# Microwave Assisted Synthesis, Antifungal Activity, and DFT Study of Some Novel Triazolinone Derivatives

Authors: Na-Bo Sun; Jian-Zhong Jin; Fang-Yue He
Journal: BioMed Research International
 (2015)

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## Abstract

A series of some novel 1,2,4-triazol-5(4H)-one derivatives were designed and synthesized under microwave irradiation via multistep reaction. The structures of 1,2,4-triazoles were confirmed by 1H NMR, MS, FTIR, and elemental analysis. The antifungal activities of 1,2,4-triazoles were determined. The antifungal activity results indicated that the compounds 5c, 5f, and 5h exhibited good activity against Pythium ultimum, and the compounds 5b and 5c displayed good activity against Corynespora cassiicola. Theoretical calculation of the compound 5c was carried out with B3LYP/6-31G (d). The full geometry optimization was carried out using 6-31G(d) basis set, and the frontier orbital energy and electrostatic potential were discussed, and the structure-activity relationship was also studied.


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## Body

## 1. Introduction

Nowadays, nitrogen-containing heterocycles became a research hot spot because they displayed excellent activities [1–9]. 1,2,4-Triazole derivatives, especially triazolinone compounds, exhibited diverse activities, such as the commercial antidepressant medicine Trazodone, herbicide azafenidin, and herbicides amicarbazone, sulfentrazone, and carfentrazone-ethyl. So the synthesis of substituted triazolinone compounds is one of the important fields for many researchers. Many references reported that triazolinone derivatives showed other interesting activities, including angiotensin II AT(1) receptor antagonists [10–12], anti-human immunodeficiency virus (HIV) activity [13, 14], acetolactate synthase (ALS) inhibitors [15, 16], protoporphyrinogen oxidase inhibitors [17], antioxidant activities [18–20], anticancer activity [21, 22], and anti-inflammatory activity [23].Microwave-assisted technique is a green method in current organic synthesis [24–28]. It is attractive, offering reduced pollution, low cost, and high yields. The green technique can often shorten the reaction time.In our previous work [29–33], some 1,2,4-triazole compounds were designed and synthesized. They showed good antifungal activities. In this paper, fifteen novel 1,2,4-triazole derivatives were designed and synthesized under microwave irradiation. Their chemical structures were confirmed by 1H NMR, FTIR, MS, and elemental analysis. The antifungal activity of 1,2,4-triazoles was determinedin vivo.


## 2. Results and Discussion

### 2.1. Synthesis

The synthetic route of target compounds was outlined in Scheme1. All the reported syntheses of O-methyl carbonisothiocyanatidate involve reaction of a thiocyanate salt (e.g., Pb2+, NH4+, K+, and Na+) with methyl carbonochloridate. If we use equal molar amounts of potassium thiocyanate and methyl carbonochloridate, approximately equal amounts of both isomers will be obtained. When the methyl carbonochloridate was reacted with potassium thiocyanate, the potassium thiocyanate was excess, while the drop speed must be slow, as fast speed decreased the yield of product. The intermediate2 was easily prepared by the reaction of methoxycarbonyl isothiocyanate and methanol. In the synthesis process of intermediate3, the intermediate2 cyclized with hydrazine hydrate. Because it is an equilibrium reaction it is reacted under nitrogen atmosphere in order to off hydrogen sulfide gas and increase the yield of intermediate3. The intermediate3 exhibits two NH groups, which may be both methylated with (CH3)2SO4. We found that the pH values of two NH groups are different. Therefore, pH value is controlled preferably about 8 to 9 which is given the intermediate4. The target compounds5a~5o were synthesized using microwave irradiation method. The signal of NCH2 proton appeared around δ 3.66–5.04 ppm. The infrared spectrum of the title compounds5a~5o showed absorption bands around 2930 cm−1 for CH2 stretching. The characteristic stretching vibration ν (C=O) appears at 1720 cm−1. The mass spectrum results showed that molecular ion is in accordance with its molecular formula. The elemental analysis results are in accordance with the calculated results.Scheme 1
The synthetic route of title compounds.


### 2.2. Antifungal Activity

Thein vivo antifungal activity results of 1,2,4-triazol-5(4H)-ones againstPhytophthora infestans, Botrytis cinerea, Corynespora cassiicola, Rhizoctonia solani, andPythium ultimum were shown in Table 1; dimethomorph, fludioxonil, chlorothalonil, validamycin, and zhongshengmycin were used as controls. From Table 1, it is shown that compounds5c,5f, and5h exhibited good control efficacy againstPythium ultimum at 500 ppm. Compounds5a,5g,5i,5m, and5n showed moderate control efficacy againstPythium ultimum. The control zhongshengmycin had no control efficacy againstPythium ultimum. For theRhizoctonia solani, most of the title compounds displayed no control efficacy, except compounds5f and5h. Surprisingly, all the compounds can not only inhibit theBotrytis cinerea, but also promote theBotrytis cinerea growth. Most of 1,2,4-triazol-5(4H)-ones displayed weak control efficacy againstCorynespora cassiicola; only compounds5b and5c showed good antifungal activity (about 70%) againstCorynespora cassiicola, which is higher than that of control chlorothalonil. Unfortunately, the title compounds exhibited weak activity againstPhytophthora infestans.Table 1
The antifungal activity of title compoundsin vivo at 500 ppm (%).
Number
Phytophthora infestans
Botrytis cinerea
Corynespora cassiicola
Rhizoctonia solani
Pythium ultimum
5a
25.66
−37.95
19.81
0
44.44
5b
−0.8
−61.1
68.6
3.33
−11.11
5c
−0.8
−61.1
73.93
0
77.78
5d
−0.8
−49.52
26.26
0
11.11
5e
−0.8
−38.91
13.08
0
−88.89
5f
−0.8
−51.45
18.13
33.89
88.89
5g
−0.8
−56.28
9.72
2.22
33.33
5h
−0.8
−52.42
6.36
29.44
66.67
5i
−0.8
−38.91
37.76
0
44.44
5j
−0.8
−48.56
39.44
0
−11.11
5k
−0.8
−33.12
34.95
0
−22.22
5l
29.16
−27.34
37.76
0
−22.22
5m
−0.8
−7.08
24.86
0
33.33
5n
−0.8
−42.77
0.19
11.11
33.33
5o
−0.8
−20.58
4.11
0
11.11
Dimethomorph
97.76
Fludioxonil
86.98
Chlorothalonil
45.89
Validamycin
62.50
Zhongshengmycin
0


### 2.3. DFT Calculation

Molecular total energy and frontier orbital energy levels are listed in Table2. Energy gap between HOMO and LUMO was calculated by B3LYP.Table 2
Total energy and frontier orbital energy.
DFT
E
total/Hartreeb
−1660.90340104
E
HOMO/Hartree
−0.21696
E
LUMO/Hartree
−0.02347
Δ
E
a/Hartree
0.19349
a
Δ
E = ELUMO-EHOMO.
b1 Hartree = 4.35974417 × 10−18 J = 27.2113845 ev.According to the frontier molecular orbital theory, HOMO and LUMO are the most important factors that affect the bioactivity. HOMO has the priority to provide electrons, while LUMO can accept electrons firstly [34–36]. Thus, study on the frontier orbital energy can provide useful information about the biological mechanism. From Figure 1, the HOMO of compound5c is mainly located on the OCH3 group and 1,2,4-triazol-5(4H)-one ring, while the LUMO of compound5c is located on the OCH3 group, 2,4-Cl2 benzene ring, and 1,2,4-triazol-5(4H)-one ring. The fact that the compound5c has strong affinity suggests the importance of the frontier molecular orbital in the π-π stacking or hydrophobic interactions. From Figure 1, the electron transfer process of the HOMO and LUMO implies that 2,4-Cl2 phenyl ring had important impact on the antifungal activity.Figure 1
Frontier molecular orbitals of compound5c: (a) LUMO of compound5c; (b) HOMO of compound5c.
(a)
(b)The electrostatic potential of compound5c was also calculated. From Figure 2, it is clear that the oxygen atom at the 1,2,4-triazole ring possessed the greatest negative charges and it is therefore possible that the oxygen atom had some interaction with the receptor or acceptor.Figure 2
The ESP of compound5c.Furthermore, the combination of MO provided meaningful clues as to the structural features of these new family fungicides that will be helpful in the design of more potent compounds in the future.


