Thiazoles, aromaticity

The fused hetero rings of aromatic or pseudoaromatic character on the 4,5 bond as, for example, benzothiazole, naphthothiazole, thieno[2,3ci]-thiazole, benzthieno[2,3d]thiazole, and so forth (Scheme 8), do not appear in the tables. 

A comparison of the reactivity of the heterocycles, selenazoie, thiazole. and pyridine, was made by Ochiai (41), who used theoretical considerations to show that the degree of aromaticity was ... 

Comparative studies have been undertaken between different heterocyclic series, especially the azoles, thiazoles. oxazoles. imidazoles, and selenazoles. In a large number of these studies, the heterocycles are condensed w ith aromatic nuclei. 

The first mass spectrometric investigation of the thiazole ring was done by Clarke et al. (271). Shortly after, Cooks et al., in a study devoted to bicydic aromatic systems, demonstrated the influence of the benzo ring in benzothiazole (272). Since this time, many studies have been devoted to the influence of various types of substitution upon fragmentation schemes and rearrangements, in the case of alkylthiazoles by Buttery (273) arylthiazoles by Aune et al. (276), Rix et al. (277), Khnulnitskii et al. (278) functional derivatives by Salmona el al. (279) and Entenmann (280) and thiazoles isotopically labeled with deuterium and C by Bojesen et al. (113). More recently, Witzhum et al. have detected the presence of simple derivatives of thiazole in food aromas by mass spectrometry (281). 

It is difficult to draw general conclusions from such a small number of values. Nevertheless, it can be noted that, like other five- or six-membered unsaturated rings (thiophene, pyridine) thiazole exhibits a certain aromatic behavior in its magnetic susceptibility. 

The aromatic character of thiazole has been deduced from the magnetic susceptibility anisotropy of the molecule (319). 

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. 

The (thermal) decomposition of thiazol-2-yldiazonium salts in a variety of solvents at 0 C in presence of alkali generates thiazol-2-yl radicals (413). The same radicals result from the photolysis in the same solvents of 2-iodothiazole (414). Their electrophilic character is shown by their ability to attack preferentially positions of high rr-electron density of aromatic substrates in which they are generated (Fig. 1-21). The major... 

Fig. 1-21. Partial rate factors for the phenylation and the thiazol-2-ylation of aromatic substrates (414).

Thiazol-2-yl radicals have also been generated by silver oxide oxidation of thiazol-2-ylhydrazine in various aromatic solvents (Scheme 69). The... 

In agreement with the theory of polarized radicals, the presence of substituents on heteroaromatic free radicals can slightly affect their polarity. Both 4- and 5-substituted thiazol-2-yl radicals have been generated in aromatic solvents by thermal decomposition of the diazoamino derivative resulting from the reaction of isoamyl nitrite on the corresponding 2-aminothiazole (250,416-418). Introduction in 5-position of electron-withdrawing substituents slightly enhances the electrophilic character of thiazol-2-yl radicals (Table 1-57). 

The reactivity of alkylthiazoles possessing a functional group linked to the side-chain is discussed here neither in detail nor exhaustively since it is analogous to that of classical aliphatic and aromatic compounds. These reactions are essentially of a synthetic nature. In fact, the cyclization methods discussed in Chapter II lead to thiazoles possessing functional groups on the alkyl chain if the aliphatic compounds to be cyclized, carrying the substituent on what will become the alkyl side chain, are available. If this is not the case, another functional substituent can be introduced on the side-chain by cyclization and can then be converted to the desired substituent by a classical reaction. 

The NMR spectra of thiazoles show the same behavior as those of aromatic compounds, but the chemical shifts also depend on the two heteroatoms. 

The mass spectra of arylthiazoles with funcmonal substituents cm the benzene ring have also been studied (125, 126). They possess the fragmentation pattern of the aromatic derivative corresponding to the substituent together with that of the thiazole ring described previously (126). 

The free-radical reactivity of thiazoles has been well studied with various radicals such as methyl, phenyl, substituted phenyl, cyclohexyl, and aromatic-heterocyclic, in nonpolar solvent or strong acids (180-182). 

