WO2009158258A1 - Herbicidal dihydro oxo six-membered azinyl isoxazolines - Google Patents

Herbicidal dihydro oxo six-membered azinyl isoxazolines Download PDF

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Publication number
WO2009158258A1
WO2009158258A1 PCT/US2009/047725 US2009047725W WO2009158258A1 WO 2009158258 A1 WO2009158258 A1 WO 2009158258A1 US 2009047725 W US2009047725 W US 2009047725W WO 2009158258 A1 WO2009158258 A1 WO 2009158258A1
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methyl
compound
alkyl
formula
mmol
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PCT/US2009/047725
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French (fr)
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Brenton Todd Smith
Thomas Paul Selby
Thomas Martin Stevenson
David Alan Clark
Andrew Edmund Taggi
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E. I. Du Pont De Nemours And Company
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Publication of WO2009158258A1 publication Critical patent/WO2009158258A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms

Definitions

  • This invention relates to certain dihydro oxo azinyl isoxazoline compounds, their iV-oxides, salts and compositions, and methods of their use for controlling undesirable vegetation.
  • the control of undesired vegetation is extremely important in achieving high crop efficiency. Achievement of selective control of the growth of weeds especially in such useful crops as rice, soybean, sugar beet, maize, potato, wheat, barley, tomato and plantation crops, among others, is very desirable. Unchecked weed growth in such useful crops can cause significant reduction in productivity and thereby result in increased costs to the consumer. The control of undesired vegetation in noncrop areas is also important. Many products are commercially available for these purposes, but the need continues for new compounds that are more effective, less costly, less toxic, environmentally safer or have different sites of action.
  • U.S. Patent 7,238,689 discloses certain six-membered heterocyclic isoxazolines as herbicides, but not the present compounds.
  • This invention is directed to compounds of Formula 1 (including all geometric and stereoisomers), iV-oxides, and salts thereof, agricultural compositions containing them and their use as herbicides or plant growth regulators:
  • W2 is N or CR10b; provided that when Q2 is N, then W2 is CR10b; W3 is N or CR1 Oc; W4 is N or CR1 od;
  • Y1 is N or CR1 la; provided that when W1 is N, then Y1 is CR1 la; Y2 is N or CR1 lb; provided that when W2 is N, then Y2 is CR1 lb;
  • Y3 is N or CR1 lc; provided that when W3 is N, then Y3 is CR1 lc; Y4 is N or CR1 ld; m is 0, 1 or 2; n is 0 or 1 ; provided that the sum of n and m is not more than 2; R1 and R2 are independently H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, Q-C6 haloalkyl, C2-C6 haloalkenyl, CzpC6 alkylcycloalkyl or C 4- C6 cycloalkylalkyl; or
  • R1 and R2 are taken together with the carbon to which they are bonded to form a C3- C6 saturated carbocyclic ring optionally substituted by C1-C3 alkyl, halogen or C1-C3 haloalkyl;
  • R3 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C1-C6 haloalkyl, C2-C6 haloalkenyl, CzpC6 alkylcycloalkyl or CzpC6 cycloalkylalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkylthio, C1-C6 haloalkylthio, -SCN, halogen, cyano, nitro, azido, -CO2H or C2-C5 alkoxycarbonyl; R4 is H, C1-C6 alkyl, C1-C6 haloalkyl or halogen; or
  • R3 and R4 are taken together with the carbon to which they are bonded to form a saturated carbocyclic C3-C6 ring optionally substituted by C1-C3 alkyl, halogen or C1-C3 haloalkyl; or
  • R1 and R4 are taken together with the carbons to which they are bonded to form a C3- C7 saturated carbocyclic ring optionally substituted by C1-C3 alkyl, halogen or
  • R5 is H, C1-C2 alkyl, halogen, cyano or Q-C5 alkoxycarbonyl
  • R6 is H, C1-C2 alkyl or halogen
  • R5 and R6 are taken together with the carbon to which they are bonded to form a C3-
  • R7 is H, -CN, C2-C4 alkoxycarbonyl, Q-C4 alkylsulfonyl, C2-C4 alkylcarbonyl or C2-C4 haloalkylcarbonyl; each R8a, R8b, R8c and R8d is independently C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C3-C7 cycloalkyl, C1-C7 haloalkyl, C2-C7 haloalkenyl, C2-C7 alkoxyalkyl, C4 ⁇ C7 cycloalkylalkyl, C3-C7 haloalkynyl, C3-C7 alkylcarbonylalkyl, C3-C7 alkoxycarbonylalkyl, C4 ⁇ C7 halocycloalkylalkyl, C2- C7 haloalkoxyalkyl, C2-C7 alkylthioalkyl
  • each R17 is independently Q-C6 alkyl, halogen, Q-C4 alkoxy, Q-C4 haloalkyl or
  • each R18 is independently Q-C6 alkyl.
  • this invention pertains to a compound of Formula 1 (including all geometric and stereoisomers), an JV-oxide or a salt thereof.
  • This invention also relates to a herbicidal composition comprising a compound of Formula 1 wherein the sum of n and m is 1 or 2 (i.e. in a herbicidally effective amount), and (i.e. together with) at least one component selected from the group consisting of surfactants, solid diluents and liquid diluents.
  • This invention further relates to a method for controlling the growth of undesired vegetation comprising contacting the vegetation or its environment with a herbicidally effective amount of a compound of Formula 1 wherein the sum of n and m is 1 or 2 (e.g., as a composition described herein).
  • compositions comprising, “comprising,” “includes,” “including,” “has,” “having”, “contains” or “containing” or any other variation thereof, are intended to cover a non-exclusive inclusion.
  • a composition, process, method, article, or apparatus that comprises a list of elements is not necessarily limited to only those elements but may include other elements not expressly listed or inherent to such composition, process, method, article, or apparatus.
  • “or” refers to an inclusive or and not to an exclusive or.
  • a condition A or B is satisfied by any one of the following: A is true (or present) and B is false (or not present), A is false (or not present) and B is true (or present), and both A and B are true (or present).
  • the indefinite articles "a” and “an” preceding an element or component of the invention are intended to be nonrestrictive regarding the number of instances (i.e. occurrences) of the element or component. Therefore “a” or “an” should be read to include one or at least one, and the singular word form of the element or component also includes the plural unless the number is obviously meant to be singular.
  • seedling used either alone or in a combination of words means a young plant developing from the embryo of a seed.
  • narrowleaf ' used either alone or in words such as “broadleaf weed” means dicot or dicotyledon, a term used to describe a group of angiosperms characterized by embryos having two cotyledons.
  • alkylating agent refers to a chemical compound in which a carbon-containing radical is bound through a carbon atom to leaving group such as halide or sulfonate, which is displaceable by bonding of a nucleophile to said carbon atom. Unless otherwise indicated, the term “alkylating” does not limit the carbon-containing radical to alkyl; the carbon-containing radicals in alkylating agents include the variety of carbon-bound substituent radicals specified for R5 and R6.
  • alkyl used either alone or in compound words such as “alkylthio” or “haloalkyl” includes straight-chain or branched alkyl, such as, methyl, ethyl, n-propyl, /-propyl, or the different butyl, pentyl or hexyl isomers.
  • Alkenyl includes straight-chain or branched alkenes such as ethenyl, 1-propenyl, 2-propenyl, and the different butenyl, pentenyl and hexenyl isomers.
  • Alkenyl also includes polyenes such as 1 ,2-propadienyl and 2,4-hexadienyl.
  • Alkynyl includes straight-chain or branched alkynes such as ethynyl, 1-propynyl, 2-propynyl and the different butynyl, pentynyl and hexynyl isomers.
  • Alkynyl can also include moieties comprised of multiple triple bonds such as 2,5-hexadiynyl.
  • Alkoxy includes, for example, methoxy, ethoxy, n-propyloxy, isopropyloxy and the different butoxy, pentoxy and hexyloxy isomers.
  • Alkoxyalkyl denotes alkoxy substitution on alkyl. Examples of “alkoxyalkyl” include CH3OCH2, CH3OCH2CH2, CH3CH2OCH2, CH3CH2CH2CH2OCH2 and CH3CH2OCH2CH2.
  • alkoxyalkoxy denotes alkoxy substitution on alkoxy.
  • Alkenyloxy includes straight-chain or branched alkenyloxy moieties.
  • alkynyloxy includes straight-chain or branched alkynyloxy moieties. Examples of “alkynyloxy” include HC ⁇ CCH2O, CH3C ⁇ CCH2O and CH3C ⁇ CCH2CH2O.
  • Alkylthio includes branched or straight-chain alkylthio moieties such as methylthio, ethylthio, and the different propylthio, butylthio, pentylthio and hexylthio isomers.
  • Alkylsulfinyl includes both enantiomers of an alkylsulfinyl group.
  • alkylsulfinyl examples include CH3S(O)-, CH3CH2S(O)-, CH3CH2CH2S(O)-, (CH3)2CHS(O)- and the different butylsulfinyl, pentylsulfinyl and hexylsulf ⁇ nyl isomers.
  • alkylsulfonyl examples include CH3S(O)2-, CH3CH2S(O)2-,
  • alkylthioalkyl denotes alkylthio substitution on alkyl.
  • alkylthioalkyl include CH3SCH2, CH3SCH2CH2, CH3CH2SCH2, CH3CH2CH2CH2SCH2 and CH3CH2SCH2CH2.
  • alkylthioalkoxy denotes alkylthio substitution on alkoxy.
  • Cyanoalkyl denotes an alkyl group substituted with one cyano group. Examples of “cyanoalkyl” include NCCH2, NCCH2CH2 and CH3CH(CN)CH2.
  • Alkylamino "dialkylamino”, and the like, are defined analogously to the above examples.
  • Cycloalkyl includes, for example, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • alkylcycloalkyl denotes alkyl substitution on a cycloalkyl moiety and includes, for example, ethylcyclopropyl, z-propylcyclobutyl, 3-methylcyclopentyl and 4-methylcyclohexyl.
  • cycloalkylalkyl denotes cycloalkyl substitution on an alkyl moiety.
  • cycloalkylalkyl examples include cyclopropylmethyl, cyclopentylethyl, and other cycloalkyl moieties bonded to straight-chain or branched alkyl groups.
  • cycloalkoxy denotes cycloalkyl linked through an oxygen atom such as cyclopentyloxy and cyclohexyloxy.
  • Cycloalkylalkoxy denotes cycloalkylalkyl linked through an oxygen atom attached to the alkyl chain.
  • cycloalkylalkoxy examples include cyclopropylmethoxy, cyclopentylethoxy, and other cycloalkyl moieties bonded to straight-chain or branched alkoxy groups.
  • cyanoalkoxy denotes a NC- moiety attached to an alkoxy group. Examples of cyanoalkoxy include NCCH2O-, NCCH2CH2O- or CH3CH(CN)CH2O-.
  • alkoxycarbonylalkoxy denotes and ester group attached to an alkoxy group. Examples of alkoxycarbonylalkoxy include CH3O2CCH2O-, CH3O2CCH2CH2O-, CH3CH2O2CCH2O-.
  • alkoxyhaloalkyl denotes an alkoxy group attached to a haloalkyl group.
  • alkoxyhaloalkyl examples include CH3OCF2O-, CH3CH2OCHFO-, or CH3CH2OCCl2O-.
  • halogen either alone or in compound words such as “haloalkyl”, or when used in descriptions such as “alkyl substituted with halogen” includes fluorine, chlorine, bromine or iodine. Further, when used in compound words such as “haloalkyl”, or when used in descriptions such as “alkyl substituted with halogen” said alkyl may be partially or fully substituted with halogen atoms which may be the same or different. Examples of “haloalkyl” or “alkyl substituted with halogen” include F3C-, ClCH2-, CF3CH2- and CF3CCl2-.
  • halocycloalkyl haloalkoxy
  • haloalkyl haloalkyl
  • haloalkoxy include CF3O-, CCl3CH2O-, HCF2CH2CH2O- and CF3CH2O-.
  • haloalkylthio include CCl3S-, CF3S-, CCl3CH2S- and ClCH2CH2CH2S-.
  • haloalkylsulfmyl examples include CF3S(O)-, CCl3S(O)-, CF3CH2S(O)- and CF3CF2S(O)-.
  • haloalkylsulfonyl examples include CF3S(O)2-, CCl3S(O)2-, CF3CH2S(O)2- and CF3CF2S(O)2-.
  • haloalkynyl examples include HC ⁇ CCHCl-, CF3C ⁇ C-, CC13C ⁇ C- and FCH2C ⁇ CCH2-.
  • haloalkoxyalkoxy examples include CF3OCH2O-, CICH2CH2OCH2CH2O-, Cl3CCH2OCH2O- as well as branched alkyl derivatives.
  • alkylcarbonyl include CH3C(K))-, CH3CH2CH2C(K))- and
  • alkoxycarbonyl examples include CH3OC(O)-, CH3CH2OC(O)-,
  • C1-C4 alkylsulfonyl designates methylsulfonyl through butylsulfonyl
  • C2 alkoxyalkyl designates CH3OCH2-
  • C3 alkoxyalkyl designates, for example, CH3CH(OCH3)-, CH3OCH2CH2- or CH3CH2OCH2-
  • C4 alkoxyalkyl designates the various isomers of an alkyl group substituted with an alkoxy group containing a total of four carbon atoms, examples including CH3CH2CH2OCH2- and CH3CH2OCH2CH2-.
  • a “ring” or “ring system” as a component of Formula 1 is carbocyclic or heterocyclic.
  • the term “ring system” denotes two or more fused rings.
  • the terms “carbocyclic ring” or “carbocycle” denotes a ring wherein the atoms forming the ring backbone are selected only from carbon.
  • “Saturated carbocyclic” refers to a ring having a backbone consisting of carbon atoms linked to one another by single bonds; unless otherwise specified, the remaining carbon valences are occupied by hydrogen atoms.
  • the terms “heterocyclic ring”, “heterocycle” or “heterocyclic ring system” denote a ring or ring system in which at least one atom forming the ring backbone is not carbon, e.g., nitrogen, oxygen or sulfur.
  • an optionally substituted group may have a substituent at each substitutable position of the group, and each substitution is independent of the other.
  • Z can be (among others) a 5- or 6-membered heterocyclic ring, which may be saturated or unsaturated, optionally substituted with up to two substituents selected from a group of substituents as defined in the Summary of the Invention.
  • Examples of a 5- or 6-membered fully unsaturated aromatic heterocyclic ring optionally substituted with from up to two substituents include the rings U-2 through U-61 illustrated in Exhibit 1 wherein Rv is any substituent as defined in the Summary of the Invention for Z (i.e. R17 on carbon ring members and R18 on nitrogen ring members) and r is an integer from 0 to 2, limited by the number of available positions on each U group.
  • r is limited to the integers 0 or 1 , and r being 0 means that the U group is unsubstituted and a hydrogen is present at the position indicated by (Rv)r.
  • Examples of saturated or partially unsaturated 5- or 6-membered heterocyclic rings include the rings G-I through G-35 as illustrated in Exhibit 2. Note that when the attachment point on the G group is illustrated as floating, the G group can be attached to the remainder of Formula 1 through any available carbon or nitrogen of the G group by replacement of a hydrogen atom. The optional substituents corresponding to Rv can be attached to any available carbon or nitrogen by replacing a hydrogen atom.
  • r is an integer from 0 to 2, limited by the number of available positions on each G group.
  • Z is a 5- or 6-membered heterocyclic ring optionally substituted with up to two substituents selected from the group of substituents as defined in the Summary of the Invention for Z
  • one or two carbon ring members of the heterocycle can optionally be in the oxidized form of a carbonyl moiety.
  • Z comprises a ring selected from G-28 through G-35
  • G2 is selected from O, S or N.
  • G2 is N
  • the nitrogen atom can complete its valence by substitution with either H or the substituents corresponding to Rv as defined in the Summary of the Invention for Z (i.e. R17 on carbon ring members and R18 on nitrogen ring members).
  • Compounds of this invention can exist as one or more stereoisomers.
  • the various stereoisomers include enantiomers, diastereomers, atropisomers and geometric isomers.
  • m 1, the compounds of the invention are sulfoxides, which can exist in two enantiomeric forms.
  • the adjacent carbon i.e. -CR6R7-
  • one stereoisomer may be more herbicidally active and/or may exhibit beneficial effects when enriched relative to the other stereoisomer(s) or when separated from the other stereoisomer(s).
  • the skilled artisan knows how to separate, enrich, and/or to selectively prepare said stereoisomers.
  • the compounds of the invention may be present as a mixture of stereoisomers, individual stereoisomers or as an optically active form.
  • Synthetic methods for the preparation of iV-oxides of heterocycles and tertiary amines are very well known by one skilled in the art including the oxidation of heterocycles and tertiary amines with peroxy acids such as peracetic and m-chloroperbenzoic acid (MCPBA), hydrogen peroxide, alkyl hydroperoxides such as t-butyl hydroperoxide, sodium perborate, and dioxiranes such as dimethyldioxirane.
  • MCPBA peroxy acids
  • alkyl hydroperoxides such as t-butyl hydroperoxide
  • sodium perborate sodium perborate
  • dioxiranes such as dimethyldioxirane
  • salts of chemical compounds are in equilibrium with their corresponding nonsalt forms, salts share the biological utility of the nonsalt forms.
  • the salts of the compounds of Formula 1 include acid-addition salts with inorganic or organic acids such as hydrobromic, hydrochloric, nitric, phosphoric, sulfuric, acetic, butyric, fumaric, lactic, maleic, malonic, oxalic, propionic, salicylic, tartaric, 4-toluenesulfonic or valeric acids.
  • salts also include those formed with organic or inorganic bases such as pyridine, triethylamine or ammonia, or amides, hydrides, hydroxides or carbonates of sodium, potassium, lithium, calcium, magnesium or barium. Accordingly, the present invention comprises compounds selected from Formula 1, JV-oxides and agriculturally suitable salts thereof.
  • Non-crystalline forms include embodiments which are solids such as waxes and gums as well as embodiments which are liquids such as solutions and melts.
  • Crystalline forms include embodiments which represent essentially a single crystal type and embodiments which represent a mixture of polymorphs (i.e. different crystalline types).
  • polymorph refers to a particular crystalline form of a chemical compound that can crystallize in different crystalline forms, these forms having different arrangements and/or conformations of the molecules in the crystal lattice.
  • polymorphs can have the same chemical composition, they can also differ in composition due the presence or absence of co- crystallized water or other molecules, which can be weakly or strongly bound in the lattice. Polymorphs can differ in such chemical, physical and biological properties as crystal shape, density, hardness, color, chemical stability, melting point, hygroscopicity, suspensibility, dissolution rate and biological availability.
  • a polymorph of a compound represented by Formula 1 can exhibit beneficial effects (e.g., suitability for preparation of useful formulations, improved biological performance) relative to another polymorph or a mixture of polymorphs of the same compound represented by Formula 1.
  • Preparation and isolation of a particular polymorph of a compound represented by Formula 1 can be achieved by methods known to those skilled in the art including, for example, crystallization using selected solvents and temperatures.
  • each R9a, R9b, R9c, R9d, R1Oa, R10b, R1Oc, R10d, Rlla, Rllb, Rllc and Rlld is other than Z).
  • a herbicidal composition comprising (a herbicidally effective amount of) a compound selected from Formula 1, JV-oxides, and salts thereof wherein the sum of n and m is 1 or 2, and each R9a, R9b, R9c, R9d, R1Oa, R10b, R1Oc, R10d, Rlla, Rllb, Rllc and Rlld is other than Z; and at least one component selected from the group consisting of surfactants, solid diluents and liquid diluents.
  • said herbicidal composition further comprising (an effective amount of) at least one additional active ingredient selected from the group consisting of other herbicides and herbicide safeners.
  • a method for controlling the growth of undesired vegetation comprising contacting the vegetation or its environment with a herbicidally effective amount of a compound selected from Formula 1, JV-oxides, and salts thereof wherein the sum of n and m is 1 or 2, and each R9a, R9b, R9c, R9d, R1Oa, R10b, R1Oc, R10d, Rlla, Rllb, Rllc and R1 ld is other than Z.
  • Embodiments of the present invention as described in the Summary of the Invention include those described below.
  • Formula 1 includes iV-oxides and salts thereof, and reference to "a compound of Formula 1" includes the definitions of substituents specified in the Summary of the Invention unless further defined in the Embodiments.
  • Embodiment 1 A compound of Formula 1 wherein R1 is methyl, ethyl, fluoromethyl (i.e. monofluoromethyl), hydroxymethyl or chloromethyl (i.e. monochloromethyl) .
  • Embodiment 2 A compound of Embodiment 1 wherein R1 is methyl, fluoromethyl or chloromethyl.
  • Embodiment 3 A compound of Embodiment 2 wherein R1 is methyl or chloromethyl
  • Embodiment 4 A compound of Embodiment 3 wherein R1 is methyl.
  • Embodiment 5. A compound of Embodiment 3 wherein R1 is chloromethyl.
  • Embodiment 6. A compound of Formula 1 or any one of Embodiments 1 through 5 wherein R2 is methyl.
  • Embodiment 7 A compound of Formula 1 or any one of Embodiments 1 through 6 wherein R3 is H, F or Br.
  • Embodiment 8 A compound of Embodiment 7 wherein R3 is F or Br.
  • Embodiment 9 A compound of Embodiment 7 wherein R3 is H.
  • Embodiment 10 A compound of Formula 1 or any one of Embodiments 1 through 9 wherein R4 is H.
  • Embodiment 11 A compound of Formula 1 or any one of Embodiments 1 through 10 wherein R5 is H, CH3 or F.
  • Embodiment 12 A compound of Embodiment 11 wherein R5 is F.
  • Embodiment 13 A compound of Embodiment 11 wherein R5 is H.
  • Embodiment 14 A compound of Formula 1 or any one of Embodiments 1 through 13 wherein R6 is H.
  • Embodiment 15 A compound of Formula 1 or any one of Embodiments 1 through 14 wherein the sum of n + m is greater than 0. Embodiment 16. A compound of Formula 1 or any one of Embodiments 1 through 15 wherein n is 0. Embodiment 17. A compound of Formula 1 or any one of Embodiments 1 through 15 wherein m is 1 or 2.
  • Embodiment 18 A compound of Embodiment 17 wherein m is 1.
  • Embodiment 19 A compound of Embodiment 17 wherein m is 2.
  • Embodiment 20 A compound of Formula 1 or any one of Embodiments 1 through 14 wherein n and m are both 0.
  • Embodiment 21 A compound of Formula 1 or any one of Embodiments 1 through 20 wherein J is J-I, J-2 or J-3.
  • Embodiment 22 A compound of Embodiment 21 wherein J is J-I or J-2.
  • Embodiment 23 A compound of Embodiment 20 wherein J is J-I .
  • Embodiment 24 A compound of Formula 1 or any one of Embodiments 1 through 23 wherein independently R8a, R8b, R8c and R8d are C1-C4 alkyl, C1-C4 haloalkyl,
  • Embodiment 25 A compound of Embodiment 24 wherein independently R8a, R8b, R8c and R8d are CH3, CH2CH3, CH2CF3, CH2OCH3, n-propyl or CH2C ⁇ CH.
  • Embodiment 26 A compound of Embodiment 25 wherein independently R8a, R8b, R8c and R8d are CH3, CH2CH3 or CH2CF3.
  • Embodiment 26a A compound of Embodiment 26 wherein R8a, R8b, R8c and R8d are
  • Embodiment 27 A compound of Formula 1 or any one of Embodiments 1 through 22 wherein independently R9a, R9b, R9c, R9d, Rllc and Rlld are H, halogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 cycloalkyl, C2-C6 alkoxyhaloalkyl or phenyl substituted with up to one R16.
  • R9a, R9b, R9c, R9d, Rllc and Rlld are H, halogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 cycloalkyl, C2-C6 alkoxyhaloalkyl or phenyl substituted with up to one R16.
  • Embodiment 29. A compound of Embodiment 28 wherein independently R9a, R9b, R9c,
  • R9d, Rllc and Rlld are CF3, Br, OCHF2 or OCH2CF3.
  • Embodiment 29a A compound of Embodiment 27 wherein R9a is CH3, CF3, CF2Cl or CF2OCH3.
  • Embodiment 29b A compound of Embodiment 29a wherein R9a, R9b, R9c and R9d are CF3.
  • Embodiment 30 A compound of Formula 1 or any one of Embodiments 1 through 29 wherein independently R1Oa, R10b, R1Oc, R10d, Rlla and Rllb are H, C1-C7 alkyl, C3-C7 cycloalkyl, C1-C7 haloalkyl, C2-C7 haloalkenyl, C3-C7 haloalkynyl, C1-C7 alkoxy, C1-C7 haloalkoxy, C3-C7 cycloalkoxy, C 4-C7 cycloalkylalkoxy, C1-C7 alkylthio, C1-C6 alkylamino, C1-C7 haloalkylamino,
  • Embodiment 31 A compound of Formula 1 or any one Embodiments 1 through 30 wherein independently R1Oa, R10b, R1Oc, R10d, Rlla and Rllb are H, CH3, CH2CH3, cyclopropyl, OCH3, OCH2CH3 or SCH3.
  • Embodiment 31a A compound of Embodiment 31 wherein R1Oa is H, CH3, CH2CH3, cyclopropyl, OCH3 or OCH2CH3.
  • Embodiment 31b A compound of Embodiment 31a wherein R1Oa is CH3, cyclopropyl
  • Embodiment 32 A compound of Formula 1 or any one of Embodiments 1 through 31 wherein independently Rlla and Rllb are H.
  • Embodiment 33 A compound of Formula 1 or any one of Embodiments 1 through 32 wherein independently Q1 is CR9a, Q2 is CR9b, Q3 is CR9c and Q4 is CR9d.
  • Embodiment 34 A compound of Formula 1 or any one of Embodiments 1 through 33 wherein when J is J-I , then Q1 is CR9a, W1 is CR1Oa and Y1 is N, or Q1 is CR9a,
  • W1 is N and Y1 is CRlla, or Q1 is CR9a, W1 is CR1Oa and Y1 is CRlla.
  • Embodiment 35 A compound of Embodiment 34 wherein when J is J-I, then Q1 is CR9a, W1 is CR1Oa and Y1 is N, or Q1 is CR9a, W1 is N and Y1 is CRlla.
  • Embodiment 36 A compound of Embodiment 35 wherein when J is J-I, then Q1 is
  • Embodiment 37 A compound of Embodiment 35 wherein when J is J-I, then Q1 is
  • Embodiment 38 A compound of Formula 1 or any one of Embodiments 1 through 37 wherein when J is J-2, then Q2 is CR9b, W2 is CR10b and Y2 is N, or Q2 is CR9b,
  • W2 is N and Y2 is CRllb, or Q2 is CR9b, W2 is R10b and Y2 is CRllb.
  • Embodiment 39 A compound of Embodiment 38 wherein when J is J-2, then Q2 is
  • Embodiment 40 A compound of Embodiment 39 wherein when J is J-2, then Q2 is CR9b, W2 is CR10b and Y2 is N, or Q2 is CR9b, W2 is N and Y2 is CR1 lb.
  • Embodiment 40 A compound of Embodiment 39 wherein when J is J-2, then Q2 is
  • Embodiment 41 A compound of Embodiment 39 wherein when J is J-2, then Q2 is
  • Embodiment 42 A compound of Formula 1 or any one of Embodiments 1 through 41 wherein when J is J-3, then Q3 is CR9c, W3 is N and Y3 is CRllc, or Q3 is CR9c,
  • W3 is CR1Oc and Y3 is CRllc.
  • Embodiment 43 A compound of Embodiment 42 wherein when J is J-3, then Q3 is
  • W3 is CR1Oc and Y3 is CRllc.
  • Embodiment 44 A compound of Formula 1 or any one of Embodiments 1 through 43 wherein when J is J-4, then Q4 is CR9d, W4 is N and Y4 is CR1 ld, or Q4 is CR9d,
  • W4 is CR10d and Y4 is CRlld.
  • Embodiment 45 A compound of Embodiment 44 wherein when J is J-4, then Q4 is
  • W4 is CR10d and Y4 is CRlld.
  • Embodiment 46 A compound of Formula 1 or any of Embodiments 1 through 45 wherein each R12 is independently H or CH3.
  • Embodiment 47 A compound of Formula 1 or any of Embodiments 1 through 46 wherein each R13 is independently H, CH3 or OCH3.
  • Embodiment 49 A compound of Formula 1 or any of Embodiments 1 through 48 wherein each R14 is CH3.
  • Embodiment 50. A compound of Formula 1 or any of Embodiments 1 through 49 wherein each R15 is H.
  • Embodiment 52 A compound of Formula 1 or any of Embodiments 1 through 51 wherein each R16 is independently C1-C6 alkyl or halogen.
  • Embodiment 53 A compound of Formula 1 or any of Embodiments 1 through 52 wherein each R17 is independently C1-C6 alkyl or halogen.
  • Embodiment 54 A compound of Formula 1 or any of Embodiments 1 through 52 wherein each R18 is independently CH3 or CH2CH3.
  • Embodiment 55 A compound of Formula 1 or any one of Embodiments 1 through 53 wherein each R9a, R9b, R9c, R9d, R1Oa, R10b, R1Oc, R10d, Rlla, Rllb, Rllc and R1 ld is other than Z.
  • Embodiments of this invention including Embodiments 1-55 above as well as any other embodiments described herein, can be combined in any manner, and the descriptions of variables in the embodiments pertain not only to the compounds of Formula 1 but also to the starting compounds and intermediate compounds useful for preparing the compounds of Formula 1.
  • embodiments of this invention, including Embodiments 1-55 above as well as any other embodiments described herein, and any combination thereof, pertain to the compositions and methods of the present invention.
  • Embodiment A A compound of Formula 1 wherein
  • R1 is methyl, ethyl, fluoromethyl, hydroxymethyl or chloromethyl;
  • R2 is methyl;
  • R5 is H, CH3 or F;
  • R6 is H;
  • n is 0;
  • m is 1 or 2;
  • R8a, R8b, R8c and R8d are C1-C4 alkyl, C1-C4 haloalkyl, C2-C4 alkyloxyalkyl or
  • R9a, R9b, R9c, R9d, Rllc and Rlld are H, halogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 cycloalkyl, C2-C6 alkoxyhaloalkyl or phenyl substituted with up to one R16;
  • Embodiment B A compound of Formula 1 or Embodiment A wherein R1 is methyl, fluoromethyl or chloromethyl;
  • R8a is CH3, CH2CH3, CH2CF3, CH2OCH3, n-propyl or CH2C ⁇ CH;
  • Q1 is CR9a, W1 is CR1Oa and Y1 is N, or
  • Q1 is CR9a, W1 is N and Y1 is CRlla;
  • R9a is CH3, CF3, CF2Cl or CF2OCH3; and R1Oa is H, CH3, CH2CH3, cyclopropyl, OCH3 or OCH2CH3.
  • Embodiment C A compound of Formula 1 or Embodiment B wherein
  • Q1 is CR9a, W1 is CR1Oa and Y1 is N; R8a is CH3
  • R9a is CF3
  • R1Oa is CH3, cyclopropyl or OCH3.
  • Specific embodiments include compounds of Formula 1 selected from the group consisting of: 5-[[(4,5-dihydro-5,5-dimethyl-3-isoxazolyl)sulfonyl]methyl]-2,3-dimethyl-6-
  • Embodiments of the present invention as described in the Summary of the Invention also include those described below.
  • Formula 1 includes N- oxides and salts thereof, and reference to "a compound of Formula 1" includes the definitions of substituents specified in the Summary of the Invention unless further defined in the Embodiments.
  • Embodiment Dl A compound of Formula 1 wherein R1 is methyl or chloromethyl (i.e. monochloromethyl) .
  • Embodiment D2 A compound of Embodiment 1 wherein R1 is methyl.
  • Embodiment D3. A compound of Embodiment 1 wherein R1 is chloromethyl.
  • Embodiment D4. A compound of Formula 1 or any one of Embodiments Dl through
  • Embodiment D5 A compound of Formula 1 or any one of Embodiments Dl through
  • Embodiment D6 A compound of Formula 1 or any one of Embodiments Dl through D5 wherein R4 is H.
  • Embodiment D7 A compound of Formula 1 or any one of Embodiments Dl through
  • Embodiment D8 A compound of Formula 1 or any one of Embodiments Dl through
  • Embodiment D9 A compound of Formula 1 or any one of Embodiments Dl through
  • Embodiment DlO A compound of Formula 1 or any one of Embodiments Dl through
  • Embodiment DI l A compound of Embodiment DlO wherein m is 2.
  • Embodiment D 12. A compound of Embodiment DlO wherein m is 1.
  • Embodiment D13 A compound of Formula 1 or any one of Embodiments Dl through
  • Embodiment D 8 wherein n and m are both 0.
  • Embodiment D 14 A compound of Formula 1 or any one of Embodiments Dl through
  • Embodiment D15 A compound of Formula 1 or any one of Embodiments Dl through
  • Embodiment D 16 A compound of Formula 1 or any one of Embodiments Dl through
  • J is J-I, J-3 or J-4.
  • Embodiment D 17 A compound of Formula 1 or any one of Embodiments Dl through D13 wherein J is J-2, J-3 or J-4.
  • Embodiment D 18 A compound of Formula 1 or any one of Embodiments Dl through
  • Embodiment D 13 wherein J is J-I.
  • Embodiment D 19 A compound of Formula 1 or any one of Embodiments Dl through
  • Embodiment D20 A compound of Formula 1 or any one of Embodiments Dl through
  • Embodiment D21 A compound of Formula 1 or any one of Embodiments Dl through
  • Embodiment D21 wherein independently R8a, R8b, R8c and R8d are C1-C2 alkyl.
  • Embodiment D23 A compound of Formula 1 or any one of Embodiments Dl through
  • R9a, R9b, R9c, R9d, Rllc and Rlld are CF3, OCHF2, OCH2CF35 F, Br or CL
  • Embodiment D24 A compound of Embodiment D23 wherein independently R9a, R9b,
  • R9c, R9d, Rllc and Rlld are CF3, OCHF2, OCH2CF3 or CL Embodiment D25.
  • R1Oa, R10b, R1Oc, R10d Rlla and Rllb are H, CH3, CH2CH3, cyclopropyl, OCH3 or OCH2CH3.
  • Embodiment D26 A compound of Formula 1 or any one of Embodiments Dl through
  • Embodiment D27 A compound of Formula 1 or any one of Embodiments Dl through
  • Embodiment D28 wherein independently Q1 is CR9a, Q2 is CR9b, Q3 is CR9c and Q4 is CR9d.
  • Embodiment D28 A compound of Formula 1 or any one of Embodiments Dl through
  • CR1Oa and Y1 is N, or Q1 is CR9a, W1 is N and Y1 is CRlla, or Q1 is CR9a, W1 is CR1 ⁇ aM Y1 is CR1 la.
  • Embodiment D29 A compound of Embodiment D28 wherein when J is J-I, then Q1 is CR9a, W1 is CR1Oa and Y1 is N, or Q1 is CR9a, W1 is N and Y1 is CR1 la.
  • Embodiment D30 A compound of Embodiment D29 wherein when J is J-I, then Q1 is
  • Embodiment D31 A compound of Embodiment D29 wherein when J is J- 1 , then Q l is
  • Embodiment D32 A compound of Formula 1 or any one of Embodiments Dl through
  • W2 is CR10b and Y2 is N, or Q2 is CR9b, W2 is N and Y2 is CR1 lb, or Q2 is
  • W2 is R10b and Y2 is CRllb.
  • Embodiment D33 A compound of Embodiment D32 wherein when J is J-2, then Q2 is CR9b, W2 is CR10b and Y2 is N, or Q2 is CR9b, W2 is N and Y2 is CR1 lb.
  • Embodiment D34 A compound of Embodiment D33 wherein when J is J-2, then Q2 is
  • Embodiment D35 A compound of Embodiment D33 wherein when J is J-2, then Q2 is
  • Embodiment D36 A compound of Formula 1 or any one of Embodiments Dl through
  • Q3 is CR9c
  • W3 is N and Y3 is CRllc
  • Q3 is CR9c
  • W3 is CR1Oc
  • Y3 is
  • Embodiment D37 A compound of Embodiment D36 wherein when J is J-3, then Q3 is
  • Embodiment D38 A compound of Formula 1 or any one of Embodiments Dl through D 13, D15 through D 17, and D21 through D27 wherein when J is J-4, then Q4 is CR9d, W4 is N and Y4 is CR1 ld, or Q4 is CR9d, W4 is CR10d and Y4 is CR1 ld.
  • Embodiment D39 A compound of Embodiment D38 wherein when J is J-4, then Q4 is
  • W4 is N and Y4 is CR1 ld.
  • Embodiment D40 A compound of Formula 1 or any one of Embodiments Dl through D39 wherein each R9a, R9b, R9c, R9d, R1Oa, R10b, R1Oc, R10d, Rlla, Rllb, Rllc and R11 d is other than Z .
  • Embodiments of this invention can be combined in any manner, and the descriptions of variables in the embodiments pertain not only to the compounds of Formula 1 but also to the starting compounds and intermediate compounds useful for preparing the compounds of Formula 1.
  • embodiments of this invention including Embodiments D1-D40 above as well as any other embodiments described herein, and any combination thereof, pertain to the compositions and methods of the present invention. Combinations of Embodiments D1-D40 are illustrated by:
  • Embodiment EA A compound of Formula 1 wherein R1 is methyl, R2 is methyl, R3 is H and R4 is H.
  • Embodiment EB A compound of Formula 1 wherein R1 is methyl, R2 is chloromethyl,
  • R3 is H and R4 is H.
  • Specific embodiments include compounds of Formula 1 selected from the group consisting of: 5-[[(4,5-dihydro-5,5-dimethyl-3-isoxazolyl)sulfinyl]methyl]-2-methoxy-3-methyl-6-
  • This invention also relates to a method for controlling undesired vegetation comprising applying to the locus of the vegetation herbicidally effective amounts of the compounds of the invention (e.g., as a composition described herein).
  • the compounds of the invention e.g., as a composition described herein.
  • embodiments relating to methods of use are those involving the compounds of embodiments described above.
  • herbicidal compositions of the present invention comprising the compounds of embodiments described above.
  • One or more of the following methods and variations as described in Schemes 1-10 can be used to prepare the compounds of Formula 1.
  • the definitions of J, R1, R2, R3, R4, R5, R6, R8, R9, R10, R11, m and n in the compounds of Formulae 1-42 below are as defined above in the Summary of the Invention unless otherwise noted.
  • Formulae Ia-Ie are various subsets of Formula 1, and all substituents for Formulae Ia-Ie are as defined above for Formula 1 unless otherwise noted.
  • Sulfoxides and sulfones of Formula 1 where m is 1 or 2 and n is 0 can be made via oxidation of the linking sulfur atom on sulfides of Formula Ia (i.e. Formula 1 where m and n are both 0).
  • compounds of Formula Ib i.e. Formula 1 wherein n is 0
  • m is 1 (i.e. sulfoxides) or 2 (i.e. sulfones) are prepared by oxidizing sulfides of Formula Ia with a suitable oxidizing agent.
  • an oxidizing agent in an amount from 1 to 4 equivalents depending on the oxidation state of the product desired is added to a solution of the compound of Formula Ia in a solvent.
  • Useful oxidizing agents include Oxone® (potassium peroxymonosulfate), hydrogen peroxide, sodium periodate, peracetic acid and 3-chloroperbenzoic acid.
  • the solvent is selected with regard to the oxidizing agent employed.
  • Aqueous ethanol or aqueous acetone is preferably used with potassium peroxymonosulfate, and dichloromethane is generally preferable with 3-chloroperbenzoic acid.
  • Useful reaction temperatures typically range from 0 to 90 0C. Particular procedures useful for oxidizing sulfides to sulfoxides and sulfones are described by Brand et al, J. Agric. Food Chem. 1984, 32, 221-226 and references cited therein.
  • sulfoximines of Formula Ic can be prepared from corresponding sulfoxides of Formula Ib (i.e. Formula 1 where m is 1 and n is 0) by treatment with hydrazoic acid.
  • the hydrazoic acid is conveniently generated in situ from sodium azide and sulfuric acid.
  • sodium azide is added to a mixture of a sulfoxide, concentrated sulfuric acid and a suitable solvent for the sulfoxide such as dichloromethane or chloroform.
  • Useful temperatures range from room temperature to the reflux temperature of the solvent.
  • substituted sulfoximines of Formula Id can be prepared from corresponding sulfoximines of Formula Ic by reaction with an appropriate electrophilic reactant comprising R7.
  • electrophilic reactant comprising R7 means a reactant capable of transferring R7 to form a bond with a nucleophile (in this case the sulfoximine nitrogen).
  • electrophilic reactants comprising R7 correspond to the formula R7X1 wherein X1 is a nucleophilic reaction leaving group, also known as a nucleofuge. Common nucleofuges, i.e.
  • X1 include, for example, halides such as Cl, Br and I, and sulfonates such as methanesulfonate, trifluoromethanesulfonate and 4-methylbenzenesulfonate.
  • Reactions with electrophilic reactants of the formula R7X1 are often conducted in the presence of a base as well as a solvent.
  • reaction of a compound of Formula Ic with cyanogen bromide (BrCN) in the presence of base gives the compound of Formula Id where R7 is cyano.
  • reaction of a compound of Formula Ic with an alkylcarbonyl halide, an alkoxycarbonyl halide or an alkylsulfonyl halide in the presence of a base gives the corresponding compound of Formula Id where R7 is alkylcarbonyl, alkoxycarbonyl or alkylsulfonyl, respectively.
  • sulf ⁇ limines of Formula Ie i.e. Formula 1 where m is 0, n is 1 and R7 is cyano or a radical bonded through a carbonyl or sulfonyl moiety
  • a sulfide of Formula Ia with a compound of formula R7NF ⁇ in the presence of a suitable oxidizing agent such as iodobenzene diacetate in a solvent such as dichloromethane.
  • the starting compound of Formula 1 (wherein at least one of R5 and R6 is hydrogen and the sum of m and n is greater than 0) is reacted with a suitable base such as sodium hydroxide, sodium hydride, potassium t-butoxide or n-butyllithium in an appropriate solvent include, for example, tetrahydrofuran, diethyl ether, dioxane, dichloromethane or JV,iV-dimethylformamide.
  • a suitable base such as sodium hydroxide, sodium hydride, potassium t-butoxide or n-butyllithium
  • an appropriate solvent include, for example, tetrahydrofuran, diethyl ether, dioxane, dichloromethane or JV,iV-dimethylformamide.
