An Alkyne Linchpin Strategy for Drug:Pharmacophore Conjugation: Experimental and Computational Realization of a meta-selective Inverse Sonogashira Coupling

The late-stage functionalization (LSF) of pharmaceutical and agrochemical compounds by the site-selective activation of C–H bonds offers immediate access to diverse structural analogs and expands the accessible chemical space. We report a C–H functionalization LSF strategy that hinges on the use of an alkyne linchpin to assemble conjugates of sp2-rich marketed pharmaceuticals and agrochemicals with sp3-rich 3D-fragments and natural products. This is accomplished through a template-assisted inverse Sonogashira reaction that displays high levels of selectivity for the meta-position. This protocol is also amenable to distal structural modifications of α-amino acids. The transformation of alkyne functionality to other functional groups further highlights the applicative potential. Computational and experimental mechanistic studies shed light on the detailed mechanism. Turnover-limiting 1,2-migratory insertion of the bromoalkyne coupling partner occurs after relatively fast C–H activation. While this insertion...