Vaclav Jurcik - Development and Application of Novel Metal Free … · 2006. 11. 8. · Aldol...

Development and Application of Novel Metal Free

Lewis Acids and Pseudo Lewis Acids

Dissertation

Zur Erlangung des Grades eines

Doktors der Naturwissenschaften

Vorgelegt von

Václav Jurčík

Aus Piešťany

Genehmigt von der

Fakultät für Natur- und Materialwissenschaften

Der Technischen Universität Clausthal

Tag der mündlicher Prüfung: 15. Mai 2006

Die vorliegende Arbeit wurde in der Zeit von Juni 2003 bis Marz 2006 am Institut für Organ-

ische Chemie der Technischen Universität Clausthal im Arbeitskreis von Prof. Dr. René Wilhelm

durchgeführt.

Dekan: Prof. Dr. Wolfgang Schade

Referent: Prof. Dr. René Wilhelm

Korreferent: Prof. Dr. Dieter E. Kaufmann

Mým rodičům, že při mě stáli v dobrém i zlém.

Table of contents

1. Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1

1.1. Introduction to Organocatalysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1

1.2. Main Types of Compounds Used as Organocatalyst . . . . . . . . . . . . . . . . . . . . . . . . . . 2

1.2.1. Catalysts Derived from Natural Products . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2

Alkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2

Amino-Acids and their Derivatives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2

1.2.2. Synthetic Molecules . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3

1.3. Organocatalytic Reactions According to the Mechanism of Catalyst Activation . . . . 4

1.3.1. Reactions Catalyzed via Covalent Transition Complexes . . . . . . . . . . . . . . . . . . . . . . 4

1.3.1.1. Nucleophilic Catalysis: Activation of the Donor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4

A. Generalized Enamine Cycle and Unique Properties of L-Proline . . . . . . . . . . . . . . . . 4

Aldol Condensation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5

Mannich reaction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6

α-Amination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6

α-Aminooxylation of Aldehydes and Ketones . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7

Asymmetric Conjugated Additions (Michael Addition). . . . . . . . . . . . . . . . . . . . . . . . 7

SN

2 Alkylation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8

[4+2] Cycloadditions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8

[2+2] Cycloaddition Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9

Morita-Baylis-Hillman Reaction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9

α-Halogenation of Carbonyl Compounds . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10

B. Asymmetric Synthesis with Carbene catalysts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11

Benzoin Condensation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11

Stetter Reaction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11

C. Asymmetric Reactions with Ylide Intermediates: Formation of Three Membered

Rings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11

D. Acyl Transfer Reactions: Desymmetrization and Kinetic Resolution . . . . . . . . . . . . 12

1.3.1.2. Electrophilic Catalysis: Activation of the Acceptor . . . . . . . . . . . . . . . . . . . . . . . . . . 12

1,4-Addition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13

1,4-Addition with Enolates or Enolate Equivalents . . . . . . . . . . . . . . . . . . . . . . . . . . 13

Epoxidation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13

1.3.2. Reactions via Noncovalent Activation Complexes . . . . . . . . . . . . . . . . . . . . . . . . . . 14

A. Asymmetric Proton Catalysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15

Catalytic Enantioselective Protonation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15

Catalytic Enantioselective Deprotonation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15

1,4-Addition to Activated Double Bond. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16

Aza-Henry Reaction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16

Reductive Amination of Ketones . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17

[4+2] Addition. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17

Hydrocyanation Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18

Trifluoromethylation of Ketones . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20

Catalytic Enantioselective Reactions Driven by Photoinduced Electron Transfer . . 20

B. Activation by Lewis Acids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20

[4+2] Cycloaddition Reaction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21

Mukaiyama Aldol Reaction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21

C. Activation of Lewis Acids by Lewis Bases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22

Allylation Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22

Aldol Reaction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23

Hydrocyanation of Imines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24

Nucleophillic Ring Opening of Epoxides. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24

Asymmetric Catalytic Reduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24

1.3.3. Enantioselective Phase Transfer Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25

Cinchona Alkaloids Phase-Transfer Catalysts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25

C2 Symmetric Phase Transfer Catalysts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26

1.4. Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27

2. Results and Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29

2.1. Preparation of the Catalysts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29

2.1.1. Imidazolinium Salts as Novel Organocatalyst . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29

2.1.1.1. Synthetic Approach to Imidazilinium Salts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29

2.1.1.2. Schematic Plan of the Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31

2.1.1.3. Preparation of the Precursors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32

2.1.1.3.1. Preparation of Diamines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32

Preparation of C2 Symmetric Diamines. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32

Preparation of Chiral Diamines from Amino-Acids. . . . . . . . . . . . . . . . . . . . . . . . . . 33

Preparation of Amides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34

BOC-Deprotection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36

Reduction of α-Amino-Amides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36

Formylation/Reduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37

Tosylation of the Amines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39

2.1.1.3.2. Preparation of Imidazolidines. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39

Water Excluding Approach . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39

Preparation of Aminals in Water. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41

Solvent Free Approach . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44

Preparation of Bisaminals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47

2.1.1.4. Preparation of the Imidazolinium Salts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49

2.1.1.4.1. Oxidation of Aminals by NBA or NBS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49

Anion Metathesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 50

Preparation of Chiral Salts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52

Preparation of Bis-Cations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 54

2.1.1.4.2. Direct Reaction of Orthoesters with Diamines in the Presence of an Anion and Acid

Sources . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 55

2.1.2. Preparation of other Lewis Acids and Pseudo Lewis Acid . . . . . . . . . . . . . . . . . . . . 59

2.1.2.1. Silacycles as an Silicon Analog to Imidazolinium Salts . . . . . . . . . . . . . . . . . . . . . . 59

2.1.2.1.1. N,N-Silacycles. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 59

2.1.2.1.2. N,O-Silacycles. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 60

2.1.2.1.3. O,O-Silacycles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 60

2.1.2.2. Chiral Thioureas as Pseudo Lewis Acids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 62

2.2. Application of the Catalysts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 63

2.2.1. Application of Imidazolinium Salts as Lewis Acid Activators . . . . . . . . . . . . . . . . . 63

2.2.1.1. Aza Diels-Alder Reaction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 63

2.2.1.2. Asymmetric Aza Diels-Alder Reactions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 68

2.2.1.3. Hetero Diels-Alder Reaction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 70

2.2.1.4. Aza Diels-Alder Reaction of in situ Generated Imines . . . . . . . . . . . . . . . . . . . . . . . 71

2.2.1.5. Inverse Electron Demand Aza Diels-Alder Reaction . . . . . . . . . . . . . . . . . . . . . . . . . 72

2.2.1.6. Diels-Alder Reaction of Suphur Containing Compounds . . . . . . . . . . . . . . . . . . . . . 76

2.2.1.7. Ring Opening of Epoxides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 77

2.2.1.8. Baylis-Hillman Reaction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 77

2.2.2. Application of Imidazolinium Salts as NCN Carbene Ligands . . . . . . . . . . . . . . . . . 80

2.2.2.1. Application of Imidazolinium Salts as Carbene Ligands for the Heck Reaction . . . 80

2.2.2.2. Application of Imidazolinium Salts as a Carbene Ligand for the Diethylzinc . . . . . 80

Addition of Et2Zn to Imines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 83

Conjugated Addition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 83

2.2.3. Imidazolinium Salt as Phase Transfer Catalyst . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 84

2.2.3.1. Imidazolinium Bis-Cation as Phase Transfer Catalyst in a Michael Reaction. . . . . . 84

2.2.4. Imidazolinium Salts as a Chiral Shift Reagents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 85

2.2.5. Imidazolidinium Salts as a Reaction Medium . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 91

2.2.5.1. Baylis-Hillman Reaction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 92

2.2.5.2. Addition of Grignard Reagents to Carbonyl Groups . . . . . . . . . . . . . . . . . . . . . . . . . 94

2.2.6. Application of Si+ Species Generated from Silacycles as Catalysts . . . . . . . . . . . . . 97

2.2.6.1. Inverse Electron Demand Aza Diels-Alder Reaction . . . . . . . . . . . . . . . . . . . . . . . . . 97

2.2.6.2. Diels-Alder Reaction of Sulphur Containing Compounds. . . . . . . . . . . . . . . . . . . . 100

2.2.6.3. Other Reactions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 100

2.2.7. Application of Thiourea Derivates as a Pseudo Lewis Acid Activators . . . . . . . . . 101

2.2.7.1. Reductive Amination of Ketones . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 101

2.2.7.2. Aza Michael Reaction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 101

2.2.7.3. Baylis-Hillman Reaction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 101

2.3. Summary and Outlook . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 102

3. Experimental . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 107

3.1. Preparation of Diamines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 109

3.2. Preparation of Imidazolidines. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 128

3.3. Preparation of Imidazolinium Salts by Oxidation of Imidazolidines. . . . . . . . . . . . 144

3.4. Preparation of the Carbene Precursors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 175

3.5. Preparation of Silacycles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 184

3.6. Preparation of Thioureas. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 187

3.7. Application of Imidazolinium Salts as Catalysts . . . . . . . . . . . . . . . . . . . . . . . . . . . 189

3.7.1. Aza Diels-Alder Reaction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 189

3.7.2. Inverse Electron Demand Aza Diels-Alder Reaction . . . . . . . . . . . . . . . . . . . . . . . . 192

3.7.3. Hetero Diels-Alder Reaction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 194

3.7.4. Baylis-Hillman Reaction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 194

3.8. Application of Carbene Precurcors. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 195

3.8.1. Et2Zn Addition to Aldehydes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 195

3.8.2. Et2Zn Addition to Imines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 195

3.8.3. Conjugated Addition of Et2Zn . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 196

3.9. Application of Imidazolinium Salts as a Phase Transfer Catalysts . . . . . . . . . . . . . 197

3.10. Application of Imidazolinium Salts as a Shift Reagents . . . . . . . . . . . . . . . . . . . . . 198

3.11. Application of Imidazolinium Based Ionic Liquid as Reaction Medium . . . . . . . . 199


3.11.2. Addition of Grignard Reagents to Benzaldehyde. . . . . . . . . . . . . . . . . . . . . . . . . . . 201

3.12. Application of Silacycles as Catalysts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 203

3.12.1. Inverse Electron Demand Aza Diels-Alder Reaction . . . . . . . . . . . . . . . . . . . . . . . . 203

3.13. Application of Chiral Thioureas in Catalysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 205


4. References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 207

A. Appendix . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 215

A1. Structural Properties of Imidazolinium Salts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 215

A2. NMR Spectras of Selected Compounds . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 216

A3. Numbering of Selected compounds . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 218

Abbreviations

Ac Acetyl

Ar Aromatic rest

aq. Aqueous

BOC t-Butoxycarbonyl

Bn Benzyl

bp Boiling point

bs Broad singlet

Bu Butyl

BuLi n-Butyllithium

°C Temperature in degrees Centigrade

CI Chemical ionization

cm Centimeter

d doublet

DABCO 1,4-Diazabicyclo[2.2.2]octane

DBE 1,2-dibromoethane

DBU 1,8-Diazabicyclo[5.4.0]undec-7-ene

DCM Dichloromethane

dd Doublet doublet

de Diastereomeric excess

dr Diastereomeric ratio

dec. Decomposition

DME 1,2-Dimethoxyethane

DMSO Dimethylsulfoxide

ee enantiomeric excess

EI Electron impact

eq. equivalent (equivalents)

ESI Electron spray ionization

Et Ethyl

EtOH Ethanol

Et2O Diethyl ether

FCC Flash collumn chromatography

h hour (hours)

HMPA Hexamethylphosphoramide

HPLC High pressure liquid chromatograpy

HRMS High resolution mass spectroscopy

Hz Herz

hν Irradiation with light

IL Ionic liquid

i isoiPr Isopropyl

IR Infrared

J Coupling constant

KHMDS Potassium hexamethyldisilazane

LAH Lithium aluminium hydride

LDA Lithium diisopropylamide

LiHMDS Lithium hexamethyldisilazane

m Medium

m metaM Molar (mol/L)

Me Methyl

MeCN Acetonitrile

MeOH Methanol

m Multiplet

min Minute (Minutes)

MHz Megaherz

mol Mole

mmol Millimol

mp Melting point

m/z mass charge ratio

MPLC Medium pressure liquid chromatography

MS Molecular sieves

MS Mass spectroscopy

NaHMDS Sodium hexamethyldisilazane

NBS N-Bromoacetamide

NBA N-Bromosuccinimide

NMR Nuclear magnetic reasonance

o orthop paraPET Photoinduced electron transfer

Ph Phenyl

PhMe Toluene

ppm Parts per million

q Quartet

R Organic rest

r.t. Room temperature (25°C)

RTIL Room temperature ionic liquid

s Second

s Singlet

s Strong

sec Secondary

t Time

t Triplet

t Tertiary

T Temperature

TADDOL α,α,α’,α’-tetraaryl-4,5-dimethoxy-1,3-dioxolane

TBAF Tetra-n-butylammonium fluoride

t-BuOK Potassium tertbutylate

Tf Triflate

THF Tetrahydrofurane

TLC Thin layer chromatography

TMS Trimethylsilyl

Tol Tolyl

Ts Tosyl

vs Very strong

w weak

δ Chemical shift

1. Introduction

Catalysts, in the definition by Berzelius and others in the 19th century, are materials

which change the rate of attaining a chemical equilibrium without themselves being

changed or consumed in the process.

Catalysis is an amazing phenomenon. Some catalysts achieve astonishing activities, so

that very small quantities of catalyst can convert thousands or millions of times their own

weight of chemicals. Equally significant is the selectivity; usually thought of in terms of a

catalyst accelerating one of a number of competing reactions, but also possible by virtue of

a catalyst selecting one reagent out of a complex mixture.

Catalysis represents an important field of chemistry and chemical industry. Since the

development of the first catalytic systems it went through a long way. The economic contri-

bution from catalysis is as remarkable as the phenomenon itself. Estimates from just four

years ago stated that 35% of global GDP depends on catalysis. Confining the analysis to the

chemicals industry, with global sales of about US$1.5 x 1012, the proportion of processes

using catalysts is 80% and increasing. The catalyst market itself is US$1010, so that cata-

lysts costs are much less than 1% of the sales revenue from the products which they help

create.1

Creating more efficient and enviromental friendly catalysts it at great importance in the

development of organic synthesis and chemical industry.

1.1. Introduction to Organocatalysis2-4

Organocatalysis can be defined as an acceleration of chemical reactions with substoichio-

metric amount of a small organic compound, which does not contain a metal atom. Depend-

ing on the mechanisms of the activation, organocatalysts can be divided into the following

subclasses:

• Catalysts activating by forming covalent activation complexesThe organic molecules form reactive intermediates. The catalyst is consumed in the reac-

tion cycle and is regenerated in a parallel catalytic cycle.

• Catalysts activating by forming noncovalent activation complexesThe catalyst is activating the substrate by its nucleophilic/electrophilic properties. The

catalyst is not degradated in the reaction and it is not necessary to regenerate it in the cat-

alytic cycle. This type of activation is similar to conventional Lewis acid/base activation.

• Phase transfer catalystsThe catalyst forms a host/guest complex with the substrate and shuttles between the stan-

dard organic solvent and a second phase (aqueous or fluorous phase).

• Molecular cavity activating catalystsMolecular-cavity-accelerated asymmetric transformations, in which the catalyst may

select between the competing substrates, depending on size and structure criteria. The

Introduction 1

rate acceleration of the given reaction is similar to the Lewis acid/base activation and it

is a consequence of the simultaneous action of different polar functions.

1.2. Main Types of Compounds Used as Organocatalyst

1.2.1. Catalysts Derived from Natural Products

Naturally occurring compounds are wide and often even cheap source of different chiral

moieties. They are defined as chiral pool.

Alkaloids

Alkaloids are representing the largest and most various group of natural products. Many

of them were screened for the ability to catalyze reactions, but just some were selected for

further examination. One of the best examples are cinchona alkaloids (Scheme 1) which are

found in Cinchona bark (esp. Cinchona pubescens, plant known for its antimalarial proper-

ties), that have shown excellent results in enantioselective Baylis-Hillman reaction. More-

over, some of the derivates are often used as phase transfer catalysts.

Scheme 1

Amino-Acids and their Derivatives

Amino-acids like L-proline (4) or L-phenylalanine (7) and their derivates have been used

as catalysts in many enantioselestive reactions. Outstanding results obtained in some reac-

tions led to the preparation of many analoges (Scheme 2). Commercial availability and low

price make amino-acids , especially naturally occurring ones, very attractive precursors for

the development of new catalysts.

N

N

H

H

O

OMe

N

N

H

H

HO

OMe

1 2 3

N

N

H

H

HO

2 Introduction

Scheme 2

1.2.2. Synthetic Molecules

There is indeed the possibility, not to be inspired by nature, but to design a catalyst from

the scratch. Synthetic molecules have the advantage, that both enantiomers are readily avail-

able and it is possible to modify their structure to meet requirements of the reaction being

catalyzed.

There is a large group of synthetic molecules, that are used in organocatalysis (Scheme

3).

Scheme 3

Many of the synthetic organic molecules are C2 symmetric, which is not a requirement

for a good catalyst and it does not have any influence on transfer of chiral information. C2symmetric molecules are often easier to prepare, which is from the synthetic point of view

their main advantage. In addition it is often easier to explain enantiomeric induction since

N+

N+

MeMe

O−

O−

N

N NH

N

N

O

iBu

Me

N

Me

CHO

16

2120

17

Si+

Me

B(C6F5)4− C

+

EtEt

Ar X−

22 23

HN

S

HN

CF3

F3C

NMe2

N

NH

O

Ph HClO4

19

18

O

NH

O

N

O24

O

NH

N

Me

N

NH Me

O

OH

O

OH

NH

OMe

NH

OH

H2N OMe

Ph O

H2N OH

Ph O

NH

OH

O

OH

O

NH

NH

Me

NH

Me

N

4 5

9

1312

8 10

6

14 15

7

OH

NH

11

Introduction 3

4 Introduction

there are only half of the possible diastereomeric transition states compared to the C1 sym-

metric catalysts.

One can also think about choosing the middle way in terms of using different naturallly

occurring molecules and synthetically modifying them into a highly selective catalyst.

1.3. Organocatalytic Reactions According to the Mechanism of Catalyst Activation

1.3.1. Reactions Catalyzed via Covalent Transition Complexes

1.3.1.1. Nucleophilic Catalysis: Activation of the Donor

Up-to-date, most of the molecules used in organocatalysis are bifunctional, usually with

a Brønsted acid and a Lewis base center.5 These compounds are able to activate the donor

and the acceptor and accelerate significantly the reaction rate.

The largest group of organocatalytic reactions are amine based. Most of these reactions

proceed through a generalized enamine cycle (Scheme 4) or through the formation of immo-

nium intermediates. These two types of activation are often complementary, so it is possi-

ble to use them as alternatives for the same transformation. A donor molecule can be acti-

vated through the formation of an enamine, which leads to an increase of electron density

at the reactive center. The acceptor molecule can be activated through the formation of an

onium salt, which leads to a decrease of the electron density at the reactive center.

A. Generalized Enamine Cycle and Unique Properties of L-Proline

Without a doubt, L-proline is the most famous catalyst for the enamine-type reactions,

that is known so far. Although the cheaper L-form is more often used, the D-form is also

commercially available, which is a big advantage compared to enzymes (class I aldolases)

which are able to catalyze a similar scope of reactions. Simplicity and versatility of proline

is even more fascinating when compared to complex natural enzymes.

What are then the main features that make the proline such an outstanding catalyst? Pro-

line is the only natural amino-acid that has a secondary amino group in the α−position and

therefore a higher pKa

value and enhanced nucleophilicity relative to other amino-acids.

Higher nucleophilicity allows proline to form iminium ions or enamines with carbonyl com-

pounds or Michael acceptors containing a carbonyl group. The carboxylic acid group of pro-

line serves as a Brønsted acid and makes proline a bifunctional catalyst.

Outstanding results given by proline can be related to the ability of this molecule to form

a highly organized transition states, which are stabilized by hydrogen bondings. A drawback

of the proline catalytic role can be seen in the fact, that almost all the reaction intermediates

are part of a complex equilibrium, that leads to a low turnover number. This drawback can

be overcome by higher catalyst loading.

In a generalized enamine cycle, a carbonyl compound 25 is activated by the formation of

an enamine 26, which is then attacked by an electrophile forming an iminium ion 27. This

is then hydrolyzed, giving the product 28 and proline (4). The latter is entering into the cat-

alytic cycle again (Scheme 4).

Scheme 4

Aldol Condensation

The aldol condensation is one of the most important C-C bond formation reactions in

organic synthesis. The enantioselective aldol reaction catalyzed by chiral amines (Mannich

like reactions) and Lewis base catalyzed aldol reactions have attracted much interest.

First of these reactions was the amino-acid catalyzed Robinson annulation reaction

(Scheme 5). The reaction was shown to be catalyzed by many natural and unnatural amino-

acids.6 Nevertheless, best results were obtained with the natural amino-acids L-proline (5)

(most universal) and L-phenylalanine (7) (gives highest ee). Reactions proceed through the

formation of an enamine, which attacks subsequently a carbonyl carbon and forms a new C-

C bond. Moreover, the carbonyl group is locked and activated by hydrogen bond formation

with the hydrogen atom from the protonated proline unit as could be seen on intermediate

29 (Scheme 6). The only drawback lies in the need of using an equimolar amount of cata-

lyst.

Scheme 5

An intermolecular application of this kind of aldol reaction showed to be difficult and

just recently, L-proline was reported to catalyze the reaction of acetone and selected aldehy-

L-phenylalanine (7), 1 eq.

d-camphorsulfonic acid 0.5 eq.

O O

O

O

O

DMSO, 65°C, 6 d

79%, 91% ee

N

R1

R2

COOH

N

R1

R2

O

OY

X

H

N

R1

R2

O

O−

Y

X

H

+

Y

X

NH

COOH

R1

O

R2

X

YH

+H2O

-H2O

R1

R2

O

electrophile

4

27

28

26

25

Introduction 5

des, providing yields up to 97% and ees up to 96%. Best results were obtained with isobu-

tyraldehyde, aromatic aldehydes gave just modest yields and ees (Scheme 6).7, 8

Scheme 6

A drawback of this kinds of aldol reactions lies in the formation of side products by self-

condensation of acetone and aldehydes. Optimization of the reaction condition is therefore

essential.

Mannich Reaction

For a good enantioselectivity of a three component condensation reactions (e.g. Man-

nich) (Scheme 7),9 two main conditions must be fulfilled:

• Nucleophilic addition of the proline formed enamine must be faster to the imine (Man-

nich), than to the aldehyde.

• Imine formation of the aldehyde with the primary amine must be faster, than the compet-

itive aldol reaction between the aldehyde and the second carbonyl species.10 Depending

on reactants, that have to be used, this could be the main drawback of this reaction.

Scheme 7

αα-Amination11, 12

Substituted azodicarboxylates can react with reactive enamines, that are generated in situfrom aldehydes13 or ketones14 and a catalytic amount of chiral secondary amines, giving α-

hydrazino carbonyl compounds (Scheme 8). After the enamine reacts with the azodicar-

boxylate, it is hydrolyzed to the corresponding carbonyl compound and the chiral amine is

entering the catalytic cycle again. Unsymmerical ketones are giving the product of amina-

tion on the more substituted α-position. A rather high catalyst loading is necessary for high

N

H

ON

Me

X

H

i-Bu

H

O

NH

O

X

HO

Me

N

H

and/or

O

+ +H i-Bu

O

H

i-Bu

NH2

OMe

L-proline (4)

(0.35 eq.)

12-48 hH

O

i-Bu

NH

OMe

90%, 93% ee

O

+L-proline (4) (30 mol%)

N

O

OHHO

H

R R

OH O

CHOR

54-97%, 60-96% ee

29

DMSO/Acetone, r.t. 2-8 h

6 Introduction

yields in short reaction times and represents a common drawback of many proline-catalyzed

systems.

Scheme 8

αα-Aminooxylation of Aldehydes and Ketones

As mentioned above for the aldol reaction, a problem in reactions with aldehydes can be

caused by their high reactivity towards self-condensation. In a hydroxylation, this side reac-

tion can be minimized by the use of nitrosobenzene as an acceptor (Scheme 9). The high

reactivity of nitrosobenzene towards enamine attack leads to a significant decrease of the

undesired selfcondensation.

These reactions are extremely fast in comparison with the other proline catalyzed reac-

tions. Another interesting observation is, that the enamine intermediate attacks selectively

the oxygen atom of the nitroso compound, while nitroso-aldol reactions are proceeding

through a selective N-attack of the nitroso group.15,16

Scheme 9

The α-aminooxylation of cyclic and acyclic ketones proceeds in the same fashion as in

the case of aldehydes. Very good chemo-, regio- and enantioselectivities were achieved.

There is a danger of double aminooxylation of ketones, which are having two enol forms,

but the double attack can be circumvented by slow addition of the nitroso electrophile.

Asymmetric Conjugated Additions (Michael Addition)17, 18

Compared to aldol-type reactions, proline mediated 1,4-conjugated addition of different

enolizable carbonyl compounds to activated double bonds proceed only with a moderate

enantioselectivity.19 A higher enantioselectivity was reported by using (S)-2-(morpholi-

nomethyl)pyrrolidine (30) (Scheme 10).20, 21 The principle of the catalysis reamains the

same. A reactive enamine species is formed with the catalyst, which is subsequently attack-

ing the activated double bond.

N

O

+

DMSO, r.t., 10-20 min

Ph

H

O

H

O

ONH

Ph

L-proline (4), 20 mol%

H

O

OH

82%, 99% ee

NaBH4

EtOH

H

O

N

NEtOOC

COOEtH

N

HNCOOEt

COOEt

O

+

DCM, r.t., 45 min

L-proline (4), 50 mol%

93%, 92% ee

Introduction 7

Scheme 10

SN2 Alkylation

An intramolecular alkylation of iodoaldehydes catalyzed by proline derivatives was

described recently (Scheme 11).22

Scheme 11

Although the mechanism of the enantiodifferentiation step has not been yet fully clari-

fied, the selectivity of the most effective catalyst (S)-α-methylproline (8) was explained as

a result of a substitution, where the equillibrium is shifted toward the anti-form of the enam-

ine to minimize 1,3-allylic strain.

[4+2] Cycloadditions

Chiral amines like cinchona alkaloids, ephedrine and prolinol derivatives are known for

more than a decade to catalyze [4+2] cycloaddition reactions, but just moderate selectivities

have been achieved.23

Recently, it was reported, that hydrochloric salt of a secondary amine 31 efficiently cat-

alyzes a Diels-Alder reaction of cinnamaldehyde and cyclopentadiene. Activation and stere-

ochemical induction is performed through the formation of an iminium ion 32 (by which the

LUMO of the dienophile is lowered), that is subsequently reacting with the diene. Follow-

ing hydrolysis is giving the desired product (Scheme 12). The presence of water was shown

to accelerate the reaction rate, which is indicating, that the iminium ion has to be hydrolyzed

during the catalytic cycle. Despite the high enantioselectivity, the reaction is giving both

endo and exo products in ratio of 1:1.3.24

NH

COOHMe

NEt3(1 eq.), CHCl3

−30 °C, 24 h

IOHC

EtOOC

EtOOC

OHC

EtOOC

EtOOC

R = H; 80% yield, 68% eeR = Me; 92% yield, 95% ee

8, 10 mol%

NH

N

+

THF, r.t., 3 dH

O 30, 20 mol %

O

PhNO2

NO2

Ph

OHC

78%, syn/anti 92/8, eesyn 72%

8 Introduction

Scheme 12

[2+2] Cycloaddition Reactions

The asymmetric [2+2] cycloaddition reaction of ketenes and aldehydes, which gives β-

lactones, was shown to be catalyzed by cinchona alkaloids more than 20 years ago.25

Recently, the reaction was extended by using N-tosyl-imine ester 34 for the enantioselec-

tive preparation of β-lactams (Scheme 13).26

The cinchona derived catalysts 1 plays a double role in the reaction mechanism: It acts

as a dehydrohalogenating agent, that forms a ketene intermediate and as the chiral nucle-

ophilic species, that is forming the chiral environment around the enolate anion and controls

the stereochemistry of the formed product.

The reaction is driven by the presence of a non-nucleophilic organic base 33, that acts

as a proton sponge and regenerates the catalyst. By this regeneration, a salt is formed, which

by precipitating from the reaction mixture, moves the equilibrium further to the product

side.

Scheme 13

Morita-Baylis-Hillman Reaction27

The reaction between aldehydes and activated alkenes (the Morita-Baylis-Hillman reac-

tion), is typically catalyzed by tertiary amines (DABCO, quinuclidine, quinuclidinol) or ter-

tiary phosphines. The catalytic effect is based on the formation of an enolate (from the acti-

vated alkene), that is subsequently attacking the aldehyde, forming a new C-C bond. Cin-

chona based amines, such as 34 are acting the same way as tertiary amines, since they are

AcO

O

Cl

•O

AcO

H

Nu−

AcO

H

O−

Nu+

NMe2NMe2

33, 1 eq.

cinchona alkaloid 1, 10 mol%

NTs

HEtOOCN

OTs

EtOOC OAcH

PhMe, −78°C to 25°C, 5 h

61%, 98% eecis/trans 99/1

34

N

NH

O

Ph .HCl

Ph

O

H

MeOH/H2O, 23°C

N

N+

O

PhH

PhPh

CHO

CHO

Ph

99%, 93%ee

endo/exo 1/1.3

+31, 5 mol%

endo

exo32

Introduction 9

containing the quinuclidine moiety.28 First, the chiral enolate intermediate 35 is formed,

which is then attacking the aldehyde. The hydroxyl group of the isochinoline ring is stabi-

lizing the transition state by hydrogen bonding (Intermedite 36, Scheme 14).

Scheme 14

αα-Halogenation of Carbonyl Compounds

Ketenes derived from acyl halides are undergoing halogenation/esterification reactions in

the presence of halogenating agents such as 39.29 This reaction was shown to be catalyzed

by cinchona alkaloids such as 1. The catalytic effect is based on the chiral enolate interme-

diate between the catalyst 1 and the ketene 37. This chiral intermediate 38 is halogenated

and the catalyst is then substituted by transacylation, ready to act in another reaction cycle

(Scheme 15). Solid supported proton sponge was used in order to form the ketene.

Scheme 15

Ph

O

Cl

OPh

H

Nu (1)

Ph

H

O-

Nu+

O

Cl

Cl

Cl

Cl

ClCl

PhOC6Cl5

Cl

O

Cinchona alkaloid

1, 10 mol%

38

39

37

proton sponge

THF, −78°C, 3 h

80%, 99% ee

O

O

CF3

CF3

N

O

N

HOH

N

O

N+

H

OH

O

O−

CF3

CF3

35

N

O

N+

H

OH

O

O

CF3

CF3

H

R

H

-O

PhCHO

Ph O

OH O CF3

CF3

55%, 95% ee

34, 10 mol%

36

DMF, −55 °C, 48 h

10 Introduction

B. Asymmetric Synthesis with Carbene catalysts

Benzoin Condensation30

The benzoin condensation between two molecules of aldehyde, giving an aldol product

was shown to perform under catalysis with a chiral heteroazolium salts such as 40. The

bulky t-butyl group, close to the carbene center is responsible for high stereoselectivity

(Scheme 16).31

Scheme 16

Stetter Reaction

In similar manner, a triazolium salt 41 was employed in an intramolecular 1,4-addition

of aldehyde based nucleophile to a Michael system. The most efficient catalyst is bearing a

big indanoyl moiety, which should be responsible for enantiomeric induction (Scheme

17).32, 33

Scheme 17

C. Asymmetric Reactions with Ylide Intermediates: Formation of Three

Membered Rings

Sulfur of nitrogen ylides, derived from chiral dialkyl sulfides or trialkyl amines can be

used in asymmetric epoxidation,34 aziridation35 or cyclopropanation36 reactions. The reac-

tions proceed via the formation of an ylide from a chiral dialkylsulfide or trialkylamine and

subsequent reaction of this ylide with a carbonyl group (imino-group or double bond) and

the formation of a three membered epoxide ring, (aziridine or cyclopropane ring, respective-

ly). This is well demonstrated by the enantioselective aziridation of cinnamylidene-N-tosy-

lamine 42 with benzyl bromide, mediated by camphor derivated sulfide 4337, 38 (Scheme 18)

Me CHO

O COOEt

Me

O

O

COOEt

O N

N+N

OMe

BF4−

KHMDS (20 mol%), xylenes

25°C, 24 h

80%, 97% ee

41, 20 mol%

N

N+N

BF4−

t-BuOK (10 mol%), THF, 18 °C, 16 h

83%, 90% ee

O

2H

O O

OH

40, 10 mol%

Introduction 11

Scheme 18

D. Acyl Transfer Reactions: Desymmetrization and Kinetic Resolution39

The enantioselective acylation is probably one of the oldest known organocatalytic reac-

tions. It was already shown in the 1920’s40 and early 1930’s,41 that optically active alkaloids,

such as brucine or strychnine can induce enantiomeric enrichment either in the esterifica-

tion of meso carboxylic acids or in the acylation of secondary alcohols. Over the decades,

this method has developed into a useful synthetic tool.

The reaction principle is quite transparent: a nucleophilic chiral Lewis base forms a chi-

ral activation complex with the acylation agent, which adds to the alcohol. One enantiomer

is acylated faster which leads to an enanioenriched product. A problem may arise when, by

consuming one enantiomer, the reaction mixture is enriched by the other one. Higher con-

tentration of the opposite enantimer can lead into this unwanted reaction. For synthetically

useful enantioselectivities, the reaction rates have to be sufficiently different.

It is also possible to run two reactions of aproximatelly the same rate, but opposite enan-

tioselectivity in one pot, which leads to two different products from each of the enantiomers

(parallel kinetic resolution PKR) (Scheme 19).42

Scheme 19

Unfortunately, the factors that are involving the stereoselectivity of different catalysts are

much less explored.

1.3.1.2. Electrophilic Catalysis: Activation of the Acceptor

Lewis acid activation in organocatalytic systems is possible through the formation of and

iminium ion. By condensation of the carbonyl group with a secondary amine, an iminium

ion is formed, whose LUMO is having a lower energy (than the LUMO of the correspon-

ding unsaturated carbonyl compound) and therefore a higher reactivity towards an attack of

a nucleophile is observed. This type of activation can be utilized in a number of reactions

R1 R2

OH

kinetic resolution

parallel kinetic

resolution

R1 R2

OH

R1 R2

OCOR

+

R1 R2

OCOR'

R1 R2

OCOR''

+

PhN

Ts

Ph

Me Me

S

Me

pTol

OH

43, 10 mol%

K2CO3, CH3CN, r.t.

52%, eetrans93%, eecis87%

trans/cis = 74/26

Ph BrPh

N

H

Ts

+

42

12 Introduction

Introduction 13

such as cycloadditions, or alkylation reactions in the presence of electron rich aromatic rings

or stabilized carbanions of malonates or nitro compounds.

1,4-Addition

A conjugated addition to activated double bonds (Michael addition) was shown to be cat-

alyzed by cinchona alkaloids as well as L-proline under either homogeneous or biphasic

conditions. The low basicity of amines is indeed limiting the range of potential Michael

donors and acceptors.

An enantioselective addition of nitroalkanes to cyclic enones was shown to be efficient-

ly catalyzed by L-proline (4) in the presence of equimolar amount of trans-2,5-

dimethylpiperazine (44) as a base (Scheme 20).43

Scheme 20

The usage of different bases has shown, that the basicity and structure of the additive play

a major role in the stereodifferentiation step (nonlinear effects were observed). Although no

mechanistic model for this reaction has been developed so far, nonlinear dependency of the

ee of the product on the ee of the proline catalyst depending on the applied base indicates a

complex multicomponent chiral catalytic system.

1,4-Addition with Enolates or Enolate Equivalents

The 1,4-addition of silyl enol ether is very efficiently catalyzed by chiral imidazolidinone

salts such as 45 (Scheme 21). The imminium ion formed from the catalyst and the carbonyl

compound lowers the electron density of the conjugated double bond and makes it more

reactive towards the silylenolether.44

Scheme 21

Epoxidation

Asymmetric epoxidations and hydroxylations of alkenes are still mainly catalyzed by

metal catalysts (osmium based epoxidation), but organocatalytic methods are also emerging.

45, 20 mol%

DCM/H2O

−60°C, 22 h

+

NH

NO

Ph

84%, 99%eesyn/anti = 11/1

+

OMeTMSO O

H O

O

H

ODNBA

−

DNBA− = 2,4-dinitrobenzoate

O

OMe OMeO

O

NO2

+

CHCl3, r.t.

L-proline (4) (3-7 eq.)

O

NO2

88%, 93%eeHN

NH

44, 1 eq.

14 Introduction

The main idea is to generate a chiral oxidation agent from a co-oxidant (H2O

2, Oxone®) and

a chiral compound (based on chiral ketones45 iminium salts46 α-amidoketones47 or imines.48

Structures of the catalysts as well as the substrates have to be optimized to prevent com-

peting Baeyer-Villiger reactions of the ketone catalysts. Strong electron withdrawing groups

near the carbonyl group is the common structural element of these catalysts (Compounds

47-50, Scheme 22).

Scheme 22

A good example of practical use is the epoxidation of trans-olefine 51 catalyzed by fruc-

tose based ketone 52, which was used in synthesis of a key intermediate in the total synthe-

sis of (−)-glabrescol 53 (Scheme 23).49, 50

Scheme 23

Chiral oxidating agents can be used in another reactions, such as the oxidative desym-

metrization of vicinal diols,51 oxidation at benzylic positions52 or asymmetric oxidation of

sulfides to sulfoxides.53 Enantioselectivities of these reactions are still low and they require

further development.

1.3.2. Reactions via Noncovalent Activation Complexes

There is growing number of reactions, that are accelerated through weak Lewis

Acid/Lewis base interactions. Because of the weak origin of these interactions, rationaliza-

tion of the mechanism of this reactions is rather difficult and the current state of knowledge

HO

OH

OH

OH

HO

OHOH

O

OO

MeMe

OO

MeMe

O

O O

O OOH

2KHSO5.KHSO4.K2SO4

MeCN/(MeO)2CH2/H2O

0°C, 16 h

52, 10 mol%

51

53

66%

F

H

N

COOEt

O

O O

OO

MeMe

Me Me

O

BzO

O

O

O

O

O

48 49 50

O

OO

MeMe

NHO

O

47

O

of the key structural elements, that are affecting the stereoselectivity of the reactions is

rather poor.

A. Asymmetric Proton Catalysis

A proton is without a doubt the most common Lewis acid. It is forming a hydrogen bond,

which can be in principle divided into polar covalent (RX-H) and polar ionic (RX+H...Y-).

In the first case, the conjugate base carries the chiral information wheras in the second case,

the anion is achiral and the proton is complexed with a chiral substrate. Activation by hydro-

gen bonding represents a very effective and powerful method of noncovalent catalysis.

Catalytic Enantioselective Protonation54

The role of the chiral additives in a catalytic enantioselective protonation has not been

fully explained yet. Beside their primary role as a chiral proton sources, they can also act as

ligands for a metal (Scheme 25).55, 56 Crucial condition for the catalytic reaction is that the

deprotonated chiral proton source reacts with the achiral proton source faster, than the achi-

ral proton source with a metal enolate. Then the chiral proton source is protonating a metal

enolate and is regenerated by proton transfer from the achiral proton source (Scheme 24).

Scheme 24

Many chiral proton sources such as imides, amides, alcohols, aminoalcohols, phenols

and amines were developed. As achiral proton sources are most widely used moderately

acidic rigid and sterically hindered systems such as cyclic imides (phtalimide), nonactivat-

ed phenols, or moderately acidic carbonyl compounds such as phenylacetone. As prochiral

enolates, lithium of samarium enolates are most widely used. Even 1 mol% of a chiral pro-

ton source can lead to acceptable enantioselectivities. The enantioselectivity increases with

higher catalyst concentrations.57

Catalytic Enantioselective Deprotonation58

Most of the chiral Brønsted bases used in asymmetric synthesis are still metal-contain-

ing. Recently, metal-free superbases showed to be an alternative. For example modified

guanidines such as 55 were shown to efficiently catalyse the asymmetric Michael reaction

of a prochiral glycine derivative 54 with acrylates or its related compounds. The key step in

this reaction is stereoselective abstraction of the proton from the prochiral glycine deriva-

tive and generation of a chiral carbanion, which is then reacting with the acrylate. The reac-

R1

OM

R2

R3 A*-HR1

O

R2

R3

H

A*-M

A-H

A-M

A-H achiral proton source

A*-H chiral proton source

Introduction 15

tion proceeds with high enantioselectivity in various solvents, however with rather low

yields (around 5 %). Best yields were obtained by performing the reaction in THF (90% in

6 days) or neat (85% in 3 days)59 (Scheme 25).

Scheme 25

1,4-Addition to Activated Double Bond

Michael addition of malonates to nitroalkenes was shown to be efficiently catalyzed by

bifunctional thiourea-based catalyst60 (Scheme 26). The transfer of stereochemical informa-

tion is made by hydrogen-bonding of the nitrogen atom of the thiourea 56, while the terti-

ary amino group acts as a base in order to deprotonate the diethylmalonate. This is also sup-

ported by the fact, that the presence of the tertiary amino group is having a significant effect

on the reaction rate, but only a minor effect on the enantioselectivity.

Scheme 26

Aza-Henry Reaction

The thiourea-based catalyst 56 can also be used to catalyze the aza Henry reaction of

nitromethane with activated imines61 (Scheme 27). The thiourea and the tertiary amino

group are showing a synergistic effect in this reaction, but they have to be tethered.

NO2

HN

S

HN

CF3

F3C

NMe2

56, 10 mol %

toluene, r.t., 24 h

NO2

EtOOC COOEt

86%, 93% ee

COOEt

COOEt

+

2 eq.

COOEt

Ph

NPh COOtBu

N N

PhPh

NOH

Ph

55, 20 mol%

neat, 20°C, 3 d

Ph

NPh COOtBu

COOEt

85%, 97% ee

+

54 3.6 eq.

16 Introduction

Scheme 27

Reductive Amination of Ketones

Just recently, the simple achiral thiourea 57 was shown to be an effective catalyst in the

reductive amination of ketones.62 Ketimines, generated in situ from ketones and amines are

subsequently activated by thiourea (57), which is allowing the reduction by the Hantsch

ester 58, giving the corresponding amine (Scheme 28).

Scheme 28

[4+2] Addition

An interesting example of a hetero Diels-Alder reaction catalyzed via hydrogen bonding

activation was presented recently.63, 64 The reaction between an activated dienophile 59 and

benzaldehyde was catalyzed by the TADDOL 60, giving the intermediate 61 as a single

diastereomer (elucidated by NMR), which gave after the hydrolysis with acetyl chloride 2,3-

dihydro-2-phenylpyran-4-onepyran-en-on (62) in 98% ee (Scheme 29). Nevertheless, this

model system is the only example of hydrogen-bonding catalyzed hetero Diels-Alder reac-

tion reported up to date with such an excellent ee.

Scheme 29

TBSO

NMeMe

H

O

Ph

OH

OHO

O

ArAr

Ar Ar

60, 10 mol%

PhMe, −40 °C O

TBSO Ph

NMeMe

DCM/PhMe

−78 °C, 15 minO

PhO

+CH3COCl

61

62

>98% ee59

Ar = 1-naphtyl

H2N

S

NH2

57, 10 mol%

PhMe, MS 5A, 50 °C, 48 h

Ph Me

HNPMP

92%

+

Ph Me

O

NH

COOEtEtOOC

MeMe

58, 1.5 eq.

H2N PMP

CH3NO2

HN

S

HN

CF3

F3C

NMe2

56, 10 mol %

DCM, r.t, 24 hPh

NO2

HNP(O)Ph2

87%, 67% ee

N

Ph

Ph2(O)P+

10 eq.

Introduction 17

The chiral amidinium ions such as 64 can also form a host-guest complex with diketone

63 and activate the double bond for a Diels-Alder reaction. This was demonstrated in the

synthesis of (−)-norgestrel (67)65 (Scheme 30).

Scheme 30

An enantioselectivity in this reaction is achieved via the formation of a favourable host-

guest complex 66, which is leading to the optimal activation. Complex 65 is disfavoured,

because of the repulsion between the ethyl group of the diketone and the OH group of cat-

alyst. The rate acceleration of the reaction was observed even when the chiral amidinium

ion 64 was used in substoichiometric amount (0.25 eq.). Nevertheless, equimolar amounts

of the catalyst gave the best yields, however, the enantioselectivity of the reaction remained

low.

Hydrocyanation Reactions

Hydrocyanation reactions of carbonyl compounds were one of the first organocatalytic

reactions discovered. The first reactions were catalyzed by optically active alkaloids.66 Low

enantioselectivities of early systems were already significantly improved. Synthetically use-

ful enantioselectivities were obtained using cyclic dipeptides like 68 and 69 (Scheme 31).67

NH2 NH

OH

HO

O

Me

H

B(C6H3(CF3)2)4−

MeOO O

+

MeO

O

OH

H

H

6367

94%, 43% ee

64 (1 eq.)

O O

HH

NNHR

H

O

+

unfavourable host-guest complex

O O

HH

NNHR

H

O

+

favourable host-guest complex

DCM, −27 °C, 7 d

+

65 66

18 Introduction

Scheme 31

Acyclic peptides were postulated to be unsuitable for asymmetric catalysis, because of

their variable conformation and flexible structure. The mechanism of the hydrocyanation

reaction still remains confusing, especially because of the complex conditions, that are

required for obtaining good asymmetric induction.68

The organocatalytic Strecker reaction is the logical extension of hydrocyanation reaction

of carbonyl compounds.67 α−Amino-nitriles obtained by the Strecker reaction are useful

precursors for α−amino-acids. Dipeptides 68 and 69 used in the Strecker reaction gave

interesting results. While 68, giving a good asymmetric induction in the cyanohydrin reac-

tion, it did not give any ee in the Strecker reaction.

However, a slight modification by replacing the imidazole unit by a guanidine unit led to

efficient enantioselectivity.69 Although aldimines derived from benzaldehyde were provid-

ing α−amino-nitriles with high enantionselectivities, a low enantioselectivity was observed

on more simple aldimines, derived from simple aliphatic or heterocyclic aldehydes.

Insight view to the efficiency of the guanidine based dipeptide can be given by analogy

with the structurally related bicyclic guanidine complex 16, which is efficiently catalyzing

the addition of HCN to achiral N-benzhydridylimines. The activation of the imine is per-

formed by hydrogen bonding from the guanidium cyanide complex (Scheme 32).69

Scheme 32

N

N NHN

Ph

Ph

N

N N

H H

C-

N Ph

Ph

HCN, PhMe, 40°C, 20 h

HN

Ph

Ph

CN

H

96%, 86% ee

16, 10 mol%

70

HN

NH

O

O

N

HN

HN

NH

O

O

HN NH2

NH

68 69

Introduction 19

Trifluoromethylation of Ketones

Chiral quarternary ammonium fluorides such as 71 were discovered to efficiently cat-

alyze nucleophilic addition reactions to carbonyl groups, such as the Mukaiyama aldol reac-

tion,70 the nitroaldol reaction of silyl nitronates71 or the trifluoromethylation of ketones72

(Scheme 33). The reactions usually proceed with excellent yields and moderate to high

enantioselectivities.

Scheme 33

Catalytic Enantioselective Reactions Driven by Photoinduced Electron Transfer73

Photoinduced electron transfer (PET) is an essential step in converting solar energy into

a chemical energy. In a photochemical conjugated addition of α-aminoalkyl radicals to

enones, chiral PET catalyst 24 serves as an antenna, collecting the photons and transferring

the energy to the substrate, generating the radicals, that are undergoing the cyclization giv-

ing the spirocompound 72. Even though the exact mechanism of the reaction is not under-

stood yet, it is supposed, that the PET catalyst is approaching the substrate and locking its

position through hydrogen bonding. The radical cyclization procceds then selectively from

just one side, resulting in the enantioenriched product.

Scheme 34

B. Activation by Lewis Acids

Despite a wide use of metal based Lewis acids in synthesis,74 there are just a few exam-

ples utilizing chiral metal free Lewis acids as catalysts. The activation is achieved via inter-

action of the Lewis acidic moiety of the catalyst with the electron rich part of the molecule

of the reactant (e. g. carbonyl group or imine).

72

64%, 70% ee

NH

O

N

NH

O

N

O

NH

O

N

O24, 30 mol%

hv, −60 °C, PhMe, 1 h

N

HO

N+

Nph

OMe

OAc

OMe

CF3TMS

DCM, −78°C

OMe

OAc

OTMSMe

F3C

F−

92% ee

71

20 Introduction

[4+2] Cycloaddition Reaction

Chiral silicon cation 22 was shown to be a very active catalyst in the Diels-Alder reac-

tion between acryloyl oxazolidinone 73 and cyclohexadiene75 (Scheme 35)

Scheme 35

Despite the high yield, only a poor enantiomeric excess of the product was observed. The

structure of the reactive species is assumed to be a five-coordinated silicon atom with two

molecules of acetonitrile.76

The silicon cation 22 was also shown to catalyze an aza Diels-Alder reaction between

Danishefsky’s diene and N-benzylidene-2-methoxyaniline, but without any enantiomeric

induction. (Scheme 36)

Scheme 36

A silicon based Lewis acid derived from (−)-myrtenal 76 was shown to efficiently cat-

alyze the Diels-Alder reaction between methylacrylate and cyclopentadiene (Scheme 37).

The obtained ee of 54% is the highest reported up to date for a chiral silicon Lewis acid.77

Scheme 37

Mukaiyama Aldol Reaction

A Mukaiyama Aldol reaction was found to be catalyzed by a chiral triarylmethyl cation

23. This is one of the rare examples of catalysis with a chiral metal-free Lewis acid based

+PhMe, −78 °C, 90 min

84%, 54%ee

MeO

SiNTf2

76, 10 mol%

O

OMe

COOMe

OMe

TMSO

N

N

O Ph

+

MeO

MeO

22, 10 mol%

CD3CN, −40 °C, 2 h

Ph

74%, 0%ee

22, 10 mol%

MeCN, −40 °C, 1 h

95%, 10% ee

ON

O

OON

OO

+

Si+

Me

B(C6F5)−

73

Introduction 21

on a carbocation. The reaction proceeded either with high yields (up to 99%) and with low

enantioselectivity (around 11% ee) or with low yields and moderate enantioselectivity (38%

ee) (Scheme 38).78

Scheme 38

C. Activation of Lewis Acids by Lewis Bases79, 80

The concept of activation of Lewis acids with Lewis bases may seem illogical according

to the general chemical intuition, which would expect averaged rather than polarized elec-

tron density of the molecule. There are nevertheless well defined conditions, under which

charge separation may take place and lead to a decrease of electron density on the central

atom, causing an increase in its Lewis acidity. The main idea is, that the electron donation

supplied by the Lewis base is causing ionization of the ligands on the Lewis acidic center,

which, once ionizied, are decreasing the electron density on the central atom, thus causing

an increase of Lewis acidity on the central atom.

This type of activation is employed in the reactions of silicon halides in the presence of

a catalytic amount of a chiral Lewis base, such as chiral HMPA analogues, pyridine N-

oxides, trialkylamines or sulfoxides. A weak Lewis acid (silicon atom), coordinated to these

bases, gives the hypervalent silyl cation, that is acting a a strong Lewis acid in a chiral envi-

roment. This type of activation provides high reaction rates and an excellent transfer of a

chiral information because of the tight transition state structure. It should be pointed out,

that the strong Lewis acid is generated from the silicon atom by the Lewis base. Therefore

this type of activation is limited to the reactions involving organosilicon compounds.

Scheme 39

Allylation Reactions

A wide range of metal free chiral Lewis bases have been used as catalysts in the enan-

tioselective allylation of aldehydes. The idea is based on the observation, that HMPA is

D AL

L

L

Lewis base

X X

X

+

Lewis acid

D A

X

L

X

L

L

X

σ− σ+

D A

LL

L

X

σ− σ+ X

X−

+

increased

positive

charge

increased

negative

charge

C+

EtEt

Ar ClO4−

23, 10 mol%OTBS

OEt

O

H +OEt

OH O

40%, 38% ee

1. DCM, −78°C, 3 h

2. HF/DCM

22 Introduction

accelerating the addition reaction of allylsilanes to aldehydes. Therefore an attempt to use

chiral analogues of HMPA was made.81 The asymmetric induction is performed, when a sil-

icon compound forms a chiral complex with the HMPA analog. The allyl transfer proceeds

through a well defined transition state (77, Scheme 40). There is the possibility to obtain antior syn addition products by using E or Z allyl silanes respectively. This is an advantage com-

paring to the Lewis acid metal-catalyzed allylations, that give syn homoallylic alcohols from

either stereoisomer of crotyltrialkylsilanes and stannanes.82 The reaction proceeds well with

aromatic aldehydes, but aliphatic aldehydes fail to give any products.

Scheme 40

Aldol Reaction83, 84

Another variation of the enantioselective aldol reaction is the Lewis base catalyzed addi-

tion of trichlorsilyl enolates to aldehydes.85-88 As the Lewis base catalyst, chiral HMPA ana-

logues such as 78 are used. The activation and a chiral information transfer is provided by

the formation of a tightly bound chiral complex between the HMPA analogue and silicon

compounds (79) (Scheme 41) in the same manner as in the case of the allylation reaction.

The reaction is giving almost exclusively anti product.

Scheme 41

DCM, −78 °C, 2 h

OSiCl3

Si

Cl

OCl

O

ClO

P* NR2

NR2

R2N

Naph

O OH

94%, 95% ee

+78

79

NP

N

PhPh

CHO O N

(iPr2EtN)

−78 °C, DCM, 6 h

Si

Cl

OCl

Nu*

ClO

R1

Ph+

R2

SiCl3R1

R2

OH

R2

R1

CHO

Nu*= N+

N+

MeMe

O−

O−

52-85%, 49-88%ee

77

17

Introduction 23

Hydrocyanation of Imines

An asymmetric Strecker reaction was shown to be promoted by an axially chiral biquino-

line N,N’-dioxide 1789. The proposed transition state model is assuming the formation of a

hypervalent silicon center through coordination of a catalyst to TMSCN (80). The hexaco-

ordination at the silicon atom results in higher nucleophilicity of the cyano group, which is

attacking the carbon atom of aldimine while a nitrogen atom of the aldimine coordinates to

the silicon center (Scheme 42). Enantioselectivities of the reaction change, depending on the

substitution of the aromatic ring of the aldimine.

Scheme 42

Nucleophillic Ring Opening of Epoxides

The enantioselective ring opening of epoxides is an important method for the preparation

of chiral alcohols. It has been shown, that metal free phosphorus based Lewis bases such as

81 are mediating this reaction with very good yields and enantioselectivities.90 The activa-

tion is in this case also done through a hypervalent silicon atom, that is mediating the con-

tact between chiral Lewis base and the oxygen atom of the oxirane ring (82, Scheme 43).

Scheme 43

Asymmetric Catalytic Reduction

The asymmetric catalytic reduction of ketones to chiral alcohols, using hypervalent sili-

con hydrides91 stays on the border line of metal free catalysis, because the presence of alkox-

ide anions is required for the reaction. However, the metal center does not participate in the

reaction mechanism, so the reaction is per definition organocatalytic.

SiCl4 (1.1 eq.) DCM, −78 °C, 3 hPh

PhO

+

NP

NHPh

OOMe

Si

ClClCl

Cl−

Ph

Ph

O

Ph

PhOH

Cl

94%, 87% ee

81, 10 mol %

82

N

N

P

N

O

N+

N+

MeMe

O−

O−

17, 1 eq.N

Ph

Ph

H TMSCN, 1.5 eq.

DCM, 0 °C, 4 d

N+

N+

Me

Me

O−

O−

Si+

Me

MeMe

NC−

N

CHPh2H

HN

Ph

Ph

CNH

96%, 95% ee

Cl

Cl

Cl

80

24 Introduction

In the reaction, the chiral complex 83, that is formed from a trialkoxysilane and a chiral

nucleophile (alkoxide), is added to the ketone molecule, forming the intermediate 84. The

stereospecific hydrogen transfer and subsequent hydrolysis of the silyl protected alcohol 85

leads to the phenyl-methyl-methanol (86) and to the release of the alkoxide molecule, which

is reentering the catalytic cycle (Scheme 44).

Scheme 44

1.3.3. Enantioselective Phase Transfer Reactions92

Phase-transfer catalysis (PTC) represents an attractive alternative for organic reactions in

which charged intermediates are involved. The reactions are usually carried out in a bi- or

tri-phasic system, most often in a vigorously stirred aqueous/apolar solvent mixture.

Cinchona Alkaloids Phase-Transfer Catalysts

Cinchona alkaloids derivatives were the first efficient phase transfer catalyst for the

asymmetric phase-transfer catalysis93 and they still remain the largest class of asymmetric

phase transfer catalysts. Despite a broad application of this type of compounds, neither the

electronic, nor steric factors that are affecting enantioselectivity are known. The formation

of a diastereotopic ion pairs is assumed. Many reactions were performed under phase trans-

fer conditions using cinchona alkaloids, e. g. the asymmetric deuteration,94 alkylation,95

Darzen reaction96 Michael reaction97 etc.

A practical use of a cinchona catalyst 87 was demonstrated in the phase transfer alkyla-

tion in the total synthesis of belactosin A (88), a potential antitumor agent (Scheme 45).98

(RO)3SiH

OH

O−

Si

RO

*RO

H OR

OR

Me

O

Me

O

Si

H OR

OR

OR*OR

−

Me

O

Si

H OR

OR

OR*OR

−

*

H

Me

OH

H

−OR* +

8384

8586

Introduction 25

Scheme 45

C2 Symmetric Phase Transfer Catalysts

Significant amount of work has been devoted towards developing of ammonium cata-

lysts from either natural compounds (tartaric acid) or purely synthetic compound such as

1,1’-(2,2’-binaphtol). Among these, N-spiro biaryl catalysts 89 and 90 got most attention99-

105 (Scheme 46), because of their remarkable selectivity and reactivity in a variety of reac-

tions, e. g. asymmetric alkylation (Scheme 47) or Michael reaction.106

Scheme 46

Scheme 47

O

COOtBu

O

COOtBu

Ph

94%, 89% ee

Ph Br

1.2 eq.

+

89a, 1 mol%

50% aq. KOH/PhMe

0 °C, 10 min.

Ar

Ar

N+

Br−

N+

Br−

Ar

Ar

Ar

Ar

Ar

Ar

Ar

Ar

89 90

Ar=

CF3

CF3

a

F

F

b c

F

N+

H

O

N

Br−

Ph

Ph N CO2tBu

INBoc2

+87, 20 mol%

Ph

Ph N

CO2tBu

NBoc2

87

O

HN

CO2H

HN

O

OO

Me

Me

H2N

88

CsOH.H2O (10 eq.)

PhMe/DCM (1/1), −40 °C, 48 h66%, 94% de

H

26 Introduction

Introduction 27

1.4. Summary

Organocatalysis is a new higly attractive research field. It develops and employs simple

metal-free compounds that are capable to efficiently catalyze chemical reactions.

Organocatalysts are principally divided into four clases:

• Catalysts activating by forming covalent activation complexes

• Catalysts activating by forming noncovalent activation complexes

• Phase transfer catalysts

• Molecular cavity activating catalysts

The fist class is dominated by L-proline (4) and MacMillan catalysts (e. g. 45), which are

activating a broad range of reactions, activating a carbonyl group by forming an

imine/enamine intermediates. This class is the largest one up to date. High catalyst loadings

are the most common problem by this class of catalysts.

The second class includes hydroden bond activators (pseudo Lewis acids), which are an

emerging type of activators. These are mainly based on chiral derivatives of thiourea,60 but

examples using chiral alcohols63, 64 or amidinium salts65 are also known. Another type of

activators in this class are metal free Lewis acids. This group is rather small, compared to

the others and not very extensively studied. Metal free Lewis acids are based on silicon

cations or triarylmethyl cation. The last type of activators in this class are metal-free Lewis

bases. Their way of activation consist in an interaction with a weak Lewis acid, that has to

be present in the molecule of the substrate or in the reagent and in forming a strong Lewis

acid, which is then acting as an activator. Due to the way of the activation, use of Lewis base

activators is limited to the reactions involving organosilicon compounds.

Phase transfer catalysts are mainly based on cinchona alkaloids or chiral N-spiro biaryl

quarternary amonium salts. The later is showing remarkable selectivity and reactivity in a

variety of reactions.

The class of molecular cavity activating catalysts includes mainly enzymes or complex

polymers and it is out of the scope of this introduction.

Despite of the good results achived by some of the organocatalysts, organocatalysis is

having potential drawbacks. Organocatalytic reactions are often caried out in dilute solu-

tions and they are not easy to be converted to industrial processes. High catalyst loadings

are also making the separation of the catalyst and the product difficult. There is also a need

of protection and deprotection of functional groups, so that the substrate is applicable to the

organocatalytis reaction. The chemistry to re move the protecting group sometimes making

the whole process impossible to be carried out on a large scale.

Even the organocatalytic systems are still not that sophisticated as the systems catalyzed

by transition-metal complexes, improvement is just the matter of development. While

metal-containing catalytic system were extensively developed over decades by many com-

panies and research groups, organocatalysis is just standing at the begining of its golden age.

It should be pointed out, that the organocatalysis or not going to be a replacement of the

metal catalysis, but it is going to be an expansion of the toolbox of the synthetic chemistry.

28 Introduction

Results and Discussion 29

2. Results and Discussion

Aim of the Work

The aim of this work is the development of novel metal free Lewis acids and pseudo

Lewis acids and the demonstration of their capability of catalyzing various organic reac-

tions. In addition some the new compounds should be investigated as ligands in metal cat-

alyzed reactions.

The Lewis acids are based on imidazolinium salts and N,N or N,O silacyles. Pseudo

Lewis acids are derived from thiourea. The emphasis on the development of an effective

synthetic route to these catalysts is also given.

2.1. Preparation of the Catalysts

2.1.1. Imidazolinium Salts as Novel Organocatalyst

Imidazolinium salts are organic salts, formally derived from a five membered imidazoli-

dine heterocycle. The positive charge at the C-2 atom is delocalized among the carbon and

the two neighbouring nitrogen atoms. Therefore, it is possible to write three mesomeric

structures.

Scheme 48

Imidazolinium salts are possesing a Lewis acidity, which makes it possible to use them

as a Lewis acids for a broad spectrum of organic reactions. Imidazolinium salts with a

hydrogen atom on the C-2 position, can be also used as hererocyclic carbene precursors.

A closer look at the imidazolinium unit shows, that there are five available positions that

can be functionalized and the properties of the imidazolinium unit might be affected.

With different substituents at the C-2, N-1 and N-3 atoms, it is possible to tune the pos-

sitive charge, by employing different electron withdrawing/donating groups. All of the five

positions might be used for introducing chirality to the molecule and affect the stereochem-

ical environment around the center of Lewis acidity.

2.1.1.1. Synthetic Approach to Imidazilinium Salts

There are three main synthetic routes to imidazolinium salts (91, Scheme 49). Each of

them has its advantages and drawbacks:

N N+

R1

R3

R2

R5

R4

+N+

N R1

R3

R2

R5

R4

91

N N R1

R3

R2

R5

R4

30 Results and Discussion

• Oxidation of a five membered aminals.107, 108

• Alkylation of imidazolines.109

• Direct reaction of diamines and orthoesters in presence of an acid.110-112

Scheme 49

A. Oxidation of Five Membered Aminals.

The oxidation of an aminal with N-bromosuccinimide (NBS) or N-bromoacetamide

(NBA) proceeds smoothly at room temperature and represents a convenient method for the

preparation of the salt. Difficulties in the preparation of the aminals, which are usually made

from diamines and aldehydes, migth be the only drawback of this method.

B. Alkylation of Imidazolines

Imidazolines represent a large group of nitrogen containing heterocycles and are conven-

ient precursors, because of their rather easy availibility. An alkylation of imidazoline gives

directly imidazolinium salt. A problem of this method lies in rather harsh conditions that

have to be sometimes used (e. g. high temperature and pressure) and side reactions that

might occur. 113

C. Direct Reaction of Diamines and Orthoesters in the Presence of a

Counter Anion Source

This method is convenient, because it gives the imidazolidinium salts from the diamines

in one step. It is a straight forward approach to the salts bearing a methyl group or a hydro-

gen substituent at the C-2 atom. Feasibility of this reaction depends strongly on the stereo-

chemical environment at the nitrogen atoms of the diamine. The reactions with triethy-

lorthoformate proceed smoothly even with very hindered diamines, while the reactions with

triethyl orthoacetate are giving the desired products just in cases, where no bulky sub-

stituents at the nitrogen atoms are present. Substituted orthoesters are often not commercial-

ly available and have to be prepared, which is another drawback of this method.

N+

N R1

R3

R2

R5

R4

N N R1

R3

R2

R5

R4

A. NBA/DME, r.t.

NH HN R1

R3

R5

R4

C. R2C(EtO)3, NH4X

120 °CN N R

1

R2

R5

R4

B. R3X

X−

91


2.1.1.2. Schematic Plan of the Synthesis

Scheme 50 shows a schematic plan of the synthesis of the imidazolinium salts.

Scheme 50

Non C2 symmetric diamines can be prepared from amino-acids via the amides. The C2symmetric diamines are accessible over a direct alkylation of amines by dibromoethane,

reduction of the imines, or addition of Grignard reagents to the imines. Subsequently, the

diamines can be converted to the imidazolinium salts via direct reaction with orthoesters, or

over the imidazolidine 91a, which is converted to the salt 91 by oxidation with NBA.

