Synthesis and bioactivity of novel strobilurin derivatives containing the pyrrolidine-2,4-dione moiety

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Gui-Hua Lu, Hai-Bin Chu, Min Chen, Chun-Long Yang.Synthesis and bioactivity of novel strobilurin derivatives containing the pyrrolidine-2,4-dione moiety[J]. Chin. Chem. Lett., 2014,25(01): 61-64 复制到剪切板

Gui-Hua Lu^a,c, Hai-Bin Chu^b,c, Min Chen^a,b,c, Chun-Long Yang^a,b,c

* Corresponding authors at:^a Jiangsu Key Laboratory of Pesticide Science, Nanjing Agricultural University, Nanjing 210095, China;
^b Key Laboratory of Monitoring and Management of Crop Diseases and Pest Insects, Ministry of Agriculture, Nanjing Agricultural University, Nanjing 210095, China;
^c College of Science, Nanjing Agricultural University, Nanjing 210095, China

Received:2013-5-21, Revised:2013-9-21, online:2013-11-12.

E-mail addresses:ycl@njau.edu.cn

Abstract: (E)-Methyl-2-(2-(bromomethyl)phenyl)-3-methoxyacrylate was reacted with substituted 1-acetylpyrrolidine-2,4-diones and 3-(1-(hydroxylamino)ethylidene)pyrrolidine-2,4-diones respectively to synthesize two series of β-methoxyacrylate derivatives containing the pyrrolidine-2,4-dione moiety. The structures of the targeted compounds were confirmed by IR, ¹H NMR, ¹³C NMR, MS and elemental analysis. The fungicidal activity against Rhizoctonia solani, Botrytis cinerea and Fusarium graminearum was evaluated. The bioassay results demonstrated that these compounds showed visible fungicidal activity.

Key words: Strobilurin Pyrrolidine-2,4-dione Synthesis Fungicidal activity

1. Introduction

As nitrogenous heterocyclic compounds with the pyrrolidine- 2,4-dione moiety, natural tetramic acids often exhibit not only antitumor and antiviral ^{[1, 2]}, but also herbicidal, insecticidal and fungicidal activity ^{[3, 4, 5]}. Using natural tetramic acid as the lead compound, many pyrrolidine-2,4-dione derivatives were designed and synthesized, a considerable part of which was found to present remarkable biological activity ^{[6, 7, 8, 9, 10]}. It is noteworthy that when proper groups, such as oxime ethers and Schiff bases, were introduced to the 3-position of the pyrrolidine-2,4-dione, the corresponding tetramic acid derivatives showed better inhibitory activity against phytopathogenic fungi than the naturally occurring tenuazonic acid (also called TeA) in the tetramic acid family ^{[11, 12, 13, 14]}.

Strobilurin fungicides were derived from another naturally occurring lead compound strobilurin A with a reactive group of β-methoxyacrylate. They have the outstanding characteristics of unique action mechanism, broad spectrum, long duration, high activity and outstanding environmental tolerability ^[15]. In this study, two reactive groups, namely pyrrolidine-2,4-dione and β-methoxyacrylate, were spliced in a same structure through an oxime ether bridging group or a methylene bridging group. This modification was expected to improve the fungicidal activity.

2. Experimental

The melting points of the synthesized compounds were measured on a WRS-1B digital melting point apparatus. IR spectra were recorded on a Bruker Tensor 27 FT-IR spectrometer with a KBr disk. Elemental analyses were determined on an Elementar Vario EL cube analyser. ¹H NMR and ¹³C NMR spectra were collected on a Bruker AV 400 MHz spectrometer with CDCl₃ as the solvent and TMS as the internal reference. Mass spectra were recorded on a GC/MS-QP2010 spectrometer using a direct injection technique.

