Thiazole phenacyl bromides

The cyclization of pentaacetyl-o-gluconic thioamide with chloroacetone and of pentaacetyl-D-galactonic acid thioamide with phenacyl bromide give the corresponding 4-substituted 2-(D-galactopentaacetoxypentyl)-thiazoles (27) (660) but in low yield (23 to 27%) (Scheme 13). The products may be deacetylated in the usual way. These compounds are interesting from a pharmacological point of view. 

Reactions of the salts 79-81 with chloroacetonitrile, methyl chloroacetate, chloroacetone, or substituted phenacyl bromide yield different products the thiazoles 90 are formed in excellent yield from the reaction with 79 (Equation 1) and when salts 80 and 81 are treated with phenacyl bromide, thiazolopyridine 91 and benzoxazine derivative 92 are formed, respectively <2004H(63)2319>. 

Thioureas serve as a convenient starting material for 2-aminothiazoles. Reaction of (3-phenethylamine (103-1) with ammonium isothiocyanate gives the thiourea (103-2). Treatment of that product with phenacyl bromide (103-3) leads to the corresponding thiazole. That compound, fanetizole (102-4) [114], shows immuno-regulating activity. 

The failure of the Tschitschibabin reaction has also been observed with other NH-aminoazoles. Werbel and Zamora214 found that 2-amino-1-methylbenzimidazole reacted rapidly with phenacyl bromide to give an intermediate that cyclized easily to the imidazo[l,2-a]benzimidazole, but 2-aminobenzimidazole gave no product. In the same way, 2-amino-thiazole yielded a bicyclic system but 3-amino-s-triazole did not.225... 

Phenacylthiazolium derivatives, relatively readily prepared from phenacyl bromide and an appropriate thiazole, react with dicarbonyls and make the C-C bond between them labile.602 This is thought to take place as depicted in Scheme 14.3. Phenacylthiazolium compounds have shown promise in preclinical studies of vascular stiffness and have reached Phase II clinical trials for systolic hypertension.603... 

Dihydro- and 2,3,5,6-tetrahydro-imidazo[2,l -6 ]thiazoles have been prepared in large numbers by condensation of phenacyl bromides with thiazolines followed by acetylation, sodium borohydride reduction, and ring closure with thionyl chloride and acetic anhydride (Scheme 2) <77JMC563, 66JMC545). 

Reaction of 3-amino-4-phenylthiazolin-2-thione with phenacyl bromides in methanol leads to thiadiazinium cation 463. The latter compounds, on treatment with triethylamine, is converted to pyrazolo[5,l-Z>]thiazole derivative (465). The same reaction in benzene first gives the S-phenacyl derivative 464, which is transformed to 465 in the presence of bases (87H1323). 

A noteworthy difference is observed in the condensation of thiosemicarbazide with aromatic a-halocarbonyl compounds in comparison to aliphatic a-halocarbonyl compounds. It has been found26 that the reaction of phenacyl bromide with thiosemicarbazide furnishes 5-phenyl-1,3,4-thiadiazin-2-amine together with a small amount of 5-phenylthiazolc-2-hydrazine, Similarly, the reactions of thiosemicarbazide with 2-bromo-l,2-diphenylethan-l-one,7 8,41 2-bro-mo-l-phenylpropan-l-one,10,41 and 2-bromo-l-phenylbutan-l-one 10,41 in ethanolic solution give 1,3,4-thiadizines. However, the main products are the thiazole-2-hydrazine derivatives (cf. Houben-Weyl, Vol. E8b, p 72ff). The addition of an equimolar amount of 48% hydro-bromic acid results in the exclusive formation of the 1,3,4-thiadiazines 2 a, c, and d. When the condensations of thiosemicarbazide with 2-bromo-l,2-diphenylethan-l-one, 2-bromo-1-phenylpropan-l-one or 2-bromo-l-phenylbutan-l-one are performed in ethanol at room temperature, the S-(oxoalkyl)-isothiosemicarbazide hydrobromides are formed as open-chain intermediates and also undergo cyclization in ethanol upon addition of an equimolar amount of 48% hydrobromic acid to furnish 2 a, c, and d. 

