Method for preparing 5-haloalkyl-4, 5-dihydroisoxazole derivatives

1. A method for preparing a compound of Formula 1

wherein

R 1 is CHX 2 , CX 3 , CX 2 CHX 2 or CX 2 CX 3 ;

each X is independently Cl or F;

Z is optionally substituted phenyl;

Q is Q a or Q b ;

Q a is phenyl substituted with one Q 1 and optionally substituted with one to four substituents independently selected from R 3 ;

Q 1 is a phenyl ring or a 5- or 6-membered saturated or unsaturated heterocyclic ring, each ring optionally substituted with one or more substituents independently selected from halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 6 cycloalkyl, C 3 -C 6 halocycloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 1 -C 6 alkylthio, C 1 -C 6 haloalkylthio, C 1 -C 6 alkylsulfinyl, C 1 -C 6 haloalkylsulfinyl, C 1 -C 6 alkylsulfonyl, C 1 -C 6 haloalkylsulfonyl, —CN, —NO 2 , —N(R 4 )R 5 , —C(═W)N(R 4 )R 5 , —C(═O)OR 5 and R 7 ;

Q b is optionally substituted 1-naphthalenyl;

each R 3 is independently halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 haloalkenyl, C 2 -C 6 alkynyl, C 3 -C 6 haloalkynyl, C 3 -C 6 cycloalkyl, C 3 -C 6 halocycloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 1 -C 6 alkylthio, C 2 -C 7 alkylcarbonyl, C 2 -C 7 haloalkylcarbonyl, C 1 -C 6 haloalkylthio, C 1 -C 6 alkylsulfinyl, C 1 -C 6 haloalkylsulfinyl, C 1 -C 6 alkylsulfonyl, C 1 -C 6 haloalkylsulfonyl, —N(R 4 )R 5 , —C(═W)N(R 4 )R 5 , —C(═W)OR 5 , —CN, —OR 11 or —NO 2 ; or a phenyl ring or a 5- or 6-membered saturated or unsaturated heterocyclic ring, each ring optionally substituted with one or more substituents independently selected from halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 6 cycloalkyl, C 3 -C 6 halocycloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 1 -C 6 alkylthio, C 1 -C 6 haloalkylthio, C 1 -C 6 alkylsulfinyl, C 1 -C 6 haloalkylsulfinyl, C 1 -C 6 alkylsulfonyl, C 1 -C 6 haloalkylsulfonyl, —CN, —NO 2 , —N(R 4 )R 5 , —C(═W)N(R 4 )R 5 , —C(═O)OR 5 and R 7 ;

each R 4 is independently H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 4 -C 7 alkylcycloalkyl, C 4 -C 7 cycloalkylalkyl, C 2 -C 7 alkylcarbonyl or C 2 -C 7 alkoxycarbonyl;

each R 5 is independently H; or C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 4 -C 7 alkylcycloalkyl or C 4 -C 7 cycloalkylalkyl, each optionally substituted with one or more substituents independently selected from R 6 ;

each R 6 is independently halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylthio, C 1 -C 6 alkylsulfinyl, C 1 -C 6 alkylsulfonyl, C 1 -C 6 alkylamino, C 2 -C 8 dialkylamino, C 3 -C 6 cycloalkylamino, C 2 -C 7 alkylcarbonyl, C 2 -C 7 alkoxycarbonyl, C 2 -C 7 alkylaminocarbonyl, C 3 -C 9 dialkylaminocarbonyl, C 2 -C 7 haloalkylcarbonyl, C 2 -C 7 haloalkoxycarbonyl, C 2 -C 7 haloalkylaminocarbonyl, C 3 -C 9 halodialkylaminocarbonyl, —OH, —NH 2 , —CN or —NO 2 ; or Q 2 ;

each R 7 is independently a phenyl ring or a pyridinyl ring, each ring optionally substituted with one or more substituents independently selected from R 8 ;

each R 8 is independently halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 1 -C 6 alkylthio, C 1 -C 6 haloalkylthio, C 1 -C 6 alkylsulfinyl, C 1 -C 6 haloalkylsulfinyl, C 1 -C 6 alkylsulfonyl, C 1 -C 6 haloalkylsulfonyl, C 1 -C 6 alkylamino, C 2 -C 6 dialkylamino, C 2 -C 4 alkylcarbonyl, C 2 -C 4 alkoxycarbonyl, C 2 -C 7 alkylaminocarbonyl, C 3 -C 7 dialkylaminocarbonyl, —OH, —NH 2 , —C(═O)OH, —CN or —NO 2 ;

each Q 2 is independently a phenyl ring or a 5- or 6-membered saturated or unsaturated heterocyclic ring, each ring optionally substituted with one or more substituents independently selected from halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 6 cycloalkyl, C 3 -C 6 halocycloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 1 -C 6 alkylthio, C 1 -C 6 haloalkylthio, C 1 -C 6 alkylsulfinyl, C 1 -C 6 haloalkylsulfinyl, C 1 -C 6 alkylsulfonyl, C 1 -C 6 haloalkylsulfonyl, C 1 -C 6 alkylamino, C 2 -C 6 dialkylamino, —CN, —NO 2 , —C(═W)N(R 9 )R 10 and —C(═O)OR 10 ;

each R 9 is independently H, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 4 -C 7 alkylcycloalkyl, C 4 -C 7 cycloalkylalkyl, C 2 -C 7 alkylcarbonyl or C 2 -C 7 alkoxycarbonyl;

each R 10 is independently H; or C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 4 -C 7 alkylcycloalkyl or C 4 -C 7 cycloalkylalkyl;

each R 11 is independently H; or C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 4 -C 7 alkylcycloalkyl, C 4 -C 7 cycloalkylalkyl, C 2 -C 7 alkylcarbonyl, C 2 -C 7 alkoxycarbonyl, C 1 -C 6 alkylsulfonyl or C 1 -C 6 haloalkylsulfonyl; and

each W is independently O or S;

comprising contacting a compound of Formula 2

wherein R 1 , Q and Z are as previously defined for Formula 1,

with hydroxylamine in the presence of a base.

