Library thiazolidinone

Preparation of a 4-thiazolidinone Library Employing a Functional Ionic Liquid Support... 

Fig. 34 Preparation of a 4-thiazolidinone library using an ionic liquid support. Reagents and conditions a MW 100 °C, l-2h, open vessel b R"NH2, t-BuOK, MW 100-150°C, 10-20 min. R = H, Me, CH2COOH R = Pr, i-Pr, i-Bu, Bn, piperonyl, CH2CH(OMe)2, CH2CH CH2 R" = Pr, Bu, Bn, or cyclic derivatives as piperonyl, piperidine, pyrrolidine,...

A small library of thiazolidinones 138 has been prepared mixing directly a primary amine (as the HCl salt), an aldehyde and mercaptoacetic acid in EtOH in the presence of Hiinig s base and molecular sieves (120 °C for 30 min) [88]. Working with a chiral amine, a 1 2 mixture of diastereoisomers was obtained (Scheme 49). 

Scheme 7.91 Generation of a 4-thiazolidinone library utilizing grafted ionic liquids.

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. 

Ault-Justus, S. E., Hodges, J. C. Wilson, M. W. Generation of a Library of 4-Thiazolidinones Utilizing Polymer Supported Quench (PSQ) Reagent Methodology, Biotechnol. Bioeng. 1998, 61, 17. 

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]. 

Where possible, it is usually preferable to have the activated species (e.g., the active ester) in solution and the substrate (e.g., the amine component) on the solid phase. If the case requires an inverted situation, as for the synthesis of a thiazolidinone library (see Fig. 13),41 identification of the best reaction conditions may be more challenging, considering the relative scarcity of literature examples. 

A number of other solid-phase chemistries have been described for the generation of combinatorial libraries. This includes the synthesis of urea-linked diamines [51], bisamide phenols [52,53], polyphenols [54], thiazolidinones [55,56], thiazolines [57], hydantoins [58], and diaminoalcohols [59,60], Readers interested in more details of these libraries are referred to the section on small molecule libraries. 

Look GC, Schullek JR, Holmes CP, Chinn JP, Gordon EM, Gallop MA, The identification of cyclooxygenase-1 inhibitors from 4-thiazolidinone combinatorial libraries, Bioorg. Med. Chem. Lett., 6 707-712, 1996. 

Structure-based design has been effectively utilized in synthesis of inhibitors of non-proteolytic enzymes. Inhibitors of MurB, an essential bacterial enzyme required for biosynthesis of peptidoglycan, were identified using the X-ray structure of the enzyme for library design. Thiazolidinone inhibitors (8) thus identified are the first examples of small molecule inhibitors of MurB. 

Reactions of amines, aldehydes and mercaptoacetic acid in ionic liquids (Scheme 47) resulted in the formation of thiazolidinones 263 in moderate to high yields [92]. The reaction was used to create a library of nucleoside thiazolidinones... 

More recently, an improved protocol has been reported wherein NJ "-dicyclohexylcarbodiimide (DCC) or 2-(lH-benzotrizo-l-yl)-l,l,3,3-tetra-methyluraniiunhexafluorophospate (HBTU) (Scheme 6) is used as a dehydrating agent to accelerate the intramolecular cychzation resulting in faster reaction and improved yields [27,28]. The DCC/HBTU-mediated protocol has the advantage of mild reaction conditions, a very short reaction time, and product formation in almost quantitative yields. More importantly, yields of the thiazolidinones are independent of the nature of the reactants. This modification is compatible with a solid-phase combinatorial approach to generate a library of compounds. 

The acid-labile carbamate linkage of type 5 has also been apphed to the paraUel synthesis of a thiazolidinone library of type 12 (Fig. 2) [22], Apphcation of trityl-based resins (see Section 2.2.2.6) for this reaction sequence was not possible as the... 

Three 4-thiazolidinone libraries were prepared and assayed for inhibition of the enzyme cyclooxygenase-1 (COX-1), a key enzyme in the conversion of arachidonic acid to prostaglandins [421, 422], From the carboxylic acid, ester and carboxamides libraries only the methyl ester library showed significant activity. A series of three rounds of testing and deconvolution led to a compound (library 37 IC50 3.7 fiM) with equivalent in vitro activity to the commercially available COX-1 inhibitors ibuprofen and phenylbutazone. 

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-... 

A library of spiro[indole-thiazolidinones] (158) was prepared sonochemically by a three-component reaction in an aqueous medium in the presence of cetyltrimethyl-ammonium bromide (CTAB) as a phase-transfer catalyst (Dandia et al. 2011b). The reaction of isatins (155), aryl or heteroaryl amines (156), and a-mercaptocarboxylic acids (157) under ultrasound for 40-50 min afforded the target molecules in good to excellent yields (80%-98%) (Scheme 8.51). 

---