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Journal of Chemistry
Volume 2015, Article ID 593738, 7 pages
http://dx.doi.org/10.1155/2015/593738
Research Article

Reaction of Nitrilimines with Pyruvaldehyde Hydrazones: Synthesis and Antimicrobial Evaluation of Some New 1,2,4-Triazole Derivatives

Department of Chemistry, Faculty of Applied Science, Al-Aqsa University of Gaza, P.O. Box 4051, Gaza 76888, State of Palestine

Received 2 December 2014; Accepted 14 February 2015

Academic Editor: Sevgi Kolaylı

Copyright © 2015 Hany M. Dalloul. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

A new series of 1,3,4,5,5-pentasubstituted-1,2,4-triazoles (4a–j, 6a–j) have been synthesized by the 1,3-dipolar cycloaddition of suitable nitrilimines 2 to pyruvaldehyde (2-oxopropanal) hydrazones having (COPh, COOMe, COOEt, Me/Me, and Me/Ph) groups 3 and 5. Both analytical and spectroscopical data of all the synthesized compounds are in full agreement with the proposed structures. The microbial features of the synthesized compounds were studied by a known method.

1. Introduction

The synthesis of heterocycles has received considerable attention in recent years. 1,2,4-Triazoles and their derivatives constitute an important class of organic compounds with diverse agricultural, industrial, and biological activities [13] including antimicrobial [4, 5] sedative, anticonvulsant [6], and anti-inflammatory properties [7], and, consequently, the synthesis of compounds containing 1,2,4-triazole rings in their structure has attracted widespread attention. 1,3-Dipolar cycloaddition is one of the most versatile methods for the construction of five-membered heterocycles [8, 9]. Recently, we have described a versatile and efficient one-pot synthesis of dispiroheterocycles containing 1,2,4-triazole moieties utilizing available ketooximes, hydrazones, and hydrazonoyl halides [10]. Keeping this observation in view and in continuation of our study on the synthesis of biologically active nitrogen containing heterocycles [1116], this paper presents the synthesis of a series of some new substituted 1,2,4-triazoles via reaction of nitrilimines 2 with different pyruvaldehyde hydrazones 3 and 5, in anticipation of expected interesting biological activities.

2. Experimental

2.1. Instruments and Reagents

Melting points were determined on an A. Krüss Melting Point Meter and are uncorrected. The IR spectra were measured as potassium bromide pellets using a Satellite 3000 Mid infrared spectrophotometer. The 1H NMR and 13C NMR spectra were recorded on a Bruker AM 300 MHz spectrometer at room temperature in DMSO-d6 solution using tetramethylsilane (TMS) as internal reference. Chemical shifts were recorded as δ values in parts per million (ppm) downfield from internal TMS. Electron impact (EI) mass spectra were run on Shimadzu GCMS-QP1000 EX spectrometer at 70 eV. Elemental analyses were performed at the Microanalytical Center of Cairo University, Egypt. The hydrazonoyl halides 1 [1719] and pyruvaldehyde hydrazones 3 and 5 [20] were prepared according to literature procedures. Pyruvaldehyde, tetrahydrofuran (THF), and triethylamine were purchased from Avocado Research Chemicals, England, and used without further purification.

2.2. Reaction of Nitrilimine 2 with Pyruvaldehyde Hydrazones 3 (General Procedure)

Triethylamine (1.5 g, 15 mmol) was added to the stirred mixture of pyruvaldehyde hydrazones 3 (7.5–10 mmol) and the appropriate hydrazonoyl halides 1 (5 mmol) in dioxane (50 mL) at room temperature and stirring was continued or refluxed for 12–16 hours. The precipitated salt was filtered off and the solvent was then evaporated under reduced pressure. The residue was washed with water (3 × 20 mL), and in few cases the oily or gummy products were triturated with ethanol or methanol (10 mL). The crude solid product was then collected and recrystallized from ethanol or methanol to give the desired compounds 4aj.

The following compounds were synthesized using this method.

