Thiazole tautomeric forms

Benzo-l,3-thiazole-2-azide reacts with metal salts to give a mixture of complexes of both possible tautomeric forms 397 and 398 (Scheme 147) (75UKZ1238). However, this conclusion was made only on analysis of the IR spectra of the reaction products and should not be considered final. 

The usual precursor to the thiazolo-fused systems is a cyclic thioamide or its tautomeric form . A convenient approach to the synthesis of bicyclic [5-5] systems, e.g., the tricyclic thiazolium salt 46 and 2,3-dihydroimidazo[2,l-A]thiazol-5-one 48, involves the N,S-dialkylation of appropriate precursors 45 and 47 with 1,2-dihaloalkanes (Scheme 31) <1999JMC2828, 2002EJC777>. 

Thiazoles and their derivatives bearing amino, hydroxy, or thio groups in the 2-position can exist in at least two tautomeric forms,... 

Substituted thiazoles at C-2 or C-4 with hydroxy, thio, and amino groups can be represented by five tautomeric forms (26a-e) (Scheme 1). However, form (26e) has never been observed <85JPR25l>. The aminothiazoles exist predominantly in the amino form when the substituent is in position two (26b, Z = NH). On the other hand, when the substituent is in position four the amino form is preferred, although there are exceptions to this rule (for instance, in the case Y = Z = NHCOMe). The hydroxy and thio derivatives predominantly exist in the oxo and thioxo forms (26a, Y, Z = O, S). The main evidence of these arguments came from the C NMR spectra of the thioxo derivatives and from the IR spectra of the oxo and amino derivatives. 

Thioglycolic acid reacts with active methylene compounds such as (288) to give 4-hydroxy thiazoles (289). The spectral analysis shows that the predominant tautomeric form is (289b) both in solid state and DMSO solution (Scheme 73) <92T9295>. 

The oxygen-substituted 1,3-azoles exist in their carbonyl tautomeric forms. The bromination of thiazol-2-one, at C-5, is a nice demonstration of relative reactivity here the double bond carries both sulfur and nitrogen, and it is the latter, i.e. the enamide rather than the enethiol ester character, that dictates the site of electrophilic attack. ... 

Another application of the Hantzsch process is found in the synthesis of a monobactam antibiotic, Tigemonam. The monobactams are follow-ups to the penicilMns, both families being unique as derivatives of azetidinones (beta-lactams). Tigemonam also possesses a thiazole ling, which component is synthesized as in Scheme 9.20 from thiourea (shown in the -SH tautomeric form) and the chloroketone 9.26. 

Numerous compounds of this series exist in their tautomeric form as 2-amino(or hydroxy or mercapto)thiazoles or as substituted thiazolidines, and are dealt with under those headings. Examples of true 4-thiazolines, containing an iV-substituent in their heterocyclic ring, are less numerous, and their literature is correspondingly less extensive. 

Tautomerism of the A-2-thiazoline-5-thiones has not been investigated intensively. A recent report shows that 2-phenylthiazo e-5-thiols exist in the thiol form in both polar and nonpolar solvents (563). This behavior is in contrast with that of corresponding thiazolones. Addition reactions involve only the exocyclic sulfur atom, and thiazole-5-thiols behave as typical heteroaromatic thiols towards unsaturated systems, giving sulfides (1533) (Scheme 80) (563),... 

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... 

The synthesis of the vinyl antibiotic cefdinir, which starts with the preformed unsaturated nucleus (30-2), illustrates a scheme that builds the almost obligatory aminothiazole in situ as the last step. Acylation of the amino group in (30-2) with 3-bromoacetoacetic acid (30-1) leads to the amide (30-3). Reaction of that intermediate with sodium nitrite proceeds on the activated methylene to form the nitrite as the initial product. This spontaneously tautomerizes to the observed oxime (30-4). Treatment with thiourea, in one of the standard procedures for forming thiazoles, then leads to (30-5). There is thus obtained cefdinir (30-5) [36]. 

The fused tetrazole 422 (Scheme 19) was originally assumed307" to be nitrated on the thiazole ring, but recent NMR studies have shown that a p-nitrophenyl derivative is formed.1836 Since 422 (and 424) display azide tetrazole tautomerism (Section IV,B,1), the exact structure of the reacting species is unknown, but the product exists predominantly as the azide. 

Investigations on the tautomerism of fused heterocyclic moieties favor the lactam form of the imidazole substructure of 16 (65CPB473) and the thiolactam tautomer in thiazoles 192 and 197 [62BCJ1998 64BCJ1526 95PS(101)167], but the hydroxy form in pyrazole 183 [82IJC(B)765]. 

As mentioned earlier in Section III,C, 6, 3-amino-2,l-benziso-thiazole displays reactions which yield fixed products of the tautomeric 3-imino form. Ross has prepared a number of 3-alkylimino and 3-arylimino derivatives.103... 

As already discussed in Section 4.19.2.2.1 hydroxyl derivatives of thiazole are tautomeric, according to Scheme 127, the oxo forms usually being the most stable. The interconversion of the hydroxyl and carbonyl forms proceeds under acid or base catalysis. This protomeric behavior of the thiazolinones corresponds to an ambident nucleophilic reactivity which is most marked for the conjugate anion arising in basic medium. 

Cyclization occurs directly through catalysis by the acid liberated when a pyridine-2(lH)-thione is heated with an a-halo acid ester. The most convenient method for preparing the thiazole, however, seems to be the cyclization of (2-pyridinethio)acetic acids in acetic anhydride in the presence of pyridine. Without base catalysis the reaction is slow, which suggests a mixed anhydride intermediate. Mixed anhydride formation with ethyl chlorofor-mate in pyridine, or carboxyl activation by DCC in pyridine, gives the mesoionic product. The cyclization reaction and the chemical stability of the thiazole are adversely affected by a pyridine 6-substituent. The initially formed acylpyridinium salt (407) undergoes rapid tautomerization to the aromatic thiazole form equilibrium between the forms (407) and (408) is verified by rapid deuteration at C-2 (R1 = H) in AcOH-d (81H(15)1349). 

Numerous applications of IR spectral data have been reported for derivatives of (5,5)-fused ring systems, especially in connection with the problem of tautomeric equilibria. For example, the IR spectra of 5,6,7,8-tetrahydro-l//,3H-pyrrolo[l,2-c][l,3]oxazole-1,3-diones (24 X=0) and corresponding thiazole-l,3-diones (24 X = S) show no carbonyl absorption, but broad bands at 3300 cm-1 due to the associated OH group, indicating that the fused structures (24) exist in the enolic forms rather than their diketonic tautomers (81BJC1844). 

Tetrahydro-6-phenylimidazo[2,l-6]thiazoIe hydrochloride (tetramisole) is a broad-spectrum anthelmintic the D-form is an antidepressant the L-form (levamisole) is known to possess immunoregulatory or immunostimulatory activity. Some phenacylthio-imidazolines which are tautomeric to cyclic carbinolamines are very potent antagonists of reserpine-induced hypothermia in mice. The corresponding 3-aryl-5,6-dihydroimidazo[2,l-6]thiazoles are also potent antidepressants. 5,6-Bis(4-methylsulfinylphenyl)-2,3-dihy-droimidazo[2,1 -b Jthiazole is used especially in the treatment of rheumatic arthritis. 

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