HETEROCYCLES

Short Paper | Regular issue | Vol. 87, No. 11, 2013, pp. 2319-2332
Received, 17th August, 2013, Accepted, 25th September, 2013, Published online, 15th October, 2013.
DOI: 10.3987/COM-13-12810

■ Hydrazones and 1,3-Thiazolidin-4-ones Incorporating Furoxan Moiety Synthesized from Eugenol, the Main Constituent of Ocimum sanctum L. Oil

Nguyen Huu Dinh,* Trinh Thi Huan, Hoang Thi Tuyet Lan, and Sang-Bae Han

Department of Chemistry, Hanoi National University of Education, 136 Xuanthuy Hanoi, Vietnam

Abstract

Two series of new hydrazones and 1,3-thiazolidin-4-ones incorporating furoxan moiety were synthesized from eugenol, the main component of Ocimum sanctum L. oil. The structure of these compounds was determined by IR, MS, 1H and 13C NMR analysis. All resonance signals of proton and carbon in the examined compounds are assigned using HSQC, HMBC and NOESY spectra. The hydrazones and the 1,3-thiazolidin-4-ones were tested for antimicrobial activities and almost all examined thiazolidinones displayed moderate activity against S. aureus and A. niger. Among screened hydrazones only one compound exhibited a significant cytotoxicity for human cancer cell line SW620.

Hydrazones constitute an important class of biologically active drug molecules which has attracted attention of medicinal chemists due to their wide range of pharmacological properties. A number of hydrazones have been reported to exert notably antimicrobial, antihypertensive, anticonvulsant, anti-inflammatory, antituberculosis, anticoagulant, antimalarial and antitumor activities in two reviews.1,2 They are also appropriate substrates for the preparation of five- or six-membered heterocyclic rings such as indole, pyrazole, pyridazin and thiazolidinone. .Thiazolidinones have become among the most extensively investigated compounds due to their valuable biological activities in the areas of medicine and agriculture. They have found uses, for example, as antimalarial,3 antimicrobial,4,5 anti-inflammatory,6,7 and antiviral agents, especially as anti-HIV agents.8-11
During recent years, furoxan derivatives were extensively studied as bioactive compounds. They possess remarkable biological activities, such as anti-microbial and anti-parasitic properties, mutagenic, immunosuppressive and anticancer effects, anti-aggregating and vasorelaxant activity.12 Several classes of hybrid compounds, obtained combining appropriate pharmacophoric groups with NO-releasing furoxan moiety (NO-donor), have been described.13 A number of them, such as NO-imidazole, NO-benzimidazole, NO-aspirin,14 NO-steroids,15 and NO-ursodeoxycholic acid,16 are now under clinical investigations.
In view of the above-mentioned findings, a series of new hydrazones and the corresponding 1,3-thiazolidin-4-ones incorporating furoxan moiety were synthesized from eugenol and to find out if the resulting compounds have any biological action. Eugenol is extracted from Ocimum sanctum L. oil. This raw material is cheap17 and should be renewable.
4,5-Dimethoxy-2-(3-methylfuroxan-4-yl)phenylamine (1) was prepared from eugenol according to our manner.18 Amine 1 was converted into 4,5-dimethoxy-2-(3-methylfuroxan-4-yl)phenylhydrazine (2) by diazotization and subsequent reduction with stannous chloride in concentrated hydrochloric acid. The condensation of 2 with aromatic aldehydes gave hydrazones 3a–l, which on reaction with thioglycolic acid in dry toluene gave the corresponding 1,3-thiazolidin-4-ones 4a–l (Figure 1, the numeration on these structures is used specifically for NMR analysis only).

