EP0934283A2 - Arthropodicidal and fungicidal cyclic amides - Google Patents

Arthropodicidal and fungicidal cyclic amides

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Publication number
EP0934283A2
EP0934283A2 EP97936152A EP97936152A EP0934283A2 EP 0934283 A2 EP0934283 A2 EP 0934283A2 EP 97936152 A EP97936152 A EP 97936152A EP 97936152 A EP97936152 A EP 97936152A EP 0934283 A2 EP0934283 A2 EP 0934283A2
Authority
EP
European Patent Office
Prior art keywords
alkyl
optionally substituted
chr
phenyl
haloalkyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP97936152A
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German (de)
English (en)
French (fr)
Inventor
Richard James Brown
Dominic Ming-Tak Chan
David Alan Clark
Joseph Eugene Drumm, Iii
Gerard Michael Koether
Stephen Frederick Mccann
Morris Padgett Rorer
Thomas Paul Selby
Michael Paul Walker
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
EIDP Inc
Original Assignee
EI Du Pont de Nemours and Co
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Application filed by EI Du Pont de Nemours and Co filed Critical EI Du Pont de Nemours and Co
Publication of EP0934283A2 publication Critical patent/EP0934283A2/en
Withdrawn legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/64—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with three nitrogen atoms as the only ring hetero atoms
    • A01N43/647—Triazoles; Hydrogenated triazoles
    • A01N43/653—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/72—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms
    • A01N43/74—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms five-membered rings with one nitrogen atom and either one oxygen atom or one sulfur atom in positions 1,3
    • A01N43/78—1,3-Thiazoles; Hydrogenated 1,3-thiazoles
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/72—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms
    • A01N43/80—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms five-membered rings with one nitrogen atom and either one oxygen atom or one sulfur atom in positions 1,2
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/72—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms
    • A01N43/82—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms five-membered rings with three ring hetero atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • C07D249/10—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D249/12—Oxygen or sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
    • C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
    • C07D261/06—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members
    • C07D261/10—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D261/12—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/0803—Compounds with Si-C or Si-Si linkages
    • C07F7/081—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te
    • C07F7/0812—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te comprising a heterocyclic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
    • C07F7/1804—Compounds having Si-O-C linkages

Definitions

  • This invention relates to certain cyclic amides, their N-oxides, agriculturally suitable salts and compositions, and methods of their use as fungicides and arthropodicides.
  • the control of plant diseases caused by fungal plant pathogens is extremely important in achieving high crop efficiency. Plant disease damage to ornamental, vegetable, field, cereal, and fruit crops can cause significant reduction in productivity and thereby result in increased costs to the consumers.
  • the control of arthropod pests is also extremely important in achieving high crop efficiency. Arthropod damage to growing and stored agronomic crops can cause significant reduction in productivity and thereby result in increased costs to the consumer.
  • the control of arthropod pests in forestry, greenhouse crops, ornamentals, nursery crops, stored food and fiber products, livestock, household, and public and animal health is also important. Many products are commercially available for these purposes, but the need continues for new compounds which are more effective, less costly, less toxic, environmentally safer or have different modes of action.
  • This invention is directed to compounds of Formula I including all geometric and stereoisomers, N-oxides, and agriculturally suitable salts thereof, agricultural compositions containing them and their use as fungicides and arthropodicides:
  • E is selected from: i) 1,2-phenylene optionally substituted with one of R 3 , R 4 , or both R 3 and
  • A is O; S; N; NR 5 ; or CR 14 ;
  • G is C or N; provided that when G is C, then A is O, S or NR 5 and the floating double bond is attached to G; and when G is N, then A is N or CR 14 and the floating double bond is attached to A; W is O; S; NH; N(C,-C 6 alkyl); or NO(C r C 6 alkyl);
  • X is OR 1 ; S-OJ r nR 1 ; or halogen;
  • R 1 is C,-C 6 alkyl; C r C 6 haloalkyl; C 2 -C 6 alkenyl; C 2 -C 6 haloalkenyl; C 2 -C 6 alkynyl; C 2 -C6 haloalkynyl; C 3 -Cg cycloalkyl; C 2 -C alkylcarbonyl; or C2-C 4 alkoxy carbonyl;
  • R 2 is H; C r C 6 alkyl; C r C 6 haloalkyl; C 2 -C 6 alkenyl; C 2 -C 6 haloalkenyl; C 2 -C 6 alkynyl; C 2 -C 6 haloalkynyl; C 3 -C 6 cycloalkyl; C 2 -C 4 alkylcarbonyl; C 2 -C 4 alkoxycarbonyl; hydroxy; C J -C2 alkoxy; or acetyloxy;
  • R 3 and R 4 are each independently halogen; cyano; nitro; hydroxy; Ci-Cg alkyl; C,-C 6 haloalkyl; C 2 -C 6 alkenyl; C 2 -C 6 haloalkenyl; C 2 -C 6 alkynyl; C 2 -C 6 haloalkynyl; C]-C 6 alkoxy; C C 6 haloalkoxy; C 2 -C 6 alkenyloxy; C 2 -C, alkynyloxy; Cj-C 6 alkylthio; Ct-C ⁇ alkylsulfmyl; Ct-Cg alkylsulfonyl; formyl; C 2 -Cg alkylcarbonyl; C2-Cg alkoxycarbonyl; NH 2 C(O); (C,-C 4 alkyl)NHC(O (C r C 4 alkyl) 2 NC(O); Si(R 25 ) 3 ; Ge(R
  • -CR 6 CR 6 -; -C ⁇ C-; -CHR 15 O- ; -OCHR 15 -; -CHR 15 S(O) n -;
  • a 2 is O; NR 15 ; or a direct bond;
  • Z 2 is selected from: i) C j -Cio alkyl, C2-C10 alkenyl and C2-C10 alkynyl, each optionally substituted with one or more R ' ° ; ii) C -Cg cycloalkyl, C 3 -Cg cycloalkenyl and phenyl, each optionally substituted with one or more R 10 ; iii) a ring system selected from 3 to 14-membered monocyclic, fused bicyclic and fused tricyclic nonaromatic heterocyclic ring systems and 5 to 14-membered monocyclic, fused bicyclic and fused tricyclic aromatic heterocyclic ring systems, each heterocyclic ring system containing 1 to 6 heteroatoms independently selected from the group nitrogen, oxygen, and sulfur,
  • each R 7 is independently H; C1-C6 alkyl; C Cg haloalkyl; Ct- alkoxy; C Cg haloalkoxy; Ci-Cg alkylthio; Ci-Cg alkylsulfinyl; Ci-Cg alkylsulfonyl; C r C 6 haloalkylthio; Cj-Cg haloalkylsulfinyl; Ci-Cs haloalkylsulfonyl; C 2 -C 6 alkenyl; C 2 -C 6 haloalkenyl; C 2 -C 6 alkynyl; C 2 -C 6 haloalkynyl;
  • C 3 -Cg cycloalkyl C 2 -C 4 alkylcarbonyl; C 2 -C 4 alkoxycarbonyl; halogen; cyano; nitro; hydroxy; amino; NH(C ⁇ -C£ alkyl); N(C j -Cg alkyl)2; or mo ⁇ holinyl;
  • Z is selected from: i) C -C 8 cycloalkyl, C -Cg cycloalkenyl and phenyl, each substituted with
  • R 9 and optionally substituted with one or more R 10 ii) a ring system selected from 3 to 14-membered monocyclic, fused bicyclic and fused tricyclic nonaromatic heterocyclic ring systems and 5 to 14-membered monocyclic, fused bicyclic and fused tricyclic aromatic heterocyclic ring systems, each heterocyclic ring system containing 1 to 6 heteroatoms independently selected from the group nitrogen, oxygen, and sulfur, provided that each heterocyclic ring system contains no more than 4 nitrogens, no more than 2 oxygens, and no more than 2 sulfurs, each nonaromatic or aromatic heterocyclic ring system substituted with R 9 and optionally substituted with one or more R l ° ; iii) a multicyclic ring system selected from 8 to 14-membered fused-bicyclic and fused-tricyclic ring systems which are an aromatic carbocyclic ring system, a nonaromatic carbocyclic ring system, or a ring system containing
  • R 9 is benzyloxy, benzyloxymethyl, phenylethynyl, phenoxy methyl, phenylthio, phenylsulfonyl, benzylthio, pyridinylmethyl, pyridinylmethyloxy, pyridinyloxymethyl, pyridinylethynyl, pyridinylthio, thienylmethyl, thienylthio, furanylmethyl, furanyloxy, furanylthio, pyrimidinylmethyl or pyrimidinylthio, each optionally substituted on the aromatic ring with one of R 1 ', R 12 , or both R 1 1 and R 12 ; or R 9 is C 2 -C 6 alkyl or C 2 -C alkoxy substituted with 1 -2 phenyl, naphthalenyl, phenoxy, benzyloxy, pyridin
  • R 7 and said adjacently attached R 10 can be taken together as -(CH 2 ) r J- such that J is attached to Z; J is -CH 2 -; -CH 2 CH 2 -; -OCH 2 -; -CH 2 O-; -SCH 2 -; -CH 2 S-; -N(R 1 «)CH 2 s or -CH 2 N(R 16 )-; each CH group of said J optionally substituted with 1 to 2
  • Z 3 is phenyl, naphthalenyl, lH-pyrrolyl, furanyl, thienyl, lH-pyrazolyl, lH-imidazolyl, isoxazolyl, oxazolyl, isothiazolyl, thiazolyl, lH-l,2,3-triazolyl, 2H-l,2,3-triazolyl, lH-l,2,4-triazolyl, 4H-l,2,4-triazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1 ,2.5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1 ,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, lH-tetrazolyl, 2H-tetrazolyl, pyridinyl,
  • R 16 , R 17 , and R 18 are each independently H; C,-C 3 alkyl; C 3 -C 6 cycloalkyl; or phenyl optionally substituted with halogen, C r C 4 alkyl, C r C 4 haloalkyl, C1-C4 alkoxy, C--C 4 haloalkoxy, nitro or cyano;
  • R 19 , R 20 , R 21 , R 22 , and R 23 are each independently C,-C 6 alkyl; C r C 4 haloalkyl; C2-C6 alkenyl; CpC alkoxy; or phenyl;
  • R 24 is C,-C 4 haloalkyl; each R 25 is independently C r C 4 alkyl; C r C 4 haloalkyl; C 2 -C 4 alkenyl; C r C 4 alkoxy; or phenyl; each R 26 is independently H; C r C 6 alkyl; C,-C 6 haloalkyl; C 2 -C 6 alkenyl; C 2 -C 6 haloalkenyl; C 2 -C 6 alkynyl; C 2 -C 6 haloalkynyl; C 3 -C 6 cycloalkyl; or phenyl or benzyl, each optionally substituted on the phenyl ring with 1-2 groups independently selected from halogen, Cj-C 4 alkyl, Cj-C haloalkyl, C j -C 4 alkoxy, C t -C 4 haloalkoxy, nitro and cyano; each R 27 is independently Ci-
  • R 29 is H; C,-C 6 alkyl; C r C 6 haloalkyl; C 2 -C 6 alkenyl; C 2 -C 6 haloalkenyl; C 2 -C 6 alkynyl; C 2 -C 6 haloalkynyl; C -C $ cycloalkyl; or benzyl optionally substituted on the phenyl ring with 1 -2 groups independently selected from halogen, C C alkyl, Cj-C 4 haloalkyl, C C 4 alkoxy, Cj-C 4 haloalkoxy, nitro and cyano;
  • alkyl used either alone or in compound words such as “alkylthio” or “haloalkyl” includes straight-chain or branched alkyl, such as, methyl, ethyl, «-propyl, /-propyl, or the different butyl, pentyl or hexyl isomers.
