umi-ku-2652_1

324 Pages·2012·3.23 MB·English

Palladium- and Ruthenium-Catalyzed Decarboxylative Allylations
and Michael Addition-Allylation Reactions. Applications in Nitrogen
Heterocycle Synthesis
By
Chao Wang
B.S. Henan University of Technology, 1999
M.S. Chem. TianJin University, 2002

Submitted to the Department of Chemistry and the Faculty of the Graduate School of
the University of Kansas in partial fulfillment of the requirements of the degree of
Doctor of Philosophy

________________________________
Jon A. Tunge, chair

________________________________
Jeffrey Aubé

________________________________
Robert G. Carlson

________________________________
Paul R. Hanson

________________________________
Helena C. Malinakova

_____________________
Date Submitted

i
The Dissertation Committee for Chao Wang certifies that this is the approved version
of the following dissertation:

Palladium- and Ruthenium-Catalyzed Decarboxylative Allylations
and Michael Addition-Allylation Reactions. Applications in Nitrogen
Heterocycle Synthesis

________________________________
Jon A. Tunge, chair

________________________________
Jeffrey Aubé

________________________________
Robert G. Carlson

________________________________
Paul R. Hanson

________________________________
Helena C. Malinakova

_____________________
Date approved

ii
Abstract
Chao Wang, Ph.D.
Department of Chemistry, June 2008
University of Kansas

Our group has a long-standing interest in Pd or Ru-catalyzed decarboxylative
coupling reactions. It has been shown that allyl β-ketoesters, upon treatment with
palladium or ruthenium, generate freely diffusing enolates and π-allyl electrophiles.
Consequently, we were curious about whether appropriate reactants (such as Michael
acceptors) could be used to intercept these intermediates during the reaction. It has
been since shown that a [Cp*RuCl] /bipyridyl catalyst effectively induces a
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regioselective tandem Michael addition-allylation reaction. This protocol works well
with a variety of allyl β-ketoesters and Michael acceptors. Interestingly, ruthenium
complexes behave as bifunctional catalysts, which activate the electrophilic allyl
fragment and catalyze the decarboxylative formation of enolate nucleophiles. In
addition, we have shown that cyclic carbamates diastereoselectively produce vinyl
azetidines in good yields via a decarboxylative ring contraction. The
diastereoselectivity is facilitated by rapid epimerization of the C stereocenter through
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π-σ-π allyl interconversion. This allows the synthesis of highly diastereoenriched
azetidines from diastereomeric mixtures of cyclic allylic carbamates. Furthermore, in
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the presence of Michael acceptors, the cyclic carbamates undergo tandem Michael
addition-allylation to produce highly substituted piperidines with good
diastereoselectivity. Moreover, we have demonstrated that vinyl benzoxazinones
undergo decarboxylative allylation to generate a series of dihydroquinoline
derivatives. Once again, reaction in the presence of Michael acceptors led to a formal
decarboxylative [4+2] cycloaddition. The analogous reaction in the presence of
nonracemic palladium catalysts led to a highly enantioselective reaction. Lastly, a
selenium-catalyzed oxidative halogenation of carbonyl compounds was developed.
Interestingly, phenylselenides were found to be efficient and selective catalysts that
enhance the electrophilicity of oxidized halogen sources such as NCS toward
α–halogenation of carbonyl containing compounds such as ketones, β-ketoesters, and
even α,β-unsaturated ketones. In most cases, monohalogenated products were
generated exclusively.

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To my wife, Lisha
and my baby, Gavin

