Improved Methodology for the Preparation of Chiral Amines

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generated trans- and cis-imine mixture. This means that the addition of Yb(OAc) 3 may results in enrichment of trans- over cis- imines before hydrogenation. This idea is only applicable if Yb(OAc) 3 was capable of isomerizing some of the cis-imine to the trans-imine. To test this proposed idea practically I synthesized N-(S)-MBA ketimine of 2- octanone using Dean-Stark trap. To the isolated imine, Yb(OAc) 3 (1.1 equiv) in anhydrous MeOH was added and stirred for half an hour at 22 °C before the addition of Raney-Ni slurry in THF and the then the whole mixture was hydrogenated at 8.1 bar (120 psi) for 12h. GC analysis after 12 h showed that all imine was consumed and the product de was 86%. Repeating the same reaction but with extended stirring time for the imine with Yb(OAc) 3 resulted in similar de (86%). These results correlate with the earlier obtained results of enhanced diastereoselectivity utilizing Yb(OAc) 3 in the reductive amination of 2-octanone. Further examination of effect of changing reaction conditions on the reaction out come as changing the solvent during prestirring period was also tested. THF was used instead of MeOH in the prestirring period resulting in lowering the de of the formed amine to 77%. This may be a direct result of low solubility of Yb(OAc) 3 in THF allowing the back round reaction to occur and showing the importance of having MeOH as the prestirring solvent. All these findings support the proposed hypothesis of Yb(OAc) 3 promoted isomerization of the in situ formed imine. In our attempt to clarify the role of Yb(OAc) 3 in reductive amination of prochiral ketones, I proposed a mechanism for the in situ imine isomerization (scheme 7.1). The reaction starts with the formation of a Lewis acid-base pair between the imine and Yb(OAc) 3 in the cis conformation. In this adduct, acetate ligand of ytterbium attacks the electrophilic carbonyl carbon of iminium ion via a six-membered transition state forming an oxygen-acetylated hemi-aminal in gauche conformation. This conformation suffers from steric crowding because of the gauche relationship between the “α-methylbenzyl” substituent on the nitrogen atom and the “R” substituent of the former carbonyl carbon. To relief this steric strain the molecule undergoes pyrimidal inversion at nitrogen atom. This process is a low energy process which readily occurs at room temperature. 132
Inversion at the nitrogen atom of the gauche conformation results in formation of anti conformation allowing an anti-relationship to exist between the “α-methylbenzyl” substituent of nitrogen and the “R” substituent of the former carbonyl carbon; this conformation also allows an antiperiplanar arrangement between the nitrogen lone pair and the acetate leaving group, allowing facile elimination of acetate and transimine formation. Through this proposed mechanism I can understand the role of ytterbium acetate imine isomerization. Ph R OAc OAc N Yb O O cis-5 R Yb N O Ph O higher energy cis-ketimine pathway R CH 3 N Yb Ph O O pyrimidal inversion at nitrogen R Yb O N O CH 3 Ph gauche-6 anti-6 lower energy trans-ketimine pathway Ph OAc OAc R N O Yb O Ph Yb N R O trans-5 O Scheme 7.1. Proposed Mechanism for In Situ Isomerization of the Ketimine during Reductive Amination 7.1.2. Reasons Behind Enhanced Diastereoselectivity for Different 133
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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
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 and 144: congested which should be favored.
Page 145: imine area % (GC analysis) time (mi
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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