  • 1-2 CH indicates that the substituent can be methyl or, when there is a hydrogen attached to the same atom, the substituent and said hydrogen can both be methyl.
  • 1-2 alkyl indicates that one or two of the available positions for that substituent may be alkyl which are independently selected.
  • Alkenyl includes straight-chain or branched alkenes such as vinyl, 1-propenyl, 2-propenyl, and the different butenyl, pentenyl and hexenyl isomers. "Alkenyl” also includes polyenes such as 1,2-propadienyl and 2,4-hexadienyl. "Alkynyl” includes straight-chain or branched alkynes such as ethynyl, 1-propynyl, 2-propynyl and the different butynyl, pentynyl and hexynyl isomers.
  • Alkynyl can also include moieties comprised of multiple triple bonds such as 2,5-hexadiynyl.
  • Alkylene denotes a straight-chain (or branched when indicated) alkanediyl. Examples of “alkylene” include CH 2 CH 2 , CH(CH 3 ), CH 2 CH 2 CH 2 , CH 2 CH(CH 3 ), CH 2 CH2CH2CH2 and CH 2 CH 2 CH 2 CH 2 CH 2 .
  • Alkoxy includes, for example, methoxy, ethoxy,
  • alkoxyalkyl denotes alkoxy substitution on alkyl. Examples of “alkoxyalkyl” include CH 3 OCH 2 , CH 3 OCH 2 CH 2 , CH 3 CH 2 OCH 2 ,
  • Alkoxyalkoxy denotes alkoxy substitution on alkoxy.
  • Alkynyloxy includes straight-chain or branched alkynyloxy moieties.
  • Alkylthio includes branched or straight-chain alkylthio moieties such as methylthio, ethylthio, and the different propylthio, butylthio, pentylthio and hexylthio isomers.
  • Alkylthioalkyl denotes alkylthio substitution on alkyl. Examples of “alkylthioalkyl” include CH 3 SCH 2 , CH 3 SCH 2 CH 2 , CH 3 CH 2 SCH 2 , CH 3 CH 2 CH 2 CH 2 SCH 2 and
  • Alkylthioalkylthio denotes alkylthio substitution on alkylthio.
  • alkoxyalkylthio denotes alkoxy substitution on alkylthio and “alkylthioalkoxy” denotes alkylthio substitution on alkoxy.
  • Alkylsulfinyl includes both enantiomers of an alkylsulfinyl group.
  • alkylsulfinyl examples include CH 3 S(O), CH 3 CH 2 S(O), CH 3 CH 2 CH 2 S(O), (CH 3 ) 2 CHS(O) and the different butylsulfinyl, pentylsulfinyl and hexylsulfinyl isomers.
  • alkylsulfonyl examples include CH 3 S(O) 2 , CH 3 CH 2 S(O) 2 , CH 3 CH 2 CH 2 S(O) 2 , (CH 3 ) 2 CHS(O) 2 and the different butylsulfonyl, pentylsulfonyl and hexylsulfonyl isomers.
  • Cyanoalkyl denotes an alkyl group substituted with one cyano group.
  • Examples of “cyanoalkyl” include NCCH 2 , NCCH 2 CH 2 and CH 3 CH(CN)CH 2 .
  • Alkenylthio "alkoxyalkynyl", and the like, are defined analogously to the above examples.
  • Cycloalkyl includes, for example, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
  • cycloalkoxy includes the same groups linked through an oxygen atom such as cyclopentyloxy and cyclohexyloxy.
  • Cycloalkenyl includes groups such as cyclopentenyl and cyclohexenyl as well as groups with more than one double bond such as 1,3- and 1,4-cyclohexadienyl.
  • Trialkylsilylalkoxyalkoxy denotes trialkylsilylalkoxy substitution on alkoxy. Examples of “trialkylsilylalkoxyalkoxy” includes, for example, (CH 3 ) 3 SiCH 2 CH 2 OCH 2 O.
  • the term “ 1 -2 phenyl” indicates that one or two of the available positions for that substituent may be phenyl.
  • aromatic carbocyclic ring system includes fully aromatic carbocycles and carbocycles in which at least one ring of a polycyclic ring system is aromatic (where aromatic indicates that the H ⁇ ckel rule is satisfied).
  • nonaromatic carbocyclic ring system denotes fully saturated carbocycles as well as partially or fully unsaturated carbocycles where the H ⁇ ckel rule is not satisfied by any of the rings in the ring system.
  • aromatic heterocyclic ring system includes fully aromatic heterocycles and heterocycles in which at least one ring of a polycyclic ring system is aromatic (where aromatic indicates that the H ⁇ ckel rule is satisfied).
  • nonaromatic heterocyclic ring system denotes fully saturated heterocycles as well as partially or fully unsaturated heterocycles where the H ⁇ ckel rule is not satisfied by any of the rings in the ring system.
  • the heterocyclic ring systems can be attached through any available carbon or nitrogen by replacement of a hydrogen on said carbon or nitrogen.
  • nitrogen containing heterocycles can form N-oxides since the nitrogen requires an available lone pair for oxidation to the oxide; one skilled in the art will recognize those nitrogen containing heterocycles which can form N-oxides.
  • tertiary amines can form N-oxides.
  • N-oxides of heterocycles and tertiary amines are very well known by one skilled in the art including the oxidation of heterocycles and tertiary amines with peroxy acids such as peracetic and w-chloroperbenzoic acid (MCPBA), hydrogen peroxide, alkyl hydroperoxides such as /-butyl hydroperoxide, sodium perborate, and dioxiranes such as dimethydioxirane.
  • MCPBA peroxy acids
  • alkyl hydroperoxides such as /-butyl hydroperoxide
  • sodium perborate sodium perborate
  • dioxiranes such as dimethydioxirane
  • halogen either alone or in compound words such as “haloalkyl”, includes fluorine, chlorine, bromine or iodine.
  • 1-2 halogen indicates that one or two of the available positions for that substituent may be halogen which are independently selected. Further, when used in compound words such as “haloalkyl", said alkyl may be partially or fully substituted with halogen atoms which may be the same or different. Examples of “haloalkyl” include F 3 C, C1CH 2 , CF 3 CH 2 and
  • haloalkynyl examples include HCsCCHCl, CF 3 CsC, CC1 3 C * ⁇ C and FCH 2 C * ECCH 2 .
  • haloalkoxy examples include CF 3 O, CCl 3 CH 2 O, HCF 2 CH 2 CH 2 O and CF 3 CH 2 O.
  • haloalkylthio include CC1 3 S, CF 3 S, CC1 3 CH 2 S and C1CH 2 CH 2 CH 2 S.
  • haloalkylsulfinyl include CF 3 S(O), CCl 3 S(O), CF 3 CH 2 S(O) and CF 3 CF 2 S(O).
  • haloalkylsulfonyl include CF 3 S(O) 2 , CCl 3 S(O) 2 , CF 3 CH 2 S(O) 2 and CF 3 CF 2 S(O) 2 .
  • the total number of carbon atoms in a substituent group is indicated by the
  • Cj-C j prefix where i and j are numbers from 1 to 10.
  • C ⁇ -C 3 alkylsulfonyl designates methylsulfonyl through propylsulfonyl.
  • alkylcarbonyl include C(O)CH 3 , C(O)CH 2 CH 2 CH 3 and C(O)CH(CH 3 ) 2 .
  • all substituents are attached to these rings through any available carbon or nitrogen by replacement of a hydrogen on said carbon or nitrogen.
  • Stereoisomers of this invention can exist as one or more stereoisomers.
  • the various stereoisomers include enantiomers, diastereomers, atropisomers and geometric isomers.
  • one stereoisomer may be more active and/or may exhibit beneficial effects when enriched relative to the other stereoisomer(s) or when separated from the other stereoisomers).
  • the skilled artisan knows how to separate, enrich, and/or to selectively prepare said stereoisomers.
  • the present invention comprises compounds selected from Formula I, N-oxides and agriculturally suitable salts thereof.
  • the compounds of the invention may be present as a mixture of stereoisomers, individual stereoisomers, or as an optically active form.
  • the salts of the compounds of the invention include acid-addition salts with inorganic or organic acids such as hydrobromic, hydrochloric, nitric, phosphoric, sulfuric, acetic, butyric, fumaric, lactic, maleic, malonic, oxalic, propionic, salicylic, tartaric, 4-toluenesulfonic or valeric acids.
  • inorganic or organic acids such as hydrobromic, hydrochloric, nitric, phosphoric, sulfuric, acetic, butyric, fumaric, lactic, maleic, malonic, oxalic, propionic, salicylic, tartaric, 4-toluenesulfonic or valeric acids.
  • the salts of the compounds of the invention also include those formed with organic bases (e.g., pyridine, ammoma, or "triemylamine) or inorganic bases (e.g., hydrides, hydroxides, or carbonates of sodium, potassium, lithium, calcium, magnesium or barium) when the compound contains an acidic group such as a phenol.
  • organic bases e.g., pyridine, ammoma, or "triemylamine
  • inorganic bases e.g., hydrides, hydroxides, or carbonates of sodium, potassium, lithium, calcium, magnesium or barium
  • Preferred compounds for reasons of better activity and/or ease of synthesis are: Preferred 1.
  • E is selected from the group 1,2-phenylene; 1,5-, 1,6-, 1,7-, 1,8-, 2,6-, 2,7-, 1 ,2-, and 2,3-naphthalenediyl; 1 H-pyrrole- 1 ,2-, 2,3- and
  • each aromatic ring system optionally substituted with one of R 3 , R 4 , or both R 3 and R 4 ;
  • W is O;
  • R 1 is C r C 3 alkyl or C r C 3 haloalkyl;
  • X is OR 1 ;
  • R 1 is C r C 3 alkyl;
  • R 2 is H or C 1 -C 2 alkyl;
  • Preferred 5 selected from the group: 4-[2-[[3-( 1 ,3-benzodioxol-5-yl)- 1 ,2,4-thiadiazol-5-yl]oxy]phenyl]-2,4-dihydro- 5-methoxy-2-methyl-3H- 1 ,2,4-triazol-3-one;
  • the compounds of Formula I can be prepared by one or more of the following methods and variations as described in Schemes 1-41.
