Abstract
In order to find new compounds with high fungicidal activity, acetamide derivatives 4a–x were rationally designed, synthesized, characterized and tested against various fungi in vivo. The bioassay results indicate that compounds 4k,m,o,r exhibit an 80% inhibition rate against Rhizoctonia solani at 500 mg/L, and compound 4j shows an 80% inhibition rate against Blumeria graminis at 500 mg/L. Therefore, compounds of 4 are promising fungicidal candidates worthy of further development.
Introduction
Dihydrobenzofuran moieties are widely distributed in natural products [1], [2]. Recently, novel dihydrobenzofuran derivatives have been designed and synthesized as antitumor, insecticidal, herbicidal and fungicidal agents [3], [4], [5], [6], [7], [8], [9], [10], [11], [12]. In order to develop new fungicides, our group has synthesized compounds A [13] and B [14] with potent fungicidal activity (Figure 1). In the present report, their analogues 4a–x (Scheme 1) were synthesized and screened for fungicidal activity in vivo.
Structures of compounds A and B synthesized previously.
Compounds of 4 were synthesized as part of this work.
Synthetic route to target compounds 4a–x.
Results and discussion
The synthetic route to compounds of 4 is outlined in Scheme 1. The intermediate products 2 were prepared as previously described [5], [15]. Compounds of 3 were obtained by treatment of compounds of 2 with hydroxylamine hydrochloride. Subsequently, compounds of 4 were prepared by the reaction of 3 with 2-chloroacetamides (R3=H) or 2-chloropropionamides (R3=Me) using the Williamson etherification catalyzed by TBAB, KI and NaOH in toluene. All synthesized compounds were characterized by 1H NMR, 13C NMR, elemental analysis or high-resolution mass spectrometry (HRMS). The crystal structure of the intermediate product 3a was determined by single crystal X-ray diffraction. The single crystal X-ray analysis of compound 3a shows the orthorhombic crystal and the space group P212121 with each crystal unit made up of four molecules. The CCDC number is 1500344. As can be seen from Figure 2, the configuration of the double bond (C11=N1) is Z [13], [16]. The distance and angle are 2.68 Å and 171.0°, respectively. The intermolecular hydrogen bond appears to play an important role in stabilizing the crystal structure (Figure 3).
Crystal structure of compound 3a.
Hydrogen bonds for compound 3a.
The preliminary bioassay results indicate that some of compounds 4 show potent activities against the selected fungi Rhizoctonia solani and Blumeria graminis (B. graminis) that are better than the activities of the lead compounds A and B at 500 mg/L [13], [14]. For instance, compound 4k with the inhibitory activity of 80%, 4m (80%), 4o (80%) and 4r (80%) are the most potent agents. Compounds 4d (60%), 4e (60%) and 4f (70%) also show better fungicidal activities than the commercial fungicide azoxystrobin (50%). Compounds 4t, 4v and 4x display a 30% inhibitory activity. Analysis of the structure-activity relationships (SARs) shows that compounds of 4 substituted with an alkoxy group (R1=OMe, OEt or OPr-n) are highly active against B. graminis at the concentration of 500 mg/L. Compound 4j shows the best inhibitory activity of 80%, followed by 4g (78%) and 4i (70%). Comparison of the activities of acetamides (R3=H, 4a–t) with the activities of propanamides (R3=Me, 4u–x) reveals that the acetamides possess better antifungal activity.
Conclusion
Twenty-four compounds 4a–x were synthesized and their structures were confirmed by 1H NMR, 13C NMR, elemental analysis, HRMS and X-ray diffraction analysis. Compounds 4k, 4m, 4o and 4r show good antifungal activities against R. solani, and compounds 4g and 4j are highly active against B. graminis.
Experimental
All reagents were of analytical grade. Melting points were measured on an X-4 electrothermal digital melting point apparatus and are uncorrected. All reactions were monitored by thin-layer chromatography (TLC) on 0.25 mm silica gel plates (60GF-254) and compounds were visualized with UV light. Flash chromatography was performed using silica gel (200–400 mesh) eluting with a mixture of petroleum ether and ethyl acetate. 1HNMR (400 MHz) and 13C NMR (100 MHz) spectra were recorded in CDCl3 on a Bruker AV-400 spectrometer with tetramethylsilane (TMS) as internal standard. Elemental analyses were performed on a Vario EL III instrument. The X-ray intensity data were collected on a Bruker AXS SMART 1000 CCD diffractometer. The preparations of compounds 2a–d have been previously reported [5], [15].
General procedure for synthesis of compounds 3a–d
A mixture of 2 (12.2 mmol), NH2OH·HCl (18.2 mmol) and CH3COONa (18.2 mmol) in EtOH (50 mL) was heated under reflux. The progress of the reaction was monitored by TLC. The mixture was cooled and filtered, and the filtrate was concentrated. The resultant precipitate of 3 was crystallized from a mixture of ethanol and water.
