A Synthesis of 4-(Hydroxymethyl)-1H-isochromen-1-one Analogs by Hydroxyl Oxetane Rearrangement in Protonic Acids

The synthesis of novel 4-hydroxymethyl isocoumarins through acid-promoted rearrangement of hydroxyl oxetane intermediates is reported. First, an oxetan-3-one 2 reacted with (hetero)aryl 1 through SN2 reaction to yield the hydroxyl oxetane intermediate 3 and then p-TsOH or H2SO4 promoted the ring-opening and subsequent carboxylic acid trapping led to the dihydropyranone formation. Dehydration furnished the isocoumarin product. In one example, a terminal hydroxyl was converted to amide via tandem Ritter reaction when MeCN was the solvent. The synthesis is metal-free, and the products contain handles for further elaboration.