C NMR

(100 MHz, CDCl3): δ 154.4 (C), 146.9 (C), 143.0 (C), 141.4 (C), 128.1 (CH), 127.2

(CH), 126.4 (CH), 124.7 (CH), 122.4 (CH), 79.5 (C), 54.2 (CHPh), 27.9 (3xCH3),

23.1 (CH2), 15.4 (CH3); IR (film): νmax 3332 (N-H), 1702, 1494, 1455, 1366, 1246,

1166, 1016, 803, 753, 699 cm-1

: HRMS (ESI-TOF) calcd for C18H23NO2SNa

[M+Na]+ 340.1347, found 340.1346.

HN O

O

N

Boc

Figure 4-44 Structure of tert-butyl 2-((tert-butoxycarbonylamino)(phenyl)methyl)-

1H-pyrrole-1-carboxylate III-8g

Compound III-8g: A pale yellow oil; Rf = 0.37 (0.5:9.5 EtOAc/ hexane,

2 eluent); 1H NMR (400 MHz, CDCl3): δ 7.90 (d, J = 8.6 Hz, 1H, NH), 7.30-7.13

(m, 5H, ArH), 6.40 (d, J = 8.6 Hz, 1H, CHPh), 6.25 (br s, 1H, CH), 6.16 (br t,

J = 3.2 Hz, 1H, CH), 5.78 (br s, 1H, CH), 1.49 (s, 9H, 3xCH3), 1.40 (s, 9H, 3xCH3);

162

13C NMR (100 MHz, CDCl3): δ 155.3 (C), 149.0 (C), 141.7 (C), 128.2 (CH), 127.0

(C), 126.6 (CH), 122.6 (CH), 114.3 (CH), 110.0 (CH), 84.2 (C), 79.6 (C), 52.4

(CHPh), 28.5 (3xCH3), 27.8 (3xCH3); IR (film): νmax 3433 (N-H), 1740, 1716, 1490,

1369, 1335, 1166, 1045, 847, 701 cm-1

: HRMS (ESI-TOF) calcd for C21H28N2O4Na

[M+Na]+ 395.1947, found 395.1946.

HN

HN

O

O

Figure 4-45 Structure of tert-butyl (1H-indol-3-yl)(phenyl)methylcarbamate III-8h

Compound III-8h: An orange solid; m.p. 131-135 oC; Rf = 0.22 (70:30:1

CH2Cl2/hexane/MeOH): 1H NMR (400 MHz, CDCl3): δ 8.08 (br s, 1H, NH), 7.55 (d,

J = 7.3 Hz, 1H, CH), 7.43-7.35 (m, 5H, ArH), 7.31-7.28 (m, 2H, CH), 7.23 (t,

J = 7.6 Hz, 1H, CH), 7.12 (t, J = 7.6 Hz, 1H, CH), 6.77 (br s, 1H, CH),), 6.24 (br d,

J = 7.2 Hz, 1H, NH), 5.25 (br s, 1H, CHPh), 1.48 (br s, 9H, 3xCH3); 13

C NMR

(100 MHz, CDCl3): δ 155.2 (C), 142.0 (C), 136.7 (C), 128.4 (CH), 127.1 (CH), 126.8

(CH), 125.9 (C), 123.2 (CH), 122.4 (CH), 119.8 (CH), 119.5 (CH), 118.0 (C), 111.3

(CH), 79.6 (C), 51.7 (CHPh), 28.4 (3xCH3); IR (film): νmax 3407, 3327, 1693, 1495,

1455, 1367, 1244, 1166, 1017, 879, 743 cm-1


C20H22N2O2Na [M+Na]+ 345.1579, found 345.1577.

HN NH

Figure 4-46 Structure of 3,3'-(phenylmethylene)bis(1H-indole) III-9h

Compound III-9h: An orange solid; m.p. 93-97 oC; Rf = 0.22 (70:30:1

CH2Cl2/hexane/MeOH): 1H NMR (400 MHz, CDCl3): δ 7.96 (br s, 1H, NH),

163

7.42-7.36 (m, 6H, ArH), 7.32-7.30 (m, 2H, CH), 7.23-7.17 (m, 3H, CH), 7.02 (t,

J = 7.5 Hz, 1H, CH), 6.69 (br d, J = 1.5 Hz, 1H, CH), 5.91(s, 1H, CHPh); 13

C NMR

(100 MHz, CDCl3): δ 144.3 (C), 136.9 (C), 129.0 (CH), 128.5 (CH), 127.3 (CH),

126.5 (C), 123.9 (CH), 122.2 (CH), 120.2, 119.8 (CH), 119.5 (CH), 111.4 (C), 40.5

(CH3); IR (Film): νmax 3414, 1601, 1492, 1456, 1417, 1337, 1265, 1217, 1152, 1093,

1010, 793, 743 cm-1

; HRMS (ESI-TOF) calcd for C23H18N2Na [M+Na]+ 345.1368,

found 345.1360.

HN O

O

MeO

OMe

MeO

Figure 4-47 Structure of tert-butyl 2-methyl-1-(2,4,5-trimethoxyphenyl)propyl-

carbamate III-10a

Compound III-10a: A white solid; m.p. 104-106 oC; Rf = 0.24 (2:8

EtOAc/hexane): 1H NMR (400 MHz, CDCl3): δ 6.68 (s, 1H, ArH), 6.52 (s, 1H, ArH),

5.47 (d, J = 8.9 Hz, 1H, NH), 4.37 (t, J = 8.9 Hz, 1H, CHPh), 3.88 (s, 3H, OCH3),

3.83 (s, 6H, 2xOCH3), 1.82-1.78 (m, 1H, CHCH3), 1.43 (s, 9H, 3xCH3), 0.98 (d,

J = 6.6 Hz, 3H, CH3), 0.75 (d, J = 6.6 Hz, 3H, CH3); 13


δ 155.5 (C), 151.0 (C), 148.2 (C), 142.4 (C), 121.5 (C), 113.6 (CH), 97.7 (CH), 78.6

(C), 58.9 (CHPh), 56.5 (OCH3), 56.0 (OCH3), 32.9 (CHCH3), 20.1 (CH3), 19.2 (CH3);

IR (film): νmax 3453 (N-H), 3327, 1699, 1508, 1466, 1365, 1206, 1172, 1038, 861,

779 cm-1

; HRMS (ESI) calcd for C18H29NO5Na [M+Na]+ 362.1943, found 362.1945.

OMe

MeO

OMe OMe

OMe

OMe

Figure 4-48 Structure of 5,5'-(2-methylpropane-1,1-diyl)bis(1,2,4-trimethoxy-

benzene) III-11a

164

Compound III-11a: A brown oil; Rf = 0.31 (4:6 EtOAc/hexane): 1H NMR

(400 MHz, CDCl3): δ 6.96 (s, 2H, 2xArH), 6.49 (s, 2H, 2x ArH), 4.20 (d, J = 11.3 Hz,

1H, CHPh), 3.86 (s, 6H, 2xOCH3), 3.84 (s, 6H, 2xOCH3), 3.78 (s, 6H, 2xOCH3),

2.52-2.46 (m, 1H, CHCH3), 0.88 (d, J = 6.4 Hz, 6H, 2xCH3), 0.75 (d, J = 6.6 Hz, 3H,

CH3); 13


113.3 (2xCH), 98.3 (2xCH), 56.8 (2xOCH3), 56.7 (2xOCH3), 56.0 (2xOCH3), 45.1

(CHPh), 30.9 (CHCH3), 21.6 (2xCH3); IR (film): νmax 1515, 1464, 1396, 1314, 1207,

1179, 1127, 876, 817, 760 cm-1

; HRMS (ESI) (m/z) calcd for C22H30O6 [M]+

390.2042, found: 390.1951.