The thiazolyl radicals are, in comparison to the phenyl radical, electrophilic as shown by isomer ratios obtained in reaction with different aromatic and heteroaromatic compounds. Sources of thiazolyl radicals are few the corresponding peroxide and 2-thiazolylhydrazine (202, 209, 210) (see Table III-34) are convenient reagents, and it is the reaction of an alky] nitrite (jsoamyl) on the corresponding (2-, 4-, or 5-) amine that is most commonly used to produce thiazolyl radicals (203-206). The yields of substituted thiazole are around 40%. These results are summarized in Tables III-35 and IIT36. 

Aza-aromatic compounds can give rise to metallic complexes, and various complexes of thiazole have been studied ... 

The higher reactivity of 2-halogenothiazoles with respect to halogenopyridines can be related to the different aromaticity of the two systems, less for thiazole than for pyridine, for example, the relatively stronger fixation of the tt bond in the thiazole than in the case of pyridine. As the data reported in Table V-1 (footnote a) indicates, the free thiophenol is more reactive than the thiolate anion toward the 2-halogenothiazoles. This fact should be considered when one prepares the thiazolyl sulfides. 

Another commercially available retarder for sulfur vulcanization is based on an aromatic sulfenamide. Like CTP, this product is most effective ki sulfenamide cure systems, but it also works well ki thiazole systems. Performance properties are generally not affected except for a slight modulus kicrease. In some cases this feature allows for the use of lower levels of accelerator to achieve the desked modulus with the added potential benefits of further scorch delay and lower cost cure system (23). 

The precise geometrical data obtained by microwave spectroscopy allow conclusions regarding bond delocalization and hence aromaticity. For example, the microwave spectrum of thiazole has shown that the structure is very close to the average of the structures of thiophene and 1,3,4-thiadiazole, which indicates a similar trend in aromaticity. However, different methods have frequently given inconsistent results. 

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. 

The carbon atoms of azole rings can be attacked by nucleophilic (Section 4.02.1.6 electrophilic (Section 4.02.1.4) and free radical reagents (Section 4.02.1.8.2). Some system for example the thiazole, imidazole and pyrazole nuclei, show a high degree of aromati character and usually revert to type if the aromatic sextet is involved in a reaction. Othei such as the isoxazole and oxazole nuclei are less aromatic, and hence more prone to additio reactions. 

The 4- and 5-hydroxy-imidazoles, -oxazoles and -thiazoles (499, 501) and 4-hydroxy-pyrazoles, -isoxazoles and -isothiazoles (503) cannot tautomerize to an aromatic carbonyl form. However, tautomerism similar to that which occurs in hydroxy-furans, -thiophenes and -pyrroles is possible (499 500 503 504 501 502), as well as a zwitterionic... 

Benzisothiazoles can be prepared by the reaction of aromatic chloro compounds with sulfur and ammonia. Thus, 2,6-dichlorobenzylidene chloride gives 4-chloro-l,2-benzisothiazole (72AHC(14)43), and 2-chlorobenzophenone gives 3-phenyl-l,2-benziso-thiazole (79GEP27 34866). 

This procedure is representative of a new general method for the preparation of noncyclic acyloins by thiazol ium-catalyzed dimerization of aldehydes in the presence of weak bases (Table I). The advantages of this method over the classical reductive coupling of esters or the modern variation in which the intermediate enediolate is trapped by silylation, are the simplicity of the procedure, the inexpensive materials used, and the purity of the products obtained. For volatile aldehydes such as acetaldehyde and propionaldehyde the reaction Is conducted without solvent in a small, heated autoclave. With the exception of furoin the preparation of benzoins from aromatic aldehydes is best carried out with a different thiazolium catalyst bearing an N-methyl or N-ethyl substituent, instead of the N-benzyl group. Benzoins have usually been prepared by cyanide-catalyzed condensation of aromatic and heterocyclic aldehydes.Unsymnetrical acyloins may be obtained by thiazol1um-catalyzed cross-condensation of two different aldehydes. -1 The thiazolium ion-catalyzed cyclization of 1,5-dialdehydes to cyclic acyloins has been reported. 

A powerful method of introducing a CF3 group into aromatics is the conversion of C02H with SF4. The use of SF4 with heterocyclics is not as widespread but it has been applied to imidazoles [81JFC(17)179], thiazoles, isothiazoles [91 JFC(55) 173], and furans (86BSF974). 

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