Microwave-Assisted Synthesis of Novel 2H-Chromene Derivatives Bearing Phenylthiazolidinones and Their Biological Activity Assessment

6-Hydroxy-2-oxo-2H-chromene-4-carbaldehyde (2), 6-chloro-2-oxo-2H-chromene-4-carbaldehyde (3) and 6-hydrazinyl-4-methyl-2H-chromen-2-one (5) were prepared as single-pharmacophore motif key intermediates. Compounds 2, 3 and 5 were incorporated in a series of multicomponent reactions (MCRs), under microwave assistance as well as conventional chemical synthesis processes, to afford a series of three and/or four-pharmacophoric-motif conjugates 8a,b, 11, 13, 16, 17, 19 and 20 in good yields. The newly synthesized compounds were characterized by IR, NMR, 13C-NMR, MS and elemental analyses. Finally the synthesized compounds have been screened for their biological activity whereupon they exhibited remarkable antimicrobial activity on different classes of bacteria and the fungus.


Introduction
Green chemistry is a new and rapidly emerging field of chemistry. Its growing importance is in utilization of the maximum possible resources in such a way that, there is negligible or minimum production of chemical waste. It is one of the best alternatives for traditional chemical synthesis processes. By applying the green synthesis method, we can not only avoid the use of hazardous, toxic solvents, but also the formation of by-products is avoided. Thus, they are perfectly amenable to automation for combinatorial synthesis [1]. In 1986, Gedye and Giguere reported for the first time that organic reactions could be conducted very rapidly under microwave irradiation.
Finally, as third motif in this preface, 4-thiazolidinones are among the most common and important groups among the small ring heterocyclic compounds. There are many references reported in the literature highlighting their chemistry and uses. 4-Thiazolidinones exhibit various biological activities such as analgesic, antibacterial, antifungal, anti-oxidant, anti-inflammatory, anticonvulsant, anticancer, anti-HIV, anti-tubercular and anthelmintic properties [22][23][24][25][26].

Chemistry
The synthetic strategies adopted for the synthesis of the intermediate and target compounds are depicted in Schemes 1-8. A one-pot, microwave assisted reaction condition was applied as well as conventional synthesis, by using 6-hydroxy-4-methyl-2H-chromen-2-one (1) in DMF containing 3-4 drops of glacial AcOH and selenium dioxide to give compound (2) (Scheme 1, Table 1). The latter compound was easily chlorinated via treatment with phosphoryl chloride in anhydrous EtOH yielding 6-chloro-2-oxo-2H-chromene-4-carbaldehyde (3) (Scheme 1, Table 1). The hydroxyl group in compound 1 was easily transformed into a chlorine to afford the 6-chlorocoumarin derivative 4, which, in turn was reacted with hydrazine hydrate in anhydrous EtOH to give 6-hydrazinyl-4-methyl-2Hchromen-2-one (5) (Scheme 1, Table 1). The IR spectrum of 2 showed the presence of absorption bands at 1695, 1710 and 3431 cm −1 due to (2 C=Ostr) and (O-Hstr) functions respectively. Its 1 H-NMR spectrum showed three singlet signals corresponding to the coumarin-C3, formyl and hydroxyl protons at δ 6.70, 10.45 and 12.01 ppm, respectively, and aromatic protons in the 7.70-7.98 ppm region, while the 13 C-NMR spectrum of 2 showed the following signals: 91.1 (coumarin-C3), 119.8, 125.7, 126.6, 128.8, 133.7 and 150.1 (Ph), 162.4 (C=O), 192.5 (CHO). The mass spectrum of 2 displayed an intense ion peak at m/z 190 (M + , 51%) corresponding to C10H6O4. The structure of 3 was established on the basis of its elemental analyses and spectral data, as well as its independent synthesis via oxidation reaction of chlorocoumarin derivative 4 with selenium dioxide which afforded a product identical in all aspects (mp and IR spectra) with that obtained previously from the reaction of 2 with phosphoryl chloride. The IR spectra of compounds 3 and 4 do not show any absorption bands corresponding to O-H groups while they show absorption bands at 1695-1710 cm −1 due to C=Ostr functions. The mass spectrum of 4 showed a molecular ion peak at m/z 194 corresponding to its molecular formula (C10H7ClO2). The mass spectrum of 5 showed a molecular ion peak at m/z 190, corresponding to a molecular formula C10H10N2O2. Its 1 H-NMR spectrum displayed new signals representing a hydrazide structure that appeared at 4.28 (-NHNH2) and 9.21 (-NHNH2) ppm (exchangeable with D2O) integrating for two protons and one proton, respectively. Scheme 1. Synthesis of 2H-chromen-2-one derivatives 2-5. Spiro compounds represent an important class of naturally occurring molecules characterized by highly pronounced biological properties [32]. In this context, we explored the synthetic versatility of 6-hydroxy-4-methyl-2H-chromen-2-one (1) for the synthesis of spiro compounds containing the coumarin moiety. Thus, a one-pot, three-component, microwave assisted reaction condition was applied, as well as conventional synthesis, using cyclohexanone (or cyclopentanone), malononitrile (1:1 molar ratio) and 3-4 drops of glacial AcOH with DMF as a solvent and compound 1, to give the pyrano[2,3-f]chromene derivatives 8a,b, as indicated by elemental analysis and spectral data (Scheme 2, Table 1). Formation of the spiro compounds 8a,b was proceeded according to the proposed mechanistic pathway (Chart 1).  The IR spectrum of product 8b, as an example, revealed absorption bands at 1695, 2217 and 3361 cm −1 characteristic for C=O, C≡N and NH2 groups, respectively. Its 1 H-NMR spectrum showed multiplet signals for protons of the methylene groups centered around δ 1.00-1.70 ppm in addition to the presence of two singlet signals, one at 2.43 ppm attributable to methyl protons and the other at 6.82 ppm, exchangeable with D2O, attributed to the NH2 protons. The mass spectrum of compound 8b revealed a molecular ion peak at m/z 322 (M + , 57%), and a base peak was observed in the spectrum at m/z 176 (100%), which is compatible with its molecular formula C19H18N2O3.

Conventional Synthesis, Method C
To a stirred mixture of 6-hydroxy-2-oxo-2H-chromene-4-carbaldehyde (2, 1.90 g, 1 mmol) and anhydrous EtOH (30 mL) was added dropwise POCl3 (5 mL) at 5-10 °C. The reaction mixture was then stirred for an additional 1 h at room temperature and then heated for 2 h at 60 °C. After the reaction was completed, the mixture was poured onto crushed ice (200 g) under vigorous stirring. The mixture was kept overnight at 0 °C; resulted solid was collected by filtration and washed successively with water and then was air-dried to provide 3, and finally recrystallized from EtOH, as an orange solid, in 60% yield;

Conclusions
In summary, an efficient synthesis of some new 2H-chromene derivatives 1-20 bearing the phenylthiazolidinone nucleus via a facile one-pot three-component reaction under microwave irradiation as well as conventional chemical synthesis processes has been reported. Most of the synthesized compounds showed mild to moderately active against the C. tetani, a gram positive strain and E. coli, a gram negative strain. The antifungal activity of the compounds shows that most of the compounds were more potent against C. albicans than against A. fumigatus. Compounds 3, 4, 8a, 13 and 20 exhibited remarkable antifungal activity against C. albicans.