HN

O

O

O

Figure 4-49 Structure of tert-butyl 2-methyl-1-(5-methylfuran-2-yl)propylcarbamate

III-10b

Compound III-10b: A yellow oil; Rf = 0.55 (1:9 EtOAc/hexane): 1H NMR

(400 MHz, CDCl3): δ 6.01 (br d, J = 2.1 Hz, 1H, CH), 5.88 (br d, J = 2.1 Hz, 1H,

CH), 4.89 (br d , J = 7.9 Hz, 1H, NH), 4.49 (br t, J = 7.9 Hz, 1H, CHCHCH3), 2.27 (s,

3H, CH3), 2.10-2.05 (m, 1H, CHCH3), 1.46 (s, 9H, 3xCH3), 0.94 (d, J = 6.8 Hz, 3H,

CH3), 0.88 (d, J = 6.7 Hz, 3H, CH3); 13

C NMR (100 MHz, CDCl3): δ 155.4 (C), 152.6

(C), 151.0 (C), 106.9 (CH), 105.8 (CH), 79.3 (C), 54.4 (CHCHCH3), 32.3 (CHCH3),

28.4 (3xCH3), 19.1 (CHCH3), 18.4 (CHCH3), 13.5 (CH3); IR (film): νmax 3347 (N-H),

1705, 1499, 1390, 1366, 1240, 1171, 1020, 874, 782 cm-1


for C14H24NO3 [M+H]+ 254.1756, found 254.1751.

165

HN O

O

O

Figure 4-50 Structure of tert-butyl 1-(5-ethylfuran-2-yl)-2-methylpropylcarbamate

III-10c

Compound III-10c: A yellow oil; Rf = 0.44 (1:9 EtOAc/hexane): 1H NMR

(400 MHz, CDCl3): δ 5.98 (d, J = 2.9 Hz, 1H, CH), 5.84 (d, J = 2.9 Hz, 1H, CH), 4.94

(br d , J = 8.2 Hz, 1H, NH), 4.48 (br t, J = 8.2 Hz, 1H, CHCHCH3), 2.56 (q,

J = 7.6 Hz, 2H, CH2CH3), 2.07-2.00 (m, 1H, CHCH3), 1.42 (s, 9H, 3xCH3), 1.17 (t,

J = 7.6 Hz, 3H, CH2CH3), 0.89 (d, J = 6.8 Hz, 3H, CH3), 0.84 (d, J = 6.8 Hz, 3H,

CH3); 13

C NMR (100 MHz, CDCl3): δ 156.7 (C), 155.4 (C), 152.4 (C), 106.6 (CH),

104.1 (CH), 79.2 (C), 56.0 (CHCHCH3), 32.5 (CHCH3), 28.4 (3xCH3), 21.3

(CH2CH3), 19.1 (CHCH3), 18.4 (CHCH3), 12.2 (CH2CH3); IR (film): νmax 3459

(N-H), 1705, 1498, 1392, 1367, 1244, 1172, 1010, 874, 778 cm-1

; HRMS (ESI-TOF)

calcd for C15H25NO3Na [M+ Na]+ 290.1732, found 290.1738.

O O

Figure 4-51 Structure of 5,5'-(2-methylpropane-1,1-diyl)bis(2-ethylfuran) III-11c

Compound III-11c: A yellow oil; Rf = 0.76 (1:9 EtOAc/hexane): 1H NMR

(400 MHz, CDCl3): δ 6.00 (d, J = 3.0 Hz, 2H, 2xCH), 5.88 (d, J = 3.0 Hz, 2H, 2xCH),

3.73 (d, J = 7.8 Hz, 1H, CHCHCH3), 2.63 (q, J = 7.6 Hz, 4H, 2xCH2CH3), 2.35-2.27

(m, 1H, CHCH3), 1.22 (t, J = 7.6 Hz, 6H, 2xCH2CH3), 0.90 (d, J = 6.7 Hz, 6H,

2xCH3); IR (film): νmax 3459 (N-H), 1705, 1498, 1392, 1367, 1244, 1172, 1010, 874,

778 cm-1

.

166

HN O

O

S

Figure 4-52 Structure of tert-butyl 2-methyl-1-(5-methylthiophen-2-yl)propyl-

carbamate III-10d


hexane); 1H NMR (400 MHz, CDCl3): δ 6.68 (br d, J = 2.7 Hz, 1H, CH), 6.59 (br d,

J = 2.7 Hz, 1H, CH), 4.80 (br s, 1H, NH), 4.68 (br s, 1H, CHCHCH3), 2.44 (s, 3H,

CH3), 2.04-1.99 (m, 1H, CHCH3), 1.44 (s, 9H, 3xCH3), 0.96 (d, J = 6.5 Hz, 3H, CH3),

0.94 (d, J = 6.5 Hz, 3H, CH3); 13

C NMR (100 MHz, CDCl3): δ 155.3 (C), 143.6 (C),

138.0 (C), 124.5 (CH), 124.0 (CH), 88.3 (C), 56.3 (CHCHCH3), 34.2 (CHCH3), 28.3

(3xCH3), 19.6 (CHCH3), 18.2 (CHCH3), 15.2 (CH3); IR (film): νmax 3446 (N-H),

1703, 1497, 1392, 1366, 1243, 1170, 1008, 873, 797 cm-1


for C14H23NO2SNa [M+Na]+ 292.1347, found 292.1345.

HN O

O

S

Figure 4-53 Structure of tert-butyl 1-(5-ethylthiophen-2-yl)-2-methylpropyl-

carbamate III-10e


hexane); 1H NMR (400 MHz, CDCl3): δ 6.69 (br d, J = 2.8 Hz,1H, CH), 6.62 (br d,

J = 2.8 Hz,1H, CH), 4.78 (br s, 1H, NH), 4.70 (br s,1H, CHCHCH3), 2.80 (q,

J = 7.5 Hz, 2H, CH2CH3), 2.05-2.00 (m, 1H, CHCH3), 1.45 (s, 9H, 3xCH3), 0.96 (d,

J = 6.0 Hz, 3H, CH2CH3), 0.93 (d, J = 6.0 Hz, 3H, CH2CH3); 13

C NMR (100 MHz,

CDCl3): δ 155.4 (C), 145.9 (C), 143.3 (C), 123.9 (CH), 122.7 (CH), 79.5 (C), 56.4

(CHCHCH2), 34.3 (CHCH3), 28.4 (3xCH3), 23.5 (CH2CH3), 19.7 (CHCH3), 18.2

167

(CHCH3), 15.9 (CH2CH3); IR (film): νmax 3450 (N-H), 1702, 1496, 1392, 1366, 1244,

1170, 1008, 873, 803 cm-1

; HRMS (ESI-TOF) calcd for C15H25NO2SNa [M+Na]+

306.1504, found 306.1501.

HN O

O

N

Boc

Figure 4-54 Structure of tert-butyl 2-(1-(tert-butoxycarbonylamino)-2-methylpropyl)-

1H-pyrrole-1-carboxylate III-10f

Compound III-10f: A yellow oil; Rf = 0.33 (0.5:9.5 EtOAc/ hexane,

2 eluent); 1H NMR (400 MHz, CDCl3): δ 7.12 (br s, 1H, CH), 6.11 (br s, 1H, CH),

6.06 (br d, J = 3.0 Hz, 1H, CH), 5.72 (br s, 1H, NH), 4.80 (br t, J = 8.4 Hz, 3H,

CHCHCH3), 2.16-2.08 (m, 1H, CHCH3), 1.61 (s, 9H, 3xCH3), 1.44 (s, 9H, 3xCH3),

0.94 (d, J = 6.7 Hz, 3H, CHCH3), 0.77 (d, J = 6.7 Hz, 3H, CHCH3); 13

C NMR (100

MHz, CDCl3): δ 155.6 (C), 149.6 (C), 135.2 (C), 122.0 (CH), 113.5 (CH), 109.8

(CH), 83.9 (C), 78.8 (C), 55.1 (CHCHCH3), 31.8 (CHCH3), 28.4 (3xCH3), 28.0

(3xCH3), 20.3 (CHCH3), 18.6 (CHCH3); IR (film): νmax 3437 (N-H), 1733, 1716,

1494, 1393, 1369, 1330, 1252, 1164, 1012, 848, 773, 726 cm-1

; HRMS (ESI-TOF)

calcd for C18H30N2O4Na [M+Na]+ 361.2103, found 361.2105.

