α-Fluorination of Nitrobenzenes and Nitropyridines via Vicarious Nucleophilic Substitution of Hydrogen

Abstract

A highly selective C–H functionalization of nitrobenzenes and nitropyridines is reported using tandem vicarious nucleophilic substitution (VNS) chemistry with electrophilic fluorination using Selectfluor^®. The process generates tertiary benzylic fluorides in good yield under simple, mild conditions and short reaction times.

Key words

fluorination - vicarious nucleophilic substitution - C–H functionalization

• References and Notes

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• 7 Tandem VNS Fluorination – General Procedure for Nitrobenzenes In a dry 5 mL microwave vial containing a stirrer bar, the nitrobenzene (1 equiv) and VNS nucleophile (1.1 equiv) were added and the vial sealed. The vial was then evacuated and filled with nitrogen three times before adding dry DMF. The vial was then cooled to –42 °C. In another 5 mL microwave vial t-BuOK (5 equiv) was added before sealing the vial and adding dry DMF. The t-BuOK solution added by syringe into the main vial and the reaction was left to stir for 1 min before a solution of Selectfluor^® (2 equiv) was added. The reaction was then left to stir for a further 60 min. The solution was diluted with ethyl acetate and washed with 1 M HCl (1 × 5 mL) and brine (2 × 50 mL). The organic extract was then dried over Na₂SO₄, filtered, the solvent removed in vacuo, and the crude product purified by column chromatography. Ethyl 2-Fluoro-2-(4-nitrophenyl)propanoate (8a) Colorless oil. (260 mg, 86%). ¹H NMR (500 MHz, CDCl₃): δ = 8.16 (d, J = 8.9 Hz, 2 H), 7.66 (d, J = 9.0 Hz, 2 H), 4.18 (m, 2 H), 2.08 (s, 3 H), 1.18 (t, J = 7.1 Hz, 3 H). ¹³C NMR (126 MHz, CDCl₃): δ = 169.6, 148.0, 145.9, 125.7, 123.7, 94.2 (d, J = 189.6 Hz), 62.6, 25.2, 14.0. ¹⁹F NMR (471 MHz, CDCl₃): δ = –153.66 (q, J = 22.8 Hz). HRMS (ESI): m/z [M + H⁺] calcd for C₁₁H₁₄NO₄F: 242.0823; found: 242.0819.