Dihydrofuran derivatives as insecticidal compounds

Abstract

The present invention relates to compounds of formula (I) wherein Q is Q1 or Q2 P is P1, heterocyclyl or heterocyclyl substituted by one to five Z; and wherein A.sup.1, A.sup.2, A.sup.3, A.sup.4, G.sup.1, Y.sup.1, Z, R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are as defined in claim 1; or a salt or N-oxide thereof. Furthermore, the present invention relates to processes and intermediates for preparing compounds of formula (I), to insecticidal, acaricidal, nematicidal and molluscicidal compositions comprising the compounds of formula (I) and to methods of using the compounds of formula (I) to control insect, acarine, nematode and mollusc pests. ##STR00001##

Claims

1. A compound of formula (I) ##STR00126## wherein Q is Q1 or Q2 ##STR00127## P is P1, pyrazolyl, triazolyl, or pyrazolyl substituted by one to five Z, or triazolyl substituted by one to five Z; ##STR00128## A.sup.1 is CR.sup.5, A.sup.2 is CH, A.sup.3 is CH or nitrogen and A.sup.4 is CH or nitrogen; G.sup.1 is oxygen or sulfur; Y.sup.1 is CH.sub.2 or CO; R.sup.1 is hydrogen, C.sub.1-C.sub.8alkyl, C.sub.1-C.sub.8alkoxy-, C.sub.1-C.sub.8alkylcarbonyl-, or C.sub.1-C.sub.8alkoxycarbonyl-; R.sup.2 is C.sub.1-C.sub.8alkyl or C.sub.1-C.sub.8alkyl substituted by one to five R.sup.6, C.sub.3-C.sub.10cycloalkyl or C.sub.3-C.sub.10cycloalkyl substituted by one to five R.sup.7, aryl-C.sub.1-C.sub.4alkylene- or aryl-C.sub.1-C.sub.4alkylene- wherein the aryl moiety is substituted by one to five R.sup.8, heterocyclyl-C.sub.1-C.sub.4alkylene- or heterocyclyl-C.sub.1-C.sub.4alkylene- wherein the heterocyclyl moiety is substituted by one to five R.sup.8, aryl or aryl substituted by one to five R.sup.8, heterocyclyl or heterocyclyl substituted by one to five R.sup.8, C.sub.1-C.sub.8alkylaminocarbonyl-C.sub.1-C.sub.4 alkylene, C.sub.1-C.sub.8haloalkylaminocarbonyl-C.sub.1-C.sub.4 alkylene, C.sub.3-C.sub.8cycloalkyl-aminocarbonyl-C.sub.1-C.sub.4 alkylene, C.sub.1-C.sub.6alkyl-ONCH, C.sub.1-C.sub.6haloalkyl-ONCH, R.sup.3 is C.sub.1-C.sub.8haloalkyl; R.sup.4 is phenyl or phenyl substituted by one to five R.sup.9; each R.sup.5 is independently halogen, cyano, nitro, C.sub.1-C.sub.8alkyl, C.sub.1-C.sub.8haloalkyl, C.sub.1-C.sub.8alkenyl, C.sub.1-C.sub.8haloalkenyl, C.sub.1-C.sub.8alkynyl, C.sub.1-C.sub.8haloalkynyl, C.sub.3-C.sub.10cycloalkyl, C.sub.1-C.sub.8alkoxy-, C.sub.1-C.sub.8haloalkoxy-, C.sub.1-C.sub.8alkylthio-, C.sub.1-C.sub.8haloalkylthio-, C.sub.1-C.sub.8alkylsulfinyl-, C.sub.1-C.sub.8haloalkylsulfinyl-, C.sub.1-C.sub.8alkylsulfonyl-, or C.sub.1-C.sub.8haloalkylsulfonyl-; each R.sup.6 is independently halogen, cyano, nitro, hydroxy, amino, C.sub.1-C.sub.8alkylamino, (C.sub.1-C.sub.8alkyl).sub.2amino, C.sub.1-C.sub.8alkylcarbonylamino, C.sub.1-C.sub.8haloalkylcarbonylamino, C.sub.1-C.sub.8alkoxy-, C.sub.1-C.sub.8haloalkoxy-, aryloxy or aryloxy substituted by one to five R.sup.10, aryloxy-C.sub.1-C.sub.4alkylene or aryloxy-C.sub.1-C.sub.4alkylene wherein the aryl moiety is substituted by one to five R.sup.10, C.sub.1-C.sub.8alkylcarbonyl-, C.sub.1-C.sub.8alkoxycarbonyl-, mercapto, C.sub.1-C.sub.8alkylthio-, C.sub.1-C.sub.8haloalkylthio-, C.sub.1-C.sub.8alkylsulfinyl-, C.sub.1-C.sub.8haloalkylsulfinyl-, C.sub.1-C.sub.8alkylsulfonyl-, C.sub.1-C.sub.8haloalkylsulfonyl-, aryl-C.sub.1-C.sub.4alkylthio- or aryl-C.sub.1-C.sub.4alkylthio- wherein the aryl moiety is substituted by one to five R.sup.10; each R.sup.7 is independently halogen, C.sub.1-C.sub.8alkyl, C.sub.1-C.sub.8alkenyl, C.sub.1-C.sub.8alkynyl, C.sub.1-C.sub.8alkyl-ON, C.sub.1-C.sub.8haloalkyl-ON; C.sub.1-C.sub.8alkoxy, C.sub.1-C.sub.8akoxycarbonyl; each R.sup.8 is independently halogen, cyano, nitro, oxo, C.sub.1-C.sub.8alkyl, C.sub.1-C.sub.8haloalkyl, C.sub.1-C.sub.8cyanoalkyl, C.sub.2-C.sub.8alkenyl, C.sub.2-C.sub.8haloalkenyl, C.sub.2-C.sub.8alkynyl, C.sub.2-C.sub.8haloalkynyl, C.sub.3-C.sub.10cycloalkyl, C.sub.3-C.sub.10cycloalkyl-C.sub.1-C.sub.4alkylene, hydroxy, C.sub.1-C.sub.8alkoxy-, C.sub.1-C.sub.8haloalkoxy-, mercapto, C.sub.1-C.sub.8alkylthio-, C.sub.1-C.sub.8haloalkylthio-, C.sub.1-C.sub.8alkylsulfinyl-, C.sub.1-C.sub.8haloalkylsulfinyl-, C.sub.1-C.sub.8alkylsulfonyl-, C.sub.1-C.sub.8haloalkylsulfonyl-, C.sub.1-C.sub.8alkylaminosulfonyl, (C.sub.1-C.sub.8alkyl).sub.2aminosulfonyl-, C.sub.1-C.sub.8alkylcarbonyl-, C.sub.1-C.sub.8alkoxycarbonyl-, aryl or aryl substituted by one to five R.sup.10, heterocyclyl or heterocyclyl substituted by one to five R.sup.10, aryl-C.sub.1-C.sub.4alkylene or aryl-C.sub.1-C.sub.4alkylene wherein the aryl moiety is substituted by one to five R.sup.10, heterocyclyl-C.sub.1-C.sub.4alkylene or heterocyclyl-C.sub.1-C.sub.4alkylene wherein the heterocyclyl moiety is substituted by one to five R.sup.10, aryloxy or aryloxy substituted by one to five R.sup.10, aryloxy-C.sub.1-C.sub.4alkylene or aryloxy-C.sub.1-C.sub.4alkylene wherein the aryl moiety is substituted by one to five R.sup.10; each R.sup.9 is independently halogen, cyano, nitro, C.sub.1-C.sub.8alkyl, C.sub.1-C.sub.8haloalkyl, C.sub.2-C.sub.8alkenyl, C.sub.2-C.sub.8haloalkenyl, C.sub.2-C.sub.8alkynyl, C.sub.2-C.sub.8haloalkynyl, hydroxy, C.sub.1-C.sub.8alkoxy-, C.sub.1-C.sub.8haloalkoxy-, mercapto, C.sub.1-C.sub.8alkylthio-, C.sub.1-C.sub.8haloalkylthio-, C.sub.1-C.sub.8alkylsulfinyl-, C.sub.1-C.sub.8haloalkylsulfinyl-, C.sub.1-C.sub.8alkylsulfonyl-, C.sub.1-C.sub.8haloalkylsulfonyl-, C.sub.1-C.sub.8alkylcarbonyl-, C.sub.1-C.sub.8alkoxycarbonyl-, aryl or aryl substituted by one to five R.sup.10, or heterocyclyl or heterocyclyl substituted by one to five R.sup.10; each R.sup.10 is independently halogen, cyano, nitro, C.sub.1-C.sub.4alkyl, C.sub.1-C.sub.4haloalkyl, C.sub.1-C.sub.4alkoxy-, or C.sub.1-C.sub.4haloalkoxy-; each Z is independently halogen, C.sub.1-C.sub.12alkyl or C.sub.1-C.sub.12alkyl substituted by one to five R.sup.6, nitro, C.sub.1-C.sub.12alkoxy or C.sub.1-C.sub.12alkoxy substituted by one to five R.sup.6, cyano, C.sub.1-C.sub.12alkylsulfinyl, C.sub.1-C.sub.12alkylsulfonyl, C.sub.1-C.sub.12haloalkylsulfinyl, C.sub.1-C.sub.12haloalkylsulfonyl, hydroxyl or thiol; or a salt or N-oxide thereof.

2. A compound according to claim 1 wherein G.sup.1 is oxygen.

3. A compound according to claim 1 wherein R.sup.1 is hydrogen, methyl, ethyl, methylcarbonyl-, or methoxycarbonyl-.

4. A compound according to claim 1 wherein R.sup.2 is C.sub.1-C.sub.8alkyl or C.sub.1-C.sub.8alkyl substituted by one to five R.sup.6, C.sub.3-C.sub.10cycloalkyl or C.sub.3-C.sub.10cycloalkyl substituted by one to five R.sup.7, aryl-C.sub.1-C.sub.4alkylene- or aryl-C.sub.1-C.sub.4alkylene- wherein the aryl moiety is substituted by one to five R.sup.8, heterocyclyl-C.sub.1-C.sub.4alkylene- or heterocyclyl-C.sub.1-C.sub.4alkylene- wherein the heterocyclyl moiety is substituted by one to five R.sup.8, aryl or aryl substituted by one to five R.sup.8, heterocyclyl or heterocyclyl substituted by one to five R.sup.8, C.sub.1-C.sub.8alkylaminocarbonyl-C.sub.1-C.sub.4 alkylene, C.sub.1-C.sub.8haloalkylaminocarbonyl-C.sub.1-C.sub.4 alkylene, C.sub.3-C.sub.8cycloalkyl-aminocarbonyl-C.sub.1-C.sub.4 alkylene, or group A ##STR00129## R.sup.11 is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, cyclopropyl, cyclopropyl-methyl, cyclobutyl, cyclobutyl-methyl, oxetanyl, thietanyl, trifluoroethyl, difluoroethyl, allyl, propargyl, cyanomethyl, benzyl, benzyl substituted by one to three R.sup.12, or R.sup.11 is pyridyl-methyl- or pyridyl-methyl-substituted by one to three R.sup.12; each R.sup.12 is independently fluoro, chloro, bromo, trifluoromethyl, trifluoromethoxy, cyano or methoxy; wherein each aryl group is a phenyl group and each heterocyclyl group is independently selected from pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrahydrothiophenyl, tetrazolyl, furanyl, thiophenyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, quinolinyl, cinnolinyl, quinoxalinyl, indolyl, indazolyl, benzimidazolyl, benzothiophenyl, benzothiazolyl, oxetanyl, thietanyl, oxo-thietanyl, dioxo-thietanyl, pyrrolidinyl, tetrahydrofuranyl, [1,3]dioxolanyl, piperidinyl, piperazinyl, [1,4]dioxanyl, and morpholinyl, 2,3-dihydro-benzofuranyl, benzo[1,3]dioxolanyl, and 2,3-dihydro-benzo[1,4]dioxinyl.

