Pd‐Catalyzed Ring Assembly by Vinylation and Intramolecular Heck Coupling: A Versatile Strategy Towards Functionalized Azadibenzocyclooctynes

A new modular approach based on Pd‐catalyzed C? C bond formation is presented for the assembly of a benzannulated azocine scaffold, the key intermediate in the synthesis of functionalized azadibenzocyclooctynes (aza‐DIBOs). The intramolecular ring‐closing Heck coupling was investigated by variation of the C? X bond. The reaction rate is limited by the initial oxidative addition step and the regiochemistry strongly depends on the auxiliary phosphine. Under optimized conditions, the 8‐endo regioisomer was obtained in 71 % yield over two steps (with no protecting group chemistry) or in one pot, inclusive of C? N bond formation. The practical generation of the octyne triple bond of a prototypical N‐benzoyl aza‐DIBO, without the need for chromatographic purification, is also described. The structural features, including those of the ring‐strained cyclic octyne, were elucidated by NMR spectroscopy and X‐ray crystallographic analysis. The high reactivity of the N‐benzoyl aza‐DIBO synthesized is demonstrated in a strain‐promoted azide–alkyne cycloaddition reaction with an alkyl azide (k=0.38 M ^?1 s^?1).