Improved Methodology for the Preparation of Chiral Amines

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In a reaction vessel the Lewis acid [Yb(OAc) 3 10 mol %, Y(OAc) 3 (15 mol %) or Ce(OAc) 3 (15 mol %)] was added and subsequently evacuated under high vacuum for 5 min before flooding with nitrogen. To the vessel, anhydrous methanol (2.5 mL, 1.0 M), ketone (2.5 mmol, 1.0 equiv), 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). A THF slurry of Raney-Ni (100 wt % based on the ketone, pre-triturated with EtOH (×3) and then with anhydrous THF (×3) before addition) was transferred to the reaction mixture using 2.5 mL of anhydrous THF (final molarity of reaction solution is 0.5 M). The vessel was then pressurized to the indicated pressure 120-290 psi (8-20 bar) of hydrogen and stirred at room temperature or at 50 °C as indicated. At 12 h (< 3 area % of ketone and intermediate imine by GC) the reaction mixture was worked-up as delineated in the section entitled: “General procedure: Stoichiometric Yb(OAc) 3 (enhanced de).” (2S)-4-methyl-N-((S)-1-phenylethyl)pentan-2-amine (2a) Reaction details: Yb(OAc) 3 (10 mol %), 4-methyl-2-pentanone (0.31 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, and then hydrogenated at 50 o C and 120 psi (8.3 bar). 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 viscous colorless oil, which then treated with etheral HCl to obtain the hydrochloride salt (0.60 g, 79 yield %). GC (program D, see Experimental section (general remarks)) retention time [min]: major (S,S)-2a isomer, 11.8; minor (R,S)-2a isomer, 11.6, matched those reported in the literature. [1] (2S)-4-phenyl-N-((S)-1-phenylethyl)butan-2-amine (2c) Reaction details: Yb(OAc) 3 (10 mol %), 4-phenyl-2-butanone (0.37 mL, 2.5 mmol, 1.0 equiv), (S)-α-methylbenzylamine (0.35 mL, 2.75 mmol, 1.1 equiv), pre-stirred 30 min at room temperature; hydrogen pressure 8.3 bar (120 psi); hydrogenation was performed at room temperature; reaction time: 12 h; 80% de. Purification by silica gel flash chromatography (Hexane/EtOAc/NH 4 OH = 83:15:2) gave the mixture of diastereomers as viscous colorless oil, which then treated with etheral HCl to obtain the hydrochloride salt (0.63 g, 87 yield %). GC (program D, see Experimental section (general remarks)) retention 148
time [min]: major (S,S)-2c isomer, 16.5 minor (R,S)-2c isomer, 16.4, matches that reported in the literature. [1] (2S)-N-((S)-1-phenylethyl)octan-2-amine (2d) Reaction details: Yb(OAc) 3 (10 mol %), 2-octanone (0.39 mL, 2.5 mmol, 1.0 equiv), (S)-αmethylbenzylamine (0.35 mL, 2.75 mmol, 1.1 equiv), pre-stirred 30 min at room temperature; hydrogen pressure 120 psi (8.3 bar); hydrogenation performed at room temperature. Reaction time: 12 h; 72% de. Purification by silica gel chromatography (Hexane/EtOAc/NH 4 OH = 58:40:2) gave the mixture of diastereomers as viscous colorless oil, which then treated with etheral HCl to obtain the hydrochloride salt (0.67 g, 83 yield %). GC (program A, see Experimental section (general remarks) retention time [min]: major (S,S)-2d isomer, 10.9; minor (R,S)-2d isomer, 10.8 match those reported in the literature. [1] (2S)-N-((S)1-phenylethyl)hexan-2-amine (2e) Reaction details: Yb(OAc) 3 (10 mol %), 2-hexanone (0.31 mL, 2.5 mmol, 1.0 equiv), (S)-αmethylbenzylamine (0.35 mL, 2.75 mmol, 1.1 equiv), pre-stirred 30 min at room temperature; hydrogen pressure 8.3 bar (120 psi); hydrogenation performed at room temperature. Reaction time: 12 h; 71% de. Purification by silica gel flash chromatography (Hexane/EtOAc/NH 4 OH = 89.5:5.5:5) gave the mixture of diastereomers as viscous colorless oil, which then treated with etheral HCl to obtain the hydrochloride salt (0.61 g, 82 yield %). GC (program A, see Experimental section (general remarks)) retention time [min]: major (S,S)-2e isomer, 9.7; minor (R,S)-2e isomer, 9.6, match those reported in the literature. [2] (2S)-N-((S)-1-phenylethyl)butan-2-amine (2f) Reaction details: Yb(OAc) 3 (10 mol %), 2-butanone (0.22 mL, 2.5 mmol, 1.0 equiv), (S)-αmethylbenzylamine (0.35 mL, 2.75 mmol, 1.1 equiv), pre-stirred 30 min at room temperature; hydrogen pressure 8.3 bar (120 psi); hydrogenation done at room temperature. Reaction time: 12 h; 79% de. Purification by silica gel chromatography (Hexane/EtOAc/NH 4 OH = 91:4:5) gave the mixture of diastereomers as viscous colorless oil, which then treated with etheral 149
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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
Page 111 and 112: 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: etention time [min]: major (S,S)-2b
Page 165 and 166: obtain the hydrochloride salt (0.41
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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