Halogenation, of 2-aminothiazoles

Halogenation of 2-aminothiazole and derivatives has been reported under a wide variety of experimental conditions in water (161, 405. 406) in aqueous acids (16. 172, 407, 408) in solvents such as chloroform (27. 172), carbon disulfide (162, 166. 320. 409). benzene (165), acetic acid (410-413, 1580). or hydrochloric acid (414) or in 20% sulfuric acid (415-417). 

All possible dichloro- or dibromothiazoles are known. The 2.5-dihalogeno derivatives can be prepared from the 5-halogeno-2-aminothiazoles by diazotization/decomposition with CuCl or CuBr (3, 12, 13, 18, 75). The 5-halogeno-2-aminothiazoles can be easily prepared by halogenation of 2-aminothiazole (65, 76-79) 2,5-dibromothiazole can also be prepared by direct bromination of 2-bromothiazole (5). 

The halogen in the 5-position of 2-aminothiazoles is usually reactive and is used for further reaction (see Chapter V). The reaction may take place in the same medium as thiocyanation (437-440), rhodanation (441). or reaction with NaNO (435). Similarly, a mixture of 2-amino-4-methylthiazole and thiourea in H2O yields 5,5 -thiobis(2-amino-4-methyDthiazole (202) after addition of iodine (Scheme 128) (442). 

An instance of an apparent electrophilic aromatic substitution (in this case 61 is an aromatic substrate, of Scheme 31), which actually is an electrophilic addition, is the halo-genation of 2-aminothiazole derivatives which was usually considered a simple attack of the electrophilic reagent on the heterocyclic aromatic substrate activated by the amino group see reaction 12. When the bromination of 2-aminothiazole derivatives is carried out in nucleophilic solvents (ROH) and at low temperatures, the partially saturated derivatives (64) of Scheme 33 were isolated in 80-95% yields133. By heating 64, the usual halogenated 2-aminothiazoles are obtained, as indicated by Scheme 33. An apparent electrophilic aromatic substitution is actually an addition reaction to the C=C double bond the elimination reaction is the following, separate step. 

Of all the methods described for the synthesis of thiazole compounds, the most efficient involves the condensation of equimolar quantities of thiourea and a-halo ketones or aldehydes to yield the corresponding 2-aminothiazoles (Scheme 167) (l888LA(249)3l). The reaction occurs more readily than that of thioamides and can be carried out in aqueous or alcoholic solution, even in a distinctly acid medium, an advantage not shared by thioamides which are often unstable in acids. The yields are usually excellent. A derived method condenses the thiourea (2 mol) with the non-halogenated methylene ketone (1 mol) in the presence of iodine (1 mol) or another oxidizing agent (chlorine, bromine, sulfuryl chloride, chlorosulfonic acid or sulfur monochloride) (Scheme 168) (45JA2242). 

The most widely used method for the synthesis of thiazoles (see Chapter 4.19) is of this type and involves the reaction of a-halo compounds (Y = halogen in Scheme 2) with a reactive component containing an N—C(=S)— structural entity. Reaction of the a-bromoketone (65) with the primary thioamide (66) in hot benzene gave the intermediate hydroxy compound (67), which could be isolated in certain instances but in most cases underwent dehydration to form the thiazole (68). The diversity in the substituents capable of being introduced into the resultant thiazole by this procedure is illustrated in Chapter 4.19. Especially noteworthy in this respect is the reaction of the bromopyruvaldehyde oxime (69) with thiourea in methanol at room temperature. Neutralization with sodium carbonate resulted in the isolation of the 2-aminothiazole-4-carbaIdehyde oxime (70) in 39% yield (73JOC806). 

Levulinic acid is fairly easily converted into thiazole derivatives by the intermediate formation of an a-halogenated ketone such as the /3-bromo derivative (XL) or /3-chloro derivative, which reacts with thiourea to form 2-amino-4-methyl-5-thiazoleacetic acid (XLI) or with thioformamide to give 4-methyl-5-thiazoleacetic acid (XLII). The aminothiazole (XLI) and its ethyl ester (XLIII) have been converted into their corresponding sulfanilamide derivatives, (XLIV) and (XLV). These sulfanilamides, particularly the acid XLIV, have considerable chemotherapeutic activity moreover the acid possesses distinct solubility advantages over sulfathiazole itself. 

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