Oxy-cope rearrangement for the manufacture of insecticidal cyclopentene compounds

Abstract

Compounds of formula I ##STR00001##
a process for preparation of compounds of formula I; precursor compounds of formula II ##STR00002##
a process for preparation of precursor compounds of formula II; compounds of formula III ##STR00003##
a process for the preparation of compounds of formula IV from compounds of formula III ##STR00004##
and the use of compounds of formula I for the preparation of compounds of formula IV.

Claims

1. A compound of formula I ##STR00023## wherein R.sup.1 is halomethyl; R.sup.2 is halogen, halomethyl, or halomethoxy; R.sup.3, R.sup.4 are independently H, or as defined for R.sup.2; R.sup.5a is H, C.sub.1-C.sub.4-alkyl, or C.sub.1-C.sub.4-haloalkyl; R.sup.5b is CN, halogen, C.sub.1-C.sub.2-alkyl, C.sub.1-C.sub.2-haloalkyl, C.sub.1-C.sub.2-alkoxy, C.sub.1-C.sub.2-haloalkoxy; or R.sup.5a and R.sup.5b form together with the C-atoms they are bound to a 5-, or 6-membered saturated, partially, or fully unsaturated ring containing none, or one heteroatom O, N(O).sub.n or S(O).sub.m as ring members; A is halogen, CN, C.sub.1-C.sub.6-alkoxy, C.sub.6-C.sub.10-aryloxy, C.sub.1-C.sub.6-haloalkoxy, C.sub.6-C.sub.10-arylalkoxy, C.sub.6-C.sub.10-aryl-C.sub.1-C.sub.6-alkoxy, OS(O).sub.2R.sup.6; or a group A.sup.1, or A.sup.2; wherein A.sup.1 is a group of following formula: ##STR00024## wherein # denotes the attachment point to the remainder of the molecule; Y OR.sup.7, or N(R.sup.8)R.sup.9; and A.sup.2 is a group of following formula: ##STR00025## wherein # denotes the attachment point to the remainder of the molecule; R.sup.6 halogen, C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-haloalkyl; phenyl, which is unsubstituted, or substituted by halogen, OH, CN, NO.sub.2, C.sub.1-C.sub.6-alkyl, or C.sub.1-C.sub.6-haloalkyl; R.sup.7 a) H; b) C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-haloalkyl, C.sub.1-C.sub.6-alkenyl, C.sub.1-C.sub.6-alkynyl, C.sub.1-C.sub.6-alkoxy-C.sub.1-C.sub.6-alkyl; or c) phenyl, or benzyl, which are unsubstituted, or substituted by halogen, C.sub.1-C.sub.2-alkyl, C.sub.1-C.sub.2-haloalkyl, or C.sub.1-C.sub.2-alkoxy; R.sup.8 H, CN; C.sub.1-C.sub.6-alkyl-C(O), C.sub.1-C.sub.6-haloalkyl-C(O), C.sub.1-C.sub.6-alkyl-OC(O), C.sub.1-C.sub.6-alkenyl-OC(O), or C.sub.6-C.sub.12-aryl-C.sub.1-C.sub.6-alkyl-OC(O); 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 are unsubstituted or substituted by R.sup.81; R.sup.81 halogen, 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, C.sub.1-C.sub.6-alkoxy, C.sub.1-C.sub.6-haloalkoxy, C.sub.3-C.sub.8-cycloalkoxy, or C.sub.3-C.sub.8-halocycloalkoxy; R.sup.9 