Base catalyzed cyclization of substituted esters of hydantoic and thiohydantoic acids

Abstract

Base catalyzed cyclization rates have been measured of 22 derivatives of hydantoic and thiohydantoic acid esters in water and methanol. The cyclization of methyl and ethyl esters of hydantoic and 5-methylhydantoic acids is accompanied by hydrolysis of the ester group, whereas with the other derivatives the hydrolysis does not take place. Hydrolysis of the cyclization products (hydantoin and thiohydantoin derivatives) is not significant under the kinetic conditions. The cyclization of methyl ester of 5-phenylhydantoic acid in methanol is reversible; the equilibrium mixture contains 30% of the starting ester. In all the cases the cyclization is subject to specific base catalysis; exceptions are esters of 5-phenylthiohydantoic and 5-phenyl-2-methylthiohydantoic acids whose cyclizations are subject to general base catalysis. Substituents always accelerate the cyclization. The 3-substituents have the greatest effects, the cyclization rate being considerably increased with bulk of the substituents; similarly large effect of 5-phenyl group consists mainly in its polar effects on the pre-equilibrium. The cyclization are slower in methanol at the same concentration of the lyate ion: the greatest difference (up to 3 orders of magnitude) is observed with the 5-phenyl derivatives.

Mechanochemical Preparation of Hydantoins from Amino Esters: Application to the Synthesis of the Antiepileptic Drug Phenytoin

“…The cyclization reaction leading to the hydantoin 2 occurred in the second step by adding K 2 CO 3 (1 equiv) ( Table 2, entry 6), which was selected instead of KOH (entry 5), because of less risk of epimerization or ester hydrolysis. 25 The synthesis of phenylalanyl urea 1 could be achieved with comparable results in terms of kinetics and yields, in both aqueous solution or planetary-mill conditions. In the case of hydantoin, the reaction in water was slower than the mechanochemical one and a very large excess of reactants needed to be used, which is not desirable from the environmental point of view.…”

“…The corresponding ureido derivative was cyclized under acidic conditions, although the base catalyzed-cyclization has also been reported. 25 This reaction has been notably used for the preparation of spirohydantoins. 26 Trimethylsilyl-isocyanate (TMS-NCO) and chlorosulfonyl-isocyanate are alternatives to cyanate salts for the preparation of 1,3-unsubstituted hydantoins.…”

Kinetics and mechanism of ring transformation of S-[1-(4-methoxyphenyl)pyrrolidin-2-on-3-yl]isothiuronium bromide to 2-methylimino-5-[2-(4-methoxyphenylamino)ethyl]thiazolidin-4-one

“…The general-acid-catalysed transformation of In into products (Scheme 3) can be explained similarly to the acid catalysis in the cyclisation of esters of hydantoic acid. 12 In our case, however, proton transfer to the more basic atom of nitrogen, which is adjacent the benzene ring, as shown in Scheme 3, will be encountered. From Table 1 it is obvious that the general-acid-catalysed transformation reaction proceeds about one order of magnitude more slowly (k BH ) than the base-catalysed transformation reaction (k B ) (Scheme 4).…”

On the disappearance of the gem-dimethyl effect: the base-catalysed cyclization of ethyl hydantoates †

“…The mechanism of the base-catalysed ring closure of hydantoic acid esters was discussed by Sterba and co-workers in their comprehensive kinetic study. 14 These authors assumed the formation of the C-N bond to be rate determining since the less basic ethoxy group should leave more readily from the tetrahedral intermediate than ureide nitrogen. They do not report general base catalysis, in contrast to the cyclization of thioureidoesters.…”