Suzuki-Miyaura Cross-Coupling of Unprotected, Nitrogen-Rich Heterocycles: Substrate Scope and Mechanistic Investigation

Reaction Scheme


A mild, efficient, and low-temperature palladium-catalyzed cyanation of (hetero)aryl halides and triflates is reported. Previous palladium-catalyzed cyanations of (hetero)aryl halides have required higher temperatures to achieve good catalytic activity. This current reaction allows the cyanation of a general scope of (hetero)aryl halides and triflates at 2?5 mol % catalyst loadings with temperatures ranging from rt to 40 �C. This mild method was applied to the synthesis of lersivirine, a reverse transcriptase inhibitor.



A medium reaction tube equipped with a magnetic stirbar was charged with precatalyst, (hetero)aryl bromide [1 mmol (if solid)], and Zn(CN)2 (0.66 mmol). The tube was capped with a septum cap and then evacuated and refilled with nitrogen (this process was repeated a total of three times). (Hetero)aryl halide (if liquid) (1 mmol), THF (0.5 mL), and degassed DI H2O (2.5 mL) were added to the reaction tube via a syringe. The reaction mixture was stirred rapidly (such that the two phases appeared homogenous and the vortex was clearly visible) at rt or 40 �C (see attached video). Upon consumption of the (hetero)aryl halide (monitored by TLC) the reaction mixture was treated with saturated aqueous NaHCO3 (2 mL) and EtOAc (3 mL). The biphasic mixture was stirred for 5 min. The organic layer (upper layer) was removed by pipette. The aqueous layer was further extracted three times with EtOAc (3 mL x 3). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The aqueous layer was treated with 20% aqueous bleach (1 mL) and then disposed of in aqueous cyanide waste.[3] The product was purified by flash chromatography with EtOAc/hexanes to afford the corresponding (Hetero)aryl nitrile. Notes: 1) To ensure full conversion and a successful reaction rapid stirring is necessary. The stirring speed needs to be rapid enough that the two phases appear homogenous and the vortex of the reaction is clearly visible. Although stirring needs to be fast, care should be taken that the reaction mixture doesn�t bump up to the cap (see attached video). 2) The H2O:THF (5:1) ratio is required to achieve full conversion. Deviation from this ratio may result in incomplete conversion. 3) ZINC CYANIDE IS TOXIC AND SHOULD BE HANDLED WITH EXTRA CARE! 4) Reactions run on a 0.2 mmol scale were carried out in a smaller tube with a smaller septum cap. 5) All waste from crude reaction mixtures and aqueous workups should be disposed of using accepted protocols.[3]



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