Pyrazoline insecticides

Rowberg, K.A., Even, M., Martin, E. and Hopfinger, A.J. (1994). QSAR and Molecular Shape Analyses of Three Series of l-(Phenylcarbamoyl)-2-Pyrazoline Insecticides. J.Agr.Food Chem., 42, 374-380. 

The pioneering work in pyrazoline insecticides by Kobus WeDinga and Rudolph Mulder provided the first leads toward the sodium channel blocking insecticides [1]. Figure 29.4.1 summarizes these early compounds. Pyrazoline PH 60-41 was found to have moderate activity on Lepidoptera, Coleoptera and Diptera. Optimization of PH 60-41 produced 5-phenyl derivatives with improved insecticidal activity across all three insect orders, with PH 1-9 perhaps the most active of the group [2]. 

Purpuric acid lb 174 Pyrazolidine derivatives la 426 3,5-Pyrazolidindione derivatives lb 20 Pyrazolinone derivatives lb 277 Pyrazolin-5-one derivatives lb 327,329 Pyrazone lb 332 Pyrene lb 379 PyrethrinI lb 18 Pyrethrin II lb 18 Pyrethroids lb 86,87 Pyrethroid insecticides la 359 Pyridine alkaloids la 66 lb 279 Pyridine derivatives lb 119,244 Pyridinium carbinols lb 65 Pyridinium glycols lb 65 Pyridoxal la 157,158,253 Pyridoxamine la 253 Pyridoxine la 253... 

Wellinga and associates reported the development of 3-aryl-2-pyrazolines acting as powerful stomach insecticides. From the point of view of biological activity and economic aspects 3-(4-chlorophenyl)-1 -(4-chlorophenylcarbamoyl)-2-pyrazoline (PH 60-41,8) appeared to be the most promising (Mulder et al., 1975 Wellinga et al, 1977). 

Introduction of a further phenyl ring at position 5 of the pyrazoline ring yielded products with comparable or enhanced insecticidal effect. 3,5-Bis(4-chlorophenyl)-... 

Fig. 29.4.1. Pyrazolines were the first insecticides in the field of sodium channel blockers.

Structure-activity relationships for oxadiazines were found to be consistent with pyrazolines, indazoles and pyridazines. The wealth of data for pyrazoline-type insecticides allowed for the rapid preparation and identification of highly active analogs. Selection of candidate DPX-JW062 was based on a combination of observed high insecticidal efficacy, safety to non-target organisms, including predatory insects as well as fish, birds and mammals, and rapid dissipation in the environment [20]. 

The diazo reaction with olefins as shown previously is still the fastest method to get hold of mixtures of diastereomers, often, however, with moderate yields due to the lack of reactivity of the olefins. Several nor-chrysanthemic esters [479], alkoxycyclopro-pane carboxylic esters [480,481], which are interesting because of their photostabihty and insecticidal activity [482], and 2,2,3,3-tetramethylcarboxyhc ester [483] were prepared by this route. Asymmetric synthesis using optically active iron carbonyl-olefin complexes afforded 1-R-configurated esters, i.e. precursors for caronaldehyde [484]. The addition of diazopropane across the double bond of olefinic esters via pyrazolines [485, 486] also provides a rapid access to sometimes more complex cyclopropane carboxylic esters with questionable purity, from which the pure compounds can be separated. 

Halogen exchange has been the most widely used process for fluorine incorporation at C-3 and C-5 of the pyrazole ring. For instance, bromine-fluorine exchange in the 3-bromopyrazoline 3 was described as an alternative approach for the preparation of the 3-fluoropyrazole derivative 5, a precursor of insecticidal fluorinated anthranilic diamides [2]. Silver fluoride was used as both fluorine source and oxidation reagent of the pyrazoline ring (Scheme 2). 

Not only oxone bnt also other oxidants can be used in the preparation of hydroxy carbonyl derivatives. So, terf-butyl hydroperoxide has been used in the enantioselective oxidation of 2-alkoxycarbonyl indanone derivatives of type 33 catalyzed by cinchonine 35 to give the expected compound with moderated enantiomeric excess (50%). This chiral compound serves as the starting material for the synthesis of pyrazoline-type insecticide indoxacarb [102]. The use of chiral dihydroquinine (double bond hydrogenated compound 11) in combination with cumyl hydroperoxide at room temperature seems to be a more promising protocol, since the expected hydroxy carbonyl compounds could be obtained with excellent chemical yields and good enantiomeric excess [103]. 

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