The synthetic routes for the targeted compounds were illustrated in Scheme 1. (E)-Methyl-2-(2-(bromomethyl)phenyl)- 3-methoxyacrylate 3 was prepared by the methylation of the hydroxy group followed by a bromination of the methyl group in (E)-methyl-2-(2-methylphenyl)-3-hydroxyacrylate 1 according to the method reported in the literatures ^{[16, 17]}. 1-Acetylpyrrolidine- 2,4-diones 5 were prepared by the cyclization of N,Ndiacetyl- amino acid methyl esters 4 according to the method reported in the literature ^[18]. Compound 5 (5 mmol) and K₂CO₃ (10 mmol) were stirred in DMF (50 mL) at room temperature for 30 min, then compound 3 (5 mmol) was added. The mixture was heated at 60 ℃ for 8 h and the reaction was monitored by TLC analysis. After the reaction completed, the mixture was diluted with 300 mL of water and extracted with ethyl acetate. The organic layer was washed with water and saturated NaCl solution sequentially, dried over MgSO₄, and concentrated in vacuo. The residue was separated by a silica gel column to afford the targeted compounds 6a-6d.

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Scheme 1.Synthetic routes for the compounds 6 and 9. Condition and regent: (1) (CH₃)₂CO, K₂CO₃, (CH₃)₂SO₄; (2) CCl₄, NBS, AIBN; (3) Na, xylene; (4) DMF, K₂CO₃; (5) NH₂OH·HCl, C₂H₅OH; (6) DMF, K₂CO₃.

3-(1-(Hydroxylamino)ethylidene)pyrrolidine-2,4-diones 8 were prepared by the reaction of 3-(1-hydroxyethylidene)pyrrolidine- 2,4-diones 7 with hydroxylamine according to the method reported in the literatures ^{[7, 19]}. K₂CO₃ (10 mmol) and compound 8 (5 mmol) were stirred in DMF (40 mL) at room temperature for 1 h. Then compound 3 (5 mmol) was dissolved in DMF (10 mL) and dripped slowly to above solution over 2 h. The mixture was stirred at room temperature for 1 h and the reaction was monitored by TLC analysis. After the reaction completed, the mixture was diluted with 200 mL of water and extracted with ethyl acetate. The organic layer was washed with water, dried over MgSO₄ and concentrated in vacuo. The residue was separated by a silica gel column (for 9a, 9c and 9d), or was recrystallized from ethanol (for 9b) to give the targeted compounds.

3. Results and discussion

Through the reactions of the key intermediate 3 with compounds 5 and 8 respectively, two series of novel β-methoxyacrylate derivatives 6a-6dand 9a-9dwere prepared in yields of 35-55%. An efficient and operationally simple route was developed to introduce substituted benzyl moieties at the 3- position of pyrrolidine-2,4-dione. By contrast, the compounds 2- (substituted benzyl)-1,3-cyclopentadiones were prepared by a two-step procedure including a Knoevenagel condensation and a hydrogenation reaction ^[20]. And the compounds 2-(substituted benzyl)-1,3-cyclohexanediones were prepared by an organocatalytic reductive alkylation between an aldehyde and the hantzsch ester ^[21]. The targeted compounds 9a-9dwere prepared using a traditional method. The heterocyclic pyrrolidine-2,4-dione was attached to the reactive structure of β-methoxyacrylate through an oxime ether group.

The structures of the targeted compounds were confirmed by IR, ¹H NMR, ¹³C NMR, MS and elemental analysis. The IR spectrum showed peaks at 1743-1627 cm^-1 assigned to the carbonyl groups and peaks at 3268-3189 cm^-1 due to N-H stretching vibration of compounds 9a-9d. Compounds 6a-6dgave peaks at 3367- 3305 cm^-1 due to O-H stretching vibration, because these four oily liquids belong to N-acyl tetramic acids and exist in both keto and enol forms ^[22]. The ¹H NMR spectrum of all the compounds showed peaks between δ 3.83 and 4.90 for the protons at the 5- postion of the pyrrolidine, and peaks between δ 3.69 and 3.85 for the protons of the OCH₃ group. Compounds 6a-6dshowed peaks at d 1.98-2.06 for the COCH₃ protons at the 1-postion of the pyrrolidine. Compounds 9a-9dshowed peaks at δ 5.59-8.19 for the proton of N-H at the 1-postion. The ¹³C NMR spectrum showed all corresponding peaks except that of PhCH₂ at the 3-position of compounds 6a-6d. This phenomenon was also observed in the compounds 2-(substituted benzyl)-1,3-cyclohexanediones ^[21]. Only compounds 9a and 9c showed [M⁺] peaks, but other targeted compounds gave matched fragment ion peaks. Moreover, all the target compounds showed satisfactory elemental analysis data. Selected characterization data of the targeted compounds are listed below.

