Nickel‐Catalyzed Cross‐Electrophile Coupling to Access Polysubstituted Cyclobutenes

Abstract The synthesis of cyclobutenes remains inefficient owing to inherent ring strain and poor regioselectivity. We describe herein a nickel‐catalyzed cross‐electrophile coupling (XEC) between readily accessible homopropargyl halides and commercially available aryl/vinyl electrophiles for direct access to polysubstituted cyclobutenes. This approach provides the first reductive 4 ‐endo‐dig cyclization with high chemo‐ and regioselectivity, which paves the way for the synthesis of diverse cyclobutene containing compounds (including synthetically challenging macrocycles). The synthesis of an antitumor‐active combretastatin A‐4 analog has been significantly optimized; the original six‐step procedure yielding 14% has been streamlined into a three‐step process with a markedly improved yield of 51%. Experimental data and computational studies support a mechanism involving an alkenyl nickel(I) intermediate, which undergoes facile back‐side S H 2 attack to produce the strained cyclobutene ring with overall stereoinversion at the homopropargylic position.