Acetic acid, with 2-aminothiazole

The previously published results [142, 143] devoted to the synthesis of thiazolo [3,2-a]imidazol-2-ones attracted attention of Krasovskii et al. [144] to synthesize corresponding ylidene derivates and to investigate biological activities, promising to be interesting for the medicinal chemistry. By heating 2-aminothiazoles with ethyl bromacetate and a variety of aromatic aldehydes at the appropriate temperature (either 80°C or reflux) in the glacial acetic acid with anhydrous sodium acetate, ylidene derivates of structures 102-104 were isolated (Scheme 48). 

In the uncondensed imidazoles the standard method reacts an a-aminocarbonyl compound with a thiocyanate (see Section 4.1 and Table 4.1.1). If a 2-alkylthioimidazole is required directly, one can combine an N-alkyT or A -arylcarbonimidodithioate in refluxing acetic acid with the aminocarbonyl substrate (see Section 4.1 and Scheme 4.1.3). Alternatively, reaction between thiourea and a two-carbon synthon (ot-hydroxy-, a-halogeno-, a-dicarbonyl) leads to imidazoline-2-thiones (see Section 4.3). In sulfuric acid, 3-butynylthiourea cyclizes to 4,5-dimethylimidazolin-2-thione (see Section 2.2.1). 1-Substituted 2-methylthioimidazoles can be made, albeit in rather poor yields, from appropriately substituted 2-azabutadienes (see Section 3.2 and Scheme 3.2.3), and 2-arylthioimidazoles are available in moderate yields from benzyl isocyanides and arylsulfenyl chlorides (see Section 4.2 and Scheme 4.2.12). Ring transformations of 5-amino-2-alkylaminothiazoles and 2-acylamino-5-aminothiazoles may have occasional applications (see Section 6.1.2.7). The ease with which a thiol group or imidazole or benzimidazole can be alkylated, in comparison with the annular nitrogens, usually makes it more convenient to prepare alkylthioimidazoles from the thiols (or thiones). 

With a-hydroxy ketones and their related tosyloxy derivatives. The imidazo [2,T ]thiazole 364 was prepared by acetic acid-catalyzed cyclocondensation of 2-hydroxy-l,2-diphenyl-ethanone with thiophenyl-substituted 2-aminothiazole 363 (Equation 163) <2002MI110>. Under MW irradiation and in the presence of montmorillonite K-10 clay, a mixture of a-tosyloxyketones 365 and 2-imidazolidinethione led to the substituted 5,6-dihydro-imidazo[2,l- ]thiazoles 366 (Equation 164) <1998J(P1)4093>. When using a-tosyloxyacetophenone, prepared by reaction of acetophenone with [hydroxyl(tosyloxy)iodo]benzene (HTIB), 5-aminopyrazole 367 could be converted to imidazo[l,2- ]pyrazole 368 in basic medium (Equation 165) <2005JHC209>. 

The aminothiazole ring of the novel opioid derivative 191 is produced on reaction of the corresponding amine with potassium thiocyanate and bromine in acetic acid (Equation 126) <2004JME1886>. 

To a suspension of 7-amino-3-vinyl-3-cephem-4-carboxylic acid (11.25 g), 2-(aminothiazol-4-yl)-2-(tert-butoxycarbonylmethoxyimino)acetic acid S-mercaptobenzothiazole ester (23.88 g) in ethylacetate (266 ml) and water (9 ml) at 2°C is added triethylamine. After completion of the reaction, water is added and pH is adjusted to 2.1 with diluted sulfuric acid. The phases are separated and the aqueous phase is extracted with ethylacetate. The organic extracts are combined and concentrated to a volume of 120 ml, then acetonitrile (100 ml) and formic acid (22 ml) are added. The mixture is stirred at 30-35°C for 1 hour. The mixture is cooled to 2°C, the precipitate is filtered, washed with acetonitrile and dried to obtain 20.86 g of 5-thia-l-azabicyclo(4.2.0)oct-2-ene-2-carboxylic acid, 7-(((2Z)-(2-amino-4-thiazolyl)(carboxymethoxy)imino)acetylamino)-3-ethenyl-8-oxo-, (6R,7R)-(Cefixime). 

Aminothiazole, with acetaldehyde, 42 to 2-mercaptothiazoie, 370 4-Aminothiazole-2,5-diphenyl, to 2,5 di-phenyl-A-2-thiazoline-4-one, 421 Ammothiazoie-A -oxide, 118 2-Aminothiazoles. 12 acidity of, 90 and acrylophenone, 42 acylations of, with acetic acid. 53 with acetic anhydride, 52 with acyl halides, 48 with chloracetyl chloride, 49 with-y-chlorobutyrylchloride, 50 with 0-chloropropionylchloride, 50 with esters, 53 with ethy acrylate, 54 with indoiyl derivatives, 48 with malonic esters, 55 with malonyl chloride, 49 with oxalyl chloride, 50 with sodium acetate, 52 with unsaturated acyl chloride, 49 additions to double bonds, 40 with aldehydes, 98 alkylations, with alcohols, 38 with benzyhydryl chloride, 34 with benzyl chloride, 80 with chloracetic acid, 33 with chloracetic esters, 33 with 2-chloropropionic acid, 32 with dialkylaminoalkyl halides, 33 with dimethylaminoethylchloride, 35 with ethylene oxide, 34, 38... 

