Palladium-catalyzed Remote Aryldifluoroalkylation Of Alkenyl Aldehydes

Due to the unique properties,fluorinated compounds are of great interest in pharmaceuticals,agrochemicals,and materials.Among these,the difluoromethylene group(CF2)is a valuable structural motif in life science,medicinal chemistry,and organic synthesis.Thus,the exploration of practical and broadly applicable methods for the introduction of CF2 group into target molecules is highly demanded.The carbodifluoroalkylation of alkenes,permitting the concurrent formation of C-CF2 and C-C bonds in a single synthetic operation,is a highly efficient and synthetically convenient approach to polyfunctionalized difluoroalkylated compounds.To date,however,the remote carbodifluoroalkylation of alkenyl compounds still constitutes an unmet goal,probably because of the challenge in controlling the site selectivity of remote functionalization.By the way of 1,n-hydrogen atom transfer(1,n-HAT),we have developed a palladium-catalyzed remote aryldifluoroalkylation of alkenyl aldehydes using readily available fluoroalkyl halides as the difluoroalkylation reagent,thus providing 5-,6-,or 7-difluoroalkylated ketones in good to excellent yields under very mild reaction conditions.It represents the first remote aryldifluoroalkylation reaction,which may be appealing for the one-pot synthesis of highly functionalized difluoroalkylated compounds.Meanwhile,a novel silver-catalyzed intramolecular decarboxylative cyclization of 5-aryl-2,2-difluoropentanoic acids has also been realized,thus allowing facile access to 1,1-difluoro-1,2,3,4-tetrahydronaphthalenes in good yields.A palladium-catalyzed three-component radical reaction between fluoroalkyl bromides,arylboronic acids,and alkenyl aldehydes has been developed and provides facile access to 5-,6-,or 7-difluoroalkylated ketones and 1,1-difluoro-1,2,3,4-tetrahydronaphthalenes.The efficient synthesis of CF2-containing tetrahydronaphthalenes makes this method very attractive for the drug discovery and development.