A modular strategy for the construction of seven- and/or eight membered unsaturated and nitrogen-containing ring systems is discussed, which is based on Pd-catalyzed bond forming reactions. This approach enables the facile construction of benzannulated (aza)ring systems, exemplified for azadibenzocyclooctynes (aza-DIBOs) � a key intermediate for the strain-promoted azide-alkine cycloaddition (SPAAC). The versatility of the method relies on the selective mono-vinylation followed by intramolecular Heck-type coupling. The proposed mechanism was elucidated by systematic variation of the C-X bond. The reaction rate and regiochemistry can be tuned by the auxiliary phosphine to favor seven- vs. eight membered ring formation, or even to facilitate the intramolecular bridging thereof. Under optimized conditions, the valuable 8-endo regioisomer was obtained in >70% yield over two steps (without protecting group chemistry) starting from abundant starting materials.  The simple generation of a related octyne is described - without the need for chromatographic purification - which shows the inherent high reactivity of the class in a typical SPAAC reaction. The structural features, including those of the ring-strained cyclic octyne, were elucidated by NMR spectroscopy and X-ray crystallographic analysis. The generality of the method is explored to (hetero)substituted dibenzo-derivatives, which is also of interest as an easy access to multifunctional benzannulated azocines and pyrrolizine derivatives.

Intramolecular Pd-catalyzed cross coupling reactions: Facile formation of medium-sized unsaturated ring systems

248th National Meeting (2014)

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