Herbicidal mixtures

Abstract

The present invention provides a composition comprising (A) a compound of formula (I): ##STR00001##
wherein R.sup.1 is methyl or methoxy, R.sup.2 is hydrogen, methyl or ethoxy and A is a substituted heteroaryl group, or an N-oxide or salt form thereof, and (B) one or more further herbicides; as well as the use of such compositions in controlling plants or inhibiting plant growth.

Claims

1. A composition, comprising: (A) a compound of formula (I): ##STR00165## wherein R.sup.1 is methyl or methoxy, R.sup.2 is hydrogen, methyl or ethoxy and A is a substituted heteroaryl group and wherein said compound is selected from the group consisting of ##STR00166## or an N-oxide or salt form thereof; and (B) one or more compounds of formula (II): ##STR00167## wherein R.sup.B1 is H, methyl, or methoxy; X is O or S; Q.sup.1 is a di-substituted pyrazole, substituted on one ring nitrogen by R.sup.B2 and on an adjacent ring carbon by R.sup.B3, wherein R.sup.B2 is C.sub.1-C.sub.3 alkyl and R.sup.B3 is independently bromo, iodo, C.sub.1-C.sub.3haloalkoxy, C.sub.1-C.sub.3alkoxy, C.sub.1-C.sub.3haloalkyl, or C.sub.1-C.sub.3alkyl; or R.sup.B2 is C.sub.1-C.sub.3 alkyl and R.sup.B3 is C.sub.1-C.sub.3fluoroalkyl or C.sub.1-C.sub.3alkyl, and R.sup.B2 and R.sup.B3 together with the atoms to which they are joined and Q.sup.1 form an eight or nine-membered fused heterocyclic bicyclic ring system; Q.sup.2 is a phenyl, pyridinyl, or thienyl ring system, optionally substituted by 1, 2, or 3 R.sup.B5 substituents; and each R.sup.B5 is independently halogen, C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6haloalkyl, C.sub.1-C.sub.6alkoxy, C.sub.1-C.sub.6haloalkoxy, cyano, nitro, C.sub.1-C.sub.6alkylthio, C.sub.1-C.sub.6alkylsulphinyl, or C.sub.1-C.sub.6alkylsulphonyl; or an N-oxide, or a salt form thereof.

2. The composition of claim 1, R.sup.B1 is H or methyl.

3. The composition of claim 1, wherein X is O.

4. The composition of claim 1, wherein Q.sup.2 is selected from the group consisting of Q.sup.2-1, Q.sup.2-2, Q.sup.2-3, Q.sup.2-4, Q.sup.2-5, and Q.sup.2-6, ##STR00168## wherein n is 0, 1, 2, or 3, R.sup.B5 is as defined in claim 1, and the jagged line represents the point of attachment to the rest of the molecule.

5. The composition of claim 1, wherein each R.sup.B5 is independently halogen, C.sub.1-C.sub.4alkyl, C.sub.1-C.sub.3haloalkyl, C.sub.1-C.sub.3alkoxy, or C.sub.1-C.sub.3haloalkoxy.

6. The composition of claim 1, wherein Q.sup.1 is selected from the group consisting of Q.sup.1-2a and Q.sup.1-2b ##STR00169## and R.sup.B3SN is independently selected from bromo, iodo, C.sub.1-C.sub.3fluoroalkyl, C.sub.1-C.sub.3haloalkoxy, C.sub.1-C.sub.3alkoxy, and C.sub.1-C.sub.3alkyl, and the jagged line denotes the point of attachment to the rest of the molecule.

7. The composition of claim 1, wherein R.sup.B2 is selected from the group consisting of methyl, ethyl, and n-propyl.

8. The composition of claim 1, wherein Q.sup.1 is a di-substituted pyrazole ring system, and R.sup.B2 and R.sup.B3 together with the atoms to which they are joined and Q.sup.1 form an eight or nine-membered fused hetero-bicyclic ring system.

9. The composition of claim 1, wherein the eight or nine-membered fused hetero-bicyclic ring system is selected from the group consisting of Q.sup.1-F1 to Q.sup.1-F12 as shown below: ##STR00170## ##STR00171## wherein the jagged line denotes the point of attachment to the rest of the molecule.

10. The composition of claim 1, further comprising a third component (C), selected from the group consisting of mesotrione, bicyclopyrone, atrazine, S-metholachlor, terbuthylazine, dimethaclor, flufenacet, glyphosate, isoxaflutole, nicosulfuron, ametryn, hexazinone, paraquat, diquat, pyridate, acetochlor, dimethenamid-P, alachlor, pethoxamid, pyroxosulfone, trifloxysulfuron sodium, flazasulfuron, prosulfocarb, metolachlor, and pretilachlor.