5. A compound according to claim 4 wherein R.sup.2 is C.sub.1-C.sub.8alkyl or C.sub.1-C.sub.8alkyl substituted by one to five R.sup.6, C.sub.3-C.sub.10cycloalkyl or C.sub.3-C.sub.10cycloalkyl substituted by one to five R.sup.7, phenyl-C.sub.1-C.sub.4alkylene- or phenyl-C.sub.1-C.sub.4alkylene- wherein the phenyl moiety is substituted by one to five R.sup.8, pyridyl-C.sub.1-C.sub.4alkylene- or pyridyl-C.sub.1-C.sub.4alkylene- wherein the pyridyl moiety is substituted by one to four R.sup.8, oxetanyl or oxetanyl substituted by one to five R.sup.8, thietanyl-C.sub.1-C.sub.4 alkylene or thietanyl-C.sub.1-C.sub.4 alkylene wherein the thietanyl moiety is substituted by one to five R.sup.8, oxo-thietanyl-C.sub.1-C.sub.4 alkylene or oxo-thietanyl-C.sub.1-C.sub.4 alkylene wherein the oxo-thietanyl moiety is substituted by one to five R.sup.8, dioxo-thietanyl-C.sub.1-C.sub.4 alkylene or dioxo-thietanyl-C.sub.1-C.sub.4 alkylene wherein the dioxo-thietanyl moiety is substituted by one to five R.sup.8, thietanyl or thietanyl substituted by one to five R.sup.8, oxo-thietanyl or oxo-thietanyl substituted by one to five R.sup.8, dioxo-thietanyl or dioxo-thietanyl substituted by one to five R.sup.8, C.sub.1-C.sub.8alkylaminocarbonyl-C.sub.1-C.sub.4 alkylene, C.sub.1-C.sub.8haloalkylaminocarbonyl-C.sub.1-C.sub.4 alkylene, or C.sub.3-C.sub.8cycloalkyl-aminocarbonyl-C.sub.1-C.sub.4 alkylene or group A ##STR00130##

6. A compound according to claim 1 wherein R.sup.3 is chlorodifluoromethyl or trifluoromethyl.

7. A compound according to claim 1, wherein P is P1; Q is Q1 or Q2; A.sup.1 is CR.sup.5, A.sup.2 is CH, A.sup.3 is CH and A.sup.4 is CH; G.sup.1 is oxygen; Y.sup.1 is CH.sub.2; R.sup.1 is hydrogen; R.sup.2 is C.sub.1-C.sub.8alkyl or C.sub.1-C.sub.8alkyl substituted by one to three halogen atoms, C.sub.3-C.sub.10cycloalkyl or C.sub.3-C.sub.10cycloalkyl substituted by one or two groups independently selected from fluoro and methyl, phenyl-C.sub.1-C.sub.4alkylene- or phenyl-C.sub.1-C.sub.4alkylene- wherein the phenyl moiety is substituted by one to five R.sup.8, pyridyl-C.sub.1-C.sub.4alkylene- or pyridyl-C.sub.1-C.sub.4alkylene- wherein the pyridyl moiety is substituted by one to four R.sup.8, thietanyl, oxo-thietanyl, dioxo-thietanyl, C.sub.1-C.sub.4alkylaminocarbonyl-C.sub.1-C.sub.4 alkylene, C.sub.1-C.sub.4haloalkylaminocarbonyl-C.sub.1-C.sub.4 alkylene, C.sub.3-C.sub.6cycloalkyl-aminocarbonyl-C.sub.1-C.sub.4 alkylene, or group A ##STR00131## R.sup.3 is trifluoromethyl; R.sup.4 is 3,5-dichloro-phenyl; R.sup.5 is methyl; each R.sup.8 is independently bromo, chloro, fluoro, cyano or methyl; R.sup.11 is methyl, ethyl or trifluoroethyl.

8. A method of controlling insects, acarines, nematodes or molluscs which comprises applying to a pest, to a locus of a pest, or to a plant susceptible to attack by a pest an insecticidally, acaricidally, nematicidally or molluscicidally effective amount of a compound of formula (I) as defined in claim 1.

9. An insecticidal, acaricidal, nematicidal or molluscicidal composition comprising an insecticidally, acaricidally, nematicidally or molluscicidally effective amount of a compound of formula (I) as defined in claim 1.

10. An insecticidal, acaricidal, nematicidal or molluscicidal composition according to claim 9 comprising at least one additional compound having biological activity.

11. A combination product comprising a pesticidally effective amount of a component A and a pesticidally effective amount of component B, wherein component A is a compound of formula (I) as defined in claim 1, and compound B is imidacloprid, enrofloxacin, praziquantel, pyrantel embonate, febantel, penethamate, moloxicam, cefalexin, kanamycin, pimobendan, clenbuterol, fipronil, ivermectin, omeprazole, tiamulin, benazepril, milbemycin, cyromazine, thiamethoxam, pyriprole, deltamethrin, cefquinome, florfenicol, buserelin, cefovecin, tulathromycin, ceftiour, selamectin, carprofen, metaflumizone, moxidectin, methoprene (including S-methoprene), clorsulon, pyrantel, amitraz, triclabendazole, avermectin, abamectin, emamectin, eprinomectin, doramectin, selamectin, nemadectin, albendazole, cambendazole, fenbendazole, flubendazole, mebendazole, oxfendazole, oxibendazole, parbendazole, tetramisole, levamisole, pyrantel pamoate, oxantel, morantel, triclabendazole, epsiprantel, fipronil, lufenuron, ecdysone or tebufenozide.

Description

PREPARATION EXAMPLES

(1) The following preparation examples describe synthesis of compounds of formula I and intermediates thereof.

Example P1: 4-(3,5-Dichloro-phenyl)-5,5,5-trifluoro-pent-2-yne-1,4-diol

(2) ##STR00095##

(3) To a stirring solution of magnesium (520 mg) in anhydrous tetrahydrofuran (50 mL) under argon at room temperature, was added ethyl bromide (1.7 mL). After stirring for 2 hours at room temperature, the solution was cooled to 0 C. and Trimethyl-prop-2-ynyloxy-silane (3.1 mL) was added. The solution was allowed to warm to room temperature and then after 40 minutes, it was cooled again to 0 C. To this cooled solution, 1-(3,5-Dichloro-phenyl)-2,2,2-trifluoro-ethanone (5 g) (Journal of Physical Organic Chemistry (1989), 2(4), 363-6) were added. The solution was stirred at 0 C. for 1 hour. The mixture was quenched with saturated ammonium chloride and then extracted with diethyl ether. The combined organic extracts were dried over magnesium sulfate and concentrated. The residue was then dissolved in ethyl acetate (60 mL) and the solution was stirred at room temperature under argon. A solution of tetrabutylammonium fluoride (21 mL of a 1 M solution in tetrahydrofuran) was added. The solution was stirred for one hour then was allowed to stand at room temperature for 21 hours. The mixture was quenched with saturated ammonium chloride and then extracted with diethyl ether. The combined organic extracts were dried over magnesium sulfate and concentrated. The residue was purified by chromatography on silica gel (eluent:heptane/ethyl acetate 1:0 to 7:3) to give 4-(3,5-Dichloro-phenyl)-5,5,5-trifluoro-pent-2-yne-1,4-diol (3.798 g) as a colorless oil.

(4) .sup.1H-NMR (CDCl.sub.3, 400 MHz): 7.61 (m, 2H), 7.43 (t, J=1.83 Hz, 1H), 4.44 (m, 2H), 3.45 (s, 1H) ppm.

Example P2: Tributyl-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-2,5-dihydro-furan-3-yl]-stannane

(5) ##STR00096##

(6) To a solution of 4-(3,5-Dichloro-phenyl)-5,5,5-trifluoro-pent-2-yne-1,4-diol (2.5 g) in toluene under argon, was added tetrakis(triphenylphosphine) palladium (190 mg) and tributyltinhydride (2.25 mL). The reaction mixture was stirred for 45 minutes then the solvent was evaporated under vacuo. The residue was then dissolved in anhydrous tetrahydrofuran (50 mL) with triphenylphosphine (2.19 g) and the solution was stirred at 0 C. under argon. To this solution was slowly added diethyl azodicarboxylate (1.31 mL). The mixture was stirred at 0 C. for 90 minutes then the solvent was evaporated under vacuo. The residue was partitioned between acetonitrile and heptane and the acetonitrile part was washed twice with heptane. The combined heptane extracts were combined and evaporated to give a residue that was purified by chromatography on silica gel (eluent:heptane) to give Tributyl-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-2,5-dihydro-furan-3-yl]-stannane (1.587 g) as a colorless oil.

(7) .sup.1H-NMR (CDCl.sub.3, 400 MHz): 7.43 (m, 2H), 7.34 (d, J=1.83 Hz, 1H), 5.93 (t, J=2.57 Hz, 1H), 5.02-4.89 (2 dd, J=2.6 and 13.6 and 1.8 Hz, 2H), 1.52-1.46 (m, 6H), 1.34-1.28 (m, 6H), 1.03-0.99 (t, J=8.1 Hz, 6H), 0.89 (t, J=7.3 Hz, 9H) ppm.

Example P3: Preparation of 4-bromo-2-methyl-benzoic acid tert-butyl ester

(8) ##STR00097##

(9) 4-Bromo-2-methyl-benzoic acid (commercially available) (50 g) was suspended in dichloromethane (500 mL). A catalytic amount of N,N-dimethylformamide (DMF) and oxalyl chloride (23 mL) were added to the suspension. The reaction mixture was stirred at ambient temperature for 3 hours. The reaction mixture was concentrated and the residue dissolved in dry tetrahydrofuran (800 mL). The solution was cooled to 2 C. and added to a solution of potassium tert-butoxide (39.2 g) in dry tetrahydrofuran (300 mL) dropwise at 5-10 C. The reaction mixture was stirred at ambient temperature for 30 minutes and then poured onto a mixture of ice and water. The mixture was extracted with ethyl acetate. The organic extract was washed with water, dried over sodium sulfate and concentrated to give 4-bromo-2-methyl-benzoic acid tert-butyl ester (65.3 g) as yellow oil.