  • the definitions of E, A, G, W, X, R ! -R 30 , Y, Z ! -Z 4 , W 1 , A ! -A 4 , Z, Q, J, m, n, p, r and s in the compounds of Formulae 1-94 below are as defined above in the Summary of the Invention.
  • Compounds of Formulae Ia-In are various subsets of the compounds of Formula I, and all substituents for Formulae Ia-In are as defined above for Formula I.
  • X' OH, SH, NH 2 NH(Ct-C 6 alkyl) o NH(C r C 6 alkoxy)
  • compounds of Formula I can also be prepared by contacting carbonyl compounds of Formula 1 with alkyl trichloroacetimidates of Formula 3 and a Lewis acid catalyst.
  • Suitable Lewis acids include trimethylsilyl triflate and tetrafluoroboric acid.
  • the alkyl trichloroacetimidates can be prepared from the appropriate alcohol and trichloroacetonitrile as described in the literature (J. Danklmaier and H. H ⁇ nig, Synth. Commun., (1990), 20, 203).
  • Compounds of Formula I can also be prepared from compounds of Formula 1 by treatment with a trialkyloxonium tetrafluoroborate (i.e., Meerwein's salt) of Formula 4 (Method 3).
  • a trialkyloxonium tetrafluoroborate i.e., Meerwein's salt
  • the use of trialkyloxonium salts as powerful alkylating agents is well known in the art (see U. Schollkopf, U. Groth, C. Deng, Angew. Chem., Int. Ed. Engl, (1981), 20, 798).
  • Appropriate bases include alkali metal alkoxides such as potassium terf-butoxide, inorganic bases such as sodium hydride and potassium carbonate, or tertiary amines such as triethylamine, pyridine, l,8-diazabicyclo[5.4.0]undec-7-ene (DBU), and triethylenediamine.
  • alkali metal alkoxides such as potassium terf-butoxide
  • inorganic bases such as sodium hydride and potassium carbonate
  • tertiary amines such as triethylamine, pyridine, l,8-diazabicyclo[5.4.0]undec-7-ene (DBU), and triethylenediamine.
  • the nucleophiles of Formula 6 are N-substituted hydroxylamines (HO- ⁇ HR 2 ) and substituted hydrazines (H ⁇ (R 5 )- ⁇ HR 2 ). Examples of such nucleophiles are N-methylhydroxylamine and methylhydrazine.
  • the malonate esters of Formula 5 can be prepared by methods described hereinafter.
  • Compounds of Formula laa can be prepared by reaction of nitrile esters of Formula 5b with ambident nucleophiles of Formula 6. See M. Scobie and G. Tennant, J. Chem. Soc, Chem. Comm., (1994), 2451. Alkylation of laa with alkyl halides in the presence of base provides compounds of Formula lab. Alternatively, treatment of laa with alkylamines or alkoxyamines provides compounds of Formula lab.
  • Esters of Formula 5a can be prepared from copper (I)-catalyzed reaction of malonate esters of Formula 7 with substituted aryl halides of Formula 8 according to methods adapted from A. Osuka, T. Kobayashi and H. Suzuki, Synthesis, (1983), 67 and M. S. Malamas, T. C. Hohman, and J. Millen, J. Med. Chem., 1994, 37, 2043-2058, and illustrated in Scheme 3. Procedures to prepare compounds of Formula 8 are described below (see Scheme 33).
  • Malonate esters of Formula 5a can also be prepared from diester carboxylic acids of Formula 5c after modification of the carboxylic acid functional group to the appropriate Y and Z group.
  • a copper (I)-catalyzed coupling of malonates of Formula 7 with orthobromocarboxylic acids of Formula 8a can be used to prepare compounds of Formula 5c as shown in Scheme 3.
  • Methods to prepare compounds of Formula 8a are common in the art (see P. Beak, V. Snieckus, Ace Chem. Res., (1982), 15, 306 and Org. React., (1979), 26, 1 and references therein).
  • malonate esters of Formula 5a can be prepared by treating aryl acetic acid esters of Formula 9 with a dialkyl carbonate or alkyl chloroformate in the presence of a suitable base such as, but not limited to, sodium metal or sodium hydride (Scheme 4).
  • a suitable base such as, but not limited to, sodium metal or sodium hydride (Scheme 4).
  • Nitrile esters of Formula 5b can be prepared similarly from compounds of Formula 10.
  • R C ] -C alkyl
  • Esters of Formula 9 can be prepared from acid-catalyzed alcoholysis of aryl acetonitriles of Formula 10 or esterification of aryl acetic acids of Formula 1 1 as illustrated in Scheme 5 (see Org. Synth. , Coll. Vol. I, ( 1941 ), 270).
  • R C ⁇ -C 4 alkyl
  • esters of Formula 9 can also be prepared by forming the Y 2 bridge using conventional nucleophilic substitution chemistry (Scheme 7).
  • Displacement of an appropriate leaving group (Lg) in electrophiles of Formula 15 or 16 with a nucleophilic ester of Formula 14 affords compounds of Formula 9b.
  • a base for example sodium hydride, is used to generate the corresponding alkoxide or thioalkoxide of the compound of Formula 14.
  • R C!-C alkyl
  • R 3 * OH, SH, CHR 15 OH, CHR 15 SH, NHR 15
  • Lg Br, O, L OS ⁇ 2CH 3 , OS ⁇ 2(4-Me-Ph)
  • esters of Formula 9 can also be prepared by forming the Y 3 bridge from substituted hydroxylamine 9d and carbonyl compounds 14a.
  • the hydroxylamine 9d is in turn prepared from esters 9c. This method has been described in EP-A-600,835 and illustrated in Scheme 8.
  • Compounds of Formula I can also be prepared by reaction of Formula 17 compounds with alkali metal alkoxides (R ⁇ 'M “1” ), alkali metal thioalkoxides (R'S-M” 1 "), or an amine derivative in a suitable solvent (Scheme 9).
  • the leaving group Lg 1 in the amides of Formula 17 are any group known in the art to undergo a displacement reaction of this type. Examples of suitable leaving groups include chlorine, bromine, and sulfonyl and sulfonate groups. Examples of suitable inert solvents are dimethylformamide or dimethyl sulfoxide, dimethoxyethane methanol.
  • L l Br, -S ⁇ 2V, or -OSC ⁇ V
  • V C j -Cg alky I, Cj-Cg haloalkyl, or 4-CH 3 -C 6 H 4
  • compounds of Formula 1 wherein X is OH by reaction with halogenating agents such as thionyl chloride or phosphorus oxybromide to form the corresponding ⁇ -halo-substituted derivatives (Scheme 10).
  • halogenating agents such as thionyl chloride or phosphorus oxybromide
  • compounds of Formula lb can be treated with an alkylsulfonyl halide or haloalkylsulfonyl anhydride, such as methanesulfonyl chloride, /7-toluenesulfonyl chloride, and trifluoromethanesulfonyl anhydride, to form the corresponding ⁇ -alkylsulfonate of Formula 17a.
  • the reaction with the sulfonyl halides may be performed in the presence of a suitable base (e.g., triethylamine).
  • Lg 2 CL Br, or-OS0 2 V
  • the diacyl compound of Formula 19 is treated with excess thionyl halide, for example excess thionyl chloride.
  • the product formed first is the ring-closed compound of Formula 20 which can be isolated or converted in situ to the compound of Formula 17c; see P. Molina, A. Tarraga, A. Espinosa, Synthesis, (1989), 923 for a description of this process.
  • the hydrazides of Formula 19 can be prepared as illustrated in Scheme 13. Condensation of the isocyanate of Formula 21 with the hydrazine of Formula H 2 NNR 2 R 32 in an inert solvent such as tetrahydrofuran affords the hydrazide.
  • etene dithioacetals of Formula 22a or 22b can be prepared by condensing aryl acetic esters of Formula 9 or amides of Formula 9f, respectively, with carbon disulfide in the presence of a suitable base, followed by reaction with two equivalents of an R ⁇ halide, such as iodomethane or propargyl bromide (Scheme 15). Conversion of 22b to 22c can be accomplished by reaction with trialkyl tetrafluoroborates.
  • T 4 - H Ci-Cg alkyl, C,-C 6 alkoxy
  • the compounds of Formula 24 can be alkyl chloroformates or dialkyl carbonates. Some of these carbonylating reactions may require the addition of a base to effect reaction.
  • Appropriate bases include alkali metal alkoxides such as potassium ter/-butoxide, inorganic bases such as sodium hydride and potassium carbonate, tertiary amines such as triemylamine and triethylenediamine, pyridine, or l,8-diazabicyclo[5.4.0]undec-7- ene (DBU).
  • Suitable solvents include polar aprotic solvents such as acetonitrile, dimethylformamide, or dimethyl sulfoxide; ethers such as tetrahydrofuran, dimethoxyethane, or diethyl ether; ketones such as acetone or 2-butanone; hydrocarbons such as toluene or benzene; or halocarbons such as dichloromethane or chloroform.
  • the reaction temperature can vary between 0°C and 150°C and the reaction time can be from 1 to 72 hours depending on the choice of base, solvent, temperature, and substrates.
  • T 1 and T 2 are independently CL, OCCl 3 , 0(C ⁇ -C alkyl), 1-imidazolyl, 1
  • a triazoryl X OH or SH X ⁇ Oor S
  • N-Amino-ureas of Formula 23 can be prepared as illustrated in Scheme 17.
  • Treatment of an arylamine of Formula 25 with phosgene, thiophosgene, N,N'-carbonyldiimidazole, or NN-thiocarbonyldiimidazole produces the isocyanate or isothiocyanate of Formula 26.
  • a base can be added for reactions with phosgene or thiophosgene.
  • Isocyanates of Formula 26 can also be prepared by heating acylazides of Formula 25a in a solvent such as toluene or benzene (Curtius rearrangement).
  • acylazides can be prepared from well known methods in the art (see March, J., Advanced Organic Chemistry; 3rd Edition, John Wiley: New York, (1985), pp 428, 637 and also Chem. Pharm. Bull (1977), 25, 165, and references therein. Subsequent treatment of the iso(thio)cyanate with an R 2 -substituted hydrazine produces the N-amino-urea of Formula 23.
  • Compounds of Formula le can be prepared by either method illustrated in Scheme 18.