The change in structure from hydrazine 2 to hydrazones 3a-l and to 1,3-thiazolidin-4-ones 4a-l is demonstrated with 1H NMR spectra of 2, 3c and 4c in Figure 2. The spectrum of hydrazone 3c differs from that of hydrazine 2 in the presence of signals of aldehyde moiety (Ph, Hi, H17), the absence of NH2 signal and also the downfield shift of NH signal. The spectrum of thiazolidinone 4c differs from that of hydrazone 3c in the appearance of the doublet of doublets at 3.94 ppm (Hk), the doublet at 3.76 ppm (Hk’), and also the upfield shift of NH and Hi signals. These are associated with the formation of thiazolidinone ring in 4c.
4,5-Dimethoxy-2-(3-methylfuroxan-4-yl)phenylhydrazine (2), hydrazones 3a–l and thiazolidinones 4a–l have not been previously reported in the literature, thus their 1H NMR and 13C NMR spectra were accurately analyzed on the basis of chemical shift, spin–spin splitting patterns, and 2D NMR spectra. For example, HSQC spectrum of 2 allowed to recognize singlet of HN (at 6.73 ppm, giving no cross peak with any carbon atom) among 3 singlets at 7.01, 6.86 and 6.73 ppm. The HMBC spectrum of 2 allowed to assign the signals of H3, H6 and to distinguish H7a and H7b.

The assignment of 1H and 13C signals of examined compounds using 2D NMR was illustrated as in Figure 3. For example, In 1H NMR spectrum of 4f (vertical axis in Figure 3) the singlet at 1.75 ppm (3H) is unambiguously attributed to H10; the doublet at 6.70 ppm (2H, J = 8.5 Hz) - to H13 and H15; the doublet at 7.29 ppm (2H, J = 8.5 Hz) - to H12 and H16; the doublet of doublets at 3.91 ppm (1H, J = 16 and 1 Hz) and the doublet at 3.74 ppm (1H, J = 16 Hz) are assigned to Hk and Hk’ (the non-equivalent, geminal methylene protons interacting with the chiral center at position i). A singlet at 9.70 ppm (was not placed in Figure 3) was assigned to OH group because it give no cross peak with any carbon atom in both HSQC and HMBC of 4. The singlet at 7.82 ppm was assigned to NH because it gives no cross peak with any carbon atom in HSQC spectrum of 4f but gives cross peaks a, b, c in HMBC spectrum.

Mallory and Cammarata19 showed that the interconversion of two isomeric methylphenylfuroxan can occur at 100 oC. Gasco and colleagues20 indicated that the resonance signal of a ring methyl group adjacent to the N-oxide oxygen of furoxans appears at 2.30-2.33 ppm, while the resonance signal of a ring methyl group remote from it or a ring methyl group of furazan appears at 2.50-2.53 ppm. The signal of the furoxan methyl group (H10) for the hydrazones 3a-l appears as a singlet at 2.01–2.04 ppm (Table 3), for the thiazolidinones 4a-l - at 1.62–1.75 ppm (Table 5). These demonstrated that the methyl group is at position 3 of the furoxan ring (adjacent to the N-oxide oxygen) and the furoxan ring of examined compounds was not isomerized in the toluene reflux during 6-8 h (see the preparation below).
In ESI MS positive mode spectra of hydrazones 3a, 3b and 3d relative intensity of pseudomolecular ions [M+H]+ is 20, 22 and 16%, but that of ion with m/z = 251 is 100%. It is possible that the pseudomolecular ions [M+H]+ fragmented to the more stable ion as in Figure 4.

In +MS spectra of thiazolidinones 4d, 4e, 4f and 4l relative intensity of ions [M+H]+ is 24, 18, 11 and 40% respectively, but that of ions [M+Na]+ are 62, 100, 100 and 100 %, in addition relative intensity of ions [2M+Na]+ are 50-100%. It is possible that in the thiazolidinones atom S having large polarization preferentially bond up with ion Na+ (being as a trace in solvent for ESI MS).
The hydrazones 3a-l and the thiazolidinones 4a-l (except 4f and 4h) were tested for antimicrobial activities. The results are listed in Table 1. It is seen that almost all examined thiazolidinones displayed moderate activity against S. aureus.

The hydrazones 3a-l were also tested for cell cytotoxicity on cancer cell line SW620, the results are listed in Table 2.

It was found that only compound 3h bearing a 3-hydroxy-4-methoxy substituent exhibited a significant cytotoxicity against this cell line. Two compounds 3c (with 4-methyl substitution) and 3f (bearing a 4-hydroxy substituent) displayed moderate cytotoxic effects. Other compounds were not active up to 30 μg/mL.