HN OH

OR4

Boc

1. NMM, i-BuOCOCl

R1-NH2

HN HN

OR4

Boc

R1

1. HCl/MeOH

2. NaOHH2N HN

OR4

R1

DCM, 0°C

O

O

O

H

NHHN

OR4

R1

OHC

LAH/THF

NHHN

R4

R1

LAH/THF

H2N HN

R4

R1

MeN

R4

N

R2

R2

NH

OEt

HCl

EtOH

reflux, 2h

R1

Ph

N N

PhPh

NH HN

Ph

R RRMgCl/Et2O

or

NaBH4/MeOH

R1X

R1

HNNHR1 R

1H2N

BrBr

neat, 100 °C, 10 h

N N+

R1

R1

R2

R5

R4

X−

R2C(OEt)3, NH4X

120 °C, 3 h

R2C(OEt)3, NH4X

120 °C, 3 h

N N R1

R3

R2

R4

R5

NBA, DME

r.t. 45 min.

R2CHO

neat, 120 °C

R2CHO

neat, 120 °C

NH HN MeMe

R5

R4

H2N NH2

R5

R4

1. CH3COCHO, 0 °C, DCM

2. LAH/THF

91

R2CHO

neat, 120 °C

R2C(OEt)3, NH4X

120 °C, 3 h

91a


2.1.1.3. Preparation of the Precursors

2.1.1.3.1. Preparation of Diamines

The synthesis of a broad variety of different secondary diamines bearing various chiral

groups is a crucial task for the preparation of imidazolinium salts, because these compounds

are serving as direct precursors for the preparation of imidazolines or imidazolidines. From

these, the salts are directly prepared. Many aspects had to be considered before the prepara-

tion of the diamine, because functional groups on the diamines and especially stereochem-

ical environment are the basis for the final imidazolinium salt.

Preparation of C2 Symmetric Diamines.

Achiral C2 symmetric diamines were obtained from commercial sources or prepared viareduction of the corresponding imines by NaBH

4/MeOH.

The chiral C2 symmetric diamine 93 was prepared by the reduction of imine 92 by

NaBH4/MeOH,114 dimines 94 and 95, by the stereoselective addition of Grignard reagents

to imine 92115 - 117(Scheme 51).

Scheme 51

Diamines 96 and 97 were obtained by monomethylation of the enantiopure diamines

96a118 and 97a,119 using a formylation/reduction sequence120 (Scheme 52).

Scheme 52

Diamines, bearing OH groups were prepared by simple alkylation of the corresponding

aminoalcohol with 1,2-dibromoethane. Some of the compounds were prepared for the first

time. There is always a danger of obtaining polyalkylated products, when using simple alkyl

halides, however, in this case, the reaction stops at the monoalkylated product giving the

HBr salt of the corresponding diamine, which is precipitating as a solid from the reaction

mixture. The HBr salt is dissolved in water, washed from impurities by CHCl3

and careful

basification of the water phase gave the corresponding free diamino diol in high purity. The

purification of these compounds by chromatography was found difficult because of their

NH2H2N

RR

DCM, 0°C

HNNH

RR

reflux, 16 h

LAH, THFHNNH

RR

Me MeCHOOHC

O

O

O

resolution

96, R=Ph

97, R=−CH2(CH2)2CH2−

Ph

N N

PhPh

NH HN

Ph

R R

92

NaBH4/MeOH

or

RMgCl/Et2O

93, R=H

94, R=Ph

95, R=t-Bu


strong affinity to stationary the phases (SiO2, Al

2O

3, reverse phase). Results of the alkyla-

tion reaction are summarized in Table 1.

Scheme 53

Table 1: Alkylation of Amines

The reaction procceded well with both enantiomers of norephedrine (100) giving the

product 104 in 79% yield (Table 1, Entry 1), which represents a slight improvement over the

literature procedure.121L-Valinol (101) and L-t-leucinol (102) gave the corresponding

diaminodiols 105 and 106 in 77% and 91% yield, respectively (Table 1, Entries 2 and 3).

Finally, when the reaction was performed with the aminodiol 103, diaminotetraol 107 was

obtained in 75% yield (Table 1, Entry 4).

Preparation of Chiral Diamines from Amino-Acids

Methods for the preparation of C2 symmetric diamines as described above are well estab-

lished. Nevertheless, they do not allow a convenient functionalization at different positions

of the diamines. One of the alternatives for the preparation of chiral, non-C2 symmetric 1,2-

diamines is via the formation of an amide,122 using comercially available N-Boc-amino-

acids and amines. The synthesis route is described in Scheme 54.

Entry Amine Diamine Yield (%)

1NH2

Ph

HO

100

NH HN

HO

Ph

OH

Ph

104

79

2OHH2N

101

NH HN

HOOH 105

77

3OHH2N

102

NH HN

HOOH 106

91

4OH

HO

Ph

NH2

103

NH HN

HO

Ph

OH

Ph

HOOH

107

75

R1

NH HN R1R

1NH2 Br

Br

1. neat, 120°C, 10 h

2. NaOH+


Scheme 54

Preparation of Amides

Naturally ocurring amino-acids are cheap and readily available from the chiral pool.They can be employed as starting material for the preparation of chiral diamines. For the

preparation of an amide, the amino group of the amino-acid has to be protected (BOC, Pht)

in order to prevent self-condensation. Since the hydroxyl group is not a good leaving group,

it must be converted to a better leaving group (e. g. acyl chloride, ester, anhydride). From

the broad range of possibilites,122 the method involving i-butyl chloroformate was applied.123

This reaction proceeds via an anhydride 108 as shown on Scheme 55.

The N-Boc-protected amino-acid is deprotonated by N-methylmorpholine. The formed

salt is reacting with i-butyl chloroformate to give a mixed anhydride 108, which is further

reacting with an amine, giving the desired amide. Amides from different amino-acids and

amines were obtained in good to excellent yields and high purity.

As amino-acids, BOC-L-valin (109), BOC-L-phenylalanine (110) and BOC-L-proline

(111) were used. Various mono and diamines were employed to obtain a broad range of dif-

ferent N-Boc-amino-amides. The results are summarized in Table 2.

Scheme 55

1. N-methyl morpholine

HN O

OR4

Boc

2. i-BuOCOCl

3. R1-NH2

HN HN

OR4

Boc

3. R1-NH2

NMM

H

HN O−

OR4

Boc HNMM+

Cl

O

OiBu HN O

OR4

Boc

O

OiBu

H2N1-R .3 NH2

108

HN OH

OR4

Boc

1. NMM, i-BuOCOCl

2. R1-NH2

HN HN

OR4

Boc

R1

1. HCl/MeOH

2. NaOHH2N HN

OR4

R1

DCM

O

O

O

H

NHHN

OR4

R1

OHC

LAH/THF

NHHN

R4

R1

LAH/THF

H2N HN

R4

R1

Me


Scheme 56

It is possible to conclude from the obtained yields, that the reaction proceeded smoothly

with simple aromatic amines (Table 2, Entries 1, 10), benzylic amines (Table 2, Entries 5,

11, 12) and amines bearing hydroxy groups (Table 2, Entries 4, 7, 13). The reaction worked

well even with sterically hindered amines 113 and 114 (Table 2, Entries 2, 3).

When a solution of MeNH2

in absolute EtOH was used in order to maintain the water free

conditions, no expected product was obtained. Therefore, a solution of the mixed anhydride

was quenched by the addition of 40% aq. solution of MeNH2, giving the expected (S)-tert-

butyl 3-methyl-1-(methylamino)-1-oxobutan-2-ylcarbamate (126) in an excellent yield of

96% (Table 2, Entry 9).

Table 2: Preparation of Amides

a2 eq. of N-Boc-L-Valin were used

Also a bis-amide was obtained by the reaction of o-phenylendiamine (115) and 2 eq. of

the BOC-L-valin (108) in an excellent yield of 99% (Table 2, Entry 6).

Entry N-BOC-Amino-acid Amine Amine Amide Yield (%)

1

HN OH

O

Boc

109

Aniline 112 119 86

2 2-t-Butylaniline 113 120 77

3 2-Amino-biphenyl 114 121 95

4 (−)-Norephedrine 100 122 87

5 (R)-(+)-Phenylethylamine 115 123 99

6a o-Pnenylendiamine 116 124 99

7 L-Valinol 101 125 87

8 MeNH2

(in EtOH) 117 126 0

9 MeNH2

(40% in H2O) 118 126 96

10

HN OH

O

Boc

Ph

110

Aniline 112 127 99

11 (R)-(+)-Phenylethylamine 115 128 96

12

OH

O

N

Boc

111

(R)-(+)-Phenylethylamine 115 129 91

13 (−)-Norephedrine 100 130 96


HN OH

OR4

Boc

2. i-BuOCOCl

3. R1-NH2

HN HN

OR4

Boc

R1


BOC-Deprotection

For obtaining the free amino-amides, the t-butoxycarbonyl group (BOC) had to be

removed. This was possible in most cases by the treatment of a solution of BOC-amide with

a 30% TFA/DCM solution (Method A) (Scheme 57).

Scheme 57

Insufficient results were obtained in the case of proline derivatives 129 and 130, which

were found to be stable in the TFA solution. Therefore HCl in Et2O (Method B) had to be

used to obtain the free amino-amide in form of the hydrochloric salt. Alternatively, a 2M

solution of HCl in abs. MeOH (Method C) was used to remove the t-butoxycarbonyl group.

Method C had also the advantage over Method A, that the excess of the HCl could be

removed by destillation, while TFA had to be neutralized.

Yields for the deprotection are shown in Table 3.

Table 3: BOC deprotection

Method A: TFA/DCM; Method B: HCl/Et2O; Method C: HCl/MeOH

Reduction of αα-Amino−−Amides

α−Amino−amides obtained by the deprotection were reduced to diamines by LAH in

THF.

Entry N-Boc-Amide R4 R1 Amino-amide Method Yield (%)

1 119 i-Pr Ph 131 A 99

2 120 i-Pr 2-t-Butyl-Ph 132 A 98

3 121 i-Pr 2-Biphenyl 133 B 55

4 123 i-Pr (R)-(+)-Methylbenzyl 135 C 94

5 124 i-Pr 2-Phenylamide 136 A 98

6 124 i-Pr 2-i-Propylethanol 137 C 68

7 126 i-Pr Me 138 C 92

8 127 Bn Ph 139 A 87

9 128 Bn (R)-(+)-Methylbenzyl 140 A 85

10 129 -(CH2)3- (R)-(+)-Methylbenzyl 141 B 74

11 130 -(CH2)3- (−)-Norephedrine 142 B 83

H2N HN

OR4

R1

HN HN

OR4

R1

Boc

1. Method A.-C

2. NaOH

A. 35% TFA/DCM

B. HCl/Et2O

C. HCl/MeOH


Scheme 58

2 eq. of LAH per 1 eq. of amide were shown to be sufficient for the successful reduction

of amides to amines.124 The reaction mixture was refluxed for 16 h. The standard workup

procedure gave in most cases amines in good to excellent yields in high purity. However,

there were also exceptions (Table 4).

Amide 134, derived from L-valine and (R)-(+)-phenylethylamine could not be reduced at

the standard conditions. Only traces of the diamine were detected in the reaction mixture

after 48 h at reflux (Table 4, Entry 2). Also amide 142 derived from L-proline and (−)-

norephedrine failed to give any product. Starting material was completely regenerated

(Table 4, Entry 6). In these cases, stronger reducing agents might be an alternative.

Table 4: Reduction of Amides

areaction time 48 h

Formylation/Reduction

A monomethylation of amino groups of aminoamide is not always trivial.125 An alkyla-

tion by the standard methods is giving often the pokyalkylated products due to the fact, that

the formed secondary amine is more nucleophilic than the starting material and is undergo-

ing further alkylation. The reductive amination can be used just in cases, where it is possi-

ble to isolate the imine species, which is not usually possible by N-methylene amines.

Successful results can be obtained, when an amino group is formylated (Scheme 59) and

the formyl group subsequenty reduced by LAH/THF.120 For the formylation of the amino-

amides, acetic-formic anhydride was used. The results are summarized in Table 5.

Scheme 59

DCM, 0 °C, 3 hH2N HN

OR4

R1

O

OO

NHHN

OR4

R1

OHC

Entry Amino-amide R4 R3 Diamine Yield (%)

1 132 i-Pr 2-t-Butyl-phenyl 143 85

2a 134 i-Pr (R)-(+)-Methylbenzyl 144 traces

3 139 Bn Phenyl 145 91

4 140 Bn (R)-(+)-Methylbenzyl 146 99

5 141 -(CH2)3- (R)-(+)-Methylbenzyl 147 91

6a 142 -(CH2)3- (−)-Norephedrine 148 0

LAHH2N HN

R4

R1

H2N HN

OR4

R1

THF, reflux, 16 h


Table 5: Formylation of Amino-Amides

The formylation was performed with some selected amino-amides, giving the correspon-

ding formamides in excellent yields and purity. Optionally, the formamides could be puri-

fied by crystallization from MeOH.

Both the formyl and amide group were then reduced by LAH in THF (Scheme 60), in

order to obtain the corresponding secondary diamines. The reaction gave the products in

high yields and good purity. (Table 6)

Scheme 60

Table 6: Reduction of N-Formyl Amides

The reduction of both formyl and amide groups proceeded smoothly, in cases where an

aryl group was present directly on the nitrogen atom of an amide (Table 6, Entries 1-3). In

case of N-formyl amides 152 and 153, only the formyl group was reduced selectively (Table

Entry N-formyl-amide Diamine R Diamine Yield (%)

1 149

NHHN

R

t-Bu 154 82

2 150 Ph 155 80

3 151NHHN

HNNH- 156 97

4 152

NHHN R

O(R)-(+)-methylbenzyl 157 97

5 153 Me 158 29

THF, reflux, 16 hNHHN

OR4

R3

NHHN

OR4

R3

OHC

LAH

Entry Amino-amide N-Formyl-amide R N-Formyl-amide Yield (%)

1 132

NHHN

O

O

R

t-Bu 149 88

2 133 Ph 150 89

3 136NHHN

O

HNNH

O

O

O

- 151 90

4 135

NHHN

O

R

O

(R)-(+)-Methylbenzyl 152 95

5 138 Me 153 96


6, Entries 4 and 5). The low yield of 29% in case of compound 158 (Table 6, Entry 5) was

caused by the extremely high solubility of the amino-amide 158 in water. In order to per-

form the extraction, the product had to be salted out.

An attempt to obtain a chiral diamine from ampicillin was also made. Commercially

available ampicillin (159) was formylated to N-formyl ampicillin (160) in an excellent yield

of 98%. This was reduced by LAH in a standard manner in order to obtain the diamine or

the corresponding alcohol. Nevertheless, a complicated reaction mixture was obtained,

which showed this approach to be unusable (Scheme 61).

Scheme 61

Tosylation of the Amines

In order to lower the electron density of a nitrogen atom of the diamine, tosylation was

performed with the diamine 143. Using standard conditions, the reaction proceeded smooth-

ly, giving after crystallization the product 161 in a moderate yield of 59% (Scheme 62).

Scheme 62

Tosylated diamines such as 149 are not only interesting as precursors towards imida-

zolinium salts, but they might be also used as hydrogen bond activators.

2.1.1.3.2. Preparation of Imidazolidines

A. Water Excluding Approach

As mentioned above, imidazolidines (five member aminals) are the key precursors for

the preparation of imidazolinium salts. The mechanism of the aminal formation is similar to

an imine/enamine formation (Scheme 63).

A nucleophilic attack of the nitrogen atom towards the carbonyl group of an aldehyde

forms a hydroxyl amine. The hydroxy group is then protonated and is leaving the molecule

to give a carbocation, that is subsequently attacked by the second nitrogen atom, resulting

in a ring closure. All steps are part of an equillibrium, which is usually driven to the side of

the products by removing water, that is formed during the reaction.

THF, 0 °CNHHN

TsCl, Et3NH2N HN Ts

143 161

59%

t-But-Bu

N

S

HH

NH

CH3

CH3

OHO

O

NH2

O

N

S

HH

NH

CH3

CH3

OHO

O

NH

O

DCM, 0°C

O

O

O

O

160

98%

LAHcomplex

mixtureTHF

159


Scheme 63

This is usually achieved by employing various drying agents, e. g. potassium carbon-

ate,126 calcium sulfate,127 boric anhydride,128 by performing reaction in strongly hygroscop-

ic solvent (abs. EtOH, abs. MeOH), or by removing the water through azeotropic distilla-

tion with benzene on a Dean-Stark water separator. If formaldehyde is used in the reaction,

often an ethanol–water mixture is used as the solvent.129

Initially, aminals from several chiral diamines were prepared, using the classical method

of azeotropic water removal on a Dean-Stark adapter (Scheme 64).

Scheme 64

The aminals 162 and 163 from Simpkins base 94 were obtained in a low yields of 50%

and 25% respectively, due to sterical hindrance of the diamine. The less hindered (1S,2S)-

N,N’-dimethyl-1,2-diphenylethane-1,2-diamine (96) gave the corresponding aminals 164

and 165 in high yields of 93% and 91% (Scheme 64).

Long reaction times of 48 h or more were necessary to obtain reasonable yield and the

products had to be purified by FCC.

In general, the purification of aminals represents a problem, because traces of water in

the solvents used for crystallization or the acidic groups on silicagel in combination with

water present in the mobile phase can cause a ring opening of the aminal. In order to cir-

cumvent this problem, dry solvents have to be used for crystallization and in case of FCC,

HNNH

Ph Ph

Ph PhR

O p-toluensulfonic acidN N

Ph Ph

R

benzene, reflux, 48 h

162, R = 2-Cl-Ph, 50%

163, R = 4-Cl-Ph, 25%

HNNH

Ph Ph

N N

Ph Ph

R

164, R = 2-Cl-Ph 93%

165, R = 4-Cl-Ph 91%

94

96

PhPh

+

R

O p-toluensulfonic acid

benzene, reflux, 48 h+

NN

R2

R3

R1

(CH2)n

HNNHR3

R3

(CH2)n

R2

O

+NHNHR

3R

3

(CH2)n

R2

−O

proton shiftNNHR

3R

1

(CH2)n

R2

HO

+H+

NNHR3

R1

(CH2)n

R2

H2O+

NNHR3

R1

(CH2)n

R2

−H2O

+

NN

H+

R3

R1

(CH2)n

R2

−H+


the silica gel has to be deactivated by triethylamine and dry solvents were used for the col-

umn chromatography.

These difficulties, next to the use of the toxic solvents such as benzene makes an alter-

native, more efficient and enviromental friendly route to aminals desirable.

B. Preparation of Aminals in Water130

Since the preparation of imines by the reaction of amines and aldehydes in water with-

out the presence of a catalyst was reported recently,131 a similar attempt was carried out

within our group to obtain imidazolidines.

In order to follow the procedure for the preparation of imines in water,131 N,N'-dibenzyl-

ethane-1,2-diamine (166) was vigorously stirred in water and benzaldehyde (167) was

added to the emulsion. During 3 h of stirring at r.t., a white precipitate formed which was

filtered of and washed with water. After drying under vacuum the desired product 168 was

obtained in 91% yield in high purity according to NMR spectral data and CHN analyses

(Scheme 67).

In comparison, when 166 was refluxed with benzaldehyde and a catalytic amount of p-toluene sulfonic acid in benzene on a Dean-Stark apparatus, the reaction took 16 h and a

flash column chromatography with deactivated silicagel had to be performed to obtain the

aminal 168 in 67% yield and proper purity.

When the reaction was carried out in abs. ethanol, the desired aminal had to be purified

again via flash column chromatography or via recrystallization, which gave the product 168

in 62% yield.

Finally, when benzaldehyde was added to the neat diamine 166, a strong exothermic

reaction was observed, which was completed after 15 min. However, due to the high tem-

perature during the reaction many impurities next to 168 were detected in the NMR spectra

and again a flash column chromatography had to be carried out, which gave the aminal 165

in 60% yield.


Scheme 65

Given those results it was concluded that for the preparation of aminal analogues of 168

a reaction of diamines and benzaldehydes in water would be the most convenient and effi-

cient procedure. The results are summarized in Table 7.

Scheme 66

First, diamine 166 was reacted with different benzaldehydes to give the corresponding

imidazolidines (Table 7, Entries 1-9). In all cases the obtained yields were very high

(between 88 and 99%) and the products were pure according to NMR spectra and CHN-

analysis.

Electron deficient (Table 7, Entries 2-6) and electron rich (Table 7, Entry 7) benzaldehy-

des gave similar results. Even the hindered 2,6-dichloro-benzaldehyde (176) gave the cor-

responding aminal 185 in a good yield of 88% (Table 7, Entry 4). In this case, the reaction

mixture had to be heated up to 80°C in order to melt the aldehyde. Again for comparison,

when the reaction with this hindered aldehyde was performed using water excluding condi-

tions (PhMe or benzene, Dean-Stark, 2 days) aminal 185 had to be purified by crystalliza-

tion and it was obtained in 48% (PhMe) and 80% (benzene) yields, respectively.

In general, a formation of a proper emulsion was found to be essential for the reaction to

perform. In cases, where the melting points of the aldehydes or amines were higher than r.t.,

the mixtures were heated up to 50-80°C in order to melt the reactants and ensure the forma-

NN

R2

R1

R1

H2O, r.t., 3 h

(CH2)n

HNNHR1

R1

(CH2)n

+R

2

O

HNNHBn Bn

Ph

O N N

Phbenzene, reflux, 16 h

168

67%

166

HNNHBn Bn

Ph

O

H2O, r.t. 3 h

168

91%

166

HNNHBn Bn

Ph

O

EtOH, reflux, 16 h

168

62%

166

BnBn

N N

Ph

BnBn

N N

Ph

BnBn

HNNHBn Bn

Ph

O

neat, 15 min

168

60%

166

N N

Ph

BnBn

167

167

167

167

+

+

+

+

p-toluensulfonic acid


tion of an emulsion containing both reagents (Table 7, Entries 3, 4, 5, 7, 14). When the alde-

hydes were not melted, yields were significantly lower.

Table 7: Preparation of Aminals in Water

c2 eq. of amine were used

In case of the polyfluorinated aminal 187 (Table 7, Entry 6) the reaction was carried out

in deoxygenated water under a nitrogen atmosphere. This was necessary to prevent the rapid

oxidation of the aldehyde to the corresponding carboxylic acid before the formation of the

desired aminal 187 was finished. The product 187 was isolated in a good yield of 92%.

Since 187 was a liquid, it was extracted from the reaction mixture with chloroform. To com-

pare the methods again, an attempt to prepare 187 in benzene with a Dean-Stark apparatus

under reflux was carried out, which gave no product at all. The same result was observed

when abs. ethanol was chosen as a solvent for the reaction. When pentafluorobenzaldehyde

was added to neat diamine 166 a strong exothermic reaction was observed, however, no

product was isolated, which may be due to the possible instability of either pentafluoroben-

zaldehyde (178) or the resulting aminal 187 at higher temperatures.

Aliphatic aldehydes can be applied in the described procedure too. Propionaldehyde

(182) gave with diamine 166 the expected aminal 191 in 85% yield (Table 7, Entry 10).

However, due to the lower reactivity of aliphatic aldehydes the reaction time had to be pro-

Entry Diamine Aldehyde T (°C) t (h) Aminal Yield (%)

1 166 (R1=Bn, n=2) Benzaldehyde 167 r.t. 3 168 91

2 166 2-Chlorobenzaldehyde 174 r.t. 3 183 96

3 166 4-Chlorobenzaldehyde 175 50 3 184 91

4 166 2,6-Dichlorobenzaldehyde 176 80 3 185 88

5 166 2,4-Dichlorobenzaldehyde 177 80 3 186 96

6 166 Pentafluorobenzaldehyde 178 r.t. 3 187 92

7 166 2-Methoxybenzaldehyde 179 50 16 188 94

8 166 Thiophene-2-carbaldehyde 180 r.t. 3 189 99

9 166 Pyridine-2-carbaldehyde 181 r.t. 3 190 99

10 166 Propionaldehyde 182 r.t. 16 191 85

11 169 (R1=Bn, n=3) 2-Chlorbenzaldehyde 174 r.t. 3 192 88

12 169 Pyridine-2-carbaldehyde 181 r.t. 3 193 93

13 170 (R1=Bn, n=4) 2-Chlorobenzaldehyde 174 r.t. 3 194 99

14 171 (R1=Ph, n=2) 2-Chlorobenzaldehyde 174 70 3 195 98

15 172 (R1=Me, n=2) Benzaldehyde 167 r.t. 3 196 96

16 172 2-Chlorobenzaldehyde 174 r.t. 3 197 94

17 173 (piperidine)c 2-Chlorobenzaldehyde 174 r.t. 3 198 99


longed to 16 h. The scope of the reaction was extended with N,N'-dibenzyl-propane-1,3-

diamine (169) and N,N'-dibenzyl-butane-1,3-diamine (170) which gave with the correspon-

ding aldehydes cyclic aminals with a six- or a seven-membered ring in good yields between

88 and 99% (Table 7, Entries 11-13).

In addition N,N'-diphenyl-ethane-1,2-diamine (171) was forming with 2-chlorobenzalde-

hyde (174) the aminal 195 in 98% yield (Table 7, Entry 14). Since the melting point of the

diamine 171 is 70 °C, the reaction mixture was heated to 80 °C to melt the diamine.

Aminals 196 and 197, derived from N,N'-dimethyl-ethane-1,2-diamine (172), benzalde-

hyde (167) and 2-chlorobenzaldehyde (174) were obtained in high yield of 96% and 94%

respectively (Table 7, Entries 15, 16).

Open aminals were also accessible as shown in Entry 17, where 2 eq. of piperidine (173)

gave with 2-chlorobenzaldehyde (174) the expected product 198 in 99 % yield..

C. Solvent Free Approach132

For the preparation of the chiral imidazolinium salts it was necessary to expand this

method for more complex and hindered systems.

As a model compound for these experiments, Simpkins base 94 was chosen. Due to its

hindrance, hydrophobicity and high melting point, it is difficult to mix this compound with

water.

Since it was found, that vigorous stirring is essential for the reaction to perform, sonica-

tion as a method of mixing was employed. However, no reaction was observed (Scheme 69).

Another attempt was made by heating the reaction mixture in deoxygenated water in a

sealed vessel to 140 °C in order to melt the diamine and to create a proper emulsion. After

16 h, just traces of aminal 163 were detected by NMR spectroscopy (Scheme 67).

Scheme 67

HNNH

Ph Ph

H2O, sonication

N N

Ph Ph

H2O, 140 °C, 16 h

163

traces

Cl

163

94

PhPh

PhPh

HNNH

Ph Ph N N

Ph Ph

Cl

94

PhPh

PhPh

+

O

Cl

175

+

O

Cl

175


Finally, heating a neat mixture of 4-chlorobenzaldehyde (175) and diamine 94 in a pres-

sure vessel under a nitrogen atmosphere at 140 °C gave the aminal 163 in quantitative yield

and reasonable purity according NMR spectroscopy. (Scheme 68)

Scheme 68

After obtaining this result, this method (Method C) was explored further in preparation

of more complex aminals, which were initially prepared using the water exclusion method

(Method A). Results are summarized in Table 8.

Scheme 69

In case of diamine 96 (Table 8, Entries 1-3), both methods were found to be comparable.

Reaction with salicylaldehyde under neat conditions (Method C) gave the corresponding

aminal 200 in 95% yield, while the reaction of the diamine with 2-chloro and 4-chloroben-

zaldehyde under water excluding conditions (Method A) furnished after the column chro-

matography the corresponding aminals 164 and 165 in 93% and 91% yields, respectively.

High yields of both methods might be explained by low sterical hindrance of the diamine

96 and by high stability of the aminals 164 and 165 on silica gel.

N1,N2-bis((R)-1-phenylethyl)ethane-1,2-diamine (93) gave using Method C with the

corresponding aldehydes the aminals 201-204 in quantitative yields (Table 8, Entries 4-7).

Simpkins base 91, which gave with the 4-chlorobenzaldehyde (175) aminal 151 in 25%

yield using Method A (Table 8, Entry 9), furnished the aminal 163 in 77% yield (after FCC),

using Method C (Table 8, Entry 10). The lower yield of Method C, compared to the other

cases, is due to the instability of aminal 163 on silica gel. Surprisingly, using Method A,

amine 94, gave with pyridine-2-carbaldehyde (181) aminal 205 in 95% yield (Table 8, Entry

11).

R2

O

N N

R5

R4

R1

R3

R2

NH HN

R5

R4

R1

R3

Method A: benzen/Dean-Stark reflux

Method C: neat, 140 °C

Method A or C

neat, 140°C, 16 h

163

quant.

HNNH

Ph Ph N N

Ph Ph

Cl

94

PhPh

PhPh

O

Cl

175

+


Table 8: Preparation of chiral aminals

a2 eq. of amine were used

When Method C was applied in the reaction of tosylated diamine 161 with benzaldehyde

(166), no formation of the corresponding aminal could be detected by NMR, probably due

to the low nucleophilicity of the nitrogen atom caused by the tosyl group (Table 8, Entry

12).

The reaction of 2 eq. of (−)-pseudoephedrine (199) with benzaldehyde (166) under neat

conditions (Method C) gave the expected open aminal 207 in quantitative yield.

Entry Diamine Aminal R2 Method Aminal Yield (%)

1

NH HN

PhPh

96

N N

PhPh

R2

2-OH-C6H

4 C 200 95

2 2-Cl-C6H

4 A 164 93

3 4-Cl-C6H

4 A 165 91

4

HNNH

PhPh93

N N

PhPh

R2

2-Cl-C6H

4 C 201 99

5 4-Cl-C6H

4 C 202 99

6 2,6-Cl-C6H

4 C 203 99

7 C4H

5N C 204 99

8

NH HN

PhPh

PhPh 94

N N

PhPh

PhPh

R2

2-Cl-C6H

4 A 162 50

9 4-Cl-C6H

4 A 163 25

10 4-Cl-C6H

4 C 163 77

11 C4H

5N A 205 95

12NHHNTs

161

t-Bu

N NTs

R2

t-Bu

Ph C 206 0

13 HO

Ph

NH

199

HO

Ph

N N

R2

Ph

OHPh Ca 207 99


Preparation of Bisaminals

The good results observed by the solvent free method (Method C) led in using this pro-

cedure for the preparation of bis-aminals (Scheme 70, Table 9), which may serve as precur-

sors for imidazolinium bis-cations.

Scheme 70

The reaction with phthaldialdehyde proceeded with high yields, only when N-methyl

substituted diamines 172, 96 and 97 were used (Table 9, Entries 1-3).

When diamine 95, with more bulky substituents on both nitrogen atoms was applied, no

formation of an aminal could be detected by NMR (Table 9, Entry 4).

In case of diamines 147 and 154, where one of the nitrogen atoms is substituted by a

small group and the second one by a more bulky group, only traces of aminals were present

in the reaction mixture after 16 h at 140°C (Table 9, Entries 5 and 6).

The reaction of bis-diamine 156 with 2 eq. of benzaldehyde gave the corresponding bis

aminal 214 in 91% yield (Table 9, Entry 7). When the same bis-diamine was reacted with

phthaldialdehyde in order to give the internally bridged bis-aminal 215, only traces of the

product were observed in the NMR spectra of the crude reaction mixture.

In conclusion, the preparation of aminals in water and under solvent-free conditions rep-

resent a useful and versatile synthetic route to these type of compounds. The sterical envi-

ronment of the reactants is the limiting factor of these reactions.

HNNH R1

R3

R4

R5

N

NN

N

R1

R3

R1

R5

R4

R3

R5

R4

CHO

CHO

neat 140 °C, 16 h

2


Table 9: Solvent Free Preparation of Bis-Aminals

adetermined by NMR; b2 eq. of benzaldehyde were used

Entry Diamine Aminal Aminal Yield (%)

1 NH HN

172

N N

N

N 208 93

2NH HN

PhPh

96

N N

PhPh

N

N

Ph

Ph209 87

3NH HN

95

N N

N

N

210 99

4NH HN

t-But-Bu

PhPh 95

N NR

tButBu

R

N

N

R

R

tBu

tBu

R = (R)-MeBn

211 0

5HN

NH

Ph147

N N R

N

N

R

R = (R)-MeBn

212 Tracesa

6NHHNMe

154

t-Bu

N

N

N

N

t-Bu

t-Bu

213 Tracesa

7b

NH

HNNH

NH

156

N

NN

N

PhPh

214 91

8N

NN

N

215 Tracesa


2.1.1.4. Preparation of the Imidazolinium Salts

2.1.1.4.1. Oxidation of Aminals by NBA or NBS

The preparation of the imidazolinium salts by an oxidation of imidazolidine with NBA

or NBS represents a very suitable synthetic route. The reaction proceeds under mild condi-

tions, giving the imidazolinium salts in high yields and purity. First, the nitrogen atom of an

aminal is brominated by NBA, followed by the elimination of the proton at the C-2 position,

resulting in the formation of the salt (Scheme 71). The original literature procedure108 was

modified by quenching the reaction, which was performed in DME, by the addition of Et2O

in order to precipitate the salt from the reaction mixture. Moreover, the usage of NBA was

found to be more convenient because of the good solubility of the resulting acetamide in

Et2O, leading to a higher purity of the products.

Scheme 71

Initially, simple achiral aminals bearing different substituents at the C-2 position and on

the nitrogen atoms were oxidized. The results are sumarized in Table 10.

Scheme 72

Table 10: Oxidation of Aminals

Entry Aminal R1 R2 Bromide Yield%

1 168 Bn C6H

5 168A 95

2 183 Bn 1-(2-Cl-C6H

4) 183A 93

3 184 Bn 1-(4-Cl-C6H

4) 184A 88

4 185 Bn 1-(2,6-Cl2-C

6H

3) 185A 77

5 186 Bn 1-(2,4-Cl2-C

6H

3) 186A 91

6 216 Bn 3-(NO2-C

6H

3) 216A 94

7 187 Bn C6F

5 187A 90

8 189 Bn 2-(C4H

3S) 189A 90

9 190 Bn 2-(C5H

4N) 190A 99

10 196 Me C6H

5 196A 99

N N R1

R1

R2

NBA

N N R1

R1

R2 Br

−DME, r.t., 1 h

N N R1

R3

R2

R5

R4

H

O

NH

Br

N+ N R

1R

3

R2

R5

R4

HBr

O

HN−

N+ N R

1R

3

R2

R5

R4

Br−


From the obtained results it is possible to conclude, that the reaction gives good results

with electron withdrawing (Table 10, Entries 2- 7 and 9) as well as electron rich (Table 9,

Entry 8) substituents at the C-2 position. Sterical hindrance at the C-2 position does not have

an influence on the yield of the reaction (Table 10, Entry 4). The sucessuful oxidation

process could be folloved by by the disapearance of the characteristic aminal singlet (around

5 ppm) in the 1H-NMR spectra (see Appendix).

Anion Metathesis

The obtained imidazolinium bromides were highly hygroscopic and difficult to handle.

Moreover, the bromide ion represents a quite hard counter anion, which is not useful for

application of the imidazolinium salts in catalysis, except for phase transfer catalysis. There-

fore, a counter anion metathesis was performed to obtain imidazolinium salts with more

liphophilic counter anions, which are interacting less with the possitive charge at the C-2

carbon than the bromide anion. For this purposes, the following four anions were chosen

(Scheme 73):

Scheme 73

Hexafluorophosphate and bis-trifluoromethyl sulfonate anions are commercially avail-

able in form of potassium hexafluorophosphate and lithium bistrifluoromethylsulfonyl

amide. Sodium tetrakis(3,5-bis(trifluoromethyl)phenyl) borate133 and potassium

terakis(pentafluorophenyl) borate134 were prepared according to literature procedures.

The counter anion exchanges were performed by vigorous stirring of imidazolinium bro-

mide and the salts of the corresponding counter anions in a water/DCM (or CHCl3) mixture.

In some cases, the counter anion exchanges were performed directly after the oxidation step

without isolating the imidazolinium bromide salt (Scheme 74).

By equillibration, the ion pair of the more lipophilic cation and anion is dissolving in the

organic phase and more the hydrophilic ion pair (NaBr, KBr or LiBr) is passing to the aque-

ous phase. The organic phase was separated, washed with water (3 x), dried over molar

sieves and the solvent was removed under reduced pressure to give the imidazolinium salt

with the desired counter anion. It was possible to follow the counter anion change in the

NMR spectras by the changed chemical shifts of the signals of the cation due to the differ-

ent interaction with the anion (see Appendix A2, page 216).

B

F3C

F3C CF3

F3C

F3C CF3

CF3

CF3

C6F5B

C6F5

C6F5

C6F5

N−

S

S

CF3

OO

OO

CF3

PF6−

EB C D

−

−


Scheme 74

Table 11: Oxidation and Counter Anion Exchange of Achiral Aminals

As seen from Table 11, the counter anion exchanges proceeded in good to excellent

yields with simple, non hindered systems bearing different substituents at the C-2 position.

Electron withdrawing (Table 11, Entries 2-13) and electron donating groups (Table 11,

Entries 14 and 15) did not have an influence on the obtained yields.

Since the results were showing a high purity of the salts, counter anion exchange was per-

formed often directly after the oxidation with NBA.

This method was explored also in the oxidation of larger rings (Scheme 75, Table 12).

Entry Imidazoline R1 R2 X− Salt Yield (%)

1 168 Bn C6H

5PF

6−

168B 88

2 183 Bn 1-(2-Cl-C6H

4) PF

6−

183B 95

3 183 Bn 1-(2-Cl-C6H

4) NTf

2−

183C 71

4 183 Bn 1-(2-Cl-C6H

4) B[C

6H

3(CF

3)2]4

−183D 88

5 184 Bn 1-(4-Cl-C6H

4) PF

6−

184B 89

6 184 Bn 1-(4-Cl-C6H

4) NTf

2−

184C 90

7 184 Bn 1-(4-Cl-C6H

4) B[C

6H

3(CF

3)2]4

−184D 48

8 185 Bn 1-(2,6-Cl2-C

6H

3) B[C

6H

3(CF

3)2]4

−185D 55

9 186 Bn 1-(2,4-Cl2-C

6H

3) PF

6−

186B 90

10 186 Bn 1-(2,4-Cl2-C

6H

3) B[C

6H

3(CF

3)2]4

−186D 84

11 187 Bn C6F

5PF

6−

187B 90

12 187 Bn C6F

5NTf

2−

187C 68

13 187 Bn C6F

5B[C

6H

3(CF

3)2]4

−187D 92

14 189 Bn 2-(C4H

3S) PF

6−

189B 92

15 189 Bn 2-(C4H

3S) B[C

6H

3(CF

3)2]4

−189D 63

16 190 Bn 2-(C5H

4N) PF

6−

190B 71

17 190 Bn 2-(C5H

4N) B[C

6H

3(CF

3)2]4

−190D 97

18 196 Me C6H

5PF

6−

196B 90

19 196 Me C6H

5NTf

2−

196C 75

20 197 Me 1-(2-Cl-C6H

4) B[C

6H

3(CF

3)2]4

−197D 70

M+X

−

N N R1

R1

R2 X

−DCM/H2O

N N R1

R1

R2 Br

−

N N R1

R1

R2

NBA

DME, r.t., 1 h


Scheme 75

Table 12: Oxidation and Counter Anion Exchange of Larger Rings

While substitution at the C-2 position did not have a signifficant influence on the yield

of the oxidation, a different situation was observed with different ring sizes.

In case of aminals 183, 192 and 194, bearing the same 2-chlorophenyl group at the C-2

position, the five membered aminal 183 gave the salt 183C in 71% yield (Table 12, Entry

2), while six membered aminal 192 furnished the corresponding salt 192C in 88% yield

(Table 12, Entry 2). The yield dropped unexpectedly, with the seven membered aminal 194,

which was giving the salt 194C in 38% yield. This could be explained by a high solubility

of the salt 194A in Et2O, which is used to precipitate the salt from the reaction mixtue. The

rather complicated 1H-NMR spectrum of 194C is indicating, that the seven membered ring

can hold different conformations at r.t..

Six membered aminal 193, substituted by the pyridine on the C-2 position gave the cor-

responding tetrahydropyrimidinium salts 193A-C in high yields (Table 12, Entries 4-6)

Preparation of Chiral Salts

Chiral imidazolinium salts were prepared from the chiral imidazolidines by oxidation

with NBA in the same manner as their achiral analogs (Scheme 76, Table 13).

Scheme 76

2. M+X

−, DCM/H2O, 1 h, r.t.

N N+

R1

R3

R2 X

−

R5

R4

N N R1

R3

R2 Br

−

R5

R4

1. NBA, DME, 1 h, r.t.

Entry Aminal n R2 X− Salt Yield (%)

1 183 0 2-Cl-C6H

4NTf

2−

183C 71

2 192 1 2-Cl-C6H

4NTf

2−

192C 88

3 194 2 2-Cl-C6H

4NTf

2−

194C 38

4 193 1 C5H

4N Br− 193A 95

5 193 1 C5H

4N PF

6−

193B 98

6 193 1 C5H

4N B[C

6H

3(CF

3)2]4

−193C 90

N N+

R2 X

−

n

2. M+X

−, DCM/H2O, 1 h, r.t.

1. NBA, DME, 1 h, r.t.N N

R2

n

BnBnBnBn


Table 13: Oxidation and Counter Anion Exchange of Chiral Aminals

The reactions gave high yields with compounds bearing simple methyl groups on the

nitrogen atoms (Table 13, Entries 1-9) as well as with the compounds containing more bulky

groups (Table 13, Entries 10-17). In most cases, the oxidation step was followed directly by

a counter anion metathesis, giving directly the suspected salt. An attempt to oxidize the open

aminal 217 was not successful (Table 13, Entry 19).

Entry Aminal Cation Anion Salt Yield (%)

1

N N

Ph Ph

Cl

164

N N+

Ph Ph

Cl

Br− 164A 99

2 PF6

−164B 88

3 NTf2

−164C 65

4 B[C6H

3(CF

3)2]4

−164D 77

5 B(C5F

6)4

−164E 89

6

N N

Ph Ph

Cl

165

N N+

Ph Ph

Cl

Br− 165A 99

7 NTf2

−165C 56

8 B[C6H

3(CF

3)2]4

−165D 71

9 B(C5F

6)4

−165E 62

10

N N

N

PhPh

201

N N+

N

PhPhB[C

6H

3(CF

3)2]4

−201D 70

11

N N

Ph Ph

Cl

162

PhPhN N

+

Ph Ph

Cl

Ph Ph

Br− 162A 89

12 PF6

−162B 94

13 B[C6H

3(CF

3)2]4

−162D 77

14 B(C5F

6)4

−162E 89

15

N N

Ph Ph

Ph Ph

Cl

163

N N+

Ph Ph

Ph Ph

Cl

PF6

−163B 72

16

N N

Ph Ph

N

Ph Ph

205

N N+

Ph Ph

N

Ph Ph

Br− 205A 96

17 PF6

−205B 86

18 NTf2

−205C 57

19 HO

Ph

N N

Ph

Ph

OH

217

HO

Ph

N N+

Ph

Ph

OH Br− 217A 0


Preparation of Bis-Cations

Similar as the monocations, attempts to prepare bis-cations were made. Because of the

high hygroscopicity, the bromide salts were not isolated and the counter anion metathesis

was performed directly after the oxidation step (Scheme 77). The result are summarized in

Table 14.

Scheme 77

Table 14: Oxidation of Bis-Aminals

The oxidation, followed by counter anion metathesis proceeded also with bis-cations. In

cases of PF6

− and NTf2

− anions (Table 14, Entries 1, 3, 5), the corresponding salts precipi-

tated from the reaction mixture, after the solutions of bis-bromide and the source of the

anion were mixed. The products were isolated by filteration and the NMR spectra indicated

a high purity of the desired compounds. This phenomena can be used for the purification of

Entry Aminal Cation Anion Salt Yield (%)

1

N

N

N

N

208

N

N+

N+

N

PF6

−208B 41

2 B[C6H

3(CF

3)2]4

−208D 80

3

N

N

Ph

Ph

N

NPh

Ph

209

N

N+

Ph

Ph

N+

NPh

Ph

NTf2

−209C 63

4 B[C6H

3(CF

3)2]4

−209D 79

5

N

N

N

N

210

N

N+

N+

N

PF6

−210B 75

6 B[C6H

3(CF

3)2]4

−210D 87

7

N

NN

N

PhPh

214

N+

NN

N+

PhPh

NTf2

−214C Traces

1. NBA (2 eq.), DME, r.t., 3 hN

+

NN+

N

R1

R3

R1

R5

R4

R3

R5

R4

N

NN

N

R1

R3

R1

R5

R4

R3

R5

R4

X−

X−

2. M+X

−(2 eq.), CHCl3/H2O, r.t., 30 min


the salts, since a FCC of the bis-cations was not always possible. PF6

− or NTf2

− anions can

be subsequently exchanged with B[C6H

3(CF

3)2]4

−.

Despite rather lipophilic NTf2

− anion, the bis-cationic salt 209C was not well soluble in

unpolar solvents (DCM, PhMe), which is limiting its use to rather polar solvents (MeCN,

DMSO, DME). When the counteanion exchange was perfomed with the polyflourinated salt

NaB[C6H

3(CF

3)2]4

−, the resulting compound 209D (Table 14, Entry 4) was showing a sig-

nificantly better solubility in unpolar solvents such as Et2O, DCM or PhMe. A similar obser-

vation was made in case of the compounds 210B and 210D, where the latter was showing

signifficantly better solubility in unpolar solvents.

In case of the bis-aminal 214, the formation of the bis-cation was confirmed by ESI-MS,

however NMR spectra were found not to be reproducible, indicating a mixture of products.

For purification purposes, crystallization was not applicable due to the oily character of the

substance and FCC was not successful. All the bis-cationic compounds had shown the cor-

responding signals in the ESI-MS, confirming that the oxidation proceeded on both imida-

zolinium rings.

In conclusion it is possible to state, that the oxidation of the imidazolidines to imidazolin-

ium salts is a mild and effective method, which gave a broad series of the imidazolinium

salts in high yields and purity. This method was also used to prepare a series of bis-cations

and tetrahydropyridinium salts. The properties of the salts were tuned using different count-

er anions.

2.1.1.4.2. Direct Reaction of Orthoesters with Diamines in the Presence of an

Anion and Acid Sources

The preparation of imidazolinium salts by the direct reaction of diamines and orthoesters

in the presence of an anion source represents a convenient route to these compounds.

The mechanism of the reaction is shown in Scheme 78. Used ammonium salt serves as a

proton source, protonating the ethoxy group of the orthoester, which is then leaving, giving

the carbocation, that it attacked by the nitrogen atom of the diamine. Protonation and leave

of the second methoxy group, followed by the subsequent nucleophillic attack by the nitro-

gen atom results in the ring closure. Further protonation of the ethoxy group and release of

ethanol results in the corresponding imidazolinium salt.


Scheme 78

Different kinds of anions can be introduced by using different ammonium salts, or by a

subsequent counter anion exchange in a mixture of CHCl3/H

2O111 (Scheme 79, Table 15).

Scheme 79

The reaction with triethyl orthoformate in the presence of ammonium tetrafluoroborate

proceeded with good yields with diamines 94 and 218, not being influenced by the presence

of bulky groups on the nitrogen atoms (Table 15, Entries 1, 6). In case of Alexakis’ base 95

(Table 15, Entry 4) the HBF4

salt of the amine was formed instead of the desired imidazolin-

ium salt 222F. When the hindered amine 155 was used, the reaction resulted in a complex

mixture, where no salt 228F could be detected by ESI-MS (Table 15, Entry 11).

Diamines bearing hydroxy groups gave by this method imidazolinium salts in satisfacto-

ry yields (Table 15, Entries 14, 17, 19, 21, 23).

The BF4

− anion was in some cases exchanged for the more lipophilic NTf2

− or

B[C6H

3(CF

3)2]4

− by stirring the imidazolinium tetrafluroborate and the corresponding anion

source in a mixture of CHCl3/H

2O (Table 15, Entries 2, 7, 10, 15, 16, 18, 20, 22). In case of

imidazolinium salts 233F and 234F, counter anion metathesis proceeded in poor yields,

resulting in 233C and 234C (Table 15, Entries 20 and 22). This is probably caused by the

high solubility of both BF4

− salts in water.

By reaction with triethyl orthoacetate (Table 15, Entries 3 and 5), the desired product

were obtained only when methyl groups were present on the nitrogen atoms (Table 15, Entry

5). When more bulky groups were present (Table 15, Entry 3), just traces of the product

HN

R4

NH

R5

neat, 120 °C

R1

R3 R

2(OEt)3/NH4X

−X

CHCl3/H2O, 30 min, r.t.

M+Y

−N N

+

R2

R5

R4

Y−

N N+

R2

R5

R4

R1

R3

R1

R3

OEt

OEt

O

Et

NH4BF4 NH4+ + BF4

−

NH HN

OEt

OEt

O+

Et

H

O Et

O EtNH NH

+

O

O

Et

Et

NH N

O

Et

N+H

N

OEt

NH4+

NH3 + H+

N N

O+

Et H

BF4−

N N+

H+

R2

R1

R1

R1

R2

R1R

2R

1R

2R

1

−EtOH R2

R2H

+− EtOH

+

+

+H+

−EtOH


were detected by NMR. This observation is already obvious from previous works.111 Nev-

ertheless, it was not especially mentioned and mainly triethyl orthoformate was used.

Table 15, Part 1: Reaction of Diamines with Orthoesters

Continue on the next page

Entry Diamine Cation R2 Anion Salt Yield (%)

1

NH HN

PhPh

PhPh 94

N N+

PhPh

PhPh

R2

H BF4

−220F 83

2 H NTf2

−220C 73

3 Me BF4

−221F traces

4NH HN

t-But-Bu

PhPh 95

N N+

t-But-Bu

PhPh

R2

H BF4

−222F 0

5NH HN

PhPh

96

N N+

PhPh

R2

Me BF4

−223F 99

6

NH HN

218

N N+

R2

H BF4

−224F 88

7 H NTf2

−224C 83

8

HNNHBn Bn

166

N N+

BnBn

R2

H Cl− 225G 99

9 Hcamphor-

sulphonate226H 99

10HN

NH

Ph147

N N+

Ph

R2

H NTf2

−227C 60

11NH HN

155

Ph

N N+

Ph

R2

H BF4

−228F 0

12NHHNTs

161

tBu

N N+

Ts

t-Bu

R2

H BF4

−229F 0

13

NH

HNNH

NH

156

N+

NN

N+

R2

R2

H BF4

−230F 0


Table 15, Part 2: Reaction of Diamines with Orthoesters

By using different ammonium salts, imidazolinium chloride 225G (Table 15, Entry 8)

and camphorsulphonate 225H (Table 15, Entry 9) were prepared in high yields.

The presence of a tosyl group on one of the nitrogen atoms in diamine 161 did not allow

the formation of the salt 229F due to a decreased nucleophilicity of the nitrogen atom (Table

15, Entry 12). The reaction of bis-diamine 156 (Table 15, Entry 13) showed that this reac-

tion is not suitable for the preparation of bis-cations, since no bis-cationic species 230F

could be detected in the reaction mixture by ESI-MS.

In conclusion it is possible to state, that direct reaction of diamines with the orthoesters

in the presence of the counter anion salt gave the corresponding imidazolinium salts in high

yields. This method was found to be mainly suitable for the imidazolinium salts bearing a

hydrogen atom at the C-2 position. Nucleophilicity of the amine, the sterical hindrance of

the diamines and unability to give the bis-cationic species might be the major limiting fac-

tor of this method. Another limitation lies in the rather limited commercial availability of

different orthoesters, compared to aldehydes.136

Entry Diamine Cation R2 Anion Salt Yield (%)

14

NH HN

HO

Ph

OH

Ph

104

N N+

HO

Ph

OH

Ph

R2

H BF4

−231F 87

15 H NTf2

−231C 93

16 H B[C6H

3(CF

3)2]4

−231D 85

17

NH HN

HO

Ph

OH

Ph

HOOH

107

N N+

HO

Ph

OH

Ph

HOOH

R2

H BF4

−232F 98

18 H B[C6H

3(CF

3)2]4

−232D 80

19

NH HN

HOOH 105

N N+

R2

HOOH

H BF4

−233F 94

20 H NTf2

−233C 52

21

NH HN

HOOH 106

N N+

R2

HOOH

H BF4

−234F 88

22 H NTf2

−234C 59

23NH HN

OH HO219

N N+

OH HOR2

H BF4

−235F 93


2.1.2. Preparation of Other Lewis Acids and Pseudo Lewis Acids

2.1.2.1. Silacycles as an Silicon Analog to Imidazolinium Salts

Heterocyclic silacycles might be seen as silicon analogues on imidazolidines. Based on

a few examples from the literature, the idea of generating heterocyclic silicon cation arised.

2.1.2.1.1. N,N-Silacycles

As an alternative to imidazolinium based Lewis acids, different N-Si-N, N-Si-O and O-

Si-O silacycles were prepared. From these silacycles, it is possible to generate in situ sili-

con cations, which are expected to show a higher reactivity, than the corresponding imida-

zolinium cations. The disadvantage of silicon compounds lies in the sensitivity of the sili-

con based cations to humidity and impossibility of regenaration.

Silacycles were prepared from the corresponding diamines or aminoalcohols by the reac-

tion with methyltrichlorosilane in the presence of DBU as a base. After stirring the reaction

mixture overnight, the solvent was removed under reduced pressure and Et2O was added in

order to precipitate the DBU.HCl. This was filtered of and and removal of the Et2O under

reduced pressure furnished the corresponding silacycle in high purity. The results for differ-

ent silacycles are summarized in Table 16.

Scheme 80

Table 16: Preparation of N,N-Silacycles

Entry Diamine Silacycle Yield (%)

1 NH HN

93 PhPh

N N

SiCl

236

PhPh 73

2NH HN

PhPh

96

PhPh

NSi

N

Cl

237

76

3NH HN

97

NSi

N

Cl

238

68

4NH HN

t-But-Bu

PhPh 95

tBu tBu

NSi

N

PhPhCl

239

0

5NHHN

t-Bu

149

N N

t-Bu

240

Si

Cl

0

DCM, −5 °CN N

SiR

1R

3NH HN R1

R3

R5R

5R

4R4

MeSiCl3, DBU

Cl


The reactions proceeded well with the unhindered amines (Table 16, Entries 1-3) giving

the corresponding silacycles in satisfactory yields. Nevertheless, when the hindered amines

95 and 149 were used (Table 16, Entries 4 and 5) no formation of the corresponding prod-

ucts 239 and 240 could be detected by NMR. N-Si-N silacycles substituted by a chlorine

atom are readily hydrolyzed by moisture and have to be stored in a freezer under a nitrogen

atmosphere.

Silacycle 241, in which the silicon atom is substituted by a hydrogen atom instead of a

chlorine was prepared from amine 93 in the same manner as the chlorinated analogs in 58%

yield (Scheme 81).

Scheme 81

This type of silacycles are more stable then their chlorine-substituted analogs. Hydride

can be then abstracted by a trityl cation in order to generate a Si+ species.

2.1.2.1.2. N,O-Silacycles

N,O-Silacyacle 242 was prepared as its N,N analogues from (+)-pseudoephedrine (199).

In this case the crude product had to be purified by a kugelrohr distillation leading to a poor

yield of 17%. The product was obtained as a mixture of diastereomers in a ratio of 3:1.

(Scheme 82)

Additionally N,O silacycle 244 was prepared in a yield of 10% from (−)-ephedrine (243).

In this case, as mixture of diastereomers in a ratio of 1:1.

Scheme 82

2.1.2.1.3. O,O-Silacycles

To follow the analogy further, an attempt for the preparation of O,O-silacycle was made.

Enantiopure BINOL (245) was reacted with MeSiCl3

in presence of DBU (Scheme 83).

After precipitating the DBU.HCl, only traces of the corresponding silacycle 246 could be

detected in the crude product by NMR spectroscopy.

Similar results were obtained, whed the reaction was performed in DCM under reflux.

The low conversion could be explained by the difficult formation of the large seven mem-

bered ring. Attempts to obtain a pure product 246 by crystallization were not successful.

DCM, −5 °CN O

Si

NH OH

PhPh Me

MeSiCl3, Et3N

Cl

Me

242

17%

241

DCM, −5 °CN N

Si

NH HN

MeSiHCl2, DBU

H

241

58%

PhPh PhPh93


Scheme 83

In conclusion, N,N-Silacycles were prepared in a moderate to good yields as a silicon

analogs of imidazolidines. These compounds can serve a a dirict presursors fo generating

silicon cations. Additionally two N,O-silacycles were prepared in low yields. Attempt to

prepare O,O-silacyle was not successful.

DCM, −5 °C

MeSiCl3, DBU

OH

OH

O

O

Si

Cl

246

Traces

245


2.1.2.2. Chiral Thioureas as Pseudo Lewis Acids

The chiral diamines 247, 248 and 249 were applied for the synthesis of chiral thioureas

250-252 by the reaction with bis-trifluoromethylisothiocyanate (Scheme 84) in THF, using

a literature procedure.137 The corresponding thioureas were obtained in quantitative yields

as shown in Table 17.

Scheme 84

Table 17: Preparation of Chiral Thioureas

These compounds can act as a hydrogen bond activators for carbonyl groups,137 nitro

groups60, 61, 138 and others and may be regarded as pseudo Lewis acids.

Entry Amine Thiourea Thiourea Yield (%)

1H2N NH2

PhPh

247

NH HN

PhPh

HNHN

SS

CF3

F3CCF3

F3C

250 99

2NH2

NH2

248

NH

HN

NH

HN

CF3

CF3

CF3

CF3

S

S

251 99

3H2N OH

PhPh

249

NH OH

PhPh

NH

S

CF3

F3C

252 99

THF, r.t., 22 hNH2

R1

R2

CF3

F3C

N

C

S

+

HN

R1

NH

S

F3C

CF3

R2


2.2. Application of the Catalysts

2.2.1. Application of Imidazolinium Salts as Lewis Acid Activators

2.2.1.1. Aza Diels-Alder Reaction

The aza Diels-Alder reaction represents a useful route to nitrogen-containing heterocy-

cles such as piperidines or tetrahydroquinolines. Although remarkable progress has been

made in the field of Lewis acid catalyzed Diels-Alder reaction, it is assumed, that in case of

the aza Diels-Alder reaction, most of the Lewis acids would be trapped by the nucleophilic

nitrogen atom of the reactans or product, making the catalytic reaction difficult. Since imi-

dazolinium salts are weak Lewis acids, they could catalyze an aza Diels-Alder reaction

without being trapped by the nitrogen of the nitrogen containing reagents.

Initially, the reaction between N-benzylideneaniline (254) and Danishefsky’s diene 253

was examined. This reaction was shown to be catalyzed by Lewis acids.139 The mechanism

of the activation by a Lewis acid consists in the interaction of the Lewis acid with the nitro-

gen atom of the imine, that decreases the electron density of the double bond. This causes a

higher “dienophilicity” and better reactivity. After the aza Diels-Alder reaction with the sily-

lated diene, the reaction mixture is hydrolyzed, to give the desired piperidinon 255 (Scheme

85).

Scheme 85

Alternatively, the reaction can proceed via a Mannich like pathway140 (Scheme 86) over

the intermediate 256, which is after acid giving hydrolysis the corresponding piperidinone.

The mechanism over which the reaction proceeds depends strongly on the solvent and cat-

alysts used.

Scheme 86

The reaction was performed for 16 h at room temperature in various solvents (Scheme

87, Table 18).

OMe

O

N

R2

R1

+

Lewis acid

NR

1

R2

OTMS

TMS

O

O

MeR

2

NR

1TMS

H+

253 256

OMe

TMSO

N

Ph

Ph

NPh

Ph

+

Lewis acid

OMe

OSi

NPh

PhO

NaHCO3

253 254 255


Scheme 87

Table 18: Aza Diels-Alder Reaction Catalyzed by Imidazolinium Salts

aionic liquid 196C was used as a solvent

Initially, control reactions were carried out in acetonitrile, DCM and PhMe (Table 18,

Entries 1-3). The reaction in the last two solvents gave no product (Table 18, Entries 2 and

3). In acetonitrile, the expected product was isolated in 10% yield (Table 18, Entry 1).

The first compound tested was the bromide salt 168A bearing a phenyl group at the C-2

position, which led to a yield of 14%, using acetonitrile as the solvent (Table 18, Entry 4).

By changing the counter anion to PF6

− (168B), the yield increased to 46% (Table 18, Entry

Entry Catalyst R1 R2 X− Mol % Solvent t (h) Yield (%)

1 - - - - 10 MeCN 16 10

2 - - - - 10 PhMe 16 0

3 - - - - 10 DCM 16 traces

4 168A Bn C6H

5 Br− 10 MeCN 16 14

5 168B Bn C6H

5PF

6−

10 MeCN 16 46

6 183B Bn 1-(2-Cl-C6H

4) PF

6−

10 MeCN 16 63

7 183C Bn 1-(2-Cl-C6H

4) NTf

2−

10 MeCN 48 98

8 183C Bn 1-(2-Cl-C6H

4) NTf

2−

10 PhMe 48 41

9 183C Bn 1-(2-Cl-C6H

4) NTf

2−

10 DCM 144 79

10 184A Bn 1-(4-Cl-C6H

4) Br− 10 MeCN 16 56

11 184B Bn 1-(4-Cl-C6H

4) PF

6−

10 MeCN 16 76

12 184C Bn 1-(4-Cl-C6H

4) NTf

2−

10 MeCN 16 82

13 186B Bn 1-(2,4-Cl2-C

6H

3) PF

6−

10 MeCN 16 72

14 187B Bn C6F

5PF

6−

10 MeCN 16 95

15 187B Bn C6F

5PF

6−

10 DCM 16 40

16 190B Bn 2-(C5H

4N) PF

6−

10 MeCN 16 73

17 190B Bn 2-(C5H

4N) PF

6−

10 DCM 16 24

18 189B Bn 2-(C4H

3S) PF

6−

10 MeCN 16 47

19 196C Me C6H

5NTf

2−

10 MeCN 16 53

20 196C Me C6H

5NTf

2−

4 eq.a - 16 0

OMe

TMSO

N

Ph

Ph

solvent, r.t.

N

O

Ph

Ph

catalyst

+

253 254 255

N N+

R2 X

−

R1

R1


5). The increase could be expected, since the PF6

− anion is a weaker coordinating anion

compared to bromide, which explains the higher reactivity of salt 168B. When the salt 183B

was tested, the yield increased to 63% (Table 18, Entry 6), which may be related to the more

electron withdrawing 2-chlorophenyl substituent of the salt. The catalyst 183C gave the

desired product in an excellent yield of 98% after 48 h (Entry 7, Table 6). 183C was then

used in different solvents.

In PhMe a yield of 41% was found, however the reaction time was extended to 48 h

(Table 18, Entry 8), while in DCM yield of 79% after 6 d (Table 18, Entry 9) was observed.

The lower yield in these two solvents and the longer reaction times can be reasoned with the

lower capability to dissociate the ion pairs, compared to acetonitrile.

Next, the salts 184A, 184B and 184C with a 4-chlorophenyl substituent were tested. As

expected the yields were increasing from the bromide 184A over the hexafluorophosphate

184B to the bis(trisfluoromethyl-sulfonyl)-imide 184C giving 56, 76 and 82% yield, respec-

tively (Table 18, Entries 10, 11 and 12). The yields for the 4-chlorophenyl and 2-

chlorophenyl substituents were quite similar. When salt 186B with a 2,4-dichlorophenyl rest

was applied (Table 18, Entry 13), the obtained yield of 76% was nearly the same as for the

4-chloro substituted 184B (Table 18, Entry 11).

The attention was then directed to the salt 187B, which has a pentafluorophenyl sub-

stituent at the C-2 position. The polyfluorinated rest may have two positive effects: First, it

can increase the positive charge of the imidazolinium unit, due to the strong electron with-

drawing capability of the fluoro-atoms; second, the fluoro-atoms are lipophilic and can help

to increase the solubility of the salt. Under standard reaction conditions salt 187B gave a

yield of 95% in acetonitrile (Table 18, Entry 14). When DCM was used as the solvent, the

desired product was isolated in 40% yield (Table 18, Entry 15).

The salt 190B, bearing a pyridine ring on the C-2 position gave in acetonitrile a yield of

73% (Table 18, Entry 16), which is comparable with the chlorophenyl substituted salts

183B, 184B and 186B (Table 18, Entries 6, 11 and 13). When 190B was evaluated in DCM,

a poor yield of 24% was found (Table 18, Entry 17) which is nearly half of the result

obtained with the more lipophilic salt 187B (Table 18, Entry 15). The salt 189B bearing a

thiophenyl rest on the C-2 position gave in acetonitrile a moderate yield of 47% yield (Table

18, Entry 18). Clearly, the electron rich thiophenyl-rest is reducing the Lewis acidity of the

imidazolinium cation.

Finally, the room temperature ionic liquid 196C, bearing a methyl group on the nitrogen

atoms and a phenyl group at the C-2 position was tested. Under the standard conditions, the

reaction gave the corresponding product in 53% yield (Table 18, Entry 19). However, when

4 eq. of 196C were used as a solvent, no reaction occured (Table 18, Entry 20).


With the standard conditions using 10 mol% of salt 187B various imines were tested in

the aza Diels-Alder reaction with Danishefsky’s diene (Scheme 88). The results are summa-

rized in Table 19.

