Improved Methodology for the Preparation of Chiral Amines

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HCl to obtain the hydrochloride salt (0.54 g, 82 yield %). GC (program A, see Experimental section (general remarks)) retention time [min]: major (S,S)-2f isomer, 8.5; minor (R,S)-2f isomer, 8.4, matches that reported in the literature. [2] (1S)-N((S)-1-cyclohexylethyl)-1-phenylethanamine (2g) Reaction details: Yb(OAc) 3 (10 mol %), cyclohexyl methyl ketone (0.34 mL, 2.5 mmol, 1.0 equiv), (S)-α-MBA (0.35 mL, 2.75 mmol, 1.1 equiv), pre-stirred 30 min at 50 °C; hydrogen pressure 20 bar (290 psi); hydrogenation performed at 50 °C. Reaction time: 12 h; 98% de. Purification by silica gel flash chromatography (Hexane/EtOAc/NH 4 OH = 83:15:2) gave the mixture of diastereomers as a viscous colorless oil, which when treated with etheral HCl provided the hydrochloride salt (0.60 g, 81 yield %). GC (program D, see Experimental section (general remarks)) retention time [min]: major (S,S)-2g isomer, 14.9; minor (R,S)-2g isomer, 14.7, matches that reported in the literature. [1] (2S)-3-Methyl-N- ((S)-1-phenylethyl) butan-2-amine (2h) Reaction details: Yb(OAc) 3 (10 mol %), 3-methyl-2-butanone (0.27 mL, 2.5 mmol, 1.0 equiv), (S)-α-methylbenzylamine (0.35 mL, 2.75 mmol, 1.1 equiv), pre-stirred 30 min at 50 °C; hydrogen pressure 20 bar (290 psi); hydrogenation performed at 50 °C. Reaction time: 12 h; 98% de. Purification by silica gel flash chromatography (Hexane/EtOAc/NH 4 OH = 92.5:3.5:4) gave the mixture of diastereomers as a viscous colorless oil, which then treated with etheral HCl provided the hydrochloride salt (0.54 g, 78 yield %). GC (program D, see Experimental section (general remarks)) retention time [min]: major (S,S)-2h isomer, 11.2; minor (R,S)-2h isomer, 11.1, matches that reported in the literature. [1] Bis((S)-1-phenylethyl)amine (2i) Reaction details: Yb(OAc) 3 (10 mol %), acetophenone (0.29 mL, 2.5 mmol, 1.0 equiv), (S)-αmethylbenzylamine (0.35 mL, 2.75 mmol, 1.1 equiv), pre-stirred 30 min at 50 °C; hydrogen pressure 20 bar (290 psi); hydrogenation performed at 50 °C. Reaction time: 12 h; 94% de. Purification by silica gel flash chromatography (Hexane/EtOAc/NH 4 OH = 74:25:1) gave the mixture of diastereomers as a viscous colorless oil, which then treated with etheral HCl to 150
obtain the hydrochloride salt (0.41 g, 63 yield %). GC (program D, see Experimental section (general remarks)) retention time [min]: major (S,S)-2i isomer, 14.4; minor (R,S)-2i isomer, 14.7, matches that reported in the literature. [2] (2S)-3,3-dimethyl-N-((S)-1-phenylethyl)butan-2-amine (2b) Reaction details: Yb(OAc) 3 (10 mol %), 3,3-dimethyl-2-butanone (0.31 mL, 2.5mmol, 1.0 equiv), (S)-α-methylbenzylamine (0.35 mL, 2.75 mmol, 1.1 equiv), pre-stirred 4h at 50 °C; then adding Pt/C (instead of Raney Ni) in four equal portions at t= 0, 6, 12, 20 h (total added Pt equals 1.0 mol %), with a total hydrogenation time of 30 h at 8.3 bar (120 psi) and at 50 o C. 92% de. Purification by silica gel flash chromatography (Hexane/EtOAc/NH 4 OH = 94.5:1.5:4) gave the mixture of diastereomers as a viscous colorless oil, which when treated with etheral HCl to obtain the hydrochloride salt (0.58 g, 78 yield %). GC (program C, see Experimental section (general remark)) retention time [min]: major (S,S)-2b isomer, 11.8; minor (R,S)-2b isomer, 11.6, matches that reported in the literature. [2] General Procedure: Brønsted acids (normal de) The reaction vessel was evacuated under high vacuum for 5 min before flooding with nitrogen. To the vessel, anhydrous methanol (2.5 mL, 1.0 M), acetic acid (20 mol %), ketone (2.5 mmol, 1.0 equiv) (1), and (S)-α-methylbenzylamine (0.35 mL, 2.75 mmol, 1.1 equiv) were added and stirred for 20-30 min at the temperature at which the hydrogenation was performed at (22 or 50 o C). The remaining procedural details should be followed as in the section entitled: “General procedure: Catalytic Yb(OAc) 3 , Y(OAc) 3 , or Ce(OAc) 3 (normal de).” (2S)-4-methyl-N-((S)-1-phenylethyl)pentan-2-amine (2a) Reaction details: 4-Methyl-2-pentanone (0.31 mL, 2.5 mmol, 1.0 equiv), (S)-αmethylbenzylamine (0.35 mL, 2.75 mmol, 1.1 equiv), acetic acid (0.028 mL, 20 mol %), prestirred 30 min at 50 °C; hydrogen pressure 8.3 bar (120 psi); hydrogenation performed at 50 °C. Reaction time: 12 h; 92% de. Purification by silica gel flash chromatography (Hexane/EtOAc/NH 4 OH = 87:9:4) gave the mixture of diastereomers as a viscous colorless 151
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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
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Et EtOH EtOAc GC h HPLC HRMS Hz J K
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Table of Contents Abstract. Acknowl
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4.1.5. Synthesis of Emitine 85 4.1.
