Synthesis of some new[(5-Aryloxymethyl-1,3,4- oxadiazol-2-yl)sulfanyl]acetamide compounds

JOURNAL OF SCIENCE OF HNUE Chemical and Biological Sci., 2014, Vol. 59, No. 9, pp. 30-36 This paper is available online at SYNTHESIS OF SOME NEW[(5-ARYLOXYMETHYL-1,3,4- OXADIAZOL-2-YL)SULFANYL]ACETAMIDE COMPOUNDS Nguyen Tien Cong, Ho Xuan Dau and Bui Thi Luong Faculty of Chemistry, Ho Chi Minh University of Education Abstract. 5-(4-Bromophenyloxymethyl)-1,3,4-oxadiazol-2-thiole (3a) and 5-(4 -methylphenyloxymethyl)-1,3,4-oxadiazol-2-thiole (3b) were synthesized starting from 4-bromophenol and 4-methylphenol (p-crezol), respectively. The 5-aryl- -oxymethyl-1,3,4-oxadiazole-2-thiole (3a, b) were treated with N-aryl-2-chloro- -acetamides to give six corresponding new N-aryl-[(5-aryloxymethyl-1,3,4- -oxadiazol-2-yl)sulfanyl]acetamides (4a1-3, 4b1-3). The structures of the compounds were confirmed by IR, 1H-NMR and MS spectral data. At concentrations up to 0.2%, the acetamide compounds (4a1-3, 4b1-3) exhibited weak antibacterial capacity against Escherichia coli and Bacillus subtilis. Keywords: 5-(4-Bromophenyloxymethyl)-1,3,4-oxadiazol-2-thiole, 5-(4-methyl- -phenyloxymethyl)-1,3,4-oxadiazol-2-thiole, tautomer, (1,3,4-oxadiazol-2-ylsulfa- -nyl)acetamide, antimicrobial activity. 1. Introduction Of the five-membered nitrogen heterocycles, 1,3,4-oxadiazoles have received attention due to their wide range of biological activities. Compounds containing a 1,3,4-oxadiazole nucleus possess antibacterial, fungicidal, insecticidal, herbicidal, anti-inflammatory, antiviral and antitumour characteristics [3, 11, 14]. Transformation of the 5-alkyl/aryl-1,3,4-oxadiazol-2-thiol compounds to thioether derivatives lead molecules for the design of potential bioactive agents. In this way, many [(5-alkyl/aryl-1,3,4-oxadiazol-2-yl)sulfanyl]acetamides were synthesized and evaluated for biological activities [2, 8-10, 12, 13]. Thus we have designed and synthesized a series of [(aryloxymethyl-1,3,4-oxadiazol-2-yl)sulfanyl]acetamides and tested them for antibacterial activity. Received August 13, 2014. Accepted October 30, 2014. Contact Nguyen Tien Cong, e-mail address: congchemist@yahoo.com 30 Synthesis of some new [(5-aryloxymethyl-1,3,4-oxadiazol-2-yl)sulfanyl]acetamide compounds 2. Content 2.1. Experiment Melting points were measured in open capillary tubes and are uncorrected. IR spectra were recorded in potassium bromide disks on a Shimadzu FTIR 8400S spectrophotometer (v max in cm−1) and 1H-NMR spectra were recorded in DMSO-d6 on a Bruker Avance spectrometer at 500 MHz using tetramethyl silane (TMS) as the internal standard (chemical shift in  ppm). Mass spectra were obtained on an Agilent 6490 Triple Quadrupole LC/MS instrument. Antibacterial activity was tested at the Microbial Laboratory, Faculty of Biology, Ho Chi Minh City University of Pedagogy. All reagents were of commercial quality and were used without further purification. The synthetic route for the preparation of [(aryloxymethyl-1,3,4-oxadiazol-2-yl)sulfanyl]acetamides is presented in Scheme 1. Scheme 1: Synthetic procedure Synthesis of hydrazides (2a, b): Starting from appropriate phenols (4-bromophenol or para-crezol), 2-(4-bromophenyloxy)acetohydrazide (2a) and 2-(4-methylphenyloxy) acetohydrazide (2b) were prepared according to the method described in our previous work [4]. 