Microbiocidal oxadiazole derivatives
11154060 · 2021-10-26
Assignee
Inventors
Cpc classification
C07D271/10
CHEMISTRY; METALLURGY
A01N43/82
HUMAN NECESSITIES
C07D413/12
CHEMISTRY; METALLURGY
C07D271/06
CHEMISTRY; METALLURGY
A01N43/90
HUMAN NECESSITIES
International classification
A01N43/82
HUMAN NECESSITIES
C07D271/10
CHEMISTRY; METALLURGY
C07D413/12
CHEMISTRY; METALLURGY
Abstract
Compounds of Formula (IA) or Formula (IB): (IA/IB) wherein the substituents are as defined in claim 1, useful as pesticides, especially as fungicides. ##STR00001##
Claims
1. A compound of Formula (IA): ##STR00084## wherein A.sup.1 is CR.sup.1 and R.sup.1 is halogen, A.sup.2 is CR.sup.2 and R.sup.2 is hydrogen, and R.sup.3 and R.sup.4 are hydrogen; or A.sup.1 is CR.sup.1 and R.sup.1 is hydrogen, A.sup.2 is CR.sup.2 and R.sup.2 is hydrogen; R.sup.3 is halogen, and R.sup.4 is hydrogen; n=0 or 1; R.sup.5 and R.sup.6 independently represent hydrogen or methyl; R.sup.7 resents hydrogen, C.sub.1-.sub.6alkyl, C.sub.3-.sub.6alkenyl, C.sub.3-.sub.6alkynyl, C.sub.1-.sub.4haloalkyl, C.sub.3-.sub.6haloalkenyl, cyanoC.sub.1-.sub.6alkyl, hydroxyC.sub.1-.sub.6alkyl, C.sub.1-.sub.4alkoxyC.sub.1-.sub.6alkyl, C.sub.1-.sub.4haloalkoxyC.sub.1-.sub.6alkyl, C.sub.1-.sub.4alkylcarbonylC.sub.1-.sub.4alkyl, C.sub.1-.sub.4alkoxycarbonylC.sub.1-.sub.4alkyl, C.sub.1-.sub.4alkylaminocarbonylC.sub.1-.sub.4alkyl, di-C.sub.1-.sub.4alkylaminocarbonylC.sub.1-.sub.4alkyl, C.sub.3-.sub.8cycloalkyl, C.sub.3-.sub.8cycloalkylC.sub.1-.sub.3alkyl, phenyl, phenylC.sub.1-.sub.3alkyl, heteroaryl, heteroarylC.sub.1-.sub.3alkyl, wherein the heteroaryl moiety of said heteroaryl and heteroarylC.sub.1-.sub.3alkyl is a 5- or 6-membered aromatic ring which comprises 1, 2, 3 or 4 heteroatoms individually selected from N, O and S, heterocyclyl, heterocyclylC.sub.1-.sub.3alkyl or heterocyclyloxyC.sub.1-3alkyl, wherein the heterocyclyl moiety of said heterocyclyl, heterocyclylC.sub.1-.sub.3alkyl and heterocyclyloxyC.sub.1-.sub.3alkyl is a 5- or 6-membered non-aromatic ring which comprises 1, 2 or 3 heteroatoms individually selected from N, O and S, and wherein any of cycloalkyl, phenyl, heteroaryl and heterocyclyl moieties are optionally substituted by 1, 2, 3 or 4 substituents, which may be the same or different, selected from R.sup.9; R.sup.8 represents hydrogen, C.sub.1-.sub.6alkyl, C.sub.3-.sub.6alkenyl, C.sub.3-.sub.6alkynyl, C.sub.1-.sub.4haloalkyl, cyanoC.sub.1-.sub.6alkyl, hydroxyC.sub.1-.sub.6alkyl, C.sub.1-.sub.4alkoxyC.sub.1-.sub.6alkyl, phenyl or phenylC.sub.1-.sub.3alkyl; R.sup.9 represents cyano, amino, halogen, hydroxy, methyl, ethyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy, difluoromethoxy, C.sub.1-.sub.4alkoxycarbonyl, C.sub.1-.sub.4alkylaminocarbonyl, di-C.sub.1-.sub.4alkylaminocarbonyl, or cyclopropyl; or R.sup.7 and R.sup.8, together with the nitrogen atom and oxygen atom to which they are bonded, respectively, form (i) a 5- or 6-membered cycle optionally containing one additional heteroatom or group selected from O, S, N and NR.sup.10, wherein R.sup.10 is H or C.sub.1-.sub.4alkyl, or (ii) a 7- to 11-membered non-aromatic cyclic bridged ring system optionally containing one additional heteroatom or group selected from O, S, N and NR.sup.10, wherein R.sup.10 is H or C.sub.1-.sub.4alkyl; or a salt or an N-oxide thereof; or a compound of Formula (TB): ##STR00085## wherein A.sup.1 is CR.sup.1, wherein R.sup.1 is hydrogen; A.sup.2 is CR.sup.2, wherein R.sup.2 is hydrogen; R.sup.3 and R.sup.4 both represent hydrogen; n=0 or 1; R.sup.5 and R.sup.6 independently represent hydrogen or methyl; R.sup.7 represents hydrogen, C.sub.1-.sub.6alkyl, C.sub.3-.sub.6alkenyl, C.sub.3-.sub.6alkynyl, C.sub.1-.sub.4haloalkyl, C.sub.3-.sub.6haloalkenyl, cyanoC.sub.1-.sub.6alkyl, hydroxyC.sub.1-.sub.6alkyl, C.sub.1-.sub.4alkoxyC.sub.1-.sub.6alkyl, C.sub.1-.sub.4haloalkoxyC.sub.1-.sub.6alkyl, C.sub.1-.sub.4alkylcarbonylC.sub.1-.sub.4alkyl, C.sub.1-.sub.4alkoxycarbonylC.sub.1-.sub.4alkyl, C.sub.1-.sub.4alkylaminocarbonylC.sub.1-.sub.4alkyl, di-C.sub.1-.sub.4alkylaminocarbonylC.sub.1-.sub.4alkyl, C.sub.3-.sub.8scycloalkyl, C.sub.3-.sub.8cycloalkylC.sub.1-.sub.3alkyl, phenyl, phenylC.sub.1-.sub.3alkyl, heteroaryl, heteroarylC.sub.1-.sub.3alkyl, wherein the heteroaryl moiety of said heteroaryl and heteroarylC.sub.1-.sub.3alkyl is a 5- or 6-membered aromatic ring which comprises 1, 2, 3 or 4 heteroatoms individually selected from N, O and S, heterocyclyl, heterocyclylC.sub.1-.sub.3alkyl or heterocyclyloxyC.sub.1-3alkyl, wherein the heterocyclyl moiety of said heterocyclyl, heterocyclylC.sub.1-.sub.3alkyl and heterocyclyloxyCi-.sub.3alkyl is a 4- to 6-membered non-aromatic ring which comprises 1, 2 or 3 heteroatoms individually selected from N, O and S, and wherein any of said cycloalkyl, phenyl, heteroaryl and heterocyclyl moieties are optionally substituted by 1, 2, 3 or 4 substituents, which may be the same or different, selected from R.sup.9; R.sup.8 represents C.sub.1-.sub.6alkyl, C.sub.3-.sub.6alkenyl, C.sub.3-.sub.6alkynyl, C.sub.1-.sub.4haloalkyl, cyanoC.sub.1-.sub.6alkyl, hydroxyC.sub.1-.sub.6alkyl, C.sub.1-.sub.4alkoxyC.sub.1-.sub.6alkyl, phenyl, or phenylC.sub.1-.sub.3alkyl; R.sup.9 represents cyano, amino, halogen, hydroxy, methyl, ethyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy, difluoromethoxy, C.sub.1-.sub.4alkoxycarbonyl, C.sub.1-.sub.4alkylaminocarbonyl, di-C.sub.1-.sub.4alkylaminocarbonyl, or cyclopropyl; or R.sup.7 and R.sup.8, together with the nitrogen atom and oxygen atom to which they are bonded, respectively, form (i) a 5- or 6-membered cycle optionally containing one additional heteroatom or group selected from O, S, N and NR.sup.10, wherein R.sup.10 is H or C.sub.1-.sub.4alkyl, or (ii) a 7- to 11-membered non-aromatic cyclic bridged ring system optionally containing one additional heteroatom or group selected from O, S, N and NR.sup.10, wherein R.sup.10 is H or C.sub.1-.sub.4alkyl; or a salt or an N-oxide thereof; with the proviso that the compound of Formula (IB) is not: N-methoxy-N-methyl-4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]benzamide; N-methoxy-4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]benzamide; N-benzyloxy-4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]benzamide; N-methoxy-N-methyl-2-[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]acetamide; or N-methoxy-2-[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]acetamide.
