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TRANSCRIPT
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
3.11.1. Baylis-Hillman Reaction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 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
3.13.1. Baylis-Hillman Reaction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 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
Results and Discussion 31
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
32 Results and Discussion
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
Results and Discussion 33
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+
34 Results and Discussion
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
Results and Discussion 35
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
1. N-methyl morpholine
HN OH
OR4
Boc
2. i-BuOCOCl
3. R1-NH2
HN HN
OR4
Boc
R1
36 Results and Discussion
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
Results and Discussion 37
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
38 Results and Discussion
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
Results and Discussion 39
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
40 Results and Discussion
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+
Results and Discussion 41
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.
42 Results and Discussion
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
Results and Discussion 43
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
44 Results and Discussion
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
Results and Discussion 45
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
+
46 Results and Discussion
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
Results and Discussion 47
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
48 Results and Discussion
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
Results and Discussion 49
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−
50 Results and Discussion
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
−
−
Results and Discussion 51
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
52 Results and Discussion
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
Results and Discussion 53
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
54 Results and Discussion
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
Results and Discussion 55
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.
56 Results and Discussion
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
Results and Discussion 57
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
58 Results and Discussion
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
Results and Discussion 59
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
60 Results and Discussion
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
Results and Discussion 61
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
62 Results and Discussion
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
Results and Discussion 63
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
64 Results and Discussion
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
Results and Discussion 65
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).
66 Results and Discussion
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
Results and Discussion 67
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
68 Results and Discussion
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
Imidazolinium catalyst
no reaction
253
253
Results and Discussion 69
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
70 Results and Discussion
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
Results and Discussion 71
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
72 Results and Discussion
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.
Results and Discussion 73
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
74 Results and Discussion
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
Results and Discussion 75
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
76 Results and Discussion
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
Results and Discussion 77
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
78 Results and Discussion
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
Results and Discussion 79
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
80 Results and Discussion
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
Results and Discussion 81
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
−PhMe t-BuOK r.t 35 44
9 233F N N+
HOOH
BF4
−PhMe t-BuOK r.t 38 35
10 234F N N+
HOOH
BF4
−PhMe t-BuOK r.t. 70 8
82 Results and Discussion
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
Results and Discussion 83
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
84 Results and Discussion
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
Results and Discussion 85
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
86 Results and Discussion
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
Results and Discussion 87
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−
88 Results and Discussion
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−
Results and Discussion 89
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)−
90 Results and Discussion
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.
Results and Discussion 91
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.
92 Results and Discussion
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.
2.2.5.1. Baylis-Hillman Reaction
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
Results and Discussion 93
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
4 Quinuclidine 48 309 66
7 181 2-C5H
4N Quinuclidine 48 310 69
8 307 4-MeO-C6H
4 Quinuclidine 48 311 38
9 292 CH2CH
2C
6H
4 Quinuclidine 48 312 44
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
94 Results and Discussion
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
Results and Discussion 95
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
96 Results and Discussion
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
Results and Discussion 97
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
98 Results and Discussion
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
Results and Discussion 99
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
100 Results and Discussion
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
Results and Discussion 101
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
2.2.7.3. Baylis-Hillman Reaction
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
102 Results and Discussion
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%
Results and Discussion 103
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%
104 Results and Discussion
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
Imidazolinium carbene precursor (0.1 eq)
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
Imidazolinium catalyst
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
*
Results and Discussion 105
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
106 Results and Discussion
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.
1. N-methyl morpholine
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)
From BOC-L-valin (109) (4.35 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 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)
From BOC-L-valin (109) (3.26 g, 15.00 mmol), N-methylmorpholine (1.65 mL 98%,
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
1. N-methyl morpholine
HN OH
O
Boc
2. i-BuOCOCl
3. 2-amino-biphenylHN HN
O
Boc
121
95%
109
Ph
1. N-methyl morpholine
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)
From BOC-L-valin (109) (10.86 g, 50.00 mmol), N-methylmorpholine (5.61 mL 98%,
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
1. N-methyl morpholine
HN OH
O
Boc
2. i-BuOCOCl
3. o-phenylendiamine, 0.5 eq.
