Organocatalyzed Morita-Baylis-Hillman Reaction: Mechanism and

166 Pages·2011·7.95 MB·English

by  Yinghao Liu

Dissertation zur Erlangung des Doktorgrades
der Fakultät für Chemie und Pharmazie
der Ludwig-Maximilians-Universität München

Organocatalyzed Morita-Baylis-Hillman Reaction:
Mechanism and Catalysis

Von
Yinghao Liu
Aus
Yantai, China

München, 2011
Erklärung

Diese Dissertation wurde im Sinne von § 13 Abs. 3 der Promotionsordnung
vom 29. Januar 1998 von Herrn Prof. Dr. Hendrik Zipse betreut.

Ehrenwörtliche Versicherung

Diese Dissertation wurde selbständig, ohne unerlaubte Hilfe erarbeitet.

München, am 15. 12. 2010

Yinghao Liu

Dissertation eingereicht am 20. 12. 2010

1. Gutachter: Prof. Dr. Hendrik Zipse
2. Gutachter: Prof. Dr. Herbert Mayr

Mündliche Prüfung am 11.01.2011

II
To GongGong and YangYang
To 龚龚 和 秧秧
III
This work was carried out from 10. 2007 to 10. 2010 under the guidance of
Prof. Dr. Hendrik Zipse at Department Chemie, Ludwig-Maximilians-Universität
München.

I appreciate all the people who have contributed to this work:
My main deep and sincere gratitude belongs to my supervisor and Doktorvater
Prof. Dr. Hendrik Zipse for giving me this opportunity to work and study in his
research group. I thank him for all the constructive discussion and critical
comments on this subject, especially for the great degree of independence and
freedom to explore. Also I am grateful for his kind help for my stay in Munich.
I would like to thank Prof. Dr. Herbert Mayr for acting as my “Zweitgutachter”
and assessing this work. Thanks also to other referees Prof. Dr. Manfred
Heuschmann, Prof. Dr. Konstantin Karaghiosoff, Prof. Dr. Paul Knochel
and Prof. Dr. Rudolf Knorr, for being willing to undertake this assessment of
my thesis.
I am especially grateful to Prof. Dr. Konstantin Karaghiosoff, who not only
worked as referee but also helped me a lot with NMR measurements.
I thank Dr. Konrad Koszinowski for the measurement of MS, Frau Dubler
and Dr. Stephenson for the measurement of NMR spectra.
Special thanks to Boris Maryasin and Florian Achrainer for careful and
patient reading and correcting this thesis. My thanks to all the members of our
research group for the nice atmosphere, especially to Dr. Ingmar Held, Dr. Yin
Wei, Evgeny Larionov, Boris Maryasin, Florian Achrainer, Christoph
Lindner, Dr. Valerio D’Elia, Johnny Hioe, Elija Wiedemann, Regina
Bleichner, Jowita Humin, Florian Barth, Michael Miserok, Cong Zhang,
IV
my nice lab-neighbor Raman Tandon, and all my friends in Germany. It was
you people who made my stay in Germany a great time. Vielen Dank, guys!
I acknowledge the China Scholarship Council and Ludwig-Maximilians-
Universität München for financial support, and the international office of LMU
for their kind help since my first arrival to Munich.
Most importantly I would like to thank my parents for their support, help and
encouragement during my life.
The last and special thank goes to my wife for her love, support and company
in these times. Thank you so much!

Yinghao Liu
25. 11. 2010

V
致 谢
在完成论文之际，我由衷地感谢我的导师 Hendrik Zipse 教授。在过去的三
年中，Prof. Zipse在学术上给我悉心的指导、谆谆的教诲以及充分的学术自由度
去发挥自我, 在生活中也给予我极大的关心和照顾, 尤其是带领我们爬遍了巴伐
利亚的”险峰”.
感谢 Prof. Manfred Heuschmann, Prof. Konstantin Karaghiosoff, Prof.
Rudolf Knorr, Prof. Paul Knochel 和Prof. Herbert Mayr 参与我的论文评审和答
辩, 尤其感谢 Prof. Herbert Mayr 作为我的第二导师对我的指导和 Prof.
Konstantin Karaghiosoff 在核磁研究方向的帮助. 感谢Dr. Konrad Koszinowski
在质谱样品测试, Frau Dubler 和Dr. Stephenson在核磁样品测试中的帮助.
特别感谢 Florian Achrainer, Boris Maryasin对于本论文细心的阅读与订正.
我要感谢 AK Zipse课题组所有的成员:
Dr. Mage, Dr. Yin Wei, Evgeny, Borix, Flo-A, ChristOOph, Prof. Vale, Jungnie,
Elija-Slave, Regina, Michael, evilta, Florian-B, CongYe, and “the kindest
human-being” Romi et al.
跟你们一起工作和滑雪、爬山、攀岩、踢球、喝酒的日子充满了欢乐. 还有我在
德国认识的朋友们: 李卓、龚子静、韩宇、张志勇、张建宏、陈宜鸿、段新华、
彭志华、王晓东、孙敏、夏惠等等, 大家在慕尼黑共同度过的时光, 难以忘怀.
谢谢你们 !
感谢国家留学基金委和慕尼黑大学给予我的经济资助, 感谢慕尼黑大学外
事办和中国驻慕尼黑领事馆对于我在慕尼黑生活的帮助.
同时, 我要感谢上海有机所的施敏教授和南京理工大学的张跃军教授, 是您
们的悉心教诲, 引领我走上了学术研究的道路. 感谢上海有机所金属有机实验室
208 组陆建梅, 钱恒新等同事和南京理工大学化工学院助剂组的王海鹰, 贾旭等
VI
同学对我过去学习生活的帮助.
感谢所有我的朋友们给予我的帮助。
最后，我要深深感谢多年来我的父母、爱人以及我所有善良的亲人们对我学
业一贯的鼓励和支持, 你们一直是支持我向前的动力, 陪我走过每一段难忘的时
光, 我的每一点进步都饱含着你们的心血; 尤其是龚龚, 感谢你多年来的爱与陪
伴、牺牲和支持, 谢谢! Vielen Dank !

刘英豪
2010年11 月
于慕尼黑大学
VII
ABBREVIATIONS

ABBREVIATIONS

Ac acetyl m multiplet
AN acceptor number Me methyl
Ar aryl min minute
BINOL 1,1'-Bi-2-naphthol mol mole
Bn benzyl MS mass spectrometry
Boc tert-butoxycarbonyl MVK methyl vinyl ketone
nuclear magnetic
br broad NMR
resonance
Bu butyl o ortho
calcd. Calculated p para
conv. conversion pent pentyl
d doublet Ph phenyl
1,4-Diazabicyclo[2.2.2]
DABCO Piv pivaloyl
octane
PNP para-nitrophenol
DCM dichloromethane
1,8-Diazabicyclo[5.4.0] PPY 4-pyrrolidinopyridine
DBU
undec-7-ene
DMAP dimethylaminopyridine i-Pr isopropyl
DMF dimethylformamide q quartet
DMSO dimethyl sulfoxide rt room temperature
equiv. equivalent s singlet
EI electron-impact t triplet
ESI Electron Spray Ionization t-Bu tert-butyl
GC gas chromatography TEMPO 2,2,6,6-Tetramethylpiperi
dine-1-oxyl
h hour TFA trifluoroacetic acid
HRMS high resolution mass THF tetrahydrofuran
spectroscopy
IR infra-red Ts 4-toluenesulfonyl
HSQC Heteronuclear Single Quantum lowest unoccupied
LUMO
Correlation molecular orbital
J coupling constant (NMR) Heteromuclear Multiple
HMBC
Bond Correlation

VIII
OUTLINE

1 INTRODUCTION ............................................................................................. 1
1.1 ORGANOCATALYSIS ..................................................................................... 1
1.1.1 General aspects ..................................................................................... 1
1.1.2 Lewis base catalysis .............................................................................. 5
1.1.3 Lewis acid catalysis ............................................................................... 7
1.1.4 BrØnsted base catalysis ......................................................................... 8
1.1.5 BrØnsted acid catalysis .......................................................................... 9
1.1.6 Multifunctional Catalysis ....................................................................... 11
1.2 MORITA-BAYLIS-HILLMAN REACTION ............................................................ 12
1.2.1 General aspects ................................................................................... 12
1.2.2 Origin and development ....................................................................... 13
1.2.3 Mechanism ........................................................................................... 13
1.2.4 Substrate diversity ............................................................................... 19
1.2.5 Catalysis .............................................................................................. 20
1.3 OBJECTIVE ................................................................................................ 27
2 RESULTS AND DISCUSSION ...................................................................... 28
2.1 AMINE-CATALYZED AZA-MORITA-BAYLIS-HILLMAN REACTION ......................... 28
2.1.1 Pyridine-derived Lewis base catalysts ................................................. 28
2.1.2 Immobilized catalysts ........................................................................... 40
2.2 PHOSPHANE-CATALYZED (AZA) MORITA-BAYLIS-HILLMAN REACTION .............. 45
2.2.1 Phosphane catalysts and their MCAs .................................................. 45
2.2.2 PPh -catalyzed aza-Morita-Baylis-Hillman reaction ............................. 48
3
2.2.3 Bifunctional phosphane catalysts ......................................................... 60
2.2.3.1 Synthesis of bifunctional phosphane catalysts .............................. 60
2.2.3.2 Application in aza-Morita-Baylis-Hillman Reactions....................... 64
2.2.3.3 Application in Morita-Baylis-Hillman Reactions ............................. 71
2.2.4 Asymmetric phosphane catalysts ......................................................... 75
2.2.4.1 Design and synthesis of asymmetric phosphane catalysts ............ 75
2.2.4.2 Asymmetric phosphane catalyzed (a)MBH reaction ...................... 76
2.3 MECHANISTIC STUDIES OF THE MORITA-BAYLIS-HILLMAN REACTION .............. 77
2.3.1 Protonation/deprotonation equilibria in the catalytic cycle .................... 77
2.3.2 Kinetic studies of the protonation/deprotonation process ..................... 86
3 CONCLUSION AND OUTLOOK .................................................................... 93
4 EXPERIMENTAL PART ................................................................................. 96
4.1 AMINE-CATALYZED MORITA-BAYLIS-HILLMAN REACTION ............................... 97
4.1.1 Synthesis of tosylimines ....................................................................... 97
4.1.2 aMBH reaction of tosylimines and activated alkenes ........................... 98
4.2 PHOSPHANE-CATALYZED AZA-MORITA-BAYLIS-HILLMAN REACTIONS ............ 112
4.2.1 Phosphane catalysts .......................................................................... 112
4.2.2 PPh -catalyzed aza-Mortia-Baylis-Hillman reaction ........................... 114
3
4.2.3 Bifunctional phosphane catalysts ....................................................... 116
IX
OUTLINE

4.2.4 Asymmetric phosphane catalysts ....................................................... 125
4.3 MECHANISTIC STUDIES OF THE MORITA-BAYLIS-HILLMAN REACTION ............ 128
4.3.1 Protonation/deprotonation equilibria in the catalytic cycle .................. 128
4.3.2 Kinetic studies of the protonation/deprotonation process ................... 142
5 APPENDIX .................................................................................................. 144
6 LITERATURE ............................................................................................... 146
7 CURRICULUM VITAE .................................................................................. 146

X