Synthesis and Non-Aqueous Medium Titrations of Some New 4-Benzylidenamino-4,5-dihydro-1H-1,2,4-triazol-5-one Derivatives

Abstract

The synthesis of 3-alkyl(aryl)-4-(3-ethoxy-4-hydroxybenzylidenamino)-4,5-dihydro-1H-1,2,4-triazol-5-ones 3 from the reactions of 3-alkyl(aryl)-4-amino-4,5-dihydro-1H-1,2,4-triazol-5-ones 2 with 3-ethoxy-4-hydroxybenzaldehyde is described. The acetylation and methylation reactions of the compounds 3 giving compounds of type 4 and 5, respectively, were investigated. The newly synthesized compounds were characterized using elemental analyses and IR, ¹H-NMR, ¹³C-NMR and UV spectral data. In addition, to investigate the effects of solvents and molecular structure upon acidity, compounds 3 were titrated potentiometrically with tetrabutylammonium hydroxide in four non-aqueous solvents (isopropyl alcohol, tert-butyl alcohol, acetonitrile and N,N-dimethylformamide). The half-neutralization potential values and the corresponding pK_a values were determined for all cases.

Introduction

1,2,4-Triazole and 4,5-dihydro-1H-1,2,4-triazol-5-one derivatives are reported to possess a broad spectrum of biological activities such as antifungal, antimicrobial, hypoglycemic, antihypertensive, analgesic, antiparasitic, hypocholesteremic, antiviral, anti-inflammatory, antitumor and anti-HIV properties [1,2,3,4,5,6,7,8,9,10,11,12,13]. In addition, several articles reporting the synthesis of some N-arylidenamino-4,5-dihydro-1H-1,2,4-triazol-5-one derivatives have been published [12,13,14,15,16]. The acetylation and methylation of 4,5-dihydro-1H-1,2,4-triazol-5-one derivatives have also been reported [11,15,16,17].

On the other hand, it is known that 1,2,4-triazole and 4,5-dihydro-1H-1,2,4-triazol-5-one rings have weak acidic properties, so some 1,2,4-triazole and 4,5-dihydro-1H-1,2,4-triazol-5-one derivatives were titrated potentiometrically with tetrabutylammonium hydroxide in non-aqueous solvents, and the corresponding pK_a values of the compounds were determined [15,16,18,19,20,21,22].

This paper describes the synthesis of a series of 3-alkyl(aryl)-4-(3-ethoxy-4-hydroxy-benzylidenamino)-4,5-dihydro-1H-1,2,4-triazol-5-ones 3 from the reactions of 3-alkyl(aryl)-4-amino-4,5-dihydro-1H-1,2,4-triazol-5-ones 2 with 3-ethoxy-4-hydroxybenzaldehyde. Moreover, the reactions of compounds 3 with acetic anhydride and NaOH/dimethyl sulphate were investigated, and compounds of types 4 and 5, respectively, were thus prepared (Scheme 1). Furthermore, we also examined the potentiometric titrations of the synthesized compounds 3a-3e with tetrabutylammonium hydroxide (TBAH) in four non-aqueous solvents (isopropyl alcohol, tert-butyl alcohol, acetonitrile and N,N‑dimethylformamide} to determine the corresponding half-neutralization potentials (HNP) and the corresponding pK_a values. The data obtained from the potentiometric titrations were interpreted and the effects of molecular structure and solvents were studied [15,16,18,19,20,21,22,23].

Scheme 1.

Scheme 1.

Results and Discussion

In this study, the structures of five new 3-alkyl(aryl)-4-(3-ethoxy-4-hydroxybenzylidenamino)-4,5-dihydro-1H-1,2,4-triazol-5-ones, 3a-e, four new 1-acetyl-3-alkyl(aryl)-4-(3-ethoxy-4-acetoxy-benzylidenamino)-4,5-dihydro-1H-1,2,4-triazol-5-ones, 4a-c and e, and two new 1-methyl-3-alkyl-(aryl)-4-(3-ethoxy-4-methoxybenzylidenamino)-4,5-dihydro-1H-1,2,4-triazol-5-ones, 5c,e, were identified using elemental analysis and IR, ¹H-, ¹³C-NMR and UV spectral data, and the observed spectral values were seen to be compatible with literature values [11,12,13,14,15,16,25].

