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Preparation and reactions of allylic zinc reagents and transition metal catalyzed cross coupling reactions [Elektronische Ressource] / von Guillaume Dunet

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Dissertation zur Erlangung des Doktorgrades der Fakultät für Chemie und Pharmazie der Ludwig-Maximilians-Universität München Preparation and Reactions of Allylic Zinc Reagents and Transition Metal-Catalyzed Cross-Coupling Reactions von Guillaume Dunet aus Orléans, Frankreich 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 15.11.2007 Guillaume Dunet Dissertation eingereicht am 15.11.2007 1. Gutachter: Prof. Dr. Paul Knochel 2. Gutachter: Prof. Dr. Manfred Heuschmann Mündliche Prüfung am 14.12.2007 This work was carried out from November 2004 to December 2007 under the guidance of Prof. Paul Knochel at the Fakultät für Chemie und Pharmazie der Ludwig-Maximilians-Universität, Munich. I would like to thank my supervisor, Prof. Dr. Paul Knochel, for giving me the opportunity of doing my Ph.D. in his group. I am also grateful to Prof. Dr. Manfred Heuschmann for agreeing to be my “Zweitgutachter”, as well as Prof. Dr. H. Zipse, Prof. Dr. H. Langhals, and Prof. Dr. K. Karaghiosoff for the interest shown in this manuscript by accepting to be referees. I thank Dr. Sylvie Perrone and Dr.

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Published 01 January 2007
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Dissertation zur Erlangung des Doktorgrades
der Fakultät für Chemie und Pharmazie
der Ludwig-Maximilians-Universität München






Preparation and Reactions of Allylic Zinc Reagents
and
Transition Metal-Catalyzed Cross-Coupling Reactions




von

Guillaume Dunet



aus

Orléans, Frankreich





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 15.11.2007








Guillaume Dunet




Dissertation eingereicht am 15.11.2007

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

Mündliche Prüfung am 14.12.2007 This work was carried out from November 2004 to December 2007 under the guidance of
Prof. Paul Knochel at the Fakultät für Chemie und Pharmazie der Ludwig-Maximilians-
Universität, Munich.





I would like to thank my supervisor, Prof. Dr. Paul Knochel, for giving me the opportunity of
doing my Ph.D. in his group.

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

I thank Dr. Sylvie Perrone and Dr. Giuliano Clososki for the careful correction of this
manuscript.

I would like to thank the DFG for financial support.

Special thanks to my actual and former lab mates: Hongjun, Genia, Pradipta, Subbu, Geogios,
Matt, Tobias and Alex for the great time we spent together in the lab.

I would like to thank Hongjun, Matt and Milica for the fruitful collaborations in the field of
the allylmetal chemistry.

I thank all past and present co-workers I have met in the Knochel’s group for the good times
we had (especially parties).

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 analytical team, Dr.
D. Stephenson, Dr. C. Dubler, Dr. W. Spahl, B. Tschuk, I. Brück, H. Schulz and G. Käser for
their help.

Very special thanks to Sylvie for her support, and for making this stay in Munich a lot more
entertaining :0)).

Finally I would like to thank my family and my friends for their great support, throughout my
time in Munich.


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


1. Dunet, G.; Knochel, P. “Iron-Catalyzed Cross-Coupling between Alkenyl and Dienyl
Sulfonates and Functionalized Arylcopper Reagents” Synlett, 2006, 3, 407-410.

2. Dunet, G.; Knochel, P. “Highly Stereoselective Cobalt-Catalyzed Allylation of
Functionalized Diarylzinc Reagents” Synlett 2007, 9, 1383.

3. Ren, H.; Dunet, G.; Mayer, P.; Knochel, P. “Highly Diastereoselective synthesis of
Homoallylic Alcohols Bearing Adjacent Quaternary Centers Using Substituted Allylic
Zinc Reagents” J. Am. Chem. Soc. 2007, 129, 5376-5377.