Scheme 88

Table 19: Aza Diels-Alder Reaction of Various Imines

It was possible to observe that neither an electron withdrawing substituent nor an elec-

tron donating group or no substituent at all on the aryl ring next to the nitrogen of the imine

had an influence in the reaction. All three imines 256, 257 and 258 gave similar good yields

(Table 19, Entries 2-4). The scope of the reaction was then explored by using different aryls

attached at the carbon atom of the imine.

When an electron withdrawing chlorine atom was placed in the para position, the yield

slightly dropped to 72% (Table 19, Entry 5). When an electron donating methoxy group was

present at the ortho position the yield decreased to 57% yield (Table 19, Entry 5), while at

the para position an even lower yield of 45% was found (Table 19, Entry 7). Finally, the

imines 260 and 261 furnished the desired products in 50 and 93% yield, respectively (Table

19, Entries 7 and 9). Interestingly the 4-nitrophenyl-group of imine 262 had a significant

influence in the yield, while the also electron deficient 2-pyridinyl-group of imine 263 did

not (Table 19, Entries 8 and 9).

In addition three more reactions in acetonitrile were carried out with 165B using a load-

ing of 5, 2.5 and 1 mol%, which gave the product in 94, 76 and 73% yield, respectively

(Table 20, Entries 2-4). The largest yield drop was between 5 mol% and 2.5 mol% (Table

20, Entries 2 and 5). This showed, that 5 mol% is the smallest efficient amount of catalyst

under these reaction conditions.

Entry Imine R1 R2 Piperidinon Yield (%)

1 254 C6H

5C

6H

5 255 95

2 256 4-Cl-C6H

4C

6H

5 264 84

3 257 4-Cl-C6H

4C

6H

5 265 73

4 258 4-MeO-C6H

4C

6H

5 266 92

5 259 C6H

54-Cl-C

6H

4 267 72

6 260 C6H

52-MeO-C

6H

4 268 57

7 261 C6H

54-MeO-C

6H

4 269 45

8 262 C6H

54-NO

2-C

6H

4 270 50

9 263 C6H

52-C

5H

4N 271 93

MeCN, r.t. 16 h

N

TMSO

OMe

N

O

R1

R2

187B

+

R1

R2

253


Scheme 89

Table 20: Different Catalyst Loading

Scheme 90

Table 21: Influence of the Ring Size on the Reactivity

Next, the influence of the ring size on the reactivity of the salts was studied briefly. The

reaction of N-benzylidene aniline (254) with Danishefsky’s diene 253 was performed under

the same conditions using salts bearing a 2-chlorophenyl substituent at the C-2 position and

having NTf2

− as a counter anion. The imidazolinium salt 183C gave the corresponding

product in 50% yield, while the dihydropyrimidine salt 192C gave 67% and seven mem-

bered 194C 82% yield. This trend was nevertheless not observed by the pyridine ring bear-

ing salts 190B and 193B, which gave the same yield of 73% (Table 21, Entries 4 and 5).

It should be pointed out, that in all cases, the workup was performed by adding a sat.

solution of NaHCO3, giving the corresponding piperidinone, which is indicating, that the

reaction does not proceed via the Mannich-like pathway.

After the successful employment of imidazolinium salts as catalysts in the reaction of

substituted N-benzylideneanilines, the scope was moved towards systems bearing a benzyl

Entry Catalyst n R2 X− Yield (%)

1 161C 0 2-Cl-C6H

4NTf

2−

50

2 170C 1 2-Cl-C6H

4NTf

2−

67

3 172C 2 2-Cl-C6H

4NTf

2−

82

4 168B 0 C5H

4N PF

6−

73

5 171B 1 C5H

4N PF

6−

73

OMe

TMSO

N

Ph

Ph

MeCN, r.t., 16 h

N

O

Ph

Ph

+

N N+

R2 X

−

n

253 254 255

BnBn

Entry Catalyst Mol % Yield (%)

1 187B 10 95

2 187B 5 94

3 187B 2.5 76

4 187B 1 73

OMe

TMSO

N

Ph

Ph

MeCN, r.t., 16 h

N

O

Ph

Ph

187B

+

253 254 255


group at the nitrogen atom of the imines and towards the exploration of a three component

aza Diels-Alder reaction. The imidazolinium catalysts showed to be not capable to catalyze

these reactions (Scheme 91).

Scheme 91

Also the reaction of N-benzylinedeaniline (254) with (E)-1-methoxybuta-1,3-diene (271)

(Scheme 92) failed to give any corresponding product.

Scheme 92

2.2.1.2. Asymmetric Aza Diels-Alder Reactions

Since simple imidazolinium salts were giving very good results in catalyzing the aza

Diels-Alder reaction of Danishefsky’s diene 253 and N-benzylideneanilines, attempts to

extend the scope of the reaction with stereochemical induction was made. Chiral imida-

zolinium salts were examined in this reaction (Scheme 93, Table 22).

Scheme 93

Imidazolinium hexafluorophosphate salts based on Simpkins’ base were tested (Table

22). Initially, the reaction was performed at r.t. with catalyst 162B bearing 2-chlorophenyl

substituent at the C-2 position. A very good yield of 82% was obtained after 16 h, however,

no ee was detected. The reaction was performed again with 162B and 205B at 0°C (Table

22, Entries 2 and 4), but no ee was detected in either case. When the reaction was performed

in DCM (Table 22, Entries 3 and 5) only a signifficant yield drop with no asymmetric induc-

tion was observed.

OMe

TMSO

N

Ph

PhN

O

Ph

Ph

Chiral imidazolinium salt

+ *Solvent, 16 h

253 254 255

OMe

N

Ph

Ph

MeCN, r.t.

Imidazolidinium catalyst

+no reaction

254271

MeCN, r.t. 16 h

N

TMSO

OMe

Imidazolinium catalyst

+

R2

Ph

no reaction

TMSO

OMe

+ R2CHOR

1NH2

+

MeCN, r.t. 16 h


no reaction

253

253


Imidazolinium salts 218F, 218C and 231C, bearing a H-atom at the C-2 position (Table

22, Entries 6-8) gave the corresponding product 255 in high yields of 93, 99 and 97%

respectively. Nevertheless, also in these cases no enantiomeric induction was detected. Imi-

dazolinium salt 223F (Table 22, Entry 9) gave racemic product in 66% yield, showing, that

a methyl group at the C-2 position decreases the ability to activate the reaction.

Table 22: Asymmetric Aza Diels-Alder Reaction

There can be several explanations for this observation:

• The imidazolinium catalysts are not interacting with the molecule of the imine efficient-

ly enough to form a transition state, which would be capable of transferring stereochem-

ical information.

• Acetonitrile, as a very polar solvent, which can destabilize the slightly more favourable

transtition state, that leads to an enantiomerical excess.

In addition it should be mentioned, that up to date, there is no catalytic system (metal

based nor metal free) capable of a stereochemical induction in an aza Diels-Alder of N-ben-

zylideneaniline. All similar systems were having either benzyl,141 tosyl142 or ester143, 144

groups attached to the nitrogen atom of the imine, or the phenyl is replaced by the o-phenol

rest.145

Therefore, additional attempts were made with tosyl imine 243146 (Scheme 94). The tosyl

group at the nitrogen atom is decreasing the electron density at the double bond, making the

whole system more reactive towards dienophile.

Entry Catalyst R2 X− Solvent T (°C) Yield (%)

1 162B

N N+

PhPh

PhPh

R2

2-Cl-C6H

4PF

6−

MeCN r.t. 82

2 162B 2-Cl-C6H

4PF

6−

MeCN 0 76

3 162B 2-Cl-C6H

4PF

6−

DCM r.t. 27

4 205B 2-C5H

4N PF

6−

MeCN 0 79

5 205B 2-C5H

4N PF

6−

DCM r.t. 26

6 218F H BF4

−MeCN r.t. 93

7 218C H NTf2

−MeCN r.t. 99

8 231CN N

+

HO

Ph

OH

Ph

R2

H NTf2

−MeCN r.t. 97

9 223F N N+

PhPh

R2

CH3

BF4

−MeCN r.t. 66


Scheme 94

Since the preferred mechanism of the reaction depends on the solvent, more unpolar sol-

vents could ensure, that the reaction proceeds via a [4+2] mechanism. Therefore, catalyst

bearing lipophilic counter anions as well as very unpolar solvents were mainly used. The

catalyst 162D, bearing the lipophilic B[C6H

3(CF

3)2]4

− counter anion gave in DCM just a

poor yield of 2 %. The PF6

− salt 205B gave in MeCN a moderate yield of 35% after 36 h

(Table 23, Entry 2).

Table 23: Aza Diels-Alder Reaction with Tosyl Imine

Salts 164E-C gave in PhMe at r.t. moderate yields of 27, 50 and 53% (Table 23, Entries

3-5), but no ee was detected. Even the use of an unpolar solvent as benzene (Table 23, Entry

9) did not led to any stereochemical induction.

The catalysts 165E-C were threfore tested at −78°C (Table 23, Entries 6-8), however, no

enantiomeric induction, just a signifficant drop of the yield was observed.

Several attempts were also made with ethyl 2-(tosylimino)acetate,147 but only low yields

of racemic product were obtained.

2.2.3.2. Hetero Diels-Alder Reaction

Several imidazolinium salts were tested in the hetero Diels-Alder reaction of benzalde-

hyde (167) and Rawal’s diene 59148 (Scheme 80), but just traces of the suspected racemic

product were isolated.

Entry Catalyst Catalyst R2 X− Solvent T (°C) t (h) Yield (%)

1 162D

N N+

PhPh

PhPh

R2

2-Cl-C6H

4B[C

6H

3(CF

3)2]4

−DCM r.t. 16 2

2 205B 2-C4H

4N PF

6−

MeCN r.t. 36 35

3 164E

N N+

PhPh

R2

2-Cl-C6H

4B(C

6F

5)4

−PhMe r.t. 36 27

4 164D 2-Cl-C6H

4B[C

6H

3(CF

3)2]4

−PhMe r.t. 36 53

5 164C 2-Cl-C6H

4NTf

2−

PhMe r.t. 36 50

6 165E

N N+

PhPh

R2

4-Cl-C6H

4B(C

6F

5)4

−PhMe −78 72 21

7 165D 4-Cl-C6H

4B[C

6H

3(CF

3)2]4

−PhMe −78 72 12

8 165C 4-Cl-C6H

4NTf

2−

PhMe −78 72 41

9 165D 4-Cl-C6H

4B[C

6H

3(CF

3)2]4

− C6H

6 r.t. 96 13

OMe

TMSO

N

Ph

Ts

solvent

N

O

Ts

Ph

Chiral imidazolinium salt

+ *

273 274253


Scheme 95

2.2.1.4. Aza Diels-Alder Reaction of in situ Generated Imines

Scheme 96

Table 24: Aza Diels-Alder Reaction of in situ Generated Imines

Entry Catalyst Cation X− ee (%)

1 163B

N N+

Ph Ph

Ph Ph

Cl

PF6

−0

2 209D N

N+

Ph

Ph

N+

NPh

Ph

B[C6H

3(CF

3)2]4

−4

3 220CN N

+

Ph Ph

Ph Ph

NTf2

−5

4 231CN N

+

HO

Ph

OH

PhNTf

2−

21

5 235FN N

+

OH HO

BF4

−15

HOCO2Me

R

NHPg

C6F5I(OCOCF3)2

MeCN, MeOH, 1 h

PgHN

OMe

CO2Me

PBr3,

CCl4, 24 h

PgHN

Br

CO2Me

N

DCM, 10 min

NPg

CO2Me

278

purity 70-90%

DCM, −78 °C

NPg

CO2Me

R = H (serine), 275a

R = Me (threonine), 275b

Catalyst

276 277

279

yield 70-80%

1. 231D, PhMe, −40 °C, 48 h

2. AcCl/DCM, -78 °C, 30 min+

N

TBSO

OHC

O

PhO

59 167 62

4 %, 0% ee


In cooperatio with group of Dr. Maison,149 which is focusing on the aza Diels-Alder reac-

tions of the highly reactive imineesters, some of the prepared imidazolinium salts were test-

ed. All the salts were efficiently catalyzing the reaction, giving the corresponding product in

approximately 70-80% yield, based on the starting α-Br-ester 277. The mono-cationic salt

163B bearing a 4-chlorophenyl substituent at the C-2 possition was not showing any enan-

tioselectivity (Table 24, Entry 1). Using the bis-cation 209D, the product was obtained in 4

% ee (Table 24, Entry 2). Better enantioselectivities were obtained with the carbene precur-

sors 220C, 231C and 235F which were giving the product in 5, 21 and 15% ee respective-

ly (Table 24, Entries 3-5). Enantiomeric excess of 21% given by compound 231C represents

the highest enantioselectivity obtained by imidazolinium catalyst so far. Evaluation of fur-

ther imidazolinium compounds is currently in progress.

2.2.1.5. Inverse Electron Demand Aza Diels-Alder Reaction

The imino Diels-Alder of N-benzylidene aniline represents a direct route to quinoline

derivates. The furoquinoline skeleton is found in alkaloids like skimmianine or balfouri-

dine,150, 151 the pyranoquinoline moiety is present in many alkaloids such as flindersine,

oricine or veprisine.152 Derivatives of these alkaloids were found to have a wide spectrum

of biological activities such as psychotropic,153 antiallergic,154 antiinflamatory155 and estro-

genic activity.156

The imino Diels-Alder reaction of of N-benzylideneaniline was shown to be catalyzed by

InCl3,157 phenyl phosphonium perchlorate,158 BF

3.Et

2O,159 lanthanide triflates,160 GdCl

3161

and protic acids such as TFA.162 Nevertheless, there are just two reported examples of cat-

alytic enantioselective imino Diel-Alder reaction.163, 164

During the investigation of the reactivity of achiral imidazolinium salts,165 187B was

found to be capable of catalyzing the inverse electron demand aza Diels-Alder reaction of

N-benzylideneaniline (254) with 2,3-dihydrofurane (280) or 3,4-dihydro-2H-pyrane (282)

(Scheme 97).

Imine 254 takes in this reaction the place of the diene and gives with 280 the product 281

in 70% yield as mixture of diastereomers 281a and 281b in a ratio of 1:1 (determined by

1H-NMR).

When 3,4-dihydro-2H-pyrane (282) was used as dienophile, only the cis product 283a

was isolated in 16% yield.


Scheme 97

The proposed mechanism of the Lewis acid activation is shown on Scheme 98. The

Lewis acid is coordinating the nitrogen atom of the double bond of an imine, lowering the

LUMO of the imine, making it more reactive towards an attack on the electron rich

dienophile. Rearomatization of the phenyl ring is giving the desired quinoline derivative.

Scheme 98

Since a higher reactivity with dihydrofurane (280) was observed in the inverse electron

demand aza Diels-Alder, this model reaction was chosen for the evaluation of the catalytic

properties of the chiral imidazolinium salts. (Table 25).

Scheme 99

N

Ph

Ph

Solvent, r.t.

Chiral imidazolinium cat.O

NH

Ph

O

+

NH

Ph

O

+

254 280 281a 281b

HNN

+ LANLA HN+

OOO

254 281a 281b

N

Ph

Ph

MeCN, r.t. 16 h

10 mol% 187BO

NH

Ph

O

+

N

Ph

Ph

NH

Ph

+

O

O

70%

NH

Ph

O

ratio 1:1

MeCN, r.t. 16 h

10 mol% 187B

+

254

254 282 283a

16%

280 281a 281b


Table 25: Inverse Electron Demand Aza Diels-Alder Reaction Catalyzed by Imidazolinium

Salts

Surprisingly, the stereochemical environment of the imidazolinium salt had a crucial

influence on the reactivity. In cases of monocationic imidazolinium species, a significant

reactivity was observed only by salts 162B and 205B, where bulky substituents were pres-

ent at the nitrogen atoms and the salt were having PF6

− as a counter anion (Table 24, Entries

4 and 5). When salt 220C, which is bearing a hydrogen atom at the C-2 position was test-

ed, only traces of the product were isolated.

Imidazolinium salts 164B, 165C and 223F, bearing methyl groups at the nitrogen atoms

were showing a poor reactivity (Table 24, Entries 7-11). Finally, bis-cations 209C and 209D

were tested. While 209C gave after 112 h product 281 in 6% yield (Table 24, Entry 13)

209D gave after 16 h 64% yield, showing the highest activity from the imidazolinium salts

tested (Table 24, Entry 14).

A problem arised in the determination of the enantiomeric excess of the furoquinoline

derivative. Since the stereocenters are on the border of 5-membered and 6-membered rings,

separation using standard OD-H and AD-H columns failed. The separation of the enan-

tiomers reported in the literature using an OD-H column164 was found not to be repro-

ducible. There is a possibility of using an OJ column, which is designed for the separation

of enantiomers, possessing an asymmetric carbon on a five membered ring, however this

Entry Cat. Cation R2 X− Solvent t (h) Yield (%) endo/exoa

1 - − - - neat 48 0 N/A

2 - − - - DCM 48 0 N/A

3 - − - - MeCN 48 0 N/A

4 162B

N N+

PhPh

PhPh

R2

2-Cl-C6H

4PF

6−

MeCN 60 65 60/40

5 205B 4-Cl-C6H

4PF

6−

MeCN 112 8 50/50

6 220C H NTf2

−MeCN 96 traces N/A

7 164B

N N+

PhPh

R2

2-Cl-C6H

4PF

6−

MeCN 112 0 N/A

8 165C 4-Cl-C6H

4NTf

2−

PhMe 96 traces N/A

9 165C 4-Cl-C6H

4NTf

2−

PhMe 96 traces N/A

10 165C 4-Cl-C6H

4NTf

2−

DCM 96 2 N/A

11 165C 4-Cl-C6H

4NTf

2−

MeCN 96 traces N/A

12 223F Me BF4

−MeCN 96 traces N/A

13 209C

N

N+

Ph

Ph

N+

NPh

Ph- NTf

2−

MeCN 112 6 50/50

14 209D - B[C6H

3(CF

3)2]4

−DCM 16 64 50/50


collumn was not available to us. Measurement of the optical rotation did not indicate the

presence of enantioenriched material.

Therefore, dihydropyrane 282 was chosen as a dienophile for further reactions. As

expected the reactivity was significantly lower, compared to dihydrofurane, but it was pos-

sible to separate the diastereomers by FCC. The separation of the enantiomers was per-

formed on an HPLC using an AD-H column.

Scheme 100

Table 26: Inverse Electron Demand Aza Diels-Alder Reaction Catalyzed by Imidazolinium

Salts

Entry Cat. Cation X− Solvent T (°C) t (h) Yield (%) endo/exoa

1 - − - DCM r.t. 48 0 N/A

2 - − - MeCN r.t. 48 0 N/A

3 163BN N

+

PhPh

PhPh

Cl

PF6

−MeCN r.t. 96 0 N/A

4 163B PF6

−DCM r.t. 96 traces N/A

5 208DN

N+

N+

N

B[C6H

3(CF

3)2]4

−DCM r.t. 96 34 50/50

6 284D

OO

NNN

+N

+

Ph Ph

B[C6H

3(CF

3)2]4

−DCM r.t. 96 67 60/40

7 210D N

N+

N+

N B[C6H

3(CF

3)2]4

−DCM 0 96 67 60/40

8 209D N

N+

Ph

Ph

N+

NPh

Ph

B[C6H

3(CF

3)2]4

−DCM −20 72 18 60/40

9 285 P

O

OH

- DCM r.t. 20 18 85/15

N

Ph

Ph Imidazolinium catalyst

NH

Ph

+

NH

Ph

+

O O

O

254 282 283a 283b

solvent


Monocationic salts failed to give any results in the reaction of dihydropyrane (Table 25,

Entries 3, 4). Using the bis-cationic salts had significantly improved the reactivity. When the

achiral salt 153C was used, the corresponding product was isolated in 35% yield (Table 25,

Entry 5). When the chiral bis-cation 284D166 was used (Table 26, Entry 6) the pyranoquino-

line was isolated in 67% yield after 96 h at r.t.. The ratio of the diastereomers changed from

50:50 in the case of the achiral bis-cation 208D (Table 26, Entry 5) to 60:40 in the case of

284D. Since no enantiomeric excess was detected in any of these cases, further chiral bis-

cations were tested at lower temperatures.

210D gave a yield of 68% with a diastereomeric ratio of 60:40 after 96 h at 0 °C without

any enantiomeric excess (Table 25, Entry 7). Lowering the temperature further to −20°C and

using 209D as a catalyst resulted just in a lower yield of 18%. The product was obtained as

a racemate (Table 25, Entry 8).

Additionally a 1,1'-binaphthyl-2,2'-diyl hydrogenphosphate (285) was tested in the reac-

tion (Table 26, Entry 9). After 20 h at r.t., the pyranoquinoline 283 was isolated in 16% yield

with a diasteremeric ratio of 85:15 (Table 26, Entry 9). The product was obtained as a race-

mate.

2.2.1.6. Diels-Alder Reaction of Suphur Containing Compounds

Some imidazolinium catalysts were also tested in the Diels-Alder reaction of (E)-O-ethyl

3-phenylprop-2-enethioate (285) and cyclopentadiene (Scheme 101, Table 27)

Scheme 101

Table 27: Diels-Alder Reaction of (E)-O-Ethyl 3-phenylprop-2-enethioate (285)

The experiments were performed by N. Clemens.167 The obtained results are showing,

that bis-cation 209D serves as an efficient catalyst for this type of reaction. The formation

Entry Cat. Cation X− T (°C) t (h) Endo/Exo Yield (%)

1 none − - 45 60 100/0 22

2 209D N

N+

Ph

Ph

N+

NPh

Ph

B[C6H

3(CF

3)2]4

−10->45 108 100/0 69

3 224CN N

+

NTf2

−25->45 60 90/10 38

Catalyst, DCM+

Ph

S

OEt

Ph

S

OEtPh

OEtSendo exo

285

286a 286b


of the product was detected already at 10 °C. At this temperature, no product was formed in

the control reaction. Despite rather high catalytic activity, no enantiomeric excess was

detected. Mono-cation 224C gave the product in 38% yield, which is just slightly higher

than the control reaction (Table 27, Entry 3). Nevertheless, also the exo product was

observed in the 1H-NMR spectra of the reaction product.

2.2.1.7. Ring Opening of Epoxides

The ring opening of epoxides with aniline is catalysed very efficiently by the imidazolin-

ium bis-cations. 209D and 210D (Scheme 102). The reactions were performed by O. Sere-

da within the framework of her PhD in our group.166 Some representative results are shown

in Table 28.

Scheme 102

Table 28: Ring Opening of the Epoxides

Best yields were obtained, when the reaction was performed neat. Due to the very

lipophilic origin of B[C6H

3(CF

3)2]4

− anion, both 209D and 210D were soluble in the mix-

ture of cyclohexeneoxide (288) and aniline (112), giving the corresponding racemic product

289 in 96 and 98% yield, respectively (Table 28, Entries 2 and 3).

2.2.1.8. Baylis-Hillman Reaction

The Baylis-Hillman reaction is a very useful C-C bond forming reaction because of its

ability to provide higly functionalized compounds.27 Nevertheless, this reaction is still hav-

ing limitations, from which the long reaction times are probably the most significant one.

This reaction is mostly performed under catalysis of tertiary amines such as DABCO

(290)168 or phosphines,169 which are used in order to form an enolate species, that is subse-

Entry Catalyst Catalyst X− Yield (%) ee (%)

1 none − - traces N/A

2 209D N

N+

Ph

Ph

N+

NPh

Ph

B[C6H

3(CF

3)2]4

−96 0

3 210D N

N+

N+

N B[C6H

3(CF

3)2]4

−98 0

neat, r.t., 48 h

O NH2

+

HO HN Ph

catalyst

288 112 289


quently attacking an aldehyde, forming the new C-C bond (Scheme 103). Since the forma-

tion of the enolate is the rate determining step, different attempts were made to accelerate

this step, including Lewis acids170 or Brønsted acids169 as cocatalysts.

Scheme 103

A. Co-Catalysis with DABCO Catalyzed Reaction

In order to evaluate the potential of our imidazolinium salts, attempts to apply the salts

in this reaction were done. Nevertheless, neither in reaction of benzaldehyde with methyl

acrylate, nor in the reaction of phenylpropionaldehyde with cyclopentenon, no formation of

the desired product could be detected (Scheme 104).

Scheme 104

B. Co-Catalysis with Phosphine Catalyzed Reaction

The Baylis-Hillmann reaction of cyclopentenon with phenylpropionaldehyde was report-

ed to be catalyzed by trialkylphosphines. Enantiomeric excess has been achieved by using

chiral Brønsted acids as cocatalysts.169 Since the reaction is catalyzed very efficiently by

Bu3P at r.t., it is necessary to perform the cocatalyzed reaction at lower temperatures, pre-

venting the formation of the racemic product via the background reaction.

Scheme 106

Ph+

cocatalyst

O

CHO

THF, Bu3P (30 mol%)

OOH

Ph

292 293 294

Ph+

Imidazolinium salt

(DABCO, 30 mol%), MeCN, r.t, 48 h

O

O

Ph

+OMe

O

CHO no reaction

Imidazolidinium salt

(DABCO, 30 mol%), MeCN, r.t, 48 hno reaction

292 293

167 290

NN

O

OMe

N+N

O−

OMe

O

H

Ph

N+N

O

OMe

O−

H

PhH

N+N

O−

OMe

OH

H

PhPh

OH

OMe

O

NN

+

290

291

292

291


Table 29: Cocatalysis of the Phosphine Catalyzed Reactions

The yield of the reaction strongly depends on the temperature and on the concentration

of the reactants. When the bis-cation 209D was used in the concentration of 0.015 mol.L-1,

the product was isolated in a low yield of 4% (Table 29, Entry 1), while when mono-cation

165C was applied in the concentration of 0.045 mol.L-1, the product was isolated in 14%

yield after 24 h (Table 29, Entry 2). In both cases, the product was obtained as a racemate.

The rather fast background reaction makes this system rather unsuitable for cocatalysts test-

ing with the prepared imidazolinium salts.171

Entry Cocat. Cation X− Concentration (mol.L-1) T (°C) t (h) Yield (%)

1 209D N

N+

Ph

Ph

N+

NPh

Ph

B[C6H

3(CF

3)2]4

−0.015 −40°C 96 4

2 165C

N N+

Ph Ph

Cl

NTf2

−0.045 −40°C 24 14


2.2.2. Application of Imidazolinium Salts as NCN Carbene Ligands

2.2.2.1. Application of Imidazolinium Salts as Carbene Ligands for the Heck

Reaction

Scheme 106

Table 30

Imidazolinium salt 231C was used as a carbene ligand for a Heck reaction (Scheme 106,

Table 30). The reaction were performed by B. Schafner in the framework of his diploma the-

sis in the group of Prof. D. Kaufmann.172 The reaction was performed at r.t. and at 40°C in

DMSO as a solvent. The desired products 297 and 298 were obtained in 29% yield and 36%

yield, however no ee was detected.

2.2.2.2. Application of Imidazolinium Salts as a Carbene Ligand for the Et2Zn

Attempts to use imidazolinium salts as the Lewis acid activators for Et2Zn addtion to

benzaldehyde were made, but the salts did not show any activity (Scheme 107)

Scheme 107

Since it is well known, that diamines, bearing OH groups can cordinate zinc, which is

then activating the carbonyl group of benzaldehyde,173 there was an attempt made to coor-

dinate Zn by a carbene precursor, that is bearing OH groups on the side chains of the imi-

dazolinium ring.

Scheme 108

Imidazolinium carbene precursor (0.1 eq)H

O

Base (0.1 eq), Et2Zn 1.1 eq., PhMe, 30 h

OH

*

167 299

Imidazolinium catalyst 0.1 eq.H

O

Et2Zn 1 eq., PhMe, r.t.no reaction

167

Entry Cat. Cation X− T (°C) t (h) Yield270

(%) Yield271

(%) ee (%)

1 231C

N N+

HO

Ph

OH

Ph

NTf2

−r.t. 40 29 36 0

2 231C NTf2

−40 16 19 44 0

+Pd(OAc)2, 231C, Et3N

I

N Ph

O

O

N Ph

O

O

PhN Ph

O

O

Ph+

DMSO

295 296 297 298


Table 31: Addition of Et2Zn to Benzaldehyde

In order to generate the carbene, imidazolinium salt 235F was deprotonated with t-BuOK

in a PhMe solution. After 5 min stirring, Et2Zn (1.1 eq.) was added, followed by benzalde-

hyde (1 eq.). After 30 h stirring at r.t., the product was isolated in 67% yield, showing 66%

ee. (Table 31, Entry 2). When no base was present, no reaction occured, indicating, that the

carbene generation is essential for the reaction to proceed (Table 31, Entry 1). Et2Zn is prob-

ably reactiong with the imidazolinium carbene, forming a complex shown on Scheme 110,

which is then activating the addition of Et2Zn to benzaldehyde.

Next, salt 231F was tested in various solvents. The reaction in DME and dioxane did not

give any product, from the reaction in THF only traces of corresponding product were iso-

lated (Table 31, Entries 3-5). Finally, reaction in PhMe gave the corresponding product in

57% yield and 40% ee (Table 31, Entry 6). When the reaction was performed at 40 °C, the

yield decreased to 46%, the ee remained the same (Table 31, Entry 7). Salt 231C, bearing a

different anion was applied and the product was isolated in 35% yield and 44% ee (Table

31, Entry 8).

L-Valinol based compound 233F gave the alcohol 299 in 38% yield and 35% ee (Table

31, Entry 9). Changing the i-Pr groups to t-Bu groups in catalyst 234F resulted in an

increase of the yield to 70% but ee of only 8% was detected (Table 31, Entry 10).

Because of the rather high volatility of alcohol 299 under high vacuum, which was not

allowing very accurate yield deteremination, further experiments were conducted with

naphtyl-2-carbaldehyde (300) (Scheme 109, Table 32).

Entry Cat. Cation X− Solvent Base T (°C) Yield (%) ee (%)

1 235F

N N+

OH HO

NTf2

−PhMe - r.t. 0 N/A

2 235F NTf2

−PhMe t-BuOK r.t. 67 66

3 231F

N N+

HO

Ph

OH

Ph

BF4

−THF t-BuOK r.t. traces N/A

4 231F BF4

−DME t-BuOK r.t. 0 N/A

5 231F BF4

−Dioxane t-BuOK r.t. 0 N/A

6 231F BF4

−PhMe t-BuOK r.t 57 40

7 231F BF4

−PhMe t-BuOK 40 46 40

8 231C NTf2


9 233F N N+

HOOH

BF4


10 234F N N+

HOOH

BF4

−PhMe t-BuOK r.t. 70 8


Scheme 109

Table 32: Addition of Et2Zn to Naphtyl-2-carbaldehyde (300)

When the reaction was conducted with catalyst 231F, using t-BuOK as a base, the cor-

responding alcohol 301 was isolated in 61% yield and 60% ee (Table 32, Entry 1). Chang-

ing the base to KHMDS resulted in a dramatic increase of the yield to 92%, however, the eedecreased to 45% (Table 32, Entry 2). Using 2 and 3 eq. of the base resulted in a decrease

of the yield to 84 and 78% respectively and and in case of 3 eq. the ee dropped to 31%

(Table 32, Entries 3 and 4)

By decreasing the reaction temperature to −5 °C, the yield decreased slightly to 85%, but

the ee increased to 55% (Table 32, Entry 5). By lowering the temperature further to −78 °C,

only traces of the compound 301 were isolated (Table 32, Entry 6). Performing the reaction

using different hexamethyldisilazanes, resulted in yields of 80 and 76% and ee’s of 47 and

33% (Table 32, Entries 7-8), showing that KHMDS is the best base for this type of reaction.

Performing the reaction with pentadentate bis-diol 232F gave the product 301 in 60%

yield and 33% ee (Table 32, Entry 9), using the compound 235F at -25 °C resulted in 58%

yield and 25% ee (Table 32, Entry 10)

Entry Catalyst Catalyst X− Base T (°C) Yield (%) ee (%)

1 231F

N N+

HO

Ph

OH

Ph

BF4

− t-BuOK (0.1 eq) r.t 61 60

2 231F BF4

−KHMDS (0.1 eq.) r.t 92 45

3 231F BF4

−KHMDS (0.2 eq.) r.t 84 45

4 231F BF4

−KHMDS (0.3 eq.) r.t 78 31

5 231F BF4

−KHMDS (0.1 eq.) −5 85 55

6 231F BF4

−KHMDS (0.1 eq.) −78 traces N/A

7 231F BF4

−NaHMDS (0.1 eq.) r.t. 80 47

8 231F BF4

−LiHMDS (0.1 eq.) r.t. 76 36

8 232F N N+

HO

Ph

OH

Ph

HOOH

BF4

−KHMDS (0.1 eq.) r.t. 60 33

10 235FN N

+

OH HO

BF4

−KHMDS (0.1 eq.) −25 58 25

Imidazolinium carbene precursor (0.1 eq)

Base, Et2Zn 1.1 eq., PhMe, 40 h

*HOO

300 301


Scheme 110

Addition of Et2Zn to Imines

Parallel to the addition to aldehydes, the addition to imines was explored with carbene

precursor 235F (Scheme 111)

Scheme 111

The addition to N-benzylideneaniline (254) did not proceed at all, while with N-benzyli-

dene-tosylamine (272) the reduction product 302 was isolated in 84% yield.

Conjugated Addition

The conjugated addition of Et2Zn to chalcone (303) proceeds in the presence of a carbene

generated from 231F with a low yield, giving the racemic product 304. (Scheme 112)

Scheme 112

231F (0.1 eq)

KHMDS (0.1 eq.), Et2Zn 1.1 eq., PhMe, 40 hPh

O

Ph Ph

O

Ph

304

37%, 0% ee303

235F (0.1 eq.)

t-BuOK (0.1 eq.), Et2Zn 1.1 eq., PhMe, r.t.

Ph

N

Ph

no reaction

235F (0.1 eq.)

t-BuOK (0.1 eq.), Et2Zn 1.1 eq., PhMe, r.t.

N

Ph

Ts

NH

Ph

Ts

302

84%

254

272

t-BuOK, Et2Zn

−BF4

PhMe, r.t.

235F

N N+

OH HO

N N

O OZn


2.2.3. Imidazolinium Salt as Phase Transfer Catalyst

2.2.3.1. Imidazolinium Bis-Cation as Phase Transfer Catalyst in a Michael Reaction

Scheme 113

Biscation 210B was tested as a phase transfer catalyst in a Michael addition of dimethyl-

malonate to chalcone (303) under biphasic conditions (K2CO

3, PhMe/DCM). After 16 h at

r.t., the reaction gave the product in 43% yield. However, no ee was detected by measuring

the optical rotation (Scheme 113). So far, no chiral imidazolinium salts have been reported

to give an asymmetric induction in this reaction.

210B, 10 mol%, K2CO3, 6 eq.

Ph

O

Ph

COOMe

COOMe

+

Ph

O

Ph

MeOOC COOMe

305

43%, 0% ee

N N+

N+

N

PF6-

PF6-

PhMe/DCM, 10/1, 16 h, r.t.

303


2.2.4. Imidazolinium Salts as a Chiral Shift Reagents

Based on the previous reports of using chiral thiazoline based ionic liquids174 or imida-

zolinium salts109 as chiral shift reagents, the prepared salts were tested on their ability to

interact with the Mosher’s carboxylate. Differences in the chemical shift of the OMe group

and the CF3

group were examined.

For the experiment rac-Mosher’s carboxylate derived from commercially available rac-

Mosher’s acid was mixed with the chiral imidazolinium salt. The mixture was dissolved in

acetone-d6 and 1H-NMR and 19F-NMR were recorded. The results are summarized in Table

33.

The methoxy group of the Mosher’s salt was showing a singlet at 3.54 and the CF3

group

was in the 19F-NMR showing a signal at −71.59 (Table 33, Entry 1, Table 34, Entry 1).

When a cationic salt was added, interactions between enantiopure cation and two enan-

tiomers of chiral Mosher’s anion causes, that the diastereomeric ion pair was formed, result-

ing in different chemical shift. In an ideal cases, each of the two diastereomers should show

different chemical shift, so a signal splitting is observed.

In order to be able to assign the signals to the corresponding enantiomers of Mosher’s

carboxylate, an enatiomerically enriched sample of 12% ee was used.

When enantiopure salt 165A bearing a phenyl ring at the C-2 position was used in com-

bination with Mosher’s carboxylate (Table 33, Entry 2), no signal splitting was seen in either

1H-NMR or 19F-NMR, however, when salt 224C was applied, a signal splitting of 10.3 Hz

was observed in the 19F-NMR. Further on, two enantiopure salts 218F and 218C that are

bearing H at the C-2 position and are differing in the counter anion were applied (Table 33,

Entries 4 and 5). None of the salts revealed a splitting in the 1H-NMR, where just a multi-

plet was observed, but BF4

− salt 218F showed a splitting of 9.1 Hz in 19F-NMR and NTf2

−

salt 218C showed a slightly higher splitting of 9.9 Hz, showing that an increasing size of

the counter anion is increasing the stereodiscrimination.

The same trend was seen, when, biscations 209C and 209D were applied. Whereas salt

209C with NTf2

− anion showed no splitting in 1H-NMR and a 13 Hz splitting in 19F-NMR,

change of the anion to B[C6H

3(CF

3)2]4

− in case of 209D resulted in 4.3 Hz splitting in 1H-

NMR and 23 Hz in 19F-NMR (Table 33, Entries 6 and 7, Table 34, Entries 4 and 5).

The opposite trend was however observed in case ot the biscations 210D and 210B.

While B[C6H

3(CF

3)2]4

− salt 210D is showing the splitting 1.2 Hz in 1H-NMR and 21.4 Hz

in 19F, PF6

− salt 210B splits the signal at 6.3 Hz and 53 Hz, respectively (Table 33, Entries

.8 and 9, Table 34, Entries 2 and 3)

Since it was expected, that the OH groups at the imidazolinium unit can help the stere-

odiscrimination, further experiments were performed with the salts bearing OH groups. In

case of L-valine based cations 233F and 233C, stereodiscrimination of 17.6 and 14.6 Hz was


observed in 19F-NMR. It should be noted that change of the counter anion from BF4

− to

NTf2

− resulted in a switch of the signals of the two enantiomers of the Mosher’s salt.

Table 33: Chemical Shifts of Mosher’s Carboxylate

a Spectrum recorded in CDCl3

BF4

− salt 235F gave the 19F-NMR signal splitting of 32 Hz. Upfield shift of the signal in

the 1H-NMR indicates, that there are interactions between imidazolinium cation and the

Mosher’s salt, however, no stereodiscrimination was observed (Table 33, Entry 12, Table

34, Entry 6).

When norephedrine based BF4

− salt 231F was applied ,no signal splitting was seen.

(Table 33, Entry 13, Table 34, Entry 7). Changing the counter anion to NTf2

− resulted in a

dramatic increase of the splitting to 17 Hz in 1H-NMR and 118 Hz in 19F-NMR (Table 33,

Entry 14, Table 34, Entry 8). Applying 3 eq. of 231C per 1 eq. of Moshers carboxylate did

not improve the splitting (Table 33, Entry 15). By changing the counter anion to

B[C6H

3(CF

3)2]4

−, the splitting increased to 24 Hz and 151 Hz respectively (Table 33, Entry

17, Table 34, Entry 9). Using the opposite enantiomer of ent-231C showed the same split-

ting and opposite order of the signals as expected (Table 33, Entry 16).

Entry Salt Ratio1H δ(S)

(ppm)

1H δ(R)

(ppm)

19F δ(S)

(ppm)

19F δ(R)

(ppm)

1H Δδ(Hz)

19F Δδ(Hz)

1 - N/A 3.54 3.54 −71.59 −71.59 0 0

2 165A 1/1 3.65 3.65 −70.40 −70.40 0 0

3 224C 1/1 3.57 3.57 −71.46 −71.49 0 10.3

4 218F 1/1 multiplet observed −71.42 −71.44 N/A 9.1

5 218C 1/1 multiplet observed −71.42 −71.45 N/A 9.9

6 209C 1/1 3.57 3.57 −71.84 −71.88 0 13

7 209D 1/1 3.59 3.60 −71.57 −71.49 4.3 27.1

8 210B 1/1 3.59 3.57 −71.50 −71.64 6.3 53.0

9 210D 1/1 3.57 3.57 −71.23 −71.17 1.2 21.4

10 233F 1/1 3.590 3.587 −71.65 −71.70 1.2 17.6

11 233C 1/1 3.58 3.58 −71.63 −71.60 0 14.6

12 235F 1/1 3.60 3.60 −71.32 −71.41 0 32

13 231F 1/1 3.54 3.54 −71.59 −71.59 0 0

14 231C 1/1 3.55 3.52 −70.90 −71.22 12 118

15 231C 3/1 3.55 3.52 −70.90 −71.22 12 118

16 ent-231C 1/1 3.52 3.56 −71.42 −71.08 17 126

17 231D 1/1 3.50 3.56 −71.39 −70.99 24 151

18 232D 1/1 3.55 3.55 −71.52 −71.50 0 6.9


Table 34: Stereodiscrimination of Mosher’s Carboxylate, Part 1

Entry1H NMR 19F-NMR

1

F3C COOK

OMe

306

2

F3C COOK

OMe

306

N

N+

N+

N

210B

2PF6−

3

F3C COOK

OMe

306

N

N+

N+

N

210D

2B[C6H3(CF3)2]4−


Table 34, part 2

Entry1H NMR 19F-NMR

4

F3C COOK

OMe

306

N

N+

N+

N

Ph

Ph

Ph

Ph

210C

2NT2−

5

F3C COOK

OMe

306

N

N+

N+

N

Ph

Ph

Ph

Ph

210D

2B[C6H3(CF3)2]4−

6

F3C COOK

OMe

306

N N+

OH HO

235F

BF4−


Table 34, Part 3

Entry1H NMR 19F-NMR

7

F3C COOK

OMe

306 231F

N N+

HO

Ph

OH

Ph BF4−

8

F3C COOK

OMe

306 231C

N N+

HO

Ph

OH

PhNTf2

−

9

F3C COOK

OMe

306 231D

N N+

HO

Ph

OH

Ph

B(C6H3(CF3)2)−


Finally, when the the salt 232D, bearing four hydroxy group was tested, no splitting was

observed in 1H-NMR and and a splitting of 6.9 Hz was observed in 19F-NMR (Table 33,

Entry 18).

For practical use, signal splitting of 12 Hz and more in 1H-NMR and 60 Hz and more in

19F-NMR are practically useful, because signal integration allows to determine the enan-

tiomeric ratio of the sample.

Salts 231C and 210B were also used in combination with the potasium salt of DL-valine,

but no stereodiscrimination was observed in 1H-NMR spectrum in case of 231C. The bis-

cation 210B was found to be totally unsuitable to be used with DL-valine, because the sig-

nal of NH2CHCH which is studied was overlapping with the signals of the bis-cation.

Another attempt was made with salt 231C and rac-methyl-tetrahydrofurane, but also in

this case, no splitting was observed.

In conclusion it was shown, that the prepared imidazolinium salts are promising shift

reagents, which are able to stereodiscrininate Mosher’s carboxylate. Best results were

obtained with the salt 231D, which is showing strong signal splitting in both 1H-NMR and

19F-NMR. The signal splitting of 151 Hz is the strongest reported for imidazolinium based

shift reagents so far.


2.2.5. Imidazolidinium Salts as a Reaction Medium

Ionic liquids, having per definition a melting point below 100 °C, and especially room

temperature ionic liquids (RTIL) have attracted much interest in recent years as novel sol-

vents for reactions and electrochemical processes.175 They are considered to be "Green sol-

vents",176 amongst others, due to their negligible vapor pressure. The scope of ionic liquids

based on various combinations of cations and anions has dramatically increased and contin-

uously new salts177-179 and solvent mixtures 180 are discovered. The most common used liq-

uids are based on imidazolium cations like [BMIM] (1-butyl-3-methylimidazolium) with an

appropriated counter anion.

However, it has been observed, that imidazolium salts, incorporating a hydrogen sub-

stituent at the C-2 position, are in some application, where bases are involved, deprotonat-

ed. The corresponding carbenes are formed, which can cause undesired side reactions,181

like in the case of the Baylis-Hillman reaction.182 Nevertheless, there are also cases where

this behaviour has a positive effect. In reactions where metals are used as catalysts the

formed carbenes are acting as ligands and stabilising the metal catalyst, e.g. in the Suzuki

reaction.183, 184 The undesired deprotonation has been partly overcome by the application of

imidazolium salts with a methyl group at the C-2 position, e.g. [BDMIM][PF6] (1-butyl-

2,3-dimethylimidazolium) in a Baylis-Hillman reaction.185 2 eq. of the catalyst DABCO, 2

eq. methyl acrylate, 1 eq. aldehyde and 0.33 equiv. of ionic liquid were the optimised con-

ditions. Recently, it has been shown that also the C-2 methyl group of these cations can be

deprotonated under mild conditions,186, 187 which would make these cations not suitable for

reactions involving strong bases. Therefore, a phosphonium ionic liquid has been shown to

be a suitable solvent for these reactions giving good GC-yields.188 The phosphonium salt

was dried by azeotropic distillation with benzene or with potassium.

Large Scale Preparation of Imidazolinium Ionic Liquid

Since imidazolidinium salts that are bearing a phenyl at the C-2 position do not have any

protons to be removed by a base, they could be employed in reactions involving strong and

medium bases.

During the investigation of imidazolinium salts,165 it has been found that some of these

salts qualify as novel ionic liquids. Imidazolinium based ionic liquids with a phenyl substi-

tutent at the C-2 carbon have not been used as solvents in reactions so far. For a practical

preparation of an ionic liquid, it is necessary to obtain the desired coumpound in high yield

and purity.


Scheme 114

In order to prepare the salt 196C (Scheme 114), aminal 196 was synthesised according

to the previously described procedure from diamine 159 and benzaldehyde in water in 95%

yield. Compound 196 was oxidized with NBS to the desired imidazolinium salt 196A in

99% yield. The cheap N-bromo-acetamide (NBS) was chosen as the oxidation agent instead

of N-bromoacetamide (NBA), which is often the superior reagent since the product can be

purified more easily. Nevertheless, no contamination by succinamide could be detected in

the final product. 196A was hydroscopic and was transferred into the salt 196C by vigorous

stirring in the presence of LiNTf2

in a mixture of water and CHCl3

for 1 h. After the aque-

ous phase was removed, the chloroform phase was washed three times with water and dried

over molecular sieves to furnish the salt 196C in 90% yield. In one run 15 g of salt 196C

was prepared. Spectral data and CHN analysis proofed the purity of the salt. 196C was a liq-

uid at room temperature. Only after days it crystallized and a melting point of 35 °C was

detected. Prior to use it was melted and it remained a liquid for several hours at r.t.. In the

reaction mixture it remained permanently a liquid.


Scheme 115

O

R

O

OMe+ionic liquid 196C

r.t., base

O

OMeR

OH

290

N N

Ph

DME, r.t., 45 minN N

+

PhBr

−

NH HN

196

95%

LiNTf2

196A

99%

r.t. H2O, 3 h CHCl3/H2ON N

+

PhNTf2

−

196C

90%

172

PhCHO NBS


Table 35: Baylis-Hillman Reaction in Ionic Liquid 196C

First, salt 196C was tested as a solvent in the Baylis-Hillman reaction with methyl acry-

late (280) and various aldehydes. The results are shown in Table 35.

When 1 eq. DABCO was used as a catalyst, benzaldehyde (167) and methyl acrylate

(262) formed the desired product 308 in 53% yield after 72 h (Table 35, Entry 1). Switch-

ing to quinuclidinol, the product 308 was isolated 52% yield after 24 h, while use of quin-

uclidine led in 48 h to a yield of 66% (Table 34, Entries 2 and 3). With the electron deficient

4-chlorobenzaldehyde (175) and quinuclidinol a yield of 52% after 48 h was achieved, while

with quinuclidine 66% were isolated (Table 34 Entries 4 and 5). 2-Pyridinecarbaldehyde

(181) gave a yield of 69% after 48 h (Table 34, Entry 6). With the electron rich 4-methoxy-

benzaldehyde (307) and quinuclidine, a yield of 38% was found (Table 34, Entry 6). The

aliphatic aldehyde, 3-phenylpropionaldehyde (292), gave a yield of 44%. A repeat of the

reaction with benzaldehyde and only 10 mol% of quinuclidine gave a slightly lower yield

of 52% compared to 1 eq. of the base (Table 34, Entry 9). 4-Chloro-benzaldehyde (175)

yielded with 10 mol% quinuclidine the product 309 in 52% (Table 34, Entry 10). However,

when only 1 mol% of quinuclidine was used, only traces of the product were isolated after

48 h (Table 34, Entry 11). In a control reaction in the absence of base, no product formation

could be detected (Table 35, Entry 12). The reaction times were not optimised and before

the work up, unreacted aldehyde and methyl acrylate were still present in the reaction mix-

ture. The ionic liquid 196C was recovered in 93% yield and could be reused after the work

up with no changes in the reactivity and NMR data proved the purity of 196C.

Entry Aldehyde R Base t (h) Product Yield (%)

1 167 C6H

5 DABCO 72 308 53

2 167 C6H

5 DABCO 2 eq. 24 308 58

3 167 C6H

5 Quinuclidinol 24 308 41

4 167 C6H

5 Quinuclidine 48 308 66

5 175 4-Cl-C6H

4 Quinuclidinol 48 309 52

6 175 4-Cl-C6H


7 181 2-C5H

4N Quinuclidine 48 310 69

8 307 4-MeO-C6H


9 292 CH2CH

2C

6H


10 167 C6H

5 Quinuclidine 10 mol% 48 308 52

11 175 4-Cl-C6H

4 Quinuclidine 10 mol% 48 309 52

12 167 C6H

5 Quinuclidine 1 mol% 48 308 traces

13 167 C6H

5 - 48 308 0


In addition, 2-cyclohexen-1-one (313) was applied in a reaction with benzaldehyde (167)

in the ionic liquid 196C with quinuclidine and product 314 was isolated in 45% yield after

48 h. With cyclopenten-1-one (293) and benzaldehyde (167), compound 315 was obtained

in 17% yield (Scheme 116).

Scheme 116

Moreover the behaviour of acrylamide (316), which is best soluble in polar solvents, was

tested. When acrylamide (316) was treated in the ionic liquid 196C with 1 eq. of quinucli-

dine and benzaldehyde (167) the product 317 was isolated in 48% yield after 48 h. The

application of 4-chlorobenzaldehyde (175) in the reaction led to the isolated product 294 in

48% yield. The last case is an example, where all reactants were solids, which were all dis-

solved in the ionic liquid. (Scheme 117)

Scheme 117

2.2.5.2. Addition of Grignard Reagents to Carbonyl Groups

Next we were interested if 196C would be also suitable as a solvent in reactions involv-

ing Grignard reagents as shown in Scheme 118.

NH2

O OOH

NH2

ClCl

O

+

NH2

O

316

O

317

48%

OH

NH2

quinuclidine (1 eq.), r.t., 48 h

196C

O

+

167

316 318

48%

175

quinuclidine (1 eq.), r.t., 48 h

196C

O

Ph

+ionic liquid 196C

1 eq. quinuclidine, r.t., 48 h

O O

Ph

OH

O

Ph

+ionic liquid 196C

1 eq. quinuclidine, r.t., 48 h

O O

Ph

OH

315

17%

314

45%

167

167 293

313


Scheme 118

Table 36: Addition of Grignard Reagents to Benzaldehyde

aPhMgCl used

A commercially available solution of phenylmagnesium chloride in THF was added to

the ionic liquid at r.t., followed by benzaldehyde. After 16 h stirring at r.t., the reaction mix-

ture was quenched with NH4Cl and the formed biphasic system was extracted with hexane.

No product formation was detected and the ionic liquid 196C was recovered (Table 36,

Entry 1).

Therefore, the more reactive PhMgBr was choosen, but no reaction occured either (Table

36, Entry 2). In order to make the reaction system more reactive, THF was evaporated from

the reaction vessel under reduced pressure, leaving a solution of the Grignard reagent in the

ionic liquid. After addition of the benzaldehyde, an exothermic reaction occured. After the

exothermic reaction had ended (1 h), the mixture was worked up and the reaction product

321 was isolated in 27% (Table 36, Entry 3).

In order to examine, if exothermic conditions are necessary for the reaction to perform,

a solution of PhMgBr (319) in ionic liquid 196C was cooled down to 0°C and PhCHO was

added successively. After 16 h at 0 °C, no product was isolated after workup (Table 36,

Entry 4), showing that higher temperatures are necassary for the reaction to occur.

Finally, benzaldehyde (1 eq.) was added to a solution of PhMgBr (3 eq.) in ionic liquid

(0.6 mL) at room temperature and after the spontaneous exothermic reaction had finished,

the reaction mixture was heated up to 40 °C (approximately boiling point of Et2O)189, 190 for

additional 3 h. After the workup, the desired diphenylmethanol (321) was isolated in 68%

yield (Table 36, Entry 5). The same reaction performed with HexMgBr (320) gave the

hexyl-phenyl methanol (296) in 77% yield (Table 36, Entry 6).

The ionic liquid 196C was recovered after the workup in 93% yield and NMR data

proved the purity of the recovered compound. When recovered ionic liquid was used in the

Entry Solvent R Time (h) T (°C) Product Yield (%)

1 196C/THF Pha 16 r.t. 321 0

2 196C/THF Ph 16 r.t. 321 0

3 196C Ph 1 r.t. 321 27

4 196C Ph 16 0 321 0

5 196C Ph 3 40 321 68

6 196C Hex 3 40 322 77

MgBrR + Ph R Ph196C

OHO

167 321 or 322R = Ph, 319

R = Hex, 320


Grignard reaction, the same results were obtained. During the work up, a triphasic system

(hexane, water, ionic liquid) was observed.

Furthermore, the addition of PhMgBr to acetone was explored, but under the described

condition, no reaction product was isolated after 3 h (Scheme 119)

Scheme 119

The stability of the ionic liquid 196C under extremely basic conditions was tested by the

addition of PhLi to benzaldehyde. Under the standard conditions, that were used for the

addition of Grignard reagents to benzaldehyde, a complex reaction mixture was obtained

and the ionic liquid was destroyed.

Williamson ether synthesis and reduction of benzophenon by NaBH4

were performed in

the ionic liquid 196C, but no expected products were isolated. Nevertheless, in these cases,

the ionic liquid was succesfuly regenerated.

In order to prove the absence of any possible deprotonation in the ionic liquid 196C, the

reaction was repeated with PhMgBr lacking the addition of benzaldehyde and after 1 h, the

mixture was quenched with deuterium oxide and an 1H-NMR spectra proved the absence of

a possible deprotonation.

In conclusion of this part, it is possible to state, that a novel ionic liquid based on a 1,3-

dimethyl-2-phenylimidazolinium cation can be used in reactions involving strong bases. A

few limits for the ionic liquid in some other applications may be possible. The presented

ionic liquid starts degradating at 1 V measured against ferrocene/ferrocinium, which makes

it less suitable for electrochemical applications.191 The measurement was performed by the

group Prof. F. Endres at TU-Clausthal. Due to the incorporation of an arene ring in the salt,

use in aromatic nitrations192 might be limited.

MgBrPh +

196CO

3h, 40°Cno reaction

319


2.2.6. Application of Si+ Species Generated from Silacycles as Catalysts193

A silicon cation can be easily generated in situ from the prepared silacycles by the reac-

tion with silver bistrifluoromethylsulfonimide,194 which is abstracting the chloride anion,

producing the silicon bistrifluoromethylsulfonimide, which can act as a silicon based Lewis

acid.

Scheme 120

2.2.6.1. Inverse Electron Demand Aza Diels-Alder Reaction

Silicon catalysts, generated from the heterocyclic silacyle were applied in an inverse

electron demand aza Diels-Alder reaction. In order to generate the active species, AgNTf2

was added to the solution of the halogen-substituted silacycle. After 5 min stirring, the for-

mation of a white precipitate of AgCl was observed. N-Benzylideneaniline and the corre-

sponding dienophile were added successively. The results from the reaction with dihydrofu-

rane are summarized in Table 37.

Scheme 121

Table 37: Inverse Electron Demand Aza Diels-Alder Reaction Catalyzed by Si Species

a Determined by ratio of signals in 1H-NMR

Entry Cat. Catalyst Solvent T (°C) t (h) Yield (%) endo/exoa

1 236

N N

SiCl

PhPh

MeCN −30 to −40 48 2 65/35

2 236 PhMe −30 to −40 48 29 86/14

3 236 PhMe r.t. 16 57 73/27

4 237

PhPh

NSi

N

Cl

PhMe r.t. 16 81 75/25

N

Ph

Ph

solvent

O

NH

O

+

NH

O

+

254 280 281a 281b

Silacycle, AgNTf2

PhMe, r.t.N N

SiR

3R

1

R4

R5

AgNTf2

NTf2

N NSi

R3

R1

R4

R5

Cl

AgCl+

catalyst generated in situ

precipitate

HN

Ph

O O

N

Ph

HN

Ph

O

+N

N

Si

R3

R1

R4

R5

NTf2

283a 283b


The catalytic activity depends strongly on the solvent used. While in MeCN, just 2%

yield of the product was isolated after 48 h at −40 to −30°C (Table 38, Entry 1), switching

the solvent to PhMe, keeping the other conditions the same, the yield increased to 29%. In

both cases, no ee was detected by measuring the optical rotation. When catalysts 236 and

237 were used at r.t., the reaction product was isolated after 16 h in 57% and 81% yields

respectively, showing, that lower sterical hindrance around the Si center increased the activ-

ity of the catalyst.

Scheme 122

Table 38: Inverse Electron Demand Aza Diels-Alder Reaction of Dihydropyrane

a determined by isolation with FCC

Because of the problematic HPLC separation of the enaniomers, mentioned in the previ-

ous chapters, further experiments were performed with dihydropyrane, despite its lower

reactivity.

Using the catalyst 237 gave the expected product in 77% yield after 16 h at r.t. with a

diastereomeric ratio of 70:30 and 0% ee (Table 38, Entry 1). When the reaction was repeat-

ed at 0 °C in DCM, the product was isolated after 96 h in 39% yield and a diastereomeric

ratio of 80:20 (Table 38, Entry 2). Finally, when the reaction temperature was lowered to −30°C, the reaction product was isolated in only 4% yield. In this case only the endo diastere-

omer was isolated (Table 38, Entry 3).

Entry Catalyst Catalyst Solvent T (°C) t (h) Yield (%) endo/exoa

1 237 PhPh

NSi

N

Cl

PhMe r.t. 16 77 70/30

2 237 DCM 0 96 39 80/20

3 237 PhMe −30 40 4 100/0

4 238N

SiN

Cl

PhMe r.t. 16 0 N/A

5 242N O

Si

PhMe

Cl

PhMe −20 96 56 90/10

6 244N O

Si

PhMe

Cl

PhMe −30 40 59 90/10

N

Ph

Ph

PhMe

Silacycle, AgNTf2

NH

+

NH

+

O

O O

254 282 283a 283b


Surprisingly, silacycle 238 did not give under the standard conditions any product (Table

38, Entry 4).

When N,O silacycle 242 was used at −20 °C, the product was isolated in 56% yield and

a diastereomeric ratio of 90:10 (Table 38, Entry 5), showing a significantly higher catalytic

activity, than similar N,N silacycle 237 (Table 38, Entry 3). N,O silacycle 242 derived from

(−)-ephedrine had shown an even higher reactivity, giving the product 283 in 59% yield,

after 40 h at −30 °C (Table 38, Entry 6). In all case the reaction products were obtained as

racemates.

Reaction with Different Dienophiles

The activity of the silicon cations in an inverese electron demand aza Diels-Alder reac-

tion of N-benzylideneaniline (254) with different dienophiles was also investigated. The

results are summarized in Table 39.

Scheme 123

Table 39: Inverse Electron Demand Aza Diels-Alder Reaction with Various Dienophiles

As seen from the previous experiments, the reaction proceeds best with dihydrofurane

(280) and dihydropyrane (282) (Table 38, Entries 1 and 2), giving the product in 81 and 77%

yield and a similar endo/exo ratio of 70:30. When cyclohexen-2-one (313) was used as

dienophile, the yield dropped dramatically to 12% and endo/exo ratio of 50:50 was observed

by 1H-NMR. Indene (297) and cyclohexadiene (298) were also used, but no product was

isolated from the reaction mixture, indicating, that the formed Si+ species is not a suitable

catalyst for these dienophiles.

Entry Cat. Catalyst Dienophile Product Yield (%) endo/exoa

1 237

PhPh

NSi

N

Cl

Dihydrofurane 280 281 81 75/25

2 237 Dihydropyrane 282 283 77 70/30

3 237 Cyclohexen-2-one 313 325 12 50/50

4 237 Indene 323 326 0 N/A

5 237 Cyclohexadiene 324 327 0 N/A

N

Ph

Ph

PhMe, r.t., 16 h

Si catalyst, AgNTf2

NH

Ph

+

NH

Ph

+

R2

R1 R

2R

2

R1R

1

223


Attempts to Generate the Catalyst by Hydride Abstraction

Scheme 124

An attempt to generate the active species from the hydrogen substituted silacycle 241 by

hydride abstraction was made (Scheme 125). Initially, a trityl cation 329 was generated from

the triphenylchloromethane (328) and AgNTf2. After filtering the precipitated AgCl, a solu-

tion of the trityl cation was added to the solution of the hydrogen substituted silacycle. By

this, the same catalytic species as from 210 should be generated. However, after addition of

N-benzylideneaniline (254) and dihydropyrane (252), no reaction occured, indicating, that

no catalycally active compound 330 was formed.

2.2.6.2. Diels-Alder Reaction of Sulphur Containing Compounds

A silicon cation was also tested in the Diels-Alder reaction of the thioester 284. After

generating the catalyst at −20°C and adding the reactants, the mixture was warmed up to r.t.

and stirred for 96 h. The corresponding product was isolated in 29% yield, showing no enan-

tiomeric excess by the optical rotation (Scheme 126).

Scheme 125

2.2.6.3. Other Reactions

Since the high catalytic activity of silicon based Lewis acids was observed in the inverse

electron demand Diels-Alder reaction, catalysts were also tested in the Baylis-Hillman reac-

tion, aza Baylis-Hillman reaction, TSMCN addition to ketones,196 aza Diels-Alder reaction

reaction of imine dienophiles with Danishefskys diene, ring opening of epoxides and thioe-

poxides. Nevertheless, no catalytic activity was observed in any of these reactions.

244 (0.1 eq),. AgNTf2 (0.1 eq.)+

S

OEt

Ph

S

OEt

PhMe, -20->0 °C, 96 h

287a

29%, 0% ee

284

AgNTf2 AgCl

catalyst generated in situ

precipitate

Ph

Ph

Ph

Cl + C+

Ph

Ph

Ph

+NTf2−

C+

Ph

Ph

Ph

NTf2− N N

Si

HPh Ph

+ CH

Ph

Ph

Ph

NTf2−

N NSi

+

Ph Ph

+

N-benzilideneaniline (254)

dihydropyrane (282)

no reaction

241

328 329

329 330


2.2.7. Application of Thiourea Derivates as a Pseudo Lewis Acid Activators

2.2.7.1. Reductive Amination of Ketones

Based on the recent report,62 that simple thiourea can catalyze the reduction of ketimines

by Hantsch ester (58), the chiral bisthiourea derivate 250 was tested in this reaction. The

reaction was performed at r.t. for 48 h, but only the ketimine 331 was isolated from the reac-

tion mixture. Further optimization of the reaction conditions is therefore necessary.

Scheme 126

2.2.7.2. Aza Michael Reaction

The same bis-thiourea 250 was found to catalyze an aza Michael reaction of cyclopen-

ten-2-one (293) and aniline (112) (Scheme 128). Also in this case, a poor yield of 17% and

no enantioselectivity requires further optimization of the reaction conditions.

Scheme 127


A Baylis-Hillman reaction between benzaldehyde (167) and cyclohexen-2-one (313) pro-

ceeds in high yield of 77% in presence of thiourea 252 (Scheme 130). However, the prod-

uct is obtained as a racemate.

Scheme 128

O

Ph

O

+252 (0.1 eq.), quinuclidine(1 eq.)

r.t., 72 h

Ph

OH O

314

77%, 0% ee313167

NH OH

PhPh

NH

S

CF3

F3C

+

DCM, r.t., 16 h

O NH2 O

NH

250, 0.1 eq.

332

17%, 0% ee

293 112

NH HN

PhPh

HNHN

SS

CF3

F3CCF3

F3C

250, 0.1 eq.

PhMe, MS 4A, r.t., 48 h

Ph

NPMP

quant.

331

+

Ph

O

NH

COOEtEtOOC

MeMe

58, 1.5 eq.

H2N PMP

NH HN

PhPh

HNHN

SS

CF3

F3CCF3

F3C


2.3. Summary and Outlook

The beginning of the chapter 2.1. dealed with the preparation of chiral diamines which

were serving as precursors for the preparation of chiral imidazolinium salts. Diamines were

prepared by simple alkylation of amines with EtBr2

or from N-BOC-amino-acids via amide

formation (Scheme 129).

Scheme 129

New, enviromental friendly methods for the preparation of aminals in water and under

neat conditions were developped. By these methods a series of achiral and chiral aminals

and bis-aminals were prepared in high yields and purities (Scheme 130). These results are

described in the section 2.1.1.3.2 of presented work.

Scheme 130

In section 2.1.1.4.1. of this work, a series of new imidazolinium salts were prepared by

oxidation of aminals by NBA, followed by counteranion metathesis. By this reaction a

series of the imidazolinium salts were prepared. Imidazolinium bis-cations were prepared in

good yields for the first time (Scheme 131). Due to low melting points, some of the salt

qualify as ionic liquids.

