Catalyzed Domino Reactions with Strained Alkenes

543 Pages·2010·49.36 MB·English

by  Praew Thansandote

Construction of Functionalized Heterocycles by Palladium-
Catalyzed Domino Reactions with Strained Alkenes
by
Praew Petcharat Thansandote
A thesis submitted in conformity with the requirements
for the degree of Doctor of Philosophy
Department of Chemistry
University of Toronto
© Copyright by Praew Thansandote 2010
Construction of Functionalized Heterocycles by Palladium-
Catalyzed Domino Reactions with Strained Alkenes
Praew Thansandote
Doctor of Philosophy
Department of Chemistry
University of Toronto
2010
Abstract
The Lautens group has a long-standing interest in developing novel approaches to heterocycle
synthesis. One such approach is a Pd-catalyzed, norbornene-mediated domino reaction which
can form up to three carbon-carbon bonds in one synthetic sequence. The key additive is
norbornene which acts similar to a catalyst by assembling the scaffold to enable the formation of
a carbon-carbon bond, though is not incorporated into the final compound. The reaction involves
C-H bond functionalization as a key step and a Pd(IV) complex as a key intermediate.
The goal of the current thesis was to introduce reactive heteroatoms to this domino reaction for
the first time, with particular focus on the introduction of nitrogen. Methodologies were
developed to present novel syntheses of heterocycles with high pharmaceutical interest. Our
initial study focused on the selective functionalization of thiophenes to give multi-substituted
sulfur compounds. To synthesize pharmaceutically important nitrogen heterocycles, we
demonstrated for the first time that an amination reaction was compatible with the domino
reaction. This development led to novel approaches to synthesize substituted indolines, indoles,
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tetrahydroquinolines, benzomorpholines, phenoxazines, dihydrodibenzoxazepines,
tetrahydroisoquinolines, tetrahydroisoquinolinones and tetrahydrobenzazepines.
In contrast to the use of norbornene in a catalytic manner, we demonstrated that heterocycles
could also be synthesized by the incorporation of strained alkenes. We developed a conceptually
novel approach to generate nitrogen heterocycles by using norbornadiene as an acetylene
synthon. A palladium-catalyzed annulation of substituted haloanilines with norbornadiene led to
functionalized indolines. These indolines could be rapidly converted to benzenoid-substituted
indoles and tricyclic indolines, which form the core of many biologically active compounds.
Extension to the use of substituted halobenzamides led to functionalized isoquinolinones.
Finally, we embarked on a study to perform selective palladium-catalyzed C-H functionalization
reactions with N-iodoarylpyrroles and strained alkenes. We will present the reaction conditions
necessary to favour aryl C-H functionalization over pyrrole C-H functionalization.
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Acknowledgments
Besides the necessary hard work and perseverance, my doctoral degree was a direct result of the
support and encouragement from the people in my personal and professional life.
Firstly, I would like to thank Mark for giving me the opportunity to be a part of his group. I have
learned so much from him and from the growing number of past and present Lautens group
members. My experiences in the group have really contributed to my growth as a chemist and
have given me the skills to continue to grow long after the completion of my degree. I am
especially thankful to Mark for giving me the independence to explore my own ideas, the
opportunity to present my work at conferences, and the experience of writing for Synfacts. I can
truly say that my graduate studies were some of the best years of my life.
I am incredibly happy to have chosen the University of Toronto for my graduate studies. Thanks
to the chemistry support staff, both administrative and technical, for assisting with all aspects of
my research and program requirements. I am grateful to have been part of the Chemistry Club
and other Department Committees. I would especially like to thank the other organic chemistry
groups at U of T for their support and friendship, in addition to creating an academically thriving
environment for research.
I feel blessed to have gone through graduate studies with the Lautens students in my year, Fred
Menard and Christopher Bryan. Thank you to both of you for teaching me so much and
supporting me through the years. The miracle tree that we planted in the Department garden in
our first year will always be a reminder of our time together. May it continue to grow!
Thank you to all of my brilliant research collaborators: Dr. Koichi Mitsudo, Dr. Thorsten
Wilhelm, Dr. Brian Mariampillai, Dr. Manuel Raemy, Dr. Alena Rudolph, Dr. David Hulcoop,
Dr. Michael Langer and David Chai. Thanks as well to the hard-working students that I have
supervised: Christina Gouliaras, Marc-Olivier Turcotte-Savard, Ollie Feldmann and Eugene
Chong. A lot less work would have been completed without you, and I am incredibly grateful
for each of your contributions.
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A special thank you to my former labmates, the Fagnou Factory. Even long after my departure, I
have always been treated like family. Thanks for all of the research support over the years and
the fun times together. Once a Fagnou always a Fagnou, and we are bonded for life.
To my friends and family around the world, thank you for supporting me through this degree
even though many of you had no clue what I was doing. Thanks for attempting to understand
organic chemistry and letting me bore you with research talks.
Finally, a deep thank you to my parents, brother, and Dave for their unwavering support. I truly
could not have done this without you.
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Dedication

To Keith Fagnou (1971-2009),
for believing in me and giving me my start. You were right (medical
school wasn’t worth it!).