EXPERIMENTAL
General
IR spectra were recorded on an IMPACK-410 NICOLET spectrometer in KBr discs at 400–4000 cm-1. ESI mass spectra were recorded using LC/MS/MS-Waters spectrometer. HR MS were recorded using Varian MS spectrometer. NMR spectra were recorded on a Bruker AVANCE 500 MHz spectrometer, in DMSO-d6 with TMS as the internal standard, at 298–300 K. C, H, and N were analyzed in Analytical Laboratory – Institute of Chemistry of Natural Compounds (in Hanoi). The antimicrobial activities were tested at the Experimental Biological Laboratory – Institute of Chemistry of Natural Compounds (in Hanoi) by the method as described in literature,21 the positive control for S. aureus: Ampicilin 50 mM, for A. niger and F. oxysporum: Nystatin 0.04 mM. The cytotoxicity against human cancer cell line SW620 was screened at College of Pharmacy, Chungbuk National University (Korea). Human cancer cell line, SW620 (colon cancer), was obtained from the American Type Culture Collection (ATCC, Manassas, VA, USA). Cells were placed at 9 × 103 cells/well in 96-well plates, incubated overnight, and treated with samples for 48 h. Compounds were dissolved in dimethyl sulfoxide (DMSO). Cytotoxicity was measured by the method as described in literature22 with slight modifications.23 The IC50 values were calculated according to the Probits method.24 The values reported for these compounds are averages of three separate determinations.
Preparation
4,5-Dimethoxy-2-(3-methylfuroxan-4-yl)phenylamine (1) was prepared from eugenol according to the literature method.17 Light yellow needle crystals, yield 70%, mp 174–175 °C (175 °C17). 1H NMR, δ (ppm), J (Hz): 6.81 s (H3); 6.49 s (H6); 5.35 s (NH2); 3.75 s (H7a); 3.62 s (H7b); 2.16 s (H10).
4,5-Dimethoxy-2-(3-methylfuroxan-4-yl)phenylhydrazine (2). At 0-5 °C, 12 mL of 1M NaNO2 solution was slowly added to a solution of 2.51g (10 mmol) of 1 in 10 mL of 3M HCl solution. The resulting solution was cooled to -10 °C and a solution of 5.69g (30 mmol) SnCl2 in 50 mL of concentrated hydrochloric acid was slowly added over 1 h and stirred at -5 °C for 3 h additional. The precipitate was collected and neutralized with 2M NaOH solution to pH 8-9. The solid was filtered out, washed with water and recrystallized from EtOH/CHCl3 3:1 by volume. Yellow needle crystals, yield 1.73g (65%), mp 180-181 °C. IR (cm-1): 3455, 3360, 3293 (NH); 3010, 2933, 2841 (C-H); 1598, 1525 (ring). 1H NMR, δ (ppm), J (Hz): 6.86 s (H3); 7.01 s (H6); 3.82 s (H7a); 3.68 s (H7b); 2.12 s (H10), 6.73 s (NH), 4.14 s (NH2). 13C NMR, δ (ppm): 152.25 (C1), 140.25 (C2), 114.27 (C3), 99.33 (C4), 146.13 (C5), 97.46 (C6), 55.31 (C7a), 56.48 (C7b), 156.82 (C8), 113.77 (C9), 8.93 (C10). Anal. Calcd for C11H14N4O4 (M 266.25): C, 49.62; H, 5.30; N, 21.04. Found: C, 49.36; H, 5.16; N, 21.32.

The general procedure for the preparation of hydrazones 3a–l:
An equimolar solution of hydrazine 2 (1 mmol) and aromatic aldehyde (1 mmol) in dry EtOH (30-50 mL) was refluxed over 4-5 h. The reaction mixture was allowed to stand at room temperature. The resulting precipitate was collected and recrystallized.
N1-[4,5-Dimethoxy-2-(3-methylfuroxan-4-yl)phenyl]-N2-benzylidenhydrazine (3a). Yellow crystals, yield 83%, mp 195-196 °C (from EtOH/CHCl3 2/1 by volume). IR (cm-1): 3286 (NH); 3000, 2943, 2900, 2829 (C-H); 1578, 1526, 1500 (ring). 1H NMR and 13C NMR see Tables 3 and 4. ESI +MS, m/z (au)/relative intensity (%): 355/20 [M+H]+; 251/100 [M+H-(N=CHPh)]+. Anal. Calcd for C18H18N4O4 (M 354.36): C, 61.01; H, 5.12; N, 15.81. Found: C, 60.75; H, 5.33; N, 16.01.

