Microwave Assisted Synthesis of Novel Functionalized Hydantoin Derivatives and Their Conversion to 5-(Z) Arylidene-4H-imidazoles

2-(Alkyl-1-yl)-1H-imidazol-5(4H)-ones 5a–n were synthesized via nucleophilic substitution of the methylsulfanyl group of the corresponding 2-(methylthio)-1H-imidazol-5(4H)-ones 3a–c with suitably substituted secondary amines. The starting 2-thioxo- imidazolidin-4-ones 2a,2b were prepared by condensation of thiohydantoin and benzo[b]-thiophene-3-carbaldehyde or benzofuran-3-carbaldehyde under microwave irracdiation (MW) conditions. 2-Methylthio derivatives 3a–c were prepared by treatment of 2a–b with methyl iodide in the presence of aqueous sodium hydroxide.


Introduction
Hydantoin derivatives have achieved considerable success as anticonvulsant agents [1]. The nucleosides of several 5-arylidene-3-arylhydantoins and 2-thiohydantoins show potent activity against human immunodeficiency virus (HIV) [2] and the leukemia subpanel [3]. A recent study showed that S-glucosylated hydantoins ( Figure 1) act against herpes simplex virus, type 1 (HSV-1) and type 2 (HSV-2) in Vero cells [4]. A further study reported that thiazolidinediones (TZDs), which are known to have potent enhancing effects on insulin sensitivity, have been developed for the treatment of noninsulin-dependent diabetes mellitus [5,6]. It also been found that TZDs are high-affinity ligands for peroxisome proliferitor-activated receptor-γ (PPAR-γ) and inhibit the production of monocyte chemo attractant protein 1 (MCP-1) in some human tissues [6]. Another group of TZDs revealed that troglitazone ( Figure 1) acts on acute liver injury induced by ethanol and lipopolysaccharide [7]. For the past few years our group has been working on biologically important compounds [8][9][10]. Herein we report on the synthesis of variety of benzo [b]thiophene and benzofuran based hydantoin derivatives with the aim of investigating their antimicrobial and neuroprotecting properties.
Although many bases shown in Table 1 can be used as catalysts [e.g., piperidine, pyridine, N-methylpiperidine (NMP), DBU)], 2,2,6,6-Tetramethylpiperidine (TMP) works best. The same reaction under conventional reflux condition using ethanol as solvent gave lower yields after longer times (5 h) and/or compounds that required rigorous purification. However the MW reaction provides cleaner reactions, shorter times (15 min) and purification of the products only required washing with cold ethanol. In addition the yields are good to excellent. The optimum temperature and condition for this MW assisted reaction was determined by a series of reactions of appropriate aldehyde 1 with hydantoin. The results are summarized in Table 1. The results indicate that MW irradiation at 90 °C for 15 min in ethanol is the optimum condition for the synthesis of 2a and 2b.  Ethanol  90  20  20  7  TMP  Acetonitrile  90  15  76  8  TMP  Acetonitrile  130  15  15  9  DBU  Acetonitrile  90  30  trace  10  TMP  DMF  90  15  45  11  NMP  DMF  90  30  10  12  DBU  DMF  120-140  15  trace  13  TMP  Water  90  15  trace  14  TMP  Water  130  15  trace  15  -water  130  30  trace  16  TMP  Tolune  90  15  trace  17  TMP  Isopropanol  90  15  45  18  TMP  THF  90  15  38  19 TMP n-Butanol 90 15 33 a All the reaction was carried out in equimolar amount of each compound in 2 mL of solvent at 150 psi pressure; b Isolated yield.
The Z configuration of the compounds 2a and 2b was confirmed by comparison of previously reported [2] hydantoin derivatives along with nuclear Overhauser effect (NOE) experiments [4]. The vinylic proton in the 1 H-NMR spectra of benzo[b]thiophene and benzofuran derivatives appeared as singlets at 6.72 ppm and 6.58 ppm, respectively. The intermediates 2a and 2b were in turn transformed into the corresponding methylsulfanyl derivatives 3(a-c) by alkylation with methyl iodide in basic medium [13]. The use of 1.3 equiv. of alkyl halide and stirring for 4 h afforded 3a while use of excess alkylating agent (2.5 equiv.) and stirring for 16 h afforded dialkylation giving 3b in high yield. The 13 C-NMR spectrum of compounds 3a-c showed the absence of C=S signal of 2a, 2b at 179.50 ppm and the appearance of the C=N signal at 170.9 ppm, corresponding to s-alkylation. On the other hand, the 1 H-NMR spectra of 2a and 2b showed two NH signals at 12.41 and 12.18 which were absent in the spectra of 3a and 3b, in which only a broad peak NH signal at 11.84 ppm appeared. Conversion of 2a to 3a via microwave irradiation was unsuccessful. The intermediate methylsulfanyl derivatives were subsequently converted into compounds 5a-n by nucleophilic substitution of the methylsulfanyl group with suitably substituted secondary amines [14] by using MW irradiation of a solution containing excess amine (>12.5 equiv.) and absolute ethanol at an elevated temperature (100 °C). The same reaction under conventional reflux condition using ethanol as solvent required longer time (16 h) and/or rigorous purification of products As shown in Table 2, the 5-(Z) arylidene-4H-imidazole compounds 5a-n were formed in good to excellent yields. In most cases, the 5-(Z) arylidene-4Himidazoles precipitated upon cooling the reaction mixture and only simple trituration with ethanolhexane followed by recrystallization from ethanol afforded the product 5a-l. But in case of 5m and 5n, the crude reaction mixtures were purified by column chromatography using 40% ethyl acetate-hexane mixture (v/v). All the products were well characterized by 1 H-NMR, 13 C-NMR, IR and HRMS.   The use of aromatic amines for the same reaction was unsuccessful. From Table 1, it can be seen that in the case of 3,5-dimethylmorpholine (entry 14) the comparatively low yield probably reflects unfavorable steric interaction between the two methyl groups.

