HERBICIDAL ARYLCYCLOPENTENE CARBOXAMIDES

Abstract

The invention relates to compounds of formula (I), and their use as herbicides. In said formula, R.sup.1 to R.sup.8 represent groups such as hydrogen, halo-gen or organic groups such as alkyl, alkenyl, alkynyl, or alkoxy; W.sup.1 and W.sup.2 are CR.sup.9R.sup.10, C(O), O, X is a bond or a divalent unit; Y is hydrogen, cyano, hydroxyl or a linear or cyclic organic group. The invention further refers to a composition comprising such compound and to the use thereof for controlling unwanted vegetation.

##STR00001##

Claims

1. A compound of formula (I) ##STR00400## wherein the substituents have the following meanings: W.sup.1, W.sup.2 each independently CR.sup.9R.sup.10, C(O), O; R.sup.1 hydrogen, (C.sub.1-C.sub.3)-alkyl, (C.sub.3-C.sub.4)-cycloalkyl, (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)-alkyl, (C.sub.1-C.sub.3)-haloalkoxy; R.sup.2 hydrogen, halogen, (C.sub.1-C.sub.3)-alkyl, (C.sub.1-C.sub.3)-haloalkyl, (C.sub.1-C.sub.3)-alkoxy, (C.sub.1-C.sub.3)-haloalkoxy; R.sup.3 hydrogen, halogen, nitro, hydroxyl, cyano, (C.sub.1-C.sub.3)-alkyl, (C.sub.1-C.sub.3)-haloalkyl, hydroxy-(C.sub.1-C.sub.3)-alkyl, (C.sub.3-C.sub.5)-cycloalkyl, (C.sub.3-C.sub.5)-halocycloalkyl, hydroxy-(C.sub.3-C.sub.5)-cycloalkyl, (C.sub.1-C.sub.3)-alkoxy, (C.sub.1-C.sub.3)-haloalkoxy, (C.sub.1-C.sub.3)-alkoxycarbonyl, (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)-alkylthio, (C.sub.1-C.sub.3)-alkylsulfinyl, (C.sub.1-C.sub.3)-alkylsulfonyl; R.sup.4 hydrogen, halogen, hydroxyl, cyano, (C.sub.1-C.sub.3)-alkyl, (C.sub.1-C.sub.3)-haloalkyl, (C.sub.3-C.sub.4)-halocycloalkyl, (C.sub.1-C.sub.3)-haloalkoxy, (C.sub.2-C.sub.3)-haloalkenyl, (C.sub.2-C.sub.3)-haloalkynyl; R.sup.5 hydrogen, halogen, nitro, hydroxyl, cyano, (C.sub.1-C.sub.3)-alkyl, (C.sub.1-C.sub.3)-haloalkyl, hydroxy-(C.sub.1-C.sub.3)-alkyl, (C.sub.3-C.sub.5)-cycloalkyl, (C.sub.3-C.sub.5)-halocycloalkyl, hydroxy-(C.sub.3-C.sub.5)-cycloalkyl, (C.sub.1-C.sub.3)-alkoxy, (C.sub.1-C.sub.3)-haloalkoxy, (C.sub.1-C.sub.3)-alkoxycarbonyl, (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)-alkylthio, (C.sub.1-C.sub.3)-alkylsulfinyl, (C.sub.1-C.sub.3)-alkylsulfonyl; R.sup.6 hydrogen, halogen, (C.sub.1-C.sub.3)-alkyl, (C.sub.1-C.sub.3)-haloalkyl, (C.sub.1-C.sub.3)-alkoxy, (C.sub.1-C.sub.3)-haloalkoxy; R.sup.7 hydrogen, halogen, cyano, or (C.sub.1-C.sub.6)-alkyl, (C.sub.3-C.sub.6)-cycloalkyl, (C.sub.2-C.sub.6)-alkenyl, (C.sub.2-C.sub.6)-alkynyl, (C.sub.1-C.sub.6)-alkoxy, each substituted by m radicals selected from the group consisting of fluorine, chlorine, bromine, iodine, hydroxyl, cyano, and (C.sub.1-C.sub.6)-alkoxy; R.sup.8 hydrogen, halogen, (C.sub.1-C.sub.3)-alkyl, (C.sub.1-C.sub.3)-haloalkyl, and (C.sub.3-C.sub.5)-cycloalkyl; R.sup.9, R.sup.10 each independently hydrogen, halogen, cyano, or (C.sub.1-C.sub.6)-alkyl, (C.sub.1-C.sub.6)-alkoxy, each substituted by m radicals selected from the group consisting of fluorine, chlorine, bromine, iodine, and cyano; or R.sup.9 and R.sup.10 form, together with the carbon atom to which they are bound, a saturated, partially or fully unsaturated three to six-membered ring containing, in addition to this carbon atom, q carbon atoms and n oxygen atoms; X a bond (X.sup.0) or a divalent unit from the group consisting of (X.sup.1), (X.sup.2), (X.sup.3), (X.sup.4), (X.sup.5), and (X.sup.6): ##STR00401## R.sup.11-R.sup.16 each independently hydrogen, fluorine, chlorine, bromine, iodine, hydroxyl, cyano, CO.sub.2R.sup.e, CONR.sup.bR.sup.d, NR.sup.bCO.sub.2R.sup.e, R.sup.a, or (C.sub.1-C.sub.6)-alkyl, (C.sub.3-C.sub.5)-cycloalkyl, (C.sub.2-C.sub.6)-alkenyl, (C.sub.2-C.sub.6)-alkynyl, each substituted by m radicals selected from the group consisting of fluorine, chlorine, bromine, iodine, hydroxyl and cyano, or (C.sub.1-C.sub.6)-alkoxy, (C.sub.3-C.sub.6)-cycloalkoxy, (C.sub.3-C.sub.6)-alkenyloxy, (C.sub.3-C.sub.6)-alkynyloxy, (C.sub.1-C.sub.3)-alkylthio, (C.sub.1-C.sub.3)-alkylsulfinyl or (C.sub.1-C.sub.3)-alkylsulfonyl, each