After the potentiometric titrations of compounds 3 with TBAH in non-aqueous solvents, the mV values from each titration were plotted against TBAH volumes used (mL) and the potentiometric titration curves were obtained for all the cases. From the titration curves, the HNP values and the corresponding pK_a values were obtained. As an example, the potentiometric titration curves for 0.001 M solutions of 3-(4-chloro-benzyl)-4-(3-ethoxy-4-hydroxybenzylidenamino)-4,5-dihydro-1H-1,2,4-triazol-5-one (3d) titrated with 0.05 N TBAH in isopropyl alcohol, tert-butyl alcohol, acetonitrile and N,N-dimethylformamide are presented in Figure 1.

Figure 1. Potentiometric titration curves of 0.001 M solutions of compound 3d titrated with 0.05 M TBAH in isopropyl alcohol (▲), tert-butyl alcohol (х), acetonitrile (◆) and N,N-dimethylformamide (■) at 25°C.

Figure 1. Potentiometric titration curves of 0.001 M solutions of compound 3d titrated with 0.05 M TBAH in isopropyl alcohol (▲), tert-butyl alcohol (х), acetonitrile (◆) and N,N-dimethylformamide (■) at 25°C.

The half-neutralization potential (HNP) values and the corresponding pK_a values of compounds 3a-3e, obtained from the potentiometric titrations with 0.05 M TBAH in isopropyl alcohol, tert-butyl alcohol, acetonitrile and N,N-dimethylformamide, are presented in Table 1, Table 2, Table 3 and Table 4.

Table 1. The half-neutralization potentials (HNP) and the corresponding pK_a values of compounds 3a-3e in isopropyl alcohol at 25 °C.

Compd. no	HNP1 (mV)	pKa1	HNP2 (mV)	pKa2
3a	-363	13.22	-495	-
3b	-367	13.92	-	-
3c	-369	13.78	-474	-
3d	-355	13.63	-460	16.00
3e	-344	12.85	-449	14.98

Table 1. The half-neutralization potentials (HNP) and the corresponding pK_a values of compounds 3a-3e in isopropyl alcohol at 25 °C.

Compd. no	HNP1 (mV)	pKa1	HNP2 (mV)	pKa2
3a	-363	13.22	-495	-
3b	-367	13.92	-	-
3c	-369	13.78	-474	-
3d	-355	13.63	-460	16.00
3e	-344	12.85	-449	14.98

Table 2. The half-neutralization potentials (HNP) and the corresponding pK_a values of compounds 3a-3e in tert-butyl alcohol at 25 °C.

Compd. no	HNP1 (mV)	pKa1	HNP2 (mV)	pKa2
3a	-384	13.65	-501	-
3b	-443	15.62	-558	-
3c	-416	14.00	-544	-
3d	-472	-	-	-
3e	-448	14.96	-	-

Table 2. The half-neutralization potentials (HNP) and the corresponding pK_a values of compounds 3a-3e in tert-butyl alcohol at 25 °C.

Compd. no	HNP1 (mV)	pKa1	HNP2 (mV)	pKa2
3a	-384	13.65	-501	-
3b	-443	15.62	-558	-
3c	-416	14.00	-544	-
3d	-472	-	-	-
3e	-448	14.96	-	-

Table 3. The half-neutralization potentials (HNP) and the corresponding pK_a values of compounds 3a-3e in acetonitrile at 25 °C.

Compd. no	HNP1 (mV)	pKa1	HNP2 (mV)	pKa2
3a	-441	15.41	-536	-
3b	-493	15.63	-	-
3c	-482	-	-578	-
3d	-474	15.28	-	-
3e	-507	-	-	-

Table 3. The half-neutralization potentials (HNP) and the corresponding pK_a values of compounds 3a-3e in acetonitrile at 25 °C.

Compd. no	HNP1 (mV)	pKa1	HNP2 (mV)	pKa2
3a	-441	15.41	-536	-
3b	-493	15.63	-	-
3c	-482	-	-578	-
3d	-474	15.28	-	-
3e	-507	-	-	-

Table 4. The half-neutralization potentials (HNP) and the corresponding pK_a values of compounds 3a-3e in N,N-dimethylformamide at 25 °C.

Compd. no	HNP1 (mV)	pKa1	HNP2 (mV)	pKa2
3a	-503	-	-	-
3b	-496	-	-655	-
3c	-499	-	-628	-
3d	-493	-	-621	-
3e	-536	-	-	-

Table 4. The half-neutralization potentials (HNP) and the corresponding pK_a values of compounds 3a-3e in N,N-dimethylformamide at 25 °C.