R = ,4- , 4- 1 ) can be converted to various pyra-zolo[5,1-b]thiazoles(247) by treatment with bromoacetaldehyde diethylacetal, phenacyl bromides, ethyl bromopyruvate, ethyl a-chloroacetate or chloroacetyl acetone2 , (248) with C1C0C0C12 1, and (249) with ArNHCMe=CHCOOEt and Na in EtOH2 2. Reaction of (247 R1=Ph,R2=Me,R3=C00Et) with PhCH,NH or (247 R1=Ph,R2=Me,... 

The 5-benzoyl-2-(2-morpholino-l-phenylethenyl)thiazole (286) reacts with phenacyl bromide at 170-200°C to give the trisubstituted pyrrolo[2,l-Z>]thiazoles (287) (Equation (29)) <88EGP262863>. 

Type FSyntheses (C—N—C—S + C). Further examples of the use of salts of cyanodithioiminocarbonates to give 2-alkylmercapto-4-amino-5-substituted thiazoles have been reported,and the reaction between benzamidines PhC(NHAr)=NC(S)NHPh and bromonitrobenzene (or phenacyl bromide) to give 2-arylamino-5-nitro(or -benzoyl)-4-phenylthiazole has been investigated. Similar products may be obtained starting from PhC(OMe)NC(S)NHPh. ... 

The 2-hydrazino-selenazoles (88 X = Se), and also the corresponding thiazoles (88 X = S), are obtained from the reaction between phenacyl bromides and seleno- or thio-semicarbazide under alkaline conditions. " Selenazolidine-2-carboxylic acid has been obtained by the reduction of selenocysteamine followed by treatment with Na02CCH0." ... 

The thiazole ring system is a useful structural motif found in numerous biologically active molecules. Addition of thioamide or thiourea to the aqueous solution of phenacyl bromide-j3-CD complex gave the corresponding thiazole or aminothiazole, respectively (>82%), without the formation of by-products or rearranged products (Figure 4.16). The role of CD appears to be to activate and solubilize the phenacyl bromide, and drive the reaction to completion in decreased reaction times. Without CD, the reaction took place but the yields were poor (20%). Selenazoles were also prepared from a-bromoketones and selenourea in the presence of )3-CD at 50 °C under atmospheric pressure. ... 

Kaupp et al. employed ball-milling technique to transform thioureas 79 by reaction with phenacyl bromide to 2-amino-4-phenyl-thiazole-hydrobromides 80 in quantitative yields from stoichiometric mixtures of the reagents at room temperature (Scheme 4.21) [14]. In soUd-state conditions, base catalyst was not needed. The water formed in the reaction does not hydrolyze phenacyl bromide under applied mild conditions and was removed by heating at 80°C in vacuo. When the same reaction was performed in a melt at 110°C, partial hydrolysis occurred, which diminishes yield, while yields obtained in solntion were lower (80-90%). This Hantzsch thiazole synthesis starts with nucleophilic snbstitution on snlfur and formation of the carbon-sulfur bond (S-alkylation), followed by further reaction cascade which results in heterocychc ring. 

NCN=C(SR)S (R = alkyl) react with chloroacetamide to give the amino-thiazoles (583). Irradiation of 2-phenyl-2-thiazoline (584) in acetonitrile leads to a mixture of the corresponding thiazole, benzonitrile, and ethylene sulphide. Heating the dithiobiuret Me2NCSNHCSNH2 with phenacyl bromide affords the 2,5 -bithiazole (585) in excellent yield. ... 

Several other syntheses of this ring system were accomplished by annulation of the triazine ring onto a five-membered ring, either oxazole (69C303) or thiazole (71JCS(C)1615), with concurrent ring opening and reclosure to form the imidazo[2,l-c][l,2,4]triazine system. For example, treatment of 2-amino-3-phenacyl-5-phenyloxazolium bromide (598) with phenyl-hydrazine produced (599). 

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