Synthesis, Crystal Structure and Fungicidal Activity of N-(4-tert-buty)-5-(1,2,4-triazol-1-yl)thiazol-2-yl)propionamide①

YE Jiao SUN Xiao-Xiao QIU Shen-Yi HU Ai-Xi

(College of Chemistry and Chemical Engineering,Hunan University, Changsha 410082, China)

1 INTRODUCTION

It is well known that thiazole derivatives have attracted a great deal of interest due to their low toxicity and a variety of biological activities[1-2]. They are known as insecticides[3], herbicides[4]and antibacterial agents[5], and also display antitumor[6],antiviral[7]and other biological activities[8-10]. On the other hand, triazole antifungals are known as potent inhibitors of the cytochrome P450 monooxygenase in the process of fungal biosynthesis of ergosterol,which is an essential component of fungal cell membrane[11]. These triazole antifungals, such as triadimefon, flutriafol, propiconazole and simeconazole, are applied widely to plant protection. Furthermore, incorporating 1H-1,2,4-triazole unit into thiazole compounds may usually improve their biological or physiological activities. Press[12]reported the synthesis and SAR of 5-heterocycle-substituted aminothiazole as adenosine receptor antagonists. Shao[13-14]designed and synthesized 1H-1,2,4-triazol-1-yl-thiazole and thiazole imide derivatives, which possessed antifungal and plant growth regulatory activities. And Hu[15]discussed the synthesis and antifungal activity of (E)-N-benzylidene-4-tert-butyl-5-(1,2,4-triazol-1-yl)thiazol-2-amines (1),some of which demonstrated high antifungal activity.Therefore, as a continuation of our studies on thiazole derivatives, we designed and synthesized a new compound N-(4-tert-buty)-5-(1,2,4-triazol-1-yl)thiazol-2-yl)propionamide (2) by using amide moiety to replace the unstable imine of compound 1.The synthesis route of 2 is depicted in Scheme 1.

Scheme 1. Design and synthetic route of the title compound 2

2 EXPERIMENTAL

2.1 Instruments and general methods

Melting point was measured on an X-4 electrothermal digital melting point apparatus and uncorrected.1H NMR (400 MHz) and13C NMR (100 MHz)spectra were recorded on a Bruker advanced instrument using TMS as internal standard and CDCl3as the solvent with chemical shifts (δ) expressed in ppm. All solvents were of reagent grade. All chemicals were of analytical reagent grade and used directly without further purification. N-(4-tert-butyl)-5-(1,2,4-triazol-1-yl)-2-aminothiazole was synthesized according to literature[16]. The strain of Rhizoctonia solani was provided by the Hunan Research Institute of Chemical Industry (Changsha).

2.2 Synthesis of the title compound 2

N-(4-tert-butyl)-5-(1,2,4-triazol-1-yl)-2-aminothiazole (3, 2 mmol) and propionic anhydride (6.0 mL)were stirred at 50 ℃ for 1 h, then the reaction solution was cooled and poured into ice water with stirring. The resultant precipitate was filtered off and dried to give compound 2. Yield: 87.2%, m.p.:159～161 ℃.1H NMR (400 MHz, CDCl3) δ: 1.13 (s,9H, 3×CH3), 1.28 (t, J = 7.6 Hz, 3H, CH3), 2.54 (q, J= 7.6 Hz, 2H, CH2), 8.15 (s, 1H, C2N3H23-H), 8.31(s, 1H, C2N3H25-H), 9.49 (s, 1H, NH);13C NMR(100 MHz, CDCl3) δ: 9.0, 29.5, 29.5, 29.5, 35.8,119.0, 147.4, 152.4, 153.8, 156.0, 171.5; MS-ESI m/z: 279 (M＋), 280 (M＋＋1).