2. The compound of Formula (IA) according to claim 1, wherein R.sup.7 is selected from hydrogen, C.sub.1-.sub.6alkyl, C.sub.1-.sub.4haloalkyl, C.sub.3-.sub.6alkynyl, hydroxyC.sub.1-.sub.6alkyl, C.sub.3-.sub.8cycloalkyl, C.sub.3-.sub.8cycloalkylC.sub.1-.sub.3alkyl, phenyl, phenylC.sub.1-.sub.3alkyl, heteroaryl, heteroarylC.sub.1-.sub.3alkyl, heterocyclyl, heterocyclylC.sub.1-.sub.3alkyl and heterocyclyloxyC.sub.1-.sub.3alkyl, wherein any of said cycloalkyl, phenyl and heterocyclyl moieties are optionally substituted by 1, 2 or 3 substituents, which may be the same or different, selected from R.sup.9.
3. The compound of Formula (IA) according to claim 1, wherein R.sup.8 is selected from hydrogen, C.sub.1-.sub.4alkyl, C.sub.3-.sub.6alkenyl, cyanoC.sub.1-.sub.6alkyl, phenyl and phenylC.sub.1-.sub.3alkyl.
4. The compound of Formula (IA) according to claim 1, wherein R.sup.7 is selected from hydrogen, C.sub.1-.sub.4alkyl, C.sub.3-.sub.4alkynyl, C.sub.1-.sub.2haloalkyl, hydroxyC.sub.1-.sub.4alkyl, C.sub.3-.sub.6cycloalkyl, C.sub.3-.sub.6cycloalkylC.sub.1-.sub.3alkyl, phenyl, phenylC.sub.1-.sub.3alkyl, furanyl, furanylC.sub.1-.sub.3alkyl, piperidinyl, piperidinylC.sub.1-.sub.3alkyl and tetrahydropyranyloxyC.sub.1-.sub.3alkyl, wherein any of said cycloalkyl, phenyl, furanyl, piperidinyl and tetrahydropyranyl moieties are optionally substituted by 1, 2 or 3 substituents, which may be the same or different, selected from R.sup.9; and R.sup.8 is selected from hydrogen, methyl, ethyl, prop-1-enyl, 1-methyl-2-cyano-ethyl or benzyl.
5. The compound of Formula (IA) according to claim 1, wherein: A.sup.1 is CR.sup.1and R.sup.1 is fluoro, A.sup.2 is CR.sup.2 and R.sup.2 is hydrogen, and R.sup.3 and R.sup.4 are hydrogen; or A.sup.1 is CR.sup.1 and R.sup.1 is hydrogen, A.sup.2 is CR.sup.2 and R.sup.2 is hydrogen; R.sup.3 is fluoro, and R.sup.4 is hydrogen.
6. The compound of Formula (TB) according to claim 1, wherein R.sup.1 is selected from hydrogen, C.sub.1-.sub.6alkyl, C.sub.3-.sub.6alkenyl, C.sub.3-.sub.6alkynyl, C.sub.1-.sub.4haloalkyl, C.sub.3-.sub.6haloalkenyl, C.sub.1-.sub.4alkoxycarbonylC.sub.1-.sub.4alkyl, C.sub.1-.sub.4alkylaminocarbonylC.sub.1-.sub.4alkyl, phenyl, phenylC.sub.1-.sub.3alkyl, heterocyclyl and heterocyclylC.sub.1-.sub.3alkyl, wherein any of said phenyl and heterocyclyl moieties are optionally substituted by 1, 2 or 3 substituents, which may be the same or different, selected from R.sup.9.
7. The compound of formula (IB) according to claim 1, wherein R.sup.7 is C.sub.3-.sub.6alkenyl, C.sub.3-.sub.6alkynyl, C.sub.1-.sub.4ha1oalkyl, C.sub.3-.sub.6haloalkenyl, cyanoC.sub.1-.sub.6alkyl, hydroxyC.sub.1-.sub.6alkyl, C.sub.1-.sub.4alkoxyC.sub.1-.sub.6alkyl, C.sub.1-.sub.4haloalkoxyC.sub.1-.sub.6alkyl, C.sub.1-.sub.4alkylcarbonylC.sub.1-.sub.4alkyl, C.sub.1-.sub.4alkoxycarbonylC.sub.1-.sub.4alkyl, C.sub.1-.sub.4alkylaminocarbonylC.sub.1-.sub.4alkyl, di-C.sub.1-.sub.4alkylaminocarbonylC.sub.1-.sub.4alkyl, C3-8cycloalkyl, C.sub.3-.sub.8cycloalkylC.sub.1-.sub.3alkyl, phenyl, phenylC.sub.1-.sub.3 alkyl, heteroaryl, heteroarylC.sub.1-.sub.3 alkyl, wherein the heteroaryl moiety of said heteroaryl and heteroarylC.sub.1-.sub.3alkyl is a 5- or 6-membered aromatic ring which comprises 1, 2, 3 or 4 heteroatoms individually selected from N, O and S, heterocyclyl, heterocyclylC.sub.1-.sub.3alkyl or heterocyclyloxyC1-3 alkyl, wherein the heterocyclyl moiety of said heterocyclyl, heterocyclylC.sub.1-.sub.3alkyl and heterocyclyloxyC.sub.1-.sub.3alkyl is a 5- or 6-membered non-aromatic ring which comprises 1, 2 or 3 heteroatoms individually selected from N, O and S, and wherein any of cycloalkyl, phenyl, heteroaryl and heterocyclyl moieties are optionally substituted by 1, 2, 3 or 4 substituents, which may be the same or different, selected from R.sup.9.
8. The compound of Formula (TB) according to claim 1, wherein R.sup.8 is selected from C.sub.1-.sub.4alkyl, C.sub.3-.sub.6alkenyl, C.sub.3-.sub.6alkynyl, phenyl and phenylC.sub.1-.sub.3alkyl.