N1-[4,5-Dimethoxy-2-(3-methylfuroxan-4-yl)phenyl]-N2-(2-methylbenzyliden)hydrazine (3b). Yellow crystals, yield 77%, mp 184-185 °C (from EtOH/CHCl3 1/2 by volume). IR (cm-1): 3286 (NH); 3010, 2965, 2900, 2837 (CH); 1579, 1526, 1500 (ring). 1H NMR and 13C NMR see Tables 3 and 4. ESI +MS, m/z (au)/relative intensity (%): 369/22 [M+H]+; 251/100 [M+H-(N=CHPhMe)]+.. Anal. Calcd for C19H20N4O4 (M 368.39): C, 61.95; H, 5.57; N, 15.21. Found: C, 61.77; H, 5.30; N, 15.48.
N1-[4,5-Dimethoxy-2-(3-methylfuroxan-4-yl)phenyl]-N2-(4-methylbenzyliden)hydrazine (3c). Yellow crystals, yield 54%, mp 186-187 oC (from EtOH/CHCl3 1/1 by volume). IR (cm-1): 3286 (NH); 3001, 2929, 2900, 2843 (CH); 1580, 1529, 1500 (ring). 1H NMR and 13C NMR see Tables 3 and 4. Anal. Calcd for C19H20N4O4 (M 368.39): C, 61.95; H, 5.57; N, 15.21. Found: C, 61.68; H, 5.72; N, 15.50.
N1-[4,5-Dimethoxy-2-(3-methylfuroxan-4-yl)phenyl]-N2-(2-chlorobenzyliden)hydrazine (3d). Yellow crystals, yield 82%, mp 172-173 °C (from EtOH/CHCl3 1/1 by volume). IR (cm-1): 3263 (NH); 3005, 2951, 2901 (C-H); 1575, 1529, 1500 (ring). 1H NMR and 13C NMR see Tables 3 and 4. ESI +MS, m/z (au)/relative intensity (%): 389/16 [M+H]+; 251/100 [M+H-(N=CHPhCl)]+. Anal. Calcd for C18H17ClN4O4 (M 388.80): C, 55.60; H, 4.41; N, 14.41. Found: C, 55.85; H, 4.19; N, 14.20.
N1-[4,5-Dimethoxy-2-(3-methylfuroxan-4-yl)phenyl]-N2-(4-chlorobenzyliden)hydrazine (3e). Yellow crystals, yield 85%, mp 183 °C (from EtOH/CHCl3 1/1 by volume). IR (cm-1): 3288 (NH); 3010, 2960, 2846 (C-H); 1581, 1527, 1495 (ring). 1H NMR and 13C NMR see Tables 3 and 4. Anal. Calcd for C18H17ClN4O4 (M 388.80): C, 55.60; H, 4.41; N, 14.41. Found: C, 55.32; H, 4.66; N, 14.13.
N1-[4,5-Dimethoxy-2-(3-methylfuroxan-4-yl)phenyl]-N2-(4-hydroxybenzyliden)hydrazine (3f). Yellow crystals, yield 73%, mp 196-197 °C (from EtOH). IR (cm-1): 3539 (OH); 3284 (NH); 3010, 2937, 2900 (C-H); 1581, 1529, 1500 (ring). 1H NMR and 13C NMR see Tables 3 and 4. Anal. Calcd for C18H18N4O5 (M 370.36): C, 58.37; H, 4.90; N, 15.13. Found: C, 58.65; H, 4.71; N, 14.90.
N1-[4,5-Dimethoxy-2-(3-methylfuroxan-4-yl)phenyl]-N2-(4-methoxybenzyliden)hydrazine (3g). Yellow crystals, yield 57%, mp 150-151 °C (from EtOH). IR (cm-1): 3277 (NH); 3010, 2937, 2900 (C-H); 1581, 1529, 1500 (ring). 1H NMR and 13C NMR see Tables 3 and 4. Anal. Calcd for C19H20N4O5 (M 384.39): C, 59.37; H, 5.24; N, 14.58. Found: C, 59.11; H, 5.49; N, 14.25.