NN

R2

R1

R1

H2O, r.t., 3 h

(CH2)n

HNNHR1

R1

(CH2)n

+

R2

O

up to 99%

HNNH R1

R3

R5

R4

N

NN

N

R1

R3

R1

R5

R4

R3

R5

R4

neat, 140 °C, 16 h

2

up to 99%

O

O

+

R1

NH HN R1R

1NH2 Br

Br

1. neat, 120°C, 10 h

2. NaOH+

HN OH

OR5

Boc

1. NMM, i-BuOCOCl

2. R3-NH2

HN HN

OR5

Boc

R3

1. HCl/MeOH

2. NaOHH2N HN

OR5

R3

DCM

O

O

O

H

NHHN

OR5

R3

OHC

LAH/THF

NHHN

R5

R3

LAH/THF

H2N HN

R5

R3

Me

up to 91%


Scheme 131

Imidazolinium carbene precursors were prepaired in high yields by the reaction of

diamine with an orthoester in the presence of an anion and acid source. By this reaction a

series of chiral salts bearing different counter anions were prepared in excellent yields

(Scheme 132). This method will be further expanded for the preparation of salts with larg-

er rings.

Scheme 132

Section 2.1.2. dealed with the preparation of various chiral silacycles. N,N and N,O sila-

cycles were prepared in a good yields by reaction of amines of aminoalcohols with MeSiCl3

(Scheme 133). These compounds served as precursors for the silicon cations

Scheme 133

The last section of the chapter 2.1. described the preparation of chiral thioureas. The

compounds were prepared in excellent yields and purities by the reaction of bis-trifluo-

romethylisothiocyanate with different amines (Scheme 134).

Scheme 134

Chapter 2.2. dealed with the application of the prepared compounds in various reactions.

Imidazolinium salts were found to be efficient catalysts for the aza Diels-Alder reaction

of N-benzylideneanilene (254) and Danischefsky’s diene (253) giving the racemic 1,2-

diphenyl-2,3-dihydropyridin-4(1H)-one (255) in excellent yields (Scheme 135). Salts with

THF, r.t., 22 hNH2

R1

R2

CF3

F3C

N

C

S

+

HN

R1

NH

S

F3C

CF3

R2

up to 99%

DCM, -5°CN N

SiR

1R

3NH HN R1

R3

R5R

5R

4R4

MeSiCl3, DBU

Cl

up to 76%

HN

R4

NH

R5

neat, 120 °C

R1

R3 CH(OEt)3/NH4X

X− CHCl3/H2O, 30 min, r.t.

M+Y

−N N

+

H

R5

R4

Y−

N N+

H

R5

R4

R1

R3

R1

R3

up to 99% up to 93%

M+X

−

DCM/H2O

Br−

NBA

DME, r.t., 1 hN N

+R

1R

3

R2

R5

R4

N N R1

R3

R2

R5

R4

N N+

R1

R3

R2 X

−

R5

R4

up to 99% up to 99%


larger rings (six and seven membered) were showing higher reactivity and therefore will be

further investigated in our group.

Scheme 135

Inverse electron demand aza Diels-Alder reaction was shown to be catalyzed by imida-

zolinium bis-cations. Products were obtained in good yields, however without any enantios-

electivity (Scheme 135).

Scheme 136

In cooperation with the group of Dr. Maison, imidazolinium salts were tested in an aza

Diels-Alder reaction with reactive imino-esters. The obtained enantioselectivity of 21 % is

the highest known for an imidazolinium salt. Compounds with larger rings will be submit-

ted for further testing.

Scheme 137

A series of chiral hydroxy-substituted imidazolinium based carbene were shown to be an

efficient NCN carbene ligands for the Et2Zn addition to aldehydes. Corresponding alcohols

were obtained in excellent yields, with enantioselectivity up to 66%

Scheme 138

Applicability of these compounds as ligands for other metals such as Zn, Cu and Fe is

going to be further explored within our group.

R


H

O

Base (0.1 eq), Et2Zn 1.1 eq., PhMe, 30 h R

OH

*

up to 92%

up to 66% ee

NPg

CO2Me

278

purity 70-90%

DCM, −78 °C

NPg

CO2Me


279

yield 70-80%

up to 21% ee

+

N

Ph

Ph Imidazolinium bis-cation

NH

Ph

+

O

O

254 282 283

up to 67%, 0% ee

solvent

OMe

TMSO

N

Ph

Ph

solvent, r.t.

N

O

Ph

Ph

+

253 254 255

up to 99%, 0% ee

N N+

R2 X

−

R1

R3

R5

R4

*


Since imidazolinium carbene precursors with TIPS-protected hydroxy groups, that were

prepared by C. Torborg were showing a good activity in palladium catalyzed coupling reac-

tions,195 imidazolinium carbene precursors with one TIPS-protected hydroxy group could be

prepared (Scheme 139) and tested as ligands Et2Zn for palladium catalyzed coupling reac-

tions such as Suzuki-, Heck, Kumada-, Negishi-, Sonogashira or Stille-couplings. More-

over, the prepared carbene ligands could be tested in ruthenium catalyzed metathesis reac-

tion. Also carbene ligands with larger rings should be tested.

Scheme 139

A novel imidazolinium based ionic liquid was prepared and it was shown to be an effi-

cient and inert reaction medium for the Baylis-Hilmann reaction and the addition of Grig-

nard reagents to aldehydes (Scheme 139).

Scheme 140

Preparation of chiral imidazolinium based ionic liquids is currently in progress. These

ionic liquids should be tested as chiral solvents for an enantioselective Baylis-Hillman reac-

tion or addition of Grignard reagents to carbonyl groups.

Some of the prepared imidazolinium salts were shown to be efficient shift reagents for

Mosher’s carboxylate. In the future, the possibilities of these compounds as a shift reagents

for carboxylic groups will be explored.

Chiral silicon cations, generated in situ from N,N and N,O silacycles were shown to cat-

alyze efficiently the inverse electron demand aza Diels-Alder reaction, giving a racemic

product in high yield.

MgBrR +

PhR Ph

3 h, 40 °C

OHO

R = Ph, 68%

R = Hex, 77%

r.t., base, 48 h

O

R

O

OMe+

O

OMe

OH

R

196C

196C

up to 69%

NH2

1. neat, 120°C, 10 h

2. NaOH+

R2

OH

R1

2

NH HN

R1

HO

R2

R1

OH

R2

N N+

R1

OH

R2

R1

OTIPS

R2

EtBr2 NH HN

R1

OH

R2

R1

OTIPS

R2

TIPSCl (0.5 eq.), KH

r.t.

HC(OEt)3, NH4BF4

neat, 120 °C


Scheme 141

Three novel chiral thioureas were prepared and tested in several reactions. To obtain sat-

isfactory results, further optimization of reaction conditions is needed. Reductive amina-

tion62 reaction should be further investigated (Scheme 141).

Scheme 141

Biological Properties of Imidazolinium Salts

In cooperation with an industrial partner, selected imidazolinium salts were submited for

biological testing. Preliminary results are indicating that some of the imidazolinium salts are

giving positive responses for fungicidal and insecticidal activity. Additional testing is in

progress.

Ph

HNPMP

331

+

Ph

O

NH

COOEtEtOOC

MeMe

58

H2N PMP

chiral thiourea

N

Ph

Ph

NH

Ph

+

O

O

254 282 283

up to 77%, 0% ee

PhMe

Silacycle, AgNTf2

Experimental 107

3. Experimental

General experimental

Chromatography: Flash column chromatography197 was performed on Sorbisil C-60.

Reactions were monitored by TLC with Merck Silica gel 60 F254 plates.

Elemental analysis: Elemental analysis were carried out by the Microanalytical Labora-

tory of the Institut für Pharmazeutische Chemie der Technische Universität Braunschweig

on “Elemental Analyzer” Model 1106 from the “Carlo Erba Instrumentazione” company.

IR: Infrared spectras were recorded on a Bruker Vektor 22 FTIR. In case of solid com-

pounds as KBr pellet, in case of oils and liquids as thin film between NaCl plates.

1H-NMR: 1H-NMR spectra were recorded at ambient temperature on a Bruker AMX

400 (400 MHz) and a Bruker AC 200F (200 MHz) in the deuterinated solvent as stated, with

tetramethylsilan as an internal standard.

13C-NMR: 13C-NMR spectra were recorded at ambient temperature on a Bruker AMX

400 (100 MHz) and a Bruker AC 200F (50 MHz) in the deuterinated solvent as stated.

19F-NMR: 19F-NMR spectra were recorded at ambient temperature on a Bruker AMX

400 (378 MHz).

LR-MS: Mass spectra (EI) were recorded on Hewlett Packard 5989B at 70 eV. Mass

spectra (ESI) were recorded on Hewlett Packard MS LC/MSD Series 1100 MSD.

HR-MS: High resolution mass spectras were measured on Bruker Daltonik Tesla-Fouri-

er Transform-Ion Cyclotron Resonance-Massspektrometer mit Electrospray-Ionisierung.

Melting points: Melting points were taken with an apparatus after Dr. Tottoli and are

uncorrected.

Commercially available compounds:

BOC-L-Valine (109), BOC-L-phenylalanine (110), BOC-L-proline (111), quinuclidine,

quinuclidinol, tributylphosphine (technical grade), NH4PF

6, KPF

6, N,N'-diphenyl-ethane-

1,2-diamine (171), N,N'-dimethyl-ethane-1,2-diamine (172) were purcased from Fluka

LiNTf2

(C), Lithium diisopropylamine (solution in THF), BuLi, PhLi, tert-butylmagne-

siumchlorid (2 M in Et2O), phenylmagnesiumbromide (1 M in THF), phenylmagnesium-

chloride (2 M in THF), hexylmagnesiumbromide (1 M in THF), diethylzinc (1 M in hexa-

ne) and diphenylzinc were purchased from Aldrich.

Aromatic amines were obtained from Aldrich and used without further purification.

Aldehydes were purchased from Aldrich and distilled before use.

N-Bromoacetamide, rac-Mosher’s acid was purchased from Lancaster.

The reactions in water were carried out with dest. water.

108 Experimental

All the other reactions were performed in oven dried glassware under a nitrogen atmos-

phere.

Absolute EtOH and MeOH were purchased from Merck.

Pentane, hexane and benzene were distilled from P2O

5

Et2O, Dioxane, THF and Toluene were distilled from sodium

MeCN and DCM were distilled from CaH2

All other solvents were purified using standard procedures. 198

Solution of HCl in MeOH (2 M) was prepared by adding AcCl (1.00 mol) into a cold

absolute MeOH (500 mL)

Following substances were prepared according to literature:

N,N'-bis-((R)1-phenyl-ethyl)-ethane-1,2-diamine (93)114

(1S,2S)-1,2-diphenyl-N,N’-bis((R)-1-phenylethyl)ethane-1,2-diamine (94) 115

(3S,4S)-2,2,5,5-tetramethyl-N3,N4-bis((R)-1-phenylethyl)hexane-3,4-diamine (95)116, 117

(1R,2R)-N,N'-dimethyl-1,2-cyclohexanediamine (97)119, 120

(1R,2R)- and (1S,2S)-1,2-diphenyl-1,2-ethylendiamine (96a)118

(1R,2R)- and (1S,2S)-N,N’-dimethyl-1,2-diphenyl-1,2-ethylendiamine (96)120

N,N'-Dibenzyl-propane-1,3-diamine (169) 131, 199

N,N'-dibenzyl-butane-1,3-diamine (170)199

N-Benzilideneaniline (254) and mines (256-263)131

Phenyl-N-tosylmethanimine (273)146

(E)-3-(tert-butyldimethylsilyloxy)-N,N-dimethylbuta-1,3-dien-1-amine (59)148

Sodium tetrakis(3,5-bis(trifluoromethyl)phenyl)borate (D) 133

Potassium terakis(pentafluoropnenyl) borate (E) was prepared by Prof. Dr. Rene Wil-

helm134

Acetic-formic anhydride200

AgNTf2

195

(1R,1'R,2R,2'R)-2,2'-(1S,2S)-cyclohexane-1,2-diylbis(azanediyl)dicyclohexanol (219)201

L-Valinol (101)202

L-Leucinol (102)203

Experimental 109

3.1. Preparation of Diamines

By reduction of imines

N,N'-bis-(1,7,7-trimethyl-bicyclo[2.2.1]hept-2-yl)-ethane-1,2-diamine (218)

Camphor (15.22 g, 100.00 mmol) was dissolved in dry PhMe (400 mL) and ethylenedi-

amine (4.00 mL, 60.00 Mmol) and BF3.Et

2O (628 µl, 5% mol) were added under a nitrogen

atmosphere. The reaction mixture was refluxed on a Dean-Stark water separator for 48 h.

After cooling down, PhMe was distilled off under reduced pressure and the crude diimine

was used directly in the subsequent step. Spectral data of the crude product were consistent

with literature values.204, 205

Camphordiimine (16.41 g, 50.00 mmol) was dissolved in absolute MeOH (300 ml) and

the reaction mixture was cooled down to −40 °C. Anhydrous NiCl2

(13.61 g, 105.00 mmol,

2.1 eq.) was added at once. Afterwards, NaBH4

(5.70 g, 150.00 mmol, 3 eq.) was added por-

tionwise, that the temperature did not exceeded −35 °C. After the addition was completed,

the cooling was removed and the reaction mixture was allowed to warm up to r.t. overnight.

The reaction mixture was filtered throught a pad of celite, quenched with water (50 mL) and

extracted with DCM (3x 30 mL). The combined organic phases were dried (Na2SO

4) and

the solvent was removed under reduced pressure to give the crude product. The crude prod-

uct was mixed with a solution of HCl (25 mL of 2.5 M solution in EtOH) and the mixture

was heated under reflux, until all the solid was dissolved. After cooling, the formed precip-

itate was filtered off, washed with Et2O (20 mL) and dried in vacuo to give the product in

the form of the dihydrochloride salt as a white solid (6.88 g, 34%). Free base is released in

standard manner by dissolving the hydrochloric salt in water, basifying the solution by 1 M

NaOH and extracting the precipitated diamine with CHCl3. This is the detailed description

of literature procedure.205

By alkylation with EtBr2

General procedure for the preparation of diamines by alkylation with EtBr2

Aminoalcohol (1.00 mmol) and dibromoethane (87 μL, 0.50 mmol) were placed into a

pressure vessel, which was flushed with nitrogen and sealed. The reaction mixture was heat-

ed up to 100 °C for 10 h, during which the reaction mixture solidified. After cooling down

to r.t., the solid was dissolved in water (10 mL) and the aqueuos phase was washed with

CHCl3

(3 x 3 mL). The aqueous phase was basified with NaOH (40 mg, 1 eq.) and the pre-

cipitated free base was extracted with CHCl3

(3 x 5 mL). The combined organic fractions

were dried (Na2SO

4) and the solvent was removed under reduced pressure giving the pure

diamine.

PhMe, reflux, 24 hO

2BF3.Et2O

NH2H2N+

MeOH, −40 °C, 12 h

NaBH4, NiCl2

218

34%

N N NH HN

110 Experimental

(1S,1'S,2R,2'R)-2,2'-(Ethane-1,2-diylbis(azanediyl))bis(1-phenylpropan-1-ol) (104)

From (−)-norephedrine (100) (5.01 g, 33.00 mmol) and and dibromoethane (1.42 mL,

16.50 mmol), basified with 2M NaOH (14.00 mL, 28.00 mmol) as yellow oil (4.15 g, 79%).

(1R,1'R,2S,2'S)-2,2'-(Ethane-1,2-diylbis(azanediyl))bis(1-phenylpropan-1-ol) (ent-104)

was prepared in the same manner from (+)-noreephedrine (ent-100). Spectral data were con-

sistent with literature values.206

(S)-2-[2-((S)-1-Hydroxymethyl-2-methyl-propylamino)-ethylamino]-3-methyl-butan-1-

ol (105)

From L-valinol (101) (1.23 g, 11.90 mmol) and dibromoethane (513 μL, 5.95 mmol),

basified with 2 M NaOH (5.10 mL, 10.20 mmol) as a yellow oil (1.06 g, 77%). [α]22D

= +14.3

(c = 0.65, CHCl3), MS (ESI, 0 V), m/z 233.3 (M++H, 100%); IR (neat) 3314s, 2958s, 2873s,

1467s, 1052s, 452s cm-1; 1H-NMR (200 MHz, CDCl3) δ = 3.67-3.59 (m, 2 H, CH

2OH),

3.42-3.33 (m, 2 H, CH2OH), 2.90-2.50 (4 H, CH

2), 2.40-2.25 (m, 2 H, CH

2CHCH), 1.90-

1.70 (m, 2 H, CH(CH3)2), 1.01-0.85 (m, 12 H, CH

3); 13C-NMR (50 MHz, CDCl

3) δ = 65.2

(CH2CHCH), 62.0 (CH

2OH), 47.4 (CH

2), 29.4 (CH(CH

3)2), 20.1 (CH

3), 18.7 (CH

3). Prepa-

ration of this compound was previously reported by the reduction of bis-imide,207 however,

no spectral data were provided.

(S)-2-[2-((S)-1-Hydroxymethyl-2-methyl-propylamino)-ethylamino]-3-methyl-butan-1-

ol (106)

From L-leucinol (102) (2.00 g, 17.10 mmol) and dibromoethane (740 μL, 8.55 mmol),

basified with 2 M NaOH (8.55 mL, 17.10 mmol) as white solid (2.01 g, 91%). For the pur-

pose of elemental analysis, the diamine was cryslallized from EtOH. mp 53 °C; [α]22D

= +53.8

(c = 0.34, CHCl3); MS (EI), m/z 261 (M++H, 10%), 229 (15), 203 (25), 144 (25), 130 (100),

100 (50), 86 (50), 74 (40), 57 (45), IR (KBr) 3314s, 2958s, 2873s, 1467s, 1052s, 452s cm-

1; 1H-NMR (400 MHz, CDCl3) δ = 3.71 (dd, J1 = 10.6 Hz, J2 = 3.52 Hz, 2 H, CH

2OH), 3.55-

2 BrBrOHH2N +

1. neat, 100 °C, 10 h

2. NaOH NH HN

HOOH 106

91%

102

2 BrBrOHH2N +

1. neat, 100 °C, 10 h

2. NaOHNH HN

HOOH 105

77%

101

NH2

Ph

OH

Br Br+2

1. neat, 100 °C, 10 h

2. NaOHNH HN

HO

Ph

OH

Ph

104

78%100

Experimental 111

3.42 (m, 2 H, NCHCH2), 3.08 (d, J = 8.6 Hz, NCH

2CH

2N), 2.73 (d, J = 8.6 Hz,

NCH2CH

2N), 2.34 (dd, J1 = 10.6 Hz, J2 = 3.52, 2 H, CH

2OH), 0.97 (s, 18 H, C(CH

3)3); 13C-

NMR (100 MHz, CDCl3) δ = 67.9 (NHCHCH

2), 62.9 (CHCH

2OH), 49.7 (NCH

2CH

2N),

34.4 (CH(CH3)3), 27.2 (CH(CH

3)3); Anal. Calcd for C

14H

32N

2O

2: C, 64.57; H, 12.39; N,

10.76 found: C, 64.44; H, 12.54; N, 10.88; HRMS (ESI) Calcd. for C14

H33

N2O

2: 261.2542,

found: 261.2546.

(1R,1'R,2R,2'R)-2,2'-(Ethane-1,2-diylbis(azanediyl))bis(1-phenylpropane-1,3-diol)

(107)

From (1R,2R)-(−)-2-amino-1-phenyl-1,3-propanediol (103) (1.15 g, 6.89 mmol) and

dibromoethane (296 μL, 3.45 mmol) as yellow oil (930 mg, 75%). [α]22D

= −78.2 (c = 0.28,

CHCl3); MS (ESI, 0 V), m/z 361.0 (M++H, 70%); IR (neat) 3356vs, 2882s, 1454s, 1027s,

759vs, 702vs cm-1; 1H-NMR (400 MHz, CDCl3) δ = 7.45-7.30 (m, 10 H, H-Ar), 4.60 (d, J

= 7.6 Hz, 2 H, PhCHOH), 3.65-3.55 (m, 2 H, CH2OH), 3.35-3.25 (m, 2 H, CH

2OH), 2.80-

2.60 (m, 4 H, NCH2CH

2N); 13C-NMR (100 MHz, CDCl

3) δ = 142.0 (C-Ar), 128.5 (C-Ar),

127.8 (C-Ar), 126.7 (C-Ar), 73.8 (PhCHOH), 64.8 (NCHCH2), 60.2 (CH

2OH), 46.8

(NCH2CH

2N); HRMS (ESI) Calcd. for C

20H

29N

2O

4: 361.2127, found: 361.2122.

From aminoacids

General procedure for the preparation of N-BOC-αα-amino amides from N-BOC-αα-

amino acids

Procedure A.

N-BOC-α-Amino-acid (10.00 mmol) was dissolved in dry THF (30 mL) and N-methyl-

morpholine (1.01 mL, 10.00 mmol) was added. The reaction mixture was cooled down to −15 °C and solution of i-butyl chloroformate (1.36 g, 1.30 mL, 10.00 mmol) in THF (5 mL)

was added dropwise over a period of 15 min. After addition was completed, the mixture was

stirred at −15 °C for another 15 min and the amine (10.00 mmol, 1 eq.) or diamine (5.00

mmol, 0.5 eq.) was added at once. The cooling was then removed and the reaction mixture

was allowed to warm up to r.t. and stirred overnight. The solvent was removed under

reduced pressure and the remaining rest was diluted with EtOAc (40 mL), washed with 10%

Na2CO

3(50 mL), 0.1 M HCl (50 mL), brine (50 mL) and dried (Na

2SO

4). The solvent was

removed under reduced pressure to give the crude N-BOC-α-amino amide.

Procedure B

N-BOC-α-Amino-acid (10.00 mmol) was disolved in dry THF (20 mL) and the mixture

was cooled down to −20 °C. N-Methylmorpholine (1.01 mL, 10.00 mmol) and i-butyl chlo-

roformate (1.36 g, 1.30 mL, 10.00 mmol) were added successively. The reaction mixture

was stirrred at −20 °C for 5 minutes and MeNH2

(4.30 mL 40% solution in H2O, 50.00

BrBr

+

1. neat, 100 °C, 10 h

2. NaOH

OH

Ph

NH22

NH HN

HO

Ph

OH

Ph

HOOH

107

75%

OH

103

112 Experimental

mmol) was added. The reaction mixture was stirred at −20 °C for additional 1 h and 5%

NaHCO3

(20 mL) was added. After stirring at r.t. for 30 min, mixture was extracted with

DCM (3 x 30 mL). The combined organic phases were washed with 5% NaHCO3

(2 x 30

mL), dried (Na2SO

4) and the solvent was removed under reduced pressure giving the crude

N-BOC-α-amino amide.

Procedure C

N-BOC-α-Amino-acid (10.00 mmol) was disolved in dry THF (20 mL) and the mixture

was cooled down to −20 °C. N-Methylmorpholine (1.10 mL, 10.00 mmol) and i-butyl chlo-

roformate (1.36 g, 1.30 mL, 10.00 mmol) were added successively. The reaction mixture

was stirrred at −20 °C for 5 min and amine (10.00 mmol) was added. The reaction mixture

was stirred at −20 °C for additional 1 h, warmed up to r.t. and stirred overnight. The solvent

was removed under reduced pressure and the remaining rest was diluted with EtOAc (40

mL), washed with 10% Na2CO

3(50 mL), 0.1 M HCl (50 mL), brine (50 mL) and dried

(Na2SO

4). The solvent was removed under reduced pressure to give the crude N-BOC-α-

amino amide.

(S)-tert-Butyl 3-methyl-1-oxo-1-(phenylamino)butan-2-ylcarbamate (119)

From BOC-L-valin (109) (435 mg, 2.00 mmol), N-methylmorpholine (224 μL 98%, 2.00

mmol), i-butylchloroformate (259 μL, 2.00 mmol in 1 mL THF) and aniline (186 mg, 2.00

mmol) in THF (6 mL) according to procedure A as a white solid (502 mg, 86%). mp 155

°C; [α]22D

= −45.3 (c = 0.1 CHCl3); MS (ESI, 0 V), m/z 393 (M++H, 100%); IR (KBr) 3312s,

1665vs, 1549s, 1501s, 1444s, 1251s, 1175s cm-1; 1H-NMR (200 MHz, CDCl3) δ = 7.99 (bs,

1 H, PCONHPh), 7.55-7.45 (m, 2 H, H-Ar), 7.37-7.28 (m, 2 H, H-Ar), 7.15-7.05 (m, 1 H,

H-Ar), 5.14 (d, J = 7.16 Hz, 1 H, CONHCH), 4.10-3.95 (m, 1 H, NHCHCH), 2.45-2.15 (m,

1H, CHCH(CH3)2), 1.46 (s, 9 H, C(CH

3)3), 1.03 (d, J = 6.8 Hz, 3 H, CH(CH

3)2), 0.99 (d, J

= 6.8 Hz, 3 H, CH(CH3)2); 13C-NMR (50 MHz, CDCl

3) δ = 170.1 (CONH), 156.2 (CONH),

137.5 (C-Ar), 129.0 (C-Ar), 124.5 (C-Ar), 120.0 (C-Ar), 80.5 (COC(CH3)3), 61.0

(NHCHCH), 30.5 (CH(CH3)2), 28.2 (C(CH

3)3), 19.5 (CH(CH

3)2), 18.0 (CH(CH

3)2). This

compound was used directly in the next step.


HN OH

O

Boc

2. i-BuOCOCl

3. aniline HN HN

O

Boc

Ph

119

86%

109

Experimental 113

(S)-tert-butyl-1-(2-tert-butylphenylamino)-3-methyl-1-oxobutan-2-ylcarbamate (120)

From BOC-L-valin (109) (8.69 g, 40.00 mmol), N-methylmorpholine (4.48 mL 98%,

40.00 mmol), i-butylchloroformate (5.18 mL, 40.00 mmol in 20 mL THF) and t-butylani-

line (6.24 mL, 40.00 mmol) in THF (120 mL) according to procedure A as a white solid

(10.67 g, 77%). Spectral data were consistent with literature values.109

(S)-tert-butyl-1-(biphenyl-2-ylamino)-3-methyl-1-oxobutan-2-ylcarbamate (121)


20.00 mmol), i-butylchloroformate (2.59 mL, 20.00 mmol in 10 mL THF) and and 2-amino-

biphenyl (3.38 g, 20.00 mmol) in THF (60 mL) according to procedure A as a white solid

(7.00 g, 95%). mp 70 °C; [α]22D

= −18.0 (c = 0.8 CHCl3); MS (ESI, 0 V), m/z 369 (M++H,

10%), 291 (40, M++Na), 759 (100, 2M+Na); IR (KBr) 3424s, 1664s, 1523s, 1175s cm-1;

1H-NMR (200 MHz, CDCl3) δ = 8.31 (d, J = 8.08 Hz, 1 H, PhNHCO), 7.81 (bs, 1 H,

CHNHCOO), 7.54-7.05 (m, 9 H, H-Ar), 3.95-3.80 (1 H, NHCHCH), 2.25-2.10 (m, 1 H,

CH(CH3)2), 1.28 (s, 9 H, C(CH

3)3), 0.90 (d, J = 6.7 Hz, 6 H, CH(CH

3)2); 13C-NMR (50

MHz, CDCl3) δ = 169.8 (CONH), 155.7 (CONH), 137.8 (C-Ar), 134.3 (C-Ar), 132.6 (C-

Ar), 130.0 (C-Ar), 129.2 (C-Ar), 129.1 (C-Ar), 128.4 (C-Ar), 128.0 (C-Ar), 124.5 (C-Ar),

121.4 (C-Ar), 80.0 (COC(CH3)3), 60.7 (NHCHCH), 30.6 (CH(CH

3)2), 28.2 (C(CH

3)3), 19.2

(CH(CH3)2), 17.4 (CH(CH

3)2); HRMS (ESI) Calcd. for C

22H

28N

2O

3Na: 391.1998, found:

391.2002.

tert-Butyl-(S)-1-((1S,2R)-1-hydroxy-1-phenylpropan-2-ylcarbamoyl)-2-methylpropyl-

carbamate (122)


15.00 mmol), i-butylchloroformate (1.94 mL, 15.00 mmol in 7.5 mL THF) and (+)-

norephedrine (2.27 g, 15.00 mmol in 10 mL THF) in THF (45 mL) according procedure A

1. N-methylmorpholine

HN OH

O

Boc

2. i-BuOCOCl

3. (+)-norephedrineHN HN

O

Boc

HO122

87%

109


HN OH

O

Boc

2. i-BuOCOCl

3. 2-amino-biphenylHN HN

O

Boc

121

95%

109

Ph


HN OH

O

Boc

2. i-BuOCOCl

3. 2-t-butyl-aniline HN HN

O

Boc

120

77%

109

t-Bu

114 Experimental

as a white solid (4.56 g, 87%). mp 35 °C; [α]22D

= +21.2 (c = 0.3, CHCl3), MS (ESI, 0 V),

m/z 360 (M+Na, 15%), 723.5 (2M+Na, 100); IR (KBr) 3310s, 1673s, 1629s, 1556s, 1529s,

1255m, 1171m cm-1; 1H-NMR (200 MHz, CDCl3) δ = 7.40-7.20 (m, 5 H, H-Ar), 6.18 (d, J

= 7.7 Hz, 1 H, NH), 5.13 (d, J = 7.8 Hz, 1 H, NH), 4.95-4.85 (m, 1 H, CHOH), 4.40-4.20

(m, 1 H, CHCH3), 3.90-3.70 (m, 1 H, NHCHCH), 3.55 (d, J = 3.6 Hz, 1 H, CHOH), 2.20-

2.00 (m, 1 H, CH(CH3)2), 1.44 (s, 9 H, C(CH

3)3), 1.05-0.80 (m, 6 H, CH(CH

3)2); 13C-NMR

(50 MHz, CDCl3) δ = 172.1 (NHCOCH), 156.0 (NHCOO), 140.6 (C-Ar), 128.2 (C-Ar),

127.5 (C-Ar), 126.2 (C-Ar), 80.2 (OC(CH3)3), 75.3 (CHOH), 60.8 (CHCH(CH

3)2), 51.0

(CHCH3), 30.6 (CH(CH

3)2), 28.3 (C(CH

3)3), 19.3 (CH(CH

3)2), 18.1 (C(CH

3)2), 14.0

(CHCH3). Anal. Calcd for C

19H

30N

2O

4: C, 65.12; H, 8.63; N, 7.99 found: C, 65.15; H, 8.64;

N, 8.04; HRMS (ESI) Calcd. for C19

H30

N2O

4Na: 373.2103, found: 373.2104.

tert-Butyl-(S)-1-((R)-1-phenylethylcarbamoyl)-2-methylpropylcarbamate (123)


50.00 mmol), i-butylchloroformate (6.85 mL, 50.00 mmol) and (R)-(+)-1-phenyl-ethyl-

amine (8.27 mL, 50.00 mmol) in THF (100 mL) according to procedure C as a white solid

(15.91 g, 99%). Spectral data were consistent with literature values.208

Bis-tert-butyl (2S,2'S)-1,1'-(1,2-phenylenebis(azanediyl))bis(3-methyl-1-oxobutane-

2,1-diyl)dicarbamate (124)

From BOC-L-valin (109) (8.69 g, 40.00 mmol), N-methylmorpholine (4.48 mL, 40.00

mmol), i-butylchloroformate (5.17 mL, 40.00 mmol in 20 mL THF) and o-phenylenedi-

amine (2.16 g, 20.00 mmol, 0.5 eq.) in THF (120 mL) according to procedure A as a brown

solid (10.10 g, 99%). Spectral data were consistent with literature values.209


HN OH

O

Boc

2. i-BuOCOCl

3. o-phenylendiamine, 0.5 eq.

NHHN

O

Boc

HNNHBoc

O

124

99%

109


HN OH

O

Boc

2. i-BuOCOCl

3. (R)-(+)-1-phenyl-ethylamineHN HN

O

Boc Ph

123

99%

109

Experimental 115

tert-Butyl-(S)-1-((S)-1-hydroxy-3-methylbutan-2-ylcarbamoyl)-2-methylpropylcarba-

mate (125)


mmol), i-butylchloroformate (6.85 mL, 50.00 mmol) and L-valinol (5.16 g, 50.00 mmol) in

THF (100 mL) according to procedure C as a yellow solid (13.10 g, 87%). Spectral data

were consistent with literature values.208

tert-Butyl-(S)-1-(methylcarbamoyl)-2-methylpropylcarbamate (126)


mmol), i-butylchloroformate (6.22 mL, 47.00 mmol) and aq. MeNH2

(20.34 mL 40%,

234.95 mmol) in THF (100 mL) according to procedure B as a white solid (10.41 g, 96%).

Spectral data were consistent with literature values.210, 211

tert-Butyl-(S)-1-(phenylcarbamoyl)-2-phenylethylcarbamate (127)

From BOC-L-phenylalanine (110) (1.06 g, 3.98 mmol), N-methylmorpholine (437 μL,

3.98 mmol), i-butylchloroformate (515 μL, 3.98 mmol in 2 mL THF) and aniline (363 μL,

3.98 mmol) in THF (12 mL) according to procedure A as a white solid (1.294 g, 99%). Spec-

tral data were consistent with literature values.212

tert-Butyl-(S)-1-((R)-1-phenylethylcarbamoyl)-2-phenylethylcarbamate (128)

From BOC-L-phenylalanine (110) (982 mg, 3.70 mmol), N-methylmorpholine (406 μL,

3.70 mmol), i-butylchloroformate (479 μL, 3.70 mmol in 2 mL THF) and (R)-(+)-1-phenyl-


HN OH

OPh

Boc

2. i-BuOCOCl

3. (R)-(+)-1-phenyl-ethylamineHN HN

OPh

Boc Ph

128

96%

110


HN OH

OPh

Boc

2. i-BuOCOCl

3. anilineHN HN

OPh

Boc

Ph

127

99%

110


HN OH

O

Boc

2. i-BuOCOCl

3. aq. MeNH2

HN HN

O

Boc

126

96%

109


HN OH

O

Boc

2. i-BuOCOCl

3. L-valinolHN HN

O

Boc

HO125

87%

109

116 Experimental

ethylamine (472 μL, 3.70 mmol) in 12 mL THF (12 mL) according to procedure A as a yel-

low oil (1.26 g, 96%). Spectral data were consistent with literature values.213, 214

(S)-tert-Butyl-2-((S)-1-phenylethylcarbamoyl)pyrrolidine-1-carboxylate (129)

From BOC-L-prolin (111) (4.30 g, 20.00 mmol), N-methylmorpholine (2.24 mL 98%,

20.00 mmol), i-butylchloroformate (2.59 mL, 20.00 mmol in 10 mL THF) and and (R)-(+)-

1-phenylethylamine (2.55 mL, 20.00 mmol) in THF (60 mL) accordinq to procedure A as a

white solid (6.00 g, 94%). Spectral data were consistent with literature values.215

(S)-tert-Butyl-2-((1R,2S)-1-hydroxy-1-phenylpropan-2-ylcarbamoyl)pyrrolidine-1-car-

boxylate (129)

From BOC-L-prolin (111) (3.28 g, 15.00 mmol), N-methylmorpholine (1.65 mL, 15.00

mmol), i-butylchloroformate (1.94 mL, 15.00 mmol in THF 7.5 mL) and (−)-norephedrine

(2.27 g, 15.00 mmol in 10 mL THF) in THF(45 mL) according to procedure A as a white

solid (4.99 g, 96%). [α]22D

= −92.1 (c = 1.4 CHCl3); mp 163 °C; MS (ESI), m/z 349 (M++H,

100%), IR (KBr) 3370s, 3271s, 2975s, 1690vs, 1659vs, 1571s, 1417s, cm-1; 1H-NMR (200

MHz, CDCl3) δ = 7.40-7.20 (m, 5 H, H-Ar), 5.00-5.85 (m, 1 H, CHOH), 4.30-410 (m, 2 H,

CHCH3, COCHCH

2), 3.70-3.70 (m, 2 H, NCH2CH2), 2.30-1.80 (4 H, CHCH

2CH

2CH

2),

1.46 (s, 9 H, C(CH3)3), 0.97 (d, J = 6.9 Hz, 3 H, CHCH


3) δ =

172.6 (NHCOCH), 160.0 (COC(CH3)3), 140.8 (C-Ar), 131.3 (C-Ar), 128.1 (C-Ar), 127.3

(C-Ar), 126.2 (C-Ar), 80.6 (COCH(CH3)3), 75.5 (CHOH), 60.4 (COCHNH), 51.1

(CHCH3), 47.2 (NHCH

2CH

2), 28.4 (C(CH

3)3), 24.3 (CHCH

2CH

2), 23.8 (CH

2CH

2CH

2),

13.9 (CHCH3). This compound was used directly in the subsequnt step.

Deprotection of BOC amides

General procedure for the BOC Deprotection with TFA (Procedure A)

N-BOC−α−Amino-amide (10.00 mmol) was dissolved in DCM (30 mL) and concentrat-

ed TFA (15 mL) was added dropwise. The Reaction mixture was stirred at r.t. for 30 min

and extracted with water (4 x 50 mL). The aqueous phase was basified with 1M NaOH and

free amine was extracted with DCM (3 x 30 mL). The organic phases were washed with

water (50 mL), brine (50 mL), dried (Na2SO

4) and the solvent was removed under reduced

pressure, effording the desired amide.


OH

O

2. i-BuOCOCl

3. (−)-norephedrineHN

O

N

Boc

N

BocPh

HO130

96%111


OH

O

2. i-BuOCOCl

3. (R)-(+)-1-phenylethylamineHN

O

N

Boc

N

BocPh

129

94%

111

Experimental 117

General procedure for BOC deprotection with HCl/Et2O (Procedure B)

N-BOC−α−Amino-amide (10.00 mmol) was dissolved in dry Et2O (30 mL) and dry HCl

gas was passed throught the reaction mixture, until the hydrochloric salt of the α-amino-

amide started to precipitate. When no more precipitate was formed, the gas stream was

stopped and the reaction mixture was stirred overnight during which additional precipitate

formed. The precipitate was filtered off, and washed with Et2O (20 mL). THe solid was dis-

solved in water (50 mL) and the aqueous phase was basified with 1 M NaOH. The precipi-

tated free base was extracted to CHCl3

(3 x 20 mL), combined organic phases were dried

(Na2SO

4) and the solvent was removed under reduced pressure to give the α-amino-amide.

General procedure for BOC deprotection with HCl/MeOH (Procedure C)

N-BOC−α−Amino-amide (10.00 mmol) was dissolved in abs. MeOH (10 mL) and the

solution was cooled down to 0 °C. 2 M solution of HCl/MeOH (40 mL, 80.00 mmol, 8 eq.)

was added dropwise and the reaction mixture was warmed up to r.t. and stirred overnight.

The solvent was removed under reduced pressure and the remaining rest was dissolved in

water (10 mL). The aqueous solution was basified with 2 M NaOH and the formed precip-

itate was extracted with CHCl3

(3 x 20 mL). The combined organic phases were dried

(Na2SO

4) and the solvent was removed under reduced pressure. The crude product was fur-

ther dried in vacuo to give the α-amino-amide, which was further used without additional

purification.

(S)-2-Amino-3-methyl-N-phenylbutanamide (131)

From (S)-tert-butyl-3-methyl-1-oxo-1-(phenylamino)butan-2-ylcarbamate (119) (404

mg, 1.38 mmol) and TFA (1.00 mL) in DCM (2.00 mL) according to procedure A as a yel-

low solid (7.332 g, 98%). Spectral data were consistent with literature values.216

(S)-2-Amino-N-(2-tert-butyl-phenyl)-3-methyl-butyramide (132)

From tert-butyl-(S)-1-(2-tert-butylphenylcarbamoyl)-2-methylpropylcarbamate (120)

(10.54 g, 30.20 mmol) and TFA (9.00 mL) in DCM (18 mL) according to procedure A as a

yellow oil (7.33 g, 98%). Spectral data were consistent with literature values.109

H2N HN

O

HN HN

O

Boc

131

98%

120

1. 35% TFA in DCM

2. NaOH

t-Bu t-Bu

H2N HN

O

PhHN HN

O

Boc

131

99%

119

1. 35% TFA in DCM

2. NaOH

118 Experimental

(S)-2-Amino-N-biphenyl-2-yl-3-methyl-butyramide (133)

From (S)-tert-butyl-1-(biphenyl-2-ylamino)-3-methyl-1-oxobutan-2-ylcarbamate (121)

(7.00 g, 19.00 mmol), and TFA (6.00 mL) in DCM (12 mL) according to procedure A as a

colorless oil (2.79 g, 55%). [α]22D

= −26.4 (c = 0.5, CHCl3); MS (EI), m/z 269 (M+, 60%), 169

(100), 84 (30), 72 (85), 55 (40); IR (neat) 3279s, 2960s, 1679vs, 1517vs, 1449vs, 753vs,

703s cm-1; 1H-NMR (200 MHz, CDCl3) δ = 9.57 (s, 1 H, PhNHCO), 8.45-8.40 (m, 1 H, H-

Ar), 7.43-7.7.11 (m, 8 H, H-Ar), 3.27 (d, J = 3.7 Hz, 1 H, NH2CHCH), 2.45-2.30 (m, 1 H,

CH(CH3)2), 1.22 (s, 2 H, NH

2), 0.95 (d, J = 7.1 Hz, 3 H, CH

3), 0.78 (d, J = 7.1 Hz, 3 H,

CH(CH3)2); 13C-NMR (50 MHz, CDCl

3) δ = 172.5 (CONH), 138.8 (C-Ar), 134.9 (C-Ar),

132.4 (C-Ar), 130.0 (C-Ar), 129.4 (C-Ar), 128.7 (C-Ar), 128.4 (C-Ar), 127.7 (C-Ar), 123.9

(C-Ar), 120.7 (C-Ar), 60.5 (NH2CHCH), 30.7 (CH(CH

3)2), 19.7 (CH(CH

3)2), 15.9

(CH(CH3)2); HRMS (ESI) Calcd. for C

17H

21N

2O: 269.1654, found: 269.1657.

(2S)-2-Amino-3-methyl-N-((R)-1-phenylethyl)butanamide (135)

From tert-butyl-(S)-1-((R)-1-phenylethylcarbamoyl)-2-methylpropylcarbamate (123)

(15.91 g, 49.66 mmol) and HCl/MeOH mixture (200 mL of 2 M solution, 0.40 mol) accord-

ing to the procedure C as colorless liquid (10.32 g, 94%). Hygroscopic. Spectral data were

consistent with literature values.217

2-Amino-N-[2-(2-amino-3-methyl-butyrylamino)-phenyl]-3-methyl-butyramide (135)

From bis-tert-butyl-(2S,2'S)-1,1'-(1,2-phenylenebis(azanediyl))bis(3-methyl-1-oxobu-

tane-2,1-diyl)dicarbamate (124) and TFA (30.00 mL) in DCM (60 mL) according to proce-

dure A as a brown oil (6.04 g, 98%). Spectral data were consistent with literature values.209

H2N HN

O

HNH2N

O

NHHN

O

HNNH

O

Boc

Boc

136

98%

124

1. 35% TFA in DCM

2. NaOH

HN HN

O

Boc Ph

H2N HN

O

Ph

135

94%

123

1. HCl/MeOH

2. NaOH

H2N HN

O

HN HN

O

Boc

133

55%

121

1. 35% TFA in DCM

2. NaOH

Ph Ph

Experimental 119

(2S)-2-Amino-N-((S)-1-hydroxy-3-methylbutan-2-yl)-3-methylbutanamide (137)

From (S)-2-amino-N-((S)-1-hydroxymethyl-2-methyl-propyl)-3-methyl-butyramide

(125) (12.82 g, 42.40 mmol) in MeOH (50 mL) and HCl/MeOH mixture (160 mL of 2 M

solution, 0.32 mol) according to procedure C as a yellow solid (5.86 g, 68%). Spectral data


(S)-2-Amino-N,3-dimethylbutanamide (138)

From tert-butyl-(S)-1-(methylcarbamoyl)-2-methylpropylcarbamate (126) (12.52 g,

54.36 mmol) and HCl/MeOH mixture (200 mL of 2 M solution, 0.40 mol, ca 5 eq.) accord-

ing to procedure C as white solid (6.48 g, 92%). Spectral data were consistent with litera-

ture values.219

(S)-2-Amino-N,3-diphenylpropanamide (139)

From tert-butyl-(S)-1-(phenylcarbamoyl)-2-phenylethylcarbamate (127) (1.25 g, 3.84

mmol) and TFA (5 mL) in DCM (10 mL) according to procedure A as a yellow solid (800

mg, 87%). Spectral data were consistent with literature values.220

(2S)-2-Amino-3-phenyl-N-((R)-1-phenylethyl)propanamide (140)

From tert-butyl-(S)-1-((R)-1-phenylethylcarbamoyl)-2-phenylethylcarbamate (128)

(1.13 g, 3.18 mmol) and TFA (5.00 mL) in DCM (10 mL) according to procedure A as as a

yellow oil (724 mg, 85%). Spectral data were consistent with literature values.221

H2N HN

OPh

HN HN

OPh

Boc Ph Ph

128 140

85%

1. 35% TFA in DCM

2. NaOH

H2N HN

OPh

PhHN HN

OPh

Boc

139

87%

127

1. 35% TFA in DCM

2. NaOH

HN HN

O

Boc

H2N HN

O

138

92%

126

1. HCl/MeOH

2. NaOH

HN HN

O

Boc

HO

H2N HN

O

HO137

68%

125

1. HCl/MeOH

2. NaOH

120 Experimental

(S)-N-((S)-1-Phenylethyl)pyrrolidine-2-carboxamide (141)

From (S)-tert-butyl-2-((S)-1-phenylethylcarbamoyl)pyrrolidine-1-carboxylate (129)

(6.00 g, 18.86 mmol) according to procedure B as a white solid (3.56 g, 74%) Specral data


(2S)-N-((1S,2R)-1-Hydroxy-1-phenylpropan-2-yl)pyrrolidine-2-carboxamide (142)

From (S)-tert-butyl-2-((1S,2R)-1-hydroxy-1-phenylpropan-2-ylcarbamoyl)pyrrolidine-

1-carboxylate (130) (4.99 g, 14.30 mmol) according to procedure B as a white solid (2.96

g, 83%). mp 93-95 °C; [α]22D

= +68.7 (c = 0.4, CHCl3), MS (ESI, 0 V), m/z 519.2 (2M+Na,

100%); IR (neat) 3292vs, 1665vs, 1531vs, 1451m, 1373m, 1120m, 1001s, 698s cm-1; 1H-

NMR (200 MHz, CDCl3) δ = 7.55 (bs, 1 H, CONH), 7.40-7.20 (m, 5 H, H-Ar), 7.78 (d, J

= 3.2 Hz, 1 H, CHOH), 4.40-4.15 (m, 1 H, COCHNH), 4.73 (q, J = 5.3 Hz, 1 H, CHCH3),

3.00-2.60 (m, 2 H, NHCH2CH

2), 2.20-1.80 (m, 2 H, CHCH

2CH

2), 1.80-1.60 (m, 2 H,

CH2CH

2CH

2), 1.08 (d, J = 6.9 Hz, 3 H, CHCH


3) δ = 176.3

(NHCO), 140.6 (C-Ar), 127.9 (C-Ar), 127.4 (C-Ar), 126.7 (C-Ar), 77.5 (CHOH), 60.3

(COCHNH), 51.1 (CHCH3), 47.2 (NHCH

2CH

2), 30.8 (CHCH

2CH

2), 26.1 (CH

2CH

2CH

2),

15.7 (CHCH3); HRMS (ESI) Calcd. for C

14H

21N

2O

2: 249.1603, found: 249.1608.

General procedure for the reduction of αα-amino-amides to αα-amino-amines

An α-aminoamide (10.00 mmol) was dissolved in dry THF (100 mL) and LAH (759 mg,

20.00 mmol, 2 eq.) was added slowly against a gentle stream of nitrogen. After the addition

was completed, the reaction mixture was refluxed for 16 h (for differences in reaction times

see the experimental details of the compound) . The reaction mixture was cooled down to 0

°C (ice/salt) and carefully quenched with water (50 mL). Formed precipitate was filtered

off, washed with DCM (50 mL) and the combined organic phases were washed with 1 M

NaOH (20 mL), dried (K2CO

3) and the solvent was removed under reduced pressure to give

the corresponding α-amino-amine.

HN

O

N

BocPh

HO

HN

O

NH

Ph

HO142

83%

130

1. 2.5M HCl.EtOH/Et2O, r.t. 16 h

2. NaOH

HN

O

NH

Ph

HN

O

N

BocPh

141

74%

129

1.HCl/Et2O, r.t. 16 h

2. NaOH

Experimental 121

((2-tert-butyl-N-((S)-2-amino-3-methylbutyl)benzenamine (143)

From (S)-N-(2-tert-butylphenyl)-2-amino-3-methylbutanamide (132) (2.57 g, 10.33

mmol) and LAH (784 mg, 30.66 mmol, 2 eq.) in THF (80 mL). Reaction mixture was

refluxed for 48 hours. Standard workup gave title compound as colorless oil (2.42 g, 85%).

Spectral data were consistent with literature values.109

N-((S)-2-Amino-3-phenylpropyl)benzenamine (145)

From tert-butyl-(S)-1-(phenylcarbamoyl)-2-phenylethylcarbamate (139) (753 mg, 3.13

mmol) and LAH (710 mg, 18.78 mmol, 6 eq.) in THF (30 mL). Standard workup gave the

title compound as white solid (650 mg, 92%). Spectral data were consistent with literature

values.223

(2S)-3-Phenyl-N1-((R)-1-phenylethyl)propane-1,2-diamine (146)

From (2S)-2-amino-3-phenyl-N-((R)-1-phenylethyl)propanamide (140) (600 mg, 2.24

mmol) and LAH (508 mg, 13.43 mmol, 6 eq.) in THF (25 mL). Workup procedure gave the

title compound as yellow oil (564 mg, 99%). Spectral date were consistent with literature

values.224

(1S)-1-phenyl-N-(((S)-pyrrolidin-2-yl)methyl)ethanamine (147)

From (2S)-N-((S)-1-phenylethyl)pyrrolidine-2-carboxamide (141) (1.93 g, 7.57 mmol),

LAH (574 mg, 15.14 mmol) in THF (75 mL). The reaction mixture was refluxed for 48 h.

Standard workup gave the title compound as yellow oil. (1.41 g, 91%). Spectral data were


LAHHN

NH

Ph

HN

O

NH

PhTHF, reflux, 48 h

147

91%

141

LAH H2N HN

Ph

Ph

H2N HN

OPh

Ph THF, reflux, 16 h146

99%

140

LAHH2N HN

Ph

H2N HN

OPh

THF, reflux, 16 h145

92%

139

THF, reflux, 48 hH2N HN

LAH

143

85%

t-Bu

H2N HN

132

t-BuO

122 Experimental

Formylation of amines

General procedure for formylation of αα-amino-amides

The α-amino-amide (10.00 mmol) was dissolved in dry DCM (20 mL) and reaction mix-

ture was cooled down to 0 °C (ice/water). The acetic-formic anhydride (1.37 mL, 15.00

mmol, 3 eq.) was added dropwise over a period of 5 min. In some cases, white precipitate

started to form immediately. After the addition was completed, the reaction mixture was

stirred at r.t. overnight. The solvent was removed under reduced pressure and the rest was

dried under vacuo to give the crude N-formyl-α-amino-amide, which was sufficiently pure

for the subsequent reduction. For additional purification, N-formyl-α-amino-amides were

crystalized from MeOH.

((S)-N-(2-tert-Butyl-phenyl)-2-formylamino-3-methyl-butyramide (149)

From (S)-2-Amino-N-(2-tert-butyl-phenyl)-3-methyl-butyramide (132) (4.33 g, 17.40

mmol) and acetic-formic anhydride (2.38 mL, 26.10 mmol, 1.5 eq.) in DCM (40 mL) as a

white solid (4.25 g, 88%). 1H-NMR (200 MHz, DMSO-d6) δ = 9.40 (s, 1 H, NHCHO), 8.30

(d, J = 9.2 Hz, 1 H, NHCHO), 8.10 (s, 1 H, NHCO), 7.50-7.40 (m, 1 H, H-Ar), 7.30-7.10

(m, 2 H, H-Ar), 7.10-6.95 (m, 1 H, H-Ar), 4.55-4.47 (m, 1 H, NHCHCH), 2.20-2.00 (m, 1

H, CH(CH3)2), 1.30 (s, 12 H, C(CH

3)3), 0.99 (d, J = 6.8 Hz, 3 H, CH(CH

3)2), 0.89 (d, J =

6.8 Hz, CH(CH3)2); 13C-NMR (50 MHz, DMSO-d6) δ = 170.7 (CHCONH), 161.0

(NHCHO), 146.4 (C-Ar), 135.8 (C-Ar), 131.1 (C-Ar), 126.9 (C-Ar), 126.5 (C-Ar), 126.4

(C-Ar), 56.2 (NHCHCH), 34.6 (C(CH3)3), 30.7 (C(CH

3)3), 30.6 (CHCH(CH

3)2), 19.4

(CH(CH3)2), 17.8 (CH(CH

3)2). This compound was used directly in the subsequent step.

(S)-N-Biphenyl-2-yl-2-formylamino-3-methyl-butyramide (150)

From (S)-2-amino-N-biphenyl-2-yl-3-methyl-butyramide (133) (2.79 g, 10.40 mmol),

acetic-formic anhydride (1.42 mL, 15.60 mmol, 1.5 eq.) in DCM (20 mL) as a white solid

(2.76 g, 89%). mp 155 °C; [α]22D

= −74.8 (c = 0.31, MeOH); MS (ESI, 0 V), m/z 319.1

(M++Na 80%), 615.3 (100, 2M+Na); IR (KBr) 3266s, 1639vs, 1535s, 749s cm-1; 1H-NMR

(200 MHz, DMSO-d6) δ = 9.44 (s, 1 H, NHCHO), 8.20 (d, J = 9 Hz, 1 H, NCCHO), 8.05

(s, 1 H, CONHPh), 7.53-7.25 (m, 9 H, H-Ar), 4.37-4.30 (m, 1 H, NHCHCH), 2.01-1.91 (m,

1 H, CH(CH3)2) 0.82 (d, J = 6.8 Hz, CH(CH

3)2), 0.75 (d, J = 6.8 Hz, 3 H, CH(CH

3)2); 13C-

NMR (50 MHz, DMSO-d6) δ = 170.0 (NHCOCH), 160.1 (NHCHO), 138.6 (C-Ar), 136.8

DCM, 0 °CNHHN

O

O

OO

O

H2N HN

O

150

89%

133

Ph Ph

DCM, 0 °C

NHHN

O

O

OO

O

H2N HN

O

149

88%

132

t-Bu t-Bu

Experimental 123

(C-Ar), 134.3 (C-Ar), 130.2 (C-Ar), 128.8 (C-Ar), 128.2 (C-Ar), 127.7 (C-Ar), 127.2 (C-

Ar), 126.9 (C-Ar), 126.1 (C-Ar), 56.1 (NHCHCH), 30.2 (CH(CH3)2), 19.2 (CH(CH

3)2),

17.4 (CH(CH3)2). Anal. Calcd for C

18H

20N

2O

2: C, 72.95; H, 6.80; N, 9.45, found: C, 72.46;

H, 6.72; N, 9.19. HRMS (ESI) Calcd. for C18

H20

N2O

2Na: 319.1422, found: 319.1422.

((2S,2'S)-N,N'-(1,2-Phenylene)bis(2-formamido-3-methylbutanamide) (151)

From (2S,2'S)-N,N'-(1,2-phenylene)bis(2-amino-3-methylbutanamide) (136) (2.69 g,

8.70 mmol) and acetic-formic anhydride (2.38 mL, 26.10 mmol, 3 eq.) as a white solid (2.85

g, 90%). mp 162 °C; [α]22D

= −8.1 (c = 0.37 MeOH); MS (EI), m/z 361 (M+−H, 10%), 235

(30), 135 (50), 125 (40), 99 (50), 85 (100), 56 (50); IR (KBr) 3275vs, 2965s, 1650vs,

1539vs, 1383s, 1216s, 1060m, 754s cm-1; 1H-NMR (200 MHz, DMSO-d6) δ = 9.75-9.40

(m, 2 H, NHCHO), 8.55-8.30 (m, 2 H, CONH), 8.15-8.10 (m, 2 H, NHCHO), 7.65-7.50 (m,

2 H, H-Ar), 7.25-7.10 (m, 2 H, H-Ar); 4.50-4.30 (m, 2 H, NHCHCH), 2.20-2.00 (m, 2 H,

CH(CH3)2), 1.00-0.80 (m, 6 H, CH(CH

3)2; 13C-NMR (50 MHz, DMSO-d6) δ = 170.0

(NHCO), 161.4 (NHCO), 130.1 (C-Ar), 125.3 (C-Ar), 124.7 (C-Ar), 57.1 (NHCHCH), 30.2

(CH(CH3)2), 21.0 (CH(CH

3)2), 17.8 (CH(CH

3)2). Anal. Calcd for C

18H

26N

4O

4: C, 59.65;

H, 7.23; N, 15.46, found: C, 58.83; H, 7.16; N, 7.65; HRMS (ESI) Calcd. for

C18

H26

N4O

4Na: 385.1852, found: 385.1848.

(S)-2-Formamido-3-methyl-N-((R)-1-phenylethyl)butanamide (152)

From (S)-2-amino-3-methyl-N-((R)-1-phenylethyl)butanamide (135) (5.46 g, 24.77

mmol), acetic-formic anhydride (4.66 mL, 37.16 mmol, 1.5 eq.) in DCM (70 mL) as a white

solid (5.86 g, 95%). mp 166 °C; [α]22D

= +24.8 (c = 1.0, MeOH); MS (ESI, 0 V), m/z 271.1

(M+Na, 100%); IR (KBr) 3274vs, 2959s, 1635vs, 1549vs, 1389s, 1228s, 745s, 698s cm-1;

1H (200 MHz, DMSO-d6) δ = 8.24 (d, J = 7.8 Hz 1 H, NHCHO), 7.94-7.22 (m, 2 H,

CONH), 7.01-6.97(m, 5 H, Ar), 4.70 (m, 1 H, NHCHCH), 4.03 (m, 1 H, CHCH3), 1.70 (m,

1 H, CH(CH3)2), 1.10 (d, J = 6.7 Hz, 3 H, CHCH

3), 0.96 (m, 6 H, CH(CH

3)2); 13C (50 MHz,

DMSO-d6) δ = 169.6 (NHCO), 160.8 (NHCO), 144.1 (C-Ar),128.1 (C-Ar), 126.6 (C-Ar),

126.0 (C-Ar), 56.1 (NHCHCH), 47.7 (CHCH3), 30.7 (CH(CH

3)2), 22.3 (CHCH

3), 19.1

(CH(CH3)2), 18.1 (CH(CH

3)2). Anal. Calcd for C

14H

20N

2O

2: C, 67.71; H, 8.12; N, 11.28,

DCM, 0°C

O

OO

H2N HN

O

Ph

NHHN

O

Ph

O

152

95%

135

DCM, 0°C

NHHN

O

HNNH

O

H2N HN

O

HNH2N

O

O

OO

O

O

151

90%

136

124 Experimental

found: C, 68.01; H, 8.12; N, 11.19.; HRMS (ESI) Calcd. for C14

H20

N2O

2Na: 271.1422,

found: 271.1421.

(S)-2-Formylamino-3,N-dimethyl-butyramide (153)

From (S)-2-amino-N,3-dimethylbutanamide (138) (2.380 g, 10.40 mmol), acetic-formic

anhydride (1.42 mL, 15.60 mmol, 1.5 eq.) in DCM (40 mL) as a white solid (2.75 g, 96%).

mp 170 °C. [α]22D

= −45.2 (c = 1.0, MeOH); MS (ESI, 0 V), m/z 339.2 (2M+Na, 100%), 181.1

(M+Na, 80%); IR (KBr) 3289vs, 1640vs, 1382m, 713m cm-1; 1H-NMR (200 MHz, DMSO-

d6) δ = 8.23 (d, J = 9.2 Hz, 1 H, NHCHO), 8.09 (s, 1 H, NHCHO), 8.08-7.90 (m, 1 H,

NHCH3), 4.25-4.15 (m, 1 H, NHCHCH), 2.64 (d, J = 4.6 Hz, 3 H, NHCH

3), 2.10-1.90 (m,

1 H, CH(CH3)2); 13C-NMR (50 MHz, DMSO-d6) δ = 170.9 (NHCO), 160.8 (NHCHO),

56.2 (NHCHCH), 30.4 (NHCH3)Ar), 25.3 (CH(CH

3)2), 19.1 (CH(CH

3)2), 17.9

(CH(CH3)2). Anal. Calcd for C

7H

14N

2O

2: C, 53.15; H, 8.92; N, 17.71, found: C, 53.26; H,

8.92; N, 17.41; HRMS (ESI) Calcd. for C9H

17N

3O

2Na: 222.1218, found: 222.1216.

(2S,5R,6R)-6-((R)-2-Formylamino-2-phenyl-acetylamino)-3,3-dimethyl-7-oxo-4-thia-1-

aza-bicyclo[3.2.0]heptane-2-carboxylic acid (160)

From ampicillin (159) (699 mg, 2.00 mmol) and acetic formic anhydride (457 μL, 5.00

mmol, 2.5 eq.) in DCM (40 mL) as a white solid (738 mg, 98%). Spectral data were consis-

tent with literature values.225

Reduction of N-formyl amides

An N-formyl-α-aminoamide (5.00 mmol) was dissolved in dry THF (100 mL) and LAH

(759 mg, 20.00 mmol, 4 eq.) was added slowly against a gentle stream of nitrogen. After the

addition was completed, the reaction mixture was refluxed for 16 h (for the differences in

reaction times see the experimental details of the compound). The reaction mixture was

cooled down to 0 °C (ice/salt) and carefully quenched with water (50 mL). Formed precip-

itate was filtered off, washed with DCM (50 mL) and the combined organic phases were

washed with 1 M NaOH (20 mL), dried (K2CO

3) and the solvent was removed under

reduced pressure to give the corresponding amine.

N

S

HH

NH

CH3

CH3

OHO

O

NH2

O

N

S

HH

NH

CH3

CH3

OHO

O

NH

O

DCM, 0°C

O

O

O

O

160

98%

159

DCM, 0 °C

NHHN

O

O

OO

O

H2N HN

O

138 153

96%

Experimental 125

2-tert-Butyl-N-((S)-3-methyl-2-(methylamino)butyl)benzenamine (154)

From ((S)-N-(2-tert-butyl-phenyl)-2-formylamino-3-methyl-butyramide (149) (4.25 g,

15.38 mmol) and LAH (2.34 g, 61.50 mmol, 4 eq.) in THF (120 mL). The reaction mixture

was refluxed for 48 h. Standard workup gave title compound as colorless oil (3.15 g, 82%).

[α]22D

= −7.0 (c = 0.37, CHCl3); MS (EI), m/z 248 (M+, 1%), 163 (20), 86 (100); IR (neat)

2959vs, 1601s, 1506vs, 1446s, 1307s, 742s cm-1; 1H-NMR (200 MHz, CDCl3) δ = 7.30-

7.10 (m, 2 H, H-Ar), 6.70-6.60 (m, 2 H, H-Ar), 4.82 (bs, 1 H, CH2NHPh), 3.30-3.00 (m, 2

H, CHCH2NH), 3.05-2.95 (m, 2 H, CH

2), 2.95-2.85 (m, 1 H, NHCHCH), 2.60-2.50 (m, 1

H, CH(CH3)2), 2.37 (s, 3 H, NHCH

3), 1.93 (q, J = 6.8 Hz, 1 H, NHCH

3), 1.41 (s, 9 H,

C(CH3)3), 1.01 (d, J = 6.8 Hz, 3 H, CH(CH

3)2), 0.95 (d, J = 6.8 Hz, 3 H, CH(CH

3)2); 13C-

NMR (50 MHz, CDCl3) δ = 147.0 (C-Ar), 133.3 (C-Ar), 127.1 (C-Ar), 126.1 (C-Ar), 116.0

(C-Ar), 111.3 (C-Ar), 64.0 (NHCHCH), 43.0 (CH2), 33.1 (C(CH

3)3), 29.8 (NHCH

3), 29.7

(C(CH3)3), 29.2 (CH(CH

3)2), 19.4 (CH(CH

3)2), 18.1 (CH(CH

3)2); HRMS (ESI) Calcd. for

C16

H29

N2: 249.2331, found: 249.2340.

