Polyfunctionalizations of N-heterocycles via chemo- and regioselective metalations [Elektronische Ressource] / von Nadège Boudet

Nadège Boudet

Informations

• Publié par: ludwig-maximilians-universitat_munchen
• Publié le: 01 janvier 2007
• 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






Polyfunctionalizations of N-Heterocycles via Chemo- and
Regioselective Metalations




von

Nadège Boudet



aus

Toulouse, Frankreich





München 2007


Erklärung

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




Ehrenwörtliche Versicherung

Diese Dissertation wurde selbständig, und ohne unerlaubte Hilfe erarbeitet.


München, am 29.11.07







Nadège Boudet



Dissertation eingereicht am 29.11.2007

1. Gutachter: Prof. Dr. Paul Knochel

2. Gutachter: Prof. Dr. Thomas Carell

Mündliche Prüfung am 10.01.2008
This work was carried out from December 2004 to September 2006 under the guidance of
Prof. Knochel at the Fakultät für Chemie und Pharmazie der Ludwig-Maximilians-
Universität, Munich.

I would like to thank Prof. Dr. Paul Knochel, for giving me the opportunity of doing my Ph.D.
in his group, for his support and for his guidance in the course of my scientific research.

I am also very grateful to Prof. Dr. Thomas Carell 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. Langhals for the interest shown in this manuscript by accepting to be referees.

I would like to thank Sanofi-Aventis for financial support.

I thank Guillaume Dunet and Dr. Andrei Gavryushin for the careful correction of this
manuscript.
I thank all past and present co-workers I have met in the Knochel’s group for their kindness
and their help. Special thanks to all my labmates (lab 2.012) for the happiest time we spent
together and the nice international atmosphere!
I would like to thank Dr. Shohei Sase, Vladimir Malakhov and Dr. Srinivas R. Dubbaka for
fruitful collaborations in the fields of zinc chemistry and amination chemistry. A special thank
to Jennifer R. Lachs for her contribution to this work.
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 of the
LMU for their invaluable help.

Special thank to Christiane Kofink for her friendship, her great support and all nice moments
shared together out the lab, in conferences or in many others events.

Very special thank to my family and to Armin for their love and endless support as well as my
friends for their visits throughout this time.

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

1) Nadège Boudet, Srinivas Reddy Dubbaka and Paul Knochel. “Amination of DNA and
RNA units via Cuprated Pyrimidine and Purine Intermediates”. Org. Lett. 2007, submitted.

2) Nadège Boudet, Jennifer R. Lachs and Paul Knochel. “Multiple Regioselective
Functionalization of Quinolines via Magnesiations”. Org. Lett. 2007, 9, 5525-5528.

3) Nadège Boudet, Shohei Sase, Pradipta Sinha, Ching-Yuan Liu, Arkady Krasovskiy, and
Paul Knochel. “Directed Ortho Insertion (DoI): a New Approach to Functionalized Aryl and
Heteroaryl Zinc Reagents”. J. Am. Chem. Soc. 2007, 129, 12358-12359.

4) Darunee Soorukram, Nadège Boudet, Vladimir Malakhov and Paul Knochel.
“Preparation of Polyfunctionalized 2,6-Dimethoxypyrimidine Derivatives via Chemo- and
Regioselective Direct Zinc Insertion”. Synthesis 2007, 24, 3915-3922.

5) Nadège Boudet and Paul Knochel. “Chemo- and Regio-selective Functionalization of
Uracil Derivatives. Application to the Synthesis of Oxipurinol and Emivirine”. Org. Lett.
2006, 8, 3737-3740.













A mes parents



Table of Contents

Table of Contents

Abbreviations

A. General Introduction .......................................................................................................... 1
1. Overview .......................................................................................................................... 2
2. Direct Preparation and Use of Organomagnesiated Aryl and Heteroaryl
Compounds ...................................................................................................................... 4
2.1. Introduction ....................................................................................................................... 4
2.2. Direct oxidative addition of magnesium to organic halides.............................................. 5
2.3. The halogen/magnesium exchange reaction ..................................................................... 6
2.4. Metalation reactions with magnesium amide bases ........................................................ 12
2.5. Recent applications of Grignard reagent for a C-N bond formation............................... 15
3. Direct Preparation and Use of Zincated Aryl and Heteroaryl Compounds............ 19
3.1 Introduction ..................................................................................................................... 19
3.2 The direct insertion of zinc metal into aryl and heteroaryl halides................................. 20
3.3 The iodine/zinc exchange reaction.................................................................................. 23
4. Objectives....................................................................................................................... 25


B. Results and Discussion...................................................................................................... 27
1. Functionalizations of Quinoline Moieties via Chemo- and Regioselective
Magnesiations ................................................................................................................ 28
1.1. Introduction ..................................................................................................................... 28
1.2. Functionalization of quinolines using selective Br/Mg exchange reactions................... 29
1.2.1 Functionalization of quinolines using halogen/metal exchanges........................ 29
1.2.2 Regioselective Br/Mg exchange on di- and tribrominated quinolines................ 30
1.2.3 Successive regioselective Br/Mg exchanges on 2,3,4-tribromoquinoline (37d) 36
1.3 Functionalization of quinolines using a combination of selective magnesiations .......... 37
1.3.1. Metalations of quinolines using lithium amide bases ......................................... 37
1.3.2. Magnesiations of quinolines using deprotonations and Br/Mg exchanges......... 38
1.3.3. An application to the synthesis of the NK3 receptor antagonist talnetant .......... 40
2. Functionalizations of Protected Uracils via Chemo- and Regioselective
Magnesiations ................................................................................................................ 42
2.1. Introduction ..................................................................................................................... 42
2.2. Chemo and regioselective Br/Mg exchanges on protected uracils ................................. 43
2.2.1. Functionalization of protected uracils using halogen/metal exchange................ 43
2.2.2. Chemoselective Br/Mg exchange on 5-bromo-4-chloro-2,6-dimethoxy-
pyrimidine (69a) .................................................................................................. 45
2.2.3. Application to the synthesis of annelated heterocycles and the xanthine oxidase
inhibitor oxypurinol............................................................................................. 47
2.2.4. Regioselective Br/Mg exchange on 4,5-dibromo-2,6-dimethoxypyrimidine (69b)
......................................................................................................................................... 49
2.2.5. Successive Br/Mg exchanges on 4,5-dibromo-2,6-dimethoxypyrimidine (69b)
and his application the synthesis of the anti-HIV drug emivirine. ...................... 52
2.3. Direct magnesiation of protected uracils......................................................................... 52
2.3.1. Deprotonation of 2,4-dimethoxypyrimidine (83a) using lithium amide bases ... 52
2.3.2. Deprotonation of 2,4-dimethoxypyrimidine (83a) using TMPMgCl·LiCl (18a) 52
2.3.3. Deprotonation of 6-functionalized 2,4-dimethoxypyrimidine using
TMPMgCl·LiCl (18a).......................................................................................... 55
3. Amination of DNA and RNA Units via Cuprated Pyrimidine and Purine
Intermediates ................................................................................................................. 57
3.1. Introduction ..................................................................................................................... 57
3.2. Selective