  • Ureas of Formula 27 are reacted with activated 2-halocarboxylic acid derivatives such as 2-halocarboxylic acid chlorides, 2-halocarboxylic acid esters or 2-haloacyl imidazoles.
  • the initial acylation on the arylamino nitrogen is followed by an intramolecular displacement of the 2-halo group to effect cyclization.
  • Base may be added to accelerate the acylation and/or the subsequent cyclization. Suitable bases include triethylamine and sodium hydride.
  • Formula le compounds can be prepared by reaction of Formula 26 iso(thio)cyanates or Formula 26a carbodiimides with Formula 28a esters. As described above, base may be added to accelerate the reaction and subsequent cyclization to Formula le compounds.
  • Carbodiimides 26a can be prepared as shown in Scheme 18, starting with compounds of Formula 26.
  • T 5 C j -Cg alkyl, C j-Cg alkoxy
  • the (thio)ureas or amidines of Formula 27 can be prepared by either of the methods illustrated in Scheme 19.
  • an iso(thio)cyanate of Formula 26 or carbodiimide of Formula 26a can be condensed with an amine of Formula R 2 -NH 2 to form the urea or amidine.
  • the arylamine and iso(thio)cyanates of Formulae 25 and 26, respectively, are commercially available or prepared by well-known methods.
  • isothiocyanates can be prepared by methods described in J. Heterocycl. Chem., (1990), 27, 407.
  • Isocyanates can be prepared as described in March, J., Advanced Organic Chemistry; 3rd ed., John Wiley: New York, (1985), pp 944, 1166 and also in Synthetic Communications, (1993), 23 (3), 335 and references therein.
  • Method 19 For methods describing the preparation of arylamines of Formula 25 that are not commercially available, see M. S. Gibson in 77 ⁇ e Chemistry of the Amino Group; Patai, S., Ed.; Interscience Publishers, 1968; p 37 and Tetrahedron Lett. (1982), 23 (7), 699 and references therein.
  • T 5 C j-Cg alkyl, Cj-Cg alkoxy
  • thionating reagents such as P S 5 or Lawesson's reagent (2,4-bis(4-methoxyphenyl)-l,3-dithia-2,4- diphosphetane-2,4-disulfide) as illustrated in Scheme 20 (see Bull. Soc. Chim. Belg, (1978), 87, 229; and Tetrahedron Lett., (1983
  • R C j -C 4 alkyl
  • T 5 C 1 -C 6 aIkyL Ci-C 6 alko)y
  • the appropriate alcohol or thiol is treated with a base, for example sodium hydride, to form the corresponding alkoxide or thioalkoxide which acts as the nucleophile.
  • aryl halides of Formula 29 can be prepared by radical halogenation of the corresponding alkyl compound (i.e., H instead of halogen in Formula 29), or by acidic cleavage of the corresponding methyl ether (i.e., OMe instead of halogen in Formula 29).
  • Other aryl halides of Formula 29 can be prepared from the appropriate alcohols of Formula 30 by well known halogenation methods in the art (see Carey, F. A.; Sundberg, R. J. Advanced Organic Chemistry; 3rd ed., Part B, Plenum: New York, (1990), p 122).
  • the olefins of Formula lg can be converted to the saturated compounds of Formula Ih by hydrogenation over a metal catalyst such as palladium on carbon as is well-known in the art (Rylander, Catalytic Hydrogenation in Organic Synthesis; Academic: New York, 1979).
  • Formula Ii alkynes can be prepared by halogenation/dehalogenation of Formula lg olefins using procedures well-known in the art (March, J. Advanced Organic Chemistry; 3rd ed., John Wiley: New York, (1985), p 924). Additionally, Formula Ii alkynes can be prepared by well-known reaction of aryl halides with alkyne derivatives in the presence of catalysts such as nickel or palladium (see J. Organomet. Chem. , (1975), P5 253-257).
  • the olefin of Formula lg can also be prepared by reversing the reactivity of the reactants in the Wittig or Homer-Emmons condensation.
  • 2-alkylaryl derivatives of Formula 33 can be converted into the corresponding dibromo-compound of Formula 34 as illustrated in Scheme 23 (see Synthesis, (1988), 330).
  • the dibromo- compound can be hydrolyzed to the carbonyl compound of Formula 35, which in turn can be condensed with a phosphonjs-containing nucleophile of Formula 36 or 37 to afford the olefin of Formula lg.
  • compounds of Formula 35 can be prepared by oxidation of the corresponding alcohols of Formula 30.
  • Vinyl halides of Formula Ij can be prepared by reacting phosphorus reagents of Formulae 37a or 37b with carbonyl compounds of Formula 35 (Scheme 23).
  • the preparations of halides of Formula 37a from the appropriate diethylphosphonoacetate are described by McKenna and Khawli in J. Org. Chem., (1986), 51, 5467.
  • the thiono esters of Formula 37b can be prepared from esters of Formula 37a by converting the carbonyl oxygen of the ester to a thiocarbonyl (see Chem. Rev., (1984), 84, 17 and Tetrahedron Lett., (1984), 25, 2639).
  • Bror I Ik Carbamates of Formula II can be prepared by reacting aryl alcohols of Formula 30 with isocyanates of Formula 39 (Scheme 25). A base such as triethylamine can be added to catalyze the reaction. As shown, carbamates of Formula II can be f rther alkylated to provide the carbamates of Formula Im.
  • suitable bases for example, K 2 CO 3 , KO-/-Bu or NaH
  • suitable solvents for example, acetone, dimethylformamide, dimethyl sulfoxide or tetrahydrofuran
  • Compounds of Formula Lg-Z may be prepared according to literature procedures, for example, Comprehensive Heterocyclic Chemistry, Pergamon Press, vol. 6, 1984, pp 463-511 orJ. Org. Chem. (1973), 38, 469 or J. Het. Chem. (1979), 961 for the preparation of 1,2,4-thiadiazoles, U.S. 5,166,165 orJ Chem. Soc, Perkin Trans. 1 (1983), 967 for the preparation of 1 ,3,4-oxadiazoles and 1 ,3,4-thiadiazoles, EP 446,010 orJ. Med. Chem. (1992), 35, 3691 for the preparation of 1,2,4-oxadiazoles.
  • the compounds of the present invention are prepared by combinations of reactions as illustrated in the Schemes 1-26 in which Z is a moiety as described in the summary.
  • Preparation of the compounds containing the radical Z 5 [Z as described in the summary, substituted with L (defined as any group attached to Z as depicted in each of the individual schemes)] can be accomplished by one skilled in the art by the appropriate combination of reagents and reaction sequences for a particular Z 5 -L.
  • Such reaction sequences can be developed based on known reactions available in the chemical art. For a general reference, see March, J. Advanced Organic Chemistry; 3rd ed., John Wiley: New York, (1985) and references therein.
  • the organometallic compounds of Formula 46 may be prepared by reductive metallation or halogen-metal exchange of a halogen-containing compound of Formula 45 using, for example, magnesium or an organolithium reagent, or by deprotonation of compounds of Formula 43 using a strong base such as a lithioamide or an organolithium reagent, followed by transmetallation.
  • Compounds of Formula 45 may be prepared by reaction of compounds of Formula 43 (Scheme 29) with, for example, bromine or chlorine, with or without additional catalysts, under free-radical or aromatic electrophilic halogenation conditions, depending on the nature of Z.
  • Alternative sources of halogen such as N- halosuccinimides, tert-butyl hypohalites or SO 2 Cl 2 , may also be used. (See March, J.
  • Compounds of Formula 36 or 37 in Scheme 23 can be prepared by reaction of compounds of Formula 49 with triphenylphosphine or trialkyl phosphites, respectively, followed by deprotonation with base. See Cadogen, "Organophosphorus Reagents in Organic Synthesis," Academic Press, New York ( 1979) for a general treatise on these reagents.
  • Compounds of Formula 50 can be prepared from compounds of Formula 4 Id by treatment with peracids such as perbenzoic or peracetic acid, or with other peroxy compounds in the presence of an acid catalysts, followed by hydrolysis of the resultant ester (Scheme 30).
  • peracids such as perbenzoic or peracetic acid
  • acid catalysts such as sodium bicarbonate
  • Scheme 30 hydrolysis of the resultant ester
  • Compounds of Formula 54 can be prepared from compounds of Formula 50 by conversion to the dialkylthiocarbamates of Formula 52 followed by rearrangement to
  • R - C--C 4 alkyl
  • Compounds of Formula 55 can be converted to compounds of Formulae 45, 50 or 54 via the diazonium compounds 56, by treatment with nitrous acid followed by subsequent reaction (Scheme 31). See reviews by Hegarty , pt. 2, pp 511-91 and Schank, pt. 2, pp 645-657, in Patai, "The Chemistry of Diazonium and Diazo Groups," Wiley, New York (1978).
  • Treatment of Formula 56 compounds with cuprous halides or iodide ions yield compounds of Formula 45.
  • Treatment of Formula 56 compounds with cuprous oxide in the presence of excess cupric nitrate provides compounds of Formula 50. (Cohen, Dietz, and Miser, J. Org Chem., (1977), 42, 2053).
  • Treatment of Formula 56 compounds with (S 2 )" 2 yields compounds of Formula 54.
  • Treatment of Formula 56 compounds with SO 2 and CI 2 yields compounds of Formula 54a.
  • Compounds of Formula 55 can be prepared from compounds of Formula 43 by mtration, followed by reduction (Scheme 32).
  • a wide variety of nitrating agents is available (see Schofield, " Aromatic Nitration," Cambridge University Press, Cambridge (1980)). Reduction of nitro compounds can be accomplished in a number of ways (see March, J. Advanced Organic Chemistry; 3rd ed., John Wiley: New York, (1985), pp 1103-4 and references therein).
  • Iodides of Formula 8 can be prepared from compounds of Formula 60 by the methods described above in Schemes 21-26 for various Y-Z combinations.
  • Compounds of Formula 60 can in turn be prepared from compounds of Formula 59 by functional group interconversions which are well known to one skilled in the art.
  • the compounds of Formula 59 can be prepared by treating compounds of Formula 58 with an organolithium reagent such as n-BuLi or LDA followed by trapping the intermediate with iodine (Beak, P., Snieckus, V. Ace. Chem. Res., (1982), 15, 306).
  • T 7 CO2H, CONR 2 , CONHR,
  • Compounds of Formula 63 can be prepared by reacting compounds of formula 61 with acylating agents of Formula 62, with or without optional base.
  • Suitable alkylating agents are, for example, alkyl chloroformates, anhydrides, carbamoyl chlorides, or carbonylimidazoles.
  • compounds of Formula 61 can be reacted with compounds of Formula 24, (e.g., phosgene, diphosgene, triphosgene, thiophosgene, NN'-carbonyldiimidazole, or NN'-thiocarbonyldiimidazole) followed by reaction with compounds of Formula 64, with or without optional base.
