Thiosemicarbazone

II. Thiazoies from a-Halocarbonyl Compounds and Derivatives 249 D. Thiosemicarbazides and Thiosemicarbazones... 

Under acidic conditions, a thiosemicarbazone intermediate (145) has been isolated, this can be cyclized in alcohol either into the corresponding 2-hydrazinothiazole (142) in the presence of benzaldehyde or into 1,3,4-thiadiazine (146) in the absence of benzaldehyde (Scheme 71) (375, 397, 408). 

Thiosemicarbazones of the general formula 155 react either with a-halocarbonyi compounds (59, 60, 67, 69, 71, 107, 743, 744, 788) or with 1-chloro-1,2-epoxides (504) to yield the corresponding 2-hydrazinothiazoles (156) (Scheme 78 and Tables 11-22 and 11-23). 

The interaction of sym-dichioroacetone with thiosemicarbazones similarly yields 2-arylidenehydrazino-4-ch]oromethylthiazoles, which are successively acetylated and brommated (Scheme 79) (636). 

TABLE li-23. HYDRAZINOTHtAZOLE DERIVATIVES FROM THIOSEMICARBAZONES AND a-HALOCARBONYL COMPOUNDS... 

Semicarbazones and thio-semicarbazones C=N— NH2 f 0 (or S) 1665-1642 (vs) 1620-1610 (vs) Aliphatic. Thiosemicarbazones fall in lower end of range. Aromatic derivatives... 

Synthesis from Aldehydes and Ketones. Treatment of aldehydes and ketones with potassium cyanide and ammonium carbonate gives hydantoias ia a oae-pot procedure (Bucherer-Bergs reactioa) that proceeds through a complex mechanism (69). Some derivatives, like oximes, semicarbazones, thiosemicarbazones, and others, are also suitable startiag materials. The Bucherer-Bergs and Read hydantoia syntheses give epimeric products when appHed to cycloalkanones, which is of importance ia the stereoselective syathesis of amino acids (69,70). 

Many compounds capable of chelation have been tested for antimicrobial properties. Those showing positive results include saHcylaldoxime [94-67-7] l-nitroso-2-naphthol [131-91-9] mercaptobenzothiazol [149-30-4], dimethylglyoxime [95-45-4], saHcylaldehyde [90-02-8], cupferron [135-20-6], phenanthroline [66-71-7], isoniazid [54-85-3], thiosemicarbazones, the sulfur analogue of oxine, and numerous antibiotics (qv) including tetracyclines. Whether these compounds function exclusively, partially, or at all by virtue of their abiHty to chelate is open to debate. 

The direction of ring closure can often be influenced by the nature of the dehydrogenation agent. The substituted thiosemicarbazone (223) with AI2O3 in chloroform formed the... 

Isothiazole substituents have been attached to /3-lactam antibiotics and to macrocyclic antibiotics such as erythromycin. The sulfa drug, Sulfasomizole (244) also has good antibacterial activity. Thiosemicarbazones of 5-formyl- and 5-acetylisothiazoles show high activity against the pox group of viruses (65AHC(4)107). 

Isothiazole, 5-acetamido-3-alkyl-nitrosation, 5, 59 6, 148 Isothiazole, 5-acetyl-thiosemicarbazone biological activity, 6, 175 Isothiazole, 4-acetyl-5-amino-3-bromo-synthesis, 6, 166 Isothiazole, 4-acetyl-3-methyl-oxime... 

The thiophene analog of chloramphenicol (255) has been synthesized,as also have been similar structures. The antibacterial activity of all was much lower than that of the natural antibiotic. The thioamide of 2-thenoic acid has been prepared in a study of potential antitubercular compounds. It did not surpass thioisonico-tinamide in antitubercular activity. The thiosemicarbazones of thio-phenealdehydes and ketones (cf. Section VII,D) show high activity against Mycobacterium tuberculosis, but are very toxic. The thiosemi-carbazone of 4-(2-thienyl)-3-buten-2-one has been reported to be capable of completely inhibiting the in vitro growth of M. tuberculosis even in relatively low concentrations. ... 