  • electrophilic reactants i.e. alkylating agents
  • the amount of base and alkylating agents required in this reaction will depend on whether the starting compound of Formula 1 in Scheme 5 is to be monoalkylated (to obtain a compound of Formula 1 where at least one R5 or R6 is other than H) or dialkylated (to obtain a compound of Formula 1 where both R5 or R6 are other than H).
  • the reaction is typically run at temperatures ranging from -78 0C to the reflux temperature of the solvent, depending upon the base and solvent used. Examples of reactions analogous to those shown in Scheme 5 are described by A. Volonterio et al, Tetrahedron Letters 2005, 46(50), 8723-8726 and S. Ostrowski et al., Heterocycles 2005, 65(10), 2339-2346.
  • sulfides of Formula Ia can be made by the reaction of a isoxazoline isothiourea salt of Formula 2 (where X2 is a chloride or bromide counterion) with a heterocyclic alkyl electrophile of Formula 3 wherein X3 is leaving group such as a halogen or a sulfonate (e.g., methanesulfonate) in the presence of excess base in a suitable solvent.
  • a halogen or a sulfonate e.g., methanesulfonate
  • the isothiourea salt of Formula 2 (which can be regarded as a protected form of a thiol nucleophile) and an electrophilic agent of Formula 3 are combined in a suitable solvent such as acetonitrile, ethanol, tetrahydrofuran, dioxane, dichloromethane, N, ⁇ /-dimethylformamide or toluene followed by the addition of base such as potassium carbonate, sodium hydride, sodium or potassium hydroxide, pyridine, lithium diisopropylamide or triethylamine.
  • the reaction can be run under a wide range of temperatures, with optimum temperatures typically ranging from 0 0C to the reflux temperature of the solvent.
  • at least two equivalents of base are used for neutralizing the two equivalents of acid (i.e. (HX2), and (HX3),) that is generated in this reaction.
  • Isoxazoline isothiourea salts of Formula 2 can be prepared by the method reported in U.S. Patent Publication US 2007/0185334 Al and European Patent Publication
  • sulfides of Formula Ia can be prepared by the method illustrated in Scheme 7, in which isoxazolines of Formula 4 wherein X4 is a suitable leaving group, such as halogen or methanesulfonate are allowed to react with a heterocyclic alkylisothiourea salt of Formula 5.
  • X4 is a suitable leaving group, such as halogen or methanesulfonate
  • Formula 5 in the presence of excess base (generally 2 to 4 equivalents) such as potassium carbonate, sodium hydride, lithium diisopropylamide, pyridine or triethylamine in a variety of solvents including acetonitrile, tetrahydrofuran, diethyl ether, dichloromethane, dioxane, N, ⁇ /-dimethylformamide and toluene.
  • excess base generally 2 to 4 equivalents
  • solvents including acetonitrile, tetrahydrofuran, diethyl ether, dichloromethane, dioxane, N, ⁇ /-dimethylformamide and toluene.
  • Optimum reaction temperatures typically range from 0 0C to the reflux temperature of the solvent.
  • Isoxazo lines of Formula 4 where X4 is halogen can be made by the method reported in
  • Sulfides of Formula Ia can also be prepared by the one pot, two-step method shown in Scheme 8, in which an isoxazoline of Formula 4 is treated with a thiolating agent such thiourea or sodium hydrosulfide, and the generated intermediate is reacted in situ with a compound of Formula 3 in the presence of a base.
  • a thiolating agent such thiourea or sodium hydrosulfide
  • an isoxazoline of Formula 4 is combined with a thiolating agent in a solvent such as ethanol, tetrahydrofuran, dioxane, dichloromethane, N, ⁇ /-dimethylformamide or toluene, followed by addition of a suitable base, such as sodium hydride, sodium or potassium hydroxide, pyridine, lithium diisopropylamide, triethylamine or potassium carbonate, and a compound of Formula 3.
  • a suitable base such as sodium hydride, sodium or potassium hydroxide, pyridine, lithium diisopropylamide, triethylamine or potassium carbonate, and a compound of Formula 3.
  • the reaction can be run under a wide range of temperatures with optimum temperatures ranging from 0 0C to the reflux temperature of the solvent. Examples of reactions analogous to the method of Scheme 8 are taught in U.S. Patent Publication 2004/0110749 Al and PCT Patent Publications WO 2006/123088 and WO 2007/003295.
  • Intermediates of Formula 3 where X3 is halogen can be made by "benzylic" halogenation of precursors of Formula 6 with an JV-halosuccinimide in an appropriate solvent, i.e. ⁇ /, ⁇ /-dimethylformamide, carbon tetrachloride, acetonitrile or dichloromethane, generally in the presence of a radical-generating catalyst such as benzoyl peroxide or AIBN (Scheme 9).
  • Compounds of Formula 3 are also obtained from alcohols of Formula 7 by treating 7 with a halogen-containing reagent such as phosphorus(V) oxychloride or phosphorus tribromide in the presence of triphenylphosphine in an appropriate solvent, i.e.
  • Alcohols of Formula 7 can also be reacted with an appropriate sulfonylating reagent in the presence of base and solvent (i.e., pyridine, triethylamine or potassium carbonate in tetrahydrofuran, dioxane, dichloromethane, ⁇ /, ⁇ /-dimethylformamide or toluene) to give compounds of Formula 3 where X3 is a sulfonate leaving group such as methanesulfonate.
  • base and solvent i.e., pyridine, triethylamine or potassium carbonate in tetrahydrofuran, dioxane, dichloromethane, ⁇ /, ⁇ /-dimethylformamide or toluene
  • Precursors to alcohols of Formula 7 where R5 and R6 are H are generally aldehydes of Formula 8 or alkyl esters of Formula 9. Reduction of compounds of Formulae 8 or 9 with an appropriately selected reducing agent (i.e. lithium borohydride, sodium borohydride or diisobutylaluminum hydride) in a compatible solvent (i.e. tetrahydrofuran, methanol, diethyl ether) provides compounds of Formula 7 as shown in Scheme 10. Esters of Formula 9 can also be reacted with Grignard reagents to give compounds of Formula 7 where R5 and R6 are other than H.
  • an appropriately selected reducing agent i.e. lithium borohydride, sodium borohydride or diisobutylaluminum hydride
  • a compatible solvent i.e. tetrahydrofuran, methanol, diethyl ether
  • Intermediates of Formula 6a can be made by alkylating compounds of Formula 10 with a suitable alkylating agent in the presence of an appropriate base such as potassium carbonate, sodium hydroxide, lithium hydroxide, sodium hydride, potassium t-butoxide in a solvent such as acetonitrile, tetrahydrofuran, dioxane, methanol, dichloromethane or N,N- dimethylformamide.
  • an appropriate base such as potassium carbonate, sodium hydroxide, lithium hydroxide, sodium hydride, potassium t-butoxide in a solvent such as acetonitrile, tetrahydrofuran, dioxane, methanol, dichloromethane or N,N- dimethylformamide.
  • an appropriate base such as potassium carbonate, sodium hydroxide, lithium hydroxide, sodium hydride, potassium t-butoxide in a solvent such as acetonitrile, tetrahydrofuran, dioxane, methanol,
  • an appropriate solvent i.e. methanol
  • Pyrimidinone esters of Formula 9a can be made as illustrated in Scheme 17 by alkylating compounds of Formula 15 with a suitable alkylating agent in the presence of an appropriate base and solvent as described for Scheme 11.
  • Scheme 17
  • an appropriate oxidizing reagent i.e. bromine or 2,3
  • Pyridazinones of Formula 10b can be made as shown in Scheme 19. Under acidic conditions, generally in the presence of acetic, hydrochloric or sulfuric acid and optionally in the presence of a solvent, acetyl carboxylate hydrazones of Formula 17 are hydro lyrically cleaved and then cyclized to provide compounds of Formula 10b.
  • Acetyl carboxylate hydrazones of Formula 17 in turn can be made by the method of Scheme 20.
  • Reaction of keto aldehydes of Formula 18 with acetylhydrazine in a solvent such as methanol, toluene or acetonitrile provides the corresponding hydrazones of Formula 19 that undergo a Wittig reaction with the triphenylphosphine carboxylates of Formula 20 in a solvent, e.g., tetrahydrofuran, dioxane, toluene or diethyl ether, to give hydrazones of Formula 17.
  • a solvent e.g., tetrahydrofuran, dioxane, toluene or diethyl ether
  • Pyridazinones of Formulae 6g and 6h can also be made directly by cyclization of a hydroxylactone of Formula 21 with a hydrazine of formula NH2NHR8 ⁇ 0 in a solvent, e.g., methanol, acetonitrile, toluene or acetic acid, at temperatures ranging from 0 0C to the reflux temperature of the solvent.
  • a solvent e.g., methanol, acetonitrile, toluene or acetic acid
  • Hydroxylactones of Formula 21 can be prepared by the method taught in Tetrahedron Lett. 1983, 24(37), pp 3959-60 whereby lithioacrylates of Formula 22 are reacted with anhydrides of formula (Rlla)2CO in a suitable solvent such as tetrahydrofuran or dioxane to give hydroxylactones of Formula 21 (Scheme 22).
  • pyridazinones of Formula 6g can be made as outlined in Scheme 23. Cyclization of bromohydroxylactones of Formula 23 with hydrazines NH2NHR8a in a solvent, e.g., methanol, acetonitrile, toluene or acetic acid, at temperatures ranging from 0 0C to the reflux temperature of the solvent provides bromopyridazinones of Formula 24.
  • a solvent e.g., methanol, acetonitrile, toluene or acetic acid
  • pyridazinones of Formula 6h can be made from hydroxylactones of Formula 25 via bromopyridazinone intermediates of Formula 26 by a method analogous to that described for Scheme 23.
  • Bromohydroxylactones of Formulae 23 and 25 are accessible from substituted maleic anhydrides of Formula 27 as outlined in Scheme 25 via reduction e.g., with an aluminum hydride reagent as taught in Tetrahedron Lett. 1975, 48, pp 4279-82 or by addition of a Grignard reagent (e.g., Rlla/llcMgBr) as taught in Synthesis 2007, 14, pp 2198-2202.
  • Pyridone carboxylates of Formula 9b can be prepared from 2-chloro-3-pyridyl esters of Formula 28 by the reaction sequence summarized in Scheme 26. Displacement of the chlorine on the compound of Formula 28 with benzyl alcohol in the presence of base, e.g., sodium hydride, in a solvent such as tetrahydrofuran, dioxane or toluene affords the corresponding benzyl ether of Formula 29.
  • base e.g., sodium hydride
  • chloropyridine esters of Formula 28 are accessible from substituted pyridines of Formula 31.
  • Oxidation of a compound of Forumla 31 to the corresponding pyridine-N-oxide with an appropriate oxidizing agent, e.g., 3- chloroperoxybenzoic acid, in a solvent such as dichloromethane followed by treatment with phosphorus oxychloride (or thionyl chloride) gives the corresponding 2-chloropyridine of Formula 32.
  • Lithiation of the compound of Formula 32 at the 3-position with a suitable base e.g., lithium diisopropylamide or n-butyllithium, in a suitable solvent such as tetrahydrofuran or dioxane, and then treating with an alkyl chlorocarbonate of formula ClC ⁇ 2Ra (where Ra is alkyl or benzyl) affords pyridine ester of Formula 28.
  • a suitable base e.g., lithium diisopropylamide or n-butyllithium
  • a suitable solvent such as tetrahydrofuran or dioxane
  • Pyridone carboxylates of Formula 30 can also be made by the method outlined in Scheme 28 whereby enol ethers of Formula 33 are acylated with an anhydride reagent of formula (R9aCO)2 ⁇ in a suitable solvent, e.g., toluene, dichloromethane or chloroform, followed by displacement with ammonia in an alcohol solvent, tetrahydrofuran or dioxane to provide acyl enamines of Formula 33a.
  • a suitable solvent e.g., toluene, dichloromethane or chloroform
  • pyridone carboxylates of Formula 9c are made in an analogous manner to that described for making compounds of Formula 9b in Scheme 26.
  • pyridinyl carboxylates of Formula 34 are made as shown in Scheme 30. This method is analogous to that for making compounds of Formula 28 in Scheme 27.
  • pyridone carboxylates of Formula 9d can also be prepared by a method analogous to that described for making compounds of Formula 9b in Scheme 26.
  • Pyridinyl carboxylates of Formula 39 are made as shown in Scheme 32 by a method analogous to that for making compounds of Formula 28 in Scheme 27. Methods for lithiating pyridines and trapping with electrophiles are reviewed in Tetrahedron 2001, 57, pp 4059-4090.
  • Step B Preparation of 2-methoxy-3,5-dimethyl-6-(trifluoromethyl)-4(3H)-pyrimidinone To a stirred solution of 2-methoxy-5-methyl-6-(trifluoromethyl)-4(3H)-pyrimidinone
  • Step C Preparation of 5 -(bromomethyl)-2-methoxy-3 -methyl-6-(trifluoromethyl)-4(3H)- pyrimidinone
  • Step D Preparation of 5-[[(4,5-dihydro-5,5-dimethyl-3-isoxazolyl)thio]methyl]-2-methoxy-
  • Example 1 Step D) (110 mg, 0.31 mmol) in a mixture of methanol and water (1 :1, 3.1 mL) was added Oxone® potassium peroxymonosulfate (227 mg, 0.37 mmol), and the mixture was stirred at 0 0C for 1 h. Water was added, and the mixture was extracted with ethyl acetate. The organic layer was dried (MgSOzj) and concentrated under reduced pressure.
  • Step D Preparation of 4-(bromomethyl)-2-methyl-5-(trifluoromethyl)-3(2H)-pyridazinone N-Bromosuccinimide (0.46 g, 2.6 mmol) was added to a solution of 2,4-dimethyl-5- trifluoromethyl-3(2H)-pyridazinone (0.47 g, 2.5 mmol) (i.e. the product of Step C) in carbon tetrachloride (12 mL). A catalytic amount of 2,2'-azobis(2-methylpropionitrile) was added to the reaction mixture. The stirred reaction mixture was heated to reflux for 20 h. The reaction mixture was cooled to room temperature.
  • Step E Preparation of 4-[[(4,5-dihydro-5,5-dimethyl-3-isoxazolyl)thio]methyl]-2-methyl-5- (trifluoromethyl)-3 (2H)-pyridazinone
  • Step F Preparation of 4-[[(4,5-dihydro-5,5-dimethyl-3-isoxazolyl)sulfonyl]methyl]-2- methyl-5 -(trifluoromethyl)-3 (2H)-pyridazinone
  • Step A Preparation of 4-bromo-2-methyl-5-(2,2,2-trifluoroethoxy)-3(2H)-pyridazinone
  • Step B Preparation of 2,4-dimethyl-5-(2,2,2-trifluoroethoxy)-3(2H)-pyridazinone
  • Step C Preparation of 4-(bromomethyl)-2-methyl-5-(2,2,2-trifluoroethoxy)-3(2H)- pyridazinone
  • N-Bromosuccinimide (1.2 g, 6.4 mmol) was added to a solution of 2,4-dimethyl-5- (2,2,2-trifluoroethoxy)-3(2H)-pyridazinone (i.e. the product of Step B) (1.3 g, 5.9 mmol) in carbon tetrachloride (10 mL).
  • a catalytic amount of 2,2'-azobis(2-methylpropionitrile) was added to the stirred reaction mixture, which was then heated to reflux for 18 h. The reaction mixture was allowed to cool to room temperature. Water was added, and the mixture was extracted with dichloromethane. The dichloromethane extracts were dried (MgSC ⁇ ) and filtered.
  • Step E Preparation of 4-[[(4,5-dihydro-5,5-dimethyl-3-isoxazolyl)thio]methyl]-2-methyl-5- (2,2,2-trifluoroethoxy)-3(2H)-pyridazinone
  • Step B Preparation of 2,3,5-trimethyl-6-(trifluoromethyl)-4(3H)-pyrimidinone Iodomethane (1.0 mL, 16 mmol) was added to a stirred mixture of 2,5-dimethyl-6-
  • Step C Preparation of 5-(bromomethyl)-2,3-dimethyl-6-(trifluoromethyl)-4(3H)- pyrimidinone
  • reaction mixture was partitioned between water (100 mL) and ethyl acetate (100 mL). The separated organic layer was washed with water (2x) and brine, dried (MgSOz ⁇ ) and concentrated to give a gummy residue. Purification by MPLC using 10 to 80% ethyl acetate in hexane as eluant provided the title product as a white solid (0.5 g).
  • Step E Preparation of 5-[[(4,5-dihydro-5,5-dimethyl-3-isoxazolyl)sulfonyl]methyl]-2,3- dimethyl-6-(trifluoromethyl)-4(3H)-pyrimidinone
  • Step C Preparation of 5 -(bromomethyl)-2-ethyl-3 -methyl-6-(trifluoromethyl)-4(3H)- pyrimidinone
  • Step E Preparation of 5-[[(4,5-dihydro-5,5-dimethyl-3-isoxazolyl)sulfonyl]methyl]-2-ethyl- 3-methyl-6-(trifluoromethyl)-4(3H)-pyrimidinone
  • 5-[[(4,5-dihydro-5,5-dimethyl-3-isoxazolyl)thio]methyl]-2- ethyl-3-methyl-6-(trifluoromethyl)-4(3H)-pyrimidinone i.e.
  • Step A Preparation of 2-ethoxy-3,5-dimethyl-6-(trifluoromethyl)-4(3H)-pyrimidinone
  • 2-methoxy-3,5-dimethyl-6-(trifluoromethyl)-4(3H)- pyrimidinone i.e. the product of Synthesis Example 1, Step B
  • sodium ethoxide 550 mg, 8.10 mmol
  • the reaction mixture was heated to reflux for 24 h.
  • the reaction mixture was diluted with water, and the ethanol was removed under reduced pressure.
  • the mixture was extracted with ethyl acetate, and the organic layer was dried (MgSOz ⁇ ) and concentrated under reduced pressure.
  • Step B Preparation of 5 -(bromomethyl)-2-ethoxy-3 -methyl-6-(trifluoromethyl)-4(3H)- pyrimidinone
  • reaction mixture was cooled to room temperature and filtered, and the filtered solid was rinsed with carbon tetrachloride.
  • the filtrate was concentrated under reduced pressure to afford the title product as an oil, which was used without further purification in the next step.
  • Step C Preparation of 5-[[(4,5-dihydro-5,5-dimethyl-3-isoxazolyl)thio]methyl]-2-ethoxy-3- methyl-6-(trifluoromethyl)-4(3H)-pyrimidinone
  • 5-(bromomethyl)-2-ethoxy-3-methyl-6-(trifluoromethyl)- 4(3H)-pyrimidinone i.e.
  • Step A Preparation of 5-[[(4,5-dihydro-5,5-dimethyl-3-isoxazolyl)sulfonyl]methyl]-2- ethoxy-3-methyl-6-(trifluoromethyl)-4(3H)-pyrimidinone
  • 5-[[(4,5-dihydro-5,5-dimethyl-3-isoxazolyl)thio]methyl]-2- ethoxy-3-methyl-6-(trifluoromethyl)-4(3H)-pyrimidinone i.e.
  • Step A Preparation of 3-ethyl-2-methoxy-5-methyl-6-(trifluoromethyl)-4(3H)-pyrimidinone To a stirred solution of 2-methoxy-5-methyl-6-(trifluoromethyl)-4(3H)-pyrimidinone
  • Step B Preparation of 5 -(bromomethyl)-3 -ethyl-2-methoxy-6-(trifluoromethyl)-4(3H)- pyrimidinone
  • Step D 5-[[(4,5-dihydro-5,5-dimethyl-3-isoxazolyl)sulfonyl]methyl]-3-ethyl-2-methoxy-6-
  • Step D) (173 mg, 0.50 mmol), 4,5-dihydro-5,5-dimethyl-3-isoxazolyl carbamimidothioate hydrochloride (1 :1) (126 mg, 0.60 mmol) and potassium carbonate (207 mg, 1.80 mmol) were combined with acetonitrile (5 mL), and the mixture was stirred at ambient temperature for 18 h. The mixture was diluted with ethyl ether, washed with water (2x), dried (MgSOz ⁇ ), filtered and concentrated. The residue was purified by column chromatography using a gradient of 100% hexanes to 10% ethyl acetate in hexanes as eluant to give the title product as a white solid (0.22 g).
  • Step G Preparation of 3-[[(4,5-dihydro-5,5-dimethyl-3-isoxazolyl)sulfonyl]methyl]-l- methyl-4-(trifluoromethyl)-2(lH)-pyridinone To a solution of 3-[[(4,5-dihydro-5,5-dimethyl-3-isoxazolyl)thio]methyl]-l-methyl)-
  • Step A Preparation of 3-fluoro-2-(phenylmethoxy)-5-(trifluoromethyl)-pyridine
  • benzyl alcohol (2.74 mL, 26.4 mmol) in N, ⁇ /-dimethylformamide (50 mL)
  • potassium carbonate 5.20 g, 37.7 mmol
  • the mixture was stirred for 16 h at ambient temperature and then diluted with hexanes, washed with water (2x), dried (MgSC ⁇ ), filtered and concentrated.
  • the residue was purified by column chromatography using a gradient of 100% hexanes to 3% ethyl acetate in hexanes as eluant to give the title product as a colorless oil (4.43 g).
  • Step B Preparation of 3-fluoro-2-(phenylmethoxy)-5-(trifluoromethyl)-4- pyridinecarboxaldehyde
  • reaction mixture was quenched by the addition of a saturated solution of ammonium chloride and then extracted with ethyl ether.
  • organic phase was dried (MgSOz ⁇ ), filtered and concentrated.
  • the residue was purified by column chromatography using a gradient of 100% hexanes to 5% ethyl acetate in hexanes as eluant followed by trituration with hexanes to give the title product as an off-white solid (1.53 g).
  • Step C Preparation of 3 -fluoro-2-(phenylmethoxy)-5 -(trifluoromethyl)-4-pyridinemethanol
  • a solution of 3-fluoro-2-(phenylmethoxy)-5-(trifluoromethyl)-4-pyridinecarbox- aldehyde (i.e. the product of Step B) (1.53 g, 5.1 mmol) in ethanol (5 mL) was treated with sodium borohydride (97 mg, 2.55 mmol), and the mixture was stirred at ambient temperature for 1 h. Water was added, and the mixture was extracted with dichloromethane (2x), dried (MgSO4), filtered and concentrated. The residue was purified by column chromatography using 5 to 15% ethyl acetate in hexanes as eluant to give the title product as a white solid (1.34 g).
  • Step D Preparation of 4-(bromomethyl)-3-fluoro-2-(phenylmethoxy)-5- (trifluoromethyl)pyridine A mixture of 3-fluoro-2-(phenylmethoxy)-5-(trifluoromethyl)-4-pyridinemethanol
  • reaction mixture was diluted with ethyl ether, washed with water (2x), dried (MgSO4), filtered and concentrated.
  • the residue was purified by column chromatography using a gradient of 100% hexanes to 5% ethyl acetate in hexanes as eluant to give the title compound as a colorless oil (1.2 g).
  • Step F Preparation of 4-[[(4,5-dihydro-5,5-dimethyl-3-isoxazolyl)thio]methyl]-3-fluoro-5- (trifluoromethyl)-2(lH)-pyridinone
  • Step G Preparation of 4-[[(4,5-Dihydro-5,5-dimethyl-3-isoxazolyl)thio]methyl]-3-fluoro-l- methyl-5-(trifluoromethyl)-2(lH)-pyridinone 4-[[(4,5-Dihydro-5,5-dimethyl-3-isoxazolyl)thio]methyl]-3-fluoro-5-(trifluoro- methyl)-2(lH)-pyridinone (i.e.
  • Step F the product of Step F (0.32 g) was dissolved in N,N- dimethylformamide (5 mL), and the solution was treated with potassium carbonate (204 mg, 1.48 mmol) and dimethyl sulfate (113 ⁇ L, 1.18 mmol) and stirred at ambient temperature for 16 h. The reaction mixture was then diluted with ethyl acetate, washed with water (3x), dried (MgSO4), filtered and concentrated. The residue was purified by column chromatography using 30 to 50% ethyl acetate in hexanes as eluant to give the title product as a white solid (0.22 g). 1H NMR (CDCl3) ⁇ 7.56 (s, IH), 4.32 (d, 2H), 3.64 (s, 3H), 2.82 (s, 2H), 1.44 (s, 6H).
  • Step H Preparation of 4-[[(4,5-dihydro-5,5-dimethyl-3-isoxazolyl)sulfonyl]methyl]-3- fluoro-1 -methyl-5-(trifluoromethyl)-2(lH)-pyridinone
  • Step B Preparation of methyl 5-chloro-2-(phenylmethoxy)-4-pyridinecarboxylate n-Butyllithium (2.5 M in hexanes, 9.7 mL, 24 mmol) was added to a solution of diisopropylamine (3.7 mL, 26 mmol) in tetrahydrofuran (80 mL) at -15 0C causing the temperature to rise to -5 0C. After 5 min, the solution was cooled to -70 0C, and a solution of 5-chloro-2-(phenylmethoxy)pyridine (i.e.
  • Step A) the product of Step A) (4.82 g, 21.9 mmol) in tetrahydrofuran (20 mL) was added dropwise, at a rate such that the temperature remained below -65 0C.
  • the reaction mixture was stirred for 1.5 h at this temperature and then carbon dioxide gas was introduced into the solution through a Drierite®-filled tube for 5 min.
  • iodomethane 5 mL was added, and the mixture was allowed to warm to ambient temperature and stir overnight.
  • the mixture was diluted with water and washed with ethyl ether.
  • the aqueous phase was acidified with concentrated hydrochloric acid and extracted with dichloromethane (2x).
  • the dichloromethane extracts were dried (MgSOz ⁇ ), filtered and concentrated to give a yellow solid (3.95 g) which was used without further purification.
  • the solid was dissolved in ⁇ /, ⁇ /-dimethylformamide (30 mL) and treated with potassium carbonate (3.10 g, 22.5 mmol) and dimethyl sulfate (1.71 mL, 18 mmol). The mixture was stirred at ambient temperature overnight before being diluted with ethyl ether, washed with water (3x), dried (MgSOz ⁇ ), filtered and concentrated.
  • Benzoyl chloride (829 ⁇ L, 7.14 mmol) was added to a solution of 5-chloro-2- (phenylmethoxy)-4-pyridinemethanol (i.e. the product of Step C) (1.62 g, 6.49 mmol) and triethylamine (1.17 mL, 8.44 mmol) in dichloromethane (20 mL), and the reaction mixture was stirred at ambient temperature for 16 h. The mixture was diluted with ethyl ether, washed with water, dried (MgSC ⁇ ), filtered and concentrated. The residue was purified by trituration with hexanes to give the title product as a white solid (2.3 g).
  • Step E Preparation of (5 -chloro- 1 ,2-dihydro-2-oxo-4-pyridinyl)methyl benzoate
  • Step F Preparation of (5 -chloro- 1 ,2-dihydro-3-iodo-2-oxo-4-pyridinyl)methyl benzoate
  • Step G Preparation of (5 -chloro- l,2-dihydro-3-iodo-l-methyl-2-oxo-4-pyridinyl)methyl benzoate To a mixture of (5 -chloro- l,2-dihydro-3-iodo-2-oxo-4-pyridinyl)methyl benzoate
  • Step I Preparation of 5-chloro-4-[[(4,5-dihydro-5,5-dimethyl-3-isoxazolyl)thio]methyl]-3- iodo-l-methy-2(lH)-pyridinone
  • reaction mixture was stirred for a further 1 h before being concentrated and purified by chromatography on silica gel using 30% to 50% ethyl acetate in hexanes as eluant to give a white solid.
  • 4,5-Dihydro- 5,5-dimethyl-3-isoxazolyl carbamimidothioate hydrochloride (1 :1) (1.29 g, 6.16 mmol) and potassium carbonate (2.12 g, 15.4 mmol) were added, followed by acetonitrile (5 mL), and the mixture was stirred at ambient temperature for 2 h.
  • the mixture was diluted with ethyl acetate, washed with water, dried (MgSOz ⁇ ), filtered and concentrated.
  • 2(lH)-pyridinone i.e. the product of Step I
  • 84 mg, 0.20 mmol was dissolved in NJV- dimethylformamide (5 mL) and treated with triphenylarsine (25 mg, 0.08 mmol), copper(I) iodide (193 mg, 1.0 mmol) and tris(dibenzylideneacetone)dipalladium(0) (9.3 mg, 0.01 mmol).
  • the mixture was degassed by sparging with nitrogen gas for 5 min before the addition of methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (129 ⁇ L, 1.0 mmol), and then the mixture was heated at 90 0C for 1.5 h.
  • Step K Preparation of 5-chloro-4-[[(4,5-dihydro-5,5-dimethyl-3- isoxazolyl)sulfonyl]methyl]-l-methyl-3-(trifluoromethyl)-2(lH)-pyridinone
  • 5-chloro-4-[[(4,5-dihydro-5,5-dimethyl-3-isoxazolyl)thio]methyl]-3- (trifluoromethyl)-2(lH)-pyridinone i.e.
  • step J) the product of step J) (41 mg, 0.12 mmol) in dichloromethane (2 mL) was added 3-chloroperoxybenzoic acid (77% maximum assay, 100 mg, 0.45 mmol), and the mixture was stirred at ambient temperature for 3 h. An additional portion of 3-chloroperoxybenzoic acid (50 mg, 0.22 mmol) was added, and the reaction mixture was stirred for an additional 1 h. The reaction was quenched by the addition of methyl sulfide (0.25 mL). After 10 min, the mixture was diluted with aqueous sodium bicarbonate solution, extracted with dichloromethane (2x), dried (MgSC ⁇ ), filtered and concentrated.
  • Example 2 (0.4 g, 1.04 mmol) and iV-fluoro bis(benzenesulfonamide) (360 mg, 0.40 mmol) in tetrahydrofuran (10 mL) at -70 0C was added sodium bis(trimethylsilyl)amide (1.0 M solution in tetrahydrofuran, 1.20 mL, 1.20 mmol) dropwise.
  • the reaction mixture was stirred at this temperature for 2 h and then quenched with saturated ammonium chloride solution.
  • the mixture was extracted with ethyl acetate (3x) and the combined organic phases were washed with brine (2x), dried (MgSOz ⁇ ), filtered and concentrated.
  • the residue was purified by column chromatography using 10 to 30% ethyl acetate in hexanes as eluant to give the title product, a compound of the present invention, as a white solid (203 mg)
  • a compound of this invention will generally be used as a herbicidal active ingredient in a composition, i.e. formulation, with at least one additional component selected from the group consisting of surfactants, solid diluents and liquid diluents, which serves as a carrier.
  • a composition i.e. formulation
  • additional component selected from the group consisting of surfactants, solid diluents and liquid diluents, which serves as a carrier.
  • the formulation or composition ingredients are selected to be consistent with the physical properties of the active ingredient, mode of application and environmental factors such as soil type, moisture and temperature.
  • Liquid compositions include solutions (including emulsif ⁇ able concentrates), suspensions, emulsions (including microemulsions and/or suspoemulsions) and the like, which optionally can be thickened into gels.
  • aqueous liquid compositions are soluble concentrate, suspension concentrate, capsule suspension, concentrated emulsion, microemulsion and suspo-emulsion.
  • nonaqueous liquid compositions are emulsif ⁇ able concentrate, microemulsifiable concentrate, dispersible concentrate and oil dispersion.
  • compositions are dusts, powders, granules, pellets, prills, pastilles, tablets, filled films (including seed coatings) and the like, which can be water-dispersible ("wettable") or water-soluble. Films and coatings formed from film- forming solutions or flowable suspensions are particularly useful for seed treatment.
  • Active ingredient can be (micro)encapsulated and further formed into a suspension or solid formulation; alternatively the entire formulation of active ingredient can be encapsulated (or "overcoated”). Encapsulation can control or delay release of the active ingredient.
  • An emulsifiable granule combines the advantages of both an emulsifiable concentrate formulation and a dry granular formulation. High-strength compositions are primarily used as intermediates for further formulation.
  • Sprayable formulations are typically extended in a suitable medium before spraying. Such liquid and solid formulations are formulated to be readily diluted in the spray medium, usually water. Spray volumes can range from about one to several thousand liters per hectare, but more typically are in the range from about ten to several hundred liters per hectare. Sprayable formulations can be tank mixed with water or another suitable medium for foliar treatment by aerial or ground application, or for application to the growing medium of the plant. Liquid and dry formulations can be metered directly into drip irrigation systems or metered into the furrow during planting.
  • the formulations will typically contain effective amounts of active ingredient, diluent and surfactant within the following approximate ranges which add up to 100 percent by weight.
  • Solid diluents include, for example, clays such as bentonite, montmorillonite, attapulgite and kaolin, gypsum, cellulose, titanium dioxide, zinc oxide, starch, dextrin, sugars (e.g., lactose, sucrose), silica, talc, mica, diatomaceous earth, urea, calcium carbonate, sodium carbonate and bicarbonate, and sodium sulfate.
  • Typical solid diluents are described in Watkins et al., Handbook of Insecticide Dust Diluents and Carriers, 2nd Ed., Dorland Books, Caldwell, New Jersey.
  • Liquid diluents include, for example, water, ⁇ /,iV-dimethylalkanamides (e.g., ⁇ /, ⁇ /-dimethylformamide), limonene, dimethyl sulfoxide, JV-alkylpyrrolidones (e.g., JV-methylpyrrolidinone), ethylene glycol, Methylene glycol, propylene glycol, dipropylene glycol, polypropylene glycol, propylene carbonate, butylene carbonate, paraffins (e.g., white mineral oils, normal paraffins, isoparaffins), alkylbenzenes, alkylnaphthalenes, glycerine, glycerol triacetate, sorbitol, triacetin, aromatic hydrocarbons, dearomatized aliphatics, alkylbenzenes, alkylnaphthalenes, ketones such as cyclohexanone, 2-heptanone, iso
  • Liquid diluents also include glycerol esters of saturated and unsaturated fatty acids (typically C6-C22), such as plant seed and fruit oils (e.g, oils of olive, castor, linseed, sesame, corn (maize), peanut, sunflower, grapeseed, safflower, cottonseed, soybean, rapeseed, coconut and palm kernel), animal-sourced fats (e.g., beef tallow, pork tallow, lard, cod liver oil, fish oil), and mixtures thereof.
  • plant seed and fruit oils e.g, oils of olive, castor, linseed, sesame, corn (maize), peanut, sunflower, grapeseed, safflower, cottonseed, soybean, rapeseed, coconut and palm kernel
  • animal-sourced fats e.g., beef tallow, pork tallow, lard, cod liver oil, fish oil
  • Liquid diluents also include alkylated fatty acids (e.g., methylated, ethylated, butylated) wherein the fatty acids may be obtained by hydrolysis of glycerol esters from plant and animal sources, and can be purified by distillation. Typical liquid diluents are described in Marsden, Solvents Guide, 2nd Ed., Interscience, New York, 1950.
  • the solid and liquid compositions of the present invention often include one or more surfactants. When added to a liquid, surfactants (also known as "surface-active agents”) generally modify, most often reduce, the surface tension of the liquid.
  • surfactants can be useful as wetting agents, dispersants, emulsif ⁇ ers or defoaming agents.
  • surfactants can be classified as nonionic, anionic or cationic.
  • Nonionic surfactants useful for the present compositions include, but are not limited to: alcohol alkoxylates such as alcohol alkoxylates based on natural and synthetic alcohols (which may be branched or linear) and prepared from the alcohols and ethylene oxide, propylene oxide, butylene oxide or mixtures thereof; amine ethoxylates, alkanolamides and ethoxylated alkanolamides; alkoxylated triglycerides such as ethoxylated soybean, castor and rapeseed oils; alkylphenol alkoxylates such as octylphenol ethoxylates, nonylphenol ethoxylates, dinonyl phenol ethoxylates and dodecyl phenol ethoxylates (prepared from the phenols and ethylene oxide, propylene oxide, butylene oxide or mixtures thereof); block polymers prepared from ethylene oxide or propylene oxide and reverse block polymers where the terminal blocks are prepared from propylene oxide
  • Useful anionic surfactants include, but are not limited to: alkylaryl sulfonic acids and their salts; carboxylated alcohol or alkylphenol ethoxylates; diphenyl sulfonate derivatives; lignin and lignin derivatives such as lignosulfonates; maleic or succinic acids or their anhydrides; olefin sulfonates; phosphate esters such as phosphate esters of alcohol alkoxylates, phosphate esters of alkylphenol alkoxylates and phosphate esters of styryl phenol ethoxylates; protein-based surfactants; sarcosine derivatives; styryl phenol ether sulfate; sulfates and sulfonates of oils and fatty acids; sulfates and sulfonates of ethoxylated alkylphenols; sulfates of alcohols; sulfates of e
  • Useful cationic surfactants include, but are not limited to: amides and ethoxylated amides; amines such as JV-alkyl propanediamines, tripropylenetriamines and dipropylenetetramines, and ethoxylated amines, ethoxylated diamines and propoxylated amines (prepared from the amines and ethylene oxide, propylene oxide, butylene oxide or mixtures thereof); amine salts such as amine acetates and diamine salts; quaternary ammonium salts such as quaternary salts, ethoxylated quaternary salts and diquaternary salts; and amine oxides such as alkyldimethylamine oxides and bis-(2-hydroxyethyl)-alkylamine oxides.
  • amines such as JV-alkyl propanediamines, tripropylenetriamines and dipropylenetetramines, and ethoxylated
  • Nonionic, anionic and cationic surfactants and their recommended uses are disclosed in a variety of published references including McCutcheon 's Emulsifiers and Detergents, annual American and International Editions published by McCutcheon's Division, The Manufacturing Confectioner Publishing Co.; Sisely and Wood, Encyclopedia of Surface Active Agents, Chemical Publ. Co., Inc., New York, 1964; and A. S. Davidson and B. Milwidsky, Synthetic Detergents, Seventh Edition, John Wiley and Sons, New York, 1987.
  • compositions of this invention may also contain formulation auxiliaries and additives, known to those skilled in the art as formulation aids (some of which may be considered to also function as solid diluents, liquid diluents or surfactants).
  • formulation auxiliaries and additives may control: pH (buffers), foaming during processing (antifoams such polyorganosiloxanes), sedimentation of active ingredients (suspending agents), viscosity (thixotropic thickeners), in-container microbial growth (antimicrobials), product freezing (antifreezes), color (dyes/pigment dispersions), wash-off (film formers or stickers), evaporation (evaporation retardants), and other formulation attributes.
  • Film formers include, for example, polyvinyl acetates, polyvinyl acetate copolymers, polyvinylpyrrolidone-vinyl acetate copolymer, polyvinyl alcohols, polyvinyl alcohol copolymers and waxes.
  • formulation auxiliaries and additives include those listed in McCutcheon 's Volume 2: Functional Materials, annual International and North American editions published by McCutcheon's Division, The Manufacturing Confectioner Publishing Co.; and PCT Publication WO 03/024222.
  • the compound of Formula 1 and any other active ingredients are typically incorporated into the present compositions by dissolving the active ingredient in a solvent or by grinding in a liquid or dry diluent.
  • Solutions, including emulsifiable concentrates can be prepared by simply mixing the ingredients. If the solvent of a liquid composition intended for use as an emulsifiable concentrate is water-immiscible, an emulsifier is typically added to emulsify the active-containing solvent upon dilution with water.
  • Active ingredient slurries, with particle diameters of up to 2,000 ⁇ m can be wet milled using media mills to obtain particles with average diameters below 3 ⁇ m.
  • Aqueous slurries can be made into finished suspension concentrates (see, for example, U.S. 3,060,084) or further processed by spray drying to form water-dispersible granules. Dry formulations usually require dry milling processes, which produce average particle diameters in the 2 to 10 ⁇ m range. Dusts and powders can be prepared by blending and usually grinding (such as with a hammer mill or fluid-energy mill). Granules and pellets can be prepared by spraying the active material upon preformed granular carriers or by agglomeration techniques.
  • Pellets can be prepared as described in U.S. 4,172,714.
  • Water-dispersible and water-soluble granules can be prepared as taught in U.S. 4,144,050, U.S. 3,920,442 and DE 3,246,493.
  • Tablets can be prepared as taught in U.S. 5,180,587, U.S. 5,232,701 and U.S. 5,208,030.
  • Films can be prepared as taught in GB 2,095,558 and U.S. 3,299,566.
  • Compound 6 65.0% dodecylphenol polyethylene glycol ether 2.0% sodium ligninsulfonate 4.0% sodium silicoaluminate 6.0% montmorillonite (calcined) 23.0%
  • Compound 5 10.0% attapulgite granules (low volatile matter, 0.71/0.30 mm; 90.0%
  • Compound 6 25.0% anhydrous sodium sulfate 10.0% crude calcium ligninsulfonate 5.0% sodium alkylnaphthalenesulfonate 1.0% calcium/magnesium bentonite 59.0%
  • sulfides may show slight herbicidal activity at commercially desirable application rates, but the primary utility of these compounds is as key intermediates for the preparation of highly herbicidally active compounds of Formula 1 wherein the sum of n + m is greater than zero (e.g., by the methods of Schemes 1 through 4). Therefore the following biological disclosure relating to compounds of Formula 1 and compounds of this invention pertains particularly to compounds wherein the sum of n + m is greater than zero. These compounds generally show highest activity for preemergence weed control (i.e. applied before weed seedlings emerge from the soil) and early postemergence weed control (i.e. applied when the emerged weed seedlings are still young).
  • Compounds of this invention may show tolerance to important agronomic crops including, but is not limited to, alfalfa, barley, cotton, wheat, rape, sugar beets, corn (maize), sorghum, soybeans, rice, oats, peanuts, vegetables, tomato, potato, perennial plantation crops including coffee, cocoa, oil palm, rubber, sugarcane, citrus, grapes, fruit trees, nut trees, banana, plantain, pineapple, hops, tea and forests such as eucalyptus and conifers (e.g., loblolly pine), and turf species (e.g., Kentucky bluegrass, St.
  • agronomic crops including, but is not limited to, alfalfa, barley, cotton, wheat, rape, sugar beets, corn (maize), sorghum, soybeans, rice, oats, peanuts, vegetables, tomato, potato, perennial plantation crops including coffee, cocoa, oil palm, rubber, sugarcane, citrus, grapes
  • Compounds of the invention are particularly useful for selective control of weeds in wheat, barley, and particularly maize, soybean, cotton and perennial plantation crops such as sugarcane and citrus.