  • Compounds of Formula 68 can be prepared by reaction of compounds of Formula 66 with sulfonylating agents of Formula 67 (for example, methanesuifonyl chloride or trifluoromethanesulfonic anhydride) with or without optional base.
  • Appropriate bases include alkali metal alkoxides such as potassium ter -butoxide, inorganic bases such as sodium hydride and potassium carbonate, tertiary amines such as triethylamine and trie ylenediamine, pyridine, or l,8-diazabicyclo[5.4.0]undec-7-ene (DBU).
  • Suitable solvents include polar aprotic solvents such as acetonitrile, dimethylformamide, or dimethyl sulfoxide; ethers such as tetrahydrofuran, dimethoxyethane, or diethyl ether; ketones such as acetone or 2-butanone; hydrocarbons such as toluene or benzene; or halocarbons such as dichloromethane or chloroform.
  • the reaction temperature can vary between 0 °C and 150 °C and the reaction time can be from 1 to 72 hours depending on the choice of base, solvent, temperature, and substrates.
  • T 1 and T 2 are independently Cl, OCCl 3 , 0(C!-C alkyl), 1-imidaz ⁇ lyl, 1,2,4-triazolyl
  • T 1 1 OR 27 , SR 27 , N(R 26 ) 2
  • Compounds of Formula 71 can be prepared by reaction of compounds of Formula 9 with isocyanates of Formula 70.
  • a base such as triethylamine can be added to catalyze the reaction.
  • Compounds of Formula 73 can be prepared by reaction of compounds of Formula 69 with silylating or germylating agents of Formulae 72a or
  • a base such as, but not limited to, pyridine or imidazole.
  • Compounds of Formula 76 can be prepared by reaction of compounds of Formula 74 with alkylating agents of Formula 75 which include alkyl-, haloalkyl- or aryl- sulfonates such as ethyl lactate methanesulfonate, 2-methoxyethyl trifluoromethanesulfonate or cyanomethybenzenesulfonate, and alkyl halides such as benzyl bromide and propargyl bromide (Scheme 36). These alky lations can be conducted with or without additional base.
  • alkylating agents of Formula 75 include alkyl-, haloalkyl- or aryl- sulfonates such as ethyl lactate methanesulfonate, 2-methoxyethyl trifluoromethanesulfonate or cyanomethybenzenesulfonate, and alkyl halides such as benzyl bromide and proparg
  • T 13 C 3 -C 6 haloalkenyl, C 3 -Cg alkynyl, C 3 -Cg haloalkynyl, C2-C5 alkoxyalkyl, C5-C9 trialkylsilylalkoxyalkyl, C 2 -C 6 alkylthioalkyl, Cj-C 3 alkyl substituted with cyano,
  • Compounds of Formula 78 can be prepared from compounds of Formula 77 by nucleophilic displacement with alkali metal alkoxides, alkali metal thioalkoxides (M + -T 14 ) (Scheme 37). Similar displacements on compounds of Formula 80 with compounds M + -T 15 provide compounds of Formula 81.
  • Compounds of Formula 79 can be prepared by reaction with amine derivatives in a suitable solvent.
  • the leaving groups Lg 1 in compounds of Formula 77 and 80 are any group known in the art to undergo a displacement reaction of this type. Examples of suitable leaving groups include chlorine, bromine, and sulfonyl and sulfonate groups. Examples of suitable inert solvents are dimethylformamide or dimethyl sulfoxide, dimethoxyethane, and methanol.
  • Lg Cl, Br, -SC--2V or OSC ⁇ V
  • V C r C 6 alkyl, C r C 6 haloalkyl, or 4-CH 3 -C,sH4
  • T 14 SCN, benzyloxy, phenylthio, benzylthio, pyrimidinylmethoxy, pyridinylthio, thienylthio, furanyloxy, furanylthio, pyrimidinylthio, each optionally substituted
  • T 1 benzyloxy, phenylthio, each optionally substituted
  • Compounds of Formula 84 can be prepared from compounds of Formula 82 by reaction with nucleophiles of Formula 83 in the presence of added base (Scheme 38). Similarly, reaction of compounds of Formula 54a with nucleophiles of Formula 85 leads to compounds of Formula 86.
  • Appropriate bases include alkali metal alkoxides such as potassium fert-butoxide, inorganic bases such as sodium hydride and potassium carbonate, or tertiary amines such as triethylamine, pyridine, l,8-diazabicyclo[5.4.0]undec-7-ene (DBU), and triethylenediamine.
  • Acid chlorides of Formula 82 can be prepared from carboxylic acids of Formula 87 by a variety of methods (see March, J. Advanced Organic Chemistry; 3rd ed., John Wiley: New York, (1985), pp 388-9 and references therein). Carboxylic acids are widely available and can be synthesized by one skilled in the art by a variety of methods. Compounds of Formula 54a can be prepared, in addition to the method described in Scheme 31, by halosulfonation of compounds of Formula 43 with chlorosulfonic acid (For a review, see Gilbert, Sulfonation and Related Reactions, Interscience, New York (1965) pp 62- 83,87-124).
  • Compounds of Formula 54a also can be prepared by oxidative chlorination of mercaptans of Formula 52 by chlorine and water. Sulfide, disulfide, and thioacetate derivatives of 52 (Formula 52a), among others, can be used to effect the same reaction. (For a review, see Gilbert, Sulfonation and Related Reactions, Interscience, New York (1965) pp 202-21). Scheme 38
  • Q 6 C)-C alkyl, benzyl, S(C]-C alkyl), S-benzyl, SCOCH 3
  • One method is the reductive metallation or halogen-metal exchange of compounds of Formula 88 using magnesium or an organolithium reagent, followed by treatment with a silyl- or germyl-substituted halide of Formula 89.
  • a second method is deprotonation of compounds of Formula 43 using a strong base such as a lithioamide or an organolithium reagent followed by treatment with a compound of Formula 89.
  • Compounds of Formula 94 can be prepared by treating compounds of Formula 93 with thionating reagents such as P2S5 or Lawesson's reagent (2,4-bis(4- methoxyphenyl)-l,3-dithia-2,4-diphosphetane-2,4-disulfide) as illustrated in Scheme 41 (see Bull. Soc. Chim. Belg, (1978), 87, 229; and Tetrahedron Lett., (1983), 24, 3815).
  • thionating reagents such as P2S5 or Lawesson's reagent (2,4-bis(4- methoxyphenyl)-l,3-dithia-2,4-diphosphetane-2,4-disulfide) as illustrated in Scheme 41 (see Bull. Soc. Chim. Belg, (1978), 87, 229; and Tetrahedron Lett., (1983), 24, 3815).
  • Lawesson's Reagent 93 94 ⁇ l8 R26, OR26, SR26 ? N(R2 ) 2
  • R 9 moieties may be introduced via a palladium(0)-catalyzed cross coupling reaction with the appropriate nucleophiles containing R 9 , such as arylboronic acids, aryl or alkyl zinc reagents, and substituted acetylenes.
  • Step A Preparation of N-(2-metho ⁇ yphenylV2.2-dimethylhvdrazinecarboxamide To a stirred solution of 15.0 g of 2-methoxyphenyl isocyanate in 100 mL of toluene at 5 °C under nitrogen was slowly added 7.65 mL of 1,1-dimethylhydrazine in 10 mL toluene. The cooling bath was then removed and the reaction was allowed to stir for an additional 10 min, and was then concentrated under reduced pressure. The resulting material was dissolved in diethyl ether and concentrated again. A solid was obtained which was triturated with hexanes to afford 21 g of the title compound of Step A as a white solid.
  • Step B Preparation of 5-chloro-2,4-dihvdro-4-(2-metho ⁇ yphenyl ' )-2-methyl-3H-
  • Step E Preparation of 2.4-dihvdro-4-r2-r(3-iodo-l .2.4-thiadiazol-5- v0oxylphenyl]-5-memoxy-2-methyl-3H-l ,2,4-triazol-3-one
  • Step D To a solution of the title compound of Step D (3.0 g, 13.6 mmol) in acetone (27 mL) was added potassium carbonate (2.44 g) and 3-iodo-5-(methylsulfonyl)- 1,2,4- thiadiazole (J. Org Chem. (1973), 38, 469) (4.33 g). The mixture was stirred at ambient temperature for 36 h before being diluted with water. The resulting mixture was extracted twice with methylene chloride and the combined extracts were dried over magnesium sulfate. The solution was concentrated to a solid which was triturated with hot ethanol to give the title compound of Step E (2.8 g, 48%).
  • Step F Preparation of 2.4-dihvdro-5-methoxy- 1 -methyl-4-f2-IT3-IT2- pyridinyllethvnvn-l. ⁇ -thiadiazol-S-vnoxylphenyll-SH-l ⁇ -triazol-S- one
  • DMF dimethyl methylmethylamine
  • 2-ethynylpyridine 186 mg, 1.78 mmol
  • bis(triphenylphosphine)palladium(II) chloride 25 mg.
  • Step A Preparation of ethyl l-(4-chlorophenvDcvclopropanecarboximidate hvdrochloride To a solution of l-(4-chlorophenyl)-l-cyclopropanecarbonitrile (10 g, 56.3 mmol) in ethyl ether (56 mL) is added absolute ethanol (3.4 mL). The solution is cooled to 0 °C and saturated with dry HC1 gas. The reaction mixture is then left to stand at ambient temperature for 11 days after which time it is filtered under a stream of dry nitrogen to give the title compound of Step A (11.60 g) as a white solid.
  • Step B Preparation of l-(4-chlorophenv0cvclopropanecarboximidamide hvdrochloride To a solution of the title compound of Step A (11.60 g, 44.6 mmol) in methanol (15 mL) is added ammoma (9.0 mL, 7N solution in methanol). This mixture was stirred for 2 days before being concentrated to give the title compound of Step B (9.78 g).
  • Step C Preparation of 5-chloro-3-[ 1 -(4-chlorophenvDcvclopropy ⁇ - 1.2,4- thiadiazole
  • methylene chloride 200 mL
  • benzyltriethylammonium chloride 0.79 g
  • perchloromethyl mercaptan 4.62 mL, 42.3 mmol
  • Step B Preparation of 1.3-benzodioxole-5-carboximidamide hvdrochloride
  • Step B To a solution of the title compound of Step A (6.38 g, 29.3 mmol) in ethanol is added ammonia (5.6 mL, 7N solution in methanol). This mixture is stirred for 6 days before being concentrated to give the title compound of Step B (5.60 g).