6a: Yellow viscous liquid, yield: 46%; IR (KBr, cm^-1): v 3344, 3066, 2942, 2851, 1743, 1627, 1557, 1436, 1263, 1197, 1132; ¹H NMR(400 MHz, CDCl₃): δ 2.06 (s, 3H, CH₃CO), 3.71 (s, 3H, COOCH₃), 3.85 (d, 3H, J = 6.8 Hz, OCH₃), 4.02-4.08 (m, 2H, NCH₂), 5.10 (s, 2H, PhCH₂), 6.07 (s, 1H, COCHCO), 7.15-7.18 (m, 1H, PhH), 7.31-7.37 (m, 2H, PhH), 7.40-7.43 (m, 1H, PhH), 7.58 (d, 1H, J = 5.3 Hz, C=CH); ¹³CNMR(100 MHz, CDCl₃): δ 22.45 (CH₃CO), 41.43 (NCH₂), 51.84 (COOCH₃), 62.16 (OCH₃), 65.41 (COCHCO), 109.55 (C=CH), 128.11, 128.32, 128.76, 131.24, 132.19, 134.31 (6C, C₆H₄), 160.71 (C=CH), 168.24, 169.90, 172.06, 187.93 (4C, 4×CO); MS m/z (%): 321(1), 204(4), 190(100), 145(35); Anal. Calcd. for C₁₈H₁₉NO₆: C, 62.60; H, 5.55; N, 4.06; Found: C, 62.98; H, 5.46; N, 4.17.

6b: Yellow viscous liquid, yield: 55%; IR (KBr, cm^-1): v 3361, 3066, 2964, 2876, 1738, 1634, 1528, 1435, 1258, 1200, 1145; ¹H NMR (400 MHz, CDCl₃): δ 0.87 (d, 3H, J = 6.9 Hz, CH₃CHCH₃), 0.93 (d, 3H, J = 6.8 Hz, CH₃CHCH₃), 2.14-2.18 (m, 1H, CH₃CHCH₃), 2.04 (s, 3H, CH₃CO), 3.72 (s, 3H, COOCH₃), 3.84 (s, 3H, OCH₃), 4.61 (dd, 1H, J = 8.8, 4.7 Hz, NCH), 5.07 (q, 2H, J = 12.6 Hz, PhCH₂), 6.00 (d, 1H, J = 7.8 Hz, COCHCO), 7.16-7.18 (dd, 1H, J = 8.3, 4.8 Hz, PhH), 7.32-7.38 (m, 2H, PhH), 7.39-7.45 (m, 1H, PhH), 7.59 (s, 1H,C=CH); ¹³C NMR (100 MHz, CDCl₃): δ 17.70 (CH₃CHCH₃), 19.00 (CH₃CHCH₃), 22.66 (CH₃CO), 31.02 (CH₃CHCH₃), 51.71 (COOCH₃), 57.40 (NCH), 62.07 (OCH₃), 65.17 (COCHCO), 109.57 (C=CH), 128.04, 128.16, 128.53, 131.22, 132.08, 134.31 (6C, C₆H₄), 160.59 (C=CH), 167.93, 171.27, 171.93, 187.87 (4C, 4×CO); MS m/z (%): 363(0.5), 205(4), 190(40), 145(19); Anal. Calcd. for C₂₁H₂₅NO₆: C, 65.10; H, 6.50; N, 3.62; Found: C, 65.26; H, 6.66; N, 3.57.