substituted by m radicals selected from the group consisting of fluorine, chlorine, bromine, iodine, cyano, and (C.sub.1-C.sub.2)-alkoxy; Y hydrogen, cyano, hydroxyl, Z, or (C.sub.1-C.sub.12)-alkyl, (C.sub.3-C.sub.8)-cycloalkyl, (C.sub.2-C.sub.12)-alkenyl or (C.sub.2-C.sub.12)-alkynyl, each substituted by m radicals selected from the group consisting of fluorine, chlorine, bromine, iodine, cyano, hydroxyl, OR.sup.d, Z, OZ, NHZ, S(O).sub.nR.sup.a, SO.sub.2NR.sup.bR.sup.d, SO.sub.2NR.sup.bCOR.sup.e, CO.sub.2R.sup.e, CONR.sup.bR.sup.h, COR.sup.b, CONR.sup.eSO.sub.2R.sup.a, NR.sup.bR.sup.e, NR.sup.bCOR.sup.e, NR.sup.bCONR.sup.eR.sup.e, NR.sup.bCO.sub.2R.sup.e, NR.sup.bSO.sub.2R.sup.e NR.sup.bSO.sub.2NR.sup.bR.sup.e, OCONR.sup.bR.sup.e, OCSNR.sup.bR.sup.e, POR.sup.fR.sup.f, and C(R.sup.b)?NOR.sup.e; Z a three-, four-, five- or six-membered saturated, partly unsaturated, fully unsaturated or aromatic ring, except phenyl, which is formed from r carbon atoms, n nitrogen atoms, n sulfur atoms and n oxygen atoms, and which is substituted by m radicals selected from the group consisting of CO.sub.2R.sup.e, CONR.sup.bR.sup.h, S(O).sub.nR.sup.a, SO.sub.2NR.sup.bR.sup.d, SO.sub.2NR.sup.bCOR.sup.e, COR.sup.b, CONR.sup.eSO.sub.2R.sup.a, NR.sup.bR.sup.e, NR.sup.bCOR.sup.e, NR.sup.bCONR.sup.eR.sup.e, NR.sup.bCO.sub.2R.sup.e, NR.sup.bSO.sub.2R.sup.e, NR.sup.bSO.sub.2NR.sup.bR.sup.e, OCONR.sup.bR.sup.e, OCSNR.sup.bR.sup.e, POR.sup.fR.sup.f, and C(R.sup.b)?NOR.sup.e, R.sup.b, R.sup.c, R.sup.e and R.sup.f, and where the sulfur atoms and carbon atoms bear n oxo groups; R.sup.a (C.sub.1-C.sub.6)-alkyl, (C.sub.3-C.sub.6)-cycloalkyl or phenyl, each of which is substituted by m radicals selected from the group consisting of fluorine, chlorine, bromine, iodine, cyano, hydroxy, and (C.sub.1-C.sub.3)-alkoxy; R.sup.b hydrogen, (C.sub.1-C.sub.3)-alkoxyl or R.sup.a; R.sup.c fluorine, chlorine, bromine, iodine, cyano, hydroxyl, S(O).sub.nR.sup.a, or (C.sub.1-C.sub.6)-alkoxy, (C.sub.3-C.sub.6)-alkenyloxy or (C.sub.3-C.sub.6)-alkynyloxy, each of which is substituted by m radicals selected from the group consisting of fluorine, chlorine, bromine, cyano, and (C.sub.1-C.sub.2)-alkoxy; R.sup.d hydrogen or (C.sub.1-C.sub.6)-alkyl, (C.sub.3-C.sub.6)-cycloalkyl, (C.sub.2-C.sub.4)-alkenyl, (C.sub.3-C.sub.6)-cycloalkyl-(C.sub.1-C.sub.3)-alkyl, phenyl-(C.sub.1-C.sub.3)-alkyl or (C.sub.2-C.sub.4)-alkynyl, each of which is substituted by m radicals selected from the group consisting of fluorine, chlorine, bromine, cyano, CO.sub.2R.sup.a, CONR.sup.bR.sup.h, (C.sub.1-C.sub.2)-alkoxy, (C.sub.1-C.sub.3)-alkylthio, (C.sub.1-C.sub.3)-alkylsulfinyl, (C.sub.1-C.sub.3)-alkylsulfonyl, phenylthio, phenylsulfinyl, and phenylsulfonyl; R.sup.e R.sup.d; R.sup.f (C.sub.1-C.sub.3)-alkyl or (C.sub.1-C.sub.3)-alkoxy; R.sup.h hydrogen or (C.sub.1-C.sub.6)-alkyl, (C.sub.1-C.sub.2)-alkoxy, (C.sub.3-C.sub.6)-cycloalkyl, (C.sub.2-C.sub.4)-alkenyl, (C.sub.1-C.sub.6)-alkoxycarbonyl-(C.sub.1-C.sub.6)-alkyl, or (C.sub.2-C.sub.4)-alkynyl, each of which is substituted by m radicals selected from the group consisting of fluorine, chlorine, bromine, cyano, CO.sub.2R.sup.a, and (C.sub.1-C.sub.2)-alkoxy; m 0, 1, 2, 3, 4, or 5; n 0, 1, or 2; q 1, 2, 3, 4, or 5; r 1, 2, 3, 4, 5, or 6; including their agriculturally acceptable salts, amides, esters or thioesters, provided the compounds of formula (I) have a carboxyl group; except the compounds N-(1,1-Dimethylethyl)-2,3-dihydro-2-methyl-3-oxo-5-phenyl-2-furancarboxamide and N,N-dimethyl-3-phenyl-cyclopent-3-ene-1-carboxamide.

2. The compound as claimed in claim 1, wherein the substituents have the following meaning: W.sup.1 CH.sub.2, C(O), or O; W.sup.2 CR.sup.9R.sup.10 or C(O).

3. The compound as claimed in claim 1, wherein the substituents have the following meaning: R.sup.1 hydrogen.

4. The compound as claimed in claim 1, wherein the substituents have the following meaning: R.sup.2 hydrogen, halogen, (C.sub.1-C.sub.3)-alkyl; R.sup.6 hydrogen, halogen, (C.sub.1-C.sub.3)-alkyl.

