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Article

Design, Synthesis, and Biological Activities of Novel 2-Cyanoacrylate Compounds Containing Substituted Pyrazolyl or 1,2,3-Triazolyl Moiety

by
Yang Wang
†,
Yudie Chen
†,
Ye Qian
,
Jia Chen
,
Xianchao Du
,
Yujun Shi
*,
Baolin Xu
,
Sheng Hua
and
Hong Dai
*
College of Chemistry and Chemical Engineering, Nantong University, Nantong 226019, China
*
Authors to whom correspondence should be addressed.
†
These authors contributed equally to this work.
Molecules 2023, 28(7), 3141; https://doi.org/10.3390/molecules28073141
Submission received: 5 March 2023 / Revised: 26 March 2023 / Accepted: 30 March 2023 / Published: 31 March 2023
(This article belongs to the Special Issue Advances in Novel Pesticide Discovery)
Browse Figures
Versions Notes

Abstract

:
To develop novel 2-cyanoacrylate derivatives with potential bioactivity, a number of 2-cyanoacrylate compounds, including substituted pyrazole or 1,2,3-triazole ring, were designed, prepared, and structurally detected by 1H NMR, 13C NMR, and elemental analysis. The biological assessment displayed that some designed compounds had significant herbicidal activities against Brassica juncea, Chenopodium serotinum, Rumex acetosa, Alopecurus aequalis, Polypogon fugax, and Poa annua at a dosage of 1500 g/ha. Furthermore, some derivatives still expressed satisfactory herbicidal activities against Brassica juncea, Chenopodium serotinum, and Rumex acetosa when the dosage was lowered to 150 g/ha, especially the inhibitory effects of compounds 9a, 9d, 9f, 9i, 10a, 10b, 10e, and 10n against Brassica juncea were all over 80%, compounds 9d, 9f, 9g, 9h, 9i, 10h, 10i, 10m, 10n, and 10o possessed more than 70% inhibition rates against Chenopodium serotinum, and compound 9d indicated 70% herbicidal activity against Rumex acetosa. These results provided an important basis for further design and discovery of biologically active 2-cyanoacrylate compounds.

1. Introduction

In recent years, 2-cyanoacrylatesplay a vital role in pesticidal and medicinal fields. Many 2-cyanoacrylate-based compounds have attracted intense attention for different bioactivities containing insecticidal [1,2], herbicidal [3,4,5], fungicidal [6], plant growth regulatory [7], and antitumor activity [8]. For example, NK-9717 (Figure 1), a potent herbicide owning 2-cyanoacrylate moiety, displayed wonderful herbicidal properties against some weeds such as Brassica campestris and Amaranthus retroflexus [9]. Recently, Wang et al. reported that isoxazole-containing 2-cyanoacrylate compound A (Figure 1) had significant herbicidal activity [10], Zhao et al. obtained 2-cyanoacrylate compound B (Figure 1) with a substituted oxazole moiety possessing interesting plant growth regulatory effect in addition to excellent herbicidal activity [11]. More recently, Shi and co-workers found that 1,3,4-oxadiazole-containing 2-cyanoacrylate analogue C (Figure 1) exhibited vital antitumor properties against human hepatoma cells [12]. This strongly promoted the research of bioactive molecules containing the 2-cyanoacrylate subunit.
On the other hand, substituted pyrazole and 1,2,3-triazole rings are significant N-containing aromatic heterocycles, which act as the main building blocks and intermediates in the synthesis of novel agricultural chemicals and drugs [13,14,15,16]. A number of pyrazole or 1,2,3-triazole derivatives were reported to possess multiple bioactivities and pharmacological properties involving herbicidal [17,18,19], fungicidal [20,21], insecticidal [22,23], anti-proliferative [24,25], antibacterial [26,27], and anticancer effects [28,29,30]. In light of the above reports, we hypothesized that the introduction of privileged pyrazole or 1,2,3-triazole pharmacophore to the parent 2-cyanoacrylate skeleton might generate some new bioactive compounds (Figure 2). Herein, we report the design and preparation of new 2-cyanoacrylate derivatives carrying pyrazolyl or 1,2,3-triazolyl moiety. Moreover, the newly synthesized 2-cyanoacrylate compounds were investigated for their herbicidal activities.

2. Results and Discussion

2.1. Chemistry

In this paper, in order to search for novel 2-cyanoacrylates with wonderful bioactivities, NK-9717 was chosen as the pesticide precursor, and the active pyrazolyl and 1,2,3-triazolyl units were introduced to replace the pyridyl ring to design and prepare new 2-cyanoacrylate compounds 9 and 10 (Figure 2). The synthesis process of the title compounds 9 and 10 was depicted in Scheme 1. The condensation of 4-fluorobenzaldehyde with 1H-pyrazole or 1H-1,2,3-triazole under alkaline conditions offered compounds 1, which were conveniently reduced to compounds 2 by treatment with NaBH4. Furthermore, intermediates 2 reacted with thionyl chloride to produce compounds 3 successfully. Intermediates 3 were easily converted into compounds 4 by the reaction with potassium phthalimide, which were further transformed into compounds 5 by the treatment with hydrazine hydrate. The key intermediates 8 were easily synthesized in two steps from compounds 6. Cyanoacetic acid was treated with 2-alkoxy or 2-aryloxy alcohols 6 to generate intermediates 7, which were reacted with carbon disulfide and dimethyl sulfate to obtain compounds 8 directly. Subsequently, the significant intermediates 5 were mixed with 2-cyanoacrylates 8 in ethanol to obtain the target compounds 9a–9i in satisfactory yields. At the same time, compounds 9 reacted with sodium alcoholate to form the aimed compounds 10a–10o successfully. Finally, the structures of compounds 9a–9i and 10a–10o were determined through 1H NMR, 13C NMR, and elemental analysis. Compounds 9a and 10b were selected as the typical examples to illustrate. In 1H NMR of 9a, the proton signal peak of the NH group was displayed at δ 10.36, a doublet signal at δ 4.80 was due to two protons of methylene group that attached to a nitrogen atom, and three protons of methylthio unit were detected as a singlet signal at δ 2.68. In 13C NMR of 9a, the carbon atom of the C=O group was noticed at δ 168.26, the carbon atom of the methylene group that attached to nitrogen was recognized at δ 48.95, and the carbon atom of methylthio moiety was shown at δ 18.33. In 1H NMR of 10b, one proton of NH moiety was detected at δ 9.78, a quartet signal at δ 4.61 belongs to two protons of methyleneoxy moiety adjacent to C=C group, and two protons of the methylene unit linked to nitrogen atom was exhibited as a singlet signal at δ 4.53. In 13C NMR of 10b, the C=O group was shown at δ 169.63, the carbon atom of methyleneoxy unit adjacent to the C=C skeleton was noticed at δ 59.86, and the carbon atom of methylene moiety attached to nitrogen was seen at δ 44.53.

