Palladium-Catalyzed Functionalization of CH Bonds and Alkenes

243 Pages·2008·10.45 MB·English

by  Smitesh Bakrania

Palladium-Catalyzed Functionalization of
C-H Bonds and Alkenes

by

Lopa Vrushank Desai

A dissertation submitted in partial fulfillment
of the requirements for the degree of
Doctor of Philosophy
(Chemistry)
in The University of Michigan
2008

Doctoral Committee:

Associate Professor Melanie S. Sanford, Chair
Professor Edwin Vedejs
Professor Erdogan Gulari
Assistant Professor John P. Wolfe
© Lopa Vrushank Desai
______________________

2008
To Dr. Sanford, Dipa
and Smitesh

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Acknowledgements

I give my deepest gratitude to all those people who made my graduate experience
a memorable and one that I will cherish forever.
I would like to start with the most influential person – Dr. Sanford. I consider
myself very fortunate that I got an advisor like you. Your passion, enthusiasm,
motivation, dedication, patience and mentorship were paramount in my growth and life.
You showed me different ways to approach a problem and guided me when I made
mistakes. You taught me how to question, write and present chemistry. Even though you
had a lot on your plate; you still devoted endless time to me. You are an amazing mentor
because you make your students your priority – you care for us, take time to understand
us, go out of your way to build our future and love us for who we are. I thank you for
everything you have done for me. I hope that you will continue to be a significant part of
my life.
I would like to thank my committee members for their support and feedback in
such short notice. Dr. Wolfe, I have learned a lot from you through group meetings and
classes. I appreciate all your insightful comments at different stages of my research. Dr.
Vedejs, your questions at seminar and in class have always been very thought provoking.
Dr. Gulari, thank you for bringing a different perspective to my committee.
Research is not possible without the help of Jim Windak, for mass spectrometry,
Eugenio for NMR and Jeff Kampf for all the cystrallography. Thank you to all three of

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you for facilitating a productive research environment. I am also grateful to Aiko,
Christina and Jerry for addressing my endless administrative questions and problems. The
candy from Aiko and Mike Kelly helped me increase my sugar level. I am also grateful to
Dr. Matzger for his help with calculations and access to his computers. I want to thank
Antek for his support, humor and being himself. I appreciate all the times when you
shared and expressed mutual feelings for my ‘arch nemesis’. Thank you for your
feedback and solving really hard crystal structures for me. I want to thank Hasnain Malik
for working with me on the Oxone project. I am surprised I didn’t scare him away that
semester. I have been lucky to have very supportive friends. Josie you are one of them. I
am so glad that we did our first rotation together. You are a great person and don’t ever
change.
I want to thank my lab mates – the ‘Sanford Mafias’ or ‘Sanfordites’ for being so
amazing. I am lucky to have worked with such a talented group of people. What I love
the most about my lab mates is no matter what, we are always there for each other. Kami-
thank you for all your help, support and feedback these past few years. Camping would
be no fun without your tent and blankets. I also appreciate all the ‘goodies’ you have
made and shared with me. Salena- your friendship, invaluable suggestions and feedback
has taught me a lot. You are a great listener. Smitesh and I will always miss your German
Chocoloate Cake and ‘Mookies’. Deprez, you are like a big brother with a kind and
supportive nature. Thank you for the frosty Nick Ball – it was very thoughtful. Andrew– I
enjoyed our ‘random’ lunch conversations. Matt, I appreciate all your probing questions.
Joy, thank you for taking care of GC’s while I was working on my dissertation. I am so
thrilled to have Dipa, Kara and Tom as my bench-mates. They bring laughter to your

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face, even when you feel like there is no hope. They make work place fun, frustrating,
crazy, hot, cold and a great homey place. I have enjoyed all the times we have danced,
sang, and debated in lab. Hum to aise hai bhaiya. I appreciate Tom’s bluntness and
Kara’s caring and sensitive nature. ‘Sorry’ Karebear! I loved working with you these
past few months. I appreciate you overlooking my occasional burst of irrationality.
Deeps, I wish I could write pages and pages expressing what you mean to me- but
I don’t want to embarrass you. Bhagwan humse bahut kush hoga isleye usne humko
tumhare jesa dost diya. You were like my second mentor, sister, mother and friend. Your
incredible work ethic and high standard of research is admirable and inspiring – you truly
deserve the best. I am so grateful for your honesty with me – you brought the best out in
me. Your meticulous guidance and invaluable suggestions helped me focus and approach
problems in different ways. Thank you for carefully reading and commenting on
countless versions of anything I have ever written or presented. You have saved me
numerous occasions- editing, thinking through problems, and giving me your laptop
endlessly. You have been there for me through hard times and good times. I know
regardless of my temperamental irrational self–you will always be there for me with your
unfaltering friendship and unconditional love.
I want to thank my family – my parents and my brother for their unconditional
support and encouragement to pursue my dreams. Thank you for loving me even after
dealing with my tantrums and frustrations. Mom, thank you for believing in me and
encouraging me to be persistent and reach my highest potential. Tushar you are a great
brother and I am lucky to have you. Thank you to my family-in-law (parents, bhai,

