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Synthesis and fungicidal activity of novel imidazo[4, 5-b]pyridine derivatives

  • Daoxin Wu EMAIL logo , Minhua Liu EMAIL logo , Zhong Li , Mingming Dang , Xingping Liu , Jianming Li , Lu Huang , Yeguo Ren , Zai Zhang , Weidong Liu and Aiping Liu EMAIL logo
Published/Copyright: April 3, 2019
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Heterocyclic Communications
From the journal Heterocyclic Communications Volume 25 Issue 1

Abstract

A series of novel imidazo[4,5-b]pyridine derivatives were synthesized and their structures were characterized by NMR spectroscopy, mass spectrometry and elemental analysis. The results of bioassays showed that some compounds exhibit good fungicidal activity against Puccinia polysora In particular, compound 7b showed an EC50 value of 4.00 mg/L, which was comparable with that of tebuconazole. Besides, preliminary structure-activity relationship was discussed.

Keywords: fungicidal activity; imidazo[4,5-b]pyridine; structure-activity relationship; synthesis

Introduction

The fungicide market has been dominated by strobilurins, triazoles and amides for a long time. As a result, pathogen resistance to these fungicides has become a serious problem [1]. Agrochemicals have been one of the most effective tools for increasing both crop quality and quantity while reducing labor costs [2, 3, 4, 5].

Imidazo[4,5-b]pyridines are an important family of heterocyclic compounds, and their derivatives possess various pharmacological properties [6, 7, 8, 9, 10, 11]. Examples of pharmacologically active compounds containing an imidazo[4,5-b]pyridine skeleton are shown in Figure 1. However, no commercial agrochemicals containing an imidazo[4,5-b] pyridine moiety have so far been found. In addition, few references about imidazo[4,5-b]pyridines with fungicidal activity have been published. Therefore, it is important to study imidazo[4,5-b]pyridines as potential fungicides.

Figure 1 Examples of pharmacologically active compounds containing an imidazo[4,5-b]pyridine skeleton[9-11].
Figure 1

Examples of pharmacologically active compounds containing an imidazo[4,5-b]pyridine skeleton[9-11].

In our previous work, we have discovered that compound Ia containing a nitropyridine core (Figure 2) displays remarkable insecticidal activities [12, 13]. In this report we tried to optimize the lead compound by synthesis of a series of novel imidazo[4,5-b]pyridine compounds (Figure 2).

Figure 2 Design strategy of the target compounds containing imidazo[4,5-b]pyridine core.
Figure 2

Design strategy of the target compounds containing imidazo[4,5-b]pyridine core.

Results and discussion

Target compounds 2a,h and 4a,b were prepared by reacting 3-nitropyridine-2-amines 1 or 3 and aryl aldehyde in the presence of saturated sodium dithionite. Compounds 7a,b were synthesized by cyclization of the corresponding amide 6. An attempted preparation of compound 7b directly by treatment of the corresponding pyridine-2,3-diamine 5 with acid was only partially successful providing the product in low yield.

The chemical formula, mass-spectral data and fungicidal activity are shown in Table 1. Bioassays show that this series of compounds have good fungicidal activity against P. polysora at the concentration of 500 mg/L. For example, compounds 2g and 7b induce the mortality over 90% at the concentration of 500 mg/L. Compounds 2e, 2h, 4a, 4b and 7a displayed 74%, 82%, 85%, 72% and 75% fungicidal activity against P. polysora at the same concentration, respectively. With the in-depth screening, only compound 7b exhibits good fungicidal activity against P. polysora. Its EC50 value is 4.00 mg/L, which is comparable with that of tebuconazole (2.00 mg/L).

Table 1

Chemical formula, MS data and fungicidal activity (%) against P. polysora at 500 mg/L of the compounds.

No.FormulaMSFungicidal activity at 500 mg/L
2aC13H11N3O22520.10
2bC15H15N3O25321.50
2cC14H11F2N3O27527.60
2dC15H13F2N3O2890.00
2eC16H15F2N3O30373.90
2fC16H15F2N3O30329.90
2gC17H17F2N3O31790.10
2hC17H17F2N3O31782.30
4aC14H13N3S25585.00
4bC15H15N3S26972.00
7aC16H14F3N3O32175.00
7bC18H12ClF3N4OS424100.00
8aC14H13N3OS27150.00
8bC15H15N3OS28533.60
8cC14H13N3O2S2870.00
8dC15H15N3O2S30132.50

