Thiazoles continued

Hantzsch s Synthesis (Type A S—C—N + C—C).—The majority of thiazoles continue to be prepared by this method. The intermediate formation of 4-hydroxy-A -thiazolines (see Vol. 3, p. 567 and Vol. 1, p. 379) has been demonstrated again,whilst Metzger s group has detected thioimidate intermediates in Hantzsch reactions by the use of n.m.r. spectroscopy. 

Amino-4-aryl-thiazoles give Meisenheimer complexes with 2,4,6-trinitro-chlorobenzene. The tautomeric properties of thiazoles continue to attract attention. Unlike most 4-hydroxy-thiazoles, which prefer to exist in their keto-forms, 4-hydroxy-2-methyl-5-phenylthiazole exists as a stable enol. The spectroscopic properties of the meso-ionic thiazole (12 = Me, R = Ph, R = / -ClC H4),... 

II. Thiazoles from a-Halocarbonyl Compounds and Derivatives 193 TABLE II-7. (continued)... 

Thiazoles are important heterocycles and continue to be interesting synthetic targets because several classes of annulated thiazoles and thiazolyl (hetero)arenes display a diverse array of biological activities. 

For five-membered heterocycles other than thiazole, (such as pyrazole [27], imidazole [28], and triazole [29]) the effect of replacement of just one pyridine moiety in 1 is greater and the [Fe N6]2+ derivatives in these instances show crossover behaviour. The [Fe N6]2+ derivative of 2-(pyridin-2-yl)imidazole 19 (Dq(Ni2+) 1150 cm-1 [22]) was shown relatively early on to be a crossover system [28]. In solid salts and in solution the transition is continuous and centred above room temperature. The dynamics for the 5T2— Ai relaxation for this system have been investigated by a number of techniques [30-32] and Beattie and McMahon have shown that in solution there is not only a spin equilibrium but also a ligand dissociation process, very reasonably ascribed to the high spin form of the tris complex [32]. 

C. N-Hydroxy-4-(p-chlorophenyl)thiazole-2(3H)-thione. O-Ethyl S-[2-oximino-2-(p-chlorophenyl)ethyl]dithiocarbonate (56.0 g, 0.19 mol) is placed in a 500-mL round-bottomed flask that is equipped with a magnetic stir bar. Diethyl ether (120 mL) is added and the slurry is treated at 0°C in small portions with solid anhydrous zinc chloride, ZnClj, 79.1 g, 0.58 mol) at such a rate that the solvent does not boil constantly (Note 8). After the addition is complete, the flask is stoppered with a drying tube (CaCl2) and stirring is continued for 48 hr at 20°C. The reaction mixture turns into a dear, dark brown solution that solidifies toward the end of the reaction. The flask is immersed in an ice bath and treated dropwise with 5.5 M hydrochloric add (140 mL, Note 9). The precipitate dissolves immediately. Stirring is continued for 30 min at 0°C whereupon a tan-colored solid separates. This material is collected by filtration. It is washed with small portions of diethyl ether (total of 110 mL) and dried to afford 39.8 g (86%) of N-hydroxy-4-(p-chlorophenyl)thiazole-2(3H)-thione (Note 10). The crude material is transferred to a 2-L, round-bottomed flask equipped with a reflux condenser. 2-Propanol (760 mL) is added and the reaction mixture is heated to reflux. Once a dear solution is obtained the heat source is immediately removed (Note 11). The solution is allowed to cool to room temperature. Precipitation of N-hydroxy-4-(p-chlorophenyl)thiazole-2(3H)-thione is completed by immersing the flask for 30 min in an acetone-dry ice bath (-78°C). The product is collected by filtration and dried to afford 21.9 g (53.5%) of N-hydroxy-4-(p-chlorophenyl)thiazole-2(3H)-thione as tan crystals (Notes 12,13). 

Scheme 32 Schematic illustrating the general reaction conditions employed for the continuous flow synthesis of thiazoles and imidazoles.

The preparation of thiazoles on solid supports continues to attract attention. A variation on this approach, whereby instead of tethering a thioamide or thiourea to a solid support the a-bromoketone is tethered, has been reported. 

In continuation of the search for more active ligands for the NPY5 receptor, Nettekoven, Cuba and co-workers [131] observed that thiazole g derivatives showed 10 times more affinity than that of thiazole h derivatives for the mouse receptor (Fig. 18). This difference in the activity profile of the thiazole isomers g and h has been explained through the conformational analysis of core scaffolds (Fig. 18). 

Diethyl phosphorocyanidate continues to be exploited for the purposes of conventional organic synthesis. Reported applications of the compound include a new conversion of carboxylic acids into esters or amides and also a ring-expansion reaction of 1,3-thiazoles in the penicillin series. Diphenyl phosphorazidate has been employed in a modified Curtius reaction/ in peptide synthesis, and for... 

The study of thiazoles and their derivatives has continued to flourish primarily due to their importance as both synthetic targets and drug candidates. This review chapter focuses on the syntheses and reactions of these 5-membered heterocyclic ring systems containing nitrogen and sulfur (or selenium or tellurium) (reported during 2005). The importance of these 7t-rich heterocycles in medicinal chemistry and natural products is also covered. 

This review, intended to continue the earlier review of benzisothiazoles1 and of benzisosulfonazoles (Saccharin and related compounds),2 covers the period between about 1970 and early 1984. In general, attention has been focused on new results however, an attempt has been made to be comprehensive. Some parts of this review have received attention elsewhere. For example, a review has appeared on the biological activity of 1,2-benziso-thiazole derivatives,3 thus that topic has received less attention. 

---