Improved Methodology for the Preparation of Chiral Amines

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t Bu O S R 1 R 2 N PPh 2 [{Ir(cod)Cl 2 }] PAr 2 O t Bu P O O t Bu Ir + Me P P BARF - t Bu Me R 1 =Ph,R 2 = i Bu Catalyst 10 11a, Ar = xyl 11b, Ar = ph, o-OMe-ph Catalyst 12 Ph 2 P O Ir H H PPh 2 O Catalyst 13 + PF 6 - Catalyst 11 O R N P Ir Ar Ar R=Bn,Ar=3,5-DiMe-Ph + BARF - BARF Ir(COD) Ph 2 P OR N Fe R=CH 3 Catalyst 15 Catalyst 14 N CONH CHO Cl 3 SiH Catalyst 16 Me N H H N O O Cl 3 SiH Catalyst 17 O * N N Cl 3 SiH Catalyst 18 Ph H 3 C N H H H N O O Cl 3 SiH N Catalyst 19 O Cl 3 SiH H N O AcO Catalyst 21 Me Me O Ph Ph H C 6 F 13 SO 2 (p- t BuPh) N N O H N Ph O Cl 3 SiH Catalyst 22 O Me S N nN H H n=5 Cl 3 SiH N H O S H N O O Cl 3 SiH N H Cl 3 SiH Catalyst 23 O S Catalyst 20 OH F O Me Me n n=3 H H N N N n H O O n=2 O Cl 3 SiH O Catalyst 24 N H PH 2 Catalyst 25 42
2.3.2. Different Substrates Categories Several organometallic and organocatalytic systems were developed for the reduction of phenyl methyl (ethyl) N-aryl imines. The hydrogen source is either molecular hydrogen or hydride reagents. Transition metals having chiral ligands on Ir, Ru, Rh and Ti were used and resulted in high yield and selectivity. Pfaltz and Leitner used cationic Ir complexes with chiral phosphinodihydrooxazoles modified with perfluroalkyl groups. [18] Using 0.09 mol % of the catalyst (catalyst 1, figure 2.4), 30 bar (435 psi) H 2 , supercritical carbon dioxide (scCO 2 ) at 40 °C an ee of 80% was accomplished with complete conversion (structure 1, figure 2.2). The choice of counter ion dramatically influenced selectivity with tetrakis-3,5-bis(trifluoromethyl)phenylborate anion (BARF), resulting in the highest selectivity. They later developed the use of scCO 2 with ionic liquids and obtained the same result. [19] Zhang and Xiao reported one of the earliest examples for the efficient reduction of aryl methyl N-aryl imines utilizing iridium. They introduced the use of air stable Irbisphospahnoferrocene catalyst (catalyst 2, figure 2.4). [20] Using 2.0 mol % of the catalyst (catalyst 2, figure 2.4), 70 bar (1015 psi) of H 2 , CH 2 Cl 2 , 25 °C over 44 h, 99% ee with 77% conversion for phenyl methyl N-aryl imines (structure 1, figure 2.3). For p-OMe-phenyl methyl N-aryl imines the ee was 98% with 77% conversion and for p-CF 3 -phenyl methyl N- aryl imine the ee was 99% with 80% conversion (structure 3, figure 2.3). Claver and Castillón introduced the use of sugar derived diphosphite ligands. [21] Using 1.0 mol % of the iridium catalyst (catalyst 3, figure 2.4), 10 bar (145 psi) H 2 , CH 2 Cl 2 , 25 °C, 18 h an ee was 57% with 83% conversion for phenyl methyl N-aryl imine (structure 1, figure 2.3). The use of 4.0 mol % Bu 4 NI improved conversion (100%) but lowered the ee (46%) at 70 bar (1015 psi) of H 2 . Later they reported the use of other diphosphinite ligands (catalyst 4, figure 2.4). Using 1.0 mol % of the catalyst, 70 bar ( 1015 psi) H 2 , CH 2 Cl 2 , 25 °C, 16 h, the ee was 70% with complete conversion. [22] 43
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Improved Methodology for the Prepar
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This dissertation is dedicated to a
Page 5 and 6: suppressing alcohol formation and p
Page 7 and 8: Prof. Mohamed El-Azizi, Prof. Abdel
Page 9 and 10: Et EtOH EtOAc GC h HPLC HRMS Hz J K
Page 11 and 12: Table of Contents Abstract. Acknowl
Page 13 and 14: 4.1.5. Synthesis of Emitine 85 4.1.
Page 15 and 16: 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: Figure 2.4 General Catalyst structu
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 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
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ethyl carbamate by acylation with e
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4.1.16. Synthesis of Ritonavir and
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4.2. Conclusion Different important
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Chapter 5 Stoichiometric Use of Ytt
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The unique feature of this methodol
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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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