2-Thiazolones

There are two mesoionic sulfur heterocycles which have been shown to undergo intramolecular cycloaddition as thiocarbonyl ylides 1,3-dithiolones130 and 1,3-thiazolones.131 Thus, the alkenyl 1,3-di-thiolone (235) gave a 90% yield of cyclization product (Scheme 70). The analogous alkynyl... 

When unsubstituted, C-5 reacts with electrophilic reagents. Thus phosphorus pentachloride chlorinates the ring (36, 235). A hydroxy group in the 2-position activates the ring towards this reaction. 4-Methylthiazole does not react with bromine in chloroform (201, 236), whereas under the same conditions the 2-hydroxy analog reacts (55. 237-239. 557). Activation of C-5 works also for sulfonation (201. 236), nitration (201. 236. 237), Friede 1-Crafts reactions (201, 236, 237, 240-242), and acylation (243). However, iodination fails (201. 236). and the Gatterman or Reimer-Tieman reactions yield only small amounts of 4-methyl-5-carboxy-A-4-thiazoline-2-one. Recent kinetic investigations show that 2-thiazolones are nitrated via a free base mechanism. A 2-oxo substituent increases the rate of nitration at the 5-position by a factor of 9 log... 

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),... 

A-2-Thiazoline-4-ones are usually obtained by the heterocydization method (38b-388). 2 Alkylthio-4(5)-thiazolones (162) are obtained by alkylation at sulfur of rhodanine (160) in nonpolar solvent (Scheme 85). 

Arylthio-5-ethyl-4(5)-thiazolone derivatives (164, 165. and 166) have been prepared by treatment of rhodanine (163) with the appropriate aryldiazonium salts (Scheme 86) (395). 

Chloro- and 2-alkylthio-4(5)-thiazolone (184) when treated in basic medium yields the corresponding 2.4-thiazolinediones (185) (Scheme 96)... 

Scheme 97). Stepanov has thoroughly studied this nucleophilic reactivity some examples are given in Refs. 423 and 424. The formation of 5-benzylidene derivatives involves the same nucleophilic reactivity (422). 5-Benzothiazoline and 5-benzose enazoline derivatives of 2-diphenylaminothiazoline-4-one, have been obtained by nucleophilic addition of the thiazolone on the corresponding benzothiazolium or ben-zoselenazolium salts (433). 

NaH must be used when the starting thiazolones are not easily enolized (453, 467). Phase-transfer catalysis could be helpful for this t pe of reactivity. 

This reaction is a clear example of the importance of tautomeric equilibrium studies in this series since, to the extent that the starting thiazolone does not epimerize in the medium, asymmetric induction may be expected in this reaction (453, 455). 

From these results it appears that the 5-position of thiazole is two to three more reactive than the 4-position, that methylation in the 2-position enhances the rate of nitration by a factor of 15 in the 5-position and of 8 in the 4-position, that this last factor is 10 and 14 for 2-Et and 2-t-Bu groups, respectively. Asato (374) and Dou (375) arrived at the same figure for the orientation of the nitration of 2-methyl and 2-propylthiazole Asato used nitronium fluoroborate and the dinitrogen tetroxide-boron trifluoride complex at room temperature, and Dou used sulfonitric acid at 70°C (Table T54). About the same proportion of 4-and 5-isomers was obtained in the nitration of 2-methoxythiazole by Friedmann (376). Recently, Katritzky et al. (377) presented the first kinetic studies of electrophilic substitution in thiazoles the nitration of thiazoles and thiazolones (Table 1-55). The reaction was followed spec-trophotometrically and performed at different acidities by varying the... 

TABLE 1-55. STANDARD RATE CONSTANTS FOR THIAZOLES AND 2-THIAZOLONES (377)... 

Certain mcso-ionic derivatives of thiazole (217) rearrange into thiazolone (219) under irradiation, a thiirenium intermediate (218) being postulated (Scheme 105) (495). 

The a-halogenated acids or their esters (105) also react with thiourea to give 2-amino-4-hydroxythiazoles (106a) or their 2-amino-4-thiazolone (106b) (1, 247, 254, 530) or 2-imino-4-oxathia2olidine (106c) tautomers (Scheme 47). 

When the carbonyl reactant is ethylchloroacetate, a 2-imino-4-thiazolone isomer (125) is formed (Scheme 59) (85). 

Thiazolones in which Ri = H, alkyl, or phenyl and R3 = CO2R CONHR. or CN (220b) have been obtained by Grobe and Heitzer (Scheme 115b) (775). 

The same products can be also obtained from 267 and benzaldehyde. This behavior indicates the presence of an active methylene group and supports the thiazolone structure (267a). Alkyl or aryl ethers of 267 are prepared by two different procedures (Scheme 139). 

Step 2 On reaction with hydrogen chloride m an anhydrous solvent the thiocarbonyl sulfur of the PTC derivative attacks the carbonyl carbon of the N terminal ammo acid The N terminal ammo acid is cleaved as a thiazolone derivative from the remainder of the peptide... 

Step 3 Once formed the thiazolone derivative isomerizes to a more stable phenylthiohydantom (PTH) derivative which IS isolated and characterized thereby providing identification of the N terminal ammo acid The remainder of the peptide (formed m step 2) can be isolated and subjected to a second Edman degradation... 

Thiazolo[2,3-/][l,6]naphthyridin-4-ium hydroxide, anhydro-3,8-dicarboxy-6-hydroxy- — see Beminamycinic acid Thiazolonaphthyridinium salts desulfurization, 6, 687 Thiazolones mesoionic... 

Diketones with Diamines—qiiinazolines 11. Diketones with NH OH—isoxazolines 12. Diketones with NH NH,—pyrazoles 13. Diketones with semi-carbazide—pyrazoles 14. Diketones with ammonia—pyrazoles 15. Carbon disulfide with ammoacetamide—thiazolone 16. Nitriles and ethylene diamines—imidazolines D D D D D A D ... 

All of the acids prepared in (74JAP(K)4, 79CPB1) were tested for their antimicrobial activities in vitro 2-Thiazolone derivatives showed far higher activity... 

Mercuric chloride, other mercury-containing antibacterials and silver will inhibit enzymes in the membrane, and for that matter in the cytoplasm, which contain thiol, -SH, groups. A similar achon is shown by 2-bromo-2-nitropropan-l,3-diol (bronopol) and iso-thiazolones. Under appropriate condihons the toxic action on cell thiol groups may be reversed by addition of an extrinsic thiol compound, for example cysteine or thioglycollic aeid (see also Chapters 12 and 23). 

Bronopol, wo-thiazolones, chlorine, chlorine-releasing agents, hypochlorites and iodine will oxidize or react with thiol groups. 

Formaldehyde, sulphur dioxide and glutaraldehyde react with amino groups. If these groups are essential for metabolic activity, cell death will follow reactions of this nature. Chlorinated fso-thiazolones as well as acting on -SH groups, (Section 3.4), can react with -NH2 groups. 

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