Carbene catalyzed asymmetric nucleophilic acylations with novel triazolium salts [Elektronische Ressource] / vorgelegt von Jianwei Han

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• Publié par: rheinisch-westfalischen_technischen_hochschule_-rwth-_aachen
• Publié le: 01 janvier 2008
• Nombre de lectures: 12
• Langue: English
• Poids de l'ouvrage: 2 Mo

Extrait

Carbene-catalyzed Asymmetric Nucleophilic Acylations
with Novel Triazolium Salts





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

Master of Science

Jianwei Han
aus ShanDong, China


Berichter: Universitätsprofessor Dr. D. Enders
Universitätsprofessor Dr. H.-J. Gais


Tag der mündlichen Prüfung: 08. 12. 2008.







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 July 2005 until December 2008 under the supervision of Prof. Dr.
Dieter Enders.











Parts of this work have already been published:

1. “Synthesis of Enantiopure Triazolium Salts from Pyroglutamic Acid and Their Evaluation in the
Benzoin Condensation”
D. Enders, J. Han, Te t r a h e d ro n: Asymmetry 2008, 19, 1367-1371.

2. “Asymmetric Intermolecular Stetter Reactions Catalyzed by a Novel Triazolium Derived
N-Heterocyclic Carbene”
D. Enders, J. Han, A. Henseler, Chem. Commun. 2008, 3989-3991.

3. “Asymmetric Intermolecular Stetter Reaction of Aromatic Heterocyclic Aldehydes with
Arylidenemalonates”
D. Enders, J. Han, Synthesis 2008, 3864.











I would like to thank Prof. Dr. D. Enders for the interesting and challenging research theme, the
constant support and the useful discussions, as well as the ideal working atmosphere.
I would like to thank Prof. Dr. Hans-Joachim Gais and Prof. Dr. U. Englert as my co-advisers.




苔

白日不到处，青春恰自来，
苔花如米小，也学牡丹开。

袁枚（清）



蒲
飞坠披轻羽, 随风不由己.
漂洋过海来,只为襟抱开.
作者自喻CONTENTS
1. Introduction 1
1.1. Carbene Organocatalysis 1
1.1.1. Organocatalysis 1
1.1.2. Introduction to carbenes 2
1.2. Nucleophilic acylation reactions 4
1.2.1. The Umpolung concept 4
1.2.2 Indirect acylations by using an auxiliary 4
1.2.2.1. Thioacetals 4
1.2.2.2. Alkyl vinyl ethers, vinyl sulfides and vinyl selenides 6
1.2.2.3. Benzotriazole and stabilized acyl anion systems 6
1.2.2.4. Aldehyde hydrazones 7
1.2.2.5. Protected cyanohydrins 7
1.2.2.6. α-Amino nitriles 9
1.2.2.7. Thiazolium carbinols 10
1.2.2.8. Tributylphosphonium ions 11
1.2.3. Direct acylations by using catalysts 11
1.2.3.1. The benzoin reaction 12
1.2.3.2. The crossed benzoin condensation 17
1.2.3.3. The intramolecular crossed benzoin condensation 18
1.2.3.4. The intermolecular Stetter reaction 20
1.2.3.5. The intramolecular Stetter reaction 22
1.2.3.6. Variants of intermolecular Stetter reactions 27
1.3. Summary 31
2. Objectives 32
3. Results and discussion 34
3.1. Development of chiral triazolium salts by variation of the steric demand and
application in nucleophilic acylations4
3.1.1. Design of the catalysts 34
3.1.2. Synthesis of the catalysts 36
3.1.3. Application of the catalysts in nuleophilic acylations 43
3.1.4. Conclusion 49
3.2. Development of chiral triazolium salts by changing the N-substituent
and their application in the intermolecular Stetter reaction 50
3.2.1. The intermolecular Stetter reaction 50
3.2.2. Some available catalysts applied in intermolecular Stetter reaction 51
3.2.3. Development of N-methyl based triazolium salts 52
3.2.4. ent of N-benzyl salts 55
3.2.4.1. Analysis of the triazolium salts 55
3.2.4.2. Synthesis of the benzylhydrazine 56
3.2.4.3. Preparation of five membered ring based N-benzyl triazolium salts 58
3.2.4.4. Application in the intermolecular Stetter reaction with the catalysts 63
3.2.4.5. Further catalyst design and preparation 63
3.2.5. Optimization of the intermolecular Stetter reaction 67
3.2.6. Substrate scope of the intermolecular Stetter reaction 71
3.2.7. Mechanism investigation of the intermolecular Stetter reaction 73
3.2.8. The configuration 74
3.2.9. Other electrophiles for the intermolecular Stetter reaction 75
3.2.10. Alkylidenemalonates as a Michael acceptors for the intermolecular
Stetter reaction 78
3.3. Summary 83
4. Nucleophilic acylations in the synthesis of natural products 84
4.1. Known examples of nucleophilic acylations applied in total synthesis 84
4.2. Attempts to synthesize (–)-eucomol 87
5. Conclusions 92
6. Outlook 96
7. Experimental part 98
7.1. General remarks 99
7.2. procedures 102
7.3. Description of the experiments 104
8. References 169
Introduction