2a: IR (v, cm−1): 3377, 3243 (N–H), 2924, 2855 (Csp3–H), 1674 (C=O) and 1605 (C=C). 2b: IR (v, cm−1): 3311, 3203 (N–H), 3032 (Csp2–H), 2912 (Csp3–H), 1660 (C=O) and 1618 (C=C). Synthesis of 1,3,4-oxadiazoles (3a, b): Acid hydrazide (2a or 2b) 0.05 mol was dissolved in absolute ethanol (100 mL) in a 250 mL round bottom flask. Carbon disulfide (4.0 mL, 0.065 mol) was then added to the flask followed by the addition of excess KOH (3.36 g, 0.06 mol). The mixture was refluxed for 6 hours. After cooling, the mixture was diluted with distilled water (100 mL) and acidified with dilute HCl to pH 2 - 3. It was then filtered, washed with distilled water and re-crystallized from ethanol. 31 Nguyen Tien Cong, Ho Xuan Dau and Bui Thi Luong 3a: Yield: 72%; mp: 170 - 172 ◦C; IR (v, cm−1): 3210 (N–H), 2965 (Csp3–H), 1643, 1580 (C=N, C=C) and 1232 (C=S); 1H-NMR (, ppm and J , Hz): 7.49 (2H, doublet, 3J = 8.5, Ar-H), 7.04 (2H, doublet, 3J = 8.5, Ar-H) and 5.26 (2H, singlet, –OCH2–). 3b: Yield: 67%; mp: 199-201◦C; IR (v, cm−1): 3227 (N–H), 3030 (Csp2-H), 2953 (Csp3–H), 1645, 1607, 1587 (C=N, C=C) and 1229 (C=S); 1H-NMR (, ppm and J , Hz): 10.12 (1H, singlet, N–H), 7.12 (1.3H, doublet, 3J = 8.5, Ar-H), 7.09 (2H, doublet, 3J = 8.5, Ar-H), 6.93 (1.3H, doublet, 3J = 8.5, Ar-H), 6.87 (2H, doublet, 3J = 8.5, Ar–H), 5.19 (1.2H, singlet, –OCH2–), 4.55 (2H, singlet, –OCH2–) and 2.23 (5H, multiplet, CH3–). EI-MS: 223 (M+H)+. Synthesis of (1,3,4-oxadiazol-2-yl)sulfanyl acetamides (4a1-3, 4b1-3): To a solution of 3a or 3b (2.5 mmol) in acetone (40 mL), appropriate N-aryl chloroacetamide (2.5 mmol) and anhydrous K2CO3 (0.35 g,  2.5 mmol) were added and the mixture was stirred at 60 ◦C for 3.0 hours. After cooling, the solution was poured into ice-cooled water. The precipitated solid was filtered, dried and recrystallized from suitable solvents to afford pure acetamide. Yields, physical properties and IR spectral data of the synthesized acetamide derivatives are shown in Table 1. Table 1. Yields, physical properties and IR spectral data of the synthesized acetamide derivatives (4a1−3, 4b1−3) Comp. R/X tnc (◦C) Yield (%) Solvents for recry IR (v, cm−1) MS N–H C–H C=O C=C C=N (4a1) Br/CH3 181 - 183 58.8 EtOH 3258 2986 2932 1711 1690 1601 434 (M + H)+ (4a2) Br/Br 207 - 209 51.2 DMF:H2O 3269 2930 1717 1690 1601 1578 500 (M + H)+ (4a3) Br/H 215 - 218 40.6 Dioxane:H2O 3264 3067 2934 1715 1688 1601 1591 442 (M + Na)+ (4b1) CH3/CH3 231 - 233 45.4 Dioxane 3259 2931 1714 1687 1600 370 (M + H)+ (4b2) CH3/OC2H5 273 - 274 59.5 EtOH:H2O 3257 2981 2931 1716 1689 1599 400 (M + H)+ (4b3) CH3/H 270 - 272 47.4 EtOH 3277 2933 1718 1687 1602 1591 - 32 Synthesis of some new [(5-aryloxymethyl-1,3,4-oxadiazol-2-yl)sulfanyl]acetamide compounds 2.2. Results and discussion The synthesis of hydrazides (2a, b) was confirmed by comparing the melting points and