Improved Methodology for the Preparation of Chiral Amines

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J. Volk, A. W. Frahm, Tetrahedron: Asymmetry 1997, 8, 3457. (h) P. Bisel, E. Breitling, A. W. Frahm, Eur. J. Org. Chem 1998, 729. (i) A. L. Gutman, M. Etinger, G. Nisnevich, F. Polyak, Tetrahedron: Asymmetry 1998, 9, 4369. (j) C. Cimarelli, G. Palmieri, Tetrahedron: Asymmetry 2000, 11, 2555. (k) L. Storace, L. Anzalone, P. N. Confalone, W. P. Davis, J. M. Fortunak, M. Giangiordano, J. J. Jr. Haley, K. Kamholz, H. –Y. Li, P. Ma, W. A. Nugent, R. L. Parsons, Jr.; P.J. Sheeran, C. E. Silverman, R. E. Waltermire, C. C. Wood, Org. Process Res. Dev. 2002, 6, 54. 140
Appendix Experimental Section General Remarks NMR spectra were recorded on a JEOL ECX 400 spectrometer, operating at 400 MHz ( 1 H) and 100 MHz ( 13 C) respectively. Chemical shifts (δ) were reported in parts per million (ppm) downfield from TMS (= 0) or relative to CHCl 3 (7.26 ppm) or D 2 O (4.79 ppm) for 1 H NMR. For 13 C NMR, chemical shifts were reported in the scale relative to CHCl 3 (77.0 ppm) or D 2 O (CH 3 OH internal reference, δ= 49.5 ppm) as an internal reference. Multiplicities are abbreviated as: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad. The coupling constants are expressed in Hz. FTIR spectra were obtained on Nicolet Avatar 370 spectrometer. Mass spectra were recorded on a Finnigan MAT 95 (EI) with an ionization potential of 70 eV. Elemental analyses were performed by an external vendor in Lindlar, Germany on an Elementar Vario EL III instrument. For amine products 2, reaction progress and diastereomeric excess measurements were obtained using a Shimadzu GC-2010 instrument with a Rtx-5 amine column (Restec, 30 m x 0.25 mm); T inj = 300 °C and T det = 300 °C, and carrier gas He @ 24 psi were always constant. Program A: 50 °C (1 min), then 14 °C/min to 280 °C (hold 2 min); Program B: 50 °C (1 min), then 14 °C/min to 130 °C (hold 9 min), then 20 °C/min to 280 °C (hold 2 min); Program C: 50 °C (1 min); then 14 °C/min to 280 °C (hold 1 min); Program D: 50 °C (1 min); then 14 °C/min to 280 °C (hold 5 min). For hydrogenolyzed product primary amine 4d the enantiomeric excess of the trifluoroacetamide derivative was determined by gas chromatography using a Shimadzu GC-2010 instrument on a Chiraldex B-DP column (Astec, 30 m x 0.25mm); T inj = 200 °C, T det = 200 °C, and carrier gas He @ 24 psi were constant. Program E: 130 °C (20 min), then 20 °C/min to 180 °C (hold 10 min), split ratio 60:1. Column chromatography was performed using silica gel 60 (0.040- 0.063 mm). Thin-layer chromatography (TLC) was performed using precoated plates of silica gel 60 F 254 and visualized under ultraviolet irradiation (254 nm). All reactions were performed under an inert atmosphere (nitrogen). All reagents were obtained from Sigma-Aldrich (except cyclohexyl methyl ketone, obtained from ABCR GmbH &Co) and used without further purification. Before using the commercially purchased 141
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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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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
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: eductive amination of a prochiral k
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 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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