Improved Methodology for the Preparation of Chiral Amines

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simplified scenario less likely. It is clear that ytterbium and the acetate ligand together are needed for the efficient reductive amination process. Historically the use of acetic acid as Brønsted acid in reductive amination is well established on laboratory and industrial scales. It is cheap, available in kilogram quantities, easy to handle and usually used in catalytic quantities. Testing acetic acid in our reaction will help to establish another reference point to our work after the comparing with Ti(O i Pr) 4 system. The use of (0.2, 0.5 and 1.0 equiv) of acetic acid inhibited alcohol formation but did not show any de improvement. The addition of acetic acid to Yb(OAc) 3 reaction resulted in the reduction of diastereoselectivity of the secondary amine (72%). All these findings proved that Yb(OAc) 3 is a unique Lewis acid for reductive amination. As mentioned previously that reductive amination does not require imine separation and purification which is achieved by the addition of proper Lewis acid. Some older reports simplify the role of Lewis acids in reductive amination to the level of an efficient desiccant promoting in situ imine formation in high yield. Extensive studies on the mechanism of reductive amination and intermediates structures contradicted these simplified speculations and proved that Lewis acids have greater role than efficient desiccants. To study this effect more closely, I examined some traditional desiccants. When Yb(OAc) 3 (1.1 equiv) is replaced by MgSO 4 (5 equiv) or 4Å molecular sieves (4 wt equiv), all vacuum oven dried at 150 ° C for 15 h before use, not only low diastereoselectivities were observed (Table 5.4, compare entries 1, 6, 7), but gross amounts of 2-octanone were reduced to the alcohol byproduct. In relation to these results, alcohol by-product formation could be significantly suppressed when Ti(O i Pr) 4 (1.25 equiv) was used, but the de remained low. These combined findings clearly establish Yb(OAc) 3 as fulfilling a greater role than that of a simple desiccant. Table 5.4. a Initial Study of the Role of Yb(OAc) 3 in the Reductive Amination of 2-Octanone. a Amine 2d entry additive time (h) (S)-α-MBA (%) b 2-octanol (%) yield (%) de (%) 1 Yb(OAc) 3 c 2 YbCl 3 d 10 0.7 0.3 90.4 86.1 23 77.4 0.0 22.5 66.2 110
3 Yb(OTf) 3 d 4 Ti(O i Pr) 4 e 5 B(O i Pr) 3 e 9 - [f] 96.4 3.5 - 10 2.8 11.4 82.3 67.0 10 14.7 24.4 59.6 71.0 6 MgSO 4 12 19 29.3 52.0 70.5 7 4 Å M.S. 12 18.7 28.8 52.5 69.6 8 none 12 24.2 34.6 41.1 70.8 9 NaOAc 23 26.5 43.3 29.7 70.8 10 HOAc 12 4.3 1.0 94.1 72 a (S)-α-MBA (2.5 mmol, 1.0 equiv), 2-octanone (1.2 equiv), and an additive (entries 1-5, 9, and 10, 1.1 equiv of additive, 4Å molecular sieves (4 wt equiv), or MgSO 4 (5.0 equiv)) are stirred in MeOH (1.0 M) for 30 min at rt, then THF (final molarity 0.5 M) and Raney-Ni are added, and the reaction pressurized with H 2 (120 psi). All data is based on GC area % analysis. b Sum of (S)-α-MBA and imine remaining at the indicated time. c This result is when Yb(OAc) 3 has not dried, 2-aminooctanone was noted in 6.5 area %. d These Yb salts were only examined in MeOH. e Under the optimal Yb(OAc) 3 conditions used here, the Ti(O i Pr) 4 and B(O-i-Pr) 3 Lewis acids did not provide optimal results. f Not integrated, to emphasize the presence of the dominant alcohol byproduct. 5.1.2. Commercial Yb(OAc) 3 vs Dried Yb(OAc) 3 : Initial studies were performed using the commercially available Yb(OAc) 3 which had a different physical appearance (powder flowability) in each bottle. Initial results for the reductive amination of 2-octanone with Yb(OAc) 3 in THF-MeOH were promising in terms of high de, but the isolated (chromatographic) yield of secondary amine was 75%. This yield is considered mediocre for a single step process. GC analysis revealed the presence of unknown peak with 10-12 area %. Reaction was performed at larger scale (8 mmol) allowing the chromatographic separation of this compounds. The isolated compound was analyzed using ( 1 H and 13 C NMR) which revealed that this compound may be as 2-aminooctane. The conditions under which this primary amine by-product formed were when (S)-α-MBA was used as the limiting reagent [(ketone 1.2 equiv and undried Yb(OAc) 3 (1.1 equiv)], 2-aminooctanone is consistently observed at 6-7 area % (GC). Surprisingly the vacuum drying of Yb(OAc) 3 , reduced the amount of 2-aminooctane dramatically to 1-3 area % (GC). Of course the isolated yield of the secondary amine increased 111
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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
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 and 120: Ruthenium(III) chloride 31.7 4 4.2
Page 121 and 122: t-Butyl methyl ether 15 - - 82 Hexa
Page 123: 2-octanone starting material. When
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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