Synthesis and Chemistry of Agrochemicals IV - ACS Publications

Chapter 26

1-Arylpyrazoline-3-carboxanilides Novel and Selective Insecticides Thomas M. Stevenson, Gary D. Annis, Charles R. Harrison, and Caleb W. Holyoke

Downloaded by AUBURN UNIV on January 27, 2016 | http://pubs.acs.org Publication Date: May 5, 1995 | doi: 10.1021/bk-1995-0584.ch026

DuPont Agricultural Products, Stine-Haskell Research Center, Chemical Discovery, Levitt Laboratories, Newark, DE 19714

Nitrile-imine cycloaddition chemistry was utilized to synthesize a new class of pyrazoline insecticides. The structure activity relationships of the pyrazoline insecticides were explored by using a wide variety of dipolarophiles to give 5-substituted and 5,5disubstituted products. In addition we have used dianion chemistry to produce a number of compounds which have 4-substitution opposite of the regiochemistry derived from cycloaddition. As described in the previous chapter, 3,4-diarylpyrazoline-l-carboxanilides have been a highly investigated area in insecticide chemistry. In 1986, Jacobson at Rohm & Haas described a new series of pyrazolines, exemplified by RH3421, (Figure 1) which lacked the 4-phenyl ring (1). Jacobson made these compounds by dianion chemistry and quenching with a variety of electrophiles (Figure 2). They reported that the optimal replacement for the phenyl group was 4,4disubstitution with a methyl group and a carbomethoxy group (2). These compounds were highly active on lepidopteran species with greatly improved activity on coleopteran pests. These compounds also had good to excellent activity on the important rice pests, plant hoppers.

C0 Me 2

N

RH3421

PH6042

Figure 1. l-Aryl-5-substitutedpyrazoline-1-carboxanilide insecticides. 0097-6156/95/0584-0291$12.00/0 © 1995 American Chemical Society

In Synthesis and Chemistry of Agrochemicals IV; Baker, Don R., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1995.

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Figure 2. Jacobson's synthesis of pyrazoline-1-carboxanilides. Synthesis With the synthesis of 1,5-diarylpyrazoline-3-carboxanilides we had shown that the attachment of the carboxanilide group did not need to be on nitrogen in order to see insecticidal activity (3). In order to make compounds related to RH3421 we needed to use methyl methacrylate, a readily available polymer intermediate, as a dipolarophile in cycloadditions with nitrile-imines. (Figure 3).

Cl

Figure 3. Retrosynthesis of l-arylpyrazoline-3-carboxanilides via nitrile-imines. Nitrile-Imine Cycloadditions. To synthesize the l-aryl-3-carboxanilide analagous to the Rohm and Haas development candidate RH3421 diketene was allowed to react with 4-trifluoromethylaniline. The acetoacetanilide was chlorinated with sulfuryl chloride and then subjected to the Japp-Klingemann reaction with 4-chlorophenyl-diazonium chloride (3). The hydrazonyl chloride and methyl methacrylate were treated with triethylamine in refluxing benzene to give the desired material in good yield (Figure 4). The compound was insecticidally active on tobacco budworm (LD50, lOppm), boll weevil (LD50,12 ppm) and aster leaf hopper (LD50, 40 ppm). The hydrazonyl chlorides proved to be versatile intermediates with which to explore pyrazoline structure-activity. Dipolar cycloaddition chemistry allows the synthesis of a much wider variety of substituents than either dianion or hydrazine cyclization chemistry. Figure 5 shows some selected examples of this work. In general the nitrile-imines are reactive dipoles and most mono and Substituted olefins will undergo cycloaddition. Most reactive are the electron deficient olefins such methyl acrylate. Electronricholefins such as hexene are less reactive, but good yield of product can be realized by using the dipolarophile as In Synthesis and Chemistry of Agrochemicals IV; Baker, Don R., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1995.

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solvent with syringe pump addition of the triethylamine. Both dimethyl fumarate and dimethyl maleate led to the same product with the ester groups trans to each other in agreement with the work of Huisgen on diphenylnitifie-irnines (4). This is due to the high acidity of the 4-position which can be easily equilibrated by the triethylamine.

