A Copper Halide Promoted Regioselective Halogenation of Coumarins Using N-Halosuccinimide as Halide Source

Abstract

A safe, convenient, and regioselective synthesis of 3-halo coumarins using a metal halide (CuX₂ alone or with ZnX₂) promoted halogenation with N-halosuccinimide (NXS) as halide source is reported. The synthesis involved the steady in situ generation of highly reactive positive halogen (X⁺) by the coordination of copper or zinc with the N-halosuccinimide and subsequent electrophilic aromatic substitution of the electron-deficient coumarins. This procedure works well also for the halogenation of less electron-rich naphthoquinones, flavones, and methoxypsoralen in moderate to quantitative yields. This protocol features simple experimental conditions using readily available inexpensive reagents and provides a convenient approach to the chlorination or bromination of some useful heteroaromatic compounds.

Key words

coumarin - halogenation - aryl halide - electrophilic aromatic substitution - N-halosuccinimide

• References and Notes

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• 26 3,7-Dichloro-2H-chromen-2-one (2b) – Typical Procedure To a 50 mL round-bottom flask, 7-chloro coumarin (180.6 mg, 1 mmol), NCS (935.2 mg, 7 mmol), CuCl₂·2H₂O (2387 mg, 14 mmol), and 20 mL anhydrous MeCN were added and refluxed until the reaction completed. The cooled mixture was concentrated in vacuum, dispensed in 25 mL 5% NaHSO₃ aqueous solution and extracted with 25 mL EtOAc for three times. The organic layer was combined, washed with 10 mL water and dried over anhydrous Na₂SO₄. After the solvent was removed, the crude product was purified by silica gel column chromatography to afford 96.2 mg 2b (44.9%). 3,7-Dichloro-2H-chromen-2-one (2b) White solid, mp 123–124 ℃ (acetone/PE, 2:1, V/V). ¹H NMR (600 MHz, CDCl₃): δ = 7.84 (s, 1 H), 7.40 (d, J = 8.3 Hz, 1 H), 7.38 (d, J = 1.9 Hz, 1 H), 7.30 (dd, J = 8.3, 1.9 Hz, 1 H). ¹³C NMR (151 MHz, CDCl₃): δ = 156.6, 152.9, 139.3, 137.9, 128.0, 125.7, 122.5, 117.4, 117.2, 100.0. IR (KBr): ν_max = 3103, 3061, 3040, 1736, 1720, 1702, 1604, 1484, 1403, 1348, 1318, 1245, 1206, 1144, 1123, 1077, 998, 969, 939, 916, 865, 825, 752, 681, 617, 595, 462 cm^–1. HRMS (ESI): m/z calcd for C₉H₅Cl₂O₂ [M + H] (³⁵Cl): 214.9661; found: 214.9661.