5. The compound as claimed in claim 1, wherein the substituents have the following meaning: R.sup.3 hydrogen, halogen, hydroxyl, cyano, (C.sub.1-C.sub.3)-alkyl; R.sup.5 hydrogen, halogen, hydroxyl, cyano, (C.sub.1-C.sub.3)-alkyl.

6. The compound as claimed in claim 1, wherein the substituents have the following meaning: R.sup.4 hydrogen, halogen.

7. The compound as claimed in claim 1, wherein the substituents have the following meaning: R.sup.7 (C.sub.1-C.sub.2)-alkyl, cyclopropyl, (C.sub.1-C.sub.2)-haloalkyl, (C.sub.2-C.sub.3)-alkenyl, (C.sub.1-C.sub.2)-alkoxy; R.sup.3 hydrogen or halogen.

8. The compound as claimed in claim 1, wherein the substituents have the following meaning: R.sup.9 hydrogen, halogen, (C.sub.1-C.sub.3)-alkyl, (C.sub.1-C.sub.3)-haloalkyl; R.sup.10 hydrogen, halogen, (C.sub.1-C.sub.3)-alkyl, (C.sub.1-C.sub.3)-haloalkyl.

9. The compound as claimed in claim 1, wherein the substituents have the following meaning: X a bond.

10. The compound as claimed in claim 1, wherein the substituents have the following meaning: X a bond; Y (C.sub.1-C.sub.8)-alkyl, (C.sub.3-C.sub.8)-cycloalkyl, (C.sub.2-C.sub.8)-alkenyl or (C.sub.2-C.sub.8)-alkynyl, each substituted by m radicals selected from the group consisting of fluorine, chlorine, bromine, iodine, cyano, hydroxyl, OR.sup.d, Z, OZ, NHZ, S(O).sub.nR.sup.a, SO.sub.2NR.sup.bR.sup.d, SO.sub.2NR.sup.bCOR.sup.e, CO.sub.2R.sup.e, CONR.sup.bR.sup.h, COR.sup.b, CONR.sup.eSO.sub.2R.sup.a, NR.sup.bR.sup.e, NR.sup.bCOR.sup.e, NR.sup.bCONR.sup.eR.sup.e, NR.sup.bCO.sub.2R.sup.e, NR.sup.bSO.sub.2R.sup.e NR.sup.bSO.sub.2NR.sup.bR.sup.e, OCONR.sup.bR.sup.e, OCSNR.sup.bR.sup.e, POR.sup.fR.sup.f, and C(R.sup.b)?NOR.sup.e.

11. The compound as claimed in claim 1, wherein the substituents have the following meaning: X a bond; Y Z; Z a four- or five-membered saturated or partly unsaturated ring, which is formed from r carbon atoms and n oxygen atoms, each substituted by selected m radicals from the group consisting of CO.sub.2R.sup.e, CONR.sup.bR.sup.h, R.sup.b, R.sup.c, R.sup.e, and R.sup.f.

12. A composition comprising at least one compound as claimed in claim 1, and at least one auxiliary, which is customary for formulating crop protection compounds.

13. The composition as claimed in claim 12, comprising a further herbicide.

14. (canceled)

15. A method for controlling unwanted vegetation which comprises contacting a herbicidally effective amount of at least one compound as claimed in claim 1 with plants, their seed, and/or their habitat.

Description

A CHEMISTRY EXAMPLES

[0603] Chemical bonds, drawn as bars in chemical formulae, indicate the relative stereochemistry on the ring system.

Example 1

Synthesis of ethyl 4-(3,5-difluorophenyl)-2,3-dihydrofuran-2-carboxylate (Inter A)

[0604] ##STR00337##

[0605] To a mixture of aryl bromide (I) (40 g, 209 mmol) in dimethoxyethane (500 mL) was added compound II (35.2 g, 209 mmol), aq. sat, Na.sub.2CO.sub.3 (500 mL) and tetrakis(triphenylphosphine)-palladium(0) (Pd(PPh.sub.3).sub.4, CAS: 14221-01-3 (7.26 g, 6.28 mmol) at 15? C. and stirred at 90? C. for 16 h under nitrogen atmosphere. The mixture was poured into water (500 mL) and extracted with EtOAc (2?500 mL). The combined organics were washed with brine, dried and concentrated. The crude was purified by flash column chromatography (hexane/EtOAc=9:1) to give compound III (26 g, 81%) as yellow oil. .sup.1H-NMR (400 MHz, CDCl.sub.3): ?=6.97 (dd, J=9.1, 2.1 Hz, 2H), 6.72 (tt, J=8.8, 2.3 Hr, 1H), 5.41 (s, 1H), 2.12 (s, 3H).

##STR00338##

[0606] To a mixture of compound III (20 g, 129 mmol) in acetonitrile (200 mL) was added glyoxylic acid ethyl ester (40 g, 389 mmol) and Yb(OTf).sub.3 (16 g, 25.67 mmol) at 15? C. and stirred at the same temperature for 16 h. The mixture was concentrated, diluted with H.sub.2O (200 mL) and extracted with EtOAc (2?200 mL). The combined organics were washed with brine, dried and concentrated. The crude was purified by flash column chromatography (hexane/EtOAc=9:1) to give compound V (14 g, 42%) as a yellow oil. .sup.1H-NMR (400 MHz, CDCl.sub.3): ?=6.98-6.92 (m, 2H), 6.74 (tt, J=8.8, 2.3 Hz, 1H), 5.45 (s, 1H), 5.30 (d, J=5.0 Hz, 1H), 4.27 (ddd, J=7.4, 5.9, 4.6 Hz, 1H), 4.22-4.10 (m, 2H), 3.00 (dd, J=14.6, 4.3 Hz, 1H), 2.83-2.73 (m, 2H), 1.28 (t, J=7.1 Hz, 3H).

