Ligand-Controlled Alkylation–Heck–C(sp³)–H Annulation Cascade for a Divergent Synthesis of Cyclobutane- and Cyclopropane-Containing Heterocycles

High Resolution Image Download MS PowerPoint Slide The ability to harness divergent reactivity and selectively dictate product outcomes from simple precursors has been a longstanding challenge in organic chemistry. Specifically, the realization of this goal in C–H functionalization remains a considerable challenge due to the inherent difficulties in achieving precise regioselective control in the presence of multiple, stereoelectronically similar C–H bonds. Herein, we report a two-component C(sp 3 )–H annulation cascade reaction that effectively unites ortho -bromophenols or ortho -bromoanilines with allylic alkyl bromides and provides direct access to two different heterocyclic scaffolds via precise ligand-controlled reactivity. Our newly developed transformation proceeds via an initial alkylation followed by a regioselective Heck carbopalladation and is terminated by a regiodivergent C(sp 3 )–H annulation of a γ-methylene or a δ-methyl C–H bond. Moreover, this C–H annulation platform provides a divergent access to spirocyclic cyclobutane or fused cyclopropane scaffolds that are frequently featured in natural products or medicinally relevant molecules. This cascade transformation possesses a broad substrate scope with respect to the aryl as well as alkyl halide components, showcased by the preparation of >60 heterocyclic products with excellent regiocontrol.