  • Compounds of this invention can be used in crops genetically transformed or bred to incorporate resistance to herbicides, express proteins toxic to invertebrate pests (such as Bacillus thuringiensis toxin), and/or express other useful traits. Those skilled in the art will appreciate that not all compounds are equally effective against all weeds. Alternatively, the subject compounds are useful to modify plant growth.
  • the compounds of the invention have both preemergent and postemergent herbicidal activity, to control undesired vegetation by killing or injuring the vegetation or reducing its growth
  • the compounds can be usefully applied by a variety of methods involving contacting a herbicidally effective amount of a compound of the invention, or a composition comprising said compound and at least one of a surfactant, a solid diluent or a liquid diluent, to the foliage or other part of the undesired vegetation or to the environment of the undesired vegetation such as the soil or water in which the undesired vegetation is growing or which surrounds the seed or other propagule of the undesired vegetation.
  • a herbicidally effective amount of the compounds of this invention is determined by a number of factors. These factors include: formulation selected, method of application, amount and type of vegetation present, growing conditions, etc. In general, a herbicidally effective amount of compounds of this invention is about 0.001 to 20 kg/ha with a typical range of about 0.004 to 1 kg/ha. One skilled in the art can easily determine the herbicidally effective amount necessary for the desired level of weed control.
  • Compounds of this invention can also be mixed with one or more other biologically active compounds or agents including herbicides, herbicide safeners, fungicides, insecticides, nematocides, bactericides, acaricides, growth regulators such as insect molting inhibitors and rooting stimulants, chemosterilants, semiochemicals, repellents, attractants, pheromones, feeding stimulants, plant nutrients, other biologically active compounds or entomopathogenic bacteria, virus or fungi to form a multi-component pesticide giving an even broader spectrum of agricultural protection.
  • Mixtures of the compounds of the invention with other herbicides can broaden the spectrum of activity against additional weed species, and suppress the proliferation of any resistant biotypes.
  • the present invention also pertains to a composition
  • a composition comprising (a herbicidally effective amount of) a compound of Formula 1 and (a biologically effective amount of) at least one additional biologically active compound or agent and can further comprise at least one of a surfactant, a solid diluent or a liquid diluent.
  • the other biologically active compounds or agents can be formulated in compositions comprising at least one of a surfactant, solid or liquid diluent.
  • one or more other biologically active compounds or agents can be formulated together with a compound of Formula 1, to form a premix, or one or more other biologically active compounds or agents can be formulated separately from the compound of Formula 1, and the formulations combined together before application (e.g., in a spray tank) or, alternatively, applied in succession.
  • a mixture of one or more of the following herbicides with a compound of this invention may be particularly useful for weed control: acetochlor, acifluorfen and its sodium salt, aclonifen, acrolein (2-propenal), alachlor, alloxydim, ametryn, amicarbazone, amidosulfuron, aminopyralid, aminocyclopyrachlor and its esters (e.g., methyl, ethyl) and its salts (e.g., sodium potassium), amitrole, ammonium sulfamate, anilofos, asulam, atrazine, azimsulfuron, beflubutamid, benazolin, benazolin-ethyl, bencarbazone, benfluralin, benfuresate, bensulfuron-methyl, bensulide, bentazone, benzobicyclon, benzofenap, bifenox, bilanafos, bispyr
  • herbicides also include bioherbicides such as Alternaria destruens Simmons, Colletotrichum gloeosporiodes (Penz.) Penz. & Sacc, Drechsiera monoceras (MTB-951), Myrothecium verrucaria (Albertini & Schweinitz) Ditmar: Fries, Phytophthora palmivora (Butl.) Butl. and Puccinia thlaspeos Schub.
  • bioherbicides such as Alternaria destruens Simmons, Colletotrichum gloeosporiodes (Penz.) Penz. & Sacc, Drechsiera monoceras (MTB-951), Myrothecium verrucaria (Albertini & Schweinitz) Ditmar: Fries, Phytophthora palmivora (Butl.) Butl. and Puccinia thlaspeos Schub.
  • Compounds of this invention can also be used in combination with plant growth regulators such as aviglycine, ⁇ /-(phenylmethyl)-lH-purin-6-amine, epocholeone, gibberellic acid, gibberellin A4 and A ⁇ , harpin protein, mepiquat chloride, prohexadione calcium, prohydrojasmon, sodium nitrophenolate and trinexapac-methyl, and plant growth modifying organisms such as Bacillus cereus strain BPOl .
  • plant growth regulators such as aviglycine, ⁇ /-(phenylmethyl)-lH-purin-6-amine, epocholeone, gibberellic acid, gibberellin A4 and A ⁇
  • harpin protein mepiquat chloride
  • prohexadione calcium prohydrojasmon
  • sodium nitrophenolate sodium nitrophenolate
  • trinexapac-methyl plant growth modifying organisms
  • the weight ratio of these various mixing partners (in total) to the compound of Formula 1 is typically between about 1 :3000 and about 3000:1. Of note are weight ratios between about 1 :300 and about 300:1 (for example ratios between about 1 :30 and about 30:1).
  • weight ratios between about 1 :300 and about 300:1 for example ratios between about 1 :30 and about 30:1.
  • One skilled in the art can easily determine through simple experimentation the biologically effective amounts of active ingredients necessary for the desired spectrum of biological activity. It will be evident that including these additional components may expand the spectrum of weeds controlled beyond the spectrum controlled by the compound of Formula 1 alone.
  • combinations of a compound of this invention with other biologically active (particularly herbicidal) compounds or agents (i.e. active ingredients) can result in a greater-than-additive (i.e. synergistic) effect on weeds and/or a less-than-additive effect (i.e. safening) on crops or other desirable plants. Reducing the quantity of active ingredients released in the environment while ensuring effective pest control is always desirable. Ability to use greater amounts of active ingredients to provide more effective weed control without excessive crop injury is also desirable.
  • synergism of herbicidal active ingredients occurs on weeds at application rates giving agronomically satisfactory levels of weed control, such combinations can be advantageous for reducing crop production cost and decreasing environmental load.
  • safening of herbicidal active ingredients occurs on crops, such combinations can allow increased application rates to more effectively reduce weed competition.
  • herbicide safeners such as allidochlor, benoxacor, BCS (l-bromo-4-[(chloromethyl)sulfonyl]benzene), cloquintocet-mexyl, cyometrinil, cyprosulfamide, dichlormid, 4-(dichloroacetyl)-l-oxa- 4-azospiro[4.5]decane (MON 4660), 2-(dichloromethyl)-2-methyl-l,3-dioxolane (MG 191), dicyclonon, dietholate, fenchlorazole-ethyl, fenclorim, flurazole, fluxofenim, furilazole, isoxadifen-ethyl, mefenpyr-diethyl, mephenate, methoxyphenone ((4-methoxy-3- methylphenyl)(3-methylphenyl)methanone),
  • herbicide safeners such as allidochlor
  • Antidotally effective amounts of the herbicide safeners can be applied at the same time as the compounds of this invention, or applied as seed treatments.
  • Preferred safeners used in combination with a compound of Formula I are benoxacor, cyometrinil, dichlormid, fenchlorazole-ethyl, furilazole, and fenclorim.
  • Partuclarly preferred safeners in combination with a compound of Forumula I for preemergence application are benoxacor and fluxofenim.
  • an aspect of the present invention relates to a herbicidal mixture comprising a compound of this invention and an (antidotally effective amount of) a herbicide safener.
  • Seed treatment is particularly useful for selective weed control, because it physically restricts antidoting to the crop plants. Therefore a particularly useful embodiment of the present invention is a method for selectively controlling the growth of undesired vegetation in a crop comprising contacting the locus of the crop with a herbicidally effective amount of a compound of this invention wherein seed from which the crop is grown is treated with an antidotally effective amount of safener.
  • Antidotally effective amounts of safeners can be easily determined by one skilled in the art through simple experimentation.
  • a composition of the present invention can further comprise (a biologically effective amount of) at least one additional herbicidal active ingredient having a similar spectrum of control but a different site of action.
  • an aspect of the present invention relates to a herbicidal composition
  • a herbicidal composition comprising (a herbicidally effective amount of) a compound selected from Formula 1, iV-oxides, and salts thereof wherein the sum of n and m is 1 or 2, at least one component selected from the group consisting of surfactants, solid diluents and liquid diluents, and further comprising (an effective amount of) at least one additional active ingredient selected from the group consisting of other herbicides and herbicide safeners.
  • Other herbicides of note regarding this aspect are the herbicides already listed (i.e. listed above) for mixtures with a compound of the invention, particularly the herbicides that are not bioherbicides.
  • Herbicide safeners of note regarding this aspect are the safeners already listed for use in combination with compounds of the invention.
  • the mass spectra value given is the molecular weight of the highest isotopic abundance parent ion (M+l) formed by addition of H+ (molecular weight of 1) to the molecule, observed by mass spectrometry using electrospray ionization (ESI).
  • Plants ranged in height from two to ten cm and were in the one- to two-leaf stage for the postemergence treatment. Treated plants and untreated controls were maintained in a greenhouse for approximately ten days, after which time all treated plants were compared to untreated controls and visually evaluated for injury. Plant response ratings, summarized in Table A, are based on a 0 to 100 scale where 0 is no effect and 100 is complete control. A dash (-) response means no test result.
  • plants selected from these crop and weed species and also winter barley (Hordeum vulgare), canarygrass (Phalaris minor), chickweed (Stellaria media) and windgrass (Apera spica-venti) were planted in pots containing Redi-Earth® planting medium (Scotts Company, 14111 Scottslawn Road, Marysville, Ohio 43041) comprising spaghnum peat moss, vermiculite, wetting agent and starter nutrients and treated with postemergence applications of some of the test chemicals formulated in the same manner. Plants ranged in height from 2 to 18 cm (1- to 4-leaf stage) for postemergence treatments. Plant species in the flooded paddy test consisted of rice (Oryza sativa), umbrella sedge
  • test pots were flooded to 3 cm above the soil surface, treated by application of test compounds directly to the paddy water, and then maintained at that water depth for the duration of the test.
  • Treated plants and controls were maintained in a greenhouse for 13 to 15 days, after which time all species were compared to controls and visually evaluated.
  • Plant response ratings, summarized in Table B, are based on a scale of 0 to 100 where 0 is no effect and 100 is complete control. A dash (-) response means no test result.
  • Seeds of plant species selected from annual bluegrass (Poa annu ⁇ ), blackgrass (Alopecurus myosuroides), canarygrass (Phalaris minor), gallium (catchweed bedstraw, Galium aparine), chickweed (Stellaria media), downy bromegrass (Bromus tectorum), field poppy (Papaver rhoeas), field violet ⁇ Viola arvensis), green foxtail (Setaria viridis), deadnettle (henbit deadnettle, Lamium amplexicaule), Italian ryegrass (Lolium multiflorum), kochia ⁇ Kochia scoparia), lambsquarters (Chenopodium album), oilseed rape (Brassica napus), pigweed (Amaranthus retroflexus), Russian thistle (Salsola kali), spring barley (Hordeum vulgare), spring wheat (Triticum aestivum), wild buckwheat (Polygonum convolvulus), wild mustard (S
  • Plant response ratings summarized in Table C, are based on a scale of 0 to 100 where 0 is no effect and 100 is complete control. A dash (-) response means no test result.
  • Plant response ratings are based on a scale of 0 to 100 where 0 is no effect and 100 is complete control. A dash (-) response means no test result.
  • Seeds of plant species selected from corn (Zea mays), large crabgrass (Digitaria sanguinalis), giant foxtail (Setaria faberii), johnsongrass ⁇ Sorghum halepense), nightshade (eastern black nightshade, Solarium ptycanthum), pigweed (Amaranthus retroflexus), soybean (Glycine max), and velvetleaf (Abutilon theophrasti) were planted into a silt loam soil and treated preemergence with test compounds formulated in a non-phytotoxic solvent mixture. Treated plants and controls were maintained in a greenhouse for 20 to 22 days, after which time all species were compared to controls and visually evaluated. Plant response ratings, summarized in Table E, are based on a scale of 0 to 100 where 0 is no effect and 100 is complete control. A dash (-) response means no test result.

Abstract

Disclosed are compounds of Formula (I), including all geometric and stereoisomers, N-oxides, and salts thereof, Formula (I) wherein J is Formula (II) and R1, R2, R3, R4, R5, R6, R7, R8a, R8b, R8c, R8d, Q1, Q2, Q3, Q4, W1, W2, W3, W4, Y1, Y2, Y3, Y4, m and n are as defined in the disclosure. Also disclosed are compositions containing the compounds of Formula (I) and methods for controlling undesired vegetation comprising contacting the undesired vegetation or its environment with an effective amount of a compound or a composition of the invention.

Description

TITLE HERBICIDAL DIHYDRO OXO SIX-MEMBERED AZINYL ISOXAZOLINES
FIELD OF THE INVENTION
This invention relates to certain dihydro oxo azinyl isoxazoline compounds, their iV-oxides, salts and compositions, and methods of their use for controlling undesirable vegetation.
BACKGROUND OF THE INVENTION
The control of undesired vegetation is extremely important in achieving high crop efficiency. Achievement of selective control of the growth of weeds especially in such useful crops as rice, soybean, sugar beet, maize, potato, wheat, barley, tomato and plantation crops, among others, is very desirable. Unchecked weed growth in such useful crops can cause significant reduction in productivity and thereby result in increased costs to the consumer. The control of undesired vegetation in noncrop areas is also important. Many products are commercially available for these purposes, but the need continues for new compounds that are more effective, less costly, less toxic, environmentally safer or have different sites of action.
U.S. Patent 7,238,689 discloses certain six-membered heterocyclic isoxazolines as herbicides, but not the present compounds.
SUMMARY OF THE INVENTION This invention is directed to compounds of Formula 1 (including all geometric and stereoisomers), iV-oxides, and salts thereof, agricultural compositions containing them and their use as herbicides or plant growth regulators:
Figure imgf000003_0001
wherein
Figure imgf000003_0002
Figure imgf000004_0001
QMs N or CR9*; Q2 is N or CR9b; Q3 is N or CR9c; Q4 is N or CR9d; W1 is N or CR1 Oa;
W2 is N or CR10b; provided that when Q2 is N, then W2 is CR10b; W3 is N or CR1 Oc; W4 is N or CR1 od;
Y1 is N or CR1 la; provided that when W1 is N, then Y1 is CR1 la; Y2 is N or CR1 lb; provided that when W2 is N, then Y2 is CR1 lb;
Y3 is N or CR1 lc; provided that when W3 is N, then Y3 is CR1 lc; Y4 is N or CR1 ld; m is 0, 1 or 2; n is 0 or 1 ; provided that the sum of n and m is not more than 2; R1 and R2 are independently H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, Q-C6 haloalkyl, C2-C6 haloalkenyl, CzpC6 alkylcycloalkyl or C 4- C6 cycloalkylalkyl; or
R1 and R2 are taken together with the carbon to which they are bonded to form a C3- C6 saturated carbocyclic ring optionally substituted by C1-C3 alkyl, halogen or C1-C3 haloalkyl;
R3 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C1-C6 haloalkyl, C2-C6 haloalkenyl, CzpC6 alkylcycloalkyl or CzpC6 cycloalkylalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkylthio, C1-C6 haloalkylthio, -SCN, halogen, cyano, nitro, azido, -CO2H or C2-C5 alkoxycarbonyl; R4 is H, C1-C6 alkyl, C1-C6 haloalkyl or halogen; or
R3 and R4 are taken together with the carbon to which they are bonded to form a saturated carbocyclic C3-C6 ring optionally substituted by C1-C3 alkyl, halogen or C1-C3 haloalkyl; or
R1 and R4 are taken together with the carbons to which they are bonded to form a C3- C7 saturated carbocyclic ring optionally substituted by C1-C3 alkyl, halogen or
C1-C3 haloalkyl; R5 is H, C1-C2 alkyl, halogen, cyano or Q-C5 alkoxycarbonyl; R6 is H, C1-C2 alkyl or halogen; or
R5 and R6 are taken together with the carbon to which they are bonded to form a C3-
C^ saturated carbocyclic ring;
R7 is H, -CN, C2-C4 alkoxycarbonyl, Q-C4 alkylsulfonyl, C2-C4 alkylcarbonyl or C2-C4 haloalkylcarbonyl; each R8a, R8b, R8c and R8d is independently C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C3-C7 cycloalkyl, C1-C7 haloalkyl, C2-C7 haloalkenyl, C2-C7 alkoxyalkyl, C4~C7 cycloalkylalkyl, C3-C7 haloalkynyl, C3-C7 alkylcarbonylalkyl, C3-C7 alkoxycarbonylalkyl, C4~C7 halocycloalkylalkyl, C2- C7 haloalkoxyalkyl, C2-C7 alkylthioalkyl, C2-C7 alkylsulfonylalkyl, C2-C7 alkylsulfinylalkyl, C2-C7 cyanoalkyl, C2-C7 haloalkylthioalkyl, C2-C7 haloalkylsulfonylalkyl, C2-C7 haloalkylsulfmylalkyl, C3-C7 haloalkoxycarbonylalkyl, C3-C7 haloalkylcarbonylalkyl; C1-Cg alkylsulfonyl, C1-C^ haloalkylsulfonyl or C3-Cg cycloalkylsulfonyl; and each R9a, R9b, R9c, R9d, R1Oa, R10b, R1Oc, R10d, Rlla, Rllb, Rllc and Rlld is independently H, halogen, cyano, C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C3-C7 cycloalkyl, C 4-C7 cycloalkylalkyl, C 4-C7 alkylcycloalkyl, C1-C7 haloalkyl, C2-C7 haloalkenyl, C3-C7 haloalkynyl, C3-C7 halocycloalkyl, C1-C7 alkoxy, C1-C7 haloalkoxy, C2-C7 alkenyloxy, C2-C7 haloalkenyloxy, C3-C7 cycloalkoxy, C3-C7 halocycloalkoxy, C2-C7 alkynyloxy, C4~C7 cycloalkylalkoxy, C 4-C7 halocycloalkylalkoxy, C1-C7 alkylthio, C1-C7 haloalkylthio, C1-C7 haloalkylsulfinyl, C1-C7 haloalkylsulfonyl, C1-Cg alkylamino, C2-C7 dialkylamino, C1-C7 haloalkylamino, C2-C7 alkylcarbonyl, C2-C7 alkoxycarbonyl, C2-C7 haloalkylcarbonyl, C2-C7 haloalkoxycarbonyl, C3-C7 alkylcarbonylalkyl, C3-C7 alkoxycarbonylalkyl, aminocarbonyl, C2-Cg alkylaminocarbonyl, C2-Cg haloalkylaminocarbonyl, C3-Cg dialkylaminocarbonyl, C3-Cg haloalkyl(alkyl)aminocarbonyl, C4~C7 cycloalkylaminocarbonyl, C5~Cg cycloalkyl(alkyl)aminocarbonyl, C4~C7 halocycloalkylalkyl, C2-C7 alkoxyalkyl, C2-C7 haloalkoxyalkyl, C2-C7 alkylthioalkyl, C2-C7 alkylsulfonylalkyl, C2-C7 alkylsulfinylalkyl, C2-C7 cyanoalkyl, C2-C7 haloalkylthioalkyl, C2-C7 haloalkylsulfonylalkyl, C2-C7 haloalkylsulfϊnylalkyl, C3-C7 haloalkoxycarbonylalkyl, C3-C7 haloalkylcarbonylalkyl, C2-C7 alkoxyalkoxy, C2-C7 haloalkoxyalkoxy, C2-C7 alkylthioalkoxy, C2-C7 haloalkylthioalkoxy, C2-C7 haloalkylsulfonylalkoxy, C2-C7 haloalkylsulfinylalkoxy, nitro, C3-C1Q trialkylsilyl, aminosulfonyl, C1-
C7 alkylaminosulfonyl, C1-C7 haloalkylaminosulfonyl, C2-Cg dialkylaminosulfonyl, C3-Cg haloalkyl(alkyl)aminosulfonyl, C3-Cg cycloalkylaminosulfonyl, C 4-C7 cycloalkyl(alkyl)aminosulfonyl or Z; each Z is independently -ON=CR12R13, -Q=NOR14)R15, C2-C6 cyanoalkoxy, C2-C6 alkoxyhaloalkyl or C3-C7 alkoxycarbonylalkoxy; or phenyl optionally substituted with up to two substituents selected from R16; or a 5- or 6-membered heterocyclic ring optionally substituted with up to two substituents selected from R17 on carbon ring members and R18 on nitrogen ring members; each R12 is independently H or Q-C6 alkyl; each R13 is independently H, Q-C6 alkyl or Q-C4 alkoxy; or a pair of R12 and R13 in an instance of -ON=CR12R13 are taken together as -(CH2)2-,
-(CH2)3-, -(CH2)4- or -(CH2)5-; each R14 and R15 is independently H or Q-C6 alkyl; or a pair of R14 and R15 in an instance of -C(=NOR14)R15 are taken together as -(CH2)2-, -(CH2)3- or -(CH2)4-; each R16 is independently Q-C6 alkyl, halogen, Q-C4 alkoxy, Q-C4 haloalkyl or
Q-C4 haloalkoxy; each R17 is independently Q-C6 alkyl, halogen, Q-C4 alkoxy, Q-C4 haloalkyl or
Q-C4 haloalkoxy; and each R18 is independently Q-C6 alkyl.
More particularly, this invention pertains to a compound of Formula 1 (including all geometric and stereoisomers), an JV-oxide or a salt thereof. This invention also relates to a herbicidal composition comprising a compound of Formula 1 wherein the sum of n and m is 1 or 2 (i.e. in a herbicidally effective amount), and (i.e. together with) at least one component selected from the group consisting of surfactants, solid diluents and liquid diluents. This invention further relates to a method for controlling the growth of undesired vegetation comprising contacting the vegetation or its environment with a herbicidally effective amount of a compound of Formula 1 wherein the sum of n and m is 1 or 2 (e.g., as a composition described herein).
DETAILS OF THE INVENTION
As used herein, the terms "comprises," "comprising," "includes," "including," "has," "having", "contains" or "containing" or any other variation thereof, are intended to cover a non-exclusive inclusion. For example, a composition, process, method, article, or apparatus that comprises a list of elements is not necessarily limited to only those elements but may include other elements not expressly listed or inherent to such composition, process, method, article, or apparatus. Further, unless expressly stated to the contrary, "or" refers to an inclusive or and not to an exclusive or. For example, a condition A or B is satisfied by any one of the following: A is true (or present) and B is false (or not present), A is false (or not present) and B is true (or present), and both A and B are true (or present). Also, the indefinite articles "a" and "an" preceding an element or component of the invention are intended to be nonrestrictive regarding the number of instances (i.e. occurrences) of the element or component. Therefore "a" or "an" should be read to include one or at least one, and the singular word form of the element or component also includes the plural unless the number is obviously meant to be singular.
As referred to herein, the term "seedling", used either alone or in a combination of words means a young plant developing from the embryo of a seed.
As referred to herein, the term "broadleaf ' used either alone or in words such as "broadleaf weed" means dicot or dicotyledon, a term used to describe a group of angiosperms characterized by embryos having two cotyledons.
As used herein, the term "alkylating agent" refers to a chemical compound in which a carbon-containing radical is bound through a carbon atom to leaving group such as halide or sulfonate, which is displaceable by bonding of a nucleophile to said carbon atom. Unless otherwise indicated, the term "alkylating" does not limit the carbon-containing radical to alkyl; the carbon-containing radicals in alkylating agents include the variety of carbon-bound substituent radicals specified for R5 and R6.
In the above recitations, the term "alkyl", used either alone or in compound words such as "alkylthio" or "haloalkyl" includes straight-chain or branched alkyl, such as, methyl, ethyl, n-propyl, /-propyl, or the different butyl, pentyl or hexyl isomers. "Alkenyl" includes straight-chain or branched alkenes such as ethenyl, 1-propenyl, 2-propenyl, and the different butenyl, pentenyl and hexenyl isomers. "Alkenyl" also includes polyenes such as 1 ,2-propadienyl and 2,4-hexadienyl. "Alkynyl" includes straight-chain or branched alkynes such as ethynyl, 1-propynyl, 2-propynyl and the different butynyl, pentynyl and hexynyl isomers. "Alkynyl" can also include moieties comprised of multiple triple bonds such as 2,5-hexadiynyl.
"Alkoxy" includes, for example, methoxy, ethoxy, n-propyloxy, isopropyloxy and the different butoxy, pentoxy and hexyloxy isomers. "Alkoxyalkyl" denotes alkoxy substitution on alkyl. Examples of "alkoxyalkyl" include CH3OCH2, CH3OCH2CH2, CH3CH2OCH2, CH3CH2CH2CH2OCH2 and CH3CH2OCH2CH2. "Alkoxyalkoxy" denotes alkoxy substitution on alkoxy. "Alkenyloxy" includes straight-chain or branched alkenyloxy moieties. Examples of "alkenyloxy" include H2C=CHCH2O, (CH3)2C=CHCH2O, (CH3)CH=CHCH2O, (CH3)CH=C(CH3)CH2O and CH2=CHCH2CH2O. "Alkynyloxy" includes straight-chain or branched alkynyloxy moieties. Examples of "alkynyloxy" include HC≡CCH2O, CH3C≡CCH2O and CH3C≡CCH2CH2O. "Alkylthio" includes branched or straight-chain alkylthio moieties such as methylthio, ethylthio, and the different propylthio, butylthio, pentylthio and hexylthio isomers. "Alkylsulfinyl" includes both enantiomers of an alkylsulfinyl group. Examples of "alkylsulfinyl" include CH3S(O)-, CH3CH2S(O)-, CH3CH2CH2S(O)-, (CH3)2CHS(O)- and the different butylsulfinyl, pentylsulfinyl and
Figure imgf000008_0001
hexylsulfϊnyl isomers. Examples of "alkylsulfonyl" include CH3S(O)2-, CH3CH2S(O)2-,
CH3CH2CH2S(O)2-, (CH3)2CHS(O)2-, and the different butylsulfonyl, pentylsulfonyl and hexylsulfonyl isomers. "Alkylthioalkyl" denotes alkylthio substitution on alkyl. Examples of "alkylthioalkyl" include CH3SCH2, CH3SCH2CH2, CH3CH2SCH2, CH3CH2CH2CH2SCH2 and CH3CH2SCH2CH2. "Alkylthioalkoxy" denotes alkylthio substitution on alkoxy. "Cyanoalkyl" denotes an alkyl group substituted with one cyano group. Examples of "cyanoalkyl" include NCCH2, NCCH2CH2 and CH3CH(CN)CH2.
"Alkylamino", "dialkylamino", and the like, are defined analogously to the above examples.
"Cycloalkyl" includes, for example, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. The term "alkylcycloalkyl" denotes alkyl substitution on a cycloalkyl moiety and includes, for example, ethylcyclopropyl, z-propylcyclobutyl, 3-methylcyclopentyl and 4-methylcyclohexyl. The term "cycloalkylalkyl" denotes cycloalkyl substitution on an alkyl moiety. Examples of "cycloalkylalkyl" include cyclopropylmethyl, cyclopentylethyl, and other cycloalkyl moieties bonded to straight-chain or branched alkyl groups. The term "cycloalkoxy" denotes cycloalkyl linked through an oxygen atom such as cyclopentyloxy and cyclohexyloxy. "Cycloalkylalkoxy" denotes cycloalkylalkyl linked through an oxygen atom attached to the alkyl chain. Examples of "cycloalkylalkoxy" include cyclopropylmethoxy, cyclopentylethoxy, and other cycloalkyl moieties bonded to straight-chain or branched alkoxy groups. The term "cyanoalkoxy" denotes a NC- moiety attached to an alkoxy group. Examples of cyanoalkoxy include NCCH2O-, NCCH2CH2O- or CH3CH(CN)CH2O-. The term alkoxycarbonylalkoxy denotes and ester group attached to an alkoxy group. Examples of alkoxycarbonylalkoxy include CH3O2CCH2O-, CH3O2CCH2CH2O-, CH3CH2O2CCH2O-. The term alkoxyhaloalkyl denotes an alkoxy group attached to a haloalkyl group. Examples of the term alkoxyhaloalkyl include CH3OCF2O-, CH3CH2OCHFO-, or CH3CH2OCCl2O-.
The term "halogen", either alone or in compound words such as "haloalkyl", or when used in descriptions such as "alkyl substituted with halogen" includes fluorine, chlorine, bromine or iodine. Further, when used in compound words such as "haloalkyl", or when used in descriptions such as "alkyl substituted with halogen" said alkyl may be partially or fully substituted with halogen atoms which may be the same or different. Examples of "haloalkyl" or "alkyl substituted with halogen" include F3C-, ClCH2-, CF3CH2- and CF3CCl2-. The terms "halocycloalkyl", "haloalkoxy", "haloalkylthio", "haloalkenyl", "haloalkynyl", and the like, are defined analogously to the term "haloalkyl". Examples of "haloalkoxy" include CF3O-, CCl3CH2O-, HCF2CH2CH2O- and CF3CH2O-. Examples of "haloalkylthio" include CCl3S-, CF3S-, CCl3CH2S- and ClCH2CH2CH2S-. Examples of "haloalkylsulfmyl" include CF3S(O)-, CCl3S(O)-, CF3CH2S(O)- and CF3CF2S(O)-. Examples of "haloalkylsulfonyl" include CF3S(O)2-, CCl3S(O)2-, CF3CH2S(O)2- and CF3CF2S(O)2-. Examples of "haloalkenyl" include (Cl)2C=CHCH2- and CF3CH2CH=CHCH2-. Examples of "haloalkynyl" include HC≡CCHCl-, CF3C≡C-, CC13C≡C- and FCH2C≡CCH2-. Examples of "haloalkoxyalkoxy" include CF3OCH2O-, CICH2CH2OCH2CH2O-, Cl3CCH2OCH2O- as well as branched alkyl derivatives.
"Alkylcarbonyl" denotes a straight-chain or branched alkyl moieties bonded to a C(=0) moiety. Examples of "alkylcarbonyl" include CH3C(K))-, CH3CH2CH2C(K))- and
(CH3)2CHC(=O)-. Examples of "alkoxycarbonyl" include CH3OC(O)-, CH3CH2OC(O)-,
CH3CH2CH2OC(O)-, (CH3)2CH0C(O)- and the different butoxy- or pentoxycarbonyl isomers.
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 10. For example, C1-C4 alkylsulfonyl designates methylsulfonyl through butylsulfonyl; C2 alkoxyalkyl designates CH3OCH2-; C3 alkoxyalkyl designates, for example, CH3CH(OCH3)-, CH3OCH2CH2- or CH3CH2OCH2-; and C4 alkoxyalkyl designates the various isomers of an alkyl group substituted with an alkoxy group containing a total of four carbon atoms, examples including CH3CH2CH2OCH2- and CH3CH2OCH2CH2-.
When a group contains a substituent which can be hydrogen, for example R1 or R3, then when this substituent is taken as hydrogen, it is recognized that this is equivalent to said group being unsubstituted. When one or more positions on a group are said to be "not substituted" or "unsubstituted", then hydrogen atoms are attached to take up any free valency.
Unless otherwise indicated, a "ring" or "ring system" as a component of Formula 1 is carbocyclic or heterocyclic. The term "ring system" denotes two or more fused rings. The term "ring member" refers to an atom or other moiety (e.g., C(O), C(=S), S(O) or S(O)2) forming the backbone of a ring or ring system. The terms "carbocyclic ring" or "carbocycle" denotes a ring wherein the atoms forming the ring backbone are selected only from carbon. "Saturated carbocyclic" refers to a ring having a backbone consisting of carbon atoms linked to one another by single bonds; unless otherwise specified, the remaining carbon valences are occupied by hydrogen atoms. The terms "heterocyclic ring", "heterocycle" or "heterocyclic ring system" denote a ring or ring system in which at least one atom forming the ring backbone is not carbon, e.g., nitrogen, oxygen or sulfur.
"Aromatic" indicates that each of the ring atoms is essentially in the same plane and has a /?-orbital perpendicular to the ring plane, and that (4n + 2) π electrons, where n is a positive integer, are associated with the ring to comply with Hϋckel's rule. Accordingly, neither the dihydro isoxazoline ring of Formula 1 nor the dihydro oxo azinyl rings of J-I, J-2, J-3 and J-4 are aromatic.
As used herein, the following definitions shall apply unless otherwise indicated. The term "optionally substituted" is used interchangeably with the phrase "substituted or unsubstituted" or with the term "(un)substituted." Unless otherwise indicated, an optionally substituted group may have a substituent at each substitutable position of the group, and each substitution is independent of the other.
As noted above, Z can be (among others) a 5- or 6-membered heterocyclic ring, which may be saturated or unsaturated, optionally substituted with up to two substituents selected from a group of substituents as defined in the Summary of the Invention. Examples of a 5- or 6-membered fully unsaturated aromatic heterocyclic ring optionally substituted with from up to two substituents include the rings U-2 through U-61 illustrated in Exhibit 1 wherein Rv is any substituent as defined in the Summary of the Invention for Z (i.e. R17 on carbon ring members and R18 on nitrogen ring members) and r is an integer from 0 to 2, limited by the number of available positions on each U group. As U-29, U-30, U-36, U-37, U-38, U-39, U- 40, U-41, U-42 and U-43 have only one available position, for these U groups r is limited to the integers 0 or 1 , and r being 0 means that the U group is unsubstituted and a hydrogen is present at the position indicated by (Rv)r.
Exhibit 1
Figure imgf000010_0001
Figure imgf000011_0001
Figure imgf000012_0001
Examples of saturated or partially unsaturated 5- or 6-membered heterocyclic rings include the rings G-I through G-35 as illustrated in Exhibit 2. Note that when the attachment point on the G group is illustrated as floating, the G group can be attached to the remainder of Formula 1 through any available carbon or nitrogen of the G group by replacement of a hydrogen atom. The optional substituents corresponding to Rv can be attached to any available carbon or nitrogen by replacing a hydrogen atom. For these G rings, r is an integer from 0 to 2, limited by the number of available positions on each G group.
Note that when Z is a 5- or 6-membered heterocyclic ring optionally substituted with up to two substituents selected from the group of substituents as defined in the Summary of the Invention for Z, one or two carbon ring members of the heterocycle can optionally be in the oxidized form of a carbonyl moiety.
Note that when Z comprises a ring selected from G-28 through G-35, G2 is selected from O, S or N. Note that when G2 is N, the nitrogen atom can complete its valence by substitution with either H or the substituents corresponding to Rv as defined in the Summary of the Invention for Z (i.e. R17 on carbon ring members and R18 on nitrogen ring members).
Exhibit 2
Figure imgf000012_0002
,
Figure imgf000013_0001
A wide variety of synthetic methods are known in the art to enable preparation of aromatic and nonaromatic heterocyclic rings and ring systems; for extensive reviews see the eight volume set of Comprehensive Heterocyclic Chemistry, A. R. Katritzky and C. W. Rees editors-in-chief, Pergamon Press, Oxford, 1984 and the twelve volume set of Comprehensive Heterocyclic Chemistry II, A. R. Katritzky, C. W. Rees and E. F. V. Scriven editors-in-chief, Pergamon Press, Oxford, 1996.
Compounds of this invention can exist as one or more stereoisomers. The various stereoisomers include enantiomers, diastereomers, atropisomers and geometric isomers. Furthermore, when m is 1, the compounds of the invention are sulfoxides, which can exist in two enantiomeric forms. The adjacent carbon (i.e. -CR6R7-) can also exist in two enantiomeric forms when the variables R6 and R7 are different. One skilled in the art will appreciate that one stereoisomer may be more herbicidally active and/or may exhibit beneficial effects when enriched relative to the other stereoisomer(s) or when separated from the other stereoisomer(s). Additionally, the skilled artisan knows how to separate, enrich, and/or to selectively prepare said stereoisomers. The compounds of the invention may be present as a mixture of stereoisomers, individual stereoisomers or as an optically active form.
One skilled in the art will appreciate that not all nitrogen-containing heterocycles can form JV-oxides since the nitrogen requires an available lone pair for oxidation to the oxide; one skilled in the art will recognize those nitrogen-containing heterocycles which can form TV-oxides. One skilled in the art will also recognize that tertiary amines can form JV-oxides. Synthetic methods for the preparation of iV-oxides of heterocycles and tertiary amines are very well known by one skilled in the art including the oxidation of heterocycles and tertiary amines with peroxy acids such as peracetic and m-chloroperbenzoic acid (MCPBA), hydrogen peroxide, alkyl hydroperoxides such as t-butyl hydroperoxide, sodium perborate, and dioxiranes such as dimethyldioxirane. These methods for the preparation of iV-oxides have been extensively described and reviewed in the literature, see for example: T. L. Gilchrist in Comprehensive Organic Synthesis, vol. 7, pp 748-750, S. V. Ley, Ed., Pergamon Press; M. Tisler and B. Stanovnik in Comprehensive Heterocyclic Chemistry, vol. 3, pp 18-20, A. J. Boulton and A. McKillop, Eds., Pergamon Press; M. R. Grimmett and B. R. T. Keene in Advances in Heterocyclic Chemistry, vol. 43, pp 149-161, A. R. Katritzky, Ed., Academic Press; M. Tisler and B. Stanovnik in Advances in Heterocyclic Chemistry, vol. 9, pp 285-291, A. R. Katritzky and A. J. Boulton, Eds., Academic Press; and G. W. H. Cheeseman and E. S. G. Werstiuk in Advances in Heterocyclic Chemistry, vol. 22, pp 390-392, A. R. Katritzky and A. J. Boulton, Eds., Academic Press.
One skilled in the art recognizes that because in the environment and under physiological conditions salts of chemical compounds are in equilibrium with their corresponding nonsalt forms, salts share the biological utility of the nonsalt forms. Thus a wide variety of salts of the compounds of Formula 1 are useful for control of undesired vegetation (i.e. are agriculturally suitable). The salts of the compounds of Formula 1 include acid-addition salts with inorganic or organic acids such as hydrobromic, hydrochloric, nitric, phosphoric, sulfuric, acetic, butyric, fumaric, lactic, maleic, malonic, oxalic, propionic, salicylic, tartaric, 4-toluenesulfonic or valeric acids. When a compound of Formula 1 contains an acidic moiety such as a carboxylic acid, salts also include those formed with organic or inorganic bases such as pyridine, triethylamine or ammonia, or amides, hydrides, hydroxides or carbonates of sodium, potassium, lithium, calcium, magnesium or barium. Accordingly, the present invention comprises compounds selected from Formula 1, JV-oxides and agriculturally suitable salts thereof.
Compounds selected from Formula 1, (including all stereoisomers, iV-oxides, and salts thereof), typically exist in more than one form, and Formula 1 thus includes all crystalline and non-crystalline forms of the compounds that Formula 1 represents. Non-crystalline forms include embodiments which are solids such as waxes and gums as well as embodiments which are liquids such as solutions and melts. Crystalline forms include embodiments which represent essentially a single crystal type and embodiments which represent a mixture of polymorphs (i.e. different crystalline types). The term "polymorph" refers to a particular crystalline form of a chemical compound that can crystallize in different crystalline forms, these forms having different arrangements and/or conformations of the molecules in the crystal lattice. Although polymorphs can have the same chemical composition, they can also differ in composition due the presence or absence of co- crystallized water or other molecules, which can be weakly or strongly bound in the lattice. Polymorphs can differ in such chemical, physical and biological properties as crystal shape, density, hardness, color, chemical stability, melting point, hygroscopicity, suspensibility, dissolution rate and biological availability. One skilled in the art will appreciate that a polymorph of a compound represented by Formula 1 can exhibit beneficial effects (e.g., suitability for preparation of useful formulations, improved biological performance) relative to another polymorph or a mixture of polymorphs of the same compound represented by Formula 1. Preparation and isolation of a particular polymorph of a compound represented by Formula 1 can be achieved by methods known to those skilled in the art including, for example, crystallization using selected solvents and temperatures.
Of note is a compound selected from Formula 1 (including all geometric and stereoisomers), TV-oxides, and salts thereof, wherein each R9a, R9b, R9c, R9d, R1Oa, R10b, R10c5 R10d5 RlIa5 RlIb5 RlIc and RlId js independently H, halogen, cyano, C1-C7 alkyl, C2- C7 alkenyl, C2-C7 alkynyl, C3-C7 cycloalkyl, C4-C7 cycloalkylalkyl, C4-C7 alkylcycloalkyl, C1-C7 haloalkyl, C2-C7 haloalkenyl, C3-C7 haloalkynyl, C3-C7 halocycloalkyl, C1-C7 alkoxy, C1-C7 haloalkoxy, C2-C7 alkenyloxy, C2-C7 haloalkenyloxy, C3-C7 cycloalkoxy, C3-C7 halocycloalkoxy, C2-C7 alkynyloxy, C4-C7 cycloalkylalkoxy, C4-C7 halocycloalkylalkoxy, C1-C7 alkylthio, C1-C7 haloalkylthio, C1- C7 haloalkylsulfmyl, C1-C7 haloalkylsulfonyl, C1-C6 alkylamino, C2-C7 dialkylamino, C1- C7 haloalkylamino, C2-C7 alkylcarbonyl, C2-C7 alkoxycarbonyl, C2-C7 haloalkylcarbonyl, C2-C7 haloalkoxycarbonyl, C3-C7 alkylcarbonylalkyl, C3-C7 alkoxycarbonylalkyl, aminocarbonyl, C2-Cg alkylaminocarbonyl, C2-Cg haloalkylaminocarbonyl, C3-Cg dialkylaminocarbonyl, C3-Cg haloalkyl(alkyl)aminocarbonyl, C4-C7 cycloalkylamino- carbonyl, C5~Cg cycloalkyl(alkyl)aminocarbonyl, C4-C7 halocycloalkylalkyl, C2-C7 alkoxyalkyl, C2-C7 haloalkoxyalkyl, C2-C7 alkylthioalkyl, C2-C7 alkylsulfonylalkyl, C2- C7 alkylsulfϊnylalkyl, C2-C7 cyanoalkyl, C2-C7 haloalkylthioalkyl, C2-C7 haloalkylsulfonylalkyl, C2-C7 haloalkylsulfϊnylalkyl, C3~C7 haloalkoxycarbonylalkyl, C3- C7 haloalkylcarbonylalkyl, C2-C7 alkoxyalkoxy, C2-C7 haloalkoxyalkoxy, C2-C7 alkylthioalkoxy, C2-C7 haloalkylthioalkoxy, C2-C7 haloalkylsulfonylalkoxy, C2-C7 haloalkylsulfϊnylalkoxy, nitro, C3-C10 trialkylsilyl, aminosulfonyl, Cj-C7 alkylaminosulfonyl, C^-C7 haloalkylaminosulfonyl, C2-Cg dialkylaminosulfonyl, C3-C8 haloalkyl(alkyl)aminosulfonyl, C3-C6 cycloalkylaminosulfonyl or C^C7 cycloalkyl(alkyl)aminosulfonyl (i.e. each R9a, R9b, R9c, R9d, R1Oa, R10b, R1Oc, R10d, Rlla, Rllb, Rllc and Rlld is other than Z). Also of note is a herbicidal composition comprising (a herbicidally effective amount of) a compound selected from Formula 1, JV-oxides, and salts thereof wherein the sum of n and m is 1 or 2, and each R9a, R9b, R9c, R9d, R1Oa, R10b, R1Oc, R10d, Rlla, Rllb, Rllc and Rlld is other than Z; and at least one component selected from the group consisting of surfactants, solid diluents and liquid diluents. Also of note is said herbicidal composition further comprising (an effective amount of) at least one additional active ingredient selected from the group consisting of other herbicides and herbicide safeners. Also of note is a method for controlling the growth of undesired vegetation comprising contacting the vegetation or its environment with a herbicidally effective amount of a compound selected from Formula 1, JV-oxides, and salts thereof wherein the sum of n and m is 1 or 2, and each R9a, R9b, R9c, R9d, R1Oa, R10b, R1Oc, R10d, Rlla, Rllb, Rllc and R1 ld is other than Z.
