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Preparation of polyfunctional arylmagnesium, or arylzinc reagents bearing a triazene moiety and their applications in organic synthesis [Elektronische Ressource] / von Ching-Yuan Liu

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Dissertation zur Erlangung des Doktorgrades der Fakultät für Chemie und Pharmazie der Ludwig-Maximilians-Universität München Preparation of Polyfunctional Arylmagnesium, or Arylzinc Reagents Bearing a Triazene Moiety and Their Applications in Organic Synthesis von Ching-Yuan Liu aus Taipeh, Taiwan 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 06.02.2007 Ching-Yuan Liu Dissertation eingereicht am 06.02.2007 1. Gutachter: Prof. Dr. Paul Knochel 2. Gutachter: Prof. Dr. Manfred Heuschmann Mündliche Prüfung am 28.02.2007 This work was carried out from October 2003 to December 2006 under the guidance of Prof. Knochel at the Fakultät für Chemie und Pharmazie der Ludwig-Maximilians-Universität München (University of Munich), 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, for his invaluable support and kindness through this time, and for his guidance in the course of scientific research presented here. I am also very grateful to Prof. 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 of Polyfunctional Arylmagnesium, or Arylzinc
Reagents Bearing a Triazene Moiety
and
Their Applications in Organic Synthesis




von

Ching-Yuan Liu



aus

Taipeh, Taiwan





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 06.02.2007








Ching-Yuan Liu




Dissertation eingereicht am 06.02.2007

1. Gutachter: Prof. Dr. Paul Knochel

2. Gutachter: Prof. Dr. Manfred Heuschmann

Mündliche Prüfung am 28.02.2007 This work was carried out from October 2003 to December 2006 under the guidance of Prof.
Knochel at the Fakultät für Chemie und Pharmazie der Ludwig-Maximilians-Universität
München (University of Munich), 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, for his invaluable support and kindness through this time, and
for his guidance in the course of scientific research presented here.

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. Konstantin Karaghiosoff,
Prof. Dr. Ingo-Peter Lorenz, and Prof. Dr. Hans Rudolf Pfaendler for the interest shown in
this manuscript by accepting to be referees.

I thank Dr. Giuliano Clososki, Dr. Vicente del Amo, and Dr. Shohei Sase for the careful
correction of this manuscript.

I would like to thank the Ludwig-Maximilians-Universität for financial support.

Special thanks to Dr. Andrey Gavryshin, Dr. Vicente del Amo, and Georg Manolikakes for
the happiest time we spent together in the lab.

I thank all past and present co-workers I have met in the Knochel’s group for their brief or
lasting friendships. I especially thank Dr. Shuji Yasuike, Dr. Xiaoyin Yang, Dr. Wenwei Lin,
and Dr. Hongjun Ren for their kindness and consideration in my study in Munich. I also thank
Dr. Oliver Baron, Dr. Darunee Soorukram, Nadège Boudet, Christian Rauhut, Simon Matthe,
Tobias Thaler, Matthias Schade, Guillaume Dunet, Marc Mosrin, Christina Despotopoulou,
Georgios Mourgas, Marcel Kienle, Armin Stoll, Murthy Narasimha Cheemala, Robert Born,
Andreas Althammer, and Ludwig T. Kaspar for the nice time we had together.

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 invaluable help.

Finally I would like to thank my family and Prof. Dr. Tien-Yau Luh in Taiwan for their love
and great support, as well as all of my friends for their friendship and consideration through
my Ph.D.-Vielen Vielen Dank!!! Parts of this Ph. D. thesis have been published:

1. C.-Y. Liu, P. Knochel, “Preparation of Polyfunctional Aryl Azides from Aryl Triazenes. A
New Synthesis of Ellipticine, 9-Methoxyellipticine, Isoellipticine, and 7-
Carbethoxyisoellipticine”, J. Org. Chem. 2007, submitted for publication.

2. C.-Y. Liu, H. Ren, P. Knochel, “Magnesiated Unsaturated Silylated Cyanohydrins as
Synthetic Equivalents of Aromatic and Heterocyclic Grignard Reagents Bearing a Ketone or
an Aldehyde”, Org. Lett. 2006, 8, 617-619.

