The discovery of thiamethoxam: a second-generation neonicotinoid�� Peter Maienfisch,* Hanspeter Huerlimann, Alfred Rindlisbacher, Laurenz Gsell, Hansruedi Dettwiler, Joerg Haettenschwiler, Evelyne Sieger and Markus Walti Novartis Crop Protection AG, Research Department, WRO-1060.1.14, CH-4002 Basel, Switzerland Abstract: Neonicotinoids represent a novel and distinct chemical class of insecticides with remarkable chemical and biological properties. In 1985, a research programme was started in this field, in which novel nitroimino heterocycles were designed, prepared and assayed for insecticidal activity. The methodology for the synthesis of 2-nitroimino-hexahydro-1,3,5-triazines, 4-nitroimino-1,3,5-oxadia- zinanes and 4-nitroimino-1,3,5-thiadiazinanes is outlined. Bioassays demonstrated that 3-(6-chloro- pyridin-3-ylmethyl)-4-nitroimino-1,3,5-oxadiazinane exhibited better insecticidal activity than the corresponding 2-nitroimino-hexahydro-1,3,5-triazine and 4-nitroimino-1,3,5-thiadiazinane. In most tests, this compound was equally or only slightly less active than imidacloprid. A series of structural modifications on this lead structure revealed that replacement of the 6-chloro-3-pyridyl group by a 2- chloro-5-thiazolyl moiety resulted in a strong increase of activity against chewing insects, whereas the introduction of a methyl group as pharmacophore substituent increased activity against sucking pests. The combination of these two favourable modifications led to thiamethoxam (CGA 293 343). Thiamethoxam is the first commercially available second-generation neonicotinoid and belongs to the thianicotinyl sub-class. It is marketed under the trademarks Actara1 for foliar and soil treatment and Cruiser1 for seed treatment. The compound has broad-spectrum insecticidal activity and offers excellent control of a wide variety of commercially important pests in many crops. Low use rates, flexible application methods, excellent efficacy and the favourable safety profile make this new insecticide well-suited for modern integrated pest management programmes in many cropping systems. # 2001 Society of Chemical Industry Keywords: insecticides neonicotinoids thiamethoxam discovery synthesis 2-nitroimino-hexahydro-1,3,5-tri- azines 4-nitroimino-1,3,5-oxadiazinanes 4-nitroimino-1,3,5-thiadiazinanes insecticidal activity structure- activity relationships 1 INTRODUCTION Neonicotinoids1 represent a novel and distinct chemi- cal class of insecticides with remarkable chemical and biological properties.2 Researchers at Shell described in 1972 for the first time the insecticidal properties of some simple nitromethylene heterocycles (Fig 1, 1).3,4 Their work resulted in the discovery of nithiazine (2),5 a compound which has never been commercialised as a crop-protection agent. This compound, however, has served as a neonicotinoid lead structure. Thirteen years later, with the synthesis of imidacloprid (3), Nihon Tokushu Nohyaku (now Nihon Bayer) achieved an important breakthrough in this chemistry. By introducing a 6-chloropyridin-3-ylmethyl group as a substituent of the nitromethylene heterocycle, the insecticidal activity against green rice leafhoppers could be enhanced by a factor of more than 100.6 First patent applications covering this new invention were published in 1985,7 and this triggered extensive research activities within several other companies. Ciba (since 1996 Novartis), Takeda, Nippon Soda, Agro Kanesho, Mitsui Chemicals and others immedi- ately entered this promising research area. Shortly after the launch of imidacloprid in 1991, nitenpyram (4)8 (Takeda, 1995) and acetamiprid (5)9 (Nippon Soda, 1996) were brought to the market. Each of these three products has a 6-chloropyrid-3-ylmethyl moiety as a heterocyclic group. This is a common structural feature of first-generation neonicotinoids.10 In 1998, Novartis launched thiamethoxam (6),10���12 a novel neonicotinoid with a unique structure and outstanding insecticidal activity. Three other pro- ducts, thiacloprid (7)13 (Bayer), clothianidin (8)14���16 (Takeda, Bayer) and dinotefuran (9)17 (Mitsui Chemicals), are currently under development and are expected to enter the marketplace in due course. (Received 1 November 2000 accepted 20 November 2000) * Correspondence to: Peter Maienfisch, Novartis Crop Protection AG, Research Department, WRO-1060.1.14, CH-4002, Basel, Switzerland E-mail: peter.maienfisch@cp.novartis.com �� Based on a paper presented at the Symposium ���New Chemistries for Crop Protection��� organised by Dr L Copping and the late Dr J Dingwall on behalf of the Bioactive Sciences and Crop Protection Groups of the SCI and held at 14/15 Belgrave Square, London, UK on 19 June 2000 # 2001 Society of Chemical Industry. Pest Manag Sci 1526���498X/2001/$30.00 165 Pest Management Science Pest Manag Sci 57:165���176 (2001)

Since the market introduction of imidacloprid, the neonicotinoids have been the fastest growing chemical class of insecticide. This tremendous success can be explained by their unique chemical and biological properties, such as broad-spectrum insecticidal activ- ity, low application rates, excellent uptake and trans- location in plants, new mode of action and favourable safety profile. Ciba started a research programme on neonico- tinoids in 1985. Our efforts resulted in the synthesis of acyclic nitroenamines, acyclic cyanoguanidines, acyclic nitroguanidines, 3-heterocyclylmethyl-2-nitro- methylene-pyrrolidines, isoxazoles and novel nitro- imino heterocycles such as 4-nitroimino-1,3,5- oxadiazinanes.10 Among these chemistries, 4-nitro- imino-1,3,5-oxadiazinane derivatives were found to possess the most interesting chemical and biological properties. Thiamethoxam (6) was identified as the best representative of this novel class of compound and selected for world-wide development. Belonging to the sub-class of thianicotinyl compounds,10 it represents the first example of second-generation neonicotinoids. The present communication reports the discovery of this compound, which is marketed under the trade names Actara1 for foliar and soil treatment, and Cruiser1 for seed treatment. 2 MATERIALS AND METHODS 2.1 Chemical synthesis Imidacloprid (3),7 nitenpyram (4),18 acetamiprid (5),19S-methyl-N-nitroisothiourea (10),20 compound 24,21 6-chloropyridin-3-ylmethylamine,18 6-chloro- pyridin-3-ylmethyl chloride,22 2-chlorothiazol-5-yl- methyl chloride23 and 2-chlorothiazol-5-ylmethyl- amine18 were prepared according to literature proce- dures. The synthetic pathways used to prepare the new nitroimino-heterocycles are discussed in detail in Section 3.2 and the syntheses of the 4-nitroimino- 1,3,5-oxadiazinanes in Section 3.3. Representative procedures are given below the yields were not optimised. All spectra were consistent with the assigned structures, and all compounds were 98% purity based on TLC and [1H]NMR spectra. Figure 1. Neonicotinoid lead, commercial and development compounds. 166 Pest Manag Sci 57:165���176 (2001) P Maienfisch et al