9. The compound of Formula (TB) according to claim 1, wherein R.sup.1 is selected from hydrogen, C.sub.1-.sub.4alkyl, C3-4alkenyl, C3-4alkynyl, C.sub.1-.sub.4haloalkyl, C.sub.3-.sub.4haloalkenyl, C.sub.1-.sub.4alkoxycarbonylC.sub.1-.sub.4alkyl, C.sub.1-.sub.4alkylaminocarbonylC.sub.1-.sub.4alkyl, phenyl, phenylC.sub.1-.sub.3alkyl, piperidinyl and piperidinylC.sub.1-.sub.3alkyl wherein any of said phenyl and piperidinyl moieties is optionally substituted by 1, 2 or 3 substituents, which may be the same or different, selected from R.sup.9; and R.sup.8 is selected from hydrogen, methyl, ethyl, prop-1-enyl, prop-1-ynyl, and benzyl.
10. The compound according to claim 1, wherein n is 0.
11. The compound of formula (IA) or formula (IB) according to claim 1, wherein: R.sup.8 represents C.sub.1-.sub.6alkyl, C.sub.3-.sub.6alkenyl, C.sub.3-.sub.6alkynyl, C.sub.1-.sub.4haloalkyl, cyanoC.sub.1-.sub.6alkyl, hydroxyC.sub.1-.sub.6alkyl, C.sub.1-.sub.4alkoxyC.sub.1-.sub.6alkyl, phenyl or phenylC.sub.1-.sub.3alkyl.
12. The compound of formula (IA) or formula (IB) according to claim 11, wherein n is 0.
13. The compound of formula (IA) or formula (IB) according to claim 1, wherein R.sup.7 and R.sup.8, together with the nitrogen atom and oxygen atom to which they are bonded, respectively, form (i) a 5- or 6-membered cycle optionally containing one additional heteroatom or group selected from O, S, N and NR.sup.10, wherein R.sup.10 is H or C.sub.1-.sub.4alkyl, or (ii) a 7- to 11-membered non-aromatic cyclic bridged ring system optionally containing one additional heteroatom or group selected from O, S, N or NR.sup.10, wherein R.sup.10 is H or C.sub.1-.sub.4alkyl.
14. The compound of formula (IA) according to claim 1.
15. The compound of formula (TB) according to claim 1.
16. The compound according to claim 1, wherein R.sup.5 and R.sup.6 are both hydrogen.
17. The compound according to claim 1, wherein R.sup.9 is independently selected from halogen, methoxy and C.sub.1-.sub.4alkoxycarbonyl.
18. An agrochemical composition comprising a fungicidally effective amount of a compound according to claim 1.
19. The agrochemical composition according to claim 18, further comprising at least one additional active ingredient and/or an agrochemically-acceptable diluent or carrier.
20. A method of controlling or preventing infestation of plants by phytopathogenic microorganisms, comprising: applying to the plants, to parts thereof or the locus thereof a fungicidally effective amount of a compound of Formula (IA) or a compound of Formula (IB), or a composition comprising the compound of Formula (IA) or the compound of Formula (IB) as an active ingredient; wherein the compound of formula (IA) is: ##STR00086## wherein A.sup.1 represents N or CR.sup.1 wherein R.sup.1 is hydrogen, halogen, methyl, ethyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy, or difluoromethoxy; A.sup.2 represents N or CR.sup.2, wherein R.sup.2 is hydrogen, halogen, methyl, ethyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy, or difluoromethoxy; R.sup.3 and R.sup.4 independently represent hydrogen or halogen; wherein when A.sup.1 is CR.sup.1 and A.sup.2 is CR.sup.2, 0 to 3 of R.sup.1 to R.sup.4 are hydrogen; n=0 or 1; R.sup.5 and R.sup.6 independently represent hydrogen or methyl; R.sup.7 represents hydrogen, C.sub.1-.sub.6alkyl, C.sub.3-.sub.6alkenyl, C.sub.3-.sub.6alkynyl, C.sub.1-.sub.4ha1oalkyl, C.sub.3-.sub.6haloalkenyl, cyanoC.sub.1-.sub.6alkyl, hydroxyC.sub.1-.sub.6alkyl, C.sub.1-.sub.4alkoxyC.sub.1-.sub.6alkyl, C.sub.1-.sub.4haloalkoxyC.sub.1-.sub.6alkyl, C.sub.1-.sub.4alkylcarbonylC.sub.1-.sub.4alkyl, C.sub.1-.sub.4alkoxycarbonylC.sub.1-.sub.4alkyl, C.sub.1-.sub.4alkylaminocarbonylC.sub.1-.sub.4alkyl, di-C.sub.1-.sub.4alkylaminocarbonylC.sub.1-.sub.4alkyl, C.sub.3-.sub.8cycloalkyl, C.sub.3-.sub.8cycloalkylC.sub.1-.sub.3alkyl, phenyl, phenylC.sub.1-.sub.3alkyl, heteroaryl, heteroarylC.sub.1-.sub.3alkyl, wherein the heteroaryl moiety of said heteroaryl and heteroarylC.sub.1-.sub.3alkyl is a 5- or 6-membered aromatic ring which comprises 1, 2, 3 or 4 heteroatoms individually selected from N, O and S, heterocyclyl, heterocyclylC.sub.1-.sub.3alkyl or heterocyclyloxyC.sub.1-3alkyl, wherein the heterocyclyl moiety of said heterocyclyl, heterocyclylC.sub.1-.sub.3alkyl and heterocyclyloxyC.sub.1-.sub.3alkyl is a 5- or 6-membered non-aromatic ring which comprises 1, 2 or 3 heteroatoms individually selected from N, O and S, and wherein any of cycloalkyl, phenyl, heteroaryl and heterocyclyl moieties are optionally substituted by 1, 2, 3 or 4 substituents, which may be the same or different, selected from R.sup.9; R.sup.8 represents hydrogen, C.sub.1-.sub.6alkyl, C.sub.3-.sub.6alkenyl, C.sub.3-.sub.6alkynyl, C.sub.1-.sub.4ha1oalkyl, cyanoC.sub.1-.sub.6alkyl, hydroxyC.sub.1-.sub.6alkyl, C.sub.1-.sub.4alkoxyC.sub.1-.sub.6alkyl, phenyl or phenylC.sub.1-.sub.3alkyl; R.sup.9 represents cyano, amino, halogen, hydroxy, methyl, ethyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy, difluoromethoxy, C.sub.1-.sub.4alkoxycarbonyl, C.sub.1-.sub.4alkylaminocarbonyl, di-C.sub.1-.sub.4alkylaminocarbonyl, or cyclopropyl; or R.sup.7 and R.sup.8, together with the nitrogen atom and oxygen atom to which they are bonded, respectively, form (i) a 5- or 6-membered cycle optionally containing one additional heteroatom or group selected from O, S, N and NR.sup.10, wherein R.sup.10 is H or C.sub.1-.sub.4alkyl, or (ii) a 7- to 11-membered non-aromatic cyclic bridged ring system optionally containing one additional heteroatom or group selected from O, S, N or NR.sup.10, wherein R.sup.10 is H or C.sub.1-.sub.4alkyl; or a salt or an N-oxide thereof; and wherein the compound of Formula (TB) is ##STR00087## wherein A.sup.1 is CR.sup.1, wherein R.sup.1 is hydrogen; A.sup.2 is CR.sup.2, wherein R.sup.2 is hydrogen; R.sup.3 and R.sup.4 both represent hydrogen; n=0 or 1; R.sup.5 and R.sup.6 independently represent hydrogen or methyl; R.sup.7 represents