4-Nitroimino-1,3,5-oxadiazinanes: A New Type of Neonicotinoid Insecticides

Chemistry and biology of thiamethoxam: a second generation neonicotinoid

“…As part of this programme we investigated novel variations of the nitroimino‐heterocycle of imidacloprid, which resulted in the synthesis of compounds 8 , 9 and 10 (Fig 3). 11, 12 Bioassays revealed that, among these compounds, the 4‐nitroimino‐1,3,5‐oxadiazinane 9 clearly exhibited better insecticidal activity than the 2‐nitroimino‐hexahydro‐1,3,5‐triazine 8 and the 4‐nitroimino‐1,3,5‐thiadiazinane 10 . Chemical and biological exploration of the lead structure 9 showed that replacement of the 6‐chloro‐3‐pyridyl group by a 2‐chloro‐5‐thiazolyl moiety resulted in a strong increase of the activity against chewing insects, whereas the introduction of a methyl group as pharmacophore substituent increased the activity against sucking pests (Fig 4).…”

The discovery of thiamethoxam: a second-generation neonicotinoid

“…We first concentrated our efforts towards the synthesis of the 2‐nitroimino‐hexahydro‐1,3,5‐triazine 12 . After some experimentation, we found a two‐step procedure which proved to be widely applicable and which produced 2‐nitroimino‐hexahydro‐1,3,5‐triazines in excellent yields starting from S ‐methyl‐ N ‐nitrothiourea ( 10 ) 25. 26 Thus, treatment of 10 with 6‐chloropyridin‐3‐ylmethylamine at 80 °C in ethanol for 3 h afforded the monosubstituted nitroguanidine 11a , which could then be converted in a Mannich type cyclisation reaction with 1 equivalent of methylamine and 2 equivalents of formaldehyde to the nitroimino‐hexahydro‐1,3,5‐triazine 12 (Fig 3).…”

“…In response to the promising biological results obtained, we started a broad optimisation programme on the lead compound 12 which resulted in the preparation of a series of 4‐nitroimino‐hexahydro‐1,3,5‐triazines A . In October 1990 we filed a patent application for these compounds 25. We did not know at that time, but must have feared due to the considerable competition in this field, that our competitors had already been pursuing the same idea and had themselves submitted patent applications for nitroimino‐hexahydro‐1,3,5‐triazines 27–29…”

“…Our first success towards the synthesis of 4‐nitroimino‐1,3,5‐oxadiazinanes was based on serendipity. Previously, we had converted monosubstituted nitroguanidines 11 or 15 to the corresponding 2‐nitroimino‐hexahydro‐1,3,5‐triazines A (Y = N–NO 2 ) in high yields with formaldehyde or paraformaldehyde and more than 40 different amines 25. In none of these reactions was the formation of a 4‐nitroimino‐1,3,5‐oxadiazinane as a side‐product observed.…”

“…In the course of our optimisation program on the oxadiazinane lead structure 13a we developed a broadly applicable method for the preparation of the novel 3‐heterocyclylmethyl‐5‐alkyl‐4‐nitroimino‐1,3,5‐oxadiazinanes 21 which allowed the introduction of the heterocyclylmethyl or arylmethyl group either from a heterocyclylmethyl or arylmethylamine 22 or a heterocyclylmethyl or arylmethyl chloride 23 (Fig 5; Table 1). 35 Thus, treatment of S ‐methyl‐ N ‐nitroisothiourea ( 10 ) with amines 22 afforded N ‐monosubstituted‐ N ′‐nitroguanidines 11 , which could be converted to 3‐monosubtituted‐4‐nitroimino‐1,3,5‐oxadiazinane 13 using a 1:1 mixture of formaldehyde and formic acid. Alkylation with an alkyl halide gave the 4‐nitroimino‐1,3,5‐oxadiazinane 21 in good yields.…”