Asymmetric Reduction of Trifluoromethyl Alkynyl Ketimines by Chiral Phosphoric Acid and Benzothiazoline

Abstract

An enantioselective transfer hydrogenation reaction of alkynyl ketimine bearing a trifluoromethyl group was accomplished. Chemoselective reduction of ketimine was achieved by the combined use of chiral phosphoric acid and benzothiazoline to give α-trifluoromethyl propargylamine in good to high yields and with excellent enantioselectivity.

Key words

alkynyl ketimine - chiral phosphoric acid - benzothiazoline - asymmetric transfer hydrogenation reaction - trifluoromethyl group

• References and Notes


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• 13 General Procedure of Asymmetric Reduction Under a nitrogen atmosphere, a mixture of ketimine 1a (0.10 mmol), benzothiazoline (0.12 mmol, 1.2 equiv), 5 Å MS (50 mg, 100 wt%, activated), and chiral phosphoric acid (0.010 mmol, 10 mol%) in CH₂Cl₂ (1.0 mL) was heated to reflux for 24 h, and the reaction was monitored with TLC. After completion of the reaction, the reaction was stopped by adding saturated aqueous NaHCO₃. The crude mixture was extracted with EtOAc (3×) and the combined organic extracts were washed with brine, dried with Na₂SO₄, and concentrated in vacuo. The residue was purified by preparative TLC to give the trifluoromethyl propargyl amine 4a (80%, 96% ee). (R)-(–)-4-Methoxy-N-(1,1,1-trifluoro-4-phenylbut-3-yn-2yl)aniline (4a, Table 1 Entry 1) Oil; yield 80%. ¹H NMR (400 MHz, CDCl₃): δ = 3.74 (1 H, br s), 3.77 (3 H, s), 4.73–4.78 (1 H, m), 6.78 (2 H, d, J = 9.2 Hz), 6.83 (2 H, d, J = 9.2 Hz), 7.30–7.45 (5 H, m). ¹³C NMR (100 MHz, CDCl₃): δ = 52.1 (q, J = 33.8 Hz), 80.8 (q, J = 2.2 Hz), 86.2, 114.8, 116.9, 121.4, 123.7 (q, J = 280 Hz), 128.3, 128.5, 129.1, 131.9, 138.8, 154.1. ¹⁹F NMR (375 MHz, CDCl₃): δ = 77.0 (3 F, d, J = 6.0 Hz).

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