Thiazole and 4-Methylthiazole

TABLE m-31. INFLUENCE OF ACIDITY ON THE REPARTmON OF PHENYL ISOMERS OF THIAZOLE AND 4-METHYLTHIAZOLE AT 115 C (196). 

The most reactive position of thiazole toward Grignard or or-ganolithium reagents is the 2-position. 4,5-Dimethylthiazole (13, 439), 4-ethyl-5-methylthiazole (437), 4-methylthiazole (13, 423, 437), 5-methyl-4-ethyl-thiazole, and 4,5-diethylthiazole (13) readily exchange their hydrogen in the 2-position against lithium or magnesium. The stability of the... 

Tautomers and conformers (T/Cs) of amthamine (2-amino-5-(2-aminoethyl)-4-methylthiazole) and its derivatives (2-amino-5-(2-aminoethyl)thiazole and 4-methyl-5-(2-aminoethyl)thiazole) in neutral and monocationic states were... 

The photoisomerization of isothiazole 3 to thiazole 4 was the first reported phototransposition in the isothiazole-thiazole heterocyclic system [3]. Methylisothiazoles have also been shown to undergo transposition. In neutral solvents, Lablache-Combier and coworkers reported that 3-methylisothiazole 41 and 4-methylisothiazole 42 each transpose to a single product, 2-methylthiazole 44 and 4-methylthiazole 45 respectively. According to this report, however, 5-methyl-isothiazole 43 transposes to three primary products, 5-methylthiazole 46, 3-methylisothiazole 41, and 4-methylisothiazole 42 [26]. 

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. 

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),... 

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). 

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. 

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). 

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). 

R. Mellon (19) but using anhydrous reagents. He obtained an oil that reacted exothermically with hydroxylamine (oxime of m.p. 135°) and that isomerized to 2-oxy-4-methylthiazole (14) upon heating with diluted hydrochloric acid. The thiazolic nature of oxymethylthiazole was clearly demonstrated by its reduction by zinc powder distillation into 4-methylthiazole (23), the first free thiazole ever described. 

Under appropriate conditions 2-amino-4-alkylthiazoles are alkylated in the 5-position 2-acetylamino-4-methylthiazole reacts with dimethyl-amine and formaldehyde to afford the corresponding Mannich base (113) (372). 2-Amino-4-methyl-thiazole is alkylated in the 5-position by heat-... 

With the exception of the nuclear amination of 4-methylthiazole by sodium amide (341, 346) the main reactions of nucleophiles with thiazole and its simple alkyl or aryl derivatives involve the abstraction of a ring or substituent proton by a strongly basic nucleophile followed by the addition of an electrophile to the intermediate. Nucleophilic substitution of halogens is discussed in Chapter V. 

All the early literature concerning thiazoles mentions numerous metallic complex-salts formed by addition to the thiazole of the aqueous solution of the metal salt and that could be used for identification purposes. The most usual complexes so obtained are platinum double salts, for example, (4-methylthiazole HC1)2 PtCU (m.p. deep 204°C) (25), or mercuric chloride derivatives, for example, 2,4-dimethyl-thiazole 2 HgCl (m.p. deep 176-177°C) (458). 

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... 

Mills and Smith (504) were the first, in 1922, to develop a systematic study of the reactivity of methyl groups fixed on nitrogen-containing heterocycles. While in alkylpyridines the 2- (or 6) and 4-positions are activated, only the 2-position in thiazole corresponds to an enhanced reactivity of the methyl groups in condensation with aldehydes 4- and 5-methylthiazoles bear inert methyl groups. Quatemization of the thiazole nitrogen enhances still further the reactivity of the methyl in the 2-position (cf. Chapter IX), but it does not increase the reactivity of a methyl group in the 4-position (504). The authors invoke the possibility for 2- (and 6) methylpyridine and 2-methylthiazole to pass, to some extent, into the reactive enamine form (245), while 4-methylthiazole could adopt such a structure only with the participation of an unusual formula such as 247 (Scheme 112). 

