Pharmaceutical-Oriented Methoxylation of Aryl C(sp²)–H Bonds using Copper Catalysts

Abstract

A pharmaceutical-oriented, copper(II)-catalyzed methoxylation of aryl C(sp²)–H bonds has been developed. This simple and environmentally benign reaction system occurs efficiently using oxygen as oxidant with broad substrate scope and high functional group tolerance.

Key words

pharmaceutical development - C–H methoxylation - copper catalysis - oxygen - DMEDA

• References and Notes

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• 12 General Procedure for Cu(II)-Catalyzed Alkoxylation: Cu₂(OH)₂CO₃ (0.04 mmol), KOCN (0.40 mmol), methenamine (0.04 mmol), 4-bromo-N-(2-(dimethylamino)ethyl)benzamide (0.20 mmol), CH₃OH (2 mL) were introduced into a 15 mL sealed tube equipped with a magnetic stirrer in O₂. The mixture was vigorously stirred at 120 °C for 24 h. After cooling to room temperature, the solvent was evaporated under vacuum. The residue was dissolved in mixed solvent of dichloromethane (30 mL) and edetate tetrasodium (EDTA) saturated aqueous solution (30 mL). After separation, the aqueous phase was extracted twice with dichloromethane (15 mL) and the organic layers were combined and evaporated under vacuum. The crude product was purified by column chromatography using silica gel to afford 4-bromo-N-(2-(dimethylamino)ethyl)-2-methoxybenzamide. Isolated yield: 0.0542 g (90%). ¹H NMR (500 MHz, CDCl₃): δ = 8.33 (s, 1 H), 8.01 (d, J = 8.4 Hz, 1 H), 6.97 (dd, J = 8.4, 1.8 Hz, 1 H), 6.89 (d, J = 1.8 Hz, 1 H), 3.92 (s, 3 H), 3.66 (q, J = 5.9 Hz, 2 H), 2.87–2.80 (m, 2 H), 2.50 (s, 6 H). ¹³C NMR (126 MHz, CHCl₃): δ = 164.84, 158.08, 138.54, 133.11, 121.34, 119.82, 112.04, 57.77, 56.29, 44.68, 36.56. HRMS (ESI): m/z [M]⁺ calcd for C₁₂H₁₈ClN₂O₂: 257.1051; found: 257.1062.