Improved Methodology for the Preparation of Chiral Amines

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Pérez reported the use of BINAP derived palladium catalyst for the reductive amination of alkyl and cycloaliphatic ketones (scheme 3.11). He used o-, m- and p-substituted aniline derivatives as the source of nitrogen, molecular hydrogen at 800 psi (55 bar), in CHCl 3 at 70 °C for 24 h. The use of molecular sieves was crucial for obtaining the product in high yields. He observed that the presence of substituents on the aniline improved stereoselectivity with a little effect on reactivity as they increase the steric bulk of the nitrogen source improving the interaction. When isobutyl methyl ketone reacted with aniline the ee was 51% but when p- anisidine was used the ee jumped to 90%. One of the remarkable examples was the success in reductive amination of 3-alkanones (2-heptanone). Although the ee was mediocre (49-59%) but it is known that these substrates are only accessible through carbanion chemistry. 2,3- butanedione underwent chemoselective reductive amination in good yields (83-85%) and low enantioselectivity (2-20% ee). Aryl ketones were also tested resulting in poor to mediocre ee (35-43%). One of the draw backs of this methodology is the harsh conditions needed for the removal of phenyl ring to obtain the primary amine. [45] (MeCN) 2 PdBr 2 + P P Benzene rt, overnight P PdBr 2 P P = P Me PPh 2 PPh 2 P(p-Tolyl) 2 PPh PPh 2 P(p-Tolyl) 2 2 Me O R 1 R 2 + R 3 NH 2 Catalyst (2.5 mol%) 5Åms,CHCl 3 H 2 (800 psi), 70 °C, 24 h HN R 1 * R 2 R 3 Scheme 3.11. BINAP Derived Palladium Catalyst in Asymmetric Reductive Amination Xiao extended his work on imine reduction and tested his iridium based catalysts for reductive amination (scheme 3.12). He reported high ees and high yields for different acetophenone derivatives with para-anisidine as nitrogen source. The catalyst loading was 1.0 mol% with 5.0 mol% of phosphoric acid derivative as Lewis acid. The addition of molecular sieves was crucial for faster reaction. Using aniline with electron withdrawing 62
groups decreased both the enantioselectivities and the yields. Ortho substituted acetophenone derivatives(o-Cl, o-Me,o-OMe, o-F) which are known to be difficult substrates for reductive amination were reduced with high yields and high enantioselectivities using less sterically hindered catalysts. Aliphatic ketones were also tested and showed high ees and high yields with para-anisidine and with aniline. [46] Ph Ph O O NH 2 Ar S N N H 2 O Ir X OMe [Ir] (1.0 mol %) 5barH 2 toluene 35 o C, 12h Ph Ph Ar = 2,4,6-(2-C 3 H 7 ) 3 C 6 H 2 a: = Cl; b: X = 7-H c: Ar = 4-CH 3 C 6 H 4 ,X=7-H d: Ar = 2,3,4,5,6-(CH 3 ) 5 C 6 ,X=7-H O Me S N N H 2 O X=7-H Ir X HN OMe OH Ar O O O P OH Ar OMe OMe OMe O HN O 2 N HN HN O 92 % yield, 95 % ee OMe 88 % yield, 81 % ee 93 % yield, 95 % ee HN Br OMe HN F HN 92 % yield, 96 % ee 85 % yield, 85 % ee 89 % yield, 95 % ee Scheme 3.12. Reductive Amination Utilizing Iridium Catalyst and Phosphoric Acid. 63
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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
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 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: Scheme 3.9. Synthesis of (S)-Metola
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 and 126: 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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