Synthesis of new 2-amino-5-hydroxymethyl-2-thiazolines

Abstract

A simple and convenient method is proposed for the synthesis of 2-amino-5-hydroxymethylthiazolines with various substituents in the amino group, which is based on hydrolysis of the corresponding 5-halomethyl derivatives of thiazoline in the presence of divalent lead oxide.Keywords: 2-amino-5-hydroxymethyl-2-thiazoline, nitric oxide, hydrolysis, X-ray structural analysis, NMR.It is familiar [1] that 2-amino-2-thiazoline derivatives provide radiation protection. Recently, interest has been shown in their capacity to act selectively on certain enzymes (e.g., NO synthase isoforms) [2,3]. This has led to a search for a convenient method of synthesizing previously unknown 2-amino-5-hydroxymethyl-2-thiazolines with alkyl, benzyl, alkylbenzyl, dibenzyl, and hetaryl substituents in the amino group. The literature bears isolated items of information on the synthesis of such compounds from the corresponding 5-haloderivatives of thiazoline in the presence of silver salts [4,5], but unfortunately they lack descriptions of the experimental methods and proof of the structures of the substances.We have examined the hydrolysis of the hydrohalides of 2-amino-substituted 5-halomethyl-2-thiazolines 1a-h made by traditional methods: iodination of the corresponding N'-derivatives of N-allylthiourea or reaction of N-(2,3-dibromopropyl)isothiocyanate with amines [6][7][8].Previous studies have shown that isomeric six-membered rings (thiazines) are formed in these reactions as well as thiazolines [9, 10]. However, these reactions are usually performed in polar media with heating, and from the reaction mixtures one isolates only five-membered thiazoline rings, because under these conditions there is an easy dihydrothiazine-thiazoline rearrangement [11]. There is published evidence for the reversibility of that rearrangement [12], so particular attention has been given to establishing the structures of the resulting hydroxyl derivatives.In order to choose the hydrolysis conditions, we examined the behavior of compounds 1a-h at various pH; according to [13] and our studies, these compounds are unstable in the presence of bases and may give rise to polymeric compounds of variable composition. Therefore, for the hydrolysis we examined the systems PbO-H 2 O or PbO-H 2 O-EtOH as appropriate to the solubility of the initial hydrogen halides of the 2-aminothiazolines 1a-h. The lead halides formed in the reaction are virtually insoluble in water, i.e., the halogen ions are removed from the reaction sphere and the equilibrium is displaced towards the formation of 2-amino-5-hydroxy-2-methylthiazolines. We found that the best conditions for the experiments were pH from 4 to 7. __________________________________________________________________________________________ 1 M.