3. C.-Y. Liu, P. Knochel, “Preparation of Polyfunctional Arylmagnesium Reagents Bearing a
Triazene Moiety. A New Carbazole Synthesis”, Org. Lett. 2005, 7, 2543-2546.

4. C.-Y. Liu, P. Knochel, “A Direct Insertion Reaction of Zn·LiCl into Functionalized Iodo-
or Bromophenyl Triazenes”, manuscript in preparation.

5. C.-Y. Liu, A. Gavryushin, P. Knochel, “Synthesis of Functionalized o-, m-, or p-
Terphenyls via Consecutive Cross-Coupling Reactions of Arylboronic Esters Bearing a
Triazene Moiety”, manuscript in preparation.






















To my family, especially Xiaofang,
with love.
































THEORETICAL PART……………………………………………………………………...1

1. Overview………………………………………………………………………………2
1.1 Preparation of organomagnesium and organozinc reagents…………………………2
1.2 Preparation of triazene as a versatile compound in organic synthesis……………….7
2. Objectives…………………………………………………………………………….15
3. Preparation of Polyfunctional Arylmagnesium Reactions Bearing a Triazene
Moiety.………………………………………………………………………………..17
3.1 Introduction…………………………………………………………………………17
3.2 Preparation of polyfunctional aryl triazenes……………………………………......18
3.3 Preparation of polyfunctional aryl iodides.…………………………………............20
3.4 A new carbazole synthesis………………………………………………………….25
4. Preparation of Polyfunctional Arylzinc Reagents Bearing a Triazene Moiety.…27
4.1 Introduction…………………………………………………………………………27
4.2 A direct zinc insertion into iodophenyl triazenes…………………………………...27
4.3 Two successive zinc insertions into diiodoaryl triazenes.……………………….....30
4.4 A direct zinc insertion into bromophenyl triazenes….……………………………..31
5. Synthesis of Functionalized o-, m-, or p-Terphenyls via Consecutive Cross-
Coupling Reactions of Arylboronic Esters Bearing a Triazene Moiety.………....34
5.1 Introduction…………………………………………………………………………34
5.2 Preparation of arylboronic esters bearing a triazene functionality………………….34
5.3 Preparation of polyfunctional aryl triazenes via Suzuki cross-coupling reactions of
triazene-substituted arylboronic esters with aryl halides…………………………...36
5.4 Synthesis of polyfunctional o-, m-, or p-terphenyls via palladium-catalyzed cross-
coupling reactions of aryl triazenes with phenylboronic acids in the presence of
BF OEt ………………………………………………………………….................41 3 2
6. Synthesis of Ellipticine and Related Derivatives via a Key Transformation from
Aryl Triazenes to Aryl Azides………………………………………………………45
6.1 Introduction.………………………………………………………………...............45
6.2 Preparation of polyfunctional aryl triazenes………………………………………..46
6.3 Preparation of polyfunctional aryl azides.……………………………….…………50
6.4 Synthesis of ellipticine and 9-methoxyellipticine by the thermal decomposition of
azides…......................................................................................................................54 6.5 Synthesis of isoellipticine and 7-carbethoxyisoellipticine by the thermal
decomposition of azides.............................................................................................58
7. Summary……………………………………………………………………………..60
7.1 Preparation of polyfunctional arylmagnesium reactions bearing a triazene moiety..60
7.2 Preparation of polyfunctional arylzinc reagents bearing a triazene moiety.………..61
7.3 Synthesis of functionalized -o, -m, or -p terphenyls via consecutive cross-coupling
reactions of arylboronic esters bearing a triazene moiety.………….........................62
7.4 Synthesis of ellipticine and related derivatives via a key transformation from aryl
triazenes to aryl azides ………………………….………………………………….63