## 2.1. Synthesis

The synthetic route of target compounds was outlined in Scheme1. All the reported syntheses of O-methyl carbonisothiocyanatidate involve reaction of a thiocyanate salt (e.g., Pb2+, NH4+, K+, and Na+) with methyl carbonochloridate. If we use equal molar amounts of potassium thiocyanate and methyl carbonochloridate, approximately equal amounts of both isomers will be obtained. When the methyl carbonochloridate was reacted with potassium thiocyanate, the potassium thiocyanate was excess, while the drop speed must be slow, as fast speed decreased the yield of product. The intermediate2 was easily prepared by the reaction of methoxycarbonyl isothiocyanate and methanol. In the synthesis process of intermediate3, the intermediate2 cyclized with hydrazine hydrate. Because it is an equilibrium reaction it is reacted under nitrogen atmosphere in order to off hydrogen sulfide gas and increase the yield of intermediate3. The intermediate3 exhibits two NH groups, which may be both methylated with (CH3)2SO4. We found that the pH values of two NH groups are different. Therefore, pH value is controlled preferably about 8 to 9 which is given the intermediate4. The target compounds5a~5o were synthesized using microwave irradiation method. The signal of NCH2 proton appeared around δ 3.66–5.04 ppm. The infrared spectrum of the title compounds5a~5o showed absorption bands around 2930 cm−1 for CH2 stretching. The characteristic stretching vibration ν (C=O) appears at 1720 cm−1. The mass spectrum results showed that molecular ion is in accordance with its molecular formula. The elemental analysis results are in accordance with the calculated results.Scheme 1
The synthetic route of title compounds.


## 2.2. Antifungal Activity

Thein vivo antifungal activity results of 1,2,4-triazol-5(4H)-ones againstPhytophthora infestans, Botrytis cinerea, Corynespora cassiicola, Rhizoctonia solani, andPythium ultimum were shown in Table 1; dimethomorph, fludioxonil, chlorothalonil, validamycin, and zhongshengmycin were used as controls. From Table 1, it is shown that compounds5c,5f, and5h exhibited good control efficacy againstPythium ultimum at 500 ppm. Compounds5a,5g,5i,5m, and5n showed moderate control efficacy againstPythium ultimum. The control zhongshengmycin had no control efficacy againstPythium ultimum. For theRhizoctonia solani, most of the title compounds displayed no control efficacy, except compounds5f and5h. Surprisingly, all the compounds can not only inhibit theBotrytis cinerea, but also promote theBotrytis cinerea growth. Most of 1,2,4-triazol-5(4H)-ones displayed weak control efficacy againstCorynespora cassiicola; only compounds5b and5c showed good antifungal activity (about 70%) againstCorynespora cassiicola, which is higher than that of control chlorothalonil. Unfortunately, the title compounds exhibited weak activity againstPhytophthora infestans.Table 1
The antifungal activity of title compoundsin vivo at 500 ppm (%).
Number
Phytophthora infestans
Botrytis cinerea
Corynespora cassiicola
Rhizoctonia solani
Pythium ultimum
5a
25.66
−37.95
19.81
0
44.44
5b
−0.8
−61.1
68.6
3.33
−11.11
5c
−0.8
−61.1
73.93
0
77.78
5d
−0.8
−49.52
26.26
0
11.11
5e
−0.8
−38.91
13.08
0
−88.89
5f
−0.8
−51.45
18.13
33.89
88.89
5g
−0.8
−56.28
9.72
2.22
33.33
5h
−0.8
−52.42
6.36
29.44
66.67
5i
−0.8
−38.91
37.76
0
44.44
5j
−0.8
−48.56
39.44
0
−11.11
5k
−0.8
−33.12
34.95
0
−22.22
5l
29.16
−27.34
37.76
0
−22.22
5m
−0.8
−7.08
24.86
0
33.33
5n
−0.8
−42.77
0.19
11.11
33.33
5o
−0.8
−20.58
4.11
0
11.11
Dimethomorph
97.76
Fludioxonil
86.98
Chlorothalonil
45.89
Validamycin
62.50
Zhongshengmycin
0


## 2.3. DFT Calculation

Molecular total energy and frontier orbital energy levels are listed in Table2. Energy gap between HOMO and LUMO was calculated by B3LYP.Table 2
Total energy and frontier orbital energy.
DFT
E
total/Hartreeb
−1660.90340104
E
HOMO/Hartree
−0.21696
E
LUMO/Hartree
−0.02347
Δ
E
a/Hartree
0.19349
a
Δ
E = ELUMO-EHOMO.
b1 Hartree = 4.35974417 × 10−18 J = 27.2113845 ev.According to the frontier molecular orbital theory, HOMO and LUMO are the most important factors that affect the bioactivity. HOMO has the priority to provide electrons, while LUMO can accept electrons firstly [34–36]. Thus, study on the frontier orbital energy can provide useful information about the biological mechanism. From Figure 1, the HOMO of compound5c is mainly located on the OCH3 group and 1,2,4-triazol-5(4H)-one ring, while the LUMO of compound5c is located on the OCH3 group, 2,4-Cl2 benzene ring, and 1,2,4-triazol-5(4H)-one ring. The fact that the compound5c has strong affinity suggests the importance of the frontier molecular orbital in the π-π stacking or hydrophobic interactions. From Figure 1, the electron transfer process of the HOMO and LUMO implies that 2,4-Cl2 phenyl ring had important impact on the antifungal activity.Figure 1
Frontier molecular orbitals of compound5c: (a) LUMO of compound5c; (b) HOMO of compound5c.
(a)
(b)The electrostatic potential of compound5c was also calculated. From Figure 2, it is clear that the oxygen atom at the 1,2,4-triazole ring possessed the greatest negative charges and it is therefore possible that the oxygen atom had some interaction with the receptor or acceptor.Figure 2
The ESP of compound5c.Furthermore, the combination of MO provided meaningful clues as to the structural features of these new family fungicides that will be helpful in the design of more potent compounds in the future.


## 3. Materials and Methods

### 3.1. Instruments

Melting points were measured using an X-4 melting apparatus and were uncorrected.1H NMR spectra were determined on a Bruker AC-P400 instrument (400 MHz) using TMS as an internal standard and CDCl3 as solvent. Mass spectra were determined on a Thermo Finnigan LCQ Advantage LC/mass detector instrument. Elemental analyses were recorded on a Yanaco MT-3CHN elemental analyzer. Microwave activation was carried out with CEM Discover Focused Microwave (2450 MHz, 300 W). All the reagents are of analytical grade or freshly prepared before use. The course of the reactions was monitored by TLC; analytical TLC was performed on silica gel GF 254.


### 3.2. Synthetic Procedures

The synthetic route is shown in Scheme1.


#### 3.2.1. Synthesis of Intermediates1 and2

The potassium thiocyanate (10.69 g, 0.11 mol) and pyridine (0.40 g) were dissolved in methyl isobutyl ketone (50 mL); methyl chloroformate (9.45 g, 0.10 mol) was added dropwise at 55°C, and the mixture was stirred for 4 h. Then MeOH (20 mL) was added to the mixture and stirred for 16 h. The mixture was washed with concentrated hydrochloric acid (3 mL) and H2O (50 mL). After filtration and evaporation of the solvent, the crude intermediate2 was collected without further purification: white solid, yield 80%, 1H NMR (400 MHz, CDCl3) δ: 3.77 (s, 3H, COOCH3), 4.12 (s, 3H, CSOCH3), 8.56 (s, 1H, NH).


#### 3.2.2. Synthesis of Intermediate3

To a solution of intermediate2 (50 mmol) in MeOH (75 mL) were added 80% NH2NH2·H2O (4.07 g, 65 mmol) and KOH (45%, 0.81 g, 6.5 mmol) at 0°C; then the mixture was stirred at 30°C for 5 h. After evaporation of the solvent, the crude intermediate3 was recrystallized by EtOH to give white crystal3: yield 78%, m.p. 172~173°C, 1H NMR (400 MHz, DMSO-d6) δ: 4.02 (s, 3H, triazolone-OCH3), 10.51 (s, 1H, NH).


