Reactions of 2-Alkylthio-3-methyl-1,4-naphthoquinones with Alkylamines

Derivatives of 1,4-naphthoquinone play an important role in various biological processes through the reaction with a nucleophile. For example, the anticancer activities in tyrosine phosphatase are due to the reactivity of 1,4-naphthoquinones with a nucleophile, the cysteine residue, in the active site. Here we study the reactivity of 2-ethylthio-3-methyl-1,4-naphthoquinones against various types of primary amines, which are one of the more important nucleophiles in the biological environment. We first synthesized 2-ethylthio-3-methyl-1,4-naphthoquinone from the reaction of 2-methyl-1,4-naphthoquinone epoxide with ethanethiol in the presence of N-methylimidazole. Then, 2-ethylthio-3-methyl-1,4-naphthoquinone was reacted with various alkylamines in different reaction conditions. The alkylamines studied here were methylamine, ethylamine, isopropylamine, and tert-butylamine. The major product of each reaction, regardless of its reaction condition, is 2-alkylamino-3-ethylthio-1,4! -naphthoquinone. In addition, in the presence of oxygen, 2-ethylthio-3-methyl-1,4-naphthoquinone epoxide was efficiently formed. In the reaction under argon (Ar) atmosphere, however, the formation of epoxide was completely excluded. Reaction with methylamine, the least hindered nucleophile in our study, is notable because unlike other alkylamines, it produces an additional minor product, regardless of the presence or the absence of oxygen. The study of elucidating this additional minor product is in progress