  • Step C Preparation of 5-chloro-3-(l .3-benzodioxol-5-vD-l .2.4-thiadiazole
  • Step D Preparation of 4-r2-rr3-(1.3-benzodioxol-5-vn-1.2.4-thiadiazol-5- ylloxylphenyll-2.4-dihvdro-5-methoxy-2-methyl-3- t -1.2.4-triazol-3-one
  • Methyl iodide (0.705 mL) is then added and the mixture is cooled in an ice bath and stirred for a further 0.5 h. The solution is concentrated and redissolved in methylene chloride. The solution is filtered through a pad of silica gel and concentrated to give the title compound of Step A (2.15 g) as a white solid.
  • Step A Preparation of 3-r(2-chlorophenyl methoxyl-5-(methylthioV 1.2.4- thiadiazole To a solution of 3-hydroxy-5-thiomethyl-l,2,4-thiadiazole (J. Het. Chem., ( 1979), 961 ) (0.8 g) in DMF (10 mL) was added potassium carbonate ( 1.12 g) and
  • Step B Preparation of 4-r2-rr3-r(2-chlorophenyl)methoxyl-l .2.4-thiadiazol-5- ylloxylphenvn-2,4-dihvdro-5-methoxy-2-methyl-3H-1.2.4-triazol-3-one
  • Step B Preparation of 5-chloro- ⁇ . ⁇ -dimethyl- 1.2.4-thiadiazole-3-acetonitrile
  • Step B To a solution of the title compound of Step B (3.52 g, 31.4 mmol) in methylene chloride (75 mL) was added perchloromethyl mercaptan (3.4 mL) and the mixture was cooled in an ice bath. Triethylamine (17.5 mL) was then added such that the internal temperature did not exceed 10 °C. Upon complete addition, the cooling bath was removed and the mixture was stirred for 1.5 h. The mixture was then washed with water, IN HC1 and dried over magnesium sulfate. The mixture was concentrated and the residue was extracted with hot hexanes, filtered through a pad of silica gel and concentrated to give the title compound of Step C (1.3 g).
  • Step D Preparation of 5-f2-( 1.5-dihvdro-3-methoxy- 1 -methyl-5-oxo-4H- 1.2.4- triazol-4-y ⁇ phenoxy]- ⁇ . ⁇ -dimethyl -1 ,2.4-thiadiazole-3-acetonitrile
  • potassium carbonate 406 mg
  • Step C 426 mg
  • Step A Preparation of 5-(memylthio>3-(phenylmethoxy)-l .2,4-thiadiazole
  • Step B Preparation of 2.4-dihydro-5-methoxy-2-methyl-4-r2-IT3-
  • Step C Preparation of 4-r2-lT3-( ' diethoxymethvD-l .2.4-thiadiazol-5- ylloxy]phenyl1-2,4-dihvdro-5-methoxy-2-methyl-3H-1.2,4-triazol-3-one
  • Step B Preparation of 2.2-dimethyl-N-r2-r3- methoxyphenoxy ⁇ phenyllhvdrazinecarboxamide
  • Step B The title compound of Step B (11.8 g, 55.0 mmol) was dissolved in 120 mL of dry toluene and to this solution was added diphosgene (10.8 g, 55.0 mmol). The mixture was then refluxed with a water scrubber in place for 4 h. The reaction mixture was cooled to room temperature, concentrated under reduced pressure to an oil which was then dissolved in dry tetrahydrofuran (100 mL). To this solution was added
  • Step D Preparation of 5-chloro-2.4-dihvdro-4-f2-(3-rnethoxyphenoxy " )phenyl]-2- methyl-3H-l .2.4-triazol-3-one
  • the title compound of Step C was dissolved in 600 mL of methylene chloride and cooled to 0 °C at which temperature triphosgene (15.9 g, 53.5 mmol) was added. The reaction mixture was refluxed for 16 h, cooled to room temperature and washed once with water.
  • Step E Preparation of 5-chloro-2.4-dihvdro-4-[2-f 3-hvdroxyphenoxy)phenyl -2- methyl-3H- 1.2.4-triazol-3-one
  • the title compound of Step D (12.6 g, 38.0 mmol) was dissolved in 300 mL of dry toluene and to this solution was added aluminum chloride (30 g, 228 mmol) at room temperature with a slight exotherm to 35 °C. The reaction mixture was subsequently refluxed for 4 h, cooled to room temperature and carefully added to crushed ice.
  • Example 12 The title compound of Example 12 (0.30 g, 0.95 mmol), 2-chlorobenzyl bromide (0.21 g, 1 mmol), and potassium carbonate (0.14 g, 1 mmol) were combined at room temperature in 10 mL of dry acetonitrile and the resulting mixture was stirred at room temperature for 16 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to solids which were triturated with hexanes and suction-dried to yield 0.32 g of the title compound of Example 13, a compound of the invention, as a solid melting at 112-114 °C.
  • Step B Preparation of 5-chloro-3- ⁇ -(4-chlorophenvOcvclopropyl]- 1.2,4- thiadiazole
  • the title compound of Step A (11.1 g, 48.1 mmol) was dissolved in water
  • 1,1-Dimethylhydrazine (55.0 g, 911 mmol) was added dropwise over 30 min and then the mixture was allowed to warm to room temperature and stir overnight. The mixture was cooled, filtered, and the solid was washed with ethyl acetate and dried to provide 200.0 g of the title compound of Step C as a white solid melting at 151 - 153 °C. ! H ⁇ MR (CDC1 3 ) ⁇ 7.58 (br s,lH), 7.10 (t,lH), 6.84 (d,lH), 6.74 (d,lH), 5.22 (br s,lH), 3.80 (s,3H), 2.63 (s,6H), 2.31 (s,3H).
  • Step D Preparation of 5-chloro-2.4-dihvdro-4-( ' 2-methoxy-6-methylphenylV2- methyl-3H- 1.2,4-triazol-3-one
  • the title compound of Step C (100.0 g, 447.9 mmol) was suspended in ethyl acetate (1 L) and added dropwise, via mechanical pump, over 3.5 h to a stirring solution of phosgene (177 g, 1.79 moles) in ethyl acetate (1.5 L) which was heated at reflux. After the addition was complete, the mixture was heated at reflux for a further 3 h, cooled to room temperature and stirred overnight.
  • Step E Preparation of 5-chloro-2.4-dihvdro-4-(2-hvdroxy-6-metaylphenvD-2- methyl-3//-l .2.4-triazol-3-one
  • benzene 200 mL
  • aluminum chloride 23.7 g, 178 mmol
  • Step F Preparation of 2.4-dihvdro-4-(2-hvdroxy-6-methylphenvD-5-methoxy-2- methyl-3H- 1.2.4-triazol-3-one
  • tetrahydrofuran 1.5 L
  • sodium methoxide 25% by weight in methanol, 382 mL, 1.67 moles
  • 1,1 -Dimethyl hydrazine (30 mL) in 20 mL of toluene was added dropwise. The reaction mixture was stirred at room temperature overnight. The precipitated solid was collected by filtration and redissolved in 1 L of dichloromethane. The organic solution was washed with 500 mL of water and then with 500 mL of saturated aqueous sodium chloride solution. The organic phase was dried (MgSO ), filtered and concentrated to give 58 g (56% yield) of the title compound of Step A as a beige solid.
  • Step B Preparation of 5-chloro-4-r2-(chloromethyl phenyl1-2,4-dihydro-2- methyl-3//- 1.2.4-triazol-3-one The title compound of Step A (58 g) was dissolved in 800 mL of dichloromethane and 86 g of triphosgene was added in one portion.
  • Step D Preparation of 5-chloro-2.4-dihvdro-4-r2-rriT 1 -( 3- hvdroxyphenv ⁇ ethylidenelaminoloxylmethyllphenyll- ⁇ -methyl-SH- 1.2.4-triazol-3-one
  • K 2 CO 3 7. g, 51 mmol
  • Step B Preparation of methyl 2-1 " Kbenzoylaminoloxylmethyllbenzeneacetate
  • Benzohydroxamic acid (17 g) and potassium carbonate (18.7 g) were suspended in 200 mL of acetonitrile and the mixture was stirred at 60 °C for 30 min.
  • a solution of 28 g of the title compound of Step A in 100 mL of acetonitrile was added dropwise over 0.5 h.
  • the mixture was stirred at 60 °C for 3 h and then cooled to room temperature overnight. Heating was resumed for an additional 4 h.
  • the mixture was cooled and filtered.
  • the filtrate was concentrated in vacuo. The residue was taken up in 200 mL of emyl acetate and washed with 100 mL of 6% aqueous potassium carbonate solution.
  • Step C Preparation of methyl 2-f(aminooxy methyl]benzeneacetate hvdrochloride To a solution of HC1 in methanol (prepared by adding 20 mL of acetyl chloride slowly to 200 mL of methanol) was added the title compound of Step B (31.5 g). The mixture was heated to 60 °C for 1.5 h. The solvent was removed in vacuo. The residue was taken up in 100 mL of diethyl ether and stirred at room temperature for 30 min. The ether was decanted off and the solid was taken up in 100 mL of tetrahydrofuran and heated to about 50 °C. The mixture was then cooled in an ice water bath and the solid was collected by filtration to provide 11.5 g (47% yield) of the title compound of Step C as a white solid melting at 169- 170°C.
  • Step D Preparation of methyl 2-rriTl-(4- hvdroxyphenyl)ethylidene]amino1oxy1methvnbenzeneacetate 4'-Hydroxyacetophenone (81.7 mg) and the title compound of Step C (1.39 g) were dissolved in 40 mL of pyridine. The solution was heated to 90 °C overnight and then cooled to room temperature.
  • Step E Preparation of dimethyl r2-riTr 4- hvdroxyphenyl)ethylidene]aminoloxylmethvnphenvnpropanedioate
  • the title compound of Step D (1.87 g , 6 mmol) was dissolved in 10 mL of dimethyl carbonate.
  • a slurry of 480 mg of sodium hydride (60% oil dispersion) in 10 mL of tetrahydrofuran was added and the mixture was heated to reflux for 1 h.
  • the mixture was cooled to room temperature overnight, quenched with 15 mL of IN HCl solution and extracted with ethyl acetate (3 x 25 mL).
  • the third-eluting component was collected to yield 200 mg of the title compound of Step F, a compound of the invention, as an amber oil.
  • a minor amount of the Z-isomer was also observed.
  • Step B Preparation of l-f3-ftris(trifluoromemv0germyl1phenyl " [ethanone
  • Step C Preparation of l ⁇ -rtrisftrifluoromethvDgermyllphenyllethanone oxime
  • Step D Preparation of 2,4-dihvdro-5-methoxy-2-methyl-4-f2-rrr ⁇ -[3- ftrisftrifluoromethv ⁇ germyllphenv ⁇ ethylidenelaminoloxylmethyljphenv ⁇ -3H-1.2.4-triazol-3-one
  • Step A Preparation of l-r3-rdimethyl(3,3,3- trifluoropropyDsilyllphenv ⁇ ethanone A 125 mL 4-neck flask was charged wi a suspension of magnesium pieces (1.09 g, 0.041 mole) in 8 mL of THF.
