Filling the Gap within 10‐Membered Heteroenediynes: Thiaenediyne – An Experimental and Theoretical Study

The heteroatom nature in 10‐membered enediynes plays a crucial role in tuning of their reactivity in the Bergman cyclization, which is a decisive factor for the biological activity of enediynes. Although benzothiophene‐fused O‐ and N‐enediynes have been identified as promising biological objects, the corresponding thiaenediyne remains unknown. To fill this gap, we synthesized the thiaanalog and studied it in both practical and theoretical terms. While the Nicholas reaction has proven to be an effective cyclization technique for the preparation of heteroenediynes, in the case of thiaenediyne it was accompanied by an unusual acid‐promoted intramolecular cyclization, forming a thiepinium salt. The S‐enediyne has reduced reactivity in the Bergman cyclization relative to the N‐ and O‐enediynes, attributed to the diminished alkyne bending and extended cd‐distance. The NBO analysis of the entire series, namely the evaluation of πin/out(C2‐CC)→σ*(C−X) hyperconjugation, revealed that the S atom in S‐enediyne provides stronger stabilization of the initial compound than the N atom in N‐enediyne, while exhibiting the weakest stabilization of the Bergman cyclization transition state. NICS values were employed to examine the change in aromaticity along the Bergman cyclization coordinate. This approach, in conjunction with the NBO analysis, provides a foundation for further rational design of unnatural enediynes. Thiaenediyne, as a member of the heteroenediynes fused to a benzothiophene core, was synthesized using the S‐type Nicholas cyclization. NBO analysis was used to demonstrate the primary role of the heteroatom in an enediyne core for the reactivity of enediynes in the Bergman cyclization.