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Chapter 1 Introduction 1.1. Chiral
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1. Cis-trans or geometric isomers.
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O O O * NH Thalidomide (R)-active a
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One enantiomer may be responsible f
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1.5.1. Synthesis of Enantiomericall
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1.5.2.2. Kinetic Resolution Kinetic
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compound by the auxiliary. The auxi
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1.5.4. Stereoselective Conversion o
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It is estimated that 3000 tonnes (a
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k R R P 1 k rac S k S P 2 Figure 1.
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(S)-(α)-Methylbenzylamine and its
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fourth chapter showing different dr
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Burk was successful in reducing ary
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Table 1.1 Rhodium Catalyzed Reducti
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[8] E. L. Eliel, S. H. Wilen, Stere
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[42] a) J. Blacker, Innovations in
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[67] a) H. Qin, N. Yamagiwa, S. Mat
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of imine reduction in the past eigh
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8 years beginning from the year 200
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2.2.3. Nguyen Special Substrates. A
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Figure 2.4 General Catalyst structu
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2.3.2. Different Substrates Categor
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H 2 , toluene, 25 °C, 4 h an ee of
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1). They described the role of each
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More recently, 2008, he described t
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[22] E. Guiu, M. Aghmiz, Y. Diaz, C
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Chapter 3 Reductive Amination 3.1.
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. CH 3 CO(CH 2 ) 5 CH 3 H 2 NCH 2 C
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superior in terms of conversion (89
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O NHR 3 R 4 R 4 R 3 N OTi(O i Pr) 3
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Scheme 3.9. Synthesis of (S)-Metola
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groups decreased both the enantiose
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progress of the reaction was monito
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attempts were directed for the asym
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hydrogen bonding, is chiral and its
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Later he utilized this methodology
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OMe OMe O HN HN HN O 2 N 71 % yield
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compared to the oil refinery indust
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[14] V. I. Tararov, R. Kadyrov, T.H
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[55] a) R. Kadyrov, T. H. Riermeier
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Chapter 4 Drugs and Reductive Amina
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Scheme 4.2. Synthesis of Muraglitaz
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Studies showed that the active isom
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aminoacid producing the protected a
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O NH 2 1. p-TsOH/toluene 2. BH 3 -T
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O O 125 NH 2 a 93% O O 126 H Bu N T
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ethyl carbamate by acylation with e
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4.1.16. Synthesis of Ritonavir and
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4.2. Conclusion Different important
Page 113 and 114: Chapter 5 Stoichiometric Use of Ytt
Page 115 and 116: The unique feature of this methodol
Page 117 and 118: Ytterbium triflate is the most comm
Page 119 and 120: Ruthenium(III) chloride 31.7 4 4.2
Page 121 and 122: t-Butyl methyl ether 15 - - 82 Hexa
Page 123 and 124: 2-octanone starting material. When
Page 125 and 126: 3 Yb(OTf) 3 d 4 Ti(O i Pr) 4 e 5 B(
Page 127 and 128: If a [1,3]-proton shift of the init
Page 129 and 130: enhanced stereoselectivity. For exa
Page 131 and 132: WO2006030017, 2006; c) T. C. Nugent
Page 133 and 134: 4 60 86 5 50 86 6 40 84 7 20 79 8 2
Page 135 and 136: The reactions described above all u
Page 137 and 138: e.g. compare entries 1, 5, 6, and 9
Page 139 and 140: solvent in the stoichiometric and c
Page 141 and 142: [2] Farina, V.; Grozinger, K.; Mül
Page 143 and 144: congested which should be favored.
Page 145 and 146: imine area % (GC analysis) time (mi
Page 147 and 148: Inversion at the nitrogen atom of t
Page 149 and 150: anti-6) would be expected to have m
Page 151 and 152: e.g. AcOH, suppresses alcohol by-pr
Page 153 and 154: eductive amination of a prochiral k
Page 155 and 156: Appendix Experimental Section Gener
Page 157 and 158: and the mixture was stirred for 30
Page 159 and 160: Reaction details: Yb(OAc) 3 (1.1 eq
Page 161 and 162: etention time [min]: major (S,S)-2b
Page 163: time [min]: major (S,S)-2c isomer,
Page 167 and 168: with etheral HCl provided the hydro
Page 169 and 170: Research experience: Date Project S
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Improved Methodology for the Preparation of Chiral Amines

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