The “Tocopherol−Acetaminophen Reaction” − A New [1,4]-Rearrangement Discovered in Vitamin E Chemistry

Abstract

Treatment of N-{4-[3,4-dihydro-6-hydroxy-2,7,8-trimethyl-2-(4,8,12-trimethyltridecyl)-2H-1-benzopyran-5-ylmethoxy]phenyl}acetamide (8a) − the Toc prodrug of acetaminophen (7) − with aqueous base yields 4-hydroxy-3-(6-O-α-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 redox process. Alternative pathways, such as an intermolecular reaction or a free radical process, have been ruled out. The formation of 10a by a multi-step sequence consisting of elimination, redox reaction, 1,4-addition to a quinone intermediate, and rearomatization has also been ruled out, by trapping reactions. During the reaction, a proton from the acetaminophen structure is selectively transferred to C-5a in the tocopheryl moiety as proven by deuteration experiments. The 4′-N-acyl structure is crucial for the reaction to proceed, with the N-acetyl group giving the highest yield of rearrangement product. As 5a-substituted tocopherols are also intermediates in many homolytic reactions of tocopherols in biological model systems, this type of rearrangement might well contribute to the “prooxidative effect” of α-tocopherol, with acetaminophen being replaced by other 5a-substituents that exhibit similar chemical behavior in the reaction.