Process for Preparation of Optically Enriched Isoxazolines

Abstract

The invention relates to a process for preparing optically enriched isoxazoline compounds of formula (I), wherein the variables are as defined in the specification, and the shown enantiomer has at least 80% ee; by oxo-Michael addition of hydroxyl amine or its salt to an enone of formula (II), wherein the variables have the meanings given for formula (I), in the presence of a catalyst of formula (III) and a base.

##STR00001##

Claims

1. A process for preparing an optically enriched isoxazoline compound of formula I ##STR00042## wherein R.sup.1 is halomethyl; each R.sup.2 is independently H, halogen, CN, N.sub.3, NO.sub.2, SCN, SF.sub.5, C.sub.1-C.sub.6-alkyl, C.sub.3-C.sub.8-cycloalkyl, C.sub.2-C.sub.6-alkenyl, C.sub.2-C.sub.6-alkynyl, which groups are unsubstituted, partially or fully halogenated and/or substituted with one or more same or different R.sup.8, Si(R.sup.12).sub.3, OR.sup.9, S(O).sub.nR.sub.9, NR.sup.10aR.sup.10b, phenyl which is unsubstituted or partially or fully substituted with R.sup.11, and a 3- to 10-membered saturated, partially or fully unsaturated heteromonocyclic or heterobicyclic ring containing 1, 2, 3 or 4 heteroatoms N, O, and/or S as ring members, which ring is unsubstituted, or substituted with one or more same or different R.sup.11; n is 0, 1, or 2; G.sup.1, G.sup.2 are each CR.sup.3, or together form a sulfur atom; each R.sup.3 is independently selected from the meanings mentioned for R.sup.2, or two R.sup.3 bonded to adjacent carbon atoms may form a five- or sixmembered saturated, partially or fully unsaturated carbocyclic ring, or a dihydrofurane, or R.sup.3 bonded to carbon atom in position G.sup.1 form a bond to the chain *-Q-Z- in group A.sup.2; A is a group A.sup.1, A.sup.2, A.sup.3, or A.sup.4; wherein  A.sup.1 is C(═W)Y;  W is O, or S;  Y is N(R.sup.5)R.sup.6, or OR.sup.9;  A.sup.2 is ##STR00043##  wherein # denotes the bond of group A, and % denotes the bond to G.sup.1;  Q-Z is % —CH.sub.2—O—*, ‘—CH.sub.2—S(O).sub.n—*, or % —C(═O)—O—*, wherein % marks the bond of Q to phenyl, and * the bond of Z to azetidin; and  R.sup.A4 is H or C(═O)R.sup.4A, wherein R.sup.4A is H, C, C.sub.6 alkyl, C.sub.1-C.sub.6-haloalkyl, C.sub.2-C.sub.6-alkenyl, C.sub.2-C.sub.6-haloalkenyl, C.sub.2-C.sub.6-alkynyl, C.sub.2-C.sub.6-haloalkynyl, C.sub.1-C.sub.4-alkylcarbonyl, which aliphatic groups are unsubstituted or substituted with one or more radicals R.sup.41;  C.sub.3-C.sub.6-cycloalkyl, C.sub.3-C.sub.6-halocycloalkyl which cyclic groups are unsubstituted or substituted with one or more R.sup.42;  C(═O)N(R.sup.43)R.sup.44, N(R.sup.43)R.sup.45, CH═NOR.sup.46;  phenyl, heterocycle, or hetaryl which rings are unsubstituted or partially or fully substituted with R.sup.A; R.sup.41 is independently OH, CN, C.sub.1-C.sub.6-alkoxy, C.sub.1-C.sub.6-haloalkoxy, S(O).sub.n-C.sub.1-C.sub.6-alkyl, S(O).sub.n-C.sub.1-C.sub.6-haloalkyl, C(═O)N(R.sup.43)R.sup.44,  C.sub.3-C.sub.6-cycloalkyl, or C.sub.3-C.sub.6-halocycloalkyl which cycles are unsubstitued or substituted with one or more R.sup.411; or  phenyl, heterocycle or hetaryl which rings are unsubstitued or partially or fully substituted with R.sup.A; R.sup.411 is independently OH, CN, C.sub.1-C.sub.2-alkyl, or C.sub.1-C.sub.2-haloalkyl; R.sup.43 is H, or C.sub.1-C.sub.6-alkyl, R.sup.44 is H, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6-haloalkyl, C.sub.2-C.sub.6-alkenyl, C.sub.2-C.sub.6-haloalkenyl, C.sub.2-C.sub.6-alkynyl, C.sub.2-C.sub.6-haloalkynyl, or C.sub.3-C.sub.6-cycloalkyl, C.sub.3-C.sub.6-halocycloalkyl, C.sub.3-C.sub.6-cycloalkylmethyl, or C.sub.3-C.sub.6-halocycloalkylmethyl which rings are unsubstituted or substituted with a cyano; R.sup.45 H, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6-haloalkyl, C.sub.2-C.sub.4-alkenyl, C.sub.2-C.sub.4-alkynyl, CH.sub.2—CN, C.sub.3-C.sub.6-cycloalkyl, C.sub.3-C.sub.6-halocycloalkyl, C.sub.3-C.sub.6-cycloalkylmethyl, C.sub.3-C.sub.6-halocycloalkylmethyl, phenyl and hetaryl which aromatic rings are unsubstituted or partially or fully substituted with R.sup.A; R.sup.42 C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-haloalkyl, or a group as defined for R.sup.41; R.sup.46 is independently H, C.sub.1-C.sub.6-alkyl, or C.sub.1-C.sub.6-haloalkyl; R.sup.A is independently selected from halogen, CN, NO.sub.2, C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-haloalkyl, C.sub.2-C.sub.4-alkenyl, C.sub.2-C.sub.4-haloalkenyl, C.sub.2-C.sub.4-alkynyl, C.sub.2-C.sub.4-haloalkynyl, C.sub.3-C.sub.6-cycloalkyl, C.sub.3-C.sub.6-halocycloalkyl, C.sub.1-C.sub.4-alkoxy, C.sub.1-C.sub.4-haloalkoxy, S(O).sub.n-C.sub.1-C.sub.4-alkyl, S(O).sub.n-C.sub.1-C.sub.4-haloalkyl, C.sub.1-C.sub.4-alkylcarbonyl, C.sub.1-C.sub.4-haloalkylcarbonyl, C(═O)N(R.sup.43)R.sup.44; or two R.sup.A present on the same carbon atom of a saturated or partially saturated ring may form together ═O or ═S; or two R.sup.A present on the same S or SO ring member of a heterocyclic ring may together form a group ═N(C.sub.1-C.sub.6-alkyl), ═NO(C.sub.1-C.sub.6-alkyl), ═NN(H)(C.sub.1-C.sub.6-alkyl) or ═NN(C.sub.1-C.sub.6-alkyl).sub.2; A.sup.3 is CH.sub.2—NR.sup.5C(═W)R.sup.6; A.sup.4 is halogen, or cyano; R.sup.5 is independently selected from the meanings mentioned for R.sup.2; R.sup.6 is H, CN, C.sub.1-C.sub.10-alkyl, C.sub.3-C.sub.8-cycloalkyl, C.sub.2-C.sub.10-alkenyl, C.sub.2-C.sub.10-alkynyl, which groups are unsubstituted, partially or fully halogenated and/or substituted with one or more same or different R.sup.8; or  S(O).sub.nR.sup.9, or C(═O)R.sup.8; or  a 3- to 8-membered saturated, partially or fully unsaturated heterocyclic ring, which ring may contain 1, 2, 3, or 4 heteroatoms O, S, N, C═O and/or C═S as ring members, which heterocyclic ring is unsubstituted or partially or fully substituted with same or different halogen, CN, C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-haloalkyl, C.sub.1-C.sub.6-alkoxy, C.sub.1-C.sub.6-haloalkoxy, C.sub.1-C.sub.6-alkylthio, C.sub.1-C.sub.6-haloalkylthio, C.sub.3-C.sub.8-cycloalkyl, C.sub.3-C.sub.8-halocycloalkyl, C.sub.2-C.sub.6-alkenyl, C.sub.2-C.sub.6-haloalkenyl, C.sub.2-C.sub.6-alkynyl, C.sub.2-C.sub.6-haloalkynyl, which groups are unsubstituted, or partially or fully substituted with same or different R.sup.8, or phenyl which may be partially or fully substituted with R.sup.11; or R.sup.5 and R.sup.6 together form a group ═C(R.sup.8).sub.2, ═S(O).sub.m(R.sup.9).sub.2, ═NR.sup.10a, or ═NOR.sup.9; R.sup.7a, R.sup.7b are each independently H, halogen, CN, C.sub.1-C.sub.6-alkyl, C.sub.3-C.sub.8-cycloalkyl, C.sub.2-C.sub.6-alkenyl, or C.sub.2-C.sub.6-alkynyl, which groups are unsubstituted, partially or fully halogenated and/or substituted with same or different R.sup.8; each R.sup.8 is independently CN, N.sub.3, NO.sub.2, SCN, SF.sub.5, C.sub.3-C.sub.8-cycloalkyl, C.sub.3-C.sub.8-halocycloalkyl, wherein the carbon chains may be substituted with one or more R.sup.13;  Si(R.sup.12).sub.3, OR.sup.9, OSO.sub.2R.sup.9, S(O).sub.nR.sup.9, N(R.sup.10a)R.sup.10b, C(═O)N(R.sup.10a)R.sup.10b,  C(═S)N(R.sup.10a)R.sup.10b, C(═O)OR.sup.9, CH═NOR.sup.9,  phenyl, which is unsubstituted or partially or fully substituted with same or different R.sup.16, or  a 3-, 4-, 5-, 6- or 7-membered saturated, partially or fully unsaturated heterocyclic ring comprising 1, 2 or 3 heteroatoms N, O, and/or S as ring members, which ring is unsubstituted or partially or fully substituted with same or different R.sup.16, or two R.sup.8 present on the same carbon atom of an alkyl, alkenyl, alkynyl or