2.2. Biological Activities

The herbicidal activities of 2-cyanoacrylates 9a–9i and 10a–10o were tested towards Brassica juncea, Chenopodium serotinum, Rumex acetosa, Alopecurus aequalis, Polypogon fugax, and Poa annua. Related data were summarized in Table 1; most target compounds indicated satisfactory herbicidal activity against Brassica juncea at 1500 g/ha, the inhibition effects of 9a, 9d, 9f, 9g, 9h, 9i, 10a, 10b, 10e, 10h, 10l, 10m, 10n, and 10o against Brassica juncea were over 90%, respectively, which were equal to that of NK-9717 (100%). At 1500 g/ha, most of the target compounds also had wonderful herbicidal activity against Chenopodium serotinum; for instance, compounds 9a, 9d, 9f, 9g, 9h, 9i, 10a, 10e, 10f, 10h, 10i, 10m, 10n, and 10o owned > 90% inhibition effects, which were near to that of the control NK-9717 (100%). At 1500 g/ha, some compounds possessed moderate to good inhibition rates against Rumex acetosa, especially compounds 9a, 9d, 10e, 10f, and 10n, and all had 100% inhibition effects against Rumex acetosa, which were close to that of NK-9717. At the same time, some title compounds were active against Alopecurus aequalis at a dosage of 1500 g/ha, and the inhibition rates of compounds 9a, 9d, 9g, 9h, 9i, 10a, 10e, 10h, 10i, 10m, 10n, and 10o against Alopecurus aequalis were 45%, 50%, 70%, 50%, 70%, 80%, 50%, 85%, 70%, 70%, 100%, and 90%, which surpassed that of NK-9717 (30%). Additionally, some 2-cyanoacrylates such as 9a, 9d, 9g, 9h, 9i, 10a, 10e, 10h, 10i, 10m, and 10n showed potent herbicidal activity against Polypogon fugax at 1500 g/ha with inhibitory values of 40%, 40%, 50%, 40%, 70%, 45%, 80%, 70%, 60%, and 100%, respectively, which were superior to that of the control NK-9717 (20%). Interestingly, some of these derivatives still displayed certain inhibition effects against Poa annu at 1500 g/ha. Among them, compounds 10h, 10m, and 10n owned 50%, 40%, and 70% inhibitory values, respectively, which were much better than that of the control NK-9717 (10%). From the data listed in Table 1, we found that when X is a C atom, among the 3-methylthio compounds 9a, 9b, 9c, 9d, and 9e, the inhibitory values of 9a (R1 = methyl) against Brassica juncea, Chenopodium serotinum, Rumex acetosa, Alopecurus aequalis, Polypogon fugax, and Poa annua were much better than those of 9b (R1 = ethyl), and the inhibition effects of 9d (R1 = 2,4-F2C6H3) against Brassica juncea, Chenopodium serotinum, Rumex acetosa, Alopecurus aequalis, Polypogon fugax, and Poa annua were superior to those of 9c (R1 = 4-FC6H4) and 9e (R1 = 3,5-F2C6H3). Among 3-methylthio derivatives, when R1 is ethyl, compound 9g (X = N) demonstrated higher inhibitory values against Brassica juncea, Chenopodium serotinum, Rumex acetosa, Alopecurus aequalis, Polypogon fugax, and Poa annua than compound 9b (X = C). Among 3-alkoxy derivatives 10a–10g (X = C), when R1 is methyl, compounds 10a (R2 = methyl) and 10b (R2 = ethyl) exhibited better inhibition rates against Brassica juncea, Chenopodium serotinum, Rumex acetosa, Alopecurus aequalis, Polypogon fugax, and Poa annua than compounds 10c (R2 = n-propyl) and 10d (R2 = n-butyl), and when R1 is ethyl, compounds 10e (R2 = methyl) and 10f (R2 = ethyl) possessed higher inhibition rates against Brassica juncea, Chenopodium serotinum, and Rumex acetosa than compounds 10g (R2 = n-propyl). Among 3-alkoxy derivatives 10h–10o (X = N), when R1 is methyl, the herbicidal activities of compounds 10h (R2 = methyl) and 10i (R2 = ethyl) against Chenopodium serotinum, Alopecurus aequalis, Polypogon fugax, and Poa annua were superior to those of compounds 10j (R1 = n-propyl), 10k (R1 = n-butyl), and 10l (R1 = n-pentyl), and when R1 is ethyl, compound 10n (R2 = ethyl) was more active against Rumex acetosa, Polypogon fugax and Poa annua than compounds 10m (R2 = methyl) and 10o (R2 = n-propyl). Herbicidal activities of some designed compounds at 150 g/ha were presented in Table 2. Among the 3-methylthio compounds 9a, 9d, 9f–9i, all of them exhibited important inhibition rates against Brassica juncea at 150 g/ha, especially compounds 9a, 9d, 9f, and 9i had over 80% inhibition effects against Brassica juncea, which were close to that of the control NK-9717. Compounds 9d, 9f, 9g, and 9i showed 90%, 80%, 80%, and 80% inhibitory values against Chenopodium serotinum, which were better than that of NK-9717 (75%). Compound 9d demonstrated a 70% inhibitory value against Rumex acetosa, which was higher than that of NK-9717 (40%). Among the 3-alkoxy compounds, 10a, 10b, 10e, 10h, 10m, and 10n displayed wonderful herbicidal activity against Brassica juncea with inhibitory rates of 80%, 80%, 80%, 75%, 75%, and 80%, which were close to NK-9717 (80%). Compounds 10h, 10i, 10m, 10n, and 10o indicated 70%, 75%, 85%, 80%, and 70% herbicidal properties against Chenopodium serotinum, which were near to that of NK-9717 (75%). Additionally, Compounds 10n and 10o both expressed 40% inhibition effects against Rumex acetosa, which were equal to that of NK-9717 (40%). From the bioactive data depicted in Table 1 and Table 2, we could find that the bioactivity spectra of 2-cyanoacrylates were greatly improved by importing the significant pyrazole and 1,2,3-triazole moieties to the lead compound NK-9717, especially some of these designed compounds displayed better herbicidal activities against Alopecurus aequalis, Polypogon fugax, and Poa annua than those of NK-9717, which implied that the introduction of vital pyrazole and 1,2,3-triazole frameworks was beneficial to broaden the herbicidal properties of 2-cyanoacrylate derivatives. Compounds 9g (X = N, R1 = ethyl), 10i (X = N, R1 = methyl, R2 = ethyl), and 10n (X = N, R1 = ethyl, R2 = ethyl) possessed extensive herbicidal properties against all the tested weeds, which could be selected as the bioactive compounds for further structural modification and bioactivity study.

