The "Tocopherol-Acetaminophen Reaction" - A new [1,4]-rearrangement discovered in vitamin E chemistry

Treatment of N-{4-[3,4-dihydro-6-hydroxy-2,7,8-trimethyl-2-(4,8,12-trimethy ltridecyl) -2H-1-benzopyran-5-ylmethoxy]-phenyl}acetamide (8a) - the Toc pr odrug of acetaminophen (7) - with aqueous base yields 4-hydroxy-3-(6-O-alph a -tocopheryl)acetanilide (10a) as the main product. This hitherto unknown reaction type can formally be regarded either as a rearrangement involving [1,4]-sigmatropic and [1,3]-sigmatropic shifts, or as an intramolecular red ox process. Alternative pathways, such as an intermolecular reaction or a f ree radical process, have been ruled out. The formation of 10a by a multi-s tep sequence consisting of elimination, redox reaction, 1,4-addition to a q uinone intermediate, and rearomatization has also been ruled out, by trappi ng reactions. During the reaction. a proton from the acetaminophen structur e is selectively transferred to C-5a in the tocopheryl moiety as proven by deuteration experiments. The 4'-N-acyl structure is crucial for the reactio n to proceed, with the N-acetyl group giving the highest yield of rearrange ment product. As Sa-substituted tocopherols are also intermediates in many homolytic reactions of tocopherols in biological model systems, this type o f rearrangement might well contribute to the "prooxidative effect" of alpha -tocopherol, with acetaminophen being replaced by other 5a-substituents th at exhibit similar chemical behavior in the reaction.