Compd. no	HNP1 (mV)	pKa1	HNP2 (mV)	pKa2
3a	-503	-	-	-
3b	-496	-	-655	-
3c	-499	-	-628	-
3d	-493	-	-621	-
3e	-536	-	-	-

The pH of weak acids can be calculated using the following equation:

pH = pK_a + log[A^-] / [HA]

where pH = pK_a when [A^-] is equal to [HA] at the half-neutralization points. Therefore, the pH values at the half-neutralization points were taken as pK_a. Taking into consideration the dielectric permittivity of the solvents, the acidity ranking might be expected to be as follows: N,N‑dimethylformamide (ε=37) > acetonitrile (ε=36) > isopropyl alcohol (ε=19.4) > tert-butyl alcohol (ε=12). However, as seen in Table 1, Table 2, Table 3 and Table 4, the observed acidity ranking for all compounds is isopropyl alcohol > tert-butyl alcohol > acetonitrile > N,N-dimethylformamide. This result thus matches the theoretical arrangement, except for acetonitrile and N,N-dimethylformamide. In N,N-dimethylformamide, all these compounds show the weakest acidic properties, but they show the strongest acidic properties in isopropyl alcohol. This situation may be attributed to the hydrogen bonding between the negative ions formed and the solvent molecules in the amphiprotic neutral solvents.

As seen Scheme 1, there is one weak acidic N-H group in the 4,5-dihydro-1H-1,2,4-triazol-5-one ring and one phenolic group on the aryl substituent in compounds 3a-3e. Thus, these compounds give two end-points as well as two half-neutralization potential (HNP) values. Thus, as expected, the potentiometric titration curves for these compounds 3a-3e titrated with TBAH in isopropyl alcohol, tert-butyl alcohol, acetonitrile and N,N-dimethylformamide resemble the titration curves for diprotic acids.

For compound 3b in isopropyl alcohol, compounds 3d and 3e in tert-butyl alcohol, compounds 3b, 3d and 3e in acetonitrile and compounds 3a and 3e in N,N-dimethylformamide, the second half-neutralization potential (HNP₂) values and the corresponding pK_a values have not been obtained. In addition, the pK_a values bigger than 16.00 have not been determined due to the fact that this value is outside the range of the pH meter.

As it is well known, the acidity of a compound depends on several factors. The two most important ones are the solvent effect and molecular structure [15,16,18,19,20,21,22,23]. Table 1, Table 2, Table 3 and Table 4 and Figure 1 show that the HNP values and corresponding pK_a values obtained from the potentiometric titrations depend on the non-aqueous solvents used and the substituents at C-3 in 4,5-dihydro-1H-1,2,4-triazol-5-one ring.

Experimental

General

Melting points were taken on a Electrothermal 9100 digital melting point apparatus and are uncorrected. IR spectra were registered on a Perkin-Elmer 1600 FTIR spectrometer. ¹H-NMR and ¹³C-NMR spectra were recorded in deuterated dimethyl sulfoxide with TMS as internal standard on a Varian Mercury spectrometer at 200 MHz and 50 MHz, respectively. UV absorption spectra were measured in 10-mm quartz cells between 200 and 400 nm using a Shimadzu UV-1201 spectrophotometer. In this study, a Jenway 3040 ion analyser pH meter equipped with an Ingold pH electrode was used for potentiometric titrations. For each compound titrated, a 0.001 M solution was separately prepared in each non-aqueous solvent. A 0.05 M solution of TBAH in isopropyl alcohol, which is widely used in the titration of acids, was used as titrant. The mV values obtained on the pH meter were recorded. Finally, the half-neutralization potential (HNP) values were determined by plotting the volume (mL) (TBAH)-mV graph. The starting compounds 2a-e were prepared from the reactions of the corresponding ester ethoxycarbonylhydrazones 1a-e with an aqueous solution of hydrazine hydrate as described in the literature [17,24].