For the preliminary structure-activity relationship analysis, the groups W, Ar and R were varied (Scheme 1). When W and Ar are kept constant, the fungicidal activity against P. polysora of target compounds is influenced by the nature of the R group. The R group is modified from H to a C1–C4 alkyl or thiazol-5-ylmethyl group. As the chain length increases, the fungicidal activity of the resultant compounds increases: 2g, 2h > 2e > 2d, 2c; 7b > 7a; 8d > 8c. When R and Ar groups are kept constant, the fungicidal activity of the synthesized compounds is influenced by the nature of the W group. Modification of the W group from an oxygen to sulfur atom, sulfoxyl, or sulfuryl groups affects the different level of fungicidal activity against P. polysora, as exemplified by the following order: 4a > 8a >> 8c; 4b > 8b > 8d > 2b. When W and R are kept constant, the fungicidal activity of target compounds is influenced by the nature of the Ar group. Modification of the Ar group from substituted phenyl to substituted phenyl showed the different level of fungicidal activity against P. polysora. The fungicidal activity is correlated as follows: 7a > 2b > 2d. In general, the structure–activity relationships of target compounds can be summarized as follows. Activity order of R: 2-chlorothiazol-5-yl-methyl > n-C4H9, i-C4H9 > n-C3H7, i-C3H7 > C2H5, CH3, H; activity order of W: S > SO > SO2 > O; activity order of Ar: 2-trifluoromethylphenyl > phenyl > 2,6-difluorophenyl.

Scheme 1 General synthetic route for the target compounds.
Scheme 1

General synthetic route for the target compounds.

Conclusions

A series of imidazo[4,5-b]pyridine derivatives were synthesized in the search for a new fungicide. Most of the synthesized compounds showed antifungal activity. In particular, compound 7b shows the mortality of 100.00% against P. polysora at 500 mg/L and its EC50 value is 4.00 mg/L, which is comparable with that of tebuconazole (2.00 mg/L).

Experimental

1H NMR (300 MHz) and 13C NMR (75 MHz) spectra were acquired with a Varian INOVA-300 spectrometer using tetramethylsilane (TMS) as the internal standard and CDCl3 as the solvent. Mass spectra were obtained using a Agilent 5973-6890 gas chromatography-mass spectrometer (GC-MS) and a Agilent 1100 series liquid chromatography-mass spectrometer (LC-MS). The uncorrected melting points were taken in the WRS-1B digital melting points apparatus (Shanghai Physical Optics). The column chromatography was performed using a 200–300 mesh silica gel. Elemental analysis data were obtained with a Vario EL III from Elementar. Reagents and solvents were used by commercial suppliers unless otherwise noted.

The general synthetic methods for the target compounds are shown in Scheme 1. Representative procedures are given as follows. Yields were not optimized. All reactions were carried out under a protective atmosphere of dry nitrogen or utilizing a calcium chloride tube.

N-butyl-6-methoxy-3-nitropyridin-2-amine (1f)

A mixture of 2-methoxyl-6-chloro-3-nitropyridine (4.30 g, 22.8 mmol) and triethylamine (2.31 g, 22.8 mmol) in N, N-dimethylformamide (40 mL) was stirred for 0.5 h at room temperature under nitrogen atmosphere. Butylamine (1.67 g, 22.8 mmol) in 10 mL of dry N, N-dimethylformamide was slowly added dropwise. The mixture was stirred at room temperature for 2–3 h then poured into water. The resultant precipitate was collected by filtration, washed with water and dried to give a yellow solid; yield 4.63 g (90%). Without further purification, compound 1f was used in the subsequent reaction.

N-ethyl-6-(methylthio)-3-nitropyridin-2-amine (3b)

N-ethyl-6-chloro-3-nitropyridin-2-amine (11.02 g, 54.7 mmol) in tetrahydrofuran (30 mL) was added dropwise to a solution of sodium methanethiolate (21.14 g, 20%, 60.3 mmol) in water (20 mL) at room temperature. After 3 h of stirring, the mixture was poured into water and the resulting precipitate was filtered and dried to yield 3b as a yellow solid; yield 11.68 g (97%).