(Z)-1-(2,2-Dimethyl-2,3-dihydrobenzofuran-5-yl)-2-(1H-1,2,4-triazol-1-yl)ethanone oxime (3a)
White solid; yield 78%; mp 149–151°C; 1H NMR: δ 1.46 (s, 6H), 2.99 (s, 2H), 5.43 (s, 2H), 6.72 (d, 1H, J=8 Hz), 7.52 (d, 1H, J=8 Hz), 7.54 (s, 1H), 7.97 (s, 1H), 8.35 (s, 1H); 13C NMR: δ 28.1, 42.5, 43.6, 87.8, 109.6, 123.3, 125.8, 127.1, 128.1, 144.3, 150.9, 151.6, 160.4. Anal. Calcd for C14H16N4O2: C, 61.75; H, 5.92; N, 20.58. Found: C, 61.67; H, 5.94, N, 20.62.
(Z)-1-(7-Methoxy-2,2-dimethyl-2,3-dihydrobenzofuran-5-yl)-2-(1H-1,2,4-triazol-1-yl)ethanone oxime (3b)
White solid; yield 94%; mp 203–206°C; 1H NMR: δ 1.52 (s, 6H), 3.04 (s, 2H), 3.88 (s, 3H), 5.44 (s, 2H), 7.20 (s, 1H), 7.26 (s, 1H), 7.96 (s, 1H), 8.35 (s, 1H). Anal. Calcd for C15H18N4O3: C, 59.59; H, 6.00; N, 18.53. Found: C, 60.02; H, 6.02; N, 18.57.
(Z)-1-(7-Ethoxy-2,2-dimethyl-2,3-dihydrobenzofuran-5-yl)-2-(1H-1,2,4-triazol-1-yl)ethanone oxime (3c)
White solid; yield 77.4%; mp 181–184°C; 1H NMR: δ 1.42 (t, 3H, J=8 Hz), 1.51 (s, 6H), 3.02 (s, 2H), 4.12 (q, 2H, J=8 Hz), 5.43 (s, 2H), 7.17 (s, 1H), 7.22 (s, 1H), 7.96 (s, 1H), 8.34 (s, 1H). Anal. Calcd for C16H20N4O3: C, 60.75; H, 6.37; N, 17.71. Found: C, 61.00; H, 6.34; N, 17.75.
(Z)-1-(2,2-Dimethyl-7-propoxy-2,3-dihydrobenzofuran-5-yl)-2-(1H-1,2,4-triazol-1-yl)ethanone oxime (3d)
White solid; yield 78%; mp 161–163°C; 1H NMR: δ 0.98 (t, 3H, J=7 Hz), 1.50 (s, 6H), 1.78 (q, 2H, J=7 Hz), 2.98 (s, 2H), 4.02 (t, 2H, J=7 Hz), 5.48 (s, 2H), 7.02 (s, 1H), 7.08 (s, 1H), 7.97 (s, 1H), 8.32 (s, 1H). Anal. Calcd for C17H22N4O3: C, 61.77; H, 6.28; N, 12.99. Found: C, 61.67; H, 6.25; N, 12.95.
General synthetic procedure for compounds 4a–x
A mixture of 3 (0.8 mmol), N-substituted-2-chloroacetamide or N-substituted-2-chloropropionamide (1 mmol), TBAB (0.4 mmol) and KI (0.8 mmol) in toluene (10 mL) was treated dropwise at room temperature with 30% NaOH (1.13 g) and then stirred at 60°C for 3 h. The mixture was extracted with EtOAc, and the combined organic layers were washed with water and brine, dried over MgSO4 and concentrated. The residue was subjected to silica gel column chromatography to give 4a–x.
N-Cyclopropyl-2-[1-(2,2-dimethyl-2,3-dihydrobenzofuran-5-yl)-2-[1,2,4]triazol-1-yl-ethylideneaminooxy]acetamide (4a)
Yellow solid; yield 59%; mp 142–144°C; 1H NMR: δ 0.56 (m, 2H), 0.75–0.85 (m, 2H), 1.47 (s, 6H), 2.75–2.79 (m, 1H), 3.01 (s, 2H), 4.74 (s, 2H), 5.41 (s, 2H), 6.72 (d, 1H, J=8 Hz), 7.35 (d, 1H, J=8 Hz), 7.42 (s, 1H), 7.46 (s, 1H), 7.97 (s, 1H), 8.20 (d, 1H, J=4 Hz); 13C NMR: δ 6.1, 22.0, 28.1, 42.4, 43.0, 73.8, 88.1, 109.6, 123.4, 124.2, 126.7, 128.6, 143.7, 151.8, 152.2, 161.1, 170.9. Anal. Calcd for C19H22N5O3: C, 61.77; H, 6.28; N, 12.99. Found: C, 61.67; H, 6.20; N, 12.90.