General Method for the Preparation of 3-Alkyl(aryl)-4-(3-ethoxy-4-hydroxy-benzylidenamino)-4,5-dihydro-1H-1,2,4-triazol-5-ones 3a-e

The corresponding compound 2 (0.01 mole) was dissolved in acetic acid (15 mL) and treated with 3-ethoxy-4-hydroxybenzaldehyde (1.66 g, 0.01 mole). The mixture was refluxed for 1 h and then evaporated at 50-55 °C in vacuo. Several recrystallizations of the residue from an appropriate solvent (AcOH-H₂O, 1:3) gave pure compounds 3a-e as colourless crystals.

3-Methyl-4-(3-ethoxy-4-hydroxybenzylidenamino)-4,5-dihydro-1H-1,2,4-triazol-5-one (3a). Yield 67%; mp. 205 °C; Calculated for C₁₂H₁₄N₄O₃ (262.27): 54.96% C, 5.38% H, 21.36% N; found: 54.96% C, 5.29% H, 21.07% N; ¹H-NMR: δ 1.40 (t, 3H, CH₃), 2.30 (s, 3H, CH₃), 4.11 (q, 2H, CH₂), 6.92 (d, 1H, Ar-H), 7.23 (d, 1H, Ar-H), 7.41 (s, 1H, Ar-H), 9.54 (s, 1H, N=CH), 9.79 (s, 1H, OH), 11.81 (s,1H, NH); ¹³C-NMR: δ 11.12, 14.61, 63.77 (aliphatic carbons), 111.17, 115.60, 122.49, 124.67, 144.17, 151.30 (aromatic carbons), 147.12 (triazole C₃), 150.30 (N=CH), 154.73 (triazole C₅); IR: 3529 (OH), 3162 (NH), 1716 (C=O), 1597 (C=N) cm^-1; UV λ_max (ε, L·mol^-1·cm^-1): 320 (18262), 235 (11377), 212 (14098) nm.

3-Ethyl-4-(3-ethoxy-4-hydroxybenzylidenamino)-4,5-dihydro-1H-1,2,4-triazol-5-one (3b). Yield 79%; mp. 174 °C; Calculated for C₁₃H₁₆N₄O₃ (276.30): 54.51% C, 5.84% H, 20.28% N; found: 54.38% C, 5.38% H, 19.70% N; ¹H-NMR: δ 1.16 (t, 3H, CH₃), 1.32 (t, 3H, CH₃), 2.61 (q, 2H, CH₂), 4.02 (q, 2H, OCH₂), 6.86 (d, 1H, Ar-H, J=8.1 Hz), 7.20 (d, 1H, Ar-H, J=8.2 Hz), 7.32 (s, 1H, Ar-H), 9.46 (s, 1H, N=CH), 9.69 (s, 1H, OH), 11.76 (s, 1H, NH); ¹³C-NMR: δ 9.90, 14.61, 18.54, 63.78 (aliphatic carbons), 111.18, 115.63, 122.39, 124.79, 147.96, 151.49 (aromatic carbons), 147.13 (triazole C₃), 150.32 (N=CH), 154.64 (triazole C₅); IR: 3527 (OH), 3222 (NH), 1701 (C=O), 1597 (C=N) cm^-1; UV λ_max (ε, L·mol^-1·cm^-1): 321 (27690), 235 (17345), 213 (22069) nm.

3-Benzyl-4-(3-ethoxy-4-hydroxybenzylidenamino)-4,5-dihydro-1H-1,2,4-triazol-5-one (3c). Yield 91%; mp. 211 °C; Calculated for C₁₈H₁₈N₄O₃ (338.37): 63.89% C, 5.36% H, 16.56% N; found: 63.66% C, 5.74% H, 16.22% N; ¹H-NMR: δ 1.44 (t, 3H, CH₃), 4.09 (s, 2H, CH₂Ph), 4.11 (q, 2H, CH₂), 6.92 (d, 1H, Ar-H, J=8.0 Hz), 7.25 (d, 1H, Ar-H, J=8.1 Hz), 7.36 (s, 5H, Ar-H), 7.38 (s, 1H, Ar-H), 9.53 (s, 1H, N=CH), 9.93 (s, 1H, OH), 12.02 (s, 1H, NH); ¹³C-NMR: δ 14.57, 31.20, 63.63 (aliphatic carbons), 110.30, 115.45, 122.85, 124.70, 126.61, 128.36 (2C), 128.66 (2C), 135.85, 146.05, 151.20 (aromatic carbons), 147.08 (triazole C₃), 150.30 (N=CH), 153.90 (triazole C₅); IR: 3165 (OH), 3055 (NH), 1712 (C=O), 1584 (C=N), 755, 699 (monosubstituted benzenoid ring) cm^-1; UV λ_max (ε, L·mol^-1·cm^-1): 265 (16250), 221 (29650) nm.