N1-[4,5-Dimethoxy-2-(3-methylfuroxan-4-yl)phenyl]-N2-(4-hydroxy-3-methoxybenzyliden)hydrazine (3h). Yellow crystals, yield 87%, mp 185-186 °C (from EtOH/CHCl3 1/1 by volume). IR (cm-1): 3494 (OH); 3309 (NH); 3010, 2953, 2846 (C-H); 1581, 1501, 1480 (ring). 1H NMR and 13C NMR see Tables 3 and 4. Anal. Calcd for C19H20N4O6 (M 400.39): C, 57.00; H, 5.03; N, 13.99. Found: C, 56.72; H, 5.27; N, 14.26.
N1-[4,5-Dimethoxy-2-(3-methylfuroxan-4-yl)phenyl]-N2-(2-nitrobenzyliden)hydrazine (3i). Purple crystals, yield 90%, mp 188-189 °C (from EtOH/CHCl3 1/3 by volume). IR (cm-1): 3314 (NH); 3010, 2939, 2834 (C-H); 1577, 1525, 1500 (ring). 1H NMR and 13C NMR see Tables 3 and 4. Anal. Calcd for C18H17N5O6 (M 399.36): C, 54.14; H, 4.29; N, 17.54. Found: C, 54.45; H, 4.06; N, 17.30.
N1-[4,5-Dimethoxy-2-(3-methylfuroxan-4-yl)phenyl]-N2-(3-nitrobenzyliden)hydrazine (3j). Deep rouge crystals, yield 89%, mp 203-204 °C (from EtOH/CHCl3 1/2 by volume). IR (cm-1): 3284 (NH); 3000, 2937, 2831 (C-H); 1583, 1525, 1505 (ring). 1H NMR and 13C NMR see Tables 3 and 4. Anal. Calcd for C18H17N5O6 (M 399.36): C, 54.14; H, 4.29; N, 17.54. Found: C, 53.86; H, 4.46; N, 17.26.
N1-[4,5-Dimethoxy-2-(3-methylfuroxan-4-yl)phenyl]-N2-(4-nitrobenzyliden)hydrazine (3k). Red crystals, yield 92%, mp 228-229 °C (from EtOH/CHCl3 1/3 by volume). IR (cm-1): 3270 (NH); 3008, 2944, 2833 (C-H); 1590, 1527, 1500 (ring). 1H NMR and 13C NMR see Tables 3 and 4. Anal. Calcd for C18H17N5O6 (M 399.36): C, 54.14; H, 4.29; N, 17.54. Found: C, 54.38; H, 4.12; N, 17.35.
N1-[4,5-dimethoxy-2-(3-methylfuroxan-4-yl)phenyl]-N2-(3-pyridylmethyliden)hydrazine (3l). Yellow crystals, yield 61%, mp 180-181 °C (from EtOH/CHCl3 1/3 by volume). IR (cm-1): 3263 (NH); 3000, 2944, 2831 (C-H); 1612, 1582, 1531, 1500 (ring). 1H NMR and 13C NMR see Tables 3 and 4. Anal. Calcd for C17H17N5O4 (M 355.35): C, 57.46; H, 4.82; N, 19.71. Found: C, 57.18; H, 5.01; N, 19.46.
The general procedure for the preparation of 1,3-thiazolidin-4-ones 4a–l:
A solution of 1 mmol of the hydrazone (3a-l) and 2 mmol (0.15 mL) of mercaptoacetic acid in 25 mL dry toluene was fluxed using a Dean–Stark trap for 6–8 h. The cooled mixture was treated with 10 mL of 0.1M NaOH solution. The resulting precipitate was collected, washed with EtOH and recrystallized.
3-[4,5-Dimethoxy-2-(3-methylfuroxan-4-yl)phenylamino]-2-phenyl-1,3-thiazolidin-4-one (4a). Light yellow crystals, yield 54%, mp 95 °C (from DMF/H2O 1/3 by volume). IR (cm-1): 3288 (NH); 2990, 2932, 2848 (C-H); 1695 (C=O); 1603, 1527, 1500 (ring). 1H NMR and 13C NMR see Tables 5 and 6. HR ESI MS, calcd for C20H21N4O5S ([M+H]+): 429.12327. Found: 429.12281.