(S)-N’-Biphenyl-2-yl-3,N’’-dimethyl-butane-1,2-diamine (155)

From (S)-N-biphenyl-2-yl-2-formylamino-3-methyl-butyramide (150) (2.67 g, 9.00

mmol) and LAH (1.37 g, 36.00 mmol, 4 eq.) in THF (80 mL). The reaction mixture was

refluxed for 16 h. Standard workup followed by FCC (DMC/MeOH, 95/5) gave the title

compound as colorless oil (1.94 g, 80%). [α]22D

= −67.0 (c = 0.3, CHCl3); MS (EI), m/z 269

(M+ + H, 1%), 183 (50), 167 (10), 86 (100); IR (neat) 3267s, 2961vs, 1684vs, 1583s,

1518vs, 1448s, 755s cm-1; 1H-NMR (200 MHz, CDCl3) δ = 7.50-7.10 (m, 7 H, H-Ar), 6.90-

6.70 (m, 2 H, H-Ar), 4.45 (bs, 1 H, NH), 3.20-2.85 (m, 2 H, CH2), 2.42-2.33 (m, 1 H,

NHCHCH), 2.30 (s, 3 H, NHCH3), 1.87-1.76 (m, 1 H, (CH(CH

3)2), 1.20 (bs, 1 H, NH),

0.96-0.89 (m, 6 H, CH(CH3)2); 13C-NMR (50 MHz, CDCl

3) δ = 145.7 (C-Ar), 139.6 (C-


63.8 (NHCHCH), 43.8 (CH2), 34.0 (NCH

3), 29.0 (CH(CH

3)2), 19.2 (CH(CH

3)2), 18.3

(CH(CH3)2). HRMS (ESI) Calcd. for C

18H

25N

2

+: 269.2012, found: 269.2014.


LAHNHHN

O

O

155

80%

150

Ph Ph


LAHNHHN

O

O

154

82%

149

t-Bu t-Bu

126 Experimental

N’,N’’-bis((S)-3-methyl-2-(methylamino)butyl)benzene-1,2-diamine (156)

From (2S,2'S)-N,N'-(1,2-phenylene)bis(2-formamido-3-methylbutanamide) (151) (1.15

g, 3.17 mmol) and LAH (965 mg, 25.40 mmol, 8 eq.) in THF (80 mL). The reaction mix-

ture was refluxed for 16 h. Standard workup gave the title compound as yellow oil (944 mg,

in 97%). [α]22D

= +0.7 (c = 0.3, CHCl3); MS (EI), m/z 306 (M+, 20%), 221 (10), 136 (50), 86

(100); IR (neat) 3320s, 2957vs, 1601vs, 1516vsm 1439vs, 1254s, 734vs cm-1; 1H-NMR

(200 MHz, CDCl3) δ = 6.75-6.64 (m, 4 H, H-Ar), 3.89 (bs, 2 H, NH), 3.21-3.14 (m, 2 H,

CH2), 2.95-2.85 (m, 2 H, NHCHCH), 2.55-4.49 (m, 2 H, CH

2), 2.42 (s, 6 H, NHCH

3), 2.02-

1.85 (m, 2 H, CH(CH3)2), 1.35-1.10 (bs, 2 H, NH), 1.02-0.92 (m, 12 H, CH(CH

3)2); 13C-

NMR (50 MHz, CDCl3) δ = 137.9 (C-Ar), 118.7 (C-Ar), 111.2 (C-Ar), 64.1 (NHCHCH),

43.9 (CH2), 34.2 (NHCH

3), 28.8 (CH(CH

3)2), 19.4 (CH(CH

3)2), 18.1 (CH(CH

3)2); HRMS

(ESI) Calcd. for C18

H35

N4: 307.2862, found: 307.2862.

(S)-3-Methyl-2-methylamino-N-((R)-1-phenyl-ethyl)-butyramide (157)

From (S)-2-formylamino-3-methyl-N-((R)-1-phenyl-ethyl)-butyramide (152) (5.49 g,

22.11 mmol) and LAH (3.36 g, 88.44 mmol, 4 eq.) in THF (250 mL). Reaction mixture was

refluxed for 36 h. Standard workup gave the title compound as white solid (4.74 g, 91%).

mp 42 °C, [α]22D

= +89.0 (c = 5.0, MeOH); MS (ESI, 0 V), m/z 491.1 (2M+Na, 100%); IR

(KBr): 3274m, 2966m, 1638s, 1546m, 1238m, 1132m, 761s, 700vs cm-1; 1H (200 MHz,

DMSO-d6) δ = 7.45 (bs, 1H, CONHPh), 7.26-7.21(m, 5 H, Ar), 5.17 (m, 1 H, NHCHCH),

2.77 (d, J = 4.5 Hz, 1 H, CH), 2.37 (d, J = 8.1 Hz, 3 H, CHCH3), 2.06 (m, 1 H, CH(CH

3)2),

1.50 (d, J = 6.9 Hz, 3 H, CHCH3), 1.12 (m, 1 H, NHCH

3), 0.95 (d, J = 7.0 Hz, 3H,

CH(CH3)2), 0.77 (d, J = 6.9 Hz, 3 H, CH(CH

3)2). 13C (50 MHz, DMSO-d6) δ = 172.4

(CONH), 143.5 (C-Ar), 128.5 (C-Ar), 127.1 (C-Ar), 126.1 (C-Ar), 70.8 (NHCHCH), 47.9

(CHCH3), 36.2 (NHCH

3), 31.4 (CH(CH

3)2), 22.0 (CHCH

3), 19.6 (CH(CH

3)2), 17.8

(CH(CH3)2). Anal. Calcd for C

14H

22N

2O, C, 71.76; H, 9.46; N, 11.95 found: C, 11.82; H,

9.39; N, 11.82.; HRMS (ESI) Calcd. for C14

H23

N2O: 235.1810, found: 235.1807.


LAHNHHN

O

O

PhPh

O

157

91%

152

THF, rexlux, 16 h

NHHN

HNNH

LAHNHHN

O

HNNH

O

O

O

156

97%

151

Experimental 127

(S)-N,3-Dimethyl-2-(methylamino)butanamide (158)

From (S)-2-formylamino-3,N-dimethyl-butyramide (153) (2.53 g, 16.00 mmol), LAH

(1.82 g, 48.00 mmol, 3 eq.) in THF (100 mL). Standard workup gave the title compound as

a white solid (600 mg, 29%), which was sublimed under reduced pressure. mp 62-64 °C.

[α]22D

= −24.8 (c = 1.0, CHCl3); MS (ESI, 0 V), m/z 144 (M+, 45%); IR (KBr) 3298vs, 2960s,

1639vs, 1568vs, 1451s, 1240s, 789s, 703s cm-1; 1H-NMR (200 MHz, CDCl3) δ = 7.14 (bs,

CONHCH3), 2.84 (d, J = 5.0 Hz, NHCNCH

3), 2.78 (d, J = 4.4 Hz, NHCHCH), 2.35 (s, 3

H, CONHCH3), 2.20-2.00 (m, 1 H, CH(CH

3)2), 1.70 (bs, 1 H, NHCH

3), 0.98 (d, J = 7.0 Hz,

3 H, CH(CH3)2), 0.86 (d, J = 7.0 Hz, 3 H, CH(CH

3)2); 13C-NMR (50 MHz, CDCl

3) δ =

174.1 (CONH), 70.8 (NHCHCH), 36.3 (CHNHCH3), 31.3 (CH(CH

3)2), 25.5 (CONHCH

3),

19.6 (CH(CH3)2), 17.7 (CH(CH

3)2); HRMS (ESI) Calcd. for C

7H

17N

2O: 145.1341, found:

145.1339.

Tosylation of amines

((2-tert-butyl-N-((S)-3-methyl-2-(tosylamino)butyl)benzenamine (161)

A solution of 2-tert-butyl-N-((S)-2-amino-3-methylbutyl)benzenamine (143) (583 mg,

2.48 mmol) in THF (25 mL) was cooled down to 0 °C (ice/water) and Et3N (1 mL) was

added. To the reaction mixture a solution of TsCl (474 mg, 2.48 mmol) in THF (5 mL) was

added dropwise. The reaction mixture was warmed up to r.t. and stirred overnight. The reac-

tion mixture was filtered, the solvent was removed under reduced pressure and the solid rest

was crystallized from EtOH, giving the title compound as a white solid (572 mg, 59%). [α]22D

= −65 (c = 0.4, CHCl3), mp 147 °C; MS (ESI, 0 V), m/z 389.2 (M++H, 70%); IR (KBr)

3299s, 2971s, 1504vs, 1443vs, 1306vs, 1287vs, 1160vs, 1092s, 745s, 667vs, 552s cm-1; 1H-

NMR (200 MHz, CDCl3) δ = 7.81-7.73 (m, 2 H, H-Ar), 7.32-7.20 (m, 3 H, H-Ar), 7.13-7.01

(m, 1 H, H-Ar), 6.76-6.65 (m, 1 H, H-Ar), 6.55-6.45 (m, 1 H, H-Ar), 4.70-4.60 (m, 1 H,

TsNHCH), 4.20-4.10 (m, 1 H, PhNHCH), 3.50-3.35 (m, NHCHCH), 3.20-3.10 (m, 2 H,

CH2), 2.42 (s, 3 H, TsCH

3), 1.90-1.70 (m, 1 H, CH(CH

3)2), 1.40 (s, 9 H, C(CH

3)3), 0.87 (d,

J = 6.87 Hz, 3 H, CH(CH3)2), 0.79 (d, J = 6.87 Hz, 3 H, CH(CH

3)2); 13C-NMR (50 MHz,

CDCl3) δ = 145.9 (C-Ar), 143.5 (C-Ar), 137.8 (C-Ar), 134.1 (C-Ar), 129.7 (C-Ar), 127.1

(C-Ar), 127.0 (C-Ar), 126.3 (C-Ar), 117.6 (C-Ar), 112.0 (C-Ar), 58.3 (NHCHCH), 45.8

(CH2), 34.1 (C(CH

3)3), 30.1 (CH(CH

3)2), 29.9 (C(CH

3)3), 21.5 (PhCH

3), 18.5 (CH(CH

3)2),

18.0 (CH(CH3)2); HRMS (ESI) Calcd. for C

22H

33N

2O

2S: 389.2263, found: 389.2263.

THF, 0 °CNHHN

TsCl, Et3NH2N HN Ts

143 161

59%

t-Bu t-Bu

LAH

NHHN

NHHN

O

THF, reflux, 72 h

O

158

29%

153

O

128 Experimental

3.2. Preparation of Imidazolidines

General procedure for the preparation of aminals in water excluding conditions

(Method A)

The diamine (1.00 mmol) was disolved in benzene (25 mL), p-toluensulfonic acid (5 mg,

0.03 mmol) and aldehyde (1.00 mmol) were added and the reaction mixture was refluxed

on Dean-Stark water separator for 24 h. Benzene was removed under reduced pressure to

give the crude product, which was purrified by FCC (petroleum ether/EtOAc/Et3N,

95/5/0.5) giving the desired aminal.

General procedure for preparation of aminals in water (Method B)

The diamine (1.00 mmol) was added to water (1.5 mL) and the mixture was vigorously

stirred. Aldehyde (1.00 mmol) was added at once. The reaction mixture was vigorously

stirred at r.t. for 3 h. For exceptions in temperatures and reaction times see the experimen-

tal details of the compounds.

Workup procedure 1

If solid precipitate has formed, it was isolated by suction filtration, washed with water (5

mL) and dried in vacuo, giving the corresponding aminal.

Workup procedure 2

In case, no solid was formed, the reaction mixture was extracted with chloroform (3 x 5

mL). The organic phases were combined, dried (Na2SO

4) and the solvent was removed

under reduced pressure. Residue was dried in vacuo to give the desired aminal.

General procedure for the preparation of aminals under solvent free conditions

(Method C)

Diamine (1.00 mmol) and aldehyde (1.00 mmol) were placed in a pressure vessel

equipped with a magnetic stirrer. The vessel was flushed with nitrogen, sealed and the reac-

tion mixture was heated up to 120 °C for 16 h. After cooling to r.t., the formed glassy solid

was dissolved in DCM and dried (Na2SO

4). The solvent was removed under reduced and

the remaining rest was dried under vacuum giving the corresponding aminal.

1,3-Dibenzyl-2-phenylimidazolidine (183)

From N,N’-dibenzylethylenediamine (166) (238 mg, 1.00 mmol) and benzaldehyde (101

μL, 1.00 mmol) in water (1.5 mL), according to method B. Workup procedure 1 gave the

title compound as a white solid (299 mg, 91%). Spectral data were consistent with literature

values.130

Ph

NH HN

Ph H2O, r.t., 3 h

N N

PhPh

+

168

91%

166Ph

Ph

O

Experimental 129

1,3-Dibenzyl-2-(2-chloro-phenyl)-imidazolidine (183)

From N,N’-dibenzylethylenediamine (166) (238 mg, 1.00 mmol) and 2-chlorobenzalde-

hyde (140 mg, 1.00 mmol) in water (1.5 mL) according to method B. Workup procedure 1

gave the title compound as a white solid (348 mg, 96%). mp 96 °C; MS (EI), m/z 361 (M+

+ H, 25%), 251 (100), 91 (75); IR (KBr) 2793m, 1365m, 1151s, 757vs, 698vs cm-1; 1H-

NMR (400 MHz, CDCl3) δ = 8.14 (d, J = 7.8 Hz, 1 H, H-Ar), 7.45-7.25 (m, 13 H, H-Ar),

4.70 (s, 1 H, NCHN), 3.85 (d, J = 13.2 Hz, 2 H, PhCH2N), 3.41 (d, J = 13.2 Hz, 2 H,

PhCH2N), 3.26-3.23 (m, 2 H, NCH

2CH

2N), 2.64-2.61 (m, 2 H, NCH

2CH

2N); 13C-NMR

(100 MHz, CDCl3) δ = 139.7 (C-Ar), 138.2 (C-Ar), 136.0 (C-Ar), 131.8 (C-Ar), 129.8 (C-

Ar), 129.3 (C-Ar), 128.9 (C-Ar), 128.6 (C-Ar), 127.7 (C-Ar), 127.3 (C-Ar), 83.6 (NCHN),

57.3 (NCH2CH

2N), 51.2 (PhCH

2N). Anal. Calcd for C

23H

23ClN

2: C, 76.12; H, 6.39; N,

7.72, found: C, 75.82; H, 6.32; N, 7.55.

1,3-Dibenzyl-2-(4-chloro-phenyl)-imidazolidine (184)

From N,N’-dibenzylethylenediamine (166) (952 mg, 4.00 mmol) and 4-chlorobenzalde-

hyde (560 mg, 4.00 mmol) in water (6 mL) according to method B. The reaction mixture

was heated up to 50 °C for 3 h. Workup procedure 1 gave the title compound as a white solid

(1.315 g, 91%). mp 106 °C; MS (EI), m/z 361 (M+ + H, 25%), 251 (75), 152 (20), 125 (20),

91 (100), 65 (20); IR (KBr) 2804m, 1493m, 1148m, 1186m, 822s, 698vs cm-1; 1H-NMR

(400 MHz, CDCl3) δ = 7.64-7.61 (m, 2 H, H-Ar), 7.44-7.38 (m, 2 H, H-Ar), 7.33-7.22 (m,

10 H, H-Ar), 4.01 (s, 1 H, NCHN), 3.79 (d, J = 13.2 Hz, 2 H, PhCH2N), 3.28-3.20 (m, 4 H,

PhCH2N, NCH

2CH

2N), 2.57-2.53 (m, 2 H, NCH

2CH


3) δ

= 139.6 (C-Ar), 139.4 (C-Ar), 134.6 (C-Ar), 131.2 (C-Ar), 128.9 (C-Ar), 128.8 (C-Ar),

128.6 (C-Ar), 127.3 (C-Ar), 88.6 (NCHN), 57.3 (NCH2CH

2N), 51.1 (PhCH

2N). Anal. Calcd

for C23

H23

ClN2: C, 76.12; H, 6.39; N, 7.72, found: C, 76.00; H, 6.39; N, 7.65.

Ph

NH HN

Ph H2O, 50 °C, 3 h

CHON N

PhPh

Cl

Cl

+

184

91%

166

Ph

NH HN

Ph H2O, r.t., 3 h

CHO

N N

PhPh

Cl

+

183

96%

Cl

166

130 Experimental

1,3-Dibenzyl-2-(2,6-dichloro-phenyl)-imidazolidine (185)

From N,N’-dibenzylethylenediamine (166) (952 mg, 4.00 mmol) and 2,6-dichloroben-

zaldehyde (700 mg, 4.00 mmol) in water (6 mL) according to method B. The reaction mix-

ture was heated up to 80 °C for 3 h. Workup procedure 1 gave the title compound as a white

solid (1.393 g, 88%). mp 145 °C; MS (EI), m/z 495 (M+ + H, 5%), 251 (90), 91 (100); IR

(KBr) 2792m, 1492m, 1436s, 1377m, 1337m, 1148m, 782m, 766m, 737vs, 698s cm-1; 1H-

NMR (400 MHz, CDCl3) δ = 7.37-7.11 (m, 13 H, H-Ar), 5.07 (s, 1 H, NCHN), 3.87 (d, J =

13.6 Hz, 2 H, PhCH2N), 3.58 (d, J = 13.6 Hz, 2 H, PhCH

2N), 3.36-3.33 (m, 2 H,

NCH2CH

2N), 2.62-2.58 (m, 2 H, NCH

2CH


3) δ = 140.1 (C-


127.1 (C-Ar), 85.0 (NCHN), 58.2 (NCH2CH

2N), 51.8 (PhCH

2N). Anal. Calcd for

C23

H22

Cl2N

2: C, 69.52; H, 5.58; N, 7.06, found: C, 69.47; H, 5.59; N, 6.88.

1,3-Dibenzyl-2-(2,4-dichloro-phenyl)-imidazolidine (186)

From N,N’-dibenzylethylenediamine (166) (2.380 g, 10.00 mmol) and 2,4-dichloroben-

zaldehyde (1.75 g, 10.00 mmol) in water (15 mL) according to method B. Reaction mixture

was heated up to 80 °C for 3 h. Workup procedure 2 gave the title compound as a yellow

solid (3.79 g, 96%). mp 84 °C; MS (EI), m/z 395 (M+ + H, 15%), 251 (100), 91 (80); IR

(KBr) 2804s, 1337s, 1152s, 854s, 697vs cm-1; 1H-NMR (400 MHz, CDCl3) δ = 8.03 (d, J

= 8.3 Hz, 1 H, H-Ar), 7.39-7.35 (m, 2 H, H-Ar), 7.31-7.20 (m, 10 H, H-Ar), 4.60 (s, 1 H,

NCHN), 3.78 (d, J = 13.1 Hz, 2 H, PhCH2N), 3.38 (d, J = 13.1 Hz, 2 H, PhCH

2N), 3.25-

3.15 (m , 2 H, NCH2CH

2N), 2.65-2.55 (m, 2 H, NCH

2CH


3)

δ = 139.4 (C-Ar), 137.2 (C-Ar), 136.4 (C-Ar), 134.7 (C-Ar), 132.8 (C-Ar), 128.9 (C-Ar),

128.8 (C-Ar), 128.6 (C-Ar), 128.1 (C-Ar), 127.3 (C-Ar), 83.1 (NCHN), 57.2 (NCH2CH

2N),

51.2 (PhCH2N). Anal. Calcd for C

23H

22Cl

2N

2: C, 69.52; H, 5.58; N, 7.05, found: C, 69.33;

H, 5.46; N, 6.81.

Ph

NH HN

Ph H2O, 80 °C, 3 h

CHO N N

PhPhCl

Cl

Cl

Cl

186

96%

+

166

Ph

NH HN

Ph H2O, 80°C, 3 h

CHON N

PhPhCl ClClCl

+

185

88%

166

Experimental 131

1,3-Dibenzyl-2-(perfluorophenyl)imidazolidine (187)

From N,N’-dibenzylethylenediamine (166) (1.202 g, 5.00 mmol) and pentafluoroben-

zaldehyde (980 mg, 621 μL, 5.00 mmol) in water (15 mL) according to method B. Workup

procedure 2 gave the title compound as a white solid (1.890 g, 90%). Spectral data were


1,3-Dibenzyl-2-(2-methoxy-phenyl)-imidazolidine (188)

From N,N’-dibenzylethylenediamine (166) (238 mg, 1.00 mmol) and 2-methoxy-ben-

zaldehyde (136 mg, 1.00 mmol) in water (1.5 mL) according to method B. The reaction mix-

ture was heated up to 50 °C for 16 h. Workup procedure 1 gave the title compound as a white

solid (335 mg, 94%). mp 70 °C; MS (EI), m/z 357 (M+ + H, 20%), 251 (100), 148 (15), 121

(20), 91 (100), 65 (20); IR (KBr) 2795s, 2492s, 1380s, 1239s, 1153s, 752s, 698s cm-1; 1H-

NMR (400 MHz, CDCl3) δ = 8.00 (dd, J1 = 7.6, J2 = 1.4 Hz, 1 H, H-Ar), 7.32-7.03 (m, 12

H, H-Ar), 6.87 (d, J = 8.3 Hz, 1 H, H-Ar), 3.59 (s, 1 H, NCHN), 3.84 (s, 3 H, OCH3), 3.80

(d, J = 13.2 Hz, 2 H, PhCH2N), 3.29 (d, J = 13.2 Hz, 2 H, PhCH

2N), 3.17-3.14 (m, 2 H,

NCH2CH

2N), 2.56-2.52 (m, 2 H, NCH

2CH


3) δ = 159.5 (C-


80.1 (NCHN), 57.5 (OCH3), 55.9 (NCH

2CH

2N), 51.1 (PhCH


C24

H26

N2O: C, 80.41; H, 7.31; N, 7.81, found: C, 80.3; H, 7.43; N, 7.71.

1,3-Dibenzyl-2-thiophen-2-yl-imidazolidine (189)

From N,N’-dibenzylethylenediamine (166) (476 mg, 2.00 mmol) and thiophen-2-car-

baldehyde (224 mg, 2.00 mmol) in water (3 mL) according to method B. Workup procedure

Ph

NH HN

Ph H2O, r.t., 3 h

S

CHO

N N

PhPh

+

189

99%

166

S

Ph

NH HN

Ph H2O, 50 °C, 16 h

CHO

N N

PhPh

OMe

OMe

+

188

94%

166

Ph

NH HN

Ph H2O, r.t., 3 h

CHO N N

PhPhF

FFF

F

F

FF

F

F

+

187

90%

166

132 Experimental

1 gave the title compound as a white solid (657 mg, 99%). mp 122 °C; MS (EI), m/z 333

(M+ + H, 1%), 124 (50), 97 (30), 91 (100); IR (KBr) 1307s, 1161s, 744s, 717s, 698s cm-1;

1H-NMR (400 MHz, CDCl3) δ = 7.42-6.99 (m, 13 H, H-Ar), 4.82 (s, 1 H, NCHN), 3.96 (d,

J = 12.9 Hz, 2 H, PhCH2N), 3.29 (d, J = 12.9 Hz, 2 H, PhCH

2N), 3.20-3.17 (m, 2 H,

NCH2CH

2N), 2.56-2.52 (m, 2 H, NCH

2CH


3) δ = 146.4 (C-


126.2 (C-Ar), 84.0 (NCHN), 57.3 (NCH2CH

2N), 50.7 (PhCH


C21

H22

N2S: C, 75.41; H, 6.63; N, 8.38, found: C, 75.41; H, 6.61; N, 8.77.

2-(1,3-Dibenzyl-imidazolidin-2-yl)-pyridine (190)

From N,N’-dibenzylethylenediamine (166) (476 mg, 2.00 mmol) and pyridine-2-car-

baldehyde (214 mg, 191 μL, 2.00 mmol) in water (3 mL) according to method B. Workup

procedure 1 gave the title compound as a white solid (652 mg, 99%). mp 80-81 °C; MS (EI),

m/z 329 (M+ + H, 5%), 251 (100), 197 (10), 238 (10), 91 (80), 65 (10); IR (KBr) 2792m,

1493m, 1434s, 1360m, 1135m, 1148m, 781s, 749s, 696vs cm-1; 1H-NMR (400 MHz,

CDCl3) δ = 8.56-8.55 (m, 1 H, H-Ar), 8.01 (dt, J1 = 8.0, J2 = 1.0 Hz, 1 H, H-Ar), 7.79 (td,

J1 = 7.7, J2 = 1.8 Hz, 1 H, H-Ar), 7.30-7.20 (m, 11 H, H-Ar), 4.14 (s, 1 H, NCHN), 3.86 (d,

J = 13.4 Hz, 2 H, NCH2Ph), 3.41 (d, J = 13.4 Hz, 2 H, NCH

2Ph), 3.27-3.23 (m, 2 H,

NCH2CH

2N), 2.61-2.57 (m, 2 H, NCH

2CH


3) δ = 161.8 (C-


123.7 (C-Ar), 123.5 (C-Ar), 89.9 (NCHN), 57.4 (NCH2CH

2N), 51.3 (NCH

2Ph). Anal. Calcd

for C22

H23

N3: C, 80.21; H, 7.04; N, 12.76, found: C, 79.89; H, 7.12; N, 12.88.

1,3-Dibenzyl-2-ethylimidazolidine (191)

From N,N’-dibenzylethylenediamine (166) (476 mg, 2.00 mmol) and propionaldehyde

(116 mg, 143 μL, 2.00 mmol) in water (3 mL), according to method B. Reaction mixture

was stirred at r.t. for 16 h. Workup procedure 2 gave the crude compound, which was purri-

fied via FCC (2.5% EtOAc in petroleum ether + 0.5% Et3N), giving the title compound as

a colorless oil (652 mg, 99%). Spectral data were consistent with literature values.130

Ph

NH HN

Ph

H2O, r.t., 16 h

N N

Et

PhPh+

191

85%

166 CH3CH2CHO

Ph

NH HN

Ph

H2O, r.t., 3 h

N

CHO

N N

N

PhPh+

190

99%

166

Experimental 133

1,3-Dibenzyl-2-(2-chloro-phenyl)-hexahydro-pyrimidine (192)

From N,N’-dibenzylpropane-1,3-diamine (169) (763 mg, 3.00 mmol) and 2-chloroben-

zaldehyde (420 mg, 3.00 mmol) in water (4.5 mL) according to method B. Workup proce-

dure 1 gave the title compound as a white solid (988 mg, 88%). mp 94-96 °C; MS (EI), m/z375 (M+ + H, 5%), 365 (100), 91 (80); IR (KBr) 2923s, 1367s, 1098s, 756vs, 739vs, 698vs

cm-1; 1H-NMR (400 MHz, CHCl3) 8.19-8.16 (m, 1 H, H-Ar), 7.41-7.19 (m, 13 H, H-Ar),

4.34 (s, 1 H, NCHN), 3.58 (d, J = 13.2 Hz, 2 H, PhCH2N), 3.03-2.99 (m, 4 H, PhCH

2N,

NCH2), 2.15-2.08 (m, 2 H, NCH

2), 1.92-1.83 (m, 1 H, CH

2CH

2CH

2), 1.51-1.47 (m, 1 H,

CH2CH

2CH

2); 13C-NMR (100 MHz, CHCl

3) 139.9 (C-Ar), 136.1 (C-Ar), 131.3 (C-Ar),


(C-Ar), 83.2 (NCHN), 58.1 (NCH2), 51.3 (PhCH

2N), 25.1 (CH

2CH

2CH

2). Anal. Calcd for

C24

H25

ClN2: C, 76.48; H, 6.69; N, 7.43, found: C, 76.08; H, 6.69; N, 7.36.

1,3-Dibenzyl-2-(pyridin-2-yl)-hexahydropyrimidine (193)

From N,N’-dibenzylpropane-1,3-diamine (169) (763 mg, 3.00 mmol) and pyridine-2-car-

baldehyde (321 mg, 287 μL, 3.00 mmol) in water (4.5 mL) according to method B. Workup

procedure 1 gave the title compound as a white solid (957 mg, 88%). Spectral data were


1,3-Dibenzyl-2-(2-chloro-phenyl)-[1,3]diazepane (194)

From N,N’-dibenzylbutane-1,4-diamine (170), (537 mg, 2.00 mmol) and 2-chloroben-

zaldehyde (280 mg, 2.00 mmol) in water (3 mL) according to method B. Workup procedure

2 gave the the title compound as a white solid (772 mg, 99%). mp 67 °C; MS (EI), m/z 390

Ph

NH HN

Ph H2O, r.t., 3 h

CHO

N N

Cl

Cl

194

99%

+

Ph Ph170

Ph

NH HN

Ph H2O, r.t., 3 h

N

CHO

N N

N

PhPh

+

193

88%

169

Ph

NH HN

Ph H2O, r.t., 3 h

CHO

N N

PhPh

Cl

Cl

+

192

88%

169

134 Experimental

(M+ + H, 1%), 160 (80), 91 (100); IR (KBr) 2791m, 1085s, 1070s, 762vs, 751vs, 697vs cm-

1; 1H-NMR (400 MHz, CDCl3) δ = 8.10 (d, J = 4 Hz, 1 H, H-Ar), 7.45-7.19 (m, 13 H, H-

Ar), 5.04 (s, 1 H, NCHN), 3.90-3.84 (m, 2 H, PhCH2N) 3.70-3.66 (m, 2 H, PhCH

2N) 3.02-

2.97 (m, 2 H, CH2CH

2CH

2CH

2), 2.88-2.82 (m, 2 H, CH

2CH

2CH

2CH

2), 1.71-1.55 (m, 4 H,

CH2CH

2CH

2CH


3) δ = 140.6 (C-Ar), 140.4 (C-Ar), 135.6 (C-


126.8 (C-Ar), 82.6 (NCHN), 55.5 (PhCH2N), 48.9 (CH

2CH

2CH

2CH

2),

26.2.(CH2CH

2CH

2CH

2); Anal. Calcd for C

22H

23N

3: C, 76.80; H, 6.96; N, 7.17, found: C,

76.42; H, 7.05; N, 6.99.

2-(2-Chloro-phenyl)-1,3-diphenyl-imidazolidine (195)

From N,N’-diphenylethylenediamine (212 mg, 1.00 mmol) and 2-chlorobenzaldehyde

(140 mg, 1.00 mmol) in water (3 mL), according to method B. Reaction mixture was heat-

ed up to 70 °C for 3 h. Workup procedure 1 gave the title compound as a white solid (338

mg, 99%). The spectral data were consistent with literature values.226

1,3-Dimethyl-2-(phenyl)-imidazolidine (196)

From N,N’-dimethylethylenediamine (172) (4.15 g, 46.16 mmol) and benzaldehyde (4.90

g, 4.67 mL, 46.16 mmol) in water (70 mL) according to method B. Workup procedure 2

gave the title compound as a colorless liquid (7.71 g, 95%). Spectral data were consistent

with literature values.227

1,3-Dimethyl-2-phenyl-imidazolidine (197)

From N,N’-dimethylethylendiamine(172) (352 mg, 425 μL, 4.00 mmol) and 2-

chlorobenzaldehyde (560 mg, 4.00 mmol) in water (6 mL) according to method B. Workup

procedure 2 gave the title compound as a colorless liquid (789 mg, 95%). MS (EI), m/z 209

NH HN

H2O, r.t., 3 h

CHO N N

ClCl+

197

94%

172

NH HN

H2O, r.t., 3 h

N N

Ph

MeMe+

196

95%

172

Ph

O

Ph NH HN Ph

H2O, 70 °C, 3 h

CHO

N N PhPhCl

Cl

+

195

99%

171

Experimental 135

(M+ − H, 20%), 166 (20), 139 (25), 91 (100); IR (KBr) 2924m, 1640s, 1110m, 1047m, 754m

cm-1; 1H-NMR (400 MHz, CDCl3) δ = 7.75-7.70 (m, 1 H, H-Ar), 7.31-7.23 (m, 2 H, H-Ar),

7.21-7.15 (m, 1 H, H-Ar), 4.07 (s, 1 H, NCHN), 3.37-3.30 (m, 2 H, NCH2CH

2N), 2.63-2.47

(m, 2 H, NCH2CH

2N), 2.20 (s, 6 H, NCH


3) δ = 137.5 (C-


53.9 (NCH2CH

2N), 39.8 (NCH

3). Anal. Calcd for C

14H

21ClN

2: C, 62.70; H, 7.18; N, 13.30,

found: C, 62.00; H, 7.06; N, 13.08.

1,1'-(2-Chloro-phenylmethanediyl)-bis-piperidine (198)

From piperidine (190 mg, 221 μL, 2.00 mmol, 2 eq.) and 2-chlorobenzaldehyde (140 mg,

1.00 mmol) in water (1.5 mL), according to method B. Workup procedure 2 gave the title

compound as a yellow liquid (290 mg, 99%). MS (EI), m/z 292 (M+, 5%), 208 (95), 125

(90), 84 (100); IR (neat) 2930s, 1470s, 1440s, 1270s, 1100s, 910s, 735s cm-1; 1H-NMR (200

MHz, CDCl3) δ = 7.44-7.12 (m, 4 H, H-Ar), 4.39 (s, 1 H, NCHN), 2.84-2.28 (m, 8 H,

CH2NCH

2), 1.56-1.34 (m, 12 H, CH

2CH

2CH


3) δ = 134.8 (C-


49.8 (CH2NCH

2), 26.2 (CH

2CH

2CH

2), 25.2 (CH

2CH

2CH

2). This compound was previous-

ly reported in the literature.228

(2-((4R,5R)-1,3-Dimethyl-4,5-diphenylimidazolidin-2-yl)phenol (200)

From (R,R)-N,N’-dimethyl-1,2-diphenylethylenediamine (96) (608 mg, 2.53 mmol) and

salicyl aldehyde (309 mg, 264 μL, 2.53 mmol) according to method C as a yellow oil which

solidified (830 mg, 95%). [α]22D

= −38.9 (c = 0.2, CHCl3); mp 40-42 °C; MS (EI), m/z 343

(M+ − H, 30%), 224 (100), 208 (30), 134 (30), 120 (25), 91 (30); IR (KBr) 2850w, 1619vs,

1480m, 1454m, 1261s, 1152m, 756s, 699s cm-1; 1H-NMR (200 MHz, CDCl3) δ = 7.40-7.13

(m, 12 H, H-Ar), 6.94-6.84 (m, 2 H, H-Ar), 4.84 (s, 1 H, NCHN), 4.09 (d, J = 8.7 Hz, 2 H,

CHPh), 3.61 (d, J = 8.7 Hz, 2 H, CHPh), 2.22 (s, 3 H, NCH3), 2.02 (s, 3 H, NCH

3); 13C-

NMR (50 MHz, CDCl3) δ = 158.5 (COH), 139.5 (C-Ar), 137.2 (C-Ar), 131.2 (C-Ar), 130.2


neat, 120 °C, 3 h

N N

NH HN

PhPh CHO

PhPh

+

OH

OH

200

95%

96

H2O, r. t., 3 h

CHO

N NCl

ClNH

2 +

198

99%

173

136 Experimental

Ar), 120.7 (C-Ar), 119.1 (C-Ar), 89.4 (NCHN), 36.9 (CHPh), 35.6 (NCH3); HRMS (ESI)

calculated for C23

H24

N2O+: 345.1967, found: 345.1981.

(4R,5R)-2-(2-Chlorophenyl)-1,3-dimethyl-4,5-diphenylimidazolidine (164)

From (R,R)-N,N’-dimethyl-1,2-diphenylethylenediamine (96) (500 mg, 2.08 mmol) and

o-chlorobenzaldehyde (246 μL, 2.18 mmol) in benzene (50 mL) according to method A.

FCC (petroleum ether / EtOAc, 95 / 5) gave the title compound as a white solid (700 mg,

93%). mp 128 °C. [α]22D

= +107.6 (c = 0.59, CHCl3); MS (EI), m/z 361 (M+ − H, 30%), 244

(40), 243 (100), 208 (40), 152 (25); IR (KBr) 2792s, 1452s, 1263s, 1011s, 756vs, 699vs cm-

1; 1H-NMR (200 MHz, CDCl3) δ = 8.02-7.98 (m, 1 H, H-Ar), 7.43-7.16 (m, 13 H, H-Ar),

5.38 (s, 1 H, NCHN), 3.84 (d, J = 8.5 Hz, 2 H, CHPh), 3.63 (d, J = 8.5 Hz, 2 H, CHPh),

2.16 (s, 3 H, NCH3), 1.91 (s, 3 H, NCH


3) δ = 139.8 (C-Ar),


(C-Ar), 128.1 (C-Ar), 128.0 (C-Ar), 127.5 (C-Ar), 127.4 (C-Ar), 126.7 (C-Ar), 83.2

(NCHN), 37.6 (CHPh), 35.6 (NCH3). Anal calculated for C

23H

23ClN

2:C, 76.12; H, 6.39; Cl,

9.77; N, 7.72, found: C, 76.36; H, 6.26, N, 7.49.

(4S,5S)-2-(2-chlorophenyl)-1,3-dimethyl-4,5-diphenylimidazolidine (ent-164) was pre-

pared in the same manner from (S,S)-N,N’-dimethyl-1,2-diphenylethylenediamine (ent-96)

(4S,5S)-2-(4-Chlorophenyl)-1,3-dimethyl-4,5-diphenylimidazolidine (165)

From (S,S)-N,N’-dimethyl-1,2-diphenylethylenediamine (ent-96) (750 mg, 3.13 mmol)

and 4-chlorobenzaldehyde (483 mg, 3.438 mmol, 1.1 eq.) in benzene (50 mL) according to

method A. FCC (petroleum ether/EtOAc, 95/5) gave the title compound as a white solid

(1.03 g, 91%). [α]22D

= −35.5 (c = 0.315, CHCl3); mp 98 °C; MS (EI), m/z 360 (M+, 40%),

244 (40), 243 (100), 165 (45), 152 (60), 139 (40), 118 (40), 91 (50), 77 (60), 69 (50), 51

(40); IR (KBr) 3425s, 2789s, 1599s, 1490s, 1451s, 1088s, 1009s, 841s, 759s, 698vs, 511s

cm-1; 1H-NMR (400 MHz, CDCl3) δ = 7.61 (d, J = 8.6 Hz, 2 H, H-Ar), 7.44 (d, J = 8.4 Hz,

benzene, Dean-Stark, reflux

N N

NH HNp-toluenesulfonic acid

PhPh

Cl

CHO

PhPh

Cl

+

165

91%

96


N N

NH HNp-toluenesulfonic acid

PhPh CHO

PhPh

+

Cl

Cl

164

93%

96

Experimental 137

2 H, H-Ar) 7.37-7.7.19 (m, 10 H, H-Ar), 4.78 (s, 1 H, NCHN), 3.91 (d, J = 8.3 Hz, 1 H,

CHPh), 3.68 (d, J = 8.3 Hz, 1 H, CHPh), 2.20 (s, 3 H, NCH3), 1.88 (s, 3 H, NCH

3); 13C-

NMR (100 MHz, CDCl3) δ = 140.1 (C-Ar), 139.78 (C-Ar), 139.73 (C-Ar), 134.4 (C-Ar),

131.1 (C-Ar), 128.8 (C-Ar), 128.7 (C-Ar), 128.5 (C-Ar), 128.3 (C-Ar), 127.96 (C-Ar),

127.92 (C-Ar), 88.2 (NCHN), 77.9 (CHPh), 37.9 (NCH3), 36.2 (NCH

3). Anal. Calcd for

C23

H23

ClN2

C, 76.12; H, 6.39; N, 7.72, found C, 76.26, H, 6.41, N, 7.73.

(4S,5S)-2-(2-Chlorophenyl)-4,5-diphenyl-1,3-bis((R)-1-phenylethyl)imidazolidine

(162)

From (1S,2S)-1,2-diphenyl-N,N’-bis((R)-1-phenylethyl)ethane-1,2-diamine (94) (1.00 g,

2.39 mmol), 2-chlorobenzaldehyde (336 mg, 2.39 mmol) and p-toluensulfonic acid (50 mg)

in benzene (75 mL) according to method A. The reaction mixture was refluxed for 48 h.

FCC (petroleum ether/EtOAc, 95/5) gave the title compound as a white solid (640 mg,

50%). [α]22D

= −99.9 (c = 1.6, CHCl3); mp 57-58 °C MS (ESI, 0 V), m/z 541.2 (M+ − H

100%); IR (KBr) 3027m, 1492s, 1453vs, 1222s, 1133s, 1027s, 756vs, 700vs cm-1; 1H-NMR

(400 MHz, CDCl3) δ = 8.02 (d, J = 7.7 Hz, 1 H, CClCH), 7.40-6.70 (m, 23 H, H-Ar), 6.00

(s, 1 H, NCHN), 4.38 (d, J = 8 Hz, 1 H, NCHPh), 4.10 (d, J = 8 Hz, 1 H, NCHPh), 3.92-

3.89 (m, 1 H, CHCH3), 3.70-3.67 (m, 1 H, CHCH

3), 1.16 (d, J = 8.1 Hz, 3 H, CHCH

3), 0.78

(d, J = 7.0 Hz, 3 H, CHCH3); 13C-NMR (100 MHz, CDCl

3) δ = 145.5 (C-Ar), 142.7 (C-Ar),



Ar), 127.67 (C-Ar), 127.2 (C-Ar), 127.0 (C-Ar), 126.97 (C-Ar), 126.93 (C-Ar), 126.3 (C-

Ar), 126.0 (C-Ar), 76.2 (NCHN), 74.7 (CHPh), 72.4 (CHPh), 58.6 (CHCH3), 56.5

(CHCH3), 21.7 (CHCH

3), 20.1 (CHCH

3). Anal. calculated for C

37H

35ClN

2: C, 81.82; H,

6.50; 6.53; N, 5.16; found: C, 81.78, H, 6.91, N, 5.05.


N N

p-toluenesulfonic acid

CHO

PhPh

+

Cl

NH HN

PhPh

PhPh

162

50%

PhPh

Cl94

138 Experimental

(4S,5S)-2-(4-Chlorophenyl)-4,5-diphenyl-1,3-bis((R)-1-phenylethyl)imidazolidine

(163)

From (1S,2S)-1,2-diphenyl-N,N’-bis((R)-1-phenylethyl)ethane-1,2-diamine (94) (821

mg, 2.00 mmol), 4-chlorobenzaldehyde (290 mg, 2.00 mmol) according to method C. The

reaction mixture was heated to 140 °C in a sealed tube for 16 h. FCC (petroleum

ether/EtOAc, 95/5) gave the title compound as a white solid. [α]22D

= −12.8 (c = 0.2, CHCl3);

mp 53 °C; MS (ESI, 0 V), m/z 541.3 (M+ − H, 10%); IR (KBr) 3026m, 1490s, 1452s,

1225m, 1088m, 832m, 765s, 700vs cm-1; 1H-NMR (200 MHz, CDCl3) δ = 7.30-6.80 (m, 24

H, H-Ar), 5.11 (s, 1 H, NCHN), 4.31 (d, J = 8.3 Hz, 1 H, NCHPh), 4.14 (d, J = 8.3 Hz, 1 H,

NCHPh), 3.90 (q, J = 7.0 Hz, 1 H, CHCH3), 3.44 (q, J = 7.0 Hz, 1 H, CHCH

3), 0.99 (d, J

= 7.0 Hz, 3 H, CHCH3), 0.67 (d, J = 7.0 Hz, 3 H, CHCH


3) δ




126.6 (C-Ar), 126.2 (C-Ar), 81.6 (NCHN), 75.8 (CHPh), 73.2 (CHPh), 60.4 (CHCH3), 58.3

(CHCH3), 24.7 (CHCH

3), 21.6 (CHCH

3). HRMS (ESI) Calculated for: C

37H

36N

2Cl:

543.2567; found: 543.2567.

(4S,5S)-2-(2-Pyridinyl)-4,5-diphenyl-1,3-bis((S)-1-phenylethyl)imidazolidine

(205)


3.57 mmol), pyridine-2-carbaldehyde (340 μL, 3.57 mmol) and p-toluensulfonic acid (10

mg) in benzene (100 mL) according to method A. The reaction mixture was refluxed for 48

h. FCC (petroleum ether/EtOAc, 95/5) gave the title compound as a white solid (1.73 g,

95%). [α]22D

= +115.0 (c=0.32, CHCl3); mp 105-108 °C MS (EI), m/z 432 (M+ − pyridinyl,

50%), 299 (60), 105 (100); IR (KBr) 3451vs, 1492s, 1453s, 1431s, 1104s, 760s, 699vs cm-

1; 1H-NMR (400 MHz, CDCl3) δ = 8.57-8.54 (m, 1 H, H-Ar), 7.40-7.00 (m, 20 H, H-Ar),

6.80-6.70 (m, 3 H, H-Ar), 5.34 (s, 1 H, NCHN), 4.65 (d, J = 7.9 Hz, 1 H, NCHPh), 4.18 (d,


N N

N

p-toluenesulfonic acidN

CHO

PhPh

+NH HN

PhPh

PhPh

205

95%

PhPh

94

neat, 140°C, 16 h

N N

CHO

PhPh

+NH HN

PhPh

PhPh

163

77%

Cl

Cl

94

PhPh

Experimental 139

J = 7.9 Hz, 1 H, NCHPh), 3.98 (q, J = 7.0 Hz, 1 H, CHCH3), 3.67 (q, J = 7.0 Hz, 1 H,

CHCH3), 1.07 (d, J = 7.1 Hz, 3 H, CHCH

3), 0.88 (d, J = 7.1 Hz, 3 H, CHCH

3); 13C-NMR

(100 MHz, CDCl3) δ = 165.4 (C-Ar), 148.5 (C-Ar), 145.4 (C-Ar), 143.2 (C-Ar), 142.9 (C-



127.1 (C-Ar), 127.05 (C-Ar), 124.6 (C-Ar), 122.0 (C-Ar), 83.2 (NCHN), 76.6 (CHPh), 73.6

(CHPh), 61.5 (CHCH3), 57.3 (CHCH

3), 23.1 (CHCH

3), 22.5 (CHCH

3); HRMS (ESI) cal-

culated for C36

H35

N3

+: 510.2909, found: 510.2912.

2-(2-Chlorophenyl)-1,3-bis((R)-1-phenylethyl)imidazolidine (201)

From N,N’-bis((R)-1-phenylethyl)ethane-1,2-diamine (93) (268 mg, 1.00 mmol) and 2-

chlorobenzaldehyde (140 mg, 1.00 mmol) according to the method C. Reaction mixture was

heated to 120 °C. for 3 h. Reaction mixture was heated to 120 °C for 3 h. The resulting mix-

ture was dried in vacuo to give the title compound as a colorless liquid (346 mg, 99%).


2-(4-Chlorophenyl)-1,3-bis((R)-1-phenylethyl)imidazolidine (202)

From N,N’-bis((R)-1-phenylethyl)ethane-1,2-diamine (93) (804 mg, 3.00 mmol) and 4-

chlorobenzaldehyde (433 mg 97%, 3.00 mmol) according to the method C. The reaction

mixture was heated to 120 °C. for 3 h. The resulting mixture was dried in vacuo to give the

title compound as a yellow oil (1.17 mg, 99%). Spectral data were consistent with literature

values.130

Ph

NH HN

Ph neat, 120 °C, 2 h

CHON N

PhPh

+

202

99%

Cl

Cl

93

Ph

NH HN


CHO

N N

PhPh

Cl

+

201

99%

Cl

93

140 Experimental

2-(2,6-Dichlorophenyl)-1,3-bis((R)-1-phenylethyl)imidazolidine (203)

From N,N’-bis((R)-1-phenylethyl)ethane-1,2-diamine (93) (381 mg, 1.42 mmol) and 2,6-

dichlorobenzaldehyde (249 mg, 1.42 mmol) according to method C. The reaction mixture

was heated to 120 °C for 3 h. The resulting mixture was dried in vacuo to give the title com-

pound as an orange oil (604 mg, 99%). [α]22D

= +19.0 (c = 0.9, CHCl3); MS (ESI, 0 V), m/z

425 (M+, 30%), 297 (M+−PhCl2, 100%); IR (NaCl) 3027s, 2971s, 2931s, 1672s, 1579s,

1562s, 1493s, 1438s, 1201s, 1127s, 762s, 701s cm-1; 1H-NMR (400 MHz, CDCl3) δ = 7.50-

7.00 (m, 13 H, H-Ar), 5.29 (s, 1 H, NCHN), 3.90-3.70 (m, 2 H, NCH2CH

2N), 3.35-3.25 (m,

1 H, CHCH3), 3.00-2.90 (m, 1 H, CHCH

3), 2.70-2.55 (m, 2 H, NCH

2CH

2N), 1.44 (d, J =

6.6 Hz, 3 H, CHCH3), 1.10 (d, J = 6.6 Hz, 3 H, CHCH


3) δ



(NCHN), 63.7 (NCH2CH

2N), 56.0 (NCH

2CH

2N), 50.9 (CHCH

3), 45.4 (CHCH

3), 23.6

(CHCH3), 14.8 (CHCH


25H

27N

2Cl

2: 425.1551; found:

425.1566.

2-(1,3-Bis((R)-1-phenylethyl)imidazolidin-2-yl)pyridine (204)

From N,N’-bis((R)-1-phenylethyl)ethane-1,2-diamine (93) (268 mg, 1.00 mmol) and

pyridine-2-carbaldehyde (96 μL, 1.00 mmol) in water (1.5 mL). The reaction mixture was

heated to 120 °C for 3 h. The resulting mixture was dried in vacuo to give the title com-

pound as an orange liquid (317 mg, 99%). [α]22D

= +62.7 (c = 0.3, CHCl3); MS (EI), m/z 357

(M+, 10%), 279 (100), 252 (40), 105 (90), 71 (70); IR (NaCl) 2971s, 2930m, 1589m,

1492m, 1453s, 1434m, 767s, 701vs cm-1; 1H-NMR (400 MHz, CDCl3) δ = 8.54-8.46 (m, 1

H, H-Ar), 7.68-7.06 (m, 13 H, H-Ar), 4.56 (s, 1 H, NCHN), 3.65 (dq, J1 = 28.7 Hz, J2 = 6.8

Hz, PhCHCH3), 3.25-3.05 (m, 2 H, NCH

2CH

2N), 2.85-2.75 (m, 2 H, NCH

2CH

2N), 1.36 (d,

J = 7.3 Hz, 3 H, CHCH3), 1.16 (d, J = 7.3 Hz, 3 H, CHCH


3)

δ = 164.1 (C-Ar), 148.4 (C-Ar), 144.8 (C-Ar),, 136.0 (C-Ar), 128.9 (C-Ar), 128.5 (C-Ar),


Ph

NH HN


N

CHO

N N

N

PhPh

+

204

99%

93

Ph

NH HN

Ph neat, 120°C, 3 h

CHO

N N

PhPh

Cl

+

203

99%

ClCl

Cl

93

Experimental 141

122.4 (C-Ar), 84.1 (NCHN), 61.5 (NCH2CH

2N), 59.0 (NCH

2CH

2N), 49.8 (CHCH

3), 47.3

(CHCH3), 23.9 (CHCH

3), 17.8 (CHCH

3). Anal calculated for C

24H

27N

3: C, 80.63; H, 7.61;

N, 11.75, found: C, 79.96; H, 7.64, N, 11.80.

((1S,1'S,2S,2'S)-2,2'-(Phenylmethylene)bis(methylazanediyl)bis(1-phenylpropan-1-

ol) (207)

From (+)-pseudoephedrine (661 mg, 4.00 mmol) and benzaldehyde (202 μL, 2.00 mmol)

according to method C. The reaction mixture was heated to 120 °C for 3 h. The resulting

mixture was dried in vacuo to give the title compound as a white solid (836 mg, 99%). [α]22D

= +58.9 (c = 0.36, CHCl3); mp 56 °C; MS (ESI, 0 V), m/z 254.2 (M+ − pseudoephedrinyl);

IR (KBr) 2966m, 1452s, 1376m, 1036s, 1021s, 750s cm-1; 1H-NMR (400 MHz, CDCl3) δ

= 7.63-7.59 (m, 2 H, H-Ar), 7.50-7.30 (m, 13 H, H-Ar), 4.99 (s, 1 H, NCHN), 4.82 (d, J =8.6 Hz, 1 H, PhCHOH), 4.22 (d, J = 8.6 Hz, 1 H, PhCHOH), 2.70-2.55 (m, 2 H, CHCH

3),

2.50 (s, 3 H, NCH3), 2.26 (s, 3 H, NCH

3), 1.28 (d, J = 6.1 Hz, 3 H, CHCH

3), 0.99 (d, J =

6.1 Hz, 3 H, CHCH3); 13C-NMR (100 MHz, CDCl

3) δ = 142.3 (C-Ar), 140.5 (C-Ar), 139.5


Ar), 127.0 (C-Ar), 126.7 (C-Ar), 99.7 (NCHN), 86.6 (PhCHOH), 77.7 (PhCHOH), 68.9

(CHCH3), 61.4 (CHCH

3), 35.2 (NCH

3), 33.6 (NCH

3), 15.7 (CHCH

3), 14.4 (CHCH

3); Anal.

Calcd for C27

H34

N2O

2: C, 77.48; H, 8.19; N, 6.69, found: C, 77.67; H, 8.33; N, 6.69.

Preparation of bis-aminals

1,3-Dimethyl-2-(2-(1,3-dimethylimidazolidin-2-yl)phenyl)imidazolidine (208)

From N,N’-dimethylethane-1,2-diamine (172) (1.50 mL, 13.65 mmol, 2 eq.) and phtal-

dialdehyde (916 mg, 6.75 mmol, 1 eq.) according to method C as a yellow solid (1.77 g,

93%). mp 66-68 °C; MS (ESI, 0 V), m/z 275.3 (M++H, 100%); IR (KBr) 3425s, 2967s,

2940vs, 2835vs, 2773vs, 1632s, 1482s, 1238s, 1158s, 1030vs, 756s cm-1; 1H-NMR (200

MHz, CDCl3) δ = 7.65-7.55 (m, 2 H, H-Ar), 7.40-7.25 (m, 2 H, H-Ar), 4.11 (s, 2 H, NCHN),

3.40-3.30 (m, 4H, CH2), 2.65-2.50 (m, 4 H, CH

2), 2.16 (s, 12 H, CH

3); 13C-NMR (50 MHz,

CDCl3) δ = 140.1 (C-Ar), 129.7 (C-Ar), 128.0 (C-Ar), 86.4 (NCHN), 53.5 (CH

2), 39.7

(CH3). HRMS (ESI) calculated for C

16H

26N

4

+: 275.2236, found: 275.2225.

neat, 120 °C, 2 h

N N

NH HN

CHO

+

CHO

2

N

N

208

93%

172

120°C, 3 h

neat+

207

99%

HO

Ph

N N

Ph

Ph

OHHO

Ph

NH2

199

Ph

O

142 Experimental

(4S,5S)-1,3-Dimethyl-2-(2-((4S,5S)-1,3-dimethyl-4,5-diphenylimidazolidin-2-

yl)phenyl)-4,5-diphenylimidazolidine (209)

(1S,2S)-N,N’-Dimethyl-1,2-diphenylethane-1,2-diamine (96) (960 mg, 4.00 mmol, 2 eq.)

and phtaldialdehyde (269 mg, 2.00 mmol, 1 eq.) according to method C as a yellow solid

(1.01 g, 87%). mp 83-85 °C; [α]22D

= −89.8 (c = 0.4, CHCl3); MS (EI), m/z 578 (M+, 1%),

368 (100), 180 (20), 142 (10), 118 (20), 91 (10), 77 (10), 52 (10); IR (KBr) 3452vs, 1631m,

1451m, 1264m, 1161m, 1103m, 755s, 699s cm-1; 1H-NMR (400 MHz, CDCl3) δ = 8.13-

8.11 (m, 2 H, H-Ar), 7.57-7.50 (m, 2 H, H-Ar), 7.48-7.27 (m, 20 H, H-Ar), 5.52 (s, 2 H,

NCHN), 3.92 (d, J = 8.4 Hz, 2 H, CHPh), 3.59 (s, 2 H, CHPh), 2.18 (s, 6 H, NCH3), 2.07

(s, 6 H, NCH3); 13C-NMR (100 MHz, CDCl

3) δ = 141.8 (C-Ar), 140.3 (C-Ar), 138.9 (C-


128.0 (C-Ar), 127.6 (C-Ar), 83.7 (NCHN), 78.8 (CHPh), 38.9 (NCH3), 38.0 (NCH

3);

HRMS calculated for C40

H43

N4

+: 579.3488; found: 579.3466.

1,2-Bis((3aR,7aR)-1,3-dimethyl-octahydro-1H-benzo[d]imidazol-2-yl)benzene (210)

((1R,2R)-N,N’-dimethylcyclohexane-1,2-diamine (95) (119 mg, 0.84 mmol, 2 eq.) and

phtaldialdehyde (56 mg, 0.42 mmol, 1 eq.) according to method C as a yellow solid (159

mg, 99%). mp 98 °C; [α]22D

= 103.6 (c = 1.48, CHCl3); MS (ESI, 0 V), m/z 383.3 (M+ + H,

100%); IR (KBr) 3441s, 2972s, 2931vs, 2455s, 2791s, 1452s, 1360s, 1190s, 1009s, 758s

cm-1; 1H-NMR (200 MHz, CDCl3) δ = 7.80-7.60 (m, 2 H, H-Ar), 7.32-7.27 (m, 2 H, H-Ar),

4.85 (s, 2 H, NCHN), 2.18 (s, 6 H, NCH3), 1.93 (s, 6 H, NCH

3) 2.50-2.00 (m, 4 H,

NCHCH2), 2.10-1.80 (m, 8 H, CH

2CH

2CH

2CH

2), 1.40-1.10 (m, 8 H, 7 H, 8 H,

CH2CH

2CH

2CH


3) δ = 139.0, (C-Ar), 129.1 (C-Ar), 127.4 (C-

Ar), 84.0 (NCHN), 69.8 (NCHCH2), 68.98 (NCHCH

2), 37.3 (NCH

3), 37.0 (NCH

3), 29.4

(CH2), 29.0 (CH

2), 24.7 (CCH

2), 24.4 (CH


24H

39N

4:

383.3096; found: 383.3169.

neat, 120 °C, 16 h

N N

CHO

+

CHO

2

N

N

210

99%

NH HN

95

neat, 120 °C, 16 h

N N

NH HN

Ph CHO

PhPh

+

CHO

2

N

N

Ph

Ph

209

89%

Ph

96

Experimental 143

(4S)-4-Isopropyl-1-(2-((4S)-4-isopropyl-3-methyl-2-phenylimidazolidin-1-yl)phenyl)-3-

methyl-2-phenylimidazolidine (214)

From N,N’-bis((S)-3-methyl-2-(methylamino)butyl)benzene-1,2-diamine (156) (125 mg,

0.41 mmol) and benzaldehyde (82 μL, 0.81 mmol, 2 eq.) according to method C as yellow

solid (180 mg, 91%). mp 157 °C; [α]22D

= +5.4 (c = 0.13, CHCl3); MS (ESI, 0 V), m/z 383

(M++H, 20%), 393 (100, M+-PhCH), 308 (80); IR (KBr) 2955s, 2778m, 1497s, 1453s,

1312s, 758m, 739s, 699s cm-1; 1H-NMR (200 MHz, CDCl3) δ = 7.56-7.51 (m, 4 H, H-Ar),

7.30-7.16 (m, 6 H, H-Ar), 6.86-6.81 (m, 2 H, H-Ar), 6.64-6.59 (m, 2 H, H-Ar), 4.51 (s, 2 H,

NCHN), 4.05-3.92 (m, 2 H, NCHCH), 2,54-2.23 (m, 4 H, NCH2CH), 2.12 (s, 6 H, NCH

3),

2.10-2.00 (m, 2 H, CH(CH3)2), 1.15 (d, J = 6.8 Hz, 6 H, CH(CH

3)2), 0.99 (d, J = 6.8 Hz, 6

H, CH(CH3)2); 13C-NMR (50 MHz, CDCl

3) δ = 141.6 (C-Ar), 140.9 (C-Ar), 129.3 (C-Ar),

128.1 (C-Ar), 127.9 (C-Ar), 120.1 (C-Ar), 117.3 (C-Ar), 85.9 (C-2, 22), 68.8 (NCHCH),

52.0 (NCH2CH), 36.8 (NCH

3), 27.4 (CH(CH

3)2), 20.0 (CH(CH

3)2), 15.1 (CH(CH

3)2);

HRMS (ESI) Calcd. for C32

H43

N4: 483.3488, found: 483.3493.

neat, 120 °C, 2 h

N

NN

N

PhPh

NH

HNNH

NH

2+

214

91%

156

Ph

O

144 Experimental

3.3. Preparation of Imidazolinium Salts by Oxidation of Imidazolidines

General procedure for the oxidation of aminals by NBA

Imidazolidine (1.00 mmol) was dissolved in a minimal amount of DME. N-Bromac-

etamide (1.00 mmol) was added in two portions (0.50 mmol each) in an interval of 15 min.

After addition of the second portion, the reaction mixture was stirred for an additional 30

min. The salt precipitated and was isolated by filtration. In cases where no precipitate was

formed, diethyl ether was added and an oily solid formed. The solvent was decanted and the

remaining rest was washed with diethyl ether and dried under high vacuum to give the cor-

responding bromide salt. This procedure is a modification of a literature procedure.108

Counter anion exchange

General procedure for counter anion exchange with potassium hexafluorophos-

phate

Imidazolinium bromide (1.00 mmol) was dissolved in DCM (3 mL) and stirred vigorous-

ly with a solution of KPF6

(1.00 mmol) in water (3 mL) for 30 min. The organic phase was

separated, washed with water (3 x 3 mL) and dried with molecular sieves 3Å. The solvent

was evaporated and the product was further dried overnight under high vacuum to give the

corresponding imidazolinium hexafluorophosphate.

General procedure for counter anion exchange with lithium bis(trifluoromethylsul-

fonyl)imide

Imidazolinium bromide (1.00 mmol) was dissolved in DCM (3 mL) and vigorously

stirred with a solution of LiNTf2

(1.00 mmol) in water (3 mL) for 30 min. The organic phase

was separated, washed with water (3 x 3 mL) and dried with molecular sieves 3Å. The sol-

vent was evaporated and the product was further dried under high vacuum overnight to give

the corresponding imidazolinium bis(trifluromethansulfonyl)-imide.

General procedure for counter anion exchange with sodium tetrakis(3,5-bis(trifluo-

romethyl)phenyl) borate.

Imidazolinium bromide (1.00 mmol) was dissolved in CHCl3

(3 mL) and

NaB[C6H

3(CF

3)2]4

(1.00 mmol, 1 eq.) and water (3 mL) were added sequentially. The reac-

tion mixture was then vigorously stirred for 30 min. The organic phase was separated (in

case that separation did not occur, centrifugation was used to improve separation), washed

with water (3 x 3 mL) and dried with molecular sieves 3Å. The solvent was evaporated and

the product was further dried under high vacuum overnight to give the corresponding imi-

dazolinium tetrakis(3,5-bis(trifluoromethyl)phenyl) borate.

General procedure for counter anion exchange with potasium tetrakis(pentafluo-

rophenyl)borate

Imidazolinium bromide (1.00 mmol) was dissolved in CHCl3

(3 mL) and KB[C6F

5)4

(1.00 mmol, 1 eq.) and water (3 mL) were added sequentially. The reaction mixture was then

vigorously stirred for 30 min. The organic phase was separated (in case that separation did

not occur, centrifugation was used to improve separation), washed with water (3 x 3 mL)

and dried with molecular sieves 3Å. The solvent was evaporated and the product was fur-

Experimental 145

ther dried under high vacuum overnight to give the corresponding imidazolinium

tetrakis(pentafluorophenyl)borate.

1,3-Dibenzyl-2-(phenyl)imidazolinium bromide (168A)

From 1,3-dibenzyl-2-phenylimidazolidine (168) (164 mg, 0.50 mmol) and NBA (73 mg

95%, 0.50 mmol) in DME (1 mL) as a white solid. (200 mg, 98%). Hygroscopic. mp 167

°C; MS (EI), m/z 326 (M+-H, 75%), 249 (45), 234 (50), 132 (25), 91 (100); IR (KBr) 3442s,

1601vs, 1581s, 1569s 1253s, 726s, 699s cm-1; 1H-NMR (400 MHz, CDCl3) δ = 8.04-8.02

(m, 1 H, H-Ar), 7.71-7.66 (m, 3 H, H-Ar), 7.42-7.23 (m, 10 H, H-Ar), 4.57 (s, 4 H,

NCH2Ph), 4.13 (s, 4 H, NCH

2CH


3) δ = 167.4 (NC+N),


128.6 (C-Ar), 122.6 (C-Ar), 52.7 (NCH2Ph), 48.7 (NCH

2CH

2N).

1,3-Dibenzyl-2-(2-phenyl)imidazolinium hexafluoro phosphate (168B)

From 1,3-dibenzyl-2-(2-phenyl)imidazolinium bromide (168A) (162 mg, 0.40 mmol)

and KPF6

(82 mg, 0.44 mmol, 1.1 eq.) in a mixture of CHCl3

(2 mL) and water (2 mL) as

a white solid (162 mg, 86%). mp 118 °C; MS (EI), m/z 326 (M+,-H, 75%), 249 (45), 234

(50), 132 (25), 91 (100); IR (KBr) 1598vs, 1441m, 1355m, 1301m 1252s, 839vs, 774s,

763s, 703s cm-1; 1H-NMR (400 MHz, CDCl3) δ = 7.75-7.68 (m, 5 H, H-Ar), 7.42-7.34 (m,

6 H, H-Ar), 7.18 (d, J = 6.8 Hz, 2 H, H-Ar), 4.48 (s, 4 H, NCH2Ph), 3.98 (s, 4 H,

NCH2CH


3) δ = 167.0 (NC+N), 133.6 (C-Ar), 132.8 (C-Ar),


(NCH2Ph), 48.0 (NCH

2CH

2N); Anal. calculated for C

23H

23N

2PF

6: C, 58.48; H, 4.91; N,

5.93, found: C, 58.48; H, 4.91; N, 5.78.

