Synthesis of 5-arylidene-3-methylrho-danines catalyzed by 1-butyl-3-methyl-imidazolium chloride in water under microwave irradiation condition

Six 5-arylidene-3-methylrhodanine derivatives were synthesized by the crossed aldolization of aromatic aldehydes with 3methylrhodanine using 1-butyl-3methylimidazolium chloride ([BMI]Cl) as phase transfer catalyst in water. The reactions, under microwave irradiation (160 watts) during 10 minutes, afforded the yield of 59–83 %. This is the first time [BMI]Cl was used as phase transfer catalyst in the aldol condensation.


INTRODUCTION
Rhodanine derivatives have showed a wide range of biological activities which include anticonvulsant, antibacterial, antiviral and antidiabetic effects [1].These have also been reported as Hepatitis C virus (HCV) protease inhibitors [2] and used as inhibitors of uridine diphospho-N-acetylmuramate/L-alanine ligase [3].Recently, substituted rhodanines were investigated for tau aggregation inhibitor properties [4].Rhodanines, classified as nonmutagenic and a long-term study on the clinical effects of the rhodanine-based Epalrestat as an anti-diabetic showed that it was well tolerated [5].Due to various possibilities the rhodanine derivatives, these compounds will probably remain a privileged scaffold in drug discovery.Therefore, the synthesis of these compounds is of considerable interest.
Condensation of aldehydes at the active methylene C-5 of 3-methylrhodanine has been performed using piperidinium benzoate in toluene or sodium acetate in glacial acetic acid [6,7].Recently, Sim et al. [8] reported the synthesis of 5-arylidenerhodanines in 6082 % yields by heating the reactants suspended in toluene at 110 o C for 3 days.Sing et al. [9] reported the condensation of rhodanine with an aldehyde (0.1 mmol) by heating in anhydrous EtOH (200 mL) at 80 o C for 6 hours.Obviously, these methods involve long reaction times, high

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temperatures, using large quantities of organic solvents.Therefore, it is useful to develop new methods, which are simple and friendly with the environment to synthesize rhodanine derivatives.Jian-Feng Zhou et al. [10] had reported the synthesis of 5-arylidenerhodanines by the aldol condensation of aromatic aldehydes with rhodanine using tetrabutylammonium bromide as phase transfer catalyst in an aqueous medium under microwave irradiation.
Microwave (MW) activation provides a valuable tool for organic synthesis.MW-assisted reactions have emerged as green methods which promote much faster, cleaner reactions than conventional heating [11][12][13][14].MW-assisted organic syntheses in green media or in the absence of solvent have received significant interest due to the simple and environmentally benign procedures [1517].
In the present paper, we report the synthesis of seven 5-arylidene-3-methylrhodanines by the crossed aldol condensation of substituted benzaldehydes with 3-methylrhodanine using 1butyl-3-methylimidazolium chloride ([BMI]Cl) as phase transfer catalyst in an aqueous medium under microwave irradiation (Fig. 1).These reactions required only 10 minutes and proceeded in 5983 % yields.Especially, this is the first time [BMI]Cl was used as phase transfer catalyst in this reaction.

Materials
Melting points were determined in a Wagner & MunzPolytherm A melting point apparatus.The 1 H NMR spectra were run on a Bruker Ultrashield 500 Plus spectrometer operating at 500 MHz for 1 H using CDCl3 as solvent.The mass spectra were scanned on a GC Agilent Technologies 7890 A spectrometer with detector MS Agilent Technologies 5975 C.

General experimental procedure
In a 5 mL test tube, a solution containing the studied aromatic aldehyde (x mmol), 3methylrhodanine (0.14 mmol), [BMI]Cl (0.14 mmol), base (0.14 mmol) and water (1 mL) was irradiated in a microwave oven at 160 watts for 10 minutes.After the reaction, the mixture was allowed to stand at room temperature to solidify.The solid was filtered, dried and recrystallized from CHCl3.The obtained compound was dried in a desiccator up to the moment the weight of the residue did not change.Then this compound was weighed for the calculation of the yield of the reaction.

RESULTS AND DISCUSSION
In order to optimize the reaction condition, we examined the influences of contributing parameters such as reaction times, molar ratios of reactants, catalytic amounts and types of base catalysts.The crossed aldol condensation of 3methylrhodanine with benzaldehyde was chosen as the model reaction and NaOH, [BMI]Cl were selected as the base and phase-transfer catalyst, respectively in an aqueous medium under microwave irradiation (Table 1).In the first series of studies, the effect of different molar ratios (from 1:1 to 1:5) of 3-methylrhodanine and benzaldehyde was investigated.The results showed that the optimal ratio for maximum yield was observed at a ratio of 1:3 (Table 1, entry 3).The high usage of benzaldehyde could be explained by its evaporation under the microwave irradiation condition in a domestic microwave oven.Next, we compared the catalytic activity of NaOH with other bases as shown in Table 2.Under the same experimental conditions, the inorganic bases (NaOH, KOH, Na2CO3 and Na2B4O7.10H2O)gave better results than organic bases [pyridine and (CH3)2NH].Among these inorganic bases, Na2CO3 was the best base catalyst (Table 2, entry 3) to give the highest yield.It was found that in the absence of base, the reaction did not proceed to desired products (Table 3, entry 6).
The result in Table 3 showed that Na2CO3 was a suitable base for this type of aldol condensation.The molar ratio between 3methylrhodanine: Na2CO3: [BMI]Cl was further investigated and the high yield was achieved at the ratio of 1:1:1 (Table 3, entry 4).
The optimized condition of this reaction was applied to synthesize various 5-arylidene-3methylrhodanine from various benzaldehydes possessing different substituents (Table 4).The results of the aldol condensation of aromatic compounds with 3-methylrhodanine showed that substituted benzaldehydes with electron withdrawing groups (Table 4, entries 5, 7) were more reactive than the ones bearing electron donating groups (Table 4, entries 14).The much electrophilic the aldehydic carbon of benzaldehyde, the much reactive it is.In general, the aldolisation of several aromatic aldehydic

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substrates with 3-methylrhodanine proceeded smoothly to give the corresponding 5-arylidene-3-methylrhodanines in good to excellent yields within short reaction times.

CONCLUSION
We reported a straightforward and effective method for the synthesis of 5-arylidene-3methylrhodanine with the assistance of microwave irradiation from 3-methylrhodanine and substituted benzaldehydes based on crossed aldol condensation in water using [BMI]Cl as phase-transfer catalyst.
The microwave irradiation was prominent with slightly higher yield 83 % in a short time 10 min compared with conventional heating method.

Table 1 .
Effect of 3-methylrhodanine:benzaldehyde molar ratio in the crossed aldol condensationa b Isolated yield after recrystallization

Table 2 .
Effect of various base catalysts on the crossed aldol condensation of b Isolated yield after recrystallisation

Table 3 .
Effect of molar ratio of 3-methylrhodanine : Na2CO3: [BMI]Cl in the crossed aldol condensation with benzaldehyde a

Table 4 .
Effect of various substituted benzaldehydesin the crossed aldol condensation of 3-methylrhodanine a