Studies on the zinc mediated phenyl and alkynyl addition to carbon heteroatom double bonds [Elektronische Ressource] / vorgelegt von Lorenzo Zani

Lorenzo Zani

Informations

• Publié par: rheinisch-westfalischen_technischen_hochschule_-rwth-_aachen
• Publié le: 01 janvier 2006
• Nombre de lectures: 37
• Langue: English
• Poids de l'ouvrage: 1 Mo

Extrait

Studies on the Zinc-Mediated Phenyl and Alkynyl Addition to
Carbon-Heteroatom Double Bonds



Von der Fakultät für Mathematik, Informatik und Naturwissenschaften der Rheinisch-
Westfälischen Technischen Hochschule Aachen zur Erlangung des akademischen Grades eines
Doktors der Naturwissenschaften
genehmigte Dissertation



vorgelegt von

Lorenzo Zani

aus Florenz (Italien)




Berichter: Universitätsprofessor Dr. Carsten Bolm
Universitätsprofessor Dr. Hans-Joachim Gais



Tag der mündlichen Prüfung: 22.5.2006


Diese Dissertation ist auf den Internetseiten der Hochschulbibliothek online verfügbar



The work presented in this thesis was carried out at the Institute of Organic Chemistry of RWTH
Aachen University between January 2003 and January 2006 under the supervision of Prof. Dr.
Carsten Bolm.


I would like to thank Prof. Dr. Carsten Bolm for the interesting research theme, the constant
support and useful discussions, as well as the ideal working atmosphere.

Moreover, I would like to thank Prof. Dr. Hans-Joachim Gais for his kind assumption of the co-
reference.








Parts of this work have already been published:

1) C. Bolm, L. Zani, J. Rudolph, I. Schiffers
“New chiral ligands derived from mandelic acid: synthesis and application in the
asymmetric phenyl transfer reaction to an aromatic aldehyde”
Synthesis 2004, 2173-2180.

2) C. Bolm, F. Schmidt, L. Zani
“New chiral hydroxy oxazolines as useful ligands for the asymmetric phenylation of
aromatic aldehydes”
Tetrahedron: Asymmetry 2005, 16, 1367-1376.

3) L. Zani, S. Alesi, P. G. Cozzi, C. Bolm
“Dimethylzinc-mediated alkynylation of imines”
J. Org. Chem. 2006, 71, 1558-1562.

Acknowledgments


It is a great privilege for me to thank all the people who supported me during the long, sometimes
stressful, but truly unforgettable months that I needed to complete the work presented in this thesis.
Needless to say, without their precious help not much of what I did would have ever been possible.

First, I would like to thank my supervisor, Prof. Carsten Bolm, for giving me the opportunity to
work in his research group. With his continous encouragement and support, always accompanied by
a genuine enthusiasm for discovery, he helped me becoming a better, more responsible chemist.

I was lucky enough to work with some very talented scientists during my research. Ingo Schiffers,
Jens Rudolph, Jacques LePaih, Julien Legros, Frank Schmidt, Toni Rantanen, Prof. Pier Giorgio
Cozzi, Silvia Alesi and Torsten Eichhorn are acknowledged for many fruitful collaborations.

I wish to thank Daniel Whelligan, Gwion Harfoot and Ingo Schiffers for proof-reading the
manuscript of my doctoral thesis and for their very useful suggestions and comments.

I am grateful to the administrative and technical personnel of the Organic Chemistry Institute of
the RWTH Aachen, for their most appreciated help during my work. In particular, my gratitude
goes to Mrs. Ingrid Voss, for her commitment in resolving all the bureaucratic problems of our
group, and her endless supply of “Büromaterial” and kindness. Thanks also to our dear
Laborantinnen Susi Grünebaum and Nicole Brendgen for their help in many practical preparations
and even more excellent coffees (said by an italian!).

Some people deserve my particular gratitude: first of all my “italian aunts” Chiara Pavan,
Elisabetta Veri and Marinella Verrucci for so many reasons that would really be too long to
mention here, and the rest of the italian community with Tecla Gasperi, Giuseppe Del Signore,
Angelino Doppiu, Daniela Giunta and Maurizio Solinas for many entertaining evenings in our
native language. Julien Legros for his excellent musical taste, even more than for his humor and
chemical skills. The keepers of the “third floor spirit” Ingo Schiffers, Jacques Le Paih, Christian
Moessner and Jean-Cedric Frison for having shown me how a lab should really look like and how
to run a column chromatography. My favourite (sorry guys!), and longest-lasting, labmate Aurelie
Labonne. My companions of many amusing and sometimes adventurous evenings Daniel
Whelligan (wherever he is now), Toni Rantanen (“I am possibly the most intelligent person you
have ever met”) and Masafumi Nakanishi for the good times we had toghether, and the LAN /
football community with Jörg Sedelmeier, Marcus Frings (the real computer administrator),
Thomas Kribber and Marco Schmitz.