3. Materials and Methods

3.1. Chemistry

Chemical agents were commercially available and treated through standard methods. 1H NMR, and 13C NMR spectra were detected by Bruker AV400 spectrometer (400 MHz, 1H; 100 MHz, 13C, Bruker, Billerica, MA, USA) in the solvent of CDCl3 or DMSO-d6. Melting points (M.p.) were performed using an X-4 apparatus. Elemental analysis was provided by a Yanaco CHN Corder MT-3 elemental analyser (Yanaco, Kyoto, Japan). Intermediates 1–3 were synthesized with reported procedures [31]. Intermediates 6–8 were prepared according to the literature method [32].

3.1.1. General Approach to Preparation of 4

Compounds 3 (5 mmol) were dissolved in 30 mL of DMF, and potassium phthalimide (6 mmol) was directly added thereto at room temperature. Next, the mixture was maintained at 50 °C for another 9 h. After cooling, the solution was dumped into 50 mL of ice water. Finally, the precipitates were filtered to get intermediates 4. Compound 4a: colorless solid (76% yield), m.p. 161–163 °C; 1H NMR (CDCl3) δ 7.88 (d, J = 2.40 Hz, 1H), 7.84–7.86 (m, 2H), 7.63–7.72 (m, 5H), 7.53 (d, J = 8.42 Hz, 2H), 6.45 (t, J = 2.40 Hz, 1H), 4.87 (s, 2H); 13C NMR (CDCl3) δ 168.04, 141.18, 139.73, 134.55, 134.11, 132.05, 129.89, 126.74, 123.44, 119.33, 107.72, 41.06. Anal. Calcd. for C18H13N3O2: C 71.28; H 4.32; N 13.85. Found: C 71.39; H 4.19; N 13.69. Compound 4b: colorless solid (70% yield), m.p. 189–190 °C; 1H NMR (CDCl3) δ 8.03 (d, J = 8.40 Hz, 2H), 7.85–7.87 (m, 2H), 7.79 (s, 2H), 7.71–7.73 (m, 2H), 7.56 (d, J = 8.42 Hz, 2H), 4.89 (s, 2H); 13C NMR (CDCl3) δ 168.03, 139.36, 135.70, 135.61, 134.14, 132.03, 129.71, 123.47, 119.15, 41.07. Anal. Calcd. for C17H12N4O2: C 67.10; H 3.97; N 18.41. Found: C 67.25; H 3.85; N 18.53. 1H NMR and 13C NMR spectra are provided in Supplementary Materials.

3.1.2. General Approach to Preparation of 5

Compounds 4 (3 mmol) were dissolved in 60 mL of anhydrous ethanol, and hydrazine hydrate (80%, 6 mmol) was slowly added thereto. Then, the above solution was kept at reflux for 3 h. After filtration, the mother liquor was condensed to afford intermediates 5. Compound 5a: colorless solid (85% yield), m.p. 129–130 °C; 1H NMR (DMSO-d6) δ 8.47 (s, 1H), 7.44–7.78 (m, 5H), 6.53 (s, 1H), 3.76 (s, 2H), 3.11 (s, 2H); 13C NMR (DMSO-d6) δ 142.26, 141.16, 138.64, 128.59, 128.01, 118.61, 108.12, 45.35. Anal. Calcd. for C10H11N3: C 69.34; H 6.40; N 24.26. Found: C 69.21; H 6.32; N 24.41. Compound 5b: colorless solid (83% yield), m.p. 169–171 °C; 1H NMR (DMSO-d6) δ 8.82 (s, 1H), 7.55–7.98 (m, 5H), 3.81 (s, 2H), 3.09 (s, 2H); 13C NMR (DMSO-d6) δ 144.95, 135.46, 134.83, 128.81, 123.56, 120.34, 45.36. Anal. Calcd. for C9H10N4: C 62.05; H 5.79; N 32.16. Found: C 62.19; H 5.68; N 32.08. 1H NMR and 13C NMR spectra are given in Supplementary Materials.

