Synthesis, crystal structure and herbicidal activity of novel 1,2,3-thiadiazole substituted 2-cyanoacrylates

A series of novel 2-cyanoacrylates containing the 1,2,3-thiadiazole ring moiety were synthesized and characterized by 1 H NMR, 13 C NMR, elemental analysis and, in one case, by X-ray crystallography. Most of these cyanoacrylates exhibited good herbicidal activities. In particular, ( Z )-methoxyethyl- and ( Z )-ethoxyethyl-2-cyano-3-isopropyl-3-(4-methyl-1,2,3-thiadiazol-5-yl)methylaminoacrylate 9h and 9g showed 100% herbicidal activities against rape and amaranth pigweed at a dose of 1.5 kg/ha. 2-Cyanoacrylates containing the thiadiazole ring are a new variation of this class of compound which still retain herbicidal activities.


Introduction
Herbicidal activity of cyanoacrylates has been the subject of intense interest for the past decades.5][6] Bayer AG reported compound C (Figure 1), but little information was given on its herbicidal activity. 7It has been reported that the D1 protein of PS II is the herbicide binding site, and the benzyl group of cyanoacrylate fits into the hydrophobic domain of the site maximizing van  domain. 4,8,9However, the complete nature and topography of this hydrophobic domain of the D1 protein are unknown, and cyanoacrylates have not been commercialized as herbicides because of their high dose rates.
In previous work on synthesis of 2-cyanoacrylates, Wang et al. reported that some compounds D (Figure 1) whose phenyl were replaced by heterocycles (pyridine or thiazole) showed higher herbicidal activity than parent compounds B and C. 10,11,12 Recently, Song et al. first reported that cyanoacrylates derivatives E and F (Figure 1) also exhibited moderate to excellent antiviral activity against tobacco mosaic virus (TMV). 13,14According to the bioisosterism principles, compounds D, E, and F are all analogues of structures A, B and C, which encouraged us to introduce novel 1,2,3-thiadiazole ring into 2-cyanoacrylates and further study the relationship of structure-herbicidal activity.Herein, we are reporting the synthesis of novel 2-cyanoacrylates containing the 1,2,3-thiadiazole moiety and the evaluation of their herbicidal activities.
Intermediates 2-cyano-3,3-dimethylthioacrylates 8a, 8b were achieved by treating corresponding esters 7 with carbon disulfide and 2 mole of dimethyl sulfate in a one pot reaction using potassium hydroxide as alkali in good yield according to the reported methods (Scheme 2). 11Intermediate (Z + E)-2-cyano-3-methoxyacrylates 8c-h were synthesized by treating esters 7 with the corresponding acid chloride followed by methylation with diazomethane in good yield according to the reported methods (Scheme 3). 11The target compounds 9a-h were synthesized by the nucleophilic addition and elimination reaction of aminomethyl compound 6 and 8a-h (Scheme 4).
To further strengthen interaction of these cyanoacrylates with the lipophilic binding domain of the PSⅡreaction center and explore influence of aromatic ring and their substitutions on the activity, we introduced a low polarity 1,2,3-thiadiazole group to the cyanoacrylates.Their herbicidal activities were evaluated as shown in Table 2. From biological assay results in Table ISSN 1551-7012 Page 335  ARKAT USA, Inc.
2, most of the compounds synthesized showed good herbicidal activities.They showed greater herbicidal activities in postemergence treatment than in preemergence treatment.So, we herein analyzed the structure-activity relationship mainly according to the data of biological assay in the postemergence treatment.
In postemergence treatment, most of the compounds showed greater herbicidal activities against dicotyledonous weeds (amaranth pigweed and rape) than monocotyledon weeds (alfalfa and hairy crabgrass).Compounds 9g and 9h, which each bear an isopropyl group at 3-position (the largest group tested), showed the highest activities.In particular, compound 9g showed excellent herbicidal activities against dicotyledonous weeds (amaranth pigweed and rape) and monocotyledonous weeds (alfalfa and hairy crabgrass) both in postemergence treatment and in preemergence treatment as compared with other compounds.

Experimental Section
Synthetic Procedures.Melting points of the products were determined on an X-4 binocular microscope (Beijing Tech.Instrument Co., Beijing, China) and were not corrected.Proton NMR spectra were obtained at 300 MHz using a Bruker AC-P 300 spectrometer and 400 MHz using a Varian Mercury Plus 400 MHz spectrometer.Chemical shift values (δ) are given in ppm and were downfield from internal tetramethylsilane. 13C NMR spectra were recorded using a Bruker AC-P 400 spectrometer (100 MHz) using CDCl3 or DMSO as a solvent.Chemical shift values (δ) are reported in parts per million from the solvent peak (77.0 ppm).X-ray single-crystal diffraction was recorded using Bruker SMART-1000 spectrometer.Elemental analyses were performed on a Yanaco CHN Corder MT-3 elemental analyzer in the State Key Laboratory of Elemento-Organic Chemistry, Nankai University, Tianjin, People's Republic of China.The products were purified by column chromatography over silica gel of 100-200 mesh.All solvents and liquid reagents were dried in advance and distilled before use.Potassium phthalimide (5)  was prepared according to the published procedure. 18SSN 1551-7012 Page 336  ARKAT USA, Inc.

General synthetic procedure for target compounds 9a-h
The mixture of 8a-h (5 mmol), (4-methyl-1,2,3-thiadiazol-5-yl)methylamine 6 (6 mmol) and anhydrous ethanol (30 mL) was heated at reflux for 3 h and then evaporated in vacuo to give crude products 9a-h.The products were purified by column chromatography over silica gel, elution with the different concentrations of co-solvents ethyl acetate-petroleum ether.

Herbicidal activity bioassay
The herbicidal activities of compounds 9a-h were evaluated using a previously reported procedure. 7,19lant material.Two dicotyledonous weeds, amaranth pigweed (Amaranthus retroflexus) and rape (Brassica napus L.), and two monocotyledonous weed, alfalfa (Medicago sativa L.) and hairy crabgrass (Digitaria sanguinalis(L.)scop.), were used to test herbicidal activities of the compounds.The seeds of amaranth pigweed were produced out doors and storded at room temperature.Seeds of alfalfa and rape and hairy crabgrass were bought from the Institute of Crop, Tianjin Agriculture Science Academy.Culture method.The seeds were planted in 6 cm diameter paper boxes containing artificial mixed soil.Before plant emerged, the boxes were covered with plastic film to retain moisture.Plants were grown in green house.Fresh weight of the above ground tissues was measured 10 days after treatment.Inhibition percentage was used to describe control efficiency of the compounds.
Treatment.Dosage (activity ingredient) for each compound corresponded to 1.5 kg/ha.Purified compounds were dissoved in 100 µL of N, N-dimethylformamide with addition of a little Tween 20 and then were sprayed using a laboratory belt sprayer delivering a 750 L/ha spray volume.
Compounds were sprayed immediately after seed planting (preemergence treament) or after the expansion of the first true leaf (postemergence treatment).The mixture of same amount of water, N, N-dimethylformamide, and Tween 20 was sprayed as the control.Each treatment was triplicated.The activity numbers represented the percent displaying herbicidal damage as compared to the control.The error of the experiments was 2%.

Figure 2 .
Figure 2. Molecular structure of 9c in the crystal.

Table 2 .
Herbicidal activities of products 9a-h and contrast compound 10 (1.5 kg/ha) a