NHHN
O
Boc
HNNHBoc
O
124
99%
109
1. N-methyl morpholine
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)
From BOC-L-valin (109) (10.860 g, 50.00 mmol), N-methylmorpholine (5.61 mL, 50.00
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)
From BOC-L-valin (109) (10.21 g, 47.00 mmol), N-methylmorpholine (5.29 mL, 47.00
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-
1. N-methyl morpholine
HN OH
OPh
Boc
2. i-BuOCOCl
3. (R)-(+)-1-phenyl-ethylamineHN HN
OPh
Boc Ph
128
96%
110
1. N-methyl morpholine
HN OH
OPh
Boc
2. i-BuOCOCl
3. anilineHN HN
OPh
Boc
Ph
127
99%
110
1. N-methyl morpholine
HN OH
O
Boc
2. i-BuOCOCl
3. aq. MeNH2
HN HN
O
Boc
126
96%
109
1. N-methyl morpholine
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); 13C-NMR (50 MHz, CDCl
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.
1. N-methyl morpholine
OH
O
2. i-BuOCOCl
3. (−)-norephedrineHN
O
N
Boc
N
BocPh
HO130
96%111
1. N-methyl morpholine
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
were consistent with literature values.218
(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
were consistent with literature values.222
(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); 13C-NMR (50 MHz, CDCl
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
consistent with literature values.124
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-
Ar), 130.6 (C-Ar), 129.3 (C-Ar), 128.7 (C-Ar), 128.66 (C-Ar), 127.8 (C-Ar), 127.1 (C-Ar),
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.
THF, reflux, 16 hNHHN
LAHNHHN
O
O
155
80%
150
Ph Ph
THF, reflux, 48 hNHHN
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.
THF, reflux, 36 hNHHN
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
2N); 13C-NMR (100 MHz, CDCl
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
2N); 13C-NMR (100 MHz, CDCl
3) δ = 140.1 (C-
Ar), 137.7 (C-Ar), 135.2 (C-Ar), 129.5 (C-Ar), 128.6 (C-Ar), 128.5 (C-Ar), 128.2 (C-Ar),
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
2N); 13C-NMR (100 MHz, CDCl
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
consistent with literature values.130
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
2N); 13C-NMR (100 MHz, CDCl
3) δ = 159.5 (C-
Ar), 140.0 (C-Ar), 130.3 (C-Ar), 129.5 (C-Ar), 128.4 (C-Ar), 121.5 (C-Ar), 110.6 (C-Ar),
80.1 (NCHN), 57.5 (OCH3), 55.9 (NCH
2CH
2N), 51.1 (PhCH
2N). Anal. Calcd for
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
2N); 13C-NMR (100 MHz, CDCl
3) δ = 146.4 (C-
Ar), 139.4 (C-Ar), 129.0 (C-Ar), 128.6 (C-Ar), 128.0 (C-Ar), 127.3 (C-Ar), 127.1 (C-Ar),
126.2 (C-Ar), 84.0 (NCHN), 57.3 (NCH2CH
2N), 50.7 (PhCH
2N). Anal. Calcd for
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
2N); 13C-NMR (100 MHz, CDCl
3) δ = 161.8 (C-
Ar), 148.6 (C-Ar), 139.4 (C-Ar), 137.3 (C-Ar), 128.9 (C-Ar), 128.5 (C-Ar), 127.2 (C-Ar),
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),
129.5 (C-Ar), 128.9 (C-Ar), 128.7 (C-Ar), 128.5 (C-Ar), 128.0 (C-Ar), 127.7 (C-Ar), 127.1
(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
consistent with literature values.130
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
2); 13C-NMR (100 MHz, CDCl
3) δ = 140.6 (C-Ar), 140.4 (C-Ar), 135.6 (C-
Ar), 130.2 (C-Ar), 129.2 (C-Ar), 128.6 (C-Ar), 128.6 (C-Ar), 128.5 (C-Ar), 127.0 (C-Ar),
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); 13C-NMR (100 MHz, CDCl
3) δ = 137.5 (C-
Ar), 135.6 (C-Ar), 130.9 (C-Ar), 129.6 (C-Ar), 129.3 (C-Ar), 127.7 (C-Ar), 86.3 (NCHN),
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
2); 13C-NMR (50 MHz, CDCl
3) δ = 134.8 (C-
Ar), 134.2 (C-Ar), 130.0 (C-Ar), 129.3 (C-Ar), 127.7 (C-Ar), 125.4 (C-Ar), 83.1 (NCHN),
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
(C-Ar), 128.7 (C-Ar), 128.3 (C-Ar), 128.2 (C-Ar), 128.1 (C-Ar), 127.8 (C-Ar), 127.7 (C-
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); 13C-NMR (50 MHz, CDCl
3) δ = 139.8 (C-Ar),
139.3 (C-Ar), 137.5 (C-Ar), 130.9 (C-Ar), 129.6 (C-Ar), 129.1 (C-Ar), 128.3 (C-Ar), 128.2
(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
benzene, Dean-Stark, reflux
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),
142.4 (C-Ar), 140.6 (C-Ar), 140.5 (C-Ar), 134.8 (C-Ar), 132.3 (C-Ar), 129.2 (C-Ar), 128.5
(C-Ar), 128.4 (C-Ar), 128.3 (C-Ar), 128.1 (C-Ar), 127.8 (C-Ar), 127.75 (C-Ar), 127.73 (C-
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.
