Design, Synthesis, and Bioactivity of Trifluoroethylthio-Substituted Phenylpyrazole Derivatives.

As the first marketed phenylpyrazole insecticide, fipronil exhibited remarkable broad-spectrum insecticidal activity. However, it poses a significant threat to aquatic organisms and bees due to its high toxicity. Herein, 35 phenylpyrazole derivatives containing a trifluoroethylthio group on the 4 position of the pyrazole ring were designed and synthesized. The predicted physicochemical properties of all of the compounds were within a reasonable range. The biological assay results revealed that compound 7 showed 69.7% lethality against Aedes albopictus (A. albopictus) at the concentration of 0.125 mg/L. Compounds 7, 7g, 8d, and 10j showed superior insecticidal activity for the control of Plutella xylostella (P. xylostella). Notably, compound 7 showed similar insecticidal activity against Aphis craccivora (A. craccivora) compared with fipronil. Potential surface calculation and molecular docking suggested that different lipophilicity and binding models to the Musca domestica (M. domestica) gamma-aminobutyric acid receptors may be responsible for the decreased activity of the tested derivatives. Toxicity tests indicated that compound 8d (LC50 = 14.28 mg/L) induced obviously 14-fold lower toxicity than fipronil (LC50 = 1.05 mg/L) on embryonic-juvenile zebrafish development.

Design, Synthesis, and Biological Activities of Novel Phenylpyrazole Derivatives Containing a Trifluoromethylselenyl Moiety.

Phenylpyrazole insecticides are widely used for crop protection and public sanitation by blocking gamma-aminobutyric acid (GABA)-gated chloride channels and glutamate-gated chloride (GluCl) channels. Herein, 36 novel phenylpyrazole derivatives containing a trifluoromethylselenyl moiety were designed and synthesized based on the strategy of introducing a selenium element. All derivative structures were characterized by nuclear magnetic resonance (NMR) and high-resolution mass spectrometry (HRMS). The insecticidal activity results indicated that some derivatives had good insecticidal activities against Aedes albopictus (A. albopictus) and Plutella xylostella (P. xylostella). The larvicidal activity against mosquitos of compounds 5, 5a, 5k, and 5l at 0.5 mg/L was 60-80%. At a concentration of 500 mg/L, compounds 5, 5a, 5h, 5k, 5l, 5r, 6, 6j, 6k, and 7 showed a 70-100% mortality against P. xylostella. Among them, derivatives 5 and 6 had a better insecticidal effect with mortality rates of 87 and 93% at 50 mg/L, respectively. It was summarized that the different binding poses of fipronil and compounds 5 and 6 in the Musca domestica (M. domestica) GABARs might lead to the disparity in bioactivity from docking studies. Toxicity tests on zebrafish suggested that compound 6 may be slightly less toxic to the embryos than fipronil on hatching rate.

N-Difluoromethylthiophthalimide Reagents for Modular Synthesis of Diversified α-Difluoromethylthiolated Ketones.

The compounds featuring α-difluorothiomethylated ketone skeleton derivatives are of particular interest in pharmaceuticals and agrochemicals. Herein, we designed novel electrophilic N-difluoromethylthiophthalimide reagents that can be easily prepared with commercially available and economical chemicals. These reagents could smoothly react with various nucleophiles, such as Grignard reagents, boronic acids, ß-keto esters, and anilines, which affords structurally diverse α-difluoromethylthiolated ketones in good to excellent yields. The formal synthesis of active antifungal compounds positively confirmed the practicability of these reagents.

Copper(II)-Catalyzed Direct C-H Trifluoroethylation of Heteroarenes.

Trifluoroethyl (CH2CF3) is an important functional group in many pharmaceutical and agrochemical compounds. Herein, we report an efficient method for the copper-catalyzed direct trifluoroethylation of heteroarenes. The reaction exhibited good compatibility to various substrates, and the desired products were obtained in good yields. Preliminary mechanistic investigations indicate the trifluoroethyl radical is involved in the catalytic circle. Moreover, the late-stage modification of bioactive molecules further confirmed the practical applications of this method.

CF2DSO2Na: An Effective Precursor Reagent for Deuteriodifluoromethylthiolation and Deuteriodifluoromethylation.

Deuteriodifluoromethythio (SCF2D) and deuteriodifluoromethyl (CF2D) are important functional groups in pharmaceutical and agrochemical compounds, and the introduction of these functional groups remains a challenging. We herein report a robust reagent for deuteriodifluoromethylthiolation and deuteriodifluoromethylation. Its potentials were successfully showcased by deuteriodifluoromethylation and deuteriodifluoromethylthiolation of indoles with high-level deuterium incorporation. The reagent also has potential for deuteriodifluoromethylation and deuteriodifluoromethylthiolation of wide range of other natural or synthetic bioactive molecules.