Pestic. Sci. 1997, 50, 319È323

Synthesis and Insecticidal Activity of NovelPyridine Methanesulfonates*

Bruce L. Finkelstein,” Melissa A. Martz & Christopher J. Strock

Dupont Agricultural Products, Stine-Haskell Research Center, PO Box 30, Newark, Delaware, 19714, USA

(Received 15 October 1996 ; revised version received 15 January 1997 ; accepted 9 April 1997)

Abstract : A model has been developed which has led to the design and synthesisof novel 6-methanesulfonyloxypyridine-2-carboxamides with insecticidal activity,low mammalian toxicity and safety to aquatic organisms. The amides formedfrom amines with a branching (e.g. isopropyl and sec-butyl) demonstrated thehighest level of activity. Rice nursery box Ðeld test results on laboratory raisedinsects gave insufficient control of the entire Japanese hopper spectrum towarrant further development of these compounds.

Pestic Sci., 50, 319È323, 1997No. of Figures : 1. No. of Tables : 2. No. of Refs : 8

Key words : insecticide, acetylcholinesterase, synthesis, methanesulfonate, pyri-dine methanesulfonates

1 INTRODUCTION

Two classes of acetylcholinesterase inhibitors are usedas insecticides, namely organophosphates and car-bamates. Relatively less well studied are meth-anesulfonates. In 1954 Myers and Kemp showed thatmethanesulfonyl Ñuoride is an inhibitor of acetyl-cholinesterase.1 Since then there have been reports ofmethanesulfonate esters with utility as either nemato-cides or insecticides,2h5 but no compounds of this typehave been successfully commercialized.

At the outset of the present work we targeted as agoal the discovery of a rice insecticide. For a compoundto be commercially acceptable, as a minimum, it needsto control the four major species (Nilaparvata lugens(Staol), Nephotettix cincticeps (Uhl), L aodelphax stri-atella (Fall), Sogatella fucifera (Horv)) of the Japaneserice hopper complex, to have good mammalian safety

and low toxicity to aquatic(LD50 [ 100 mg kg~1)

* Based on a paper presented at the meeting “Advances in theChemistry of Crop ProtectionÏ organised by P. J. Crowley, G.Mitchell, G. Keen, J. Pickett and P. D. Riordan on behalf ofthe SCI Pesticide Group and the RSC Biological and Medici-nal Chemistry Group and held on 9È11 September 1996 atChurchill College Cambridge.” To whom correspondence should be addressed.

organisms. Particularly of interest to us in this regardwas a report of 6-alkylthio-2-pyridyl methanesulfonates(Fig. 1, I) with good activity against Japanese ricepests.6 These compounds were active in addition oninsects resistant to organophosphate and carbamateinsecticides. Unfortunately these compounds also pos-sessed a high level of acute mammalian toxicity. In ourhands 6-isobutylthio-2-pyridyl methanesulfonate (Ia)had a rat oral approximate lethal dose (ALD) of3 mg kg~1.

Kato et al.7 have also reported a strong correlationbetween the insecticidal activity of the compounds Iand the acetylcholinesterase inhibition of the corre-sponding sulfone derivatives (II). This result suggeststhat the active insecticidal form is the sulfone species.In addition Carr et al.8 have disclosed 6-methanesulfonyloxypyridine-2-sulfonamides as insecti-cides (III). From this information we devised a model(IV) to help us design compounds for synthesis fromwhich we hoped to obtain compounds with improvedproperties. This model consists of a nitrogen heterocyclewith a methanesulfonate group on one side of the nitro-gen atom and on the other side a branched lipophilicside chain containing an oxo-substitution. From thismodel we conceived of pyridine-2-carboxamides (V) asinsecticides.

3191997 SCI. Pestic. Sci. 0031-613X/97/$17.50. Printed in Great Britain(

320 Bruce L . Finkelstein, Melissa A. Martz, Christopher J. Strock

Fig. 1. Structures of compounds discussed.