cycloalkyl group together form a group ═O, ═C(R.sup.13).sub.2; ═S; ═S(O).sub.m(R.sup.15).sub.2,  ═S(O).sub.mR.sup.15N(R.sup.14a)R.sup.14b, ═NR.sup.10a, ═NOR.sup.9; or ═NN(R.sup.10a)R.sup.10b; or  two radicals R.sup.8, together with the carbon atoms of the alkyl, alkenyl, alkynyl or cycloalkyl group which they are bonded to, form a 3-, 4-, 5-, 6-, 7- or 8-membered saturated or partially unsaturated carbocyclic or heterocyclic ring, which heterocyclic ring comprises 1, 2, 3 or 4 heteroatoms N, O, and/or S as ring members, and which ring is unsubstituted, or partially or fully substituted with same or different R.sup.16; and R.sup.8 as a substituent on a cycloalkyl ring may additionally be C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-haloalkyl, C.sub.2-C.sub.6-alkenyl, C.sub.2-C.sub.6-haloalkenyl, C.sub.2-C.sub.6-alkynyl, and C.sub.2-C.sub.6-haloalkynyl, which groups are unsubstituted, or partially or fully substituted with same or different R.sup.13; and R.sup.8 in the groups C(═O)R.sup.8 and ═C(R.sup.8).sub.2 may additionally be H, halogen, C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-haloalkyl, C.sub.2-C.sub.6-alkenyl, C.sub.2-C.sub.6-haloalkenyl, C.sub.2-C.sub.6-alkynyl, or C.sub.2-C.sub.6-haloalkynyl, which groups are unsubstituted, or partially or fully substituted with same or different R.sup.13; each R.sup.9 is independently H, CN, C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-haloalkyl, C.sub.3-C.sub.8-cycloalkyl, C.sub.3-C.sub.8-cycloalkyl-C.sub.1-C.sub.4-alkyl-, C.sub.3-C.sub.8-halocycloalkyl, C.sub.2-C.sub.6-alkenyl, C.sub.2-C.sub.6-haloalkenyl, C.sub.2-C.sub.6-alkynyl, or C.sub.2-C.sub.6-haloalkynyl, which groups are unsubstituted, or partially or fully substituted with same or different R.sup.13, or  C.sub.1-C.sub.6-alkyl-C(═O)OR.sup.15, C.sub.1-C.sub.6-alkyl-C(═O)N(R.sup.14a)R.sup.14b, C.sub.1-C.sub.6-alkyl-C(═S)N(R.sup.14a)R.sup.14b, C.sub.1-C.sub.6-alkyl-C(═NR.sup.14)N(R.sup.14a)R.sup.14b, Si(R.sup.12).sub.3, S(O).sub.nR.sup.15, S(O).sub.nN(R.sup.14a)R.sup.14b, N(R.sup.10a)R.sup.10b, N═C(R.sup.13).sub.2, C(═O)R.sup.13, C(═O)N(R.sup.14a)R.sup.14b, C(═S)N(R.sup.14a)R.sup.14b, C(═O)OR.sup.15, or  phenyl, which is unsubstituted, or partially or fully substituted with R.sup.16; and  a 3- to 7-membered saturated, partially or fully unsaturated heterocyclic ring comprising 1, 2 or 3 heteroatoms N, O, and/or S as ring members, which ring is unsubstituted, or partially or fully substituted with same or different R.sup.16; and R.sup.9 in the groups S(O).sub.nR.sup.9 and OSO.sub.2R.sup.9 may additionally be C.sub.1-C.sub.6-alkoxy, or C.sub.1-C.sub.6-haloalkoxy; R.sup.10a, R.sup.10b are independently from one another H, C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-haloalkyl, C.sub.3-C.sub.8-cycloalkyl, C.sub.3-C.sub.8-halocycloalkyl, C.sub.2-C.sub.6-alkenyl, C.sub.2-C.sub.6-haloalkenyl, C.sub.2-C.sub.6-alkynyl, C.sub.2-C.sub.6-haloalkynyl, which groups are unsubstituted, or partially or fully substituted with same or different R.sup.13;  C.sub.1-C.sub.6-alkyl-C(═O)OR.sup.15, C.sub.1-C.sub.6-alkyl-C(═O)N(R.sup.14a)R.sup.14b, C.sub.1-C.sub.6-alkyl-C(═S)N(R.sup.14a)R.sup.14b,  C.sub.1-C.sub.6-alkyl-C(═NR.sup.14)N(R.sup.14a)R.sup.14b, C.sub.1-C.sub.6-alkoxy, C.sub.1-C.sub.6-haloalkoxy, C.sub.1-C.sub.6-alkylthio, C.sub.1-C.sub.6-haloalkylthio, S(O).sub.nR.sup.15, S(O).sub.nN(R.sup.14a)R.sup.14b, C(═O)R.sup.13, C(═O)OR.sup.15, C(═O)N(R.sup.14a)R.sup.14b,  C(═S)R.sup.13, C(═S)SR.sup.15, C(═S)N(R.sup.14a)R.sup.14b, C(═NR.sup.14)R.sup.13;  phenyl, which is unsubstituted, or partially or fully substituted with same or different R.sup.16; and  a 3-, 4-, 5-, 6- or 7-membered saturated, partially or fully unsaturated heterocyclic ring comprising 1, 2, 3 or 4 heteroatoms N, O, and/or S as ring members, which ring