Improved Methodology for the Preparation of Chiral Amines

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Bismuth(III) acetate 34.8 - - 68.49 Yttrium(III) trifluoroacetate hydrate 2.86 - - 76.79 Ytterbium(III) acetate hydrate - - - 85 Ytterbium(III) acetate tetrahydrate 1.5 - - 84 a All reactions performed using 1.0 mmol of Benzylacetone, 1.1 mmol of (S)-(−)-α-Methylbenzylamine, 1.1 equiv of the indicated Lewis acid, room temperature, 120 psi (8.3 bar) of H 2 , 100 wt % Raney Nickel, and methanol as a solvent. All components (except the Raney Ni and H 2 ) are added together and pre-stirred for 30 min. The heterogeneous hydrogenation catalyst (Raney Ni) is then added and the system pressurized with 8 bar of H 2 . The indicated data is at 12 h of reaction from the onset of hydrogenation. The data from the table indicates that most of the used Lewis acids showed inferior results compared to Ti(O i Pr) 4 . The reaction did not even proceed using certain Lewis acids. Only ytterbium acetate hydrate and ytterbium acetate tetrahydrate showed improvement in the de. These results were encouraging to test ytterbium acetate hydrate or tetrahydrate under different reaction conditions aiming for further improvement in the de. Different solvents were tested. The best solvent in terms of reaction rate was methanol. This may be due to partial solubility of ytterbium in methanol. The results of solvent screening are summarized in the (table 5.3). Table 5.3. Solvent Screeing with Ytterbium Acetate Hydrate. a Solvent Ketone Left% Alc. Formed Imine Left de% Methylene chloride 77 - - 78 Isopropanol 15 - - 76 Toluene 23 - - 80 106
t-Butyl methyl ether 15 - - 82 Hexane 60 - - 75 THF 20 - - 86 Methanol - - - 81 a All reactions performed using 1.0 mmol of Benzylacetone, 1.1 mmol of (S)-(−)-α-Methylbenzylamine, 1.1 equiv of Yb(OAc) 3 , room temperature, 120 psi (8.3 bar) of H 2 , 100 wt % Raney Nickel, and solvent as indicated. All components (except the Raney Ni and H 2 ) are added together and pre-stirred for 30 min. The heterogeneous hydrogenation catalyst (Raney Ni) is then added and the system pressurized with 8 bar of H 2 . The indicated data is at 12 h of reaction from the onset of hydrogenation. The use of THF improved the de but the reaction was slower. Other solvents showed slower reaction rate with low de. The high de resulting from the use of THF and the fast reaction rate resulting from the use of methanol was the driving force to test the solvent combination of THF-MeOH (1:1). The rate of the reaction was acceptable with high de (87-89%). Other solvent combinations also were tested (table 5.3). Table 5.3. Screening of Different Solvent Combinations with Ytterbium Acetate Hydrate. a Solvent Ketone Left% Alc. Formed Imine Left de% THF-DMF >90 - - NA DCM-MeOH 77 - - 78 Isopropanol- MeOH 15 - - 76 Toluene-MeOH 24 - - 82 EtOAc-MeOH 6 - - 86 THF-MeOH 2 - - 89 DME-MeOH 50 - - 85 DCE-MeOH 51 - - 80 DEE-MeOH 55 - - 84 a All reactions performed using 1.0 mmol of Benzylacetone, 1.1 mmol of (S)-(−)-α-Methylbenzylamine, 1.1 equiv of Yb(OAc) 3 , room temperature, 120 psi (8.3 bar) of H 2 , 100 wt % Raney Nickel, and solvent as 107
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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.
Page 69 and 70: . CH 3 CO(CH 2 ) 5 CH 3 H 2 NCH 2 C
Page 71 and 72: superior in terms of conversion (89
Page 73 and 74: O NHR 3 R 4 R 4 R 3 N OTi(O i Pr) 3
Page 75 and 76: Scheme 3.9. Synthesis of (S)-Metola
Page 77 and 78: groups decreased both the enantiose
Page 79 and 80: progress of the reaction was monito
Page 81 and 82: attempts were directed for the asym
Page 83 and 84: hydrogen bonding, is chiral and its
Page 85 and 86: Later he utilized this methodology
Page 87 and 88: OMe OMe O HN HN HN O 2 N 71 % yield
Page 89 and 90: compared to the oil refinery indust
Page 91 and 92: [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: Ruthenium(III) chloride 31.7 4 4.2
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 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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