AU2002229049A1 - Aryl and heteroarylcyclopropyl oxime ethers and their use as fungicides - Google Patents

Aryl and heteroarylcyclopropyl oxime ethers and their use as fungicides

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AU2002229049A1
AU2002229049A1 AU2002229049A AU2904902A AU2002229049A1 AU 2002229049 A1 AU2002229049 A1 AU 2002229049A1 AU 2002229049 A AU2002229049 A AU 2002229049A AU 2904902 A AU2904902 A AU 2904902A AU 2002229049 A1 AU2002229049 A1 AU 2002229049A1
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halo
alkyl
cyclopropyl
methyl
phenyl
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AU2002229049A
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Duyan Vuong Nguyen
Ronald Ross Jnr.
Steven Howard Shaber
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Corteva Agriscience LLC
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Dow AgroSciences LLC
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C271/06—Esters of carbamic acids
    • C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
    • C07C271/26—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atom of at least one of the carbamate groups bound to a carbon atom of a six-membered aromatic ring
    • C07C271/28—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atom of at least one of the carbamate groups bound to a carbon atom of a six-membered aromatic ring to a carbon atom of a non-condensed six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C251/00—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton
    • C07C251/32—Oximes
    • C07C251/34—Oximes with oxygen atoms of oxyimino groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals
    • C07C251/42—Oximes with oxygen atoms of oxyimino groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals with the carbon atom of at least one of the oxyimino groups bound to a carbon atom of a ring other than a six-membered aromatic ring
    • 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
    • A01N47/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom not being member of a ring and having no bond to a carbon or hydrogen atom, e.g. derivatives of carbonic acid
    • A01N47/08—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom not being member of a ring and having no bond to a carbon or hydrogen atom, e.g. derivatives of carbonic acid the carbon atom having one or more single bonds to nitrogen atoms
    • A01N47/10—Carbamic acid derivatives, i.e. containing the group —O—CO—N<; Thio analogues thereof
    • A01N47/24—Carbamic acid derivatives, i.e. containing the group —O—CO—N<; Thio analogues thereof containing the groups, or; Thio analogues thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
    • C07D213/61—Halogen atoms or nitro radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/09—Geometrical isomers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/02—Systems containing only non-condensed rings with a three-membered ring

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Dentistry (AREA)
  • Wood Science & Technology (AREA)
  • Plant Pathology (AREA)
  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Agronomy & Crop Science (AREA)
  • General Health & Medical Sciences (AREA)
  • Pest Control & Pesticides (AREA)
  • Zoology (AREA)
  • Environmental Sciences (AREA)
  • Agricultural Chemicals And Associated Chemicals (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Pyridine Compounds (AREA)

Description

ARYL and HETEROARYLCYCLOPROPYL OXIME ETHERS AND THEIR USE
AS FUNGICIDES
This application claims a priority from U.S. Provisional Application 60/254,120 which was filed on December 8, 2000.
The present invention relates to certain aryl cyclopropyl oxime ether compounds, compositions containing these compounds, and methods for controlling fungi by the use of a fungitoxic effective amount of these compounds.
Compounds having certain oxime ether structures are disclosed in U.S. Patent 5,824,705. We have discovered a group of cyclopropyl oxime ethers which possess substituted aryl and heterocyclic moieties which possess broad spectrum fungicidal properties.
The cyclopropyloxime ethers of the present invention have the Formula (I)
(I) wherein:
A is hydrogen, halo, cyano, (C1-C12)alkyl, or (Cj-C12)alkoxy;
R. is (C1-C12)alkyl or halo(Cι-Ci2)alkyl;
R2 is hydrogen, (C1-C12)alkyl, halo(C1-C12)alkyl, (C3-C7)cycloalkyl, halo(C3- C7)cycloalkyl, (C2-C8)alkenyl, halo(C2-C8)alkenyl, (C2-C8)alkynyl, halo(C2- C8)alkynyl, or cyano;
R3 is hydrogen;
R4 and R5 are independently hydrogen, (C1-C12)alkyl, halo(C1-C12)alkyl, (C3- C7)cycloalkyl, halo(C3-C7)cycloalkyl, (C2-C8)alkenyl, halo(C2-C8)alkenyl, (C2- C8)alkynyl, halo(C 2-C8)alkynyl, halo, cyano, or (Cj-C^alkoxycarbonyl; and wherein:
A) R7 is aryl, arylalkyl, heterocyclic or heterocyclic(C1-C4)alkyl wherein the aryl or heterocyclic ring is substituted with from 2 to 5 substituents and wherein the positions on the aryl or heterocyclic ring adjacent to the bond to the cyclopropyl ring are both substituted and R6 is hydrogen, (Cj-C^alkyl, halo(Cj-C12)alkyl, (C3- C7)cycloalkyl, halo(C3-C7)cycloalkyl, (C2-C8)alkenyl, halo(C2-C8)alkenyl, (C2- C8)alkynyl, halo(C2-C8)alkynyl, halo, cyano, or (Cj-C4)alkoxycarbonyl; or B) R7 is aryl, arylalkyl, heterocyclic or heterocyclic(C1-C4)alkyl wherein the aryl or heterocyclic ring is unsubstituted or substituted from 1 to 4 substituents wherein at least one of the positions on the aryl or heterocyclic ring adjacent to the bond to the cyclopropyl ring is a hydrogen and R6 is hydrogen, (CrC12)alkyl, halo(Cr C12)alkyl, (C3-C7)cycloalkyl, halo(C3-C7)cycloalkyl, (C2-C8)alkenyl, halo(C2- C8)alkenyl, (C2-C8)alkynyl, halo(C2-C8)alkynyl, halo, cyano or (Cj- C4)alkoxycarbonyl; and their salts, complexes, enantiomorphs, stereoisomers, and mixtures thereof.
The aforementioned (C1-C12)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl and (C3- C7)cycloalkyl groups may be optionally and independently substituted with up to three substituents selected from nitro, halomethyl, (d-C )alkoxycarbonyl, and cyano.
The term alkyl includes both branched and straight chain alkyl groups from 1 to 12 carbon atoms. Typical alkyl groups are methyl, ethyl, n-propyl, iso-propyl, n- butyl, sec-butyl, isobutyl, t-butyl, n-pentyl, isopentyl, n-hexyl, n-heptyl, isooctyl, nonyl, decyl, undecyl, dodecyl and the like. The term haloalkyl refers to an alkyl group substituted with from 1 to 3 halogens.
The term alkenyl refers to an ethylenically unsaturated hydrocarbon group, straight or branched, having a chain length of from 2 to 8 carbon atoms and 1 or 2 ethylenic bonds. The term haloalkenyl refers to an alkenyl group substituted with from 1 to 3 halogen atoms. The term alkynyl refers to an unsaturated hydrocarbon group, straight or branched, having a chain length of from 2 to 8 carbon atoms and 1 or 2 acetylenic bonds.
The term aryl includes phenyl and naphthyl which maybe substituted with up to five substituents independently selected from halogen, cyano, nitro, trihalomethyl, trihalomethoxy, phenyl, phenoxy, (C1-C4)alkyl, (C3-C7)cycloalkyl, (C2-C8)alkenyl, (CrC4)alkoxy, (CrC4)alkylthio, (CrC4)alkylsulfoxide, halo(CrC4)alkyl, halo(Cr C4)alkoxy, halo(C3-C7)cycloalkyl, halo(C2-C8)alkenyl, or (Cj-C4)alkoxycarbonyl. Typical phenyl substituents, wherein at least one of the positions on the phenyl ring adjacent to the bond to the cyclopropyl ring is substituted with hydrogen include but are not limited to 2-chloro, 3-chloro, 4-chloro, 2-fluoro, 3-fluoro, 4-fluoro, 2-bromo, 3-bromo, 4-bromo, 2-methyl, 3-methyl, 4-methyl, 2-trifluoromethyl, 3- trifluoromethyl, 4-trifluoromethyl, 2-methoxy, 3-methoxy, 4-methoxy, 2- trifluoromethoxy, 3-trifluoromethoxy, 4-trifluoromethoxy, 2-cyano, 3-cyano, 4-cyano, 2,3-dichloro, 2,3-difluoro, 2,3-dibromo, 2,3-dimethyl, 2,3-dimethoxy, 2,3- bis(trifluoromethyl), 2,3bis-(trifluoromethoxy), 2,4-difluoro, 2,4-dichloro, 2,4- dibromo, 2,4-dimethyl, 2,4-dimethoxy, 2,4-bis(trifluoromethyl), 2,4- bis(trifluoromethoxy), 2,5-difluoro, 2,5-dichloro, 2,5-dibromo, 2,5-dimethyl, 2,5- dimethoxy, 2,5-bis(trifluoromethyl), 2,5-bis-(trifluoromethoxy), 3,4-difluoro, 3,4- dichloro, 3,4-dibromo, 3,4-dimethyl, 3,4-dimethoxy, 3,4-bis(trifluoromethyl), 3,4- bis(trifluoromethoxy), 3,5-difluoro, 3,5-dichloro, 3,5-dibromo, 3,5-dimethyl, 3,5- bis(trifluoromethyl), 3,5-bis(trifluoro-methoxy), 2,3,4-trifluoro, 2,3,4-trichloro, 2,3,4- tribromo, 2,3,4-trimethyl, 2,3,4-trimethoxy, 2,3,4-tris(trifluoromethyl), 2,3,4- tris(trifluoromethoxy), 2,3,5-rrifluoro, 2,3,5-trichloro, 2,3,5-tribromo, 2,3,5-trimethyl, 2,3,5-tris(trifluoromethyl), 2,3,5-tris(trifluoromethoxy), 2,4,5-trifluoro, 2,4,5-trichloro, 2,4,5-tribromo, 2,4,5-trimethyl, 2,4,5-trimethoxy, 2,4,5-tris(trifluoromethyl), 2,4,5- tris(trifluoromethoxy) , 3,4,5-trifluoro, 3,4,5-trichloro, 3,4,5-tribromo, 3,4,5- trimethyl, 3,4,5-trimethoxy, 3,4,5-tris(trifluoromethyl), 3,4,5-tris(trifluoromethoxy), 2,3,4,5-tetrafluoro, 2,3,4,5-tetrachloro, 2,3,4,5-tetrabromo, 2,3,4,5-tetramethyl, 2,3,4,5-tetramethoxy, 2,3,4,5-tetra(trifluoromethyl), and 2,3,4,5- tetra(tetrafluoromethoxy.
Typical phenyl substituents, where both positions on the phenyl ring adjacent to the bond to the cyclopropyl ring are substituted include but are not limited to 2,6- dichloro, 2,3,6-trichloro, 2,4,6-trichloro, 2,6-difluoro, 2,3,6-trifluoro, 2,4,6-trifluoro, 2,6-dibromo, 2,3,6-tribromo, 2,4,6-tribromo 2,3,4,6-tetrachloro, 2,3,5,6-tetrachloro, 2,3,4,5,6-pentachloro, 2,3,4,6-tefrabromo, 2,3,5,6-tefrabromo, 2,3,4,5,6-pentabromo, 2,3,4,6-tetrafluoro, 2,3,5,6-tetrafluoro, 2,3,4,5,6-pentafluoro, 2,6-dimethyl, 2,3,6- trimethyl, 2,4,6-trimethyl, 2,6-dimethoxy, 2,3,6-trimethoxy, 2,4,6-trimethoxy, 2,6- diethoxy, 2,3,6-triethoxy, 2,4,6-triethoxy, 2,3,4,6-tetramethyl, 2,3,5,6-tetramethyl, 2,3,4,5,6-pentamethyl, 2,3,4,6-tetramethoxy, 2,3,5,6-tetramethoxy, 2,3,4,5,6- pentamethoxy, 2,3,4,6-tetraethoxy, 2,3,5,6-tetraethoxy, 2,3,4,5,6-pentaethoxy, 2,6- dicyano, 2,3,6-tricyano, 2,4,6-tricyano, 2,6-dinitro, 2,6-diphenyl , 2,6-diphenoxy, 2,6- dibenzyl, 2,6-bis(trifluoromethyl), 2,3,6-tris(trifluoromethyl), 2,4,6-tris-(trifluoro- methyl), 2,3,4,6-tetra(trifluoromethyl), 2,3,5,6-tetra(trifluoromethyl), 2,3,4,5,6- penta(trifluoromethyl), 2,6-bis-(trifluoromethoxy), 2,3,6-tris(trifluoromethoxy), 2,4,6- tris(trifluoromethoxy), 2,3,4,5-tetra(trifluoromethoxy), 2,3,4,6-tetra-(trifluoro- methoxy), 2,3,5,6-tetra(trifluoromethoxy), 2,3,4,5,6-penta(trifluoromethoxy), 2- bromo-6-chloro, 2-bromo-6-fluoro, 2-bromo-6-(trifluoromethyl), 2-bromo-6-methyl, 2-bromo-6-methoxy, 2-bromo-6-(trifluoromethoxy), 2-bromo-6-cyano, 2-chloro-6- fluoro, 2-chloro-6-(trifluoromethyl), 2-chloro-6-methyl, 2-chloro-6-methoxy, 2- chloro-6-trifluoromethoxy), 2-chloro-6-cyano, 2-fluoro-6-(trifluoromethyl), 2-fluoro- 6-methyl, 2-fluoro-6-methoxy, 2-fluoro-6-(trifluoromethoxy), 6-cyano-2-fluoro, 2- methyl-6-(trifluoromethyl), 6-methoxy-2-methyl, 2-methyl-6-(trifluoromethoxy), 6- cyano-2-methyl, 3,6-dichoro-2-fluoro, 3-chloro-2,6-difluoro, 4-chloro-2,6-difluoro, 2- bromo-3,6-dichoro, 2,3-dibromo-6-chloro, 3-chloro-2,6-dibromo, 2,6-dichloro-3- fluoro, 2,3-dichloro-6-fluoro, 2-chloro-3,6-difluoro, 3-bromo-2,6-dichloro, 3-bromo- 2,6-fluoro, 3-bromo-6-chloro-2-fluoro, 2-bromo-5-chloro-6-fluoro, 2,6-dibromo-3- fluoro, 2,5-dibromo-6-fluoro, 2,4-dichloro-6-fluoro, 2,6-chloro-4-fluoro, 2,4,- dichloro-6-bromo, 2,6-dichloro-4-bromo, 2,4-difluoro-6-chloro, 2,4-difluoro-6-bromo, 2,6-difluoro-4-bromo, 2,4-dibromo-6-fluoro, 2,4-dibromo-6-chloro, 2,6-dibromo-4- chloro, 2,6-dibromo-4-fluoro, 2,4-dichloro-6-methyl, 2,6-dichloro-4-methyl, 2-chloro- 4,6-dimethyl, 4-chloro-2,6-dimethyl, 2,4-difluoro-6-methyl, 2,6-difluoro-4-methyl, 2- fluoro-4,6-dimethyl, 4-fluoro-2,6-dimethyl, 2,4-dibromo-6-methyl, 2,6-dibromo-4- methyl, 2-bromo-4,6-dimethyl, 4-bromo-2,6-dimethyl, 2,4-dichloro-6-methoxy, 2,6- dichloro-4-methoxy, 2-chloro-4,6-dimethoxy, 4-chloro-2,6-dimethoxy, 2,4-difluoro-6- methoxy, 2,6-difluoro-4-methoxy-, 2-fluoro-4,6-dimethoxy, 4-fluoro-2,6-dimethoxy, 2,4-dibromo-6-methoxy, 2,6-dibromo-4-methoxy, 4-bromo-2,6-dimethoxy, 4-bromo- 2,6-dimethoxy, 2,4-dichloro-6-(trifluoromethyl), 2,6-dichloro-4-(frifluoromethyl), 2- chloro-4,6-bis(trifluoromethyl), 4-chloro-2,6-bis(trifluoromethyl), 2,4-difluoro-6- (trifluoromethyl), 2,6-difluoro-4-(trifluoromethyl), 2-fluoro-4,6-bis(trifluoromethyl), 4-fluoro-2,6-bis(trifluoromethyl), 2,4-dibromo-6-(trifluoromethyl), 2,6-dibromo-4- (trifluoromethyl), 2-bromo-4,6-bis(trifluoromethyl), 4-bromo-2,6-bis(trifluoromethyl), 2-chloro-4,6-bis(trifluoromethoxy), 4-chloro-2,6-bis(trifluoromethoxy), 2,4-difluoro- 6-(trifluoromethoxy), 2,6-difluoro-4-(trifluoromethoxy), 2-fluoro-4,6-bis(trifluoro- methoxy), 4-fluoro-2,6-bis(trifluoromethoxy), 2,4-dibromo-6-(trifluoromethoxy), 2,6- dibromo-4-(trifluoromethoxy), 2-bromo-4,6-bis(trifluoromethoxy), 4-bromo-2,6- bis(trifluoromethoxy), 4,6-dichloro-2-nitro, 4,6-dibromo-2-nitro, 4,6-difluoro-2-nitro, 2,6-dichloro-4-nitro, 2-bromo-3,4,6-trichloro, 6-fluoro-2,4,5-trichloro, 6-chloro- 2,4,5-tribromo, 6-fluoro-2,4,5-tribromo, 2-bromo-3,4,6-trifluoro, 2-chloro-3,4,6- trifluoro, 6-methyl-2,4,5-trichloro, 6-methyl-2,4,5-trbromo, 6-methyl-2,4,5-trifluoro, 6-(trifluoromethyl)-2,4,5-trichloro, 6-(trifluoromethyl)-2,4,5-tribromo, 2-(trifluoro- methyl)-3,4,6-trifluoro, 6-(trifluoromethoxy)-2,4,5-tribromo, 2-(trifluoromethoxy)- 3,4,6-trifluoro, 6-(trifluoromethoxy)-2,4,5-trichloro, 2-bromo-3,5,6-trichloro, 6- fluoro-2,3,5-trichloro, 6-chloro-2,3,5-tribromo, 6-fluoro-2,3,5-tribromo, 2-bromo- 3,5,6-trifluoro, 2-chloro-3,5,6-trifluoro, 6-methyl-2,3,5-trichloro, 6-methyl-2,3,5- tribromo, 2-methyl-3,5,6-trifluoro, 2,3,5-trichloro-6-trifluoromethyl, 2,3,5-tribromo-6- trifluoromethyl), 3,5,6-trifluoro-2-(trifluoromethyl), 3,5,6-trichloro-2-trifluoro- methoxy, 2,3,5-tribromo-6-trifluoromethoxy, 3,5,6-trifluoro-2-trifluoromethoxy, 4- bromo-2,3,5,6-tetrachloro, 4-fluoro-2,3,5,6-tetrachloro,4-chloro-2,3,5,6-tetrabromo-, 4-fluoro-2,3,5,6-tetrabromo, 4-chloro-2,3,5,6-tetrafluoro, 4-bromo-2,3,5,6-tetrafluoro, 2-bromo-3,4,5,6-tetrachloro, 6-fluoro-2,3,4,5-tetrachloro-, 2-chloro-3,4,5,6- tetrafluoro, 2-bromo-3,4,5,6-tetrafluoro, 2-chloro-3,4,5,6-tetrabromo, 2-fluoro-3,4,5,6- tetrabromo, 4-methyl-2,3,5,6-tetrachloro, 4-methyl-2,3,5,6-tetrabromo, 4-methyl- 2,3,5,6-tetrafluoro, 2,3,5,6-tetrachloro-4-(trifluoromethyl), 2,3,5,6-tetrabromo-4- (trifluoromethyl), 2,3,5,6-tetrafluoro-4-(trifluoromethyl), 2,3,5,6-tetrachloro-4- (trifluoromethoxy), 2,3,5,6-tetrabromo-4-(trifluoromethoxy, 2,3,5,6-tetrafluoro-4- (trifluoromethoxy), 6-methyl-2,3,4,5-tetrachloro, 6-methyl-2,3,4,5-tetrabromo, 2- methyl-3,4,5,6-tetrafluoro, 2,3,4,5-tetrachloro-6-(trifluoromethyl), 2,3,4,5-tetrabromo- 6-(trifluoromethyl), 3,4,5,6-tetrafluoro-2-(trifluoromethyl), 2,3,4,5-tetrachloro-6- (trifluoromethoxy), 2,3,4,5-tetrabromo-6-(trifluoromethoxy), and 3,4,5,6-tetrafluoro2- (trifluoromethoxy).
