Mild and General Conditions for Negishi Cross-Coupling Enabled by the Use of Palladacycle Precatalysts

Reaction Scheme

Abstract

A wide range of biaryls were synthesized by palladium-catalyzed Negishi cross-couplings at ambient temperature or with low catalyst loading. This protocol features the use of a recently reported aminobiphenyl palladacycle precatalyst to generate the catalytically active XPhos-�Pd(0) species. Significantly, a wide range of challenging heterocyclic and polyfluorinated aromatic substrates can be employed to give products in excellent yields.

Substrates

Procedure

An oven-dried test tube was equipped with a magnetic stir bar and fitted with a teflon septum. If the (hetero)aryl bromide or the (hetero)aromatic compound (1.3 mmol) was a solid, it was 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 (hetero)aryl bromide or the (hetero)aromatic compound was a liquid, it was added to the test tube along with THF (2 mL) via syringe. The solution was cooled to -78 �C, and nbutyllithium (2.5 M in hexanes, 0.57 mL, 1.43 mmol) was added dropwise via syringe. The reaction mixture was allowed to stir at -78 �C for 1 h. A solution of ZnCl2 (1.5 M in THF, 1.1 mL, or 1.9 M in 2-MeTHF, 0.82 mL, 1.56 mmol) 3 was added dropwise via syringe at -78 �C. The reaction was warmed to room temperature and allowed to stir for an additional 1 h. If the aryl halide was a solid, it was added by quick removal and replacement of the septum. If the aryl halide was a liquid, it was added via syringe. If the aryl halide was a solid, it was added by quick removal and replacement of septum, after which XPhos-Pd-G3 (3c) and XPhos (L3) (0.25 mol% - 2 mol% 3c, 0.25 mol% - 2 mol% L3) was added. The reaction mixture was left at room temperature and stirred for 12 h, and then quenched with water (5 mL) and extracted with ethyl acetate (3 � 15 mL). The combined organic phases were dried over MgSO4, concentrated in vacuo, and purified via a Biotage SP4 instrument.

Products

Materials

     
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