N

Boc

HN

HNO

O O

O* *

Figure 4-55 Structure of (syn/anti)-tert-butyl 2,5-bis(1-(tert-butoxycarbonylamino)-

2-methylpropyl)-1H-pyrrole-1-carboxylate III-12a

Compound (syn/anti)-III-12a: A yellow oil; Rf = 0.12 (0.5:9.5 EtOAc/

hexane, 2 eluent); 1H NMR (400 MHz, CDCl3): δ 5.99 (br s, 2H, 2xCH), 5.27 (br d,

J = 9.1 Hz, 2H, 2xNH), 4.88 (br t, J = 9.1 Hz, 2H, 2xCHCHCH3), 2.03-1.96 (m, 2H,

168

2xCHCH3), 1.67 (s, 9H, 3xCH3), 1.43 (s, 18H, 6xCH3), 0.92 (d, J = 6.4 Hz, 6H,

2xCHCH3), 0.82 (d, J = 6.4 Hz, 6H, 2xCHCH3); 13


δ 156.4 (2xC), 151.8 (C), 137.1 (2xC), 111.6 (2xCH), 86.1 (C), 79.5 (2xC), 55.2

(2xCHCHCH3), 32.9 (2xCHCH3), 28.7 (6xCH3), 28.1 (3xCH3), 20.4 (2xCHCH3),

18.6 (2xCHCH3); IR (film): νmax 3440 (N-H), 1738, 1716, 1489, 1369, 1252, 1168,

1118, 1066, 1012, 848, 773, 725 cm-1

; HRMS (ESI-TOF) calcd for C27H47N3O6Na

[M+Na]+ 532.3363, found 532.3361.

N

Boc

HN

HNO

O O

O* *

Figure 4-56 Structure of (syn/anti)-tert-butyl 2,5-bis(1-(tert-butoxycarbonylamino)-

2-methylpropyl)-1H-pyrrole-1-carboxylate III-12a

Compound III-12a: A yellow solid; m.p. 143-147 oC; Rf = 0.09 (0.5:9.5

EtOAc/ hexane, 2 eluent); 1H NMR (400 MHz, CDCl3): δ 5.98 (br d, J = 10.8 Hz, 2H,

2xCH), 5.22 (br d, J = 8.8 Hz, 2H, 2xNH), 4.95 (br t, J = 8.8 Hz, 2H, 2xCHCHCH3),

1.96-1.92 (m, 2H, 2xCHCH3), 1.66 (s, 9H, 3xCH3), 1.45 (s, 18H, 6xCH3), 0.87 (d,

J = 6.4 Hz, 6H, 2xCHCH3), 0.83 (d, J = 6.4 Hz, 6H, 2xCHCH3); 13

C NMR (100

MHz, CDCl3): δ 156.5 (2xC), 151.8 (C), 137.2 (2xC), 111.0 (2xCH), 85.8 (C), 79.6

(2xC), 55.2 (2xCHCHCH3), 32.9 (2xCHCH3), 28.7 (6xCH3), 28.1 (3xCH3), 20.2

(2xCHCH3), 18.6 (2xCHCH3); IR (film): νmax 3442 (N-H), 1738, 1716, 1489, 1369,

1252, 1168, 1118, 1066, 1012, 848, 773, 725 cm-1


C27H47N3O6Na [M+Na]+ 532.3363, found 532.3360.

169

Spectral data of unsymmetrical triarylmethane derivatives

OMeO

MeO OMe

Figure 4-57 Structure of 2-methyl-5-(phenyl(2,4,6-trimethoxyphenyl)methyl)furan

III-13a

Compound III-13a: A white solid; m.p. 78-80 oC; Rf = 0.34 (0.5:9.5

EtOAc/hexane, 3 eluent); 1H NMR (400 MHz, CDCl3): δ 7.24-7.21 (m, 4H, 4xArH),

7.18-7.13 (m, 1H, ArH), 6.16 (s, 2H, 2xArH), 5.96 (s, 1H, CHPh), 5.87 (br d,

J = 2.6 Hz, 1H, furyl-H), 5.80 (br d, J = 2.6 Hz, 1H, furyl-H), 3.82 (s, 3H, OCH3),

3.66 (s, 6H, 2xOCH3), 2.26 (s, 3H, CH3); 13

C NMR (100 MHz, CDCl3): δ 160.2 (C),

159.2 (2xC), 155.2 (C), 149.9 (C), 143.1 (C), 128.5 (2xCH), 127.6 (2xCH), 125.6

(CH), 112.2 (C), 107.4 (CH), 106.0 (CH), 91.8 (2xCH), 55.9 (2xOCH3), 55.3 (OCH3),

39.7 (CHPh), 13.7 (CH3); IR (film): νmax 2938, 2838, 1606, 1590, 1494, 1455, 1417,

1223, 1204, 1149, 1116, 1059, 812, 699 cm-1

; HRMS (ESI) calcd for C21H22O4Na

[M+Na]+ 361.1416, found 361.1417.

OMe

OMeMeO

Figure 4-58 Structure of 1,3,5-trimethoxybenzene III-1a


hexane); 1H NMR (400 MHz, CDCl3): δ 6.11 (s, 3H, 3xArH), 3.79 (s, 9H, 3xOCH3).

170

OMeO

MeO

OMe

Figure 4-59 Structure of 2-methyl-5-(phenyl(2,4,5-trimethoxyphenyl)methyl)furan

III-13b

Compound III-13b: A brown solid; m.p. 58-60 oC; Rf = 0.42 (2:8 EtOAc/

hexane); 1H NMR (400 MHz, CDCl3): δ 7.32-7.28 (m, 2H, 2xArH) , 7.24-7.18 (m,

3H, 3xArH), 6.64 (s, 1H, ArH), 6.57 (s, 1H, ArH), 5.89 (br d, J = 2.4 Hz, 1H,

furyl-H), 5.80 (s, 1H, CHPh), 5.76 (d, J = 2.4 Hz, 1H, furyl-H), 3.90 (s, 3H, OCH3),

3.76 (s, 3H, OCH3) , 3.74 (s, 3H, OCH3), 2.28 (s, 3H, CH3); 13

C NMR (100 MHz,

CDCl3): δ 155.1 (C), 151.2 (C), 148.5 (C), 143.1 (C), 142.3 (C), 128.6 (2xCH), 128.2

(2xCH), 126.3 (CH), 122.4 (C), 114.1 (CH), 108.8 (CH), 105.9 (CH), 98.1 (CH), 56.8

(OCH3), 56.7 (OCH3), 56.1 (OCH3), 43.1 (CHPh), 13.6 (CH3); IR (film): νmax 2936,

2848, 2832, 1610, 1599, 1561, 1509,1464, 1453, 1397, 1316, 1177, 1210, 1036, 876,

739, 701 cm-1

; HRMS (ESI-TOF) calcd for C21H22O4Na [M+Na]+ 361.1416, found

361.1412.

