Improved Methodology for the Preparation of Chiral Amines

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(2S)-4-Methyl-N-((S)-1-phenylethyl)pentan-2-amine (2a) Reaction details: Yb(OAc) 3 (1.1 equiv), 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). Reaction time: 12 h; 94% de. Purification by silica gel flash chromatography (hexanes/EtOAc/NH 4 OH, 83:15:2) gave the mixture of diastereomers as a colorless viscous liquid, which was then treated with etheral HCl to obtain the hydrochloride salt (0.467 g, 78% yield) after high vacuum drying. GC (program A, see: Experimental section (general remarks)): retention time [min]: major (S,S)- 2a isomer, 10.9; minor (R,S)-2a isomer, 10.6. The NMR data of (S,S)-2a (free base) matches that reported in the literature. [1] Major (S,S)-2a: 1 H NMR (400 MHz, CDCl 3 ): δ 7.36-7.20 (m, 5H), 3.89 (q, J = 6.8 Hz, 1H), 2.60-2.52 (m, 1H), 1.63-1.56 (m, 1H), 1.43-1.36 (m 1H), 1.32 (d, J = 6.8 Hz, 3H), 1.13-1.07 (m, 1H), 0.94 (d, J = 6.4 Hz, 3H), 0.89 (d, J = 6.8 Hz, 3H), 0.76 (d, J = 6.8 Hz, 3H). 13 C NMR (100 MHz, CDCl 3 ): δ 146.5, 128.3, 126.7, 126.5, 55.2, 48.4, 46.6, 25.1, 24.4, 23.6, 22.3, 21.6. (2S)-4-Phenyl-N-((S)-1-phenylethyl)butan-2-amine (2c) Reaction details: Yb(OAc) 3 (1.1 equiv), 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). Reaction time: 12 h; 89% de. Purification by silica gel flash chromatography (hexanes/EtOAc/NH 4 OH, 78:20:2) gave the mixture of diastereomers as a colorless viscous liquid, which was then treated with etheral HCl to obtain the hydrochloride salt (0.625 g, 87% yield) after high vacuum drying. GC (program D, see Experimental section (general remarks)): retention time [min]: major (S,S)- 2c isomer, 15.5; minor (R,S)-2c isomer, 15.4. The NMR data of (S,S)-2c (free base) matches that reported in the literature. [1] Major (S,S)-2c: 1 H NMR (CDCl3, 400 MHz): δ 7.30-7.14 (m, 10 H), 3.85 (q, J = 6.4 Hz, 1H), 2.69-2.49 (m, 3 H), 1.85-1.83 (m, 1H), 1.63-1.55 (m, 1H), 1.29 (d, J = 6.4 Hz, 3H), 1.02 (d, J = 6.4 Hz, 3H). 13 C NMR (CDCl3, 100 MHz): δ 146.3, 142.5, 128.3, 128.2, 126.6, 126.4, 125.6, 54.9, 49.6, 37.9, 31.9, 24.4, 21.2. (2S)-N-((S)-1-Phenylethyl)octan-2-amine (2d) 144
Reaction details: Yb(OAc) 3 (1.1 equiv), 2-octanone (0.39 mL, 2.5 mmol, 1.0 equiv), (S)-αmethylbenzylamine (0.35 mL, 2.75 mmol, 1.1 equiv). Reaction time: 12 h; 87% de. Purification by silica gel flash chromatography (hexanes/EtOAc/NH 4 OH, 78:20:2) gave the mixture of diastereomers as a colorless viscous liquid, which was then treated with etheral HCl to obtain the hydrochloride salt (0.580 g, 86% yield) after high vacuum drying. GC (program A, see Experimental section (general remarks)): retention time [min]: major (S,S)- 2d isomer, 12.9; minor (R,S)-2d isomer, 13.1. The NMR data of (S,S)-2d (free base) matches that reported in the literature. [1] Major (S,S)-2d: 1 H NMR (400 MHz, CDCl 3 ): δ 7.33-7.20 (m, 5H), 3.88 (q, J = 6.4 Hz, 1H), 2.53-2.46 (m, 1H), 1.34-1.20 (m, 14H), 0.94 (d, J = 6.4 Hz, 3H), 0.88 (t, J = 6.4 Hz, 3H). 13 C NMR (100 MHz, CDCl 3 ): δ 146.5, 128.3, 126.6, 126.5, 55.1, 50.1, 36.4, 31.8, 29.5, 25.7, 24.6, 22.6, 21.3, 14.1. (2S)-N-((S)-1-Phenylethyl)hexan-2-amine (2e) Reaction details: Yb(OAc) 3 (1.1 equiv), 2-hexanone (0.31 mL, 2.5 mmol, 1.0 equiv), (S)-αmethylbenzylamine (0.35 mL, 2.75 mmol, 1.1 equiv). Reaction time: 12 h; 85% de. Purification by silica gel flash chromatography (hexanes/EtOAc/NH 4 OH, 88:8:2) gave the mixture of diastereomers as a colorless viscous liquid, which was then treated with etheral HCl to obtain the hydrochloride salt (0.480 g, 80% yield) after high vacuum drying. GC (program A, see Experimental section (general remarks)): retention time [min]: major (S,S)- 2e isomer, 11.3; minor (R,S)-2e isomer, 11.1. The NMR data of (S,S)-2e (free base) matches that reported in the literature. [2] Major (S,S)-2e: 1 H NMR (CDCl3, 400 MHz): δ 7.33-7.19 (m, 5H), 3.88 (q, J = 6.5 Hz, 1H), 2.51-2.45 (m, 1H),1.52-1.46 (m, 1H), 1.32 (d, J = 6.5 Hz, 3H), 1.28-1.15 (m, 6H), 0.94 (d, J = 6.34 Hz, 3H), 0.88 (t, J = 6.95 Hz, 3H). 13 C NMR (CDCl3, 100 MHz): δ 146.4, 128.3, 126.6, 126.5, 55.1, 50.1, 36.0, 27.9, 24.6, 22.9, 21.3, 14.1 (2S)-N-((S)-1-Phenylethyl)butan-2-amine (2f) Reaction details: Yb(OAc) 3 (1.1 equiv), 2-butanone (0.22 mL, 2.5 mmol, 1.0 equiv), (S)-αmethylbenzylamine (0.35 mL, 2.75 mmol, 1.1 equiv). Reaction time: 12 h; 79% de. After 145
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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
Page 107 and 108: ethyl carbamate by acylation with e
Page 109 and 110: 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
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Page 153 and 154: eductive amination of a prochiral k
Page 155 and 156: Appendix Experimental Section Gener
Page 157: and the mixture was stirred for 30
Page 161 and 162: etention time [min]: major (S,S)-2b
Page 163 and 164: time [min]: major (S,S)-2c isomer,
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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