benzene, Dean-Stark, reflux
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); 13C-NMR (50 MHz, CDCl
3) δ
= 145.6 (C-Ar), 143.4 (C-Ar), 143.3 (C-Ar), 141.5 (C-Ar), 140.9 (C-Ar), 132.5 (C-Ar),
130.9 (C-Ar), 128.3 (C-Ar), 128.25 (C-Ar), 128.1 (C-Ar), 128.0 (C-Ar), 127.9 (C-Ar),
127.8 (C-Ar), 127.6 (C-Ar), 127.3 (C-Ar), 127.13 (C-Ar), 127.06 (C-Ar), 126.9 (C-Ar),
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)
From (1S,2S)-1,2-diphenyl-N,N’-bis((R)-1-phenylethyl)ethane-1,2-diamine (94) (1.50 g,
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,
benzene, Dean-Stark, reflux
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-
Ar), 142.5 (C-Ar), 135.3 (C-Ar), 128.9 (C-Ar), 128.6 (C-Ar), 128.34 (C-Ar), 128.30 (C-Ar),
128.28 (C-Ar), 128.2 (C-Ar), 128.0 (C-Ar), 127.4 (C-Ar), 127.3 (C-Ar), 127.2 (C-Ar),
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%).
Spectral data were consistent with literature values.130
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
Ph neat, 120 °C, 3 h
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); 13C-NMR (100 MHz, CDCl
3) δ
= 146.6 (C-Ar), 144.8 (C-Ar), 138.2 (C-Ar), 131.3 (C-Ar), 128.9 (C-Ar), 128.8 (C-Ar),
128.6 (C-Ar), 128.0 (C-Ar), 127.6 (C-Ar), 127.5 (C-Ar), 127.0 (C-Ar), 126.6 (C-Ar), 80.2
(NCHN), 63.7 (NCH2CH
2N), 56.0 (NCH
2CH
2N), 50.9 (CHCH
3), 45.4 (CHCH
3), 23.6
(CHCH3), 14.8 (CHCH
3). HRMS (ESI) Calculated for: C
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); 13C-NMR (100 MHz, CDCl
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),
128.3 (C-Ar), 127.92 (C-Ar), 127.90 (C-Ar), 127.1 (C-Ar), 126.9 (C-Ar), 124.2 (C-Ar),
Ph
NH HN
Ph neat, 120 °C, 3 h
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
(C-Ar), 129.1 (C-Ar), 128.4 (C-Ar), 128.3 (C-Ar), 128.0 (C-Ar), 127.9 (C-Ar), 127.7 (C-
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-
Ar), 129.6 (C-Ar), 128.9 (C-Ar), 128.8 (C-Ar), 128.5 (C-Ar), 128.4 (C-Ar), 128.3 (C-Ar),
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
2); 13C-NMR (50 MHz, CDCl
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
2). HRMS (ESI) Calculated for: C
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
2N); 13C-NMR (100 MHz, CDCl
3) δ = 167.4 (NC+N),
133.4 (C-Ar), 133.2 (C-Ar), 130.5 (C-Ar), 129.7 (C-Ar), 129.32 (C-Ar), 129.28 (C-Ar),
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
2N); 13C-NMR (100 MHz, CDCl
3) δ = 167.0 (NC+N), 133.6 (C-Ar), 132.8 (C-Ar),
130.8 (C-Ar), 129.8 (C-Ar), 129.4 (C-Ar), 128.7 (C-Ar), 128.4 (C-Ar), 122.2 (C-Ar), 52.2
(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
2N); 13C-NMR (100 MHz, CDCl
3) δ = 164.1 (NC+N), 134.7 (C-Ar),
133.6 (C-Ar), 132.4 (C-Ar), 132.0 (C-Ar), 130.6 (C-Ar), 129.7 (C-Ar), 126.44 (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
(151 mg, 0.80 mmol, 1.1 eq.) in a mixture of CHCl3
(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),
132.3 (C-Ar), 132.0 (C-Ar), 131.8 (C-Ar), 131.0 (C-Ar), 129.8 (C-Ar), 129.63 (C-Ar),
129.59 (C-Ar), 129.0 (C-Ar), 121.0 (C-Ar), 52.3 (NCH2Ph), 48.1 (NCH
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.