(10) .sup.1H-NMR (CDCl.sub.3, 400 MHz): 7.70 (d, 1H), 7.40 (s, 1H), 7.35 (d, 1H), 2.58 (s, 3H), 1.60 (s, 9H).

Example P4: 4-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-2,5-dihydro-furan-3-yl]-2-methyl-benzoic acid tert-butyl ester

(11) ##STR00098##

(12) To a solution of Tributyl-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-2,5-dihydro-furan-3-yl]-stannane (1.587 g) in toluene (15 mL) under argon was successively added 4-Bromo-2-methyl-benzoic acid tert-butyl ester (630 mg), lithium chloride (600 mg) and then tetrakis(triphenylphosphine) palladium (110 mg). The reaction was refluxed at 100 C. under argon for 3 hours 30 minutes. The reaction was allowed to cool down to room temperature then after 3 hours, more tetrakis(triphenylphosphine) palladium (45 mg) was added. The solution was refluxed for a further 1 h 45 and then the reaction was stopped. The mixture was cooled to room temperature and then the solvent was evaporated in vacuo to give a residue which was purified by chromatography on silica gel (eluent:heptanes\diethyl ether, from 1:0 to 9:1) to give 4-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-2,5-dihydro-furan-3-yl]-2-methyl-benzoic acid tert-butyl ester (704 mg) as a white solid. Recrystallisation in heptane/ethyl acetate provided white crystals, m.p=160-162 C.

(13) .sup.1H-NMR (CDCl.sub.3, 400 MHz): 7.83 (d, J=8.4 Hz, 1H), 7.50 (m, 2H), 7.38 (t, J=1.4 Hz, 1H), 7.22 (m, 2H), 6.39 (m, 1H), 5.32 (dd, J=2.2 and 12.5 Hz, 1H), 5.20 (m, 1H), 2.59 (s, 3H), 1.61 (s, 9H) ppm.

Example P5: 4-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-2,5-dihydro-furan-3-yl]-2-methyl-benzoic acid

(14) ##STR00099##

(15) To a solution of 4-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-2,5-dihydro-furan-3-yl]-2-methyl-benzoic acid tert-butyl ester (322 mg) in dichloromethane (8 mL) was added trifluoroacetic acid (0.5 mL). The reaction mixture was stirred at room temperature for 3 h 30 then the solution was concentrated under vacuo to give 4-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-2,5-dihydro-furan-3-yl]-2-methyl-benzoic acid (200 mg) as a white foam.

(16) .sup.1H-NMR (CDCl.sub.3, 400 MHz): 8.07 (d, J=8.8 Hz, 1H), 7.49 (m, 2H), 7.39 (t, J=1.4 Hz, 1H), 7.3-7.26 (m, 2H), 6.46 (m, 1H), 5.34 (dd, J=2.2 and 12.5 Hz, 1H), 5.22 (m, 1H), 2.67 (s, 3H) ppm.

Example P6 (Compound A1 from Table A): 4-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-2,5-dihydro-furan-3-yl]-2-methyl-N-[2-oxo-2-[(2,2,2-trifluoroethyl)amino]ethyl]-benzamide

(17) ##STR00100##

(18) To a stirred solution of 4-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-2,5-dihydro-furan-3-yl]-2-methyl-benzoic acid (50 mg) in dichloromethane (2 mL) was added triethylamine (0.04 mL) at ambient temperature. The solution was then stirred for 5 min under argon and the trifluoroacetate salt of 2-amino-N-(2,2,2-trifluoro-ethyl)-acetamide (39 mg, prepared according to JP2009173621) was added. To this solution, 1-hydroxyazabenzotriazole (18 mg) then N,N-Dicyclohexylcarbodiimide (27 mg) were added. The solution was stirred for 80 minutes then was allowed to stand at ambient temperature for 3 days. The solution was concentrated under vacuo and then the crude residue was first purified by chromatography on silica gel (eluent:heptane/ethyl acetate, from 1:0 to 6:4). The residue was further recrystallised and repurified by preparative HPLC to give 4-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-2,5-dihydro-furan-3-yl]-2-methyl-N-[(2,2,2-trifluoro-ethylcarbamoyl)-methyl]-benzamide (30 mg) as a white solid.

(19) .sup.1H-NMR (CDCl.sub.3, 400 MHz): 7.49 (m, 2H), 7.44 (d, 1H, J=7.7 Hz), 7.38 (m, 1H), 7.26-7.22 (m, 2H), 7.00 (m, 1H), 6.69 (m, 1H), 6.39 (m, 1H), 5.32 (dd, J=2.2 and 12.5 Hz, 1H), 5.19 (m, 1H), 4.22 (d, J=5.14 Hz, 2H), 4.00-3.92 (m, 2H), 2.47 (s, 3H) ppm.

(20) Similarly, using the trifluoroacetate salt of (S)-4-Amino-2-ethyl-isoxazolidin-3-one and 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 1-hydroxyazabenzotriazole as coupling agents, 4-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-2,5-dihydro-furan-3-yl]-N((S)-2-ethyl-3-oxo-isoxazolidin-4-yl)-2-methyl-benzamide (compound A16 from Table A): could be prepared. .sup.1H-NMR (CDCl.sub.3, 400 MHz): 7.49-7.48 (m, 3H), 7.38 (m, 1H), 7.27-7.21 (m, 2H), 6.43 (s, 1H), 6.39 (s, 1H), 5.32 (dd, J=2.2 and 12.4 Hz, 1H), 5.18 (bd, 1H, J=12.2 Hz), 5.00 (t, 1H, J=8.07 Hz), 4.88-4.82 (m, 1H), 4.08-4.03 (m, 1H), 3.75-3.62 (m, 2H), 2.49 (s, 3H), 1.27 (m, 3H) ppm. .sup.19F-NMR (CDCl.sub.3, 376 MHz): 78.13 ppm.

(21) Similarly, using 2-Chloro-6-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-2,5-dihydro-furan-3-yl]-nicotinic acid as a starting material and 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 1-hydroxyazabenzotriazole as coupling agents, 2-Chloro-6-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-2,5-dihydro-furan-3-yl]-N-[(2,2,2-trifluoro-ethylcarbamoyl)-methyl]-nicotinamide (compound F1 from Table F) could be prepared. .sup.1H-NMR (CDCl.sub.3, 400 MHz): 8.16 (d, 1H, J=7.70 Hz), 7.49 (m, 2H), 7.46-7.43 (m, 2H), 7.39 (t, 1H, J=1.83 Hz), 6.81 (m, 1H), 6.69 (m, 1H), 5.40 (dd, J=2.2 and 13.2 Hz, 1H), 5.27 (bd, 1H, J=13.2 Hz), 4.26 (d, 2H, J=5.14 Hz), 4.02-3.94 (m, 2H) ppm. .sup.19F-NMR (CDCl.sub.3, 376 MHz): 77.88 and 72.44 ppm.

(22) Similarly, using 2-Chloro-6-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-2,5-dihydro-furan-3-yl]-nicotinic acid as a starting material, 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 1-hydroxyazabenzotriazole as coupling agents, and the trifluoroacetate salt of 1,1-Dioxo-1lambda*6*-thietan-3-ylamine, 2-Chloro-6-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-2,5-dihydro-furan-3-yl]-N-(1,1-dioxo-1lambda*6*-thietan-3-yl)-nicotinamide (compound F2 from Table F) could be prepared. .sup.1H-NMR (CDCl.sub.3, 400 MHz): 8.20 (d, 1H, J=8.07 Hz), 7.50-7.46 (m, 3H), 7.40-7.37 (m, 2H), 6.82 (m, 1H), 5.40 (dd, J=2.2 and 13.2 Hz, 1H), 5.28 (bd, 1H, J=13.2 Hz), 4.96-4.90 (m, 1H), 4.67-4.61 (m, 2H), 4.12-4.09 (m, 2H) ppm. .sup.19F-NMR (CDCl.sub.3, 376 MHz): 77.87 ppm.

Example P7: 4-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-2,5-dihydro-furan-3-yl]-2-methyl-benzamide

(23) ##STR00101##

(24) A solution of 4-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-2,5-dihydro-furan-3-yl]-2-methyl-benzoic acid (330 mg) was suspended in dichloromethane (4 mL). A catalytic amount of N,N-dimethylformamide (DMF) and oxalyl chloride (0.08 mL) were added to the suspension. The reaction mixture was stirred at ambient temperature for one hour. The reaction mixture was concentrated and the residue dissolved in dry tetrahydrofuran (4 mL). To the solution was added a solution of ammonium hydroxide (2 mL, 25%). The reaction mixture was stirred at ambient temperature for one hour. It was then quenched by addition of water and extracted with ethyl acetate. The organic extract was washed with water, dried over sodium sulfate and concentrated in vacuo. The crude residue was treated with Diisopropylether (ca 0.1 mL) and pentane (1 mL). The mixture was stirred at room temperature for 30 minutes then the precipitate was filtered, washed twice with pentane and dried under vacuo to give the title compound (308 mg) as a bright red solid. .sup.1H-NMR (CDCl.sub.3, 400 MHz): 7.49 (m, 3H), 7.48 (m, 1H), 7.27-7.21 (m, 2H), 6.38 (s, 1H), 5.74 (bs, 2H), 5.32 (dd, J=2.2 and 12.4 Hz, 1H), 5.20 (bd, 1H, J=12.2 Hz), 2.53 (s, 3H) ppm. .sup.19F-NMR (CDCl.sub.3, 376 MHz): 78.14 ppm.

Example P8 (Compound A86 from Table A): (E)-4-[5-(3,5-Dichlorophenyl)-5-trifluoromethyl-2,5-dihydro-furan-3-yl]-N-[(methoxyimino)methyl]-2-methylbenzamide

(25) ##STR00102##

(26) A solution of 4-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-2,5-dihydro-furan-3-yl]-2-methyl-benzamide (100 mg) and N,N-Dimethylformamide dimethylacetal (4.2 mL) was refluxed under Argon for 30 min then the solution was concentrated in vacuo. The residue was dissolved in 1,4-dioxane (2 mL) and a solution of methoxyamin hydrochloride (56 mg) and sodium hydroxide (58 mg) in water (1.6 mL) and acetic acid (1.6 mL) was added. The solution was stirred at rt for one hour. It was then quenched by addition of water and extracted with methyl tert-butyl ether. The combined organic extracts were washed with brine, dried (Na.sub.2SO.sub.4) and evaporated.

