Improved Methodology for the Preparation of Chiral Amines

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to 86%, and the de was consistently reported between 87-88%. Aiming to understand the concept behind this effect, H 2 O or AcOH (50 or 100 mol %) was added to the reaction mixture containing dried Yb(OAc) 3 . The amount of 2-aminooctane formed increased also to ~10 area % (GC). For this reason I decided to conduct all experiments using only dried Yb(OAc) 3 . Another significant finding from this observation was the importance of using ketone as the limiting reagent instead of α-MBA (1.1 equiv) to obtain the optimal de and yield. The use of ketone as a limiting reagent adds to the advantages of our methodology as it reduces the expenses of starting materials especially when using expensive ketones on larger scale. Regarding the formation of 2-aminooctane, our initial speculation was that the reductive amination products (S,S)- and (R,S)-secondary amine (scheme 5.1.) were slowly being hydrogenolyzed under the reaction conditions, but chiral GC analysis (trifluoroacetamide derivative) established the primary amine side product as a racemate. Based on our prior experience, regarding the stereoinducing capabilities of (S)- or (R)-α-MBA with Ti(O i Pr) 4 and 2-octanonone, I considered it unlikely that a racemate would form if a sequential reductive amination-hydrogenolysis scenario had occurred. This led us to examine the possibility that (S)- α-MBA was being hydrogenolyzed by Raney-Ni, in the presence of Yb(OAc) 3 , in a small but significant amount, and thereby producing ammonia and ethylbenzene in situ. The subsequent, but non-productive, reductive amination of ammonia with 2-octanone would then account for racemic 2-aminooctane formation. In an effort to support this hypothesis, several reactions were examined by GC in an effort to identify ethylbenzene (relative to an authentic reference standard), but none was ever observed. To further corroborate those findings, I treated α-MBA (in the absence of 2-octanone) with Raney-Ni/H 2 . Several repetitions of this experiment failed to allow the identification of ethylbenzene. The major obstacle for identification of ethylbenzene was its low boiling point (136 °C). Any low quantities produced could potentially evaporate on quenching the reaction aliquot at room temperature (work-up: drop aliquot into sat. aq NaHCO 3 /EtOAc). Hoping to reduce ethyl benzene evaporation the quenching solution of aqueous NaHCO 3 /EtOAc was cooled to 0 °C. Unfortunately, this did not allow the observation of ethylbenzene by GC. While [1,3]-proton shift of imine is known, it is to our knowledge only accomplished under the presence of a strong base. [16] 112
If a [1,3]-proton shift of the initially formed imine occurred, followed by hydrolysis, 2- aminooctane and acetophenone would result. When 2-octanone (1.0 equiv), (S)-α-MBA (1.1 equiv), and Yb(OAc) 3 (1.1 equiv) were added to THF-MeOH (standard reaction conditions), and stirred in the absence of Raney-Ni and H 2 , a very small quantity of new compound (
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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
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 and 124: 2-octanone starting material. When
Page 125: 3 Yb(OTf) 3 d 4 Ti(O i Pr) 4 e 5 B(
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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