H; C.sub.1-C.sub.6-alkyl, C.sub.2-C.sub.6-alkenyl, C.sub.2-C.sub.6-alkynyl, which are unsubstituted, or substituted by R.sup.91; C.sub.3-C.sub.6-cycloalkyl, C.sub.3-C.sub.6-halocycloalkyl, which are unsubstituted, or substituted by R.sup.92; N(R.sup.93)R.sup.94; phenyl, heterocyclyl, or hetaryl, which are unsubstituted, or substituted by R.sup.D; or C.sub.1-C.sub.6-alkyl-C(O), C.sub.1-C.sub.6-haloalkyl-C(O), C.sub.1-C.sub.6-alkyl-OC(O), C.sub.1-C.sub.6-alkenyl-OC(O), or C.sub.6-C.sub.12-aryl-C.sub.1-C.sub.6-alkyl-OC(O); R.sup.91 halogen, OH, CN, C.sub.1-C.sub.4-alkoxy, C.sub.1-C.sub.4-haloalkoxy, C.sub.1-C.sub.4-alkyl-S(O).sub.m, C.sub.1-C.sub.4-haloalkyl-S(O).sub.m, C(O)N(R.sup.A)R.sup.B; C.sub.3-C.sub.6-cycloalkyl, C.sub.3-C.sub.6-halocycloalkyl, which are unsubstituted, or substituted by R.sup.C; phenyl, heterocyclyl, or hetaryl which are unsubstituted, or substituted by R.sup.D; R.sup.A, R.sup.93 H, C.sub.1-C.sub.3-alkyl, or C.sub.1-C.sub.3-haloalkyl; R.sup.B H, C.sub.1-C.sub.3-alkyl, C.sub.1-C.sub.3-haloalkyl, C.sub.2-C.sub.3-alkenyl, C.sub.2-C.sub.3-haloalkenyl, C.sub.2-C.sub.3-alkynyl, C.sub.2-C.sub.3-haloalkynyl, C.sub.1-C.sub.3-alkoxy, C.sub.1-C.sub.3-haloalkoxy, C.sub.3-C.sub.4-halocycloalkyl; or C.sub.3-C.sub.4-cycloalkyl, C.sub.3-C.sub.4-halocycloalkyl, C.sub.3-C.sub.4-cycloalkylmethyl, C.sub.3-C.sub.4-halocycloalkylmethyl, wherein the cyclic groups are unsubstituted, or substituted by CN; R.sup.C OH, CN, C.sub.1-C.sub.2-alkyl, or C.sub.1-C.sub.2-haloalkyl; R.sup.D 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.3-C.sub.4-cycloalkylmethyl, or C.sub.3-C.sub.4-halocycloalkylmethyl; or two R.sup.D present on the same carbon atom of a saturated, or partially saturated ring form together a carbonyl group (O); R.sup.92 C.sub.1-C.sub.2-alkyl, C.sub.1-C.sub.2-haloalkyl, or a group as defined for R.sup.91; R.sup.94 C(O)N(R.sup.A)R.sup.B, C(O)OR.sup.A; or phenyl, heterocyclyl, or hetaryl which rings are unsubstituted, or substituted by R.sup.D; R.sup.10 H, CN, methyl, or halomethyl; R.sup.11 H, C.sub.1-C.sub.6-alkyl-C(O), C.sub.1-C.sub.6-haloalkyl-C(O), C.sub.1-C.sub.6-alkyl-OC(O), C.sub.1-C.sub.6-alkenyl-OC(O), or C.sub.6-C.sub.12-aryl-C.sub.1-C.sub.6-alkyl-OC(O); R.sup.12 H, C.sub.1-C.sub.6-alkyl, C.sub.2-C.sub.6-alkenyl, C.sub.2-C.sub.6-alkynyl, which are unsubstituted, or substituted by R.sup.91; C.sub.3-C.sub.6-cycloalkyl, C.sub.3-C.sub.6-halocycloalkyl, which are unsubstituted, or substituted by R.sup.92; or phenyl, heterocycyl, or hetaryl which rings are unsubstituted, or substituted by R.sup.D; n is 0, or 1; m is 0, 1, or 2; and the N-oxides, stereoisomers and agriculturally or veterinarily acceptable salts thereof.