#### 3.2.3. Synthesis of Intermediate4

To a solution of 3 (65 mmol) and K2CO3 (9.52 g) in CH3CN (100 mL) was added (CH3)2SO4 (68 mmol) at 55°C, and the mixture was stirred for another 2 h. The organic phase was extracted with CH2Cl2 (3 × 10 mL). After drying over sodium sulphate and evaporation of the solvent, the crude was collected without being purified to give the corresponding intermediate4.


#### 3.2.4. General Procedure for Thioether5

DMF (5 mL),4 (0.25 g, 1.00 mmol), RCH2Cl (1.10 mmol), and NaOH (0.05 g, 1.20 mmol) were charged into a CEM designed 10 mL pressure-rated vial. Then it was irradiated in a CEM Discover Focused Synthesizer (150 w, 90°C, 200 psi, 15 minutes). The mixture was cooled below 50°C. The mixture was poured into crushed ice and the title compound 1,2,4-triazole was collected after being recrystallized.1-(3,4-Dichlorobenzyl)-3-methoxy-4-methyl-1H-1,2,4-triazol-5(4H)-one (
5a
). m.p. 136–140°C, Yield 88%, 1H NMR (400 M, CDCl3): 3.16 (s, 3H, N-CH3), 3.96 (s, 3H, OCH3), 4.83 (s, 2H, NCH2), 7.18–7.21 (m, 1H, Ph), 7.40–7.45 (m, 2H, Ph); IR/cm−1: 3449.33, 2957.94, 1710.43, 1615.33, 1518.36, 1470.76, 1425.27, 1403.40, 1307.42, 1233.37 1135.45, 1009.21, 914.98, 812.11, 743.63, 662.08, 595.11; ESI-MS: 289 [M+H]+. Elemental anal. (%), calculated: C, 45.85; H, 3.85; N, 14.58; found: C, 45.98; H, 3.77; N, 14.43.1-(4-Bromobenzyl)-3-methoxy-4-methyl-1H-1,2,4-triazol-5(4H)-one (
5b
). m.p. 138–140°C, Yield 84%, 1H NMR (400 M, CDCl3): 3.15 (s, 3H, N-CH3), 3.95 (s, 3H, OCH3), 4.84 (s, 2H, NCH2), 7.24 (d,J = 6.4 Hz, 2H, Ph), 7.47 (d,J = 6.4 Hz, 2H, Ph); IR/cm−1: 3450.50, 2942.58, 1711.13, 1607.26, 145.83, 1424.33, 1382.18, 1301.13, 1067.47, 1008.00, 910.76, 847.46, 798.29, 727.42, 600.46; ESI-MS: 299 [M+H]+. Elemental anal. (%), calculated: C, 44.31; H, 4.06; N, 14.09; found: C, 44.25; H, 3.92; N, 14.21.1-(2,4-Dichlorobenzyl)-3-methoxy-4-methyl-1H-1,2,4-triazol-5(4H)-one (
5c
). m.p. 113–115°C, Yield 89%, 1H NMR (400 M, CDCl3): 3.17 (s, 3H, N-CH3), 3.97 (s, 3H, OCH3), 4.99 (s, 2H, NCH2), 7.24 (d,J = 8.4 Hz, 1H, Ph), 7.22 (d,J = 8.4 Hz, 1H, Ph), 7.41 (s, 1H, Ph); IR/cm−1: 3440.43, 2943.89, 1710.82, 1606.45, 1522.24, 1490.26, 1455.07, 1424.03, 1382.14, 1318.96, 1229.32, 1091.39, 1006.22, 849.44, 803.25, 599.99; ESI-MS: 289 [M+H]+. Elemental anal. (%), calculated: C, 45.85; H, 3.85; N, 14.58; found: C, 45.67; H, 3.77; N, 14.64.1-(4-Chlorobenzyl)-3-methoxy-4-methyl-1H-1,2,4-triazol-5(4H)-one (
5d
). m.p. 125–127°C, Yield 82%, 1H NMR (400 M, CDCl3): 3.15 (s, 3H, N-CH3), 3.95 (s, 3H, OCH3), 4.80 (s, 2H, NCH2), 7.28–7.31 (m, 4H, Ph); IR/cm−1: 3430.91, 2954.61, 1723.39, 1611.41, 1517.41, 1470.16, 1414.48, 1352.86, 1302.39, 1230.3, 1050.80, 1010.51, 912.22, 878.42, 829.12, 788.23, 741.01, 691.10, 592.31, 468.63; ESI-MS: 254 [M+H]+. Elemental anal. (%), calculated: C, 52.08; H, 4.77; N, 16.56; found: C, 51.89; H, 4.87; N, 16.65.4-((3-Methoxy-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)benzonitrile (
5e
). m.p. 160–162°C, Yield 89%, 1H NMR (400 M, CDCl3): 3.15 (s, 3H, N-CH3), 3.96 (s, 3H, OCH3), 4.94 (s, 2H, NCH2), 7.44 (d,J = 8.16 Hz, 2H, Ph), 7.64 (d,J = 8.16 Hz, 2H, Ph); IR/cm−1: 3434.79, 2955.79, 2229.46, 1715.92, 1613.56, 1523.56, 1421.90, 1230.01, 1016.35, 857.47, 735.86, 640.39, 596.36, 552.70; ESI-MS: 245 [M+H]+. Elemental anal. (%), calculated: C, 59.01; H, 4.95; N, 22.94; found: C, 58.88; H, 5.12; N, 23.13.(E)-Methyl 2-(2-((3-Methoxy-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)phenyl)-2-(methoxyimino)acetate (
5f
). m.p. 103–107°C, Yield 89%,1H NMR (400 M, CDCl3): 3.15 (s, 3H, N-CH3), 3.96 (s, 3H, OCH3), 4.94 (s, 2H, NCH2), 7.44 (d,J = 8.16 Hz, 2H, Ph), 7.64 (d,J = 8.16 Hz, 2H, Ph); IR/cm−1: 3455.02, 2936.45, 1720.46, 1611.72, 1522.17, 1431.39, 1230.32, 1005.55, 86.57, 741.29, 711.75, 681.57, 598.40, 572.80; ESI-MS: 245 [M+H]+. Elemental anal. (%), calculated: C, 53.89; H, 5.43; N, 16.76; found: C, 53.98; H, 5.13; N, 16.88.3-Methoxy-4-methyl-1-undecyl-1H-1,2,4-triazol-5(4H)-one (
5g
). m.p. 102–105°C, Yield 78%, 1H NMR (400 M, CDCl3): 0.86 (t,J = 6.71 Hz, 3H, CH3), 1.24–1.29 (m, 16H, CH2), 1.66–1.68 (m, 2H, CH2), 3.10 (s, 3H, N-CH3), 3.66 (s,J = 7.21 Hz, 2H, NCH2), 3.95 (s, 3H, OCH3); IR/cm−1: 3446.77, 2941.81, 1708.02, 1622.82, 1258.48, 1131.46, 1101.03, 763.78, 661.94; ESI-MS: 285 [M+H]+. Elemental anal. (%), calculated: C, 63.57; H, 10.31; N, 14.83; found: C, 63.76; H, 10.52; N, 14.97.1-(3-Chlorobenzyl)-3-methoxy-4-methyl-1H-1,2,4-triazol-5(4H)-one (
5h
). m.p. 97–100°C, Yield 90%, 1H NMR (400 M, CDCl3): 3.17 (s, 3H, N-CH3), 3.96 (s, 3H, OCH3), 4.87 (s, 2H, NCH2), 7.27–7.34 (m, 4H, Ph); IR/cm−1: 3441.67, 2960.00, 1716.14, 1621.83, 1520.80, 1391.88, 1267.10, 1228.92, 014.96, 789.51, 740.97, 593.84; ESI-MS: 254 [M+H]+. Elemental anal. (%), calculated: C, 52.08; H, 4.77; N, 16.56; found: C, 52.21; H, 4.87; N, 16.77.1-(2-Chlorobenzyl)-3-methoxy-4-methyl-1H-1,2,4-triazol-5(4H)-one (
5i
). m.p. 120–122°C, Yield 87%, 1H NMR (400 M, CDCl3): 3.19 (s, 3H, N-CH3), 3.97 (s, 3H, OCH3), 5.04 (s, 2H, NCH2), 7.19–7.25 (m, 2H, Ph), 7.37–7.39 (m, 2H, Ph); IR/cm−1: 3439.30, 2947.24, 1718.79, 1614.24, 1523.69, 745.45, 595.23; ESI-MS: 254 [M+H]+. Elemental anal. (%), calculated: C, 52.08; H, 4.77; N, 16.56; found: C, 52.22; H, 4.88; N,6.67.3-((3-Methoxy-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)benzonitrile (
5j
). m.p. 130°C, Yield 89%, 1H NMR (400 M, CDCl3): 3.17 (s, 3H, N-CH3), 3.97 (s, 3H, OCH3), 4.91 (s, 2H, NCH2), 7.46–7.48 (m, 1H, Ph), 7.58–7.62 (m, 3H, Ph); IR/cm−1: 3446.70, 2946.55, 2231.74, 1706.17, 1522.05, 1383.55, 1229.24, 1007.72, 786.75, 743.50, 702.92; ESI-MS: 245 [M+H]+. Elemental anal. (%), calculated: C, 59.01; H, 4.95; N, 22.94; found: C, 58.88; H, 4.89; N, 22.78.3-Methoxy-1-(4-methoxybenzyl)-4-methyl-1H-1,2,4-triazol-5(4H)-one (
5k
). m.p. 88–90°C, Yield 93%, 1H NMR (400 M, CDCl3): 3.14 (s, 3H, N-CH3), 3.81 (s, 3H, OCH3), 3.95 (s, 3H, OCH3), 4.82 (s, 2H, NCH2), 6.87 (d,J = 8.14 Hz, 2H, Ph), 7.31 (d,J = 8.14 Hz, 2H, Ph); IR/cm−1: 3444.95, 2924.39, 1721.08, 1612.50, 1523.71, 1434.36, 1230.54, 742.97, 598.46; ESI-MS: 250 [M+H]+. Elemental anal. (%), calculated: C, 57.82; H, 6.07; N, 16.86; found: C, 58.01; H, 6.21; N, 16.76.1-(3-Fluorobenzyl)-3-methoxy-4-methyl-1H-1,2,4-triazol-5(4H)-one (
5l
). m.p. 102-103°C, Yield 87%, 1H NMR (400 M, CDCl3): 3.14 (s, 3H, N-CH3), 3.94 (s, 3H, OCH3), 4.86 (s, 2H, NCH2), 6.96–7.30 (m, 4H, Ph); IR/cm−1: 3448.98, 2936.21, 1720.91, 1612.49, 1517.26, 1244.10, 1018.13, 595.24; ESI-MS: 238 [M+H]+. Elemental anal. (%), calculated: C, 55.69; H, 5.10; N, 17.71; found: C, 55.79; H, 5.12; N, 17.77.1-(4-Fluorobenzyl)-3-methoxy-4-methyl-1H-1,2,4-triazol-5(4H)-one (
5m
). m.p. 102-103°C, Yield 91%, 1H NMR (400 M, CDCl3): 3.15 (s, 3H, N-CH3), 3.95 (s, 3H, OCH3), 4.97 (s, 2H, NCH2), 7.05–7.12 (m, 2H, Ph), 7.27–7.29 (m, 2H, Ph); IR/cm−1: 3427.88, 2956.26, 1709.34, 1611.3, 1519.26, 1453.60, 1399.75, 1235.67, 1134.51, 1012.75, 783.65, 745.36, 700.77; ESI-MS: 238 [M+H]+. Elemental anal. (%), calculated: C, 55.69; H, 5.10; N, 17.71; found: C, 55.76; H, 5.22; N, 17.89.1-((5-Chloropyridin-2-yl)methyl)-3-methoxy-4-methyl-1H-1,2,4-triazol-5(4H)-one (
5n
). m.p. 111–113°C, Yield 88%, 1H NMR (400 M, CDCl3): 3.15 (s, 3H, N-CH3), 3.95 (s, 3H, OCH3), 4.48 (s, 2H, NCH2), 7.30–7.33 (m, 1H, Py), 7.68(d,J = 8.0 Hz, 1H, Py), 8.42 (s, 1H, Py); IR/cm−1: 3436.68, 2955.93, 1711.34, 1611.26, 1519.05, 1399.59, 1235.83, 1134.81, 1012.73, 783.64, 701.50; ESI-MS: 256 [M+H]+. Elemental anal. (%), calculated: C, 47.16; H, 4.35; N, 22.00; found: C, 47.32; H, 4.44; N, 22.12.1-(2-Fluorobenzyl)-3-methoxy-4-methyl-1H-1,2,4-triazol-5(4H)-one (
5o
). m.p. 103-104°C, Yield 91%, 1H NMR (400 M, CDCl3): 3.19 (s, 3H, N-CH3), 3.97 (s, 3H, OCH3), 5.04 (s, 2H, NCH2), 7.19–7.22 (m, 1H, Ph), 7.24–7.28 (m, 2H, Ph), 7.37–7.39 (m, 1H, Ph); IR/cm−1: 3436.50, 2934.06, 1716.72, 1613.09, 1521.04, 1416.95, 1299.19, 1230.77, 1106.39, 1004.22, 826.93, 595.53; ESI-MS: 238 [M+H]+. Elemental anal. (%), calculated: C, 55.69; H, 5.10; N, 17.71; found: C, 55.47; H, 5.12; N, 17.88.


### 3.3. Antifungal Activities

The biological activities of title compounds againstPhytophthora infestans, Botrytis cinerea, Corynespora cassiicola, Rhizoctonia solani, andPythium ultimum were evaluated according to [37–40], and a potted plant test method was adopted.Germination was conducted by soaking cucumber seeds in water for 2 h at 50°C and then keeping the seeds moist for 24 h at 28°C in an incubator. When the radicles were 0.5 cm, the seeds were grown in plastic pots containing a 1 : 1 (v/v) mixture of vermiculite and peat. Cucumber and tomato plants used for inoculations were at the stage of two seed leaves. Tested compounds and commercial fungicides were sprayed with a hand spray on the surface of the seed leaves on a fine morning at the standard concentration of 500μg/mL; dimethomorph, fludioxonil, chlorothalonil, validamycin, and zhongshengmycin were used as control. After 2 h, inoculation ofPhytophthora infestans was carried out by spraying fungal suspension, inoculation ofRhizoctonia solani andCorynespora cassiicola was carried out by spraying mycelial suspension, and inoculation ofBotrytis cinerea was carried out by radicle soaking.Pythium ultimum was found in the cucumber in nature. The experiment was repeated 4 times. After inoculation, the plants were maintained at 18–30°C (mean temperature of 24°C and above 80% relative humidity (RH)). The fungicidal activity was evaluated when the nontreated cucumber plant (blank) fully developed symptoms. The area of inoculated treated leaves covered by disease symptoms was assessed and compared to that of nontreated ones to determine the average disease index. The relative control efficacy of compounds compared to the blank assay was calculated via the following equation:(1)relativecontrolefficacy(%)=CK-PTCK×100%,where CK is the average disease index during the blank assay and PT is the average disease index after treatment during testing.


### 3.4. DFT Calculation

DFT-B3LYP/6-31G (d) methods in Gaussian 03 package [41] were used to optimize the structure of5c. Vibration analysis showed that the optimized structures were in accordance with the minimum points on the potential energy surfaces. All the convergent precisions were the system default values, and all the calculations were carried out on the DELL personal computer.


## 3.1. Instruments

Melting points were measured using an X-4 melting apparatus and were uncorrected.1H NMR spectra were determined on a Bruker AC-P400 instrument (400 MHz) using TMS as an internal standard and CDCl3 as solvent. Mass spectra were determined on a Thermo Finnigan LCQ Advantage LC/mass detector instrument. Elemental analyses were recorded on a Yanaco MT-3CHN elemental analyzer. Microwave activation was carried out with CEM Discover Focused Microwave (2450 MHz, 300 W). All the reagents are of analytical grade or freshly prepared before use. The course of the reactions was monitored by TLC; analytical TLC was performed on silica gel GF 254.


