EP0623125A1 - Bridged heterocyclic fungicides - Google Patents

Bridged heterocyclic fungicides

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Publication number
EP0623125A1
EP0623125A1 EP93902842A EP93902842A EP0623125A1 EP 0623125 A1 EP0623125 A1 EP 0623125A1 EP 93902842 A EP93902842 A EP 93902842A EP 93902842 A EP93902842 A EP 93902842A EP 0623125 A1 EP0623125 A1 EP 0623125A1
Authority
EP
European Patent Office
Prior art keywords
alkyl
halogen
alkoxy
independently
ring
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Application number
EP93902842A
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German (de)
French (fr)
Inventor
John Powell Daub
Bruce Lawrence Finkelstein
Daniel Anthony Kleier
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
EIDP Inc
Original Assignee
EI Du Pont de Nemours and Co
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Filing date
Publication date
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Publication of EP0623125A1 publication Critical patent/EP0623125A1/en
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/34—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom
    • A01N43/40—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom six-membered rings
    • A01N43/42—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom six-membered rings condensed with carbocyclic rings
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/48—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with two nitrogen atoms as the only ring hetero atoms
    • A01N43/54—1,3-Diazines; Hydrogenated 1,3-diazines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems

Definitions

  • the disclosed invention generally is directed to the field of fungicidal compounds and compositions.
  • This invention comprises compounds of Formula I including all geometric and stereoisomers and
  • X is N or CR 4 ;
  • Y is N or CR 5 ;
  • Z is N or CR 6 ;
  • Q is a fused benzene, naphthalene, thiophene,
  • R 1 , R 2 , R 3 and R 4 are independently H; halogen; cyano; hydroxy; C 1 -C 6 alkyl; C 1 -C 4 haloalkyl; C 1 -C 4 alkylthio; C 1 -C 4 alkylsulfinyl; C 1 -C 4 alkylsulfonyl; C 3 -C 6 cycloalkyl optionally substituted with 1-2 methyl groups; C 1 -C 4 alkoxy; C 1 -C 4 haloalkoxy; C 2 -C 4 alkoxyalkyl; C 2 -C 4 alkenyl; C 2 -C 4 haloalkenyl; C 2 -C 4 alkenyloxy; C 2 -C 4 alkynyl; C 2 -C 4 alkynyloxy;
  • R 1 and R 4 , R 2 and R 4 or R 2 and R 5 can be taken together to form -(CH 2 ) 3 -, -(CH 2 ) 4 - or a fused phenyl ring;
  • R 5 and R 6 are independently H, halogen, C 1 -C 2
  • R 7 is halogen; cyano; nitro; hydroxy;
  • R 8 and R 14 are independently 1-2 halogen, 1-2 C 1 -C 3 alkyl, C 1 -C 2 haloalkyl, C 1 -C 2 alkoxy or C 1 -C 2 haloalkoxy;
  • R 9 , R 10 and R 11 are independently H or C 1 -C 2 alkyl
  • R 12 , R 13 , R 15 , R 16 , R 17 , and R 18 are independently H or C 1 -C 2 alkyl
  • R 12 and R 13 , R 15 and R 16 or R 17 and R 18 can be taken together with the nitrogen to which they are attached to form a piperidino, pyrrolidino or morpholino ring;
  • R 19 is halogen, C 1 -C 2 alkyl, C 1 -C 2 haloalkyl, C 1 -C 2 alkoxy or C 1 -C 2 haloalkoxy;
  • p 0, 1 or 2;
  • the compounds are other than 2-[4,6-bis(tri- chloromethyl)-1,3,5-triazin-2-yl]-1,10-phenanthroline or 2-(2-pyridinyl)-1,10-phenanthroline.
  • X is N or CR 4 ;
  • Y is N or CR 5 ;
  • Z is N or CR 6 ;
  • Q is a fused benzene, naphthalene, thiophene,
  • A is a bridge -G 1 -G 2 -G 3 -G 4 -, wherein G 1 , G 2 , G 3 or
  • G 4 are independently O, S(O) p , NR 9 , CR 10 R 11 ,
  • R 1 , R 2 , R 3 and R 4 are independently H; halogen; cyano; hydroxy; C 1 -C 6 alkyl; C 1 -C 4 haloalkyl; C 1 -C 4 alkylthio; C 1 -C 4 alkylsulfinyl; C 1 -C 4 alkylsulfonyl; C 3 -C 6 cycloalkyl optionally substituted with 1-2 methyl groups; C 1 -C 4 alkoxy; C 1 -C 4 haloalkoxy; C 2 -C 4 alkoxyalkyl; C 2 -C 4 alkenyl; C 2 -C 4 haloalkenyl; C 2 -C 4 alkenyloxy; C 2 -C 4 alkynyl; C 2 -C 4 alkynyloxy; NR 12 R 13; phenyl or phenoxy optionally
  • R 1 and R 4 , R 2 and R 4 or R 2 and R 5 can be taken together to form -(CH 2 ) 3 -, -(CH 2 ) 4 - or a fused phenyl ring;
  • R 5 and R 6 are independently H, halogen, C 1 -C 2
  • R 7 is halogen; cyano; nitro; hydroxy;
  • alkylsulfinyl C 1 -C 4 alkylsulfonyl; (C 1 -C 4 alkyl) 3 silyl; C 3 -C 6 cycloalkyl; C 2 -C 5
  • alkylcarbonyl C 2 -C 4 alkenyl; C 2 -C 4
  • R 8 and R 14 are independently 1-2 halogen, 1-2 C 1 -C 3 alkyl, C 1 -C 2 haloalkyl, C 1 -C 2 alkoxy or C 1 -C 2 haloalkoxy;
  • R 9 , R 10 and R 11 are independently H or C 1 -C 2 alkyl
  • R 12 , R 13 , R 15 , R 16 , R 17 , and R 18 are independently H or C 1 -C 2 alkyl; or R 12 and R 13 , R 15 and R 16 or
  • R 17 and R 18 can be taken together with the nitrogen to which they are attached to form a piperidino, pyrrolidino or morpholino ring;
  • R 19 is halogen, C 1 -C 2 alkyl, C 1 -C 2 haloalkyl, C 1 -C 2 alkoxy or C 1 -C 2 haloalkoxy; p is 0, 1 or 2;
  • alkyl used either alone or in compound words such as “alkylthio” or “haloalkyl” denotes straight chain or branched alkyl; e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl, sec-butyl, t-butyl, n-pentyl or n-hexyl.
  • Alkenyl denotes straight chain or branched alkenes; e.g., vinyl, 1-propenyl, 2-propenyl, 3- propenyl and the different butenyl isomers.
  • CH 2 CHCH 2 CH 2 O.
  • Alkynyl includes straight chain or branched alkynes; e.g., ethynyl, 1-propynyl, 3-propynyl and the different butynyl isomers.
  • Alkynyloxy denotes straight or branched
  • alkynyloxy moieties examples include HC ⁇ CCH 2 O and CH 3 C ⁇ CCH 2 O.
  • Alkylthio includes methylthio, ethylthio, and the different propylthio and butylthio isomers.
  • Alkylsilyl includes (CH 3 ) 2 (t-C 4 H 9 ) Si, (CH 3 ) 3 Si and (CH 3 CH 2 ) 3 Si.
  • alkylsulfinyl examples include CH 3 S(O),
  • alkylsulfonyl examples include CH 3 S(O) 2 , CH 3 CH 2 S(O) 2 , CH 3 CH 2 CH 2 S(O) 2 , (CH 3 ) 2 CHS (O) 2 and the different butylsulfonyl isomers.
  • Alkoxy includes methoxy, ethoxy, n-propyloxy, isopropyloxy and the different butoxy isomers.
  • Cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • halogen either alone or in compound words such as “haloalkyl” includes fluorine, chlorine, bromine or iodine. Further, when used in compound words such as “haloalkyl” said alkyl may be partially or fully substituted with halogen atoms which may be the same or different. Examples of “haloalkyl” include CF 3 , CH 2 Cl, CH 2 CF 3 and CF 2 CF 3 . Examples of “haloalkoxy” include CF 3 O, Cl 3 CCH 2 O, CF 2 HCH 2 CH 2 O and CF 3 CH 2 O.
  • C i -C j The total number of carbon atoms in a substituent group is indicated by the "C i -C j " prefix where i and j are numbers from 1 to 6. For example, C 1 -C 3
  • alkylsulfonyl designates methylsulfonyl
  • C 2 alkoxyalkoxy designates CH 3 OCH 2 O
  • C 3 alkoxyalkoxy designates, for example, CH 3 OCH 2 CH 2 O
  • C 4 alkoxyalkoxy designates the various isomers of an alkoxy group substituted with a second alkoxy group containing a total of 4 carbon atoms
  • alkoxyalkyl examples include CH 3 OCH 2 , CH 3 OCH 2 CH 2 and
  • alkoxycarbonyl examples include CO 2 CH 3 , CO 2 CH 2 CH 3 , CO 2 CH 2 CH 2 CH 3 , CO 2 CH(CH 3 ) 2 and the different butoxycarbonyl isomers.
  • salts of the compounds of the invention include those formed with organic or inorganic bases when the compound contains an acidic group such as a carboxylic acid, phenol, or mercapto group.
  • the metal complexes of the compounds of the invention include complexes with metal salts such as copper, zinc, manganese, and iron salts. These complexes can be prepared prior to formulating the compound or can be prepared by adding the appropriate metal salt to the formulation.
  • Preferred compounds of Formula I for reasons of greatest fungicidal activity and/or ease of synthesis are:
  • X is N or CR 4 ;
  • Y is N or CR 5 ;
  • Z is N or CR 6 ;
  • Q is a fused benzene, naphthalene, thiophene, furan, pyrrole, pyridine or pyrimidine ring each optionally substituted with R 7 and R 8 ;
  • A is a bridge selected from the group
  • R 1 , R 2 , R 3 and R 4 are independently H; halogen; cyano; hydroxy; C 1 -C 6 alkyl; C 1 -C 4
  • alkylsulfinyl C 1 -C 4 alkylsulfonyl; C 3 -C 6 cycloalkyl optionally substituted with 1-2 methyl groups; C 1 -C 4 alkoxy; C 1 -C 4
  • R 4 , R 2 and R 4 or R 2 and R 5 can be taken together to form -(CH 2 ) 3 -, -(CH 2 ) 4 - or a fused phenyl ring;
  • R 5 and R 6 are independently H, halogen, C 1 -C 2 alkyl or C 1 -C 2 alkoxy;
  • R 7 is halogen; cyano; nitro; hydroxy; hydroxy- carbonyl; C 1 -C 6 alkyl; C 1 -C 4 haloalkyl;
  • R 9 , R 10 and R 11 are independently H or C 1 -C 2
  • R 12 , R 13 , R 15 , R 16 , R 17 , and R 18 are
  • R 12 and R 13 , R 15 and R 16 or R 17 and R 18 can be taken together with the nitrogen to which they are attached to form a piperidino,
  • R 19 is halogen, C 1 -C 2 alkyl, C 1 -C 2 haloalkyl, C 1 -C 2 alkoxy or C 1 -C 2 haloalkoxy;
  • p 0, 1 or 2;
  • X is CR 4 ;
  • Y is N or CH
  • Z is N or CH
  • A is a bridge selected from the group
  • Q is a fused benzene, thiophene, furan or
  • A is selected from the group consisting of
  • R 1 , R 2 , R 3 and R 4 are independently H, halogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, cyclopropyl,
  • R 7 is halogen, cyano, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy or C 2 -C 4 alkoxyalkoxy.
  • Q is a fused benzene ring optionally
  • a method of controlling fungus disease in plants that comprises treating the locus to be
  • X is N or CR 4 ;
  • Y is N or CR 5 ;
  • Z is N or CR 6 ;
  • Q is a fused benzene, naphthalene, thiophene, furan, pyrrole, pyridine or pyrimidine ring each optionally substituted with R 7 and R 8 ;
  • A is a bridge selected from the group consisting of: -CR 10 R 11 -; -G-;
  • a taken together with the attached atoms forms a 5-8 membered ring; and the directionality of A may be that the left side of A is bonded to the Q ring and the right side is bonded to the pyridyl
  • R 1 , R 2 , R 3 and R 4 are independently H;
  • halogen cyano; hydroxy; C 1 -C 6 alkyl; C 1 -C 4 haloalkyl; C 1 -C 4 alkylthio; C 1 -C 4 alkylsulfinyl; C 1 -C 4 alkylsulfonyl; C 3 -C 6 cycloalkyl optionally substituted with
  • R 1 and R 4 , R 2 and R 4 or R 2 and R 5 can be taken together to form -(CH 2 ) 3 -, -(CH 2 ) 4 - or a fused phenyl ring;
  • R 5 and R 6 are independently H, halogen, C 1 -C 2 alkyl or C 1 -C 2 alkoxy;
  • R 7 is halogen; cyano; nitro; hydroxy;
  • alkylsulfinyl C 1 -C 4 alkylsulfonyl; (C 1 -C 4 alkyl) 3 silyl; C 3 -C 6 cycloalkyl; C 2 -C 5 alkylcarbonyl; C 2 -C 4 alkenyl; C 2 -C 4 alkenyloxy; C 2 -C 4 alkynyl; C 2 -C 4
  • R 8 and R 14 are independently 1-2 halogen, 1-2 C 1 -C 3 alkyl, C 1 - C2 haloalkyl, C 1 -C 2 alkoxy or C 1 -C 2 haloalkoxy;
  • R 9 , R 10 and R 11 are independently H or C 1 -C 2 alkyl
  • R 12 , R 13 , R 15 , R 16 , R 17 , and R 18 are independently H or C 1 -C 2 alkyl; or R 12 and R 13 , R 15 and R 16 or R 17 and R 18 can be taken together with the nitrogen to which they are attached to form a piperidino, pyrrolidino or morpholino ring;
  • R 19 is halogen, C 1 -C 2 alkyl, C 1 -C 2 haloalkyl,
  • p 0, 1 or 2;
  • X is CR 4 ;
  • Y is N or CH
  • Z is N or CH
  • A is a bridge selected from the group consisting of: -(CR 10 R 11 -CR 10 R 11 )-;
  • Q is a fused benzene, thiophene, furan or pyridine ring each optionally substituted with R 7 and R 8 ;
  • A is selected from the group consisting of:
  • R 1 , R 2 , R 3 and R 4 are independently H,
  • R 7 is halogen, cyano, C 1 -C 4 alkyl, C 1 -C 4
  • haloalkyl C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy or C 2 -C 4 alkoxyalkoxy.
  • Q is a fused benzene ring optionally
  • Preferred for greatest fungicidal activity and/or ease of synthesis is a method according to Preferred 4 wherein the compound is 6,7-dihydro-2- (4-methyl-2-pyrimidinyl)-5-H-benzo[6,7]cyclohepta[1,2- b]pyridine.
  • Compounds of Formula I when Y is N and X is CR 4 , can be prepared by the reaction of amidines of Formula II with Formula III compounds in the presence of a suitable base as illustrated in Scheme 1.
  • Typical reactions involve the combination of an amidine II or its conjugate acid salt (such as a hydrochloride) with 1 to 1.5 equivalents of a Formula III compound in an inert solvent in the presence of a catalytic amount to 2.5 equivalents of base.
  • Typical bases include alkali metal alkoxides (such as sodium methoxide and sodium ethoxide) and organic amine bases (such as
  • Typical solvents include alcohols (such as methanol and ethanol), cyclic ethers (such as tetrahydrofuran and dioxane), pyridine, and dimethylformamide.
  • the reaction temperature typically ranges from 50°C to the reflux temperature of the particular solvent being used and the reaction is usually complete in 1 to 6 h. This method is not applicable when R 1 or R 2 are substituents which are attached through a heteroatom such as alkoxy and halogen.
  • Compounds of Formula III are known in the art or can be prepared by related methods.
  • R 20 is C 1 -C 4 alkyl
  • Typical reactions involve the combination of an amidine II or its conjugate acid salt (such as a hydrochloride) with 1 to 1.5 equivalents of a Formula IV compound in an inert solvent in the presence of 0 to 2.5 equivalents of base.
  • Typical bases include alkali metal alkoxides (such as methoxide and sodium ethoxide) and organic amine bases (such as triethylamine and diethylaniline).
  • Typical solvents include alcohols (such as methanol and ethanol), cyclic ethers (such as tetrahydrofuran), pyridine, and dimethylformamide.
  • the reaction temperature typically ranges from 50°C to the reflux temperature of the particular solvent being used and the reaction is usually complete in 24 h. This method is not applicable when R 1 and R 2 are
  • Typical reactions involve the combination of an amidine of
  • Formula II or its conjugate acid salt (such as a
  • Typical bases include alkali metal alkoxides (such as sodium methoxide and sodium ethoxide) and organic amine bases (such as triethylamine and diethylaniline).
  • Typical solvents include alcohols (such as methanol and ethanol), cyclic ethers (such as tetrahydrofuran and dioxane), pyridine, and dimethyIformamide.
  • the reaction temperature typically ranges from 50°C to the reflux temperature of the particular solvent being used and the reaction is usually complete in 24 h. This method is not
  • R 1 is a substituent which is attached through a heteroatom such as alkoxy and halogen. This method also is not applicable when R 2 is a better leaving group than L 1 since the latter would be retained in the product.
  • Compounds of Formula V are well known in the art or can be prepared by related methods (Abdulla et al., Tetrahedron, 1979, 35,
  • heteroatom such as alkoxy and halogen.
  • R 20 is C 1 -C 4 alkyl.
  • hydrogen can be prepared by reductive removal of a halogen, alkylthio, alkylsulfinyl, or alkylsulfonyl group as outlined in Scheme 5.
  • a catalyst such as palladium on carbon under hydrogen gas in an inert solvent such as water, an alcohol (such as methanol or ethanol), ethyl acetate, or toluene at 25° to 50°C.
  • the dehalogenation can be conducted in the presence of an equivalent of a base (such as ammonia, sodium hydroxide, sodium carbonate, or sodium acetate) to neutralize the liberated hydrogen halide.
  • the reaction is typically conducted as above using Raney nickel as the catalyst in the absence of base and optionally under hydrogen gas.
  • Compounds of Formula I when R 1 or R 2 are alkyl or haloalkyl, can be prepared by the reaction of compounds of Formula I, where R 1 or R 2 are leaving groups such as halogen, alkylsulfinyl, or alkylsulfonyl, with dialkyl malonates of Formula VII in the presence of base followed by hydrolysis and decarboxylation as outlined in Scheme 6.
  • the first reaction is carried out by combining a compound of Formula I, where R 1 or R 2 are leaving groups, with 1 to 2 equivalents of a Formula VII compound in the presence of 1 to 4 equivalents of a suitable base in an inert solvent.
  • Typical bases include alkali metal hydrides (such as sodium hydride and potassium hydride), alkyllithiums (such as
  • alkali metal amides such as lithium diisopropylamide
  • alkali metal hydroxides such as sodium hydroxide
  • Typical solvents include nitriles (such as acetonitrile), ethers (such as diethyl ether and tetrahydrofuran), halohydrocarbons (such as
  • the reaction temperature typically ranges from 0°C to the reflux temperature of the particular solvent being used and the reaction is usually complete in 0.5 to 24 h.
  • the hydrolysis reaction is typically carried out in water with an optional organic cosolvent (such as methanol, ethanol, tetrahydrofuran, or
  • reaction temperature typically ranges from 0°C to the reflux temperature of the solvent mixture being used and the hydrolysis is usually complete after 0.2 to 24 h.
  • the hydrolysis product (malonic acid intermediate) need not be
  • R 20 is C 1 -C 4 alkyl
  • R 21 is C 1 -C 5 alkyl or C 1 -C 3 haloalkyl.
  • R 1 or R 2 when R 1 or R 2 are cyano, hydroxy, alkylthio, alkoxy, haloalkoxy, alkenyloxy, alkynyloxy, (di) alkylamino, or substituted phenoxy, can be prepared by the reaction of compounds of Formula I, where R 1 or R 2 are leaving groups such as halogen, alkylsulfinyl, or alkylsulfonyl, with a nucleophile L 2 - M 1 in the presence of an optional base as outlined in Scheme 7.
