A New Palladium Precatalyst Allows for the Fast Suzuki-Miyaura Coupling Reactions of Unstable Polyfluorophenyl and 2-Heteroaryl Boronic Acids

Reaction Scheme

Abstract

A method for the Pd-catalyzed coupling of 2-aminothiazole derivatives with aryl bromides and triflates is described. Significantly, for this class of nucleophiles, the coupling exhibits a broad substrate scope and proceeds with a reasonable catalyst loading. Furthermore, an interesting effect of acetic acid as an additive is uncovered that facilitates catalyst activation.

Substrates

Procedure

An oven-dried test tube equipped with a magnetic stir bar and fitted with a Teflon screw cap was charged with Pd(OAc)2 (3.6 mg, 1.5 mol%) and tBuBrettPhos (16.7 mg, 3.3 mol %). The vessel was evacuated and backfilled with argon (this sequence was carried out a total of three times). To this vessel was added tBuOH (2.0 mL) and degassed H2O (1.1 �l, 6 mol %) via syringe, and the solution was placed in an oil bath at 110 �C for 1.5 min. A second oven-dried test tube equipped with a magnetic stir bar was charged with the amine (1 mmol), K2CO3 (192 mg, 1.4 mmol), and the aryl bromide or triflate if solid (1 mmol). The tube was then sealed, evacuated, and backfilled with argon (this sequence was carried out a total of three times). To this tube was added tBuOH (2.0 mL), along with the aryl bromide or triflate if liquid (1 mmol). The hot catalyst solution was then cannulated into the second tube containing the substrates (cannulation was finished within 1 min after heating of the catalyst solution was complete), and the second tube was then placed into an oil bath at 110 �C for 3 h unless otherwise noted. The reaction mixture was then cooled to room temperature, diluted with ethyl acetate, and washed once each with water and brine, dried over Mg2SO4, filtered, and concentrated in vacuo. The crude product was then purified by silica gel chromatography or by Biotage SP4 technique as noted.

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