(27) Flash Chromatography eluting with Cyclohexane:EtOAc afforded 78 mg of the title compound. .sup.1H-NMR (CDCl.sub.3, 400 MHz): 8.5 (m, 1H), 7.8 (m, 1H), 7.55-7.48 (m, 3H), 7.40 (m, 1H), 7.32-7.25 (m, 3H), 6.42 (m, 1H), 5.32 (dd, 1H), 5.20 (bd, 1H), 3.9 (s, 3H), 2.53 (s, 3H) ppm.

Example P9 (Compound D24 from Table D): 4-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-furan-3-yl]-N-(1,1-dioxo-1lambda*6*-thietan-3-yl)-2-methyl-benzamide

(28) ##STR00103##

Step A: 2-(3,5-Dichloro-phenyl)-1,1,1-trifluoro-pent-4-yn-2-ol

(29) ##STR00104##

(30) n-BuLi (15.7 mL, 1.5 equiv) was added dropwise to a solution of diisopropylamine (2.62 mL, 1.5 equiv) in tetrahydrofuran (40 mL) at 0 C. under argon. The reaction mixture was stirred for 10 min, and cooled down to 20 C. Then trimethylsilylpropyne (2.21 mL, 1.2 equiv) was added dropwise. The reaction mixture was then stirred at 20 C. for 90 minutes. The reaction mixture was cooled down to 78 C., and 1-(3,5-Dichloro-phenyl)-2,2,2-trifluoroethanone (3 g, 12.35 mmol) in tetrahydrofuran (20 mL) was added dropwise. The reaction mixture was allowed to warm up to room temperature and stirred for two hours 30 minutes. It was then quenched by addition of saturated aqueous ammonium chloride and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried (Na.sub.2SO.sub.4) and evaporated. This crude residue was then redissolved in methanol (60 mL) and treated with potassium carbonate (3.4 g, 2 equiv). The reaction mixture was stirred for 3 h and then filtered and evaporated. Flash Chromatography eluting with Cyclohexane:EtOAc (9/1) afforded 1.896 g (54%) of the title compound. .sup.1H-NMR (CDCl.sub.3, 400 MHz): 7.51-7.468 (m, 2H), 7.45-7.38 (m, 1H), 3.18-2.96 (m, 3H), 2.16-2.11 (m, 1H) ppm. .sup.19F-NMR (CDCl.sub.3, 376 MHz): 79.02 ppm.

Step B: 5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-dihydrofuran-3-one

(31) ##STR00105##

(32) 5-Bromo-1-oxy-nicotinic acid methyl ester (3.00 g, 1.5 equiv) (prepared according to AstraZeneca SB; AstraZeneca UK Ltd Patent WO2005/26149), triflimide (2.66 g, 1.1 equiv) and Ph.sub.3PAuNTf.sub.2 (338 mg, 2.5 mol %) were added in this order to a solution of 2-(3,5-Dichloro-phenyl)-1,1,1-trifluoro-pent-4-yn-2-ol (2.44 g, 8.6 mmol) in 1,2-dichloroethane (86 mL) under argon. The reaction mixture was left to stir at rt overnight. It was then concentrated in vacuo. Column chromatography eluting with cyclohexane:ethyl acetate (92/8) afforded 952 mg of the expected compound (37%).

(33) .sup.1H-NMR (CDCl.sub.3, 400 MHz): 7.46-7.40 (m, 3H), 4.37 (d, 1H), 4.24 (d, 1H), 3.26 (d, 1H), 2.87 (d, 1H) ppm. .sup.19F-NMR (CDCl.sub.3, 376 MHz): 79.42 ppm.

Step C: 4-[5-(3,5-Dichloro-phenyl)-3-hydroxy-5-trifluoromethyl-tetrahydro-furan-3-yl]-2-methyl-benzoic acid tert-butyl ester

(34) ##STR00106##

(35) To a solution of 4-Bromo-2-methyl-benzoic acid tert-butyl ester (234 mg, 1.2 equiv) under argon at 100 C. in tetrahydrofuran (2.6 mL) was added n-BuLi (0.62 mL, 1.2 equiv) dropwise over 5 min. The reaction mixture was left to stir for 20 min at 100 C. A solution of 5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-dihydrofuran-3-one (215 mg, 0.72 mmol) in 1.0 mL tetrahydrofurane was then added dropwise. It was stirred at this temperature for one hour. The reaction mixture was quenched with water and extracted with ethyl acetate. The combined organic extracts were then washed with brine, dried (Na.sub.2SO.sub.4) and evaporated. Column chromatography eluting with cyclohexane:ethyl acetate (9/1) afforded 62 mg (17%) of the expected compound.

(36) .sup.1H-NMR (CDCl.sub.3, 400 MHz): 7.77 (d, 1H), 7.52-7.32 (m, 3H), 7.22 (s, 1H), 7.15 (dd, 1H), 4.26 (d, 1H), 4.00 (d, 1H), 3.16 (dd, 1H), 2.95 (s, 1H), 2.81 (d, 1H), 2.54 (s, 3H), 1.58 (bs, 9H) ppm.

Step D: 4-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-furan-3-yl]-2-methylbenzoic acid tert-butyl ester

(37) ##STR00107##

(38) A solution of 4-[5-(3,5-Dichloro-phenyl)-3-hydroxy-5-trifluoromethyl-tetrahydro-furan-3-yl]-2-methyl-benzoic acid tert-butyl ester (62 mg, 0.12 mmol) in dichloromethane (1.2 mL) under argon at 78 C. was treated with thionyl chloride (26 L, 3 equiv) followed by triethylamine (0.13 mL, 7.5 equiv). The reaction mixture was stirred at 78 C. until complete consumption of starting material. It was quenched with water and extracted with EtOAc. The combined organic extracts were then washed with brine, dried (Na.sub.2SO.sub.4) and evaporated. Column chromatography eluting with cyclohexane:ethyl acetate (95/5) afforded a mixture of the title compound and its isomer in a 3:2 ratio.

Step D: 4-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-furan-3-yl]-2-ethylbenzoic acid tert-butyl ester

(39) A solution of trimethylsilyldiazomethane (0.74 mL, 2.0 M in Et2O, 2.2 equiv) in dimethoxyethane (4 mL) under argon at 78 C. was treated with MeLi (0.92 mL, 1.6 M in Et.sub.2O, 2.2 equiv). After 15 min at 78 C., a solution of 4-[3-(3,5-dichlorophenyl)-4,4,4-trifluoro-3-hydroxybutyryl]-2-methylbenzoic acid tert-butyl ester (321 mg, 0.67 mmol) in dimethoxyethane (2+0.7 mL) was added to the reaction mixture, which was stirred at 78 C. for one hour and then warmed up to room temperature. It was left to stir at this temperature for 2 h. It was then quenched by addition of AcOH (85 L, 2.2 equiv) and a 1M solution of TBAF in THF was added (2 mL, 3 equiv). The reaction mixture was left to stir overnight. It was quenched by addition of water and extracted with ethyl acetate. The combined organic layers were dried (Na.sub.2SO.sub.4) and evaporated. Flash Chromatography eluting with cyclohexane:ethyl acetate (98/2) afforded 85 mg of the title compound (27%) as a light yellow oil which solidifies upon standing.

(40) .sup.1H-NMR (CDCl.sub.3, 400 MHz): 7.79 (d, 1H), 7.52-7.45 (m, 2H), 7.43-7.37 (m, 1H), 7.08 (dd, 1H), 7.05 (s, 1H), 7.01 (s, 1H), 3.74 (dd, 1H), 3.31 (dd, 1H), 2.56 (s, 3H), 1.60 (bs, 9H) ppm. .sup.19F-NMR (CDCl.sub.3, 376 MHz): 80.85 ppm.

Step E: 4-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-furan-3-yl]-2-methyl-benzoic acid

(41) ##STR00108##

(42) A solution of 4-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-furan-3-yl]-2-methyl-benzoic acid tert-butyl ester (35 mg, 0.074 mmol) in dichloromethane (0.4 mL) at room temperature was treated with trifluoroacetic acid (0.055 mL, 10 equiv). The reaction mixture was stirred for 6 hours. The volatiles were removed in vacuo. Flash Chromatography eluting with cyclohexane:ethyl acetate (7/3) afforded 23 mg of the title compound (74%).

(43) .sup.1H-NMR (CDCl.sub.3, 400 MHz): 8.03 (d, 1H), 7.52-7.46 (m, 2H), 7.45-7.39 (m, 1H), 7.16 (dd, 1H), 7.11 (s, 1H), 7.08 (s, 1H), 3.77 (dd, 1H), 3.33 (dd, 1H), 2.65 (s, 3H) ppm. .sup.19F-NMR (CDCl.sub.3, 376 MHz): 80.82 ppm.

Step F: 4-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-furan-3-yl]-N-(1,1-dioxo-1lambda*6*-thietan-3-yl)-2-methyl-benzamide

(44) ##STR00109##

(45) 4-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-furan-3-yl]-2-methyl-benzoic acid (23 mg, 0.055 mmol) was dissolved in dichloromethane (0.6 mL), and oxalyl chloride (22 L, 5 equiv) was added. One drop of dimethylforamide was added as a catalyst, and the reaction mixture was stirred at room temperature for 18 hours. Volatiles were evaporated to give the expected acid chloride. The residue was dissolved in dichloromethane. Triethylamine (17 L, 2.2 equiv) followed by the trifluoroacetate salt of 1,1-Dioxo-1lambda*6*-thietan-3-ylamine (14 mg, 1.05 equiv) were added. The reaction mixture was then stirred at room temperature for 5 hours. The reaction was quenched by adding water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried (Na.sub.2SO.sub.4) and evaporated. Flash Chromatography eluting with cyclohexane:ethyl acetate (7/3) afforded the title compound.

(46) .sup.1H-NMR (CDCl.sub.3, 400 MHz): 7.51-7.47 (m, 2H), 7.42 (t, 1H), 7.36 (d, 1H), 7.13-7.07 (m, 2H), 7.03-6.98 (m, 1H), 6.46 (d, 1H), 4.94-4.74 (m, 1H), 4.63-4.58 (m, 2H), 4.07-3.98 (m, 2H), 3.74 (dd, 1H) 3.31 (dd, 1H), 2.46 (s, 3H) ppm. .sup.19F-NMR (CDCl.sub.3, 376 MHz): 80.87 ppm. m.p.=211-213 C.

Example P10: 4-(3,5-Dichloro-phenyl)-5,5,5-trifluoro-4-hydroxy-pent-2-ynoic acid methyl ester

(47) ##STR00110##

Step A

(48) To a solution of 4-(3,5-Dichloro-phenyl)-5,5,5-trifluoro-pent-2-yne-1,4-diol (1.8 g) in acetone (90 mL) at 0 C. was slowly added a solution of Jones' reagent (9 mL), under argon. The solution became brown and after 90 minutes, more Jone's reagent (0.8 mL) was added at 0 C. The solution was stirred for another 4 hours then it was diluted with water. The mixture was extracted with ethyl acetate, washed with a solution of sodium metabisulfite, dried over magnesium sulphate and concentrated to give 4-(3,5-Dichloro-phenyl)-5,5,5-trifluoro-4-hydroxy-pent-2-ynoic acid (1.839 g) as a colorless oil. .sup.19F-NMR (CDCl.sub.3, 376 MHz): 79.61 ppm.