  • Typical reactions involve the combination of a compound of Formula I, where R 1 or R 2 are a leaving group, with 1 to 2 equivalents of a L 2 -M 1 compound in an inert solvent.
  • Typical bases include alkali metal hydrides (such as sodium hydride), alkali metals (such as sodium), and alkyllithiums (such as butyllithium).
  • Typical solvents include alcohols (such as methanol and ethanol), ethers (such as diethyl ether, tetrahydrofuran, and dioxane), nitriles (such as acetonitrile), dimethylformamide, and dimethyl sulfoxide.
  • Potentially nucleophilic solvents, such as alcohols should be used only when they will not compete with the nucleophile L 2 -M 1 .
  • the reaction temperature typically ranges from 0°C to the reflux temperature of the particular solvent used, and the reaction is usually complete within 2 days.
  • L 2 -M 1 represent common reagents such as sodium alkoxides, alcohols, phenols, sodium cyanide, sodium hydroxide, (di) alkylamines, and the like.
  • Catalysts such as copper, copper(I) chloride, copper (II) chloride, and copper (II) oxide may be added to facilitate the reaction.
  • L 2 is cyano, hydroxy, C 1 -C 4 alkylthio, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, C 2 -C 4 alkenyloxy, C 2 -C 4 alkynyloxy, NR 12 R 13 , or phenoxy substituted with R 14 ;
  • M 1 is H or alkali metal.
  • alkylsulfinyl or alkylsulfonyl can be prepared by the oxidation of compounds of Formula I, where R 1 or R 2 are alkylthio, as outlined in Scheme 8.
  • Typical reactions involve the combination of a compound of Formula I (R 1 or R 2 is alkylthio) with a suitable oxidant in an inert solvent.
  • R 1 or R 2 are alkylsulfinyl in the desired product I, 1 to 1.1 equivalents of oxidant are used, and when R 1 or R 2 are alkylsulfonyl in the product I, 2 to 2.2 equivalents of oxidant are used.
  • Typical oxidants are 3-chloroperoxybenzoic acid, magnesium monoperoxyphthalate, peracetic acid, hydrogen peroxide, and the like.
  • Typical solvents include halohydrocarbons (such as dichloromethane, 1,2- dichloroethane, and chloroform) and aromatic hydrocarbons (such as dichloromethane, 1,2- dichloroethane, and chloroform) and aromatic hydrocarbons (such as halohydrocarbons (such as dichloromethane, 1,2- dichloroethane, and chloroform) and aromatic
  • hydrocarbons such as toluene
  • R 20 is C 1 -C 4 alkyl .
  • Compounds of Formula I when R 1 or R 2 are halogen, can be prepared by the reaction of compounds of Formula I, where R 1 or R 2 are hydroxy, with a halogenating agent such as phosphorus trichloride, phosphorus pentachloride, phosphorus tribromide, phosphorus pentabromide, phosphorus oxychloride, phosphorus oxybromide, thionyl chloride, phosgene, and the like as illustrated in Scheme 9.
  • Typical reactions involve the combination of compounds of Formula I, when R 1 or R 2 is hydroxy, with an excess of the halogenating agent ranging from 1.1 to 10 equivalents, with 2 to 4
  • reaction can be conducted in the absence of solvent or in the presence of a suitable inert solvent including aromatic hydrocarbons (such as benzene and toluene),
  • halohydrocarbons such as dichloromethane and
  • reaction temperature can range from -10°C to 200°C with 25°C to 100°C being preferred.
  • the reaction is
  • alkali metal alkoxides such as sodium methoxide and sodium ethoxide.
  • solvents include alcohols (such as methanol and
  • reaction temperature typically ranges from ambient temperature to the reflux temperature of the particular solvent being used and the reaction is usually complete in 1 to 24 h.
  • An example of this method is taught by Lafferty et al. (J. Org. Chem. 1967, 32, 1591-1596).
  • R 2 is attached through a heteroatom (such as alkoxy)
  • the product usually loses R 2 giving product I wherein R 2 is hydroxy
  • an example of this reaction using a dialkylmalonate VIII (R 2 is alkoxy) giving a dihydroxypyrimidine also may be found in the above reference by Lafferty et al.
  • reaction temperature can range from 0°C to 50°C (preferably ambient temperature) and the reaction is usually complete after 1 to 48 h.
  • the reaction is typically worked up by neutralizing with an acid (such as acetic acid), concentrating the reaction mixture, dissolving in an appropriate solvent (such as ether), filtering off the salt by-product (e.g., sodium
  • the intermediate amidines of Formula II can be prepared by the reaction of an imidate of Formula XII with 1.0 to 1.1 equivalents of an ammonium salt (such as ammonium chloride, ammonium bromide, ammonium acetate, and ammonium formate) in an alcohol
  • an ammonium salt such as ammonium chloride, ammonium bromide, ammonium acetate, and ammonium formate
  • the reaction temperature can range from ambient temperature to the reflux temperature of the particular solvent being used and the reaction is usually complete after 30 min to 5 h.
  • the reaction mixture is
  • amidine salt (HL 3 ) which is purified by recrystallization or trituration.
  • the amidine salts can be used in the previously described reactions or can be first converted to their conjugate bases.
  • amidines of Formula II can be prepared directly from carbonitriles XI by the reagent MeAl (Cl)NH 2 as described by Garigipati (Tetrahedron Lett., 1990, 31, 1969-1972).
  • the esters of Formula IX can be prepared from imidates of Formula XII by aqueous hydrolysis with an optional organic cosolvent.
  • Typical reactions involve the combination of an imidate XII with an excess of acid (such as sulfuric acid or hydrochloric acid) in an optional organic cosolvent (such as methanol, ethanol, tetrahydrofuran, and dioxane).
  • acid such as sulfuric acid or hydrochloric acid
  • an optional organic cosolvent such as methanol, ethanol, tetrahydrofuran, and dioxane
  • reaction is usually complete within 6 h.
  • R 20 is C 1 -C 4 alkyl
  • M 2 is an alkali metal
  • L 3 is a counterion such as Cl, Br, OAc, or OCHO.
  • N-oxide intermediates of Formula XIV can be prepared by oxidation of compounds of Formula XIII with 1 to 1.2 equivalents of a suitable oxidizing reagent such as 3-chloroperoxybenzoic acid, magnesium
  • Typical solvents include
  • halohydrocarbons such as dichloromethane, 1,2- dichloroethane, and chloroform
  • aromatic hydrocarbons such as dichloromethane, 1,2- dichloroethane, and chloroform
  • reaction temperature can range from 0°C to the reflux temperature of the particular solvent being used and the reaction is usually complete in 24 h.
  • Z is N
  • a mixture of N-oxides may be formed; both of these regioisomeric N-oxides can be used for the subsequent Fife cyanation to intermediates XI.
  • these compounds of Formula XIII, when Z is CR 6 can be prepared using -one of several pyridine annulation procedures known in the art. Two such procedures are outlined in Scheme 13.
  • Formula XV The starting ketones of Formula XV are known in the art or can be obtained by methods analogous to known procedures.
  • Formula XV compounds includes indanones, tetralones, benzosuberones, chromanones and homologs, thiochromanones and homologs, isochromanones, benzofuran-3-ones, and others.
  • ketones of Formula XV can be converted to compounds of Formula XIX, where L 4 is a leaving group, by methods known in the art.
  • R 20 is C 1 -C 4 alkyl
  • L 4 is a leaving group such as halogen, alkoxy, alkylthio, (di) alkylamino, (halo) alkylsulf onyloxy, and arylsulf onyloxy.
  • N-cyanoamidines of Formula XXII can be prepared by the reaction of imidates of Formula XII with
  • R 20 is C 1 -C 4 alkyl.
  • R 2 is a leaving group such as alkoxy in Formula XXIV, then R 2 will be hydroxy in the product which can be
  • R 20 is C 1 -C 4 alkyl.
  • Compounds of Formula I when X and Y are CR 4 and CR 5 , respectively, can be prepared from intermediate carbonitriles of Formula XI as outlined in Scheme 17. The addition of organometallic reagents to nitriles to give ketones represented by Formula XXVI is well known in the art. Ketones of Formula XXVI can be converted to intermediates of Formula XXVII by methods well known in the art.
  • M 3 is alkali or alkaline earth metal; and L 1 is hydrogen or a leaving group such as halogen, alkoxy, alkylthio, (di) alkylamino, (halo) alkylsulfonyloxy, and arylsulfonyloxy.
  • compounds of Formula I can be prepared by transition-metal catalyzed aryl coupling reactions as illustrated in Scheme 18.
  • Intermediates of Formula XXIX, when L 5 is halogen, can be prepared by the reaction of N-oxide intermediates of Formula XIV with a halogenating agent such as phosphorus
  • Aryltin intermediates of Formula XXX can be prepared from
  • Formula XXIX compounds by the displacement of L 5 with a trialkylstannylsodium reagent as taught by Wursthorn et al. (J. Am. Chem. Soc. 1978, 100, 2779-2789) or, when Z is CR 6 , by metal-halogen exchange with an alkyllithium (such as butyllithium) and reaction with a trialkyltin halide (such as tributyltin chloride).
  • an alkyllithium such as butyllithium
  • a trialkyltin halide such as tributyltin chloride
  • Typical palladium catalysts include tetrakis (triphenylphosphine) palladium (0) and bis (triphenylphosphine)palladium (II) chloride.
  • Typical solvents include aromatic hydrocarbons (such as benzene and toluene), cyclic ethers (such as tetrahydrofuran and dioxane), and dimethylformamide.
  • Related coupling reactions are known in the art as discussed by Solberg et al. (Acta Chem. Scand. 1989, 43, 62-68), Undheim et al. (Heterocycles 1990, 30, 1155-1193), Gronowitz et al. (Chem. Scripta 1986, 26, 305-309), Fu et al.
  • compounds of Formula I can be prepared by similar palladium-catalyzed couplings of intermediates of Formula XXIX with arylstannanes of Formula XXXII as illustrated in Scheme 18.
  • Compounds of Formula XXXI are well known in the art or can be prepared by analogous methods and compounds of Formula XXXII can be prepared from these compounds by
  • L 5 is a leaving group such as halogen
  • R 20 is C 1 -C 4 alkyl.
  • L 4 is a leaving group such as halogen, alkoxy, alkylthio, (di) alkylamino, (halo) alkylsulfonyloxy, and arylsulfonyloxy.
  • L 4 is a leaving group such as halogen, alkoxy, alkylthio, (di)alkylamino, (halo)alkylsulfonyloxy, and
  • halopyridines and halopyrimidines which are well known in the art or can be prepared by related methods.
  • Groups A 1 and A 2 are chosen so that a bond or bonds can be made between them to construct the particular bridge A.
  • lactonization using an activating agent gives compounds of Formulae XIII and I where A is -OC(O)CH 2 -.
  • an activating agent such as 1,3- dicyclohexylcarbodiimide
  • etherification by treatment with base gives compounds where A is -OCH 2 -
  • a 1 and A 2 are CH 2 C(O)H
  • acetal formation with 2,2-dimethoxypropane gives compounds where A is -OC(Me) 2 O-.
  • a specific example of the strategy in Scheme 21 is reported by Fu et al. (J. Org.
  • M 4 is a metallic group such as Sn(R 20 ) 3 , B(OH) 2 , B(OR 20 ) 2 ,
  • L 5 is a leaving group such as halogen
  • L6 is hydrogen or
  • a 1 and A 2 are suitable groups for creating bonds between them to construct bridge A.
  • Scheme 22 illustrates the strategy where the bridge A is first constructed using methods similar to those discussed for Scheme 21 .
  • Suitable synthetic methods include, but are not limited to,
  • the intermediate XXXIX can be converted by an intramolecular Ullman or related aryl coupling to compounds of Formula I or
  • L 5 and L 7 are independently leaving groups such as halogen
  • L 6 is hydrogen or and A 1 and A 2 are suitable groups for creating bonds between them to construct bridge A.
  • the metal complexes of the compounds of the invention include complexes with copper, zinc, iron, magnesium or manganese cations. These complexes can be made by combining the compound with the metal salt, either in aprotic solvents such as ether or
  • tetrahydrofuran or they can be generated in protic solvents such as methanol or mixtures of such solvents.
  • the complex may crystallize and precipitate from solution or the complex is crystallized as the solvent is removed.
  • N, N-dimethylhydrazine 37.51 g, 624.1 mmol
  • the reaction mixture is concentrated under reduced pressure.
  • the residue is dissolved in ethanol and reconcentrated; this is repeated once more with ethanol and twice more with dichloromethane to yield 32.65 g of the crude title hydrazone.
  • Step B 6-[ 2- (1,3-Dioxolan-2-yl)ethyl]-6,7,8,9- tetrahydro-5H-benzocyclohepten-5-one dimethylhydrazone
  • reaction mixture is then kept at -78°C for 1 h.
  • the reaction mixture is allowed to come to room temperature and is left at room temperature overnight.
  • the reaction mixture is slowly quenched with water and is then poured into water (250 mL).
  • the resulting mixture is extracted three times with diethyl ether.
  • Step E To a stirred solution of the product of Step E (8.25 g, 37.45 mmol) in methanol (75 mL) under a nitrogen atmosphere at room temperature is added a solution of sodium methoxide (3.0 mL of commercial 25 wt. % solution in methanol, 13.11 mmol) and the reaction is allowed to stir at room temperature
  • Step G 6,7-Dihydro-5H-benzo[6,7]cyclohepta[ 1 ,2- b ]pyridine-2-carboximidamide hydrochloride
  • To ar solution of the crude imidate from Step F (37.45 mmol) in absolute ethanol (48.3 mL) under a nitrogen atmosphere at room temperature is added a solution of ammonium chloride (2.003 g, 37.45 mmol) in water (18.3 mL) and the resulting mixture is heated under reflux for 3 h. The reaction mixture is allowed to cool, concentrated under reduced pressure and, finally, concentrated in vacuo .
  • Step H 6,7-Dihydro-2-(4-methyl-2-pyrimidinyl)-5H- benzo[ 6,7]cyclohepta[1,2-b]pyridine y
  • methanol 92 mL
  • acetylacetaldehyde dimethyl acetal 1.83 mL, 1.815 g, 13.74 mmol
  • Step B 2-(4,6-Dimethyl-2-pyrimidinyl)-6,7-dihydro- 5H-benzo[6,7]cyclohepta[1,2-b]pyridine
  • Step A 8-Bromo-6,7-dihydro-5H-benzo[6,7]cyolohepta- [1,2-b]pyridine and 10-bromo-6,7-dihydro-5H- benzo[6,7]cyclohepta[1,2-b]pyridine
  • 6-bromo-6,7-dihydro-5H- benzo[6,7]cyclohepta[1,2-b]pyridine To a stirred solution of 6,7-dihydro-5H- benzo[6,7]cyclohepta[1,2-b]pyridine (60.00 g,
  • Step B 8-Bromo-6,7-dihydro-2-(4-methyl-2- pyrimidinyl)-5H-benzo[6,7]cyclohepta[1,2-b]- pyridine
  • n- is normal CO 2 H is hydroxycarbonyl
  • NHEt is ethylamino n-Pr is normal-propyl
  • SPh is phenylthio t-Bu is tertiary-butyl
  • i-Pr isopropyl O-n-Bu is normal-butoxy
  • O-i-Pr is isopropoxy n-Bu is normal-butyl
  • Hex is hexyl sec-Bu is secondary-butyl
  • CN is cyano S-i-Pr is isopropylthio
  • OPh is phenoxy CO 2 Me is methoxycarbonyl
  • c-Hex is cyclo-hexyl S(O)Me is methylsulfinyl
  • NO 2 is nitro S(O) 2 Me is methylsulfonyl
  • SEt is ethylthio S(O) 2 Et is ethylsulfonyl
  • SMe is methylthio S(O) 2 -n-Bu is normal-butylsulfonyl OH is hydroxy
  • TBS is tertiary-butyldimethylsilyl OMe is methoxy Et is ethyl
  • c- is cyclo NMe 2 is dimethylamino Me is methyl NEt 2 is diethylamino Ac is acetyl
  • X and Z are CH; Y is N; R 1 is Me; R 2 , R 3 , R 7 and R' 8 are H
  • the fungicidal compositions of the present invention comprise an effective amount of at least one compound of Formula I as defined above and at least one of (a) a surfactant, (b) an organic solvent, and (c) at least one solid or liquid diluent.
  • Useful formulations can be prepared in conventional ways.
  • Sprayable formulations can be extended in suitable media and used at spray volumes from about one to several hundred liters per hectare. High strength compositions are primarily used as intermediates for further
  • the formulations will typically contain effective amounts of active ingredient, diluent and surfactant within the following approximate ranges which add up 100 weight percent .
  • Solutions are prepared by simply mixing the ingredients. Fine solid compositions are made by blending and, usually, grinding as in a hammer mill or fluid energy mill. Water-dispersible granules can be produced be agglomerating a fine powder composition; see for example, Cross et al., Pesticide Formulations, Washington, D.C., 1988, pp 251-259. Suspensions are prepared by wet-milling; see, for example, U.S.
  • Granules and pellets can be made by
  • Pellets can be prepared as described in U.S. 4,172,714. Water-dispersible and water-soluble granules can be prepared as taught in DE 3,246,493.
  • Compound 1 65.0% dodecylphenol polyethylene glycol ether 2.0% sodium ligninsulfonate 4.0% sodium silicoaluminate 6.0% montmorillonite (calcined) 23.0%
  • Compound 1 25.0% anhydrous sodium sulfate 10.0% crude calcium ligninsulfonate 5.0% sodium alkylnaphthalenesulfonate 1.0% calcium/magnesium bentonite 59.0%
  • the compounds of this invention are useful as plant disease control agents.
  • the present invention therefore further comprises a method for controlling plant diseases caused by fungal plant pathogens
  • the compounds and compositions of this invention provide control of diseases caused by a broad spectrum of fungal plant pathogens in the Basidiomycete,
  • Ascomycete, Oomycete and Deuteromycete classes are effective in controlling a broad spectrum of plant diseases, particularly foliar pathogens of ornamental, vegetable, field, cereal, and fruit crops. These pathogens include Plasmopara viticola, Phytophthora infestans, Peronospora tabacina, Pseudoperonospora cubensis, Pythium aphanidermatum, Alternaria brassicae, Septoria nodorum, Cercosporidium personatum, Cercospora arachidicola, Pseudocercosporella herpotrichoides.
  • Puccinia striiformis Puccinia arachidis
  • Rhizoctonia solani Sphaerotheca fuliginea
  • Fusarium oxysporum Verticillium dahliae
  • Pythium aphanidermatum Phytophthora megasperma and other generea and species closely related to these pathogens.
  • Compounds of this invention can also be mixed with one or more other insecticides, fungicides,
  • insecticides such as monocrotophos, carbofuran, tetrachlorvinphos,
  • esfenvalerate permethrin, profenofos, sulprofos, triflumuron, diflubenzuron, methoprene, buprofezin, thiodicarb, acephate, azinphosmethyl, chlorpyrifos, dimethoate, fipronil, flufenprox, fonophos, isofenphos, methidathion, methamidophos, phosmet, phosphamidon, phosalone, pirimicarb, phorate, terbufos, trichlorfon, methoxychlor, bifenthrin, biphenate, cyfluthrin, fenpropathrin, fluvalinate, flucythrinate,
  • fungicides such as carbendazim, thiuram, dodine, maneb, chloroneb, benomyl, cymoxanil, fenpropidine, fenpropimorph, triadimefon, captan, thiophanate-methyl, thiabendazole, phosethyl-A1, chlorothalonil, dichloran, metalaxyl, captafol, iprodione, oxadixyl, vinclozolin, kasugamycin, myclobutanil, tebuconazole,
  • fungicides such as carbendazim, thiuram, dodine, maneb, chloroneb, benomyl, cymoxanil, fenpropidine, fenpropimorph, triadimefon, captan, thiophanate-methyl, thiabendazole, phosethyl-A1, chlorothalonil, dichlor
  • ipconazole metconazole, penconazole, propiconazole, uniconzole, flutriafol, prochloraz, pyrifenox,
  • nematocides such as aldoxycarb, fenamiphos and
  • bactericides such as oxytetracyline, streptomycin and tribasic copper sulfate; acaricides such as binapacryl, oxythioquinox, chlorobenzilate, dicofol, dienochlor, cyhexatin, hexythiazox, amitraz, propargite, tebufenpyrad and fenbutatin oxide; and biological agents such as Bacillus thuringiensis, baculovirus and avermectin B.