3-(4-Chlorobenzyl)-4-(3-ethoxy-4-hydroxybenzylidenamino)-4,5-dihydro-1H-1,2,4-triazol-5-one (3d). Yield 71%; mp. 232 °C; Calculated for C₁₈H₁₇N₄O₃Cl (373.82): 57.99% C, 4.60% H, 15.03% N; found: 57.29% C, 4.36% H, 14.79% N; ¹H-NMR: δ 1.42 (t, 3H, CH₃), 4.08 (s, 2H, CH₂Ph), 4.09 (q, 2H, CH₂), 6.92 (d, 1H, Ar-H), 7.24 (d, 1H, Ar-H), 7.30-7.55 (m, 5H, Ar-H), 9.52 (s, 1H, N=CH), 9.92 (s, 1H, OH), 12.02 (s, 1H, NH); ¹³C-NMR: δ 14.57, 30.80, 63.63 (aliphatic carbons), 110.31, 115.46, 122.89, 124.59, 128.57 (2C), 130.54 (2C), 131.45, 134.88, 145.80, 151.30 (aromatic carbons), 147.10 (triazole C₃), 150.28 (N=CH), 153.98 (triazole C₅); IR: 3170 (OH), 3110 (NH), 1712 (C=O), 1587 (C=N), 805 (1,4-disubstituted benzenoid ring) cm^-1; UV λ_max (ε, L·mol^‑1·cm^-1): 357 (5794), 321 (18320), 213 (28038) nm.

3-Phenyl-4-(3-ethoxy-4-hydroxybenzylidenamino)-4,5-dihydro-1H-1,2,4-triazol-5-one (3e). Yield 82%; mp. 206 °C (AcOH-water, 1:3); Calculated for C₁₇H₁₆N₄O₃ (324.34): 62.95% C, 4.97% H, 17.27% N; found: 62.43% C, 4.95% H, 16.90% N. ¹H-NMR: δ 1.41 (t, 3H, CH₃), 4.11 (q, 2H, CH₂), 6.97 (d, 1H, Ar-H, J=8.2 Hz), 7.32 (d, 1H, Ar-H, J=8.3 Hz), 7.42 (s, 1H, Ar-H), 7.56-7.60 (m, 3H, Ar-H), 7.95-8.05 (m, 2H, Ar-H), 9.48 (s, 1H, N=CH), 9.89 (s, 1H, OH), 12.42 (s, 1H, NH); ¹³C-NMR: δ 14.54, 63.63 (aliphatic carbons), 111.10, 115.70, 122.80, 124.48, 126.85, 127.76 (2C), 128.39 (2C), 130.00, 144.40, 151.40 (aromatic carbons), 147.09 (triazole C₃), 150.55 (N=CH), 157.30 (triazole C₅); IR: 3373 (OH), 3076 (NH), 1701 (C=O), 1607,1584 (C=N), 758,680 (monosubstituted benzenoid ring) cm^-1; UV λ_max (ε, L·mol^-1·cm^-1) : 325 (17886), 282 (12032), 215 (21952) nm.

General Method for the Preparation of 1-Acetyl-3-alkyl(aryl)-4-(3-ethoxy-4-acetoxybenzylidenamino)-4,5-dihydro-1H-1,2,4-triazol-5-ones 4a-c and e

The corresponding compound 3 (0.01 mol) was refluxed with acetic anhydride (15 mL) for 0.5 h. After addition of absolute ethanol (50 mL), the mixture was refluxed for 1 h. more. Evaporation of the resulting solution at 40-45 °C in vacuo and several recrystallizations of the residue from EtOH gave pure compounds 4a-c and e as colourless crystals.

