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Preparation and applications of benzylic zinc chlorides [Elektronische Ressource] : lewis-acid promoted additions of organomagnesium and organozinc reagents to carbonyl derivatives ; transition metal-catalyzed cross-coupling reactions with methylthio-substituted N-heterocycles / von Albrecht Metzger

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Dissertation zur Erlangung des Doktorgrades der Fakultät für Chemie und Pharmazie der Ludwig-Maximilians-Universität München Preparation and Applications of Benzylic Zinc Chlorides. Lewis-Acid Promoted Additions of Organomagnesium and Organozinc Reagents to Carbonyl Derivatives. Transition Metal-Catalyzed Cross-Coupling Reactions With Methylthio-Substituted N-Heterocycles. von Albrecht Metzger aus Halle (Saale) München 2010 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 bearbeitet. München, am 12. April 2010 …..…………………………………… Albrecht Metzger Dissertation eingereicht am 13. April 2010 1. Gutachter: Prof. Dr. Paul Knochel 2. Gutachter: Prof. Dr. Thomas Carell Mündliche Prüfung am 18. Mai 2010 This work was carried out from June 2006 to Februar 2010 under the guidance of Prof. Dr. Paul Knochel at the Department Chemie und Pharmazie of the Ludwig-Maximilians-Universität, Munich. Firstly, 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.

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Published 01 January 2010
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Dissertation zur Erlangung des Doktorgrades
der Fakultät für Chemie und Pharmazie
der Ludwig-Maximilians-Universität München






Preparation and Applications of Benzylic Zinc Chlorides.
Lewis-Acid Promoted Additions of Organomagnesium and
Organozinc Reagents to Carbonyl Derivatives.
Transition Metal-Catalyzed Cross-Coupling Reactions With
Methylthio-Substituted N-Heterocycles.




von

Albrecht Metzger


aus Halle (Saale)





München 2010

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 bearbeitet.


München, am 12. April 2010




…..……………………………………
Albrecht Metzger



Dissertation eingereicht am 13. April 2010

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

Mündliche Prüfung am 18. Mai 2010


This work was carried out from June 2006 to Februar 2010 under the guidance of Prof. Dr. Paul
Knochel at the Department Chemie und Pharmazie of the Ludwig-Maximilians-Universität,
Munich.



Firstly, 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. Thomas Carell for agreeing to be my “Zweitgutachter” as well
as Prof. Dr. Heinz Langhals, Prof. Dr. Konstantin Karaghiosoff, Prof. Dr. Klaus T. Wanner and
Prof. Dr. Hans Rudolf Pfaendler for their interest shown in this manuscript by accepting to be
referees.

I really would like to thank Andreas Wagner, Dr. Andrei Gavryushin, Sebastian Bernhardt,
Matthias Schade and Silvia Zimdars 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 and
their help. Special thanks to my actual and former lab mates Milica Jaric, Tobias Blümke, Dr.
Murthy N. Cheemala, Dr. Shohei Sase, Dr. Felix Kopp and especially Dr. Yi-Hung Chen.

I would like to thank Matthias Schade, Dr. Georg Manolikakes, Fabian Piller and Andreas
Wagner for the fruitful collaboration in the field of the benzylic zinc chemistry, Sebastian
Bernhardt and Dr. Andrei Gavryushin for their great support in the area of the addition of
organometallics to carbonyl derivatives. I would also like to thank Cora Dunst for her help on the
carbometalation reactions as well as Laurin Melzig and Dr. Christina Despotopoulou for their
contribution during the thioether cross-coupling projects.

I would also like to thank Vladimir Malakhov, Simon Matthe, Beatrix Cammelade, 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.

I thank Christian Argyo, Annette Frischmuth, Teresa Dennenwaldt and Nadja Barl for their
contributions to this work in course of their internship in the Knochel group.

I’d like to thank all members of our incredible band for the fun we had together. Rock on!

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

Finally, I thank my wife Teresa for her love and patience.