## 3.2. Synthetic Procedures

The synthetic route is shown in Scheme1.


### 3.2.1. Synthesis of Intermediates1 and2

The potassium thiocyanate (10.69 g, 0.11 mol) and pyridine (0.40 g) were dissolved in methyl isobutyl ketone (50 mL); methyl chloroformate (9.45 g, 0.10 mol) was added dropwise at 55°C, and the mixture was stirred for 4 h. Then MeOH (20 mL) was added to the mixture and stirred for 16 h. The mixture was washed with concentrated hydrochloric acid (3 mL) and H2O (50 mL). After filtration and evaporation of the solvent, the crude intermediate2 was collected without further purification: white solid, yield 80%, 1H NMR (400 MHz, CDCl3) δ: 3.77 (s, 3H, COOCH3), 4.12 (s, 3H, CSOCH3), 8.56 (s, 1H, NH).


### 3.2.2. Synthesis of Intermediate3

To a solution of intermediate2 (50 mmol) in MeOH (75 mL) were added 80% NH2NH2·H2O (4.07 g, 65 mmol) and KOH (45%, 0.81 g, 6.5 mmol) at 0°C; then the mixture was stirred at 30°C for 5 h. After evaporation of the solvent, the crude intermediate3 was recrystallized by EtOH to give white crystal3: yield 78%, m.p. 172~173°C, 1H NMR (400 MHz, DMSO-d6) δ: 4.02 (s, 3H, triazolone-OCH3), 10.51 (s, 1H, NH).


### 3.2.3. Synthesis of Intermediate4

To a solution of 3 (65 mmol) and K2CO3 (9.52 g) in CH3CN (100 mL) was added (CH3)2SO4 (68 mmol) at 55°C, and the mixture was stirred for another 2 h. The organic phase was extracted with CH2Cl2 (3 × 10 mL). After drying over sodium sulphate and evaporation of the solvent, the crude was collected without being purified to give the corresponding intermediate4.


