DENG Xi-Le ZHOU Xio-Mo WANG Zn-Yong

RUI Chang-Huic YANG Xin-Lingb②

a (Hunan Agriculture Biotechnology Research Institute,Hunan Academy of Agricultural Sciences, Changsha 410125, China)

b (Department of Applied Chemistry, College of Science,China Agricultural University, Beijing 100193, China)

c (Laboratory of Integrated Pest Management in Crops, Ministry of Agriculture,Institute of Plant Protection, Chinese Academy of Agricultural Sciences, Beijing 100193, China)

1 INTRODUCTION

Pyrazole amide derivatives, a common type of nitrogen-containing heterocyclic compounds,have received considerable attention due to their diverse biological activities.Recently, a number of pyrazole amide derivatives have demonstrated unique pharmacological activity for use as antimalarials[1], cannabinoid receptor agonists[2],EP1 receptor antagonists[3], BCR-ABL kinase inhibitors[4]and HDAC inhibitors[5].Additionally,pyrazole amides are also used as pesticides[6-9],especially for insecticides[10], represented by chlorantraniliprole (3-bromo-N-[4-chloro-2-methyl-6-[(methylamino)carbonyl]phenyl]-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxamide),a novel ryanodine receptor insecticide, which is highly efficacious in the control of lepidopteran pests.

As part of our ongoing work on the synthesis of pyrazole amide insecticides, a type of hexahydrocyclohepta[c]pyrazole-3-carboxamides showed potent activity against diamondback moth(Plutella xylostella) and cotton bollworm(Helicoverpa armigera)[11].To further explore the bioactivity of bicyclic pyrazole amides, the title compound 5, N-(pyridine-2-ylmethyl)-1-phenyl-1,4,5,6,7,8-hexahydrocyclohepta[c]pyrazole-3-carboxamide, was designed, maintaining bicyclic pyrazolecarboxamide as the parent skeleton, using a strategy involving amide replacement, which transformed the position of carboxamide on the pyrazole ring and extended carbon chain between aromatic nucleus and amide (Scheme 1).Herein,we report the synthesis, crystal structure and insecticidal activity of 5.Scheme 2 illustrates the synthetic approach towards 5.A cyclic ketone and diethyl oxalate were chosen as starting materials,which reacted via Claisen condensation,cyclization, hydrolysis and acylation to produce 5[12-14].

Scheme 1. Design strategy of the title compound 5

Scheme 2. Synthetic route for the title compound 5

2 EXPERIMENTAL

2.1 Materials and physical measurements

The melting point of the title compound 5 was determined on an X-5 binocular (Fukai Instrument Co., Beijing, China).The1H NMR and13C NMR spectra were obtained using an INOVA-400 spectrometer, CDCl3as the solvent, and TMS as the internal standard.Chemical shifts were reported in δ(parts per million).The IR spectra were obtained on a Perkin Elmer Spectrum 100 FT-IR spectrometer(KBr presser method).High resolution mass spectrometry (HRMS) data were obtained on an FTICR-MS Varian 7.0T FTICR-MS instrument.Single-crystal X-ray diffraction was obtained by a Bruker SMART APEX-II diffractometer equipped with graphite-monochromatic CuKα radiation (λ =1.54178 ?) at 173(2) K.All the reagents were purchased from commercial sources and used without further purification.

2.2 Synthesis of N-(pyridin-2-ylmethyl)-1-phenyl-1,4,5,6,7,8-hexahydrocyclohepta[c]pyrazole-3-carboxamide

A mixture of cyclic ketone 1 (10.0 g, 89.2 mmol)and diethyl oxalate (13.0 g, 89.2 mmol) was added dropwise to a solution of ethanol (50 mL) containing thinly sliced sodium (2.1 g, 89.2 mmol) at room temperature.The mixture was stirred overnight and then acidified with 20% H2SO4(pH =3.0).After filtration, the filtrate was extracted with dichloromethane (50 mL) twice, dried with anhydrous MgSO4, and concentrated in vacuo to yield yellow liquid 2 (8.51 g, 40.1 mmol, 45.0% yield).

A solution of intermediate 2 (1.06 g, 5.0 mmol) in methanol (10 mL) was added dropwise to a solution of hydrazinobenzene (0.49 g, 5.0 mmol) in methanol (5 mL) at room temperature, and then stirred overnight.The resulting mixture was concentrated under vacuum and the pyrazole ester 3 was obtained as white solid (1.00 g, 3.5 mmol,70.0% yield) after purification by column chromatography using a mixture of petroleum ether and ethyl acetate (V/V 7:1), m.p.: 165～166oC.

A solution of 3 (1.00 g, 3.5 mmol) was combined with 6 mol/L NaOH (aq) (3 mL) and the mixture was stirred at 80oC for 2 h.Ice water (50 mL) was then added, and the mixture was acidified (pH = 1)with concentrated HCl.The thusly-formed solid was collected by filtration and then dried in air for overnight.Carboxylic acid 4 was purified by recrystallization to afford 4 (0.75 g, 2.9 mmol,84.0% yield).m.p.: 278～279oC.

