English

• 1. INTRODUCTION

  Heterocyclic compounds received important attention due to their various biological activities^[1-5]. Pyridine derivatives displayed diverse activities, such as nematicidal activity^[6-8], fungicidal activity^[9-16], antimicrobial activity^[17], herbicidal activity^{[18, 19]}, antitumor activity^[20], anti-HIV activity^[21] and p38 MAP kinase inhibitors^[22]. Lots of pyridine compounds were developed as commericial drugs or pesticides. In addition, acyl urea group is also an important key building block in many drugs or pesticides. They always exhibited diversity bioactivities, such as insecticidal activity^[23], anti-tumor activity^[24], fungicidal activity^[25-28], insecticidal activity^[29], anti-inflammatory activity^[30], antioxidant activity^[31].

  In view of these facts mentioned above, and also as a part of our work on the synthesis of bioactive lead compounds for drug discovery^[32-49], the title compound 2-chloro-N-(o-tolylcarbamoyl)nicotinamide was designed and synthesized. The structure was characterized by ¹H NMR and H RMS. The single crystal structure was determined by X-ray diffraction, and the fungicidal activity of the title compound was tested.

  2. EXPERIMENTAL

  2.1 Instruments

  Melting points were determined using an X-4 apparatus and uncorrected. ¹H NMR spectra were measured on a Bruker AC-P500 instrument using TMS as an internal standard and CDCl₃ as the solvent. HR-ESI-MS was tested using an Agilent 1100 HPLC-JEOL AccuTOF instrument. All the reagents were of analytical grade or freshly prepared before use.

  2.2 General procedure

  The intermediates 1, 2 and 3 were synthesized according to our previous work^[50-52]. To a solution of intermediate 3 (2 mmol) in CH₂Cl₂ (8 mL) was added 2 mmol o-toluidine with stirring for overnight. After the reaction is over, the solvent was evaporated, and the mixture was purified by chromatography on a silica gel to give 2-chloro-N-(o-tolylcarbamoyl)nicotinamide (4): white solid, yield 65.7%, m.p. 168~171 ℃, ¹H NMR (CDCl₃, 500 MHz), δ: 2.40 (s, 3H, CH₃₎, 7.09~7.12 (m, 1H, Ph), 7.23 (t, J = 6.2 Hz, 2H, Ph), 7.42~7.44 m, 1H, Py), 7.91 t, J = 6.4 Hz, 1H, Ph), 8.13~8.15 m, 1H, Py), 8.60~8.61 m, 1H, Py), 9.45 s, 1H, NH), 10.41 s, 1H, NH); H RMS (ESI) for C₁₄H₁₂ClN₃O₂ m/z: calculated, 290.0691. Found: 290.0648 [M+H]⁺.

  2.4 Structure determination

  A colorless crystal suitable for X-ray diffraction study was cultivated in the test tube from EtOH by self-volatilization. A crystal with dimensions of 0.36mm × 0.32mm × 0.20mm was mounted on a Rigaku Saturn diffractometer equipped with a graphite-monochromatic MoKα radiation (λ = 0.71073 Å). Intensity data were collected at 296(2) K by using a multi-scan mode in the range of 5.912≤θ≤58.778° with the following index ranges: –7≤h≤10, –16≤k≤16 and –13≤l≤13. A total of 11712 reflections were collected and 3334 were independent (R_int = 0.0286), of which 2467 with I > 2σ(I) were observed. The crystal structure was solved by direct methods with SHELXS-97 and refined by full-matrix least-squares refinements based on F² with SHELXL-97^[53]. All non-hydrogen atoms were refined anisotropically, and all hydrogen atoms were located in the calculated positions and refined with a riding model. The final refinement converged at R = 0.0416 and wR = 0.0971.

  3. RESULTS AND DISCUSSION

  3.1 Synthesis and spectra analysis

  The synthetic route of 2-chloro-N-(o-tolylcarbamoyl)nicotinamide is depicted in Scheme 1. In this paper, 2-chloronicotinic acid was used as the starting material. 2-Chloronicotinic acid reacted with SOCl₂ to afford 2-chloronicotinoyl chloride which was used for the next step without purification. Then, the 2-chloronicotinoyl chloride was dropwise added into the ammonia solution, obtaining white solid. The amide intermediate 2 reacted with oxalyl chloride under reflux condition, then the colorless liquid 2-chloronicotinoyl isocyanate was given. Finally, the target compound was afforded after o-toluidine was added into the isocyanate solution. The structure of the pure title product was confirmed by ¹H NMR and HRMS. From the ¹H NMR data, the appearance of signal at 2.40 ppm belongs to the methyl protons of phenyl ring. The protons of pyridne and phenyl rings are found at 7~8 ppm. The signals of 9.45 and 10.41 ppm are the NH protons of urea bridge. The high resolution mass spectroscopy of the title compound is in agreement with the molecular formula C₁₄H₁₂ClN₃O₂.

