Mapping the Undirected Borylation of C(sp ³ )–H Bonds in Strained Rings

Aliphatic small saturated carbocycles and azacycles are increasingly used as bioisosteres and structural cores in medicinally active compounds due to the beneficial pharmacological and physicochemical properties they can impart. Therefore, a need exists to modify these motifs and to install groups that enable their incorporation into organic structures; these goals can be accomplished by introducing functional groups at the position of the C-H bonds on the rings. However, functionalization of secondary C-H bonds in strained rings, such as cyclopropanes and cyclobutanes, confronts several challenges, including the greater strength of these bonds than those in unstrained rings. Although catalytic, undirected borylation has been reported to functionalize the C-H bonds of selected strained rings, the examples of such reactions in earlier studies are limited in scope, principally involving rings with a small number and size of substituents. We report the borylation of fused, spirocyclic, and polysubstituted cyclopropanes, cyclobutanes, azetidines, and β-lactams with high diastereoselectivity with the most recent generation of catalysts for the borylation of alkyl C-H bonds. Important for the formation of more complex structures, reactions occur, unlike reactions of larger rings, with steric hindrance on adjacent carbon atoms. The stoichiometry of the diboron reagent, the <i>s</i>-character of the C-H bond, and the disposition of substituents influence reactivity and product distribution in ways charted by our results. With these advances, the borylation of C-H bonds becomes a viable approach for the modification and incorporation of these ring systems into pharmaceutically active structures.