Nitromethylene heterocycle

Kleier D, I Holden, JE Casida, LO Ruzo (1985) Novel photoreactions of an insecticidal nitromethylene heterocycle. J Agric Food Chem 33 998-1000. 

Zwart R, Oortgiesen M, and Vijverberg HPM (1992) The nitromethylene heterocycle l-(pyridin-3-yl-methyl)-2-nitromethylene-imidazolidine distinguishes mammalian from insect nicotinic receptor subtypes. European Journal of Pharmacology 228 165-169. 

Kollmeyer WD, Flattum RE, Foster JP, et al. (1999) Discovery of the nitromethylene heterocycle insecticides. In Yamamoto I and Casida JE (eds.) Nicotinoid Insecticides and the Nicotinic Acetylcholine Receptor, ch. 3, pp. 71-89. Berlin Springer. 

My thanks go to Drs. P. E. Dunn and J. V. Osmun for critically reading this manuscript, and to Dr. M. E. Schroeder for providing unpublished information regarding the discovery of the nitromethylene heterocyclic insecticides. Journal Paper No. 10994, Agricultural Experiment Station, Purdue University, W. Lafayette, IN 47907. 

Nagata, K., Song, J.H. and Narahashi, T. (1998). Modnlation of the neuronal nicotinic acetylcholine receptor-channel by the nitromethylene heterocycle imidacloprid. J. Pharmacol. Exp. Ther. 285,731-738. 

Shell s pioneering work [6-8] in the 1970s on insectiddal nitromethylene heterocycles led to the invention of the nitroenamine and nitroguanidine pharmacophores and cumulated in the discovery of nithiazine (6), a compound that has never been commercialized as a crop protection agent but has been for animal health use. This was mainly due to rapid degradation under both hydrolytic and photochemical conditions [7] as well as its limited potency as an insecticide in crop protection. 

Corey, C.A. Horne, Nitromethylene heterocycles as insecticides. Pestic. Venom Neurotoxic. 15th [Sel. Pap. 

These consecutive structural transformations towards newer generation compounds could be called "lead evolution" (5). Examples of the simplified lead evolution "tree" for azole fungicides starting from clotrimazole (I) (5,9), nitromethylene heterocycles leading to imidacloprid (II) and analogs (5,70, Iwataki, 1., Nippon Soda Co., personal communication, 1992), and synthetic pyrethroids (4J1) are shown in Figs. 1-3, respectively. The prototype structure has been transformed enormously with improvements in the activity profile through the lead evolution processes in these examples. 

The 1,3-dipolar addition to terminal alkenes of nitrile oxides, generated from nitromethylene derivatives of bicycloheptane, provides 9,ll-ethano-13,15-isoxazolinoprostanoids, PGH analogs, with alkyl, phenyl, or additional heterocyclic fragment in the oo-chain (461). Chemical transformations of 9,11-ethano-13,15-isoxazolinoprostanoids furnish prostanoids with bifunctional fragments of P-hydroxyketone and a-aminoalcohol in the oo-chain. The reaction of P-hydroxy ketones with methanesulfonyl chloride gives rise to prostanoids with an enone component in the oo-chain. 9,ll-Ethano-16-thiaprostanoids have been prepared, for the first time, by nucleophilic addition of thiols to the polarized double bond in the oo-chain. The 1,3-dipolar addition to terminal alkenes of nitrile oxides, generated from nitromethylene derivatives of bicycloheptane provides 9,ll-ethano-13,15-isoxazolinoprostanoids with an alkyl, phenyl, or additional heterocyclic fragment in the oo-chain (462). 

Tricationic and dicationic intermediates were suggested to be involved in the intramolecular cyclization of 2-nitromethylene-l-phenylalkyl-substituted /V-heterocycles with the participation of superelectorophilic hydroxynitrilium cation 99 to give tricyclic products in triflic acid327 (Scheme 5.37). Likewise, the intramolecular trapping of the intermediate hydroxynitrilium cation affords the six- to nine-membered ring oximinoorthodithiolactones328 [Eq. (5.127)]. 

Nithiazine (Figure 2) was the first neonicotinoid developed by Shell (Modesto, USA) in the 1970s. Nithiazine is a 2-nitromethylene tetrahydro-1, 3-thiazine selected from a series of nitroalkyl heterocyclic compounds, the molecular models being distinct from nicotine but acting on the nicotinic... 

The lead compound, which initiated interest in the neonicotinoids, is a nitro-methylene heterocycle, nithiazine (Figure 1) [1]. Nifhiazine, with its unique nitromethylene moiety, showed low mammalian toxicity, but its insecticidal potency and field stability were inferior to commercial organophosphates and pyrethroids. Thus, nithiazine was not of commercial use for pest control. However, the introduction of 6-choloronicotinyl and 2-nitroimino-imidazolidine moieties led to the development of the first commercial neonicotinoid imidacloprid (Figure 1)... 

Whereas S. B. Soloway had originally assumed that the for insecticidal activity critical nitromethylene unit would have to be attached to a heterocycle, scientists at Takeda Chemicals were able to show that acyclic compoimds possessed good insecticidal properties as well. They developed a product to control two important pests in rice, both are cicada species the brown planthopper (Nilaparvata lugens) and the green rice leafhopper Nephotettix cincticeps) (Fig. 8.45). 

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