Synthesis of 1,3-disubstituted hydantoins as possible anticonvulsants

Seven newer 1,3-disubstituted hydantoins ( 17–23 ) were synthesized from 4-alkoxyanilines. The anticonvulsant activity of these substituted hydantoins and their precursor carbamides ( 10–16 ) was reflected by their ability to provide 28–80% and 30–70% protection, respectively, against pentylenetetrazol-induced convulsions in mice. In general, substituted hydantoins possessed greater anticonvulsant activity than their corresponding precursor carbamides.     

One‐Pot Synthesis and Characterization of Some New Types of 5,5′‐Disubstituted Bis(imidazolidine‐2,4‐diones)

The synthesis and structural elucidation of some novel 5,5′‐disubstituted spiro and nonspiro‐bis‐hydantoins are reported. The Bucherer Burge's method has been modified for the preparation of some 5,5′‐substituted bis(imidazolidine‐2,4‐dione) derivatives starting with diketones ( 1–5 ) and dialdehydes ( 6 , 7 ). In some cases, diastereoisomeric mixtures of compounds were obtained. The resulting bis‐hydantoins ( 8–11 , 13 , 14 ) have not to our knowledge been previously reported in the literature.     

Synthesis of Unsymmetrically Substituted Hexahydroimidazo [4,5-d] Imidazole-2,5-diones and Elucidation of Reaction Pathways

We have reported the synthesis and structural elucidation of a series of hexahydroimidazo [4,5-d] imidazole-2,5-diones and hydantoins from glyoxal and substituted ureas.^1,2 The general equation of this condensation reaction and a few representative compounds: those reported, current and hypothetical, are depicted in Scheme 1.     

A new approach for the synthesis of N-sulfonyl hydantoins

Two methods are described for the synthesis of a new series of hydantoins using the same reagents. The best process is based on the addition of N-aryloxy(alkoxy)sulfonyl isocyanates to an equimolar mixture of bromoamides and triethylamine dissolved in anhydrous acetone. This reaction is violent and provides the urea salts in situ which are transformed into the corresponding substituted hydantoins.     

One pot synthesis of maleimide and hydantoin by Fe(CO)5 catalyzed [2 + 2 + 1] co-cyclization of acetylene, isocyanate and CO

In the presence of a catalytic amount of Fe(CO)(5), terminal acetylenes, isocyanates and CO undergo [2 + 2 + 1] cyclization to form substituted maleimides and hydantoins; when internal alkynes are used, exclusive maleimide formation is observed. While the maleimides can be obtained as the major products, in up to 90% yield, when the reaction is carried out in CO atmosphere, in absence of CO, the hydantoins are formed in up to 87% yield. Formation of maleimides has been shown to occur via the formation of a ferrole intermediate, whereas the hydantoins are proposed to form through successive insertion of isocyanate into the iron-acetylide bond. All compounds were characterized by spectroscopic methods and molecular structures of some compounds were established by single crystal X-ray diffraction method.     

Highly efficient dialkylphosphate-mediated syntheses of hydantoins and a bicyclohydantoin under solvent-free conditions

Diversely substituted hydantoins have been synthesized by new strategy from cyanamide based precursor, that is, methyl N-cyano-N-alkyl/arylaminoacetate. Dialkylphosphates were employed as the mild reagent to hydrolyze and cyclize the substrate in one step to give quantitative yields of the desired products. Syntheses of multivalent hydantoins viz bis-hydantoin, bicyclohydantoin have potentially widened the scope and applicability of the present method. Solvent-free conditions and very easy work-up procedure make the reaction convenient and eco-friendly. Single crystal structures of some of the representative compounds are also reported.     

A facile protocol for the preparation of 5-alkylidene and 5-imino substituted hydantoins from N,N′-disubstituted parabanic acids

A convenient procedure for the preparation of various substituted (thio)hydantoins is described. The method is based on Wittig and aza-Wittig reactions of parabanic acids with phosphonium ylides. The reactions occurred both regio- and stereo-selectively.     

Intramolecular ring opening in 3-aminoalkyl hydantoins

Certain hydantoins substituted in the 3-position with aminoalkyl groups have been found to undergo hydrolytie ring-opening under very mild conditions. The effects of varying the side chain have been studied and an intramolecular mechanism is suggested.     

Multicomponent Approach to Hydantoins and Thiohydantoins Involving a Deep Eutectic Solvent

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.     

Synthesis of fused hydantoins by intramolecular amidoalkylation

Several 1-(2-arylcthyl)hydantoins 2 have been cyclized through their 5-bromo derivatives. The hydantoins 2a and 2b , unsubstituted in the 5-posilion, require stannic chloride catalysis of the cyclization to 3a and 3b , respectively. However, the 5-phenyl analog 2c (n = 2) cyclizes spontaneously and essentially quantitatively to 5 during bromination. This reaction is limited to the formation of a 6-membered ring.     