##STR00339##

[0607] To a mixture of compound V (14 g, 55 mmol) in ethyl vinyl ether (105 mL) was added trifluoroacetic acid (21 mL) at 15? C. and stirred at 50? C. for 16 h. After concentrating the mixture, the crude was purified by flash column chromatography (hexane/EtOAc=10:1) to afford compound VI (12.5 g, 69%) as a yellow oil. .sup.1H-NMR (400 MHz, CDCl.sub.3): ?=7.02-6.91 (m, 2H), 6.80-6.69 (m, 1H), 5.44 (d, J=7.3 Hz, 1H), 5.31-5.25 (m, 1H), 4.76-4.84 (m, 1H), 4.32-4.05 (m, 4H), 3.64-3.31 (m, 2H), 2.98-2.78 (m, 2H), 1.31-1.25 (m, 5H), 1.12-1.02 (m, 3H).

##STR00340##

[0608] To a solution of compound VI (12.5 g, 36.6 mmol) in dichloromethane (130 mL) was added triethylamine (7.6 mL, 55 mmol) and trimethylsilyl triflate (8.75 mL, 47.5 mmol) at 0? C. und a nitrogen atmosphere. After stirring for 16 h at room temperature, the mixture was diluted with water (100 mL) and extracted with dichloromethane (2?100 mL). The combined extracts were washed with brine, dried over Na.sub.2SO.sub.4 and concentrated. The residue was purified by flash column chromatography (hexane/EtOAc=10:1) to afford compound VII (7.2 g, 60%) as a yellow oil. .sup.1H-NMR (400 MHz, CDCl.sub.3): ?=6.99-6.87 (m, 2H), 6.76-6.71 (m, 1H), 6.34 (dd, J=14.3, 6.8 Hz, 1H), 5.44 (s, 1H), 5.28 (s, 1H), 4.37-4.32 (m, 1H), 4.25-4.13 (m, 3H), 4.07 (dd, J=6.8, 2.5 Hz, 1H), 3.01-2.93 (m, 2H), 1.27 (t, J=7.1 Hz, 3H).

##STR00341##

[0609] To a solution of compound VII (2.0 g, 6.1 mmol) in 1,2-dichloroethane (1 L) was added Grubb's second generation catalyst (CAS: 301224-40-8) (2.0 g, 2.4 mmol) at 0? C. under a nitrogen atmosphere. After stirring for 16 h at 90? C. under nitrogen, the mixture was diluted with water (10 mL) and stirred for 30 min at room temperature. After concentrating the mixture, the residue was purified by flash column chromatography (hexane/EtOAc=10:1) to afford compound VIII (3.0 g, 64%) as a yellow oil. .sup.1H-NMR (400 MHz, CDCl.sub.3): ?=6.93 (s, 1H), 6.76-6.69 (m, 2H), 6.65-6.58 (m, 1H), 5.16 (dd, J=11.5, 7.3 Hz, 1H), 4.29 (q, J=7.2 Hz, 2H), 3.34-3.25 (m, 1H), 3.11 (ddd, J=14.8, 7.2, 1.8 Hz, 1H), 1.34 (t, J=7.1 Hz, 3H).

Example 2

Synthesis of 4-(3,5-difluorophenyl)-2-methyl-3H-furan-2-carboxylic acid (Inter B)

[0610] ##STR00342##

[0611] To a solution of Inter A (2.0 g, 7.9 mmol) in THF (100 mL) was added methyl iodide (5.6 g, 39 mmol) and a solution of lithium bis(trimethylsilyl)amide (1 M in THF, 23.6 mL, 23.6 mmol) at 0? C. under a nitrogen atmosphere. After stirring for 2 h at 0? C. under nitrogen, the mixture was poured into water (50 mL), acidified with aq. HCl (1 M) to pH=3 and extracted with EtOAc (2?100 mL). The combined extracts were washed with brine, dried over Na.sub.2SO.sub.4 and concentrated. The residue was purified by flash column chromatography (hexane/EtOAc=10:1) to afford compound VIII (1.0 g, 47%) as a yellow oil. .sup.1H-NMR (400 MHz, CDCl.sub.3): ?=6.87 (t, J=1.8 Hz, 1H), 6.74-6.69 (m, 2H), 6.63-6.59 (m, 1H), 4.31-4.23 (m, 2H), 3.36 (dd, J=14.9, 2.0 Hz, 1H), 2.84 (dd, J=14.9, 2.0 Hz, 1H), 1.68 (s, 3H), 1.33 (t, J=7.2 Hz, 3H).

##STR00343##

[0612] To a solution of compound VIII (0.78 g, 2.9 mmol) in THF (9 mL) was added lithium hydroxide hydrate (367 mg, 8.73 mmol) and water (3 mL). After stirring for 2 h at room temperature, the mixture was diluted with water (10 mL), acidified with aq. HCl (1 M) until pH=3 and extracted with EtOAc (3?10 mL). The combined extracts were washed with brine, dried over Na.sub.2SO.sub.4 and concentrated to provide Inter B (1.0 g, quantitative) as a yellow oil. This product was used without further purification in the next step. LC-MS (M+H).sup.+: 240.0.

Example 3

Synthesis of methyl (3S)-3-[[4-(3,5-difluorophenyl)-2-methyl-3H-furan-2-carbonyl]amino]butanoate (Cpd I.1 and Cpd I.2)

[0613] ##STR00344##

[0614] To a solution of Inter B (0.72 g, 3.0 mmol) in THF (10 mL) was added the HCl salt of amine XI (0.73 g, 4.5 mmol), triethylamine (0.83 mL, 6.0 mmol) and HATU (CAS: 148893-10-1) (1.4 g, 3.6 mmol). After stirring for 2 h at room temperature, the mixture was diluted with water (10 mL) and extracted with methyl tert-butyl ether (3?10 mL). The combined extracts were washed with brine, dried over Na.sub.2SO.sub.4 and concentrated. The residue was purified by prep-HPLC (TFA, to give Cpd I.1 (110 mg, 10%) as yellow oil and Cpd I.2 (100 mg, 10%) as yellow oil (the stereocenter of the diastereomers was not elucidated). Cpd I.1: .sup.1H-NMR (400 MHz, CDCl.sub.3): ?=7.12 (br d, J=8.3 Hz, 1H), 6.85 (t, J=1.75 Hz, 1H), 6.75-6.67 (m, 2H), 6.63-6.59 (m, 1H), 4.39-4.29 (m, 1H), 3.64 (s, 3H), 3.31 (dd, J=15.1, 2.0 Hz, 1H), 2.83 (dd, J=15.1, 2.0 Hz, 1H), 2.52 (dd, J=5.5, 2.0 Hz, 2H), 1.64 (s, 3H), 1.27 (d, J=6.6 Hz, 3H). Cpd I.2: .sup.1H-NMR (400 MHz, CDCl.sub.3): ?=7.07 (br d, J=8.4 Hz, 1H), 6.87-6.83 (m, 1H), 6.74-6.67 (m, 2H), 6.63-6.59 (m, 1H), 4.39-4.29 (m, 1H), 3.70 (s, 3H), 3.33 (dd, J=15.2, 1.9 Hz, 1H), 2.83 (dd, J=15.2, 1.9 Hz, 1H), 2.56 (dd, J=5.5, 2.7 Hz, 2H), 1.62 (s, 3H), 1.24 (d, J=6.8 Hz, 3H).