Figure 4. First synthesis of a 1 -aryl-5-methyl-5-carbomethoxypyrazoline.

Figure 5. Dipolar cycloaddition reactions of the nitrUe-irriine. In Synthesis and Chemistry of Agrochemicals IV; Baker, Don R., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1995.

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Optimization Program. Since the 5-methyl-5-carbomethoxy compounds had high activity, the initial phase of our optimization program involved variation of these substitutents (Figure 6). We used commercially available methyl 2-chloroacetoacetate as the precursor to the hydrazonyl chloride. The reaction with methyl methacrylate proceeds in excellent yield. Conversion to the anilide was more facile than expected. The 3-carbomethoxy group is much more reactive towards nucleophiles than the one at the 5-position. Reaction with aluminum amides only occurred at the 3-position. It is also possible to selectively hydrolyze the ester at the 3-position using 1.5 eq. of potassium or sodium hydroxide in methanol. This allowed the synthesis of the anilides through the acid chloride. o o

Rl= Alkyl, Aryl, H R2= Ester, Aldehyde, Nitrile, Alkyl, Phosphonate, Alkene, Benzyl, Benzoyl, Alkyl Ketone, Etc Figure 6. Synthetic scheme for the optimization program. Instability of Pyrazoline-5-Carboxylic Acids. In trying to find a common intermediate to make a variety of esters at the 5-position, we were unable to produce the free carboxylic acid at the 5-position. Attempts to prepare the free acid resulted in spontaneous decarboxylation (Figure 7 ) . For example, saponification of the ester group produced die sodium carboxylate which evolved C O 2 on neutralization. Oxidation of the aldehyde produced the same result as did acid catalyzed deprotection of a t-butylester. Finally, we were able to solve the problem by preparing the substituted methacrylates and carrying them individually through the sequence.



26. STEVENSON ET AL.

l-Arylpyrazjoline-3-carboxanilide Insecticides

Figure 7. Chemical instability of pyrazoline-5-carboxylic acids. Dianion Chemistry, We also wanted to see if we could complement the cycloaddition route to the pyrazolines by trying dianion chemistry on pyrazoline carboxanilides. Since the cycloaddition route led to 5-substituted products with mono substituted olefins and gave low yields with 1, 2-disubstituted olefins, we needed an alternative route to make 4-substituted pyrazolines. We began by metallating a l,5-diphenylpyrazoline-3-carboxanilide with 2.2 equivalents of lithium diisopropylamide and quenching with methyl iodide. The methyl group was incorporated in the 4-position trans to the phenyl group. We also used a variety of other electrophiles to give trans substituted compounds (Figure 8).

Figure 8. Use of dianion chemistry to introduce 4-substituents. Preparation of 4-substituted compounds unsubstituted at the 5-position required the use of ethylene or an ethylene equivalent as dipolarophile followed by the dianion chemistry. Our initial attempts with ethylene either in a pressure tube or by bubbling ethylene through the solution of the hydrazonyl chloride gave very low yields (> 10%). We then turned to a reaction of hydrazonyl chlorides


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with several equivalents of a sulfoxonium ylide (5). This process did produce the desired product, but in similarly low yield (Figure 9).

a

Cl

Figure 9. Attempted synthesis of 4,5-unsubstituted pyrazolines. We were able to solve the problem by using vinyl-trimethylsilane as an ethylene equivalent. When the reaction was performed as usual and the crude product treated with fluoride the desired unsubstituted pyrazoline was produced in around 60 % yield. This intermediate was transformed to the anilide in the usual manner. The metallation sequence worked well and quenching with a variety of electrophiles was straightforward as exemplified in Figure 10. A one-pot procedure for the introduction of 2 substituents at the 4-position was also investigated. Treatment of the anilide with 3.2 equivalents of base followed by one equivalent of electrophile and then a second electrophile gave the 4,4disubstituted products. These adducts made by dianion chemistry were chemically and physically distinct from the isomeric 5,5-disubstituted compounds made from cycloaddition chemistry. This serves as unambiguous evidence in favor of our proposed regiochemistry for nitrile-imine cycloadditions with substituted acrylates. Ring Constrained Pyrazolines. Another class of targets we investigated were pyrazolines containing rings to restrict their conformational mobility. There are several ways to do this (Figure 11). First, we investigated indene and dihydronaphthalene as dipolarophiles which led to tricyclic pyrazolines as products. Essentially these were just 1,5-diphenylpyrazolines in which the phenyl group is restrained as part of a ring to the 4-position. Another type of constrained system was madefroman unsaturated lactone. The overall effect of this is to form a bond between the methyl group and the methoxy carbon of the ester function while retaining the same number of carbons. Even though these compounds contained all the requisite functionality for activity, the anilides from both types of conformationally restricted pyrazolines had substantially reduced activity as insecticides.