2.2.1. 3-Acetyl-4-benzoylamino-5-methyl-1-phenyl-1,2,4-triazole-5-carbaldehyde (4a)

Yield 64%; mp. 163–165°C; 1H NMR (DMSO-d6) δ/ppm 9.73 (1H, s, NH), 8.64 (1H, s, H-C=O), 7.76–7.14 (10H, m, arom. H), 2.56 (3H, s, COCH3), 1.92 (3H, s, CH3); 13C NMR (DMSO-d6) δ/ppm 193.6 (C=O acetyl), 168.8 (N-C=O), 162.7 (H-C=O), 147.6 (C=N), 143.7–117.9 (8 arom. C.), 90.1 (C-5), 24.2 (CH3), 23.8 (CH3 acetyl); IR (KBr) ν/cm−1 3256 (NH), 1691 (C=O), 1682 (H-C=O), 1676 (N-C=O), 1622 (C=N) cm−1; MS: m/z = 350 [M+]; Analysis (% Calculated/found) for C19H18N4O3 (Mw 350.38) C: 65.13/65.45, H: 5.18/4.90, N: 15.99/16.15.

2.2.2. 3-Acetyl-1-(4-chlorophenyl)-4-ethoxycarbonylamino-5-methyl-1,2,4-triazole-5-carbaldehyde (4b)

Yield 65%; mp. 146–148°C; 1H NMR (DMSO-d6) δ/ppm 8.72 (1H, s, H-C=O), 6.96 (1H, s, NH), 7.39–7.17 (4H, m, arom. H), 2.69 (2H, q, J 7.5, CH2), 2.54 (3H, s, COCH3), 1.90 (3H, s, CH3), 1.08 (3H, t, J 7.5, CH3); 13C NMR (DMSO-d6) δ/ppm 193.3 (C=O acetyl), 162.8 (H-C=O), 158.1 (N-C=O), 147.5 (C=N), 143.4–121.3 (4 arom. C.), 89.9 (C-5), 63.2 (CH2), 24.2 (CH3), 23.8 (CH3 acetyl), 14.8 (CH3 ethyl); IR (KBr) ν/cm−1 3255 (NH), 1730 (O-C=O), 1694 (C=O), 1687 (H-C=O), 1629 (C=N) cm−1; MS: m/z = 352/354 []; Analysis (% Calculated/found) for C15H17ClN4O4 (Mw 352.87) C: 51.07/50.85, H: 4.86/4.70, N: 15.88/16.05.

2.2.3. 3-Acetyl-1-(4-chlorophenyl)-4-methoxycarbonylamino-5-methyl-1,2,4-triazole-5-carbaldehyde (4c)

Yield 70%; mp. 152–154°C; 1H NMR (DMSO-d6) δ/ppm 8.71 (1H, s, H-C=O), 6.93 (1H, s, NH), 7.30–7.12 (4H, m, arom. H), 3.68 (3H, s, OCH3), 2.56 (3H, s, COCH3), 1.91 (3H, s, CH3); 13C NMR (DMSO-d6) δ/ppm 193.8 (C=O acetyl), 162.5 (H-C=O), 158.3 (N-C=O), 147.3 (C=N), 142.9–120.9 (4 arom. C.), 90.0 (C-5), 53.4 (OCH3), 24.2 (CH3), 23.5 (CH3 acetyl); IR (KBr) ν/cm−1 3275 (NH), 1735 (O-C=O), 1692 (C=O), 1682 (H-C=O), 1626 (C=N) cm−1; MS: m/z = 338/340 [M+]; Analysis (% Calculated/found) for C14H15ClN4O4 (Mw 338.875) C: 49.64/49.40, H: 4.46/4.60, N: 16.54/16.40.

2.2.4. 3-Benzoyl-4-benzoylamino-1-(4-chlorophenyl)-5-methyl-1,2,4-triazole-5-carbaldehyde (4d)

Yield 66%; mp. 189–191°C; 1H NMR (DMSO-d6) δ/ppm 9.43 (1H, s, NH), 8.55 (1H, s, H-C=O), 8.12–7.15 (14H, m, arom. H), 1.86 (3H, s, CH3); 13C NMR (DMSO-d6) δ/ppm 184.3 (C=O benzoyl), 168.8 (N-C=O), 162.6 (H-C=O), 147.1 (C=N), 141.3–118.7 (12 arom. C.), 89.1 (C-5), 24.2 (CH3); IR (KBr) ν/cm−1 3257 (NH), 1682 (H-C=O), 1673 (N-C=O), 1656 (C=O), 1612 (C=N) cm−1; MS: m/z = 446/448 [M+]; Analysis (% Calculated/found) for C24H19ClN4O3 (Mw 446.90) C: 64.50/64.25, H: 4.29/4.45, N: 7.60/7.45.

