Thiourea intermediates

Azine approach. 6-Aminouracils are attacked by electrophiles at C-5. With an isothiocyanate as electrophile a thiocarbamoyl derivative (156) is formed which undergoes oxidative cyclization. Sometimes a minor product, the thiazole (158), may be formed via the thiourea intermediate (157). The course of the reaction may perhaps be rationalized on the HSAB principle the hard iso thiocyanate electrophile has to choose between the hard nucleophilic centre at C-5 or the soft nucleophilic centre at 6-NH2. Isothiocyanates of aminosugars have also been used in these reactions (79CPB1147). 

Isothiocyanates are also major starting materials for carbodiimides either by converting them into 1,3-disubstituted thiourea intermediates, which are subsequently desulfurized, or by treating them with iminophosphoranes. 

Thiourea, diphenylthiourea and ammonium dithiocarbamate are often simply masked versions of HjS in single (equation HV) - and double additions (equation 148) . Although acyclic thiourea intermediates have sometimes been... 

Condensation of 2-aminobenzenesulfonamide (175) with an alkyl or acyl isothiocyanate in the presence of triethylamine affords a 3-alkylamino- or 3-acylamino-2ff-l,2,4-benzothiadiazine 1,1-dioxide (177) via cyclization of a thiourea intermediate (176 X = S) (Scheme 27) <90MI 6l4-04>. In contrast, the corresponding ureas (176 X = O) in hot DMF suffer elimination of the alkylamine residue to form 277-l,2,4-benzothiadiazin-3(4Ff)-one (178) in 90% yield <90JHC1909>. 

When diamine 149 is successively treated with isothiocyanate and with dicyclohexylcarbodiimide, the latter being the acceptor of hydrogen sulphide on cyclization of the thiourea intermediate, IP 150 is obtained in satisfactory yield (90JHC1821). 

Anthranilonilrile derived isothiocyanale 84 was also used to construct quinazolinones. Nanni and co-workers reported a dimerization of 84 in the presence of Mn(OAc)j in HOAc to give fused quinazolinc 86 in excellent yield <01T7221>. In contrast, dimerization of the anthranilate ester 85 gave quinazoline 87 as the major product, though in only 30% yield. It was assumed that a thiourea intermediate was initially formed which then cyclized through an ionic and/or radical mechanism. However, when thiourea 88 was treated under the same conditions, 89 was the major product along with minor products 90, 91,92 and 93. 

To a stirred solution of primary aromatic amine (1 1 mmol) in chloroform (4 mL) was added alkylthiocyanate (2 1 mmol), and stirred at room temperature. On disappearance of the reagents forming the thiourea intermediate (within 0.2-0.5 h as checked by TLC), 1,2-diaza-1,3-diene 3 was added solid or dissolved in CHCI3 (1 mL) to the reaction vessel and the reaction mixture was allowed to stand at room temperature until completion of the reaction (0.5-6 h). The solvent was then removed under reduced pressure and the crude reaction mixture was piuified by colunm chromatography (cyclohexane/ethyl acetate... 

The mechanism of the Hantzsch s synthesis was studied at a very early stage by several authors. The intermediates were generally assumed to be open-chain a-thioketones, but in a series of papers by Murav eva and Schukina (470, 490) the isolation of hydroxythiazolines from the reaction between a-haloketones and a variety of thioureas was reported. 

In many cases, the a-haloketone does not appear to be an intermediate in this reaction, since reagents such as sulfur trioxide, sulfuric, or 60% nitric add lead to 2-aminothiazole but with lower yields (11 to 43%). Formamidine disulfide [-S-C(=NH)NH2]2, a product of the oxidation of thiourea, seems to be the intermediate in this reaction, since upon treatment with ketones, it gives 2-aminothiazole (604). However, the true mechanism of this reaction has not yet been completely elucidated. 

Labeled 2-aminothiazole (an intermediate in the synthesis of an antiparasitic drug) has been obtained from "C-thiourea (666). 

But the reaction with aliphatic a-halocarbonyl compounds is usually complex, and a variety of compounds can be formed depending on the reactants and the reaction conditions. With chloroacetone in neutral medium (alcohol) the acyclic intermediate (144) analogous to those obtained with thiourea and thioamides was isolated (Scheme 70). 