### 3.2.4. General Procedure for Thioether5

DMF (5 mL),4 (0.25 g, 1.00 mmol), RCH2Cl (1.10 mmol), and NaOH (0.05 g, 1.20 mmol) were charged into a CEM designed 10 mL pressure-rated vial. Then it was irradiated in a CEM Discover Focused Synthesizer (150 w, 90°C, 200 psi, 15 minutes). The mixture was cooled below 50°C. The mixture was poured into crushed ice and the title compound 1,2,4-triazole was collected after being recrystallized.1-(3,4-Dichlorobenzyl)-3-methoxy-4-methyl-1H-1,2,4-triazol-5(4H)-one (
5a
). m.p. 136–140°C, Yield 88%, 1H NMR (400 M, CDCl3): 3.16 (s, 3H, N-CH3), 3.96 (s, 3H, OCH3), 4.83 (s, 2H, NCH2), 7.18–7.21 (m, 1H, Ph), 7.40–7.45 (m, 2H, Ph); IR/cm−1: 3449.33, 2957.94, 1710.43, 1615.33, 1518.36, 1470.76, 1425.27, 1403.40, 1307.42, 1233.37 1135.45, 1009.21, 914.98, 812.11, 743.63, 662.08, 595.11; ESI-MS: 289 [M+H]+. Elemental anal. (%), calculated: C, 45.85; H, 3.85; N, 14.58; found: C, 45.98; H, 3.77; N, 14.43.1-(4-Bromobenzyl)-3-methoxy-4-methyl-1H-1,2,4-triazol-5(4H)-one (
5b
). m.p. 138–140°C, Yield 84%, 1H NMR (400 M, CDCl3): 3.15 (s, 3H, N-CH3), 3.95 (s, 3H, OCH3), 4.84 (s, 2H, NCH2), 7.24 (d,J = 6.4 Hz, 2H, Ph), 7.47 (d,J = 6.4 Hz, 2H, Ph); IR/cm−1: 3450.50, 2942.58, 1711.13, 1607.26, 145.83, 1424.33, 1382.18, 1301.13, 1067.47, 1008.00, 910.76, 847.46, 798.29, 727.42, 600.46; ESI-MS: 299 [M+H]+. Elemental anal. (%), calculated: C, 44.31; H, 4.06; N, 14.09; found: C, 44.25; H, 3.92; N, 14.21.1-(2,4-Dichlorobenzyl)-3-methoxy-4-methyl-1H-1,2,4-triazol-5(4H)-one (
5c
). m.p. 113–115°C, Yield 89%, 1H NMR (400 M, CDCl3): 3.17 (s, 3H, N-CH3), 3.97 (s, 3H, OCH3), 4.99 (s, 2H, NCH2), 7.24 (d,J = 8.4 Hz, 1H, Ph), 7.22 (d,J = 8.4 Hz, 1H, Ph), 7.41 (s, 1H, Ph); IR/cm−1: 3440.43, 2943.89, 1710.82, 1606.45, 1522.24, 1490.26, 1455.07, 1424.03, 1382.14, 1318.96, 1229.32, 1091.39, 1006.22, 849.44, 803.25, 599.99; ESI-MS: 289 [M+H]+. Elemental anal. (%), calculated: C, 45.85; H, 3.85; N, 14.58; found: C, 45.67; H, 3.77; N, 14.64.1-(4-Chlorobenzyl)-3-methoxy-4-methyl-1H-1,2,4-triazol-5(4H)-one (
5d
). m.p. 125–127°C, Yield 82%, 1H NMR (400 M, CDCl3): 3.15 (s, 3H, N-CH3), 3.95 (s, 3H, OCH3), 4.80 (s, 2H, NCH2), 7.28–7.31 (m, 4H, Ph); IR/cm−1: 3430.91, 2954.61, 1723.39, 1611.41, 1517.41, 1470.16, 1414.48, 1352.86, 1302.39, 1230.3, 1050.80, 1010.51, 912.22, 878.42, 829.12, 788.23, 741.01, 691.10, 592.31, 468.63; ESI-MS: 254 [M+H]+. Elemental anal. (%), calculated: C, 52.08; H, 4.77; N, 16.56; found: C, 51.89; H, 4.87; N, 16.65.4-((3-Methoxy-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)benzonitrile (
5e
). m.p. 160–162°C, Yield 89%, 1H NMR (400 M, CDCl3): 3.15 (s, 3H, N-CH3), 3.96 (s, 3H, OCH3), 4.94 (s, 2H, NCH2), 7.44 (d,J = 8.16 Hz, 2H, Ph), 7.64 (d,J = 8.16 Hz, 2H, Ph); IR/cm−1: 3434.79, 2955.79, 2229.46, 1715.92, 1613.56, 1523.56, 1421.90, 1230.01, 1016.35, 857.47, 735.86, 640.39, 596.36, 552.70; ESI-MS: 245 [M+H]+. Elemental anal. (%), calculated: C, 59.01; H, 4.95; N, 22.94; found: C, 58.88; H, 5.12; N, 23.13.(E)-Methyl 2-(2-((3-Methoxy-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)phenyl)-2-(methoxyimino)acetate (
5f
). m.p. 103–107°C, Yield 89%,1H NMR (400 M, CDCl3): 3.15 (s, 3H, N-CH3), 3.96 (s, 3H, OCH3), 4.94 (s, 2H, NCH2), 7.44 (d,J = 8.16 Hz, 2H, Ph), 7.64 (d,J = 8.16 Hz, 2H, Ph); IR/cm−1: 3455.02, 2936.45, 1720.46, 1611.72, 1522.17, 1431.39, 1230.32, 1005.55, 86.57, 741.29, 711.75, 681.57, 598.40, 572.80; ESI-MS: 245 [M+H]+. Elemental anal. (%), calculated: C, 53.89; H, 5.43; N, 16.76; found: C, 53.98; H, 5.13; N, 16.88.3-Methoxy-4-methyl-1-undecyl-1H-1,2,4-triazol-5(4H)-one (
5g
). m.p. 102–105°C, Yield 78%, 1H NMR (400 M, CDCl3): 0.86 (t,J = 6.71 Hz, 3H, CH3), 1.24–1.29 (m, 16H, CH2), 1.66–1.68 (m, 2H, CH2), 3.10 (s, 3H, N-CH3), 3.66 (s,J = 7.21 Hz, 2H, NCH2), 3.95 (s, 3H, OCH3); IR/cm−1: 3446.77, 2941.81, 1708.02, 1622.82, 1258.48, 1131.46, 1101.03, 763.78, 661.94; ESI-MS: 285 [M+H]+. Elemental anal. (%), calculated: C, 63.57; H, 10.31; N, 14.83; found: C, 63.76; H, 10.52; N, 14.97.1-(3-Chlorobenzyl)-3-methoxy-4-methyl-1H-1,2,4-triazol-5(4H)-one (
5h
). m.p. 97–100°C, Yield 90%, 1H NMR (400 M, CDCl3): 3.17 (s, 3H, N-CH3), 3.96 (s, 3H, OCH3), 4.87 (s, 2H, NCH2), 7.27–7.34 (m, 4H, Ph); IR/cm−1: 3441.67, 2960.00, 1716.14, 1621.83, 1520.80, 1391.88, 1267.10, 1228.92, 014.96, 789.51, 740.97, 593.84; ESI-MS: 254 [M+H]+. Elemental anal. (%), calculated: C, 52.08; H, 4.77; N, 16.56; found: C, 52.21; H, 4.87; N, 16.77.1-(2-Chlorobenzyl)-3-methoxy-4-methyl-1H-1,2,4-triazol-5(4H)-one (
5i
). m.p. 120–122°C, Yield 87%, 1H NMR (400 M, CDCl3): 3.19 (s, 3H, N-CH3), 3.97 (s, 3H, OCH3), 5.04 (s, 2H, NCH2), 7.19–7.25 (m, 2H, Ph), 7.37–7.39 (m, 2H, Ph); IR/cm−1: 3439.30, 2947.24, 1718.79, 1614.24, 1523.69, 745.45, 595.23; ESI-MS: 254 [M+H]+. Elemental anal. (%), calculated: C, 52.08; H, 4.77; N, 16.56; found: C, 52.22; H, 4.88; N,6.67.3-((3-Methoxy-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)benzonitrile (
5j
). m.p. 130°C, Yield 89%, 1H NMR (400 M, CDCl3): 3.17 (s, 3H, N-CH3), 3.97 (s, 3H, OCH3), 4.91 (s, 2H, NCH2), 7.46–7.48 (m, 1H, Ph), 7.58–7.62 (m, 3H, Ph); IR/cm−1: 3446.70, 2946.55, 2231.74, 1706.17, 1522.05, 1383.55, 1229.24, 1007.72, 786.75, 743.50, 702.92; ESI-MS: 245 [M+H]+. Elemental anal. (%), calculated: C, 59.01; H, 4.95; N, 22.94; found: C, 58.88; H, 4.89; N, 22.78.3-Methoxy-1-(4-methoxybenzyl)-4-methyl-1H-1,2,4-triazol-5(4H)-one (
5k
). m.p. 88–90°C, Yield 93%, 1H NMR (400 M, CDCl3): 3.14 (s, 3H, N-CH3), 3.81 (s, 3H, OCH3), 3.95 (s, 3H, OCH3), 4.82 (s, 2H, NCH2), 6.87 (d,J = 8.14 Hz, 2H, Ph), 7.31 (d,J = 8.14 Hz, 2H, Ph); IR/cm−1: 3444.95, 2924.39, 1721.08, 1612.50, 1523.71, 1434.36, 1230.54, 742.97, 598.46; ESI-MS: 250 [M+H]+. Elemental anal. (%), calculated: C, 57.82; H, 6.07; N, 16.86; found: C, 58.01; H, 6.21; N, 16.76.1-(3-Fluorobenzyl)-3-methoxy-4-methyl-1H-1,2,4-triazol-5(4H)-one (
5l
). m.p. 102-103°C, Yield 87%, 1H NMR (400 M, CDCl3): 3.14 (s, 3H, N-CH3), 3.94 (s, 3H, OCH3), 4.86 (s, 2H, NCH2), 6.96–7.30 (m, 4H, Ph); IR/cm−1: 3448.98, 2936.21, 1720.91, 1612.49, 1517.26, 1244.10, 1018.13, 595.24; ESI-MS: 238 [M+H]+. Elemental anal. (%), calculated: C, 55.69; H, 5.10; N, 17.71; found: C, 55.79; H, 5.12; N, 17.77.1-(4-Fluorobenzyl)-3-methoxy-4-methyl-1H-1,2,4-triazol-5(4H)-one (
5m
). m.p. 102-103°C, Yield 91%, 1H NMR (400 M, CDCl3): 3.15 (s, 3H, N-CH3), 3.95 (s, 3H, OCH3), 4.97 (s, 2H, NCH2), 7.05–7.12 (m, 2H, Ph), 7.27–7.29 (m, 2H, Ph); IR/cm−1: 3427.88, 2956.26, 1709.34, 1611.3, 1519.26, 1453.60, 1399.75, 1235.67, 1134.51, 1012.75, 783.65, 745.36, 700.77; ESI-MS: 238 [M+H]+. Elemental anal. (%), calculated: C, 55.69; H, 5.10; N, 17.71; found: C, 55.76; H, 5.22; N, 17.89.1-((5-Chloropyridin-2-yl)methyl)-3-methoxy-4-methyl-1H-1,2,4-triazol-5(4H)-one (
5n
). m.p. 111–113°C, Yield 88%, 1H NMR (400 M, CDCl3): 3.15 (s, 3H, N-CH3), 3.95 (s, 3H, OCH3), 4.48 (s, 2H, NCH2), 7.30–7.33 (m, 1H, Py), 7.68(d,J = 8.0 Hz, 1H, Py), 8.42 (s, 1H, Py); IR/cm−1: 3436.68, 2955.93, 1711.34, 1611.26, 1519.05, 1399.59, 1235.83, 1134.81, 1012.73, 783.64, 701.50; ESI-MS: 256 [M+H]+. Elemental anal. (%), calculated: C, 47.16; H, 4.35; N, 22.00; found: C, 47.32; H, 4.44; N, 22.12.1-(2-Fluorobenzyl)-3-methoxy-4-methyl-1H-1,2,4-triazol-5(4H)-one (
5o
). m.p. 103-104°C, Yield 91%, 1H NMR (400 M, CDCl3): 3.19 (s, 3H, N-CH3), 3.97 (s, 3H, OCH3), 5.04 (s, 2H, NCH2), 7.19–7.22 (m, 1H, Ph), 7.24–7.28 (m, 2H, Ph), 7.37–7.39 (m, 1H, Ph); IR/cm−1: 3436.50, 2934.06, 1716.72, 1613.09, 1521.04, 1416.95, 1299.19, 1230.77, 1106.39, 1004.22, 826.93, 595.53; ESI-MS: 238 [M+H]+. Elemental anal. (%), calculated: C, 55.69; H, 5.10; N, 17.71; found: C, 55.47; H, 5.12; N, 17.88.


## 3.2.1. Synthesis of Intermediates1 and2

The potassium thiocyanate (10.69 g, 0.11 mol) and pyridine (0.40 g) were dissolved in methyl isobutyl ketone (50 mL); methyl chloroformate (9.45 g, 0.10 mol) was added dropwise at 55°C, and the mixture was stirred for 4 h. Then MeOH (20 mL) was added to the mixture and stirred for 16 h. The mixture was washed with concentrated hydrochloric acid (3 mL) and H2O (50 mL). After filtration and evaporation of the solvent, the crude intermediate2 was collected without further purification: white solid, yield 80%, 1H NMR (400 MHz, CDCl3) δ: 3.77 (s, 3H, COOCH3), 4.12 (s, 3H, CSOCH3), 8.56 (s, 1H, NH).