2.2.5. 4-Methoxycarbonylamino-5-methyl-1-phenyl-3-phenylaminocarbonyl-1,2,4-triazole-5-carbaldehyde (4e)

Yield 71%; mp. 199–201°C; 1H NMR (DMSO-d6) δ/ppm 10.43 (1H, s, PhNH), 8.53 (1H, s, H-C=O), 7.72–7.18 (10H, m, arom. H), 6.93 (1H, s, NH), 3.67 (3H, s, OCH3), 1.91 (3H, s, CH3); 13C NMR (DMSO-d6) δ/ppm 166.4 (PhNH-C=O), 162.6 (H-C=O), 158.4 (N-C=O), 147.6 (C=N), 143.2–115.7 (8 arom. C.), 89.2 (C-5), 53.4 (OCH3), 24.3 (CH3); IR (KBr) ν/cm−1 3362 (PhNH), 3257 (NH), 1682 (H-C=O), 1732 (O-C=O), 1655 (C=O), 1618 (C=N) cm−1; MS: m/z = 365 [M+]; Analysis (% Calculated/found) for C19H19N5O3 (Mw 365.39) C: 62.46/62.25, H: 5.24/5.35, N: 19.17/19.05.

2.2.6. 1-(4-Bromophenyl)-4-benzoylamino-5-methyl-3-phenylaminocarbonyl-1,2,4-triazole-5-carbaldehyde (4f)

Yield 74%; mp. 204–206°C; 1H NMR (DMSO-d6) δ/ppm 10.46 (1H, s, PhNH), 9.53 (1H, s, NH), 8.52 (1H, s, H-C=O), 7.76–7.21 (14H, m, arom. H), 1.87 (3H, s, CH3); 13C NMR (DMSO-d6) δ/ppm 168.5 (N-C=O), 166.4 (PhNH-C=O), 162.6 (H-C=O), 147.3 (C=N), 143.1–120.7 (12 arom. C.), 88.7 (C-5), 24.2 (CH3); IR (KBr) ν/cm−1 3365 (PhNH), 3270 (NH), 1689 (H-C=O), 1675 (N-C=O), 1650 (C=O), 1619 (C=N) cm−1; MS: m/z = 506/508 [M+]; Analysis (% Calculated/found) for C24H20BrN5O3 (Mw 506.36) C: 56.93/57.20, H: 3.98/4.15, N: 13.83/13.70.

2.2.7. 4-Benzoylamino-1-(4-fluorophenyl)-5-methyl-3-phenylaminocarbonyl-1,2,4-triazole-5-carbaldehyde (4g)

Yield 72%; mp. 216–218°C; 1H NMR (DMSO-d6) δ/ppm 10.71 (1H, s, PhNH), 9.62 (1H, s, NH), 8.65 (1H, s, H-C=O), 7.76–7.16 (14H, m, arom. H), 1.93 (3H, s, CH3); 13C NMR (DMSO-d6) δ/ppm 168.8 (N-C=O), 166.7 (PhNH-C=O), 162.6 (H-C=O), 147.5 (C=N), 143.4–115.7 (12 arom. C.), 89.6 (C-5), 24.5 (CH3); IR (KBr) ν 3360 (PhNH), 3258 (NH), 1691 (H-C=O), 1678 (N-C=O), 1655 (C=O), 1622 (C=N) cm−1; MS: m/z = 445/447 [M+]; Analysis (% Calculated/found) for C24H20FN5O3 (Mw 445.46) C: 64.71/64.45, H: 4.53/4.70, N: 15.72/15.55.

