Boron–Heteroatom Addition Reactions via Borylative Heterocyclization: Oxyboration, Aminoboration, and Thioboration

ConspectusOrganoboron compounds and heterocycles are powerful building blocks and precursors for organic synthesis, including for drug discovery and agrochemical and material synthesis. The common strategy for the synthesis of borylated heterocycles involves two separate synthetic steps: first, synthesis of the heterocyclic core, and second, borylation of the core through established methods such as transition-metal-catalyzed C–H or C–X activation/borylation or lithiation/borylation.In this Account, we describe our laboratory's development of borylative heterocyclization reactions that access the heterocyclic core and install boron in one synthetic step. These methods provide complementary bond disconnections, regiochemistry, and functional-group compatibility to current methods. We describe our methods with two categories: a direct borylation method that refers to addition reactions starting from a preformed B–element σ bond, which is essential in the mechanistic route to product formation, and a formal borylation method that refers to addition reactions that do not require formation of a B–element bond but instead proceed through carbon–carbon π-bond activation by an electrophilic boron source followed by dealkylation or deacylation. Through electrophilic activation of the alkyne rather than activation of the B–element bond, formal borylation provides a complementary strategy toward neutral organoboron reagents. We first studied direct oxyboration toward the formation of borylated benzofurans, where a preformed boron–oxygen σ bond is added across an alkyne activated by a carbophilic gold catalyst. We describe detailed mechanistic and kinetic studies of this class of reactions. Application of the knowledge gained from these studies aided in the future development of additional direct borylation reactions involving boron–nitrogen and boron–oxygen σ bonds to form borylared indoles and isoxazoles, respectively.Formal addition of boron/oxygen equivalents to effect oxyboration to form borylated lactones from o-alkynyl esters is then described. This class of reactions takes advantage of bifunctional ClBcat as a carbophilic carbon–carbon π-bond activator and eventual dealkylating agent. We describe our motivation in developing this new class of catalyst-free borylation reactions and subsequently applying the formal borylation strategy to the thioboration of o-alkynylthioanisole substrates to form borylated benzothiophenes. We then proceed to describe our investigations into the details of the mechanism of the formal thioboration reaction. These collaborative mechanistic studies included experimental and computational findings that elucidated the rate-determining step and intermediates of the reaction. These studies further compared different boron sources as electrophiles, including those used in other known reactions, providing fundamental knowledge about the capabilities of commercially available boron reagents toward borylative heterocyclization. Our findings provide guiding principles for reaction design and information leading toward the design of a diverse set of boron–heteroatom addition reactions and their formal equivalents that proceed through borylative heterocyclization.