Also Thiohydantoin

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). 

Thiohydantoin 9 was obtained from the treatment of carbonyl 1 with carbon disulfide and ammonium cyanide in aqueous methanol. The transformation could also be carried out step-wise, that is, treatment of 1 with ammonium cyanide to form aminonitrile 10 followed by reaction with carbon disulfide to produce thiohydantoin 9. Alternatively, 5,5-disubstituted 4-thiohydantoins could be prepared by the reaction of ketones with ammonium monothiocarbamate and sodium cyanide. ... 

The cyclization reaction can also be carried out with oligopeptides in the solid phase. Thiohydantoins are obtained analogously by conversion of oligopeptides with ImCSIm [55]... 

In analogy to the thiohydantoin synthesis, the PEG-bound diamines have also been treated with various alkyl and aryl isothiocyanates and, after applying traceless cyclative cleavage, the desired thioxotetrahydropyrimidinones were obtained in excellent yields. In contrast to the thiohydantoin synthesis, purification of the products was more complicated if the excess of isothiocyanate amounted to more than 2.2 equivalents [85],... 

Imino derivatives 61 were obtained directly from 3-formylchromone [36] 59 and creatinine [37] 60, with DM SO as solvent and boric acid as catalyst, and with micro-wave irradiation and classical heating (Tab. 8.4). The authors have also investigated the preparation of the 2-thioxo-5-imidazolidin-4-ones 63 from thiohydantoin 62 in... 

A)-5,5-Dimethyl-thiazoline-4-carboxylic acid reacted efficiently with alkyl and aryl isothiocyanates to give bicyclic thiohydantoins 418. A similar diastereo- and regioselective cyclization of chiral l,3-thiazolidine-2,4-dicarboxylic acids was also reported (Equation 191) <1996JHC1099, 1998HCA744>. 

Substituted hydrazines have been extensively investigated as nucleating agents. In many compounds the hydrazine is attached to a heterocyclic nucleus and may also be blocked with an acyl substituent. Rhodanines (23), 2-thiohydantoins (24) and 2-thiooxazolidin-4-ones (25) have all been employed as carriers of the active hydrazine substituent (81BRP1583471). 

Eyem and Sjoquist have suggested the use of short (4.5 m) glass capillary columns and reported the separation of 19 of 20 silylated methyl thiohydantoin (MTH) derivatives of the amino acids (62). The histidine derivative can be separated on the same column by starting at a higher temperature. Separation of some of the silylated PTH derivatives was also demonstrated, though not in as much detail as the MTH derivatives. 

This procedure is reputedly more suitable than silylation with BSTFA under the same conditions or with BSA—pyridine at room temperature. Other workers [272] accomplished the silylation of thiohydantoins with the aid of BSTFA-pyridine (1 1) at 50°C for 10 min. Gly and Thr, however, provide two products which are not stable. A good separation of silylated 2-thiohydantoins was obtained on a 4 ft. X 2 mm I.D. column packed with 10% of SP-400 on Chromosorb W HP with temperature programming (145— 260°C). The analysis was also performed on 1% of Dexsil 300 GC and 5% of OV-17 with identification by means of mass spectrometry. A number of mass spectra of thiodantoins and their TMS derivatives have been published [271]. 

Thiohydantoin analogues (IV) were also prepared in a previous investigation by the author (3) as illustrated in Eq. 1 ... 

A fluorous catch and release method was used by Zhang in the synthesis of di-substituted pyrimidines.A fluorous route to hydantoins and thiohydantoins was also reported by the same group. 

We also describe the development of chemistry based on the DPP-ITC/pyridine reaction which permits the efficient derivatization and hydrolysis of peptidyl C-terminal proline to a thiohydantoin and discuss the integration of this chemistry into an automated method for the C-terminal sequence analysis of polypeptides containing C-terminal proline. 

In the experiments of Haurowitz et al. (1957) proteins and peptides were in an acetic anhydride/acetic acid medium during thiohydantoin formation. Their results with a-peptides and poly-a-glutamic acid indicated that very little a —> 7 interconversion took place, but they accepted that it could occur if glutamic acid residues were adjacent to certain other amino acid residues. These authors also suggested that possible y a conversion... 

