1,3-Thiazole alkylation

Thiazole, 2-acetylamino-4-methyl-alkylation, 6, 256 Thiazole, 2-acylamino-4-hydroxy-synthesis, 6, 297 Thiazole, 5-alkoxy-cleavage, 6, 289 synthesis, 6, 302 Thiazole, 2-alkyl-A7-alkylation, 6, 253 hydrogen exchange, 6, 276 methylation, 6, 253 quatemization, 6, 253-254 reactions, S, 88 Thiazole, 4-alkyl-A7-alkylation, 6, 253 methylation, 6, 253 quatemization, 6, 253-254 Thiazole, 5-alkyl-A7-alkylation, 6, 253 methylation, 6, 253 Thiazole, 2-alkylamino-tautomerism, 6, 248 Thiazole, 4-alkyl-2,5-dimethyl-quatemization, 6, 253-254 Thiazole, 2-alkylthio-reactions, S, 103 rearrangement, 5, 103 6, 291 Thiazole, 3-allyl-4-hydroxy-2-imino-synthesis, 6, 297 Thiazole, 2-allyloxy-rearrangement, 6, 289 Thiazole, 2-amino-diazo coupling, 6, 257 nitration, 6, 255... 

Alkylation of 2-methylaminothiazole (204) with ROH in 85% sulfuric acid gives 2-methylimino-3-alkyl-4-thiazoline (54). 2-Amino-4-methvl-thiazole alkylated with an excess of isopropanol, however, gives 95% of 2-isopropylamino-4-methyl-5-isopropylthiazole (56). The same result is obtained with cyclohexanol (242). These results and those reported in Sections III.l.C and IV.l.E offer interesting new synthetic possibilities in thiazole chemistry. The reactive species in these alkylations is the conjugate acid of 2-aminothiazole. and the diversity of the products obtained suggests that three nucleophilic centers may be operative in this species. 

Thin layer chromatography and gas-liquid chromatography have been widely applied for the separation and for the identification of thiazoles in reaction mixtures. From systematic studies it appears that thiazole, alkyl- and aryl-thiazoles and benzothiazoles are best separated on stationary phase of low polarity in GLC and with eluents of low polarity in TLC. It has been possible to correlate, for these series of compounds, the RF of TLC or the specific volume of retention in GLC with the number of carbon atoms in the aliphatic side chain, and also with the rate constants of quaternization of the cyclic nitrogen atom. This last observation indicates a significant participation of the nitrogen atom in the chromatographic processes (67BSF846). 

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). 

The HSAB pattern may also be reversed by steric effects a Japanese patent describes the preparation of 3-(4-R-thiazolyl-2)thioallophanic acid esters (151) by reaction between 2-amino-4-R-thiazoles (4-R = H or low alkyl) and isothiocyanate formic acid ester (Scheme 96) (309). 

The general pattern of alkylation of 2-acylaininothiazoles parallels that of 2-aminothia2ole itself (see Section III.l). In neutral medium attack occurs on the ring nitrogen, and in alkaline medium a mixture of N-ring and N-amino alkylation takes place (40, 43, 161. 163). In acidic medium unusual behavior has been reported (477) 2-acetamido-4-substituted thiazoles react with acetic anhydride in the presence of sulfuric acid to yield 2-acetylimino-3-acetyl-4-phenyl-4-thiazolines (255) when R = Ph. but when R4 = Me or H no acetylation occurs (Scheme 151). The explanation rests perhaps in an acid-catalyzed heterocyclization with an acetylation on the open-chain compound (253), this compound being stabilized... 

The nitro group increases the acidity of the hydrogen born by the exocyclic nitrogen, and alkylation of 2-nitraminothiazole with diazomethane is possible (87), The formed 2-(A"-methylnitramino)-thiazole also may be obtained from the reaction of 2-nitraminothiazole with dimethylsulfate in basic medium (194). 

Nucleophilic reactivity of the sulfur atom has received most attention. When neutral or very acidic medium is used, the nucleophilic reactivity occurs through the exocyclic sulfur atom. Kinetic studies (110) measure this nucleophilicity- towards methyl iodide for various 3-methyl-A-4-thiazoline-2-thiones. Rate constants are 200 times greater for these compounds than for the isomeric 2-(methylthio)thiazole. Thus 3-(2-pyridyl)-A-4-thiazoline-2-thione reacts at sulfur with methyl iodide (111). Methyl substitution on the ring doubles the rate constant. This high reactivity at sulfur means that, even when an amino (112, 113) or imino group (114) occupies the 5-position of the ring, alkylation takes place on sulfiu. For the same reason, 2-acetonyi derivatives are sometimes observed as by-products in the heterocyclization reaction of dithiocarba-mates with a-haloketones (115, 116). 

The nucleophUic reactivity in neutral medium has been used extensively to prepare various thioethers of thiazole (122). In acidic medium, alkylation may be performed with alcohols (123, 124). An unexpected reaction encountered was the decarboxylation of 2-mercapto-4-methyl-5-thiazolecarboxyhc acid (60) when treated with butyl alcohol under acidic conditions (Scheme 27) (123). Reaction between A-4-thiazoline-2-thione... 

