A simple route for synthesis of 5-(furan-3-yl)barbiturate/thiobarbiturate derivatives via a multi-component reaction between arylglyoxals, acetylacetone and barbituric/thiobarbituric acid

An effective protocol for the synthesis of 5-(furan-3-yl)barbiturate and 5-(furan-3-yl)thiobarbiturate derivatives through a one-pot three - component reaction of readily available starting materials arylglyoxals, barbituric acid or thiobarbituric acid and acetylacetone in water as solvent is reported


Introduction
−3 Combination of barbituric/thiobarbituric acid moieties with other pharmacophoric moieties may result in new types of scaffold with potential biological activities.Many efforts have been made in fusing barbiturates and thiobarbiturates with other molecular skeletons such as 1,3diketones, 4,5 isatins, 6−8 Meldrum's acid, 9 4-hydroxycoumarin 10 and pyrroles. 11Barbiturates have also been widely used in the manufacturing of plastics, 12 textiles, 13 and polymers. 14uran moieties are important substructures that have been found in numerous natural products, such as kailolides 15 and combranolides. 16These heterocycles are also found in a variety of commercial products such as pharmaceuticals, fragrances, and dyes. 17ulti-component reactions (MCRs), especially those conducted in water, offer significant advantages over conventional linear-type syntheses, because the reaction components combine with each other in a single step to generate new products.On the other hand, the low cost, and the lack of inflammability, explosive, and carcinogenic properties of water are some of the economic and environmental benefits of using water as solvent. 18,19rylglyoxals with a carbonyl group adjacent to the aldehyde functionality, are reactive and versatile species which have been widely used for the synthesis of various heterocyclic and carbocyclic compounds.4][25] In continuation of these works, here we report a new threecomponent reaction of arylglyoxals with acetylacetone and barbituric or thiobarbituric acid for the synthesis of a series of new polyfunctionalized 5-(furan-3-yl)barbiturates and 5-(furan-3-yl)thiobarbiturates.
To investigate the scope of the reaction, different arylglyoxals were treated with acetylacetone and barbituric acid and the corresponding 5-furyl-3-barbiturates 4a-g were obtained in good yields (Table 1).Next, reactions were carried out between acetylacetone, arylglyoxals and thiobarbituric acid in water at similar conditions and the corresponding 5-(furan-3-yl)thiobarbiturates 4h-m were obtained in good yields.Table 1.Three-component reaction between arylglyoxals, barbituric acid or thiobarbituric acid and acetylacetone for synthesis of 5-(furan-3-yl)barbiturate/thiobarbiturate derivatives The structures of compounds 4a-m were inferred from their elemental analyses and their IR, 1 H NMR, and 13 C NMR spectroscopic data.Compounds 4a-m may exist as two tautomers 4 or 4 ' (Table 1).The tautomerism of barbituric acid and thiobarbituric acid derivatives has been extensively studied.These studies showed that 5-substituted barbiturates usually exist as the keto form in polar solvents such as DMSO in contrast to 5substituted thiobarbiturates which exist mainly as the enol form in polar solvents. 26,27The NMR spectra of compounds 4a-4f showed that those compounds which include the barbiturate moiety in their structures existed mainly as keto tautomer 4 in DMSO-d 6 solution.In contrast, compounds 4h-4m with a thiobarbiturate moiety in their structure existed as the enol tautomer 4 ' .The NMR spectra of compound 4g with nitrophenyl and barbiturate moieties showed the presence of two isomers in nearly equal amounts.The 500-MHz 1 H NMR spectrum of 4a exhibited three sharp signals at δ 2.19, 2.47, 3.72, ppm for two methyl groups and one methoxy.The CH proton of the barbiturate moiety resonated as a singlet signal at 4.93 ppm.This signal was not observed at the 1 H NMR spectrum of thiobarbiturate derivative 4h, which showed that this compound exists as the enol form.The aromatic protons of 4a resonated as two doublet signals at 6.88 and 7.54 ppm.Two NH protons were observed at 9.22 ppm as a broad signal.The 13 C NMR spectrum of compound 4a showed fifteen distinct signals in agreement with the proposed structure.The CH carbon of the barbiturate moiety resonated at 40.89 ppm.In derivatives that are in the enol form, such as 4h, this carbon was observed at about 90 ppm.The structural assignments made on the basis of the NMR spectra of compound 4a were supported by its IR spectrum.The amide carbonyl groups exhibited a strong absorption band at about 1666 cm -1 .The ketone carbonyl was observed at 1701 cm -1 as a strong absorption band.
The suggested mechanism for formation of furanyl barbiturate/thiobarbiturate derivatives 4a-m by the reaction between arylglyoxals, acetylacetone and barbituric/thiobarbituric acids is shown in Scheme 2. The Michael addition of barbituric/thiobarbituric acid to the Intermediate obtained from Knoevenagel condensation of arylglyoxals with acetylacetone afforded reactive 1,4-diketone 6.The Paal-Knorr cyclization of this intermediate afforded product 4.

Conclusions
In conclusion, we report a simple three-component reaction between arylglyoxal monohydrates, acetylacetone and barbituric or thiobarbituric acid for the synthesis of polyfunctionalized 5-(furan-3-yl)barbiturates and 5-(furan-3-yl)thiobarbiturate derivatives in good yields.The method employs readily available starting materials, neutral reaction conditions and water as an environmentally green solvent.

Experimental Section
General.All solvents and chemicals except arylglyoxals were purchased from commercial sources and used without further purification.The utilized arylglyoxals were prepared by the SeO 2 -oxidation of the related aryl methylketones on the basis of the reported procedure, and used as their monohydrates. 28Melting points were determined on a Melt-Tem II melting point apparatus and are uncorrected.IR spectra were recorded on a Shimadzu IR-470 spectrometer.All of the NMR spectra were recorded on a Varian model UNITY Inova 500 MHz ( 1 H: 500 13 C: 125 MHz) NMR spectrometer.Chemical shifts of 1 H, 13 C NMR are reported in parts per million (ppm) from tetramethylsilane (TMS) as an internal standard in DMSO-d 6 as a solvent.
General procedure.A mixture of arylglyoxal (1 mmol) and acetylacetone (1 mmol) in water (15 mL) was stirred at 60 o C for 20 min.Then, barbituric or thiobarbituric acid (1 mmol) was added to this mixture.The reaction mixture was then stirred at 60 o C for 10 h more.The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica-gel, using EtOAc-EtOH mixture (7:1) as eluent.