N2-[(2-Chlorothiazol-5-yl)methyl]-6-methoxypyridine-2, 3-diamine (5b)

N-[(2-chlorothiazol-5-yl)methyl]-6-methoxy-3-nitropyridin-2-amine (3.01 g, 10.0 mmol), and iron dust (1.68 g, 30.1 mmol) were successively added to 60 mL of acetic acid at room temperature for 2–3 h. The mixture was filtered. After the solvent was removed under reduced pressure, the residue was dissolved in dichloromethane, and the solution was washed with water, dried over Na2SO4 and concentrated under reduced pressure to yield 5b as a black solid; yield 2.46 g (91%).

N-{2-[((2-Chlorothiazol-5-yl)methyl)amino]-6-methoxypyridin-3-yl}-2-(trifluoromethyl)benzamide (6b)

A solution of compound 5b (2.97 g, 11.0 mmol) in dichloromethane (30 mL) was added dropwise to a solution of 2-(trifluoromethyl)benzoyl chloride (3.43 g, 16.5 mmol) in dichloromethane (20 mL) at 0˚C. After 3 h of stirring, the mixture was poured into water and the aqueous phase was extracted with dichloromethane. The extract was washed twice with water, dried over Na2SO4, filtered and concentrated under reduced pressure to yield 6b as a gray solid; yield 3.01 g (62%).

3-Ethyl-2-(2,6-difluorophenyl)-5-methoxy-3H-imidazo[4,5-b]pyridine (2g )

A solution of Na2S2O4 (6.06 g, 34.8 mmol) in water (20 mL) was added dropwise to a solution of n-butyl-6-methoxy-3-nitropyridin-2-amine (1.73 g, 7.7 mmol) and 2,6-difluorobenzaldehyde (1.09 g, 7.7 mmol) in ethanol (80 mL). After 16 h of heating under reflux, the mixture was poured into water and the resulting precipitate was filtered and crystallized from ethyl acetate/petroleum ether to yield 2g as a yellowish solid; yield 1.44 g (59%).

5-Chloro-2-[(5-methoxy-2-(2-(trifluoromethyl)phenyl)-3H-imidazo[4,5-b]pyridin-3-yl)methyl]thiazole (7b)

Compound 6b (2.59 g, 5.8 mmol) was added to 15 mL of phosphorus oxychloride. After 3 h of heating under reflux, the solvent was removed under reduced pressure. The residue was treated with 200 mL of ethyl acetate and Na2CO3 aqueous solution. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with petroleum ether/ethyl acetate, 5:1 to afford compound 7b as a white solid; yield 0.89 g (36%).

3-Ethyl-5-(methylsulfinyl)-2-phenyl-3H-imidazo[4,5-b] pyridine (8b)

Compound 4b (1.54 g, 5.7 mmol) in dichloromethane (40 mL) was added dropwise to a solution of 3-chloroperbenzoic acid (1.18 g, 85%, 5.8 mmol) in dichloromethane (20 mL) at 0˚C. After 2 h of stirring, the reaction was poured into water and the aqueous phase was extracted with EA, washed twice with water, dried over Na2SO4, filtered, and concentrated under reduced pressure to give the crude product, and the residue was purified by silica-gel column chromatography to afford compound 8b as a white solid (0.69 g, 2.3 mmol, yield: 40%).

3-Ethyl-2-(2,6-difluorophenyl)-5-(methylsulfonyl)-3H-imidazo[4,5-b]pyridine (8d)

Compound 4b (0.58 g, 2.2 mmol) in dichloromethane (40 mL) was added dropwise to a solution of 3-chloroperbenzoic acid (0.98 g, 85%, 4.8 mmol) in dichloromethane (20 mL) at room temperature. After 2 h of stirring, the reaction was poured into water and the aqueous phase was extracted with dichloromethane. The combined organic layer was washed twice with water, dried over Na2SO4, filtered, and concentrated under reduced pressure to give the crude product. The residue was purified by silica-gel column chromatography to afford compound 8d as a white solid (0.42 g, 1.4 mmol, yield: 64%).

The preparations of other intermediates compounds and final products were conducted in a similar way.

5-Methoxy-2-phenyl-3H-imidazo[4,5-b]pyridine (2a)

White solid, mp: 208.5 - 210.2˚C; 1H NMR (300 MHz, CDCl3): δ 3.97 (s, 3H, CH3), 6.68 (d, J = 8.7 Hz, 1H, Ar H), 7.41-7.49 (m, 3H, Ar H), 7.87 (d, J = 8.7 Hz, 1H, Ar H), 8.00-8.07 (m, 2H, Ar H); 13C NMR (CDCl3, 75 MHz): δ 53.8, 106.6, 126.3, 127.9, 129.0, 129.6, 130.2, 150.4, 153.2, 155.4, 161.8; GC-MS: m/z 225, M+, base peak at m/z 225; Elemental analysis: Calcd: C, 69.32; H, 4.92; N, 18.66; Found: C, 69.40; H, 4.93; N, 18.63.