N-Phenyl-2-[1-(2,2-dimethyl-2,3-dihydrobenzofuran-5-yl)-2-[1,2,4]triazol-1-ylethylideneaminooxy]acetamide (4b)
White solid; yield 49.3%; mp 46–48°C; 1H NMR: δ 1.50 (s, 6H), 3.03 (s, 2H), 4.73 (s, 2H), 5.23 (s, 2H), 6.78 (d, 1H, J=8 Hz), 7.14 (m, 2H), 7.39 (m, 5H), 7.90 (s, 1H), 8.07 (s, 1H); 13C NMR: δ 28.4, 42.5, 43.0, 73.9, 88.2, 109.4, 123.6, 124.3, 125.7, 126.8, 127.5, 127.6, 127.9, 128.6, 128.8, 138.2, 143.7, 152.0, 152.2, 161.1, 169.6. Anal. Calcd for C22H23N5O3: C, 65.17; H, 5.72; N, 11.84. Found: C, 65.07; H, 5.63; N, 11.74.
N-(2,6-Dimethylphenyl)-2-[1-(2,2-dimethyl-2,3-dihydrobenzofuran-5-yl)-2-[1,2,4]triazol-1-yl-ethylideneaminooxy]acetamide (4c)
Brown solid; yield 45%; mp 74–76°C; 1H NMR: δ 1.47 (s, 6H), 2.18 (s, 6H), 3.10 (s, 2H), 4.94, 4.95 (2s, 2H), 5.43 and 5.49 (2s, 2H), 7.20 (m, 3H), 7.35 (m, 3H), 8.17 (s, 1H), 8.62 (s, 1H), 9.00 (s, 1H); 13C NMR: δ 18.4, 28.1, 42.4, 74.2, 88.6, 109.8, 123.4, 124.1, 126.8, 127.4, 128.2, 128.3, 128.6, 129.6, 133.4, 135.7, 136.0, 143.9, 152.1, 161.0, 161.4, 168.3. Anal. Calcd for C24H27N5O3: C, 66.49; H, 6.28; N, 16.16. Found: C, 66.39; H, 6.20; N, 16.10.
N-(4-Fluorophenyl)-2-[1-(2,2-dimethyl-2,3-dihydrobenzofuran-5-yl)-2-[1,2,4]triazol-1-yl-ethylideneaminooxy]acetamide (4d)
Brown solid; yield 55%; mp 61–63°C; 1H NMR: δ 1.28 (s, 6H), 2.82 (s, 2H), 4.72 (s, 2H), 5.41 (s, 2H), 6.53 (d, 1H, J=8 Hz), 6.86 (t, 2H, JH-F=8 Hz), 7.27 (d, 1H, J=8 Hz), 7.38 (m, 3H), 7.70 (s, 1H), 8.35 (s, 1H), 9.43 (s, 1H); 13C NMR: δ 28.1, 42.4, 73.9, 88.3, 109.8, 115.5, 115.7, 116.4, 116.6, 122.8, 123.6, 124. 1, 126.8, 128.8, 133.3, 144.0, 152.3, 152.6, 160.9, 161.4, 167.9. Anal. Calcd for C22H22FN5O3: C, 62.40; H, 5.24; N, 16.54. Found: C, 62.30; H, 5.14; N, 16.46.
N-(4-Chlorophenyl)-2-[1-(2,2-dimethyl-2,3-dihydrobenzofuran-5-yl)-2-[1,2,4]triazol-1-yl-ethylideneaminooxy]acetamide (4e)
Yellow solid; yield 40%; mp 57–59°C; 1H NMR: δ 1.46 (s, 6H), 2.99 (s, 2H), 4.88 (s, 2H), 5.49 (s, 2H), 6.72 (d, 1H, J=8.0 Hz), 7.27 (m, 2H), 7.38 (m, 2H), 7.55 (d, 2H, J=8 Hz), 7.91 (s, 1H), 8.26 (s, 1H), 9.20 (s, 1H); 13C NMR: δ 28.1, 43.0, 73.8, 88.3, 109.8, 121.1, 122.3, 123.5, 124.2, 124.7, 125.7, 126.9, 128.8, 128.9, 129.1, 129.7, 136.1, 152.3, 155.5, 161.4, 167.9. Anal. Calcd for C22H22ClN5O3: C, 60.07; H, 5.04; N, 15.92. Found: C, 59.90; H, 4.92; N, 15.82.
