Chapter 15
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Insecticidal Pyrroles D. G. Kuhn, R. W. Addor, R. E. Diehl, J. A. Furch, V. M . Kamhi, K. E. Henegar, K. A. Kremer, G. T. Lowen, B. C. Black, T. P. Miller, and M . F. Treacy Agricultural Research Division, American Cyanamid Company, P.O. Box 400, Princeton, NJ 08543-0400
The development of a new series of insecticidal pyrroles, based on the natural product dioxapyrrolomycin, is described. In particular, new chemistry leading to halogenated and trifluoromethyl -containing pyrroles is presented. This new class of insect control agents has been shown to be active on a broad spectrum of insect pests. It is proposed that the mode of action for this series is the uncoupling of oxidative phosphorylation. One member of this series, AC 303,630 [4-bromo-2-(4-chlorophenyl)-1-(ethoxymethyl)-5-(trifluoromethyl)pyrrole-3-carbonitrile] is currently undergoing development as a broad spectrum insecticide/miticide.
The discovery of new strategies, whether chemical or biological, for the control of insect pests remains one of the premier challenges facing scientists today. A variety of approaches to lead generation and optimization of biological activity has been developed. In particular, the world of natural products has been the starting point for many compounds with insecticidal activity. This chapter details our effort to develop a new, effective insect control agent based on a naturally occurring compound. The genesis of this work was our screening group's discovery of the insecticidal activity of a fermentation brothfroma Streptomyces strain. The active component was isolated and identified by our scientists at our Lederle Laboratories and was shown to have the structure in Figure 1. It has been named dioxapyrrolomycin (7). At about the same time, the identical pyrrole was reported by Meiji Seika and SS Pharmaceutical Company in Japan to have activity against Gram-positive and some Gram-negative bacteria (2, 3). Neither group reported insecticidal activity. While dioxapyrrolomycin had moderate, broad spectrum insecticidal activity as shown in Figure 1, the compound was found to be highly toxic to mice (oral L D of about 14 mg/kg). This combination preculed the natural product as a candidate for development. However, the simplicity of the structure suggested this compound as a starting point for synthetic modification (4,5). 5 0
0097-6156/93/0524-0219S06.00/0 © 1993 American Chemical Society In Pest Control with Enhanced Environmental Safety; Duke, S., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1993.
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PEST CONTROL WITH ENHANCED ENVIRONMENTAL SAFETY
Synthesis
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We chose the left portion of the dioxapyrrolomycin molecule, i.e., the dihalonitropyrrole, as our starting point, thereby eliminating the methylenedioxy subunit At the outset of this work, we found the need to develop synthetic methodology suitable to highly functionalized pyrroles. 2- Aryl-3-cyano/nitro-4,5-dihalo Pyrroles, Our initial efforts required an efficient synthesis of the dihalo pyrrole nucleus that allowed for variation of substituents on the aryl ring and also the ability to change the electron withdrawing group at the 3-position. The synthesis that was developed is shown in Figure 2. Condensation of the ketones (1) with aminoacetaldehyde diethylacetal gave the enamines (2) as a mixture of isomers. Treatment with trifluoroacetic acid gave the 2-aryl-3cyano/nitro pyrroles (3) in good yield. Halogenation using bromine or sulfuryl chloride gave the desired 4,5-dibromo or 4,5-dichloropyrroles (4). 2-Aryl-5-trifluromethyl Pyrrole Derivatives. Synthesis efforts have been directed toward replacing the halogen substituents at the 4 and/or 5 positions of the molecule. A particularly intriguing candidate is the trifluoromethyl (CF ) group. This group, considered a "pseudo-halogen", often imparts interesting biological activity when introduced into molecules (6). However, methods for the direct introduction of the CF group onto deactivated aromatic systems were scarce. Therefore, it was necessary to develop new procedures that would allow for the pyrrole to be formed with the C F group in place. This was accomplished using cycloaddition chemistry (Figure 3). Although 1,3-dipolar cycloadditions have been utilized extensively to prepare heterocycles (7), these methods were not used to prepare pyrroles substituted with a trifluoromethyl group. In this procedure, an oxazolinone (6) derived from a suitably substituted phenylglycine (5), reacts with an olefin bearing an electron-withdrawing group and a leaving group such as a halogen (7) in the presence of a base to give the 2-aryl-5-trifluoromethylpyrrole (8) in good to excellent yield (5). This reaction is rapid, usually requiring less than one hour, and occurs under mild conditions. It has been found that the reaction is regiospecific, and yields only the isomer shown. If R*= H, in the olefin (7) the 4-unsubstituted pyrrole is produced. Treatment of (8) ( R H) with bromine/sodium acetate/acetic acid cleanly introduces bromine into the 4-position to give (9). In a similar manner, using an olefin substituted with a trifluoromethyl group (7) (R = CF ) gives the desired 4,5-Z?w-tafluoromethylpyrrole (8) (R = CF ) analog of the lead 4,5-dihalopyrroles. By using various substituted phenylglycines available via the Strecker synthesis, a series of mono- or to-trifluoromemylsubstituted pyrroles has been prepared. A special case of this chemistry has been used as a key step in the preparation of the 2-aryl-3-nitro-5-trifluoromethylpyrroles (Figure 4). Cyclo addition of the oxazolinone (6) (R= 4-C1) with the pyridinium salt (10) in pyridine gave the 2-aryl-5-trifluoromethyl pyrrole (11) in good yield. In this reaction, the pyridine acts as both an activating group for the olefin and also as the leaving group. Nitration of (11) gave a separable mixture of the 3- and 3,4-dinitropyrroles of which the 3-nitro isomer (12) predominates. Bromination of (12) gives the desired 2-aryl-3-mtro-4-bromo-5-trifluoromethylpyrrole (13). During the course of our work aimed at optimizing the insecticidal activity, we encountered an unexpected drawback. Certain of these compounds were highly phytotoxic. In an attempt to overcome this deficiency and to see if other benefits might accrue, the effect of N-derivatization of these pyrroles was studied (Figure 5). Alkylation of the parent pyrroles (8) produced the N-protected compounds (14). A number of N-derivatized pyrroles were found to retain the high biological activity of the parent with little or no observed phytotoxicity. 3
3
3
1=
l
3
r
3
In Pest Control with Enhanced Environmental Safety; Duke, S., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1993.
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15. KUHN ET AL.
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Insecticidal Pyrroles
Dioxapyrrolomycin Insecticidal Activity LC (ppm) 50
Southern Armyworm Spodoptera ertdania 3rd instar 40
Figure 1.
Tobacco Budworm Helothis virescens 3rd instar 32
2-Spotted Mite Tetranychus urticae P-Resistant 10
Western Potato Leafhopper Empoassa abrypta Mixed
