UC Santa Barbara

Suzuki–Miyaura (SM) cross-couplings of 2-pyridyl MIDA boronates can be successfully carried out in the complete absence of copper by attenuation of the Lewis basicity associated with the pyridyl nitrogen using selected substituents (e.g., fluorine or chlorine) on the ring. This strategy imparts additional synthetic options compared with existing approaches based on the use of Lewis acids or N-oxides. Thus, access to highly valued 2-substituted pyridyl rings via an initial Suzuki–Miyaura coupling can be followed by dehalogenation, SNAr reactions, or a second SM coupling to arrive at 2,6-disubstituted pyridyl arrays, all run in a single pot, enabled by micellar catalysis in water. Accessing targets within drug-like space is demonstrated in a four-step, one-pot sequence. Computational data suggest that the major role being played by electron-withdrawing substituents in promoting these cross-couplings without the need for copper is to slow the rates of protodeboronation of intermediate 2-pyridylboronic acids.