Synthesis and insecticidal activity of novel benzothiazole derivatives containing the coumarin moiety

A series of novel benzothiazole derivatives containing a coumarin moiety was designed and synthesized. Their structures were characterized in detail via 1 H NMR, 13 C NMR, HRMS spectra and single-crystal X-ray diffraction analysis. The bioassay results indicated that some compounds showed encouraging insecticidal activity against Plutella xylostella and Aphis fabae at 400 mg/L. The preliminary structure-activity relationships were also discussed


Introduction
The growth, transportation and storage of crops are endangered by various agricultural diseases, insects, grasses, and rats.These agricultural harmful organisms have seriously affected the growth of crops, the appearance, yield and quality of agricultural products.Because agricultural pests are characterized by many types, large quantities, and serious damage, it is an important task in agricultural production to control agricultural pests and reduce their damage. 1Pesticides have played an important role in the prevention and control of agricultural pests.However, drug resistances, environmental hazards and other problems have become increasingly prominent with the use of insecticides, 2,3 which objectively require the discovery of new insecticide candidates.
Benzothiazole derivatives exhibit a wide variety of biological activities such as anticancer, 4 analgesic, 5 antiinflammatory, 6 anti-tubercular, 7 antimicrobial, 8 and insecticidal activity. 9The compounds A and B (Figure 1) containing benzothiazole moiety possessed insecticidal activity against Prodenia litura and Plutella xylostella, respectively. 10,11The compound C containing phenyl benzothiazole moiety showed acaricidal activity. 12oumarins are frequently used to develop novel lead compounds for agrochemical and pharmaceutical because of their wide spectrum of bioactivities. 13Coumarin derivatives have often acted as anticancer prodrugs, 14 or as antimalarial, 15 anti-inflammatory, 16 antioxidant and antimicrobial agents. 17In particular, compounds D and E, which both contain coumarin skeleton in their structures have been reported to show insecticidal activity. 18,19However, almost no coumarin insecticides have actually been used to control agricultural insects.So the design and synthesis of the compounds containing the coumarin moiety is very meaningful for the development of novel insecticides with unique molecular skeleton.
In view of the above reports, two pharmacophores benzothiazole and coumarin were connected by an alkylene linker in the same molecule to design and synthesize a series of benzothiazole derivatives containing the coumarin group according to the "active substructure combination principle" (Figure 1).Subsequently, the insecticidal activity against Plutella xylostella and Aphis fabae (broad bean aphid) were evaluated.The preliminary structure-activity relationships between the title compounds and insecticidal activity were also analyzed.The 1 H NMR, 13 C NMR, and HRMS spectra data of the title compounds were fully in accordance with their assigned structures.The structures of some key intermediates were also confirmed by 1 H NMR spectra.The yields, melting points and spectra data of the title compounds and intermediates are listed in the Experimental Section.This is the first report of all of the title compounds.Crystal structure of compound 6v.The structure of compound 6v was further studied using the single crystal X-ray analysis.The corresponding crystal structure and crystal packing diagrams are shown by Figure 2. and Figure 3, respectively.As shown in Figure 2   Insecticidal activity.The results in Table 1 indicated that the title compounds showed moderate to significant insecticidal activity at 400 μg/mL.Ten of the compounds showed high activity with the mortalities of more than 50% against P. xylostella.Among them, the compounds 6d, 6k, 6w and 6z possessed the mortalities of over 85%, especially the compounds 6d and 6w, which reached 100% and 93.10% mortalities, respectively.Meanwhile, twenty-three of the compounds showed high activity against the aphids, their mortalities were higher than 50%.While the compounds 6e, 6l, 6s, 6t and 6u presented noticeable activity with the mortalities of 90% above.Compared with the activity against P. xylostella, the title compounds showed higher insecticidal activity against A. fabae.Among them, the compounds 6u-6z and 6aa-6dd gave good activity against the aphids with the mortalities ranging from 56.67 to 96.51%.That is to say, the alkylene linked at 3-position of benzothiazol-2-phenyl was beneficial to the bioactivity against the aphids.In addition, the compounds 6c, 6h, 6m, 6r, 6w and 6bb all exhibited evident activity against the aphids with the mortalities ranging from 60.00 to 88.41%.These six compounds contain a same alkylene linker with four carbon atoms (n=4).

Conclusions
In summary, a series of novel benzothiazole derivatives containing a coumarin group were designed, prepared and evaluated for their insecticidal activities against Plutella xylostella and Aphis fabae in vivo.The structures of title compounds were well supported by spectroscopic data and single-crystal X-ray diffraction analysis.The compounds 6d and 6w showed outstanding activity against P. xylostella.And the compounds 6e, 6l, 6s, 6t and 6u possessed good activity against A. fabae.The structure-activity relationship analysis demonstrated that the alkylene was linked at 3-position of benzothiazol-2-phenyl was beneficial to improve the bioactivity of title compounds against the aphids.Meanwhile, the compounds containing a alkylene linker with four carbon

Experimental Section
General.The melting points of the products were determined on a WRS-1B digital melting-point apparatus.NMR spectra were performed in DMSO-d 6 or CDCl 3 on a Bruker Avance III 400 NMR spectrometer at room temperature with TMS as an internal standard.Thin-layer chromatography (TLC) was performed on silica gel GF254.High resolution mass spectrometry was recorded on an Agilent Technologies 6540 UHD Accurate-Mass Q-TOF LC/MS.All reagents were analytical reagent grade pure and used directly without further purification.Synthesis of coumarin intermediates 2. 7-Hydroxy coumarin 2a was synthesized according to the reported literature. 20Resorcinol (11.0 g, 0. and 60 (±5)% relative humidity in a greenhouse.The bioactivity of title compounds against P. xylostella and aphid (A.fabae) were tested according to the modified leaf-dip method using the reported procedure. 24,25The compounds were dissolved in DMF and then diluted with water (containing 0.1% Triton X-100).The disks of Chinese cabbage leaves were prepared and dipped in a test solution for 10 s.After drying, the leaves were placed in a plastic dish with ten third instar larvae (P.xylostella).The mortality was determined after 120 h by the dead insect number in the treated dishes relative to that in the untreated controls.At the same time, Horsebean seedlings with apterous adult A. fabae were prepared and dipped in a test solution for 10 s.After drying, the seedlings were placed in a glass bottle.The mortality was determined after 72 h.All the treatments and controls were carried out in three replicates.