Improved Methodology for the Preparation of Chiral Amines

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stream of organic chemistry. Hydrogenation catalysts as nickel, palladium platinum and other transition metal catalysts received the maximum attention. These catalysts were initially introduced for alkene hydrogenation and they were later tested for other transformations as reductive amination. [3] Reductive alkylation of ammonia was one of the earliest examples described in literatures. It generally proceeds under mild conditions using heterogeneous catalyst. The reductive alkylation of ammonia with carbonyl compounds may produce primary, secondary, and tertiary amines, as well as alcohol as a side product. The origin of product selectivity depends primarily on the molar ratio of carbonyl compound to ammonia, the nature of catalyst and structure of the carbonyl compound. The reaction of benzaldehyde in the presence of 1.0 equivalent of ammonia in ethanol over Raney Ni gave benzylamine in an 89.4% yield while with 0.5 equivalent of ammonia dibenzylamine was obtained in an 80.8% yield. [4] Reductive amination of aliphatic aldehydes having α-hydrogen atoms, especially of the type RCH 2 CHO, usually results in lower yields due to the formation of by products through aldol or other condensation reactions. Also lower aliphatic aldehydes usually produce mixture of primary, secondary, and tertiary amines. The reaction of butyraldehyde with 0.5 equivalent of ammonia over Raney Ni also resulted in a mixture of 31% of butylamine, 17% of dibutylamine, and 8% tributylamine. [5] Higher aldehydes usually react selectively with ammonia producing less by products. [6] The reductive alkylation of ammonia with ketones is performed under conditions similar to those for aldehydes, but appears to proceed with more difficulty. Initially, reductive amination of ketones with ammonia was tested without any additives resulting in lower yields. [7,8] Primary amines are considered better neocluophihes compared to ammonia. Despite their higher nucleophilicity they are more sterically hindered. They were tested in reductive amination of carbonyl compounds utilizing different heterogeneous catalysts as nickel, platinum oxide, platinum sulphide and nickel sulphide. The following examples are some early trials for the preparation of secondary amines from primary amines (scheme 3.1). [9-12] NH 2 CH(CH 2 ) 2 CHO (0.5mol) Ni-kieselguhr 125 o C,100 bar H 2 ,1h (0.55mol) 54 (91%) NHC 4 H 9
. CH 3 CO(CH 2 ) 5 CH 3 H 2 NCH 2 CH 2 OH Pt oxide* C 6 H 13 CH(CH 3 )NHCH 2 CH 2 OH (1.3mol) (1mol) 100ml EtOH RT, 1-2 bar H 2 ,7h (96%) *Prereduced in 50ml EtOH at 1 bar H 2 O (1.0mol) NH 2 (1.90mol) Ni sulfide* 180 o C,100-120 bar H 2 ,14h *Supported on montmorillonite (15% Ni) NH (95.5%) PhHN NH 2 MeCOCH 2 CHMe 2 Pt sulfide-C PhHN NHCH(CH 3 )CH 2 CHMe 2 175-180 o C, 30-40 bar H 2 ,4.5h (0.86mol) (0.95mol) (99%) Scheme 3.1. Preparation of Secondary Amines In their attempts to overcome the problems associated with reductive amination, scientists tested the effect of additives on this transformation. It was found that the addition of a small quantity of Brønsted acid improved the yield dramatically. Dialkyl ketones, especially sterically hindered ones, tended to produce the corresponding alcohols to significant extents under the conditions of reductive amination decreasing the overall yield of the amine. The addition of a small amount of acetic acid or ammonium acetate is effective in suppressing alcohol formation. Thus, the formation of 2-nonanol could be depressed effectively in the presence of ammonium acetate in the reductive amination of 2-nonanone (scheme 3.2). [3] CH 3 OC 7 H 15 10 mL EtOH/0.8 g (0.047mol) NH 3 50 o C, 80 bar H 2 ,Ra-Ni,Brønstedacid CH 3 CH(NH 2 )C 7 H 15 CH 3 CHOHC 7 H 15 100% 0% Scheme 3.2. Reductive Amination of 2-nonanone 3.1.2. Reductive Amination Utilizing Homogenous Catalysis: As mentioned before heterogeneous catalysts were first utilized for reductive amination. After the introduction of Wilkinson catalyst which opened the door for the use of homogenous catalysts in organic synthesis. Interest has been expressed in the use of homogeneous catalysts for reductive amination. Bakos was the first to utilize homogenous 55
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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
Page 17 and 18: 1. Cis-trans or geometric isomers.
Page 19 and 20: O O O * NH Thalidomide (R)-active a
Page 21 and 22: One enantiomer may be responsible f
Page 23 and 24: 1.5.1. Synthesis of Enantiomericall
Page 25 and 26: 1.5.2.2. Kinetic Resolution Kinetic
Page 27 and 28: compound by the auxiliary. The auxi
Page 29 and 30: 1.5.4. Stereoselective Conversion o
Page 31 and 32: It is estimated that 3000 tonnes (a
Page 33 and 34: k R R P 1 k rac S k S P 2 Figure 1.
Page 35 and 36: (S)-(α)-Methylbenzylamine and its
Page 37 and 38: fourth chapter showing different dr
Page 39 and 40: Burk was successful in reducing ary
Page 41 and 42: Table 1.1 Rhodium Catalyzed Reducti
Page 43 and 44: [8] E. L. Eliel, S. H. Wilen, Stere
Page 45 and 46: [42] a) J. Blacker, Innovations in
Page 47 and 48: [67] a) H. Qin, N. Yamagiwa, S. Mat
Page 49 and 50: of imine reduction in the past eigh
Page 51 and 52: 8 years beginning from the year 200
Page 53 and 54: 2.2.3. Nguyen Special Substrates. A
Page 55 and 56: Figure 2.4 General Catalyst structu
Page 57 and 58: 2.3.2. Different Substrates Categor
Page 59 and 60: H 2 , toluene, 25 °C, 4 h an ee of
Page 61 and 62: 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: Chapter 3 Reductive Amination 3.1.
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 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
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Ruthenium(III) chloride 31.7 4 4.2
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t-Butyl methyl ether 15 - - 82 Hexa
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2-octanone starting material. When
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3 Yb(OTf) 3 d 4 Ti(O i Pr) 4 e 5 B(
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If a [1,3]-proton shift of the init
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enhanced stereoselectivity. For exa
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WO2006030017, 2006; c) T. C. Nugent
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4 60 86 5 50 86 6 40 84 7 20 79 8 2
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The reactions described above all u
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e.g. compare entries 1, 5, 6, and 9
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solvent in the stoichiometric and c
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[2] Farina, V.; Grozinger, K.; Mül
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congested which should be favored.
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imine area % (GC analysis) time (mi
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Inversion at the nitrogen atom of t
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anti-6) would be expected to have m
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e.g. AcOH, suppresses alcohol by-pr
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eductive amination of a prochiral k
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Appendix Experimental Section Gener
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and the mixture was stirred for 30
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Reaction details: Yb(OAc) 3 (1.1 eq
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etention time [min]: major (S,S)-2b
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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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