N-Benzyl-2-[1-(2,2-dimethyl-2,3-dihydrobenzofuran-5-yl)-2-[1,2,4]triazol-1-yl-ethylidene aminooxy]acetamide (4f)
Yellow solid; yield 65%; mp 78–80°C; 1H NMR: δ 1.47 (s, 6H), 2.99 (s, 2H), 4.54 (d, 2H, J=6 Hz), 4.83 (s, 2H), 5.39 (s, 2H), 6.69 (d, 1H, J=8 Hz), 7.22 (d, 1H, J=8 Hz), 7.28 (m, 5H), 7.42 (s, 1H), 8.04 (s, 1H), 8.11 (s, 1H); 13C NMR: δ 27.9, 42.2, 42.7, 73.5, 76.7, 87.9, 109.4, 123.3, 124.1, 126.6, 127.2, 127.6, 128.3, 137.9, 143.6, 151.8, 160.8, 169.5. Anal. Calcd for C23H25N5O3: C, 65.85; H, 6.01; N, 11.94. Found: C, 65.80; H, 5.93; N, 11.87.
N-(2,6-Dimethylphenyl)-2-[1-(7-methoxy-2,2-dimethyl-2,3-dihydrobenzofuran-5-yl)-2-[1,2,4]triazol-1-yl-ethylideneaminooxy]acetamide (4g)
Yellow solid; yield 47%; mp 55–57°C; 1H NMR: δ 1.52 (s, 6H), 2.20 (s, 6H), 3.03 (s, 2H), 3.86 (s, 3H), 4.95 (s, 2H), 5.48 (s, 2H), 7.05 (m, 3H), 7.17 (s, 1H), 7.54 (s, 1H), 8.18 (s, 1H), 8.92 (s, 1H); 13C NMR: δ 18.4, 28.2, 42.8, 43.0, 55.9, 73.8, 76.8, 77.0, 77.25, 88.9, 109.1, 115.9, 124.7, 127.4, 128.1, 128.3, 133.3, 135.6, 143.8, 144.9, 149.9, 152.2, 152.2, 168.2. Anal. Calcd for C25H29N5O4: C, 64.78; H, 6.31; N, 15.11. Found: C, 64.68; H, 6.23; N, 15.01. HRMS. Calcd for C25H30N5O4, (M+H)+: m/z 464.2220. Found: m/z 464.2289.
N-(4-Fluorophenyl)-2-[1-(7-methoxy-2,2-dimethyl-2,3-dihydrobenzofuran-5-yl)-2-[1,2,4]triazol-1-yl-ethylideneaminooxy]acetamide (4h)
Gray solid; yield 32%; mp 73–75°C; 1H NMR: δ 1.51 (s, 6H), 3.02 (s, 2H), 3.86 (s, 3H), 4.89 (s, 2H), 5.48 (s, 2H), 7.01 (s, 1H), 7.03 (s, 1H), 7.07 (m, 2H), 7.50–7.57 (m, 2H), 7.91 (s, 1H), 8.26 (s, 1H), 9.11 (s, 1H); 13C NMR: δ 27.8, 42.6, 43.0, 55.7, 73.6, 88.7, 108.9, 115.7, 120.6, 124.4, 128.2, 128.6, 137.0, 143.5, 144.1, 144.7, 149.5, 152.0, 152.2, 154.4, 166.1, 167.4. Anal. Calcd for C23H24FN5O4: C, 60.92; H, 5.33; N, 15.44. Found: C, 60.83; H, 5.23; N, 15.34.
N-Benzyl-2-[1-(7-methoxy-2,2-dimethyl-2,3-dihydrobenzofuran-5-yl)-2-[1,2,4]triazol-1-yl-ethylideneaminooxy]acetamide (4i)
Yellow solid; yield 59%; mp 143–145°C; 1H NMR: δ 1.52 (s, 6H), 3.02 (s, 2H), 3.86 (s, 3H), 4.55 (s, 2H), 5.39 (s, 2H,), 6.93 (s, 1H), 7.07 (s, 1H), 7.28 (m, 5H), 8.00 (s, 1H), 8.11 (s, 1H); 13C NMR: δ 28.1, 42.5, 43.1, 55.8, 55.9, 74.3, 89.2, 109.1, 116.0, 124.9, 127.5, 128.4, 128.6, 138.2, 143.6, 144.8, 149.8, 151.8, 152.1, 153.6, 163.1, 169.6. Anal. Calcd for C24H27N5O4: C, 64.13; H, 6.05; N, 15.58. Found: C, 64.03; H, 5.96; N, 15.48.