The term heterocyclic refers to a substituted 6 membered unsaturated ring selected from 3- or 4-pyridinyl, 5-pyrimidinyl, 3-pyridazinyl or a 5 membered unsaturated ring selected from 3-thienyl, 3-furyl, 3-pyrrolyl, 4-isoxazolyl, 4- isothiazolyl or 4-pyrazolyl wherein both the positions on the heterocyclic ring adjacent to the bond to the cyclopropyl ring are substituted and the ring is substituted with from 2 to 4 substituents independently selected from (Ct-C4) alkyl, (C3-C7)cycloalkyl, trihalomethyl, trihalomethoxy, halogen, cyano, (Cj-C4)alkoxycarbonyl, nitro, phenyl, and phenoxy. The term heterocyclic also refers to a substituted or unsubstituted 6 membered unsaturated ring containing one, two or three heteroatoms, preferably one, two or three heteroatoms independently selected from oxygen, nitrogen, and sulfur or a 5 membered unsaturated ring containing one, two or three heteroatoms, preferably one or two heteroatoms independently selected from oxygen, nitrogen, and sulfur wherein the heterocyclic ring is unsubstituted or is substituted with from 1 to 3 substituents wherein at least one of the positions of the heterocyclic ring adjacent to the bond to the cyclopropyl ring is a hydrogen substituent. Examples of heterocycles include but are not limited to 2-, 3- or 4-pyridinyl, pyrazinyl, 4-, or 5-pyrimidinyl, pyridazinyl, pyrazole, imidazolyl, 2 or 3-thienyl, 2 or 3-furyl, 3-pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, and thiadiazolyl. These rings may be optionally substituted with up from 1 to 3 substituents independently selected from (Cj-C4) alkyl, (C3-C7)cycloalkyl, trihalomethyl, halogen, cyano, (Cχ- C4)alkoxycarbonyl, nitro, phenyl, and phenoxy.
The term arylalkyl is used to describe a group wherein the alkyl chain is from 1 to 10 carbon atoms and can be branched or straight chain, preferably a straight chain, with the aryl portion, as defined above, forming a terminal portion of the arylalkyl moiety. Typical arylalkyl moieties are optionally substituted benzyl, phenethyl, phenpropyl, and phenbutyl moieties.
Typical benzyl moieties wherein at least one of the positions on the phenyl ring, adjacent to the methylene which is bonded to the cyclopropyl ring, is substituted with hydrogen include but are not limited to 2-chlorobenzyl, 3-chlorobenzyl, 4-chloro- benzyl, 2-fluorobenzyl, 3-fluorobenzyl, 4-fluorobenzyl, 2-bromobenzyl, 3- bromobenzyl, 4-bromobenzyl, 2-trifluoromethylbenzyl, 3-trifluoromethylbenzyl, 4- trifluoromethylbenzyl, 2-methylbenzyl, 3-methylbenzyl, 4-methylbenzyl 2,3- difluorobenzyl, 2,3-dichlorobenzyl, 2,3-dibromobenzyl, 2,3-dimethylbenzyl, 2,4- difluorobenzyl, 2,4-dichlorobenzyl, 2,4-dibromobenzyl, 2,4-dimethylbenzyl, 2,5- difluorobenzyl, 2,5-dichlorobenzyl, 2,5-dibromobenzyl, 2,5-dimethylbenzyl, 3,4- difluorobenzyl, 3,4-dichlorobenzyl, 3,4-dibromobenzyl, 3,4-dimethylbenzyl, 3,5- difluorobenzyl, 3,5-dichlorobenzyl, 3,5-dibromobenzyl, 3,5-dimethylbenzyl,.2,3,4- triifluorobenzyl, 2,3,4-trichlorobenzyl, 2,3,4-tribromobenzyl, and 3,4,5- trichlorobenzyl. Typical benzyl moieties wherein both positions on the phenyl ring, adjacent to the methylene which is bonded to the cyclopropyl ring, are substituted include but are not limited to 2,6-dichlorobenzyl, 2,3,6-trichlorobenzyl, 2,4,6- trichlorobenzyl, 2,6-difluorobenzyl, 2,3,6-fluorobenzyl, 2,4,6-trifluorobenzyl, 2,6- bis(trifluoromethyl)benzyl, 2,3,6-tris(trifluoromethyl)benzyl, 2,4,6- tris(trifluoromethyl)benzyl, 2,3,4,6-tetrachlorobenzyl, 2,3,5,6-tetrachlorobenzyl, 2,3,4,5,6-pentachlorobenzyl, 2,3,4,6-tetrabromobenzyl, 2,3,5,6-tetrabromobenzyl, 2,3,4,5,6-pentabromobenzyl, 2,3,4,6-tefrafluorobenzyl, 2,3,5,6-tefrafluorobenzyl, and 2,3,4,5,6-pentafluorobenzyl. Typical phenethyl moieties wherein at least one of the positions on the phenyl ring, adjacent to the ethyl moiety which is bonded to the cyclopropyl ring, is substituted with hydrogen include but are not limited to 2-(2- chlorophenyl)ethyl, 2-(3-chlorophenyl)ethyl, 2-(4-chlorophenyl)ethyl, 2-(2- fluorophenyl)ethyl, 2-(3-fluorophenyl)ethyl, 2-(4-fluoro- phenyl)ethyl, 2-(2-methylphenyl)ethyl, 2-(3-methylphenyl)ethyl, 2-(4-methylphenyl)- ethyl, 2-(4-trifluoromethylphenyl)ethyl, 2-(2,4-dichlorophenyl)ethyl, and 2-(3,5- dimethoxyphenyl)ethyl. Typical phenethyl moieties wherein both positions on the phenyl ring, adjacent to the ethyl moiety which is bonded to the cyclopropyl ring, are substituted include but are not limited to 2-(2,6-dichlorophenyl)ethyl, 2-(2,3,6- trichlorophenyl)ethyl, 2-(2,4,6-trichlorophenyl)ethyl, 2-(2,6-difluorophenyl)ethyl, 2- (2,3 ,6-trifluorophenyl)ethyl, 2-(2,4,6-trifluorophenyl)ethyl, 2-(2,6-dimethylphenyl)- ethyl, 2-(2,3,6-trimethylρhenyl)ethyl, 2-(2,4,6-trimethylphenyl)ethyl, 2-(2,6-bis- (trifluoromethyl)phenyl)ethyl, 2-(2,3,6-tris(trifluoromethyl)phenyl)ethyl, 2-(2,4,6-tris- (trifluoromethyl)phenyl)ethyl, 2-(2,6-dimethoxyphenyl)ethyl, 2-(2,3 ,6-trimethoxy- phenyl)ethyl, and 2-(2,4,6-trimethoxyphenyl)ethyl. Typical phenpropyl moieties wherein at least one of the positions on the phenyl ring, adjacent to the propyl moiety which is bonded to the cyclopropyl ring, is substituted with hydrogen include but are not limited to 3-phenylpropyl, 3-(2-chlorophenyl)propyl, 3-(3-chlorophenyl)- propyl, 3-(4-chlorophenyl)propyl, 3-(2,4-dichlorophenyl)propyl, 3-(2-fluorophenyl)- propyl, 3-(3-fluorophenyl)propyl, 3-(4-fluorophenyl)propyl, 3-(2-methylphenyl)- propyl, 3-(3-methylphenyl)propyl, 3-(4-methylphenyl)propyl, 3-(4-trifluoromethyl- phenyl)propyl, 3-(2,4-dichlorophenyl)propyl, and 3-(3,5-dimethylphenyl)propyl. Typical phenpropyl moieties wherein both positions on the phenyl ring, adjacent to the propyl moiety which is bonded to the cyclopropyl ring, are substituted include but are not limited to 3-(2,6-dichlorophenyl)propyl, 3-(2,3,6-trichlorophenyl)propyl, 3-(2,4,6- trichlorophenyl)propyl, 3-(2,6-difluorophenyl)propyl, 3-(2,3 ,6-trifluorophenyl)propyl, 3-(2,4,6-trifluorophenyl)propyl, 3-(2,6-dimethylphenyl)propyl, 3-(2,3,6-trimethyl- phenyl)propyl, 3-(2,4,6-trimethylphenyl)propyl and 3-(2,6-bis(trifluoromethyl)phenyl) propyl. Typical phenbutyl moieties wherein at least one of the positions on the phenyl ring, adjacent to the butyl moiety which is bonded to the cyclopropyl ring, is substituted with hydrogen include but are not limited to 4-phenylbutyl, 4-(2-chloro- phenyl)butyl, 4-(3-chlorophenyl)butyl, 4-(4-chlorophenyl)butyl, 4-(2-fluorophenyl)- butyl, 4-(3-fluorophenyl)butyl, 4-(4-fluorophenyl)butyl, 4-(2-methylphenyl)butyl, 4- (3-methylphenyl)butyl, 4-(4-methylphenyl)butyl and 4-(2,4-dichlorophenyl)butyl. Typical phenbutyl moieties wherein both positions on the phenyl ring, adjacent to the butyl moiety which is bonded to the cyclopropyl ring, are substituted include but are not limited to 4-(2,6-di-chlorophenyl)butyl, 4-(2,3,6-trichlorophenyl)butyl, 4-(2,4,6- trichlorophenyl)butyl, 4-(2,6-difluorophenyl)butyl, 4-(2,3,6-trifluorophenyl)butyl, 4- (2,4,6-trifluorophenyl)-butyl, 4-(2,6-dimethylphenyl)butyl, 4-(2,3 ,6-trimethyl- phenyl)butyl, 4-(2,4,6-trimethylphenyl)butyl and 4-(2,6-bis(trifluoromethyl)- phenyl)butyl.
Halogen or halo includes iodo, fluoro, bromo and chloro.
The compounds of the general Formula I may be obtained in preparation as E/Z isomeric mixtures. These isomers can be separated into individual components by conventional means. The substituted cyclopropanes of Formula I may be obtained in preparation as cis and trans isomeric mixtures which can be separated into individual components by conventional means. Both the individual isomeric compounds and mixtures thereof form subjects of the present invention and can be used as fungicides and insecticides.
One preferred embodiment of this invention is the compounds, enantiomorphs, salts and complexes of Formula I wherein A, R4, and R5 are hydrogen; Rj and R2 are independently (Cj-C4)alkyl; R7 is phenyl, phenylalkyl, or heterocyclic such that the positions on the phenyl ring and heterocyclic ring adjacent to the bond to the cyclopropyl ring are substituted, and R6 is selected from hydrogen, (Cj-Cj^alkyl, halo(CrC12)alkyl, (C3-C7)cycloalkyl, halo(C3-C7)cycloalkyl, (C2-C8)alkenyl, halo(C2- C8)alkenyl, (C2-C8)alkynyl, and halo(C2-C8)alkynyl.
A more preferred embodiment of this invention is the compounds, enantiomorphs, salts and complexes of Formula I wherein A, R4, and R5 are hydrogen; Rj and R2 are independently (Cj-C4)alkyl; R6 is hydrogen or (C1-C12)alkyl; and R7 is 2,6-disubstitutedphenyl, 2,3,6-trisubstitutedphenyl,or 2,4,6- trisubstitutedphenyl. An even more preferred embodiment of this invention is the compounds, enantiomorphs, salts and complexes of Formula I wherein A, R4, and R5 are hydrogen; Rj and R2 are CH3; R6 is hydrogen or (C1-C4)alkyl; and R7 is 2,6-dihalophenyl, 2,3,6- trihalophenyl, or 2,4,6-trihalophenyl
A second preferred embodiment of this invention is the compounds, enantiomorphs, salts and complexes of in Formula I wherein A, R4, and R5 are hydrogen; Rj and R2 are independently (Cj-C^alkyl; R7 is phenyl, phenylalkyl, or heterocyclic wherein at least one of the positions on the phenyl or heterocyclic ring adjacent to the bond to the cyclopropyl ring is a hydrogen substituent; and R6 is hydrogen, (Cj-C12)alkyl, halo(C1-C12)alkyl, (C3-C7)cycloalkyl, halo(C3-C7)cycloalkyl, (C2-C8)alkenyl, halo(C2-C8)alkenyl, (C2-C8)alkynyl, or halo(C2-C8)alkynyl.
A second more preferred embodiment of this invention is the compounds, enantiomorphs, salts and complexes of Formula I wherein; A, R4, and R5 are hydrogen; Rj and 1^ is CH3; R7 is phenyl, 2-substitutedphenyl, 3-substitutedphenyl, 4- substitutedphenyl, 2,3-disubstitutedphenyl 2,4-disubstitutedphenyl, 2,5- disubstitutedphenyl, 3,4-disubstitutedphenyl, 3,5-disubstituted, 2,3,4- trisubstitutedphenyl, 2,3,5-trisubstitutedphenyl, 2,4,5-trisubstitutedphenyl, 3,4,5- trisubstitutedphenyl, or 2,3,4,5-tetrasubstitutedphenyl; and R6is hydrogen, (C1(C1- C4)alkyl or halo(CrC4)alkyl.
A second even more preferred embodiment of this invention is the compounds, enantiomorphs, salts and complexes of Formula I wherein A, R4, and R5 are hydrogen; Rj and j are CH3; R7 is phenyl, 2-halophenyl, 3-halophenyl, 4-halophenyl, 2,3- dihalophenyl 2,4-dihalophenyl, 2,5-dihalophenyl, 3,4-dihalophenyl, 3,5-dihalophenyl, 2,3,4-trihalophenyl, 2,3,5-trihalophenyl, 2,4,5-trihalophenyl, or 3,4,5-trihalophenyl, and R6 is hydrogen or (Cj-C4)alkyl.
