Improved Methodology for the Preparation of Chiral Amines

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4 1d O 2d HN Ph 86 87 15 5 1e O 2e HN Ph 82 85 14 6 1f O 2f HN Ph 80 79 5 a Ketone (2.5 mmol, 1.0 equiv), dried Yb(OAc) 3 (1.1 equiv), (S)-α-methylbenzylamine (1.1 equiv) equiv), Raney-Ni, H 2 (120 psi), MeOH-THF (1:1) 0.50 M, 22 °C, 12 h. b Isolated yield of both diastereomers after chromatography. c determined by GC analysis of crude product 2. d Compared to the best previously reported results. Pinacolone is a Pt-C substrate and requires a T= 50 °C over 22 h. The 6% increase in de only represents an increase over the best reported reductive amination procedure, vs a previously reported stepwise method there is no change in de. Through examining the results presented in table 5.5 It seems that our methodology is highly efficient for reductive amination of ketones having the general class R S C(O)CH 3 , linear 2- alkanones. The subscript serves as a generic reference to the steric bulk of the substituent: R S = small (any straight chain alkyl substituent, but not a methyl group); R M = medium, e.g. – CH 2 CH 2 Ph or -CH 2 CH(CH 3 ) 2 ; R L = e.g. -Ar, -i-Pr, -c-hexyl. For example, the longer straight chain 2-alkanones, e.g. 2-octanone (1d) and 2-hexanone (1e), showed dramatic improvements in de, 15% and 14% respectively, with good isolated yield (table 5.5, entries 4 and 5). As mentioned before the highest reported de for the reductive amination of 2-octanone (1d) with α-MBA in the presence of Ti(O i Pr) 4 /Raney- Ni/H 2 , was 72%. Aiming to prove that the addition of Yb(OAC) 3 had a dramatic effect on the de of amine product, I synthesized the ketimine of 2-octanone. This ketimine was reduced with Raney-Ni/H 2 in THF-MeOH (1:1) providing 2d in only 64% de. As the chain of 2-alkanone gets shorter as the steric bulkiness gets smaller reducing the enhancement effect of Yb(OAc) 3 addition. The short chain 2-butanone (1f) showed a small but consistent and significant 5% increase in de vs the best previously reported result (Ti(O i Pr) 4 /CH 2 Cl 2 /Raney-Ni: 74% de). Shifting to substrates having medium sized R substituent residing on 2-alkanone, R M C(O)CH 3 helps to define the boundary substrates for 114
enhanced stereoselectivity. For example when the γ-branched benzylacetone (1c) was examined a 9% increase in de was observed vs the previous best reported methods. The use of Yb(OAc) 3 for reductive amination of β-branched i-butyl methyl ketone (1a), did show any significant improvement in stereoselectivity (1% increase) (table 5.5, entry 1). Also α- Branched 2-alkanones, e.g. i-propyl methyl ketone or cyclohexyl methyl ketone, which have been reductively aminated with a very high diastereoselectivity using Ti(O i Pr) 4 (>98% de), did not show any improvement when using Yb(OAc) 3 . Examination of alkyl-aryl ketones, e.g. acyclic acetophenone or cyclic benzosuberone, or a non-2-alkanone, e.g. i-propyl n-propyl ketone, proved problematic. Acetophenone required higher temperature, 60 °C with 120 psi of H 2 , and produced the product in 92% de, but with large amounts of the corresponding alcohol noted (~20 area %, GC). For benzosuberone and i-propyl n-propyl ketone repeated attempts to obtain the intended product by heating and/or increasing the hydrogen pressure failed. The previous substrates were successfully reductively amianted using Ti(O i Pr) 4 with good yield and de. As mentioned previously the heterogeneous catalyst used was Raney-Ni. Pt-C was tested for the reductive amination of i-propyl n-propyl ketone, a 35 area % of the product was noted in 76% de (GC). This ketone has been previously reductively aminated with Ti(O i Pr) 4 /Raney-Ni providing the desired product in 76% yield and 87% de. From previous studies done in our group, it was noted that ketone substrates with an α- tertiary carbon cannot be reductively aminated using Raney-Ni, even under forcing conditions, instead Pt-C is the catalyst of choice for this class of prochiral ketones. Examination of pinacolone (1b) with Yb(OAc) 3 /Pt-C/H 2 , provided a consistent 93% de, which is 6% greater than the previously best reported result reductive amination result (87% Ti(O i Pr) 4 /Pt-C/H 2 ), but is the same as compared to a previously reported stepwise approach. [17] 5.2. Conclusion: 115
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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
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
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: If a [1,3]-proton shift of the init
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,
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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