A Simple Synthesis of New 2-Thioxoimidazolidine-4,5-dicarboxylates from Vicinal Diisothiocyanatocarboxylates

Abstract

A simple synthesis of novel symmetrical and unsymmetrical 2-thioxoimidazolidine-4,5-dicarboxylates is described. The symmetrical 2-thioxoimidazolidine-4,5-dicarboxylates were obtained through partial hydrolysis of vicinal 2,3-diisothiocyanatocarboxylates. The unsymmetrical 2-thioxoimidazolidine-4,5-dicarboxylates were prepared by addition of a stoichiometric amount of primary and secondary amines to vicinal 2,3-diisothiocyanatocarboxylates. The resulting imidazolidine derivatives were found to be convenient reactants for the construction of a new bicyclic imidazo[2,1-b]thiazole system. The addition of a twofold excess of amine to vicinal 2,3-diisothiocyanatocarboxylates gave rise to competitive condensations yielding bi-imidazolidine and bi-1,2,4-triazine derivatives.Numerous 2-thioxoimidazolidine derivatives attract attention as compounds of medical use, for example, as octopaminergic agonists, 1a,b and because they exhibit antimicrobial activity. 1c They also have industrial applications as vulcanization accelerators. 1d However, there have so far been no reports regarding the synthesis of 2-thioxoimidazolidine-4,5-dicarboxylates and only several examples of 2-thioxoimidazolidines mono-substituted by an ester group. 2 The known preparative methods are based on catalytic asymmetric aza-Henry reactions 3 or rearrangement of thiohydantoins by the ANRORC mechanism. 4 The closest known homologues of 2-thioxoimidazolidine-4,5-dicarboxylates, the 2-oxoimidazolidine-4,5-dicarboxylic acids and esters, have found numerous applications. The synthetic utility of the 2-oxoimidazolidine-4,5-dicarboxylic derivatives can be seen in their uses in the synthesis of d-biotin 5 and in the preparation of a streptolidine lactam, which is the core structure of streptothricin antibiotics. 6 Some methods for the synthesis of imidazolidine-4,5-dicarboxylic acids from aspartates 7 and glycinate Schiff bases 8 have been reported but all the mentioned protocols consist of multistep reactions.Our investigations on titanium(IV) mediated oxidative coupling reactions of 2-isothiocyanatocarboxylic esters 1 resulted in a novel method for diastereoselectively preparing vicinal diisothiocyanatocarboxylates 2. 9 We have found that the prepared new vicinal dl-diisothiocyanatocarboxylates 2 were useful in the direct synthesis of symmetrical and unsymmetrical dl-2-thioxoimidazolidine-4,5-dicarboxylates. Following the general procedure of acidic transformations of isothiocyanates into amines, 10 we hydrolyzed the obtained vicinal diisothiocyanates 2a and 2b in 50% perchloric acid. After addition of a stoichiometric amount of sodium hydroxide, we isolated crystalline products 3a and 3b with good yields (Scheme 1). Their structures were determined by spectroscopic methods and confirmed by an X-ray diffraction analysis of compound 3a (Figure 1). Scheme 1 Reagents and conditions: (a) See Cież; 9 (b) (i) 50% HClO 4 , dioxane, 60°C, 24 h; (ii) aq NaOH.The asymmetric unit of compound 3a contains only half of the molecule; the remainder can be rebuilt by rotati...

Enolates of 2-Isothiocyanatocarboxylic Esters: Synthesis of Thiazolo[5,4-d]-thiazole Derivatives and 2-Thioxo-1,3-thiazolidine-4-carboxylates

“…7 Titanium(IV)-promoted oxidative coupling reactions of 2-isothiocyanatocarboxylic esters have been used in attempts to synthesize masked symmetric 2,3diaminosuccinates 8 and 2-thioxoimidazolidine rings. 9 More recently, 2-isothiocyanatocarboxylic esters have been used as substrates in stereoselective Mannich additions leading to 2-thioxo-1,3-imidazolidines, which are derivatives of 2,3-diaminosuccinic acid. 10 Titanium(IV) enolates of carboxylic esters can serve as very convenient and useful intermediates for C-C bondformation reactions.…”