IR spectral data from literature [4]. These hydrazides were converted into 5-aryloxymethyl-1,3,4-oxadiazol-2-thiol (3a, b) on treatment with carbon disulfide and potassium hydroxide in ethanol as a literature procedure [2, 5, 7]. The products were obtained in good yields and characterized by their spectral data (the synthesis of the 3a compound was reported in the literature [6] without spectral data while the structure of oxadiazole 3b appeared in the literature [1] with it’s IR spectral data). In the IR spectra of the products there are a disappearance of carbonyl peaks in the range of 1650 - 1670 cm−1 and NH, and NH2 absorptions in the range of 3200 - 3400 cm−1, in a comparison with IR spectra of the hydrazides. Besides that, weak absorptions in the regions 1580 - 1645 cm−1 and 1229 - 1232 cm−1 indicate a presence of C=N and C=S bonds, respectively. Melting point and characteristics in IR spectrum of oxadiazoles 3a and 3b agreed with data in the literature [1, 6]. 5-Alkyl-1,3,4-oxadiazole-2-thiol compounds may be found in two tautomeric form as thione and thiol [7, 13]. The 1H-NMR spectral data indicated that (3a) existed in only one tautomer while (3b) existed in two tautomers in a ratio of 3:2. According to Tashfeen Akhtar [13], proton N–H of 5-alkyloxymethyl-1,3,4-oxadiazol-2-thione compounds appeared in the region 9.91 - 11.62 ppm while proton S–H of 5-alkyloxymethyl-1,3,4-oxadiazol-2-thiole compounds appeared around at 1.27 ppm. Therefore, in our case, the set of signals with a higher intensity (1:2:2:2:3) in the 1H-NMR spectrum of the (3b) compound corresponded with the thione formwhile the other set with a lower intensity (1.3:1.3:1.3:2) corresponded with the thiol form. Lively hydrogen atoms (SH or NH) of the (3a) compound did not appear in the 1H-NMR spectrum. However, in chemical shift, the signal of methylen protons in the OCH2 group of (3a) at 5.26 ppm was rather similar to the signal of the OCH2 group of the thione form of (3b) at 5.19 ppm but was not similar to the signal of the OCH2 group of the thiol form of (3b) at 4.55 ppm. So, (3a) might exist mostly in thione form, too. These are also in agreement with previous reports [7, 13] where the thione tautomer of 1,3,4-oxadiazole compounds was proven more stable than the thiol form. 5-Aryloxymethyl-1,3,4-oxadiazole-2-thiols (3a, b) were treated with N-aryl-2-chlo- -roacetamides to give the correspondingN-aryl-(5-aryloxymethyl-1,3,4-oxadiazol-2-ylsul- -fanyl) acetamides (4a1-3, 4b1-3) in the presence of anhydrous K2CO3 in acetone. The structures of (4a1-3, 4b1-3) were first confirmed via their IR spectral data in which the presence of a characteristic absorption band around 3360 cm−1 and two strong ones around 1715 cm−1 and 1690 cm−1 was in turn represented for N–H bond and C=O group in the acetamide molecules. The MS of some acetamide derivatives were recorded on an LC/MS instrument and all of these spectra showed molecular ion peaks in agreement with the desired formulas (see Table 1). 