Example 4

Synthesis of methyl (1S,4R)-4-[[4-(3,5-difluorophenyl)-2-methyl-3H-furan-2-carbonyl]amino]cyclopent-2-ene-1-carboxylate (Cpd I.5)

[0615] ##STR00345##

[0616] According to the synthesis of example 3, to a solution of Inter B (2.0 g, 8.3 mmol) in DMF (100 mL) was added the HCl salt of amine X (1.63 g, 9.16 mmol), diisopropylethylamine (4.3 mL, 25 mmol) and HATU (CAS: 148893-10-1) (3.48 g, 9.16 mmol). After stirring for 16 h at room temperature, the mixture was diluted with water (10 mL) and extracted with EtOAc (3?100 mL). The combined extracts were washed with brine, dried over Na.sub.2SO.sub.4 and concentrated. The residue was purified by flash column chromatography (hexane/EtOAc=9:1) to afford Cpd I.5 (1.84 g, 61%) as a 1:1-mixture of diastereomers. .sup.1H-NMR (400 MHz, CDCl.sub.3): ?=7.12-7.02 (m, 2H), 6.89-6.85 (m, 1H), 6.84 (t, J=2.0 Hz, 1H), 6.76-6.65 (m, 4H), 6.64-6.55 (m, 2H), 5.97-5.82 (m, 4H), 5.10-5.01 (m, 2H), 3.74 (s, 3H), 3.71 (s, 3H), 3.57-3.50 (m, 2H), 3.35 (dd, J=4.4, 2.0 Hz, 1H), 3.31 (dd, J=4.4, 2.0 Hz, 1H), 2.86 (t, J=2.2 Hz, 1H), 2.82 (t, J=2.1 Hz, 1H), 2.58-2.41 (m, 2H), 1.92 (dt, J=13.9, 3.6 Hz, 1H), 1.85 (dt, J=13.9, 3.5 Hz, 1H), 1.65 (s, 3H), 1.64 (s, 3H).

Example 5

Synthesis of 4-(3,5-dichlorophenyl)-2-methyl-3H-furan-2-carboxylic acid (Inter C)

[0617] ##STR00346##

[0618] To a solution of compound XI (50 g, 431 mmol) in THF (200 mL) was added propargyl bromide (103 g, 862 mmol) and Zn (64.5 g, 1.08 mol) at room temperature. After heating the reaction to 80? C., the suspension was stirred for 3 h. After cooling to room temperature, the mixture was filtered and the filtrate was quenched with HCl (2N) and extracted with EtOAc. The combined organics were washed with brine, dried over Na.sub.2SO.sub.4 and concentrated. The crude was purified by flash column chromatography (hexane/EtOAc=100:0 to 7:3) to give the compound XIII (34.6 g, 51.6%) as a yellow oil. .sup.1H-NMR (400 MHz, CDCl.sub.3): ?=4.36-4.16 (m, 2H), 2.72-2.50 (m, 2H), 2.06 (t, J=2.57 Hz, 1H), 1.47 (s, 3H), 1.34-1.28 (m, 3H).

##STR00347##

[0619] To a mixture of compound XIII (17 g, 110 mmol) in acetone (300 ml) was added Ag.sub.2O (12.6 g, 55 mmol) and triethylamine (11.1 g, 110 mmol) at room temperature. After stirring the reaction at 50? C. for 2 h, the suspension was filtered and the filtrate was concentrated. The crude was purified by flash column chromatography (hexane/EtOAc=100:0 to 1:1) to give the compound XIV (17 g, 100%) as a yellow oil. .sup.1H-NMR (400 MHz, CDCl.sub.3): ?=6.30 (q, J=2.4 Hz, 1H), 4.87 (q, J=2.5 Hz, 1H), 4.30-4.18 (m, 2H), 3.04 (dt, J=15.7, 2.3 Hz, 1H) 2.54 (dt, J=15.7, 2.32 Hz, 1H), 1.58 (s, 3H), 1.29-1.33 (t, 3H).

##STR00348##

[0620] To a solution of compound XIV (17 g, 110 mmol) in dichloromethane (250 mL) was added bromine (17.4 g, 110 mmol) in dichloromethane (50 mL) dropwise at ?78? C. and stirred at ?78? C. for 10 min. 1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU, CAS: 6674-22-2) (67 g, 440 mmol) was added at ?78? C. dropwise. After removing the cold bath, the mixture was stirred for 1 h at room temperature. The mixture was quenched with HCl (1 M) and extracted with dichloromethane (2?50 mL). The combined extracts were washed with brine, dried over Na.sub.2SO.sub.4 and concentrated. The crude was purified by flash column chromatography (hexane/EtOAc=100:0 to 1:1) to give the compound XV (16.5 g, 65%) as a yellow amorphous solid. .sup.1H-NMR (400 MHz, CDCl.sub.3): ?=6.37 (t, J=2.1 Hz, 1H), 4.32-4.20 (m, 2H), 3.26 (dd, J=15.3, 2.1 Hz, 1H), 2.74 (dd, J=15.4, 2.2 Hz, 1H), 1.62 (s, 3H), 1.32 (t, J=7.15 Hz, 3H).