CHCl3/H2O, r.t., 30 min

N N+

Ph

PhPh PF6−KPF6

N N+

Ph

PhPh Br−

168B

86%

168A

DME, r.t., 45 min

N N+

Ph

PhPh

N N

Ph

PhPhBr

−

NBA

168 168A

98%

146 Experimental

1,3-Dibenzyl-2-(2-chlorophenyl)imidazolinium bromide (183A)

From 1,3-dibenzyl-2-(2-chlorophenyl)imidazolidine (183) (180 mg, 0.50 mmol) and

NBA (73 mg 95%, 0.50 mmol) in DME (0.5 mL) as a yellow oil (205 mg, 93%). Hygro-scopic. MS (EI), m/z 360 (M+, 30%), 269 (50), 151 (30), 91 (100); IR (neat) 3355s, 3177s,

1664vs, 1598vs, 1291s, 1254s, 759s, 703s cm-1; 1H-NMR (400 MHz, CDCl3) δ = 8.95-8.92

(m, 1 H, H-Ar), 7.69-7.61 (m, 3 H, H-Ar), 7.43-7.35 (m, 10 H, H-Ar), 4.64 (d, J = 15.1 Hz,

2 H, NCH2Ph), 4.52-4.47 (m, 2 H, NCH

2CH

2N), 4.42 (d, J = 14.8 Hz, 2 H, NCH

2Ph), 3.77-

3.72 (m, 2 H, NCH2CH


3) δ = 164.1 (NC+N), 134.7 (C-Ar),


129.36 (C-Ar), 129.1 (C-Ar), 122.2 (C-Ar), 52.7 (NCH2Ph), 48.6 (NCH

2CH

2N).

1,3-Dibenzyl-2-(2-chlorophenyl)imidazolinium hexafluoro phosphate (183B)

From 1,3-dibenzyl-2-(2-chlorophenyl)imidazolinium bromide (183A) (300 mg, 0.73

mmol) and KPF6


(3 mL) and water (3

mL) as a white solid (252 mg, 72%). mp 144 °C; MS (EI), m/z 360 (M+, 70%), 324 (40),

283 (20), 91 (100); IR (Neat) 1598vs, 1441m, 1355m, 1301m 1252s, 839vs, 774s, 763s,

703s cm-1; 1H-NMR (400 MHz, CDCl3) δ = 8.09-8.07 (m, 1 H, H-Ar), 7.76-7.68 (m, 3 H,

H-Ar), 7.44-7.27 (m, 10 H, H-Ar), 4.49-4.39 (m, 4 H, NCH2Ph), 4.22-4.17 (m, 2 H, H-4, 5),

3.84-3.79 (m, 2 H, H-4, 5); 13C-NMR (100 MHz, CDCl3) δ = 163.9 (NC+N), 135.0 (C-Ar),



2CH

2N); Anal. cal-

culated for C23

H22

ClN2PF

6: C, 54.50; H, 4.37; N, 5.53, found: C, 54.57; H, 4.22; N, 5.40.


N N+

PhPh

PF6−

KPF6

N N+

PhPh

Br−

Cl Cl

183A 183B

72%

DME, r.t., 45 min

N N+

PhPh

Cl

N N

PhPh

Cl

Br−

NBA

183 183A

93%

Experimental 147

1,3-Dibenzyl-2-(2-chlorophenyl)imidazolinium bis(trifluoromethylsulfonyl)-imide

(183C)


mmol) and LiNTf2


(6 mL) and water

(3 mL) as a white solid (373 mg, 71%). mp 83 °C; MS (EI), m/z 360 (M+ −H, 100%), 151

(5), 91 (60); IR (KBr) 1604vs, 1471m, 1458m, 1441m, 1355vs, 1304s, 1192vs, 1135s,

1056s, 772s, 702s, 616s cm-1; 1H-NMR (400 MHz, CDCl3) δ = 8.09-8.07 (m, 1 H, H-Ar),

7.76-7.70 (m, 3 H, H-Ar), 7.45-7.40 (m, 4 H, H-Ar), 7.30-7.27 (m, 6 H, H-Ar), 4.50-4.39

(m, 4 H, NCH2Ph), 4.24-4.19 (m, 2 H, NCH

2CH

2N), 3.80-3.75 (m, 2 H, NCH

2CH

2N); 13C-

NMR (100 MHz, CDCl3) δ = 163.8 (NC+N), 135.0 (C-Ar), 132.2 (C-Ar), 131.9 (C-Ar),


52.3 (NCH2Ph), 47.9 (NCH

2CH


25H

22ClF

6N

3O

4S

2: C, 46.77; H,

3.45; N, 6.54, found: C, 46.45; H, 3.34; N, 6.57.

1,3-Dibenzyl-2-(2-chlorophenyl)imidazolinium tetrakis(3,5-

bis(trifluoromethyl)phenyl) borate (183D)

From 1,3-Dibenzyl-2-(2-chlorophenyl)imidazolidine (183) (180 mg, 0.50 mmol) and

NBA (72 mg 95%, 0.50 mmol) in DME (0.5 mL), followed by counter anion exchange with

NaB[C6H

3(CF

3)2]4

(443 mg, 0.50 mmol) in water (3 mL) and Et2O (5 mL) mixture. Title

compound was obtained as a brown solid (535 mg, 88%). mp 135 °C; MS (EI), m/z 360 (M+

− H, 100%), 91 (20); IR (KBr) 1598s, 1356vs, 1278vs, 1126vs cm-1; 1H-NMR (400 MHz,

CDCl3) δ = 7.78-7.70 (m, 10 H, H-Ar), 7.62-7.50 (m, 4 H, H-Ar), 7.45-7.32 (m, 8 H, H-Ar),

7.08-7.03 (m, 4 H, H-Ar), 4.40-4.25 (m, 4 H, NCH2Ph), 3.90-3.80 (m, 4 H, NCH

2CH

2N);

13C-NMR (100 MHz, CDCl3) δ = 164.1 (NC+N), 162.1 (q, J = 49.5 Hz, BC), 136.0 (C-Ar),

135.2 (BCCH), 132.9 (C-Ar), 132.1 (C-Ar), 130.6 (C-Ar), 130.4 (C-Ar), 130.1 (C-Ar),

129.6 (C-Ar), 129.5 (C-Ar), 129.3 (q, J = 28.4 Hz, CHCCF3), 128.6 (C-Ar), 124.9 (q, J =

271.2 Hz, CCF3), 120.6 (C-Ar), 117.9 (CHCCF

3), 52.4 (NCH

2CH

2N), 47.6 (NCH

2Ph);

Anal. calculated for C55

H34

BClF24

N2: C, 53.92; H, 2.66; N, 2.29, found: C, 53.52; H, 2.66;

N, 2.26.

N N+

PhPh

N N

PhPh

1. NBA, DME, r.t., 45 min

2. NaB[C6H3(CF3)2]4, Et2O/H2O, 30 min

B[C6H3(CF3)2]4−

183

Cl Cl

183D

88%


N N+

PhPh

NTf2−

N N+

PhPh

Br−

LiNTf2

ClCl

183C

71%

183A

148 Experimental

1,3-Dibenzyl-2-(4-chlorophenyl)imidazolinium bromide (184A)

From 1,3-dibenzyl-2-(4-chlorophenyl)imidazolidine (184) (360 mg, 1.00 mmol) and

NBA (145 mg 95%, 1.00 mmol) in DME (3 ml) as a white solid (390 mg, 88%). Hygroscop-ic. mp 155 °C; MS (EI), m/z 360 (M+- H 15%), 269 (40), 151 (40), 91 (100); IR (KBr)

3026m, 2996m, 1605vs, 1581s, 1565s,1482s, 1253s, 834s, 707vs cm-1; 1H-NMR (400 MHz,

CDCl3) δ = 8.05-8.02 (m, 2 H, H-Ar), 7.65-7.63 (m, 2 H, H-Ar), 7.39-7.35 (m, 6 H, H-Ar),

7.25-7.22 (m 4 H, H-Ar), 4.56 (s, 4 H, NCH2Ph), 4.12 (s, 4 H, NCH

2CH

2N); 13C-NMR (100

MHz, CDCl3) δ = 166.6 (NCN), 140.1 (C-Ar), 132.9 (C-Ar), 130.9 (C-Ar), 129.8 (C-Ar),


2CH

2N).

1,3-Dibenzyl-2-(4-chlorophenyl)imidazolinium hexafluoro phosphate (184B)


mmol) and KPF6


(3 mL) and water (3

mL) as a white solid (103 mg, 89%). mp 71 °C; MS (EI), m/z 361 (M+, 5%), 270 (10), 151

(15), 107 (15), 91 (100), 55 (60); IR (KBr) 1602vs, 1565s, 1456s, 1360s, 1288s, 1095s,

834vs, 749s, 702s cm-1; 1H-NMR (400 MHz, CDCl3) δ = 8.05-8.02 (m, 2 H, H-Ar), 7.65-

7.63 (m, 2 H, H-Ar), 7.39-7.35 (m, 6 H, H-Ar), 7.25-7.22 (m 4 H, H-Ar), 4.56 (s, 4 H,

NCH2Ph), 4.12 (s, 4 H, NCH

2CH


3) δ = 166.6 (NC+N),


(C-Ar), 52.7 (NCH2Ph), 48.8 (NCH

2CH


23H

22ClF

6N

2P: C, 54.50;

H, 4.37; N, 5.53, found: C, 54.31; H, 4.09; N, 5.37.


N N+

PhPh

PF6−

KPF6

N N+

PhPh

Br−

Cl Cl

184B

89%

184A

DME, r.t., 45 min

N N+

PhPh

N N

PhPh

NBA

Cl Cl

Br−

184

88%

184

Experimental 149

1,3-Dibenzyl-2-(4-chlorophenyl)imidazolinium bis(trifluoromethylsulfonyl)-imide

(184C)


mmol) and LiNTf2


(3 mL) and water

(3 mL) as a white solid (169 mg, 90%). mp 80 °C; MS (EI), m/z 360 (M+ − H, 100%), 227

(70), 152 (70), 89 (70), 77 (40); IR (KBr) 1596s, 1563m, 1354s, 1289m, 1289m, 1227s,

1203vs, 1182m, 1063s, 703m, 614s cm-1; 1H-NMR (400 MHz, CDCl3) δ = 7.76-7.68 (m, 4

H, H-Ar), 7.46-7.38 (m, 6 H, H-Ar), 7.23-7.21 (m, 4 H, H-Ar), 4.50 (s, 4 H, NCH2Ph), 4.00

(s, 4 H, NCH2CH


3) δ = 166.3 (NC+N), 140.5 (C-Ar), 132.5


Ar), 120.36 (q, J = 319 Hz, CF3), 120.35 (C-Ar), 118.8 (C-Ar), 52.5 (NCH

2Ph), 47.8

(NCH2CH


25H

22ClF

6N

3O

4S

2: C, 46.77; H, 3.45; N, 6.54, found:

C, 46.46; H, 3.42; N, 6.38.

1,3-Dibenzyl-2-(4-chlorophenyl)imidazolinium tetrakis(3,5-

bis(trifluoromethyl)phenyl) borate.(184D)

From 1,3-dibenzyl-2-(4-chlorophenyl)imidazolinium (184) (25 mg, 0.07 mmol) and

NBA (10 mg 95%, 0.07 mmol) in DME (0.2 mL), followed by counter anion exchange, with

NaB[C6H

3(CF

3)2]4

(D) (62 mg, 0.07 mmol) in a mixture of CHCl3

(1.5 mL) and water (1.5

mL) gave the title compound as an yellow solid solid (78 mg, 92%). mp 108 °C; MS (EI),

m/z 360 (M+ − H, 1%), 91 (100), 84 (30), 51 (10); IR (KBr) 1608m, 1593s, 1357vs, 1279vs,

1123vs, 887m, 838m, 712m, 682m, 670m cm-1; 1H-NMR (400 MHz, CDCl3) δ = 7.73 (bs,

10 H, H-Ar), 7.54 (bs, 4 H, H-Ar), 7.43-7.35 (m, 8 H, H-Ar), 7.02-6.95 (m, 4 H, H-Ar), 4.35

(s, 4 H, NCH2Ph), 3.81 (s, 4 H, NCH

2CH


3) δ = 166.2

(NC+N), 162.0 (q, J = 49.5 Hz, BC), 142.0 (C-Ar), 135.2 (C-Ar), 131.9 (C-Ar), 130.9 (C-

Ar), 130.40 (C-Ar), 130.3 (C-Ar), 129.4 (C-Ar), 129.3 (q, J = 28.4 Hz, CHCCF3), 128.1 (C-

Ar), 124.9 (q, J = 271.2 Hz, CCF3), 118.9 (C-Ar), 117.9 (C-Ar), 52.5 (NCH

2CH

2N), 47.6

(NCH2Ph); HRMS (ESI) Calcd. for C

23H

22N

2Cl: 361.1466, found: 361.1468.

N N+

PhPh

N N

PhPh

ClCl

184D

92%


2. NaB[C6H4(CF3)2]4,CHCl3/H2O, 30 min

B[C6H3(CF3)2]4−

184


N N+

PhPh

NTf2−

N N+

PhPh

Br−

LiNTf2

Cl Cl

184A 184C

90%

150 Experimental

1,3-Dibenzyl-2-(2,6-dichlorophenyl)imidazolinium bromide (185A)

From 1,3-dibenzyl-2-(2,6-dichlorophenyl)imidazolidine (185) (395 mg, 1.00 mmol) and

NBA (145 mg 95%, 1.00 mmol) in DME (7 mL). The reaction mixture was stirred for 3 h.

Standard workup gave the title compound as a white solid (368 mg, 77%). mp 140 °C; MS

(ESI, 0 V), m/z 395.0 (M+, 100%); IR (KBr) 3417s, 1597vs, 1428s, 1187s, 697s cm-1; 1H-

NMR (200 MHz, DMSO-d6) δ = 7.90 (s, 3 H, H-Ar), 7.60-7.20 (m, 10 H, H-Ar), 4.52 (s, 4

H, NCH2Ph), 4.10 (s, 4 H, NCH

2CH

2N); 13C-NMR (50 MHz, DMSO-d6) δ = 160.3

(NC+N), 136.1 (C-Ar), 133.3 (C-Ar), 132.6 (C-Ar), 129.6 (C-Ar), 128.8 (C-Ar), 128.7 (C-

Ar), 128.6 (C-Ar), 120.1 (C-Ar), 50.5 (NCH2CH

2N), 48.1 (NCH

2Ph).

1,3-Dibenzyl-2-(2,6-dichlorophenyl)imidazolinium tetrakis(3,5-



NBA (73 mg 95%, 0.50 mmol) in DME (3.5 mL), followed by counter anion exchange with

NaB[C6H

3(CF

3)2]4

(443 mg, 0.50 mmol) in a mixture of Et2O (5 mL) and water (5 mL)

gave the title compound as a brown solid (343 mg, 55%). mp 124 °C; MS (ESI, 0 V), m/z395 (M+, 100%); IR (KBr) 1609m, 1358vs, 1280vs, 1127vs, 887m, 838m, 712m, 682m cm-

1; 1H-NMR (400 MHz, CDCl3) δ = 7.75-7.70 (m, 8 H, H-Ar), 7.54 (bs, 4 H, H-Ar), 7.45-

7.35 (m, 6 H, H-Ar), 7.28 (bs, 3 H, H-Ar), 7.15-7.10 (m, 4 H, H-Ar), 4.33 (s, 4 H, NCH2Ph),

3.90 (s, 4 H, NCH2CH


3) δ = 162.1 (q, J = 49.5 Hz, BC),

161.8 (NC+N), 136.5 (C-Ar), 135.2 (BCCH), 134.4 (C-Ar), 130.5 (C-Ar), 130.2 (C-Ar),

130.15 (C-Ar), 130.13 (C-Ar), 129.6 (q, J = 28.4 Hz, CHCCF3), 129.0 (C-Ar), 124.9 (q, J

= 271.2 Hz, CCF3), 120.3 (C-Ar), 117.9 (CHCCF

3), 52.5 (NCH

2CH

2N), 47.8 (NCH

2Ph);


H21

N2Cl

2: 395.1082, found: 395.1091.

N N+

PhPh

N N

PhPh


2. NaB[C6H3(CF3)2]4, Et2O/H2O, 30 min

B[C6H3(CF3)2]4−

185

Cl Cl

185

55%

ClCl

N N+

PhPh

N N

PhPh

Br−

185

Cl Cl

185A

77%

ClCl

NBA

DME, r.t., 3 h

Experimental 151

1,3-Dibenzyl-2-(2,4-dichlorophenyl)imidazolinium bromide (186A)


NBA (73 mg 95%, 0.50 mmol) in DME (1 mL) as a yellow oil (217 mg, 91%). Hygroscop-ic. MS (EI), m/z 394 (M+, 10%), 304 (10), 185 (15), 91 (100), 65 (20); IR (CDCl

3) δ =

2360s, 1600vs, 1455m, 910vs, 730vs cm-1; 1H-NMR (400 MHz, CDCl3) δ = 9.10 (d, J = 8.4

Hz, 1 H, H-Ar,), 7.68-7.62 (m, 2 H, H-Ar), 7.47-7.35 (m, 10 H, H-Ar), 4.65 (d, J = 14.8 Hz,

2 H, NCH2Ph), 4.52-4.47 (m, 2 H, NCH

2CH

2N), 4.41 (d, J = 14.8 Hz, 2 H, NCH

2Ph), 3.75-

3.70 (m, 2 H, NCH2CH


3) δ = 163.4 (NC+N), 140.7 (C-Ar),


(C-Ar), 129.1 (C-Ar), 120.7 (C-Ar), 52.8 (NCH2Ph), 48.7 (NCH

2CH

2N).

1,3-Dibenzyl-2-(2,4-dichlorophenyl)imidazolinium hexafluorophosphate (186B)

From 1,3-dibenzyl-2-(2,4-dichlorophenyl)imidazolinium bromide (186A) (400 mg, 0.89

mmol) and KPF6


(3 mL) and water (3

mL) as a white solid (399 mg, 90%). mp 130 °C; MS (EI), m/z 394 (M+− H, 50%), 358 (40),

317 (20), 282 (20), 91 (100), 65; IR (KBr) 3095m, 1599vs, 1254s, 840vs, 702s, 557s cm-1;

1H-NMR (400 MHz, CDCl3) δ = 8.01 (d, 1 H, J = 8.4 Hz, H-Ar), 7.70-7.69 (m, 1 H, H-Ar),

7.65-7.22 (m, 1H, H-Ar), 7.42-7.36 (m, 6 H, H-Ar), 7.28-7.24 (m, 4 H, H-Ar), 4.46-4.37 (m,

4 H, NCH2Ph), 4.17-4.12 (m, 2 H, NCH

2CH

2N), 3.85-3.80 (m, 2 H, NCH

2CH

2N); 13C-

NMR (100 MHz, CDCl3) δ = 163.1 (NC+N), 141.1 (C-Ar), 133.3 (C-Ar), 132.6 (C-Ar),


(C-Ar), 52.3 (NCH2Ph), 48.2 (NCH

2CH

2N). Anal. calculated for C

23H

21Cl

2N

2PF

6: C,

51.03; H, 3.91; N, 5.18, found: C, 50.73; H, 3.81; N, 4.86.


N N+

PhPh

PF6−

KPF6

N N+

PhPh

Br−

Cl Cl

ClCl

186A 186B

90%

DME, r.t., 45 min

N N+

PhPh

N N

PhPh

Br−

NBA

Cl Cl

Cl Cl

186A

91%

186

152 Experimental

1,3-Dibenzyl-2-(2,4-dichlorophenyl)imidazolinium tetrakis(3,5-


From 1,3-dibenzyl-2-(4-chlorophenyl)imidazolinium (186) (198 mg, 0.50 mmol) and

NBA (36.3 mg 95%, 0.25 mmol) in DME (1 mL), followed by counter anion exchange with

NaB[C6H

3(CF

3)2]4

(D) (443 mg, 0.5 mmol) in the mixture of Et2O (5 mL) and water (3

mL).gave the title compound as a brown solid (525 mg, 84%). mp 93 °C; MS (EI), m/z 394

(M+ − H, 100%), 360 (40), 91 (20); IR (KBr) 1598s, 1356vs, 1278vs, 1125vs, 887s, 713s,

670s cm-1; 1H-NMR (400 MHz, CDCl3) δ = 7.80-7.70 (m, 4 H, H-Ar), 7.60-7.52 (m, 2 H,

H-Ar), 7.40-7.32 (m, 4 H, H-Ar), 7.08-7.00 (m, 2 H, H-Ar), 4.40-4.25 (m, 4 H, NCH2Ph),

3.90-3.80 (m, 4 H, NCH2CH


3) δ = 163.3 (NC+N), 162.1

(q, J = 49.5 Hz, BC), 135.2 (C-Ar), 133.9 (C-Ar), 132.3 (C-Ar), 130.52 (C-Ar), 130.48 (C-

Ar), 130.4 (C-Ar), 130.2 (C-Ar), 129.3 (q, J = 28.4 Hz, CHCCF3), 128.5 (C-Ar), 124.9 (q,

J = 271.2 Hz, CCF3), 118.9 (C-Ar), 117.9 (CHCCF

3), 52.5 (NCH

2CH

2N), 47.7 (NCH

2Ph);


H33

BCl2F

24N

2: C, 52.45; H, 2.64; N, 2.22, found: C, 52.20; H, 2.50;

N, 2.20.

1,3-Dibenzyl-2-(3-nitrophenyl)imidazolinium bromide (216A)

From 1,3-dibenzyl-2-(3-nitrophenyl)imidazolidine (216) (172 mg, 0.50 mmol) and NBA

(73 mg 95%, 0.50 mmol) in DME (1.5 mL) as a brown solid (197 mg, 94%). mp 175 °C;

MS (ESI, 0 V), m/z 372.1 (M+, 100%); IR (KBr) 1607s, 1530s, 1352s, 735m, 698m cm-1;

1H-NMR (400 MHz, CDCl3) δ = 8.95 (d, J = 7.6 Hz, 1 H, H-Ar), 8.70-8.65 (m, 1 H, H-Ar),

8.55-8.48 (m, 1 H, H-Ar), 7.95 (t, J = 8.12 Hz, 1 H, H-Ar), 7.41-7.22 (m, 10 H, H-Ar). 4.58

(dd, J1 = 41.5 Hz, J2 = 15 Hz, 4 H, NCH2Ph), 4.40-4.30 (m, 2 H, NCH

2CH

2N), 4.10-3.95

(m, 2 H, NCH2CH


3) δ = 165.2 (NC+N), 148.8 (C-Ar),


(C-Ar), 127.9 (C-Ar), 124.4 (C-Ar), 124.1 (C-Ar), 52.9 (NCH2CH

2N), 49.3 (NCH

2Ph).

N N+

PhPh

N N

PhPh

216 216A

94%

NO2 NO2

Br−

NBA

DME, r.t., 45 min

N N+

PhPh

N N

PhPh

ClCl

186D

84%

1. NBA, DME, r.t.

2. NaB[C6H4(CF3)2]4, Et2O/H2O

B[C6H3(CF3)2]4−

186

Cl Cl

Experimental 153

1,3-Dibenzyl-2-(pentafluorophenyl)imidazolinium bromide (187A)

From 1,3-dibenzyl-2-(perfluorophenyl)imidazolidine (187) (1.842 g, 4.45 mmol) and

NBA (0.614 g, 4.45 mmol) in DME (3 mL) as a yellow oil. (1.991 g, 90%). Hygroscopic.


1,3-Dibenzyl-2-(pentafluorophenyl)imidazolinium hexafluorophosphate (187B)

From 1,3-dibenzyl-2-(pentafluorophenyl)imidazolinium bromide (187A) (861 mg, 1.73

mmol) and KPF6

(353 mg, 1.90 mmol, 1.1 eq.) in a mixture of DCM (3 mL) and water (3

mL) as a white solid (876 mg, 90%). Spectral data were consistent with literature values.165

1,3-Dibenzyl-2-(pentafluorophenyl)imidazolinium bis(trifluoromethylsulfonyl)-imide

(187C)


mmol) and LiNTf2


(3 mL) and water

(3 mL) as a yellow oil (816 mg, 68%). MS (ESI, 0 V), m/z 417 (M+, 100%); IR (neat)

1663m, 1607s, 1519s, 1458m, 1353s, 1183vs, 1058s, 571m cm-1; 1H-NMR (200 MHz,

CDCl3) δ = 7.40-7.10 (m, 10 H, H-Ar), 4.53 (s, 4 H, NCH

2Ph), 4.06 (s, 4 H, NCH

2CH

2N);

13C-NMR (50 MHz, CDCl3) δ = 154.7 (NC+N), 130.8 (C-Ar), 129.4 (C-Ar), 128.2 (C-Ar),

119.8 (q, J = 319 Hz, CF3), 52.4 (NCH

2Ph), 48.5 (NCH

2CH

2N); HRMS (ESI) Calcd. for

C23

H18

N2F

5

+: 417.1390, found: 417.1408.


N N+

PhPh

NTf2−

LiNTf2N N

+

PhPh

Br−

F F

FF

FF

F

FF

F

187C

68%

187A


N N+

PhPh

PF6−

KPF6

N N+

PhPh

Br−

F F

FF

FF

F

FF

F

187B

90%

187A

DME, r.t., 45 min

N N+

PhPh

N N

PhPh

Br−

NBA

F F

F FF

F F F

F

F

187A

90%

187

154 Experimental

1,3-Dibenzyl-2-(pentafluorophenyl)imidazolinium tetrakis(3,5-



mmol) and NaB[C6H

3(CF

3)2]4

(179 mg, 0.20 mmol) in a mixture of CHCl3

(3 mL) and

water (3 mL) as white solid (256 mg, 92%). mp 95 °C; MS (ESI. 0V), m/z 417 (M+, 100%);

IR (KBr) 1610m, 1517m, 1356s, 1279vs, 1160s, 1124vs cm-1; 1H-NMR (400 MHz, CDCl3)

δ = 7.70 (bs, 8 H, H-Ar), 7.50 (bs, 4 H, H-Ar), 7.45-7.00 (m, 10 H, H-Ar), 4.41 (s, 4 H,

NCH2Ph), 3.94 (s, 4 H, NCH

2CH


3) δ = 166.1 (NC+N),

162.1 (q, J = 49.5 Hz, BC), 135.2 (BCCH), 130.9 (C-Ar), 130.5 (C-Ar), 130.4 (C-Ar), 129.5

(q, J = 28.4 Hz, CHCCF3), 128.2 (C-Ar), 124.9 (q, J = 271.2 Hz, CCF

3), 117.9 (m,

CHCCF3), 53.0 (NCH

2Ph), 48.5 (NCH

2CH


55H

30BClF

29N

2: C,

51.58; H, 2.36; N, 2.19, found: C, 51.13; H, 2.36; N, 2.31.

1,3-Dibenzyl-2-(2-thiophenyll)imidazolinium bromide (189A)

From 1,3-dibenzyl-2-(thiophen-2-yl)imidazolidine (189) (304 mg, 1.00 mmol) and NBA

(145 mg 95%, 1.00 mmol) in DME (10 mL) as a yellow solid (324 mg, 86%). Hygroscop-ic. mp 157 °C; MS (EI), m/z 332 (M+-H, 10%), 241 (30), 123 (30), 91 (100), 65 (20); IR

(KBr) 1593s, 1577s, 1287m, 761m, 733m cm-1; 1H-NMR (400 MHz, CDCl3) δ = 8.17-8.15

(m, 1 H, H-Ar), 7.81 (dd, J1 = 6.8 Hz, J2 = 1.24 Hz, 1 H, H-Ar), 7.40-7.28 (m, 11 H, H-Ar),

4.69 (s, 4 H, NCH2Ph), 4.08 (s, 4 H, NCH

2CH


3) δ = 162.9


Ar), 128.6 (C-Ar), 119.7 (C-Ar), 53.1 (NCH2Ph), 48.7 (NCH

2CH

2N).

DME, r.t., 45 min

N N+

PhPh

N N

PhPh

Br−

NBA

S S

189A

86%

189


N N+

PhPh

B[C6H3(CF3)2]4−

NaB[(C6H3(CF3)2]4N N

+

PhPh

Br−

F F

FF

FF

F

FF

F

187D

92%

187A

Experimental 155

1,3-Dibenzyl-2-(2-thiophenyl)imidazolinium hexafluoro phosphate (189B)

From 1,3-dibenzyl-2-(2-thiophenyl)imidazolinium bromide (189A) (162 mg, 0.42

mmol) and KPF6


(3 mL) and water as a

yellow solid (181 mg, 88%). mp 110-112 °C; MS (EI), m/z 332 (M+, 20%), 240 (30), 132

(20), 91 (100), 65 (20); IR (KBr) 1596s, 1580s, 1283m, 836vs, 731m, 698m cm-1; 1H-NMR

(400 MHz, CDCl3) δ = 7.86-7.82 (m, 2 H, H-Ar), 7.44-7.34 (m, 7 H, H-Ar), 7.28-7.25 (m,

4 H, H-Ar), 4.61 (s, 4 H, NCH2Ph), 3.98 (s, 4 H, NCH

2CH

2N); 13C-NMR (100 MHz,

CDCl3) δ = 162.3 (NC+N), 135.2 (C-Ar), 133.3 (C-Ar), 132.8 (C-Ar), 129.83 (C-Ar),

129.80 (C-Ar), 129.4 (C-Ar), 128.4 (C-Ar), 119.1 (C-Ar), 52.6 (NCH2Ph), 48.1

(NCH2CH

2N). Anal. calculated for C

21H

21N

2SPF

6: C, 52.72; H, 4.42; N, 5.86, found: C,

52.36; H, 4.39; N, 5.68.

1,3-Dibenzyl-2-(2-thiophenyl)imidazolinium tetrakis(3,5-bis(trifluoromethyl)phenyl)

borate (189D)

From 1,3-Dibenzyl-2-(2-thiophenyl)imidazolidine (189) (167 mg, 0.50 mmol) and NBA

(72 mg 95%, 0.50 mmol) in DME (7 mL), followed by counter anion exchange with

NaB[C6H

3(CF

3)2]4

(443 mg, 0.50 mmol) in the mixture of water (3 mL) and Et2O (5 mL).

The title compound was obtained as a brown solid (526 mg, 63%). mp 153 °C; MS (EI), m/z332 (M+ − H, 100%), 91 (35); IR (KBr) 1593s, 1357vs, 1278vs, 1126vs cm-1; 1H-NMR (400

MHz, CDCl3) δ = 7.94 (dd, J1 = 5.0 Hz, J2 = 1.1 Hz, 1 H, H-Ar), 7.75-7.70 (m, 8 H, H-Ar),

7.56-7.52 (m, 5 H, H-Ar), 7.42-7.36 (m, 7 H, H-Ar), 7.10-7.05 (m, 4 H, H-Ar), 4.51 (s, 4 H,

NCH2Ph), 3.80 (s, 4 H, NCH

2CH


3) δ = 162.1 (q, J = 49.5

Hz, BC), 162.0 (NC+N), 135.2 (BCCH), 134.8 (C-Ar), 134.7 (C-Ar), 131.2 (C-Ar), 130.3

(C-Ar), 130.2 (C-Ar), 129.3 (q, J = 28.4 Hz, CHCCF3), 128.1 (C-Ar), 124.9 (q, J = 271.2

Hz, CCF3), 118.0 (CHCCF

3), 52.9 (NCH

2Ph), 47.6 (NCH

2CH

2N); Anal. calculated for

C53

H33

BClF24

N2S: C, 53.19; H, 2.78; N, 2.34, found: C, 53.08; H, 2.71; N, 2.25.

N N+

PhPh

N N

PhPh



B[C6H3(CF3)2]4−

189 189D

63%

S S


N N+

PhPh

PF6−

KPF6

N N+

PhPhBr

−

S S

189A 189B

88%

156 Experimental

1,3-Dibenzyl-2-(2-pyridinyl)imidazolinium bromide (190A)

From 2-(1,3-dibenzylimidazolidin-2-yl)pyridine (190) (100 mg, 0.30 mmol) and NBA

(44 mg 95%, 0.30 mmol) in DME (1 ml) as a yellow oil (124 mg, 99%). Hygroscopic. MS

(EI), m/z 328 (M+, 20%), 237 (30), 105 (35), 91 (100), 78 (35), 65 (35), 51 (35); IR (CHCl3)

1668m, 1601s, 910vs, 732vs 650s cm-1; 1H-NMR (400 MHz, CDCl3) δ = 8.97 (d, J = 8.3

Hz, 1 H, H-Ar), 7.63-7.59 (m, 2 H, H-Ar), 7.38-7.27 (m, 11 H, H-Ar), 4.50 (d, J = 14.9 Hz

, 2 H, NCH2Ph), 4.44-4.35 (m, 4 H, NCH

2Ph, NCH

2CH

2N), 3.73-3.68 (m, 2 H,

NCH2CH


3) δ = 163.4, 140.8 (C-Ar), 134.6 (C-Ar), 132.9


Ar), 52.8 (NCH2Ph), 48.7 (NCH

2CH

2N).

1,3-Dibenzyl-2-(2-pyridinyl)imidazolinium hexafluoro phosphate (190B)

From 1,3-dibenzyl-2-(2-pyridinyl)imidazolinium bromide (190A) (408 mg, 1.00 mmol)

and KPF6


(3 mL) and water (3 mL) as

a white solid (434 mg, 98%). mp 120 °C; MS (EI), m/z 327 (M+, 30%), 236 (30), 105 (20),

91 (100), 65 (20); IR (KBr) 1619m, 1599m, 839s, 557m cm-1; 1H-NMR (400 MHz, CDCl3)

δ = 8.94 (d, J = 4.7 Hz, 1 H, H-pyridine), 8.21 (d, J = 7.6 Hz, 1 H, H-pyridine), 8.14-8.10

(m, 1 H, H-pyridine), 7.71-7.68 (m, 1 H, H-pyridine), 7.44-7.32 (m, 10 H, H-Ar), 4.50 (s, 4

H, NCH2Ph), 4.00 (s, 4 H, NCH

2CH


3) δ = 163.8 (NC+N),


(C-Ar), 127.8 (C-Ar), 126.9 (C-Ar), 52.1 (PhCH2N), 48.0 (NCH

2CH

2N). Anal. calculated

for C22

H22

F6N

3P: C, 55.82; H, 4.68; N, 8.88, found: C, 55.97; H, 4.63; N, 8.57.


N N+

N

PhPh

PF6−

KPF6

N N+

N

PhPh

Br−

190B

98%

190A

DME, r.t., 45 min

N N+

N

PhPh

N N

N

PhPh

Br−

NBA

190A

99%

190

Experimental 157

1,3-Dibenzyl-2-(2-pyridinyl)imidazolinium tetrakis(3,5-bis(trifluoromethyl)phenyl)

borate (190D)

From 1,3-Dibenzyl-2-(2-pyridinyl)imidazolidine (190) (33 mg, 0.10 mmol) and NBA

(15 mg 95%, 0.10 mmol) in DME (1 mL), followed by counter anion exchange with

NaB[C6H

3(CF

3)2]4

(89 mg, 0.10 mmol) in the mixture of DCM (2 mL) and water (2 mL).

gave the title compound as a brown solid (114 mg, 97%). mp 128 °C; MS (EI), m/z 327 (M+

− H, 100%), 91 (20); IR (KBr) 1602s, 1356vs, 1278vs, 1124vs, 887m, 712m, 699m, 682m,

670m cm-1; 1H-NMR (400 MHz, CDCl3) δ = 8.97 (d, J = 4.8 Hz, 1 H, H-pyridine), 8.97 (t,

J = 7.8 Hz, 1 H, H-pyridine), 7.75-7.70 (m, 8 H, H-Ar), 7.70-7.57 (m, 2 H, H-pyridine), 7.53

(bs, 4 H, H-Ar), 7.45-7.35 (m, 6 H, H-Ar), 7.20-7.10 (m, 4 H, H-Ar), 4.43 (s, 4 H, NCH2Ph),

3.86 (s, 4 H, NCH2CH


3) δ = 163.8 (NC+N), 162.1 (q, J =

49.5 Hz, BC), 152.6 (C-Ar), 141.0 (C-Ar), 139.0 (C-Ar), 135.2 (BCCH), 131.2 (C-Ar),

130.3 (C-Ar), 130.1 (C-Ar), 129.6 (q, J = 28.4 Hz, CHCCF3), 128.8 (C-Ar), 128.6 (C-Ar),

125.5 (C-Ar), 124.9 (q, J = 271.2 Hz, CCF3), 117.9 (CHCCF

3), 52.4 (NCH

2Ph), 47.7

(NCH2CH


54H

34BF

24N

3: C, 54.43; H, 2.88; N, 3.53, found: C,

53.99; H, 2.83; N, 3.53.

1,3-Dimethyl-2-(phenyl)imidazolinium bromide (196A)

From 1,3-dimethyl-2-phenylimidazolidine (196) (3.53 g, 20.00 mmol) and NBS (3.57 g,

20.00 mmol) in DME (20 mL) as a yellow solid (5.05 g, 99%). Hygroscopic. MS (ESI) m/z175.1 (cation); IR (KBr) 3417s, 1710s, 1616vs, 1576m, 1353m, 1302m, 1183s cm-1; 1H-

NMR (200 MHz, CDCl3) δ = 7.80-7.60 (m, 5 H, H-Ar), 4.32 (s, 4 H, NCH

2CH

2N), 3.06 (s,

6 H, NCH3); 13C-NMR (50 MHz, CDCl

3) δ = 166.3 (NCHN), 132.7 (C-Ar), 129.7 (C-Ar),

128.7 (C-Ar), 121.7 (C-Ar), 50.8 (NCH2CH

2N), 35.0 (NCH

3).

DME, r.t., 45 min

N N+

Ph

N N

Ph Br−

NBS

196A

99%

196

N N+

PhPh

N N

PhPh

NN



B[C6H3(CF3)2]4−

190 190D

97%

158 Experimental

1,3-Dimethyl-2-(phenyl)imidazolinium hexafluorophosphate (196B)

From 1,3-dimethyl-2-(phenyl)imidazolinium bromide (196A) (1.91 g, 7.50 mmol) and

KPF6

(1.52 g, 7.50 mmol, 1 eq.) in a mixture of CHCl3

(10 mL) and water (10 mL) as a

white solid (2.16 g, 90%). mp 105 °C; MS (ESI, 0 V): m/z 175.1 (M+); IR (KBr) 3426s,

1623s, 835vs, 557s cm-1; 1H-NMR (200 MHz, CDCl3) δ = 7.70-8.40 (m, 5 H, H-Ar), 4.03

(s, 4 H, NCH2CH

2N), 2.86 (s, 6 H, NCH


3) δ = 165.1 (NC+N),

131.8 (C-Ar), 128.8 (C-Ar), 127.3 (C-Ar), 120.8 (C-Ar), 49.1 (NCH2CH

2N), 33.4 (NCH

3);


H15

F6N

2P: C, 41.26; H, 4.72; N, 8.75, found: C, 41.26; H, 4.66; N,

8.45.

1,3-Dimethyl-2-(phenyl)imidazolinium bis(trifluoromethylsulfonyl)-imide (196C)

1,3-Dimethyl-2-(phenyl)imidazolinium bromide (196A) (11.17 g, 43.74 mmol) was dis-

solved in CHCl3

(10 mL) and vigorously stirred with a solution of LiNTf2

(13.81 g, 48.11

mmol, 1.1 eq.) in water (10 mL) for 30 min. The organic layer was washed with a saturat-

ed solution of Na2S

2O

3(20 mL), water (3 x 20 mL), dried over molar sieves (3Å) and the

solvent was evaporated giving the 1,3-dimethyl-2-(phenyl)imidazolinium bis(trifluo-

romethylsulfonyl)-imide (196C) as a colorless liquid (15.00 g, 75%). mp 35 °C; MS (ESI,

0 V) m/z 175.1 (cation); IR (KBr) 1623s, 1578s, 1357vs, 1180vs, 1051vs, 773s, 707s, 614vs

570s, 516s cm-1; 1H-NMR (200 MHz, CDCl3) δ = 7.61-7.49 (m, 5 H, H-Ar), 4.11 (s, 4 H,

NCH2CH

2N), 2.96 (s, 6 H, NCH


3) δ = 166.3 (NC+N), 133.0

(C-Ar), 129.8 (C-Ar), 128.3 (C-Ar), 121.4 (C-Ar), 119.9 (q, J = 319.3 Hz) 50.1

(NCH2CH

2N), 34.5 (NCH

3). HRMS (ESI) Calculated for C

11H

15N

2175.1235 found:

175.1230. Anal. calculated for C13

H15

F6N

3O

4S

2: C, 34.29; H, 3.32; N, 9.23; found: C,

34.26, N, 9.14, H, 3.40.


N N+

Ph

NTf2−

N N+

Ph

LiNTf2

Br−

196A 196C

75%


N N+

PhPF6

−

N N+

Ph

KPF6

Br−

196A 196B

90%

Experimental 159

1,3-Dimethyl-2-(2-chlorophenyl)imidazolinium tetrakis(3,5-

bis(trifluoromethyl)phenyl) borate. (197D)

From 1,3-dimethyl-2-(2-chlorophenyl)imidazolidine (197) (370 mg, 1.76 mmol) and

NBA (256 mg 95%, 1.76 mmol) in DME (1 mL), followed by counter anion exchange with

NaB[C6H

3(CF

3)2]4

(1.56 g, 1.76 mmol) in a mixture of DCM (3 mL) and water (3 mL) gave

the title compound as a yellow solid (1.21 g, 64%) mp 135 C; MS (ESI, 0V): m/z 209.1 (M+,

100%); IR (KBr) 3424s, 1618s, 1355s, 1280vs, 1128vs cm-1; 1H-NMR (400 MHz, acetone-

d6) δ = 7.85-7.70 (m, 4 H, H-Ar), 7.81 (bs, 8 H, H-Ar), 7.69 (bs, 4 H, H-Ar), 4.41-4.31 (m,

4 H, NCH2CH

2N), 2.95 (s, 6 H, NCH

3); 13C-NMR (100 MHz, acetone-d6) δ = 163.9

(NC+N), 161.7 (q, J = 49.4 Hz, BC), 134.8 (C-Ar), 132.1 (C-Ar), 130.8 (C-Ar), 130.3 (C-

Ar), 129.1 (q, J = 28.4 Hz, CHCCF3), 128.7 (C-Ar), 124.5 (q, J = 271.2 Hz, CCF

3), 121.5

(C-Ar), 118.2 (m, C-Ar), 114.7 (C-Ar), 50.6 (NCH2CH

2N), 33.7 (NCH

3). HRMS (ESI) Cal-

culated for C11

H14

N2Cl 209.0846 found: 209.0848.

1,3-Dibenzyl-2-chlorophenyl-2-yl-3,4,5,6-tetrahydro-pyrimidin-1-ium bis(trifluo-

romethylsulfonyl)imide (192C)

From 1,3-dibenzyl-2-(2-chloro-phenyl)-hexahydro-pyrimidine (192) (300 mg, 0.80

mmol) and NBA (116 mg 95%, 0.80 mmol) in DME (2 mL), followed by counter anion

exchange with LiNTf2

(235 mg, 0.80 mmol) in a mixure of CHCl3

(3 mL) and water (3 mL)

as a yellow oil which solidified (458 mg, 88%). mp 82 °C; MS (ESI, 0 V), m/z 375.0 (M+,

100%); IR (KBr) 3424m, 1614s, 1354s, 1194s, 1063m, 612m cm-1; 1H-NMR (200 MHz,

CDCl3) δ = 8.10-7.90 (m, 1 H, H-Ar), 7.60 (s, 3 H, H-Ar), 7.50-7.05 (m, 10 H, H-Ar), 4.55-

4.30 (m, 2 H, NCH2Ph), 3.75-3.30 (m, 2 H, NCH

2CH

2), 2.40-1.90 (m, 2 H, CH

2CH

2CH

2);

13C-NMR (50 MHz, CDCl3) δ = 160.1 (NC+N), 133.8 (C-Ar), 132.1 (C-Ar), 131.2 (C-Ar),


(C-Ar), 123.1 (C-Ar), 57.7 (NCH2Ph), 45.4 (NCH

2CH

2), 18.7 (CH

2CH

2CH

2); HRMS (ESI)

Calcd. for C24

H24

N2Cl+: 375.1623, found: 375.1636.

N N

PhPh

192

N N+

PhPh

NTf2−

192C

88%


2. LiNTf2, CHCl3/H2O, r.t., 30 min

Cl Cl

N N+

N N1. NBA, DME, r.t., 45 min

2. NaB[C6H3(CF3)2]4, DCM/H2O

B[C6H3(CF3)2]4−

197

Cl Cl

197D

64%

160 Experimental

(E)-1,3-dibenzyl-2-(2-chlorophenyl)-4,5,6,7-tetrahydro-3H-1,3-diazepin-1-ium (194C)

From 1,3-dibenzyl-2-(2-chloro-phenyl)-[1,3]diazepane (194) (300 mg, 0.67 mmol) and

NBA (111 mg 95%, 0.67 mmol) in DME (5 mL), followed by counter anion exchange with

LiNTf2

(227 mg, 0.67 mmol, 1 eq.) in a mixure of CHCl3

(3 mL) and water (3 mL) gave the

title compound as a yellow oil which solidified (198 mg, 38%). mp 80 °C; MS (ESI, 0 V),

m/z 389.0 (M+, 100%); IR (KBr) 1597m, 1354s, 1198vs, 1058s, 615m cm-1; 1H-NMR (400

MHz, CDCl3) δ = 8.05-7.95 (m, 1 H, H-Ar), 7.70-7.55 (m, 3 H, H-Ar), 7.50-7.20 (m, 10 H,

H-Ar), 4.55-4.20 (m, 2 H, NCH2Ph), 4.10 (s, 2 H, NCH

2Ph), 4.00-3.55 (m, 2 H, NCH

2CH

2),

3.13-2.90 (s, 2 H, NCH2CH

2), 1.90-1.50 (d, J = 37.1 Hz, 4 H, CH

2CH

2CH

2CH

2); 13C-NMR

(100 MHz, CDCl3) δ = 165.25 (NC+N), 134.6 (C-Ar), 132.4 (C-Ar), 132.3 (C-Ar), 131.7


Ar), 128.0 (C-Ar), 122.8 (C-Ar), 116.4 (C-Ar), 59.6 (NCH2Ph), 53.2 (NCH

2Ph), 52.6

(NCH2CH

2), 47.2 (NCH

2CH

2), 23.3 (CH

2CH

2CH

2CH

2), 22.7 (CH

2CH

2CH

2CH

2); HRMS

(ESI) Calcd. for C24

H24

N2Cl: 389.1785, found: 389.1783.

1,3-Dibenzyl-2-pyridin-2-yl-3,4,5,6-tetrahydro-pyrimidin-1-ium bromide (193A)

From 1,3-dibenzyl-hexahydro-2-(pyridin-2-yl)pyrimidine (193) (400 mg, 1.16 mmol)

and NBA (161 mg, 1.16 mmol) in DME (1 ml) as a white solid (464 mg, 95%). Hygroscop-ic. mp 215 °C; MS (ESI, 0 V), m/z 342.2 (M+, 75%); IR (KBr) 1619vs, 1448m, 1331s, 765m

737s, 718m cm-1; 1H-NMR (400 MHz, CDCl3) δ = 9.04 (d, J = 7.8 Hz, 1 H, H-Ar), 8.78

(dt, J1 = 5.4 Hz, J2 = 1 Hz, 1 H, H-Ar), 7.99 (dt, J1 = 7.8 Hz, J2 = 1.8 Hz, 1 H, C-Ar), 7.53-

7.49 (m, 1 H, H-Ar), 7.42-7.32 (m, 10 H, H-Ar), 4.41 (q, J = 15.4 Hz, 4 H, NCH2Ph), 4.15-

4.05 (m, 2 H, NCH2CH

2CH

2N), 3.35-3.25 (m, 2 H, NCH

2CH

2CH

2N) 2.52-2.42 (m, 1 H,

CH2CH

2CH

2), 2.00-1.90 (m, 1 H, CH

2CH

2CH


3) δ = 161.3

(NCN), 150.9 (C-Ar), 147.9 (C-Ar), 138.9 (C-Ar), 133.6 (C-Ar), 129.6 (C-Ar), 129.2 (C-

Ar), 128.6 (C-Ar), 127.2 (C-Ar), 126.7 (C-Ar), 58.0 (NCH2Ph), 45.4 (NCH

2CH

2CH

2N),

19.5 (CH2CH

2CH

2).

DME, r.t., 45 min

N N+

N

PhPh

N N

N

PhPh

Br−

NBA

193A

95%

193

N N+

Cl

194C

38%

Ph Ph

N N

Cl

194

Ph Ph1. NBA, DME, r.t., 45 min

2. LiN(Tf)2, CHCl3/H2O, r.t., 30 min

NTf2−

Experimental 161

1,3-Dibenzyl-2-pyridin-2-yl-3,4,5,6-tetrahydro-pyrimidin-1-ium hexafluorophosphate

(193B)

From 1,3-dibenzyl-2-pyridin-2-yl-3,4,5,6-tetrahydro-pyrimidin-1-ium bromide (193A)

(116 mg, 0.28 mmol) and KPF6

(56 mg, 0.30 mmol, 1.1 eq.) in a mixture of DCM (3 mL)

and water (3 mL) as a white solid (131 mg, 98%). mp 123 °C; MS (ESI, 0 V), m/z 342.1

(M+, 100%); IR (KBr) 1619vs, 1455s, 1327s, 838vs 741m, 698m, 557s cm-1; 1H-NMR (400

MHz, CDCl3) δ = 8.85-8.80 (m, 1 H, H-Ar), 8.20 (dt, J1 = 7.8 Hz, J2 = 1 Hz, 1 H, H-Ar),

8.03 (td, J1 = 7.8 Hz, J2 = 1.8 Hz, 1 H, H-Ar), 7.58-7.54 (m, 1 H, H-Ar), 7.45-7.32 (m, 10

H, H-Ar), 4.35 (q, J = 15.4 Hz, 4 H, NCH2Ph), 3.83-3.75 (m, 2 H, NCH

2CH

2CH

2N), 3.37-

3.30 (m, 2 H, NCH2CH

2CH

2N) 2.40-2.30 (m, 1 H, CH

2CH

2CH

2), 1.97-1.87 (m, 1 H,

CH2CH

2CH


3) δ = 161.1 (NCN), 151.2 (C-Ar), 147.4 (C-Ar),


(C-Ar), 57.7 (NCH2Ph), 45.4 (NCH

2CH

2CH

2N), 19.5 (CH

2CH

2CH

2); HRMS (ESI) Calcd.

for C23

H24

N3

+: 342.1970, found: 342.1972.

1,3-Dibenzyl-2-pyridin-2-yl-3,4,5,6-tetrahydro-pyrimidin-1-ium tetrakis(3,5-bis(trifluo-

romethyl)phenyl) borate (193D)

1,3-Dibenzyl-2-pyridin-2-yl-3,4,5,6-tetrahydro-pyrimidin-1-ium bromide (193A) (112

mg, 0.26 mmol) and NaB[C6H

3(CF

3)2]4

(236 mg, 0.26 mmol) in a mixture of Et2O (3 mL)

and water (3 mL) as a brown solid (288 mg, 90%). mp 110 °C; MS (ESI, 0 V), m/z 342.2

(M+, 100%); IR (KBr) 1609m, 1358s, 1280vs, 1128vs, 887m, 712m, 682m cm-1; 1H-NMR

(400 MHz, CDCl3) δ = 8.90-8.87 (m, 1 H, H-Ar), 7.90-7.82 (m, 1 H, H-Ar), 7.72 (bs, 8 H,

H-Ar), 7.60-7.50 (m, 5 H, H-Ar), 7.47-7.35 (m, 6 H, H-Ar), 7.15-7.25 (m, 4 H, H-Ar), 4.36

(d, J = 11 Hz, 2 H, NCH2Ph), 4.15 (d, J = 11 Hz, 2 H, NCH

2Ph), 3.50-3.40 (m, 4 H,

NCH2CH

2CH

2N), 2.20-2.00 (m, 2 H, CH

2CH

2CH


3) δ =

162.1 (q, J = 49.5 Hz, BC), 161.0 (NC+N), 152.3 (C-Ar), 146.2 (C-Ar), 139.0 (C-Ar), 135.2

(BCCH), 131.8 (C-Ar), 130.1 (C-Ar), 130.0 (C-Ar), 129.3 (q, J = 28.4 Hz, CHCCF3), 128.0

(C-Ar), 127.6 (C-Ar), 124.9 (q, J = 271.2 Hz, CCF3), 123.8 (C-Ar), 117.9 (CHCCF

3), 58.2

N N+

N

PhPh

Br−

193A

N N+

N

PhPh

B[C6H3(CF3)2]4−

193D

90%

NaB[C6H3(CF3)2]4

Et2O/H2O, r.t.

N N+

N

PhPh

Br−

193A

95%

N N+

N

PhPh

PF6−

193B

98%

DCM/H2O, r.t., 30 min

KPF6

162 Experimental

(NCH2Ph), 45.7 (NCH

2CH

2CH

2N), 19.1 (NCH

2CH

2CH

2N); HRMS (ESI) Calcd. for

C23

H24

N3

+: 342.1970, found: 342.1973.

Preparation of chiral imidazolinium salts

(4S,5S)-2-(2-Chlorophenyl)-1,3-dimethyl-4,5-diphenylimidazolinium hexaflurophos-

phate (164B)

From (4S,5S)-2-(2-chlorophenyl)-1,3-dimethyl-4,5-diphenylimidazolidine (164) (200

mg, 0.55 mmol) and NBA (80 mg, 0.55 mmol) in DME (2 mL), followed by counter anion

exchange with KPF6

(103 mg, 0.55 mmol) in a mixure of DCM (3 mL) and water (3 mL)

as a white solid (245 mg, 88%). [α]22D

= −116.7 (c = 0.36, CHCl3); mp 277 °C; MS (ESI, 0

V), m/z 361.1 (M+, 100%); IR (KBr) 3453s, 1608vs, 837vs, 754s, 702s, 557s cm-1; 1H-NMR

(200 MHz, CDCl3) δ = 8.20-8.10 (m, 1 H, H-Ar), 7.56-7.32 (m, 13 H, H-Ar), 5.42 (d, J =

12.2 Hz, 1 H, CH), 5.00 (d, J = 12.2 Hz, 1 H, CHPh) 2.87 (s, 3 H, NCH3), 2.78 (s, 3 H,

NCH3); 13C-NMR (50 MHz, CDCl

3) δ = 164.3 (NC+N), 134.5 (C-Ar), 134.3 (C-Ar), 132.7


Ar), 129.8 (C-Ar), 129.2 (C-Ar), 128.5 (C-Ar), 127.9 (C-Ar), 121.5 (C-Ar), 75.8 (CHPh),

74.4 (CHPh), 32.8 (NCH3), 32.6 (NCH

3). HRMS (ESI) calculated for C

23H

22N

2Cl+:

361.1472, found: 361.1458.

(4R,5R)-2-(2-Chlorophenyl)-1,3-dimethyl-4,5-diphenylimidazolinium bis(trifluo-

romethylsulfonyl)imide (ent-164C)

From (4R,5R)-2-(2-chlorophenyl)-1,3-dimethyl-4,5-diphenylimidazolidine (ent-164) (61

mg, 0.169 mmol) and NBA (25 mg 95%, 0.17 mmol) in DME (1 mL), followed by counter

anion exchange with LiNTf2


(3 mL) and water

(3 mL) as a colorless oil (63 mg, 58%). [α]22D

= +86.5 (c = 0.28, CHCl3); MS (ESI, 0 V), m/z

361.0 (M+, 100%); IR (KBr) 1607s, 1352s, 1195vs, 1135s, 1058s, 760m, 653m cm-1; 1H-

NMR (400 MHz, CDCl3) δ = 8.18-8.12 (m, 1 H, H-Ar), 7.75-7.65 (m, 3 H, H-Ar), 7.55-7.45

(m, 8 H, H-Ar), 7.40-7.32 (m, 2 H, H-Ar), 5.43 (d, J = 12.1 Hz, 1 H, CHPh), 4.99 (d, J =11.8 Hz, 1 H, CHPh), 2.88 (s, 3 H, NCH

3), 2.80 (s, 3 H, NCH

3); 13C-NMR (100 MHz,

N N+

NTf2−

N N

ClCl

PhPh PhPh

ent-164C

58%

1. NBA/DME, r.t., 45 min

2. LiNTf2/CHCl3/H2O, r.t.

ent-164

N N+

PF6−

Cl

PhPh

N N

Cl

PhPh

164 164B

88%


2. KPF6, DCM/H2O, r.t., 30 min

Experimental 163

CDCl3) δ = 164.9 (NC+N), 135.1 (C-Ar), 134.7 (C-Ar), 133.1 (C-Ar), 131.9 (C-Ar), 131.8


Ar), 128.8 (C-Ar), 128.3 (C-Ar), 121.9 (C-Ar), 121.88 (C-Ar), 76.5 (CHPh), 75.1 (CHPh),

33.6 (NHCH3), 33.1 (NHCH

3); HRMS (ESI) calculated for C

23H

22N

2Cl+: 361.1472, found:

361.1477.

(4S,5S)-2-(2-Chlorophenyl)-1,3-dimethyl-4,5-diphenylimidazolinium tetrakis(3,5-


From (4S,5S)-2-(2-chlorophenyl)-1,3-dimethyl-4,5-diphenylimidazolidin (164) (61 mg,

0.17 mmol) and NBA (25 mg, 95%, 0.17 mmol), followed by counter anion exchange with

NaB[C6H

3(CF

3)2]4

(150 mg, 0.17 mmol) in a mixture of DCM (3 mL) and water (3 mL) as

a brown oily solid (160 mg, 77%). [α]22D

= −138.0 (c = 0.27, CHCl3); MS (EI), m/z 360 (M+,

30%), 269 (50), 151 (30), 91 (100); IR (neat) 3355s, 3177s, 1664vs, 1598vs, 1291s, 1254s,

759s, 703s cm-1; 1H-NMR (200 MHz, CDCl3) δ = 7.75-7.20 (m, 26 H, H-Ar), 5.03 (d, J =

2 Hz, 2 H, CHPh), 2.83 (s, 2 H, NCH3), 2.79 (s, 2 H, NCH


3)

δ = 164.4 (NC+N), 161.6 (q, J = 49.6 Hz, BC), 135.5 (C-Ar), 134.7 (BCCH), 133.5 (C-Ar),

133.4 (C-Ar), 132.1 (C-Ar), 131.5 (C-Ar), 131.1 (C-Ar), 130.42 (C-Ar), 130,39 (C-Ar),

129.0 (C-Ar), 128.7 (C-Ar), 128.9 (q, J = 28.4 Hz, CCF3), 127.0 (C-Ar), 126.5 (C-Ar),

124.5 (q, J = 271 Hz, CCF3), 120.4 (C-Ar), 117.4 (m, CHCCF

3), 75.2 (NCHPh), 32.9

(NCH3), 32.7 (NCH


23H

22N

2Cl+: 361.1472, found:

361.1475.

(4S,5S)-2-(2-Chlorophenyl)-1,3-dimethyl-4,5-diphenylimidazolinium tetrakis(penta-

fluorophenyl)borate (164E)


mg, 0.28 mmol) and NBA (40 mg, 95%, 0.28 mmol), followed by counter anion exchange

with KB(C6F

5)4

(198 mg, 0.28 mmol) in a mixture of DCM (3 mL) and water (3 mL) as a

white solid (256 mg, 89%). [α]22D

= −145.7 (c = 0.40, CHCl3); mp 80 °C. MS (ESI, 0 V) m/z

361 (M+, 100%); IR (KCl) 1644s, 1606s, 1514s, 1464vs, 1274s, 1086s, 979s, 774s, 756s,

N N+

N N

B(C6F5)4−

PhPh PhPh

Cl Cl

164E

89%

164


2. KB(C6F5)4, DCM/H2O, r.t.

N N+

B[C6H4(CF3)2]4−

N N

PhPh PhPh

ClCl

164 164D

77%


2. NaB[C6H4(CF3)2]4, DCM/H2O, r.t.

164 Experimental

699s, 686s, 660s cm-1; 1H-NMR (200 MHz, CDCl3) δ = 7.80-7.15 (m, 14 H, H-Ar), 5.07 (s,

2 H, CHPh), 2.86 (s, 3 H, NCH3), 2.81 (s, 3 H, NCH


3) δ =

164.3 (NC+N), 150.5 (m, CF), 145.7 (m, CF), 138.5 (m, CF), 135.4 (C-Ar), 133.7 (C-Ar),


(C-Ar), 127.1 (C-Ar), 126.7 (C-Ar), 120.6 (C-Ar), 75.2 (NCHPh), 75.1 (NCHPh), 32.8

(NCH3), 32.6 (NCH


23H

22N

2Cl+: 361.1472, found:

361.1478.

(4S,5S)-2-(4-Chlorophenyl)-1,3-dimethyl-4,5-diphenylimidazolinium bromide (165A)


mg, 0.99 mmol) and NBA (143.8 mg, 0.99 mmol) in DME (3 mL) as a white solid (446 mg,

99%). Hygroscopic. [α]22D

= −56.5 (c = 0.35, CHCl3); mp 98 °C. MS (ESI, 0 V), m / z 361

(M+, 100%); IR (KBr) 1605s, 1345s, 1327s, 1199vs, 1138s, 1058s, 616s cm-1; 1H-NMR

(200 MHz, CDCl3) δ = 8.08 (d, J = 8.34 Hz, 2 H, H-Ar), 7.58-7.55 (m, 6 H, H-Ar), 7.38-

7.35 9 (m, 6 H, H-Ar), 5.33 (s, 2 H, CHPh), 2.87 (s, 6 H, CH3); 13C-NMR (50 MHz, CDCl

3)

δ = 166.6 (NCN), 139.9 (C-Ar), 133.4 (C-Ar), 130.43 (C-Ar), 130.38 (C-Ar), 130.1 (C-Ar),

129.7 (C-Ar), 128.3 (C-Ar), 120.3 (C-Ar), 75.2 (NCHPh), 33.6 (NCH3); HRMS (ESI) cal-

culated for C23

H22

N2Cl+: 361.1472, found: 361.1482.

(4S,5S)-2-(4-Chlorophenyl)-1,3-dimethyl-4,5-diphenylimidazolinium bis(trifluo-


From (4S,5S)-2-(4-chlorophenyl)-1,3-dimethyl-4,5-diphenylimidazoliniumbromide

(165A) (330 mg, 0.75 mmol) and LiNTf2

(236 mg, 0.82 mmol, 1.1 eq.) in a mixture of

CHCl3

(2 mL) and water (2 mL) as a white solid (347 mg, 82%). [α]22D

= −62.4 (c = 0.34,

CHCl3), mp 102 °C; MS (EI), m/z 360 (M+ − H, 100%), 327 (5), 283 (5), 152 (10), 78 (5),

69 (30); IR (KBr) 1604vs, 1346vs, 1199vs, 1138s, 1158s, 616s, 512s cm-1; 1H-NMR (200

MHz, CDCl3) δ = 7.70-7.59 (m, 4 H, H-Ar), 7.43-7.31 (m, 10 H, H-Ar), 5.05 (s, 2 H,


N N+

NTf2−

N N+

Br−

LiNTf2

PhPh PhPh

Cl Cl

165C

82%

165A

DME, r.t., 45 min

N N+

N NNBA

PhPh PhPh

ClCl

Br−

165 165A

99%

Experimental 165

CHPh), 4.64 (s, 6 H, NCH3); 13C-NMR (50 MHz, CDCl

3) δ = 166.6 (NC+N), 140.2 (C-Ar),

133.3 (C-Ar), 130.5 (C-Ar), 130.3 (C-Ar), 130. 2 (C-Ar), 129.8 (C-Ar), 128.1 (C-Ar), 120.0

(C-Ar), 75.2 (CHPh), 33.6 (NCH3). HRMS (ESI) calculated for C

23H

22N

2Cl+: 361.1472,

found: 361.1470.

(4S,5S)-2-(4-Chlorophenyl)-1,3-dimethyl-4,5-diphenylimidazolinium tetrakis(3,5-


From (4S,5S)-2-(4-chlorophenyl)-1,3-dimethyl-4,5-diphenylimidazolinium bromide

(165A) (150 mg, 0.34 mmol) and NaB[C6H

3(CF

3)2]4

(300 mg, 0.34 mmol) in a mixture of

CHCl3

(3 mL) and water (3 mL) as a white solid (48 mg, 71%). mp 114 °C; [α]22D

= −39.4

(c = 0.31, CHCl3); MS (EI), m/z 361 (M+, 20%), 243 (100), 228 (20), 165 (20), 152 (20),

118 (25); IR (KBr) 3426m, 1604s, 1356vs, 1278vs, 1127vs, 839s, 713s, 682s, 669m cm-1;

1H-NMR (400 MHz, CDCl3) δ = 7.80-7.69 (m, 10 H, H-Ar), 7.59-7.46 (m, 12 H, H-Ar),

7.26-7.25 (m, 4 H, H-Ar), 4.98 (s, 2 H, CH), 2.92 (s, 6 H, CH3); 13C-NMR (50 MHz,

CDCl3) δ = 166.4 (NC+N), 162.1 (q, J = 49.6 Hz, BC), 142.3 (C-Ar), 135.2 (BCCH), 133.8

(C-Ar), 131.7 (C-Ar), 131.5 (C-Ar), 130.9 (C-Ar), 129.5 (C-Ar), 129.3 (q, J = 28.4 Hz,

CCF3), 126.9 (C-Ar), 126.3 (C-Ar), 125.0 (q, J = 271 Hz, CCF

3), 118.9 (C-Ar), 117.95 (m,

CHCCF3), 75.5 (NCHPh), 34.2 (NCH

3). Anal. calculated for C

55H

34BClF

24: C, 53.92; H,

2.80; N, 2.29, found: C, 53.72; H, 2.84; N, 2.20; HRMS (ESI) calculated for C23

H22

N2Cl+:

361.1472, found: 361.1483.

