Thiazol-5-ones, synthesis

This review collects a part of the results of work on the thiazole-aldehyde synthesis that has been carried out over several years by various individuals whose names are reported in the references. One of us (A.D.) would like to express to all of them his gratitude and appreciation for their contribution. Financial support came from the Progetto Finalizzato Chitnica Fine e Secondaria n. 2 (Rome), the Consiglio Nazionale delle Ricerche (CNR, Rome), the Ministero della University e della Ricerca Scientifica (MURST, Rome). One of us (A. M.) is grateful to the University of Ferrara for having been appointed as Lecturer in Organic Chemistry at the Faculty of Engineering. 

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). 

The photochemical rearrangement of the mesolonic thiazole (33) provides an original synthesis of the 4-methylthio-derivatives of the A-4-thia2oline-2-one (34) (Scheme 15) (33). 

Besides being useful precursors to pyrroles pyridine-2-ones -4-ones, -4-thiones. and -4-imines 4-alkylidene-dihydropyridines thiophenes 1,2,4-triazoles thiapyrane-2-thiones, isoquinoline-3-ones isoben-zothiophenes and 4-mercaptoimidazolium hydroxide inner salts, mesoionic thiazoles are potentially useful in the construction of molecules with herbicidic (39). central nerve stimulating, and antiinflammatory properties (40,41). Application in dye synthesis has likewise been reported (42). 

The reaction of phosphorus pentasulfide with a-acylamino carbonyl compounds of type Ilia also yields thiazoles. Even more commonly, a mercaptoketone is condensed with a nitrile of type IVa or a-mercaptoacids or their esters with Schiff bases. This ring closure is limited to the thiazolidines. In the Va ring-closure type, /3-mercaptoalkylamines serve as the principal starting materials, and ethylformate is the reactant that supplies the carbon at the 2-position of the ring. These syntheses constitute the most important route for the preparation of many thiazolidines and 2-thiazohnes. In the Vb t3fpe of synthesis, one of the reactant supplies only the carbon at the 5-position of the resultant thiazole. Then in these latter years new modern synthetic methods of thiazole ring have been developed (see Section 7 also Refs. 515, 758, 807, 812, 822). 

C=N, C=S, C=C, and N N containing substrates. Thus oxa2oles, imidazoles, thiazoles, p rrroles, and 1,2,4-triazoles have been prepared, respectively. Furthermore, p-tolylsulfonylmethyl isocyanide has found use in a one-step conversion of ketones into cyan-idea and in a two-step synthesis of a-hydroxyaldehydes from ketones. ... 

Reaction of /3-carbonyl amides with the Lawesson s reagent under microwave irradiation gave thiazoles in acceptable yields [37]. The reaction was the same one previously reviewed for the synthesis of thiophenes and was also employed for the preparation of thiadiazoles (Scheme 10, X = NH, Y = CH). 

Phenyliodonium ylids of cyclic dicarbonyl compounds (46) react with thiourea to form the thiouronium ylid (47) which on heating is converted into the fused thiazole (48), this method is applicable to subtituted thioureas provided they have at least one free amino group. This reaction can be considered to be a modification of the Hantzsch thiazole synthesis <96JHC575>. 

Samuel Danishefsky s group at the Sloan Kettering Institute for Cancer Research in New York has also been active in the synthesis of the natural epothilones and biologically active analogs. One of their syntheses also used the olefin metathesis reaction (not shown). The synthesis in Scheme 13.62 used an alternative approach to create the macrocycle, as indicated in the retrosynthetic scheme. The stereochemistry at C(6), C(7), and C(8) was established by a TiCl4-mediated cyclocondensation (Step A). The thiazole-containing side chain was created by reaction sequences F and G. The... 

A recent total synthesis of tubulysin U and V makes use of a one-pot, three-component reaction to form 2-acyloxymethylthiazoles <06AG(E)7235>. Treatment of isonitrile 25, Boc-protected Z-homovaline aldehyde 26, and thioacetic acid with boron trifluoride etherate gives a 3 1 mixture of two diastereomers 30. The reaction pathway involves transacylation of the initial adduct 27 to give thioamide 28. This amide is in equilibrium with its mercaptoimine tautomer 29, which undergoes intramolecular Michael addition followed by elimination of dimethylamine to afford thiazole 30. The major diastereomer serves as an intermediate in the synthesis of tubulysin U and V. 

The group of Bolognese has disclosed a synthesis of thiazolidin-4-ones by condensation of benzylidene-anilines and mercaptoacetic acid (Scheme 6.215 a) [386]. The authors found that microwave heating of an equimolar mixture of the two components in benzene at 30 °C for just 10 min provides excellent yields of the thiazol-idin-4-one heterocycles. Surprisingly, when the same transformation was carried out at reflux temperature (80 °C), much longer reaction times (2 h) were required and the products were obtained in significantly lower yields (25-69%). 

In another approaeh [88IJC(B)570], reaetion of 2-mereapto-4,5-di-p-tol-ylimidazole 43 with a-halo carboxylie acids enabled the synthesis of several imidazo[2,l-h]thiazoles. Acylative ring closure of 4,5-di-p-tolylimidazo-2-thioacetic acid (44, R = H) or 2-thiopropionic acid (44, R = Me) provides 5,6-di-p-tolylimidazo[2,l-h]thiazole-3(2//)-one (45, R = H) or its 2-methyl analog (45, R = Me). The synthesis of annelated imidazo[2,l-h]thiazoles (e.g., 46) can be achieved in one step by reaction of 2,3-dichloroquinoxaline with 43. The intramolecular eyelization of l-vinylimidazole-2-thiones to 2,5-dimethyl-3,6-arylimidazo[2,l-h]thiazoles with excellent yield has been reported (93T6619). 

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