3-Ethyl-5-methoxy-2-phenyl-3H-imidazo[4,5-b]pyridine (2b)

Gray solid; mp 118.3 - 118.7˚C; 1H NMR: δ 1.46 (t, J = 7.2 Hz, 3H, CH3), 4.02 (s, 3H, CH3), 4.34 (q, J = 7.2 Hz, 2H, CH2), 6.7 (d, J = 8.4 Hz, 1H, Ar H), 7.49 - 7.57 (m, 3H, Ar H), 7.72 - 7.77 (m, 2H, Ar H), 7.94 (d, J = 8.4 Hz, 1H, Ar H); 13C NMR: δ 15.1, 38.6, 53.6, 106.0, 128.7, 128.8, 129.5, 130.0, 130.8, 145.9, 151.4, 161.2; GC-MS: m/z 253, M+, base peak at m/z 253. Anal. Calcd: C, 71.13; H, 5.97; N, 16.59. Found: C, 71.08; H, 5.99; N, 16.64.

2-(2,6-Difluorophenyl)-5-methoxy-3-methyl-3H-imidazo[4,5-b]pyridine (2c)

White solid, mp 158.5 - 159.8˚C; 1H NMR: δ 3.73 (s, 3H, CH3), 4.03 (s, 3H, CH3), 6.73 (d, J = 8.4 Hz, 1H, Ar H), 7.05-7.14 (m, 2H, Ar H), 7.46 - 7.56 (m, 1H, Ar H), 7.98 (d, J = 8.4 Hz, 1H, Ar H); 13C NMR: δ 29.0, 53.6, 106.5, 111.7 (d, J = 6.9 Hz), 112.0 (d, J = 6.9 Hz), 130.5, 132.0 (t, J = 10.3 Hz), 141.0, 145.6, 159.4, 159.5, 161.7, 162.7, 162.8; GC-MS: m/z 275, M+, base peak at m/z 275. Anal. Calcd: C, 61.09; H, 4.03; N, 15.27. Found: C, 61.05; H, 4.02; N, 15.28.

2-(2,6-Difluorophenyl)-3-ethyl-5-methoxy-3H-imidazo[4,5-b]pyridine (2d)

Gray solid; mp 123.9 - 126.5˚C; 1H NMR: δ 1.37 (t, J = 7.2 Hz, 3H, CH3), 4.02 (s, 3H, CH3), 4.13 (q, J = 7.5 Hz, 2H, CH2), 6.73 (d, J = 8.7 Hz, 1H, Ar H), 7.06 - 7.12 (m, 2H, Ar H), 7.49 - 7.52 (m, 1H, Ar H), 7.97 (d, J = 8.4 Hz, 1H, Ar H); 13C NMR: δ 14.7, 38.5, 53.6, 106.5, 111.7, 112.0, 130.5, 132.1 (t, J = 9.8 Hz), 140.3, 145.1, 159.5, 159.6, 161.5, 162.8, 162.9; GC-MS: m/z 289, M+, base peak at m/z 289. Anal. Calcd: C, 62.28; H, 4.53; N, 14.53. Found: C, 62.25; H, 4.52; N, 14.50.

2-(2,6-Difluorophenyl)-5-methoxy-3-propyl-3H-imidazo[4,5-b]pyridine (2e)

White solid; mp 108.0 - 108.3˚C; 1H NMR: δ 0.77 (t, J = 7.5 Hz, 3H, CH3), 1.76 - 1.84 (m, 2H, CH2), 4.02 (s, 3H, CH3), 4.08 (q, J = 6.9 Hz, 2H, CH2), 6.73 (d, J = 8.7 Hz, 1H, Ar H), 7.06 - 7.12 (m, 2H, Ar H), 7.49 - 7.55 (m, 1H, Ar H), 7.98 (d, J = 8.7 Hz, 1H, Ar H); 13C NMR: δ 11.0, 22.5, 44.9, 53.6, 106.4, 111.6, 112.0, 130.5, 132.0 (t, J = 10.0 Hz), 140.6, 145.4, 159.4, 159.5, 161.5, 162.7, 162.8; GC-MS: m/z 303, M+, base peak at m/z 303. Anal. Calcd: C, 63.38; H, 5.02; N, 13.80. Found: C, 63.36; H, 5.01; N, 13.85.

