Preparation and Reactions of Polymagnesiated Aromatics and Heteroaromatics, Functionalized

191 Pages·2007·1.61 MB·English

by  Felix Kopp

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

Preparation and Reactions of Polymagnesiated Aromatics
and Heteroaromatics, Functionalized Cyclopropane
Carbenoids and Soluble Lanthanide Reagents

von

Felix Kopp

aus

Augsburg

München 2007
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, und ohne unerlaubte Hilfe erarbeitet.

München, am _____________

_____________________
Felix Kopp

Dissertation eingereicht am 12. 01. 2007

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

Mündliche Prüfung am 07. 02. 2007
This work was carried out from March 2003 to December 2006 under the guidance of Prof.
Paul Knochel at the Department Chemie und Pharmazie of the 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 invaluable support and help throughout this time.

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

I thank Christoph Rohbogner and Dr. Darunee Soorukram for the careful correction of this
manuscript.

I would like to thank the G.I.F. (German Israeli Foundation for Research and Development)
for the financial support (grant I-693-7.5/01) and I am also very thankful to Prof. Ilan Marek
and Genia Sklute for the fruitful collaboration in the field of carbenoid chemistry.
Further thanks go to the co-workers of Chemetall’s lithium division for the very stimulating
collaboration on the lanthanide project.

I thank all past and present co-workers I have met in the Knochel group throughout the years
for their support and for creating a wonderful, highly international working atmosphere which
I really enjoyed. Particularly, I want to mention Dr. Ralf Klötzing, Murthy Narasimha
Cheemala, Dr. Shohei Sase and Albrecht Metzger for being fantastic labmates.
I also want to thank Dr. Nina Gommermann and Dr. Tobias Korn for the great days in Canada
at the OMCOS. Thanks as well to Fabian Piller for numerous culinary and musical highlights,
rock on! Very special thanks to my dear friends Dr. Arkady Krasovskiy and Valeria
Krasovskaya, for the good times inside as well as outside the lab, the wonderful trip to Russia,
for their lasting friendship and support.

I would like to thank Christian Cervino and Stefan Wunderlich for their contributions to this
work in course of their “F-Praktika” and undergraduate research assistant time.

I would also like to thank Vladimir Malakhov, Beatrix Cammelade, Simon Matthe, and Yulia
Tsvik for their help in organizing everyday life in the lab, as well as the routine analytics team
of the department, especially Dr. D. Stephenson for his patient help with the 2D NMR
spectroscopy and Dr. Kurt Polborn for the X-ray analysis.

Very special thanks to my friends and family, especially Matthias, Sebastian and my parents
for their loving and patient support throughout the time of my PhD.
Parts of this Ph.D. thesis have been published:

Communications:

1 F. Kopp, A. Krasovskiy, P. Knochel: “Convenient magnesiation of aromatic and
heterocyclic rings bearing a hydroxy group in presence of LiCl” Chem. Commun.
2004, 20, 2288.

2 F. Kopp, G. Sklute, K. Polborn, I. Marek, P. Knochel: “Stereoselective
Functionalization of Cyclopropane Derivatives Using Bromine/Magnesium and
Sulfoxide/Magnesium Exchange Reactions” Org. Lett. 2005, 7, 3789.

3 A. Krasovskiy, F. Kopp, P. Knochel: “New Soluble Lanthanide Salts for the improved
Addition of Magnesium Organometallics to Carbonyl Derivatives” Angew. Chem.
2006, 118, 511; Angew. Chem. Int. Ed. 2006, 45, 497.

4 F. Kopp, S. Wunderlich, P. Knochel: “Halogen-Magnesium Exchange on Unprotected
Aromatic and Heteroaromatic Carboxylic Acids”, Chem. Commun. 2007, 23, in press.

5 F. Kopp, P. Knochel: “Functionalization of Unprotected Uracil Derivatives Using a
Halogen-Magnesium Exchange”, manuscript submitted for publication.

6 F. Kopp, P. Knochel: “Iodine-Magnesium Exchange on Unprotected Imidazoles in the
Presence of LiCl”, Synlett 2007, in press.

Reviews and Book Chapters:

1 P. Knochel, W. Dohle, N. Gommermann, F. F. Kneisel, F. Kopp, T. Korn, I.
Sapountzis, V. A. Vu: “Highly functionalized organomagnesium reagents prepared
through halogen-metal exchange” Angew. Chem. 2003, 115, 4438; Angew. Chem. Int.
Ed. 2003, 42, 4302.

2 P. Knochel, F. Kopp: Introduction in “Handbook of Functionalized Organometallics”;
P. Knochel, Ed.; Wiley-VCH, Weinheim 2005, 1.
“...manchmal bestätigt uns das, was wir
versuchen nicht weniger als das, was wir
erreichen.”