The title compound 5 was prepared using an acyl chloride derived from intermediate 4.A solution of 4(0.50 g, 2.0 mmol) in thionyl chloride (10 mL) was refluxed for 6 h and then concentrated under vacuum.The resulting crude acyl chloride was then added dropwise to a cooled solution of pyridin-2-ylmethanamine (0.22 g, 2.0 mmol) and triethylamine (0.40 g,4.0 mmol) in dichloromethane (10 mL) at room temperature.The resulting mixture was stirred overnight at room temperature and then purified via column chromatography using a mixture of petroleum ether and ethyl acetate (V/V 2:1) as eluent to afford the title compound 5 (1.2 mmol, 0.41 g; 59.2%yield).m.p.: 130～131oC.IR (KBr): ν = 3278, 2920,1711, 1521, 757.1H NMR (CDCl3, 400 MHz), δ(ppm): 1.67～1.76 (m, 2H, CH2), 1.87～1.88 (m, 2H,CH2), 2.73～2.77 (m, 2H, CH2), 3.17～3.21 (m, 2H,CH2), 4.56 (d, J = 3.00 Hz, 2H, CH2), 7.30 (m, 4H,NH+ArH), 7.36～7.41 (m, 3H, ArH), 7.44～7.52 (m,4H, ArH).13C NMR (CDCl3, 100 MHz), δ (ppm):162.62, 156.66, 148.16, 143.80, 141.31, 138.29,135.66, 128.06, 127.27, 124.73, 122.92, 121.11,120.84, 43.29, 30.77, 26.89, 25.99, 25.81, 22.84.HRMS (ESI-TOF) (m/z): calculated for C21H22N4O,[M+H]+347.1866; observed 347.1867.

2.3 X-ray crystal structure determination

Single crystals suitable for X-ray diffraction were obtained from slow evaporation of a solution of the title compound 5 in ethanol at room temperature.Compound 5 exists as colorless crystals.A crystal of compound 5 (0.20mm × 0.20mm × 0.20mm) was selected for data collection, which was performed on a Bruker APEX-II CCD equipped with graphite-monochromatic CuKα radiation (λ =1.54178 ?) at 173(2) K.In a range of 5.617＜θ＜68.373°, a total of 15394 reflections were collected by employing a ψ-ω scan mode, of which 3234 were unique with Rint= 0.0294 and 3099 were observed with I ＞ 2σ(I) based on F2.The hydrogen atoms were fixed geometrically at the calculated distances on constrained refinement.All non-hydrogen atoms were refined by full-matrix leastsquares techniques on F2for 3234 observed reflections with I ＞ 2σ(I) to the final R = 0.0354, wR =0.0924 (w = 1/[σ2(Fo2) + (0.0433P)2+ 0.5895P],where P = (Fo2+ 2Fc2)/3), S = 1.027, (Δ/σ)max=0.001, (Δρ)max= 0.237 and (Δρ)min= –0.180 e/?3.All calculations were performed by the SHELXTL 2014 program.

2.4 Biological assay

Diamondback moth (Plutella xylostella) and cotton bollworm (Helicoverpa armigera) were used to test the insecticidal activities of the title compound 5 using a previously reported method[15]and chloranthraniliprole was used as the positive control.

3 RESULTS AND DISCUSSION

3.1 Structure description of compound 5

The crystal structure of the title compound 5 with atomic numbering and hydrogen-bonding interactions are shown in Figs.1 and 2, respectively.The selected bond lengths and bond angles for 5 are described in Table 1.

Table 1. Selected Bond Lengths (?) and Bond Angles (°) for the Title Compound 5

Fig.1. Crystal structure of the title compound 5

Fig.2. Hydrogen-bonding interactions (dashed lines) in the molecule of compound 5

As listed in Table 1, the C–C bond lengths of aromatic ring are from 1.373(2) to 1.3899(17) ?.The C–N bond lengths of pyrazole and pyridine rings are from 1.3396(15) to 1.3762(16) ?, which is longer than typical C=N (1.28 ?) in the previously reported structure[16].The N(1)–N(2) bond length is 1.3537(14) ?, which is in good agreement with typical N–N (1.358 ?) in literature[17].The C(9)=O(1) and C(9)–N(3) bond lengths are 1.2334(15) and 1.3378(15) ?, respectively, corresponding to typical values for C(sp2)–O and C(sp3)–N bond lengths.All nonhydrogen atoms of phenyl,pyridine and pyrazole ring are in good planarity.As for the cycloheptane ring, it shows large distortions due to its lack of conjugation.The benzene and pyrazole rings are nearly coplanar with a dihedral angle of 50.977(46)°, while the dihedral angle between the central pyrazole and pyridine rings is 11.688(46)°.Analysis of the crystal packing indicated no classical hydrogen bonds were found in the molecules.Two adjacent molecules in crystal packing of compound 5 were linked by two weak hydrogen-bonding interaction C(15)–H(15)···O(1)to generate an extensive network.

3.2 Biological activities

Bioassay results of the insecticidal activities in vivo are depicted in Table 2.Unfortunately, after transforming the position of carboxamide, the title compound 5 only exhibited weak insecticidal activity at 600 mg/L against the diamondback moth(Plutella xylostella), but showed relative higher insecticidal activity at 600 mg/L against cotton bollworm (Helicoverpa armigera).

Table 2. Insecticidal Activity of the Title Compound 5 (600 mg/mL)against Plutella xylostella and Helicoverpa Armigeraa, b

4 CONCLUSION

In summary, a novel bicyclic pyrazole-3-carboxamide derivative 5 was prepared, and its structure was confirmed by IR spectra,1H NMR, H RMS and single-crystal X-ray determination.The biological activity showed that the title compound 5 had weak insecticidal activity against diamondback moth(Plutella xylostella), while exhibited higher activity against cotton bollworm (Helicoverpa armigera).These results provided some insights towards the design and synthesis of novel pyrazole amide pesticides and further studies are currently in progress.

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