G. Sundaram, C. Venkatesh, H. Ila
Feb 1, 2007
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Journal
Synlett
Abstract
An efficient three-component one-pot synthesis of 3,5- and 1,3,5-substituted 2-thiohydantoins employing easily accessible amino acid esters, primary amines and 1-(methyldithiocarbonyl)im- idazole as thiocarbonyl transfer reagent has been reported. Hydantoins and their 2-thio analogues represent an impor- tant class of heterocycles displaying a broad range of biological (anticonvulsant, antiarrythmic, antimuscarine, antineuralgic, anticancer) activities. 1 Derivatives of 2- thiohydantoins also play an important role in organic syn- thesis, especially as starting materials for the preparation of synthetic intermediates with wide range of applications as therapeutics 2 as well as fungicides and herbicides. 3 They have also been used widely for the sequence analy- sis of polypeptides and proteins (Edman degradation). 4 These compounds are usually prepared by reaction of amino acids or amino acid esters with an isothiocyanate. 5 A few of the 2-thiohydantoins have been synthesized by reaction of amino acids with dithiocarbamate esters. 6 We have recently 7 reported synthetic application of 1-(meth- yldithiocarbonyl)imidazole as a useful thiocarbonyl transfer reagent 8 for the synthesis of symmetrical and un- symmetrical mono-, di- and trisubstituted thioureas and dithiocarbamates under mild and simple non-hazardous reaction conditions. In the present communication, we wish to report further application of this reagent for the ef- ficient synthesis of a broad range of 3,5- and 1,3,5-sub- stituted-2-thiohydantoins by its reaction with amino acid esters and amines in a three-component one-pot process. 1-(Methyldithiocarbonyl)imidazole (3) was prepared ac- cording to our earlier reported procedure 7 by treatment of imidazole with carbon disulfide in the presence of sodium hydride as base followed by alkylation with methyl io- dide. In a typical experiment, 9 when equimolar quantities of alanine ethyl ester hydrochloride, benzylamine and 1- (methyldithiocarbonyl)imidazole were refluxed in etha- nol (7-8 h) in the presence of triethylamine, the corre- sponding (S)-3-benzyl-5-methyl-2-thiohydantoin (4a) was obtained in 87% yield, whereas the use of corre- sponding free alanine, benzylamine and 1-(methyldithio- carbonyl)imidazole resulted in the formation of only 1,3- dibenzylthiourea and no trace of thiohydantoin 4a was obtained. The reaction was equally facile in the presence of K2CO3 as base in acetonitrile yielding 4a in comparable