A most preferred embodiment of this invention is the compounds, enantiomorphs, salts and complexes of Formula II wherein R7 is 2,6-dichlorophenyl,
2,3,6-trichlorophenyl or 2,4,6-trichlorophenyl.
π
Another most preferred embodiment of this invention is the compounds, enantiomorphs, salts and complexes of Formula IF wherein R7 is phenyl, 2- chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-fluorophenyl, 3 -fluorophenyl or 4- fluorophenyl and R6 is CH3.
IF Typical compounds of Formula I encompassed by the present invention wherein A, R4 and R5 are hydrogen; and Rj is methyl include those compounds presented in Table 1 of Formula III where R2, R6, and R7 are as defined in Table 1
Formula III Table 1
Compd# £2 £7
1.1 H H Ph
1.2 H H 4-Cl(Ph)
1.3 H H 4-Br(Ph)
1.4 H H 4-F(Ph)
1.5 H H 4-OCH3(Ph)
1.6 H H 4-CF3(Ph)
1.7 H H 4-N02(Ph)
1.8 H H 2,4-Cl(Ph)
1.9 H H 2,4-F(Ph)
1.10 H H 3,4-F(Ph)
1.11 CH. H Ph
1.12 CH H 2-Cl(Ph)
1.13 CH H 3-Cl(Ph)
1.14 CH H 4-Cl(Ph)
1.15 CH H 2-Br(Ph)
1.16 CH H 3-Br(Ph)
1.17 CH H 4-Br(Ph)
1.18 CH H 2-F(Ph)
1.19 CH H 3-F(Ph)
1.20 CH. H 4-F(Ph)
1.21 CH. H 2-OCH3(Ph)
1.22 CH. H 3-OCH3(Ph)
1.23 CH H 4-OCH3(Ph)
1.24 CH H 2-CH3(Ph)
1.25 CH H 3-CH3(Ph)
1.26 CH H 4-CH3(Ph)
1.27 CH H 2-CF3(Ph)
1.28 CH H 3-CF3(Ph)
O O O O O O O O Q O O O O O O Q Q O O O Q O O O Q O O Q O O O Q O O O O O O O O O O O O O
ffi |ι| !- i-ι-| ffi |---! l---l K ffi l---! l-ι-i l---! W
1.77 CH3 CH3 2,4-F(Ph)
1.78 CH3 CH3 2,5-F(Ph)
1.79 CH3 CH3 3,4-F(Ph)
1.80 CH3 CH3 3,5-F(Ph)
1.81 CH3 CH3 2,4,5-F(Ph)
1.82 CH3 CH3 2,4,5-Cl(Ph)
1.83 CH3 CH3 3,4,5-Cl(Ph)
1.84 CH3 CH3 2,3,4,5-Cl(Ph)
1.85 CH3 CH3 2,3,5-F(Ph)
1.86 CH3 CH3 3,4,5-F(Ph)
1.87 CH3 CH3 2,3,4,5-F(Ph)
1.88 CH3 CH3 Ph
1.89 n-C2H5 CH3 2-Cl(Ph)
1.90 n-C2H5 CH3 3-Cl(Ph)
1.91 n-C2H5 CH3 4-Cl(Ph)
1.92 n-C2H5 CH3 4-Br(Ph)
1.93 n-C2H5 CH3 2-F(Ph)
1.94 n-C2H5 CH3 3-F(Ph)
1.95 n-C2H3 CH3 4-F(Ph)
1.96 n-C2H5 CH3 2-OCH3(Ph)
1.97 n-C2H5 CH3 3-OCH3(Ph)
1.98 n-C2H5 CH3 4-OCH3(Ph)
1.99 n-C2H5 CH3 2-CH3(Ph)
1.100 n-C3H7 CH3 3-CH3(Ph)
1.101 n-C3H7 CH3 4-CH3(Ph)
1.102 n-C3H7 CH3 2-CF3(Ph)
1.103 n-C3H7 CH3 3-CF3(Ph)
1.104 cyclopropyl H Ph
1.105 cyclopropyl H 2-Cl(Ph)
1.106 cyclopropyl H 3-Cl(Ph)
1.107 cyclopropyl H 4-Cl(Ph)
1.108 cyclopropyl H 4-Br(Ph)
1.109 cyclopropyl H 2-F(Ph)
1.110 cyclopropyl H 3-F(Ph)
1.111 cyclopropyl H 4-F(Ph)
1.112 cyclopropyl H 2-OCH3(Ph)
1.113 cyclopropyl H 3-OCH3(Ph)
1.114 cyclopropyl H 4-OCH3(Ph)
1.115 cyclopropyl H 2-CH3(Ph)
1.116 cyclopropyl H 3-CH3(Ph)
1.117 cyclopropyl H 4-CH3(Ph)
1.118 cyclopropyl H 2-CF3(Ph)
1.119 cyclopropyl H 3-CF3(Ph)
1.120 cyclopropyl H 4-CF3(Ph)
1.121 cyclopropyl H 2-N02(Ph)
1.122 cyclopropyl H 2-N02(Ph)
1.123 cyclopropyl H 4-N02(Ph)
1.124 cyclopropyl H 2,3-Cl(Ph)
1.125 cyclopropyl H 2,4-Cl(Ph) 1.126 cyclopropyl H 2,5-Cl(Ph)
1.127 cyclopropyl H 3,4-Cl(Ph)
1.128 cyclopropyl H 3,5-Cl(Ph)
1.129 cyclopropyl H 2,3,5-Cl(Ph)
1.130 cyclopropyl H 2,4-Br(Ph)
1.131 cyclopropyl H 2,6-Br(Ph)
1.132 cyclopropyl H 2,3-F(Ph)
1.133 cyclopropyl H 2,4-F(Ph)
1.134 cyclopropyl H 2,5-F(Ph)
1.135 cyclopropyl H 3,4-F(Ph)
1.136 cyclopropyl H 3,5-F(Ph)
1.137 cyclopropyl H 2,4,5-F(Ph)
1.138 cyclopropyl H 2,4,5-Cl(Ph)
1.139 cyclopropyl H 3,4,5-Cl(Ph)
1.140 cyclopropyl H 2,3,4,5-Cl(Ph)
1.141 cyclopropyl H 2,3,5-F(Ph)
1.142 cyclopropyl H 3,4,5-F(Ph)
1.143 cyclopropyl H 2,3,4,5-F(Ph)
1.144 cyclopropyl CH3 Ph
1.145 cyclopropyl CH3 2-Cl(Plι)
1.146 cyclopropyl CH3 3-Cl(Ph)
1.147 cyclopropyl CH3 4-Cl(Ph)
1.148 cyclopropyl CH3 4-Br(Ph)
1.149 cyclopropyl CH3 2-F(Ph)
1.150 cyclopropyl CH3 3-F(Ph)
1.151 cyclopropyl CH3 4-F(Ph)
1.152 cyclopropyl CH3 2-OCH3(Ph)
1.153 cyclopropyl CH3 3-OCH3(Ph)
1.154 cyclopropyl CH3 4-OCH3(Ph)
1.155 cyclopropyl CH3 2-CH3(Ph)
1.156 cyclopropyl CH3 3-CH3(Ph)
1.157 cyclopropyl CH3 4-CH3(Ph)
1.158 cyclopropyl CH3 2-CF3(Ph)
1.159 cyclopropyl CH3 3-CF3(Ph)
1.160 cyclopropyl CH3 4-CF3(Ph)
1.161 cyclopropyl CH3 2-N02(Ph)
1.162 cyclopropyl CH3 3-N02(Ph)
1.163 cyclopropyl CH3 4-N02(Ph)
1.164 cyclopropyl CH3 2,3-Cl(Ph)
1.165 cyclopropyl CH3 2,4-Cl(Ph)
1.166 cyclopropyl CH3 2,5-Cl(Ph)
1.167 cyclopropyl CH3 3,4-Cl(Ph)
1.168 cyclopropyl CH3 3,5-Cl(Ph)
1.169 cyclopropyl CH3 2,3,5-Cl(Ph)
1.170 cyclopropyl CH3 2,3-F(Ph)
1.171 cyclopropyl CH3 2,4-F(Ph)
1.172 cyclopropyl CH3 2,5-F(Ph)
1.173 cyclopropyl CH3 3,4-F(Ph) 1.174 cyclopropyl CH3 3,5-F(Ph)
1.175 cyclopropyl CH3 2,4,5-FCPh)
1.176 cyclopropyl CH3 2,4,5-Cl(Ph)
1.177 cyclopropyl CH3 3,4,5-Cl(Ph)
1.178 cyclopropyl CH3 2,3,4,5-Cl(Ph)
1.179 cyclopropyl CH3 2,3,5-F(Ph)
1.180 cyclopropyl CH3 3,4,5-F(Ph)
1.181 cyclopropyl CH3 2,3,4,5-F(Ph)
1.182 CN H Ph
1.183 CN H 2-Cl(Ph)
1.184 CN H 3-Cl(Ph)
1.185 CN H 4-Cl(Ph)
1.186 CN H 4-Br(Ph)
1.187 CN H 2-F(Ph)
1.188 CN H 3-F(Ph)
1.189 CN H 4-F(Ph)
1.190 CN H 2-OCH3(Ph)
1.191 CN H 3-OCH3(Ph)
1.192 CN H 4-OCH3(Ph)
1.193 CN H 2-CH3(Ph)
1.194 CN H 3-CH3(Ph)
1.195 CN H 4-CH3(Ph)
1.196 CN H 2-CF3(Ph)
1.197 CN H 3-CF3(Ph)
1.198 CN H 4-CF3(Ph)
1.199 CN H 2-N02(Ph)
1.200 CN H 3-N02(Ph)
1.201 CN H 4-N02(Ph)
1.202 CN H 2,3-Cl(Ph)
1.203 CN H 2,4-Cl(Ph)
1.204 CN H 2,5-Cl(Ph)
1.205 CN H 3,4-Cl(Ph)
1.206 CN H 3,5-Cl(Ph)
1.207 CN H 2,3,5-CKPh)
1.208 CN H 2,3-F(Ph)
1.209 CN H 2,4-F(Ph)
1.210 CN H 2,5-F(Ph)
1.211 CN H 3,4-F(Ph)
1.212 CN H 3,5-F(Ph)
1.213 CN H 2,4,5-F(Ph)
1.214 CN H 2,4,5-Cl(Ph)
1.215 CN H 3,4,5-Cl(Ph)
1.216 CN H 2,3,4,5-Cl(Ph)
1.217 CN H 2,3,5-F(Ph)
1.218 CN H 3,4,5-F(Ph)
1.219 CN H 2,3,4,5-F(Ph)
1.220 CN CH3 Ph
1.221 CN CH, 2-Cl(Ph) to ι-o to to to ι-0 1-o to N- to .o .o -o to ιo to ι-o ι-o to ι-o to . to to to to .-o to t
CΛ σ. -^ σ. -Λ Λ -^ -Λ -Λ σ- .Λ -Λ -Λ -Λ -Λ Lft Ul Uι t-rt -^ -ti .|-^ ^0 -∞ . σN l 4^ U-' .O -' O O -X- * -Λ -Λ 4^ ω *>O he ^ OO ^ σ. .-*l 4^ ω tO h--. 0 ^ ∞
D D G Q G G G G Q G Q G Q Q Q Q Q Q Q Q Q Q Q Q Q Q o ^ n n n n n n o n Q Q O O O O O O
-z- z -zi z ≥i -zi -z; --, !-?;
O Ω
1.271 CH3 -.SO-C4H9 4-Cl(Ph)
1.272 CH3 iso-C4H9 4-F(Ph)
1.273 CN C2H5 Ph
1.274 CN C2H5 4-Cl(Ph)
1.275 CN C2H5 4-F(Ph)
1.276 CN n-C3H7 Ph
1.277 CN n-C3H7 4-Cl(Ph)
1.278 CN n-C3H7 4-F(Ph)
1.279 CN iso-C3H7 Ph
1.280 CN iso-C3H7 4-Cl(Ph)
1.281 CN iso-C3H7 4-F(Ph)
1.282 CF3 C2H5 Ph
1.283 CF3 n-C3H7 Ph
1.284 CF3 iso-C3H7 Ph
1.285 CF3 n-C4H9 Ph
1.286 H H PhCH2
1.287 H H 4-Cl(Ph)CH2
1.288 H H 4-Br(Ph)CH2
1.289 H H 4-F(Ph)CH2
1.290 H H 4-OCH3(Ph)CH2
1.291 H H 4-CF3(Ph)CH2
1.288 H H 4-N02(Ph)CH2
1.289 H H 2,4-Cl(Ph)CH2
1.290 H H 2,4-F(Ph)CH2
1.291 H H 3,4-F(Ph)CH2
1.288 H H 3,5-F(Ph)CH2
1.289 H H 2,3,5-F(Ph)CH2
1.290 H H 2,4,5-F(Ph)CH2
1.291 H H 3,4,5-F(Ph)CH2
1.292 CH3 H PhCH2
1.293 CH3 H 4-Cl(Ph)CH2
1.294 CH3 H 4-Br(Ph)CH2
1.295 CH3 H 4-F(Ph)CH2
1.296 CH3 H 4-OCH3(Ph)CH2
1.297 CH3 H 4-CF3(Ph)CH2
1.298 CH3 H 4-N02(Ph)CH2
1.299 CH3 H 2,3-Cl(Ph)CH2
1.300 CH3 H 2,3-F(Ph)CH2
1.301 CH3 H 2,4-Cl(Ph)CH2
1.302 CH3 H 2,4-F(Ph)CH2
1.303 CH3 H 2,5-Cl(Ph)CH2
1.304 CH3 H 2,5-F(Ph)CH2
1.305 CH3 H 3,4-Cl(Ph)CH2
1.306 CH3 H 3,4-F(Ph)CH2
1.307 CH3 H 3,5-Cl(Ph)CH2
1.308 CH3 H 3,5-F(Ph)CH2
1.309 CH3 H 2,3,5-Cl(Ph)CH2 iθ UJ UJ .- υJ ω ω ω -iJ υ-' υ-' -j-' -<- --* -*- -i-' > ω u-' ω -- -Λ -> --Λ σ. --* ->- -Λ 4^ ^ 4-^ ^ 4^ 4-' 4-. 4^ 4^ ω ω -jJ ω σ. -Λ 4^ ω t>θ h-> o o ' -*- ^ σ. -Λ -. ---- . -ι o ^o ∞ -^ -Λ -Λ 4^ υ-> . - > ∞
O n o O O O O O Ω O O O O O O O O O O O O Q O O O O Q Q O O Q Q O O O O O Q O Q Q O O O O -^ 2 -z; 2 -z- ---522 ^ 22 at. ---, - :--? - -3 -^ ^ OAOAW js , OAOAW , OAW , w a a , a a , a S K K K K S B a a a a a a
a a a. a a a a a. . a. a a a a a a a a a a a. a. a. a. a. a. a. a. a. a a a. a. a. , a. a a a a a a oo a a a a
1.367 CN CH3 2,3,5-F(Ph)CH2
1.368 CN CH3 2,4,5-F(Ph)CH2
1.369 CN CH3 3,4,5-F(Ph)CH2
1.370 CN CH3 PhCH2
1.371 CN CH3 4-Cl(Ph)CH2
1.372 CN CH3 4-Br(Ph)CH2
1.373 CN CH3 4-F(Ph)CH2
1.374 CF3 H 4-OCH3(Ph)CH2
1.375 CF3 H 4-CF3(Ph)CH2
1.376 CF3 H 4-N02(Ph)CH2
1.377 CF3 H 2,3-Cl(Ph)CH2
1.378 CF3 H 2,3-F(Ph)CH2
1.379 CF3 H 2,4-Cl(Ph)CH2
1.380 CF3 H 2,4-F(Ph)CH2
1.381 CF3 H 2,5-Cl(Ph)CH2
1.382 CF3 H 2,5-F(Ph)CH2
1.383 CF3 H 3,4-Cl(Ph)CH2
1.384 CF3 CH3 3,4-F(Ph)CH2
1.385 CF3 CH3 3,5-Cl(Ph)CH2
1.386 CF3 CH3 3,5-F(Ph)CH2
1.387 CF3 CH3 2,3,5-Cl(Ph)CH2
1.388 CF3 CH3 2,4,5-Cl(Ph)CH2
1.389 CF3 CH3 3,4,5-Cl(Ph)CH2
1.390 CF3 CH3 2,3,5-F(Ph)CH2
1.391 CF3 CH3 2,4,5-F(Ph)CH2
1.392 CF3 CH3 3,4,5-F(Ph)CH2
1.393 CF3 CH3 PhCH2
1.394 CF3 CH3 4-Cl(Ph)CH2
1.395 CF3 CH3 4-Br(Ph)CH2
1.396 CF3 CH3 4-F(Ph)CH2
1.397 cyclopropyl H 4-OCH3(Ph)CH2
1.398 cyclopropyl H 4-CF3(Ph)CH2
1.399 cyclopropyl H 4-N02(Ph)CH2
1.400 cyclopropyl H 2,3-Cl(Ph)CH2
1.401 cyclopropyl H 2,3-F(Ph)CH2
1.402 cyclopropyl H 2,4-Cl(Ph)CH2
1.403 cyclopropyl H 2,4-F(Ph)CH2
1.404 cyclopropyl H 2,5-Cl(Ph)CH2
1.405 cyclopropyl CH3 2,5-F(Ph)CH2
1.406 cyclopropyl CH3 3,4-Cl(Ph)CH2
1.407 cyclopropyl CH3 3,4-F(Ph)CH2
1.408 cyclopropyl CH3 3,5-Cl(Ph)CH2
1.409 cyclopropyl CH3 3,5-F(Ph)CH2
1.410 cyclopropyl CH3 2,3,5-Cl(Ph)CH2
1.411 cyclopropyl CH3 2,4,5-Cl(Ph)CH2
1.412 cyclopropyl CH3 3,4,5-Cl(Ph)CH2
1.413 cyclopropyl CH3 2,3,5-F(Ph)CH2
1.414 cyclopropyl CH3 2,4,5-F(Ph)CH2
1.415 cyclopropyl CH3 3,4,5-F(Ph)CH2 4-. 4-- Λ -Λ ω tθ
H t"ϋ t-r t
0 0
P-H ffi
OaOa
1.464 CF3 iso-C3H7 PhCH2CH2
1.465 CF3 n-C4H9 PhCH2CH2
1.466 CF3 -S0-C4H9 PhCH2CH2
1.467 CF3 CH2=CH PhCH2CH2
1.468 CF3 CH3CH=CH PhCH2CH2
1.469 cyclopropyl CH3 PhCH2CH2
1.470 cyclopropyl C2H5 PhCH2CH2
1.471 cyclopropyl n-C3H7 PhCH2CH2
1.472 cyclopropyl iso-C3H7 PhCH2CH2
1.463 cyclopropyl n-C4H9 PhCH2CH2
1.464 cyclopropyl iso-C4H9 PhCH2CH2
1.465 cyclopropyl CH2=CH PhCH2CH2
1.466 cyclopropyl CH3CH=CH PhCH2CH2
1.467 CH3 H 4Cl(Ph)CH2CH2
1.468 CH3 CH3 4Cl(Ph)CH2CH2
1.469 CH3 C2H5 4Cl(Ph)CH2CH2
1.470 cyclopropyl H 4Cl(Ph)CH2CH2
1.471 CH3 H 4F(Ph)CH2CH2
1.472 CH3 CH3 4F(Ph)CH2CH2
1.473 CH3 C2H5 4F(Ph)CH2CH2
1.474 cyclopropyl H 4F(Ph)CH2CH2
1.475 cyclopropyl CH3 4F(Ph)CH2CH2
1.476 H CH3 PhCH2CH2CH2
1.477 CH3 CH3 PhCH2CH2CH2
1.478 CH3 C2H5 PhCH2CH2CH2
1.479 CH3 n-C3H7 PhCH2CH2CH2
1.480 CH3 iso-C3H7 PhCH2CH2CH2
1.481 CH3 n-C-pHg • PhCH2CH2CH2
1.482 CH3 iso-C4H9 PhCH2CH2CH2
1.483 CH3 CH2=CH PhCH2CH2CH2
1.484 CH3 GH3GH=C.H- PhCH2CH2CH2
1.485 CN CH3 PhCH2CH2CH2
1.486 CN C2H5 PhCH2CH2CH2
1.487 CN n-C3H7 PhCH2CH2CH2
1.488 CN iso-C3H7 PhCH2CH2CH2
1.489 CN n- -4H9 PhCH2CH2CH2
1.480 CN iso-C^g PhCH2CH2CH2
1.481 CN CH2=CH PhCH2CH2CH2
1.482 CN CH3CH=CH PhCH2CH2CH2
1.483 CF3 CH3 PhCH2CH2CH2
1.484 CF3 C2H5 PhCH2CH2CH2
1.485 CF3 n-C3H7 PhCH2CH2CH2
1.486 CF3 iso-C3H7 PhCH2CH2CH2
1.487 CF3 n-C4H9 PhCH2CH2CH2
1.488 CF3 isO-C^g PhCH2CH2CH2
1.489 CF3 CH2=CH PhCH2CH2CH2
1.490 CF3 CH3CH=CH PhCH2CH2CH2 Typical compounds of Formula I encompassed by the present invention wherein A, R4 and R5 are hydrogen; and Rj is methyl include those compounds presented in Table 2 of Formula III where R2, R6, and R7 are as defined in Table 2.