is unsubstituted, or partially or fully substituted with same or different R.sup.16, preferably unsubstituted or substituted hetaryl; or R.sup.10a and R.sup.10b together with the nitrogen atom they are bonded to form a 3- to 8-membered saturated, partially or fully unsaturated heterocyclic ring, which ring may additionally contain one or two heteroatoms N, O, and/or S as ring members, which ring is unsubstituted, or partially or fully substituted with same or different halogen, C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-haloalkyl, C.sub.1-C.sub.6-alkoxy, C.sub.1-C.sub.6-haloalkoxy, C.sub.1-C.sub.6-alkylthio, C.sub.1-C.sub.6-haloalkylthio, C.sub.3-C.sub.8-cycloalkyl, C.sub.3-C.sub.8-halocycloalkyl, C.sub.2-C.sub.6-alkenyl, C.sub.2-C.sub.6-haloalkenyl, C.sub.2-C.sub.6-alkynyl, C.sub.2-C.sub.6-haloalkynyl, phenyl which may be partially or fully substituted with R.sup.16, and a 3-, 4-, 5-, 6,- or 7-membered saturated, partially or fully unsaturated heterocyclic ring comprising 1, 2 or 3 heteroatoms N, O, and/or S as ring members, which ring is unsubstituted, or partially or fully substituted with same or different R.sup.16; or R.sup.10a and R.sup.10b together form a group ═C(R.sup.13).sub.2, ═S(O).sub.m(R.sup.15).sub.2,  ═S(O).sub.mR.sup.15N(R.sup.14a)R.sup.14b, ═NR.sup.14, or ═NOR.sup.15; R.sup.11 is halogen, CN, N.sub.3, NO.sub.2, SCN, SF.sub.5, C.sub.1-C.sub.10-alkyl, C.sub.3-C.sub.8-cycloalkyl, C.sub.2-C.sub.10-alkenyl, C.sub.2-C.sub.10-alkynyl, which groups are unsubstituted, partially or fully halogenated, and/or may be substituted with same or different R.sup.8, or  OR.sup.9, NR.sup.10aR.sup.10b, S(O).sub.nR.sup.9, Si(R.sup.12).sub.3;  phenyl, which is unsubstituted, or partially or fully substituted with same or different R.sup.16; and  a 3- to 7-membered saturated, partially or fully unsaturated aromatic heterocyclic ring comprising 1, 2, 3, or 4 heteroatoms N, O, and/or S as ring members, which ring is unsubstituted, or partially or fully substituted with same or different R.sup.16; or two R.sup.11 present on the same ring carbon atom of an unsaturated or partially unsaturated heterocyclic ring may together form a group ═O, ═C(R.sup.13).sub.2, ═S, ═S(O).sub.m(R.sup.15).sub.2, ═S(O).sub.mR.sup.15N(R.sup.14a)R.sup.14b, ═NR.sup.14, ═NOR.sup.15, or ═NN(R.sup.14a)R.sup.14b; or two R.sup.11 bound on adjacent ring atoms form together with the ring atoms to which they are bound a saturated 3- to 9-membered ring, which ring may contain 1 or 2 heteroatoms O, S, N, and/or NR.sup.14, and/or 1 or 2 groups C═O, C═S, C═NR.sup.14 as ring members, and which ring is unsubstituted, or partially or fully substituted with same or different halogen, C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-haloalkyl, C.sub.1-C.sub.6-alkoxy, C.sub.1-C.sub.6-haloalkoxy, C.sub.1-C.sub.6-alkylthio, C.sub.1-C.sub.6-haloalkylthio, C.sub.3-C.sub.8-cycloalkyl, C.sub.3-C.sub.8-halocycloalkyl, C.sub.2-C.sub.6-alkenyl, C.sub.2-C.sub.6-haloalkenyl, C.sub.2-C.sub.6-alkynyl, C.sub.2-C.sub.6-haloalkynyl, phenyl which may be partially or fully substituted with same or different R.sup.16, and a 3- to 7-membered saturated, partially or fully unsaturated heterocyclic ring containing 1, 2, or 3 heteroatoms N, O, and/or S as ring members, which ring is unsubstituted, or partially or fully substituted with same or different R.sup.16; each R.sup.12 is independently C.sub.1-C.sub.4-alkyl and phenyl, which is unsubstituted, or partially or fully substituted with same or different C.sub.1-C.sub.4-alkyl; each R.sup.13 is independently CN, NO.sub.2, OH, SH, SCN, SF.sub.5, C.sub.1-C.sub.6-alkoxy, C.sub.1-C.sub.6-haloalkoxy, SO.sub.n-C.sub.1-C.sub.6-alkyl, SO.sub.n-C.sub.1-C.sub.6-haloalkyl, Si(R.sup.12).sub.3, —C(═O)N(R.sup.14a)R.sup.14b, C.sub.3-C.sub.8-cycloalkyl which