Thiazoles from thioureas

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-... 

Hydantoins from urea, and thiazoles from thiourea or thioamides. 

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

There is an enormous literature on thiocarbonyl compounds, due in part to the technical and industrial importance of many of them, including thioamides, thioureas, xanthates, dithiocarbamates and so forth. An excellent, and recent, general review is available.107 There are also specialized reviews germane to the present chapter Griffin, Woods, and Klayman2 discussed the use of thioureas in the synthesis of heterocycles the preparation of thiazoles from thioamides is included in a three-part volume on Thiazoles 108 the use of carbon disulfide in the synthesis of trithiones and related heterocycles has been reviewed by Mayer109 and Huisgen110 has reported numerous examples of 1,3-dipolar cycloadditions in which carbon disulfide was used. 

Amino-4-methoxycaibonyb5-(l-inethoxy-alkyl) thiazoles, from 2,4-di-chloro-2,4, epoxyalkanoates and thiourea,... 

Aiiiino-4-phenylthiazoles, from o-diazo-acetophenone and thiourea, 231 2-Amino-5-phenylthiazole, diuretic prope ties of Schiffs bases of, 167 synthesis of, by condensation of ammonia with At(ary 1-1,3-oxathiol-2-yIidine) tertiary iminium salts. 300 2-(p-Ammophenyl) thiazoles, syntheses of, 4,5-disubstituted derivatives of, 191 2-Amino5-substituted thiazoles, from o-haloaiddiydes and thiourea, 224, 225 /V,At -bis (2-Amino-4 substituted thiazolyl)-p biphenylene, from p-biphenylene dithiourea and o-halocarbonyl compounds, 243... 

Hydrazo-bis-thiazoles, from l-(2-thia-zolyl) semicarbazides (or from bis-thiourea), and o-halocarbonyl compounds, 255... 

Synthesis. - Hantzsch s Synthesis (Type A S—C—N + C-C) From thioureas. Starting from thioureas, the following compounds have been obtained 2-amino-4-(4-benzyloxyphenyl)thiazoles, 2-(2-amino-5-hydroxythiazol-4-yl)-1 -(4-chloro-3-methylphenyl)ethanone, 2-benzylidenehydrazino-4-( 1,5 -di-... 

Under certain conditions tt,/ -dichloro ethers (cf. page 170) react as a mixture of chloroacetaldehyde, alcohol, and HC1, e.g., in the synthesis of 2-amino-thiazole from 1,2-dichloroethyl ethyl ether and thiourea in water. 

Simple examples of this strategy, which for the synthesis of thiazoles is known as the Hantzsch synthesis, are shown below the syntheses of 2,4-dimethylthiazole where the heteroatoms are provided by thioacetamide, " and 2-aminothiazole, in which 1,2-dichloroethyl ethyl ether is utilised as a synthon for chloroethanal and the heteroatoms derive from thiourea. " The use of thioureas as the sulfur component with 2-chloroacetamides as the second unit gives rise to 2,4-diaminothiazoles. " Conversion of 1,3-diketones into their 2-phenyliodonium derivatives and reaction of these with thioureas produces 2-amino-5-acylthiazoles. The first step in such ring syntheses is 5-alkylation. " A useful variant is the use of an a-diazo ketone in place of the a-halocarbonyl component. " ... 

Another application of the Hantzsch process is found in the synthesis of a monobactam antibiotic, Tigemonam. The monobactams are follow-ups to the penicilMns, both families being unique as derivatives of azetidinones (beta-lactams). Tigemonam also possesses a thiazole ling, which component is synthesized as in Scheme 9.20 from thiourea (shown in the -SH tautomeric form) and the chloroketone 9.26. 

Figure 9.16 Synthesis of 2-amino[2-" C]thiazoles from [ " C]thiourea and a-halocarbonyls...

Besides thiazoles, five-membered heterocycles of different types are obtainable from thioureas. Total loss of sulphur takes place in the condensation with arylacetonitriles, 2-amino-imidazoles (43) being formed, whereas in the... 

C- (112, 113), 4- C- and 5- C-thiazoles (112) were prepared by the same general pathway from the corresponding " C-labeled 2-aminothiazoles synthesized by the Hantzsch cyclization of C-thiourea, l- C-2-bromoethanal, and 2- C-2-bromoethanal, respectively (112). A mixture of 4- and 5- C-thiazoles was prepared by the same general... 

The symmetrical disubstituted thioureas such as 137 do not give a thiazolic ring (Scheme 66), but give compounds of type 138 or 139, which are derived from the tautomer imino form of the 2-aminothiazole (86). 

Other sulfur compounds such as thiourea, ammonium dithiocarbamate, or hydrogen sulfide also lead to 2-mercaptothiazoles. Thus thiourea has been used in the syntheses of 4,5-dimethyl (369) and 4-aryl-2-mercapto-thiazoles (Table 11-30) (519). The reactions were carried out by condensing the ia -thiocyanatoketones with thiourea in alcohol and water acidified with hydrochloric acid. By this procedure, 4-aryl-2-mercaptothiazoles were obtained in yields of 40 to 80% with bis-(4-aryl-2-thiazolyl) sulfides as by-products (519). These latter products (194) have also been observed as a result of the action of thiourea on 2-chloro-4-arylthiazole under the same experimental conditions. They can be separated from 2-mercaptothiazoles because of their different degrees of solubility in sodium hydroxide solution at 5%. In this medium bis-(4-phenyl-2-thiazolyl)sulfide is... 

DiaminO 4,4-dimethyl-l,3,5-thiadiazine hydrobromide was isolated as by-product (418). Benzene sulfonates of cyanohydrin prepared from sodium cyanide and an halobenzoaldehyde, when treated with thiourea or its derivatives, afford 2,4-diamino-5-(p-halogenophenyl)-thiazole benzene sulfonates (447). Similarly, cyanoamido thiocarbamates obtained from cyanamide and isothiocyanates yield substituted 2,4-diaminothiazoles (598). 

A variation of the general method for the synthesis of 2-amino-selenazoles is to avoid the use of the free a-halogenocarbonyl compound and in its place react the corresponding ketone and iodine with selenourea.This procedure is also taken from thiazole chemistry. By contrast with thiourea, the reaction with selenourea needs a longer reaction time and the work up of the reaction mixture is somewhat more difficult. Usually an excess of the ketone is used. In the preparation of 2-amino-4-( n-nitrophenyl)selenazole, a very high yield, calculated on the amount of iodine used, was obtained. To explain this peculiar result, the oxidative action of the nitro group was invoked. This liberates free iodine from some of the hydrogen iodide eliminated in the condensation reaction, and the free iodine then re-enters into the reaction. 

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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