2.2.8. 4-Benzoylamino-1-(4-clorophenyl)-3-(2-furoyl)-5-methyl-1,2,4-triazole-5-carbaldehyde (4h)

Yield 65%; mp. 165–167°C; 1H NMR (DMSO-d6) δ/ppm 9.35 (1H, s, NH), 8.68 (1H, s, H-C=O), 8.31–7.20 (12H, m, arom. H), 1.86 (3H, s, CH3); 13C NMR (DMSO-d6) δ/ppm 173.7 (C=O), 169.0 (N-C=O), 162.6 (H-C=O), 146.8 (C=N), 144.4–115.4 (12 arom. C.), 89.7 (C-5), 24.1 (CH3); IR (KBr) ν/cm−1 3272 (NH), 1686 (H-C=O), 1676 (N-C=O), 1660 (C=O), 1609 (C=N) cm−1; MS: m/z = 436/438 [M+]; Analysis (% Calculated/found) for C22H17ClN4O4 (Mw 436.86) C: 60.49/60.25, H: 3.92/4.10, N: 12.82/13.70.

2.2.9. 4-Benzoylamino-1-(4-clorophenyl)-5-methyl-3-(2-thenoyl)-1,2,4-triazole-5-carbaldehyde (4i)

Yield 63%; mp. 176–178°C; 1H NMR (DMSO-d6) δ/ppm 9.23 (1H, s, NH), 8.53 (1H, s, H-C=O), 8.26–7.15 (12H, m, arom. H), 1.88 (3H, s, COCH3); 13C NMR (DMSO-d6) δ/ppm 174.6 (C=O), 168.7 (N-C=O), 162.6 (H-C=O), 146.6 (C=N), 144.6–114.9 (12 arom. C.), 89.4 (C-5), 24.0 (CH3); IR (KBr) ν/cm−1 3275 (NH), 1687 (H-C=O), 1678 (N-C=O), 1665 (C=O), 1612 (C=N) cm−1; MS: m/z = 452/454 [M+]; Analysis (% Calculated/found) for C22H17ClN4O3S (Mw 452.92) C: 58.34/58.60, H: 3.78/3.65, N: 12.37/12.50.

2.2.10. 4-Benzoylamino-1-(4-clorophenyl)-5-methyl-3-(2-naphthoyl)-1,2,4-triazole-5-carbaldehyde (4j)

Yield 58%; mp. 186–188°C; 1H NMR (DMSO-d6) δ/ppm 9.62 (1H, s, NH), 8.64 (1H, s, H-C=O), 8.76–7.24 (16H, m, arom. H), 1.82 (3H, s, CH3); 13C NMR (DMSO-d6) δ/ppm 184.5 (C=O naphthoyl), 168.8 (N-C=O), 162.6 (H-C=O), 146.8 (C=N), 141.4–119.3 (18 arom. C.), 88.7 (C-5), 23.8 (CH3); IR (KBr) ν/cm−1 3225 (NH), 1687 (H-C=O), 1675 (N-C=O), 1640 (C=O), 1621 (C=N) cm−1; MS: m/z = 496/498 [M+]; Analysis (% Calculated/found) for C28H21ClN4O3 (Mw 496.96) C: 68.67/68.40, H: 4.26/4.45, N: 11.27/11.15.

2.3. Reaction of Nitrilimine 2 with Pyruvaldehyde Hydrazones 5 (General Procedure)

Triethylamine (10 mmol) in THF (10 mL) was slowly added to the stirred mixture of pyruvaldehyde hydrazones 5 (5 mmol) and the appropriate hydrazonoyl halides 1 (5 mmol) in THF (50 mL) at room temperature and then refluxed for 12 hours. The cooled and precipitated salt was filtered off, and the solvent was then evaporated under reduced pressure. The residue was washed with water (2 × 25 mL), and in few cases the oily or gummy products were triturated with ethanol or methanol (10 mL). The crude solid product was collected and recrystallized from ethanol or methanol to give the desired compounds.

The following compounds were synthesized using this method.

