Improved Methodology for the Preparation of Chiral Amines

More documents

Recommendations

Info

a 2-Octanone (2.5 mmol), Brønsted acid (20 mol %), (S)-α-methylbenzylamine (2.75 mmol), Raney Ni, 0.50 M (MeOH), 12 h, T= 22 o C, H 2 pressure = 8.3 bar. b Determined by GC analysis at 12 h. As mentioned previously, the main byproduct of reductive amination is alcohol. The use of optimum Brønsted or Lewis acids inhibit byproduct formation. Brønsted acids were used historically on industrial scale for reductive amination. Despite their importance there is a great lack of detailed study for useful Brønsted acids in primary literatures. I decided to test the effect of using different Brønsted and mineral acids under different loadings in reductive amination of 2-ocatnone. Acetic acid, trichloroacetic acid, or formic acid at 20 mol % successfully catalyzed reductive amination of 2-octanone with α-MBA. Reducing the loading of AcOH (5 mol %) had detrimental effect of allowing significant alcohol by-product formation (> 5 area %, GC). When the loading of acetic acid, trichloroacetic acid, or formic acid was increased to stoichiometric quantities no improvement of de was noticed compared to the use of stoichiometric quantities of Yb(OAC) 3 (de 87%). Strong mineral and organic acids were also tested showing different reaction profile compared to other Brønsted and Lewis acids. The use of stoichiometric or catalytic (5 or 10 mol %) quantities of 12 N HCl or 18 M H 2 SO 4 , which were diluted in MeOH, p-TsOH, or trifluoroacetic acid, resulted in high alcohol by-product formation (15-30 area %, GC). Despite the lower yields of secondary amine of 2-octanone, the de was always consistent (70- 72%) and no reduction was noted. In all cases the use of weak and strong Brønsted acids for reductive amination of 2-octanone shows them be a minimum of 15% lower than when using 110 mol % Yb(OAc) 3 . Solvent screening was also needed for choosing the best solvent for acetic acid promoted reductive amination. Protic solvents as MeOH and EtOH were optimal solvents allowing completing the reaction within 8 h. The use of THF-MeOH (which was optimal for stoichiometric Yb(OAc) 3 study) slowed down the reaction (12 h). When THF was used as a sole solvent with 20 mol % AcOH for reductive amination of 2-octanone the reaction rate was extremely slow showing 30-45% of the starting ketone after 24 h. Despite this slow rate reaction, no alcohol was detected after 24 h only starting ketone. The use of THF as sole 124
solvent in the stoichiometric and catalytic Lewis acid promoted reactions resulted in complete reaction within 24 h under identical reaction conditions. This different reactivity profile for different Brønsted and Lewis acids in protic vs aprotic reaction solvent may allow future substrates with acid labile functional groups or restricted solubility to be reductively aminated. Acetic acid (20 mol %) was used as the Brønsted acid of choice to be tested for the reductive amination. The solvent of choice was dry MeOH and different ketones were reductively aminated as 2-octanone (83% isolated yield, 72% de, T= 22 o C, 120 psi (8.0 bar) H 2 ), i-butyl methyl ketone (80% isolated yield, 92% de, T= 50 o C, 120 psi (8.0 bar) H 2 ), cyclohexyl methyl ketone (82% isolated yield, 98% de, T= 50 o C, 290 psi (20 bar) H 2 ), and acetophenone (55% isolated yield, 93% de, T= 50 o C, 435 psi (30 bar) H 2 ). The reaction rate, isolated yield and de were almost the same as the optimal catalytic Lewis acids [Yb(OAc) 3 (10 mol %), Y(OAc) 3 (15 mol %), and Ce(OAc) 3 (15 mol %)] results, but never showed the enhanced diastereoselectivity possible when using 50-110 mol % Yb(OAc) 3 . The use of 20 mol % of AcOH failed to promote reductive amination of sterically hindered ketone substrates benzosuberone, 1-phenylbutanone, or i-propyl n-propyl ketone, Even under forcing conditions of high temperatures (22-50 o C) and hydrogen pressure [120-580 psi (8-40 bar)]. 1-phenylbutanone provided the desired product only in very low yield (20-25 area %, GC) after >24 h of reaction. These results add to the general conclusion that for such sterically congested substrates the only effective system for their reductive amination is the use of stoichiometric quantities of Ti(O i Pr) 4 . [3] Ti(O i Pr) 4 system has another major advantage as it allows α-branched and β-branched methyl ketones to be reductively aminated at mild condition ( 22 o C and 120 psi within 12 h), on the other hand, the same ketones under acetic acid promoted reductive amination require harsher conditions of elevated temperature (50 o C and 120 psi) for β-branched 2-alkanones or elevated temperature and pressure (50 o C and 290 psi) for α-branched 2-alkanones. Acetic acid provides a mediocre yield for acetophenone (55%) and no improvement even under harsher conditions. 125
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 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: e.g. compare entries 1, 5, 6, and 9
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?