##STR00349##

[0621] To the emulsion of compound XV (1.5 g, 6.4 mmol) in a 5:1-mixture of toluene (30 mL) and water (6 mL), aryl boronic acid XVI (1.35 g, 7.05 mmol), Cs.sub.2CO.sub.3 (10 g, 32 mmol) and Pd(dppf)Cl.sub.2 (CAS: 72287-26-4) (300 mg, 0.41 mmol) were added at room temperature and the mixture was stirred at 110? C. for 2 h under nitrogen atmosphere. The reaction was quenched with H.sub.2O (20 mL) and extracted with EtOAc (3?30 mL). The combined organics were washed with brine, dried over Na.sub.2SO.sub.4 and concentrated. The crude was purified by flash column chromatography (hexane/EtOAc=100:0 to 1:1) to provide compound XVII (1.3 g, 68%) as a yellow oil. .sup.1H-NMR (400 MHz, CDCl.sub.3): ?=7.14 (t, J=1.6 Hz, 1H), 7.07 (d, J=1.6 Hz, 2H), 6.88 (s, 1H), 4.27 (q, J=7.3 Hz, 2H), 3.36 (dd, J=14.9, 1.9 Hz, 1H), 2.84 (dd, J=14.9, 1.9 Hz, 1H), 1.67 (s, 3H), 1.33 (t, J=7.2 Hz, 3H).

##STR00350##

[0622] To a solution of compound XVII (1.3 g, 4.3 mmol) in a 3:1 mixture of THF (15 mL) and water (5 mL) was added lithium hydroxide (364 mg, 3.34 mmol) at room temperature. After stirring for 2 h, the mixture was quenched with H.sub.2O, acidified with aq. HCl (6 M) until pH=3 and extracted with EtOAc (3?20 mL). The combined organics were washed with brine, dried over Na.sub.2SO.sub.4 and concentrated to give Inter C (900 mg, 77%) as an amorphous yellow solid. The crude was used in the next step without further purification. For analytic purposes a small sample of Inter C was purified by prep-HPLC (TFA, CH.sub.3CNH.sub.2O). .sup.1H-NMR (400 MHz, DMSO-d.sub.6): ?=13.09 (br s, 1H), 7.44 (s, 1H), 7.35 (d, J=1.6 Hz, 2H), 7.31 (s, 1H), 3.24 (br d, J=13.8 Hz, 1H), 2.85 (br d, J=13.7 Hz, 1H), 1.53 (s, 3H).

Example 6

Synthesis of methyl (3S)-3-[[4-(3,5-dichlorophenyl)-2-methyl-3H-furan-2-carbonyl]amino]butanoate (Cpd I.3 and Cpd I.4)

[0623] ##STR00351##

[0624] According to the synthesis of example 3, to a solution of Inter C (900 mg, 3.3 mmol) in a mixture of THF (10 mL) and water (2 mL) was added the HCl salt of amine XI (655 mg, 3.97 mmol), triethylamine (667 mL, 6.6 mmol) and HATU (CAS: 148893-10-1) (1.5 g, 4.0 mmol). After stirring for 2 h at room temperature, the mixture was diluted with water (10 mL) and extracted with methyl tert-butyl ether (3?10 mL). The combined extracts were washed with brine, dried over Na.sub.2SO.sub.4 and concentrated. The residue was purified by prep-HPLC (TFA, to give Cpd I.3 (57 mg, 4%) as a yellow oil and Cpd I.4 (57 mg, 4%) as a yellow oil (the stereocenter of the diastereomers was not elucidated). Cpd I.3: .sup.1H-NMR (400 MHz, CDCl.sub.3): ?=7.15 (t, J=1.8 Hz, 1H), 7.11 (br d, J=8.6 Hz, 1H), 7.07 (d, J=1.8 Hz, 2H), 6.86 (t, J=1.9 Hz, 1H), 4.40-4.28 (m, 1H), 3.65 (s, 3H), 3.32 (dd, J=15.2, 2.0 Hz, 1H), 2.84 (dd, J=15.2, 2.0 Hz, 1H), 2.53 (dd, J=5.5, 1.3 Hz, 2H), 1.64 (s, 3H), 1.27 (d, J=6.6 Hz, 3H). Cpd I.4: .sup.1H-NMR (400 MHz, CDCl.sub.3): ?=7.15 (t, J=1.7 Hz, 1H), 7.08 (d, J=1.7 Hz, 2H), 7.05 (br d, J=8.6 Hz, 1H), 6.86 (s, 1H), 4.41-4.25 (m, 1H), 3.71 (s, 3H), 3.34 (dd, J=15.3, 2.0 Hz, 1H), 2.83 (dd, J=15.2, 2.0 Hz, 1H), 2.65-2.49 (m, 2H), 1.69-1.61 (m, 3H), 1.24 (d, J=6.9 Hz, 3H).

Example 7

Synthesis of 4-(3,5-difluorophenyl)-2-(trifluoromethyl)-3H-furan-2-carboxylic acid (Inter D)

[0625] ##STR00352##

[0626] According to the synthesis of Inter C, to a solution of compound XVIII (20 g, 13 mmol) in THF (200 mL) was added propargyl bromide (XII) (30.5 g, 256 mmol) and Zn (20.5 g, 321 mmol) at room temperature. After stirring for 2 h, the mixture was filtered, poured into water (100 mL), acidified with HCl (6 M) to pH=3 and extracted with methyl tert-butyl ether (3?100 mL). The combined extracts were washed with brine, dried over Na.sub.2SO.sub.4 and concentrated. The crude was purified by flash column chromatography (hexane/EtOAc=100:0 to 0:100) to give the compound XIX (36 g, 40%) as a yellow oil. The analytical and spectroscopic data are in alignment with the reported data from Tetrahedron 2003, 59, 1389-1394.