2-(2,6-Difluorophenyl)-3-isopropyl-5-methoxy-3H-imidazo[4,5-b]pyridine (2f)

White solid; mp 120.4 - 122.9˚C; 1H NMR: δ 1.70 (d, J = 6.9 Hz, 6H, 2CH3), 4.01 (s, 3H, CH3), 4.34 - 4.39 (m, 1H, CH), 6.71 (d, J = 8.7 Hz, 1H, Ar H), 7.05 - 7.10 (m, 2H, Ar H), 7.48 - 7.53 (m, 1H, Ar H ), 7.95 (d, J = 8.4 Hz, 1H, Ar H ); 13C NMR: δ 20.8, 49.4, 53.4, 106.1, 111.4, 111.7, 130.3, 131.9 (t, J = 10.0 Hz), 139.9, 144.8, 159.4, 159.5, 160.5, 162.7, 162.8; GC-MS: m/z 303, M+, base peak at m/z 303. Anal. Calcd: 63.36; H, 4.98; N, 13.85. Found: C, 63.30; H, 4.97; N, 13.87.

3-Butyl-2-(2,6-difluorophenyl)-5-methoxy-3H-imidazo[4,5-b]pyridine (2g)

Yellowish solid; mp 66.3 - 66.9˚C; 1H NMR: δ 0.80 (t, J = 7.5 Hz, 3H, CH3), 1.17 - 1.24 (m, 2H, CH2), 1.71 (t, J = 7.2 Hz, 2H, CH2), 4.02 (s, 3H, CH3), 4.12 (t, J = 7.2 Hz, 2H, CH2), 6.72 (d, J = 8.7 Hz, 1H, Ar H), 7.06 - 7.11 (m, 2H, Ar H), 7.48 - 7.54 (m, 1H, Ar H), 7.97 (d, J = 8.7 Hz, 1H, Ar H); 13C NMR: δ 13.3, 19.4, 31.2, 42.8, 53.6, 106.4, 111.6 (d, J = 2.3 Hz), 111.9 (d, J = 1.7 Hz), 130.4, 132.1 (t, J = 10.4 Hz), 140.6, 145.2, 159.3, 159.4, 161.4, 162.6, 162.7.; GC-MS: m/z 317, M+, base peak at m/z 317. Anal. Calcd: C, 64.34; H, 5.40; N, 13.24. Found: C, 64.31; H, 5.39; N, 13.20.

3-(sec-Butyl)-2-(2,6-difluorophenyl)-5-methoxy-3H-imidazo[4,5-b]pyridine (2h)

Yellow solid; mp: 102.7 - 103.2˚C; 1H NMR: δ 0.77 (d, J = 6.9 Hz, 6H, 2CH3), 2.15 - 2.19 (m, 1H, CH), 3.94 (d, J = 7.5 Hz, 2H, CH2), 4.01 (s, 3H, CH3), 6.72 (d, J = 8.7 Hz, 1H, Ar H), 7.05 - 7.11 (m, 2H, Ar H), 7.48 - 7.54 (m, 1H, Ar H), 7.97 (d, J = 8.7 Hz, 1H, Ar H); 13C NMR: δ 19.8, 28.4, 50.5, 53.6, 106.4, 111.6, 111.9, 130.0, 132.0 (t, J = 10.0 Hz), 140.9, 145.5, 159.2, 159.3, 161.4, 162.6, 162.7; GC-MS: m/z 317, M+, base peak at m/z 261. Anal. Calcd: C, 64.34; H, 5.40; N, 13.24. Found: C, 64.38; H, 5.38; N, 13.21.

3-Methyl-5-(methylthio)-2-phenyl-3H-imidazo[4,5-b] pyridine (4a)

White solid, mp: 150.3 - 150.6˚C; 1H NMR: δ 2.68 (s, 3H, CH3), 3.97 (s, 3H, CH3), 7.14 (d, J = 8.4 Hz, 1H, Ar H), 7.52 - 7.57 (m, 3H, Ar H), 7.81 - 7.86 (m, 2H, Ar H), 7.89 (d, J = 8.1 Hz, 1H, Ar H); 13C NMR: δ 13.8, 30.4, 116.7, 127.2, 128.7, 128.9, 129.8, 129.9, 131.9, 148.9, 152.8, 153.9; HPLC-MS Pos [M+1]+ = 256. Anal. Calcd: C, 65.86; H, 5.13; N, 16.46. Found: C, 65.90; H, 5.10; N, 16.49.