CHCl3/H2O, r.t., 30 min
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)
From 1,3-dibenzyl-2-(2-chlorophenyl)imidazolinium bromide (183A) (360 mg, 0.82
mmol) and LiNTf2
(364 mg, 1.23 mmol, 1.5 eq.) in a mixture of CHCl3
(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),
131.0 (C-Ar), 129.8 (C-Ar), 129.69 (C-Ar), 129.66 (C-Ar), 129.1 (C-Ar), 121.9 (C-Ar),
52.3 (NCH2Ph), 47.9 (NCH
2CH
2N); Anal. calculated for C
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%
CHCl3/H2O, r.t., 30 min
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),
129.4 (C-Ar), 128.5 (C-Ar), 120.9 (C-Ar), 52.7 (NCH2Ph), 48.8 (NCH
2CH
2N).
1,3-Dibenzyl-2-(4-chlorophenyl)imidazolinium hexafluoro phosphate (184B)
From 1,3-dibenzyl-2-(4-chlorophenyl)imidazolinium bromide (184A) (100 mg, 0.22
mmol) and KPF6
(45 mg, 0.24 mmol, 1.1 eq.) in a mixture of CHCl3
(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
2N); 13C-NMR (100 MHz, CDCl
3) δ = 166.6 (NC+N),
140.1 (C-Ar), 132.9 (C-Ar), 130.9 (C-Ar), 129.8 (C-Ar), 129.4 (C-Ar), 128.5 (C-Ar), 120.9
(C-Ar), 52.7 (NCH2Ph), 48.8 (NCH
2CH
2N); Anal. calculated for C
23H
22ClF
6N
2P: C, 54.50;
H, 4.37; N, 5.53, found: C, 54.31; H, 4.09; N, 5.37.
CHCl3/H2O, r.t., 30 min
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)
From 1,3-dibenzyl-2-(2-chlorophenyl)imidazolinium bromide (184A) (129 mg, 0.29
mmol) and LiNTf2
(126 mg, 0.45 mmol, 1.5 eq.) in a mixture of CHCl3
(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
2N); 13C-NMR (100 MHz, CDCl
3) δ = 166.3 (NC+N), 140.5 (C-Ar), 132.5
(C-Ar), 131.2 (C-Ar), 130.3 (C-Ar), 129.9 (C-Ar), 129.5 (C-Ar), 128.4 (C-Ar), 121.0 (C-
Ar), 120.36 (q, J = 319 Hz, CF3), 120.35 (C-Ar), 118.8 (C-Ar), 52.5 (NCH
2Ph), 47.8
(NCH2CH
2N); Anal. calculated for C
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
2N); 13C-NMR (100 MHz, CDCl
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%
1. NBA, DME, r.t., 45 min
2. NaB[C6H4(CF3)2]4,CHCl3/H2O, 30 min
B[C6H3(CF3)2]4−
184
CHCl3/H2O, r.t., 30 min
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-
bis(trifluoromethyl)phenyl) borate (185D)
From 1,3-dibenzyl-2-(2,6-dichlorophenyl)imidazolidine (185) (198 mg, 0.50 mmol) and
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
2N); 13C-NMR (100 MHz, CDCl
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);
HRMS (ESI) Calcd. for C23
H21
N2Cl
2: 395.1082, found: 395.1091.
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−
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)
From 1,3-dibenzyl-2-(2,4-dichlorophenyl)imidazolidine (186) (198 mg, 0.50 mmol) and
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
2N); 13C-NMR (100 MHz, CDCl
3) δ = 163.4 (NC+N), 140.7 (C-Ar),
134.9 (C-Ar), 132.9 (C-Ar), 132.3 (C-Ar), 130.6 (C-Ar), 130.0 (C-Ar), 129.7 (C-Ar), 129.4
(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
(186 mg, 0.99 mmol, 1.1 eq.) in a mixture of CHCl3
(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),
131.8 (C-Ar), 131.1 (C-Ar), 130.1 (C-Ar), 129.8 (C-Ar), 129.6 (C-Ar), 129.0 (C-Ar), 120.3
(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.