TABLE 111-24. PRODUCTS FORMED BY THE DECOMPOSITION OF BENZOYL PEROXIDE IN THIAZOLE, 4-METHYLTHIAZOLE, AND 2.4-DIMETHYLTHIAZOLE WITH A MOLAR RATIO OF AND A REACTION TIME OF 20 hr AT 78°C (184)... 

Halogenation (e.g., bromination) takes place in chloroform for the 2,4-dialkylthiazoles, and the majority of studies have been of 2,4-dimethylthiazole (227, 228). In other cases and in acetic or stronger acids, substitution occurs at the 5-position and is promoted by electronreleasing groups in the 2-position. When the releasing group is in the 4-(or 5-)-position, steric hindrance may decrease the yield of substitution at the 5- (or 4-) position. Nevertheless, the thiazole nucleus is not very reactive since 4-methylthiazole and 2.5-dimethylthiazole are inert in dilute sulfuric acid with bromine (229-231). 

Only one reaction of thiazole N-oxides has been studied in detail. The rearrangement in acetic anhydride of 2,4-dimethylthiazoIe-3-oxide gave 2-acetoxy-4-methylthiazole and 4-acetoxymethyl-2-methylthiazole in a ratio of about 4.5 to 1(264). 

NMR data for 4-methyloxazole have been compared with those of 4-methylthiazole the data clearly show that the ring protons in each are shielded. In a comprehensive study of a range of oxazoles. Brown and Ghosh also reported NMR data but based a discussion of resonance stabilization on pK and UV spectral data (69JCS(B)270). The weak basicity of oxazole (pX a 0.8) relative to 1-methylimidazole (pK 7.44) and thiazole (pK 2.44) demonstrates that delocalization of the oxygen lone pair, which would have a base-strengthening effect on the nitrogen atom, is not extensive. It must be concluded that not only the experimental measurement but also the very definition of aromaticity in the azole series is as yet poorly quantified. Nevertheless, its importance in the interpretation of reactivity is enormous. 

Reaction of thiazoles with DMAD illustrates the overall reaction and the rearrangements which may be encountered. Thiazole or 2-methylthiazole (411 R=H and Me, respectively) in DMF reacted with DMAD to give an initial 1,4-dipolar species (412). Reaction with a second DMAD gave the 1 2 molar adduct, presumably (413). Ring opening to (414), followed by cyclization in the alternative mode, resulted in the formation of (415), the structure of which (R = Me) was established by X-ray analysis (78AHC(23)263) (see also Chapter 4.19). 

The irradiation of thiazole did not give any interesting products [69JCS(CC) 1018]. However, 2-, 4-, and 5-methylthiazole gave the corresponding isothiazoles in low yields when irradiated in trifluoroacetic acid (Scheme 31) (93JOC3407). 

The irradiation of isothiazole with a low-pressure mercury arc leads to the formation of thiazole [69JCA(CC)1018], The photochemical behavior of alkyliso-thiazoles has been studied. 3-Methylisothiazole gave 2-methylthiazole in a low yield. 4-Methylisothiazole was converted into 4-methylthiazole, and 5-methyliso-thiazole gave a mixture of 5-methylthiazole (55%) and 4-methylisothiazole (Scheme 38) (72T3141 93JOC3407). Either a ZI (72T3141) or an ICI mechanism was invoked to justify these reactions (93JOC3407). 

Thiazoles also undergo Diels-Alder additions, but have been used less. In the examples shown, 5-ethoxy-4-methylthiazole is converted into the pyridinedicarboxylic acid (738), and into pyridoxine (737) (65FRP1400843). The mechanism must be similar to that proposed for the oxazole additions. In both cases the initial adducts are treated with hydrochloric acid sulfur dioxide is said to be given off in the first case, hydrogen sulfide in the second, the latter providing an analogy with the oxazole mechanism. 

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