hydrogen, C.sub.1-.sub.6alkyl, C.sub.3-.sub.6alkenyl, C.sub.3-.sub.6alkynyl, C.sub.1-.sub.4ha1oalkyl, C.sub.3-.sub.6haloalkenyl, cyanoC.sub.1-.sub.6alkyl, hydroxyC.sub.1-.sub.6alkyl, C.sub.1-.sub.4alkoxyC.sub.1-.sub.6alkyl, C.sub.1-.sub.4haloalkoxyC.sub.1-.sub.6alkyl, C.sub.1-.sub.4alkylcarbonylC.sub.1-.sub.4alkyl, C.sub.1-.sub.4alkoxycarbonylC.sub.1-.sub.4alkyl, C.sub.1-.sub.4alkylaminocarbonylC.sub.1-.sub.4alkyl, di-C.sub.1-.sub.4alkylaminocarbonylC.sub.1-.sub.4alkyl, C.sub.3-.sub.8cycloalkyl, C.sub.3-.sub.8cycloalkylC.sub.1-.sub.3alkyl, phenyl, phenylC.sub.1-.sub.3alkyl, heteroaryl, heteroarylC.sub.1-.sub.3alkyl, wherein the heteroaryl moiety of said heteroaryl and heteroarylC.sub.1-.sub.3alkyl is a 5- or 6-membered aromatic ring which comprises 1, 2, 3 or 4 heteroatoms individually selected from N, O and S, heterocyclyl, heterocyclylC.sub.1-.sub.3alkyl or heterocyclyloxyC.sub.1-.sub.3alkyl, wherein the heterocyclyl moiety of said heterocyclyl, heterocyclylC.sub.1-.sub.3alkyl and heterocyclyloxyC.sub.1-.sub.3alkyl is a 4- to 6-membered non-aromatic ring which comprises 1, 2 or 3 heteroatoms individually selected from N, O and S, and wherein any of said cycloalkyl, phenyl, heteroaryl and heterocyclyl moieties are optionally substituted by 1, 2, 3 or 4 substituents, which may be the same or different, selected from R.sup.9; R.sup.8 represents hydrogen, C.sub.1-.sub.6alkyl, C.sub.3-.sub.6alkenyl, C.sub.3-.sub.6alkynyl, C.sub.1-.sub.4haloalkyl, cyanoC.sub.1-.sub.6alkyl, hydroxyC.sub.1-.sub.6alkyl, C.sub.1-.sub.4alkoxyC.sub.1-.sub.6alkyl, phenyl, or phenylC.sub.1-.sub.3alkyl; R.sup.9 represents cyano, amino, halogen, hydroxy, methyl, ethyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy, difluoromethoxy, C.sub.1-.sub.4alkoxycarbonyl, C.sub.1-.sub.4alkylaminocarbonyl, di-C.sub.1-.sub.4alkylaminocarbonyl, or cyclopropyl; or R.sup.7 and R.sup.8, together with the nitrogen atom and oxygen atom to which they are bonded, respectively, form (i) a 5- or 6-membered cycle optionally containing one additional heteroatom or group selected from O, S, N and NR.sup.10, wherein R.sup.10 is H or C.sub.1-.sub.4alkyl, or (ii) a 7- to 11-membered non-aromatic cyclic bridged ring system optionally containing one additional heteroatom or group selected from O, S, N or NR.sup.10, wherein R.sup.10 is H or C.sub.1-.sub.4alkyl; or a salt or an N-oxide thereof; with the proviso that the compound of Formula (IB) is not: N-methoxy-N-methyl-4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]benzamide; N-methoxy-4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]benzamide; N-benzyloxy-4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]benzamide; or N-methoxy-N-methyl-2-[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]acetamide.
Description
EXAMPLES
(1) The Examples which follow serve to illustrate the invention. The compounds of the invention can be distinguished from known compounds by virtue of greater efficacy at low application rates, which can be verified by the person skilled in the art using the experimental procedures outlined in the Examples, using lower application rates if necessary, for example 50 ppm, 12.5 ppm, 6 ppm, 3 ppm, 1.5 ppm, 0.8 ppm or 0.2 ppm.
(2) Compounds of Formula (I) may possess any number of benefits including, inter alia, advantageous levels of biological activity for protecting plants against diseases that are caused by fungi or superior properties for use as agrochemical active ingredients (for example, greater biological activity, an advantageous spectrum of activity, an increased safety profile (including improved crop tolerance), improved physico-chemical properties, or increased biodegradability).
(3) Throughout this description, LC/MS means Liquid Chromatography Mass Spectrometry and the description of the apparatus and the method (Methods A, B and C) is as follows:
(4) The Description of the LC/MS Apparatus and the Method A is:
(5) SQ Detector 2 from Waters
(6) Ionisation method: Electrospray
(7) Polarity: positive and negative ions
(8) Capillary (kV) 3.0, Cone (V) 30.00, Extractor (V) 2.00, Source Temperature (° C.) 150, Desolvation Temperature (° C.) 350, Cone Gas Flow (L/Hr) 0, Desolvation Gas Flow (L/Hr) 650
(9) Mass range: 100 to 900 Da
(10) DAD Wavelength range (nm): 210 to 500
(11) Method Waters ACQUITY UPLC with the Following HPLC Gradient Conditions:
(12) TABLE-US-00003 (Solvent A: Water/Methanol 20:1 + 0.05% formic acid and Solvent B: Acetonitrile + 0.05% formic acid) Time (minutes) A (%) B (%) Flow rate (ml/min) 0 100 0 0.85 1.2 0 100 0.85 1.5 0 100 0.85
Type of column: Waters ACQUITY UPLC HSS T3; Column length: 30 mm; Internal diameter of column: 2.1 mm; Particle Size: 1.8 micron; Temperature: 60° C.
The Description of the LC/MS Apparatus and the Method B is:
SQ Detector 2 from Waters
Ionisation method: Electrospray
Polarity: positive ions
Capillary (kV) 3.5, Cone (V) 30.00, Extractor (V) 3.00, Source Temperature (° C.) 150, Desolvation Temperature (° C.) 400, Cone Gas Flow (L/Hr) 60, Desolvation Gas Flow (L/Hr) 700
Mass range: 140 to 800 Da
DAD Wavelength range (nm): 210 to 400
Method Waters ACQUITY UPLC with the Following HPLC Gradient Conditions
(13) TABLE-US-00004 (Solvent A: Water/Methanol 9:1 + 0.1% formic acid and Solvent B: Acetonitrile + 0.1% formic acid) Time (minutes) A (%) B (%) Flow rate (ml/min) 0 100 0 0.75 2.5 0 100 0.75 2.8 0 100 0.75 3.0 100 0 0.75
Type of column: Waters ACQUITY UPLC HSS T3; Column length: 30 mm; Internal diameter of column: 2.1 mm; Particle Size: 1.8 micron; Temperature: 60° C.
The Description of the LC/MS Apparatus and the Method C is:
SQ Detector 2 from Waters
Ionisation method: Electrospray
ACQUITY H Class UPLC, Mass Spectrometer from Waters
Polarity: positive and Negative Polarity Switch
Scan Type MS1 Scan
Capillary (kV) 3.00, Cone (V) 40.00, Desolvation Temperature (° C.) 500, Cone Gas Flow (L/Hr) 50,
Desolvation Gas Flow (L/Hr) 1000
Mass range: 0 to 2000 Da
DAD Wavelength range (nm): 200 to 350
Method Waters ACQUITY UPLC with the Following HPLC Gradient Conditions
(14) TABLE-US-00005 (Solvent A: Water + 0.1% formic acid and Solvent B: Acetonitrile) Time (minutes) A (%) B (%) Flow rate (ml/min) 0 70 30 0.5 0.05 70 30 0.5 0.8 5 95 0.5 1.8 5 95 0.5 2.45 70 30 0.5 2.50 70 30 0.5
Type of column: Waters ACQUITY UPLC BEH C18; Column length: 50 mm; Internal diameter of column: 2.1 mm; Particle Size: 1.7 micron; Temperature: 35° C.