3-Ethyl-5-(methylthio)-2-phenyl-3H-imidazo[4,5-b] pyridine (4b)

White solid; mp 127.9 - 130.0˚C; 1H NMR: δ 1.48 (t, J = 7.5 Hz, 3H, CH3), 2.67 (s, 3H, CH3), 4.39 (q, J = 7.5 Hz, 2H, CH2), 7.13 (d, J = 8.4 Hz, 1H, Ar H), 7.52 - 7.58 (m, 3H, Ar H), 7.74 - 7.79 (m, 2H, Ar H), 7.87 (d, J = 8.1 Hz, 1H, Ar H); 13C NMR: δ 13.7, 15.0, 38.6, 116.7, 127.1, 128.7, 128.8, 129.8, 130.3, 132.1, 148.4, 152.5, 153.7; GC-MS: m/z 269, M+, base peak at m/z 236. Anal. Calcd: C, 66.88; H, 5.61; N, 15.60. Found: C, 66.92; H, 5.62; N, 15.57.

3-Ethyl-5-methoxy-2-(2-(trifluoromethyl)phenyl)-3H-imidazo[4,5-b]pyridine (7a)

Yellow solid; mp 83.3 - 85.5˚C; 1H NMR: δ 2.25 (s, 3H, CH3), 4.14 (s, 3H, CH3), 4.78 (dd, J = 5.1, 0.6 Hz, 2H, CH2), 7.21 (s, 1H, thiazole-H), 7.43 - 7.48 (m, 3H, Ar H), 7.58 (bs, 1H, NH), 7.92 - 7.97 (m, 2H, Ar H); 13C NMR: δ 14.5, 38.2, 53.6, 106.1, 117.0 (q, J = 272 Hz), 126.6 (q, J = 4.6 Hz), 128.8, 129.3, 129.6 (q, J = 34 Hz), 130.3, 130.6, 131.5, 132.0, 144.9, 148.1, 161.4; GC-MS: m/z 321, M+, base peak at m/z 321. Anal. Calcd: C, 59.81; H, 4.39; N, 13.08; Found: C, 59.87; H, 4.38; N, 13.10.

5-Chloro-2-[(5-methoxy-2-(2-(trifluoromethyl)phenyl)-3H-imidazo[4,5-b]pyridin-3-yl)methyl]thiazole (7b)

White solid; mp 136.6 - 137.4 ; 1H NMR: δ 2.24 (s, 3H, CH3), 4.14 (s, 3H, CH3), 4.64 (dd, J = 5.7, 0.6 Hz, 2H, CH2), 7.34 (bs, 1H, NH), 7.35 - 7.43 (m, 2H, Ar H), 7.50 - 7.53 (m, 1H, Ar H), 7.53 (s, 1H, thiazole-H), 7.96 - 7.99 (m, 1H, Ar H ); 13C NMR: δ 38.7, 53.9, 107.2, 117.8 (q, J = 273 Hz), 126.8 (q, J = 4.8 Hz), 128.1, 129.2, 129.8 (q, J = 30 Hz), 130.8, 130.9, 131.8, 132.2, 134.9, 140.5, 144.2, 147.2, 153.0, 161.7; GC-MS: m/z 424, M+, base peak at m/z 132. Anal. Calcd: C, 50.89; H, 2.85; N, 13.19. Found: C, 50.95; H, 2.86; N, 13.14;

3-Methyl-5-(methylsulfinyl)-2-phenyl-3H-imidazo[4,5-b] pyridine (8a)

White solid, mp: 166.5 - 167.3˚C; 1H NMR (300 MHz, CDCl3): δ 2.92 (s, 3H, CH3), 4.00 (s, 3H, CH3), 7.56 - 7.61 (m, 3H, Ar H), 7.83 - 7.88 (m, 2H, Ar H), 7.95 (d, J = 8.4 Hz, 1H, Ar H), 8.26 (d, J = 8.1 Hz, 1H, Ar H); 13C NMR (CDCl3, 75 MHz): δ 30.6, 41.7, 113.6, 128.2, 128.8, 129.0, 129.2, 130.5, 136.4, 148.7, 156.4, 158.6; GC-MS: m/z 271, M+, base peak at m/z 224. Anal. Calcd: C, 61.97; H, 4.83; N, 15.49; Found: C, 61.95; H, 4.82; N, 15.46.