  Scheme 1

  

  Scheme 1.  Synthetic route of the title compound

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  3.2 Crystal structure

  The crystal belongs to monoclinic system with space group P2₁/n. The molecular structure of the title compound is shown in Fig. 1 and the packing of the title compound is shown in Fig. 2. The selected bond lengths and bond angles for the title compound are given in Table 1.

  Figure 1

  

  Figure 1.  Molecular structure of the title compound

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  Figure 2

  

  Figure 2.  Packing of the title compound

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  Table 1

  

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

  DownLoad: CSV

  Bond	Dist.		Angle	(°)
  O(1)–C(7)	1.2191(18)		C(7)–N(1)–C(1)	127.87(13)
  O(2)–C(8)	1.2188(18)		C(8)–N(2)–C(7)	128.61(13)
  N(1)–C(1)	1.415(2)		C(6)–C(1)–N(1)	122.82(14)
  O(2)–C(7)	1.2333(15)		C(6)–C(1)–C(2)	120.67(15)
  N(2)–C(7)	1.401(2)		O(1)–C(7)–N(2)	118.41(14)
  N(2)–C(8)	1.3707(19)		N(1)–C(7)–N(2)	115.87(13)
  N(3)–C(10)	1.311(2)		O(2)–C(8)–N(2)	122.72(15)
  N(3)–C(11)	1.337(2)		O(2)–C(8)–C(9)	122.60(14)
  C(1)–C(2)	1.398(2)		N(2)–C(8)–C(9)	114.62(13)
  C(1)–C(6)	1.387(2)		C(10)–C(9)–C(8)	123.15(14)
  C(2)–C(3)	1.386(2)		C(13)–C(9)–C(8)	120.66(14)

  Generally, the average bond lengths and bond angles of ring system (phenyl and pyridine ring) are in the normal ranges^[54]. The N(3)–C(10) (1.311(2) Å) and N(3)–C(11) (1.337(2) Å) bonds were longer than the general C=N double bond in 1.27 Å, which indicated significant electron delocalization in the fused ring system. However, the C(7)–N(2) (1.401(2) Å) and C(7)–N(2) (1.401(2) Å) bonds are longer than the general C=N double bond of 1.28 Å^[55]. In the other planar pyridine and phenyl rings, the C–C bond lengths range from 1.373(3) to 1.492(2) Å, almost equal to the values of typical bonds of aromatic structure^[56] with the average bond angle of 120°. The torsion angles of C(1)– N(1)–C(7)–N(2), N(1)–C(7)–N(2)–C(8) and C(7)– N(2)–C(8)–C(9) are –173.90(15)°, 0.4(3)° and 171.30(16)°, respectively, which indicated the two carbonyl groups are opposite and the acyl urea bridge is in the same plane.

  In the intermolecular face-to-face π-π stacking pattern of the title compound, it is worth to mention that the two molecules of each stacking unit are cetrosymmetric, which can be proved by the relative position of the phenyl rings (C(1) to C(6)) and pyridine ring: the centroid separation of them is 3.801 Å. As shown in Fig. 1, between the phenyl ring (C(1)~C(6)) and pyridine ring (C(9), C(10), N(3), C(11), C(12), C(13)), there is a small dihedral angle (θ) of 52.4º with plane equation 7.005x + 5.729y – 0.657z = 1.7214 and 7.050x – 5.578y – 0.717z = –1.3901 respectively, and the largest deviation from the least-squares plane is 0.0065 and 0.0040 nm. The title compound has an extensive network of hydrogen bonding. The parameters of intramolecular and intermolecular bonds are given in Table 2. They are linked together by O–H···N and C–H···O hydrogen bonds. From Fig. 1, the N(1)–H(1)···O(1) and C(6)–H(6)···O(1) hydrogen bonds formed a six-membered ring in the molecule. In the bc plane, they are linked together by N(2)–H(2)···O(1) hydrogen bonds (Fig. 2). This hydrogen-bonding sequence is repeated to form a ring. The ring is shaped like a decagon and has two N(2) and two O(1) atoms at the vertices, leading to a hydrogen-bond network defining cyclic motifs denoted $ R_2^2 $(8). The hydrogen bonds and weak π-π interactions strengthen the integration of the 3D network. These interactions are estimated to play a role in stabilizing the crystal structure.