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bhabhi, and nephews Viraj and Laksh) for their love and support. Mom- you spoilt me
these past few months with your cooking.
The last – but not least- person I want to thank is my husband, Smitesh. As corny
as this may sound – you complete me. Your constant patience, tolerance of my ‘ups’ and
‘downs’, ‘highs’ and ‘lows’ is a testament in itself of your unyielding love, sacrifice and
compromise. Your kindness, love, incredible smartness, zeal to learn, patience, and
creativity are the bedrock of my life. Thank you for everything you do to make my life
comfortable, full of love, happiness, adventures, emotions and stories. I cannot express
how thankful I am of all those times you have come to my rescue – making my posters,
designing, formatting my dissertation, generating my table of contents, scheme and
figures. Your creativity and aspiration for knowledge is refreshing and inspirational.
Thank you for having faith in me and supporting and inspiring my ambitions. You have
taught me a lot of values in life and made me a better person. I thank god for making you
part of my life and for everything else I have been given. JSK.

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Table of Contents

Dedication ...............................................................................................................ii
Acknowledgements .................................................................................................iii
List of Schemes .......................................................................................................x
List of Figures .........................................................................................................xviii
List of Tables ..........................................................................................................xx
Abstract ...................................................................................................................xxii

Chapter 1
Introduction .............................................................................................................1

1.1 References .........................................................................................................6

Chapter 2
Palladium-Catalyzed Acetoxylation of sp3 C-H Bonds .............................................7

2.1 Background and Significance .............................................................................7
2.2 Initial Results .....................................................................................................14
2.3 Substrate Scope of Pd-Catalyzed Acetoxylation of 1º sp3 C-H Bonds .................15
2.4 Competition Studies: sp2 versus sp3 C–H bonds .................................................25
2.5 Functionalization of Secondary sp3 C-H bonds ..................................................33
2.6 Stereochemical Nature of Reductive Elimination ...............................................39
2.7 Deprotection of Directing Groups ......................................................................45
2.8 Conclusion .........................................................................................................47
2.9 Experimental Procedure .....................................................................................47
2.10 References .......................................................................................................68

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Chapter 3
Oxone and K S O as Alternative Oxidants for C-H Bond Oxygenation ..................71
2 2 8

3.1 Background and Significance .............................................................................71
3.2 Initial Screenings of Peroxides ...........................................................................73
3.3 Scope of Acetoxylation of sp2 C–H Bonds with Oxone and K S O ...................76
2 2 8
3.4 Scope of Acetoxylation of sp3 C–H Bonds with Oxone and K S O ...................82
2 2 8
3.5 Formation of Methyl Ethers with Oxone and K S O .........................................84
2 2 8
3.6 Introduction of Other Nucleophiles at Carbon with Oxone and K S O ...............88
2 2 8
3.7 Conclusions .......................................................................................................89
3.8 Experimental Procedure .....................................................................................89
3.9 References .........................................................................................................108

Chapter 4
Factors Governing the Dominance of a Directing Group ..........................................110

4.1 Background and Significance .............................................................................110
4.2 Substrate Selection and Optimizations ...............................................................112
4.3 Competition Studies ...........................................................................................116
4.4 Individual Rate Studies ......................................................................................122
4.5 Kinetic Isotope Effect Studies ............................................................................124
4.6 Order of PhI(OAc) ............................................................................................125
2
4.7 Discussion .........................................................................................................127
4.8 Application ........................................................................................................134
4.9 Conclusions .......................................................................................................137
4.10 Experimental Procedure ...................................................................................137
4.11 References .......................................................................................................153

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Chapter 5
Palladium-Catalyzed 1,2-Difunctionalization of Alkenes .........................................155

5.1 Background and Significance .............................................................................155
5.2 Initial Investigation ............................................................................................162
5.3: Cyclization of Alcohols ....................................................................................169
5.4 Cyclization of Amines .......................................................................................172
5.5: Cyclization of Acids .........................................................................................174
5.6 Mechanistic Investigations of the Cyclization Reactions ....................................175
5.7 Aminooygenation Cyclization Reactions with 3-Alken1-ols ..............................178
5.8 Mechanistic Investigations of Amiooxygenation Cyclization .............................181
5.9 Conclusion .........................................................................................................192
5.10 Experimental Procedure ...................................................................................192
5.11 References .......................................................................................................219

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