Nickel‐Catalyzed Cross‐Electrophile Coupling to Access Polysubstituted Cyclobutenes

The synthesis of cyclobutene remains inefficient due to inherent ring strain and poor regioselectivity. We demonstrate here a nickel‐catalyzed cross‐electrophile coupling (XEC) between readily accessible homopropargyl halides and commercially available aryl/vinyl electrophiles for the 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 synthesis of diverse cyclobutene containing compounds (including synthetically challenging macrocycles). The synthesis of antitumor‐active Combretastatin A‐4 analog has been significantly optimized, the original six‐step procedure yielding 14% has been streamlined into a three‐steps process that achieves 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 SH2 attack to produce the strained cyclobutene ring with overall stereo‐inversion at the homopropargylic position.