Syntheses, Crystal Structures and Herbicide Activities of Two Pyrazole Derivatives①

FU Ying YI Ke-Han LI Ming-Qiang WANG Meng-Xia HOU Yu-Wen YE Fei

(College of Science, Northeast Agricultural University, Harbin 150030, China)

Two novel N-acyl-3-phenylpyrazol benzophenones were designed and synthesized via cyclization and acylation with 1,3-diphenylpropane-1,3-dione and dimethylformamide dimethylacetal as the starting materials.The two compounds both crystallize in the triclinic space group P 1.And the presence of van der Waals forces stabilizes the crystal structures.

1 INTRODUCTION

4-Hydroxyphenylpyruvate dioxygenase (HPPD), a Fe(II)-dependent and non-heme dioxygenase, catalyzes the conversion of 4-hydroxyphenylpyruvic acid(HPPA) to homogentisate (HGA)[1,2].HGA is an essential precursor for the biosynthesis of tocopherol and plastoquinone, which are crucial for the plants normal growth[3].The plastoquinone is involved in the photosynthetic electron transport chain that allows for phytoene desaturase-mediated oxidation of phytoene to carotenoids.On the basis of this pathway, inhibition of pigment biosynthesis by the repression of HPPD activity results in photodestruction of chlorophyll and whitening of plant tissues[4-6].Therefore, HPPD inhibitors are also termed as bleaching herbicides.These inhibitors show many advantages, such as wide weed-control spectrum, excellent crop selectivity,compatibility for tank mixes with other herbicides and benign environment effects[7-9].

To date, HPPD herbicides have been developed into a number of different structure types, such as triketone, pyrazole, and isoxazole[10,11].In the past forty years, there are several commercial pyrazole HPPD herbicides with good weed control containing pyrazolynate, pyrazoxyfen, topramezone and pyrasulfotole.The first pyrazole HPPD inhibitor pyrazolynate was created by Sankyo in 1980 used to protect rice against injury caused by annual or perennial weeds[12].Kimura first reported the pyrazoxyfen in 1984, which was then marketed by Ishihara industrial company.However, its safety was greatly affected by temperature when it was used in paddy fields[13].Topramezone, developed by BASF in 2006, was the most safe and efficient HPPD herbicide in corn fields[14].Another pyrazole HPPD herbicide first used in grain fields was pyrasulfotole,and it significantly improved the crop resistance and made it excellent for all varieties of wheat, barley and triticale when mixed with safener mefenpyrdiethyl[15].

To summarize the structures of all commercial pyrazole HPPD herbicides, the minimum substructure of these inhibitors is 2-benzoylethen-1-ol (Fig.1).In order to continue our study on searching novel HPPD herbicides[16,17], two novel pyrazole derivatives were designed and synthesized via cyclization and acylation to obtain novel pyrazole HPPD herbicides (Scheme 1).The single crystal was determined by X-ray diffraction analysis in order to further investigate the relationship between the HPPD herbicides’ molecular structures and their bioactivities.

Fig.1.Skeleton structure of the template compound

Scheme 1.Route for the synthesis of the target compound

2 EXPERIMENTAL

2.1 Materials and characterization

All the reagents were of analytical grade and used without further purification.Analytical thin-layer chromatography (TLC) was performed on silica gel GF254 (Qingdao Haiyang Chemical Co.Ltd).The melting point was measured using a Beijing Taike point apparatus (X-4) and the thermometer was uncorrected.The Infrared (IR) spectra were taken on a KJ-IN-27G infrared spectrophotometer (KBr).The NMR spectra were recorded on a Bruker AV600 spectrometer with CDCl3or DMSO-d6as the solvent and TMS as the internal standard.High-resolution mass spectrometry (HRMS) was obtained by FTICR-MS.Pyrazoxyfen was purchased from Tianjin Sigma Technology Co., Ltd.

2.2 Preparation of 2-dimethylaminome thylene-1,3-diphenylpropane-1,3-dione (3)

Compound3was synthesized according to the reference[18].A mixture of dimethylformamide dimethylacetal1(1.19 g, 10 mmol) and 1,3-diphenylpropane-1,3-dione2(2.24 g, 10 mmol) in anhydrous toluene (50 mL) was heated and refluxed for 8 h,then cooled to room temperature.Compound3was obtained as faint yellow solid in 44% yield, m.p.131～132 ℃.1H NMR (600 MHz, CDCl3) δ (ppm):7.64 (s, 1H, N–CH=C), 7.59～7.16 (m, 10H, Ar–H),3.14～2.83 (m, 6H, –CH3).13C NMR (150 MHz,CDCl3) δ (ppm): 194.86, 158.10, 140.96, 131.17,129.01, 127.94, 111.54, 47.34, 43.30.IR (KBr) v(cm-1): 3051～2923 (m, C–H), 1651 (s, C=O),1584～1562 (s, CH-CH=CH).