Embodiments of the present invention as described in the Summary of the Invention include those described below. In the following Embodiments, Formula 1 includes iV-oxides and salts thereof, and reference to "a compound of Formula 1" includes the definitions of substituents specified in the Summary of the Invention unless further defined in the Embodiments.
Embodiment 1. A compound of Formula 1 wherein R1 is methyl, ethyl, fluoromethyl (i.e. monofluoromethyl), hydroxymethyl or chloromethyl (i.e. monochloromethyl) .
Embodiment 2. A compound of Embodiment 1 wherein R1 is methyl, fluoromethyl or chloromethyl.
Embodiment 3. A compound of Embodiment 2 wherein R1 is methyl or chloromethyl
(i.e. monochloromethyl).
Embodiment 4. A compound of Embodiment 3 wherein R1 is methyl. Embodiment 5. A compound of Embodiment 3 wherein R1 is chloromethyl. Embodiment 6. A compound of Formula 1 or any one of Embodiments 1 through 5 wherein R2 is methyl.
Embodiment 7. A compound of Formula 1 or any one of Embodiments 1 through 6 wherein R3 is H, F or Br. Embodiment 8. A compound of Embodiment 7 wherein R3 is F or Br.
Embodiment 9. A compound of Embodiment 7 wherein R3 is H.
Embodiment 10. A compound of Formula 1 or any one of Embodiments 1 through 9 wherein R4 is H. Embodiment 11. A compound of Formula 1 or any one of Embodiments 1 through 10 wherein R5 is H, CH3 or F.
Embodiment 12. A compound of Embodiment 11 wherein R5 is F. Embodiment 13. A compound of Embodiment 11 wherein R5 is H. Embodiment 14. A compound of Formula 1 or any one of Embodiments 1 through 13 wherein R6 is H.
Embodiment 15. A compound of Formula 1 or any one of Embodiments 1 through 14 wherein the sum of n + m is greater than 0. Embodiment 16. A compound of Formula 1 or any one of Embodiments 1 through 15 wherein n is 0. Embodiment 17. A compound of Formula 1 or any one of Embodiments 1 through 15 wherein m is 1 or 2.
Embodiment 18. A compound of Embodiment 17 wherein m is 1. Embodiment 19. A compound of Embodiment 17 wherein m is 2. Embodiment 20. A compound of Formula 1 or any one of Embodiments 1 through 14 wherein n and m are both 0.
Embodiment 21. A compound of Formula 1 or any one of Embodiments 1 through 20 wherein J is J-I, J-2 or J-3.
Embodiment 22. A compound of Embodiment 21 wherein J is J-I or J-2. Embodiment 23. A compound of Embodiment 20 wherein J is J-I . Embodiment 24. A compound of Formula 1 or any one of Embodiments 1 through 23 wherein independently R8a, R8b, R8c and R8d are C1-C4 alkyl, C1-C4 haloalkyl,
C2-C4 alkyloxyalkyl or C2-C4 alkynyl. Embodiment 25. A compound of Embodiment 24 wherein independently R8a, R8b, R8c and R8d are CH3, CH2CH3, CH2CF3, CH2OCH3, n-propyl or CH2C≡CH. Embodiment 26. A compound of Embodiment 25 wherein independently R8a, R8b, R8c and R8d are CH3, CH2CH3 or CH2CF3. Embodiment 26a. A compound of Embodiment 26 wherein R8a, R8b, R8c and R8d are
CH3.
Embodiment 27. A compound of Formula 1 or any one of Embodiments 1 through 22 wherein independently R9a, R9b, R9c, R9d, Rllc and Rlld are H, halogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 cycloalkyl, C2-C6 alkoxyhaloalkyl or phenyl substituted with up to one R16. Embodiment 28. A compound of Embodiment 27 wherein independently R9a, R9b, R9c, R9d, Rllc and Rlld are H, halogen, CH2CH3, /-propyl, n- propyl, /-butyl, cyclopropyl, CF3, CF2Cl, CF2Br, CF2CF3, OCHF2, OCH2CF3, CF2OCH3, phenyl, 2-fluorophenyl or 4-fluorophenyl. Embodiment 29. A compound of Embodiment 28 wherein independently R9a, R9b, R9c,
R9d, Rllc and Rlld are CF3, Br, OCHF2 or OCH2CF3.
Embodiment 29a. A compound of Embodiment 27 wherein R9a is CH3, CF3, CF2Cl or CF2OCH3.
Embodiment 29b. A compound of Embodiment 29a wherein R9a, R9b, R9c and R9d are CF3.
Embodiment 30. A compound of Formula 1 or any one of Embodiments 1 through 29 wherein independently R1Oa, R10b, R1Oc, R10d, Rlla and Rllb are H, C1-C7 alkyl, C3-C7 cycloalkyl, C1-C7 haloalkyl, C2-C7 haloalkenyl, C3-C7 haloalkynyl, C1-C7 alkoxy, C1-C7 haloalkoxy, C3-C7 cycloalkoxy, C 4-C7 cycloalkylalkoxy, C1-C7 alkylthio, C1-C6 alkylamino, C1-C7 haloalkylamino,
C2-C7 alkoxycarbonyl, C3-Cg dialkylaminocarbonyl, C2-C7 alkoxyalkoxy, C2- C7 haloalkylsulfmylalkoxy, -C(=NOR14)R15, C2-C6 cyanoalkoxy, C2-C6 alkoxyhaloalkyl or C3-C7 alkoxycarbonylalkoxy; or phenyl optionally substituted with up to two substituents selected from R16; or furanyl, pyrazolyl, isoxazolyl, thienyl, pyrrolidinyl or pyridinyl, each optionally substituted with up to two substituents selected from R17 on carbon ring members and R18 on nitrogen ring members.
Embodiment 31. A compound of Formula 1 or any one Embodiments 1 through 30 wherein independently R1Oa, R10b, R1Oc, R10d, Rlla and Rllb are H, CH3, CH2CH3, cyclopropyl, OCH3, OCH2CH3 or SCH3.
Embodiment 31a. A compound of Embodiment 31 wherein R1Oa is H, CH3, CH2CH3, cyclopropyl, OCH3 or OCH2CH3.
Embodiment 31b. A compound of Embodiment 31a wherein R1Oa is CH3, cyclopropyl
Or OCH3. Embodiment 32. A compound of Formula 1 or any one of Embodiments 1 through 31 wherein independently Rlla and Rllb are H.
Embodiment 33. A compound of Formula 1 or any one of Embodiments 1 through 32 wherein independently Q1 is CR9a, Q2 is CR9b, Q3 is CR9c and Q4 is CR9d.
Embodiment 34. A compound of Formula 1 or any one of Embodiments 1 through 33 wherein when J is J-I , then Q1 is CR9a, W1 is CR1Oa and Y1 is N, or Q1 is CR9a,
W1 is N and Y1 is CRlla, or Q1 is CR9a, W1 is CR1Oa and Y1 is CRlla.
Embodiment 35. A compound of Embodiment 34 wherein when J is J-I, then Q1 is CR9a, W1 is CR1Oa and Y1 is N, or Q1 is CR9a, W1 is N and Y1 is CRlla. Embodiment 36. A compound of Embodiment 35 wherein when J is J-I, then Q1 is
CR9a, W1 is CR1Oa and Y1 is N. Embodiment 37. A compound of Embodiment 35 wherein when J is J-I, then Q1 is
CR9a, W1 is N and Y1 is CRlla. Embodiment 38. A compound of Formula 1 or any one of Embodiments 1 through 37 wherein when J is J-2, then Q2 is CR9b, W2 is CR10b and Y2 is N, or Q2 is CR9b,
W2 is N and Y2 is CRllb, or Q2 is CR9b, W2 is R10b and Y2 is CRllb. Embodiment 39. A compound of Embodiment 38 wherein when J is J-2, then Q2 is
CR9b, W2 is CR10b and Y2 is N, or Q2 is CR9b, W2 is N and Y2 is CR1 lb. Embodiment 40. A compound of Embodiment 39 wherein when J is J-2, then Q2 is
CR9b, W2 is CR10b and Y2 is N. Embodiment 41. A compound of Embodiment 39 wherein when J is J-2, then Q2 is
CR9b, W2 is N and Y2 is CR1 lb.
Embodiment 42. A compound of Formula 1 or any one of Embodiments 1 through 41 wherein when J is J-3, then Q3 is CR9c, W3 is N and Y3 is CRllc, or Q3 is CR9c,
W3 is CR1Oc and Y3 is CRllc. Embodiment 43. A compound of Embodiment 42 wherein when J is J-3, then Q3 is
CR9c, W3 is CR1Oc and Y3 is CRllc.
Embodiment 44. A compound of Formula 1 or any one of Embodiments 1 through 43 wherein when J is J-4, then Q4 is CR9d, W4 is N and Y4 is CR1 ld, or Q4 is CR9d,
W4 is CR10d and Y4 is CRlld. Embodiment 45. A compound of Embodiment 44 wherein when J is J-4, then Q4 is
CR9d, W4 is CR10d and Y4 is CRlld.
Embodiment 46. A compound of Formula 1 or any of Embodiments 1 through 45 wherein each R12 is independently H or CH3.
Embodiment 47. A compound of Formula 1 or any of Embodiments 1 through 46 wherein each R13 is independently H, CH3 or OCH3. Embodiment 48. A compound of Formula 1 or any of Embodiments 1 through 45 wherein R12 and R13 in an instance of -ON=CR12R13 are taken together as -CH2CH2CH2CH2-.
Embodiment 49. A compound of Formula 1 or any of Embodiments 1 through 48 wherein each R14 is CH3. Embodiment 50. A compound of Formula 1 or any of Embodiments 1 through 49 wherein each R15 is H. Embodiment 51. A compound of Formula 1 or any of Embodiments 1 through 48 wherein R14 and R15 in an instance of -C(=NOR14)R15are taken together as
-CH2CH2-. Embodiment 52. A compound of Formula 1 or any of Embodiments 1 through 51 wherein each R16 is independently C1-C6 alkyl or halogen. Embodiment 53. A compound of Formula 1 or any of Embodiments 1 through 52 wherein each R17 is independently C1-C6 alkyl or halogen. Embodiment 54. A compound of Formula 1 or any of Embodiments 1 through 52 wherein each R18 is independently CH3 or CH2CH3.
Embodiment 55. A compound of Formula 1 or any one of Embodiments 1 through 53 wherein each R9a, R9b, R9c, R9d, R1Oa, R10b, R1Oc, R10d, Rlla, Rllb, Rllc and R1 ld is other than Z. Embodiments of this invention, including Embodiments 1-55 above as well as any other embodiments described herein, can be combined in any manner, and the descriptions of variables in the embodiments pertain not only to the compounds of Formula 1 but also to the starting compounds and intermediate compounds useful for preparing the compounds of Formula 1. In addition, embodiments of this invention, including Embodiments 1-55 above as well as any other embodiments described herein, and any combination thereof, pertain to the compositions and methods of the present invention.
Combinations of Embodiments 1-55 are illustrated by: Embodiment A. A compound of Formula 1 wherein
R1 is methyl, ethyl, fluoromethyl, hydroxymethyl or chloromethyl; R2 is methyl;
R3 is H, F or Br; R4 is H;
R5 is H, CH3 or F; R6 is H; n is 0; m is 1 or 2;
R8a, R8b, R8c and R8d are C1-C4 alkyl, C1-C4 haloalkyl, C2-C4 alkyloxyalkyl or
C2-C4 alkynyl;
R9a, R9b, R9c, R9d, Rllc and Rlld are H, halogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 cycloalkyl, C2-C6 alkoxyhaloalkyl or phenyl substituted with up to one R16;
R10a5 R10b? RlOc5 RlOd Rlla and Rllb are H, C1-C7 alkyl, C3-C7 cycloalkyl, C1-C7 haloalkyl, C2-C7 haloalkenyl, C3-C7 haloalkynyl, C1-C7 alkoxy, C1-C7 haloalkoxy, C3-C7 cycloalkoxy, C4-C7 cycloalkylalkoxy, C1-C7 alkylthio, C1-C6 alkylamino, C1-C7 haloalkylamino, C2-C7 alkoxycarbonyl, C3-Cg dialkylaminocarbonyl, C2-C7 alkoxyalkoxy, C2-C7 haloalkylsulfmylalkoxy, -C(=NOR14)R15, C2-C6 cyanoalkoxy, C2-C6 alkoxyhaloalkyl or C3-C7 alkoxycarbonylalkoxy; or phenyl optionally substituted with up to two substituents selected from R16; or pyridinyl, furanyl or pyrrolidinyl, each optionally substituted with up to two substituents selected from R17 on carbon ring members and R18 on nitrogen ring members; R14 is CH3; R15 is H; each R16 is Cj-C6 alkyl or halogen; each R17 is Cj-C6 alkyl or halogen; and each R18 is C1-C6 alkyl.
Embodiment B. A compound of Formula 1 or Embodiment A wherein R1 is methyl, fluoromethyl or chloromethyl;
R3 is H; R5 is H J is J-I;
R8a is CH3, CH2CH3, CH2CF3, CH2OCH3, n-propyl or CH2C≡CH; Q1 is CR9a, W1 is CR1Oa and Y1 is N, or Q1 is CR9a, W1 is N and Y1 is CRlla;
R9a is CH3, CF3, CF2Cl or CF2OCH3; and R1Oa is H, CH3, CH2CH3, cyclopropyl, OCH3 or OCH2CH3. Embodiment C. A compound of Formula 1 or Embodiment B wherein
Q1 is CR9a, W1 is CR1Oa and Y1 is N; R8a is CH3
R9a is CF3; and
R1Oa is CH3, cyclopropyl or OCH3.
Specific embodiments include compounds of Formula 1 selected from the group consisting of: 5-[[(4,5-dihydro-5,5-dimethyl-3-isoxazolyl)sulfonyl]methyl]-2,3-dimethyl-6-
(trifluoromethyl)-4(3H)-pyrimidinone, 5-[[(4,5-dihydro-5,5-dimethyl-3-isoxazolyl)sulfonyl]methyl]-2-ethyl-3-methyl-6-
(trifluoromethyl)-4(3H)-pyrimidinone,
5-[[(4,5-dihydro-5,5-dimethyl-3-isoxazolyl)sulfonyl]methyl]-2-ethoxy-3-methyl-6- (trifluoromethyl)-4(3H)-pyrimidinone or
5-[[(4,5-dihydro-5,5-dimethyl-3-isoxazolyl)sulfonyl]methyl]-3-ethyl-2-methoxy-6-
(trifluoromethyl)-4(3H)-pyrimidinone.
Embodiments of the present invention as described in the Summary of the Invention also include those described below. In the following Embodiments, Formula 1 includes N- oxides and salts thereof, and reference to "a compound of Formula 1" includes the definitions of substituents specified in the Summary of the Invention unless further defined in the Embodiments. Embodiment Dl. A compound of Formula 1 wherein R1 is methyl or chloromethyl (i.e. monochloromethyl) .
Embodiment D2. A compound of Embodiment 1 wherein R1 is methyl. Embodiment D3. A compound of Embodiment 1 wherein R1 is chloromethyl. Embodiment D4. A compound of Formula 1 or any one of Embodiments Dl through
D3 wherein R2 is methyl. Embodiment D5. A compound of Formula 1 or any one of Embodiments Dl through
D4 wherein R3 is H.
Embodiment D6. A compound of Formula 1 or any one of Embodiments Dl through D5 wherein R4 is H.
Embodiment D7. A compound of Formula 1 or any one of Embodiments Dl through
D6 wherein R5 is H. Embodiment D8. A compound of Formula 1 or any one of Embodiments Dl through
D7 wherein R6 is H. Embodiment D9. A compound of Formula 1 or any one of Embodiments Dl through
D8 wherein the sum of n + m is greater than 0. Embodiment DlO. A compound of Formula 1 or any one of Embodiments Dl through
D9 wherein n is 0.
Embodiment DI l. A compound of Embodiment DlO wherein m is 2. Embodiment D 12. A compound of Embodiment DlO wherein m is 1.
Embodiment D13. A compound of Formula 1 or any one of Embodiments Dl through
D 8 wherein n and m are both 0. Embodiment D 14. A compound of Formula 1 or any one of Embodiments Dl through
D13 wherein J is J-I, J-2 or J-3. Embodiment D15. A compound of Formula 1 or any one of Embodiments Dl through
D13 wherein J is J-I, J-2 or J-4. Embodiment D 16. A compound of Formula 1 or any one of Embodiments Dl through
D13 wherein J is J-I, J-3 or J-4.
Embodiment D 17. A compound of Formula 1 or any one of Embodiments Dl through D13 wherein J is J-2, J-3 or J-4.
Embodiment D 18. A compound of Formula 1 or any one of Embodiments Dl through
D13 wherein J is J-I. Embodiment D 19. A compound of Formula 1 or any one of Embodiments Dl through
D13 wherein J is J-2. Embodiment D20. A compound of Formula 1 or any one of Embodiments Dl through
D13 wherein J is J-3. Embodiment D21. A compound of Formula 1 or any one of Embodiments Dl through
D13 wherein J is J-4. Embodiment D22. A compound of Formula 1 or any one of Embodiments Dl through
D21 wherein independently R8a, R8b, R8c and R8d are C1-C2 alkyl. Embodiment D23. A compound of Formula 1 or any one of Embodiments Dl through
D22 wherein independently R9a, R9b, R9c, R9d, Rllc and Rlld are CF3, OCHF2, OCH2CF35 F, Br or CL
Embodiment D24. A compound of Embodiment D23 wherein independently R9a, R9b,
R9c, R9d, Rllc and Rlld are CF3, OCHF2, OCH2CF3 or CL Embodiment D25. A compound of Formula 1 or any one of Embodiments Dl through
D24 wherein independently R1Oa, R10b, R1Oc, R10d Rlla and Rllb are H, CH3, CH2CH3, cyclopropyl, OCH3 or OCH2CH3.
Embodiment D26. A compound of Formula 1 or any one of Embodiments Dl through
D25 wherein independently Rlla and Rllb are H. Embodiment D27. A compound of Formula 1 or any one of Embodiments Dl through
D26 wherein independently Q1 is CR9a, Q2 is CR9b, Q3 is CR9c and Q4 is CR9d. Embodiment D28. A compound of Formula 1 or any one of Embodiments Dl through
D16, D18, and D22 through D27 wherein when J is J-I, then Q1 is CR9a, W1 is
CR1Oa and Y1 is N, or Q1 is CR9a, W1 is N and Y1 is CRlla, or Q1 is CR9a, W1 is CR1^ aM Y1 is CR1 la.
Embodiment D29. A compound of Embodiment D28 wherein when J is J-I, then Q1 is CR9a, W1 is CR1Oa and Y1 is N, or Q1 is CR9a, W1 is N and Y1 is CR1 la.
Embodiment D30. A compound of Embodiment D29 wherein when J is J-I, then Q1 is
CR9a, W1 is CR1Oa and Y1 is N. Embodiment D31. A compound of Embodiment D29 wherein when J is J- 1 , then Q l is
CR9a, W1 is N and Y1 is CRlla. Embodiment D32. A compound of Formula 1 or any one of Embodiments Dl through
D 15, D 17, D 19, and D22 through D27 wherein when J is J-2, then Q2 is CR9b,
W2 is CR10b and Y2 is N, or Q2 is CR9b, W2 is N and Y2 is CR1 lb, or Q2 is
CR9b, W2 is R10b and Y2 is CRllb.
Embodiment D33. A compound of Embodiment D32 wherein when J is J-2, then Q2 is CR9b, W2 is CR10b and Y2 is N, or Q2 is CR9b, W2 is N and Y2 is CR1 lb.
Embodiment D34. A compound of Embodiment D33 wherein when J is J-2, then Q2 is
CR9b, W2 is CR10b and Y2 is N. Embodiment D35. A compound of Embodiment D33 wherein when J is J-2, then Q2 is
CR9b, W2 is N and Y2 is CR1 lb. Embodiment D36. A compound of Formula 1 or any one of Embodiments Dl through
D 14, D16 through D 17, D20, and D22 through D27 wherein when J is J-3, then
Q3 is CR9c, W3 is N and Y3 is CRllc, or Q3 is CR9c, W3 is CR1Oc and Y3 is
CRllc. Embodiment D37. A compound of Embodiment D36 wherein when J is J-3, then Q3 is
CR9c, W3 is N and Y3 is CRllc.
Embodiment D38. A compound of Formula 1 or any one of Embodiments Dl through D 13, D15 through D 17, and D21 through D27 wherein when J is J-4, then Q4 is CR9d, W4 is N and Y4 is CR1 ld, or Q4 is CR9d, W4 is CR10d and Y4 is CR1 ld.
Embodiment D39. A compound of Embodiment D38 wherein when J is J-4, then Q4 is
CR9d, W4 is N and Y4 is CR1 ld.
Embodiment D40. A compound of Formula 1 or any one of Embodiments Dl through D39 wherein each R9a, R9b, R9c, R9d, R1Oa, R10b, R1Oc, R10d, Rlla, Rllb, Rllc and R11 d is other than Z .
Embodiments of this invention, including Embodiments D1-D40 above as well as any other embodiments described herein, can be combined in any manner, and the descriptions of variables in the embodiments pertain not only to the compounds of Formula 1 but also to the starting compounds and intermediate compounds useful for preparing the compounds of Formula 1. In addition, embodiments of this invention, including Embodiments D1-D40 above as well as any other embodiments described herein, and any combination thereof, pertain to the compositions and methods of the present invention. Combinations of Embodiments D1-D40 are illustrated by:
Embodiment EA. A compound of Formula 1 wherein R1 is methyl, R2 is methyl, R3 is H and R4 is H.
Embodiment EB. A compound of Formula 1 wherein R1 is methyl, R2 is chloromethyl,
R3 is H and R4 is H.
Specific embodiments include compounds of Formula 1 selected from the group consisting of: 5-[[(4,5-dihydro-5,5-dimethyl-3-isoxazolyl)sulfinyl]methyl]-2-methoxy-3-methyl-6-
(trifluoromethyl)-4(3H)-pyrimidinone; and
5-[[(4,5-dihydro-5,5-dimethyl-3-isoxazolyl)sulfonyl]methyl]-2-methoxy-3-methyl-6- (trifluoromethyl)-4(3H)-pyrimidinone.
This invention also relates to a method for controlling undesired vegetation comprising applying to the locus of the vegetation herbicidally effective amounts of the compounds of the invention (e.g., as a composition described herein). Of note as embodiments relating to methods of use are those involving the compounds of embodiments described above. Also of note is the use of compounds of the invention for selective control of weeds in wheat, barley, and particularly maize, soybean, cotton and perennial crops such as sugarcane and citrus.
Also noteworthy as embodiments are herbicidal compositions of the present invention comprising the compounds of embodiments described above. One or more of the following methods and variations as described in Schemes 1-10 can be used to prepare the compounds of Formula 1. The definitions of J, R1, R2, R3, R4, R5, R6, R8, R9, R10, R11, m and n in the compounds of Formulae 1-42 below are as defined above in the Summary of the Invention unless otherwise noted. Formulae Ia-Ie are various subsets of Formula 1, and all substituents for Formulae Ia-Ie are as defined above for Formula 1 unless otherwise noted.
Sulfoxides and sulfones of Formula 1 where m is 1 or 2 and n is 0 can be made via oxidation of the linking sulfur atom on sulfides of Formula Ia (i.e. Formula 1 where m and n are both 0). As illustrated in Scheme 1, compounds of Formula Ib (i.e. Formula 1 wherein n is 0) wherein m is 1 (i.e. sulfoxides) or 2 (i.e. sulfones) are prepared by oxidizing sulfides of Formula Ia with a suitable oxidizing agent. In a typical procedure, an oxidizing agent in an amount from 1 to 4 equivalents depending on the oxidation state of the product desired is added to a solution of the compound of Formula Ia in a solvent. Useful oxidizing agents include Oxone® (potassium peroxymonosulfate), hydrogen peroxide, sodium periodate, peracetic acid and 3-chloroperbenzoic acid. The solvent is selected with regard to the oxidizing agent employed. Aqueous ethanol or aqueous acetone is preferably used with potassium peroxymonosulfate, and dichloromethane is generally preferable with 3-chloroperbenzoic acid. Useful reaction temperatures typically range from 0 to 90 0C. Particular procedures useful for oxidizing sulfides to sulfoxides and sulfones are described by Brand et al, J. Agric. Food Chem. 1984, 32, 221-226 and references cited therein.
Scheme 1
Figure imgf000025_0001
As shown in Scheme 2, sulfoximines of Formula Ic (i.e. Formula 1 wherein m and n are 1 and R7 is H) can be prepared from corresponding sulfoxides of Formula Ib (i.e. Formula 1 where m is 1 and n is 0) by treatment with hydrazoic acid. The hydrazoic acid is conveniently generated in situ from sodium azide and sulfuric acid. In a typical procedure, sodium azide is added to a mixture of a sulfoxide, concentrated sulfuric acid and a suitable solvent for the sulfoxide such as dichloromethane or chloroform. Useful temperatures range from room temperature to the reflux temperature of the solvent. Scheme 2
Figure imgf000026_0001
As shown in Scheme 3, substituted sulfoximines of Formula Id (i.e. Formula 1 where m and n are 1 and R7 is other than H) can be prepared from corresponding sulfoximines of Formula Ic by reaction with an appropriate electrophilic reactant comprising R7. In the present context, "electrophilic reactant comprising R7" means a reactant capable of transferring R7 to form a bond with a nucleophile (in this case the sulfoximine nitrogen). Many electrophilic reactants comprising R7 correspond to the formula R7X1 wherein X1 is a nucleophilic reaction leaving group, also known as a nucleofuge. Common nucleofuges, i.e. X1, include, for example, halides such as Cl, Br and I, and sulfonates such as methanesulfonate, trifluoromethanesulfonate and 4-methylbenzenesulfonate. Reactions with electrophilic reactants of the formula R7X1 are often conducted in the presence of a base as well as a solvent. For example, reaction of a compound of Formula Ic with cyanogen bromide (BrCN) in the presence of base gives the compound of Formula Id where R7 is cyano. As further examples, reaction of a compound of Formula Ic with an alkylcarbonyl halide, an alkoxycarbonyl halide or an alkylsulfonyl halide in the presence of a base gives the corresponding compound of Formula Id where R7 is alkylcarbonyl, alkoxycarbonyl or alkylsulfonyl, respectively.
Scheme 3
Figure imgf000026_0002
As shown in Scheme 4, sulfϊlimines of Formula Ie (i.e. Formula 1 where m is 0, n is 1 and R7 is cyano or a radical bonded through a carbonyl or sulfonyl moiety) can be made by reaction of a sulfide of Formula Ia with a compound of formula R7NF^ in the presence of a suitable oxidizing agent such as iodobenzene diacetate in a solvent such as dichloromethane. Scheme 4
Figure imgf000027_0001
A variety of general procedures have been reported in the literature for converting sulfoxides to sulfoximines, and sulfides to sulfϊlimines; see, for example, U.S. Patent Publication 2005/0228027, PCT Patent Publication WO 2006/037945, Organic Letters 2004, 5(8) 1307-1307, Organic Letters 2006, S(11), 2349-2352, and Synlett 2002 (1), 116-118.
An alternative method for preparing compounds of Formula 1 is illustrated in Scheme 5 wherein at least one of R5 and R6 is other than hydrogen involves deprotonating corresponding compounds of Formula 1 wherein at least one of R5 and R6 is hydrogen and the sum of m and n is greater than 0 with a base to form a carbanion, followed by addition of electrophilic reactant(s) to the carbanion to provide the desired R5 and R6 substituents. This method is particularly useful for preparing compounds of Formula 1 wherein R5 or R6 is halogen or alkyl. In the method of Scheme 5, the starting compound of Formula 1 (wherein at least one of R5 and R6 is hydrogen and the sum of m and n is greater than 0) is reacted with a suitable base such as sodium hydroxide, sodium hydride, potassium t-butoxide or n-butyllithium in an appropriate solvent include, for example, tetrahydrofuran, diethyl ether, dioxane, dichloromethane or JV,iV-dimethylformamide. One skilled in the art knows the appropriate electrophilic reactants (i.e. alkylating agents) to provide particular R5 and R6 substituents. The amount of base and alkylating agents required in this reaction (generally 1 to 4 equivalents of base and/or alkylating agent) will depend on whether the starting compound of Formula 1 in Scheme 5 is to be monoalkylated (to obtain a compound of Formula 1 where at least one R5 or R6 is other than H) or dialkylated (to obtain a compound of Formula 1 where both R5 or R6 are other than H). The reaction is typically run at temperatures ranging from -78 0C to the reflux temperature of the solvent, depending upon the base and solvent used. Examples of reactions analogous to those shown in Scheme 5 are described by A. Volonterio et al, Tetrahedron Letters 2005, 46(50), 8723-8726 and S. Ostrowski et al., Heterocycles 2005, 65(10), 2339-2346. Scheme 5
Figure imgf000028_0002
As shown in Scheme 6, sulfides of Formula Ia can be made by the reaction of a isoxazoline isothiourea salt of Formula 2 (where X2 is a chloride or bromide counterion) with a heterocyclic alkyl electrophile of Formula 3 wherein X3 is leaving group such as a halogen or a sulfonate (e.g., methanesulfonate) in the presence of excess base in a suitable solvent. In a typical procedure, the isothiourea salt of Formula 2 (which can be regarded as a protected form of a thiol nucleophile) and an electrophilic agent of Formula 3 are combined in a suitable solvent such as acetonitrile, ethanol, tetrahydrofuran, dioxane, dichloromethane, N,Λ/-dimethylformamide or toluene followed by the addition of base such as potassium carbonate, sodium hydride, sodium or potassium hydroxide, pyridine, lithium diisopropylamide or triethylamine. The reaction can be run under a wide range of temperatures, with optimum temperatures typically ranging from 0 0C to the reflux temperature of the solvent. Generally, at least two equivalents of base are used for neutralizing the two equivalents of acid (i.e. (HX2), and (HX3),) that is generated in this reaction.
Scheme 6
Figure imgf000028_0001
Isoxazoline isothiourea salts of Formula 2 can be prepared by the method reported in U.S. Patent Publication US 2007/0185334 Al and European Patent Publication
EP 1 829868 Al . One skilled in the art will recognize that the free 3-thiol form of 2 or other protected forms of the thiol (e.g., 3-acetylthioisoxazoline derivative) can also be used in place of 2 in the reaction shown in Scheme 6.
Alternatively, sulfides of Formula Ia can be prepared by the method illustrated in Scheme 7, in which isoxazolines of Formula 4 wherein X4 is a suitable leaving group, such as halogen or methanesulfonate are allowed to react with a heterocyclic alkylisothiourea salt of Formula 5. In a typical procedure a compound of Formula 4 is mixed with a compound of
Formula 5 in the presence of excess base (generally 2 to 4 equivalents) such as potassium carbonate, sodium hydride, lithium diisopropylamide, pyridine or triethylamine in a variety of solvents including acetonitrile, tetrahydrofuran, diethyl ether, dichloromethane, dioxane, N,Λ/-dimethylformamide and toluene. Optimum reaction temperatures typically range from 0 0C to the reflux temperature of the solvent.
Scheme 7
Figure imgf000029_0001
Isoxazo lines of Formula 4 where X4 is halogen can be made by the method reported in
U.S. Patent Publication 2007/0185334 and PCT Patent Publication WO 2007/0965776, and isoxazolines of Formula 4 where X4 is methylsulfonyl can be made by the method reported in European Patent Publication EP 1203768 and PCT Patent Publication WO 2003/010165. One skilled in the art will also recognize that the free 3 -thiol form of 5 or other protected forms of the thiol (e.g., 3-acetylthioisoxazoline derivative) can also be used in place of 5 in the reaction shown in Scheme 7.
Sulfides of Formula Ia can also be prepared by the one pot, two-step method shown in Scheme 8, in which an isoxazoline of Formula 4 is treated with a thiolating agent such thiourea or sodium hydrosulfide, and the generated intermediate is reacted in situ with a compound of Formula 3 in the presence of a base. In a typical procedure an isoxazoline of Formula 4 is combined with a thiolating agent in a solvent such as ethanol, tetrahydrofuran, dioxane, dichloromethane, N,Λ/-dimethylformamide or toluene, followed by addition of a suitable base, such as sodium hydride, sodium or potassium hydroxide, pyridine, lithium diisopropylamide, triethylamine or potassium carbonate, and a compound of Formula 3. The reaction can be run under a wide range of temperatures with optimum temperatures ranging from 0 0C to the reflux temperature of the solvent. Examples of reactions analogous to the method of Scheme 8 are taught in U.S. Patent Publication 2004/0110749 Al and PCT Patent Publications WO 2006/123088 and WO 2007/003295.
Scheme 8
Figure imgf000029_0002
One skilled in the art will recognize that the order of addition of compounds of
Formulae 3 and 4 in the reaction shown in Scheme 8 can be reversed so that the compound of Formula 3 is thiolated in a suitable solvent prior to addition of the compound of Formula 4 and base.
Intermediates of Formula 3 where X3 is halogen can be made by "benzylic" halogenation of precursors of Formula 6 with an JV-halosuccinimide in an appropriate solvent, i.e. Λ/,Λ/-dimethylformamide, carbon tetrachloride, acetonitrile or dichloromethane, generally in the presence of a radical-generating catalyst such as benzoyl peroxide or AIBN (Scheme 9). Compounds of Formula 3 are also obtained from alcohols of Formula 7 by treating 7 with a halogen-containing reagent such as phosphorus(V) oxychloride or phosphorus tribromide in the presence of triphenylphosphine in an appropriate solvent, i.e. toluene, carbon tetrachloride, dichloroethane or dichloromethane. Alcohols of Formula 7 can also be reacted with an appropriate sulfonylating reagent in the presence of base and solvent (i.e., pyridine, triethylamine or potassium carbonate in tetrahydrofuran, dioxane, dichloromethane, Λ/,Λ/-dimethylformamide or toluene) to give compounds of Formula 3 where X3 is a sulfonate leaving group such as methanesulfonate. Scheme 9
Figure imgf000030_0001
Precursors to alcohols of Formula 7 where R5 and R6 are H are generally aldehydes of Formula 8 or alkyl esters of Formula 9. Reduction of compounds of Formulae 8 or 9 with an appropriately selected reducing agent (i.e. lithium borohydride, sodium borohydride or diisobutylaluminum hydride) in a compatible solvent (i.e. tetrahydrofuran, methanol, diethyl ether) provides compounds of Formula 7 as shown in Scheme 10. Esters of Formula 9 can also be reacted with Grignard reagents to give compounds of Formula 7 where R5 and R6 are other than H.
Scheme 10
Figure imgf000030_0002
Intermediates of Formula 6a can be made by alkylating compounds of Formula 10 with a suitable alkylating agent in the presence of an appropriate base such as potassium carbonate, sodium hydroxide, lithium hydroxide, sodium hydride, potassium t-butoxide in a solvent such as acetonitrile, tetrahydrofuran, dioxane, methanol, dichloromethane or N,N- dimethylformamide. One skilled in the art knows the appropriate electrophilic reactants to provide particular R8a substituents on nitrogen. This reaction is typically run at temperatures ranging from -78 0C to the reflux temperature of the solvent, depending upon the base and solvent used.
Scheme 11
Figure imgf000031_0001
Likewise, intermediates of 6b, 6c, and 6d can be made in a similar manner from compounds of Formula 11, 12, and 13, respectively, as illustrated in Schemes 12, 13, and 14, respectively, under the same conditions. Scheme 12
Figure imgf000031_0002
Pyrimidinone intermediates of Formula 10a can be made as outlined in Scheme 15 by reacting a beta-ketoester of Formula 14 with an amidine salt of formula HX-(H)N=CR10aNH2 (where X is a halogen or sulfonate counter ion) in the presence of excess base such as sodium alkoxide or potassium carbonate in an appropriate solvent, i.e. methanol, generally at the reflux temperature of the solvent. US Patent 5,185,340 (Example 3 in column 3) discloses a representative example of this cyclization method. In some cases, the free base form of the amidine salt can be used in this coupling.
Scheme 15
Figure imgf000032_0001
As illustrated in Scheme 16, pyrimidinone intermediates of Formulae 6e and 6f can be made directly by reacting ketoesters of Formula 14 with amidine salts of formula HX*(R8a/8b)N=CPv10aNH2 (where X is a halogen or sulfonate counter ion) in an appropriate solvent such as methanol, and in the presence of excess base such as sodium alkoxide or potassium carbonate. This reaction is generally carried out at the reflux temperature of the solvent. In some cases, the free base form of the amidine salt can be used in the coupling with the ketoester of Formula 14.
Scheme 16
Figure imgf000032_0002
Pyrimidinone esters of Formula 9a can be made as illustrated in Scheme 17 by alkylating compounds of Formula 15 with a suitable alkylating agent in the presence of an appropriate base and solvent as described for Scheme 11. Scheme 17
Figure imgf000033_0001
Pyrimidinone esters of Formula 15 can be made by the method of Scheme 18 whereby an ethylene malonate of Formula 16 is cyclized with an amidine salt of formula HX-NH=CR10aNH2 (where X is a halogen or sulfonate counter ion) in the presence of excess base such as sodium alkoxide or potassium carbonate in an appropriate solvent such as methanol (generally at the reflux temperature of the solvent) to give a dihydropyrimidinone of Formula 15a that is directly converted to the compound of Formula 15 by treating with an appropriate oxidizing reagent (i.e. bromine or 2,3-dichloro-5,6- dicyano-/?-benzoquinone). Examples of this synthetic procedure are reported in Z. Physiol. Chem. 1936, 242, pp 89-96, J. Org. Chem. 1993, 55(16) pp 4490-93 and EP 606011 (1994).
Scheme 18
Figure imgf000033_0002
Pyridazinones of Formula 10b can be made as shown in Scheme 19. Under acidic conditions, generally in the presence of acetic, hydrochloric or sulfuric acid and optionally in the presence of a solvent, acetyl carboxylate hydrazones of Formula 17 are hydro lyrically cleaved and then cyclized to provide compounds of Formula 10b.
Scheme 19
Figure imgf000033_0003
Acetyl carboxylate hydrazones of Formula 17 in turn can be made by the method of Scheme 20. Reaction of keto aldehydes of Formula 18 with acetylhydrazine in a solvent such as methanol, toluene or acetonitrile provides the corresponding hydrazones of Formula 19 that undergo a Wittig reaction with the triphenylphosphine carboxylates of Formula 20 in a solvent, e.g., tetrahydrofuran, dioxane, toluene or diethyl ether, to give hydrazones of Formula 17.
Scheme 20
Figure imgf000034_0001
Pyridazinones of Formulae 6g and 6h can also be made directly by cyclization of a hydroxylactone of Formula 21 with a hydrazine of formula NH2NHR8^0 in a solvent, e.g., methanol, acetonitrile, toluene or acetic acid, at temperatures ranging from 0 0C to the reflux temperature of the solvent.
Scheme 21
Figure imgf000034_0002
Hydroxylactones of Formula 21 can be prepared by the method taught in Tetrahedron Lett. 1983, 24(37), pp 3959-60 whereby lithioacrylates of Formula 22 are reacted with anhydrides of formula (Rlla)2CO in a suitable solvent such as tetrahydrofuran or dioxane to give hydroxylactones of Formula 21 (Scheme 22).
Scheme 22
Figure imgf000034_0003
Alternatively, pyridazinones of Formula 6g can be made as outlined in Scheme 23. Cyclization of bromohydroxylactones of Formula 23 with hydrazines NH2NHR8a in a solvent, e.g., methanol, acetonitrile, toluene or acetic acid, at temperatures ranging from 0 0C to the reflux temperature of the solvent provides bromopyridazinones of Formula 24. Cross- coupling of bromopyridazinones with trimethylboroxine in the presence of a palladium catalyst, e.g., PdC^dppf) or Pd(PPli3)4, and base, e.g., a metal carbonate), in a suitable solvent such as dioxane or tetrahydrofuran (generally at temperatures ranging from room temperature to the reflux temperature of the solvent) affords compounds of Formula 6g.
Scheme 23
Figure imgf000035_0001
Likewise, as outlined in Scheme 24, pyridazinones of Formula 6h can be made from hydroxylactones of Formula 25 via bromopyridazinone intermediates of Formula 26 by a method analogous to that described for Scheme 23.
Scheme 24
Figure imgf000035_0002
Bromohydroxylactones of Formulae 23 and 25 are accessible from substituted maleic anhydrides of Formula 27 as outlined in Scheme 25 via reduction e.g., with an aluminum hydride reagent as taught in Tetrahedron Lett. 1975, 48, pp 4279-82 or by addition of a Grignard reagent (e.g., Rlla/llcMgBr) as taught in Synthesis 2007, 14, pp 2198-2202. Scheme 25
Figure imgf000036_0001
Pyridone carboxylates of Formula 9b can be prepared from 2-chloro-3-pyridyl esters of Formula 28 by the reaction sequence summarized in Scheme 26. Displacement of the chlorine on the compound of Formula 28 with benzyl alcohol in the presence of base, e.g., sodium hydride, in a solvent such as tetrahydrofuran, dioxane or toluene affords the corresponding benzyl ether of Formula 29. Removal of the benzyl group is achieved with a suitable reagent such as trifluoroacetic acid or by hydrogenolysis, and the resulting pyridone carboxylate of Formula 30 is alkylated in the presence of base, e.g., a metal carbonate or metal hydroxide in alcohol, acetonitrile or N,Λ/-dimethylformamide to provide the compound of Formula 9b (where R8a is transferred from the alkylating agent to the ring nitrogen).
