Amino thiocarbamoylation

Isothiocyanates react with many nucleophiles, but only the products with amines (thiocarbamoyl derivatives) are stable.16 Although the increased specificity is desirable, the reaction with the amino group changes the charge on the protein, and this may be needed in order to maintain the activity or the conformation, or both. The linkage formed is alkali-labile, and, as with the azo derivatives, the aromatic ring is a liability. 

It has been shown also that both thiocarbamoylimidazoles 147 and 148 can react with sodium azide. These compounds were successfully used to prepare heterocycle-peptide conjugates as peptidomimetics. A-Terminal aminothiatriazole modified amino acids have been synthesized using two methods (Scheme 35). To prepare monosubstituted aminothiatriazoles 151 the amino acid derivatives were converted into the thiocarbamoyl imidazoles of type 147 that can react with azide ion to form the thiatriazole ring. On the other hand, for the synthesis of disubstituted amino acid derivatives of 1,2,3,4-thiatriazoles 153 and 155 the activation of the thiocarbonyl group via a salt of type 148 was required. The reaction conditions and the yields of thiatriazoles 151, 153, and 154 prepared by this approach are shown in Scheme 35. 

According to REM, hydrazine hydrate is reacted with 2 mols of ammonium thiocyanate to produce l,2-bis(thiocarbamoyl)hydrazine which by loss of ammonia and rearrangement produces 5-amino-2-mercapto-l,3,4-thiadiazole. That compound is acetyled with acetic anhydride. 

Reaction of 3,4-dihydro-7-nitro-2//-l, 4-benzoxazine-4,5-dicarboxylic anhydride with diethyl malonate in the presence of 60% NaH in N, yV-dimethylacetamide at 120°C afforded ethyl 7-hydroxy-9-nitro-5-oxo-2,3-dihydro-5//-pyrido[l,2,3-cte]-l,4-benzoxazine-6-carboxylate (93MIP4). 9-Chloro-2,3-dihydro-7-hydroxy-6-(jV,./V-disubstituted thiocarbamoyl)-5//-pyrido[l,2,3-de]-l,4-benzoxazin-5-ones were prepared from 7-chloro-3,4-dihydro-2//-1,4-benzoxazine-4,5-dicarboxylic anhydride with 3-(N,N-disubstituted amino)-3-thioxopropionates in the presence of 60% NaH in yV,yV-dimethylacetamide (95MIP5). 

Heated with POCl3, 2-formylaminothioacetamide (322 R2, R4 = H) affords 5-aminothiazole (323 R2, R4 = H). In a similar manner, ethyl 2-acetamido-2-thiocarbamoyl-acetate (322 R2 = Me, R4 = C02Et) gives 5-amino-4-ethoxycarbonyl-2-methylthiazole (323 R2 = Me, R4 = C02Et Scheme 213). 

A simple and efficient synthesis of 9-substituted guanines by cyclodesulfurization of 1-substituted 5-[(thiocarbamoyl)amino]imidazole-4-carboxamides under aqueous basic conditions has been described, e.g. formation of 9-methylguanine 12. °... 

A -Alkyl(thiocarbamoyl)]pyrazines have also been obtained by heating the 2-(A -alkylcarbamoyl)pyrazine with phosphorus pentasulfide and potassium sulfide in xylene at 100° (1268) and 2-amino-3-carbamoyl-5,6-diphenylpyrazine refluxed with phosphorus pentasulfide in pyridine gave 2-amino-5,6-diphenyl-3-thiocarbamoylpyrazine and the 3-A -butyl(thiocarbamoyl) analogue was prepared similarly (455). 2-Amino-5-chloro-3-(C-imino-C-methylthiomethyl)pyrazine with hydrogen sulfide in pyridine gave 2-amino-5-chloro-3-thiocarbamoylpyrazine (1218). 

A series of 2-cyano-6-substituted aminopyrazines (and imidoesters) refluxed with hydroxylamine in methanol gave 2-(C-amino-C-hydroxyiminomethyl)-6-(substituted amino)pyrazines (943, 1424), and 2-cyano(or thiocarbamoyl)-6-ethylthiopyrazine refluxed with hydroxylamine in aqueous methanol gave 2-(C-amino-C-hydroxyiminomethyl)-6-ethylthiopyrazine (992). 

Treatment of thionhydrazides, RC(==S)—NH—NH2 with nitrous acid should lead to thiocarbonyl azides, RC(=S)—N3, and it seems likely that these azides are indeed formed as short-lived intermediates. The isolated products are 1,2,3,4-thiatriazoles. When thiosemi-carbazides are nitrosated, 5-amino-l,2,3,4-thiatriazoles or/and 5-mercaptotetrazoles are obtained. Freundformulated his products as such in 1895, while Oliveri-Mandala considered them thiocarbamoyl azides on the basis of some chemical evidence. Lieber resolved this controversy by recording the infrared spectra of the compounds and demonstrating the absence of an azide band . He did the same for the 5-alkylmercapto-l,2,3,4-thiatriazoles , which had earlier been reported as azido-dithiocarbonates , and for the products from azide ion and thiophosgene and carbon disulphide , all of which possess thiatriazole structures. Lieber also demon-... 

It appears quite probable that this reaction occurs by the same mechanism as the reaction of nitrous acid with thiosemicarbazides and of sodium azide with isothiocyanates. The primary reaction product is a thiocarbamoyl azide (CCXIII) to which, however, the cyclic structure of a 5-amino-l,2,3,4-thiatriazole (CCXIV) is attributed. In alkaline medium these compounds rearrange to the corresponding 1 -substituted-Zla-tetrazoline-5-thiones (CCXII) 236, 237). A survey of these compounds, prepared from the dithiocarbamic acid esters, is given in Table 33. 

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