Improved Methodology for the Preparation of Chiral Amines

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Chapter 6 Catalytic Lewis Acids in Reductive Amination. 6.1. Introduction. Historically Lewis acids were used in reductive amination in stoichiometric quantities. Through extensive literature search I did not find any previous example for the catalytic use of Lewis acids in reductive amination. This was one of the limitations for scaling up the use of Lewis acids in reductive amination. The high diastereoselectivity obtained with the use of Yb(OAc) 3 in reductive amination motivated us to investigate deeply for the possibility of using Lewis acids in catalytic quantities. Table 6.1 shows the effect of slowly decreasing the mol % of dried Yb(OAc) 3 from 110 mol % to 10 mol %. The data shows that 80 mol % Yb(OAc) 3 produces the same results as 110 mol %, and interestingly 50 mol % Yb(OAc) 3 is capable of maintaining very similar de (1% less) as compared to 110 mol %. Rapid deterioration in the diastereoselectivity was noticed when the Yb(OAc) 3 loading was reduced below 40%. When the Yb(OAC) 3 loading was reduced to 10 mol % no improvement in the de was noticed the de’s observed were similar to the previously reported with non-Yb(OAc) 3 based methods with α-MBA. [1] Table 6.1. Relationship Between Mol % of Yb(OAc) 3 and Diastereoselectivity of Amine Product. a entry Yb(OAC) 3 mol% de% 1 110 87 2 100 87 3 80 87 118
4 60 86 5 50 86 6 40 84 7 20 79 8 20 80 b 9 10 72 a Ketone (2.5 mmol, 1 equiv), dried Yb(OAc) 3 (1.1 equiv), (S)-α-methylbenzylamine (1.1 equiv), Raney-Ni, H 2 (120 psi), MeOH-THF (1:1) 0.50 M, 22 °C, 12 h. b 4 Å molecular sieves (4 wt equiv) were also added. Further reduction in the Yb(OAc) 3 loading below 10 mol % led to increase the formation of alcohol byproduct. When 5 mol % of Yb(OAc) 3 was used, alcohol by product was detected in aquantity greater than 2 area % (GC). For this detailed study I reached to the conclusion that the least Yb(OAc) 3 loading is 10 mol % which should be used the rest of the study. Encouraged by these results I investigated a variety of transition metal, lanthanide, and metalloid halide, acetates, alkoxides, and sulfonates, for their ability to allow fast and high yielding reductive amination reactions to occur. From this extensive study Ce(OAc) 3 (15 mol %) and Y(OAc) 3 (15 mol %) emerged as useful Lewis acids inhibiting alcohol formation. The results obtained through using these two Lewis acids were consistently similar to the results of Yb(OAc) 3 (10 mol %), regarding reaction times, yield, and diastereoselectivity for the reductive amination of 2-octanone with (S)-α-MBA. Stoichiometric use of Ce(OAc) 3 or Y(OAc) 3 , did not provide enhanced de or any other added benefit over those reactions examined at the 15 mol % level. Other transition metal acetate salts showed interesting results in terms of promoting reductive amination in an acceptable time frame. On the other hand, the use of these Lewis acids resulted in formation of alcohol byproduct in concentration typically 5-15 area % by GC analysis. These Lewis acids are : In(OAc) 3 , Sc(OAc) 3 , CuOAc, Er(OAc) 3 , Gd(OAc) 3 , Dy(OAc) 3 , AgOAc, Zn(OAc) 2 , and Cd(OAc) 2 , they were tested at 15 mol % concentration. Other commercially available salts of these elements were tested but none of them proved useful as the alcohol byproduct concentration was always above 25 area % by GC analysis. From this study it is obvious that all interesting Lewis acids have acetate as counter ion. Exceptions to this general observation were noted for Bi(OTf) 3 , AgCl, ScCl 3 , and scandium 119
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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
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 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: WO2006030017, 2006; c) T. C. Nugent
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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