N-Cyclopropyl-2-[1-(7-ethoxy-2,2-dimethyl-2,3-dihydrobenzofuran-5-yl)-2-[1,2,4]triazol-1-yl-ethylideneaminooxy]acetamide (4j)
Gray solid; yield 35%; mp 80–82°C; 1H NMR: δ 0.57 (t, 2H, J=4 Hz), 0.79 (t, 2H, J=7 Hz), 1.02 (t, 3H, J=7 Hz), 1.51 (s, 6H), 2.77–2 (m, 1H), 3.02 (s, 3H), 4.12 (q, 2H, J=7 Hz), 4.75 (d, 2H, J=4 Hz), 5.45 (s, 2H), 7.03 (s, 1H), 7.08 (s, 1H), 7.99 (s, 1H), 8.33 (s, 1H); 13C NMR: δ 6.5, 13.7, 22.0, 24.3, 28.4, 43.1, 43.2, 64.9, 73.9, 88.4, 111.1, 115.8, 124.8, 129.1, 136.4, 144.0, 150.2, 152.6, 162.0, 171.1. Anal. Calcd for C21H27N5O4: C, 61.00; H, 6.58; N, 16.94. Found: C, 60.93; H, 6.50; N, 16.84.
N-(2,6-Dimethylphenyl)-2-[1-(7-ethoxy-2,2-dimethyl-2,3-dihydrobenzofuran-5-yl)-2-[1,2,4]triazol-1-yl-ethylideneaminooxy]acetamide (4k)
Brown solid; yield 35%; mp 83–85°C; 1H NMR: δ 1.42 (t, 3H, J=7 Hz), 1.52 (s, 6H), 2.20 (m, 6H), 3.01 (d, 2H, J=3.5 Hz), 4.09 (t, 2H, J=7 Hz), 4.81 (s, 1H), 4.96 (s, 1H), 5.51 (s, 2H), 7.02 (s, 1H), 7.08 (s, 1H), 7.12–7.20 (m, 3H), 8.23 (s, 1H), 8.58 (s, 1H), 8.88 (s, 1H); 13C NMR: δ 14.6, 18.3, 28.1, 42.5, 42.9, 64.5, 73.6, 88.6, 110.5, 110.6, 115.7, 124.4, 127.3, 128.0, 128.5, 133.2, 135.5, 143.9, 150.0, 151.9, 152.1, 168.3. Anal. Calcd for C26H31N5O4: C, 65.39; H, 6.54; N, 14.66. Found: C, 65.29; H, 6.46; N, 14.56.
N-(4-Fluorophenyl)-2-[1-(7-ethoxy-2,2-dimethyl-2,3-dihydrobenzofuran-5-yl)-2-[1,2,4]triazol-1-yl-ethylideneaminooxy]acetamide (4l)
Gray solid; yield 45%; mp 136–138°C; 1H NMR: δ 1.26 (t, 3H, J=7 Hz), 1.49 (s, 6H), 3.03 (s, 2H), 3.74 (q, 2H, J=7 Hz), 4.73 (s, 2H), 5.23 (s, 2H), 6.77 (s, 1H), 7.12 (t, 2H, JH-F=8 Hz), 7.35 (s, 1H), 7.43 (d, 2H, J=8 Hz), 7.74 (s, 1H), 7.91 (s, 1H), 8.09 (s, 1H); 13C NMR: δ 15.0, 28.4, 43.0, 54.3, 64.3, 89.8, 112.9, 115.8, 118.5, 122.4, 126.2, 127.5, 128.1, 128.5, 133.3, 137.9, 142.7, 144.0, 153.7, 154.8, 160.8, 169.8. Anal. Calcd for C24H26FN5O4: C, 61.66; H, 5.61; N, 14.98. Found: C, 61.56; H, 5.53; N, 14.88.
N-(4-Chlorophenyl)-2-[1-(7-ethoxy-2,2-dimethyl-2,3-dihydrobenzofuran-5-yl)-2-[1,2,4]triazol-1-yl-ethylideneaminooxy]acetamide (4m)
Gray solid; yield 43%; mp101–103°C; 1H NMR: δ 1.47 (d, 3H, J=7 Hz), 1.57 (s, 6H), 3.10 (s, 2H) 4.10 (m, 2H), 4.89 (s, 2H), 5.49 (s, 2H), 7.02 (s, 1H), 7.08 (s, 1H), 7.31 (d, 2H, J=8 Hz), 7.56 (d, 2H, J=8 Hz), 7.94 (s, 1H), 8.32 (s, 1H), 9.14 (s, 1H). Anal. Calcd for C24H26ClN5O4: C, 59.56; H, 5.42; N, 14.47. Found: C, 59.46; H; 5.33; N, 14.40.
