University of Southern California Dissertations and Theses

New organoboron based multicomponent methodologies for the synthesis of novel heterocycles

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New organoboron based multicomponent methodologies for the synthesis of novel heterocycles

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Content NEW ORGANOBORON BASED MULTICOMPONENT METHODODLOGIES
FOR THE SYNTHESIS OF NOVEL HETEROCYCLES

by
Malgorzata Myslinska

A Dissertation Presented to the
FACULTY OF THE USC GRADUATE SCHOOL
UNIVERISTY OF SOUTHERN CALIFORNIA
In Partial Fulfillment of the
Requirements for the Degree
DOCTOR OF PHILOSOPHY
(CHEMISTRY)

December 2009

Copyright 2009 Malgorzata Myslinska
ii
Dedication

This work is dedicated to my parents and my sister.

iii
Acknowledgments
I would like to gratefully acknowledge Professor Nicos A. Petasis for his
endless support and supervision. I greatly appreciate his guidance and endless
energy.
I wish to thank my committee members Professors: G. S. K. Prakash,
Robert Bau, Amy Barrios, Kyung Jung and Axel Schönthal for their time and
guidance while I completed my degree.
I would like to thank all of the members of the Petasis Research Group both
former and current, in particular Dr. Jeffrey C. Raber, Dr. Wei Huang, Dr. Rong
Yang, Dr. Jasim Uddin, Dr. Fotini Liepouri, Dr. Brad J. Douglass and Alexey N.
Butkevich, Charles Arden, Anne-Marie Finaldi who made the laboratory an
enjoyable place to work at. I wish to express my gratitude to faculty and staff of
USC Chemistry Department and Loker Hydrocarbon Institute for all of their help
and support. Finally thank you to the USC football teams and coaches for making
tough times bearable.
I would like to thank my family; my mom, dad, sister Kasia and my
grandma who are supporting me from overseas. I am grateful for their
unconditional love and sacrifices they have been making for me. Last, but not the
least, I want to thank my Jeff who has always been there for me when I needed, for
his endless love, support and fun we have together.

iv
Table of Contents
Dedication..................................................................................................................ii
Acknowledgments.................................................................................................... iii
List of Figures...........................................................................................................ix
List of Tables ............................................................................................................xi
List of Schemes.......................................................................................................xiv
Abstract.................................................................................................................xxiv
Chapter 1: Synthesis of Novel Heterocycles via Boron-based
Multicomponent Reactions ......................................................................1
1.1 Introduction 1
1.1.1 Multicomponent Reactions - General Aspects and History 1
1.2 Petasis Reaction with Boronic Acids and Boronic Acid Esters 3
1.2.1 Organoboronic Acids and Organoboronic Acids Esters- General
Aspects and Synthesis 3
1.2.2 Multicomponent Condensation between Amines, Carbonyls and
Organoboronic Acid and Esters– General Aspects and Mechanism 8
1.3 Petasis Reaction with Organotrifluoroborates 12
1.3.1 Potassium Organotrifluoroborates – General Aspects and Synthesis 12
1.3.2 Multicomponent Condensation between Amines, Carbonyls and
Potassium Organotrifluoroborates – General Aspects and Mechanism 18
1.4 Synthesis of Novel Heterocycles via Petasis Reaction 21
1.4.1 Synthesis of 2-Oxopiperazines and 3,4-Dihydro-quinoxalin-2-ones 22
1.4.2 Synthesis of Tetrahydro-1,4-benzodiazepin-3-ones and Tetrahydro-
1,4-benzodiazepin-2-ones 24
1.4.3 Synthesis of 2-Hydroxymorpholines and 1,2,3,4-Tetrahydropyrazines 29
1.4.4 Synthesis of 2H-Chromenes and 1,2-Dihydroquinolines 31
1.4.5 Synthesis of Polyhydroxy Piperidines 32
1.4.6 Synthesis of Oxazolidin-2-ones, Polyhydroxy Pyrrolidines,
Iminocyclitols, Tetrahydroxyazepan-2-ones and Amino Sugars 34
1.4.7 Synthesis of Tetrahydroisoquinolines 41
1.4.8 Synthesis of Heterocycles via Cycloaddition Processes 44
1.4.9 Synthesis of Heterocycles via Five Component Union of Petasis-Grigg
Reaction 45
1.4.10 Synthesis of Cyclic Peptides 47
1.5 Conclusion 49
v
Chapter 2: Novel One Step Synthesis of Highly Functionalized
N-Substituted Propargylamines, Their Derivatives and Other
Heterocycles via Novel Boron Based Multicomponent Reactions........50
2.1 Introduction 50
2.1.1 Importance of Propargylamines 50
2.1.2 Synthetic Approaches towards Propargylamines 52
2.2 Results and Discussion 65
2.2.1 Novel Approach to Propargylamines Using Air-Stable Potassium
Alkynyl Trifluoroborates 66
2.2.1.1 Potassium Alkynyltrifluoroborates – General Aspects and
Synthesis 66
2.2.1.2 Petasis Reaction with Potassium Organotrifluoroborates - General
Aspects and Mechanism 69
2.2.1.4 One Step Synthesis of N-Substituted Propargylamines Using
Paraformaldehyde 72
2.2.1.5 Use of Alkyl and Fluorinated-alkyl Aldehydes in the Three
Component Condensation 83
2.2.1.6 Use of Aryl Aldehydes in the Petasis Reaction with Potassium
Alkynyl Trifluoroborates 87
2.2.2 Use of Salicylaldehyde in the Three Component Reaction 89
2.2.3 Use of Glycolaldehyde Dimer in the Petasis Reaction with Potassium
Alkynyltrifluoroborates 90
2.2.4 Use of (D,L)-Glyceraldehyde in the Multicomponent Reaction 92
2.2.5 Use of Unprotected Sugars in the Three Component Condensation 94
2.2.6 Synthesis of Piperazin-2-ones 97
2.2.6.1 Synthesis of Propargylic Amino Acids and New Alkynyl
Derivatives of Piperazin-2-ones 97
2.2.7 New Four Component Reaction Based on Click Chemistry Concept 104
2.2.7.1 1,3-Dipolar Cycloaddition Processes of Azides to Alkynes 104
2.2.7.2 New Four Component Reaction with Potassium
Ethynyltrifluoroborate via Click Chemistry Approach 106
2.2.8 Synthesis of Novel N-Heterocycles from N-Substituted
Propargylamines 107
2.2.8.1 Novel N-Heterocycles via the Pauson-Khand Reaction 107
2.2.8.2 Novel N-Heterocycles via Pd-Catalyzed Borylative Cyclization 111
2.3 Conclusion 114
2.4 Experimental 115
2.4.1 General Information 115
2.4.2 Synthesis and Physical Properties 116
2.4.3 Chapter 2 NMR Spectra 160

vi
Chapter 3: Indole Synthesis ..................................................................................240
3.1 Introduction 240
3.2 Synthetic Approaches to Indoles 242
3.2.1 Indole Ring Formation via Class I Disconnection 244
3.2.1.1 Fischer Indole Synthesis 245
3.2.1.2 Fischer Indole Synthesis via Japp-Klingemann Reaction 248
3.2.1.3 Fischer Indole Synthesis via Buchwald Approach 249
3.2.1.4 Fischer Indole Synthesis via Metal Catalyzed Reaction with
Alkynes and Alkenes. 250
3.2.1.5 Indole Synthesis from N-Aryl-O-hydroxylamines 252
3.2.1.6 Gassman Indole Synthesis 253
3.2.1.7 Sugasawa Indole Synthesis 254
3.2.1.8 Bischler Indole Synthesis 255
3.2.1.9 Bartoli Indole Synthesis 256
3.2.1.10 Copper-Catalyzed Synthesis of 2,3-Disubstituted Indoles 258
3.2.1.11 Palladium-Mediated Indole Syntheses 258
3.2.1.12 Zinc triflate catalyzed indole cyclization 260
3.2.2 Formation C2-C3 Bond 261
3.2.2.1 Titatnium Mediated Indole Synthesis 261
3.2.2.2 Madelung Indole Synthesis 262
3.2.2.3 Indoles via Intramolecular Wittig Reaction 263
3.2.2.4 Palladium-Catalyzed Intramolecular Cyclization of Alkynes
and Imines 264
3.2.2.5 Indoles from o-Acylanilines - Schmid Indole Synthesiss 264
3.2.3 C-acylation of o-Aminobenzyl Anion 265
3.2.4 Disconnection IV 267
3.2.4.1 Transition Metal-Catalyzed Cyclization of N-Allyl and
N-Propargylanilines 268
3.2.4.2 Intramolecular Pd-mediated Cyclization of N-Vinyl-o-
Haloanilines 269
3.2.4.3 Palladium-Catalyzed Synthesis of 2-Aminoindoles 270
3.2.4.4 Photocyclization of N-Vinylanilines 271
3.2.4.5 Indoles via Acid Catalyzed Cyclization 272
3.2.5 Formation of N1-C2 bond 273
3.2.5.1 Leimgruber-Batcho Indole Synthesis 273
3.2.5.2 Reductive Cyclization of o,β-Dinitrostyrenes 274
3.2.5.3 Reductive Cyclization of o-Nitrobenzylcarbonyl Compounds 275
3.2.5.4 Furan Recyclizations in Indole Syntheses 277
3.2.5.5 Indoles from o-Aminophenylacetylenes 279
3.2.5.6 Hegedus Indole Synthesis 281
3.2.6 Disconnection VI 282
3.2.6.1 Hemetsberger Indole Synthesis 282
3.2.6.1 Neber Indole Synthesis 283
vii
3.2.7 Disconnection VII 284
3.2.7.1 Nenitzescu Synthesis 284
3.2.8 Ring Contractions 286
3.2.8.1 Synthesis of Indoles from Quinolines 286
3.2.9 Disconnection IX and XI 288
3.2.9.1 Natsume Indole Synthesis 289
3.2.9.2 Indoles via Electrophilic Cyclization at C-2 290
3.2.10 Indole synthesis through cycloaddition routes 291
3.2.10.1 Indoles from Pyrrole-2,3-quinodimethane Intermediates 291
3.2.10.2 Indoles from Vinylpyrroles 293
Chapter 4: Novel Approach to Indoles .................................................................295
4.1 Introduction 295
4.1.1 Importance of Indoles 295
4.2 Results and Discussion 296
4.2.1 Synthesis of 2-Amino Aryl Ketones and Aldehydes 297
4.2.1.1 Importance of 2-Amino Aryl Ketones and Aldehydes 297
4.2.1.2. Synthetic Approaches to 2-Amino Aryl Ketones and
Aldehydes 298
4.2.1.3. Synthesis of 2-Amino Aryl Ketones and Aldehydes 307
4.2.2 Synthesis of α-Anilino Amino Acids via Petasis Reaction 319
4.2.3 Novel Synthetic Approach to Indoles 337
4.3 Conclusion 352
4.4 Experimental 353
4.4.1 General Information 353
4.4.2 Synthesis and Physical Properties 354
4.4.3 Chapter 4 NMR spectra 399
Chapter 5: Novel Approach to Fused N-Heterocycles ........................................491
5.1 Introduction 491
5.1.1 Importance of Aromatic Fused N-Heterocycles 491
5.2 Results and discussion 491
5.2.1 Importance and Syntheses of 2-Amino Heteroaryl Ketones 492
5.2.2 Synthesis of α-Amino Acids via Petasis Reaction 498

viii
5.2.3 Novel Synthetic Approach to New Heterocyclic Scaffolds 506
5.2.3.1 Novel Approach to 6H-Thieno[2,3-b]pyrroles 506
5.2.3.2 New Synthesis of 4H-Thieno[3,2-b]pyrroles 509
5.2.3.3. Novel Synthesis of Benzofuro[3,2-b]pyrroles 511
5.2.3.4 New Synthetic Approach to 1,4-dihydropyrrolo[3,2-b]indoles 513
5.3 Conclusion 516
5.4 Experimental 517
5.4.1 General information 517
5.4.2 Synthesis and physical properties 518
5.4.3 Chapter 5 NMR Spectra 546
Bibliography ..........................................................................................................589
ix
List of Figures
Figure 1.1 Structures of Nifedipine and Crixivan 2
Figure 1.2 The History of Multicomponent Reactions 2
Figure 1.3 Oxygenated organoboron compounds 3
Figure 1.4 Structure of Bortezomib 4
Figure 1.5 Structure of Potassium Organotrifluoroborates 13
Figure 1.6 Syntheses of Heterocycles via Petasis Reaction 21
Figure 1.7 Structures of Piperazin-2-one and Benzopiperazinone 22
Figure 1.8 Structures of Tetrahydro-1,4-benzodiazepin-2-ones and Tetrahydro-
1,4-benzodiazepin-3-ones 25
Figure 1.9 Structures of Heterocycles Synthesized from Polyhydroxypiperidines 34
Figure 2.1 General Structure of Propargylamine 50
Figure 2.2 Examples of Biologically Active Molecules with Propargylamine
Moiety 52
Figure 2.3 Synthetic Approaches to Propargylamines 53
Figure 2.4 Propargyalamines and N-Heterocycles via Petasis Reaction with
Alkynyl Trifluoroborates 65
Figure 2.5 Retrosynthetic Route to Oxybutynin 81
Figure 2.6 Structure of Naturally Occurring Ethynyl Glycine 98
Figure 3.1 Indole Structure and Numbering 241
Figure 3.2 Examples of Indole Derivatives 242
Figure 3.3 Retrosynthetic Approaches towards the Synthesis of Indole Moiety 244
Figure 3.4 Retrosynthetic Approach to Disconnection I 245
Figure 3.5 Indole Formation Trough C2-C3 Bond 261
x
Figure 3.6 Retrosynthetic Pathway for Formation N1-C2 and C2-C3 Bonds
in Indole Synthesis 265
Figure 3.7 Indole Formation via the C3-C3a Bond 267
Figure 3.8 Retrosynthetic Approach - Disconnection V 273
Figure 3.9 Retrosynthetic Pathways to o-Aminobenzyl Ketones. 276
Figure 3.10 DisconnectionVI 282
Figure 3.11 Retrosynthetic Analysis VII 284
Figure 3.12 Disconnection IX 289
Figure 3.13 Disconnection XI 289
Figure 3.14 Disconnection X - Indole Synthesis via [2+4] Cycloaddition 291
Figure3.15 Disconnection XII 293
Figure 3.16 Disconnection XIII 293
Figure 4.1 Examples of Biologically Active Indoles 296
Figure 4.2 Heterocycles Generated from 2-Amino aryl Ketones and Aldehydes 298
Figure 4.3 Synthetic Approaches to 2-Amino Aryl Ketones and Aldehydes 299
Figure 5.1 Structures of Fused N-Heterocycles 491
Figure 5.2 Synthesis of Novel N-Heterocycles 492

xi
List of Tables
Table 2.1 Synthesis of Potassium Alkynyltrifluoroborates 67
Table 2.2 Use of Eschenmoser’s Salt 71
Table 2.3 Synthesis of tert-Butylammonium Alkynyltrifluoroborates 73
Table 2.4 Use of Paraformaldehyde and Secondary Amines in the
Multicomponent Reaction 75
Table 2.5 Use of Primary Amines and Diamines in Petasis Reaction 82
Table 2.6 Exploring Reaction Conditions with Alkyl Aldehydes 84
Table 2.7 Use of Alkyl Aldehydes in Three Component Reaction 85
Table 2.8 Trifluoro-1-methoxyethanol in Petasis Reaction 87
Table 2.9 Use of Aryl Aldehydes in Petasis Reaction with Potassium
Alkynyltrifluoroborates 88
Table 2.10 Use of Salicylaldehyde in the Three Component Condensation with
Potasssium Alkynyltrifluoroborates 89
Table 2.11 Use of Glycolaldehyde Dimer in the Multicomponent Reaction 91
Table 2.12 Use of Glyceraldehyde in the Petasis Reaction with Potassium
Alkynyltrifluoroborates 93
Table 2.13 Use of Unprotected Sugars in The Petasis Reaction with Potassium
Alkynyltrifluoroborates 95
Table 2.14 Synthesis of Propargylamines via Decarboxylation of β,γ-Alkynyl
α-Amino Acids 100
Table 2.15 Use of Diamines, Glyoxylic Acid and Potassium
Alkynyltrifluoroboartes: Synthesis of Piperazin-2-ones 102
Table 2.16 Four Component Reaction with Potassium Ethynyltrifluoroborate 107
Table 2.17 Novel N-Heterocycles via the Pauson-Khand Reaction 110
Table 2.18 Palladium-Catalyzed Borylative Cyclization of Propargylamines 112
xii
Table 4.1 Synthesis of 2-Amino Aryl Ketones via ortho-Lithiation of
N-pivaloylanilines 310
Table 4.2 The Sugasawa Reaction with Anilines 315
Table 4.3 Synthesis of 2-Amino Benzamides 319
Table 4.4 α-Anilino Amino Acids via Petasis Reaction with Styryl Boronic
Acid 321
Table 4.5 α-Anilino Carboxylic Acids via Petasis Reaction with Boronic Acids 323
Table 4.6 α-Amino Acids from (2-Amino-5-Chloro-Phenyl)-Phenylmethanone 326
Table 4.7 α-Amino Acids via Petasis Reaction with p-Methoxyphenyl Boronic
Acid 330
Table 4.8 Synthesis α-Amino Acids via Petasis Reaction 333
Table 4.9 α-Amino Acids via Petasis Reaction with Secondary Anilines 336
Table 4.10 Investigation of the α-Anilino Carboxylic Acid Activation 340
Table 4.11 Indole Synthesis via p-Toluenesulfonyl Chloride Activation 343
Table 4.12 Indole Synthesis via Acetic Acid Activation 346
Table 4.13 Synthesis of Indoles with Acetic Acid Anhydride Activation 349
Table 5.1 Synthesis of 2-Amino Heteroaryl Ketones via the Gewald Reaction 494
Table 5.2 Synthesis of 2-Aminobenzofuran Ketones 496
Table 5.3 Preparation of 2-Aminoindole Ketones 498
Table 5.4 Synthesis of α-Amino Acids via Petasis Reaction from
Aminoheteroaryl Ketones 499
Table 5.5 Preparation of 6H-Thieno[2,3-b]pyrroles 507
Table 5.6 Synthesis of 6H-Thieno[2,3-b]pyrroles without Purification of
α-Amino Acids 508
Table 5.7 Synthesis of 4H-Thieno[3,2-b]pyrroles 510
xiii
Table 5.8 Preparation of Benzofuro[3,2-b]pyrroles 511
Table 5.9 Synthesis of 1,4-dihydropyrrolo[3,2-b]indoles 514

xiv
List of Schemes
Scheme 1.1 Synthesis of Boronic Acid from Corresponding Halides 5
Scheme 1.2 Synthesis of Boronic Acids via Lithiation Reaction 6
Scheme 1.3 Synthesis of Boronates from Corresponding Halides 6
Scheme 1.4 Synthesis of Boronates via Lithiation Reaction 6
Scheme 1.5 Synthesis of Boronic Acids via Hydroboration 7
Scheme 1.6 Synthesis of Boronic Acids via Ortho-lithiation-Silylation-ipso-
Boro-Desilylation 7
Scheme 1.7 Synthesis of Boronates via Palladium-Catalyzed Coupling Reaction 8
Scheme 1.8 The Three Component Petasis Reaction 9
Scheme 1.9 Plausible General Mechanism of Petasis Reaction with Boronic
Acids and Esters 10
Scheme 1.10 Synthesis of α-Amino Acids via Petasis Reaction 11
Scheme 1.11 Preparation of Potassium Organotrifluoroborates from
Organostannenes 14
Scheme 1.12 Preparation of Potassium Organotrifluoroborates from
Organodihaloboranes 15
Scheme 1.13 Formation of Potassium Aryltrifluoroborates Using KHF
2
as
Fluorinating Agent 15
Scheme 1.14 Major Methods for Preparation of Potassium
Organotrifluoroborates 17
Scheme 1.15 Plausible General Mechanism of Petasis Reaction with
Organotrifluoroborates 19
Scheme 1.16 Synthesis of Piperazin-2-ones 23
Scheme 1.17 Synthesis of Benzopiperazinones 24
Scheme 1.18 Synthesis of Tetrahydro-1,4-benzodiazepin-3-ones 26
xv
Scheme 1.19 Synthesis of Tetrahydro-1,4-benzodiazepin-2-ones 27
Scheme 1.20 Synthesis of 5-Substituted Tetrahydro-1,4-benzodiazepin-2-ones 28
Scheme 1.21 One Step Synthesis of 2-Hydroxymorpholines 30
Scheme 1.22 Synthesis of 1,2,3,4-Tetrahydropyrazines 30
Scheme 1.23 One Step Synthesis of Aminophenol Derivatives 31
Scheme 1.24 Synthesis of 2H-Chromenes from Salicylaldehydes and Alkenyl
Boronic Acids 31
Scheme 1.25 Synthesis of 2H-Chromenes from Salicylaldehydes and Potassium
Alkenyltrifluoroborates 32
Scheme 1.26 Synthesis of 1,2-Dihydroquinolines from Potassium
Alkenyltrifluoroborates 32
Scheme 1.27 Intramolecular Version of Petasis Reaction with α-Hydroxy
Aldehydes 33
Scheme 1.28 Synthesis of Polyhydroxy Piperidines 33
Scheme 1.29 Synthesis of Oxazolidin-2-ones 35
Scheme 1.30 Syntheses of Polyhydroxy Pyrrolidines 37
Scheme 1.31 Synthesis of Iminocyclitols 38
Scheme 1.32 Synthesis of Amino Sugars 39
Scheme 1.33 Synthesis of Tetrahydroxyazepan-2-ones 41
Scheme 1.34 Synthesis of Tetrahydroisoquinoline 43
Scheme 1.35 Synthesis of Heterocycles via Friedel-Crafts Type Cyclization 43
Scheme 1.36 Syntheses of Heterocycles via Cycloaddition Processes 44
Scheme 1.37 The Grigg Three Component Reaction 46
Scheme 1.38 Mechanism of the Grigg Three Component Reaction 46
Scheme 1.39 The Five Component Union of Petasis-Grigg Reaction 47
xvi
Scheme 1.40 Synthesis of Cyclic Peptides via Petasis Reaction 48
Scheme 2.1 Synthesis of Propargylamides via Three Component Reaction 54
Scheme 2.2 Addition of Alkynyl Organometallics to preformed imines 55
Scheme 2.3 Metal-catalyzed Addition of Alkynes to Imines 56
Scheme 2.4 Metal-catalyzed Three Component Synthesis of Propargylamines 56
Scheme 2.5 Addition of Organozinc or Organocerium Reagents to
Alkynylimines 57
Scheme 2.6 Katritzky’s Approach to Propargylamines 58
Scheme 2.7 Addition of 1-Alkynyllithium Reagents to α-Amidoalkyl Sulfones 58
Scheme 2.8 Synthesis of Tertiary Propargylamines 59
Scheme 2.9 Lewis Acid Activation of 2-Trifluoromethyl-1,3-oxazolidines 59
Scheme 2.10 Synthesis of Propargylamines by Copper-catalyzed Addition of
Alkynes to Enamines 60
Scheme 2.11 Copper-catalyzed Coupling of Tertiary Aliphatic Amines with
Terminal Alkynes 60
Scheme 2.12 Aminolysis of Bromoallenes in Aqueous Alkaline Medium 61
Scheme 2.13 Tandem Amine Propargylation-Sonogashira coupling for the
Synthesis of Functionalized Propargylamines 62
Scheme 2.14 Alkynylation of N,O-Acetals 62
Scheme 2.15 Asymmetric Synthesis of Propargylamides 63
Scheme 2.16 Petasis Reaction of Alkynylboronate with Glycol Aldehyde Dimer 64
Scheme 2.17 Synthesis of Potassium Alkynyltrifluoroborates 66
Scheme 2.18 Plausible Mechanism of Petasis Reaction with Potassium
Organotrifluoroborates 70
Scheme 2.19 Use of Eschenmoser’s Salts with Potassium Alkynyl Trifluoroborate
71
xvii
Scheme 2.20 Synthesis of tert-Butylammonium Alkynyltrifluoroborates 72
Scheme 2.21 Use of Paraformaldehyde in Petasis Reaction with Secondary
Amines 75
Scheme 2.22 Use of Primary Amines and Diamines in Petasis Reaction 82
Scheme 2.23 Exploring Reaction Conditions with Alkyl Aldehydes 84
Scheme 2.24 Use of Alkyl Aldehydes in the Three Component Reaction 85
Scheme 2.25 Use of Trifluoro-1-methoxyethanol in Petasis Reaction 86
Scheme 2.26 Use of Aryl Aldehydes in Petasis Reaction 88
Scheme 2.27 Salicylaldehyde in Petasis Reaction with Potassium
Alkynyltrifluoroborates 89
Scheme 2.28 Use of Glycol Aldehyde Dimer in Petasis Reaction 91
Scheme 2.29 Glyceraldehyde in the Three Component Reaction 93
Scheme 2.30 Carbohydrates in Petasis Reaction with Potassium
Alkynyltrifluoroborates 95
Scheme 2.31 Synthesis of α-Amino Acid via Petasis Reaction 98
Scheme 2.32 Attempted Synthesis of β,γ-Alkynyl α-Amino Acids 99
Scheme 2.33 Plausible Mechanism of Decarboxylation of β,γ-Alkynyl
α-amino acid 101
Scheme 2.34 Synthesis of Piperazin-2-ones via Petasis Reaction with
Potassium Alkynyl Trifluoroborates, Glyoxylic Acids
and Diamines 102
Scheme 2.35 Uncatalyzed, Thermal Cycloaddition of Azides to Alkynes 104
Scheme 2.36 Copper-catalyzed Cycloaddition of Azides to Alkynes –
Synthesis of 1,4-disubstituted-1,2,3-triazoles 105
Scheme 2.37 Synthesis of 1,5-disubstituted-1,2,3-triazoles through
Grignard Reagents 105
xviii
Scheme 2.38 Ruthenium-Catalyzed Cycloaddition of Alkynes to Organic
Azides – Synthesis of 1,5-disubstituted-1,2,3-triazoles 106
Scheme 2.39 Four Component Reaction with Potassium Ethynyltrifluoroborate 106
Scheme 2.40 General Idea of the Pauson-Kand Reaction 108
Scheme 2.41 The Pauson-Khand Reaction for the Synthesis of N-Heterocycles 109
Scheme 2.42 Palladium-Catalyzed Borylative Cyclization of Propargylamines 111
Scheme 2.43 Plausible Mechanistic Pathways for Pd-catalyzed Cyclization-
Borylation of Propargylamines 113
Scheme 3.1 The Fischer Indole Reaction 246
Scheme 3.2 The Fischer indole Synthesis with Amino Ketones 247
Scheme 3.3 Fischer Indole Synthesis with Cyclic Imines 247
Scheme 3.4 Fischer Indole Synthesis with β-Ketoesters Utilizing Japp-
Klingemann Reaction 248
Scheme 3.5 Fischer Indole Synthesis with β-Ketoacids Utilizing Japp-
Klingemann Reaction 249
Scheme 3.6 Fischer Indole Synthesis via Buchwald Modification 249
Scheme 3.7 Titanium-Catalyzed Hydroformulation/Fischer Cyclization 250
Scheme 3.8 Example of Titanium-Catalyzed Fischer Synthesis of
Tryptamine Analogues 251
Scheme 0.9 Fischer Indole Synthesis via Metal-Catalyzed Hydroformylation
of Alkenes 252
Scheme 3.10 Indoles from N-Arylhydroxylamines 252
Scheme 3.11 Indole Synthesis from Allenes and N-Phenylhydroxylamines 253
Scheme 3.12 Gassman Indole Synthesis 253
Scheme 3.13 Sugasawa Indole Synthesis 254
Scheme 3.14 Bischler Indole Synthesis 255
xix
Scheme 3.15 Bartoli Indole Synthesis 256
Scheme 3.16 Mechanism of Bartoli Indole Synthesis 257
Scheme 3.17 One Step Copper-Catalyzed Indole Synthesis 258
Scheme 3.18 One-Pot, Three Component Approach for the Synthesis of
2,3-Disubstituted Indoles 259
Scheme 3.19 Synthesis of 3-Iodoindoles 259
Scheme 3.20 Zinc Triflate Catalyzed Cyclization of Propargyl Alcohols with
Anilines 260
Scheme 3.21 Indole Synthesis via Reductive Coupling Reaction 262
Scheme 3.22 Madelung Indole Synthesis 262
Scheme 3.23 Indoles via Intramolecular Wittig Condensation 263
Scheme 3.24 Indoles via Intramolecular Palladium-Catalyzed Cyclization 264
Scheme 3.25 Schmid Indole Synthesis 265
Scheme 3.26 C-alkylation of o-Aminobenzyl Anions 266
Scheme 3.27 Indoles from 2-Aminobenzyl Phosphonium Salts 266
Scheme 3.28 Indoles via Intramolecular Heck Reaction of N-Allylanilines 268
Scheme 3.29 Synthesis of Indoles via Transition Metal Catalyzed Cyclization
of N-Propargylanilines 269
Scheme 3.30 Palladium-Mediated Cyclization of N-Vinyl-o-haloanilines 269
Scheme 3.31 Construction of 2-Aminoindoles via Palladium-Catalyzed 270
Scheme 3.32 General Example of Photocyclization of N-Vinylanilines 271
Scheme 3.33 Photocyclization to Indole-2-carboxylate 271
Scheme 3.34 Indole Synthesis via Acid Catalyzed Cyclization 272
Scheme 3.35 The Nordlander Indole Synthesis from Acetals 272
Scheme 3.36 Leimgruber-Batcho Indole Synthesis 274
xx
Scheme 3.37 Indoles from o,β-Dinitrostyrenes 275
Scheme 3.38 Reductive Cyclization of o-Nitrobenzyl-carbonyl Compounds 275
Scheme 3.39 Reissert Indole Synthesis 276
Scheme 3.40 Furan as a 1,4-Diketone Equivalent 277
Scheme 3.41 Furan Ring Opening - Indole Ring Closure 278
Scheme 0.42 Mechanism of Furan Ring Opening - Indole Ring Closure 278
Scheme 3.43 Furan as a 1,3-Diketone Equivalent in Indole Cyclizations 279
Scheme 3.44 Mechanism of Furan Recyclization Type 2 to Indoles 279
Scheme 3.45 Indoles from o-Aminophenylacetylenes 280
Scheme 0.46 Synthesis of 2-Substituted-3-heteroarylindoles from
o-Trifluoroacetanilides 280
Scheme 3.47 Hegedus Indole Synthesis 281
Scheme 3.48 Hemetsberger Indole Synthesis 282
Scheme 3.49 Neber Indole Synthesis 283
Scheme 3.50 Nenitzescu Indole Synthesis 284
Scheme 3.51 Mechanism of Nenitzescu Synthesis 285
Scheme 3.52 Preparation of LY311727 via Nenitzescu Synthesis 286
Scheme 3.53 3-Formyl-indoles via 1,4-Dihydroquinolines 287
Scheme 3.54 Synthesis of 2-Formyl-indoles 288
Scheme 3.55 Natsume Indole Synthesis 290
Scheme 3.56 Indoles via electrophilic cyclization at C-2 pyrrole 291
Scheme 3.57 Indoles from 1,5-Dihydropyrano[3,4-b]pyrrol-5-(1H)-ones 292
Scheme 3.58 Indoles from 1,6-Dihydropyrano[4,3-b]pyrrole-6-(1H)-ones 292
Scheme 3.59 Indoles from 2-Vinylpyrroles 293
xxi
Scheme 3.60 Indoles from 3-Vinylpyrroles 294
Scheme 4.1 Novel Approach to Indoles 296
Scheme 4.2 2-Amino Aryl Ketones from 2-Chloronitrobenzenes 300
Scheme 4.3 2-Amino Aryl Ketones and Aldehydes from N-pivaloylanilines 300
Scheme 4.4 The Sugasawa Reaction 301
Scheme 4.5 Synthesis of 2-Amino Aryl Ketones from Isatoic Anhydride 301
Scheme 4.6 Synthesis of 2-Amino Aryl Ketones from 3,1-Benzoxazin-4-ones 302
Scheme 4.7 2-Halo Aryl Ketones as Precursors to 2-Amino Aryl Ketones 303
Scheme 4.8 Syntheses of 2-Amino Aryl Ketones from Anthranilic Acid 303
Scheme 4.9 Synthesis of 2-Amino Aryl Ketones from 2-Aminobenzonitriles 304
Scheme 4.10 2-Amino Aryl Ketones from 2-Nitrobenzoyl Chloride 304
Scheme 4.11 2-Amino Aryl Ketones from 2-Nitrobenzoic Acid 305
Scheme 4.12 2-Amino Aryl Ketones from 2-Nitrobenzyl Chloride 306
Scheme 4.13 2-Amino Aryl Ketones and Aldehydes from Indoles 306
Scheme 4.14 2-Amino Aryl Ketones and Aldehydes from 2,1-Benzisoxazoles 307
Scheme 4.15 2-Amino Aryl Ketones and Aldehydes from 2-Keto Benzoic
Acids 307
Scheme 4.16 Directed Ortho-Lithiation of N-Protectedanilines 308
Scheme 4.17 Synthesis of N-Pivaloylanilines 309
Scheme 4.18 Synthesis of ortho-Substituted Anilines via Directed Ortho-
Lithiation of N-Pivaloylanilines 309
Scheme 4.19 The Sugasawa Reaction with Anilines 312
Scheme 4.20 Plausible Mechanism of Sugasawa Reaction 313
Scheme 4.21 Synthesis of 2-Amino Aryl Ketones via Sugasawa Reaction 314
xxii
Scheme 4.22 The Sugasawa Reaction with Secondary Anilines 316
Scheme 4.23 Syntheses of 7-Aminoindanone and 8-Aminotetralone 316
Scheme 4.24 Reaction Between Isatin and Dimethylamine 317
Scheme 4.25 Reaction Between Isatin and Morpholine 318
Scheme 4.26 Nuclephilic Ring Opening of Isatoic Anhydride 318
Scheme 4.27 α-Amino Acid Synthesis via Petasis Reaction 320
Scheme 4.28 Synthesis of α-Anilino Amino Acids via Petasis Reaction with
Styryl Boronic Acid 320
Scheme 4.29 Preparation of α-Anilino Carboxylic Acids via Petasis Reaction
with Boronic Acids 323
Scheme 4.30 Synthesis of α-Amino Acids via Petasis Reaction with (2-Amino
-5-Chloro-Phenyl)-Phenyl-Methanone 325
Scheme 4.31 Synthesis of α-Amino Acids via Petasis Reaction with
p-Methoxyphenyl Boronic Acid 329
Scheme 4.32 α-Amino Acids via Petasis Reaction 333
Scheme 4.33 α-Amino Acids via Petasis Reaction with Secondary Anilines 336
Scheme 4.34 Novel Synthetic Approach to Indoles 338
Scheme 4.35 Investigation of Acid Activator 340
Scheme 4.36 2,3-Disubstitutedindole Synthesis Using p-Toluenesulfonyl
Chloride 342
Scheme 4.37 345
Scheme 4.38 1,2,3-Trisubstitutedindole Synthesis via Acetic Acid Activation 345
Scheme 4.39 Indole Synthesis via Acetic Acid Activation 348
Scheme 4.40 Intramolecular Pyrrole Synthesis via Münchnone Intermediate 350
Scheme 4.41 1,2,3-Trisubstituted Indole Synthesis from Tertiary α-Anilino
Carboxylic Acids 351
xxiii
Scheme 4.42 Three Step Synthesis of 4.221 352
Scheme 5.1 Synthesis of Polysubstituted 2-Aminothiophenes via the Gewald
Reaction 492
Scheme 5.2 Plausible Mechanism of the Gewald Reaction 493
Scheme 5.3 Synthesis of 2-Aminobenzofuran Ketones 495
Scheme 5.4 Syntheses of Salicylonitriles 496
Scheme 5.5 Synthesis of 2-Aminoindole Ketones 497
Scheme 5.6 Synthesis of N-Protected Anthranilonitriles 497
Scheme 5.7 Synthesis of α-Amino Acids via the Petasis Reaction 499
Scheme 5.8 Synthesis of 6H-Thieno[2,3-b]pyrroles 506
Scheme 5.9 Synthesis of 6H-Thieno[2,3-b]pyrroles without Purification of
α-Amino Acids 508
Scheme 5.10 Preparation of 4H-Thieno[3,2-b]pyrroles 509
Scheme 5.11 Synthesis of Benzofuro[3,2-b]pyrroles 511
Scheme 5.12 Synthesis of 1,4-dihydropyrrolo[3,2-b]indoles 513

xxiv
Abstract
This dissertation describes the development of new, efficient and facile
synthetic methodologies for the practical synthesis of novel heterocycles and highly
substituted amine derivatives.
Chapter 1 is an introduction to the boron based multicomponent reaction
known in the literature as the Petasis reaction. The reaction utilizes simple and
easily available starting materials such as amines, carbonyls and organoboron
compounds. This section describes the developments in the synthesis of
heterocyclic scaffolds based on the three component Petasis reaction.
Chapter 2 describes the use of potassium alkynyl trifluoroborates in the
Petasis reaction for the synthesis of highly functionalized propargyl amine
derivatives. Furthermore, it shows the utility of the propargylamines for the
synthesis of heterocycles via the Pauson-Khand reaction and other palladium
catalyzed transformations.
Chapter 3 is an overview of existing methods for the indole synthesis. It
presents a number of methodologies and discusses their utility and practicality.
Chapter 4 introduces a novel, highly efficient and facile synthetic approach
towards the synthesis of 2,3-disubstitued indoles. The new method utilizes an
intramolecular cyclization of α-amino acids via a simple one pot transformation.
The starting amino acids are synthesized via the three component Petasis reaction
using 2-amino aryl ketones and a wide range of boronic acids. This method can be
utilized for combinatorial library synthesis and has a potential to be used for the
xxv
manufacture of pharmaceutically active ingredients. The section describes the
synthesis of 2-amino aryl ketones as well.
Chapter 5 provides details of the facile synthesis of fused novel
heterocycles. A description of the three component condensation for the synthesis
of α-amino acids derivatives of 2-amino heteroaryl ketones and their use in the
construction of complex heterocyclic structures is presented. This section discusses
utilization of the Gewald reaction for the synthesis of 2-amino heteroaryl ketones as
well.
N
N
R
2
O
R
1
R
3
R
3
N
R
5
R
2
R
1
H
R
3
N
OH
OH
OH
R
1
R
2
n
N OH
R
2
R
1
R
3
R
3
N
OH
R
1
R
2
R
2
N
R
3
B
O
O
N
O
R
2
R
3
R
4
N
N
N
Ph
N
R
2
R
1
S
N
R
2
R
3 R
6
R
7
S
R
4
R
5
N
R
1
R
3
N
O R
2
N
R
3
O
N
R
2
R
3
R
1
R
1
R
1
R
2
N
R
1
R
3
R
2
New
Methodologies

1
Chapter 1. Synthesis of Novel Heterocycles via Boron-
based Multicomponent Reactions
1.1 Introduction
1.1.1 Multicomponent Reactions - General Aspects and History
Multicomponent reactions (MCRs) are very different from two component
reactions. They are generally defined as reactions where three or more starting
materials react in one pot to form a product which posses mostly all of the atoms of
the starting materials. The starting materials do not react at the same time with each
other but in a programmed cascade sequence of elementary reactions
.
1
Contrary to two component reactions, MCRs are very efficient processes. A lot of
diversified products can be synthesized from only a few starting materials. With
MCRs being one pot reactions they are very easy to carry out as well.
From a medicinal chemistry perspective, MCRs are very advantageous.
They allow for easy, fast and high-throughput synthesis of diverse molecules with
little synthetic efforts. MCRs have found applications for example in the synthesis
of a highly active calcium antagonist - nifedipine 1.01 (via Hantsch reaction) or in
the synthesis of the core structure of Crixivan® 1.02 (via four component Ugi
reaction).
2

1
Dömling, A.; Ugi, I. Angew. Chem. Int. Ed. 2000, 39, 3169.
2
Zhu, J.; Bienayme, H. Multicomponent Reactions Wiley; Weinheim, 2005.
2
N
H
H
3
C
H
3
CO
O
OCH
3
O
CH
3
NO
2
1.01
Nifedipine
N N
N
H
H
OH
H
N
O
HO
H
1.02
Crixivan
NH
O

Figure 1.1 Structures of Nifedipine and Crixivan
Multicomponent reactions has been very trendy over the past two decades,
nevertheless they have a long history of over 150 years as shown in Figure 1.2.
1850
1882
1893
1912
1921
1959
1997
2020
1934
1961
1971
Strecker Reaction
Hantzsch Dihydropyridine Synthesis
Bignelli Reaction
Mannich Reaction
Passerini Reaction
Ugi Reaction
Petasis Reaction
Pauson-Khand Reaction
Gewald Reaction
Bucherer-Bergs Reaction
Radziszewski Imidazole Synthesis
1890 Hantzsch Pyrrole Synthesis
2000
1917 Robinson's Synthesis of Tropinone
Miscellaneous MCRs
1988 Grigg Reaction

Figure 1.2 The History of Multicomponent Reactions
3
The rich history of MCRs, latest successful applications of MCRs in drug discovery
and recent developments of new multicomponent reactions indicate a need for
continuous efforts to improve upon these types of synthetic methodologies.
1.2 Petasis Reaction with Boronic Acids and Boronic Acid Esters
1.2.1 Organoboronic Acids and Organoboronic Acids Esters- General
Aspects and Synthesis
Recent development of palladium cross coupling reactions and new
methodologies in modern organic synthesis have resulted in the increasing use of
growing importance of organoboron compounds, especially organoboronic acids
and organoboronates.
Structurally organoboronic acids and organoboronates are trivalent boron
compounds containing one C-B bond and two C-O bonds (1.05 and 1.08
correspondingly) as shown in Figure 1.3.
B
R
2
R
1
R
3
B
R
2
R
1
OH
B
OH R
1
OH
B
OH HO
OH
B
OR R
1
OR
O
B
O
B
O
B
R
1
R
1
R
1
1.03 1.04 1.05 1.07 1.08 1.06
borane borinic acid boronic acid boric acid boronic ester boroxine

Figure 1.3 Oxygenated organoboron compounds
Since trivalent boron has a vacant p-orbital these organoboron compounds have
Lewis acidic character. As a result they tend to be air-sensitive and in some cases
even pyrophoric. Boronic acids are very mild Lewis acids and most of them are
crystalline solids that can be easily handled in the presence of moisture and air
4
however not for a long time. They tend to degrade to benign boric acid. In general,
boronic acids have relatively low intrinsic toxicity and recent applications in
medicine support this statement.
3
For example Bortezomib (Velcade®) 1.09 is the
first therapeutic agent that contains boron in the core structure as presented in
Figure 1.04. It is an anti-cancer agent approved in the US for the treatment of
multiple myeloma.
N
N
O
N
H
O
H
N B(OH)
2
1.09
Bortezomib

Figure 1.4 Structure of Bortezomib
The reactivity of boronic acids and esters depends significantly on the
nature of the carbon group (R) directly connected to the boron atom (Figure 1.3).
Based on this group boronic acids and boronates are classified in subcategories
such as alkyl- alkenyl-, aryl-, allyl- boronic acids (esters). In contrast to boronic
acids most boronic acid esters with a low molecular weight are liquids at room
temperature and can be purified easily by distillation.

3
Hall, D. G. Boronic Acids, Wiley-VCH, Weinheim, 2005.
5
The first synthesis and isolation of a boronic acid was reported by
Frankland in 1860.
4
Since then boronic acids were forgotten for over 100 years till
the 1970’s when new applications came to light. The increasing significance of
boronic acids and esters as synthetic intermediates has justified the development of
new the preparation methods. Nevertheless, the most common and the cheapest
method used for preparation organoboronic acids or esters, involves
organomagnesium or organolithium reagents. As shown in Scheme 1.1 appropriate
halide 1.10 is transformed at first into a Grignard reagent or lithiated intermediate
at low temperature. By treating the organometallic intermediate with a borate ester
followed by subsequent aqueous hydrolysis, the appropriate boronic acid 1.05 is
prepared.
1) Mg
2) B(OiPr)
3
1) n-BuLi
3) H
3
O
+
B
OH R
1
OH
Br R
1
2) B(OiPr)
3
3) H
3
O
+
B
OH R
1
OH
1.05 1.10 1.05

Scheme 1.1 Synthesis of Boronic Acid from Corresponding Halides
If instead of organic halide a proton derivative of starting material 1.11 is used as
presented in Scheme 1.2, the lithiated intermediate has to be generated with the n-
butyllithium reagent. Subsequent treatment with borate and aqueous acid leads to
boronic acid 1.05.

4
Frankland, E.; Duppa, B. F. Justus Liebigs Ann. Chem. 1860, 115, 319.
6
1) n-BuLi
H R
1
2) B(OiPr)
3
3) H
3
O
+
B
OH R
1
OH
1.11 1.05

Scheme 1.2 Synthesis of Boronic Acids via Lithiation Reaction
Similarly appropriate boronic esters 1.12 can be prepared (Scheme 1.3 and Scheme
1.4), however, non-aqueous hydrolytic conditions have to be applied.
1) Mg
2) B(OiPr)
3
1) n-BuLi
B
OiPr R
1
OiPr
Br R
1
2) B(OiPr)
3
3) HCl/Et
2
O
B
OiPr R
1
OiPr
1.12 1.10 1.12
3) HCl/Et
2
O

Scheme 1.3 Synthesis of Boronates from Corresponding Halides
The above described methods are commonly used for the synthesis of aryl,
heteroaryl and alkenyl- boronic acids and boronates.
1) n-BuLi
H R
1
2) B(OiPr)
3
B
OiPr R
1
OiPr
1.11 1.12
3) HCl/ Et
2
O

Scheme 1.4 Synthesis of Boronates via Lithiation Reaction
Hydroboration of alkynes with catecholborane or
diissopinocampheylborane is often used for the preparation of alkenyl boronic
acids, as presented in Scheme 1.5. This method is very convenient and provides
alkenyl boronic acids in geometrically pure form after hydrolysis.
7
1) X
2
BH
R
1
X
2
BH: catecholborane,
diisopinocampheylborane etc.
1.13
2) H
2
O
B(OH)
2 R
1.14

Scheme 1.5 Synthesis of Boronic Acids via Hydroboration
This methodology can be used for the synthesis alkylboronic acids and their ester
derivatives as well if an alkene is used as starting material. Other methods for the
synthesis of aryl- and heteroaryl- boronic acids or boronates involve a directed
metalation reaction developed by Snieckus.
5
This methodology was one year later
improved into an ortho-lithiation-silylation-ipso-boro-desilylation sequence with
boron tribromide as shown in Scheme 1.6.
6

O
NEt
2
O
1) n-BuLi
2) TMSCl
O
NEt
2
O
TMS
1) BBr
3
2) MeOH
3) H
3
O
+
O
NEt
2
O
B(OH)
2
1.15 1.16 1.17

Scheme 1.6 Synthesis of Boronic Acids via Ortho-lithiation-Silylation-ipso-
Boro-Desilylation

5
Sharp, M. J.; Snieckus, V. Tetrahedron Lett. 1985, 26, 5997.
6
Haubold, W.; Herdtle, J.; Gollinger, W.; Einholz, W. J. Organomet. Chem. 1986,
315, 1.
8
A major advance in the synthesis of boronates came with the report by
Miyaura on the palladium-catalyzed coupling reaction of aryl halides 1.18 with
diboron esters, especially bis(pinacolato)diboron 1.19, as presented in Scheme 1.7.
7

X
O
B
O
B
O
O PdCl
2
(dppf)
KOAc, DMSO
1.18 1.19
B
O
O
1.20

Scheme 1.7 Synthesis of Boronates via Palladium-Catalyzed Coupling
Reaction
The major advantage of this process is tolerance of a wide range of functional
groups such as esters, nitriles, nitro, acyl and ketones. Recently there have been
many methods developed for the synthesis of boronic acids and their ester
derivatives via transition metal catalyzed diboration reactions and a detailed
discussion about it has been published by Marder and Norman.
8

1.2.2 Multicomponent Condensation between Amines, Carbonyls and
Organoboronic Acid and Esters– General Aspects and Mechanism
In 1993 a new report was published in the literature for the synthesis of
allylamines via stepwise condensation between amines and paraformaldehyde
followed by reaction with alkenyl boronic acids.
9
Subsequently the reaction was

7
Ishiyama, T.; Itoh, Y.; Kitano, T.; Miyaura, N. J. Org. Chem. 1995, 60, 7508.
8
Marder, T. B.; Norman, N. C. Topics Cataly. 1998, 5, 63.
9
Petasis, N. A.; Akritopoulou, I. Tetrahedron Lett. 1993, 34, 583.
9
transformed into a one pot, three-component condensation between an amine 1.21,
carbonyl component 1.22 and boronic acid 1.23 as presented in Scheme 1.8.
10,11

R
2
N
H
R
1
R
3
R
4
O
1.21 1.22
B
OH R
5
OH
1.23
R
2
N
R
1
R
4
R
3
R
5
1.24
-B(OH)
3

Scheme 1.8 The Three Component Petasis Reaction
In the initial paper the reaction was named the “Boronic Acid Mannich Reaction”
but currently is cited as the Petasis Reaction as the process developed into a more
versatile and general approach towards a variety of amine derivatives. Many
experiments were performed in order to investigate the mechanism of the reaction.
The mechanistic pathway of the reaction is quite complex and involves a series of
equilibria between the starting materials and diverse intermediates that form in the
process in order to end with a non-equilibrium process which leads to the desired
final product. The plausible accepted version of the mechanism of the Petasis
reaction is presented in Scheme 1.9. The reaction of amine 1.21 and carbonyl
component 1.22 leads to two major possible intermediates, the aminol 1.25 and the
aminal 1.26. In the presence of an electrophilic boronic acid or boronic acid ester
1.23 these intermediates can be transformed into the nucleophilic, highly reactive
organobor-“ate” complexes such as 1.28 and 1.29 which can irreversibly rearrange

10
Petasis, N. A.; Zavialov, I. A. Special Publication – Royal Society of Chemistry
1997, 201, 179.
11
Petasis, N. A.; Zavialov, I. A. 2001, US Patent 6,232,467.
10
to the final product 1.24 or reversibly into electrophilic iminium species 1.27 and
organoborate intermediate 1.30.
B
OH R
5
OH
1.23
R
2
N
H
R
1
R
3
R
4
O
N
R
3
R
1
R
2
R
4
R
2
N
R
1
R
4
R
3
OH
R
2
N
R
1
R
4
R
3
N
R
2
R
1
H
2
O
R
2
N
H
R
1
R
5
B
OR
Z
OR
R
2
N
R
1
R
4
R
3
OH
R
2
N
R
1
R
4
R
3
N
R
2
R
1
B
OR
R
5
OR
R
2
N
R
1
R
4
R
3
R
5
B
R
5
OR
OR
1.28
1.24
1.29
1.30
1.21
1.21
1.22
1.26
1.25
1.27
B
OH R
5
OH
1.23

Scheme 1.9 Plausible General Mechanism of Petasis Reaction with Boronic
Acids and Esters
The iminium ions 1.27 can react with borate species 1.30 irreversibly as well to
form the final product. Nevertheless, we believe that the key to the reaction is the
formation of the tetravalent boron species such as 1.28, 1.29 or 1.30 which allow
for formation in one way or another to the final product.
A wide variety of amines can be utilized in the Petasis reaction including
aromatic, electron poor aromatic, aliphatic amines, diamines and their derivatives
such as amino alcohols, amino acids, hydrazines and even less nucleophilic
11
sulfonamides. It turned out that the secondary amines proved to be the best
candidates, the primary amines also react with somewhat lower yield.
As far as carbonyl component is concerned, a plethora of oxo compounds
can be used in the Petasis three component condensation. One of the most
important carbonyl components is glyoxylic acid 1.31 which allows for the
synthesis of α-amino acids as presented in Scheme 1.10.
R
2
N
H
R
1
H
O
1.21 1.31
B
OH R
5
OH
1.23
R
2
N
R
1
R
4
R
3
1.32
-B(OH)
3
O
OH
OH
O

Scheme 1.10 Synthesis of α-Amino Acids via Petasis Reaction
Glyoxylic acid 1.31 belongs to the class of α-hydroxy aldehydes which are
exceptionally reactive in the Petasis reaction. These compounds posses a hydroxy
group in the α-position which can participate in activation of the boronic acids
intramolecularly to the “ate” complex. Ultimately the reaction might be facilitated
via the presence of the additional hydroxy group.
Other carbonyl components such as pyruvic acid, salicylaldehyde, glycolaldehyde
dimer, unprotected sugars, glyceraldehyde dimer, paraformaldehyde,
dihydroxyacetone, ketoses, pyridylaldehyde have been utilized in the Petasis
reaction. However the main advantage in using chiral α-hydroxyaldehydes
translates into obtaining great enantioselectivity and diastereoselectivity in the
12
reaction. As a result optically pure chiral anti β-aminopolyols can be synthesized in
one step.
In terms of organoboron compounds, a wide range: heteroaryl-, aryl-,
alkenyl-, allenyl- allyl-boronic acid participate easily in the three component
condensation. However the synthesis and purification of some of the boronic acids
is not simple. They tend to form anhydride products such as boroxines so their
analysis and stoichiometric measures are difficult. The C-B bond in particular
(alkynyl, vinyl, aryl) boronic acids is quite labile and makes storage and handling
difficult. Therefore the use of boronic acid esters which are considered more stable
analogs became a very important aspect of the research. However, it turned out that
participation of boronates in the Petasis reaction is highly solvent dependent and
they are usually less reactive.
12

1.3 Petasis Reaction with Organotrifluoroborates
1.3.1 Potassium Organotrifluoroborates – General Aspects and
Synthesis
One class of compounds that has gained the attention of several research
group over the past twenty years is tetravalent organotrifluoroborate salts. They
often show greater stability towards atmospheric moisture and oxidation than their
trivalent counterparts while retaining their reactivity in a variety of reactions.
Potassium organotrifluoroborates 1.33 of the general structure depicted in Figure

12
Jourdan, H.; Gouhier, G.; Hijfte, L. V.; Angibaud, P.; Piettre, S. R. Tetrahedron
Lett. 2005, 46, 8027.
13
1.5 can be stored at room temperature indefinitely without noticeable degradation.
This is not the case for other organoboron reagents.
1.33
F
B
R
5
F
F
K

Figure 1.5 Structure of Potassium Organotrifluoroborates
The isolation and purification of potassium organotrifluoroborates are also less
difficult than that of other organoboron compounds. Their purification can be
usually accomplished by recrystallization in boiling acetone or acetonitrile.
The tetravalent organotrifluoroborate salts are electron-donating
(nucleophilic) species in contrast to the electrophilic properties of trivalent
organoboron moieties. The organotrifluoroborates are sensitive to both acids and
bases. In the presence of a Lewis acid at high temperatures organotrifluoroborates
can undergo a single boron-fluorine bond heterolysis to cleanly generate an
organodifluoroborane species.
13
A variety of Lewis acids have been utilized for this
process such as BF
3
•Et
2
O
14
, TMSCl
15
, AsF
5
16
and SiCl
4
17
. On the other hand, in

13
Stafford, S. C. Can. J. Chem. 1963, 41, 807.
14
a) Billard, T.; Langlois, B. R. Tetrahedron Lett. 2002, 67, 997. b) Batey, R. A.;
Thadani, A. N.; Smil, D.V. Tetrahedron Lett. 1999, 40, 4289.
15
Vedejs, E.; Chapman, R. W.; Fields, S. C.; Lin, S.; Schrimpf, M. R.; J. Org.
Chem. 1995, 60, 3020.
16
Frohn, H. J.; Bardin, V.V. Z. Anorg. Allg. Chem. 2001, 627, 15.
17
Matteson, D. S.; Kim, G. Y. Org. Lett. 2002, 4, 2153.
14
aqueous basic conditions organotrifluoroborates slowly undergo nucleophilic
substitution at boron. The fluoride substituents on boron are replaced by hydroxyl
groups.
18

Organotrifluoroborates have been present in the literature since 1940 when
Fowler and Kraus described for the first time the preparation of tetra-
alkylammonium triphenylfluoroborates by treatment of a triphenylborane-ammonia
complex with tetraalkylammonium fluoride.
19
The next appearance of
organotrifluoroborates in the literature occurred in 1960 when Chambers described
the synthesis of potassium organotrifluoroborates 1.36 from the corresponding
organostannes 1.34 by reaction with gaseous boron trifluoride and subsequent
treatment with potassium fluoride as presented in Scheme 1.11.
20

RSnMe
3
BF
3
gas
CCl
4
KF
H
2
O
RBF
2
RBF
3
K
1.34 1.36 1.35

Scheme 1.11 Preparation of Potassium Organotrifluoroborates from
Organostannenes
Treatment of dihalogenoorganoboranes with excess potassium fluoride also allows
for the synthesis of organotrifluoroborates. In this way potassium (1S)-

18
Batey, R. A.; Quach, T. D. Tetrahedron Lett. 2001, 42, 9099.
19
Fowler, D. L.; Kraus, C. A. J. Am. Chem. Soc. 1940, 62, 1143.
20
a) Chambers, R. D.; Clark, H. C.; Willis, C. J. Prod. Chem. Soc. 1960, 114. b)
Chambers, R. D.; Clark, H. C.; Willis, C. J. J. Am. Chem. Soc. 1960, 82, 5298.
15
isopinocampheyltrifluoroborate 1.38 was obtained in 89% yield from the
corresponding dibromoborane 1.37 derivative as shown in Scheme 1.12.
21

BBr
2
1.37
BF
3
K
1.38
KF
H
2
O

Scheme 1.12 Preparation of Potassium Organotrifluoroborates from
Organodihaloboranes
All the above methods for the preparation of organotrifluoroborates were not
satisfactory due to the fact they involve highly reactive, unstable and toxic
intermediates. Therefore the use of organotrifluoroborates in organic synthesis
started with the improvement in their preparation methods. It happened in 1995
when Vadejs and coworkers described a highly efficient method for the preparation
of potassium organotrifluoroborates using inexpensive potassium hydrogen
difluoride (KHF
2
) as fluorinating agent for trivalent boron reagents.
15
In his report
arylboronic acids 1.39 were efficiently converted into potassium
aryltrifluoroborates 1.40 as shown in Scheme 1.13.
ArB(OH)
2
KHF
2
MeOH/H
2
O
ArBF
3
K
1.40 1.39

Scheme 1.13 Formation of Potassium Aryltrifluoroborates Using KHF
2
as
Fluorinating Agent

21
Bir, G.; Schacht, W.; Kaufmann, D. J. Organomet. Chem. 1988, 340, 267.
16
In addition, it was found that using KHF
2
, boroxines and boronic acid dimers
(always present in isolated samples of boronic acids) can be transformed into
potassium organotrifluoroborates as well. Interestingly potassium fluoride (KF)
was not able to displace the hydroxyl ligands of trivalent boronic acids.
22

The organotrifluoroborate salts do not have to be prepared directly from the
pre-prepared and purified boronic acids or esters (Route A). They can be prepared
in situ from other borate intermediates. The Scheme 1.14 presents a summary of
major pathways for the preparation of potassium organotrifluoroborates. As shown
they can be prepared from organohalides by a lithium/halogen exchange reaction
(Route D) or Grignard formation (Route E). The Grignard- or organolithium
reagents are trapped with trialkylborate followed by subsequent treatment with an
aqueous solution of KHF
2
to afford potassium organotrifluoroborates.

22
Darses, S.; Genet, J.-P. Chem. Rev. 2008, 108, 288.
17
3) KHF
2
aq.
RBr
1) Mg
2) B(OiPr)
3
RBF
3
K
1) n-BuLi
2) B(OiPr)
3
3) KHF
2
aq.
RH
2) KHF
2
aq.
1) X
2
BH
BF
3
K
R
R
RB
OH
OH
KHF
2
aq.
MeOH
X
2
BH: catecholborane, pinacolborane,
diisopinocampheylborane etc.
RBr
1) n-BuLi
2) B(OiPr)
3
3) KHF
2
aq.
Route A
Route B
Route C
Route D
Route E

Scheme 1.14 Major Methods for Preparation of Potassium
Organotrifluoroborates
Addition of dialkylboranes, dialcoxyboranes or dihaloboranes to alkenes or
alkynes gives alkenylboron or alkylboron compounds respectively. Taking
advantage of this classical methods followed by treatment with potassium
hydrogendifluoride KHF
2
, potassium organotrifluoroborates can be synthesized as
well (Route B). There are many other more specific methods for the preparation of
organotrifluoroborate salts which are described in great detail in a few good
reviews that have been recently published.
23

23
Stefani, H. A.; Cella, R.; Vieira, A. S. Tetrahedron 2007, 63, 3623.
18
1.3.2 Multicomponent Condensation between Amines, Carbonyls and
Potassium Organotrifluoroborates – General Aspects and Mechanism
Potassium organotrifluoroborates have recently attracted considerable
attention in new applications. In fact, one of the first applications of
organotrifluoroborate salts was developed in our group. It was found that potassium
styrytrifluoroborate can be converted into fluorinated alcohols and amides using
highly electrophilic fluorinating agents.
24
Next we established that potassium
organotrifluoroborates participate in the three component Petasis reaction as well.
The process most likely operates under a slightly different mechanism than with
boronic acids. Due to the fact that potassium organotrifluoroborates 1.33 are
already tetravalent (nucleophilic) species, in contrast to trivalent boronic acid, there
are two major mechanic implications related to this matter.

