Thiazole. 4-methyl. basicity

Thiazole. 4-methyl, basicity of, 75 pK value of, 62 4-phenyl, basicity of. 75 quaternization of, 31... 

The basicity of a 4-phenyl-substituted thiazole is less than the corresponding methyl-substituted thiazole (16) and the pKa values of quaiemarv salts are in the same order (25). 

As early as 1889 Walker (320), using samples of thiazole, 2,4-dimethylthiazoie, pyridine, and 2,6-dimethylpyridine obtained from Hantzsch s laboratory, measured the electrical conductivity of their chlorhydrates and compared them with those of salts of other weak bases, especially quinoline and 2-methylquinoline. He observed the following order of decreasing proton affinity (basicity) quinaldine>2,6-dimethyl-pyridine>quinoline>pyridine>2,4-dimethylthiazole> thiazole, and concluded that the replacement of a nuclear H-atom by a methyl group enhanced the basicity of the aza-aromatic substrates. 

In all its reactions the lone pair of thiazole is less reactive than that of pyridine. Table 1-61 shows three sets of physicochemical data that illustrate this difference. These are (1) the thermodynamic basicity, which is three orders of magnitude lower for thiazole than for pyridine (2) the enthalpy of reaction with BF3 in nitrobenzene solution, which is 10% lower for thiazole than for pyridine and (3) the specific rate of quaterni-zation by methyl iodide in acetone at 40°C, which is about 50% lower for... 

Another bright blue dye from diazotized 2-amiao-6-methoxybenzothiazole [1747-60-0] by azo coupling, eg, with 2(/V-ethy1ani1ino)ethano1 is Basacryl Blue X-3GL [12270-13-2] (133) (Cl Basic Blue 41 Cl 1110S). After couphng, the water-iusoluble dye is methylated at the thiazole nitrogen. 

The basicities of the parent azole systems in water are shown in Table 1. When both heteroatoms are nitrogen, the mesomeric effect predominates when the heteroatoms are in the 1,3-positions, whereas the inductive effect predominates when they are in the 1,2-positions. The predominance of the mesomeric effect is illustrated by the pK value of imidazole (82 Z = NH), which is 7.0, whereas that of pyrazole (83 Z = NH) is 2.5 cf. pyridine, 5.2). An fV-methyl group is base-strengthening in imidazole, but base-weakening in pyrazole, probably because of steric hindrance to hydration. When the second heteroatom is oxygen or sulfur the inductive, base-weakening effect increases the pK of thiazole (82 Z = S) is 3.5 and that of isoxazole (83 Z = 0) is 1.3. 

Prior to the 1947 report by Cook and Heilbron on their novel synthesis, 5-aminothiazoles were mostly unknown in the literature. Previous syntheses included the Curtius degradation of ethyl thiazole-5-carboxylates which did not have general applicability there was also difficultly in obtaining the necessary starting materials. During a study on penicillin, Cook and Heilbron found that the reaction between methyl dithiophenylacetate and ethyl aminocyanoacetate gave what was initially believed to be ethyl phenylthionacetamidocyanoacetate 4. However further studies proved the compound to be 5-amino-4-carbethoxy-2-benzyl-thiazole 5, which was basic. 

Care must be taken in the choice of organic solvent. Chloroform should never be used under the basic conditions due to the risk of the formation of isocyanides (see Chapter 7) and the use of carbon disulphide can lead to formation of dithiocarba-mates, e.g. dimethyl A -(ethoxycarbonylmethyl)iminodithiocarbonate is formed (35-39%), as the major product in high purity, in the liquiddiquid two-phase methyl-ation of ethyl glycinate in carbon disulphide [15]. The product is useful as an intermediate in the synthesis of thiazoles [15] and dihydrooxazoles [16]. 

Despite the weak basicity of isoxazoles, complexes of the parent methyl and phenyl derivatives with numerous metal ions such as copper, zinc, cobalt, etc. have been described (79AHC(25)147). Many transition metal cations form complexes with imidazoles the coordination number is four to six (70AHC(12)103). The chemistry of pyrazole complexes has been especially well studied and coordination compounds are known with thiazoles and 1,2,4-triazoles. Tetrazole anions also form good ligands for heavy metals (77AHC(2l)323). 