2 MATERIALS AND METHODS

2.1 Synthesis of compounds

All of the methanesulfonates were prepared by reactionof the hydroxypyridine with methanesulfonyl chloridein the presence of triethylamine in dichloromethane.The 6-hydroxypyridine-2-carboxamides were preparedby activation of the corresponding carboxylic acids with1,1@-carbonyldiimidazole. Representative procedures aregiven below.

2.1.1 N-Isopropyl-6-hydroxypyridine-2-carboxamideTo a suspension of 6-hydroxypyridine-2-carboxylic acid(20 g, 0É15 mol ; Lonza) in tetrahydrofuran (1 litre) wasadded 1,1@-carbonyldiimidazole (25É9 g, 0É16 mol). Thismixture was allowed to reÑux for 90 min. After coolingin an ice bath isopropylamine (16 ml, 0É19 mol) wasadded dropwise. The reaction mixture was stirred over-night at room temperature. The solvent was removedwith a rotary evaporator. Dichloromethane and waterwere added. The product was isolated by Ðltration. Itwas dried in a vacuum oven to give 22É5 g of the titlecompound as a white solid.

[1H]NMR (hexadeuterodimethylsulfoxide) d 1É17 (d, 6),4É03 (m, 1), 5É70 (d, 1), 7É23 (br, 1), 7É68 (dd, 1), 8É18 (br,1), 11É05 (br, 1).

2.1.2 N-Isopropyl-6-methanesulfonyloxypyridine-2-carboxamide (4)To a suspension of N-isopropyl-6-hydroxypyridine-2-carboxamide (22É5 g, 0É125 mol) in dichloromethane(625 ml) at 0¡C was added triethylamine (24É4 ml,0É175 mol) followed by dropwise addition of meth-anesulfonyl chloride (13É6 ml, 0É175 mol). The reactionmixture was stirred at room temperature overnight. Itwas washed with water, dried (sodium sulfate), Ðlteredand the solvent was removed with a rotary evaporator.The residue was puriÐed by Ñash chromatography onsilica gel (ethyl acetate] hexane (40] 60 by volume) aseluant) to a†ord 30É25 g of the title compound as awhite solid ; m.p. 87È88¡C.

[1H]NMR (deuterochloroform) : d 1É29 (d, 6) 3É40 (s, 3),7É29 (dd, 1), 7É40 (br, 1), 8É00 (dd, 1), 8É19 (d, 1).

2.1.3 N-Isopropyl-3-chloro-6-methanesulfonyloxy-pyridine-2-carboxamide (25) and N-Isopropyl-5-chloro-6-methylsulfonyloxypyridine-2-carboxamide (26)To a solution of N-isopropyl-6-hydroxypyridine-2-car-boxamide (0É5 g, 2É8 mmol) in chloroform (15 ml) wasadded N-chlorosuccinimide (0É41 g, 3É1 mmol) andbenzoyl peroxide (5 mg). The reaction mixture washeated to reÑux overnight. The solvent was removedwith a rotary evaporator, and the residue was dissolvedin dichloromethane (25 ml). After cooling to 0¡C, tri-ethylamine (0É55 ml, 3É9 mmol) and methanesulfonylchloride (0É32 ml, 3É9 mmol) were added. The reaction

Insecticidal activity of novel pyridine methanesulfonates 321

TABLE 1Insecticidal Activity of 6-Methylsulfonyloxypyridine-2-carboxamides

L D90(mg litre~1)

No. R1 R2 R3 D.u.h.a N.l.b N.c.c

1 CH3 H H [ 1000 n.d.d n.d.2 C2H5 H H 520 n.d. n.d.3 n-C3H7 H H 290 n.d. n.d.4 i-C3H7 H H 4É7 \2É5 215 cyclo-C3H5 H H 360 n.d. n.d.6 s-C4H9 H H \0É5 \2É5 127 (R) s-C4H9 H H \0É5 \2É5 \2É58 (S) s-C4H9 H H 22 \2É5 8.19 t-C4H9 H H 4É5 29 [100