3-[4,5-Dimethoxy-2-(3-methylfuroxan-4-yl)phenylamino]-2-(2-methylphenyl)-1,3-thiazolidin-4-one (4b). Yellow crystals, yield 30%, mp 126-127 oC (from EtOH/H2O 1/1 by volume). IR (cm-1): 3292 (NH); 3000, 2944, 2845 (C-H); 1686 (C=O); 1608, 1525, 1500 (ring). 1H NMR and 13C NMR see Tables 5 and 6. HR ESI MS, calcd for C21H23N4O5S ([M+H]+): 443.13892. Found: 443.14161.
3-[4,5-Dimethoxy-2-(3-methylfuroxan-4-yl)phenylamino]-2-(4-methylphenyl)-1,3-thiazolidin-4-one (4c). Yellow crystals, yield 45%, mp 103-104 oC (from EtOH/H2O 1/1 by volume). IR (cm-1): 3288 (NH); 2985, 2932, 2850 (C-H); 1701 (C=O); 1605, 1525, 1504 (ring). 1H NMR and 13C NMR see Tables 5 and 6. Anal. Calcd for C21H22N4O5S (M 442.49): C, 57.00; H, 5.01; N, 12.66. Found: C, 57.27; H, 4.82; N, 12.41.
3-[4,5-Dimethoxy-2-(3-methylfuroxan-4-yl)phenylamino]-2-(2-chlorophenyl)-1,3-thiazolidin-4-one (4d). Yellow crystals, yield 41%, mp 125-126 oC (from EtOH/H2O 1/1 by volume). IR (cm-1): 3286 (NH); 3000, 2943, 2844 (C-H); 1698 (C=O); 1607, 1520, 1500 (ring). 1H NMR and 13C NMR see Tables 5 and 6. ESI MS, m/z (au)/relative intensity (%): 463/24 [M+H]+; 485/62 [M+Na]+; 947/100 [2M+Na]+. Anal. Calcd for C20H19ClN4O5S (M 462.91): C, 51.89; H, 4.14; N, 12.10. Found: C, 52.18; H, 4.35; N, 12.36.