A heterocyclic sulfur-containing compound, 2-methyl-thiophene, was identified in boiled crayfish tail meat and pasteurized crabmeat. Thiazole and 3-methylthiopropanal were identified in the crayfish hepatopancreas. Heterocyclic sulfur-containing compounds play important roles in generating meaty aromas in a variety of meat products and are considered important volatile aroma components of marine crustaceans (12— 14). The 2-methylthiophene could be an important flavor cemponent in boiled crayfish tail meat. Both thiazole find 3-methylthiopropanal were important contributors to the desirable meaty aroma associated with crayfish hepatopancreas. The 3-methyl-thiopropanal, identified in boiled crayfish hepatopancreas, is derived from Strecker degradation of methionine (15), and has been considered to be an important cemponent in basic meat flavor (16). Pyridine was detected in the headspace of the hepatopancreas from freshly boiled crayfish. Pyridine and 2-ethylpyridine have been previously reported as components in the atmospheric distillate from a sample of crayfish hepatopancreas frozen for three months (2). 

Of the substituted pyridines, the halogenated derivatives have been the most intensively studied.144,145 Treatment of 3,5-dichloropyridine A-oxide at 74° with 0.1 A NaOD led to exchange in three positions of the molecule, whereas with 3-chloropyridine iV-oxide relative rates of exchange were position 2>6>4>5. In l-methyl-4-pyridone, 1,3,5-trimethyl-4-pyridone, and 3,5-dibromo-l-methyl-4-pyridone, deuteration in basic D20 at 100° gives 2- and 6-substitution.146 With the poly-azaindenes (45) -(47) already discussed in the acid exchange section,141 base-catalyzed deuteration occurs in the positions indicated 45 3 and 5 46 2, 3, 5, and 6 and 47 2, 5, 6, and 7. In other isolated heterocycles some selectivity is observed in base-catalyzed exchange, e.g., certain imidazoles,147 thiazole,148 isothiazole,148 benzothiazole,149 and benzoxazole.149... 

A special case in which a strongly basic catalyst was used to produce 4-methyl thiazole in a simplified reaction sequence (replacing a five step synthesis with a two step s>Tithesis) has been reported recently [146]. The catalysts (Cs loaded MFI and BEA) proved to be effective for the conversion of a ketone to an imine, more specifically acetone and methylamine into the corresponding imine. In the second step this imine is converted with SOt into 4-methyl thiazole (Scheme 17). Using Cs sulfate as the Cs source resulted in the... 

Under basic conditions thiamine degrades to 5-(2-hydroxyethyl)-4-methylthiazole (45, sulfurol) and the pyrimidine derivative 46 [71]. Sulfurol is used in compounded flavourings in the flavour industry. It is almost odourless as such [73] however, it can decompose giving rise to thiazole and its derivatives such as 4-methylthiazole (47), 4,5-dimethylthiazole (48), 4-methyl-5-ethylthiazole (49) and 4-methyl-5-vinylthia-zole (50) ]71, 74], which possess nutty, green notes [75]. 

X-3GL [12270-13-2] (133) (Cl Basic Blue 41 Cl 11103). After coupling, the water-insoluble dye is methylated at the thiazole nitrogen. 

The rate of RLi additions to methyl isothiocyanate seems to be strongly dependent upon the basicity of RLi [9]. Whereas phenyllithium reacts rapidly at — 90 °C, the addition of the much more weakly basic 2-thiazolyllithium (pK of 1,3-thiazole is about 29) has to be carried out at —30 to —50 °C and the reaction with lithium acetylides RC=CLi (pK acetylenes is 26 or lower) requires 0 to 20 °C (all reactions were carried out at the same 0.5 to 1 mol/1 concentrations). These temperatures indicate the conditions for other organolithium compounds and also the chance of success for other reactions. A rough estimation of the pK values of RH has to be made first, taking into account stabilizing effects of substituents. Side reactions have not yet been observed in the conversions of isothiocyanates with lithium compounds. 

Comparative experiments with aryllithium compounds (phenyllithium and para-fluorophenyllithium), however, resulted in low yields of the methyl esters in spite of the fact that a 300 % excess of chloroformic ester had been used. Reactions of C1COOR with lithio derivatives of heterocycles containing an azomethine function (e.g. lithiated thiazole, imidazole, pyridine) cannot succeed, since the excess of chloroformate will react with the basic nitrogen atom. A comparable situation arises if the organolithium intermediate has been generated by means of LDA reaction of C1COOR with the diisopropylamine liberated in the metallation will provide HC1 which will of course inactivate the organolithio compound. 

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