Search

The novel and one-pot synthesis of 5-hydroxyl hydantoins from Ugi five-component condensation procedures is reported. The transformation was promoted via a microwave heating method and provided 5-hydroxyl hydantoins in workable yields, representing a direct approach to this synthetically challenging and biologically interesting pharmacophore.

A novel method for the direct synthesis of 5-arylidene-2-thiohydantoins from thioureas and aromatic aldehydes in the presence of base in ethanol was developed. Application of this efficient method allowed preparing thiohydantoins, which are difficult to synthesis by traditional methods.

The reaction of α-keto acids with carbodiimides provides O-acyl urea intermediates which undergo visible light induced rearrangement to form unexpected hydantoine derivatives.

The reaction of 4-phenylurazole and fumaric esters in the presence of tetrabutylammonium bromide results in the formation of 5-alkylidene derivatives of hydantoin under solvent-free conditions.

A mild method to convert optically pure amino acid thiourea and urea derivatives to thiohydantoins and hydantoins, respectively, is described. It provides an efficient way to realize enantioselective synthesis of thiohydantoins and hydantoins with good to high isolated yields and enantiomeric purities. We found that the enantiomeric purities were highly dependent on the reaction conditions including bases, solvents, and temperature.

Amino-acid-derived ureas (I) and (VI) are modified with pseudoephedrine as a chiral auxiliary to yield compounds (III) and (VII), which undergo LDA-promoted rearrangement including an aryl shift to yield hydantoins (IV) and (VIII).

Simple hydrazides and hydrazones are used as precursors of the required N-substituted isocyanates.

The triethylamine mediated reaction of α-bromoacetamides with N-sulfonyl isocyanates gives urea salts which undergo intramolecular cyclization to N-sulfonyl hydantoins under thermal conditions.

The use of cyclododecanone-protected thiosemicarbazide (I) for the synthesis of highly functionalized 3-amino-2-thiohydantoins (IV) is demonstrated.

Base-promoted facile synthesis of thiohydantoins has been described via intramolecular amidolysis of C-3 functionalized 2-azetidinones. This approach provides a convenient and rapid access to diversely functionalized thiohydantoins compared to conventional protocols.

New 5-substituted hydantoins (III) and (IV) and symmetrical twin-drug type hydantoin derivatives (VII) are synthesized.

An efficient one-pot, two-step sequence starting from azide derivatives is described: first, formation of iminophosphoranes (Staudinger reaction) and condensation with carbon disulfide to form nonisolated isothiocyanates; then, condensation with α-amino esters to provide new N-3-substituted 2-thiohydantoins.

A rapid and highly efficient synthesis of 5-substituted hydantoin derivatives is achieved by three-component condensation of carbonyl compounds with KCN and (NH4)2CO3 under ultrasound irradiation conditions.

The treatment of 1-cyanoethyl ureas (I) with sBuLi leads to iminohydantoins (II) as a result of an aryl migration and a cyclization.

Unsaturated ketoacids (I) are readily converted into functionalized hydantoins (III) in a low melting mixture of N,N′-dimethylurea and L-tartaric acid.

Several new bis-hydantoins are successfully synthesized via a modified Bucherer—Berg reaction.

Steric factors as well as the nucleophilic character of the amino moiety in the isocyanate play an important role in the outcome of the reaction with α-azide esters.

The reaction of aminonitriles (I) with isocyanates leads to desired ureas (III) in high isolated yields, whilst crude ureas derived from aminonitriles (IV) are prone to a cyclization during chromatographic purification affording hydantoins (V).

The title reaction proceeds via a trienamine mechanism and gives rise to the formation of spirocyclic compounds (III) and (V) in good yields and excellent stereoselectivities.

The development of new practical and green methods for the synthesis of small heterocycles is an attractive area of research due to the well-known potential of heterocyclic small molecule scaffolds in the drug discovery process. Herein we report a one-pot, three-component sequential procedure for the synthesis of diversely 1,3,5- and 1,3,5,5-substituted hydantoins, in high yields and very mild conditions, using readily accessible starting materials such as azides, iso(thio)cyanates and substituted α-halo-acetic carboxylic acids. This methodology is especially convenient for the synthesis of spiro-hydantoins, which are particularly interesting bioactive compounds in medicinal chemistry.

Treatment of aminoester substrates with aqueous NH3 at room temperature renders possible the access to a library of title compounds whose structure includes an amide and a guanidine functionality.

Selective N- and C-alkenylation of hydantoin followed by metathesis allows an easy and efficient access to various spirocyclic and fused bicyclic hydantion derivatives.