Another approach to 2-aminothiazole derivatives was recently developed by Zbiral and Hengstberger (667, 700) thus the condensation of )3-acylvinylphosphonium salts (248) with thiourea affords the thiazolyl-methylphosphonium salt (249) via an acyclic intermediate analogous to the Hantzsch s synthesis. Final alkaline hydrolysis of 249 furnishes the 2-aminothiazoles (250) (Scheme 127) (700). 

Acetoiicetyliition Reactions. The best known and commercially most important reaction of diketene is the aceto acetylation of nucleophiles to give derivatives of acetoacetic acid (Fig. 2) (1,5,6). A wide variety of substances with acidic hydrogens can be acetoacetylated. This includes alcohols, amines, phenols, thiols, carboxyHc acids, amides, ureas, thioureas, urethanes, and sulfonamides. Where more than one functional group is present, ring closure often follows aceto acetylation, giving access to a variety of heterocycHc compounds. These reactions often require catalysts in the form of tertiary amines, acids, and mercury salts. Acetoacetate esters and acetoacetamides are the most important industrial intermediates prepared from diketene. 

Isomerization. Maleic acid is isomerized to fumaric acid by thermal treatment and a variety of catalytic species. Isomerization occurs above the 130 to 140°C melting point range for maleic acid but below 230°C, at which point fumaric acid is dehydrated to maleic anhydride. Derivatives of maleic acid can also be isomerized. Kinetic data are available for both the uncatalyzed (73) and thiourea catalyzed (74) isomerizations of the cis to trans diacids. These data suggest that neither carbonium ion nor succinate intermediates are involved in the isomerization. Rather, conjugate addition imparts sufficient single bond character to afford rotation about the central C—C bond of the diacid (75). 

Furium. N[4-(5-Nitro-2-furanyl)-2-thia2olyl]acetamide, has demonstrated activity against baciUi and pathogenic enterobacteria (24). The product, prepared from thiourea and 2-bromo-l-(5-nitro-2-furanyl)ethanone followed by acetylation of the intermediate aminothia2ole with acetic anhydride in pyridine (25), is marketed in several countries for both human and veterinary use. 

AminothiaZoles. In contrast to the pyrazolones, pyridones, and indoles just described, aminotliiazoles are used as diazo components. As such they provide dyes that ate more bathochromic than their benzene analogues. Thus aminothiazoles are used chiefly to provide dyes in the red-blue shade areas. The most convenient synthesis of 2-aminothiazoles is by the condensation of thiourea with an a-chlorocarbonyl compound for example, 2-aminothiazole [96-50A-] (94) is prepared by condensing thiourea [62-56-6J with a-chloroacetaldehyde [107-20-0J both readily available intermediates. 

In addition to modification of the catalyst, several variants of the Biginelli reaction have emerged as viable alternatives however, each method requires pre-formation of intermediates that are normally formed in the one-pot Biginelli reaction. First, Atwal and coworkers reported the reaction between aldol adducts 39 with urea 40a or thiourea 40b in the presence of sodium bicarbonate in dimethylformamide at 70°C to give 1,4-dihydropyrimidines 41. DHPM 42 was then produced by deprotection of 41. 

Undoubtedly these reactions proceed via an intermediate ureido or thioureido derivative. These compounds have been obtained by Dornow and Hahmann by the action of potassium cyanate or ammonium isothiocyanate on 2-amino-4,6-dimethylnicotinic acid (11), but whereas the urea (12, X = 0) was converted into the pyrido[2,3-li]-pyrimidine-2,4(lI/,3/7)-dione (13, X = 0) by the action of heat, the thiourea (12, X = S) was unchanged after similar treatment. 

Disubstitution of 2,4-dichloropyrimidine with thiourea proceeds more readily than with hydrosulfide ion, principally because the former intermediate (229) contains the activating, cationic acylated thio group compared to the highly anionized mercapto group in the latter reaction. 

Dihydrothiazoloquinoline is a key intermediate in the synthesis of natural sulfur-containing pyridoacridine alkaloids—kuanoniamines and derdercitins, where the starting dienone is converted after a multistep reaction sequence to an a-bromo-ketone, which in turn was cyclized with thiourea to the desired dihydrothiazoloquinoline, photochemically convertible to the final alkaloid derivatives 39 (Scheme 21) (92JA10081, 95TL4709, 95JA12460). 

The aminothiazole, 123, required for preparation of sulfa-thiazole (102), one of the older sulfonamides still in use, is available directly from the reaction of 1,2-dichloroethoxyethane with thiourea. The intermediate, 122, is not observed, as elimination of ethanol is spontaneous under the reaction conditions. 

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