Reactions of Condensed 4-Thiazolidinones

A one pot formation and purification of a 5-arylidine 4-thiazolidinone library has also been reported using polymer scavenging as the principle method of purification. An automated synthesizer was employed to make a parallel array of 4080 4-thiazolidinones, prepared simultaneously from a 3-component condensation of mercaptoacetic acid with an amine and a carbonyl compound. Further structural decoration was then introduced using the libraries from libraries principle where the core template was derivatized via an aldol reaction with a second carbonyl unit at the 5-methylene position (Scheme 2.57) [84]. After both synthetic steps. 

The methylene carbon atom in a condensed 4-thiazolidinone flanked by a sulfur atom and a carbonyl group possesses enhanced nucleophilic activity and attacks an electrophilic center with ease. If the structure permits, the reaction product loses a molecule of water, and an unsaturated derivative is formed. The reaction is carried out in the presence of a base which abstracts a methylene proton. It is the anion thus formed that attacks the electrophilic center. Generally, the anion condenses with aromatic aldehydes, nitroso compounds, aryidiazonium salts, and ethyl orthoformate, as well as undergoing Vilsmeier-Haack and Mannich reactions. 

Synthesis of thiazolidinones [PEG -RMIM]X ionic liquids have been used for rapid synthesis of a small library of amido 4-thiazolidinones from amine, aldehyde, and mercaptoacid components (Scheme 7.22) [74]. In an initial feasibility study, acid-functionalized benzaldehydes were first coupled to the [PEG -RMIM]X ionic liquids. Imines were formed by reaction of the supported aldehydes with primary amines. The reactions were run in open vessels. Optimum results were obtained by irradiating the reaction mixture with low power at 100 °C for 20 min. The imines were then condensed with mercaptoacids to give the desired thiazolidinones which were then cleaved from the ionic liquid support by amide formation. Microwave irradiation was again used in this cleavage step. The procedure entailed addition of a small amount of solid potassium tert-butoxide to a premixed mixture of the amine and supported thiazolidinone and microwave exposure for 10-20 min at 100 or 150 °G depending on the amine used. In another study, a series of one-... 

The catalysed alkylation of l//,4//-pyrazol-5-ones is solvent dependent. In benzene, bis-alkylation occurs at the 4-position whereas, in a carbon disulphide benzene mixture, O-alkylation is observed, although the major product (4, Scheme 5.22) results from nucleophilic attack by the pyrazolone on the carbon disulphide, followed by alkylation of the dithiolate dianion [92]. The catalysed reaction of 2-thiono-3-aryl-thiazolidin-4-ones with alkylating agents under soliddiquid two-phase conditions results in alkylation at the 5-position (60-80%) [93]. The aldol condensation of the thiazolidinones with aryl aldehydes is also catalysed by quaternary ammonium salts. 

Condensation of monochloroacetic acid with an arylthiourethan (41) in glacial acetic acid leads to 42 [Eq. (12)].76 With alkylthiourethans, reaction temperatures must be maintained at 160°-170°.77 Simultaneous reaction of the starting materials or 42 with aromatic aldehydes affords high yields of the 5-arylidene derivatives.76 Similarly, arylamides of arylsulfonylcyano-thioacetic acids condense with a-halocarboxy compounds to afford 2-substituted 4-thiazolidinones.78... 

A convenient synthesis [Eq. (13)] of 2-ary lidenehydrazono-4-thia-zolidinone (43) from ethyl thiocyanoacetate (44), arylideneazines (45), and hydrazine hydrate (46) has been reported.79 Presumably, the reaction proceeds via the intermediary hydrazone, which condenses with 44 to give 43. Subsequently, condensation of 43 with the aromatic aldehyde, generated in situ from disproportionation of the azine with hydrazine, affords the 5-arylidene derivative. The reaction of 44 with ammonium acetate and an aromatic aldehyde gives 5-arylidene-2-imino-4-thiazolidinones.80... 

Reaction of 4-oxoquinazolinyl-2-thione (332) with DMAD gives four major products (359-362) and one minor product (363) whose structures were unequivocally established by C-NMR spectroscopy and X-ray crystallographic analysis [86JCS(P1)2095] (Scheme 83). Surprisingly, no condensed thiazolidinone (364 or 365) was isolated from the reaction mixture. This is in contrast to the behavior of other thiones (20,28,53,65, 155, 185, 247, 276 (R = H), 276, 280, and 352) that react with DMAD to give the corresponding condensed thiazolidinones (21,48,54,67,160,188, 23, 277, 279, 281, and 357). 

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. 

The condensation of 2-amino-5-(2,4-dichloro-5-fluorophenyl)-67/-l,3,4-thiadiazine 176 with various aromatic aldehydes under microwave irradiation furnished 2-arylideneamino-6/7-l,3,4-thadiazines 177. The cyclocondensation of 177 with chloroacetyl chloride under microwave irradiation afforded 2-oxoazetidine derivatives 178 in excellent yields. The reaction of 177 with 2-sulfanylacetic acid yielded 4-thiazolidinones 179 (Scheme 26) <2005IJB2158>. 

Gududuru et al. (2004) have reported a convenient microwave method for the synthesis of 4-thiazolidinones via the one pot condensation of a primary amine, an aldehyde, and mercaptoacetic acid. The reactions were conducted using an environmentally benign solvent ethanol in open vessels at atmospheric pressure in the... 

The interaction of ethyl thiocyanoacetate (191) with aromatic aldehydes and NN -dialkylthioureas yields the linear condensation products (192). With thiourea or N-methylthiourea, reaction continues with cyclization, yielding 5-benzylidene-2-imino-4-thiazolidinone [(193) from thiourea]. The suggested reaction sequence is supported by the isolation of the intermediates in selected instances. ... 

The chloroacetyl residue has proved a suitable protective entity for amino-groups, being removable by thiourea under mild conditions. Applied to peptides, however, the reaction proceeds in unsatisfactory yields, because further condensation occurs between the liberated amino-acids and thiazolidinone (359). The use of an iSW-disubstituted thiourea, e.g. iVA-pentamethylenethiourea, removes this difficulty, since the reaction now terminates with the production of 2-piperidino-4-thiazolin-5-one (360)... 

The synthesis of thiazolo[5,4-d]pyrimidines 194 can be achieved from different 5-thiazolidinones, 2-butyl-lH-imidazole-5-carbaldehyde, and thiourea using microwave irradition within 5 min in the presence of HCl. These reactions study the Biginelli condensation reaction, in which the condensation between an aldehyde and urea has some similarities to the Mannich condensation. The generated iminium intermediate 193 (Scheme 85) acts as an electrophile for... 

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