Arylacetic acid Fenacs

The prototype for this class of compounds is ibufenac (42-3), developed by a group at Boots in the UK. This drug was to be quickly superseded by its a-methylated congener, ibuprofen, from the same laboratory [43]. The mechanistically very complex Wilgerodt reaction constitutes the key to the preparation of ibufenac. Thus, reaction of the acetylation product (42-1) from isobutyl benzene and acetyl chloride with sulfur and morpholine leads to the transposition of the oxidized function to the terminal carbon and formation of thiomorpholide (42-2). Hydrolysis of the thioamide 

Construction of the closely related NSAID bromefenac (46-8) depends on the Gassman indolone synthesis [46] for incorporation of the acetic acid chain. That reaction involves an anion-initiated electrocyclic rearrangement related conceptually to the little-known Hauser ortho substitution rearrangement. The simplest example of the latter depends on the formation of a carbanion by abstraction of one of the acidic protons from a benzyltrimethyl quaternary salt to give I (the 

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