Step B

(49) To a stirring solution of 4-(3,5-Dichloro-phenyl)-5,5,5-trifluoro-4-hydroxy-pent-2-ynoic acid (1.345 g) in toluene/MeOH (27 and 9 mL) under argon at 0 C. was slowly added a solution of TMSCHN2 (3.3 mL, 2M in hexane). The reaction was exothermic and some gas evolution was observed. The solution was stirred for 4 hours at 0 C then acetic acid (2 mL) was added. The solvent was then evaporated in vacuo to give a crude residue. The residue was purified by chromatography on silica gel (eluent:heptane/ethyl acetate 1:0 to 8:2) to give 4-(3,5-Dichloro-phenyl)-5,5,5-trifluoro-4-hydroxy-pent-2-ynoic acid methyl ester (1.2 g) as a white solid. .sup.1H-NMR (CDCl.sub.3, 400 MHz): 7.60 (m, 2H), 7.46 (s, 1H), 3.87 (s, 3H) ppm.

Example P11: 2-Methyl-4-(boronic acid)-benzoic acid tert-butyl ester

Steps 1 and 2

(50) ##STR00111##

Step A

(51) To a solution of 4-Bromo-2-methyl-benzoic acid tert-butyl ester (5 g) in DMF (70 mL) then 4,4,5,5,4,4,5,5-Octamethyl-[2,2]bi[[1,3,2]dioxaborolanyl] (4.68 g), potassium acetate (5.43 g) and palladium acetate (124 mg) were successfully added. The reaction mixture was stirred at room temperature for 2 days then more palladium acetate (124 mg) was added and the mixture was stirred at 80 C. After 6 hours, more palladium acetate (124 mg) was added and the reaction mixture was stirred at 80 C. for 18 hours. Then 4,4,5,5,4,4,5,5-Octamethyl-[2,2]bi[[1,3,2]dioxaborolanyl] (2.35 g), potassium acetate (2.7 g) and palladium acetate (124 mg) were added again to the reaction mixture. After stirring at 80 C. for 6 hours, more palladium acetate (250 mg) was added and the reaction mixture was stirred at 80 C. for 18 hours. The reaction mixture was then allowed to cool to room temperature and was diluted with ethyl acetate. The organic layer was washed with brine and HCl 1 N. It was then dried over magnesium sulfate, filtered, and concentrated in vacuo to give a crude residue that was used as such in the following step.

Step B

(52) To a solution of 2-Methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoic acid tert-butyl ester (1.6 g) in water/acetone (16/32 mL) at room temperature, was added ammonium acetate (1.02 g) then sodium periodate (3.1 g). The reaction was stirred at rt for 5 hours then was diluted with ethyl acetate and 1 N HCl solution. The aqueous solution was extracted with ethyl acetate. The combine organic solutions were dried with sodium sulfate, filtered, and concentrated in vacuo. The crude residue was purified by chromatography on silica gel (eluent:heptane\ethyl acetate, 1:1) to give 2-Methyl-4-(boronic acid)-benzoic acid tert-butyl ester (750 mg) as a white solid. .sup.1H-NMR (CDCl.sub.3, 400 MHz): 7.82 (d, J=7.70 Hz, 1H), 7.59-7.57 (m, 2H), 2.59 (s, 3H), 1.60 (s, 9H) ppm.

Example P12: 4-[5-(3,5-Dichloro-phenyl)-2-oxo-5-trifluoromethyl-2,5-dihydro-furan-3-yl]-2-methyl-benzoic acid tert-butyl ester

(53) ##STR00112##

(54) To a solution of 4-(3,5-Dichloro-phenyl)-5,5,5-trifluoro-4-hydroxy-pent-2-ynoic acid methyl ester (690 mg) and 2-Methyl-4-(boronic acid)-benzoic acid tert-butyl ester (750 mg) in 1,4-dioxane (10 mL) under argon, was successively added acetic acid (0.01 mL), palladium acetate (16 mg) and tri(tert-butyl)phosphine (0.03 mL). The reaction was refluxed under argon for 1 hour then stirred at room temperature for 18 hours. Then more palladium acetate (17 mg), tri(tert-butyl)phosphine (0.03 mL) and acetic acid (0.04 mL) were added. The reaction was refluxed for 4 hours then more palladium acetate (20 mg) was added. A Tricyclohexylphosphine solution (0.18 mL, 20 wt. % in toluene) was added and the solution was refluxed for 45 min. More 2-Methyl-4-(boronic acid)-benzoic acid tert-butyl ester (200 mg) was then added and the reaction was stirred at room temperature for 18 hours. It was then refluxed for 2 hours and then allowed to cool to room temperature. The reaction was concentrated under vacuo. The crude residue was purified by chromatography on silica gel (eluent:heptanes\dichloromethane, 7:3) to give 4-[5-(3,5-Dichloro-phenyl)-2-oxo-5-trifluoromethyl-2,5-dihydro-furan-3-yl]-2-methyl-benzoic acid tert-butyl ester (499 mg) as an colorless oil. .sup.1H-NMR (CDCl.sub.3, 400 MHz): 7.89 (d, J=8.07 Hz, 1H), 7.80 (s, 1H), 7.76 (m, 2H), 7.54 (m, 2H), 7.49 (m, 1H), 2.62 (s, 3H), 1.61 (s, 9H).

Example P13: 4-[5-(3,5-Dichloro-phenyl)-2-oxo-5-trifluoromethyl-2,5-dihydro-furan-3-yl]-2-methyl-benzoic acid methyl ester

(55) ##STR00113##

(56) To a solution of 4-(3,5-Dichloro-phenyl)-5,5,5-trifluoro-4-hydroxy-pent-2-ynoic acid methyl ester (200 mg) and tributylamine (0.49 mL) in DMF (1.2 mL) under argon, was successively added 4-Iodo-2-methyl-benzoic acid methyl ester (404 mg), palladium acetate (14 mg), Tri(o-tolyl)phosphine (36 mg). After 30 min, formic acid (0.06 mL) was added. The reaction was stirred under argon then heated at 70 C for one hour. The reaction was quenched by addition of water and EtOAc. The mixture was extracted with diethyl ether, water, dried over magnesium sulfate, filtered and concentrated under vacuo. The crude residue was purified by chromatography on silica gel (eluent:heptanes\diethyl ether, 7:3) to give 4-[5-(3,5-Dichloro-phenyl)-2-oxo-5-trifluoromethyl-2,5-dihydro-furan-3-yl]-2-methyl-benzoic acid methyl ester (84 mg) as an orange oil. .sup.1H-NMR (CDCl.sub.3, 400 MHz): 7.99 (d, J=8.80 Hz, 1H), 7.83 (s, 1H), 7.76 (m, 2H), 7.54 (m, 2H), 7.49 (m, 1H), 3.93 (s, 3H), 2.66 (s, 3H) ppm.

Example P14: Preparation of 2-Chloro-6-iodo-nicotinic acid methyl ester

(57) ##STR00114##

Step A

(58) 2-(Dimethylamino)-ethanol (20.5 mL) was dissolved in Hexane (150 mL) and the solution was stirred under argon and cooled to 5 C. n-Butyl Lithium (184 mL, 2.5 M in hexanes) was added dropwise at 5 C. and further stirred at 0 C. for 45 min. The solution was then cooled to 75 C. and a solution of 2-Chloro-3-methyl-pyridine (9.78 g) in hexane (150 mL) was added dropwise. The orange solution was stirred at 75 C. for two hours then a solution of iodine (78 g) in tetrahydrofuran (540 mL) was added dropwise at 75 C. After stirring for 2 hours, the solution was allowed to warm slowly at room temperature and stirred over night. The reaction mixture was then cooled to 0 C. and 50 ml water was added dropwise added. The solution was then extracted with diethyl ether. The organic layers were combined, dried over magnesium sulfate, filtered and concentrated under vacuo. The crude residue was purified by chromatography on silica gel (eluent:heptane\dichloromethane, 3:1) to give 2-Chloro-6-iodo-3-methyl-pyridine (16 g) as a brown solid. .sup.1H-NMR (CDCl.sub.3, 400 MHz): 7.53 (d, J=7.70 Hz, 1H), 7.19 (d, J=7.34 Hz, 1H), 2.33 (s, 3H) ppm.

Step B

(59) 2-Chloro-6-iodo-3-methyl-pyridine (12 g) was suspended in water (250 mL) then potassium permanganate (18 g) was added. The solution was refluxed for 18 hours then the mixture was cooled to room temperature and filtered through Hyflo. The mixture was extracted with methyl tert-butyl ether. The aqueous layer was then acidified with HCl 1M to pH 2 and extracted with ethyl acetate. The organic layers were combined, dried over magnesium sulfate, filtered and concentrated to give 2-Chloro-6-iodo-nicotinic acid (4.32 g) as a white solid. .sup.1H-NMR (CD.sub.3OD, 400 MHz): 7.91 (d, J=7.70 Hz, 1H), 7.87 (d, J=8.07 Hz, 1H) ppm.

Step C

(60) 2-Chloro-6-iodo-nicotinic acid (3 g) was suspended in dichloromethane (40 ml). A catalytic amount of N,N-dimethylformamide (DMF) and oxalyl chloride (1.1 ml) were added to the suspension. The reaction mixture was stirred at ambient temperature for 1.5 hours then methanol (2 mL) was added. The reaction mixture was stirred for 30 minutes than water was added to the reaction. The mixture was extracted with methyl tert-butyl ether. The organic extract was washed with brine, dried over sodium sulfate and concentrated to give 2-Chloro-6-iodo-nicotinic acid methyl ester (3.1 g) as a brown solid. .sup.1H-NMR (CDCl.sub.3, 400 MHz): 7.78 (m, 2H), 3.96 (s, 3H) ppm.

Example P15: 5-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-2,5-dihydro-furan-3-yl]-2-fluoro-benzonitrile

(61) ##STR00115##

(62) To a solution of Tributyl-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-2,5-dihydro-furan-3-yl]-stannane (300 mg) in N,N-dimethylformamide (12 mL) under argon was successively added 2-Fluoro-5-iodo-benzonitrile (630 mg), copper iodide (20 mg) and then tetrakis(triphenylphosphine) palladium (42 mg). The reaction was heated at 100 C under argon for 20 hours. The reaction was allowed to cool down to room temperature then water was added and the mixture was extracted with ethyl acetate. The organic extract was washed with water, dried over sodium sulfate and concentrated in vacuo to give a residue which was purified by chromatography on silica gel (eluent:heptanes\dichloromethane, 2:1) to give 5-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-2,5-dihydro-furan-3-yl]-2-fluoro-benzonitrile (182 mg) as a brown solid.

