Catalytic Intramolecular Frdel-Crafts Reaction Of ?-Carbonyl Amides:Highly Efficient Synthesis Of 3-hydroxyoxindoles And Isatins

The 3-hydroxyoxindole frameworks have been widely found in natural products and drug candidates possessing intriguing bioactivities.Furthermore,3-hydroxyoxindoles are synthetically versatile building blocks for the synthesis of various heterocyclic compounds.Consequently,intense efforts have been devoted to their synthesis.Although significant success has been made,the present methods still have some problems.The intramolecular Friedel-Crafts reaction of?-carbonyl amides represent theoretically the most efficient and straightforward methodology for the synthesis of 3-hydroxyoxindoles.However,in contrast to the intermolecular Friedel-Crafts reaction,the intramolecular Friedel-Crafts reaction of?-ketoamides was rarely investigated owing to the significant side reactions.The reaction still suffered from significant problems of harsh reaction conditions,narrow substrate scope and bad regioselectivity.Thus,searching for an efficient catalyst system,which could efficiently catalyze the Friedel-Crafts reaction of?-carbonyl amides is still challenging and interesting.Herein,we describe a Fe?OTf?₃ catalyzed intramolecular Friedel-Crafts reaction of?-carbonyl amides for the synthesis of 3-hydroxyoxindoles.The process delivered a wide substrate scope,giving the products in high yields and excellent regioselectivities.A distinct difference of regioselectivity was observed for the intramolecular Friedel-Crafts reaction of?-ketoamides and?-formyl amides.Based on the previous reports and our investigations,a change in the transition state structure of the Friedel-Crafts alkylation reaction was proposed to account for the alteration of the regioselectivity.The methodology was further successfully extended to the synthesis of isatins via domino intramolecularFriedel-Crafts reaction/oxidation reaction.Given the importance of the 3-hydroxyoxindoles and isatins,our methods has its potential application.