Intramolecular Friedel-Crafts Acylation Promoted by Hexafluoroisopropanol

Abstract

The Friedel-Crafts (FC) acylation, discovered by Charles Friedel and James Crafts, is utilized to synthesize aryl ketones. The traditional intermolecular FC acylation requires a stoichiometric amount of Lewis acid (i.e., AlCl3) catalysts to drive the reaction to completion due to complex formation between product ketones and catalysts.We have discovered a modified FC acylation where hexafluoroisopropanol (HFIP) was used as a promoter and solvent. Due to the strong hydrogen-bond donor ability of HFIP, it was shown that multiple arylalkyl acyl chlorides are able to undergo intramolecular FC acylation in HFIP at room temperature. In this work, we seek to refine this procedure for the optimized synthesis of 6,7-dimethoxy-3,4-dihydronaphthalen-1(2H)-one. The procedure involves (1) the conversion of 4-(3,4-dimethoxyphenyl)butanoic acid to 4-(3,4-dimethoxyphenyl)butanoyl chloride with thionyl chloride, followed by (2) the FC acylation of 4-(3,4-dimethoxyphenyl)butanoyl chloride to form 6,7-dimethoxy-3,4-dihydronaphthalen-1(2H)-one in HFIP.This methodology illustrates an improvement over traditional FC acylation as it requires no additional reagents or catalysts and generates no byproducts. In addition, it is operationally simple, requiring only solvent evaporation and product purification after reaction completion.