(63) .sup.1H-NMR (CDCl.sub.3, 400 MHz): 7.65-7.63 (m, 2H), 7.47 (m, 2H), 7.40 (m, 1H), 7.29 (m, 1H), 6.40 (bs, 1H), 5.30 (dd, J=2.2 and 12.8 Hz, 1H), 5.17 (m, 1H) ppm. .sup.19F-NMR (CDCl.sub.3, 376 MHz): 78.11 and 104.17 ppm.

(64) Similarly, 2-Chloro-6-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-2,5-dihydro-furan-3-yl]-nicotinic acid methyl ester could be prepared using 2-Chloro-6-iodo-nicotinic acid methyl ester as a coupling partner. .sup.1H-NMR (CDCl.sub.3, 400 MHz): 8.21 (d, 1H, J=8.07 Hz), 7.49 (m, 2H), 7.39-7.37 (m, 2H), 6.82 (m, 1H), 5.40 (dd, J=2.57 and 13.2 Hz, 1H), 5.28 (m, 1H), 3.97 (s, 3H) ppm. .sup.19F-NMR (CDCl.sub.3, 376 MHz): 77.87 ppm

(65) Similarly, 6-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-2,5-dihydro-furan-3-yl]-2-methyl-nicotinic acid ethyl ester could be prepared using 6-Bromo-2-methyl-nicotinic acid ethyl ester as a coupling partner. .sup.1H-NMR (CDCl.sub.3, 400 MHz): 8.21 (d, 1H, J=8.07 Hz), 7.50 (m, 2H), 7.38 (m, 1H), 7.31 (m, 1H), 6.73 (m, 1H), 5.42 (dd, J=2.57 and 13.2 Hz, 1H), 5.30 (m, 1H), 4.39 (q, J=6.97 Hz, 2H), 2.82 (s, 3H), 1.42 (t, J=6.97 Hz, 3H) ppm. .sup.19F-NMR (CDCl.sub.3, 376 MHz): 77.94 ppm

(66) Similarly, 4-(3-Chloro-4-methyl-phenyl)-2-(3,5-dichloro-phenyl)-2-trifluoromethyl-2,5-dihydro-furan could be prepared using 2-Chloro-4-iodo-1-methyl-benzene as a coupling partner. .sup.1H-NMR (CDCl.sub.3, 400 MHz): 7.48 (m, 2H), 7.37 (m, 2H), 7.25 (m, 1H), 7.16 (m, 1H), 6.31 (m, 1H), 5.28 (dd, J=2.57 and 12.47 Hz, 1H), 5.16 (m, 1H), 2.40 (s, 3H) ppm. .sup.19F-NMR (CDCl.sub.3, 376 MHz): 78.19 ppm.

(67) Similarly, 5-Bromo-2-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-2,5-dihydro-furan-3-yl]-4-methyl-pyridine could be prepared using 5-Bromo-2-iodo-4-methyl-pyridine as a coupling partner. .sup.1H-NMR (CDCl.sub.3, 400 MHz): 8.61 (s, 1H), 7.49 (m, 2H), 7.38 (m, 1H), 7.32 (m, 1H), 6.64 (m, 1H), 5.38 (dd, J=2.20 and 13.2 Hz, 1H), 5.27 (m, 1H), 2.43 (s, 3H) ppm. .sup.19F-NMR (CDCl.sub.3, 376 MHz): 78.07 ppm

(68) Similarly, 6-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-2,5-dihydro-furan-3-yl]-nicotinic acid methyl ester could be prepared using 6-Bromo-nicotinic acid methyl ester as a coupling partner. .sup.1H-NMR (CDCl.sub.3, 400 MHz): 9.18 (m, 1H), 8.31 (m, 1H), 7.54 (m, 1H), 7.50 (m, 2H), 7.38 (m, 1H), 6.78 (m, 1H), 5.45 (dd, J=2.20 and 13.2 Hz, 1H), 5.32 (m, 1H), 3.98 (s, 3H) ppm. .sup.19F-NMR (CDCl.sub.3, 376 MHz): 77.94 ppm

Example P16: (Compound G1 from Table G): 5-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-2,5-dihydro-furan-3-yl]-2-[1,2,4]-triazol-1-yl-benzonitrile

(69) ##STR00116##

(70) To a solution of 5-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-2,5-dihydro-furan-3-yl]-2-fluoro-benzonitrile (82 mg) in acetonitrile (3 mL) was successively added potassium carbonate (62 mg) and 1H-[1,2,4]Triazole (40 mg). The reaction was heated at 80 C for 5 hours. The reaction was allowed to cool down to room temperature then the suspension was filtered. The filtrate was concentrated under vacuo to give a residue which was purified by chromatography on silica gel (eluent:ethyl acetate\dichloromethane, 4:1) to give 5-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-2,5-dihydro-furan-3-yl]-2-[1,2,4]triazol-1-yl-benzonitrile (74 mg) as a white foam.

(71) .sup.1H-NMR (CDCl.sub.3, 400 MHz): 8.86 (bs, 1H), 8.22 (bs, 1H), 7.88 (d, J=8.44 Hz, 1H), 7.82 (bs, 1H), 7.77 (m, 1H), 7.49 (s, 2H), 7.41 (m, 1H), 6.54 (bs, 1H), 5.37 (dd, J=2.2 and 12.8 Hz, 1H), 5.24 (d, J=12.4 Hz, 1H) ppm. .sup.19F-NMR (CDCl.sub.3, 376 MHz): 78.00 ppm.

(72) Similarly, 2-(4-Bromo-pyrazol-1-yl)-5-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-2,5-dihydro-furan-3-yl]-benzonitrile (compound G2 from Table G) was obtained using 4-Bromo-1H-pyrazole as a nucleophile. .sup.1H-NMR (CDCl.sub.3, 400 MHz): 8.86 (bs, 1H), 8.22 (bs, 1H), 7.88 (d, J=8.44 Hz, 1H), 7.82 (bs, 1H), 7.77 (m, 1H), 7.49 (s, 2H), 7.41 (m, 1H), 6.54 (bs, 1H), 5.37 (dd, J=2.2 and 12.8 Hz, 1H), 5.24 (d, J=12.4 Hz, 1H) ppm. .sup.19F-NMR (CDCl.sub.3, 376 MHz): 78.03 ppm.

Example P17: 2-Chloro-6-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-2,5-dihydro-furan-3-yl]-nicotinic acid

(73) ##STR00117##

(74) To a solution of 2-Chloro-6-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-2,5-dihydro-furan-3-yl]-nicotinic acid methyl ester (280 mg) in tetrahydrofuran/water (1.4 mL of each) was added lithium hydroxyde (30 mg). The reaction mixture was stirred at room temperature for 24 hours. The solution was then diluted by addition of water and extracted with methyl tert-butyl ether. The aqueous extract was acidified with a solution of hydrochloric acid (1M) and extracted with dichloromethane. All the organic phases were gathered, dried over sodium sulfate and concentrated in vacuo to give 4-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-2,5-dihydro-furan-3-yl]-2-methyl-benzoic acid (190 mg) as a white foam.

(75) .sup.1H-NMR (CDCl.sub.3, 400 MHz): 8.37 (d, J=8.08 Hz, 1H), 7.50 (m, 2H), 7.44 (d, J=8.07 Hz, 1H), 7.39 (t, J=1.4 Hz, 1H), 6.87 (m, 1H), 5.42 (dd, J=2.2 and 13.2 Hz, 1H), 5.29 (m, 1H) ppm.

(76) Similarly, 6-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-2,5-dihydro-furan-3-yl]-2-methyl-nicotinic acid was obtained from the hydrolysis of 6-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-2,5-dihydro-furan-3-yl]-2-methyl-nicotinic acid ethyl ester. .sup.19F-NMR (CDCl.sub.3, 376 MHz): 77.91 ppm.

(77) Similarly, 6-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-2,5-dihydro-furan-3-yl]-nicotinic acid was obtained from the hydrolysis of 6-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-2,5-dihydro-furan-3-yl]-nicotinic acid methyl ester. .sup.19F-NMR (CDCl.sub.3, 376 MHz): 77.92 ppm.

(78) Similarly, 4-[5-(3,5-Dichloro-phenyl)-2-oxo-5-trifluoromethyl-2,5-dihydro-furan-3-yl]-2-methyl-benzoic acid was obtained from the hydrolysis of 4-[5-(3,5-Dichloro-phenyl)-2-oxo-5-trifluoromethyl-2,5-dihydro-furan-3-yl]-2-methyl-benzoic acid methyl ester. .sup.19F-NMR (CDCl.sub.3, 376 MHz): 76.42 ppm.

(79) LC/MS Method A

(80) TABLE-US-00003 MS ACQUITY SQD Mass Spectrometer from Waters (Single quadrupole mass spectrometer) Ionisation method: Electrospray Polarity: positive ions Capillary (kV) 3.00, Cone (V) 20.00, Extractor (V) 3.00, Source Temperature ( C.) 150, Desolvation Temperature ( C.) 400, Cone Gas Flow (L/Hr) 60, Desolvation Gas Flow (L/Hr) 700 Mass range: 100 to 800 Da DAD Wavelength range (nm): 210 to 400 LC Method Waters ACQUITY UPLC with the following HPLC gradient conditions (Solvent A: Water/Methanol 9:1, 0.1% formic acid and Solvent B: Acetonitrile, 0.1% formic acid) Time (minutes) A (%) B (%) Flow rate (ml/min) 0 100 0 0.75 2.5 0 100 0.75 2.8 0 100 0.75 3.0 100 0 0.75 Type of column: Waters ACQUITY UPLC HSS T3; Column length: 30 mm; Internal diameter of column: 2.1 mm; Particle Size: 1.8 micron; Temperature: 60 C.
LC/MS: Method B

(81) TABLE-US-00004 MS ZQ Mass Spectrometer from Waters (single quadrupole mass spectrometer), ionization method: electrospray, polarity: negative ionization, capillary (kV) 3.00, cone (V) 45.00, source temperature ( C.) 100, desolvation temperature ( C.) 250, cone gas flow (L/Hr) 50, desolvation gas flow (L/Hr) 400, mass range: 150 to 1000 Da. LC HP 1100 HPLC from Agilent: solvent degasser, binary pump, heated column compartment and diode-array detector. Column: Phenomenex Gemini C18, length (mm) 30, internal diameter (mm) 3, particle size (m) 3, temperature ( C.) 60, DAD wavelength range (nm): 200 to 500, solvent gradient: A = 0.05% v/v formic acid in water and B = 0.04% v/v formic acid in acetonitrile/methanol (4:1). Time (min) A % B % Flow (ml/min) 0.0 95 5.0 1.7 2.0 0.0 100 1.7 2.8 0.0 100 1.7 2.9 95 5.0 1.7 3.1 95 5 1.7