Formula III
Table 2
Compd # £2 £6 £7
2.1 H H 2-pyridyl
2.2 H H 3-pyridyl
2.3 H H 4-pyridyl
2.4 H H 2-pyrazinyl
2.5 H H 4-pyrimidinyl
2.6 H H 5-pyrimidinyl
2.7 H H 3-pyridazinyl
2.8 H H 4-pyridazinyl
2.9 H H 2-furyl
2.10 H H 3-furyl
2.11 H H 2-thienyl
2.12 H H 3-thienyl
2.13 CH H 2-pyridyl
2.14 CH H 3-pyridyl
2.15 CE H 4-pyridyl
2.16 CH H 2-pyrazinyl
2.17 CH; H 4-pyrimidinyl
2.18 CH H 5-pyrimidinyl
2.19 CH H 3-ρyridazinyl
2.20 CH H 4-pyridazinyl
2.21 CH H 2-furyl
2.22 CH H 3-furyl
2.23 CH H 2-thienyl
2.24 CH H 3-thienyl
2.25 CH H l-CH3-3-(lH)-
2.26 CH H l-CH3-4-(lH)-
2.27 CH H 5-(lH)-pyrazolyl
2.28 CH H 4-( 1 H)-imidazolyl
2.29 CH H 5-(lH)---midazolyl
2.30 CH H 5-(lH)-pyrazolyl
2.31 CH H 3-isothiazolyl
2.32 CH H 4-isothiazolyl
2.33 CH H 5-isothiazolyl
2.34 CH H 4-thiazolyl
2.35 CH H 5-thiazolyl 2.36 CH3 H 3-isooxazolyl
2.37 CH3 H 4-isooxazolyl
2.38 CH3 H 5-isooxazolyl
2.39 CH3 H 4-oxazolyl
2.40 CH3 H 5-oxazolyl
2.41 CH3 H l-methyl-2-(lH)-
2.42 CH3 H l-methyl-3-(lH)-
2.43 CH3 H 2-quinolinyl
2.44 CH3 H 3-quinolinyl
2.45 CH3 H 4-quinolinyl
2.46 CH3 H 3-Cl-pyrid-2-yl
2.47 CH3 H 2-Cl-pyrid-3-yl
2.48 CH3 H 2-Cl-pyrid-4-yl
2.49 CH3 H 4-Cl-furan-2-yl
2.50 CH3 H 2-Cl-furan-3-yl
2.51 CH3 CH3 2-ρyridyl
2.52 CH3 CH3 3-pyridyl
2.53 CH3 CH3 4-pyridyl
2.54 CH3 CH3 2-fixryl
2.55 CH3 CH3 3-furyl
2.56 CH3 CH3 2-thienyl
2.57 CH3 CH3 3-thienyl
2.58 C2H5 H 2-pyridyl
2.59 C2H5 H 3-pyridyl
2.60 C2H5 H 4-pyridyl
2.61 C2H5 CH3 2-furyl
2.62 C2H5 CH3 3-furyl
2.63 C2H5 CH3 2-thienyl
2.64 C2H5 CH3 3-thienyl
2.65 n-C3H7 H 2-pyridyl
2.66 n-C3H7 H 3-pyridyl
2.67 n-C3H7 H 4-pyridyl
2.68 n-C3H7 CH3 2-furyl
2.69 n-C3H7 CH3 3-furyl
2.70 n-C3H7 CH3 2-thienyl
2.71 n-C3H7 CH3 3-thienyl
2.72 n-C4H9 H 2-pyridyl
2.73 n-C4H9 H 3-pyridyl
2.74 n-C4H9 H 4-pyridyl
2.75 n-C4H9 CH3 2-furyl
2.76 n-C4H9 CH3 3-furyl
2.77 n-C4H9 CH3 2-thienyl
2.78 n-C4H9 CH3 3-thienyl
2.79 iso-C H9 H 2-pyridyl
2.80 iso-C4H9 H 3-pyridyl
2.81 iso-C4H9 H 4-pyridyl
2.82 iso-CtHg CH3 2-foryl
2.83 iso-C4H9 CH3 3-furyl to to to to to to
--O l- OJ ) t t u w π o '-' ∞
l-- | > --J -O ) t φ ) O OJ t Φ' J tO 4--. ω to oj to Φ- ) to ω Φ- ω to -*> to Φ>- w to _ to Φ- -. to l- to ω to ft ft O O "- ft ft O O *■-* ft ft "T-l O TJ 43 *-_t "a ft ft i Ό *-J *τj T-S -j I 4 O3 O *τ_* O *T-J ft ft i 43 43 t3 ft ft
* -π t* "
Q 3 P---. ■ P----. \ a P--i. PI. p--- E ffi' P p≤. £ a E . § m. H n. ^ P a.. S pp--J.. "2 pp.. o o-π B- Q P. P. P. o' g' P P Ci.. 3c--.. P--u. QP ffi P' P p.. 3 p.. P p.. s P' P p.. 3 p.. P p..
*^ p. < p. ^ p-. •< P ^ P p. o, B -p- p. p. .p p h p. ■--. p.131 p g <-J p. p, ft P P
^ '≤.'≤. '≤- '≤- '≤. '≤. ^ •i-i -i-i *- * «
2.134 CF3 CH3 2-pyridyl
2.135 CF3 CH3 3-pyridyl
2.136 CF3 CH3 4-pyridyl
2.134 CF3 CH3 2-furyl
2.135 CF3 CH3 3-furyl
2.136 CF3 CH3 2-thienyl
2.137 CF3 CH3 3-thienyl
2.138 CF3 C2H5 2-pyridyl
2.139 CF3 C2H5 3-pyridyl
2.140 CF3 C2H5 4-pyridyl
2.141 CF3 C2H5 2-furyl
2.142 CF3 C2H5 3-furyl
2.143 CF3 C2H5 2-thienyl
2.144 CF3 C2H5 3-thienyl
2.145 CN CH3 2-pyridyl
2.146 CN CH3 3-pyridyl
2.147 CN CH3 4-pyridyl
2.148 CN CH3 2-furyl
2.149 CN CH3 3-furyl
2.150 CN CH3 2-thienyl
2.151 CN CH3 3-thienyl
2.152 CN Q2H5 2-pyridyl
2.153 CN C2H5 3-pyridyl
2.154 CN C2H5 4-pyridyl
2.155 CN C2H5 2-furyl
2.156 CN C2H5 3-furyl
2.157 CN C2H5 2-thienyl
2.158 CN C2H5 3-thienyl
Typical compounds of Formula I encompassed by the present invention wherein A, R4 and R5 are hydrogen and Rt is methyl include those compounds presented in Table 3 of Formula III 3
Formula III
Table 3
Compd # S6 £7
3.1 H H 2,6-CΪ(Ph)
3.2 H H 2,3,6-Cl(Ph)
3.3 H H 2,4,6-Cl(Ph)
3.4 H H 2,6-Br(Ph)
3.5 H H 2,3,6-Br(Ph) oj ω u- . ln -Λ ln Ln ω tθ h-> o
O aOaOaOaOaOaOaOaOaQ a,Q a,O a,O aO aO a,O a,O a,O a,O a O a,O a,O a,O a,O a,O aO aOaOaQa OaOaOaOaOaOaOaOaOaWwMaMaMaWa aμarf aHaμa^,
a a a a a a a a a a a a a a a a a a a a a a a a a a a a a a a a a a a a a a a a a a a a a a a a
3.54 CH3 H 2,3,5,6-PhO(Ph)
3.55 CH3 H 2,3,4,5,6-PhO(Ph)
3.56 CH3 H 2;3,4,6-Br(Ph)
3.57 CH3 H 2,3,5,6-Br(Ph)
3.58 CH3 H 2,3,4,5,6-Br(Ph)
3.59 CH3 H 2,3,4,6-F(Ph)
3.60 CH3 H 2,3,5,6-F(Ph)
3.61 CH3 H 2,3,4,5,6-F(Ph)
3.62 CH3 H 2,3,4,6-CH3(Ph)
3.63 CH3 H 2,3,5,6-CH3(Ph)
3.64 CH3 H 2,3,4,5,6-CH3(Ph)
3.65 CH3 H 2,3,4,6-C2H5(Ph)
3.66 CH3 H 2,3,5,6-C2H5(Ph)
3.67 CH3 H 2,3,4,5,6-C2H5(Ph)
3.68 CH3 H 2,3,4,6-CH30(Ph)
3.69 CH3 H 2,3,5,6-CH30(Ph)
3.70 CH3 H 2,3,4,5,6-CH30(Ph)
3.71 CH3 H 2,3,4,6-CF3(Ph)
3.72 CH3 H 2,3,5,6-CF3(Ph)
3.73 CH3 H 2,3,4,5,6-CF3(Ph)
3.74 CH3 H 2,3,4,6-CF30(Ph)
3.75 CH3 H 2,3,5,6-CF30(Ph)
3.76 CH3 H 2,3,4,5,6-CF30(Ph)
3.77 CH3 H 2,3,4,6-CN(Ph)
3.78 CH3 H 2,3,5,6-CN(Ph)
3.79 CH3 H 2,3,4,5,6-CN(Ph)
3.80 CH3 H 2-Br-6-Cl(Ph)
3.81 CH3 H 2-Br-6-F(Ph)
3.82 CH3 H 2-Br-6-CH3(Ph)
3.83 CH3 H 2-Br-6-CF3(Ph)
3.84 CH3 H 2-Br-6-CH30(Ph)
3.85 CH3 H 2-Br-6-CF30(Ph)
3.86 CH3 H 2-Br-6-CN(Ph)
3.87 CH3 H 2-Cl-6-F(Ph)
3.88 CH3 H 2-Cl-6-CH3(Ph)
3.89 CH3 H 2-Cl-6-CF3(Ph)
3.90 CH3 H 2-Cl-6-CH30(Ph)
3.91 CH3 H 2-Cl-6-CF30(Ph)
3.92 CH3 H 2-Cl-6-CN(Ph)
3.93 CH3 H 2-F-6-CH3(Ph)
3.94 CH3 H 2-F-6-CF3(Ph)
3.95 CH3 H 2-F-6-CH30(Ph)
3.96 CH3 H 2-F-6-CF30(Ph)
3.97 CH3 H 6-CN,-F(Ph)
3.98 CH3 H 2-CH3-6-CF3(Ph)
3.99 CH3 H 6-CH30-2-CH3(Ph)
3.100 CH3 H 2-CH3-6-CF30(Ph)
3.101 CH3 H 6-CN-20Me(Ph) ι-o ι-o -o - t-o t-o ι-o u-' -o ι-o ι-o t-o ι-o ι-o t-o --o ω t-o w uJ t-o t-o -o ω
4--. 4-. -^ -^ φ-. 4--. φ-. φ-. 4--. 4--. ι-o .J l-o ι-o -o -o (-o t- t-o -o to t to t t^ *O C» l ft t-i. -^ ω tO h- O ' 00 l ft t-Λ 4^ -0 tO h-- O 0 00 --0 ιft -Λ φ^ -0 tO ι—' O O oo ^ ft t-/
O O O O O O O O O O O Q O O O O O O O O O Q Q O O Q Q O O O Q O O Q H pp H H pp pp PH PH PP PH , PH PH PH PH PH PH E P PH HH K HH H PH HH PH PH PH HH
ffi ffi ffi W ffi K ffi π ffi ffl ffi W M ffi ffi ffi
t-o t-o tjj i-o -o i-o i-o i-o -o i-o i-o t-o i-o i-o t-o i-o t-o -o i-o t-o i-o t-o t-o ω
^ ! ^ ∞ l l ^ * l l ! . l l ft ft ft ft ft ft ft ft ft ft Λ t-n -Λ t-n <-Λ lΛ t-Λ lΛ t-Λ t-rt 4i φ^ -^ l-0 tO O 0 00 ^ ft (-Λ Φ-. ω tO h-^ O * 00 ---! ft t-fl -^ W tO h-' O V0 00 ----l ft -Λ Φ- t-0 tO h^
o o o o o o o o o o o Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Q O o o o o o o o o o o o o o
a a a a a a a a a a a a a a a a a a a a a a a a a a a a a a a a a a a a a a a a a a a a a a a a
3.175 CH3 H 4-F-2,3,5,6-Br(Ph)
3.176 CH3 H 4-Cl-2,3,5,6-FPh)
3.177 CH3 H 4-Br-2,3,5,6-F(Ph)
3.178 CH3 H 2-Br-3,4,5,6-Cl(Ph)
3.179 CH3 H 2-F-3,4,5,6-Cl(Ph)
3.180 CH3 H 2-Cl-3,4,5,6-F(Ph)
3.181 CH3 H 2-Br-3,4,5,6-F(Ph)
3.182 CH3 H 6-Cl-2,3,4,5-Br(Ph)
3.183 CH3 H 6-F-2,3,4,5-Br(Ph)
3.184 CH3 H 4-CH3-2,3,5,6-Cl(Ph)
3.185 CH3 H 4-CH3-2,3,5,6-Br(Ph)
3.186 CH3 H 4-CH3-2,3,5,6-F(Ph)
3.187 CH3 H 4-CF3-2,3,5,6-Cl(Ph)
3.188 CH3 H 4-CF3-2,3,5,6-Br(Ph)
3.189 CH3 H 4-CF3-2,3,5,6-F(Ph)
3.190 CH3 H 4-CH3 O 2,3,5,6-Cl(Ph)
3.191 CH3 H 4-CF30 -2,3,5,6-Br(Ph)
3.192 CH3 H 4-CF30-2,3,5,6-F(Ph)
3.193 CH3 H 4-CF30-2,3,5,6-Cl(Ph)
3.194 CH3 H 6-CH3-2,3,4,5-Cl(Ph)
3.195 CH3 H 6-CH3-2,3,4,5-BrPh)
3.196 CH3 H 2-CH3-3,4,5,6-F(Ph)
3.197 CH3 H 6-CF30-2,3,4,5-Cl(Ph)
3.198 CH3 H 6-CF30-2,3,4,5-BrPh)
3.199 CH3 H 2-CF30-3,4,5,6-F(Ph)
3.200 CH3 CH3 2,6-Cl(Ph)
3.201 CH3 CH3 2,3,6-Cl(Ph)
3.202 CH3 CH3 2,4,6-Cl(Ph)
3.203 CH3 CH3 2,6-Br(Ph)
3.204 CH3 CH3 2,3,6-Br(Ph)
3.205 CH3 CH3 2,4,6-Br(Ph)
3.206 CH3 CH3 2,6-F(Ph)
3.207 CH3 CH3 2,3,6-F(Ph)
3.208 CH3 CH3 2,4,6-F(Ph)
3.209 CH3 CH3 2,6-CH3(Ph)
3.210 CH3 CH3 2,3,6-CH3(Ph)
3.211 CH3 C2H5 2,4,6-CH3(Ph)
3.212 CH3 n-C3H7 2,6-Cl(Ph)
3.213 CH3 iso-C3H7 2,3,6-Cl(Ph)
3.214 CH3 n-C4H9 2,4,6-Cl(Ph)
3.215 CH3 iso-C4H9 2,6-Cl(Ph)
3.216 CH3 CH2=CH 2,3,6-Cl(Ph)
3.217 CH3 CH3CH=CH 2;4,6-Cl(Ph)
3.218 CN H 2,6-Cl(Ph)
3.219 CN CH3 2,3,6-Cl(Ph)
3.220 CN C2H5 2,4,6-Cl(Ph)
3.221 CN n-C3H7 2,6-Cl(Ph)
3.222 CN iso-C3H7 2,3,6-Cl(Ph) 3.223 CN n-C H9 2,4,6-Cl(Ph)
3.224 CN iso-C4H9 2,6-Cl(Ph)
3.225 CN CH2=CH 2,3,6-Cl(Ph)
3.226 CN CH3CH=CH 2,4,6-Cl(Ph)
3.227 CF3 H 2,6-Cl(Ph)
3.228 CF3 CH3 2,3,6-Cl(Ph)
3.229 CF3 C2H5 2,4,6-Cl(Ph)
3.230 CF3 n-C3H7 2,6-Cl(Ph)
3.231 CF3 iso-C3H7 2,3,6-Cl(Ph)
Typical compounds of Formula I encompassed by the present invention wherein A, R4 and R5 are hydrogen; X is CH and Z is O; and Rj is methyl include those compounds presented in Table 4 of Formula III where ^ R6, and R7 are defined in Table 4.