3-[4,5-Dimethoxy-2-(3-methylfuroxan-4-yl)phenylamino]-2-(4-chlorophenyl)-1,3-thiazolidin-4-one (4e). Light yellow crystals, yield 67%, mp 174-175 °C (from EtOH/H2O 2/1 by volume). IR (cm-1): 3335 (NH); 3092, 3000, 2938, 2846 (C-H); 1702 (C=O); 1605, 1530, 1505 (ring). 1H NMR and 13C NMR see Tables 5 and 6. ESI MS, m/z (au)/relative intensity (%): 463/18 [M+H]+; 485/100 [M+Na]+; 947/83 [2M+Na]+. Anal. Calcd for C20H19ClN4O5S (M 462.91): C, 51.89; H, 4.14; N, 12.10. Found: C, 52.14; H, 4.32; N, 11.82.
3-[4,5-Dimethoxy-2-(3-methylfuroxan-4-yl)phenylamino]-2-(4-hydroxyphenyl)-1,3-thiazolidin-4-one (4f). Yellow crystals, yield 62%, mp 145-146 °C (from DMF/H2O 1/3 by volume). IR (cm-1): 3480 (OH); 3319 (NH); 2995, 2944, 2850 (C-H); 1680 (C=O); 1610, 1522, 1500 (ring). 1H NMR and 13C NMR see Tables 5 and 6. ESI MS, m/z (au)/relative intensity (%): 445/11 [M+H]+; 467/100 [M+Na]+; 911/54 [2M+Na]+. Anal. Calcd for C20H20N4O6S (M 444.46): C, 54.05; H, 4.54; N, 12.61. Found: C, 53.82; H, 4.68; N, 12.32.
3-[4,5-Dimethoxy-2-(3-methylfuroxan-4-yl)phenylamino]-2-(4-methoxyphenyl)-1,3-thiazolidin-4-one (4g). Light yellow crystals, yield 62%, mp 145-146 °C (from DMF/H2O 1/3 by volume). IR (cm-1): 3320 (NH); 3022, 2930, 2845 (C-H); 1704 (C=O); 1614, 1590, 1508 (ring). 1H NMR and 13C NMR see Tables 5 and 6. HR ESI MS, calcd. for C21H23N4O6S ([M+H]+): 459.13383. Found: 459.13084.
3-[4,5-Dimethoxy-2-(3-methylfuroxan-4-yl)phenylamino]-2-(4-hydroxy-3-methoxyphenyl)-1,3-thiazolidin-4-one (4h). Yellow crystals, yield 37%, mp 128-129 °C (from EtOH/H2O 1/2 by volume). IR (cm-1): 3414 (OH); 3380 (NH); 3000, 2928, 2837 (C-H); 1693 (C=O); 1608, 1517 (ring). 1H NMR and 13C NMR see Tables 5 and 6. HR ESI MS, calcd for C21H23N4O7S ([M+H]+): 475.12875. Found: 475.13220.
3-[4,5-Dimethoxy-2-(3-methylfuroxan-4-yl)phenylamino]-2-(2-nitrophenyl)-1,3-thiazolidin-4-one (4i). Deep rouge crystals, yield 54%, mp 114-115 °C (from EtOH/H2O 2/1 by volume). IR (cm-1): 3270 (NH); 3010, 2944, 2845 (C-H); 1702 (C=O); 1605, 1530, 1500 (ring). 1H NMR and 13C NMR see Tables 5 and 6. Anal. Calcd for C20H19N5O7S (M 473.46): C, 50.74; H, 4.04; N, 14.79. Found: C, 50.45; H, 4.25; N, 14.51.
3-[4,5-Dimethoxy-2-(3-methylfuroxan-4-yl)phenylamino]-2-(3-nitrophenyl)-1,3-thiazolidin-4-one (4j). Yellow crystals, yield 60%, mp 118-119 °C (from EtOH/H2O 1/2 by volume). IR (cm-1): 3321 (NH); 3081, 3980, 2909, 2850 (C-H); 1708 (C=O); 1611, 1528, 1500 (ring). 1H NMR and 13C NMR see Tables 5 and 6. HR ESI MS, Calcd. for C20H20N5O7S ([M+H]+): 474.10835. Found: 474.11138.
3-[4,5-Dimethoxy-2-(3-methylfuroxan-4-yl)phenylamino]-2-(4-nitrophenyl)-1,3-thiazolidin-4-one (4k). Deep rouge crystals, yield 64%, mp 124-125 °C (from EtOH/H2O 1/2 by volume). IR (cm-1): 3324 (NH); 3092, 3000, 2938, 2846 (C-H); 1702 (C=O); 1605, 1530, 1495 (ring). 1H NMR and 13C NMR see Tables 5 and 6. Anal. Calcd for C20H19N5O7S (M 473.46): C, 50.74; H, 4.04; N, 14.79. Found: C, 50.98; H, 4.22; N, 14.49.
3-[4,5-Dimethoxy-2-(3-methylfuroxan-4-yl)phenylamino]-2-(3-pyridyl)-1,3-thiazolidin-4-one (4l). White crystals, yield 35%, mp 142-143 °C (from EtOH/H2O 1/1 by volume). IR (cm-1): 3165 (NH); 2950, 2919, 2856 (C-H); 1694 (C=O); 1605, 1535, 1485 (ring). 1H NMR and 13C NMR see Tables 5 and 6. ESI MS, m/z (au)/relative intensity (%): 430/40 [M+H]+; 452/100 [M+Na]+; 881/51 [2M+Na]+. Anal. Calcd for C19H19N5O5S (M 429.45): C, 53.14; H, 4.46; N, 16.31. Found: C, 52.88; H, 4.62; N, 16.05.

ACKNOWLEDGEMENTS
This research is funded by Vietnam National Foundation for Science and Technology Development (NAFOSTED) under grant number 104.01-2012.55.

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