Hydantoin ring

Mass spectral fragmentation patterns of alkyl and phenyl hydantoins have been investigated by means of labeling techniques (28—30), and similar studies have also been carried out for thiohydantoins (31,32). In all cases, breakdown of the hydantoin ring occurs by a-ftssion at C-4 with concomitant loss of carbon monoxide and an isocyanate molecule. In the case of aryl derivatives, the ease of formation of Ar—NCO is related to the electronic properties of the aryl ring substituents (33). Mass spectrometry has been used for identification of the phenylthiohydantoin derivatives formed from amino acids during peptide sequence determination by the Edman method (34). 

Der Uracil-Ring wird in 1,3,10-Trimethyl-flavinium-perchlorat durch Reduktion mit Natriumboranat in Wasser zu dem Hydantoin-Ring umgelagert3. 

Sequential pyrrolidine and hydantoin ring-forming reactions via intramolecular [2+3] cycloaddition have been applied to the stereoselective solid-phase synthesis of conformationally constrained tricyclic triazacyclopenta [C]pentalene scaffold 43 < 1999JOC8342>. These novel compounds 43 share the structural complexity characteristic of certain alkaloid natural products, angular triquinanes. The retrosynthetic analysis is shown in Scheme 87. 

Note that the hydantoin ring can also be cleaved after an initial oxidative step [146]. Indeed, the major metabolic route of 1-methylhydantoin (4.234,... 

Belafdal, 0., M. Bergon, and J.P. Calmon. Mechanism of hydantoin ring opening in iprodione in aqueous media, Pestic. Sci.,... 

Finally, there are numerous purely synthetic heterocycles. These are discussed in many places throughout this book. The hydantoin ring of phenytoin and the barbiturate ring of phenobarbital are good examples of these. There are a variety of drugs containing pyrrolidine, furan, pyrazole, pyridine, and indole rings. 

S. Mio, Y. Kumagawa, and S. Sugai, Synthetic studies on (+)-hydantocidin (3) A new synthetic method for construction of the spiro-hydantoin ring at the anomeric position of D-ribofuranose, Tetrahedron 47 2133 (1991). 

Scheme 16 shows parallel syntheses of cyclic and acyclic amide compounds. Fluorous benzaldehydes were first subjected to reductive amination reactions. The resulting amines were then reacted with isocyanates to form substituted hydantoin rings 14 or with benzoyl chlorides to form amides 15. Purified F-sulfonates were used for palladium-catalyzed cross-coupling reactions to form corresponding biaryl 16 [31] and arylsulfide 17 [32] products, respectively. 

The cyclative cleavage approach can be applied building the hydantoin ring and simultaneously releasing in solution the pure tricycle at the end of the SPS. 

One of the most widely used enzymatic methods for D-amino acid production is the hydantoinase process [4]. The great advantage of this process is that, potentially, any optically pure D-amino acid can be obtained using the corresponding substrate from a wide spectrum of D,L-5-monosubstituted hydantoins, which are readily accessible by chemical synthesis [5]. In this cascade of reachons the chemically synthesized D,L-5-monosubstituted hydantoin ring is first hydrolyzed by a stereoselective hydantoinase enzyme (D-hydantoinase). Further hydrolysis of the resulting N-carbamoyl D-amino acid to the free D-amino acid is catalyzed... 

Monosubshtuted hydantoins are a-amino acids cyclically protected at both the carboxyl- and the a-amino group. They can be easily prepared from an aldehyde and isocyanate or by the Bucherer-Bergs synthesis and similar methods. Indeed, the hydantoin synthesis is also a prachcal method for the preparahon of the racemic amino acid. Enzymes belonging to the dihydro-pyrimidinase family hydrolyze hydantoins to the carbamoyl amino acid. The latter can be hydrolyzed in turn to the amino acid by a second enzyme, a carbamoylase. Both enzymes can discriminate between enantiomers and, if their action is cooperative, either the L- or the D-amino acid can be obtained (Scheme 13.10) [36]. What makes the system of special interest is that the proton in the 5-position of the hydantoin ring (it will become the a-hydrogen in the a-amino acid) is considerably more acidic than conventional protons in amino acid esters or amides and much more acidic than the amino acid itself. Thus, the hydantoin can be often racemized in situ at slightly basic pH where the enzymes are stiU stable and active. If these condihons are met. 

The compounds have a trophism toward antigencralized loDic-donic rather than antiabsence activity. This is not an inuinsic activity of the hydantoin ring. system. All of the cGnically useful antigeneralized tonic-clonic compounds liable 14-4) possess an aryl suKstituent on the S position, conesponding to the branched atom of the general pharma-to )hore. Hydantoins with lower alkyl sub.stituents report- ily have antiabsence activity. 

In addition to an extensive summary provided previously on this moiety (8), Brouillette et al. (209) employed comparative molecular field analysis (CoMFA), a three-dimensional structure-activity technique, to provide a new potential anticonvulsant, 2-hydroxy-2-phe-nylnonanamide (40), whose Na-i-channel inhibition (IC50 = 9 fiM) compared favorably to 40 yM for phenytoin (1). This study suggested that the hydantoin ring system is not necessary in Na+channel binding. Research on water-soluble prodrugs of phenytoin has continued since the work by Stella, which led to the synthesis of fosphenytoin (Id) (8,209-215). A... 