2.3 Preparation of phenyl-(3-phenyl-1H-pyrazol-4-yl) methanone (4)

Synthesis of compound4was based on the method presented earlier[18-21].Compound3(2.7 g, 10 mmol)was treated with N2H4·2HCl (1.04 g, 10 mmol) and refluxed in ethanol for 1.5 h, and appropriate distilled water was added to the solution before heating.The faint yellow solid product was filtered and recrystallized from EtOH with the yield of 90%, m.p.165～166 ℃.1H NMR (600MHz, DMSO-d6) δ(ppm): 13.63 (br, 1H, NH), 8.10 (s, 1H, N–CH=C),7.78～7.38 (m, 10H, Ar–H).13C NMR (150 MHz,DMSO-d6) δ (ppm): 190.05, 139.43, 132.85, 129.55,129.10, 128.92, 128.58, 118.29.IR (KBr) v (cm-1):3345 (m, N–H), 3124～3026 (w, C–H), 1651 (s,C=O), 1562～1433 (s, CH–CH=CH).

2.4 Preparation of N-acyl-3-phenylpyrazol benzophenone (5)

Acyl chloride (12 mmol) was added dropwise to a solution of compound4(2.48 g, 10 mmol), and Et3N(1.52 g, 15 mmol) served as the attaching acid agent in CH2Cl2.Then the mixture was refluxed for 4 h until the reaction was complete (monitored by TLC).The organic phase was washed with water until pH =7.The organic layer was dried over anhydrous MgSO4and vacuum distillation solvent.Compounds5were obtained by recrystallization with CH2Cl2and light petroleum or column chromatography with CH2Cl2and EtOH.The physical and spectra data of compounds5are as follows:

3-Phenyl-1-o-methylbenzoyl-pyrazole-4-benzophe none (5a)White solid, 90% yield, m.p.: 150～152℃.1H NMR (600MHz, CDCl3) δ (ppm): 8.66 (s, 1H,N–CH=C), 7.93～7.26 (m, 14H, Ar–H), 2.48 (s, 3H,–CH3).13C NMR (150 MHz, CDCl3) δ (ppm): 189.79,167.64, 155.90, 138.43, 138.01, 134.61, 133.45,131.87, 131.26, 131.10, 130.96, 130.28, 129.68,129.68, 129.40, 128.86, 128.86, 128.70, 128.70,128.31, 128.31, 125.33, 122.68, 20.25.IR (KBr)v(cm-1): 3031～2981 (m, C–H), 1713 (s, C–C=O),1655 (s, N–C=O), 1599～1449 (s, CH–CH=CH).HRMS (ESI): m/z [M+H+] calculated for monoisotopic mass 367.1368, found 367.1443.

3-Phenyl-1-p-fuorobenzoyl-pyrazole-4-benzophenone (5b) White solid, 78% yield, m.p.: 174～176℃.1H NMR (600 MHz, CDCl3) δ (ppm): 8.75 (s, 1H,N–CH=C), 8.45～7.21 (m, 14H, Ar–H).13C NMR(150 MHz, CDCl3) δ (ppm): 189.72, 164.59, 155.92,138.04, 135.45, 135.16, 135.04, 133.47, 130.99,129.67, 129.67, 129.51, 129.51, 128.84, 128.84,128.71, 128.71, 128.42, 128.42, 126.69, 122.35,115.83, 115.54.IR (KBr) v (cm-1): 3152～3002 (m,C–H), 1692 (s, C–C=O), 1668 (s, N–C=O), 1589～1448 (s, CH–CH=CH).HRMS (ESI): m/z [M+H+]calculated for monoisotopic mass 371.1118, found 371.1193.

