2-Thiohydantoins

Benzylthio or 2-benzyloxy derivatives of A-2-thiazoline-5-one (224) are readily opened by amines to give the amide derivatives (225) (Scheme 115) (459. 471). Compound 225 can be cyclized thermally to the corresponding thiohydantoins (459). Similarly, treatment of 4-substituted-2-phenylthiazol-5(4H)-ones (226) with amino acids, peptides, or hydrazine affords the corresponding Nfcti-thiobenzamidoacetylated derivatives (227) (Scheme 116) (455). 

Merocyanines belong to the class of nonionic methine dyes combining two nuclei, one of which is a ketomethylene of acidic nature such as pyrazolone, rhodanine, oxazolone, thiohydantoin,. 

Among the thiazole derivatives known for a long time, but whose structure was not at once acknowledged as such, leading to some controversies, are so-called thiocyanoacetic acid, thiohydantoine, rhodanine, mercaptothiazole, and sulfuvinuric acid. 

In 1873, almost simultaneously, Maly (24), Volhard (38), and Nencki (42) studied the action of thiourea on chloroacetic acid. As mentioned previously, they believed the product to be the thioanalog of hydantoin and called it thiohydantoin with formula 34. 

In 1874, Volhard (39) showed that thiohydantoin resisted desulfuration, proving its sulfur atom to be more firmly bonded than formula 34 indicated. 

In 1875, Mulder (43) extended the synthesis reaction of thiohydantoine to the ethyl ester and amide of chloroacetic acid. Claus (44) demonstrated the acidic properties of thiohydantoin and its ability to form metallic salts. 

In 1877, Maly (45) discussing formula 34 applied to thiohydantoine found it unable to explain the basic properties of the compound. He preferred a structure in which the -CH2-CO- group would be bonded to only one nitrogen atom. Meyer (46) prepared a monophenyl thiohydantoin (m.p. 178°C) by condensing diloroacetanilide with thiourea and proposed 42 for its structure. 

The formation of a sulfur-containing ring was justified by the attack of the halogenated carbon of the cMoroacetyl derivative by the sulfur atom of thiourea, a fact in accordance with the results just discussed by Wallach (49,50) and Claus (51). The new formula (37) of thiohydantoine explained why, contrary to thiourea, its desulfuration was difficult. 

In 1880, R. Andreasch (52) confirmed the new formula (37) by preparing thiohydantoine through condensation of thioglycolic acid with cyanamide (the reverse reaction of the basic hydrolysis of thiohydantoin). 

In 1891, Miolati (75) confirmed the cyclic formula of Liebermann and Lange by preparing the compound by three new pathways (1) reaction of CS2 on thiohydantoin, (2) condensation of ammonium dithiocarbamate with chloroacetic ester, (3) reaction of HjS on thiocyanoacetic acid. 

Thiohydantoin [503-87-7] (pi C 8.5) is a slightly stronger acid than hydantoin (pi C 9.0). 4-Thiohydantoins appear to be weaker acids (4). 

Hydantoin derivatives show weak absorption in the uv-visible region, unless a part of the molecule other than the imidazohdinedione ring behaves as a chromophore (13) however, piC values have been determined by spectrophotometry in favorable cases (14). Absorption of uvby thiohydantoins is more intense, and the two bands observed have been attributed to n — tt and n — tr transitions of the thiocarbonyl group (15,16). Several piC values of thiohydantoins have been determined by uv-visible spectrophotometry (16). 

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). 

Reactions at G-5. The C-5 atom of hydantoins can be considered as an active methylene group, and therefore is a suitable position for base-cataly2ed condensation reactions with aldehydes (44). 2-Thiohydantoins give the reaction more readily than their oxygen counterparts ... 

Synthesis from Thiohydantoins. A modification (71) of the Bucherer-Bergs reaction consisting of treatment of an aldehyde or ketone with carbon disulfide, ammonium chloride, and sodium cyanide affords 2,4-dithiohydantoias (19). 4-Thiohydantoias (20) are available from reaction of amino nitriles with carbon disulfide (72). Compounds (19) and (20) can be transformed iato hydantoias. 

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 reaction of carbon oxysulphide with a-aminonitriles results in 5-amino-2-hydroxy thiazoles these are structurally similar to the 2-mercaptothiazoles but are found to be less stable, readily undergoing cleavage or rearrangement to give 4-thiohydantoins. Thus the reaction between ethyl aminocyanoacetate and carbon oxysulphide 31 in ether afforded 5-amino-2-hydroxy-4-carbethoxythiazole 32, which in the presence of aqueous ammonia was converted into 5-carbethoxy-4-thiohydantoin 33. When using sodium... 

Free amino acids can be derivatized with isothiocyanates to phenyl- or methyl-thiohydantoin derivatives. The thiohydantoins can be separated on a CSP with poly-[Af-acryloyl-L-phenylalanine ethylester] (Chiraspher ) as a chiral selector [25]. This CSP offers a known selectivity for many five-membered heterocyclic rings. 

The mechanism involves the initial formation of a substituted urea followed by ring closure to form the thiohydantoin. The amino acid is dissolved in 60% aqueous pyridine containing the phenylisothiocyanate... 

A one-pot synthesis of thiohydantoins has been developed using microwave heating [72]. A small subset of p-substituted benzaldehydes, prepared in situ from p-bromobenzaldehyde by microwave-assisted Suzuki or Negishi reactions, was reacted in one pot by reductive amination followed by cyclization with a thioisocyanate catalyzed by polystyrene-bound dimethyl-aminopyridine (PS-DMAP) or triethylamine, all carried out under microwave irradiation, to give the thiohydantoin products in up to 68% isolated yield (Scheme 16). 

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