Study of the Reactions of 1,4-naphthoquinone Derivatives with Bifunctional Nucleophiles

Abstract

Vitamin K, a member of a class of compounds called 1,4-naphthoquinones, is an important factor in blood clotting as well as the post-translational modification of various proteins in the body. These molecules are highly biologically active and are capable of covalently modifying proteins by binding to sulfur or nitrogen atoms in the side chains of amino acids. In this study we attempted to characterize the reactions of 1,4-naphthoquinone derivatives with bifunctional nucleophiles containing both thiol and amino groups as a model for their activity in biological systems. As they are excellent electrophiles, 1,4-naphthoquinones are prone to substitution at the 2- and 3- positions given suitable leaving groups. We primarily worked with 2-bromo-3-methoxy-1,4-naphthoquinone in reactions with compounds having the basic molecular backbone of 2-aminoethanethiol. It is known from previous work that sulfur nucleophiles selectively replace the bromine atom, while nitrogen nucleophilespreferentially substitute for the methoxy group. We found that in reactions with 2-aminoethanethiol hydrochloride and with 2-(butylamino)ethanethiol, in a presence of a catalytic amount of triethylamine, a cyclized product is formed. In reactions where the amino group is unable to react, a single replacement of the bromine atom occurs: this is the case with N-methylmercaptoacetamide and 2-(diethylamino)ethanethiol. These results provide a basis for further study of the reactivity of 1,4-naphthoquinones with the goal of better understanding their role in the body.