24
Petasis, N. A.; Yudin, A. K.; Zavialov, I. A.; Prakash, G. K.S.; Olah, G. A.
Synlett, 1997, 606.
19
R
2
N
R
1
R
4
R
3
OH
B
F
R
5
F
1.42
F
B
R
5
F
F
K
+
1.33
TMSCl
1.41
F
B
R
5
F
1.21
N R
2
R
1
OH
R
3
R
4
LA
F
B
R
5
F
F
LA
N
R
2
R
1
R
4
R
3
N
R
2
R
1
N
R
3
R
4
R
2
R
1
R
2
N
R
1
H
H
2
O
LA
K
+
R
3
R
4
O
R
2
N
R
1
H
1.22
1.28
1.33
1.27
1.29
1.24
1.21
N
R
3
R
1
R
2
R
4
R
2
N
R
1
R
4
R
3
OH
R
2
N
R
1
R
4
R
3
N
R
2
R
1
H
2
O
R
2
N
H
R
1 R
5
B
F
Z
F
R
2
N
R
1
R
4
R
3
N
R
2
R
1
R
2
N
R
1
R
4
R
3
R
5 B
R
5
F
F
1.24
143
1.30
1.21
1.26 1.25 1.27
1.41
F
B
R
5
F
Z= OH
Z=
R
2
N
R
1
R
4
R
3
R
5
N
R
2
R
1

Scheme 1.15 Plausible General Mechanism of Petasis Reaction with
Organotrifluoroborates
First of all, for the nucleophilic organotrifluoroborate 1.33 an electrophilic
partner for the reaction is needed. It was identified that iminium ions 1.27 can be
the second important reactive intermediate. Therefore, in order to facilitate the
iminium ion formation a Lewis acid (LA) activator is necessary. Secondly and
20
alternatively, a trivalent boron species such as 1.41 can be generated from
tetravalent counterparts 1.33 and the reaction can follow a similar pathway to the
one with boronic acids. It is known that organotrifluoroborate salts undergo a single
boron-fluorine bond cleavage when strong Lewis acids and high temperatures are
applied.
13
Either way, the need for a Lewis acid has been identified. The plausible
mechanistic pathways are presented in Scheme 1.15.
The reactivity of a variety of potassium organotrifluoroborates has been
explored in the Petasis reaction however not in a full scope. It was demonstrated by
Huang
25
and Bryce
26
that potassium E-styryltrifluoroborate reacts with heterocyclic
aldehydes in the presence of trimethylsilyl chloride. Various organotrifluoroborate
salts were explored by Tremblay
27
and Yiannikourous
28
including potassium
vinyltrifluoroborate and aryltrifluoroborates. Very nice work by Liepouri
developed the use of potassium allenyltrifluoroborates in the Petasis reaction for
the synthesis of homopropragylamine derivatives.
29

25
Huang, W. PhD Thesis, University of Southern California, 2007.
26
Schliengen, N.; Bryce, M. R.; Hansen, T. K. Tetrahedron Lett. 2000, 41, 1303.
27
Tremblay- Morin, J. –P.; Raeppel, S.; Gaudette, F. Tetrahedron Lett. 2004, 45,
3471.
28
Yiannikourous, P. C. PhD Thesis, University of Southern California, 2006.
29
Liepouri, F. PhD Thesis, University of Southern California, 2007.
21
1.4 Synthesis of Novel Heterocycles via Petasis Reaction
The key advantage of every multicomponent reaction is its ability to
assemble highly functionalized molecules quickly and efficiently.
O
HO
HO
OH
NHBoc
OH
N
N O
R
5
R
1
R
2
R
6
R
7
N
N O
R
5
R
1
R
2
N
N
O
R
5
R
2
R
1
N
R
5
R
5
OH HO
R
2
N
R
5
O
R
2
HO
OH
OH
HO
N
N
R
2
R
1
O
R
5
N
N R
6
R
5
R
2
R
2
N
O R
5
OH
R
2
R
3
R
6
R
7
R
6
N
R
1
R
5
HO
OH
OH
O HN
R
5
O
OH
O R
5
R
6
N
N
O
CH
3
O
R
1
R
5 R
6
N
NH HN
N
O O
O R
6
R
5
R
2
N
EWG
R
5
N
R
5
R
1
R
6
N
H
N
R
6
R
2
R
5
N
N
O
R
1
R
5
H
3
C
R
6
R
2
N
H
R
1
R
3
R
4
O
B
OR R
5
OR
H
N
R
5
R
5
OH HO

Figure 1.6 Syntheses of Heterocycles via Petasis Reaction
22
These methods provide a great opportunity for further modifications and
additional variations of the process. As a result effective syntheses of novel
structures and heterocycles are enabled.
As summarized in Figure 1.6 the Petasis three component reaction generates
a large variety of heterocycles starting from simple starting materials. In this
section a comprehensive overview of the syntheses of the above shown
heterocycles in Figure1.6 is presented.
1.4.1 Synthesis of 2-Oxopiperazines and 3,4-Dihydro-quinoxalin-2-ones
2-Oxopiperazinones (piperazin-2-ones) 1.44 and 3,4-dihydro-quinoxalin-2-
ones (benzopiperazinones) 1.45 are among the molecules that can mimic a peptide
conformation due to the fact they posses conformationally restricted peptide like
bonds.
30
Their design and syntheses are powerful tools for medicinal chemistry.
N
N
R
2
O
R
5
R
1
1.44
R
6
R
7
N
N
R
2
O
R
5
R
1
1.45

Figure 1.7 Structures of Piperazin-2-one and Benzopiperazinone

30
Shuman, R. T.; Rothenberger, R. B.; Campbell, C. S.; Smith, G. F.; Gifford-
Moore, D. S. Gesellschen, P. D. J. Med. Chem. 1993, 36, 314.
23
Accordingly, the synthesis of piperazin-2-ones 1.44 and benzopiperazinones 1.45
has been comprehensively investigated and reported.
31
Many of the procedures are
target oriented that makes them lengthy, complex and impractical. The growing
interest in these structures generated a need for a new more general and practical
synthesis.
Having established the synthesis of α-amino acids via the three component
reaction with glyoxylic acid (Chapter 1, Section 1.2.2), as the next step diamines
1.46 were investigated as the amine component as presented in Scheme 1.16 for the
synthesis of piperazin-2-ones 1.44.
31

H
O
O
OH
NH
NH
R
1
R
1
N
N
R
2
O
R
5
R
1
1.46 1.23 1.31 1.44
R
5
B(OH)
2
R
6
R
7
R
6
R
7
NH
N
R
1
R
1
1.47
R
6
R
7
R
5
OH
O

Scheme 1.16 Synthesis of Piperazin-2-ones
The reaction at first produces the α-amino acids intermediate 1.47 followed by in
situ cyclization to the piperazin-2-one 1.44. The interesting part of this process is
the dual role of the boronic acid 1.23. Based on Yamamoto’s report the boronic
acid might not only participate as a reactant but also a catalyst for the final amide
bond formation.
32
The reaction could also be driven to the thermodynamically
stable product upon heating. The best results were obtained in refluxing

31
Patel. Z. D. PhD Thesis, University of Southern California, 2002.
32
Yamamoto, H.; Ohara, S.; Kazuaki, I. J Org. Chem. 1996, 61, 4196.
24
acetonitrile and the yields of the process vary from moderate to good. Similarly
benzopiperazinones 1.45 were synthesized as shown in Scheme 1.17.
H
O
O
OH
NH
NH
R
2
R
1
N
N
R
2
O
R
5
R
1
1.48 1.23 1.31 1.45
R
5
B(OH)
2
CH
3
CN
reflux

Scheme 1.17 Synthesis of Benzopiperazinones
In summary, under very mild, environmentally friendly conditions from very
inexpensive and readily available starting materials in one step a variety of
piperzion-2-ones and benzopiperazinones can be synthesized.
33

1.4.2 Synthesis of Tetrahydro-1,4-benzodiazepin-3-ones and Tetrahydro-
1,4-benzodiazepin-2-ones
Due to a wide range of biological properties, 1,4-benzodiazepines and their
derivatives are an important class of compounds in medicinal chemistry. In our
group using the unique condensation reaction, novel methodologies for the
synthesis of tetrahydro-1,4-benzodiazepin-3-ones 1.50 and tetrahydro-1,4-
benzodiazepin-2-ones 1.49 were introduced (Figure 1.8).
34,35

33
Petasis, N. A.; Patel, Z. D. Tetrahedron Lett. 2000, 41, 9607.
34
Raber, J. C. PhD Thesis, University of Southern California, 2002.
35
Yao, X. PhD Thesis, University of Southern California, 2002.
25
N
N
O
R
5
R
2
R
1
N
N
R
2
R
1
O
R
5
R
6
1.49 1.50

Figure 1.8 Structures of Tetrahydro-1,4-benzodiazepin-2-ones and
Tetrahydro-1,4-benzodiazepin-3-ones
The approach towards the synthesis of tetrahydro-1,4-benzodiazepin-3-ones 1.50 is
basically an extension of the methodology developed for the synthesis of
benzopiperazinones 1.45. The sequence starts with rapid, almost quantitative
protection of o–aminobenzylamine 1.51 as presented in Scheme 1.18.
Subsequently, the compound 1.52 is utilized in the Petasis three component
reaction for the α-amino acid synthesis of 1.53. The reaction is performed in
refluxing acetonitrile for a few hours generally producing high yields. The next step
involves Boc deprotection. A dry, in situ formed hydrochloric acid has been
utilized in the process followed by the final amide bond formation with EDCI to
yield desired product 1.54.
26
NH
2
NH
2
Boc
2
O
DCM
1.51
NHBoc
NH
2
1.52
H
O
O
OH
1.23
1.31
R
5
B(OH)
2
CH
3
CN
NHBoc
NH
1.53
R
5
OH
O
1) TMSCl, Phenol
DCM
2) EDCI, (iPr)
2
NEt
CH
3
CN
N
H
NH
O
R
5
1.54

Scheme 1.18 Synthesis of Tetrahydro-1,4-benzodiazepin-3-ones
Generally, the four step procedure gives overall good yields of tetrahydro-1,4-
benzodiazepin-3-ones 1.54.
34

The extension of the above methodology has been nicely developed for the
synthesis of tetrahydro-1.4-benzodiazepin-2-ones 1.60 as shown in Scheme 1.19.
This approach is based on an intramolecular cyclization of a glyoxamide, amine
and boronic acid.
27
NHBoc
NH
2
1.52
DCM
Pyridine
Cl
O
1.55
NHBoc
NH
1.56
O
1) HCl /AcOH
2) MeOH
R
1
H
O
1.57
3) NaBH
4
N
H
NH
1.58
O
R
1
1) HCl/Et
2
O
2) O
3
, MeOH
-78
o
C
3) (CH
3
)
2
S
4) NaOH
N
H
N
O
R
1
OH
1.59
1.23
R
5
B(OH)
2
N
H
N
O
R
1
R
5
1.60

Scheme 1.19 Synthesis of Tetrahydro-1,4-benzodiazepin-2-ones
Starting from selectively protected o-aminobenzylamine 1.52, acylation of
the aniline was accomplished with 3,3-dimethylacryolychloride 1.55 in order to
synthesize in high yields (above 80%) compound 1.56. Next, the compound 1.56
was easily deprotected and alkylated with aldehyde 1.57 via reductive amination to
obtain secondary amine 1.58. Subsequently, compound 1.58 was subjected to
ozonolysis as the HCl salt. After the process the intermediate was treated with base
in order to afford aminol 1.59. Without isolation and further purification compound
1.59 was reacted with boronic acid 1.23 in refluxing acetonitrile and the desired
product 1.60 was obtained. Overall yields are very high and vary between 60 to
80% taking into account that this is a multistep process.
34

28
With this methodology being so successful, a further expansion was
implemented as presented in Scheme 1.20. This route introduces a substituent at the
5 (benzylic) position of the tetrahydro-1,4-benzodiazepin-2-ones.
DCM
Pyridine
Cl
O
1.55
R
1
O
NH
2
1.61
R
1
O
NH
1.62
O
R
6
H
2
N
1.63
1)
Ti(OiPr)
4
2) NaBH
4
N
H
NH
1.64
O
R
6
R
1
1) HCl/Et
2
O
2) O
3
, MeOH
-78
o
C
3) (CH
3
)
2
S
4) NaOH
1.23
R
5
B(OH)
2
N
H
N
O
R
1
OH
1.65
R
6
N
H
N
O
R
1
R
5
1.66
R
6

Scheme 1.20 Synthesis of 5-Substituted Tetrahydro-1,4-benzodiazepin-2-ones
The procedure utilized 2-amino aryl ketones 1.61 as starting materials. As a
first step the high yielding acylation procedure with 3,3-dimethylacryloylchloride
1.55 was performed in order to obtain compound 1.62. Next, step-wise reductive
amination with amine 1.63, in the presence of titanium(IV) isopropoxide and
further treatment with sodium borohydride afforded compound 1.64. When
compound 1.64 was subjected to the same procedures as before the 5-substituted
29
tetrahydro-1,4-benzodiazepin-2-ones 1.66 were prepared in good overall yields
(above 50%).
35

1.4.3 Synthesis of 2-Hydroxymorpholines and 1,2,3,4-
Tetrahydropyrazines
2-Hydroxymorpholines can be found in a plethora of biologically active
compounds.
36
The main methodologies for their preparation include condensations
of 1,2-aminalcohols with α-hydroxy-
37
, α-halo-ketones
38
, and the reduction of
morpholine-2-ones
39
. Other methods involve organometallic reagents and have
been used for the synthesis of non-racemic 2-hydroxymorpholines.
40,41
The first
multicomponent approach to 2-hydroxymorpholines 1.69 was reported by Carboni
and coworkers utilizing the three component Petasis reaction of secondary 1,2-
aminoalcohols 1.67 with α-keto-aldehydes 1.68 and boronic acids 1.23 as presented
in Scheme 1.21.
42,43

36
Witjmans, R.; Vink, M. K. S.; Schoemaker, H. E.; van Delft, F. L.; Blaauw, R.
H.; Rutjes, F. P. Synthesis 2004, 641.
37
Griffin, C. E.; Lutz, R. E. J. Org. Chem. 1956, 21, 1131.
38
Cromwell, N. H.; Tsou, K. C. J. Am. Chem. Soc. 1949, 71, 993.
39
Shafer, C. M.; Molinski, T. F. J. Org. Chem. 1996, 61, 2044.
40
Marco, J. L.; Royer, J.; Husson, H.-P. Tetrahedron Lett. 1985, 26, 6345.
41
Agami. C.; Couty, F.; Prince, B.; Puchot, C. Tetrahedron 1991, 47, 4343.
42
Berree, F.; Debache, A.; Marsac, Y.; Carboni, B. Tetrahedron Lett. 2001, 42,
3591.
43
Berree, F.; Debache, A.; Marsac, Y.; Collet, B.; Bleiz, P. G.-L.; Carboni, B.
Tetrahedron, 2006, 62, 4027.
30
1.67
R
3
O
OH
OH
1.68 1.23
R
5
B(OH)
2
1.69
MeOH
N
O
R
1
NH
R
6
OH
R
7
R
3
R
5
R
6
R
7
OH
R
1

Scheme 1.21 One Step Synthesis of 2-Hydroxymorpholines
The proposed mechanism for the reaction involves addition of the activated
neighboring hydroxyl group by a boronic acid to form an iminium salt.
42
In our
group the use of chiral 1,2-aminoalcohols was investigated. When (S)-N-
benzylphenylglycinol, phenylglyoxal hydrate and 4-methoxyphenylboronic acid
were mixed together in methanol at room temperature, the reaction proceeded with
great diastereoselectivity (>99% d.e.) and enantioselectivity (>99% e.e) yielding
only one product in good yield.
34

As the next step the use of diamines 1.70 with α-keto-aldehydes 1.68
and boronic acids 1.23 was explored for the synthesis of 1,2,3,4-
tetrahydropyrazines 1.71 as shown in Scheme 1.22.
34

NH
NH
R
1
R
1
1.70
R
3
O
OH
OH
1.68 1.23
R
5
B(OH)
2
N
N
R
1
R
1
1.71
R
5
R
3
MeOH

Scheme 1.22 Synthesis of 1,2,3,4-Tetrahydropyrazines
The reaction was successfully performed in methanol, at room temperature, over 24
hours with yields of the final product being over 50%.
31
1.4.4 Synthesis of 2H-Chromenes and 1,2-Dihydroquinolines
The Petasis reaction between salicylaldehydes 1.72, amines 1.21 and
boronic acids 1.23 at room temperature forms aminophenol derivatives 1.73 as
shown in Scheme 1.23.
44

H
O
OH
N
H
R
2
R
1
1.72 1.21
OH
1.73 1.23
R
5
B(OH)
2
R
5
N
R
2
R
1
rt

Scheme 1.23 One Step Synthesis of Aminophenol Derivatives
However, when alkenyl boronic acids 1.74 are used at elevated temperatures the
reaction leads to formation of 2H-chromenes 1.75 which was reported by Finn and
coworkers under a catalytic amounts of the amine component as presented in
Scheme 1.24.
45
,
H
O
OH
N
H
R
2
R
1
B(OH)
2
R
5
1.72 1.21 1.74
O R
5
dioxane
1.75
∆

Scheme 1.24 Synthesis of 2H-Chromenes from Salicylaldehydes and Alkenyl
Boronic Acids
Similarly, when potassium alkenyltrifluoroborates 1.76 are employed in the
reaction with catalytic amounts of secondary amines 1.09 at higher temperatures
2H-chromenes 1.09 are produced in good yields as well.

44
Petasis, N. A.; Boral, S. Tetrahedron Lett. 2001, 42, 539.
45
Wang, Q.; Finn, M. G. Org. Lett. 2000, 2, 4063.
32
BF
3
K
R
5
H
O
OH
N
H
R
2
R
1
1.72 1.21 1.76
O R
5
DMF
1.75
∆

Scheme 1.25 Synthesis of 2H-Chromenes from Salicylaldehydes and Potassium
Alkenyltrifluoroborates
An extension of this methodology has been developed in our lab for the
synthesis of 1,2-dihydroquinolines 1.78 from 2-sulfamidobenzaldehydes 1.78 and
potassium alkenyltrifluoroborates 1.76 as shown in Scheme 1.26.
46

H
O
NH
1.77
BF
3
K
R
5
1.76
N R
5
TMSCl
1.78
toluene
Et
3
N
SO
2
Me
SO
2
Me

Scheme 1.26 Synthesis of 1,2-Dihydroquinolines from Potassium
Alkenyltrifluoroborates
It was found that the best results (yields around 50%) are obtained in toluene at
80
o
C and in the presence of two equivalents of trimethylsilyl chloride (TMSCl) and
triethylamine.
1.4.5 Synthesis of Polyhydroxy Piperidines
Chiral α-hydroxyaldehydes, such as unprotected sugars, participate in the
Petasis reaction with boronic acids and as a result optically pure aminopolyols are
prepared with great enantioselectivity and diastereoselectivity.
2

46
Petasis, N. A.; Butkevich, A. N. J. Organomet. Chem. 2009, 694, 1747.
33
An intramolecular version of this process as generally depicted in Scheme
1.27 was elegantly developed by Yao.
35

NH
R
1
O
OH
1.79
N
R
1
OH
OH
1.80
1.23
R
5
B(OH)
2
N
R
1
R
5
OH
1.81

Scheme 1.27 Intramolecular Version of Petasis Reaction with α-Hydroxy
Aldehydes
For this purpose compound 1.85 was prepared from commercially available 1,2-O-
isopropylidene-D-xylofuranose 1.82. Compound 1.82 was at first selectively
tosylated in the primary alcohol position followed by nucleophilic substitution by
allylamine 1.84, in order to prepare the secondary amine 1.85.
O
HO
HO
O
O
TsCl, Et
3
N
DMAP, DCM
O
TsO
HO
O
O
1.82
1.83
NH
2
CH
3
CN
reflux
1.84
O
HO
O
O
1.85
NH
DCM,
TFA:H
2
O
N
1.87
OH
OH
HO
R
5
1.23
R
5
B(OH)
2
N
1.86
OH
OH
HO
HO
H

Scheme 1.28 Synthesis of Polyhydroxy Piperidines
34
Next, the secondary amine 1.85 was treated carefully with aqueous TFA in
dichloromethane at 0
o
C to afford intermediate 1.86 which, after evaporation of the
volatiles (no purification) was treated with boronic acid 1.23. As a result the
desired product trihydroxypiperidine 1.87 was obtained. The stereochemistry of the
product was determined at first by 2D NMR spectroscopy based on the value of
coupling constants and further confirmed by X-ray crystallography. The
polyhydroxy piperidines were used as intermediates for the synthesis of
polyhydroxy indolizidines 1.91, quinolizidines 1.88, pipecolic acid 1.89 and other
molecules 1.90 as shown in Figure 1.9.
N
N
H
N
N
OH
OH HO
HO
OH
HO OH
HO
O
H
HO
OH
OH
HO
HO
H
HO
OH
OH
1.88
1.90 1.91
1.89

Figure 1.9 Structures of Heterocycles Synthesized from
Polyhydroxypiperidines
Additionally, this methodology can be further expanded to products with different
stereochemistry simply by changing the starting sugar for the process.
1.4.6 Synthesis of Oxazolidin-2-ones, Polyhydroxy Pyrrolidines,
Iminocyclitols, Tetrahydroxyazepan-2-ones and Amino Sugars
The three component Petasis reaction gives rapid access to aminopolyols
that can be converted into many complex and novel heterocyclic structures with
35
minimal synthetic efforts. For example, chiral amino alcohols, such as compound
1.94 prepared in one step via the Petasis reaction, can be converted easily to the
corresponding chiral oxazolidin-2-ones 1.95 as presented in Scheme 1.29.
34,47

1.93 1.94
R
5
NHBoc
R
2
OH
2eq. KOtBu
THF
R
5
O HN
O
R
2
1.95
Ph NH
2
Ph
1.23
R
5
B(OH)
2
H
O
R
2
OH
1.92
1) MeOH, rt
2) H
2
, Pd/C
Boc
2
O, Et
3
N
MeOH

Scheme 1.29 Synthesis of Oxazolidin-2-ones
Oxazolidin-2-ones have recently become quite useful compounds. They posses
biological activity by themselves
48
but mostly they have been employed as chiral
auxiliaries
49
. There are many methods for their synthesis, nevertheless they are
deficient in generality and scope.
50
The methodology presented in Scheme 1.29
definitely does not lack generality and is very efficient with yields being above
90%.
Polyhydroxylate aza-sugars are important potential therapeutics and are
known to mimic natural sugars.
51
Based on our unique methodology that involves
the three component condensation a new route to polyhydroxylate pyrrolidines such
as 1.101 and 1.102 has been established as shown in Scheme 1.30. At first the

47
Sugiyama, S.; Arai, S.; Ishii, K. Tetrahedron; Asymmetry 2004, 15, 3149.
48
Seki, M.; Mori, K. Eur. J. Org. Chem. 1999, 2965.
49
Ager, D. J.; Prakash, I.; Schaad, D. R. Aldrichimica Acta 1997, 30, 3.
50
Takacs, J. M.; Jaber, M. R.; Velekoop, A. S. J. Org. Chem. 1998, 63, 2742.
51
Davis, B. G.; Maughan, M. A. T.; Chapman, T. M.; Villard, R.; Courtney, S.;
Org. Lett. 2002, 4, 103.
36
Petasis reaction enables the rapid construction of β-aminopolyols 1.98 in one step
from natural chiral sugars. The aza-sugars, such as 1.101 and 1.102, can be
prepared from the corresponding β-aminopolyols 1.98 in four steps without
isolation of any intermediates in good overall yields (over 50%). The four steps
include formation of the carbonate, oxidation of the diol to the aldehyde using
sodium periodate, removal of carbonate moiety and finally an additional the three
component condensation with the same or different boronic acid for introducing
more diversity into the final product. It is worth mentioning that secondary and
easily cleavable amines such as diallylamine can be utilized in the process which at
the end affords NH-analogs of polyhydroxy pyrrolidines.
37
O OH
OH
R
1
NH
2
1.96 1.97
3) R
5
B(OH)
2
1.23
DMF
KOtBu (15 mol%)
Et
2
CO
3
excess
R
5
NH
O
R
1
1.99
1) NaIO
4
2) 1N NaOH
N
R
5
R
5
OH HO
R
1
O
HO
OH
O
1.101
3) R
6
B(OH)
2
1.100
1) NaIO
4
2) 1N NaOH
N
R
5
R
6
OH HO
R
1
1.102
1.23
R
5
B(OH)
2
MeOH
50
o
C
HO
OH
R
5
NH
OH
OH
OH
OH
1.98
R
1

Scheme 1.30 Syntheses of Polyhydroxy Pyrrolidines
Recently, based on a similar approach a concise synthesis of iminocyclitols
1.107 with high stereocontrol was reported as shown in Scheme 1.31.
52
The starting
material is commercially available 3.4-O-isopropylidene-D-mannitol 1.103 which
is converted in situ into polyhydroxyl dialdehyde 1.104 that is subsequently is
treated with acid to remove the acetone protecting group. In the next step, ammonia
and styrylboronic acid 1.105 are utilized in a double Petasis reaction.

52
Hong, Z.; Lei, L.; Sugiyama, M.; Fu, Y.; Wong, C.-H. J. Am. Chem. Soc. 2009,
131, 8352.
38
O OH
OH
O
OH
OH
1.103
1) PhI(OAc)
2
2) 0.1 M H
2
SO
4
NH
3
aq.
H
N
OH HO
1.106
B(OH)
2
Ph
1.105
Ph
Ph
d.e>98%
yield 70%
1) O
3
, HClO
4
MeOH
2) NaBH
4
in situ
H
N
OH HO
1.107
HO OH
85%
OH
O
HO
O
1.104

Scheme 1.31 Synthesis of Iminocyclitols
As a result dihydroxy pyrrolidine 1.106 can be obtained. Subsequent ozonolysis
followed by in situ reduction yield the iminocyclitols 1.107 in good yields. This
methodology can also be used for the synthesis of six-membered iminocyclitols as
well. The most interesting parts of this method are the unusual diastereoselectivity
of the process and the participation of ammonia. It is known that arabinose is able
to participate in the three component condensation with primary or secondary
amines but not with ammonia. Interestingly, when dialdehyde 1.104 is utilized in
the same process the reaction proceeds with ammonia. As far as stereochemistry is
concerned the authors claim that the reaction mechanism proceeds through a cyclic
iminium ion intermediate which results in a different than expected stereochemistry
of the process.
52

39
As previously described inexpensive and readily available diallylamines
react easily in the Petasis reaction with α-hydroxy aldehydes to give the highest
yields of amino-polyols. Another advantage diallylamine carries is the easy
removal of the allyl groups from the nitrogen. Taking advantage of these features a
rapid synthesis of a variety of amino sugars 1.111 has been established as shown in
Scheme 1.32.
31

O OH
OH
1.108 1.97
EtOH
HO
OH
N
OH
OH
OH
OH
1.109
B(OH)
2
R
5
1.74
1.111
N
H
1) Pd(dba)/DPPB
thiosalicyclic
acid
THF, 60
o
C
2) Boc
2
O
Et
3
N, MeOH
R
5
NHBoc
OH
OH
OH
OH R
5
1.110
1) O
3
, MeOH
2) (CH
3
)
2
S
O
HO
HO
OH
NHBoc
OH
75% overall yield from D-ribose
>99% d.e. and e.e

Scheme 1.32 Synthesis of Amino Sugars
After the allyl groups are removed, the amine can be protected with Boc
2
O (or
Ac
2
O) to yield compound 1.110. Subsequent ozonolysis allows for the synthesis of
amino sugar derivatives in high overall yields with great diastereoselectivities and
40
enantioselectivities. Moreover, the methodology can produce a variety of amino
sugars by changing the starting sugar component. Overall, the method extends the
length of the starting sugar by one carbon. Therefore starting with a pentose sugar,
a hexose amino sugar is obtained. Additionally, if allyl boronic acid is used instead
of an alkenyl boronic acid in the process 3-amino sugars are produced following
the same synthetic sequence.
31

Another type of heterocycle that can be derived from the amino-polyols is
tetrahydroxyazepan-2-ones, 1.116 and 1.117, as presented in Scheme 1.33. Their
synthesis starts with the Petasis reaction between cleavable allylamine 1.108, D-
glucuronic acid 1.112 and any boronic acid 1.23. The next step involves either
double or mono Pd-catalyzed deallylation which can be performed respectively at
60
o
C or ambient temperature. Subsequent amide coupling yielded 7-membered
polyhydroxylated lactams 1.116 and 1.117 in enantiomerically pure forms with
good overall yields (over 60%).
31

41
OH
O
HO
OH
OH
OH
N
R
5
1.113
OH
O
HO
OH
OH
OH
NH
3
+
Cl
-
R
5
1.114
OH
O
HO
OH
OH
OH
NH
2
+
Cl
-
R
5
1.115
N
R
5
O
HO
OH
OH
HO
H
N
R
5
O
HO
OH
OH
HO
1.116
1.117
EDC-HCl, Et
3
N, MeOH, 50
o
C
O
O
HO
MeOH
OH
OH
HO OH
1.112
1.23
R
5
B(OH)
2
HN
1.108
Pd(dba)
DPPB
thiosalicyclic
acid
60
o
C 25
o
C
THF

Scheme 1.33 Synthesis of Tetrahydroxyazepan-2-ones
1.4.7 Synthesis of Tetrahydroisoquinolines
The tetrahydroisoquinoline core can be found in many alkaloids and
biologically active compounds.
53
There are numerous methodologies describing the
synthesis of tetrahydroisoquinolines. The most common utilize the Pictet-Spengler

53
Shamma, M. The Isoquinoline Alkaloids, Chemistry and Pharmacology;
Academic Press; New York, 1977.
42
reaction and its modifications.
54
Other methods include a modified Pomerantz-
Fritsch approach
55
and Friedel-Crafts routes.
56

Based on our unique methodology that allows for the synthesis of β-amino-
alcohols in one step, a new process for the synthesis of tetrahydroisoquinolines
1.121 was developed as presented in Scheme 1.34. The approach involves
intramolecular cyclization of β-amino alcohols 1.120 promoted by TFA in the
presence of 2,6-lutidine. Five-membered ring analogs such as compound 1.124 can
be prepared as well as shown in Scheme 1.35.

In comparison to other
methodologies this approach is more practical. The synthetic sequence is shorter
because it constitutes only two steps. Moreover, it gives more diversified products
in much higher yields.
57

54
Pictet, A.; Spengler, T. Ber. 1911, 44, 2030.
55
Bobbit, J. M.; Steinfield, A.S.; Weisgaber, K. H.; Dutta, S. J. J. Org. Chem.
1969, 34, 2478.
56
Chandrasekhar, S.; Reddy, N. R.; Reddy, M. V.; Jagannadh, B.; Nagaraju, A.;
Sankar, A. R. Kunwar, A. C. Tetrahedron Lett. 2002, 43, 1885.
57
Huang, W. PhD Thesis, University of Southern California, 2007.
43
OMe
OMe
N
H
Ph
1.118
O
O
HO
OH
1.119
EtOH, reflux
85%
R
5
1.120
N
HO
Ph
MeO OMe
Tf
2
O
2,6-lutidine
DCM, -78
o
C
R
5
1.121
N
Ph
MeO OMe
85%
1.23
R
5
B(OH)
2

Scheme 1.34 Synthesis of Tetrahydroisoquinoline
OMe
OMe
H
N Ph
1.122
O
O
HO
OH
1.119
EtOH, reflux
86%
R
5
1.123
N
HO
Ph
OMe
OMe
Tf
2
O
2,6-lutidine
DCM, -78
o
C
1.124
Ph
MeO OMe
52%
OMe
OMe
OMe
N
R
5
1.23
R
5
B(OH)
2

Scheme 1.35 Synthesis of Heterocycles via Friedel-Crafts Type Cyclization
44
1.4.8 Synthesis of Heterocycles via Cycloaddition Processes
The Petasis reaction gives a rapid access to β-amino diols utilizing simple
starting materials: amines 1.126, glyceraldehyde 1.125 and boronic acids 1.23.
Taking advantage of this process a novel methodology has been introduced as
depicted in Scheme 1.36.
57

N
H
N
Ph
R
5
H
O
OH
OH
1.125
1.129
1.126
N
H
Ph Ph
R
5
1.127
N
HO
Ph
Ph OH
EtOH
reflux
86%
NaIO
4
silica gel
R
5
1.128
N
Ph
Ph
O
NH
2
TFA, 0
o
C-rt
TFA, 0
o
C-rt
CH
3
H
N
HO
1.131
HCl
N
N
O
R
5
H
3
C
Ph
Ph
1.132
95%
1.130
Ph
1.23
R
5
B(OH)
2

Scheme 1.36 Syntheses of Heterocycles via Cycloaddition Processes
45
The approach employs the amino diols 1.127, synthesized via three component
condensation in high yields that upon treatment with sodium periodate are
converted into α-amino aldehyde 1.128 derivatives. These intermediates are proven
to be excellent partners for the cycloaddition processes as reported earlier by
Bartlett and coworkers.
58
Exposing intermediate 1.128 to a primary amine 1.129,
compound 1.130 is synthesized via [4+2] cycloaddition. When N-methyl
hydroxylamine hydrochloride 1.131 was utilized in the reaction with 1.132 a
different product was prepared as a result of [3+2] cycloaddition.
1.4.9 Synthesis of Heterocycles via Five Component Union of Petasis-
Grigg Reaction
As mentioned in the Section 1.1.1 multicomponent reactions are powerful
tools for synthetic chemists. They allow for the synthesis of highly functionalized
molecules in a one step, one pot procedure from simple and inexpensive starting
materials.
One of the less explored multicomponent processes is the three component
Grigg reaction shown in Scheme 1.37.
59

58
Spaller, M. R.; Thielemann, W. T.; Brennan, P. E.; Bartlett, P. A. J. Comb.
Chem. 2002, 4, 516.
59
Grigg, R.; Idle, J.; McMeekin, P.; Vipond, J. J. Chem. Soc. Perkin Trans. 1.
1988, 2703.
46
1.133 1.134
R
1
H
N
R
2
OH
O
R
3
H
O
R
5
R
6
R
4
O
∆
-CO
2
N
R
2
R
1
R
3
R
6
R
5
R
4
O
1.135 1.136

Scheme 1.37 The Grigg Three Component Reaction
The reaction involves an amino acid component 1.133, a carbonyl component 1.134
and a dipolarophile 1.135. The mechanistic details of the Grigg reaction are
presented in Scheme 1.38.
1.133
R
1
H
N
R
2
OH
O
1.134
R
3
H
O
1.137
R
1
N
R
2
OH
O
R
3
HO
1.138
R
1
N
R
2
O
O
∆
1.139
R
1
N
R
2
-CO
2
R
5
R
6
R
4
O
1.135
R
3
R
3
N
R
2
R
1
R
3
R
6
R
5
R
4
O
1.136

Scheme 1.38 Mechanism of the Grigg Three Component Reaction
The Grigg reaction employs an amino acid 1.133 as a main component in the
sequence. One of the main applications of the Petasis reaction is in the synthesis of
α-amino acids. By putting components from the Petasis and Grigg reaction together
a novel five component process was born as shown in Scheme 1.39. This union of
two multicomponent reactions was possible due to the fact that neither simple
47
aldehydes nor dipolarophiles are reactive in the Petasis reaction with boronic acids.
The new reaction provides the best results when performed in toluene at elevated
temperatures in order to enhance decarboxylation of the α-amino acid.
R
3
1.23
R
1
NH
2
R
5
B(OH)
2
1.140
1.31
H
O
OH
OH
O
H
1.134
X
O
O
1.141
toluene
reflux
N
X
O
O
R
1
R
2
R
3
1.142
CO
2
B(OH)
3

Scheme 1.39 The Five Component Union of Petasis-Grigg Reaction
In summary, the five component process turned out to be more effective than a
step-wise synthesis although the yields were moderate.
60

1.4.10 Synthesis of Cyclic Peptides
The three component Petasis reaction was utilized in many processes in
heterocycles syntheses as described above. Below, as shown in Scheme 1.40 the
condensation was applied in the synthesis of cyclic peptides utilizing an approach
similar to the one used for the synthesis of 1,4-benzodiazepin-2-ones (Chapter 1,
Section 1.4.2). The Petasis reaction was implemented in the most important part of
the synthesis –the final cyclization. The yields of the final products such as 1.145
vary from 15% to 30%. However taking into account the size of the molecule and

60
Douglass, B. J. PhD Thesis, University of Southern California, 2006.

48
importance of cyclic peptides (Restasis, Vasopressin, Oxytocin) one can say that
this is quite a powerful synthetic approach.
60

F
N
Boc
N
Ph
O
NH
HN
O
1.143
1) O
3
, MeOH, -78
o
C
2) (CH
3
)
2
S
3) 1N HCl in AcOH
N
N
H
N
HN
O
O
Ph
O
OH
F
1.144
1.23
R
5
B(OH)
2
CH
3
CN,
reflux
N
N
H
N
HN
O
O
Ph
O
R
5
F
1.145

Scheme 1.40 Synthesis of Cyclic Peptides via Petasis Reaction

49
1.5 Conclusion
Overall, using the methodologies described above, considering the
heterocycles that can be synthesized and their importance, presents tremendous
evidence that the Petasis reaction is an extremely powerful methodology. For a one
step process coupled to a few other synthetically simple transformations, the pool
of the molecules that can be generated based on this method is impressive.
Therefore, the Petasis reaction is an example of remarkable chemistry that its story
continues in this publication.
50
Chapter 2. Novel One Step Synthesis of Highly
Functionalized N-Substituted Propargylamines, Their
Derivatives and Other Heterocycles via Novel Boron Based
Multicomponent Reactions
2.1 Introduction
2.1.1 Importance of Propargylamines
Propargylmines 2.01 (Figure 2.1) and their derivatives are important
synthetic intermediates as they offer multiple diversity sites (five different R and
triple bond modifications).
2.01
R
3
N
R
4
R
2
R
1
R
5

Figure 2.1 General Structure of Propargylamine
Propargylamines are both biologically important and synthetically useful amine
derivatives. They exhibit significant biological activity. Their substructures are
present in several valuable biomolecules such as oxotremorine 2.08 and oxybutynin
2.06 - muscarinic receptor inhibitors (Figure 2.3).
61
Oxybutynin is widely

61
Ricci, A. Amino Group Chemistry: from synthesis to the life sciences, Wiley-
VCH, 2008.
51
prescribed for the treatment of urinary frequency, urgency and urge incontinence.
62

The propargyl amine moiety was found to inhibit the monoamine oxidases (MAOs)
therefore they are useful agents in the symptomatic treatment of Parkinson’s
disease. This group includes compounds such as Selegiline 2.02, Clorgyline 2.05,
Rasagiline 2.03 and Ladostigil 2.04.
63
Aside from neuroprotective properties,
propargylamines are also present in non-nucleoside reverse transcriptase inhibitors
such as compound 2.09.

62
Gupta, P.; Fernandes, R. A.; Kumar, P. Tetrahedron Lett. 2003, 44, 4231.
63
Maruyama, W.; Akao, Y.; Carrillo, M. C.; Kitani, K. -I.; Youdium, M. B. H.;
Naoi, M. Neurotoxicology and Teratology, 2002, 24, 675.
52
CH
3
N
CH
3
2.02
Selegiline
HN
Rasagiline
2.03
Cl
Cl
O
N
CH
3
Clorgyline
2.05
CH
3
N
CH
3
(R)-2HMP
2.07
N
O
O
HO
Oxybutynin
2.06
HN
O
O
N
CH
3
Ladostigil
2.04
N
N
O
Oxotremorine
2.08
Cl
N
H
NH
O
N
HIV inhibitor
2.08

Figure 2.2 Examples of Biologically Active Molecules with Propargylamine
Moiety
2.1.2 Synthetic Approaches towards Propargylamines
There has been a substantial interest in the development of synthetic
methods towards propargylamines due to their great synthetic potential and
53
biological properties. In addition, propargylamines are known to be useful synthons
in the formation of heterocycles
64,65
and biomimetic polymers
66
.
R
3
N
R
4
R
2
R
1
R
5
R
3
R
4
N
R
2
R
3
Li
H
N
OSOPh
R
4
O
RO
R
3
Li
R
2
N
R
1
S
R
3
Li
N
N
N
R
4
N
R
2
R
1
R
3
M
R
4
N
R
2
R Cl
O
R
3
Ti (OiPr)
3
R
3
TMS
N
N O
X
R
O
N
H
Ph
CF
3
R
4
M
N
R
2
R
3
R
3
N
R
2
R
1
R
4
CuBr
R
3
N
H
R
2
R
1
CuBr
R
4
O
R
3
N
R
2
R
1
R
4
ZnI
2
X
R
3
N
R
2
R
1
R
4
R
5
CuCl
R
3
CuI
R
4
N
N
H
R
2
R
1
Br
I
CuI
PdCl
2
(PPh
3
)
2
R
5
R
4
Br
H
N
H
R
2
R
1
KOH aq.
I
II
III
IV
V
VI
VII
VIII
IX
X
XI
XII
XIII
XIV
XV
CuI
R
2

Figure 2.3 Synthetic Approaches to Propargylamines

64
Arcadi, A.; Cacchi, S.; Cascia, L.; Fabrizi, G.; Marinelli, F. Org. Lett. 2001, 3,
2501.
65
Wipf, P.; Aoyama, Y.; Benedum, T. E.;Org. Lett. 2004, 6, 3593.
66
Tabei, J.; Nomura, R.; Masuda, T. Macromlecules 2002, 35, 5404.
54
Figure 2.3 summarizes major synthetic approaches to propargylamines. As
is illustrated numerous, different approaches have been developed to date. The
propargylamines can be assembled from diverse building blocks such as imines,
aldehydes, amines, acid chlorides and alkynes using a wide range of metal
catalysts. One of the most recently developed methodologies (Route I, Figure 2.3)
relies on the multicomponent reaction approach. It utilizes an imine 2.10, acid
chloride 2.11 and alkyne 2.12 to synthesize secondary propargylamides 2.13 in a
one pot procedure with copper (I) iodide as a catalyst as is presented in Scheme
3.01.
67

R
1
H
N
R
2
2.10
R
3
Cl
O
R
4
2.12 2.11
10% CuI
NR
3
, rt
N
R
2
R
1
2.13
O
R
3
R
4

Scheme 2.1 Synthesis of Propargylamides via Three Component Reaction
The reaction usually proceeds at room temperature and the products are obtained in
good yields generally from 60 to 90%. In addition, the authors reported the use of
zinc (II) triflate as a more efficient catalyst if N-trimethylsilyl-imines are used in
the reaction instead.
Addition of alkynes to imines is one of the most important and commonly
used approaches towards generating substituted propargylamines. The classical

67
Black, D. A.; Arndtsen, B. A. Tetrahedron 2005, 61, 11317.
55
addition reactions (Route XV, Figure 2.3) require the use of stoichiometric amounts
of organometallic reagents such as organolithium, organosodium or Grignard
reagents. Furthermore, activation of the imine by the addition of Lewis acids (such
as boron trifluoride complex) is necessary due to poor reactivity of imines to
nucleophilic organometallic reagent as presented in Scheme 2.2.
68

R
1
H
N
R
2
2.10
R
4
2.14
NH
R
2
R
1
2.15
R
4
M
M= Li, Na, MgBr
BF
3
.
Et
2
O

Scheme 2.2 Addition of Alkynyl Organometallics to preformed imines
Wada and coworkers proposed that the reaction proceeds through alkynylborate
species that are formed in situ from lithium (or other metal) acetylides and a boron
trifluoride complex.
69
Crousse and coworkers described the synthesis of
trifluoromethyl propargylamines from trifluoromethyl aldimines and acetylides
without any Lewis acid in good yields, usually above 70%. The reaction is
performed in toluene with low temperatures typically at -78
o
C.
Major progress in the synthesis of propargylamines was marked by the use
of copper, gold and silver salts as catalysts in the reaction of imines 2.10 with
alkynes 2.12 as shown in Scheme 2.3 (Route II, Figure 2.3).

68
Layer, R. W. Chem. Rev. 1963, 63, 489.
69
Wada. M.; Sakurai, Y.; Akiba, K.-Y. Tetrahedron Lett. 1984, 25, 1083.
56
R
1
H
N
R
2
2.10
R
4
2.12
10% CuX
NH
R
2
R
1
2.15
R
4

Scheme 2.3 Metal-catalyzed Addition of Alkynes to Imines
Usually catalytic amounts of the appropriate metal salts are needed in order to
achieve good yields. The design of the reaction even allows for the synthesis of
enantiomerically pure propargylamines by using chiral ligands with the appropriate
metal catalyst.
70
One of the disadvantages of this process is the necessity for the
synthesis and isolation of the imines. Therefore the development of
multicomponent metal-catalyzed synthesis of propargylamines was a major
advance in the field as shown in Scheme 2.4 (Route VII, Figure 2.3). Diverse metal
catalysts can be used as demonstrated by Li and coworkers.
71

2.17
R
4
2.12
2% CuI
N
R
2
2.18
R
4
R
1
N
H
R
2
2.16
R
1
R
3
H
O
R
3

Scheme 2.4 Metal-catalyzed Three Component Synthesis of Propargylamines
Chiral propargylamines can be accessed through this methodology as is reported by
Knochel and coworkers. They utilized non-enolizable aldehydes 2.17, secondary
amines 2.16 and alkynes 2.12 in the presence of copper bromide (5 mol%), (R)-

70
Wei, E. Li, C.-J. J. Am. Chem. Soc. 2002, 124, 5638.
71
Wei, C. Li, C.-J. J. Am. Chem. Soc. 2003, 125, 9584.
57
Quinap and molecular sieves in order to enantioselectively (up to 96% e.e.)
synthesize chiral propargylamines in excellent yields (up to 99%).
72

An alternative methodology involves addition of organometallic reagents
2.20 to preformed alkynyl imines 2.19 (Route V, Figure 2.3) as Scheme 2.5
illustrates. Organozinc and organocerium reagents were found to show great
reactivity toward alkynyl imines at low temperatures.
73

R
4
M
N
R
2
R
3
2.20 2.19
NH
R
2
R
4
2.21
R
3
THF
-100
o
C

Scheme 2.5 Addition of Organozinc or Organocerium Reagents to
Alkynylimines
Additions of organometallic species to other types of electrophiles have also
been reported. A conceptually different approach was introduced by Katritzky and
coworkers in 1989 (Route XIV, Figure 2.3). The approach involves organolithium
74

or organomagnesium
75
reagents 2.22 with 1-(dialkylaminomethyl)-benzotriazoles
2.21 as stable iminium salt precursors as illustrated in Scheme 2.6.

72
Gommermann, N.; Koradin, C.; Polborn, K.; Knochel, P. Angew. Chem. Int. Ed.
2003, 42, 5763.
73
Enders, D.; Schankat, J. Helvetica Chimica Acta 1995, 78, 970.
74
Katritzky, A. R.; Gallos, J. K.; Yannakopoulou, K. Synthesis 1989, 31.
75
Katritzky, A. R.; Nair, S. K.; Qui, G. Synthesis 2002, 199.
58
N
N
N
R
3
N
R
2
R
1
R
4
2.22
N
R
2
R
1
R
3
2.18
R
4
2.21
Li
THF
-78
o
C

Scheme 2.6 Katritzky’s Approach to Propargylamines
α-Amidoalkyl sulfones 2.23 can be utilized for the synthesis of
propargylamines in good yields (65-90%) using 1-alkynyllithium reagents 2.22 as
shown in Scheme 2.7 (Route XIII, Figure 2.3).
76

H
N
OSOPh
R
3
O
RO
2.22 2.23
R
4
Li
NH
R
3
2.24
R
4
THF
-78
o
C
RO
O

Scheme 2.7 Addition of 1-Alkynyllithium Reagents to α-Amidoalkyl Sulfones
α-Amidoalkyl sulfones 2.23 are considered N-acyl imine equivalents and can be
prepared from a suitable aldehyde, carbamate and sodium benzenesulfinate in the
presence of formic acid.
77

Tertiary propargylamines 2.28 can be accessed via sequential reactions of in
situ generated thioiminium salts with organolithium 2.22 and organomagnesium
2.28 reagents as shown in Scheme 2.8 (Route XII, Figure 2.3).
78

76
Mecozzi, T.; Petrini, M. J. Org. Chem. 1999, 64, 8970.
77
Kanazawa, A. M.; Denis, J. N.; Greene, A. E. J. Org. Chem. 1994, 59, 1238.
59
R
2
N
R
1
S
2.22 2.25
R
4
Li
N
R
2
R
1
SMe
2.26
R
4
MeOTf, rt
Et
2
O
2.27
R
5
MgBr
N
R
2
R
1
2.28
R
5
R
4

Scheme 2.8 Synthesis of Tertiary Propargylamines
Thioiminium salts are generated from thioamides 2.25 and methyl triflate (MeOTf).
Alkynyltriisopropoxytitanium reagents can be employed for the synthesis of
propragylamines as well (Route III, Figure 2.3).
79
However, the
alkynyltriisopropoxytitanium reagents are usually prepared via transmetalation of
1-alkynyllithium reagents and are less reactive than the parent compounds as well.
Trifluoromethyl-propargylamines 2.31 can be synthesized from 2-
trifluoromethyl-1,3-oxazolidines 2.29 and bis-trimethylsilylacetylene 2.30 under
Lewis acid activation as shown in Scheme 2.09 (Route IV, Figure 2.3).
80

O
N
H
Ph
CF
3
2.29
TMS
2.30
TMS
HN
CF
3
2.31
TMS
BF
3
.
Et
2
O
OH
Ph
DCM
Reflux

Scheme 2.9 Lewis Acid Activation of 2-Trifluoromethyl-1,3-oxazolidines

78
Murai, T.; Mutoh, Y.; Ohta, Y.; Murakami, M. J. Am. Chem. Soc. 2004, 126,
5968.
79
Gunderson, L.-L.; Rise, F.; Undheim, K. Tetrahedron 1992, 48, 5647.
80
Lebouvier, N.; Laroche, C.; Huguenot, F.; Brigaud, T. Tetrahedron Lett. 2002,
43, 2827.
60
However, the yields of the reaction are low and only modest diastereoselectivities
were obtained.
Knochel and coworkers developed a new copper-catalyzed addition of
alkynes 2.12 to enamines 2.32 as Scheme 2.10 illustrates (Route XI, Figure 2.3).
81

N
R
2
R
1
R
3
CuBr (5mol%)
2.12
R
4
2.32
toluene
R
5
N
R
2
R
3
2.33
R
4
R
1
R
5

Scheme 2.10 Synthesis of Propargylamines by Copper-catalyzed Addition of
Alkynes to Enamines
The reaction conditions are pretty mild (toluene at room temperature or 60
o
C) and a
wide range of functionalized alkynes participate in the reaction. The use of chiral
ligand such Quinap allows for the enantioselective synthesis of propargylamines.
A very interesting approach was recently developed by Fu and coworkers
(Route VI, Figure 2.3). Their methodology gives access to propargylamines 2.18
via C-H activation with copper bromide (Scheme 2.11).
82

N
R
2
R
1
R
3
2.34 2.12
R
4
CuBr, NBS
CH
3
CN
80
o
C
N
R
2
R
1
R
3
2.18
R
4

Scheme 2.0.11 Copper-catalyzed Coupling of Tertiary Aliphatic Amines with
Terminal Alkynes

81
Koradin, C.; Polborn, K.; Knochel, P. Angew. Chem. Int. Ed. 2002, 41, 2535.
82
Niu, M.; Yin, Z.; Fu, H.; Jiang, Y.; Zhao, Y. J. Org. Chem. 2008, 73, 3961.
61
This approach utilized a very simple and effective catalyst/free radical initiator
system (CuBr/NBS) to promote alkynylation of tertiary aliphatic amines 2.34.
Caporusso and coworkers have studied reactions of nitrogen nucleophiles
with 1-bromoallenes 2.35. They also developed a new method for the synthesis of
propargylamines 2.36 as Scheme 2.12 illustrates (Route VIII, Figure 2.3).
83

R
5
R
4
Br
H
N
H
R
2
R
1
KOH aq.
2.35 2.16
N
R
2
R
1
R
4
2.36
R
3

Scheme 2.12 Aminolysis of Bromoallenes in Aqueous Alkaline Medium
The reaction usually produced lots of side products and yields were moderate. The
authors improved the reaction outcome significantly by adding copper bromide as a
catalyst and switching to acetonitrile as a reaction medium.
In recent years, Sonogashira coupling of aryl halides with propargylamines
has received considerable attention.
84
Based on this approach Alami and coworkers
have developed a new three component metal-catalyzed coupling reaction leading
to substituted propargylamines 2.39 as presented in Scheme 2.13 (Route IX, Figure
2.3).
85

83
Geri, R.; Polizzi, C.; Lardicci, L.; Caporusso, A. M. Gazzetta Chimica Italiana
1994, 124, 241.
84
Mladenova, M.; Alami, M.; Linstrumelle, G. Synth. Commun. 1995, 25, 1401.
85
Olivi, N.; Spruyt, P.; Peyrat, J.-F.; Alamin, M.; Brion, J.-D. Tetrahedron Lett.
2004, 45, 2607.
62
N
H
R
2
R
1
Br
I
CuI
PdCl
2
(PPh
3
)
2
2.37 2.38 2.16 2.39
N
R
2
R
1

Scheme 2.13 Tandem Amine Propargylation-Sonogashira coupling for the
Synthesis of Functionalized Propargylamines
The reaction utilizes simple and readily available starting materials propargyl
bromide 2.37, aryl halide 2.38 and amine 2.16 and generates desired product in
high yields (70-95%).
Very mild conditions for the synthesis of propargylamines 2.18 were
developed by Sakai and coworkers as shown in Scheme 2.14 (Route X, Figure
2.3).
86

N
R
2
R
1
R
3
MeO
2.40 2.12
R
4
N
R
2
R
1
R
3
2.18
R
4
InBr
3
, Et
3
N
rt, Et
2
O

Scheme 2.14 Alkynylation of N,O-Acetals
The process utilizes N,O-acetals 2.40 and alkynes 2.12 in the presence of indium
bromide and triethylamine. The reaction conditions are very mild and usually yields
are above 70%.
The existing methodologies for the synthesis of propargylamines often
utilize organometallic reagents and they lack generality and versatility.

86
Sakai, N.; Hirasawa, M.; Konakahara, T. Tetrahedron Lett. 2003, 44, 4171.
63
Nevertheless, there has been some movement in the recent literature towards use of
non-metallic intermediates for the synthesis of propargylamines. In particular, there
is a two-component process that utilizes chiral binaphthol alkynylbornates 2.42 and
N-acyl imines 2.41 for the enantioselective synthesis of propargylamides 2.43 as
presented in Scheme 2.15.
87

R
1
H
N CH
3
O
Ph
O
O
Ph
B R
2
R
1
HN CH
3
O
R
2
DCM, 24 h
-78
o
C to rt
2.41 2.42 2.43

Scheme 2.15 Asymmetric Synthesis of Propargylamides
High enantioselectivities were obtained (> 90% ee) however the preparation and
cost of chiral binaphthol alkynylboronates 2.42 make this process lack practicality
and generality.
The other method that uses alkynyl diisopropylboronates 2.44 was
developed in our group.
88
It is based on the Petasis three component reaction which
was described extensively in Chapter 1.

87
Wu, T. R.; Chong, J. M. Org. Lett. 2006, 8, 15.
88
Liepouri, F. PhD Thesis, University of Southern California, 2007.
64
R
1
N
R
2
H
B(OiPr)
2
DCM, rt
N
R
2
R
1
2.44 2.16 2.46 2.45
MeO
O
O OH
HO
MeO
OH

Scheme 2.16 Petasis Reaction of Alkynylboronate with Glycol Aldehyde Dimer
It is commonly known that alkynylboronates such as 2.44 are usually unstable
compounds. The carbon-boron bond readily hydrolyzes in aqueous media or in the
presence of oxygen nucleophiles.
89
As it is shown in Scheme 2.16 the alkynyl
boronate 2.44 seems to be stable enough to be isolated and used under controlled
conditions in the multicomponent condensation. However, the only successful
results were recorded with glycol aldehyde dimer 2.45 as a carbonyl component
using both primary and secondary amines. Although the yields of the reaction are
good to excellent the use of quasi stable alkynylboronates lacks of generality.
In summary, while there are many methods developed for the synthesis of
propargylamines, the copper catalyzed Mannich type reaction has received the most
attention. Yet the reaction utilizes metal catalysts and purification of the final
product from the metal residues (especially for the use as pharmacologically active
agents) can be challenging and costly. Therefore, taking into account that
propargylamines are extremely important building blocks and they possess valuable
biological properties, there is still a need for better methodology. The new

89
Hall, D. G. Boronic Acids; Wiley-VCH 2006
65
methodology should utilize a multicomponent approach with minimal synthetic
efforts for the preparation of the starting materials.
2.2 Results and Discussion
This section discusses the use of the multicomponent reaction known as the
Petasis reaction with potassium alkynyltrifluoroborates for the synthesis of highly
functionalized and structurally diverse propargylamines and other heterocycles as
shown in Figure 2.1. The approach accommodates a wide range of functional
groups and the starting materials are readily available.
R
1
N
R
2
H
R
3
BF
3
K
R
4
H
O
N
N
R
2
O
R
1
R
3
R
3
N
R
5
R
2
R
1
H
R
3
N
OH
OH
OH
R
1
R
2
n
N OH
R
2
R
1
R
3
R
3
N
OH
R
1
R
2
R
3
N
H
R
2
R
1
H
R
2
N
R
3
B
O
O
N
O
R
2
R
3
R
4
N
N
N
Ph
N
R
2
R
1

Figure 2.4 Propargyalamines and N-Heterocycles via Petasis Reaction with
Alkynyl Trifluoroborates
66
In general, the process is quite effective and overcomes limitations of other
methodologies. Additionally, a few post-multicomponent transformations were
performed in order to show applications of the methodology and obtain novel
heterocyclic scaffolds.
2.2.1 Novel Approach to Propargylamines Using Air-Stable Potassium
Alkynyl Trifluoroborates
2.2.1.1 Potassium Alkynyltrifluoroborates – General Aspects and Synthesis
There are many synthetic approaches towards potassium
organotrifluoroborates as described in the Chapter 1 of this publication. However,
for the synthesis of potassium alkynyltrifluoroborates 2.48 two major methods were
employed as shown in Scheme 2.17.
1) n-BuLi
2) B(OiPr)
3
3) KHF
2
aq.
R H R BF
3
K
2.47
R MgBr
2.49 2.48
2) KHF
2
aq.
1) B(OiPr)
3
Method A Method B

Scheme 2.17 Synthesis of Potassium Alkynyltrifluoroborates
Depending on the availability of the starting materials, the corresponding method
was utilized as is summarized in Table 2.1. One of the methods employs alkynyl
Grignard reagents 2.49 that can be transformed in one pot into the corresponding
potassium alkynyltrifluoroborates 2.48 (Method B). However, the most common
applied synthesis involves deprotonation of 1-alkynes 2.47 with n-butyllithium,
followed by transmetallation with an appropriate borate species and in situ
treatment with inexpensive KHF
2
(Method A).
67
Table 2.1 Synthesis of Potassium Alkynyltrifluoroborates
Entry
Potassium
Alkynyltrifluoroborate
Yield [%] Method
1
BF
3
K

2.50
86 A
2
CH
3
(CH
2
)
3
BF
3
K

2.51
76 A
3
TMS BF
3
K

2.52
45 A
4
(Pri)
3
Si BF
3
K

2.53
46 A
5
H BF
3
K

2.54
54 B
6
BF
3
K
O
O
2.55
40 A

This method is considered to be a very efficient and versatile procedure for the
synthesis of potassium alkynyltrifluoroborates. It was described for the first time by
Genet and coworkers
90
and later applied in the cross-coupling reactions by

90
Darses, S.; Michaud, G.; Genêt, J. P. Eur. J. Org. Chem 1999, 1875.
68
Molander
91
. In addition to cross-coupling reactions, potassium
alkynyltrifluoroborates have recently found applications in 1,4-alkynylation of
acyclic enones
92
, tandem cationic 2-aza-Cope rearrangement – Lewis Acid
promoted Petasis reaction
93
, synthesis of monofluorinated propargylamines from
fluoroaziridines
94
and synthesis of α-C-glycosides
95
. Kabalka and coworkers
utilized potassium alkynyltrifluoroborates in the Mannich reaction with
salicylaldehydes in ionic liquids.
96
In addition to the use of potassium
alkynyltrifluoroborates there are a few reports that utilized lithium
alkynyltriisopropoxyborates in the palladium catalyzed synthesis of ynones
97
as
well as alkynyl(pinacol)boronic esters for the cycloaddition processes
98
.
Nevertheless, the stability of potassium alkynyltrifluoroborates over its pinacol
ester derivatives is much higher which makes them more practical to use.

91
Molander, G. A.; Katona, B. W.; Machrouhi, F. J. Org. Chem. 2002, 67, 8416.
92
Berolini, F.; Woodward, S. Synlett 2009, 1, 51.
93
Stas, S. Tehrani, K. A.; Laus, G. Tetrahedron 2008, 64, 3457.
94
Konev, A. S.; Stas, S.; Novikov, M. S.; Khlebnikov, A. F.; Tehrani, K. A.
Tetrahedron 2008, 64, 117.
95
Vieira, A. S.; Fiorante, P. F.; Hough, T., L. S.; Ferreira, F. P.; Lüdtke, D. S.;
Stefani, H. A. Org. Lett. 2008, 10, 5215.
96
Kabalka, G. W.; Venkataiah, B.; Dong, G. Tetrahedron Lett. 2004, 45, 729.
97
Oh, C. H.; Reddy, V. R. Tetrahedron Lett. 2004, 45, 8545.
98
Geny, A. Lebeouf, D.; Rouquie, G,; Vollhardt, K. P. C.; Malacria, M.; Gandon,
V.; Aubert, C. Chem. Eur. J. 2007, 13, 5408.
69
In summary, we have been able to synthesize a series of potassium alkynyl
trifluoroborates and we have investigated their applications in the three component
Petasis reaction.
2.2.1.2 Petasis Reaction with Potassium Organotrifluoroborates - General
Aspects and Mechanism
With potassium alkynyltrifluoroborates 2.48 in hand, we investigated their
use in the Petasis reaction. Having a theory of the mechanism as shown in Scheme
2.18 and described in detail in Chapter 1 that presumably involves formation of
iminium ion 2.19 we wanted to first test our mechanistic hypothesis.
70
R
2
N
R
1
R
4
R
3
OH
B
F
R
5
F
2.59
F
B
R
5
F
F
K
+
2.56
TMSCl
2.57
F
B
R
5
F
2.16
N R
2
R
1
OH
R
3
R
4
LA
F
B
R
5
F
F
LA
N
R
2
R
1
R
4
R
3
N
R
2
R
1
N
R
3
R
4
R
2
R
1
R
2
N
R
1
H
H
2
O
LA
K
+
R
3
R
4
O
R
2
N
R
1
H
2.64
2.65
2.56
2.19
2.61
2.63
2.16
N
R
3
R
1
R
2
R
4
R
2
N
R
1
R
4
R
3
OH
R
2
N
R
1
R
4
R
3
N
R
2
R
1
H
2
O
R
2
N
H
R
1 R
5
B
F
Z
F
R
2
N
R
1
R
4
R
3
N
R
2
R
1
R
2
N
R
1
R
4
R
3
R
5 B
R
5
F
F
2.63
2.60
2.62
2.16
2.61 2.58 2.19
2.57
F
B
R
5
F
Z= OH
Z=
R
2
N
R
1
R
4
R
3
R
5
N
R
2
R
1

Scheme 2.18 Plausible Mechanism of Petasis Reaction with Potassium
Organotrifluoroborates
For this purpose we utilized the preformed iminium ion known as
Eschenmoser’s salt 2.66 with potassium alkynyltrifluoroborates 2.48 as indicated in
Scheme 2.19. We did not have to use any Lewis Acid as catalyst because of the
preformed iminium ion.
71
30 min
PhMe, 100
o
C
R
5
BF
3
K
N
Me Me
H H
R
5
N
H
Me Me
H
No Lewis acid
2.48 2.66 2.67

Scheme 2.19 Use of Eschenmoser’s Salts with Potassium Alkynyl
Trifluoroborates
It turned out that the reaction proceeded well at higher temperature in toluene as
shown in Table 2.2.
Table 2.2 Use of Eschenmoser’s Salt
Entry Product Yield [%]
1
N
CH
3
CH
3

2.68
88
2
CH
3
(CH
2
)
5
N
CH
3
CH
3

2.69
74

Encouraged by the results with preformed iminium ions as a next step we explored
the three component reaction with potassium alkynyltrifluoroborates 2.48.

72
2.2.1.4 One Step Synthesis of N-Substituted Propargylamines Using
Paraformaldehyde
As a model reaction to determine the best conditions for the three
component condensation we utilized potassium (phenylethynyl)trifluoroborate,
paraformaldehyde and morpholine. We have investigated a number of solvents
such as toluene, dimethylformamide, dioxane, acetonitrile, methanol and
dichloromethane. We have determined the best yields were obtained in toluene and
dioxane. We established that the reaction proceeds well at higher temperatures,
usually above 80
o
C, which probably has a lot to do with the solubility of potassium
alkynyltrifluoroborates. The potassium alkynyl trifluoroborates as mentioned above
are very hydrolytically stable compounds, but at the same time the solubility of
these salts in organic solvents at room temperature is quite limited.
In order to solve the problem of solubility of potassium
alkynyltrifluoroborates 2.48 we have prepared the corresponding tert-
butylammonium salts 2.70 according to the procedure shown in Scheme 2.20. The
reaction is very simple and involves the use of tert-butylammonium hydroxide in
DCM at room temperature.
R
5
BF
3
K
2.48
R
5
BF
3
N(tBu)
4
2.70
DCM, rt
(tBu)
4
NOH

Scheme 2.20 Synthesis of tert-Butylammonium Alkynyltrifluoroborates
The tert-butylammonium-trifluoroborate salts were isolated in almost quantitative
yields and as expected they are soluble in many organic solvents.
73
While the solubility of tert-butylammonium alkynyltrifluoroborates
increased significantly the reactivity in the three component reaction did not
improve at all. In fact, the yields of the isolated product were much lower than in
the case of potassium alkynyltrifluoroborates. The main reason is most likely the
presence of a big counter ion which might interfere with or block the reaction site.
Table 2.3 Synthesis of tert-Butylammonium Alkynyltrifluoroborates
Entry
Tert-butylammonium
Alkynyltrifluoroborate
Yield [%]
1
BF
3
N(tBu)
4

2.71
99
2
CH
3
(CH
2
)
3
BF
3
N(tBu)
4
2.72
99
3
TMS BF
3
N(tBu)
4
2.73
99

If the theory of the mechanism going through a tight ion pair is correct, the
presence of a bulky counter ion such as tert-butylammonium might solvate the
borate and prevent it from participating in the reaction.
Knowing that formation of an iminium ion is a key step for the reaction to
proceed we have investigated the use of many Lewis acids as promoters for the
iminium ion formation. Although the Petasis reaction with potassium
74
alkynyltrifluororborates proceeds without the presence of Lewis acids the yields are
very low (20-30%) and the reaction time is quite long (over one week at 100
o
C).
Therefore we explored use of iminium ion formation enhancers such as TMSCl,
BF
3
.
Et
2
O, Sc(OTf)
3
, Yb(OTf)
3
and Zn(OTf)
2
. Generally, the reaction proceeds well
with each Lewis acid. However, stronger Lewis acids such as TMSCl and BF
3
.
Et
2
O
require use of moisture and oxygen free atmosphere. In addition, they have to be
used in stoichiometric amounts and as discussed in Chapter 1 the mechanistic
pathway of the reaction might be going through in situ formation of
alkynyldifluoroborane. On the other hand, the lanthanide salts are considered to be
mild Lewis acids. They are hydrolytically stable and work well even in aqueous
conditions. In contrast to stronger Lewis acids their role in the reaction relies
mostly on activation of the aldehyde and enabling formation of the iminium ion.
Their biggest advantage is that they can be used catalytically (typically 5 mol%)
and they can be recycled if needed. Therefore we decided that we are going to
utilize ytterbium triflate Yb(OTf)
3
in the multicomponent reaction when possible.
As a result of using Yb(OTf)
3
we have been able to demonstrate the
reactivity of potassium alkynyltrifluoroborte salts in the Petasis reaction. As shown
in Scheme 2.21 we explored the use of paraformaldehyde (in its polymerized form)
with a wide range of secondary amines.
75
R
1
N
R
2
H
R
5
BF
3
K
PhMe, 100
o
C
5 mol% Yb(OTf)
3
30 min.
R
5
N
H
R
2
R
1
H
(CH
2
=O)n
2.48 2.16 2.75 2.74

Scheme 2.21 Use of Paraformaldehyde in Petasis Reaction with Secondary
Amines
Table 2.4 summarizes the results.
Table 2.4 Use of Paraformaldehyde and Secondary Amines in the
Multicomponent Reaction

Entry Amine Product Yield[%]
1
N
H
O

2.76
N
O

2.77
82
2
N
H
2.78
N

2.79
82
3
N
Boc
H
N

2.80
N
NBoc

2.81
84
4 Ph N
H
CH
3

2.82
N
CH
3
Ph

2.83
77
76
Table 2.4 Cont.
Entry Amine Product Yield[%]
5
N
H
2.78
TMS
N

2.84
69
6
N
H
O

2.76
TMS
N
O

2.85
67
7
N
H
2.78
CH
3
(CH
2
)
5
N

2.86
94
8
N
Boc
H
N

2.80
CH
3
(CH
2
)
5
N
NBoc

2.87
99
9
NH
MeO

2.88
N
OMe
2.89
83
10
HN
Ph
Ph

2.90
N
Ph
Ph

2.91
88
77
Table 2.4 Cont.
Entry Amine Product Yield[%]
11
Ph
NH

2.92
N
Ph

2.93
36
12
Ph N
H
CH
3

2.82
CH
3
(CH
2
)
5
N
CH
3
Ph

2.94
95
13
Ph
H
N Ph

2.95
CH
3
(CH
2
)
5
N
Ph Ph
2.96
74
14
Ph
H
N H
3
C

2.97
N
Ph CH
3

2.98
87
15
Ph N
H
CH
3

2.82
Si(iPr)
3
N
CH
3
Ph

2.99
74
16
Ph
H
N

2.100
N
Ph

2.101
94

78
Table 2.4 Cont.
Entry Amine Product Yield[%]
17
Ph
NH

2.102
N Ph

2.103
72
18
Ph
N
H
2.104
N
Ph
2.105
73
19
Ph N
H
CH
3

2.82
N
CH
3
Ph
2.106
94
20
Ph
N
H
Ph

2.103
N
Ph
Ph

2.107
57
21
Ph
NH

2.102
CH
3
(CH
2
)
5
N
Ph

2.108
76
22
Ph
HN
I

2.109
N
I
Ph

2.110
76

79
Table 2.4 Cont.
Entry Amine Product Yield[%]
23
N
H
2.116
N
O O

2.111
99
24
Ph
HN
I

2.109
CH
3
(CH
2
)
5
N
Ph
I

2.112
63
25
Ph
H
N Ph

2.95
TMS
N
Ph Ph
2.113
N Ph
Ph
2.114
45

45
26
Ph N
H
CH
3

2.82
N
CH
3
Ph
2.106
TMS
N
CH
3
Ph
2.115
37

26

80
Table 2.4 Cont.
Entry Amine Product Yield[%]
27
NH
MeO

2.88
N
OMe

2.117
TMS
N
OMe

2.118
75

25
28
N
H
H
N

2.119
Ph
N
N
Ph

2.120
97

As Table 2.4 indicates the secondary amines react with paraformaldehyde and
potassium trifluoroborates very well. The yields are high to excellent and the
reaction time is very short as well. Secondary diamines react in a similar fashion
(Entry 28). In the case of potassium trimethylsilylethynyltrifluoroborate 2.52 and
arylamines a mixture of two products was obtained. Removal of the trimethylsilyl
group under these mild was quite surprising. It is worth mentioning that the
commercially available 40% aqueous solution of paraformaldehyde participates in
the reaction under the same conditions with a similar outcome.
81
The propargylamines are very important intermediates in the synthesis of
pharmaceutically active ingredients. One of these ingredients is oxybutynin 2.121,
(sold under the brand name Ditropan®, which is widely prescribed for the
symptoms associated with urinary track infections. The synthesis of oxybutynin
involves the intermediate 2.123 as shown in Figure 2.05.
N
O
O
HO
2.121
OH
O
HO
2.122
N
OH
2.123
HO
OH
2.124
Oxybutynin

Figure 2.5 Retrosynthetic Route to Oxybutynin
The intermediate 2.123 is prepared from compound 2.124 through a four step
synthesis.
62
We have been able to synthesize the THP ether protected intermediate
2.110 in almost quantitative yield from simple staring materials (Entry 23, Table
2.3) in one step. Based on these results it can be concluded that the multicomponent
methodology offers a great advantage over traditional synthetic methods.
As a next step we have explored primary amines 2.125 in the reaction with
paraformaldehyde 2.74 and potassium alkynyltrifluoroborates 2.48 under our
82
previously established conditions to obtain secondary amines as shown in Scheme
2.22.
H
2
NR
1
Ph BF
3
K (CH
2
=O)n
2.48 2.125 2.74
Ph
N
H
R
1
5 mol% Yb(OTf)
3
30 min.
PhMe, 100
o
C
2.126

Scheme 2.22 Use of Primary Amines and Diamines in Petasis Reaction
As Table 2.5 illustrates the yields of the products are not as impressive as in the
case of secondary amines. The main reason is that the formation of the imine from
primary amines is a much faster process than from secondary amines. Imines do
not participate in the Petasis three component reaction as easily and are harder to
activate to iminium ions. Additionally, double alkylated products form and lead to a
lower yield of the desired product.
Table 2.5 Use of Primary Amines and Diamines in Petasis Reaction
Entry Amine Product Yield [%]
1
Ph
Ph
NH
2
2.127
Ph
N
H
Ph
Ph

2.128
33
2
Ph NH
2
CH
3

2.129
Ph
NH
Ph CH
3
2.130
46

83
Table 2.5 Cont.
Entry Amine Product Yield [%]
3
Ph NH
2
2.131
CH
3
(CH
2
)
5
N
H
Ph

2.132
30
4
H
2
N
NHBoc

2.133
Ph
N
H
NHBoc

2.134
18
2.2.1.5 Use of Alkyl and Fluorinated-alkyl Aldehydes in the Three Component
Condensation
Next we wanted to check the reactivity of simple and fluorinated-alkyl
aldehydes in the three component reaction with potassium alkynyltrifluoroborates
2.48. Simple aldehydes are known not to participate in the Petasis reaction with
organoboronic acids and organoboronic acid esters, and it was thus considered a
significant challenge. Encouraged by our earlier results with preformed iminium
ions we thought that there is a real possibility that simple aldehydes could be good
partners in this type of Petasis reaction. We have explored a number of other
conditions according to Scheme 2.23 and those presented in Table 2.6.

84
BF
3
K
N
2.128 2.48 2.127
O
H
2.129
N
R

Scheme 2.23 Exploring Reaction Conditions with Alkyl Aldehydes
We started with the mild conditions using Yb(OTf)
3
as a catalyst. We also explored
the use of N-trimethylsilyl-amines as an amine component. We utilized different
catalyst systems (stronger Lewis acids) as well. Surprisingly, it turned out that the
reaction takes place in every single case only the yields of the reactions are
different (Table 2.6).
Table 2.6 Exploring Reaction Conditions with Alkyl Aldehydes
Entry R Conditions Yield
99
[%]
1
H
Yb(OTf)
3
,
toluene, 100
o
C
30 min
78
2 TMS
Yb(OTf)
3
,
toluene, 100
o
C
30 min
44
3 H
TMSCl, toluene,
100
o
C
30 min
64
4 TMS
TMSCl, toluene,
100
o
C
30 min
76

99
Isolated Yield
85
The best results were obtained when mild reaction conditions were utilized (Entry
1, Table 2.6). As Scheme 2.23 and Table 2.7 illustrate we have been able to
synthesize propargylamine derivatives from alkyl aldehydes for the first time using
trifluoroborate salts in the Petasis reaction under very mild conditions.
R
1
N
H
R
2
R
5
BF
3
K
PhMe, 100
o
C
R
3
N
R
2
R
1
R
5
2.131 2.130 2.48 2.16
O
H R
3
R
3
=alkyl
5 mol% Yb(OTf)
3
30 min.

Scheme 2.24 Use of Alkyl Aldehydes in the Three Component Reaction
Table 2.7 Use of Alkyl Aldehydes in Three Component Reaction
Entry Amine Product Yield [%]
1
N
H
2.132
N

2.129
78
2
N
H
2.132
N

2.133
45

86
Table 2.7 Cont.
Entry Amine Product Yield [%]
3
N
H
O

2.76
N
O

2.134
77

Continuing on we investigated the use of fluorinated derivatives of
aldehydes such as trifluoroacetyl aldehyde. We used 2,2,2-trifluoro-ethane-1,1-diol
as a carbonyl component that provided a reaction with very low yield (10-15%).
We also utilized trifluoro-1-methoxyethanol 2.135 and explored a variety of
reaction conditions. Nevertheless, the desired product was obtained only in the case
of N-trimethylsilyl-amine 2.136 being used as an amine component and
trimethylsilyl chloride as a catalyst (Scheme 2.25).
R
1
N
R
2
TMS
R
5
BF
3
K
PhMe, 100
o
C
F
3
C
N
R
2
R
1
R
5
2.137 2.135 2.48 2.136
TMSCl
F
3
C
OH
OMe

Scheme 2.25 Use of Trifluoro-1-methoxyethanol in Petasis Reaction
The reaction time varies from 30 minutes to 1 hour. The obtained results are
presented in Table 2.8.