Thanks to all the members of AK Bolm, past and present, for the great atmosphere that they
contributed to create, both on the workplace and outside. Our B-seminars, group-outs and parties
seriously menaced to drastically reduce my “motivation factor” (according to the various
definitions…)!
In particular, I thank some people in- and outside the AK for their friendship: Juan Rodriguez
Dehli, Iuliana & Nicolae Atodiresei, Christian Hackenberger, Jens Rudolph, Pauline Remy, Helene
Villar, Martin Langner, Bernhard Füger, Torsten Eichhorn, Yuan Yu, Vincent Lecomte, Frank
Schmidt (der Präsident), Salih Özçubukçu, René Stemmler, Belen Rodriguez, Christine
Beemelmanns, Gwion Harfoot, Monica Carril-Garcia, Olga Garcia, Gae Young Cho, Katherine
Turton, Sebastien Schoumacker, Julien Barbion, Marianna Vrettou, Oliver Niemeier and Matthias
Hüttl.

As you can see, this list is already very long, but still I fear I forgot someone. If this is the case,
please forgive me, you know that was not done on purpose.

I learned very much from all the people mentioned here. I hope I was able to give at least
something in return. Grazie.





“…the inadequacy of our preparation, and the need to make up for it with luck, intuition,
stratagems and a river of patience. […] I wanted to put on display […] the strong and bitter
flavour of our trade, which is only a more strenuous version of the business of living”

Primo Levi, The Periodic Table






“Provando e riprovando
[Trying and trying again]”

Motto of the “Accademia del Cimento”, the first
european scientific society, founded in Florence in 1657














Index

1. INTRODUCTION 1
1.1. Organometallic Compounds in Organic Synthesis
1.2. Zinc-Mediated Organic Reactions 9
2. ADDITION OF ORGANOMETALLIC REAGENTS TO CARBON-HETEROATOM
DOUBLE BONDS 11
2.1. Addition of Alkylzinc Reagents to Carbonyl Compounds and Imines 11
2.2. Zinc-Mediated Arylation of Carbon-Heteroatom Double Bonds 18
2.2.1. Diarylmethanols and Diarylmethylamines: Important Targets for Stereoselective
Synthesis 18
2.2.2. Phenyl Transfer Reactions Employing Diphenylzinc as a Phenyl Source 20
2.2.3. Variation of the Ligand Structure 25
2.2.4. Use of Alternative Aryl Sources 28
2.2.5. Additive Effects 32
2.2.6. Zinc-Mediated Phenyl Transfer Reaction to Imines 33
2.2.7. Phenyl and Aryl Transfer to Ketones: Synthesis of Quaternary Stereogenic
Centers 34
22.2.8. Enantioselective Addition of Other C(sp )-Zn Nucleophiles 36
2.3. Addition of Alkynes to Carbon-Heteroatom Double Bonds 40
2.3.1. Propargylic Alcohols and Amines in Organic Synthesis 40
2.3.2. Direct Addition of Alkynes to Aldehydes 43
2.3.2.1. Metal Salt-Promoted Addition and Double Activation Strategy 43
2.3.2.2. Dialkylzinc-Promoted Enantioselective Additions of Acetylenes to Aldehydes 48
2.3.2.3. Titanium-Promoted Enantioselective Additions of Acetylenes to Aldehydes
Employing Dialkylzinc Reagents. 56
2.3.3. Direct Addition of Alkynes to Ketones 60
2.3.4. Direct Addition of Alkynes to Imines and Related C=N Electrophiles 66
2.3.4.1. Racemic and Diastereoselective Metal-Mediated and Metal-Catalyzed Direct
Alkynylation of C=N Electrophiles 66
2.3.4.2. Enantioselective Metal-Mediated and Metal-Catalyzed Direct Alkynylation of
C=N Electrophiles 75
3. RESEARCH OBJECTIVE 83
iIndex
4. RESULTS AND DISCUSSION 86
4.1. Synthesis and Application of Chiral Hydroxy Oxazolines Derived from Mandelic
Acid 86
4.1.1. Synthesis of Diastereomerically Pure α-Hydroxy-2-oxazolines 203a-c 87
4.1.2. Enantioselective Phenyl Transfer Reaction 90
4.2. Synthesis and Applications of New Chiral Hydroxy Oxazolines Possessing a
Quaternary Benzylic Position 94
4.2.1. Synthesis of New Chiral α, α-Disubstituted Hydroxy Oxazolines 212a-k 95
4.2.2. Enantioselective Phenyl Transfer Reactions 100
4.3. Development of a Dimethylzinc-Mediated Alkynyl Addition to Imines 106
4.3.1. Direct Alkyne Addition to Activated Imines Mediated by Dimethylzinc 108
4.3.2. Zinc-Mediated Three-Component Synthesis of Propargylic Amines 114
4.4. Studies Towards the Enantioselective Dimethylzinc-Mediated Alkynylation of
Imines 118
5. SUMMARY AND OUTLOOK 139
6. EXPERIMENTAL SECTION 144
6.1. General Remarks
6.1.1. Solvents 144
6.1.2. Chemicals 145