General
The 1 H-and 13 C-NMR spectra were recorded on a 500-MHz Jeol multinuclear NMR spectrometer; chemical shifts were referenced to tetramethylsilane (TMS) as internal standard. Infrared (IR) spectra were obtained on a Varian 3100 Fourier transform (FT)-IR Spectrometer. Melting points were taken on a Meltemp apparatus. All chemicals and reagents were purchased from commercial sources. Mass spectra were obtained from Washington University, St. Louis. MO. Microwave experiments were carried out on CEM Discover microwave instrument.
An equimolar quantity of benzo[b]thiophene-3-carbaldehyde and thiohydantoin were mixed in a mortar pestle and charged into a specially designed MW test tube. After the addition of ethanol (2 mL) followed by 1-2 drops of 2,2,6,6-tetramethylpiperidine, the test tube was sealed then irradiated for 15 min at 90 °C and 150 psi pressure. After cooling, the solid mass was scraped out of the test tube and placed into a flask containing 95% ethanol (20 mL) and filtered. The solid mass was collected then washed with ethanol (20 mL) and dried under reduced pressure and the residue was recrystallized from ethanol to afford 0.49 g (96%) of (Z)-5-(benzo

(Z)-4-(Benzo[b]thiophen-3-ylmethylene)-2-(piperidin-1-yl)-1H-imidazol-5(4H)-one (5a)
. Compound 3a and piperidine (excess, 12.5 equiv.) were mixed then placed in a specially designed MW test tube. Ethanol (2 mL) was added to the mixture. The test tube was then sealed and then irradiated for 30 min at 100 °C and 150 psi pressure. After cooling, the solid mass was filtered and crashed into 20 mL of 95% ethanol. The solid mass collected was washed with ethanol-hexane mixture (1:5 v/v) and dried over vacuum to get the desired product. The titled compound was obtained as bright yellow solid.

Conclusions
In summary we have successfully developed a synthetic method that provides ready access to novel biologically important benzo[b]thiophene and benzofuran based thiohydantoin derivatives. We are currently investigating the synthesis of a number of other thiohydantoin-based drug molecules by this method. A detailed biological activity study (antibacterial, antifungal, anticancer and neuroprotective kinase inhibitor activity) of these important compounds is being carried out. Preliminary results indicate that many of the thiohydantoins exhibit excellent neuroprotective properties.