11. The composition of claim 1, further comprising one or more safeners selected from the group consisting of AD 67, benoxacor, cloquintocet-mexyl, cyometrinil, cyprosulfamide, dichlormid, dicyclonon, dietholate, fenchlorazole-ethyl, fenclorim, flurazole, fluxofenim, furilazole, furilazome, isoxadifen-ethyl, mefenpyr-diethyl, mephenate, oxabetrinil, naphthalic anhydride, TI-35, N-isopropyl-4-(2-methoxy-benzoylsulfamoyl)-benzamide, and N-(2-methoxybenzoyl)-4-Rmethylaminocarbonyl)aminoThenzenesulfonamide.

Description

PREPARATION EXAMPLES FOR COMPOUNDS OF FORMULA (II)

General Experimental

(1) Chiral HPLC was recorded on the columns below with the solvents and gradients stated.

(2) Column:

(3) Regis Whelk 01 (s,s) 4.6×100 mm, 3.5 μm

(4) Chiralpak IC 4.6×100 mm, 3.0 μm

(5) Solvents:

(6) A: iso-Hexane+0.1% glacial Acetic Acid (v/v)

(7) B: Ethanol+0.1% glacial Acetic Acid (v/v)

(8) Gradient:

(9) TABLE-US-00011 Time (mins): Flow (mL/min): % A: % B: 0.0 1.0 85 15 1.0 1.0 85 15 7.0 1.0 50 50 15.0 1.0 40 60

Synthesis Method (I): Racemic Synthesis Route

Exemplar compound: ′N-(2,3-difluorophenyl)-1-methyl-4-[1-methyl-5-(trifluoromethyl)pyrazol-3-yl]-2-oxo-pyrrolidine-3-carboxamide

(10) ##STR00146##

(11) Salt (I) can be prepared as described in Tetrahedron Lett. 1995, 36, 9409.

Step 1 Ethyl (E)-3-[1-methyl-5-(trifluoromethyl)pyrazol-3-yl]prop-2-enoate

(12) In a large microwave vial 3-iodo-1-methyl-5-(trifluoromethyl)pyrazole (3.62 mmol, 1.00 g) was dissolved in acetonitrile (15.2 mL), and ethyl acrylate (1.19 mL, 10.9 mmol), triethylamine (0.507 mL, 3.64 mmol), tri-ortho-tolylphosphine (0.362 mmol, 0.110 g) and palladium(II) acetate (0.362 mmol, 0.0813 g) were added, the air space above the stirred orange solution was swept with nitrogen, and the vial sealed and heated at 110° C. under microwave irradiation for 60 minutes. The reaction mixture was filtered (rinsing through with small portions of EtOAc), and the combined filtrate and washings were concentrated to remove the bulk of solvent. The residual orange-brown liquid was diluted with water (12 mL) and extracted with EtOAc (3×15 mL). The organic extracts were combined, washed with water (10 mL), passed through a phase separation cartridge then concentrated. Column chromatography (EtOAc/iso-hexane gradient elution) gave ethyl (E)-3-[1-methyl-5-(trifluoromethyl)pyrazol-3-yl]prop-2-enoate as a yellow oil, 0.51 g (57%).

(13) .sup.1H NMR: (400 MHz, CDCl.sub.3): δ=7.58 (d, J=16.1 Hz, 1H), 6.81 (s, 1H), 6.43 (d, J=16.1 Hz, 1H), 4.26 (q, J=7.1 Hz, 2H), 4.01 (d, J=0.6 Hz, 3H), 1.33 (t, J=7.1 Hz, 3H).

Step 2 Ethyl-6-Methyl-8-[1-Methyl-5-(Trifluoromethyl)Pyrazol-3-Yl]-1,4-Dithia-6-Azaspiro[4.4]Nonane-9-Carboxylate

(14) To a suspension of finely divided cesium fluoride (12.7 mmol, 1.93 g) in tetrahydrofuran (9.51 mL) stirred at −50° C., under a nitrogen atmosphere, was added a solution of ethyl (E)-3-[1-methyl-5-(trifluoromethyl)pyrazol-3-yl]prop-2-enoate (3.17 mmol, 0.787 g) and 1,3-dithiolan-2-ylidene-methyl-(trimethylsilylmethyl)ammonium;trifluoromethanesulfonic acid (5.55 mmol, 2.06 g) in tetrahydrofuran (39.51 mL) drop-wise over approx. 15 minutes, keeping the reaction temperature below −45° C. The resulting very pale yellow cloudy suspension was allowed to warm slowly to room temperature and stirring was continued overnight. The reaction mixture was then diluted with DCM and filtered, washing through with further portions of DCM. The combined filtrate and washings were concentrated, and the crude material purified by column chromatography (EtOAc/cyclohexane gradient elution) giving ethyl-6-methyl-8-[1-methyl-5-(trifluoromethyl)pyrazol-3-yl]-1,4-dithia-6-azaspiro[4.4]nonane-9-carboxylate as a pale yellow oil, 566 mg (45%).