is unsubstituted, partially or fully halogenated or substituted with 1 or 2 same or different C.sub.1-C.sub.4-alkyl, C.sub.3-C.sub.4-cycloalkyl, C.sub.1-C.sub.4-alkoxy, C.sub.1-C.sub.4-haloalkoxy and/or oxo; phenyl, benzyl, phenoxy, where the phenyl moiety may be substituted with one or more same or different R.sup.16; and  a 3- to 7-membered saturated, partially or fully unsaturated heterocyclic ring containing 1, 2, or 3 heteroatoms N, O, and/or S, as ring members, which ring is unsubstituted, or partially or fully substituted with same or different R.sup.16; or two R.sup.13 present on the same carbon atom of an alkyl, alkenyl, alkynyl or cycloalkyl group may together be ═O, ═CH(C.sub.1-C.sub.4-alkyl), ═C(C.sub.1-C.sub.4-alkyl)C.sub.1-C.sub.4-alkyl, ═N(C.sub.1-C.sub.6-alkyl) or ═NO(C.sub.1-C.sub.6-alkyl); and R.sup.13 as a substituent of a cycloalkyl ring may additionally be C.sub.1-C.sub.6-alkyl, C.sub.2-C.sub.6-alkenyl or C.sub.2-C.sub.6-alkynyl, which groups are unsubstituted, partially or fully halogenated, or substituted with 1 or 2 CN, C.sub.3-C.sub.4-cycloalkyl, C.sub.1-C.sub.4-alkoxy, C.sub.1-C.sub.4-haloalkoxy, and oxo; and R.sup.13 in groups ═C(R.sup.13).sub.2, N═C(R.sup.13).sub.2, C(═O)R.sup.13, C(═S)R.sup.13, and C(═NR.sup.14)R.sup.13 may additionally be H, halogen, C.sub.1-C.sub.6-alkyl, C.sub.2-C.sub.6-alkenyl, or C.sub.2-C.sub.6-alkynyl, which groups are unsubstituted, partially or fully halogenated, or substituted with 1 or 2 CN, C.sub.3-C.sub.4-cycloalkyl, C.sub.1-C.sub.4-alkoxy, C.sub.1-C.sub.4-haloalkoxy, and oxo; each R.sup.14 is independently H, CN, C.sub.1-C.sub.6-alkoxy, C.sub.1-C.sub.6-haloalkoxy, SO.sub.n-C.sub.1-C.sub.6-alkyl, SO.sub.n-C.sub.1-C.sub.6-haloalkyl, Si(R.sup.12).sub.3;  C.sub.1-C.sub.6-alkyl, C.sub.2-C.sub.6-alkenyl, C.sub.2-C.sub.6-alkynyl, which groups are unsubstituted, partially or fully halogenated, or substituted with 1 or 2 CN, C.sub.1-C.sub.4-alkoxy, C.sub.1-C.sub.4-haloalkoxy, SO.sub.n-C.sub.1-C.sub.4-alkyl, C.sub.3-C.sub.6-cycloalkyl which is unsubstituted or substituted with 1 or 2 substituents halogen and CN;  and oxo;  C.sub.3-C.sub.8-cycloalkyl which is unsubstituted, or partially or fully halogenated or substituted with 1 or 2 CN, C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-alkoxy, C.sub.1-C.sub.4-haloalkoxy, SO.sub.n-C.sub.1-C.sub.6-alkyl, C.sub.3-C.sub.4-cycloalkyl, C.sub.3-C.sub.4-cycloalkyl-C.sub.1-C.sub.4-alkyl-, which groups are unsubstituted, or substituted with 1 or 2 substituents selected from halogen and CN;  phenyl, benzyl, pyridyl, phenoxy, which cyclic moieties are unsubstituted, or substituted with one or more same or different halogen, CN, NO.sub.2, C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-haloalkyl, C.sub.1-C.sub.6-alkoxy, C.sub.1-C.sub.6-haloalkoxy, C.sub.1-C.sub.6-alkylthio, C.sub.1-C.sub.6-haloalkylthio, C.sub.2-C.sub.4-alkenyl, C.sub.2-C.sub.4-haloalkenyl, C.sub.2-C.sub.4-alkynyl, C.sub.2-C.sub.4-haloalkynyl, C.sub.3-C.sub.6-cycloalkyl, C.sub.3-C.sub.6-halocycloalkyl, and C.sub.1-C.sub.6-alkoxycarbonyl;  and a 3-, 4-, 5- or 6-membered saturated, partially or fully unsaturated heterocyclic ring comprising 1, 2 or 3 heteroatoms N, O, and/or S as ring members, which ring is unsubstituted, or partially or fully substituted with same or different R.sup.16; R.sup.14a and R.sup.14bindependently of each other, have one of the meanings given for R.sup.14; or R.sup.14a and R.sup.14b, together with the nitrogen atom to which they are bound, form a 3- to 7-membered saturated, partially, or fully unsaturated heterocyclic ring, wherein the ring may additionally contain 1 or 2 heteroatoms N, O, and/or S as ring members, which ring is unsubstituted, or partially or fully substituted with same or different