Process for Preparing Substituted Isoxazoline Compounds and Their Precursors

A process for preparing a compound of the formula (I)

• wherein
• R1 is H, CH3, CF3, CH2CH3, CH2CF3, Cl, Br, I, CN, NO2, SF5, OCH3, OCF3 or OCHF2;
• R2 is H, F, Cl, Br, I or CF3;
• R3 is H, F, Cl, Br or CN;
• R4 is H, F, Cl, Br, I or CF3;
• R5 is H, F, Cl or CF3;
• R8 is H, C1-C6-alkyl, optionally substituted with n substituents R10, or Z-A,
• wherein
• Z is a chemical bond, CH2, CH2CH2 or C═O and
• A is selected from the group consisting of
• wherein the “#” in the formulae of variables A indicate the bond to Z;
• n is an integer 1, 2, 3 or 4 and
• each R10 is, independently from the value of n, selected from the group consisting of hydrogen, halogen, cyano, azido, nitro, —SCN, SF5, C1-C6-alkyl, C1-C6-haloalkyl, C1-C6-alkoxy-C1-C6-alkyl, C3-C8-cycloalkyl, C3-C8-halocycloalkyl, C2-C6-alkenyl, C2-C6-haloalkenyl, C2-C6-alkynyl, C2-C6-haloalkynyl, —Si(R17)2R18, —OR11, —OSO2R11, —SR(O)mR11, —S(O)nN(R12)R13, —N(R12)R13, —C(═O)N(R12)R13, —C(═S)N(R12)R12)R13, —C(═O)OR11, phenyl which may be substituted by 1, 2, 3, 4 or 5 radicals R14, and a 3-, 4-, 5-, 6- or 7-membered saturated, partially unsaturated or aromatic heterocyclic ring containing 1, 2 or 3 heteroatoms or heteroatom groups selected from the group consisting of N, O, S, NO, SO and SO2, as ring members, where the heterocyclic ring may be substituted by one or more radicals R14;
• or two vicinally bound radicals R10 together form a group selected from the group consisting of ═CR15R16, ═S(O)mR11, ═S(O)mN(R12)R13, ═NR12, ═NOR11 and ═NNR12,
• or two radicals R10 together with the carbon atoms to which they are bound, form a 3-, 4-, 5-, 6-, 7- or 8-membered saturated or partially unsaturated carbocyclic or heterocyclic ring containing 1, 2 or 3 heteroatoms or heteroatom groups selected from the group consisting of N, O, S, NO, SO and SO2, as ring members;
• wherein
• R11 is selected from the group consisting of hydrogen, cyano, C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkinyl, C3-C8-cycloalkyl, wherein the four last mentioned radicals may be unsubstituted, partially or fully halogenated and/or oxygenated;
• and/or may carry 1-2 radicals selected from the group consisting of C1-C4 alkoxy);
• C1-C6-alkoxy, C1-C6-haloalkoxy, C1-C6-alkylthio, C1-C6-alkylsulfinyl, C1-C6-alkylsulfonyl, C1-C6-haloalkylthio, trimethylsilyl, triethylsilyl, tertbutyldimethylsilyl, phenyl, benzyl, pyridyl, and phenoxy,
• it being possible for phenyl, benzyl, pyridyl and phenoxy to be unsubstituted, partially or fully halogenated and/or to carry 1-3 substituents selected from the group consisting of C1-C6-alkyl, C1-C6-haloalkyl, C1-C6-alkoxy, C1-C6 haloalkoxy);
• and (C1-C6-alkoxy)carbonyl;
• R12, R13 are, independently from one another, selected from the group consisting of hydrogen, cyano, C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkinyl, C3-C8-cycloalkyl,
• wherein the four last mentioned radicals may be unsubstituted, partially or fully halogenated and/or oxygenated;
• and/or may carry 1-2 radicals selected from the group consisting of C1-C4 alkoxy);
• C1-C6-alkoxy, C1-C6-haloalkoxy, C1-C6-alkylthio, C1-C6-alkylsulfinyl, C1-C6-alkylsulfonyl, C1-C6-haloalkylthio, trimethylsilyl, triethylsilyl, tertbutyldimethylsilyl, phenyl, benzyl, pyridyl, phenoxy, and (C1-C6-alkoxy)carbonyl;
• it being possible for phenyl, benzyl, pyridyl and phenoxy to be unsubstituted, partially or fully halogenated and/or to carry 1-3 substituents selected from the group consisting of C1-C6-alkyl, C1-C6-haloalkyl, C1-C6-alkoxy, and C1-C6 haloalkoxy;
• or, when R12 and R13 are on the same nitrogen, the two groups may form a 3- to 7-membered saturated, partly saturated or unsaturated ring together with the nitrogen atom to which they are attached by forming a C2-C6 alkylene chain;
• wherein said alkylene chain may contain 1-2 oxygen atoms, sulfur atoms or nitrogen atoms, and may optionally be substituted with halogen atoms, C1-C4-haloalkyl, C1-C4-alkoxy, or C1-C4-haloalkoxy;