Formula III Table 4
Compd # E2 R R7
4.1 H H 2,4-Cl-pyrid-3-yl
4.2 H H 2,4-F-pyrid-3-yl
4.3 H H 2-Cl-4-F-pyrid-3-yl
4.4 H H 2,4-(CH3)2-pyrid-3-yl
4.5 H H 3,5-Cl-pyrid-4-yl
4.6 H H 3,5-F-pyrid-4-yl
4.7 H H 3-Cl-5-F-pyrid-4-yl
4.8 H H 3,5-(CH3)2-pyrid-4-yl
4.9 H H 4,6-Cl-pyrimidin-5-yl
4.10 H H 4,6-F-pyrimidin-5-yl
4.11 H H 4,6-(CH3)2-pyrimidi--.-5-yl
4.12 H H 4-Cl-6-F-pyrimidin-5-yl
4.13 CH3 H 2,4-Cl-pyrid-3-yl
4.14 CH3 H 2,4-F-pyrid-3-yl
4.15 CH3 H 2-Cl-4-F-ρyrid-3-yl
4.16 CH3 H 2,4-(CH3)2-pyrid-3-yl
4.17 CH3 H 3,5-Cl-pyrid-4-yl
4.18 CH3 H 3,5-F-ρyrid-4-yl
4.19 CH3 H 3-Cl-5-F-pyrid-4-yl
4.20 CH3 H 3,5-(CH3)2-pyrid-4-yl
4.21 CH3 H 4,6-Cl-pyrimidi-α-5-yl
4.22 CH3 H 4,6-F-pyrimidin-5-yl
4.23 CH3 H 4,6-(CH3)2-pyrimidrn-5-yl 4-. φ Φ 4- 4-. Φ 4-. 4- J-. 4- Φ Φ 4-. 4i φ Φ Φ Φ Φ 1 1 l -.. -.. -.. _. Φ. -o -*i Lo Lo Lo -o -o -o -o -o to to 3 o to to to >— ' O so OO -0 ft
jOs Ofl ωO03 ωOa ωOa jOu ωOa ωOa jOn jOu jOn ωOa --Qa jOa jOu ω Oa ω O jOs Oϋ jOu ωp Oi. ω Oa -jQn ωO ωOa jOn ωQa O K JOU ω O ωQa ωO ωOa ,Ω* Ω--, Ω-q ωΩw Ω--, Ω--, Ω---: jΩ-q Ω---. jΩ-
t-s
P A Pa- θa Oa Oa Oa aO Oa Oa Oa Oa Oa Oa Oa Oa Oa Oa Qa Oa Qa Oa Oa Oa Oa Oa Oa Oa Oa Oa Oa Oa Oa Oa Oa Oa Oa Oa o- ιEτ. haH haH ai-H ha1H -aτ. -aτ< haH -a-H haH
4.73 CH3 iso-C3H7 2,4-(CH3)2-pyrid-3-yl
4.74 CH3 n-C4H9 3,5-Cl-pyrid-4-yl
4.75 CH3 iso-C4H9 3,5-F-pyrid-4-yl
4.76 CH3 CH2=CH 3-Cl-5-F-pyrid-4-yl
4.77 CN CH3CH=CH 2,4-Cl-pyrid-3-yl
4.78 CN CH3 2,4-F-pyrid-3-yl
4.79 CN CH3 2-Cl-4-F-pyrid-3-yl
4.80 CN CH3 2,4-(CH3)2-pyrid-3-yl
4.81 CN CH3 3,5-Cl-pyrid-4-yl
4.82 CN CH3 3,5-F-pyrid-4-yl
4.83 CN CH3 3-Cl-5-F-pyrid-4-yl
4.84 CN CH3 4,6-Cl-pyrimidin-5-yl
4.85 CN CH3 4,6-F-pyr-midin-5-yl
4.86 CN CH3 2,4-Cl-thien-3-yl
4.87 CN CH3 2,4-F-thien-3-yl
4.88 CN CH3 2-Cl-4-F-thien-3-yl
4.89 CN CH3 2-F-4-Cl-thien-3-yl
4.90 CN CH3 2,4-(CH3)2-thien-3-yl
4.89 CN CH3 2,4,5-Cl-thien-3-yl
4.90 CN CH3 2,4,5-F-thien-3-yl
4.91 CN CH3 2,4,5-CH3-thien-3-yl
4.92 CN C2H5 2,4-Cl-pyrid-3-yl
4.93 CN n-C3H7 2,4-Cl-pyrid-3-yl
4.94 CN iso-C3H7 2,4-Cl-thien-3-yl
4.95 CN n-C4H9 2,4-F-thien-3-yl
4.96 CN iso-C H9 2-Cl-4-F-thien-3-yl
4.97 CN CH2=CH 2-F-4-Cl-thiea-3-yl
4.98 CN CH3CH=CH 2,4-(CH3)2-thieιι-3-yl
4.99 CF3 CH3 2,4-Cl-pyrid-3-yl
4.100 CF3 CH3 2,4-F-pyrid-3-yl
4.101 CF3 CH3 2,4-Cl-thien-3-yl
4.102 CF3 CH3 2,4-F-thien-3-yl
4.103 CF3 CH3 2-Cl-4-F-thien-3-yl
4.104 CF3 CH3 2-F-4-Cl-thien-3-yl
4.105 CF3 CH3 2,4-(CH3)2-thien-3-yl
4.106 CF3 CH3 3,5-Cl-isothiazol-4-yl
4.107 CF3 CH3 3,5-F-isothiazol-4-yl
4.108 CF3 n-C3H7 2,4-Cl-pyrid-3-yl
4.109 CF3 iso-C3H7 2,4-F-pyrid-3-yl
4.110 CF3 n-C-JHg 3,5-Cl-pyrid-4-yl
4.111 CF3 iso-C H9 3,5-F-pyrid-4-yl
4.112 CF3 CH2=CH 2,4-Cl-pyrid-3-yl
4.113 CF3 CH3CH=CH 2,4-F-pyrid-3-yl
As used in Tables 1 to 4 Ph is understood to be phenyl.
Compounds of the present invention are prepared according to the following synthetic schemes. Scheme A describes the preparation of compounds of the Formula (P) where A and Rj to R7 are as defined in Tables 1-4. The cyclopropyl oximes (N) are reacted with the appropriately substituted benzyl derivatives (IN), where Z is a halogen, such as bromo, chloro or iodo, preferably a benzyl bromide. A cyclopropyl substituted oxime represented by the general formula (V) is treated, at room temperature, with an appropriate base to form an anion, followed by the addition of the benzyl bromide (IN). Typical bases employed are metal hydrides such as sodium hydride, alkoxides such as sodium methoxide and hydroxide bases such as sodium or potassium hydroxide and alkali bases such as sodium or potassium carbonate. Typical solvents employed with hydride bases are Ν,Ν-dimethylformamide (DMF) and tetrahydrofuran (THF); with hydroxide bases DMF, THF, methyl ethyl ketone (MEK) and acetone and with alkali bases solvents such as DMF, acetone, and MEK. in the E
position (assuming 7 - is the larger substituent), It should be recognized that the Z isomer can also be produced as well as mixtures. When isomers are produced they are designated isomer A (higher Rf on thin layer chromatography) and isomer B (lower Rf on thin layer chromatography). The determination of which isomer, A or B possesses the E or Z geometry can be made by such conventional techniques as X ray crystallography or by spectroscopic means such as nuclear magnetic resonance spectroscopy. For the compounds of the present invention isomer A has been assigned the E iminoxy configuration and isomer B, the Z iminoxy configuration.
Scheme A
Compounds of formula I are prepared by alkylation with methyl N-(2- bromomethylphenyl)-N-alkoxycarbamate in the presence of a base, preferably NaOH or KOH, in a solvent, preferably acetone or methyl ethyl ketone. Specifically, as shown in Scheme A (where Z is bromo), methyl N-(2-bromomethylphenyl)-N- methoxycarbamate (IN) is reacted with the oxime (N) to provide the compounds of Formula V. Methyl Ν-(2-bromomethylphenyl)-Ν-alkoxycarbamate and specifically methyl N-(2-bromomethylphenyl)-N-methoxycarbamate (IN, where Z is bromo), are prepared as described in US 5,650,434 in a 4 step sequence as shown in scheme B. As described in the aforementioned European patent applications o-nitrotoluene is reacted with ammonium chloride in the presence of zinc to provide Ν-2- methylhydroxylamine (XI) as described in Organic Synthesis Collective Volume III, p.668.. The hydroxylamine is acylated with methyl chloroformate to provide the methyl N-hydroxycarbamate (XII) which is alkylated, for example with dimethylsulfate (R is methyl), to provide (XIII) which is brominated under standard conditions such as N-bromosuccinimide in carbontetrachloride in the presence of a catalyst such as benzoyl peroxide to afford the intermediate benzylbromide (XIV).
Scheme B
The oximes of the general formula (V) can be obtained, as shown in Scheme C, by reacting the corresponding cyclopropyl aldehyde or ketone (X) with hydroxylamine hydrochloride from room temperature to reflux, preferably at room temperature, in an appropriate solvent such as methanol or ethanol in the presence of an appropriate alkali such as sodium hydroxide, potassium carbonate or pyridine. A general description of the synthesis of oximes with hydroxylamine is described in March, Advanced Organic Chemistry. 4th Ed, pp. 906-907 and references therein. The oximes of the general formula (III) when obtained as a mixture of syn or anti oxime isomers can be separated into individual isomers and alkylated as described in scheme A and B. When a mixture of oximes of the general formula (III) are used in Schemes A and B the compounds of the formula VI, Nil and IX can be separated into their individual isomers by conventional chromatographic techniques. Scheme C
The cyclopropyl aldehydes or ketones (X) are prepared by conventional techniques. The unsaturated intermediate XI (Scheme D) is reacted with a sulfur ylide, prepared from a dimethylsulfoxonium salt in the presence of a base, resulting in the substituted acyl cyclopropanes, X, as shown in Scheme D. The chemistry of sulfur ylides is described in Trost and Melvin, Sulfur Ylids , Academic Press, New York, NY 1975 and in Block, Reactions of Organosulfur Compounds, pp. 91-123, Academic Press, New York, NY 1978. Typical reaction conditions for sulfur ylide formation from a dimethylsulfoxonium salt utilizes bases such as hydroxides, metal hydrides and alkoxides in solvents such as dimethoxyethane, dimethylsulfoxide and water depending on the base employed. The reactions are conducted from 0 to 20°C preferably from 10-15°C and preferably with alkali metal hydroxides in dimethylsulfoxide. Typically dimethylsulfoxonium methylide is prepared from trimethylsulfoxonium iodide in dimethylsulfoxide in the presence of powdered sodium hydroxide at room temperature. The unsaturated aldehydes or ketones (XI) are added dropwise to the ylide and stirred at room temperature.
Scheme D
XI X
The α,β-unsaturated aldehydes or ketones XI can be prepared by conventional condensation techniques. A extensive description of the synthesis of α,β-unsaturated aldehydes or ketones (enones) is described in March, Advanced Organic Chemistry. 4th Ed, pp. 937-955 and references therein. For example Organic Reactions, Volume 16 describes the general aldol condensation of ketones and aldehydes. For intermediates of formula XI of this invention, in general the ketones and aldehydes are R7COR6 (XII) and R2COCH2R3 (XIII) where R2, R3, R6, and R7 are defined previously. When R6 is hydrogen, the aldehydes R7CHO (XIV), are for example benzaldehydes (arylCHO) or heterocyclic aldehydes substituted with from 2 to 5 substituents wherein the positions on the aryl and heterocyclic ring adjacent to the bond to the cyclopropyl ring, in Formula I, are both substituted. These substituted benzaldehyes or heterocyclic aldehydes are commerically available or prepared by conventional techniques. The aldehydes R7CHO (XIN) are reacted with the ketones R2COCH2R3, XIII, (as shown in Scheme E) to provide the intermediates enones XV. Typically the ketone, R2COCH2R3, is dissolved in a hydroxylic solvent, such as methanol or ethanol, to which is added dropwise the aldehyde R7CHO followed by the base or alternatively a solution of the aldehyde in an aqueous basic solution is added. The typical bases used can be alkali metal hydroxides, such as barium, potassium or sodium hydroxide and the dropwise addition is conducted from 0°C to 35°C preferably at ambient temperature. When the enone is derived from acetone (R2 is methyl and R3 is hydrogen) the solvent can be acetone to which is added R7COR6 followed by the aqueous hydroxide solution. Preferably the aldehyde is dissolved in a solvent mixture of acetone:water (1 :5) to which is added the base while stirring at room temperature.