halogen, C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-haloalkyl, C.sub.1-C.sub.4-alkoxy, or C.sub.1-C.sub.4-haloalkoxy; or R.sup.14a and R.sup.14 or R.sup.14b and R.sup.14, together with the nitrogen atoms to which they are bound in the group C(═NR.sup.14)N(R.sup.14a)R.sup.14b, form a 3- to 7-membered partially, or fully unsaturated heterocyclic ring, wherein the ring may additionally contain 1 or 2 heteroatoms N, O, and/or S as ring members, which ring is unsubstituted, or partially or fully substituted with same or different halogen, C.sub.1-C.sub.4-haloalkyl, C.sub.1-C.sub.4-alkoxy, or C.sub.1-C.sub.4-haloalkoxy; each R.sup.15 is independently H, CN, Si(R.sup.12).sub.3  C.sub.1-C.sub.6-alkyl, C.sub.2-C.sub.6-alkenyl, C.sub.2-C.sub.6-alkynyl, which groups are unsubstituted, partially or fully halogenated, or substituted with 1 or 2 radicals C.sub.3-C.sub.4-cycloalkyl, C.sub.1-C.sub.4-alkoxy, C.sub.1-C.sub.4-haloalkoxy, SO.sub.n-C.sub.1-C.sub.6-alkyl, or oxo;  C.sub.3-C.sub.8-cycloalkyl which is unsubstituted, partially or fully halogenated or substituted with 1 or 2 radicals C.sub.1-C.sub.4-alkyl, C.sub.3-C.sub.4-cycloalkyl, C.sub.1-C.sub.4-alkoxy, C.sub.1-C.sub.4-haloalkoxy, SO.sub.n-C.sub.1-C.sub.6-alkyl, or oxo;  phenyl, benzyl, pyridyl, and phenoxy, which rings are unsubstituted, partially or fully halogenated, or substituted with 1, 2 or 3 substituents C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-haloalkyl, C.sub.1-C.sub.6-alkoxy, C.sub.1-C.sub.6-haloalkoxy, or (C.sub.1-C.sub.6-alkoxy)carbonyl; each R.sup.16 is independently halogen, NO.sub.2, CN, OH, SH, C.sub.1-C.sub.6-alkoxy, C.sub.1-C.sub.6-haloalkoxy, SO.sub.n-C.sub.1-C.sub.6-alkyl, SO.sub.n-C.sub.1-C.sub.6-haloalkyl, C.sub.1-C.sub.4-alkylcarbonyl, C.sub.1-C.sub.4-haloalkylcarbonyl, C.sub.1-C.sub.4-alkoxycarbonyl, C.sub.1-C.sub.4-haloalkoxycarbonyl, aminocarbonyl, C.sub.1-C.sub.4-alkylaminocarbonyl, di-(C.sub.1-C.sub.4-alkyl)-aminocarbonyl, Si(R.sup.12).sub.3;  C.sub.1-C.sub.6-alkyl, C.sub.2-C.sub.6-alkenyl, C.sub.2-C.sub.6-alkynyl, which groups are unsubstituted, partially or fully halogenated, or substituted with 1 or 2 radicals CN, C.sub.3-C.sub.4-cycloalkyl, C.sub.1-C.sub.4-alkoxy, C.sub.1-C.sub.4-haloalkoxy, or oxo;  C.sub.3-C.sub.8-cycloalkyl which is unsubstituted, partially or fully halogenated or substituted with 1 or 2 radicals CN, C.sub.1-C.sub.4-alkyl, C.sub.3-C.sub.4-cycloalkyl, C.sub.1-C.sub.4-alkoxy, C.sub.1-C.sub.4-haloalkoxy, or oxo;  phenyl, benzyl, pyridyl and phenoxy, which rings are unsubstituted, partially or fully halogenated, or substituted with 1, 2 or 3 substituents C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-haloalkyl, C.sub.1-C.sub.6-alkoxy, C.sub.1-C.sub.6-haloalkoxy, or (C.sub.1-C.sub.6-alkoxy)carbonyl; or two R.sup.16 present together on the same atom of an unsaturated or partially unsaturated ring may be ═O, ═S, ═N(C.sub.1-C.sub.6-alkyl), ═NO-C.sub.1-C.sub.6-alkyl, ═CH(C.sub.1-C.sub.4-alkyl), or ═C(C.sub.1-C.sub.4-alkyl).sub.2; or two R.sup.16 on two adjacent carbon atoms form together with the carbon atoms they are bonded to a 4- to 8-membered saturated, partially or fully unsaturated ring, wherein the ring may contain 1 or 2 heteroatoms N, O, and/or S as ring members, which ring is unsubstituted, or partially or fully substituted with same or different halogen, C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-haloalkyl, C.sub.1-C.sub.4-alkoxy, or C.sub.1-C.sub.4-haloalkoxy; each n is independently 0, 1, or 2; and each m is independently 0, or 1; wherein the shown enantiomer has at least 80% ee; comprising an oxo-Michael addition of hydroxyl amine or its salt to an enone of formula II, ##STR00044## wherein the variables have the meanings given for formula I, in the presence of a catalyst of formula III ##STR00045## wherein X is a counteranion; and a base.