4. Dunet, G.; Mayer, P.; Knochel,P. “Highly Diastereoselective Addition of
Cinnamylzinc Reagents to α-Chiral Carbonyl Derivatives” Org. Lett. In press

















Après la pluie, le beau temps…


6
Table of Contents

THEORETICAL PART ......................................................................................................................................... 9
1. Introduction......................................................................................................................................... 10
1.1. Overview......................................................................................................................................... 10
1.1.1. Allylic zinc reagents ...................................................................................................................... 10
1.1.2. Cross-coupling reactions .............................................................................................................. 21
1.2. Objectives....................................................................................................................................... 29
3. LiCl-mediated preparation of allylic zinc reagents and their reaction with
electrophiles.............................................................................................................................................. 31
3.1. Introduction.................................................................................................................................... 31
3.2. LiCl-mediated preparation of allylic zinc reagents ............................................................ 32
3.3. Diastereoselective reaction of allylic zinc reagents with aldehydes and ketones...... 34
3.4. Reaction with α-chiral ketones................................................................................................. 40
3.4.1. Reaction with α-chiral cyclohexanones......................................................................................... 40
3.4.2. Reaction with acyclic α-chiral ketones.......................................................................................... 45
3.4.3. Application to enantioenriched α-chiral ketones .......................................................................... 46
3.5. Direct “zinc-ene” reaction from allylic chlorides ............................................................... 47
3.6. Conclusion...................................................................................................................................... 52
4. New transition metal-catalyzed cross-coupling reaction............................................ 54
4.1. Highly stereoselective cobalt-catalyzed allylation of functionalized diarylzinc
reagents.......................................................................................................................................................... 54
4.2. Iron-catalyzed cross-coupling between alkenyl and dienyl sulfonates and
functionalized arylcopper reagents........................................................................................................ 60
4.3. Nickel-catalyzed cross-coupling between aryl phosphates and arylmagnesium
reagents.......................................................................................................................................................... 65
5. Summary and outlook.................................................................................................................... 70
5.1. LiCl-mediated preparation of allylic zinc reagents and their reaction with
electrophiles ................................................................................................................................................. 70
5.2. Highly stereoselective cobalt-catalyzed allylation of functionalized diarylzinc
reagents.......................................................................................................................................................... 72 7
5.3. Iron-catalyzed cross-coupling between alkenyl and dienyl sulfonates and
functionalized arylcopper reagents........................................................................................................ 73
5.4. Nickel-catalyzed cross-coupling between aryl phosphates and arylmagnesium
reagents.......................................................................................................................................................... 74
EXPERIMENTAL PART .................................................................................................................................... 76
6. General considerations.................................................................................................................. 77
7. Preparation and reactions of allylic zinc reagents ......................................................... 81
7.1. Typical Procedures (TPs)........................................................................................................... 81
7.1.1. Typical procedure for the formation of allylic zinc reagents from allylic chlorides or phosphates
(TP1): ....................................................................................................................................................... 81
7.1.2. Typical procedure for the reaction of allylic zinc reagents with aldehydes, ketones or imines
(TP2): ....................................................................................................................................................... 81
7.1.3. Typical procedure for the intramolecular “zinc-ene” reaction (TP3):......................................... 82
7.2. Experimental section:.................................................................................................................. 82
8. Cross-coupling reaction .............................................................................................................. 131
8.1. Typical Procedures (TPs)......................................................................................................... 131
8.1.2. Typical procedure for the formation of diarylzinc reagents via an I/Zn-exchange (TP4): ......... 131
8.1.3. Typical procedure for the cobalt-catalyzed reaction of allylic chlorides or phosphates with
diarylzinc reagents (TP5):......................................................................................................................... 131
8.1.4. Typical procedure for the iron-catalyzed cross-coupling between alkenyl sulfonates and
arylcopper reagents (TP6): ....................................................................................................................... 132
8.1.5. Typical procedure for the iron-catalyzed cross-coupling between dienyl nonaflates and
arylcopper reagents (TP7): ....................................................................................................................... 133
8.1.6. Typical procedure for the preparation of aryl phosphates from the corresponding phenol
derivatives (TP8):...................................................................................................................................... 133
8.1.7. Typical procedure for the nickel-catalyzed cross-coupling between aryl phosphates and
arylmagnesium reagents (TP9): ................................................................................................................ 134
8.2. Experimental section................................................................................................................. 135
9. Appendix ............................................................................................................................................. 171
9.1. X-ray Data .................................................................................................................................... 171
9.2. Resume.......................................................................................................................................... 177


