Improved Methodology for the Preparation of Chiral Amines

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(S)-α-methylbenzylamine[(S)-α-MBA] 1.0 798.00 (R)-α-methylbenzylamine[(S)-α-MBA] 1.0 2.220.00 This auxiliary has been previously explored in literature for the synthesis of chiral amines. The previous methods were based on the reduction of N-α-methylbenzyl ketimines, not on reductive amination. [4] For reductive amination, the principal side-reaction is the formation of an alcohol from the competing hydrogenation of the carbonyl starting material. It could be stated that a desirable attributes of an effective reductive amination method is the one capable of using atom efficient reducing reagents and ideally do not allow alcohol formation. In that sense, molecular hydrogen is an ideal source of hydride and the reduction of imine or iminium ion intermediates must be fast relative to the reduction of the starting carbonyl compounds. Thus, in reductive amination the correct combination of hydride source, catalyst and additives is an important prerequisite for its success. Few reports are available and they require further development for optimum reactions. It is a two step process for the final α-chiral primary amine inhibiting any possibility of imine isolation which is time consuming and low yielding process. The prochiral ketone is converted to the corresponding secondary amine in a good to high diastereoselectivity and yield in the presence of Lewis acid/(R)- or (S)-α-MBA/H 2 . The absolute configuration of the major and minor diastereomer depends on the absolute configuration of the chiral amine source. This amine can then be purified by column chromatography or by crystallization. The chiral primary amine is produced from the secondary amine through hydrogenolysis. As motioned before, Nugent et al have succeeded to establish a new methodology for synthesizing α-chiral amines. Reaction conditions as hydrogen pressure, temperature and time were milder compared to other available methodologies. Reaction time is short compared to other methodologies adding to the advantages of this strategy. The use of minute quantities of metal catalysts (Pd and Pt) is another advantage. Another factor which makes this reaction attractive is the low hydrogen pressure needed; almost 80% of all ketones are hydrogenated at 8.0 bar and also at room temperature. Usually other methodologies require the use of higher (up to 100 Bar). 100
The unique feature of this methodology is the ability to use a wide variety of structurally different substrates. Aliphatic and aromatic ketones with different steric and electronic environment are successfully reductively aminated in this reaction. The diversity of the used ketones will help to broad the scope of the reaction applications. [5] The success in synthesizing a wide variety of amines by this methodology encouraged us to investigate other commercially available Lewis acids. I thought that changing the Lewis acid will have an effect on the reaction based on our previous results. The use of titanium isopropoxide as a Lewis acid has many advantages and some disadvantages. It is cheap and available in kg quantities and it is already in use for in industrial processes. On the other hand it is moisture sensitive and it should be used in stoichiometric quantities which complicates the work up process. Different Lewis acids were tested and some of the tested Lewis acids showed promising results. The most pronounced results obtained through using stoichiometric quantity of ytterbium acetate. The use of this Lewis acid improved the de of the reaction tremendously. The effect of this Lewis acid was significant when aliphatic ketones were used as substrates. The increase in the de reached in certain cases more than 10%. Ytterbium acetate is a solid Lewis acid and less moisture sensitive compared to titanium isopropoxide which makes it easier in handling. In the following paragraphs I will try to give a brief overview about ytterbium and its applications in organic synthesis. 5.1.1. Ytterbium. 5.1.1.1. Electronic Overview: Ytterbium is one of the Lanthanides rare earth metals. Symbol Yb; atomic number 70; atomic weight 173.04; valence +2, +3; atomic radius 1.945Å; ionic radius, Yb3+ 0.868Å and 0.98Å for CN 6 and 8; respectively; seven naturally occurring stable isotope: Yb-170 (3.05%), Yb- 171 (14.32%), Yb-172 (21.93%), Yb-173 (16.12%), Yb-174 (31.84%), Yb-176 (12.72%); twenty-three artificial radioactive isotopes in the mass range 151-167, 169, 175, 177-180; the 101
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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
Page 63 and 64: More recently, 2008, he described t
Page 65 and 66: [22] E. Guiu, M. Aghmiz, Y. Diaz, C
Page 67 and 68: Chapter 3 Reductive Amination 3.1.
Page 69 and 70: . CH 3 CO(CH 2 ) 5 CH 3 H 2 NCH 2 C
Page 71 and 72: 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: Chapter 5 Stoichiometric Use of Ytt
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 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,
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obtain the hydrochloride salt (0.41
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with etheral HCl provided the hydro
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Research experience: Date Project S
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Improved Methodology for the Preparation of Chiral Amines

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