2.3.1. 3-Acetyl-4-dimethylamino-5-methyl-1-phenyl-1,2,4-triazole-5-carbaldehyde (6a)

Yield 77%; mp. 133–135°C; 1H NMR (DMSO-d6) δ/ppm 8.63 (1H, s, H-C=O), 7.76–7.14 (4H, m, arom. H), 3.25 (6H, s, 2CH3) 2.56 (3H, s, COCH3), 1.92 (3H, s, CH3); 13C NMR (DMSO-d6) δ/ppm 193.6 (C=O acetyl), 162.8 (H-C=O), 147.8 (C=N), 142.7–117.9 (4 arom. C.), 90.1 (C-5), 43.2 (2CH3), 24.2 (CH3), 23.8 (CH3 acetyl); IR (KBr) ν/cm−1 1696 (C=O), 1686 (H-C=O), 1628 (C=N) cm−1; MS: m/z = 274 [M+]; Analysis (% Calculated/found) for C14H17N4O2 (Mw 274.33) C: 61.30/61.45, H: 6.61/6.77, N: 20.42/20.25.

2.3.2. 3-Acetyl-1-(4-chlorophenyl)-4-dimethylamino-5-methyl-1,2,4-triazole-5-carbaldehyde (6b)

Yield 75%; mp. 141–143°C; 1H NMR (DMSO-d6) δ/ppm 8.62 (1H, s, H-C=O), 7.39–7.17 (4H, m, arom. H), 3.25 (6H, s, 2CH3), 2.54 (3H, s, COCH3), 1.90 (3H, s, CH3); 13C NMR (DMSO-d6) δ/ppm 193.3 (C=O acetyl), 162.8 (H-C=O), 148.0 (C=N), 142.4–120.9 (4 arom. C.), 89.9 (C-5), 43.2 (2CH3), 24.1 (CH3), 23.6 (CH3 acetyl); IR (KBr) ν/cm−1 1696 (C=O), 1688 (H-C=O), 1630 (C=N) cm−1; MS: m/z = 308/310 []; Analysis (% Calculated/found) for C15H17ClN4O2 (Mw 308.77) C: 54.46/54.75, H: 5.55/5.38, N: 18.15/18.05.

2.3.3. 3-Acetyl-1-(4-chlorophenyl)-4-methylphenylamino-5-methyl-1,2,4-triazole-5-carbaldehyde (6c)

Yield 76%; mp. 122–124°C; 1H NMR (DMSO-d6) δ/ppm 8.60 (1H, s, H-C=O), 7.30–7.12 (9H, m, arom. H), 3.18 (3H, s, CH3), 2.56 (3H, s, COCH3), 1.91 (3H, s, CH3); 13C NMR (DMSO-d6) δ/ppm 193.8 (C=O acetyl), 162.5 (H-C=O), 147.9 (C=N), 142.6–120.5 (8 arom. C.), 90.0 (C-5), 43.4 (CH3), 24.3 (CH3), 23.1 (CH3 acetyl); IR (KBr) ν/cm−1 1697 (C=O), 1684 (H-C=O), 1628 (C=N) cm−1; MS: m/z = 370/372 [M+]; Analysis (% Calculated/found) for C19H19ClN4O2 (Mw 370.84) C: 61.54/61.27, H: 5.16/4.98, N: 15.11/14.95.

2.3.4. 3-Benzoyl-1-(4-chlorophenyl)-4-dimethylamino-5-methyl-1,2,4-triazole-5-carbaldehyde (6d)

Yield 71%; mp. 159–161°C; 1H NMR (DMSO-d6) δ/ppm 8.52 (1H, s, H-C=O), 8.12–7.15 (9H, m, arom. H), 3.21 (6H, s, 2CH3), 1.86 (3H, s, CH3); 13C NMR (DMSO-d6) δ/ppm 184.3 (C=O benzoyl), 162.6 (H-C=O), 147.1 (C=N), 141.3–118.7 (8 arom. C.), 89.7 (C-5), 43.5 (2CH3), 24.2 (CH3); IR (KBr) ν/cm−1 1685 (H-C=O), 1660 (C=O), 1623 (C=N) cm−1; MS: m/z = 370/372 [M+]; Analysis (% Calculated/found) for C19H19ClN4O2 (Mw 370.84) C: 61.54/61.35, H: 5.16/5.30, N: 15.11/15.25.