(15) .sup.1H NMR: (400 MHz, CDCl.sub.3): δ=6.45 (s, 1H), 4.31-4.17 (m, 2H), 3.90 (d, J=0.6 Hz, 3H), 3.89-3.79 (m, 2H), 3.35-3.06 (m, 5H), 2.97-2.91 (m, 1H), 2.47 (s, 3H), 1.31 (t, J=7.2 Hz, 3H).

Step 3 1-Methyl-4-[1-Methyl-5-(Trifluoromethyl)Pyrazol-3-Yl]-2-Thioxo-Pyrrolidine-3-Carboxylic Acid

(16) To a solution of ethyl 6-methyl-8-[1-methyl-5-(trifluoromethyl)pyrazol-3-yl]-1,4-dithia-6-azaspiro[4.4]nonane-9-carboxylate (1.43 mmol, 0.566 g) in dioxane (34.3 mL) and water (11.4 mL) was added LiOH (14.3 mmol, 0.343 g), and the stirred mixture heated to 60° C. under a nitrogen atmosphere for 1 hour. The reaction mixture was then allowed to cool to around 35° C. then concentrated to remove the bulk of dioxane. The residual mixture was diluted with water (10 mL), and partitioned between dilute HCl (5 mL, to pH3) and DCM (20 mL). The two-phase mixture was filtered to remove fine solids then the organic phase was separated. The aqueous was further extracted with DCM (2×15 mL), and all organic extracts combined, dried over MgSO.sub.4, filtered and the filtrate concentrated giving 1-methyl-4-[1-methyl-5-(trifluoromethyl)pyrazol-3-yl]-2-thioxo-pyrrolidine-3-carboxylic acid as a light yellow solid, 399 mg (90%).

(17) .sup.1H NMR: (400 MHz, CDCl.sub.3): δ=6.66 (s, 1H), 4.19-4.03 (m, 4H), 3.93 (d, J=0.5 Hz, 3H), 3.34 (s, 3H).

Step 4 N-(2,3-Difluorophenyl)-1-Methyl-4-[1-Methyl-5-(Trifluoromethyl)Pyrazol-3-Yl]-2-Thioxo-Pyrrolidine-3-Carboxamide

(18) To a solution of 1-methyl-4-[1-methyl-5-(trifluoromethyl)pyrazol-3-yl]-2-thioxo-pyrrolidine-3-carboxylic acid (0.340 g, 1.11 mmol) in DCM (8.0 mL) was added 2,3-difluoroaniline (0.112 mL, 1.11 mmol) giving a pale yellow solution. Propylphosphonic anhydride (50 mass %) in ethyl acetate (1.88 mmol, 1.12 mL) was added, followed by the N,N-diisopropylamine (3.32 mmol, 0.578 mL) and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was then quenched by the addition of water (2 mL) with stirring, transferred to a phase separation cartridge and the organics collected and concentrated. Column chromatography (EtOAc/iso-hexane gradient elution) gave N-(2,3-difluorophenyl)-1-methyl-4-[1-methyl-5-(trifluoromethyl)pyrazol-3-yl]-2-thioxo-pyrrolidine-3-carboxamide as a colourless crystalline solid, 264 mg (57%).

(19) .sup.1H NMR: (400 MHz, CDCl.sub.3): δ=10.25 (br s, 1H), 8.01 (tdd, J=1.6, 6.6, 8.3 Hz, 1H), 7.04 (ddt, J=2.1, 5.9, 8.3 Hz, 1H), 6.94-6.86 (m, 1H), 6.58 (s, 1H), 4.40 (td, J=6.3, 8.6 Hz, 1H), 4.20 (d, J=6.4 Hz, 1H), 4.13 (dd, 1H), 4.00 (dd, 1H), 3.93 (d, 3H), 3.33 (s, 3H).

Step 5 N-(2,3-Difluorophenyl)-1-Methyl-4-[1-Methyl-5-(Trifluoromethyl)Pyrazol-3-Yl]-2-Oxo-Pyrrolidine-3-Carboxamide

(20) To a solution of N-(2,3-difluorophenyl)-1-methyl-4-[1-methyl-5-(trifluoromethyl)pyrazol-3-yl]-2-thioxo-pyrrolidine-3-carboxamide (0.621 mmol, 0.260 g) in acetonitrile (6.21 mL) stirred and cooled to around 0 to −5° C., in an ice-salt bath, was added 50% hydrogen peroxide (0.746 mL) drop-wise and a white suspension resulted. After 5 minutes 45% aq. hydrobromic acid (0.0750 mL, 0.621 mmol) was added drop-wise and after stirring for 10 minutes the mixture was allowed to warm to room temperature. After 3 hours the reaction mixture was re-cooled to 5° C., and quenched with sodium thiosulfate solution (˜10 mL). The mixture was diluted with EtOAc (15 mL) and water (10 mL), and the organic phase separated. The aqueous was further extracted with EtOAc (2×10 mL), then the organic extracts were combined, run through a phase separation cartridge then concentrated giving a colourless gum. Column chromatography (EtOAc/iso-hexane gradient elution) gave N-(2,3-difluorophenyl)-1-methyl-4-[1-methyl-5-(trifluoromethyl)pyrazol-3-yl]-2-oxo-pyrrolidine-3-carboxamide as a white crystalline solid, 210 mg (84%).