## 3.2.2. Synthesis of Intermediate3

To a solution of intermediate2 (50 mmol) in MeOH (75 mL) were added 80% NH2NH2·H2O (4.07 g, 65 mmol) and KOH (45%, 0.81 g, 6.5 mmol) at 0°C; then the mixture was stirred at 30°C for 5 h. After evaporation of the solvent, the crude intermediate3 was recrystallized by EtOH to give white crystal3: yield 78%, m.p. 172~173°C, 1H NMR (400 MHz, DMSO-d6) δ: 4.02 (s, 3H, triazolone-OCH3), 10.51 (s, 1H, NH).


## 3.2.3. Synthesis of Intermediate4

To a solution of 3 (65 mmol) and K2CO3 (9.52 g) in CH3CN (100 mL) was added (CH3)2SO4 (68 mmol) at 55°C, and the mixture was stirred for another 2 h. The organic phase was extracted with CH2Cl2 (3 × 10 mL). After drying over sodium sulphate and evaporation of the solvent, the crude was collected without being purified to give the corresponding intermediate4.


## 3.2.4. General Procedure for Thioether5

DMF (5 mL),4 (0.25 g, 1.00 mmol), RCH2Cl (1.10 mmol), and NaOH (0.05 g, 1.20 mmol) were charged into a CEM designed 10 mL pressure-rated vial. Then it was irradiated in a CEM Discover Focused Synthesizer (150 w, 90°C, 200 psi, 15 minutes). The mixture was cooled below 50°C. The mixture was poured into crushed ice and the title compound 1,2,4-triazole was collected after being recrystallized.1-(3,4-Dichlorobenzyl)-3-methoxy-4-methyl-1H-1,2,4-triazol-5(4H)-one (
5a
). m.p. 136–140°C, Yield 88%, 1H NMR (400 M, CDCl3): 3.16 (s, 3H, N-CH3), 3.96 (s, 3H, OCH3), 4.83 (s, 2H, NCH2), 7.18–7.21 (m, 1H, Ph), 7.40–7.45 (m, 2H, Ph); IR/cm−1: 3449.33, 2957.94, 1710.43, 1615.33, 1518.36, 1470.76, 1425.27, 1403.40, 1307.42, 1233.37 1135.45, 1009.21, 914.98, 812.11, 743.63, 662.08, 595.11; ESI-MS: 289 [M+H]+. Elemental anal. (%), calculated: C, 45.85; H, 3.85; N, 14.58; found: C, 45.98; H, 3.77; N, 14.43.1-(4-Bromobenzyl)-3-methoxy-4-methyl-1H-1,2,4-triazol-5(4H)-one (
5b
). m.p. 138–140°C, Yield 84%, 1H NMR (400 M, CDCl3): 3.15 (s, 3H, N-CH3), 3.95 (s, 3H, OCH3), 4.84 (s, 2H, NCH2), 7.24 (d,J = 6.4 Hz, 2H, Ph), 7.47 (d,J = 6.4 Hz, 2H, Ph); IR/cm−1: 3450.50, 2942.58, 1711.13, 1607.26, 145.83, 1424.33, 1382.18, 1301.13, 1067.47, 1008.00, 910.76, 847.46, 798.29, 727.42, 600.46; ESI-MS: 299 [M+H]+. Elemental anal. (%), calculated: C, 44.31; H, 4.06; N, 14.09; found: C, 44.25; H, 3.92; N, 14.21.1-(2,4-Dichlorobenzyl)-3-methoxy-4-methyl-1H-1,2,4-triazol-5(4H)-one (
5c
). m.p. 113–115°C, Yield 89%, 1H NMR (400 M, CDCl3): 3.17 (s, 3H, N-CH3), 3.97 (s, 3H, OCH3), 4.99 (s, 2H, NCH2), 7.24 (d,J = 8.4 Hz, 1H, Ph), 7.22 (d,J = 8.4 Hz, 1H, Ph), 7.41 (s, 1H, Ph); IR/cm−1: 3440.43, 2943.89, 1710.82, 1606.45, 1522.24, 1490.26, 1455.07, 1424.03, 1382.14, 1318.96, 1229.32, 1091.39, 1006.22, 849.44, 803.25, 599.99; ESI-MS: 289 [M+H]+. Elemental anal. (%), calculated: C, 45.85; H, 3.85; N, 14.58; found: C, 45.67; H, 3.77; N, 14.64.1-(4-Chlorobenzyl)-3-methoxy-4-methyl-1H-1,2,4-triazol-5(4H)-one (
5d
). m.p. 125–127°C, Yield 82%, 1H NMR (400 M, CDCl3): 3.15 (s, 3H, N-CH3), 3.95 (s, 3H, OCH3), 4.80 (s, 2H, NCH2), 7.28–7.31 (m, 4H, Ph); IR/cm−1: 3430.91, 2954.61, 1723.39, 1611.41, 1517.41, 1470.16, 1414.48, 1352.86, 1302.39, 1230.3, 1050.80, 1010.51, 912.22, 878.42, 829.12, 788.23, 741.01, 691.10, 592.31, 468.63; ESI-MS: 254 [M+H]+. Elemental anal. (%), calculated: C, 52.08; H, 4.77; N, 16.56; found: C, 51.89; H, 4.87; N, 16.65.4-((3-Methoxy-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)benzonitrile (
5e
). m.p. 160–162°C, Yield 89%, 1H NMR (400 M, CDCl3): 3.15 (s, 3H, N-CH3), 3.96 (s, 3H, OCH3), 4.94 (s, 2H, NCH2), 7.44 (d,J = 8.16 Hz, 2H, Ph), 7.64 (d,J = 8.16 Hz, 2H, Ph); IR/cm−1: 3434.79, 2955.79, 2229.46, 1715.92, 1613.56, 1523.56, 1421.90, 1230.01, 1016.35, 857.47, 735.86, 640.39, 596.36, 552.70; ESI-MS: 245 [M+H]+. Elemental anal. (%), calculated: C, 59.01; H, 4.95; N, 22.94; found: C, 58.88; H, 5.12; N, 23.13.(E)-Methyl 2-(2-((3-Methoxy-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)phenyl)-2-(methoxyimino)acetate (
5f
). m.p. 103–107°C, Yield 89%,1H NMR (400 M, CDCl3): 3.15 (s, 3H, N-CH3), 3.96 (s, 3H, OCH3), 4.94 (s, 2H, NCH2), 7.44 (d,J = 8.16 Hz, 2H, Ph), 7.64 (d,J = 8.16 Hz, 2H, Ph); IR/cm−1: 3455.02, 2936.45, 1720.46, 1611.72, 1522.17, 1431.39, 1230.32, 1005.55, 86.57, 741.29, 711.75, 681.57, 598.40, 572.80; ESI-MS: 245 [M+H]+. Elemental anal. (%), calculated: C, 53.89; H, 5.43; N, 16.76; found: C, 53.98; H, 5.13; N, 16.88.3-Methoxy-4-methyl-1-undecyl-1H-1,2,4-triazol-5(4H)-one (
5g
). m.p. 102–105°C, Yield 78%, 1H NMR (400 M, CDCl3): 0.86 (t,J = 6.71 Hz, 3H, CH3), 1.24–1.29 (m, 16H, CH2), 1.66–1.68 (m, 2H, CH2), 3.10 (s, 3H, N-CH3), 3.66 (s,J = 7.21 Hz, 2H, NCH2), 3.95 (s, 3H, OCH3); IR/cm−1: 3446.77, 2941.81, 1708.02, 1622.82, 1258.48, 1131.46, 1101.03, 763.78, 661.94; ESI-MS: 285 [M+H]+. Elemental anal. (%), calculated: C, 63.57; H, 10.31; N, 14.83; found: C, 63.76; H, 10.52; N, 14.97.1-(3-Chlorobenzyl)-3-methoxy-4-methyl-1H-1,2,4-triazol-5(4H)-one (
5h
). m.p. 97–100°C, Yield 90%, 1H NMR (400 M, CDCl3): 3.17 (s, 3H, N-CH3), 3.96 (s, 3H, OCH3), 4.87 (s, 2H, NCH2), 7.27–7.34 (m, 4H, Ph); IR/cm−1: 3441.67, 2960.00, 1716.14, 1621.83, 1520.80, 1391.88, 1267.10, 1228.92, 014.96, 789.51, 740.97, 593.84; ESI-MS: 254 [M+H]+. Elemental anal. (%), calculated: C, 52.08; H, 4.77; N, 16.56; found: C, 52.21; H, 4.87; N, 16.77.1-(2-Chlorobenzyl)-3-methoxy-4-methyl-1H-1,2,4-triazol-5(4H)-one (
5i
). m.p. 120–122°C, Yield 87%, 1H NMR (400 M, CDCl3): 3.19 (s, 3H, N-CH3), 3.97 (s, 3H, OCH3), 5.04 (s, 2H, NCH2), 7.19–7.25 (m, 2H, Ph), 7.37–7.39 (m, 2H, Ph); IR/cm−1: 3439.30, 2947.24, 1718.79, 1614.24, 1523.69, 745.45, 595.23; ESI-MS: 254 [M+H]+. Elemental anal. (%), calculated: C, 52.08; H, 4.77; N, 16.56; found: C, 52.22; H, 4.88; N,6.67.3-((3-Methoxy-4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)benzonitrile (
5j
). m.p. 130°C, Yield 89%, 1H NMR (400 M, CDCl3): 3.17 (s, 3H, N-CH3), 3.97 (s, 3H, OCH3), 4.91 (s, 2H, NCH2), 7.46–7.48 (m, 1H, Ph), 7.58–7.62 (m, 3H, Ph); IR/cm−1: 3446.70, 2946.55, 2231.74, 1706.17, 1522.05, 1383.55, 1229.24, 1007.72, 786.75, 743.50, 702.92; ESI-MS: 245 [M+H]+. Elemental anal. (%), calculated: C, 59.01; H, 4.95; N, 22.94; found: C, 58.88; H, 4.89; N, 22.78.3-Methoxy-1-(4-methoxybenzyl)-4-methyl-1H-1,2,4-triazol-5(4H)-one (
5k
). m.p. 88–90°C, Yield 93%, 1H NMR (400 M, CDCl3): 3.14 (s, 3H, N-CH3), 3.81 (s, 3H, OCH3), 3.95 (s, 3H, OCH3), 4.82 (s, 2H, NCH2), 6.87 (d,J = 8.14 Hz, 2H, Ph), 7.31 (d,J = 8.14 Hz, 2H, Ph); IR/cm−1: 3444.95, 2924.39, 1721.08, 1612.50, 1523.71, 1434.36, 1230.54, 742.97, 598.46; ESI-MS: 250 [M+H]+. Elemental anal. (%), calculated: C, 57.82; H, 6.07; N, 16.86; found: C, 58.01; H, 6.21; N, 16.76.1-(3-Fluorobenzyl)-3-methoxy-4-methyl-1H-1,2,4-triazol-5(4H)-one (
5l
). m.p. 102-103°C, Yield 87%, 1H NMR (400 M, CDCl3): 3.14 (s, 3H, N-CH3), 3.94 (s, 3H, OCH3), 4.86 (s, 2H, NCH2), 6.96–7.30 (m, 4H, Ph); IR/cm−1: 3448.98, 2936.21, 1720.91, 1612.49, 1517.26, 1244.10, 1018.13, 595.24; ESI-MS: 238 [M+H]+. Elemental anal. (%), calculated: C, 55.69; H, 5.10; N, 17.71; found: C, 55.79; H, 5.12; N, 17.77.1-(4-Fluorobenzyl)-3-methoxy-4-methyl-1H-1,2,4-triazol-5(4H)-one (
5m
). m.p. 102-103°C, Yield 91%, 1H NMR (400 M, CDCl3): 3.15 (s, 3H, N-CH3), 3.95 (s, 3H, OCH3), 4.97 (s, 2H, NCH2), 7.05–7.12 (m, 2H, Ph), 7.27–7.29 (m, 2H, Ph); IR/cm−1: 3427.88, 2956.26, 1709.34, 1611.3, 1519.26, 1453.60, 1399.75, 1235.67, 1134.51, 1012.75, 783.65, 745.36, 700.77; ESI-MS: 238 [M+H]+. Elemental anal. (%), calculated: C, 55.69; H, 5.10; N, 17.71; found: C, 55.76; H, 5.22; N, 17.89.1-((5-Chloropyridin-2-yl)methyl)-3-methoxy-4-methyl-1H-1,2,4-triazol-5(4H)-one (
5n
). m.p. 111–113°C, Yield 88%, 1H NMR (400 M, CDCl3): 3.15 (s, 3H, N-CH3), 3.95 (s, 3H, OCH3), 4.48 (s, 2H, NCH2), 7.30–7.33 (m, 1H, Py), 7.68(d,J = 8.0 Hz, 1H, Py), 8.42 (s, 1H, Py); IR/cm−1: 3436.68, 2955.93, 1711.34, 1611.26, 1519.05, 1399.59, 1235.83, 1134.81, 1012.73, 783.64, 701.50; ESI-MS: 256 [M+H]+. Elemental anal. (%), calculated: C, 47.16; H, 4.35; N, 22.00; found: C, 47.32; H, 4.44; N, 22.12.1-(2-Fluorobenzyl)-3-methoxy-4-methyl-1H-1,2,4-triazol-5(4H)-one (
5o
). m.p. 103-104°C, Yield 91%, 1H NMR (400 M, CDCl3): 3.19 (s, 3H, N-CH3), 3.97 (s, 3H, OCH3), 5.04 (s, 2H, NCH2), 7.19–7.22 (m, 1H, Ph), 7.24–7.28 (m, 2H, Ph), 7.37–7.39 (m, 1H, Ph); IR/cm−1: 3436.50, 2934.06, 1716.72, 1613.09, 1521.04, 1416.95, 1299.19, 1230.77, 1106.39, 1004.22, 826.93, 595.53; ESI-MS: 238 [M+H]+. Elemental anal. (%), calculated: C, 55.69; H, 5.10; N, 17.71; found: C, 55.47; H, 5.12; N, 17.88.


