Synthesis of 5-arylalkylidenerhodanines catalyzed by tetrabutylammonium bromine in water under microwave irradiation

A series of benzylidenerhodanine derivatives were synthesized by the crossed Aldol condensation of aromatic aldehydes with rhodanine using tetrabutylammonium bromide (TBAB) as phase transfer catalyst in water under microwave irradiation. The reactions were completed in 8~10 min with 71~96% yield, short reaction times, environmentally benign conditions and easy work-up.


Introduction
Rhodanine derivatives have proven to be attractive compounds due to their outstanding biological activities and have undergone rapid development as anticonvulsant, antibacterial, antiviral and antidiabetic agents. 1 At the same time, rhodanine derivatives have been reported also as Hepatitis C Virus (HCV) protease inhibitors 2 and used as inhibitors of uridine diphospho-N-acetylmuramate/L-alanine ligase. 3Therefore, the synthesis of these compounds is of considerable interest.The rhodanine (2-thiono-4-thiazolidinone) moiety has been synthesized by various methods such as the addition of isothiocyanate to mercaptoacetic acid followed by acidcatalyzed cyclization, or the reaction of ammonia or primary amines with carbon disulfide and chloroacetic acid in the presence of bases. 4Condensation of aromatic aldehydes at the nucleophilic C-5 active methylene has been performed using piperidinium benzoate in refluxing toluene 5 or sodium acetate in refluxing glacial acetic acid. 4Recently, Sim et al. 6 reported the synthesis of 5-arylalkylidene rhodanines in 60-82% yields by heating the reactants suspended in toluene at 110˚C for 3 days.Sing et al. 7 reported the condensation of rhodanine with an aldehyde (0.1 mmol) by heating in anhydrous EtOH (200 mL) for 6 h at 80˚C.Alternatively, rhodanine (0.1 mmol), ketone (0.1 mmol) and NH 4 OAc (0.2 mmol) were refluxed in toluene (500 mL) for 3 days ( 61-92% yields).Obviously, these methods involve long reaction times, high temperatures, use large quantities of organic solvents and some give unsatisfactory yields.Therefore, it is useful to develop new methods, which are simple and environmentally friendly for the synthesis of 5-arylalkylidene rhodanines.
The wide applicability of microwave irradiation in chemical reaction enhancement is due to high reaction rates, formation of cleaner products, and operational simplicity. 8,9,10 Zang, Alloum et al. reported the successful synthesis of some 5-arylalkylidene rhodanines on solid inorganic supports in dry media under microwave irradiation. 11,12 ince then, Toda et al. 13 have reported the first examples of aldol condensation in the absence of solvent.Due to stringent and growing environmental regulations, organic chemists have endeavored to develop clean, economical, and environmentally safer methodologies.One of the most promising approaches is to utilize water as reaction medium. 14,15 he use of microwave irradiation to carry out organic reactions is a well-established procedure since the reactions are clean, rapid and economical.Application of phase-transfer catalysis (PTC) instead of traditional technologies for industrial processes provides substantial benefits to the environment.The combination of the these techniques has shown excellent results. 16e have reported previously a high yield synthesis of bis(benzylidene)cycloalkanones by the aldol condensation in an aqueous medium under phase-transfer catalysis and microwave irradiation. 17This paper reports an efficient and clean synthesis of 5-arylalkylidenerhodanines by the aldol condensation of aromatic aldehydes with rhodanine using tetrabutylammonium bromide (TBAB) as phase-transfer catalyst in an aqueous medium under microwave irradiation (Scheme 1).This reaction requires only 8-10 minutes, proceeds in 71~96% yields, is environmentally benign, with low energy consumption and easy work-up.

Results and Discussion
The reaction of m-nitrobenzaldehyde (1e) with rhodanine was tested as a model reaction and was explored initially without any catalyst using water as a solvent under microwave irradiation for 20 min.Unfortunately, the target compound could not be obtained (Table 1, entry 1) presumably due to the fact that the reactants exist as a non-miscible mixture of oil and water.Therefore, TBAB as phase-transfer catalyst, was applied for this reaction.The results showed that when the molar ratio of TBAB, aromatic aldehyde and rhodanine was 0.3:1:1, the reaction proceeded efficiently (Table 1, entry 2).An attempt to maximize the yield and shorten the reaction time, by increasing the amounts of TBAB, did not increase the rate of the reactions nor the yield of 3e (Table 1, entry 3-4).At the same time, various phase-transfer catalysts such as tetraethylammonium bromine (TEAB), triethylbenzylammonium chloride (TEBAC), PEG-400 and PEG-600 were also investigated for this reaction.The reaction proceeded with TBAB, TEAB and TEBAC as phase-transfer catalyst and gave 3e in 96, 74 and 63% yield, respectively (Table 1, entries 2, 5, 7).However, with PEG-400 and PEG-600 as phase-transfer catalysts, compound 3e was not obtained after microwave irradiation for 20 minutes (Table 1, entry 8, 9).It is believed that Q 4 N + X -(TBAB) serves both as a phase-transfer catalyst and as a base because the reactants would exist as a non-miscible mixture of oil and water in the absence of Q 4 N + X -, and 5-CH 2 of rhodanine cannot be removed by the alkali effectively.Therefore, the carbanion or enolate ions would not be formed in the reaction, which would explain why the reaction does not take place in the presence of polyethylene glycol, or in the absence of TBAB.It

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Page 178 © ARKAT is also obvious that the rates of the reactions were accelerated by microwave irradiation.For instance, in the case of 3e, the yield is only 65% after refluxing for 4 hrs (Table 1, entry 6).
In addition to our study in an aqueous medium, the aldol condensations of aromatic aldehydes with rhodanine in acetic acid using sodium acetate as catalyst under microwave irradiation was investigated.The results show that the reaction requires long times and proceeds in low yields in organic media when compared with the aqueous medium (Table 2).

Table 1 .
Influence of type and amount of catalyst on the reaction of 3e with rhodanine a bCarried out under conventional reflux heating instead of microwave irradiation.