Treatment of a-azido esters 1290 with triphenylphosphine gives -phosphazides 1291, which subsequently react with isothiocyanates to afford thiohydantoins 1292 after aqueous work-up. The cyclization conditions can also be adapted to hydantoin synthesis when isocyanates are used (Scheme 328) <2004TL1655>. 

While the procedure shown in Scheme 4 [26], Hke the original method, introduces much of the diversity (i. e., up to three variable positions) off the solid phase, thereby limiting the combinatorial potential available for split-and-mix protocols, another recently described scheme [30] builds up the diversity in a stepwise manner on the solid phase, which simpHfies the logistics for automated library production. Intermediates may also be used to access thiohydantoins (see Scheme 6). 

N3-Substituted hydantoins and 2-thiohydantoins (9) are prepared by acid-catalyzed cyclization of the substituted ureido or thioureido acids (8) obtained from a reaction of a-amino acids with alkyl or aryl isocyanates and isothiocyanates.1 3,12 This method has been applied to prepare 2-selenohy-dantoins,13 and also in the stereospecific synthesis of (S)-(+)-l,5-cyclotrimethylene-3-phenyl-2-thiohydantoin.14... 

Acid treatment of the substituted thioureas resulting from the treatment of esters, amides, or peptides of a-amino acids (10) with isothiocyanates (usually phenyl isothiocyanate) also affords 2-thiohydantoins (11). These reactions furnish the basis of the Edman s method for the stepwise degradation of peptides.3... 

Substitution of (NH4)2C03 by H2NCOSNH4 (prepared from COS and alcoholic NH3) in the presence of NaCN gives 4-thiohydantoins. Preformed a-amino nitriles also give 4-thiohydantoins, employing carbonyl sulfide.45... 

Nucleophilic carbenoids (also called ylides by some authors) react with heterocumulenes, such as isocyanates and isothiocyanates, to yield hy-dantoins, 2-thiohydantoins, and 2,4-dithiohydantoins via dipolar intermediates. Thus dimethoxycarbene adds to aryl isocyanates and isothiocyanates to form 5,5-dimethoxyhydantoins and dithiohydantoins.107 Thiazolium ylides (61) (resulting from thiazolium salts and NEt3 in DMF) give dipolar 1 1 adducts (62) or l 2-cycloadducts (63) with isocyanates or isothiocyanates.108-110 Other substrates are imidazolidine111 or 2-imidazoline derivatives.112... 

Treatment of the 5-arylidene derivatives of l,3-diphenyl-2-thiohydantoin with malononitrile affords tetrahydropyrano(2,3-d)imidazoles (110), while 3-phenyl- or unsubstituted 2-thiohydantoins originate pyrrolo(l,2-c)imidazoles (111). These products are also obtained in a Michael-type reaction of 2-thiohydantoins with activated nitriles.282... 

Condensation products of aromatic aldehydes and 4-thiohydantoins react with Grignard reagents to give the colorless products 112. Compounds 113 and 114 are formed by alkylation and diazomethane addition reactions.285 These condensation products also react as dienes with acrylonitrile, ethyl acrylate, and other dienophiles giving adducts 115.286... 

Amino acids have also been obtained by acid hydrolysis of hydantoins and 2-thiohydantoins under relatively drastic conditions.1,3 4-Thiohydantoin is hydrolyzed with hot concentrated hydrochloric acid to hydantoin, and boiling 20% aqueous chloroacetic acid completely removes sulfur from 2,4-dithiohy-dantoin to form hydantoin derivatives. (Scheme 8). These reactions reflect the intrinsic stability of the hydantoin ring. 

Hydantoins, thiohydantoins, and their substituted products are particularly useful as catalysts and as stabilizer agents in polymer chemistry and also in the preparation of epoxy resins.356,357 Thus hydantoins 148 are readily hardened, giving suitable polymers for the preparation of molding and lacquers. 

Thiohydantoins have been similarly prepared following the first route but using isothiocyanates [98]. Sulfahydantoins have been also prepared using sulfamoyl chloride [99]. The phoxime resin (phosgenated oxime resin, 19, see Section 15.2.1.1.1) has been used to synthesize 3-aminohydantoins from the oxime carbamates [100]. 

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