CHCl3/H2O, r.t., 30 min
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-
bis(trifluoromethyl)phenyl) borate (186D)
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
2N); 13C-NMR (100 MHz, CDCl
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);
Anal. calculated for C55
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
2N); 13C-NMR (100 MHz, CDCl
3) δ = 165.2 (NC+N), 148.8 (C-Ar),
136.8 (C-Ar), 132.6 (C-Ar), 132.4 (C-Ar), 129.8 (C-Ar), 129.5 (C-Ar), 128.6 (C-Ar), 127.9
(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.
Spectral data were consistent with literature values.165
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)
From 1,3-dibenzyl-2-(pentafluorophenyl)imidazolinium bromide (187A) (861 mg, 1.73
mmol) and LiNTf2
(595 mg, 2.08 mmol, 1.2 eq.) in a mixture of CHCl3
(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.
CHCl3/H2O, r.t., 30 min
N N+
PhPh
NTf2−
LiNTf2N N
+
PhPh
Br−
F F
FF
FF
F
FF
F
187C
68%
187A
CHCl3/H2O, r.t., 30 min
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-
bis(trifluoromethyl)phenyl) borate (187D)
From 1,3-dibenzyl-2-(pentafluorophenyl)imidazolinium bromide (187A) (100 mg, 0.20
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
2N); 13C-NMR (100 MHz, CDCl
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
2N); Anal. calculated for C
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
2N); 13C-NMR (100 MHz, CDCl
3) δ = 162.9
(NC+N), 135.9 (C-Ar), 133.1 (C-Ar), 132.9 (C-Ar), 129.7 (C-Ar), 129.5 (C-Ar), 129.3 (C-
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
CHCl3/H2O, r.t., 30 min
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
(87 mg, 0.46 mmol, 1.1 eq.) in a mixture of CHCl3
(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
2N); 13C-NMR (100 MHz, CDCl
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
1. NBA, DME, r.t., 30 min
2. NaB[C6H4(CF3)2]4, Et2O/H2O
B[C6H3(CF3)2]4−
189 189D
63%
S S
CHCl3/H2O, r.t., 30 min
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
2N); 13C-NMR (100 MHz, CDCl
3) δ = 163.4, 140.8 (C-Ar), 134.6 (C-Ar), 132.9
(C-Ar), 132.2 (C-Ar), 130.7 (C-Ar), 129.9 (C-Ar), 129.7 (C-Ar), 129.8 (C-Ar), 129.1 (C-
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
(207 mg, 1.10 mmol, 1.1 eq.) in a mixture of CHCl3
(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
2N); 13C-NMR (100 MHz, CDCl
3) δ = 163.8 (NC+N),
151.6 (C-Ar), 142.2 (C-Ar), 139.2 (C-Ar), 132.6 (C-Ar), 129.7 (C-Ar), 129.5 (C-Ar), 128.8
(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.
CHCl3/H2O, r.t., 30 min
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
2N); 13C-NMR (100 MHz, CDCl
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
2N); Anal. calculated for C
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
1. NBA, DME, r.t., 45 min
2. NaB[C6H4(CF3)2]4, Et2O/H2O
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); 13C-NMR (50 MHz, CDCl
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);
Anal. calculated for C11
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); 13C-NMR (50 MHz, CDCl
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.
CHCl3/H2O, r.t., 30 min
N N+
Ph
NTf2−
N N+
Ph
LiNTf2
Br−
196A 196C
75%
CHCl3/H2O, r.t., 30 min
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),
130.6 (C-Ar), 129.3 (C-Ar), 129.2 (C-Ar), 129.0 (C-Ar), 128.2 (C-Ar), 127.4 (C-Ar), 126.9
(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%
1. NBA, DME, r.t., 45 min
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
(C-Ar), 131.1 (C-Ar), 130.0 (C-Ar), 129.8 (C-Ar), 129.4 (C-Ar), 129.4 (C-Ar), 128.7 (C-
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
2); 13C-NMR (100 MHz, CDCl
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
2); 13C-NMR (100 MHz, CDCl
3) δ = 161.1 (NCN), 151.2 (C-Ar), 147.4 (C-Ar),
139.2 (C-Ar), 133.3 (C-Ar), 129.7 (C-Ar), 129.4 (C-Ar), 128.4 (C-Ar), 126.9 (C-Ar), 125.7
(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
2); 13C-NMR (100 MHz, CDCl
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
(C-Ar), 131.6 (C-Ar), 131.0 (C-Ar), 130.4 (C-Ar), 130.3 (C-Ar), 130.2 (C-Ar), 129.9 (C-
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
(50 mg, 0.17 mmol) in a mixture of CHCl3
(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%
1. NBA, DME, r.t., 45 min
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
(C-Ar), 131.0 (C-Ar), 130.7 (C-Ar), 130.65 (C-Ar), 130.4 (C-Ar), 130.3 (C-Ar), 129.8 (C-
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-
bis(trifluoromethyl)phenyl) borate (164D)
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); 13C-NMR (50 MHz, CDCl
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
3); HRMS (ESI) calculated for C
23H
22N
2Cl+: 361.1472, found:
361.1475.