(82) TABLE-US-00005 TABLE A (I-a) Comp No. R.sup.1 R.sup.2 RT (min) MH.sup.+ Method A1 H (2,2,2-Trifluoro-ethylcarbamoyl)-methyl 1.96 555 A A2 H Thietan-3-yl 2.09 488 A A3 H 2,2,2-Trifluoro-ethyl 2.10 498 A A4 H Ethyl 2.02 444 A A5 H n-Butyl 2.18 472 A A6 H 2-Methoxy-1-methyl-ethyl 2.05 488 A A7 H (Tetrahydro-furan-2-yl)-methyl 2.04 500 A A8 H Benzyl 2.18 506 A A9 H 2-Fluoro-benzyl 2.19 524 A A10 H 4-Methoxy-benzyl 2.16 536 A A11 H 4-Methyl-thiazol-2-yl 2.20 513 A A12 H 3-Methyl-thietan-3-yl 2.19 502 A A13 H 1-Oxo-thietan-3-yl 1.81 504 A A14 H Cyclobutyl 2.14 470 A A15 H 1,1-Dioxo-thietan-3-yl 1.91 520 A A16 H (S)-2-ethyl-isoxazolidin-3-one-4-yl 2.11 527/529 (M H.sup.+) B A17 H (1-Methyl-1H-imidazol-4-yl)-methyl 1.98 510 A A18 H (1H-Benzoimidazol-2-yl)-methyl 1.66 546 A A19 H 3-Bromo-propyl 2.07 536 A A20 H 3,3,3-Trifluoro-propyl 2.09 512 A A21 H Dihydro-thiophen-2-one-3-yl 2.01 516 A A22 H 6-Ethoxycarbonyl-cyclohex-3-enyl 2.24 568 A A23 H 2-Benzo 2.14 564 A A24 H 2-Benzylsulfanyl-ethyl 2.26 566 A A25 H 4-Methanesulfonyl-benzyl 1.95 584 A A26 H N,N-Dimethylamino-ethyl 1.49 487 A A27 H sec-Butyl 2.13 472 A A28 H Butan-1-ol-2-yl 1.90 488 A A29 H 2,2-Difluoro-ethyl 2.01 480 A A30 H 1-Ethynyl-cyclohexyl 2.26 522 A A31 H 2-[1,3]Dioxolan-2-yl-ethyl 1.97 516 A A32 H 2-Methyl-cyclohexyl 2.29 512 A A33 H 2-Morpholin-4-yl-ethyl 1.44 529 A A34 H 3-Pyrrolidin-1-yl-propyl 1.47 527 A A35 H (Pyrid-3-yl)-methyl 1.67 507 A A36 H 3-Piperidin-1-yl-propyl 1.50 541 A A37 H [3-(4-Chloro-phenyl)-isoxazol-5-yl]- methyl 2.27 607 A A38 H 1-Phenyl-ethyl 2.19 520 A A39 H Phenethyl 2.19 520 A A40 H 1,2,2,6,6-Pentamethyl-piperidin-4-yl 1.54 569 A A41 H 2-Thiophen-2-yl-ethyl 2.17 526 A A42 H 2-Phenoxy-ethyl 2.18 536 A A43 H 3-Chloro-benzyl 2.23 540 A A44 H (2,3-Dihydro-benzo[1,4]dioxin-6-yl)- methyl 2.10 564 A A45 H 2-Acetylamino-ethyl 1.77 501 A A46 H 4-Pyrazol-1-yl-benzyl 2.10 572 A A47 H 2-(1H-Indol-3-yl)-ethyl 2.12 559 A A48 H 2-Trifluoromethyl-benzyl 2.26 574 A A49 H 2-Methylsulfanyl-ethyl 2.06 490 A A50 H 2-Piperidin-1-yl-benzyl 1.95 589 A A51 H 4-Phenoxy-benzyl 2.33 598 A A52 H (6-Chloro-pyridin-3-yl)-methyl 2.06 541 A A53 H 1-Benzyl-pyrrolidin-3-yl 1.62 575 A A54 H 2-(4-Benzyl-piperazin-1-yl)-ethyl 1.61 618 A A55 H Furan-2-yl-methyl 2.06 496 A A56 H 2-Chloro-phenyl 2.32 526 A A57 H Quinolin-5-yl 1.95 543 A A58 H 2,4-Dimethoxy-phenyl 2.24 552 A A59 H 3-Fluoro-phenyl 2.23 510 A A60 H 1H-Indazol-5-yl 1.96 532 A A61 H 4-Pyrrol-1-yl-phenyl 2.29 557 A A62 H 4-Piperidin-1-yl-phenyl 1.86 575 A A63 H 2-Methylsulfanyl-phenyl 2.33 538 A A64 H Benzothiazol-6-yl 2.13 549 A A65 H 4-Methyl-2-oxo-2H-chromen-7-yl 2.16 574 A A66 H 4-Dimethylsulfamoyl-phenyl 2.14 599 A A67 H 2,5-Dimethyl-2H-pyrazol-3-yl 1.98 510 A A68 H 5-Methylsulfanyl-1H-[1,2,4]triazol-3-yl 2.15 529 A A69 H 4-Hydroxy-6-methyl-pyrimidin-2-yl 1.94 524 A A70 H Quinolin-2-yl 2.30 543 A A71 H 5-Methyl-3-phenyl-isoxazol-4-yl 2.17 573 A A72 H 9H-Purin-6-yl 1.84 534 A A73 H 5-Acetyl-4-methyl-thiazol-2-yl 2.17 555 A A74 H 4-Methyl-benzothiazol-2-yl 2.42 563 A A75 H 5-Methyl-[1,3,4]thiadiazol-2-yl 2.05 514 A A76 H 4,6-Dimethyl-2H-pyrazolo[3,4-b]pyridin- 1.98 561 A 3-yl A77 H 1-Oxo-thietan-3-yl 1.78 504 A A78 H Thietan-3-yl-methyl 2.07 502 A A79 H 3-(2,2,2-Trifluoro-ethoxyimino)- cyclobutyl 2.14 581 A A80 H Thietan-2-yl-methyl 2.09 502 A A81 H (1,1-Dioxo-thietan-2-yl)-methyl 1.88 534 A A82 H 2-Thietan-3-yl-ethyl 2.12 516 A A83 H 2-(1,1-Dioxo-thietan-3-yl)-ethyl 1.87 548 A A84 H 3-Oxo-2-(2,2,2-trifluoro-ethyl)- 2.03 583 A isoxazolidin-4-yl A85 H H See NMR See NMR See NMR A86 H See NMR See NMR See NMR

(83) TABLE-US-00006 TABLE B (I-b) 0 Comp RT Meth- No. R.sup.1 R.sup.2 (min) MH.sup.+ od B1 H 2,2,2-Trifluoro-ethyl 1.99 485 A B2 H Ethyl 1.87 431 A B3 H n-Butyl 2.05 459 A B4 H 2-Methoxy-1-methyl-ethyl 1.91 475 A B5 H (2,2,2-Trifluoro-ethylcarbamoyl)-methyl 1.82 542 A B6 H 3,3,3-Trifluoro-propyl 2.00 499 A B7 H sec-Butyl 2.03 459 A B8 H (Tetrahydro-furan-2-yl)-methyl 1.89 487 A B9 H Benzyl 2.06 493 A B10 H 2-Fluoro-benzyl 2.07 511 A B11 H 1-Phenyl-ethyl 2.10 507 A B12 H 4-Methoxy-benzyl 2.04 523 A B13 H 1,1-Dioxo-thietan-3-yl 1.77 507 A B14 H (6-Chloro-pyrid-3-yl)-methyl 1.96 528 A B15 H 3-Fluoro-phenyl 2.15 497 A B16 H (Pyrid-2-yl)-methyl 1.72 494 A B17 H 2,5-Dimethyl-2H-pyrazol-3-yl 1.87 497 A B18 H 4-Methyl-thiazol-2-yl 2.07 500 A B19 H 3-Methyl-thietan-3-yl 2.05 489 A B20 H 1,1-Dimethyl-2-methylsulfanyl-ethyl 2.14 505 A B21 H Thietan-3-yl 1.96 475 A B22 H Bicyclo[2.2.1]hept-2-yl 2.17 497 A B23 H Cyclobutyl 2.00 457 A B24 H 1-Oxo-thietan-3-yl 1.69 491 A

(84) TABLE-US-00007 TABLE C (I-c) Comp RT Meth- No. R.sup.1 R.sup.2 (min) MH.sup.+ od C1 H 2,2,2-Trifluoro-ethyl 2.07 499 A C2 H Ethyl 1.94 445 A C3 H n-Butyl 2.12 473 A C4 H 2-Methoxy-1-methyl-ethyl 1.99 489 A C5 H (2,2,2-Trifluoro-ethylcarbamoyl)-methyl 1.90 556 A C6 H 3,3,3-Trifluoro-propyl 2.07 513 A C7 H sec-Butyl 2.10 473 A C8 H (Tetrahydro-furan-2-yl)-methyl 1.97 501 A C9 H Benzyl 2.13 507 A C10 H 2-Fluoro-benzyl 2.14 525 A C11 H 1-Phenyl-ethyl 2.17 521 A C12 H 4-Methoxy-benzyl 2.10 537 A C13 H 1,1-Dioxo-thietan-3-yl 1.85 521 A C14 H (6-Chloro-pyrid-3-yl)-methyl 2.04 542 A C15 H 3-Fluoro-phenyl 2.22 511 A C16 H 2,5-Dimethyl-2H-pyrazol-3-yl 1.96 511 A C17 H 3-Methyl-thietan-3-yl 2.12 503 A C18 H 1,1-Dimethyl-2-methylsulfanyl-ethyl 2.21 519 A C19 H Thietan-3-yl 2.03 489 A C20 H Bicyclo[2.2.1]hept-2-yl 2.23 511 A C21 H Cyclobutyl 2.06 471 A C22 H 1-Oxo-thietan-3-yl 1.76 505 A

(85) TABLE-US-00008 TABLE D (I-d) Comp RT Meth- No. R.sup.1 R.sup.2 (min) MH.sup.+ od D1 H 2,2,2-Trifluoro-ethyl 2.10 498 A D2 H Ethyl 1.99 444 A D3 H n-Butyl 2.16 472 A D4 H 2-Methoxy-1-methyl-ethyl 2.04 488 A D5 H (2,2,2-Trifluoro-ethylcarbamoyl)-methyl 1.95 555 A D6 H 3,3,3-Trifluoro-propyl 2.10 512 A D7 H sec-Butyl 2.15 472 A D8 H (Tetrahydro-furan-2-yl)-methyl 2.02 500 A D9 H Benzyl 2.16 506 A D10 H 2-Fluoro-benzyl 2.17 524 A D11 H 1-Phenyl-ethyl 2.21 520 A D12 H 4-Methoxy-benzyl 2.14 536 A D13 H (6-Chloro-pyrid-3-yl)-methyl 2.07 541 A D14 H 3-Fluoro-phenyl 2.29 510 A D15 H (Pyrid-2-yl)-methyl 1.85 507 A D16 H 2,5-Dimethyl-2H-pyrazol-3-yl 1.99 510 A D17 H 4-Methyl-thiazol-2-yl 2.19 513 A D18 H 3-Methyl-thietan-3-yl 2.16 502 A D19 H 1,1-Dimethyl-2-methylsulfanyl-ethyl 2.27 518 A D20 H 1-Oxo-thietan-3-yl 1.80 504 A D21 H Thietan-3-yl 2.07 488 A D22 H Bicyclo[2.2.1]hept-2-yl 2.29 510 A D23 H Cyclobutyl 2.11 470 A D24 H 1,1-Dioxo-thietan-3-yl 1.90 520 A