Scheme E
XIN XV
When R6 is not hydrogen, R7COR6 (XII) are the ketones arylCOR6 or heterocyclic ketones, substituted with from 2 to 5 substituents wherein the positions on the aryl and heterocyclic rings adjacent to the bond to the cyclopropyl ring, in Formula I, are both substituted or aryl or heterocyclic ring is unsubstituted or substituted from 1 to 4 substituents wherein at least one of the positions on the aryl or heterocyclic rings adjacent to the bond to the cyclopropyl ring, in Formula I, is a hydrogen. For the compounds of formula I where R6 is not hydrogen the intermediate unsaturated aldehydes and ketones XI are prepared, as shown in Scheme F, according to the procedures described in US Patent Number 3,950,427, col. 17 line 20, to provide after purification the E diastereiosmer (R7 is trans to R2CO in XI). In a typical preparation a ketone such as R7COR6 is reacted with an ethyl trans 3- ethoxycrotonate in dimethylformamide in the presence of potassium t-butoxide followed by acidic hydrolysis and decarboxylation to give XL The crotonates, XVI , can be prepared from substituted ethyl acetoketones by conventional techniques Scheme F
XII XI
Alternatively the ,β-unsaturated cyclopropyl ketones X can be prepared from cyclopropyl nitriles XIN which are prepared via cyclopropanation of the acrylonitriles XNIII as is described in Scheme G. The acrylonitriles XNIII starting materials, shown in Scheme G can be prepared by conventional synthetic methods as described in March, Advanced Organic Chemistry, 4th Ed, pp. 937-955 and references therein . For example the nitrile derivative R3CH2CΝ is condensed with the ketone or aldehyde R7COR6 in the presence of a base to provide the acrylonitriles XIII. Typically the a nitrile is dissolved in a solvent such as ethanol and water to which is added the aldehyde or ketone followed by a base. Typical bases used can be alkali metal hydroxides, such as barium, potassium or sodium hydroxide and the mixture is stirred typically at ambient temperature.
The acrylonitrile XNIII is treated as is described in Scheme D with a sulfur ylide to provide the cyclopropyl nitriles XVII. The cyclopropyl nitrile XVII is transformed to the cyclopropyl ketone by organometallic addition to the nitrile followed by hydrolysis. For example the standard Grignard reagents R2MgX or organolithium reagents, R2Li, add to the nitrile functionality to provide the ketone X. The addition reaction to nitriles is described in March, Advanced Organic Chemistry, 4th Ed, pp.935-936 and references cited therein. The cyclopropyl nitrile XVII can be transformed to the cyclopropyl aldehyde X' (where R2 is H) by standard reductive methods such as with diisobutylaluminum hydride (DiBAL). The formation of aldehydes from the reduction of nitriles is described in March, Advanced Organic Chemistry, 4th Ed, pp.919-920 and references cited therein.
Scheme G
XVIII XVII X
A direct synthesis of compounds of the formula VII or IX is shown in Scheme H. Compounds of the Formula VII or IX can be prepared directly from the functionalized cyclopropyl ketones or aldehydes, X, by condensation with the -iminoxy intermediate XIX. The preparation of aminoxy intermediate XIX is described in US Patent Number 5,194,662. The aminoxy intermediate XIX is prepared in a two step sequence by the alkylation of IV (where X is N) with N- hydroxyphthalimide which is treated with hydrazine to provide XIX. The aminoxy intermediate XIX is condensed with ketones or aldehydes X to provide VII which are treated as shown in scheme B to provide IX.
Scheme H
XIX X
The compounds of this invention can be made according to the following procedures: Example 1
Preparation of E and Z aminoxy isomers; Methyl N-methoxy-N- f2-((E) and (Z)-( l-(trans-2-phenylcycIopropyl)ethylidene aminooxymethyl)phenvncarbamate Compound 1.11A and 1.11B Table 1
Preparation of trans-2-phenylcvclopropylmethyl ketone
To a 2000 ml round-bottom flask equipped with magnetic stirrer was charged the 150 g of trimethylsulfoxonium iodide (0.685 moles, l.Oeq.), 28g of powdered sodium hydroxide (0.685 moles, l.Oeq.) and 1000 mis of DMSO. The flask was stoppered and stirred at ambient temperature for 15 min., after lOOg of trans-4-phenyl-3-buten- 2-one (0.685 moles) was added in one portion. The reaction was stirred at ambient temperature for 5 min., then poured into 500 mis of water and extracted with 3 x 200 ml of ethyl ether. The ether extract was washed successively with 2 x 200 mis of water and 200 mis of brine, dried over anhydrous. MgSO4, filtered and stripped after which 94 g of a yellow liquid (86% yield.) was isolated which was consistent with the desired product trans-2-cyclopropylmethyl ketone upon analysis by 300 MHz 1H NMR.
300 MHz, 1H, CDCI3, TMS=0 ppm): 1.3 (m, 1H), 1.7 (m, 1H), 2.2 (m, 1H), 2.3 (s, 3H), 2.6 (m, 1H), 7.1 (d, 2H), 7.2-7.4 (m, 3H).
E and Z imine isomers: (E) and (Z)-Methyl N-methoxy-N-[2-((trans-l-(2- phenylcvclopropyDethylidene^aminooxymethvDphenyllcarbamate
To a 20 ml glass vial were added methyl N-methoxy-N-[2-(aminooxymethyl) phenyl]carbamate(600 mg, 2.65 mmol), trans-2-cyclopropylmethyl ketone (400 mg, 2.4 mmol), and MeOH (15 ml). The resulting mixture was stirred overnight at ambient temperature. The reaction progress was monitored by GC and TLC. When the reaction was complet, water was added, followed by extractive work-up with ether. The crude product was purified by silica column with 70:30 hexane/ethyl acetate solvent mixture to provide 300 mg of isomer A as (Methyl-N-methoxy-N-[2-((E)-(l- (trans-2-phenylcyclopropyl)ethylidene)aminooxymethyl)phenyl]carbamate and 270mg of isomer B as Methyl N-methoxy-N- [2-((Z)-(l-(trans-2-phenylcyclopropyl)- ethylidene)aminooxymethyl)phenyl]carbamate for a total isolated yield of 65% NMR isomer A: (E)-isomer: 300 MHz, 1H, CDC13, TMS=0 ppm): 1.1-1.2 (m,lH), 1.35-1.45 (m,lH), 1.75-1.80 (m,lH), 1.84 (s,3H), 3.74 (s,3H), 3.77 (s,3H), 5.12 (s,2H), 7.05-7.6 (m,9H).
NMR isomer B: (Z)-isomer: 300 MHz, 1H, CDC13, TMS=0 ppm): 1.2-1.4 (m,2H), 1.68 (s,3H), 2.2-2.3 (m,lH), 1.65-1.75 (m,lH), 3.65 (s,3H),3.72 (s,3H), 5.11 (s,2H), 7.0-7.5 (m,9H). 3.72 (s,3H), 5.11 (s,2H), 7.0-7.5 (m,9H).
Preparation of Methyl N-methoxy-N- [2-(an--inooxymethyl)phenyl1carbamate as an intermediate used in the examples of this invention
Methyl N-methoxy-N- 2-(O-phthalimidoxymethyl)phenylcarbamate
To a dry 1000 ml round bottom flask equipped with magnetic stirrer, and nitrogen inlet was charged 8.4 g (0.0512 moles) of N-hydroxyphthalimide, 2.1 g (0.0521 moles) of powdered sodium hydroxide, and 500 ml DMF. The dark red solution was stirred at ambient temperature for 20 min., followed by the addition of 20 g (0.0512 moles) of 70% pure methyl N-(2-bromomethylphenyl)-N-methoxycarbamate in one portion. The reaction was stirred at ambient temperature overnight, then poured into
500 mis of water and stirred for 1 hour to afford a white solid which was collected by vacuum filtration and washed with water, and hexane. The tan solid was dried under vacuum at 40°C overnight. Isolated 17.1 g of N-methoxy-N-methyl [2-(O- phthalimidoxymethyl)- phenyl}carbamate as a light brown solid in a 94% isolated yield.
300 MHz 1H NMR (CDC13, tms=0ppm) 3.76 (s, 3H); 3.78 (s, 3H); 5.25 (s, 2H); 7.4
(m, 3H), 7.8 (m, 5H).
Preparation of Methyl N-methoxy-N-[2-(aminooxymethyl)phenyllcarbamate
To a 250ml round bottom flask equipped with magnetic stirrer was charged the 5 g (0.0195 moles) of N-methoxy-N-methyl [2-(O- phthalimidoxymethyl)phenyl]carbamate, 100 mis of anhydrous methanol, and 1.08 g (0.0215 moles) of hydrazine monohydrate. The flask was stoppered, and the reaction was stirred at ambient temperature for 2 hours. The resulting solid was removed by filtration and the filtrate was stripped on the rotavap. The residue was slurried in 150 ml of anhydrous ether, filtered, and stripped to afford 4.1 g of methyl N-methoxy-N-
[2-(aminooxymethyl)phenyl] carbamate as a thick yellow liquid, which was stored at -20°C until needed for future synthesis, in a 93% isolated yield.
300 MHz 1H NMR (CDC13, tms=0ppm) 3.75 (s, 3H); 3.78 (s, 3H); 4.75 (s, 2H); 5.2
(bs, 2H), 7.35 (m, 3H); 7.4 (m, 1H).
Preparation of Methyl N-(2-bromomethylphenyl)-N-methoxycarbamate
Preparation of N-2-methylphenylhvdroxylamine
To a 1-L 3-neck round bottom flask was charged 28.6 g (1.0 eq., 0.21 moles) o- nitrotoluene in 200ml ethyl alcohol and 28.7 g (2.1 eq, 0.44moles) zinc powder neat. The reaction solution was heated to 45°C and 13.5 g (1.2 eq., 0.25 moles) ammonium chloride in 120ml water was added with an addition funnel controlling the exotherm in 50°C - 55°C range with an ice-bath. The reaction was monitored by glc analysis and after 30 min. an additional 7.2g (0.11 mole) zinc was added neat followed by 3.3 g (0.06 moles) ammonium chloride in 10ml water. The reaction was worked up after 45 min. by vacuum filtering the reaction mixture through celite, washing the wet cake with 50ml ethyl alcohol and removing the solvent at 30°C on the rotary evaporator to give orange oil. To the oil was added 300ml ether and 200ml water. The organic phase was separated and washed with 3 x 200ml water using NaCl to break up the emulsion, dried over MgSO -anhyd., and the ether was removed at 30°C on the rotary evaporator to give 16. lg product as an orange oil (62.3% yield) which was used directly in the next step.
Preparation of Methyl N-hvdroxy-N-2-methylphenylcarbamate To a 250ml 3-neck round bottom flask, stirring under nitrogen atmosphere, was charged 16.1 g (1.0 eq., 0.13 moles) N-2-methylphenylhydroxyamine in 40ml methylene chloride and 16.8g (1.5 eq., 0.20 moles) sodium bicarbonate neat. With a pipet added 13. lg (1.05eq, 0.37moles) methyl chloroformate neat to the mixture at - 5°C to +5°C. The reaction mixture was stirred at 0°C for 30 min. following the addition and the reaction was monitored by GC. After 45 minutes the reaction was quenched by the addition of 100ml methylene chloride and 100ml water while cooling in an ice-bath. The reaction was worked up with an additional 100ml of methylene chloride and water. The organic phase was separated, washed with 3 x 200ml water, and the solvent removed at 30°C on the rotary evaporator to give 21.3 g of the crude product as an orange gummy solid. Triturated with 40ml hexanes and after crushing with a mortar and pestle the resulting solid was washed with 3 x 20ml hexanes to give 15.35g product as an off-white solid (65.3% yield). 300 MHz, 1H, CDC13, TMS=0 ppm): 2.3 l(s, 3H), 3.76 (s, 3H), 7.25-7.26(m, 4H), and 7.78-7.8 l(br,lH).
Preparation of Methyl N-methoxy-N-2-methyl phenylcarbamate To a 250ml 3-neck round bottom flask, stirring under nitrogen atmosphere, was charged 15.25g (1.0 eq., 84.25 mmoles) methyl N-hydroxy-N-2-methyl phenylcarbamate in 30ml methylene chloride and 17.4 g (1.5 eq., 0.126 moles) potassium carbonate neat causing a solid cake to form almost immediately. To the reaction mixture was added 150ml more methylene chloride and the large cake was broken up into lumps with a spatula. To the reaction mixture was added 12.74 g (1.2 eq, 0.101 moles) dimethyl sulfate neat and the mixture was heated at 40°C. TLC was used to monitor the reaction after 1 hour and 3 hours and after lhr. 1.2 g(9.5 mmole) of dimethyl sulfate neat was added. The reaction mixture was quenched by pouring the reaction into 250ml water after 3hr. The reaction was worked up up by the addition of 150 methylene chloride to the quenched reaction and partitioned the organic phase, washed with 3 by 250ml water, dried over magnesium sulfate anhyrous. The solvent was removed at 45°C on the rotary evaporator to give 20.8 g crude of product as light brown oil which contained dimethyl sulfate. 1.5 g of the crude product was washed with 10% ammonium hydroxide which removed the dimethyl sulfate and gave 0.9g product. The remaining 19.3 g crude product containing the dimethyl sulfate was taken up in 250ml ether, washed with 3 x 200ml 10%) ammonium hydroxide, with 3 x 200ml water, dried over magnesium sulfate- anhyd. The solvent was removed at 45°C on the rotary evaporator to give 12.4g plus 0.9 g for a total of 13.3 g of methyl N-methoxy-N-2 -methyl phenylcarbamate as a brown/orange oil (81.1% yield).
300 MHz, 1H, CDC13, TMS=0 ppm): 2.29(s, 3H), 3.73(s,3H), 3.78(s, 3H), 7.26(m, 4H)
Methyl N-2-bromomethylphenyl-N-methoxycarbamate
To a 500ml 3-neck round bottom flask under N2 atmosphere was charged 12.0g (l.Oeq, 61.5mm) methyl N-methoxy-N-2-methyl phenylcarbamate in 70ml CCI4, 12.0g (l.leq, 67.7mmoles) N-bromosuccinimide (NBS) neat, 36 milligrams (mg.) of 2,2-azobis (2-methylpropionitrile) (AIBN), and heated at 77°C reflux with a high intensity lamp for lOh. During this time period an additional 300 mg. of AIBN and an additonal 3 g NBS was added.The reaction mixture was worked up by vacuum filtration, washing the filtrate with 200ml 2.5% sodium bisulfite, 200ml 2.5% sodium bicarbonate, 2 x 200ml water and drying with magnesium sulfate anhyd. The solvent was removed at 40°C with the rotary evaporator to give 16.0 g of product as an orange oil (71% purity, 68.0% yield). 300 MHz, 1H, CDC13, TMS=0 ppm): 3.79(s, 3H), 3.80(s,3H), 4.5(s, 2H), 7.2-7.4(m,
4H)
Example 2
Preparation of E aminoxy isomer; Methyl N-methoxy-N-F2-(E-(l-(trans-(2-(4'- fluorophenvI)-2-methyl)cvclopropyl)ethylidene)aminooxymethvi)phenyll carbamate Compound 1.58A of Table 1
Preparation of 4-(4-fluorophenyl -3 -penten-2-one
A) Preparation of of ethyl-trans-3-ethoxycrotonate
To a 500 ml round bottom flask equipped with magnetic stirrer, and nitrogen inlet was charged 81.5 g (0.626 moles) of ethyl acetoacetate, 95 g (0.64 moles) of triethyl orthoformate, and 20 drops of concentrated sulfuric acid, (catalyst) The reaction was stirred overnight at ambient temperature. GC analysis of an aliquot indicated a complete reaction, with one major product. A slight excess (about 40 drops) of quinoline was added to neutralize the sulfuric acid. The reaction was then distilled at 15mm Hg (85-90°C) to afford 94 g of ethyl-trans-3-ethoxycrotonate, as a clear colorless liquid which crystallized upon standing, in a 95% isolated yield. 300 MHz !H NMR (CDC13, tms=0ppm) 1.3 (t, 3H); 1.33 (t, 3H); 2.3 (s, 3H); 3.8 (q, 2H); 4.14 (q, 2H), 5.0 (s, lH)
B) Preparation of 4-(4-fluorophenylV3-penten-2-one
To a 3000 ml round bottom flask equipped with mechanical stirrer, nitrogen inlet and addition funnel was charged 100 g (0.72 moles) of 4'-fluoroacetophenone, 115g (0.72 moles) of ethyl-trans-3-ethoxycrotonate, and 500 mis of dry dimethylformamide. To this solution was then added 89 g (0.79 g) of potassium t-butoxide in one portion and 250 mis of DMF. The reaction was then stirred at ambient temperature under nitrogen for a total of two days. The reaction mixture was then poured into 1000 mis of water and the aqueous solution was extracted with 3 x 200 mis of ethyl ether to remove any unreacted starting material. The aqueous fraction was then acidified to pH 2 with 6 N aqueous HC1, and a yellow solid was formed which was collected by filtration, washed with water, hexane, and air dried. This solid was re-suspended in 500 mis of 6 N aqueous HC1, and warmed to 50 °C for one hour. Analysis of an aliquot by TLC and GC indicated no starting material remained, and one new product was formed. The aqueous mixture was cooled to room temperature, then poured into 500 mis of water and extracted with 3 x 200 ml of ethyl ether. The ether extract was washed with 2 x 200 mis of water, 100 mis of brine, dried over anhydrous magnesium sulfate, filtered, and stripped to afford 82 g of 4-(4-fluorophenyl)-3-penten-2-one as a pale yellow liquid, which was 95% trans, 5% cis isomer mixture, in a 65%> overall yield. 300 MHz 1H NMR (CDC13, tms=0ppm) 2.3 (s, 3H); 2.5 (s, 3H); 6.5 (s, 1H); 7.1 (t, 2H), 7.5 (m, 2H). Preparation of trans- 1 -methyl- 1 -(4-fluorophenyl)-2-acetyl-cvclopropane
To a 2000ml round bottom flask equipped with mechanical stirrer, nitrogen inlet and addition funnel was charged 112 g (0.51 g) of trimethyl sulfoxonium iodide, 20.4 g (0.51 moles) of powdered sodium hydroxide, and 500 mis of dry DMSO. The mixture was stirred at room temperature for 1 hour, followed by the rapid addition of 82 g (0.0461 moles) of 4-(4-fluoroρhenyl)-3-ρenten-2-one in 100 mis DMSO. The reaction was stirred for 3 days at ambient temperature, then poured into 200 mis of ice water and extracted with 3 x 200 ml of ethyl ether. The ether extract was washed with 2 x 100 mis of water, 100 mis of brine, dried over anhydrous magnesium sulfate, filtered through 2" of silica gel, and stripped to afford 97 g of a thick pale yellow oil which was fractionally distilled at 0.2 mm Hg. The purest fractions were combined to afford 74 g of a pale yellow liquid which was about 88% pure by GC analysis, with several minor impurities remaining. This material was then chromatographed on silica gel with 90%hexane/10% ethyl acetate. The pure fractions were combined to afford 37g of trans- 1 -methyl- l-(4-fluorophenyl)-2-acetyl-cyclopropane as a clear colorless liquid., in a 42% isolated yield.
