Synthesis of 3-Substituted 4-Sulfanyl-8-methoxyisoquinolin-1(2H)-ones by the Reaction of Ethyl 2-[Lithio(sulfanyl)methyl]-6-methoxybenzoates with Aliphatic and Aromatic Nitriles

A convenient method for the synthesis of 3-substituted 4-alkyl(or aryl)sulfanyl-8-methoxyisoquinolin-1(2H)-ones has been developed.Ethyl 2-(alkyl(or aryl)sulfanyl)methyl-6-methoxybenzoates, prepared by the reaction of readily available ethyl 2-halomethyl-6-methoxybenzoates with sodium thiolates, are deprotonated on treatment with lithium diisopropylamide (LDA) to generates the corresponding benzyl anions, which react cleanly with a variety of nitriles to provide generally good yields of the corresponding desired isoquinolin-1(2H)-ones.Many compounds having the isoquinolin-1(2H)-one unit have shown variety of biological activities. 1Therefore, development of new routes for the synthesis of isoquinolin-1(2H)-ones have recently been extensively explored. 2However, there have been few reports on the synthesis of 4-(alkyl(or aryl)sulfanyl)isoquinolin-1(2H)-ones. 3 This led us to explore a method for preparing this type of isoquinolin-1(2H)-ones.We decided to examine the reaction of the benzyl anions of 2-[(alkyl(or aryl)sulfanyl)methyl]benzoates with various nitriles as a quick route to access the required isoquinolin-1(2H)-one derivatives.We wish to report here the results of our study, which provide a facile method for the preparation of 3-substituted 4-alkyl(or aryl)sulfanyl-8-methoxyisoquinolin-1(2H)-ones.We first conducted reaction of ethyl 2-(ethylsulfanyl)benzoate with lithium diisopropylamide (LDA) and then benzonitrile.However, it resulted in the formation of a considerably complex mixture of products, from which no more than a trace amount of the desired isoquinolin-1(2H)-one derivative was obtained.This result imply that the carbanion generated from ethyl 2-(ethylsulfanyl)benzoate is not enough stable to react the nitrile cleanly.We anticipated that introduction of a methoxy group at the 6-position of 2-(ethylsulfanyl)benzoate should stabilize the benzyl carbanions, because the benzyl anion (4) could be