87
Table 2.8 Trifluoro-1-methoxyethanol in Petasis Reaction
Entry Amine Product Yield [%]
1
N
H
O

2.76
N
CF
3
O

2.138
43
2
N
H
2.132
N
CF
3

2.139
46
3
N
H
2.78
CH
3
(CH
2
)
5
N
CF
3

2.140
41

2.2.1.6 Use of Aryl Aldehydes in the Petasis Reaction with Potassium Alkynyl
Trifluoroborates
Other carbonyl components which did not show much reactivity with
boronic acids or boronic acid esters in the Petasis reaction are aryl aldehydes,
excluding salicylaldehyde derivatives (α-hydroxy aldehydes) which will be
88
discussed later. We have investigated a number of conditions and satisfactory
results were obtained in the case of N-trimethylsilyl-amines with trimethylsilyl
chloride as a catalyst as presented in Scheme 2.26. Table 2.8 summarizes our
results. The yields of the reaction are generally very good.
R
1
N
R
2
TMS
R
5
BF
3
K
PhMe, 100
o
C
H
O
N
R
2
R
1
R
5
2.142 2.141 2.48 2.136
TMSCl

Scheme 2.26 Use of Aryl Aldehydes in Petasis Reaction
Table 2.9 Use of Aryl Aldehydes in Petasis Reaction with Potassium
Alkynyltrifluoroborates
Entry Amine Product Yield [%]
1
N
TMS
2.143
N
Br

2.144
98
2
N
TMS
2.145
C
6
H
13
N
Br
2.146
78
89
2.2.2 Use of Salicylaldehyde in the Three Component Reaction
Salicylaldehyde is one of the α-hydroxyaldehydes that exhibit great
reactivity in the Petasis reaction with boronic acids and esters. Expanding their
scope we explored the use of salicylaldehyde in the three component reaction with
potassium alkynyltrifluoroborates 2.48 as shown in Scheme 2.27.
R
1
N
R
2
H
R
5
BF
3
K
PhMe, 100
o
C
5 mol% Yb(OTf)
3
1hr
H
O
OH
N
OH
R
2
R
1
R
5
2.148 2.147 2.48 2.16

Scheme 2.27 Salicylaldehyde in Petasis Reaction with Potassium
Alkynyltrifluoroborates
Table 2.10 Use of Salicylaldehyde in the Three Component Condensation with
Potasssium Alkynyltrifluoroborates
Entry Amine Product Yield [%]
1
N
H
2.78
OH
N

2.149
45
2
N
H
2.78
OH
N
(CH
2
)
5
CH
3

2.150
51

90
Table 2.10 Cont.
Entry Amine Product Yield [%]
3
N
Boc
H
N

2.80
OH
N
Boc
N

2.229
56
4
Ph
H
N Ph

2.95
OH
N
SiMe
3
Ph
Ph

2.151
46

Using our established mild conditions we have been able to synthesize N-
substituted propargylamines as Table 2.10 illustrates. The reaction time usually
takes about hour to come to completion and the desired products are isolated in fair
yields.
2.2.3 Use of Glycolaldehyde Dimer in the Petasis Reaction with
Potassium Alkynyltrifluoroborates
The next α-hydroxy aldehyde we investigated in the three component
reaction is glycolaldehyde dimer 2.45 as we wanted to synthesize β-amino alcohols
2.152 as shown in Scheme 2.28.
91
PhMe, 100
o
C
5 mol% Yb(OTf)
3
5hr
HO
N
R
2
R
1
R
5
O
O OH
HO
R
1
N
R
2
H
R
5
BF
3
K
2.48 2.16 2.45 2.152

Scheme 2.28 Use of Glycol Aldehyde Dimer in Petasis Reaction
Secondary aliphatic and aromatic amines participate in the reaction under mild
conditions. Nevertheless, the yields of the reaction vary from low to high as shown
in Table 2.11.
Table 2.11 Use of Glycolaldehyde Dimer in the Multicomponent Reaction
Entry Amine Product Yield [%]
1
Ph
N
H
Ph

2.103
Ph
N
Ph
OH
Ph
2.153
87
2
Ph
N
H
Ph

2.103
CH
3
(CH
2
)
5
N
Ph
OH
Ph
2.154
44
3
Ph
N
H
Ph

2.103
Me
3
Si
N
Ph
OH
Ph
2.155
38

92
Table 2.11 Cont.
Entry Amine Product Yield [%]
4
N
H
2.78
Ph
N
OH

2.156
32
5
N
H
2.78
CH
3
(CH
2
)
5
N
OH

2.157
25
6 N
Boc
H
N

2.80
Me
3
Si
N
OH
NBoc

2.158
25

We have also explored use of chiral amines such as R-(-)-N-benzyl-2-phenyl
glycinol that could lead to high diastereocontrol, however this reaction did not
proceed at all.
2.2.4 Use of (D,L)-Glyceraldehyde in the Multicomponent Reaction
Chiral α-hydroxy aldehydes in the Petasis reaction are known to generate
products with high diastereocontrol. Therefore we decided to investigate the use of
93
(D,L)-glyceraldehyde 2.159 according to Scheme 2.29 as D-glyceraldehyde is not
commercially available anymore.
PhMe, 100
o
C
5 mol% Yb(OTf)
3
5hr
OH
N
R
2
R
1
R
5
O R
1
N
R
2
H
R
5
BF
3
K
2.48
2.16 2.159 2.160
OH
OH
OH
99% d.e.

Scheme 2.29 Glyceraldehyde in the Three Component Reaction
As a result we were able to generate two enantiomers in a diastereomerically
fashion.
Table 2.12 Use of Glyceraldehyde in the Petasis Reaction with Potassium
Alkynyltrifluoroborates
Entry Amine Product Yield [%]
1
H
N Ph

2.104
CH
3
(CH
2
)
5
OH
N
Ph
OH

2.161
75

94
Table 2.12 Cont.
Entry Amine Product Yield [%]
2
H
N
MeO
MeO
OMe

2.162
OH
N
OH
OMe
OMe
MeO

2.163
73
3
H
N
MeO
MeO
2.162
OH
N
OH
OMe
MeO

2.164
74

2.2.5 Use of Unprotected Sugars in the Three Component Condensation
Use of unprotected carbohydrates in the Petasis reaction with boronic acids
yield very high diastereoselectivity and enantioselectivity due to the fact the
iminium ion is attacked by a borate complex from the least hindered site. We
95
extended their use in the Petasis reaction using a series of carbohydrates and
secondary amines as presented in Scheme 2.30 and Table 2.13.
PhMe/MeOH
reflux
5 mol% Yb(OTf)
3
5hr
O OH
OH
(OH)n
R
3
N
OH
OH
OH
R
1
R
2
n
R
1
N
R
2
H
R
5
BF
3
K
2.48 2.16 2.165 2.166

Scheme 2.30 Carbohydrates in Petasis Reaction with Potassium
Alkynyltrifluoroborates
It is worth mentioning that only one compound was formed in the reaction as it was
established in the case for boronic acids.
Table 2.13 Use of Unprotected Sugars in The Petasis Reaction with Potassium
Alkynyltrifluoroborates
Entry
Amine
(Carbohydrate)
Product
Yield [%]
(d.e.%,
e.e.%)
1
N
H
2.78
(D-arabinose 2.167)
OH
N OH
OH
OH

2.168
53 (99, 99)

96
Table 2.13 Cont.
Entry
Amine
(Carbohydrate)
Product
Yield [%]
(d.e.%,
e.e.%)
2
N
H
2.78
(D-xylose 2.169)
OH
N OH
OH
OH

2.170
24 (99, 99)
3
N
H
2.78
(D-ribose 2.171)
OH
N OH
OH
OH

2.172
46 (99, 99)
4
N
Boc
H
N

2.80
(D-arabinose 2.167)
CH
3
(CH
2
)
5
OH
N OH
OH
OH
Boc
N

2.173
46 (99, 99)

97
Table 2.13 Cont.
Entry
Amine
(Carbohydrate)
Product
Yield [%]
(d.e.%,
e.e.%)
5
H
N Ph

2.104
(D-arabinose 2.167)
OH
N
Ph
OH
OH
OH

2.174
87 (99, 99)
6
H
N Ph

2.105
(D-arabinose 2.167)
OH
N
Ph
OH
OH
OH

2.175
71 (99, 99)

2.2.6 Synthesis of Piperazin-2-ones
2.2.6.1 Synthesis of Propargylic Amino Acids and New Alkynyl Derivatives of
Piperazin-2-ones
One of the most important applications of the Petasis reaction is the use of
glyoxylic acid 2.09 in the synthesis of unnatural α-amino acids 2.10 as Scheme 2.2
illustrates.
98
B(OR)
2
R
5
H
O
O
OH
2.176 2.177
R
1
N
R
2
H
2.16
R
5
N
H
R
2
R
1
CO
2
H
2.178

Scheme 2.31 Synthesis of α-Amino Acid via Petasis Reaction
Encouraged by the variety of good results with potassium alkynyltrifluoroborates
2.48 in the Petasis reaction we wanted to investigate the application of glyoxylic
acid 2.177 for the synthesis of propargyl amino acids 2.179. It is recognized that α-
ethynyl or α-vinyl substituents can profoundly perturb the biological properties of
certain natural α-amino acids converting them from enzyme substrates to
irreversible inhibitors with potential therapeutic properties.
100
The only naturally
occurring unusual α-amino acid from the propargyl series is ethynyl glycine as
shown in Figure 2.6 which exhibits antimicrobial activity.
101

NH
3
+
CO
2
-
H
2.179

Figure 2.6 Structure of Naturally Occurring Ethynyl Glycine
Nevertheless, the synthesis of β,γ-alkynyl α-amino acids is considered as a
synthetic challenge. These small polyfunctional compounds tend to be very labile

100
Rando, R. R. Methods Enzymol. 1977, 46, 158.
101
Meffre, P.; Le Goffic, F. Amino Acids 1996, 11, 313.
99
and usually lengthy syntheses of partially protected forms have been performed.
102

Thereby indentifying a need for new synthetic methodology of β,γ-alkynyl α-amino
acids and we rationalized that a new multicomponent process can solve a number
of synthetic problems.
We have explored potassium alkynyltrifluoroborates in the three component
reaction with glyoxylic acid 2.177 employing a variety of amines. However, instead
of β,γ-alkynyl α-amino acids we obtained only the decarboxylation product as
shown in Scheme 2.32.
R
5
BF
3
K
PhMe, 100
o
C
5 mol% Yb(OTf)
3
5-30 min.
H
O
O
OH
2.48 2.177 2.75
R
1
N
R
2
H
2.16
R
5
N
H
R
2
R
1
H

Scheme 2.32 Attempted Synthesis of β,γ-Alkynyl α-Amino Acids
The yields of the decarboxylated product were good as shown in Table 2.14. Any
attempts of modification to the reaction conditions yielded the decarboxylated
product every time.

102
Meffre, P.; Gauzy, L.; Perdigues, C.; Desanges- Levecque, F.; Branquet, E.;
Durand, P.; Le Goffic, F. Tetrahedron Lett. 1995, 36, 877.
100
Table 2.14 Synthesis of Propargylamines via Decarboxylation of β,γ-Alkynyl
α-Amino Acids
Entry Product Yield [%]
1
Ph
N
H H
O

2.77
67
2
Ph
N
H H

2.79
69

It can be easily imagined that the mechanism of decarboxylation presumably goes
through formation of the β,γ-alkynyl α-amino acid intermediate 2.181 which is
electron rich and unstable as presented in Scheme 2.33. Providing the reaction
conditions, the intermediate can easily lose carbon dioxide and form the
corresponding propargylamine.
101
R
5
BF
3
K
PhMe, 100
o
C
5 mol% Yb(OTf)
3
5-30 min.
H
O
O
OH
2.48 2.177 2.75
R
1
N
R
2
H
2.16
R
5
N
H
R
2
R
1
H
H
O
O
OH
2.177
R
1
N
R
2
H
2.16
H
N
O
OH
2.180
R
1
R
2
2.181
R
5
N
H
R
2
R
1
O
O
H
- CO
2
R
5
BF
3
K

Scheme 2.33 Plausible Mechanism of Decarboxylation of β,γ-Alkynyl α-amino
acid
To study the mechanism, we designed a trapping experiment using a secondary
diamine in the three component Petasis condensation. Intramolecular trapping of
the carboxylate 2.181 was anticipated to provide the propargyl derivatives of
piperazin-2-ones as presented in Scheme 3.34.
The methodology for the synthesis of piperazin-2-ones 2.183 has previously been
developed in our laboratory by Patel.
103
However, only boronic acids were utilized
in the process as it was described in Chapter 1.

103
Patel, Z. D. Ph. D. Thesis USC, 2002.
102
R
5
BF
3
K
PhMe, 100
o
C
5 mol% Yb(OTf)
3
30 min.
H
O
O
OH
HN
HN
R
2
R
1
N
N
R
2
O
R
1
R
3
2.48 2.182 2.177 2.183

Scheme 2.34 Synthesis of Piperazin-2-ones via Petasis Reaction with Potassium
Alkynyl Trifluoroborates, Glyoxylic Acids and Diamines
Fortunately, we have been able to apply the methodology and synthesize series of
piperazion-2-ones using potassium alkynyltrifluoroborates as Table 2.15 indicates.
Table 2.15 Use of Diamines, Glyoxylic Acid and Potassium
Alkynyltrifluoroboartes: Synthesis of Piperazin-2-ones
Entry Amine Product Yield [%]
1
NH
NH
Ph
Ph
2.184
N
N O
Ph
Ph

2.185
47
2
NH
NH
Ph
Ph
2.184
N
N O
TMS
Ph
Ph
2.186
26

103
Table 2.15 Cont.
Entry Amine Product Yield [%]
3
NH
NH
Ph
Ph
2.184
N
N O
(CH
2
)
5
CH
3
Ph
Ph
2.187
70
4 NH
NH

2.188
N
N O

2.189
45
5
NH
NH

2.188
N
N O
(CH
2
)
5
CH
3

2.190
28

The yields of the process vary significantly. Nevertheless this confirmed our
hypothesis that decarboxylation happens after the β,γ-alkynyl α-amino acid
intermediates forms.
104
2.2.7 New Four Component Reaction Based on Click Chemistry Concept
2.2.7.1 1,3-Dipolar Cycloaddition Processes of Azides to Alkynes
Typical, thermal Huisgen’s dipolar cycloaddition of organic azides to
alkynes is the most direct methodology for the synthesis of 1,2,3-triazoles.
104

However, these thermal cycloaddition processes are often very slow even at high
temperatures and produce mixture of regioisomers 1,4-disubstituted-1,2,3-triazoles
and 1,5-disubstituted-1,2,3-triazoles as shown in Scheme 2.35.
R
3
N
N
N
R
1
R
2
N
N
N
N
N
N
R
1
R
2
R
3
R
2
R
3
R
3
∆
2.191 2.192 2.193 2.194

Scheme 2.35 Uncatalyzed, Thermal Cycloaddition of Azides to Alkynes
The major advance in the cycloaddition processes was the discovery of copper-
catalyzed cycloaddition of terminal alkynes 2.195 to organic azides 2.191.
105
This
process is highly regioselective producing only 1,4-disubstituted-1,2,3-triazoles
2.196 under very mild condition as Scheme 2.36 illustrates.

104
Huisgen, R. in 1,3-Dipolar Cycloaddition Chemistry, Padwa, A. Wiley: New
York, 1984.
105
Rostovtsev, V. V.; Green, L. G.; Fokin, V. V.; Sharpless, K. B. Angew. Chem.,
Int. Ed. 2002, 41, 2596.
105
R
3
N
N
N
R
2
N
N
N
R
2
R
3
2.191 2.195 2.196
Cu catalyst

Scheme 2.36 Copper-catalyzed Cycloaddition of Azides to Alkynes – Synthesis
of 1,4-disubstituted-1,2,3-triazoles
Complementary, the direct synthesis of 1,5-disubstituted-1,2,3-triazoles 2.199 was
developed by Fokin and coworkers and involves regioselective addition of
bromomagnesium acetylides to azides as shown in Scheme 2.37.
106

R
3
N
N
N
R
2
2.191 2.197
N
N
N
R
2
R
3
2.198
MgBr
E
+
N
N
N
R
2
R
3
MgBr
E
2.199

Scheme 2.37 Synthesis of 1,5-disubstituted-1,2,3-triazoles through Grignard
Reagents
This method is quite effective but lacks practicality and convenience. Therefore
Fokin and coworkers developed another route to 1,5-disubstituted-1,2,3-triazoles
2.200 that involves ruthenium catalyzed cycloaddition of alkynes 2.195 to azides
2.191 as shown in Scheme 2.38.
107

106
Krasinski, A,; Fokin, V. V.; Sharpless, K. B. Org. Lett. 2004, 6, 1237.
107
Zhang, L.; Chen, X.; Xue, P.; Sun, H. H. Y.; Williams, I. D.; Sharpless, K. B.;
Fokin, V. V.; Jia, G. J. Am. Chem. Soc. 2005, 127, 15998.
106
R
3
N
N
N R
2
2.191 2.195
N
N
N
R
2
R
3
2.200
Cp*RuCl(PPh
3
)
2

Scheme 2.38 Ruthenium-Catalyzed Cycloaddition of Alkynes to Organic
Azides – Synthesis of 1,5-disubstituted-1,2,3-triazoles
These above described methods have become very powerful tools for constructing
pharmaceutically active compounds and have found many applications.
108

2.2.7.2 New Four Component Reaction with Potassium Ethynyltrifluoroborate
via Click Chemistry Approach
Inspired by recent developments in the area of click chemistry we wanted to
contribute to this field as well. Since our work evolves around multicomponent
processes we wanted to combine our three component process with the click
chemistry. As a result, we have combined the three components (amine, potassium
ethynyltrifluoroborate and paraformaldehyde) with benzyl azide in one pot
producing the desired aminotriazole as Scheme 2.39 illustrates.
N
N
N
Ph
N
R
2
R
1
R
1
N
R
2
H
BF
3
K
PhMe/tBuOH/H
2
O,
80
o
C
5 mol% Yb(OTf)
3
10 mol% CuSO
4
.
5H
2
O
(CH
2
=O)n
2.54 2.16 2.74 2.201
N
3
2.202
20 mol% sodium
ascorbate

Scheme 2.39 Four Component Reaction with Potassium
Ethynyltrifluoroborate

108
Wu. P.; Fokin, V. V. Aldrichchimica Acta 2007, 50, 1.
107
With minimal adjustments to the reaction conditions we have created a new
four component reaction. We have been able to generate the desired product with
fair yield taking into account that this is a four component process as shown in
Table 2.16. The reaction can be performed as a step-wise process as well, but the
yield of the two step synthesis is lower and equals about 44%. Again, the triumph
of one pot multicomponent reactions over step-wise synthesis is undeniable.
Table 2.16 Four Component Reaction with Potassium Ethynyltrifluoroborate
Entry Amine Product Yield [%]
1
N
H
H
3
C
Ph

2.82
N
N
N
Ph
N
H
3
C
Ph

2.203
52

2.2.8 Synthesis of Novel N-Heterocycles from N-Substituted
Propargylamines
2.2.8.1 Novel N-Heterocycles via the Pauson-Khand Reaction
The Pauson-Khand reaction (PKR) is formally a [2+2+1] cycloaddition
process in which a triple bond, a double bond and carbon monoxide form a
cyclopentanone 2.204 as shown in Scheme 2.40.
108
CO O
PKR
2.204

Scheme 2.40 General Idea of the Pauson-Kand Reaction
As a result three new bonds and one or two cycles are formed. One cycle is formed
when the reaction is performed intermolecularly and two cycles when
intramolecularly. This reaction was discovered in the early seventies as an expected
result in exploration of new methodologies for the synthesis of new organometallic
cobalt complexes.
109
Dicobalt octacarbonyl (Co
2
(CO)
8
) was the only cluster used to
mediate the reaction at the time. Now many new cobalt species and other catalysts
have been discovered. The Pauson-Khand reaction can be considered as one of the
most powerful transformations in organic chemistry. In terms of functional group
compatibility, ethers, esters, alcohols, tertiary amines, acetals, amides and
heterocycles are compatible with the Pauson-Khand reaction conditions.
110
The
mechanism of the reaction is quite complex however a generally accepted
mechanism has been proposed by Magnus.
111
The main drawback of the PKR was
originally related to poor conversions. Nevertheless, over the past years the reaction
conditions were modified significantly. It was found that amine N-oxides promote

109
Perez-Castells, J. Top Organomet. Chem. 2006, 19, 207.
110
Bonaga, L. V. R.; Krafft, M. E. Tetrahedron 2004, 60, 9795.
111
Magnus, P.; Principe, L., -M. Tetrahedron Lett. 1985, 26, 4851.
109
the PKR.
112
It was discovered that the N-oxides act by oxidizing one of the CO
ligands into CO
2
and making a vacant site in the cobalt cluster. The most
commonly used amine N-oxides includes NMO (N-methylmorpholine N-oxide)
and TMANO (trimethylamine N-oxide).
Most intramolecular PKR approaches utilize systems derived from
propargyl allyl ether or amines. Since in our lab we have discovered a new way to
make efficiently highly functionalized propargylamine derivatives under mild
conditions, we wanted to utilize the Pauson-Khand approach to synthesize novel N-
heterocycles as shown in Scheme 2.41
1 eq. Co
2
(CO)
8
, DCM
NMO, 12 hours
RT
R
3
N
R
2
N
O
R
2
R
3
R
4
R
4
2.205 2.206

Scheme 2.41 The Pauson-Khand Reaction for the Synthesis of N-Heterocycles
We employed the most common non-catalytic conditions for Pauson-Khand
reaction. As a result we have been able to synthesize novel N-heterocycles in good
yields as summarized in Table 2.17.

112
Shambayati, S.; Crowe, W. E.; Schreiber, S. L. Tetrahedron Lett. 1990, 31,
5289.
110
Table 2.17 Novel N-Heterocycles via the Pauson-Khand Reaction
Entry Amine Product Yield [%]
1
Ph
N

2.79
N
O
Ph

2.207
78
2
Ph
N
MeO

2.89
N
O
Ph
OMe
2.208
75
3
Ph
N

2.103
N
O
Ph
Ph
Me

2.209
41
4
Ph OH
N OH
OH
OH

2.168
N
O
OH
HO
OH
OH

2.210
49

111
2.2.8.2 Novel N-Heterocycles via Pd-Catalyzed Borylative Cyclization
Enynes are employed in a wide range of metal catalyzed reactions such as
cycloisomerization, rearrangements, the Pauson-Khand reaction and others.
113
In
our group having developed a quick access to propargylamine derivatives via a
multicomponent reaction we wanted to explore new applications of the diversified
propargylamines. For this purpose we employed a palladium-catalyzed cyclization
of propargylamines based on new methodology developed by Cardenas and
coworkers.
114
The main idea of our approach is depicted in Scheme 2.42.
R
2
N
B B
O
O
O
O
MeOH
toluene, 50
o
C
10 mol% Pd(OAc)
2
R
2
N
R
3
B
O
O
R
3
2.211 2.212 2.213

Scheme 2.42 Palladium-Catalyzed Borylative Cyclization of Propargylamines
We have employed palladium acetate as the catalyst and toluene as a solvent in the
presence of methanol and bis(pinacolato)diboron 2.212. As a result, we have been
able to generate the desired alkylboronates 2.213 in fair yields as presented in Table
2.18.
The reaction mechanism is quite complex and can proceed through different
pathways as shown in Scheme 2.43.
114

113
Aubert, C.; Buisine, O.; Malacria, M. Chem. Rev. 2002, 102, 813.
114
Marco-Martinez, J.; Lopez-Carrilo, V.; Bunuel, E.; Simancas, R.; Cardenas, D.
J. J. Am. Chem. Soc. 2007, 129, 1874.
112
Table 2.18 Palladium-Catalyzed Borylative Cyclization of Propargylamines
Entry Amine Product Yield[%]
1
Ph
N
MeO

2.89
MeO
N
B O
O

2.214
50
2
Ph
N Ph
CH
3

2.98
N
B O
O
Me

2.215
44

113
R
2
N
R
3
Pd
0
L
n
MeOH
L
m
Pd-H
MeO
-
L
m
Pd-H
R
2
N
PdLm
H
R
3
2.216 2.217
N R
2
R
3
LnPd
2.218
B
2
(pin)
2 MeO
-
N
R
2
R
3
Pd
L
B
O
O
Pd
0
L
n
R
2 N
R
3
B
O
O
2.221 2.213
R
2
N
2.220
R
3
Pd
0
L
n
N PdL
n
R
2
R
3
2.219
MeOH MeO
-
Path A
Path B

Scheme 2.43 Plausible Mechanistic Pathways for Pd-catalyzed Cyclization-
Borylation of Propargylamines

114
2.3 Conclusion
In summary, the multicomponent reaction involving potassium
alkynyltrifluoroborates turned out to be very effective for the synthesis of
substituted and highly functionalized propargylamines. The reaction has a wide
scope of applications as the propargylamines are important intermediates for the
synthesis of more complex molecules. Our one step synthesis has a great advantage
over the known methodologies as the synthesis is very rapid and employs very mild
conditions.

115
2.4 Experimental
2.4.1 General Information
All reagents and commonly available starting materials were purchased from
commercial sources. Tetrahydrofuran was freshly distilled from sodium-
benzophenone, dichloromethane from CaH
2
and anhydrous dimethylformamide,
diethyl ether, toluene, benzene, ethanol, and methanol were purchased from
commercial sources.
1
H,
19
F,
13
C NMR spectra were recorded on a Varian Mercury
400 and a Bruker AC-250 using residual
1
H or
13
C signals of deuterated solvents as
internal standards.
11
B NMR spectra were performed on a Bruker 500 MHz using
BF
3
•Et
2
O as an external standard. Thin layer chromatography was performed using
glass precoated TLC plates (silica gel 60 F
254
). Flash chromatography was
performed using Silica Gel 60, particle size range between 0.040-0.063 mm (230-
400 Mesh).
116
2.4.2 Synthesis and Physical Properties
Potassium (phenylethynyl)trifluoroborate (2.50)
To a solution of phenylacetylene (2.222) (2.5 ml, 22.8
mmol) in 23 ml of dry THF cooled to -78
o
C under
argon atmosphere n-BuLi (1.6 M solution in hexanes,
10 ml, 22.8 mmol) was added dropwise. The solution was stirred for 1 hour at this
temperature and trimethylborate (1.5 eq., 3.82 ml, 34.2 mmol) was then added
dropwise. The reaction mixture was stirred for the next hour at -78
o
C after which it
was warmed up to -20
o
C and hold there for 1 hour. After this time a saturated
aqueous solution of potassium hydrogen difluoride (6 eq., 10.7 g) was added and
the reaction mixture was stirred at -20
o
C for additional 1 hour. The resulting
mixture was allowed to warm up to room temperature. The solvent was removed
under reduced pressure and the white solid was dried under high vacuum for 4
hours in order to remove any remaining water. The solid was washed at first two
times with ambient acetone and then four times with hot acetone. The organic
solvent was collected and the volatiles removed and white fluffy solid was
obtained. The resulting solid was redissolved in hot acetone and triturated with
diethyl ether. The product was collected as a white crystalline solid in high yield
(4.2 g, 86%).
BF
3
K
117
1
H NMR (400 MHz, acetone-d
6
): δ 7.37-7.22 (m, 5H).
19
F NMR (376 MHz,
acetone-d
6
): δ −135.0 (q, J = 35.4 Hz).
11
B NMR (64.2 MHz, acetone-d
6
): δ -0.78
(q, J
B-F
= 36.8 Hz)
13
C NMR (62.5 MHz, acetone-d
6
): δ 132.1, 128.8, 127.1.

Potassium (octynyl)trifluoroborate (2.51)
Prepared analogously to (2.50) from 1-octyne
(2.223) as a white solid in good yield (76%).
1
H NMR (400 MHz, acetone-d
6
): δ 2.09 (m, 2H), 1.45-1.26 (m, 8H), 0.91 (t, J= 6.7
Hz, 3H).
19
F NMR (376 MHz, acetone-d
6
): δ -134.4 (q, J= 32.0 Hz).
11
B NMR
(64.2 MHz, acetone-d
6
): δ -1.08 (q, J = 37.8 Hz).
13
C NMR (62.5 MHz, acetone-
d
6
): δ 32.2, 30.4, 29.4, 23.2, 20.0, 14.3.

Potassium (trimethylsilylethynyl)trifluoroborate
(2.52)
Prepared analogously to (2.50) from ethynyl-trimethyl-silane (2.224) in moderate
yield (45%). The final product is a white fluffy solid.
1
H NMR (acetone-d
6
): δ 0.03 (s, 9H).
19
F NMR (376 MHz, acetone-d
6
): δ -

135.5
(q, J=34.7 Hz).
11
B NMR (64.2 MHz, acetone-d
6
): δ -1.49 (q, J = 36.8 Hz).

TMS BF
3
K
CH
3
(CH
2
)
5
BF
3
K
118
Potassium(triisopropylsilylethynyl)trifluoro-
borate (2.53)
Prepared analogously to (2.50) from ethynyl-triisopropyl-silane (2.225) in moderate
yield (46%).
19
F NMR (376 MHz, acetone-d
6
): δ -

134.9.
11
B NMR (64.2 MHz, acetone-d
6
): δ -
1.49 (q, J = 32.7 Hz).
13
C NMR (62.5 MHz, acetone-d
6
): δ 19.1, 12.2.

Potassium(ethynyl)trifluoroborate (2.54)
To a solution of trimethylborate (1.5 eq., 38 mmol, 4.25
ml) in dry THF at -78
o
C a solution of ethynylmagnesium
bromide (2.226) (1 eq., 0.5 M solution in THF, 25 mmol, 50 ml) was added. The
resulting solution was stirred at this temperature for 1 hour then stirring was
continued at -20
o
C for an additional hour. At this temperature solid KHF
2
(6 eq.,
150 mmol, 12g) was added in one portion followed by slow addition of water (20
ml). The reaction mixture was stirred at this temperature for one hour followed by
warming up to room temperature for another hour. The solvent was removed under
reduced pressure and the white solid was dried under high vacuum for 4 hours in
order to remove remaining water. The solid was extracted at first twice with
ambient acetone and then four times with hot acetone. The organic solvent was
pooled and evaporated and a white fluffy solid was obtained. The resulting solid
was redissolved in hot acetone and triturated with diethyl ether. The product was
collected as white crystals in good yield (1.75 g, 54 %).
(Pri)
3
Si BF
3
K
H BF
3
K
119
1
H NMR (400 MHz, acetone-d
6
): δ 1.71 (m, 1H).
19
F NMR (376 MHz, acetone-d
6
):
δ -135.5 (q, J=38.1 Hz).
11
B NMR (64.2 MHz, acetone-d
6
): δ -1.46 (q, J = 35.7 Hz).

4-(3-Phenyl-prop-2-ynyl)-morpholine
(2.77)
To a suspension of potassium
(phenylethynyl)trifluoroborate (2.50) (0.5
mmol, 104 mg) and paraformaldehyde (2.74) (0.5 mmol, 15 mg) in toluene (2 ml),
morpholine (2.76) (0.5 mmol, 43.6 µl) was added followed by addition of
ytterbium triflate (5 mol%, 0.025mmol, 16 mg). The resulting suspension was
stirred at 100
o
C till no staring materials were left. The reaction was monitored by
TLC (10% ethyl acetate: hexanes). After 30 minutes, the reaction was allowed to
cool down and the solution was diluted with ethyl acetate (20 ml). The organic
were washed with 1H HCl (3x15 ml). The aqueous layer was cooled to 0
o
C and 1N
NaOH was added to pH slightly basic. The aqueous layer was extracted with ethyl
acetate (3x20 ml). The organics were combined, dried over Na
2
SO
4
, filtered and
concentrated. The resulting residue was purified using flash chromatography (2%
ethyl acetate: hexanes) to isolate a viscous colorless liquid in good yield (83 mg,
82%).
N
O
120
1
H NMR (250 MHz, CDCl
3
): δ 7.46-7.42 (m, 2H), 7.31-7.29 (m, 3H), 3.79 (m,
4H), 3.54 (s, 2H), 2.67 (m, 4H).
13
C NMR (62.5 MHz, CDCl
3
): δ 131.8, 128.34,
128.31, 123.0, 85.9, 83.8, 66.9, 52.5, 48.2.

Diallyl-(3-phenyl-prop-2-ynyl)-amine (2.79)
Prepared analogously to compound (2.77)
from potassium (phenylethynyl)trifluoroborate
(2.50), diallylamine (2.78) and
paraformaldehyde (2.74). The product was isolated as a yellow oil good yield (85
mg, 82 %).
1
H NMR (250 MHz, CDCl
3
): δ 7.46-7.42 (m, 2H), 7.32-7.29 (m, 3H), 5.94 (m,
2H), 5.31 (m, 1H), 5.24 (m, 1H), 5.21 (m, 1H), 5.17 (m, 1H), 3.60 (s, 2H), 3.20 (d,
J= 6.7 Hz, 4H).
13
C NMR (62.5 MHz, CDCl
3
): δ 135.3, 131.7, 128.2, 128.0, 123.3,
118.3, 85.4, 84.2, 56.5, 42.2.

4-(3-Phenyl-prop-2-ynyl)-piperazine-1-
carboxylic acid tert-butyl ester (2.81)
Prepared analogously to compound (2.77)
from potassium (phenylethynyl)-
trifluoroborate (2.50), piperazine-1-carboxylic acid tert-butyl ester (2.80) and
paraformaldehyde (2.74). The final product was obtained in good yield (125 mg, 84
%).
N
N
NBoc
121
1
H NMR (250 MHz, CDCl
3
): δ 7.40-7.36 (m, 2H), 7.26-7.23 (m, 3H), 3.48 (s, 2H),
3.45 (m, 4H), 2.53 (m, 4H), 1.42 (s, 9H).
13
C NMR (62.5 MHz, CDCl
3
): δ 154.6,
131.6, 128.2, 128.1, 122.8, 85.5, 83.9, 79.6, 51.8, 47.8, 43.2, 28.3.

Benzyl-methyl-(3-phenyl-prop-2-ynyl)-
amine (2.83)
Prepared analogously to compound (2.77)
from potassium (phenylethynyl)-trifluoroborate (2.50), benzyl-methyl-amine (2.82)
and paraformaldehyde (2.74). The final product was obtained in good yield (90 mg,
77%).
1
H NMR (250 MHz, CDCl
3
): δ 7.47-7.45 (m, 2H), 7.35-7.29 (m, 8H), 3.64 (s, 2H),
3.51 (s, 2H), 2.40 (s, 3H).
13
C NMR (62.5 MHz, CDCl
3
): δ 149.0, 138.7, 131.8,
129.2, 128.7, 128.3, 128.2, 127.2, 127.1, 123.1, 118.2, 114.3, 85.4, 84.1, 55.3, 40.8.

Diallyl-(3-trimethylsilanyl-prop-2-ynyl)-
amine (2.84)
Prepared analogously to compound (2.77)
from potassium (trimethylsilylethynyl)-
trifluoroborate (2.52), diallylamine (2.78) and paraformaldehyde (2.74). The
product is an oil and was obtained in good yield (71 mg, 69%).
TMS
N
N
CH
3
Ph
122
1
H NMR (250 MHz, CDCl
3
): δ 5.93-5.77 (m, 2H), 5.29 (m, 1H), 5.22 (m, 2H), 5.17
(m, 1H), 3.42 (s, 2H), 3.17 (d, J=6.8 Hz, 4H), 0.17 (s, 9H).
13
C NMR (62.5 MHz,
methanol-d
4
): δ 136.4, 120.4, 102.1, 92.2, 58.2, 43.7, 1.0.

4-(3-Trimethylsilanyl-prop-2-ynyl)-
morpholine (2.85)
Prepared analogously to compound (2.77) from
potassium (trimethylsilylethynyl) trifluoroborate (2.52), morpholine (2.76) and
paraformaldehyde (2.74) as a viscous oil in good yield (67%).
1
H NMR (250 MHz, CDCl
3
): δ 3.72 (m, 4H), 3.27 (m, 2H), 2.53 (m, 4H), 0.14 (s,
9H).
13
C NMR (62.5 MHz, CDCl
3
): δ 100.6, 90.4, 66.9, 52.3, 48.3, 0.1.

Diallyl-non-2-ynyl-amine (2.86)
Prepared analogously to compound (2.77)
from potassium (octynyl)trifluoroborate
(2.51), diallylamine (2.78) and
paraformaldehyde (2.74) as a colorless oil in high yield (104 mg, 94%).
1
H NMR (250 MHz, CDCl
3
): δ 5.89-5.72 (m, 2H), 5.21 (m, 1 H), 5.15 (m, 1H),
5.13 (m, 1H), 5.09 (m, 1H), 3.36 (t, J= 2.5 Hz, 2H), 3.07 (d, J=6.8 Hz, 4H), 2.17
(m, 2H), 1.51-1.24 (m, 8H), 0.86 (t, J=7.0 Hz, 3 H).
13
C NMR (62.5 MHz, CDCl
3
):
δ 135.5, 117.8, 85.4, 74.2, 56.3, 41.8, 31.3, 28.9, 28.5, 22.5, 18.6. 14.0.
TMS
N
O
CH
3
(CH
2
)
5
N
123
4-Non-2-ynyl-piperazine-1-carboxylic
acid tert-butyl ester (2.87)
Prepared analogously to compound
(2.77) from potassium (octynyl-)-
trifluoroborate (2.51), piperazine-1-carboxylic acid tert-butyl ester (2.80) and
paraformaldehyde (2.74) in excellent yield (153 mg, 99%).
1
H NMR (250 MHz, CDCl
3
): δ 3.45 (m, 4H), 3.25 (m, 2H), 2.47 (m, 4H), 2.17 (m,
2H), 1.45 (s, 9H), 1.41-1.23 (m, 8H), 0.87 (m, 3 H).
13
C NMR (62.5 MHz, CDCl
3
):
δ 154.7, 85.9, 79.6, 74.3, 51.8, 47.5, 43.3, 31.3, 28.7, 28.5, 28.4, 22.5, 18.7. 14.0.

Allyl-(4-methoxy-benzyl)-(3-phenyl-
prop-2-ynyl)-amine (2.89)
Prepared analogously to compound
(2.77) from potassium (phenylethynyl)
trifluoroborate (2.50), allyl-(4-methoxy-benzyl)-amine (2.88) and
paraformaldehyde (2.77) in good yield (83%).
1
H NMR (250 MHz, CDCl
3
): δ 7.50-7.46 (m, 2H), 7.34-7.30 (m, 5H), 6.87 (d, J=9
Hz, 2H), 6.03-5.85 (m, 1H), 5.31 (d, J=19.3, 1H), 5.20 (d, J=10 Hz, 1Hz), 3.81 (s,
3H), 3.66 (s, 2H), 3.52 (s, 2H), 3.24 (d, J=6.6 Hz, 2H).
13
C NMR (62.5 MHz,
CDCl
3
): δ 158.8, 135.7, 131.7, 130.5, 130.4, 128.2, 128.0, 123.4, 118.0, 113.7,
85.7, 84.5, 56.8, 56.7, 55.2, 41.9.

CH
3
(CH
2
)
5
N
NBoc
N
OMe
124
Benzyl-(3-phenyl-allyl)-(3-phenyl-prop-2-
ynyl)-amine (2.91)
Prepared analogously to compound (2.77)
from potassium (phenylethynyl)-
trifluoroborate (2.50), benzyl-(3-phenyl-allyl)-amine (2.90) and paraformaldehyde
(2.74) in high yield (88%).
1
H NMR (400 MHz, CDCl
3
): δ 7.54-7.26 (m, 15H), 6.67 (d, J=16 Hz, 1H), 6.37
(dt, J=16.4 Hz, 1H), 3.81 (s, 2H), 3.61 (s, 2H), 3.45 (d, J=8.2 Hz, 2H).
13
C NMR
(62.5 MHz, CDCl
3
): δ 138.7, 137.1, 133.0, 131.8, 129.2, 128.5, 128.33, 128.28,
128.0, 127.4, 127.3, 127.2, 126.4, 85.9, 84.5, 57.6, 56.2, 42.3.

Benzyl-(3-phenyl-prop-2-ynyl)-prop-2-
ynyl-amine (2.93)
Prepared analogously to compound (2.77)
from potassium (phenylethynyl)-
trifluoroborate (2.50), benzyl-prop-2-ynyl-amine (2.92) and paraformaldehyde
(2.74) in moderate yield (93 mg, 36%).
1
H NMR (250 MHz, CDCl
3
): δ 7.47-7.24 (m, 10H), 3.76 (s, 2H), 3.62 (s, 2H), 3.48
(d, J=2.4 Hz, 2H), 2.28 (t, J=2.5 Hz, 1H).
13
C NMR (62.5 MHz, CDCl
3
): δ 138.7,
131.7, 129.3, 128.4, 128.2, 128.1, 127.4, 122.9, 85.3, 84.4, 79.0, 73.2, 57.2, 42.8,
42.0.

N
Ph
Ph
N
Ph
125
Benzyl-methyl-non-2-ynyl-amine
(2.94)
Prepared analogously to compound
(2.77) from potassium (octynyl)trifluoroborate (2.52), benzyl-methyl-amine (2.82)
and paraformaldehyde (2.74) in excellent yield (95%).
1
H NMR (250 MHz, CDCl
3
): δ 7.39-7.27 (m, 5H), 3.60 (s, 2H), 3.30 (t, J=2Hz,
2H), 2.35 (s, 3H), 2.28 (m, 2H), 1.64-1.33 (m, 8H), 0.94 (t, J=7 Hz, 3H).
13
C NMR
(62.5 MHz, CDCl
3
): δ 138.5, 129.2, 128.2, 127.1, 85.8, 74.5, 60.1, 45.4, 41.8, 31.3,
28.9, 28.6, 22.6, 18.7, 14.0.

Dibenzyl-non-2-ynyl-amine (2.96)
Prepared analogously to compound
(2.77) from potassium
(octynyl)trifluoroborate (2.52),
dibenzylamine (2.95) and paraformaldehyde (2.74) in good yield (74%).
1
H NMR (250 MHz, CDCl
3
): δ 7.43-7.25 (m, 10H), 3.68 (s, 4H), 3.25 (t, J=2.1Hz,
2H), 2.29 (m, 2H), 1.64-1.27 (m, 8H), 0.93 (t, J=6.5 Hz, 3H).
13
C NMR (62.5 MHz,
CDCl
3
): δ 139.1, 129.0, 128.2, 127.0, 85.9, 74.4, 57.4, 41.7, 31.4, 29.1, 28.6, 22.6,
18.8, 14.1.

CH
3
(CH
2
)
5
N
CH
3
CH
3
(CH
2
)
5
N
126
Allyl-(1-phenyl-ethyl)-(3-phenyl-prop-2-
ynyl)-amine (2.98)
Prepared analogously to compound (2.77)
potassium (phenylethynyl)trifluoroborate
(2.50), allyl-(1-phenyl-ethyl)-amine (2.97) and paraformaldehyde (2.74) in high
yield (87%).
1
H NMR (400 MHz, CDCl
3
): δ 7.55 (m, 2H), 7.48 (m, 2H), 7.40 (m, 5 H), 7.32 (t,
J=7.8 Hz, 1H), 5.97-5.87 (m, 1H), 5.35 (d, J=17.2 Hz, 1H), 5.22 (d, J=10.1Hz, 1H),
3.92 (q, J=7.1 Hz, 1H), 3.84-3.63 (m, 2H), 3.26 (d, J=6.4 Hz, 2H), 1.51 (d, J=7 Hz,
3H).
13
C NMR (100 MHz, CDCl
3
): δ 145.0, 136.1, 131.8, 128.4, 128.3, 128.0,
127.6, 127.0, 123.6, 117.6, 85.2, 85.0, 60.8, 53.8, 39.7, 21.1.

Benzyl-methyl-(3-triisopropylsilanyl-
prop-2-ynyl)-amine (2.99)
Prepared analogously to compound (2.77)
from potassium (triisopropylsilylethynyl)-
trifluoroborate (2.53), benzyl-methyl-amine (2.82) and paraformaldehyde (2.74) in
good yield (74%).
1
H NMR (400 MHz, CDCl
3
): δ 7.40-7.30 (m, 5H), 3.66 (s, 2H), 3.41 (s, 2H), 2.42
(s, 3H), 1.16 (s, 24H).
13
C NMR (100 MHz, CDCl
3
): δ 138.3, 129.3, 128.3, 127.3,
101.9, 86.5, 59.7, 45.7, 41.8, 18.7, 11.3.

N
H
3
C
Si
N
CH
3
127
Benzyl-(3-methyl-but-2-enyl)-(3-
phenyl-prop-2-ynyl)-amine (2.101)
Prepared analogously to compound
(2.77) from potassium (phenylethynyl)-
trifluoroborate (2.50), benzyl-(3-
methyl-but-2-enyl)-amine (2.100) and paraformaldehyde (2.74) in high yield
(94%).
1
H NMR (400 MHz, CDCl
3
): δ 7.54-7.51 (m, 2H), 7.47-7.44 (m, 2H), 7.40-7.36
(m, 5H), 7.33-7.30 (m, 1H), 5.36 (tt, J=7.1 Hz, 1H), 3.76 (s, 2H), 3.57 (s, 2H), 3.26
(d, J=7.3 Hz, 2H), 1.81 (s, 3H), 1.77 (s, 3H).
13
C NMR (62.5 MHz, CDCl
3
):
δ 138.8, 136.0, 131.7, 129.3, 128.3, 127.9, 123.4, 121.5, 85.5, 84.8, 57.7, 51.2,
41.9, 26.0, 18.1.

Benzyl-(2-methyl-allyl)-(3-phenyl-prop-
2-ynyl)-amine (2.103)
Prepared analogously to compound (2.77)
from potassium (phenylethynyl)-
trifluoroborate (2.50), benzyl-(2-methyl-allyl)-amine (2.102) and paraformaldehyde
(2.74) in good yield (72%).
1
H NMR (250 MHz, CDCl
3
): δ 7.48-7.23 (m, 10H), 5.02 (s, 1H), 4.90 (s, 1H), 3.67
(s, 2H), 3.48 (s, 2H), 3.13 (s, 2H), 1.80 (s, 3H).
13
C NMR (62.5 MHz, CDCl
3
):
N
N
128
δ 143.1, 139.1, 131.7, 129.0, 128.3, 127.9, 127.0, 123.5, 113.4, 85.6, 84.6, 60.4,
57.2, 42.1, 20.7.

Allyl-phenyl-(3-phenyl-prop-2-ynyl)-amine
(2.105)
Prepared analogously to compound (2.77)
from potassium (phenylethynyl)-
trifluoroborate (2.50), allyl-phenyl-amine (2.104) and paraformaldehyde (2.74) in
good yield (73%).
1
H NMR (400 MHz, CDCl
3
): δ 7.32-7.30 (m, 2H), 7.21-7.17 (m, 5H), 6.85-6.82
(m, 2H), 6.72 (t, J=7.2 Hz, 1H), 5.91-5.82 (m, 1H), 5.23 (dq, J=15 Hz, J=2Hz, 1H),
5.13 (dq, J=9 Hz, J=2Hz, 1H), 4.16 (s, 2H), 3.96 (d, J=4.7 Hz, 2H).
13
C NMR (100
MHz, CDCl
3
): δ 148.6, 134.1, 131.8, 129.1, 128.2, 128.1, 123.0, 117.9, 116.7,
114.1, 85.6, 83.8, 53.9, 40.5.

N
129
Benzyl-methyl-prop-2-ynyl-amine (2.106)
Prepared analogously to compound (2.77) from
potassium (ethynyl)trifluoroborate (2.54), benzyl-
methyl-amine (2.82) and paraformaldehyde (2.74) in high yield (94%).
1
H NMR (400 MHz, CDCl
3
): δ 7.38-7.30 (m, 5H), 3.61 (s, 2H), 3.34 (d, J=2 Hz,
2H), 2.39 (s, 3H), 2.32 (t, J=2.3 Hz, 1H).
13
C NMR (100 MHz, CDCl
3
): δ 138.3,
129.2, 128.4, 127.3, 78.5, 73.4, 60.0, 44.8, 41.8.

Benzyl-phenyl-(3-phenyl-prop-2-ynyl)-
amine (2.107)
Prepared analogously to compound (2.77)
from potassium (phenylethynyl)-
trifluoroborate (2.50), benzyl-phenyl-amine (2.103) and paraformaldehyde (2.74) in
good yield (57%).
1
H NMR (400 MHz, CDCl
3
): δ 7.47-7.39 (m, 6H), 7.35-7.31 (m, 6H), 7.01 (d,
J=7.5 Hz, 2H), 6.88 (t, J=8 Hz, 1H), 4.70 (s, 2H), 4.32 (s, 2H).
13
C NMR (62.5
MHz, CDCl
3
): δ 138.3, 129.2, 128.4, 127.3, 78.5, 73.4, 60.0, 44.8, 41.8.

N
N
CH
3
130
Benzyl-(2-methyl-allyl)-non-2-ynyl-
amine (2.108)
Prepared analogously to compound
(2.77) from potassium (octynyl)-
trifluoroborate (2.52), benzyl-(2-methyl-allyl)-amine (2.102) and paraformaldehyde
(2.74) in good yield (76%).
1
H NMR (400 MHz, CDCl
3
): δ 7.43-7.27 (m, 5H), 5.03 (s, 1H), 4.93 (s, 1H), 3.64
(s, 2H), 3.29 (t, J=2.2 Hz, 2H), 3.10 (s, 2H), 2.29 (tt, J=6.9 Hz, 2H), 1.83 (s, 3H),
1.61-1.49 (m, 4H), 1.38-1.36 (m, 4H), 0.96 (t, J=7.1 Hz, 3H).
13
C NMR (100 MHz,
CDCl
3
): δ 143.3, 139.4, 129.0, 128.2, 126.9, 113.1, 85.5, 74.4, 60.3, 57.0, 41.8,
31.4, 29.1, 28.6, 22.7, 20.8, 18.8, 14.2.

Benzyl-(2-iodo-phenyl)-(3-phenyl-prop-2-
ynyl)-amine (2.110)
Prepared analogously to compound (2.77)
from potassium (phenylethynyl)-
trifluoroborate (2.50), benzyl-(2-iodo-
phenyl)-amine (2.109) and paraformaldehyde (2.74) in good yield (76 %).
1
H NMR (250 MHz, CDCl
3
): δ 7.90 (d, J=7.7 Hz, 1H), 7.55 (d, J=7.3 Hz, 2H),
7.43-7.25 (m, 10H), 6.87 (m, 1H), 4.35 (s, 2H), 3.93 (s, 2H),
13
C NMR (62.5 MHz,
CDCl
3
): δ 151.5, 139.7, 137.9, 131.7, 129.0, 128.7, 128.32, 128.27, 128.1, 127.3,
126.5, 125.0, 123.2, 99.8, 85.9, 84.4, 56.4, 43.3.
CH
3
(CH
2
)
5
N
N
I
131
Diethyl-[4-(tetrahydro-pyran-2-yloxy)-but-2-
ynyl]-amine (2.111)
Prepared analogously to compound (2.77) from
potassium [3-(tetrahydro-pyran-2-yloxy)-prop-1-
ynyl]trifluoroborate (2.55), diethylamine (2.116) and paraformaldehyde (2.74) in
excellent yield (99%).
1
H NMR (400 MHz, CDCl
3
): δ 4.85 (t, J=7.0Hz, 1H), 4.30 (qt, J=10.0 Hz, J=2 Hz,
2H), 3.86 (m, 1H), 3.54 (m, 1H), 3.48 (t, J=1.4 Hz, 2H), 2.56 (q, J=7.2 Hz, 4H),
1.88-1.52 (m, 4H), 1.08 (t, J=6.8 Hz, 6H).
13
C NMR (100 MHz, CDCl
3
): δ 96.5,
80.7, 80.4, 62.0, 54.3, 47.2, 40.9, 30.3, 25.4, 19.1, 12.5.

Benzyl-(2-iodo-phenyl)-non-2-ynyl-
amine (2.112)
Prepared analogously to compound (2.77)
from potassium (octynyl)trifluoroborate
(2.52), benzyl-(2-iodo-phenyl)-amine
(2.109) and paraformaldehyde (2.74) in good yield (63 %).
1
H NMR (400 MHz, CDCl
3
): δ 7.78 (d, J=7.8 Hz, 1H), 7.43 (d, J=7.4 Hz, 2H),
7.26-7.15 (m, 5H), 6.78-6.72 (m, 1H), 4.19 (s, 2H), 3.61 (t, J=2.1 Hz, 2H), 2.12 (tt,
J=6.9 Hz, J=2.2 Hz, 2H), 1.45-1.18 (m, 8H), 0.83 (t, J=6.9 Hz, 3H).
13
C NMR (100
MHz, CDCl
3
): δ 151.8, 139.7, 138.1, 128.9, 128.6, 128.3, 127.2, 126.2, 124.8, 99.8,
86.1, 74.5, 56.2, 42.9, 31.4, 29.0, 28.6, 22.7, 18.7, 14.2.
N
O
O
CH
3
(CH
2
)
5
N
I
132
Dimethyl-(3-phenyl-prop-2-ynyl)-amine (2.68)
To a suspension of potassium
(phenylethynyl)trifluoroborate (2.50) (0.5 mmol,
104 mg) in toluene Eschenmoser’s Salt
(dimethylmethyleneammonium iodide) (2.66) was added (0.5 mmol, 92.5 mg). The
reaction mixture was stirred at 100
o
C for 1 hour, cooled down, diluted with ethyl
acetate and water and extracted. The organic solvents were collected and removed
under reduced pressure. The residue was purified using flash chromatography (5%
methanol: 95% ethyl acetate) to isolate a yellow oil in high yield (67 mg, 85%).
1
H NMR (250 MHz, CDCl
3
): δ 7.43-7.39 (m, 2H), 7.28-7.24 (m, 3H), 3.44 (s, 2H),
2.34 (s, 6H).
13
C NMR (62.5 MHz, CDCl
3
): δ 131.6, 128.1, 128.0, 123.1, 85.2,
84.4, 48.4, 44.1.

Dimethyl-non-2-ynyl-amine (2.69)
Prepared analogously to (2.68) from potassium
(octynyl)trifluoroborate (2.52) and
dimethylmethyleneammonium iodide (2.66) as yellowish oil in good yield (74%).
1
H NMR (250 MHz, CDCl
3
): δ 4.44 (t, J=2 Hz, 2H), 3.52 (s, 6H), 3.46-3.39 (m,
2H), 2.78-2.48 (m, 8H), 2.11 (t, J=6.8 Hz, 3H).
13
C NMR (62.5 MHz, CDCl
3
):
δ 85.9, 74.4, 48.2, 44.1, 31.3, 28.9, 28.6, 22.6, 18.7, 14.0.

N
CH
3
CH
3
CH
3
(CH
2
)
5
N
CH
3
CH
3
133
Dibenzyl-(3-trimethylsilanyl-prop-2-ynyl)-
amine (2.113)
Prepared analogously to (2.77) as a 50:50
mixture of products (dibenzyl-prop-2-ynyl-
amine (2.114) as a second product) in high total yield (90%). The products are not
separable by column chromatography.
1
H NMR (400 MHz, CDCl
3
): δ 7.17-6.98 (m, 20 H), 3.44 (s, 4H), 3.43 (s, 4H), 3.02
(s, 2H), 3.00 (s, 2H), 2.03 (t, J=2.3 Hz, 1H), 0.002 (s, 9 H).
13
C NMR (100 MHz,
CDCl
3
): δ 138.6, 138.5, 128.8, 128.7, 128.0, 126.8, 100.7, 90.2, 78.4, 73.1, 57.2,
57.1, 41.9, 40.9, 0.04.

Benzyl-methyl-prop-2-ynyl-amine (2.106)
Prepared analogously to (2.77) as a yellow oil and
major product in moderate yield (46 mg, 37%).
1
H NMR (250 MHz, CDCl
3
): δ 7.32-7.19 (m, 5H), 3.54 (s, 2H), 3.27 (d, J = 2.6 Hz,
2H), 2.31 (s, 3H), 2.24 (t, J = 2.3 Hz, 1H).
13
C NMR (62.5 MHz, CDCl
3
): δ 138.3,
129.1, 128.2, 127.2, 78.4, 73.3, 59.9, 44.8, 41.7.
Benzyl-methyl-(3-trimethylsilanyl-prop-
2-ynyl)-amine (2.115).
Prepared analogously to (2.77) as a yellow
oil and minor product in low yield (45 mg, 26%).
TMS
N
N
CH
3
TMS
N
CH
3
134
1
H NMR (250 MHz, CDCl
3
): δ 7.37-7.27 (m, 5H), 3.59 (s, 2H), 3.33 (s, 2H), 2.36
(s, 3H), 0.24 (s, 9H).
13
C NMR (62.5 MHz, CDCl
3
): δ 138.4, 129.2, 128.3, 127.2,
100.9, 90.3, 60.1, 45.9, 41.8, 0.12.

Allyl-(4-methoxy-benzyl)-prop-2-ynyl-
amine (2.117)
Prepared analogously to (2.77) providing a
yellow oil and major product in good yield
(112 mg, 75 %).
1
H NMR (250 MHz, CDCl
3
): δ 7.28 (d, J = 8.8 Hz, 2H), 6.87 (d, J= 8.7 Hz, 2H),
5.99-5.78 (m, 1H), 5.28 (d, J =19.2 Hz, 1H), 5.18 (d, J=10.1 Hz, 1H), 3.81 (s, 3H),
3.59 (s, 2H), 3.31 (d, J= 2.4 Hz, 2H), 3.18 (d, J = 6.4 Hz, 2H), 2.25 (t, J=2.4 Hz,
1H).
13
C NMR (62.5 MHz, CDCl
3
): δ 158.8, 135.6, 130.3, 117.8, 113.7, 78.5, 73.2,
56.5, 56.4, 55.3, 41.0.
Allyl-(4-methoxy-benzyl)-(3-
trimethylsilanyl-prop-2-ynyl)-amine
(2.118).
Prepared as a minor product together
with (2.117) in low yield as a yellow oil (54 mg, 25%).
1
H NMR (400 MHz, CDCl
3
): δ 7.05 (d, J=8.7 Hz, 2H), 6.63 (d, J=8.5 Hz, 2H), 5.65
(m, 1H), 5.04 (dm, J=17.2 Hz, 1H), 4.95 (dm, J=10.2, 1H), 3.58 (s, 3H), 3.35 (s,
TMS
N
OMe
N
OMe
135
2H), 3.07 (s, 2H), 2.93 (d, J=7.4 Hz, 2H), 0.002 (s, 9H).
13
C NMR (100 MHz,
CDCl
3
): δ 159.0, 135.8, 130.7, 130.6, 118.2, 113.8, 101.2, 90.4, 56.8, 55.4, 42.3,
0.4.

Benzhydryl-(3-phenyl-prop-2-ynyl)-amine
(2.128)
Prepared analogously to (2.77) in low yield (48
mg, 33%).
1
H NMR (400 MHz, CDCl
3
): δ 7.39-7.35 (m, 5H), 7.25-7.21 (m, 7H), 7.16-7.14
(m, 3H), 5.10 (s, 1H), 3.51 (s, 2H).
13
C NMR (100 MHz, CDCl
3
): δ 143.3, 131.7,
128.6, 128.3, 128.1, 128.0, 127.5, 127.2, 123.3, 87.6, 83.7, 65.5, 37.1.

(1-Phenyl-ethyl)-(3-phenyl-prop-2-ynyl)-
amine (2.130).
Prepared analogously to (2.77) in moderate
yield (51 mg, 46 %). Purified using flash
chromatography (20% ethyl acetate: 80% hexanes).
1
H NMR (250 MHz, CDCl
3
): δ 7.43-7.24 (m, 10H), 4.07 (q, J=6.4 Hz, 1H), 3.47
(m, 2H), 1.39 (d, J=6.9 Hz, 3H).
13
C NMR (62.5 MHz, CDCl
3
): δ 144.5, 131.6,
128.5, 128.2, 128.0, 127.5, 127.1, 126.9, 123.2, 87.7, 83.3, 56.5, 36.8, 23.9.

N
H
Ph
Ph
NH
H
3
C
136
Benzyl-non-2-ynyl-amine (2.132)
Prepared analogously to (2.77) in low
yield (35 mg, 30%) as an oil from
benzylamine 2.131. Purified using flash chromatography (10% ethyl acetate: 90%
hexanes).
1
H NMR (250 MHz, CDCl
3
): δ 7.42-7.21 (m, 5H), 3.67 (s, 1H), 3.36 (t, J=2.1Hz,
2H), 2.25-2.18 (m, 2H), 1.58-1.25 (m, 10H), 0.89 (t, J=7 Hz, 3H).
13
C NMR (100
MHz, CDCl
3
): δ 138.3, 129.4, 128.2, 127.1, 85.5, 74.9, 56.9, 42.3, 31.3, 28.9, 28.6,
22.5, 18.8, 14.1.

[2-(3-Phenyl-prop-2-ynylamino)-
ethyl]-carbamic acid tert-butyl ester
(2.134)
Prepared analogously to (2.77) in low
yield (25 mg, 18%). Purified using flash chromatography (50% ethyl acetate:
hexanes).
1
H NMR (250 MHz, CDCl
3
): δ 7.41-7.36 (m, 2H), 7.30-7.26 (m, 3H), 4.96 (broad
s, 1H), 3.63 (s, 2H), 3.25 (q, J=5.7 Hz, 2H), 2.87 (t, J=6 Hz, 2H), 1.42 (s 9H).
13
C
NMR (62.5 MHz, CDCl
3
): δ 156.1, 131.6, 128.3, 128.1, 123.1, 87.1, 83.7, 79.2,
48.0, 40.0, 38.6, 28.4.

CH
3
(CH
2
)
5
N
H
N
H
NHBoc
137
1,4-Bis-(3-phenyl-prop-2-
ynyl)-piperazine (2.120)
To a suspension of
potassium (phenylethynyl)-
trifluoroborate (2.50) (2eq. 1 mmol, 208 mg) and paraformaldehyde (2.74) (2eq., 1
mmol, 30 mg) in toluene (2 ml), piperazine (2.119) (1 eq., 0.5 mmol, 21.5 µl) was
added followed by addition of ytterbium triflate (5 mol%, 0.025 mmol, 16 mg). The
resulting suspension was stirred at 100
o
C till no staring materials were left. The
reaction was monitored by TLC (50% ethyl acetate: hexanes). After 30 minutes, the
reaction was allowed to cool down, diluted with ethyl acetate and water and
extracted. The combined organic solvents were evaporated and the residue was
purified using flash chromatography (50% ethyl acetate: hexanes) to isolate a white
solid in excellent yield (76 mg, 97%).
1
H NMR (250 MHz, CDCl
3
): δ 7.46-7.39 (m, 2H), 7.31-7.26 (m, 3H), 3.55 (s, 2H),
2.76 (s, 4H).
13
C NMR (62.5 MHz, CDCl
3
): δ 131.8, 128.3, 128.2, 123.1, 85.6,
84.3, 52.0, 47.7.

N
N
138
2-(1-Diallylamino-3-phenyl-prop-2-ynyl)-
phenol (2.149)
To a suspension of potassium
(phenylethynyl)trifluoroborate (2.50) (0.5
mmol, 104 mg) and salicylaldehyde (2.147)
(0.5 mmol, 53.2 µl) in toluene (2 ml),
diallylamine (2.78) (0.5 mmol, 62 µl) was added followed by addition of the
ytterbium triflate (5 mol%, 0.025 mmol, 16 mg) . The resulting suspension was
stirred at 100
o
C till no staring materials were left. The reaction was monitored by
TLC (50% ethyl acetate: hexanes). After 30 minutes, the reaction was allowed to
cool down, diluted with ethyl acetate-water and extracted. The combined organic
solvent were evaporated and the residue was purified using flash chromatography
(5% ethyl acetate: hexanes) to isolate the final product in moderate yield (68 mg,
45%).
1
H NMR (250 MHz, CDCl
3
): δ 7.61-7.55 (m, 3H), 7.40-7.36 (m, 3H), 7.23-7.19
(m, 1H), 6.91-6.84 (m, 2H), 5.95-5.83 (m, 2H), 5.40-5.24 (m, 5H), 3.45 (dm,
J=13.5 Hz, 2H), 3.11 (dd, J=13.7 Hz, 2H).
13
C NMR (62.5 MHz, CDCl
3
): δ 157.2,
134.1, 132.0, 129.5, 128.9, 128.7, 128.5, 122.6, 121.7, 119.9, 119.4, 116.6, 89.8,
82.0, 55.9, 53.5.

OH
N
139
2-(1-Diallylamino-non-2-ynyl)-phenol
(2.150)
Prepared analogously to (2.149) in moderate
yield. (51%)
1
H NMR (250 MHz, CDCl
3
): δ 7.59-7.50 (m,
1H), 7.23-7.16 (m, 1H), 7.06-6.98 (m, 1H), 6.87-6.80 (m, 1H), 5.95-5.79 (m, 2H),
5.29-5.13 (m, 5H), 3.38-3.31 (m, 2H), 2.99 (dd, J=13.6 Hz, 2H), 2.37 (td, J=6.7 Hz,
2H), 1.68-1.25 (m, 8H), 0.91 (m, 3H).
13
C NMR (100 MHz, CDCl
3
): δ 157.2,
134.3, 129.2, 128.9, 122.2, 119.5, 119.1, 116.3, 90.3, 72.3, 55.4, 53.3, 31.3, 28.9,
28.6, 22.6, 18.8, 14.1.

4-[1-(2-Hydroxy-phenyl)-3-phenyl-prop-
2-ynyl]-piperazine-1-carboxylic acid tert-
butyl ester (2.229)
Prepared analogously to (2.149) in good
yield (56%).
1
H NMR (250 MHz, CDCl
3
): δ 7.58-
7.49(m, 3H), 7.39-7.34 (m, 3H), 7.28-7.21 (m, 1H), 6.92-6.85 (m, 2H), 5.14 (s,
1H), 3.52 (broad s, 4H), 2.73 (broad s, 4H), 1.45 (s, 9H).
13
C NMR (62.5 MHz,
CDCl
3
): δ 156.9, 154.5, 131.9, 129.8, 128.8, 128.7, 124.2, 120.7, 119.5, 116.6,
90.6, 81.4, 80.5, 60.5, 48.6, 43.4, 28.4.

OH
N
Boc
N
OH
N
(CH
2
)
5
CH
3
140
2-(1-Dibenzylamino-3-trimethylsilanyl-prop-2-
ynyl)-phenol (2.151)
Prepared analogously to (2.149) in moderate yield
(39%).
1
H NMR (250 MHz, CDCl
3
): δ 7.50-7.09 (m,
12H), 6.81-6.75 (m, 2H), 4.88 (s, 1H), 3.76 (d, J=12.6 Hz, 4H), 3.38 (d, J=12.6 Hz,
2H), 0.30 (s, 9H).
13
C NMR (62.5 MHz, CDCl
3
): δ 156.5, 136.9, 129.7, 129.5,
128.8, 128.7, 127.8, 121.6, 119.4, 116.3, 97.7, 95.5, 55.3, 54.6, 0.2.

2-(Benzyl-phenyl-amino)-4-phenyl-but-3-
yn-1-ol (2.153)
To a suspension of potassium
(phenylethynyl)trifluoroborate (2.50) (0.5
mmol, 104 mg) and glycol aldehyde dimer
(2.45) (0.30 mmol, 36 mg) in toluene (2 ml), N-benzyl-phenylamine (2.103) (0.5
mmol, 91.6 mg) was added followed by addition of ytterbium triflate (5 mol%,
0.025 mmol, 16 mg). The resulting suspension was stirred at 100
o
C. The reaction
was monitored by TLC (30 % ethyl acetate: hexanes). After 60 minutes, the
reaction was allowed to cool down and acid/base extraction was performed with
ethyl acetate. The solvent was evaporated and the residue was purified using flash
chromatography (30% ethyl acetate: hexanes) to isolate the final product in high
yield (142 mg, 87% yield).
OH
N
SiMe
3
Ph
Ph
N
Ph
OH
Ph
141
1
H NMR (250 MHz, CDCl
3
): δ 7.25-6.76 (m, 12H), 6.94-6.90 (m, 2H), 6.76 (t,
J=7.2 Hz, 1H), 4.74 (t, J=7.2 Hz, 1H), 4.48 (s, 2H), 3.67 (s, 2H).
13
C NMR (100
MHz, CDCl
3
): δ 149.5, 139.7, 131.8, 129.2, 128.8, 128.5, 128.3, 127.1, 127.0,
120.1, 117.2, 86.7, 84.9, 63.3, 55.8, 52.8.

2-(Benzyl-phenyl-amino)-dec-3-yn-
1-ol (2.154)
Prepared analogously to (2.153) in
moderate yield (44%).
1
H NMR (400 MHz, CDCl
3
): δ 7.42-
7.36 (m, 4H), 7.31-7.26 (m, 3H), 7.03 (d, J=8.6 Hz, 2H), 6.91 (t, J=6.8 Hz, 1H),
4.74-4.70 (m, 1H), 4.60 (s, 2H), 3.75-3.72 (m, 2H), 2.25 (td, J= 6.9 Hz, 2H), 2.19
(broad s, 1H), 1.54-1.50 (m, 2H), 1.43-1 .31 (m, 6H), 0.96 (t, J= 7.8 Hz, 3H).
13
C
NMR (62.5 MHz, CDCl
3
): δ 149.4, 139.8, 129.0, 128.6, 126.83, 126.78, 119.6,
116.7, 87.4, 75.4, 63.4, 55.2, 52.4, 31.2, 28.5, 28.4, 22.5, 18.6, 14.0.

