SusChemE 2015
International Conference on Sustainable Chemistry & Engineering
October 8-9, 2015, Hotel Lalit, Mumbai
pH Dependent Asymmetric Transfer Hydrogenation of Imines in Water
Vaishali S. Shende, Sudhindra H. Deshpande, Savita K. Shingote, Ashutosh A. Kelkar
Chemical Engineering and Process Development Division, CSIR-National Chemical Laboratory, Pune -411008
vs.shende@ncl.res.in, aa.kelkar@ncl.res.in
1. Introduction:
Enantiomerically enriched active amines are significant synthetic precursors for biologically active molecules,
flavor, and fragrance industries [1]. The choice of reaction medium and H donor is important in achieving an ATH reaction
with high efficiency. The metal catalyzed ATH of imines is mostly performed in an azeotropic mixture of formic acid
(HCOOH) and triethylamine (NEt3) (F−T), with the F/T molar ratio being 5:2 or with HCOONa as H donor and water as the
solvent [2, 3]. Herein we wish to report our results on the pH dependent ATH of imines in water with F/T as the H donor.
2. Material and Methods:
Experimental procedure: Round bottom flask containing a magnetic stirring bar, and [Ru (p-cymene) Cl2]2 (1.5 mg, 0.0025
mmol) and (1S, 2S)-lig A (2.75 mg, 0.007 5mmol) in distilled H2O (0.5 mL) was stirred for 1h at 40°C to generate the precatalyst. To the above pre-catalyst solution imine (0.5 mmol), MeOH (0.5 mL), 1.2 F/T mixture 1 mL was added. The
reaction mixture was stirred at 40°C for the time indicated, then cooled to room temperature and basified with 0.5M Na 2CO3
and extracted with DCM (3ml x 2). Organic phase was dried over Na 2SO4 and solvent was removed under reduced pressure.
Conversion was determined on GC, while enantioselectivity was determined on HPLC with Chiralcel OD-H column.
3. Significant Results and Discussion
Asymmetric transfer hydrogenation (ATH) of imines was found to be strongly pH dependent with water as solvent.
Reaction was investigated at different F/T ratio (0.5 to 5.0) with H2O-MeOH (v/v, 1:1, 1 mL) as solvent (Scheme 1). Figure
1a shows the graph of turnover frequency (TOF) and ee versus initial pH of the F/T−H2O mixture respectively. At high F/T
ratio (F/T ratio 5.0−2.0, pH range 2.4−3.8), the reaction medium was strongly acidic and only 16% conversion was achieved
in 24 h.
Scheme 1. ATH of imine 1a with Ru-Lig A with F/T in H2O-MeOH
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SusChemE 2015
International Conference on Sustainable Chemistry & Engineering
October 8-9, 2015, Hotel Lalit, Mumbai
b) Initial pH vs ee
a) Initial pH vs TOF/h
100
70
60
90
ee(%)
TOF (h-1)
50
40
30
80
70
20
60
10
0
50
0
2
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pH
2
4
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pH
Figure 1. (a)TOF against initial pH; (b) ee against initial pH of F/T solution
Activity increased significantly with the increase in initial pH of the F/T solution in the range 4.8−5.6, and the
highest TOF value of 66 h−1 was observed at pH 5.4. The results indicate that at acidic pH (2.4−4.1) ee values were very low
(3−56%). As the pH increased, the ee values increased up to 93%. Use of methanol as a co-solvent enhanced reduction
activity. A variety of imine substrates have been reduced, affording high yields (78−98%) and excellent enantioselectivities
(89−91%).
4. Conclusion
The initial pH of F/T mixture affects the reduction rate and enantioselectivity, with the optimum ratio being 1.2. In
comparison with the common azeotropic 2.5/1 F/T system, the reduction with 1.2/1 F/T is faster.
References
(1) Kobayashi, S.; Ishitani, H. Chem. Rev. 1999, 99, 1069−1094.
(2) Uematsu, N.; Fujii, A.;Hashiguchi, S.; Ikariya, T.; Noyori, R. J. Am. Chem. Soc. 1996, 118, 4916−4917
(3) Hashiguchi, S.; Fujii, A.; Takehara, J.; Ikariya, T.; Noyori, R. J. Am. Chem. Soc. 1995, 117, 7562−7563.
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