(15) Where necessary, enantiomerically pure final compounds may be obtained from racemic materials as appropriate via standard physical separation techniques, such as reverse phase chiral chromatography, or through stereoselective synthetic techniques, e.g., by using chiral starting materials.
FORMULATION EXAMPLES
(16) Wettable Powders
(17) TABLE-US-00006 a) b) c) active ingredient [compound of 25% 50% 75% Formula (IA) or (IB)] sodium lignosulfonate 5% 5% — sodium lauryl sulfate 3% — 5% sodium diisobutylnaphthalenesulfonate — 6% 10% phenol polyethylene glycol ether — 2% — (7-8 mol of ethylene oxide) highly dispersed silicic acid 5% 10% 10% Kaolin 62% 27% —
(18) The active ingredient is thoroughly mixed with the adjuvants and the mixture is thoroughly ground in a suitable mill, affording wettable powders that can be diluted with water to give suspensions of the desired concentration.
(19) Powders for Dry Seed Treatment
(20) TABLE-US-00007 a) b) c) active ingredient [compound of 25% 50% 75% Formula (IA) or (IB)] light mineral oil 5% 5% 5% highly dispersed silicic acid 5% 5% — Kaolin 65% 40% — Talcum — 20%
(21) The active ingredient is thoroughly mixed with the adjuvants and the mixture is thoroughly ground in a suitable mill, affording powders that can be used directly for seed treatment.
(22) Emulsifiable Concentrate
(23) TABLE-US-00008 active ingredient [compound of Formula (IA) or (IB)] 10% octylphenol polyethylene glycol ether 3% (4-5 mol of ethylene oxide) calcium dodecylbenzenesulfonate 3% castor oil polyglycol ether (35 mol of ethylene oxide) 4% Cyclohexanone 30%
(24) Emulsions of any required dilution, which can be used in plant protection, can be obtained from this concentrate by dilution with water.
(25) Dusts
(26) TABLE-US-00009 a) b) c) Active ingredient [compound of 5% 6% 4% Formula (IA) or (IB)] Talcum 95% — — Kaolin — 94% — mineral filler — — 96%
(27) Ready-for-use dusts are obtained by mixing the active ingredient with the carrier and grinding the mixture in a suitable mill. Such powders can also be used for dry dressings for seed.
(28) Extruder Granules
(29) TABLE-US-00010 Active ingredient [compound of 15% Formula (IA) or (IB)] sodium lignosulfonate 2% Carboxymethylcellulose 1% Kaolin 82%
(30) The active ingredient is mixed and ground with the adjuvants, and the mixture is moistened with water. The mixture is extruded and then dried in a stream of air.
(31) Coated Granules
(32) TABLE-US-00011 Active ingredient [compound of 8% Formula (IA) or (IB)] polyethylene glycol (mol. wt. 200) 3% Kaolin 89%
(33) The finely ground active ingredient is uniformly applied, in a mixer, to the kaolin moistened with polyethylene glycol. Non-dusty coated granules are obtained in this manner.
(34) Suspension Concentrate
(35) TABLE-US-00012 active ingredient [compound of Formula (IA) or (IB)] 40% propylene glycol 10% nonylphenol polyethylene glycol ether (15 mol of ethylene oxide) 6% Sodium lignosulfonate 10% Carboxymethylcellulose 1% silicone oil (in the form of a 75% emulsion in water) 1% Water 32%
(36) The finely ground active ingredient is intimately mixed with the adjuvants, giving a suspension concentrate from which suspensions of any desired dilution can be obtained by dilution with water. Using such dilutions, living plants as well as plant propagation material can be treated and protected against infestation by microorganisms, by spraying, pouring or immersion.
(37) Flowable Concentrate for Seed Treatment
(38) TABLE-US-00013 active ingredient [compound of Formula (IA) or (IB)] 40% propylene glycol 5% copolymer butanol PO/EO 2% tristyrenephenole with 10-20 moles EO 2% 1,2-benzisothiazolin-3-one (in the form of a 20% solution 0.5%.sup. in water) monoazo-pigment calcium salt 5% Silicone oil (in the form of a 75% emulsion in water) 0.2%.sup. Water 45.3%
(39) The finely ground active ingredient is intimately mixed with the adjuvants, giving a flowable concentrate from which suspensions of any desired dilution can be obtained by dilution with water. Using such dilutions, living plants as well as plant propagation material can be treated and protected against infestation by microorganisms, by spraying, pouring or immersion.
(40) Slow-Release Capsule Suspension
(41) 28 parts of a combination of the compound of Formula (IA) or (IB) are mixed with 2 parts of an aromatic solvent and 7 parts of toluene diisocyanate/polymethylene-polyphenylisocyanate-mixture (8:1). This mixture is emulsified in a mixture of 1.2 parts of polyvinylalcohol, 0.05 parts of a defoamer and 51.6 parts of water until the desired particle size is achieved. To this emulsion a mixture of 2.8 parts 1,6-diaminohexane in 5.3 parts of water is added. The mixture is agitated until the polymerization reaction is completed.
(42) The obtained capsule suspension is stabilized by adding 0.25 parts of a thickener and 3 parts of a dispersing agent. The capsule suspension formulation contains 28% of the active ingredients. The medium capsule diameter is 8-15 microns.
(43) The resulting formulation is applied to seeds as an aqueous suspension in an apparatus suitable for that purpose.
List of Abbreviations
(44) ° C.=degrees Celsius CDCl.sub.3=chloroform-d DMSO=dimethyl sulfoxide d=doublet EtOAc=ethyl acetate HCl=hydrochloric acid m=multiplet MHz=mega hertz mp=melting point NBS=N-bromosuccinimide ppm=parts per million s=singlet t=triplet TFAA=trifluoroacetic acid anhydride THF=tetrahydrofuran LC/MS=Liquid Chromatography Mass Spectrometry (description of the apparatus and the methods used for LC/MS analysis are given above)
PREPARATION EXAMPLES
Example 1: This Example Illustrates the Preparation 2-fluoro-N-methoxy-4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]benzamide (Compound 1.1 of Table T1)
(45) ##STR00017##
Step 1: Preparation of 2-fluoro-4-(N-hydroxycarbamimidoyl)-benzoic Acid
(46) ##STR00018##
(47) A solution of hydroxyamine hydrochloride (3.0 g) in water (20 mL) was added at room temperature to a stirred solution of 4-cyano-2-fluorobenzoic acid (3.52 g, 21.3 mmol) in ethanol (35 mL), followed by dropwise addition of potassium carbonate (1.60 g). Then 8-hydroxyquinoline (0.041 g, 0.28 mmol) was added. The resulting thick suspension was heated to reflux for 3 hours to obtain a yellow solution. After removal of ethanol, under reduced pressure, the residue was acidified with 2N HCl to pH 3. The white precipitate was filtered, washed with water and dried under reduced pressure at 50° C. to yield 2-fluoro-4-(N-hydroxycarbamimidoyl)-benzoic acid as beige solid. mp: >250° C.
(48) .sup.1H NMR (400 MHz, DMSO-d6) δ ppm: 13.22 (s, 1H), 10.00 (s, 1H), 7.85 (t, 1H), 7.63 (m, 1H), 7.54-7.61 (m, 1H).