(21) .sup.1H NMR: (400 MHz, CDCl.sub.3): δ=10.15 (br s, 1H), 8.04 (dd, J=6.6, 8.3 Hz, 1H), 7.06-6.99 (m, 1H), 6.89 (br dd, J=1.1, 8.6 Hz, 1H), 6.69 (s, 1H), 4.09 (q, 1H), 3.94 (s, 3H), 3.78 (d, J=9.5 Hz, 1H), 3.76-3.65 (m, 2H), 2.98 (d, 3H).

(22) The racemic N-(2,3-difluorophenyl)-1-methyl-4-[1-methyl-5-(trifluoromethyl)pyrazol-3-yl]-2-oxo-pyrrolidine-3-carboxamide could be separated to afford the enantiomers (3S,4R)—N-(2,3-difluorophenyl)-1-methyl-4-[1-methyl-5-(trifluoromethyl)pyrazol-3-yl]-2-oxo-pyrrolidine-3 carboxamide and (3R,4S)—N-(2,3-difluorophenyl)-1-methyl-4-[1-methyl-5-(trifluoromethyl)pyrazol-3-yl]-2-oxo-pyrrolidine-3-carboxamide using a Chiralpak IA, 10×250 mm, 5 μm column with sc-CO.sub.2 (solvent A) B=Isopropanol (solvent B) as solvents under isocratic conditions: 85% solvent A:15% solvent B at 15 mL/min.

Synthesis Method (II): Asymmetric Synthesis Route

Exemplar compound: ′(3S,4R)—N-(2,3-difluorophenyl)-1-methyl-4-[1-methyl-5-(trifluoromethyl)pyrazol-3-yl]-2-oxo-pyrrolidine-3-carboxamide

(23) ##STR00147##

(24) The Nickel catalyst used in step 3, which catalyses the asymmetric malonate addition to the nitro olefin, can be prepared as in J. Am. Chem. Soc. 2005, 127, 9958-9959.

Step 1 3-Iodo-1-Methyl-5-(Trifluoromethyl)Pyrazole

(25) The compound 1-methyl-5-(trifluoromethyl)pyrazol-3-amine (5.00 g, 30.3 mmol) was stirred in 9M sulfuric acid (818 mmol, 91 mL) in a 500 mL beaker, using an overhead stirrer at 0° C. (ice bath) until a homogenous mixture resulted. Sodium nitrite (60.6 mmol, 4.18 g), in 10 mL of water, was then added dropwise over 5 minutes, resulting in a colourless solution and the reaction was stirred at 0° C. for a further 20 minutes. Potassium iodide (75.7 mmol, 12.6 g), in 20 mL of water, was added dropwise to the reaction and the mixture was then stirred for a further 4 hours. The reaction was quenched with saturated sodium thiosulfate until the mixture became clear. The mixture was then diluted with dichloromethane and the phases were separated. The aqueous was further extracted with dichloromethane and the combined organic extracts were washed with water, dried (MgSO4), filtered and concentrated under vacuum to afford a pale yellow oil. The crude product was purified by column chromatography (EtOAc/hexanes gradient elution) to afford 3-iodo-1-methyl-5-(trifluoromethyl)pyrazole as a colourless oil, 3.9 g, (47%).

(26) .sup.1H NMR (400 MHz, CDCl.sub.3)=6.76 (s, 1H) 4.01 (d, J=0.61 Hz, 3H).

Step 2 1-Methyl-3-[(E)-2-Nitrovinyl]-5-(Trifluoromethyl)Pyrazole

(27) Isopropylmagnesium chloride-Lithium chloride in THF (23.55 mmol, 1.3 mol/L) was added dropwise to 3-iodo-1-methyl-5-(trifluoromethyl)pyrazole (5.0 g, 18.12 mmol) in THF (90 mL) at −20° C. and the mixture was stirred for 2 hours. 1-Dimethylamino-2-nitroethylene (27.17 mmol, 3.321 g) was added and the reaction was slowly warmed to RT over 1 hour. The reaction mixture was then carefully quenched with 2 M HCl, and extracted with ethyl acetate. The organic extracts were washed with brine, dried (MgSO4), filtered, concentrated and purified by chromatography (EtOAc/cyclohexane gradient elution) to afford 1-methyl-3-[(E)-2-nitrovinyl]-5-(trifluoromethyl)pyrazole (74.6%) as a yellow oil, 2.99 g (74.6%).