Scheme 26
Figure imgf000036_0002
By the method in Scheme 27, chloropyridine esters of Formula 28 are accessible from substituted pyridines of Formula 31. Oxidation of a compound of Forumla 31 to the corresponding pyridine-N-oxide with an appropriate oxidizing agent, e.g., 3- chloroperoxybenzoic acid, in a solvent such as dichloromethane followed by treatment with phosphorus oxychloride (or thionyl chloride) gives the corresponding 2-chloropyridine of Formula 32. Lithiation of the compound of Formula 32 at the 3-position with a suitable base, e.g., lithium diisopropylamide or n-butyllithium, in a suitable solvent such as tetrahydrofuran or dioxane, and then treating with an alkyl chlorocarbonate of formula ClCθ2Ra (where Ra is alkyl or benzyl) affords pyridine ester of Formula 28.
Scheme 27
Figure imgf000037_0001
Pyridone carboxylates of Formula 30 can also be made by the method outlined in Scheme 28 whereby enol ethers of Formula 33 are acylated with an anhydride reagent of formula (R9aCO)2θ in a suitable solvent, e.g., toluene, dichloromethane or chloroform, followed by displacement with ammonia in an alcohol solvent, tetrahydrofuran or dioxane to provide acyl enamines of Formula 33a. Cyclization of acyl enamines with diethyl malonate in the presence of base, a metal alkoxide or hydride, in an alcohol solvent, dioxane, tetrahydrofuran or toluene affords the intermediates of Formula 30 wherein Ra is ethyl.
Scheme 28
Figure imgf000037_0002
As illustrated in Scheme 29, pyridone carboxylates of Formula 9c are made in an analogous manner to that described for making compounds of Formula 9b in Scheme 26.
Scheme 29
Figure imgf000038_0001
Likewise, pyridinyl carboxylates of Formula 34, are made as shown in Scheme 30. This method is analogous to that for making compounds of Formula 28 in Scheme 27.
Scheme 30
Figure imgf000038_0002
As outlined in Scheme 31, pyridone carboxylates of Formula 9d can also be prepared by a method analogous to that described for making compounds of Formula 9b in Scheme 26.
Scheme 31
Figure imgf000039_0001
Pyridinyl carboxylates of Formula 39 are made as shown in Scheme 32 by a method analogous to that for making compounds of Formula 28 in Scheme 27. Methods for lithiating pyridines and trapping with electrophiles are reviewed in Tetrahedron 2001, 57, pp 4059-4090.
Scheme 32
Figure imgf000039_0002
It is recognized that some reagents and reaction conditions described above for preparing compounds of Formula 1 may not be compatible with certain functionalities present in the intermediates. In these instances, the incorporation of protection/deprotection sequences or functional group interconversions into the synthesis will aid in obtaining the desired products. The use and choice of the protecting groups will be apparent to one skilled in chemical synthesis (see, for example, Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic Synthesis, 2nd Ed.; Wiley: New York, 1991). One skilled in the art will recognize that, in some cases, after the introduction of a given reagent as it is depicted in any individual scheme, it may be necessary to perform additional routine synthetic steps not described in detail to complete the synthesis of compounds of Formula 1. One skilled in the art will also recognize that it may be necessary to perform a combination of the steps illustrated in the above schemes in an order other than that implied by the particular sequence presented to prepare the compounds of Formula 1.
One skilled in the art will also recognize that compounds of Formula 1 and the intermediates described herein can be subjected to various electrophilic, nucleophilic, radical, organometallic, oxidation, and reduction reactions to add substituents or modify existing substituents.
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. Steps in the following Examples illustrate a procedure for each step in an overall synthetic transformation, and the starting material for each step may not have necessarily been prepared by a particular preparative run whose procedure is described in other Examples or Steps. MPLC refers to medium pressure liquid chromatography on silica gel. Percentages are by weight except for chromatographic solvent mixtures or where otherwise indicated. Parts and percentages for chromatographic solvent mixtures are by volume unless otherwise indicated. 1H NMR spectra are reported in ppm downfϊeld from tetramethylsilane; "br s" means broad singlet, "s" means singlet, "d" means doublet, "t" means triplet, "q" means quartet, "br q" means broad quartet, "m" means multiplet "dd" means doublet of doublets. SYNTHESIS EXAMPLE 1
Preparation of 5-[[(4,5-dihydro-5,5-dimethyl-3-isoxazolyl)thio]methyl]-2-methoxy-3- methyl-6-(trifluoromethyl)-4(3H)-pyrimidinone (Compound 16)
Step A: Preparation of 2-methoxy-5-methyl-6-(trifluoromethyl)-4(3H)-pyrimidinone
To a stirred solution of methyl carbamimidate sulfate (2:1) (also known as 0-methylisourea hemisulfate) (4.56 g, 37 mmol) in methanol (50 mL) was added ethyl 4,4,4-trifluoro-2-methyl-3-oxobutanoate (5.00 g, 25 mmol) followed by a methanol solution of sodium methoxide (30 wt% 11.35 g, 63 mmol). The reaction mixture was warmed to reflux and stirred for 24 h. Then the reaction mixture was concentrated under reduced pressure. To the residue was added water (50 mL) followed by 1 N hydrochloric acid until the pH was 2-3, and the mixture was extracted with ethyl acetate. The organic layer was dried (MgSC^) and concentrated under reduced pressure to afford the title product as a white solid (5.50 g), which was used without further purification in the next step. 1H NMR (CDCl3) δ 4.01 (s, 3H), 2.16 (m, 3H).
Step B: Preparation of 2-methoxy-3,5-dimethyl-6-(trifluoromethyl)-4(3H)-pyrimidinone To a stirred solution of 2-methoxy-5-methyl-6-(trifluoromethyl)-4(3H)-pyrimidinone
(i.e. the product of Step A) (1.3 g, 6.3 mmol) in N,7V-dimethylformamide (21 mL) was added potassium carbonate (3.5 g, 25 mmol) and iodomethane (1.56 mL, 25 mmol). The reaction mixture was stirred at room temperature for 24 h. Water was added, and the mixture extracted with ethyl acetate. The organic layer was dried (MgSO4) and concentrated under reduced pressure. The residue was purified by column chromatography (20% ethyl acetate, 80% hexanes) to afford the title product as a white solid (1.22 g). 1H NMR (CDCl3) δ 4.09 (s, 3H), 3.44 (s, 3H), 2.17 (m, 3H).
Step C : Preparation of 5 -(bromomethyl)-2-methoxy-3 -methyl-6-(trifluoromethyl)-4(3H)- pyrimidinone
To a stirred solution of 2-methoxy-3,5-dimethyl-6-(trifluoromethyl)-4(3H)- pyrimidinone (i.e. the product of Step B) (250 mg, 1.13 mmol) in carbon tetrachloride (1.7 mL) was added N-bromosuccinimide (248 mg, 1.4 mmol) and 2,2'-azobis(2- methylpropionitrile) (10 mg, 0.057 mmol). The reaction mixture was heated to reflux for 2 h. The reaction mixture was cooled to room temperature and filtered, and the filtered solid was rinsed with carbon tetrachloride. The filtrate was concentrated under reduced pressure to afford the title product as an oil (350 mg), which was used without further purification in the next step.
Step D: Preparation of 5-[[(4,5-dihydro-5,5-dimethyl-3-isoxazolyl)thio]methyl]-2-methoxy-
3-methyl-6-(trifluoromethyl)-4(3H)-pyrimidinone To a stirred solution of 5-(bromomethyl)-2-methoxy-3-methyl-6-(trifluoromethyl)-
4(3H)-pyrimidinone (i.e. the product of Step C) (350 mg, 1.2 mmol) in acetonitrile (4.3 mL) was added 4,5-dihydro-5,5-dimethyl-3-isoxazolyl carbamimidothioate hydrochloride (1 :1)
(273 mg, 1.3 mmol) and potassium carbonate (332 mg, 2.4 mmol). The reaction mixture was heated to reflux for 2.5 h. Water was added, and the mixture extracted with ethyl acetate. The organic layer was dried (MgSO4) and concentrated under reduced pressure.
The residue was purified by column chromatography (40% ethyl acetate, 60% hexanes) to afford the title product, a compound of the present invention, as an oil (240 mg).
1H NMR (CDCl3) δ 4.31 (m, 2H), 4.09 (s, 3H), 3.46 (3H), 2.84 (s, 2H), 1.42 (s, 6H).
SYNTHESIS EXAMPLE 2 Preparation of 5-[[(4,5-dihydro-5,5-dimethyl-3-isoxazolyl)sulfonyl]methyl]-2-methoxy-3- methyl-6-(trifluoromethyl)-4(3H)-pyrimidinone (Compound 5) To a stirred solution of 5-[[(4,5-dihydro-5,5-dimethyl-3-isoxazolyl)thio]methyl]-2- methoxy-3-methyl-6-(trifluoromethyl)-4(3H)-pyrimidinone (i.e. the product of Synthesis Example 1, Step D) (110 mg, 0.31 mmol) in dichloromethane (3.1 mL) was added 3-chloroperoxybenzoic acid (77% maximum assay, 230 mg, 0.93 mmol). The reaction mixture was stirred at room temperature for 4 days. The mixture was diluted with dichloromethane and then washed with aqueous 5% sodium bisulfite solution and saturated aqueous sodium bicarbonate solution. The organic layer was dried (MgSO4) and concentrated under reduced pressure. The residue was purified by column chromatography (50% ethyl acetate, 50% hexanes) to afford the title product, a compound of the present invention, as a white solid (85 mg).
1H NMR (CDCl3) δ 4.7 (m, 2H), 4.12 (s, 3H), 3.44 (s, 3H), 3.19 (s, 2H), 1.53 (s, 6H).
SYNTHESIS EXAMPLE 3 Preparation of 5-[[(4,5-dihydro-5,5-dimethyl-3-isoxazolyl)sulfinyl]methyl]-2-methoxy-3- methyl-6-(trifluoromethyl)-4(3H)-pyrimidinone (Compound 6)
To a stirred solution of 5-[[(4,5-dihydro-5,5-dimethyl-3-isoxazolyl)thio]methyl]-2- methoxy-3-methyl-6-(trifluoromethyl)-4(3H)-pyrimidinone (i.e. the product of Synthesis
Example 1, Step D) (110 mg, 0.31 mmol) in a mixture of methanol and water (1 :1, 3.1 mL) was added Oxone® potassium peroxymonosulfate (227 mg, 0.37 mmol), and the mixture was stirred at 0 0C for 1 h. Water was added, and the mixture was extracted with ethyl acetate. The organic layer was dried (MgSOzj) and concentrated under reduced pressure.
The residue was purified by column chromatography (50% ethyl acetate, 50% hexanes) to afford the title product, a compound of the present invention, as a white solid (54 mg). 1H NMR (CDCl3) δ 4.53 (m, IH), 4.28 (m, IH), 4.10 (s, 3H), 3.42 (s, 3H), 3.29 (m, IH),
3.20 (m, IH), 1.55 (s, 3H), 1.44 (s, 3H)
SYNTHESIS EXAMPLE 4
Preparation of 4-[[(4,5-dihydro-5,5-dimethyl-3-isoxazolyl)sulfonyl]methyl]-2-methyl-5- (trifluoromethyl)-3(2H)-pyridazinone (Compound 2) Step A: Preparation of ethyl 3-[[2-(aminocarbonyl)hydrazinylidene]methyl]-4,4,4-trifluoro- 2-methyl-2-butenoate
Sodium acetate (6.1 g, 74 mmol) was added to l,l-dibromo-3,3,3-trifluoroacetone (5.0 g, 19 mmol) in water (50 mL) and heated to 80 0C for 90 min. The reaction mixture was cooled to room temperature, semicarbazide hydrochloride (2.4 g, 22 mmol) was added, and the reaction mixture was stirred for 5 h. A white precipitate formed, which was filtered and dried in- vacuo. The dried solids were combined with l-(ethoxycarbonyl)ethylidene triphenylphosphorane (6.7 g, 19 mmol) in tetrahydrofuran (25 mL) and stirred for 18 h. The reaction mixture was then concentrated. Water was added to the concentrate, and the mixture was extracted with ethyl acetate. The combined extracts were washed with brine, dried with MgSC>4 and filtered. The filtrate was concentrated and purified by MPLC using 30 to 100% ethyl acetate in hexanes as eluant to provide the title product as a clear colorless oil (1.9 g).
1H NMR (CDCl3) δ 10.44 (s, IH), 7.46 (s, IH), 6.07-5.34 (m, 2H), 4.22 (q, 2H), 2.23-2.18 (m, 3H), 1.28 (t, 3H). Step B: Preparation of 4-methyl-5-trifluoromethyl-3(2H)-pyridazinone
Ethyl 3-[[2-(aminocarbonyl)hydrazinylidene]methyl]-4,4,4-trifluoro-2-methyl-2- butenoate (1.9 g, 7.1 mmol) (i.e. the product of Step A) was heated at reflux in concentrated hydrochloric acid (15 mL) for 4 h. The reaction mixture was allowed to cool to room temperature over 18 h. Water (20 mL) was added, and the mixture was extracted with dichloromethane. The combined extracts were dried (MgSC^) and filtered. The filtrate was concentrated and purified by MPLC using 20 to 50% ethyl acetate in hexanes as eluant to give the title product as a white solid (1.8 g). 1H NMR (CDCl3) δ 12.61 (br s, IH), 7.98 (s, IH), 2.55-2.30 (m, 3H). Step C: Preparation of 2,4-dimethyl-5-(trifluoromethyl)-3(2H)-pyridazinone
Potassium carbonate (0.78 g, 5.6 mmol) was added to a stirred mixture of 4-methyl- 5-trifluoromethyl-3(2H)-pyridazinone (0.50 g, 2.8 mmol) (i.e. the product of Step B) and iodomethane (0.52 mL, 8.4 mmol) in N,Λ/-dimethylformamide (15 mL) at 0 0C. The reaction mixture was allowed to warm to room temperature over 2 h. Water was added, and the reaction mixture was extracted with ethyl acetate. The organic extract was dried (MgSOz^) and filtered through silica gel using 20% ethyl acetate in hexanes as eluant. The filtrate was concentrated to provide the title product as a light-yellow oil (0.34 g). 1H NMR (CDCl3) δ 7.86 (s, IH), 3.83 (s, 3H), 2.37 (q, 3H).
Step D: Preparation of 4-(bromomethyl)-2-methyl-5-(trifluoromethyl)-3(2H)-pyridazinone N-Bromosuccinimide (0.46 g, 2.6 mmol) was added to a solution of 2,4-dimethyl-5- trifluoromethyl-3(2H)-pyridazinone (0.47 g, 2.5 mmol) (i.e. the product of Step C) in carbon tetrachloride (12 mL). A catalytic amount of 2,2'-azobis(2-methylpropionitrile) was added to the reaction mixture. The stirred reaction mixture was heated to reflux for 20 h. The reaction mixture was cooled to room temperature. Water was added, and the mixture was extracted with dichloromethane. The dichloromethane extracts were dried (MgSOz^) and filtered. The filtrate was concentrated onto silica gel and purified by MPLC using 5 to 40% ethyl acetate in hexanes as eluant to provide the title product as a clear-yellow oil (0.48 g). 1H NMR (CDCl3) δ 7.92 (s, IH), 4.53 (d, 2H), 3.88 (s, 3H).
Step E: Preparation of 4-[[(4,5-dihydro-5,5-dimethyl-3-isoxazolyl)thio]methyl]-2-methyl-5- (trifluoromethyl)-3 (2H)-pyridazinone
Potassium carbonate (0.61 g, 4.4 mmol) was added to a stirred mixture of 4- (bromomethyl)-2-methyl-5-(trifluoromethyl)-3(2H)-pyridazinone (0.48 g, 1.8 mmol) (i.e. the product of Step D) and [5,5-dimethyl(4,5-dihydroisoxazol-3-yl)]thiocarboxamidine hydrobromide (0.46 g, 1.8 mmol) in acetonitrile (10 mL). The reaction mixture was stirred at ambient temperature for 18 h. Water was added to the mixture, followed by extraction with ethyl acetate. The extracts were washed with water, followed by a brine wash, dried (MgSC^), and filtered. The filtrate was concentrated and purified by MPLC using 20 to 40% ethyl acetate in hexanes as eluant to provide the title product as a clear oil (0.25 g). 1H NMR (CDCl3) δ 7.91 (s, IH), 4.40 (d, 2H), 3.85 (s, 3H), 2.85 (s, 2H), 1.44 (s, 6H).
Step F: Preparation of 4-[[(4,5-dihydro-5,5-dimethyl-3-isoxazolyl)sulfonyl]methyl]-2- methyl-5 -(trifluoromethyl)-3 (2H)-pyridazinone
To a solution of 4-[[(4,5-dihydro-5,5-dimethyl-3-isoxazolyl)thio]methyl]-2-methyl-5- (trifluoromethyl)-3(2H)-pyridazinone (0.12 g, 0.37 mmol) (i.e. the product of Step E) in dichloromethane (4 rnL) was added 3-chloroperoxybenzoic acid (77% maximum assay, 0.21 g, 0.93 mmol). The mixture was stirred at ambient temperature for 18 h. Water was added, and the reaction mixture was extracted with ethyl acetate. The organic extract was dried (MgSC^) and filtered. The filtrate was concentrated onto silica gel and purified by MPLC using 20 to 60% ethyl acetate in hexanes as eluant to provide the title product, a compound of the present invention, as a yellow solid (94 mg). 1H NMR (CDCl3) δ 7.98 (s, IH), 4.86 (s, 2H), 3.84 (s, 3H), 3.22 (s, 2H), 1.56 (s, 6H). SYNTHESIS EXAMPLE 5
Preparation of 4-[[(4,5-dihydro-5,5-dimethyl-3-isoxazolyl)thio]methyl]-2-methyl-5-(2,2,2- trifluoroethoxy)-3(2H)-pyridazinone (Compound 209)
Step A: Preparation of 4-bromo-2-methyl-5-(2,2,2-trifluoroethoxy)-3(2H)-pyridazinone
To a solution of 2,2,2-trifluoroethanol (0.81 mL, 11.2 mmol) in N,N- dimethylformamide (50 mL) at ambient temperature was added sodium hydride (60% in oil,
0.45 g, 11.2 mmol). After stirring the reaction mixture at room temperature for 15 min, the mixture was cooled to 0 0C, and 4,5-dibromo-2-methyl-3(2H)-pyridazinone (3.0 g, 11 mmol) was added. The stirred reaction mixture was allowed to warm to room temperature over 2 h.
Water was added, and the mixture was extracted with ethyl acetate. The extracts were dried (MgSC^) and filtered. The filtrate was concentrated and purified by MPLC using 20 to 50% ethyl acetate in hexanes as eluant to provide the title product as a white solid (1.9 g).
1H NMR (CDCl3) δ 7.62 (s, IH), 4.59 (q, 2H), 3.84 (s, 3H).
Step B: Preparation of 2,4-dimethyl-5-(2,2,2-trifluoroethoxy)-3(2H)-pyridazinone
To a mixture of 4-bromo-2-methyl-5-(2,2,2-trifluoroethoxy)-3(2H)-pyridazinone (1.9 g, 6.6 mmol) (i.e. the product of Step A), trimethylboroxine (0.74 mL, 5.3 mmol) and cesium carbonate (3.2 g, 9.9 mmol) in wet dioxane (15 mL) (i.e. 0.5 mL water added to 14.5 mL dioxane) was added dichloro[l,l'-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (0.15 g). The reaction mixture was heated to reflux for 2 h and then cooled to room temperature. Water was added, and the reaction mixture was extracted with dichloromethane. The organic extracts were combined, dried (MgSC^) and filtered. The filtrate was concentrated onto silica gel and purified by MPLC using 20 to75% ethyl acetate in hexanes as eluant to provide the title product as a tan solid (1.3 g). 1H NMR (CDCl3) δ 7.65 (s, IH), 4.46 (q, 2H), 3.78 (s, 3H), 2.11 (s, 3H).
Step C: Preparation of 4-(bromomethyl)-2-methyl-5-(2,2,2-trifluoroethoxy)-3(2H)- pyridazinone
N-Bromosuccinimide (1.2 g, 6.4 mmol) was added to a solution of 2,4-dimethyl-5- (2,2,2-trifluoroethoxy)-3(2H)-pyridazinone (i.e. the product of Step B) (1.3 g, 5.9 mmol) in carbon tetrachloride (10 mL). A catalytic amount of 2,2'-azobis(2-methylpropionitrile) was added to the stirred reaction mixture, which was then heated to reflux for 18 h. The reaction mixture was allowed to cool to room temperature. Water was added, and the mixture was extracted with dichloromethane. The dichloromethane extracts were dried (MgSC^) and filtered. The filtrate was concentrated and purified by MPLC using 5 to 30% ethyl acetate in hexanes as eluant to provide the title product as a clear oil (1.3 g). 1H NMR (CDCl3) δ 7.79 (s, IH), 4.65 (q, 2H), 4.45 (s, 2H), 3.80 (s, 3H). Step D: Preparation of S-[[2,3-dihydro-2-methyl-3-oxo-5-(2,2,2-trifluoroethoxy)-4- pyridazinyljmethyl] ethanethioate
Potassium thioacetate (0.50 g, 4.4 mmol) was added to a solution of 4- (bromomethyl)-2-methyl-5-(2,2,2-trifluoroethoxy)-3(2H)-pyridazinone (i.e. the product of Step C) (1.3 g, 4.4 mmol) in ethanol (25 mL) and the mixture was stirred at ambient temperature. After 2 h, the reaction mixture was filtered through Celite diatomaceous filter aid, using dichloromethane as eluant. The filtrate was concentrated to provide the title product in crude form as an orange solid (1.2 g). 1H NMR (CDCl3) δ 7.71 (s, IH), 4.56 (q, 2H), 4.12 (s, 2H), 3.78 (s, 3H), 2.32 (s, 3H).
Step E: Preparation of 4-[[(4,5-dihydro-5,5-dimethyl-3-isoxazolyl)thio]methyl]-2-methyl-5- (2,2,2-trifluoroethoxy)-3(2H)-pyridazinone
Potassium carbonate (1.4 g, 10 mmol) was added to a mixture of 5*-[[2,3-dihydro-2- methyl-3-oxo-5-(2,2,2-trifluoroethoxy)-4-pyridazinyl]methyl] ethanethioate (i.e. the product of Step D) (1.2 g, 4.1 mmol) and 3-methanesulfonyl-5,5-dimethyl-4,5-dihydroisoxazole (0.72 g, 4.1 mmol) in ethanol (20 mL). The stirred reaction mixture was heated at 60 0C for 2 h. The reaction mixture was cooled to room temperature and stirred for an additional 18 h. Water was added and the mixture was extracted with ethyl acetate. The organic extract was washed with brine, dried (MgSOz^), and filtered. The filtrate was concentrated and purified by MPLC using 20 to 50% ethyl acetate in hexanes as eluant to provide the title product, a compound of the present invention, as a yellow solid (0.80 g). 1H NMR (CDCl3) δ 7.74 (s, IH), 4.58 (q, 2H), 4.20 (s, 2H), 3.78 (s, 3H), 2.83 (s, 2H), 1.40 (s, 6H). SYNTHESIS EXAMPLE 6
Preparation of 4-[[(4,5-dihydro-5,5-dimethyl-3-isoxazolyl)sulfonyl]methyl]-2-methyl-5-
(2,2,2-trifluoroethoxy)-3(2H)-pyridazinone (Compound 4)
To 4-[[(4,5-dihydro-5,5-dimethyl-3-isoxazolyl)thio]methyl]-2-methyl-5-(2,2,2- trifluoroethoxy)-3(2H)-pyridazinone (i.e. the product of Example 5, Step E) (0.20 g, 0.57 mmol) in dichloromethane (6 mL) was added 3-chloroperoxybenzoic acid (77% maximum assay, 0.32 g, 1.4 mmol). The mixture was stirred at ambient temperature for 18 h. Water was added, and the reaction mixture was extracted once with dichloromethane. The organic extract was dried (MgSC^) and filtered. The filtrate was concentrated onto silica gel and purified by MPLC using 30 to 70% ethyl acetate in hexanes as eluant to provide the title product, a compound of the present invention as a white solid (0.22 g) metling at 157—
162 0C.
1H NMR (CDC^) δ 7.78 (s, IH), 4.64-4.52 (m, 4H), 3.77 (s, 3H), 3.24 (s, 2H), 1.54 (s, 6H).
SYNTHESIS EXAMPLE 7 Preparation of 5-[[(4,5-dihydro-5,5-dimethyl-3-isoxazolyl)sulfonyl]methyl]-2,3-dimethyl-6-
(trifluoromethyl)-4(3H)-pyrimidinone (Compound 3)
Step A: Preparation of 2,5-dimethyl-6-(trifluoromethyl)-4(3H)-pyrimidinone
To a stirred mixture of acetamidine hydrochloride (6 g, 60 mmol) and ethyl 4,4,4-trifluoro-2-methyl-3-oxobutanoate (10 g, 50 mmol) in methanol (100 mL) was added sodium methoxide (25 wt% in methanol, 15 g, 66 mmol), and the reaction mixture was heated to reflux for 24 h. After concentrating almost to dryness under reduced pressure, water (75 mL) was added to the residue, and the mixture was acidified with 1 N hydrochloric acid to pΗ 2-3. The resulting aqueous mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, then dried (MgSOz^) and concentrated. The resulting solid residue was suspended in 1-chlorobutane, filtered and oven-dried to give the title product as a white solid (7 g), which was used directly without further purification in the next step. 1H NMR (CDCl3) δ 2.54 (s, 3H), 2.23 (d, 3H).
Step B: Preparation of 2,3,5-trimethyl-6-(trifluoromethyl)-4(3H)-pyrimidinone Iodomethane (1.0 mL, 16 mmol) was added to a stirred mixture of 2,5-dimethyl-6-
(trifluoromethyl)-4(3H)-pyrimidinone (i.e. the product of Step A) (1.5 g, 7.8 mmol) and powdered potassium carbonate (2.5 g, 18 mmol) in Λ/,Λ/-dimethylformamide (15 mL), and the suspension was stirred at room temperature for 24 h. The reaction mixture was then partitioned between water (100 mL) and ethyl acetate (100 mL). The separated organic layer was washed with excess water (2x) and brine, dried (MgSOz^) and concentrated to dryness. Hexane was added to the remaining oily residue, and a solid crystallized. Three crops were collected by filtration and combined to provide the title product (1.4 g). 1H NMR (CDCl3) δ 3.57 (s, 3H), 2.57 (s, 3H), 2.22 (d, 3H).
Step C: Preparation of 5-(bromomethyl)-2,3-dimethyl-6-(trifluoromethyl)-4(3H)- pyrimidinone
A stirred mixture of 2,3,5-trimethyl-6-(trifluoromethyl)-4(3H)-pyrimidinone (i.e. the product of Step B), N-bromosuccinimide (1.8 g, 10 mmol) and 2,2'-azobis(2- methylpropionitrile) (40 mg, 0.24 mmol) in carbon tetrachloride (40 mL) was heated to reflux for 2 h. The reaction mixture was cooled to room temperature, filtered, and the filtered solid was rinsed with carbon tetrachloride. The filtrate was concentrated under reduced pressure to give an oil that was triturated with hexanes to form a solid. The solid was collected by filtration and dried to give 2.5 g of the title compound, which was used directly in the next step without further purification. 1H NMR (CDCl3) δ 4.52 (d, 2H), 3.61 (s, 3H), 2.62 (s, 3H). Step D: Preparation of 5-[[(4,5-dihydro-5,5-dimethyl-3-isoxazolyl)thio]methyl]-2,3- dimethyl-6-(trifluoromethyl)-4(3H)-pyrimidinone
To a stirred mixture of 5-(bromomethyl)-2,3-dimethyl-6-(trifluoromethyl)-4(3H)- pyrimidinone (i.e. the product of Step C) (1.1 g, 3.9 mmol) and 4,5-dihydro-5,5-dimethyl-3- isoxazolyl carbamimidothioate hydrobromide (prepared by the method of US Patent Application 2008/0275249) (1 g, 3.9 mmol) in acetonitrile (25 mL) was added potassium carbonate (1.5 g, 11 mmol), and the mixture stirred at room temperature for 20 h. The reaction mixture was partitioned between water (100 mL) and ethyl acetate (100 mL). The separated organic layer was washed with water (2x) and brine, dried (MgSOz^) and concentrated to give a gummy residue. Purification by MPLC using 10 to 80% ethyl acetate in hexane as eluant provided the title product as a white solid (0.5 g).
1H NMR (CDCl3) δ 4.33 (d, 2H), 3.59 (s, 3H), 2.85 (s, 2H), 2.60 (s, 3H), 1.43 (s, 6H).
Step E: Preparation of 5-[[(4,5-dihydro-5,5-dimethyl-3-isoxazolyl)sulfonyl]methyl]-2,3- dimethyl-6-(trifluoromethyl)-4(3H)-pyrimidinone
To a solution of 5-[[(4,5-dihydro-5,5-dimethyl-3-isoxazolyl)thio]methyl]-2,3- dimethyl-6-(trifluoromethyl)-4(3H)-pyrimidinone (i.e. the product of Step D) (0.4 g, 1.2 mmol) in dichloromethane (10 mL) was added 3-chloroperoxybenzoic acid (77% maximum assay, 1.5 g, 6.7 mmol), and the reaction mixture was stirred at room temperature for 20 h.
The solvent was evaporated, and the remaining residue was dissolved in ethyl acetate (100 mL). The solution was washed with saturated aqueous sodium bicarbonate (4 x 75 mL) and brine. The organic layer was dried (MgSOz^) and concentrated to give a solid residue, which was re-crystallized from 1-chlorobutane to afford the title product, a compound of the present invention, as a white solid (300 mg). 1H NMR (CDCl3) δ 4.76 (d, 2H), 3.56 (s, 3H), 3.19 (s, 2H), 2.62 (s, 3H), 1.54 (s, 6H).
SYNTHESIS EXAMPLE 8
Preparation of 5-[[(4,5-dihydro-5,5-dimethyl-3-isoxazolyl)sulfonyl]methyl]-2-ethyl-3- methyl-6-(trifluoromethyl)-4(3H)-pyrimidinone (Compound 10) Step A: Preparation of 2-ethyl-5-methyl-6-(trifluoromethyl)-4(3H)-pyrimidinone
To a stirred solution of propanimidamide monohydrochloride (3.4 g, 31.5 mmol) in methanol (50 mL) was added ethyl 4,4,4-trifluoro-2-methyl-3-oxobutanoate (5.00 g, 25 mmol) followed by sodium methoxide (30 wt% in methanol, 11.4 g, 63 mmol). The stirred reaction mixture was heated to reflux for 24 h. The reaction mixture was then concentrated under reduced pressure. Water (50 mL) was added to the resulting residue, followed by 1 N hydrochloric acid until the pΗ was 2-3, and the mixture was extracted with ethyl acetate. The organic layer was dried (MgSOz^) and concentrated to give the title product as a white solid (2.3 g), which was used without further purification in the next step. 1H NMR (CDCl3) δ 2.78 (m, 2H), 2.23 (m, 3H), 1.65 (br s, IH), 1.37 (m, 3H). Step B: Preparation of 2-ethyl-3,5-dimethyl-6-(trifluoromethyl)-4(3H)-pyrimidinone
To a stirred solution of 2-ethyl-5-methyl-6-(trifluoromethyl)-4(3H)-pyrimidinone (i.e. the product of Step A) (500 mg, 2.4 mmol) in dioxane (7.7 mL) was added potassium carbonate (1.3 g, 9.6 mmol) and iodomethane (0.60 mL, 9.6 mmol). The reaction mixture was stirred at room temperature for 24 h. Water was added, and the mixture was extracted with ethyl acetate. The organic layer was dried (MgSC^) and concentrated under reduced pressure. The residue was purified by column chromatography using 50% ethyl acetate in hexanes as eluant to afford the title product as a white solid (480 mg). 1H NMR (CDCl3) δ 3.57 (s, 3H), 2.78 (m, 2H), 2.23 (m, 3H), 1.34 (m, 3H).
Step C : Preparation of 5 -(bromomethyl)-2-ethyl-3 -methyl-6-(trifluoromethyl)-4(3H)- pyrimidinone
To a stirred solution of 2-ethyl-3,5-dimethyl-6-(trifluoromethyl)-4(3H)-pyrimidinone (i.e. the product of Step B) (480 mg, 2.2 mmol) in carbon tetrachloride (9.6 mL) was added Λ/-bromosuccinimide (305 mg, 2.6 mmol) and 2,2'-azobis(2-methylpropionitrile) (18 mg, 0.11 mmol). The reaction mixture was heated to reflux for 2 h. The reaction mixture was cooled to room temperature and filtered, and the filtered solid was rinsed with carbon tetrachloride. The filtrate was concentrated under reduced pressure to give the title product as an oil (580 mg), which was used without further purification in the next step. 1H NMR (CDCl3) δ 4.54 (m, 2H), 3.61 (s, 3H), 2.81 (m, 2H), 1.36 (m, 3H). Step D: Preparation of 5-[[(4,5-dihydro-5,5-dimethyl-3-isoxazolyl)thio]methyl]-2-ethyl-3- methyl-6-(trifluoromethyl)-4(3H)-pyrimidinone
To a stirred solution of 5-bromomethyl-2-ethyl-3-methyl-6-(trifluoromethyl)-4(3H)- pyrimidinone (i.e. the product of Step C) (580 mg, 1.9 mmol) in acetonitrile (9.5 mL) was added 4,5-dihydro-5,5-dimethyl-3-isoxazolyl carbamimidothioate hydrochloride (1 :1) (440 mg, 2.1 mmol) and potassium carbonate (788 mg, 5.7 mmol). The reaction mixture was stirred at room temperature for 72 h. Water was added, and the mixture extracted with ethyl acetate. The organic layer was dried (MgSC^) and concentrated under reduced pressure.
The residue was purified by column chromatography using 50% ethyl acetate in hexanes as eluant to afford the title product, a compound of the present invention, as an oil (380 mg).
1H NMR (CDCl3) δ 4.35 (m, 2H), 3.59 (s, 3H), 2.85-2.78 (m, 4H), 1.46-1.43 (m, 6H), 1.36 (m, 3H).
Step E: Preparation of 5-[[(4,5-dihydro-5,5-dimethyl-3-isoxazolyl)sulfonyl]methyl]-2-ethyl- 3-methyl-6-(trifluoromethyl)-4(3H)-pyrimidinone To a stirred solution of 5-[[(4,5-dihydro-5,5-dimethyl-3-isoxazolyl)thio]methyl]-2- ethyl-3-methyl-6-(trifluoromethyl)-4(3H)-pyrimidinone (i.e. the product of Step D) (200 mg, 0.57 mmol) in dichloromethane (5.7 mL) was added 3-chloroperoxybenzoic acid (77% maximum assay, 492 mg, 1.71 mmol). The reaction mixture was stirred at room temperature for 24 h. The mixture was diluted with dichloromethane and then washed with aqueous 5% sodium bisulfite solution and saturated aqueous sodium bicarbonate. The organic layer was dried (MgSOz^) and concentrated under reduced pressure. The residue was purified by column chromatography using 30% ethyl acetate in hexanes as eluant to afford the title product, a compound of the present invention, as a white solid (178 mg). 1H NMR (CDCl3) δ 4.77 (m, 2H), 3.56 (s, 3H), 3.20 (s, 2H), 2.83 (m, 2H), 1.54 (m, 6H), 1.37 (m, 3H).
SYNTHESIS EXAMPLE 9
Preparation of 5-[[(4,5-dihydro-5,5-dimethyl-3-isoxazolyl)sulfonyl]methyl]-2-ethoxy-3- methyl-6-(trifluoromethyl)-4(3H)-pyrimidinone (Compound 18)
Step A: Preparation of 2-ethoxy-3,5-dimethyl-6-(trifluoromethyl)-4(3H)-pyrimidinone To a stirred solution of 2-methoxy-3,5-dimethyl-6-(trifluoromethyl)-4(3H)- pyrimidinone (i.e. the product of Synthesis Example 1, Step B) (1.2 g, 5.4 mmol) in ethanol (27 mL) was added sodium ethoxide (550 mg, 8.10 mmol). The reaction mixture was heated to reflux for 24 h. The reaction mixture was diluted with water, and the ethanol was removed under reduced pressure. The mixture was extracted with ethyl acetate, and the organic layer was dried (MgSOz^) and concentrated under reduced pressure. The residue was purified by column chromatography using 20% ethyl acetate in hexanes as eluant to afford the title product as a yellow oil (1.1 g). 1H NMR (CDCl3) δ 4.50 (m, 2H), 3.44 (s, 3H), 2.17 (m, 3H), 1.43 (m, 3H).
Step B : Preparation of 5 -(bromomethyl)-2-ethoxy-3 -methyl-6-(trifluoromethyl)-4(3H)- pyrimidinone
To a stirred solution of 2-ethoxy-3,5-dimethyl-6-(trifluoromethyl)-4(3H)- pyrimidinone (i.e. the product of Step A) (400 mg, 1.5 mmol) in carbon tetrachloride (7.5 mL) was added N-bromosuccinimide (320 mg, 1.8 mmol) and 2,2'-azobis(2- methylpropionitrile) (12 mg, 0.07 mmol). The reaction mixture was heated to reflux for 2 h.
The reaction mixture was cooled to room temperature and filtered, and the filtered solid was rinsed with carbon tetrachloride. The filtrate was concentrated under reduced pressure to afford the title product as an oil, which was used without further purification in the next step.
1H NMR (CDCl3) δ 4.60-4.52 (m, 4H), 3.48 (s, 3H), 1.45 (m, 3H).
Step C: Preparation of 5-[[(4,5-dihydro-5,5-dimethyl-3-isoxazolyl)thio]methyl]-2-ethoxy-3- methyl-6-(trifluoromethyl)-4(3H)-pyrimidinone To a stirred solution of 5-(bromomethyl)-2-ethoxy-3-methyl-6-(trifluoromethyl)- 4(3H)-pyrimidinone (i.e. the product of Step B) (1.5 mmol) in acetonitrile (7.5 mL) was added 4,5-dihydro-5,5-dimethyl-3-isoxazolyl carbamimidothioate hydrochloride (1 :1) (356 mg, 1.7 mmol) and potassium carbonate (442 mg, 3.2 mmol). The reaction mixture was stirred at room temperature for 72 h. Water was added, and the reaction mixture was extracted with ethyl acetate. The organic layer was dried (MgSC^) and concentrated under reduced pressure. The residue was purified by column chromatography using 30% ethyl acetate in hexanes as eluant to afford the title product, a compound of the present invention, as an oil (490 mg).
1H NMR (CDCl3) δ 4.53 (m, 2H), 4.32 (m, 2H), 3.46 (s, 3H), 2.84 (s, 2H), 1.46-1.43 (m, 9H). SYNTHESIS EXAMPLE 10
Preparation of 5-[[(4,5-dihydro-5,5-dimethyl-3-isoxazolyl)sulfonyl]methyl]-2-ethoxy- 3-methyl-6-(trifluoromethyl)-4(3H)-pyrimidinone (Compound 17)
Step A: Preparation of 5-[[(4,5-dihydro-5,5-dimethyl-3-isoxazolyl)sulfonyl]methyl]-2- ethoxy-3-methyl-6-(trifluoromethyl)-4(3H)-pyrimidinone To a stirred solution of 5-[[(4,5-dihydro-5,5-dimethyl-3-isoxazolyl)thio]methyl]-2- ethoxy-3-methyl-6-(trifluoromethyl)-4(3H)-pyrimidinone (i.e. the product of Step C, Synthesis Example 9) (150 mg, 0.68 mmol) in dichloromethane (4 mL) was added 3-chloroperoxybenzoic acid (77% maximum assay, 472 mg, 1.6 mmol). The reaction mixture was stirred at room temperature for 24 h. The reactin mixture was diluted with dichloromethane and then washed with aqueous 5% sodium bisulfite solution and saturated aqueous sodium bicarbonate solution. The organic layer was dried (MgSC^) and concentrated under reduced pressure. The residue was purified by column chromatography using 30% ethyl acetate in hexanes as eluant to afford the title product, a compound of the present invention, as a white solid (120 mg).
1H NMR (CDCl3) δ 4.70 (m, 2H), 4.58 (m, 2H), 3.43 (s, 3H), 3.20 (s, 2H), 1.55 (m, 6H), 1.46 (m, 3H).
SYNTHESIS EXAMPLE 11
Preparation of 5-[[(4,5-dihydro-5,5-dimethyl-3-isoxazolyl)sulfonyl]methyl]-3-ethyl-2- methoxy-6-(trifluoromethyl)-4(3H)-pyrimidinone (Compound 19)
Step A: Preparation of 3-ethyl-2-methoxy-5-methyl-6-(trifluoromethyl)-4(3H)-pyrimidinone To a stirred solution of 2-methoxy-5-methyl-6-(trifluoromethyl)-4(3H)-pyrimidinone
(i.e. the product of Synthesis Example 1, Step A) (2.0 g, 9.6 mmol) in NJV- dimethylformamide (32 mL) was added potassium carbonate (5.3 g, 38 mmol) and iodoethane (3.1 mL, 38 mmol). The reaction mixture was stirred at room temperature for 24 h. Water was added, and the mixture was extracted with ether. The organic layer was dried (MgSC^) and concentrated under reduced pressure. The residue was purified by column chromatography using 20% ethyl acetate in hexanes as eluant to afford the title product as a white solid (1.40 g). 1H NMR (CDCl3) δ 4.08-4.04 (m, 5H), 2.16 (m, 3H), 1.26 (m, 3H).