OMeO

MeO

OMe

Figure 4-60 Structure of 2-ethyl-5-(phenyl(2,4,5-trimethoxyphenyl)methyl)furan

III-13c

Compound III-13c: A brown solid; m.p. 51-53 oC; Rf = 0.59 (2:8 EtOAc/

hexane); 1H NMR (400 MHz, CDCl3): δ 7.32-7.29 (m, 2H, 2xArH), 7.25-7.19 (m, 3H,

3xArH), 6.65 (s, 1H, CH), 6.58 (s, 1H, CH), 5.92 (d, J = 2.8 Hz, 1H, furyl-H), 5.82 (s,

1H, CHPh), 5.78 (d, J = 2.8 Hz, 1H, furyl-H), 3.91 (s, 3H, OCH3), 3.76 (s, 3H,

171

OCH3), 3.75 (s, 3H, OCH3), 2.64 (q, J = 7.5 Hz, 2H, CH2CH3), 1.23 (t, J = 7.5 Hz,

3H, CH2CH3); 13


(C), 143.0 (C), 142.4 (C), 128.5 (2xCH), 128.1 (2xCH), 126.2 (CH), 122.4 (C), 114.8

(CH), 108.6 (CH), 104.4 (CH), 98.1 (CH), 56.7 (OCH3), 56.6 (OCH3), 56.1 (OCH3),

43.1 (CHPh), 21.4 (CH2CH3), 12.3 (CH2CH3); IR (film): νmax 2970, 2936, 2848, 2832,

1610, 1560, 1509, 1464, 1397, 1317, 1209, 1180, 1111, 1036, 982, 876, 739, 701

cm-1

; HRMS (ESI-TOF) calcd for C22H24O4Na [M+Na]+ 375.1572, found 375.1579.

SMeO

MeO

OMe

Figure 4-61 Structure of 2-methyl-5-(phenyl(2,4,5-trimethoxyphenyl)methyl)-

thiophene III-13d


hexane); 1H NMR (400 MHz, CDCl3): δ 7.32-7.22 (m, 5H, 5xArH), 6.69 (s, 1H, CH),

5.58 (br d, J = 3.0 Hz, 1H, thienyl-H), 6.56 (s,1H, CH), 6.46 (d, J = 3.0 Hz, 1H,

thienyl-H), 5.98 (s, 1H, CHPh), 3.91 (s, 3H, OCH3), 3.75 (s, 3H, OCH3), 3.73 (s, 3H,

OCH3), 2.44 (s, 3H, CH3); 13

C NMR (100 MHz, CDCl3): δ 151.2 (C), 148.6 (C),

145.7 (C), 144.2 (C), 143.1 (C), 138.6 (C), 128.7 (2xCH), 128.2 (2xCH), 126.4 (CH),

125.9 (CH), 124.5 (CH), 124.4 (C), 114.4 (CH), 98.2 (CH), 56.9 (OCH3), 56.8

(OCH3), 56.2 (OCH3), 44.5 (CHPh), 15.4 (CH3); IR (film): νmax 2933, 2848, 1608,

1600, 1509, 1463, 1453, 1316, 1396, 1247, 1207, 1178, 1103, 1036, 979, 740, 701

cm-1

; HRMS (ESI-TOF) calcd for C21H22O3SNa [M+Na]+ 377.1187, found 377.1190.

172

SMeO

MeO

OMe

Figure 4-62 Structure of 2-ethyl-5-(phenyl(2,4,5-trimethoxyphenyl)methyl)-

thiophene III-13e

Compound III-13e: A brown solid; m.p. 84-85 oC; Rf = 0.42 (2:8 EtOAc/

hexane); 1H NMR (400 MHz, CDCl3): δ 7.34-7.25 (m, 5H, 5xArH), 6.74 (s, 1H, CH),

6.64 (d, J = 3.2 Hz, 1H, thienyl-H), 6.58 (s, 1H, CH), 6.52 (d, J = 3.2 Hz, 1H,

thienyl-H), 6.03 (s, 1H, CHPh), 3.92 (s, 3H, OCH3), 3.77 (s, 3H, OCH3), 3.76 (s, 3H,

OCH3), 2.82 (q, J = 7.5 Hz, 2H, CH2CH3), 1.31 (t, J = 7.5 Hz, 3H, CH2CH3);


143.0 (C), 128.7 (2xCH), 128.1 (2xCH), 126.3 (CH), 125.7 (CH), 124.3 (C), 122.5

(CH), 114.2 (CH), 98.0 (CH), 56.8 (OCH3), 56.7 (OCH3), 56.1 (OCH3), 44.4 (CHPh),

23.5 (CH2CH3), 15.8 (CH2CH3); IR (film): νmax 2964, 2933, 2848, 2832, 1609, 1600,

1508, 1461, 1453, 1396, 1317, 1246, 1207, 1178, 1103, 1036, 979, 739, 701 cm-1

;

HRMS (ESI-TOF) calcd for C22H24O3SNa [M+Na]+ 391.1344, found 391.1346.

NMeO

MeO

OMe

Boc

Figure 4-63 Structure of tert-butyl 2-(phenyl(2,4,5-trimethoxyphenyl)methyl)-1H-

pyrrole-1-carboxylate III-13f

Compound III-13f: A purple solid; m.p. 104-106 oC; Rf = 0.34 (2:8 EtOAc/

hexane); 1H NMR (400 MHz, CDCl3): δ 7.33 (br dd, J = 2.6, 3.1 Hz, 1H, pyrrolyl-H),

7.28-7.19 (m, 3H, 3xArH), 7.06-7.05 (m, 2H, 2xArH), 6.55 (s, 1H, CH), 6.28 (m, 2H,

CH and pyrrolyl-H), 6.08 (t, J = 4.0 Hz, 1H, pyrrolyl-H), 5.58 (d, J = 1.1 Hz, 1H,

173

CHPh), 3.90 (s, 3H, OCH3), 3.69 (s, 3H, OCH3), 3.65 (s, 3H, OCH3), 1.37 (s, 9H,

3xCH3); 13


143.8 (C), 137.6 (C), 129.7 (3x CH), 128.8 (2xCH), 126.8 (CH), 125.4 (C), 122.8

(CH), 115.8 (CH), 114.8 (CH), 110.2 (CH), 98.9 (CH), 84.1 (C), 57.3 (OCH3), 57.0

(OCH3), 56.6 (OCH3), 43.6 (CHPh), 27.8 (3xCH3); IR (film): νmax 2979, 2935, 2844,

2832, 1738, 1605, 1602, 1509, 1463, 1455, 1327, 1251, 1210, 1162, 1119, 1037, 852,

736, 702 cm-1

; HRMS (ESI-TOF) calcd for C25H29NO5Na [M+Na]+ 446.1943, found

446.1949.

NHMeO

MeO

OMe

Figure 4-64 Structure of 2-ethyl-5-(phenyl(2,4,5-trimethoxyphenyl)methyl)-1H-

pyrrole III-13g

Compound III-13g: A brown oil; Rf = 0.65 (3:7 EtOAc/ hexane); 1H NMR

(400 MHz, CDCl3): δ 7.76 (br s, 1H, NH), 7.32-7.18 (m, 5H, 5xArH), 6.66 (s, 1H,

CH), 6.55 (s,1H, CH), 5.81 (br s, 1H, pyrrolyl-H), 5.70 (s, 1H, CHPh), 5.67 (br s, 1H,

pyrrolyl-H), 3.90 (s, 3H, OCH3), 3.74 (s, 3H, OCH3), 3.69 (s, 3H, OCH3), 2.58 (q,

J = 7.6 Hz, 2H, CH2CH3), 1.21 (t, J = 7.6 Hz, 3H, CH2CH3); IR (film): νmax 3366,

2935, 2847, 1645, 1609, 1509, 1464, 1395, 1315, 1275, 1207, 1032, 933, 702 cm-1

.