3-Ethyl-5-(methylsulfinyl)-2-phenyl-3H-imidazo[4,5-b] pyridine (8b)

White solid, mp: 165.3 - 165.4˚C; 1H NMR (300 MHz, CDCl3): δ 1.47 (t, J = 7.2 Hz, 3H, CH3), 2.92 (s, 3H, CH3), 4.42(q, J = 7.2 Hz, 2H, CH2), 7.56 - 7.61 (m, 3H, Ar H), 7.77 - 7.83 (m, 2H, Ar H), 7.95 (d, J = 8.4 Hz, 1H, Ar H), 8.25 (d, J = 8.1 Hz, 1H, Ar H); 13C NMR (CDCl3, 75 MHz): δ 15.0, 39.0, 41.7, 113.6, 128.3, 128.9, 129.0, 129.6, 130.5, 136.5, 148.2, 156.2, 158.6; GC-MS: m/z 285, M+, base peak at m/z 270; Elemental analysis: Calcd: C, 63.13; H, 5.30; N, 14.73; Found: C, 63.15; H, 5.31; N, 14.76.

3-Methyl-5-(methylsulfonyl)-2-phenyl-3H-imidazo[4,5-b] pyridine (8c)

Yellow solid; mp 183.9 - 186.3˚C; 1H NMR: δ 3.31 (s, 3H, CH3), 4.08 (s, 3H, CH3), 7.60 - 7.64 (m, 3H, Ar H), 7.88 - 7.91 (m, 2H, Ar H), 8.11 (d, J = 8.1 Hz, 1H, Ar H), 8.28 (d, J = 8.1 Hz, 1H, Ar H); 13C NMR: δ 30.9, 40.7, 116.1, 127.8, 128.9, 129.2, 131.0, 138.0, 148.5, 151.0, 158.4; GC-MS: m/z 287, M+, base peak at m/z 287; Elemental analysis: Calcd: C, 61.97; H, 4.83; N, 15.49. Found: C, 61.92; H, 4.82; N, 15.47.

3-Ethyl-5-(methylsulfonyl)-2-phenyl-3H-imidazo[4,5-b] pyridine (8d)

White solid; mp 187.4 - 188.1˚C; 1H NMR: δ 1.50 (t, J = 7.5 Hz, 3H, CH3), 3.31 (s, 3H, CH3), 4.49 (q, J = 7.5 Hz, 2H, CH2), 7.56 - 7.65 (m, 3H, Ar H), 7.79 - 7.85 (m, 2H, Ar H), 8.09 (d, J = 8.1 Hz, 1H, Ar H), 8.24 (d, J = 8.4 Hz, 1H, Ar H); 13C NMR: δ 15.0, 39.2, 40.5, 115.9, 127.8, 128.9, 129.2, 130.8, 138.0, 147.9, 150.9, 158.1; GC-MS: m/z 300, M+, base peak at m/z 300. Anal. Calcd: C, 52.26; H, 3.29; N, 11.43. Found: C, 52.20; H, 3.30; N, 11.40.

N-Methyl-6-(methylthio)-3-nitropyridin-2-amine (3a)

1H NMR: δ 2.60 (s, 3H, CH3), 3.21 (d, J = 5.1 Hz, 2H, CH2), 6.50 (d, J = 9.0 Hz, 1H, Py H), 8.17 (d, J = 9.0 Hz, 1H, Py H), 8.51 (bs, 1H, NH); 13C NMR: δ 13.3, 28.0, 109.8, 123.8, 134.0, 151.8, 168.9; GC-MS: m/z 199, M+, base peak at m/z 199.

N-Ethyl-6-(methylthio)-3-nitropyridin-2-amine (3b)

1H NMR: δ 1.31 (t, J = 7.2 Hz, 3H, CH3), 2.58 (s, 3H, CH3), 3.69 – 3.73 (m, 2H, CH2), 6.48 (d, J = 8.7 Hz, 1H, Py H), 8.15 (d, J = 8.7 Hz, 1H, Py H), 8.54 (bs, 1H, NH); 13C NMR: δ 13.2, 14.6, 36.0, 109.7, 123.9, 133.9, 151.9, 168.7; GC-MS: m/z 213, M+, base peak at m/z 213.

