Sulfoxide-controlled functionalization of arenes and heterocycles transition metal-catalyzed cross-coupling reactions of thioethers chlorine-zinc exchange reactions [Elektronische Ressource] / Laurin Melzig

Laurin Melzig

Informations

• Publié par: ludwig-maximilians-universitat_munchen
• Publié le: 01 janvier 2011
• Nombre de lectures: 20
• Langue: English
• Poids de l'ouvrage: 2 Mo

Extrait

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




Sulfoxide-Controlled Functionalization of Arenes and Heterocycles
Transition Metal-Catalyzed Cross-Coupling Reactions of Thioethers
Chlorine-Zinc Exchange Reactions







Laurin Melzig





aus

Starnberg






2011
Erklärung

Diese Dissertation wurde im Sinne von § 13 Abs. 3 bzw. 4 der Promotionsordnung vom 29.
Januar 1998 von Herrn Prof. Dr. Paul Knochel betreut.




Ehrenwörtliche Versicherung

Diese Dissertation wurde selbständig, ohne unerlaubte Hilfe bearbeitet.
München, am 21. Januar 2011









…..……………………………………
Laurin Melzig





Dissertation eingereicht am 25. Januar 2011

1. Gutachter: Prof. Dr. Paul Knochel
2. Gutachter: Prof. Dr. Manfred Heuschmann

Mündliche Prüfung am 3. März 2011
This work was carried out from March 2007 to December 2010 under the guidance of Prof.
Dr. Paul Knochel at the Department Chemie und Pharmazie of the Ludwig-Maximilians-
Universität, Munich.

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

I am also very grateful to Prof. Dr. Manfred Heuschmann for agreeing to be my
“Zweitgutachter” as well as Prof. Dr. Heinz Langhals, Prof. Dr. Klaus Wanner, Prof. Dr.
Konstantin Karaghiosoff and Prof. Dr. Rudolf Knorr for their interest shown in this
manuscript by accepting to be referees.

Furthermore, I would like to express my gratitude to Andreas Wagner, Sebastian Bernhardt,
and Dr. Coura Diène for the careful correction of this manuscript.

I thank all past and present co-workers I have met in the Knochel group for their kindness,
their help in every respect and the good times we had. Special thanks to my actual and former
lab mates Zhihua Peng, Zhi-Liang Shen, Dr. Anukul Jana, Dr. Georg Manolikakes, Dr.
Shigeyuki Yamada, Dr. Carmen Muñoz Hernández, Camille Gignoux, Kohsuke “Baba”
Kawabata and Prof. Kimihiro Komeyama and last but the most: Dr. “cumon” Andrei
Gavryushin.

I would like to bow to Dr. Christian Rauhut for the fruitful collaboration in the field of
sulfoxide chemistry and nerdism, Dr. Albrecht Metzger and Dr. Christina Despotopoulou for
their work on the thiomethyl cross-coupling reactions and the very bad or rather very good
influence on my manners (συγγνώη!), and Dr. Coura Diène for her great patience with the
hard road of our chlorine-zinc exchange and for making me blush.

I would also like to thank Vladimir Malakhov, Simon Matthe, Renate Schröder and Yulia
Tsvik for their help in organizing everyday life in the lab and in the office, as well as the
analytical team of the LMU for their invaluable help.

Sincere props to Niko Naredi-Rainer, Teresa Dennenwaldt, and Jérémy Stemper for easing up
the lab work in course of their internships in the Knochel group.

I would like to thank my family and my friends for their great support, throughout my studies
and my Ph.D.

Finally, I thank Marilena for her never-ending love and only rarely ending patience with me.
Parts of this Ph.D. thesis have been published
1) Christian B. Rauhut, Laurin Melzig and Paul Knochel, „Meta- and para-
Difunctionalization of Arenes via a Sulfoxide-Magnesium Exchange Reaction”, Org. Lett.
2008, 10, 3891.

2) Laurin Melzig, Christian B. Rauhut, and Paul Knochel, „Meta- and para-
Difunctionalization of Arenes via an ortho-Magnesiation and a Subsequent Sulfoxide-
Magnesium Exchange”, Synthesis 2009, 6, 1041.

3) Laurin Melzig, Christian B. Rauhut, and Paul Knochel, „2,3-Functionalization of Furans,
Benzofurans and Thiophenes via Magnesiation and Sulfoxide-Magnesium Exchange”, Chem.
Commun. 2009, 24, 3536, selected as „Hot Article”.