##STR00353##

[0627] To a mixture of compound XIX (36 g, 0.18 mol) in acetone (700 ml) was added Ag.sub.2O (21.3 g, 91.8 mmol) and triethylamine (25.5 mL, 114 mmol) at room temperature. After stirring the reaction for 2 h in the dark, the suspension was filtered and the filtrate was concentrated. The crude was purified by flash column chromatography (hexane/EtOAc=100:0 to 0:100) to give the compound XX (20 g, 55%) as a yellow oil. .sup.1H-NMR (400 MHz, CDCl.sub.3): ?=6.37 (d, J=2.3 Hz, 1H), 5.03 (d, J=2.3 Hz, 1H), 3.89 (s, 3H), 3.13 (d, J=2.4 Hz, 2H).

##STR00354##

[0628] To a solution of compound XX (15 g, 77 mmol) in dichloromethane (200 mL) was added bromine (12 g, 77 mmol) dropwise at ?78? C. and stirred at ?78? C. for 15 min. 1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU, CAS: 6674-22-2) (46.5 g, 306 mmol) was added at ?78? C. dropwise and stirred for 1 h at the same temperature. The mixture was poured into water (100 mL), acidified with HCl (6 M) to pH=3 and extracted with dichloromethane (2?50 mL). The combined extracts were washed with brine, dried over Na.sub.2SO.sub.4 and concentrated. The crude (8.5 g) was used in the next step without further purification.

##STR00355##

[0629] To the emulsion of compound XXII (7.5 g, 27 mmol) in a 5:1-mixture of toluene (80 mL) and water (16 mL), aryl boronic acid XXIII (4.3 g, 27 mmol), Cs.sub.2CO.sub.3 (44.9 g, 137 mmol) and Pd(dppf)Cl.sub.2 (CAS: 72287-26-4) (1.28 g, 1.75 mmol) were added at room temperature and the mixture was stirred at 110? C. for 1 h under nitrogen atmosphere. The reaction was quenched with H.sub.2O (40 mL) and extracted with EtOAc (3?30 mL). The combined organics were washed with brine, dried over Na.sub.2SO.sub.4 and concentrated. The crude (1.8 g, 7%) was used in the next step without further purification. For analytic purposes a small sample of compound XXIV (55 mg) was purified by prep-HPLC (TFA, CH.sub.3CNH.sub.2O). .sup.1H-NMR (400 MHz, CDCl.sub.3): ?=6.91 (s, 1H), 6.77-6.72 (m, 2H), 6.68 (tt, J=8.8, 2.1 Hz, 1H), 3.92 (s, 3H), 3.50-3.36 (m, 2H).

##STR00356##

[0630] To a solution of compound XXIV (1.5 g, 4.9 mmol) in a 3:1 mixture of THF (15 mL) and water (5 mL) was added lithium hydroxide (0.31 g, 7.3 mmol) at room temperature. After stirring for 2 h, the mixture was quenched with H.sub.2O, acidified with aq. HCl (6 M) until pH=3 and extracted with EtOAc (3?20 mL). The combined organics were washed with brine, dried over Na.sub.2SO.sub.4 and concentrated to give Inter C (900 mg, 77%) as an amorphous yellow solid. The crude (1.5 g, 21%) was used in the next step without further purification. For analytic purposes a small sample of Inter D was purified by prep-HPLC (TFA, CH.sub.3CNH.sub.2O). .sup.1H-NMR (400 MHz, CDCl.sub.3): ?=7.59 (s, 1H), 7.16 (br dd, J=9.3, 2.2 Hz, 2H), 7.05 (tt, J=9.3, 2.1 Hz, 1H), 3.45 (d, J=1.8 Hz, 2H).

Example 8

Synthesis of methyl (3S)-3-[[4-(3,5-difluorophenyl)-2-(trifluoromethyl)-3H-furan-2-carbonyl]amino]butanoate (Cpd I.7)

[0631] ##STR00357##

[0632] According to the synthesis of example 3, to a solution of Inter D (800 mg, 2.7 mmol) in THF (10 mL) was added the HCl salt of amine IX (642 mg, 5.44 mmol), triethylamine (0.76 mL, 5.4 mmol) and HATU (CAS: 148893-10-1) (1.55 g, 4.08 mmol). After stirring for 2 h at room temperature, the mixture was diluted with water (10 mL), acidified to pH=3 with aq. HCl (2 N) and extracted with EtOAc (3?10 mL). The combined extracts were washed with brine, dried over Na.sub.2SO.sub.4 and concentrated. The residue was purified by prep-HPLC (TFA, to give Cpd I.7 (180 mg, 17%) as a 1:1 mixture of diastereomers. .sup.1H-NMR (400 MHz, CDCl.sub.3): ?=7.44-7.28 (m, 2H), 6.89 (s, 2H), 6.79-6.73 (m, 4H), 6.71-6.6.68 (m, 2H), 4.45-4.33 (m, 2H), 3.71 (s, 3H), 3.68 (s, 3H), 3.57-3.47 (m, 2H), 3.40-3.31 (m, 2H), 2.62-2.53 (m, 4H), 1.32-I.26 (m, 6H).

Example 9

Synthesis of ethyl 4-(3,5-difluorophenyl)-1-methyl-2-oxo-cyclopent-3-ene-1-carboxylate (Inter E)

[0633] ##STR00358##

[0634] Following the reported experimental procedure described in Org. Lett. 2006, 8, 1419-1422, to a mixture of compound diethyl 2-methylpropanedioate (XXVII) (4.5 g, 26 mmol) in toluene (60 mL) was added NaH (1.0 g, 26 mmol) at 0? C. and the suspension stirred at 15? C. for 1 h. The mixture was added to a solution of 1,3-difluoro-5-iodo-benzene (XXV) (3.0 g, 13 mmol), compound 2-allenyl-4,4,5,5-tetramethyl-(1,3,2)-dioxaborolane (XXVI, CAS: 865350-17-0) (4.26 g, 25.6 mmol), Pd.sub.2(dba).sub.3 (300 mg, 0.425 mmol) and P(C.sub.6H4CF.sub.3-4).sub.3 (600 mg, 1.3 mmol) at 15? C. and stirred at 80? C. for 16 h under nitrogen atmosphere. The mixture was filtered through ca. 2 cm plug of silica gel, rinsed with toluene and the combined filtrates were concentrated. The residue was purified by flash column chromatography (hexane/EtOAc=9:1) and the combined mixed fractions were repurified by prep-HPLC (NH.sub.4HCO.sub.3H.sub.2O-MeCN) to give compound XXVIII (1 g, 17%) as a yellow oil. .sup.1H-NMR (400 MHz, CDCl.sub.3): ?=6.83 (dd, J=8.5, 1.9 Hz, 2H), 6.69-6.60 (m, 1H), 5.67 (s, 1H), 4.27-4.15 (m, 4H), 3.96-3.76 (m, 2H), 1.42 (s, 3H), 1.31-I.24 (m, 12H), 1.15 (t, J=7.1 Hz, 6H).