Parts of this Ph.D. thesis have been published

1) Albrecht Metzger, Matthias A. Schade, Paul Knochel, “LiCl-Mediated Preparation of
Highly Functionalized Benzylic Zinc Chlorides”, Org. Lett. 2008, 10, 1107-1110.
2) Matthias A. Schade, Albrecht Metzger, Stefan Hug, Paul Knochel, “Nickel-Catalyzed
Cross-Coupling Reactions of Benzylic Zinc Reagents With Aromatic Bromides, Chlorides
and Tosylates”, Chem. Commun. 2008, 3046-3048.
3) Albrecht Metzger, Matthias A. Schade, Georg Manolikakes, Paul Knochel, “A General
Preparation of Polyfunctional Benzylic Zinc Organometallic Compounds”, Chem. Asian
J. 2008, 3, 1678-1691. (special issue in honor of Professor Ryoji Noyori (Nobel prize
th
2001) on the occasion of his 70 birthday)
4) Shohei Sase, Milica Jaric, Albrecht Metzger, Vladimir Malakhov, Paul Knochel, “One-
Pot Negishi Cross-Coupling Reactions of In Situ Generated Zinc Reagents With Aryl
Chlorides, Bromides and Triflates”, J. Org. Chem. 2008, 73, 7380-7382.
5) Georg Manolikakes, Carmen Munoz Hernandez, Matthias A. Schade, Albrecht Metzger,
Paul Knochel, “Palladium- and Nickel-Catalyzed Cross-Couplings of Unsaturated Halides
Bearing Relatively Acidic Protons With Organozinc Reagents”, J. Org. Chem. 2008, 73,
8422-8436.
6) Albrecht Metzger, Fabian M. Piller, Paul Knochel, “Polyfunctional Benzylic Zinc
Chlorides by the Direct Insertion of Magnesium Into Benzylic Chlorides in the Presence
of LiCl and ZnCl ”, Chem. Commun. 2008, 5824-5826. 2
7) Paul Knochel, Prasad Appukkuttan, Andrei Gavryushin, Georg Manolikakes, Albrecht
Metzger, Marc Mosrin, Fabian M. Piller, Christoph J. Rohbogner, Matthias A. Schade,
Stefan H. Wunderlich, “Functionalization of Heterocyclic Compounds Using
Polyfunctional Magnesium and Zinc Reagents”, Pfizer In-House Journal Synthon, 2008.
8) Albrecht Metzger, Andrei Gavryushin, Paul Knochel, “LaCl ·2LiCl-Catalyzed Addition 3
of Grignard Reagents to Ketones”, Synlett 2009, 1433-1436.
9) Fabian M. Piller, Albrecht Metzger, Matthias A. Schade, Benjamin A. Haag, Andrei
Gavryushin, Paul Knochel, “Preparation of Polyfunctional Arylmagnesium, Arylzinc and
Benzylic Zinc Reagents by Using Magnesium in the Presence of LiCl”, Chem. Eur. J.
2009, 15, 7192-7202.

10) Albrecht Metzger, Laurin Melzig, Christina Despotopoulou, Paul Knochel, “Pd-Catalyzed
Cross-Coupling of Functionalized Organozinc Reagents With Thiomethyl-Substituted
Heterocycles”, Org. Lett. 2009, 11, 4228-4231.
(Highlighted in: Org. Res. Proc. Dev. 2010, 14, 2 and Synfacts 2009, 1384)
11) Albrecht Metzger, Christian Argyo, Paul Knochel, “Large-Scale Preparation of
Polyfunctional Benzylic Zinc Reagents by Direct Insertion of Zinc Dust Into Benzylic
Chlorides in the Presences of Lithium Chloride”, Synthesis 2010, 882-891.
12) Laurin Melzig, Albrecht Metzger, Paul Knochel, “Room Temperature Cross-Coupling of
Highly Functionalized Organozinc Reagents With Thiomethylated N-Heterocycles by
Nickel Catalysis”, J. Org. Chem. 2010, 75, 2131-2133.
13) Albrecht Metzger, Sebastian Bernhardt, Georg Manolikakes, Paul Knochel, “MgCl -2
Accelerated Addition of Functionalized Organozincs Reagents to Aldehydes, Ketones and
Carbon Dioxide” Angew. Chem. Int. Ed. 2010, in press.
14) Albrecht Metzger, Laurin Melzig, Paul Knochel, “Up-Scaled Transition Metal-Catalyzed
Cross-Coupling Reactions of Thioether-Substituted N-Heterocycles With Organozinc
Reagents”, Synthesis 2010, accepted.
15) Sebastian Bernhardt, Albrecht Metzger, Paul Knochel, “Direct Addition of Functionalized
Organozinc Reagents to Carbon Dioxide, Ketones and Aldehydes in the Presence of
MgCl ”, manuscript in preparation. 2
16) Andreas J. Wagner, Albrecht Metzger, Paul Knochel, "Preparation and Applications of
Heterobenzylic Zinc Reagents”, manuscript in preparation.
17) Cora Dunst, Albrecht Metzger, Elena Zaburdaeva, Paul Knochel, "An Easy Access to
Tetrasubstituted Olefins by Cu(I)-Mediated Carbometalation Reactions Using Highly
Functionalized Arylzinc Reagents”, manuscript in preparation.




















































To Teresa, my love!