NH

MeO

OMe

MeO

Figure 4-65 Structure of 3-(phenyl(2,4,5-trimethoxyphenyl)methyl)-1H-indole

III-13h

174

Compound III-13h: : A pink solid; m.p. 164-165 oC; Rf = 0.26 (2:8 EtOAc/

hexane); 1H NMR (400 MHz, CDCl3): δ 8.08 (br s, 1H, NH), 7.35-7.25 (m, 7H,

5xArH and 2xindolyl-H), 7.20 (t, J = 7.5 Hz, 1H, indolyl-H), 7.03 (t, J = 7.5 Hz, 1H,

indolyl-H), 6.70 (s, 1H, CH), 6.64 (s, 1H, CH), 6.59 (s, 1H, indolyl-H), 6.10 (s, 1H,

CHPh), 3.94 (s, 3H, OCH3), 3.78 (s, 3H, OCH3), 3.64 (s, 3H, OCH3); 13

C NMR

(100 MHz, CDCl3): δ 151.3 (C), 148.1 (C), 144.3 (C), 142.9 (C), 136.8 (C), 128.8

(2xCH), 128.0 (2xCH), 127.0 (C), 125.9 (CH), 124.5 (C), 124.0 (CH), 122.1 (C),

121.8 (CH), 119.9 (CH), 119.5 (C), 119.1 (CH), 114.6 (CH), 111.0 (CH), 98.3 (CH),

56.9 (OCH3), 56.6 (OCH3), 56.1 (OCH3), 40.9 (CHPh); IR (film): νmax 3411, 3369,

2958, 2941, 2832, 1509, 1456, 1397, 1316, 1205, 1178, 1035, 742, 702 cm-1

;

Compound is literature known, see: [Thirupathi, P. & Kim, S. S. (2005). Eur. J. Org.

Chem., 1798–1808].

NH

MeO

OMe

MeO

MeO

Figure 4-66 Structure of 5-methoxy-3-(phenyl(2,4,5-trimethoxyphenyl)methyl)-1H-

indole III-13i

Compound III-13i: A purple solid; m.p. 140-142 oC; Rf = 0.08 (3:7 EtOAc/

hexane, 3 eluent); 1H NMR (400 MHz, CDCl3): δ 7.87 (br s, 1H, NH), 7.30-7.19 (m,

6H, 5xArH and 1xindolyl-H), 6.83 (dd, J = 2.4, 8.7 Hz, 1H, indolyl-H), 6.68 (d,

J = 2.2 Hz, 1H, indolyl-H), 6.64 (s, 1H, indolyl-H), 6.59 (s, 2H, 2xArH), 5.32 (s, 1H,

CHPh), 3.91 (s, 3H, OCH3), 3.75 (s, 3H, OCH3), 3.70 (s, 3H, OCH3), 3.62 (s, 3H,

OCH3); 13


132.1 (C), 129.0 (2xCH), 128.1 (2xCH), 127.8 (C), 127.8 (C), 126.0 (CH), 124.7

(CH), 124.6 (C), 119.7 (C), 114.7 (CH), 112.1 (CH), 111.6 (CH), 102.4 (CH), 98.6

(CH), 57.1 (OCH3), 56.8 (OCH3), 56.3 (OCH3), 55.9 (OCH3), 41.0 (CHPh); IR

(film): νmax 3354, 2936, 2830, 1583, 1508, 1485, 1453, 1438, 1396, 1319, 1265, 1205,

175

1172, 1109, 1031, 831, 734, 701 cm-1


[M+Na]+ 426.1681, found 426.1697.

NH

MeO

OMe

MeO

F

Figure 4-67 Structure of 6-fluoro-3-(phenyl(2,4,5-trimethoxyphenyl)methyl)-1H-

indole III-13j

Compound III-13j: A yellow oil; Rf = 0.33 (3:7 EtOAc/ hexane); 1H NMR

(400 MHz, CDCl3): δ 8.04 (br s, 1H, NH), 7.32-7.23 (m, 5H, 5xArH), 7.14 (dd,

J = 5.4, 8.6 Hz, 1H, indolyl-H), 7.01 (dd, J = 1.7, 9.6 Hz, 1H, indolyl-H), 6.76 (td,

J = 2.1, 9.3, 1H, indolyl-H), 6.62 (s, 1H, CH), 6.61 (s, 1H, CH), 6.55, (s, 1H,

indolyl-H), 6.02 (s, 1H, CHPh), 3.92 (s, 3H, OCH3), 3.76 (s, 3H, OCH3), 3.62 (s, 3H,

OCH3); 13

C- NMR (100 MHz, CDCl3): δ 160.1 (1J = 236.0 Hz, C-F), 151.5 (C), 148.4

(C), 144.1 (C), 143.1 (C), 136.8 (3J = 12.0 Hz, C-F), 128.9 (2xCH), 128.2 (2xCH),

126.1 (CH), 124.3 (CH), 123.9 (C), 120.9 (3J = 10 Hz, CH-F), 120.1 (C), 114.7 (CH),

108.1 (2J = 24 Hz, CH-F), 98.4 (CH), 97.4 (

2J = 26 Hz, CH-F), 57.1 (OCH3), 56.8

(OCH3), 56.3 (OCH3), 41.0 (CHPh); IR (film): νmax 3421, 3362, 2936, 2833, 1626,

1608, 1600, 1508, 1456, 1396, 1320, 1249, 1206, 1140, 1035, 952, 836, 804, 736, 702

cm-1

.

O

O

Figure 4-68 Structure of 2-ethyl-5-((5-methylfuran-2-yl)(phenyl)methyl)furan

III-13k

176

Compound III-13k: A yellow oil; Rf = 0.59 (2:8 EtOAc/ hexane); 1H NMR

(400 MHz, CDCl3): δ 7.42-7.31 (m, 5H, 5xArH), 5.96 (br d, J = 3.4 Hz, 4H,

4xfuryl-H), 5.45 (s, 1H, CHPh), 2.69 (q, J = 7.5 Hz, 2H, CH2CH3), 2.33 (s, 3H, CH3),

1.28 (t, J = 7.5 Hz, 3H, CH2CH3); 13

C NMR (100 MHz, CDCl3): δ 157.2 (C), 153.0

(C), 152.7 (C), 151.4 (C), 140.1 (C), 128.4 (4xCH), 127.0 (CH), 108.2 (CH), 108.0

(CH), 106.1 (CH), 104.4 (CH), 45.2 (CHPh), 21.4 (CH2CH3), 13.6 (CH3), 12.2

(CH2CH3); IR (film): νmax 2973, 2922, 2880, 1603, 1558, 1496, 1453, 1219, 1184,

1075, 1058, 1021, 964, 954, 778, 731, 699 cm-1


C18H18O2Na [M+Na]+ 289.1204, found 289.1205.

O

ONO2

Figure 4-69 Structure of 2-ethyl-5-((5-methylfuran-2-yl)(4-nitrophenyl)methyl)furan

III-13l

Compound III-13l: A brown oil; Rf = 0.59 (2:8 EtOAc/ hexane); 1H NMR

(400 MHz, CDCl3): δ 8.20 (d, J = 8.6 Hz, 2H, 2xArH), 7.43 (d, 2H, J = 8.6 Hz,

2xArH), 5.96 (d, J = 3.3 Hz, 2H, 2xfuryl-H), 5.94 (d, J = 4.1 Hz, 2H, 2xfuryl-H), 5.46

(s, 1H, CHPh), 2.62 (q, J = 7.5 Hz, 2H, CH2CH3), 2.27 (s, 3H, CH3), 1.22 (t,

J = 7.5 Hz, 3H, CH2CH3); 13

C NMR (100 MHz, CDCl3): δ 157.9 (C), 152.1 (C),

151.1 (C), 150.9 (C), 147.6 (C), 147.1 (C), 129.4 (2xCH), 123.8 (2xCH), 108.9 (CH),

108.7 (CH), 106.3 (CH), 104.7 (CH), 44.9 (CHPh), 21.4 (CH2CH3), 13.6 (CH3), 12.2

(CH2CH3); IR (film): νmax 2974, 2938, 2880, 1717, 1605, 1560, 1520, 1348, 1217,

1182, 1110, 1016, 860, 782, 735 cm-1


[M+Na]+ 334.1055, found 334.1053.

