Improved Methodology for the Preparation of Chiral Amines

More documents

Recommendations

Info

hexafluoroacetylacetone which provided 5-15 area % of the alcohol by-product and/or observably longer reaction times than Yb(OAc) 3 (10 mol %), Y(OAc) 3 (15 mol %), or Ce(OAc) 3 (15 mol %). Thionylchloride which was tested industrially for promoting ketimine formation at 5 mol % concentration was also tested in our study. [2] Contradicting to their findings, the replacement of the Lewis acid by thionylchloride, led to the amine product in 50% de, which is even lower than the normally achieved 72% de for 2-octanone. Phosphorous oxychloride which has not been previously reported for reductive amination was also tested. Its use at a concentration 10 mol % was beneficial in obtaining 72% de for 2-octanone but the alcohol by-product was observed in ~4 area % (GC). The above listed Lewis acids were available commercially in their semi-hydrated forms, and used without further purification for the catalytic screening studies. According to the findings from the stoichiometric use Yb(OAc) 3 , drying Yb(OAc) 3 was extremely important for consistent results. In the initial catalytic screening studies, metalloids Bi(OAc) 3 and Sb(OAc) 3 were included with Yb(OAc) 3 , Y(OAc) 3 , and Ce(OAc) 3 as useful in inhibiting alcohol formation. During the optimization stage of the catalytic study I recognized that the purchased Bi(OAc) 3 and Sb(OAc) 3 smelled strongly of AcOH. This raised the question of what was catalyzing the reductive amination, the Lewis acid or co-existing acetic acid. The Lewis acids [Yb(OAc) 3 , Y(OAc) 3 , Ce(OAc) 3 , Bi(OAc) 3 , and Sb(OAc) 3 ] were then dried until each maintained a constant weight. Reexamination of these dried salts showed Bi(OAc) 3 and Sb(OAc) 3 were no longer efficient catalysts for reductive amination, high alcohol by-product formation (>15 area %, GC) was noted. In stark contrast, Yb(OAc) 3 , Y(OAc) 3 , and Ce(OAc) 3 , were as effective as before, although their solubility in the binary reaction solvent system, THF-MeOH, was visibly reduced. The effect of adding H 2 O (1.0 equiv) to the reactions with dried Yb(OAc) 3 , Y(OAc) 3 , or Ce(OAc) 3 , resulted in increased alcohol byproduct formation. While this intentional addition of water was clearly not beneficial, the indicated dried Lewis acids were routinely weighed without precaution for atmospheric moisture and had no ill effect on the reaction profile and reaction time, but dry solvents are always used for the reactions. 120
The reactions described above all used 100 wt % Raney-Ni, based on the limiting ketone reagent, and this quantity is not untypical for the use of this heterogeneous hydrogenation catalyst regarding reductive amination and imine reduction. [3] I tried to study the effect of reducing heterogeneous catalyst loading on the rate of the reaction and the de. I found that using 50 wt % of Raney-Ni in combination with dried Yb(OAc) 3 did not allow complete consumption of the ketone (8 area % remained unreacted) within the standard room temperature and 12 h reaction time. It is known that increasing the temperature increases reaction rate, so I increased the temperature (40 o C) and pressure (20 bar) simultaneously (table 6.2, compare entries 2 and 3), the reaction could be completed before 12 h without compromising the diastereoselectivity of the secondary amine. When 25 wt % of Raney-Ni was used 50% of unreacted ketone was detected after 12 h. Table 6.2. Raney-Ni loading: Reductive Amination of 2-Octanone for 12 h a Entry Raney-Ni (wt %) Ketone (area %) [b] de [b] 1 100 0 72 2 50 8 72 3 [c] 50 0 71 4 25 47 71 a Reaction conditions: 2-octanone (2.5 mmol), Yb(OAc) 3 (15 mol %), (S)-α-methylbenzylamine (1.1 equiv), Raney-Ni, H 2 (8.3 bar), 0.5 M, 12 h, 22 o C. b GC analysis. c H 2 (20 bar), T= 40 o C. After finalizing the different useful Lewis acids categories, I tested the use of 10 mol % of Yb(OAc) 3 for reductive amination of different ketone substrates. The following table summarizes the results obtained from our study. Table 6.3. 10 mol % Yb(OAc) 3 Catalyzed Reductive Amination: Substrate Breadth. a entry ketone 1 secondary amine 2 yield % b de % c 121
Page 1 and 2:
Improved Methodology for the Prepar
Page 3 and 4:
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 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 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
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: 4 60 86 5 50 86 6 40 84 7 20 79 8 2
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
show all

Improved Methodology for the Preparation of Chiral Amines

Create successful ePaper yourself

Delete template?

Save as template?