2.3.5. 4-Dimethylamino-5-methyl-1-phenyl-3-phenylaminocarbonyl-1,2,4-triazole-5-carbaldehyde (6e)

Yield 66%; mp. 189–181°C; 1H NMR (DMSO-d6) δ/ppm 10.43 (1H, s, PhNH), 8.55 (1H, s, H-C=O), 8.12–7.15 (10H, m, arom. H), 3.12 (6H, s, 2CH3), 1.86 (3H, s, CH3); 13C NMR (DMSO-d6) δ/ppm 167.8 (N-C=O), 166.6 (PhNH-C=O), 162.6 (H-C=O), 147.1 (C=N), 142.3–118.7 (8 arom. C.), 88.7 (C-5), 43.0 (2CH3), 24.4 (CH3); IR (KBr) ν/cm−1 3363 (PhNH), 1687 (H-C=O), 1655 (C=O), 1622 (C=N) cm−1; MS: m/z = 351 [M+]; Analysis (% Calculated/found) for C19H21N5O2 (Mw 351.41) C: 64.94/65.22, H: 6.02/5.92, N: 19.93/20.05.

2.3.6. 1-(4-Bromophenyl)-4-dimethylamino-5-methyl-3-phenylaminocarbonyl-1,2,4-triazole-5-carb-aldehyde (6f)

Yield 64%; mp. 194–196°C; 1H NMR (DMSO-d6) δ/ppm 10.42 (1H, s, PhNH), 8.52 (1H, s, H-C=O), 7.76–7.21 (9H, m, arom. H), 3.14 (6H, s, 2CH3), 1.87 (3H, s, CH3); 13C NMR (DMSO-d6) δ/ppm 167.5 (N-C=O), 166.5 (PhNH-C=O), 162.6 (H-C=O), 147.6 (C=N), 143.1–120.9 (8 arom. C.), 89.8 (C-5), 43.1 (2CH3), 24.3 (CH3); IR (KBr) ν/cm−1 3365 (PhNH), 1689 (H-C=O), 1650 (C=O), 1629 (C=N) cm−1; MS: m/z = 392/394 [M+]; Analysis (% Calculated/found) for C24H22BrN5O2 (Mw 492.38) C: 58.55/58.37, H: 4.50/4.35, N: 14.22/14.30.

2.3.7. 1-(4-Flourophenyl)-5-methyl-4-methylphenylamino-3-phenylaminocarbonyl-1,2,4-triazole-5-carbaldehyde (6g)

Yield 68%; mp. 176–178°C; 1H NMR (DMSO-d6) δ/ppm 10.35 (1H, s, PhNH), 8.57 (1H, s, H-C=O), 7.76–7.16 (14H, m, arom. H), 3.20 (3H, s, CH3), 1.93 (3H, s, CH3); 13C NMR (DMSO-d6) δ/ppm 168.8 (N-C=O), 166.7 (PhNH-C=O), 162.6 (H-C=O), 148.7 (C=N), 143.8–116.1 (12 arom. C.), 89.3 (C-5), 43.7 (N-CH3), 24.6 (CH3); IR (KBr) ν/cm−1 3366 (PhNH), 1687 (H-C=O), 1650 (C=O), 1626 (C=N) cm−1; MS: m/z = 431/433 [M+]; Analysis (% Calculated/found) for C24H22FN5O2 (Mw 431.47) C: 66.81/66.65, H: 5.14/5.05, N: 16.23/16.34.

2.3.8. 1-(4-Chlorophenyl)-4-dimethylamino-3-(2-furoyl)-5-methyl-1,2,4-triazole-5-carbaldehyde (6h)

Yield 76%; mp. 145–147°C; 1H NMR (DMSO-d6) δ/ppm 8.61 (1H, s, H-C=O), 8.31–7.20 (7H, m, arom. H), 3.28 (6H, s, 2CH3), 1.86 (3H, s, CH3); 13C NMR (DMSO-d6) δ/ppm 174.6 (C=O), 162.6 (H-C=O), 147.8 (C=N), 144.9–115.4 (8 arom. C.), 89.7 (C-5), 43.0 (2CH3), 23.7 (CH3); IR (KBr) ν/cm−1 1688 (H-C=O), 1655 (C=O), 1619 (C=N) cm−1; MS: m/z = 360/362 [M+]; Analysis (% Calculated/found) for C17H17ClN4O3 (Mw 360.80) C: 56.59/56.33, H: 4.75/4.63, N: 15.53/15.70.