6c: Yellow viscous liquid, yield: 45%; IR (KBr, cm^-1): v 3367, 3067, 2963, 2878, 1738, 1630, 1537, 1456, 1255, 1205, 1143; ¹H NMR (400 MHz, CDCl₃): δ 0.82-0.94 (m, 6H, CH₃CH₂ + CH₃CH), 1.07-1.42 (m, 2H, CH₃CH₂), 1.84-1.99 (m, 1H, CH₃CH), 2.03 (d, 3H, J = 4.4 Hz, CH₃CO), 3.71 (s, 3H, COOCH₃), 3.84 (s, 3H, OCH₃), 4.63, 4.74 (dd, dd, 1H, J = 8.7, 5.0, 9.1, 3.8 Hz, NCH), 5.01-5.12 (m, 2H, PhCH₂), 6.00 (dd, 1H, J = 30.2, 8.6 Hz, COCHCO), 7.14-7.20 (m, 1H, PhH), 7.31-7.38 (m, 2H, PhH), 7.38-7.44 (m, 1H, PhH), 7.59 (s, 1H, C=CH); ¹³C NMR (100 MHz, CDCl₃): δ 11.72 (CH₃CH₃), 15.45 (CH₃CH), 22.76 (CH₃CO), 26.16 (CH₃CH₃), 37.55 (CH₃CH), 51.83 (COOCH₃), 55.66 (NCH), 62.16 (OCH₃), 65.43 (COCHCO), 109.66 (C=CH), 128.14, 128.26, 128.54, 131.26, 132.02, 134.24(6C, C₆H₄), 160.59 (C=CH), 168.06, 171.35, 171.91, 187.83 (4C, 4×CO); MS m/z (%): 377(1), 205(5), 190(40), 145(25); Anal. Calcd. for C₂₂H₂₇NO₆: C, 65.82; H, 6.78; N, 3.49; Found: C, 65.58; H, 6.86; N, 3.37.

6d: Yellow viscous liquid, yield: 55%; IR (KBr, cm^-1): v 3305, 3063, 2948, 2844, 1741, 1703, 1634, 1541, 1495, 1434, 1253, 1130; ¹H NMR (400 MHz, CDCl₃) d: 1.98 (s, 3H, CH₃CO), 3.11 (ddd, 2H, J = 30.4, 13.8, 5.7 Hz, phCH₂), 3.69 (s, 3H, COOCH₃), 3.82 (s, 3H, OCH₃), 4.90 (dt, 1H, J = 7.7, 5.6 Hz, NCH), 5.06 (s, 2H, phCH₂), 5.95 (d, 1H, J = 7.6 Hz, COCHCO), 7.00-7.03 (m, 2H, PhH), 7.18 (d, 1H, J = 6.4 Hz, PhH), 7.23-7.26 (m, 3H, PhH), 7.31-7.40(m, 3H, PhH), 7.59 (s, 1H, C=CH); ¹³C NMR (100 MHz, CDCl₃): δ 22.70 (CH₃CO), 37.60 (phCH₂), 51.75 (COOCH₃), 53.53 (NCH), 62.07 (OCH₃), 65.39 (COCHCO), 109.67 (C=CH), 127.02, 128.09, 128.27, 128.56, 128.77, 129.32, 131.29, 132.26, 134.27, 136.24 (12C, C₆H₅ + C₆H₄), 160.62 (C=CH), 167.94, 170.69, 171.57, 187.95 (4C, 4×CO); MS m/z (%): 411(1), 205(45), 190(62), 145(76); Anal. Calcd. for C₂₅H₂₅NO₆: C, 68.95; H, 5.79; N, 3.22; Found: C, 68.78; H, 5.86; N, 3.27.

