Palladium-catalyzed highly chemo- and regioselective formal [2+2+2] sequential cycloaddition of alkynes: A renaissance of the well known trimerization reaction?

A new concept of highly chemo- and regioselective formation of the benzene ring by a palladium-catalyzed formal [2 + 2 + 2] sequential intermolecular trimerization of alkynes is proposed. Homodimerization of terminal alkynes and subsequent [4 + 2] benzannulation with diynes gives tetrasubstituted be nzenes in moderate to good yields. The introduction of two different alkyne s (terminal and internal) in the first step of the sequence allows for cons truction of pentasubstituted benzenes from three different acyclic acetylen ic units. In all cases the tetra- and pentasubstituted benzenes are formed as a single reaction product without being accompanied by any of regio- or chemoisomers. A significant acceleration of the sequential trimerization re action in the presence of Lewis acid/phosphine combined system was observed . Mechanistic studies reveal that the Lewis acid assisted isomerization of the E-enyne formed in the first step of the sequence to the more reactive Z -isomer is responsible for the observed acceleration effect. The proposed m ethodology provides a conceptually new and synthetically useful route to mu ltifunctional aromatic compounds.