  • Step B Preparation of l-r3-rdimethyl(3.3.3- trifluoropropyOsilyllphenyl ' [ethanone oxime Sodium acetate trihydrate (7.76 g, 0.057 mole) was added to a solution of hydroxylamine hydrochloride (3.96 g, 0.057 mole) in water (59 mL), and this solution was added to a solution of the title compound of Step A (10.7 g, 0.039 mole) in methanol (78 mL). The mixture was then refluxed overnight and concentrated in vacuo. The mixture was treated with water and then extracted with methylene chloride (3 x 120 mL).
  • Step C Preparation of 4-r2-rrr ⁇ -r3-rdimethyl-(3.3.3- trifluoropropynsilvnphenyllethylidenelamino]oxy]methyllphenvn-2.4- dihvdro-5-methoxy-2-methyl-3H- 1 ,2.4-triazol-3-one
  • sodium hydride (0.84 g, 0.021 mole, 60% mineral oil dispersion) was suspended in 50 mL of dry THF.
  • the title compound of Step B (2.0 g, 6.9 mmol) was dissolved in dry THF (15 mL) and added dropwise causing gas evolution.
  • R J 3-(2-CN-Ph-C ⁇ C-).
  • R 2 Me.
  • R 3 3-Me.
  • R 4 6-Me.
  • Compounds of this invention will generally be used as a formulation or composition with an agriculturally suitable carrier comprising at least one of a liquid diluent, a solid diluent or a surfactant.
  • the formulation or composition ingredients are selected to be consistent with the physical properties of the active ingredient, mode of application and environmental factors such as soil type, moisture and temperature.
  • Useful formulations include liquids such as solutions (including emulsifiable concentrates), suspensions, emulsions (including microemulsions and/or suspoemulsions) and the like which optionally can be thickened into gels.
  • Useful formulations further include solids such as dusts, powders, granules, pellets, tablets, films, and the like which can be water-dispersible ("wettable") or water-soluble.
  • Active ingredient can be (micro)encapsulated and further formed into a suspension or solid formulation; alternatively the entire formulation of active ingredient can be encapsulated (or "overcoated”). Encapsulation can control or delay release of the active ingredient.
  • Sprayable formulations can be extended in suitable media and used at spray volumes from about one to several hundred liters per hectare. High-strength compositions are primarily used as intermediates for further formulation.
  • the formulations will typically contain effective amounts of active ingredient, diluent and surfactant within the following approximate ranges which add up to 100 percent by weight.
  • Typical solid diluents are described in Watkins, et al., Handbook of Insecticide Dust Diluents and Carriers, 2nd Ed., Dorland Books, Caldwell, New Jersey. Typical liquid diluents are described in Marsden, Solvents Guide, 2nd Ed., Interscience, New York, 1950. McCutcheon 's Detergents and Emulsifiers Annual, Allured Publ. Corp., Ridgewood, New Jersey, as well as Sisely and Wood, Encyclopedia of Surface Active Agents, Chemical Publ. Co., Inc., New York, 1964, list surfactants and recommended uses.
  • All formulations can contain minor amounts of additives to reduce foam, caking, corrosion, microbiological growth and the like, or thickeners to increase viscosity.
  • Surfactants include, for example, polyethoxylated alcohols, polyethoxylated alkylphenols, polyethoxylated sorbitan fatty acid esters, dialkyl sulfosuccinates, alkyl sulfates, alkylbenzene sulfonates, organosilicones, NN-dialkyltaurates, lignin sulfonates, naphthalene sulfonate formaldehyde condensates, polycarboxylates, and polyoxyethylene/polyoxypropylene block copolymers.
  • Solid diluents include, for example, clays such as bentonite, montmorillonite, attapulgite and kaolin, starch, sugar, silica, talc, diatomaceous earth, urea, calcium carbonate, sodium carbonate and bicarbonate, and sodium sulfate.
  • Liquid diluents include, for example, water, NN-dimethylformamide, dimethyl sulfoxide, N-alkylpyrrolidone, ethylene glycol, polypropylene glycol, paraffins, alkylbenzenes, alkylnaphthalenes, oils of olive, castor, linseed, tung, sesame, corn, peanut, cotton-seed, soybean, rape-seed and coconut, fatty acid esters, ketones such as cyclohexanone, 2-heptanone, isophorone and 4-hydroxy-4- methyl-2-pentanone, and alcohols such as methanol, cyclohexanol, decanol and tetrahydro * ojrfuryl alcohol.
  • Solutions can be prepared by simply mixing the ingredients. Dusts and powders can be prepared by blending and, usually, grinding as in a hammer mill or fluid-energy mill. Suspensions are usually prepared by wet-milling; see, for example, U.S. 3,060,084. Granules and pellets can be prepared by spraying the active material upon preformed granular carriers or by agglomeration techniques. See Browning, "Agglomeration", Chemical Engineering, December 4, 1967, pp 147-48, Perry 's Chemical Engineer 's Handbook, 4th Ed., McGraw-Hill, New York, 1963, pages 8-57 and following, and WO 91/13546. Pellets can be prepared as described in U.S.
  • Water-dispersible and water-soluble granules can be prepared as taught in U.S. 4,144,050, U.S. 3,920,442 and DE 3,246,493. Tablets can be prepared as taught in U.S. 5,180,587, U.S. 5,232,701 and U.S. 5,208,030. Films can be prepared as taught in GB 2,095,558 and U.S. 3,299,566. For further information regarding the art of formulation, see U.S. 3,235,361 ,
  • Compound 39 65.0% dodecylphenol polyethylene glycol ether 2.0% sodium ligninsulfonate 4.0% sodium silicoaluminate 6.0% montmorillonite (calcined) 23.0%.
  • Example B Granule Compound 39 10.0% attapulgite granules (low volatile matter
  • Example C Extruded Pellet Compound 39 25.0% anhydrous sodium sulfate 10.0% crude calcium ligninsulfonate 5.0% sodium alky lnaphthalenesulfonate 1.0% calcium/magnesium bentonite 59.0%.
  • Example D Extruded Pellet Compound 39 25.0% anhydrous sodium sulfate 10.0% crude calcium ligninsulfonate 5.0% sodium alky lnaphthalenesulfonate 1.0% calcium/magnesium bentonite 59.0%.
  • Example D Extruded Pellet Compound 39 25.0% anhydrous sodium sulfate 10.0% crude calcium ligninsulfonate 5.0% sodium alky lnaphthalenesulfonate 1.0% calcium/magnesium bentonite 59.0%.
  • Compound 39 20.0% blend of oil soluble sulfonates and polyoxyethylene ethers 10.0% isophorone 70.0%.
  • the compounds of this invention are useful as plant disease control agents.
  • the present invention therefore further comprises a method for controlling plant diseases caused by fungal plant pathogens comprising applying to the plant or portion thereof to be protected, or to the plant seed or seedling to be protected, an effective amount of a compound of the invention or a fimgicidal composition containing said compound.
  • the compounds and compositions of this invention provide control of diseases caused by a broad spectrum of fungal plant pathogens in the Basidiomycete, Ascomycete, Oomycete and Deuteromycete classes. They are effective in controlling a broad spectrum of plant diseases, particularly foliar pathogens of ornamental, vegetable, field, cereal, and fruit crops.
  • pathogens include Plasmopara viticola, Phytophthora infestans, Peronospora tabacina, Pseudoperonospora cubensis, Pythium aphanidermatum, Alternaria brassicae, Septoria nodorum, Septoria tritici, Cercosporidium personatum, Cercospora arachidicola, Pseudocercosporella herpotrichoides, Cercospora beticola, Botrytis cinerea, Monilinia fructicola. Pyricularia oryzae.
  • Puccinia arachidis, Rhizoctonia solani, Sphaerotheca fuliginea, Fusarium oxysporum, Verticillium dahliae, Pythium aphanidermatum, Phytophthora megasperma, Sclerotinia sclerotiorum,
  • the compounds of this invention also exhibit activity against a wide spectrum of foliar- feeding, fruit-feeding, stem or root feeding, seed-feeding, aquatic and soil-inhabiting arthropods (term “arthropods” includes insects, mites and nematodes) which are pests of growing and stored agronomic crops, forestry, greenhouse crops, ornamentals, nursery crops, stored food and fiber products, livestock, household, and public and animal health.
  • arthropods includes insects, mites and nematodes which are pests of growing and stored agronomic crops, forestry, greenhouse crops, ornamentals, nursery crops, stored food and fiber products, livestock, household, and public and animal health.
  • all of the compounds of this invention display activity against pests that include: eggs, larvae and adults of the Order Lepidoptera; eggs, foliar-feeding, fruit- feeding, root-feeding, seed- feeding larvae and adults of the Order Coleoptera; eggs, immatures and adults of the Orders Hemiptera and Homoptera; eggs, larvae, nymphs and adults of the Order Acari; eggs, immatures and adults of the Orders Thysanoptera, Orthoptera and
  • the compounds of this invention are also active against pests of the Orders Hymenoptera, Isoptera, Siphonaptera, Blattaria, Thysanura and Psocoptera; pests belonging to the Class Arachnida and Phylum Platyhelminthes.
  • the compounds are active against southern corn rootworm (Diabrotica undecimpunctata howardi), aster leafhopper (Mascrosteles fascifrons), boll weevil (Anthonomus grandis), two-spotted spider mite (Tetranychus urticae), fall armyworm (Spodoptera frugiperda), black bean aphid (Aphis fabae), green peach aphid (Myzus persica), cotton aphid (Aphis gossypii), Russian wheat aphid (Diuraphis noxia), English grain aphid (Sitobion avenae), tobacco budworm (Heliothis virescens), rice water weevil (Lissorhoptrus oryzophilus), rice leaf beetle (Oulema oryzae), whitebacked planthopper (Sogatella furcifera), green leafhopper (Nephotettix cincticeps), brown planthopper (
  • the compounds are active on mites, demonstrating ovicidal, larvicidal and chemosterilant activity against such families as Tetranychidae including Tetranychus urticae, Tetranychus cinnabarinus, Tetranychus mcdanieli, Tetranychus pacificus, Tetranychus turkestani, Byrobia rubriocuius.
  • Compounds of this invention can also be mixed with one or more other insecticides, fungicides, nematocides, bactericides, acaricides, growth regulators, chemosterilants, semiochemicals, repellents, attractants, pheromones, feeding stimulants or other biologically active compounds to form a multi-component pesticide giving an even broader spectrum of agricultural protection.
