Improved Methodology for the Preparation of Chiral Amines

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This is a straight forward, environmentally friendly with easy procedures, but incompatible with the coexisting functional groups such as nitro, cyano and C-C multiple bonds. [19] The second strategy is based on the transfer hydrogenation conditions utilizing formic acid or one of its derivative (Leuckart-Wallach type). [20] The third strategy uses hydride reductants e.g. NaBH 3 CN, [21] LiBH 3 CN, [22] [23] [24] [25] NaBH 3 CN-ZnCl 2, NaBH 3 CNMg(ClO 4 ) 2, NaBH 4 -NiCl 2, [26] NaBH 4 -ZnCl 2, borohydride exchange resin, [27] [28] [29] ZnBH 4, ZnBH 4 -ZnCl 2, pyridineborane, [30] picoline-borane, [31] etc. Recently organocatalysts were used in reductive amination utilizing Hantzsch esters or silanes as hydride sources with organocatalysts as chiral phosphoric acid and its derivatives. [32] Reviewing the literature of the last 50 years it is obvious that among the different reductive amination strategies discussed above, hydride reduction with NaBH 3 CN which was introduced by Borch [33] has been used extensively. This may be due to the ease of use of these hydride sources. Borohydride salts are furthermore cheap, available in kg quantities and do not require special precautions in handling. Despite these advantages borohydride salts suffer from other drawbacks. This reductant is used in excess quantity, toxic and produces toxic byproducts such as HCN and NaCN upon workup which limits its applications according to the new environmental standards. Abdel-Magid aimed to avoid this toxicity by using NaBH(OAc) 3 , (introduced by Gribble) as a mild reductant. [34,35] The mild nature of this reductant is due to the steric and electronic effects of the acetoxy groups which stabilize the B-H bond. His system was applicable for different types of aldehydes and unhindered aliphatic ketones. In spite of the significant applications of the above reductants they are not free from limitations regarding functional group tolerance and side reactions. [36] Also the formation of tertiary or secondary amine from primary amine (the desired product) due to over alkylation represents another limitation. [37] Bhattacharyya and coworkers developed a highly efficient mild system for reductive amination utilizing Ti(O i Pr) 4 , and NaBH 4 as the hydride donor and an amine source e.g. ammonia, ammonium chloride or methylamine. He was able to obtain high yields for different aldehydes, cyclic ketones and ketone with acid labile groups (scheme 3.7). [38] 58
O NHR 3 R 4 R 4 R 3 N OTi(O i Pr) 3 NaBH 3 CN R 4 R 3 N R 1 R 2 Ti(O i Pr) 4 R 1 R R 1 2 Scheme 3.7. Reductive Amination in the Presence of Ti(O i Pr) 4 . H R 2 Ti(O i Pr) 4 is considered as a mild and effective Lewis acid for suppressing alcohol formation in the reductive amination of ketones and aldehydes. It is compatible with most of acidsensitive functional groups (e.g. acetonides, silyl ethers, esters, amides etc.). [39] In order to understand the role of titaiunm isopropoxide in reductive amination, Matson mixed equimolar ratios of amine and ketone with excess amount of Ti(O i Pr) 4 . He tried to isolate and detect the intermediates. Neither imine nor enamine could be detected (by IR measurements) or isolated. Therefore, he predicted the formation of hemiaminal titanate intermediate (Scheme 3.8) which is an unstable complex and is reduced with NaBH 3 CN to form the amine product. Earlier findings by other scientists supported this proposal. Reetz has also predicted a similar titanium intermediate in his reaction between ketone and titanium amides with diisobutyl aluminium hydride (DIBAL-H) as a reductant. [40] Also reductive amination was tested under solvent free conditions. The aldehyde or the ketone is mixed with the amine and the mixture is mixed in a mortar with NaBH 4 or α- picoline borane until TLC showed disappearance of starting material (scheme 3.8). [41] X O H + PhNH 2 NaBH 4 .H 3 BO 3 (1:1) grinding a: x = COMe d: x = CO 2 Me b: x = CN e: x = NHCOMe c: x =CO 2 H f: x =NO 2 X NHPh H Scheme 3.8. Solvent Free Reductive Amination. Baba developed the use of dibutylchlorotin hydride-HMPA complex as a mild hydride source for the reductive amination of various ketones and aldehydes. Various aromatic aldehydes with para or ortho electron withdrawing and electron donating groups were tested producing 59
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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
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 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: superior in terms of conversion (89
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
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
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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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Improved Methodology for the Preparation of Chiral Amines

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