3.1.3. General Approach to Preparation of Title Compounds 9a–9i

Compounds 8 (2 mmol) were dissolved in anhydrous ethanol (35 mL), and intermediate 5 (2 mmol) was put in the above solution. Next, the mixture was maintained at reflux for 4–6 h. When the reaction was finished, the resulting solution was condensed to form crude products, which were further refined through column chromatography and washed by ethyl acetate/petroleum ether (1:4, v/v) to obtain compounds 9a–9i, and the spectral data of compounds 9a–9i are depicted below. 1H NMR and 13C NMR spectra are listed in Supplementary Materials.
Data for 9a: yellow solid (64% yield), m.p. 71–73 °C; 1H NMR (CDCl3) δ 10.36 (s, 1H), 7.93 (d, J = 2.40 Hz, 1H), 7.70–7.73 (m, 3H), 7.34 (d, J = 8.42 Hz, 2H), 6.48 (t, J = 2.40 Hz, 1H), 4.80 (d, J = 5.60 Hz, 2H), 4.31 (t, J = 4.80 Hz, 2H), 3.66 (t, J = 4.80 Hz, 2H), 3.41 (s, 3H), 2.68 (s, 3H); 13C NMR (CDCl3) δ 172.76, 168.26, 141.32, 139.97, 134.52, 128.36, 126.73, 119.66, 118.06, 107.91, 75.32, 70.30, 63.92, 59.27, 48.95, 18.33. Anal. Calcd. for C18H20N4O3S: C 58.05; H 5.41; N 15.04.Found: C 58.19; H 5.29; N 15.17.
Data for 9b: yellow solid (65% yield), m.p. 79–81 °C; 1H NMR (CDCl3) δ 10.37 (s, 1H), 7.93 (d, J = 2.40 Hz, 1H), 7.70–7.74 (m, 3H), 7.33 (d, J = 8.42 Hz, 2H), 6.48 (t, J = 2.40 Hz, 1H), 4.81 (d, J = 5.60 Hz, 2H), 4.30 (t, J = 5.00 Hz, 2H), 3.70 (t, J = 5.00 Hz, 2H), 3.58 (q, J = 6.80 Hz, 2H), 2.67 (s, 3H), 1.21 (t, J = 6.80 Hz, 3H); 13C NMR (CDCl3) δ 172.71, 168.27, 141.32, 139.95, 134.56, 128.34, 126.73, 119.66, 118.04, 107.91, 75.40, 68.09, 66.87, 64.15, 48.93, 18.33, 15.17. Anal. Calcd. for C19H22N4O3S: C 59.05; H 5.74; N 14.50. Found: C 58.90; H 5.86; N 14.63.
Data for 9c: colorless solid (62% yield), m.p. 103–105 °C; 1H NMR (CDCl3) δ 10.34 (s, 1H), 7.93 (d, J = 1.60 Hz, 1H), 7.71–7.74 (m,3H), 7.34 (d, J = 8.02 Hz, 2H), 6.85–6.98 (m, 4H), 6.49 (s, 1H), 4.81 (d, J = 5.60 Hz, 2H), 4.48 (t, J = 4.80 Hz, 2H), 4.19 (t, J = 5.00 Hz, 2H), 2.68 (s, 3H); 13C NMR (CDCl3) δ 173.01, 168.14, 158.74, 156.36, 154.66, 141.32, 139.95, 134.46, 128.39, 126.77, 119.71, 117.95, 116.10, 116.02, 115.75, 107.96, 75.07, 66.68, 63.00, 49.00, 18.34. Anal. Calcd. for C23H21FN4O3S: C 61.05; H 4.68; N 12.38. Found: C 61.18; H 4.53; N 12.24.
Data for 9d: yellow solid (61% yield), m.p. 93–95 °C; 1H NMR (CDCl3) δ 10.34 (s, 1H), 7.93 (d, J = 2.40 Hz, 1H), 7.71–7.74 (m, 3H), 7.34 (d, J = 8.82 Hz, 2H), 7.00–7.06 (m, 1H), 6.79–6.87 (m, 2H), 6.49 (t, J = 2.00 Hz, 1H), 4.81 (d, J = 6.00 Hz, 2H), 4.50 (t, J = 4.80 Hz, 2H), 4.28 (t, J = 5.20 Hz, 2H), 2.69 (s, 3H); 13C NMR (CDCl3) δ 173.05, 168.06, 158.37, 155.96, 154.33, 151.85, 143.11, 141.32, 139.96, 134.45, 128.37, 126.76, 119.69, 117.93, 117.67, 110.78, 107.94, 104.96, 75.00, 68.72, 62.95, 49.00, 18.34. Anal. Calcd. for C23H20F2N4O3S: C 58.72; H 4.28; N 11.91. Found: C 58.57; H 4.43; N 11.99.
