Efficient synthesis and fungicidal activities of strobilurin analogues containing benzofuro [3,2-d]-1,2,4-triazolo[1,5-a]pyrimidinone side chains

Introduction

Strobilurin fungicides have been an important class of agricultural fungicides since being launched first in 1996 [1, 2]. Some of them exhibit strong fungicidal activity against various fungi by interacting with the ubiquinol-oxidation center of the bc1-enzyme complex (complex III) [3]. The general structure of strobilurin fungicides consists of three parts: pharmacophore, bridge ring, and side chain. It has been demonstrated that modification of the side chain, especially heterocyclic side chain, is the most effective way to obtain new strobilurin analogues with a higher activity [4–8]. Many strobilurin containing various N- or S-heterocyclic side chains, such as pyridine, pyrazole, imidazole, benzothiazole, and oxodiazole, have been synthesized and they display broad-spectrum biological activities. The heterocycles containing the benzofuropyrimidinone system are of great importance because of their remarkable biological properties, such as analgesic, anti-inflammatory and antimicrobial activities [9, 10]. On the other hand, heterocycles containing the 1,2,4-triazole nucleus also exhibit various biological activities. Several of such compounds have been used as fungicidal, bactericidal, insecticidal, antitumor and anti-inflammatory agents [11–13]. The introduction of a triazole ring to the benzofuro-[3,2-d]pyrimidin-4(3H)-one system is expected to influence the biological activities significantly. However, the resultant tetracyclic system, benzofuro[3,2-d]-1,2,4-triazolo-[1,5-a]pyrimidinone, has been much less investigated, probably due to the fact that this tetracyclic system is not easily accessible by routine synthetic methods. Here we wish to report synthesis and fungicidal activities of a series of new strobilurin analogues containing this tetracyclic side chain.

Results and discussion

The synthesis of compounds 1 and 2 was accomplished [14–16] from a commercially available salicylic nitrile (Scheme 1). Iminophosphoranes 2 were allowed to reacted with excess carbon disulfide in a refluxing mixture of dichloromethane and acetonitrile to give 2-thioxobenzofuro[3,2-d]-1,2,4-triazolo[1,5-a]pyrimidin-5(1H)-ones 4 in good yields (Scheme 1). The formation of 4 can be viewed as an initial aza-Wittig reaction between the iminophosphorane 2 and CS₂ affording the intermediate isothiocyanate 3 which undergoes cyclization to give 4.

Scheme 1

Treatment of 4 with methyl 3-(2-(bromomethyl)phenyl)-3-methoxyacrylate in the presence of potassium carbonate at 50°C gave strobilurin analogues 5 in good yields. The method was used to prepare additional analogues 6. The structures of compounds 4-6 were confirmed by analysis of their spectral data.

The fungicidal activities against six kinds of fungi, Fusarium oxysporium, Rhizoctonia solani, Botrytis cinereapers, Gibberella zeae, Dothiorella gregaria, and Colletotrichum gossypii, were tested according to the reported method [7] using kresoxim-methyl as control. The results indicate that the majority of the synthesized compounds show only moderate fungicidal activities at a dosage of 50 mg/L. The notable exceptions are compounds 5b (R¹ = 4-F-Ph) and 5c (R¹ = 4-Cl-Ph) with an electron-withdrawing halogen atom (see Experimental for complete structures). These two compounds show the highest inhibition activities (67% and 70%) against R. solani. These values are essentially identical to the activities of the reference drug. In general, strobilurin analogues 5 show increased bioactivities in comparison with analogues 6.

Conclusions

An efficient synthesis of strobilurin analogues containing a benzofuro[3,2-d]-1,2,4-triazolo[1,5-a]pyrimidin-5(1H)-one side chain was described. The protocol provides good to excellent yields, mild reaction condition, and simple purification procedure. The preliminary investigations on the biological activities show that some compounds exhibit excellent fungicidal activities.

Experimental

Samples of F. oxysporium, R. solani, B. cinereapers, G. zeae, D. gregaria, and C. gossypii, were provided through the courtesy of the Center for Bioassay, Central China Normal University. ¹H NMR spectra (400 MHz) were recorded on a Mercury-Plus 400 spectrometer in CDCl₃ or DMSO-d₆ with TMS as the internal reference. Electron-impact mass spectra were determined at 70 eV using a Trace MS 2000 mass spectrometer. IR spectra were recorded on a PE-983 infrared spectrometer in KBr pellets. Elemental analyses were performed on a Vario EL III elemental analysis instrument. Melting points were taken on an X-4 binocular microscope melting point apparatus (Beijing Tech Instruments Co., Beijing, China) and are uncorrected. The iminophosphorane 2 and 3-(2-(bromomethyl)phenyl)-3-methoxyacrylate were prepared according to the reported methods [15, 16].