Improved Methodology for the Preparation of Chiral Amines

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were reduced with 80% ee with 99% yield. For p-OMe phenyl methyl N-aryl imines the ee was 81% with 100% yield (structure 3, figure 2.3). New chiral phosphine oxazoline ligands was prepared by Zhou for the Ir reduction of imines (Ir-SIPHOX) (catalyst 14, figure 2.4). [33] Using 1.0 mol % of the catalyst, 1 bar (14.5) of H 2 , t-butyl methyl ether (TBME), 4 Å MS, 10 °C over 20 h, the ee was 93% with complete conversion for phenyl methyl N-aryl imine (structure 1, figure 2.3). He investigated the application of his catalyst on the reduction of different substituted phenyl methyl N-aryl imine, for p-Me the (94% ee), p-Cl (90% ee), p-Br (91% ee), m-Cl (93% ee), m-Br (92% ee) phenyl methyl N-aryl imine derivatives with full conversion in all cases. For 3,4- Di-Me phenyl methyl N-aryl imine the ee was 94% (structure 3, figure 2.3). New ferrocenyl P,N-ligands was introduced by Knochel and used iridium for the reduction of N-aryl imines. [34] Using 1.0 mol % of the catalyst (catalyst 15, figure 2.4), 10 bar (145 psi) of H 2 , toluene/ MeOH (4:1) at 25 °C over 2 h, the ee was 94% with full conversion for phenyl methyl N-aryl imine(structure 1, figure 2.3). He also tested his catalyst for the reduction of substituted phenyl methyl N-aryl imine. p-Ph and p-Cl (92% ee), m-Me (93% ee), o-Me (94% ee), m-F (93% ee) and p-CF 3 (89% ee) phenyl methyl N-aryl imine were reduced with high ees (structure 3, figure 2.3). 2-naphthyl methyl N-aryl imine was reduced with 93% ee. For the reduction of this category of chiral imines organocatalytic methods have proved to be highly effective. Different organocatalysts have been developed utilizing various silane derivatives or Hantzsch ester as a source of hydride. Although these sources of hydrides are not atom economic, they are commercially available in large quantities at rather reasonable prices and offer the potential of chemoselectivity not possible in the presence of H 2 . In 2001 Matsumura and coworkers developed the use of proline (catalyst 16, figure 2.4) derivatives for the hydrosilylation of imines. They achieved mediocre enantioselectivity reporting 66% ee with 52% yield for phenyl methyl N-aryl imine (structure 1, figure 2.3). [35] Inspired by the research of Matsumura, Kočovský and coworkers developed the use of valine derived (formamide/amide based) catalysts for the hydrosilylation of N-aryl imine. [36] Using 10 mol % of the catalyst (catalyst 17, figure 2.4), 1.5 equiv of Cl 3 SiH, CHCl 3 , -20 °C, 16 h, the ee was 92% with 94% isolated yield for phenyl methyl N-aryl imine (Structure 1, Figure 46
1). They described the role of each functional group in the catalyst and its importance in controlling stereoselectivity. They also marked the important structural features in the imine which controls the total outcome of the reaction. They tested their system also for the reduction of substituted phenyl methyl N-aryl imines. p-OMe (85% ee, 86% yield), p-CF 3 (89% ee, 86% yield), o-Me (92% ee, 90% yield) phenyl, methyl N-aryl imines were successfully reduced (structure 3, figure 2.3). In 2007 he reported the use of his catalyst with fluorous tag for imine reduction. [37] Fluorous tags are used to enable recycling of the catalyst. He was able to reuse the catalyst 4-5 times without significant loss of enantioselectivity and yield. Using 10 mol % of valine derived catalyst (catalyst 19, figure 2.4), 2.0 equiv of HSiCl 3 , toluene, 18 °C, 16 h, the ee was 90% with 98% yield for phenyl methyl N-aryl imine (structure 1, figure 2.3). p-CF 3 (92% ee, 72% yield, 10 °C) and p-OMe (84% ee, 84% yield) phenyl methyl N-aryl imines were reduced with high yields and ees (structure 3, figure 2.3). 2-naphthyl methyl N-aryl imine was reduced with 92% ee and 93% yield. In 2008 he reported the use of his catalyst with polymer support, which can be used up to 5 times without significant loss of catalyst activity. [38] Using 15 mol % of the catalyst (catalyst 20, figure 2.4), 2.0 equiv Cl 3 SiH, CH 3 Cl, 25 °C, 16 h, the ee was 82% with 84% yield for phenyl methyl N-aryl imine (structure 1, figure 2.3). He expanded his study to cover other substituted phenyl methyl N-aryl imines. p-OMe (77% ee, 63% yield) and p-CF 3 (81% ee, 67% yield) phenyl methyl N-aryl imines were reduced. Also 2,5 Me-3-furyl phenyl, methyl N-aryl imine was reduced with 78% ee and 67% yield (structure 3, figure 2.3). In 2006 he introduced the use of oxazoline catalyst for reduction of N-aryl imines. [39] Using 20 mol % of the catalyst (catalyst 18, figure 2.4), 2.0 equiv of HSiCl 3 , CHCl 3 , –20 °C, 24 h, resulted in 87% ee and 65% yield phenyl methyl N-aryl imine (structure 1, figure 2.3). p- OMe (87% ee, 51% yield) and p-CF 3 (87% ee, 65% yield) phenyl methyl N-aryl imines were reduced successfully (structure 3, figure 2.3). The group of Sun also prepared several organocatalysts for the hydrosilylation of imines. In 2006, they tested pipecolinic acid derived formamides catalyst. [40] Using 10 mol % of the catalyst (catalyst 21, figure 2.4), 2.0 equiv of Cl 3 SiH, CH 2 Cl 2 , 0 °C, 16 h, the ee was 95% 47
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Improved Methodology for the Prepar
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This dissertation is dedicated to a
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suppressing alcohol formation and p
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Prof. Mohamed El-Azizi, Prof. Abdel
Page 9 and 10: Et EtOH EtOAc GC h HPLC HRMS Hz J K
Page 11 and 12: Table of Contents Abstract. Acknowl
Page 13 and 14: 4.1.5. Synthesis of Emitine 85 4.1.