(4S,5S)-2-(4-Chlorophenyl)-1,3-dimethyl-4,5-diphenylimidazolinium tetrakis(penta-

fluorophenyl)borate. (165E)

From (4S,5S)-2-(4-chlorophenyl)-1,3-dimethyl-4,5-diphenylimidazolinium bromide

(165A) (100 mg, 0.23 mmol) and KB(C6F

5)4


(4 mL) and water (4 mL) a a white solid (154 mg, 62%). [α]22D

= −45.5 (c = 0.38, CHCl3).

mp 82 °C. MS (EI), m/z 361 (M+, 100%), 277 (15), 227 (15), 152 (40); IR (KBr) 3452m,


N N+

N N+

Br− B(C6F5)4

−

PhPh PhPh

Cl Cl

KB(C6F5)4

165E

62%

165A


N N+

B[C6H4(CF3)2]4−

N N+

Br− NaB[C6H3(CF3)2]4

PhPh PhPh

Cl Cl

165D

71%

165A

166 Experimental

1603m, 1515s, 1464vs, 1279m, 1095s, 980s cm-1; 1H-NMR (200 MHz, CDCl3) δ = 7.75-

7.72 (m, 2 H, H-Ar), 7.55-7.47 (m, 8 H, H-Ar), 7.28-7.26 (m, 4 H, H-Ar), 5.07 (s, 2 H,

CHPh), 2.94 (s, 6 H, NCH3); 13C-NMR (50 MHz, CDCl

3) δ = 166.4 (NC+N), 149.7 (C-F),

147.4 (C-F), 142.0 (C-Ar), 139.8 (C-F), 137.9 (C-F), 135.4 (C-F), 133.9 (C-Ar), 131.6 (C-


34.1 (NCH3); HRMS (ESI) calculated for C

23H

22N

2Cl: 361.1483, found: 361.1472.

1,3-Bis((R)-1-phenylethyl)-2-(pyridin-2-yl)-imidazolinium tetrakis (3,5-bis(trifluo-


From 2-(1,3-Bis((R)-1-phenylethyl)imidazolidin-2-yl)pyridine (204) (179 mg, 0.50

mmol) and NBA (72 mg 95%, 0.50 mmol) in DME (2 mL), followed by counter anion

exchange with NaB(C6H

3(CF

3)2)4

(443 mg, 0.50 mmol) in water (3 mL) and Et2O (5 mL)

mixture. Title compound was obtained as a brown oil (424 mg, 70%). [α]22D

= +53.5 (c = 0.17

CHCl3); MS (ESI, 0 V), m/z 356.1 (M+, 100%); IR (KBr) 3424m, 1356s, 1279vs, 1125vs

cm-1; 1H-NMR (200 MHz, CDCl3) δ = 8.98-8.89 (m, 1 H, H-Ar), 8.10-7.00 (m, 26 H, H-

Ar), 4.77 (q, J = 8.3 Hz, 2 H, PhCHCH3), 4.00-3.50 (m, 4 H, NCH

2CH

2N), 1.58 (d, J = 7.0

Hz, 6 H, CHCH3); 13C-NMR (50 MHz, CDCl

3) δ = 162.5 (NC+N), 161.7 (q, J = 49.5 Hz,

BC), 152.2 (c-Ar), 141.6 (C-Ar), 138.5 (C-Ar), 135.0 (C-Ar), 134.8 (BCCH), 129.6 (C-Ar),

129.5 (C-Ar), 129.0 (q, J = 28.4 Hz, CHCCF3), 127.8 (C-Ar), 126.6 (C-Ar), 124.5 (q, J =

271.2 Hz, CCF3), 124.2 (C-Ar), 117.5 (CHCCF

3), 56.3 (NCHCH

3), 43.0 (NCH

2CH

2N),

16.5 (NCHCH3); HRMS (ESI) calculated for C

24H

26N

3

+: 356.2121, found: 356,2122.

(4S,5S)-2-(2-Chlorophenyl)-4,5-diphenyl-1,3-bis((R)-1-phenylethyl)imidazolinium

bromide (162A)

From (4S,5S)-2-(2-chlorophenyl)-4,5-diphenyl-1,3-bis((R)-1-phenylethyl)imidazolidine

(162) (100 mg, 0.18 mmol) and NBA (26.8 mg 95%, 0.18 mmol) in DME (1 mL) as a white

solid (102 mg, 89%). Hygroscopic. [α]22D

= −131.6 (c = 0.29, CHCl3), 1H-NMR (400 MHz,

CDCl3) δ = 9.41 (d, J = 7.2, 1 H, H-Ar), 7.90 (t, J = 7.2 Hz, H, H-Ar), 7.70 (t, J = 7. Hz, 1

H, H-Ar), 7.55-6.90 (m, 18 H, H-Ar), 6.65-6.58 (m, 2 H, H-Ar), 6.63 (d, J = 10.3 Hz, 1 H,

DME, r.t., 45 min

N N+

N N

Br−

NBA

PhPh PhPh

PhPh PhPh

162A

89%

162

Cl Cl

N N+

N

PhPh

N N

N

PhPh


2. NaB[C6H3(CF3)2]4, Et2O/H2O, r.t., 30 min

204D

70%

204

B[C6H3(CF3)2]4−

Experimental 167

CHPh), 5.34 (q, J = 7.2 Hz, 1 H, CHCH3), 5.08 (d, J = 10.3 Hz, 1 H, CHPh), 4.83 (q, J =



3) δ

= 165.3 (NC+N), 138.03 (C-Ar), 138.0 (C-Ar), 136.0 (C-Ar), 134.7 (C-Ar), 134.2 (C-Ar),



(C-Ar), 128.2 (C-Ar), 127.7 (C-Ar), 123.5 (C-Ar), 73.4 (CHPh), 72.9 (CHPh), 60.7

(NCHCH3), 57.2 (NCHCH

3), 19.8 (CHCH

3), 17.0 (CHCH

3). This compound was used

directly in the subsequent step.

(4S,5S)-2-(2-Chloro-phenyl)-4,5-diphenyl-1,3-bis-((R)-1-phenyl-ethyl)-imidazolinium

hexaflurophosphate (162B)

From (4S,5S)-2-(2-chlorophenyl)-4,5-diphenyl-1,3-bis((R)-1-phenylethyl)imidazolinium

bromide (162A) (88 mg, 0.14 mmol) and KPF6


CHCl3


= −82.7 (c = 2.75,

CHCl3); mp 160 °C; MS (ESI, 0 V), m/z 541.3 (M+, 100%); IR (KBr) 2360m, 2341m,

1533s, 1456m, 840vs, 697s, 558s cm-1; 1H-NMR (400 MHz, CDCl3) δ = 8.49 (dd, J1 = 7.7

Hz, J2 = 1.4 Hz, 1 H, H-Ar), 8.01-7.95 (m, 1 H, H-Ar), 7.78 (td, J1 = 5.6 Hz, J2 = 1.5 Hz, 1

H, H-Ar), 7.64 (d, J = 8.0 Hz, 1 H, H-Ar), 7.40-6.95 (m, 16 H, H-Ar), 6.85-6.80 (m, 2 H,

H-Ar), 6.65 (d, J = 7.4 Hz, 2 H, H-Ar), 5.19 (d, J = 8.4 Hz, 1 H, CHPh), 5.00 (d, J = 8.4

Hz, 1 H, CHPh), 4.98 (q, J = 7.1 Hz, 1 H, CHCH3), 4.88 (q, J = 7.1 Hz, 1 H, CHCH

3), 1.74

(d, J = 7.1 Hz, 3 H, CHCH3), 1.68 (d, J = 7.1 Hz, 3 H, CHCH

3); 13C-NMR (100 MHz,

CDCl3) δ = 164.9 (NC+N), 137.8 (C-Ar), 136.6 (C-Ar), 135.5 (C-Ar), 135.2 (C-Ar), 132.5



127.65 (C-Ar), 123.0 (C-Ar), 72.6 (CHPh), 72.6 (CHPh), 59.8 (NCHCH3), 57.7 (NCHCH

3),

18.4 (CHCH3), 17.6 (CHCH


37H

24N

2Cl+: 541.2421, found:

541.2421.


N N+

PhPh

PF6−

KPF6

N N+

PhPh

Br−

PhPh PhPh

162A 162B

94%

Cl Cl

168 Experimental


tetrakis (3,5-bis(trifluoromethyl)phenyl) borate (162C)

From (4S,5S)-2-(2-chloro-phenyl)-4,5-diphenyl-1,3-bis-((R)-1-phenyl-ethyl)-4,5-imida-

zolinium bromide (162A) (51 mg, 0.08 mmol) and NaB(C6H

3(CF

3)2)4

(73 mg, 0.08 mmol)

in a mixture of CHCl3

(2 mL) and water (2 mL) as a white solid (89 mg, 77%). [α]22D= −53.0

(c = 0.40, CHCl3), mp 122 °C; MS (ESI, 0 V), m/z 541.1 (M+, 100%); IR (KBr) 1550s,

1356s, 1278vs, 1161s, 1127vs cm-1; 1H-NMR (400 MHz, CDCl3) δ = 7.80-7.70 (m, 10 H,

H-Ar), 7.65-7.50 (m, 6 H, H-Ar), 7.30-6.80 (m, 18 H, H-Ar), 6.58 (d, J = 7.4 Hz, 2 H, H-

Ar), 4.99 (d, J = 6.1 Hz, 1 H, NCHPh), 4.85 (d, J = 6.1 Hz, 1 H, NCHPh), 4.85-4.70 (m, 2

H, NCHCH3), 1.71 (d, J = 7.0, 3 H, NCHCH

3), 1.52 (d, J = 7.0, 3 H, CHCH

3); 13C-NMR

(100 MHz, CDCl3) δ = 164.0 (NC+N), 162.1 (q, J = 49.5 Hz, BC), 137.1 (C-Ar), 137.0 (C-



(C-Ar), 129.3 (q, J = 28.4 Hz), 129.3 (C-Ar), 129.2 (C-Ar), 129.0 (C-Ar), 128.2 (C-Ar),

127.7 (C-Ar), 126.6 (C-Ar), 126.1 (C-Ar), 124.9 (q, J = 271.2 Hz), 122.5 (C-Ar), 118.0 (C-

Ar), , 118.9 (C-Ar), 117.9 (C-Ar), 73.0 (CHPh), 71.2 (CHPh), 58.8 (NCHCH3), 58.7

(NCHCH3), 18.4 (CHCH

3), 18.3 (CHCH


37H

34N

2Cl+:

541.2411, found: 541.2401.


tetrakis(pentafluorophenyl)borate. (162E)

From (4S,5S)-2-(2-chloro-phenyl)-4,5-diphenyl-1,3-bis-((R)-1-phenyl-ethyl)-imida-

zolinium bromide (162A) (59 mg, 0.10 mmol) and KB(C6F

5)4

(71 mg, 0.10 mmol) in a mix-

ture of CHCl3


= −35.5 (c =

0.43, CHCl3), mp 109 °C; MS (ESI, 0 V), m/z 541.3 (M+, 100%); IR (KBr) 3424m, 1644m,

1515s, 1464 vs, 1276m, 1087s, 980vs cm-1; 1H-NMR (200 MHz, CDCl3) δ = 7.90-7.50 (m,

4 H, H-Ar), 7.30-6.80 (m, 18 H, H-Ar), 6.61 (d, J = 3.8 Hz, H-Ar), 5.01 (d, J = 3.0 Hz, 1

H, NCHPh), 4.90 (d, J = 3.0 Hz, 1 H, NCHPh), 4.90-4.75 (m, 2 H, NCHCH3), 1.73 (d, J =



3) δ =

CHCl3/H2O, r.t.

N N+

B(C6F5)4−

N N+

Br−

KB(C6F5)4

PhPh PhPh

ClCl

PhPhPhPh

162E

89%

162A


N N+

B[C6H4(CF3)2]4−

N N+

Br−

NaB[C6H4(CF3)2]4

PhPh PhPh

ClCl

PhPhPhPh

162D

77%

162A

Experimental 169

164.1 (NC+N), 137.1 (C-Ar), 137.0 (C-Ar), 136.0 (C-Ar), 135.1 (C-Ar), 134.7 (C-Ar), 133.0



127.8 (C-Ar), 126.7 (C-Ar), 126.2 (C-Ar), 122.5, 72.9 (CHPh), 71.4 (CHPh), 58.9

(NCHCH3), 58.7 (NCHCH

3), 18.3 (CHCH

3), 18.2 (CHCH

3); HRMS (ESI) calculated for

C37

H34

N2Cl+: 541.2411, found: 541.2407.


hexaflurophosphate (163B)

From (4S,5S)-2-(4-chlorophenyl)-4,5-diphenyl-1,3-bis((R)-1-phenylethyl)imidazolidine

(163) (200 mg, 0.37 mmol) and NBA (52 mg 95%, 0.37 mmol) in DME (1 mL), followed

by counter anion exchange with KPF6


(5 mL)

and water (5 mL) gave the title compound as a yellow solid (183 mg, 72%). [α]22D

= +5.7 (c

= 0.39, CHCl3); mp 87 °C; MS (ESI, 0 V), m/z 541.0 (M+, 100%); IR (KBr) 3441s, 1543m,

848vs, 696s, 557s cm-1; 1H-NMR (200 MHz, CDCl3) δ = 7.85 (dd, J1 = 27.8 Hz, J2 = 8.6

Hz, 4 H, H-Ar), 7.40-6.75 (m, 20 H, H-Ar), 4.97 (s, 2 H, NCHPh), 5.00-4.85 (m, 2H,

NCHMe), 1.60 (d, J = 7.2 Hz, 6 H, CHCH3); 13C-NMR (50 MHz, CDCl3) δ = 166.7


Ar), 129.5 (C-Ar), 128.7 (C-Ar), 128.6 (C-Ar), 126.6 (C-Ar), 120.9 (C-Ar), 71.7 (2C,

NCHPh), 58.0 (2C, NCHCH3), 17.9 (2C, CHCH

3); HRMS (ESI) calculated for

C37

H34

N2Cl: 541.2411, found: 541.2418.

(4S,5S)-2-(2-Pyridinyl)-4,5-diphenyl-1,3-bis((R)-1-phenylethyl)imidazolinium bromide

(205A)

From (4S,5S)-2-(pyridinyl)-4,5-diphenyl-1,3-bis((R)-1-phenylethyl)imidazolidine (205)

(1.13 g, 2.23 mmol) and NBA (308 mg 95%, 2.23 mmol) in DME (5 mL) as a yellow oil

(1.26 g, 96%). Hygroscopic. [α]22D

= −85.9 (c = 0.67, CHCl3), 1H-NMR (200 MHz, CDCl

3)

δ = 9.57 (d, J = 7.7 Hz, 1 H, H-Ar), 8.90 (d, J = 3.8 Hz, 1 H, H-Ar), 8.32 (t, J = 7.7 Hz, 1

DME, r.t., 45 min

N N+

N

N N

NBr

−

NBA

PhPh PhPh

PhPh PhPh

205A

96%

205

N N+

PhPh

PF6−

N N

PhPh

PhPh PhPh

Cl Cl

1. NBA, DME, r.t. 1 h

2. KPF6, CHCl3/H2O, r.t., 30 min

163B

72%

163

170 Experimental

H, H-Ar), 7.80-7.70 (m, 1 H, H-Ar), 7.30-6.90 (m, 20 H, H-Ar), 5.20-4.90 (m, 4 H, NCHPh,

PhCHCH3), 1.65 (bs, 6 H, CHCH


3) δ = 164.2 (NCN), 150.3



57.8 (NCHCH3), 18.1 (CHCH


36H

34N

3

+: 508.2753, found:

508.2758.

(4S,5S)-2-(2-Pyridinyl)-4,5-diphenyl-1,3-bis-((R)-1-phenyl-ethyl)-imidazolinium hexa-

flurophosphate (205B)

From (4S,5S)-2-(2-pyridyl)-4,5-diphenyl-1,3-bis((R)-1-phenylethyl)imidazolinium bro-

mide (205A) (105 mg, 0.18 mmol) and KPF6


CHCl3


= −65.4 (c = 0.48,

CHCl3) mp 87 °C. MS (ESI, 0 V), m/z 508 (M+, 100%); IR (KBr) 3423w, 1556s, 1456m,

1278m, 838vs, 757m, 696s, 557s cm-1; 1H-NMR (200 MHz, CDCl3) δ = 9.00 (d, J = 4.2 Hz,

1 H, H-pyridine) 8.58 (d, J = 7.8 Hz, 1 H, H-pyridine), 8.34-8.30 (m, 1H, H-pyridine), 7.79-

7.73 (m, 1 H, H-pyridine), 7.26-6.99 (m, 20 H, H-Ar), 5.00-4.80 (m, 4 H, CHPh, CHCH3),

1.56 (d, J = 6.8 Hz, 6 H, NCH3); 13C-NMR (50 MHz, CDCl

3) δ = 164.1 (CN+C), 151.4 (C-



(CHPh), 57.8 (NCHCH3), 17.9 (CHCH


36H

34N

3

+:

508.2753, found: 508.2752.

(4S,5S)-2-(2-Pyridinyl)-4,5-diphenyl-1,3-bis-((R)-1-phenyl-ethyl)-imidazolinium

bis(trifluoromethylsulfonyl)imide (205C)

From (4S,5S)-2-(2-pyridyl)-4,5-diphenyl-1,3-bis((R)-1-phenylethyl)imidazolinium bro-

mide (205A) (300 mg, 0.51 mmol) and LiNTf2

(176 mg, 0.61 mmol, 1.2 eq.) in a mixture

of DCM (3 mL) and water (3 mL) as a colorless liquid (230 mg, 57%). [α]22D

= −50.0 (c =

0.46, CHCl3); MS (ESI, 0 V), m/z 508.3 (M+, 100%); IR (KBr) 1556m, 1353s, 1196vs,

1135m, 1058s, 696m cm-1; 1H-NMR (200 MHz, CDCl3) δ = 8.95-8.87 (m, 1 H, H-pyridine)


N N+

N

PhPh

LiNTf2N N

+

N

PhPh

Br−

PhPh PhPh

205C

57%

205A

NTf2−


N N+

N

PhPh

PF6−

KPF6

N N+

N

PhPh

Br−

PhPh PhPh

205B

86%

205A

8.50 (d, J = 6.8 Hz, 1 H, H-pyridine), 8.27 (td, J1 = 7.7 Hz, J2 = 1.7 Hz, 1 H, H-pyridine),

7.75-7.60 (m, 1 H, H-pyridine), 7.25-6.70 (m, 20 H, H-Ar), 4.90-4.70 (m, 4 H, CHPh,

CHCH3), 1.50 (d, J = 7.0 Hz, 6 H, NCH


3) δ = 163.1 (NC+N),



Ar), 125.4 (C-Ar), 119.0 (q, J = 64.9 Hz, CF3), 70.5 (CHPh), 56.8 (NCHCH

3), 12.0

(CHCH3); HRMS (ESI) calculated for C

36H

34N

3

+: 508.2753, found: 508.2767.

Preparation of dications

2,2'-(1,2-Phenylene)bis(1,3-dimethyl-imidazolinium) bis hexaflurophosphate (208B)

(1,3-Dimethyl-2-(2-(1,3-dimethylimidazolidin-2-yl)phenyl)imidazolidine (208) (300

mg, 1.09 mmol) was disolved in a minimal amount of DME (1 mL) and NBA (158 mg 95%,

1.09 mmol) was added. An exothermic reaction occured. After cooling down, the reaction

mixture was stirred for 15 min at r.t. and a second portion of NBA (158 mg 95%, 1.09 mmol)

was added. The mixture was stirred for 3 h during which a solid precipitated. The solvent

was removed by inverse filtration and the solid was washed with Et2O. Natrium thiosulfate

was added to decolorize the mixture from bromine. KPF6

(403 mg, 2.19 mmol) was added

and mixture was vigorously stirred overnight. The formed white precipitate was filtered off,

washed with CHCl3

(5 mL), water (5 mL) and dried in vacuo, giving the title compound as

a white solid (266 mg, 41%); mp 278 °C; MS (ESI, 0 V), m/z 136.1 (M2+, 100%); IR (KBr)

3441m, 2952m, 1621vs, 1423m, 1377s, 1313vs, 1220s, 935s, 827vs, 767s, 558vs cm-1; 1H-

NMR (200 MHz, DMSO-d6) δ = 8.20-7.90 (m, 4 H, H-Ar), 4.30 (m, 8 H, CH2), 2.89 (s, 12

H, CH3); 13C-NMR (50 MHz, DMSO-d6) δ = 161.7 (C+), 134.0 (C-Ar), 131.3 (C-Ar), 121.0

(C-Ar), 50.5 (NCH2CH

2N), 34.7 (NCH


16H

24N

4

2+:

136.1000, found 136.1000.

N N+

N+

N

PF6−

N N

N

N

1. NBA (2 eq.), DME, r.t., 2 h

2. KPF6 (2 eq.), CHCl3/H2O, r.t., 45 min

PF6−

208B

41%

208

Experimental 171

172 Experimental

2,2'-(1,2-Phenylene)bis(1,3-dimethyl-imidazolinium) bis tetrakis(3,5-bis(trifluo-


From 2,2'-(1,2-phenylene)bis(1,3-dimethyl-imidazolinium) bis hexaflurophosphate

(208B) (100 mg, 0.17 mmol) and NaB[C6H

3(CF

3)2]4

(299 mg, 0.34 mmol, 2 eq.) in a mix-

ture of DCM (5 mL) and water (5 mL) as a white solid (270 mg, 80%); mp 155 °C; MS

(ESI, 0 V), m/z 136.1 (M2+, 100%); IR (KBr) 3425w, 1612m, 1357vs, 1278vs, 1121vs,

888m, 839m, 713m, 682m cm-1; 1H-NMR (200 Hz, DMSO-d6) δ = 8.20-8.10 (m, 2 H, H-

Ar), 8.00-7.90 (m, 2 H, H-Ar), 7.68 (bs, 24 H, H-Ar), 4.25-4.00 (m, 8 H, NCH2CH

2N), 2.93

(s, 12 H, NCH3); 13C-NMR (50 MHz, DMSO-d6) δ = 162.1 (q, J = 49.5 Hz, BC), 161.7

(NC+N), 134.0 (C-Ar), 131.3 (C-Ar), 128.4 (q, J = 28.4 Hz, CCF3), 124.9 (q, J = 271.2 Hz,

CCF3), 120.9 (C-Ar), 117.5 (m, CHCCF

3), 50.5 (NCH

2CH

2N), 34.7 NCH

3). HRMS (ESI)

calculated for C16

H24

N4

2+: 136.1000, found 136.1001.


yl)phenyl)-4,5-diphenylimidazolinium bis bis(trifluoromethylsulfonyl)imide (209C)


yl)phenyl)-4,5-diphenylimidazolidine (209) (500 mg, 0.86 mmol) was dissolved in DME (3

mL) and NBA (128 mg 95%, 0.86 mmol) was added. After 15 minutes stirring, second por-

tion of NBA (128 mg 95%, 0.86 mmol) was added. The reaction mixture was stirred at r.t.

for 16 h. Et2O (5 mL) was added in order to precipitate the formed bromide salt. The pre-

cipitate was washed with Et2O (2 x 5mL) and dried in vacuo for 30 min. The bromide salt

was dissolved in CHCl3

(3 mL) and solution of LiNTf2

(574 mg, 2.00 mmol, 2.3 eq.) in H2O

(2 mL) was added. The reaction mixture was stirred vigorously for 30 min during which a

white precipitate formed. This was filtered off (frite S4), washed with CHCl3(3 mL), water

(3 mL) and dried in vacuo to give the title compound as a white solid (622 mg, 80%). [α]22D

= −21 (c = 0.20, Acetone). mp 165 °C. MS (ESI, 0 V), m/z 288 (M2+, 100%), 856 (M+ +

anion, 20); IR (KBr) 3425m, 1602s, 1350vs, 1197vs, 1058s, 616s cm-1; 1H-NMR (400

MHz, DMSO-d6) δ = 8.40-8.20 (m, 4 H, H-Ar), 7.80-7.30 (m, 20 H, H-Ar), 5.82 (d, J =

N N+

PhPh

N+

N

Ph

Ph

NTf2−

N N

PhPh

N

N

Ph

Ph1. NBA (2 eq.), DME, r.t., 16 h

2. LiNTf2 (2 eq.), CHCl3/H2O, r.t., 45 min

209C

80%

209

NTf2−

N N+

N+

N

NaB[C6H4(CF3)2]4 (2 eq.)


208D

80%

B[C6H4(CF3)2]4−

N N+

N+

N

PF6−

PF6− B[C6H4(CF3)2]4

−

208B

14.0 Hz, 2 H, CHPh), 5.39 (d, J = 14.0 Hz, 2 H, CHPh), 3.00-2.80 (m, 12 H, NCH3); 13C-

NMR (100 MHz, DMSO-d6) δ = 164.9 (NC+N), 135.5 (C-Ar), 134.6 (C-Ar), 132.0 (C-Ar),


129.85 (C-Ar), 121.9 (C-Ar), 120.4 (q, J = 314.3 Hz, CF3), 76.4 (CHPh), 72.0 (CHPh), 35.4

(NCH3), 34.9 (NCH


40H

40N

4

2+: 288.1626, found: 288.1621.

(4S,5S)-1,3-dimethyl-2-(2-((4S,5S)-1,3-dimethyl-4,5-diphenylimidazolidin-2-

yl)phenyl)-4,5-diphenylimidazolinium bis tetrakis(3,5-bis(trifluoromethyl)phenyl)

borate (209D)

From (4S,5S)-1,3-dimethyl-2-(2-((4S,5S)-1,3-dimethyl-4,5-diphenylimidazolidin-2-

yl)phenyl)-4,5-diphenylimidazolidine (209) (250 mg, 0.43 mmol) and NBA (124 mg 95%,

0.86 mmol) in DME (2 mL) (reaction time 16 h), followed by counter anion exchange with

NaB[Ph(CF3)2]4

(766 mg, 0.86 mmol) in a mixture of DCM (5 mL) and and water (3 mL).

The title compound was obtained as a light brown solid (792 mg, 80%). [α]22D

= −25 (c =

0.45, Acetone); mp 66-68 °C; MS (ESI, 0 V), m/z 288.2 (M2+, 100%); IR (KBr) 1605m,

1356s, 1279vs, 1126s, 682m cm-1; 1H-NMR (400 MHz, DMSO-d6) δ = 8.30-8.20 (m, 4 H,

H-Ar), 7.60-7.40 (m, 44 H, H-Ar), 5.91 (d, J = 14.0 Hz, 2 H, CHPh), 5.47 (d, J = 14.0 Hz,

2 H, CHPh), 2.99 (d, J = 5.1 Hz, 12 H, NCH3); 13C-NMR (100 MHz, DMSO-d6) δ = 164.5

(NC+N), 161.5 (q, J = 49.6 Hz, BC), 135.1 (C-Ar), 134.2 (m, BCCH), 134.4 (C-Ar), 133.6


Ar), 129.4 (C-Ar), 128.9 (q, J = 50 Hz, CHCCF3), 124.4 (q, J = 271.2 Hz, CCF

3), 121.6 (C-

Ar), 118.0 (CHCCF3), 79.6 (NCHPh), 71.6 (NCHPh), 35.0 (NCH

3), 34.5 (NCH

3). HRMS

(ESI) calculated for C20

H20

N2

2+ 288.1626, found 288.1616.

(4R,5R)-1,3-Dimethyl-2-(2-((4R,5R)-1,3-dimethyl-4,5-diphenylimidazolidin-2-

yl)phenyl)-4,5-diphenylimidazolinium bis hexaflurophosphate (210B)

1,2-Bis((3aR,7aR)-1,3-dimethyl-octahydro-1H-benzo[d]imidazol-2-yl)benzene (210)

(140 mg, 0.37 mmol) was disolved in a minimal amount of DME (1.5 mL) and NBA (53

N N+

N+

N

PF6−

N N

N

N

1. NBA (2 eq.), DME, r.t., 4 h

2. KPF6 (2 eq.), CHCl3/H2O, r.t., 16 h

PF6−

210B

75%

210

N N+

PhPh

N+

N

Ph

Ph

B(C6H3(CF3)2)4−

N N

PhPh

N

N

Ph

Ph

1. NBA (2 eq.), DME, r.t., 16 h

2. NaB(C6H3(CF3)2)4, 2 eq.


B(C6H3(CF3)2)4−

209D

80%

209

Experimental 173

174 Experimental

mg 95%, 0.37 mmol) was added. After 15 min strirring at r.t. a second portion of NBA (53

mg 95%, 0.37 mmol) was added. The reaction mixture was stirred for 3 h during which a

brown precipitate formed. The solvent was decanted and the precipitate washed was with

Et2O and dissolved in CHCl

3(2 mL). A solution of KPF

6(135 mg, 0.73 mmol) in water (3

mL) was added and the mixture was vigorously stirred for 16 h during which a brown pre-

cipitate formed. The solvents were carefully removed and the rest was dried in vacuo giv-

ing the title compound as a brown solid (184 mg, 75%); [α]22D

= −7.7 (c = 0.3, Acetone); mp

145-150 °C; MS (ESI, 50 V), m/z 190.1 (M2+, 100%); IR (KBr) 2360m, 1589m, 839vs, 558s

cm-1; 1H-NMR (400 MHz, DMSO-d6) δ = 8.20-8.10 (m, 2 H, H-Ar), 8.10-7.95 (m, 2 H, H-

Ar), 3.65-3.50 (m, 4 H, NCHCH2), 3.05 (s, 6 H, NCH

3), 2.85 (s, 6 H, NCH

3), 2.40-2.25 (m,

4 H, CH2CH

2CH

2CH

2), 2.00-1.85 (m, 4 H, CH

2CH

2CH

2CH

2), 1.60-1.25 (m, 8 H,

CH2CH

2CH

2CH

2); 13C-NMR (100 MHz, DMSO-d6) δ = 165.3 (NC+N), 134.5 (C-Ar),

131.8 (C-Ar), 121.8 (C-Ar), 69.2 (NCHCH2), 67.6 (NCHCH

2), 33.7 (NCH

3), 32.8 (NCH

3),

27.4 (CH2CH

2CH

2CH

2), 27.3 (CH

2CH

2CH

2CH

2), 23.9 (CH

2CH

2CH

2CH

2), 23.7

(CH2CH

2CH

2CH


24H

36N

4

2+ 190.1471, found: 190.1470.

(4R,5R)-1,3-Dimethyl-2-(2-((4R,5R)-1,3-dimethyl-4,5-diphenylimidazolidin-2-

yl)phenyl)-4,5-diphen ylimidazolinium bis tetrakis(3,5-bis(trifluoromethyl)phenyl)

borate (210D)

From 1,2-bis((3aR,7aR)-1,3-dimethyl-octahydro-1H-benzo[d]imidazol-2-yl)benzene

(210) (145 mg, 0.38 mmol) and NBA (110 mg 95%, 0.76 mmol) in DME (3 mL), (reaction

time 3 h), followed by counter anion exchange with NaB[Ph(CF3)2]4

(673 mg, 0.76 mmol)

in the mixture of DCM (3 mL) and water (3 mL). The title compound was obtained as a

brown solid which turned into a brown oil (677 mg, 87%); [α]22D

= −5.9 (c = 0.7, Acetone);

mp 115 °C; MS (ESI, 20 V), m/z 190.1 (M2+, 100%); IR (KBr) 1612w, 1357s, 1280vs,

1125vs, 713m cm-1; 1H-NMR (400 MHz, DMSO-d6) δ = 8.10-7.95 (m, 4 H, H-Ar), 7.70-

7.50 (m, 24 H, H-Ar), 3.60-3.50 (m, 4 H, NCHCH2), 3.01 (s, 6 H, NCH

3), 2.83 (s, 6 H,

CH3), 2.40-2.20 (m, 4 H, CH

2), 1.90-1.80 (m, 4 H, CH

2), 1.60-1.40 (m, 4 H, CH

2), 1.40-

1.20 (m, 4 H, CH2), 13C-NMR (50 MHz, DMSO-d6) δ = 164.9 (NC+N), 160.0 (q, J = 49.6

Hz, BC), 134.0 (C-Ar), 131.3 (C-Ar), 128.4 (q, J = 62.4 Hz, CCF3), 123.9 (q, J = 271 Hz,

CCF3), 121.2 (C-Ar), 117.3 (C-Ar), 68.7 (NCHCH

2), 67.1 (NCHCH

2), 33.1 (CH

3), 32.2

(CH3), 26.7 (CH

2), 23.2 (CH

2), 23.0 (CH


24H

36N

4

2+

190.1470, found: 190.1469.

N N+

N+

N

B[C6H3(CF3)2]4−

N N

N

N

1. NBA (2 eq.), DME, r.t., 3 h

2. NaB[C6H3(CF3)2]4 (2 eq.), DCM/H2O, r.t., 45 min

B[C6H3(CF3)2]4−

210 210D

87%

Experimental 175

3.4. Preparation of the Carbene Precursors

General procedure for preparation of imidazolium tetrafluroborate salts

A diamine (1.00 mmol) was placed to a flask, the counter anion source (typically

NH4BF

4) (1.00 mmol) and triethylorthoformate (148 mg, 165 μL, 1.00 mmol) or triethy-

lorthoacetate (127 μL 97%, 0.66 mmol) were added. Reaction vessel was flushed with nitro-

gen, seaeled and the mixture was heated up to 120 °C for 2 h. After cooling down, the mix-

ture was dried in vacuo, in order to remove the EtOH, formed during the reaction, giving

the crude salt in high purity. Optionally the product was crystallized from absolute ethanol.

General procedure for counter anion exchange with lithium bis(trifluoromethylsul-

fonyl)imide

Imidazolinium tetrafluroborate (1.00 mmol) was dissolved in DCM (3 mL) and vigorous-

ly stirred with a solution of LiNTf2

(1.00 mmol) in water (3 mL) for 3 h. The organic phase

was separated, washed with water (3 x 3 mL) and dried with molecular sieves 3Å. The sol-

vent was evaporated and the product was further dried dried in vacuo to give the correspon-

ding imidazolinium bis(trifluromethansulfonyl)-imide.

General procedure for counter anion exchange with sodium tetrakis(3,5-bis(trifluo-


Imidazolinium tetrafluroborate (1.00 mmol) was dissolved in CHCl3

(3 mL) and

NaB[Ph(CF3)2]4

(1.00 mmol, 1 eq.) and water (3 mL) were added sequentially. The reaction

mixture was then vigorously stirred for 3 h. Organic phase was separated (in case that sep-

aration did not occur, centrifugation was used to improve separation), washed with water (3

x 3 mL) and dried with molecular sieves 3Å. The solvent was evaporated and the product

was further dried in vacuo to give the corresponding imidazolinium tetrakis(3,5-bis(trifluo-


(4S,5S)-4,5-Diphenyl-1,3-bis-((R)-1-phenyl-ethyl)-4,5-imidazolinium tetrafluoro

borate (220F)


3.00 mmol), NH4BF

4(324 mg 97%, 3.00 mmol), CH(OEt)

3(494 μL, 3.00 mmol) accord-

ing to the general procedure. The crude product was crystallized from abs. EtOH and

washed with hot hexane, giving the title compound as a white solid (1.03 g, 66%). [α]22D

= −172.5 (c = 0.48, CHCl

3); mp 157 °C; MS (ESI, 0 V), m/z 431 (cation); IR (KBr) 3423s,

1632vs, 1269s, 1086vs, 1056vs, 709s cm-1; 1H-NMR (200 MHz, CDCl3) δ = 9.18 (s, 1 H,

NCHN), 7.39-7.18 (m, 16 H, H-Ar), 6.97-6.93 (m, 4 H, H-Ar), 4.44-4.37 (m, 4 H, CHPh,

CHCH3), 2.01 (d, J = 6.9 Hz, 6 H, CHCH


3) δ = 153.0

(NCHN), 137.3 (C-Ar), 135.4 (C-Ar), 130.0 (C-Ar), 129.8 (C-Ar), 129.4 (C-Ar), (129.1 (C-

Ar), 126.9 (C-Ar), 126.86 (C-Ar), 72.6 (CPh), 57.9 (CHCH3), 20.1 (CHCH

3). HRMS (ESI)

(EtO)3CH, NH4BF4

BF4−120 °C, 3 h

220F

66%

N N+

PhPh

PhPh

94

NH HN

PhPh

PhPh

176 Experimental

calculated for C31

H31

N2

+: 431.2487, found: 431.2485.This compound was reported in liter-

ature229 however, no spectral data were provided.

(4S,5S)-4,5-Diphenyl-1,3-bis-((R)-1-phenyl-ethyl)-imidazolinium bis(trifluoromethyl-

sulfonyl)imide (220C)

From (4S,5S)-4,5-diphenyl-1,3-bis-((R)-1-phenyl-ethyl)-4,5-imidazolinium tetrafluoro

borate (220F) (900 mg, 1.74 mmol) and LiNTf2

(548 mg, 1.90 mmol, 1.1 eq.) in a mixture

of CHCl3

(5 mL) and water (5 mL) as a white crystalline solid (904 mg, 73%). [α]22D

= −150.3

(c = 0.6, CHCl3); mp 63 °C; MS (ESI, 0 V), m/z 431 (M+); IR (KBr) 1633s, 1351s, 1196vs,

1135s, 1058s, 706s cm-1; (200 MHz, CDCl3) δ = 8.88 (s, 1 H, NCHN), 7.48-7.30 (m, 12 H,

H-Ar), 7.23-7.10 (m, 4 H, H-Ar), 7.00-6.90 (m, 4 H, H-Ar), 4.50-4.30 (m, 4 H, CHPh,

CHCH3), 1.94 (d, J = 6.9 Hz, 6 H, CHCH


3) δ = 152.1

(NCHN), 137.0 (C-Ar), 135.0 (C-Ar), 130.2 (C-Ar), 129.9 (C-Ar), 129.5 (C-Ar), 129.3 (C-

Ar), 127.0 (C-Ar), 126.7 (C-Ar), 72.7 (CPh), 57.8 (CHCH3), 20.2 (CHCH

3). Anal. calculat-

ed for C33

H31

F6N

3O

4S

2: C, 55.69; H, 4.39; N, 5.90; found: C, 55.47; H, 4.28; N, 5.65;


H31

N2

+: 431.2487, found: 431.2487

(4R,5R)-1,2,3-Trimethyl-4,5-diphenyl-4,5-imidazolinium tetrafluoro borate (223F)

From (1R,2R)-N,N'-Dimethyl-1,2-diphenyl-ethane-1,2-diamine (96) (158 mg, 0.66

mmol), NH4BF

4(71 mg 97%, 0.66 mmol) and triethylorthoacetate (127 μL 97%, 0.66

mmol). The reaction mixture was heated to 120 °C in a sealed vessel for 12 h. Workup pro-

cedure gave the title compound as a yellow solid (230 mg, 99%). [α]22D

= −173.5 (c = 0.46,

Acetone); mp 135 °C; MS (ESI, 0 V), m/z 265 (cation); IR (KBr) 3423s, 1611s, 1057vs,

769s, 705s cm-1; 1H-NMR (200 MHz, CDCl3) δ = 7.45-7.10 (m, 10 H, H-Ar), 4.86 (s, 2 H,

CHPh), 3.00 (s, 6 H, NCH3), 2.55 (s, 3 H, CCH


3) δ = 167.9

(NC+N), 134.3 (C-Ar), 129.8 (C-Ar), 129.6 (C-Ar), 128.0 (C-Ar), 74.8 (CHPh), 32.3

(NCH3), 11.9 (CCH


18H

21N

2

+: 265.1713, found: 265.1405.

(EtO)3CCH3, NH4BF4

BF4−

120 °C, 12 h

223F

99%

96

N N+

PhPh

NH HN

PhPh

BF4−

NTf2−CHCl3/H2O, r.t.

LiNTf2

220F 220C

73%

N N+

PhPh

PhPh

N N+

PhPh

PhPh

Experimental 177

N,N´-Dinorbornylimidazolinium tetrafluoroborate (224F)

From N,N´-dinorbornyletylendiamine (218) (1.00 g, 3.02 mmol), NH4BF

4(317 mg, 3.02

mmol) and triethylortoformate (498 μL, 3.02 mmol) according to the general procedure.

Crystallization from abs. EtOH gave the title compound as a white solid (859 mg, 66%).

Spectral date were consistent with literature values.112

N,N´-Dinorbornylimidazolinium bis(trifluoromethylsulfonyl)imide (224C)

From N,N´-dinorbornylimidazolinium tetrafluoroborate (224F) (500 mg, 1.16 mmol) and

LiNTf2


(5 mL) and water (5 mL) as a

white solid (602 mg, 83%). [α]22D

= −71.6 (c = 0.5, CHCl3); mp 143 °C; MS (ESI, 0 V), m/z

343.4 (M+, 100%); IR (KCl) 2962s, 1637s, 1354s, 1191vs, 1136s, 1056s, 616m cm-1; 1H-

NMR (200 MHz, CDCl3) δ = 7.93 (s, 1 H, NCHN), 4.12-3.86 (m, 4 H, NCH

2CH

2N), 3.67-

3.60 (m, 2 H, NCH), 2.10-1.50 (m, 10 H, CH2CH

2CH), 1.27-1.18 (m, 4 H, CHCH

2CH),

0.98-0.85 (m, 18 H, CH3); 13C-NMR (50 MHz, CDCl

3) δ = 157.0 (NCHN), 66.5 (NCH),

49.4 (NCH2CH

2N), 48.6, 46.1, 43.5, 35.8 (CH

2CH

2), 33.1 (CH

2CH

2), 25.3 (CHCH

2CH),

19.6 (C(CH3)2), 19.0 (C(CH

3)2), 12.0 (CHCH

3); Anal. Calcd for C

25H

39F

6N

3O

4S

2: C,

48.14; H, 6.30; N, 6.74 found: C, 48.19; H, 6.21; N, 6.81.; HRMS (ESI) Calcd. for

C23

H39

N2

+: 343.3113, found: 343.3124.

1,3-Dibenzyl-4,5-imidazolinium chloride (225G)

From N,N’-dibenzylethane-1,2-diamine (166) (988 mg, 4.11 mmol), triethylorhoformate

(684 μL, 4.11 mmol) and ammonium chloride (220 mg, 4.11 mmol) according to the gen-

eral procedure. The reaction mixture was heated to 120 °C for 16 h to give the title com-

pound as a yellow solid (1.17 g, 99%). mp 88 °C. MS (ESI, 0 V), m/z 251.1 (cation); IR

(KBr) 3422s, 2923m, 1647vs, 1455m, 1302m, 1205m, 705s cm-1; 1H-NMR (200 MHz,

CDCl3) δ = 10.60 (s, 1 H, NCHN), 7.50-7.20 (m, 10 H, H-Ar), 4.87 (s, 4 H, NCH

2Ph), 3.70

(s, 4 H, NCH2CH


3) δ = 159.0 (NC+N), 132.5 (C-Ar), 129.2

(C-Ar), 129.0 (C-Ar), 128.8 (C-Ar), 52.3 (NCH2Ph), 47.5 (NCH

2CH

2N); HRMS (ESI) cal-

culated for C17

H19

N2

+: 251.1548, found: 251.1551.

120 °C, 16 hN N

+

PhPh

NH HN

PhPh

CH(OEt)3, NH4Cl

Cl−

225G

99%

166

BF4−

NTf2−CHCl3/H2O, r.t.

LiNTf2

224F

N N+

224F

83%

N N+

BF4−

(EtO)3CH, NH4BF4

120 °C, 3 h

224F

66%

N N+

218

NH HN

178 Experimental

1,3-Dibenzyl-4,5-imidazolinium camphorsulfonate (225H)

From N,N’-dibenzylethane-1,2-diamine (166) (1.29 g, 5.35 mmol), triethylorhoformate

(891 μL, 5.35 mmol) and ammonium camphosulfonate (1.33 g, 5.35 mmol) according to the

general procedure as a yellow oil (2.56 g, 99%). [α]22D

= −33.4 (c = 0.67, CHCl3); MS (ESI,

0 V), m/z 251.1 (cation); IR (KBr) 3516s, 3454s, 2957s, 1740s, 1651vs, 1173s, 1037s, 705s

cm-1; 1H-NMR (200 MHz, CDCl3) δ = 9.64 (s, 1H, NCHN), 7.45-7.10 (m, 10 H, H-Ar),

4.82 (s, 4 H, NCH2Ph), 3.74 (s, 4 H, NCH

2CH

2N), 3.10 (dd, J1 = 99.6 Hz, J2 = 14.6 Hz, 2

H, CH2SO

3), 2.40-2.20 (m, 1 H, CHC(CH

3)2), 2.10-1.70 (m, 4 H, CH

2CH

2), 1.55-1.25 (m,

2 H, CHCH2CO), 1.11 (s, 3 H, C(CH

3)2), 0.83 (s, 3 H, C(CH

3)2); 13C-NMR (50 MHz,

CDCl3) δ = 217.1 (CCOCH

2), 159.3 (NCHN), 133.0 (C-Ar), 129.1 (C-Ar), 128.9 (C-

Ar),128.8 (C-Ar), 58.6 (COCC(CH3)2, 52.2 (NCH

2CH

2N), 47.9 (C(CH

3)2), 47.6

(NCH2Ph), 47.4 (CH

2SO

3), 43.0 (CHC(CH

3)2, 42.6 (COCH

2CH), 27.1 (CH

2CH

2), 24.5

(CH2CH

2), 20.0 (C(CH

3)2), 19.8 (C(CH

3)2). HRMS (ESI) calculated for C

17H

19N

2

+:

251.1548, found: 251.1551.

(S)-2-((R)-1-Phenylethyl)-5,6,7,7a-tetrahydro-1H-pyrrolo[1,2-e]imidazol-2-ium bis(tri-

fluoromethylsulfonyl)imide (227C)

From (R)-1-phenyl-N-((S)-pyrrolidin-2-ylmethyl)ethanamine (147) (420 mg, 2.01

mmol), NH4BF

4(222 mg 97%, 2.01 mmol) and triethylorthoformate (342 μL, 2.01 mmol),

followed by counter anion exchange with LiNTf2

(597 mg, 2.01 mmol) in the mixture of

CHCl3

(3 mL) and water (3 mL). The crude product was purrified by FCC (DCM/EtOH,

95/5), giving the title compound as a colorless liquid (138 mg, 60%). [α]22D

= −161.9 (c =

0.27, CHCl3); MS (ESI, 0 V), m/z 215.1 (M+); IR (neat) 1624m, 1351m, 1188s, 1135s,

1055s cm-1; 1H-NMR (200 MHz, CDCl3) δ = 8.20 (s, 1 H, NCHN), 7.50-7.20 (m, 5 H, H-

Ar), 4.87 (q, J = 7.0 Hz, 1 H, CHCH3), 4.42-4.22 (m, 1 H, CH

2CHCH

2), 4.07-3.41 (m, 4 H,

CH2), 2.40-1.50 (m, 4 H, CH

2), 1.74 (d, J = 3.7 Hz, 3 H, CHCH

3); 13C-NMR (50 MHz,

CDCl3) δ = 157.0 (NCH+N), 136.9 (C-Ar), 129.5 (C-Ar), 129.3 (C-Ar), 126.7 (C-Ar), 119.8

(q, J = 318.9 Hz, CF3), 63.4 (CHCH

3), 58.7 (NCHCH

2), 50.9 (NCH

2CH

2), 45.4 (NCH

2CH),

30.2 (CH2CH

2CH

2), 24.4 (CHCH

2CH

2), 18.9 (CCH

3). HRMS (ESI) calculated for

C14

H19

N2

+: 215.1543, found: 215.1543.

1. (EtO)3CCH3, NH4BF4, 120 °C, 12 h

2. LiNTf2, CHCl3/H2O, 30 min

227C

60%

HNNH

Ph147

N N+

PhNTf2

−

120 °C, 3 h

N N+

PhPhNH HN

PhPh

CH(OEt)3, ammonium camphorsulfonate

O

SO3−

225H

99%

166

Experimental 179

1,3-Bis-((1R,2S)-2-hydroxy-1-methyl-2-phenyl-ethyl)-4,5-imidazolinium tetrafluoro

borate (231F)

From (1R,2S)-2-[2-((1S,2R)-2-Hydroxy-1-methyl-2-phenyl-ethylamino)-ethylamino]-1-

phenyl-propan-1-ol (104) (657 mg, 2.00 mmol), NH4BF

4(216 mg 97%, 2.00 mmol),

CH(OEt)3

(326 μL, 2.00 mmol) according to the general procedure. The reaction mixture

was heated to 120 °C in a sealed vessel for 8 h giving the title compound as a yellow solid

(743 mg, 87%). [α]22D

= +17.9 (c = 1.2, MeOH); mp 162 °C. MS (ESI, 0 V), m/z 339 (M+,

100%); IR (KBr) 3273s, 1652vs, 1265s, 1139s, 1070vs, 1015s, 988s, 704s cm-1; 1H-NMR

(200 MHz, DMSO-d6) δ = 8.32 (s, 1 H, NCHN), 7.50-7.20 (m, 10 H, H-Ar), 5.95 (bs, 2 H,

CHOH), 4.81 (d, J = 4.0 Hz, 2 H, CHOH), 4.00-3.70 (m, 6 H, NCH2CH

2N, CHCH

3), 1.08

(d, J = 6.9 Hz, CHCH3); 13C-NMR (50 MHz, DMSO-d6) δ = 156.2 (NCHN), 141.4 (C-Ar),

128.1 (C-Ar), 127.4 (C-Ar), 126.1 (C-Ar), 72.7 (CHOH), 58.6 (CHCH3), 47.0

(NCH2CH

2N), 12.1 (CHCH


21H

27N

2O

2

+: 339.2073, found:

339.2074.

1,3-Bis-((1S,2R)-2-hydroxy-1-methyl-2-phenyl-ethyl)-4,5-imidazolinium tetrafluoro

borate (ent-231F) was prepared in the same manner from (1S,2R)-2-[2-((1R,2S)-2-Hydroxy-

1-methyl-2-phenyl-ethylamino)-ethylamino]-1-phenyl-propan-1-ol (ent-104).

1,3-Bis-((1R,2S)-2-hydroxy-1-methyl-2-phenyl-ethyl)-imidazolinium bis(trifluo-


From 1,3-Bis-((1R,2S)-2-hydroxy-1-methyl-2-phenyl-ethyl)-4,5-imidazolinium tetraflu-

oroborate (231F) (300 mg, 0.70 mmol) and LiNTf2

(208 mg 97%, 0.70 mmol) in a mixture

of DCM (5 mL) and water (5 mL) as a yellow oil (404 mg, 93%). MS (ESI, 0 V), m/z 339.2

(M+, 100%); [α]22D

= +20.8 (c = 0.9, MeOH); IR (neat) 3523s, 1642vs, 1352vs, 1197vs,

1137vs, 1057vs, 706s, 617s, 442vs cm-1; 1H-NMR (200 MHz, CDCl3) δ = 7.78 (s, 1 H,

NCHN), 7.37-7.20 (m, 10 H, H-Ar), 4.96 (d, J = 3.2 Hz, 2 H, CHOH), 4.00-3.70 (m, 4 H,

CH2), 3.16 (bs, 2 H, OH), 1.17 (d, J = 7.0 Hz, 6 H, CH


3) δ =

155.6 (NCHN), 139.2 (C-Ar), 128.7 (C-Ar), 128.3 (C-Ar), 125.9 (C-Ar), 73.6 (CHOH),

59.5 (NCHCH3), 47.6 (CH

2), 12.2 (CH


21H

27N

2O

2

+:

339.2073, found: 339.2073.

NTf2−BF4

− DCM/H2O, r.t., 30 min

LiNTf2

231C

93%

231F

N N+

HO

Ph

OH

Ph

N N+

HO

Ph

OH

Ph

(EtO)3CH, NH4BF4

120 °C, 8 h

104 231F

87%

BF4−

N N+

HO

Ph

OH

Ph

NH HN

HO

Ph

OH

Ph

180 Experimental

1,3-Bis-((1S,2R)-2-hydroxy-1-methyl-2-phenyl-ethyl)-4,5-imidazolinium bis(trifluo-

romethylsulfonyl)imide (ent-231C) was prepared in the same manner from 1,3-bis-

((1S,2R)-2-hydroxy-1-methyl-2-phenyl-ethyl)-4,5-imidazolinium tetrafluoro borate (ent-231F).

1,3-bis((1R,2S)-1-hydroxy-1-phenylpropan-2-yl)-imidazolinium tetrakis(3,5-


From 1,3-bis((1R,2S)-1-hydroxy-1-phenylpropan-2-yl)-imidazolinium tetrafluoroborate

(231F) (200 mg, 0.47 mmol) and NaB[C6H

3(CF

3)2]4

(416 mg, 0.47 mmol) in a mixture of

DCM (5 mL) and water (5 mL) as a brown oil (477 mg, 84%). MS (ESI, 0 V), m/z 339.2

(M+, 100%); [α]22D

= −53.2 (c = 0.5, CHCl3); IR (KBr) 1641m, 1356s, 1279vs, 1124vs, 682m

cm-1; 1H-NMR (400 MHz, acetone-d6) δ = 8.33 (s, 1 H, NCHN), 7.08 (bs, 8 H, C-Ar), 7.69

(bs, 4 H, C-Ar), 7.50-7.30 (m, 10 H, H-Ar), 5.20-5.05 (m, 2 H, CHOH), 4.25-4.05 (m, 6 H,

NCH2CH

2N), 2.88 (bs, 2 H, CHOH), 1.29 (d, J = 8.1 Hz, 6 H, CH

3); 13C-NMR (100 MHz,

acetone-d6) δ = 161.7 (q, J = 49.5 Hz, BC), 156.4 (NCHN), 140.9 (C-Ar), 134.6 (C-Ar),

129.3 (q, J = 28.4 Hz, CHCCF3), 128.4 (C-Ar), 127.9 (C-Ar), 126.2 (C-Ar), 124.5 (q, J =

269.8 Hz, CCF3), 117.6 (C-Ar), 52.5 (NCH

2CH

2N), 47.6 (NCH

2Ph) 73.8 (CHOH), 59.6

(NCHCH3), 47.8 (NCH

2CH

2N), 12.1 (CHCH


21H

27N

2O

2

+:

339.2073, found: 339.2079.

1,3-Bis((1R,2R)-1,3-dihydroxy-1-phenylpropan-2-yl)-imidazolinium tetrafluoroborate

(232F)

From (1R,1'R,2R,2'R)-2,2'-(ethane-1,2-diylbis(azanediyl))bis(1-phenylpropane-1,3-diol)

(107) (320 mg, 0.89 mmol), NH4BF

4(93 mg 97%, 0.89 mmol), CH(OEt)

3(146 μL, 0.89

mmol) according to the general procedure. The mixture was heated to 120 °C for 16 h to

give the title compound as a yellow solid (400 mg, 99%). [α]22D

= −116.2 (c = 0.37, Acetone);

mp 80-85 °C. MS (ESI, 0 V), m/z 371 (M+, 100%); IR (KBr) 3386m, 1641vs, 1063vs, 704s

cm-1; 1H-NMR (200 MHz, acetone-d6) δ = 8.27 (s, NCHN), 7.40-7.05 (m, 10 H, H-Ar),

4.92 (d, J = 6.3 Hz, 2 H, PhCHOH), 4.10-3.40 (m, 10 H, NCH2CH

2N, NCHCH

2OH); 13C-

NMR (50 MHz, acetone-d6) δ = 160.1 (NC+N), 142.4 (C-Ar), 129.4 (C-Ar), 128.8 (C-Ar),

127.3 (C-Ar), 71.4 (PhCHOH), 67.2 (NCHCH2), 60.3 (CH

2OH), 48.4 (NCH

2CH

2N);

HRMS (ESI) calculated for C21

H27

N2O

4

+: 371.1971, found: 371.1980.

(EtO)3CH, NH4BF4

BF4−120 °C, 16 h

232F

99%

107

N N+

HO

Ph

OH

Ph

HOOH

NH HN

HO

Ph

OH

Ph

HOOH

BF4−

231F

N N+

HO

Ph

OH

Ph

N N+

HO

Ph

OH

Ph

B[C6H3(CF3)2]4−

DCM/H2O, r.t.

NaB[C6H3(CF3)2]4

231D

84%

Experimental 181

1,3-bis((1R,2R)-1,3-dihydroxy-1-phenylpropan-2-yl)-imidazolinium tetrakis(3,5-


From 1,3-bis((1R,2R)-1,3-dihydroxy-1-phenylpropan-2-yl)-imidazolinium tetrafluorob-

orate (232F) (100 mg, 0.22 mmol) and NaB[C6H

3(CF

3)2]4

(193 mg, 0.22 mmol) in a mix-

ture of DCM (3 mL) and water (3 mL) as a yellow solid (215 mg, 80%). [α]22D

= −42.5 (c =

4.7, acetone); mp 50 °C. MS (ESI, 0 V), m/z 371 (M+, 100%); IR (KBr) 1640w, 1357s,

1279vs, 1124s cm-1; 1H-NMR (200 MHz, acetone-d6) δ = 8.32 (s, NCHN), 7.70 (bs, 8 H,

H-Ar), 7.55 (bs, 4 H, H-Ar), 7.40-7.00 (m, 10 H, H-Ar), 5.10-4.90 (m, 2 H, PhCHOH), 4.30-

3.60 (m, 10 H, NCH2CH

2N, NCHCH

2OH); 13C-NMR (50 MHz, acetone-d6) δ = 161.6 (q,

J = 49.5 Hz, BC), 160.1 (NC+N), 142.4 (C-Ar), 135.5 (C-Ar), 120.0 (q, J = 28.4 Hz,

CHCCF3), 129.4 (C-Ar), 128.9 (C-Ar), 127.2 (C-Ar), 125.3 (q, J = 269.8 Hz, CCF

3), 118.4

(m, C-Ar), 71.6 (PhCHOH), 67.2 (NCHCH2), 60.4 (CH

2OH), 48.5 (NCH

2CH

2N); HRMS

(ESI) calculated for C21

H27

N2O

4

+: 371.1971, found: 371.1974.

1,3-Bis-((S)-1-hydroxymethyl-2-methyl-propyl)-4,5-imidazolinium tetrafluoro borate

(233F)

From (2S,2'S)-2,2'-(ethane-1,2-diylbis(azanediyl))bis(3-methylbutan-1-ol) (105) (312

mg, 1.34 mmol), NH4BF

4(141 mg 97%, 1.34 mmol) and CH(OEt)

3(220 μL, 1.34 mmol)

according to the general procedure gave the title compound as a yellow oil (418 mg, 94%).

[α]22D

= −10.6 (c = 0.68, Acetone) MS (ESI, 0 V), m/z 243.2 (cation); IR (neat) 3548s, 2968s,

2881s, 1644vs, 1472s, 1394s, 1254s, 1074vs, 446s cm-1; 1H-NMR (200 MHz, acetone-d6)

δ =8.20 (s, 1 H, NCHN), 4.07 (bs, 2 H, CH2OH), 4.00-3.85 (m, 4 H, CH

2OH), 3.75-3.25

(m, 6 H, NCH2CH

2N, NCHCH), 2.00-1.70 (m, 2 H, CH(CH

3)2), 0.91 (d, J = 6.5 Hz, 12 H,

CH(CH3)2); 13C-NMR (50 MHz, acetone-d6) 160.1 (NCHN), 67.5 (NCHCH), 59.8

(CH2OH), 46.2 (NCH

2CH

2N), 27.9 (CH(CH

3)2), 20.1 (CH(CH

3)2), 19.4 (CH(CH

3)2);

HRMS (ESI) calculated for C13

H27

N2O

2

+: 243.2073, found: 243.2073.

(EtO)3CH, NH4BF4

BF4−

120 °C, 3 hN N

+

105 233F

94%

HOOH

NH HN

HOOH

DCM/H2O, r.t., 5 h

232F

NaB[C6H3(CF3)2]4

B[C6H3(CF3)2]4−BF4

−

232D

80%

N N+

HO

Ph

OH

Ph

HOOH

N N+

HO

Ph

OH

Ph

HOOH

182 Experimental

1,3-Bis-((S)-1-hydroxymethyl-2-methyl-propyl)-4,5-imidazolinium bis(trifluo-


From 1,3-bis-((S)-1-hydroxymethyl-2-methyl-prop yl)-4,5-imidazolinium tetrafluoro

borate (233F) (235 mg, 0.71 mmol) and LiNTf2

(204 mg, 0.71 mmol, 1 eq.) in a mixture of

DCM (5 mL) and water (5 mL) as a yellow oil (197 mg, 52%). [α]22D

= −18.9 (c = 0.28,

CHCl3) MS (ESI, 0 V), m/z 243.3 (M+); IR (neat) 3537m, 2971s, 1644vs, 1352vs, 120vs,

1137vs, 1058vs, 617vs cm-1; 1H-NMR (200 MHz, CDCl3) δ = 8.16 (s, 1 H, NCHN), 4.00-

3.80 (m, 4 H, CH2OH), 3.70-3.30 (m, 4 H, NCH

2CH

2N), 3.09 (bs, 2 H, CH

2OH), 2.00-1.75

(m, 2 H, CH(CH3)2), 0.99 (d, J = 6.7 Hz, 12 H, CH(CH

3)2); 13C-NMR (50 MHz, CDCl

3) δ

= 159.2 (NCHN), 66.9 (NCHCH), 59.4 (CH2OH), 45.3 (NCH

2CH

2N), 27.6 (CH(CH

3)2),

19.7 (CH(CH3)2), 18.9 (CH(CH

3)2); HRMS (ESI) calculated for C

13H

27N

2O

2

+: 243.2073,

found: 243.2077.

1,3-bis((S)-1-hydroxy-3,3-dimethylbutan-2-yl)-imidazolinium tetrafluoroborate (234F)

From (2S,2'S)-2,2'-(ethane-1,2-diylbis(azanediyl))bis(3,3-dimethylbutan-1-ol) (234F)

(1.00 g, 3.85 mmol), NH4BF

4(615 mg 97%, 3.85 mmol) and CH(OEt)

3(633 μL, 3.85

mmol). Reaction mixture was heated to 120 °C for 8 h. Standard workup gave the title com-

pound as a colorless oil (1.30 g, 88%). [α]22D

= +24.4 (c = 0.46, CHCl3) MS (ESI, 0 V), m/z

271.3 (M+cation); IR (neat) 3541s, 2967vs, 1699m, 1639vs, 1479s, 1409m, 1373s, 1283s,

1237m, 1058vs, 451s, 415m, 406m cm-1; 1H-NMR (400 MHz, CDCl3) δ = 8.15 (s, 1 H,

NCHN), 4.20-4.10 (m, 2 H, CH2OH), 4.10-4.00 (m, 2 H, CH

2OH), 3.95 (dd, J1 = 12.3 Hz,

J2 = 3.7 Hz, 2 H, NCH2CH

2N), 3.82 (t, J = 10.8 Hz, 2 H, CH

2CHN), 3.60 (dd, J1 = 12.3 Hz,

J2 = 3.7 Hz, 2 H, NCH2CH

2N), 1.04 (s, 18 H, C(CH

3)3); 13C-NMR (100 MHz, CDCl

3) δ =

160.2 (NC+N), 69.9 (NCHCH2), 57.8 (CHCH

2OH), 49.7 (NCH

2CH

2N), 33.8 (CH(CH

3)3),

27.3 (CH(CH3)3); HRMS (ESI) calculated for C

15H

31N

2O

2

+: 271.2386, found: 271.2396.

(EtO)3CH, NH4BF4

BF4−

120 °C, 8 hN N

+

106 234F

88%

OH HO

NH HN

OH HO

LiNTf2

NTf2−


233C

52%

BF4−

N N+

233F

HOOH

N N+

HOOH

Experimental 183

1,3-Bis((S)-1-hydroxy-3,3-dimethylbutan-2-yl)-imidazolinium bis(trifluoromethylsul-

fonyl)imide (234C)

From 1,3-bis((S)-1-hydroxy-3,3-dimethylbutan-2-yl)-imidazolinium tetrafluoroborate

(234F) (294 mg, 0.86 mmol) and LiNTf2

(246 mg, 0.86 mmol, 1 eq.) in a mixture of DCM


= +19.7 (c = 0.36, CHCl3);

MS (ESI, 0 V), m/z 271.3 (M+); IR (KBr) 3423s, 1637s, 1194s, 1057s cm-1; 1H-NMR (200

MHz, acetone-d6) δ = 8.36 (s, 1 H, NCHN), 4.25-4.05 (m, 4 H, CH2OH), 4.00-3.80 (m, 4

H, NCH2CH

2N, CH

2CHN), 3.60-3.45 (m, J = 10.8 Hz, 2 H, NCH

2CH

2N), 0.93 (s, 18 H,

C(CH3)3); 13C-NMR (50 MHz, acetone-d6) δ = 161.7 (NC+N), 121.0 (q, J = 319.5 Hz, CF

3),

70.9 (NCHCH2), 57.9 (CHCH

2OH), 48.8 (NCH

2CH

2N), 34.4 (CH(CH

3)3), 27.5

(CH(CH3)3). HRMS (ESI) Calculated for: C

15H

31N

2O

2: 271.2386; found: 271.2381.

