Thiazole rings

This preparation illustrates the ready formation of the thiazole ring by the condensation of an ot-halogeno-ketone and a thioamide. Thus chloroacetone, which may conveniently be represented in the enol form (I), condenses with thiourea (II) to give 2-amino-4-methylthiazolc (III). 

These genera] trends direct the organization of Chapters VI and VII syntheses from the already formed thiazole ring, physicochemical studies, ambident reactivity ring carbon reactivity, main derivatives, and aminothiazole applications. 

Halothiazoles are usually obtained from 2-aminothiazoles through the Sandmeyer reaction. Nevertheless, ammonolysis has sometimes proved useful for the preparation of 2-aminothiazole derivatives. Detweiler et al. (18) obtained 2-(u-pyridinylamino)thiazole (1) from 2-bromothiazole (Scheme 1). The reaction is easier if a nitro group occupies the 5-position of the thiazole ring (19-21). Ethylene diamine derivatives undergo this reaction with 2-haiothiazoles (22-24). 

The fragmentation patterns of 2-acetamido-5-nitrothia2oie (17) and 2-diraethylaminothiazole are reported to be characterized by the stabilization brought by the amino group to the thiazole ring (137). The proposed fragmentation scheme (Scheme 19) displays two major features,... 

Fig. Vl-4. Geometry of thiazole ring in 2-arniro-4-phenylthiazole hydrobromide. Italicized values are interatomic distances (A) other numbers are angles in degrees. From Ref. 342.

The amino group activates the thiazole ring toward electrophilic centers. This point is illustrated by the rate constants of the reaction between 2-dialkylaminothiazoles (32) and methyl iodide in nitromethane at 25 C (Scheme 23) (158). The steric effects of substituents on nitrogen are... 

An alkyi group occupying the 4-position of the thiazole ring may condense if the 5-position is substituted. 2-Acetamido-4-methy]-5-nitrothiazole (80) and p-cyanobenzaldehyde when refluxed with small amounts of piperidine yield the 4-styryl derivative (81) (Scheme 57) (238, 239). 

For ionic reactivity two cases must be considered depending on the electron demand the thiazole ring may either be electron donating or electron accepting. 

Xmino substituents in both neutral and protonated thiazole rings should favor electrophilic reactivity. 

Acetamidothiazole is nitrated in the same way (58, 378, 379). 2-Acetamido-4-phenylthiazole is reported to be nitrated on C-5 (380) as opposed to 2-amino-4-phenylthiazole, where nitration occurs on the phenyl ring (381). This latter result is not consistent with the other data on electrophilic reactivity in most cases 2-amino-4-arylthiazole derivatives react with electrophilic reagents at the C-5 position (see Sections rV.l.B and D). Furthermore, N-pyridy]-(2)-thiazolyl-2-amine (178) is exclusively nitrated on the thiazole ring (Scheme 113) (132, 382). 

An interesting rearrangement of the (4-methyl-2-thiazolyl)thioureas (263) has recently been reported (Scheme 160) (303). The reaction mechanism is currently under investigation. This reaction does not occur if the 4-methyl substituent in the thiazole ring of 263 is replaced by an hydrogen, which suggests an electrophilic attack on C-5 as the mechanism of this reaction. 

Special mention obviously must be given to sulfonamide derivatives of the thiazole ring. A complete coverage of the field is beyond the scope of this review however, some examples of their activity may be given here ... 

A-4-Thiazoline-2-ones and ring substituted derivatives are usually prepared by the general ring-closure methods described in Chapter II. Some special methods where the thiazole ring is already formed have been used, however. An original synthesis of 4- 2-carboxyphenyl)-A-4-thiazoline-2-one (18) starting from 2-thiocyanato-2-halophenyl-l-3-indandione (19) has been proposed (Scheme 8) (20, 21). Reaction of bicyclic quaternary salts (20) may provide 3-substituted A-4-thiazoline-2-one derivatives (21) (Scheme 9) (22). Sykes et al. (23) report the formation of A-4-thiazoline-2-ones (24) by treatment ef 2-bromo (22) or 2-dimethylaminothiazole (23) quaternary salts with base (Scheme 10). 

A 2-methylthio substituent decreases the basicity of thiazole pK = 2.52) by 0.6 pK unit (269). The usual bathochromic shift associated with this substituent in other heterocycles is also found for the thiazole ring (41 nm) (56). The ring protons of thiazole are shielded by this substituent the NMR spectrum of 2-methylthiothiazole is (internal TMS, solvent acetone) 3.32 (S-Me) 7.3 (C -H) 6.95 (Cj-H) (56, 270). Typical NMR spectra of 2-thioalkylthiazoles are given in Ref. 266. 

Alkoxythiazoles are easily cleaved by acids yielding A-4-thiazoline-2-ones (36). C-5 Nitration of the thiazole ring is favored by the 2-alkoxy group (288. 297, 307). Recent kinetic investigations have shown that the rate enhancement is 3 log units (893). 

A-2-Thiazoline-5-thiones are generally not obtained by direct heterocyclization reactions (352). Instead, most of the reported preparations involve reactions in which the thiazole ring is already formed with the suitable mercapto precursors in the 5-position. 

Nucleophilic substitution of the 5-halo substituent on a thiazole ring by a thiocyanato group (348, 362, 370-376) or a thiouronium group (364, 377) affords the thiocyanato and thiouronium precursors."... 

Only noncondensed thiazoles in which mcsoionic charge delocalization involves atoms directly bonded to the thiazole ring are considered here. Two such svstems, 1 and 2. exist (Scheme 1). Structure 1 (X = Oi is... 

Another objective is to discuss briefly recent and major trends in the field of methine dyes color. Indeed, because of its relatively simple structure, the thiazole ring has been chosen in the past for studying color-structure relations. Using Brooker s basicity concepts (5), numerous valuable attempts in different countries succeeded in establishing semiempirical rules for explaining the effects of structural changes on color. 

Rhodacyanines possess two chromophoric systems. They are at the same time neutrocyanine derivatives, which involves position 5 of the ketomethylene, and methine cyanine, which involves position 2. Following lUPAC s standard nomenclature rules, structure 7 is named 3-ethyl-4-phenyl-2- 4-oxo-3-ethyl-5-[2-(3-ethy]-2,3-dihydro-benzo-l,3-thiazo-lylidene)ethylidene]-tetrahydro-l,3-thiazolylidene-methyl -1.3-thiazolium iodide (Scheme 5). It implies that the 4-phenyl thiazole ring having the... 

All dyes of various types that are classified in the tables are derivatives of the thiazole ring with various substituents in positions 2. 3, 4, or 5. 

Many monomeric heterocyclic anhydrobases can be isolated now using specific methods (44), but application of these methods to thiazole ring did not succeed however, appropriate conditions lead to the separation of a dimer, the structure of which has been established by its NMR Spectra and chemical reactivity (26). The most probable mechanism of its formation appears identical with the one previously described in the benzothiazolium series (24). A second molecule of quaternary salt A3... 

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). 

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