1. Introduction

1.1. Carbene Organocatalysis
1.1.1. Organocatalysis
The word, organocatalysis was coined by David MacMillan, however, the term,
“Organische Katalysatoren ” was already used by Langenbeck in the thirties of last
century. It was defined as the catalysis by small organic metal-free compounds. Two
pioneering papers were published in 2000: 1) List and co-workers have developed the
1intermolecular version of the aldol reaction catalyzed by L-proline (Scheme 1). 2)
MacMillan has documented a highly enantioselective Diels-Alder reaction catalyzed
2by a chiral secondary amine·HCl salt (Scheme 2). Subsequently, the last few years
have witnessed an explosive and impressive growth in this field with new catalysts
3and novel methodologies.

O OHO O L-proline, 30mol% O
+ H C R3H C CH3 3 NR H DMSO OHH
R= Ph, 62% yield, 60% ee. L-proline
R=i-Pr, 97% yield, 96% ee.
Scheme 1. The aldol reaction catalyzed by L-proline.

O Me
O 5mol% cat. N
CHOR ++ Me
R H RMeOH-H O, r.t. CHO N2 MePh H(2S)-exo(2S)-endo .HCl
R = Ph, 99%yield, endo/exo=1.3:1, ee 93% (endo), 93%(exo)
R = Me, 75%yield, endo/exo=1:1, ee 90% (endo), 86%(exo)
Scheme 2. The Diels-Alder reaction catalyzed by Macmillan salts.

To date, a large number of organocatalyzed reactions were reported in the literature.
In a review article, List presented a system which is guided by a mechanistic
classification for the reactions promoted by organocatalysts. Four categories are
4considered: Lewis Base, Lewis Acid, Brønsted Acid and Brønsted Base catalysis.
_____________________________________________________________________ 1Introduction

Generally, the majority of organocatalysts are N-, C-, O-, P-, or S-based Lewis bases
that operate through diverse mechanisms and convert the substrates either into
activated nucleophiles or electrophiles. Among them the only C-based organocatalysts
are N-heterocyclic carbenes, which react with aldehydes to form the nucleophilic
5Breslow intermediate, and then facilitates the addition to an electrophile, overall a
nucleophilic acylation (Figure 1).

El
O NNuO NN NCH2 R1 1R R
O-H O2 2 R H2R R
Iminium catalysis 1-Ammonium enolate catalysis
O ElO NO NN El H 1RH 1R1 1R R N-HXX2 -H O2 2R R
Enamine catalysis 2-Ammonium enolate catalysis
O N O ElO NN H 1H HH R1REl -HX-H O2 N
R R
3-Ammonium enolate catalysisDienanime catalysis