384. The condensation of N-substituted maleimides with thioureas

Abstract

The products, which are additive in molecular formula, are shown t o be thiocarbanilide. probably thiazolidones of type (111).To further the investigation of the reactivity of maleimides towards free thiol groups (Friedmann, Marrian, and Simon-Reuss, Brit. J . PharmacoZ., 1949, 4, 105; Marrian, this vol., p. 1515) * Bougault and Chabrier (Compt. re?zd., 1947, 224, 656) have shown that benzoylacrylic acid and thiourea react analogously.

Thiazol-4-one derivatives from the reaction of monosubstituted thioureas with maleimides: structures and factors determining the selectivity and tautomeric equilibrium in solution

“…First, we repeated some experiments reported by Marrian [9], namely, the reactions of N -phenylthiourea ( 1a ) with N -phenyl- and N -ethylmaleimides 2a , b . The experimental protocol [9] required reflux temperature for reaction with 2a and room temperature for 2b .…”

“…The experimental protocol [9] required reflux temperature for reaction with 2a and room temperature for 2b . We obtained thiazolidines 3a , b as single products in both cases according to the 1 H NMR spectra of the reaction mixtures (Scheme 2).…”

“…In particular, the addition of monoalkyl(aryl)thioureas to N-substituted maleimides provides the corresponding thiazolidinylacetamides. First described by Marrian in 1949 [9] and later developed further by Augustin and co-workers [10–11], a plausible mechanism for this transformation was postulated. It includes a nucleophilic attack of the thiourea sulfur atom on the C=C bond of the maleimide followed by a proton transfer and nucleophilic attack of the thiourea nitrogen atom on one of the two carbonyl groups; the latter step is considered rate determining (Scheme 1).…”

“…It was reported that the substituent on the maleimide nitrogen atom, particularly a group in the para -position of the phenyl ring in N -arylmaleimides, affects the reactivity of the maleimide toward nucleophilic addition [10]. Strange as it may seem, N -phenylthiourea reacts with N -phenylmaleimide providing thiazolidine with the exocyclic position of the phenyl group, whereas an isomer with the phenyl group on the endocyclic nitrogen atom was obtained from the same thiourea and N -ethylmaleimide (Scheme 1) [9]. This behavior has not been explained and there is lack of more recent information on the regioselectivity of this reaction.…”

“…The regioselectivities of the reaction between monosubstituted thioureas and maleimides according to [9]. …”