2. The compound of claim 1, wherein R.sup.1 is CF.sub.3; R.sup.2 is F, Cl, Br, CF.sub.3, or OCF.sub.3; R.sup.3, R.sup.4 are independently H, or as defined for R.sup.2; R.sup.5a is H; and R.sup.5b is F, Cl, Br, CH.sub.3, or CF.sub.3; or R.sup.5a and R.sup.5b form together with the C-atoms they are bound to a bridging group selected from CHCHCHCH, CHCHCHN, CHCHNCH, CHNCHCH, NCHCHCH, CH.sub.2CH.sub.2CH.sub.2, CH.sub.2CH.sub.2CH.sub.2CH.sub.2, CH.sub.2CH.sub.2O, OCH.sub.2CH.sub.2, CH.sub.2CH.sub.2CH.sub.2O, OCH.sub.2CH.sub.2CH.sub.2, CH.sub.2CH.sub.2S(O).sub.p, S(O).sub.pCH.sub.2CH.sub.2; and wherein p is 0, 1, or 2.

3. The compound of claim 1, wherein A is A.sup.1; Y is OR.sup.7; and R.sup.7 is as defined in claim 1.

4. The compound of claim 3, wherein R.sup.7 is C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-haloalkyl, C.sub.1-C.sub.6-alkenyl, C.sub.1-C.sub.6-alkynyl, phenyl, or benzyl.

5. The compound of claim 2, wherein A is A.sup.1; Y is N(H)R.sup.9.

6. The compound of claim 1, wherein A is Cl, Br, I, or CN.

7. The compound of claim 1, wherein A is A.sup.2; R.sup.10 H; and R.sup.12 C.sub.1-C.sub.4-alkyl, and C.sub.1-C.sub.4-haloalkyl, which are unsubstituted, or substituted by R.sup.91; C.sub.3-C.sub.5-cycloalkyl, C.sub.3-C.sub.5-halocycloalkyl, which are unsubstituted, or substituted by R.sup.92; R.sup.91 is independently OH, CN, C.sub.1-C.sub.4-alkoxy, C.sub.1-C.sub.4-haloalkoxy, C.sub.1-C.sub.4-alkyl-S(O).sub.m, C.sub.1-C.sub.4-haloalkyl-S(O).sub.m; C.sub.3-C.sub.5-cycloalkyl, C.sub.3-C.sub.5-halocycloalkyl, which are unsubstituted, or substituted by R.sup.C; R.sup.C is independently OH, CN, C.sub.1-C.sub.2-alkyl, or C.sub.1-C.sub.2-haloalkyl; R.sup.92 is independently C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-haloalkyl, or a group as defined for R.sup.91; and m is 0, 1, or 2.

8. A process for preparing the compound of claim 1 comprising reacting a compound of formula II ##STR00026## with a base at a temperature from 100 to 50 C., followed by rearrangement at a temperature from 50 to 150 C.

9. The process of claim 8, wherein the reaction of the compound of formula (II) with the base is carried out in a solvent selected from the selected from an aliphatic C.sub.5-C.sub.16-hydrocarbon, aromatic C.sub.6-C.sub.10-hydrocarbon, halogenated aliphatic C.sub.1-C.sub.6-hydrocarbon, halogenated aromatic C.sub.6-C.sub.10-hydrocarbon, a C.sub.1-C.sub.6-cycloalkyl ether, a C.sub.1-C.sub.6-alkyl-C.sub.1-C.sub.6-alkyl ether, and a C.sub.1-C.sub.6-alkyl-C.sub.6-C.sub.10-aryl ether, or a mixture thereof.

10. The process of claim 8, wherein the rearrangement is carried out at a temperature from 10 to 40 C.

11. The process of claim 8, wherein compound of formula I are subsequently reacted with an olefinating agent to compound of formula III ##STR00027## wherein all substituents have a meaning as defined for compound of formula I.

12. The process of claim 11, wherein the olefinating agent is selected from methylphosphonium ylides, Tebbe's reagent, Petasis reagent, Lombardo reagent, or Kauffmann reagent.