Table of Contents
Abbreviations
A. INTRODUCTION ..................................................................................................................... 1
1. Overview ........................................................................................................................................................... 2
2. Preparation of Functionalized Organozinc Reagents ...................................................................................... 3
2.1. Introduction ................................................................................................................................................... 3
2.2. Direct zinc insertion into organic halides using zinc metal ........................................................................... 5
2.3. The iodine-zinc exchange reaction ................................................................................................................ 7
2.4. Preparation of highly functionalized arylzinc reagents by directed metalations ........................................... 8
3. Lewis-Acid Promoted Additions of Functionalized Organomagnesium and Organozinc Reagents to
Carbonyl Derivatives ........................................................................................................................................ 11
4. Transition Metal-Catalyzed Cross-Coupling Reactions of Functionalized Organometallics With
Unsaturated Thioethers ................................................................................................................................... 15
5. Objectives ......................................................................................................................................................... 19
B. RESULTS AND DISCUSSION............................................................................................... 23
1. Preparation and Applications of Benzylic Zinc Chlorides ............................................................................ 24
1.1. Preparation of functionalized benzylic zinc chlorides by LiCl-mediated zinc insertion into benzylic
chlorides ...................................................................................................................................................... 24
1.1.1. Introduction ........................................................................................................................................... 24
1.1.2. Direct zinc insertion into benzylic chlorides in the presence of LiCl .................................................... 27
1.1.3. Reaction of functionalized benzylic zinc chlorides with various electrophiles ..................................... 33
1.1.4. Synthesis of papaverine ......................................................................................................................... 42
1.2. Efficient Nickel-catalyzed cross-coupling reactions of benzylic zinc chloride with aromatic halides ........ 44
1.2.1. Introduction ........................................................................................................................................... 44
1.2.2. Ni-catalyzed cross-coupling reactions with benzylic zinc chlorides using Ni(acac) /PPh ................... 46 2 3
1.3. Pd-catalyzed cross-couplings of benzylic zinc chlorides with unsaturated bromides bearing relatively
acidic protons .............................................................................................................................................. 47
1.4. Palladium-catalyzed one-pot reaction of in situ generated benzylic zinc chlorides with aromatic
bromides ...................................................................................................................................................... 50

1.4.1. Introduction ........................................................................................................................................... 50
1.4.2. PEPPSI-IPr catalyzed cross-coupling reactions of benzylic zinc chlorides with aryl bromides in
the presence of zinc dust ........................................................................................................................ 51
1.5. Preparation of diheterobenzylic zinc reagents and heterobenzylic zinc chlorides ...................................... 54
1.5.1. Introduction ........................................................................................................................................... 54
1.5.2. Preparation of heterobenzylic zinc reagents and further reactions ........................................................ 55
1.6. Preparation of benzylic zinc chlorides by the direct insertion of magnesium into benzylic chlorides
in the presence of ZnCl and LiCl ............................................................................................................... 59 2
1.6.1. Introduction ........................................................................................................................................... 59
1.6.2. Preparation of benzylic zinc chlorides by the Mg/ZnCl /LiCl method .................................................. 60 2
2. Lewis-Acid Promoted Additions of Functionalized Organomagnesium and Organozinc Reagents
to Carbonyl Derivatives ................................................................................................................................... 67
2.1. Addition of Grignard reagents to ketones in the presence of catalytic amounts of LaCl ·2LiCl ................ 67 3
2.1.1. Introduction ........................................................................................................................................... 67
2.1.2. LaCl ·2LiCl-catalyzed addition of organomagnesium reagents to enolizable ketones.......................... 67 3
2.2. Addition of functionalized organozinc reagents to aldehydes, ketones and carbon dioxide under
mediation of MgCl ..................................................................................................................................... 71 2
2.2.1. Introduction ........................................................................................................................................... 71
2.2.2. Addition of functionalized organozinc reagents to carbonyl derivatives ............................................... 72
3. Carbocupration of Alkynes With Functionalized Diorganozinc Reagents .................................................. 83
3.1. Introduction ................................................................................................................................................. 83
3.2. Carbocupration reaction on thioether-substituted alkynes .......................................................................... 84
4. Transition Metal-Catalyzed Cross-Coupling Reactions of Functionalized Organozinc Reagents
With Methylthio-Substituted N-Heterocycles ................................................................................................ 88
4.1. Introduction ................................................................................................................................................. 88
4.2. Palladium-catalyzed cross-coupling reactions of functionalized organozinc reagents with methylthio-
substituted N-heterocycles .......................................................................................................................... 89
4.3. Nickel-catalyzed cross-coupling reactions of functionalized organozinc reagents with methylthio-
substituted N-heterocycles .......................................................................................................................... 95
5. Summary and Outlook ..................................................................................................................................... 99
5.1. Preparation and applications of benzylic zinc chlorides ............................................................................. 99