N2-Ethyl-6-methoxypyridine-2,3-diamine (5a)

1H NMR: δ 1.22 (t, J = 7.2 Hz, 3H, CH3), 2.81 (bs, 2H, NH2), 3.43 (q, J = 7.5 Hz, 2H, CH2), 3.83 (s, 3H, CH3), 4.37 (bs, 1H, NH), 5.87 (d, J = 8.1 Hz, 1H, Py H), 6.86 (d, J = 7.8 Hz, 1H, Py H); 13C NMR: δ 15.3, 36.0, 53.3, 95.7, 119.3, 128.0, 135.0, 150.2; GC-MS: m/z 167, M+, base peak at m/z 167.

N2-((2-Chlorothiazol-5-yl)methyl)-6-methoxypyridine-2,3-diamine (5b)

1H NMR: δ 3.73 (s, 3H, CH3), 4.13 (bs, 2H, NH2), 4.64 (d, J = 6.0 Hz, 2H, CH2), 5.84 (d, J = 7.8 Hz, 1H, Py H), 6.32 (t, J = 5.7 Hz, 1H, NH), 6.79 (d, J = 8.1 Hz, 1H, Py H), 7.59 (s, 1H, Ar H); 13C NMR: δ 37.4, 53.5, 96.6, 120.1, 128.9, 138.4, 140.5, 147.7, 151.1, 158.0; GC-MS: m/z 270, M+, base peak at m/z 138.

N-(2-(Ethylamino)-6-methoxypyridin-3-yl)-2-(trifluoromethyl)benzamide (6a)

1H NMR: δ 1.23 (t, J = 7.5 Hz, 3H, CH3), 3.45 – 3.52 (m, 2H, CH2), 3.89 (s, 3H, CH3), 6.02 (d, J = 8.4 Hz, 1H, Py H), 6.99 (bs, 1H, NH), 7.32 (d, J = 8.4 Hz, 1H, Ar H), 7.57 - 7.71 (m, 3H, Ar H), 7.75 (d, J = 7.5 Hz, 1H, Py H); 13C NMR: δ 14.8, 36.2, 53.3, 95.8, 108.7, 118.2 (q, J = 271 Hz), 126.2 (q, J = 4.6 Hz), 126.7, 128.5, 129.6 (q, J = 29.8 Hz), 131.3, 132.0, 137.2, 152.6, 162.2, 167.2; GC-MS: m/z 339, M+, base peak at m/z 166.

N-{2-[((2-Chlorothiazol-5-yl)methyl)amino]-6-methoxypyridin-3-yl}-2-(trifluoro-methyl)benzamide (6b)

1H NMR: δ 3.93 (s, 3H, CH3), 4.78 (s, 2H, CH2), 6.15 (d, J = 8.1 Hz, 1H, Py H), 7.11 (bs, 1H, NH), 7.34 (d, J = 8.4 Hz, 1H, Ar H), 7.44 (s, 1H, Ar H), 7.59 - 7.69 (m, 3H, Ar H), 7.76 (d, J = 7.2 Hz, 1H, Py H); 13C NMR: δ 38.1, 53.7, 98.7, 109.7, 118.5 (q, J = 272 Hz), 126.5 (q, J = 5.1 Hz), 127.0, 128.1, 128.6, 128.9 (q, J = 30 Hz), 130.4, 132.3, 137.6, 138.7, 140.2, 151.2, 158.5, 166.9; GC-MS: m/z 442, M+, base peak at m/z 173.

Biological Assay

Stock solution of every test compound was prepared in DMF at a concentration of 1000 mg /L and then the solution was diluted to the required test concentration (50-500 mg/L) with water containing Tween 80 (0.40 mg/L) [14, 15, 16, 17].

For Fungicidal activity against P. polysora, the corn leaves with P. polysora were dipped in the test solutions to wash the spores. After filtration with 2-4 layers of gauze, and spore suspension was prepared. The spore suspension was inoculated, and cultured 24 h under weak light. Each assay contained three replications. After 24 h, mortality was recorded. The test was run three times, and results were averaged.

Acknowledgments

We acknowledge the financial support from the National Natural Science Foundation of China (21572050) and Natural Science Foundation of Hunan Province of China (2016JJ2047).

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Received: 2018-04-26
Accepted: 2018-09-27
Published Online: 2019-04-03

© 2019 Daoxin Wu et al., published by De Gruyter

This work is licensed under the Creative Commons Attribution 4.0 Public License.

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https://doi.org/10.1515/hc-2019-0003
Keywords for this article
fungicidal activity; imidazo[4,5-b]pyridine; structure-activity relationship; synthesis
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