Practical and innate carbon–hydrogen functionalization of heterocycles

It is shown that zinc sulphinate salts can be used to transfer alkyl radicals to heterocycles, allowing for the mild, direct and operationally simple formation of medicinally relevant carbon–carbon bonds while reacting in a complementary fashion to other innate carbon–hydrogen functionalization methods. Nitrogen-rich heterocycles feature widely in pharmaceuticals, and their synthesis has been simplified by a series of advances in transition-metal-mediated cross-coupling reactions. However, the development of practical and selective C–H functionalization methods that do not rely upon pre-functionalized starting materials is an underdeveloped area. Here the authors report that zinc sulphinate salts can be used to transfer alkyl radicals to heterocycles, allowing for a mild, direct and operationally simple formation of medicinally relevant C–C bonds while reacting in an orthogonal fashion to other innate C–H functionalization methods. Nitrogen-rich heterocyclic compounds have had a profound effect on human health because these chemical motifs are found in a large number of drugs used to combat a broad range of diseases and pathophysiological conditions. Advances in transition-metal-mediated cross-coupling have simplified the synthesis of such molecules; however, C–H functionalization of medicinally important heterocycles that does not rely on pre-functionalized starting materials is an underdeveloped area1,2,3,4,5,6,7,8,9. Unfortunately, the innate properties of heterocycles that make them so desirable for biological applications—such as aqueous solubility and their ability to act as ligands—render them challenging substrates for direct chemical functionalization. Here we report that zinc sulphinate salts can be used to transfer alkyl radicals to heterocycles, allowing for the mild (moderate temperature, 50 °C or less), direct and operationally simple formation of medicinally relevant C–C bonds while reacting in a complementary fashion to other innate C–H functionalization methods2,3,4,5,6 (Minisci, borono-Minisci, electrophilic aromatic substitution, transition-metal-mediated C–H insertion and C–H deprotonation). We prepared a toolkit of these reagents and studied their reactivity across a wide range of heterocycles (natural products, drugs and building blocks) without recourse to protecting-group chemistry. The reagents can even be used in tandem fashion in a single pot in the presence of water and air.