  • Plant disease control is ordinarily accomplished by applying an effective amount of a compound of this invention either pre- or post-infection, to the portion of the plant to be protected such as the roots, stems, foliage, fruit, seeds, tubers or bulbs, or to the media (soil or sand) in which the plants to be protected are growing.
  • the compounds can also be applied to the seed to protect the seed and seedling.
  • Rates of application for these compounds can be influenced by many factors of the environment and should be determined under actual use conditions.
  • Foliage can normally be protected when treated at a rate of from less than 1 g/ha to 5,000 g/ha of active ingredient. Seed and seedlings can normally be protected when seed is treated at a rate of from 0.1 to 10 g per kilogram of seed.
  • Test compounds were first dissolved in acetone in an amount equal to 3% of the final volume and then suspended at a concentration of 200 ppm in purified water containing 250 ppm of the surfactant Trem ® 014 (polyhydric alcohol esters). The resulting test suspensions were then used in the following tests.
  • Trem ® 014 polyhydric alcohol esters
  • test suspension was sprayed to the point of run-off on wheat seedlings. The following day the seedlings were inoculated with a spore dust of Erysiphe graminis f. sp. tritici, (the causal agent of wheat powdery mildew) and incubated in a growth chamber at 20°C for 7 days, after which disease ratings were made.
  • test suspension was sprayed to the point of run-off on wheat seedlings.
  • seedlings were inoculated with a spore suspension of Puccinia recondita (the causal agent of wheat leaf rust) and incubated in a saturated atmosphere at 20°C for 24 h, and then moved to a growth chamber at 20°C for 6 days, after which disease ratings were made.
  • Puccinia recondita the causal agent of wheat leaf rust
  • test suspension was sprayed to the point of run-off on rice seedlings.
  • seedlings were inoculated with a spore suspension of Pyricularia oryzae (the causal agent of rice blast) and incubated in a saturated atmosphere at 27°C for 24 h, and then moved to a growth chamber at 30°C for 5 days, after which disease ratings were made.
  • Pyricularia oryzae the causal agent of rice blast
  • test suspension was sprayed to the point of run-off on tomato seedlings.
  • seedlings were inoculated with a spore suspension of Phytophthora infestans (the causal agent of potato and tomato late blight) and incubated in a saturated atmosphere at 20°C for 24 h, and then moved to a growth chamber at 20°C for 5 days, after which disease ratings were made.
  • Phytophthora infestans the causal agent of potato and tomato late blight
  • test suspension was sprayed to the point of run-off on grape seedlings.
  • seedlings were inoculated with a spore suspension of Plasmopara viticola (the causal agent of grape downy mildew) and incubated in a saturated atmosphere at 20°C for 24 h, moved to a growth chamber .at 20°C for 6 days, and then incubated in a saturated atmosphere at 20°C for 24 h, after which disease ratings were made.
  • Plasmopara viticola the causal agent of grape downy mildew
  • test suspension was sprayed to the point of run-off on cucumber seedlings.
  • seedlings were inoculated with a spore suspension of Botrytxs cinerea (the causal agent of gray mold on many crops) and incubated in a saturated atmosphere at 20°C for 48 h, and moved to a growth chamber at 20°C for 5 days, after which disease ratings were made.
  • Botrytxs cinerea the causal agent of gray mold on many crops
  • Couplings are designated by (s)-singlet, (d)-doublet, (t)- triplet, (q)-quartet, (p)-pentet, (m)-multiplet, (dd)-doublet of doublets. Samples dissolved in CDCl 3 unless otherwise indicated.

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Abstract

Cette invention concerne des composés fongicides de formule (I).This invention relates to fungicidal compounds of formula (I).

Description

TITLE
BRIDGED HETEROCYCLIC FUNGICIDES BACKGROUND OF THE INVENTION
The disclosed invention generally is directed to the field of fungicidal compounds and compositions.
Kröhnke, F. (Synthesis 1976, 1 , 1-24) discloses the synthesis of
No fungicidal utility for this compound is disclosed.
U.S. 4,189,323 (Hoechst) discloses the compound
as a photoinitiator for free radical or acid-catalyzed reactions.
Haginiwa et al. ( Yakugaku Zasshi, 1975, 95, 204- 210) disclose the synthesis of
SUMMARY OF THE INVENTION
This invention comprises compounds of Formula I including all geometric and stereoisomers and
agricultural compositions containing such compounds
wherein:
X is N or CR4;
Y is N or CR5;
Z is N or CR6;
Q is a fused benzene, naphthalene, thiophene,
furan, pyrrole, pyridine. or pyrimidine ring each optionally substituted with R7 and R8; A is a bridge -G1-G2-G3-G4-, wherein G1, G2, G3 or G4 are independently O, S(O)p, NR9, CR10R11, C(=O), a direct bond, or G1-G2, G2-G3 or G3-G4 may be taken together to form -CH=CH-; such that at least one of G1, G2, G3 and G4 is other than a direct bond;
R1, R2, R3 and R4 are independently H; halogen; cyano; hydroxy; C1-C6 alkyl; C1-C4 haloalkyl; C1-C4 alkylthio; C1-C4 alkylsulfinyl; C1-C4 alkylsulfonyl; C3-C6 cycloalkyl optionally substituted with 1-2 methyl groups; C1-C4 alkoxy; C1-C4 haloalkoxy; C2-C4 alkoxyalkyl; C2-C4 alkenyl; C2-C4 haloalkenyl; C2-C4 alkenyloxy; C2-C4 alkynyl; C2-C4 alkynyloxy;
NR12R13' phenyl or phenoxy optionally substituted with R14; or R1 and R4, R2 and R4 or R2 and R5 can be taken together to form -(CH2)3-, -(CH2)4- or a fused phenyl ring; R5 and R6 are independently H, halogen, C1-C2
alkyl or C1-C2 alkoxy;
R7 is halogen; cyano; nitro; hydroxy;
hydroxycarbonyl; C1-C6 alkyl; C1-C4 haloalkyl; C1-C4 alkylthio; C1-C4
alkylsulfinyl; C1-C4 alkylsulfonyl; (C1-C4 alkyl) 3silyl; C3-C6 cycloalkyl; C2-C5 alkylcarbonyl; C2-C4 alkenyl; C2-C4 alkenyloxy; C2-C4 alkynyl; C2-C4 alkynyloxy; C1-C4 alkoxy; C1-C4 haloalkoxy; C2-C4 alkoxyalkyl; C2-C5 alkoxycarbonyl; C2-C4 alkoxyalkoxy; NR15R16; C (=O)NR17R18; or phenyl, phenoxy or phenylthio each optionally substituted with R19;
R8 and R14 are independently 1-2 halogen, 1-2 C1-C3 alkyl, C1-C2 haloalkyl, C1-C2 alkoxy or C1-C2 haloalkoxy;
R9, R10 and R11 are independently H or C1-C2 alkyl; R12, R13, R15, R16, R17, and R18 are independently H or C1-C2 alkyl; or R12 and R13, R15 and R16 or R17 and R18 can be taken together with the nitrogen to which they are attached to form a piperidino, pyrrolidino or morpholino ring;
R19 is halogen, C1-C2 alkyl, C1-C2 haloalkyl, C1-C2 alkoxy or C1-C2 haloalkoxy;
p is 0, 1 or 2;
or their agriculturally suitable salts or metal
complexes thereof;
provided that:
i) when any of G1, G2, G3 or G4 are O, then they are not directly bonded to O or S(O)p;- ii) when any of G1, G2, G3 or G4 are S (O) or
S(O)2, then they are not bonded directly to C (=O); iii) the total number of heteroatoms in the ring containing A does not exceed two;
iv) when X, Y and Z are CH; A is CH2; Q is fused unsubstituted benzene; and R1 and R2 are H; then R3 is not unsubstituted phenyl; and
v) the compounds are other than 2-[4,6-bis(tri- chloromethyl)-1,3,5-triazin-2-yl]-1,10-phenanthroline or 2-(2-pyridinyl)-1,10-phenanthroline.
This invention further comprises methods of controlling fungus disease in plants comprising treating the locus to be protected with an effective amount of a compound of Formula IA
wherein:
X is N or CR4;
Y is N or CR5;
Z is N or CR6;
Q is a fused benzene, naphthalene, thiophene,
furan, pyrrole, pyridine or pyrimidine ring each optionally substituted with R7 and R8; A is a bridge -G1-G2-G3-G4-, wherein G1, G2, G3 or
G4 are independently O, S(O)p, NR9, CR10R11,
C(=O), a direct bond, or G1-G2, G2-G3 or G3-G4 may be taken together to form -CH=CH-; such that at least one of G1, G2, G3 and G4 is other than a direct bond;
R1, R2, R3 and R4 are independently H; halogen; cyano; hydroxy; C1-C6 alkyl; C1-C4 haloalkyl; C1-C4 alkylthio; C1-C4 alkylsulfinyl; C1-C4 alkylsulfonyl; C3-C6 cycloalkyl optionally substituted with 1-2 methyl groups; C1-C4 alkoxy; C1-C4 haloalkoxy; C2-C4 alkoxyalkyl; C2-C4 alkenyl; C2-C4 haloalkenyl; C2-C4 alkenyloxy; C2-C4 alkynyl; C2-C4 alkynyloxy; NR12R13; phenyl or phenoxy optionally
substituted with R14; or R1 and R4, R2 and R4 or R2 and R5 can be taken together to form -(CH2)3-, -(CH2)4- or a fused phenyl ring;
R5 and R6 are independently H, halogen, C1-C2
alkyl or C1-C2 alkoxy;
R7 is halogen; cyano; nitro; hydroxy;
hydroxycarbonyl; C1-C6 alkyl; C1-C4
haloalkyl; C1-C4 alkylthio; C1-C4
alkylsulfinyl; C1-C4 alkylsulfonyl; (C1-C4 alkyl) 3silyl; C3-C6 cycloalkyl; C2-C5
alkylcarbonyl; C2-C4 alkenyl; C2-C4
alkenyloxy; C2-C4 alkynyl; C2-C4 alkynyloxy; C1-C4 alkoxy; C1-C4 haloalkoxy; C2-C4
alkoxyalkyl; C2-C5 alkoxycarbonyl; C2-C4 alkoxyalkoxy; NR15R16; C (=O)NR17R18; or phenyl, phenoxy or phenylthio each optionally substituted with R19;
R8 and R14 are independently 1-2 halogen, 1-2 C1-C3 alkyl, C1-C2 haloalkyl, C1-C2 alkoxy or C1-C2 haloalkoxy;
R9, R10 and R11 are independently H or C1-C2 alkyl;
R12, R13, R15, R16, R17, and R18 are independently H or C1-C2 alkyl; or R12 and R13, R15 and R16 or
R17 and R18 can be taken together with the nitrogen to which they are attached to form a piperidino, pyrrolidino or morpholino ring;
R19 is halogen, C1-C2 alkyl, C1-C2 haloalkyl, C1-C2 alkoxy or C1-C2 haloalkoxy; p is 0, 1 or 2;
or their agriculturally suitable salts or metal complexes thereof;
provided that:
i) when any of G1, G2, G3 or G4 are O, then they are not directly bonded to O or S(O)p;
ii) when any of G1, G2, G3 or G4 are S (O) or S(O)2, then they are not bonded directly to C(=O); and iii) the total number of heteroatoms in the ring containing A does not exceed two.
In the above recitations, the term "alkyl", used either alone or in compound words such as "alkylthio" or "haloalkyl" denotes straight chain or branched alkyl; e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl, sec-butyl, t-butyl, n-pentyl or n-hexyl.
"Alkenyl" denotes straight chain or branched alkenes; e.g., vinyl, 1-propenyl, 2-propenyl, 3- propenyl and the different butenyl isomers.
"Alkenyloxy" denotes straight chain or branched alkenyloxy moieties. Examples of alkenyloxy include H2C=CHCH2O, (CH3)CH-CHCH2O, CH2=CH(CH3) CH2O and
CH2=CHCH2CH2O.
"Alkynyl" includes straight chain or branched alkynes; e.g., ethynyl, 1-propynyl, 3-propynyl and the different butynyl isomers.
"Alkynyloxy" denotes straight or branched
alkynyloxy moieties. Examples include HC≡CCH2O and CH3C≡CCH2O.
"Alkylthio" includes methylthio, ethylthio, and the different propylthio and butylthio isomers.
"Alkylsilyl" includes (CH3) 2 (t-C4H9) Si, (CH3)3Si and (CH3CH2)3Si.
Examples of "alkylsulfinyl" include CH3S(O),
CH3CH2S(O), CH3CH2CH2S (O) , (CH3) 2CHS (O) and
CH3CH2CH2CH2S(O). Examples of "alkylsulfonyl" include CH3S(O)2, CH3CH2S(O)2, CH3CH2CH2S(O)2, (CH3) 2CHS (O) 2 and the different butylsulfonyl isomers.
"Alkoxy" includes methoxy, ethoxy, n-propyloxy, isopropyloxy and the different butoxy isomers.
"Cycloalkyl" includes cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
The term "halogen", either alone or in compound words such as "haloalkyl", includes fluorine, chlorine, bromine or iodine. Further, when used in compound words such as "haloalkyl" said alkyl may be partially or fully substituted with halogen atoms which may be the same or different. Examples of "haloalkyl" include CF3, CH2Cl, CH2CF3 and CF2CF3. Examples of "haloalkoxy" include CF3O, Cl3CCH2O, CF2HCH2CH2O and CF3CH2O.
The total number of carbon atoms in a substituent group is indicated by the "Ci-Cj" prefix where i and j are numbers from 1 to 6. For example, C1-C3
alkylsulfonyl designates methylsulfonyl through
propylsulfonyl; C2 alkoxyalkoxy designates CH3OCH2O; C3 alkoxyalkoxy designates, for example, CH3OCH2CH2O; and C4 alkoxyalkoxy designates the various isomers of an alkoxy group substituted with a second alkoxy group containing a total of 4 carbon atoms, examples
including CH3CH2CH2OCH2O, and CH3CH2OCH2CH2O. Examples of "alkoxyalkyl" include CH3OCH2, CH3OCH2CH2 and
CH3CH2OCH2. C2 alkylcarbonyl designates C(=O)CH3 and C4 alkylcarbonyl designates C (=O) CH2CH2CH3 and
C(=O)CH(CH3)2. Examples of "alkoxycarbonyl" include CO2CH3, CO2CH2CH3, CO2CH2CH2CH3, CO2CH(CH3)2 and the different butoxycarbonyl isomers.
The salts of the compounds of the invention
includes acid addition salts with inorganic or organic acids such as hydrochloric, nitric, sulfuric, acetic, oxalic, or 4-toluenesulphonic acids. The salts of the compounds of the invention also include those formed with organic or inorganic bases when the compound contains an acidic group such as a carboxylic acid, phenol, or mercapto group.
The metal complexes of the compounds of the invention include complexes with metal salts such as copper, zinc, manganese, and iron salts. These complexes can be prepared prior to formulating the compound or can be prepared by adding the appropriate metal salt to the formulation.
Preferred compounds of Formula I for reasons of greatest fungicidal activity and/or ease of synthesis are:
1.. Compounds of Formula I wherein:
X is N or CR4;
Y is N or CR5;
Z is N or CR6;
Q is a fused benzene, naphthalene, thiophene, furan, pyrrole, pyridine or pyrimidine ring each optionally substituted with R7 and R8;
A is a bridge selected from the group
consisting of:
-CR10R11-; -G-; -(CR10R11-CR10R11)-;
-(G-CR10R11)-; - (CH=CH)-; - [O-C(=O)]-;
- [NR9-C(=O)]-; - (CR10R11-CR10R11-CR10R11)-;
- (G-CR10R11-CR10R11)-; - (CR10R11-G-CR10R11)-;
- (CR10R11-CH=CH)-; -(O-CR10R11-O)-;
- [O-C(=O)-CR10R11]-; - [CR10R11-O-C(=O)]-;
- [NR9-C (=O) -CR10R1 1] -;
- [CR10R11-NR9-C (=O) ] -; - [C (=O) -CH=CH] -;
- [O-C (=O) -O] -; - [NR9-C (=O) -NR9] -;
- (CR10R11-CR10R11-CR10R11-CR10R11) -;
- (G-CR10R11-CR10R11-CR10R11) -;
- (CR10R11-G-CR10R11-CR10R11) -;
- (CR10R11-CR10R11-CH=CH) -; - (CR10R11-CH=CH-CR10R11)-; - (CH=CH-CH=CH)-;
- (O-CR10R11-O-CR10R11)-;
- (O-CR10R11-CR10R11-O)-;
- [O-C(=O)-CR10R11-CR10R11]-;
-[CR10R11-O-C(=O)-CR10R11]-;
- [CR10R11-CR10R11-O-C(=O)]-;
- [NR9-C(=O)-CR10R11-CR10R11]-;
- [CR10R11-NR9-C(=O)-CR10R11]-; and
- [CR10R11-CR10R11-NR9-C(=O)]-;
such that A taken together with the
attached atoms forms a 5-8 membered ring; and the directionality of A may be that the left side of A is bonded to the Q ring and the right side is bonded to the pyridyl (when Z=CR6) or pyrimidinyl (when Z=N) ring, or that the left side of A is bonded to the pyridyl or pyrimidinyl ring and the right side is bonded to Q;
G is O; S(O)p; NR9; or C(=O);
R1, R2, R3 and R4 are independently H; halogen; cyano; hydroxy; C1-C6 alkyl; C1-C4
haloalkyl; C1-C4 alkylthio; C1-C4
alkylsulfinyl; C1-C4 alkylsulfonyl; C3-C6 cycloalkyl optionally substituted with 1-2 methyl groups; C1-C4 alkoxy; C1-C4
haloalkoxy; C2-C4 alkoxyalkyl; C2-C4
alkenyl; C2-C4 haloalkenyl; C2-C4
alkenyloxy; C2-C4 alkynyl; C2-C4
alkynyloxy; NR12R13; phenyl or phenoxy optionally substituted with R14; or R1 and
R4, R2 and R4 or R2 and R5 can be taken together to form -(CH2)3-, -(CH2)4- or a fused phenyl ring;
R5 and R6 are independently H, halogen, C1-C2 alkyl or C1-C2 alkoxy; R7 is halogen; cyano; nitro; hydroxy; hydroxy- carbonyl; C1-C6 alkyl; C1-C4 haloalkyl;
C1-C4 alkylthio; C1-C4 alkylsulfinyl; C1-C4 alkylsulfonyl; (C1-C4 alkyl) 3silyl; C3-C6 cycloalkyl; C2-C5 alkylcarbonyl; C2-C4 alkenyl; C2-C4 alkenyloxy; C2-C4 alkynyl; C2-C4 alkynyloxy; C1-C4 alkoxy; C1-C4 haloalkoxy; C2-C4 alkoxyalkyl; C2-C5 alkoxycarbonyl; C2-C4 alkoxyalkoxy; NR15R16; C(=O)NR17R18; or phenyl, phenoxy or phenyl- thio each optionally substitued with R19; R8 and R14 are independently 1-2 halogen; 1-2 C1-C3 alkyl, C1-C2 haloalkyl, C1-C2 alkoxy or C1-C2 haloalkoxy;
R9, R10 and R11 are independently H or C1-C2
alkyl;
R12, R13, R15, R16, R17, and R18 are
independently H or C1-C2 alkyl; or R12 and R13, R15 and R16 or R17 and R18 can be taken together with the nitrogen to which they are attached to form a piperidino,
pyrrolidino or morpholino ring;
R19 is halogen, C1-C2 alkyl, C1-C2 haloalkyl, C1-C2 alkoxy or C1-C2 haloalkoxy;
p is 0, 1 or 2;
or their agriculturally suitable salts or metal complexes thereof.
