Transfer C–H borylation of alkenes under Rh(I) catalysis: Insight into the synthetic capacity, mechanism, and selectivity control

Transfer C–H borylation of alkenes bears the potential to unlock a range of attractive transformations for modular synthesis and late-stage derivatization of complex molecules. However, its scarce precedence and a limited mechanistic understanding hinders the development of practical synthetic protocols. Here, we report a Rh(I)-catalyzed transfer C–H borylation that is applicable to various terminal and internal alkenes and compatible with a plethora of functional groups, including often problematic motifs. The successful late-stage borylation of bioactive molecules, including derivatives of macrocyclic zearalenol and the drug brompheniramine, underscores its synthetic capacity. A thorough mechanistic investigation involving a series of catalytic and stoichiometric experiments as well as computational studies gave insight into the full catalytic cycle employing a β-boryl elimination, which is unprecedented for Rh-catalysis, and elucidated the features controlling the activity and the selectivity. This work sets the stage for the development of other hydrogen-for-functional group exchange reactions undergoing similar pathways. The method is applicable to a variety of alkenes, including complex bioactive molecules The reaction tolerates various functional groups and transfers different boryl groups Studies revealed the mechanism with an unprecedented β-boryl elimination Analyses provided detailed insight into the selectivity-controlling features The discovery of pharmaceuticals and agrochemicals requires the synthesis of libraries of molecules that exhibit promising activities, typically complex molecules containing many functional groups. The access to organoboron derivatives of lead molecules is appealing because they can be converted to families of derivatives through established divergent post-functionalization reactions. Ideally, such intermediates can be prepared by borylation of a C–H bond in available starting materials, thereby allowing the derivatization of existing libraries of bioactive compounds. However, the C–H borylation of alkenes is underdeveloped and suffers from persistent issues restricting its application in fine-chemical synthesis. Herein, we report a method employing transfer catalysis that provides high efficiency and functional group tolerance. Successful derivatization of a range of pharmaceuticals and natural products underlines its prospective utility in fine-chemical development campaigns. We present a broadly applicable method for the C–H borylation of various alkenes, that is, a valuable transformation in the synthesis of fine chemicals, such as pharmaceuticals and agrochemicals. Importantly, the reaction tolerates a plethora of functional groups and can be used for the late-stage functionalization of complex bioactive molecules, such as derivatives of zearalenol and brompheniramine. The study provides insight into the reaction mechanism and the features controlling the selectivity, thereby setting the stage for the development of other related valuable reactions.