An investigation into the unusual formation of an isocoumarin by acylation of 2,3,6-trimethoxytoluene with (E)-2-methylbut-2-enoic acid and trifluoroacetic anhydride

Abstract

Prolonged reaction of 2,3,6-trimethoxytoluene with an excess of premixed (E)-2-methylbut-2-enoic acid and trifluoroacetic anhydride in air affords 5,6,8-trimethoxy-3,4,7-trimethylisocoumarin 11 in 66% yield as the sole product isolated, the structure of which was confirmed by X-ray crystallography. Shorter reaction times afford products which enable the identification of the reaction mechanism. This involves initial regioselective acylation, cyclisation of the derived α,β-unsaturated aryl ketone 5 to the cis/trans mixture of indanones 18 and 19 and O-acylation of these indanones to yield the indenyl ester 17. The indanones and compound 17 can all react with trifluoroacetic acid in the presence of atmospheric oxygen to afford the isocoumarin by a mechanism which requires the intermediacy of an α-keto indanyl hydroperoxide, which in turn undergoes an acid-catalysed Baeyer–Villiger-type rearrangement to incorporate oxygen, thereby giving the isocoumarin.