(4S,5S)-2-(2-Chlorophenyl)-1,3-dimethyl-4,5-diphenylimidazolinium tetrakis(penta-
fluorophenyl)borate (164E)
From (4S,5S)-2-(2-chlorophenyl)-1,3-dimethyl-4,5-diphenylimidazolidine (164) (100
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
1. NBA, DME, r.t., 45 min
2. KB(C6F5)4, DCM/H2O, r.t.
N N+
B[C6H4(CF3)2]4−
N N
PhPh PhPh
ClCl
164 164D
77%
1. NBA, DME, r.t., 45 min
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); 13C-NMR (50 MHz, CDCl
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),
133.4 (C-Ar), 132.0 (C-Ar), 131.4 (C-Ar), 130.9 (C-Ar), 130.3 (C-Ar), 129.1 (C-Ar), 128.9
(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
3). HRMS (ESI) calculated for C
23H
22N
2Cl+: 361.1472, found:
361.1478.
(4S,5S)-2-(4-Chlorophenyl)-1,3-dimethyl-4,5-diphenylimidazolinium bromide (165A)
From (4S,5S)-2-(4-chlorophenyl)-1,3-dimethyl-4,5-diphenylimidazolidine (165) (359
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-
romethylsulfonyl)imide (165C)
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,
CHCl3/H2O, r.t., 30 min
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-
bis(trifluoromethyl)phenyl) borate (165D)
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
(177 mg, 0.23 mmol) in a mixture of CHCl3
(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,
CHCl3/H2O, r.t., 30 min
N N+
N N+
Br− B(C6F5)4
−
PhPh PhPh
Cl Cl
KB(C6F5)4
165E
62%
165A
CHCl3/H2O, r.t., 30 min
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-
Ar), 131.3 (C-Ar), 130.7 (C-Ar), 129.6 (C-Ar), 127.1 (C-Ar), 119.1 (C-Ar), 75.5 (CHPh),
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-
romethyl)phenyl) borate (204D)
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
1. NBA, DME, r.t., 45 min
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 =
7.2 Hz, 1 H, CHCH3), 1.75 (d, J = 7.1 Hz, 6 H, CHCH
3); 13C-NMR (100 MHz, CDCl
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),
137.7 (C-Ar), 132.8 (C-Ar), 130.6 (C-Ar), 129.95 (C-Ar), 129.87 (C-Ar), 129.7 (C-Ar),
129.6 (C-Ar), 129.5 (C-Ar), 128.9 (C-Ar), 128.7 (C-Ar), 128.6 (C-Ar), 128.5 (C-Ar), 128.4
(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
(29 mg, 0.16 mmol, 1.1 eq.) in a mixture of
CHCl3
(3 mL) and water (3 mL) as a white solid (92 mg, 94%). [α]22D
= −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
(C-Ar), 132.4 (C-Ar), 131.1 (C-Ar), 130.5 (C-Ar), 130.0 (C-Ar), 129.9 (C-Ar), 129.87 (C-
Ar), 129.8 (C-Ar), 128.9 (C-Ar), 128.7 (C-Ar), 128.3 (C-Ar), 127.8 (C-Ar), 127.7 (C-Ar),
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
3); HRMS (ESI) calculated for C
37H
24N
2Cl+: 541.2421, found:
541.2421.
CHCl3/H2O, r.t., 30 min
N N+
PhPh
PF6−
KPF6
N N+
PhPh
Br−
PhPh PhPh
162A 162B
94%
Cl Cl
168 Experimental
(4S,5S)-2-(2-Chloro-phenyl)-4,5-diphenyl-1,3-bis-((R)-1-phenyl-ethyl)-imidazolinium
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-
Ar), 135.9 (C-Ar), 135.2 (C-Ar), 135.0 (C-Ar), 134.5 (C-Ar), 133.0 (C-Ar), 132.4 (C-Ar),
130.5 (C-Ar), 130.4 (C-Ar), 130.3 (C-Ar), 130.2 (C-Ar), 130.1 (C-Ar), 130.0 (C-Ar), 129.7
(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
3); HRMS (ESI) calculated for C
37H
34N
2Cl+:
541.2411, found: 541.2401.
