4.5- Disubstituted-2-aminothiazoles

Diorthohydroxazo, 153 1,3-Dipolar cyclo additions, with dimethyl acetylenodicarboxylate, 426, 427 with methyl fumarate, 425,426 with methyl maleate, 425, 426 of A-2-thiazoline-4-one, 425, 426 Dipole moment, 2-ammothiazole. 29 2-imino-4-thiazoline, 29 A-4-thiazoline-2-one, 389 in A-4-thiazoline-2-thione, in relation with protomery, 379 Disproportionation, 107 2-Disubstituted aminothiazoles, 259-267... 

The JV,N-disubstituted thioureas (135) condensed with a-halocarbonyl compounds give 2-disubstituted aminothiazoles (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 N,7V -dialkyl-2-aminothiazo]es in 136, Rj = R2 = methyl (342, 404, 436, 637), ethyl (343, 436), n-propyl (518), n-butyl (518), allyl (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. 

Methyl (299), phenyl (299), acetyl (394). benzoyl (299, 394), and carbethoxy (292) isothiocyanates (221), R, = Me, Ph, Ac, PhCO, COjEt. have been successfully used. In some cases, a 2,5-disubstituted aminothiazole (224) was isolated as by-product (292). 

The 2-monosubstituted or disubstituted aminothiazoles obtained reaction between Halo carbonyl and N-substituted thiourea compounds [38]. 

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). 

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-... 

Potassium salts of cyanoimidodithiocarbonates (291) react successively with an alkyl halide and a-halo esters, nitriles, amides or ketones (293) in basic medium to yield 2,5-disubstituted 4-aminothiazoles (294 Scheme 204) (67JPR(309)97). 

An aromatic halide linked to a polystyrene resin 52 was treated with tributyl(l-ethoxyvinyl)tin under Stille conditions to give a vinyl ether which was treated with NBS to afford the a-bromoketone 53. Subsequent reaction with a thioamide or thiourea gives 2,4-disubstituted or 2-aminothiazoles 54, after cleavage of the resin, in good to excellent yields <02TL3193>. 

TABLE n-20, N,N-DISUBSTITUTED 2-AMINOTHIAZOLES FROM -HALOCARBONYL COMPOUNDS AND... 

It is well known that halomethyleneiminium salts, often prepared in situ (see Section 2.1.2.2) react with ammonium salts, primary amines, secondary amides, urea and IV-substituted ureas to afrbrd amidinium salts, from which the free amidines can be obtained by addition of bases. > 4 Some recent results are given below. Dimethylformamide chloride and other 7V,iV-disubstituted formamide chlorides were reacted with acetanilides, chloroacetanilides, 6-aminopenam derivatives, 2-aminopyrimidine, 4-aminouracil, 2-amino-4-chloropyridazine, 2-aminothiazole, 2-aminobenzothiazole and thiobenzamides to give the amidines via the amidinium salts. In the reaction of MA -disubstituted formamide chlorides with thiobenzamides the solvent seems to be decisive for the course of the reaction. In tertiary formamides the thiobenzamides are desulfurized to nitriles, whereas in CHCI3 or CCI4 amidinium salts (296 Scheme 45) are formed. From trimethylsilyl isocyanate and the fluorinated amine (297) the /V-fluorocarbonylamidine (298) is accessible. ... 

Thiazoles may also be intermediate in some other imidazole syntheses <87CJC282>. Dimroth rearrangement of 5-aminothiazoles ((255), (256)) gives hydantoin analogues <86BSBll29>. While 2,4-disubstituted thiazole A(-oxides are converted by aryl isocyanates into imidazoles, the 2,5-isomers are unreactive (Scheme 191) <82CPB1722>. 

Aminothiazoles are deprotonated by butyllithium at the C-5. For instance, using two equivalents of base, compound (61) yields the 5-lithio derivative (62) (Equation (15)) <9lJHCioi7>. In the case of A,A-disubstituted 2-aminothiazoles only 1.0 equivalent of base is necessary. 

Disubstituted 2-aminothiazoles can be synthesized from enamines (314) prepared from enol-... 

Other Type A (S—C—N + C—Q Syntheses. —Aminothiocyanogen (12) reacts with a variety of ketones in ether to afford satisfactory yields of 4,5-disubstituted 2-aminothiazoles (13). iST-Methylthiazolines, e.g, (15), are similarly accessible from iV-methylaminothiocyanogen (14). The reaction appears to proceed by way of intermediate enamines in the... 

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