Improved Methodology for the Preparation of Chiral Amines

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Yb(OAc) 3 (Aldrich catalog number 544973, 99.999% grade), Y(OAc) 3 (Aldrich catalog number, 326046, 99.9% grade), and Ce(OAc) 3 (Aldrich catalog number, 529559, 99.999% grade ), each was dried at 80 °C under high vacuum until a constant weight was achieved (12 h). The dried Lewis acids could be stored in dry screw cap glass bottles at room temperature, and these containers could be repeatedly opened to the atmosphere (at least 6 times without detrimental effect) without special precaution or need for a glovebox. In this way constant and repeatable results were always observed. The (S)-α-methylbenzylamine (Aldrich catalog number, 115568) was of 98% chemical purity and 98% ee. The Raney-Nickel (in water) was purchased from Fluka (Catalog number, 83440). Pd(OH) 2 /C [≤ 50% water, 20 wt % loading (dry basis)] was purchased from Aldrich (catalog number, 212911). Pt/C (1-4% water, 5 wt % loading) was purchased from Aldrich (Catalog number, 205931). Experimental Section Synthesis of N-(S)-α-MBA ketimine of 2-octanone p-Toluene sulphonic acid (2 mol %, 80 mg) was added to a double neck 100 mL round bottom flask, 60 mL of toluene was added, 2-octanone (22 mmol, 1.00 equiv, 3.45 mL), and (S)-α-methylbenzylamine (24.2 mmol, 1.10 equiv, 3.08 mL) were added to the flask. The flask was connected to a Dean-Stark trap which was connected to a refluxing condenser. The mixture was refluxed for 24 h at 120 °C. The mixture was allowed to cool and then the toluene was evaporated under vacuum. The residue was dissolved in hexane (~30 mL), the solution was passed through filter paper and into a separatory funnel. Aqueous NaHCO 3 (1.0 M, 40 mL) was added and after very brief mixing, the hexane layer was separated, washed with brine, dried over MgSO 4 and filtered. The organic layer was concentrated under rotary evaporation then under high vacuum at 40 °C (with stirring) for 24 h (3.7 g, 57% yield). GC analysis showed 96 area % of the imine and 4 area % of the starting ketone and amine. This imine was used for the further experiments. General procedure for the reduction of the N-(S)-α-MBA ketimine of 2-octanone The imine (2.0 mmol, 462 mg) was added to a hydrogenation vessel, and then anhydrous MeOH (2.5 mL) or THF (2.5 mL) was added. Dried Yb(OAc) 3 or Yb(OTf) 3 was then added, 142
and the mixture was stirred for 30 min. A THF slurry of Raney-Ni (100 wt % based on the imine, pre-triturated with EtOH (×3) and then with anhydrous THF (×3) before addition) (final reaction molarity 0.4 M) was then added and the reaction vessel pressurized at 120 psi (8.3 bar) of hydrogen. GC samples were worked-up using NaHCO 3 / EtOAc. General procedure: Stoichiometric Yb(OAc) 3 (enhanced de) In a dry reaction vessel Yb(OAc) 3 (0.96 g, 2.75 mmol, 1.1 equiv) was added and subsequently evacuated under high vacuum for 5 min before flooding with nitrogen, anhydrous MeOH (2.5 mL, 1.0 M) was then added. To this solution a prochiral ketone 1 (2.5 mmol, 1.0 equiv) and (S)-α-methylbenzylamine (0.35 mL, 2.75 mmol, 1.1 equiv) were added and subsequently stirred at room temperature for 20-30 min. 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) and the reaction vessel pressurized at 120 psi (8.3 bar) of hydrogen. After 12 h at 22 o C,
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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
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 and 154: eductive amination of a prochiral k
Page 155: Appendix Experimental Section Gener
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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