Methylthiazoles

Amino-4 -methylthiazole slowly decomposes on storage to a red viscous mass. It can be stored as the nitrate, which is readily deposited as pink crystals when dilute nitric acid is added to a cold ethanolic solution of the thiazole. The nitrate can be recrystallised from ethanol, although a faint pink colour persists. Alternatively, water can be added dropwise to a boiling suspension of the nitrate in acetone until the solution is just clear charcoal is now added and the solution, when boiled for a short time, filtered and cooled, deposits the colourless crystalline nitrate, m.p. 192-194° (immersed at 185°). The thiazole can be regenerated by decomposing the nitrate with aqueous sodium hydroxide, and extracting the free base with ether as before. 

Amino-5-methylthiazole. Suspend 76 g. of thiourea in 200 ml. of water in a 500 ml. three-necked flask equipped as in the preceding pre paration. Stir and add 92 -5 g. (80 ml.) of monochloroacetone (1) over a period of 30 minutes. The thiourea dissolves as the reaction proceeds and the temperature rises. Reflux the yellow solution for 2 hours. To the cold solution immersed in an ice bath add, with stirring, 200 g. of solid sodium hydroxide. Transfer to a separatory funnel, add a little ice water, separate the upper oil layer and extract the aqueous layer with three 100 ml. portions of ether. Dry the combined oil and ether extracts with anhydrous magnesium sulphate, remove the ether by distillation from a steam bath, and distil the residual oil under diminished pressure. Collect the 2-amino-5-methylthiazole at 130-133°/18 mm. it solidifies on coohng in ice to a solid, m.p. 44-45°. The yield is 84 g. 

Determination of structural features. The ultraviolet spectrum has been of value in the determination of the structure of several vitamins. Thus the presence of an a-naphthoquinone system in vitamin K was first detected by this means. Also the 4-methylthiazole and the 2 5-dimethyl-6-aminopyridine system was first identified in vitamin Bj (thiamine), a- and /3-Ionones can be distinguished since the former contains two conjugated chromophores and the latter three conjugated chromophores. 

This reaction, thoroughly studied for 2-aminopyridine (14, 15), has received less attention in the case of the thiazole nucleus. 2-Amino-4-methylthiazole is formed when 4-methylthiazole is heated with sodium amide for 15 hr at 150°C (16). This reaction was used to identify 2-amino-4-butylthiazok (17). 

The mass spectra of 2-aminothiazole and 2-amino-4-methylthiazole are characterized by the following peaks (136). 

During the course of biochemical studies (138). the mass spectrum of 2-acetamidothiazole was recorded its main peaks are the molecular ion (m/e= 142, relative intensity = 26%) and fragments 100 (100), 58 (2. 5), and 43 (39). For 2-acetamido-5-bromothiazole the main peak results again from the loss of C2H2O by the molecular ion. 2-AcetyIacet-amido-4-methylthiazole (2S) exhibits significant loss of from the... 

With the more acidic 2-acetamido-4-R-thiazoles. using the weaker base NaOH as condensation agent, a mixture of ring (45) and exocyclic N-alkylation (46) may be observed (Scheme 33) (121). Reaction of 2-acetamido-4-methylthiazole in alcoholic sodium ethoxide solution with a variety of alkylating agents has been reported (40-44). 

Zugravescu et al. (263) showed that ethyl chloroformate reacts on the exocyclic nitrogen of 2-amino-4-methylthiazole to yield the carbamate (101) (Scheme 70) (see also Refs. 264 and 265). With an excess of chloroformate (2 moles for one of the thiazole) under Schotten-Bauman conditions the jV.A -dicarbamate of 2-imino-4-methylthiazoline (102) is obtained (263),... 

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). 

Takatori (274) formylated 2-amino-4-methylthiazole with formic acid. When NHj is bubbled for 6 hr into a mixture of 2-amino-4-methyl-thiazole and propionic acid at 100°C, 2-propionamido-4-methylthiazole is obtained (275). 

Vollmann found that the reaction between l-imino-3-amino isoin dolenine (124) and 2-amino-4-methylthiazole is catalyzed by ammonium chloride and involves the exocyclic nitrogen (285). This reaction (Scheme 82) was later used to prepare dyes (286). 

Picryl halides react with 2-amino-4-methylthiazole. Again, the exocyclic nitrogen is the reactive center (288). and the product formed (128) is... 

Amino-4-methylthiazole also gives a complex with Hg(II) that has been used in a gravimetric determination of this metal (366). 

When 2-amino-4-methylthiazole is nitrated under mild conditions, 2-nitramino-4-methylthiazole (180) is isolated (Scheme 114) (16, 194. 374). 

When the 5-position is occupied, as in 2-acetamido-5-methylthiazole (182), small amounts of 4-nitration are observed (Scheme 116) (27). 

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. 

Attempts to prepare the diprOpylamino-5-sulfonic acid by sulfonation in oleum failed (385). With 2-piperidino-4-methylthiazole Ochiai reports cleavage of the 2-piperidino ring (391). 

Amino-5-methylthiazole does not react with diazotized p-nitroaniline in solutions acidified with acetic or hydrochloric acid (391). 2-Amino-4,5-dimethylthiazole with the diazonium salts of para-substituted anilines, however, gives product 193, involving reactivity of the exocyclic nitrogen (Scheme 122) (399). 