(28) .sup.1H NMR (400 MHz, CDCl.sub.3)=7.89 (d, J=13.7 Hz, 1H), 7.63 (d, J=13.7 Hz, 1H), 6.88 (s, 1H), 4.05 (d, J=0.6 Hz, 3H).

Step 3 Diethyl 2-[(1 S)-1-[1-Methyl-5-(Trifluoromethyl)Pyrazol-3-Yl]-2-Nitro-Ethyl]Propanedioate

(29) To a solution of 1-methyl-3-[(E)-2-nitrovinyl]-5-(trifluoromethyl)pyrazole (0.650 g, 2.94 mmol) in toluene (19.5 mL) was added diethyl malonate (0.676 mL, 4.41 mmol) followed by Nickel(II)Bis[(1R,2R)—N1,N2-bis(phenylmethyl)-1,2-cyclohexanediamine-N1,N2]dibromide (0.0588 mmol, 0.0472 g), and the mixture was stirred at ambient temperature for 20 hours.

(30) The reaction mixture was washed with water (2×10 mL) and the organic phase separated, concentrated and purified by chromatography (EtOAc/cyclohexane gradient elution) to afford diethyl 2-[(1S)-1-[1-methyl-5-(trifluoromethyl)pyrazol-3-yl]-2-nitro-ethyl]propanedioate as pale yellow oil, 1.07 g (95%).

(31) .sup.1H NMR (400 MHz, CDCl.sub.3)=6.53 (s, 1H), 5.01 (dd, 1H), 4.88 (dd, J=4.3, 13.9 Hz, 1H), 4.35 (ddd, J=4.4, 7.7, 9.0 Hz, 1H), 4.22 (q, 2H), 4.16 (q, J=7.1 Hz, 2H), 3.90 (s, 3H), 3.89 (d, 1H), 1.26 (t, 3H), 1.20 (t, J=7.2 Hz, 3H).

Step 4 Ethyl (3R,4R)-4-[1-Methyl-5-(Trifluoromethyl)Pyrazol-3-Yl]-2-Oxo-Pyrrolidine-3-Carboxylate

(32) To a solution of diethyl 2-[(1R)-1-[1-methyl-5-(trifluoromethyl)pyrazol-3-yl]-2-nitro-ethyl]propanedioate (1.07 g, 2.81 mmol) in ethanol (42.1 mL) cooled to 0-5° C. (ice bath) under nitrogen, was added dichloronickel hexahydrate (2.95 mmol, 0.700 g). Sodium borohydride (8.42 mmol, 0.325 g) was then added portionwise to the pale greenish-blue solution. After 30 minutes the cooling was removed and the reaction mixture allowed to warm to ambient temperature. After stirring for 5 hours, at ambient temperature, the reaction mixture was cooled to 5-10° C., in an ice-water bath, and slowly quenched with ammonium chloride solution, and the mixture stirred for a further 20 minutes. The mixture was then diluted with EtOAc (20 mL), and filtered through a bed of celite, washing through with portions of water and EtOAc. The collected two-phase mixture was concentrated to remove the bulk of solvent and the residue transferred to a separating funnel, diluted with EtOAc (20 mL) and the organic phase separated. The aqueous phase was further extracted with EtOAc (2×25 mL) and all organic extracts combined, passed through a phase separation concentrated and purified by chromatography (EtOAc/hexanes gradient elution) to afford a pale yellow oil, 0.61 g (77%) which crystallised on standing. 1H NMR (400 MHz, CDCl.sub.3) b=6.91 (br s, 1H), 6.47 (s, 1H), 4.28 (q, J=7.2 Hz, 2H), 4.14 (q, 1H), 3.94 (d, 3H), 3.80 (dt, J=1.0, 9.0 Hz, 1H), 3.63 (d, J=9.3 Hz, 1H), 3.52 (dd, J=8.2, 9.5 Hz, 1H), 1.32 (t, J=7.2 Hz, 3H).

Step 5 (3R,4R)-4-[1-Methyl-5-(Trifluoromethyl)Pyrazol-3-Yl]-2-Oxo-Pyrrolidine-3-Carboxylic Acid

(33) To a solution of ethyl (3R,4R)-4-[1-methyl-5-(trifluoromethyl)pyrazol-3-yl]-2-oxo-pyrrolidine-3-carboxylate (0.61 g, 2.0 mmol) in ethanol (6.0 mL) and water (2.0 mL) at 0° C. (ice bath) was added 2M sodium hydroxide (3 mL, 6.0 mmol). The reaction mixture was stirred at 0° C. for 30 minutes and then diluted with water (15 mL) and extracted with EtOAc (25 mL). The organic extracts were washed with water (10 mL), and the aqueous extracts combined and acidified to pH 2 with dilute HCl. The acidified aqueous extracts were then re-extracted with EtOAc (3×20 mL) and these organic extracts were run through a phase separation cartridge and concentrated affording a pale yellow oil, 0.54 g (quantitative) which crystallised on standing.

