2-Substituted aminothiazole

Substituted aminothiazole. 211-212 5-Substituted-2-aminothiazole, 183-185 4-Substituted-2-aminothiazoles, 172-177 4-Substituted-2-arylaminothiazoles, 204-209 4-Substituted-2-hetarylaminothiazoles, 210... 

Mane RA, Ingle DB (1982) Synthesis and biological activity of some new 1, 5-henzothia-zepines containing thiazole moiety 2-aryl-4-(4-methyl-2-substituted-aminothiazol-5-yl)-2, 3-dihydro-l,5-henzothiazepines. Indian J Chem Sect B 21B 973-974... 

Properties.— The known rearrangement of 3-substituted 2-imino-4-thiazolines into 2-(substituted)aminothiazoles has been further exemplified by the very ready conversion, under mildest conditions, of 3-ethyl-2-imino-5-nitro-4-thiazoline (255 R = Et, and analogues) into the isomers (256). ... 

N-Substituted aminothiazoles, with R = H, Me, CHMCj, R, =H. Me-Rz = H, Me, CHMcj, Ph, and Rj, R2 = CH2CH2, have been recently obtained by condensing thioureas with 1,2-dichloroethylisothiocyanate (Scheme 131) (805). 

As described above, a series of 5-pyridylaminothiazoles had been designed and synthesised as highly potent and selective antagonists at the adenosine A3 receptor (Press et al. 2004). It was essentially an extension of the structure-activity relationship to involve 5-imidazo and 5-triazolo substituted aminothiazoles which enabled the rapid identification of several dual A2B/A3 receptor antagonists with acceptable selectivity over the A and A2a receptors. Of the lead compounds, the mesylate salt of 3-[5-(meth-ylimidazol-l-yl)-2-(pyrazin-2-ylamino)-thiazol-4-yl benzonitrile (QAF805) was considered to be the superior compound (Compound 5f - Press et al. 2005). 

The preparation of a sequence of quinazolines inserted at C4 by aminothiazole ring is reported [111]. Their in vitro structure-activity relationships against Aurora A and B serine-threonine kinases are examined. The results reveal that quinazolines with a substituted aminothiazole... 

Physicochemical studies on aminothiazoles are mainly centered on two problems the position of imino-amino protomeric equilibrium and IsRR substitution effects on the thiazole nucleus. 

Infrared absorption properties of 2-aminothiazole were reported with those of 52 other thiazoles (113). N-Deuterated 2-aminothiazole and 2-amino-4-methylthiazo e were submitted to intensive infrared investigations. All the assignments were performed using gas-phase studies of the shape of the vibration-rotation bands, dichroism, isotopic substitution, and separation of frequencies related to H-bonded and free species (115). With its ten atoms, this compound has 24 fundamental vibrations 18 for the skeleton and 6 for NHo. For the skeleton (Cj symmetry) 13 in-plane vibrations of A symmetry (2v(- h, 26c-h- Irc-N- and 7o)r .cieu.J and... 

Intensities of the deformation vibration band near 1600 cm plotted for 2-aminothiazole and other 2-substituted thiazoles versus the Hammett constant give a linear relationship (123). 

The dipole moment of thiazole is increased by 2-amino group substitution (140). 2-lmino-4-thiazolines are more polar than their 2-aminothiazoles isomers (141). 

Maleic anhydride condenses with 2-aminothiazole-4-carboxylic acid giving the raaleimide 107 (269) another report claims, however, that the reaction of 2-amino-4-methylthiazole with this anhydride gives the N-substituted maleamic acid (108) (Scheme 73) (270). 

Even when deactivated by nitro substitution on C-5, the 2-aminothiazoles still undergo diazotization (35, 338-340). As with carbonyl derivatives (Section III.2.B), competition may occur between N nucleophilic reactivity and nitrosation of the 5-position when it is unsubstituted (341-344). 

In 2-aminothiazole the two N-bonded hydrogens are substituted by the trimethylsilyl group with the reagent trimethylsilyl chloride-triethylamine (Scheme 105) (348). 

Experimental requirements for the isolation of these nitramino derivatives are developed in Ref. 87. They rearrange easily to ring nitro-substituted isomers (see Section V.6). In the 2-aminothiazole series, nitration may proceed through direct electrophilic substitution competing with rearrangement of nitramino derivatives. Dickey et al. have shown that the rearrangement proceeds rapidly in 96% sulfuric acid at 2(fC, but in 85% sulfuric add it is very slow so. according the concentration of add various mechanisms can participate in the formation of the 5-nitro derivative. 

In fuming sulfuric acid (20% oleum) 2 aminothiazole (16. 27. 375. 389) and 2-amino-4-methylthiazole (374. 390) are sulfonated in the 5-position. When this position is substituted as in 2-amino-5-methyl-thiazole (27, 391) very small amounts of 4-sulfonation occur. 