13. The process of claim 8, wherein compound of formula III are subsequently reacted to compound of formula IV ##STR00028## in the presence of an alkylidene-metal catalyst; wherein all substituents have a meaning as defined for compound of formula I.

14. The process of claim 13, wherein the metal is selected from W, Ta, Mo, and Ru.

15. The process of claim 8, wherein compound of formula II are produced by reaction of compound of formula V ##STR00029## with an allylation reagent; wherein all substituents have a meaning as defined for compound of formula I.

16. Compound of formula II, as defined in claim 8.

17. Compound of formula III, as defined in claim 11.

18. A process for preparing the compound of formula IV ##STR00030## comprising reacting a compound of formula III ##STR00031## in the presence of an alkylidene-metal catalyst, as defined in claim 13.

Description

EXAMPLES

(1) I. Characterization

(2) The characterization can be done by coupled High Performance Liquid Chromatography/mass spectrometry (HPLC/MS), by NMR or by their melting points. HPLC/MS. The gradient for HPLC/MS was 5-100% B in 1.5 min, 100% B for 0.2 min (0.8-1.0 mL/min flow rate). Mobile phase A was water, mobile phase B was MeCN (acetonitrile). Column temperature was 60 C. The column used for the chromatography was a UPLC Phenomenex Kinetex column with 1.7 m XB-C18 100 A and dimensions of 502.1 mm. MS-method: ESI positive.

(3) Abbreviations used are: h for hour(s), min for minute(s), eq for equivalent(s). Abbreviations used for NMR are: s for singlet, d for doublet, t for triplet, q for quartet, dd for doublet of doublets, dt for doublet of triplets, qd for quartet of doublets, ddd for doublet of doublets of doublets, m for multiplet, J for coupling constant, H for the integrated intensity of one hydrogen atom, Hz is Hertz.

PREPARATION EXAMPLES

Example 1: Preparation of 4-(4-bromophenyl)-6-(3,5-dichlorophenyl)-7,7,7-trifluoro-hepta-1,5-dien-4-ol (Compound II.1)

(4) To 1-(4-bromophenyl)-3-(3,5-dichlorophenyl)-4,4,4-trifluoro-but-2-en-1-one (5.5 g) in anhydrous THF (30 mL) was added allylmagnesium chloride (1.43 g) in diethylether (13 mL) at 0 C. under argon atmosphere. The resulting mixture was stirred at 0 C. for 2 h. Saturated aqueous NH.sub.4Cl-solution (15 mL) was then added to the mixture, which was subsequently stirred for 15 min. The phases were separated and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried and concentrated in vacuo. Compound II.1 was isolated from the residue by silica column chromatography with a yield of 96%. LC-MS: mass found 463.1; retention time 1.400 min.

(5) Chemical shift of compound II.1 in .sup.1H NMR (400 MHz, CDCl.sub.3) 7.46-7.39 (d, J=8.7 Hz, 2H), 7.29 (t, J=1.8 Hz, 1H), 7.13-7.05 (d, J=8.7 Hz, 2H), 6.84 (d, J=1.9 Hz, 2H), 6.77 (q, J=1.6 Hz, 1H), 5.60 (ddt, J=17.5, 10.3, 7.3 Hz, 1H), 5.33-5.13 (m, 2H), 2.68-2.67 (d, J=7.4 Hz, 2H)

Example 2: Preparation of 1-(4-bromophenyl)-3-(3,5-dichlorophenyl)-3-(trifluoromethyl)hex-5-en-1-one (Compound I.1)

(6) A mixture of potassium hexamethyldisilazide (KHMDS, 0.371 g), and 18-crown-6 ether (0.25 g) in toluene (10.8 mL) was produced. A solution of compound II.1 of Example 1 (0.400 g) in toluene (2.5 mL) was added at 78 C. to the mixture. The resulting mixture was stirred at 78 C. for 10 min, and then stirred for another 30 min at 20 to 25 C. An aqueous saturated NaHCO.sub.3 solution (20 mL) was added to the mixture, followed by addition of an aqueous saturated NH.sub.4Cl solution (100 mL). The mixture was then extracted with ethyl acetate. The organic extracts were combined and concentrated in vacuo. Compound I.1 was isolated from the residue by silica column chromatography with a yield of 75%. LC-MS: mass found 466.9; retention time 1.592 min.