2. Compounds of Preferred 1 wherein:
X is CR4;
Y is N or CH;
Z is N or CH; and
A is a bridge selected from the group
consisting of :
- (CR10R11-CR10R11) -; - (G-CR10R11) -;
- (CH=CH) -; - [O-C (=O) ] -; - [NR9-C (=O) ] -; - (CR10R11-CR10R11-CR10R11) -;
- (G-CR10R11-CR1 0R11 ) -; - (CR 10R11-G-CR10R11) -;
- (CR10R1 1-CH=CH) -; - (O-CR10R11-O) -;
-[O-C(=O)-CR10R11]-; -[CR10R11-O-C(=O)]-; -[NR9-C(=O)-CR10R11]-;
-[CR10R11-NR9-C(=O)]-; -[C(=O)-CH=CH]-;
-[O-C(=O)-O]-; and -[NR9-C(=O)-NR9]-.
3. Compounds of Preferred 2 wherein :
Q is a fused benzene, thiophene, furan or
pyridine ring each optionally substituted with R7 and R8;
A is selected from the group consisting of
-(CH2-CH2)-; -[CH2-C(=O)]-; -(CH-CH) -;
-[C(=O)-O]-; -[C(=O)-NR9]-; -(CH2-CH2-CH2)-; -(O-CH2-O)-; -(CH2-CH2-O)-;
-[CH2-CH2-S(O)p]-; -(CH2-CH2-NR9)-;
-(CH2-O-CH2)-; -[CH2-S(O)p-CH2]-;
-(CH2-NR9-CH2)-; -[O-C(=O)-O]-;
R1, R2, R3 and R4 are independently H, halogen, C1-C4 alkyl, C1-C4 haloalkyl, cyclopropyl,
C1-C4 alkoxy or C2-C3 alkynyl; and
R7 is halogen, cyano, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy or C2-C4 alkoxyalkoxy.
4. Compounds of Preferred 3 wherein:
Q is a fused benzene ring optionally
substituted with R7 and R8; and A is selected from the group consisting of
-(CH2-CH2)-; -(CH-CH)-; -[C(=O)-O]-;
-[C(=O)-NR9]-; -(CH2-CH2-CH2)-; -(O-CH2-O)-;
-(CH2-CH2-O)-; -[CH2-CH2-S(O)p]-;
-(CH2-CH2-NR9)-; -(CH2-O-CH2)-;
-[CH2-S(O)p-CH2]- and -(CH2-NR9-CH2)-.
Specifically Preferred for greatest fungicidal activity and/or ease of synthesis is 6,7-dihydro-2-(4- methyl-2-pyrimidinyl)-5-H-benzo[6,7]cycloheptal[1,2- b]pyridine.
Preferred methods for reasons of greatest
fungicidal activity and/or ease of synthesis are:
1. A method of controlling fungus disease in plants that comprises treating the locus to be
protected with an effective amount of a compound of Formula IA wherein:
X is N or CR4;
Y is N or CR5;
Z is N or CR6;
Q is a fused benzene, naphthalene, thiophene, furan, pyrrole, pyridine or pyrimidine ring each optionally substituted with R7 and R8;
A is a bridge selected from the group consisting of: -CR10R11-; -G-;
-(CR10R11-CR10R11)-; -(G-CR10R11)-;
-(CH-CH)-; -[O-C(-O)]-; -[NR9-C(=O)]-; -(CR10R11-CR10R11-CR10R11)-;
-(G-CR10R11-CR10R11)-;
-(CR10R11-G-CR10R11)-; -(CR10R11-CH=CH)-;
-(O-CR10R11-O)-; -[O-C(=O)-CR10R11]-;
-[CR10R11-O-C(=O)]-;
-[NR9-C(=O)-CR10R11]-;
-[CR10R11-NR9-C(=O)]-; -[C(=O)-CH-CH]-; -[O-C(=O)-O]-; - [NR9-C(=O)-NR9]-;
-(CR10R11-CR10R11-CR10R11-CR10R11)-;
-(G-CR10R11-CR10R11-CR10R11)-;
-(CR10R11-G-CR10R11-CR10R11)-;
-(CR10R11-CR10R11-CH=CH)-;
-(CR10R11-CH=CH-CR10R11)-;
-(CH-CH-CH-CH)-; -(O-CR10R11-O-CR10R11)-;
-(O-CR10R11-CR10R11-O)-;
-[O-C(=O)-CR10R11-CR10R11]-; - [CR10R1 1-O-C (=O) -CR10R1 1] -;
- [CR10R11-CR10R11-O-C (=O) ] -;
- [NR9-C (=O) -CR10R11-CR10R11] -;
- [CR10R1 1-NR9-C (=O) -CR10R1 1] -; and
- [CR10R11-CR10R11-NR9-C (-=O) ] -; such that
A taken together with the attached atoms forms a 5-8 membered ring; and the directionality of A may be that the left side of A is bonded to the Q ring and the right side is bonded to the pyridyl
(when Z-CR6) or pyrimidinyl (when Z=N) ring, or that the left side of A is bonded to the pyridyl or pyrimidinyl ring and the right side is bonded to Q; G is O; S(O)p; NR9; or C (=O);
R1, R2, R3 and R4 are independently H;
halogen; cyano; hydroxy; C1-C6 alkyl; C1-C4 haloalkyl; C1-C4 alkylthio; C1-C4 alkylsulfinyl; C1-C4 alkylsulfonyl; C3-C6 cycloalkyl optionally substituted with
1-2 methyl groups; C1-C4 alkoxy; C1-C4 haloalkoxy; C2-C4 alkoxyalkyl; C2-C4 alkenyl; C2-C4 haloalkenyl; C2-C4
alkenyloxy; C2-C4 alkynyl; C2-C4
alkynyloxy; NR12R13; phenyl or phenoxy optionally substituted with R14; or R1 and R4, R2 and R4 or R2 and R5 can be taken together to form -(CH2)3-, -(CH2)4- or a fused phenyl ring;
R5 and R6 are independently H, halogen, C1-C2 alkyl or C1-C2 alkoxy;
R7 is halogen; cyano; nitro; hydroxy;
hydroxycarbonyl; C1-C6 alkyl; C1-C4 haloalkyl; C1-C4 alkylthio; C1-C4
alkylsulfinyl; C1-C4 alkylsulfonyl; (C1-C4 alkyl) 3silyl; C3-C6 cycloalkyl; C2-C5 alkylcarbonyl; C2-C4 alkenyl; C2-C4 alkenyloxy; C2-C4 alkynyl; C2-C4
alkynyloxy; C1-C4 alkoxy; C1-C4
haloalkoxy; C2-C4 alkoxyalkyl; C2-C5 alkoxycarbonyl; C2-C4 alkoxyalkoxy;
NR15R16; C(=O)NR17R18; or phenyl, phenoxy or phenylthio each optionally
substituted with R19;
R8 and R14 are independently 1-2 halogen, 1-2 C1-C3 alkyl, C1-C2 haloalkyl, C1-C2 alkoxy or C1-C2 haloalkoxy;
R9, R10 and R11 are independently H or C1-C2 alkyl;
R12, R13, R15, R16, R17, and R18 are independently H or C1-C2 alkyl; or R12 and R13, R15 and R16 or R17 and R18 can be taken together with the nitrogen to which they are attached to form a piperidino, pyrrolidino or morpholino ring;
R19 is halogen, C1-C2 alkyl, C1-C2 haloalkyl,
C1-C2 alkoxy or C1-C2 haloalkoxy;
p is 0, 1 or 2;
or their agriculturally suitable salts or metal
complexes thereof.
2. A method according to Preferred 1 wherein:
X is CR4;
Y is N or CH;
Z is N or CH; and
A is a bridge selected from the group consisting of: -(CR10R11-CR10R11)-;
-(G-CR10R11)-; - (CH-CH)-; -[O-C(=O)]-; -[NR9-C(=O)]-;
-(CR10R11-CR10R11-CR10R11)-; -(G-CR10R11-CR10R11)-;
-(CR10R11-G-CR10R11)-; -(CR10R11-CH=CH)-; -(O-CR10R11-O)-; -[O-C(=O)-CR10R11]-;
-[CR10R11-O-C(=O)]-;
-[NR9-C(=O)-CR10R11]-;
-[CR10R11-NR9-C(=O)]-; -[C(=O)-CH=CH]-; -[O-C(=O)-O]-; and -[NR9-C(=O)-NR9]-.
3. A method according to Preferred 2 wherein:
Q is a fused benzene, thiophene, furan or pyridine ring each optionally substituted with R7 and R8;
A is selected from the group consisting of:
-(CH2-CH2)-; -[CH2-C(=O)]-; -(CH-CH)-;
-[C(=O)-O]-; -[C(=O)-NR9]-;
-(CH2-CH2-CH2)-; -(O-CH2-O)-;
-(CH2-CH2-O)-; -[CH2-CH2-S(O)p]-;
-(CH2-CH2-NR9)-; -(CH2-O-CH2)-;
-[CH2-S(O)p-CH2]-; -(CH2-NR9-CH2)-;
-[O-C(=O)-O]-;
R1, R2, R3 and R4 are independently H,
halogen, C1-C4 alkyl, C1-C4 haloalkyl, cyclopropyl, C1-C4 alkoxy or C2-C3 alkynyl; and
R7 is halogen, cyano, C1-C4 alkyl, C1-C4
haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy or C2-C4 alkoxyalkoxy.
4. A method according to Preferred 3 wherein:
Q is a fused benzene ring optionally
substituted with R7 and R8; and A is selected from the group consisting of
-(CH2-CH2)-; -(CH-CH)-; -[C(-O)-O]-;
-[C(=O)-NR9]-; -(CH2-CH2-CH2)-;
-(O-CH2-O)-; -(CH2-CH2-O)-;
-[CH2-CH2-S(O)p]-; -(CH2-CH2-NR9)-; -(CH2-O-CH2)-; -[CH2-S(O)p-CH2]- and -(CH2-NR9-CH2)-.
Specifically Preferred for greatest fungicidal activity and/or ease of synthesis is a method according to Preferred 4 wherein the compound is 6,7-dihydro-2- (4-methyl-2-pyrimidinyl)-5-H-benzo[6,7]cyclohepta[1,2- b]pyridine.
DETAILS OF THE INVENTION
One or more of the following methods, or
variations obvious to one skilled in the art, can be used to prepare the compounds of the invention. The substituents in the following methods are as previously defined unless noted otherwise. One skilled in the art will recognize that these methods may require the use of protecting groups or subsequent functional group interconversions to avoid undesired side reactions with substituents which may be sensitive to the reaction conditions. One skilled in the art will also recognize that compounds of Formula I and the intermediates described below can be subjected to various
electrophilic, nucleophilic, radical, organometallic, oxidation, and reduction reactions to add substituents or modify existing substituents.
Compounds of Formula I, when Y is N and X is CR4, can be prepared by the reaction of amidines of Formula II with Formula III compounds in the presence of a suitable base as illustrated in Scheme 1. Typical reactions involve the combination of an amidine II or its conjugate acid salt (such as a hydrochloride) with 1 to 1.5 equivalents of a Formula III compound in an inert solvent in the presence of a catalytic amount to 2.5 equivalents of base. Typical bases include alkali metal alkoxides (such as sodium methoxide and sodium ethoxide) and organic amine bases (such as
triethylamine and diethylaniline). Typical solvents include alcohols (such as methanol and ethanol), cyclic ethers (such as tetrahydrofuran and dioxane), pyridine, and dimethylformamide. The reaction temperature typically ranges from 50°C to the reflux temperature of the particular solvent being used and the reaction is usually complete in 1 to 6 h. This method is not applicable when R1 or R2 are substituents which are attached through a heteroatom such as alkoxy and halogen. Compounds of Formula III are known in the art or can be prepared by related methods.
Scheme 1
wherein R20 is C1-C4 alkyl;
Alternatively, compounds of Formula I, when Y is N and X is CR4, can be prepared by the reaction of
amidines of Formula II with Formula IV compounds in the presence of an optional base as illustrated in Scheme 2. Typical reactions involve the combination of an amidine II or its conjugate acid salt (such as a hydrochloride) with 1 to 1.5 equivalents of a Formula IV compound in an inert solvent in the presence of 0 to 2.5 equivalents of base. Typical bases include alkali metal alkoxides (such as methoxide and sodium ethoxide) and organic amine bases (such as triethylamine and diethylaniline). Typical solvents include alcohols (such as methanol and ethanol), cyclic ethers (such as tetrahydrofuran), pyridine, and dimethylformamide. The reaction temperature typically ranges from 50°C to the reflux temperature of the particular solvent being used and the reaction is usually complete in 24 h. This method is not applicable when R1 and R2 are
substituents which are attached through a heteroatom such as alkoxy and halogen. Compounds of Formula IV are known in the art or can be prepared by related methods (Hauser et al., Organic Reactions, 1954, 8, 59-196).
Scheme 2
Alternatively, compounds of Formula I, when Y is N and X is CR4, can be prepared by the reaction of
amidines of Formula II with Formula V compounds where L1 is hydrogen or a suitable leaving group such as halogen, alkoxy, alkylthio, dialkylamino, (halo) alkyl- sulfonyloxy, or arylsulfonyloxy in the presence of an optional base as illustrated in Scheme 3. Typical reactions involve the combination of an amidine of
Formula II or its conjugate acid salt (such as a
hydrochloride) with 1 to 2.5 equivalents of a Formula V compound in an inert solvent in the presence of 0 to 2.5 equivalents of base. When L1 is hydrogen, at least 2 equivalents of the Formula V compound are used since this reagent also serves as an oxidant for the
dihydropyrimidine intermediate. Typical bases include alkali metal alkoxides (such as sodium methoxide and sodium ethoxide) and organic amine bases (such as triethylamine and diethylaniline). Typical solvents include alcohols (such as methanol and ethanol), cyclic ethers (such as tetrahydrofuran and dioxane), pyridine, and dimethyIformamide. The reaction temperature typically ranges from 50°C to the reflux temperature of the particular solvent being used and the reaction is usually complete in 24 h. This method is not
applicable when R1 is a substituent which is attached through a heteroatom such as alkoxy and halogen. This method also is not applicable when R2 is a better leaving group than L1 since the latter would be retained in the product. Compounds of Formula V are well known in the art or can be prepared by related methods (Abdulla et al., Tetrahedron, 1979, 35,
1675-1735; Tominaga et al., Heteroeycles, 1989, 29, 1409-1429; and "The Chemistry of Enones", Patai and Rappoport, Eds., Wiley, 1989).
Scheme 3
Alternatively, compounds of Formula I, when Y is N, X is CR4, and R2 is H, can be prepared by the
reaction of amidines of Formula II with Formula VI compounds as illustrated in Scheme 4. Typical
reactions involve the combination of an amidine of Formula II or its conjugate acid salt (such as a hydrochloride) with 1 to 3 equivalents of a Formula VI compound in the absence of solvent and heating at 50 to 150°C for 1 to 6 h. This method is not applicable when R1 is a substituent which is attached through a
heteroatom such as alkoxy and halogen.
Scheme 4
wherein R20 is C1-C4 alkyl.
Compounds of Formula I, where R1 or R2 is
hydrogen, can be prepared by reductive removal of a halogen, alkylthio, alkylsulfinyl, or alkylsulfonyl group as outlined in Scheme 5. For reductive removal of halogen, the reaction is conducted using a catalyst such as palladium on carbon under hydrogen gas in an inert solvent such as water, an alcohol (such as methanol or ethanol), ethyl acetate, or toluene at 25° to 50°C. The dehalogenation can be conducted in the presence of an equivalent of a base (such as ammonia, sodium hydroxide, sodium carbonate, or sodium acetate) to neutralize the liberated hydrogen halide.
For reductive removal of alkylthio, alkylsulfinyl, or alkylsulfonyl, the reaction is typically conducted as above using Raney nickel as the catalyst in the absence of base and optionally under hydrogen gas.
Scheme 5
I (R1=halogen, alkylthio, 2
alkylsulfinyl or
alkylsulfonyl)
I (R2=halogen, alkylthio, 2
alkylsulfinyl or
alkylsulfonyl) 2=
Compounds of Formula I, when R1 or R2 are alkyl or haloalkyl, can be prepared by the reaction of compounds of Formula I, where R1 or R2 are leaving groups such as halogen, alkylsulfinyl, or alkylsulfonyl, with dialkyl malonates of Formula VII in the presence of base followed by hydrolysis and decarboxylation as outlined in Scheme 6. The first reaction is carried out by combining a compound of Formula I, where R1 or R2 are leaving groups, with 1 to 2 equivalents of a Formula VII compound in the presence of 1 to 4 equivalents of a suitable base in an inert solvent. Typical bases include alkali metal hydrides (such as sodium hydride and potassium hydride), alkyllithiums (such as
butyllithium), alkali metal amides (such as lithium diisopropylamide), and alkali metal hydroxides (such as sodium hydroxide). Typical solvents include nitriles (such as acetonitrile), ethers (such as diethyl ether and tetrahydrofuran), halohydrocarbons (such as
chloroform), aromatic hydrocarbons (such as benzene and toluene), ketones (such as acetone), and dimethyl sulfoxide. The reaction temperature typically ranges from 0°C to the reflux temperature of the particular solvent being used and the reaction is usually complete in 0.5 to 24 h. The hydrolysis reaction is typically carried out in water with an optional organic cosolvent (such as methanol, ethanol, tetrahydrofuran, or
dioxane) in the presence of 2 to 4 equivalents of a base, typically an alkali metal hydroxide (such as sodium hydroxide) or an alkali metal carbonate (such as sodium carbonate). The reaction temperature typically ranges from 0°C to the reflux temperature of the solvent mixture being used and the hydrolysis is usually complete after 0.2 to 24 h. The hydrolysis product (malonic acid intermediate) need not be
isolated, so the decarboxylation is typically performed by adding 2.5 to 6 equivalents of acid (such as
sulfuric acid, hydrochloric acid, or acetic acids) directly to the hydrolysis reaction mixture. The acidified mixture then is heated between ambient
temperature and the reflux temperature of the mixture for 0.2 to 24 h to effect the decarboxylation to give a compound of Formula I where R1 or R2 are alkyl or haloalkyl. Compounds of Formula VII are well known in the art or can be prepared by related methods. Scheme 6
I (R1=halogen, alkylsulfinyl
or alkylsulfonyl)
I (R2=halogen, alkylsulfinyl
or alkylsulfonyl)
wherein
R20 is C1-C4 alkyl; and
R21 is C1-C5 alkyl or C1-C3 haloalkyl.
Compounds of Formula I, when R1 or R2 are cyano, hydroxy, alkylthio, alkoxy, haloalkoxy, alkenyloxy, alkynyloxy, (di) alkylamino, or substituted phenoxy, can be prepared by the reaction of compounds of Formula I, where R1 or R2 are leaving groups such as halogen, alkylsulfinyl, or alkylsulfonyl, with a nucleophile L2- M1 in the presence of an optional base as outlined in Scheme 7. Typical reactions involve the combination of a compound of Formula I, where R1 or R2 are a leaving group, with 1 to 2 equivalents of a L2-M1 compound in an inert solvent. When M1 is hydrogen, 1 to 2.2 equivalents of base are added to the reaction. Typical bases include alkali metal hydrides (such as sodium hydride), alkali metals (such as sodium), and alkyllithiums (such as butyllithium). Typical solvents include alcohols (such as methanol and ethanol), ethers (such as diethyl ether, tetrahydrofuran, and dioxane), nitriles (such as acetonitrile), dimethylformamide, and dimethyl sulfoxide. Potentially nucleophilic solvents, such as alcohols, should be used only when they will not compete with the nucleophile L2-M1. The reaction temperature typically ranges from 0°C to the reflux temperature of the particular solvent used, and the reaction is usually complete within 2 days. L2-M1 represent common reagents such as sodium alkoxides, alcohols, phenols, sodium cyanide, sodium hydroxide, (di) alkylamines, and the like. Catalysts (such as copper, copper(I) chloride, copper (II) chloride, and copper (II) oxide) may be added to facilitate the reaction.