Scope and Limitations of Optical Pure Hydantoins as Chiral Auxiliaries in Asymmetric Mannich Reactions

The Mannich reaction of various 5-substituted and N-acyl substituted chiral hydantoins with a series of aldimines smoothly occurred with full stereochemical control. These Mannich adducts have been cleaved by alcoholysis to afford several synthetically useful chiral building blocks like β-amino esters and β-lactams in good yields and in enantiopure form.     

The structure of hydantoins in solution and in the solid state

The results of NMR spectroscopic and X-ray crystallographic studies are critically discussed with respect to the structure of hydantoins, their tautomerism, and their acidity. The imide NH proton of the preferred, nearly planar 2,4-imidazolidine-dione tautomer proved to be more acidic than the corresponding amide NH proton. Phenyl substituents at the ring nitrogen atoms and at C-5 are twisted from the plane of the hydantoin ring; in case ofortho substituents restricted rotation about the N-aryl bond was found and the barrier to rotation determined by dynamic NMR spectroscopy. For 5-benzyl substituents, afolded conformation of the two rings, due to intramolecular interactions, was found and for 5-exo-methylene substituted hydantoins the relevant E/Z isomerism at theexo-cyclic C, C double bond was studied. In addition, the¹H and¹³C chemical shifts of the hydantoins proved to excellently indicate the electronic distribution along the hydantoin ring moiety. Finally, the mass spectrometric fragmentation of the hydantoins is critically discussed.Dedicated to Prof. Rolf Borsdorf on the occasion of his 65th birthday.     

Synthesis of 3‐Ω‐aminohydantoins

Several 3‐Ω‐amino monosubstituted hydantoins have been obtained in the reaction of isocyanate of glycine ethyl ester with the appropriate aliphatic or aromatic diamine. It was found, that the 3‐(aminoaryl) monosubstituted hydantoins may be diazotized and their diazonium salts may be coupled and hydrolysed without changes in the hydantoin ring.     

Study of the rotational isomerism of the side chain of 3,5-disubstituted hydantoins

The rotational isomerism of 3-alkyl(aryl)-5-alkyl(aralkyl)hydantoins in which the methylene group of the side chain, together with the methylidyne group in the 5 position of the ring, forms the structure of a substituted ethane was investigated by means of PMR spectroscopy.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 3, pp. 337–338, March, 1987.     

Synthesis of axinohydantoins

A short synthesis of the hydantoin-containing marine sponge metabolites axinohydantoins is described. A key feature of the synthesis is a putative biomimetic, intramolecular cyclization of alpha-functionalized imidazolone 5, which affords the tricyclic pyrroloazepinone framework comprising 6. In addition, the conversion of imidazolones to alpha,beta-unsaturated hydantoins is outlined and represents a new approach to these heterocyclic systems.     

New,Diastereoselective One‐Pot Synthesis of Tetrasubstituted Hydantoins

An effective route to hydantoins is described, based on the 2 : 1 : 1 addition of arylsulfonyl isocyanates, dialkyl acetylenedicarboxylates, and dialkyl trialkylsilyl phosphites. The resulting tetrasubstituted, stable hydantoins 4 / 4′ (Table) were obtained in excellent yields, and their structures were corroborated spectroscopically (IR, ¹H‐, ¹³C‐, ³¹P‐NMR, EI‐MS) and by elemental analyses. A plausible mechanism for this type of cyclization is proposed (Scheme 2).     

Reaction of Aziridinones with Thiourea: A Novel Synthesis of Specifically Substituted Glycocyamidines and Hydantoins

The reaction of aziridinones with thiourea produces glycocyamidines bearing substituents at positions 1 and 5, which have been converted into hydantoins.     

Synthesis and nitrosation of 3- and 3,5-substituted hydantoins

The cyclization of N-alkylated (arylated) -ureidocarboxylic acids gives a series of 3-mono- and 3,5-disubstituted hydantoins, and nitrosation of the latter yields their nitroso derivatives. The rotational isomerism of 3-(-naphthyl)hydantoins has been studied by PMR spectroscopy.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 10, pp. 1404–1406, October,Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 10, pp. 1404–1406, October,     

A novel convenient approach to the synthesis of 2-substituted analogs of ornithine and homolysine

A novel efficient method for the synthesis of earlier unknown 2-substituted analogs of ornithine and homolysine from substituted 5-aminopentyl- and 3-midopropylhydantoins (prepared from cyclic imines and amino and amido ketones) was developed. Hydrolysis of hydantoins with a solution of Ba(OH)₂ gave the target amino acids in high yields.__________Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 12, pp. 2749–2753, December, 2004.     

Synthesis of hydantoins from enantiomerically pure alpha-amino amides without epimerization

A method for the preparation of enantiomerically pure hydantoins from optically pure alpha-amino amides utilizing triphosgene is described. We also propose that the racemization observed with 1,1'-carbonyldiimidazole (CDI) for this type of reaction is due to the imidazole carbamate intermediates.