9a: Yellow viscous liquid, yield: 35%; IR (KBr, cm^-1): v 3268, 2923, 2852, 1704, 1633, 1565, 1431, 1256, 1129, 1109; ¹H NMR (400 MHz, CDCl₃): δ 1.37 (dd, 3H, J = 6.9, 4.5Hz, CH₃CH), 2.41 (s, 3H, CH₃CNH), 3.69 (s, 3H, COOCH₃), 3.82 (s, 3H, OCH₃), 3.93-4.02 (m, 1H, CHNH), 4.93 (s, 2H, CH₂O), 5.59 (br, 1H,CHNH), 7.22 (d, 1H, J = 7.3 Hz, PhH), 7.36-7.45 (m, 3H, PhH), 7.62 (s, 1H, C=CH), 7.78(br, 1H, NHO); ¹³C NMR (100 MHz, CDCl₃): δ 11.31 (CH₃CNH), 17.62 (CH₃CH), 51.63 (COOCH₃), 53.02 (CHNH), 62.04 (OCH₃), 75.93 (CH₂O), 96.18 (COCCO), 109.83 (C=CH), 128.10, 128.60, 129.16, 131.41, 132.63, 134.26 (6C, C₆H₄), 160.22 (C=CH), 160.36 (CNH), 167.81, 172.08, 189.66 (3C, 3×CO); MS m/z (%): 374[M⁺](1), 205(20), 190(80), 145(60); Anal. Calcd. for C₁₉H₂₂N₂O₆: C, 60.95; H, 5.92; N, 7.48; Found: C, 60.76; H, 5.86; N, 7.57.

9b: White powder, yield: 50%, mp 127.2-128.5 ℃; IR (KBr, cm^-1): v 3189, 2955, 2874, 1707, 1679, 1631, 1567, 1487, 1253, 1128, 1105; ¹H NMR (400 MHz, CDCl₃): δ 0.86 (dd, 3H, J = 5.8, 2.4 Hz, CH₃CHCH₃), 1.04 (dd, 3H, J = 6.8, 3.1 Hz, CH₃CHCH₃), 2.21 (br, 1H, CH₃CHCH₃), 2.39 (s, 3H, CH₃CNH), 3.69 (s, 3H, COOCH₃), 3.83 (br, 4H, OCH₃ + CHNH), 4.94 (s, 2H, CH₂O), 7.23 (d, 1H, J = 6.4 Hz, PhH), 7.35-7.47 (m, 3H, PhH), 7.63 (d, 1H, J = 7.4 Hz, C=CH), 8.19 (br, 1H, CHNH), 10.28(br, 1H, NHO); ¹³C NMR (100 MHz, CDCl₃): δ 11.36 (CH₃CNH), 15.75 (CH₃CHCH₃), 19.40 (CH₃CHCH₃), 29.88 (CH₃CHCH₃), 51.77 (COOCH₃), 62.07 (OCH₃), 62.20 (CHNH), 75.86 (CH₂O), 97.91 (COCCO), 110.02 (C=CH), 128.15, 128.60, 129.08, 131.38, 132.51, 134.39 (6C, C₆H₄), 160.22 (C=CH), 160.43 (CNH), 167.80, 172.49, 187.43 (3C, 3×CO); MS m/z (%): 279(2), 190(65), 161(38), 140(65); Anal. Calcd. for C₂₁H₂₆N₂O₆: C, 62.67; H, 6.51; N, 6.96; Found: C, 63.26; H, 6.50; N, 6.85.

9c: Yellow viscous liquid, yield: 41%; IR (KBr, cm^-1): v 3207, 2960, 2868, 1709, 1679, 1634, 1568, 1431, 1257, 1130, 1110; ¹H NMR (400 MHz, CDCl₃): δ 0.76-1.01 (m, 6H, CH₃CH2 + CH₃CH), 1.23-1.48(m, 2H, CH₃CH₂), 1.92-1.98 (m, 1H, CH₃CH), 2.39 (d, 3H, J = 3.9 Hz, CH₃CNH), 3.69 (s, 3H, COOCH₃), 3.82 (s, 3H, OCH₃), 3.88- 3.95 (m, 1H, CHNH), 4.94 (s, 2H, CH₂O), 7.22 (d, 1H, J = 7.4 Hz, PhH), 7.34-7.40 (m, 2H, PhH), 7.40-7.46 (m, 1H, PhH), 7.62 (s, 1H, C=CH), 8.06 (br, 1H, CHNH), 11.48 (br, 1H, NHO); ¹³C NMR (100 MHz, CDCl₃): δ 11.20 (CH₃CNH), 11.81 (CH₃CH2), 15.52 (CH₃CH), 26.68 (CH₃CH2), 36.72 (CH₃CH), 51.59 (COOCH₃), 60.62 (CHNH), 61.91 (OCH₃), 75.66 (CH₂O), 98.24 (COCCO), 109.86 (C=CH), 127.95, 128.39, 128.99, 131.33, 132.53, 134.59 (6C, C₆H₄), 160.04 (CNH), 160.29 (C=CH), 167.76, 172.73, 187.13 (3C, 3×CO); MS m/z (%): 416(M⁺, 1), 205(23), 190(60), 140(100); Anal. Calcd. for C₂₂H₂₈N₂O₆: C, 63.45; H, 6.78; N, 6.73; Found: C, 63.56; H, 6.86; N, 6.57.