N-Benzyl-2-[1-(7-ethoxy-2,2-dimethyl-2,3-dihydroben-zofuran-5-yl)-2-[1,2,4]triazol-1-yl-ethylideneaminooxy]acetamide (4n)
Yellow solid; yield 41%; mp 86–88°C; 1H NMR: δ 1.03 (t, 3H, J=7 Hz), 1.51 (s, 6H), 3.01 (s, 2H), 4.11 (q, 2H, J=7 Hz), 4.56 (d, 2H, J=4 Hz), 4.85 (s, 2H), 5.44 (s, 2H), 7.00 (s, 1H), 7.07 (s, 1H), 7.24 (s, 1H), 7.27 (m, 2H), 7.29 (s, 2H), 7.99 (s, 1H), 8.23 (s, 1H); 13C NMR: δ 13.7, 19.7, 24.3, 28.1, 43.3, 59.6, 73.7, 88.3, 111.1, 116.0, 121.0, 122.1, 124.8, 127.3, 127.7, 128.7, 131.1, 138.1, 144.0, 150.2, 152.0, 155.1, 167.2, 169.6. Anal. Calcd for C25H29N5O4: C, 64.78; H, 6.31; N, 15.11. Found: C, 64.68; H, 6.21; N, 15.01.
N-Cyclopropyl-2-[1-(7-propoxy-2,2-dimethyl-2,3-dihydrobenzofuran-5-yl)-2-[1,2,4]triazol-1-yl-ethylideneaminooxy]acetamide (4o)
Gray solid; yield 38%; mp 95–97°C; 1H NMR: δ 0.57 (t, 2H, J=7 Hz), 0.81–1.00 (m, 2H), 1.50 (s, 6H), 1.83 (m, 2H), 2.77 (m, 1H), 3.01 (s, 2H), 4.00 (t, 2H, J=7 Hz), 4.75 (s, 2H), 5.42 (s, 2H), 7.00 (s, 1H), 7.06 (s, 1H), 7.98 (s, 1H), 8.24 (s, 1H). Anal. Calcd for C22H29N5O4: C, 61.81; H, 6.84; N, 16.38. Found: C, 61.71; H, 6.74; N, 16.28.
N-Phenyl-2-[1-(7-propoxy-2,2-dimethyl-2,3-dihydrobenzofuran-5-yl)-2-[1,2,4]triazol-1-yl-ethylideneaminooxy]acetamide (4p)
Yellow solid; yield 51%; mp 120–122°C; 1H NMR: δ 0.99 (t, 3H, J=7 Hz), 1.50 (s, 6H), 1.80 (q, 2H, J=7 Hz), 3.00 (s, 2H), 3.98 (t, 2H, J=7 Hz), 4.89 (s, 2H), 5.48 (s, 2H), 7.02 (s, 1H), 7.08 (s, 1H), 7.14 (t, 1H, J=8 Hz), 7.34 (t, 2H, J=8 Hz), 7.59 (d, 2H, J=8 Hz), 7.97 (s, 1H), 8.32 (s, 1H), 9.05 (s, 1H); 13C NMR: δ 10.6, 22.3, 28.2, 42.9, 43.4, 71.0, 74.0, 88.7, 111.4, 116.0, 120.8, 124.6, 124.7, 128.8, 128.8, 137.3, 140.7, 144.1, 146.7, 150.3, 152.4, 158.7, 161.4, 167.8. Anal. Calcd for C25H29N5O4: C, 64.78; H, 6.31; N, 15.11. Found: C, 64.63; H, 6.23; N, 15.01.
N-(4-Fluorophenyl)-2-[1-(7-propoxy-2,2-dimethyl-2,3-dihydrobenzofuran-5-yl)-2-[1,2,4]triazol-1-yl-ethylideneaminooxy]acetamide (4q)
White solid; yield 44%; mp 136–138°C; 1H NMR: δ 1.00 (t, 3H, J=7 Hz), 1.51 (s, 6H), 1.80 (m, 2H), 3.01(s, 2H), 3.99 (t, 2H, J=7 Hz), 4.90 (s, 2H), 5.49 (s, 2H), 6.99 (s, 1H), 7.01 (s, 1H), 7.05 (d, 2H, J=8 Hz), 7.43 (m, 2H), 7.93 (s, 1H), 8.36 (s, 1H), 9.15 (s, 1H); 13C NMR: δ 10.4, 22.4, 28.2, 43.0, 43.3, 70.9, 73.9, 88.7, 111.4, 115.5, 115.7, 116.0, 122.0, 122.8, 124.5, 129.0, 133.3, 139.7, 144.2, 150.4, 152.1, 152.3, 157.0, 160.9, 167.9. Anal. Calcd for C25H28FN5O4: C, 62.36; H, 5.86; N, 14.54. Found: C, 62.26; H, 5.79; N 14.48.