(34) .sup.1H NMR (400 MHz, CDCl3) □=6.59 (s, 1H), 4.09 (q, 1H), 3.94 (s, 3H), 3.85-3.77 (m, 1H), 3.72 (d, J=10.0 Hz, 1H), 3.66-3.58 (m, 1H).

Step 6 (3R,4R)-1-Methyl-4-[1-Methyl-5-(Trifluoromethyl)Pyrazol-3-Yl]-2-Oxo-Pyrrolidine-3-Carboxylic Acid

(35) To a stirred solution of (3R,4R)-4-[1-methyl-5-(trifluoromethyl)pyrazol-3-yl]-2-oxo-pyrrolidine-3-carboxylic acid (0.57 g, 2.1 mmol, 0.57 g) in tetrahydrofuran (16 mL), at room temperature, under a nitrogen atmosphere was added potassium tertiary butoxide (1.0M in THF) (4.5 mL, 4.5 mmol) giving a pale yellow fine suspension. To this suspension was added iodomethane (0.19 mL, 3.1 mmol), and stirring at room temp was continued for 20 h. The stirred reaction mixture was acidified to pH2 with dilute HCl and the mixture was diluted with water (10 mL) and extracted with EtOAc (3×30 mL). The combined organic extracts were washed with brine (15 mL), dried over magnesium sulfate, filtered and the filtrate concentrated giving a transparent amber gum, 0.63 g ((quantitative).

(36) .sup.1H NMR: (400 MHz, CDCl3) b=6.68 (s, 1H), 3.97 (q, 1H), 3.94 (s, 3H), 3.76-3.68 (m, 3H), 2.99 (s, 3H).

Step 7 (3S,4R)—N-(2,3-Difluorophenyl)-1-Methyl-4-[1-Methyl-5-(Trifluoromethyl)Pyrazol-3-Yl]-2-Oxo-Pyrrolidine-3-Carboxamide

(37) To a solution of (3R,4R)-1-methyl-4-[1-methyl-5-(trifluoromethyl)pyrazol-3-yl]-2-oxo-pyrrolidine-3-carboxylic acid (0.61 g, 2.1 mmol) in dichloromethane (15 mL) was added 2,3-difluoroaniline (0.21 mL, 2.1 mmol). Propylphosphonic anhydride (50 mass %) in ethyl acetate (2.3 g, 3.6 mmol, 2.1 mL) was then added, and the reaction mixture was then immersed in a room temp water bath. N,N-Diisopropylethylamine (1.1 mL, 6.3 mmol) was added drop-wise, and the reaction was stirred at room temperature for 2.5 hour. The reaction mixture was quenched by the addition of water (15 mL) and transferred to a phase sep cartridge. The aqueous was further extracted with DCM (2×10 mL) and the combined organic extracts were concentrated and purified by chromatography (EtOAc/hexanes gradient elution) to afford a pink oil. Trituration with iso-hexane afforded a pale pink solid 398 mg (47%). 1H NMR: (400 MHz, CDCl.sub.3) b=10.16 (br s, 1H), 8.08-8.01 (m, 1H), 7.02 (ddt, J=2.1, 5.9, 8.3 Hz, 1H), 6.93-6.84 (m, 1H), 6.69 (s, 1H), 4.09 (q, 1H), 3.94 (s, 3H), 3.78 (d, J=9.5 Hz, 1H), 3.76-3.65 (m, 2H), 2.98 (s, 3H).

(38) Chiral HPLC analysis, by the methods stated above, confirmed an enantiomeric ratio of 97:3.

(39) Further compounds of formula (II) were synthesized in an analogous manner using the above described two synthetic routes. These are shown in Tables 3 and 4 below.

