Br-Mg exchange on 1,2-dibromocyclopentene derivatives and regio- and chemoselective functionalizations of pyrazoles and related heterocycles [Elektronische Ressource] / von Christina Despotopoulou

Christina Despotopoulou

Informations

• Publié par: ludwig-maximilians-universitat_munchen
• Publié le: 01 janvier 2009
• Nombre de lectures: 35
• Langue: English

Extrait

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






Br/Mg-Exchange on
1,2-Dibromocyclopentene Derivatives and
Regio- and Chemoselective Functionalizations of
Pyrazoles and Related Heterocycles




von

Christina Despotopoulou



aus

Athen, Griechenland





München 2009

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 18.06.09







Christina Despotopoulou



Dissertation eingereicht am 18.06.2009

1. Gutachter: Prof. Dr. Paul Knochel

2. Gutachter: Prof. Dr. Manfred Heuschmann

Mündliche Prüfung am 15.07.2009
This work was carried out from May 2006 to June 2009 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 to do my Ph.D. in
his group, for his invaluable support and guidance throughout this time.

I am also very grateful to Prof. Dr. Manfred Heuschmann for agreeing to be my
“Zweitgutachter”, as well as Prof. Dr. Konstantin Karaghiosoff, Prof. Dr. Heinz Langhals,
Prof. Dr. Hans Rudolf Pfaendler and Prof. Dr. Rudolf Knorr for the interest they showed in
this manuscript by accepting to be referees.

For the careful correction of this manuscript I thank Dr. Andrei Gavryushin, Dr. Francois
Crestey, Andreas Wagner, Tobias Blümke and Marc Mosrin.

I would also like to thank Boehringer Ingelheim GmbH, and especially Dr. Ioannis
Sapountzis for the opportunity to spend three months in his R&D laboratory in Vienna as well
as for all his invaluable support and friendship throughout my studies. I am also very thankful
to Dr. Darryl McConnell, and Dr. Matthias Treu for the fruitful collaborations and stimulating
discussions.

Special thanks also to Dr. Rick Bauer and Camille Gignoux for the fruitful collaborations and
their friendship. Many thanks also to Albrecht Metzger and Laurin Melzig for the
collaboration in the field of cross-couplings.

Furthermore I thank all the past and present members I met in the Knochel group, for their
support and the great times we had, especially my labmates Marc Mosrin, Matthias Schade,
Christoph Rohbogner, Tomke Bresser, Benoit Blanc, Benjamin Haag, Dr. Darunee
Soorukram, Dr. Christiane Kofink, Dr. Nina Gommermann and Dr. Tobias Korn for the great
atmosphere! A big thank you also to all the people at Boehringer Ingelheim in Vienna for 3
fantastic months! Special thanks as well to Dr. Darunee Soorukram, Dr. Murthy Cheemala,
Dr. Ludwig Kaspar, Dr. Arkady Krasovskiy, Milica Jaric, Florian Achrainer, Nadine Götz and
Theresa Soltner for all their help and friendship and to Dr. Andrei Gavryushin for the
innumerable tipps and suggestions!

I would like to thank especially my lab neighbour Marc Mosrin for his constant support and
motivation, and for all the fun we had in the lab, in Sausalitos and of course in Tunesia!

I would also like to thank Vladimir Malakhov, Beatrix Cammelade, Simon Matthe, Yulia
Tsvik, Raimund Berchthold and Christine Schliski for their help in organizing everyday life in
the lab as well as the analytical team of the LMU, especially Dr. David Stephenson, Claudia
Dubler and Sonja Kosak for their invaluable help.

Furthermore I thank my students Lydia Klier and Katharina Böck for their contributions to
this thesis and Timotheus Hohl for his help in the lab.

Finaly very special thanks go to my whole family, my parents, my grandparents, my sister
Alexia and Klif for their constant love and support throughout my Ph.D.
Parts of this Ph. D. thesis have been published:

1) C. Despotopoulou, R. C. Bauer; A. Krasovskiy; P. Mayer; J. M. Stryker; P. Knochel
„ Selective Mono- and 1,2-Difunctionalisation of Cyclopentene Derivatives via Mg and Cu
Intermediates” Chem. Eur. J. 2008, 14, 2499-506.

2) C. Despotopoulou, C. Gignoux, D. McConnel, P. Knochel „ Metallation of 4,5-
Dihydrobenzo[g]indazoles”, Synthesis, 2009, manuscript in press.

3) C. Despotopoulou, L. Klier, P. Knochel, „ Total Functionalization of Pyrazole Derivatives
by Selective Magnesiations”, Org. Lett. 2009, manuscript in press.

4) A. Metzger, L. Melzig, C. Despotopoulou, P. Knochel „ Pd-catalyzed Cross-Coupling of
Functionalized Organozinc Reagents with Thiomethyl-Substituted Heterocycles”, manuscript
submitted.
















Στη ν οικογένεια µ ου



Table of Contents

Table of Contents

Abbreviations

A: General Introduction .......................................................................................................... 1
1. Overview........................................................................................................................... 2
2. The Halogen-Metal Interconversion ................................................................................. 3
3. Hydrogen-Metal ......................................................................................9
4. Objectives........................................................................................................................ 14
B: Results and Discussion...................................................................................................... 16
1. Functionalization of 1,2-Dibromocyclopentenyl Systems .............................................. 17
1.1 Introduction..........................................................................................................17
1.2 Selective mono-and 1,2-difunctionalization of cyclopentene derivatives ........... 18
1.2.1 Monofunctionalization using Br/Mg-exchange...........................................18
1.2.2 Difunctionalization via Cu-intermediates .................................................... 21
1.2.3 Mechanistic studies......................................................................................24
1.3 Difunctionalization of cyclohexene derivatives................................................... 28
2. Functionalization of 4,5-Dihydrobenzo[g]indazoles using Mg- and Zn- Heterocyclic
Intermediates...... 32
2.1 Introduction32
2.2 I/Mg-exchange on 4,5-Dihydro[g]indazoles........................................................ 33
2.3 Regioselective metallations on 4,5-dihydro[g]indazoles ..................................... 39
3. Synthesis of Fully Substituted Pyrazoles via Regio- and Chemoselective Metallations 44
3.1 Introduction..........................................................................................................44
3.2 Choosing the protecting group ............................................................................. 46
3.2.1 Starting material synthesis ........................................................................... 46
3.2.2 Metallations of the differently protected pyrazoles...................................... 47
3.3 Functionalization at the C5-position .................................................................... 49
3.3.1 Deprotonation at the C5- position ................................................................ 49
3.3.2 Direct cross coupling reaction of the S-Me moiety of the pyrazole............. 51
3.4 Selective C3- metallation of pyrazole derivatives................................................ 52
3.5 Selective C4-metallation ................................................. 54
3.6 Synthesis of the acaricide Tebufenpyrad via successive functionalizations of the
pyrazole core. ................................................................................................................... 57
4. Summary and Outlook .................................................................................................... 60
4.1 Functionalization of 1,2-dibromocyclopentenes.................................................. 60
4.2 Functionalization of 4,5-Dihydrobenzo[g]indazoles using Mg- and Zn-
Heterocyclic Intermediates............................................................................................... 62
4.3 Synthesis of fully substituted pyrazoles via regio- and chemoselective
metallations ...................................................................................................................... 64
C: Experimental Section........................................................................................................ 66
1. General Considerations...................................................................................................67
2. Typical Procedures (TP)...........................................................................................