Bis-heterobiaryls are structures containing two heterocycles linked directly together and this motif is commonly found in pharmaceuticals with examples including Etoricoxib and Imatinib. Coupling of two different electron deficient heterocycles to make drug-like bis-heterobiaryls is challenging using metal catalysis due to functional group incompatibilities with the catalyst and a prerequisite for pre-functionalized starting material. A different approach is to use phosphorus ligand-coupling. By successive selective C-H functionalization on two different pyridines or diazines a bis-heterobiaryl phosphonium salt is formed. Heating the phosphonium salt in an acidic ethanol solution induces selective coupling of the two heterocycles. This reaction begins with attack of the alcohol on the phosphonium salt resulting in a phosphorane. From the P(V) intermediate, a stepwise ligand-coupling process occurs by migration of one heterocycle on to the other heterocycle forming a C-C bond. This strategy of selective C-P bond formation to make a bis-heterobiaryl phosphonium salt followed by ligand-coupling can be applied to a range of complex pyridines and diazines to make bis-heterobiaryls.

Bis-heterobiaryl synthesis through phosphorus ligand-coupling

2019 Spring National Meeting

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