Increasing saturation: development of broadly applicable photocatalytic C sp2 –C sp3 cross-couplings of alkyl trifluoroborates and (hetero)aryl bromides for array synthesis

Visible light photocatalysis has emerged as an enabling technology capable of providing access to architecturally complex molecules. This article describes a systematic investigation of the nickel-mediated photocatalytic cross-coupling of alkyl trifluoroborates and (hetero)aryl bromides aided by high-throughput experimentation (HTE). The results obtained from HTE were utilized to select catalysts, bases and solvents for the production of chemical libraries. Six fourteen-member libraries were generated through couplings with secondary alkyl, primary α-alkoxymethyl, benzyl and secondary α-amino trifluoroborates, demonstrating that the optimized conditions were general, robust and exhibited broad functional group tolerance. The conditions were also successfully adapted for use in a flow reactor, showing the impact micro-scale screening can have in the development of scale-up procedures. These studies enabled the generation of a data-rich reaction guide that provides favorable conditions, as well as alternative conditions that can be used to address issues with substrate solubility or catalyst availability.