Data for 9e: yellow solid, (61% yield), m.p. 91–93 °C; 1H NMR (CDCl3) δ 10.34 (s, 1H), 7.93 (d, J = 2.00 Hz, 1H), 7.73 (d, J = 8.42 Hz, 3H), 7.35 (d, J = 8.38 Hz, 2H), 6.42–6.49 (m, 4H), 4.82 (d, J = 5.60 Hz, 2H), 4.49 (t, J = 5.20 Hz, 2H), 4.19 (t, J = 5.20 Hz, 2H), 2.69 (s, 3H); 13C NMR (CDCl3) δ 173.17, 168.08, 164.94, 162.49, 160.35, 141.34, 140.00, 134.38, 128.40, 126.77, 119.72, 117.86, 107.96, 98.73, 98.45, 96.81, 74.87, 66.36, 62.45, 49.03, 18.34. Anal. Calcd. for C23H20F2N4O3S: C 58.72; H 4.28; N 11.91. Found: C 58.86; H 4.16; N 11.78.
Data for 9f: colorless solid (55% yield), m.p. 100–102 °C; 1H NMR (CDCl3) δ 10.40 (s, 1H), 8.10 (d, J = 8.40 Hz, 2H), 7.83 (s, 2H), 7.37 (d, J = 8.42 Hz, 2H), 4.83 (d, J = 6.00 Hz, 2H), 4.32 (t, J = 5.20 Hz, 2H), 3.66 (t, J = 5.20 Hz, 2H), 3.41(s, 3H), 2.68 (s, 3H); 13C NMR (CDCl3) δ 172.83, 168.25, 139.54, 135.75, 135.71, 128.17, 119.48, 118.08, 75.30, 70.28, 63.92, 59.29, 48.91, 18.34. Anal. Calcd. for C17H19N5O3S: C 54.68; H 5.13; N 18.75. Found: C 54.75; H 5.22; N 18.63.
Data for 9g: colorless solid (48% yield), m.p. 105–107 °C; 1H NMR (CDCl3) δ 10.40 (s, 1H), 8.11 (d, J = 8.40 Hz, 2H), 7.83 (s, 2H), 7.37 (d, J = 8.42 Hz, 2H), 4.83 (d, J = 5.60 Hz, 2H), 4.30 (t, J = 4.80 Hz, 2H), 3.71 (t, J = 5.20 Hz, 2H), 3.57 (q, J = 6.80 Hz, 2H), 2.67 (s, 3H), 1.22 (t, J = 6.80 Hz, 3H); 13C NMR (CDCl3) δ 172.79, 168.25, 139.53, 135.75, 128.14, 119.48, 118.07, 75.40, 68.07, 66.87, 64.15, 48.89, 18.34, 15.17. Anal. Calcd. for C18H21N5O3S: C 55.80; H 5.46; N 18.08. Found: C 55.67; H 5.57; N 18.20.
Data for 9h: colorless solid (60% yield), m.p. 122–124 °C; 1H NMR (CDCl3) δ 10.38 (s, 1H), 8.11 (d, J = 8.82 Hz, 2H), 7.83 (s, 2H), 7.38 (d, J = 8.82 Hz, 2H), 6.91–7.09 (m, 4H), 4.84 (d, J = 6.00 Hz, 2H), 4.54 (t, J = 4.80 Hz, 2H), 4.31 (t, J = 4.80 Hz, 2H), 2.68 (s, 3H); 13C NMR (CDCl3) δ 173.08, 168.05, 154.16, 151.72, 146.52, 139.55, 135.75, 135.66, 128.15, 124.41, 121.97, 121.90, 119.49, 117.95, 116.44, 116.10, 75.08, 67.50, 62.86, 48.94, 18.35. Anal. Calcd. for C22H20FN5O3S: C 58.27; H 4.45; N 15.44. Found: C 58.38; H 4.32; N 15.53.
Data for 9i: colorless solid (58% yield), m.p. 65–67 °C; 1H NMR (CDCl3) δ 10.36 (s, 1H), 8.10 (d, J = 8.42 Hz, 2H), 7.83 (s, 2H), 7.37 (d, J = 8.42 Hz, 2H), 6.80–7.06 (m, 3H), 4.84 (d, J = 6.02 Hz, 2H), 4.50 (t, J = 5.00 Hz, 2H), 4.28 (t, J = 5.00 Hz, 2H), 2.69 (s, 3H); 13C NMR (CDCl3) δ 173.13, 168.04, 158.38, 155.89, 154.12, 143.02, 139.57, 135.77, 135.61, 128.17, 119.50, 117.95, 117.58, 117.48, 110.76, 110.54, 104.96, 74.99, 68.61, 62.93, 48.96, 18.35. Anal. Calcd. for C22H19F2N5O3S: C 56.04; H 4.06; N 14.85. Found: C 56.17; H 3.94; N 14.72.