2.3 X-ray structure determination

The crystals of the title compound suitable for X-ray structure determination were obtained by slowly evaporating an ethanol solution for about 60 days at room temperature. A colorless block crystal with dimensions of 0.43mm × 0.41mm × 0.27mm was selected and mounted in air onto thin glass fibers. X-ray intensity data were measured at 173(2)K on a Bruker AXS SMART 1000 CCD diffractometer equipped with a graphite-monochromatic MoKα (λ = 0.71073 Å) radiation. Corrections for incident and diffracted beam absorption effects were applied using SADABS[17]. The structure was solved by direct methods with SHELXS-97[18]and expanded by difference Fourier techniques. The nonhydrogen atoms were refined anisotropically, and hydrogen atoms were added according to the theoretical models. The structure was refined by full-matrix least-squares techniques on F2with SHELXL-97[19]. The final refinement gave R = 0.0349, wR =0.0876 (w = 1/[σ2(Fo2) + (0.0497P)2+ 1.1715P],where P = (Fo2+ 2Fc2)/3), (Δ/σ)max= 0.000, S =1.033, (Δρ)max= 0.340 and (Δρ)min= –0.218 e/Å3for 2629 observed reflections with I ＞ 2σ(I). The selected bond lengths and bond angles are given in Table 1.

2.4 Bioassay of the fungicidal activities

Fungicidal activity of the title compound against R. Solani was evaluated according to the literature method[20]. The inhibition was calculated according to the formula:

where Ac and At are the average diameters of mycelia in the blank test and in the presence of the test compound, respectively. The compound was tested at the concentration of 25 mg/L in vitro. The experiments were performed in triplicate and the average inhibition was reported.

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

3 RESULTS AND DISCUSSION

The1H NMR,13C NMR and MS-ESI data for the product are in good agreement with the structure of compound 2. X-ray analysis reveals that crystals of the title compound are made up of orthorhombic unit cells, each containing eight molecules. The structure of the title compound with atomic numbering is shown in Fig. 1. This figure shows that the triazole ring makes a dihedral angle of 64.1(1)° with the planar of thiazole, which is coplanar with the amide part N(5)–C(10)–O(1).

Fig. 1. X-ray crystal structure of the title compound 2

In the molecule, the bond lengths and bond angles are normal in general. The bond lengths of C(8)–N(3), C(9)–N(4) and C(8)–N(4) in the triazole ring are 1.3160(19), 1.3167(19) and 1.359(2) Å, respectively, between the typical C=N bond (1.279 Å)[21]and C–N single bond (1.47 Å)[21]. The corresponding unsaturated bond lengths in the substituted thiazole are 1.3635(19) Å for C(1)–C(2) and 1.3167(19) Å for C(9)–N(4). The bond lengths of S(1)–C(1)(1.7428(14) Å) and S(1)–C(3) (1.7273(14) Å) in the thiazole ring are shorter than the typical S–C bond distance of 1.82 Å, with partial double bond character. Similarly, due to the conjugation effect, the C(1)–N(2) (1.4176(18) Å) is significantly shorter than the typical C–N single bond.

In addition, the bond angles of C(3)–S(1)–C(1)(86.78(7)°), C(2)–C(1)–S(1) (112.71(11)°) and N(1)–C(3)–S(1) (116.62(11)°) are consistent with the values found for similar compound[22].

As shown in Fig. 2, the one-dimensional structure of compound 2 is stabilized by N(5)–H(5)··N(4)hydrogen-bonding interaction involving the amide and triazole groups. The bond distance and angle of N(5)–H(5)··N(4) are 2.8715(18) Å and 174.2°,which are beneficial to the overlap of electron cloud and the stability of the hydrogen bonding.

The fungicidal activity of the title compound 2 and its analogues compounds 4～6 were measured against R. Solani according to the reported method[20]. The result indicated that compounds 2, 4, 5 and 6 exhibited 80.0%, 10.0%, 20.0% and 50.0%inhibitory of fungicidal activity at the dosage of 25 mg/L, respectively. As a result, compound 2 may be a good backbone for fungicidal activity. Introducing the aromatic ring or extending the carbon chain may find new and more potent fungicides. The study of the structure modification is underway.

Fig. 2. Intermolecular hydrogen bonding diagram of compound 2(H atoms have been omitted for clarity)

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