## 3.3. Antifungal Activities

The biological activities of title compounds againstPhytophthora infestans, Botrytis cinerea, Corynespora cassiicola, Rhizoctonia solani, andPythium ultimum were evaluated according to [37–40], and a potted plant test method was adopted.Germination was conducted by soaking cucumber seeds in water for 2 h at 50°C and then keeping the seeds moist for 24 h at 28°C in an incubator. When the radicles were 0.5 cm, the seeds were grown in plastic pots containing a 1 : 1 (v/v) mixture of vermiculite and peat. Cucumber and tomato plants used for inoculations were at the stage of two seed leaves. Tested compounds and commercial fungicides were sprayed with a hand spray on the surface of the seed leaves on a fine morning at the standard concentration of 500μg/mL; dimethomorph, fludioxonil, chlorothalonil, validamycin, and zhongshengmycin were used as control. After 2 h, inoculation ofPhytophthora infestans was carried out by spraying fungal suspension, inoculation ofRhizoctonia solani andCorynespora cassiicola was carried out by spraying mycelial suspension, and inoculation ofBotrytis cinerea was carried out by radicle soaking.Pythium ultimum was found in the cucumber in nature. The experiment was repeated 4 times. After inoculation, the plants were maintained at 18–30°C (mean temperature of 24°C and above 80% relative humidity (RH)). The fungicidal activity was evaluated when the nontreated cucumber plant (blank) fully developed symptoms. The area of inoculated treated leaves covered by disease symptoms was assessed and compared to that of nontreated ones to determine the average disease index. The relative control efficacy of compounds compared to the blank assay was calculated via the following equation:(1)relativecontrolefficacy(%)=CK-PTCK×100%,where CK is the average disease index during the blank assay and PT is the average disease index after treatment during testing.


## 3.4. DFT Calculation

DFT-B3LYP/6-31G (d) methods in Gaussian 03 package [41] were used to optimize the structure of5c. Vibration analysis showed that the optimized structures were in accordance with the minimum points on the potential energy surfaces. All the convergent precisions were the system default values, and all the calculations were carried out on the DELL personal computer.


## 4. Conclusion

In summary, this paper reported some novel 1,2,4-triazol-5(4H)-one derivatives were successfully synthesized. The bioassay results showed that some of the title compounds exhibited considerable antifungal activity. The bioactivity of these novel compounds deserves further investigation.



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*Source: 916059-2015-03-12.xml*