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Hydantoins and their sulfur containing analogues, thiohydantoins, are an important and interesting moiety. They represent a big group of structurally diverse compounds with intriguing physical, chemical and biological properties, which enabled them to be used in therapy, medicine in general, material science and industry. With the goal of broadening the set of potentially applicable hydantoin derivatives, we have synthesized a series of 2-thiohydantoins from vanillin and its derivatives, which themselves posses interesting biological properties. All compounds were fully characterized by NMR and IR spectroscopy. The compounds will be subjected to intensive biological screening to determine their biological properties and application opportunities.

We report an efficient synthetic strategy to diverse hydantoins and thiohydantoins involving a three-component reaction with the aid of deep eutectic solvent. Here, N,N'-dimethyl urea and N,N'-dimethyl thiourea play a dual role as reactant and reaction medium along with l-(+)-tartaric acid. The three-component reaction provides an easy access to 5-amino-1,3-dialkyl-substituted hydantoins and thiohydantoins in good yields.

Generally, synthesis of hydantoin derivatives involve use of carbonyl compounds which in turn require multistep synthesis. Here, we report a new approach to assemble spirohydantoins via [2+2+2] cyclotrimerization reaction using commercially available, inexpensive hydantoin as a starting material. (C) 2018 Elsevier Ltd. All rights reserved.

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.

A reinvestigation of the Biltz synthesis of phenytoin was undertaken to selectively produce the hydantoin derivative instead of a mixture of the hydantoin and the glycoluryl derivative. A solution of this problem was found in carrying out the reaction in a two-phase system (n-butanol:water) and in the presence of a phase-transfer catalyst (poly(ethyleneglycol)600). In these conditions, a 87–93 yield of phenytoin can be obtained. Extension of this approach to the synthesis of other hydantoin derivatives was also found superior to one-phase conditions.

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

We describe here a multicomponent reaction that converts aryl/heteroaryl aldehydes efficiently into arylmethylene 2-thiohydantoins. 3-Formylindole behaves exceptionally giving a gem-diacetylthio derivative. A mechanistic study of the behaviour of 3-formylindole, which provides a new class of indole derivative, is described.

N-(1,5-Dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl)cyanothioformamide was synthesized from the corresponding 4-amino-pyrazole. Various cyanothioformamides were reacted with different arylidenes of cyanothioacetamide to produce either 4-imino-5-thioxo-3-(pyrroline & pyrrolidine)carbonitrile or pyrrolo[3,2-d]thiazole. Interaction of thiohydantoin with the arylidenes of either malononitrile or cyanothioacetamide furnished the same 5-aminothiopyrano[2,3-d]-imidazole-6-carbonitriles. Also, thiohydantoin reacted with the anilide of chloroacetic acid and with anthranilic acid to produce thieno[2,3-d]-imidazole-2-one and imidazo[4,5-b]quinoline-2,9-dione, respectively.

A facile access to 1,3,5-trisubstituted hydantoins is achieved by combining an Ugi four-component condensation with a base-induced cyclization. This two-step sequence, which differs from any other method; is experimentally simple and allows a wide variety in the substitution pattern. In this synthesis the acid component, namely trichloroacetic acid, acts as a carbonic acid equivalent.

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.

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.

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.

A novel, three-component process for the preparation of a small library of unprecedented nonracemic N-carbamoyl hydantoins under very mild conditions, as well as the hypothetic mechanism, are presented.

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

The target compounds are prepared from 1,3-dicarbonyl compounds, ureas and methyl ketones or aromatic terminal alkenes.

Three series of cyclic arylsulfonylureas are synthesized comprising the sulfonylurea pharmacophores that are structurally related to sulofenur and its cyclic form.

The synthesis of new N3-arylciclohexanespiroimidazolidine-2,4-diones, N3-arylciclohexanespiroimidazolidine-2-tio-4-ones and the 4-hydroxy derivatives is described and their structures discussed on the basis of I.R. and 1H-N.R.M. data. The anthelmintic activity of these compounds was tested.

The reaction of thiohydantoins with 1-(bromo-acetyl)benzenes afforded the corresponding hydantoin derivatives and 1-(mercaptoacetyl)benzenes instead of the expected oxoimidazothiazoles.

Design and synthesis of the title aminohydantoins as highly potent BACE1 inhibitors are described.

The 5-acylamino-3-acetylhydantoin derivatives 8 were designed as potential antibiotics mimicking lactivicin 1. The racemic compounds 19a-c, prepared in six steps from 5-oxohydantoin, were inactive onto bacterial tests.

Solid phase synthesis of hydantoin 4-imides via the ‘Ugi’ 4-component condensation reaction is reported. This process is then shown to proceed well in a combinatorial fashion, by immobilization of the isocyanide component on Wang resin. The desired product is then released from the support upon treatment with 20% trifluoroacetic acid-CH 2 Cl 2 .

A rapid, highly efficient and mild green synthesis of 5,5-diphenylhydantoin derivatives was achieved from the reaction of symmetrical or unsymmetrical benzil derivatives with urea in the presence of ethanolic KOH under ultrasound irradiation. This simple method affords 5,5-diphenylhydantoin derivatives at room temperature in short reaction time with high yield and purity. This study aimed to overcome the limitations and drawbacks of the reported methods such as tedious work-up, low yield and long reaction time.

An efficient procedure for the preparation of 5-dialkylaminomethylhydantoins 3, which are easily obtained from cyclization of the corresponding urea derivatives 2 starting with beta-aminoalanines 1, is described. Methylenehydantoin and the corresponding 2-thio analogue (4a, 4b) were obtained from hydantoins 3a and 3b, respectively. Some new chemical properties of these hydantoin derivatives are reported.

1,5-Disubstituted hydantoins/thiohydantoins 3a-p have been synthesized in 8l-95% yield by a microwave-promoted solvent-free condensation of arylglyoxals 1 and phenylurea/thiourea 2 using PPE as a reaction mediator. This method can be extended towards the parallel synthesis of 3. The workup is simple and involves treatment with ice-cold water.

A mono-modal microwave oven was used to expedite the synthesis of small libraries of 3-substituted 1-methyl-2-thiohydantoins and 3-substituted 5-arylidene-1-methyl-2-thiohydantoins. In comparison with the traditional reflux methods, similar or higher yields were obtained.

An effective route to functionalized C5-unsaturated hydantoin derivatives is described. This involves the reaction of a urea derivative, derived from the addition of a primary amine to an arylsulfonyl isocyanate, and a dialkyl acetylenedicarboxylate in the presence of isoquinoline.

2-Methyleneaziridines can be transformed into 5,5′-disubstituted hydantoins in moderate to good yield (48–75%) via a ‘one-pot’ process that brings together up to six components in an orchestrated way.