STEVENSON ET AL.

l-Arylpyrazoline-3-carboxanitide Insecticides

Figure 10. Synthesis of 4,4-disubstituted pyrazolines via dianion chemistry.

Figure 11. Conformationally restrained pyrazoline-3-carboxanilides.


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Structure Activity Trends

x Figure 12. Generic structure of l-aryl-5-substituted pyrazolines. Many of the pyrazolines studied here (Figure 12) were highly active insecticides (6). Depending on the substitution pattern the optimal activity was on either coleopteran or lepidopteran pests. The structure activity trends in this area are very similar to those found in the publications of FMC (7) and Rohm and Haas (1,2) for traditional pyrazoline insecticides. For coleopteran pests the 5,5-methylcarbomethoxy pattern was best. It is interesting to note that in spite of the wide latitude for substitution on aryl rings at the 5-position, replacement of the methyl or carbomethoxy group with an ethyl or carboethoxy group greatly reduces activity. Replacing the ester group with other small electron withdrawing groups such as an aldehyde, nitrile, phosphonate, or ketone also caused the activity to drop. The optimal substitution on the carboxanilide (Z-substituent) and 1-phenyl (X-substituent) rings was essentially the same as that reported for the 1,5marylpyrazoline-3-carboxanilides in the preceding chapter (3). Of the many other substitutions we explored at the 5-position, other than the previously discussed aryl groups (3), alkyl groups showed the highest activity. The highest activity was found for 3 and 4-carbon chains. As for traditional pyrazolines (7), branching of the alkyl chain improved activity and branching adjacent to the ring was optimal. While directly substituted aryl rings had high activity inserting an alkyl or acyl spacer between the pyrazoline and die aryl ring reduced activity. Acknowledgments We would like to thank all of the biologists involved with the bioassays for these compounds, especially Dave Leva, Jim Gilmour and Bruce Stanley. Excellent technical support for this project was provided by Carole Beaman, Martin Currie, Kevin Poff, Barry Hart, Ron Mattson, and Kathy Russell. Literature Cited

1. U. S. Patent 4,663,341 (to Rohm and Haas) 2. Jacobson, R. M. in Recent Advances in the Chemistry of Insect Contro Crombie, L., Ed.; The Royal Society of Chemistry: London, 1989; p 206. 3. Stevenson, T. M., Harrison, C. R.; Holyoke, C. W.; Brown, T. L.; Annis, G. D. in Synthesis and Chemistry of AgrochemicalsIV, Baker, D. R.; Basar G. R.; Feynes, J. G., Eds.; ACS Symposium Series; American Chemical Society: Washington DC; 1994; preceding paper in this book. 4. Huisgen, R.; Seidel, M.; Wallbillich, G.; Knupfer, H. Tetrahedron 1962, 17, 3.


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5. Gaudiano, G.; Ponti, P. P.; Umani-Ronchi, A. Gazz. Chim. Ital. 1968, 98, 48. 6. U. S. Patent 5,091,405 (to DuPont) 7. Meier, G.A.; Silverman, R.; Ray, P. S.; Cullen, T. G.; Ali, S. F.; Marek, F. L.; Webster, C. A. in Synthesis and Chemistry of Agrochemicals III, B D. R.; Fenyes, J. G.; Steffens, J. J., Eds.; ACS Symposium Series No. 504; American Chemical Society: Washington DC; 1992; p. 313. September 27, 1994


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