3.1.4. General Approach to Preparation of Title Compounds 10a–10o

Compounds 9 (3 mmol) were dissolved in 30 mL of alkyl alcohol under an ice bath. Subsequently, sodium alkyl alcohol (6 mmol) in alkyl alcohol (15 mL) was added dropwise slowly. The reaction was well stirred under an ice bath for 4-5 h. On completion, the solvent was steamed to generate crude products, which were finally separated through column chromatography and washed by ethyl acetate/petroleum ether (1:6, v/v) to produce the designed compounds 10a–10o, and corresponding spectral data of compounds 10a–10o are provided below. 1H NMR and 13C NMR spectra are depicted in Supplementary Materials.
Data for 10a: colorless solid (64% yield), m.p. 76–78 °C; 1H NMR (CDCl3) δ 9.75 (s, 1H), 7.93 (d, J = 2.40 Hz, 1H), 7.69–7.74 (m, 3H), 7.31 (d, J = 8.42 Hz, 2H), 6.49 (t, J = 2.00 Hz, 1H), 4.30–4.52 (m, 4H), 4.24 (s, 3H), 3.64 (t, J = 5.20 Hz, 2H), 3.41 (s, 3H); 13C NMR (CDCl3) δ 172.04, 169.58, 141.30, 139.81, 134.73, 128.33, 126.72, 119.54, 117.76, 107.88, 70.38, 63.82, 61.53, 59.28, 44.58. Anal. Calcd. for C18H20N4O4: C 60.66; H 5.66; N 15.72. Found: C 60.52; H 5.81; N 15.85.
Data for 10b: colorless solid (62% yield), m.p. 68–70 °C; 1H NMR (CDCl3) δ 9.78 (s, 1H), 7.93 (d, J = 2.40 Hz, 1H), 7.69–7.75 (m, 3H), 7.31 (d, J = 8.42 Hz, 2H), 6.49 (t, J = 2.40 Hz, 1H), 4.61 (q, J = 6.80 Hz, 2H), 4.53 (d, J = 6.00 Hz, 2H), 4.31 (t, J = 5.00 Hz, 2H), 3.66 (t, J = 5.00 Hz, 2H), 3.41 (s, 3H), 1.35 (t, J = 7.20 Hz, 3H); 13C NMR (CDCl3) δ 171.41, 169.63, 141.21, 139.69, 134.96, 128.28, 126.80, 119.56, 117.97, 107.88, 71.06, 70.40, 63.77, 59.86, 59.28, 44.53, 15.35. Anal. Calcd. for C19H22N4O4: C 61.61; H 5.99; N 15.13. Found: C 61.48; H 5.87; N 15.26.
Data for 10c: colorless solid (61% yield), m.p. 56–58 °C; 1H NMR (CDCl3) δ 9.78 (s, 1H), 7.94 (d, J = 2.40 Hz, 1H), 7.69–7.75 (m, 3H), 7.34 (d, J = 8.42 Hz, 2H), 6.49 (d, J = 2.00 Hz, 1H), 4.50–4.54 (m, 4H), 4.31 (t, J = 5.20 Hz, 2H), 3.66 (t, J = 5.20 Hz, 2H), 3.41 (s, 3H), 1.70–1.77 (m, 2H), 0.97 (t, J = 7.60 Hz, 3H); 13C NMR (CDCl3) δ 171.41,169.69, 141.27, 139.77, 134.83, 128.21, 119.54, 118.07, 107.87, 76.45, 70.41, 63.76, 59.28, 53.45, 44.48, 23.14, 10.09. Anal. Calcd. for C20H24N4O4: C 62.49; H 6.29; N 14.57. Found: C 62.64; H 6.15; N 14.46.
Data for 10d: yellow solid (60% yield), m.p. 66–68 °C; 1H NMR (CDCl3) δ 9.78 (s, 1H), 7.93 (d, J = 2.40 Hz, 1H), 7.69–7.74 (m, 3H), 7.33 (d, J = 8.42 Hz, 2H), 6.49 (t, J = 2.00 Hz, 1H), 4.52–4.58 (m, 4H), 4.31 (t, J = 5.20 Hz, 2H), 3.65 (t, J =4.80 Hz, 2H), 3.41 (s, 3H), 1.37–1.73 (m, 4H), 0.93 (t, J = 7.60 Hz, 3H); 13C NMR (CDCl3) δ 171.43, 169.69, 141.25, 139.75, 134.87, 128.22, 126.75, 119.54, 118.05, 107.87, 74.79, 70.41, 63.75, 59.28, 44.49, 31.70, 18.75, 13.63. Anal. Calcd. for C21H26N4O4: C 63.30; H 6.58; N 14.06. Found: C 63.17; H 6.73; N 14.19.
Data for 10e: colorless solid (64% yield), m.p. 75–77 °C; 1H NMR (CDCl3) δ 9.75 (s, 1H), 7.92 (d, J = 2.40 Hz, 1H), 7.69–7.72 (m, 3H), 7.31 (d, J = 8.42 Hz, 2H), 6.48 (t, J = 2.00 Hz, 1H), 4.29–4.52 (m, 4H), 4.23 (s, 3H), 3.55–3.71 (m, 4H), 1.22 (t, J = 6.80 Hz, 3H); 13C NMR (CDCl3) δ 172.11, 169.61, 141.32, 139.86, 134.79, 128.33, 126.72, 119.58, 117.73, 107.89, 68.19, 66.87, 64.07, 61.54, 59.42, 44.60, 15.20. Anal. Calcd. for C19H22N4O4: C 61.61; H 5.99; N 15.13. Found: C 61.73; H 5.85; N 15.01.
Data for 10f: yellow solid (63% yield), m.p. 97–99 °C; 1H NMR (CDCl3) δ 9.78 (s, 1H), 7.93 (d, J = 2.40 Hz, 1H), 7.69–7.73 (m, 3H), 7.31 (d, J = 8.42 Hz, 2H), 6.48 (t, J = 2.40 Hz, 1H), 4.52–4.63 (m, 4H), 4.30 (t, J = 5.20 Hz, 2H), 3.55–3.70 (m, 4H), 1.35 (t, J = 6.80 Hz, 3H), 1.22 (t, J = 6.80 Hz, 3H); 13C NMR (CDCl3) δ 171.46, 169.64, 141.30, 139.82, 134.93, 128.24, 126.70, 119.53, 117.93, 107.86, 71.06, 68.19, 66.86, 64.00, 59.92, 44.54, 15.34, 15.18. Anal. Calcd. for C20H24N4O4: C 62.49; H 6.29; N 14.57. Found: C 62.34; H 6.43; N 14.70.
Data for 10g: colorless solid (60% yield), m.p. 57–59 °C; 1H NMR (CDCl3) δ 9.79 (s, 1H), 7.94 (d, J = 2.40 Hz, 1H), 7.69–7.75 (m, 3H), 7.34 (d, J =8.42Hz, 2H), 6.49 (t, J =2.00 Hz, 1H), 4.50–4.55 (m, 4H), 4.30 (t, J = 5.22 Hz, 2H), 3.55–3.71 (m, 4H), 1.72–1.77 (m, 2H), 1.22 (t, J = 6.80 Hz, 3H), 0.97 (t, J = 7.60 Hz, 3H); 13C NMR (CDCl3) δ 171.42, 169.69, 141.22, 139.70, 134.93, 128.19, 126.80, 119.57, 118.04, 107.88, 76.45, 68.19, 66.85, 63.98, 59.66, 44.46, 23.14, 15.18, 10.09. Anal. Calcd. for C21H26N4O4: C 63.30; H 6.58; N 14.06. Found: C 63.42; H 6.45; N 13.96.