Abbreviations


[α] specific rotaion [expressed HRMS high resolution mass
without units; the actual spectroscopy
units, deg mL/(g dm), are IR infra-red
understood J coupling constant (NMR)
Ac acetyl M molarity
Acac acetylacetone m meta
Ar aryl m multiplet
Bn benzyl Me methyl
br broad min minute
Bu butyl mol. mole
n-Bu n-butyl mp. melting point
calcd. calculated MS mass spectroscopy
δ chemical shift in ppm Ms mesyl (-SO CH ) 2 3
d doublet Nf nonaflate (-SO C F ) 2 4 9
DMAP 4-dimethylaminopyridine NMR nuclear magnetic resonance
DME 1,2-dimethoxyehtane o ortho
DMSO dimethyl sulfoxide Oct octyl
dppe Ph P(CH ) PPh p para 2 2 2 2
dr diastereomeric ratio Ph phenyl
ee enantiomeric excess Piv pivaloyl
equiv. equivalent i-Pr iso-propyl
EI electron-impact q quartet
Et ethyl rt room temperature
FAB fast-atom bombardment s singlet
FG functional group t triplet
GC gas chromatography TBAF Bu NF 4
h hour Tf triflate (-SO CF ) 2 3
Hex hexyl Ts 4-toluenesulfonyl
c-Hex cyclohexyl TP typical procedure
















Theoretical Part


10 Theoretical Part
1. Introduction

1.1. Overview

“Many new synthetic processes have been discovered as a result of a perceived need in
connection with specific problems involving novel or complicated structures and a deliberate
search for suitable methodology”. Those words of E. J. Corey point out the issues organic
chemists have been facing for the past decades: respond to the need of an ever-growing
agrochemical and pharmaceutical industry for new, efficient, and environmentally friendly
methodologies to perform chemical transformations. Among these transformations, the
creation of a carbon-carbon bond is certainly of the greatest importance, as it constitutes a
unique tool for the construction of complex molecules.
1
The synthesis of diethylzinc by Frankland in 1849, and the remarkable work of
2
Grignard on organomagnesium reagents have paved the way for the development of modern
organometallic chemistry. Nowadays, organometallic species are among the most powerful
tools offered to organic chemists as, depending on the very nature of the metal, reactivity and
selectivity can be tuned. For instance, organolithium reagents, though highly reactive, are
hardly compatible with sensitive functional groups and present a poor selectivity, whereas the
use of less reactive species, such as organozinc, -tin, or –boron reagents, increases the
tolerance towards functionalities, but often requires transition metal catalysts to perform the
reaction efficiently.

1.1.1. Allylic Zinc reagents

Allylmetals

Allylic organometallic species have been thoroughly studied since the 1960s. At first,
efforts were put on the structural determination of allylmetals, e.g. the stereochemistry of the

1
(a) Frankland, E. Liebigs Ann. Chem. 1848-9, 71, 171. (b) Frankland, E. J. Chem. Soc. 1848-9, 2, 263.
2 (a) Grignard, V. Compt. Rend. Acad. Sci. Paris 1900, 130, 1322. (b) Grignard, V. Ann. Chim. 1901, 24, 433.