177

O

O

HO

Figure 4-70 Structure of (5-((5-methylfuran-2-yl)(phenyl)methyl)furan-2-yl)-

methanol III-13m

Compound III-13m: A yellow oil; Rf = 0.30 (2:8 EtOAc/ hexane); 1H NMR

(400 MHz, CDCl3): δ 7.36-7.26 (m, 5H, 5xArH), 6.25 (d, J = 3.0 Hz, 1H, furyl-H),

5.98 (d, J = 3.0 Hz, 1H, furyl-H), 5.91 (br s, 1H, furyl alcohol-H), 5.88 (br d,

J = 2.8 Hz, 1H, furyl alcohol-H), 5.40 (s, 1H, CHPh), 4.57 (s, 2H, CH2OH), 2.27 (s,

3H, CH3), 1.79 (s, 1H, OH); 13

C NMR (100 MHz, CDCl3): δ 155.0 (C), 153.5 (C),

152.4 (C), 151.7 (C), 139.7 (C), 128.6 (2xCH), 128.5 (2xCH), 127.2 (CH), 108.6

(CH), 108.4 (CH), 106.2 (CH), 57.7 (CH2), 45.3 (CHPh), 13.6 (CH3); IR (film): νmax

3367 (OH), 2924, 1599, 1496, 1368, 1217, 1164, 1022, 968, 783, 735, 700 cm-1

;

HRMS (ESI-TOF) calcd for C17H16O3Na [M+Na]+ 291.0997, found 291.0992.

S

O

Figure 4-71 Structure of 2-methyl-5-((5-methylthiophen-2-yl)(phenyl)methyl)furan

III-13o

Compound III-13o: A brown oil; Rf = 0.64 (1:9 EtOAc/ hexane); 1H NMR

(400 MHz, CDCl3): δ 7.36-7.26 (m, 5H, 5xArH), 6.58 (br d, J = 3.2 Hz,1H,

thienyl-H), 6.57 (br d, J = 3.2 Hz, 1H, thienyl-H), 5.94 (br d, J = 2.9 Hz, 1H, furyl-H),

5.90 (br s, 1H, furyl-H), 5.52 (s,1H, CHPh), 2.44 (s, 3H, thienyl-CH3), 2.28 (s, 3H,

furyl-CH3); 13


(C), 139.0 (C), 128.5 (2xCH), 128.4 (2xCH), 127.0 (CH), 125.6 (CH), 124.6 (CH),

178

108.5 (CH), 106.1 (CH), 46.5(2xCHPh), 15.3 (thienyl-CH3), 13.6 (furyl-CH3); IR

(film): νmax 2920, 2858, 1717, 1634, 1600, 1560, 1494, 1452, 1219, 1167, 1022, 964,

787, 723, 699 cm-1

; HRMS (ESI-TOF) calcd for C17H16OSNa [M+Na]+ 291.0820,

found 291.0827.

S

ONO2

Figure 4-72 Structure of 2-methyl-5-((5-methylthiophen-2-yl)(4-nitrophenyl)methyl)-

furan III-13p

Compound III-13p: A brown solid; m.p. 152-154 oC; Rf = 0.33 (1:9

EtOAc/ hexane, 2 eluent); 1H NMR (400 MHz, CDCl3): δ 8.19 (d, J = 8.6 Hz, 2H,

2xArH), 7.45 (d, J = 8.6 Hz, 2H, 2xArH), 6.61 (br s, 1H, thienyl-H), 6.58 (br d,

J = 3.4 Hz, 1H, thienyl-H), 5.98 (br d, J = 2.8 Hz, 1H, furyl-H), 5.94 (br s, 1H,

furyl-H), 5.60 (s,1H, CHPh), 2.45 (s, 3H, thienyl-CH3), 2.28 (s, 3H, furyl-CH3);


129.2 (2xCH), 126.2 (CH), 124.8 (CH), 123.8 (2xCH), 109.1 (CH), 106.2 (CH), 46.1

(CHPh), 15.3 (thienyl-CH3), 13.6 (furyl-CH3), 26.3 (CH2), 26.1(2xCH2), 15.3 (CH3);

IR (film): νmax 2925, 2855, 1716, 1633, 1520, 1600, 1520, 1447, 1347, 1109, 839, 736

cm-1

; HRMS (ESI-TOF) calcd for C17H15NO3SNa [M+Na]+ 336.0670, found

336.0663.

S

O

Figure 4-73 Structure of 2-((5-ethylthiophen-2-yl)(phenyl)methyl)-5-methylfuran

III-13q

179

Compound III-13q: A yellow oil; Rf = 0.67 (2:8 EtOAc/ hexane); 1H NMR

(400 MHz, CDCl3): δ 7.37-7.28 (m, 5H, 5xArH), 6.62 (d, J = 3.3 Hz, 1H, furyl-H),

6.60 (d, J = 3.3 Hz, 1H, furyl-H), 5.96 (d, J = 2.8 Hz, 1H, thienyl-H), 5.92 (br s, 1H,

thienyl-H), 5.53 (s, 1H, CHPh), 2.80 (q, J = 7.5 Hz, 2H, CH2CH3), 2.28 (s, 3H,

furyl-CH3), 1.29 (t, J = 7.5 Hz, 3H, CH2CH3); 13

C- NMR (100 MHz, CDCl3): δ 154.4

(C), 151.6 (C), 146.7 (C), 142.8 (C), 142.0 (C), 128.5 (2xCH), 128.4 (2xCH), 127.0

(CH), 125.4 (CH), 122.7 (CH), 108.5 (CH), 106.1 (CH), 46.5 (CHPh), 23.5

(CH2CH3), 15.8 (CH2CH3), 13.7 (CH3); IR (film): νmax 2966, 2924, 1634, 1494, 1452,

1219, 1022, 785, 699 cm-1

; HRMS (ESI-TOF) calcd for C18H18OSNa [M+Na]+

305.0976, found 304.2592.

S

ONO2

Figure 4-74 Structure of 2-((5-ethylthiophen-2-yl)(4-nitrophenyl)methyl)-5-methyl-

furan III-13r

Compound III-13r: A brown oil; Rf = 0.62 (2:8 EtOAc/ hexane); 1H NMR


2xArH), 6.64 (d, J = 3.0 Hz, 1H, thienyl-H), 6.60 (d, J = 3.0 Hz, 1H, thienyl-H), 6.00

(d, J = 2.9 Hz, 1H, furyl-H), 5.94 (br s, 1H, furyl-H), 5.62 (s, 1H, CHPh), 2.81 (q,

J = 7.5 Hz, 2H, CH2CH3), 2.28 (s, 3H, furyl-CH3), 1.29 (t, 3H, J = 7.5 Hz, CH2CH3);

13C- NMR (100 MHz, CDCl3): δ 152.7 (C), 152.3 (C), 147.6 (C), 147.0 (C), 140.7

(C), 129.3 (2xCH), 126.0 (C), 123.8 (2xCH), 122.9 (CH), 109.2 (CH), 106.3 (CH),

46.2 (CHPh), 23.5 (CH2CH3), 15.8 (CH3), 13.7 (CH2CH3); IR (film): νmax 2970, 2931,

2874, 1717, 1640, 1598, 1520, 1446, 1347, 1266, 1218, 1109, 1022, 858, 839, 807,

737, 703 cm-1

; HRMS (ESI-TOF) calcd for C18H17NO3SNa [M+Na]+ 350.0827, found

350.0824.