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Table of Contents
Abstract ii
Acknowledgements iv
Dedication vi
Table of Contents vii
List of Tables xiv
List of Figures xvii
List of Schemes xix
List of Appendices xxvii
List of Publications xxviii
Abbreviations xxix

General Introduction 1
1 Domino Reaction 1
1.1 Introduction to Domino Reactions 1
1.2 Types of Domino Reactions 2
1.3 Transition-Metal Catalyzed Domino Reactions 2
2 The Catellani Reaction 6
2.1 Introduction to the Catellani Reaction 6
2.2 Support for the Catellani Reaction 8
2.2.1 Oxidative addition 8
2.2.2 Carbopalladation of norbornene 9
2.2.3 Palladacycle formation 9
2.2.4 Oxidative addition to the palladacycle 9
2.2.5 Reductive elimination from the Pd(IV) intermediate 11
2.2.6 Norbornene extrusion 11
2.2.7 Termination step 12
2.3 Diversity of the Catellani Reaction 12
2.4 Relevant Examples of the Catellani Reaction 15
2.4.1 Heck reaction termination 15
2.4.2 Reduction termination 16
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2.4.3 Cyanation termination 17
2.4.4 Heck reaction/Aza-Michael termination 19
2.4.5 Amidation termination 20
3 Notable Pd-Catalyzed Transformations for the Catellani Reaction 21
3.1 C-H Bond Functionalization 21
3.2 The Heck Reaction 23
3.3 The Buchwald-Hartwig Coupling 26
4 Conclusions 31
Part I: Norbornene-Mediated, ortho-Functionalization Methodologies 32
Chapter 1: Selective Substitution of Halothiophenes 33
1 Introduction 33
1.1 Utility of Functionalized Thiophenes 33
1.2 Preparation of Functionalized Thiophenes 35
1.2.1 Thiophene core construction using functionalized substrates 37
1.2.2 Direct arylation of thiophenes 39
2 Research Goals 41
3 Starting Material Preparation 42
4 Results and Discussion 43
4.1 Initial Studies and Optimization of Domino Alkylation/Heck Reaction 43
4.2 Proposed Mechanism 45
4.3 Continued Optimization Studies of the Domino Alkylation/Alkenylation 46
4.4 Scope of the Domino ortho-Alkylation/Heck Coupling 48
4.5 Limitations of the ortho-Alkylation/Heck Coupling 49
4.6 Creating Unsymmetrically Substituted Thiophenes 50
4.6.1 Reaction of 3-Bromo-2-iodothiophene 50
4.6.2 Substitution by Sonogashira coupling 51
4.6.3 Substitution by Heck coupling 52
4.6.4 Substitution by Suzuki coupling 52
4.6.5 Substitution by Kumada-Tamao type coupling 53
4.7 Optimization of the Synthesis of 2,4-Disubstituted Thiophenes 54
4.8 Synthesis of 2,4-Disubstituted Thiophenes 59
4.9 Limitations for the Synthesis of 2,4-Disubstituted Thiophenes 60
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4.10 Diversity of Thiophene Products 61
4.11 Extension to Other Heterocycles 62
5 Conclusions 64
6 Experimental Information 65
Chapter 2: Synthesis of Benzannulated Nitrogen Heterocycles 77
1 Introduction 77
1.1 Utility of Functionalized Indolines 77
1.2 Preparation of Functionalized Indolines 78
1.2.1 Metal-catalyzed processes 79
1.2.2 Non-metal catalyzed processes 81
1.2.3 Radical reactions 82
1.2.4 C-H bond functionalization 82
1.3 Preparation of Functionalized Tetrahydroquinolines 84
2 Research Goals 85
3 Starting Material Preparation 86
4 Results and Discussion 89
4.1 Initial Studies of the Domino ortho-Alkylation/Aromatic Amination 89
4.2 Proposed Mechanism 91
4.3 Optimization of the Domino ortho-Alkylation/Aromatic Amination 92
4.4 Scope of the Domino ortho-Alkylation/Aromatic Amination 98
4.5 Limitations of the ortho-Alkylation/Aromatic Amination 100
4.6 Diversity of Indole Products by ortho-Alkylation/Aromatic Amination 101
4.6.1 Formation of indoles 101
4.6.2 Formation of 3-methylindolines 105
4.6.3 Formation of tetrahydroquinolines 106
4.7 Deprotection of para-Nitrophenyl Group 106
5 Conclusions 110
6 Experimental Information 112
Chapter 3: Synthesis of Benzomorpholines, Phenoxazines and 123
Dihydrodibenzoxazepines
1 Introduction 123
1.1 Utility of Benzomorpholines, Phenoxazines and Dihydrodibenzoxazepines 123
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1.2 Preparation of Functionailzed Benzomorpholines 125
1.3 Preparation of Functionalized Phenoxazines 126
1.4 Preparation of Functionalized Dihydrodibenzoxazepines 126
2 Research Goals 127
3 Starting Material Preparation 129
4 Results and Discussion 133
4.1 Initial Studies of the Benzomorpholine Synthesis 133
4.2 Proposed Mechanism 135
4.3 Continued Studies of the Benzomorpholine Synthesis 136
4.4.1 Ligand optimization 137
4.4.2 Palladium source optimization 139
4.4.3 Base and temperature optimization 140
4.4.4 Solvent optimization 142
4.4.5 Reaction time optimization 143
4.4.6 Microwave irradiation 143
4.4 Scope of Benzomorpholine Synthesis 144
4.5 Synthesis of Phenoxazines 145
4.6.1 Concentration, temperature and reaction optimization 146
4.6.2 Ligand optimization 147
4.6.3 Base optimization 147
4.6.4 Effects of additives and heating method 149
4.6.5 Catalyst optimization 150
4.6 Scope of the Phenoxazine Synthesis 152
4.7 Synthesis of Dihydrodibenzoxazepines 154
4.8 Limitations of the Phenoxazine and Dihydrobenzoxapine Synthesis 156
5 Conclusions 157
6 Experimental Information 158
Chapter 4: Synthesis of Tetrahydroisoquinolines 180
1 Introduction 180
1.1 Utility of Tetrahydroisoquinolines and Their Homologues 180
1.2 Preparation of Functionalized Tetrahydroisoquinolines 181
1.2.1 Bischler-Napieralski reaction 181
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