4) Albrecht Metzger, Laurin Melzig, Christina Despotopoulou and Paul Knochel, „Pd-
Catalyzed Cross-Coupling of Functionalized Organozinc Reagents with Thiomethyl-
Substituted Heterocycles”, Org. Lett. 2009, 11, 4228, selected for Synfacts 2009, 12, 1384,
selected in „Highlights from the literature”, Org. Process Res. Dev. 2010, 14, 2.

5) Laurin Melzig, Albrecht Metzger and Paul Knochel, „Ni-Catalyzed Cross-Coupling of
Functionalized Organozinc Reagents with Thiomethyl-Substituted Heterocycles”, J. Org.
Chem. 2010, 75, 2131.

6) Laurin Melzig, Jeremy Stemper and Paul Knochel, „A novel Palladium-Catalyzed Cross-
Coupling of Thiomethylated Alkynes with Functionalized Organozinc Reagents”, Synthesis
2010, 12, 2085.

7) Albrecht Metzger, Laurin Melzig and Paul Knochel, „Up-Scaled Transition Metal-
Catalyzed Cross-Couplings of Thioether-Substituted N-Heterocycles with Organozinc
Reagents”, Synthesis 2010, 16, 2853.

8) Laurin Melzig, Albrecht Metzger and Paul Knochel, „Pd- and Ni-catalyzed Cross-Coupling
Reactions of Functionalized Zinc Reagents with Thioethers”, Chem Eur. J. 2011, 17, 2948.

9) Laurin Melzig, Christian B. Rauhut, Niko Naredi-Rainer and Paul Knochel,
„Difunctionalization of Arenes and Heteroarenes via a Sulfoxide-Magnesium Exchange
Reaction”, Chem Eur. J., ASAP.

10) Laurin Melzig, Coura R. Diène, C. J. Rohbogner and Paul Knochel, „Preparation of
Polyfunctional Zinc Organometallics using a Fe- or Co-Catalyzed Cl/Zn-Exchange”, Angew.
Chem. Int. Ed., submitted.























To Marilena

















Don't walk behind me; I may not lead. Don't walk in front of me; I may not follow.
Just walk beside me and be my friend.

Albert Camus
Table of Contents

A. Introduction .................................................................................................................... 11
1. General Introduction ....................................................................................................................... 11
2. Halogen-Metal Exchange Reactions ......................................................................................... 14
3. Other Metal Exchange Reactions ....................................................................... 19
4. Metalation Reactions ..................................................................... .2.3. ......
5. Cross-Coupling Reactions of Organometallics with Unsaturated Thioethers ....................... 28
6. Objectives .................................................................................................................................... 31
B. Results and Discussion .................................................................................................. 34
1. Preparation of 1,2,4-Trisubstituted Arenes via DoM and Sulfoxide-Magnesium Exchange 34
1.1 Synthetic Strategy .................................................................................................................... 34
1.2 Preparation of Diaryl Sulfoxides ............................................................................................... 35
1.3 Ortho-Metalation of Diaryl Sulfoxides ..................................................................................... 36
2. Preparation of Functionalized 5-Membered Heterocycles via DoM and Sulfoxide-
Magnesium Exchange ........................................................................ .5.0. ...
2.1 Synthetic Strategy and Preparation of Hetaryl Sulfoxides ........................................................... 50
2.2 Ortho-Metalation and Sulfoxide-Magnesium Exchange on 5-Membered Hetaryl Sulfoxides .......... 52
2.3 Full Functionalization of Thiophene by Metalation Reaction ...................................................... 54
3. Preparation of Disubstituted Pyridines via DoM, Sulfoxide-Magnesium Exchange and
Ligand Coupling................................................................................ 56
3.1 Synthetic Strategy and Preparation of Pyridinyl Sulfoxides ........................................................... 56
3.2 Preparation of 3,4-Disubstituted and Tetrasubstituted Pyridines .................................................. 57
3.3 Ligand Coupling reactions of 2-Pyridinyl Sulfoxides .................................................................. 59
3.4 Preparation of a Cyclooxygenase-2 Inhibitor using the Ligand Coupling Reaction .......................... 60
4. Transition Metal-Catalyzed Cross-Coupling Reactions of Functionalized Organozinc
Reagents with Unsaturated Thioethers .................................................................. 61
4.1 Synthetic Goals and Synthesis of Unsaturated N-Heterocyclic and Alkynyl Thioethers .................. 61
4.2 Optimization of the Pd-Catalyzed Cross-Co