Synthesis, Crystal Structure and Biological Activities of 3-Bromo-5-(4-chlorophenyl)-4-cyanopyrrole-N,N-dimethyl-2-carboxamide①

XU Qing-Bo HUA Yun-Tao TANG Qiang ZHOU Bao-Han CHEN Kun XU Bao-Ming②

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Synthesis, Crystal Structure and Biological Activities of 3-Bromo-5-(4-chlorophenyl)-4-cyanopyrrole-,-dimethyl-2-carboxamide①

XU Qing-Bo HUA Yun-Tao TANG Qiang ZHOU Bao-Han CHEN Kun XU Bao-Ming②

(430068,)

The title compound 3-bromo-5-(4-chlorophenyl)-4-cyanopyrrole-,-dimethyl-2- amide (3) was synthesized with 4-bromo-2-(4-chlorophenyl)-5-(trifluoromethyl)-1-pyrrole-3- carbonitrile (1)and,-dimethylformamide (2) by the-acylation reaction catalyzed by potassium-butoxide, and characterized by IR,1H-NMR and X-ray single-crystal diffraction. It crystallizes in monoclinic, space group21/with= 12.789(2),= 13.783(2),= 17.980(3) ?,= 109.230(3)°,= 2992.5 ?3,M= 352.62,D= 1.565 mg/m3,= 8,= 2.924 mm-1,(000) = 1408, the final= 0.0424 and= 0.0973 for 3518observed reflections with> 2(). A total of 23559 reflections were collected, of which 6242 were independent (int= 0.0566). The insecticidal, herbicidal and antibacterial activities of compound 3 were determined, and the experimental results showed that the mortality of 3 at the concentration of 100 ppm on the Fipronil against Linnaeus was 76.6%, the growth inhibition rateof 3 against Cynodon Dactylon under the condition of 100 ppm was 35.8% and the inhibitory activity of 3 at the concentration of 25 ppm against Fusarium graminearum reached 50.9%. Hence, the title compound has the value of further research and application prospect.

3-bromo-5-(4-chlorophenyl)-4-cyanopyrrole-N,N-dimethyl-2-amide, synthesis, crystal structure, biological activity;

1 INTRODUCTION

Pyrrole has been widely used in the field of pesticides because of their unique molecular structures and good biological activity[1-5]. The early studies of pyrrole compounds were mainly con- centrated on the chemistry and application of natural biological compounds and active com- pounds. By the middle and late 80s, structural modification of natural products was carried out and a breakthrough was achieved[6, 7]. Chlorfenapyr[8-10], 4-bromo-2-(4-chlorophenyl)-5-(trifluoromethyl)pyrrole-3-carbonitrile, was synthesized by the US Cyanide Agricultural Research Department, and was proved to be a new kind of pyrrole insecticide and miticide. However, a large area of its appli- cations has been limited due to the long synthesis process, inconvenient operation, low yield, high toxicity and high price for the raw materials.

Furthermore, the introduction of trifluoromethyl to the pyrrole can not only increase the biological activity, but also enhance the ester solubility of theoriginal pesticide molecules in the organism, but trifluoromethyl is very toxic to plants[11]. As we know, the amide groups have been widely used in pesticides and have low toxicity[12], and thus the amide was judiciously selected to substitute for trifluoromethyl.

In this paper, 3-bromo-5-(4-chlorophenyl)-4- cyanopyrrole-,-dimethyl-2-amide (compound3) was synthesized with 4-bromo-2-(4-chlorophenyl)- 5-(trifluoromethyl)-1-pyrrole-3-carbonitrile (compound 1) and,-dimethylformamide (compound 2) by the-acylation reaction catalyzed by potassium-butoxide. It is hoped that compound 3 has good water solubility and low price. Compound 3 was characterized by IR,1H-NMR, and X-ray single-crystal diffraction, and its biological activity was discussed.