CH
3
(CH
2
)
5
N
OH
142
2-Diallylamino-4-phenyl-but-3-yn-1-ol
(2.156)
Prepared analogously to (2.153) in moderate
yield (32%).
1
H NMR (250 MHz, CDCl
3
): δ 7.47-7.28 (m,
5H), 5.98-5.79 (m, 2H), 5.31-5.19 (m, 5H), 4.04-3.98 (m, 1H), 3.69-3.65 (m, 2H),
3.46-3.41 (m, 2H), 3.39 -3.11 (m, 2H), 2.65 (broad s, 1H).
13
C NMR (62.5 MHz,
CDCl
3
): δ 135.7, 131.8, 128.3, 122.8, 118.1, 86.7, 83.8, 61.5, 54.3, 53.7.

2-Diallylamino-dec-3-yn-1-ol (2.157)
Prepared analogously to (2.153) in low
yield (25%).
1
H NMR (250 MHz, CDCl
3
): δ 5.90-5.73
(m, 2H), 5.26-5.12 (m, 4H), 3.77-3.70 (m, 1H), 3.57-3.51 (m, 2H), 3.35-3.27 (m,
2H), 2.93 (dd, J = 14.3 Hz, 2H), 2.20 (td, J = 6.9 Hz, 2H), 1.55-1.25 (m, 8H), 0.92-
0.87 (m, 3H).
13
C NMR (62.5 MHz, CDCl
3
): δ 135.9, 117.8, 87.1, 74.2, 61.8, 53.8,
53.5, 31.3, 27.8, 28.5, 22.6, 18.6, 14.1.

N
OH
CH
3
(CH
2
)
5
N
OH
143
4-(1-Hydroxymethyl-3-trimethylsilanyl-
prop-2-ynyl)-piperazine-1-carboxylic acid
tert-butyl ester (2.158)
Prepared analogously to (2.153) in low yield
(25%).
1
H NMR (250 MHz, CDCl
3
): δ 3.62-3.38 (m, 7H), 2.71-2.58 (m, 2H), 2.47-2.38
(m, 2H), 1.47 (s, 9H), 0.16 (s, 9H).
13
C NMR (62.5 MHz, CDCl
3
): δ 155.0, 98.7,
93.0, 60.9, 59.2, 48.8, 43.8, 28.5, 0.1.

3-(Allyl-benzyl-amino)-undec-4-yne-1,2-
diol (2.161)
To a suspension of potassium-
(octynyl)trifluoroborate (2.52) (0.5 mmol,
102 mg) and (D,L)-glyceraldehyde dimer
(2.159) (0.6 eq., 0.30 mmol, 54 mg) in
toluene (2 ml), N-allyl-benzylamine (2.104) (0.5 mmol, 73.5 mg) was added
followed by addition of ytterbium triflate (5 mol%, 0.025 mmol, 16 mg). The
resulting suspension was stirred at 100
o
C till no staring materials were left. The
reaction was monitored by TLC (30 % ethyl acetate: hexanes). After 60 minutes,
the reaction was allowed to cool down, diluted with ethyl acetate-water and
extracted. The combined organic solvents were dried with Na
2
SO
4
and
concentrated under reduced pressure. The crude
1
H NMR taken indicated that only
Me
3
Si
N
OH
NBoc
CH
3
(CH
2
)
5
OH
N
OH
144
one diastereomer was present. The residue was purified using flash
chromatography via flash chromatography (30% ethyl acetate: hexanes) to isolate
the final product in good yield (124 mg, 75%, 99 % d.e.).
1
H NMR (400 MHz, methanol-d
4
): δ 7.36-7.23 (m, 5H), 5.96-5.83 (m, 1H), 5.26 (d,
J=17.3 Hz, 1H), 5.17 (d, J=10.1 Hz, 1H), 3.92 (d, J=13.7 Hz, 1H), 3.79- 3.72 (m,
2H), 3.52-3.29 (m, 4H), 3.00 (dd, J=13.6 Hz, 1H), 2.33 (t, J=6.6 Hz, 2H), 1.66-1.50
(m, 4H), 1.41-1.35 (m, 4H), 0.97 (t, J=7.2 Hz, 3H).
13
C NMR (100 MHz, methanol-
d
4
): δ 139.1, 136.1, 128.7, 128.1, 126.8, 116.8, 86.3, 74.5, 72.1, 64.6, 55.9, 55.6,
54.5, 31.2, 28.8, 28.4, 22.4, 18.2, 13.2.

3-[Allyl-(3,4,5-trimethoxy-benzyl)-
amino]-5-phenyl-pent-4-yne-1,2-diol
(2.163)
Prepared analogously to (2.161) in good
yield (73%, 99% d.e.).
1
H NMR (400 MHz, CDCl
3
): δ 7.44-7.42
(m, 2H),7.27-7.25 (m, 3H), 6.52 (s, 2H),
5.84-5.74 (m, 1H), 5.20 (d, J=18.1 Hz, 1H), 5.10 (d, J=10.1 Hz,1H), 4.49 (q, J=7.6
Hz, 1H), 4.16 (t, J = 9.4 Hz, 1H), 4.00 (dd, J = 9.2 Hz, 1H), 3.90 (d, J = 14.1 Hz,
1H), 3.78 (s, 6H), 3.77 (s, 3H), 3.57 (d, J=7 Hz, 1H), 3.36 (m, 2H), 3.03 (dd, J=14.2
Hz, 1H).
13
C NMR (100 MHz, CDCl
3
): δ 153.2, 136.8, 136.0, 135.1, 132.0, 128.3,
122.9, 118.0, 105.2, 86.7, 83.8, 78.3, 69.2, 60.9, 58.0, 56.2, 56.0, 55.4.
OH
N
OH
OMe
OMe
MeO
145
3-[Allyl-(3,4-dimethoxy-benzyl)-amino]-5-
phenyl-pent-4-yne-1,2-diol (2.164)
Prepared analogously to (2.161) in good
yield (74 %, 99% d.e.).
1
H NMR (400 MHz, CDCl
3
): δ 7.56-7.53 (m,
2H), 7.40-7.38 (m, 3H), 6.91-6.85 (m, 3H),
5.97-5.86 (m, 1H), 5.36-5.26 (m, 1H), 3.98-
3.91 (m, 2H), 3.92 (s, 3H), 3.91 (s, 3H), 3.86-382 (m 1H), 3.80-3.77 (m, 1H), 3.71-
3.67 (m, 1H), 3.46-3.41 (m, 2H), 3.10 (dd, J=13.9 Hz, 1H).
13
C NMR (100 MHz,
CDCl
3
): δ 149.0, 148.4, 135.2, 132.0, 130.5, 128.6, 128.4, 122.4, 121.4, 118.8,
111.8, 110.8, 87.8, 83.8, 70.3, 65.7, 58.1, 56.0, 55.9, 54.9.

(2R, 3S, 4R, 5R)-5-Diallylamino-7-
phenyl-hept-6-yne-1,2,3,4-tetraol
(2.168)
To a suspension of potassium
(phenylethynyl)-trifluoroborate (2.50)
(0.5 mmol, 104 mg) and D-arabinose
(2.167) (0.50 mmol, 75 mg) in a toluene/ methanol mixture (4:1, 2 ml),
diallylamine (2.78) (0.5 mmol, 62 µg) was added followed by addition of ytterbium
triflate (5 mol %). The resulting suspension was stirred at 100
o
C till no staring
materials were left. The reaction was monitored by TLC. After 60 minutes, the
OH
N
OH
OMe
MeO
OH
N OH
OH
OH
146
reaction was allowed to cool down and diluted with ethyl acetate and water. After
the extraction the organic solvents were dried using Na
2
SO
4
and concentrated under
reduced pressure The NMR of crude reaction mixture indicated that only one
diastereomer formed (99% d.e. and 99% e.e.). The solvent was evaporated and the
residue was purified using flash chromatography (5% methanol: 95%
dichloromethane) to isolate white solid in good yield (87 mg, 53%)
1
H NMR (250 MHz, methanol-d
4
): δ 7.48-7.44 (m, 2H), 7.32-7.29 (m, 3H), 5.98-
5.80 (m, 2H), 5.26-5.10 (m, 4H), 4.06-3.61 (m, 6H), 3.41-3.32 (m, 2H), 3.01 (dd,
J=14.1Hz, 2H).
13
C NMR (62.5 MHz, methanol-d
4
): δ 137.8, 132.9, 129.5, 129.1,
125.0, 117.9, 87.7, 87.2, 73.3, 71.7, 71.1, 65.4, 56.9, 56.0.

(2R, 3R, 4S, 5S)-5-Diallylamino-7-
phenyl-hept-6-yne-1,2,3,4-tetraol
(2.170)
Prepared analogously to (2.168) from
D-xylose (2.169) in low yield (24%,
99% d.e., 99 % e.e.).
1
H NMR (250 MHz, methanol-d
4
): δ 7.49-7.43 (m, 2H), 7.33-7.28 (m, 3H), 6.00-
5.83 (m, 2H), 5.27-5.10 (m, 4H), 4.07-3.99 (m, 2H), 3.90-3.46 (m, 4H), 3.46-3.35
(m, 2H), 3.05 (dd, J=14 Hz, 2H).
13
C NMR (62.5 MHz, methanol-d
4
): δ 137.7,
132.9, 129.5, 129.2, 125.0, 117.9, 87.4, 87.2, 74.9, 73.3, 71.2, 64.4, 57.3, 56.1.

OH
N OH
OH
OH
147
(2R, 3S, 4S, 5S) - 5-Diallylamino-7-
phenyl-hept-6-yne-1,2,3,4-tetraol
(2.172)
Prepared analogously to (2.168) from
D-ribose (2.171) in moderate yield
(46%, 99 % d.e., 99 % e.e.).
1
H NMR (400 MHz, methanol-d
4
): δ 7.53-7.50 (m, 2H), 7.40-7.34 (m, 3H), 6.00-
5.89 (m, 2H), 5.34-5.24 (m, 4H), 4.13 (d, J=7.5 Hz, 1H), 3.92-3.69 (m, 5H), 3.58-
3.51 (m, 2H), 3.12 (dd, J=13.9, 2H).
13
C NMR (62.5 MHz, methanol-d
4
): δ 136.8,
133.4, 130.0, 129.9, 124.9, 119.9, 88.6, 85.5, 77.2, 75.5, 73.2, 64.6, 59.8, 56.5.

(2R, 3S, 4R, 5R)-4-[1-(1,2,3,4-
Tetrahydroxy-butyl)-non-2-ynyl]-
piperazine-1-carboxylic acid tert-
butyl ester (2.173)
Prepared analogously to (2.168) from
D-arabinose (2.167) in moderate
yield (46%, 99% d.e., 99 % e.e.).
1
H NMR (400 MHz, methanol-d
4
): δ 3.93-3.84 (m, 3H), 3.75-3.70 (m, 1H), 3.67-
3.63 (m, 1H), 3.57-3.55 (m, 1H), 3.45 (s, 4H), 2.61-2.45 (m, 4H), 2.29 (t, J=4.9 Hz,
2H), 1.59-1.52 (m, 3H), 1.49 (s, 9H),1.40-1.30 (m, 5H), 0.94 (t, J=4.6 Hz, 3H).
13
C
OH
N OH
OH
OH
CH
3
(CH
2
)
5
OH
N OH
OH
OH
Boc
N
148
NMR (62.5 MHz, methanol-d
4
): δ 156.9, 88.5, 81.6, 76.9, 73.3, 71.5, 71.4, 65.8,
61.2, 51.2, 45.6, 45.2, 33.0, 30.6, 30.1, 29.2, 24.2, 29.9, 14.7.

(2R, 3S, 4R, 5R)-5-(Allyl-benzyl-
amino)-7-phenyl-hept-6-yne-1,2,3,4-
tetraol (2.174)
Prepared analogously to (2.168) from
D-arabinose (2.167) in high yield
(87%, 99% d.e., 99% e.e.).
1
H NMR (400 MHz, methanol-d
4
): δ 7.54-7.52 (m, 2H), 7.42-7.31 (m, 7H), 7.27-
7.24 (m, 1H), 6.00-5.90 (m, 1H), 5.31-5.15 (m, 2H), 4.17-3.95 (m, 3H), 3.88-3.84
(m, 1H), 3.75-3.64 (m, 2H), 3.53 (d J=13.1, 1H), 3.38-3.36 (m, 1H), 3.31-3.30 (m,
1H), 3.08 (dd, J=14.0 Hz, 1H).
13
C NMR (100 MHz, methanol-d
4
): δ 139.2, 136.2,
131.4, 128.9, 128.3, 128.0, 127.9, 127.6, 126.7, 116.5, 86.1, 85.8, 71.6, 70.1, 69.5,
63.8, 55.29, 55.25, 54.6.

OH
N OH
OH
OH
149
(2R, 3S, 4R, 5R)-5-(Benzyl-
isopropenyl-amino)-7-phenyl-hept-6-
yne-1,2,3,4-tetraol (2.175)
Prepared analogously to (2.168) from
D-arabinose (2.167) in good yield
(71%, 99% d.e., 99% e.e.).
1
H NMR (400 MHz, CDCl
3
): δ 7.56-
7.54 (m, 2H), 7.37-7.35 (m, 8H), 5.05 (s, 1H), 4.97 (s, 1H), 4.09-4.05 (m, 1H),
3.97-3.90 (m, 3H), 3.77-3.74 (m, 1H), 3.69-3.60 (m, 2H), 3.41 (d, J=13.2, 1H),
3.23-3.19 (m, 1H), 3.08 (d, J=13.2 Hz, 1H), 1.80 (s, 3H).
13
C NMR (62.5 MHz,
CDCl
3
): δ 142.5, 138.5, 132.0, 130.1, 129.3, 128.5, 128.3, 127.4, 122.7, 114.4,
87.4, 84.6, 72.2, 70.3, 70.2, 64.2, 58.5, 55.7, 55.1, 20.9.

1,4-Dibenzyl-3-phenylethynyl-piperazin-2-
one (2.185)
To a suspension of potassium (phenylethynyl)-
trifluoroborate (2.50) (0.5 mmol, 104 mg) and
diamine (2.184) (0.50 mmol, 120 mg) in
toluene, glyoxylic acid (2.177) (0.5 mmol, 46 mg) was added followed by addition
of ytterbium triflate (5 mol%. 0.025 mmol, 16 mg). The resulting suspension was
stirred at 100
o
C till no staring materials were left. The reaction was monitored by
TLC. After 60 minutes, the reaction was allowed to cool down and diluted with
OH
N OH
OH
OH
N
N O
Ph
Ph
150
N
N O
TMS
Ph
Ph
ethyl acetate-water. After the extraction was performed the solvent was evaporated
and the residue was purified using flash chromatography (15% ethyl acetate:
hexanes) to isolate a white solid in moderate yield (89 mg, 47%).
1
H NMR (250 MHz, CDCl
3
): δ 7.52-7.47 (m, 2H), 7.37-7.22 (m, 13H), 4.80-4.74
(m, 1H), 4.43-4.74 (m, 1H), 3.79-3.68 (m, 2H), 3.38-3.27 (m, 1H), 3.09-2.98 (m,
2H), 2.72-2.62 (m, 1H).
13
C NMR (100 MHz, CDCl
3
): δ 165.2, 136.9, 136.5, 132.1,
129.3, 128.7, 128.5, 128.3, 128.1, 127.6, 127.5, 122.8, 87.1, 82.8, 58.5, 57.2, 49.7,
46.1, 44.6.

1,4-Dibenzyl-3-trimethylsilanylethynyl-
piperazin-2-one (2.186)
Prepared analogously to (2.185) in low yield
(26%).
1
H NMR (250 MHz, CDCl
3
): δ 7.12-7.00 (m,
10H), 4.62 (d, J=15 Hz, 1H), 4.08 (d, J=15 Hz, 1H), 3.96 (s, 1H), 3.44 (s, 2H),
3.17-3.03 (m, 1H), 2.83-2.68 (m, 2H), 2.47-2.34 (m, 1H), 0.004 (s, 9H).
13
C NMR
(62.5 MHz, CDCl
3
): δ 165.0, 136.7, 136.5, 129.1, 128.5, 128.3, 127.9, 127.5,
127.4, 98.3, 92.0, 58.2, 57.2, 49.5, 45.8, 44.3, 0.08.

151
1,4-Dibenzyl-3-oct-1-ynyl-piperazin-2-one
(2.187)
Prepared analogously to (2.185) in good yield
(70%).
1
H NMR (250 MHz, CDCl
3
): δ 7.35-7.21 (m,
10H), 4.78 (d, J=15 Hz, 1 H), 4.34 (d, J= 15 Hz, 1H), 4.17 (s, 1H), 3.65 (s, 2H),
3.32-3.21 (m, 1H), 3.05-2.87 (m, 2H), 2.64-2.56 (m, 1H), 2.31-2.24 (m, 2H), 1.61-
1.23 (m, 8H), 0.90-0.84 (m, 3H).
13
C NMR (62.5 MHz, CDCl
3
): δ 165.9, 137.1,
136.6, 129.2, 128.6, 128.4, 128.1, 127.4, 84.7, 72.9, 58.4, 56.8, 49.7, 46.0, 44.3,
31.3, 28.8, 28.6, 25.6, 18.9, 14.1.

1,4-Diallyl-3-phenylethynyl-piperazin-2-one
(2.189)
To a suspension of tetrabutylammonium
(phenylethynyl)-trifluoroborate (2.71) (0.5
mmol, 205.5 mg) and N,N'-diallyl-ethane-1,2-
diamine (2.188) (0.50 mmol, 70 mg) in toluene,
glyoxylic acid (2.177) (0.5 mmol, 46 mg) was added followed by addition of
ytterbium triflate (5 mol%, 0.025 mmol, 16 mg). The resulting suspension was
stirred at room temperature till no staring materials were left. The reaction was
monitored by TLC. After 12 hours the reaction was allowed to cool down and
diluted with ethyl acetate-water. After the extraction was performed the solvent was
N
N O
N
N O
(CH
2
)
5
CH
3
Ph
Ph
152
evaporated and the residue was purified via flash chromatography (25% ethyl
acetate: hexanes) to isolate the desired product in moderate yield (73 mg, 45%).
1
H NMR (250 MHz, methanol-d
4
): δ 7.40-7.25 (m, 5H), 5.90-5.66 (m, 2H), 5.31-
5.13 (m, 4H), 4.36 (s, 1H), 4.06-3.85 (m, 2H), 3.45-3.34 (m, 1H), 3.23 (d, J=6.5
Hz, 4H), 3.03-2.92 (m, 1H), 2.83-2.76 (m, 1H).
13
C NMR (62.5 MHz, methanol-
d
4
): δ 167.5, 135.5, 133.4, 133.3, 130.3, 130.1, 124.0, 120.2, 118.7, 88.5, 83.6,
58.6, 50.6, 47.8, 45.9.

1,4-Diallyl-3-oct-1-ynyl-piperazin-2-one
(2.190)
Prepared analogously to (2.185) in low
yield (28%).
1
H NMR (250 MHz, CDCl
3
): δ 5.85-5.70
(m, 2H), 5.29-5.13 (m, 4H), 4.20 (s, 1H),
4.12-3.85 (m, 2H), 3.41-3.29 (m, 1H), 3.17-3.07 (m, 3H), 3.00-2.88 (m, 1H), 2.73-
2.65 (m, 1H), 2.25-2.19 (m, 2H), 1.54-1.24 (m, 8H), 0.90-0.85 (m, 3H).
13
C NMR
(62.5 MHz, CDCl
3
): δ 165.5, 133.9, 132.2, 118.9, 117.7, 87.4, 72.6, 57.1, 56.8,
48.9, 45.9, 44.1, 31.3, 28.6, 28.5, 22.5, 18.8, 14.0.

N
N O
153
4-(3-Phenyl-1-trifluoromethyl-prop-2-ynyl)-
morpholine (2.138)
To a suspension of potassium
(phenylethynyl)trifluoroborate (2.50) (0.5 mmol, 104
mg) and 2,2,2-trifluoro-1-methoxy-ethanol (2.135)
(0.5 mmol, 54 µl) in toluene (2 ml) under argon, 4-trimethylsilyl-morpholine
(2.227) (0.5 mmol, 88.2 µl) was added followed by addition of
chlorotrimethylsilane (2 eq., 1 mmol, 125.2 µl). The resulting suspension was
stirred at 100
o
C for one hour. The reaction was allowed to cool down and diluted
with ethyl acetate-water. After the extraction was performed the solvent was dried
using Na
2
SO
4
, evaporated and the residue was purified using flash chromatography
(10% ethyl acetate: hexanes) to isolate a viscous colorless liquid in moderate yield
(58 mg, 43% yield).
1
H NMR (400 MHz, CDCl
3
): δ 7.55-7.52 (m, 2H), 7.43-7.35 (m, 3H), 4.13 (q,
J=14.8 Hz, 4H), 3.86-3.77 (m, 4H), 2.91-2.75 (m, 4H).
19
F NMR (400 MHz,
CDCl
3
): δ -71.4.
13
C NMR (100 MHz, CDCl
3
): δ 132.0, 129.1, 128.4, 123.8 (q),
121.6, 89.1, 77.3, 66.9, 60.5 (q), 50.7.

N
CF
3
O
154
1-(3-Phenyl-1-trifluoromethyl-prop-2-ynyl)-
pyrrolidine (2.139)
Prepared analogously to (2.138) in moderate yield
(46%).
1
H NMR (400 MHz, CDCl
3
): δ 7.54-7.51 (m, 2H),
7.40-7.35 (m, 3H), 4.45 (q, J= 7.0 Hz, 1H), 2.96-2.88 (m, 4H), 1.90-1.86 (m, 4H).
19
F NMR (400 MHz, CDCl
3
): δ -72.4.
13
C NMR (100 MHz, CDCl
3
): δ 132.0, 128.9,
128.4, 123.7 (q), 121.9, 88.3, 78.1, 57.3 (q), 56.8, 50.4, 23.8.

Diallyl-(1-trifluoromethyl-non-2-ynyl)-amine
(2.140)
Prepared analogously to (2.138) in moderate
yield (41 %).
1
H NMR (400 MHz, CDCl
3
): δ 5.79-5.69 (m,
2H), 5.16 (d, J=17.2, 2Hz), 5.08 (d, J =10.1, 2H), 4.04-3.97 (m, 1H), 3.33 (d, J =
15.2, 2H), 2.93 (d, J = 7.3 Hz, 1H), 2.89 (d, J = 8.4 Hz, 1H), 2.17 (td, J = 7.2 Hz, J=
2.2 Hz, 2H), 1.50-1.18 (m, 8H), 0.83 (t, J=6.8 Hz, 3H).
19
F NMR (400 MHz,
CDCl
3
): δ -73.0.
13
C NMR (100 MHz, CDCl
3
): δ 135.6, 124.3 (q, J
C-F
= 282.4),
117.9, 88.6, 69.3, 54.7, 54.5 (q, J = 30 Hz), 31.2, 28.4, 22.6, 18.6, 14.0.

CH
3
(CH
2
)
5
N
CF
3
N
CF
3
155
1-[1-(4-Bromo-phenyl)-3-phenyl-prop-2-
ynyl]-pyrrolidine (2.144)
Prepared analogously to (2.138) in moderate
yield (46%).
1
H NMR (400 MHz, CDCl
3
): δ 7.55-7.51 (m,
6H), 7.38-7.36 (m, 3H), 4.89 (s, 1H), 2.72-2.70
(m, 4H), 1.85-1.82 (m, 1H).
13
C NMR (100 MHz, CDCl
3
): δ 138.7, 131.8, 131.4,
129.9, 128.3, 128.2, 123.0, 121.5, 87.3, 85.9, 58.4, 50.1, 23.5.

Diallyl-[1-(4-bromo-phenyl)-non-2-
ynyl]-amine (2.146)
Prepared analogously to (2.138) in
moderate yield (46%).
1
H NMR (400 MHz, CDCl
3
): δ 7.43-7.19
(m, 4H), 5.75-5.67 (m, 2H), 5.15 (d, J = 15.2 Hz, 2H), 5.03 (d, J =10.1, 2H), 4.69
(s, 1H), 3.08-3.04 (m, 2H), 2.85 (d, J = 8.1 Hz, 1H), 2.81 (d, J = 8.2 Hz, 1H), 2.26
(t, J = 7.4 Hz, 2H), 1.55-1.18 (m, 8H), 0.85-0.81 (m, 3H).
13
C NMR (100 MHz,
CDCl
3
): δ 156.5, 139.2, 136.5, 131.0, 130.0, 121.0, 117.3, 88.6, 74.7, 70.2, 55.6,
53.4, 31.3, 29.0, 28.6, 22.6, 18.8, 14.1.

CH
3
(CH
2
)
5
N
Br
N
Br
156
1-(1-Isopropyl-3-phenyl-prop-2-ynyl)-pyrrolidine
(2.129)
To a suspension of potassium
(phenylethynyl)trifluoroborate (2.50) (0.5 mmol,
104 mg) and 2-methyl-propionaldehyde (2.228) (0.5
mmol, 45.7 mg) in toluene (2 ml), pyrrolidine (2.132) (0.5 mmol, 41.7 µl) was
added followed by Yb(OTf)
3
(5 mol%, 0.025 mmol, 16 mg). The resulting
suspension was stirred at 100
o
C for 30 minutes. The reaction was allowed to cool
down and diluted with ethyl acetate-water. After the extraction was performed the
solvent was dried using Na
2
SO
4
, evaporated and the residue was purified using
flash chromatography (20% ethyl acetate: hexanes) to isolate colorless liquid in
good yield (78%).
1
H NMR (400 MHz, CDCl
3
): δ 7.49-7.47 (m, 2H), 7.35-7.32 (m, 3H), 3.29 (d,
J=8.6 Hz, 1H), 2.81-2.75 (m, 2H), 2.72-2.67 (m, 2H), 1.99-1.96 (m, 1H), 1.85 -1.82
(m, 4H), 1.15 (d, J= 6.9 Hz, 3H), 1.10 (d, J=6.0 Hz, 3H).
13
C NMR (100 MHz,
CDCl
3
): δ 131.7, 128.2, 127.7, 123.8, 87.8, 85.5, 62.5, 50.4, 31.9, 23.5, 20.2, 19.4.

N
157
1-(1-Phenylethynyl-pentyl)-pyrrolidine
(2.133)
Prepared analogously to (2.129) in moderate
yield (45%).
1
H NMR (400 MHz, CDCl
3
): δ 7.47-7.45 (m,
2H), 7.34-7.30 (m, 3H), 3.74-3.70 (m, 1H), 2.82-2.73 (m, 4H), 1.86-1.29 (m, 10H),
0.96 (t, J=7.9 Hz, 3H).
13
C NMR (100 MHz, CDCl
3
): δ 131.7, 128.2, 127.9, 123.4,
88.2, 85.3, 55.2, 49.8, 34.8, 28.9, 23.5, 22.5, 14.1.

Benzyl-(1-benzyl-1H-[1,2,3]triazol-4-ylmethyl)-
methyl-amine (2.203)
To a suspension of potassium ethynyltrifluoroborate
(2.45) (0.5 mmol, 66 mg), N-methyl benzylamine
(2.82) (0.5 mmol, 64.4 µl), paraformaldehyde (2.74)
(0.5 mmol, 15 mg) in toluene/ tBuOH/ water mixture, ytterbium triflate (5 mol%,
0.025 mmol, 16 mg) and sodium ascorbate (20 mol%, 20 mg) were added followed
by addition of benzyl azide (0.5 mmol, 63 µl). The reaction flask was flashed with
argon in order to get rid of oxygen and the reaction was heated up to 80
o
C. After 2
hours the reaction was completed by TLC. The solvent was evaporated and the
residue was purified via flash chromatography using 100% ethyl acetate. The
desired product was isolated in good yield (52%).
N
N
N
N
Ph
N
H
3
C
Ph
158
1
H NMR (400 MHz, CDCl
3
): δ 7.45 (s, 1H), 7.41-7.26 (m, 10H), 5.55 (s, 2H), 3.74
(s, 2H), 3.57 (s, 2H), 2.26 (s, 3H).
13
C NMR (100 MHz, CDCl
3
): δ 145.6, 138.3,
134.8, 129.1, 128.7, 128.3, 128.0, 127.2, 122.6, 61.4, 54.1, 52.0, 42.1.

2-Allyl-6-phenyl-2,3,3a,4-tetrahydro-1H-
cyclopenta[c]pyrrol-5-one (2.207)
To a solution of propargylamine (2.79) (1 eq., 0.36 mmol)
in dry dichloromethane (10 ml) in a flamed dried flask
Co
2
(CO)
8
(2 eq., 0.72 mmol, 246 mg) was added in the
glove box. The reaction was stirred at room temperature
until the formation of the complex was complete (TLC monitoring). The reaction
was cooled to 0
o
C and N-methylmorpholine oxide (NMO) dissolved in dry DCM
(10-12 eq.; 0.5 g) was added by cannula in three portions. After the reaction was
complete (monitor by TLC), the reaction was filtered through a silica plug and
flushed with ethyl acetate. Flash chromatography on the residue gave product as a
colorless solid in good yield (78%).
1
H NMR (400 MHz, CDCl
3
): δ 7.50 (d, J = 7.8 Hz, 2H), 7.35-7.24 (m, 3H), 6.00-
5.90 (m, 1H), 5.20 (d, J = 17.1 Hz, 1H), 5.12 (d, J = 10.2Hz, 1H), 4.30 (d, J = 17.7
Hz, 1H), 3.41-3.14 (m, 5H), 2.75 (dd, J = 17.7 Hz, J = 6.5 Hz, 1H), 2.26 (dd, J =
17.7 Hz, J = 4.0 Hz, 1H), 1.96 (t, J = 8.3 Hz, 1H).
13
C NMR (62.5 MHz, CDCl
3
):
δ 207.2, 134.2, 130.9, 128.5, 128.2, 127.9, 118.2, 58.6, 57.7, 54.0, 43.2, 41.1.

N
O
Ph
159
2-(4-Methoxy-benzyl)-6-phenyl-
2,3,3a,4-tetrahydro-1H-
cyclopenta[c]pyrrol-5-one (2.208)
Prepared analogously to (2.207) in high
yield (75 %).
1
H NMR (400 MHz, CDCl
3
): δ 7.57-7.54
(m, 2H), 7.42-7.27 (m, 5H), 6.91-6.87 (m, 2H), 4.26 (d, J = 19.1 Hz, 1H), 3.84 (d, J
= 12.3 Hz, 1H), 3.82 (s, 3H), 3.65 (d, J = 13.1 Hz, 1H), 3.44-3.19 (m, 3H), 2.79
(dd, J = 18.2 Hz, J = 6.3 Hz, 1H), 2.32 (dd, J = 17.7 Hz, J = 4.0 Hz, 1H), 2.07-2.00
(m, 1H).
13
C NMR (62.5 MHz, CDCl
3
): δ 207.3, 179.5, 159.1, 134.4, 131.2, 129.9,
128.5, 128.2, 128.1, 59.5, 58.0, 55.3, 54.3, 43.5, 41.2.

N
O
MeO
160
2.4.3 Chapter 2 NMR Spectra
acetone
water
10 8 6 4 2 0 PPM
1
H NMR (400 MHz, acetone-d
6
) of 2.50
-110 -120 -130 -140 -150 -160 PPM

19
F NMR (376 MHz, acetone-d
6
) of 2.50
BF
3
K
BF
3
K
161

11
B NMR (64.2 MHz, acetone-d
6
) of 2.50
10 5 0 -5 -10 -15 PPM
11
B NMR (64.2 MHz, acetone-d
6
) of 2.50

BF
3
K
162
180 160 140 120 100 80 60 40 20 PPM
13
C NMR (62.5 MHz, acetone-d
6
) of 2.50
water
5 4 3 2 1 0 PPM
1
H NMR (400 MHz, acetone-d
6
) of 2.51

CH
3
(CH
2
)
3
BF
3
K
163
-100 -110 -120 -130 -140 -150 -160 PPM
19
F NMR (376 MHz, acetone-d
6
) of 2.51
10 5 0 -5 -10 PPM
11
B NMR (64.2 MHz, acetone-d
6
) of 2.51

CH
3
(CH
2
)
3
BF
3
K
164
35 30 25 20 15 PPM
13
C NMR (62.5 MHz, acetone-d
6
) of 2.51
water
acetone
3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0 PPM
1
H NMR (400 MHz, acetone-d
6
) of 2.52

TMS BF
3
K
165
0 -20 -40 -60 -80 -100 -120 -140 -160 -180 PPM
19
F NMR (376 MHz, acetone-d
6
) of 2.52
15 10 5 0 -5 -10 -15 PPM
11
B NMR (64.2 MHz, acetone-d
6
) of 2.52

TMS BF
3
K
166
0 -50 -100 -150 PPM
19
F NMR (376 MHz, acetone-d
6
) of 2.04
4 2 0 -2 -4 -6 -8 PPM
11
B NMR (64.2 MHz, acetone-d
6
) of 2.53

(Pri)
3
Si BF
3
K
(Pri)
3
Si BF
3
K
167
50 40 30 20 10 0 PPM
13
C NMR (62.5 MHz, acetone-d
6
) of 2.53
10 8 6 4 2 0 PPM
1
H NMR (400 MHz, acetone-d
6
) of 2.54

H BF
3
K
168
-120 -125 -130 -135 -140 -145 -150 PPM
19
F NMR (376 MHz, acetone-d
6
) of 2.54
6 4 2 0 -2 -4 -6 -8 -10 PPM
11
B NMR (64.2 MHz, acetone-d
6
) of 2.54

H BF
3
K
169

8 6 4 2 0PPM
1
H NMR (250 MHz, CDCl
3
) of 2.77

N
O
170
200 150 100 50 0PPM
13
C NMR (62.5 MHz, CDCl
3
) of 2.77
6.0 5.8 5.6 5.4 5.2 PPM
8 6 4 2 0PPM
1
H NMR (250 MHz, CDCl
3
) of 2.79

N
171
140 135 130 125 120 PPM
200 150 100 50 0PPM
13
C NMR (62.5 MHz, CDCl
3
) of 2.79
8 6 4 2 0PPM
1
H NMR (250 MHz, CDCl
3
) of 2.81

N
NBoc
172
200 150 100 50 0PPM
13
C NMR (62.5 MHz, CDCl
3
) of 2.81
10 8 6 4 2 0 PPM
1
H NMR (250 MHz, CDCl
3
) of 2.83

N
CH
3
Ph
173
200 150 100 50 0PPM
13
C NMR (62.5 MHz, CDCl
3
) of 2.83
10 8 6 4 2 0 PPM
1
H NMR (250 MHz, CDCl
3
) of 2.84

TMS
N
174
200 150 100 50 0 PPM
13
C NMR (62.5 MHz, methanol-d
4
) of 2.84
10 8 6 4 2 0 PPM
1
H NMR (250 MHz, CDCl
3
) of 2.85

TMS
N
O
175
150 100 50 0PPM
13
C NMR (62.5 MHz, CDCl
3
) of 2.85
10 8 6 4 2 0 PPM
1
H NMR (250 MHz, CDCl
3
) of 2.86

CH
3
(CH
2
)
5
N
176
200 150 100 50 0PPM
13
C NMR (62.5 MHz, CDCl
3
) of 2.86
10 8 6 4 2 0 PPM
1
H NMR (250 MHz, CDCl
3
) of 2.87

CH
3
(CH
2
)
5
N
NBoc
177
32 31 30 29 28 27 PPM
200 150 100 50 0PPM
13
C NMR (62.5 MHz, CDCl
3
) of 2.87
10 8 6 4 2 0 PPM
1
H NMR (250 MHz, CDCl
3
) of 2.89

N
OMe
178
200 150 100 50 0PPM
13
C NMR (62.5 MHz, CDCl
3
) of 2.89
8 6 4 2 0 PPM
1
H NMR (400 MHz, CDCl
3
) of 2.91

N
179
134 132 130 128 126 124 122 PPM
200 150 100 50 0PPM
13
C NMR (62.5 MHz, CDCl
3
) of 2.91
10 8 6 4 2 0 PPM
1
H NMR (250 MHz, CDCl
3
) of 2.93

N
180
200 150 100 50 0PPM
13
C NMR (62.5 MHz, CDCl
3
) of 2.93
10 8 6 4 2 PPM
1
H NMR (250 MHz, CDCl
3
) of 2.94

CH
3
(CH
2
)
5
N
CH
3
Ph
181
200 150 100 50 0PPM
13
C NMR (62.5 MHz, CDCl
3
) of 2.94
10 8 6 4 2 0 PPM
1
H NMR (250 MHz, CDCl
3
) of 2.96

CH
3
(CH
2
)
5
N
Ph Ph
182
200 150 100 50 0PPM
13
C NMR (62.5 MHz, CDCl
3
) of 2.96

8 6 4 2 0 PPM
1
H NMR (400 MHz, CDCl
3
) of 2.99
N
H
3
C
183
150 100 50 0PPM
13
C NMR (100 MHz, CDCl
3
) of 2.99
8 6 4 2 0 PPM
1
H NMR (400 MHz, CDCl
3
) of 2.99

Si
N
CH
3
184
150 100 50 0PPM
13
C NMR (100 MHz, CDCl
3
) of 2.99
8 6 4 2 0 PPM
1
H NMR (400 MHz, CDCl
3
) of 2.100

N
185
200 150 100 50 0PPM
13
C NMR (62.5 MHz, CDCl
3
) of 2.100
10 8 6 4 2 0PPM
1
H NMR (250 MHz, CDCl
3
) of 2.103

N
186
200 150 100 50 0PPM
13
C NMR (62.5 MHz, CDCl
3
) of 2.103
6.0 5.8 5.6 5.4 5.2 5.0 PPM
8 6 4 2 0 PPM
1
H NMR (400 MHz, CDCl
3
) of 2.105

N
187
150 100 50 0PPM
13
C NMR (100 MHz, CDCl
3
) of 2.105
8 6 4 2 0 PPM
1
H NMR (400 MHz, CDCl
3
) of 2.106

N
188
150 100 50 0PPM
13
C NMR (100 MHz, CDCl
3
) of 2.106
8 6 4 2 PPM
1
H NMR (400 MHz, CDCl
3
) of 2.107

N
189
200 150 100 50 0PPM
13
C NMR (62.5 MHz, CDCl
3
) of 2.107
8 6 4 2 0 PPM
1
H NMR (400 MHz, CDCl
3
) of 2.108

CH
3
(CH
2
)
5
N
190
150 100 50 0PPM
13
C NMR (100 MHz, CDCl
3
) of 2.108
10 8 6 4 2 0 PPM
1
H NMR (250 MHz, CDCl
3
) of 2.110

N
I
191
200 150 100 50 0PPM
13
C NMR (62.5 MHz, CDCl
3
) of 2.110
8 6 4 2 0 PPM
1
H NMR (400 MHz, CDCl
3
) of 2.111

N
O
O
192
120 100 80 60 40 20 0PPM
13
C NMR (100 MHz, CDCl
3
) of 2.111
8 6 4 2 0 PPM
1
H NMR (400 MHz, CDCl
3
) of 2.112

CH
3
(CH
2
)
5
N
I
193
150 100 50 0PPM
13
C NMR (100 MHz, CDCl
3
) of 2.112
10 8 6 4 2 0 PPM
1
H NMR (250 MHz, CDCl
3
) of 2.68

N
194
200 150 100 50 0 PPM
13
C NMR (62.5 MHz, CDCl
3
) of 2.68
6 5 4 3 2 PPM
1
H NMR (250 MHz, CDCl
3
) of 2.69

CH
3
(CH
2
)
5
N
195
90 80 70 60 50 40 30 20 10 PPM
13
C NMR (62.5 MHz, CDCl
3
) of 2.69
10 8 6 4 2 0 PPM
1
H NMR (250 MHz, CDCl
3
) of 2.106

N
196
200 150 100 50 PPM
13
C NMR (62.5 MHz, CDCl
3
) of 2.106
9 8 7 6 5 4 3 2 1 0 PPM
1
H NMR (250 MHz, CDCl
3
) of 2.115

TMS
N
197
200 150 100 50 0PPM
13
C NMR (62.5 MHz, CDCl
3
) of 2.115
8 7 6 5 4 3 2 1 PPM
1
H NMR (250 MHz, CDCl
3
) of 2.117

N
OMe
198
200 150 100 50 0PPM
13
C NMR (62.5 MHz, CDCl
3
) of 2.117
8 6 4 2 0 PPM
1
H NMR (400 MHz, CDCl
3
) of 2.118

TMS
N
OMe
199
150 100 50 0PPM
13
C NMR (100 MHz, CDCl
3
) of 2.118
10 8 6 4 2 0PPM
1
H NMR (400 MHz, CDCl
3
) of 2.128

N
H
200
200 150 100 50 0PPM
13
C NMR (100 MHz, CDCl
3
) of 2.128
10 8 6 4 2 0 PPM
1
H NMR (250 MHz, CDCl
3
) of 2.130

NH
201
200 150 100 50 0PPM
13
C NMR (62.5 MHz, CDCl
3
) of 2.130
10 8 6 4 2 0 PPM
1
H NMR (250 MHz, CDCl
3
) of 2.132

CH
3
(CH
2
)
5
N
H
202
200 150 100 50 0PPM
13
C NMR (100 MHz, CDCl
3
) of 2.132
9 8 7 6 5 4 3 2 1 PPM
1
H NMR (250 MHz, CDCl
3
) of 2.134

N
H
NHBoc
203
200 150 100 50 0PPM
13
C NMR (62.5 MHz, CDCl
3
) of 2.134
10 8 6 4 2 0 PPM
1
H NMR (250 MHz, CDCl
3
) of 2.120

N
N
204
200 150 100 50 0PPM
13
C NMR (250 MHz, CDCl
3
) of 2.120
8 7 6 5 4 3 2 1 PPM
1
H NMR (250 MHz, CDCl
3
) of 2.149

OH
N
205
200 150 100 50 0PPM
13
C NMR (62.5 MHz, CDCl
3
) of 2.149
8 6 4 2 0PPM
1
H NMR (250 MHz, CDCl
3
) of 2.150

OH
N
206
150 100 50 0PPM
13
C NMR (100 MHz, CDCl
3
) of 2.150
10 8 6 4 2 0 PPM
1
H NMR (250 MHz, CDCl
3
) of 2.229

OH
N
Boc
N
207
200 150 100 50 0PPM
13
C NMR (62.5 MHz, CDCl
3
) of 2.229
10 8 6 4 2 0 PPM
1
H NMR (250 MHz, CDCl
3
) of 2.151

OH
N
SiMe
3
208
200 150 100 50 0PPM
13
C NMR (62.5 MHz, CDCl
3
) of 2.151
8 6 4 2 0 PPM
1
H NMR (250 MHz, CDCl
3
) of 2.153
OH
N
SiMe
3
N
OH
209
200 150 100 50 0PPM

13
C NMR (400 MHz, CDCl
3
) of 2.153
10 8 6 4 2 0PPM
1
H NMR (400 MHz, CDCl
3
) of 2.154

N
OH
210
200 150 100 50 0 PPM
13
C NMR (250 MHz, CDCl
3
) of 2.154
9 8 7 6 5 4 3 2 1 PPM
1
H NMR (250 MHz, CDCl
3
) of 2.156

N
OH
211
150 100 50 PPM
13
C NMR (250 MHz, CDCl
3
) of 2.156
10 8 6 4 2 0 PPM
1
H NMR (250 MHz, CDCl
3
) of 2.157

N
OH
212
150 100 50 PPM
13
C NMR (250 MHz, CDCl
3
) of 2.157
8 6 4 2 0 PPM
1
H NMR (250 MHz, CDCl
3
) of 2.158

Me
3
Si
N
OH
NBoc
213
200 150 100 50 0PPM
13
C NMR (250 MHz, CDCl
3
) of 2.158
8 6 4 2 0 PPM
1
H NMR (400 MHz, methanol-d
4
) of 2.161

OH
N
OH
214
150 100 50 0PPM
13
C NMR (100 MHz, methanol-d
4
) of 2.161
9 8 7 6 5 4 3 2 1 0 PPM
1
H NMR (400 MHz, CDCl
3
) of 2.163

OH
N
OH
OMe
OMe
MeO
215
200 150 100 50 0PPM
13
C NMR (100 MHz, CDCl
3
) of 2.163
8 6 4 2 0 PPM
1
H NMR (400 MHz, CDCl
3
) of 2.164

OH
N
OH
OMe
MeO
216
200 150 100 50 0PPM
13
C NMR (100 MHz, CDCl
3
) of 2.164
8 6 4 2 PPM
1
H NMR (250 MHz, methanol-d
4
) of 2.168

OH
N OH
OH
OH
217
200 150 100 50 0 PPM
13
C NMR (62.5 MHz, methanol-d
4
) of 2.168
10 8 6 4 2 0 PPM
1
H NMR (250 MHz, methanol-d
4
) of 2.170

OH
N OH
OH
OH
218
160 140 120 100 80 60 40 20 0PPM
13
C NMR (62.5 MHz, methanol-d
4
) of 2.170
8 6 4 2 0 PPM
1
H NMR (400 MHz, methanol-d
4
) of 2.172

OH
N OH
OH
OH
219
200 150 100 50 0 PPM
13
C NMR (62.5 MHz, methanol-d
4
) of 2.172
8 7 6 5 4 3 2 1 0PPM
1
H NMR (400 MHz, methanol-d
4
) of 2.173

CH
3
(CH
2
)
5
OH
N OH
OH
OH
Boc
N
220
200 150 100 50 0 PPM
13
C NMR (62.5 MHz, methanol-d
4
) of 2.173
8 6 4 2 0 PPM
1
H NMR (400 MHz, methanol-d
4
) of 2.174

OH
N OH
OH
OH
221
150 100 50 0PPM
13
C NMR (100 MHz, methanol-d
4
) of 2.174
8 6 4 2 0 PPM
1
H NMR (400 MHz, CDCl
3
) of 2.175

OH
N OH
OH
OH
222
200 150 100 50 0PPM
13
C NMR (62.5 MHz, CDCl
3
) of 2.175
10 8 6 4 2 0PPM
1
H NMR (250 MHz, CDCl
3
) of 2.185

N
N O
Ph
Ph
223
200 150 100 50 0PPM
13
C NMR (100 MHz, CDCl
3
) of 2.185
8 6 4 2 0 PPM
1
H NMR (250 MHz, CDCl
3
) of 2.186

N
N O
TMS
Ph
Ph
224
200 150 100 50 0 PPM
13
C NMR (62.5 MHz, CDCl
3
) of 2.186
10 8 6 4 2 0 PPM
1
H NMR (250 MHz, CDCl
3
) of 2.187

N
N O
Ph
Ph
225
200 150 100 50 0PPM
13
C NMR (62.5 MHz, CDCl
3
) of 2.187
10 8 6 4 2 0PPM
1
H NMR (250 MHz, methanol–d
4
) of 2.189

N
N O
226
150 100 50 PPM
13
C NMR (62.5 MHz, methanol–d
4
) of 2.189
8 6 4 2 0 PPM
1
H NMR (250 MHz, CDCl
3
) of 2.190

N
N O
227
200 150 100 50 0PPM
13
C NMR (62.5 MHz, CDCl
3
) of 2.190
10 8 6 4 2 0 PPM
1
H NMR (400 MHz, CDCl
3
) of 2.138

N
CF
3
O
228
0 -20 -40 -60 -80 -100 -120 -140 -160 PPM
19
F NMR (400 MHz, CDCl
3
) of 2.138
200 150 100 50 0PPM
13
C NMR (100 MHz, CDCl
3
) of 2.138

N
CF
3
O
229

10 8 6 4 2 0 PPM
1
H NMR (400 MHz, CDCl
3
) of 2.139
0 -50 -100 -150 PPM
19
F NMR (400 MHz, CDCl
3
) of 2.139
N
CF
3
230

200 150 100 50 PPM
13
C NMR (100 MHz, CDCl
3
) of 2.139

N
CF
3
231

8 7 6 5 4 3 2 1 PPM
1
H NMR (400 MHz, CDCl
3
) of 2.140

CH
3
(CH
2
)
5
N
CF
3
232
-40 -50 -60 -70 -80 -90 -100 -110 -120 PPM
19
F NMR (400 MHz, CDCl
3
) of 2.140
180 160 140 120 100 80 60 40 20 PPM
13
C NMR (100 MHz, CDCl
3
) of 2.140

CH
3
(CH
2
)
5
N
CF
3
233

10 8 6 4 2 0PPM
1
H NMR (400 MHz, CDCl
3
) of 2.144

N
Br
234
200 150 100 50 PPM
13
C NMR (100 MHz, CDCl
3
) of 2.144
9 8 7 6 5 4 3 2 1 PPM
1
H NMR (400 MHz, CDCl
3
) of 2.146

CH
3
(CH
2
)
5
N
Br
235
180 160 140 120 100 80 60 40 20 PPM
13
C NMR (100 MHz, CDCl
3
) of 2.146
10 8 6 4 2 0PPM
1
H NMR (400 MHz, CDCl
3
) of 2.129

N
236
200 150 100 50 PPM
13
C NMR (100 MHz, CDCl
3
) of 2.129
10 8 6 4 2 0 PPM
1
H NMR (400 MHz, CDCl
3
) of 2.133

N
237
150 100 50 PPM
13
C NMR (100 MHz, CDCl
3
) of 2.133
9 8 7 6 5 4 3 2 1 PPM

1
H NMR (400 MHz, CDCl
3
) of 2.203

N
N
N
Ph
N
H
3
C
Ph
238
180 160 140 120 100 80 60 40 20 PPM
13
C NMR (100 MHz, CDCl
3
) of 2.203
8 7 6 5 4 3 2 1 PPM
1
H NMR (400 MHz, CDCl
3
) of 2.207

N
O
Ph
239
200 150 100 50 PPM
13
C NMR (62.5 MHz, CDCl
3
) of 2.207
8 7 6 5 4 3 2 1 PPM
1
H NMR (250 MHz, CDCl
3
) of 2.208

N
O
MeO
240
200 150 100 50 PPM
13
C NMR (62.5 MHz, CDCl
3
) of 2.208
Chapter 3. Indole Synthesis
3.1 Introduction
The indole moiety is one the most abundant heterocyclic frameworks in
nature. The history of indole began in 1866 when Baeyer and Knop were studying
the structure of the dye indigo.
115
As a result of their work in 1869 the chemical
formula and structure of indole, which is today accepted, was discovered.
116
The
current nomenclature system sets the nitrogen as number 1 atom and with
clockwise assignment of the numbers to the position as shown in Figure 3.1.

115
Baeyer, A.; Knop, C. A. Ann. 1866, 140, 1.
116
Baeyer, A.; Emmering, A. Ber. 1869, 2, 679.
241
5
6
7
4
N
H
2
3

Figure 3.1 Indole Structure and Numbering
Indole research continued to be important for the dye industry until new dyes
started replacing indole in the beginning of twentieth century. After years of
decreased activity, indole chemistry was rediscovered again in the 1930s when
many indoles found in nature exhibited valuable biological activity.
117
It was
discovered that indole posses a wide range of biological properties including
antipsychotic, antihypertensive
118
, psychotropic and many others. Well known
indoles include indole-3-acetic acid 3.01 - an important plant growth hormone and
tryptophan 3.02 - an essential amino acid. Among many biologically active indole
derivatives (Figure 2), serotonin 3.03 (5-hydroxytryptamine) and numerous
serotonin-like compounds are under investigation for the treatment of migraine
headaches. Sumatriptan, known as Imitrex® 3.06, is the first one to be
commercialized.
119

117
Van Order, R. B.; Lindwall, H. G. Chem. Rev. 1942, 30, 69.
118
Chae, J.; Buchwald, S. L. J. Org. Chem. 2004, 69, 3336.
119
Hopkins, S. J. Drugs Today 1992, 28, 155.
242
N
H
HO
NH
2
N
H
NH
2
CO
2
H
N
H
SO
2
NHCH
3
N
H
3
CO
CO
2
H
CH
3
N
H
CO
2
H
N
OH
OH
O
ONa
F
O
Cl
N(CH
3
)
2
Indole-3-acetic acid 3.01 Tryptophan 3.02 Serotonin 3.03
Indomethacin 3.04 Lescol 3.05 Sumaptriptan 3.06

Figure 3.2 Examples of Indole Derivatives
The indole moiety is not only found in many naturally occurring compounds (ergot
alkaloids, ambiguine alkaloids, gramines and tryptamines) but in numerous
therapeutic agents (Indomethacin 3.04, Lescol 3.05) as is presented in Figure 3.2.
3.2 Synthetic Approaches to Indoles
The prevalence of the indole moiety in nature and its valuable biological
properties directed tremendous interest in the development of useful syntheses of
indoles. As a matter of fact, indole was first synthesized by Baeyer in 1868, via
reduction of isatin to oxoindole using zinc dust followed by further reduction of
243
oxoindole over hot zinc oxide.
120
Nevertheless, one of the most significant
discoveries in the history of indole endeavors marks the year of 1883 when Fischer
discover a very useful and broadly applicable synthetic method.
121
Since then a
plethora of original synthetic strategies have been developed for a general and more
efficient access to indole derivatives.
122,123
Additionally the synthetic trends of the
last four decades have concentrated more on transition-metal catalyzed reactions
that give a quick way to access highly functionalized indole derivatives.
124

Taking into account that numerous synthetic methods exist toward
constructing the indole moiety they can be classified and generalized into particular
categories based on the concept of bond disconnection as shown in Figure 3.3.
122

120
Baeyer, A. Ber. 1868, 1, 17.
121
Fischer, E.; Jourdan, F. Ber. 1883, 16, 2241.
122
Sundberg, R. J. Indoles. Academic Press Ltd., San Diego 1996.
123
Humphrey, G. R.; Kuethe, J. T. Chem. Rev.,2006, 106, 2875.
124
Cacchi, S.; Fabrizi, G. Chem. Rev. 2005, 105, 2873.
244
N
H
N
H
N
H
N
H
N
H
X
XI
XII
XIII
IX
5
6
7
4
N
H
2
3
N
H
N
H
N
H
N
H
N
H
N
H
N
H
RING
CONTRACTION
I
II
III
IV
V
VI
VII
VIII

Figure 3.3 Retrosynthetic Approaches towards the Synthesis of Indole Moiety
3.2.1 Indole Ring Formation via Class I Disconnection
Disconnection I can be further divided into smaller subcategories as is
presented in Figure 3.4. It includes the most famous and useful indole syntheses:
Fischer approach and its modifications (A group), Sugasawa- (G group), Gassman-
(C group), Bichler- (H group), Bartoli –indole synthesis (F group), and other metal
catalyzed reactions (B, D, E groups).
245
A
F
E
B
C
D
H
G
5
6
7
4
N
H
2
3
NHNH
2
CH
2
R
O R
NHCl
CH
2
SCH
3
O R
NH
2
ClCH
2
CN
NH
2
CH
2
Br
O R
X
N
H
R
1
R
2
R
3
NHOH
X
I
NH
2
R
O
R
1
O
2
C
NO
2
X
BrMg R
1
R
2

Figure 3.4 Retrosynthetic Approach to Disconnection I
3.2.1.1 Fischer Indole Synthesis
The Fischer indole reaction is one of the most extensively used and studied
methods.
125
The first discovery of this method dates back to 1883. Since that year
the reaction has been expanded significantly with several improvements and novel
applications.
126
In this approach, as Scheme 3.1 illustrates, the condensation of an
enolizable ketone or aldehyde 3.07 with an arylhydrazine 3.08 produces an
arylhydrazone 3.09. The arylhydrazone 3.09 tautomerizes into an ene-hydrazine
3.10 under acidic conditions and usually at elevated temperatures. The ene-

125
Robinson, R. The Fischer Indole Synthesis, Wiley-Interscience, New York,
1982.
126
Humphrey, G. R.; Kuethe, J. T. Chem. Rev. 2006, 106, 2875.
246
hydrazine 3.10 undergoes a [3,3]-sigmatropic rearrangement creating a diimine
intermediate 3.13. The following intramolecular cyclization and loss of ammonia
produces desired indole 3.13.
NH
NH
2
R
2
O
R
1
N
H
R
1
R
2
Acid catalyst
N
H
N
R
2
R
1
NH
R
1
NH
R
2
N
H
R
2
NH
2
R
1
- NH
3
3.08 3.07
3.09 3.11 3.12
3.13
N
H
NH
R
2
R
1
3.10
∆

Scheme 3.1 The Fischer Indole Reaction
A wide range of Lewis acids, Bronsted acids and acidic solid supports have been
applied with great success. The advantages of the reaction include the compatibility
of a wide range of substituents around the aromatic ring of the arylhydrazine.
Elegant ways using the Fischer approach were developed by Nenajdenko
and coworkers for the synthesis of substituted tryptamines (Scheme 3.2 and 3.3).
127

127
Zakurdaev, E. P.; Balenkova, E. S.; Nenajdenko, V. G. Russ. Chem. Bull. Int.
Ed. 2005, 54, 1219.
247
N
NH
2
N
O
H
2
N
AcOH
N N
NH
2
reflux
3.15 3.14 3.16

Scheme 3.2 The Fischer indole Synthesis with Amino Ketones
They showed that not only amino ketones 3.15 can easily participate in the reaction
(Scheme 3.2) but cyclic imines 3.17 as well (Scheme 3.3) in good yields.
N
H
NH
2
N
R
HCl
iPrOH
N
H
NH
2
R H
2
N
O
R
3.17
3.08 3.18

Scheme 3.3 Fischer Indole Synthesis with Cyclic Imines
One of the problems of the classic Fischer indole synthesis is the limited
commercial availability of arylhydrazines mostly because they are usually difficult
to handle. Substituted arylhydrazines can be generally prepared by reduction of aryl
diazonium salts. The required ketones or aldehydes are also accessible via
conventional methodologies; however, the additional synthetic steps may make the
method less efficient overall.
248
3.2.1.2 Fischer Indole Synthesis via Japp-Klingemann Reaction
The Japp-Klingemann reaction provides a very useful and clever alternative
route to number of arylhydrazones that can be utilized in the Fischer process.
128
A
combination of this reaction with the Fischer indole process has provided quite
concise routes to indoles.
129
When aryldiazonium salts 3.19 (Scheme 3.4) are
treated with β-ketoesters 3.20 azo compounds such as 3.21 are produced that are
deacylated and cyclized under basic and acidic conditions to give indole 2-
carboxylate esters 3.22.
N
2
R
O
CO
2
R
1
R
2
N
H
N CO
2
R
1
CH
2
R
2
N
H
R
2
CO
2
R
1
3.20 3.21 3.22 3.19

Scheme 3.4 Fischer Indole Synthesis with β-Ketoesters Utilizing Japp-
Klingemann Reaction
Alternatively, if β-ketoacids 3.23 are used, decarboxylation takes place and 2-
acylindole 3.25 can be formed as shown in Scheme 3.5.

128
Meyer, M. D.; Kruse, L. I. J. Org. Chem. 1984, 49, 3195.
129
Chen, Y.; Shibata, M.; Rajeswaran, M.; Srikkrishnan, T.; Dugar, S.; Pandey, R.
K. Tetrahedron Lett. 2007, 2353.
249
N
2
R
O
CO
2
H
R
2
N
H
N CO
2
H
CH
2
R
2
N
H
R
2
CO
2
H
3.23 3.19 3.24 3.25

Scheme 3.5 Fischer Indole Synthesis with β-Ketoacids Utilizing Japp-
Klingemann Reaction
3.2.1.3 Fischer Indole Synthesis via Buchwald Approach
Another attempt to overcome limitations of certain substituted aryl
hydrazines was presented by Buchwald and coworkers.
130
They reported a
palladium catalyzed methodology for the preparation of N-aryl benzophenone
hydrazones 3.28 from commercially available and relatively inexpensive
benzophenone hydrazone 3.27 and aryl bromides 3.26 (Scheme 3.6).

Br
N
NH
2
Ph Ph
cat Pd
N
H
N Ph
Ph
p-TSA
ketone
N
H
R
1
R
2
Binap
3.27 3.26 3.28 3.29

Scheme 3.6 Fischer Indole Synthesis via Buchwald Modification
The stable and non-enolizable benzophenone hydrazones 3.28 undergo a facile
Fischer reaction to form indoles upon treatment with an acid. The most suitable
acid for this transformation was found to be p-toluenesulfonic acid (p-TSA). The

130
Wagaw, S.; Yang, B. H.; Buchwald, S. L. J. Am. Chem. Soc. 1998, 120, 6621.
250
only disadvantage of this process from a practical point of view is the side product
– benzophenone, and its separation from the final indole.
3.2.1.4 Fischer Indole Synthesis via Metal Catalyzed Reaction with Alkynes
and Alkenes.
Regardless of the fact that the Fischer indole process utilizes a broad range
of substrates, the reaction of hydrazines and unprotected aldehydes proceeds with
low yields and lots of unwanted side products.
131
A number of methodologies have
been developed to overcome this shortcoming. Among them, titanium-catalyzed
intramolecular hydroamination of alkynes 3.31 with aryl hydrazines 3.30 was
developed by Odom and coworkers.
132
. The reaction produces hydrazones 3.32 that
can be cyclized in one pot to create the desired indole 3.33 (Scheme 3.7)
N
NH
2
Ph
R
Ti catalyst
100
o
C
N
N
R
Ph
ZnCl
2
N
Ph
R
R
1
R
1
R
1
3.31 3.30 3.32 3.33

Scheme 3.7 Titanium-Catalyzed Hydroformulation/Fischer Cyclization

131
Chen, C.; Senanayake, C. H.; Bill, T. J.; Larsen, R. D.; Verhoeven, T. R.;
Reider, P. J. J. Org. Chem. 1994, 59, 3738.
132
Cao, C.; Shi, Y.; Odom, A. L. Org. Lett. 2002, 4, 2853.
251
This strategy was further adequately explored for the synthesis of
tryptamine analogues 3.35 from chloroalkynes 3.34 (Scheme 3.8).
133

Cl
N
NH
2
R
1
3.30 3.34 3.35
100
o
C
N
CH
3
R
1
NH
2
Cl
CH
3
O
(H
3
CN)
2
Ti

Scheme 3.8 Example of Titanium-Catalyzed Fischer Synthesis of Tryptamine
Analogues
Some aldehydes that are useful for the Fischer process can be accessed
through hydroformylation of alkenes. Nevertheless the tandem hydroformylation/
Fischer synthesis as a one pot process seems to be a quite clever methodology.
134

The process originally developed by Eilbracht, involves generation of the aldehyde
from an alkene 3.36 in situ, followed by condensation with an aryl hydrazine 3.08
as in the classic version of the Fischer reaction (Scheme 3.9).

133
Khedkar, V.; Tillack, A.; Michalik, M.; Beller, M. Tetrahedron Lett. 2004, 45,
3123.
134
Linnepe, P.; Schmidt, A. M.; Eilbracht, P. Org. Biomol. Chem. 2006, 4, 302.
252
R
1
R
2
N
H
NH
2
CO/H
2
Rh(CO)
2
acac
N
H
R
2
R
1
3.36 3.08 3.37

Scheme 0.9 Fischer Indole Synthesis via Metal-Catalyzed Hydroformylation of
Alkenes
3.2.1.5 Indole Synthesis from N-Aryl-O-hydroxylamines
The process presented in Scheme 3.10 might be considered as the oxygen
version of the Fischer cyclization because it similarly involves a [3,3]-sigmatropic
rearrangement. This process typically utilizes O-vinyl derivatives of N-phenyl-
hydroxylamines 3.40 as the starting materials. These compounds are unfortunately
less accessible than the arylhydrazones for the Fischer process. Nevertheless they
can be quickly transformed into indoles 3.42.
135

NHOH
X
3.39 3.38
NHOCH
2
=CH
2
NH
2
O
N
H
3.42 3.40 3.41

Scheme 3.10 Indoles from N-Arylhydroxylamines
A very nice application of this process was developed by Blechert
(Scheme 3.11). Addition of N-phenyl-hydroxylamines 3.43 to electrophilic allenes
3.44 gives quick access to O-vinyl derivatives 3.45 which are further cyclized to
indole derivatives 3.47 by treating compound 3.46 with formic acid. It is worth

135
Martin, P. Helv. Chim. Acta 1984, 67, 1647.
253
mentioning that the yields of these processes are overall usually higher than
80%.
136

NOH
X
3.44 3.43
N
3.45
R
1 R
1
O
CH
2
X H
2
C
N
3.47
CH
2
X
NH
R
1
R
1
CH
2
X
O
3.46
Base
∆
HCO
2
H

Scheme 3.11 Indole Synthesis from Allenes and N-Phenylhydroxylamines
3.2.1.6 Gassman Indole Synthesis
Gassmann and coworkers developed a novel synthetic route to indoles from
anilines 3.48 which involves [2,3]-sigmatropic rearrangement of anilinosulfonium
ylides 3.49.
137

NH
R
1) t-BuOCl
2)
SCH
3
O
R
1
N
R
S
R
1
O
Base
N
SCH
3
R
1
R
N
R
1
R
Raney-Ni
3.49 3.52
CH
3
3.51
3.50 3.49

Scheme 3.12 Gassman Indole Synthesis

136
Blechert, S. Helv. Chim. Acta 1985, 68, 1835.
137
Gassman, P. G.; van Bergen, T. J.; Gilbert, D. P.; Cue, Jr, B. W. J. Am. Chem.
Soc. 1974, 96, 5495.
254
The ylides 3.49 typically can be prepared from N-chloroanilines and α-
thiomethylketones 3.52 or from aniline and chlorosulfonium salts.
137
The
rearrangement and cyclization usually occurs upon treatment of the ylides 3.49 with
triethylamine. The 3-(methylthio)-indole 3.50 can be desulfurized with Raney
nickel or with trifluoroacetic acid/thiosalicylic acid.
138

3.2.1.7 Sugasawa Indole Synthesis
The Sugasawa indole synthesis is a three step process. It utilizes at first
boron trichloride in the ortho-exclusive Friedel-Crafts type reaction of unprotected
anilines 3.53 with electrophiles such as nitriles 3.54 in order to form the aniline
derivative 3.55. The next step entails the reduction of the ketone group to an
alcohol, followed by intramolecular cyclization to indole 3.42 under basic condition
and at room temperature (Scheme 3.13).
139

NH
2
CN Cl
BCl
3
CH
2
Cl
NH
2 2) NaOMe
N
H
O
Lewis
Acid
3.54 3.53 3.42 3.55
1) NaBH
4

Scheme 3.13 Sugasawa Indole Synthesis

138
Gassman, P. G.; Schenk, W. N. J. Org. Chem. 1977, 42, 3240.
139
Sugasawa, T.; Adachi, M.; Sasakura, K.; Kitagawa, A. J. Org. Chem. 1979, 44,
578.
255
3.2.1.8 Bischler Indole Synthesis
The Bischler indole synthesis involves monoalkylation of ortho-
unsubstituted anilines 3.53 with the α-halogenated ketone 3.56, followed by
treatment with hydrobromic acid at high temperatures (Scheme 3.14).
140

NH
2
O
Ar
X
HBr
200
o
C
N
H
Ar
3.57 3.56 3.53

Scheme 3.14 Bischler Indole Synthesis
Although the reaction utilizes very simple and readily available starting
materials it has received very limited attention compared to other methods for the
indole synthesis. The main reason is that the reaction conditions are usually pretty
harsh and yields are generally low. The mechanism of the reaction is not quite clear
as well and seems to be surprisingly complex.
141
Therefore there have been only a
few attempts to improve this process. For instance, Menendez and coworkers
developed a solvent free, microwave assisted Bischler indole synthesis. These
conditions seemed to improve the yields and regioselectivity of the reaction
producing only 2-substituted indole derivatives.
142

140
a) Bischler, A.; Brion, H. Chem. Ber. 1892, 25, 2860. b) Bischler, A.; Firemann,
P. Chem. Ber. 1893, 26, 1336.
141
Vara, Y.; Aldaba, E.; Arrieta, A.; Pizzarro, J. L.; Arriorta, M. I.; Cossio, F. P.
Org. Biomol. Chem. 2008, 6, 1763.
142
Sridharan, V.; Perumal, S.; Avendano, C.; Menendez, J. C. Synlett 2006, 1, 91.
256
3.2.1.9 Bartoli Indole Synthesis
In 1989, Bartoli reported that the reaction of 3 equivalents of vinyl
magnesium bromide 3.59 with 2-substituted nitro arenes 3.58 results in the indole
moiety (Scheme 3.15).
143
This methodology is particularly useful for making 7-
substitued indoles 3.60.
NO
2
R
BrMg
R
1
R
2
N
H
R
R
2
R
1
THF
-78
o
C
R = Me, Br, Cl, F, OSiMe
3
3.59 3.58 3.60

Scheme 3.15 Bartoli Indole Synthesis
The presence of the ortho substituent on the arene 3.58 is extremely crucial
for the success of the reaction. On the other hand di-ortho-substituted nitro arenes
are not tolerated in the reactions. The reaction mechanism has been studied in detail
in order to rationalize the observed results.
144
The currently accepted mechanism
(Scheme 3.16) starts with the addition of the Grignard reagent 3.61 to nitro arene
3.58 followed by spontaneous decomposition to from the nitrosoarene 3.64 and
magnesium salt 3.63. Next, the second equivalent of the Grignard reagent 3.61
reacts and forms further intermediate 3.65.