(40) TABLE-US-00012 TABLE 3 Compounds of formula (II) prepared using synthesis method (I) NMR data corresponds to that for the repective racemates Compound No. Structure 1HNMR (CDCl.sub.3) 2.1 δ = 10.15 (br s, 1H), 8.04 (tdd, J = 1.6, 6.6, 8.3 Hz, 1H), 7.02 (ddt, J = 2.1, 5.9, 8.3 Hz, 1H), 6.93-6.85 (m, 1H), 6.69 (s, 1H), 4.09 (q, 1H), 3.94 (s, 3H), 3.81-3.65 (m, 3H), 2.98 (d, 3H) 2.2 δ = 10.04 (br s, 1H), 8.31- 8.25 (m, 1H), 7.13-7.00 (m, 3H), 6.69 (s, 1H), 4.11 (q, 1H), 3.94 (s, 3H), 3.80-3.65 (m, 3H), 2.98 (d, 3H) 2.3 0 δ = 9.98 (br s, 1H), 8.22 (dt, J = 6.0, 8.9 Hz, 1H), 6.90-6.80 (m, 2H), 6.69 (s, 1H), 4.09 (q, 1H), 3.94 (d, 3H), 3.80-3.65 (m, 3H), 2.97 (d, J = 0.7 Hz, 3H) 2.4 δ = 10.40 (s, 1H), 8.17 (td, J = 1.5, 8.5 Hz, 1H), 7.26-7.19 (m, 1H), 6.92 (ddd, J = 1.4, 8.4, 9.7 Hz, 1H), 6.69 (s, 1H), 4.07 (q, J = 9.0 Hz, 1H), 3.94 (s, 3H), 3.77 (d, 1H), 3.74- 3.64 (m, 2H), 2.98 (s, 3H) 2.5 δ = 10.16 (br s, 1H), 7.99 (d, J = 8.3 Hz, 1H), 7.46 (dt, J = 6.0, 8.4 Hz, 1H), 7.00-6.92 (m, 1H), 6.68 (s, 1H), 4.09 (q, J = 8.9 Hz, 1H), 3.94 (s, 3H), 3.79-3.66 (m, 3H), 2.98 (d, 3H) 2.6 δ = 10.21 (s, 1H), 8.13 (td, J = 1.3, 8.4 Hz, 1H), 6.96 (dt, J = 5.7, 8.3 Hz, 1H), 6.81 (ddd, J = 1.5, 8.4, 11.1 Hz, 1H), 6.68 (s, 1H), 4.13 (q, J = 9.0 Hz, 1H), 4.03 (d, J = 1.7 Hz, 3H), 3.94 (d, 3H), 3.78-3.63 (m, 3H), 2.97 (d, J = 0.7 Hz, 3H) 2.7 δ = 10.08 (br s, 1H), 8.01- 7.94 (m, 1H), 6.92 (ddt, J = 2.4, 7.7, 9.7 Hz, 1H), 6.68 (s, 1H), 4.07 (q, 1H), 3.94 (s, 3H), 3.77 (d, 1H), 3.75-3.65 (m, 2H), 2.98 (d, 3H) 2.8 δ = 10.17 (br s, 1H), 8.83- 8.76 (m, 1H), 6.80 (dd, J = 2.9, 8.6 Hz, 1H), 6.67 (s, 1H), 4.07 (q, J = 8.9 Hz, 1H), 3.95 (d, 3H), 3.83-3.65 (m, 3H), 2.98 (d, 3H) 2.9 δ = 10.04 (s, 1H), 8.01 (dd, J = 1.8, 7.9 Hz, 1H), 7.75 (q, J = 8.1 Hz, 1H), 6.65 (s, 1H), 6.64 (dd, 1H), 4.12 (q, J = 9.0 Hz, 1H), 3.94 (s, 3H), 3.77- 3.61 (m, 3H), 2.96 (s, 3H) 2.10 δ = 10.29 (s, 1H), 8.17 (td, J = 1.3, 8.4 Hz, 1H), 7.17 (dt, J = 5.9, 8.5 Hz, 1H), 6.89 (ddd, J = 1.3, 8.5, 10.0 Hz, 1H), 6.68 (s, 1H), 6.67 (t[large F coupling], 1H), 4.09 (q, J = 9.0 Hz, 1H), 3.94 (s, 3H), 3.78 (d, J = 9.5 Hz, 1H), 3.75-3.63 (m, 2H), 2.98 (m, 3H) 2.11 δ = 9.73 (s, 1H), 8.05 (d, 1H), 7.34-7.27 (m, 1H), 7.22- 7.16 (m, 1H), 7.10-7.05 (m, 1H), 6.72 (s, 1H), 4.17-4.07 (m, 1H), 3.94 (s, 3H), 3.77- 3.66 (m, 3H), 2.97 (d, 3H), 2.77-2.65 (m, 2H), 1.27 (t, 3H) 2.12 δ = 9.75 (br s, 1H), 8.11 (dd, J = 5.1, 9.0 Hz, 1H), 7.21 (dd, J = 2.9, 9.2 Hz, 1H), 7.13-7.06 (m, 1H), 6.67 (s, 1H), 4.13 (q, J = 8.9 Hz, 1H), 3.94 (s, 3H), 3.76-3.64 (m, 3H), 2.97 (s, 3H), 1.98 (t, 3H) 2.43 0 δ = 10.14 (s, 1H), 8.09- 7.97 (m, 1H), 7.08-6.97 (m, 1H), 6.92-6.82 (m, 1H), 6.27 (s, 1H), 4.10- 3.97 (m, 1H), 3.88-3.75 (m, 1H), 3.80 (s, 3H), 3.74-3.60 (m, 2H), 2.95 (s, 3H). 2.45 δ = 9.96 (brs, 1H), 8.28- 8.18 (m, 1H), 6.91- 6.77 (m, 2H), 6.27 (s, 1H), 4.05 (q, J = 9.0 Hz, 1H), 3.83-3.60 (m, 3H), 3.79 (s, 3H), 2.96 (s, 3H) 2.49 δ = 10.06 (s, 1H), 8.03- 7.93 (m, 1H), 6.98-6.85 (m, 1H), 6.27 (s, 1H), 4.03 (q, 1H), 3.83-3.60 (m, 3H), 3.80 (s, 3H), 2.97 (s, 3H).

