Phenylthiazoles

The reaction of 2-mercapto-4-phenylthiazole with morpholine yields 2-morpholino-4-phenylthiazole (3) (Scheme 3) (31). 

The action of ammonia on N-(5-aryl-l,3-oxathioI-2-ylidene) tertiary iminium salts (7) affords linear intermediates that cyclize to 2-amino-4-phenylthiazoles (Scheme 7) (45). 

An intramolecular charge transfer toward C-5 has been proposed (77) to rationalize the ultraviolet spectra observed for 2-amino-5-R-thiazoles where R is a strong electron attractor. Ultraviolet spectra of a series of 2-amino-4-p-R-phenylthiazoles (12) and 2-amino-5-p-R-phenylthiazoles (13) were recorded in alcoholic solution (73), but, reported in an article on pK studies, remained undiscussed. Solvent effects on absorption spectra of 2-acetamido and 2-aminothiazoles have been studied (92). 

The crystal and molecular structures of 2-amino-4-phenylthiazole hydrobromide have been determined by radiocrystallography the angle between the thiazole and phenyl rings was found to be 19 . The major features are reported in Fig. VI-4 (142). 

Fig. Vl-4. Geometry of thiazole ring in 2-arniro-4-phenylthiazole hydrobromide. Italicized values are interatomic distances (A) other numbers are angles in degrees. From Ref. 342.

Both carbonyl groups of terephthaldehyde are reported to react with the exocyclic nitrogen of 2-aminothiazole yielding 1.4-phenylene bis(2-methyleneamino)thiazole. The same report describes the reactions of 2-amino-4-phenylthiazole with terephth aldehyde and salicylaldehyde as yielding 64 and 65, respectively (Scheme 45) (215), whose structures are based on ultraviolet and infrared spectra. 

The metabolite of 2-amino-4-phenylthiazole (used as an anaesthetic for fish) was identified (223) as 2-amino-4-phenylthiazole 2-N, -d-glucopyranosiduronic acid (71) (Scheme 50). The formation of this compound probably involves the reaction of the exocyclic nitrogen on the Open-chain form of the acid. The isolation of this metabolite is part of a very Systematic study by Japanese researchers related to the anaesthetic... 

In acidic medium and at higher temperatures, condensation of 2-amino-4-phenylthiazole takes place when it reacts with benzaidehyde... 

Diamino-4-phenylthiazole condenses with benzaldehyde, yielding 2-amino-4-pheny]-5-benzalaminothiazole (241). 

Rumpf et al. (97) studied the ultraviolet spectra of products obtained when 2-amino-4 phenylthiazole is acylated by /3-chloropropionyl chloride and y-chlorobutyrylchloride and showed that their structures were 94 and 95, respectively (Scheme 66). The open-chain intermediate to 95, 2-(3-... 

Acetamidothiazole is nitrated in the same way (58, 378, 379). 2-Acetamido-4-phenylthiazole is reported to be nitrated on C-5 (380) as opposed to 2-amino-4-phenylthiazole, where nitration occurs on the phenyl ring (381). This latter result is not consistent with the other data on electrophilic reactivity in most cases 2-amino-4-arylthiazole derivatives react with electrophilic reagents at the C-5 position (see Sections rV.l.B and D). Furthermore, N-pyridy]-(2)-thiazolyl-2-amine (178) is exclusively nitrated on the thiazole ring (Scheme 113) (132, 382). 

Yields can be very good Beyer (402) reports a 90% yield when coupling 2-amino-4-phenylthiazole with the diazonium salt of aniline. The coupling of diazotized anilines under modified conditions has been reported in a work treating the preparation of antineoplastics (403). 

The diazonium salt of 2-aminothiazole couples with 2-dimethylamino-4-phenylthiazole, giving the corresponding azo dye (194) (Scheme 123) used for dyeing synthetic fibers (404). 

Amino-4-phenylthiazole when heated with Raney Ni is reported to yield acetophenone (469). In the course of a general study on reductive cleavage in heterocyclic systems Hoff et al. studied the reaction of 2-amino-4-methylthiazole with Na in liquid ammonia. Two equivalents of Na are necessary to obtain a mixture of 4-methyl-3-thiazoline (240) and... 

These compounds are easily prepared from the appropriate 2-aminothiazole and acyl chloride (see Section III.2.D) or by general heterocydization methods. Acyl chlorides may be replaced by the corresponding anhydrides (471). Acids themselves may be used as acylating agents provided that the imidazole-triphenyl phosphine mixture is used as a catalyst (472). The Curtius degradation of 247 yields 2-acetamido-4-phenylthiazole (248) (Scheme 149) (473). 

