Improved Methodology for the Preparation of Chiral Amines

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Table 7.1. Closer Examination of the Reductive Amination of 2-Octanone. a Amine 2d fully consistent with that found at the end of the reaction (table 7.1). The consistent diastereoselectivity throughout the whole reaction suggests that one mechanism is operating from the first minute till the end of the reaction. This conclusion is applicable on Yb(OAc) 3 ,Ti(O i Pr) 3 system and even when no Lewis acid was used. Despite the importance of this conclusion the origin of enhanced diastereoselectivity was not clarified. entry additive time (h) 2-octanone (S)-α- (%) b MBA (%) 2-octanol (%) yield (%) de (%) 1 Yb(OAc) 3 1 c 3 d 18.1 12.5 6.5 2.5 0.5 1.0 73.9 81.5 87.1 87.2 2 Ti(O i Pr) 4 1 43.9 7.9 0.63 47.6 67.0 3 8.5 4.0 2.1 85.4 67.0 3 none 1 47.1 10.5 16.6 25.8 72.0 3 29.2 1.1 27.6 42.2 72.1 a 2-octanone (2.5 mmol, 1.0 equiv), (S)-α-MBA (1.1 equiv), Yb(OAc) 3 or Ti(O i Pr) 4 (1.1 equiv) are stirred in MeOH (1.0 M) for 90 min at rt, then THF (final molarity 0.5 M) and Ra-Ni (100 wt %) are added, and the reaction pressurized with H 2 (8.3 bar/120 psi). All data is based on GC area % analysis. b Sum of (S)-α-MBA and imine remaining. c 1.0 area % of (±)-2-aminooctane was noted. d 2.5 area % (±)-2-aminooctane was noted. In the process of searching for the origin of enhanced diastereoselectivity I tried to collect information about the in situ imine formation. Samples were taken from mixture of 2- octanone and (S)-α-MBA after 30 min with no additive or with Ti(O i Pr) 4 (1.25 equiv) and analyzed by GC. In both reactions the area % of the imine was almost similar. Comparing these results with results obtained from mixing 2-octanone and (S)-α-MBA after 30 min with Yb(OAc) 3 (1.1 equiv) showed that no appreciable amounts of imine (< 3 area %) was detected when Yb(OAc) 3 was used. Extending the reaction time upto 12 h aiming to force the imine formation did not show any success (table 7.2). Table 7.2. In Situ Imine Formation Study: 2-Octanone and (S)-α-MBA. a 130
imine area % (GC analysis) time (min) no additive Ti(O i Pr) 4 (1.25 equiv) Yb(OAc) 3 (1.1 equiv) 30 16 38
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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
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
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: congested which should be favored.
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 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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