(41) TABLE-US-00013 TABLE 4 Compounds of formula (II) prepared using synthesis method (II) NMR data corresponds to that for the single enantiomer as shown Compound No. Structure 1HNMR (CDCl.sub.3) 2.1 δ = 10.15 (br s, 1H), 8.04 (dd, J = 6.6, 8.3 Hz, 1H), 7.06-6.99 (m, 1H), 6.89 (br dd, J = 1.1, 8.6 Hz, 1H), 6.69 (s, 1H), 4.09 (q, 1H), 3.94 (s, 3H), 3.78 (d, J = 9.5 Hz, 1H), 3.76-3.65 (m, 2H), 2.98 (d, 3H) 2.15 δ = 10.05 (br s, 1H), 8.04- 7.97 (m, 1H), 7.46 (s, 1H), 7.01 (ddt, J = 2.1, 5.9, 8.3 Hz, 1H), 6.93-6.84 (m, 1H), 4.21 (q, J = 8.8 Hz, 1H), 4.00 (s, 3H), 3.75 (t, J = 9.5 Hz, 1H), 3.64 (d, J = 9.4 Hz, 1H), 3.27 (dd, J = 8.1, 9.9 Hz, 1H), 2.97 (s, 3H)

Biological Examples

(42) Herbicidal Efficacy of Compounds of Formula (II)

(43) Seeds of a variety of test species [Ipomoea hederacea (IPOHE); Zea mays (ZEAMX); Echinochloa crus-galli (ECHCG); Setaria faberi (SETFA); Abutilon theophrasti (ABUTH); Amaranthus retroflexus (AMARE)] were sown in standard sterilised soil in pots. After cultivation for one day (pre-emergence) or after 8 days cultivation (post-emergence) under controlled conditions in a glasshouse (at 24/16° C., day/night; 14 hours light; 65% humidity), the plants were sprayed with an aqueous spray solution derived from the formulation of the technical active ingredient in acetone/water (50:50) solution containing 0.5% Tween 20 (polyoxyethelyene sorbitan monolaurate, CAS RN 9005-64-5), subsequently diluted in water, and sprayed to give the stated application rate.

(44) The test plants were then grown under controlled conditions in a glasshouse (at 24/16° C., day/night; 14 hours light; 65% humidity) and watered twice daily.

(45) After 13 days for pre and post-emergence, the test was evaluated visually for percentage phytotoxicity to the plant (where 100=total damage to plant; 0=no damage to plant). Results are shown in Tables B1 and B2.

(46) TABLE-US-00014 TABLE B1 Application post-emergence Compound Rate Number (g/ha) AMARE ABUTH SETFA ECHCG ZEAMX IPOHE 2.1 250 20 0 90 90 80 0 2.3 250 10 60 70 70 60 10 2.2 250 0 0 90 90 50 0 2.4 250 0 0 70 70 0 0 2.7 250 50 0 80 80 80 0 2.6 250 0 0 70 70 80 50 2.5 250 30 0 80 80 10 0 2.11 250 20 0 80 80 0 0 2.8 250 0 0 80 80 80 30 2.10 250 0 0 80 80 80 30 2.9 250 0 0 80 80 40 50 2.12 250 0 0 90 90 80 50 2.15 250 0 0 80 80 30 40

(47) TABLE-US-00015 TABLE B2 Application pre-emergence Compound Rate Number (g/ha) AMARE ABUTH SETFA ECHCG ZEAMX IPOHE 2.1 250 70 10 90 100 90 30 2.3 250 50 70 90 90 60 10 2.2 250 20 0 90 90 20 0 2.4 250 0 0 90 90 30 50 2.7 250 20 10 90 100 90 20 2.6 250 0 0 90 90 80 20 2.5 250 0 0 90 90 20 10 2.11 250 70 0 90 90 20 0 2.8 250 20 0 90 90 40 0 2.10 250 0 0 90 90 40 20 2.9 250 0 0 90 100 80 40 2.12 250 0 0 90 90 90 70 2.15 250 0 40 100 100 40 20