Example 3: Preparation of 1-[1-allyl-3-(4-bromophenyl)-1-(trifluoromethyl)but-3-enyl]-3,5-dichloro-benzene (Compound III.1)

(7) To a stirred suspension of methyltriphenylphosphonium bromide (0.506 g) in THF (5 mL) was added potassium tert-butanolate (0.144 g) portion wise at 20 to 25 C., and the resulting mixture was stirred at 20 to 25 C. for 30 min. To this mixture was added compound I.1 (0.3 g) of Example 2 in THF (2 mL) at 0 C. The mixture was stirred over night at 20 to 25 C., upon which water was added. The mixture was subsequently extracted with ethyl acetate. The combined organic phases were dried and concentrated in vacuo. Compound III.1 was isolated from the residue by silica column chromatography with a yield of 80%. LC-MS: mass found 466.9; retention time 1.648 min.

(8) Chemical shifts of compound III.1 in .sup.1H NMR (400 MHz, CDCl.sub.3) 7.37-7.27 (m, 4H), 7.18-7.12 (m, 3H), 6.97-6.90 (m, 2H), 5.78-5.56 (m, 1H), 5.24 (d, J=1.1 Hz, 1H), 5.18-5.04 (m, 2H), 5.00 (q, J=1.1 Hz, 1H), 3.16 (dd, J=14.6, 1.2 Hz, 1H), 3.02 (dd, J=14.6, 0.9 Hz, 1H), 2.84 (dd, J=15.5, 6.2 Hz, 1H), 2.64 (dd, J=15.6, 7.7 Hz, 1H).

Example 4: Preparation of 1-[3-(4-bromophenyl)-1-(trifluoromethyl)cyclopent-3-en-1-yl]-3,5-dichloro-benzene (Compound IV.1)

(9) To a solution of (1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene)dichloro-(phenylmethylene)(tricyclohexylphosphine)ruthenium (15.5 mg) in CH.sub.2Cl.sub.2 (3.5 mL) was added compound III.1 of Example 3 (0.17 g) at 20 to 25 C. under argon. The resulting mixture was stirred for 3 h at 20 to 25 C. The solvent was evaporated in vacuo. Compound IV.1 was isolated from the residue by silica column chromatography with a yield of 63%. LC-MS: no mass observed; retention time 1.7 min.

(10) Chemical shifts of compound IV.1 in .sup.1H NMR (400 MHz, CDCl.sub.3) 7.48 (d, J=8.6 Hz, 2H), 7.36-7.27 (m, 5H), 6.15 (s, 1H), 3.50 (d, J=16.5 Hz, 1H), 3.35 (d, J=17.9 Hz, 1H), 3.24 (dd, J=16.5, 2.4 Hz, 1H), 3.08 (dd, J=18.0, 2.5 Hz, 1H).

Example 5: Preparation of methyl 4-[1-allyl-3-(3-chloro-4-fluoro-phenyl)-4,4,4-trifluoro-1-hydroxy-but-2-enyl]-2-chloro-benzoate (Compound II.2)

(11) To a mixture of methyl 2-chloro-4-[3-(3-chloro-4-fluoro-phenyl)-4,4,4-trifluoro-but-2-enoyl]benzoate (0.25 g) in DMF (5 mL) was added zinc dust (0.194 g) and allyl bromide (0.215 g) at 0 C. The resulting mixture was stirred for 2 h at 0 C., and then stirred for 48 h at 20 to 25 C. Solids particles were removed from the mixture by filtration. To the filtrate was added saturated aqueous NH.sub.4Cl-solution (25 mL) and water (25 mL). The aqueous phase was then extracted with ethyl acetate. The combined organic phases were washed, dried and concentrated in vacuo. Compound II.2 was isolated from the residue by silica column chromatography with a yield of 91%. LC-MS: mass found 463.1; retention time 1.380 min.

