Negishi cross-couplings compatible with unprotected amide functions

The reaction conditions that allow a general Pd-catalyzed Negishi cross-coupling of a functionalized alkyl, aryl, heteroaryl, and benzylic zinc reagents with aryl acidic hydrogens were investigated. A dry and argon flushed 10 mL Schlenk-tube was charged with N-benzyl-4-bromobenzamide, Pd(OAc) ₂, S-PHOS, and THF. 3-pentanoyl-benzylzinc chloride was added slowly over 90 minutes with a syringe pump. The reaction mixture was stirred for 1 hour at 25 °C. The reaction mixture was quenched with a saturated NH ₄Cl solution and extracted with diethyl ether. The combined phases were then washed with a aqueous thiourea solution and dried over Na ₂SO₄. It was observed that the mild conditions considerably increase the ability of the Negishi cross-coupling in the synthesis of complex molecules and natural products.