10 i-C4H9 H H [1000 n.d. n.d.11 CH(C2H5)2 H H 2É9 \2É5 7É812 t-C5H11 H H 29 n.d. n.d.13 CH(CH3)CH(CH3)2 H H 170 \2É5 \2É514 CH(CH3)CH2CH2CH3 H H 11 4É8 4815 CH2CH2F H H 210 n.d. n.d.16 CH(CH3)CH2CN H H \0É5 \2É5 7É717 CH(CH3)CH2OH H H [1000 n.d. n.d.18 CH(CH3)CH2OCH3 H H 180 \2É5 1819 CH(CH3)SCH3 H H 100 n.d. n.d.20 C2H5 CH3 H 5É2 \2É5 7É821 i-C3H7 CH3 H 55 n.d. n.d.22 s-C4H9 CH3 H 32 n.d. n.d.23 CH2CH2OCH2CH2 H 68 n.d. n.d.24 i-C3H7 H 3-F 59 4É7 4425 i-C3H7 H 3-Cl 35 n.d. n.d.26 i-C3H7 H 5-Cl 27 n.d. [10027 i-C3H7 H 5-OCH3 670 n.d. n.d.28 i-C3H7 H 3-Br 86 n.d. n.d.29 s-C4H9 H 3-Cl 24 6.0 8.030 CH(CH3)CH2CN H 3-Cl 43 \2É5 7.4

a Diabrotica undecimpunctata howardi.b Nilaparvata lugens.c Nephotettix cincticeps.d Not determined.

mixture was allowed to stand at room temperatureovernight. It was washed with water, dried (sodiumsulfate), Ðltered and the solvent was removed with arotary evaporator. The residue was puriÐed by Ñashchromatography on silica gel (ethyl acetate] hexane(25 ] 75 by volume) as eluant) to a†ord 0É47 g of amixture of the title compounds as a white solid. Thismixture was further puriÐed by HPLC to give 0É27 g ofN- isopropyl-3-chloro-6-methylsulfonyloxypyridine-2-carboxamide (25), m.p. 129¡C (eluting Ðrst) and 0É10 gof N-isopropyl-5-chloro-6-methanesulfonyloxypyridine-2-carboxamide (26), m.p. 100È101¡C.

3-Chloro isomer : [1H]NMR (deuterochloroform) : d1É28 (d, 6), 3É46 (s, 3), 4É22 (m, 1). 7É28 (br, 1), 8É00 (d, 1),8É12 (d, 1).

5-Chloro isomer : [1H]NMR (deuterochloroform) : d1É28 (d, 6), 3É41 (s, 3), 4É22 (m, 1). 6É98 (br, 1), 7É19 (d, 1),7É93 (d, 1).

2.2 Insecticidal tests

To measure contact activity, test units, each consistingof a 230 ml plastic cup containing a sprouted corn seed

322 Bruce L . Finkelstein, Melissa A. Martz, Christopher J. Strock

TABLE 2Rat Oral Approximate Lethal Dose for Selected 6-

Methanesulfonyloxypyridine-2-carboxamides

AL DNo. (mg kg~1)

4 1306 25

13 ^1216 2525 ^2528 25

were prepared. The test chemical was dissolved inacetone] water (3] 1 by volume). Sets of three testunits were sprayed at six di†erent rates (1000, 250, 50,10, 2É5, 0É5 mg litre~1) by passing the test units on aconveyer belt directly beneath a Ñat fan hydraulicnozzle. Five third-instar larvae of Diabrotica unde-cimpunctata howardi Barb. were placed into each cup. Amoistened dental wick was inserted into each cup toprevent drying and the cups were sealed. The cups wereheld at 27¡C and 50% relative humidity for 48 h, afterwhich time mortality readings were taken. Selectedcompounds showing good activity in this test werefurther tested in a systemic test.