(3aS,7aS)-1,3-Bis((1R,2R)-2-hydroxycyclohexyl)-3a,4,5,6,7,7a-hexahydro-3H-

benzo[d]imidazol-1-ium tetrafluoroborate (235F)

From (1R,1'R,2R,2'R)-2,2'-(1S,2S)-cyclohexane-1,2-diylbis(azanediyl)dicyclohexanol

(219) (310 mg, 1.00 mmol), NH4BF

4(113 mg 97%, 1.00 mmol) and CH(OEt)

3(163 μL,

1.00 mmol) according to the general procedure as a yellow solid (380 mg, 93%). [α]22D

= +7.1

(c = 0.1, CHCl3); mp 56 °C. MS (ESI, 0 V), m/z 321 (M+, 100%); IR (KBr) 3528s, 2940vs,

2865s, 1607vs, 1453s, 1226s, 1074vs, 530m cm-1; 1H-NMR (200 MHz, CDCl3) δ = 8.33 (s,

1 H, NCHN), 4.23 (bs, 2 H, CHOH), 3.90-3.30 (m, 6 H, CHOH, NCHCH2), 2.50-0.80 (m,

24 H, CH2); 13C-NMR (50 MHz, CDCl

3) δ = 158.8 (NCHN), 72.0 (CHOH), 68.9

(NCHCHN), 63.7 (NCHCHOH), 34.6 (CH2), 30.3 (CH

2), 28.5 (CH

2), 24.6 (CH

2), 24.0

(CH2), 23.9 (CH


19H

33N

2O

2

+: 321.2542, found: 321.2540.

(EtO)3CH, NH4BF4

BF4−120 °C, 3 h

235F

93%

219

NH HN

OH HO

N N+

OH HO

LiNTf2

NTf2−DCM/H2O, r.t., 30 min.

234C

59%

234F

BF4−

N N+

OH HO

N N+

OH HO

184 Experimental

3.5. Preparation of Silacycles

General procedure for preparation of N,N-silacycles

Mixture of MeSiCl3

(141 μL, 1.20 mmol, 1.2 eq.) and DBU (358 μL, 2.40 mmol, 2.4 eq.)

in DCM (5 mL) was cooled down to −5 °C and a solution of diamine (1.00 mmol) in DCM

(3 mL) was added dropwise over the period of 10 min. The reaction mixture was stirred for

2 h at −5 °C and then allowed to warm up to r.t. overnight. The mixture was concentrated

in vacuo. Benzene (10 mL) was added and the mixture was vigorously stirred for 2 h in

order to precipitate DBU.HCl. The suspension was filtered through a pad of dry celite and

the filter cake was washed with an additional portion of dry benzene (15 mL). The filtrate

was concentrated and further dried in vacuo giving the title compound.

2-Chloro-2-methyl-1,3-bis((R)-1-phenylethyl)-1,3,2-diazasilolidine (236)

From N,N’-bis((R)-1-phenylethyl)ethane-1,2-diamine (93) (941 mg, 3.51 mmol),

MeSiCl3

(487 μL, 4.16 mmol) and DBU (1.249 mL, 8.32 mmol) in DCM (20 mL) as a white

solid (882 mg, 73%). 1H-NMR (200 MHz, C6D

6) 7.40-7.00 (m, 10 H, H-Ar), 4.10-3.90 (m,

2 H, PhCHCH3), 2.80-2.55 (m, 4 H, NCH

2CH

2N), 1.48 (d, J = 5.6 Hz, 3 H, CHCH

3), 1.45

(d, J = 5.6 Hz, CHCH3), , 0.51 (s, 3 H, Si-CH

3); 13C-NMR (50 MHz, C

6D

6) 146.0 (C-Ar),

128.5 (C-Ar), 128.0 (C-Ar), 127.5 (C-Ar), 57.5 (CHCH3), 56.6 (CHCH

3), 46.7

(NCH2CH

2N), 45.3 (NCH

2CH

2N), 23.1 (CHCH

3), 22.3 (CHCH

3), 5.9 (SiCH

3).

((4R,5R)-2-chloro-1,2,3-trimethyl-4,5-diphenyl-1,3,2-diazasilolidine (237)

From (1R,2R)-N1,N2-dimethyl-1,2-diphenylethane-1,2-diamine (96) (638 mg, 2.66

mmol) MeSiCl3

(457 μL, 3.85 mmol) and DBU (946 μL, 6.37 mmol) in DCM (15 mL) as

a white solid (637 mg, 76%). 1H-NMR (200 MHz, C6D

6) 7.20-6.80 (m, 10 H, H-Ar), 3.90-

3.85 (m, 2 H, CH), 2.21 (s, 3 H, CH3), 2.15 (s, 3 H, CH

3), 0.53 (s, 3 H, SiCH

3); 13C-NMR

(100 MHz, C6D

6) 140.9 (C-Ar), 135.8 (C-Ar), 128.6 (C-Ar), 128.0 (C-Ar), 127.6 (C-Ar),

127.5 (C-Ar), 127.0 (C-Ar), 74.1 (CHPh), 73.8 (CHPh), 30.7 (NCH3), 29.8 (NCH

3), 0.0

(SiCH3).

DCM, -5°CN N

Si

NH HN

PhPh PhPh

MeSiCl3, DBU

Cl

237

76%

96

DCM, −5 °CN N

Si

MeSiCl3, DBU

Cl

236

73%

Ph Ph

NH HN

Ph Ph93

Experimental 185

(3aR,7aR)-2-Chloro-octahydro-1,2,3-trimethyl-1H-benzo[d][1,3,2]diazasilole (238)

From (1R,2R)-N1,N2-dimethylcyclohexane-1,2-diamine (238) (500 mg, 3.51 mmol)

MeSiCl3

(487 μL, 4.16 mmol) and DBU (1.249 mL, 8.32 mmol) in DCM (20 mL) as a white

oily solid (521 mg, 68%). 1H-NMR (200 MHz, CDCl3) δ = 2.41 (s, 3 H, NCH

3), 2.33 (s, 3

H, NCH3), 2.45-2.35 (m, 2 H, CH), 2.05-1.95 (m, 2 H, CH

2), 1.75-1.65 (m, 2 H, CH

2), 1.30-

0.90 (m, 4 H, CH2), 0.43 (s, 3 H, SiCH


3) δ = 66.8 (CH), 65.7

(CH), 30.6 (CH2), 30.2 (CH

2), 29.7 (CH

2), 29.4 (CH

2), 25.1 (NCH

3), 25.0 (NCH

3), 0.0 (Si-

CH3)

2-Methyl-1,3-bis((R)-1-phenylethyl)-1,3,2-diazasilolidine (241)

From N1,N2-bis((R)-1-phenylethyl)ethane-1,2-diamine (93) (2.33 g, 8.69 mmol) in DCM

(15 mL), MeSiHCl2

(1.18 g, 10.30 mmol, 1.09 mL) and DBU (3.10 mL, 20.76 mmol) in

DCM (40 mL) as a white oily solid (1.56 g, 58%). 1H-NMR (400 MHz, CDCl3) δ = 7.60-

7.30 (m, 10 H, H-Ar), 5.33 (s, 1 H, SiH), 4.22-4.19 (m, 2 H, CH), 3.10-2.90 (m, 4 H, CH2),

1.68-1.60 (m, 6 H, CH3), 0.40 (s, 3 H, Si-CH


3) δ = 147.0 (C-


127.2 (C-Ar), 58.9 (CH), 58.2 (CH), 48.7 (CH2), 48.2 (CH

2), 24.7 (CH

3), 24.4 (CH

3), 4.4

(Si-CH3).

General procedure for preparation of N,O-silacycles

A solution of MeSiCl3

(1.22 mL, 10.40 mmol, 1.04 eq.) in DCM (20 mL) was cooled

down to

−5 °C and Et3N (2.89 mL, 20.80 mmol, 2.08 eq.) was added. After 5 min stirring at −5 °C,

an aminoalcohol (10.00 mmol) was added portionwise. The reaction mixture was allowed

to warm up to r.t. overnight. The solvent was removed under reduced pressure, dry pentane

(50 mL) was added and the mixture was stirred for 2 h to precipitate the Et3N.HCl. The reac-

tion mixture was filtered through a pad of dry celite and the solvent was removed under

reduced pressure. The crude product was distilled on a Kugelrohr giving the corresponding

oxazasilolidine as mixture of diastereomers.

DCM, −5 °CNH HN

MeSiCl3, DBU

PhPh

N N

PhPh SiH

241

58%

93

DCM, −5 °C

MeSiCl3, DBU

NH HN N NSi

Cl

238

68%

97

186 Experimental

(4S,5S)-2-Chloro-2,3,4-trimethyl-5-phenyl-1,3,2-oxazasilolidine (242)

From (+)-pseudoephedrine (199) (3.00 g, 18.20 mmol), MeSiCl3

(2.22 mL, 18.90 mmol)

and Et3N (5.25 mL, 37.90 mmol) in DCM (40 mL) as a colorless oil (764 mg, 17%, mix-

ture of diastereomers 3:1). 1H-NMR (400 MHz, CDCl3) δ = minor 7.50-7.35 (m, 5 H, H-

Ar), 6.63 (d, J = 8.44 Hz, 1 H, CHPh), 3.10-3.00 (m, 1 H, CHCH3), 2.53 (s, 3 H, NCH

3),

1.14 (d, J = 6.04 Hz, 3 H, CHCH3), 0.71 (s, 3 H, SiCH

3); major 7.50-7.35 (m, 5 H, H-Ar),

4.78 (d, J = 6.6 Hz, 1 H, CHPh), 3.25-2.90 (m, 1 H, CHCH3), 2.60 (s, 3 H, NCH

3), 1.23 (d,

J = 6.24 Hz, 3 H, CHCH3), 0.72 (s, 3 H, SiCH


3) δ = minor

141.5 (C-Ar), 128.4 (C-Ar), 128.0 (C-Ar), 126.3 (C-Ar), 84.1 (CHPh), 63.3 (CHCH3), 29.1

(NCH3), 17.3 (CHCH

3), 0.3 (SiCH

3); major 140.9 (C-Ar), 128.4 (C-Ar), 128.1 (C-Ar),

126.9 (C-Ar), 85.6 (CHPh), 62.8 (CHCH3), 29.7 (NCH

3), 16.2 (CHCH

3), 0.6 (SiCH

3).

(4S,5R)-2-Chloro-2,3,4-trimethyl-5-phenyl-1,3,2-oxazasilolidine (244)

From (−)-ephedrine (243) (3.00 g, 18.20 mmol), MeSiCl3

(2.569 mL, 21.66 mmol) and

DBU (6.58 mL, 43.32 mmol) in DCM (40 mL) as a colorless oil (440 mg, 10%, mixture of

diastereomers 1:1). 1H-NMR (400 MHz, CDCl3) δ = 7.45-7.25 (m, 10 H, 2 x H-Ar), 5.45

(d, J = 6.1 Hz, 1 H, CHPh), 5.43 (d, J = 6.1 Hz, 1 H, CHPh), 3.45-3.45 (m, 2 H, 2 x CHCH3),

2.70-2.60 (m, 3 H, CHCH3), 0.73 (d, J = 6.6 Hz, 3 H, NCH

3) 0.73 (s, 3 H, SiCH

3), 0.69 (s,

3 H, SiCH3), 0.67 (d, J = 6.6 Hz, 3 H, NCH


3) δ = 139.6 (C-


125.7 (C-Ar), 80.7 (CHPh), 79.6 (CHPh), 60.6 (CHCH3), 60.5 (CHCH

3), 30.1 (NCH

3), 29.9

(NCH3), 14.9 (CHCH

3), 13.0 (CHCH

3), 1.1 (SiCH

3), 0.6 (SiCH

3).

DCM, −5 °CN O

Si

NH OH

PhPh Me

MeSiCl3, DBU

Cl

Me

244

10%

243

DCM, −5 °CN O

Si

NH OH

PhPh Me

MeSiCl3, Et3N

Cl

Me

242

17%

199

Experimental 187

3.6. Preparation of Thioureas

General Procedure for Preparation of Thiourea Derivatives

An amine (1.00 mmol) was dissolved in THF (3 mL) and the mixture was cooled down

to 0 °C. 1,3-bis(trifluoromethyl)-5-isothiocyanatobenzene (271 mg, 186 μL 98%, 1.00

mmol, 1 eq., 2 eq. in case of diamines) was added dropwise. The cooling was removed and

the reaction mixture was stirred at r.t. overnight. The solvent was removed under reduced

pressure and the reamining rest further dried in vacuo giving the corresponding thiourea

derivative.

1,1'-((1R,2R)-1,2-Diphenylethane-1,2-diyl)bis(3-(3,5-bis(trifluoromethyl)-

phenyl)thiourea) (250)

From (1R,2R)-1,2-diphenylethane-1,2-diamine (247) (500 mg, 2.35 mmol) and 1,3-

bis(trifluoromethyl)-5-isothiocyanatobenzene (1.28 g, 878 μL 98%, 4.71 mmol, 2 eq.) in

THF (10 mL) as a white solid (1.77 g, 99%). [α]22D

= −4.4 (c = 0.68, Acetone); mp 171 °C;

MS (EI), m/z 753 (M++H, 1%), 376 (10), 269 (15), 106 (100); IR (KBr) 3285m, 1543s,

1383s, 1280vs, 1184vs, 1135vs, 685m, 649m cm-1; 1H-NMR (200 MHz, acetone-d6) δ =

9.50 (bs, 2 H, PhNHCS), 8.10-7.70 (bs, 6 H, H-Ar), 7.46 (bs, 2 H, CSNHCH), 7.30-7.70 (m,

10 H, H-Ar), 6.20-6.00 (m, 2 H, CHPh); 13C-NMR (50 MHz, acetone-d6) δ = 182.1

(NCSN), 142.0 (C-Ar), 139.0 (C-Ar), 132.2 (q, J = 33.4 Hz, CF3), 129.5 (C-Ar), 128.9 (C-

Ar), 128.9 (C-Ar), 124.0 (q, J = 270.7 Hz, CF3), 123.5 (C-Ar), 64.6 (CHPh). Anal. calcu-

lated for C32

H22

F12

N4S

2: C, 50.93; H, 2.94; N, 7.42, found: C, 50.80; H, 2.79; N, 7.18.

(R)-1,1'-(1,1'-Binaphthyl-2,2'-diyl)bis(3-(3,5-bis(trifluoromethyl)phenyl)thiourea) (251)

From R-2,2’-diamino-1,1’-binaphthalene (248) (284 mg, 1.00 mmol) and 1,3-bis(trifluo-

romethyl)-5-isothiocyanatobenzene (542 mg, 372 μL 98%, 2.00 mmol, 2 eq.) in THF (3

mL) as a white solid (1.770 g, 99%). [α]22D

= 82.1 (c = 1.1, Acetone); mp 116 °C; MS (ESI,

0 V), m/z 827.0 (M+, 40); IR (KBr) 3373m, 1508s, 1380s, 1278vs, 1179vs, 1134vs, 672m

cm-1; 1H-NMR (400 MHz, CDCl3) δ = 8.24 (bs, 2 H, PhNHCS), 8.15-8.10 (m, H-Ar), 7.98

THF, r.t., 22 hCF3F3C

N

C

S

+ 2

NH2

NH2

251

99%

248

NH

HN

NH

HN

CF3

CF3

CF3

CF3

S

S

THF, r.t., 22 hH2N NH2

PhPh

CF3F3C

N

C

S

+ 2

NH HN

PhPh

HNHN

SS

CF3

F3CCF3

F3C

250

99%

247

188 Experimental

(d, J = 8.8 Hz, 2 H, H-Ar), 7.89 7.98 (d, J = 8.8 Hz, 2 H, H-Ar), 7.75 (bs, 2 H, H-Ar), 7.70

(bs, 4 H, H-Ar), 7.56 (bs, 2 H, CSNHPh), 7.55-7.43 (m, 2 H, H-Ar), 7.35-7.25 (m, 2 H, H-

Ar), 7.14 (d, J = 8.8 Hz, 2 H, H-Ar); 13C-NMR (100 MHz, CDCl3) δ = 180.1 (NCSN), 138.8

(C-Ar), 133.6 (C-Ar), 132.8 (C-Ar), 132.4 (C-Ar), 131.9 (q, J = 34.3 Hz, CCF3), 130.7 (C-


124.4 (C-Ar), 122.8 (q, J = 271.2 Hz, CF3), 119.6 (C-Ar). Anal. calculated for

C38

H22

F12

N4S

2C, 55.21; H, 2.68; N, 6.78, found: C, 55.03; H, 2.73; N, 6.44.

(S)-1-(3,5-bis(trifluoromethyl)phenyl)-3-(1-hydroxy-3-methyl-1,1-diphenylbutan-2-

yl)thiourea (252)

From (S)-2-amino-3-methyl-1,1-diphenylbutan-1-ol (249) (336 mg, 1.314 mmol) and

1,3-bis(trifluoromethyl)-5-isothiocyanatobenzene (356 mg, 240 μL 98%, 1.314 mmol) in

THF (3 mL) as a white solid (690 mg, 99%). [α]22D

= −24.0 (c = 0.4, CHCl3); mp 160 °C; MS

(EI), m/z 526 (M+, 1%), 343 (50), 106 (90), 73 (100), 56 (45); IR (KBr) 1543s, 1385s,

1277vs, 1149vs, 702s cm-1; 1H-NMR (200 MHz, CDCl3) δ = 8.25 (bs, 1 H, PhNHCS), 7.80-

6.70 (m, 14 H, H-Ar, CSNHCH), 5.53 (d, J = 6.8 Hz, 1 H, NHCHCH), 2.74 (s, 1 H,

Ph2COH), 2.10-1.80 (m, 1 H, CH(CH

3)2), 1.01 (d, J = 6.9 Hz, 3 H, CH(CH

3)2), 0.82 (d, J =

6.9 Hz, 3 H, CH(CH3)2); 13C-NMR (50 MHz, CDCl

3) δ = 180.6 (NCSN), 144.9 (C-Ar),

144.3 (C-Ar), 138.3 (C-Ar), 133.0 (q, J = 33.4 Hz, CCF3), 128.6 (C-Ar), 127.4 (C-Ar),

127.36 (C-Ar), 124.4 (C-Ar), 125.3 (C-Ar), 123.9 (C-Ar), 122.7 (q, J = 270.7 Hz, CF3),

119.4 (C-Ar), 83.2 (Ph2COH), 63.6 (NHCHCH), 29.7 (CH(CH

3)2), 23.5 (CH(CH

3)2), 18.4

(CH(CH3)2). Anal. calculated for C

26H

24F

6N

2OS: C, 59.31; H, 4.59; N, 5.32; found:C,

59.08; H, 4.54; N, 5.19.

THF, r.t., 22 hH2N OH

CF3F3C

N

C

S

+

252

99%

PhPh

NH OH

PhPh

NH

S

CF3

F3C

249

Experimental 189

3.7. Application of Imidazolinium Salts as Catalysts

3.7.1. Aza Diels-Alder Reaction

General procedure for the aza Diels-Alder reaction

The imine (0.20 mmol) and the catalyst (0.02 mmol, 10 mol%) were placed into a dry

Schlenk flask under a nitrogen atmosphere. The reaction mixture was dissolved in dry ace-

tonitrile (2 mL) and Danishefsky’s diene (43 µL, 0.22 mmol) was added at once. After 16 h

stirring at r.t., the mixture was quenched by the addition of a saturated solution of potassi-

um hydrogencarbonate (2 mL) and extracted with ethyl acetate (3 x 5 mL). The combined

organic phases were dried (Na2SO

4) and the solvent was evaporated under reduced pressure.

FCC (petroleum ether/EtOAc, 1/1) gave the desired product.

2,3-Dihydro-1,2-diphenylpyridin-4(1H)-one (255)

From N-Benzilidene-aniline (36 mg, 0.20 mmol) and Danishefsky’s diene (43 µL, 0.22

mmol) in presence of imidazolinium catalyst (0.02 mmol) as a yellow solid (14 - 99%

yield). (for differences in catalysts, reaction times, temperatures and solvents see Table 18,

page 64; Table 20, page 67; Table 21, page 67 and Table 22, page 69). Spectral datas were

consistent with literature values.140 Enantiomeric excess was determined by HPLC (OD-H,

30% i-prop/hexane, 0.5 mL/min) t1

= 30 min., t2

= 39 min.

1-(4-Chlorophenyl)-2,3-dihydro-2-phenylpyridin-4(1H)-one (264)

From (E)-N-benzylidene-4-chlorobenzenamine (256) (43 mg, 0.20 mmol) and Danishef-

sky’s diene (43 µL, 0.22 mmol) in presence of imidazolinium catalyst 187B (0.02 mmol) as

yellow solid (48 mg, 84%). Spectral data were consistent with literature values.140

OMe

TMSO

N

Ph

MeCN, r.t. 16 h

N

O Ph

187B

+

ClCl

264

84%253 256

OMe

TMSO

N

MeCN, r.t. 16 h

N

O

catalyst

+

255

up to 99%

190 Experimental

1-(4-Fluorophenyl)-2,3-dihydro-2-phenylpyridin-4(1H)-one (265)

From (E)-N-benzylidene-4-fluorobenzenamine (257) (40 mg, 0.20 mmol) and Danishef-

sky’s diene (43 µL, 0.22 mmol) in the presence of imidazolinium catalyst 187C (0.02 mmol)

as yellow solid (54 mg, 73%). Spectral data were consistent with literature values.230

1-(4-Methoxyphenyl)-2,3-dihydro-2-phenylpyridin-4(1H)-one (266)

From (E)-N-benzylidene-4-methoxybenzenamine (258) (42 mg, 0.20 mmol) and Dan-

ishefsky’s diene (43 µL, 0.22 mmol) in presence of imidazolinium catalyst 187B (0.02

mmol) as yellow solid (51 mg, 92%). Spectral datas were consistent with literature values.140

2,3-Dihydro-2-(4-chlorophenyl)-1-phenylpyridin-4(1H)-one (267)

From (E)-N-(4-chlorobenzylidene)benzenamine (259) (43 mg, 0.20 mmol) and Dan-

ishefsky’s diene (43 µL, 0.22 mmol) in the presence of imidazolinium catalyst 187B (0.02


2,3-Dihydro-2-(2-methoxyphenyl)-1-phenylpyridin-4(1H)-one (268)

From (E)-N-(2-methoxybenzylidene)benzenamine (260) (43 mg, 0.20 mmol) and Dan-

ishefsky’s diene (43 µL, 0.22 mmol) in the presence of imidazolinium catalyst 187B (0.02


OMe

TMSO

NPh

MeCN, r.t. 16 h

N

O

Ph

187B+

268

57%

MeOMeO

260253

OMe

TMSO

NPh

MeCN, r.t. 16 h

N

O

Ph187B

+

ClCl 267

72%

259253

OMe

TMSO

N

Ph

MeCN, r.t. 16 h

N

O Ph

187B

+

OMeOMe

266

92%253 258

OMe

TMSO

N

Ph

MeCN, r.t. 16 h

N

O Ph

187B

+

FF

265

73%253 257

Experimental 191

2,3-Dihydro-2-(4-methoxyphenyl)-1-phenylpyridin-4(1H)-one (269)

From (E)-N-(3-methoxybenzylidene)benzenamine (261) (42 mg, 0.20 mmol) and Dan-

ishefsky’s diene (43 µL, 0.22 mmol) in presence of imidazolinium catalyst 187B (0.02

mmol) in as a yellow solid (25 mg, 45%). Spectral data were consistent with literature val-

ues.140

2,3-Dihydro-2-(4-nitrophenyl)-1-phenylpyridin-4(1H)-one (270)

From (E)-N-(4-nitrobenzylidene)benzenamine (262) (45 mg, 0.20 mmol) and Danishef-

sky’s diene (43 µL, 0.22 mmol) in presence of imidazolinium catalyst (0.02 mmol) in as yel-

low solid (29 mg, 50%). Spectral data were consistent with literature values.140

1-(2-Pyridinyl)-2,3-dihydro-2-phenylpyridin-4(1H)-one (JUR271)

From (E)-N-(pyridin-2-ylmethylene)benzenamine (263) (42 mg, 0.23 mmol) and and

Danishefsky’s diene (49 µl, 0.25 mmol) in presence of imidazolinium catalyst 187B (0.02

mmol) as a solid (56 mg, 98%). Spectral data were consistent with literature values.140

2-Phenyl-1-tosyl-2,3-dihydropyridin-4(1H)-one (274)

From (E)-N-(benzylidene)tosylamine (273) (52 mg, 0.20 mmol) and Danishefsky’s diene

(43 µL, 0.22 mmol) in the presence of imidazolinium catalyst (0.02 mmol) as a white solid

. For different reaction conditions see Table 23, page 70. Spectral data were consistent with

literature values.142

OMe

TMSO

N

Ph

Ts

MeCN, r.t., 16 h

N

O

Ts

Ph

catalyst

+

274

35%

273273

OMe

TMSO

NPh

MeCN, r.t. 16 h

N

O

Ph187B

+N

N

271

98%

263253

OMe

TMSO

NPh

MeCN, r.t. 16 h

N

O

Ph187B

+

NO2

NO2270

50%

262253

OMe

TMSO

NPh

MeCN, r.t. 16 h

N

O

Ph187B

+

OMe269

45%

OMe

261253

192 Experimental

3.7.2. Inverse Electron Demand Aza Diels-Alder Reaction

General procedure

In MeCN, catalyzed by monocations: N-benzylideneaniline (36 mg, 0.20 mmol) and the

catalyst (0.02 mmol, 10 mol%) were placed into a dry Schlenk flask under a nitrogen atmos-

phere. The reaction mixture was dissolved in dry acetonitrile (2 mL) and dienophile (2,3-

dihydrofurane (30 µl, 0.40 mmol) or 3,4-dihydro-2H-pyran (280) (36 μL, 0.40 mmol) was

added at once. Reaction mixture was stirred at r.t. (for differences in reaction times and tem-

peratures, see Table 25, page 74 and Table 26, page 75). Solvent was evaporated under

reduced pressure. Products were isolated by FCC (petroleum ether/EtOAc 95/5) to give the

corresponding quinolines.

In DCM, catalyzed by bis-cations: N-benzylideneaniline (54 mg, 0.30 mmol) and the cat-

alyst (0.03 mmol, 10 mol%) were placed into a dry Schlenk flask under a nitrogen atmos-

phere. The reaction mixture was dissolved in dry DCM (1 mL) and a dienophile (2,3-dihy-

drofurane (45 µL, 0.6 mmol) or 3,4-dihydro-2H-pyran (51 mg, 56 μL, 0.60 mmol) was

added at once. Reaction mixture was stirred at r.t. (for differences in reaction times and tem-

peatures, see Table 25, page 74 and Table 26, page 75). The mixture was transferred on the

collumn and the products were isolated by FCC (petroleum ether/EtOAc 95/5) to give the

corresponding quinolines.

2,3,3a,4,5,9b-Hexahydro-4-phenylfuro[3,2-c]quinoline (281)

From N-benzylideneaniline (254) (54 mg, 0.30 mmol) and dihydrofurane (280) (45 μL,

0.60 mmol, 2 eq.) (for solvents and temperature diferences, Table 25, page 74) as a mixture

of cis and trans diastereomers. Ratio of the diastereomers was determined by ratio of the

signals area in 1H-NMR. Spectral date were consistent with literature values.161

281a: 1H-NMR (200 MHz, CDCl3) δ = 7.50-7.25 (m, 6 H, H-Ar), 7.20-7.00 (m, 1 H, H-

Ar), 6.78 (t, J = 7.4 Hz, 1 H, H-Ar), 6.60 (dd, J1 = 8.1 Hz, J2 = 1 Hz, 1 H, H-Ar), 5.28 (d, J= 8.0 Hz, 1 H, CHPh), 4.69 (d, 2.9 Hz, CHO), 3.90-3.65 (m, 3 H, NH, CH

2O), 2.90-2.55

(m, 1 H, CHCH2), 2.30-2.10 (m, 1 H, CHCH

2CH

2), 1.60-1.40 (m, 1 H, CHCH

2CH

2); 13C-

NMR (50 MHz, CDCl3) δ = 143.9 (C-Ar), 141.1 (C-Ar), 129.1 (C-Ar), 127.6 (C-Ar), 127.3

(C-Ar), 126.6 (C-Ar), 125.5 (C-Ar), 121.7 (C-Ar), 118.1 (C-Ar), 113.9 (C-Ar), 74.9

(CCHOCH2), 65.7 (OCH

2CH

2), 56.5 (NHCHPh), 44.7 (CHCHCH

2), 23.6 (CHCH

2CH

2).

281b: isomer 1H-NMR (200 MHz, CDCl3) δ = 7.50-7.30 (m, 6 H, H-Ar), 7.15-7.00 (m,

1 H, H-Ar), 6.85-6.72 (m, 1 H, H-Ar), 6.65-6.55 (m, 1 H, H-Ar), 4.60 (d, J = 8.0 Hz, 1 H,

N

solvent

catalyst+

O

NH

O

NH

O

281a

+

281b280254

Experimental 193

CHPh), 4.10 (bs, 1 H, NH), 4.05-3.60 (m, 3 H, CHO, CH2O), 2.55-2.40 (m, 1 H, CHCH

2),

2.10-1.90 (m, 1 H, CHCH2CH

2), 1.80-1.60 (m, 1 H, CHCH

2CH

2); 13C-NMR (50 MHz,


(C-Ar), 119.0 (C-Ar), 117.3 (C-Ar), 113.7 (C-Ar), 75.2 (CCHOCH2), 64.2 (OCH

2CH

2),

56.7 (NHCHPh), 42.3 (CHCHCH2), 27.8 (CHCH

2CH

2).

3,4,4a,5,6,10b-Hexahydro-5-phenyl-2H-pyrano[3,2-c]quinoline (283)

From N-benzylideneaniline (254) (54 mg, 0.30 mmol) and dihydropyrane (282) (50 μL,

0.60 mmol, 2 eq.) (for solvents and temperature diferences, see Table 26, page 75) as a mix-

ture of cis and trans diastereomers. The ratio of the diastereomers determined FCC by iso-

lation. Spectral date were consistent with literature values.161

283a: as a white solid 1H-NMR (200 MHz, CDCl3) δ = 7.50-7.24 (m, 6 H, H-Ar), 7.10

(tq, J1 = 7.3 Hz, J1 = 0.8 Hz, 1 H, H-Ar),6.80 (td, J1 = 7.4 Hz, J2 = 1.1 Hz, 1 H, H-Ar), 6.60

(dd, J1 = 8 Hz, J2 = 1.2 Hz, 1 H, NHCCH), 5.33 (d, J = 5.5 Hz, 1 H, NHCHPh), 4.69 (d, J= 2.6 Hz, 1 H, CHOCH

2), 3.87 (bs, 1 H, NH), 3.65-3.35 (m, 2 H, CHOCH

2CH

2), 2.25-2.10

(m, 1 H, CHCHCH2), 1.65-1.20 (m, 4 H, CHCH

2CH

2CH


3) δ


126.8 (C-Ar), 119.9 (C-Ar), 118.3 (C-Ar), 114.4 (C-Ar), 72.8 (CCHO), 60.6

(CHOCH2CH

2), 59.3 (NHCHPh), 38.9 (CHCHCH

2), 25.4 (CH

2CH

2CH

2), 18.0

(CH2CH

2CH). HPLC conditions: AD-H (2.5% i-prop/hexane, 0.3 mL/min) t

1= 71.2 min t

2

= 83.8 min.

283b as yellow oil. 1H-NMR (200 MHz, CDCl3) δ = 7.50-7.20 (m, 6 H, H-Ar), 7.15-7.05

(m, 1 H, H-Ar), 6.70 (td, J1 = 7.4 Hz, J2 = 1.1 Hz, 1 H, H-Ar), 6.53 (dd, J1 = 8 Hz, J2 = 1.2

Hz, 1 H, NHCCH), 4.72 (d, J = 10.1 Hz, 1 H, NHCHPh), 4.40 (d, J = 2.7 Hz, 1 H,

CHOCH2), 4.20-4.00 (m, 2 H, OCH

2CH

2), 3.72 (td, J1 = 11.3 Hz, J2 = 2.3 Hz, 1 H, NH),

2.15-2.05 (m, 1 H, CHCHCH2), 1.95-1.20 (m, 4 H, CHCH

2CH

2CH

2); 13C-NMR (50 MHz,


(C-Ar), 127.8 (C-Ar), 120.7 (C-Ar), 117.5 (C-Ar), 114.1 (C-Ar), 74.5 (CCHO), 68.7

(CHOCH2CH

2), 54.8 (NHCHPh), 38.9 (CHCHCH

2), 24.1 (CH

2CH

2CH

2), 22.0

(CH2CH

2CH). HPLC conditions: AD-H (2.5% i-prop/hexane, 0.4 mL/min) t

1= 38.5 min t

2

= 59.1 min.

N

solvent

catalyst+

NH

NH

283b283a

+

O O

O

282254

194 Experimental

3.7.3. Hetero Diels-Alder Reaction

2-phenyl-2,3-dihydropyran-4-one (62)

Catalyst (231D) (36 mg, 0.03 mmol) was disolved in dry PhMe (0.6 mL) and the mix-

ture was cooled to −40°C. Rawals’ diene (59) (80 mL, 0.30 mmol) and benzaldehyde (167)

(61 μL, 0.60 mmol) were added succesively. The reaction mixture was stirred at −40°C for

48 h. The mixture was cooled to −78°C, diluted with DCM (2 mL) and the reaction was

quenched by addition of AcCl (21 μL, 0.60 mmol). Solvent was removed under reduced

pressure and the crude product was purified by FCC (petroleum ether/EtOAc, 95/5) to give

the title compound as yellow oil (2 mg, 4 %). Spectral data were consistent with literature

values.64 Enantiomeric excess was determined via HPLC: OD-H (i-prop/hexane, 10/90, 0.9

mL/min) t1

= 12.9 min, t2

= 15 min.

3.7.4. Baylis-Hillman Reaction

2-(1-Hydroxy-3-phenylpropyl)cyclopent-2-enone (294)

Catalyst (0.05 mmol, 10 mol%) was placed into a dry Schlenk flask and dissolved in

THF. (1 mL) Phenyl-propionyl aldehyde (68 μL 97%, 0.50 mmol) and cyclopenten-2-one

(43 μL 98%, 0.50 mmol) were added sequentially. The mixture was cooled down to −78 °C

and Bu3P (27 μL 90%, 0.10 mmol, 25 mol%) was added dropwise. The reaction mixture was

warmed up to −10 °C and stirred overnight. The mixture was transferred on the collumn and

FCC (petroleum ether/EtOAc, 70/30) gave the title compound as an yellow oil. Spectral data


Ph+


O

CHO

THF, Bu3P (25 mol%)

OOH

Ph

292 293 294

1. 231D, PhMe, −40 °C, 48 h

2. AcCl/DCM, -78 °C, 30 min+

N

TBSO

OHC

O

PhO

59 167 62

4 %, 0% ee

Experimental 195

3.8. Application of Carbene Precurcors

3.8.1. Et2Zn Addition to Aldehydes

General procedure for carbene catalyzed Et2Zn addtion to aldehydes

Imidazolinium carbene precursor (0.04 mmol) and t-BuOK (4.5 mg, 0.04 mmol) were

placed to a dry Schlenk flask and dissolved in dry PhMe. (1 mL). After 5 min. stirring, Et2Zn

(0.5 mL of 1 M solution in hexane) was added. After another 5 min, aldehyde (0.40 mmol)

was added. The mixture was stirred at r.t. for 30 h. (for differences in reaction times and

temperatures see Table 31, page 81 and Table 32, page 82). The reaction mixture was

quenched by the addtion of 1M HCl (0.5 mL) and extracted with Et2O (3 x 5 mL). The com-

bined organic phases were dried (Na2SO

4) and the solvent was removed under reduced pres-

sure giving the crude product which was purified by FCC (petroleum ether/EtOAc, 9/1) giv-

ing the corresponding alcohol.

1-Phenylpropan-1-ol (299)

From benzaldehyde (187) (40 μL, 0.40 mmol) and Et2Zn (0.50 mL 1 M solution in hexa-

ne) in PhMe (1 mL), catalyzed by carbene generated from imidazolinium carbene precursor

(0.04 mmol) and t-BuOK (4.5 mg, 0.04 mmol) as colorless oil. (For catalysts and yields see

Table 31, page 81). Spectral data were consistent with literature values.173 Enantiomeric

ratio was determined by HPLC (OD-H, i-prop/hexane, 10/90, 0.2 mL/min, t1

= 32.6 min, t2

= 38.8 min.)

1-(Naphthalen-2-yl)propan-1-ol (301)

From naphtyl-1-cabaldehyde (300) (56 μL, 0.40 mmol) and Et2Zn (0.5 mL 1 M solution

in hexane) in PhMe, catalyzed by carbene generated from imidazolinium carbene precursor

(0.04 mmol) and t-BuOK (4.5 mg, 0.04 mmol) as colorless oil. For catalysts and yields se

Table 32, page 82. Spectral data were consistent with literature values.231 Enantiomeric ratio

was determined by HPLC (OD-H, i-prop/hexane, 5/95, 0.4 mL/min, t1

= 28.4 min, t2

= 55.4

min.)

3.8.2. Et2Zn Addition to Imines

General procedure for carbene catalyzed Et2Zn addition to imines

An imidazolinium carbene precursor (0.03 mmol) and t-BuOK (3.4 mg, 0.03 mmol) were

placed to a dry Schlenk flask and dissolved in dry PhMe. (1 mL). After 5 min stirring, Et2Zn

(0.5 mL of 1 M solution in hexane) was added. After another 5 min, imine (0.30 mmol) was


Base (0.1 eq), Et2Zn 1.1 eq., PhMe, r.t.

O

300 301

HO*


O

Base (0.1 eq), Et2Zn 1.1 eq., PhMe, r.t.

OH

*

187 299

196 Experimental

added. Reaction mixture was stirred at r.t. for 20 h. The reaction mixture was quenched by

addtion of 1M HCl (0.5 mL) and extracted with Et2O (3 x 5 mL). The combined organic

phases were dried over Na2SO

4and the solvent was removed under reduced pressure giv-

ing the crude product which was purified by FCC (petroleum ether/EtOAc, 9/1).

N-Benzyl-4-methylbenzenesulfonamide (302)

From (E)-N-benzylidene-4-methylbenzenesulfonamide (272) (79 mg, 0.30 mmol) and

Et2Zn (0.5 mL 1 M solution in hexane, 0.50 mmol) in PhMe (1 mL), catalyzed by the car-

bene generated from 235F (12 mg, 0.03 mmol) and t-BuOK (3 mg, 0.03 mmol) as a white

solid (64 mg, 81%). Spectral data were consistent with literature values.173

3.8.3. Conjugated Addition of Et2Zn

Carbene catalyzed conjugated addition of Et2Zn to chalcone

1,3-Diphenylpentan-1-one (304)

231F (13 mg, 0.03 mmol) was suspended in PhMe (1 mL) and KHMDS (60 μL, 0.03

mmol) was added. After 5 min stirring, Et2Zn (0.5 mL of 1 M solution in hexane, 0.50

mmol) was added. After another 5 minutes, chalcone (62 mg, 0.30 mmol) was added. The

mixture was stirred at r.t. for 40 h. The mixture was quenched by addition of 1M HCl (0.5

mL) and extracted with Et2O (3 x 5 mL). The combined organic phases were dried over

Na2SO

4and the solvent was removed under reduced pressure giving the crude product

which was purified by FCC (petroleum ether/EtOAc, 9/1) giving the title compound as a

white solid (26 mg, 37%). Spectral data were consistent with literature values.232

231F (0.1 eq)

KHMDS (0.1 eq.), Et2Zn 1.1 eq., PhMe, 40 hPh

O

Ph Ph

O

Ph

304

37%, 0% ee303

235F (0.1 eq)

t-BuOK (0.1 eq), Et2Zn 1.1 eq., PhMe, r.t.

NTs

NH

Ts

302

81%

272

Experimental 197

3.9. Application of Imidazolinium Salts as a Phase Transfer Catalysts

Michael reaction under solid-liquid phase transfer conditions

Dimethyl 2-(3-oxo-1,3-diphenylpropyl)malonate (305)

Catalyst (210B) (13 mg, 0.02 mmol, 0.1 eq.) was placed to a Schlenk flask, followed by

chalcone (42 mg, 0.20 mmol) and K2CO

3(166 mg, 1.20 mmol, 6 eq.). To the mixture, PhMe

(900 μL) and DCM (100 μL) were added successively. After 5 min stirring, dimethyl-

malonate (40 mg, 34 μL, 0.30 mmol, 1.5 eq.) was added. The mixture was vigorously stirred

at r.t. for 16 h. The reaction was quenched by the addition of water (2 mL) and the organic

phase was separated and the aqueous phase extracted with EtOAc (3 x 5 mL). The combined

organic phases were dried (Na2SO

4) and the solvent was removed under reduced pressure.

The crude product was purified by FCC (petroleum ether/EtOAc, 9/1) giving the title com-

pound as a white solid (30 mg, 43%). Spectral data were consistent with literature values.233

Enantiomeric excess was determined by optical rotation.

210B, 10 mol%, K2CO3 (6 eq.)

Ph

O

Ph

COOMe

COOMe

+

Ph

O

Ph

MeOOC COOMe

305

43%, 0% ee

PhMe/DCM, 10/1, r.t., 16 h

303

198 Experimental

3.10. Application of Imidazolinium Salts as a Shift Reagents

NMR experiments with Mosher’s salt

Preparation of Mosher salt

rac-Mosher’s acid (302 mg, 1.29 mmol) was dissolved in water (1 mL) and solution of

KOH (72 mg, 1.29 mmol) in water (3 mL) was added. The mixture was stirred at r.t. for 15

min and water was removed under reduced pressure. Remaining solid was further dried in

vacuo giving the potassium Mosher’s carboxylate as a white solid (351 mg, quant.).

(S)-Mosher’s carboxylate was prepared in the same manner from the (S)-Mosher’s acid.

Experiment for stereodiscrimination of potassium Mosher’s carboxylate

rac-Mosher’s salt (0.50 mmol) and corresponding imidazolinium salt (0.50 mmol, 1 eq.)

were dissolved in acetone-d6 and the 1H-NMR and 19F-NMR were recorded at r.t. For

chemical shifts and stereodiscrimination see Table 33, page 86 and Table 34, PAge 87.

Regeneration of salt

Regeneration of imidazolinium salt 231C. Acetone-d6 was removed under reduced pres-

sure and the remaining rest was dissolved in CHCl3

(2 mL). The organic phase was washed

with water (4 x 3 mL), dried over MS 3Å and evaporated, giving the pure imidazolinium

salt 231C.

MeO COOH

CF3

KOH(aq.)

r.t., 15 min.

MeO COO−

CF3

K+

JUR682

quant.

Experimental 199

3.11. Application of Imidazolinium Based Ionic Liquid as Reaction Medium


General procedure

The amine catalyst (1.00 mmol) was placed in a dry Schlenk flask and ionic liquid 196C

(400 µL, ca 600 mg) was added. An aldehyde (1.00 mmol) and methyl acrylate (5) (135 µL,

1.50 mmol, 1.5 eq.) were added sequentially. The reaction was stirred at r.t. for 48 h. The

reaction mixture was extracted with Et2O (4 x 5 mL) and the combined ether fractions were

evaporated. The crude product was purified by FCC (petroleum ether/EtOAc, 95/5), giving

the desired product.

Regeneration of ionic liquid

Remaining ionic liquid after the extraction was dissolved in CHCl3

(5 mL) and washed

with 0.5 M HCl (5 mL), water (3 x 5 mL) and dried (Na2SO

4). The solvent was removed

under reduced pressure. The ionic liquid was further dried in vacuo, giving 1,3-dimethyl-2-

(phenyl)imidazolinium bis(trifluoromethylsulfonyl)-imide (196C) (470 mg, 78%), NMR

data were identical with the reference sample of 196C. An additional portion of 196C (80

mg, 15%) was obtained from FCC, by eluation with DCM/MeOH (95/5).

Methyl 2-(hydroxy(phenyl)methyl)acrylate (308)

From benzaldehyde (167) (102 µL, 1.00 mmol), methyl acrylate (290) (135 µL, 1.50

mmol) and quinuclidine (115 mg, 1.00 mmol) in ionic liquid 196C (400 µL) as a colorless

oil (127 mg, 66%). Spectral data were consistent with literature values.234

Methyl 2-((4-chlorophenyl)(hydroxy)methyl)acrylate (309)

From 4-chlorobenzaldehyde (175) (145 mg, 1.00 mmol), methyl acrylate (290) (135 µL,

1.50 mmol) and quinuclidine (115 mg, 1.00 mmol) in ionic liquid 196C (400 µL) as color-

less oil (127 mg, 66%). Spectral data were consistent with literature values.235

quinuclidine, r.t., 48 h

O

+

O

O

O

O

OH

Cl Cl

175 290 309

66%

196C

quinuclidine, r.t., 48 hPh

O

+

O

O

O

O

OH

Ph

196C

167 290 308

66%

200 Experimental

Methyl 2-(hydroxy(pyridin-2-yl)methyl)acrylate (310)

From 2-pyridinecarbaldehyde (181) (96 µL, 107 mg, 1.00 mmol), methyl acrylate (290)

(135 µL, 1.50 mmol) and quinuclidine (115 mg, 1.00 mmol) in ionic liquid (196C) (400 µL)

as colorless oil (133 mg, 69%). Spectral data were consistent with literature values.236

Methyl 2-((4-methoxyphenyl)(hydroxy)methyl)acrylate (311)

From 4-methoxybenzaldehyde (307) (122 µL, 1.00 mmol), methyl acrylate (290) (135

µL, 1.5 mmol) and quinuclidine (115 mg, 1.00 mmol) in ionic liquid 196C (400 µL) as col-

orless oil (84 mg, 38%). Spectral data were consistent with literature values.234

Methyl 3-hydroxy-2-methylene-5-phenylpentanoate (312)

From phenylpropionaldehyde (292) (137 µL, 1.00 mmol), methyl acrylate (290) (135 µL,

1.50 mmol) and quinuclidine (115 mg, 1.00 mmol) in ionic liquid 196C (400 µL) as color-

less oil (97 mg, 44%). Spectral data were consistent with literature values.237

2-(Hydroxy(phenyl)methyl)cyclopent-2-enone (315)

From benzaldehyde (167) (102 μL, 1.00 mmol) and cyclopenten-2-one (293) (128 μL,

1.50 mmol) and quinuclidine (115 mg, 1.00 mmol) in ionic liquid 196C (400 μL) as yellow

oil (33 mg, 17%). Spectral data were consistent with literature values.238


Ph

OHO

+

O O

196C

167 293 315

17%

quinuclidine, r.t., 48 h+

O

O

O

O

OH

CHO

292 290 312

49%

196C


O

+

O

O

O

O

OH

MeO MeO

307 209 311

69%

196C

Nquinuclidine, r.t., 48 h

O

+

O

O

O

O

OH

N

196C

181 290 310

69%

Experimental 201

2-(Hydroxy(phenyl)methyl)cyclohex-2-enone (314)

From benzaldehyde (167) (102 µL, 1.00 mmol), 1-cyclohexen-2-one (313) (147 µL, 1.50

mmol) and quinuclidine (115 mg, 1.00 mmol) in ionic liquid 196C (400 µL) as colorless oil

(92 mg, 46%). Spectral data were consistent with literature values.239

2-(Hydroxy(phenyl)methyl)acrylamide (317)

From benzaldehyde (167) (102 µL, 1.00 mmol), acrylamide (316) (106 mg, 1.50 mmol)

and quinuclidine (115 mg, 1.00 mmol) in ionic liquid 196C (400 µL) as a white solid (85

mg, 48%). Spectral data were consistent with literature value.240

2-((4-chlorophenyl)(hydroxy)methyl)acrylamide (318)

From 4-chlorobenzaldehyde (175) (145 mg, 1.00 mmol) and acrylamide (316) (106 mg,

1.50 mmol) and quinuclidine (115 mg, 1.00 mmol) in ionic liquid 196C (400 µL) as a white

solid (105 mg, 49%). mp 111-112 °C, MS (EI), m / z 210 (M+ − H, 40%), 166 (40), 139

(95), 77 (100), 71 (50), 55 (60); IR (KBr) 3385vs, 3189s, 1658vs, 1624s, 1604s, 1491m,

1198m, 606m cm-1; 1H-NMR (200 MHz, DMSO-d6) δ = 7.47 (s, 1 H, NH2) 7.39-7.28 (m,

4 H, H-Ar), 7.01 (s, 1 H, NH2), 5.82-5.77 (m, 2 H, COCCH

2), 5.62-5.60 (m, 1 H, CHOH),

5.50-5.48 (m, 1 H, CHOH); 13C-NMR (50 MHz, DMSO-d6) δ = 168.4 (CONH2), 147.0

(CCH2), 142.3 (C-Ar), 131.4 (C-Ar), 128.5 (C-Ar), 127.8 (C-Ar), 117.5 (CCH

2), 70.3

(CHOH). HRMS (EI) Calculated for C10

H10

NO2ClNa 234.0294, found 234.0292.

3.11.2. Addition of Grignard Reagents to Benzaldehyde

General procedure

Commercially available Grignard reagent (phenylmagnesium bromide (1 M in THF) or

hexylmagnesium bromide (2M in Et2O) (3.00 mmol) was placed to a dry Schlenk flask

under nitrogen and the solvent was removed in vacuo. Ionic liquid 196C (600 μL, ca 900

mg) was added and reaction mixture formed a clear solution. Benzaldehyde (101 µL, 1.00

mmol) was added at once. The reaction mixture warmed up spontaneusly. After the exother-


+

O

NH2

OH

NH2

O

ClCl

318

49%

O

196C

316175


O

+

O

NH2

O

NH2

OH

167 167 317

48%

196C


Ph

OH

O

+

O O

167 313 314

45%

196C

202 Experimental

mic reaction ended, the reaction mixture was heated up to 40 °C for 3 h. The reaction mix-

ture was quenched with saturated solution of NH4Cl and extracted with hexane (4 x 10 mL).

The combined organic layers were dried (Na2SO

4) and the solvent was distilled of under

reduced pressure. The crude product was purified by FCC (petroleum ether/EtOAc, 95/5),

giving the corresponding alcohol.

Regeneration of ionic liquid

The Ionic liquid remained after the extraction with hexane as a phase below the aqueous

phase. It was dissolved in CHCl3

(5 mL) and washed with water (3 x 5 mL) and dried

(Na2SO

4). The solvent was removed under reduced pressure and the ionic liquid was further

dried in vacuo, giving 1,3-dimethyl-2-(phenyl)imidazolinium bis(trifluoromethylsulfonyl)-

imide (196C) (837 mg, 93%), the NMR data were identical with the reference sample 196C.

Diphenyl methanol (321)

From phenylmagnesium bromide (319) (3 mL 1M THF solution, 3.00 mmol) and ben-

zaldehyde (167) (102 µL, 1.00 mmol) in ionic liquid 196C (600 µL) as a white solid (125

mg, 68%). Spectral data were consistent with literature values.241, 242

1-Phenyl-heptan-1-ol (322)

From hexylmagnesium bromide (322) (1.5 mL 2 M Et2O solution, 3.00 mmol) and ben-

zaldehyde (167) (102 µL, 1.00 mmol) in ionic liquid 196 (600 µL) as a colorless oil (136

mg, 71%). Spectral data were consistent with literature values.243

Deuterium exchange experiment using ionic liquid and hexylmagnesium bromide

Hexylmagnesium bromide (320) (1 mL, 2.00 mmol) was placed to a Schlenk flask and

the solvent was evaporated in vacuo. Ionic liquid 196C (300 mg, 0.75 mmol) was added and

the reaction mixture was stirred at 40 °C for 1 h. The reaction mixture was quenched by the

addition of D2O. The ionic liquid was separated from the aqueous phase and dissolved in

CHCl3. The organic phase was washed with water (3 x 3 mL), dried (Na

2SO

4) and the sol-

vent was distilled of under reduced pressure. The ionic liquid was dried in vacuo. Record-

ed 1H-NMR were shown to be identical with the reference sample of 196C.

40 °C, 3 hPh

Ph

OHO

+MgBr

196C

167 320 322

40 °C, 3 hPh

Ph Ph

OHO

+Ph

MgBr

196C

167 319 321

Experimental 203

3.12. Application of Silacycles as Catalysts

3.12.1. Inverse Electron Demand Aza Diels-Alder Reaction

General procedure for silicon Lewis acid catalyzed Inverse electron demand aza

Diels-Alder reaction

Catalyst precursor (0.04 mmol, 10 mol%) and AgNTf2

(12 mg, 0.03 mmol, 10 mol%)

were placed to a dry Schlenk flask and the solvent (1 mL) (see table) was added. Reaction

mixture was stirred at r.t. for 5 minutes and then cooled down to appropriate temperature

(see Table 37, page 97 and Table 38, page 98). (E)-N-benzylideneaniline (54 mg, 0.30

mmol) and dienophile (0.60 mmol, 2 eq.) were added successively. The reaction mixture

was stirred and the progress was monitored by TLC (petroleum ether/EtOAc 9:1) The reac-

tion mixture was quenched by the addition of saturated NaHCO3

(2 mL) and extracted with

EtOAc (3 x 5 mL). THe combined organic phases were dried (Na2SO

4) and the solvent was

removed under reduced pressure. FCC (petroleum ether/EtOAc, 95/5) gave the correspon-

ding quinoline.

2,3,3a,4,5,9b-Hexahydro-4-phenylfuro[3,2-c]quinoline (281)

From (E)-N-benzylideneaniline (254) (54 mg, 0.30 mmol) and dihydrofurane (280) (45

μL, 0.60 mmol, 2 eq.), catalyzed by silicon species generated from silacycle (0.04 mmol)

and AgNTf2

(12 mg, 0.03 mmol, 10 mol %) as a mixture of diastereomers. For reaction

yields see Table 37, page 97. For spectral data see page 192.

3,4,4a,5,6,10b-Hexahydro-5-phenyl-2H-pyrano[3,2-c]quinoline (283)

From (E)-N-benzylidenebenzenamine (254) (54 mg, 0.30 mmol) and dihydropyrane

(282) (56 μL, 0.60 mmol, 2 eq.), catalyzed by silicon species generated from silacycle (0.04

mmol) and AgNTf2

(12 mg, 0.03 mmol, 10 mol %). For reaction yields see Table 37, page

97. For spectral data see page 193.

solvent

Silacycle, AgNTf2N +

NH

NH

283b283a

+

O O

O

282254

N +

O

NH

O

NH

O

281a

+

281b280254

solvent

Silacycle, AgNTf2

4-Phenyl-3,3a,4,5-tetrahydro-2H-cyclopenta[c]quinolin-1(9bH)-one (325)

From (E)-N-benzylidenebenzenamine (254) (54 mg, 0.30 mmol) and cyclopenten-2-one

(313) (58 μL, 0.60 mmol, 2 eq.), catalyzed by silicon species generated from 237 (0.04

mmol) and AgNTf2

(12 mg, 0.03 mmol, 10 mol %) as a colorless liquid (15 mg, 17%).

Diels-Alder reaction of sulphur containing compounds

O-Ethyl-3-phenylbicyclo[2.2.1]hept-5-ene-2-carbothioate (287a)

Catalyst precursor (244) (7 mg, 0.03 mmol) and AgNTf2

(12 mg, 0.03 mmol, 10 mmol)

were placed to a dry Schlenk flask and PhMe (1 mL) was added. The mixture was stirred at

r.t. for 5 min and then cooled down to −20 °C. (E)-O-Ethyl 3-phenylprop-2-enethioate (284)

(53 μL, 0.30 mmol) and cyclopentadiene (50 mL, 0.60 mmol) were added successively. The

mixture was warmed up to r.t. and stirred for 96 h. FCC (petroleum ether) gave the title com-

pound as colorless oil. Spectral data were consistent with literature values.167 Enantiomeric

excess was determined by HPLC: OD-H (hexane, 0.1 mL/min, t1

= 52 min, t2

= 55 min).

244 (0.1 eq),. AgNTf2 (0.1 eq.)+

S

OEt

Ph

S

OEt

PhMe, −20 to 0 °C, 96 h

287a

29%, 0% ee

284

N +

NH

NH

325b325a

+solvent

237, AgNTf2

O

O O

254 313

204 Experimental

Experimental 205

3.13. Application of Chiral Thioureas in Catalysis


2-(hydroxy(phenyl)methyl)cyclohex-2-enone (314)

Thiourea (252) (17 mg, 0.01 mmol) and quinuclidine (119 mg, 1.00 mmol) were added

placed to a dry Schlenk flask, followed by benzaldehyde (167) (101 μL, 1.00 mmol) and

cyclohexen-2-one (147 μL 97%, 1.50 mmol). The mixture was stirred at r.t. for 72 h. FCC

(petroleum ether/EtOAc, 90/10) gave the title compound as a colorless liquid. Spectral data

were consistent with literature values.239 Enantiomeric excess was determined by measure-

ment of optical rotation.

O

Ph

O

+252 (0.1 eq.), quinuclidine(1 eq.)

r.t., 72 h

Ph

OH O

314

77%, 0% ee313167

References 207

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Appendix 215

A. Appendix

A1. Structural Properties of Imidazolinium Salts

X-Ray structure of an imidazolinium salts were measured from the selected samples. For

the increase of the possitive charge on the C-2 carbon of the salt it was proposed, that dif-

ferent EWG groups on the phenyl ring could via −I effect decrease the electron density on

the NC+N unit of the imidazolinium ring, thus resulting in higher Lewis acidity and higher

reactivity. Differences in reactivity depending on the substituent on the phenyl ring were

observed (See Table 17, page 64), confirming the role of the different EWG groups in effect-

ing the Lewis acidity/reactivity, nevertheless, the differences were not that dramatic. From

the X-ray structure of the (4R,5R)-2-(4-chlorophenyl)-1,3-dimethyl-4,5-diphenylimida-

zolinium bromide 165A (Figure 1) it is possible to see, the the phenyl ring and the imida-

zolinium ring containg torsion angle of 112° (68° respectively), which is showing that the

outflow of electron density from imidazolinium NC+N unit should process mainly over the

σ bond and that the NC+N and the phenyl ring are not conjugated. Since there is a possibil-

ity of free rotation of the phenyl ring a −M effect is also expected.

Figure 1: X-Ray Structure of Imidazolinium bromide 165A

More dramatic changes in reactivity were observed when different counter anions were

used with the same cation.

216 Appendix

A2. 1H-NMR Spectras of the Selected Compounds

1

1H-NMR of 189

2

1H-NMR of 189A

3

1H-NMR of 189B

Appendix 217

A2. 1H-NMR Spectras of the Selected Compounds

4

1H-NMR of 189D

5

1H-NMR of 174C

218 Appendix

Table A1: Numbering of Achiral Imidazolinium Salts

Br-

PF6-

NTf2−

B[C6H3(CF3)2]4−

N N+

Ph

PhPh168A 168B 168C

N N+

PhPh

Cl183A 183B 183C 183D

N N+

PhPh

Cl

184A 184B 184C 184D

N N+

PhPh

ClCl185A 185D

N N+

PhPh

Cl

Cl

186A 186B

N N+

PhPh

FF

F

F

F

187A 187B 187C 187D

N N+

PhPh

S

189A 189B 189D

N N+

PhPh

N

190A 190B 190D

N N+

Ph

196A 196B 196C

N N+

PhPh

Cl192C

N N+

ClPhPh 194C

N N+

N

PhPh 193A 193B 193C

Appendix 219

Table A2: Numbering of Chiral Imidazolinium Salts and Bis-Cations

Br-

PF6-

NTf2−

B[C6H3(CF3)2]4−

B(C6F5)4−

N N+

PhPh

Cl

164A 164B 164C 164D 164E

N N+

PhPh

Cl

165A 165B 165C 165D 165E

N N+

N

PhPh201D

N N+

PhPh

PhPh

Cl

162A 162B 162D 162E

N N+

PhPh

PhPh

Cl

163B

N N+

N

PhPh

PhPh 205A 205B 187C

N

N+

N+

N

208B 208D

N

N+

Ph

Ph

N+

NPh

Ph

209C 209D

N

N+

N+

N210B 190D

220 Appendix

Table A3: Numbering of Imidazolinium carbene precursors

BF4− NTf2

−B[C6H3(CF3)2]4

−

N N+

PhPh

164A

N N+

PhPh

PhPh

220F 220C

N N+

224F 224C

N N+

HO

Ph

OH

Ph231F 231D

N N+

HO

Ph

OH

Ph

HOOH

232F 232D

N N+

HOOH

233F 233C

N N+

HOOH

234F 234C

N N+

OH HO

235F

Václav Jurčík

Development and Application of Novel Metal Free Lewis Acids and Pseudo Lewis Acids

The thesis deals with the development of new metal free catalyst and their application in

organocatalysis. The development of more efficient and environmental friendly catalysts is of great

importance for the field of organic synthesis and industrial processes.

The presented work is divided into three main sections: Introduction, Results and Discussion and

the Experimental.In the Introduction, a brief summary of organocatalysis is given, based on the different modes of

activation through the catalyst.

The first chapter of the Results and Discussion section, starts with a discussion of methods to pre-

pare imidazolinium salts. It continues with the synthesis of chiral diamines as potential precursors

for the imidazolinium salts. The diamines are prepared in high yields, using BOC-protected amino-

acids as starting material. Additionally, the development of a new route to aminals is presented. The

reaction of aldehydes and diamines in water or without the presence of solvent leads to the aminals

in high yields and purity. This method has a great advantage over the conventional methods to pre-

pare aminals. Preparation of imidazolinium salts via the oxidation of aminals is described. In addi-

tion, the synthesis of imidazolinium carbene precursor is presented. By these methods, large series

of achiral and chiral imidazolinium salts were prepared. Chiral imidazolinium based dications were

synthesized for the first time. The properties of the salts were then modified by using different count-

er anions.

In the next part, the preparation of novel chiral N,N and N,O silacycles is described. These com-

pounds could be oxidized in situ giving a high reactive NSi+N species, which can be used as metal

free Lewis acids

Finally the synthesis of novel chiral thiourea based pseudo Lewis acids (H- bonding activators)

is described in last part.

The second chapter of section two deals with the application of the prepared compounds in catal-

ysis.

Imidazolinium salts are used as catalysts in the aza Diels-Alder reaction and the inverse electron

demand aza Diels-Alder reaction. The desired products of the reactions were obtained in excellent

yields. The effect of different substituents at C-2 position is presented. Chiral imidazolinium salts

were also used, but no enantioselectivity was observed. These results are discussed.

In part two, some of the chiral imidazolinium carbene precursors are applied in addition of Et2Zn

to aldehydes, giving the corresponing alcohols in high yields and moderate enantioselectivities.

In part four, some of the chiral imidazolinium salts are presented as efficient shift reagents. Their

ability of stereodiscrimination of Mosher's carboxylate is studied.

In part five, one of the imidazolinium salts is shown to be a room temperature ionic liquid (RTIL)

stable under basic conditions. It is demonstrated, that it can be used as an inert and recyclable reac-

tion medium for the Baylis-Hillman reaction and the addition of Grignard reagents to the aldehydes.

In the part six, application of Si+ catalysts in the inverse electron demand aza Diels-Alder reac-

tion is described. The compounds are shown to be highly efficient catalysts even at low tempera-

tures.

The application of chiral thiourea catalysts in Baylis-Hillman reaction and others is described in

last part.

In the Experimental, details of the preparation and characterization of described compounds and

procedures are given as well as the crystal structures of selected compounds.

Acknowledgements

On the first place, I would like to thank Prof. Dr. René Wilhelm for his invaluable help

and guidance over the last three years and for a very interesting research topic. He truly was

a Doktorvater, with whom I never felt as an orphan in the jungle of organic chemistry.

I would also like to thank Prof. Dr. Dieter Kaufmann for being a co-referee of this work,

for his support during my stay at the Institute of Organic Chemistry and for stimulating dis-

cussions.

My group coleagues and friends, Amélie Blanrue, Nicole Clemens, Dheeraj Jain, Chris-

tian Torborg, Andreas Winkel, Oksana Sereda and Muzhar Gilani, I thank for good times in

the lab and out of it. Muzhar Amjad Gilani, I am very grateful for proofreading parts of this

thesis and Andreas Winkel, I would like to thank for translation of the abstract to German.

Many thanks go to all the coworkers in the Institute for Organic Chemistry for kind

cooperation and for making the institute such a pleasant place to work.

This work could not be done without the help technical staff of the institute of Organic

Chemistry. Therefore I would like to thank Dr. Jan Namyslo, Claudia Stanitzek and. Birgit

Stövesant for measuring the NMR spectras, PD Dr. Schmidt for measuring the ESI-MS and

Maike Weigert and Marko Spillner for measuring the EI-MS.

I would also like to ackowledge former F-Practicum students: Benjamin Schäffner,

Johanna Reuber, Timo Carstens, Christian Torborg, Susanne Flügge, Antje Oelmann, Stefan

Dumke, Julia Ganzel, Andreas Winkel, Marcel Albrecht, Lars Nothdurft, Mathis Duwel,

Niels Pook, Werner Telle, Tian Heng, Heinrike Rempel, Jutta Ivens and Christian Kaldun

for performing some reactions.

For measuring X-ray structure, I acknowledge Björn Blaschkowski.

Závěrem, ale o to víc a upříměji bych chtěl poděkovat svým rodičům a bratrovi za jejich

podporu a lásku po celé ty roky.

Vaclav Jurcik - Development and Application of Novel Metal Free … · 2006. 11. 8. · Aldol...

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Transcript of Vaclav Jurcik - Development and Application of Novel Metal Free … · 2006. 11. 8. · Aldol...