2. The process according to claim 1, wherein group A in formula I is A.sup.1.

3. The process according to claim 1, wherein group A in formula I is A.sup.2.

4. The process according to claim 1, wherein group A in formula I is A.sup.3.

5. The process according to claim 1, wherein group A in formula I is A.sup.4.

6. The process according to claim 5, which further comprises reduction of I to a compound of formula Ic ##STR00046## and acylation with a carboxylic acid derivative of formula V ##STR00047## wherein the variables are as defined for formula I, ##STR00048## to yield a compound of formula I wherein A is A.sup.3.

7. The process according to claim 1, wherein the phenyl ring in formula I bearing the R.sup.2.sub.n substitution is a group P ##STR00049## wherein R.sup.2a is F, Cl, Br, CF.sub.3, or OCF.sub.3, and R.sup.2b and R.sup.2c are H, or as defined for R.sup.2a.

8. The process according to claim 1, wherein R.sup.1 is CF.sub.3.

9. The process according to claim 1, wherein G.sup.1 is C—CH.sub.3, or C—Cl, and G.sup.2 is CH.

10. The process according to claim 1, wherein in formula I group A is COOR.sup.9, wherein R.sup.9 is C.sub.1-C.sub.4-alkyl.

11. The process according to claim 1, wherein in formula I the variables have following meanings: R.sup.1 is CF.sub.3; R.sup.2a is F, Cl, Br, CF.sub.3, or OCF.sub.3; R.sup.2b and R.sup.2c are independently from each other H, F, Cl, Br, CF.sub.3, or OCF.sub.3; A is A.sup.1, A.sup.2, or A.sup.3; wherein  A.sup.1 is C(═O)N(R.sup.5)R.sup.6, C(═O)OR.sup.9, wherein  A.sup.2 is ##STR00050##  wherein # denotes the bond of group A, and % denotes the bond to G.sup.1;  Q-Z is % —CH.sub.2—O—*, wherein % marks the bond of Q to phenyl, and * the bond of Z to azetidin; and  R.sup.A4 is H, or C(═O)R.sup.4A, wherein  R.sup.4A is H, C.sub.1-C.sub.4-alkylcarbonyl, which is unsubstituted or substituted with S(O).sub.n-C.sub.1-C.sub.6-alkyl; A.sup.3 is CH.sub.2—NR.sup.5C(═O)R.sup.6; G.sup.1, and G.sup.2 are each CR.sup.3, or together form a sulfur atom; R.sup.3 is H or C.sub.1-C.sub.4-alkyl, or two R.sup.3 bonded to adjacent carbon atoms may form a five- or sixmembered saturated or aromatic carbocyclic ring, or a dihydrofurane, or R.sup.3 bonded to a carbon atom in position G.sup.1 form a bond to the chain *-Q-Z- in group A.sup.2; R.sup.5 is H; R.sup.6 is H, or C.sub.1-C.sub.6-alkyl which is unsubstituted, or substituted with one or two R.sup.8; or R.sup.5 and R.sup.6, together with the nitrogen atom to which they are bound, form a 5- or 6-membered saturated, heterocyclic ring, which ring contain 1 or 2 groups selected from O, S, N, and C═O as ring members, which heterocyclic ring is unsubstituted or partially substituted with same or different C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-haloalkyl, C.sub.1-C.sub.6-alkoxy, C.sub.1-C.sub.6-haloalkoxy, C.sub.1-C.sub.6-alkylthio, C.sub.1-C.sub.6-haloalkylthio, C.sub.3-C.sub.8-cycloalkyl, C.sub.3-C.sub.8-halocycloalkyl, C.sub.2-C.sub.6-alkenyl, C.sub.2-C.sub.6-haloalkenyl, C.sub.2-C.sub.6-alkynyl, C.sub.2-C.sub.6-haloalkynyl; each R.sup.8 is C(═O)N(R.sup.10a)R.sup.10b, or two R.sup.8 present on the same carbon atom of an alkyl group together form ═NOR.sup.9; R.sup.9 being C.sub.1-C.sub.4-alkyl; R.sup.10a, R.sup.10b are independently from one another H, C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-haloalkyl, C.sub.2-C.sub.6-alkenyl, C.sub.2-C.sub.6-haloalkenyl, C.sub.2-C.sub.6-alkynyl, C.sub.2-C.sub.6-haloalkynyl.

12. The process according to claim 1, wherein formula I represents isocycloseram.

13. The process according to claim 1, wherein formula I is formula IA, ##STR00051## wherein R.sup.5 is H or CH.sub.3, and R.sup.6 is H, C.sub.1-C.sub.6-alkyl, or C.sub.2-C.sub.6-alkenyl.

14. The process according to claim 1, wherein formula I is formula IB, ##STR00052## wherein p is 1 or 2, R.sup.x5 is H or CH.sub.3, and R.sup.x6 is CH.sub.3, C.sub.2H.sub.5, CH.sub.2(CH.sub.3).sub.2, CH.sub.2CH═CH.sub.2, CH.sub.2CF.sub.3, CH.sub.2CH.sub.2CF.sub.3, CH.sub.2C.sub.6H.sub.5, or CH.sub.2C(═O)OCH.sub.3.