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). 

Acetamido-4-methylthiazole does not react with acetyl chloride in the Friedel-Crafts reaction (172. 407, 449). 

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... 

The sulfur atom of the thiocarbonyl group is a good nucleophile, and reaction between benzyl bromide and l-(2-thiazolyl)thiourea yields the isothiouronium salt (496). The sulfur atom may also be engaged in a chelate, as exemplified by the Cu chelate of 2-thioureido-4-methylthiazole (491). These chelates with metal ions were thoroughly studied in acidic, neutral, and alkaline media for 66 metal ions in order to define their analytical use. They are formed in the molar ratio of 1 2 for metal II compounds (498). 

Diazo coupling involves the N exocyclic atom of the diazonium salt, which acts as an electrophilic center. The diazonium salts of thiazoles couple with a-naphthol (605). 2-nitroresorcinol (606), pyrocatechol (607-609), 2.6-dihydroxy 4-methyl-5-cyanopyridine (610). and other heteroaromatic compounds (404. 611) (Scheme 188). The rates of coupling between 2-diazothicizolium salts and 2-naphthol-3.6-disulfonic acid were measured spectrophotometrically and found to be slower than that of 2-diazopyridinium salts but faster than that of benzene diazonium salts (561 i. The bis-diazonium salt of bis(2-amino-4-methylthiazole) couples with /3-naphthol to give 333 (Scheme 189) (612). The products obtained from the diazo coupling are usuallv highly colored (234. 338. 339. 613-616). 

Perfused rat liver rapidly converts 4-m thyI-5-/3-chloroethy]thiazole to 2-hydroxy -4-methylthiazol-5-y) acetic acid (40. 41). Finally, tw o new human metabolites of chlormethiazole have been isolated and identified by mass spectra as 2-hydroxy-4-methyl-5-/S-chloroethylthiazole and 2-hydroxy-4-methyl-5-ethylthiazole (42). 

Very small amounts of 2-hydroxy-4-methylthiazole-5-acetic acid were determined by chromatographic techniques in bacterial culture medium (41). 

Recently, Hoff and Blok report the reductive ring opening of 4-methyl-A-4-thiazoline-2-thione anion (80) (Scheme 39) (204) when treated with two equivalents of sodium in liquid amonia. Treatment of the prop-enethiolate (83) by 4N aqueous HCl affords 4-methylthiazole. The... 

The rearrangement discovered by Kolosova et al. probably involves such reactivit (159). This reaction provides a good preparative method for various 5-amino-methylthiazoles (Scheme 43). No mechanism is proposed in the report, and it is not easy to understand how the C-5 enamine-like position competes with the very nucleophilic thiocarbonyl group of the formed A-4-thiazoline-2-thione. An alternative mechanism could start with ethanol addition at C-2. leading to the A-4-thiazoline (90) (Scheme 44). In this intermediate, C-5 nucleophilic reactivity would be favored bv the true enaminic structure. After alkylation on C-5,... 

When unsubstituted, C-5 reacts with electrophilic reagents. Thus phosphorus pentachloride chlorinates the ring (36, 235). A hydroxy group in the 2-position activates the ring towards this reaction. 4-Methylthiazole does not react with bromine in chloroform (201, 236), whereas under the same conditions the 2-hydroxy analog reacts (55. 237-239. 557). Activation of C-5 works also for sulfonation (201. 236), nitration (201. 236. 237), Friede 1-Crafts reactions (201, 236, 237, 240-242), and acylation (243). However, iodination fails (201. 236). and the Gatterman or Reimer-Tieman reactions yield only small amounts of 4-methyl-5-carboxy-A-4-thiazoline-2-one. Recent kinetic investigations show that 2-thiazolones are nitrated via a free base mechanism. A 2-oxo substituent increases the rate of nitration at the 5-position by a factor of 9 log... 

Methylthio- and 2-ethylthio-4-methylthiazoles undergo reductive ring opening when treated by sodium in liquid ammonia (204). The first step of this reaction consists of the formation of the A-4-thiazoline anion (80). The next steps are analogous to those given for 80a to 83. 

Direct sulfonation of thiazole, as well as of 2-substituted thiazoles, leads mostly to substitution m the 5-position (330-332). 4-Thiazole sulfonic acid has been prepared through direct sulfonation of 2.5-dibromothiazole with subsequent Rane% Ni reduction (330). Sulfonation of 2.5-dimethyl- and 2-piperidyl-5-methylthiazoles affords the corresponding 4-sulfonic acids as barium salts (247). The 2-hydroxy group facilitates the sulfonation (201. 236). When the 4- and 5-positions are occupied direct sulfonation can occur in the 2-position. 5-hydroxyethyl-4-methyl-2-thiazole sulfonic acid has been prepared in this manner (7). 

Thus reduction of the 5-thiocyanato group of 151 by zinc (333, 360, 361) or aqueous sodium sulfide (348. 362), hydrolysis of the thiouronium group (7, 363, 364), and deacetylation of the 5-acetylthiothiazole with cold piperidine (365) have been performed to yield the 5-mercapto-thiazole (Scheme 78). It must be pointed out that depending on the experimental conditions, bis(5-thiazolyl(sulfide may be observed as a byproduct (363, 365). Thus 5-amino-4-methylthiazole (152) treated with... 

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). 

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