Step B : Preparation of 5 -(bromomethyl)-3 -ethyl-2-methoxy-6-(trifluoromethyl)-4(3H)- pyrimidinone
To a stirred solution of 3-ethyl-2-methoxy-5-methyl-6-(trifluoromethyl)-4(3H)- pyrimidin-4-one (i.e. the product of Step A) (700 mg, 2.6 mmol) in carbon tetrachloride (13 mL) was added N-bromosuccinimide (550 mg, 3.1 mmol) and 2,2'-azobis(2- methylpropionitrile) (21 mg, 0.13 mmol). The reaction mixture was heated to reflux for 2 h. The reaction mixture was then cooled to room temperature and filtered, and the filtered solid was rinsed with carbon tetrachloride. The filtrate was concentrated under reduced pressure to afford the title product as an oil, which was used without further purification in the next step. 1H NMR (CDCl3) δ 4.52 (m, 2H), 4.10 (m, 5H), 1.29 (m, 3H). Step C: Preparation of 5-[[(4,5-dihydro-5,5-dimethyl-3-isoxazolyl)thio]methyl]-3-ethyl-2- methoxy-6-(trifluoromethyl)-4(3H)-pyrimidinone
To a stirred solution of 5-(bromomethyl)-3-ethyl-2-methoxy-6-(trifluoromethyl)-
4(3H)-pyrimidinone (i.e. the product of Step B) (940 mg, 2.6 mmol) in acetonitrile (13 mL) was added 4,5-dihydro-5,5-dimethyl-3-isoxazolyl carbamimidothioate hydrochloride (1 :1) (607 mg, 2.9 mmol) and potassium carbonate (1.48 g, 10.7 mmol). The reaction mixture was stirred at room temperature for 24 h. Water was added, and the mixture was extracted with ethyl acetate. The organic layer was dried (MgSC^) and concentrated under reduced pressure. The residue was purified by column chromatography using 50% ethyl acetate in hexanes as eluant to afford the title product, a compound of the present invention, as an oil (710 mg). 1H NMR (CDCl3) δ 4.31 (m, 2H), 4.08 (m, 5H), 2.84 (s, 2H), 1.43 (s, 6H), 1.27 (m, 3H).
Step D: 5-[[(4,5-dihydro-5,5-dimethyl-3-isoxazolyl)sulfonyl]methyl]-3-ethyl-2-methoxy-6-
(trifluoromethyl)-4(3H)-pyrimidinone
To a stirred solution of 5-[[(4,5-dihydro-5,5-dimethyl-3-isoxazolyl)thio]methyl]-3- ethyl-2-methoxy-6-(trifluoromethyl)-4(3H)-pyrimidinone (i.e. the product of Step C) (250 mg, 0.68 mmol) in dichloromethane (6.8 mL) was added 3-chloroperoxybenzoic acid (77% maximum assay, 500 mg, 2.0 mmol). The reaction mixture was stirred at room temperature for 24 h. The mixture was diluted with dichloromethane and then washed with aqueous 5% sodium bisulfite solution and saturated aqueous sodium bicarbonate. The organic layer was dried (MgSC^) and concentrated under reduced pressure. The residue was purified by column chromatography using 50% ethyl acetate in hexanes as eluant to afford the title product, a compound of the present invention, as a white solid (220 mg). 1H NMR (CDCl3) δ 4.67 (m, 2H), 4.11 (s, 3H), 4.05 (m, 2H), 3.02 (s, 2H), 1.54 (s, 6H), 1.26 (m, 3H).
SYNTHESIS EXAMPLE 12 Preparation of 3-[[(4,5-dihydro-5,5-dimethyl-3-isoxazolyl)sulfonyl]methyl]-l-methyl-4-
(trifluoromethyl)-2(lH)-pyridinone (Compound 203)
Step A. Preparation of phenylmethyl 2-chloro-4-(trifluoromethyl)-3-pyridinecarboxylate
To a solution of diisopropylamine (1.85 mL, 13.2 mmol) in tetrahydrofuran (30 mL) at -45 0C was added n-butyllithium (2.5 M in hexanes, 4.85 mL, 12.1 mmol), casuing the temperature rise to -25°C. After stirring for 5 min at this temperature, the mixture was cooled to -78 0C, and 2-chloro-4-trifluoromethylpyridine (2.0 g, 11.0 mmol) was added dropwise such that the temperature did not exceed -70 0C. After stirring for 20 min, benzyl chloroformate (1.86 mL, 13.2 mmol) was added dropwise such that the temperature of the mixture did not exceed -68 0C. The mixture was stirred at -68 0C for 1.5 h and then warmed to 0 0C. The reaction mixture was quenched with a saturated solution of ammonium chloride, extracted with ethyl ether, dried (MgSOz^), filtered and concentrated. The residue was purified by column chromatography using a gradient of 100% hexanes to 10% ethyl acetate in hexanes as eluant to give the title product (1.35 g). 1H NMR (CDCl3) δ 8.63 (d, IH), 7.52 (d, IH), 7.46-7.35 (m, 5H), 5.42 (s, 2H). Step B: Preparation of phenylmethyl 2-(phenylmethoxy)-4-(trifluoromethyl)-3- pyridinecarboxylate
To a suspension of sodium hydride (60% in oil, 188 mg, 4.71 mmol) in
JV-methylpyrrolidinone (5 mL) was added benzyl alcohol (533 μL, 5.14 mmol), and the reaction mixture was stirred at ambient temperature for 10 min before being added to a solution of phenylmethyl 2-chloro-4-(trifluoromethyl)-3-pyridinecarboxylate (i.e. the product of Step A) (1.35 g, 4.28 mmol) in JV-methylpyrrolidinone (20 mL) cooled with an external ice-water bath. The reaction mixture was allowed to warm to ambient temperature and stirred for 2 h. The reaction mixture was diluted with hexanes, washed twice with water, dried (MgSC^), filtered and concentrated. The residue was purified by column chromatography using a gradient of 100% hexanes to 10% ethyl acetate in hexanes as eluant to give the title product as a colorless oil (0.65 g).
1H NMR (CDCl3) δ 8.34 (d, IH), 7.38-7.29 (m, 10H), 7.13 (d, IH), 5.45 (s, 2H), 5.35 (s, 2H). Step C: Preparation of 2-(phenylmethoxy)-4-(trifluoromethyl)-3-pyridinemethanol
To a solution of the phenylmethyl 2-(phenylmethoxy)-4-(trifluoromethyl)-3- pyridinecarboxylate (i.e. the product of Step B) (0.65 g, 1.68 mmol) in dichloromethane (15 mL) at -78 0C was added diisobutylaluminum hydride (1.5 M in toluene, 2.80 mL, 4.20 mmol), and the reaction mixture was stirred at this temperature for 2.5 h. Additional diisobutylaluminum hydride (1.5 M in toluene, 0.80 mL, 1.20 mmol) was added, and the reaction mixture was allowed to warm slowly to 0 0C. Ethyl acetate was then added, and the mixture was stirred for a further 10 min before the addition of saturated aqueous sodium potassium tartrate solution. The mixture was warmed to ambient temperature and stirred overnight. The layers were separated, and the aqueous phase was extracted with dichloromethane. The combined organic phase was dried (MgSOz^), filtered and concentrated. The residue was purified by column chromatography using a gradient of 5 to 15% ethyl acetate in hexanes as eluant to give the title product as a colorless oil (0.40 g). 1H NMR (CDCl3) δ 8.27 (d, IH), 7.45 (d, 2H), 7.40 (d, 2H), 7.35 (t, IH), 7.16 (d, IH), 5.51 (s, 2H), 4.81 (s, 2H), 2.51 (t, IH). Step D: Preparation of 3-(bromomethyl)-2-(phenylmethoxy)-4-(trifluoromethyl)pyridine
2-(Phenylmethoxy)-4-(trifluoromethyl)-3-pyridinemethanol (i.e. the product of Step C) (0.40 g, 1.41 mmol) was dissolved in toluene, and the solution was concentrated under reduced pressure. Triphenylphosphine (481 mg, 1.84 mmol) was added, followed by dichloromethane (10 mL) and tetrabromomethane (610 mg, 1.84 mmol), and the mixture was stirred at ambient temperature for 1.5 h. The solution was concentrated, and the residue was purified by column chromatography using a gradient of 100% hexanes to 5% ethyl acetate in hexanes as eluant to give the title product (173 mg). 1H NMR (CDCl3) δ 8.28 (d, IH), 7.53 (d, 2H), 7.40 (d, 2H), 7.34 (t, IH), 7.14 (d, IH), 5.52 (s, 2H), 4.63 (s, 2H).
Step E: Preparation of 3-[[(4,5-dihydro-5,5-dimethyl-3-isoxazolyl)thio]methyl]-2-
(phenylmethoxy)-4-(trifluoromethyl)pyridine 3-(Bromomethyl)-2-(phenylmethoxy)-4-(trifluoromethyl)pyridine (i.e. the product of
Step D) (173 mg, 0.50 mmol), 4,5-dihydro-5,5-dimethyl-3-isoxazolyl carbamimidothioate hydrochloride (1 :1) (126 mg, 0.60 mmol) and potassium carbonate (207 mg, 1.80 mmol) were combined with acetonitrile (5 mL), and the mixture was stirred at ambient temperature for 18 h. The mixture was diluted with ethyl ether, washed with water (2x), dried (MgSOz^), filtered and concentrated. The residue was purified by column chromatography using a gradient of 100% hexanes to 10% ethyl acetate in hexanes as eluant to give the title product as a white solid (0.22 g).
1H NMR (CDCl3) δ 8.25 (d, IH), 7.48 (d, 2H), 7.37 (d, 2H), 7.31 (t, IH), 7.14 (d, IH), 5.50 (s, 2H), 4.52 (s, 2H), 2.77 (s, 2H), 1.41 (s, 6H). Step F: Preparation of 3-[[(4,5-dihydro-5,5-dimethyl-3-isoxazolyl)thio]methyl]-l-methyl)-
4-(trifluoromethyl)-2(lH)-pyridinone
3-[[(4,5-Dihydro-5,5-dimethyl-3-isoxazolyl)thio]methyl]-2-(phenylmethoxy)-4- (trifluoromethyl)pyridine (i.e. the product of Step E) (0.22 g, 0.55 mmol) was dissolved in trifluoroacetic acid (5 mL), and the solution was allowed to stand for 1 h before being concentrated under reduced pressure. The residue was re-dissolved in NJV- dimethylformamide (5 mL), treated with potassium carbonate (307 mg, 2.2 mmol) and methyl sulfate (79 μL, 0.83 mmol), and stirred at ambient temperature overnight. The mixture was diluted with ethyl ether, washed with water (2x), dried (MgSC^), filtered and concentrated. The residue was purified by column chromatography using 40 to 60% ethyl acetate in hexanes as eluant to give the title product as a white solid (0.09 g).
1H NMR (CDCl3) δ 7.39 (d, IH), 6.37 (d, IH), 4.41 (s, 2H), 3.61 (s, 3H), 2.86 (s, 2H), 1.43 (s, 6H).
Step G: Preparation of 3-[[(4,5-dihydro-5,5-dimethyl-3-isoxazolyl)sulfonyl]methyl]-l- methyl-4-(trifluoromethyl)-2(lH)-pyridinone To a solution of 3-[[(4,5-dihydro-5,5-dimethyl-3-isoxazolyl)thio]methyl]-l-methyl)-
4-(trifluoromethyl)-2(lH)-pyridinone (i.e. the product of step F) (0.09 g, 0.28 mmol) in dichloromethane (10 mL) was added 3-chloroperoxybenzoic acid (77% maximum assay, 208 mg, 0.92 mmol), and the mixture was stirred at ambient temperature for 3 h. The reaction mixture was quenched by the addition of methyl sulfide (1 mL), and the mixture was washed with saturated sodium bicarbonate solution. The aqueous phase was extracted with dichloromethane, and the combined organic phase was dried (MgSC^), filtered and concentrated. The residue was purified by chromatography using 40 to 60% ethyl acetate in hexanes as eluant to give the title product, a compound of the present invention, as a white solid (66 mg).
1H NMR (CDCl3) δ 7.47 (d, IH), 6.45 (d, IH), 4.82 (s, 2H), 3.59 (s, 3H), 3.24 (s, 2H), 1.55 (s, 6H).
SYNTHESIS EXAMPLE 13
Preparation of 4-[[(4,5-dihydro-5,5-dimethyl-3-isoxazolyl)sulfonyl]methyl]-3-fluoro-l- methyl-5-(trifluoromethyl)-2(lH)-pyridinone (Compound 240)
Step A: Preparation of 3-fluoro-2-(phenylmethoxy)-5-(trifluoromethyl)-pyridine To a solution of 2,3-difluoro-5-trifluoromethylpyridine (4.6 g, 25.1 mmol) and benzyl alcohol (2.74 mL, 26.4 mmol) in N,Λ/-dimethylformamide (50 mL) was added potassium carbonate (5.20 g, 37.7 mmol). The mixture was stirred for 16 h at ambient temperature and then diluted with hexanes, washed with water (2x), dried (MgSC^), filtered and concentrated. The residue was purified by column chromatography using a gradient of 100% hexanes to 3% ethyl acetate in hexanes as eluant to give the title product as a colorless oil (4.43 g).
1H NMR (CDCl3) δ 8.24 (m, IH), 7.54 (dd, IH), 7.48 (d, 2H), 7.39 (t, 2H), 7.34 (t, IH), 5.52 (s, 2H).
Step B: Preparation of 3-fluoro-2-(phenylmethoxy)-5-(trifluoromethyl)-4- pyridinecarboxaldehyde
3-Fluoro-2-(phenylmethoxy)-5-(trifluoromethyl)-pyridine (i.e. the product of Step A) (5.04 g, 17.6 mmol) was dissolved in tetrahydrofuran, and the solution cooled to -78 0C and treated dropwise with n-butyllithium (2.5 M solution in hexanes, 6.9 mL, 17.2 mmol) such that the temperature did not exceed -68 0C. After stirring for 30 min at this temperature, Λ/,Λ/-dimethylformamide (3.0 mL) was added, and the reaction mixture was stirred for an additional 30 min and then warmed slowly to 5 0C. The reaction mixture was quenched by the addition of a saturated solution of ammonium chloride and then extracted with ethyl ether. The organic phase was dried (MgSOz^), filtered and concentrated. The residue was purified by column chromatography using a gradient of 100% hexanes to 5% ethyl acetate in hexanes as eluant followed by trituration with hexanes to give the title product as an off-white solid (1.53 g).
1H NMR (CDCl3) δ 10.38 (q, IH), 8.37 (s, IH), 7.48 (d, 2H), 7.42-7.34 (m, 3H), 5.56 (s, 2H).
Step C : Preparation of 3 -fluoro-2-(phenylmethoxy)-5 -(trifluoromethyl)-4-pyridinemethanol A solution of 3-fluoro-2-(phenylmethoxy)-5-(trifluoromethyl)-4-pyridinecarbox- aldehyde (i.e. the product of Step B) (1.53 g, 5.1 mmol) in ethanol (5 mL) was treated with sodium borohydride (97 mg, 2.55 mmol), and the mixture was stirred at ambient temperature for 1 h. Water was added, and the mixture was extracted with dichloromethane (2x), dried (MgSO4), filtered and concentrated. The residue was purified by column chromatography using 5 to 15% ethyl acetate in hexanes as eluant to give the title product as a white solid (1.34 g).
1H NMR (CDCl3) δ 8.26 (s, IH), 7.47 (d, 2H), 7.39 (t, 2H), 7.34 (m, IH), 5.52 (s, 2H), 4.84 (d, 2H), 1.97 (t, IH).
Step D: Preparation of 4-(bromomethyl)-3-fluoro-2-(phenylmethoxy)-5- (trifluoromethyl)pyridine A mixture of 3-fluoro-2-(phenylmethoxy)-5-(trifluoromethyl)-4-pyridinemethanol
(i.e. the product of Step C) (1.34 g, 4.45 mmol) and triphenylphosphine (1.4 g, 5.34 mmol) in dichloromethane (20 mL) was treated with tetrabromomethane (1.77 g, 5.34 mmol) and the mixture was stirred at ambient temperature for 2 h. Additional triphenylphosphine (0.28 g) and tetrabromomethane (0.35 g) were added, and the mixture was stirred at ambient temperature for 16 h. Methanol was added, and the mixture was stirred for an additional 30 min, concentrated, and then re-dissolved in a mixture of methylene chloride and toluene (1 : 1). This solution was concentrated to half volume, filtered and concentrated. The residue was extracted with hexanes (3x), and the combined extracts were concentrated to give the title product as a white solid, (2.13 g) which was used without further purification. 1H NMR (CDCl3) δ 8.25 (s, IH), 7.48 (d, 2H), 7.39 (t, 2H), 7.35 (m, IH), 5.52 (s, 2H), 4.51 (d, 2H).
Step E. Preparation of 4-[[(4,5-dihydro-5,5-dimethyl-3-isoxazolyl)thio]methyl]-3-fluoro-2-
(phenylmethoxy)-5-(trifluoromethyl)pyridine 4-(Bromomethyl)-3-fluoro-2-(phenylmethoxy)-5-(trifluoromethyl)pyridine (i.e. the product of Step D) (2.13 g, -85 mol%), 4,5-dihydro-5,5-dimethyl-3-isoxazolyl carbamimidothioate hydrochloride (1 :1) (1.29 g, 6.16 mmol) and potassium carbonate (2.12 g, 15.4 mmol) were combined in acetonitrile (30 mL), and the mixture was stirred at ambient temperature for 3 h. The reaction mixture was diluted with ethyl ether, washed with water (2x), dried (MgSO4), filtered and concentrated. The residue was purified by column chromatography using a gradient of 100% hexanes to 5% ethyl acetate in hexanes as eluant to give the title compound as a colorless oil (1.2 g).
1H NMR (CDCl3) δ 8.24 (s, IH), 7.48 (d, 2H), 7.39 (t, 2H), 7.34 (m, IH), 5.51 (s, 2H), 4.45 (s, 2H), 2.81 (s, 2H), 1.44 (s, 6H).
Step F: Preparation of 4-[[(4,5-dihydro-5,5-dimethyl-3-isoxazolyl)thio]methyl]-3-fluoro-5- (trifluoromethyl)-2(lH)-pyridinone
4-[[(4,5-Dihydro-5,5-dimethyl-3-isoxazolyl)thio]methyl]-3-fluoro-2-(phenyl- methoxy)-5-(trifluoromethyl)pyridine (i.e. the product of Step E) (1.2 g, 2.90 mmol) was dissolved in trifluoroacetic acid (10 niL), and the solution was allowed to stand for 45 min before being concentrated under reduced pressure. The residue was dissolved in toluene and then concentrated. The residue was filtered through a pad of silica gel using ethyl ether as eluant to give a white solid (1.22 g) consisting of a mixture of the desired product and benzyl alcohol, which was used without further purification.
1H NMR (CDCl3) δ 12.00-8.00 (br s, IH), 7.70 (s, IH), 4.38 (d, 2H), 2.83 (s, 2H), 1.45 (s, 6H).
Step G: Preparation of 4-[[(4,5-Dihydro-5,5-dimethyl-3-isoxazolyl)thio]methyl]-3-fluoro-l- methyl-5-(trifluoromethyl)-2(lH)-pyridinone 4-[[(4,5-Dihydro-5,5-dimethyl-3-isoxazolyl)thio]methyl]-3-fluoro-5-(trifluoro- methyl)-2(lH)-pyridinone (i.e. the product of Step F) (0.32 g) was dissolved in N,N- dimethylformamide (5 mL), and the solution was treated with potassium carbonate (204 mg, 1.48 mmol) and dimethyl sulfate (113 μL, 1.18 mmol) and stirred at ambient temperature for 16 h. The reaction mixture was then diluted with ethyl acetate, washed with water (3x), dried (MgSO4), filtered and concentrated. The residue was purified by column chromatography using 30 to 50% ethyl acetate in hexanes as eluant to give the title product as a white solid (0.22 g). 1H NMR (CDCl3) δ 7.56 (s, IH), 4.32 (d, 2H), 3.64 (s, 3H), 2.82 (s, 2H), 1.44 (s, 6H).
Step H: Preparation of 4-[[(4,5-dihydro-5,5-dimethyl-3-isoxazolyl)sulfonyl]methyl]-3- fluoro-1 -methyl-5-(trifluoromethyl)-2(lH)-pyridinone
To a solution of 4-[[(4,5-dihydro-5,5-dimethyl-3-isoxazolyl)thio]methyl]-3-fluoro-l- methyl-5-(trifluoromethyl)-2(lH)-pyridinone (i.e. the product of step G) (0.22 g, 0.65 mmol) in dichloromethane (10 mL) was added 3-chloroperoxybenzoic acid (77% maximum assay, 895 mg, 4.0 mmol), and the mixture was stirred at ambient temperature for 4 h. The reaction mixture was then quenched by the addition of methyl sulfide (0.5 mL). After 10 min, the mixture was diluted with ethyl ether, washed with saturated aqueous sodium bicarbonate (2x), dried (MgSO4), filtered and concentrated. The residue was purified by column chromatography using 30 to 50% ethyl acetate in hexanes as eluant followed by trituration in ethyl ether to give the title product, a compound of the present invention, as a white solid (0.12 g).
1H NMR (CDCl3) δ 7.63 (s, IH), 4.82 (d, 2H), 3.67 (s, 3H), 3.12 (s, 2H), 1.53 (s, 6H).
SYNTHESIS EXAMPLE 14
Preparation of 5-chloro-4-[[(4,5-dihydro-5,5-dimethyl-3-isoxazolyl)sulfonyl]methyl]-l- methyl-3-(trifluoromethyl)-2(lH)-pyridinone (Compound 241) Step A: Preparation of 5-chloro-2-(phenylmethoxy)pyridine
To a solution of 2,5-dichloropyridine (14.8 g, 0.1 mol) and benzyl alcohol (11.4 rnL, 0.11 mol) in N,Λ/-dimethylformamide (100 mL) cooled using an external ice-water bath was added potassium t-butoxide (12.3 g, 0.11 mol) in portions. The mixture was stirred at 0 0C for 1 h and then at ambient temperature for 1.5 h before being diluted with hexanes and washed with water (2x). The organic phase was concentrated, and the residue was purified by filtration through a pad of silica gel using 10% 1-chlorobutane in hexanes as eluant. Concentration of the eluant afforded the title product as white crystals (16 g). 1H NMR (CDCl3) δ 8.11 (d, IH), 7.53 (dd, IH), 7.44 (d, 2H), 7.37 (t, 2H), 7.33 (m, IH), 6.76 (d, IH), 5.34 (s, 2H).
Step B: Preparation of methyl 5-chloro-2-(phenylmethoxy)-4-pyridinecarboxylate n-Butyllithium (2.5 M in hexanes, 9.7 mL, 24 mmol) was added to a solution of diisopropylamine (3.7 mL, 26 mmol) in tetrahydrofuran (80 mL) at -15 0C causing the temperature to rise to -5 0C. After 5 min, the solution was cooled to -70 0C, and a solution of 5-chloro-2-(phenylmethoxy)pyridine (i.e. the product of Step A) (4.82 g, 21.9 mmol) in tetrahydrofuran (20 mL) was added dropwise, at a rate such that the temperature remained below -65 0C. The reaction mixture was stirred for 1.5 h at this temperature and then carbon dioxide gas was introduced into the solution through a Drierite®-filled tube for 5 min. After 20 min, iodomethane (5 mL) was added, and the mixture was allowed to warm to ambient temperature and stir overnight. The mixture was diluted with water and washed with ethyl ether. The aqueous phase was acidified with concentrated hydrochloric acid and extracted with dichloromethane (2x). The dichloromethane extracts were dried (MgSOz^), filtered and concentrated to give a yellow solid (3.95 g) which was used without further purification. The solid was dissolved in Λ/,Λ/-dimethylformamide (30 mL) and treated with potassium carbonate (3.10 g, 22.5 mmol) and dimethyl sulfate (1.71 mL, 18 mmol). The mixture was stirred at ambient temperature overnight before being diluted with ethyl ether, washed with water (3x), dried (MgSOz^), filtered and concentrated. The residue was purified by column chromatography using a gradient of hexanes to 10% ethyl acetate in hexanes as eluant to give the title product as a white solid (2.58 g). 1H NMR (CDCl3) δ 8.23 (s, IH), 7.43 (d, 2H), 7.37 (t, 2H), 7.34 (m, IH), 7.17 (s, IH), 5.37 (s, 2H), 3.94 (s, 3H).
Step C: Preparation of 5-chloro-2-(phenylmethoxy)-4-pyridinemethanol
To a solution of methyl 5-chloro-2-(phenylmethoxy)-4-pyridinecarboxylate (i.e. the product of Step B) (3.2 g, 11.5 mmol) in dichloromethane (30 mL) at -78 0C was added diisobutylaluminum hydride (1.5 M in toluene, 16.9 mL, 25.4 mmol), and the reaction mixture was stirred at this temperature for 6 h before being allowed to warm slowly to ambient temperature and stir overnight. Ethyl acetate, methanol and a saturated aqueous sodium potassium tartrate solution were added sequentially, and the mixture was stirred for 1 h. The layers were separated, and the organic phase was dried (MgSC^), filtered and concentrated. The residue was purified by column chromatography using 5 to 30% ethyl acetate in hexanes as eluant to give the title product as a white solid (1.62 g). 1H NMR (CDCl3) δ 8.07 (s, IH), 7.44 (d, 2H), 7.37 (t, 2H), 7.31 (m, IH), 7.02 (s, IH), 5.36 (s, 2H), 4.74 (d, 2H), 1.88 (t, IH).
Step D: Preparation of [5-chloro-2-(phenylmethoxy)-4-pyridinyl]methyl benzoate
Benzoyl chloride (829 μL, 7.14 mmol) was added to a solution of 5-chloro-2- (phenylmethoxy)-4-pyridinemethanol (i.e. the product of Step C) (1.62 g, 6.49 mmol) and triethylamine (1.17 mL, 8.44 mmol) in dichloromethane (20 mL), and the reaction mixture was stirred at ambient temperature for 16 h. The mixture was diluted with ethyl ether, washed with water, dried (MgSC^), filtered and concentrated. The residue was purified by trituration with hexanes to give the title product as a white solid (2.3 g). 1H NMR (CDCl3) δ 8.14 (s, IH), 8.11 (d, 2H), 7.61 (t, IH), 7.48 (t, 2H), 7.44 (d, 2H), 7.37 (t, 2H), 7.32 (m, IH), 6.93 (s, IH), 5.41 (d, 2H), 5.35 (s, 2H).
Step E : Preparation of (5 -chloro- 1 ,2-dihydro-2-oxo-4-pyridinyl)methyl benzoate
[5-Chloro-2-(phenylmethoxy)-4-pyridinyl]methyl benzoate (i.e. the product from Step D) (2.15 g, 6.08 mmol) was dissolved in trifluoroacetic acid (7 mL), and the reaction mixture was stirred at ambient temperature for 2 d. Ethyl ether was added, and the resulting white precipitate was collected by filtration to provide the title product (1.7 g).
1H NMR (CDCl3) δ 9.00-6.00 (br s, IH), 8.12 (d, 2H), 7.64 (t, IH), 7.54 (s, IH), 7.50 (t, 2H), 6.87 (s, IH), 5.38 (d, 2H).
Step F: Preparation of (5 -chloro- 1 ,2-dihydro-3-iodo-2-oxo-4-pyridinyl)methyl benzoate
To a solution of (5 -chloro- l,2-dihydro-2-oxo-4-pyridinyl)methyl benzoate (i.e. the product of Step E) (1.62 g, 6.1 mmol) in N,Λ/-dimethylformamide (20 mL) was added N- iodosuccinimide (1.70 g, 7.59 mmol), and the mixture was heated at 65 0C for 3 h before being cooled and diluted with water (25 mL). After stirring at ambient temperature for 1 h, the precipitate was filtered and rinsed with hexanes and then a small amount of ethyl ether.
The solid was dissolved in dichloromethane, dried (MgSOz^), filtered and concentrated to give the title product as a yellow solid (1.26 g).
1H NMR (CDCl3) δ 12.6 (br s, IH), 8.06 (d, 2H), 7.59 (t, IH), 7.58 (s, IH), 7.45 (t, 2H),
5.57 (s, 2H).
Step G: Preparation of (5 -chloro- l,2-dihydro-3-iodo-l-methyl-2-oxo-4-pyridinyl)methyl benzoate To a mixture of (5 -chloro- l,2-dihydro-3-iodo-2-oxo-4-pyridinyl)methyl benzoate
(i.e. the product of Step F) (1.26 g, 3.23 mmol) and potassium carbonate (670 mg, 4.86 mmol) in N,N-dimethylformamide (10 niL) was added dimethyl sulfate (370 μL, 3.88 mmol). The reaction mixture was stirred at ambient temperature for 18 h. The mixture was diluted with ethyl acetate, washed with water (3x), dried (MgSC^), filtered and concentrated. The residue was purified by column chromatography using 30 to 50% ethyl acetate in hexanes as eluant to give the title product as a yellow solid (0.90 g).
1H NMR (CDCl3) δ 8.04 (d, 2H), 7.58 (t, IH), 7.44 (m, 3H), 5.53 (s, 2H), 3.64 (s, 3H).
Step H: Preparation of 5-chloro-4-(hydroxymethyl)-3-iodo-l-methyl-2(lH)-pyridinone
Sodium hydroxide (1 M aqueous solution, 2.38 mL, 2.38 mmol) was added to a solution of (5-chloro-l,2-dihydro-3-iodo-l-methyl-2-oxo-4-pyridinyl)methyl benzoate (i.e. the product of Step G) (0.8 g, 2 mmol) in ethanol (10 mL), and the mixture was stirred at ambient temperature for 1 h. The precipitate was filtered to give a white solid (0.43 g). The filtrate was kept overnight and then diluted with saturated aqueous sodium bicarbonate solution and extracted with dichloromethane (2x). The combined extracts were dried (MgSC^), filtered and concentrated to give additional title product as a yellow solid (0.11 g). 1H NMR (DMSO-4) δ 8.04 (s, IH), 5.37 (t, IH), 4.62 (d, 2H), 3.49 (s, 3H).
Step I: Preparation of 5-chloro-4-[[(4,5-dihydro-5,5-dimethyl-3-isoxazolyl)thio]methyl]-3- iodo-l-methy-2(lH)-pyridinone
5-Chloro-4-(hydroxymethyl)-3-iodo-l-methyl-2(lH)-pyridinone (i.e. the product of Step Η) (103 mg, 0.34 mmol), triphenylphosphine (108 mg, 0.41 mmol) and tetrabromomethane (137 mg, 0.41 mmol) were combined in dichloromethane (5 mL), and the reaction mixture was stirred at ambient temperature before the addition of more tetrabromomethane (45 mg) and triphenylphosphine (30 mg). The reaction mixture was stirred for a further 1 h before being concentrated and purified by chromatography on silica gel using 30% to 50% ethyl acetate in hexanes as eluant to give a white solid. 4,5-Dihydro- 5,5-dimethyl-3-isoxazolyl carbamimidothioate hydrochloride (1 :1) (1.29 g, 6.16 mmol) and potassium carbonate (2.12 g, 15.4 mmol) were added, followed by acetonitrile (5 mL), and the mixture was stirred at ambient temperature for 2 h. The mixture was diluted with ethyl acetate, washed with water, dried (MgSOz^), filtered and concentrated. The residue was purified by column chromatography using 30 to 50% ethyl acetate in hexanes as eluant to give a white solid (84 mg) containing the title compound (85%) and the isomeric thionoamide (15%), which was used without further purification. 1H NMR (CDCl3) δ 7.40 (s, IH), 4.58 (s, 2H), 3.61 (s, 3H), 2.84 (s, 2H), 1.45 (s, 6H).
Step J: Preparation of 5-chloro-4-[[(4,5-dihydro-5,5-dimethyl-3-isoxazolyl)thio]methyl]-3-
(trifluoromethyl)-2(lH)-pyridinone 5-Chloro-4-[[(4,5-dihydro-5,5-dimethyl-3-isoxazolyl)thio]methyl]-3-iodo-l-methy-
2(lH)-pyridinone (i.e. the product of Step I) (84 mg, 0.20 mmol) was dissolved in NJV- dimethylformamide (5 mL) and treated with triphenylarsine (25 mg, 0.08 mmol), copper(I) iodide (193 mg, 1.0 mmol) and tris(dibenzylideneacetone)dipalladium(0) (9.3 mg, 0.01 mmol). The mixture was degassed by sparging with nitrogen gas for 5 min before the addition of methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (129 μL, 1.0 mmol), and then the mixture was heated at 90 0C for 1.5 h. The mixture was cooled, diluted with ethyl acetate and filtered through a cartridge containing Celite® diatomaceaus filter aid. The filtrate was washed with water (2x), dried (MgSC^), filtered and concentrated. The residue was purified by column chromatography using a gradient of 100% chloroform to 5% acetone in chloroform as eluant. The resulting white solid was triturated with ethyl ether to give the title product (41 mg). 1H NMR (CDCl3) δ 7.61 (s, IH), 4.49 (s, 2H), 3.57 (s, 3H), 2.81 (s, 2H), 1.44 (s, 6H).
Step K: Preparation of 5-chloro-4-[[(4,5-dihydro-5,5-dimethyl-3- isoxazolyl)sulfonyl]methyl]-l-methyl-3-(trifluoromethyl)-2(lH)-pyridinone To a solution of 5-chloro-4-[[(4,5-dihydro-5,5-dimethyl-3-isoxazolyl)thio]methyl]-3- (trifluoromethyl)-2(lH)-pyridinone (i.e. the product of step J) (41 mg, 0.12 mmol) in dichloromethane (2 mL) was added 3-chloroperoxybenzoic acid (77% maximum assay, 100 mg, 0.45 mmol), and the mixture was stirred at ambient temperature for 3 h. An additional portion of 3-chloroperoxybenzoic acid (50 mg, 0.22 mmol) was added, and the reaction mixture was stirred for an additional 1 h. The reaction was quenched by the addition of methyl sulfide (0.25 mL). After 10 min, the mixture was diluted with aqueous sodium bicarbonate solution, extracted with dichloromethane (2x), dried (MgSC^), filtered and concentrated. The residue was purified by column chromatography using 30 to 50% ethyl acetate in hexanes as eluant to give the title product, a compound of the present invention, as a white solid (31 mg). 1H NMR (CDCl3) δ 7.70 (s, IH), 5.15 (s, 2H), 3.61 (s, 3H), 3.14 (s, 2H), 1.53 (s, 6H). SYNTHESIS EXAMPLE 15
Preparation of 5 - [ 1 - [(4,5 -dihydro-5 ,5 -dimethyl-3 -isoxazolyl)sulfonyl] ethyl]-2-methoxy-3 - methyl-6-(trifluoromethyl)-4(3H)-pyrimidinone (Compound 223) To a solution of 5-chloro-4-[[(4,5-dihydro-5,5-dimethyl-3-isoxazolyl)sulfonyl]- methyl]-l-methyl-3-(trifluoromethyl)-2(lH)-pyridinone (i.e. the product from Synthesis Example 2) (0.2 g, 0.52 mmol) and iodomethane (1 mL) in tetrahydrofuran (5 mL) at -70 0C was added sodium bis(trimethylsilyl)amide (1.0 M solution in tetrahydrofuran, 0.58 mL, 0.58 mmol) dropwise. The reaction mixture was allowed to warm slowly to ambient temperature and stir for 16 h. Saturated aqueous ammonium chloride solution was added, and the mixture was extracted with ethyl acetate (3x). The combined organic phases were washed with brine (2x), dried (MgSOz^), filtered and concentrated. The residue was purified by column chromatography using 10 to 50% ethyl acetate in hexanes as eluant to give the title product, a compound of the present invention, as a colorless oil (105 mg). 1H NMR δ (CDCl3) 5.09 (br q, IH), 4.11 (s, 3H), 3.44 (s, 3H), 3.17 (d, IH), 3.14 (d, IH), 1.86 (d, 3H), 1.53 (s, 3H), 1.52 (s, 3H).
SYNTHESIS EXAMPLE 16
Preparation of 5-[[(4,5-dihydro-5,5-dimethyl-3-isoxazolyl)sulfonyl]fluoromethyl]-2- methoxy-3-methyl-6-(trifluoromethyl)-4(3H)-pyrimidinone (Compound 222)
To a solution of the 5-chloro-4-[[(4,5-dihydro-5,5-dimethyl-3-isoxazolyl)sulfonyl]- methyl]-l-methyl-3-(trifluoromethyl)-2(lH)-pyridinone (i.e. the product of Synthesis
Example 2) (0.4 g, 1.04 mmol) and iV-fluoro bis(benzenesulfonamide) (360 mg, 0.40 mmol) in tetrahydrofuran (10 mL) at -70 0C was added sodium bis(trimethylsilyl)amide (1.0 M solution in tetrahydrofuran, 1.20 mL, 1.20 mmol) dropwise. The reaction mixture was stirred at this temperature for 2 h and then quenched with saturated ammonium chloride solution. The mixture was extracted with ethyl acetate (3x) and the combined organic phases were washed with brine (2x), dried (MgSOz^), filtered and concentrated. The residue was purified by column chromatography using 10 to 30% ethyl acetate in hexanes as eluant to give the title product, a compound of the present invention, as a white solid (203 mg)
1H NMR (CDCl3) δ 6.64 (d, IH), 4.17 (s, 3H), 3.44 (s, 3H), 3.30 (d, IH), 3.22 (d, IH), 1.54 (s, 3H), 1.52 (s, 3H).
By the procedures described herein together with methods known in the art, the following compounds of Tables 1 to 9 can be prepared. The following abbreviations are used in the Tables which follow: -CN means cyano, S(O)2Me means methylsulfonyl and Ph means phenyl.
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A compound of this invention will generally be used as a herbicidal active ingredient in a composition, i.e. formulation, with at least one additional component selected from the group consisting of surfactants, solid diluents and liquid diluents, which serves as a carrier. The formulation or composition ingredients are selected to be consistent with the physical properties of the active ingredient, mode of application and environmental factors such as soil type, moisture and temperature.
Useful formulations include both liquid and solid compositions. Liquid compositions include solutions (including emulsifϊable concentrates), suspensions, emulsions (including microemulsions and/or suspoemulsions) and the like, which optionally can be thickened into gels. The general types of aqueous liquid compositions are soluble concentrate, suspension concentrate, capsule suspension, concentrated emulsion, microemulsion and suspo-emulsion. The general types of nonaqueous liquid compositions are emulsifϊable concentrate, microemulsifiable concentrate, dispersible concentrate and oil dispersion.
The general types of solid compositions are dusts, powders, granules, pellets, prills, pastilles, tablets, filled films (including seed coatings) and the like, which can be water-dispersible ("wettable") or water-soluble. Films and coatings formed from film- forming solutions or flowable suspensions are particularly useful for seed treatment. Active ingredient can be (micro)encapsulated and further formed into a suspension or solid formulation; alternatively the entire formulation of active ingredient can be encapsulated (or "overcoated"). Encapsulation can control or delay release of the active ingredient. An emulsifiable granule combines the advantages of both an emulsifiable concentrate formulation and a dry granular formulation. High-strength compositions are primarily used as intermediates for further formulation.
Sprayable formulations are typically extended in a suitable medium before spraying. Such liquid and solid formulations are formulated to be readily diluted in the spray medium, usually water. Spray volumes can range from about one to several thousand liters per hectare, but more typically are in the range from about ten to several hundred liters per hectare. Sprayable formulations can be tank mixed with water or another suitable medium for foliar treatment by aerial or ground application, or for application to the growing medium of the plant. Liquid and dry formulations can be metered directly into drip irrigation systems or metered into the furrow during planting.
The formulations will typically contain effective amounts of active ingredient, diluent and surfactant within the following approximate ranges which add up to 100 percent by weight.
Figure imgf000083_0001
Solid diluents include, for example, clays such as bentonite, montmorillonite, attapulgite and kaolin, gypsum, cellulose, titanium dioxide, zinc oxide, starch, dextrin, sugars (e.g., lactose, sucrose), silica, talc, mica, diatomaceous earth, urea, calcium carbonate, sodium carbonate and bicarbonate, and sodium sulfate. Typical solid diluents are described in Watkins et al., Handbook of Insecticide Dust Diluents and Carriers, 2nd Ed., Dorland Books, Caldwell, New Jersey.