Scheme 7
I (R1 =halogen, aikylsulflnyl; L
or alkylsulfonyl)
I (R2=halogen, alkylsulfinyl,
or alkylsulfonyl)
wherein
L2 is cyano, hydroxy, C1-C4 alkylthio, C1-C4 alkoxy, C1-C4 haloalkoxy, C2-C4 alkenyloxy, C2-C4 alkynyloxy, NR12R13, or phenoxy substituted with R14; and
M1 is H or alkali metal.
Compounds of Formula I, when R1 or R2 are
alkylsulfinyl or alkylsulfonyl, can be prepared by the oxidation of compounds of Formula I, where R1 or R2 are alkylthio, as outlined in Scheme 8. Typical reactions involve the combination of a compound of Formula I (R1 or R2 is alkylthio) with a suitable oxidant in an inert solvent. When R1 or R2 are alkylsulfinyl in the desired product I, 1 to 1.1 equivalents of oxidant are used, and when R1 or R2 are alkylsulfonyl in the product I, 2 to 2.2 equivalents of oxidant are used. Typical oxidants are 3-chloroperoxybenzoic acid, magnesium monoperoxyphthalate, peracetic acid, hydrogen peroxide, and the like. Typical solvents include halohydrocarbons (such as dichloromethane, 1,2- dichloroethane, and chloroform) and aromatic
hydrocarbons (such as toluene). The reaction
temperature typically ranges from 0°C to the reflux temperature of the particular solvent being used and the reaction is usually complete within 24 h.
Scheme 8
I (R1=SR20
I (R2=SR20)
wherein R20 is C1-C4 alkyl .
Compounds of Formula I, when R1 or R2 are halogen, can be prepared by the reaction of compounds of Formula I, where R1 or R2 are hydroxy, with a halogenating agent such as phosphorus trichloride, phosphorus pentachloride, phosphorus tribromide, phosphorus pentabromide, phosphorus oxychloride, phosphorus oxybromide, thionyl chloride, phosgene, and the like as illustrated in Scheme 9. Typical reactions involve the combination of compounds of Formula I, when R1 or R2 is hydroxy, with an excess of the halogenating agent ranging from 1.1 to 10 equivalents, with 2 to 4
equivalents being preferred. The reaction can be conducted in the absence of solvent or in the presence of a suitable inert solvent including aromatic hydrocarbons (such as benzene and toluene),
halohydrocarbons (such as dichloromethane and
chloroform), and hydrocarbons (such as hexane). The reaction temperature can range from -10°C to 200°C with 25°C to 100°C being preferred. The reaction is
generally complete after 1 to 24 h.
Scheme 9
I (R1=OH) halogenating agent I (R1=halogen) I (R2=OH) halogenating agent I (R2=halogen)
Compounds of Formula I, when Y is N, X is CR4, and R1 is hydroxy, can be prepared by the reaction of amidines of Formula II with β-ketoesters of Formula VIII in the presence of base as illustrated in Scheme 10. Typical reactions involve the combination of an amidine II or its conjugate acid salt (such as a hydrochloride) with 1 to 1.5 equivalents of a Formula VIII compound in the presence of a catalytic amount to 1.5 equivalents of base in an inert solvent. Typical bases include alkali metal hydroxides (such as sodium hydroxide), alkali metal carbonates (such as potassium carbonate), amines (such as triethylamine and
diethylaniline), and alkali metal alkoxides (such as sodium methoxide and sodium ethoxide). Typical
solvents include alcohols (such as methanol and
ethanol), cyclic ethers (such as tetrahydrofuran and dioxane), pyridine, dimethylformamide, and water. The reaction temperature typically ranges from ambient temperature to the reflux temperature of the particular solvent being used and the reaction is usually complete in 1 to 24 h. An example of this method is taught by Lafferty et al. (J. Org. Chem. 1967, 32, 1591-1596). When R2 is attached through a heteroatom (such as alkoxy), then the product usually loses R2 giving product I wherein R2 is hydroxy; an example of this reaction using a dialkylmalonate VIII (R2 is alkoxy) giving a dihydroxypyrimidine also may be found in the above reference by Lafferty et al. Also illustrated in Scheme 10 is the preparation of a compound of Formula I, when Y is N, X is CR4, and R1 is hydroxy, by the reaction of an ester of Formula IX with a Formula X compound as taught by Brown et al. (Aust. J. Chem.
1982, 35, 1203-1207).
Alternatively, the method of Kato et al. (Chem. Pharm. Bull. 1976, 24, 356-359) can be used on an imidate of Formula XII (see Scheme 11 for structure) to prepare these same compounds.
Scheme 10
wherein R20 is C1-C4 alkyl. Intermediates of Formulae XII, II, and IX can be prepared from compounds of Formula XI as outlined in Scheme 11. Imidates of Formula XII can be prepared by the combination of a carbonitrile of Formula XI with 0.1 to 1 equivalent of an alkali metal alkoxide
(preferably sodium methoxide or sodium ethoxide) in an alcoholic solvent (preferably methanol or ethanol). The reaction temperature can range from 0°C to 50°C (preferably ambient temperature) and the reaction is usually complete after 1 to 48 h. The reaction is typically worked up by neutralizing with an acid (such as acetic acid), concentrating the reaction mixture, dissolving in an appropriate solvent (such as ether), filtering off the salt by-product (e.g., sodium
acetate), and concentrating the filtrate to give the imidate XII which is usually used without purification.
The intermediate amidines of Formula II can be prepared by the reaction of an imidate of Formula XII with 1.0 to 1.1 equivalents of an ammonium salt (such as ammonium chloride, ammonium bromide, ammonium acetate, and ammonium formate) in an alcohol
(preferably methanol or ethanol) or an alcohol-water mixture.
The reaction temperature can range from ambient temperature to the reflux temperature of the particular solvent being used and the reaction is usually complete after 30 min to 5 h. The reaction mixture is
concentrated to give the amidine salt (HL3) which is purified by recrystallization or trituration. The amidine salts can be used in the previously described reactions or can be first converted to their conjugate bases.
Alternatively, amidines of Formula II can be prepared directly from carbonitriles XI by the reagent MeAl (Cl)NH2 as described by Garigipati (Tetrahedron Lett., 1990, 31, 1969-1972).
The esters of Formula IX can be prepared from imidates of Formula XII by aqueous hydrolysis with an optional organic cosolvent. Typical reactions involve the combination of an imidate XII with an excess of acid (such as sulfuric acid or hydrochloric acid) in an optional organic cosolvent (such as methanol, ethanol, tetrahydrofuran, and dioxane). The reaction
temperature can range from 0°C to the reflux
temperature of the particular solvent being used
(preferably 0°C to ambient temperature) and the
reaction is usually complete within 6 h.
Scheme 11
wherein
R20 is C1-C4 alkyl,
M2 is an alkali metal, and
L3 is a counterion such as Cl, Br, OAc, or OCHO. Intermediates of Formula XI can be prepared from
N-oxides of Formula XIV by the method of Fife (J. Org . Chem . , 1983, 48, 1375-1377; review: Hetero cycles 1984, 22, 2375-2394) as illustrated in Scheme 12. There are several other modifications of the Reissert-Henze reaction which are useful on pyridine and pyrimidine N- oxides as discussed by Sakamoto et al. (Chem. Pharm. Bull. 1985, 33, 565-571) and Yamanaka et al.
(Heterocycles 1990, 31, 923-967), so no further
detailed discussion of these methods will be presented.
The N-oxide intermediates of Formula XIV can be prepared by oxidation of compounds of Formula XIII with 1 to 1.2 equivalents of a suitable oxidizing reagent such as 3-chloroperoxybenzoic acid, magnesium
monoperoxyphthalate, peracetic acid, hydrogen peroxide, and the like. Typical solvents include
halohydrocarbons (such as dichloromethane, 1,2- dichloroethane, and chloroform) and aromatic
hydrocarbons (such as benzene and toluene). The reaction temperature can range from 0°C to the reflux temperature of the particular solvent being used and the reaction is usually complete in 24 h. When Z is N, a mixture of N-oxides may be formed; both of these regioisomeric N-oxides can be used for the subsequent Fife cyanation to intermediates XI.
Scheme 12
Numerous compounds of Formula XIII are known in the art or can be prepared by related methods.
Alternatively, these compounds of Formula XIII, when Z is CR6, can be prepared using -one of several pyridine annulation procedures known in the art. Two such procedures are outlined in Scheme 13.
The method of Chelucci et al. (J. Heterocyclic Chem. 1988, 25, 1761-1765) involves the alkylation of a N, N-dimethylhydrazone anion with 2-(2-bromoethyl)-1,3- dioxolane to give intermediate XVI which cyclizes in refluxing acetic acid to the annulated pyridine XIII (Z is CH; R3 is H). An effective, safer modification of Chelucci's method substitutes 1,3-dimethyl-3,4,5,6- tetrahydro-2(1H)-pyrimidinone (DMPU) for the toxic, cancer suspect agent hexamethylphosphoramide (HMPA) as cosolvent in the alkylation reaction.
The method of Kusumi et al. (Synthesis 1979, 221- 223), and Koyama et al. (Chem. Pharm. Bull. 1983, 11, 2601-2606) proceeds through O-allyloximes XVII which, upon pyrolysis at 180°C to 200°C, cyclize to the annulated pyridine XIII (Z is CH; R3 is H).
Alternative pyridoannulation methods are discussed in publications by Bell et al. (J. Am. Chem. Soc. 1991, 113, 6283-6284), Thummel (Tetrahedron 1991, 34, 6851- 6886), Westerwelle et al. (Chem. Ber. 1991, 124, 571- 576), Potts et al. (J. Org. Chem. 1982, 3027-3038), Ciufolini et al. (J. Am. Chem. Soc. 1991, 113, 8016- 8024 and J. Chem. Soc., Chem. Commun. 1988, 1230-1231), and Kröhnke (Synth, 1976, 1-24).
The starting ketones of Formula XV are known in the art or can be obtained by methods analogous to known procedures. Formula XV compounds includes indanones, tetralones, benzosuberones, chromanones and homologs, thiochromanones and homologs, isochromanones, benzofuran-3-ones, and others. Scheme 13
Intermediates of Formula XIII, when Z is N, can be prepared from ketones of Formula XV as outlined in Scheme 14. Formula XV compounds can be converted to acylated derivatives XVIII using methods well known in the art (Hauser et al., Organic Reactions 1954, 8, 59- 196). These, in turn, can be converted to the
pyrimidines XIII by reaction with formamide as taught by Bredereck et al. (Chem. Ber. 1957, 90, 942-952), formamidine, or thiourea followed by Raney nickel desulfurization as taught by Foster et al. (Org. Syn. Coll. Vol. 1963, 1, 638-640).
Alternatively, ketones of Formula XV can be converted to compounds of Formula XIX, where L4 is a leaving group, by methods known in the art.
Intermediates of Formula XIX can be converted into the intermediate pyrimidines XIII (Z=N) by reaction with thiourea followed by Raney nickel desulfurization or with formamidine .
Scheme 14
wherein
R20 is C1-C4 alkyl; and
L4 is a leaving group such as halogen, alkoxy, alkylthio, (di) alkylamino, (halo) alkylsulf onyloxy, and arylsulf onyloxy.
Compounds of Formula I, when X and Y are nitrogen, can be prepared as outlined in Scheme 15. Amidines of Formula II can be converted to compounds of Formula I (X=Y=N; R1=R2) by reaction with imidates of Formula XX as taught by Schaeffer (J. Org. Chem. 1962, 27, 3608- 3613). This method is not applicable when R1 is a substituent which is attached through a heteroatom such as halogen and alkoxy.
Also shown in Scheme 15 is the preparation of compounds of Formula I, when X and Y are nitrogen and R2 is chlorine, by the reaction of amidines of Formula II with compounds of Formula XXI as taught by Schmelzer et al. (Angew. Cham. Int. Ed. Engl. 1966, 5, 960-961) or by the reaction of N-cyanoamidines of Formula XXII with chloromethyleneiminium salts as taught by Harris
(Aust. J. Chem. 1981, 34, 623-634 and Synth. 1980, 841- 842). N-cyanoamidines of Formula XXII can be prepared by the reaction of imidates of Formula XII with
cyanamide as taught by Huffman et al. (J. Org. Chem. 1963, 28, 1812-1816). Additionally, the method of
Bader (J. Org. Chem. 1965, 30, 707-11) can be used to prepare other compounds of Formula I (X=Y=N).
Scheme 15
wherein R20 is C 1-C4 alkyl.
Compounds of Formula I, when X is N and Y is CR5, can be prepared from esters of Formula IX as outlined in Scheme 16. Claisen-like condensations between esters and ketones (Hauser et al . , Organic Reactions 1954, 8, 59-196) and Claisen condensations between two different esters (Hauser et al . , Organic Reactions
1942, 1, 266-302) to give 1 , 3-dicarbonyl compounds such as intermediates of Formula XXIV are well known in the art. The reaction between intermediates of Formula XXIV and amidines of Formula XXV can be carried out as previously discussed for Scheme 2. Formula XXV
compounds include amidines, thiourea, urea, O- alkylisoureas, and 5-alkylisothioureas. Also, when R2 is a leaving group such as alkoxy in Formula XXIV, then R2 will be hydroxy in the product which can be
converted to several other substituents as described in previous schemes.
Scheme 16
wherein R20 is C1-C4 alkyl. Compounds of Formula I, when X and Y are CR4 and CR5, respectively, can be prepared from intermediate carbonitriles of Formula XI as outlined in Scheme 17. The addition of organometallic reagents to nitriles to give ketones represented by Formula XXVI is well known in the art. Ketones of Formula XXVI can be converted to intermediates of Formula XXVII by methods well known in the art. Michael-type reactions of intermediate XXVII with a ketone followed by cyclization with ammonium acetate (when L1 is a leaving group) or hydroxylamine (when L1 is hydrogen) affords pyridines of Formula I (X=CR4, Y=CR5); examples of these methods are discussed by Jameson et al. (Tetrahedron Lett.
1991, 32, 1999-2002), Potts et al. (J. Am. Chem. Soc. 1981, 103, 3585-3586), and Jones (Comprehensive
Heterocyclic Chemistry Vol. 2, 395-510, Katritzky and Rees, Eds., Pergamon). Similar Michael-type reactions between ketones of Formula XXVI with Formula XXVIII compounds provides, after cyclization, pyridines of Formula I (X=CR4, Y=CR5).
Scheme 17
wherein
M3 is alkali or alkaline earth metal; and L1 is hydrogen or a leaving group such as halogen, alkoxy, alkylthio, (di) alkylamino, (halo) alkylsulfonyloxy, and arylsulfonyloxy.
Alternatively, compounds of Formula I can be prepared by transition-metal catalyzed aryl coupling reactions as illustrated in Scheme 18. Intermediates of Formula XXIX, when L5 is halogen, can be prepared by the reaction of N-oxide intermediates of Formula XIV with a halogenating agent such as phosphorus
pentachloride, phosphorus oxychloride, phosphorus oxybromide, and the like. Typical reaction conditions are analogous to those discussed for Scheme 9. Aryltin intermediates of Formula XXX can be prepared from
Formula XXIX compounds by the displacement of L5 with a trialkylstannylsodium reagent as taught by Wursthorn et al. (J. Am. Chem. Soc. 1978, 100, 2779-2789) or, when Z is CR6, by metal-halogen exchange with an alkyllithium (such as butyllithium) and reaction with a trialkyltin halide (such as tributyltin chloride).
Palladium-catalyzed coupling of intermediate stannanes of Formula XXX with compounds of Formula XXXI, where L5 is halogen, then provides compounds of Formula I.
Typical palladium catalysts include tetrakis (triphenylphosphine) palladium (0) and bis (triphenylphosphine)palladium (II) chloride. Typical solvents include aromatic hydrocarbons (such as benzene and toluene), cyclic ethers (such as tetrahydrofuran and dioxane), and dimethylformamide. Related coupling reactions are known in the art as discussed by Solberg et al. (Acta Chem. Scand. 1989, 43, 62-68), Undheim et al. (Heterocycles 1990, 30, 1155-1193), Gronowitz et al. (Chem. Scripta 1986, 26, 305-309), Fu et al.
(Tetrahedron Lett. 1990, 31, 1665-8), Bailey
(Tetrahedron Lett. 1986, 27, 4407-4410), and Heck (in Palladium Reagents in Organic Syntheses, 179-321, Academic 1985).
Alternatively, compounds of Formula I can be prepared by similar palladium-catalyzed couplings of intermediates of Formula XXIX with arylstannanes of Formula XXXII as illustrated in Scheme 18. Compounds of Formula XXXI are well known in the art or can be prepared by analogous methods and compounds of Formula XXXII can be prepared from these compounds by
displacing L5 with a trialkyltin sodium reagent. One skilled in the art will recognize that there are numerous methods for aryl coupling reactions as
discussed, for example, by Mitchell et al. (Tetrahedron Lett. 1991, 32, 2273-2276), Oae et al. (Acc. Chem. Res. 1991, 24, 202-208 and Adv. Heterocyclic Chem. 1990, 48, 1-63), Tamao et al. (The Chemistry of the Metal-Carbon Bond Vol. 4, 819-887, Hartley, Ed., Wiley), and
Strekowski et al. (J. Heterocyclic Chem. 1990, 27, 1393-1400).
Scheme 18
wherein
L5 is a leaving group such as halogen; and
R20 is C1-C4alkyl.
Compounds of Formula I, when Z is nitrogen, can be prepared by the reaction of compounds of Formulae XVIII or XIX with amidines of Formula XXXIII (Scheme 19). Typical reaction conditions are those discussed for Scheme 2 and Scheme 3, respectively. Amidines of
Formula XXXIII can be prepared from the corresponding nitriles, which are known in the art, using the methods previously discussed in Scheme 11. Scheme 19
wherein
L4 is a leaving group such as halogen, alkoxy, alkylthio, (di) alkylamino, (halo) alkylsulfonyloxy, and arylsulfonyloxy.
Compounds of Formula I, when Z is CR6, can be prepared from intermediates of Formula XIX by a
Michael-type reaction with a Formula XXXIV compound followed by cyclization as illustrated in Scheme 20. Refer to the discussion for Scheme 17 for further details and references for this method. Intermediates of Formula XXXIV are known in the art or can be prepared by analogous methods .
Scheme 20
wherein
L4 is a leaving group such as halogen, alkoxy, alkylthio, (di)alkylamino, (halo)alkylsulfonyloxy, and
arylsulfonyloxy.
Compounds of Formula I and intermediates of
Formula XIII can be prepared using the general
strategies outlined in Schemes 21 and 22. In Scheme 21, an organometallic compound of Formula XXXV is coupled to a heterocyclic halide of Formula XXXVI in the presence of a catalyst (such as a suitable
palladium or nickel catalyst) following procedures well known in the art (refer to references given in the discussion for Scheme 18). Compounds of Formula XXXV are arylboronic acids, arylstannanes, arylzincs, aryl Grignards, and the like, which are well known in the art. Also, compounds of Formula XXXVI are
halopyridines and halopyrimidines which are well known in the art or can be prepared by related methods.