143
Bartoli, G.; Palmieri, G.; Bosco, M.; Dalpozzo, R. Tetrahedron Lett. 1989, 30,
2129.
144
Dalpozzo, R. and Bartoli, G. Curr. Org. Chem. 2005, 9, 163.
257
R
N
O
O
MgBr
R
N
O
O
MgBr
3.61 3.58 3.62
R
N
O
MgBr
BrMgO
3.63
3.64
R
N
O
3.65
MgBr R
N
O
MgBr
3.66
3.67
N
R
H
OMgBr
N
R
OMgBr
MgBr
3.69
H
+
N
H
R
OH
2
3.70
H
N
H
R
3.71
3.68
MgBr
3.61
3.61

Scheme 3.16 Mechanism of Bartoli Indole Synthesis
Thanks to steric effects of the ortho-substituent the [3,3]-sigmatropic
rearrangement happens, followed by the cyclization of intermediate 3.66. The third
equivalent of the Grignard reagent 3.61 reacts with compound 3.67 to give the
dimagnesium salt 3.69. The reaction work-up eliminates water and yields the final
product 3.71. It was confirmed that if nitrosoarene 3.64 (pre-prepared in another
258
manner) is taken into the reaction with two equivalents of Grignard reagent the
process yield the same indole derivative.
145

3.2.1.10 Copper-Catalyzed Synthesis of 2,3-Disubstituted Indoles
Scheme 3.17 represents a one-pot synthesis of 2,3-disubstituted indoles 3.74
via a copper-catalyzed domino reaction with 2-iodoanilines 3.72 and β-ketoesters
3.73.
I
NH
2
R
O
OR
1
O
N
H
R
O
OR
1
CuI (10 mol %)
BINOL (20 mol %)
Cs
2
CO
3
, DMSO
50
o
C
3.74 3.73 3.72

Scheme 3.17 One Step Copper-Catalyzed Indole Synthesis
The mechanism of the reaction is not fully investigated yet. However, it was
found that the best results can be obtained with copper iodide and cesium carbonate
as the base in DMSO with BINOL (racemate) at 50
o
C. A series of examples were
produced in good yields.
146

3.2.1.11 Palladium-Mediated Indole Syntheses
Scheme 3.18 shows an example of a regiospecific procedure involving a
domino indolization. It involves a consecutive palladium-catalyzed Sonogashira

145
Bosco M., Dalpozzo R., Bartoli G., Palmieri G.; Petrini M. J. Chem. Soc. Perkin
Trans. 2, 1991, 657.
146
Tanimori, S.; Ura, H.; Kirihata, M. Eur. J. Org. Chem. 2007, 3977.
259
reaction followed by aminopalladation and reductive elimination starting from 2-
iodo-N-trifluoroacetylanilide 3.75, an alkyne 3.76 and bromoarene 3.77. The
presence of the trifluoroacetyl group is very advantageous because it is readily
hydrolyzable.
I
NH
R
1
3.75 3.76
COCF
3
3.77
N
H
Ph
R
1
3.78
Pd(OAc)
2
(5 mol%)
PPh
3
, K
2
CO
3
DMF, 60
o
C
Br

Scheme 3.18 One-Pot, Three Component Approach for the Synthesis of
2,3-Disubstituted Indoles
Another example of a palladium-mediated indole synthesis was explored by
the Larock group. They developed a nice protocol for the synthesis of 3-
iodoindoles 3.81. The process involves a two-step procedure. At first a palladium-
and copper-mediated coupling reaction between N,N-dialkyl-2-iodoanilines 3.79
with terminal alkynes 3.76 takes place followed by the iodine promoted
electrophilic cyclization of 3.80 to provide 3-iodoindole 3.81.
147

I
NMe
R
1
3.79 3.76
R
2
PdCl
2
(PPh
3
)
2
(2 mol%)
CuI (1 mol%), Et
3
N NMe
3.80
R
2
R
1
I
2
CH
2
Cl
2
N
I
R
1
3.81
R
2

Scheme 3.19 Synthesis of 3-Iodoindoles

147
Yue, D.; Yao, T.; Larock, R. C. J. Org. Chem. 2006, 71, 62.
260
The authors reported that N,N-dialkyl-2-iodoanilines 3.79 are highly reactive in the
Sonogashira coupling and the substitution pattern of the alkyne affects the
cyclization step. Usually, the more conjugated the system the higher the yield of the
3-iodoindole 3.81. Interestingly, when there are two different alkyl groups present
in N,N-dialkyl-2-iodoanilines 3.79, the less hindered group is removed easier. In
addition, 3-iodoindole 3.81 can be further derivatized via cross-coupling reactions.
3.2.1.12 Zinc triflate catalyzed indole cyclization
Liu reported a new indole synthesis approach using anilines 3.53 and
propargyl alcohols 3.82 as starting materials. The method is fairly effective and
yields indoles in good to high yields (Scheme 3.20).
148

NH
2
OH R
2
Zn(OTf)
2
Toluene
100
o
C
N
H
CH
3
R
2
3.83 3.53 3.82

Scheme 3.20 Zinc Triflate Catalyzed Cyclization of Propargyl Alcohols with
Anilines
The catalytic amount (10 mol%) of zinc triflate is enough to activate both
the alcohol addition and subsequent cyclization step. The proposed mechanism
involves formation of α-amino ketone intermediates and their isomerization
through a 1,2-nitrogen shift which explains the great chemoselectivity of the
reaction.
148

148
Kumar, M. P.; Liu, R-S. J. Org. Chem. 2006, 71, 4951.
261
A D
B C
3.2.2 Formation C2-C3 Bond
Formation of the C2-C3 bond via numerous transformations is shown in
Figure 3.5. Variations of intramolecular aldol condensation processes (class B),
cyclization from o-alkylanilides (class A), metal-catalyzed intramolecular
cyclization (class C) and reductive coupling reactions (class D) are included here.
CH
2
X
N
R
O R
N R
R
2
N
H
N
H
O
R
O
O 5
6
7
4
N
H
2
3
X= H, CN, R, PR
3

Figure 3.5 Indole Formation Trough C2-C3 Bond
3.2.2.1 Titatnium Mediated Indole Synthesis
In 1992, Fürstner published a new methodology that involves a low valent
titanium reagent to afford 2,3-disubstituted indoles 3.85 in good yields (Scheme
3.18).
149

149
Fürstner, A.; Jumbam, D. N. Tetrahedron 1992, 48, 5991.
262
O Ph
H
N
O
N
O
F
3
C
TiCl
3
, Zn, THF
reflux
N
H
Ph
N
COCF
3
3.84
3.85

Scheme 3.21 Indole Synthesis via Reductive Coupling Reaction
This reaction is an intramolecular version of a McMurry type coupling reaction
involving ketoamides 3.84.
3.2.2.2 Madelung Indole Synthesis
Like the Fischer and Bischler indole syntheses, Madelung’s approach has a
long history since it discovery in 1912.
150
The original method involves the reaction
of ortho-alkylanilides 3.86 with a base such as sodium amide, usually at high
temperatures. However, the cyclization can be achieved at much lower
temperatures (for instance at room temperature) as well by using alkyllithium
reagents as the base (Scheme 3.22).
CH
3
NH
2eq. n-BuLi
CH
2
Li
N
OLi
R N
H
R
R O
3.86 3.87 3.88

Scheme 3.22 Madelung Indole Synthesis

150
Madelung, W. Chem. Ber. 1912, 45, 1128.
263
The reaction proceeds through the dilithiated intermediate 3.87 which easily
cyclizes to indole 3.88.
151

3.2.2.3 Indoles via Intramolecular Wittig Reaction
A variation of the Madelung cyclization is presented in Scheme 3.23. It
involves an intramolecular Wittig condensation.
CH
2
P
+
Ph
3
NH
O R
KOt-Bu
N
H
R
3.89 3.88

Scheme 3.23 Indoles via Intramolecular Wittig Condensation
A nice application of this approach was developed by Hughes. He utilized
the phosphonium group as a traceless linker for the indole synthesis on a solid
support.
152
A huge advantage of this process is that the phosphine oxide remains
bound to the polymer and can be easily removed after the reaction is completed
simply by filtration.

151
Fuhrer, W.; Gschwend, H. W. J. Org. Chem. 1979, 44, 1133.
152
Hughes, I. Tetrahedron Lett. 1996, 37, 7595.
264
3.2.2.4 Palladium-Catalyzed Intramolecular Cyclization of Alkynes and Imines
Yamamoto and coworkers have recently reported a novel intramolecular
palladium-mediated cyclization starting from 2-(1-alkynyl)-N-alkylideneanilines
3.90.
153

N R
1
N
H
R
1
3.90 3.91
Pd(OAc)
2
P(nBu)
3
dioxane, ∆
R
2
R
3 R
3
R
2

Scheme 3.24 Indoles via Intramolecular Palladium-Catalyzed Cyclization
The reaction proceeds smoothly in dioxane at elevated temperatures with catalytic
amounts of palladium acetate and tributylphosphine and produces 2,3-disubstituted
indoles in good yields (Scheme 3.24).
3.2.2.5 Indoles from o-Acylanilines - Schmid Indole Synthesiss
Scheme 3.25 represents a “reverse-Madelung” reaction. The procedure was
originally discovered by Greuter and Schmid.
154

153
Takeda, A.; Kamijo, S.; Yamamoto, Y. J. Am. Chem. Soc. 2000, 122, 5662.
154
Greuter, H.; Schmid, H. Helv. Chim. Acta 1974, 57, 281.
265
O
R
3
N
R
1
R
2
Base
N
R
3
R
2
R
1
OH
-H
2
O
N
R
2
3.92 3.93
R
1
R
3
3.94

Scheme 3.25 Schmid Indole Synthesis
The starting materials for this reaction are o-acylaniline derivatives such as 3.92
and as a base, usually LDA is utilized. The presented examples utilized an aryl or
electron withdrawing group on the N-substituent because they facilitate the
deprotonation process.
3.2.3 C-acylation of o-Aminobenzyl Anion
The synthetic pathway shown in Figure 3.6 usually represents C-acylation
of an o-aminobenzyl carboanion. The acylation usually is followed by in situ
cyclization and aromatization.
122
The important part for this type of cyclization
there is no need for the isolation of the intermediates.
5
6
7
4
N
H
2
3
CH
2
N
P
O
R
Y
Y= Cl, OR, NR(OMe)
P= protecting group

Figure 3.6 Retrosynthetic Pathway for Formation N1-C2 and C2-C3 Bonds in
Indole Synthesis

266
One of type of o-aminobenzyl anion synthons is presented in Scheme 3.26.
It can be prepared from N-trimethylsilyl-o-toluidine 3.95 with 2.2 eq. of n-
butyllithium. Acylation of the intermediate 3.96 with esters gives indoles in one
pot. This route was utilized in the preparation of the alkaloid cinchonamine.
155

CH
3
NHX
X= TMS, Boc
N
X
R
3.95 3.97
2.2 BuLi RCO
2
Me
CH
2
Li
NLiX
X= TMS, Boc
3.96

Scheme 3.26 C-alkylation of o-Aminobenzyl Anions
Kraus and coworkers developed a new method for the preparation of 2-aryl
and/or 2-vinyl indoles from commercially or readily available starting materials
utilizing microwave conditions (Scheme 3.27).
156

NH
2
PPh
3
Br
R
O
H
3.98 3.99
2) KOt-Bu, THF, RT N
H
R
3.88
1) AcOH, MW
MeOH, 10 min

Scheme 3.27 Indoles from 2-Aminobenzyl Phosphonium Salts
The strategy involves the reaction of 2-aminobenzyl-triphenylphosphonium
bromide 3.98 with aromatic aldehydes or α,β-unsaturated aldehydes 3.99 at first, to
form the imine which in the presence of potassium tert-butoxide cyclizes to indoles

155
Smith III, A. B.; Visnick, M.; Haseltine, J. N.; Sprengeler, P. A. Tetrahedron
1986, 42, 2957.
156
Kraus, G. A.; Guo, H. Org. Lett. 2008, 10, 3061.
267
A
B
C
D
D
3.88. A wide range of functionalized aldehydes participate smoothly in the reaction
with the exception of alkyl aldehydes.
3.2.4 Disconnection IV
Category IV shown in Figure 3.7 involves intramolecular cyclizations and
therefore requires substituted aniline derivatives ready for the indole formation.
Some cyclizations also need an ortho-substituent which is in most cases a halogen.
X
N
R
3
R
1
R
N
H
R
N
R
N
R
O
X
N
R
R
2
X
R
2
N
R
R
1
R
2
R
5
6
7
4
N
H
2
3
3a

Figure 3.7 Indole Formation via the C3-C3a Bond
The classes A, B and D represent transition metal-mediated cyclization,
mostly palladium cross-coupling reactions. Class C is a photochemical
transformation while class E involves an intramolecular Friedel-Crafts type
reaction.
268
3.2.4.1 Transition Metal-Catalyzed Cyclization of N-Allyl and N-
Propargylanilines
Hegedus and coworkers developed the first palladium-catalyzed
intramolecular Heck coupling of o-halo-N-anilines 3.100 (Scheme 3.28).
157

X
N
R
Pd(II)
N
R
N
R
CH
2
Pd(II)
N
R
CH
3
3.100 3.101 3.102 3.103
Pd(OAc)
2
Et
3
N
CH
3
CN

Scheme 3.28 Indoles via Intramolecular Heck Reaction of N-Allylanilines
The procedure involves heating of N-allyl-o-haloanilines 3.100 with
palladium acetate (Pd(OAc)
2
) in acetonitrile in the presence of triethylamine. The
reaction mechanism presumably involves formation of a palladium (II) species
3.101, followed by intramolecular cyclization to yield intermediate 3.102 which
undergoes elimination to form indole 3.103 regenerating Pd(0).
The indole moiety 3.105 can be constructed via palladium-catalyzed
cyclization of N-propargyl-o-haloanilines 3.104 (Scheme 3.29) followed by a
transmetalation reaction with, for example, organozinc reagents.
158

157
Odle, R.; Blevins, B.; Ratcliff, M.; Hegedus, L. S. J. Org. Chem. 1980, 45,
2709.
158
Burns, B.; Grigg, R.; Sridharan, V.; Stevenson, S.; Sukirthalingam, S.;
Worakun, T. Tetrahedron Lett. 1989, 30, 1135.
269
X
N
R
1
1) Pd
0
2) R
2
ZnCl
N
R
1
R
2
3.104 3.105

Scheme 3.29 Synthesis of Indoles via Transition Metal Catalyzed Cyclization
of N-Propargylanilines
3.2.4.2 Intramolecular Pd-mediated Cyclization of N-Vinyl-o-Haloanilines
The intramolecular approach can be also applied to N-vinyl-o-haloanilines
(Scheme 3.30). Usually β-(2-halophenyl)amino substituted α,β-unsaturated ketones
or esters 3.106 are utilized as starting materials because the electron withdrawing
character of these groups stabilizes the intermediate enamine.
X
N
H
EWG
Pd(OAc)
2
N
H
EWG
R
R
3.106
3.107
Et
3
N, CH
3
CN
∆

Scheme 3.30 Palladium-Mediated Cyclization of N-Vinyl-o-haloanilines
This protocol was developed by Yamanaka and coworkers for the synthesis
of 2,3-disubstituted indoles 3.107. The authors found that optimum conditions for
the palladium-catalyzed cyclizations involve palladium acetate, triethylamine at
elevated temperatures and acetonitrile as a solvent.
159
The starting materials 3.106
for the reaction can be prepared according to methods known in the literature.
160

159
Sakamoto, T.; Nagano, T.; Kondo, Y.; Yamanaka, H. Synthesis 1990, 215.
160
Bozell, J. J.; Hegedus, L. S. J. Org. Chem. 1981, 46, 2561.
270
3.2.4.3 Palladium-Catalyzed Synthesis of 2-Aminoindoles
Although the 2-aminoindole moiety can be found in naturally occurring
compounds, its synthesis has been quite limited.
161
Therefore a need for quick
access to 2-aminoindoles seems to be highly desirable. A novel approach was
developed by Witulski and coworkers (Scheme 3.31).
162

I
N
Ts
R
1
3.108 3.110
N
Ts
R
1
N
R
2
R
3
N
R
2
R
3
H
3.109
Pd
0
Base (2 eq.)
∆

Scheme 3.31 Construction of 2-Aminoindoles via Palladium-Catalyzed
Their approach is based on the palladium-catalyzed intramolecular cyclization
reaction of alkynyl-2-halogenanilides 3.108 with primary or secondary amines
3.109. As a result a wide range of 2-aminoindoles 3.110 can be prepared. The
reaction utilizes cesium carbonate as a base and [PdCl
2
(PPh
3
)
2
] as a catalyst.
Consequently a diversified group of 2-aminoindoles can be synthesized which are
difficult to obtain by other methods.

161
Ishizumi, K.; Inaba, S.; Yamamoto, H. J. Org. Chem. 1974, 39, 2581.
162
Witulski, B.; Alayrac, C.; Tevzadze-Saeftel, L. Angew. Chem. Int. Ed. 2003, 42,
4257.
271
3.2.4.4 Photocyclization of N-Vinylanilines
Scheme 3.32 represents a general example of a photocyclization reaction of
N-vinylanilines 3.111.
163
The vinyl group usually possesses a potential leaving
group. The sequence starts with intramolecular cyclization, followed by
aromatization of the cyclized intermediate 3.113 to provide indole derivative
3.114.
122

N
R
1
N
R
1
R
2
R
2
hv
3.111 3.114
X
N
R
1
H
X
R
2
3.112
-HX
N
R
1
R
2
3.113

Scheme 3.32 General Example of Photocyclization of N-Vinylanilines
An example of this type of reaction is illustrated in Scheme 3.33 as α-
anilino-β-ketoesters 3.115 undergo photocyclization to form desired indole-2-
carboxylate esters 3.117.
164

N
H
CO
2
CH
3
3.116
CH
3
HO
N
H
CO
2
CH
3
CH
3
O
3.115
N
H
CO
2
CH
3
3.117

Scheme 3.33 Photocyclization to Indole-2-carboxylate

163
Schultz, A. G. Acc. Chem. Res. 1983, 16, 210.
164
Schultz, A. G.; Hagmann, W. K. J. Org. Chem. 1978, 43, 3391.
272
3.2.4.5 Indoles via Acid Catalyzed Cyclization
The category shown in Scheme 3.34 includes cyclizations of α-anilino
aldehydes or ketones 3.118 under acidic conditions to form the corresponding
indole derivative 3.119.
N
R
1
R
2
O
Acid
N
R
1
R
2
3.118 3.119

Scheme 3.34 Indole Synthesis via Acid Catalyzed Cyclization
This intramolecular Friedel-Crafts type reaction utilizes the most common and
readily available acids such as zinc (II) chloride, titanium tetrachloride,
trifluoroacetic acid (TFA), acetic anhydride and others.
The Nordlander modification of this methodology utilizes a combination of
trifluoroacetic acid with trifluoroacetic acid anhydride (TFAA) to achieve
cyclization of N-trifluoroacetyl-2-anilino acetal 3.120 to provide the corresponding
N-trifluoroacetylindole 3.121 (Scheme 3.34).
165

N
OEt EtO
TFA
N
3.120 3.121
CF
3
O
CF
3
O
TFAA
∆

Scheme 3.35 The Nordlander Indole Synthesis from Acetals

165
Nordlander, J. E.; Catalane, D. B.; Kotian, K. D.; Stevens, R. M., Haky, J. E. J.
Org. Chem. 1981, 46, 778.
273
A
C B
D
3.2.5 Formation of N1-C2 bond
Figure 3.8 represents formation of N1-C2 bonds in the pyrrole ring of the
indole framework.
NH
2
X
R
NH
2
R
R
N
5
6
7
4
N
H
2
3
NH
2
Figure 3.8 Retrosynthetic Approach - Disconnection V
This category includes palladium-catalyzed intramolecular cross-coupling
reactions (Class C and D) and the Leimgruber-Batcho indole synthesis which is the
main example of Class A. The remaining group B constitutes reductive cyclizations
of o-nitro-styrenes.
3.2.5.1 Leimgruber-Batcho Indole Synthesis
The Leimgruber-Batcho synthesis is a two-step procedure (Scheme 3.36)
that gives an access to indoles that are only substituted on the benzene ring. It
involves a condensation of an o-nitrotoluene 3.122 with N,N-dimethylformamide
dimethylacetal 3.123 and pyrrolidine 3.124 to form the enamine intermediate 3.125.
274
CH
3
NO
2
N
H
3
C
H
3
C OCH
3
OCh
3
NO
2
N
NH
H
2
, Pd/C
N
H
3.122 3.123 3.125 3.126 3.124

Scheme 3.36 Leimgruber-Batcho Indole Synthesis
The second step is a reductive cyclization to form indole 3.126. A plethora of
reducing agents have been utilized. However, the most commonly used method is
the classic hydrogenation methodology over a palladium catalyst.
166
The reaction
has been used for the synthesis of several rigid analogues of serotonin.
167

3.2.5.2 Reductive Cyclization of o,β-Dinitrostyrenes
Like the Leimgruber-Batcho method, this approach yields indoles only with
substituents on the benzene ring of the indole moiety (Scheme 3.37). The formation
of the starting materials such as o,β-dinitrostyrenes 3.127 can be achieved by Henry
reaction (a condensation of o-nitrobenzaldehydes 3.128 with nitromethane 3.130)
168

or by the nitration reaction of nitrostyrene 3.129
169
.

166
Clark, R. D.; Repke, D. B. Heterocycles 1984, 22, 195.
167
Macor, J. E.; Ryan, K.; Newman, M. E. Tetrahedron 1992, 48, 1039.
168
Rogers, C. B.; Blum, C.A.; Murphy, B. P. J. Hetreocycl Chem. 1987, 24, 941.
169
Sinhababu, A. K.; Bortchardt, R. T. J. Org. Chem. 1983, 48, 3347.
275
NO
2
NO
2 H
2
, Pd/C
N
H
NO
2
NO
2
HNO
3
H
O
CH
3
NO
2
3.128
3.129
3.127
3.126
3.130

Scheme 3.37 Indoles from o,β-Dinitrostyrenes
For the reductive cyclization process several reducing agents have been
utilized including iron powder with acetic acid, Pd/C and ammonium formate and
classic catalytic hydrogenation (Pd/C, hydrogen).
170

3.2.5.3 Reductive Cyclization of o-Nitrobenzylcarbonyl Compounds
Ortho-nitrobenzyl aldehydes or ketones 3.131 are very useful synthetic
intermediates that smoothly undergo in situ cyclization and aromatization to yield
indole derivatives 3.88 upon reduction to introduce the amino group.
R
O
NO
2
N
H
[H]
R
3.131 3.88

Scheme 3.38 Reductive Cyclization of o-Nitrobenzyl-carbonyl Compounds

170
Mantus, E. K.; Clardy, J. Tetrahedron Lett. 1993, 34, 1085.
276
There are many methods for the synthesis of the starting compound 3.131
however none of them can be considered as general and applicable to most of the
cases. Figure 3.10 represents the possible routes to o-aminobenzyl ketones 3.132.
122

O
R
NH
2
O
R
NO
2
R
NO
2
OH
R
NO
2
NO
2
CN
NO
2
NO
2
OCOR
A
B
C
D
E
F
3.131
3.137
3.136
3.135
3.134
3.133
3.132

Figure 3.9 Retrosynthetic Pathways to o-Aminobenzyl Ketones.
Category A represents the classic Reissert procedure (Scheme 3.39). The
Reissert reaction involves acylation of o-nitrobenzyl anions with diethyl oxalate to
generate compound 3.139.
CH
3
NO
2
Base
(CO
2
Et)
2
CO
2
Et
O
NO
2
N
H
[H]
CO
2
Et
3.138 3.140 3.139

Scheme 3.39 Reissert Indole Synthesis
277
Next, the intermediate 3.139 can be reductively cyclized to indole-2-carboxylate
esters 3.140.
In the retrosynthetic pathway B compound 3.133 can be obtained via
Meerwein arylation of vinyl acetate with o-nitrophenyldiazonium salt.
Category C involves a simple oxidation reaction of 2-(o-nitrophenyl)ethanol
3.134. Ortho-nitrobenzyl cyanides 3.135 can also be intermediates for the synthesis
of 3.132 as class D demonstrates. Category E requires a regioselective oxidation of
o-nitrostyrene 3.136. This can be achieved by the Wacker oxidation process. The
last pathway F represents the ozonolysis of o-nitro-allylbenzene derivative 3.137.
171

3.2.5.4 Furan Recyclizations in Indole Syntheses
As mentioned above, the key intermediate for Reissert conditions is o-
aminobenzylcarbonyl intermediate. It turned out that diverse o-aminobenzylfurans
3.141 can serve as o-aminobenzylcarbonyl synthons as they can easily undergo ring
opening to 1,4 dicarbonyl compounds 3.142 (Scheme 3.40) under acidic conditions.
NHTs
R
O
CH
3
NHTs
R
O
O
CH
3
3.141 3.142
H
+

Scheme 3.40 Furan as a 1,4-Diketone Equivalent

171
Plieninger, H.; Meyer, E.; Sharif-Nassirian, F.; Weidmann, E. Liebigs Ann.
Chem. 1976, 1475.
278
However, the intermediates 3.142 cannot be isolated because they spontaneously
cyclize to indoles 3.143 (Scheme 3.41).
172

NHTs
R
O
CH
3
NHTs
R
O
O
CH
3
Ts
N
R CH
3
O
HCl
∆
3.141 3.143 3.142
HCl

Scheme 3.41 Furan Ring Opening - Indole Ring Closure
The mechanism of the transformation is presented in Scheme 3.42.
NHTs
R
O
CH
3
H
+
NHTs
R O
CH
3
H
Ts
N
O
R
CH
3
H
Ts
N
R CH
3
OH
Ts
N
R CH
3
O
3.141 3.144
3.143
3.145
3.146

Scheme 0.42 Mechanism of Furan Ring Opening - Indole Ring Closure
As a continuation of this research Butin and coworkers studied o-
aminoarylfurans 3.147 as a 1,3-diketone equivalent 3.148 in the indole cyclization
(Scheme 3.43).
173

172
Butin, A. V.; Strooganova, T. A.; Lodina, I. V.; Krapivin, G. D. Tetrahedron
Lett. 2001, 42, 2031.
173
Butin, A. V. Tetrahedron Lett. 2006, 47, 4113.
279
NHTs
O
Ts
N
CH
3
O
CH
3
HCl
∆
NHTs
O O
3.147 3.149 3.148
HCl

Scheme 3.43 Furan as a 1,3-Diketone Equivalent in Indole Cyclizations
As a result a variety of 2-substituted indoles 3.149 can be synthesized in good
yields. The plausible mechanism for this reaction is shown in Scheme 4.44.
NHTs
O
CH
3
H
+
O
CH
3
H
NHTs
TsN
O
CH
3
H
H
Ts
N
CH
3
HO
Ts
N
CH
3
O
3.149
3.147 3.150 3.151
3.152

Scheme 3.44 Mechanism of Furan Recyclization Type 2 to Indoles
3.2.5.5 Indoles from o-Aminophenylacetylenes
N-Protected and unprotected o-aminophenylacetylenes 3.153 can be
cyclized to indoles via palladium catalysis (Scheme 3.45).
280
Indol-3-yl-palladium intermediates 3.154 are involved in the cyclization
process and can be further functionalized through tandem cross-coupling reactions
(Path A, Scheme 3.45) yielding 3.155.
NHX
R
1
Pd(II)
N
H
Pd(II)
R
1
R
2
X
N
H
R
2
R
1
N
H
R
1
X= H, Ac, Ms etc.
3.153
3.154
3.155
Path A
Path B
3.156

Scheme 3.45 Indoles from o-Aminophenylacetylenes
Cacchi and coworkers utilized this approach for the synthesis of 2-
substituted-3-heteroarylindoles 3.159 starting from o-trifluoroacetanilides 3.157
(Scheme 3.46).
174

NHCOCF
3
R
1
N
H
R
1
S
N
Br
N
S
Pd(PPh
3
)
4
Cs
2
CO
3
MeCN, ∆
3.157 3.158 3.159

Scheme 0.46 Synthesis of 2-Substituted-3-heteroarylindoles from
o-Trifluoroacetanilides

174
Cacchi, S.; Fabrizi, G.; Lamba, D.; Marinelli, F.; Parisi, L. M. Synthesis, 2003,
728.
281
3.2.5.6 Hegedus Indole Synthesis
In 1976, Hegedus reported an intramolecular palladium mediated amination
of olefins (Scheme 3.47).
175

NH
2
THF, TEA
PdCl
2
(CH
3
CN)
2
N
H
3.160
CH
3
3.161

Scheme 3.47 Hegedus Indole Synthesis
Starting from 2-allylphenylamine 3.160, 2-methylindole 3.161 was
delivered in 84% yield. The original procedure involved stoichiometric amounts of
palladium catalyst with triethylamine in tetrahydrofuran. In 1978, Hegedus reported
a catalytical version of this reaction with 10 mol% of palladium catalyst with
stoichiometric amounts of benzoquinone or copper (II) chloride as the oxidant.
176

He discovered that lithium chloride present in the reaction mixture as an additive is
very beneficially for the yield of the reaction.

175
Hegedus, L. S.; Allen, G. F.; Waterman, E. L. J. Am. Chem. Soc. 1976, 98,
2674.
176
Hegedus, L. S.; Allen, G. F.; bozell, J. J.; Waterman, E. L. J. Am. Chem. Soc.
1978, 100, 5800.
282
3.2.6 Disconnection VI
N
H
5
6
7
4
N
H
2
3

Figure 3.10 DisconnectionVI
The category shown in Figure 3.10 represents examples of Hemetsberger
and Neber procedures to form indoles.
3.2.6.1 Hemetsberger Indole Synthesis
The Hemetsberger synthesis is a quick approach to indole-2-carboxylate
esters 3.164 and utilizes α-azidocinnamates 3.162 as starting materials (Scheme
3.48).
CO
2
R
N
3
CO
2
R
N
N
H
∆
∆
3.163 3.164 3.162
CO
2
R

Scheme 3.48 Hemetsberger Indole Synthesis
The α-azidocinnamates 3.162 undergo thermolysis to form azirine
derivatives 3.163 which thermally rearrange to indoles 3.164 in high yields.
177
The
α-azidocinnamates 3.162 usually can be obtained in a condensation of aromatic
aldehydes with an azidoacetate ester under very carefully controlled conditions that
prevent N
2
loss.

177
Hemetsberger, H.; Knittel, D.; Weidmann, H. Monatsh. Chem. 1970, 101, 161,
283
3.2.6.1 Neber Indole Synthesis
The α-aryl azirines 3.166 can be synthesized via Neber’s approach that
utilizes α-aryl ketones 3.165 and hydroxylamine as starting materials.
178

CH
3
N
N
H
R
∆
O
CH
3
1) NH
2
-OH
2) -H
2
O
R R
CH
3
3.165 3.166 3.167

Scheme 3.49 Neber Indole Synthesis
For monoaryl acyclic ketones such as 3.165 exposure of the corresponding
oxime to mesyl chloride and triethylamine at 20
o
C followed by addition of DBU
resulted in azirine 3.166 formation. For the diaryl or cyclic ketones, Mitsunobu
conditions (DIAD with tributylphosphine) gave more satisfactory results. In
general, this approach can be very useful for the preparation of indoles having
highly substituted benzene rings.

178
Taber, D. T.; Tian, W. J. Am. Chem. Soc. 2006, 128, 1058.
284
3.2.7 Disconnection VII
The category presented in Figure 3.11 belongs to the classical Nenitzescu
indole synthesis.
5
6
7
4
N
H
2
3
O
O
H
R
2
NH R
3
R
1
3.168 3.169

Figure 3.11 Retrosynthetic Analysis VII
3.2.7.1 Nenitzescu Synthesis
The original Nenitzescu indole synthesis involves the condensation between
p-benzoquinones 3.168 and enamines 3.169 in order to obtain 1,2,3-trisubstitued-5-
hydroxy-indole derivatives 3.170 (Scheme 3.50). The reaction conditions are
usually mild. The reaction proceeds with equimolar amounts of quinone and
enamine at elevated temperatures in ethanol or ethyl acetate as solvents.
O
O
H
R
2
NH R
3
R
1
R
1
=EWG
∆
N
R
3
R
1
R
2
HO
3.168 3.169
3.170

Scheme 3.50 Nenitzescu Indole Synthesis
While this method provides a quick access to highly substituted 5-hydroxyindoles
3.170 from readily available starting materials, the isolated yields are generally low
285
due to the elaborate mechanism and possibilities of numerous side reactions.
123
The
mechanism of the reaction is a very interesting process and presumably goes trough
an internal oxidation-reduction sequence (Scheme 3.51).
179

O
O
H
R
2
NH R
3
R
1
N
R
1
R
2
OH
3.170
O
OH
3.171
R
1
N
R
2
R
3
H
OH
OH
R
1
R
2
N
R
3
3.172
H
OH
OH
R
1
R
2
HN
R
3
3.173
O
O
R
1
R
2
HN
R
3
3.174
O
3.175
N
R
2
R
1
HO
R
3
O
3.176
N
R
2
R
1
R
3
R
3
3.168 3.169

Scheme 3.51 Mechanism of Nenitzescu Synthesis

179
Pawlak, J. M.; Khau, V. V.; Hutchinson, D. R.; Martinelli, M. J. J. Org. Chem.
1996, 61, 9055.
286
The mechanism presented above involves at first a Michael addition of the terminal
carbon of the enamine 3.169 to quinone 3.168. The next important part of the
process is the oxidation of the resulting hydroquinone 3.173 to quinone 3.174 by
the original quinone 3.168 or quinonimmonium ion 3.176. The oxidation step is
followed by cyclization to yield the intermediate 3.175 and finally reduction by the
compound 3.171, 3.172 or 3.173 to form the desired indole 3.170.
Despite the limitations of the reaction, applications of this reaction are
known. Martinelli and coworkers utilized the Nenitzescu approach for the synthesis
of LY311727 3.179 (Scheme 3.52) on a large scale.
179

N
O P
O
MeO
OMe
O
NH
2
CH
3
HN
H
3
CO
2
C
CH
3
N
CO
2
Me
HO
CH
3
O
O
3.179 3.178 3.168 3.177

Scheme 3.52 Preparation of LY311727 via Nenitzescu Synthesis
3.2.8 Ring Contractions
3.2.8.1 Synthesis of Indoles from Quinolines
Novel ring transformations of quinolines to indole derivatives were
investigated by Sugiura and coworkers. They developed new methods for the
synthesis of 3-formyl-indoles 3.183 and 2-formylindoles 3.186 starting from
287
quinolines 3.180 (Scheme 3.53 and 3.54 respectively).
180,181
For the synthesis of 3-
formylindoles 3.183 the procedure involves at first a formation of the
Meisenheimer salts of diphenyl 1-phenoxycarbonyl-1,4-dihydroquinoline-4-
phosphonates 3.181 from quinoline 3.180, phenyl chloroformate and triphenyl
phosphite (Scheme 3.53). Next, the ozonolysis and base treatment (sodium
bicarbonate) yields indoles 3.183 in high yields.
P(OPh)
3
N
3.180
R
1
COCl
N
COR
1
Cl
R
1
= OPh
N
COR
1
PO(OPh)
2
3.181 3.182
1) O
3
2) base
N
3.183
COR
1
O
H

Scheme 3.53 3-Formyl-indoles via 1,4-Dihydroquinolines
The formation of 2-formylindoles 3.186 engages a similar protocol. The
dimethyl 1-acyl-1,2-dihydroquinoline-2-phosphonates 3.185 are obtained at first

180
Sugiura, M.; Yamaguchi, N.; Saya, T.; Ito, M.; Asai, K.; Maeba, I. Tetrahedron
Lett. 2002, 43, 5295.
181
Sugiura, M.; Yamaguchi, N.; Asai, K.; Maeba, I. Tetrahedron Lett. 2003, 44,
6241.
288
from the corresponding quinoline 3.180. Subsequent ozonolysis and the base
treatment (usually sodium bicarbonate) in order to obtain 2-formylindoles 3.186.

N
3.180
R
1
COCl
N
3.184
COR
1
Cl
P(OMe)
3
N
3.185
R
1
= OMe, Ph
COR
1
PO(OMe)
3
1) O
3
2) base
N
3.186
COR
1
H
O

Scheme 3.54 Synthesis of 2-Formyl-indoles
3.2.9 Disconnection IX and XI
Indoles are usually built from the phenyl derivatives via formation of the
pyrrole ring as was presented previously. However there are methodologies that use
pyrrole derivatives to form the benzene ring of the indole framework. Figure 3.12
and 3.13 illustrate two possible disconnections. These pathways are closely related
and differ only in the point of cyclization. They both represent examples of
electrophilic ring closure.
289
N
H
R
5
6
7
4
N
H
2
3

Figure 3.12 Disconnection IX

N
H
R
5
6
7
4
N
H
2
3

Figure 3.13 Disconnection XI
3.2.9.1 Natsume Indole Synthesis
A nice example of the electrophilic substitution at C-3 (Category XI) was
reported by Natsume and coworkers.
182

182
Muratake, H.; Natsume, M. Heterocycles 1990, 31, 683.
290
N
Ts
CH
3
O
MgBr
O
O
N
Ts
CH
3
HO
O
O
3.187 3.188 3.189
H
2
SO
4
∆
N
Ts
CH
3
3.190

Scheme 3.55 Natsume Indole Synthesis
Their protocol involves formation of 2-substituted pyrrole 3.189 capable of
electrophilic substitution at C-3 via Grignard 3.188 addition to 2-acylpyrroles
3.187. Compound 3.189 undergoes cyclization followed by aromatization reaction
with sulfuric acid in isopropanol to yield indole derivative 3.190. This method can
be considered as a general route for the synthesis of 7-alkyl or 7-arylindoles.
3.2.9.2 Indoles via Electrophilic Cyclization at C-2
A representative example for Category IX is shown in Scheme 3.56.
291
N
H
N HO
O
RO
2
C
CHO
TBDMSOTf
N
H
N
CHO
RO
2
C
3.191 3.192

Scheme 3.56 Indoles via electrophilic cyclization at C-2 pyrrole
The reaction involves a cyclization strategy of 3.191 with tert-
butyldimethylsilyl triflate to form substituted indole 3.192.
183

3.2.10 Indole synthesis through cycloaddition routes
3.2.10.1 Indoles from Pyrrole-2,3-quinodimethane Intermediates
The category shown in Figure 3.14 represents a cyclization based on [2+4]
cycloadditions of pyrrole-2,3-diquinomethane intermediates 3.193.

N
H
5
6
7
4
N
H
2
3
3.193

Figure 3.14 Disconnection X - Indole Synthesis via [2+4] Cycloaddition

183
Kozikowski, A. P.; Sato, K.; Basu, A.; Lazo, J. S. J. Am. Chem. Soc. 1989, 111,
6228.
292
Both 1,5-dihydropyrano[3,4-b]pyrrol-5-(1H)-ones 3.194 and 1,6-
dihydropyrano[4,3-b]pyrrole-6-(1H)-ones 3.198 can serve as pyrrole-2,3-
diquinomethane precursors. The reactions shown in Scheme 3.57 and Scheme 3.58
are very useful for the synthesis 5,6-disubstituted indoles 3.197.
184

O
N
H
O
X
X
N
H
O
O
X
X
N
H
X
X
- CO
2
3.194 3.195 3.196 3.197

Scheme 3.57 Indoles from 1,5-Dihydropyrano[3,4-b]pyrrol-5-(1H)-ones
The adducts of the cycloaddition processes such as 3.196 and 3.199 undergo
elimination of carbon dioxide to generate indoles 3.197.
185

O
N
H
X
X
N
H
X
X
N
H
X
X
- CO
2
O
O
O
3.198 3.195 3.199 3.197

Scheme 3.58 Indoles from 1,6-Dihydropyrano[4,3-b]pyrrole-6-(1H)-ones

184
Jackson, P. M.; Moody, C. J. Tetrahedron 1992, 48, 7447.
185
Andrews, J. F. P.; Jackson, P. M.; Moody, C. J. Tetrahedron 1993, 49, 7353.
293
3.2.10.2 Indoles from Vinylpyrroles
Both 2-vinylpyrroles (Figure 3.16) and 3-vinylpyrroles (Figure 3.17) can be
used for the synthesis of indoles. However, they are relatively reactive and very
sensitive compounds so their synthetic applications are limited.
N
H
5
6
7
4
N
H
2
3

Figure3.15 Disconnection XII
N
H
5
6
7
4
N
H
2
3

Figure 3.16 Disconnection XIII
Scheme 3.59 illustrates the use of 2-vinylpyrrole 3.200 in the synthesis of
indole 3.202 with ethyl propiolate 3.201. Unfortunately the yields of the reaction
are low to modest so clearly there is some room for improvement.
186

N
CO
2
Me
CO
2
Me
N
CO
2
Me
CO
2
Me
OH
OTMS
3.202 3.200
3.201
∆

Scheme 3.59 Indoles from 2-Vinylpyrroles

186
Ohno, M.; Shimizu, S.; Eguchi, S. Tetrahedron Lett. 1990, 31, 4613.
294
Scheme 3.60 represents an example of the use of 3-vinylpyrroles 3.204 with
acetylenic dienophiles 3.203 that leads to fully aromatic indole derivative 3.205.
187

N
H
MeO
2
C CO
2
Me
N
MeO
2
C
CO
2
Me
3.205 3.204 3.203
CH
3
CH
3

Scheme 3.60 Indoles from 3-Vinylpyrroles
In summary there has been a plethora methods developed for the synthesis
of indoles as it is overviewed above. Nevertheless the biological importance of
indoles drives the research for development new more general, economical and
practical methodologies.

187
Jones, R. A.; Saliente, T. A.; Arques, J. S. J. Chem. Soc. Perkin Trans. 1 1984,
2541.
295
Chapter 4. Novel Approach to Indoles
4.1 Introduction
4.1.1 Importance of Indoles
Indoles are widely recognized as one of the most important heterocyclic
scaffolds known due to being present in many natural products and
pharmaceuticals. Indoles exhibit a wide range of valuable biological properties
including anti-inflammatory, antimalarial, antidepressant, antitumor and other
activities. Their chemical structures are often simple like for example, serotonin
4.01, which plays an important role in neurochemistry
188
or the psychotomimetic
indoles psilocin 4.04 and psilocybin 4.03 isolated from mushrooms
189
, but they can
be quite complex as well like the tranquilizer reserpine
190
4.02 (Figure 4.01). As a
result of the large structural varieties and a wide range of biological activities
modulated from these compounds, a very strong interest exists for the development
of novel and efficient synthetic strategies towards indoles as was presented in
Chapter 3. Herein, we present our contribution to the indole chemistry.

188
Kikuchi, C.; Nagaso, H.; Hiranuma, T.; Koyama, M. J. Med. Chem., 1999, 42,
533.
189
Gatherhood, N.; Scammells, P. J. Org. Lett., 2003, 5, 921.
190
Mehta, G.; Reddy, D. S. J. Chem. Soc. Perkin Trans., 1 1998, 14, 2125
296
N
H
OH
N(CH
3
)
2
N
H
O
N(CH
3
)
2
P
HO
HO
O
N
H
NH
2
HO
4.03
4.01
4.04
N
H
4.02
H
3
CO
N
H
H
H
H
3
CO
2
C
O
OCH
3
O
OCH
3
OCH
3
OCH
3

Figure 4.1 Examples of Biologically Active Indoles
4.2 Results and Discussion
We have developed a conceptually novel indole synthesis based on the
intramolecular cyclization of α-anilino carboxylic acids 4.08 as presented in
Scheme 4.1. The α-amino acids 4.08 are synthesized through a boron-based
multicomponent reaction from readily (commercially or synthetically) available
starting materials (2-aminoaryl ketones, glyoxylic acid and organoboronic acids).
NH
4.05
O
R
1
H
O
O
OH
R
3
B(OR)
2
4.06 4.07
N
4.08
O
R
1
R
3
HO
O
N
4.09
R
1
R
3
R
2
R
2
R
2

Scheme 4.1 Novel Approach to Indoles
297
4.2.1 Synthesis of 2-Amino Aryl Ketones and Aldehydes
4.2.1.1 Importance of 2-Amino Aryl Ketones and Aldehydes
2-Amino aryl ketones and aldehydes are widely used as starting materials
for the syntheses of variety of heterocyclic systems.
191
They have been utilized for
the synthesis of substituted quinolines 4.10 via acid catalyzed Friedländer
synthesis
192
, quinazolinone derivatives 4.11
193
and many others.
194
Nevertheless,
the most important application of 2-amino aryl ketones turned out to be the
preparation of 1,4-benzodiazepines 4.12 and their derivatives 4.13, 4.14 (Figure
4.02).
195

191
Simpson, J. C. E.; Atkinson, C. M.; Schofield, K.; Stephenson, O. J. Chem. Soc.,
1945, 646.
192
Fehnel, E. A. J. Org. Chem., 1966, 31, 2899.
193
Ott, H.; Denzer, M. J. Org. Chem., 1968, 33, 4263.
194
Walsh, D. A. Synthesis, 1980, 677.
195
Sternbach, L. H. Angew. Chem. Int. Ed. Engl., 1971, 10, 34.
298
N R
3
R
2
R
1
N
N
R
4
O
R
5
4.10 4.11
N
N
R
9
O
R
11
R
10
R
12
N
N
R
13
R
15
O
R
14
R
16
4.13 4.14
N
N
R
6
R
7
4.12
R
8
O

Figure 4.2 Heterocycles Generated from 2-Amino aryl Ketones and Aldehydes

4.2.1.2. Synthetic Approaches to 2-Amino Aryl Ketones and Aldehydes
There are many synthetic methodologies developed for the synthesis of 2-
amino aryl ketones and aldehydes as they are key intermediates in many
heterocycle syntheses.
194

299
R
O
NH
2
R
O
CO
2
H
N
H
R
N
O
R
Cl
NO
2
Cl
NO
2
O
OH
NO
2
O
Cl
NO
2
CN
NH
2
OH
NH
2
O
N
O
O
CH
3
N
H
O
O
O
NH
2
NH
R
1
O
CN
Br
N A
C
B
M
D
E
F
G
L
K
J
I
H

Figure 4.3 Synthetic Approaches to 2-Amino Aryl Ketones and Aldehydes
Figure 4.3 represents a summary of the most utilized synthetic methods for
generating 2-amino aryl ketones. However, some of the approaches can be used for
the syntheses of 2-amino aryl aldehydes as well.
Category A shows the synthesis of 2-amino aryl ketones 4.19 from 2-
chloronitrobenzene 4.15. Scheme 4.02 illustrates the methodology. 2-
Chloronitrobenzene 4.15 is treated with masked acyl anion 4.16 in order to obtain
300
2-nitro aryl ketone 4.18 which is reduced to the corresponding amino analog
4.19.
196

Cl
NO
2
4.15
R CN
N
O
4.16
NaH
DMF
R
O
NH
2
4.19
AcOH
Fe
R
O
NO
2
4.18
NO
2
4.17
CN
R
N
O

Scheme 4.2 2-Amino Aryl Ketones from 2-Chloronitrobenzenes
Pathway B in Figure 4.3 is an example of an ortho-lithiation reaction of N-
pivaloylanilines 4.20.
NH
R
1
O
4.20
n-BuLi
N
R
1
OLi
4.21
Li
R
O
4.22
R = OR
2
, NR
2
R
3
, CO
2
R
2
6N HCl
O
NH
2
4.23

Scheme 4.3 2-Amino Aryl Ketones and Aldehydes from N-pivaloylanilines
Pivaloylanilines 4.20 are readily converted into dilithiated species 4.21 which react
with a variety of electrophiles (amides, esters, anhydrides) to give ortho-substituted
aniline derivatives 4.23 in high yields.
197

The most straightforward synthetic methodology towards 2-amino aryl
ketones is presented in Category C, Figure 4.03. It requires the least number of
steps and utilizes very simple and commercially available starting materials:

196
McEvoy, F. J.; Albright, J. D. J. Org. Chem., 1979, 44, 4597.
197
Furer, W.; Gschwend, H. W. J. Org. Chem., 1979, 44, 1133.
301
anilines 4.24 and nitriles 4.25. The method is known in the literature as the
Sugasawa Reaction (Scheme 4.4).
198

NH
2
4.24
CN
4.25
BCl
3
AlCl
3
O
NH
2
4.26

Scheme 4.4 The Sugasawa Reaction
This methodology is a modification of the Friedel-Crafts reaction and provides a
general approach for the preparation of exclusively ortho-substituted anilines 4.26.
The procedure involves boron trichloride and a second “auxiliary” Lewis acid to
facilitate ortho-substitution of aniline 4.24 with electrophilic nitriles 4.25.
Category D corresponds to the syntheses of 2-amino aryl ketones such as
4.28 and 4.29 from isatoic anhydride 4.27 (Scheme 4.05).
N
H
O
O
O
4.27
AlCl
3
benzene
O
NH
2
4.28
2) AlCl
3

toluene
O
NH
2
4.29
CH
3
Route I
Route II
1) SOCl
2

Scheme 4.5 Synthesis of 2-Amino Aryl Ketones from Isatoic Anhydride

198
Sugasawa, T.; Toyoda, T.; Adachi, M.; Sasakura, K. J. Am. Chem. Soc., 1978,
100, 4842.
302
These two methodologies are Friedel-Crafts type reactions as well. Nevertheless,
route II gives much better yields than route I.
199
Additionally when N-substituted
derivatives of isatoic anhydride are used instead it is possible to use Grignard
reagents or lithium reagents to open the anhydride ring for preparation of N-
substituted-2-amino aryl ketones.
200

Scheme 4.6 illustrates an example of addition of a Grignard reagent 4.31 to
3,1-benzoxazine-4-one 4.30.
N
O
O
CH
3
4.30
MgBr
4.31
O
NH
4.32
THF
O CH
3
O
NH
2
4.33
6N HCl

Scheme 4.6 Synthesis of 2-Amino Aryl Ketones from 3,1-Benzoxazin-4-ones
This approach (Category E, Figure 4.3) has been used extensively and the yields of
the reaction can reach even 90%.
201
The 3,1-benzoxazine-4-ones 4.30 can be
prepared from anthranilic acid and acetic anhydride.
2-Amino aryl ketones can be synthesized from 2-halo aryl ketones 4.36 by
displacement of the halogen with ammonia as shown in Scheme 4.06.
202

199
Misra, B. K.; Rao, Y. R.; Mahapotra, S. N. Indian J. Chem. [B], 1979, 18, 19.
200
Garcia, E. E.; Arfaei, A.; Fryer, R. I. J. Heterocycl. Chem., 1970, 7, 1616.
201
Coombs, R. V.; Danna, R. P.; Denzer, M..; Hardtmann, G. E.; Huegi, B.;
Koletar, G.; Koletar, J.; Ott, H. J. Med. Chem., 1973, 16, 1237.
202
Gassman, P. G.; Drewes, H. R. J. Am. Chem. Soc., 1978, 100, 7600.
303
CN
Br
4.34
MgBr
4.35
1) THF
OCH
3
2) H
3
O
+
O
Br
4.36
OCH
3
O
NH
2
4.37
OCH
3
1) NH
3
2) H
3
O
+

Scheme 4.7 2-Halo Aryl Ketones as Precursors to 2-Amino Aryl Ketones
The 2-halo aryl ketones 4.36 can be easily accessed via reaction of the appropriate
Grignard reagent 4.35 with benzonitrile derivative 4.34 followed by acid
hydrolysis.
Anthranilic acid 4.38 is probably one of the most explored starting materials
for the syntheses of 2-amino aryl ketones as being easily available from isatins.
203

OH
NH
2
O
SOCl
2
DMF
4.38
OH
N
O
4.39
N(CH
3
)
2
.
HCl
1) PCl
5
2) AlCl
3

toluene
3) NaOH
O
NH
2
4.40
CH
3
TsCl
Na
2
CO
3
OH
NHTs
O
4.41
1) PCl
5
2) AlCl
3

benzene
3) H
2
SO
4
∆
O
NH
2
4.42
Route A
Route B

Scheme 4.8 Syntheses of 2-Amino Aryl Ketones from Anthranilic Acid
The amino group in anthranilic acid 4.38 can be protected by formation of amidine
adduct 4.39 with dimethylformamide as Route A in the Scheme 4.08 illustrates.
Subsequently, this adduct is converted in situ into the acid chloride which

203
Sumpter, W. C. Chem. Rev., 1951, 213.
304
undergoes a Friedel-Crafts type reaction with toluene in order to form product
4.40.
204
Another option for protecting the amino group in anthranilic acid 4.38 is
the use of p-toluenesulfonyl chloride (Route B, Scheme 4.08). Then the conversion
of compound 4.41 into an acid chloride in situ generates the partner for the
subsequent Friedel-Crafts reaction. The acid hydrolysis at the end of the process
generates the final product 4.42.
205

Scheme 4.09 represents the reaction of 2-aminobenzonitriles 4.43 with Grignard- or
lithium reagents 4.44 (Category H in Figure 4.01).
201

CN
NH
2
4.43
M
M = MgX or Li
4.44
1) Et
2
O
2) HCl
O
NH
2
4.42

Scheme 4.9 Synthesis of 2-Amino Aryl Ketones from 2-Aminobenzonitriles
2-Nitrobenzoyl chlorides 4.45 usually are not the best partners for the
Friedel-Crafts reaction due to the complexation of the nitro group with the catalyst.
Cl
NO
2
O
4.46
AlCl
3
O
NO
2
4.47 4.45
AcOH
Fe
O
NH
2
4.42

Scheme 4.10 2-Amino Aryl Ketones from 2-Nitrobenzoyl Chloride

204
Reeder, E., Sternbach, L. H. US Patent 3239564, 1966, Hoffmann-La Roche,
Inc.; CA, 64, 19498, 1966.
205
Scheifele, Jr., H. J.; DeTar, D. F. Org. Synth. Col. Vol. IV, 1963, 34.
305
Nevertheless, attempts for the synthesis of 2-amino aryl ketones from compounds
such as 4.45 are known in the literature (Scheme 4.10).
194
Once compound 4.47 is
obtained, reduction of the nitro group yields the final product 4.42.
A Russian group developed an improved process. The activation of the
carboxylic acid group in 2-nitrobenzoic acid 4.48 via treatment with trichlorosilyl-
chloride generated more efficiently the Friedel-Crafts reaction partner 4.49
(Scheme 4.11). Subsequent reduction of 4.47 afforded the final product 4.42.
OH
NO
2
O
SiCl
4 OSiCl
3
NO
2
O
AlCl
3
4.48 4.49
O
NO
2
4.47
AcOH
Fe
O
NH
2
4.42
benzene

Scheme 4.11 2-Amino Aryl Ketones from 2-Nitrobenzoic Acid
The yields reported for the reaction vary from 50 to 80%.
206

Similar problems exist in case of 2-nitrobenzyl chloride 4.50 utilized as
starting material. The Friedel-Crafts reaction yields are not very high (Scheme
4.12). However, once 2-nitrophenylmethane 4.51 is formed, conversion into the 2-
nitrobenzophenone can be accomplished by many oxidizing agents.
207
Similarly,
the nitro group reduction can be achieved in many ways.

206
Yurev, Y. K.; Belyakova, Z. V.; Volkov, V. P. Zh. Obshsch. Khim., 1959, 29,
3873.
207
Schaarschmidt, A.; Herzenberg, J.; Ber. Dtsch. Chem. Ges. [B], 1969, 8, 277.
306
4.50
Cl
NO
2
4.46
AlCl
3
NO
2
4.51
O
NH
2
4.42
1) Oxidation
2) Reduction

Scheme 4.12 2-Amino Aryl Ketones from 2-Nitrobenzyl Chloride
As Scheme 4.13 shows, 2-aminoaryl ketones and aldehydes can be obtained
directly from indoles 4.52 via ozonolysis.
208

N
H
R
O
3
AcOH
R
O
NH
4.53 4.52
O Ph
R
O
NH
2
4.54
AcOH

Scheme 4.13 2-Amino Aryl Ketones and Aldehydes from Indoles
The process is quite efficient however, 2-aminoaryl ketones 4.54 are often the
starting materials for the syntheses of indoles.
Derivatives of 2-amino aryl ketones and aldehydes 4.56 can be obtained by
careful reduction of 2,1-benzisoxazoles 4.55 (Scheme 4.14). Nevertheless, the
reaction has some limitations. One of them is requiring certain substituents in the
para position.
209

208
Sternbach, L. H.; Fryer, R. I.; Metlesics, W.; Sach, G.; Stempel, A. J. Org.
Chem., 1962, 27, 3781.
209
Walker, G. N.; J. Org. Chem., 1962, 27, 1929.
307
N
O
R
2
4.55 4.56
R
1
R
2
O
NH
2
H
2
10% Pd-C
R
1

Scheme 4.14 2-Amino Aryl Ketones and Aldehydes from 2,1-Benzisoxazoles
Scheme 4.15 shows a general synthesis of 2-amino aryl ketones 4.54 from 2-keto
benzoic acid derivatives 4.57.
R
O
CO
2
H
R
O
CO
2
NH
2
1) PCl
5
2) NH
3
R
O
NH
2
Br
2
NaOH
4.57 4.58 4.54

Scheme 4.15 2-Amino Aryl Ketones and Aldehydes from 2-Keto Benzoic Acids
The reaction involves a Hofmann rearrangement of the amide 4.58 as illustrated in
Scheme 4.15 (or alternatively the Curtius reaction can be applied). The yields are
usually good but several steps are required in order to obtain the desired product.
The process is limited with availability of the starting materials as well.
210

4.2.1.3. Synthesis of 2-Amino Aryl Ketones and Aldehydes
Nowadays, one expects that 2-amino aryl ketones and aldehydes would be
commercially available. Surprisingly, only few compounds of our interest can be
purchased from commercial sources. The others we synthesized ourselves. For this
purpose we have utilized mostly the ortho-lithiation reactions of N-

210
Miller, H. F.; Bachmann, G. B. J. Am. Chem. Soc., 1935, 57, 2443.
308
pivaloylanilines, the Sugasawa reaction and nucleophilic addition of amines to
isatins.
We started exploring the synthesis of 2-amino aryl ketones and aldehydes
with the directed ortho-lithiation method presented in Scheme 4.16.
211

NH
R O
2.2. eq. n-BuLi
THF
Electrophile
NH
R O
E
N
Li
O
R
Li
4.59 4.60 4.61

Scheme 4.16 Directed Ortho-Lithiation of N-Protectedanilines
The concept of directed or facilitated lithiation has recently become a
powerful tool in organic synthesis.
212
There are many examples of ortho-
functionalization of N-protected anilines 4.59 in the literature.
213
The reaction
proceeds through di-lithiated intermediate 4.60 that enables a regiospecific
electrophilic substitution. The electrophiles used in these types of transformations
include: dimethylformamide, aldehydes, nitriles, dimethyldisulfide, esters, amides,
anhydrides, lactones and many others.
213

We chose N-pivaloylanilines 4.59 over N-(tert-butoxycarbonyl)anilines as
starting materials for the lithiation due to a couple of reasons. First of all, the
lithiation reaction can be carried out with n-butyllithium reagent instead of

211
Cho, I.-S.; Gong, L.; Muchowski, J. M. J. Org. Chem., 1991, 56, 7288.
212
Gschwend, H. W.; Rodriguez, H. R. Org. Reac., 1979, 1, 26.
213
Sniecus, V. Chem. Rev., 1990, 90, 879.
309
pyrophoric t-butyllithium reagent which has to be used in case of N-(tert-
butoxycarbonyl)-anilines. Secondly, N-pivaloylanilines are easier to prepare as the
protection of less nucleophilic aromatic amines with di-tert-butyl dicarbonate
(Boc
2
O) is not as efficient as that of aliphatic amines.
214

NH
2
4.24
Cl
O
4.62
Na
2
CO
3
aq.
DCM, rt
NH
O
4.63

Scheme 4.17 Synthesis of N-Pivaloylanilines
We have accomplished the synthesis of N-pivaloylanilines 4.63 in almost
quantitative yields and in short time from corresponding anilines 4.24 and very
electrophilic pivaloyl chloride 4.62 as shown in Scheme 4.17. We have utilized
them in the synthesis of 2-amino aryl ketones as shown in Scheme 4.18.
NH
O
4.63
1) 2.2. eq. n-BuLi
THF
2) Electrophile
NH
O
E
reflux
6N HCl
NH
2
E
4.64 4.65

Scheme 4.18 Synthesis of ortho-Substituted Anilines via Directed Ortho-
Lithiation of N-Pivaloylanilines

214
Vilaivan, T. Tetrahedron Lett., 2006, 47, 6739.
310
As the electrophile in the acylation reaction of dilithiated intermediate 4.60 we
have used mostly morpholine amides which analogously to Weinreb amides
215
are
known to participate in effective acylation of organolithium or organomagnesium
reagents.
216
As illustrated in Scheme 4.18 the final step involves an acid catalyzed
deprotection reaction to yield the final product. Table 1 shows the details of the
process including the electrophiles utilized and the yields of the products calculated
based on starting unprotected anilines.
Table 4.1 Synthesis of 2-Amino Aryl Ketones via ortho-Lithiation of
N-pivaloylanilines
Entry Electrophile Product Yield [%]
1
ON
O
CF
3
4.66
Cl
NH
2
O
CF
3

4.67
82
2
ON
O
CF
2
H

4.68
Cl
NH
2
O
CF
2
H

4.69
59

215
Balasubramaniam, S.; Aidhen, I. S. Synthesis, 2008, 23, 3707.
216
Olah, G. A.; Ohannesian, L.; Arvanaghi, M. J. Org. Chem., 1984, 49, 3856.
311
Entry Electrophile Product Yield [%]
3
O
CH
3
O

4.70
CH
3
O
OH
Cl
NH
2

4.71
29

The third example in Table 1 represents the use of γ-valerolactone 4.70 as the
electrophile in the acylation reaction. The overall yield of the process in this case is
quite low due to many possible side reactions. The morpholine amides were
synthesized according to existing literature precedence from morpholine and the
corresponding anhydride.
Generally, Friedel-Crafts reactions of unprotected anilines are thought to be
impossible and there are only a few examples showing good yields.
217
Usually, the
formation of p-isomer is inevitable unless this position is already substituted.
Additionally, the yields are lower than 50%.
218
Therefore the reaction discovered in
1978 by Tsutomu Sugasawa is an attractive alternative to a classic Friedel-Craft
reaction or even the ortho-lithiation approach (Scheme 4.19).
198

217
Olah, G. “Friedel Crafts and Related Reactions” Interscience Publisher, New
York, London, Sydney 1964, Vol. I, 100; Vol III 57; Vol. III 225.
218
Sternbach. L H.; Reeder, E.; Keller, O.; Metlesics, W. J. Org. Chem., 1961, 26,
4488.
312
NH
2
RCN
BCl
3
AlCl
3
R
O
NH
2
4.24
∆
4.72 4.54

Scheme 4.19 The Sugasawa Reaction with Anilines
The Sugasawa approach employs readily available starting materials such as
anilines 4.24 and nitriles 4.72 with boron trichloride in the presence of another
“auxiliary” Lewis acid such as aluminum trichloride or other commonly employed
Lewis acids in the Friedel-Crafts reaction. The reaction mechanism has been well
studied by in situ NMR spectroscopy.
219
It presumably proceeds through a cyclic
transition state 4.74, a “supercomplex” which requires all four components to be
present (Scheme 4.20). As a product precursor, the intermediate 4.76 forms which
is hydrolyzed to the final exclusively ortho-substituted product. One important
point is that other common Lewis acids in place of a boron trichloride do not work
in the reaction. It was established that it has to be boron-based Lewis acid with at
least one chlorine or bromine atom to retain its electrophilicity.
220
The ortho-
selectivity of this reaction is due to two factors. First, anilinochloroboranes 4.73
retain enough Lewis acidity in order to accept the nucleophilic centers of nitriles

219
Douglas, A. W.; Abramson, N. L.; Houpis, I. N.; Karady, S. Molina, A.; Xavier,
L. C.; Yasuda, N. Tetrahedron Lett., 1994, 35, 6807.
220
Sugaswa, T. Studies in Org. Chem,. 1986, 25, 63.
313
4.72. Secondly, the N-B boron having a double bond character makes it stronger
than any other N-metal bonds (N-Al, N-Zn, N-Mg).
221

NH
2
BCl
3
NH
2
.
BCl
3
MCl
x
N
B
H H
Cl
N
Cl
R
.
MCl
-
(x+1)
-HMCl
(x+1)
N
H
B
N
R
H
R
O
Cl
Cl
NH
2
H
2
O
- HCl
N
B
N
R
H
Cl
4.24 4.73 4.72
4.75
4.74
4.54 4.76
RCN

Scheme 4.20 Plausible Mechanism of Sugasawa Reaction
Although the Sugasawa reaction utilizes very simple starting materials and it is the
shortest methodology available for the synthesis of ortho-substituted anilines, it has
not received much attention since its discovery. We tried to revitalize the reaction
for the synthesis of 2-amino aryl ketones as in our opinion it is an underappreciated
reaction. We have explored a model reaction between p-chloroaniline and 2-
chloropropionitrile with boron trichloride in dichloroethane with a variety of
auxiliary Lewis acids (zinc (II) chloride, titatinum tetrachloride, aluminum
trichloride and gallium trichloride). The reaction turned out to give the best results
with gallium trichloride which was a confirmation of findings published by

221
Greenwood, N. N.; Thomas, B. S. ‘The Chemistry of Boron” Pergamon Texts in
Inorganic Chemistry, vol.8, Pergamon Press, 1973, 925.
314
Houpis
222
and Prasad
223
. We have utilized these conditions for the synthesis of a
number of 2-amino aryl ketones as shown in Table 2 (Scheme 4.21).
NH
2
RCN
BCl
3
GaCl
3
, DCE
R
O
NH
2
4.24
∆
4.72 4.54

Scheme 4.21 Synthesis of 2-Amino Aryl Ketones via Sugasawa Reaction
Meanwhile, we have learned that reaction requires a quite complicated set up as the
forming during the reaction hydrogen hydrochloride needs to be purged off in order
to provide higher yields. In the case of Entry 6 in Table 2 we have started from p-
methoxyaniline and we obtained the hydroxy analog which was not a big surprise
taking into account the reaction conditions. Boron trichloride similarly to boron
tribromide is able to cleave the methoxy group to form the hydroxy equivalent.

222
Houpis, I. N.; Molina, A.; Douglas, A. W.; Xavier, L. C.; Lynch, J.; Volante, R.
P.; Reider, P. J. Tetrahedron Lett. 1994, 35, 6811.
223
Prasad, K.; Lee, G. T.; Chaudhary, A.; Girgis, M. J.; Streemke, J. W.; Repi č, O.
Organic Process Research & Development, 2003, 7, 723.
315
Table 4.2 The Sugasawa Reaction with Anilines
Entry Nitrile Product Yield [%]
1
CN F
3
C

4.77
O
NH
2
CF
3

4.78
55
2 CN

4.79
O
NH
2
4.80
76
3
CN

4.81
O
NH
2
4.82
75
4
N
CN

4.83
O
N
NH
2
4.84
75
5
CN
Cl
4.85
O
NH
2
Cl

4.86
33
6
CN
Cl
4.85
O
NH
2
Cl
HO

4.87
45

316
It turned out that the Sugasawa reaction proceeds with secondary anilines
4.88 as well as it illustrates in Scheme 4.22.
224

O
NH F
4.89 4.90
NH
NC
F
BCl
3
GaCl
3
, DCE
∆
51%
4.88

Scheme 4.22 The Sugasawa Reaction with Secondary Anilines
We have utilized the same reaction conditions as for the primary anilines and we
have been able to prepare (4-fluoro-phenyl)-(2-isopropylamino-phenyl)-methanone
4.90 in a moderate 51% yield.
In the course of our ongoing project we wanted to utilize bicyclic structures
of amino ketones such as 7-aminoindanone 4.93 and 8-aminotetralone 4.96. For
their synthesis we employed a protocol developed by Heidelbaugh and coworkers
(Scheme 4.23).
225

n
n = 1, 4.91
n = 2, 4.94
NH
2
1) Ac
2
O, EtOH
2) KMnO
4
, MgSO
4
Acetone
n
n = 1, 4.92
n=2, 4.95
NHAc
O
reflux
6N HCl
n
n = 1, 93%, 4.93
n = 2, 48%, 4.96
NH
2
O

Scheme 4.23 Syntheses of 7-Aminoindanone and 8-Aminotetralone

224
Sugasawa, T.; Hamana, H.; Toyoda, T.; Adachi, M. Syn Comm., 1979, 99.
225
Nguyen, P.; Corpuz, E.; Heidelbaugh, T. M.; Chow, K.; Garst, M. E. J. Org.
Chem., 2003, 68, 10195.
317
This protocol is based on a general and divergent regioselective oxidation method
of indan-4-ylamine 4.91 and 5,6,7,8-tetrahydro-naphthalen-1-ylamine 4.94 with
KMnO
4
in acetone in the presence of MgSO
4
.
226

For the synthesis of 2-(2-amino-phenyl)-N,N-dimethyl-2-oxo-acetamide
4.98 we have employed a nucleophilic ring opening of isatin 4.97 by
dimethylamine as shown in Scheme 4.24.
227

N
H
O
O
O
NH
2
O
N(CH
3
)
2
(CH
3
)
2
NH 40% aq.
reflux, neat
4.97 4.98

Scheme 4.24 Reaction Between Isatin and Dimethylamine
In addition, we have utilized a similar protocol for the preparation of 2-(2-
amino-5-nitro-phenyl)-N,N-dimethyl-2-oxo-acetamide 4.101 from 5-nitroisatin
4.99 and morpholine 4.100 in excellent yield (92%) as Scheme 4.25 illustrates.
228

226
Shaabani, A.; Bazgir, A.; Teimouri, F.; Lee, D. G. Tetrahedron Lett., 2002, 43,
6165.
227
Bergman, J.; Stalhandske, C.; Vallberg, H. Acta Chem. Scan., 1997, 51, 753.
228
Hlavac, J.; Soural, M.; Hradil, P.; Frysova, P.; Slouka, J. J. Heterocyclic Chem.,
2004, 41, 633.
318
N
H
O
O
O
NH
2
O
N
reflux
4.99 4.101
O
H
N
4.100
MeOH
O
2
N O
2
N
O

Scheme 4.25 Reaction Between Isatin and Morpholine
The synthesis of 2-amino N-substituted benzamides 4.103 was
accomplished via nucleophilic ring opening of isatoic anhydride 4.27 as shown in
Scheme 4.26.
N
H
O
O
O
4.27
R
N
H
reflux
4.102
CH
3
CN
NH
2
N
O
4.103
R
R
R

Scheme 4.26 Nuclephilic Ring Opening of Isatoic Anhydride
Table 4.3 illustrates the specific examples with primary and secondary amines as
nucleophiles.

