Catalytic undirected borylation of tertiary C–H bonds in bicyclo[1.1.1]pentanes and bicyclo[2.1.1]hexanes

Catalytic borylations of sp3 C–H bonds occur with high selectivities for primary C–H bonds or secondary C–H bonds that are activated by nearby electron-withdrawing substituents. Catalytic borylation at tertiary C–H bonds has not been observed. Here we describe a broadly applicable method for the synthesis of boron-substituted bicyclo[1.1.1]pentanes and (hetero)bicyclo[2.1.1]hexanes by an iridium-catalysed borylation of the bridgehead tertiary C–H bond. This reaction is highly selective for the formation of bridgehead boronic esters and is compatible with a broad range of functional groups (>35 examples). The method is applicable to the late-stage modification of pharmaceuticals containing this substructure and the synthesis of novel bicyclic building blocks. Kinetic and computational studies suggest that C–H bond cleavage occurs with a modest barrier and that the turnover-limiting step of this reaction is an isomerization that occurs prior to reductive elimination that forms the C–B bond. Borylated bicyclopentanes and bicyclohexanes are valuable compounds in drug research but are difficult to prepare. Now, an iridium-catalysed method has been developed for the borylation of the bridgehead tertiary C–H bonds in bicyclopentanes and bicyclohexanes, providing access to a variety of highly decorated bicyclic cores.