Towards a C4-Selective Minisci-type Addition to Heteroarenes

Construction of basic heteroarenes with varied substitution patterns is of great importance, but direct transformation of heterocyclic C-H bonds is a major challenge, often due to incompatibility with metal catalysts. Minisci-type additions are radical addition processes in which a basic heterocycle is protonated with a concomitant lowering of its LUMO, before attack by 'nucleophilic' radicals. This is a deceptively simple method with no catalyst required. The problem that has held back its widespread use is a lack of regioselectivity on heterocycles such as pyridines and quinolines due to insufficiently different LUMO coefficients of the C2 and C4 positions. We will develop a catalytic approach to Minisci additions that will allow us to control regioselectivity and direct it to the C4 position. We will also investigate the control of absolute stereochemistry when prochiral radicals are added to the C4 position in analogy with work that we have recently published (Science, 2018, 360, 419). We anticipate that successful realisation of this strategy will allow the wealth of radical chemistry to be applied to valuable basic heterocycles with new-found region- and enantio- control.