Groups A1 and A2 are chosen so that a bond or bonds can be made between them to construct the particular bridge A. There are numerous synthetic methods for effecting cyclizations to compounds of Formula I and
intermediates of Formula XIII including, but not limited to, lactonizations, lactamizations,
etherifications, Friedel-Crafts reactions, low-valent titanium carbonyl couplings (McMurray reaction), Wittig reactions, acetal formations, and condensations. For example, when A1 is hydroxy and A2 is CH2CO2H,
lactonization using an activating agent (such as 1,3- dicyclohexylcarbodiimide) gives compounds of Formulae XIII and I where A is -OC(O)CH2-. Similarly, when A1 is hydroxy and A2 is CH2Br, etherification by treatment with base gives compounds where A is -OCH2-; when A1 and A2 are CH2C(O)H, the McMurray reaction gives compounds where A is -CH2CH=CHCH2-; and when A1 and A2 are hydroxy, acetal formation with 2,2-dimethoxypropane gives compounds where A is -OC(Me)2O-. A specific example of the strategy in Scheme 21 is reported by Fu et al. (J. Org. Chem. 1991, 56,, 1683-1685) using a palladium-catalyzed coupling between arylboronates and arylhalides followed by an anionic Friedel-Crafts equivalent giving an intermediate of Formula XIII where Q is benzene ring, A is -C(O)-, R3 is H, and Z is CH. The roles of the two aryl intermediates XXXV and XXXVI can be reversed, i.e., coupling of an aryl halide derivative analogous to XXXV with a heteroaromatic metal derivative analogous to XXXVI will give the same intermediates of Formula XXXVII.
Scheme 21
wherein
M4 is a metallic group such as Sn(R20)3, B(OH)2, B(OR20)2,
ZnCl, ZnBr, MgCl, MgBr, and the like,
L5 is a leaving group such as halogen,
L6 is hydrogen or and
A1 and A2 are suitable groups for creating bonds between them to construct bridge A.
Scheme 22 illustrates the strategy where the bridge A is first constructed using methods similar to those discussed for Scheme 21 . Suitable synthetic methods include, but are not limited to,
esterifications, etherifications, amide formations, Wittig reactions, and the like. The intermediate XXXIX can be converted by an intramolecular Ullman or related aryl coupling to compounds of Formula I or
intermediates of Formula XIII. Compounds of Formulae XXXVIII and XXXVI are aryl and heteroaryl halides which are known in the art or can be prepared by analogous procedures. Examples of this strategy can be found in papers by Rebek et al. (J. Am. Chem. Soc. 1985, 107, 7487-7493) and Botteghi et al. (Synth. Commun. 1991, 21, 1819-1823).
Scheme 22
wherein
L5 and L7 are independently leaving groups such as halogen,
L6 is hydrogen or and A1 and A2 are suitable groups for creating bonds between them to construct bridge A.
The metal complexes of the compounds of the invention include complexes with copper, zinc, iron, magnesium or manganese cations. These complexes can be made by combining the compound with the metal salt, either in aprotic solvents such as ether or
tetrahydrofuran or they can be generated in protic solvents such as methanol or mixtures of such solvents. The complex may crystallize and precipitate from solution or the complex is crystallized as the solvent is removed.
Without further elaboration, it is believed that one skilled in the art using the preceding description can utilize the present invention to its fullest extent. The following examples are, therefore, to be construed as merely illustrative, and not limiting of the disclosure in any way whatsoever.
EXAMPLES EXAMPLE 1
6, 7-Dihydrp-2-(4-methyl-2-pyrimidinyl)- 5H-benzo[6,7]-cyclohepta[1,2-b]pyridine step A: 6,7,8,9-Tetrahydro-5H-benzocyclohepten-5-one dimethylhydrazone
To a stirred solution of 1-benzosuberone (25.00 g, 156.0 mmol) in ethanol (39 mL) under a nitrogen
atmosphere is added N, N-dimethylhydrazine (37.51 g, 624.1 mmol) and the resulting mixture is heated under reflux overnight. After cooling to room temperature, the reaction mixture is concentrated under reduced pressure. The residue is dissolved in ethanol and reconcentrated; this is repeated once more with ethanol and twice more with dichloromethane to yield 32.65 g of the crude title hydrazone. Chromatography of this material on silica gel (1000 mL) with 1:25 ethyl acetate-hexahe affords the title compound (28.36 g, 90%) as a yellow oil which is a mixture of syn and anti isomers: Rf 0.05 (silica gel, 1:25 ethyl acetate- hexane); 200.MHz 1H NMR (CDCI3) major isomer δ 1.75 (m, 4H), 2.61 (s, 6H), 2.76 (m, 4H), 7.1 (dd, 1H), 7.2 (m, 2H), 7.5 (dd, 1H) and minor isomer δ 1.85 (m, 4H), 2.38 (s, 6H), 2.45 (m, 2H), 2.7 (m, 2H), 7.2-7.3 (m, 4H).
Step B: 6-[ 2- (1,3-Dioxolan-2-yl)ethyl]-6,7,8,9- tetrahydro-5H-benzocyclohepten-5-one dimethylhydrazone
To a stirred solution of lithium diisopropylamide [prepare by the addition of n-butyllithium (4.35 mL,
10.87 mmol of a 2.5 M solution in hexanes) to a stirred solution of diisopropylamine (1.66 mL, 11.86 mmol) in anhydrous tetrahydrofuran (11.6 mL) under a nitrogen atmosphere cooled to 0°C] is added a solution of the product of Step A (2.000 g, 9.886 mmol) in
tetrahydrofuran (5 mL) over 15 min maintaining the temperature below 5°C. The resulting solution is maintained at 0°C for 2 h and is then cooled to -78°C. To this solution is added a solution of 2-(2- bromoethyl)-1,3-dioxolane (1.28 mL, 10.9 mmol) in 1,3- dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone
(1.32 mL) over 15 min. at a rate such that the
temperature of the reaction stays below -65°C, the mixture is then kept at -78°C for 1 h. The reaction mixture is allowed to come to room temperature and is left at room temperature overnight. The reaction mixture is slowly quenched with water and is then poured into water (250 mL). The resulting mixture is extracted three times with diethyl ether. After drying (Na2SO4), the combined organic extracts are concentrated under reduced pressure and chromatography of the residue on silica gel (300 mL) with 1:4 ethyl acetate-hexaήe affords the title compound (2.765 g, 92.5%) as a yellow oil which is essentially a single geometric isomer: Rf 0.04 (silica gel, 1:4 ethyl acetate-hexane); 200 MHz 1H NMR (CDCI3) δ 1.35 (m, 2H), 1.52 (m, 2H), 1.81 (m, 2H), 1.91 (m, 2H), 2.56 (s, 6H), 2.75 (m, 2H), 3.77 (m, 3H), 3 . 9 (m, 2H) , 4 . 69 (t, 1H) , 7 .05 (m, 1H) , 7 .15-7 .25 (m, 3H).
Step C: 6,7-Dihydro-5H-benzo[6,7]cyolohepta[1,2- b]pyridine
A stirred solution of the title compound from Step B (31.23 g, 103.3 mmol) in glacial acetic acid (207 mL) under a nitrogen atmosphere is heated under reflux for 2 h. The reaction mixture is allowed to cool to room temperature and is concentrated under reduced pressure. The residue is dissolved in n-heptane and concentrated under reduced pressure several times to azeotrope off residual acetic acid. The residue is dissolved in 1 N aqueous HCl (800 mL) and extracted with four 200 mL portions of diethyl ether to remove undesired by- products. The aqueous layer is then basified to pH 9 with 1 N aqueous NaOH. The basic aqueous layer is extracted with three 200 mL portions of diethyl ether and these combined extracts are dried (MgSO4) and concentrated under reduced pressure. Chromatography of the residue on silica gel (1200 mL) with
dichloromethane affords the title compound (12.675 g, 63%) as a golden-brown oil: Rf 0.50 (silica gel, 1:1 ethyl acetate-hexane); 200 MHz 1H NMR (CDCI3) δ 2.20 (pentet, 2H), 2.50 (t, 2H), 2.54 (t, 2H), 7.2 (m, 2H), 7.37 (m, 2H), 7.54 (d, 1H), 7.7 (d, 1H), 8.61 (dd, 1H). Step D: 6,7-Dihydro-5H-benzo[6-7]cyclohepta[1,2- b]pyridine 1-oxide
To a stirred solution of the product of Step C (10.17 g, 52.08 mmol) in 1, 2-dichloroethane (130 mL) under a nitrogen atmosphere at room temperature is added portionwise 3-chloroperoxybenzoic acid (50-60% commercial, 19.77 g, 57.29 mmol) and the reaction is allowed to stir overnight at room temperature. The reaction is quenched by the addition of 1.5 mL of dimethylsulfide and, after 1.5 h, is washed with saturated aqueous Na2CO3 (800 mL). The aqueous wash is extracted with five 200 mL portions of dichloromethane. After drying (MgSO4), the combined organic layers are concentrated under reduced pressure and chromatography of the residue on silica gel (1000 mL) with 1:40 methanol-dichloromethane affords the title compound (10.45 g, 95%) as a white solid melting at 84-87°C: Rf 0.12 (silica gel, 1:20 methanol-dichloromethane); 400 MHz 1Η NMR (CDCI3) δ 2.1-2.2 (m, 3H), 2.45 (m, 1H), 2.6 (m, 2H), 7.15 (m, 2H), 7.27 (m, 1H), 7.37 (m, 2H), 8.05 (m, 1H), 8.3 (t, 1H).
Step E: 6,7-Dihydro-5H-benz[6,7]cyclohepta[ 1,2- b]pyridine-2-carbonitrile
To a stirred solution of the product of Step D (8.955 g, 42.40 mmol) in anhydrous dichloromethane (85 mL) under a nitrogen atmosphere at room temperature is added first trimethylsilyl cyanide (6.22 mL, 4.63 g, 46.6 mmol) over 10 min and then, after 15 min, is added dimethylcarbamyl chloride (4.1 mL, 4.8 g, 44.5 mmol) over 10 min. After 2 days at room temperature, the reaction is diluted with saturated aqueous NaHCO3
(800 mL) and the layers are separated. The aqueous layer is extracted with three 200 mL portions of dichloromethane. After drying (MgSO4), the combined organic layers are concentrated under reduced pressure and chromatography of the residue on silica gel
(900 mL) with 1:20 ethyl acetate-hexane affords the title compound (8.257 g, 88%) as a white solid melting at 65.5-66.5°C: Rf 0.07 (silica gel, 1:20 ethyl acetate-hexane); 400 MHz 1H NMR (CDCI3) δ 2.28 (pentet, 2H), 2.54 (t, 2H), 2.57 (t, 2H), 7.25 (m, 1H), 7.4 (m, 2H), 7.6 (d, 1H), 7.68 (d, 1H), 7.73 (m, 1H). Step F: Methyl 6,7-dihydro-5H-benzo[6,7]cyclohepta- [1,2-b]pyridine-2-carboximidate
To a stirred solution of the product of Step E (8.25 g, 37.45 mmol) in methanol (75 mL) under a nitrogen atmosphere at room temperature is added a solution of sodium methoxide (3.0 mL of commercial 25 wt. % solution in methanol, 13.11 mmol) and the reaction is allowed to stir at room temperature
overnight. The reaction is quenched by adding glacial acetic acid (0.75 mL, 787 mg, 13.1 mmol) and is then concentrated under reduced pressure. The residue is triturated with diethyl ether and filtered. The filtrate is concentrated under reduced pressure to afford the crude title compound (11.4 g) as a light yellow oily solid melting at 91.5-98°C: Rf 0.25
(silica gel, 1:30 methanol-dichloromethane); 400 MHz 1H NMR (CDCI3) δ 2.26 (pentet, 2H), 2.55 (t, 4H), 4.03 (s, 3H), 7.26 (d, 1H), 7.39 (t, 1H), 7.43 (t, 1H), 7.63 (d, 1H), 7.74 (d, 1H), 7.78 (d, 1H). Step G: 6,7-Dihydro-5H-benzo[6,7]cyclohepta[ 1 ,2- b ]pyridine-2-carboximidamide hydrochloride To ar solution of the crude imidate from Step F (37.45 mmol) in absolute ethanol (48.3 mL) under a nitrogen atmosphere at room temperature is added a solution of ammonium chloride (2.003 g, 37.45 mmol) in water (18.3 mL) and the resulting mixture is heated under reflux for 3 h. The reaction mixture is allowed to cool, concentrated under reduced pressure and, finally, concentrated in vacuo . The resulting solid is triturated with acetone (50 mL) and filtered to afford the title compound (8.185 g, 80%) as a white solid which does not melt below 250°C: Rf 0.02 (silica gel, 1:30 methanol-dichloromethane); 400 MHz 1H NMR
(Me2SO-d6) δ 2.24 (pentet, 2H), 2.49 (t, 2H), 2.56 (t, 2H), 7.37 (m, 1H), 7.45 (m, 2H), 7.87 (m, 1H), 8.09 (d, 1H), 8.23 (d, 1H), 9.44 (s, 2H), 9.55 (s, 2H).
The acetone filtrate is concentrated under reduced pressure and triturated with dichloromethane (10 mL) to afford additional title compound as a white solid
(695 mg, 7%).
Step H: 6,7-Dihydro-2-(4-methyl-2-pyrimidinyl)-5H- benzo[ 6,7]cyclohepta[1,2-b]pyridine y To a stirred solution of the product from Step G (2.507 g, 9.158 mmol) in methanol (92 mL) under a nitrogen atmosphere at room temperature is added first a solution of sodium methoxide (3.14 mL .of commercial 25 wt. % solution in methanol, 13.74 mmol) and then acetylacetaldehyde dimethyl acetal (1.83 mL, 1.815 g, 13.74 mmol). The resulting solution is heated under reflux for 2 h, allowed to cool to room temperature, and then concentrated under reduced pressure. The residue is dissolved in dichloromethane and
reconcentrated under reduced pressure (twice) to remove residual methanol. Chromatography of the residue on silica gel (280 mL) with 1:50 methanol-dichloromethane affords the title compound (2.55 g, 97%) as a yellow solid melting at 161.5-164.5°C contaminated with
acetylacetaldehyde dimethyl acetal (4% by weight).
This solid is recrystallized from 1-chlorobutane (45 mL) /hexane (25 mL) to give pure title compound (1.990 g, 76%) as a cream-colored granular solid melting at 166-166.5°C: Rf 0.25 (silica gel, 1:20 methanol-dichloromethane); 200 MHz 1H NMR (CDCl3) δ 2.26 (pentet, 2H), 2.56 (t, 2h), 2.58 (t, 2H), 2.65 (s, 3H), 7.15 (d, 1H), 7.22 (dd, 1H), 7.34 (dt, 1H), 7.41 (dt, 1H), 7.70 (d, 1H), 7.91 (dd, 1H), 8.36 (d, 1H), 8.77 (d, 1H).
The mother liquor is concentrated under reduced pressure and the residue is triturated with hexane
(8 mL) /1-chlorobutane (2 mL) to afford additional title compound (265 mg, 10%) as a tan solid.
EXAMPLE 2
6,7-Dihydro-2-(4-methyl-2-pyrimidinyl)-5 H- benzo[6,7]cyclohepta[1,2-b]pyridine.
complex with zinc chloride
To a stirred solution of 6,7-dihydro-2-(4-methyl- 2-pyrimidiny1)-5H-benzo[6,7]-cyclohepta[1,2-b]pyridine (150 mg, 0.52 mmol) in anhydrous tetrahydrofuran (8 mL) under a nitrogen atmosphere at room temperature is added a 1 M solution of zinc chloride in diethyl ether (0.468 mL, 63.8 mg, 0.468 mmol). During the addition a precipitate forms. After 2 h at room temperature, the reaction mixture is concentrated under reduced
pressure. The resulting orange solid is triturated with tetrahydrofuran and concentrated under reduced pressure four successive times to yield the title complex (0.242 g) as an orange solid which does not melt below 250°C: IR (KBr) 1578, 1396, 774 cm-1. EXAMPLE 3
2-(4,6-Dimethyl-2-pyrimidinyl)-6.7-dihydro-5H- benzo[6,7]cyclohepta[1,2-b]pyridine Step A: 2-[(Dimethylamino)methylenel-2,3,4,5- tetrahydro-1H-benzocyclohepten-1-one
A stirred solution of 1-benzosuberone (14.01 mL, 15.00 g, 93.62 mmol) in N, N-dimethylformamide dimethyl acetal (24.88 mL, 22.31 g, 187.2 mmol) under a nitrogen atmosphere is heated under reflux for 26 h. The reaction mixture is allowed to cool to room
temperature, concentrated under reduced pressure, and finally concentrated in vacuo. The resulting yellow- orange solid is triturated with hexane (65 mL) and filtered to afford the title compound (18.60 g, 92%) as a light yellow solid melting at 88.5-89.5°C: Rf 0.06 (silica gel, eluting first with 1:4 ethyl acetate- hexane and then with 1:2 ethyl acetate-hexane); 200 MHz 1H NMR (CDCl3) δ 1.85 (pentet, 2H), 2.34 (t, 2H), 2.76 (t, 2H), 3.13 (s, 6H), 7.11 (dd, 1H), 7.31 (m, 2H), 7.65 (dd, 1H), 7.77 (s, 1H).
Step B: 2-(4,6-Dimethyl-2-pyrimidinyl)-6,7-dihydro- 5H-benzo[6,7]cyclohepta[1,2-b]pyridine
To a stirred solution of potassium tert-butoxide (316 mg, 2.82 mmol) in anhydrous tetrahydrofuran (7 mL) under a nitrogen atmosphere at room temperature is added 1-(4,6-dimethyl-2-pyrimidinyl)-ethanone (212 mg, 1.41 mmol). After 2 h at room temperature, the product of Step A (304 mg, 1.41 mmol) is added in one portion and the reaction is allowed to stir overnight at room temperature. Ammonium acetate (1.087 g, 14.10 mmol) and then glacial acetic acid (3.5 mL) are added to the reaction. The reaction is heated under a distillation head and the tetrahydrofuran is distilled off over 4 h. After cooling to room temperature, the reaction is concentrated under reduced pressure. The residue is diluted with saturated aqueous sodium carbonate such that the resulting mixture is basic (pH 10), and extracted twice with chloroform. After drying (MgSO4), the combined organic extracts are concentrated under reduced pressure and chromatography of the residue on silica gel (50 mL) eluting first with 1:4 ethyl
acetate-hexane and then with 1 : 3 ethyl acetate-hexane affords the title compound (335 mg, 78%) as a tan solid melting at 120.5-123°C: Rf 0.27 (silica gel, 1:1 ethyl acetate-hexane); 400 MHz 1H NMR (CDCl3) δ 2.26 (pentet, 2H), 2.57 (m, 4H), 2.60 (s, 6H), 7.03 (s, 1H), 7.22 (d, 1H), 7.34 (t, 1H), 7.41 (t, 1H), 7.69 (d, 1H), 7.95 (d, 1H), 8.32 (d, 1H).
EXAMPLE 4
6,7-Pihydro-2-(2-pyridinyl)-5H- benzo[6,7]cyclohepta[1,2-b]pyridine To a stirred solution of potassium tert-butoxide (1.042 g, 9.290 mmol) in anhydrous tetrahydrofuran (23.2 mL) under a nitrogen atmosphere at room
temperature is added 2-acetylpyridine (0.52 mL, 563 mg, 4.64 mmol). After 2 h at room temperature, the product of Step A in Example 3 (1.00 g, 4.64 mmol) is added in one portion and the reaction is allowed to stir
overnight at room temperature. Ammonium acetate
(3.58 g, 46.45 mmol) and then glacial acetic acid
(11.6 mL) are added to the reaction. The reaction is heated under a distillation head and the
tetrahydrofuran is distilled off over 2 h. After cooling to room temperature, the reaction is
concentrated under reduced pressure. The residue is diluted with water and a little chloroform, solid sodium carbonate is added until the aqueous layer is basic (pH 10), and the mixture is then extracted with three portions of chloroform. After drying (MgSO4), the combined organic extracts are concentrated under reduced pressure and chromatography of the residue on silica gel (140 mL) with chloroform affords the title compound (750 mg, 59%) as a dark brown oil: Rf 0.08
(silica gel, chloroform); 400 MHz 1H NMR (CDCl3) δ 2.27 (pentet, 2H), 2.56 (t, 2H), 2.59 (t, 2H), 7.29 (m, 2H), 7.38 (t, 1H), 7.44 (t, 1H), 7.68 (d, 1H), 7.81 (t, 1H), 7.87 (d, 1H), 8.32 (d, 1H), 8.57 (d, 1H), 8.68 (d, 1H).
