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Highly Selective Palladium-Catalyzed Cross-Coupling of Secondary Alkylzinc Reagents with Heteroaryl Halides

Abstract

The highly selective palladium-catalyzed Negishi coupling of secondary alkylzinc reagents with heteroaryl halides is described. The development of atseries of biarylphosphine ligands has led to the identification of an improved catalyst for the coupling of electron-deficient heterocyclic substrates. Preparation and characterization of oxidative addition complex (L)(Ar)PdBr provided insight into the unique reactivity of catalysts based on CPhos-type ligands in facilitating challenging reductive elimination processes. 

Sample Procedure

An oven-dried screw-cap test tube, which was equipped with a magnetic stir bar and fitted with a teflon septum, was charged with CPhos-Pd-G3 (8.1 mg, 0.01 mmol), CPhos (4.4 mg, 0.01 mmol). If the heteroaryl halide was a solid, it is also added at this time. The test tube was evacuated and backfilled with argon (this process was repeated a total of 3 times). If the heteroaryl halide was a liquid, it was added at this time along with toluene (1 mL) via syringe. The reaction mixture was cooled to 0 °C in an ice bath and then a THF solution of the secondary alkylzinc halide (1.30 mmol) was added dropwise via syringe. The ice bath was removed after the addition and the reaction mixture was stirred at room temperature for 2 h, and then quenched by water (5 mL) and extracted with ethyl acetate (3x10 mL). The combined organic phases were dried over MgSO4, concentrated in vacuo, and purified by Biotage Isolera to afford the desired product. The n/r ratio of coupled product was determined by GC or 1H NMR analysis of the crude reaction mixture.

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