319
Table 4.3 Synthesis of 2-Amino Benzamides
Entry Amine Product Yield [%]
1
NH N
Ph

4.104
NH
2
N
O
N
Ph

4.105
99
2
H
2
N OMe

4.106
NH
2
N
H
O
OMe

4.107
50

4.2.2 Synthesis of α-Anilino Amino Acids via Petasis Reaction
One of the most important applications of the Petasis reaction is the
synthesis of α-amino acids as they are valuable compounds by themselves and they
are often key intermediates in the field of organic synthesis. In this aspect, as it is
described in Chapter 1 of this publication, the reaction employs three components:
amine 4.102, boronic acid or boronic acid ester 4.109 and glyoxylic acid 4.108
(Scheme 4.27).
320
R
1
H
N
H
O
O
OH
R
3
B(OR)
2
R
1
N
R
3
OH
O
R
2
R
2
4.102 4.108 4.109 4.110

Scheme 4.27 α-Amino Acid Synthesis via Petasis Reaction
As a result, in one step from simple starting materials many highly diversified and
functionalized α-amino acids 4.110 can be prepared.
Although a plethora of amines have been explored in the three component
condensation we have focused on employing aniline and its derivatives with
particular attention on 2-amino aryl ketones and aldehydes. Scheme 4.28 illustrates
the use of anilines 4.111 with styryl boronic acid 4.112 for the synthesis of α,β-
unsaturated α-anilino amino acid 4.113. In the course of our research we studied
the solvent effect on the reaction. It turned out the best solvent for the
transformation is acetonitrile. The reaction takes place quickly (from few minutes
to 12 hours depending on starting materials) at room temperature. In addition, the
only side product of the reaction- boric acid is not soluble in acetonitrile and its
precipitation drives the reaction to completion.
NH
H
O
O
OH
N
HO
O
R
2
MeCN
rt
R
1
R
1
R
2
B(OH)
2
Ph
4.108 4.112 4.111 4.113

Scheme 4.28 Synthesis of α-Anilino Amino Acids via Petasis Reaction with
Styryl Boronic Acid
321
The use of protic polar solvents like ethanol or methanol resulted in much longer
reaction times and lower yields. Table 4.4 summarizes our findings. Both electron
donating and electron withdrawing anilines participate readily in the reaction. The
yields however are slightly lower in the case of electron withdrawing groups.
Primary as well as secondary anilines (Entry 8) were employed in the reaction with
good results.
Table 4.4 α-Anilino Amino Acids via Petasis Reaction with Styryl Boronic
Acid
Entry Aniline Product Yield [%]
1
Br
NH
2
F

4.114
Br
H
N
CO
2
H
Ph F

4.115
60
2
Cl
NH
2
4.116
Cl
H
N
CO
2
H
Ph

4.117
73
3
NH
2
NO
2

4.118
H
N
CO
2
H
Ph
NO
2

4.119
52

322
Table 4.4 Cont.
Entry Aniline Product Yield [%]
4
NH
2
CN

4.120
H
N
CO
2
H
Ph
CN

4.121
99
5
NH
2
OMe

4.122
H
N
CO
2
H
Ph MeO

4.123
74
6
NH
2
4.24
H
N
CO
2
H
Ph

4.124
74
7
NH
2
H
3
C

4.125
H
N
CO
2
H
Ph
H
3
C

4.126
80
8 N
H
4.127
N
HO
2
C Ph

4.128
95
9
NH
2
OH
O

4.129
H
N
CO
2
H
Ph
OH O

4.130
89
323
Following a similar protocol we investigated the use of a variety of boronic
acids in the α- anilino carboxylic acids and their derivatives syntheses (Scheme
4.29). Table 5 illustrates the results.
NH
H
O
O
OH
R
3
B(OR)
2
N
R
3
HO
O
R
2
MeCN
rt
R
1
R
1
R
2
4.108 4.111 4.109 4.131

Scheme 4.29 Preparation of α-Anilino Carboxylic Acids via Petasis Reaction
with Boronic Acids
Table 4.5 α-Anilino Carboxylic Acids via Petasis Reaction with Boronic Acids
Entry Boronic Acid Aniline Product
Yield
[%]
1
B(OH)
2
MeO
4.132
OMe
O
NH
2
4.133
OMe
O
NH
HO
2
C
OMe
4.134
97
2
S
B(OH)
2

4.135
OMe
O
NH
2
4.133
OMe
O
NH
HO
2
C
S

4.136
63
324
Table 4.5 Cont.
Entry Boronic Acid Aniline Product
Yield
[%]
3
S
B(OH)
2

4.132
NH
2
O
NH
2
4.137
NH
2
O
NH
HO
2
C
S

4.138
89
4
B(OH)
2
MeO
4.132
NH
2
O
NH
2
4.137
NH
2
O
NH
HO
2
C
OMe
4.139
84
5
B(OH)
2
MeO
4.132
HN
O H
2
N
OMe
4.
N
H
O
NH
HO
2
C
OMe
OMe

4.140
74

325
Table 4.5 Cont.
Entry Boronic Acid Aniline Product
Yield
[%]
6
B(OH)
2
MeO
4.132
O
NH
2
O
NMe
2
4.
O
NH
HO
2
C
OMe
O
NMe
2

4.141
65
7
B(OH)
2
MeO
4.132
O H
2
N
O
N
NO
2
O
4.107
O
NH
HO
2
C
OMe
O
N O
2
N
O

4.142
76

In the next step of our research we explored the use of 2-amino-5-chloro-
phenyl)-phenyl-methanone 4.143 in the Petasis reaction with a variety of boronic
acid or boronic acid esters as shown in Scheme 4.30.
Cl
O
Ph
NH
HO
2
C R
3
H
O
O
OH
R
3
B(OR)
2
4.143 4.108 4.109
MeCN
rt
Cl
O
Ph
NH
2
4.144

Scheme 4.30 Synthesis of α-Amino Acids via Petasis Reaction with (2-Amino-
5-Chloro-Phenyl)-Phenyl-Methanone
326
Table 4.6 summarizes the results. The reactions were performed in acetonitrile and
at room temperature.
Table 4.6 α-Amino Acids from (2-Amino-5-Chloro-Phenyl)-Phenyl-Methanone
Entry Boronic Acid Product Yield [%]
1
B(OH)
2
MeO
4.132
Cl
O
Ph
NH
HO
2
C
OMe
4.145
96
2
S
B(OH)
2

4.146
O
Ph
NH
HO
2
C
S
Cl

4.147
86
3
O
B(OH)
2

4.148
O
Ph
NH
HO
2
C
O
Cl

4.149
58

327
Table 4.6 Cont.
Entry Boronic Acid Product Yield [%]
4
N
Boc
B(OH)
2

4.150
O
Ph
NH
HO
2
C
Boc
N
Cl

4.151
50
5
N
Boc
B(OH)
2

4.152
Ph
O
NH
HO
2
C
Cl
Boc
N

4.153
86
6
O
B(OH)
2

4.154
O
Ph
NH
HO
2
C
O
Cl

4.155
83

328
Table 4.6 Cont.
Entry Boronic Acid Product Yield [%]
7
S
B(OH)
2

4.135
O
Ph
NH
HO
2
C
S
Cl

4.156
97
8
B(OH)
2
Br
4.157
Ph
O
NH
HO
2
C
Cl
Br
4.158
82
9
B
O
O

4.159
Ph
O
NH
HO
2
C
Cl

4.160
62
10
B(OH)
2

4.112
Ph
O
NH
HO
2
C
Ph
Cl

4.161
96
329
Table 4.6 Cont.
Entry Boronic Acid Product Yield [%]
11
B(OH)
2
MeO
4.132
Cl
O
Ph
NH
MeO
2
C
OMe
4.162
78

The reaction times vary from 1 hour to 12 hours depending on starting materials.
The yields of the α-amino acids differ depending on the boronic acid or ester used.
Subsequently, we investigated a variety of 2-amino aryl ketones in the three
component reaction with p-methoxyphenyl boronic acid 4.132 as illustrated in
Scheme 4.31 and Table 4.7.
O
R
1
NH
HO
2
C
H
O
O
OH
4.163 4.108 4.132
MeCN
rt
O
R
1
NH
2
4.164
R
2
R
2
B(OH)
2
MeO
OMe

Scheme 4.31 Synthesis of α-Amino Acids via Petasis Reaction with
p-Methoxyphenyl Boronic Acid

330
Table 4.7 α-Amino Acids via Petasis Reaction with p-Methoxyphenyl Boronic
Acid
Entry Amine Product Yield [%]
1
Cl
O
CF
3
NH
2
4.67
Cl
O
CF
3
NH
HO
2
C
OMe
4.165
84
2
O
CH
3
NH
2
4.166
O
CH
3
NH
HO
2
C
OMe
4.167
98
3
O
NH
2
Cl OH
CH
3

4.71
O
NH
HO
2
C
OMe
Cl OH
CH
3

4.168
87

331
Table 4.7 Cont.
Entry Amine Product Yield [%]
4
H
O
NH
2
Cl

4.169
H
O
NH
HO
2
C
OMe
Cl

4.170
89
5
NH
2
O

4.93
NH
O
CO
2
H
MeO

4.171
61
6
NH
2
O

4.96
NH
CO
2
H
MeO
O

4.172
76
7
O
NH
2
4.82
O
NH
HO
2
C
OMe
4.173
94
332
Table 4.7 Cont.
Entry Amine Product Yield [%]
8 CH
2
CF
3
O
NH
2
4.78
CH
2
CF
3
O
NH
HO
2
C
OMe
4.174
94
9
O
NH
2
4.80
O
NH
HO
2
C
OMe
4.175
74
10
O
Ph
NH
2
4.176
O
Ph
NH
HO
2
C
OMe
4.177
85

Next, we explored a variety of 2-amino aryl ketones with a variety of
boronic acids to form α-amino acids as shown in Scheme 4.32 and Table 4.8.
333
O
R
1
NH
HO
2
C R
3
H
O
O
OH
R
3
B(OR)
2
4.163 4.108 4.109
MeCN
rt
O
R
1
NH
2
4.178
R
2
R
2

Scheme 4.32 α-Amino Acids via Petasis Reaction
Table 4.8 Synthesis α-Amino Acids via Petasis Reaction
Entry Boronic Acid Aniline Product
Yield
[%]
1
N
Boc
B(OH)
2

4.150
O
CH
3
NH
2
4.166
O
CH
3
NH
HO
2
C
Boc
N

4.179
67
2
O
B(OH)
2
4.154
O
CH
3
NH
2
4.166
O
CH
3
NH
HO
2
C
O

4.180
85

334
Table 4.8 Cont.
Entry Boronic Acid Aniline Product
Yield
[%]
3
O
B(OH)
2
4.154
CF
3
O
NH
2
Cl

4.67
CF
3
O
NH
HO
2
C
Cl
O

4.181
92
4
CH
3
B(OH)
2
CH
3
4.182
O
CH
3
NH
2
4.166
CH
3
O
NH
HO
2
C
CH
3
CH
3
4.183
71
5
O
B(OH)
2
4.154
CF
2
H
O
NH
2
Cl
4.69
CF
2
H
O
NH
HO
2
C
Cl
O

4.184
75

335
Table 4.8 Cont.
Entry Boronic Acid Aniline Product
Yield
[%]
6
S
B(OH)
2

4.135
O
CH
3
NH
2
4.166
O
CH
3
NH
HO
2
C
S

4.185
77
7
B(OH)
2
4.112
NH O
NH
2
OMe

4.107
N
H
O
NH
HO
2
C
Ph
OMe

4.186
75
8
S
B(OH)
2

4.135
O
O
NH
2

4.187
O
O
N
H
CO
2
H
S
4.188
54

Finally we have utilized secondary anilines in the synthesis of α-amino acids
(Scheme 4.33, Table 4.9).
336
O
R
1
N
HO
2
C
H
O
O
OH
4.189 4.108 4.132
MeCN
rt
O
R
1
NH
4.190
R
2
R
2
B(OH)
2
MeO
OMe
R
3
R
3

Scheme 4.33 α-Amino Acids via Petasis Reaction with Secondary Anilines
Generally, the reaction with secondary anilines proceeds with good yield at room
temperature in acetonitrile as solvent.
Table 4.9 α-Amino Acids via Petasis Reaction with Secondary Anilines
Entry Amine Product Yield [%]
1
Cl
O
Ph
N
H
Ph

4.191
Cl
O
Ph
N
HO
2
C
OMe
Ph

4.192
40
2
O
Ph
NH
OMe
4.193
O
Ph
N
HO
2
C
OMe
OMe

4.194
73

337
The secondary anilines such as 4.191 or 4.193 can be prepared via alkylation
reaction with the corresponding halides or via the three component Petasis reaction
with paraformaldehyde and the corresponding boronic acids.
4.2.3 Novel Synthetic Approach to Indoles
To date, the developed methodologies for the synthesis of indoles exhibit
some limitations or disadvantages such as lengthy synthetic sequences, which
lower the overall yield, or lack of commercial availability of starting materials.
Even the most popular and widely used synthesis of indoles (Fischer’s approach)
utilizes cancer-suspect agent phenylhydrazines as one of the starting materials and
the reaction conditions are usually strongly acidic and very corrosive. Traditionally,
scientists have been mostly focused on improving and modifying the existing
strategies. This could be a reason for transition metal catalyzed reactions being
recently very popular as they can tolerate a wide range of functional groups. On the
other hand, the use of transition metals can be expensive or problematic due to their
water and oxygen sensitivity, toxicity (tin used for Stille coupling), solubility
difficulties and problems of separation from the product.
229

In our lab, following the philosophy of developing new facile synthetic
methodologies we have discovered a novel approach to the synthesis of indoles.
The idea behind the approach is quite straightforward. The newly created indole

229
Mukai, C.; Takahashi, Y. Org. Lett., 2005, 7, 26, 5793.
338
methodology amplifies the Petasis three component reaction by exploiting the
readily available 2-keto-α-anilino carboxylic acid building blocks.
N
4.195
O
R
1
R
3
HO
O
N
4.198
R
1
R
3
R
2
R
2
N
4.196
O
R
1
R
2
R
3
O
N
R
3
R
2
O
R
1
O
4.197
- CO
2

Scheme 4.34 Novel Synthetic Approach to Indoles
We proposed that α-anilino carboxylic acids such as 4.195 shown in Scheme 4.34
can be great (arylamino)ketene precursors 4.196, generated in situ, which can
undergo an intramolecular [2+2] cycloaddition reaction with the carbonyl moiety in
order to form the polycyclic β-lactone intermediate 4.197. This intermediate can
aromatize to indole 4.198 upon losing carbon dioxide. The loss of carbon dioxide
can be spontaneous or induced by heat. Spontaneous decarboxylation readily takes
place due to the strains in the system and formation of the extended aromatic
system of indole. The example of unprompted decarboxylation of strained lactones
is already known in the literature in the case of benzofuran synthesis.
230

The crucial step of the proposed methodology however is the in situ
formation of (arylamino)-ketene intermediate 4.196 from the corresponding α-
amino acid followed by [2+2] cycloaddition to the carbonyl group. In favor of the

230
Brady, W. T.; Giang, Y. F. J. Org. Chem., 1986, 51, 2145.
339
cycloaddition process is the proximity of the two reacting functional groups, ketene
and carbonyl, which was postulated to facilitate the intramolecular cyclization.
Amino-ketenes are known in the literature and have already found
applications in stereoselective [2+2] cycloadditions.
231
Brady and coworkers have
previously utilized them along with cycloalkenes for the intermolecular synthesis of
bicyclocyclobutanones.
232
They exploited (alkylarylamino)-ketenes in the
intermolecular synthesis of β-lactams as well. They reported that (alkylarylamino)-
ketenes can be generated in situ at room temperature from N-alkyl-N-aryl glycine
and p-toluenesulfonyl chloride in the presence of triethylamine. As a result a mixed
anhydride forms which eliminates p-toluenesulfonic acid to give the amino-
ketene.
233
To date numerous methods for the generation of ketenes have been
developed.
234
Most of them can be applied for the synthesis of aminoketenes as
well from corresponding precursors. The methods include base-promoted
elimination of acid chlorides
235
, the mentioned earlier use of tosylate as the leaving
group
236
and other common carboxylic acid group activators used for β-lactam
synthesis
237,238
.

231
Tidwell, T. T. Ketenes. Willey, New Jersey, 2006.
232
Brady, W. T.; Gu, Y. Q. J. Org. Chem., 1989, 54, 2834.
233
Brady, W. T.; Gu, Y. Q. J. Org. Chem., 1989, 54, 2838.
234
Snider, B. B.; Chem. Rev., 1988, 88, 793.
235
Sauer, J. C. J. Am. Chem. Soc., 1947, 69, 2444.
236
Brady, W. T.; Marchand, A. P.; Giang, Y. F.; Wu, A.-H. Synthesis 1987, 395.
237
Mukaiyama, T. Angew. Chem. Int. Ed. Eng. 1979, 18, 707.
340
To realize our conceptually new approach for the indole synthesis we
explored the use of a few carboxylic acid group activating reagents according to
Scheme 4.35. The results are presented in Table 4.10.
N
R
1
R
3
R
6
R
1
O
N
R
3
O
R
4
Acid Activator R
2
R
2
R
7
R
6
R
5
OH
R
7
R
4
R
5
4.199 4.200

Scheme 4.35 Investigation of Acid Activator
We applied Brady’s conditions for the generation of nitrogen-substituted
ketenes at first. As a solvent for the reaction toluene was used as an apolar, non-
nucleophilic solvent which provides minimum side reaction possibilities.
Table 4.10 Investigation of the α-Anilino Carboxylic Acid Activation
Entry
Substituents of
amino acid 4.11
Acid
activator
Reaction
Time
Reaction
conditions
Yield
239

[%]
1
R
1
=Ph,
R
2
=R
4
=R
5
=R
7
=H,
R
3
=pMeOPh, R
6
=Cl
TsCl, Et
3
N 3 hours
Toluene,
RT
72
2
R
1
=Ph,
R
2
=R
4
=R
5
=R
7
=H,
R
3
=pMeOPh, R
6
=Cl
TsCl, Et
3
N 30 min
Toluene,
90
o
C
97
3
R
1
=Ph,
R
2
=R
4
=R
5
=R
7
=H,
R
3
=pMeOPh, R
6
=Cl
TsCl, Et
3
N 7 hours
CH
3
CN,
RT
36

238
Georg, G. I.; Mashawa, P. M.; Guan, X. Tetrahedron Lett. 1991, 32, 581.
239
Isolated Yield
341
Table 4.10 Cont.

Entry
Substituents of
amino acid 4.11
Acid
activator
Reaction
Time
Reaction
conditions
Yield
240

[%]
4
R
1
=Ph,
R
2
=R
4
=R
5
=R
7
=H,
R
3
=pMeOPh, R
6
=Cl
NsCl, Et
3
N 3 hours
Toluene,
RT
55
5
R
1
=Ph,
R
2
=R
4
=R
5
=R
7
=H,
R
3
=pMeOPh, R
6
=Cl
Mukaiyama’s
Reagent,
Et
3
N
3 hours
Toluene,
RT
44
6
R
1
=Me,
R
2
=R
4
=R
5
=R
6
=R
7
=H,
R
3
=(N-Boc)-indolyl
Mukaiyama’s
Reagent,
Et
3
N
3 hours
Toluene,
RT
52
7
R
1
=Ph,
R
2
=R
4
=R
5
=R
7
=H,
R
3
=pMeOPh, R
6
=Cl
Ac
2
O, Et
3
N
20-30
min
Neat,
90
o
C
R
2
=Ac,
84
R
2
=H,
10
8
R
1
=Ph,
R
2
=R
4
=R
5
=R
7
=H,
R
3
=pMeOPh, R
6
=Cl
TFAA, Et
3
N 20 min
Neat,
0
o
C-RT
Basic
work-up
R
2
=H,
66

It turned out that p-toluenesulfonyl chloride in the presence of triethylamine
in toluene at 90
o
C is one of the most effective conditions (Entry 2). Nevertheless,
the reaction proceeds at room temperature and the indole product can be isolated in
high yields as well (Entry 1). The reaction in acetonitrile was not as productive as
in toluene, the yields were lower and the time needed for the reaction to reach
completion was significantly longer (Entry 3).

240
Isolated Yield
342
Surprisingly nosyl chloride (Entry 4) was not as an effective activator as p-
toluenesulfonyl chloride. We investigated the use of Mukaiyama’s reagent in the
reaction as well (Entry 5 and 6). As a result the reaction proceeds with moderate
yields. Next we examined acetic acid anhydride (Ac
2
O) and trifluoroacetic acid
anhydride (TFAA) in the indole synthesis (Entry 7 and 8). When using acetic acid
anhydride in some cases we obtained a mixture of products (N-acetylated and N-
non-acetylated indoles). TFAA was less effective in terms of yield however only
one product was obtained. The basic work-up conditions were applied to cleave in
situ the trifluoroacetyl group, therefore the product obtained was the NH-indole
derivative. The use of TFAA required lower reaction temperatures to be employed
(from -40
o
C to 0
o
C).
Consequently we chose to use p-toluenesulfonyl chloride (TsCl) with
triethylamine in toluene at room temperature to generate a series of 2,3-
disubstituted indoles as presented in Scheme 4.36 and Table 4.11.
NH
4.201
O
R
1
R
3
HO
O
N
H
4.202
R
1
R
3
Et
3
N
toluene
5 hr, rt
TsCl

Scheme 4.36 2,3-Disubstitutedindole Synthesis Using p-Toluenesulfonyl
Chloride

343
Table 4.11 Indole Synthesis via p-Toluenesulfonyl Chloride Activation
Entry Product Yield [%]
1
N
H
CH
3
OMe

4.203
46
2
N
H
Ph
OMe
Cl

4.204
97
3
N
H
Ph
OMe

4.205
99
4
N
H
CH
3
Boc
N

4.206
52
5
N
H
Ph
Boc
N
Cl

4.207
83

344
Table 4.12 Cont.
Entry Product Yield [%]
6
N
H
Ph
S
Cl

4.208
83
7
N
H
OMe
NMe
2
O

4.209
55
8
N
H
Ph
Boc
N
Cl

4.210
73
9
N
H
OMe

4.211
63

As shown in Table 4.11 the yields of the reactions vary from moderate to excellent.
Generally, the purity of the α-amino acid used in the synthesis has a big influence
on the reaction yield.
345
Interestingly, when the same reaction conditions were employed for [4-
chloro-2-(2,2,2-trifluoro-acetyl)-phenylamino]-(4-methoxy-phenyl)-acetic acid
4.198 no indole formation was observed (Scheme 4.37).
NH
4.212
O
CF
3
HO
O
Et
3
N
toluene
12 hr, rt
Cl
OMe
NR
TsCl

Scheme 4.37
We decided to investigate the use of acetic anhydride in the presence of
triethylamine in neat conditions (Scheme 4.38). As a result compound 4.212 was
successfully synthesized utilizing these conditions. The results presented in Table
4.12 show examples that only one product, N-acetylated indole, was produced.
NH
4.213
O
R
1
R
3
HO
O
N
4.214
R
1
R
3
Et
3
N
Ac
2
O
∆
H
3
C
O

Scheme 4.38 1,2,3-Trisubstitutedindole Synthesis via Acetic Acid Activation

346
Table 4.12 Indole Synthesis via Acetic Acid Activation
Entry Product Yield [%]
1
N
H
Cl
OMe
CH
3
O
4.215
99
2
N
CF
3
OMe
Cl
CH
3
O
4.216
84
3
N
Ph
Ph
Cl
CH
3
O
4.217
90
4
N
Ph
Cl
CH
3
O
4.218
46
5
N
NHAc
OMe
CH
3
O
4.219
79
347
Table 4.12 Cont.
Entry Product Yield [%]
6
N
CF
2
H
Cl
CH
3
O
O

4.220
42
7
N
CH
2
CF
3
OMe
CH
3
O
4.221
50
8
N
OMe
Cl
CH
3
O
OAc
H
3
C

4.222
39
9
N
O
H
3
C

4.223
46

348
Table 4.12 Cont.
Entry Product Yield [%]
10
O
N
S H
3
C
O

4.224
33

The yields of the reaction vary from moderate to excellent. The purity of the amino
acid is probably an issue as well. As it is mentioned above not all of the α-anilino
carboxylic acids converted cleanly into one N-acetylated indole product (Scheme
4.39). There are examples illustrated in the Table 4.13 that the reaction produced
additionally NH-indole product. It turned out that even increasing the reaction time
does not have any impact on the ratio of the isolated products.
NH
4.213
O
R
1
R
3
HO
O
N
4.214
R
1
R
3
Et
3
N
Ac
2
O
∆
H
3
C
O
N
H
R
1
R
3
4.225

Scheme 4.39 Indole Synthesis via Acetic Acid Activation
349
Obviously the steric effect around of the center of the α-amino acid has an
influence on the ratio of the products. When bulkier benzofuryl substituent (Entry
3) was present the yield of N-acetylated indole dropped significantly.
Table 4.13 Synthesis of Indoles with Acetic Acid Anhydride Activation
Entry Product I Product II Ratio I:II
1
N
Ph
OMe
Cl
CH
3
O
4.226
N
H
Ph
OMe
Cl

4.205
8.4:1
2 N
OMe
CH
3
O
4.227
N
H
OMe

4.228
6:1
3
N
CF
3
Cl
CH
3
O
O

4.229
N
H
CF
3
Cl
O

4.230
0.5:1

The use of acetic anhydride was reported by Berney for the intramolecular
formation of pyrrole derivatives from potassium glycine salt. Unfortunately, the
350
author did not study the mechanism.
241
Later on, the mechanism was presented by
Gabbutt and coworkers and it favors a formation of aminoketene from mixed
anhydride but through a complex mechanism (Scheme 4.40).
242

N
O
O
N
H
3
C
R
O
O
O
R
H
3
C
O
N
O
H
3
C
O
R
O
N
O
R
O
O
H
3
C
N
R
O
H
3
C
NH
R
O
OH
O
Ac
2
O, Et
3
N
∆
- CO
2
4.233 4.231 4.232
4.236 4.235
4.234

Scheme 4.40 Intramolecular Pyrrole Synthesis via Münchnone Intermediate
The authors explained that under those conditions acylation of NH-enamino acid
takes place, than the ketene is generated followed by possible formation of a
münchnone intermediate 4.233 which might facilitate formation of a lactone 4.234
and then decarboxylation. As an obvious result only N-acetyl pyrrole derivatives
can be obtained. It is worth mentioning that the authors only studied acetic acid

241
Berney, D. Helvetica Chimica Acta, 1982, 65, 1694.
242
Gabbutt, C. D.; Hepworth, J. D.; Heron, B. H.; Pugh, S. L. J. Chem. Soc. Perkin
Trans 1, 2002, 2799.
351
anhydride promoted cyclization of secondary NH-enamino acid such as compound
4.231.
This mechanism cannot operate in our indole synthesis because we have
demonstrated examples where we obtained a mixture of the products N-acylated
and non-acetylated. The mechanism presented in Scheme 4.40 does not include
possibility of the formation of non-acetylated product. Secondly, we have been able
to synthesize indoles from tertiary α-amino acids in moderate yields (51%)
(Scheme 4.41) and this would not be possible with the mechanism going through a
münchnone as the intermediate.
N
Ph
OMe
Cl
Et
3
N
Ac
2
O
∆
4.237
O
Ph
N
HO
2
C
OMe
Cl
4.192

Scheme 4.41 1,2,3-Trisubstituted Indole Synthesis from Tertiary α-Anilino
Carboxylic Acids
Based on our new approach we performed a 1g synthesis of 4.221 in order
to evaluate scaling up properties of reaction as shown in Scheme 4.42. The three
step synthesis was carried out in overall 26% yield starting from aniline 4.24.
352
NH
2
BCl
3
, GaCl
3
O
NH
2
CF
3
NCCH
2
CF
3
N
CF
3
CH
3
O
OMe
4.24 4.77
ClCH
2
CH
2
Cl
reflux
4.78
H
O
O
OH
4.108 4.132
1) MeCN, rt
B(OH)
2
MeO
2) Ac
2
O, Et
3
N
4.221

Scheme 4.42 Three Step Synthesis of 4.221
4.3 Conclusion
Overall, the novel synthesis of indoles proved to be highly efficient. The
wide range of boronic acids and 2-amino aryl ketones allows for the introduction of
a vast amount of structural diversity. This method could be utilized for
combinatorial library design as the reaction conditions are mild and rapid. This
method is also applicable towards the syntheses of generic drug. This methodology
offers quick access to a wide range of structurally novel 2,3-disubstituted indoles.
Additionally, it has potential to be used for the synthesis of pharmaceutically active
ingredients.

353
4.4 Experimental
4.4.1 General Information
All reagents and commonly available starting materials were purchased from
commercial sources. Tetrahydrofuran was freshly distilled from sodium-
benzophenone, dichloromethane from CaH
2
and anhydrous dimethylformamide,
diethyl ether, toluene, benzene, ethanol, and methanol were purchased from
commercial sources.
1
H,
19
F,
13
C NMR spectra were recorded on a Varian Mercury
400 and a Bruker AC-250 using residual
1
H or
13
C signals of deuterated solvents as
internal standards.
11
B NMR spectra were performed on a Bruker 500 MHz using
BF
3
•Et
2
O as an external standard. Thin layer chromatography was performed using
glass precoated TLC plates (silica gel 60 F
254
). Flash chromatography was
performed using Silica Gel 60, particle size range between 0.040-0.063 mm (230-
400 Mesh).

354
4.4.2 Synthesis and Physical Properties
1-(2-Amino-phenyl)-3,3,3-trifluoro-propan-1-one
(4.78)
To a stirred solution of BCl
3
(10 mmol, 10 ml, 1M) in
dichloroethane at 0
o
C was added aniline (4.24) (10
mmol, 0.91 ml), followed by addition of 3,3,3-trifluoropropionitrile (4.77) (10
mmol, 0.852 ml) and gallium trichloride (10 mmol, 1.76 g). The reaction mixture
was allowed to warm up to room temperature and then brought to reflux for another
18 hours. After cooling, 20 ml of water was added and the reaction was refluxed for
additional hour. The reaction mixture was neutralized with base (1N NaOH) to pH
being slightly basic and extracted with dichloromethane (3x30ml). The combined
organic layers were dried using Na
2
SO
4
and evaporated under reduced pressure.
The residue was purified via flash chromatography (15% ethyl acetate: hexanes) in
order to isolate the desired product in good yield (1.12 g, 55%).
1
H NMR (400 MHz, CDCl
3
): δ 7.57 (d, J=8.2 Hz, 1H), 7.34 (t, J=7.0 Hz, 1H), 6.69
(t, J=8.2 Hz, 2H), 6.40 (broad s, 2H), 3.79 (q, J=10.3 Hz, 2H).
19
F NMR (62.5
MHz, CDCl
3
): δ -62.0.  13
C NMR (100 MHz, CDCl
3
): δ 191.4, 151.2, 135.4, 130.9,
128.6 (q), 117.6, 116.8, 116.0, 42.5 (q).

O
NH
2
CF
3
355
(2-Amino-phenyl)-cyclopropyl-methanone (4.80)
Prepared analogously to compound (4.78) from aniline
(4.24) and cyclopropanecarbonitrile (4.79) as a yellow
liquid in good yield (76%).
1
H NMR (400 MHz, CDCl
3
): δ 7.99 (d, J=8.1Hz, 1H), 7.29 (t, J= 8.7Hz, 1H),
6.74-6.67 (m, 2H), 6.19 (broad s, 2H), 2.70-2.64 (m, 1H), 1.23-1.19 (m, 2H), 1.02-
0.97 (m, 2H).
13
C NMR (100 MHz, CDCl
3
): δ 202.0, 149.8, 134.0, 131.2, 119.2,
117.2, 115.9, 17.3, 10.8.

(4-Fluoro-phenyl)-(2-isopropylamino-phenyl)-
methanone (4.90)
Prepared analogously to compound (4.78) from N-
isopropylaniline (4.88) and 4-fluoro-benzonitrile
(4.89) in good yield (51%).
1
H NMR (400 MHz, CDCl
3
): δ 8.55 (broad s, 1H), 7.68-7.65 (m, 2H), 7.49-7.47
(m, 1H), 7.40 (t, J=7.2 Hz, 1H), 7.16 (t, J=9.2 Hz, 2H), 6.82 (d, J=7.7 Hz, 1H), 6.54
(t, J=6.8Hz, 1H), 3.87-3.79 (m, 1H), 1.35 (d, J=6.4 Hz, 6H).
19
F NMR (100 MHz,
CDCl
3
): δ -108.9.
13
C NMR (100 MHz, CDCl
3
): δ 197.7, 165.5, 163.0, 151.0,
136.7, 135.4, 135.0, 131.5, 116.7, 115.2, 115.0, 113.3, 112.1, 43.4, 22.8.

O
NH
2
O
NH F
356
(2-Amino-phenyl)-cyclohexyl-methanone (4.82)
Prepared analogously to compound (4.78) from
aniline (4.24) and cyclohexanecarbonitrile (4.81) in
good yield (75%).
1
H NMR (400 MHz, CDCl
3
): δ 7.76 (d, J=7.6 Hz,
1H), 7.24 (t, J=7.7 Hz, 1H), 6.67-6.63 (m, 2H), 6.38 (broad s, 2H), 3.31-3.26 (m,
1H), 1.90-1.25 (m, 11H).
13
C NMR (100 MHz, CDCl
3
): δ 206.4, 151.0, 134.0,
130.9, 117.6, 116.8, 115.6, 45.8, 29.1, 26.1, 26.0.

(2-Amino-phenyl)-pyridin-4-yl-methanone (4.84)
Prepared analogously to compound (4.78) from aniline
(4.24) and isonicotinonitrile (4.83) in good yield (75%).
1
H NMR (400 MHz, CDCl
3
): δ 8.66 (d, J= 5.7 Hz, 2H),
7.35 (d, J=5.7 Hz, 2H), 7.23 (t, J= 7.5 Hz, 2H), 6.65 (d, J=9.1 Hz, 1H), 6.50 (t, J=
7.0 Hz, 1H), 6.32 (broad s, 2H).
13
C NMR (100 MHz, CDCl
3
): δ 196.9, 151.6,
150.0, 147.3, 135.3, 134.4, 122.4, 117.2, 116.5, 115.6.

O
NH
2
O
N
NH
2
357
1-(2-Amino-phenyl)-3-chloro-propan-1-one (4.86)
Prepared analogously to compound (4.78) from
aniline (4.24) and 3-chloro-propionitrile (4.85) in
moderate to low yield (33%).
1
H NMR (400 MHz, CDCl
3
): δ 7.71 (d, J=7.2 Hz, 1H), 7.31 (t, J=7.9 Hz, 1H),
6.70-6.67 (m, 2H), 6.32 (broad s, 2H), 3.96-3.92 (m, 2H), 3.47-3.43 (m, 2H).
13
C
NMR (100 MHz, CDCl
3
): δ 198.5, 150.5, 134.7, 130.9, 117.4, 115.9, 41.6, 39.2.

2-(2-Amino-phenyl)-N,N-dimethyl-2-oxo-
acetamide (4.98)
A solution of isatin (4.97) (50 mmol, 7.36 g) and
aqueous dimethylamine (40%, 40ml) was refluxed for
10 min. The reaction was allowed to cool down to room temperature. The
precipitated yellow product was collected by filtration in good yield (6.15g, 64%).
1
H NMR (250 MHz, CDCl
3
): δ 7.36 (d, J=9.4 Hz, 1H), 7.29-7.21 (m, 1H), 6.65-
6.55 (m, 2H), 3.05 (s, 3H, Me), 2.91 (s, 3H, Me).
13
C NMR (62.5 MHz, CDCl
3
):
δ 194.2, 167.4, 151.6, 135.8, 133.0, 117.0, 116.2, 114.0, 37.1, 33.8.

O
NH
2
Cl
O
NMe
2
O
NH
2
358
1-(2-Amino-5-nitro-phenyl)-2-morpholin-
4-yl-ethane-1,2-dione (4.101)
A solution of 5-nitroisatin (4.99) (2.5 mmol,
480 mg) and morpholine (4.100) (6 mmol,
.523 ml) was refluxed for 20 min in 5ml of methanol. The reaction was allowed to
cool down to room temperature. The precipitated yellow solid was collected by
filtration in good yield (643 mg, 92%).
1
H NMR (400 MHz, DMSO-d
6
): δ 8.46 (broad s, 2H), 8.28 (d, J=2.4 Hz, 1H), 8.16
(dd, J=9.8 Hz, 1H), 6.99 (d, J=9.3 Hz, 1H), 3.74-3.63 (m, 4H), 3.57-3.50 (m, 2H),
3.41-3.31 (m, 2H).
13
C NMR (100 MHz, DMSO-d
6
): δ 192.7, 164.4, 156.8, 135.7,
130.9, 130.5, 118.3, 111.3, 66.7, 66.5, 46.3, 41.7. #651

8-Amino-3,4-dihydro-2H-naphthalen-1-one (4.96)
To acetic anhydride (5 ml) in anhydrous ethanol (30 ml) at
0
o
C 5,6,7,8-tetrahydro-naphthalen-1-ylamine (4.94) (18
mmol, 2.5 ml) was added. The mixture was stirred at room
temperature for 18 hours. The solvent was removed under reduced pressure to yield
N-(5,6,7,8-tetrahydro-naphthalen-1-yl)-acetamide as a white solid (3.4g crude). The
product was used without any further purification.
To a solution of crude N-(5,6,7,8-tetrahydro-naphthalen-1-yl)-acetamide (3.4 g, 18
mmol) in acetone (50 ml) 15% aqueous MgSO
4
(3g in 20ml) was added followed
by treatment with solid KMnO
4
at room temperature. The reaction mixture was
NH
2
O
O
N
O
NH
2
O
2
N
O
359
allowed to stirr at room temperature overnight. The brown mixture was filtered
through Celite and washed with chloroform and water. The filtrate was extracted
several times with chloroform. Organic layers were combined and washed with
brine, dried and concentrated to give crude N-(8-oxo-5,6,7,8-tetrahydro-
naphthalen-1-yl)-acetamide (4.95). The product was used for the next step without
any purification.
The crude N-(8-oxo-5,6,7,8-tetrahydro-naphthalen-1-yl)-acetamide (4.95) was
suspended in 10ml of 6N HCl and the reaction mixture was refluxed for 5 hours.
After cooling to room temperature 2N NaOH was added in small portions until the
pH of the mixture reached pH=8. The aqueous layer was extracted with ethyl
acetate and organic layers were combined, washed with brine, dried with Na
2
SO
4
,
filtered and concentrated. The residue was purified by flash chromatography (10%
ethyl acetate: hexanes) to give 8-amino-3,4-dihydro-2H-naphthalen-1-one (4.96) in
good yield (1.4g, 48% over three steps).
1
H NMR (400 MHz, CDCl
3
): δ 7.16 (t, J = 7.1 Hz, 1H), 6.50-6.43 (m, 2H), 6.45
(broad s, 2H, NH
2
), 2.88 (t, J = 6.7 Hz, 2H), 2.64 (t, J = 5.7 Hz, 2H), 2.04 (m, 2H).
(
13
C NMR (100 MHz, CDCl
3
): δ 201.3, 151.3, 146.0, 134.3, 115.8, 115.4, 114.7,
40.3, 30.9, 22.9.

360
7-Amino-indan-1-one (4.93)
Prepared analogously to compound (4.10) from indan-4-
ylamine (4.91) in high yield (2.5g, 93 %).
1
H NMR (250 MHz, CDCl
3
): δ 7.31 (t, J = 7.4 Hz, 1H),
6.95 (d, J = 7.5 Hz, 1H), 6.48 (d, J = 8.3 Hz, 1H), 5.57 (broad s, 2H), 3.05 (m, 2H),
2.67 (m, 2H).
13
C NMR (62.5 MHz, CDCl
3
): δ 208.1, 156.1, 147.5, 136.2, 113.7,
112.0, 36.2, 25.5.

2,2,2-Trifluoro-1-morpholin-4-yl-ethanone (4.66)
To a solution of morpholine (4.100) (30 mmol, 2.62 ml) in
minimal volume of diethyl ether trifluoroacetic acid
anhydride was added dropwise while the reaction flask was chilled in an ice bath.
After 3 hours, the reaction mixture was diluted with ethyl acetate, extracted with
1N HCl. The organic layers were washed with sodium carbonate and brine, dried
over sodium sulfate and volatiles removed under reduced pressure. The residue was
purified on silica (50% ethyl acetate: hexanes) to isolate colorless liquid in good
yield (2.15 g, 78%).
1
H NMR (400 MHz, CDCl
3
): δ 3.68 (m, 8H).
19
F NMR (376 MHz, CDCl
3
): δ -69.1.
13
C NMR (100 MHz, CDCl
3
): δ 155.6 q, 116.6 (q, J
C-F
= 297.7 Hz), 66.4, 46.3,
43.5.

NH
2 O
ON
O
CF
3
361
N-(4-Chloro-phenyl)-2,2-dimethyl-
propionamide (4.238)
To a biphasic solution of p-chloroaniline (4.239)
(15 mmol, 1.92 g) in DCM and 10% aqueous
solution of sodium carbonate, pivaloyl chloride
was added dropwise. The reaction mixture was stirred intensively for 30 min. the
reaction progress was followed by TLC (10 % ethyl acetate: hexanes). After
reaction was completed, organic layer was separated and volatiles removed under
reduced pressure to obtain a white solid in excellent yield (3.1g, 98%).
1
H NMR (400 MHz, CDCl
3
): δ 7.50 (m, 2H), 7.28 (m, 2H), 1.33 (s, 9H).
13
C NMR
(100 MHz, CDCl
3
): δ 176.7, 136.6, 129.1, 128.9, 121.3, 39.6, 27.6.

1-(2-Amino-5-chloro-phenyl)-2,2,2-trifluoro-
ethanone (4.67)
To a solution of N-(4-chloro-phenyl)-2,2-dimethyl-
propionamide (4.238) (14.2 mmol, 3g) in dry THF,
in a flame dried flask, was added 22 ml of a 1.6 M solution of n-butyl lithium in
hexanes under argon atmosphere at -50
o
C. The reaction mixture was stood (no
stirring) for 2 hours at 0
o
C during which time a white precipitate formed. The
mixture was cooled to -40
o
C and a solution of 2,2,2-trifluoro-1-morpholin-4-yl-
ethanone (4.66) (17 mmol, 3.2 g) in 10 ml of dry THF was added dropwise. After
stirring for 1 hour at this temperature, the reaction mixture was quenched with a
Cl
NH
O
Cl
NH
2
O
CF
3
362
saturated aqueous solution of ammonium chloride. The mixture was extracted with
dichloromethane (2x50ml), the organic layer was dried over anhydrous sodium
sulfate, and evaporated under reduced pressure. The crude residue was used for the
next step without further purification. The residue was dissolved in dioxane and 80
ml of 3 N HCl was added. The solution was refluxed for 12 hours. After cooling to
room temperature, the solution was treated with ammonia and a 1N solution of
sodium hydroxide until ph was basic and extracted with dichloromethane. The
organic layer was dried over anhydrous sodium sulfate and evaporated to yield a
crude product. Purification was performed using flash chromatography (8% ethyl
acetate: hexanes) to obtain a yellow solid in good yield (2.6 g, 82% yield).
1
H NMR (400 MHz, CDCl
3
): δ 7.72 (m, 1H), 7.35 (m, 1H), 6.71 (d, J = 9.1 Hz,
1H), 6.51 (broad s, 2H).
19
F NMR (376 MHz, CDCl
3
): δ -69.8.
13
C NMR (100
MHz, CDCl
3
): δ 180.3 (q), 151.5, 136.9, 130.1, 130.0, 120.9, 119.0, 116.7 (q, J
C-F
=
291.4 Hz), 111.4.

363
2,2-Difluoro-1-morpholin-4-yl-ethanone (4.68)
Prepared analogously to compound (4.66) in good
yield (4.1 g, 83%).
1
H NMR (400 MHz, CDCl
3
): δ 6.11 (t, J = 53.4 Hz,
1H), 3.71 (m, 4H), 3.63 (m, 4H).
19
F NMR (376 MHz, CDCl
3
): δ -121.5 (d).
13
C
NMR (100 MHz, CDCl
3
): δ 160.6 (t, J
C-F
= 28.1 Hz), 110.5 (t, J
C-F
= 244.9 Hz),
66.5, 66.4, 45.3, 42.6.

1-(2-Amino-5-chloro-phenyl)-2,2-difluoro-
ethanone (4.69)
Prepared analogously to compound (4.67) in good
yield (59%).
1
H NMR (400 MHz, CDCl
3
): δ 7.79 (d, J = 2 Hz, 1H), 7.32 (m, 1H), 6.70 (d, J =
9.0 Hz, 1H), 6.45 (broad s, 2H), 6.31 (t, J
H-F
= 53.2 Hz, 1H).
19
F NMR (376 MHz,
CDCl
3
): δ -120.6 (d).
13
C NMR (100 MHz, CDCl
3
): δ 187.4 (t, J
C-F
= 35.5 Hz),
150.8, 136.3, 130.0, 129.9, 129.8, 120.6, 118.9, 113.6, 111.1 (t, J
C-F
=256.1 Hz).

ON
O
CF
2
H
Cl
NH
2
O
CF
2
H
364
1-(2-Amino-5-chloro-phenyl)-4-hydroxy-
pentan-1-one (4.71)
To a solution of N-(4-chloro-phenyl)-2,2-
dimethyl-propionamide (4.238) (14.2 mmol, 3g)
in dry THF was added 22 ml of a 1.6 M solution
of n-butyl lithium in hexanes under argon atmosphere at -50
o
C. The reaction
mixture was stood for 2 hours at 0
o
C during which time a white precipitate formed.
The mixture was cooled to -40
o
C and solution of γ-valerolactone (4.240) (17 mmol,
1.6 ml) in 10 ml of dry THF was added dropwise. After stirring for 1 hour at this
temperature, the reaction mixture was quenched with saturated aqueous solution of
ammonium chloride. The mixture was extracted with dichloromethane (2x50ml),
the organic layer was dried over anhydrous sodium sulfate, and evaporated under
reduced pressure. The crude residue was used for the next step without further
purification. The residue was dissolved in dioxane and 80 ml of 3N solution of
hydrochloric acid was added. The solution was refluxed for 12 hours. After cooling
to room temperature, the solution was neutralized with 1N solution of sodium
hydroxide followed by extraction with dichloromethane. The organic layer was
dried over anhydrous sodium sulfate, evaporated to yield a crude product.
Purification was performed on silica gel (30% ethyl acetate: hexanes) to obtain
yellow solid in low yield (0.96 g, 29%).
1
H NMR (250 MHz, CDCl
3
): δ 7.73 (d, J = 2.4 Hz, 1H), 7.18 (dd, J = 8.8 Hz, 1H),
6.60 (d, J = 8.7 Hz, 1H), 6.25 (broad s, 2H), 3.92-3.81 (m, 1H), 3.10-3.04 (m, 2H),
O
OH
Cl
NH
2
365
1.89-1.81 (m, 2H), 1.24 (d, J = 6.2 Hz, 3H).
13
C NMR (250 MHz, CDCl
3
): δ 202.0,
148.8, 134.3, 130.3, 120.0, 118.8, 67.5, 35.5, 33.3, 23.8.

(2-Benzylamino-5-chloro-phenyl)-phenyl-
methanone (4.191)
To a solution of (2-amino-5-chloro-phenyl)-
phenyl-methanone (4.143) (5 mmol, 1.16 g) in
acetonitrile, cesium carbonate (5.5 mmol, 1.8
g) was added followed by addition of benzyl
bromide (4.241) (5.5 mmol, 0.65 ml). The reaction mixture was heated up to 60
o
C
and stirred at this temperature for 12 hours. The solvent was evaporated and the
residue was dissolved in a water/ethyl acetate mixture. The organic layer was
concentrated under reduced pressure and the residue was purified via flash
chromatography (5% ethyl acetate: hexanes) in order to obtain a yellow solid in
moderate yield (750 mg, 47%).
1
H NMR (400 MHz, CDCl
3
): δ 9.00 (broad s, 1H), 7.70-7.28 (m, 12H), 6.72 (d, J =
9.2 Hz, 1H), 4.52 (s, 2H).
13
C NMR (100 MHz, CDCl
3
): δ 198.4, 150.0, 138.1,
134.8, 134.1, 131.3, 129.1, 128.8, 128.6, 128.4, 128.3, 127.4, 127.1, 118.9, 118.3,
113.8, 47.1.

O
Ph
NH
Cl
366
2-(4-Bromo-3-fluoro-phenylamino)-4-
phenyl-but-3-enoic acid (4.115)
To a solution of 4-bromo-3-fluoro-
phenylamine (4.114) (1 mmol, 190 mg) and
glyoxylic acid monohydrate (4.108) (1
mmol, 92 mg) in 2 ml of acetonitrile, 1 mmol
of styryl boronic acid (148 mg) (4.112) was
added. The resulting reaction mixture was stirred at room temperature till TLC
indicated that starting materials disappeared. The resulting suspension was
concentrated under reduced pressure and the residue was purified via flash
chromatography (85% ethyl acetate: 10% methanol: 5% ammonia) to afford the
desired product as a yellow solid in good yield (210 mg, 60%).
1
H NMR (400 MHz, acetone-d
6
): δ 7.49 (d, J = 8.3 Hz, 2H), 7.39-7.27 (m, 4H),
6.89 (d, J = 15.8 Hz, 1H), 6.72 (dd, J = 11.4 Hz, 1H), 6.64 (dd, J = 9.2 Hz, 1H),
4.48 (dd, J = 16.0 Hz, 1H), 5.93 (broad s, 1H), 4.91 (d, J = 6.5 Hz, 1H).
13
C NMR
(62.5 MHz, acetone-d
6
): δ 171.8, 161.8, 149.1, 136.6, 133.6, 133.0, 129.0, 128.3,
126.9, 125.2, 111.32, 111.28, 101.6, 101.1, 58.3.

Br
NH
HO
2
C
F
367
2-(4-Chloro-phenylamino)-4-phenyl-but-3-
enoic acid (4.117)
Prepared analogously to compound (4.115) in
good yield (209 mg, 73%).
1
H NMR (400 MHz, acetone-d
6
): δ 7.48 (d,
J=8.1 Hz, 2H), 7.37 (t, J = 6.7 Hz, 2H), 7.29
(t, J = 7.4 Hz, 1H), 7.16 (d, J = 9.2 Hz, 2H), 6.90-6.80 (m, 3H), 6.47 (dd, J = 15.9
Hz, 2H), 5.88 (broad s, 1H), 4.86 (d, J = 5.5 Hz, 1H).
13
C NMR (62.5 MHz,
acetone-d
6
): δ 172.7, 147.1, 137.3, 133.4, 129.7, 129.6, 129.5, 128.7, 127.4, 126.1,
115.5, 59.0.

2-(2-Nitro-phenylamino)-4-phenyl-but-3-enoic
acid (4.119)
Prepared analogously to compound (4.115) in good
yield (52%).
1
H NMR (400 MHz, acetone-d
6
): δ 8.91 (broad s,
1H), 8.21 (d, J = 6.7 Hz, 1H), 7.58-7.51 (m, 3H),
7.39-7.29 (m, 3H), 7.05 (d, J = 8.0 Hz, 1H), 6.92 d, J = 15.8 Hz, 1H), 6.81 (t, J =
7.4 Hz, 1H), 6.56 (dd, J = 15.8 Hz, 1H), 5.83 (broad s, 1H), 5.23 (t, J = 5.9 Hz, 1H).
13
C NMR (62.5 MHz, acetone-d
6
): δ 171.6, 144.4, 137.1, 129.5, 129.0, 127.6,
127.2, 125.3, 117.1, 116.4, 58.3.

Cl
NH
HO
2
C
NH
HO
2
C
NO
2
368
2-(2-Cyano-phenylamino)-4-phenyl-but-3-enoic
acid (4.120)
Prepared analogously to compound (4.115) in
excellent yield (99%).
1
H NMR (400 MHz, acetone-d
6
): δ 7.55-7.27 (m,
7H), 6.94-6.78 (m, 3H), 6.53 (dd, J =15.9 Hz, J =
6.3 Hz, 1H), 5.90 (broad s, 1H), 5.05 (d, J =6.5 Hz, 1H).
13
C NMR (62.5 MHz,
acetone-d
6
): δ 172.0, 149.3, 136.9, 135.0, 133.8, 133.4, 129.4, 128.8, 127.4, 125.3,
118.1, 113.0, 97.3, 58.2.

2-(3-Methoxy-phenylamino)-4-phenyl-but-3-
enoic acid (4.123)
Prepared analogously to compound (4.115) in
moderate yield (50%).
1
H NMR (400 MHz, methanol-d
4
): δ 7.43-7.23
(m, 6H), 7.04 (t, J = 8.0 Hz, 1H), 6.80 (d, J = 15.8
Hz, 1H), 6.43-6.27 (m, 2H), 4.69 (d, J = 5.8 Hz,
1H), 3.74 (s, 3H).
13
C NMR (250 MHz, methanol-d
4
): δ 176.0, 162.4, 150.0, 138.2,
133.8, 131.0, 129.8, 129.0, 127.7, 127.2, 107.8, 104.5, 100.9, 60.8, 55.6.

NH
HO
2
C
CN
NH
HO
2
C
OMe
369
4-Phenyl-2-phenylamino-but-3-enoic acid
(4.124)
Prepared analogously to compound (4.115) in
good yield (74 %).
1
H NMR (400 MHz, acetone-d
6
): δ 7.49 (d, J = 8.0
Hz, 2H), 7.39-7.27 (m, 3H), 7.16 (t, J = 7.8 Hz,
2H), 6.89 (d, J = 15.9 Hz, 1H), 6.79 (d, J =7.6 Hz, 2H), 6.68 (t, J =7.5 Hz, 1H), 6.49
(dd, J = 15.9 Hz, J = 6.5 Hz, 1H), 5.88 (broad s, 1H), 4.85 (d, J = 6.2 Hz, 1H).
13
C
NMR (62.5 MHz, acetone-d
6
): δ 173.1, 148.0, 133.1, 129.7, 129.4, 128.7, 127.4,
126.6, 118.3, 114.2, 59.1.

4-Phenyl-2-p-tolylamino-but-3-enoic acid
(4.126)
Prepared analogously to compound (4.115)
in good yield (80 %).
1
H NMR (400 MHz, acetone-d
6
): δ 7.50-7.27
(m, 5H), 6.97 (d, J = 8.1 Hz, 2H), 6.87 (d, J =
16.5 Hz, 1H), 6.70 (d, J =8.4 Hz, 2H), 6.47 (dd, J = 16.5 Hz, J = 6.8 Hz, 1H), 5.88
(broad s, 1H), 4.81 (d, J = 6.6 Hz, 1H), 2.20 (s, 3H).
13
C NMR (62.5 MHz, acetone-
d
6
): δ 173.3, 137.7, 133.1, 130.4, 130.3, 129.53, 129.47, 128.7, 127.4, 126.9, 122.4,
114.5, 59.6, 20.5.

NH
HO
2
C
NH
HO
2
C
H
3
C
370
2-(Allyl-phenyl-amino)-4-phenyl-but-3-enoic
acid (4.128)
Prepared analogously to compound (4.115) in
high yield (95%).
1
H NMR (400 MHz, methanol-d
4
): δ 7.36-7.13
(m, 7H), 6.78 (d, J = 8.3 Hz, 2H), 6.72-6.60 (m,
2H), 6.53-6.47 (m, 1H), 5.98-5.88 (m, 1H), 5.26 (d, J = 17.1 Hz, 1H), 5.12 (d, J =
10.4 Hz, 1H), 5.06 (d, J = 5.0 Hz, 1H), 4.13-3.98 (m, 2H).
13
C NMR (100 MHz,
methanol-d
4
): δ 178.0, 152.3, 140.5, 139.8, 137.3, 132.4, 132.2, 131.5, 130.1,
127.9, 121.5, 118.9, 117.9, 67.9, 56.0.

2-(1-Carboxy-3-phenyl-allylamino)-benzoic
acid (4.130)
Prepared analogously to compound (4.115) in
high yield (89%).
1
H NMR (400 MHz, acetone-d
6
): δ 8.80 (broad
s, 1H), 8.01 (d, J = 7.7 Hz, 1H), 7.50 (d, J =8.6
Hz, 2H), 7.42-7.27 (m, 4H), 6.86 (d, J = 16.6 Hz, 1H), 6.78 (d, J = 8.1 Hz, 1H),
6.69 (t, J = 7.8 Hz, 1H), 6.52 (dd, J =15.8 Hz, J = 6.0 Hz, 1H), 5.99 (broad s, 1H),
5.03 (d, J= 5.5 Hz, 1H).
13
C NMR (100 MHz, acetone-d
6
): δ 172.2, 170.5, 150.6,
137.2, 135.4, 133.3, 132.9, 129.5, 128.8, 127.4, 126.2, 116.1, 113.2, 111.5, 58.4.

N
HO
2
C
NH
HO
2
C
OH
O
371
2-{[Carboxy-(4-methoxy-phenyl)-methyl]-
amino}-benzoic acid methyl ester (4.134)
Prepared analogously to compound (4.115) in
excellent yield (97%).
1
H NMR (400 MHz, methanol-d
4
): δ 7.88 (d,
J= 8.0 Hz, 1H), 7.42 (d, J= 8.5 Hz, 2H), 7.21 (t, J= 7.1 Hz, 1H), 6.89 (d, J = 8.7 Hz,
2H), 6.57 (t, J = 6.9 Hz, 1H), 6.49 (d, J = 7.9 Hz, 1H), 5.13 (s, 1H), 3.87 (s, 3H),
3.74 (s, 3H).
13
C NMR (100 MHz, methanol-d
4
): δ 173.8, 168.8, 159.6, 148.9,
134.1, 131.2, 130.0, 128.1, 115.0, 113.8, 112.3, 110.6, 59.2, 54.3, 50.7.

2-[(Benzo[b]thiophen-2-yl-carboxy-methyl)-
amino]-benzoic acid methyl ester (4.136)
Prepared analogously to compound (4.115) in
good yield (63%).
1
H NMR (250 MHz, methanol-d
4
): δ 7.89 (d, J =
9.3 Hz, 1H), 7.76-7.67 (m, 2H), 7.44 (s, 1H),
7.28-7.23 (m, 3H), 6.66-6.60 (m, 2H), 5.57 (s, 1H), 3.88 (s, 3H).
13
C NMR (100
MHz, methanol-d
4
): δ 171.4, 168.8, 148.6, 142.8, 139.4, 134.2, 131.2, 124.0, 123.1,
122.6, 121.9, 115.7, 112.2, 111.0, 56.2, 50.6.

OMe
O
NH
HO
2
C
OMe
OMe
O
NH
HO
2
C
S
372
Benzo[b]thiophen-2-yl-(2-carbamoyl-
phenylamino)-acetic acid (4.138)
Prepared analogously to compound (4.115) in
high yield (89%).
1
H NMR (250 MHz, methanol-d
4
): δ 7.77-
7.61 (m, 4H), 7.44 (s, 1H), 7.30-7.19 (m, 3H),
6.74-6.68 (m, 2H), 5.57 (s, 1H).
13
C NMR (62.5 MHz, methanol-d
4
): δ 174.5,
172.7, 147.8, 143.4, 141.0, 134.2, 130.2, 125.63, 125.58, 125.52, 124.7, 124.4,
124.3, 123.3, 118.5, 115.0, 58.3.

(2-Carbamoyl-phenylamino)-(4-methoxy-
phenyl)-acetic acid (4.139)
Prepared analogously to compound (4.115) in
good yield (84%).
1
H NMR (400 MHz, methanol-d
4
): δ 7.11 (d,
J= 6.3 Hz, 1H), 7.44 (d, J = 5.4 Hz, 2H), 7.21
(t, J= 6.6 Hz, 1H), 6.93 (d, J = 8.5 Hz, 2H), 6.64 (t, J = 7.9 Hz, 1H), 6.54 (d, J = 8.5
Hz, 1H), 5.13 (s, 1H), 3.80 (ds, 3H).
13
C NMR (62.5 MHz, methanol-d
4
): δ 174.8,
161.2, 148.9, 133.9, 131.3, 130.1, 129.6, 116.9, 115.2, 114.1, 60.9, 55.8.

NH
2
O
NH
HO
2
C
S
NH
2
O
NH
HO
2
C
OMe
373
(4-Methoxy-phenyl)-[2-(4-methoxy-
phenylcarbamoyl)-phenylamino]-acetic
acid (4.140)
Prepared analogously to compound (4.115)
in good yield (74 %).
1
H NMR (400 MHz, methanol-d
4
): δ 7.64
(d, J = 6.5 Hz, 1H), 7.52 (d, J = 9.6 Hz, 2H), 7.44 (d, J =8.2 Hz, 2H), 7.17 (t, J =7.9
Hz, 1H), 6.89-6.84 (m, 4H), 6.63 (t, J = 7.3 Hz, 2H), 6.53 (d, J =8.3 Hz, 1H), 3.74
(s, 3H), 3.69 (s, 3H).
13
C NMR (100 MHz, methanol-d
4
): δ 173.9, 169.1, 159.5,
156.7, 147.3, 132.3, 131.3, 130.2, 128.3, 128.2, 123.1, 116.9, 115.6, 113.8, 113.6,
112.5, 59.7, 54.5, 54.4.

(2-Dimethylaminooxalyl-phenylamino)-(4-
methoxy-phenyl)-acetic acid (4.141)
Prepared analogously to compound (4.115) in
good yield (65%).
1
H NMR (250 MHz, methanol-d
4
): δ 7.39 (d,
J=8.6 Hz, 2H), 7.28 (t, J = 7.7 Hz, 1H), 6.89 (d,
J= 8.5 Hz, 2H), 6.64-6.58 (m, 2H), 5.24 (s, 1H), 3.72 (s, 3H), 3.05 (s, 3H), 2.92 (s,
3H).
13
C NMR (62.5 MHz, methanol-d
4
): δ 195.3, 174.0, 169.2, 161.1, 151.2,
137.7, 134.8, 130.8, 129.4, 116.9, 115.3, 114.4, 60.2, 55.7, 37.5, 34.1.

N
H
O
NH
HO
2
C
OMe
OMe
O
NH
HO
2
C
OMe
O
NMe
2
374
(4-Methoxy-phenyl)-[2-(2-morpholin-
4-yl-2-oxo-acetyl)-4-nitro-
phenylamino]-acetic acid (4.142)
Prepared analogously to compound
(4.115) in good yield (76 %).
1
H NMR (400 MHz, acetone-d
6
): δ 8.52
(m, 1H), 8.19 (m, 1H), 7.52 (d, J = 8.2 Hz, 2H), 6.98 (d, J = 6.0 Hz, 2H), 6.87 (d,
J= 9.5 Hz, 1H), 5.58 (s, 1H), 3.79 (m, 7H), 3.68 (m, 2H), 3.52 (m, 2H).
13
C NMR
(62.5 MHz, acetone-d
6
): δ 194.2, 172.0, 164.9, 160.8, 153.9, 137.3, 131.6, 131.4,
131.3, 130.8, 129.5, 129.3, 118.4, 115.2, 11.8, 114.0, 67.4, 67.2, 59.8, 55.6, 47.1,
42.3.

(2-Benzoyl-4-chloro-phenylamino)-(4-
methoxy-phenyl)-acetic acid (4.145)
Prepared analogously to compound (4.115)
in excellent yield (96 %).
1
H NMR (400 MHz, acetone-d
6
): δ 9.52 (d,
J = 5.5 Hz, 1H), 7.71 - 7.53 (m, 6H), 7.45
(d, J = 2.7 Hz, 1H), 7.35 (d, J =9.1 Hz, 1H), 6.99 (d, J =8.6 Hz, 2H), 6.76 (d, J = 9.2
Hz, 1H), 5.41 (d, J = 5.2 Hz, 1H), 3.83 (s, 3H).
13
C NMR (62.5 MHz, acetone-d
6
):
δ 198.9, 172.4, 160.8, 148.9, 140.6, 135.1, 134.4, 132.3, 130.4, 129.8, 129.4, 129.2,
120.0, 119.7, 115.9, 115.2, 59.7, 55.6.
O
NH
HO
2
C
OMe
O
N O
2
N
O
Cl
O
Ph
NH
HO
2
C
OMe
375
[4-Chloro-2-(2,2,2-trifluoro-acetyl)-
phenylamino]-(4-methoxy-phenyl)-
acetic acid (4.165)
Prepared analogously to compound
(4.115) in good yield (84 %).
1
H NMR (400 MHz, methanol-d
4
): δ 7.72
(broad s, 1H), 7.45-7.38 (m, 3H), 7.06 (m, 1H), 6.96-6.92 (m, 2H), 6.73 (m, 1H),
6.35 (d, J = 9.0 Hz, 1H), 5.29 (s, 1H), 5.02 (d, J= 15.7 Hz, 1H), 3.80 (s, 3H).
19
F
NMR (376 MHz, methanol-d
4
): δ -70.8.
13
C NMR (250 MHz, methanol-d
4
):
δ 181.0 (q, J
C-F
= 33.9 Hz), 174.9, 161.3, 151.3, 145.7, 138.2, 131.6, 131.4, 130.6,
129.5, 129.4, 121.4 (t, J
C-F
= 28.8 Hz), 117.1, 115.5, 114.9, 61.1, 55.8.

(2-Acetyl-phenylamino)-(4-methoxy-
phenyl)-acetic acid (4.167)
Prepared analogously to compound (4.115) in
excellent yield (98 %).
1
H NMR (400 MHz, methanol-d
4
): δ 7.87 (m,
1H), 7.41 (d, J = 8.3 Hz, 2H), 7.26 (t, J = 8.3
Hz, 1H), 6.91 (d, J = 8.4 Hz, 2H), 6.63 (t, J = 7.7 Hz, 1H), 6.54 (d, J = 8.2 Hz, 1H),
5.17 (s, 1H), 3.78 (s, 3H), 2.61 (s, 3H).
13
C NMR (62.5 MHz, methanol-d
4
):
Cl
O
CF
3
NH
HO
2
C
OMe
O
CH
3
NH
HO
2
C
OMe
376
δ 203.0, 174.6, 161.0, 150.1, 136.0, 134.0, 131.3, 129.4, 119.5, 116.2, 115.2, 114.0,
60.5, 55.7, 28.0.

(4-Chloro-2-formyl-phenylamino)-(4-
methoxy-phenyl)-acetic acid (4.170)
Prepared analogously to compound (4.115)
in high yield (89 %).
1
H NMR (400 MHz, methanol-d
4
): δ 9.79
(s, 1H), 7.52 (s, 1H), 7.38 (m, 2H), 7.18 (m,
1H), 6.88 (m, 2H), 6.48 (s, 1H), 5.16 (s, 1H), 3.74 (s, 3H).
13
C NMR (400 MHz,
methanol-d
4
): δ 193.3, 172.7, 159.7, 146.7, 135.1, 134.9, 129.3, 128.0, 119.9,
119.8, 113.9, 113.8, 58.9, 54.3.

(4-Methoxy-phenyl)-(3-oxo-indan-4-ylamino)-
acetic acid (4.171)
Prepared analogously to compound (4.115) in good
yield (61 %).
1
H NMR (250 MHz, methanol-d
4
): δ 7.39 (d, J = 9.0
Hz, 2H), 7.24 (d, J = 8.2 Hz, 1H), 6.88 (d, J = 8.6
Hz, 2H), 6.60 (d, J = 7.7 Hz, 1H), 6.25 (d, J = 8.1 Hz, 1H), 5.13 (s, 1H), 3.76 (s,
3H), 3.00-2.97 (m, 2H), 2.65-2.61 (m, 2H).
13
C NMR (62.5 MHz, methanol-d
4
):
H
O
NH
HO
2
C
OMe
Cl
NH
O
CO
2
H
MeO
377
δ 205.8, 174.3, 161.2, 158.5, 147.7, 138.0, 136.7, 131.2, 121.7, 116.8, 115.2, 114.4,
109.6, 60.1, 55.7, 37.0, 26.3.

(4-Methoxy-phenyl)-(8-oxo-5,6,7,8-tetrahydro-
naphthalen-1-ylamino)-acetic acid (4.172)
Prepared analogously to compound (4.115) in good
yield (76 %).
1
H NMR (400 MHz, methanol-d
4
): δ 7.39 (d, J =
8.5 Hz, 2H), 7.08 (m, 1H), 6.86 (d, J = 8.6 Hz, 2H),
6.38 (d, J = 7.7 Hz, 1H), 6.32 (d, J = 8.6 Hz, 1H), 5.12 (s, 1H), 3.71 (s, 3H), 2.80
(m, 2H), 2.59 (m, 2H), 1.95 (m, 2H).
13
C NMR (100 MHz, methanol-d
4
): δ 201.9,
173.0, 159.6, 149.5, 146.8, 135.2, 134.7, 129.8, 128.0, 115.3, 115.1, 113.8, 112.8,
110.2, 59.2, 54.3, 39.9, 30.6, 22.7.