Siegfried Lenz
in „Die Auflehnung“

Table of Contents

Table of Contents.....................................................................................................................1

A General Introduction...........................................................................................................5

1. Overview............................................................................................................................7

2. Preparation and Use of Organomagnesium Compounds...................................................8
2.1. Conventional Preparation Methods.............................................................................8
2.2. The Halogen/Magnesium Exchange Reaction..........................................................10

3. Objectives.........................................................................................................................18

B. Results and Discussion......................................................................................................21

1. Halogen/Magnesium Exchange Reactions in the Presence of Unprotected Acidic Groups
..............................................................................................................................................23

1.1. Introduction...............................................................................................................23
1.2. Iodine/Magnesium Exchange Reactions on Unprotected Aromatic and
Heteroaromatic Alcohols..................................................................................................25
1.2.1. Starting Material Synthesis................................................................................25
1.2.2. Preliminary Studies and Optimization of the Reaction Conditions...................26
1.2.3. Exchange on Aromatic Substrates......................................................................28
1.2.4. Exchange on Heteroaromatic Substrates............................................................31
1.3. Halogen/Magnesium Exchange Reactions on Unprotected Aromatic and
Heteroaromatic Carboxylic Acids....................................................................................35
1.3.1. Starting Material Synthesis................................................................................35
1.3.2. Exchange on Aromatic Substrates......................................................................37
1.3.2. Exchange on Heteroaromatic Substrates............................................................42
1.4. Iodine/Magnesium-Exchange Reactions on Unprotected Imidazole Derivatives.....45
1.5. Halogen/Magnesium-Exchange Reactions on Unprotected Uracil Derivatives.......48
1.5.1. Exchange on 5- and 6-Iodouracil.......................................................................48
1.5.2. Synthesis of Precursors for HEPT (69) and Emivirine (70)...............................52

2. Diastereoselective Synthesis of Cyclopropane Carbenoids Bearing a Nitrile Function..55

2.1. Introduction...............................................................................................................55
2.2. Starting Material Synthesis and Preliminary Experiments.......................................56
2.3. Functionalization of 2,2-Dibromo-1-methyl-cyclopropane-carbonitrile (76) via
Halogen/Magnesium and Sulfoxide/Magnesium Exchange Reactions...........................58

3. Preparation of Soluble Lanthanide Salts and Their Applications in Organomagnesium
Chemistry.............................................................................................................................64

3.1. Introduction...............................................................................................................64
3.2. Preparation of Soluble Lanthanide Salts of the Type LnCl ·2LiCl...........................66
3
1
3.3. Addition Reactions to Carbonyl Functions...............................................................69
3.4. Solutions of the Second Generation..........................................................................75

4. Summary and Outlook.....................................................................................................79

4.1. Halogen/Magnesium Exchange Reactions in the Presence of Unprotected Acidic
Groups..............................................................................................................................79
4.2. Diastereoselective Synthesis of Cyclopropane Carbenoids Bearing a Nitrile Function
..........................................................................................................................................81
4.3. Preparation of Soluble Lanthanide Salts and Their Applications in
Organomagnesium Chemistry..........................................................................................82

C. Experimental Section........................................................................................................83

1. General Considerations....................................................................................................85

2. Typical Procedures (TP)..................................................................................................91

2.1. Typical procedure for the preparation of the functionalized iodophenols (TP01)...91
2.2. Typical procedure for the I/Mg-exchange on unprotected phenols and the reaction
with electrophiles (TP02).................................................................................................91
2.3. Typical procedure for the I/Mg-exchange on unprotected 2-iodo-pyridin-3-ol (33a)
and the reaction with electrophiles (TP03)......................................................................91
2.4. Typical procedure for the I/Mg-exchange on unprotected 5,7-diiodo-quinolin-8-ol
(36) and the reaction with electrophiles (TP04)..............................................................92
2.5. Typical procedure for the double metallation of ortho-, metha-, and para-
iodobenzoic acid (40d-40f) (TP05).................................................................................92
2.6. Typical procedure for the double metallation of functionalized iodobenzoic acids
(40g; 40h-40j) (TP06).....................................................................................................92
2.7. Typical procedure for the double metallation of 3,5-diiodobenzoic acid (40a) (TP07)
..........................................................................................................................................93
2.8. Typical procedure for the double metallation of 5-bromo-2-furoic acid (48a) and 5-
bromothiophene-2-carboxylic acid (48b) (TP08)............................................................93
2.9. Typical procedure for the bromine/magnesium-exchange on 4,5-dibromo-2-
thiophenecarboxylic acid (48c) (TP09)...........................................................................93
2.10. Typical procedure for the double metallation of iodoimidazoles of type 52 (TP10)
..........................................................................................................................................94
2.11. Typical procedure for the exchange on 4-iodo-5-(phenylthio)-1H-imidazole (54g)
(TP11)..............................................................................................................................94
2.12. Typical procedure for the triple metallation of 5-iodouracil (57a) (TP12)............94
2.13. Typical procedure for the triple metallation of 5-bromouracil (57b) (TP13).........95
2.14. Typical procedure for the triple metallation of 6-iodouracil (57c) (TP14).............95
2.15. Typical procedure for the synthesis of the Grignard reagents of type 66 (TP15)..95
2.16. Typical procedure for the synthesis of functionalized cyclopropane carbonitriles of
type 81 (TP16).................................................................................................................96
2.17. Typical procedure for the exchange on 2-bromo-1-methyl-2-
(phenylsulfanyl)cyclopropane-carbonitrile (81e) (TP17)................................................96
2.18. Typical procedure for the reactions of Grignard reagents with ketones (TP18)....96
2.19. Typical procedure for the catalytical Michael additions of benzyl amine (106) to
ethyl (2Z)-but-2-enoate (107) (TP 19).............................................................................97
2