Method for preparing 3-trifluoromethyl chalcones

1. A method for preparing a compound of Formula 7

wherein

Z is optionally substituted phenyl; and

Q is phenyl or 1-naphthalenyl, each optionally substituted;

using a compound of Formula 1

wherein said compound of Formula 1 is prepared by a method that comprises the steps of:

distilling water from a mixture comprising

a) a compound of Formula 2

b) a compound of Formula 3

and either

c) a base comprising at least one compound selected from the group consisting of alkaline earth metal hydroxides of Formula 4

M(OH) 2   4

wherein M is Ca, Sr or Ba,

1,5-diazabicyclo[4.3.0]non-5-ene, and

1,8-diazabicyclo[5.4.0]undec-7-ene,

and

d) an aprotic solvent capable of forming a low-boiling azeotrope with water;

or

c) a base comprising at least one compound selected from the group consisting of alkali metal carbonates of Formula 4a

(M 1 ) 2 CO 3   4a

wherein M 1 is Li, Na or K,

and

d) an aprotic solvent capable of forming a low-boiling azeotrope with water, wherein the aprotic solvent capable of forming a low-boiling azeotrope with water comprises acetonitrile.

2. The method of claim 1 wherein

Z is

 Q is

R 2a is halogen, C 1 -C 2 haloalkyl or C 1 -C 2 haloalkoxy;

R 2b is H, halogen or cyano;

R 2c is H, halogen or CF 3 ;

R 4 is H, C 2 -C 7 alkylcarbonyl or C 2 -C 7 alkoxycarbonyl; and

R 5 is C 1 -C 6 alkyl or C 1 -C 6 haloalkyl, each substituted with one substituent independently selected from hydroxy, C 1 -C 6 alkoxy, C 1 -C 6 alkylthio, C 1 -C 6 alkylsulfinyl, C 1 -C 6 alkyl sulfonyl, C 2 -C 7 alkylaminocarbonyl, C 3 -C 9 dialkylaminocarbonyl, C 2 -C 7 haloalkylaminocarbonyl and C 3 -C 9 halodialkylaminocarbonyl.

3. The method of claim 1 wherein the base comprises an alkaline earth metal hydroxide of Formula 4 and the mixture further comprises a polar aprotic solvent.

4. The method of claim 3 wherein M is Ca.

5. The method of claim 3 wherein the polar aprotic solvent comprises N,N-dimethylformamide.

6. The method of claim 3 wherein the aprotic solvent capable of forming a low-boiling azeotrope with water comprises tert-butyl methyl ether.

7. The method of claim 1 wherein the base comprises 1,5-diazabicyclo[4.3.0]non-5-ene, 1,8-diazabicyclo[5.4.0]undec-7-ene, or a mixture thereof.

8. The method of claim 7 wherein the aprotic solvent capable of forming a low-boiling azeotrope with water comprises acetonitrile.

9. The method of claim 1 wherein the base comprises an alkali metal carbonate of Formula 4a.

10. The method of claim 9 wherein M 1 is K.

11. The method of claim 1 wherein

Z is phenyl optionally substituted with up to 5 substituents independently selected from R 2 ;

Q is phenyl or 1-naphthalenyl, each optionally substituted with up to four substituents independently selected from R 3 ;

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 ;

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 1 ;

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 1 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.

12. The method of claim 11 wherein

Z is

 Q is

R 2a is halogen, C 1 -C 2 haloalkyl or C 1 -C 2 haloalkoxy;

R 2b is H, halogen or cyano;

R 2c is H, halogen or CF 3 ;

R 3 is C(O)N(R 4 )R 5 or C(O)OR 5a ;

R 4 is H, C 2 -C 7 alkylcarbonyl or C 2 -C 7 alkoxycarbonyl; and

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

R 5a is C 1 -C 6 alkyl, C 2 -C 6 alkenyl or C 2 -C 6 alkynyl, each optionally substituted with one or more substituents independently selected from halogen, C 1 -C 2 alkoxy and phenyl optionally substituted with up to 5 substituents selected from halogen and C 1 -C 3 alkyl.

13. The method of claim 1 wherein

Z is phenyl optionally substituted with up to 5 substituents independently selected from R 2 ; and

each R 2 is independently F, Cl, Br, C 1 -C 6 alkyl, C 1 -C 6 fluoroalkyl, C 1 -C 6 alkoxy, C 1 -C 6 fluoroalkoxy, C 1 -C 6 alkylthio or C 1 -C 6 fluoroalkylthio;

further comprising preparing the compound of Formula 2 by

(1) forming a reaction mixture comprising a Grignard reagent derived from a compound of Formula 5

wherein X is Cl, Br or I,

by contacting the compound of Formula 5 with

(a) magnesium metal, or

(b) an alkylmagnesium halide

in the presence of an ethereal solvent; and then

(2) contacting the reaction mixture with a compound of Formula 6

wherein

Y is OR 11 or NR 12 R 13 ;

R 11 is C 1 -C 5 alkyl; and

R 12 and R 13 are independently C 1 -C 2 alkyl; or R 12 and R 13 are taken together as —CH 2 CH 2 OCH 2 CH 2 —.

14. The method of claim 13 wherein

Z is

R2a is F, Cl, Br, C 1 -C 2 fluoroalkyl or C 1 -C 2 fluoroalkoxy;

R2b is H, F, Cl or Br; and

R2c is H, F, Cl, Br or CF 3 .