(86) TABLE-US-00009 TABLE E (I-e) Comp RT Meth- No. R.sup.1 R.sup.2 (min) MH.sup.+ od E1 H 2,2,2-Trifluoro-ethyl 2.01 512 A E2 H Ethyl 1.91 458 A E3 H n-Butyl 2.07 486 A E4 H 2-Methoxy-1-methyl-ethyl 1.96 502 A E5 H (2,2,2-Trifluoro-ethylcarbamoyl)-methyl 1.88 569 A E6 H 3,3,3-Trifluoro-propyl 2.03 526 A E7 H (Tetrahydro-furan-2-yl)-methyl 1.93 514 A E8 H Benzyl 2.10 520 A E9 H 2-Fluoro-benzyl 2.11 538 A E10 H 1-Phenyl-ethyl 2.15 534 A E11 H 4-Methoxy-benzyl 2.06 550 A E12 H (6-Chloro-pyrid-3-yl)-methyl 2.00 555 A E13 H (Pyrid-2-yl)-methyl 1.78 521 A E14 H 2,5-Dimethyl-2H-pyrazol-3-yl 1.92 524 A E15 H 4-Methyl-thiazol-2-yl 2.10 527 A E16 H 3-Methyl-thietan-3-yl 2.10 516 A E17 H Thietan-3-yl 2.02 502 A E18 H Cyclobutyl 2.04 484 A E19 H 1-Oxo-thietan-3-yl 1.73 518 A

(87) TABLE-US-00010 TABLE F (I-f) Comp No. R.sup.1 R.sup.2 RT (min) MH.sup.+ Method F1 H (2,2,2-Trifluoro-ethylcarbamoyl)-methyl See NMR See NMR See NMR F2 H 1,1-Dioxo-thietan-3-yl See NMR See NMR See NMR

(88) TABLE-US-00011 TABLE G (I-g) Comp No. R.sup.1 Het RT (min) MH.sup.+ Method G1 CN [1,2,4]triazol-1-yl See NMR See NMR See NMR G2 CN 4-Bromo-pyrazol-1-yl See NMR See NMR See NMR

Biological Examples

(89) Spodoptera littoralis (Systemic) (Egyptian Cotton Leaf Worm)

(90) Test compounds were applied by pipette into 24 well plates and mixed with agar. Salad seeds were placed on the agar and the multi well plate is closed by another plate which contains also agar. After 7 days the roots have absorbed the compound and the salad has grown into the lid plate. The salad leafs were now cut off into the lid plate. Spodoptera eggs were pipette through a plastic stencil on a humid gel blotting paper and the plate closed with it. The samples are checked for mortality, repellent effect, feeding behavior, and growth regulation 5 days after infestation. Application rate: 12.5 ppm

(91) The following compound gave at least 80% control of Spodoptera littoralis: A1, A2, A13, A15, A16, C5, C13, A77, D24, F1, D1, D24, D5, D8, D15, D20, D21

(92) Spodoptera littoralis (Egyptian Cotton Leafworm):

(93) Cotton leaf discs were placed on agar in a 24-well microtiter plate and sprayed with test solutions at an application rate of 200 ppm. After drying, the leaf discs were infested with 5 L1 larvae. The samples were checked for mortality, feeding behavior, and growth regulation 3 days after treatment (DAT).

(94) The following compound gave at least 80% control of Spodoptera littoralis: A1, A2, A3, A4, A5, A6, A7, A8, A9, A10, A11, A12, A13, A14, A15, A16, C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C17, C18, C19, C20, C21, C22, A86, G1, G2, A17, A19, A20, A21, A25, A26, A27, A28, A29, A31, A35, A38, A42, A43, A44, A49, A52, A53, A55, A57, A59, A60, A64, A67, A72, A77, A78, A79, A80, A81, A82, A83, A84, D24, F1, D1, D24, D3, D4, D5, D6, D7, D8, D9, D10, D11, D12, D13, D14, D15, D16, D17, D18, D19, D20, D21, D23, F2, E5, E6, E8, E13, E15, E19.

(95) Heliothis virescens (Tobacco Budworm):

(96) Eggs (0-24 h old) were placed in 24-well microtiter plate on artificial diet and treated with test solutions at an application rate of 200 ppm (concentration in well 18 ppm) by pipetting. After an incubation period of 4 days, samples were checked for egg mortality, larval mortality, and growth regulation.

(97) The following compound gave at least 80% control of Heliothis virescens: A1, A2, A3, A4, A5, A6, A7, A8, A9, A10, A11, A12, A13, A14, A15, A16, B5, B14, C1, C3, C5, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C20, C21, C22, A86, G1, A17, A18, A19, A20, A21, A25, A27, A29, A35, A38, A39, A42, A44, A46, A49, A52, A54, A55, A56, A57, A58, A59, A60, A64, A66, A67, A69, A77, A78, A79, A80, A81, A82, A83, A84, D24, F1, D1, D24, D3, D4, D5, D6, D7, D8, D9, D10, D11, D12, D13, D14, D15, D16, D17, D18, D19, D20, D21, D23, F2, E5.

(98) Plutella xylostella (Diamond Back Moth):

(99) 24-well microtiter plate (MTP) with artificial diet was treated with test solutions at an application rate of 200 ppm (concentration in well 18 ppm) by pipetting. After drying, the MTPs were infested with L2 larvae (7-12 per well). After an incubation period of 6 days, samples were checked for larval mortality and growth regulation.

(100) The following compound gave at least 80% control of Plutella xylostella: A1, A2, A3, A4, A5, A6, A7, A8, A9, A10, A11, A12, A13, A14, A15, A16, B1, B7, B8, B9, B23, C1, C2, C3, C5, C6, C7, C9, C10, C11, C12, C13, C14, C15, C16, C17, C19, C20, C21, C22, A86, G1, A17, A18, A19, A20, A21, A25, A27, A29, A30, A31, A32, A35, A38, A39, A41, A44, A46, A49, A52, A55, A56, A57, A58, A59, A60, A63, A64, A67, A69, A77, A78, A79, A80, A81, A82, A83, A84, D24, F1, D1, D24, D3, D4, D5, D6, D7, D8, D9, D10, D11, D12, D13, D14, D15, D16, D17, D18, D19, D20, D21, D22, D23, F2, E3, E5, E6, E9, E11, E13.

(101) Diabrotica balteata (Corn Root Worm):

(102) A 24-well microtiter plate (MTP) with artificial diet was treated with test solutions at an application rate of 200 ppm (concentration in well 18 ppm) by pipetting. After drying, the MTPs were infested with L2 larvae (6-10 per well). After an incubation period of 5 days, samples were checked for larval mortality and growth regulation.

(103) The following compound gave at least 80% control of Diabrotica balteata: A1, A2, A3, A4, A5, A6, A7, A8, A9, A10, A11, A12, A13, A14, A15, A16, B2, B6, B12, B19, C1, C2, C3, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C17, C18, C19, C20, C21, C22, A86, G1, A17, A18, A19, A20, A21, A25, A27, A29, A30, A31, A32, A35, A38, A39, A41, A42, A43, A44, A46, A48, A49, A50, A52, A53, A54, A55, A56, A57, A58, A59, A60, A61, A63, A64, A65, A66, A67, A69, A75, A77, A78, A79, A80, A81, A82, A83, A84, D24, F1, D1, D24, D3, D4, D5, D6, D7, D8, D9, D10, D11, D12, D13, D14, D15, D16, D17, D18, D19, D20, D21, D22, D23, E5, E13, E15, E17.

(104) Myzus persicae (Sachet) (Green Peach Aphid) Mixed Population

(105) Test compounds were applied by pipette into 24 well plates and mixed with Sucrose solution. The plates were closed with a stretched Parafilm. A plastic stencil with 24 holes is placed onto the plate and infested pea seedlings were placed directly on the Parafilm. The infested plate is closed with a gel blotting paper and another plastic stencil and then turned upside down. 5 days after infestation the samples were checked on mortality. Application rate: 12.5 ppm.

(106) The following compounds gave at least 80% control of Myzus persicae: A1, A2, A8, A13, A15, A16, C5, C13, C22, A25, A77, A78, A82, A83, A84, D24, F1, D24, D3, D4, D5, D6, D7, D8, D9, D10, D11, D12, D13, D14, D15, D16, D17, D18, D19, D20, D21, D23.

(107) Thrips tabaci (Onion Thrips):

(108) Sunflower leaf discs were placed on agar in a 24-well microtiter plate and sprayed with test solutions at an application rate of 200 ppm. After drying, the leaf discs were infested with an aphid population of mixed ages. After an incubation period of 7 days, samples were checked for mortality.

(109) The following compounds gave at least 80% control of Thrips tabaci: A1, A2, A4, A5, A6, A7, A12, A13, A14, A15, A16, C2, C4, C5, C7, C13, C17, C19, C20, C21, C22, A86, A17, A19, A20, A27, A29, A30, A31, A59, A77, A78, A79, A82, A84, D24, F1, D1, D24, D3, D4, D5, D6, D8, D9, D10, D11, D12, D14, D15, D16, D18, D20, D21, D22, D23, E18.

(110) Tetranychus urticae (Two-Spotted Spider Mite):

(111) Bean leaf discs on agar in 24-well microtiter plates were sprayed with test solutions at an application rate of 200 ppm. After drying, the leaf discs are infested with mite populations of mixed ages. 8 days later, discs are checked for egg mortality, larval mortality, and adult mortality.

(112) The following compound gave at least 80% control of Tetranychus urticae: A1, A2, A3, A4, A5, A6, A7, A8, A9, A10, A11, A12, A13, A14, A15, A16, B9, C2, C5, C13, C14, C17, C19, C22, A86, A17, A18, A19, A20, A25, A27, A28, A29, A30, A31, A35, A38, A40, A43, A45, A46, A49, A52, A56, A57, A58, A63, A77, A78, A79, A80, A81, A82, A83, A84, D24, F1, D24, D3, D4, D5, D6, D8, D9, D10, D11, D12, D13, D14, D15, D18, D19, D20, D21, D23, F2, E5, E16.