Enantioselective Cyanoformylation of Aldehydes Catalyzed by a Chiral Quaternary Ammonium Salt and Triethylamine

Abstract

An efficient enantioselective cyanoformylation of aldehydes with ethyl cyanoformate, catalyzed by a chiral quaternary ammonium salt and triethylamine, has been developed. The reaction can be carried out in excellent yields (up to 97%) with moderate enantioselectivity (up to 72% ee).

Key words

cyanation - aldehyde - ethyl cyanoformate - quaternary ammonium salt - organocatalysis

References and Notes

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• 14 Typical Procedure: To a mixture of benzaldehyde (0.1 mmol), quaternary ammonium salt 2h (0.01 mmol, 10 mol%) and Et₃N (0.01 mmol) in CH₂Cl₂ (2 mL) under a N₂ atmosphere, was added ethyl cyanoformate (0.15 mmol, 1.5 equiv) at -78 °C. The reaction was monitored by TLC, and after the reaction time indicated in Table 3, the residue was directly purified by silica gel column chromatography (PE-Et₂O, 10:1) to afford the title compound as a colorless oil in 96% yield with 67% ee as determined by HPLC analysis with a Chiralcel OD-H column [λ = 254 nm, hexane-2-propanol = 99:1, 1.0 mL/min, t _R(major) = 9.2 min, t _R(minor) = 10.9 min]; [α]_D ²⁵ = 6.49 (c = 0.154, CHCl₃). ¹H NMR (300 MHz, CDCl₃): δ = 7.53-7.56 (m, 2 H, ArH), 7.45-7.49 (m, 3 H, ArH), 6.27 (s, 1 H, OCHCN), 4.26-4.32 (m, 2 H, OCH₂), 1.34 (t, J = 7.1 Hz, 3 H, OCH₂CH ₃)
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12

Procedure for Preparation of 2h: To a solution of 2g (0.100 g, 0.158 mmol) in CH₂Cl₂ (10 mL) at r.t. was added MeCOOAg (0.0277 g, 0.166 mmol, 1.05 equiv), and the mixture was stirred in the dark at r.t. for one week. The residue was centrifuged for half an hour. Then the precipitate was filtered off and the filtrate was concentrated under reduced pressure to afford a yellow solid; mp 142-143 °C; [α]_D ²⁵ 121 (c = 0.108, CHCl₃). IR (KBr): 3411, 2931, 2361, 1622, 1509, 1374, 1280, 1178, 1136, 905, 683 cm^-1. ¹H NMR (300 MHz, CDCl₃): δ = 8.57 (d, J = 4.5 Hz, 1 H), 8.02 (s, 1 H), 7.66-7.81 (m, 4 H), 7.24-7.25 (m, 1 H), 6.94-6.98 (dd, J = 2.3, 9.2 Hz, 1 H), 6.49 (d, J = 12.5 Hz, 1 H), 6.37 (s, 1 H), 5.82-5.94 (sept, 1 H), 5.41 (d, J = 13.1 Hz, 1 H), 5.17-5.25 (m, 1 H), 4.70 (t, J = 10.5 Hz, 1 H), 4.52 (t, J = 10.1 Hz, 1 H), 4.15 (t, J = 8.9 Hz, 1 H), 3.72 (s, 3 H), 3.05 (t, J = 11.3 Hz, 1 H), 2.51-2.61 (q, 1 H), 2.30-2.39 (q, 1 H), 2.14 (t, J = 12.1 Hz, 1 H), 2.03 (s, 3 H), 1.70-1.87 (m, 3 H), 0.70-0.76 (m, 1 H). ¹³C NMR (100 MHz, DMSO-d ₆): δ = 175.1, 157.9, 147.9, 145.1, 144.2, 137.9, 135.1, 132.2, 131.9, 131.8, 131.4, 131.1, 130.8, 126.1, 125.0, 124.3, 122.3, 121.3, 121.0, 117.4, 102.9, 68.9, 64.2, 61.2, 56.1, 54.0, 37.6, 27.1, 24.9, 23.8, 21.2. HRMS (ESI): m/z [M⁺ - MeCOO] calcd for C₂₉H₂₉F₆N₂O₂: 551.2128; found: 551.2020.

15

Only 50% ee was obtained for the corresponding product of cyclohexanal and isopropanal.