180

NBoc

O

Figure 4-75 Structure of tert-butyl 2-((5-methylfuran-2-yl)(phenyl)methyl)-1H-

pyrrole-1-carboxylate III-13s

Compound III-13s: A yellow oil; Rf = 0.62 (1:9 EtOAc/ hexane); 1H NMR

(400 MHz, CDCl3): δ 7.33-7.25 (m, 4H, 4xArH), 7.16 (d, J = 7.4 Hz, 2H, 1xArH and

1xpyrrolyl-H), 6.10 (br t, J = 2.0 Hz, 1H, pyrrolyl-H), 6.02 (s, 1H, CHPh), 5.88 (brs,

1H, pyrrolyl-H), 5.71 (br d, J = 1.9 Hz, 1H, furyl-H), 5.64 (br d, J = 1.9 Hz, 1H,

furyl-H), 2.27 (s, 3H, furyl-CH3), 1.46 (s, 9H, 3xCH3); 13


δ 154.8 (C), 151.0 (C), 149.4 (C), 141.2 (C), 134.9 (C), 128.8 (2xCH), 128.2 (2xCH),

126.7 (CH), 122.2 (CH), 114.5 (CH), 109.8 (CH), 108.3 (CH), 106.1 (CH), 83.9 (C),

44.5 (CHPh), 27.8 (3xCH3), 13.7 (CH3); IR (film): νmax 2980, 2922, 1743, 1561,

1453, 1488, 1405, 1370, 1331, 1161, 1117, 1063, 1022, 848, 778, 728, 699 cm-1

;


NBoc

ONO2

Figure 4-76 Structure of tert-butyl 2-((5-methylfuran-2-yl)(4-nitrophenyl)methyl)-

1H-pyrrole-1-carboxylate III-13t

Compound III-13t: A brown oil; Rf = 0.70 (2:8 EtOAc/ hexane); 1H NMR


2xArH), 6.17 (s, 1H, CHPh), 6.14 (t, J = 3.2 Hz, 1H, pyrrolyl-H), 5.90 (br d,

J = 1.81 Hz, 1H, furyl-H), 5.79 (br s, 1H, furyl-H), 5.70 (br d, J = 2.7 Hz, 1H,

pyrrolyl-H), 2.27 (s, 3H, CH3), 1.46 (s, 9H, 3xCH3); 13


δ 152.7 (C), 151.6 (C), 148.8 (C), 148.6 (C), 146.6 (C), 133.3 (C), 129.4 (2xCH),

123.3 (2xCH), 122.2 (CH), 114.5 (CH), 109.8 (CH), 108.7 (CH), 106.0 (CH), 83.9

181

(C), 44.0 (CHPh), 27.7 (3xCH3), 13.5 (CH3); IR (film): νmax 2924, 2851, 1740, 1522,

1370, 1347, 1157, 1120, 849, 733 cm-1

; HRMS (ESI-TOF) calcd for C21H22N2O5Na

[M+Na]+ 405.1426, found 405.1423.

NH

O

Figure 4-77 Structure of 2-ethyl-5-((5-methylfuran-2-yl)(phenyl)methyl)-1H-pyrrole

III-13u

Compound III-13u: A brown oil; Rf = 0.50 (2:8 EtOAc/ hexane); IR (film):

νmax 3307, 2927, 1715, 1361, 1269, 1180, 735, 701 cm-1

.

NH

ONO2

Figure 4-78 Structure of 2-ethyl-5-((5-methylfuran-2-yl)(4-nitrophenyl)methyl)-1H-

pyrrole III-13v

Compound III-13v: A brown oil; Rf = 0.37 (2:8 EtOAc/ hexane); 1H NMR

(400 MHz, CDCl3): δ 8.18 (d, J = 8.6 Hz, 2H, 2xArH), 7.82 (br s, 1H, NH), 7.40 (d,

J = 8.6 Hz, 2H, 2xArH), 6.00 (d, J = 2.9 Hz, 1H, furyl-H), 5.95 (br s, 1H, furyl-H),

6.85 (br s, 1H, pyrrolyl-H), 5.75 (br t, J = 2.7 Hz, 1H, pyrrolyl-H), 5.45 (s, 1H,

CHPh), 2.61 (q, J = 7.5 Hz, 2H, CH2CH3), 2.28 (s, 3H, furyl-CH3), 1.24 (t, 3H,

J = 7.5 Hz, CH2CH3); IR (film): νmax 3411 (N-H), 1702, 1497, 1452, 1364, 1245,

1168, 1009, 747 cm-1

; HRMS (ESI-TOF) calcd for C18H18N2O3Na [M+Na]+

333.1215, found 333.1214.

182

NH

O

Figure 4-79 Structure of 3-((5-methylfuran-2-yl)(phenyl)methyl)-1H-indole III-13w

Compound III-13w: A red oil; Rf = 0.33 (1:9 EtOAc/ hexane); 1H NMR

(400 MHz, CDCl3): δ 8.02 (br s, 1H, NH), 7.43-7.25 (m, 7H, 5xArH and

2xindolyl-H), 7.20 (t, J = 7.4 Hz, 1H, indolyl-H), 7.06 (t, J = 7.4 Hz, 1H, indolyl-H),

6.80 (s, 1H, indolyl-H), 5.90 (br d, J = 2.5 Hz, 1H, furyl-H), 5.85 (d, J = 2.5 Hz, 1H,

furyl-H), 5.65 (s, 1H, CHPh), 2.29 (s, 3H, CH3); 13

C- NMR (100 MHz, CDCl3):

δ 155.1 (C), 151.2 (C), 142.2 (C), 136.6 (C), 128.6 (2xCH), 128.4 (2xCH), 126.9 (C),

126.6 (CH), 123.4 (CH), 122.1 (CH), 119.7 (CH), 119.5 (CH), 117.8 (C), 111.2 (CH),

108.2 (CH), 106.0 (CH), 42.8 (CH), 13.8 (CH3); IR (film): νmax 3417, 3059, 3027,

2921, 1602, 1561, 1494, 1456, 1416, 1338, 1218, 1095, 1021, 963, 783, 741, 700 cm-

1; HRMS (ESI-TOF) calcd for C20H17NONa [M+Na]

+ 310.1208, found 310.1209.

NH

ONO2

Figure 4-80 Structure of 3-((5-methylfuran-2-yl)(4-nitrophenyl)methyl)-1H-indole

III-13x

Compound III-13x: A yellow oil; Rf = 0.30 (3:7 EtOAc/ hexane); 1H NMR

(400 MHz, CDCl3): δ 8.18 (d, J = 8.4 Hz, 2H, 2xArH), 8.14 (s, 1H, NH), 7.41 (d,

J = 8.4 Hz, 2H, 2xArH), 7.35 (d, J = 7.9 Hz, 1H, indolyl-H), 7.22 (t, J = 7.4 Hz, 1H,

indolyl-H), 7.08 (t, J = 7.7 Hz, 1H, indolyl-H), 6.85 (s, 1H, indolyl-H), 5.93 (br s, 1H,

furyl-H), 5.90 (br d, J = 2.9 Hz, 1H, furyl-H), 5.73 (s, 1H, CHPh), 2.29 (s, 3H, CH3);


129.4 (2xCH), 126.4 (C), 123.7 (2xCH), 123.4 (CH), 122.5 (CH), 119.9 (CH), 119.4

183

(CH), 116.2 (C), 111.4 (CH), 108.8 (CH), 106.3 (CH), 42.6 (CHPh), 13.7 (CH3);

IR (film): νmax 3406, 3330, 2979, 2928, 1715, 1607, 1521, 1367, 1349, 1245, 1166,

1109, 1048, 1023, 858, 788, 715 cm-1

.

NH

O

MeO

Figure 4-81 Structure of 5-methoxy-3-((5-methylfuran-2-yl)(phenyl)methyl)-1H-

indole III-13y

Compound III-13y: A brown solid; m.p. 90-92 oC; Rf = 0.44 (3:7 EtOAc/

hexane); IR (film): νmax 3419, 2940, 2831, 1705, 1625, 1584, 1487, 1455, 1216, 1171,

1051, 1022, 787, 724, 700 cm-1


340.1313, found 310.1209. 340.1314.