Step 2: Preparation of 2-fluoro-4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic Acid
(49) ##STR00019##
(50) Trifluoroacetic anhydride (4.1 mL) was added dropwise to a stirred suspension of 2-fluoro-4-(N-hydroxycarbamimidoyl)-benzoic acid (3.80 g, 19.0 mmol) in THF (77 mL) at 10 to 15° C. The beige suspension was warmed to room temperature and stirred overnight. After evaporation, the crude product was stirred with heptane/ethylacetate (95:5), filtered and dried under reduced pressure at 50° C. to yield 2-fluoro-4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as yellow solid. mp: 175-177° C.
(51) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm: 13.55 (s, 1H), 8.12 (t, 1H), 8.00 (d, 1H), 7.94 (d, 1H).
Step 3: Preparation of 2-fluoro-4-(5-(trifluoromethyl)-[1,2,4]oxadiazol-3-yl)-benzoyl Chloride
(52) ##STR00020##
(53) To a white suspension of 2-fluoro-4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid (3.6 g, 13.0 mmol) and CH.sub.2Cl.sub.2 (130 mL) at room temperature was added thionyl chloride (1.51 mL) dropwise. The resulting suspension was heated to reflux and stirred for 3 hours, to obtain a yellow solution. The solvent was evaporated under reduced pressure at 30° C. to yield 2-fluoro-4-(5-(trifluoromethyl)-[1,2,4]oxadiazol-3-yl)-benzoyl chloride as yellowish solid that was used directly without purification.
(54) .sup.1H NMR (400 MHz, CDCl.sub.3) δ ppm: 8.26 (t, 1H), 8.07 (m, 1H), 7.99 (m, 1H).
Step 4: Preparation of 2-fluoro-N-(2-oxooxazolidin-3-yl)-4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]benzamide
(55) To a screw-cap vial containing 2-fluoro-4-(5-(trifluoromethyl)-[1,2,4]oxadiazol-3-yl)-benzoyl chloride (0.13 g, 0.44 mmol) suspended in CH.sub.2Cl.sub.2 (10 mL) cooled to 0° C. was added methoxyamine hydrochloride (37 mg, 0.44 mmol) dissolved in CH.sub.2Cl.sub.2 (1 mL) then triethylamine (0.14 mL) was introduced dropwise. After stirring for 4 hours, the volatile reaction components were removed under reduced pressure and the crude residue was purified by flash chromatography over silica gel (heptane/ethyl acetate gradient) to give the title compound as a white solid (mp: 122-125° C.). LC/MS retention time=0.88 minutes, 306 (M+H).
(56) .sup.1H NMR (400 MHz, CDCl.sub.3): δ 9.27 (d, 1H), 8.29 (m, 1H), 8.07 (dd, 1H), 7.96 (dd, 1H), 3.94 (s, 3H).
Example 2: this Example Illustrates the Preparation of N-(cyclopropylmethyl)-2-fluoro-N-methoxy-4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]benzamide (Compound 1.8 of Table T1)
(57) ##STR00021##
(58) To a screw-cap vial containing 2-fluoro-N-(2-oxooxazolidin-3-yl)-4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]benzamide (0.07 g, 0.24 mmol) dissolved in acetone (10 mL) was added potassium carbonate (0.08 g, 0.58 mmol) and bromomethyl cyclopropane (0.03 mL, 0.26 mmol). After stirring overnight, bromomethyl cyclopropane (0.03 mL, 0.26 mmol) was re-introduced and the reaction was stirred for 24 hours. Upon completion, volatiles were removed under reduced pressure and the crude contents were poured into a separating funnel containing EtOAc and water. The organic layer was separated, washed with brine and dried over Na.sub.2SO.sub.4. The solvent was removed under reduced pressure and the crude residue was purified by flash chromatography over silica gel (heptane/ethyl acetate gradient) to give the title compound as a yellow oil (35 mg, 41% yield). LC/MS retention time=1.10 minutes, 360 (M+H).
(59) .sup.1H NMR (400 MHz, CDCl.sub.3): δ 7.96 (d, 1H), 7.89 (d, 1H), 7.71 (t, 1H), 3.95 (s, 3H), 1.23 (m, 3H), 0.61 (m, 2H), 0.26 (m, 2H).
Example 3: Preparation of N-allyloxy-2-[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]acetamide (Compound 2.14 of Table 2)
(60) ##STR00022##
Step 1: Preparation of N′-hydroxy-4-methyl-benzamidine
(61) ##STR00023##
(62) To a stirring suspension of 4-methylbenzonitrile (35 g, 0.29 mol) in ethanol (220 mL) and water (440 mL) was added at room temperature hydroxylamine hydrochloride (41.1 g, 0.58 mol), potassium carbonate (65.4 g, 0.47 mol) and 8-hydroxyquinoline (0.22 g, 1.5 mmol). The reaction mixture was heated at 80° C. for 4 hours. The mixture was cooled to room temperature and diluted with 2N HCl until pH 8. Ethanol was evaporated under reduced pressure then the mixture was filtered, washed with water, and dried under vacuum to afford 39.1 g of N′-hydroxy-4-methyl-benzamidine which was used without further purification. LC/MS (Method A) retention time=0.23 minutes, 151.0 (M+H).
Step 2: Preparation of 3-(p-tolyl)-5-(trifluoromethyl)-1,2,4-oxadiazole
(63) ##STR00024##
(64) To a stirring solution of N′-hydroxy-4-methyl-benzamidine (38.7 g, 0.25 mol) in 2-methyltetrahydrofuran (750 mL) was added TFAA at 0° C. The reaction mixture was stirred at 15° C. for two hours then diluted with water. The organic layer was separated, washed successively with an aqueous sodium bicarbonate solution, aqueous ammonium chloride solution, and water. The organic phase was then dried over sodium sulfate, filtered and evaporated to dryness. The crude material was subjected to flash chromatography over silica gel (eluent heptane/EtOAc 99:1 to 90:10) to afford 54.1 g of 3-(p-tolyl)-5-(trifluoromethyl)-1,2,4-oxadiazole as clear oil, which solidified after storage. LC/MS (Method A) retention time=1.15 minutes, mass not detected.
(65) .sup.1H NMR (400 MHz, CDCl.sub.3) δ ppm: 8.00 (d, 2H), 7.32 (d, 2H), 2.45 (s, 3H).
(66) .sup.19F NMR (400 MHz, CDCl.sub.3) δ ppm: −65.41 (s).
Step 3a: Preparation of 3-[4-(bromomethyl)phenyl]-5-(trifluoromethyl)-1,2,4-oxadiazole
(67) ##STR00025##
(68) A stirring mixture of 3-(p-tolyl)-5-(trifluoromethyl)-1,2,4-oxadiazole (56.0 g, 0.24 mol) and NBS (45.4 g, 0.25 mol) in tetrachloromethane (480 mL) under argon was heated to 70° C. AIBN (4.03 g, 24 mmol) was added and the reaction mixture was stirred at 65° C. for 18 hours. The mixture was cooled to 25° C. and diluted with dichloromethane and water. The organic layer was washed with sodium bicarbonate solution, dried over sodium sulfate, filtered and evaporated to dryness. The crude material was subjected to flash chromatography over silica gel (eluent cyclohexane/EtOAc 100:0 to 95:5) to afford 44.7 g of 3-[4-(bromomethyl)phenyl]-5-(trifluoromethyl)-1,2,4-oxadiazole as a white solid mp: 58-63° C.
(69) .sup.1H NMR (400 MHz, CDCl.sub.3) δ ppm: 8.11 (d, 2H), 7.55 (d, 2H), 4.53 (s, 2H).
(70) .sup.19F NMR (400 MHz, CDCl.sub.3) δ ppm: −65.32 (s).
