Imines with mercapto acids

Thiazolidin-4-ones have been prepared by condensation of support-bound imines with a-mercapto carboxylic acids (Entry 11, Table 15.18). These thioaminals are quite stable and tolerate, for example, treatment with TFA [228,229]. Thiazolidines, which can be prepared from resin-bound cysteine and aldehydes (Entry 12, Table 15.18), are also remarkably stable towards acid-promoted hydrolysis. Libraries of thiazolidinones have been used to identify new cyclooxygenase-1 inhibitors [230]. 

Hexafluoroacetone and certain perfluorinated or partially fluorinated ketones, aldehydes, and imines react with a-functionalized carboxylic acids (e.g., a-amino, a-At-methylamino [S3, 84], a-hydroxy [S5], and a-mercapto [Sd] acids) to give five-membered heterocyclic systems (equation 13). 

Formation of compounds like 115 seems to have occurred in the similar way as it was established for anilines and other primary amines [167]. The initial step of this reaction is treatment of aldehyde with aminozole giving Schiff base 116. Further, nucleophilic attack of imine carbon by mercapto moiety of the acid leads to the intermediate 117 and its subsequent cyclization via gem-diol 118 yields target heterocycles 115 (Scheme 55). 

In 1821 Wohler discovered that a solid deposited from concentrated aqueous solutions of thiocyanic acid. The solid, which was called isoperthiocyanic acid (3-imino-5-mercapto-1,2,4-dithiazole) (361), formed a new product perthiocyanic acid (3,5-dimercapto-l,2,4-thiadiazole) (18) when treated with alkali and then acid. On storage perthiocyanic acid (18) readily reverted to isoperthiocyanic acid (361) (65AHC(5)119). The mechanisms of these interconversions are still not known with certainty but the transformations outlined in Scheme 130 are suggested. Wohler proposed the initial formation of a dimer of thiocyanic acid for which structure (359) appears resonable. Addition of the imine function of (359) to the nitrile function of HSCN would produce the trimer (360) which could readily eliminate hydrogen cyanide to produce isoperthiocyanic acid (361). 

Thiazolidines (76) undergo facile ring-chain tautomerism, thus affording a latent source of thiol-imine, which can be trapped with ethyl mercapto-acetate at 100°-110° to afford 77 in low yield [Eq. (22)].63 If the corresponding acid is used and water is continuously removed, the yield of 77 approaches 75%. 

Murphy et al. [39] reported the synthesis of pyrrolidine 7 combinatorial libraries. Starting from polystyrene resin-bound amino acids, the a-amino ester was condensed with aromatic and heteroaromatic aldehydes in neat trimethylorthoformate to afford the resin-bound aryl imine. Pyrrolidine and pyrroline derivatives were obtained through cycloaddition of the 1,3-dipoles azomethine ylides to olefin and acetylene dipolarophiles. A library of 500 compounds was reported. The screening of this library for in vivo inhibition of angiotensin-converting enzyme (ACE) led to the identification of l-(3 -mercapto-2 -(S)-methyl-1 -oxopropyl)-5-phenyl-2,4-pyrrolidinedicarboxy-lic acid 4-methyl ester as a potent ACE inhibitor that incorporates the mer-captoisobutyryl side chain (Fig. 3e). 

Thiazolidones are another class of heterocycles that attract much attention because of their wide ranging biological activity [106], They are usually synthesized by three-component condensation of a primary amine, an aldehyde, and mercapto-acetic acid with removal, by azeotropic distillation, of the water formed [107]. The reaction is believed to proceed via imine formation then attack of sulfur on the imine carbon. Finally, an intramolecular cyclization with concomitant elimination of water occurs, generating the desired product. The general applicability of the reaction is limited, however, because it requires prolonged heating with continuous removal of water. To circumvent these difficulties and to speed up the synthesis, Miller et al. developed a microwave-accelerated three-component reaction for the synthesis of 4-thiazolidinones 63 [108]. In this one-pot procedure, a primary amine, an aldehyde, and mercaptoacetic acid were condensed in ethanol under MW conditions for 30 min at 120 °C (Scheme 17.44). The desired 4-thiazolidinones 63 were obtained in 55-91% yield. 

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