Mechanochemical Alkynylation of Isatin with Calcium Carbide: Experimental and Computational Insights into Selectivity

Alkynylation of isatins with calcium carbide (CaC 2 ) in solution has been reported to selectively yield mono‐alkynylation products (i.e., 3‐ethynyl‐3‐hydroxy‐2‐oxindoles). In this work, we studied the reaction under mechanochemical conditions, finding that upon ball milling, the acetylenic anions [C 2 ] 2– present in CaC 2 react with isatin, leading preferentially to the bis ‐alkynylation addition product [i.e., 3‐ethynyl‐ bis (3‐hydroxy‐2‐oxindole)]. Through experimental work and computational mechanistic studies within the framework of density functional theory, we investigated the change in selectivity and identified i) the highly concentrated reaction environment under ball milling and ii) the avoidance of bulk water as conditions that favor the bis ‐alkynylation of two isatin molecules with a single [C 2 ] 2– fragment. In addition, we found that the reaction occurs through several variants of the same overall mechanism, in which some cationic metal counterions play a relevant role through noncovalent interactions.