300 MHz 1H NMR (CDC13, tms=0ppm) 1.4 (m, 1H); 1.45 (s, 3H); 1.6 (m, 1H); 2.25 (m, 1H), 2.35 (s, 3H); 7.0 (t, 2H); 7.35 (m, 2H)
Preparation of Methyl N-methoxy-N-[2-(E-(l-(trans-('2-('4,-fluorophenylV2- methvDcvclopropyπethylidene)aminooxymethyl)phenyllcarbamate
To a 50 ml round bottom flask equipped with magnetic stirrer, and nitrogen inlet was charged 0.6 g (0.0031 moles) of trans- 1 -methyl- l-(4-fluorophenyl)-2-acetyl- cyclopropane and 0.82 g (0.0035 moles) of methyl N-methoxy-N- [2- (aminooxymethyl)phenyl]carbamate. The mixture was dissolved in 20 mis of anhydrous methanol, and 2 drops of glacial acetic acid was added as a catalyst. The flask was stirred at ambient temperature overnight then poured into 100 mis of water and extracted with 3 x 100 ml of ethyl ether. The ether extract was washed with 2X100 mis of water, 100 mis of brine, dried over anhydrous magnesium sulfate, filtered, and stripped to afford 1.3 g of a thick brown oil which was chromatographed on silica with 20 % ethyl acetate/ 80% hexane. The pure fractions were combined and stripped to afford 0.72 g of Methyl N-methoxy-N-[2-(E-(l-(trans-(2-(4'-fluorophenyl) -2-methyl)cyclopropyl)ethylidene)aminooxymethyl)phenyl]carbamate as a clear pale yellow liquid in a 58% isolated yield.
300 MHz JH NMR (CDC13, tms=0ppm) 1.1 (m, 1H); 1.2 (s, 3H); 1.35 (m, 1H); 1.85 (m, 1H); 2.1 (s, 3H); 3.75 (s, 3H); 3.8 (s, 3H); 5.15 (s, 2H); 7.1 (t, 2H), 7.35 (m, 2H); 7.4 (m, 3H); 7.5 (m, 1H) Example 3
Preparation of E aminoxy isomer; Methyl N-methoxy-N-f2-(E-(l-(trans-2-(2 '-,6'- dichlorophenyl)cvclopropyl)ethv--idene)aminooxymethyl)phenyll carbamate Compound 3.16A of Table 1
Preparation of 4-(2,6-dichlorophenylV3-buten-2-one
To a 1000 ml round bottom flask equipped with mechanical stirrer, and nitrogen inlet were charged 26.5 g (0.15 moles) of 2,6-dichlorobenzaledhyde, 125 mis of acetone,
600 mis of water, and 9.3 g (0.23 moles) of sodium hydroxide. The mixture was stirred for 12 hours at room temperature. Analysis of an aliquot by GC indicated complete reaction. The resulting solid was collected by vacuum filtration, and washed with 100 mis of water, 100 mis of hexane, and dried in vacuuo at 40°C for 3 hours.
31.4 g of the title compound, 4-(2,6-dichlorophenyl)-3-buten-2-one, was isolated as a pale yellow solid in a 98% isolated yield.
300 MHz, 1H, CDC13, TMS=0 ppm): 2.43 (s, 3H); 6.80 (d, 1H); 7.18-7.38 (m, 1H);
7.4 (d, 2H); 7.6 (d, 1H).
Preparation of trans- 1 -(2,6 dichlorophenylV2-acetyl-cvclopropane To a 1000 ml round bottom flask equipped with magnetic stirrer, nitrogen inlet and addition funnel were charged 33.2 g (0.151 moles) of trimethyl sulfoxonium iodide, 6.1 g (0.151 moles) of powdered sodium hydroxide, and 300 mis DMSO. The mixture was stirred at room temperature for 1 hour, followed by the rapid addition of the 4-(2,6-dichlorophenyl)-3-buten-2-one (32.3 g, 0.151 moles) in one portion. The reaction was then stirred for 10 minutes at ambient temperature, then poured into 200 mis of ice water and extracted with 3 x 100 ml of ethyl ether. The ether extract was washed with 2 x 100 mis of water, lOOmls of brine, dried over anhydrous MgSO4, filtered through 2" of silica gel, and concentrated in vacuuo on a rotary evaporator to afford 31.7 g of a thick pale yellow oil which was chromatographed on silica gel with 90% hexane, 10% ethyl acetate. The pure fractions were combined and concentrated in vacuuo on a rotary evaporator to afford 27.9 g of trans- 1 -(2,6 dichlorophenyl)-2- acetyl-cyclopropane as a free flowing pale yellow liquid.in 81% yield.
300 MHz, 1H, CDC13, TMS=0 ppm): 1.4-1.48 (m, 1H); 1.78-1.86 (m, 1H); 2.21-2.30 (m, 1H); 2.34-2.4 (m, 1H); 2.41 (s, 3H), 7.2 (m, 1H), 7.3 (d, 2H).
Preparation of E aminoxy isomer: Methyl N-methoxy-N-r2-(E-(l-ftrans-2-(2^6,- dichlorophenv cvclopropyl)ethylidene aminooxymethyl)phenyllcarbamate
Following the procedure of Example 2 using 0.6 g (0.00262 moles) of of trans- 1 -(2,6 dichlorophenyl)-2-acetylcyclopropane and 0.7 g (0.00288 moles) of methyl N- methoxy-N-[2-(aminooxymethyl)phenyl] carbamate gave 0.6 g of Methyl N-methoxy- N-[2-(E-(l-(trans-2-(2\6'-dichlorophenyl)cyclopropyl)e lidene)aminooxymethyl) phenyljcarbamate in a 53% isolated yield.
300 MHz 1H NMR (CDC13, tms=0ppm) 1.2 (m, 1H); 1.6 (m, 1H); 1.85 (m, 1H); 1.9
(s, 3H); 2.2 (m, 1H); 3.75 (s, 3H); 3.8 (s, 3H); 5.15 (s, 2H); 7.1 (t, 2H), 7.35 (d, 2H);
7.4 (m, 2H); 7.55 (m, 1H)
Example 4
Preparation of E and Z aminoxy isomers; Methyl N-methoxy-N- [2-(E and Z-(l- (trans-2-(4'-chlorophenyl)cvclopropyl)ethylidene^aminooxymethyl)phenyll carbamate Compound 1.14A and 1.14B of Table 1
Preparation of 4-(4-chlorophenylV3-buten-2-one
To a 250 ml round bottom flask were were charged 2g (0.0142 moles) of 4- chlorobenzaledhyde, 10.5 ml of acetone (0.142moles), 50ml of ethanol and 10ml of water. .After stirring for about 1 minute, 0.27g of barium hydroxide (0.00142moles) was added and the resulting mixture was stirred overnight at ambient temperature. When the reaction was completed, water was added followed by extractive work-up with ether. The ether solvent was removed in vacuuo and afforded 2.3 g of 4-(4- chlorophenyl)-3-buten-2-one as brown oil.
Preparation of trans- 1 -(4-chlorophenyl)-2-acetyl-cyclopropane To a 250 ml round bottom flask were charged 100ml of DMSO, 3.10 g (0.014 moles) of trimethyl sulfoxonium iodide and 0.56g of NaOH (0.014moles). The resulting mixture was stirred at room temperature for 1 hour. The mixture was stirred at room temperature for 1 hour, followed by the rapid addition of 2.3g of 4-(4-chlorophenyl)- 3-buten-2-one (0.0128 moles) in one portion. The resulting mixture was stirred for another 5 minutes at ambient temperature and the reaction was monitored by GLC. When the reaction was complete water was added followed by extractive work up with ether. Removal of the ether solvent in vacuuo afforded 1.8 grams of trans- 1 -(4- chlorophenyl)-2-acetyl-cyclopropane as brown oil.
Preparation of E and Z aminoxy isomer: Methyl N-methoxy-N-r2-(E and Z-(l-(trans- 2-(4'-chlorophenyl)cvclopropyl)ethylidene)aminooxymethyl)phenyl]carbamate Following the procedure of Example 2 using 0.96 g (0.0049 moles) of trans-l-(4- chlorophenyl)-2-acetylcyclopropane and 1.3 g (0.0055 moles) of methyl N-methoxy- N-[2-(aminooxymethyl)phenyl]carbamate gave, in order of elution from the silica gel chromatography column (20% Ethyl acetate, 80% hexane) 0.42 g of isomer A:methyl N-methoxy-N-[2-(E-(l-(trans-2-(4'-chlorophenyl)cyclopropyl)ethylidene) aminooxymethyl)phenyl] carbamate and 0.34 g of isomer B "methyl N-methoxy-N-[2- (Z-(l-(fr- s-2-(4'-cMorophenyl)cyclopropyl)ethylidene)aminooxymethyl)phenyl]- carbamate. In a 21% and 17%) isolated yields, respectively. NMR: Isomer A (E aminoxy isomer) 300 MHz 1H NMR (CDC13, tms=0ppm) 1.1 (m,
IH); 1.5 (m, IH); 1.8 (m, IH); 1.85 (s, 3H); 2.2 (m, IH); 3.7 (s, 3H); 3.75 (s, 3H); 5.1
(s, 2H); 7.0 (d, 2H), 7.2 (d, 2H); 7.4 (m, 3H); 7.5 (m, IH)
NMR: Isomer B (Z aminoxy isomer)300 MHz !H NMR (CDC13, tms=0ppm) 1.1 (m,
IH); 1.3 (m, IH); 1.65 (s, 3H); 2.2 (m, IH); 2.7 (m, IH); 3.65 (s, 3H); 3.7 (s, 3H); 5.1
(s, 2H); 7.0 (d, 2H), 7.3 (d, 2H); 7.4 (m, 3H); 7.5 (m, IH)
Example 5
Numerous compounds of this invention were tested for fungicidal activity in vivo against the diseases described below. The compounds were dissolved in a 1 :1 mixture of acetone and methanol and then diluted with a 2: 1 : 1 mixture of water, acetone and methanol (by volume) to achieve the appropriate concentration. The solution was sprayed onto the plants and allowed to dry for two hours. The plants were then inoculated with fungal spores. Each test utilized control plants which were sprayed with the appropriate solvent and inoculated. For these protective tests, the plants were inoculated one day after treating the plants with the compounds of this invention. The remainder of the technique of each of the tests is given below along with the results for various compounds described herein by the Compound # against the various fungi at a dose of 150 grams per hectare. The results are percent disease control as compared to the untreated check, wherein one hundred was rated as complete disease control and zero as no disease control. The application of the test fungal spores to the test plants was as follows: Wheat Leaf Rust (WLR)
Puccinia recondita (f. sp. tritici ) was cultured on 7-day old wheat plants (cv. Fielder) over a 12-day period in the greenhouse. Spores were collected from the leaves by settling on aluminum foil. The spores were cleaned by sieving through a 250-micron opening screen and stored dry. The dried spores were used within one month. A spore suspension was prepared from dry uredia by adding 20 mg (9.5 million spores) per ml of Soltrol oil. The suspension was dispensed into gelatin capsules (0.7 ml capacity) which attach to the oil atomizers. One capsule is used per flat of twenty 2-inch square pots of 7-day old plants, cultivar Fielder. After waiting for at least 15 minutes for the oil to evaporate from the wheat leaves, the plants were placed in a Dew Chamber for 24 hours. The plants were then placed in the greenhouse and evaluated after 12 days for disease. Wheat Leaf Blotch (SNW)
Cultures of Septoria nodorum was maintained on Czapek-Dox V-8 juice agar plates in an incubator at 20°C with alternating periods of 12 hours of light and 12 hours of darkness for 2 weeks. A water suspension of the spores was obtained by shaking the portion of the plate with fungal material in deionized water and filtering through cheesecloth. The spore-containing water suspension was diluted to a spore concentration of 3.0 x 106 spores per ml. The inoculum was dispersed by a DeVilbiss atomizer over one-week old wheat plants (cv. Fielder) which had been previously sprayed with the fungicide compound. The inoculated plants were placed in a Dew Chamber at 20°C with alternating 12 hours of light and 12 hours of darkness for 4 days. The inoculated seedlings were then moved to a controlled environment room at 20°C and 80% humidity for 2 days. Disease control values were recorded as percent control. Wheat Powdery Mildew (WP-λ-D
Erysiphe graminis (f. sp. tritici) was cultured on wheat seedlings (cv. Fielder) in a controlled temperature room at 18°C. Mildew spores were shaken from the culture plants onto 7-day old wheat seedlings which had been previously sprayed with the fungicide compound. The inoculated seedlings were kept in a controlled temperature room at 18°C and subirrigated. The percent disease control was rated 7 days after the inoculation. Disease control values were recorded as percent control. Cucumber Powdery Mildew fCPM)
Sphaerotheca fulginea was maintained on cucumber plants (cv. Bush Champion hybrid) in the greenhouse. Inoculum was prepared by placing five to ten heavily mildewed leaves in a glass jar with 500 ml of water containing 1 drop of Tween 80 (polyoxyethylene monooleate) per 100 ml. After shaking the liquid and leaves, the inoculum was filtered through cheese cloth and misted onto the plants with a squirt bottle mister. The spore count was 100,000 spores per ml. The plants were then placed in the greenhouse for infection and incubation. The plants were scored seven days after inoculation. Disease control values were recorded as percent control. Tomato Late Blight (TLB)
Cultures of Phytophthora infestans were maintained on green pea-amended agar for two to three weeks. The spores were washed from the agar with water and dispersed with a DeVilbiss atomizer over the leaves of 3-week old Patio hybrid tomato plants which had been previously treated with compound of the present invention. The inoculated plants were placed in a Dew Chamber at 20°C for 24 hours for infection. The plants were then removed to a controlled environment room at 20°C and 90%> humidity. The plants were scored for disease control after five days. Rice Blast (RB)
Cultures of Pyricularia oyrzae were maintained on potato dextrose agar for two to three week. The spores were washed from the agar with water containing 1 drop of Tween 80 per 100ml. After filtering the spore suspension through two layers of cheese cloth, the spore count was adjusted to 5 x 105 per ml of water. The spore suspension was sprayed onto 12-day old rice plants (cv. M-201) using a DeVilbiss atomizer. The inoculated plants were placed in a totally dark Dew Chamber 20°C for 36 hours to allow for infection. After the infection period the plants were placed in the greenhouse. After 6 days, the plants were scored for disease control. Disease control values were recorded as percent control. Cucumber Anthracnose (CA
The fungal pathogen Colletotrichum lagenarium was cultured on potato dextrose agar (PDA) in the dark at 22°C for a period of 8 to 14 days. Spores of C. lagenarium were removed from the PDA plates by flooding the plate surface with distilled water, amended with 0.5% v/w of yeast extract. The upper surface of the fungal colony was scraped with a blunt plastic instrument until most of the spores were released into the aqueous environment. The spore suspension was filtered though cheesecloth, and the spore count was adjusted by adding more water, containing the yeast extract, until 3.0 x 106 spores per ml of water was achieved. The chemically-treated cucumber plants were 15-days old (cv. Bush Champion hybrid). The upper leaf surface of the plants were sprayed with the spore suspension until runoff, using a hand-held pump spray bottle. The plants were placed in a fluorescent- lighted mist chamber (12 hr light, 12 hr dark) for 48 hours. After that infection period, the plants were placed in a growth chamber for 3 days at 25°C and 80% humidity. The treated plants were then evaluated for disease control. Disease control values were recorded as percent control. Tomato Early Blight (TEB)
Cultures of Alternaria solani were grown on V-8 juice agar plates at room temperature under fluorescent lights (12 hr light, 12 hr dark) for 2 weeks. A suspension of the spores was obtained flooding the surface of the agar plate with a 0.5% solution of yeast extract in distilled water. The surface of the agar plate was scraped lightly with a blunt plastic instrument to release the spores into the liquid. The spore suspension was filtered through cheesecloth, and the spore concentration was adjusted to approximately 80,000 spores per ml. Tomato plants (cv. Patio hybrid) were approximately 18-days old at time of treatment with experimental compounds. Following treatment, the plants were placed in the greenhouse for 1 day. After this period, the plants were inoculated with freshly prepared spore suspension using a DeVilbiss atomizer. The spore suspension was applied to the upper surface of the leaves. After inoculation, the plants were placed in a Dew Chamber at 20°C for 24 hr to allow for infection. The plants were then transferred to a growth chamber at 22°C and 80% humidity for three days. Disease control values were recorded a percent control. When tested against wheat leaf rust at 150 grams per hectare compounds 1.11 A exhibited 95% control and at 100 grams per hectare 1.1 IB, 1.14A, 1.58A and 3.16A exhibited 95% or better control.