Aminothiazole reacts with both ferrocenecarboxaldehyde and ferrocenecarboxylic acid chlorideto give the expected imine and amide, respectively. Ferrocenecarboxylic acid chloride also reacts with phenothiazine to give both N- and C-acetylation. Ferrocene-carboxaldehyde and rhodanine gave 134, while reaction of the thiosemicarbazone of ferrocenecarboxaldehyde with chloroacetic acid in acetic acid gave 135. ... 

Treatment of polymer-bound methyl 2-acetylamino-3-(dimethylamino)prop-2-enoate 68 with excess 2-aminothiazole in a mixture of toluene, DMF, and acetic acid at 60°C (Scheme 32) yielded the corresponding thiazolo[3,2-a]pyrimidin-6-yl)acetamide 69 [57],... 

Several examples exist for the conversion of 5-aminothiazoles into the corresponding thiazolopyrimidines. Shaw and Butler report the formation of aminothiazole thiocarboxyamide 27 from the thioamide 26 and carbon disulphide using Cook and Heilbron s procedure. Methylation of 27 gave carboxythioimidate 28 which then reacted with sodium hydroxide to give amino-nitrile 29, and with formic acid and acetic anhydride to give the thiazolopyrimidine 30. 

Several new syntheses of thiazoles from thioureas have been developed in recent years. Werbel95 was able to prepare 2-aminothiazoles by reaction of thioureas with bis(/3-chloroethyl) ether. 1,3-Disubstituted thioureas, however, yielded disubstituted 4-thiazolines. In a German patent, Rcisinger96 reported that 2-aminothiazole was formed in 88% yield from thiourea and vinyl acetate in the presence of sulfuryl chloride. A method for the preparation of the 4-hydroxy-2-amino-thiazole (47), which probably exists in the tautomer shown, has been developed by Delaby et al.97 via the reaction of thiourea with jS-acyl-acrylic acid or its esters. Zbiral98 has observed that acylvinylphos-... 

A mixture of 7-[(Z)-2-ethoxyimino-2-(2-tritylaminothiazol-4-yl)acetamido]-3-iodomethyl-3-cephem-4-carboxilate (4.5 g, 4.83 mmoles) and N-methylpyrrolidine (0.65 ml, 6.28 mmoles) in CH2CI2 (45 ml) was stirred at room temperature for 20 min. Ether (300 ml) was added to the mixture to separate the quaternary salt of the blocked cephalosporin, which was collected by filtration and treated with 90% trifluoroacetic acid (TFA) (40 ml) at room temperature for 1 hour. The mixture was then evaporated under reduced pressure below 20°C. The residue was triturated with ether to give the TFA salt of 7-[(Z)-2-methoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-[(l-methyl-l-pyrrolidinium)methyl]-3-cephem-4-carboxylate (2.40 g), which was dissolved in methanol (5 ml) and treated with 1 M solution of sodium-2-ethylhexoate in ethyl acetate (8 ml) at room temperature for 30 min. After the addition of ethyl acetate (100 ml), the precipitate (1.94 g) formed was collected by filtration. HPLC analysis showed that the crude product was 7% pure with a 1 8 ratio of the S3 isomer to the S2 isomer. Purification of the product by HPLC was repeated three times (Lichrosorb RP-18, eluted with 5% aqueous methanol or 0.01 M ammonium phosphate buffer (pH 7.2 containing 5% of methanol) to give 35 mg (1.5%) of the title product as a colorless powder of 7-[(Z)-2-methoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-[(l-methyl-l-pyrrolidinium)methyl]-3-cephem-4-carboxylate. Estimated purity (by HPLC) 90%. M.p. 150°C (dec.). 

The general pattern of alkylation of 2-acylaminothiazoles parallels that of 2-aminothiazole itself (see Section III.l). In neutral medium attack occurs on the ring nitrogen, and in alkaline medium a mixture of N-ring and N-amino alkylation takes place (40, 43, 161, 163). In acidic medium unusual behavior has been reported (477) 2-acetamido-4-substituted thiazoles react with acetic anhydride in the presence of sulfuric acid to yield 2-acetylimino-3-acetyl-4-phenyl-4-thiazolines (255) when R = Ph. but when R4 = Me or H no acetylation occurs (Scheme 151). The explanation rests perhaps in an add-catalyzed heterocyclization with an acetylation on the open-chain compound (253), this compound being stabilized... 

---