Halocarbonyl compounds

Another similar example concerns the alkylation of enamines. This reaction works well with reactive a-halocarbonyl compounds (frames 175ff) but simple alkyl hahdes often react on nitrogen ... 

Diazomethane alkylation of A-4-thiazoline-2-ones (36, 214) or the Williamson reaction of 2-halogenothiazoles (6. 287-300) provide good yields of 2-alkoxythiazole otherwise obtained by reaction between O-esters of monothiocarbamic acid with a-halocarbonyl compounds (see Chapter II). 

Furthermore, they react with carbonyl derivatives such as acetone and benzaldehyde to give selenohydrazones identical to those prepared from the condensation of selenosemicarbazones with an a-halocarbonyl compound. 

In 1893, Miolati (95) generalized the reaction of Marchesini to a-halocarbonyl compounds. 

The cyclization of -halocarbonyl compounds is carried out with a great variety of reactants including thioamides, thioureas, their mono- or disubstituted derivatives, and salts and esters of monothiocar-bamic acid, leading to variously substituted thiazoles. 

The reaction of a thioamide with a-halocarbonyl compounds has been applied extensively, and many thiazoles (10) with alkyl, aryl, aralkyl, or heteroaryl functional groups at the three 2-, 4-, or 5-positions have been reported (Scheme 6). 

The reaction can be carried out in two steps (641). First, equimolar amounts of amide and phosphorus pentasulfide are mixed under stirring in dioxane, the temperature being kept below 45°C. After 20 minutes, the a-halocarbonyl compounds (in dioxane solution) are added in small portions. At the end of the addition the temperature reaches 80 to 100°C, and the reaction mixture is kept at this temperature for another hour. 

II. Thiazoles from a-Halocarbonyl Compounds and Derivatives 193 TABLE II-7. (continued)... 

N-Monosubstituted thioamides (96) have been cyclized with a-halocarbonyl compounds to give thiazolium salts (97) in excellent yields (89, 99. 102, 305, 722). 

II. Thiazoles from -Halocarbonyl Compounds and Derivatives 213 3. Reaction with Thiourea... 

The cyclization of N-substituted thioureas (123) with halocarbonyl compounds gives 2-monosubstituted aminothiazoles (124) (Scheme 58)... 

Ortho and para phenylene dithioureas (128) treated with a-halocarbonyl compounds afford NN -ortho- and para-phenylene-bis(2-amino-4-R-thiazole) (129) (Scheme 62) (653). 

The N,N-disubstituted thioureas (135) condensed with a-halocarbonyl compounds give 2-disubstituted aminothiazoies (136) but in lower yields (30 to 70%) (Scheme 65 and Table 11-20) (518). For example, N,N-dialkylthioureas condensed with chloroacetaldehyde or dibromoether lead to Ar,At-dialkyl-2-aminothiazoles in 136, Ri=R2 = methyl (342, 404, 436, 637), ethyl (343, 436), n-propyl (518), n-butyl (518), ally] (518), and benzyl (26, 29). When chloroacetone and dichloroacetone are the carbonyl reactants the corresponding 4-methyl (518) and 4-chloromethyl derivatives (572) were obtained. 

TABLE IM9. DITHIAZOLYLAMINES FROM DITHIOBIURET AND a-HALOCARBONYL COMPOUNDS... 

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

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). 

Several sulfonamides (142), Rj = p-H2NS02CeH4, have been obtained by condensing the corresponding thiosemicarbazide (141), R, = p-H2NSO2C6H4, with a-halocarbonyl compounds (396, 466) in alcohol solution. 

Condensation of thiosemicarbazides of nicotinic and isonicotinic acids (528) and their hydrochlorides, with a-halocarbonyl compounds gave the corresponding hydrazinylthiazoles (149), in which Rj = methyl, phenyl, or aryl and R2 = H (Scheme 74). 

Hydroxythiazoles give 2-chIorothiazole derivatives almost quantitatively upon treatment with phosphorus oxychloride (221, 229, 428). This constitutes a convenient synthesis method for these compounds when the conversion of 2-aminothiazoles to 2-chlorothiazole derivatives fails. Esters of thiocarbamic acid or thiourethanes also react with a-halocarbonyl compounds to give the corresponding 2-alkoxythiazoles (50, 68, 209, 272). 

Initiated by Miolati in 1893 (27), taken up later by Levi (82), and successively by many other authors, the reaction of ammonium dithiocar-bamate (162) with a-halocarbonyl compounds gives 2-mercaptothiazole derivatives with yields varying greatly according to experimental conditions (Table 11-25). 

TABI.R n-25. 2-MERCAPTOTHIAZOLE DERIVATIVES FROM AMMONIUM DITHIOCARBAMATE AND o-HALOCARBONYL COMPOUNDS (163s)... 

This result was confirmed more recently by Chanon and Metzger (597, 611), who investigated the mechanism of the A4-thiazoline-2-thione formation from a dithiocarbamate and a-halocarbonyl compounds. During this study, it was possible by precise control of the pH to isolate an acyclic intermediate (178) analogous to 176, which is in equilibrium with its cyclic isomer (179) (Scheme 92). 

The a-thiocyanatoketones are easily obtainable from a-halocarbonyl compounds and metal thiocyanates (sodium, potassium, barium, or lead thiocyanate) (416, 484, 519, 659) in an alcoholic solution. Yields ranged from 80 to 95%. They are very sensitive substances that isomerize when reacted upon by acids, bases, or labile hydrogen and sulfur compounds. 

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