15. The process according to claim 1, wherein the catalyst of formula III is applied in 0.01 to 0.5 mol equivalents of compound II.

16. The process according to claim 1, wherein an alkali metal or alkaline earth metal hydroxide is used as base in from 0.05 to 6 mol equivalents.

17. The process according to claim 1, wherein an amount of hydroxylamine is from 1 to 10 mol equivalents.

Description

EXAMPLES

A. Preparation Examples

[0167] With appropriate modification of the starting materials, the procedures given in the synthesis description were used to obtain further compounds I. The compounds obtained in this manner are listed in the table that follows, together with physical data.

[0168] The products shown below were characterized by melting point determination, by NMR spectroscopy or by the masses ([m/z]) or retention time (RT; [min.]) determined by HPLC-MS or HPLC spectrometry.

[0169] HPLC-MS=high performance liquid chromatography-coupled mass spectrometry;

[0170] HPLC method A: Shimadzu LC2010, Column: Waters XBridge C18, 150 mm*4.6 mm ID*5μ; Mobile Phase: A: water+0.1% TFA; B: acetonitrile+0.1% TFA; Temperature: 400° C.; Gradient: 10% B to 100% B in 5 min; 100% B 2 min; 10% B 3 min; Flow: 1.4 ml/min; Run Time: 10 min; PDA detector.

[0171] HPLC method B: Shimadzu LC2010, Column: CHIRALPAK AD-RH, 150 mm*4.6 mm*5μ; Mobile Phase: A: water+0.1% TFA; B: acetonitrile+0.1% TFA; Temperature: 400° C.; Gradient: 65% B to 100% B in 12 min; 100% B 1 min; 35% B 7 min; Flow: 1.4 ml/min; Run Time: 20 min; PDA detector.

Example 1: Preparation of N-[[4-[(5S)-5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]-2,3-dihydrobenzofuran-7-yl]methyl]propenamide

[0172] a) According to the invention with catalyst (R)-[1-[[10-[[2-[(R)-hydroxy-(6-methoxy-4-quinolyl)methyl]-5-vinyl-quinuclidin-1-ium-1-yl]methyl]-9-anthryl]methyl]-5-vinyl-quinuclidin-1-ium-2-yl]-(6-methoxy-4-quinolyl)methanol dibromide (III-Br.sub.2)

##STR00040##

[0173] A round bottom glass flask was charged with 1 g (1 eq) of N-[[4-[(E)-3-(3,5-dichloro-4-fluoro-phenyl)-4,4,4-trifluoro-but-2-enoyl]-2,3-dihydrobenzofuran-7-yl]methyl]propenamide in 20 ml of DCE, the reaction mass was cooled to 0° C. and III-Br.sub.2 0.103 g (0.05 eq) was added. The reaction mass was stirred at 0° C. for 30 min. A premixed solution of 0.7 ml (5 eq) 50% NH.sub.2OH solution in 2.5 ml (6 eq) of 20% NaOH was added dropwise in 90 mins and reaction mass was stirred at 0° C. for 5-6 hrs. After complete consumption of educts, water was added, and organic phase separated. Organic layer was washed with 6M HCl and water and evaporation of organic layer yielded 0.98 g (95.1% yield) of the title compound (99% HPLC purity, 92:8 S:R).

[0174] .sup.1H-NMR (500 MHz, CDCl.sub.3): 1.12-1.18 (t, 3H, J=7.5 Hz), 2.19-2.26 (q, 2H, J=7.8 Hz), 3.43-3.50 (m, 2H), 3.67-3.73 (dd, 1H, J=17 Hz), 4.06-4.12 (dd, 1H, J=17.1 Hz), 4.41-4.43 (d, 2 H, J=6 Hz), 4.63-4.69 (t, 2H, J=8.7 Hz), 6.03 (bs, 1H), 6.67-6.79 (d, 1H, J=7.8 Hz), 7.13-7.16 (d, 1H, J=7.8 Hz), 7.57-7.59 (d, 2H, 6Hz)

[0175] b) Comparison with (R)-[1-(9-anthrylmethyl)-5-vinyl-quinuclidin-1-ium-2-yl]-(6-methoxy-4-quinolyl)methanol chloride (PTC-1)

##STR00041##

[0176] Analogously to Example 1, except replacement of the catalyst by 0.061 g (0.05 eq) of PTC-1 were obtained 0.75 g (72.8% yield) of the title compound (99.8% HPLC purity & 84:16 S:R).

Example 2: Preparation of 4-[(5S)-5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]-N-[(4R)-2-ethyl-3-oxo-isoxazolidin-4-yl]-2-methyl-benzamide (isocycloseram, I.1)

[0177] Analogously to the protocol described in Example 1, isocycloseram was obtained

[0178] a) With III-Br.sub.2: Enantiomeric ratio at isoxazoline=95:5 (S:R), 82% yield;

[0179] b) With PTC-1: Enantiomeric ratio at isoxazoline=81:19 (S:R), 81% yield.