Improved Methodology for the Preparation of Chiral Amines

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supported by the fact that other ytterbium salts, e.g. YbCl 3 and Yb(OTf) 3 , were ineffective at providing efficient product formation and could not do so with enhanced diastereoselectivity. Furthermore none of the other Lanthanides or transition metals examined allowed enhanced diastereoselectivity. Lastly, Yb(OTf) 3 could in theory undergo a similar imine isomerization process via its sulfonate oxygen, but as noted earlier only provided the alcohol by-product under the reductive amination conditions noted here, implying it is too Lewis acidic. To further probe this, I preformed the N-α-MBA ketimine of 2-octanone and then added Yb(OTf) 3 (110 mol%) to it. After 30 min Raney Ni (THF slurry) was added followed by the onset of hydrogenation, the desired product was observed in 50% de. 7.1.3. Key Findings for Reductive Amination with α-MBA These studies, and our earlier ones, complete a body of research regarding the reductive amination of prochiral ketones with (R)- or (S)-α-MBA (1.1 equiv) under the influence of an optimal Lewis acid or Brønsted acid. The findings show that prochiral alkyl-alkyl' and aryl-alkyl ketones can be readily reductively aminated, and by doing so higher yields and much shorter reaction times are achieved compared to the previously practiced two-step strategy via preformed (R)- or (S)-α-methylbenzyl ketimines. [5] Furthermore, the reducing system of choice is a heterogeneous hydrogenation catalyst in the presence of hydrogen, due to the superior diastereoselectivity afforded with good isolated yield and reaction time vs all other reducing systems examined to date. [2] Use of the correct acid (Lewis or Brønsted) catalyst is crucial for a successful outcome when reductively aminating a prochiral ketone with α-MBA in the presence of Raney-Ni (generally the most useful heterogeneous catalyst) and hydrogen (120 psi). Failure to have the optimal Lewis acid or Brønsted acid, or no acid at all, results in gross alcohol by-product formation. Adding catalytic quantities of Yb(OAc) 3 , Y(OAc) 3 , Ce(OAc) 3 , or catalytic or stoichiometric quantities of a weak Brønsted acid, 136
e.g. AcOH, suppresses alcohol by-product formation for 2-alkanones below 2%, providing the desired amine product in good yield. Application of the catalytic Lewis acid or Brønsted acid systems to aryl-alkyl ketones reveals that only acetophenone will react and then only under forcing conditions (50 ° C, 30 bar) with low yield (63% and 55 % respectively) of the desired product. When stoichiometric quantities of Ti(O i Pr) 4 , a Lewis acid, are used for reductive amination the reactions are complete within the same reaction time and again alcohol by-product formation is suppressed below 2%; but unlike the above mentioned systems, which require elevated temperature (50 ° C) and/or H 2 pressure (290 psi) for α-branched (R L C(O)CH 3 ) and β-branched (R M C(O)CH 3 ) ketones, Ti(O i Pr) 4 only requires 22 ° C and 120 psi for these hindered 2-alkanones. Additionally, aryl-alkyl ketones and more sterically demanding alkyl-alkyl' ketones, e.g. i-propyl n-propyl ketone, can be reductively aminated in good yield and de when using Ti(O i Pr) 4 . When comparing the de of the reductive amination products that are common to Ti(O i Pr) 4 , Brønsted acids (catalytic or stoichiometric, e.g. AcOH), Yb(OAc) 3 (10 mol %), Y(OAc) 3 (15 mol %), and Ce(OAc) 3 (15 mol %), the de of the amine product is the same. Furthermore, if preformed (R)- or (S)-α-MBA ketimines are reductively aminated the same de is observed as when the above noted Lewis or Brønsted acids catalysts are used for reductive amination of the corresponding ketone. In stark contrast to these stereoselectivity trends, 2-alkanones without branching at the α- or β-carbons, e.g. 2-octanone or benzylacetone, can be reductively aminated with dramatically increased diastereoselectivity when using as little as 50 mol % Yb(OAc) 3 , again alcohol by-product formation is suppressed below 2% and good yields are always realized. These combined findings are summarized in table 7.3. Table 7.3. Useful Substrate Classes, Optimal Acid Catalysts, and Trends for α- MBA Reductive Amination a 137
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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
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Later he utilized this methodology
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OMe OMe O HN HN HN O 2 N 71 % yield
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compared to the oil refinery indust
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[14] V. I. Tararov, R. Kadyrov, T.H
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[55] a) R. Kadyrov, T. H. Riermeier
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Chapter 4 Drugs and Reductive Amina
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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 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: anti-6) would be expected to have m
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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