(4S,5S)-2-(2-Chloro-phenyl)-4,5-diphenyl-1,3-bis-((R)-1-phenyl-ethyl)-imidazolinium
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
(2 mL) and water (2 mL) as a white solid (106 mg, 89%). [α]22D
= −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 =
3.5 Hz, 3 H, CHCH3), 1.55 (d, J = 3.5 Hz, 3 H, CHCH
3); 13C-NMR (50 MHz, CDCl
3) δ =
CHCl3/H2O, r.t.
N N+
B(C6F5)4−
N N+
Br−
KB(C6F5)4
PhPh PhPh
ClCl
PhPhPhPh
162E
89%
162A
CHCl3/H2O, r.t., 30 min
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
(C-Ar), 132.4 (C-Ar), 130.6 (C-Ar), 130.3 (C-Ar), 130.2 (C-Ar), 130.15 (C-Ar), 130.0 (C-
Ar), 129.9 (C-Ar), 129.7 (C-Ar), 129.4 (C-Ar), 129.1 (C-Ar), 129.0 (C-Ar), 128.3 (C-Ar),
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.
(4S,5S)-2-(4-Chloro-phenyl)-4,5-diphenyl-1,3-bis-((R)-1-phenyl-ethyl)-imidazolinium
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
(68 mg, 0.37 mmol) in a mixture of CHCl3
(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
(NC+N), 140.1 (C-Ar), 136.1 (C-Ar), 135.5 (C-Ar), 131.0 (C-Ar), 130.2 (C-Ar), 129.6 (C-
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); 13C-NMR (50 MHz, CDCl
3) δ = 164.2 (NCN), 150.3
(C-Ar), 143.1 (C-Ar), 139.4 (C-Ar), 136.4 (C-Ar), 135.1 (C-Ar), 129.3 (C-Ar), 129.2 (C-
Ar), 128.4 (C-Ar), 128.3 (C-Ar), 127.9 (C-Ar), 127.6 (C-Ar), 127.4 (C-Ar), 72.1 (CHPh),
57.8 (NCHCH3), 18.1 (CHCH
3); HRMS (ESI) calculated for C
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
(36 mg, 0.20 mmol, 1.1 eq.) in a mixture of
CHCl3
(3 mL) and water (3 mL) as a white solid (100 mg, 86%). [α]22D
= −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-
Ar), 142.7 (C-Ar), 139.4 (C-Ar), 136.0 (C-Ar), 135.2 (C-Ar), 129.5 (C-Ar), 129.4 (C-Ar),
128.7 (C-Ar), 128.5 (C-Ar), 127.9 (C-Ar), 127.7 (C-Ar), 126.6 (C-Ar), 126.4 (C-Ar), 71.4
(CHPh), 57.8 (NCHCH3), 17.9 (CHCH
3); HRMS (ESI) calculated for C
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)
DCM/H2O, r.t., 30 min
N N+
N
PhPh
LiNTf2N N
+
N
PhPh
Br−
PhPh PhPh
205C
57%
205A
NTf2−
CHCl3/H2O, r.t., 30 min
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); 13C-NMR (50 MHz, CDCl
3) δ = 163.1 (NC+N),
152.8 (C-Ar), 150.1 (C-Ar), 141.7 (C-Ar), 138.5 (C-Ar), 135.1 (C-Ar), 134.2 (C-Ar), 129.9
(C-Ar), 128.4 (C-Ar), 127.8 (C-Ar), 127.5 (C-Ar), 126.9 (C-Ar), 126.7 (C-Ar), 125.6 (C-
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
3). HRMS (ESI) calculated for C
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-
romethyl)phenyl) borate (208D)
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.
(4S,5S)-1,3-Dimethyl-2-(2-((4S,5S)-1,3-dimethyl-4,5-diphenylimidazolidin-2-
yl)phenyl)-4,5-diphenylimidazolinium bis bis(trifluoromethylsulfonyl)imide (209C)
(4S,5S)-1,3-Dimethyl-2-(2-((4S,5S)-1,3-dimethyl-4,5-diphenylimidazolidin-2-
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.)