Data for 10h: colorless solid (52% yield), m.p. 99–100 °C; 1H NMR (CDCl3) δ 9.77 (s, 1H), 8.08 (d, J = 8.40 Hz, 2H), 7.82 (s, 2H), 7.35 (d, J = 8.42 Hz, 2H), 4.53 (d, J = 6.00 Hz, 2H), 4.31 (t, J = 4.80 Hz, 2H), 4.24 (s, 3H), 3.65 (t, J = 4.80 Hz, 2H), 3.41 (s, 3H); 13C NMR (CDCl3) δ 172.06, 169.59, 139.44, 135.96, 135.71, 128.14, 119.38, 117.74, 70.38, 63.84, 61.54, 59.34, 59.28, 44.59. Anal. Calcd. for C17H19N5O4: C 57.14; H 5.36; N 19.60. Found: C 57.03; H 5.48; N 19.52.
Data for 10i: colorless solid (53% yield), m. p. 54–56 °C; 1H NMR (CDCl3) δ 9.81 (s, 1H), 8.09 (d, J = 8.80 Hz, 2H), 7.82 (s, 2H), 7.35 (d, J = 8.42 Hz, 2H), 4.62 (q, J = 6.80 Hz, 2H), 4.54 (d, J = 6.00 Hz, 2H), 4.32 (t, J = 4.80 Hz, 2H), 3.65 (t, J = 4.80 Hz, 2H), 3.41 (s, 3H), 1.35 (t, J = 6.80 Hz, 3H); 13C NMR (CDCl3) δ 171.43, 169.63, 139.41, 136.12, 135.71, 128.07, 119.35, 117.95, 71.07, 70.40, 63.78, 59.84, 59.28, 44.54, 15.33. Anal. Calcd. for C18H21N5O4: C 58.21; H 5.70; N 18.86. Found: C 58.33; H 5.59; N 18.97.
Data for 10j: colorless solid (49% yield), m.p. 57–59 °C; 1H NMR (CDCl3) δ 9.81 (s, 1H), 8.08 (d, J = 8.40 Hz, 2H), 7.83 (s, 2H), 7.35 (d, J = 8.82 Hz, 2H), 4.51–4.57 (m, 4H), 4.31 (t, J = 4.80 Hz, 2H), 3.65 (t, J = 4.80 Hz, 2H), 3.42 (s, 3H), 1.71–1.76 (m, 2H), 0.96 (t, J = 7.60 Hz, 3H); 13C NMR (CDCl3) δ 171.43, 169.68, 139.42, 136.06, 135.70, 128.01, 119.36, 118.03, 76.46, 70.41, 63.77, 59.65, 59.28, 44.48, 23.13, 10.08. Anal. Calcd. for C19H23N5O4: C 59.21; H 6.02; N 18.17. Found: C 59.08; H 6.14; N 18.06.
Data for 10k: colorless solid (52% yield), m.p. 47–49 °C; 1H NMR (CDCl3) δ 9.81 (s, 1H), 8.07–8.10 (m, 2H), 7.83 (s, 2H), 7.34 (d, J = 8.82 Hz, 2H), 4.54–4.58 (m, 4H), 4.31–4.33 (m, 2H), 3.65–3.67 (m, 2H), 3.42 (s, 3H), 1.65–1.72 (m, 2H), 1.36–1.42 (m, 2H), 0.92 (t, J = 6.80 Hz, 3H); 13C NMR (CDCl3) δ 171.46, 169.69, 139.42, 136.08, 135.70, 128.01, 119.36, 118.04, 74.81, 70.41, 63.78, 59.65, 59.28, 44.50, 31.68, 18.74, 13.62. Anal. Calcd. for C20H25N5O4: C 60.14; H 6.31; N 17.53. Found: C 60.05; H 6.43; N 17.65.
Data for 10l: colorless solid (57% yield), m.p. 48–50 °C; 1H NMR (CDCl3) δ 9.81 (s, 1H), 8.07 (d, J = 8.38 Hz, 2H), 7.83 (s, 2H), 7.34 (d, J = 8.42 Hz, 2H), 4.53–4.57 (m, 4H), 4.31 (t, J = 4.80 Hz, 2H), 3.64 (t, J = 5.20 Hz, 2H), 3.42 (s, 3H), 1.66–1.71 (m, 2H), 1.30–1.34 (m, 4H), 0.87 (t, J = 6.80 Hz, 3H); 13C NMR (CDCl3) δ 171.45, 169.70, 139.42, 136.10, 135.70, 128.00, 119.35, 75.09, 70.42, 63.78, 59.30, 44.50, 29.39, 27.56, 22.19, 13.88. Anal. Calcd. for C21H27N5O4: C 61.00; H 6.58; N 16.94. Found: C 61.13; H 6.70; N 16.81.
Data for 10m: colorless solid (51% yield), m.p. 78–79 °C; 1H NMR (CDCl3) δ 9.78 (s, 1H), 8.08 (d, J = 8.42 Hz, 2H), 7.82 (s, 2H), 7.34 (d, J = 8.42 Hz, 2H), 4.53 (d, J = 6.00 Hz, 2H), 4.30 (t, J = 5.20 Hz, 2H), 4.23 (s, 3H), 3.55–3.78 (m, 4H), 1.22 (t, J = 6.80 Hz, 3H); 13C NMR (CDCl3) δ 172.09, 169.59, 139.45, 136.00, 135.72, 128.12, 119.39, 117.72, 68.17, 66.86, 64.07, 61.54, 59.40, 44.58, 15.18. Anal. Calcd. for C18H21N5O4: C 58.21; H 5.70; N 18.86. Found: C 58.12; H 5.82; N 18.97.
Data for 10n: colorless solid (54% yield), m.p. 69–71 °C; 1H NMR (CDCl3) δ 9.81 (s, 1H), 8.07 (d, J = 8.42 Hz, 2H), 7.82 (s, 2H), 7.35 (d, J = 8.42 Hz, 2H), 4.54–4.64 (m, 4H), 4.30 (t, J = 5.20 Hz, 2H), 3.55–3.71 (m, 4H), 1.35 (t, J = 6.80 Hz, 3H), 1.22 (t, J = 6.80 Hz, 3H); 13C NMR (CDCl3) δ 171.45, 169.63, 139.41, 136.16, 135.70, 128.05, 119.36, 117.96, 71.08, 68.19, 66.86, 64.01, 59.90, 44.53, 15.33, 15.18. Anal. Calcd. for C19H23N5O4: C 59.21; H 6.02; N 18.17. Found: C 59.15; H 6.12; N 18.06.
Data for 10o: colorless solid (55% yield), m.p. 72–74 °C; 1H NMR (CDCl3) δ 9.82 (s, 1H), 8.07–8.10 (m, 2H), 7.83 (s, 2H), 7.34 (d, J = 8.42 Hz, 2H), 4.50–4.56 (m, 4H), 4.31 (t, J = 5.20 Hz, 2H), 3.55–3.71 (m, 4H), 1.71–1.76 (m, 2H), 1.22 (t, J = 7.00 Hz, 3H), 0.97 (t, J = 7.00 Hz, 3H); 13C NMR (CDCl3) δ 171.45, 169.69, 139.42, 136.09, 135.70, 127.99, 119.36, 118.02, 76.45, 68.19, 66.86, 64.00, 59.71, 44.47, 23.13, 15.19, 10.08. Anal. Calcd. for C20H25N5O4: C 60.14; H 6.31; N 17.53. Found: C 60.27; H 6.19; N 17.41.