(71) 3-[4-(dibromomethyl)phenyl]-5-(trifluoromethyl)-1,2,4-oxadiazole (see below) was isolated as by-product as white solid (mp 61-66° C.).
(72) ##STR00026##
(73) .sup.1H NMR (400 MHz, CDCl.sub.3) δ ppm: 8.15 (d, 2H), 7.73 (d, 2H), 6.68 (s, 1H).
(74) .sup.19F NMR (400 MHz, CDCl.sub.3) δ ppm: −65.34 (s).
Step 3b: Preparation of 3-[4-(bromomethyl)phenyl]-5-(trifluoromethyl)-1,2,4-oxadiazole
(75) ##STR00027##
(76) To a stirring 1:9 ratio mixture of 3-[4-(bromomethyl)phenyl]-5-(trifluoromethyl)-1,2,4-oxadiazole and 3-[4-(dibromomethyl)phenyl]-5-(trifluoromethyl)-1,2,4-oxadiazole (10.2 g) in acetonitrile (95 mL), water (1.9 mL) and DIPEA (6.20 mL, 35.7 mmol), was added diethylphosphite (4.7 mL, 35.7 mmol) at 5° C. The mixture was stirred at 5-10° C. for two hours, water and 1M HCl were added, and acetonitrile was evaporated under reduced pressure. The white slurry was extracted with dichloromethane and the combined organic layers were dried over sodium sulfate, and filtered. The solvent was removed under reduced pressure and the resultant crude material was subjected to flash chromatography over silica gel (eluent cyclohexane/EtOAc 99:1 to 9:1) to afford 7.10 g of 3-[4-(bromomethyl)phenyl]-5-(trifluoromethyl)-1,2,4-oxadiazole.
(77) .sup.1H NMR (400 MHz, CDCl.sub.3) δ ppm: 8.11 (d, 2H), 7.55 (d, 2H), 4.53 (s, 2H).
(78) .sup.19F NMR (400 MHz, CDCl.sub.3) δ ppm: −65.32 (s).
Step 4: Preparation of 2-[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]acetonitrile
(79) ##STR00028##
(80) To a solution of 3-[4-(bromomethyl)phenyl]-5-(trifluoromethyl)-1,2,4-oxadiazole (10.0 g, 32.6 mmol) and trimethylsilylformonitrile (4.2 g, 43.9 mmol) in acetonitrile (400 mL) at 0° C. was added a 1M THF solution of tetrabutylammonium hydrofluoride (42.3 mL, 42.3 mmol). The reaction was stirred for 3 hours while reaching room temperature then the reaction contents were diluted with water and extracted with ethyl acetate. The combined organic layer organic was washed with water, brine, dried over Na.sub.2SO.sub.4, and concentrated under reduced pressure. The resultant crude material was subjected to flash chromatography over silica gel (eluent cyclohexane/EtOAc 8:2) to afford 2-[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]acetonitrile (7.0 g, 82% yield).
(81) .sup.1H NMR (400 MHz, CDCl.sub.3) δ ppm: 8.15 (m, 2H), 7.55 (m, 2H), 3.88 (m, 2H).
Step 5: Preparation of methyl 2-[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]acetate
(82) ##STR00029##
(83) To a solution of 2-[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]acetonitrile (7.0 g, 27.6 mmol) in methanol (70 mL) was added chloro(trimethyl)silane (18.0 g, 165.9 mmol) at room temperature then the reaction was heated at 65° C. for 12 hours. After the contents were cooled to room temperature methanol was removed under reduced pressure and the resultant residue was diluted with water and extracted with ethyl acetate. The organic layer organic was washed with a saturated aqueous NaHCO.sub.3 solution, brine, dried over Na.sub.2SO.sub.4, and concentrated under reduced pressure. The resultant crude material was subjected to flash chromatography over silica gel (eluent cyclohexane/EtOAc 99:1 to 9:1) to afford methyl 2-[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]acetate (6.5 g, 23 mmol, 71% yield).
(84) .sup.1H NMR (400 MHz, CDCl.sub.3) δ ppm: 8.11 (d, 2H), 7.48 (d, 2H), 3.75 (s, 2H), 3.74 (s, 3H).
Step 6: Preparation of 2-[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]acetic Acid
(85) ##STR00030##
(86) To a solution of methyl 2-[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]acetate (2.90 g, 10.1 mmol) in methanol (116 mL) was added dihydroxybarium octahydrate (6.39 g, 20.3 mmol) at 0° C. and the reaction was stirred for 1 hour while reaching room temperature. The reaction contents were then diluted with water and washed with ethyl acetate. The aqueous layer was acidified to pH 2 using a 1M HCl aqueous solution and extracted with ethyl acetate. The combined organic layer organic was washed with water, brine, dried over Na.sub.2SO.sub.4, and concentrated under reduced pressure. The resultant crude material was subjected to flash chromatography over silica gel (eluent cyclohexane/EtOAc 8:2) to afford 2-[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]acetic acid (2.6 g, 94% yield).
(87) .sup.1H NMR (400 MHz, CDCl.sub.3) δ ppm: 12.49 (brs, 1H), 8.02 (d, 2H), 7.53 (d, 2H), 3.72 (s, 2H).
Step 7: Preparation of N-allyloxy-2-[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]acetamide
(88) A 10 mL vial was charged with O-allylhydroxylamine hydrochloride (0.091 g, 0.83 mmol), N,N-dimethylformamide (2.5 mL) and DIPEA (0.214 g, 1.65 mmol) then stirred at for 30 minutes. 2-[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]acetic acid (0.15 g, 0.55 mmol) was added followed by HATU (0.314 g, 0.83 mmol) and the reaction was stirred 1 h. The reaction solution was diluted with water 5 and ethyl acetate then extracted with ethyl acetate. The combined organic layer was washed with water, dried over Na.sub.2SO.sub.4, and concentrated under reduced pressure. The resultant crude material was subjected to flash chromatography over silica gel (eluent cyclohexane/EtOAc 99:1 to 9:1) to afford N-allyloxy-2-[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]acetamide (0.11 g, 59% yield) as a white solid. mp 153-158° C.; LC/MS retention time=0.95 minutes, 328.2 (M+H).
(89) .sup.1H NMR (400 MHz, CDCl.sub.3) δ ppm: 8.10 (d, 2H), 7.95 (brs, 1H), 7.46 (d, 2H), 5.93 (m, 1H), 5.32 (m, 2H), 4.38 (m, 2H), 3.80 (m, 1H), 3.57 (m, 1H).
(90) .sup.19F NMR (400 MHz, CDCl.sub.3) δ ppm: −65.66 (s).
(91) TABLE-US-00014 TABLE T1 Melting point (mp) data and/or retention times (RT) for compounds according to Formula (IA): Compound RT [M + H] mp Entry Name Structure (min) (measured) Method (° C.) 1.1 2-fluoro-N- methoxy-4-[5- (trifluoromethyl)- 1,2,4-oxadiazol-3- yl]benzamide
(92) TABLE-US-00015 TABLE T2 Melting point (mp) data and/or retention times (RT) for compounds according to Formula (IB): Compound RT [M + H] mp Entry Name Structure (min) (measured) Method (° C.) 2.1 methyl 4-[hydroxy- [4-[5- (trifluoromethyl)- 1,2,4-oxadiazol-3- yl]benzoyl]amino]-1- methoxy-piperidine- 4-carboxylate
BIOLOGICAL EXAMPLES
General Examples of Leaf Disk Tests in Well Plates
(93) Leaf disks or leaf segments of various plant species are cut from plants grown in a greenhouse. The cut leaf disks or segments are placed in multiwell plates (24-well format) onto water agar. The leaf disks are sprayed with a test solution before (preventative) or after (curative) inoculation. Compounds to be tested are prepared as DMSO solutions (max. 10 mg/ml) which are diluted to the appropriate concentration with 0.025% Tween20 just before spraying. The inoculated leaf disks or segments are incubated under defined conditions (temperature, relative humidity, light, etc.) according to the respective test system. A single evaluation of disease level is carried out 3 to 14 days after inoculation, depending on the pathosystem. Percent disease control relative to the untreated check leaf disks or segments is then calculated.