2.5 Crystal structure determination

The suitable colorless single crystals of the title compounds were obtained by slow diffusion in EtOAc and petroleum ether.The X-ray data were collected on a Rigaku RAXIS-RAPID diffractometer (Japan) with MoKα radiation (l = 0.71073 ?) at 293(2) K.Selected crystallographic and experimental details are summarized in Table 1.The structure was solved by direct methods using SHELXS-97[22], and refined by full-matrix least-squares on F2, SHELXL-97[23].All non-hydrogen atoms were refined anisotropically.The hydrogen atoms were included in calculated positions,and refined in terms of riding model (Uiso(H) =1.5Ueq(C) for the atoms of methyl and Uiso(H) =1.2Ueq(C) for others).Selected bond lengths and bond angles are given in Table 2.

Table 1.Summary of Crystallographic Data for 5a and 5b

Table 2.Selected Bond Lengths (?) and Bond Angles (°) of Compounds 5a and 5b

3 RESULTS AND DISCUSSION

The molecular structures of compounds5aand5bwith atomic numbering scheme are shown in Fig.2.According to X-ray analysis, compounds5aand5bboth crystallize in triclinic space group P 1.The crystal structures of them contained three benzene rings and one pyrazole ring.For compound5a, the bonds of N(1)–C(8) (1.43(3) ?) and C(10)–C(12)(1.49(4) ?) are shorter than the typical C–N (1.47 ?)and standard single C–C (1.54 ?) bonds due to the existence of p-π-p conjunction effect between pyrazole ring and two carbonyls[24].And the bond distance of C(9)–C(10) (1.36(4) ?) is a little longer than a typical C=C bond (1.34 ?)[24], which results in the conjugated system, too.There are similar experimental results in5b.The bond distances of C(7)–N(1), C(9)–C(17) and C(8)–C(9) are 1.42(2),1.49(2) and 1.36(2) ?, respectively.In addition, the torsion angle of C(9)–N(1)–N(2)–C(11) in compound5ais 1.75(3)° which indicates a coplanar conformation in the pyrazole ring.And the second benzene ring (C(13)～C(18)) is almost vertical to the third one (C(19)～C(24)) with the dihedral angle being 87.70(9)°.Owing to the similarity of the structure, the analogous experimental data occurred in compound5b, andthe torsion angle of C(8)–N(1)–N(2)–C(10) in compound5bis –2.43(2)°.The dihedral angle of the second benzene ring(C(11)～C(16)) and the third one (C(19)～C(24))in5bis 84.36(7)°, which shows that these two rings are perpendicular.In both compounds5aand5b, the presence of the van der Waals forces stabilizes the crystal structures.

Certainly, there are some differences between the crystal structures of compounds5aand5bdue to the different types and positions of the substituent.For compound5a, the pyrazole ring is not in the same plane with any benzene rings with the dihedral angle being 55.57(9)° (C(1)～C(6)),61.77(8)° (C(13)～C(18)), and 34.67(8)° (C(19)～C(24)), respectively.However, the dihedral angle between pyrazole ring and the first benzene ring(C(1)～C(6)) is only 29.29(5)° in compound5b.Meanwhile, the dihedral angles between pyrazole ring and other benzene rings are 23.85(5)°(C(11)～C(16)) and 83.62(7)° (C(18)～ C(23)),respectively.

Fig.2.Molecular diagram of compounds 5a and 5b, showing 30% probability ellipsoids

4 BIOLOGICAL ACTIVITIES

The greenhouse experiment was employed to measure the herbicidal activity of compounds5aand5bto barnyard grass at a dosage of 0.05 mmol·m-2after initial screening with pyrazoxyfen, and pyrazoxyfen was also used as the reference substance.As shown in Table 3, compound5bdisplays extent herbicidal activities via decreasing the content of chlorophyll, while it doesn’t show obvious herbicidal activities.It reveals that the substituent at the benzoyl of electron-withdrawing may be the critical active group and that the herbicidal activities are improved significantly.

Table 3.Chlorophyll Content of Barnyard Grass Treated with Compounds 5a and 5b (0.05 mmol·m-2)

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基于移動端傳播技術(shù)，自媒體傳播的廣度和速度呈現(xiàn)了指數(shù)級的飆升，特別是垂直領域的自媒體更能觸及目標人群，在細分專業(yè)領域中有更大的話語權(quán)，一個看似不起眼的行業(yè)公號的一篇閱讀量“10萬+”文章，足以在特定領域中掀起一場輿論風暴。動輒在朋友圈刷屏的傳播態(tài)勢，也足以讓相關行業(yè)的企業(yè)心驚膽戰(zhàn)、唯命是從。

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