Improved Methodology for the Preparation of Chiral Amines

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1 1g O 2g HN Ph 81 98 2 1h O 2h HN Ph 78 98 3 1i O 2i HN Ph 63 94 1b O 2b HN Ph 78 92 5 4 d 92 O 1a HN Ph 2a 79 6 1c O 2c HN Ph 87 80 7 1f O 2f HN Ph 82 e 79 8 1d O 2d HN Ph 83 72 9 1e O 2e HN Ph 82 71 a Ketone (2.5 mmol), dried Yb(OAc) 3 (10 mol %), (S)-α-methylbenzylamine (1.1 equiv), Raney Ni, 0.50 M (MeOH-THF, 1:1), 12 h. Entries 1-4: T= 50 o C, H 2 pressure = 290 psi (20 bar); entry 5: T= 50 o C, H 2 pressure = 120 psi (8.3 bar), entries 6-9: T= 22 o C, H 2 pressure = 120 psi (8.3 bar). b Isolated yield of both diastereomers after chromatography. c Determined by GC analysis of the crude product. d Pt-C was used instead of Raney Ni, T= 50 o C, H 2 pressure = 120 psi. e Non-Yb(OAc) 3 based methods provide 74% de. Table 6.3 shows the breadth of prochiral ketones that serve as good substrates for our catalytic method. As might be expected, based on the steric considerations, the diastereoselectivity of the reductive amination product increases in a fairly undisturbed and linear progression (72–98%), on changing the R substituent of the 2-alkanone, RC(O)CH 3 , from a straight chain alkyl group to those having –γ, -β, and finally -α branching (table 6.3, 122
e.g. compare entries 1, 5, 6, and 9). This general trend is interrupted only when the R substituent is t-butyl, e.g. pinacolone (table 6.3, entry 4). Pinacolone again fails to react under the standard Raney-Ni catalyst conditions, but the desired product is produced when using Pt- C as the hydrogenation catalyst. It is interesting to note that unlike our earlier findings with Raney-Ni/Ti(O i Pr) 4 , [3] which allow 2-alkanones with α-branching (table 6.3, entries 1-4) to be reductively aminated at 22 o C and 120 psi H 2 in 12 h, the use of Raney-Ni/10 mol % Yb(OAc) 3 requires the more forcing conditions of 50 o C and 290 psi (20 bar) for 12 h reaction times to be accomplished with complete consumption of the starting ketone. Regarding aryl-alkyl ketones, acetophenone (table 6.3, entry 3) was sluggish to react even at 50 o C and 432 psi (30 bar) of hydrogen, with isolated yields varying between 60-65% and concomitant alcohol by-product formation always noted. Examination of 1-phenylbutanone at 50 o C and 432 psi (30 bar) of hydrogen only allowed ~20 area % (GC) of the expected product to form after 24 h. Benzosuberone (cyclic aryl-alkyl ketone) and i-propyl n-propyl ketone, under similar forcing conditions (50 o C, 580 psi (40 bar) H 2 , >24 h), showed that these sterically challenging substrates could not be reductively aminated. 6.2. Stoichiometric and Catalytic Brønsted Acid Promoted Reductive Amination Table 6.4. Brønsted Acid Based Reductive Amination of 2-Octanone with (S)-α-MBA. a Entry Brønsted acid ( 20 mol %) 2-octanone remaining (area %) alcohol formed (area de b %) b 1 Acetic acid 1 2 72 2 Trifluoroacetic acid - 22.34 71 3 Trichloroacetic acid 1 2.1 72 4 Formic acid - 2.67 71 5 Oxalic acid 1.65 24 73 6 Thiophenol 51.76 3.47 26 7 Phenol - 29 70 123
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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
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Scheme 3.9. Synthesis of (S)-Metola
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groups decreased both the enantiose
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progress of the reaction was monito
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attempts were directed for the asym
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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(
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: The reactions described above all u
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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