• each R14 is, independently of each occurrence and independently from one another, selected from the group consisting of hydrogen, cyano, C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkinyl, C3-C8-cycloalkyl,
• wherein the four last mentioned radicals may be unsubstituted, partially or fully halogenated and/or oxygenated, and/or may carry 1-2 radicals selected from the group consisting of C1-C4-alkoxy, C1-C6-alkoxy, C1-C6-haloalkoxy, C1-C6-alkylthio, C1-C6-alkylsulfinyl, C1-C6-alkylsulfonyl, C1-C6-haloalkylthio, trimethylsilyl, triethylsilyl, tertbutyldimethylsilyl, phenyl, benzyl, pyridyl, phenoxy, and (C1-C6-alkoxy)carbonyl;
• it being possible for phenyl, benzyl, pyridyl and phenoxy to be unsubstituted, partially or fully halogenated and/or to carry 1-3 substituents selected from the group consisting of C1-C6-alkyl, C1-C6-haloalkyl, C1-C6-alkoxy, and C1-C6 haloalkoxy;
• or two R14 together may form =C(C1-C4-alky)2, =N(C1-C6-alky), =NO(C1-C6-alky);
• =O;
• or, when two R14 are on the same nitrogen atom, the two adjacent R14s may form a 3- to 7-membered saturated, partly saturated or unsaturated ring together with the nitrogen atom to which they are attached by forming a C2-C6 alkylene chain;
• in this case, the alkylene chain may contain 1-2 oxygen atoms, sulfur atoms or nitrogen atoms, and may be arbitrarily substituted with halogen atoms, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy;
• R15, R16 are, independent from one another, selected from the group consisting of hydrogen, halogen, cyano, azido, nitro, —SCN, SF5, C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkinyl, C3-C8-cycloalkyl, wherein the four last mentioned radicals may be unsubstituted, partially or fully halogenated and/or oxgenated, and/or may carry 1-2 radicals selected from C1-C4 alkoxy;
• C1-C6-alkoxy, C1-C6-haloalkoxy, C1-C6-alkylthio, C1-C6-alkylsulfinyl, C1-C6-alkylsulfonyl, C1-C6-haloalkylthio, trimethylsilyl, triethylsilyl, tertbutyldimethylsilyl, —OH, —SH, phenyl, benzyl, pyridyl, and phenoxy,
• it being possible for phenyl, benzyl, pyridyl and phenoxy to be unsubstituted, partially or fully halogenated and/or to carry 1-3 substituents selected from the group consisting of C1-C6-alkyl, C1-C6-haloalkyl, C1-C6-alkoxy, C1-C6 haloalkoxy;
• (C1-C6-alkoxy)carbonyl, (C1-C6-alkyl)amino, and di-(C1-C6-alkyl)amino;
• or
• R15 and R16 on the same carbon atom may together form =C(C1-C4-alky)2, =N(C1-C6-alky), =NO(C1-C6-alky), or =O;
• R17, R18 are, independently of each other, selected from the group consisting of C1-C4-alkyl, C3-C6-cycloalkyl, C1-C4-alkoxy-C1-C4-alkyl, phenyl and benzyl;
• and
• R9 is H, CH3, CH2CH3, CH2CH2CH3, C(═O)CH3 or C(═O)OCH3.
• comprising
• A.3:
• reacting a compound of the formula (VIII) with a compound of formula (IV) in the presence a chlorinating agent and a base to form a compound of formula (XV)
• wherein
• R6 is H;
• A.4:
• reacting the compound of the formula (XV) with carbon monoxide and an amine in presence of a palladium catalyst to a compound of formula (I)
• wherein the compound of formula (VIII) is obtained by
• A.2:
• reacting a compound of formula (VII)
• with a methylenating agent to form a compound of formula (VIII), wherein said methylenating agent is selected from the group consisting of dimethyltitanocene, diphenylmethylphosphine oxide, dimethoxymethylphosphine sulfide, pentamethylphosphonic diamide, dimethyl sulfoxide, (trialkylstannyl)(trimethylsilyl)methane, trimethylsilyl(phenylthio)methane, titanium tetrachloride and diiodomethane or dibromomethane, dichlorotitanocene and aluminum trimethyl, methylenetriphenylphosphine, trimethylsulfonium iodide, dichloro(cyclopentadienyl)zirconium and diiodomethane or dibromomethane dimethyl methanephosphonate, methanesulfonyl chloride, (chloromethyl)trimethylsilylane, diazomethyltrimethyl silane, and Nysted's reagent or a precursor thereof,
• and the compound of formula (IV) is prepared in a process step B by reacting a compound of formula (II) with formoxime: