Preparation of condensed N-heterocycles via chemoselective benzylic C-H activations and preparation of alkenylmagnesium reagents, allylic zinc reagents and their applications in organic synthesis [Elektronische Ressource] / von Hongjun Ren

Hongjun Ren

Sujets

• Gesundheit

Informations

• Publié par: ludwig-maximilians-universitat_munchen
• Publié le: 01 janvier 2006
• Nombre de lectures: 17
• Langue: English
• Poids de l'ouvrage: 1 Mo

Extrait

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






Preparation of Condensed N-Heterocycles via
Chemoselective Benzylic C-H Activations
and
Preparation of Alkenylmagnesium Reagents,
Allylic Zinc Reagents
and their Applications in Organic Synthesis





von

Hongjun Ren

aus

Jiangsu, China


München, 2006



Erklärung

Diese Dissertation wurde im Sinne von § 13 Abs.3 bzw. 4 der Promotionsordnung vom 01.
August 2003 von Professor Dr. P. Knochel betreut.



Ehrenwörtliche Versicherung

Diese Dissertation wurde selbständig und ohne unerlaubte Hilfe erarbeitet.


München, am 16.November, 2006





Hongjun Ren


Dissertation eingereicht am 16.November, 2006


1. Gutachter: Prof. Dr. Paul Knochel
2. Gutachter: Prof. Dr. Thomas Lindel


Mündliche Prüfung am 18.December.2006








This work was carried out under the guidance of Prof. Knochel at the Fakultät für Chemie und
Pharmazie der Ludwig-Maximilians-Universität, München from Aug. 2003 to Oct. 2006.


I would like to thank my supervisor, Prof. Dr. Paul Knochel, for giving me the opportunity of
doing my Ph.D. in his group, for his invaluable support and kindness through this time, and
for his guidance in the course of scientific research presented here.

I am also very grateful to Prof. Dr. Thomas Lindel for agreeing to be my “Zweitgutachter”, as
well as Prof. Dr. K. Karaghiosoff, Prof. Dr. M. Heuschmann, Prof. Dr. H. R. Pfaendler, and
Prof. Dr. H. Zipse for the interest shown in this manuscript by accepting to be referees.

I thank Miss Xixi Jia, Dr. Srinivas Reddy Dubbaka, Dr. Vicente del Amo, Guilaume Dunet
for the careful correction of this manuscript.

I would like to thank the Ludwig-Maximilians-Universität for financial support.

Special thanks to Prof. Dr. Liuzhu Gong, Dr. Pradipta Sinha, Guilaume Dunet, Zhuo Li,
Tobias Thaler, Maximilian Dochnahl for the happiest time we spent together in the lab.

I would like to thank all past and present co-workers I have met in the Knochel’s group for
their brief or lasting friendships. I especially thank Dr. Xiaoyin Yang, Wenwei Lin, Murthy
Narasimha Cheemala, Ching-Yuan Liu, Simon Matthe, Andrei Gavryshin, Ralf Klötzing and
Arkady Krasovskiy for their kindness and consideration in my study in Munich. I also thank
Dr. Lutz Ackermann, Sylvie Perrone, Oliver Baron, Nadège Boudet, Darunee Soorukram,
Armin Stoll, Christina Despotopoulou, Felix Kopp, Dr. Giuliano Clososki, Marc Mosrin and
Christian Rauhut for the nice time we had together.

I would also like to thank Vladimir Malakov, Beatrix Cammelade, Simon Matthe and Yulia
Tsvik for their help in organizing everyday life in the lab, as well as the analytical team, Dr.
D. Stephenson, Dr. C. Dubler, Dr. W. Spahl, B. Tschuk, I. Brück, H. Schulz and G. Käser for
their invaluable help. Especially, I thank Dr. Peter Mayer for measuring X-ray structures.

Finally I would like to thank my family and my teachers in China for their love and great
support, as well as all of my friends in China, USA and Germany for their friendship and
consideration through my Ph.D.--Thank you very much!







Parts of this Ph. D. thesis have been published:

1) Chemoselective Benzylic C-H Activations for the Preparation of Condensed N-
Heterocycles
Hongjun Ren, Paul Knochel* Angew. Chem., Int. Ed. 2006, 45, 3462;

2) Magnesiated Unsaturated Silylated Cyanohydrins as Synthetic Equivalents of Aromatic
and Heterocyclic Grignard Reagents Bearing a Ketone or an Aldehyde
Ching-Yuan Liu, Hongjun Ren, and Paul Knochel* Org. Lett. 2006, 8, 617;

3) Regioselective Functionalization of Trisubstituted Pyridines Using a Bromine-Magnesium
Exchange
Hongjun Ren, Paul Knochel* Chem. Comm. 2006, 726;

4) Stereoselective Preparation of Functionalized Acyclic Alkenylmagnesium Reagents Using
i-PrMgClLiCl
Hongjun Ren, Arkady Krasovskiy and Paul Knochel* Org. Lett. 2004, 6, 4215;

5) Preparation of Cyclic Alkenylmagnesium Reagents via an Iodine/Magnesium Exchange
Hongjun Ren, Arkady Krasovskiy and Paul Knochel* Chem. Comm. 2005, 543;

6) Highly Diastereoselective Synthesis of Homoallylic Alcohols Bearing Adjacent
Quaternary Centers Using Trisubstituted Allylic Zinc Reagents
Hongjun Ren and Paul Knochel*, manuscript in preparation;

7) Chemoselective Benzylic sp3 C-H Bond activation and Domino C-H Activation for
Preparation of Condensed N-Heterocycles
Hongjun Ren, Zhuo Li and Paul Knochel*, manuscript in preparation.

















To my parents, sister
and my girl friend
with love.



THEORETICAL PART……………………………………………………………………...1

1. Overview………………………………………………………………………………1
1.1 C-H bond activation………………………………………………………………….2
1.1.1 Intermolecular arylation reaction …………………………………………….2
1.1.2 Intramolecular C-C bond formation via C-H activation ………………………4
1.2 Preparation of organozinc and organomagnesium reagents…………………………7
2. Objectives…………………………………………………………………………….13
3. Preparation of Condensed N-Heterocycles by Chemoselective Benzylic C-H
Activations ………………………………………………………………………….15
33.1 Introduction: a catalytic approach for the functionalization of sp C-H bond ……15
3.2 Design of the starting materials for the preparation polycyclic heterocycles via C-H
activation ………………………………………………………………………….21
3.3 Optimization of the reaction conditions ……………………………………………23
3.4 Preparation of the bromo or iodo-N-arylpyrrole derivatives ………………………24
3.5 Scope of the C-H activation reaction and preparation of functionalized 9H-
pyrrolo[1,2-a]indoles………………………………………………………………30
3.6 Mechanistic investigations…………………………………………………………38
3.7 Extending the C-H activation reaction ……………………………………………42
3.8 Tandem reactions involving a Suzuki cross-coupling and a C-H activation
………………………………………………………………………………………44
3.9 Conclusion …………………………………………………………………………46
4. Preparation of Functionalized Alkenylmagnesium Reagents and Polysubstituted
Pyridylmagnesium Reagents Using i-PrMgCl•LiCl………………………………47
4.1 Introduction…………………………………………………………………………47
4.2 Extension of the usage of i-PrMgClLiCl in the preparation of alkenylmagnesium
reagents and synthetic applications…………………………………………………50
4.3 Regioselective functionalization of dibromo and tribromo pyridines via a Br/Mg
exchange……………………………………………………………………………61
4.4 Conclusion …………………………………………………………………………67
5. Preparation of Allylic Zinc Reagents and their Applications ……………………….68
5.1 Introduction…………………………………………………………………………68
5.2 Preparation of acyclic and cyclic zinc reagents ……………………………………68
5.3 Applications of 2-cyclohexenylzinc chloride………………………………………70



5.4 Preparation of the starting materials of allylic chloride ……………………………71
5.5 Preparation of allylic zinc reagents using zinc·LiCl insertion ……………………72
5.6 Highly diastereoselective synthesis of homoallylic alcohols bearing adjacent
quaternary centers using trisubstituted allylic zinc reagents ………………………73
5.7 Conclusion …………………………………………………………………………81
6. Summary and outlook ……………………………………………………………..82
6.1 Chemoselective Benzylic C-H Activations for the Preparation of Condensed N-
Heterocycles ………………………………………………………………………82
6.2 Preparation of Functionalized Alkenylmagnesium Reagents and Polysubstituted
Pyridylmagnesium Reagents Using i-PrMgClLiCl ………………………………83
6.3 Preparation of Polysubstituted Allylic Zinc Reagents and their Applications ……84
EXPERIMENTAL PART………………………………..…………………………………85
7. General Conditions………………………………………………………………….85
8. Typical Procedure………………………………………………………………..….88
8.1 Typical procedure for preparation of bromo or iodo-N-arylpyrrole derivatives……88
8.2 Typical procedure for preparation of polycyclic heterocycles via C-H activation
reaction…………………………………………………………………………………88
8.3 Typical procedure for preparation of functionalized acyclic alkenyl compounds…89
8.4 Typical procedure for preparation of functionalized cyclic alkenyl compounds …89
8.5 Typical procedure for the performance of punctionalized pyridines ………………90
8.6 Typical procedure for the preparation of homoallylic alcohols ……………………90
3
9. Preparation of Condensed N-Heterocycles by sp C-H Bond Activation Reactions
……………...…………………………………………………………………………92
10. Preparation of Functionalized Alkenyl Organomagnesium Reagents and
Polysubstituted Pyridylmagnesium Reagents Using i-PrMgCl·LiCl
………………………………………………………………………………………150
11. Highly Diastereoselective Synthesis of Homoallylic Alcohols Bearing Adjacent
Quaternary Centers Using Trisubstituted Allylic Zinc Reagents
……………