Mild and general palladium-catalyzed synthesis of methyl aryl ethers enabled by the use of a palladacycle precatalyst

Reaction Scheme


A general method for the Pd-catalyzed coupling of methanol with (hetero)aryl halides is described. The reactions proceed under mild conditions with a wide range of aryl and heteroaryl halides to give methyl aryl ethers in high yield.



An oven-dried 20 mL resealable screw-cap test tube?(A) equipped with a Teflon-coated magnetic stir bar was?charged with t BuBrettPhos (L2) (4.8 mg, 0.010 mmol, 1 mol %), sodium tert-butoxide (134.5 mg, 1.4 mmol, 1.4 equiv),?and (hetero)aryl halide (if solid) (1.0 mmol, 1 equiv). Tube A was evacuated and backfilled with argon (this sequence?was repeated a total of three times), and methanol (203??L, 5.0 mmol, 5 equiv) and (hetero)aryl halide (if liquid) (1.0?mmol, 1 equiv) were then added into tube A via syringe. Simultaneously, an oven-dried 10 mL re-sealable screw-cap?test tube (B) equipped with a Teflon-coated magnetic stir bar?was charged with Pd precatalyst 3 (8.5 mg, 0.010 mmol, 1?mol %). Tube B was then evacuated and backfilled with argon?(this sequence was repeated a total of three times), and?1,4-dioxane (2.0 mL) was added into tube B via syringe. The?reaction mixture in tube B was stirred at room temperature?for ~1 min to form a homogeneous solution. The precatalyst?solution from tube B was transferred into tube A via syringe.?The resulting reaction mixture in tube A was stirred at 50?�C for 20 h. After cooling to room temperature, the crude?product was diluted with ethyl acetate and concentrated in?vacuo with the aid of a rotary evaporator. The crude product?residue was purified by flash column chromatography with?silica gel using a solvent mixture (ethyl acetate (EtOAc) /?hexanes) as an eluent to afford the isolated product



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