General Examples of Liquid Culture Tests in Well Plates
(94) Mycelia fragments or conidia suspensions of a fungus prepared either freshly from liquid cultures of the fungus or from cryogenic storage, are directly mixed into nutrient broth. DMSO solutions of the test compound (max. 10 mg/ml) are diluted with 0.025% Tween20 by a factor of 50 and 10 μl of this solution is pipetted into a microtiter plate (96-well format). The nutrient broth containing the fungal spores/mycelia fragments is then added to give an end concentration of the tested compound. The test plates are incubated in the dark at 24° C. and 96% relative humidity. The inhibition of fungal growth is determined photometrically after 2 to 7 days, depending on the pathosystem, and percent antifungal activity relative to the untreated check is calculated.
Example 1: Fungicidal Activity Against Puccinia recondita f. Sp. tritici/Wheat/Leaf Disc Preventative (Brown Rust)
(95) Wheat leaf segments cv. Kanzler are placed on agar in multiwell plates (24-well format) and sprayed with the formulated test compound diluted in water. The leaf disks are inoculated with a spore suspension of the fungus 1 day after application. The inoculated leaf segments are incubated at 19° C. and 75% rh under a light regime of 12 h light/12 h darkness in a climate cabinet and the activity of a compound is assessed as percent disease control compared to untreated when an appropriate level of disease damage appears in untreated check leaf segments (7-9 days after application).
(96) The following compounds gave at least 80% control of Puccinia recondita f. sp. tritici at 200 ppm when compared to untreated control under the same conditions, which showed extensive disease development:
(97) Compounds (from Table T1) 1.1, 1.2, 1.5, 1.6, 1.7, 1.8, 1.10, 1.11, 1.13, 1.14, 1.15, 1.16, 1.17, 1.18, 1.19, 1.20, 1.21, 1.22, 1.23, 1.24, 1.26, and 1.27.
(98) Compounds (from Table T2) 2.1, 2.2, 2.4, 2.5, 2.6, 2.7, 2.8, 2.10, 2.11, 2.12, 2.13, 2.14, 2.15, 2.16, 2.17, 2.18, 2.19, 2.23, and 2.26.
Example 2: Fungicidal Activity Against Puccinia recondita f. Sp. tritici/Wheat/Leaf Disc Curative (Brown Rust)
(99) Wheat leaf segments cv. Kanzler are placed on agar in multiwell plates (24-well format). The leaf segments are inoculated with a spore suspension of the fungus. Plates are stored in darkness at 19° C. and 75% rh. The formulated test compound diluted in water is applied 1 day after inoculation. The leaf segments are incubated at 19° C. and 75% rh under a light regime of 12 h light/12 h darkness in a climate cabinet and the activity of a compound is assessed as percent disease control compared to untreated when an appropriate level of disease damage appears in untreated check leaf segments (6-8 days after application).
(100) The following compounds gave at least 80% control of Puccinia recondita f. sp. tritici at 200 ppm when compared to untreated control under the same conditions, which showed extensive disease development:
(101) Compounds (from Table T1) 1.1, 1.2, 1.5, 1.6, 1.7, 1.8, 1.10, 1.11, 1.12, 1.14, 1.15, 1.16, 1.17, 1.18, 1.19, 1.20, 1.21, 1.22, 1.23, 1.25, 1.26, and 1.27.
(102) Compounds (from Table T2) 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 2.10, 2.11, 2.12, 2.13, 2.16, 2.17, 2.18, 2.19, 2.22, 2.23, 2.24, and 2.26.
Example 3: Fungicidal Activity Against Phakopsora pachyrhizi/Soybean/Leaf Disc Preventative (Asian Soybean Rust)
(103) Soybean leaf disks are placed on water agar in multiwell plates (24-well format) and sprayed with the formulated test compound diluted in water. One day after application leaf discs are inoculated by spraying a spore suspension on the lower leaf surface. After an incubation period in a climate cabinet of 24-36 hours in darkness at 20° C. and 75% rh leaf disc are kept at 20° C. with 12 h light/12 h darkness and 75% rh. The activity of a compound is assessed as percent disease control compared to untreated when an appropriate level of disease damage appears in untreated check leaf disks (12-14 days after application).
(104) The following compounds gave at least 80% control of Phakopsora pachyrhizi at 200 ppm when compared to untreated control under the same conditions, which showed extensive disease development:
(105) Compounds (from Table T1) 1.1, 1.2, 1.5, 1.6, 1.7, 1.8, 1.10, 1.11, 1.16, 1.17, 1.18, 1.19, 1.22, and 1.27.
(106) Compounds (from Table T2) 2.1, 2.2, 2.4, 2.5, 2.6, 2.7, 2.8, 2.10, 2.11, 2.12, 2.13, 2.16, 2.17, 2.22, 2.23, and 2.24.
Example 4: Fungicidal Activity Against Glomerella lagenarium (Colletotrichum lagenarium) Liquid Culture/Cucumber/Preventative (Anthracnose)
(107) Conidia of the fungus from cryogenic storage are directly mixed into nutrient broth (PDB potato dextrose broth). After placing a (DMSO) solution of test compound into a microtiter plate (96-well format), the nutrient broth containing the fungal spores is added. The test plates are incubated at 24° C. and the inhibition of growth is measured photometrically 3-4 days after application.
(108) The following compounds gave at least 80% control of Glomerella lagenarium at 20 ppm when compared to untreated control under the same conditions, which showed extensive disease development:
(109) Compounds (from Table T1) 1.1, 1.5, 1.6, 1.7, 1.8, 1.9, 1.10, 1.11, 1.12, 1.13, 1.14, 1.15, 1.16, 1.17, 1.18, 1.19, 1.20, 1.21, 1.22, 1.23, 1.24, 1.25, 1.26, and 1.27.
(110) Compounds (from Table T2) 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 2.10, 2.11, 2.12, 2.13, 2.14, 2.15, 2.16, 2.17, 2.18, 2.19, 2.20, 2.21, 2.22, 2.23, 2.24, 2.25, and 2.26.
Example 5: Fungicidal Activity Against Uromyces viciae-Fabae/Field Bean/Leaf Disc Preventative (Faba-Bean Rust)
(111) Field bean leaf discs are placed on water agar in multiwell plates (96-well format) and 10 μl of the formulated test compound diluted in acetone and a spreader pipetted onto the leaf disc. Two hours after application leaf discs are inoculated by spraying a spore suspension on the lower leaf surface. The leaf discs are incubated in a climate cabinet at 22° C. with 18 hour day and 70% relative humidity. The activity of a compound is assessed as percent disease control compared to untreated when an appropriate level of disease damage appears in untreated check leaf disks (12 days after application).
(112) The following compounds at 100 ppm in the applied formulation give at least 80% disease control in this test when compared to untreated control leaf discs under the same conditions, which show extensive disease development.
(113) Compounds (from Table T1) 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 1.10, 1.11, 1.12, 1.26, and 1.27.
(114) Compounds (from Table T2) 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 2.10, 2.11, 2.12, 2.23, and 2.24.