Page 15 and 16: Chapter 1 Introduction 1.1. Chiral
Page 17 and 18: 1. Cis-trans or geometric isomers.
Page 19 and 20: O O O * NH Thalidomide (R)-active a
Page 21 and 22: One enantiomer may be responsible f
Page 23 and 24: 1.5.1. Synthesis of Enantiomericall
Page 25 and 26: 1.5.2.2. Kinetic Resolution Kinetic
Page 27 and 28: compound by the auxiliary. The auxi
Page 29 and 30: 1.5.4. Stereoselective Conversion o
Page 31 and 32: It is estimated that 3000 tonnes (a
Page 33 and 34: k R R P 1 k rac S k S P 2 Figure 1.
Page 35 and 36: (S)-(α)-Methylbenzylamine and its
Page 37 and 38: fourth chapter showing different dr
Page 39 and 40: Burk was successful in reducing ary
Page 41 and 42: Table 1.1 Rhodium Catalyzed Reducti
Page 43 and 44: [8] E. L. Eliel, S. H. Wilen, Stere
Page 45 and 46: [42] a) J. Blacker, Innovations in
Page 47 and 48: [67] a) H. Qin, N. Yamagiwa, S. Mat
Page 49 and 50: of imine reduction in the past eigh
Page 51 and 52: 8 years beginning from the year 200
Page 53 and 54: 2.2.3. Nguyen Special Substrates. A
Page 55 and 56: Figure 2.4 General Catalyst structu
Page 57 and 58: 2.3.2. Different Substrates Categor
Page 59: H 2 , toluene, 25 °C, 4 h an ee of
Page 63 and 64: More recently, 2008, he described t
Page 65 and 66: [22] E. Guiu, M. Aghmiz, Y. Diaz, C
Page 67 and 68: Chapter 3 Reductive Amination 3.1.
Page 69 and 70: . CH 3 CO(CH 2 ) 5 CH 3 H 2 NCH 2 C
Page 71 and 72: superior in terms of conversion (89
Page 73 and 74: O NHR 3 R 4 R 4 R 3 N OTi(O i Pr) 3
Page 75 and 76: Scheme 3.9. Synthesis of (S)-Metola
Page 77 and 78: groups decreased both the enantiose
Page 79 and 80: progress of the reaction was monito
Page 81 and 82: attempts were directed for the asym
Page 83 and 84: hydrogen bonding, is chiral and its
Page 85 and 86: Later he utilized this methodology
Page 87 and 88: OMe OMe O HN HN HN O 2 N 71 % yield
Page 89 and 90: compared to the oil refinery indust
Page 91 and 92: [14] V. I. Tararov, R. Kadyrov, T.H
Page 93 and 94: [55] a) R. Kadyrov, T. H. Riermeier
Page 95 and 96: Chapter 4 Drugs and Reductive Amina
Page 97 and 98: Scheme 4.2. Synthesis of Muraglitaz
Page 99 and 100: Studies showed that the active isom
Page 101 and 102: aminoacid producing the protected a
Page 103 and 104: O NH 2 1. p-TsOH/toluene 2. BH 3 -T
Page 105 and 106: O O 125 NH 2 a 93% O O 126 H Bu N T
Page 107 and 108: ethyl carbamate by acylation with e
Page 109 and 110: 4.1.16. Synthesis of Ritonavir and
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4.2. Conclusion Different important
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Chapter 5 Stoichiometric Use of Ytt
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The unique feature of this methodol
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Ytterbium triflate is the most comm
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Ruthenium(III) chloride 31.7 4 4.2
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t-Butyl methyl ether 15 - - 82 Hexa
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2-octanone starting material. When
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3 Yb(OTf) 3 d 4 Ti(O i Pr) 4 e 5 B(
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If a [1,3]-proton shift of the init
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enhanced stereoselectivity. For exa
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WO2006030017, 2006; c) T. C. Nugent
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4 60 86 5 50 86 6 40 84 7 20 79 8 2
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The reactions described above all u
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e.g. compare entries 1, 5, 6, and 9
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solvent in the stoichiometric and c
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[2] Farina, V.; Grozinger, K.; Mül
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congested which should be favored.
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imine area % (GC analysis) time (mi
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Inversion at the nitrogen atom of t
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anti-6) would be expected to have m
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e.g. AcOH, suppresses alcohol by-pr
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eductive amination of a prochiral k
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Appendix Experimental Section Gener
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and the mixture was stirred for 30
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Reaction details: Yb(OAc) 3 (1.1 eq
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etention time [min]: major (S,S)-2b
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time [min]: major (S,S)-2c isomer,
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obtain the hydrochloride salt (0.41
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with etheral HCl provided the hydro
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Research experience: Date Project S
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Improved Methodology for the Preparation of Chiral Amines

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