Hydroxylation of one aromatic ring Conjugation of phenolic products with glucuronic acid or sulfate Hydrolytic scission of the hydantoin ring at the bond between carbons-3 and -4 to give 5,5-diphenylhydantoic acid... 

Epoxy resins based on glycidylation of bisphenols, cresol and phenol novolacs, polycarboxylic acids, polyols, amines, and aminophenols have been long known. Epoxidized linear and cyclic olefins have also been used as specialty epoxy resins. More recently, glycidylated heterocycles have been introduced, initially as specialty resins promising improved resistance to weathering. One heterocycle in particular, the hydantoin ring, has become of particular interest as an epoxy substrate (J ). 

Table I lists typical properties of a baker s dozen of these resins, produced by typical direct preparations, without extensive purification. Overall, the viscosities of these resins were quite low, particularly by comparison to the well known general purpose epoxy resins based on the diglycidyl ether of bisphenol A (DGEBA). The more shielded higher alkylsubstituted hydantoin rings favored lower viscosities. Some anomalies in these viscosities presumably reflected either a tendency of certain resins to crystallize, or the presence of some species of higher molecular weight, formed by reaction of the glycidyl group with a second hydantoin ring.

Note that the highest IDT was obtained with the cyclopenta-methylenehydantoin resin derived from cyclohexanone. It is tempting to speculate that this inflexible alkylene moiety was ineffective in shielding the hydantoin ring, but subsequent comparison of the hydrophobic-hydrophilic balance of amine-cured resins appeared to rule out this explanation probably the stiff spiro structure contributed to the high Tg, just as it contributed to the high melting point of the resin itself (lie). 

Since the hydrophobic-hydrophilic balance of amine-cured resins was so sensitive to alkyl substituents on the hydantoin ring, it is not surprising that it was also sensitive to the hydrocarbon moieties of the amine curatives. The range of behavior depended on the resin substituents. For example, the already hydrophobic ethyl amyl substituted Resin Ilk showed moderate but significant increases in hydrophobicity when cured with cycloaliphatic, highly branched aliphatic, or formulated aromatic amines. See Table V. 

As has been pointed out by Habermeier ( ), the non-equivalence of the 1- and 3- positions of the hydantoin ring readily permitted monosubstitution. Subsequent glycidylation provided the diepoxide JV. 

The hydrophobic shielding of the hydantoin ring by alkyl substituents affected all the solvent-solute interactions of cured resins. Two of the resins and the DMH-based resin mixture were cured with a commercially available aromatic amine mixture derived from aniline-formaldehyde condensation, identified in Table VII. Weight gain and solvent plasticization were followed in a number of solvents and aqueous media. Some of the exposure was at 60 C as well as at room temperature. 

Higher alkyl substituents shielded the hydantoin rings and gave lower glass temperatures. The same shielding effect was observed in the reduced hydrophilicity of higher alkyl-substituted hydantoin epoxy resins cured with triethylenetetramine. 

Steric factors - branching at or close to the hydantoin ring - raised the glass transition temperature while maintaining the shielding effect. Amines of different structures were used as room temperature curatives with a few representative resins, to observe the effect on hydrophilic-hydrophobic balance. Solvent effects were examined on aromatic amine-cured resins the most hydrophilic cured system proved to have the broadest range of lyophobicity. 

A different means of opening the hydantoin ring is presented by the molecule F (JCj = 0.016 mM) [105] (for molecular structure see Fig. 14). Though there has not yet been a synthetic counterpart of F in the N-acyl-glycosylamie series, a comparison with molecule A (from Fig. 13 (Ki -... 

Dimethylol-5,5-dimethylhydantoin (DMDMH) and 3-methylol-2,2,5,5-tetramethylimidazolidinone (MTMIO) were mixed in different ratios in textile finishing systems for cellulose fabrics. The mixtures of 2,2,5,5-tetrame thylimidazolidinone (TMIO) and hydantoin rings on the grafted cellulose provided a combination of imide, amide and amine halamine stmctuies in different ratios after chlorination. These combinations improved both the power and stability of the biocidal properties of the treated cotton and polyester/cotton blend fabrics studied. Repeated laundering tests showed that even a small amount of added amine halamines could substantially reduce the loss of active chlorine and increase the power of the biocidal functions on the fabrics. The results were discussed. 12 refs. 

In another example, Weinstock and Dunoff53 selectively monochloro-sulfonated 5-(3-chlorobenzyl)-5-methylhydantoin (70) followed by treatment in situ with ammonia, which gave 8-chloro-10a-methyl-10,10a-dihydro-lH-imidazo[3,4-b][l,2]benzothiazine-l,3(2ff)-dione 5,5-dioxide (71) in high yield. Basic hydrolysis of the hydantoin ring in 71 followed by loss of cyanate anion afforded 6-chloro-3-methyl-3,4-dihydro-27/-l,2-benzothiazine-3-car-boxylic acid 1,1-dioxide (72) (Eq. 16). 

Mechanistic and preparative aspects of the formation of the hydantoin ring show considerable development since Ware s review. Some synthetic routes previously reviewed continue to be of prime importance, especially the Bucherer-Bergs method.4... 

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