1-Acetyl-3-methyl-4-(3-ethoxy-4-acetoxybenzylidenamino)-4,5-dihydro-1H-1,2,4-triazol-5-one (4a). Yield 83%; mp. 189 °C; Calculated for C₁₆H₁₈N₄O₅ (346.34): 55.49% C, 5.24% H, 16.18% N; found: 54.98% C, 5.29% H, 16.00% N; ¹H-NMR: δ 1.37 (t, 3H, CH₃), 2.33 (s, 3H, CH₃), 2.40 (s, 3H, NCOCH₃), 2.54 (s, 3H, OCOCH₃), 4.17 (q, 2H, CH₂), 7.29 (d, 1H, Ar-H), 7.54 (d, 1H, Ar-H), 7.64 (s, 1H, Ar-H), 9.60 (s, 1H, N=CH); ¹³C-NMR: δ 11.20, 14.41, 20.30, 23.45, 64.14 (aliphatic carbons), 112.38, 120.39, 123.51, 131.77, 142.38, 146.77 (aromatic carbons), 147.85 (triazole C₃), 150.52 (N=CH), 155.17 (triazole C₅), 166.08 (CO), 168.34 (CO); IR: 1776, 1760 (C=O), 1625, 1580 (C=N) cm^-1; UV λ_max (ε, L·mol^-1·cm^-1): 306 (13788), 257 (32072), 215 (24697) nm.

1-Acetyl-3-ethyl-4-(3-ethoxy-4-acetoxybenzylidenamino)-4,5-dihydro-1H-1,2,4-triazol-5-one (4b). Yield 88%; mp. 162 °C; Calculated for C₁₇H₂₀N₄O₅ (360.37): 56.66% C, 5.59% H, 15.55% N; found: 56.44% C, 5.46% H, 15.20% N; ¹H-NMR: δ 1.33 (t, 3H, CH₃), 1.37 (t, 3H, CH₃), 2.34 (s, 3H, NCOCH₃), 2.55 (s, 3H, OCOCH₃), 2.81 (q, 2H, CH₂), 4.20 (q, 2H, OCH₂), 7.30 (d, 1H, Ar-H), 7.54 (d, 1H, Ar-H), 7.65 (s, 1H, Ar-H), 9.65 (s, 1H, N=CH); ¹³C-NMR: δ 9.35, 14.37, 18.52, 20.27, 23.43, 64.08 (aliphatic carbons), 112.34, 120.76, 123.48, 131.76, 142.34, 150.17 (aromatic carbons), 148.03 (triazole C₃), 150.47 (N=CH), 155.03 (triazole C₅), 165.96 (CO), 168.28 (CO); IR: 1776, 1766 (C=O), 1621, 1579 (C=N) cm^-1; UV λ_max (ε, L·mol^-1·cm^-1): 321 (16396), 215 (32072) nm.

1-Acetyl-3-benzyl-4-(3-ethoxy-4-acetoxybenzylidenamino)-4,5-dihydro-1H-1,2,4-triazol-5-one (4c). Yield 87%; mp. 173 °C; Calculated for C₂₂H₂₂N₄O₅ (422.44): 62.55% C, 5.25% H, 13.26% N; found: 62.20% C, 5.23% H, 12.95% N; ¹H-NMR: δ 1.37 (t, 3H, CH₃), 2.31 (s, 3H, NCOCH₃), 2.54 (s, 3H, OCOCH₃), 4.12 (q, 2H, OCH₂), 4.17 (s, 2H, CH₂Ph), 7.18-7.60 (m, 8H, Ar-H), 9.55 (s, 1H, N=CH); ¹³C-NMR: δ 14.35, 20.26, 23.49, 31.08, 64.03 (aliphatic carbons), 111.40, 121.46, 123.42, 126.91, 128.46 (2C), 128.81 (2C), 131.73, 134.71, 142.35, 148.19 (aromatic carbons), 147.97 (triazole C₃), 150.42 (N=CH), 154.16 (triazole C₅), 165.98 (CO), 168.29 (CO); IR: 1782, 1752 (C=O), 1616, 1578 (C=N), 741, 708 (monosubstituted benzenoid ring) cm^-1; UV λ_max (ε, L·mol^‑1·cm^‑1): 263 (15053), 215 (32368) nm.