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Acknowledgement
Five years of graduate study is not that easy, which were composed with both
joys and tears. When I looked back, there are so many peoples I have been worked
with, and without their help, I can never stick to my graduate study and summit such
a big mountain in my life. So I feel like to say something and express my great
appreciation of their companionship.
I want to say “thank you” to my wife, Lisha. You always believe in me and have
been supportive during my graduate study. Even though we are different in majors,
you are willing to talk about chemistry and apparently chemistry is not your favorite
spot. I still remembered those times you had to listen to my practice talks and provide
me with valuable feedbacks. In living, I really enjoyed your company, which makes
things easier. Though you seldom cook, I must admit that I did enjoy cooking. You
are an extremely smart, smart PhD candidate and just need a little bit more focus. My
baby-Gavin is really a blessing to us. I just can not imagine you are almost two years
old now. To watch you growing up make me happy everyday. Being a daddy is not
only changing dippers, feeding, but to spend a lot of time together and have fun. I
love you both very much.
To Jon, you are a very nice and acknowledge advisor. Sometimes I just curious
where did you learn all those chemistry. You are a hardworking “boss” with so many
smart ideas. I could not have asked for a better PhD mentor. I know it must be very
hard to guide me through my graduate study since my native language is not English.
I remembered those times we sat together, going though my slides, my drafts and
more importantly, my dissertation. I just can not imagine that you actually went
through my dissertation four times. As to your personality, you have always been very
nice and considerate. More importantly, you treat every lab members in a fair manner.
Your inquisitiveness and curiosity about science impressed me the most and will
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impact my whole life. You do set up a model for me to follow in the future.
I also want to express my gratitude to other committee members, Dr Carlson,
Helena, Jeff and Paul. You taught me that there are a lot of funs in chemistry, which
made my journey to my PhD degree more pleasant. I really appreciate your
mentorship. Dr Carlson, you are my advisor on organic colloquium and taught me the
spectroscopy course. I am always impressed at your organization and dedication to
your students. Jeff and Paul, your knowledge and provoking points at the problem
sets make learning more fun, and I did have a wonderful time at KU. Helena, I sat in
your synthesis course and have been working as a GTA with you. Your innovative
ways of teaching is awesome. Again, I would like to thank Helena and Paul for being
the readers of my dissertation.
To Erin and Shelli and Dr Li, it is lucky to have you as the seniors in the lab. Erin,
your attitude and dedication to chemistry impressed me the most. Shelli, without you,
the Tunge’s lab would not run so smoothly. I did enjoy working with you fellows and
truly appreciate your help with my oral proposal. Dr Li, you are the first post-doc I
ever worked with. Many thanks for teaching me those experimental “tricks” and
discussion chemistry with me in Chinese. I felt sorry for the rest of the members of
Tunge’s group for suffering those blablabla…; however it does show that “learning a
second language is important”.
I also want to thank other members of Tunge’s group. Jimmie Weaver, Robert
Torregrosa, Alex Greening, Antonio Recio, Rushi Trivedi, Ranjan Jana, Nirmal
Pahadi and Shaofeng Duan. You fellows are great members and I have a good time
working with you in the lab. I am expecting to see Tunge’s group gets bigger and
stronger in the near future.
I also wish to take this chance to express my gratitude to the molecular structure
group at KU, Dave Vander Velde and Sarah Neuenswander for NMR sepectroscopy
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analysis, Todd Williams and Bob Drake for Mass Spectroscopy analysis and Victor
Day for X-ray crystallographic analysis.
Finally, I want to share my joy with my family. I have been very lucky to live
with them in the past two years. My parents, Wenzhi Wang and Xuejie Zhang, your
encouragement and supportiveness hold me up and help me go through the good
times and bad times of my graduate study, and here I become the first member of the
family with a PhD degree. My parents-in-law, Ruxing Zhang and Ying Du, You are
great and I can not imagine to finish my study here at KU without your help. I enjoy
playing games together and I love you all.

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Palladium- and Ruthenium-Catalyzed Decarboxylative Tandem Michael
Additon-Allylation Reactions and Further Applications in Nitrogen Heterocycles
Synthesis
Contents Page #

Title Page i
Abstract ii
Table of Contents iv
Abbreviations vi

Chapter 1: Ruthenium-Catalyzed Decarboxylative Insertion of Michael
Acceptors into Allyl ketoesters 1

1.1 Overview of Ruthenium-Catalyzed Allylation Reactions 2
1.2 Pd-Catalyzed Decarboxylative Generation of Enolate Nucleophiles 9
1.3 Ru-Catalyzed Tandem Michael Addition Allylation Reactions 17
1.4 References 36
Appendix A: General Methods and Compound
Characterization for Chapter 1 41
References for Appendix A 65

Chapter 2: The Synthesis of Nitrogen-Containing Hetereocycles via the
Palladium-Catalyzed Decarboxylative Allylation 67

2.1 Importance of Nitrogen Heterocycles in Pharmaceutical Industry 68
2.2 Overview of Azetidine Synthesis 71
2.3 Pd-Catalyzed Azetidine Synthesis via Decarboxylative Ring Contractions 74
2.4 The Importance of Bioactive Quinolines and Their Derivatives 86
2.5 Overview of 1,2-Dihydroquinoline Synthesis 87
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Contents (continued) Page #
2.6 Decarboxylative Dihydroquinoline Synthesis via Aza-ortho-xylylene
Intermediates 96
2.7 References 105
Appendix B: General Methods and Compound
Characterization for Chapter 2 113
References for Appendix B 150

Chapter 3: Palladium-Catalyzed Decarboxylative Cycloaddition Reactions 151

3.1 Introduction 152
3.2 Synthesis of Highly-substituted Piperidines 158
3.3 Palladium-Catalyzed Asymmetric, Diastereoselective Cycloadditions in
Hydroquinoline Synthesis 174
3.4 References 194
Appendix C: General Methods and Compound
Characterization for Chapter 3 199
References for Appendix C 287

Chapter 4: Selenium-Catalyzed Oxidative Halogenation 288

4.1 Importance of Catalytic α-Halogenation of Carbonyl Compounds 289
4.2 Selenium-Catalyzed Halogenation of Carbonyl Compounds 292
4.3 References 299
Appendix D: General Methods and Compound
Characterization for Chapter 4 302
References for Appendix D 309
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