Attack on the electrophilic C-2 may occur as in the 2-aminothiazoles series, which probably explains the rearrangements observed in acidic medium (121, 711, 712, 723, 724), in aqueous medium with NaOAc (725), or with aqueous NaHCOj (725) (Scheme 232). That the initial attack probably involves the C-2 atom is substantiated by the fact that this rearrangement occurs under extremely mild conditions for 2-iinino-3-substituted-5-nitro-4-thiazolines (725). As the whole mechanism proposed (see p. 92) is reversible, when imino derivatives are submitted to such rearrangement conditions the rearrangement is expected to occur faster if steric interaction between 3- and 4-substituents exists in the 2-imino isomer. Another reaction may occur in acidic medium phenylimino-2-bipheny]-3,4-4-thiazoline hydrolyzed with hydrochloric acid gives the corresponding 4-thiazoline-2-one and aniline (717). 

An interesting set of central nervous system properties has also been discovered and studied (Table VI-10). The work devoted to piscaine must be emphasized besides finding hypnotic properties of 2-amino-4-phenyl-thiazole on fish, the authors studied the structure of the metabolite, as well as the localization of the (radio labeled) metabolic product in various organs. Recently, thiazol-4-yl methoxyamine was shown to inhibit the development of morphine tolerance (1607). 5-Aminothiazole derivatives such as 419a were proposed as cardiovascular agents (1608, 1610). Substitution of the 5-aminothiazole radical on the cephalophosphorin structure gives a series of antibacterial products (1609). 

In agreement with the theory of polarized radicals, the presence of substituents on heteroaromatic free radicals can slightly affect their polarity. Both 4- and 5-substituted thiazol-2-yl radicals have been generated in aromatic solvents by thermal decomposition of the diazoamino derivative resulting from the reaction of isoamyl nitrite on the corresponding 2-aminothiazole (250,416-418). Introduction in 5-position of electron-withdrawing substituents slightly enhances the electrophilic character of thiazol-2-yl radicals (Table 1-57). 

Arylamino-2-chloroprop-2- enoic esters (72) obtained from 2-chloroaceto acetic ester (71) and arylamines, react with thiourea to yidd substituted 2-aminothiazoles (73), probably by initial nucleophilic substitution of the chloro atom of 72, followed by cyclization with loss of aniline (Scheme 33) (729). 

Some 5-substituted 2-aminothiazoles with alkyl (15, 173, 175, 224, 366, 396), ester (173, 184, 220), aryl (115, 265, 396, 414), a-naphthyl (463), sulfur and sulfones derivatives (329, 373), isonitrosomethyl (772), and chloro groups were synthetized from the corresponding a-haloaldehyde and thiourea in lower yield (Table 11-14). 

A variation of Hantzsch s synthesis, using thioureas in conjunction with a-diazoketones in place of a-halogenoketones, has proved to be generally applicable. In this manner, King and MUler (310) obtained 2-amino-4-phenylthiazole in 67% yield. A wide range of 4-substituted 2-aIkyl (or aryl) aminothiazoles and 2-arylimino-3,4-diarylthiazolines have been prepared by Hampel and Muller (627, 665, 666). 

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

This type of synthesis, which was investigated by Cook and Heilbron (323) and Takahashi (393, 394) between 1947 and 1953, gives 5-aminothiazoles variously substituted in the 2-position by reacting an aminonitrile with salts and esters of dithioacids, carbon disulfide, carbon oxysulfide, and isothiocyanates under exceptionally mild conditions. 

Carbon disulfide readily reacts with a-aminonitriles giving 2-mercapto-5-aminothiazoles (213), (271, 293) which can be converted to 5-aminothiazoles unsubstituted in the 2-position (Scheme 110 and Table II-34a). If this reaction is carried out in the presence of benzyl chloride in phosphorus tribromide, a 2-S-substituted thiazole derivative (214) is obtained in quantitative yield (Scheme 111), with R = hydrogen or phenyl (68, 304). 

By condensing carbon oxysulfide with o-aminOnitriles the corresponding 2-hydroxy-5-aminothiazoles can be obtained. In the presence of benzaldehyde or its substituted derivatives the reaction leads to 5-benzy-lideneaminothiazole derivatives (218) in good yields (Scheme 114 and Table 11.35) (393, 442). However, the reaction fails with or-amino acetonitrile (206), R = H (317). The 2-alkoxy analogs (220), R = Me, Et, Pr, Bu, vinyl, were similarly obtained from 219 and benzylideneamino acetonitrile (Scheme 115a) (393). 

Isothiocyanates of general formula 221 condensed with a-aminonitriles lead to 2-substituted 5-aminothiazoles (223) (Table 11-36) through an acyclic intermediate (222) (Scheme 116). 

For example, the condensation of the O-ethyl-a-chlorothioacetate, R2 = C( = S)OEt, with the potassium salt of thioacetylcyanamide (263), Rj = Me, produces the substituted 4-aminothiazole (257), in 79% yield (776). 2-Substituted 4-amino-5-cyanothiazoles (257), Ri = Me and R2 = CN, have been similarly obtained. 

The 2-nitrothiazole can be reduced to the corresponding aminothiazole by catalytic or chemical reduction (82, 85, 89). The 5-nitrothiazole can also be reduced with low yield to impure 5-aminothiazole (1, 85). All electrophilic substitution reactions are largely inhibited by the presence of the nitro substituent. Nevertheless, the nitration of 2-nitrothiazoIe to 2,4-dinitrothiazole can be accomplished (see Section IV). 

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