1-Acetyl-3-phenyl-4-(3-ethoxy-4-acetoxybenzylidenamino)-4,5-dihydro-1H-1,2,4-triazol-5-one (4e). Yield 99%; mp. 160 °C; Calculated for C₂₁H₂₀N₄O₅ (408.41): 61.76% C, 4.94% H, 13.72% N; found: 61.68% C, 4.64% H, 13.59% N; ¹H-NMR: δ 1.36 (t, 3H, CH₃), 2.34 (s, 3H, NCOCH₃), 2.63 (s, 3H, OCOCH₃), 4.13 (q, 2H, OCH₂), 7.28 (d, 1H, Ar-H), 7.46 (d, 1H, Ar-H), 7.53-7.92 (m, 4H, Ar-H), 7.98 (m, 2H, Ar-H), 9.55 (s, 1H, N=CH); ¹³C-NMR: δ 14.32, 20.26, 23.51, 63.95 (aliphatic carbons), 112.08, 121.15, 123.56, 125.13, 128.56 (2C), 128.61 (2C), 131.28, 131.58, 142.50, 145.90 (aromatic carbons), 148.07 (triazole C₃), 150.46 (N=CH), 157.31 (triazole C₅), 166.18 (CO), 168.28 (CO); IR: 1768, 1743, 1723 (C=O), 1605, 1582 (C=N), 758, 692 (monosubstituted benzenoid ring) cm^-1; UV λ_max (ε, L·mol^-1·cm^-1): 323 (14286), 266 (20714), 215 (30408) nm.

General Method for the Preparation of 1-Methyl-3-alkyl(aryl)-4-(3-ethoxy-4-methoxybenzyliden-amino)-4,5-dihydro-1H-1,2,4-triazol-5-ones 5c,e

The corresponding compound 3 (0.01 mol) was dissolved in 2N NaOH (10 mL) and treated dimethyl sulphate (3.2 mL). After stirring of the mixture at room temperature for 1 hr, the solid formed was filtered, washed with cold water (15 mL) and dried in vacuo. Several recrystallizations of crude product from 1:3 AcOH-water gave pure compounds 5c,e as colourless crystals.

1-Methyl-3-benzyl-4-(3-ethoxy-4-methoxybenzylidenamino)-4,5-dihydro-1H-1,2,4-triazol-5-one (5c). Yield 55%; mp. 198 °C; Calculated for C₂₀H₂₂N₄O₃ (366.42): 65.56% C, 6.05% H, 15.29% N; found: 65.99% C, 5.72% H, 15.26% N; ¹H-NMR: δ 1.42 (t, 3H, CH₃), 3.42 (s, 3H, NCH₃), 3.87 (s, 3H, OCH₃), 4.11 (m, 4H, OCH₂ + CH₂Ph), 7.05-7.60 (m, 8H, Ar-H), 9.55 (s, 1H, N=CH); ¹³C-NMR: δ 14.81, 31.25, 32.12, 55.74, 63.81 (aliphatic carbons), 109.27, 111.64, 123.26, 125.99, 126.94, 128.65 (2C), 128.95 (2C), 135.90, 144.82, 152.05 (aromatic carbons), 148.40 (triazole C₃), 149.72 (N=CH), 153.88 (triazole C₅); IR: 1709 (C=O), 1624, 1577 (C=N), 756, 712 (monosubstituted benzenoid ring) cm^-1; UV λ_max (ε, L·mol^-1·cm^-1): 323 (12195), 215 (14268) nm.

1-Methyl-3-phenyl-4-(3-ethoxy-4-methoxybenzylidenamino)-4,5-dihydro-1H-1,2,4-triazol-5-one (5e). Yield 64%; mp. 152 °C; Calculated for C₁₉H₂₀N₄O₃ (352.39): 64.76% C, 5.72% H, 15.90% N; found: 64.89% C, 5.94% H, 15.82% N; ¹H-NMR: δ 1.36 (t, 3H, CH₃), 3.50 (s, 3H, NCH₃), 3.85 (s, 3H, OCH₃), 4.13 (q, 2H, OCH₂), 7.10 (d, 1H, Ar-H), 7.34 (d, 1H, Ar-H), 7.36 (s, 1H, Ar-H), 7.55 (m, 3H, Ar-H), 7.90-7.96 (m, 2H, Ar-H), 9.46 (s, 1H, N=CH); ¹³C-NMR: δ 14.51, 32.24, 55.47, 63.43 (aliphatic carbons), 109.59, 111.43, 122.77, 125.56, 126.14, 127.79 (2C), 128.36 (2C), 130.08, 142.66, 151.93 (aromatic carbons), 148.12 (triazole C₃), 149.58 (N=CH), 156.49 (triazole C₅); IR: 1702 (C=O), 1602, 1577 (C=N), 761, 691 (monosubstituted benzenoid ring) cm^-1; UV λ_max (ε, L·mol^‑1·cm^‑1): 322 (10286), 280 (10529), 215 (14912) nm.