2. The method of claim 1 wherein

Z is phenyl optionally substituted with one to five substituents independently selected from R 2 ; and

each R 2 is independently halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 1 -C 6 alkylthio, C 1 -C 6 haloalkylthio, C 1 -C 6 alkylamino, C 2 -C 6 dialkylamino, —CN or —NO 2 .

3. The method of claim 2 wherein

R 1 is CF 3 ;

Z is phenyl substituted with one to three substituents independently selected from R 2 , said substituents attached at the 3-, 4- or 5-positions of the phenyl ring; and

each R 2 is independently halogen, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, C 1 -C 3 haloalkoxy or —CN.

4. The method of claim 3 wherein

Q is Q a .

5. The method of claim 4 wherein

Q a is phenyl substituted with one Q 1 attached at the 4-position of the phenyl ring, said phenyl ring further optionally substituted with one or two substituents independently selected from R 3 ;

Q 1 is a 5-membered heteroaromatic ring optionally substituted with one or two substituents independently selected from halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 6 cycloalkyl, C 3 -C 6 halocycloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, —CN, —C(═W)N(R 4 )R 5 and —C(═O)OR 5 ; and

each R 3 is independently halogen, C 1 -C 6 alkyl or —CN.

6. The method of claim 5 wherein

Q 1 is a pyrazole or triazole ring optionally substituted with one or two substituents independently selected from halogen, —CN and —C(═W)N(R 4 )R 5 ;

one R 3 is Cl, CH 3 or —CN and is attached at the 3-position of the phenyl ring adjacent to Q 1 ;

R 4 is H; and

R 5 is H; or C 1 -C 3 alkyl, cyclopropyl or cyclopropylmethyl, each optionally substituted with halogen and further optionally substituted with 1 or 2 CH 3 .

7. The method of claim 3 wherein

Q is Q b .

8. The method of claim 7 wherein

Q b is 1-naphthalenyl substituted with one or two substituents independently selected from R 3 .

9. The method of claim 8 wherein

one R 3 is halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, —N(R 4 )R 5 , —C(═W)N(R 4 )R 5 , —C(═W)OR 5 , —CN, —OR 11 or —NO 2 , and said R 3 is attached at the 4-position of the naphthalene ring;

each R 4 is independently H, C 1 -C 6 alkyl, C 2 -C 7 alkylcarbonyl or C 2 -C 7 alkoxycarbonyl;

R 5 is C 1 -C 6 alkyl substituted with one substituent selected from hydroxy, C 1 -C 6 alkoxy, C 1 -C 6 alkylthio, C 1 -C 6 alkylsulfinyl, C 1 -C 6 alkylsulfonyl, C 2 -C 7 alkylaminocarbonyl, C 3 -C 9 dialkylaminocarbonyl, C 2 -C 7 haloalkylaminocarbonyl, C 3 -C 9 halodialkylaminocarbonyl and Q 2 ;

Q 2 is a pyridinyl ring optionally substituted with one to four halogen; and

R 11 is H, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 2 -C 7 alkylcarbonyl, C 2 -C 7 alkoxycarbonyl, C 1 -C 6 alkylsulfonyl or C 1 -C 6 haloalkylsulfonyl.

10. The method of claim 9 wherein

Q b is 1-naphthalenyl substituted with one R 3 attached at the 4-position of the naphthalene ring;

R 3 is —C(═O)N(R 4 )R 5 ;

R 4 is H; and

R 5 is C 1 -C 2 alkyl substituted with C 2 -C 7 haloalkylaminocarbonyl.

11. The method of claim 1 wherein the hydroxylamine is derived from a hydroxylamine salt.

12. The method of claim 11 wherein the hydroxylamine salt is a hydroxylamine salt of hydrochloric acid, sulfuric acid, phosphoric acid, or a mixture thereof.

13. The method of claim 1 wherein the base comprises one or more compounds selected from amine bases, alkali metal hydroxide bases, alkali metal alkoxide bases and alkali metal carbonate bases.

14. The method of claim 13 wherein the base comprises sodium carbonate, potassium carbonate, or a mixture thereof.

15. The method of claim 13 wherein the base comprises sodium hydroxide, potassium hydroxide, or a mixture thereof.

16. The method of claim 1 wherein the compound of Formula 2 is 4-[3-[3-chloro-5-(trifluoromethyl)phenyl]-4,4,4-trifluoro-1-oxo-2-buten-1-yl]-N-[2-oxo-2-[(2,2,2-trifluoroethyl)amino]ethyl]-1-naphthalenecarboxamide.

17. The method of claim 10 wherein R 5 is CH 2 C(O)NHCH 2 CF 3 .