NH

O

MeO

NO2

Figure 4-82 Structure of 5-methoxy-3-((5-methylfuran-2-yl)(4-nitrophenyl)methyl)-

1H-indole III-13z

Compound III-13z: A brown solid; m.p. 116-120 o

C; Rf = 0.09 (1:9 EtOAc/

hexane); 1H NMR (400 MHz, CDCl3): δ 8.18 (d, J = 8.6 Hz, 2H, 2xArH), 8.03 (br s,

1H, NH), 7.49 (d, J = 8.6 Hz, 2H, 2xArH), 7.29 (d, J = 7.6 Hz, 1H, indolyl-H), 6.87

(dd, J = 8.8, 2.2 Hz, 1H, indolyl-H), 6.81 (br s, 1H, indolyl-H), 6.76 (d, J = 2.1 Hz,

1H, indolyl-H), 5.92 (br s, 1H, furyl-H), 5.90 (br d, J = 3.0 Hz, 1H, furyl-H), 5.67 (s,

1H, CHPh), 3.76 (s, 3H, OCH3), 2.28 (s, 3H, CH3); 13


δ 154.1 (C), 153.1 (C), 151.8 (C), 149.8 (C), 131.6 (C), 129.3 (2xCH), 126.8 (C),

124.0 (CH), 123.6 (2xCH), 115.8 (C), 112.4 (CH), 112.0 (CH), 108.7 (CH), 106.2

184

(CH), 101.3 (CH), 55.8 (OCH3), 42.5 (CHPh), 13.6 (CH3); IR (film): νmax 3366,

2924, 2851, 1710, 1597, 1519, 1488 1347, 1214, 1172, 1025, 848, 731 cm-1

; HRMS

(ESI-TOF) calcd for C21H17N2O4+ [M

+-H] 361.1183, found 361.1174.

NH

O

F

Figure 4-83 Structure of 6-fluoro-3-((5-methylfuran-2-yl)(phenyl)methyl)-1H-indole

III-13aa

Compound III-13aa: A red oil; Rf = 0.48 (2:8 EtOAc/ hexane); 1H NMR

(400 MHz, CDCl3): δ 8.00 (br s, 1H, NH), 7.34-7.27 (m, 6H, 5xArH and

1xindolyl-H), 7.04 (dd, J = 9.6, 1.7 Hz, 1H, indolyl-H), 6.82 (td, J = 9.2, 2.2 Hz, 1H,

indolyl-H), 6.77 (s, 1H, indolyl-H), 5.92 (br d, J = 2.6 Hz, 1H, furyl-H), 5.84 (d,

J = 2.6 Hz, 1H, furyl-H), 5.60 (s, 1H, CHPh), 2.29 (s, 3H, CH3); 13

C NMR (100 MHz,

CDCl3): δ 160.0 (1J = 263.0 Hz, C-F), 154.9 (C), 151.3 (C), 142.0 (C), 136.5

(4J = 13.0 Hz, C-F), 128.5 (2xCH), 128.4 (2xCH), 126.7 (CH), 123.6 (CH), 123.5 (C),

120.5 (3J = 10.0 Hz, C-F), 117.9 (C), 108.3 (

2J = 22.0 Hz, CH-F), 108.2 (CH), 106.1

(CH), 97.4 (2J = 22.0 Hz, CH-F), 42.8 (CHPh), 13.7 (CH3); IR (film): νmax 3426,

3063, 3028, 2922, 1627, 1559, 1497, 1456, 1342, 1251, 1217, 1140, 1022, 952, 837,

803, 738, 724, 700 cm-1

; HRMS (ESI-TOF) calcd for C20H16FNONa [M+Na]+

328.1114, found 328.1113.

NH

O

F

NO2

Figure 4-84 Structure of 6-fluoro-3-((5-methylfuran-2-yl)(4-nitrophenyl)methyl)-1H-

indole III-13ab

185

Compound III-13ab: A brown solid; m.p. 172-176 oC; Rf = 0.24 (1:9

EtOAc/ hexane, 3 eluent); 1H NMR (400 MHz, CDCl3): δ 8.18 (d, J = 8.6 Hz, 2H,

2xArH), 8.13 (br s, 1H, NH), 7.46 (d, J = 8.6 Hz, 2H, 2xArH), 7.23 (dd, J = 5.3, 8.7

Hz, 1H, indolyl-H), 7.08 (dd, J = 9.5, 2.1 Hz, 1H, indolyl-H), 6.83 (td, J = 8.4, 1.9 Hz,

1H, indolyl-H), 6.81 (br s, 1H, indolyl-H), 5.92 (br d, J = 2.1 Hz, 1H, furyl-H), 5.88

(d, J = 3.0 Hz, 1H, furyl-H), 5.68 (s, 1H, CHPh), 2.28 (s, 3H, CH3); IR (film): νmax

3342, 2924, 2853, 1714, 1626, 1598, 1520, 1450, 1347, 1216, 1141, 1108, 1015, 952,

848, 736 cm-1

; HRMS (ESI-TOF) calcd for C20H15FN2O3Na [M+Na]+ 373.0964,

found 373.0960.

NH

S

Figure 4-85 Structure of 3-((5-methylthiophen-2-yl)(phenyl)methyl)-1H-indole

III-13ac

Compound III-13ac: A red solid; m.p. 98-100 oC; Rf = 0.50 (50:50:1

CH2Cl2/hexane/MeOH); 1H NMR (400 MHz, CDCl3): δ 8.00 (br s, 1H, NH),

7.40-7.24 (m, 7H, 5xArH and 2xindolyl-H), 7.20 (t, J = 7.6 Hz, 1H, indolyl-H), 7.05

(t, J = 7.6 Hz, 1H, indolyl-H), 6.83 (s, 1H, indolyl-H), 6.58 (br s, 2H, 2xthienyl-H),

5.82 (s, 1H, CHPh), 2.44 (s, 3H, CH3); IR (film): νmax 3418, 2917, 2858, 1618, 1560,

1493, 1456, 1417, 1338, 1220, 1095, 800, 740, 700 cm-1

.

NH

N

Boc

Figure 4-86 Structure of tert-butyl 2-((1H-indol-3-yl)(phenyl)methyl)-1H-pyrrole-1-

carboxylate III-13ad

186

Compound III-13ad: A red solid; m.p. 78-82 oC; Rf = 0.34 (0.5:9.5 EtOAc/

hexane, 4 eluent); 1H NMR (400 MHz, CDCl3): δ 7.95 (br s, 1H, NH), 7.39-7.34 (m,

3H, 3xArH), 7.30-7.26 (m, 2H, 2xArH), 7.23-7.17 (m, 4H, 4xindolyl-H), 6.54 (br s,

1H, pyrrolyl-H), 6.26 (br s, 1H, pyrrolyl-H), 6.07 (t, J = 3.2 Hz, 1H, pyrrolyl-H), 5.68

(s, 1H, CHPh), 1.34 (s, 9H, 3xCH3); 13

C NMR (100 MHz, CDCl3): δ 149.7 (C), 143.5

(C), 136.9 (C), 136.6 (C), 128.8 (2xCH), 128.1 (2xCH), 127.0 (C), 126.2 (CH), 123.4

(CH), 122.0 (CH), 121.9 (CH), 119.8 (CH), 119.3 (CH), 114.7 (CH), 111.1 (CH),

119.8 (CH), 83.7 (C), 41.9 (CHPh), 27.7 (3xCH3); IR (film): νmax 3418, 2980, 1733,

1489, 1456, 1403, 1370, 1330, 1160, 1117, 1063, 1012, 847, 739 cm-1

; HRMS (ESI-

TOF) calcd for : C24H24N2O2Na [M+Na]+ 395.1735, found 395.1732.

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194

BIOGRAPHY

Name Miss Sureeporn Ruengsangtongkul

Date of birth March 23, 1989

Place of birth Chon Buri, Thailand

Present address 52/143, Village No. 5, Nongprue sub-district,

Banglamung district, Chon Buri province

Education

2009-2012 Bachelor of Science (B.Sc.),

Faculty of Science, Burapha University,

Chonburi, Thailand

2012-2015 Master of Science (M.Sc.),

Faculty of Science, Burapha University,

Chonburi, Thailand

iron(iii) chloride hexahydrate catalyzed one-pot...

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