Preparation of substituted 3-aryl-5-trifluoromethyl-1,2,4-oxadiazoles

A process for preparing an oxadiazole compound of formula I,

• wherein
• A is phenyl or a 5- or 6-membered aromatic heterocycle;
• wherein the ring member atoms of the aromatic heterocycle include besides carbon atoms 1, 2, 3, or 4 heteroatoms selected from N, O, and S as ring member atoms with the provision that the heterocycle cannot contain 2 contiguous atoms selected from O and S;
• and wherein A is further unsubstituted or further substituted with additional n identical or different radicals RA;
• wherein
• n is 0,1, 2, 3, or 4;
• RA is independently selected from the group consisting of halogen, cyano, C1-C6-alkyl, C1-C6-haloalkyl, C1-C6-alkoxy, and C1-C6-haloalkoxy;
• R is methyl, chloromethyl, hydroxymethyl, trichloromethyl, ethyl, iso-propyl, OH, SH, cyano, halogen, CH2F, CHF2, 2,2,2-trifluoroethyl, cyclopropyl, —C(═O)H, —C(═NOR2)H, —C(═O)OH, —C(═O)OR1, —C(═W)NR1R2, —CR3R4NR1R2, —CR3R4OR1, —CR3(═NR1), —CR3(═O), —CR3R4C(═O)OH, —CR3R4C(═O)R1, —CR3R4C(═W)NR1R2, —OCR3R4C(═O)OH, —OCR3R4C(═O)R1, —OCR3R4C(═W)NR1R2, —CR3R4—N(R2)—C(═W)R1, —CR3R4S(═O)2R1, or —CR3R4—N(R2)—S(═O)2R1;
• wherein
• W is O or S;
• R2 is hydrogen, C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C6-alkoxy, C3-C11-cycloalkyl, —C(═O)—C1-C6-alkyl, —C(═O)—C3-C11-cycloalkyl, or —C(═O)—O—C1-C6-alkyl;
• and wherein any of the aliphatic or cyclic groups in R2 are unsubstituted or substituted with 1, 2, 3, or up to the maximum possible number of identical or different radicals selected from the group consisting of halogen, hydroxy, oxo, cyano, C1-C6-alkyl, C1-C6-alkoxy, and C3-C11-cycloalkyl;
• R1 is C1-C6-alkyl, C1-C6-alkoxy, C3-C11-cycloalkyl, C3-C-cycloalkenyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C6-alkoxyimino-C1-C4-alkyl, C2-C6-alkenyloxyimino-C1-C4-alkyl, C2-C6-alkynyloxyimino-C1-C4-alkyl, C1-C6-alkylamino, diC1-C6-alkylamino, —C(═O)—C1-C6-alkyl, —C(═O)—O—C1-C6-alkyl, phenyl-C1-C4-alkyl, phenyl-C1-C4-alkenyl, phenyl-C1-C4-alkynyl, heteroaryl-C1-C4-alkyl, phenyl, naphthyl, or a 3- to 10-membered saturated, partially unsaturated or aromatic mono- or bicyclic heterocycle, wherein the ring member atoms of said mono- or bicyclic heterocycle include besides carbon atoms further 1, 2, 3 or 4 heteroatoms selected from N, O and S as ring member atoms with the provision that the heterocycle cannot contain 2 contiguous atoms selected from O and S;
• and wherein the heteroaryl group in the group heteroaryl-C1-C4-alkyl is a 5- or 6-membered aromatic heterocycle, wherein the ring member atoms of the heterocyclic ring include besides carbon atoms 1, 2, 3 or 4 heteroatoms selected from N, O, and S as ring member atoms with the provision that the heterocycle cannot contain 2 contiguous atoms selected from O and S;
• and wherein any of the above-mentioned aliphatic or cyclic groups are unsubstituted or substituted with 1, 2, 3, or up to the maximum possible number of identical or different groups R1a;
• or
• R1 and R2, together with the nitrogen atom to which they are attached, form a saturated or partially unsaturated mono- or bicyclic 3- to 10-membered heterocycle, wherein the heterocycle includes beside one nitrogen atom and one or more carbon atoms no further heteroatoms or 1, 2 or 3 further heteroatoms independently selected from N, O, and S as ring member atoms with the provision that the heterocycle cannot contain 2 contiguous atoms selected from O and S;
• and wherein the heterocycle is unsubstituted or substituted with 1, 2, 3, 4, or up to the maximum possible number of identical or different groups R1a;
• wherein
• R1a is halogen, oxo, cyano, NO2, OH, SH, NH2, C1-C6-alkyl, C1-C6-haloalkyl, C1-C6-alkoxy, C1-C6-haloalkoxy, C1-C6-alkylthio, C1-C6-haloalkylthio, C3-C8-cycloalkyl, —NHSO2—C1-C4-alkyl, —C(═O)—C1-C4-alkyl, —C(═O)—O—C1-C4-alkyl, C1-C6-alkylsulfonyl, hydroxyC1-C4-alkyl, —C(═O)—NH2, —C(═O)—NH(C1-C4-alkyl), C1-C4-alkylthio-C1-C4-alkyl, aminoC1-C4-alkyl, C1-C4-alkylamino-C1-C4-alkyl, diC1-C4-alkylamino-C1-C4-alkyl, aminocarbonyl-C1-C4-alkyl, or C1-C4-alkoxy-C1-C4-alkyl;
• R3, R4 independently of each other are selected from the group consisting of hydrogen, halogen, cyano, C1-C4-alkyl, C1-C4-alkenyl, C1-C4-alkynyl, C1-C4-haloalkyl and C1-C4-alkoxy;
• or
• R3 and R4 together with the carbon atom to which they are bound form a cyclopropyl group;
• the process comprising reacting an amidoxime of formula II,
• wherein the variables A and R are as defined above for compounds of formula I, with a haloacetic ester of formula II.a,
• wherein R5 is C1-C6-alkyl, in the presence of a solvent and a base;
• whereas the base comprises a metal alkoxylate of formula IV,
• [C1-C6-alkyl-O]xMx+ IV
• wherein a metal M is an alkali metal, wherein x is 1, or M is an alkaline earth metal, wherein x is 2;
• and the solvent comprises an alkyl alcohol of formula III, or mixtures thereof,
• C1-C6-alkyl-OH III.