  • insecticides such as abamectin, acephate, azinphos-methyl, bifenthrin, buprofezin, carbofuran, chlorpyrifos, chlorpyrifos-methyl, cyfluthrin, beta-cyfluthrin, cyhalothrin, lambda-cyhalothrin, deltamethrin, diafenthiuron, diazinon, diflubenzuron, dimethoate, esfenvalerate, fenoxycarb, fenpropathrin, fenvalerate, fipronil, flucythrinate, tau-fluvalinate, fonophos, imidacloprid, isofenphos, malathion, metaldehyde, methamidophos, methidathion, methomyl, methoprene, methoxychlor
  • Preferred for better control of plant diseases caused by fungal plant pathogens e.g., lower use rate or broader spectrum of plant pathogens controlled
  • resistance management are mixtures of a compound of this invention with a fungicide selected from the group cyproconazole, cyprodinil (CGA 219417), epoxiconazole (BAS 480F), fenpropidin, fenpropimorph, fiusilazole and tebuconazole.
  • Specifically preferred mixtures are selected from the group: compound 9 and cyproconazole; compound 9 and cyprodinil (CGA 219417); compound 9 and epoxiconazole (BAS 480F); compound 9 and fenpropidin; compound 9 and fenpropimorph; compound 9 and fiusilazole; compound 9 and tebuconazole; compound 12 and cyproconazole; compound 12 and cyprodinil (CGA 219417); compound 12 and epoxiconazole (BAS 480F); compound 12 and fenpropidin; compound 12 and fenpropimorph; compound 12 and fiusilazole; compound 12 and tebuconazole; compound 39 and cyproconazole; compound 39 and cyprodinil (CGA 219417); compound 39 and epoxiconazole (BAS 480F); compound 39 and fenpropidin; compound 39 and fenpropidin; compound 39 and fenpropidin; compound
  • Plant disease control is ordinarily accomplished by applying an effective amount of a compound of this invention either pre- or post-infection, to the portion of the plant to be protected such as the roots, stems, foliage, fruit, seeds, tubers or bulbs, or to the media (soil or sand) in which the plants to be protected are growing.
  • the compounds can also be applied to the seed to protect the seed and seedling.
  • rates of application for these compounds can be influenced by many factors of the environment and should be determined under actual use conditions.
  • Foliage can normally be protected when treated at a rate of from less than 1 g/ha to 5,000 g/ha of active ingredient.
  • Seed and seedlings can normally be protected when seed is treated at a rate of from 0.1 to 10 g per kilogram of seed.
  • Arthropod pests are controlled and protection of agronomic, horticultural and specialty crops, animal and human health is achieved by applying one or more of the compounds of this invention, in an effective amount, to the environment of the pests including the agronomic and/or nonagronomic locus of infestation, to the area to be protected, or directly on the pests to be controlled.
  • the present invention further comprises a method for the control of foliar and soil inhabiting arthropods and nematode pests and protection of agronomic and/or nonagronomic crops, comprising applying one or more of the compounds of the invention, or compositions containing at least one such compound, in an effective amount, to the environment of the pests including the agronomic and/or nonagronomic locus of infestation, to the area to be protected, or directly on the pests to be controlled.
  • a preferred method of application is by spraying.
  • granular formulations of these compounds can be applied to the plant foliage or the soil.
  • Other methods of application include direct and residual sprays, aerial sprays, seed coats, microencapsulations, systemic uptake, baits, eartags, boluses, foggers, fumigants, aerosols, dusts and many others.
  • the compounds can be incorporated into baits that are consumed by the arthropods or in devices such as traps and the like.
  • the compounds of this invention can be applied in their pure state, but most often application will be of a formulation comprising one or more compounds with suitable carriers, diluents, and surfactants and possibly in combination with a food depending on the contemplated end use.
  • a preferred method of application involves spraying a water dispersion or refined oil solution of the compounds.
  • Combinations with spray oils, spray oil concentrations, spreader suckers, adjuvants, other solvents, and synergists such as piperonyl butoxide often enhance compound efficacy.
  • the rate of application required for effective control will depend on such factors as the species of arthropod to be controlled, the pest ' s life cycle, life stage, its size, location, time of year, host crop or animal, feeding behavior, mating behavior, ambient moisture, temperature, and the like. Under normal circumstances, application rates of about 0.01 to 2 kg of active ingredient per hectare are sufficient to control pests in agronomic ecosystems, but as little as 0.001 kg/hectare may be sufficient or as much as 8 kg hectare may be required.
  • control efficacy represents inhibition of arthropod development (including mortality) that causes significantly reduced feeding.
  • pathogen and arthropod pest control protection afforded by the compounds is not limited, however, to these species. See Index Tables A-C for compound descriptions.
  • R 3a H or R 3
  • a l NMR data are in ppm downfield from tetramethylsilane. Couplings are designated by (s)-singlet, (d)-doublet, (t)-triplet, (q)-quartet, (m)-multiplet, (AB q)-AB quartet, (dd)-doublet of doublets, (br s)-broad singlet and (br m)-broad multiplet.
  • BIOLOGICAL EXAMPLES OF THE INVENTION Test compounds were first dissolved in acetone in an amount equal to 3% of the final volume and then suspended at a concentration of 200 ppm in purified water containing 250 ppm of the surfactant Trem® 014 (polyhydric alcohol esters). The resulting test suspensions were then used in Tests A-F. Spraying these 200 ppm test suspensions to the point of run-off on the test plants is the equivalent of a rate of 500 g/ha. TEST A The test suspension was sprayed to the point of run-off on wheat seedlings. The following day the seedlings were inoculated with a spore dust of Erysiphe graminis f. sp. tritici, (the causal agent of wheat powdery mildew) and incubated in a growth chamber at 20°C for 7 days, after which disease ratings were made.
  • TEST B The test suspension was sprayed to the point of run-off on wheat seedlings. The following day the seedlings were inoculated with a spore suspension of Puccinia recondita (the causal agent of wheat leaf rust) and incubated in a saturated atmosphere at 20°C for 24 h, and then moved to a growth chamber at 20°C for 6 days, after which disease ratings were made.
  • Puccinia recondita the causal agent of wheat leaf rust
  • TEST C The test suspension was sprayed to the point of run-off on rice seedlings. The following day the seedlings were inoculated with a spore suspension of Pyricularia oryzae (the causal agent of rice blast) and incubated in a saturated atmosphere at 27°C for 24 h, and then moved to a growth chamber at 30°C for 5 days, after which disease ratings were made.
  • Pyricularia oryzae the causal agent of rice blast
  • TEST D The test suspension was sprayed to the point of run-off on tomato seedlings. The following day the seedlings were inoculated with a spore suspension of Phytophthora infestans (the causal agent of potato and tomato late blight) and incubated in a saturated atmosphere at 20°C for 24 h, and then moved to a growth chamber at 20°C for 5 days, after which disease ratings were made.
  • Phytophthora infestans the causal agent of potato and tomato late blight
  • TEST E The test suspension was sprayed to the point of run-off on grape seedlings. The following day the seedlings were inoculated with a spore suspension of Plasmopara viticola (the causal agent of grape downy mildew) and incubated in a saturated atmosphere at 20°C for 24 h, moved to a growth chamber at 20°C for 6 days, and then incubated in a saturated atmosphere at 20°C for 24 h, after which disease ratings were made.
  • Plasmopara viticola the causal agent of grape downy mildew
  • TEST F The test suspension was sprayed to the point of run-off on cucumber seedlings. The following day the seedlings were inoculated with a spore suspension of Botrytis cinerea (the causal agent of gray mold on many crops) and incubated in a saturated atmosphere at 20°C for 48 h, and moved to a growth chamber at 20°C for 5 days, after which disease ratings were made.
  • Botrytis cinerea the causal agent of gray mold on many crops
  • Results for Tests A-F are given in Table A.
  • a rating of 100 indicates 100% disease control and a rating of 0 indicates no disease control (relative to the controls).
  • a dash (-) indicates no test results.
  • ND indicates disease control not determined due to phytotoxicity.
  • a Compound was tested at 10 ppm (equivalent to 25 g ha).
  • b Compound was tested at 40 ppm (equivalent to 100 g/ha).
  • c Compound was tested at 2 ppm (equivalent to 5 g/ha).
  • d Compound was tested at 100 ppm (equivalent to 250 g/ha).
  • Test units each consisting of a 230-mL (8-ounce) plastic cup containing a 6.5-cm 2 (1 -square-inch) plug of a wheatgerm diet, were prepared. Solutions of each of the test compounds in 75:25 acetone-distilled water solvent were sprayed into the tray and cup. Spraying was accomplished by passing the tray and cup on a conveyer belt directly beneath a flat fan hydraulic nozzle which discharged the spray at a rate of 0.138 kilograms of active ingredient per hectare (about 0.13 pounds per acre) at 207 kPa (30 p.s.i.). After the spray on the cups had dried, five second-instar larvae of the southern corn rootworm (Diabrotica undecimpunctata howardi) were placed into each cup.
  • Pieces of kidney bean leaves each approximately 6.5 cm 2 (1 square inch) in area, that had been infested on the undersides with 25 to 30 adult mites (Tetranychus urticae), were sprayed with their undersides facing up on a hydraulic sprayer with a solution of the test compound in 75:25 acetone-distilled water solvent. Spraying was accomplished by passing the leaves, on a conveyor belt, directly beneath a flat fan hydraulic nozzle which discharged the spray at a rate of 0.138 kilograms of active ingredient per hectare (about 0.13 pounds per acre) at 207 kPa (30 p.s.i.).
  • the leaf squares were then placed underside-up on a square of wet cotton in a petri dish and the perimeter of the leaf square was tamped down onto the cotton with forceps so that the mites could not escape onto the untreated leaf surface.
  • the test units were held at 27°C and 50% relative humidity for 48 hours, after which time mortality readings were taken. Of the compounds tested, the following gave mortality levels of 80% or higher: 12, 13, 45, 54, 86, 88, 89, 90, 111, 113, 114, 115, 116, 117, 118, 119 and 126.
  • the treated cups were held in a vented enclosure to dry for about 2 h. After drying, the cups were placed into conical-shaped test units and the surface of the soil covered with 2 to 3 mm of quartz sand. Eight to ten 3rd-instar nymphs of the green leafhopper (Nephotettix cincticeps) were transferred into the test units using an aspirator. The test units were held at
  • Solutions of the test compounds were prepared by dissolving in a minimum of acetone and then adding water containing a wetting agent until the concentration of the compound was 50 ppm.
  • Two-week old red kidney bean plants infested with two-spotted spider mites eggs were sprayed to run-off (equivalent to 28 g/ha) with the test solution using a turntable sprayer. Plants were held in a chamber at 25°C and 50% relative humidity. Of the compounds tested, the following gave larvicide/ovicide activity of 80% or higher seven days after spraying: 54 and 89.

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WO2003059897A1 (fr) 2002-01-17 2003-07-24 Sumitomo Chemical Company, Limited Composes de thiadiazole
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