2 EXPERIMENTAL

2. 1 Materials and measurements

The compound, 4-bromo-2-(4-chlorophenyl)-5- three fluorine methyl pyrrole-3-nitrile (98%) was purchased from Aladdin,,-dimethylformamide (DMF) was from Sinopharm Chemical Reagent Co., and Ltd and potassium t-butoxide (tBuOK) (98%) were obtained from Heowns. Melting points were determined with XT4A micro melting point apparatus and uncorrected.1H-NMR spectra were recorded on a Mercury Plus-400 spectrometer. IR spectra were recorded on a Perkin-Elmer PE-983 IR spectrometer with pressed KBr pellets in the range of 4000～400 cm-1.

2. 2 Synthesis of compound 3

The title compound was synthesized according to the route shown in Scheme 1. A mixture of com- pound 1 (3.495 g, 0.01 mol) and DMF (7.31 g, 0.1 mol, compound 2) was heated to 130～140 °C with stirring for 30min. When the temperature of the mixture dropped to 40 °C, 0.224 gtBuOK was added into, then the mixture was refluxed at 145～155 °C for 8 h. The reaction process was tracked by TLC. After the reaction was stopped to cool to room temperature, the residual DMF was removed by evaporating under reduced pressure, then the remaining mixture was washed with distilled water, and filtrated to obtain the product. Product 3 was separated and purified by chromatography at atmospheric pressure to obtain 2.89 g of fine product as white powder. Yield: 82%. m.p.: 213.1～216.9 ℃. IR (KBr, cm-1): 3446s, 2960s, 2860s, 1647s, 532s.1H-NMR (400 MHz, DMSO-d6):13.10 (s, 1H, N-H), 7.79 (d,= 8.6 Hz, 2H, Ph-H), 7.63 (d,= 8.6 Hz, 2H, Ph-H), 3.02 (s, 6H, CH3). The solid of compound 3 was re-crystallized from ethyl acetate to give colorless block crystals of 3 suita- ble for single-crystal X-ray diffraction after 14 d.

Scheme 1. Synthetic procedure of the title compound 3

2. 3 Structure determination

A colorless block crystal 3 with dimensions of 0.16mm × 0.12mm × 0.10mm was selected and mounted on a glass fiber tube for measurement. Crystallographic data of the compound were collected on a Bruker SMART CCD diffractometer with a graphite-monochromated Moradiation (= 0.71073 ?). A total of 23559 reflections were collected in the range of 1.781≤≤26.629° by using anscan mode. Among them 6242 inde- pendent reflections were observed (int= 0.0566). The crystal structure was solved by direct methods with SHELXS-97 program and expanded usingdifference techniques[13]. All calculations were performed using the Crystal Structure crystallographic software package except for the refinement, and refinements were done by full-matrix least-squares on2with SHELXL-97[14]. All of the non-H atoms were refined anisotropically by full-matrix least-squares to give the final= 0.0424 and= 0.0973 (= 1/[2(F2) + (0.0560)2+ 0.4371], where= (F2+ 2F2)/3),= 0.974, (?)max= 0.408 and (?)min= –0.553 e/?3. The hydrogen atoms were placed in the calculated positions and refined isotropically. The selected bond lengths and bond angles for 3 are listed in Table 1, and the hydrogen bonds for 3 are shown in Table 2.

Table 1. Selected Bond Lengths (nm) and Bond Angles (°)

Table 2. Hydrogen Bond Lengths (nm) and Bond Angles (°)

Symmetry codes: (a)–1,,; (b) –+1/2,–1/2, –+3/2; (c) –+1/2,+1/2, –+3/2

2. 4 Biological activity

The herbicidal activity, insecticidal activity and antibacterial activity of compounds 1 and 3 were tested in the Hubei Academy of Agricultural Sciences. The experiments were carried out accor- ding to the SOP of pesticide biological activity test standard[15].

3 RESULTS AND DISCUSSION

3. 1 Crystal structure

The molecular structure of compound 3 is shown in Fig. 1. It could be seen from X-ray single-crystal analysis that the molecule consists of one benzene ring and one pyrrole ring. The benzene and pyrrole rings are connected through the C(4) atom of the benzene ring and the C(7) atom of pyrrole ring, and the dihedral angles of benzene and pyrrole rings are34.2(1)°, respectively. As shown in Table 1, the bond lengths of Br(1)–C(9), C(10)–C(11), C(11)– N(3) and C(14)–N(3) are 0.1872(3), 0.1458(5), 0.1338(4) and 0.1459(5) nm, respectively. The bond lengths of C(7)–N(1) (0.1346(4) nm) and C(10)– N(1) (0.1376(4) nm) are shorter than the normal C–N single bond (0.149 nm)[16]. The C(11)–O(1) bond in 0.1232(4) nm belongs to the typical C=O double bond. According to Fig. 1, the bond of C–F (0.1327 nm)[16]does not appear in the crystal structure of compound 3, while C(11)–N(3) (0.1338 nm) and C(11)–O(1) (0.1232 nm) appear, so we can confirm that the amides have successfully substituted for the trifluoromethyl.