9d: Yellow viscous liquid, yield: 41%; IR (KBr, cm^-1): v 3245, 2923, 2843, 1704, 1633, 1567, 1431, 1363, 1256, 1130, 1110; ¹H NMR (400 MHz, CDCl₃): δ 2.35 (d, 3H, J = 2.8 Hz, CH₃CNH), 2.66- 2.82 (m, 1H, phCH₂), 3.24 (dd, 1H, J = 13.9, 3.6 Hz, phCH₂), 3.66- 3.71 (m, 3H, COOCH₃), 3.81 (d, 3H, J = 8.4 Hz, OCH₃), 4.05-4.14 (m, 1H, CHNH), 4.92 (s, 2H, CH₂O), 5.76 (br, 1H, CHNH), 7.19-7.47 (m, 9H, PhH), 7.62 (s, 1H, C=CH), 7.71 (m, 1H, NHO); ¹³C NMR (100 MHz, CDCl₃): δ 11.35 (CH₃CNH), 38.39 (phCH₂), 51.80 (COOCH₃), 59.01 (CHNH), 62.08 (OCH₃), 76.31 (CH₂O), 96.37 (COCCO), 109.89 (C=CH), 126.84, 128.17, 128.57, 128.85, 129.34, 129.93, 131.54, 132.81, 133.95, 136.86 (12C, C₆H₅ + C₆H₄), 160.43 (C=CH), 161.75 (CNH), 167.86, 172.10, 189.37 (3C, 3×CO); MS m/z (%): 230(29), 190(53), 161(32), 139(100); Anal. Calcd. for C₂₅H₂₆N₂O₆: C, 66.66; H, 5.82; N, 6.22; Found: C, 66.55; H, 5.96; N, 6.27.

The targeted compounds were evaluated for fungicidal activity against R. solani, B. cinerea and F. graminearum at the concentration of 100 mg/L according to the method reported in the literature ^[13]. The results were summarized in Table 1. These compounds showed fungicidal activity at different degree. Most compounds exhibited good activity against R. solani, among them the inhibitory rates of compounds 9b, 9c and 9d reached 65.2%, 58.5% and 56.1%, respectively, obviously superior to that of the lead compound TeA, which demonstrated an inhibitory rate of only 9.0%. As a whole the oxime ether derivatives 9a-9dshowed better bioactivity than the benzyl derivatives 6a-6d. Compound 9d with a benzyl group at the 5-position of pyrrolidine-2,4-dione exhibited better bioactivity than other compounds 9a-9c.

Table 1
Oligonucleotides designed in the present study.^a

4. Conclusion

In summary, two series of β-methoxyacrylate derivatives containing the pyrrolidine-2,4-dione moiety were designed and synthesized. A preliminary analysis of the structure-activity relationship revealed that the fungicidal activity of compounds 9a-9d with an oxime ether bridging group were better than that of compounds 6a-6dwith a methylene bridging group, especially against R. solani and B. cinerea. Introducing the oxime ether groups at the 3-position and a benzyl group at the 5-position of tetramic acid was helpful to improve the bioactivity of strobilurin derivatives containing the pyrrolidine-2,4-dione moiety.

Acknowledgments

This work was financially supported by the National Key Technologies R & D Program of China (No. 2011BAE06B04), Science & Technology Pillar Program of Jiangsu Province (No. BE2012371), the National Natural Science Foundation of China (No. 31171889), 863 Program of China (No. 2011AA10A206), and the Fundamental Research Funds for the Central Universities of China (No. KYZ201223).

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