N-Alkyl-N-(5-isothiazolyl)- and N-(Alkylisothiazolin-5-ylidene)- phenylacetamides. Synthesis and Biological Activity

Treatment of 5-amino-4-chloro-3-methylisothiazole (3) with the acid chloride of [p-[(α,α,α-trifluoro-p-tolyl)oxy]phenyl]acetic acid (6) afforded the amide N-(4-chloro-3-methyl-5-isothiazolyl)-2-[p-[(α,α,α-trifluoro-p-tolyl)oxy]phenyl]acetamide (1), which was substituted with various alkyl groups in an effort to alleviate toxicity toward non-target organisms through a proinsecticide approach. Alkylations of 1 under a variety of reaction conditions afforded two major products which were derived from amide-nitrogen substitution, N-alkyl-N-(4-chloro-3-methyl-5-isothiazolyl)-2-[p-[(α,α,α-trifluoro-p-tolyl)oxy]phenyl]acetamides (7), and ring-nitrogen substitution, N-(2-alkyl-4-chloro-3-methyl-3-isothiazolin-5-ylidene)-2-[p-[(α,α,α-trifluoro-p-tolyl)oxy]phenyl]acetamides (8). Derivatives 7 and 8 were found to exhibit lessened toxicity to trout as well as insects, but, in general, efficacy toward insects was retained to a greater degree. In particular methoxymethyl, ethoxymethyl, ethyl, and ethyl-d5 substituents demonstrated the best combination of insect efficacy and safening toward trout. Significantly different in vivo efficacies of the N-methyl and N-CD3 analogs suggest that 7 and 8 are proinsecticides requiring activation by dealkylation. Keywords: Isothiazolylphenylacetamides; isothiazolinylidenephenylacetamides; insect control; proinsecticide; synthesis