Liquid diluents include, for example, water, Λ/,iV-dimethylalkanamides (e.g., Λ/,Λ/-dimethylformamide), limonene, dimethyl sulfoxide, JV-alkylpyrrolidones (e.g., JV-methylpyrrolidinone), ethylene glycol, Methylene glycol, propylene glycol, dipropylene glycol, polypropylene glycol, propylene carbonate, butylene carbonate, paraffins (e.g., white mineral oils, normal paraffins, isoparaffins), alkylbenzenes, alkylnaphthalenes, glycerine, glycerol triacetate, sorbitol, triacetin, aromatic hydrocarbons, dearomatized aliphatics, alkylbenzenes, alkylnaphthalenes, ketones such as cyclohexanone, 2-heptanone, isophorone and 4-hydroxy-4-methyl-2-pentanone, acetates such as isoamyl acetate, hexyl acetate, heptyl acetate, octyl acetate, nonyl acetate, tridecyl acetate and isobornyl acetate, other esters such as alkylated lactate esters, dibasic esters and γ-butyrolactone, and alcohols, which can be linear, branched, saturated or unsaturated, such as methanol, ethanol, n-propanol, isopropyl alcohol, n-butanol, isobutyl alcohol, n-hexanol, 2-ethylhexanol, n-octanol, decanol, isodecyl alcohol, isooctadecanol, cetyl alcohol, lauryl alcohol, tridecyl alcohol, oleyl alcohol, cyclohexanol, tetrahydrofurfuryl alcohol, diacetone alcohol and benzyl alcohol. Liquid diluents also include glycerol esters of saturated and unsaturated fatty acids (typically C6-C22), such as plant seed and fruit oils (e.g, oils of olive, castor, linseed, sesame, corn (maize), peanut, sunflower, grapeseed, safflower, cottonseed, soybean, rapeseed, coconut and palm kernel), animal-sourced fats (e.g., beef tallow, pork tallow, lard, cod liver oil, fish oil), and mixtures thereof. Liquid diluents also include alkylated fatty acids (e.g., methylated, ethylated, butylated) wherein the fatty acids may be obtained by hydrolysis of glycerol esters from plant and animal sources, and can be purified by distillation. Typical liquid diluents are described in Marsden, Solvents Guide, 2nd Ed., Interscience, New York, 1950. The solid and liquid compositions of the present invention often include one or more surfactants. When added to a liquid, surfactants (also known as "surface-active agents") generally modify, most often reduce, the surface tension of the liquid. Depending on the nature of the hydrophilic and lipophilic groups in a surfactant molecule, surfactants can be useful as wetting agents, dispersants, emulsifϊers or defoaming agents. Surfactants can be classified as nonionic, anionic or cationic. Nonionic surfactants useful for the present compositions include, but are not limited to: alcohol alkoxylates such as alcohol alkoxylates based on natural and synthetic alcohols (which may be branched or linear) and prepared from the alcohols and ethylene oxide, propylene oxide, butylene oxide or mixtures thereof; amine ethoxylates, alkanolamides and ethoxylated alkanolamides; alkoxylated triglycerides such as ethoxylated soybean, castor and rapeseed oils; alkylphenol alkoxylates such as octylphenol ethoxylates, nonylphenol ethoxylates, dinonyl phenol ethoxylates and dodecyl phenol ethoxylates (prepared from the phenols and ethylene oxide, propylene oxide, butylene oxide or mixtures thereof); block polymers prepared from ethylene oxide or propylene oxide and reverse block polymers where the terminal blocks are prepared from propylene oxide; ethoxylated fatty acids; ethoxylated fatty esters and oils; ethoxylated methyl esters; ethoxylated tristyrylphenol (including those prepared from ethylene oxide, propylene oxide, butylene oxide or mixtures thereof); fatty acid esters, glycerol esters, lanolin-based derivatives, polyethoxylate esters such as polyethoxylated sorbitan fatty acid esters, polyethoxylated sorbitol fatty acid esters and polyethoxylated glycerol fatty acid esters; other sorbitan derivatives such as sorbitan esters; polymeric surfactants such as random copolymers, block copolymers, alkyd peg (polyethylene glycol) resins, graft or comb polymers and star polymers; polyethylene glycols (pegs); polyethylene glycol fatty acid esters; silicone-based surfactants; and sugar-derivatives such as sucrose esters, alkyl polyglycosides and alkyl polysaccharides. Useful anionic surfactants include, but are not limited to: alkylaryl sulfonic acids and their salts; carboxylated alcohol or alkylphenol ethoxylates; diphenyl sulfonate derivatives; lignin and lignin derivatives such as lignosulfonates; maleic or succinic acids or their anhydrides; olefin sulfonates; phosphate esters such as phosphate esters of alcohol alkoxylates, phosphate esters of alkylphenol alkoxylates and phosphate esters of styryl phenol ethoxylates; protein-based surfactants; sarcosine derivatives; styryl phenol ether sulfate; sulfates and sulfonates of oils and fatty acids; sulfates and sulfonates of ethoxylated alkylphenols; sulfates of alcohols; sulfates of ethoxylated alcohols; sulfonates of amines and amides such as 7V,iV-alkyltaurates; sulfonates of benzene, cumene, toluene, xylene, and dodecyl and tridecylbenzenes; sulfonates of condensed naphthalenes; sulfonates of naphthalene and alkyl naphthalene; sulfonates of fractionated petroleum; sulfosuccinamates; and sulfosuccinates and their derivatives such as dialkyl sulfosuccinate salts.
Useful cationic surfactants include, but are not limited to: amides and ethoxylated amides; amines such as JV-alkyl propanediamines, tripropylenetriamines and dipropylenetetramines, and ethoxylated amines, ethoxylated diamines and propoxylated amines (prepared from the amines and ethylene oxide, propylene oxide, butylene oxide or mixtures thereof); amine salts such as amine acetates and diamine salts; quaternary ammonium salts such as quaternary salts, ethoxylated quaternary salts and diquaternary salts; and amine oxides such as alkyldimethylamine oxides and bis-(2-hydroxyethyl)-alkylamine oxides.
Also useful for the present compositions are mixtures of nonionic and anionic surfactants or mixtures of nonionic and cationic surfactants. Nonionic, anionic and cationic surfactants and their recommended uses are disclosed in a variety of published references including McCutcheon 's Emulsifiers and Detergents, annual American and International Editions published by McCutcheon's Division, The Manufacturing Confectioner Publishing Co.; Sisely and Wood, Encyclopedia of Surface Active Agents, Chemical Publ. Co., Inc., New York, 1964; and A. S. Davidson and B. Milwidsky, Synthetic Detergents, Seventh Edition, John Wiley and Sons, New York, 1987. Compositions of this invention may also contain formulation auxiliaries and additives, known to those skilled in the art as formulation aids (some of which may be considered to also function as solid diluents, liquid diluents or surfactants). Such formulation auxiliaries and additives may control: pH (buffers), foaming during processing (antifoams such polyorganosiloxanes), sedimentation of active ingredients (suspending agents), viscosity (thixotropic thickeners), in-container microbial growth (antimicrobials), product freezing (antifreezes), color (dyes/pigment dispersions), wash-off (film formers or stickers), evaporation (evaporation retardants), and other formulation attributes. Film formers include, for example, polyvinyl acetates, polyvinyl acetate copolymers, polyvinylpyrrolidone-vinyl acetate copolymer, polyvinyl alcohols, polyvinyl alcohol copolymers and waxes. Examples of formulation auxiliaries and additives include those listed in McCutcheon 's Volume 2: Functional Materials, annual International and North American editions published by McCutcheon's Division, The Manufacturing Confectioner Publishing Co.; and PCT Publication WO 03/024222.
The compound of Formula 1 and any other active ingredients are typically incorporated into the present compositions by dissolving the active ingredient in a solvent or by grinding in a liquid or dry diluent. Solutions, including emulsifiable concentrates, can be prepared by simply mixing the ingredients. If the solvent of a liquid composition intended for use as an emulsifiable concentrate is water-immiscible, an emulsifier is typically added to emulsify the active-containing solvent upon dilution with water. Active ingredient slurries, with particle diameters of up to 2,000 μm can be wet milled using media mills to obtain particles with average diameters below 3 μm. Aqueous slurries can be made into finished suspension concentrates (see, for example, U.S. 3,060,084) or further processed by spray drying to form water-dispersible granules. Dry formulations usually require dry milling processes, which produce average particle diameters in the 2 to 10 μm range. Dusts and powders can be prepared by blending and usually grinding (such as with a hammer mill or fluid-energy mill). Granules and pellets can be prepared by spraying the active material upon preformed granular carriers or by agglomeration techniques. See Browning, "Agglomeration", Chemical Engineering, December 4, 1967, pp 147-48, Perry's Chemical Engineer's Handbook, 4th Ed., McGraw-Hill, New York, 1963, pages 8-57 and following, and WO 91/13546. Pellets can be prepared as described in U.S. 4,172,714. Water-dispersible and water-soluble granules can be prepared as taught in U.S. 4,144,050, U.S. 3,920,442 and DE 3,246,493. Tablets can be prepared as taught in U.S. 5,180,587, U.S. 5,232,701 and U.S. 5,208,030. Films can be prepared as taught in GB 2,095,558 and U.S. 3,299,566.
For further information regarding the art of formulation, see T. S. Woods, "The Formulator's Toolbox - Product Forms for Modern Agriculture" in Pesticide Chemistry and Bioscience, The Food-Environment Challenge, T. Brooks and T. R. Roberts, Eds., Proceedings of the 9th International Congress on Pesticide Chemistry, The Royal Society of Chemistry, Cambridge, 1999, pp. 120-133. See also U.S. 3,235,361, Col. 6, line 16 through Col. 7, line 19 and Examples 10-41; 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; Hance et al, Weed Control Handbook, 8th Ed., Blackwell Scientific Publications, Oxford, 1989; and Developments in formulation technology, PJB Publications, Richmond, UK, 2000.
In the following Examples, all percentages are by weight and all formulations are prepared in conventional ways. Compound numbers refer to compounds in Index Tables A- B. 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. Percentages are by weight except where otherwise indicated. Example A
High Strength Concentrate
Compound 5 98.5% silica aerogel 0.5% synthetic amorphous fine silica 1.0%
Example B
Wettable Powder
Compound 6 65.0% dodecylphenol polyethylene glycol ether 2.0% sodium ligninsulfonate 4.0% sodium silicoaluminate 6.0% montmorillonite (calcined) 23.0%
Example C
Granule
Compound 5 10.0% attapulgite granules (low volatile matter, 0.71/0.30 mm; 90.0%
U.S.S. No. 25-50 sieves)
Example D
Extruded Pellet
Compound 6 25.0% anhydrous sodium sulfate 10.0% crude calcium ligninsulfonate 5.0% sodium alkylnaphthalenesulfonate 1.0% calcium/magnesium bentonite 59.0%
Example E
Emulsifiable Concentrate
Compound 5 10.0% polyoxyethylene sorbitol hexoleate 20.0%
Co-CiO fatty acid methyl ester 70.0%
Example F
Microemulsion
Compound 6 5.0% polyvinylpyrrolidone -vinyl acetate copolymer 30.0% alkylpolyglycoside 30.0% glyceryl monooleate 15.0% water 20.0% Test results indicate that the compounds of Formula 1 wherein the sum of n + m is greater than zero are highly active preemergent and/or postemergent herbicides and/or plant growth regulants. Compounds of Formula 1 wherein the sum of n + m is zero (i.e. sulfides) may show slight herbicidal activity at commercially desirable application rates, but the primary utility of these compounds is as key intermediates for the preparation of highly herbicidally active compounds of Formula 1 wherein the sum of n + m is greater than zero (e.g., by the methods of Schemes 1 through 4). Therefore the following biological disclosure relating to compounds of Formula 1 and compounds of this invention pertains particularly to compounds wherein the sum of n + m is greater than zero. These compounds generally show highest activity for preemergence weed control (i.e. applied before weed seedlings emerge from the soil) and early postemergence weed control (i.e. applied when the emerged weed seedlings are still young). Many of them have utility for broad-spectrum pre- and/or postemergence weed control in areas where complete control of all vegetation is desired such as around fuel storage tanks, industrial storage areas, parking lots, drive-in theaters, air fields, river banks, irrigation and other waterways, around billboards and highway and railroad structures. Many of the compounds of this invention, by virtue of selective metabolism in crops versus weeds, or by selective activity at the locus of physiological inhibition in crops and weeds, or by selective placement on or within the environment of a mixture of crops and weeds, are useful for the selective control of grass and broadleaf weeds within a crop/weed mixture. One skilled in the art will recognize that the preferred combination of these selectivity factors within a compound or group of compounds can readily be determined by performing routine biological and/or biochemical assays. Compounds of this invention may show tolerance to important agronomic crops including, but is not limited to, alfalfa, barley, cotton, wheat, rape, sugar beets, corn (maize), sorghum, soybeans, rice, oats, peanuts, vegetables, tomato, potato, perennial plantation crops including coffee, cocoa, oil palm, rubber, sugarcane, citrus, grapes, fruit trees, nut trees, banana, plantain, pineapple, hops, tea and forests such as eucalyptus and conifers (e.g., loblolly pine), and turf species (e.g., Kentucky bluegrass, St. Augustine grass, Kentucky fescue and Bermuda grass). Compounds of the invention are particularly useful for selective control of weeds in wheat, barley, and particularly maize, soybean, cotton and perennial plantation crops such as sugarcane and citrus. Compounds of this invention can be used in crops genetically transformed or bred to incorporate resistance to herbicides, express proteins toxic to invertebrate pests (such as Bacillus thuringiensis toxin), and/or express other useful traits. Those skilled in the art will appreciate that not all compounds are equally effective against all weeds. Alternatively, the subject compounds are useful to modify plant growth.
As the compounds of the invention have both preemergent and postemergent herbicidal activity, to control undesired vegetation by killing or injuring the vegetation or reducing its growth, the compounds can be usefully applied by a variety of methods involving contacting a herbicidally effective amount of a compound of the invention, or a composition comprising said compound and at least one of a surfactant, a solid diluent or a liquid diluent, to the foliage or other part of the undesired vegetation or to the environment of the undesired vegetation such as the soil or water in which the undesired vegetation is growing or which surrounds the seed or other propagule of the undesired vegetation.
A herbicidally effective amount of the compounds of this invention is determined by a number of factors. These factors include: formulation selected, method of application, amount and type of vegetation present, growing conditions, etc. In general, a herbicidally effective amount of compounds of this invention is about 0.001 to 20 kg/ha with a typical range of about 0.004 to 1 kg/ha. One skilled in the art can easily determine the herbicidally effective amount necessary for the desired level of weed control.
Compounds of this invention can also be mixed with one or more other biologically active compounds or agents including herbicides, herbicide safeners, fungicides, insecticides, nematocides, bactericides, acaricides, growth regulators such as insect molting inhibitors and rooting stimulants, chemosterilants, semiochemicals, repellents, attractants, pheromones, feeding stimulants, plant nutrients, other biologically active compounds or entomopathogenic bacteria, virus or fungi to form a multi-component pesticide giving an even broader spectrum of agricultural protection. Mixtures of the compounds of the invention with other herbicides can broaden the spectrum of activity against additional weed species, and suppress the proliferation of any resistant biotypes. Thus the present invention also pertains to a composition comprising (a herbicidally effective amount of) a compound of Formula 1 and (a biologically effective amount of) at least one additional biologically active compound or agent and can further comprise at least one of a surfactant, a solid diluent or a liquid diluent. The other biologically active compounds or agents can be formulated in compositions comprising at least one of a surfactant, solid or liquid diluent. For mixtures of the present invention, one or more other biologically active compounds or agents can be formulated together with a compound of Formula 1, to form a premix, or one or more other biologically active compounds or agents can be formulated separately from the compound of Formula 1, and the formulations combined together before application (e.g., in a spray tank) or, alternatively, applied in succession.
A mixture of one or more of the following herbicides with a compound of this invention may be particularly useful for weed control: acetochlor, acifluorfen and its sodium salt, aclonifen, acrolein (2-propenal), alachlor, alloxydim, ametryn, amicarbazone, amidosulfuron, aminopyralid, aminocyclopyrachlor and its esters (e.g., methyl, ethyl) and its salts (e.g., sodium potassium), amitrole, ammonium sulfamate, anilofos, asulam, atrazine, azimsulfuron, beflubutamid, benazolin, benazolin-ethyl, bencarbazone, benfluralin, benfuresate, bensulfuron-methyl, bensulide, bentazone, benzobicyclon, benzofenap, bifenox, bilanafos, bispyribac and its sodium salt, bromacil, bromobutide, bromofenoxim, bromoxynil, bromoxynil octanoate, butachlor, butafenacil, butamifos, butralin, butroxydim, butylate, cafenstrole, carbetamide, carfentrazone-ethyl, catechin, chlomethoxyfen, chloramben, chlorbromuron, chlorflurenol-methyl, chloridazon, chlorimuron-ethyl, chlorotoluron, chlorpropham, chlorsulfuron, chlorthal-dimethyl, chlorthiamid, cinidon-ethyl, cinmethylin, cinosulfuron, clethodim, clodinafop-propargyl, clomazone, clomeprop, clopyralid, clopyralid-olamine, cloransulam-methyl, CUH-35 (2-methoxyethyl 2-[[[4-chloro- 2-fluoro-5-[(l -methyl-2-propynyl)oxy]phenyl](3-fluorobenzoyl)amino]carbonyl]- 1 - cyclohexene-1-carboxylate), cumyluron, cyanazine, cycloate, cyclosulfamuron, cycloxydim, cyhalo fop-butyl, 2,4-D and its butotyl, butyl, isoctyl and isopropyl esters and its dimethylammonium, diolamine and trolamine salts, daimuron, dalapon, dalapon-sodium, dazomet, 2,4-DB and its dimethylammonium, potassium and sodium salts, desmedipham, desmetryn, dicamba and its diglycolammonium, dimethylammonium, potassium and sodium salts, dichlobenil, dichlorprop, diclofop-methyl, diclosulam, difenzoquat metilsulfate, diflufenican, diflufenzopyr, dimefuron, dimepiperate, dimethachlor, dimethametryn, dimethenamid, dimethenamid-P, dimethipin, dimethylarsinic acid and its sodium salt, dinitramine, dinoterb, diphenamid, diquat dibromide, dithiopyr, diuron, DNOC, endothal, EPTC, esprocarb, ethalfluralin, ethametsulfuron-methyl, ethofumesate, ethoxyfen, ethoxysulfuron, etobenzanid, fenoxaprop-ethyl, fenoxaprop-P-ethyl, fentrazamide, fenuron, fenuron-TCA, flamprop-methyl, flamprop-M-isopropyl, flamprop-M-methyl, flazasulfuron, florasulam, fluazifop-butyl, fluazifop-P-butyl, fluazolate, flucarbazone, flucetosulfuron, fluchloralin, flufenacet, flufenpyr, flufenpyr-ethyl, flumetsulam, flumiclorac-pentyl, flumioxazin, fluometuron, fluoroglycofen-ethyl, flupoxam, flupyrsulfuron-methyl and its sodium salt, flurenol, flurenol-butyl, fluridone, flurochloridone, fluroxypyr, flurtamone, fluthiacet-methyl, fomesafen, foramsulfuron, fosamine-ammonium, glufosinate, glufosinate-ammonium, glyphosate and its salts such as ammonium, isopropylammonium, potassium, sodium (including sesquisodium) and trimesium (alternatively named sulfosate), halosulfuron-methyl, haloxyfop-etotyl, haloxyfop-methyl, hexazinone, HOK-201 (N-(2,4- difluorophenyl)- 1 ,5 -dihydro-iV-( 1 -methylethyl)-5 -oxo- 1 - [(tetrahydro-2H-pyran-2-yl)- methyl]-4H-l,2,4-triazole-4-carboxamide), imazamethabenz -methyl, imazamox, imazapic, imazapyr, imazaquin, imazaquin-ammonium, imazethapyr, imazethapyr-ammonium, imazosulfuron, indanofan, iodosulfuron-methyl, ioxynil, ioxynil octanoate, ioxynil-sodium, isoproturon, isouron, isoxaben, isoxaflutole, isoxachlortole, lactofen, lenacil, linuron, maleic hydrazide, MCPA and its salts (e.g., MCPA-dimethylammonium, MCPA-potassium and MCPA-sodium, esters (e.g., MCPA-2-ethylhexyl, MCPA-butotyl) and thioesters (e.g., MCPA-thioethyl), MCPB and its salts (e.g., MCPB-sodium) and esters (e.g., MCPB-ethyl), mecoprop, mecoprop-P, mefenacet, mefluidide, mesosulfuron-methyl, mesotrione, metam-sodium, metamifop, metamitron, metazachlor, methabenzthiazuron, methylarsonic acid and its calcium, monoammonium, monosodium and disodium salts, methyldymron, metobenzuron, metobromuron, metolachlor, S-metolachlor, metosulam, metoxuron, metribuzin, metsulfuron-methyl, molinate, monolinuron, naproanilide, napropamide, naptalam, neburon, nicosulfuron, norflurazon, orbencarb, orthosulfamuron, oryzalin, oxadiargyl, oxadiazon, oxasulfuron, oxaziclomefone, oxyfluorfen, paraquat dichloride, pebulate, pelargonic acid, pendimethalin, penoxsulam, pentanochlor, pentoxazone, perfluidone, pethoxyamid, phenmedipham, picloram, picloram-potassium, picolinafen, pinoxaden, piperophos, pretilachlor, primisulfuron-methyl, prodiamine, profoxydim, prometon, prometryn, propachlor, propanil, propaquizafop, propazine, propham, propisochlor, propoxycarbazone, propyzamide, prosulfocarb, prosulfuron, pyraclonil, pyraflufen-ethyl, pyrasulfotole, pyrazolynate, pyrazoxyfen, pyrazosulfuron-ethyl, pyribenzoxim, pyributicarb, pyridate, pyriftalid, pyriminobac-methyl, pyrimisulfan, pyrithiobac, pyrithiobac-sodium, pyroxasulfone, pyroxsulam, quinclorac, quinmerac, quinoclamine, quizalofop-ethyl, quizalofop-P-ethyl, quizalofop-P-tefuryl, rimsulfuron, sethoxydim, siduron, simazine, simetryn, sulcotrione, sulfentrazone, sulfometuron-methyl, sulfosulfuron, 2, 3,6-TB A, TCA, TCA-sodium, tebutam, tebuthiuron, tefuryltrione, tembotrione, tepraloxydim, terbacil, terbumeton, terbuthylazine, terbutryn, thenylchlor, thiazopyr, thiencarbazone, thifensulfuron-methyl, thiobencarb, tiocarbazil, topramezone, tralkoxydim, tri-allate, triasulfuron, triaziflam, tribenuron-methyl, triclopyr, triclopyr-butotyl, triclopyr-triethylammonium, tridiphane, trietazine, trifloxysulfuron, trifluralin, triflusulfuron-methyl, tritosulfuron and vernolate. Other herbicides also include bioherbicides such as Alternaria destruens Simmons, Colletotrichum gloeosporiodes (Penz.) Penz. & Sacc, Drechsiera monoceras (MTB-951), Myrothecium verrucaria (Albertini & Schweinitz) Ditmar: Fries, Phytophthora palmivora (Butl.) Butl. and Puccinia thlaspeos Schub.
Compounds of this invention can also be used in combination with plant growth regulators such as aviglycine, Λ/-(phenylmethyl)-lH-purin-6-amine, epocholeone, gibberellic acid, gibberellin A4 and Aγ, harpin protein, mepiquat chloride, prohexadione calcium, prohydrojasmon, sodium nitrophenolate and trinexapac-methyl, and plant growth modifying organisms such as Bacillus cereus strain BPOl .
General references for agricultural protectants (i.e. herbicides, herbicide safeners, insecticides, fungicides, nematocides, acaricides and biological agents) include The Pesticide Manual, 13th Edition, C. D. S. Tomlin, Ed., British Crop Protection Council, Farnham, Surrey, U.K., 2003 and The BioPesticide Manual, 2nd Edition, L. G. Copping, Ed., British Crop Protection Council, Farnham, Surrey, U.K., 2001.
For embodiments where one or more of these various mixing partners are used, the weight ratio of these various mixing partners (in total) to the compound of Formula 1 is typically between about 1 :3000 and about 3000:1. Of note are weight ratios between about 1 :300 and about 300:1 (for example ratios between about 1 :30 and about 30:1). One skilled in the art can easily determine through simple experimentation the biologically effective amounts of active ingredients necessary for the desired spectrum of biological activity. It will be evident that including these additional components may expand the spectrum of weeds controlled beyond the spectrum controlled by the compound of Formula 1 alone.
In certain instances, combinations of a compound of this invention with other biologically active (particularly herbicidal) compounds or agents (i.e. active ingredients) can result in a greater-than-additive (i.e. synergistic) effect on weeds and/or a less-than-additive effect (i.e. safening) on crops or other desirable plants. Reducing the quantity of active ingredients released in the environment while ensuring effective pest control is always desirable. Ability to use greater amounts of active ingredients to provide more effective weed control without excessive crop injury is also desirable. When synergism of herbicidal active ingredients occurs on weeds at application rates giving agronomically satisfactory levels of weed control, such combinations can be advantageous for reducing crop production cost and decreasing environmental load. When safening of herbicidal active ingredients occurs on crops, such combinations can allow increased application rates to more effectively reduce weed competition.
Compounds of this invention can also be used in combination with herbicide safeners such as allidochlor, benoxacor, BCS (l-bromo-4-[(chloromethyl)sulfonyl]benzene), cloquintocet-mexyl, cyometrinil, cyprosulfamide, dichlormid, 4-(dichloroacetyl)-l-oxa- 4-azospiro[4.5]decane (MON 4660), 2-(dichloromethyl)-2-methyl-l,3-dioxolane (MG 191), dicyclonon, dietholate, fenchlorazole-ethyl, fenclorim, flurazole, fluxofenim, furilazole, isoxadifen-ethyl, mefenpyr-diethyl, mephenate, methoxyphenone ((4-methoxy-3- methylphenyl)(3-methylphenyl)methanone), naphthalic anhydride (1,8-naphthalic anhydride) and oxabetrinil to increase safety to certain crops. Antidotally effective amounts of the herbicide safeners can be applied at the same time as the compounds of this invention, or applied as seed treatments. Preferred safeners used in combination with a compound of Formula I are benoxacor, cyometrinil, dichlormid, fenchlorazole-ethyl, furilazole, and fenclorim. Partuclarly preferred safeners in combination with a compound of Forumula I for preemergence application are benoxacor and fluxofenim.
Therefore an aspect of the present invention relates to a herbicidal mixture comprising a compound of this invention and an (antidotally effective amount of) a herbicide safener. Seed treatment is particularly useful for selective weed control, because it physically restricts antidoting to the crop plants. Therefore a particularly useful embodiment of the present invention is a method for selectively controlling the growth of undesired vegetation in a crop comprising contacting the locus of the crop with a herbicidally effective amount of a compound of this invention wherein seed from which the crop is grown is treated with an antidotally effective amount of safener. Antidotally effective amounts of safeners can be easily determined by one skilled in the art through simple experimentation.
Of note is a combination of a compound of Formula 1 with at least one other herbicidal active ingredient. Of particular note is such a combination where the other herbicidal active ingredient has a different site of action from the compound of Formula 1. In certain instances, a combination with at least one other herbicidal active ingredient having a similar spectrum of control but a different site of action will be particularly advantageous for resistance management. Thus, a composition of the present invention can further comprise (a biologically effective amount of) at least one additional herbicidal active ingredient having a similar spectrum of control but a different site of action.
Accordingly, an aspect of the present invention relates to a herbicidal composition comprising (a herbicidally effective amount of) a compound selected from Formula 1, iV-oxides, and salts thereof wherein the sum of n and m is 1 or 2, at least one component selected from the group consisting of surfactants, solid diluents and liquid diluents, and further comprising (an effective amount of) at least one additional active ingredient selected from the group consisting of other herbicides and herbicide safeners. Other herbicides of note regarding this aspect are the herbicides already listed (i.e. listed above) for mixtures with a compound of the invention, particularly the herbicides that are not bioherbicides. Herbicide safeners of note regarding this aspect are the safeners already listed for use in combination with compounds of the invention.
The following Tests demonstrate the control efficacy of the compounds of this invention against specific weeds. The weed control afforded by the compounds is not limited, however, to these species. See Index Tables A-F for compound descriptions. The following abbreviation is used in the Index Tables which follow: c-Pr is cyclopropyl and Ph is phenyl. The abbreviation "Ex." stands for "Example" and is followed by a number indicating in which example the compound is prepared. After the melting point, a "D" indicates apparent decomposition.
Figure imgf000093_0001
Figure imgf000093_0002
Figure imgf000094_0001
Figure imgf000095_0001
Figure imgf000096_0001
Figure imgf000097_0001
Figure imgf000098_0001
Figure imgf000099_0001
Figure imgf000100_0004
Figure imgf000100_0001
Figure imgf000100_0003
Figure imgf000100_0002
Figure imgf000100_0005
Figure imgf000101_0001
Figure imgf000101_0003
Figure imgf000101_0002
Figure imgf000101_0004
(*) See Index Table F for 1H NMR data.
Index Table F
Compd. 1H NMR Data (CDCl3 solution at 400 MHz unless indicated otherwise)a
7 δ 8.22, (s, IH), 4.78 (m, 2H), 4.03 (m, 2H), 3.20 (m, 2H), 1.54 (s, 6H), 1.42 (m, 3H)
8 δ 8.18 (s, IH), 4.63 (m, IH), 4.37 (m, IH), 3.56 (s, 3H), 3.33 (m, IH), 3.19 (m, IH), 1.56 (s, 3H), 1.45 (s, 3H)
9 δ 8.23 (s, IH), 4.80 (m, 2H), 3.58 (s, 3H), 3.19 (s, 2H), 1.54 (s, 6H)
11 δ 4.72 (m, 2H), 4.09 (m, 2H), 3.21 (s, 2H), 2.85 (m, 2H), 1.54 (s, 6H), 1.39-1.31 (m, 6H)
12 δ 4.33 (m, 2H), 4.12 (m, 2H), 2.85 (s, 2H), 2.62 (s, 3H), 1.43 (s, 6H), 1.36 (m, 3H)
13 δ 4.73 (m, 2H), 3.72 (s, 3H), 3.20 (s, 2H), 1.98 (m, IH), 1.54 (s, 6H), 1.37 (m, 2H), 1.22 (m, 2H)
14 δ 4.73 (m, 2H), 4.09 (m, 2H), 3.21 (s, 2H), 2.65 (s, 3H), 1.54 (s, 6H), 1.34 (m, 3H)
15 δ 4.68 (m, 2H), 3.45 (s, 3H), 3.20 (s, 2H), 3.02 (s, 6H), 1.53 (s, 6H) 20 δ 4.86 (m, 2H), 4.73 (s, 2H), 3.50 (s, 3H), 3.19 (s, 2H), 1.54 (s, 6H)
22 δ 8.16 (s, IH), 4.30 (s, 2H), 3.55 (s, 3H), 2.80 (s, 2H), 1.38 (s, 6H)
23 δ 8.24 (s, IH), 4.78 (s, 2H), 3.75 (m, IH), 3.62 (m, IH), 3.58-3.53 (m, 4H), 3.20 (m, IH), 1.67 (s, 3H)
24 δ 8.17 (s, IH), 4.64 (m, IH), 4.30 (m, IH), 4.01 (m, 2H), 3.34 (m, IH), 3.19 (m, IH), 1.57 (s, 3H), 1.41 (m, 6H)
25 δ 8.19 (m, IH), 4.64 (m, IH), 4.37 (m, IH), 3.74 (m, IH), 3.65-3.19 (m, 6H), 1.60 (m, 3H)
26 δ 4.86 (m, 2H), 3.71 (m, 3H), 3.18 (m, 2H), 1.55 (m, 6H)
27 δ 4.84 (m, 2H), 4.54 (m, IH), 4.29 (m, IH), 3.49 (s, 3H), 3.32 (m, IH), 3.18 (m, IH), 1.56 (s, 3H), 1.45 (s, 3H)
28 δ 8.43 (m, IH), 6.81 (m, IH), 4.81 (m, 2H), 3.85 (s, 3H), 3.21 (s, 2H), 1.55 (s, 6H)
29 δ 4.69 (m, 2H), 4.28 (m, 2H), 3.22 (m, 2H), 1.98 (m, IH), 1.54 (m, 6H), 1.41-1.37 (m, 5H), 1.20 (m, 2H)
30 δ 4.61 (m, IH), 4.26 (m, IH), 4.12 (m, IH), 4.01 (m, IH), 3.36 (m, IH), 3.19 (m, IH), 2.63 (m, 3H), 1.57 (m, 3H), 1.44 (m, 3H), 1.34 (m, 3H)
31 δ 4.73 (m, 2H), 3.95 (m, 2H), 3.21 (s, 2H), 2.64 (s, 3H), 1.72 (m, 2H), 12.53 (s, 6H), 1.02 (m, 3H)
35 δ 4.31 (m, 2H), 4.09 (s, 3H), 3.59 (m, IH), 3.51 (m, IH), 3.46 (s, 3H), 3.25 (m, IH), 2.87 (m, IH), 1.56 (s, 3H)
37 δ 4.32 (m, 2H), 3.55 (s, 3H), 2.84 (s, 2H), 2.62 (s, 3H), 1.42 (s, 6H) 46 δ 7.56 (m, 5H), 4.41 (m, 2H), 3.54 (s, 3H), 2.87 (s, 2H), 1.44 (s, 6H)
52 δ 4.61 (ddd, IH), 4.35 (ddd, IH), 3.55 (s, 3H), 3.37 (d, IH), 3.20 (d, IH), 2.60 (s, 3H), 1.57 (s, 3H), 1.45 (s, 3H) δ 4.58 (ddd, IH), 4.22 (ddd, IH), 4.06 (s, 3H), 4.03 (m, 2H), 3.39 (d, IH), 3.19 (d, IH), 1.58 (s, 3H),
1.44 (s, 3H), 1.26 (t, 3H) δ 4.64 (ddd, IH), 4.29 (ddd, IH), 4.06 (ddq, 2H), 3.40 (d, IH), 3.19 (d, IH), 2.63 (s, 3H), 1.58 (s, 3H), 1.44 (s, 3H), 1.34 (t, 3H) δ 4.58 (ddd, IH), 4.29 (ddd, IH), 4.11 (s, 3H), 3.42 (s, 3H), 3.38 (d, IH), 3.19 (d, IH), 1.56 (s, 3H),
1.45 (s, 3H) δ 7.83 (d, 2H), 7.73 (d, 2H), 4.86 (s, 2H), 3.51 (s, 3H), 3.23 (s, 2H), 1.56 (d, 6H) δ 7.82 (d, 2H), 7.72 (d, 2H), 4.64 (s, 2H), 4.42 (d, IH), 3.50 (s, 3H), 3.34 (d, IH), 3.24 (d, IH), 1.59 (d, 6H) δ 7.81 (d, 2H), 7.72 (d, 2H), 4.41 (s, 2H), 3.53 (s, 3H), 2.88 (s, 2H), 1.45 (d, 6H) δ 7.85 (d, 2H), 7.75 (d, 2H), 4.85 (s, 2H), 3.80 (d, IH), 3.70-3.55 (m, 2H), 3.52 (s, 3H), 3.25 (d, IH), 1.69 (d, 3H) δ 7.85 (d, 2H), 7.75 (d, 2H), 4.41 (s, 2H), 3.65 (d, IH), 3.60-3.50 (m, 4H), 3.30 (d, IH), 2.90 (d, IH), 1.58 (s, 3H) δ 7.82 (d, 2H), 7.71 (d, 2H), 4.68 (d, IH), 4.44 (d, IH), 3.64 (d, IH), 3.58 (d, 2H), 3.50 (s, 3H), 3.42 (d, IH), 1.70 (s, 3H) δ 4.50 (m, 2H), 4.05 (s, 3H), 3.76 (m, IH), 3.64-3.55 (m, 2H), 3.73 (s, 3H), 3.27-3.17 (m, 2H), 1.64 (s, 3H), 1.21 (m, 6H) δ 4.46 (m, 2H), 4.04 (s, 3H), 3.98 (m, 2H), 3.72 (m, IH), 3.62-3.55 (m, 2H), 3.29-3.19 (m, 2H), 1.65 (s, 3H), 1.22 (m, 9H) δ 4.60 (m, IH), 4.03 (m, 4H), 3.47 (m, IH), 3.55 (s, 3H), 3.20-3.11 (m, 2H), 1.52 (s, 3H), 1.44 (s, 3H), 1.24-1.19 (m, 6H) δ 4.63 (m, IH), 4.03-3.90 (m, 6H), 3.48 (m, IH), 3.20 (m, 2H), 1.54 (s, 3H), 1.43 (s, 3H), 1.25-1.19 (m, 9H) δ 4.51 (s, 2H), 4.03 (s, 3H), 3.35 (s, 3H), 3.21 (m, 3H), 1.49 (s, 6H), 1.21 (m, 6H) δ 4.46 (s, 2H), 4.01-3.95 (m, 5H), 3.21 (m, 3H), 1.49 (s, 6H), 1.20 (m, 9H) δ 4.85 (s, 2H), 3.80 (s, 3H), 3.17 (s, 2H), 1.54 (s, 6H) δ 4.82-4.73 (m, 2H), 3.50 (s, 3H), 3.26-3.13 (dd, 2H), 2.60 (s, 3H), 1.76-1.70 (q, 2H), 1.41 (s, 3H), 0.90-0.87 (t, 3H) δ 4.35 (s, 2H), 3.59 (s, 3H), 2.91-2.87 (d, IH), 2.78-2.74 (d, IH), 2.60 (s, 3H), 1.74-1.68 (m, 2H), 1.38 (s, 3H), 0.97-0.94 (t, 3H) δ 4.52 (m, 2H), 3.75 (m, IH), 3.58 (m, 2H), 3.50 (s, 3H), 3.25 (m, IH), 2.72 (m, 2H), 2.54 (s, 3H), 1.65 (s, 3H), 1.26 (m, 3H) δ 7.72 (d, 2H), 7.49 (d, 2H), 4.82 (s, 2H), 3.80 (d, IH), 3.70-3.55 (m, 2H), 3.52 (s, 3H), 3.15 (d, IH), 1.69 (s, 3H) 93 δ 7.68 (d, 2H), 7.47 (d, 2H), 4.70 (d, IH), 4.40 (d, IH), 3.60 (d, 2H), 3.51 (s, 3H), 3.40 (d, 2H), 1.70 (s, 3H)
94 δ 7.69 (d, 2H), 7.45 (d, 2H), 4.40 (s, 2H), 3.59 (dd, 2H), 3.54 (s, 3H), 3.28 (d, IH), 2.90 (d, IH), 1.58 (s, 3H)
95 δ 7.81 (d, 2H), 7.55 (d, IH), 7.40 (t, IH), 4.83 (s, 2H), 3.80 (d, IH), 3.65 (d, 2H), 3.52 (s, 3H), 3.25 (d, IH), 1.69 (s, 3H)
96 δ 7.75 (d, 2H), 7.55-7.40 (m, 2H), 4.70-4.60 (m, 2H), 4.40 (t, IH), 3.70 (d, 2H), 3.51 (s, 3H), 3.35 (dd, IH), 1.70 (s, 3H)
97 δ 7.72 (d, 2H), 7.50-7.40 (m, 2H), 4.41 (s, 2H), 3.59 (dd, 2H), 3.53 (s, 3H), 3.28 (d, IH), 2.90 (d, IH), 1.58 (s, 3H)
98 δ 4.84 (s, 2H), 4.00 (s, 3H), 3.82 (m, IH), 3.61-3.39 (m, 2H), 3.34 (s, 3H), 3.13 (m, IH), 1.65 (s, 3H), 1.43 (s, 9H)
100 δ 4.48 (m, 2H), 4.04 (s, 3H), 3.75 (m, IH), 3.61-3.55 (m, 2H), 3.37 (s, 3H), 3.25 (m, IH), 2.67 (m, 2H), 1.75 (m, 2H), 1.64 (s, 3H), 0.99 (m, 3H)
101 δ 4.49 (m, 2H), 4.03 (s, 3H), 3.37 (s, 3H), 3.23 (s, 2H), 2.67 (m, 2H), 1.74 (m, 2H), 1.51 (s, 6H), 0.99 (s, 3H)
103 δ 7.73 (d, 2H), 7.55 (d, IH), 7.45 (t, IH), 4.85 (s, 2H), 3.51 (s, 3H), 3.23 (s, 2H), 1.55 (d, 6H)
104 δ 7.75 (d, 2H), 7.50 (t, IH), 7.45 (t, IH), 4.65 (d, IH), 4.40 (d, IH), 3.50 (s, 3H), 3.35 (d, IH), 3.20 (d, IH), 1.58 (s, 3H), 1.54 (s, 3H)
105 δ 7.70 (d, 2H), 7.48-7.40 (m, 2H), 4.41 (s, 2H), 3.52 (s, 3H), 2.87 (s, 2H), 1.45 (s, 6H)
106 δ 7.69 (d, 2H), 7.49 (d, 2H), 4.83 (s, 2H), 3.52 (s, 3H), 3.23 (s, 2H), 1.56 (s, 6H)
107 δ 7.68 (d, 2H), 7.46 (d, 2H), 4.40 (s, 2H), 3.53 (s, 3H), 2.87 (s, 2H), 1.44 (s, 6H)
108 δ 4.85 (s, 2H), 4.01-3.95 (m, 5H), 3.24 (s, 2H), 1.54 (s, 6H), 1.45 (s, 9H), 1.23 (m, 3H)
110 δ 4.45 (s, 2H), 4.04-3.97 (m, 5H), 3.24 (s, 2H), 2.72 (m, 2H), 1.52 (s, 6H), 1.28-1.20 (m, 6H)
111 δ 4.45 (s, 2H), 4.02-3.97 (m, 5H), 3.24 (s, 2H), 2.67 (m, 2H), 1.74 (m, 2H), 1.52 (s, 6H), 1.22 (m, 3H), 0.99 (m, 3H)
113 δ 7.60-7.55 (m, 5H), 4.65 (d, IH), 4.40 (d, IH), 3.51 (s, 3H), 3.38 (d, IH), 3.23 (d, IH), 1.58 (s, 3H), 1.47 (s, 3H)
114 δ 7.65-7.50 (m, 5H), 4.83 (s, 2H), 3.80 (d, IH), 3.64 (d, 2H), 3.53 (s, 3H), 3.25 (d, IH), 1.69 (s, 3H)
115 δ 7.65-7.55 (m, 5H), 4.65 (d, IH), 4.45 (d, IH), 3.85 (d, IH), 3.72 (s, 2H), 3.52 (s, 3H), 3.25 (d, IH), 1.62 (s, 3H)
116 δ 7.60-7.50 (m, 5H), 4.41 (s, 2H), 3.61 (d, IH), 3.54 (s, 3H), 3.51 (d, IH), 3.30 (d, IH), 2.90 (d, IH), 1.58 (s, 3H)
120 ESI-MS: 360 (M+l)b
123 δ 5.02 (s, 2H), 4.72 (s, 2H), 3.82 (s, 3H), 3.53 (s, 3H), 3.20 (s, 2H), 1.55 (s, 6H) 124 δ 4.76 (s, 2H), 3.82-3.79 (d, IH), 3.62-3.57 (m, 2H), 3.56 (s, 3H), 3.14-3.09 (d, IH), 2.64 (s, 3H), 1.52 (s, 3H)
125 δ 4.71 (s, 2H), 4.35-4.33 (d, 2H), 3.47 (s, 3H), 3.21 (s, 2H), 1.55 (s, 6H), 1.35-1.28 (m, IH), 0.71- 0.70 (t, 2H), 0.40 (s, 2H)
126 δ 6.30-6.01 (m, IH), 4.73-4.66 (m, 4H), 3.50 (s, 3H), 3.20 (s, 2H), 1.55 (s, 6H)
127 δ 4.31 (s, 2H), 4.11 (s, 3H), 3.46 (s, 3H), 2.91-2.87 (d, IH), 2.77-2.73 (d, IH), 1.74-1.66 (m, 2H), 1.37 (s, 3H), 0.97-0.95 (t, 3H)
128 δ 4.31 (s, 2H), 4.13-4.08 (q, 2H), 2.90-2.86 (d, IH), 2.77-2.73 (d, IH), 2.62 (s, 3H), 1.73-1.66 (m, 2H), 1.37-1.33 (m, 6H), 0.95-0.92 (t, 3H)
129 δ 4.32 (s, 4H), 3.49 (s, 3H), 2.85 (s, 2H), 1.43 (s, 6H), 1.26 (m, IH), 0.68-0.66 (m, 2H), 0.42-0.40 (m, 2H)
130 δ 6.29-6.01 (m, IH), 4.71-4.63 (dt, 2H), 4.33 (s, 2H), 3.50 (s, 3H), 2.85 (s, 2H), 1.42 (s, 6H)
138 (300 MHz) δ 4.99 (s, 2H), 4.32 (s, 2H), 3.81 (s, 3H), 3.55 (s, 3H), 2.84 (s, 2H), 1.43 (s, 6H)
139 δ 4.73 (t, 2H), 4.33 (s, 2H), 3.86 (t, 2H), 3.52 (s, 3H), 2.85 (s, 2H), 1.44 (s, 6H)
144 (mixture of diastereomers) δ 4.64-4.56 (q, 2H), 4.31-4.25 (t, 2H), 4.17-4.10 (m, 2H), 4.06-4.00 (m, 2H), 3.38-3.33 (d, IH), 3.27 (s, 2H), 3.14-3.09 (d, IH), 2.63 (s, 6H), 1.89-1.74 (q, 2H), 1.74-1.69 (q, 2H), 1.62 (s, 3H), 1.53 (s, 3H), 1.39-1.27 (m, 6H), 1.04-1.00 (t, 3H), 0.97-0.93 (t, 3H)
146 (CD3OD, mixture of diastereomers) δ 4.64-4.57 (m, 2H), 4.42-4.35 (m, 2H), 3.61-3.59 (s, 6H), 3.39- 3.34 (d, IH), 3.27-3.26 (d, 2H), 3.14-3.09 (d, IH), 2.61 (s, 6H), 1.86-1.80 (q, 2H), 1.77-1.71 (q, 2H), 1.50 (s, 3H), 1.40 (s, 3H), 1.02-0.99 (t, 3H), 0.97-0.94 (t, 3H)
155 δ 4.71 (s, 2H), 4.71-4.65 (m, 2H), 3.77-3.75 (m, 2H), 3.47 (s, 3H), 3.43 (s, 3H), 3.21 (s, 2H), 1.54 (s, 6H)
156 δ 5.17 (s, 2H), 4.73 (s, 2H), 3.50 (s, 3H), 3.19 (s, 2H), 1.54 (s, 6H)
159 δ 5.15 (s, 2H), 4.33 (s, 2H), 3.52 (s, 3H), 2.85 (s, 2H), 1.44 (s, 6H)
160 δ 4.31 (s, 2H), 4.11-4.06 (m, 5H), 2.91-2.87 (d, IH), 2.78-2.74 (d, IH), 1.74-1.67 (m, 2H), 1.37 (t, 3H), 1.29-1.27 (t, 3H), 0.97-0.93 (t, 3H)
161 δ 4.65-4.62 (m, 2H), 4.32 (s, 2H), 3.77-3.74 (m, 2H), 3.49 (s, 3H), 3.42 (s, 3H), 2.85 (s, 2H), 1.26 (s, 6H)
162 δ 5.40 (m, IH), 4.31 (s, 2H), 3.78 (s, 3H), 3.54 (s, 3H), 2.85 (s, 2H), 1.68-1.66 (d, 3H), 1.44 (s, 6H)
163 δ 8.17 (s, IH), 4.37 (s, 2H), 3.60 (s, 3H), 2.92-2.88 (d, IH), 2.78-2.74 (d, IH), 1.74-1.68 (m, 2H), 1.39 (s, 3H), 0.98-0.94 (t, 3H)
164 (300 MHz) δ 8.18 (s, IH), 4.36 (s, 2H), 3.69-3.65 (d, IH), 3.59 (s, 3H), 3.54-3.50 (d, IH), 3.27-3.22 (d, IH), 2.80-2.75 (d, IH), 1.39 (s, 3H)
165 δ 8.16 (s, IH), 4.37 (s, 2H), 4.08-4.02 (q, 2H), 2.92-2.88 (d, IH), 2.79-2.75 (d, IH), 1.74-1.69 (m, 2H), 1.58 (s, 3H), 1.46-1.39 (t, 3H), 0.98-0.94 (t, 3H)
166 δ 7.58 (d, 2H), 7.03 (d, 2H), 4.82 (s, 2H), 3.89 (s, 3H), 3.56 (s, 3H), 3.23 (s, 2H), 1.56 (s, 6H) 167 δ 7.56 (d, 2H), 7.02 (d, 2H), 4.63 (d, IH), 4.38 (d, IH), 3.89 (s, 3H), 3.55 (s, 3H), 3.38 (d, IH), 3.22 (d, IH), 1.58 (s, 3H), 1.47 (s, 3H)
168 δ 7.55 (d, 2H), 7.02 (d, 2H), 4.40 (s, 2H), 3.88 (s, 3H), 3.58 (s, 3H), 2.87 (s, 2H), 1.44 (s, 6H)
171 δ 7.58 (d, 2H), 7.04 (s, 2H), 4.81 (s, 2H), 3.89 (s, 3H), 3.78 (d, IH), 3.65 (d, 2H), 3.57 (s, 3H), 3.24 (d, IH), 1.69 (s, 3H)
172 δ 7.56 (d, 2H), 7.03 (d, 2H), 4.67 (dd, 2H), 4.39 (dd, IH), 3.89 (s, 3H), 3.80 (dd, IH), 3.60 (dd, IH), 3.56 (s, 3H), 3.42 (d, IH), 3.25 (d, IH), 1.71 (s, 3H)
173 δ 7.55 (d, 2H), 7.03 (d, 2H), 4.40 (s, 2H), 3.88 (s, 3H), 3.60-3.50 (m, 5H), 3.28 (d, IH), 2.90 (d, IH), 1.58 (s, 3H)
174 δ 6.51 (m, IH), 4.38 (s, 2H), 3.74 (m, 3H), 2.84 (s, 2H), 1.44 (s, 6H)
177 δ 5.31-5.28 (t, IH), 4.69 (s, 2H), 4.32-4.24 (m, 2H), 3.46 (s, 3H), 3.21 (s, 2H), 1.55 (s, 6H)
183 (300 MHz) δ 4.30 (s, 2H), 4.09 (s, 3H), 3.67-3.64 (d, IH), 3.54-3.50 (d, IH), 3.47 (s, 3H), 3.26-3.21 (d, IH), 2.80-2.74 (d, IH), 1.39 (s, 3H)
184 δ 7.40-7.30 (m, 4H), 4.42 (s, 2H), 3.52 (s, 3H), 2.88 (s, 2H), 2.44 (s, 3H), 1.44 (s, 6H)
185 δ 7.45-7.35 (m, 4H), 4.85 (s, 2H), 3.51 (s, 3H), 3.23 (s, 2H), 2.44 (s, 3H), 1.56 (s, 6H)
186 δ 7.45-7.35 (m, 4H), 4.83 (s, 2H), 3.78 (d, IH), 3.60 (dd, 2H), 3.51 (s, 3H), 3.25 (d, IH), 2.45 (s, 3H), 1.69 (s, 3H)
187 δ 7.45-7.35 (m, 4H), 4.41 (s, 2H), 3.65 (d, IH), 3.53 (s, 3H), 3.52 (d, IH), 3.25 (d, IH), 2.80 (d, IH), 2.45 (s, 3H), 1.58 (s, 3H)
190 (300 MHz) δ 4.43-4.21 (m, 2H), 4.31 (s, 2H), 3.59 (s, 3H), 3.20-3.14 (d, IH), 2.97-2.89 (d, IH), 2.61 (s, 3H), 1.50 (s, 3H)
192 δ 4.54 (m, IH), 4.29 (m, IH), 3.72 (m, 3H), 3.37-3.08 (m, 2H), 1.97 (m, IH), 1.84 (m, IH), 1.72 (m, IH), 1.51-1.40 (m, 3H), 1.34 (m, 2H), 1.20 (m, 2H), 1.03-0.93 (m, 3H)
193 (300 MHz) δ 4.43-4.24 (m, 2H), 4.32 (s, 2H), 4.10 (s, 3H), 3.47 (s, 3H), 3.20-3.14 (d, IH), 2.89-2.73 (d, IH), 1.26 (s, 3H)
195 δ 8.18 (s, IH), 4.45-4.24 (m, 2H), 4.37 (s, 2H), 3.60 (s, 3H), 3.20-3.16 (d, IH), 2.89-2.84 (d, IH), 1.48 (s, 3H)
204 δ 7.23 (s, IH), 4.94 (m, 2H), 3.54 (s, 3H), 3.23 (s, 2H), 2.22 (m, 3H), 1.54 (s, 6H)
205 δ 5.83 (s, IH), 4.74 (s, 2H), 4.01 (s, 3H), 3.49 (s, 3H), 3.23 (s, 2H), 1.54 (s, 6H)
210 δ 7.91 (s, IH), 4.64-4.63 (m, 2H), 4.33 (dd, 2H), 4.08 (s, 3H), 3.28 (dd, 2H), 1.50 (d, 6H)
211 δ 7.96 (s, IH), 4.74 (d, 2H), 4.53 (s, 2H), 4.10 (s, 3H), 3.20 (s, 2H), 1.53 (s, 6H)
218 δ 5.19 (d, IH), 5.09 (d, IH), 3.58 (s, 3H), 3.36 (d, IH), 3.13 (d, IH), 2.65 (s, 3H), 1.57 (s, 3H), 1.55 (s, 3H)
219 δ 5.14 (dd, IH), 5.04 (m, IH), 4.15 (s, 3H), 3.45 (s, 3H), 3.36 (d, IH), 3.11 (d, IH), 1.56 (s, 3H), 1.54 (s, 3H) 220 δ 5.59 (d, IH), 4.85 (m, 2H), 3.57 (s, 3H), 2.63 (s, 3H), 1.58 (d, 3H), 1.48 (s, 3H)
221 δ 5.59 (d, IH), 4.80 (s, 2H), 4.13 (s, 3H), 3.44 (s, 3H), 1.58 (d, 3H), 1.48 (s, 3H)
224 δ 6.78 (d, IH), 3.58 (s, 3H), 3.31 (d, IH), 3.20 (d, IH), 2.66 (s, 3H), 1.59 (s, 3H), 1.53 (s, 3H)
237 δ 7.68 (s, IH), 4.45 (s, 2H), 3.65 (s, 3H), 2.82 (s, 2H), 1.45 (s, 6H)
238 δ 7.74 (s, IH), 5.10 (s, 2H), 3.68 (s, 3H), 3.13 (s, 2H), 1.53 (s, 6H)
239 δ 7.76 (s, IH), 6.89 (s, IH), 4.65 (s, 2H), 3.59 (s, 3H), 3.10 (s, 2H), 1.51 (s, 6H)
242 δ 4.87 (m, IH), 4.07-4.01 (m, 5H), 3.01 (m, 2H), 2.11 (m, 3H), 1.78 (m, 3H), 1.49-1.46 (m, 6H), 1.25 (m, 3H)
243 δ 4.69 (m, IH), 4.00 (s, 3H), 3.66 (m, 2H), 3.00 (m, 2H), 2.27 (m, 2H), 2.04 (s, 3H), 1.48-1.45 (m, 6H), 1.33 (m, 3H), 0.92 (m, 3H)
244 δ 6.96 (s, IH), 4.96 (s, 2H), 3.79 (s, 3H), 3.13 (s, 2H), 1.53 (s, 6H) a ^H NMR data are in ppm downfield from tetramethylsilane. Couplings are designated by (s)-singlet, (d)-doublet, (t)-triplet, (q)-quartet, (m)-multiplet, (dd)-doublet of doublets, (dt)-doublet of triplets, (ddd)-double doublet of doublets or (ddq)-double doublet of quartets.