N-(4-Chlorophenyl)-2-[1-(7-propoxy-2,2-dimethyl-2,3-dihydrobenzofuran-5-yl)-2-[1,2,4]triazol-1-yl-ethylideneaminooxy]acetamide (4r)
Yellow solid; yield 40%; mp 179–181°C; 1H NMR: δ 1.00 (t, 3H, J=7 Hz), 1.51 (s, 6H), 1.81 (m, 2H), 3.01 (s, 2H), 3.99 (t, 2H, J=7 Hz), 4.90 (s, 2H), 5.49 (s, 2H), 7.02 (s, 1H), 7.08 (s, 1H), 7.30 (d, 2H, J=8 Hz), 7.56 (d, 2H, J=8 Hz), 7.97 (s, 2H), 9.14 (s, 1H); 13C NMR: δ 10.7, 22.6, 28.2, 43.1, 43.3, 71.2, 74.2, 88.9, 111.3, 116.0, 122.3, 124.5, 128.9, 129.7, 136.0, 144.1, 150.3, 150.9, 152.4, 152.7, 160.3, 167.9. Anal. Calcd for C25H28ClN5O4: C, 60.30; H, 5.67; N, 14.06. Found: C, 60.23; H, 5.60; N, 14.00.
N-Benzyl-2-[1-(7-propoxy-2,2-dimethyl-2,3-dihydrobenzofuran-5-yl)-2-[1,2,4]triazol-1-yl-ethylideneaminooxy]acetamide (4s)
Yellow solid; yield 61%; mp 125–127°C; 1H NMR: δ: 1.01 (t, 3H, J=7 Hz), 1.50 (s, 6H), 1.80 (m, 2H), 2.99 (s, 2H), 3.99 (t, 2H, J=7 Hz), 4.54 (d, 2H, J=6 Hz), 4.84 (s, 2H), 5.37 (s, 2H), 6.93 (s, 1H), 7.04 (s, 1H), 7.25 (m, 5H), 7.96 (s, 1H), 8.15 (m, 1H). Anal. Calcd for C26H31N5O4: C, 65.39; H, 6.54; N, 14.66. Found: C, 65.31; H, 6.48; N, 14.58.
N-(Pyridin-2-yl)-2-[1-(7-methoxy-2,2-dimethyl-2,3-dihydrobenzofuran-5-yl)-2-[1,2,4-triazol-1-yl]ethylideneaminooxy]acetamide (4t)
White solid; yield 52%; mp 65–67°C; 1H NMR: δ 1.50 (s, 6H), 2.20 (s, 6H), 2.99–3.01 (m, 2H), 3.84 (m, 3H), 4.90 (m, 2H), 5.46–5.49 (m, 2H), 7.06 (m, 3H), 7.68–7.71 (m, 1H), 8.26 (m, 4H), 9.67 (s, 1H); 13C NMR: δ 28.2, 42.9, 43.5, 56.0, 74.0, 88.9, 109.4, 114.6, 116.3, 120.1, 125.0, 128.4, 138.2, 143.7, 144.8, 149.8, 151.1, 152.9, 168.3. HRMS. Calcd for C22H25N6O4, (M+H)+: m/z 437.1893. Found: m/z 437.1932.
N-Phenyl-2-[1-(7-methoxy-2,2-dimethyl-2,3-dihydrobenzofuran-5-yl)-2-(1,2,4-triazol-1-yl)ethylideneaminooxy]propanamide (4u)
White solid; yield 55%; mp 66–68°C; 1H NMR: δ 1.51 (s, 6H), 1.64 (d, 3H, J=4.0 Hz), 3.02 (s, 2H), 3.84 (s, 3H), 5.00 (q, 1H, J=4 Hz), 5.20 (d, 1H, J=12 Hz), 5.78 (d, 1H, J=12 Hz), 7.04 (s, 1H), 7.10 (s, 1H), 7.12 (t, 1H, J=8 Hz), 7.33 (t, 2H, J=4 Hz), 7.59 (d, 2H, J=8 Hz), 7.95 (s, 1H), 8.22 (s, 1H), 8.89 (s, 1H); 13C NMR: δ 17.6, 28.2, 43.0, 43.4, 56.0, 81.1, 88.9, 109.4, 116.1, 120.8, 124.6, 125.1, 128.5, 128.9, 137.6, 143.8, 144.9, 149.8, 152.0, 152.6, 170.7. HRMS. Calcd for C24H28N5O4, (M+H)+: m/z 450.2063. Found: m/z 450.2130.