2.3.9. 1-(4-Chlorophenyl)-4-dimethylamino-5-methyl-3-(2-thenoyl)-1,2,4-triazole-5-carbaldehyde (6i)

Yield 73%; mp. 156–158°C; 1H NMR (DMSO-d6) δ/ppm 8.58 (1H, s, H-C=O), 8.26–7.15 (7H, m, arom. H), 3.25 (6H, s, 2CH3), 1.88 (3H, s, CH3); 13C NMR (DMSO-d6) δ/ppm 176.2 (C=O), 162.6 (H-C=O), 147.6 (C=N), 144.6–115.3 (8 arom. C.), 89.4 (C-5), 43.2 (2CH3), 23.8 (CH3); IR (KBr) ν/cm−1 1686 (H-C=O), 1660 (C=O), 1620 (C=N) cm−1; MS: m/z = 376/378 [M+]; Analysis (% Calculated/found) for C17H17ClN4O2S (Mw 376.87) C: 54.18/54.40, H: 4.55/4.65, N: 14.87/14.75.

2.3.10. 1-(4-Chlorophenyl)-5-methyl-4-methylphenylamino-3-(2-naphthoyl)-1,2,4-triazole-5-carbaldehyde (6j)

Yield 68%; mp. 202–204°C; 1H NMR (DMSO-d6) δ/ppm 8.60 (1H, s, H-C=O), 8.76–7.24 (16H, m, arom. H), 3.06 (3H, s, CH3), 1.82 (3H, s, CH3); 13C NMR (DMSO-d6) δ/ppm 183.9 (C=O naphthoyl), 162.2 (H-C=O), 146.8 (C=N), 142.4–120.3 (18 arom. C.), 88.7 (C-5), 42.9 (NCH3), 23.8 (CH3); IR (KBr) ν/cm−1 1685 (H-C=O), 1645 (C=O), 1622 (C=N) cm−1; MS: m/z = 482/486 [M+]; Analysis (% Calculated/found) for C28H23ClN4O2 (Mw 482.97) C: 69.63/69.40, H: 4.80/4.91, N: 11.60/11.48.

2.4. Antimicrobial Activity Screening

Antimicrobial activity screening of the synthesized compounds was determined by the agar dilution technique as recommended by the Clinical and Laboratory Standard Institute (CLSI) [21]. The tested compounds were dissolved in dimethyl formamide (DMF). An inoculum of about 1.5 × 108 colony forming units per spot was applied to the surfaces of Mueller-Hinton agar plates containing graded concentrations of the respective compounds; plates were incubated at 37°C for 18 h. The spot with the lowest concentration of compound showing no growth was defined as the minimum inhibitory concentration (MIC). All organisms used in this study were standard strains obtained from the Microbiology Laboratory (Al-Aqsa University) and included bacterial strains such as Enterococci, Escherichia coli, Staphylococcus aureus, Klebsiella spp., and Proteus spp. and fungi strains such as Aspergillus niger and Candida albicans. The MIC of tetracycline and fluconazole was determined concurrently as reference for antibacterial and antifungal activities, respectively (Table 1). Control DMF was carried out with each experiment.

Table 1: Antimicrobial screening results of the tested compounds*.

3. Results and Discussion

3.1. Chemistry

1,3-Dipolar cycloaddition of nitrilimines 2, generated in situ from hydrazonoyl halides 1 in tetrahydrofuran or 1,4-dioxane in the presence of triethylamine, to 2-oxopropanal hydrazones 3 (Y = COPh, COOMe, and COOEt) was carried out at room temperature for 12 h, leading to the formation of 1,2,4-triazole derivatives 4aj as cycloaddition products rather than the cyclocondensation 1,2,4,5-tetrazines 4aj (Scheme 1). It is worth mentioning that the latter products 4aj were obtained from the reaction of hydrazonoyl halides with methyl hydrazones of aliphatic aldehydes and ketones [22]. This can be explained on the basis of the weak nucleophilicity of the nitrogen atom of the hydrazones carrying the electron withdrawing groups in comparison to that of the nitrogen atom carrying methyl group in methyl hydrazones. The purity of obtained compounds was controlled by TLC and elemental analyses. Both the analytical and spectral data (IR, 1H NMR, 13C NMR, and mass spectra) of the synthesized triazoles 4aj were in full agreement with the proposed structures and were depicted in Experimental.