DCM/H2O, r.t., 45 min
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),
133.2 (C-Ar), 131.2 (C-Ar), 130.8 (C-Ar), 130.4 (C-Ar), 130.2 (C-Ar), 129.9 (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
3). HRMS (ESI) calculated for C
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
(C-Ar), 132.8 (C-Ar), 130.7 (C-Ar), 130.3 (C-Ar), 130.0 (C-Ar), 129.7 (C-Ar), 129.5 (C-
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.
DCM/H2O, r.t., 45 min
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
2). HRMS (ESI) calculated for C
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
2). HRMS (ESI) calculated for C
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-
romethyl)phenyl) borate.
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-
romethyl)phenyl) borate.
(4S,5S)-4,5-Diphenyl-1,3-bis-((R)-1-phenyl-ethyl)-4,5-imidazolinium tetrafluoro
borate (220F)
From (1S,2S)-1,2-diphenyl-N,N’-bis((R)-1-phenylethyl)ethane-1,2-diamine (94) (1.26 g,
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); 13C-NMR (50 MHz, CDCl
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); 13C-NMR (50 MHz, CDCl
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;
HRMS (ESI) Calcd. for C31
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); 13C-NMR (50 MHz, CDCl
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
3). HRMS (ESI) calculated for C
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
(378 mg, 1.28 mmol, 1.1 eq.) in a mixture of CHCl3
(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
2N); 13C-NMR (50 MHz, CDCl
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
3); HRMS (ESI) calculated for C
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-
romethylsulfonyl)imide (231C)
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); 13C-NMR (50 MHz, CDCl
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
3); HRMS (ESI) calculated for C
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-
bis(trifluoromethyl)phenyl) borate (231D)
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
3); HRMS (ESI) calculated for C
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-
bis(trifluoromethyl)phenyl) borate (232D)
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-
romethylsulfonyl)imide (233C)
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−
DCM/H2O, r.t., 30 min
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
(5 mL) and water (5 mL) as a white solid (277 mg, 59%). [α]22D
= +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
2). HRMS (ESI) calculated for C
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); 13C-NMR (50 MHz, CDCl
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); 13C-NMR (100 MHz, CDCl
3) δ = 147.0 (C-
Ar), 146.8 (C-Ar), 129.1 (C-Ar), 128.9 (C-Ar), 128.8 (C-Ar), 127.5 (C-Ar), 127.3 (C-Ar),
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); 13C-NMR (100 MHz, CDCl
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); 13C-NMR (100 MHz, CDCl
3) δ = 139.6 (C-
Ar), 139.5 (C-Ar), 128.2 (C-Ar), 128.1 (C-Ar), 127.4 (C-Ar), 127.3 (C-Ar), 126.0 (C-Ar),
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-
Ar), 128.8 (C-Ar), 128.1 (C-Ar), 127.5 (C-Ar), 127.1 (C-Ar), 125.4 (C-Ar), 124.8 (C-Ar),
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
mmol) as yellow solid (41 mg, 72%). Spectral datas were consistent with literature values.140
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
mmol) as yellow solid (28 mg, 57%). Spectral datas were consistent with literature values.139
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,
CDCl3) δ = 144.4 (C-Ar), 140.6 (C-Ar), 130.2 (C-Ar), 127.9 (C-Ar), 127.3 (C-Ar), 127.1
(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
2); 13C-NMR (50 MHz, CDCl
3) δ
= 145.2 (C-Ar), 141.1 (C-Ar), 128.4 (C-Ar), 128.1 (C-Ar), 127.6 (C-Ar), 127.5 (C-Ar),
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,
CDCl3) δ = 144.7 (C-Ar), 142.3 (C-Ar), 130.9 (C-Ar), 129.3 (C-Ar), 128.7 (C-Ar), 127.9
(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
were consistent with literature values.169
Ph+
Imidazolinium catalyst
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
Imidazolinium carbene precursor (0.1 eq)
Base (0.1 eq), Et2Zn 1.1 eq., PhMe, r.t.
O
300 301
HO*
Imidazolinium carbene precursor (0.1 eq)
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
3.11.1. Baylis-Hillman Reaction
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
quinuclidine, r.t., 48 hPh
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
quinuclidine, r.t., 48 h
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-
quinuclidine, r.t., 48 h
+
O
NH2
OH
NH2
O
ClCl
318
49%
O
196C
316175
quinuclidine, r.t., 48 h
O
+
O
NH2
O
NH2
OH
167 167 317
48%
196C
quinuclidine, r.t., 48 hPh
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
3.13.1. Baylis-Hillman Reaction
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.
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