Example 6: Preparation of methyl 2-chloro-4-[3-(3-chloro-4-fluoro-phenyl)-3-(trifluoromethyl)hex-5-enoyl]benzoate (Compound I.2)

(12) To a solution of KHMDS (2.239 g) and 18-crown-6-ether (2.51 g) in toluene (95.6 mL) was added compound II.2 of Example 5 (5 g) in toluene (15 mL) at 78 C. The resulting mixture was stirred at 78 C. for 10 min. The mixture was then stirred for 30 min at 20 to 25 C. The mixture was then diluted with an aqueous saturated solution of NaHCO.sub.3 (50 mL), followed by a saturated aqueous solution of NH.sub.4Cl (100 mL). The mixture was then extracted with ethyl acetate. The combined organic phases were washed, dried and concentrated in vacuo. Compound I.2 was isolated from the residue by silica column chromatography with a yield of 95%.

(13) Chemical shifts of compound I.2 in .sup.1H NMR (400 MHz, CDCl.sub.3) 7.94 (s, 1H), 7.89 (dd, J=8.1, 1.5 Hz, 1H), 7.81 (d, J=8.1 Hz, 1H), 7.44 (d, J=6.8 Hz, 1H), 7.32-7.04 (m, 4H), 5.85 (dt, J=16.4, 8.3 Hz, 1H), 5.23-4.89 (m, 2H), 3.97 (s, 3H), 3.83 (d, J=18.5 Hz, 1H), 3.65 (dd, J=18.5, 1.5 Hz, 1H), 3.17 (qd, J=14.3, 7.3 Hz, 2H).

Example 7: Preparation of methyl 2-chloro-4-[3-(3-chloro-4-fluoro-phenyl)-1-methylene-3-(trifluoromethyl)hex-5-enyl]benzoate (Compound III.2)

(14) A suspension of methyltriphenylphosphonium bromide (0.506 g) in toluene (50 mL) was concentrated in vacuo three times. THF (4 mL) was added to the resulting residue, which was subsequently cooled to 0 C. A mixture of KHMDS (0.258 g) in THF (1.3 mL) was then added dropwise. The resulting mixture was then stirred for 30 min, upon which a solution of compound I.2 of Example 6 (0.3 g) in THF (2 mL) was admixed.

(15) The mixture was then stirred at 20 to 25 C. for 18 h. Subsequently, water (50 mL) and ethyl acetate (50 mL) were added to the mixture. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The combined organic phases were washed, dried and concentrated in vacuo. Compound III.2 was isolated from the residue by silica column chromatography with a yield of 30%.

(16) Chemical shifts of compound III.2 in .sup.1H NMR (400 MHz, CDCl.sub.3) 7.69 (d, J=8.2 Hz, 1H), 7.32 (dd, J=6.9, 2.5 Hz, 1H), 7.21 (ddd, J=8.9, 4.4, 2.6 Hz, 1H), 7.13 (d, J=1.8 Hz, 1H), 7.04 (dd, J=8.2, 1.8 Hz, 1H), 6.98 (t, J=8.7 Hz, 1H), 5.82-5.53 (m, 1H), 5.32 (d, J=0.9 Hz, 1H), 5.17-5.03 (m, 3H), 3.93 (s, 3H), 3.18 (dd, J=14.7, 1.2 Hz, 1H), 3.10-3.01 (m, 1H), 2.91-2.7 (m, 1H), 2.67 (dd, J=15.6, 7.6 Hz, 1H).