Scheme 1: Synthetic pathway for the preparation of 1,2,4-triazoles 4aj.

The electron impact (EI) mass spectra displayed the correct molecular ions in accordance with the suggested structures. Their IR spectra showed absorption bands in the regions 3275–3225 cm−1, 1690–1680 cm−1, and 1620–1610 cm−1 assignable to NH, formyl, and C=N groups, respectively. Their 1H NMR spectra revealed aromatic protons at 8.3–7.1 ppm and singlet signal at 8.7–8.5 ppm assigned to H-C=O proton and singlet signal in the region 1.9-1.8 ppm assignable to the CH3 proton at quaternary carbon. The detailed 1H NMR data is shown in Experimental. Their 13C NMR spectra showed all the signals corresponding to the proposed structures, especially C-5 (quaternary carbon) which was found to resonate at about 90–85 ppm. This is similar to reported values of quaternary carbon flanked by two nitrogen atoms in five-membered heterocycles [2224], which provide strong evidence in support of the structures 4aj rather than the six-membered heterocyclic structures 4aj which is expected to have a C-6 signal at about 70–65 ppm. The complete 13C NMR data are presented in Experimental.

On the other hand, the reaction of the same nitrilimines 2 with 2-oxopropanal hydrazones 5 having N,N-dimethyl or N-methyl-N-phenyl substituents, under ambient temperature, affords only one isolable product in each case. On the bases of their spectroscopical data, the structures of the reaction products were identified as 1,3,4,5,5-substituted-1,2,4-triazoles 6aj (Scheme 2) in good yields.

Scheme 2: Synthetic pathway for the preparation of triazoles 6aj.

The synthesized compounds 6aj gave satisfactory analysis for the proposed structures which are confirmed on the bases of their spectroscopical data. The electron impact (EI) mass spectra displayed the correct molecular ions (M) in accordance with the suggested structures. Their IR spectra showed absorption bands in the region 1695–1950 cm−1 assignable to carbonyl and formyl group. The absorption band of C=N appeared in 1630–1620 cm−1 region. Their 1H NMR spectrum revealed characteristic signals for the N-CH3 at about δ 3.3–3.1 ppm in addition to the signals resulting from the formyl and aromatic hydrogens. 13C NMR spectrum exhibited the characteristic signals of the suggested structures. The signal for quaternary carbon (C-5) appeared around δ 90 ppm. The signal at δ 37.8–37.2 ppm is attributed to the N-CH3 carbon. The entire 13C NMR data are presented in Experimental.

3.2. Antimicrobial Activity

Most of the synthesized compounds were screened in vitro for their antimicrobial activity against a variety of bacterial strains such as Enterococci, Escherichia coli, Staphylococcus aureus, Klebsiella spp., and Proteus spp. and fungi such as Aspergillus niger and Candida albicans, employing the nutrient agar disc diffusion method [25, 26] at 10 mg/mL concentration in dimethyl formamide (DMF) used as solvent control, by measuring the average diameter of the inhibition zone in mm. The results showed that all the tested compounds exhibited weak to moderate degree of activity against bacteria and fungi compared with well-known antibacterial and antifungal substances such as tetracycline and fluconazole, respectively. The results are given in Table 1. According to NCCLS (2004), zones of inhibition for tetracycline and fluconazole <14 mm were considered resistant, between 15 and 18 mm were considered weakly sensitive, and >19 mm were considered sensitive. Also, the results showed the degree of inhibition varied with the tested compounds.

4. Conclusion

In conclusion, the reaction of several nitrilimines with pyruvaldehyde hydrazones having electron withdrawing or electron releasing groups leads to formation of pentasubstituted-1,2,4-triazoles and some of them were found to possess various antimicrobial activities towards all the microorganisms tested. The results confirm that the antimicrobial activity is strongly dependent on the nature of the substituents on triazole rings.

Conflict of Interests

The author declares that there is no conflict of interests regarding the publication of this paper.

Acknowledgment

The author wishes to thank Dr. A. Abu Samaha for screening of the selected synthesized compounds for their antimicrobial activities.

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