The packing structure of compound 3 is shown in Fig. 2. In the crystal packing, the molecules in the asymmetric unit are linked into a dimer by two N–H···O hydrogen bonds, i.e. N(1)–H(1)···O(2) and N(5)–H(5)×××O(1). These dimers are linked by two intermolecular C–H···O interactions (C(19)–H(19)···O(1) and C(20)–H(20)×××O(2)), forming the one-dimensional chain along the axis. Adjacent chains are finally joined together into the three-dimensional network byand Cl–Cl interactions. As for theinteractions, they are formed between symmetry-related C(1)–C(6) benzene rings with the centroid-to-centroid distance of 0.3742(2) nm. And the Cl–Cl interactions exist between Br(1)···Cl(2) with their separated distance of 0.3406(2) nm.

Fig. 1. X-ray crystal structure of compound 3

Fig. 2. A view of packing diagram of compound 3

3. 2 Biological activity

The insecticidal activities of compounds 1 and 3against Linnaeus and Bollworm are shown in Table 3, respectively. The concentrations of 100, 50 and 25 ppm were used for compounds 1 and 3, and the mortality of targets is the evaluation basis of insec- ticidal activity.

Table 3. Insecticidal Activity of Compounds 1 and 3

The herbicidal activities of compounds 1 and 3 against Lemna minor, Chinese cabbage and Cynodon Dactylon are shown in Table 4. The con- centrations of 100, 50 and 25 ppm were used for compounds 1 and 3, and the evaluation basis of herbicidal activity is the growth inhibition rate of targets.

Table 4. Herbicidal Activity of Compounds 1 and 3

Table 5 shows the antibacterial activities of compounds 1 and 3 against bacteria includingpy- thium ultimate, botrytis cinerea, septoria nodorum berk, alernaria sonali, rhizoctonia solani and fusa- rium graminearum. The concentrations of 100, 50 and 25 ppm were used for compounds 1 and 3, and the evaluation basis of herbicidal activity is the inhibition rate of targets.

The experimental observation showed that the mortality of compound 3 against Linnaeus at the 100 ppm on Fipronil was 76.6%, the growth inhibition rateof 3 against Cynodon Dactylon under the condition of 100 ppm was 35.8%, and the inhibitory activity of 3 at the concentration of 25 ppm against Fusarium graminearum reached 50.9%. Furthermore, the above results indicated when the amide groups of compound 3substituted the trifluo- romethyl of compound 1, compound 3 still exhibit- ted good insecticidal activity, even better antibac- terial activity against Fusarium graminearum com- pared with compound 1. According to the relation- ship between the conformation and biological activity of compounds, when the trifluoromethyl was substituted for amide, compound 3 showed relatively good antibacterial activity, so it has potential for further researches.

4 CONCLUSION

In summary, we have synthesized a new com- pound, 3-bromo-5-(4-chlorophenyl)-4-cyanopyrro-le-,- dimethyl-2-amide, and characterized by IR,1H-NMR and X-ray single-crystal diffraction. In compound 3, the amide groups substituted suc- cessfully the trifluoromethyl of compound 1. The biological activity tests of compound 3 show that it has relatively good activities to the Linnaeus, Cynodon Dactylon and the Fusarium Graminearum, so it has deep research value and application prospect.

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24 October 2017;

11 January 2018

①This work was supported by the National Natural Science Foundation of China (No. 21272086)

. Xu Bao-Ming, born in 1966, professor, master degree, major in organic synthesis. E-mail: xubaoming897@163.com

10.14102/j.cnki.0254-5861.2011-1863