(2-Cyclohexanecarbonyl-phenylamino)-(4-
methoxy-phenyl)-acetic acid (4.173)
Prepared analogously to compound (4.115) in
high yield (94%).
1
H NMR (400 MHz, acetone-d
6
): δ 10.05 (broad
s, 1H), 7.96 (d, J = 7.0 Hz, 1H), 7.50 (d, J = 9.4
Hz, 2H), 7.28 (t, J = 8.8 Hz, 2H), 6.97 (d, J = 9.4 Hz, 2H), 6.66 (t, J = 6.9 Hz, 2H),
5.30 (s, 1H), 3.81 (s, 3H), 3.47 (m, 1H), 1.91-1.74 (m, 5H), 1.60-1.25 (m, 5H).
13
C
NH
CO
2
H
MeO
O
O
NH
HO
2
C
OMe
378
NMR (62.5 MHz, acetone-d
6
): δ 172.7, 160.6, 150.1, 153.1, 132.4, 130.9, 129.3,
118.0, 115.7, 115.0, 113.9, 59.8, 55.5, 46.3, 30.8, 30.7, 26.8, 26.5.

(4-Methoxy-phenyl)-[2-(3,3,3-trifluoro-
propionyl)-phenylamino]-acetic acid (4.174)
Prepared analogously to compound (4.115) in
high yield (94%).
1
H NMR (400 MHz, acetone-d
6
): δ 9.92 (broad
s, 1H), 7.91 (d, J = 8.3 Hz, 1H), 7.5 (d, J = 7.9
Hz, 2H), 7.36 (t, J = 7.2 Hz, 1H), 6.98 (d, J = 9.2 Hz, 2H), 6.69 (m, 2H), 5.82
(broad s, 1H), 5.37 (d, J = 6.3 Hz, 1H), 4.21 (q, J
H-F
= 11.3 Hz, 2H), 3.82 (s, 3H).
19
F NMR (376 MHz, acetone-d
6
): δ -62.6.
13
C NMR (62.5 MHz, acetone-d
6
):
δ 193.3, 172.5, 160.8, 150.3, 136.4, 133.2, 130.6, 129.4, 126.1 (q, J
C-F
= 278.5 Hz),
116.1, 115.2, 114.1, 59.7, 55.6, 43.0 (q, J
C-F
= 27.3 Hz).

(2-Cyclopropanecarbonyl-phenylamino)-(4-
methoxy-phenyl)-acetic acid (4.175)
Prepared analogously to compound (4.115) in
good yield (74 %).
1
H NMR (250 MHz, acetone-d
6
): δ 8.13 (d,
J=8.3 Hz, 1H), 7.45 (d, J = 8.7 Hz, 2H), 7.27 (t,
CH
2
CF
3
O
NH
HO
2
C
OMe
O
NH
HO
2
C
OMe
379
J= 8.6 Hz, 1H), 6.93 (d, J = 8.6 Hz, 2H), 6.62 (m, 2H), 5.26 (s, 3H), 2.83 (m, 1H),
1.11-0.93 (m, 4H).
13
C NMR (62.5 MHz, acetone-d
6
): δ 202.3, 172.5, 160.6, 149.1,
135.1, 132.7, 130.9, 129.3, 120.1, 116.0, 115.0, 113.6, 59.6, 55.5, 17.6, 10.9, 10.8.

(2-Benzoyl-phenylamino)-(4-methoxy-
phenyl)-acetic acid (4.177)
Prepared analogously to compound (4.115) in
high yield (85%).
1
H NMR (400 MHz, acetone-d
6
): δ 9.58 (broad
s, 1H), 7.68-7.49 (m, 7H), 7.35 (m, 1H), 6.99
(d, J =8.3 Hz, 2H), 6.74 (d, J = 8.0 Hz, 1H), 6.63 (t, J = 6.5 Hz, 1H), 5.39 (s, 1H),
3.83 (s, 3H).
13
C NMR (62.5 MHz, acetone-d
6
): δ 199.4, 172.5, 160.7, 150.2, 141.3,
135.7, 135.4, 131.8, 130.7, 129.7, 129.3, 128.9, 119.0, 115.5, 115.0, 113.7, 59.7,
55.5.

(2-Benzoyl-4-chloro-phenylamino)-thiophen-2-
yl-acetic acid (4.147)
Prepared analogously to compound (4.115) in
high yield (86%).
1
H NMR (400 MHz, acetone-d
6
): δ 9.47 (s, 1H),
7.76 - 7.36 (m, 10H), 7.07 (m, 1H), 6.90 (d, J =
O
Ph
NH
HO
2
C
OMe
O
Ph
NH
HO
2
C
S
Cl
380
8.7 Hz, 1H), 5.79 (s, 1H).
13
C NMR (100 MHz, methanol-d
4
): δ 198.3, 172.0,
147.7, 141.3, 139.3, 134.3, 133.5, 131.3, 128.7, 128.1, 126.7, 126.1, 125.2, 119.4,
119.0, 114.4, 56.0.

(2-Acetyl-phenylamino)-benzofuran-2-yl-
acetic acid (4.180)
Prepared analogously to compound (4.115) in
good yield (85%).
1
H NMR (400 MHz, methanol-d
4
): δ 7.83-7.81
(m, 1H), 7.52-7.43 (m, 2H), 7.28-7.16 (m, 3H),
6.84-6.64 (m, 3H), 5.55 (s, 1H), 2.57 (s, 3H).
13
C NMR (100 MHz, methanol-d
4
):
δ 201.8, 170.3, 154.9, 153.2, 148.5, 134.8, 132.7, 128.0, 124.2, 122.7, 120.8, 118.4,
115.4, 112.5, 112.1, 110.7, 104.8, 54.0, 26.7.

Benzo[b]thiophen-2-yl-(2-benzoyl-4-
chloro-phenylamino)-acetic acid (4.156)
Prepared analogously to compound (4.115)
in excellent yield (97 %).
1
H NMR (400 MHz, acetone-d
6
): δ 9.95 (d,
J = 5.6 Hz, 1H), 7.90 (d, J = 7.5 Hz, 1H),
7.86 (d, J = 8.5 Hz, 1H), 7.73-7.58 (m, 6H), 7.48 (d, J = 6.1 Hz, 1H), 7.42-7.35 (m,
3H), 6.96 (d, J = 9.0 Hz, 1H), 5.91 (d, J = 5.1 Hz, 1H).
13
C NMR (100 MHz,
O
CH
3
NH
HO
2
C
O
O
Ph
NH
HO
2
C
S
Cl
381
acetone-d
6
): δ 197.6, 170.1, 147.6, 142.4, 139.8, 139.5, 134.2, 133.4, 131.7, 129.0,
128.4, 124.6, 124.5, 123.7, 123.5, 122.4, 119.6, 119.4, 115.0, 59.3, 48.9.

Benzofuran-2-yl-[4-chloro-2-(2,2,2-
trifluoro-acetyl)-phenylamino]-acetic acid
(4.181)
Prepared analogously to compound (4.115)
in high yield (92%).
1
H NMR (400 MHz, acetone-d
6
): δ 9.64 (d,
J= 6.1 Hz, 1H), 7.60 (m, 1H), 7.48 (d, J = 7.6 Hz, 1H), 7.41-7.37 (m, 2H), 7.19 (t,
J= 8.3 Hz, 1H), 7.11 (t, J = 8.7 Hz, 1H), 7.00-6.98 (m, 2H), 5.76 (d, J =5.6 Hz, 1H).
13
C NMR (62.5 MHz, acetone-d
6
): δ 180.3 (q, J
C-F
= 39 Hz), 169.3, 155.8, 153.0,
150.8, 138.1, 131.0 (q, J
C-F
= 4.2 Hz), 128.8, 125.7, 124.0, 122.2, 116.7, 112.0,
107.0. 54.7.

(2-Acetyl-phenylamino)-(2,5-dimethyl-phenyl)-
acetic acid (4.183)
Prepared analogously to compound (4.115) in
good yield (71 %).
1
H NMR (400 MHz, acetone-d
6
): δ 9.98 (s, 1H),
7.90 (d, J = 9.1 Hz, 1H), 7.31 (t, J =8.2 Hz, 1H),
7.26 (s, 1H), 7.17 (d, J = 7.8 Hz, 1H), 7.06 (d, J=7.6 Hz, 1H), 6.65 (t, J =6.5 Hz,
CF
3
O
NH
HO
2
C
Cl
O
CH
3
O
NH
HO
2
C
CH
3
CH
3
382
1H), 6.51 (d, J = 8.0 Hz, 1H), 5.49 (d, J= 5.6 Hz, 1H), 2.62 (s, 3H), 2.59 (s, 3H),
2.26 (s, 3H).
13
C NMR (62.5 MHz, acetone-d
6
): δ 201.3, 172.7, 149.6, 137.3, 136.6,
135.6, 134.4, 133.8, 131.8, 129.6, 127.9, 119.4, 115.8, 113.2, 57.2, 28.2, 21.1, 19.2.

Benzofuran-2-yl-[4-chloro-2-(2,2-difluoro-
acetyl)-phenylamino]-acetic acid (4.184)
Prepared analogously to compound (4.115) in
good yield (75 %).
1
H NMR (400 MHz, acetone-d
6
): δ 9.83 (d, J
= 5.5 Hz, 1H), 7.90 (s, 1H), 7.60-7.44 (m,
3H), 7.31-7.24 (m, 2H), 7.04 (m, 2H), 5.81 (s, 1H), 4.09 (q, J = 6.8 Hz, 1H).
19
F
NMR (376 MHz, acetone-d
6
): δ −124.9 (q, J = 18.2 Hz).
13
C NMR (62.5 MHz,
acetone-d
6
): δ 188.0 (t, J = 23 Hz), 170.2, 155.7, 153.8, 149.9, 137.0, 131.4, 128.9,
125.4, 123.9, 122.1, 120.6, 116.0, 115.3, 114.3, 112.0, 110.4, 106.6, 55.1.

(2-Benzoyl-4-chloro-phenylamino)-(2-bromo-
phenyl)-acetic acid (4.158)
Prepared analogously to compound (4.115) in
high yield (82 %).
1
H NMR (400 MHz, methanol-d
4
): δ 7.63 -7.16
(m, 11H), 6.51 (d, J = 8.7 Hz, 1H), 5.69 (s, 1H).
CF
2
H
O
NH
HO
2
C
Cl
O
Ph
O
NH
HO
2
C
Cl
Br
383
13
C NMR (100 MHz, methanol-d
4
): δ 198.2, 171.6, 147.4, 139.4, 137.5, 134.3,
133.6, 133.0, 131.3, 129.6, 128.7, 128.1, 128.0, 127.9, 124.1, 119.4, 118.8, 114.3,
58.7.

(2-Acetyl-phenylamino)-benzo[b]thiophen-2-
yl-acetic acid (4.185)
Prepared analogously to compound (4.115) in
good yield (77 %).
1
H NMR (250 MHz, methanol-d
4
): δ 7.78-7.61
(m, 3H), 7.39 (s, 1H), 7.23-7.16 (m, 3H), 6.63-
6.57 (m, 2H), 5.54 (s, 1H), 2.52 (s, 3H).
13
C NMR (62.5 MHz, methanol-d
4
):
δ 203.1, 172.7, 149.8, 144.0, 141.0, 140.9, 136.3, 134.1, 125.6, 125.5, 124.7, 124.2,
123.4, 119.9, 117.0, 113.9, 57.6, 28.2.

2-(2-Benzoyl-4-chloro-phenylamino)-4-
phenyl-but-3-enoic acid (4.161)
Prepared analogously to compound (4.115) in
excellent yield (96 %).
1
H NMR (400 MHz, CDCl
3
): δ 7.70 (d, J =
6.9 Hz, 2H), 7.60 (m, 1H), 7.55-7.51 (m,
3H), 7.44-7.42 (m, 2H), 7.38-7.26 (m, 4H),
6.82 (d, J = 15.9 Hz, 1H), 6.70 (d, J=9.4 Hz, 1H), 6.36 (dd, J = 15.9 Hz, J = 6.2 Hz,
O
CH
3
NH
HO
2
C
S
Ph
O
NH
HO
2
C
Cl
384
1H), 4.90 (d, J = 6.6 Hz, 1H).
13
C NMR (250 MHz, CDCl
3
): δ 198.2, 170.8, 147.7,
139.3, 135.7, 134.6, 134.1, 133.7, 131.5, 129.2, 128.6, 128.3, 126.7, 123.5, 120.1,
119.4, 114.1, 58.5.

2-[2-(4-Methoxy-phenylcarbamoyl)-
phenylamino]-4-phenyl-but-3-enoic acid
(4.186)
Prepared analogously to compound (4.115)
in good yield (75 %).
1
H NMR (400 MHz, acetone-d
6
): δ 8.89
(broad s, 1H), 8.22 (broad s, 1H), 7.73 (d, J
= 7.3 Hz, 1H), 7.50-7.27 (m, 12H), 6.87 (d, J = 15. 9 Hz, 1H), 6.75 (d, J = 8.4 Hz,
1H), 6.64 (t, J = 7.5 Hz, 1H), 6.51 (dd, J = 15. 9 Hz, J = 6.1 Hz, 1H), 4.95 (d, J =
6.3 Hz, 1H), 4.65 (s, 3H).
13
C NMR (62.5 MHz, acetone-d
6
): δ 172.4, 170.0, 148.8,
140.7, 133.2, 130.1, 129.4, 129.1, 128.8, 128.7, 128.3, 127.6, 127.4, 126.5, 116.2,
113.3, 58.6, 43.5.

N
H
O
NH
HO
2
C
OMe
385
[(2-Benzoyl-phenyl)-(4-methoxy-benzyl)-
amino]-(4-methoxy-phenyl)-acetic acid
(4.194)
Prepared analogously to compound (4.115)
in good yield (73 %).
1
H NMR (400 MHz, methanol-d
4
): δ 7.63
(s, 1H), 7.38 (d, J = 8.9 Hz, 1H), 7.04 (m,
3H), 6.86 (d, J = 8.8 Hz, 3H), 6.79 (d, J = 9.2 Hz, 2H), 6.44 (d, J = 8.6 Hz, 1H),
5.10 (s, 1H), 3.76 (s, 2H), 3.74 (s, 3H), 3.73 (s, 3H), 2.53 (s, 3H).
13
C NMR (100
MHz, methanol-d
4
): δ 201.5, 173.7, 159.6, 147.1, 135.5, 134.7, 133.5, 132.6, 132.2,
130.1, 129.3, 128.0, 117.9, 113.7, 113.4, 112.9, 59.4, 54.3, 54.2, 39.3, 26.7.

(2-Benzoyl-4-chloro-phenylamino)-(4-
methoxy-phenyl)-acetic acid methyl ester
(4.226)
To a suspension of the amino acid (4.145)
(1.5 mmol, 592.5 mg) in anhydrous
methanol (5 ml) thionyl chloride (0.5 ml)
was added dropwise at 0
o
C. After the addition was finished the reaction mixture
was refluxed overnight. During cooling to room temperature lots of precipitate
formed. The solid was filtered off and dried under vacuum. The product is a yellow
solid soluble in chloroform and was obtained in good yield (480 mg, 78 %).
O
Ph
N
HO
2
C
OMe
OMe
Cl
O
Ph
NH
MeO
2
C
OMe
386
1
H NMR (400 MHz, CDCl
3
): δ 7.68 (d, J = 6.8 Hz, 2H), 7.59 (t, J = 7.4 Hz, 1H),
7.54-7.46 (m, 5H), 7.25 (d, J = 9.0 Hz, 1H), 6.93 (d, J = 8.9 Hz, 2H), 6.50 (d, J =
6.7 Hz, 1H), 5.17 (s, 1H), 3.83 (s, 3H), 3.79 (s, 3H).
13
C NMR (100 MHz, CDCl
3
):
δ 198.2, 171.4, 159.8, 148.1, 139.4, 134.7, 134.4, 131.5, 129.2, 128.4, 128.3, 119.7,
119.2, 114.5, 114.0, 59.9, 55.3, 52.9.

2-(4-Methoxy-phenyl)-3-methyl-1H-indole
(4.203)
To a suspension of the amino acid (0.2 mmol,
59.8 mg) in toluene, p-toluenesulfonic acid
chloride was added (1 eq., 0.2 mmol, 38.2 mg), followed by addition of
triethylamine (2 eq. 0.4 mmol, 55.6µl). The reaction mixture was stirred at room
temperature for 4 hours and diluted with water and extracted with ethyl acetate. The
organic residue was dried with sodium sulfate then purified via flash
chromatography (10% ethyl acetate: hexane) to afford white solid in moderate yield
(22 mg, 46%).
1
H NMR (400 MHz, CDCl
3
): δ 7.97 (broad s, 1H), 7.58 (d, J = 8.1 Hz, 1H), 7.50
(d, J = 9.0 Hz, 2H), 7.34(d, J = 7.7 Hz, 1H), 7.20-7.12 (m, 2H), 7.00 (d, J = 9.1 Hz,
2H), 3.86 (s, 3H), 2.43 (s, 3H).
13
C NMR (100 MHz, CDCl
3
): δ 159.0, 129.0,
125.9, 121.9, 119.4, 118.7, 114.3, 110.5, 107.7, 55.4, 9.6.

N
H
CH
3
OMe
387
5-Chloro-2-(4-methoxy-phenyl)-3-
phenyl-1H-indole (4.204)
Prepared analogously to compound
(4.203) in excellent yield (97%).
1
H NMR (400 MHz, CDCl
3
): δ 8.23 (broad s, 1H), 7.65 (s, 1H), 7.43-7.21 (m, 8H),
7.20 (d, J = 10.8 Hz, 1H), 6.90 (d, J = 9.1 Hz, 2H), 3.85 (s, 3H).
13
C NMR (62.5
MHz, CDCl
3
): δ 159.5, 130.0, 129.4, 128.6, 126.4, 126.1, 124.6, 122.6, 118.9,
114.2, 111.7, 55.3.

2-(4-Methoxy-phenyl)-3-phenyl-1H-indole
(4.205)
Prepared analogously to compound (4.203) in
excellent yield (99%).
1
H NMR (400 MHz, CDCl
3
): δ 8.20 (broad s, 1H), 7.78 (d, J = 8.7 Hz, 1H), 7. 54
(m, 2H), 7.49-7.23 (m, 8H), 6.92 (d, J = 7.6 Hz, 2H), 3.87 (s, 3H).
13
C NMR (100
MHz, CDCl
3
): δ 159.3, 135.8, 135.4, 134.2, 130.2, 129.5, 128.6, 126.2, 125.2,
122.4, 120.4, 119.5, 114.2, 110.9, 55.3.

N
H
Ph
OMe
Cl
N
H
Ph
OMe
388
3'-Methyl-1'H-[2,2']biindolyl-1-carboxylic
acid tert-butyl ester (4.206)
Prepared analogously to compound (4.203) in
good yield (52%).
1
H NMR (250 MHz, CDCl
3
): δ 8.20 (m, 1H), 7.59 (d, J = 7.2 Hz, 2H), 7.42-7.28
(m, 4H), 7.25-7.11 (m, 2H), 6.72 (s, 1H), 2.33 (s, 3H), 1.32 (s, 9H).
13
C NMR (62.5
MHz, CDCl
3
): δ 184.4, 128.2, 124.8, 123.8, 123.1, 122.6, 120.7, 119.3, 119.1,
116.5, 116.0, 155.5, 112.7, 111.8, 110.6, 83.8, 27.7, 9.4.

5'-Chloro-3'-phenyl-1'H-[2,2'] bis-
indolyl -1-carboxylic acid tert-butyl
ester (4.207)
Prepared analogously to compound
(4.203) in good yield (81%).
1
H NMR (400 MHz, CDCl
3
): δ 8.38 (s, 1H), 8.12 (d, J = 8.3 Hz, 1H), 7.69 (s, 1H),
7.39 (d, J = 7.6 Hz, 2H), 7.32-7.11 (m, 8H).
13
C NMR (100 MHz, CDCl
3
): δ 149.8,
137.0, 134.2, 130.1, 129.0, 128.8, 128.6, 128.4, 128.1, 126.4, 126.1, 125.1, 123.3,
123.2, 121.0, 119.4, 117.1, 115.5, 113.5, 111.9, 83.9, 27.7.

N
H
CH
3
Boc
N
N
H
Ph
Boc
N
Cl
389
2-Benzo[b]thiophen-2-yl-5-chloro-3-
phenyl-1H-indole (4.208)
Prepared analogously to compound
(4.203) in good yield (83%).
1
H NMR (400 MHz, CDCl
3
):δ 8.32 (s, 1H), 7.66-7.58 (m, 2H), 7.44-7.11 (m, 11H).
13
C NMR (100 MHz, CDCl
3
): δ 138.6, 133.4, 132.9, 132.4, 129.4, 128.9, 128.3,
127.7, 127.3, 126.3, 125.5, 124.4, 123.7, 123.6, 122.7, 122.6, 121.1, 120.8, 118.2,
110.8.

2-(4-Methoxy-phenyl)-1H-indole-3-
carboxylic acid dimethylamide (4.209)
Prepared analogously to compound (4.203)
in good yield (55%).
1
H NMR (400 MHz, CDCl
3
): δ 9.07 (s, 1H), 7.56 (d, J = 9.0 Hz, 1H), 7.36 (d, J =
9.0 Hz, 2H), 7.13 (m, 2H), 6.76 (d, J = 8.7 Hz, 2H), 3.78 (s, 3H), 3.14 (s, 3H), 2.74
(s, 3H).
13
C NMR (100 MHz, methanol-d
4
): δ 170.1, 160.2, 136.8, 136.1, 128.4,
127.2, 124.4, 122.1, 120.1, 118.6, 114.0, 110.8, 54.3, 37.6, 33.9.

N
H
Ph
S
Cl
N
H
OMe
NMe
2
O
390
2-(5-Chloro-3-phenyl-1H-indol-2-yl)-
pyrrole-1-carboxylic acid tert-butyl ester
(4.210)
Prepared analogously to compound (4.203) in
good yield (73%).
1
H NMR (400 MHz, CDCl
3
): δ 8.73 (broad s, 1H), 7.76 (s, 1H), 7.42-7.20 (m, 8H),
6.28 (m, 1H), 6.23 (t, J = 3.0 Hz, 1H), 1.34 (s, 9H).
13
C NMR (100 MHz, CDCl
3
):
δ 149.0, 134.7, 133.9, 129.1, 128.5, 128.2, 128.0, 126.2, 125.8, 124.5, 123.1, 122.9,
119.1, 118.2, 117.1, 111.9, 111.1, 84.2, 27.6.

2-(4-Methoxy-phenyl)-1,3,4,5-tetrahydro-
benzo[cd]indole (4.211)
Prepared analogously to compound (4.203)
in good yield (63 %).
1
H NMR (400 MHz, CDCl
3
): δ 7.97 (broad s, 1H), 7.57 (d, J = 8.7 Hz, 2H), 7.21-
7.12 (m, 2H), 7.04 (d, J = 9.1 Hz, 2H), 6.89 (d, J = 6.8 Hz, 2H), 3.90 (s, 3H), 3.08
(t, J = 6.1 Hz, 2H), 3.01 (t, J = 6.1 Hz, 2H), 2.14 (m, 2H).
13
C NMR (100 MHz,
CDCl
3
): δ 158.7, 134.1, 132.1, 130.3, 128.9, 127.4, 126.3, 122.6, 116.2, 114.4,
110.3, 107.8, 55.4, 29.7, 27.5, 24.6, 23.1.

N
H
Ph
Boc
N
Cl
N
H
OMe
391
1-[5-Chloro-2-(4-methoxy-phenyl)-
indol-1-yl]-ethanone (4.215)
In a 1 dram vial acetic anhydride as a
solvent, triethylamine (0.2 ml) and
amino acid (0.3 mmol, 96 mg) were
mixed together. The reaction mixture was heated till 90
o
C and let stirred at this
temperature for 30 minutes. After the reaction was completed (no amino acid on
TLC plate was left) the solvent was evaporated under reduced pressure. The residue
was purified by flash chromatography 10% ethyl acetate: hexanes to isolate a white
solid in excellent (90 mg, 99%).
1
H NMR (400 MHz, CDCl
3
): δ 8.33 (d, J = 8.9 Hz, 1H), 7.77 (s, 1H), 7.42-7.39 (m,
4H), 7.06 (d, J = 9.3 Hz, 2H), 3.93 (s, 3H), 1.96 (s, 3H).
13
C NMR (100 MHz,
CDCl
3
): δ 171.5, 160.2, 140.9, 135.9, 130.4, 130.3, 129.0, 125.8, 124.8, 119.7,
117.2, 114.3, 110.0, 55.4, 27.8.

1-Benzyl-5-chloro-2-(4-methoxy-
phenyl)-3-phenyl-1H-indole (4.216)
Prepared analogously to compound
(4.215) in good yield (51%).
1
H NMR (250 MHz, CDCl
3
): δ 7.77 (s,
1H), 7.32-7.14 (m, 12H), 7.00 (d, J = 6.7 Hz, 2H), 6.84 (d, J = 8.9 Hz, 2H), 5.27 (s,
2H), 3.80 (s, 3H).
13
C NMR (100 MHz, CDCl
3
): δ 159.7, 139.1, 137.8, 135.3,
N
H
Cl
OMe
CH
3
O
N
Ph
OMe
Cl
392
134.6, 132.2, 129.8, 128.8, 128.4, 127.4, 126.1, 126.0, 125.8, 123.4, 122.4, 119.0,
115.0, 114.0, 111.5, 55.1, 47.7.

1-[5-Chloro-2-(4-methoxy-phenyl)-3-
trifluoromethyl-indol-1-yl]-ethanone
(4.216)
Prepared analogously to compound
(4.215) in good yield (84%).
1
H NMR (400 MHz, CDCl
3
): δ 8.33 (d, J = 8.9 Hz, 1H), 7.77 (s, 1H), 7.42-7.39 (m,
3H), 7.06 (d, J = 9.3 Hz, 2H), 3.93(s, 3H), 1.96 (s, 3H).
19
F NMR (376 MHz,
CDCl
3
): δ −54.5.
13
C NMR (62.5 MHz, CDCl
3
): δ 171.3, 161.1, 132.9 (q, J = 352.3
Hz), 131.5, 126.2, 122.3, 119.2 (q), 117.3, 114.3, 55.4, 27.6.

1-(5-Chloro-3-phenyl-2-styryl-indol-1-yl)-
ethanone (4.217)
Prepared analogously to compound (4.215)
in high yield (90%).
1
H NMR (400 MHz, CDCl
3
): δ 8.24 (d, J= 9.0 Hz, 1H), 7.52-7.29 (m, 12H), 7.22
(d, J = 16.4 Hz, 1H), 6.62 (d, J = 16.4 Hz, 1H), 2.72 (s, 3H).
13
C NMR (100 MHz,
CDCl
3
): δ 171.2, 136.4, 136.3, 135.0, 134.8, 132.9, 131.2, 130.1, 129.4, 128.9,
128.8, 128.5, 127.6, 126.5, 125.5, 123.0, 119.2, 118.3, 116.7, 28.1.

N
CF
3
OMe
Cl
CH
3
O
N
Ph
Ph
Cl
CH
3
O
393
N
NHAc
OMe
CH
3
O
1-(2-Allyl-5-chloro-3-phenyl-indol-1-yl)-
ethanone (4.218)
Prepared analogously to compound (4.215) in
moderate yield (46%).
1
H NMR (400 MHz, CDCl
3
): δ 7.86 (d, J = 8.9
Hz, 1H), 7.42-7.32 (m, 6H), 7.19 (dd, J = 8.9 Hz, J = 2.9 Hz, 1H), 6.00-5.91 (m,
1H), 5.05 (d, J = 12.4 Hz, 1H), 4.84 (d, J = 19.5, 1H), 3.70 (m, 2H), 2.70 (s, 3H).
13
C NMR (100 MHz, CDCl
3
): δ 170.1, 136.0, 135.7, 134.3, 132.6, 131.5, 129.8,
129.0, 128.8, 127.8, 124.4, 123.1, 119.2, 116.4, 116.3, 31.3, 27.2.

N-[1-Acetyl-2-(4-methoxy-phenyl)-1H-
indol-3-yl]-acetamide (4.219)
Prepared analogously to compound (4.215) in
good yield (79%).
1
H NMR (400 MHz, CDCl
3
): δ 8.45 (d, J =
8.3 Hz, 1H), 7.41-7.29 (m, 5H), 7.01 (d, J = 8.4 Hz, 2H), 3.88 (s, 3H), 2.25 (s, 3H),
2.03 (s, 3H).
13
C NMR (100 MHz, CDCl
3
): δ 171.2, 169.3, 160.4, 134.9, 133.3,
131.1, 128.2, 126.0, 123.8, 123.1, 122.6, 117.2, 116.6, 114.4, 55.2, 27.7, 20.3.

N
Ph
Cl
CH
3
O
394
1-(2-Benzofuran-2-yl-5-chloro-3-
difluoromethyl-indol-1-yl)-ethanone
(4.220)
Prepared analogously to compound
(4.215) in moderate yield (42%).
1
H NMR (400 MHz, CDCl
3
): δ 8.30 (d, J = 9.1 Hz, 1H), 7.85 (s, 1H), 7.65 (d, J =
7.7 Hz, 1H), 7.51 (d, J = 8.2 Hz, 1H), 7.38 (m, 2H), 7.31 (t, J = 7.0 Hz, 1H), 7.08
(s, 1H), 6.58 (t, J
H-F
= 54.2 Hz, 1H), 2.14 (s, 3H).
19
F NMR (376 MHz, CDCl
3
):
δ −108.7 (d, J = 53.4 Hz).
13
C NMR (62.5 MHz, CDCl
3
): δ 170.4, 155.7, 143.4,
130.3, 127.5, 126.6, 124.2, 122.1, 120.6, 117.6, 115.9, 112.2, 111.8, 111.3, 108.5,
25.1.

1-[2-(4-Methoxy-phenyl)-3-(2,2,2-
trifluoro-ethyl)-indol-1-yl]-ethanone
(4.221)
Prepared analogously to compound (4.215)
in moderate yield (50 %).
1
H NMR (400 MHz, CDCl
3
): δ 8.48 (d, J = 8.1 Hz, 1H), 7.63 (d, J = 7.5 Hz, 1H),
7.46-7.35 (m, 4H), 7.07 (d, J = 8.5 Hz, 2H), 3.93 (s, 3H), 3.34 (q, J = 10.5 Hz, 2H),
2.00 (s, 3H).
19
F NMR (376 MHz, CDCl
3
): δ −64.1.
13
C NMR (100 MHz, CDCl
3
):
N
CF
2
H
Cl
CH
3
O
O
N
CH
2
CF
3
OMe
CH
3
O
395
δ 171.2, 160.4, 138.6, 136.6, 131.7, 128.8, 127.4, 125.6, 124.6, 124.0, 123.9, 121.9,
119.0, 116.5, 114.4, 111.2, 55.4, 30.3 (q, J= 31.2 Hz), 27.6.

Acetic acid 3-[1-acetyl-5-chloro-2-(4-
methoxy-phenyl)-1H-indol-3-yl]-1-
methyl-propyl ester (4.222)
Prepared analogously to compound
(4.215) in moderate yield (39%).
1
H NMR (400 MHz, CDCl
3
): δ 8.40 (d,
J = 9.0 Hz, 1H), 7.50 (s, 1H), 7.35-7.30 (m, 3H), 7.05 (d, J =8.5 Hz, 2H), 4.84 (m,
1H), 3.92 (s, 3H), 2.54 (m, 2H), 1.99 (s, 3H), 1.97 (s, 3H), 1.89-1.72 (m, 2H), 1.20
(d, J =6.2 Hz, 3H).
13
C NMR (100 MHz, CDCl
3
): δ 171.0, 170.8, 160.1, 136.3,
135.2, 131.5, 130.6, 128.9, 125.1, 124.7, 120.8, 118.1, 117.8, 114.3, 70.4, 55.3,
36.0, 27.5, 21.3, 20.2, 19.7.

N
OMe
Cl
CH
3
O
OAc
396
2-Acetyl-1-benzo[b]thiophen-2-yl-2H-2-
aza-aceanthrylen-6-one (4.224)
Prepared analogously to compound (4.215) in
moderate yield (33%).
1
H NMR (400 MHz, CDCl
3
): δ 8.67 (d, J =
7.6 Hz, 1H), 8.54 (d, J = 8.8 Hz, 1H), 8.29
(d, J = 7.6 Hz, 1H), 8.06-8.00 (m, 2H), 7.72 (t, J = 8.8 Hz, 2H), 7.60-7.57 (m, 2H),
7.48 (t, J =7.2 Hz, 1H), 7.41-7.35 (m, 2H), 2.35 (s, 3H).
13
C NMR (100 MHz,
CDCl
3
): δ 183.3, 170.8, 141.5, 139.2, 135.7, 133.0, 132.9, 132.7, 131.8, 129.0,
128.7, 128.0, 127.6, 126.1, 125.4, 124.8, 124.2, 122.9, 122.8, 122.2, 116.6, 26.1.

1-[5-Chloro-2-(4-methoxy-phenyl)-3-
phenyl-indol-1-yl]-ethanone (4.226)
Prepared analogously to compound
(4.215) in 84% yield as a major product
along with 10% yield of compound
(4.205).
1
H NMR (400 MHz, CDCl
3
): δ 8.42 (d, J = 8.9 Hz, 1H), 7.54 (d, J = 1.6 Hz, 1H),
7.38-7.22 (m, 8H), 6.93 (d, J = 8.6 Hz, 2H), 3.87 (s, 3H), 2.04 (s, 3H).
13
C NMR
(100 MHz, CDCl
3
): δ 171.6, 160.1, 136.2, 135.0, 132.7, 132.0, 130.5, 129.9, 129.4,
128.4, 127.1, 125.3, 124.5, 122.4, 119.0, 117.4, 114.2, 55.3, 27.9.

O
N
S
CH
3
O
N
Ph
OMe
Cl
CH
3
O
397

1-[3-Cyclopropyl-2-(4-methoxy-phenyl)-
indol-1-yl]-ethanone (4.227)
Prepared analogously to compound (4.215) in
moderate yield (42%) as a major product
along with cyclopropyl-2-(4-methoxy-
phenyl)-1H-indole (7 %) (4.228).
1
H NMR (400 MHz, CDCl
3
) major product: δ 8.44 (d, J = 7.4 Hz, 1H), 7.67 (d, J =
8.3 Hz, 1H), 7.39 (d, J = 8.8 Hz, 3H), 7.36-7.30 (m, 2H), 7.04 (d, J = 7.7 Hz, 2H),
3.93 (s, 3H), 2.00 (s, 3H), 1.82-1.72 (m, 1H), 0.80-0.75 (m, 2H), 0.60-0.56 (m, 2H).
13
C NMR (100 MHz, CDCl
3
) major product: δ 171.5, 159.7, 136.7, 136.1, 131.7,
129.7, 125.8, 124.9, 123.3, 122.0, 119.1, 116.3, 114.0, 55.3, 27.8, 6.6, 5.7.

N
OMe
CH
3
O
398

1-(2-Benzofuran-2-yl-5-chloro-3-trifluoromethyl-indol-1-yl)-ethanone (4.229)
Prepared analogously to compound (4.215) in 23% yield as a minor product along
with major product 2-benzofuran-2-yl-5-chloro-3-trifluoromethyl-1H-indole
(4.230).
1
H NMR (400 MHz, CDCl
3
) minor product (4.92): δ 8.36 (d, J = 9.6 Hz, 1H), 7.81
(s, 1H), 7.72 (d, J = 7.7 Hz, 1H), 7.59 (d, J = 8.2 Hz, 1H), 7.47-7.44 (m, 2H), 7.39-
7.35 (m, 1H), 7.22 (s, 1H), 2.12 (s, 3H).
19
F NMR (376 MHz, CDCl
3
): δ −55.1.
13
C
NMR (100 MHz, CDCl
3
): δ 170.4, 155.3, 142.7, 134.7, 130.5, 128.8, 127.6, 127.5,
126.4, 125.4, 124.0, 122.1, 121.5, 119.8, 117.5, 114.0 (q, J = 35.9 Hz), 111.8, 25.0.
1
H NMR (400 MHz, CDCl
3
) major product (4.93): δ 9.13 (s, 1H), 7.73 (s, 1H), 7.58
(d, J = 7.2 Hz, 1H), 7.44 (d, J =7.9 Hz, 1H), 7.32-7.17 (m, 5H).
19
F NMR (376
MHz, CDCl
3
): δ −54.9.
13
C NMR (100 MHz, CDCl
3
): δ 154.3, 144.9, 132.9, 128.9,
127.8, 126.5, 125.7, 124.6, 123.7, 122.0, 121.5, 119.6, 112.4, 111.5, 111.1, 107.8.

N
CF
3
Cl
CH
3
O
O
N
H
CF
3
Cl
O
399
4.4.3 Chapter 4 NMR spectra
10 8 6 4 2 0 PPM
1
H NMR (400 MHz, CDCl
3
) of 4.78
0 -20 -40 -60 -80 -100 -120 -140 -160 PPM
19
F NMR (400 MHz, CDCl
3
) of 4.78
O
NH
2
CF
3
400
200 150 100 50 PPM
13
C NMR (100 MHz, CDCl
3
) of 4.78

O
NH
2
CF
3
401
10 8 6 4 2 0PPM
1
H NMR (400 MHz, CDCl
3
) of 4.80

200 150 100 50 0 PPM
13
C NMR (100 MHz, CDCl
3
) of 4.80

O
NH
2
402
10 8 6 4 2 0 PPM
1
H NMR (400 MHz, CDCl
3
) of 4.90

0 -20 -40 -60 -80 -100 -120 -140 -160 -180 PPM
19
F NMR (400 MHz, CDCl
3
) of 4.90

O
NH F
403
200 150 100 50 0 PPM
13
C NMR (100 MHz, CDCl
3
) of 4.90

O
NH F
404
10 8 6 4 2 0 PPM
1
H NMR (400 MHz, CDCl
3
) of 4.82

200 150 100 50 0 PPM
13
C NMR (100 MHz, CDCl
3
) of 4.82

O
NH
2
405
10 8 6 4 2 0 PPM
1
H NMR (400 MHz, CDCl
3
) of 4.84

200 150 100 50 0 PPM
13
C NMR (100 MHz, CDCl
3
) of 4.84

O
N
NH
2
406
10 8 6 4 2 0 PPM
1
H NMR (400 MHz, CDCl
3
) of 4.86

200 150 100 50 0 PPM
13
C NMR (100 MHz, CDCl
3
) of 4.86

O
NH
2
Cl
407
8 7 6 5 4 3 2 1 PPM
1
H NMR (250 MHz, CDCl
3
) of 4.98

200 150 100 50 0 PPM
13
C NMR (62.5 MHz, CDCl
3
) of 4.98

O
NMe
2
O
NH
2
408
10 8 6 4 2 0 PPM
1
H NMR (400 MHz, DMSO-d
6
) of 4.101

200 150 100 50 0 PPM
13
C NMR (100 MHz, DMSO-d
6
) of 4.101

O
N
O
NH
2
O
2
N
O
409
10 8 6 4 2 PPM
1
H NMR (400 MHz, CDCl
3
) of 4.96

200 150 100 50 0 PPM
13
C NMR (100 MHz, CDCl
3
) of 4.96

NH
2
O
410
8 7 6 5 4 3 2 1 PPM
1
H NMR (250 MHz, CDCl
3
) of 4.93

200 150 100 50 0 PPM
13
C NMR (62.5 MHz, CDCl
3
) of 4.93

NH
2 O
411
7 6 5 4 3 2 1 PPM
1
H NMR (400 MHz, CDCl
3
) of 4.66

-20 -40 -60 -80 -100 -120 PPM
19
F NMR (376 MHz, CDCl
3
) of 4.66
ON
O
CF
3
412
200 150 100 50 0 PPM
13
C NMR (100 MHz, CDCl
3
) of 4.66

ON
O
CF
3
413
9 8 7 6 5 4 3 2 1 0 PPM
1
H NMR (400 MHz, CDCl
3
) of 4.238
200 150 100 50 0 PPM
13
C NMR (100 MHz, CDCl
3
) of 4.238

Cl
NH
O
414
8 7 6 5 4 3 2 1 PPM
1
H NMR (400 MHz, CDCl
3
) of 4.67

0 -20 -40 -60 -80 -100 -120 -140 PPM
19
F NMR (376 MHz, CDCl
3
) of 4.67

Cl
NH
2
O
CF
3
415
200 180 160 140 120 100 80 60 PPM
13
C NMR (100 MHz, CDCl
3
) of 4.67

Cl
NH
2
O
CF
3
416
8 7 6 5 4 3 2 1 PPM
1
H NMR (400 MHz, CDCl
3
) of 4.68

-119.0 -119.5 -120.0 -120.5 -121.0 -121.5 -122.0 -122.5 -123.0 PPM
0 -50 -100 -150 PPM
19
F NMR (376 MHz, CDCl
3
) of 4.68

ON
O
CF
2
H
417
150 100 50 PPM
13
C NMR (100 MHz, CDCl
3
) of 4.68

ON
O
CF
2
H
418
9 8 7 6 5 4 3 2 1 PPM
1
H NMR (400 MHz, CDCl
3
) of 4.69

-90 -100 -110 -120 -130 -140 -150 PPM
19
F NMR (376 MHz, CDCl
3
) of 4.69

Cl
NH
2
O
CF
2
H
419
200 180 160 140 120 100 80 60 40 PPM
13
C NMR (100 MHz, CDCl
3
) of 4.69

Cl
NH
2
O
CF
2
H
420
9 8 7 6 5 4 3 2 1 PPM
1
H NMR (250 MHz, CDCl
3
) of 4.71
200 150 100 50 0 PPM
13
C NMR (62.5 MHz, CDCl
3
) of 4.71
O
OH
Cl
NH
2
421
8 6 4 2 0 PPM
1
H NMR (400 MHz, CDCl
3
) of 4.191

200 150 100 50 0 PPM
13
C NMR (100 MHz, CDCl
3
) of 4.191

O
Ph
NH
Cl
422
8 7 6 5 4 3 2 1 PPM
1
H NMR (400 MHz, acetone-d
6
) of 4.115

200 150 100 50 0 PPM
13
C NMR (62.5 MHz, acetone-d
6
) of 4.115

Br
NH
HO
2
C
F
423
8 7 6 5 4 3 2 1 PPM
1
H NMR (400 MHz, acetone-d
6
) of 4.117

150 100 50 PPM
13
C NMR (62.5 MHz, acetone-d
6
) of 4.117

Cl
NH
HO
2
C
424
10 8 6 4 2 PPM
1
H NMR (400 MHz, acetone-d
6
) of 4.119

150 100 50 0 PPM
13
C NMR (62.5 MHz, acetone-d
6
) of 4.119

NH
HO
2
C
NO
2
425
10 8 6 4 2 0 PPM
1
H NMR (400 MHz, acetone-d
6
) of 4.121

180 160 140 120 100 80 60 40 20 PPM
13
C NMR (62.5 MHz, acetone-d
6
) of 4.121

NH
HO
2
C
CN
426
water
8 7 6 5 4 3 2 1 PPM
1
H NMR (400 MHz, methanol-d
4
) of 4.123

200 150 100 50 0 PPM
13
C NMR (62.5 MHz, methanol-d
4
) of 4.123

NH
HO
2
C
OMe
427
9 8 7 6 5 4 3 2 1 PPM
1
H NMR (400 MHz, acetone-d
6
) of 4.124

180 160 140 120 100 80 60 40 20 PPM
13
C NMR (62.5 MHz, acetone-d
6
) of 4.124

NH
HO
2
C
428
8 7 6 5 4 3 2 1 PPM
1
H NMR (400 MHz, acetone-d
6
) of 4.126

180 160 140 120 100 80 60 40 20 PPM
13
C NMR (62.5 MHz, acetone-d
6
) of 4.126

NH
HO
2
C
H
3
C
429
8 7 6 5 4 3 2 1 PPM
1
H NMR (400 MHz, methanol-d
4
) of 4.128

180 160 140 120 100 80 60 40 20 PPM
13
C NMR (100 MHz, methanol-d
4
) of 4.128

N
HO
2
C
430
10 8 6 4 2 PPM
1
H NMR (400 MHz, acetone-d
6
) of 4.130

180 160 140 120 100 80 60 40 20 PPM
13
C NMR (100 MHz, acetone-d
6
) of 4.130

NH
HO
2
C
OH
O
431
8 7 6 5 4 3 PPM
1
H NMR (400 MHz, methanol-d
4
) of 4.134

180 160 140 120 100 80 60 40 20 PPM
13
C NMR (100 MHz, methanol-d
4
) of 4.134

OMe
O
NH
HO
2
C
OMe
432
water
8 7 6 5 4 3 2 1 PPM
1
H NMR (250 MHz, methanol-d
4
) of 4.136

180 160 140 120 100 80 60 40 20 PPM
13
C NMR (100 MHz, methanol-d
4
) of 4.136

OMe
O
NH
HO
2
C
S
433
8 7 6 5 4 3 2 1 PPM
1
H NMR (250 MHz, methanol-d
4
) of 4.138

180 160 140 120 100 80 60 40 20 PPM
13
C NMR (62.5 MHz, methanol-d
4
) of 4.138

NH
2
O
NH
HO
2
C
S
434
8 7 6 5 4 3 2 1 PPM
1
H NMR (400 MHz, methanol-d
4
) of 4.139

180 160 140 120 100 80 60 40 20 PPM
13
C NMR (62.5 MHz, methanol-d
4
) of 4.139

NH
2
O
NH
HO
2
C
OMe
435
8 7 6 5 4 3 2 1 PPM
1
H NMR (400 MHz, methanol-d
4
) of 4.140

200 150 100 50 PPM
13
C NMR (100 MHz, methanol-d
4
) of 4.140

N
H
O
NH
HO
2
C
OMe
OMe
436
8 7 6 5 4 3 2 1 PPM
1
H NMR (250 MHz, methanol-d
4
) of 4.141

200 150 100 50 0 PPM
13
C NMR (62.5 MHz, methanol-d
4
) of 4.141

O
NH
HO
2
C
OMe
O
NMe
2
437
9 8 7 6 5 4 3 2 1 PPM
1
H NMR (400 MHz, acetone-d
6
) of 4.142

200 150 100 50 PPM
13
C NMR (62.5 MHz, acetone-d
6
) of 4.142

O
NH
HO
2
C
OMe
O
N O
2
N
O
438
10 8 6 4 2 PPM
1
H NMR (400 MHz, acetone-d
6
) of 4.145

200 150 100 50 0 PPM
13
C NMR (62.5 MHz, acetone-d
6
) of 4.145

Cl
O
Ph
NH
HO
2
C
OMe
439
8 7 6 5 4 3 2 1 PPM
1
H NMR (400 MHz, methanol-d
4
) of 4.165

-20 -40 -60 -80 -100 -120 PPM
19
F NMR (376 MHz, methanol-d
4
) of 4.165

Cl
O
CF
3
NH
HO
2
C
OMe
440
180 160 140 120 100 80 60 40 20 PPM
13
C NMR (62.5 MHz, methanol-d
4
) of 4.165

Cl
O
CF
3
NH
HO
2
C
OMe
441
8 7 6 5 4 3 2 1 0 PPM
1
H NMR (400 MHz, methanol-d
4
) of 4.167

200 150 100 50 0 PPM
13
C NMR (62.5 MHz, methanol-d
4
) of 4.167

O
CH
3
NH
HO
2
C
OMe
442
10 8 6 4 2 0PPM
1
H NMR (400 MHz, methanol-d
4
) of 4.170

200 150 100 50 PPM
13
C NMR (100 MHz, methanol-d
4
) of 4.170

H
O
NH
HO
2
C
OMe
Cl
443
8 7 6 5 4 3 2 1 PPM
1
H NMR (250 MHz, methanol-d
4
) of 4.171

200 150 100 50 0 PPM
13
C NMR (62.5 MHz, methanol-d
4
) of 4.171

NH
O
HO
2
C
OMe
444
7 6 5 4 3 2 1 PPM
1
H NMR (400 MHz, methanol-d
4
) of 4.172

200 150 100 50 PPM
13
C NMR (100 MHz, methanol-d
4
) of 4.172

NH
CO
2
H
MeO
O
445
10 8 6 4 2 PPM
1
H NMR (400 MHz, acetone-d
6
) of 4.173

180 160 140 120 100 80 60 40 20 PPM
13
C NMR (62.5 MHz, acetone-d
6
) of 4.173

O
NH
HO
2
C
OMe
446
10 8 6 4 2 0 PPM
1
H NMR (400 MHz, acetone-d
6
) of 4.174

0 -20 -40 -60 -80 -100 -120 PPM
19
F NMR (376 MHz, acetone-d
6
) of 4.174

CH
2
CF
3
O
NH
HO
2
C
OMe
447
200 150 100 50 PPM
13
C NMR (62.5 MHz, acetone-d
6
) of 4.174

CH
2
CF
3
O
NH
HO
2
C
OMe
448
8 7 6 5 4 3 2 1 0 PPM
1
H NMR (250 MHz, acetone-d
6
) of 4.175

200 150 100 50 PPM
13
C NMR (62.5 MHz, acetone-d
6
) of 4.175

O
NH
HO
2
C
OMe
449
10 8 6 4 2 PPM
1
H NMR (400 MHz, acetone-d
6
) of 4.177

200 150 100 50 PPM
13
C NMR (62.5 MHz, acetone-d
6
) of 4.177

O
Ph
NH
HO
2
C
OMe
450
10 8 6 4 2 PPM
1
H NMR (400 MHz, acetone-d
6
) of 4.147

200 150 100 50 0 PPM
13
C NMR (100 MHz, methanol-d
4
) of 4.147

O
Ph
NH
HO
2
C
S
Cl
451
10 8 6 4 2 PPM
1
H NMR (400 MHz, methanol-d
4
) of 4.180

200 150 100 50 PPM
13
C NMR (100 MHz, methanol-d
4
) of 4.180

O
CH
3
NH
HO
2
C
O
452
10 8 6 4 2 PPM
1
H NMR (400 MHz, acetone-d
6
) of 4.156

150 100 50 PPM
13
C NMR (100 MHz, acetone-d
6
) of 4.156

O
Ph
NH
HO
2
C
S
Cl
453
10 8 6 4 2 PPM
1
H NMR (400 MHz, acetone-d
6
) of 4.181

180 160 140 120 100 80 60 40 20 PPM
13
C NMR (62.5 MHz, acetone-d
6
) of 4.181

CF
3
O
NH
HO
2
C
Cl
O
454
10 8 6 4 2 PPM
1
H NMR (400 MHz, acetone-d
6
) of 4.183

200 150 100 50 PPM
13
C NMR (62.5 MHz, acetone-d
6
) of 4.183

CH
3
O
NH
HO
2
C
455
10 8 6 4 2 PPM
1
H NMR (400 MHz, acetone-d
6
) of 4.184

-121 -122 -123 -124 -125 -126 -127 PPM
-20 -40 -60 -80 -100 -120 -140 -160 -180 PPM
19
F NMR (376 MHz, acetone-d
6
) of 4.184

CF
2
H
O
NH
HO
2
C
Cl
O
456

180 160 140 120 100 80 60 40 20 PPM
13
C NMR (62.5 MHz, acetone-d
6
) of 4.184

CF
2
H
O
NH
HO
2
C
Cl
O
457
8 7 6 5 4 3 2 1 0 PPM
1
H NMR (400 MHz, methanol-d
4
) of 4.158

200 150 100 50 PPM
13
C NMR (100 MHz, methanol-d
4
) of 4.158

Ph
O
NH
HO
2
C
Cl
Br
458
8 7 6 5 4 3 2 1 PPM
1
H NMR (250 MHz, methanol-d
4
) of 4.185

200 150 100 50 0 PPM
13
C NMR (62.5 MHz, methanol-d
4
) of 4.185

O
CH
3
NH
HO
2
C
S
459
8 7 6 5 4 3 2 PPM
1
H NMR (400 MHz, CDCl
3
) of 4.161

200 150 100 50 0 PPM
13
C NMR (62.5 MHz, CDCl
3
) of 4.161

Ph
O
NH
HO
2
C
Cl
460
9 8 7 6 5 4 3 2 1 PPM
1
H NMR (400 MHz, acetone-d
6
) of 4.186

180 160 140 120 100 80 60 40 20 PPM
13
C NMR (62.5 MHz, acetone-d
6
) of 4.186

N
H
O
NH
HO
2
C
OMe
461
8 7 6 5 4 3 2 1 0 PPM
1
H NMR (400 MHz, methanol-d
4
) of 4.194

200 150 100 50 0 PPM
13
C NMR (100 MHz, methanol-d
4
) of 4.194

O
Ph
N
HO
2
C
OMe
OMe
462
8 7 6 5 4 3 2 1 PPM
1
H NMR (400 MHz, CDCl
3
) of 4.162

200 150 100 50 0 PPM
13
C NMR (100 MHz, CDCl
3
) of 4.162

Cl
O
Ph
NH
MeO
2
C
OMe
463
8 7 6 5 4 3 2 1 PPM
1
H NMR (400 MHz, CDCl
3
) of 4.203

180 160 140 120 100 80 60 40 20 PPM
13
C NMR (100 MHz, CDCl
3
) of 4.203

N
H
CH
3
OMe
464

9 8 7 6 5 4 3 2 1 PPM
1
H NMR (400 MHz, CDCl
3
) of 4.204
180 160 140 120 100 80 60 40 20 PPM
13
C NMR (62.5 MHz, CDCl
3
) of 4.204
N
H
Ph
OMe
Cl
465
9 8 7 6 5 4 3 2 1 0 PPM
1
H NMR (400 MHz, CDCl
3
) of 4.205

180 160 140 120 100 80 60 40 20 PPM
13
C NMR (100 MHz, CDCl
3
) of 4.205

N
H
Ph
OMe
466
8 6 4 2 PPM
1
H NMR (250 MHz, CDCl
3
) of 4.206

200 150 100 50 PPM
13
C NMR (62.5 MHz, CDCl
3
) of 4.206

N
H
CH
3
Boc
N
467
8 6 4 2 PPM
1
H NMR (400 MHz, CDCl
3
) of 4.207

160 140 120 100 80 60 40 20 PPM
13
C NMR (100 MHz, CDCl
3
) of 4.207

N
H
Ph
Boc
N
Cl
468
9 8 7 6 5 4 3 2 1 0PPM
1
H NMR (400 MHz, CDCl
3
) of 4.208

160 140 120 100 80 60 40 20 PPM
13
C NMR (100 MHz, CDCl
3
) of 4.208

N
H
Ph
S
Cl
469
10 8 6 4 2 PPM
1
H NMR (400 MHz, CDCl
3
) of 4.209

150 100 50 PPM
13
C NMR (100 MHz, methanol-d
4
) of 4.209

N
H
OMe
NMe
2
O
470
9 8 7 6 5 4 3 2 1 PPM
1
H NMR (400 MHz, CDCl
3
) of 4.210

200 150 100 50 PPM
13
C NMR (100 MHz, CDCl
3
) of 4.210

N
H
Ph
Boc
N
Cl
471
8 6 4 2 PPM
1
H NMR (400 MHz, CDCl
3
) of 4.211

200 150 100 50 PPM
13
C NMR (100 MHz, CDCl
3
) of 4.211

N
H
OMe
472
9 8 7 6 5 4 3 2 1 PPM
1
H NMR (400 MHz, CDCl
3
) of 4.215

200 150 100 50 0 PPM
13
C NMR (100 MHz, CDCl
3
) of 4.215

N
H
Cl
OMe
CH
3
O
473
8 7 6 5 4 3 2 1 PPM
1
H NMR (400 MHz, CDCl
3
) of 4.237

180 160 140 120 100 80 60 40 20 PPM
13
C NMR (100 MHz, CDCl
3
) of 4.237

N
Ph
OMe
Cl
474
9 8 7 6 5 4 3 2 1 PPM
1
H NMR (400 MHz, CDCl
3
) of 4.216

-20 -40 -60 -80 -100 -120 PPM
19
F NMR (376 MHz, CDCl
3
) of 4.216

N
CF
3
OMe
Cl
CH
3
O
475

150 100 50 PPM
13
C NMR (62.5 MHz, CDCl
3
) of 4.216

N
CF
3
OMe
Cl
CH
3
O
476
10 8 6 4 2 PPM
1
H NMR (400 MHz, CDCl
3
) of 4.217

180 160 140 120 100 80 60 40 20 PPM
13
C NMR (100 MHz, CDCl
3
) of 4.217

N
Ph
Ph
Cl
CH
3
O
477
9 8 7 6 5 4 3 2 1 0 PPM
1
H NMR (400 MHz, CDCl
3
) of 4.218

180 160 140 120 100 80 60 40 20 PPM
13
C NMR (100 MHz, CDCl
3
) of 4.218

N
Ph
Cl
CH
3
O
478
9 8 7 6 5 4 3 2 1 PPM
1
H NMR (400 MHz, CDCl
3
) of 4.219

180 160 140 120 100 80 60 40 20 PPM
13
C NMR (100 MHz, CDCl
3
) of 4.219

N
NHAc
OMe
CH
3
O
479
10 8 6 4 2 0 PPM
1
H NMR (400 MHz, CDCl
3
) of 4.220

-106 -107 -108 -109 -110 -111 -112 PPM
-20 -40 -60 -80 -100 -120 -140 -160 -180 PPM
19
F NMR (376 MHz, CDCl
3
) of 4.220

N
CF
2
H
Cl
CH
3
O
O
480

180 160 140 120 100 80 60 40 20 PPM
13
C NMR (62.5 MHz, CDCl
3
) of 4.220

N
CF
2
H
Cl
CH
3
O
O
481
9 8 7 6 5 4 3 2 1 PPM
1
H NMR (400 MHz, CDCl
3
) of 4.221

30 -40 -50 -60 -70 -80 -90 -100 PPM
19
F NMR (376 MHz, CDCl
3
) of 4.221

N
CH
2
CF
3
OMe
CH
3
O
482

200 150 100 50 PPM
13
C NMR (100 MHz, CDCl
3
) of 4.221

N
CH
2
CF
3
OMe
CH
3
O
483
10 8 6 4 2 0 PPM
1
H NMR (400 MHz, CDCl
3
) of 4.222

180 160 140 120 100 80 60 40 20 PPM
13
C NMR (100 MHz, CDCl
3
) of 4.222

N
OMe
Cl
CH
3
O
OAc
484
9 8 7 6 5 4 3 2 1 PPM
1
H NMR (400 MHz, CDCl
3
) of 4.224

180 160 140 120 100 80 60 40 20 PPM
13
C NMR (100 MHz, CDCl
3
) of 4.224

O
N
S
CH
3
O
485
8 6 4 2 PPM
1
H NMR (400 MHz, CDCl
3
) of 4.226

180 160 140 120 100 80 60 40 20 PPM
13
C NMR (100 MHz, CDCl
3
) of 4.226

N
Ph
OMe
Cl
CH
3
O
486
8 6 4 2 PPM
1
H NMR (400 MHz, CDCl
3
) of 4.227

150 100 50 PPM
13
C NMR (100 MHz, CDCl
3
) of 4.227

N
OMe
CH
3
O
487
10 8 6 4 2 0 PPM
1
H NMR (400 MHz, CDCl
3
) of 4.229

-55.048
0 -20 -40 -60 -80 -100 PPM
19
F NMR (376 MHz, CDCl
3
) of 4.229

N
CF
3
Cl
CH
3
O
O
488

150 100 50 PPM
13
C NMR (100 MHz, CDCl
3
) of 4.229

N
CF
3
Cl
CH
3
O
O
489
10 8 6 4 2 PPM
1
H NMR (400 MHz, CDCl
3
) of 4.230

0 -20 -40 -60 -80 -100 PPM
19
F NMR (376 MHz, CDCl
3
) of 4.230

N
H
CF
3
Cl
O
490
180 160 140 120 100 80 60 40 20 PPM
13
C NMR (100 MHz, CDCl
3
) of 4.230

N
H
CF
3
Cl
O
491
Chapter 5. Novel Approach to Fused
N-Heterocycles
5.1 Introduction
5.1.1 Importance of Aromatic Fused N-Heterocycles
A vast majority of compounds produced by mature contain an aromatic
heterocyclic moiety as a part of their structures. Aromatic heterocycles can be
found in pharmaceuticals, agrochemicals, polymers, perfumes etc. Fused N-
heterocycles such as presented in Figure 5.1 have recently gained some attention.
However there is no general and practical route for their synthesis.
X
Y N
R
3
R
2
R
1
5.01
X
Y
N
R
2
R
3
R
1
5.02

Figure 5.1 Structures of Fused N-Heterocycles
5.2 Results and discussion
This section discusses utilization of the Petasis reaction with 2-
aminoheteroaryl ketones for the synthesis of α-amino acids which serve as starting
materials for the synthesis of novel N-heterocyclic structures as shown in Figure
5.2.
492
R
1
N
R
2
H
B(OR)
2
R
3
H
O
O
HO
S
N
R
R
3 R
6
R
7
S
R
4
R
5
N
R
R
3
N
O R
N
R
3
O
N
R
R
3
R1 R
1
R
1
R
1

Figure 5.2 Synthesis of Novel N-Heterocycles
Additionally, the syntheses of novel 2-aminoheteroaryl ketones are described.
5.2.1 Importance and Syntheses of 2-Amino Heteroaryl Ketones
In our quest for the synthesis of 2-aminoheteroaryl ketones we discovered
that polysubstituted 2-aminothiophenes 5.06 can be prepared via the Gewald
reaction as shown in Scheme 5.01.
243

R
1
O
R
2
R
3
O
CN S
8
S
NH
2
R
3
O
R
1
R
2
5.06 5.03 5.04 5.05
Base
EtOH

Scheme 5.1 Synthesis of Polysubstituted 2-Aminothiophenes via the Gewald
Reaction

243
Gewald, K.; Schinke, E.; Böttcher, H. Ber. 1966, 99, 94.
493
The Gewald reaction is a multicomponent condensation that involves sulfur 5.05,
α-methylene carbonyl compound 5.03 and α-cyano-compound 5.04 (originally α-
cyanoester). The mechanism of the reaction is known only partially. The first step
is a Knoevenagel condensation between ketone 5.03 and activated nitrile 5.04 in
order to produce a stable intermediate 5.07 as presented in Scheme 5.02. The exact
mechanism of the remainder of the sequence that involves addition of the elemental
sulfur is unknown.
244

Base
R
1
O
R
2
R
3
O
CN
5.03 5.04
- H
2
O
R
3
O
CN
R
1
R
2
5.07
S
8
S
NH
2
R
3
O
R
1
R
2
5.06

Scheme 5.2 Plausible Mechanism of the Gewald Reaction
We have quickly recognized that if α-cyanocarbonyl compounds are utilized in the
process instead of α-cyanoesters, 2-aminothiophene ketones can be prepared. Using
typical Gewald reaction conditions, ethanol and triethylamine as base, we have
been able to synthesize a variety of 2-aminothiophene ketones in good yields from
different α-methylene carbonyl compounds and α-cyano-compounds as Table 5.1
demonstrates.

244
Sabnis, R. W.; Rangnekar, D. W.; Sonawane, N. D. J. Heterocyclic Chem. 1999,
36, 333
494
Table 5.1 Synthesis of 2-Amino Heteroaryl Ketones via the Gewald Reaction
Entry Carbonyl Compound Product Yield [%]
1
O

5.08
S
O
Ph
NH
2

5.09
84
2
N
Me
O

5.10
MeN
S
O
Ph
NH
2

5.11
61
3
H
O

5.12
Ph
S
O
Ph
NH
2

5.13
88
4
O

5.14
S
O
Ph
NH
2

5.15
64
5
O
5.16
H
3
C
H
3
C
S
O
Ph
NH
2

5.17
33

495
Table 5.1 Table Cont.
Entry Carbonyl Compound Product Yield [%]
6
O

5.08
S
O
NH
2
NO
2

5.18
46

We wanted to explore syntheses of other 2-amino heteroaryl ketones such
as benzofuran-, benzothiophene- or indole- derivatives. It turned out that these
compounds are intermediates for the syntheses of corresponding [3,2-
b]quinolines.
245

We have utilized this known approach for preparation of 2-aminobenzofuran
ketones 5.21 as presented in Scheme 5.3.
O
NH
2
O
CN
OH
5.19
O
Br
5.20 5.21
K
2
CO
3
acetone

Scheme 5.3 Synthesis of 2-Aminobenzofuran Ketones

245
Radl, S.; Konvicka, P.; Vachal, P. J. Heterocyclic Chem. 2000, 37, 855.
496
Table 5.2 Synthesis of 2-Aminobenzofuran Ketones
Entry Product Yield [%]
1
O
NH
2
O
5.22
66
2
O
NH
2
O
Br

5.23
95

The process utilizes α-bromoketones 5.20 and salicylonitriles 5.19. In the presence
of base, such as potassium carbonate in dry acetone we have been able to prepare
the desired product as Table 5.2 illustrates. Nevertheless, we had to synthesize the
salicylonitriles 5.19 due to their limited commercial availability. Their three step
synthesis from salicylaldehyde derivatives 5.24 is presented in Scheme 5.4.
CN
OH
5.19
H
O
OH
5.24 5.25
H
N
OH
HO
DDQ, DCM
NH
2
OH
.
HCl
PPh
3
CH
3
COONa
aq. EtOH
O
N
5.26
3N NaOH

Scheme 5.4 Syntheses of Salicylonitriles
497
Similarly to the synthesis of 2-aminobenzofuran ketones we have prepared
2-aminoindole ketones 5.28. As staring materials we have utilized N-protected
anthranilonitrile 5.27 and α-bromo-ketone 5.20 as presented in Scheme 5.5.
N
P
NH
2
O
CN
NHP
5.27
O
Br
5.20 5.28
K
2
CO
3
acetone

Scheme 5.5 Synthesis of 2-Aminoindole Ketones
Table 5.3 summarizes the results. The N-protected anthranilonitriles 5.35 were
prepared according to literature procedures as presented in Scheme 5.6 starting
from 2-aminobenzonitrile 5.29.
CN
NH
5.35
CN
NH
2
5.29
R
O
Cl
5.33
R O
(RC=O)
2
O
5.34

Scheme 5.6 Synthesis of N-Protected Anthranilonitriles

498
Table 5.3 Preparation of 2-Aminoindole Ketones
Entry Product Yield [%]
1
N
NH
2
O
Ph
O
Ph
5.30
71
2
N
NH
2
O
Ph
O
H
3
C

5.31
55
3
N
NH
2
O
Ph
O
Cl

5.32
84

5.2.2 Synthesis of α-Amino Acids via Petasis Reaction
We have utilized the above prepared 2-aminoheteroaryl ketones in the
synthesis of corresponding α-amino acids as shown in Scheme 5.7.
499
O
R
1
NH
HO
2
C R
4
H
O
O
OH
R
4
B(OR)
2
5.36 5.37 5.38
MeCN
rt
O
R
1
NH
2
5.39
Y
Z
X
Y
Z
X

Scheme 5.7 Synthesis of α-Amino Acids via the Petasis Reaction
A variety of amines (2-amino-, 3-amino-hetroaryl ketones) and boronic acids were
employed in the condensation with great success in usually short time (1 hour to 12
hours maximum). The yields of the reaction vary from moderate to excellent
depending on starting materials used in the process. The reaction was performed at
room temperature using acetonitrile as a solvent.
Table 5.4 Synthesis of α-Amino Acids via Petasis Reaction from
Aminoheteroaryl Ketones
Entry Amine Product Yield [%]
1
S
O
Ph
NH
2

5.09
S
O
Ph
NH Ph
HO
O
5.40
83

500
Table 5.4 Cont.
Entry Amine Product Yield [%]
2
S
O
NH
2
NO
2

5.18
S
O
NH Ph
HO
O
NO
2

5.41
82
3
S
O
Ph
NH
2

5.09
S
O
Ph
NH
OMe
O
OH
5.42
55
4
Ph
S
O
Ph
NH
2

5.13
Ph
S
O
Ph
NH
OMe
O
OH
5.43
81
5
S
O
Ph
NH
2

5.15
S
O
Ph
NH Ph
HO
O
5.44
45

501
Table 5.4 Cont.
Entry Amine Product Yield [%]
6
S
NH
2
O
CH
3

5.45
S
NH
O
CH
3
HO O
MeO

5.46
82
7
S
NH
2
O
CH
3

5.45
S
NH
O
CH
3
Ph OH
O

5.47
99
8
S
NH
2
O
CH
3

5.45
S
NH
O
CH
3
OH
O
S

5.48
54
9
S
NH
2
O
CH
3

5.45
S
NH
O
CH
3
OH
O
Br

5.49
40

502
Table 5.4 Cont.
Entry Amine Product Yield [%]
10
H
3
C
H
3
C
S
O
Ph
NH
2

5.50
H
3
C
H
3
C
S
O
Ph
NH
O
OH
OMe

5.51
75
11
S
NH
2
O
CH
3

5.45
S
NH
O
CH
3
OH
O
H
3
C
H
3
C

5.52
96
12
S
NH
2
O
CH
3

5.45
S
NH
O
CH
3
OH
O
O

5.53
67
13
O
NH
2
O
Ph

5.22
O
NH
O
Ph
HO
O
MeO

5.54
55
503
Table 5.4 Cont.
Entry Amine Product Yield [%]
14
O
NH
2
O
Ph
Br

5.23
O
NH
O
Ph
HO
O
Ph
Br

5.55
66
15
O
NH
2
O
Ph
O
2
N

5.56
O
NH
O
Ph
HO
O
MeO
O
2
N

5.57
77
16
O
NH
2
O
Ph

5.22
O
NH
O
Ph
HO
O
O

5.58
71
17
O
NH
2
O
Ph
O
2
N

5.56
O
NH
O
Ph
OH
O
O
2
N
S

5.59
61
504
Table 5.4 Cont.
Entry Amine Product Yield [%]
18
N
NH
2
O
Ph
O
H
3
C

5.31
N
NH
O
Ph
OH
O
O
O
H
3
C

5.60
55
19
N
NH
2
O
Ph
O
H
3
C

5.31
N
NH
O
Ph
OH
O
S
O
H
3
C

5.61
27
20
N
NH
2
O
Ph
O
Cl

5.32
N
NH
O
Ph
OH
O
S
O
Cl

5.62
84

505
Table 5.4 Cont.
Entry Amine Product Yield [%]
21
N
NH
2
O
Ph
O
Cl

5.32
N
NH
O
Ph
OH
O
O
O
Cl

5.63
55
22
N
NH
2
O
Ph
O
Cl

5.32
N
NH
O
Ph
HO
O
O
Cl
Ph

5.64
68
23
N
NH
2
O
Ph
O
Ph
5.33
N
NH
O
Ph
OH
O
O
O
Ph
5.65
55

506
5.2.3 Novel Synthetic Approach to New Heterocyclic Scaffolds
Having a variety of α-amino acids synthesized we decided to explore their
reactivity in the intramolecular cyclization we recently developed and previously
described in detail in Chapter 4.
5.2.3.1 Novel Approach to 6H-Thieno[2,3-b]pyrroles
We have investigated the use of different reaction conditions including a
variety of activating agents. However the best results were obtained with acetic
acid anhydride and triethylamine. We explored these conditions for the synthesis of
6H-thieno[2,3-b]pyrroles 5.67 as shown in Scheme 5.8.
NH
S
R
3
O
R
1
R
2
S
R
1
R
2
N
R
3
R
4
CH
3
O
Ac
2
O
Et
3
N
R
4
HO
2
C
5.66 5.67

Scheme 5.8 Synthesis of 6H-Thieno[2,3-b]pyrroles
Table 5.5 represents the results. The yields of the desired products are very high
and the reaction time is usually short (30 minutes). As it is shown we have been
able to generate a variety of 6H-thieno[2,3-b]pyrroles 5.67 that are usually hard to
prepare in a facile way otherwise.