3.2. Biological Activity Test

All bioassays were accomplished on six kinds of typical weeds cultured in the laboratory. The herbicidal activities against Brassica juncea, Chenopodium serotinum, Rumex acetosa, Alopecurus aequalis, Polypogon fugax, and Poa annua of designed compounds were measured using a pot culture method [33]. First, tested compounds were dissolved with DMF, including 0.1% Tween-80 emulsifying agent, which was subsequently diluted by water to the required doses of 1500 and 150 g/ha. Flowerpots with a diameter of 7.5 cm were plated with composite soil, and then the seeds of six weeds were sowed at 25 °C in the greenhouse. When the weeds grew to their three-leaf stage, each title compound was sprayed by post-emergence application. After air-drying, the weeds were kept in the greenhouse for normal cultivation at 25 °C. A mixture of an equivalent quantity of DMF, Tween-80, and water was sprayed as a negative contrast. Additionally, NK-9717 was used as a positive control. The fresh weight of the aforementioned ground tissues was surveyed 25 days after post-emergence treatment. The inhibition effect of each compound on the growth of the above weeds was assessed by the percentage change in the weed weight compared to that of the control, as 0% (no effect) and 100% (complete death). Each assessment was repeated in triplicate, and the results were averaged.

4. Conclusions

In summary, twenty-four 2-cyanoacrylate derivatives, including pyrazolyl or 1,2,3-triazolyl unit, were synthesized and screened the herbicidal properties against six weeds. Bioassay results demonstrated that some target compounds showed wonderful herbicidal activities against Brassica juncea and Chenopodium serotinum at dosages of 1500 and 150 g/ha, and some title compounds expressed moderate to satisfactory herbicidal activities towards Rumex acetosa, Alopecurus aequalis, Polypogon fugax, and Poa annua at 1500 g/ha. Among them, compounds 9g, 10i, and 10n presented a wide range of herbicidal activities towards all six weeds. These compounds can be selected as lead pesticides for further structural improvement and bioactivity optimization.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/molecules28073141/s1, 1H NMR and 13C NMR spectra of compounds 4a, 4b, 5a, 5b, 9a–9i, and 10a–10o.

Author Contributions

Y.S. designed the experiment; Y.W., Y.C., Y.Q., J.C., X.D., B.X., and S.H. accomplished the experiment; H.D. wrote this manuscript. All authors have read and agreed to the published version of the manuscript.

Funding

This study was funded by the National Natural Science Foundation of China (21372135, 22177057) and the Science and Technology Innovation Foundation for the College Students of Jiangsu Province (202210304022Z).

Data Availability Statement

Not applicable.

Conflicts of Interest

The authors declare no conflict of interest.

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Molecules 28 03141 g001 550
Figure 1. Structures of NK-9717 and compounds A–C.
Figure 1. Structures of NK-9717 and compounds A–C.
Molecules 28 03141 g001
Molecules 28 03141 g002 550
Figure 2. Design strategy of 2-cyanoacrylate derivatives 9 and 10.
Figure 2. Design strategy of 2-cyanoacrylate derivatives 9 and 10.
Molecules 28 03141 g002
Molecules 28 03141 sch001 550
Scheme 1. Synthesis of the designed compounds 9a–9i and 10a–10o. Reagents and conditions: (a) potassium carbonate, DMF, 120 °C, 8 h; (b) NaBH4, C2H5OH, 0 °C, 5 h; (c) thionyl chloride, CH2Cl2, 0 °C, 30 min, r.t., 6 h; (d) potassium phthalimide, DMF, 50 °C, 9 h; (e) hydrazine hydrate, C2H5OH, reflux, 3 h; (f) sodium bisulfate monohydrate or condensed sulfuric acid, toluene, reflux, 8–10 h; (g) potassium hydroxide, carbon disulfide, acetonitrile, 0 °C, 4 h, and then dimethyl sulfate, r.t., 10–12 h; (h) compounds 5, C2H5OH, reflux, 4–6 h; (i) R2ONa, R2OH, 0 °C, 4–5 h.
Scheme 1. Synthesis of the designed compounds 9a–9i and 10a–10o. Reagents and conditions: (a) potassium carbonate, DMF, 120 °C, 8 h; (b) NaBH4, C2H5OH, 0 °C, 5 h; (c) thionyl chloride, CH2Cl2, 0 °C, 30 min, r.t., 6 h; (d) potassium phthalimide, DMF, 50 °C, 9 h; (e) hydrazine hydrate, C2H5OH, reflux, 3 h; (f) sodium bisulfate monohydrate or condensed sulfuric acid, toluene, reflux, 8–10 h; (g) potassium hydroxide, carbon disulfide, acetonitrile, 0 °C, 4 h, and then dimethyl sulfate, r.t., 10–12 h; (h) compounds 5, C2H5OH, reflux, 4–6 h; (i) R2ONa, R2OH, 0 °C, 4–5 h.
Molecules 28 03141 sch001
Table
Table 1. Herbicidal activity(inhibition rate, %) of title compounds at 1500 g/ha.
Table 1. Herbicidal activity(inhibition rate, %) of title compounds at 1500 g/ha.
Compd.DoseBrassica
juncea		Chenopodium
serotinum		Rumex
acetosa		Alopecurus
aequalis		Polypogon
fugax		Poa
annua
(g/ha)
9a1500100100100454030
9b1500000000
9c1500000000
9d1500100100100504030
9e15003000000
9f1500909030303020
9g150010010080705030
9h150090900503030
9i15009510020704030
10a150010010080807030
10b15001008050303030
10c1500000000
10d1500000000
10e1500100100100504520
10f150060100100000
10g1500000000
10h15001001000858050
10i1500859060707030
10j1500504003000
10k1500508003000
10l150010000000
10m1500909030706040
10n150010010010010010070
10o1500100100609000
NK-97171500100100100302010
Table
Table 2. Herbicidal activity (inhibition rate, %) of some compounds at 150 g/ha.
Table 2. Herbicidal activity (inhibition rate, %) of some compounds at 150 g/ha.
Compd.DoseBrassica
juncea		Chenopodium
serotinum		Rumex
acetosa		Alopecurus
aequalis		Polypogon
fugax		Poa
annua
(g/ha)
9a150802020000
9d150909070000
9f15080802020200
9g150608030202020
9h15070700202020
9i15085800000
10a150806020000
10b150802030000
10e150804020000
10f150205020000
10h15075700000
10i150707520303020
10k1500300000
10l150000000
10m150758520000
10n150808040303020
10o1506070402000
NK-9717150807540000
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MDPI and ACS Style

Wang, Y.; Chen, Y.; Qian, Y.; Chen, J.; Du, X.; Shi, Y.; Xu, B.; Hua, S.; Dai, H. Design, Synthesis, and Biological Activities of Novel 2-Cyanoacrylate Compounds Containing Substituted Pyrazolyl or 1,2,3-Triazolyl Moiety. Molecules 2023, 28, 3141. https://doi.org/10.3390/molecules28073141

AMA Style

Wang Y, Chen Y, Qian Y, Chen J, Du X, Shi Y, Xu B, Hua S, Dai H. Design, Synthesis, and Biological Activities of Novel 2-Cyanoacrylate Compounds Containing Substituted Pyrazolyl or 1,2,3-Triazolyl Moiety. Molecules. 2023; 28(7):3141. https://doi.org/10.3390/molecules28073141

Chicago/Turabian Style

Wang, Yang, Yudie Chen, Ye Qian, Jia Chen, Xianchao Du, Yujun Shi, Baolin Xu, Sheng Hua, and Hong Dai. 2023. "Design, Synthesis, and Biological Activities of Novel 2-Cyanoacrylate Compounds Containing Substituted Pyrazolyl or 1,2,3-Triazolyl Moiety" Molecules 28, no. 7: 3141. https://doi.org/10.3390/molecules28073141

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