Asymmetric Electrophilic Fluorination of α-Cyanoalkylphosphonates ­Catalyzed by Chiral Palladium Complexes

Abstract

The catalytic enantioselective fluorination of α-cyano­alkylphosphonates catalyzed by chiral palladium complexes was examined. Treatment of α-cyanoalkylphosphonates with N-fluoro­benzenesulfonimide as the electrophilic fluorinating reagent under mild reaction conditions afforded the corresponding α-fluorinated α-cyanoalkylphosphonates in excellent yields with high enantiomeric excesses (80-91%).

electrophilic fluorination - asymmetric catalysis - chiral palladium catalysts - α-cyanoalkylphosphonates - α-fluoroalkylphosphonates

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<A NAME="RY01806ST-16">16</A>

Typical procedure: To a stirred solution of 1-phenyl-1-cyanomethylphosphonate (1a, 12.6 mg, 0.05 mmol), Pd catalyst 4g (3.0 mg, 0.0025 mmol) and 2,6-di-tert-butyl-4-methylpyridine (20.5 mg, 0.1 mmol) in EtOH (0.5 mL) at r.t. was added NFSI (2, 18.9 mg, 0.06 mmol). The reaction mixture was stirred for 12 h at r.t. The mixture was diluted with sat. NH₄Cl solution (10 mL) and extracted into EtOAc (3 × 10 mL). The combined organic layers were dried over MgSO₄, filtered, concentrated, and purified by flash column chromatography to afford diethyl 1-fluoro-1-phenyl-1-cyanomethylphosphonate 3a (12.2 mg, 90%): [α]_D ¹⁷ -27.7 (c 0.6, CHCl₃, 85% ee); ¹H NMR (200 MHz, CDCl₃): δ = 1.26-1.38 (m, 6 H), 4.03-4.32 (m, 4 H), 7.42-7.50 (m, 3 H), 7.55-7.67 (m, 2 H); ¹³C NMR (50 MHz, CDCl₃): δ = 16.1, 65.7 (d, J = 7 Hz), 65.8 (d, J = 7 Hz), 87.6 (dd, J = 170, 195 Hz), 114.3 (d, J = 27 Hz), 125.8, 125.9, 128.7, 131.4; MS (EI): m/z = 271 [M⁺], 134, 109, 91, 81, 65, 43; HPLC (hexane-i-PrOH, 9:1, 220 nm, 1.0 mL/min, Chiralcel OJ column): t _R = 11.1 min(minor), t _R = 14.8 (major).