Prodrug-Oriented Molecular Design of Neonicotinoids: Preparation of Imidacloprid-Related 5,5-Dimethoxy-1,3-diazacyclohexane Derivatives and Their Insecticidal Activity

Abstract

Prodrug-oriented molecular design was attempted for the potent acyclic neonicotinoid insecticide, clothianidin (1-(2-chloro-5-thiazolylmethyl)-3-methyl-2-nitroguanidine). Molecules bearing a CH 2 COCH 2 bridge linking the 1,3-NH ends of clothianidin or their acetals would possibly be hydrolyzed, regenerating the mother compounds. This strategy was used to prepare seven acetals of clothianidin-based molecules that combined 2-chloro-5-thiazolylmethyl, 6-chloro-3-pyridylmethyl or 3-tetrahydrofurfuryl with a nitroimine, cyanoimine or nitromethylene group. The key intermediate, 1,3-diamino-2,2-dimethoxypropane, was prepared from the dihydroxyacetone dimer in four steps. A selected acetal showed a characteristic nerve-impulse pattern for neonicotinoids on an excised American cockroach ganglion, although the neuroblocking activity was fairly low. Some acetals were highly insecticidal against the pea aphid at 0.8-20 ppm 7 days after a spray treatment, this being in a contrast to their far weaker activity by injection into American cockroaches. The biological results suggest that the intrinsic insecticidal activities of the acetals are weak, but would exhibit enhanced activity if hydrolyzed in an external environment.

Proneonicotinoid

“…7. 40) Although we have so far failed to isolate the ketones (17), 41) some of the ketals were observed to be highly insecticidal against green peach aphids seven days (8) and diacyl derivatives (13) of dinotefuran (14).…”

“…40) Considering the far lower activity of mono-or dialkyl and monoalkoxy substituted compounds of a similar steric or hydrophilic increment at the fifth position in place of the ketal, 37,42) the exhibited insecticidal phenomenon with seven-day exposure is presumably exerted by the ketone, the hydrolytic product of the ketal, or the subsequent decomposition product(s).…”

1,6-Bis[1-(2-chloro-5-thiazolylmethyl)-2-nitroiminoimidazolidin-3-yl]hexane and 1,3,5-tris[1-(6-chloronicotinyl)-2-nitroiminoimidazolidin-3-ylmethyl]benzene-Synthesis and insecticidal and neuroblocking activities in American cockroaches, Periplaneta americana

“…4,[14][15][16][17] Various volumes (1-10 ml) of each compound dissolved in dimethyl sulfoxide (DMSO) containing some amount of methanol were injected into the abdomen. Organic solvents alone in this range did not have any toxic effect.…”

“…4,16,17) In brief, a nerve preparation containing the abdominal fifth and sixth ganglia of a male adult American cockroach was excised and placed in a saline solution. One of two bundles of the nerve cord was taken up from the thoracic side with saline into a glass tube, in which a silver wire was set as an electrode.…”

“…Measurements were con- ducted at 22-25°C. The neuroblocking concentration of compound 5 (BC in M) to suppress the frequency below 10 counts/30 sec as defined previously 4,16,17) is listed in Table 1.…”