When tested against wheat leaf blotch at 100 grams per hectare compounds 1.14A, 1.58A and 3.16A exhibited 95% or better control.
When tested against wheat powdery mildew at 150 grams per hectare compounds 1.11A exhibited 95% control and at 100 grams per hectare 1.1 IB, 1.14A, 1.58 A and 3.16A exhibited 80% or better control.
When tested against cucumber powdery mildew at 150 grams per hectare compounds 1.11A exhibited 85% control and at 100 grams per hectare 1.14A, 1.58A and 3.16A exhibited 80% or better control.
When tested against tomato late blight at 150 grams per hectare compounds 1.11 A exhibited 100%) or better control.
When tested against rice blast at 150 grams per hectare compounds 1.11 A exhibited 95%> control and at 100 grams per hectare 1.14A, 1.58A and 3.16A exhibited 95% or better control.
When tested against cucumber anthracnose at 150 grams per hectare compounds 1.11 A exhibited 90%> control and at 100 grams per hectare 1.14A, 1.58 A and 3.16A exhibited 80% or better control.
When tested against tomato early blight at 150 grams per hectare compounds 1.11A exhibited 80% control and at 100 grams per hectare 1.14A, 1.58A and 3.16A exhibited 95%o or better control.
The compounds of this invention are useful as agricultural fungicides and, as such, can be applied to various loci such as the seed, the soil or the foliage of plants to be protected.
The compounds of this invention can be applied as ftmgicidal sprays by methods commonly employed, such as conventional high- volume hydraulic sprays, low- volume sprays, air-blast spray, aerial sprays and dusts. The dilution and rate of application will depend upon the type of equipment employed, the method of application, plants to be treated and diseases to be controlled. Generally, the compounds of this invention will be applied in amount of from about 0.005 kilogram to about 50 kilograms per hectare and preferably from about 0.025 to about 25 kilograms per hectare of the active ingredient.
As a seed protectant, the amount of toxicant coated on the seed is usually at a dosage rate of from about 0.05 to about 20, preferably from about 0.05 to about 4, and more preferably from about 0.1 to about 1 grams per hundred kilograms of seed. As a soil fungicide the chemical can be incorporated in the soil or applied to the surface usually at a rate of from about 0.02 to about 20, preferably from about 0.05 to about 10, and more preferably from about 0.1 to about 5 kilograms per hectare. As a foliar fungicide, the toxicant is usually applied to growing plants at a rate of from about 0.01 to about 10, preferably from about 0.02 to 5, and more preferably from about 0.25 to about 1 kilograms per hectare.
Inasmuch as the compounds of this invention display fungicidal activity, these compounds can be combined with other known fungicides to provide broad spectrum activity. Suitable fungicides include, but are not limited to, those compounds listed in U.S. Patent Number 5,252,594 (see in particular columns 14 and 15). Other known fungicides which an be combined with the compounds of this invention are dimethomorph, cymoxanil, thifluzamide, furalaxyl, ofurace, benalaxyl, oxadixyl, propamocarb, cyprofuram, fenpiclonil, fludioxonil, pyrimethanil, cyprodinil, triticonazole, fluquinconazole, metconazole, spiroxamine, carpropamid, azoxystrobin, kresoxim-methyl, metominostrobin and trifloxystrobin.
The compounds of this invention can be advantageously employed in various ways. Since these compounds possess broad spectrum fungicidal activity, they can be employed in the storage of cereal grain. These compounds can also be employed as fungicides in cereals including wheat, barley and rye, in rice, peanuts, beans and grapes, on turf, in fruit, nut and vegetable orchards, and for golf course applications.
Examples of diseases against which the compounds of the invention are useful include helminthosporium of com and barley, wheat and barley powdery mildew, wheat leaf and stem rusts, barley stripe and leaf rust, tomato early blight, tomato late blight, peanut early leaf spot, grape powdery mildew, grape black rot, apple scab, apple powdery mildew, cucumber powdery mildew, brown rot of fruits, botrytis, bean powdery mildew, cucumber anthracnose, wheat septoria nodorum, rice sheath blight and rice blast
Compositions and formulations according to the present invention may also include known pesticidal compounds. This expands the spectrum of activity of the preparation and may give rise to synergism. Suitable insecticides known in the art include those listed in U.S. Patent 5,075,471, see in particular columns 14 and 15.
The compounds of the present invention can be used in the form of compositions or formulations. Examples of the preparation of compositions and formulations can be found in the American Chemical Society publication "Pesticidal Formulation Research," (1969), Advances in Chemistry Series No. 86, written by Wade Van Valkenburg; and the Marcel Dekker, Inc. publication "Pesticide Formulations", (1973) edited by Wade Van Valkenburg. In these compositions and formulations, the active substance is mixed with conventional inert agronomically acceptable (i.e., plant compatible and/or pesticidally inert) pesticide diluents or extenders such as solid carrier material or liquid carrier material, of the type usable in conventional pesticide compositions or formulations. By "agronomically acceptable carrier" is meant any substance which can be used to dissolve, disperse of diffuse the active ingredient in the composition without impairing the active ingredient's effectiveness and which by itself has no significant detrimental effect on the soil, equipment, desirable plants, or agronomic environment. If desired, adjuvants such as surfactants, stabilizers, antifoam agents and anti-drift agents may also be combined.
Examples of compositions and formulations according to the invention are aqueous solutions and dispersions, oily solutions and oil dispersions, pastes, dusting powders, wettable powders, emulsifiable concentrates, flowables, granules, baits, invert emulsions, aerosol compositions and fumigating candles. Wettable powders, pastes, flowables and emulsifiable concentrates are concentrated preparations which are diluted with water before or during use. In such formulations, the compounds are extended with a liquid or solid carrier and, when desired, suitable surfactants are incorporated. Baits are preparations generally comprising a food or other substance attractive to insects, that includes at least one compound of the instant invention.
It is usually desirable, particularly in the case of foliar spray formulations, to include adjuvants, such as wetting agents, spreading agents, dispersing agents, stickers, adhesive and the like in accordance with agricultural practices. A listing of such adjuvants commonly used in the art, and a discussion of adjuvants, can be found in many references, such as in the John W. McCutcheon, Inc. publication "Detergents and Emulsifiers, Annual."
The active compounds of the present invention may be employed alone or in the form of mixtures with one another and/or with such solid and/or liquid dispersible carrier vehicles and/or with other known compatible active agents, especially plant protection agents, such as other insecticides, arthropodicides, nematicides, fungicides, bactericides, rodenticides, herbicides, fertilizers, growth-regulating agents, synergists.
In the compositions of the invention, the active compound is present in an amount from 0.0001 percent to 99 percent by weight. For compositions suitable for storage or transportation, the amount of active ingredient is preferably between 0.5 and 90 percent by weight, and more preferably between 1 and 75 percent by weight of the mixture. Compositions suitable for direct application or field application generally contain the active compound in an amount between 0.0001 and 95 percent, preferably between 0.0005 and 90 percent by weight, and more preferably between 0.001 and 75 percent by weight of the mixture. The composition can also be stated as a ratio of the compound to the carrier. In the present invention the weight ratio of these materials (active compound/carrier) can vary from 99:1 to 1:4 and more preferably from 10:1 to 1 :3. In general, the compounds of this invention can be dissolved in certain solvents such as acetone, methanol, ethanol, dimethylformamide, pyridine or dimethyl sulfoxide and such solutions can be diluted with water. The concentrations of the solution can vary from 1%> to 90% with a preferred range being from 5% to 50%.
For the preparation of emulsifiable concentrates, the compound can be dissolved in suitable organic solvents, or a mixture of solvents, together with an emulsifying agent to enhance dispersion of the compound in water. The concentration of the active ingredient in emulsifiable concentrates is usually from 10% to 90%, and in flowable emulsion concentrates, can be as high as 75%.
Wettable powders suitable for spraying, can be prepared by admixing the compound with a finely divided solid, such as clay, inorganic silicate and carbonate, and silica and incorporating wetting agents, sticking agents, and/or dispersing agents in such mixtures. The concentration of active ingredients in such formulations is usually in the range of from 20% to 99%, preferably from 40%o to 75%. A typical wettable powder is made by blending 50 parts of a compound of Formula 1, 45 parts of a synthetic precipitated hydrated silicon dioxide and 5 parts of sodium lignosulfonate. In another preparation a kaolin type (Barden) clay is used in place of the synthetic precipitated hydrated silicon dioxide in the above wettable powder, and in another such preparation 25% of the silicon dioxide is replaced with a synthetic sodium silicoaluminate.
Dusts are prepared by mixing the compound with finely divided inert solids which can be organic or inorganic in nature. Materials useful for this purpose include botanical flours, silicas, silicates, carbonates and clays. One convenient method of preparing a dust is to dilute a wettable powder with a finely divided carrier. Dust concentrates containing from 20%> to 80% of the active ingredient are commonly made and are subsequently diluted to from 1% to 10% use concentration.
In addition to the aforementioned ingredients the preparations according to the invention may also contain other substances commonly used in preparations of this kind. For example, a lubricant, such as calcium stearate or magnesium stearate, may be added to a wettable powder or to a mixture to be granulated. Furthermore there may, for example, be added "adhesives" such as polyvinylalcohol-cellulose derivatives or other colloidal materials, such as casein, to improve the adherence of the pesticide to the surface to be protected.

Claims (10)

WE CLAIM:
1. A compound of the formula:
wherein:
A is hydrogen, halo, cyano, (C1-C12)alkyl, or (Cj-C12)alkoxy;
Rj is (CrC12)alkyl or halo(Cι-Ci2)alkyl;
R2 is hydrogen, (C1-C12)alkyl, halo(C1-C12)alkyl, (C3-C7)cycloalkyl, halo(C3-
C7)cycloalkyl, (C2-C8)alkenyl, halo(C2-C8)alkenyl, (C2-C8)alkynyl, halo(C2-C8)alkynyl, or cyano; R3 is hydrogen; R4 and R5 are independently hydrogen, (Cj-Cj^alkyl, halo(C1-C12)alkyl, (C3-
C7)cycloalkyl, halo(C3-C7)cycloalkyl, (C2-C8)alkenyl, halo(C2-C8)alkenyl,
(C2-C8)alkynyl, halo(C2-C8)alkynyl, halo, cyano, or (Cj-
C4)alkoxycarbonyl; and wherein:
A) R7 is aryl, arylalkyl, heterocyclic or heterocyclic(C1-C4)alkyl wherein the aryl or heterocyclic ring is substituted with from 2 to 5 substituents and wherein the positions on the aryl or heterocyclic ring adjacent to the bond to the cyclopropyl ring are both substituted and R6 is hydrogen, (Cj- C12)alkyl, halo(Cj-C12)alkyl, (C3-C7)cycloalkyl, halo(C3-C7)cycloalkyl, (C2-C8)alkenyl, halo(C2-C8)alkenyl, (C2-C8)alkynyl, halo(C2-C8)alkynyl, halo, cyano, or (C1-C4)alkoxycarbonyl; or B) R7 is aryl, arylalkyl, heterocyclic or heterocyclic(Cj-C4)alkyl wherein the aryl or heterocyclic ring is unsubstituted or substituted from 1 to 4 substituents wherein at least one of the positions on the aryl or heterocyclic ring adjacent to the bond to the cyclopropyl ring is a hydrogen and R6 is hydrogen, (Cj-Cj^alkyl, halo(CrC12)alkyl, (C3-C7)cycloalkyl, halo(C3-C7)cycloalkyl, (C2- C8)alkenyl, halo(C2-C8)alkenyl, (C2-C8)alkynyl, halo(C2-C8)alkynyl,halo, cyano, or (Cj-C4)alkoxycarbonyl; and their salts, complexes, enantiomorphs, stereoisomers;and mixtures thereof.
2. The compound of claim 1 wherein Rj and R2 are CH3 and R6 is hydrogen or .(Cr C12)alkyl.
3. The compound of claim 1 wherein Rj and R2 are CH3, R6 is hydrogen or .(Cj- C12)alkyl, and R7 is 2,6-dichlorophenyl, 2,6difluorophenyl, 2,6- dibromophenyl, 2,6-bis(frifluoromethyl)phenyl, 2,3,6-trichlorophenyl, 2,3,6- trifluorophenyl, 2,3,6-tribromophenyl, 2,3,6-tris(trifluoromethyl)phenyl, 2,4,6- trichlorophenyl, 2,4,6-trifluorophenyl, 2,4,6-tribromophenyl, or 2,4,6- tris(trifluoromethyl)phenyl and R6 is hydrogen
4. The compound of claim 1 where the compound is N-methyl-2-[2-((trans-l-(2-N- Methoxy-N-methyl-N-[2-((trans- 1 -(2-(2 ' ,6 '-dichlorophenyl)cyclopropyl)- ethylidene)aminooxymethyl)phenyl]carbamate
5. The compound of claim 1 wherein Rj and R2 are CH3; R6 is hydrogen or .(Cj- C12)alkyl, and R7 is phenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 4- fluorophenyl, 4-bromophenyl, 2-(trifluoromethyl)- phenyl, 2,4-dichlorophenyl, 2,4-diifluorophenyl, 2,4-dibromophenyl, or 2,4-bis(trifluoromethyl)phenyl and R6 is (CrC12)alkyl.
6. The compound of claim 5 wherein R7 is phenyl, 4-chlorophenyl, or 4- fluorophenyl, and R6 is CH3
7. The compound of claim 1 where the compound is N-Methoxy-N-methyl-N-[2- ((trans-l-(2-(4'-fluorophenyl-2-methyl)cyclopropyl)ethylidene)aminooxymethyl) phenyl] carbamate
8. A method to prepare compounds of claim 4, wherein R6 is (Cj-C^alkyl, comprising the step of reacting N-Methoxy-N-methyl (E)-2-(aminooxymethyl)- phenyl carbamate with l-aryl-l-(C1-C12)alkyl-2-(C(=:O)(CH3))cyclopropane. or 1- heteroaryl-l-(CrC12)alkyl-2-(C(=O)(CH3))cycloρroρane.
9. A fungicidal composition for controlling phytopathogenic fungi which comprises an agronomically acceptable carrier and the compound of claim 1 wherein the ratio of the carrier to the compound is between 99:1 and 1:2.
10. A method for controlling phytopathogenic fungi which comprises applying the compound of claim 1 to the locus where control is desired, at a rate of from 0.005 to 50 kilograms per hectare.
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JP2004515486A (en) 2004-05-27
MXPA03005093A (en) 2004-06-25
KR20030059315A (en) 2003-07-07
BR0116471A (en) 2004-01-06
CN1479718A (en) 2004-03-03
WO2002046142A1 (en) 2002-06-13
EP1347952A4 (en) 2005-10-26

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