33 Nguyen Tien Cong, Ho Xuan Dau and Bui Thi Luong The 1H-NMR spectral data of (4a1-3, 4b1-3) as shown in Table 2 were in agreement with the formation of acetamide compounds. All of these spectra showed three singlet signals in addition to new signals of the protons in the benzene ring in the aromatic region. The first singlets with intensity of 1H around 10.50 ppm were assigned to the NH protons of the acetamide moiety; two singlet peaks around 4.55 ppm and 4.17 ppm, both with intensity of 2H, were attributed to protons in OCH2 and SCH2 groups, respectively. Changing substituent group X had a strong effect on chemical shifts of protons in the benzene ring bonded to X but almost no effect on chemical shifts of protons in the benzene ring bonded to R (see Table 2). Acetamide compounds (4a1-3, 4b1-3) at a concentration of 0.1% and 0.2% were screened for antibacterial activity against Gram-positive bacteria (Bacillus subtilis) and Gram-negative (Escherichia coli) according to the method of Egorov. The solvent used was DMSO and the zone of inhibition was measured in millimeters. The results are depicted in Table 3. The results show that at a concentration up to 0.2%, all of the tested compounds have a weak antibacterial capacity. Table 2. Signals in the 1H-NMR spectra of 4a1−3 and 4b1−3 compounds (, ppm and J, Hz) Comp. R/X H1 (2H,d) H2 (2H,d) H3 (2H,s) H4 (2H,s) H5 (2H,s) H6 (2H,d) H7 (2H) other (4a1) Br/CH3 7.45 J = 9.0 6.91 J = 9.0 4.59 4.17 10.43 7.18 J = 8.0 7.29 (d) J = 8.0 2.35 (3H) (4a2) Br/Br 7.45 J = 9.0 6.91 J = 9.0 4.60 4.17 10.48 7.30 J = 8.5 7.71(d) J = 8.5 - (4a3) Br/H 7.45 (m) 6.92 J = 8.0 4.60 4.18 10.46 7.32 J = 8.0 7.50 (d-d) J = 8.0 7.45(1H, m) (4b1) CH3/CH3 7.18 J = 8.5 6.83 J = 8.0 4.53 4.16 10.37 7.09 J = 8.0 7.29 (d) J = 8.5 2.25 (3H, s) 2.22 (3H, s) (4b2) CH3/OC2H5 7.20 J = 8.5 6.83 J = 8.5 4.52 4.15 10.35 7.20 J = 8.5 7.01(d) J = 8.5 2.22 (3H, s) 1.34 (3H, t) 4.26 (2H, q) (4b3) CH3/H 7.08 J = 8.5 6.83 J = 8.5 4.52 4.18 10.38 7.32 J = 7.5 7.50 (d-d) J = 7.5 7.43 (1H, t) 2.22 (3H, s) 34 Synthesis of some new [(5-aryloxymethyl-1,3,4-oxadiazol-2-yl)sulfanyl]acetamide compounds Table 3. Diameter of the inhibited zone (d, mm) Conc. Bacteria (4a1) (4a2) (4a3) (4b1) (4b2) (4b3) 0.1% Escherichia coli 10.0 12.0 11.0 9.0 6.0 9.5 Bacillus subtilis 12.0 14.0 11.0 9.0 7.0 8.0 0.2% Escherichia coli 13.0 14.0 13.0 12.0 8.5 11.0 Bacillus subtilis 15.0 17.0 17.0 14.0 9.0 12.5 (Note. d:  25 mm: very high activity, d  20 mm: high activity, d  15 mm: average activity, d  15 mm: low activity) 3. Conclusion Six new N-aryl-[5-aryloxymethyl-1,3,4-oxadiazol-2-ylsylfanyl]acetamides were synthesized based on a reaction of 5-(4-bromophenyloxymethyl)-1,3,4-oxadiazol-2-thiole or 5-(4-methylphenyloxymethyl)-1,3,4-oxadiazol-2-thiole with appropriate chloroacetamide. The structures of these compounds were confirmed by IR, 1H-NMR and MS spectral data. At a concentration of up to 0.2%, the N-aryl-[5-aryloxymethyl-1,3,4-oxadiazol-2-ylsylfanyl]acetamides exhibited low activity against Escherichia coli and Bacillus subtilis. REFERENCES [1] Ao Yang Gui Ping, Chen Xue Hui, Fan Tian Yi, 2003. Chinese patent CN 1408712A. 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