New cascade and multiple cross-coupling reactions for the efficient construction of complex molecules

Abstract

Multiple palladium-catalyzed cross-coupling reactions of the Heck, Suzuki and Stille types on oligofunctionalized cycloalkenes and arenes can be performed in very high yields. While Heck type reactions on 1,2-dibromocycloalkenes or 2-bromocyclohexenyl triflates lead only to the twofold coupling products, the Stille coupling of the latter substrates occurs chemoselectively at the site of the triflate leaving group to give bromobutadienes which readily undergo subsequent Heck reactions. The thus obtained 1,3,5-hexatrienes undergo thermal 6π-electrocyclizations to furnish bicyclic skeletons, among others cyclohexenone-annelated systems after acidic work-up. Cascades of carbopalladation, rearrangement and [4+2] cycloaddition with bicyclopropylidene, aryl iodides and dienophiles constitute a new class of three-component reactions with a remarkable combinatorial potential, especially since they can be performed on the solid phase using the triazene linker. With nucleophiles instead of dienophiles yet another domino reaction consisting of carbopalladation, rearrangement and nucleophilic substitution can be performed with bicyclopropylidene, aryl or alkenyl iodides and C-, O- and N-centered nucleophiles to give a wide variety of interesting compounds. Under properly adjusted conditions even sixfold coupling reactions on hexabromoarenes can be achieved. When using Heck type reactions the initially formed intermediates en route to hexaalkenylarenes undergo intramolecular ring closures to yield multi-component mixtures of isomers of the expected products, but sixfold Stille and Suzuki couplings give pure hexaalkenylarenes in up to 73% yield. Crystal structure analyses reveal that depending on the nature of the alkenyl groups the six arms are positioned either on the same side of the central ring making it an interesting cup-shaped molecule or alternating above and below the central plane.