EXPERIMENTAL PART………………………………..…………………………………65

8. General Conditions………………………………………………………………….66
9. Typical Procedure………………………………………………………………..….70
9.1 Typical procedure for the preparation of functionalized bromo- or iodophenyl
triazenes via the reaction of pyrrolidine with diazonium salts generated from the
corresponding anilines (TP1)…………………………………………………….....70
9.2 Typical procedure for the preparation of polyfunctional aryl triazenes via the
reaction of electrophiles with the arylmagnesium reagents bearing a triazene moiety
generated from the corresponding bromophenyl triazenes (TP2)…………...……...70
9.3 Typical procedure for the preparation of polyfunctional aryl triazenes via the
reaction of electrophiles with the arylmagnesium reagents bearing a triazene moiety
generated from the corresponding iodophenyl triazenes (TP3)………………….....70
9.4 Typical procedure for the preparation of functionalized aryl iodides via the reaction
of aryl triazenes with methyl iodide (TP4)…………………………………………71
9.5 Typical procedure for the preparation of functionalized aryl iodides via the reaction
of aryl triazenes with trimethylsilyl iodide (TP5)……………...…………………...71
9.6 Typical procedure for the preparation of silylated cyanohydrins via CsF-catalyzed
silylcyanations of the corresponding iodoketones with trimethylsilyl cyanide
(TP6)………………………………………………………………………………..71
9.7 Typical procedure for the preparation of polyfunctional ketones via the reaction of
magnesiated silylated cyanohydrins with an electrophile followed by a deprotection
(TP7) ………………………………………………………………...……………..72 9.8 Typical procedure for the preparation of polyfunctional aryl triazenes via Negishi
cross-coupling reactions of aryl halides with the arylzincs derived from
arylmagnesium reagents (TP8)…………………………………….……………….72
9.9 Typical procedure for the preparation of functionalized carbazoles (TP9)………..73
9.10 Typical procedure for the preparation of functionalized aryl triazenes via the
reactions of arylzinc iodides or brimides with electrophiles in the presence of
CuCN·2LiCl (TP10)………………………………………………………………...73
9.11 Typical procedure for the preparation of functionalized aryl triazenes via the
reactions of arylzinc iodides or brimides with electrophiles in the absence of
CuCN·2LiCl (TP11)………………………………………………………………...74
9.12 Typical procedure for the preparation of functionalized aryl triazenes via Negishi
cross-coupling reactions of arylzinc iodides or brimides with aryl halides (TP12)...74
9.13 Typical procedure for the preparation of functionalized arylboronic esters bearing a
triazene moiety (TP13)……………………………………………………………...75
9.14 Typical procedure for the preparation of functionalized aryl triazenes via Suzuki
cross-coupling reactions of arylboronic esters with aryl halides (TP14)…………...75
9.15 Typical procedure for the preparation of polyfunctional o-, m-, or p-terphenyls via
palladium-catalyzed cross-coupling reactions of aryl triazenes with phenylboronic
acids in the presence of BF OEt (TP15)……..........................................................75 3 2
9.16 Typical procedure for the preparation of functionalized aryl azides from aryl
triazenes via the addition of BF ·OEt and CF COOH in the presence of NaN 3 2 3 3
(TP16)………………………………………………………………………………76
9.17 Typical procedure for the preparation of functionalized aryl azides from aryl
triazenes via the addition of KHSO in the presence of NaN (TP17)…….………..76 4 3
10. Preparation of Polyfunctional Arylmagnesium Reactions Bearing a Triazene
Moiety………………………………………………………………………………...77
11. Preparation of Polyfunctional Arylzinc Reagents Bearing a Triazene Moiety...105
12. Synthesis of Functionalized o-, m-, or p-Terphenyls via Consecutive Cross-
Coupling Reactions of Arylboronic Esters Bearing a Triazene Moiety...............123
13. Synthesis of Ellipticine and Related Derivatives via a Key Transformation from
Aryl Triazenes to Aryl Azides……………………………………………………..147
14. Curriculum Vitae………………………….…………………………………….…179 ABBREVIATIONS

Ac acetyl
AcOH acetic acid
Ar aryl
Bn benzyl
Boc tert-butoxycarbonyl
br. broad
calcd. calculated
CH Cl dichloromethane 2 2
Cy cyclohexyl
d double
dba trans,trans-dibenzylideneacetone
dec. decomposition
DMAP 4-dimethylaminopyridine
DME 1,2-dimethoxyethane
DMF N,N-dimethylformamide
DMSO dimethyl sulfoxide
equiv. equivalent
EI electron-impact
Et ethyl
FAB fast-atom bombardment
FG functional group
GC gas chromatography
h hour
HMPT hexamethylphosphorous triamide
HRMS high resolution mass spectroscopy
n-Bu n-butyl
i-Pr isopropyl
IR infra-red
J coupling constant (NMR)
LG leaving group
M molarity
m meta
m multiplet