In continuing their previous work Bougault and Daniel observed that thiosemicarbazones of a-keto acids (51) also undergo a cyclization resulting in 3-thioxo-5-oxo-2,3,4,5-tetrahydro-l,2,4-triazines (52). In contrast with the cyclization of semicarbazones this cyclization... 

The cyclization of thiosemicarbazones has therefore recently served as the basis for further syntheses of 6-azauracil and 6-azathymine. Barlow and Welch proceeded from thiosemicarbazone of mesoxalic acid (51, 52 R = COOH). The corresponding methylmercapto derivative (53 R = COOH, R = CHs) was hydrolyzed and decarboxylated... 

The last of the procedures of preparation of A -alkyl derivatives of dioxotriazines is the cyclization of A-alkylated semicarbazones of a-keto acids. It was employed only in a few cases and it appears that its yields are very low. Despite the fact that even here a fundamental effect of substitution on the yield of cyclization can be expected, as the case is with analogous thiosemicarbazones (e.g., Section II,B,4,b), the method is of no particular preparative value. 

The preparation of the 6-propyl to 6-undecyl derivatives, however, was performed by boiling for 30 min with potassium carbonate. Sodium methoxide in a mixture of ethanol and benzene was used for the cyclization of the thiosemicarbazone of phenylglyoxylic acid ester. ... 

Substitution in position 4 displays a more complex influence. Cyclization of the 4-methyl- and 4-ethyl-thiosemicarbazones of phenylpyruvic acid and of the 4-methylthiosemicarbazone of phenyl-glyoxylic acid (103) was readily achieved (104), whereas it was not possible to cyclize the analogous 4-methyl derivatives of pyruvic and glyoxylic acids. It thus appears that cyclization is hindered by substitution in position 4 and that this unfavorable effect can be partly relieved by the known favorable effect of an aryl or aralkyl group in the a-position. 

However, for the preparation of derivatives which contain a functional group directly attached to position 6, the application of the foregoing cyclization method is considerably limited by the availability or existence of the required derivatives of -keto acids and may also be affected by differences in their reactivity. Cyclization of thiosemicarbazones was, therefore, used for these substances only in the case of the 6-carboxylic acid (see also Section II,B,2,a). Of the other derivatives known, the 6-acetic acid ester should be mentioned. Recently some further derivatives of dioxotriazine-6-carboxylic acid were reported. ... 

Formyl-3-methylisothiazole is prepared by hydrolysis of the appropriate Reissert compound and, as the thiosemicarbazone, in poor yield by the McFadyen-Stevens reaction. 4-Formylisothiazole has been obtained by oxidation of 4-methylisothiazole although no details of the preparation have been reported. 

Thiosemicarbazones of 5-formyl- and 5-acetyl-isothiazoles are riBported to have high activity against the pox group of viruses. ... 

Itnidazole-2-carbaldehyde thiosemicarbazone forms the 5-chelate complex 21 upon reaction with dimethyltin oxide (00JCS(D)2267). 

Acetaldehyde thiosemicarbazone p-Acetaminobenzolsulfonyl chloride Calcium ferricyanide... 

The thiosemicarbazone 3a (from 2-methylthiosemicarbazide and ethyl acetoacetate) similarly undergoes ring closure to the 1,2,4-triazepinone-thione 4a in the presence of sodium and pro-pan-2-01.333 334... 

Na (2.0 g, 87 g-atom) was added over 30 min to a stirred suspension of the thiosemicarbazone 3a (4.0 g, 18.4 mmol) in i-PrOH (40 ntL). After 14 h, the mixture was concentrated under reduced pressure, acidified with HOAc. treated with H20 (10 mL) and extracted with CHC1,. The extract was dried and evaporated, leaving the product yield 2.6g (83%) tnp 136 — 137 C (i-PrOH). 

It has been said that the above procedure cannot be applied to the synthesis of the corresponding nitro derivative, 8-nitro[l,2,4]triazino[5,6-b]indole-3-thione. Thus, heating 5-nitroisatin-3-thiosemicarbazone in aqueous potassium carbonate gave after acidification a mixture of oxotria-zinethione 137 and 5-nitroindazole 3-carboxylic acid (90ZOR1327). 

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