Further elution afford additional title compound (245 mg, 13% corrected for impurities) which is 65% pure by weight.
EXAMPLE 5
6,7-Dihydro-2-( 6-methyl-2-pyridinyl) -5H- benzo[6,7]cyclohepta[1,2-b]pyridine
To a stirred solution of 6,7-dihydro-2-(2- pyridinyl)-5H-benzo[6,7]cyclohepta[1,2-b]pyridine
(250 mg, 0.918 mmol) in anhydrous diethyl ether
(4.6 mL) under a nitrogen atmosphere cooled to 0°C is added a 1.4 M. solution of methyllithium in diethyl ether (0.66 mL, 20 mg, 0.92 mmol) over 10 min. The reaction is allowed to warm to room temperature and, after 1 h it is heated under reflux overnight. After cooling to room temperature, the reaction is quenched by the slow addition of water. The layers are
separated and the aqueous layer is extracted twice with diethyl ether. After drying (MgSO4), the combined organic layers are concentrated under reduced pressure. To a stirred solution of the residue in acetone at room temperature under a nitrogen atmosphere is added a saturated solution of potassium permanganate in acetone until a violet color persists, and then this mixture is filtered through Celite®. The filtrate is concentrated under reduced pressure and chromatography of the
residue on silica gel (50 mL) with 1:50 ethyl acetate- hexane affords first the title compound (10 mg, 4%) as a white solid melting at 144-145°C: Rf 0.34 (silica gel, 1:10 ethyl acetate-hexane); 400 MHz 1H NMR (CDCl3) δ 2.27 (pentet, 2H), 2.57 (m, 4H), 2.64 (s, 3H), 7.16 (d, 1H), 7.29 (m, 1H), 7.38 (m, 1H), 7.44 (m, 1H), 7.69 (m, 2H), 7.87 (d, 1H), 8.35 (m, 2H).
Further elution affords the starting material (title compound from Example 4, 125 mg, 50%) as a white solid melting at 72-73.5°C.
EXAMPLE 6
6,7-Dihydro-2-(6-methyl-2-pyridinyl--5H- benzp[6,7]cyclohepta[1,2-d]pyrimidine To a stirred mixture of 2-(4,6-dimethyl-2- pyrimidinyl)-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2- b]pyridine (1.311 g, 6.090 mmol) and the hydrochloride salt of 6-methyl-2-pyridine. carboximidamide (1.045 g, 6.090 mmol) in absolute ethanol (15.2 mL) at room temperature under a nitrogen atmosphere is added triethylamine (1.70 mL, 1.23 g, 12.2 mmol) and then the mixture is heated under reflux overnight. After cooling to room temperature, the reaction is
concentrated under reduced pressure. The residue is diluted with dichloromethane (80 mL) and washed
successively with saturated aqueous sodium hydrogen carbonate (25 mL) and water (25 mL). Each of these aqueous layer are extracted with dichloromethane.
After drying (MgSO4), the combined organic layers are concentrated under reduced pressure and chromatography of the residue on silica gel (350 mL) with ethyl acetate affords impure title compound (1.17 g) as a yellow solid. Chromatography of this material on silica gel (100 mL) with 1:1 ethyl acetate- dichloromethane and then rechromatography on neutral activity I alumina (100 mL) eluting first with 1:1 dichloromethane-hexane, then with dichloromethane, and finally with 1:1 ethylacetate-dichloromethane affords pure title compound (565 mg, 32%) as a white solid melting at 151-153°C: Rf 0.17 (silica gel, 1:20
methanol-dichloromethane); 200 MHz 1H NMR (CDCl3) δ 2.31 (pantet, 2H), 2.57 (t, 2H), 2.60 (t, 2H), 2.74 (s, 3H), 7.27 (m, 2H), 7.45 (m, 2H), 7.73 (t, 1H), 7.90 (m, 1H), 8.42 (d, 1H), 8.78 (s, 1H).
EXAMPLE 7
8-Bromo-6,7-dihydro-2-(4-methyl-2-pyrimidinyl)- 5H-benzo[6,7]cyclohepta[1,2-b ]pyridine and
10-bromo-6,7-dihydro-2-(4-methyl-2-pyrimidinyl) - 5H-benzo[6,7]cyclohepta(1,2b]pyridine
Step A: 8-Bromo-6,7-dihydro-5H-benzo[6,7]cyolohepta- [1,2-b]pyridine and 10-bromo-6,7-dihydro-5H- benzo[6,7]cyclohepta[1,2-b]pyridine To a stirred solution of 6,7-dihydro-5H- benzo[6,7]cyclohepta[1,2-b]pyridine (60.00 g,
307.3 mmol) in trifluoroacetic, acid (1025 mL) under a nitrogen atmosphere at room temperature is added portionwise N-bromosuccinimide (60.159 g, 338.00 mmol) and the reaction is allowed to stir for four days at room temperature. The reaction mixture is concentrated under reduced pressure and the residue is diluted with IN aqueous sodium hydroxide. The resulting basic aqueous mixture is extracted with three portions of ethyl acetate. After drying (MgSO4), the combined organic extracts are concentrated under reduced
pressure and chromatography of the residue on silica gel (1200 mL) with 1:3 dichloromethane-hexane affords first the 10-bromo isomer (31.015 g, 37%) as a light brown oil: Rf 0.43 (silica gel, dichloromethane);
400 MHz 1H ΝMR (CDCl3) δ 2.23 (pentet, 2H), 2.49 (t, 4H), 7.12 (d, 1H), 7.21 (dd, 1H), 7.46 (dd, 1H), 7.55 (dd, 1H), 7.87 (d, 1H), 8.61 (dd, 1H). Further elution with 1 : 3 dichloromethane-hexane and then with dichloromethane affords mixtures of the 8-bromo isomer, 10-bromo isomer, and unreacted starting material (total of 33.00 g representing approximately 7.68 g of the 10-bromo isomer, 17.58 g of the 8-bromo isomer, and 7.74 g of unreacted starting material). Rechromatography of some of the mixed fractions on silica gel with 1:20 ethyl acetate-hexane or 1:1 dichloromethane-hexane affords the 8-bromo isomer
(8.35 g, 10%, contaminated with a small amount of unreacted starting material): Rf 0.33 (silica gel, dichloromethane); 400 MHz, 1H NMR (C6D6) δ 1.82
(pentet, 2H), 2.01 (t, 2H), 2.58 (t, 2H), 6.66 (t, 1H), 6.83 (t, 1H), 6.89 (d, 1H),7.41 (d, 1H), 7.87 (d, 1H), 8.53 (d, 1H).
Step B: 8-Bromo-6,7-dihydro-2-(4-methyl-2- pyrimidinyl)-5H-benzo[6,7]cyclohepta[1,2-b]- pyridine
Following the synthetic methods taught in Example 1 (Steps D through H), a portion of the 8-bromo isomer from Step A is converted into the title compound contaminated with 7% of 6,7-dihydro-2-(4-methyl-2- pyrimidinyl)-5H-benzo[6,7]cyclohepta[1,2-b]pyridine) which is obtained as a yellow solid melting at
112-116°C: Rf 0.07 (silica gel, 1:1 ethyl acetate- hexane); 400 MHz 1H NMR (CDCl3) δ 2.25 (pentet, 2H), 2.56 (t, 2H), 2.66 (s, 3H), 2.78 (t, 2H), 7.17 (d, 1H), 7.24 (t, 1H), 7.61 (d, 1H), 7.72 (d, 1H), 7.83 (d, 1H), 8.40 (d, 1H), 8.77 (d, 1H). Step C: 10-Bromo-6,7-dihydro-2-(4-methyl)-2- pyrimidinyl)-5H-benzo[6,7]cyclohepta[1,2-b]- pyridine
Following the synthetic methods taught in Example 1 (Steps D through H), a portion of the 10-bromo isomer from Step A is converted into the title compound which is obtained as yellow oily solid melting at 137-138°C: Rf 0.10 (silica gel, 1:2 ethyl acetate-hexane); 400 MHz 1H NMR (CDCl3) δ 2.25 (pentet, 2H), 2.51 (t, 2H), 2.58 (t, 2H), 2.67 (s, 3H), 7.10 (d, 1H), 7.18 (d, 1H), 7.46 (d, 1H), 7.72 (d, 1H), 8.05 (s, 1H), 8.40 (d, 1H), 8.78 (d, 1H).
Examples of compounds of the invention are shown in Tables 1-9. These compounds readily can be
converted to their conjugate acid salts or metal complexes. Abbreviations are as follows: t- is tertiary c-Pr is cyclo-propyl
sec- is secondary TMS is trimethylsilyl
n- is normal CO2H is hydroxycarbonyl
NHEt is ethylamino n-Pr is normal-propyl
SPh is phenylthio t-Bu is tertiary-butyl
i-Pr is isopropyl O-n-Bu is normal-butoxy
O-i-Pr is isopropoxy n-Bu is normal-butyl
Bu is butyl n-Hex is normal-hexyl
Hex is hexyl sec-Bu is secondary-butyl
CN is cyano S-i-Pr is isopropylthio
OPh is phenoxy CO2Me is methoxycarbonyl
c-Hex is cyclo-hexyl S(O)Me is methylsulfinyl
NO2 is nitro S(O)2Me is methylsulfonyl
SEt is ethylthio S(O)2Et is ethylsulfonyl
SMe is methylthio S(O)2-n-Bu is normal-butylsulfonyl OH is hydroxy TBS is tertiary-butyldimethylsilyl OMe is methoxy Et is ethyl
i- is iso OEt is ethoxy Ph is phenyl Pr is propyl
c- is cyclo NMe2 is dimethylamino Me is methyl NEt2 is diethylamino Ac is acetyl
T le 5
Table 9
wherein the left side of A is bonded to the phenyl ring and the right side of is bonded to the pyridyl (when Z = CR6) or pyrimidinyl (when Z = N) ring.
X and Z are CH; Y is N; R1 is Me; R2, R3, R7 and R' 8 are H
)
Formulation/Utility
Compounds of this invention will generally be used in formulation with an agriculturally suitable
composition. The fungicidal compositions of the present invention comprise an effective amount of at least one compound of Formula I as defined above and at least one of (a) a surfactant, (b) an organic solvent, and (c) at least one solid or liquid diluent. Useful formulations can be prepared in conventional ways.
They include dusts, granules, pellets, solutions, suspensions, emulsions, wettable powders, emulsifiable concentrates, dry flowables and the like. Sprayable formulations can be extended in suitable media and used at spray volumes from about one to several hundred liters per hectare. High strength compositions are primarily used as intermediates for further
formulation. The formulations will typically contain effective amounts of active ingredient, diluent and surfactant within the following approximate ranges which add up 100 weight percent .
Active
Typical solid diluents are described in Watkins, et al., Handbook of Insecticide Dust Diluents and
Carriers, 2nd Ed., Dorland Books, Caldwell, New Jersey. Typical liquid diluents and solvents are described in Marsden, Solvents Guide, 2nd Ed., Interscience, New York, 1950. McCutcheon 's Detergents and Emulsifiers Annual, Allured Publ. Corp., Ridgewood, New Jersey, as well as Sisely and Wood, Encyclopedia of Surface Active Agents, Chemical Publ. Co., Inc., New York, 1964, list surfactants and recommended uses. All formulations can contain minor amounts of additives to reduce foam, caking, corrosion, microbiological growth, etc.
Methods for formulating such compositions are well known. Solutions are prepared by simply mixing the ingredients. Fine solid compositions are made by blending and, usually, grinding as in a hammer mill or fluid energy mill. Water-dispersible granules can be produced be agglomerating a fine powder composition; see for example, Cross et al., Pesticide Formulations, Washington, D.C., 1988, pp 251-259. Suspensions are prepared by wet-milling; see, for example, U.S.
3,060,084. Granules and pellets can be made by
spraying the active material upon preformed granular carriers or by agglomeration techniques. See Browning, "Agglomeration", Chemical Engineering, December 4, 1967, pp 147-148, Perry 's Chemical Engineer ' s Handbook, 4th Ed., McGraw-Hill, New York, 1963, pp 8-57 and following, and WO 91/13546. Pellets can be prepared as described in U.S. 4,172,714. Water-dispersible and water-soluble granules can be prepared as taught in DE 3,246,493.
For further information regarding the art of formulation, see U.S. 3,235,361, Col. 6, line 16 through Col. 7, line 19 and Examples 10 through 41;
U.S. 3,309,192, Col. 5, line 43 through Col. 7, line 62 and Examples 8, 12, 15, 39, 41, 52, 53, 58, 132, 138- 140, 162-164, 166, 167 and 169-182; U.S. 2,891,855, Col. 3, line 66 through Col. 5, line 17 and Examples 1- 4; Klingman, Weed Control as a Science, John Wiley and Sons, Inc., New York, 1961, pp 81-96; and Hance et al., Weed Control Handbook, 8th Ed., Blac.kwell Scientific Publications, Oxford, 1989.
In the following Examples, all percentages are by weight and all formulations are worked up in
conventional ways. Compound numbers refer to Index Table A hereinafter.
EXAMPLE A
Wettable Powder
Compound 1 65.0% dodecylphenol polyethylene glycol ether 2.0% sodium ligninsulfonate 4.0% sodium silicoaluminate 6.0% montmorillonite (calcined) 23.0%
EXAMPLE B
Granule
Compound 1 10.0% attapulgite granules (low volative
matter, 0.71/0.30 mm; U.S.S. No. 25-50 sieves) 90.0%
EXAMPLE C
Extruded Pellet
Compound 1 25.0% anhydrous sodium sulfate 10.0% crude calcium ligninsulfonate 5.0% sodium alkylnaphthalenesulfonate 1.0% calcium/magnesium bentonite 59.0%
EXAMPLE D
Emulsifiable Concentrate
Compound 1 20.0% blend of oil soluble sulfonates
and polyoxyethylene ethers 10.0% isophorone 70.0% The compounds of this invention are useful as plant disease control agents. The present invention therefore further comprises a method for controlling plant diseases caused by fungal plant pathogens
comprising applying to the plant or portion thereof to be protected, or to the plant seed or seedling to be protected, an effective amount of a compound of Formula I or a fungicidal composition containing said compound. The compounds and compositions of this invention provide control of diseases caused by a broad spectrum of fungal plant pathogens in the Basidiomycete,
Ascomycete, Oomycete and Deuteromycete classes. They are effective in controlling a broad spectrum of plant diseases, particularly foliar pathogens of ornamental, vegetable, field, cereal, and fruit crops. These pathogens include Plasmopara viticola, Phytophthora infestans, Peronospora tabacina, Pseudoperonospora cubensis, Pythium aphanidermatum, Alternaria brassicae, Septoria nodorum, Cercosporidium personatum, Cercospora arachidicola, Pseudocercosporella herpotrichoides.
Cercospora beticola, Botrytis cinerea, Monilinia fructicola, Pyricularia oryzae, Podosphaera
leucotricha, Venturia inaequalis, Erysiphe graminis, Uncinula necatur, Puccinia recondita, Puccinia
graminis, Hemileia vastatrix. Puccinia striiformis, Puccinia arachidis, Rhizoctonia solani, Sphaerotheca fuliginea, Fusarium oxysporum, Verticillium dahliae, Pythium aphanidermatum, Phytophthora megasperma and other generea and species closely related to these pathogens.
Compounds of this invention can also be mixed with one or more other insecticides, fungicides,
nematocides, bactericides, acaricides, semiochemicals, repellants, attractants, pheromones, feeding stimulants or other biologically active compounds to form a multicomponent pesticide giving an even broader spectrum of agricultural protection. Examples of other
agricultural protectants with which ec-npounds of this invention can be formulated are: insecticides such as monocrotophos, carbofuran, tetrachlorvinphos,
malathion, parathion-methyl, methomyl, chlordimeform, diazinon, deltamethrin, oxamyl, fenvalerate,
esfenvalerate, permethrin, profenofos, sulprofos, triflumuron, diflubenzuron, methoprene, buprofezin, thiodicarb, acephate, azinphosmethyl, chlorpyrifos, dimethoate, fipronil, flufenprox, fonophos, isofenphos, methidathion, methamidophos, phosmet, phosphamidon, phosalone, pirimicarb, phorate, terbufos, trichlorfon, methoxychlor, bifenthrin, biphenate, cyfluthrin, fenpropathrin, fluvalinate, flucythrinate,
tralomethrin, metaldehyde and rotenone; fungicides such as carbendazim, thiuram, dodine, maneb, chloroneb, benomyl, cymoxanil, fenpropidine, fenpropimorph, triadimefon, captan, thiophanate-methyl, thiabendazole, phosethyl-A1, chlorothalonil, dichloran, metalaxyl, captafol, iprodione, oxadixyl, vinclozolin, kasugamycin, myclobutanil, tebuconazole,
difenoconazole, diniconazole, fluquinconazole,
ipconazole, metconazole, penconazole, propiconazole, uniconzole, flutriafol, prochloraz, pyrifenox,
fenarimol, triadimenol, diclobutrazol, copper
oxychloride, furalaxyl, folpet, flusilazol, blasticidin S, diclomezine, edifenphos, isoprothiolane, iprobenfos, mepronil, neo-asozin, pencycuron, probenazole,
pyroquilon, tricyclazole, validamycin, and flutolanil; nematocides such as aldoxycarb, fenamiphos and
fosthietan; bactericides such as oxytetracyline, streptomycin and tribasic copper sulfate; acaricides such as binapacryl, oxythioquinox, chlorobenzilate, dicofol, dienochlor, cyhexatin, hexythiazox, amitraz, propargite, tebufenpyrad and fenbutatin oxide; and biological agents such as Bacillus thuringiensis, baculovirus and avermectin B.
In certain instances, combinations with other fungicides having a similiar spectrum of control but a different mode of action will be particularly
advantageous for resistance management.
Plant disease control is ordinarily accomplished by applying an effective amount of a compound of this invention either pre- or post-infection, to the portion of the plant to be protected such as the roots, stems, foliage, fruit, seeds, tubers or bulbs, or to the media (soil or sand) in which the plants to be protected are growing. The compounds can also be applied to the seed to protect the seed and seedling.
Rates of application for these compounds can be influenced by many factors of the environment and should be determined under actual use conditions.
Foliage can normally be protected when treated at a rate of from less than 1 g/ha to 5,000 g/ha of active ingredient. Seed and seedlings can normally be protected when seed is treated at a rate of from 0.1 to 10 g per kilogram of seed.
The following Tests demonstrate the control efficacy of compounds of this invention on specific pathogens. The pathogen control protection afforded by the compounds is not limited, however, to these
species. See Index Table A for compound descriptions.
Test compounds were first dissolved in acetone in an amount equal to 3% of the final volume and then suspended at a concentration of 200 ppm in purified water containing 250 ppm of the surfactant Trem® 014 (polyhydric alcohol esters). The resulting test suspensions were then used in the following tests.
TEST A
The test suspension was sprayed to the point of run-off on wheat seedlings. The following day the seedlings were inoculated with a spore dust of Erysiphe graminis f. sp. tritici, (the causal agent of wheat powdery mildew) and incubated in a growth chamber at 20°C for 7 days, after which disease ratings were made.
TEST B
The test suspension was sprayed to the point of run-off on wheat seedlings. The following day the seedlings were inoculated with a spore suspension of Puccinia recondita (the causal agent of wheat leaf rust) and incubated in a saturated atmosphere at 20°C for 24 h, and then moved to a growth chamber at 20°C for 6 days, after which disease ratings were made.
TEST C
The test suspension was sprayed to the point of run-off on rice seedlings. The following day the seedlings were inoculated with a spore suspension of Pyricularia oryzae (the causal agent of rice blast) and incubated in a saturated atmosphere at 27°C for 24 h, and then moved to a growth chamber at 30°C for 5 days, after which disease ratings were made.
