Palladium-Catalyzed Alkyl Heck-Type Cyclization And Functionalization

Heterocyclic compounds are a class of important structural units.More than two-thirds of modern drugs and natural products possess heterocyclic molecular skeletons,which endow compounds with special pharmacological and biological activities.Therefore,the development of efficient,environmental-friendly,convenient,and atom-economic novel methodologies for the chemical preparation of heterocyclic derivatives has always been an attractive area.Due to the high bond energy of alkyl carbon-halide bonds,it is difficult to oxidative addition with metal atom.Moreover,the formed alkyl-metal species are very prone to premature β-H elimination.Therefore,alkyl-Heck reaction has always been a greatly challenging research subject.This thesis focuses on the relatively underdeveloped Pd-catalyzed intramolecular alkyl-Heck-type cyclization,realizing a variety of efficient intramolecular cyclization strategies.These strategies not only provide new methods for the construction of frameworks such as 6-membered heterocycles,7-membered heterocycles,and [1,2-a] indoles,but also greatly expand the application range of Pd-catalyzed alkyl-Heck-type cyclization.(i)In response to the concept of green chemistry,a visible-light-induced Pd-catalyzed intramolecular 6-endo Heck reaction of alkyl halides was developed to avoid the high-temperature reaction conditions in classical alkyl-Heck reactions.This strategy achieved 6-endo cyclization of alkyl iodides and alkyl bromides under light-induced conditions without requiring additional heating sources or heat dissipation devices,while only alkyl iodides can be employed under traditional thermal conditions in the same type conversion.The key to this conversion is an excited state of palladium complex under blue light conditions,which is formed from a suitable Pd(0)source and ligand.The carbon halide bond forms a hybrid species of the alkyl radical and Pd(I)via single electron transfer(SET)process,followed by the radical addition to form a tertiary benzyl radical intermediate,which is also the critical factor for the 6-endo selectivity.(ii)We developed an Pd-catalyzed intramolecular 7-endo alkyl-Heck reaction of epoxides with olefins via ring-opening of epoxides and C-C bond coupling,providing a series of 6-phenyl-2,3,4,7-tetrahydro-1H-azepin-3-ol derivatives and6-phenyl-2,3,4,7-tetrahydrooxepin-3-ol derivatives.Moreover,the compounds constructed through this strategy not only provides the 7-membered heterocyclic skeleton,but also bears secondary or tertiary hydroxyl groups,providing a convenient way for further modification.Moreover,only a catalytic amount of Pd-catalyst(10 mol%),ligand(20mol%),and Et3N·HI(20 mol%)was used to promote the conversion in a high atom-economic way,without any atom loss during the reaction process.Moreover,Et3N·HI,as a common industrial waste,has been recycled in this protocal.The catalytic system is eco-friendly and efficient,which is conforming to the concept of green chemistry.According to the experimental results of mechanism exploration and density functional theory(DFT)calculations,a possible catalytic cycle was proposed for the reaction.The stable tertiary benzyl radical intermediate is the critical factor for the 7-endo selectivity for the cyclization.(iii)A Pd-catalyzed intramolecular Heck-type C-H bond activation/alkylation at the C-2 position of indole with epoxides was further realized.Selective 5,6,7-exo cyclization was achieved by adjusting the carbon-chain length of the epoxy portion,providing a new way for the preparation of 5-membered,6-membered,and 7-membered [1,2-a] indole derivatives.The molecular skeleton is widely found in natural products and modern drugs.Although the mechanism investigation experiments indicate that this conversion undergoes a free radical pathway,the selectivity of epoxide ring-opening is not affected by the stability of radical intermediates,but is controlled by the catalyst leading to specific terminal selective ring-opening.In addition,two possible reaction pathways have been established for this conversion:(i)the reaction is initiated by HPd(II)I species and undergoes a synergistic "epoxides ring-opening and C-C coupling" process to form a double radical intermediate;(ii)a β-hydroxyl iodide,which is formed from epoxides and Et3N·HI via ring-opening,reacts with Pd(0)through a Heck-type pathway.