Considering the importance of hydantoin derivatives in treatment of status epilepticus, four 5-phenylhydantoins, whose lipophilicities were estimated to be similar to that of phenytoin, were synthesized. Evaluation of their anticonvulsant activities was performed on rats by subcutaneous pentylenetetrazol seizure test and intravenous pentylenetetrazol threshold test, and spontaneous locomotor activity test was used to assess possible sedative effects. X-ray analysis of three compounds suggested that certain analogies might be drawn between interactions in crystal packing and biological interactions responsible for their anticonvulsant activity. It was found that 5-ethyl-5-phenyl-3-propylhydantoin exhibits the most favorable pharmacological properties among the synthesized compounds, i.e., anticonvulsant activity comparable to phenytoin with lower liability for induction of sedation in rats.

via three-component, one-pot condensation of various isocyanides, isoquinoline, and thiohydantoins

Trisubstituted hydantoins (VI) are obtained in low yields from malonic acid derivative (IV) via activation with oxalyl dichloride and subsequent treatment with aromatic amines.

1,2-Epoxyoctafluorobutane reacted with urea in DMSO and aqueous DMSO, dioxane, and acetonitrile to give 40–42% of 5-hydroxy-5-pentafluoroethylimidazolidine-2,4-dione. 5-Hydroxy-5-tridecafluorohexylimidazolidine-2,4-dione was formed in 54% yield in analogous reaction of 1,2-epoxytridecafluorooctane with urea in aqueous DMSO. The reactions of 1,2-epoxyoctafluorobutane and 1,2-epoxytridecafluorooctane with urea in anhydrous dioxane and acetonitrile unexpectedly afforded heterocyclization products, 2-amino-5-fluoro-5-perfluoroalkyloxazol-4(5H)-ones (yield 11–82%). Fluorine-containing allantoin, 5-tridecafluorohexyl-5-ureidoimidazolidine-2,4-dione (yield 19%), and N-(1-hydroxy-2,2,3,3,4,4,5,5,6,6,7,7,7-tridecafluoroheptyl)-urea (yield 46%) were synthesized for the first time by reaction of 1,2-epoxytridecafluoroctane with urea in DMSO and aqueous DMSO.

The method allows a ready preparation of the pharmaceutically relevant heterocycles in good to excellent yields and high purity.

The chemistry of thiohydantoins has gained increased interest in both synthetic organic chemistry and biological fields. Many of these compounds exhibit considerable biological activities in various fields. This review covers the literature regarding the synthesis, reactions, and applications of such compounds.

4,5-Dihydroxy-1,3-dialkyl-4,5-diarylimidazolidine-2-thione are obtained in good yields from the 1:1 addition reaction between benzil derivatives and thiourea derivatives in the solid phase. These compounds undergo smooth rearrangement followed by a hydrogen shift to produce thiohydantoins in excellent yields.

The method is highly efficient for the preparation of 2-thiohydantoins and 2-iminothiazolidinones.

The [3 + 2] cycloaddition of (1,3) amphoteric aziridine aldehydes [released from dimers (I) and (VII)] with isocyanates provides access towards reduced aziridino-fused hydantoins (III) and (IX), resp., with three contiguous stereocenters.

Title compounds are produced from 5-carboxymethylene hydantoins generated by reaction of carbodiimides and acetylenedicarboxylic acid monoesters under mild conditions.

A novel synthesis of hydantoins with a variety of substituents is achieved by thermal cyclocondensation.

Thiazolidinones (IV) and (VII), thiazolidinediones (V), and imidazolidinediones (IX) are synthesized in one step by three-component condensation of aromatic aldehydes or amines with chloroacetic acid and thiourea or urea.

A novel synthetic route is developed which can be applied to a wide range of aromatic isocyanates and various acrylates.

The adducts produced in the reaction between trialkyl phosphites and acetylenic esters were trapped by thiohydantoins to produce highly functionalized 5-oxo-2-thioxoimidazolidines and 4,5-dihydro-2-(methylthio)-5-oxoimidazoles in good yields.

A new approach to the synthesis of 3,5-disubstituted thiohydantoins, which uses a functionalized ionic liquid as soluble support, is described.

The compounds (I) are screened for their anticonvulsant activity using intraperitoneal maximal electroshock (MES) and subcutaneous pentylenetetrazole seizures tests on mice.

P4S10-induced reaction of urea derivatives with aldehydes results in formation of the title compounds in a short time.

1,2-Diaza-1,3-dienes are used for the construction of diversified trisubstituted 1,3,5-hydantoins with a controlled regioselectivity.

A series of acetylene-based hydantoin inhibitors of the TACE enzyme is obtained in a convergent manner.

Twenty new title derivatives are synthesized via conversion of monoester (I) to the corresponding acyl azide, Curtius reaction, followed by reaction of the formed isocyanate with arylacethydrazides (II) to afford the semicarbazides (III), which cyclize upon treatment with a base to provide the spirohydantoins (IV) as racemic mixtures.

Hydantoins, thiohydantoins, and glycocyamidines have been prepared in moderate to excellent yields at room temperature under solvent-free conditions. 3N-amino and carboamide derivatives of hydantoin (7–8) were prepared in single step by condensing benzil with semicarbazide and biuret respectively.