Example 8: Preparation of methyl 2-chloro-4-[4-(3-chloro-4-fluoro-phenyl)-4-(trifluoromethyl)cyclopenten-1-yl]benzoate (Compound IV.2)

(17) To a solution of (1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene)dichloro(phenylmethylene)(tricyclohexylphosphine)ruthenium (1 mg) in CH.sub.2Cl.sub.2 (1.5 mL) was added compound III.2 of Example 7 (75 mg) at 20 to 25 C. under argon. The resulting mixture was stirred for 5 h at 20 to 25 C. The solvent was evaporated in vacuo. Compound IV.2 was isolated from the residue by silica column chromatography with a yield of 57%.

(18) Chemical shifts of compound IV.2 in .sup.1H NMR (400 MHz, CDCl.sub.3) 7.85 (d, J=8.2 Hz, 1H), 7.48 (dd, J=6.7, 2.1 Hz, 2H), 7.37 (dd, J=8.1, 1.7 Hz, 1H), 7.32 (ddd, J=7.2, 4.1, 2.5 Hz, 1H), 7.15 (t, J=8.7 Hz, 1H), 6.30 (d, J=2.3 Hz, 1H), 3.93 (s, 3H), 3.53 (dd, J=16.3, 1.4 Hz, 1H), 3.40 (d, J=18.2 Hz, 1H), 3.28 (dd, J=16.3, 2.4 Hz, 1H), 3.14 (dd, J=18.2, 2.6 Hz, 1H).

Example 9: Preparation of 1-(4-bromophenyl)-3-(3,5-dichloro-4-fluoro-phenyl)-3-(trifluoromethyl)hex-5-en-1-one (Compound I.3)

(19) To a solution of KHMDS (151 mg) and 18-crown-6-ether (120 mg) in THF (5 mL) was added 4-(4-bromophenyl)-6-(3,5-dichloro-4-fluoro-phenyl)-7,7,7-trifluoro-hepta-1,5-dien-4-ol (200 mg, prepared analogously to Example 5) in THF (1 mL) at 78 C. The resulting mixture was stirred at 78 C. for 10 min. The mixture was then stirred for 30 min at 20 to 25 C. The mixture was then diluted with an aqueous saturated solution of NaHCO.sub.3 (10 mL), followed by a saturated aqueous solution of NH.sub.4Cl (10 mL). The mixture was then extracted with ethyl acetate. The combined organic phases were washed, dried and concentrated in vacuo. Compound I.3 was isolated from the residue by silica column chromatography with a yield of 68%.

(20) 1H NMR (400 MHz, Chloroform-d) 7.76 (d, J=8.6 Hz, 2H), 7.61 (d, J=8.6 Hz, 2H), 7.28 (s, 2H), 5.84 (m, 1H), 5.07 (m, 2H), 3.79 (d, J=18.4 Hz, 1H), 3.65 (d, J=18.4 Hz, 1H), 3.17 (m, 2H).

Example 10: Preparation of 1-(4-bromophenyl)-3-(3,5-dichloro-4-fluoro-phenyl)-3-(trifluoromethyl)hex-5-en-1-one (Compound I.3)

(21) To a solution consisting of KHMDS (134 mg), toluene (0.95 mL), 18-crown-6-ether (90 mg) and xylenes (2.5 mL) was added 4-(4-bromophenyl)-6-(3,5-dichloro-4-fluorophenyl)-7,7,7-trifluoro-hepta-1,5-dien-4-ol (150 mg, prepared analogously to Example 5) in xylenes (1 mL) at 40 C. The resulting mixture was stirred at 40 C. for 10 min. The mixture was then stirred for 30 min at 20 to 25 C. The mixture was then diluted with an aqueous saturated solution of NaHCO.sub.3 (10 mL), followed by a saturated aqueous solution of NH.sub.4Cl (10 mL). The mixture was then extracted with ethyl acetate. The combined organic phases were washed, dried and concentrated in vacuo. Compound I.3 was isolated from the residue by silica column chromatography with a yield of 60%.