The methylthio group is removed by treatment with zinc powder in HCl (276) to give the 2-unsubstituted thiazole. The action of aluminum-mercury amalgam in methanol on various thioethers is reported to yield the expected thiazole (108) when Rj is an alkyl group and the corresponding A-4-thiazoline-2-thione (109) when Rj PhCH - (Scheme 55) (169). 

Whatever their nature may be, phenyl or alkyl, the substituents of the thiazole ring in position 4 or 5 give a bathochromic shift (110, 111) of the absorption of a symmetrical trimethine thiazolocyanine compared to an unsubslituted dye. For a given substituent, this shift is greater for position 5 than for 4 (112). 

Alkylselenazoles are oily alkaline liquids possessing a smell similar to that of the corresponding thiazole or pyridine derivatives. The crystalline picrates or 3-methylselenazolium iodides have been used for the purpose of characterization. Alkyl derivatives are partially soluble in water aryl derivatives are insoluble. 

III. Alkyl, Aryl, Aralkyl aud Related Thiazole Derivatives... 

Quantum chemistry methods allow the prediction of the ultraviolet transitions in good agreement with the experimental values in the case of thiazole and its three methyl derivatives (Table 1-18). A very weak absorption has been indicated at 269.5 nm that could correspond to an n- TT transition given by calculation at 281.5 nm (133). Ultraviolet absorption spectroscopy has been investigated in connection with steric interactions in the A-4-thiazoline-2-thione (74) series (181). It was earlier demonstrated by NMR technique that 4-alkyl-3 isopropyl-A-4-thiazoline-2-thiones exist in solution as equilibrium mixtures of two conformers (75 and 76), the relative populations of which vary with the size of R4 (182) for R4 = rBu the population of rotamer A is 100%, whereas for R4 = Me it is only 28%. Starting from the observed absorption wavelength for... 

Ultraviolet photoelectron spectroscopy allows the determination of ionization potentials. For thiazole the first experimental measurement using this technique was preformed by Salmona et al. (189) who later studied various alkyl and functional derivatives in the 2-position (190,191). Substitution of an hydrogen atom by an alkyl group destabilizes the first ionization potential, the perturbation being constant for tso-propyl and heavier substituents. Introduction in the 2-position of an amino group strongly destabilizes the first band and only slightly the second. 

Until 1962 the infrared and Raman spectra of thiazole in the liquid state were described by some authors (173, pp. 194-200) with only fragmentary assignments. At that date Chouteau et al. (201) published the first tentative interpretation of the whole infrared spectrum between 4000 and 650 cm for thiazole and some alkyl and haloderivatlves. They proposed a complete assignment of the normal modes of vibration of the molecule. 

The molar refraction deduced for alkyl derivatives, compared to the value obtained by addition, to the experimental molar refraction of thiazole, of the classical (CH2) increment of Eisenlohr Rch 4.618 cm ), show specific exaltations which are typical for each position of the thiazole ring (Table 1-49). 

Potentiometric determinations of the pK of thiazole and essentially its alkyl derivatives are summarized in Table T50. The most reliable values are given by Phan-Tan-Luu et al. (321), who realized a critical study of the classical Henderson method for the determination of pK. ... 

A radically different course is followed when the reaction of 2-alkyl-substituted thiazoles is periormed in methanol or acetonitrile (335), 2 1 adducts containing seven-membered azepine rings (91) are being formed in which two of the original activated hydrogen atoms have altered positions (Scheme 55). A similar azepine adduct (92) was obtained by... 

Thiazole Nitration Sulfonation Brominadon Mercuration Alkylation... 

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-... 

More quantitative results are available for the nitration of alkyl-thiazoles Dou et al. (373) determined the reactivity, relative to benzene, of the nitration site of various mono- and dialkylthiazole by competition experiments (Table 1-53). 

The radical phenylation of a large number of mono- and dialkyl-thiazoles has been investigated (393,395,396,399-405, for a general review cf. 398) and analyzed in terms of partial rate factors. As in other instances the alkyl groups slightly activate the substrate in certain positions toward phenyl radicals, but they also induce some steric hindrance to the approach of the aryl radical from the onho positions (Fig. 1-19). 

Methyl free radicals, generated either by thermolysis of lead tetracetate in acetic acid solution (401) or by radical cleavage of dimethylsulfoxide by H2O2 and iron (II) salts (408), afford 2- and 5-methylthiazole in the proportion of 86 and 14%, respectively, in agreement with the nucleophilic character of alkyl free radicals and the positive charge of the 2-carbon atom of the thiazole (6). 

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. 

The 2-metalated thiazoles react with a variety of electrophilic substrates in a standard way, leading to addition products with aldehydes, ketones, carbon dioxide, epoxides, nitriles, Schiff bases, and to substitution products with alkyl iodides (12, 13, 437, 440). 

The same situation is observed in the series of alkyl-substituted derivatives. Electron-donating alkyl substituents induce an activating effect on the basicity and the nucleophilicity of the nitrogen lone pair that can be counterbalanced by a deactivating and decelerating effect resulting from the steric interaction of ortho substituents. This aspect of the reactivity of thiazole derivatives has been well investigated (198, 215, 446, 452-456) and is discussed in Chapter HI. 

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