The terminal amino group of 2-hydrazino-4-phenylthiazole is also the reactive center in reactions with activated aryl halides such as 288. A solution of the product (289) obtained from this reaction when shaken with PbOj gives a deeply colored radical, whose structure has been studied by ESR (Scheme 173) (532. 533). 

Aniino4-methyl-5-phenylthiazole-3-oxide (353) was synthesized from the a-chlorooxime and Ba(SCN)2 (Scheme 202) (682). This class of compounds is usually prepared by such heterocyclizations (683). 

Oxidative dimerization of various 2-benzyloxy-2-thiazoline-5-ones (222) catalyzed by iodine and triethylamine is another example of the nucleophilic reactivity of the C-4 atom (469) (Scheme 112). Treatment of 212 with pyrrolidinocyclohexene yields the amide (223) (Scheme 113). The mechanism given for the formation of 223 is proposed by analogy with the reactivitx of oxazolones with enamines (4701. 4-Substituted 2-phenylthiazol-5(4Hi-ones react with A -morphoiino-l-cyclohexene in a similar manner (562j. Recently. Barret and Walker have studied the Michael addition products... 

Benzylthio or 2-benzyloxy derivatives of A-2-thiazoline-5-one (224) are readily opened by amines to give the amide derivatives (225) (Scheme 115) (459. 471). Compound 225 can be cyclized thermally to the corresponding thiohydantoins (459). Similarly, treatment of 4-substituted-2-phenylthiazol-5(4H)-ones (226) with amino acids, peptides, or hydrazine affords the corresponding Nfcti-thiobenzamidoacetylated derivatives (227) (Scheme 116) (455). 

Applying this rule, the preceding dyes are written (3-methyl-4-phenyl-thiazole-2)(3-methylthiazole-2)methine cyanine iodide (3a) and (3-methyl-4-phenylthiazole-2)( l-methylquinoline-2)methine cyanine iodide (4), respectively. Any substituent in the chain is named and its position designated by a, ft or y, for example, (3-methyl-4-phenylthia2ole-2)(3-methylthiazole-2)-/S-methyltrimethine cyanine iodide (3b). 

The structure of 20 also explains why the MOl s reaction (43) leads to (3-methylbenzothiazole-2)(3-methy -4-phenylthiazole)monomethine iodide. 

The symmetrical dye, bis-(3-methyl-4-phenylthiazole)monomethine cyanine (not mentioned by Mills), has also been identified, and its formation is explained by the enamine character of 20 (Scheme 27). 

The steric bulk of the base added to 2-methyl-4-phenylthiazole (171b) is another factor of the orientation for the kinetic metalation of 4-substituted 2-methylthiazoles (Table 1-60). Even though the C-5 proton... 

Schatzmann, in 1891, tried to prepare 2-thiazolines by hydrogenation of thiazoles and by the action of sodium and ethanol on 2,4-dimethyl-thiazole, 2-methylthiazole, and 2-methyl-4-phenylthiazole (476). None of these substrates was reduced to thiazoline the second gave no reaction and the first underwent ring cleavage, leading to a mixture of n-propylmercaptan and ethylamine (Scheme 90). Three years later the same... 

Vernin et al. independently observed that during the irradiation in benzene of 2-iodothiazole to generate 2-thiazolyl radicals, the resulting 2-phenylthiazole (216) isomerized into a mixture of 4-phenylthiazole (214) and 3-phenylisothiazole (213) (Scheme 103) (489). Marking the 4- and... 

Another method of aldehyde bromination, apart from Riehl s established method (432) from bromine at 20°C, is to use trimethylphenyl-ammonium bromide in tetrahydrofuran solution, prepared by Vorlander and Siebert s method (50). However, the yield of 5-phenylthiazole using this method with thioformamide dissolved in dioxane is only 8% (513). 

Iminothiobutyramide (30), containing four nucleophilic centers (only two of which might react with two electrophilic sites in phenacylbromide), undergoes the Hantzsch reaction preferentially, yielding the enamine (31) in dry dioxane or (4-phenylthiazol-2-yl)acetone (32) in isopropanol. Other enamines are obtainable from the ketone (32) by standard methods (626) (Scheme 15). 

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). 

Thioacids (191) react with ia -thiocyanatoacetophenone to produce 2-mercapto-4-phenylthiazole (192) (Scheme 99). With tbioacetic acid 192 is obtained directly while with thiobenzoic acid, an acyclic intermediate (193) has been isolated that is cyclized by heating with dilute acid (Scheme 100) (143). 

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