Regio- and Stereoselective Coupling of Heteroaryl-Substituted Alkynes:  New Insights into the Mechanism of Zirconium-Mediated Cyclodimerization of Alkynes and a Facile Route to 3-Methylenecyclobutenes

The cyclodimerization of (2-pyridyl)alkynes tethered with an amino group mediated by zirconium was achieved cleanly under controlled reaction conditions. This methodology provided an efficient route for the synthesis of tetrasubstituted cyclobutenes with high regio- and diastereoselectivity when the reaction was quenched by water. However, by quenching with saturated NaHCO3 solution, a 3-methylenecyclobutene derivative was readily constructed. The effect of other quenching reagents on the product distribution was also investigated. This cyclization/elimination was influenced strongly by the nature of the substituent on the amino group. The reaction worked well with aryl/methyl-, aryl/benzyl-, or diaryl/aminomethyl-substituted alkynes, giving generally good yields of the corresponding products. Conversely, the phenyl/hydrogen or dialkyl (except 1k) substitutions on nitrogen gave either lower chemical yields or different products. The zirconium intermediate was isolated successfully, which has been fully characterized by NMR experiments and mass analysis. Extensive NMR experiments (DEPT, COSY, HMQC, and HMBC) revealed its structure is in agreement with that of zirconacyclopentadiene, and this structure was further confirmed by DFT calculations. Subsequent cyclization to yield a cyclobutadiene skeleton was induced by the attack of the coordinative species. This is different with the reactions of late transition metal mediated cyclodimerization of alkynes (e.g., Co) via direct reductive elimination. To account for the formation of 3-methylenecyclobutenes, an E1cb reaction pathway was suggested.