507
Table 5.5 Preparation of 6H-Thieno[2,3-b]pyrroles
Entry Amino Acid Product Yield[%]
1 S
O
Ph
NH
OMe
O
OH
5.42
S
N
Ph
CH
3
O
OMe

5.68
86
2
Ph
S
O
Ph
NH
OMe
O
OH
5.43
Ph
S N
Ph
H
3
C
O
OMe

5.69
95
3
S
O
NH Ph
HO
O
NO
2

5.41
S
N
Ph
H
3
C
O
O
2
N

5.70
76
4
S
O
Ph
NH Ph
HO
O
5.40
S
N
Ph
Ph
H
3
C
O

5.71
95
508
We have explored the possibility to prepare 6H-thienopyrroles in a
sequence without purification of the corresponding α-amino acids as presented in
Scheme 5.9. The main reason we have investigated this approach was that some of
the α-amino acids can be unstable and tend to decompose rather quickly.
NH
S
R
3
O
R
1
R
2
S
R
1
R
2
N
R
3
R
4
CH
3
O
Ac
2
O
Et
3
N
R
4
HO
2
C
5.66 5.67
NH
2
S
R
3
O
R
1
R
2
MeCN
H
O
O
OH
5.72
5.37
R
4
B
OH
OH
5.38

Scheme 5.9 Synthesis of 6H-Thieno[2,3-b]pyrroles without Purification of α-
Amino Acids
Table 5.6 Synthesis of 6H-Thieno[2,3-b]pyrroles without Purification of α-
Amino Acids
Entry Amine Product Yield [%]
1
H
3
C
H
3
C
S
O
Ph
NH
2

5.17
H
3
C
H
3
C
S N
Ph
H
3
C
O
OMe

5.73
70
2
S
O
Ph
NH
2

5.15
S
N
Ph
Ph
CH
3
O
5.74
55

509
Table 5.6 represents the results. We did synthesize the desired products however,
the yields are generally lower than in the use of pre-purified α-amino acids.
5.2.3.2 New Synthesis of 4H-Thieno[3,2-b]pyrroles
As a next step we wanted to expand the scope of the intramolecular
cyclization. For this purpose we made use of α-amino acids of 3-aminothiophene
pyrroles in order to synthesize 4H-thieno[3,2-b]pyrrole derivatives as presented in
Scheme 5.10.
S
R
1
R
2
NH
O
R
3
Ac
2
O
Et
3
N
S
N
CH
3
O
R
3
R
4
R
1
R
2
S
N
H
R
3
R
4
R
1
R
2
CO
2
H
R
4
5.75 5.76 5.77
A
B

Scheme 5.10 Preparation of 4H-Thieno[3,2-b]pyrroles
The results were quite surprising because we obtained two products in the reaction
both, N-acetylated 5.76 and N-non acetylated 4H-thieno[3,2-b]pyrroles 5.77. No
matter how long the reaction was carried out the outcome was the same. Table 5.7
shows the results. Only in two cases have we been able to synthesize only one
product (Entry 1 and 4). The other cases provided mixtures of products with good
yields.

510
Table 5.7 Synthesis of 4H-Thieno[3,2-b]pyrroles
Entry Product A Product B Ratio A:B
1
S
N
CH
3
H
3
C
O
S

5.78
NA 19 % A
2
S
N
CH
3
H
3
C
O
CH
3
CH
3

5.79
S
H
N
CH
3
CH
3
CH
3

5.80
4.9:1
3
S
N
CH
3
OMe
H
3
C
O

5.81
S
H
N
CH
3
OMe

5.82
1.7:1
4
S
N
CH
3
H
3
C
O

5.83
NA 67% A

511
5.2.3.3. Novel Synthesis of Benzofuro[3,2-b]pyrroles
In our quest for expanding the scope of our methodology we explored the
synthesis of benzofuro[3,2-b]pyrroles 5.85 as presented in Scheme 5.11.
O
NH
R
3
R
O
R
4
O
OH
Ac
2
O
Et
3
N
O
N
CH
3
O
R
3
R
4
R
5.84 5.85

Scheme 5.11 Synthesis of Benzofuro[3,2-b]pyrroles
Applying the usual conditions we have been able to synthesize a variety of
benzofuro[3,2-b]pyrroles as presented in Table 5.8 in moderate to good yields. The
synthesis of this heterocyclic scaffold has not been explored in the literature and we
have established a new synthetic route to this class of heterocycles.
Table 5.8 Preparation of Benzofuro[3,2-b]pyrroles
Entry Amino Acid Product Yield [%]
1
O
NH
O
Ph
HO
O
Ph
Br

5.55
O
N
Ph
Ph
O
CH
3
Br

5.86
41

512
Table 5.8 Cont.
Entry Amino Acid Product Yield [%]
2
O
NH
O
Ph
HO
O
OMe
O
2
N

5.57
O
O
2
N
N
Ph
OMe
O
CH
3

5.87
25
3
O
NH
O
Ph
HO
O
O
2
N
S

5.56
O
O
2
N
N
Ph
O
CH
3
S

5.88
25
4
O
NH
O
Ph
HO
O
OMe

5.54
O
N
Ph
OMe
O
CH
3

5.89
75

513
Table 5.8 Cont.
Entry Amino Acid Product Yield [%]
5
O
NH
O
Ph
HO
O
O

5.58
O
N
Ph
O
CH
3
O

5.90
36

5.2.3.4 New Synthetic Approach to 1,4-dihydropyrrolo[3,2-b]indoles
Next we investigated the synthesis of 1,4-dihydropyrrolo[3,2-b]indoles 5.92
from the corresponding α-amino acids 5.91 as presented in Scheme 5.12.
Ac
2
O
Et
3
N
N
NH
O
O
R
R
4
HO
O
N
O
R
N
O
CH
3
R
4
5.91 5.92

Scheme 5.12 Synthesis of 1,4-dihydropyrrolo[3,2-b]indoles
We have been able to generate a variety of polysubstituted 1,4-dihydropyrrolo[3,2-
b]indoles as is shown in Table 5.9. The yields of the desired product are good.

514
Table 5.9 Synthesis of 1,4-dihydropyrrolo[3,2-b]indoles
Entry Amino Acid Product Yield [%]
1
N
NH
O
Ph
OH
O
S
O
Ph
5.93
N
N
Ph
O
CH
3
S
O
Ph
5.94
51
2
N
NH
O
Ph
HO
O
O
Ph
O

5.65
N
N
Ph
O
CH
3
O
Ph
O

5.95
64
3
N
NH
O
Ph
OH
O
O
O
Cl

5.63
N
N
Ph
O
CH
3
O
O
Cl

5.96
65

515
Table 5.9 Cont.
Entry Amino Acid Product Yield [%]
4
N
NH
O
Ph
OH
O
S
O
Cl

5.97
N
N
Ph
O
CH
3
S
O
Cl

5.98
65
5
N
NH
O
Ph
OH
O
S
O
H
3
C

5.61
N
N
Ph
O
CH
3
S
O
H
3
C

5.99
18
6
N
NH
O
Ph
OH
O
O
O
H
3
C

5.60
N
N
Ph
O
CH
3
O
O
H
3
C

5.100
51

516
5.3 Conclusion
In summary we have demonstrated that use of multicomponent reactions for
the synthesis of α-amino acid derivatives of 2-amino heteroaryl ketones is a very
practical and universal route. We have showed that the intramolecular cyclization
of α-amino acid derivatives of 2-amino heteroaryl ketones is a general and useful
synthetic methodology for constructing complex heterocyclic scaffolds. While our
quest might have been long, it certainly was eventful, exciting and knowledge
producing. Many drugs wait to be found through exploitation of the methodologies
described herein.
517
5.4 Experimental
5.4.1 General information
All reagents and commonly available starting materials were purchased from
commercial sources. Tetrahydrofuran was freshly distilled from sodium-
benzophenone, dichloromethane from CaH
2
and anhydrous dimethylformamide,
diethyl ether, toluene, benzene, ethanol, and methanol were purchased from
commercial sources.
1
H,
19
F,
13
C NMR spectra were recorded on a Varian Mercury
400 and a Bruker AC-250 using residual
1
H or
13
C signals of deuterated solvents as
internal standards.
11
B NMR spectra were performed on a Bruker 500 MHz using
BF
3
•Et
2
O as an external standard. Thin layer chromatography was performed using
glass precoated TLC plates (silica gel 60 F
254
). Flash chromatography was
performed using Silica Gel 60, particle size range between 0.040-0.063 mm (230-
400 Mesh).

518
5.4.2 Synthesis and physical properties

(2-Amino-4,5,6,7-tetrahydro-benzo[b]thiophen-3-
yl)-phenyl-methanone (5.09)
To a solution of 3-oxo-3-phenyl-propionitrile
(5.101) (5 mmol, 725 mg), cyclohexanone (5.08) (5
mmol, 0.52 ml) and triethylamine (5 mmol, 0.44ml) in 10 ml of ethanol, pulverized
sulfur (5 mmol, 164 mg) was added. The reaction mixture was refluxed for two
hours. The solvent was evaporated and the residue was washed with water and
extracted with ethyl acetate. The organic layer was dried with sodium sulfate and
the volatiles removed under reduced pressure. The residue was purified by flash
chromatography (25% ethyl acetate: hexanes) in order to isolate 1.08 g of a yellow
solid (84% yield).
1
H NMR (400 MHz, CDCl
3
): δ 7.48-7.37 (m, 5H), 6.47 (broad s, 2H), 2.50 (m, 2
H), 1.79 (m, 2H), 1.72 (m, 2H), 1.49-1.43 (m, 2H).
13
C NMR (100 MHz, CDCl
3
):
δ 192.7, 164.5, 142.2, 131.3, 130.3, 128.0, 127.5, 118.5, 115.9, 27.8, 24.7, 23.1,
22.9.

S
O
NH
2
519
(2-Amino-6-methyl-4,5,6,7-tetrahydro-
thieno[2,3-c]pyridin-3-yl)-phenyl-methanone
(5.11)
Prepared analogously to compound (5.09) as a
yellow solid in good yield (61%).
1
H NMR (400 MHz, CDCl
3
): δ 7.49-7.38 (m, 5H), 6.77 (broad s, 2H), 3.38 (m,
2H), 2.39 (m, 5H), 1.97 (m, 2H).
13
C NMR (100 MHz, CDCl
3
): δ 192.5, 165.6,
142.0, 130.2, 129.3, 129.2, 128.1, 127.3, 115.0, 114.6, 53.5, 52.2, 45.5, 27.9.

(2-Amino-5-phenyl-thiophen-3-yl)-phenyl-
methanone (5.13)
Prepared analogously to compound (5.09) as a
brown solid in high yield (88%).
1
H NMR (400 MHz, CDCl
3
): δ 7.77-7.75 (m,
2H), 7.59-7.50 (m, 3H), 7.44-7.42 (m, 2H), 7.37-7.33 (m, 2H), 7.30-7.16 (m, 4H).
13
C NMR (100 MHz, CDCl
3
): δ 191.3, 166.0, 140.8, 133.8, 130.9, 128.8, 128.3,
128.2, 126.8, 124.8, 124.0, 122.8, 116.3.

MeN
S
O
NH
2
S
O
NH
2
520
(2-Amino-4,5-dimethyl-thiophen-3-yl)-phenyl-
methanone (5.17)
Prepared analogously to compound (5.09) as a
yellow solid in low yield (33%).
1
H NMR (400 MHz, CDCl
3
): δ 7.55-7.42 (m, 5H), 6.57 (broad s, 2H), 2.14 (s, 3H),
1.56 (s, 3H).
13
C NMR (100 MHz, CDCl
3
): δ 193.1, 163.0, 141.8, 130.9, 130.5,
128.8, 128.1, 127.9, 117.2, 115.0, 102.7, 15.4, 12.6.

(2-Amino-5,6-dihydro-4H-cyclopenta[b]thiophen-3-
yl)-phenyl-methanone (5.15)
Prepared analogously to compound (5.09) as a yellow
solid in good yield (64%).
1
H NMR (400 MHz, CDCl
3
): δ 7.43-7.18 (m, 5H), 6.67 (broad s, 2H), 2.58 (m,
2H), 2.09-1.95 (m, 4H).
13
C NMR (100 MHz, CDCl
3
): δ 192.3, 170.5, 141.7, 141.5,
130.0, 127.9, 121.8, 111.8, 31.3, 28.8, 27.6.

H
3
C
H
3
C
S
O
NH
2
S
O
NH
2
521
(2-Amino-4,5,6,7-tetrahydro-
benzo[b]thiophen-3-yl)-(4-nitro-phenyl)-
methanone (5.18)
Prepared analogously to compound (5.09) as a
yellow solid in moderate yield (46%).
1
H NMR (400 MHz, CDCl
3
): δ 8.30 (d, J = 9.0Hz, 2H), 7.63 (d, J = 9.5 Hz, 2H),
7.07 (broad s, 2H), 2.54 (m, 2H), 1.79-1.70 (m, 4H), 1.51 (m, 2H).
13
C NMR (100
MHz, CDCl
3
): δ 189.9, 166.5, 130.0, 128.1, 125.5, 125.4, 123.5, 118.9, 115.1, 28.1,
24.6, 22.9, 22.7.

(3-Amino-benzofuran-2-yl)-phenyl-methanone
(5.22)
To a solution of 2-hydroxy-benzonitrile (5.19) (10
mmol, 1.19 g) in acetone (5 ml), 2-bromo-1-phenyl-
ethanone (5.20) (11 mmol, 2.2 g) and anhydrous potassium carbonate (2.2 eq., 22
mmol, 3.04 g) were added. The reaction was refluxed for 8 hours. The solid was
filtered off and washed with copious amounts of acetone 200 ml. The filtrate was
concentrated under reduced pressure in order to obtain a yellow solid in good yield
(66 %, 1.55 g).
1
H NMR (400 MHz, CDCl
3
): δ 8.17-8.15 (m, 2H), 7.56 (d, J = 7.4 Hz, 1H), 7.49-
7.37 (m, 5H), 7.21-7.17 (m, 1H), 5.99 (broad s, 2H).
13
C NMR (100 MHz, CDCl
3
):
S
O
NH
2
NO
2
O
NH
2
O
522
δ 183.0, 154.4, 142.4, 137.6, 135.0, 131.7, 129.8, 129.1, 128.2, 122.2, 120.7, 120.3,
112.5.

(3-Amino-5-bromo-benzofuran-2-yl)-phenyl-
methanone (5.23)
Prepared analogously to compound (5.22) from
5-bromo-2-hydroxy-benzonitrile (5.102) as a
yellow solid in excellent yield (95%).
1
H NMR (400 MHz, acetone-d
6
): δ 8.12 - 8.07 (m, 3H), 7.57 – 7.36 (m, 5H), 6.96
(broad s, 2H).
13
C NMR (62.5 MHz, acetone-d
6
): δ 183.0, 153.9, 142.8, 138.8,
136.8, 136.0, 134.9, 133.4, 132.6, 129.9, 129.1, 125.1, 124.1, 123.2, 115.3.

5-Bromo-2-hydroxy-benzonitrile (5.102)
A solution of 5-bromo-benzo[d]isoxazole (5.103) (5.05
mmol, 1g) was dissolved in ethanol (10 ml) and was added
to a 2:3 solution of 3N sodium hydroxide and water. The reaction was stirred at
room temperature for 15 minutes. A solution of 3N hydrochloric acid was added
slowly (pH=1) and the reaction was extracted with dichloromethane. The organic
layer was dried with magnesium sulfate and evaporated under reduced pressure.
The residue was purified via flash chromatography using 30% ethyl acetate:
hexanes as eluent. The product was isolated as a white powder in high yield (83 %,
3.5 g).
O
NH
2
O
Br
CN
OH
Br
523
1
H NMR (400 MHz, CDCl
3
): δ 7.59 (d, J = 2.3 Hz, 1H), 7.54 (dd, J = 8.9 Hz, J =
2.7 Hz, 1H), 6.88 (d, J = 9.0 Hz, 1H).
13
C NMR (100 MHz, CDCl
3
): δ 157.7,
137.7, 134.8, 118.4, 112.3, 101.4.

5-Bromo-benzo[d]isoxazole (5.103)
To a solution of triphenylphosphine (1.5 eq., 24.9 mmol,
6.53 g) in dichloromethane (10 ml), 2,3-dichloro-5,6-
dicyanobenzoquinone (1.5 eq., 24.9 mmol, 5.65 g) was added in portion at room
temperature. After the addition was complete, 5-bromo-2-hydroxy-benzaldehyde
oxime (5.104) (1 eq., 16.6 mmol, 3.6 g) was added in portions at room temperature.
After 10 min, TLC indicated that no starting material was left. The solvent was
evaporated and the residue was purified via flash chromatography (15% ethyl
acetate: hexanes). The product was isolated as a white solid in high yield (92%, 3
g).
1
H NMR (400 MHz, CDCl
3
): δ 8.70 (s, 1H), 7.89 (s, 1H), 7.65 (s, 1H), 7.52 (m,
1H).
13
C NMR (100 MHz, CDCl
3
): δ 161.3, 145.5, 133.1, 124.5, 123.2, 116.6,
111.2.

O
N
Br
524
5-Bromo-2-hydroxy-benzaldehyde oxime (5. 104)
A solution of sodium acetate trihydrate (40 mmol, 3.28
g in 10 ml of water) was added to warm solution of 5-
bromo-2-hydroxy-benzaldehyde (5.105) (20 mmol, 4.02
g) and hydroxylamine (40 mmol, 2.78 mmol) in 80% aqueous ethanol (50 ml).
After refluxing for 3 hours, the reaction mixture was diluted with hot water and
then cooled to -10
o
C. The precipitated white solid was filtered off and washed with
water to provide the product in high yield (86%, 3.6g).
1
H NMR (400 MHz, CDCl
3
): δ 9.90 (broad s, 1H), 8.15 (s, 1H), 7.85 (broad s,
1H), 7.36 (dd, J = 9.2Hz, J = 2.8 Hz, 1H), 7.29 (d, J = 2.6 Hz, 1H), 6.88 (d, J = 9.3
Hz, 1H).
13
C NMR (100 MHz, CDCl
3
): δ 156.3, 151.8, 133.9, 132.8, 118.6, 118.0,
111.4.

(3-Amino-1-benzoyl-1H-indol-2-yl)-phenyl-
methanone (5.30)
Prepared analogously to compound (5.22) from N-
(2-cyano-phenyl)-benzamide (5.106) as a yellow
solid in good yield (71%).
1
H NMR (400 MHz, CDCl
3
): δ 8.18 (d, J = 8.0 Hz,
1H), 7.62 (d, J = 8.2 Hz, 1H), 7.50 (t, J = 8.1 Hz, 1H), 7.31-7.23 (m, 3H), 7.12-
7.02 (m, 8H), 5.86 (broad s, 2H).
13
C NMR (100 MHz, CDCl
3
): δ 186.9, 173.0,
Br
OH
H
N
OH
N
NH
2
O
O
525
142.8, 138.5, 134.4, 134.0, 133.9, 133.7, 133.4, 132.8, 131.5, 130.4, 129.9, 129.2,
128.9, 128.5, 128.1, 123.6, 121.5, 119.5, 116.0, 112.5.

N-(2-cyano-phenyl)-benzamide (5.106)
To a solution of 2-amino-benzonitrile (5.29) (10 mmol, 1.18
g) and triethylamine (15 mmol, 2.1 ml), benzoyl chloride
(5.107) (11 mmol, 1.28 ml) was added at room temperature.
The reaction was stirred at room temperature for 3 days.
The solvent was evaporated and the residue was purified via flash chromatography
(10% ethyl acetate: 90 % hexanes) to yield a white solid in high yield (91%, 2 g).
1
H NMR (400 MHz, CDCl
3
): δ 8.60 (d, J = 8.0 Hz, 1H), 8.42 (broad s, 1H), 7.94
(d, J =7.9 Hz, 1H), 7.68-7.51 (m, 5H), 7.22 (t, J = 7.7 Hz, 1H).
13
C NMR (100
MHz, CDCl
3
): δ 165.5, 140.7, 134.4, 133.7, 132.7, 132.2, 129.1, 127.2, 124.3,
121.2, 116.5, 102.2.

1-(3-Amino-2-benzoyl-indol-1-yl)-ethanone (5.31)
Prepared analogously to compound (5.22) from N-
(2-cyano-phenyl)-acetamide (5.106) in good yield as
a yellow solid (55 %).
1
H NMR (400 MHz, CDCl
3
): δ 8.32 (d, J = 8.4 Hz,
1H), 7.77 (d, J = 7.0 Hz, 2H), 7.68 (d, J = 8.0 Hz, 1H), 7.59-7.43 (m, 4H), 7.31 (t, J
= 7.0 Hz, 1H), 6.20 (broad s, 2H), 1.99 (s, 3H).
13
C NMR (100 MHz, CDCl
3
):
CN
NH
O
N
NH
2
O
O
H
3
C
526
δ 185.8, 171.0, 145.4, 140.3, 138.7, 131.8, 130.9, 128.9, 128.3, 123.6, 121.7, 119.8,
116.7, 26.8.

N-(2-Cyano-phenyl)-acetamide (5.108)
Prepared analogously to compound (5.106) from 2-amino-
benzonitrile (5.29) and acetyl chloride (5.109) in 85 % yield
as a yellow solid.
1
H NMR (250 MHz, CDCl
3
): δ 8.35 (d, J = 8.8 Hz, 1H), 7.78 (broad s, 1H), 7.61-
7.55 (m, 2H), 7.16 (t, J =8.9 Hz, 1H), 2.26 (s, 3H).
13
C NMR (62.5 MHz, CDCl
3
):
δ 168.8, 140.6, 134.3, 132.4, 124.2, 121.6, 116.5, 24.8.

[3-Amino-1-(2-chloro-benzoyl)-1H-indol-2-yl]-
phenyl-methanone (5.32)
Prepared analogously to compound (5.22) from 2-
chloro-N-(2-cyano-phenyl)-benzamide (5.110) as a
yellow solid in high yield (84%).
1
H NMR (400 MHz, CDCl
3
): δ 8.07 (d, J = 8.3 Hz,
1H), 7.59 (d, J = 7.9 Hz, 1H), 7.49 (t, J=7.7 Hz, 1H), 7.35-7.08 (m, 8H), 6.89 (t, J
= 6.8 Hz, 1H), 6.70 (d, J = 8.0 Hz, 1H), 5.85 (broad s, 2H).
13
C NMR (100 MHz,
CDCl
3
): δ 185.7, 166.8, 144.5, 140.2, 138.4, 135.2, 132.5, 131.6, 131.5, 130.7,
130.0, 128.6, 127.6, 126.6, 124.1, 122.2, 119.6, 116.9, 116.4.
CN
NH
H
3
C O
N
NH
2
O
O
Cl
527
2-Chloro-N-(2-cyano-phenyl)-benzamide (5.110)
Prepared analogously to compound (5.106) from 2-amino-
benzonitrile (5.29) and 2-chloro-benzoyl chloride (5.111) in
high yield as a yellow solid (85 %).
1
H NMR (400 MHz, CDCl
3
): δ 8.60 (m, 2H), 7.83 (d, J =
7.2 Hz, 1H), 7.70-7.65 (m, 1H), 7.52-7.41 (m, 2H), 7.29-7.25 (m, 2H).
13
C NMR
(100 MHz, CDCl
3
): δ 164.8, 140.2, 134.3, 133.9, 132.5, 132.4, 131.4, 130.9, 130.7,
130.6, 127.5, 126.7, 124.8, 121.7, 116.3, 102.6.

2-(3-Benzoyl-4,5,6,7-tetrahydro-
benzo[b]thiophen-2-ylamino)-4-
phenyl-but-3-enoic acid (5.40)
To a solution of (2-amino-4,5,6,7-
tetrahydro-benzo[b]thiophen-3-yl)-
phenyl-methanone (5.09) (1 mmol, 257 mg) and glyoxylic acid monohydrate (5.37)
(1 mmol, 92 mg) in 2 ml of acetonitrile, 1 mmol of styryl boronic acid (5.112) (147
mg) was added. The resulting reaction mixture was stirred at room temperature till
TLC indicated that starting materials disappeared. The resulting suspension was
concentrated under reduced pressure and the residue was purified via flash
chromatography (85% ethyl acetate: 10% methanol: 5% ammonia) to afford the
desired product as a yellow solid in high yield (346 mg, 83 %).
CN
NH
O
Cl
S
O
NH
OH
O
528
1
H NMR (400 MHz, acetone-d
6
): δ 9.98 (d, J = 6.3 Hz, 1H), 7.59-7.32 (m, 9H),
6.95 (d, J = 6.0 Hz, 1H), 6.46 (dd, J = 16.0 Hz, J =7.1Hz, 1H), 5.83 (broad s, 1H),
4.87 (t, J = 7.0 Hz, 1H), 2.58-2.54 (m, 2H), 1.86-1.83 (m, 2H), 1.75 – 1.72 (m, 2H),
1.49-1.46 (m, 2H).
13
C NMR (62.5 MHz, acetone-d
6
): δ 191.4, 170.2, 164.4, 143.0,
136.2, 134.5, 131.8, 129.9, 128.8, 128.4, 128.1, 127.3, 126.9, 123.8, 118.5, 114.9,
61.6, 27.8, 24.4, 23.0, 22.8.

2-[3-(4-Nitro-benzoyl)-4,5,6,7-
tetrahydro-benzo[b]thiophen-2-
ylamino]-4-phenyl-but-3-enoic acid
(5.41)
Prepared analogously to compound (5.40)
as an orange solid in high yield (82 %).
1
H NMR (400 MHz, acetone-d
6
): δ 10.27 (d, J = 6.3 Hz, 1H), 8.37 (d, J = 9.5 Hz,
2H), 7.74 (d, J = 8.7 Hz, 2H), 7.58 (d, J = 7.0 Hz, 2H), 7.42-7.32 (m, 3H), 6.97 (d,
J = 15.8 Hz, 1H), 6.46 (dd, J = 16.0 Hz, J = 6.9 Hz, 1H), 4.92 (t, J = 6.0 Hz, 1H),
2.57-2.54 (m, 2H), 1.81-1.71 (m, 4H), 1.51-1.46 (m, 2H).
13
C NMR (62.5 MHz,
acetone-d
6
): δ 188.8, 170.0, 165.8, 148.8, 136.2, 134.8, 130.9, 128.9, 128.4, 126.9,
123.6, 123.5, 119.1, 114.3, 61.7, 28.0, 24.4, 22.9, 22.8.

S
O
NH
OH
O
NO
2
529
(3-Benzoyl-5-phenyl-thiophen-2-
ylamino)-(4-methoxy-phenyl)-acetic
acid (5.43)
Prepared analogously to compound
(5.40) as a yellow solid in high yield
(81 %).
1
H NMR (400 MHz, acetone-d
6
): δ 10.55 (d, J = 6.0 Hz, 1H), 7.80 (d, J = 6.0 Hz,
2H), 7.61-7.55 (m, 2H), 7.45 (d, J = 8.3 Hz, 2H), 7.37-7.33 (m, 1H), 7.23 (m, 1H),
7.05 (d, J = 8.5 Hz, 2H), 5.82 (s, 1H), 5.31 (d, J = 6.3 Hz, 1H), 3.85 (s, 3H).
13
C
NMR (100 MHz, acetone-d
6
): δ 189.9, 170.5, 164.7, 160.3, 141.2, 133.8, 130.7,
129.0, 128.9, 128.3, 128.2, 127.9, 126.6, 124.4, 124.2, 122.9, 115.2, 114.3.

(2-Acetyl-thiophen-3-ylamino)-(4-methoxy-
phenyl)-acetic acid (5.46)
Prepared analogously to compound (5.40) as a
yellow solid in high yield (82%).
1
H NMR (400 MHz, acetone-d
6
): δ 7.54 (d, J =
6.0 Hz, 1H), 7.47 (d, J = 8.4 Hz, 2H), 6.98 (d, J = 9.4 Hz, 2H), 6.67 (d, J =5.3 Hz,
1H), 5.38 (s, 1H), 3.82 (s, 3H), 2.36 (s, 3H).
13
C NMR (100 MHz, acetone-d
6
):
δ 190.7, 172.4, 160.9, 154.5, 133.3, 131.2, 129.3, 118.4, 115.1, 112.1, 61.2, 55.7,
28.5.
S
O
NH
OMe
O
OH
S
NH
O
CH
3
OH
O
MeO
530
(2-Acetyl-thiophen-3-ylamino)-
benzo[b]thiophen-2-yl-acetic acid (5.48)
Prepared analogously to compound (5.40) as a
yellow solid in good yield (54%).
1
H NMR (400 MHz, acetone-d
6
): δ 9.23 (d, J =
6.2 Hz, 1H), 7.91 (d, J = 9.3 Hz, 1H), 7.86 (d, J = 1 H), 7.62 (s, 1H), 7.58 (d, J =
5.9 Hz, 1H), 7.39 (m, 2H), 6.85 (d, J = 6.1 Hz, 1H), 5.87 (d, J = 6.1 Hz, 1H), 5.87
(d, J = 6.5 Hz, 1H), 2.39 (s, 3H).
13
C NMR (62.5 MHz, acetone-d
6
): δ 191.0, 170.7,
154.1, 143.6, 140.5, 133.4, 125.5, 125.4, 124.6, 124.1, 123.3, 118.3, 112.8, 58.2,
28.4.

(2-Acetyl-thiophen-3-ylamino)-(3,4-
dimethyl-phenyl)-acetic acid (5.52)
Prepared analogously to compound (5.40) as a
white solid in excellent yield (96%).
1
H NMR (400 MHz, acetone-d
6
): δ 7.54 (d, J =
5.6 Hz, 1H), 7.16 (d, J = 2.0 Hz, 1H), 7.07 (dd, J =8.3 Hz, J =1.7 Hz, 1H), 6.97 (d,
J =8.3 Hz, 1H), 6.70 (d, J =5.0 Hz, 1H), 5.35 (s, 1H), 3.83 (s, 6H), 2.36 (s, 3H).
13
C
NMR (62.5 MHz, acetone-d
6
): δ 190.4, 172.0, 150.3, 133.0, 131.4, 120.1, 118.2,
112.7, 111.8, 61.3, 55.9, 28.2.

S
NH
O
CH
3
OH
O
S
S
NH
O
CH
3
OH
O
H
3
C
H
3
C
531
(2-Acetyl-thiophen-3-ylamino)-benzofuran-2-
yl-acetic acid (5.53)
Prepared analogously to compound (5.40) as a
white solid in good yield (67 %).
1
H NMR (400 MHz, acetone-d
6
): δ 9.16 (d, J =
6.9 Hz, 1H), 7.65 (d, J = 7.6 Hz, 1H), 7.60 (d, J
=5.2 Hz, 1H), 7.54 (d, J =8.3 Hz, 1H), 7.34 (t, J = 7.7 Hz, 1H), 7.27 (t, J = 6.7 Hz,
1H), 7.06 (s, 1H), 6.97 (d, J = 5.3 Hz, 1H), 5.81 (d, J = 7.8 Hz, 1H), 2.37 (s, 3H).
13
C NMR (62.5 MHz, acetone-d
6
): δ 190.9, 169.6, 155.8, 154.3, 133.5, 128.9,
125.5, 123.9, 122.2, 118.0, 112.0, 106.4, 56.3, 28.3.

(2-Benzoyl-benzofuran-3-ylamino)-(4-methoxy-
phenyl)-acetic acid (5.54)
Prepared analogously to compound (5.40) as a
brown solid in good yield (55 %).
1
H NMR (400 MHz, acetone-d
6
): δ 8.30 (d, J = 6.1
Hz, 2H), 7.98 (d, J = 8.5 Hz, 1H), 7.68 - 7.53 (m,
7H), 7.27 - 7.22 (m, 1H), 6.99 (d, J =8.3 Hz, 2H),
6.04 (s, 1H), 3.80 (s, 3H).
13
C NMR (62.5 MHz, acetone-d
6
): δ 182.5, 172.4, 160.8,
155.7, 143.4, 139.1, 132.6, 130.8, 130.0, 129.2, 124.7, 123.4, 120.9, 115.2, 113.6,
60.7, 55.6.
S
NH
O
CH
3
OH
O
O
O
NH
O
HO
O
OMe
532
1-[2-(4-Methoxy-phenyl)-3-phenyl-4,5,6,7-
tetrahydro-8-thia-1-aza-cyclopenta[a]inden-
1-yl]-ethanone (5.68)
In a 1 dram vial 0.5 ml of acetic anhydride
triethylamine (0.2 ml) and (0.3 mmol, 126.3 mg)
of α-amino acid (5.42) were mixed together.
The reaction mixture was heated to 90
o
C and stirred at this temperature for 30
minutes. After the reaction was completed (no amino acid by TLC) the volatiles
were evaporated under reduced pressure. The residue was purified by flash
chromatography (10% ethyl acetate: hexanes) in order to obtain a yellow solid in
high yield (90 mg, 86%).
1
H NMR (400 MHz, CDCl
3
): δ 7.26-7.22 (m, 7H), 6.90 (d, J = 9.0 Hz, 2H), 3.83 (s,
3H), 2.89-2.86 (m, 2H), 2.43-2.39 (m, 2H), 2.02 (s, 3H), 1.92-1.85 (m, 2H), 1.77-
1.71 (m, 2H).
13
C NMR (62.5 MHz, CDCl
3
): δ 168.5, 159.7, 133.1, 132.9, 130.2,
127.5, 126.6, 124.9, 113.8, 55.2, 25.4, 25.3, 25.0, 23.5, 22.7.

S
N
CH
3
O
OMe
533
1-[5-(4-Methoxy-phenyl)-2,4-
diphenyl-thieno[2,3-b]pyrrol-6-yl]-
ethanone (5.69)
Prepared analogously to compound
(5.68) in excellent yield (95 %).
1
H NMR (400 MHz, CDCl
3
): δ 7.58 (d,
J = 7.8 Hz, 2H), 7.31-7.16 (m, 11H), 6.86 (d, J =8.5 Hz, 2H), 3.76 (s, 3H), 1.92 (s,
3H).
13
C NMR (100 MHz, CDCl
3
): δ 168.5, 160.2, 141.4, 135.4, 134.0, 133.6,
133.1, 132.7, 131.2, 129.0, 128.8, 128.3, 127.2, 126.7, 125.7, 124.8, 122.9, 114.3,
112.6, 55.3, 25.0.

1-[3-(4-Nitro-phenyl)-2-styryl-4,5,6,7-
tetrahydro-8-thia-1-aza-
cyclopenta[a]inden-1-yl]-ethanone (5.70)
Prepared analogously to compound (5.68)
in good yield (76 %).
1
H NMR (400 MHz, CDCl
3
): δ 8.15 (d, J =
9.4 Hz, 2H), 7.50 (d, J = 8.7 Hz, 2H), 7.21 -7.11 (m, 6H), 6.18 (d, J = 16.1 Hz,
1H), 2.73-1.70 (m, 2H), 2.60 (s, 3H), 2.20-2.17 (m, 2 H), 1.78-1.74 (m, 2H), 1.65-
1.59 (m, 2H),.
13
C NMR (100 MHz, CDCl
3
): δ 168.3, 147.0, 142.2, 136.3, 135.3,
S
N
H
3
C
O
OMe
S
N
H
3
C
O
O
2
N
534
133.9, 132.9, 132.1, 131.3, 130.3, 128.8, 128.3, 126.3, 124.9, 123.5, 121.4, 118.1,
29.7, 25.5, 25.4, 23.3, 22.6.

1-(3-Phenyl-2-styryl-4,5,6,7-tetrahydro-8-
thia-1-aza-cyclopenta[a]inden-1-yl)-
ethanone (5.71)
Prepared analogously to compound (5.68) as
a yellow solid in excellent yield (95 %).
1
H NMR (400 MHz, CDCl
3
): δ 7.46-7.22 (m, 11H), 6.36 (d, J = 16.1 Hz, 1H),
2.85-2.82 (m, 2H), 2.72 (s, 3H), 2.33-2.30 (m, 2H), 1.91-1.85 (m, 2H), 1.75-1.70
(m, 2H).
13
C NMR (100 MHz, CDCl
3
): δ 168.5, 137.4, 134.7, 133.4, 133.0, 132.4,
131.7, 131.2, 130.3, 128.6, 128.2, 127.7, 127.2, 126.2, 125.6, 124.1, 118.8, 25.5,
25.4, 25.1, 23.5, 22.6.

1-(5-Benzo[b]thiophen-2-yl-6-methyl-
thieno[3,2-b]pyrrol-4-yl)-ethanone (5.78)
Prepared analogously to compound (5.68) in
low yield (19%).
1
H NMR (400 MHz, CDCl
3
): δ 7.91-7.88 (m, 2H), 7.67 (d, J = 5.1 Hz, 1H), 7.48-
7.42 (m, 2H), 7.37 (s, 1H), 7.33 (d, J = 5.0 Hz, 1H), 2.30 (s, 3H), 2.21 (s, 3H).
13
C
S
N
H
3
C
O
S
N
CH
3
H
3
C
O
S
535
NMR (100 MHz, CDCl
3
): δ 168.6, 141.2, 139.6, 139.3, 134.4, 128.7, 127.0, 125.8,
125.4, 125.1, 124.8, 124.1, 122.3, 120.5, 116.9, 25.1, 11.3.

S
N
CH
3
H
3
C
O
CH
3
CH
3 S
H
N
CH
3
CH
3
CH
3

1-[5-(3,4-Dimethyl-phenyl)-6-methyl-thieno[3,2-b]pyrrol-4-yl]-ethanone (5.79)
Prepared analogously to compound (5.68) in high yield (83 %) along with 17 % of
5-(3,4-Dimethyl-phenyl)-6-methyl-4H-thieno[3,2-b]pyrrole (5.80).
1
H NMR (400 MHz, CDCl
3
) (5.79): δ 7.64 (d, J = 5.2 Hz, 1H), 7.24 (d, J = 5.0 Hz,
1H), 7.00-6.94 (m, 2H), 6.88 (d, J = 1.0 Hz, 1H), 3.98 (s, 3H), 3.91 (s, 3H), 2.10 (s,
3H), 2.05 (s, 3 H).
13
C NMR (100 MHz, CDCl
3
): δ 169.0, 149.3, 149.0, 138.5,
133.5, 128.7, 125.8, 124.3, 123.4, 116.9, 113.6, 111.0, 56.0, 55.9, 25.7, 11.0.
1
H NMR (400 MHz, CDCl
3
) (5.80): δ 8.17 (broad s, 1H), 7.30 (s, 1H), 7.11-6.97
(m, 4H), 3.96 (s, 6H), 2.41 (s, 3H).
13
C NMR (100 MHz, CDCl
3
): δ 149.1, 148.1,
137.0, 133.4, 132.5, 127.0, 126.7, 122.9, 120.7, 120.0, 111.5, 111.3, 110.7, 108.4,
56.0, 29.7, 11.5.

536
S
N
CH
3
OMe
S
N
H
CH
3
OMe
H
3
C
O

1-[5-(3,4-Dimethyl-phenyl)-6-methyl-thieno[3,2-b]pyrrol-4-yl]-ethanone (5.81)
Prepared analogously to compound (5.68) in 40 % yield along with 24% of 5-(3,4-
dimethyl-phenyl)-6-methyl-4H-thieno[3,2-b]pyrrole (5.82)
1
H NMR (400 MHz, CDCl
3
) (5.81): δ 7.66 (d, J = 5.1 Hz, 1H), 7.31 (d, J = 8.6 Hz,
2H), 7.24 (d, J =5.1 Hz, 1H), 7.03 (d, J = 8.2 Hz, 2H), 3.91 (s, 3H), 2.09 (s, 3H),
2.04 (s, 3H).
13
C NMR (100 MHz, CDCl
3
): δ 168.9, 159.7, 138.5, 133.6, 131.9,
128.7, 125.6, 124.2, 116.9, 116.8, 114.1, 55.3, 26.0, 11.0.
1
H NMR (400 MHz, CDCl
3
) (5.82): δ 7.98 (broad s, 1H), 7.33 (d, J = 8.5 Hz, 2H),
7.18 (s, 1H), 6.98 (d, J = 5.2 Hz, 1H), 6.91 (d, J = 8.5 Hz, 2H), 6.87 (d, J = 5.0 Hz,
1H), 3.78 (s, 3H), 2.29 (s, 3H).
13
C NMR (100 MHz, CDCl
3
): δ 158.5, 137.0,
133.3, 128.4, 127.0, 126.4, 122.8, 114.3, 111.3, 108.2, 55.3, 29.7, 11.5.

537
1-[5-(4-Methoxy-phenyl)-2,3-dimethyl-4-
phenyl-thieno[2,3-b]pyrrol-6-yl]-ethanone
(5.73)
To a solution of (2-amino-4,5-dimethyl-
thiophen-3-yl)-phenyl-methanone (5.17) (1
mmol, 231 mg) and glyoxylic acid
monohydrate (5.37) (1 mmol, 92 mg) in 2 ml of acetonitrile, 1 mmol of p-methoxy
phenylboronic acid (5.112) (152 mg) was added. The resulting reaction mixture
was stirred at room temperature till TLC indicated that starting materials
disappeared. The resulting suspension was filtered off and the solid was dissolved
and the volatiles evaporated for a few times with methanol in order to remove of
boric acid. (2-Acetyl-thiophen-3-ylamino)-(3,4-dimethyl-phenyl)-acetic acid was
isolated in 75 % yield and used as prepared for the next reaction.
In a 1 dram vial 0.5 ml of acetic anhydride, triethylamine (0.2 ml) and (0.3 mmol,
119 mg) of amino acid were mixed together. The reaction mixture was heated till
90
o
C and let stirred at this temperature for 30 minutes. After the reaction was
completed the solvent was evaporated under reduced pressure. The residue was
purified by flash chromatography 10% ethyl acetate: hexanes to yield of 90 mg (70
%) of desired product.
1
H NMR (400 MHz, CDCl
3
): δ 7.30-7.23 (m, 7H), 6.87 (d, J = 9.5 Hz, 2H), 3.83
(s, 3H), 2.44 (s, 3H), 2.02 (s, 3H), 1.97 (s, 3H).
13
C NMR (100 MHz, CDCl
3
):
H
3
C
H
3
C
S
N
H
3
C
O
OMe
538
δ 168.5, 159.7, 133.8, 132.9, 130.9, 130.8, 130.5, 130.2, 129.7, 127.7, 126.7, 124.8,
124.4, 122.7, 122.3, 113.8, 55.2, 25.0, 13.3, 12.6.

1-(3-Phenyl-2-styryl-5,6-dihydro-4H-7-
thia-1-aza-cyclopenta[a]pentalen-1-yl)-
ethanone (5.74)
Prepared analogously to compound (5.68) via
two step procedure. The first step was the
amino acid synthesis of 2-(3-benzoyl-5,6-dihydro-4H-cyclopenta[b]thiophen-2-
ylamino)-4-phenyl-but-3-enoic acid in 45% yield. The final product (5.74) was
isolated in 55 % yield as a yellow solid.
1
H NMR (400 MHz, CDCl
3
): δ 7.40-7.38 (m, 2H), 7.29 (t, J = 7.3 Hz, 2H), 7.22-
7.14 (m, 6H), 6.38 (d, J = 16.0 Hz, 1H), 2.86 (t, J =7.1 Hz, 2H), 2.60 (s, 3H), 2.55
(t, J = 6.7 Hz, 2H), 2.35 - 2.27 (m, 2H).
13
C NMR (100 MHz, CDCl
3
): δ 168.5,
139.1, 137.1, 136.9, 134.7, 134.2, 131.8, 131.7, 129.8, 128.7, 128.3, 127.9, 127.0,
126.8, 126.3, 123.4, 118.8, 29.2, 28.5, 25.7.

S
N
H
3
C
O
539
1-(6-Methyl-5-styryl-thieno[3,2-b]pyrrol-4-
yl)-ethanone (5.83)
Prepared analogously to compound (5.68) in a
two-step procedure. The first step was the
amino acid synthesis of 2-(2-acetyl-thiophen-3-ylamino)-4-phenyl-but-3-enoic acid
in 99% yield. The final product (5.83) was isolated in 67 % yield.
1
H NMR (400 MHz, CDCl
3
): δ 7.56 (d, J = 7.5 Hz, 2H), 7.45-7.30 (m, 5H), 7.26
(d, J = 5.2 Hz, 1H), 6.70 (d, J = 16.6 Hz, 1H), 2.69 (s, 3H), 2.39 (s, 3H).
13
C NMR
(100 MHz, CDCl
3
): δ 168.7, 137.5, 137.2, 133.7, 132.0, 130.6, 128.7, 127.8, 126.4,
124.9, 120.5, 116.8, 115.9, 26.2, 12.4.

1-(5-Bromo-1-phenyl-2-styryl-8-oxa-3-
aza-cyclopenta[a]inden-3-yl)-ethanone
(5.86)
Prepared analogously to compound (5.68)
in a two-step procedure. The first step
was the amino acid synthesis of 2-(2-
benzoyl-5-bromo-benzofuran-3-ylamino)-4-phenyl-but-3-enoic acid in 66 % yield.
The final product (5.86) was isolated in 41 % yield.
1
H NMR (400 MHz, CDCl
3
): δ 8.21 (s, 1H), 7.58 (d, J = 8.3 Hz, 2H), 7.34-7.21
(m, 10H), 7.09 (d, J = 16.3 Hz, 1H), 6.55 (d, J = 16.3 Hz, 1H), 2.59 (s, 3H).
13
C
S
N
CH
3
H
3
C
O
O
N
O
CH
3
Br
540
NMR (100 MHz, CDCl
3
): δ 169.4, 157.8, 150.8, 136.9, 136.3, 131.6, 131.2, 129.1,
128.6, 127.5, 126.5, 123.7, 121.5, 120.9, 118.3, 116.2, 114.3, 113.4, 26.7.

1-(2-Benzo[b]thiophen-2-yl-6-nitro-1-
phenyl-8-oxa-3-aza-
cyclopenta[a]inden-3-yl)-ethanone
(5.88)
Prepared analogously to compound
(5.68) via two-step procedure. The first
step was the amino acid synthesis of benzo[b]thiophen-2-yl-(2-benzoyl-6-nitro-
benzofuran-3-ylamino)-acetic acid in 77% yield. The final product (5.88) was
isolated in 25 % yield.
1
H NMR (400 MHz, CDCl
3
): δ 8.39 (d, J = 2.1 Hz, 1H), 8.29 (d, J = 9.0 Hz, 1H),
8.18 (dd, J = 8.4 Hz, J = 1.8 Hz, 1H), 7.83-7.77 (m, 2H), 7.47-7.39 (m, 5H), 7.27-
7.18 (m, 3H), 2.22 (s, 3H).
13
C NMR (100 MHz, CDCl
3
): δ 169.1, 157.6, 152.9,
142.2, 141.3, 138.9, 132.8, 129.8, 129.4, 128.8, 128.2, 128.1, 125.9, 125.2, 125.0,
124.6, 122.6, 122.2, 121.6, 119.1, 116.7, 108.5, 24.8.

O
O
2
N
N
O
CH
3
S
541
1-[2-(4-Methoxy-phenyl)-1-phenyl-8-oxa-
3-aza-cyclopenta[a]inden-3-yl]-ethanone
(5.89)
Prepared analogously to compound (5.68)
in 75 % yield as a yellow solid.
1
H NMR (400 MHz, CDCl
3
): δ 8.30 (d, J = 9.3 Hz, 1H), 7.62 (d, J = 9.0 Hz, 1H),
7.47-7.23 (m, 9H), 7.04 (d, J =7.7 Hz, 2H), 3.92 (s, 3H), 2.06 (s, 3H).
13
C NMR
(100 MHz, CDCl
3
): δ 169.6, 160.4, 159.0, 149.3, 132.9, 131.7, 131.5, 128.4, 128.3,
127.0, 125.1, 123.7, 123.0, 122.3, 121.4, 120.2, 114.6, 114.1, 112.0, 55.4, 26.2.

1-(2-Benzofuran-2-yl-1-phenyl-8-oxa-3-
aza-cyclopenta[a]inden-3-yl)-ethanone
(5.90)
Prepared analogously to compound (5.68)
in a two-step procedure. The first step was
the amino acid synthesis of benzofuran-2-
yl-(2-benzoyl-benzofuran-3-ylamino)-acetic acid in 71 % yield. The final product
(5.90) was isolated in 36 % yield.
1
H NMR (400 MHz, CDCl
3
): δ 8.23-8.21 (m, 1H), 7.53-7.47 (m, 3H), 7.42-7.39
(m, 2H), 7.34-7.15 (m, 7H), 6.79 (s, 1H), 2.11 (s, 3H).
13
C NMR (100 MHz,
CDCl
3
): δ 168.9, 159.7, 155.0, 148.5, 146.5, 130.6, 128.7, 128.5, 128.1, 127.9,
O
N
O
CH
3
O
O
N
OMe
O
CH
3
542
125.7, 124.8, 123.6, 123.5, 123.2, 122.2, 121.8, 119.8, 119.7, 118.7, 112.2, 111.8,
111.2, 23.5.

1-(8-Acetyl-2-benzofuran-2-yl-1-phenyl-
8H-3,8-diaza-cyclopenta[a]inden-3-yl)-
ethanone (5.94)
Prepared analogously to compound (5.68) in
a two-step procedure. The first step was the
amino acid synthesis of 1-acetyl -2-benzoyl-
1H-indol-3-ylamino)-benzofuran -2-yl-acetic acid in 57% yield. The final product
(5.94) was isolated in 51 % yield.
1
H NMR (400 MHz, CDCl
3
): δ 8.58 (d, J = 7.7 Hz, 1H), 7.93 (d, J = 8.2 Hz, 1H),
7.55 (d, J = 8.2 Hz, 1H), 7.51 (d, J = 7.9 Hz, 1H), 7.43-7.41 (m, 6H), 7.26 (t, J =
7.9 Hz, 1H), 7.19 (t, J = 7.4 Hz, 2H), 7.10-7.01 (m, 3H), 6.95-6.93 (m, 2H), 6.60 (s,
1H), 2.28 (s, 3H).
13
C NMR (100 MHz, CDCl
3
): δ 169.6, 168.4, 154.7, 146.2,
141.5, 135.2, 132.4, 132.3, 131.3, 129.5, 129.4, 128.3, 128.0, 127.9, 127.1, 125.7,
125.3, 125.2, 123.4, 123.3, 123.0, 122.3, 121.9, 121.5, 119.5, 114.6, 111.4, 110.1,
23.9.

N
N
O
CH
3
O
O
H
3
C
543
1-(8-Benzoyl-2-furan-2-yl-1-phenyl-8H-3,8-
diaza-cyclopenta[a]inden-3-yl)-ethanone
(5.95)
Prepared analogously to compound (5.68) in a
two-step procedure. The final product (5.95)
was isolated in 64% yield.
1
H NMR (400 MHz, CDCl
3
): δ 8.43 (d, J = 9.0
Hz, 1H), 7.79 (d, J = 8.9 Hz, 1H), 7.42 (s, 1H), 7.30-7.20 (m, 5H), 7.05 (t, J =7.5
Hz, 2H), 6.97-6.88 (m, 3H), 6.75 (d, J =7.5 Hz, 2H), 6.25 (m, 1H), 6.12 (d, J =3.1
Hz, 1H), 2.07 (s, 3H).
13
C NMR (100 MHz, CDCl
3
): δ 169.6, 168.4, 143.9, 143.2,
141.3, 135.3, 132.5, 132.4, 131.1, 129.6, 129.3, 128.3, 127.7, 126.9, 124.9, 123.3,
123.1, 122.3, 121.7, 119.7, 114.6, 114.1, 111.6, 23.5.

1-[2-Benzofuran-2-yl-8-(2-chloro-benzoyl)-
1-phenyl-8H-3,8-diaza-cyclopenta[a]
inden-3-yl]-ethanone (5.96)
Prepared analogously to compound (5.68).
The final product was isolated in 65 % yield.
1
H NMR (400 MHz, CDCl
3
): δ 8.41 (d, J =
8.6 Hz, 1H), 7.58 (d, J = 8.3 Hz, 1H), 7.38
(d, J = 8.3 Hz, 1H), 7.35 (d, J =7.7 Hz, 1H), 7.28-6.96 (m, 11H), 6.89-6.87 (m, 2H),
N
N
O
CH
3
O
O
N
N
O
CH
3
O
O
Cl
544
6.39 (s, 1H), 2.11 (s, 3H).
13
C NMR (100 MHz, CDCl
3
): δ 169.7, 165.3, 154.7,
146.2, 141.0, 134.7, 132.7, 132.6, 132.2, 130.5, 130.3, 130.2, 129.4, 128.0, 127.8,
127.1, 126.8, 126.7, 125.6, 125.2, 124.0, 123.4, 123.3, 122.3, 122.0, 121.5, 120.1,
114.9, 111.3, 110.0, 24.0.

1-[2-Benzo[b]thiophen-2-yl-8-(2-chloro-
benzoyl)-1-phenyl-8H-3,8-diaza-
cyclopenta[a]inden-3-yl]-ethanone (5.98)
Prepared analogously to compound (5.68) in
a two-step procedure. The final product
(5.98) was isolated in 65 % yield.
1
H NMR (400 MHz, CDCl
3
): δ 8.51 (d, J =
7.0 Hz, 1H), 7.78-7.69 (m, 3H), 7.42-7.01 (m, 14H), 2.33 (s, 3H).
13
C NMR (100
MHz, CDCl
3
): δ 170.1, 165.3, 141.1, 140.7, 138.9, 134.8, 133.5, 132.8, 132.6,
132.2, 130.4, 130.2, 129.4, 128.4, 127.8, 126.9, 126.8, 126.2, 126.0, 125.3, 125.2,
124.7, 124.1, 123.9, 122.1, 122.0, 120.9, 120.2, 114.9, 25.6.

N
N
O
CH
3
S
O
Cl
545
1-(8-Acetyl-2-benzo[b]thiophen-2-yl-1-
phenyl-8H-3,8-diaza-cyclopenta[a]inden-
3-yl)-ethanone (5.99)
Prepared analogously to compound (5.68) in
a two-step procedure. The final product was
isolated in 18 % yield.
1
H NMR (400 MHz, CDCl
3
): δ 8.48-8.45 (m, 2H), 7.81-7.76 (m, 2H), 7.43-7.28
(m, 10H), 2.33 (s, 3H), 2.04 (s, 3H).
13
C NMR (100 MHz, CDCl
3
): δ 170.0, 141.1,
138.9, 133.9, 133.6, 130.3, 130.2, 128.4, 128.3, 127.9, 126.4, 125.9, 125.7, 125.2,
124.7, 124.2, 123.7, 122.2, 121.7, 120.3, 119.7, 116.4, 26.8, 25.7.

N
N
O
CH
3
S
O
H
3
C
546
5.4.3 Chapter 4 NMR Spectra
10 8 6 4 2 PPM
1
H NMR (400 MHz, CDCl
3
) of 5.09
200 150 100 50 PPM
13
C NMR (100 MHz, CDCl
3
) of 5.09
S
O
NH
2
547
9 8 7 6 5 4 3 2 1 PPM
1
H NMR (400 MHz, CDCl
3
) of 5.11

200 150 100 50 PPM
13
C NMR (100 MHz, CDCl
3
) of 5.11

MeN
S
O
NH
2
548
8.2 8.0 7.8 7.6 7.4 7.2 7.0 PPM
8 6 4 2 0 PPM
1
H NMR (400 MHz, CDCl
3
) of 5.13

200 150 100 50 PPM
13
C NMR (100 MHz, CDCl
3
) of 5.13

S
O
NH
2
549
8 7 6 5 4 3 2 1 PPM
1
H NMR (400 MHz, CDCl
3
) of 5.17

200 150 100 50 PPM
13
C NMR (100 MHz, CDCl
3
) of 5.17

H
3
C
H
3
C
S
O
NH
2
550
9 8 7 6 5 4 3 2 1 0 PPM
1
H NMR (400 MHz, CDCl
3
) of 5.15

200 150 100 50 PPM
13
C NMR (100 MHz, CDCl
3
) of 5.15

S
O
NH
2
551
9 8 7 6 5 4 3 2 1 PPM
1
H NMR (400 MHz, CDCl
3
) of 5.18

200 150 100 50 PPM
13
C NMR (100 MHz, CDCl
3
) of 5.18

S
O
NH
2
NO
2
552
10 8 6 4 2 PPM

1
H NMR (400 MHz, CDCl
3
) of 5.21

200 150 100 50 PPM
13
C NMR (100 MHz, CDCl
3
) of 5.21
O
NH
2
O
553
9 8 7 6 5 4 3 2 1 PPM
1
H NMR (400 MHz, acetone-d
6
) of 5.23

150 100 50 PPM
13
C NMR (62.5 MHz, acetone-d
6
) of 5.23
O
NH
2
O
Br
554
7.8 7.6 7.4 7.2 7.0 6.8 PPM
9 8 7 6 5 4 3 2 1 0PPM
1
H NMR (400 MHz, CDCl
3
) of 5.102

180 160 140 120 100 80 60 40 20 PPM
13
C NMR (100 MHz, CDCl
3
) of 5.102
CN
OH
Br
555
10 8 6 4 2 PPM
1
H NMR (400 MHz, CDCl
3
) of 5.103

180 160 140 120 100 80 60 40 20 PPM
13
C NMR (100 MHz, CDCl
3
) of 5.103
O
N
Br
556
10 8 6 4 2 PPM
1
H NMR (400 MHz, CDCl
3
) of 5.104

150 100 50 PPM
13
C NMR (100 MHz, CDCl
3
) of 5.104
Br
OH
H
N
OH
557
9 8 7 6 5 4 3 2 1 PPM
1
H NMR (400 MHz, CDCl
3
) of 5.30

150 100 50 PPM
13
C NMR (100 MHz, CDCl
3
) of 5.30
N
NH
2
O
O
558
8 6 4 2 PPM
1
H NMR (400 MHz, CDCl
3
) of 5.106

150 100 50 PPM
13
C NMR (100 MHz, CDCl
3
) of 5.106
CN
NH
O
559
9 8 7 6 5 4 3 2 1 0 PPM
1
H NMR (400 MHz, CDCl
3
) of 5.31

200 150 100 50 PPM
13
C NMR (100 MHz, CDCl
3
) of 5.31
N
NH
2
O
O
H
3
C
560
9 8 7 6 5 4 3 2 1 PPM
1
H NMR (250 MHz, CDCl
3
) of 5.108

180 160 140 120 100 80 60 40 20 PPM
13
C NMR (62.5 MHz, CDCl
3
) of 5.108
CN
NH
H
3
C O
561
9 8 7 6 5 4 3 2 1 PPM
1
H NMR (400 MHz, CDCl
3
) of 5.32

150 100 50 PPM
13
C NMR (100 MHz, CDCl
3
) of 5.32
N
NH
2
O
O
Cl
562
9 8 7 6 5 4 3 2 1 PPM
1
H NMR (400 MHz, CDCl
3
) of 5.110

180 160 140 120 100 80 60 40 20 PPM
13
C NMR (100 MHz, CDCl
3
) of 5.110
CN
NH
O
Cl
563
10 8 6 4 2 PPM
1
H NMR (400 MHz, acetone-d
6
) of 5.40

200 150 100 50 PPM
13
C NMR (62.5 MHz, acetone-d
6
)) of 5.40

S
O
NH
OH
O
564
10 8 6 4 2 PPM
1
H NMR (400 MHz, acetone-d
6
) of 5.41

150 100 50 PPM
13
C NMR (62.5 MHz, acetone-d
6
)) of 5.41

S
O
NH
OH
O
NO
2
565
10 8 6 4 2 PPM
1
H NMR (400 MHz, acetone-d
6
) of 5.42

150 100 50 PPM
13
C NMR (100 MHz, acetone-d
6
) of 5.42

S
O
NH
OMe
O
OH
566
8 7 6 5 4 3 2 1 PPM
1
H NMR (400 MHz, acetone-d
6
) of 5.45

200 150 100 50 PPM
13
C NMR (62.5 MHz, acetone-d
6
) of 5.46
S
NH
O
CH
3
OH
O
MeO
567
10 8 6 4 2 PPM
1
H NMR (400 MHz, acetone-d
6
) of 5.48

180 160 140 120 100 80 60 40 20 PPM
13
C NMR (62.5 MHz, acetone-d
6
) of 5.48

S
NH
O
CH
3
OH
O
S
568
8 7 6 5 4 3 2 1 PPM
1
H NMR (400 MHz, acetone-d
6
) of 5.52

150 100 50 PPM
13
C NMR (62.5 MHz, acetone-d
6
) of 5.52

S
NH
O
CH
3
OH
O
H
3
C
H
3
C
569
8 6 4 2 PPM
1
H NMR (400 MHz, acetone-d
6
) of 5.53

200 150 100 50 PPM
13
C NMR (62.5 MHz, acetone-d
6
) of 5.53

S
NH
O
CH
3
OH
O
O
570
9 8 7 6 5 4 3 2 1 PPM
1
H NMR (400 MHz, acetone-d
6
) of 5.54

180 160 140 120 100 80 60 40 20 PPM
13
C NMR (62.5 MHz, acetone-d
6
) of 5.54

O
NH
O
HO
O
OMe
571
9 8 7 6 5 4 3 2 1 PPM
1
H NMR (400 MHz, CDCl
3
) of 5.68

180 160 140 120 100 80 60 40 20 PPM
13
C NMR (62.5 MHz, CDCl
3
) of 5.68

S
N
CH
3
O
OMe
572
8 7 6 5 4 3 2 1 PPM
1
H NMR (400 MHz, CDCl
3
) of 5.69

180 160 140 120 100 80 60 40 20 PPM
13
C NMR (100 MHz, CDCl
3
) of 5.69

S
N
H
3
C
O
OMe
573
9 8 7 6 5 4 3 2 1 0PPM
1
H NMR (400 MHz, CDCl
3
) of 5.70

160 140 120 100 80 60 40 20 PPM
13
C NMR (100 MHz, CDCl
3
) of 5.70

S
N
H
3
C
O
O
2
N
574
8 7 6 5 4 3 2 1 PPM
1
H NMR (400 MHz, CDCl
3
) of 5.71

150 100 50 PPM
13
C NMR (100 MHz, CDCl
3
) of 5.71

S
N
H
3
C
O
575
9 8 7 6 5 4 3 2 1 PPM
1
H NMR (400 MHz, CDCl
3
) of 5.78

180 160 140 120 100 80 60 40 20 PPM
13
C NMR (100 MHz, CDCl
3
) of 5.78

S
N
CH
3
H
3
C
O
S
576
8 7 6 5 4 3 2 1 PPM
1
H NMR (400 MHz, CDCl
3
) of 5.79

180 160 140 120 100 80 60 40 20 PPM
13
C NMR (100 MHz, CDCl
3
) of 5.79

S
N
CH
3
H
3
C
O
CH
3
CH
3
577
9 8 7 6 5 4 3 2 1 0 PPM
1
H NMR (400 MHz, CDCl
3
) of 5.80

160 140 120 100 80 60 40 20 PPM
13
C NMR (100 MHz, CDCl
3
) of 5.80

S
H
N
CH
3
CH
3
CH
3
578
9 8 7 6 5 4 3 2 1 0 PPM
1
H NMR (400 MHz, CDCl
3
) of 5.73

180 160 140 120 100 80 60 40 20 PPM
13
C NMR (100 MHz, CDCl
3
) of 5.73

H
3
C
H
3
C
S
N
H
3
C
O
OMe
579
8 7 6 5 4 3 2 1 0 PPM
1
H NMR (400 MHz, CDCl
3
) of 5.74

180 160 140 120 100 80 60 40 20 PPM
13
C NMR (100 MHz, CDCl
3
) of 5.74

S
N
H
3
C
O
580
8 7 6 5 4 3 2 1 0PPM
1
H NMR (400 MHz, CDCl
3
) of 5.83

180 160 140 120 100 80 60 40 20 PPM
13
C NMR (100 MHz, CDCl
3
) of 5.83

S
N
CH
3
H
3
C
O
581
9 8 7 6 5 4 3 2 1 0 PPM
1
H NMR (400 MHz, CDCl
3
) of 5.86

180 160 140 120 100 80 60 40 20 PPM
13
C NMR (100 MHz, CDCl
3
) of 5.86

O
N
O
CH
3
Br
582
9 8 7 6 5 4 3 2 1 PPM
1
H NMR (400 MHz, CDCl
3
) of 5.88

180 160 140 120 100 80 60 40 20 PPM
13
C NMR (100 MHz, CDCl
3
) of 5.88

O
O
2
N
N
O
CH
3
S
583
9 8 7 6 5 4 3 2 1 PPM
1
H NMR (400 MHz, CDCl
3
) of 5.89

180 160 140 120 100 80 60 40 20 PPM
13
C NMR (100 MHz, CDCl
3
) of 5.89

O
N
OMe
O
CH
3
584
9 8 7 6 5 4 3 2 1 0 PPM
1
H NMR (400 MHz, CDCl
3
) of 5.100

180 160 140 120 100 80 60 40 20 PPM
13
C NMR (100 MHz, CDCl
3
) of 5.100

N
N
O
CH
3
O
O
H
3
C
585
9 8 7 6 5 4 3 2 1 PPM
1
H NMR (400 MHz, CDCl
3
) of 5.95

180 160 140 120 100 80 60 40 20 PPM
13
C NMR (100 MHz, CDCl
3
) of 5.95

N
N
O
CH
3
O
O
586
9 8 7 6 5 4 3 2 1 PPM
1
H NMR (400 MHz, CDCl
3
) of 5.96

180 160 140 120 100 80 60 40 20 0PPM
13
C NMR (100 MHz, CDCl
3
) of 5.96

N
N
O
CH
3
O
O
Cl
587
9 8 7 6 5 4 3 2 1 PPM
1
H NMR (400 MHz, CDCl
3
) of 5.98

180 160 140 120 100 80 60 40 20 PPM
13
C NMR (100 MHz, CDCl
3
) of 5.98

N
N
O
CH
3
S
O
Cl
588
9 8 7 6 5 4 3 2 1 PPM
1
H NMR (400 MHz, CDCl
3
) of 5.99

180 160 140 120 100 80 60 40 20 PPM
13
C NMR (100 MHz, CDCl
3
) of 5.99

N
N
O
CH
3
S
O
H
3
C
589
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Abstract (if available)

Abstract This dissertation describes the development of new, efficient and facile synthetic methodologies for the practical synthesis of novel heterocycles and highly substituted amine derivatives.

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University of Southern California Dissertations and Theses

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Asset Metadata

Creator Myslinska, Malgorzata (author)

Core Title New organoboron based multicomponent methodologies for the synthesis of novel heterocycles

School College of Letters, Arts and Sciences

Degree Doctor of Philosophy

Degree Program Chemistry

Publication Date 11/04/2011

Defense Date 09/17/2009

Publisher University of Southern California (original), University of Southern California. Libraries (digital)

Tag indole synthesis,multicomponent reactions,OAI-PMH Harvest,organotrifluoroborates,Petasis reaction,propargylamines

Language English

Contributor Electronically uploaded by the author (provenance)

Advisor Petasis, Nicos A. (committee chair), Prakash, G.K. Surya (committee member), Schonthal, Axel (committee member)

Creator Email m.myslinska@gmail.com,myslinsk@usc.edu

Permanent Link (DOI) https://doi.org/10.25549/usctheses-m2714

Unique identifier UC1424239

Identifier etd-Myslinska-3297 (filename),usctheses-m40 (legacy collection record id),usctheses-c127-277397 (legacy record id),usctheses-m2714 (legacy record id)

Legacy Identifier etd-Myslinska-3297.pdf

Dmrecord 277397

Document Type Dissertation

Rights Myslinska, Malgorzata

Type texts

Source University of Southern California (contributing entity), University of Southern California Dissertations and Theses (collection)

Repository Name Libraries, University of Southern California

Repository Location Los Angeles, California

Repository Email cisadmin@lib.usc.edu