  Table 2

  

  Table 2.  Hydrogen-bond Parameters (Å) of the Title Compound 4

  DownLoad: CSV

  D–H···A	d(D–H)	d(H···A)	d(D···A)	∠(DHA)
  N(2)–H(2)···O(1)#	0.86	2.66	2.865(6)	170
  N(1)–H(1)···O(2)	0.86	1.96	2.656(6)	138
  C(6)–H(6)···O(1)	0.93	2.29	2.873(2)	120.
  Symmetry transformations used to generate the equivalent atoms: #: –x, 1 – y, 1 – z

  3.3 Fungicidal activity

  Fungicidal activities of compound 2-chloro-N(o-tolylcarbamoyl)nicotinamide against Gibberella zeae (GZ), Phytophthora infestans (PI), Phytophthora capsici (PC), Sclerotinia sclerotiorum (SS), Rhizoctonia solani (RS), Alternaria solani (AS), Botrytis cinerea (BC), Fusarium oxysporum (FO), Cercospora arachidicola (CA) and Physalospora piricola (PP) were evaluated at 50 μg/mL according to our previous work^[50] with fluxapyroxad used as controls, and the results are listed in Table 3. The primary bioassay shows the title compound exhibits good inhibiting activity against Fusarium oxysporum (40.0%), Cercospora arachidicola (40.0%) and Gibberella zeae (57.1%), which is better than that of control fluxapyroxad (29.4% and 28.6%). The title compound exhibits moderate inhibiting activity against Cercospora arachidicola (40.0%) and Botrytis cinerea (45.5%), which is a little weaker than that of control fluxapyroxad (100% and 63.6%). For the other six fungals Phytophthora infestans, Phytophthora capsici, Sclerotinia sclerotiorum, Rhizoctonia solani, Alternaria solani and Physalospora piricola, they exhibited weak activity (< 40%) with inhibitory activity at 50 μg/mL, respectively.

  Table 3

  

  Table 3.  Fungicidal Activity of the Title Compound 4

  DownLoad: CSV

  No.	FO	CA	BB	AI	GZ	SS	BC	RS	PI	PC
  4	40.0	40.0	22.2	33.3	57.1	11.1	45.5	18.5	5.9	10.0
  Control	29.4	100	63.6	88.9	28.6	96.4	63.6	88.4	27.3	16.7

  
  
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  Scheme 1  Synthetic route of the title compound

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  Figure 1  Molecular structure of the title compound

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  Figure 2  Packing of the title compound

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

  Bond	Dist.		Angle	(°)
  O(1)–C(7)	1.2191(18)		C(7)–N(1)–C(1)	127.87(13)
  O(2)–C(8)	1.2188(18)		C(8)–N(2)–C(7)	128.61(13)
  N(1)–C(1)	1.415(2)		C(6)–C(1)–N(1)	122.82(14)
  O(2)–C(7)	1.2333(15)		C(6)–C(1)–C(2)	120.67(15)
  N(2)–C(7)	1.401(2)		O(1)–C(7)–N(2)	118.41(14)
  N(2)–C(8)	1.3707(19)		N(1)–C(7)–N(2)	115.87(13)
  N(3)–C(10)	1.311(2)		O(2)–C(8)–N(2)	122.72(15)
  N(3)–C(11)	1.337(2)		O(2)–C(8)–C(9)	122.60(14)
  C(1)–C(2)	1.398(2)		N(2)–C(8)–C(9)	114.62(13)
  C(1)–C(6)	1.387(2)		C(10)–C(9)–C(8)	123.15(14)
  C(2)–C(3)	1.386(2)		C(13)–C(9)–C(8)	120.66(14)

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  Table 2.  Hydrogen-bond Parameters (Å) of the Title Compound 4

  D–H···A	d(D–H)	d(H···A)	d(D···A)	∠(DHA)
  N(2)–H(2)···O(1)#	0.86	2.66	2.865(6)	170
  N(1)–H(1)···O(2)	0.86	1.96	2.656(6)	138
  C(6)–H(6)···O(1)	0.93	2.29	2.873(2)	120.
  Symmetry transformations used to generate the equivalent atoms: #: –x, 1 – y, 1 – z

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  Table 3.  Fungicidal Activity of the Title Compound 4

  No.	FO	CA	BB	AI	GZ	SS	BC	RS	PI	PC
  4	40.0	40.0	22.2	33.3	57.1	11.1	45.5	18.5	5.9	10.0
  Control	29.4	100	63.6	88.9	28.6	96.4	63.6	88.4	27.3	16.7

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