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Nature Chemistry 2023, 15 (5), 685–693

DOI: 10.1038/s41557-023-01159-4

Yu I.; Manske J.; Diéguez-Vázquez A.; Misale A.; Pashenko A.; Mykhailiuk P.; Ryabukhin S.; Volochnyuk D.; Hartwig J.

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.

 

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