Example 11: Preparation of 1-(4-bromophenyl)-3-(3,5-dichloro-4-fluoro-phenyl)-3-(trifluoromethyl)hex-5-en-1-one (Compound I.3)

(22) To a solution consisting of KHMDS (134 mg), toluene (0.95 mL), 18-crown-6-ether (90 mg), and 1,4-dioxane (2.5 mL) was added 4-(4-bromophenyl)-6-(3,5-dichloro-4-fluorophenyl)-7,7,7-trifluoro-hepta-1,5-dien-4-ol (150 mg, prepared analogously to Example 5) in 1,4-dioxane (1 mL) at 78 C. The resulting mixture was stirred at 78 C. for 10 min. The mixture was then stirred for 30 min at 20 to 25 C. The mixture was then diluted with an aqueous saturated solution of NaHCO.sub.3 (10 mL), followed by a saturated aqueous solution of NH.sub.4Cl (10 mL). The mixture was then extracted with ethyl acetate. The combined organic phases were washed, dried and concentrated in vacuo. Compound I.3 was isolated from the residue by silica column chromatography with a yield of 59%.

Example 12: Preparation of methyl 2-chloro-4-[3-(3-chloro-4-fluoro-phenyl)-3-(trifluoromethyl)hex-5-enoyl]benzoate (Compound I.2)

(23) To a solution of KOtBu (26.4 g) and 18-crown-6-ether (62.26 g) in THF (290 mL) at 0 C. was added compound II.2 of Example 5 (46.2 g) in THF (430 mL) at 25 C. to 20 C. The resulting mixture was stirred at 20 C. for 30 min. The mixture was then stirred for 15 min at 0 C. Water (1 L) was added to the mixture, the layers were separated and the organic layer was washed with water three times. The organic phase was dried and concentrated in vacuo. Compound I.2 was isolated from the residue by silica column chromatography with a yield of 64%.

(24) Chemical shifts of compound I.2 in .sup.1H NMR (400 MHz, CDCl.sub.3) 7.94 (s, 1H), 7.89 (dd, J=8.1, 1.5 Hz, 1H), 7.81 (d, J=8.1 Hz, 1H), 7.44 (d, J=6.8 Hz, 1H), 7.32-7.04 (m, 4H), 5.85 (dt, J=16.4, 8.3 Hz, 1H), 5.23-4.89 (m, 2H), 3.97 (s, 3H), 3.83 (d, J=18.5 Hz, 1H), 3.65 (dd, J=18.5, 1.5 Hz, 1H), 3.17 (qd, J=14.3, 7.3 Hz, 2H).

Example 13: Preparation of 1-(4-bromo-3-chlorophenyl)-3-(3,5-dichloro-4-fluorophenyl)-3-(trifluoromethyl)hex-5-en-1-one (Compound I.4)

(25) To a suspension of NaH (11 mg of a 60% mineral oil suspension) and 18-crown-6-ether (75 mg) in THF (5 mL) was added 4-(4-bromo-3-chlorophenyl)-6-(3,5-dichloro-4-fluoro-phenyl)-7,7,7-trifluoro-hepta-1,5-dien-4-ol (prepared analogously to example 5) (130 mg) in THF (1 mL) at 78 C. The resulting mixture was stirred at 78 C. for 1 h. The mixture was then stirred for 30 min at 20 to 25 C. The mixture was then diluted with an aqueous saturated solution of NaHCO.sub.3 (10 mL), followed by a saturated aqueous solution of NH.sub.4Cl (10 mL). The mixture was then extracted with ethyl acetate. The combined organic phases were washed, dried and concentrated in vacuo. Compound I.4 was isolated from the residue by silica column chromatography with a yield of 30%. 1H NMR (500 MHz, Chloroform-d) 7.96 (d, J=2.1 Hz, 1H), 7.75 (d, J=8.3 Hz, 1H), 7.63 (dd, J=8.4, 2.1 Hz, 1H), 7.34 (d, J=5.9 Hz, 2H), 6.14-5.72 (m, 1H), 5.32-4.85 (m, 2H), 3.75 (d, J=18.5 Hz, 1H), 3.64 (d, J=18.5 Hz, 1H). 3.14 (m, 2H).