TEST D
The test suspension was sprayed to the point of run-off on tomato seedlings. The following day the seedlings were inoculated with a spore suspension of Phytophthora infestans (the causal agent of potato and tomato late blight) and incubated in a saturated atmosphere at 20°C for 24 h, and then moved to a growth chamber at 20°C for 5 days, after which disease ratings were made.
TEST E
The test suspension was sprayed to the point of run-off on grape seedlings. The following day the seedlings were inoculated with a spore suspension of Plasmopara viticola (the causal agent of grape downy mildew) and incubated in a saturated atmosphere at 20°C for 24 h, moved to a growth chamber .at 20°C for 6 days, and then incubated in a saturated atmosphere at 20°C for 24 h, after which disease ratings were made.
TEST F
The test suspension was sprayed to the point of run-off on cucumber seedlings. The following day the seedlings were inoculated with a spore suspension of Botrytxs cinerea (the causal agent of gray mold on many crops) and incubated in a saturated atmosphere at 20°C for 48 h, and moved to a growth chamber at 20°C for 5 days, after which disease ratings were made.
Index Table A
Results for Tests A-F are given in Table 1. In the table, a rating of 100 indicates 100% disease control and a rating of 0 indicates no disease control (relative to the controls). NT = not tested.
a1H NMR data for oils are given in Index Table C.
b97% compound plus 3% dimethylformamide.
c90% compound plus 10% 2-[(dimethylamino)methylene]-3,4-dihydro-
1(2H)-naphthalenone
d93% compound plus 7% of compound No. 1.
INDEX TABLE B
No. 1H R D a 1 1H s
s,
a1H NMR data are in ppm downfield from tetramethylsilane.
Couplings are designated by (s)-singlet, (d)-doublet, (t)- triplet, (q)-quartet, (p)-pentet, (m)-multiplet, (dd)-doublet of doublets. Samples dissolved in CDCl3 unless otherwise indicated.
TABLE
*The compound was sprayed at a concentration of 40 ppm.

Claims

WHAT IS CLAIMED IS:
1. Compounds of Formula I
including all geometric and stereoisomers wherein:
X is N or CR4;
Y is N or CR5;
Z is N or CR6;
Q is a fused benzene, naphthalene, thiophene,
furan, pyrrole, pyridine or pyrimidine ring each optionally substituted with R7 and R8; A is a bridge -G1-G2-G3-G4-, wherein G1, G2, G3 or G4 are independently O, S(O)p, NR9, CR10R11, C(=O), a direct bond, or G1-G2, G2-G3 or G3-G4 may be taken together to form -CH=CH-; such that at least one of G1, G2, G3 and G4 is other than a direct bond;
R1, R2, R3 and R4 are independently H; halogen; cyano; hydroxy; C1-C6 alkyl; C1-C4 haloalkyl; C1-C4 alkylthio; C1-C4 alkylsulfinyl; C1-C4 alkylsulfonyl; C3-C6 cycloalkyl optionally substituted with 1-2 methyl groups; C1-C4 alkoxy; C1-C4 haloalkoxy; C2-C4 alkoxyalkyl; C2-C4 alkenyl; C2-C4 haloalkenyl; C2-C4 alkenyloxy; C2-C4 alkynyl; C2-C4 alkynyloxy; NR12R13; phenyl or phenoxy optionally substituted with R14; or R1 and R4, R2 and R4 or R2 and R5 can be taken together to form -(CH2)3-, -(CH2)4- or a fused phenyl ring; R5 and R6 are independently H, halogen, C1-C2
alkyl or C1-C2 alkoxy;
R7 is halogen; cyano; nitro; hydroxy;
hydroxycarbonyl; C1-C6 alkyl; C1-C4 haloalkyl; C1-C4 alkylthio; C1-C4
alkylsulfinyl; C1-C4 alkylsulfonyl; (C1-C4 alkyl) 3silyl; C3-C6 cycloalkyl; C2-C5 alkylcarbonyl; C2-C4 alkenyl; C2-C4 alkenyloxy; C2-C4 alkynyl; C2-C4 alkynyloxy; C1-C4 alkoxy; C1-C4 haloalkoxy; C2-C4 alkoxyalkyl; C2-C5 alkoxycarbonyl; C2-C4 alkoxyalkoxy; NR15R16; C (=O)NR17R18; or phenyl, phenoxy or phenylthio each optionally substituted with R19;
R8 and R14 are independently 1-2 halogen, 1-2 C1-C3 alkyl, C1-C2 haloalkyl, C1-C2 alkoxy or C1-C2 haloalkoxy;
R9, R10 and R11 are independently H or C1-C2 alkyl; R12, R13, R15, R16, R17, and R18 are independently H or C1-C2 alkyl; or R12 and R13, R15 and R16 or R17 and R18 can be taken together with the nitrogen to which they are attached to form a piperidino, pyrrolidino or morpholino ring; R19 is halogen, C1-C2 alkyl, C1-C2 haloalkyl, C1-C2 alkoxy or C1-C2 haloalkoxy;
p is 0, 1 or 2;
or their agriculturally suitable salts or metal
complexes thereof;
provided that:
i) when any of G1, G2, G3 or G4 are O, then they are not directly bonded to O or S(O)p; ii) when any of G1, G2, G3 or G4 are S (O) or
S(O)2, then they are not bonded directly to C (=O);
iii) the total number of heteroatoms in the ring containing A does not exceed two;
iv) when X, Y and Z are CH; A is CH2; Q is fused unsubstituted benzene; R1 and R2 are H; then R3 is not unsubstituted phenyl; and
v) the compounds are not 2-[4,6- bis (trichloromethyl)-1,3,5-triazin-2-yl]-
1,10-phenanthroline or 2-(2-pyridinyl)-1,10- phenanthroline.
2. Compounds of Claim 1 wherein:
A is a bridge selected from the group
consisting of: -CR10R11-; -G-;
-(CR10R11-CR10R11)-; -(G-CR10R11)-;
-(CH=CH)-; - [O-C(=O)]-; -[NR9-C(=O)]-;
-(CR10R11-CR10R11-CR10R11)-;
-(G-CR10R11-CR10R11)-;
-(CR10R11-G-CR10R11)-; -(CR10R11-CH=CH)-;
-(O-CR10R11-O)-; -[O-C(=O)-CR10R11]-; -[CR10R11-O-C(=O)]-;
-[NR9-C(=O)-CR10R11]-;
-[CR10R11-NR9-C(=O)]-; -[C(=O)-CH=CH]-; -[O-C(=O)-O]-; -[NR9-C(=O)-NR9]-;
-(CR10R11-CR10R11-CR10R11-CR10R11)-;
-(G-CR10R11-CR10R11-CR10R11)-;
-(CR10R11-G-CR10R11-CR10R11)-;
-(CR10R11-CR10R11-CH=CH)-;
-(CR10R11-CH=CH-CR10R11)-;
-(CH=CH-CH=CH)-; -(O-CR10R11-O-CR10R11)-;
-(O-CR10R11-CR10R11-O)-;
-[O-C(=O)-CR10R11-CR10R11]-;
-[CR10R11-O-C(=O)-CR10R11]-;
-[CR10R11-CR10R11-O-C(=O)J-; -[NR9-C(=O)-CR10R11-CR10R11]-;
-[CR10R11-NR9-C(=O)-CR10R11]-; and
-[CR10R11-CR10R11-NR9-C(=O)]-;
such that A taken together with the attached atoms forms a 5-8 membered ring; and the directionality of A may be that the left side of A is bonded to the Q ring and the right side is bonded to the pyridyl (when Z=CR6) or pyrimidinyl (when Z=N) ring, or that the left side of A is bonded to the pyridyl or pyrimidinyl ring and the right side is bonded to Q; and
G is O; S(O)p; NR9; or C(=O).
3. Compounds of Claim 2 wherein:
X is CR4;
Y is N or CH;
Z is N or CH; and
A is a bridge selected from the group
consisting of: -(CR10R11-CR10R11)-;
-(G-CR10R11)-; -(CH=CH)-; -[O-C(=O)]-; -[NR9-C(=O)]-;
-(CR10R11-CR10R11-CR10R11)-;
-(G-CR10R11-CR10R11)-;
-(CR10R11-G-CR10R11)-; - (CR10R11-CH=CH)-;
-(O-CR10R11-O)-; - [O-C(=O)-CR10R11]-;
-[CR10R11-O-C(=O)]-;
-[NR9-C (=O) -CR10R11] -;
-[CR10R11-NR9-C(=O)]-; -[C(=O)-CH=CH]-; -[O-C(=O)-O]-; and -[NR9-C(=O)-NR9]-.
4. Compounds of Claim 3 wherein:
Q is a fused benzene, thiophene, furan or
pyridine ring each optionally
substituted with R7 and R8; A is selected from the group consisting of
-(CH2-CH2)-; -[CH2-C(=O)]-; -(CH=CH)-;
-[C(=O)-O]-; -[C(=O)-NR9]-;
-(CH2-CH2-CH2)-; -(O-CH2-O)-;
-(CH2-CH2-O)-; -[CH2-CH2-S(O)p]-;
-(CH2-CH2-NR9)-; -(CH2-O-CH2)-;
-[CH2-S(O)p-CH2]-; -(CH2-NR9-CH2)-;
-[O-C(=O)-O]-;
R1, R2, R3 and R4 are independently H,
halogen, C1-C4 alkyl, C1-C4 haloalkyl, cyclopropyl, C1-C4 alkoxy or C2-C3 alkynyl; and
R7 is halogen, cyano, C1-C4 alkyl, C1-C4
haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy or C2-C4 alkoxyalkoxy.
5. Compounds of Claim 4 wherein:
Q is a fused benzene ring optionally substituted with R7 aad R8; and
A is selected from the group consisting of -(CH2-CH2)-; -(CH=CH)-; -[C(=O)-O]-;
-[C(=O)-NR9]-; -(CH2-CH2-CH2)-;
-(O-CH2-O)-; -(CH2-CH2-O)-;
-[CH2-CH2-S(O)p]-; -(CH2-CH2-NR9)-;
-(CH2-O-CH2)-; -[CH2-S(O)p-CH2]- and -(CH2-NR9-CH2)-.
6. A compound of Claim 5 which is 6,7-dihydro-2- (4-methyl-2-pyrimidinyl)-5H-benzo[6,7]cyclohepta[1,2- b]pyridine.
7.2 A fungicidal composition comprising an effective amount of a compound of Formula I
wherein :
X is N or CR4;
Y is N or CR5;
Z is N or CR6;
Q is a fused benzene; naphthalene; thiophene; furan; pyrrole; pyridine or pyrimidine ring each optionally substituted with R7 and R8; A is a bridge selected from- the group consisting of: -CR10R11-; -G-; - (CR10R11-CR10R11)-;
-(G-CR10R11)-; -(CH=CH)-; -[O-C(=O)]-;
-[NR9-C(=O)]-; -(CR10R11-CR10R11-CR10R11)-;
-(G-CR10R11-CR10R11)-; -(CR10R11-G-CR10R11)-;
-(CR10R11-CH=CH)-; -(O-CR10R11-O)-; -[O-C(=O)-CR10R11]-; -[CR10R11-O-C(=O)]-;
-[NR9-C(=O)-CR10R11]-; -[CR10R11-NR9-C(=O)]-; -[C(=O)-CH=CH]-; -[O-C(=O)-O]-;
-[NR9-C(=O)-NR9]-;
-(CR10R11-CR10R11-CR10R11-CR10R11)-;
-(G-CR10R11-CR10R11-CR10R11)-;
-(CR10R11-G-CR10R11-CR10R11)-;
-(CR10R11-CR10R11-CH=CH)-;
-(CR10R11-CH=CH-CR10R11)-; -(CH=CH-CH=CH)-;
-(O-CR10R11-O-CR10R11)-;
-(O-CR10R11-CR10R11-O)-;
-[O-C(=O)-CR10R11-CR10R11]-;
-[CR10R11-O-C(=O)-CR10R11]-;
-[CR10R11-CR10R11-O-C(=O)]-; - [NR9-C (=O) -CR 10R11-CR10R11] -;
- [CR10R11-NR9-C (=O) -CR10R11] -; and
- [CR10R11-CR10R11-NR9-C (=O) ] -;
such that A taken together with the attached atoms forms a 5-8 membered ring; and the directionality of A may be that the left side of A is bonded to the Q ring and the right side is bonded to the pyridyl (when Z=CR6) or pyrimidinyl (when Z=N) ring, or that the left side of A is bonded to the pyridyl or
pyrimidinyl ring and the right side is bonded to Q;
G is O; S(O)p; NR9; or C (=O);
p is 0, 1 or 2;
R1, R2, R3 and R4 are independently H; halogen; cyano; hydroxy; C1-C6 alkyl; C1-C4 haloalkyl; C1-C4 alkylthio; C1-C4 alkylsulfinyl; C1-C4 alkylsulfonyl; C3-C6 cycloalkyl optionally substituted with 1-2 methyl groups; C1-C4 alkoxy; C1-C4 haloalkoxy; C2-C4 alkoxyalkyl;
C2-C4 alkenyl; C2-C4 haloalkenyl; C2-C4 alkenyloxy; C2-C4 alkynyl; C2-C4 alkynyloxy; NR12R13' phenyl or phenoxy optionally
substituted with R14; or R1 and R4, R2 and R4 or R2 and R5 can be taken together to form
-(CH2)3-, -(CH2)4- or a fused phenyl ring;
R5 and R6 are independently H; halogen; C1-C2
alkyl or C1-C2 alkoxy;
R7 is halogen; cyano; nitro; hydroxy;
hydroxycarbonyl; C1-C6 alkyl; C1-C4
haloalkyl; C1-C4 alkylthio; C1-C4
alkylsulfinyl; C1-C4 alkylsulfonyl; (C1-C4 alkyl) 3silyl; C3-C6 cycloalkyl; C2-C5
alkylcarbonyl; C2-C4 alkenyl; C2-C4
alkenyloxy; C2-C4 alkynyl; C2-C4 alkynyloxy; C1-C4 alkoxy; C1-C4 haloalkoxy; C2-C4
alkoxyalkyl; C2-C5 alkoxycarbonyl; C2-C4 alkoxyalkoxy; NR15R16; C (=O)NR17R18; or phenyl, phenoxy or phenylthio each optionally substituted with R19;
R8 and R14 are independently 1-2 halogen; 1-2 C1-C3 alkyl; C1-C2 haloalkyl; C1-C2 alkoxy or C1-C2 haloalkoxy;
R9, R10 and R11 are independently H or C1-C2 alkyl; R12, R13, R15, R16, R17, and R18 are independently H or C1-C2 alkyl; or R12 and R13, R15 and R16 or R17 and R18 can be taken together with the nitrogen to which they are attached to form a piperidino, pyrrolidino or morpholino ring; R19 is halogen; C1-C2 alkyl; C1-C2 haloalkyl; C1-C2 alkoxy or C1-C2 haloalkoxy;
or the agriculturally suitable salts or metal complexes thereof;
provided that:
i) when any of G1, G2, G3 or G4 are 0, then they are not directly bonded to O or S(O)p;
ii) when any of G1, G2, G3 or G4 are S (O) or S(O)2, then they are not bonded directly to C (=O) ;
iii) the total number of heteroatoms in the
ring containing A does not exceed two;
iv) when X, Y and Z are CH; A is CH2, Q is
fused unsubstituted benzene; and R1 and R2 are H; then R3 is not unsubstituted phenyl; and
v) the compounds are other than 2-[4,6- bis (trichloromethyl)-1,3,5-triazin-2-yl]- 1,10-phenanthroline or 2-(2-pyridinyl)- 1,10-phenanthroline and at least one of (a) a surfactant, (b) an organic solvent, and (c) at least one solid or liquid diluent.
8. A method for controlling plant diseases caused by fungal plant pathogens comprising applying to the plant or portion thereof to be protected, or to the plant seed or seedling to be protected, an effective amount of a compound of Formula IA:
wherein:
X is N or CR4;
Y is N or CR5;
Z is N or CR6;
Q is a fused benzene, naphthalene, thiophene,
furan, pyrrole, pyridine or pyrimidine ring each optionally substituted with R7 and R8; A is a bridge -G1-G2-G3-G4-, wherein G1, G2, G3 or G4 are independently O, S(O)p, NR9, CR10R11, C(=O), a direct bond, or G1-G2, G2-G3 or G3-G4 may be taken together to form -CH=CH-; such that at least one of G1, G2, G3 and G4 is other than a direct bond;
R1, R2, R3 and R4 are independently H; halogen;
cyano; hydroxy; C1-C6 alkyl; C1-C4 haloalkyl; C1-C4 alkylthio; C1-C4 alkylsulfinyl; C1-C4 alkylsulfonyl; C3-C6 cycloalkyl optionally substituted with 1-2 methyl groups; C1-C4 alkoxy; C1-C4 haloalkoxy; C2-C4 alkoxyalkyl; C2-C4 alkenyl; C2-C4 haloalkenyl; C2-C4 alkenyloxy; C2-C4 alkynyl; C2-C4 alkynyloxy; NR12R13; phenyl or phenoxy optionally
substituted with R14; or R1 and R4, R2 and R4 or R2 and R5 can be taken together to form
-(CH2)3-, -(CH2)4- or a fused phenyl ring; R5 and R6 are independently H, halogen, C1-C2
alkyl or C1-C2 alkoxy;
R7 is halogen; cyano; nitro; hydroxy;
hydroxycarbonyl; C1-C6 alkyl; C1-C4 haloalkyl; C1-C4 alkylthio; C1-C4
alkylsulfinyl; C1-C4 alkylsulfonyl; (C1-C4 alkyl) 3silyl; C3-C6 cycloalkyl; C2-C5 alkylcarbonyl; C2-C4 alkenyl; C2-C4 alkenyloxy; C2-C4 alkynyl; C2-C4 alkynyloxy; C1-C4 alkoxy; C1-C4 haloalkoxy; C2-C4 alkoxyalkyl; C2-C5 alkoxycarbonyl; C2-C4 alkoxyalkoxy; NR15R16; C(=O)NR17R18; or phenyl, phenoxy or phenylthio each optionally substituted with R19;
R8 and R14 are independently 1-2 halogen, 1-2 C1-C3 alkyl, C1-C2 haloalkyl, C1-C2 alkoxy or C1-C2 haloalkoxy;
R9, R10 and R11 are independently H or C1-C2 alkyl; R12, R13, R15, R16, R17, and R18 are independently H or C1-C2 alkyl; or R12 and R13, R15 and R16 or R17 and R18 can be taken together with the nitrogen to which they are attached to form a piperidino, pyrrolidino or morpholino ring; R19 is halogen, C1-C2 alkyl, C1-C2 haloalkyl, C1-C2 alkoxy or C1-C2 haloalkoxy;
p is 0, 1 or 2;
or their agriculturally suitable salts or metal
complexes thereof;
provided that: i) when any of G1, G2, G3 or G4 are O, then they are not directly bonded to O or S(O)p;
ii) when any of G1, G2, G3 or G4 are S (O) or S(O)2, then they are not bonded directly to C(=O); and iii) the total number of heteroatoms in the ring containing A does not exceed two.
9. A method for controlling plant diseases caused by fungal plant pathogens comprising applying to the plant or portion thereof to be protected, or to the plant seed or seedling to be protected, an effective amount of a composition of Claim 7.
EP93902842A 1992-01-15 1992-12-30 Bridged heterocyclic fungicides Withdrawn EP0623125A1 (en)

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US821724 1992-01-15
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WO2009081222A1 (en) 2007-12-21 2009-07-02 Glenmark Pharmaceuticals, S.A. Substituted tricyclic pyridine or pyrimidine vanilloid receptor ligands
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KR101840313B1 (en) * 2011-02-14 2018-03-21 에스에프씨 주식회사 Pyridine derivative compound and organic electroluminescent device comprising the same
GB2503789A (en) * 2012-05-15 2014-01-08 Syngenta Participations Ag Quinazoline derivatives as antifungal agents
WO2013180376A1 (en) * 2012-05-30 2013-12-05 Alpha Chem Co., Ltd. New electron transport material and organic electroluminescent device using the same
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