N-(2,6-Dimethylphenyl)-2-[1-(7-methoxy-2,2-dimethyl-2,3-dihydrobenzofuran-5-yl)-2-(1,2,4-triazol-1-yl)ethylideneaminooxy]propanamide (4v)
White solid; yield 46%; mp 79–81°C; 1H NMR: δ 1.52 (s, 6H), 1.70 (d, 3H, J=4 Hz), 2.16 (s, 6H), 3.02 (s, 2H), 3.86 (s, 3H), 5.05 (q, 1H, J=4 Hz), 5.18 (d, 1H, J=12 Hz), 5.78 (d, 1H, J=12 Hz), 7.03 (d, 2H, J=4 Hz), 7.05 (s, 1H), 7.09 (m, 1H), 7.57 (s, 1H), 8.18 (s, 1H), 8.66 (s, 1H); 13C NMR: δ 17.8, 18.3, 28.2, 28.2, 42.9, 43.0, 56.0, 81.2, 88.9, 109.0, 115.9, 125.0, 127.3, 128.1, 128.3, 133.4, 135.6, 143.8, 144.9, 149.8, 151.6, 152.2, 171.3. HRMS. Calcd for C26H31N5O4, (M+H)+: m/z 478.2376. Found: m/z 478.2445.
N-(4-Chlorophenyl)-2-[1-(7-methoxy-2,2-dimethyl-2,3-dihydrobenzofuran-5-yl)-2-(1H-1,2,4-triazol-1-yl)ethylideneaminooxy]propanamide (4w)
White solid; yield 40%; m.p. 68–70°C; 1H NMR: δ 1.51 (s, 6H), 1.64 (d, 3H, J=4 Hz), 3.02 (s, 2H), 3.85 (s, 3H), 5.00 (q, 1H, J=4 Hz), 5.18 (d, 1H, J=12 Hz), 5.78 (d, 1H, J=12 Hz), 7.02 (s, 1H), 7.09 (s, 1H), 7.28 (d, 2H, J=8 Hz), 7.55 (d, 2H, J=8 Hz), 7.93 (s, 1H), 8.22 (s, 1H), 9.00 (s, 1H); 13C NMR: δ 14.2, 17.6, 28.2, 43.0, 43.4, 56.1, 81.0, 89.0, 109.4, 116.0, 122.0, 125.0, 128.5, 128.9, 129.6, 136.3, 143.9, 144.9, 149.9, 152.0, 152.5, 170.9. HRMS. Calcd for C24H27 ClN5O4, (M+H)+: m/z 484.1673. Found: m/z 484.1741.
N-(Pyridin-2-yl)-2-[1-(7-methoxy-2,2-dimethyl-2,3-dihydrobenzofuran-5-yl)-2-(1H-1,2,4-triazol-1-yl)ethylidene)amino)oxy]propanamide (4x)
White solid; yield 43%; mp 63–65°C; 1H NMR: δ 1.51, (m, 6H), 1.65 (d, 3H, J=4 Hz), 2.04 (s, 2H), 3.85 (s, 3H), 4.14 (q, 1H, J=4 Hz), 5.34 (d, 1H, J=12 Hz), 5.62 (d, 1H, J=12 Hz), 7.05 (m, 1H), 7.07 (s, 1H), 7.27 (s, 1H), 7.71 (m, 1H), 8.14 (s, 1H), 8.23 (s, 1H), 8.24 (d, 1H, J=8 Hz), 8.32 (s, 1H), 9.43 (s, 1H); 13C NMR: δ 17.5, 28.2, 42.98, 43.7, 56.0, 81.0, 88.9, 109.5, 114.4, 116.3, 120.0, 125.2, 128.4, 138.2, 143.7, 144.7, 147.9, 149.7, 151.3, 152.7, 152.7, 171.2. HRMS. Calcd for C23H27 N6O4, (M+H)+: m/z 451.2016. Found: m/z 451.2072.
Crystal structure determination
The crystal of 3a was analyzed at 150(2) K on a Bruker SMART CPEX 1000 CCD diffractometer equipped with a graphite-monochromatic MoKα (λ=0.071073 nm) radiation source. The data were restored using Bruker’s SCINTPLUS program [17], while the empirical absorption correction was performed using the SADABS procedure [18]. The structure was solved and refined by SHELXS-97 and SHELXL-97 [19]. The non-hydrogen atoms were refined anisotropically, and hydrogen atoms were added according to theoretical models.
Fungicidal activity assay
The toxicities of compounds 4a–x against 6 fungi were tested according to the Pesticide Biological Activity Evaluation Standard (SOP) [13]. The fungi were Rhizoctonia (R. solani), Phytophythora capsici (P. capsici), Sclerotonia sclerotiorum (S. sclerotiorum), Gibberella zeae (G. zeae), Alternaria alternate (A. alternate) and Blumeria graminis (B. graminis), R. solani and B. graminis were tested in vivo by a small plant assay at 500 mg/L, while P. capsici, S. sclerotiorum, G. zeae and A. alternate were tested by toxic medium method at 25 mg/L.
Funding: Natural Science Foundation of Hebei Province of China, Grant Number: H2018201273.
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