" The mass spectra value given is the molecular weight of the highest isotopic abundance parent ion (M+l) formed by addition of H+ (molecular weight of 1) to the molecule, observed by mass spectrometry using electrospray ionization (ESI).
BIOLOGICAL EXAMPLES OF THE INVENTION TEST A
Seeds of barnyardgrass {Echinochloa crus-galli), large crabgrass {Digitaria sanguinalis), giant foxtail (Setaria faberi), morningglory (Ipomoea spp.), pigweed
(Amaranthus retroflexus), velvetleaf (Abutilon theophrasti), wheat (Triticum aestivum), and corn (Zea mays) were planted into a blend of loam soil and sand and treated preemergence with a directed soil spray using test chemicals formulated in a non-phytotoxic solvent mixture which included a surfactant. At the same time these species were also treated with postemergence applications of test compounds formulated in the same manner.
Plants ranged in height from two to ten cm and were in the one- to two-leaf stage for the postemergence treatment. Treated plants and untreated controls were maintained in a greenhouse for approximately ten days, after which time all treated plants were compared to untreated controls and visually evaluated for injury. Plant response ratings, summarized in Table A, are based on a 0 to 100 scale where 0 is no effect and 100 is complete control. A dash (-) response means no test result.
Figure imgf000107_0001
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Figure imgf000125_0001
Figure imgf000126_0001
TEST B Seeds of plant species selected from blackgrass (Alopecurus myosuroides), downy bromegrass (Bromus tectorum), green foxtail (Setaria viridis), Italian ryegrass (Lolium multiflorum), wheat (Triticum aestivum), wild oat (Avena fatua), galliam (catchweed bedstraw, Galium aparine), bermudagrass (Cynodon dactyloή), Surinam grass {Brachiaria decumbens), cocklebur (Xanthium strumarium), corn (Zea mays), large crabgrass (Digitaria sanguinalis), woolly cupgrass {Eήochloa villosa), giant foxtail (Setaria faberii), goosegrass (Eleusine indica), johnsongrass {Sorghum halepense), kochia (Kochia scoparia), lambsquarters (Chenopodium album), morningglory (Ipomoea coccinea), nightshade, (eastern black nightshade, Solanum ptycanthum), yellow nutsedge (Cyperus esculentus), pigweed (Amaranthus retroflexus), ragweed (common ragweed, Ambrosia elatior), soybean (Glycine max), sunflower (common oilseed sunflower, Helianthus annuus), Russian thistle (Salsola kali), and velvetleaf (Abutilon theophrasti) were planted into a blend of loam soil and sand and treated preemergence with test compounds formulated in a non-phytotoxic solvent mixture which included a surfactant.
At the same time, plants selected from these crop and weed species and also winter barley (Hordeum vulgare), canarygrass (Phalaris minor), chickweed (Stellaria media) and windgrass (Apera spica-venti) were planted in pots containing Redi-Earth® planting medium (Scotts Company, 14111 Scottslawn Road, Marysville, Ohio 43041) comprising spaghnum peat moss, vermiculite, wetting agent and starter nutrients and treated with postemergence applications of some of the test chemicals formulated in the same manner. Plants ranged in height from 2 to 18 cm (1- to 4-leaf stage) for postemergence treatments. Plant species in the flooded paddy test consisted of rice (Oryza sativa), umbrella sedge
(Cyperus dijformis), ducksalad (Heteranthera limosa) and barnyardgrass (Echinochloa crus- galli) grown to the 2-leaf stage for testing. At time of treatment, test pots were flooded to 3 cm above the soil surface, treated by application of test compounds directly to the paddy water, and then maintained at that water depth for the duration of the test. Treated plants and controls were maintained in a greenhouse for 13 to 15 days, after which time all species were compared to controls and visually evaluated. Plant response ratings, summarized in Table B, are based on a scale of 0 to 100 where 0 is no effect and 100 is complete control. A dash (-) response means no test result.
Figure imgf000127_0001
Figure imgf000128_0001
Figure imgf000129_0001
Figure imgf000130_0001
Figure imgf000131_0001
Figure imgf000132_0001
Figure imgf000133_0001
Figure imgf000134_0001
Figure imgf000135_0001
Figure imgf000136_0001
Figure imgf000137_0001
Figure imgf000138_0001
Figure imgf000139_0001
Figure imgf000140_0001
Figure imgf000141_0001
Figure imgf000142_0001
Figure imgf000143_0001
Figure imgf000144_0001
Figure imgf000145_0001
Figure imgf000146_0001
Figure imgf000147_0001
Figure imgf000148_0001
Figure imgf000149_0001
Figure imgf000150_0001
Figure imgf000151_0001
Figure imgf000152_0001
Figure imgf000153_0001
Figure imgf000154_0001
TEST C
Seeds of plant species selected from annual bluegrass (Poa annuά), blackgrass (Alopecurus myosuroides), canarygrass (Phalaris minor), gallium (catchweed bedstraw, Galium aparine), chickweed (Stellaria media), downy bromegrass (Bromus tectorum), field poppy (Papaver rhoeas), field violet {Viola arvensis), green foxtail (Setaria viridis), deadnettle (henbit deadnettle, Lamium amplexicaule), Italian ryegrass (Lolium multiflorum), kochia {Kochia scoparia), lambsquarters (Chenopodium album), oilseed rape (Brassica napus), pigweed (Amaranthus retroflexus), Russian thistle (Salsola kali), spring barley (Hordeum vulgare), spring wheat (Triticum aestivum), wild buckwheat (Polygonum convolvulus), wild mustard (Sinapis arvensis), wild oat (Avena fatua), wild radish (Raphanus raphanistrum), windgrass (Apera spica-venti), winter barley (Hordeum vulgare), and winter wheat (Triticum aestivum) were planted and treated preemergence with test chemicals formulated in a non- phytotoxic solvent mixture which included a surfactant. At the same time, plants selected from these crop and weed species were treated with postemergence applications of some of the test chemicals formulated in the same manner. Plants ranged in height from 2 to 18 cm (1- to 4-leaf stage) for postemergence treatments.
Treated plants and controls were maintained in a controlled growth environment for 14 to 21 days after which time all species were compared to controls and visually evaluated. Plant response ratings, summarized in Table C, are based on a scale of 0 to 100 where 0 is no effect and 100 is complete control. A dash (-) response means no test result.
Figure imgf000155_0001
Figure imgf000156_0001
Figure imgf000157_0001
Figure imgf000158_0001
Figure imgf000159_0001
Figure imgf000160_0001
Figure imgf000161_0001
TEST D
Seeds of plant species selected from bermudagrass (Cynodon dactylon), Surinam grass (Brachiaria decumbens), large crabgrass (Digitaria sanguinalis), green foxtail (Setaria viridis), goosegrass (Eleusine indicά), johnsongrass {Sorghum halepense), kochia (Kochia scopariά), morningglory (pitted morningglory, Ipomoea lacunosa), purple nutsedge (Cyperus rotundus), ragweed (common ragweed, Ambrosia elatior), black mustard (Brassica nigra), guineagrass (Panicum maximum), dallisgrass (Paspalum dilatatum), barnyardgrass (Echinochloa crus-gallϊ), sandbur (southern sandbur, Cenchrus echinatus), sowthistle (common sowthistle, Sonchus oleraceous), prickly sida (Sida spinosa), Italian ryegrass (Lolium multiflorum), purslane (common purslane, Portulaca oleracea), broadleaf signalgrass {Brachiaria platyphylla), groundsel (common groundsel, Senecio vulgaris), common chickweed (Stellaria media), Virginia (VA) dayflower (Commelina virginica), bluegrass (annual bluegrass, Poa annua), naked crabgrass (Digitaria nuda), itchgrass (Rottboellia cochinchinensis), quackgrass (Elytrigia repens), field bindweed (Convolvulus arvensis), spanishneedles (Bidens bipinnata), mallow (common mallow, Malva sylvestris), and Russian thistle (Salsola kali), were planted into a blend of loam soil and sand and treated preemergence with test chemicals formulated in a non- phytotoxic solvent mixture which included a surfactant. Treated plants and controls were maintained in a greenhouse for 21 days, after which time all species were compared to controls and visually evaluated. Plant response ratings, summarized in Table D, are based on a scale of 0 to 100 where 0 is no effect and 100 is complete control. A dash (-) response means no test result.
Figure imgf000162_0001
Figure imgf000163_0001
Figure imgf000164_0001
Figure imgf000165_0001
TEST E
Seeds of plant species selected from corn (Zea mays), large crabgrass (Digitaria sanguinalis), giant foxtail (Setaria faberii), johnsongrass {Sorghum halepense), nightshade (eastern black nightshade, Solarium ptycanthum), pigweed (Amaranthus retroflexus), soybean (Glycine max), and velvetleaf (Abutilon theophrasti) were planted into a silt loam soil and treated preemergence with test compounds formulated in a non-phytotoxic solvent mixture. Treated plants and controls were maintained in a greenhouse for 20 to 22 days, after which time all species were compared to controls and visually evaluated. Plant response ratings, summarized in Table E, are based on a scale of 0 to 100 where 0 is no effect and 100 is complete control. A dash (-) response means no test result.
Figure imgf000165_0002
Figure imgf000166_0001

Claims

CLAIMSWhat is claimed is:
1. A compound selected from Formula 1, JV-oxides and salts thereof,
Figure imgf000167_0001
wherein
Figure imgf000167_0002
QMs N or CR9^
Q2 is N or CR9b;
Q3 is N or CR9c;
Q4 is N or CR9d; W1 is N or CR1 Oa;
W2 is N or CR10b; provided that when Q2 is N, then W2 is CR10b;
W3 is N or CR1 Oc;
W4 is N or CR1 od;
Y1 is N or CR1 la; provided that when W1 is N, then Y1 is CR1 la; Y2 is N or CR1 lb; provided that when W2 is N, then Y2 is CR1 lb;
Y3 is N or CR1 lc; provided that when W3 is N, then Y3 is CR1 lc;
Y4 is N or CR1 ld; m is 0, 1 or 2; n is 0 or 1 ; provided that the sum of n and m is not more than 2; R1 and R2 are independently H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C1-C6 haloalkyl, C2-C6 haloalkenyl, C4-C6 alkylcycloalkyl or C4- C6 cycloalkylalkyl; or
R1 and R2 are taken together with the carbon to which they are bonded to form a C3- C6 saturated carbocyclic ring optionally substituted by C1-C3 alkyl, halogen or
C1-C3 haloalkyl;
R3 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C1-C6 haloalkyl, C2-C6 haloalkenyl, C4-C6 alkylcycloalkyl or C4-C6 cycloalkylalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkylthio, C1-C6 haloalkylthio, -SCN, halogen, cyano, nitro, azido, -CO2H or C2-C5 alkoxycarbonyl;
R4 is H, C1-C6 alkyl, C1-C6 haloalkyl or halogen; or
R3 and R4 are taken together with the carbon to which they are bonded to form a saturated carbocyclic C3-C6 ring optionally substituted by C1-C3 alkyl, halogen or C1-C3 haloalkyl; or R1 and R4 are taken together with the carbons to which they are bonded to form a C3-
C7 saturated carbocyclic ring optionally substituted by C1-C3 alkyl, halogen or C1-C3 haloalkyl;
R5 is H, C1-C2 alkyl, halogen, cyano or C2-C5 alkoxycarbonyl;
R6 is H, C1-C2 alkyl or halogen; or R5 and R6 are taken together with the carbon to which they are bonded to form a C3-
C6 saturated carbocyclic ring;
R7 is H, -CN, C2-C4 alkoxycarbonyl, C1-C4 alkylsulfonyl, C2-C4 alkylcarbonyl or C2-C4 haloalkylcarbonyl; each R8a, R8b, R8c and R8d is independently C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C3-C7 cycloalkyl, C ^C7 haloalkyl, C2-C7 haloalkenyl, C2-C7 alkoxyalkyl, C4-C7 cycloalkylalkyl, C3-C7 haloalkynyl, C3-C7 alkylcarbonylalkyl, C3-C7 alkoxycarbonylalkyl, C4-C7 halocycloalkylalkyl, C2- C7 haloalkoxyalkyl, C2-C7 alkylthioalkyl, C2-C7 alkylsulfonylalkyl, C2-C7 alkylsulfinylalkyl, C2-C7 cyanoalkyl, C2-C7 haloalkylthioalkyl, C2-C7 haloalkylsulfonylalkyl, C2-C7 haloalkylsulfmylalkyl, C3-C7 haloalkoxycarbonylalkyl, C3-C7 haloalkylcarbonylalkyl; C1-C6 alkylsulfonyl, C1-C6 haloalkylsulfonyl or C3-C6 cycloalkylsulfonyl; and each R9a, R% R9c? R9d R10a? R10b? R10c? R10d RlIa, RlIb RlIc and RlId is independently H, halogen, cyano, C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C3-C7 cycloalkyl, C4-C7 cycloalkylalkyl, C4-C7 alkylcycloalkyl, C ^C7 haloalkyl, C2-C7 haloalkenyl, C3-C7 haloalkynyl, C3-C7 halocycloalkyl, C1-C7 alkoxy, C1-C7 haloalkoxy, C2-C7 alkenyloxy, C2-C7 haloalkenyloxy, C3-C7 cycloalkoxy, C3-C7 halocycloalkoxy, C2-C7 alkynyloxy, C4-C7 cycloalkylalkoxy, C4-C7 halocycloalkylalkoxy, Q -C 7 alkylthio, Q -C 7 haloalkylthio, Q -C 7 haloalkylsulfϊnyl, Q -C 7 haloalkylsulfonyl, Q-C6 alkylamino, C2-C7 dialkylamino, Q-Q haloalkylamino, C2-C7 alkylcarbonyl, C2-C7 alkoxycarbonyl, C2-C7 haloalkylcarbonyl, C2-C7 haloalkoxycarbonyl, C3-C7 alkylcarbonylalkyl, C3-C7, alkoxycarbonylalkyl, aminocarbonyl, C2-Cg alkylaminocarbonyl, C2-Cg haloalkylaminocarbonyl, Q-Cg dialkylaminocarbonyl, Q-Cg haloalkyl(alkyl)aminocarbonyl, C4-C7 cycloalkylaminocarbonyl, Q-Cg cycloalkyl(alkyl)aminocarbonyl, C4-C7 halocycloalkylalkyl, C2-C7 alkoxyalkyl, C2-C7 haloalkoxyalkyl, C2-C7 alkylthioalkyl, C2-C7 alkylsulfonylalkyl, C2-C7 alkylsulfmylalkyl, C2-C7 cyanoalkyl, C2-C7 haloalkylthioalkyl, C2-C7 haloalkylsulfonylalkyl, C2-C7 haloalkylsulfϊnylalkyl, Q-Q haloalkoxycarbonylalkyl, Q-Q haloalkylcarbonylalkyl, C2-C7 alkoxyalkoxy, C2-C7 haloalkoxyalkoxy, C2-C7 alkylthioalkoxy, C2-C7 haloalkylthioalkoxy, C2-C7 haloalkylsulfonylalkoxy, C2-C7 haloalkylsulfϊnylalkoxy, nitro, Q-Qo trialkylsilyl, aminosulfonyl, Q-
C7 alkylaminosulfonyl, Q-Q haloalkylaminosulfonyl, C2-Cg dialkylaminosulfonyl, Q-Cg haloalkyl(alkyl)aminosulfonyl, C3-C6 cycloalkylaminosulfonyl or C4-C7 cycloalkyl(alkyl)aminosulfonyl or Z; each Z is independently -ON=CR12R13, -Q=NOR1 ^R15, C2-C6 cyanoalkoxy, C2-C6 alkoxyhaloalkyl or C3-C7 alkoxycarbonylalkoxy; or phenyl optionally substituted with up to two substituents selected from R16; or a 5- or 6-membered heterocyclic ring optionally substituted with up to two substituents selected from R17 on carbon ring members and R18 on nitrogen ring members; each R12 is independently H or Q-C6 alkyl; each R13 is independently H, Q-C6 alkyl or Q-C4 alkoxy; or a pair of R12 and R13 in an instance of -ON=CR12R13 are taken together as -(CH2)2-, -(CH2)3-, -(CH2)4- or -(CH2)S-; each R14 and R15 is independently H or Q-C6 alkyl; or a pair of R14 and R15 in an instance of -C(=NOR14)R15 are taken together as -(CH2)2-, -(CH2)3- or -(CH2)4-; each R16 is independently Q-C6 alkyl, halogen, Q-C4 alkoxy, Q-C4 haloalkyl or Q-C4 haloalkoxy each R17 is independently Q-C6 alkyl, halogen, Q-C4 alkoxy, Q-C4 haloalkyl or
Q-C4 haloalkoxy; and each R18 is independently Q-C6 alkyl.
2. A compound of Claim 1 wherein
R1 is methyl, ethyl, fluoromethyl, hydroxymethyl or chloromethyl; R2 is methyl; R3 is H, F or Br; R4 is H;
R5 is H, CH3 or F; R6 is H; n is 0; m is 1 or 2; each R8a, R8b, R8c and R8d is independently C1-C4 alkyl, C1-C4 haloalkyl, C2-C4 alkyloxyalkyl or C2-C4 alkynyl; each R9a, R9b, R9c, R9d, Rllc and Rlld is independently H, halogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 cycloalkyl, C2-C6 alkoxyhaloalkyl or phenyl substituted with up to one R16; each R1Oa, R10b, R1Oc, R10d, Rlla and Rllb is independently H, C1-C7 alkyl, C3-C7 cycloalkyl, C1-C7 haloalkyl, C2-C7 haloalkenyl, C3-C7 haloalkynyl, C1-C7 alkoxy, C1-C7 haloalkoxy, C3-C7 cycloalkoxy, C4-C7 cycloalkylalkoxy, C1- C7 alkylthio, C1-C6 alkylamino, C1-C7 haloalkylamino, C2-C7 alkoxycarbonyl, C3-Cg dialkylaminocarbonyl, C2-C7 alkoxyalkoxy, C2-C7 haloalkylsulfϊnylalkoxy, -C(=NOR14)R15, C2-C6 cyanoalkoxy, C2-C6 alkoxyhaloalkyl or C3-C7 alkoxycarbonylalkoxy; or phenyl optionally substituted with up to two substituents selected from R16; or furanyl, pyrazolyl, isoxazolyl, thienyl, pyrrolidinyl or pyridinyl, each optionally substituted with up to two substituents selected from R17 on carbon ring members and R18 on nitrogen ring members; R14 is CH3; R15 is H; each R16 is C1-C6 alkyl or halogen; each R17 is C1-C6 alkyl or halogen; and each R18 is C1-C6 alkyl.
3. A compound of Claim 2 wherein
R1 is methyl, fluoromethyl or chloromethyl; R3 is H;
R5 is H;
J is J-I;
R8a is CH3, CH2CH3, CH2CF3, CH2OCH3, n-propyl or CH2C≡CH;
Q1 is CR9a, W1 is CR1Oa and Y1 is N, or Q1 is CR9a, W1 is N and Y1 is CRlla; R9a is CH3, CF3, CF2Cl Or CF2OCH3;
R1Oa is H, CH3, CH2CH3, cyclopropyl, OCH3 or OCH2CH3; and
Rlla is H, CH3, CH2CH3, cyclopropyl, OCH3, OCH2CH3 or SCH3.
4. A compound of Claim 3 wherein
Q1 is CR9a, W1 is CR1Oa and Y1 is N; R8a is CH3; R9a is CF3; R1 Oa is CH3 , cyclopropyl or OCH3.
5. A compound Claim 2 wherein
R1 is methyl; R3 is H; R5 is H; J is J-2;
Q2 is CR9b, W2 is CR10b and Y2 is N; R8b is CH3; R9b is CF3; and R10b is CH3.
6. A compound of Claim 2 wherein
R1 is methyl;
R3 is H;
R5 is H or CH3;
J is J-3; Q3 is CR9c, W3 is N and Y3 is CR1 lc, or Q3 is CR9c, W3 is CR1Oc and Y3 is CR1 lc;
R8c is CH3 or CH2CF3;
R9c is CF3, Br, OCHF2 or OCH2CF3;
R1Oc is H or OCH3; and
Rllc is CF3, Br, OCHF2 or OCH2CF3.
7. A compound of Claim 2 wherein
R1 is methyl;
R3 is H;
R5 is H;
J is J-4; Q4 is CR9d, W4 is CR10d and Y4 is CR1 ld;
R8d is CH3;
R9d is CF3;
R10d is H; and
Rlld is CF3.
8. A compound of Claim 1 that is
5-[[(4,5-dihydro-5,5-dimethyl-3-isoxazolyl)sulfinyl]methyl]-2-methoxy-3-methyl-6- (trifluoromethyl)-4(3H)-pyrimidinone or 5 -[ [(4,5 -dihydro-5 ,5 -dimethyl-3 -isoxazolyl)sulfonyl]methyl] -2-methoxy-3 -methyl-6- (trifluoromethyl)-4(3H)-pyrimidinone.
9. A compound of Claim 1 that is
5-[[(4,5-dihydro-5,5-dimethyl-3-isoxazolyl)sulfonyl]methyl]-2,3-dimethyl-6- (trifluoromethyl)-4(3H)-pyrimidinone,
5-[[(4,5-dihydro-5,5-dimethyl-3-isoxazolyl)sulfonyl]methyl]-2-ethyl-3-methyl-6-
(trifluoromethyl)-4(3H)-pyrimidinone, 5-[[(4,5-dihydro-5,5-dimethyl-3-isoxazolyl)sulfonyl]methyl]-2-ethoxy-3-methyl-6-
(trifluoromethyl)-4(3H)-pyrimidinone or 5-[[(4,5-dihydro-5,5-dimethyl-3-isoxazolyl)sulfonyl]methyl]-3-ethyl-2-methoxy-6-
(trifluoromethyl)-4(3H)-pyrimidinone.
10. A herbicidal composition comprising a compound of Claim 1 wherein the sum of n and m is 1 or 2, and at least one component selected from the group consisting of surfactants, solid diluents and liquid diluents.
11. The herbicidal composition of Claim 10 further comprising at least one additional active ingredient selected from the group consisting of other herbicides and herbicide safeners.
12. A method for controlling the growth of undesired vegetation comprising contacting the vegetation or its environment with a herbicidally effective amount of a compound of Claim 1 wherein the sum of n and m is 1 or 2.
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US9271978B2 (en) 2012-12-21 2016-03-01 Zenith Epigenetics Corp. Heterocyclic compounds as bromodomain inhibitors
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US9663520B2 (en) 2013-06-21 2017-05-30 Zenith Epigenetics Ltd. Bicyclic bromodomain inhibitors
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US10041068B2 (en) 2013-01-01 2018-08-07 A. B. Seeds Ltd. Isolated dsRNA molecules and methods of using same for silencing target molecules of interest
US10179125B2 (en) 2014-12-01 2019-01-15 Zenith Epigenetics Ltd. Substituted pyridines as bromodomain inhibitors
US10231953B2 (en) 2014-12-17 2019-03-19 Zenith Epigenetics Ltd. Inhibitors of bromodomains
US10240161B2 (en) 2012-05-24 2019-03-26 A.B. Seeds Ltd. Compositions and methods for silencing gene expression
US10292968B2 (en) 2014-12-11 2019-05-21 Zenith Epigenetics Ltd. Substituted heterocycles as bromodomain inhibitors
US10378012B2 (en) 2014-07-29 2019-08-13 Monsanto Technology Llc Compositions and methods for controlling insect pests
US10557138B2 (en) 2013-12-10 2020-02-11 Beeologics, Inc. Compositions and methods for virus control in Varroa mite and bees
US10612019B2 (en) 2013-03-13 2020-04-07 Monsanto Technology Llc Methods and compositions for weed control
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US10888579B2 (en) 2007-11-07 2021-01-12 Beeologics Inc. Compositions for conferring tolerance to viral disease in social insects, and the use thereof
WO2021002484A3 (en) * 2019-10-31 2021-03-11 クミアイ化学工業株式会社 Herbicide and production method for intermediate thereof
US10968449B2 (en) 2015-01-22 2021-04-06 Monsanto Technology Llc Compositions and methods for controlling Leptinotarsa
US10988764B2 (en) 2014-06-23 2021-04-27 Monsanto Technology Llc Compositions and methods for regulating gene expression via RNA interference
CN112789266A (en) * 2018-09-27 2021-05-11 Fmc公司 Intermediate for preparing herbicide pyridazinone
US11026926B2 (en) 2013-06-21 2021-06-08 Zenith Epigenetics Ltd. Substituted bicyclic compounds as bromodomain inhibitors
US11091770B2 (en) 2014-04-01 2021-08-17 Monsanto Technology Llc Compositions and methods for controlling insect pests
US11807857B2 (en) 2014-06-25 2023-11-07 Monsanto Technology Llc Methods and compositions for delivering nucleic acids to plant cells and regulating gene expression

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1364946A1 (en) * 2001-02-08 2003-11-26 Kumiai Chemical Industry Co., Ltd. Isoxazoline derivative and herbicide comprising the same as active ingredient
EP1405853A1 (en) * 2001-06-21 2004-04-07 Kumiai Chemical Industry Co., Ltd. Isoxazoline derivatives and herbicides
US20050256004A1 (en) * 2002-08-07 2005-11-17 Satoru Takahashi Herbicide compositions
WO2006024820A1 (en) * 2004-09-03 2006-03-09 Syngenta Limited Isoxazoline derivatives and their use as herbicides
WO2006037945A1 (en) * 2004-10-05 2006-04-13 Syngenta Limited Isoxazoline derivatives and their use as herbicides
WO2007003294A1 (en) * 2005-07-06 2007-01-11 Bayer Cropscience Ag 3-[1-halo-1-aryl-methane-sulfonyl]- and 3-[1-halo-1-heteroaryl-methane-sulfonyl]-isoxazoline derivatives, method for the production thereof, and use of the same as herbicides and plant growth regulators
WO2007071900A1 (en) * 2005-12-21 2007-06-28 Syngenta Limited Novel herbicides

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1364946A1 (en) * 2001-02-08 2003-11-26 Kumiai Chemical Industry Co., Ltd. Isoxazoline derivative and herbicide comprising the same as active ingredient
EP1405853A1 (en) * 2001-06-21 2004-04-07 Kumiai Chemical Industry Co., Ltd. Isoxazoline derivatives and herbicides
US20050256004A1 (en) * 2002-08-07 2005-11-17 Satoru Takahashi Herbicide compositions
WO2006024820A1 (en) * 2004-09-03 2006-03-09 Syngenta Limited Isoxazoline derivatives and their use as herbicides
WO2006037945A1 (en) * 2004-10-05 2006-04-13 Syngenta Limited Isoxazoline derivatives and their use as herbicides
WO2007003294A1 (en) * 2005-07-06 2007-01-11 Bayer Cropscience Ag 3-[1-halo-1-aryl-methane-sulfonyl]- and 3-[1-halo-1-heteroaryl-methane-sulfonyl]-isoxazoline derivatives, method for the production thereof, and use of the same as herbicides and plant growth regulators
WO2007071900A1 (en) * 2005-12-21 2007-06-28 Syngenta Limited Novel herbicides

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Publication number Priority date Publication date Assignee Title
US10888579B2 (en) 2007-11-07 2021-01-12 Beeologics Inc. Compositions for conferring tolerance to viral disease in social insects, and the use thereof
US10801028B2 (en) 2009-10-14 2020-10-13 Beeologics Inc. Compositions for controlling Varroa mites in bees
US11812738B2 (en) 2010-03-08 2023-11-14 Monsanto Technology Llc Polynucleotide molecules for gene regulation in plants
US9988634B2 (en) 2010-03-08 2018-06-05 Monsanto Technology Llc Polynucleotide molecules for gene regulation in plants
US9121022B2 (en) 2010-03-08 2015-09-01 Monsanto Technology Llc Method for controlling herbicide-resistant plants
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US10934555B2 (en) 2012-05-24 2021-03-02 Monsanto Technology Llc Compositions and methods for silencing gene expression
US10240162B2 (en) 2012-05-24 2019-03-26 A.B. Seeds Ltd. Compositions and methods for silencing gene expression
US10240161B2 (en) 2012-05-24 2019-03-26 A.B. Seeds Ltd. Compositions and methods for silencing gene expression
US9765039B2 (en) 2012-11-21 2017-09-19 Zenith Epigenetics Ltd. Biaryl derivatives as bromodomain inhibitors
US9278940B2 (en) 2012-11-21 2016-03-08 Zenith Epigenetics Corp. Cyclic amines as bromodomain inhibitors
US9598367B2 (en) 2012-12-21 2017-03-21 Zenith Epigenetics Ltd. Heterocyclic compounds as bromodomain inhibitors
US9271978B2 (en) 2012-12-21 2016-03-01 Zenith Epigenetics Corp. Heterocyclic compounds as bromodomain inhibitors
US9861637B2 (en) 2012-12-21 2018-01-09 Zenith Epigenetics Ltd. Heterocyclic compounds as bromodomain inhibitors
US10041068B2 (en) 2013-01-01 2018-08-07 A. B. Seeds Ltd. Isolated dsRNA molecules and methods of using same for silencing target molecules of interest
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US10609930B2 (en) 2013-03-13 2020-04-07 Monsanto Technology Llc Methods and compositions for weed control
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US10363257B2 (en) 2013-06-21 2019-07-30 Zenith Epigenetics Ltd. Bicyclic bromodomain inhibitors
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US9777288B2 (en) 2013-07-19 2017-10-03 Monsanto Technology Llc Compositions and methods for controlling leptinotarsa
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US11377667B2 (en) 2013-07-19 2022-07-05 Monsanto Technology Llc Compositions and methods for controlling Leptinotarsa
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US10500209B2 (en) 2013-07-31 2019-12-10 Zenith Epigenetics Ltd. Quinazolinones as bromodomain inhibitors
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US10927374B2 (en) 2013-11-04 2021-02-23 Monsanto Technology Llc Compositions and methods for controlling arthropod parasite and pest infestations
US10100306B2 (en) 2013-11-04 2018-10-16 Monsanto Technology Llc Compositions and methods for controlling arthropod parasite and pest infestations
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US10334848B2 (en) 2014-01-15 2019-07-02 Monsanto Technology Llc Methods and compositions for weed control using EPSPS polynucleotides
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US11091770B2 (en) 2014-04-01 2021-08-17 Monsanto Technology Llc Compositions and methods for controlling insect pests
US10988764B2 (en) 2014-06-23 2021-04-27 Monsanto Technology Llc Compositions and methods for regulating gene expression via RNA interference
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US10179125B2 (en) 2014-12-01 2019-01-15 Zenith Epigenetics Ltd. Substituted pyridines as bromodomain inhibitors
US10710992B2 (en) 2014-12-01 2020-07-14 Zenith Epigenetics Ltd. Substituted pyridinones as bromodomain inhibitors
US10292968B2 (en) 2014-12-11 2019-05-21 Zenith Epigenetics Ltd. Substituted heterocycles as bromodomain inhibitors
US10231953B2 (en) 2014-12-17 2019-03-19 Zenith Epigenetics Ltd. Inhibitors of bromodomains
US10968449B2 (en) 2015-01-22 2021-04-06 Monsanto Technology Llc Compositions and methods for controlling Leptinotarsa
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