To test for systemic activity, the test chemical wasdissolved in 10 ml of distilled water. This solution waspoured into a conical test unit. Three rice seedlings werethen positioned in the unit by a notched sponge disk.The rice seedlings were allowed to absorb the chemicalfrom the solution for 24 h in a growth chamber held at27¡C and 65% relative humidity. Eight to ten third-instar nymphs of N. lugens or N. cincticeps were trans-ferred into the test units using an aspirator. The testunits were held in the growth chamber for 48 h. Countswere taken of the number of live and dead insects.Insects which could not walk were counted as dead.

2.3 Oral approximate lethal dose determinations

The test compound was administered as a single oraldose by intragastric intubation to male rats. The testsubstance was suspended in acetone] corn oil (15 ] 85by volume) and administered to one rat per dose. Therats were held for 14 days. The ALD was estimated tobe the lowest dose at which a rat did not survive thetest.

3 RESULTS AND DISCUSSION

Table 1 shows the insecticidal activity for a series of6-methanesulfonyloxypyridine-2-carboxamides in eithera contact test (D. undecimpunctata howardi) or a solu-tion systemic test (N. lugens, N. cincticeps). All com-

pounds tested against the Japanese rice pests were moreactive against N. lugens than N. cincticeps. From thesedata it can be seen that the compounds that mostclosely Ðt our model (i.e. contain branching in theamide side chain a to the amine ; 4, 6, 9 and 11) had themost activity. Of the sec-butyl enantiomers the R-enantiomer was more active than the S. Additionalfunctionality in the side chain (15, 17È19) was notadvantageous with the exception of 16, containing acyano group, which was highly active. Secondaryamides were more active than tertiary ones (21È23) withthe exception of 20 which showed increased activityover 1 and 2. Additional substituents on the pyridinering (24È30) also resulted in compounds with reducedactivity.

Table 2 shows rat oral ALD measurements for selec-ted 6-methanesulfonyloxypyridine-2-carboxamides. Ingeneral the carboxamides showed much reduced levelsof mammalian acute toxicity over the correspondingalkylthio compounds. Compound 4 showed the highestlevel of safety. A chlorine or bromine atom ortho to thecarboxamide reduced the level of mammalian safety.These observations suggest that metabolism of the iso-propyl carboxamide (which would be more hinderedwith an ortho substituent) may be responsible for theobserved level of mammalian safety.

Compound 4 was tested in a 24-h acute static testagainst Daphnia magna Straus and Pimephales promelasRaf. (fathead minnow). Against both species the LC50was estimated to be greater than 10 mg litre~1 demon-strating an excellent level of aquatic safety.

Field test results in rice (nursery box application,1É5 g AI per box) using laboratory-raised insects for 4and 6 were disappointing. Compound 4 gave 14-daycontrol of N. lugens and L . striatella, but gave little orno control of N. cincticeps. Similarly compound 6 gave28-day control of N. lugens and L . striatella, but gavelittle or no control of N. cincticeps.

4 CONCLUSIONS

We have developed a model which has helped us designand synthesize 6-methanesulfonyloxypyridine-2-carb-oxamides with insecticidal activity and improved mam-malian safety. While lack of control over the completespectrum of Japanese rice hoppers prevented the devel-opment of these compounds for use in rice, this modelshould prove useful in designing other insecticidal sul-fonates.

ACKNOWLEDGEMENTS

We wish to thank Mr Eric Hartline and the DuPontAgricultural Products Primary Evaluation Team forcarrying out the D. undecimpunctata howardi tests. Drs

Insecticidal activity of novel pyridine methanesulfonates 323

Michael Priminani, Yuji Tsurubuchi and Ms MaryKoechert are thanked for the hopper tests. Dr PatrickHardesty and the sta† of Haskell Laboratory arethanked for the toxicological results. Drs George Lahm,George Holan and Keith Watson are thanked forhelpful discussions.

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