##STR00359##

[0635] Following the reported experimental procedure described in Org. Lett. 2006, 8, 1419-1422, to a solution of alkenyl boronate XXVII (300 mg, 0.77 mmol) in 1,4-dioxane (8 ml) was added 1,4-bis(diphenylphosphino)-butane (dppb, CAS: 7688-25-7) (165 mg, 0.386 mmol), Cs.sub.2CO.sub.3 (753 mg, 2.31 mmol), H.sub.2O (42 mg, 2.31 mmol) and bis-(1,5-cyclooctadiene)-dirhodium(I)-dichloride ([RhCl(cod)].sub.2, CAS: 12092-47-6) (95 mg, 0.19 mmol) at 15? C. and stirred at 95? C. for 4 h. The mixture was filtered and concentrated. The crude was purified by prep-HPLC (TFA-H.sub.2O-MeCN) to afford Inter E (100 mg, 46.38%) as a white amorphous solid. .sup.1H-NMR (400 MHz, CDCl.sub.3): ?=7.17 (dd, J=8.03, 2.1 Hz, 2H), 6.96 (tt, J=8.6, 2.2 Hz, 1H), 6.54-6.50 (m, 1H), 4.19 (qd, J=7.1, 3.2 Hz, 2H), 3.58 (dd, J=17.9, 1.8 Hz, 1H), 2.83 (dd, J=17.9, 1.63 Hz, 1H), 1.51 (s, 3H), 1.25 (t, J=7.15 Hz, 3H).

Example 10

Synthesis of 3-(3,5-difluorophenyl)-1-methyl-2-oxo-cyclopent-3-ene-1-carboxylic acid (Inter F)

[0636] ##STR00360##

[0637] To a mixture of compound ethyl 2-oxocyclopentanecarboxylate (XXIX) (10 g, 64 mmol) in acetonitrile (100 ml) was added K.sub.2CO.sub.3 (26.5 g, 190 mmol) and methyl iodide (18 g, 0.13 mmol) at 15? C. The mixture was stirred at 40? C. for 16 h. After filtration of the suspension, the filtrate was concentrated. The residue was purified by flash column chromatography (EtOAc/hexane=0:100 to 100:0) to give the compound ethyl 1-methyl-2-oxo-cyclopentanecarboxylate (XXX) (10 g, 92%) as a yellow oil. .sup.1H-NMR (400 MHz, CDCl.sub.3): ?=4.23-4.10 (m, 2H), 2.57-2.24 (m, 3H), 2.12-1.80 (m, 3H), 1.31 (s, 3H), 1.25 (t, J=7.1 Hz, 3H).

##STR00361##

[0638] To a mixture of compound XXX (5.0 g, 29 mmol) in DMSO (150 ml) was added 2-iodoxybenzoic acid (IBX, CAS: 61717-82-6) (24.7 g, 88 mmol) at 15? C. The mixture was stirred at 80? C. for 16 h. After filtration of the suspension, the filtrated was quenched with aq. sat. NaHCO.sub.3 (100 mL) and extracted with EtOAc. The combined organics were washed with brine, dried over Na.sub.2SO.sub.4 and concentrated. The crude was purified by flash column chromatography (EtOAc/hexane=0:100 to 100:0) to give the compound ethyl 1-methyl-2-oxo-cyclopent-3-ene-1-carboxylate (XXXI) (3.8 g, 78%) as a yellow oil. .sup.1H-NMR (400 MHz, CDCl.sub.3): ?=7.75 (td, J=2.8, 5.6 Hz, 1H), 6.19 (dt, J=5.7, 2.2 Hz, 1H), 4.20-4.10 (m, 2H), 3.26 (dt, J=19.1, 2.4 Hz, 1H), 2.55 (dt, J=19.2, 2.3 Hz, 1H), 1.41 (s, 3H), 1.27-1.19 (m, 3H).

##STR00362##

[0639] To a mixture of compound XXXI (3.4 g, 20 mmol) in dichloromethane (20 mL) was added bromine (3.2 g, 20 mmol) dropwise at 0? C. After stirring for 15 min at the same temperature, triethylamine (4.08 g, 40.4 mmol) was added. After stirring for 15 min at room temperature, the mixture was quenched with sat. sodium thiosulfate (20 mL) and extracted with dichloromethane (3?20 mL). The combined organics were washed with brine, dried over Na.sub.2SO.sub.4 and concentrated to give the compound ethyl 3-bromo-1-methyl-2-oxo-cyclopent-3-ene-1-carboxylate (XXXII) (4.5 g, 90%) as a yellow oil. .sup.1H-NMR (400 MHz, CDCl.sub.3): ?=7.80 (t, J=3.0 Hz, 1H), 4.22-4.13 (m, 2H), 3.22 (dd, J=18.9, 3.1 Hz, 1H), 2.53 (dd, J=19.0, 3.0 Hz, 1H), 1.46 (s, 3H), 1.24 (t, J=7.0 Hz, 3H).

##STR00363##

[0640] In analogy to the synthesis of Inter C in example 5, the mixture containing of compound XXXII (1.5 g, 6.0 mmol), aryl boronic acid XXIII (1.7 g, 9.1 mmol), Cs.sub.2CO.sub.3 (5.8 g, 18 mmol) and Pd(dppf)Cl.sub.2 (150 mg) in a 5:1 mixture of toluene (15 mL) and water (3 mL) was stirred at 100? C. under a nitrogen atmosphere for 0.5 h. The reaction was quenched with H.sub.2O and extracted with EtOAc. The combined organics were washed with brine. Dried and concentrated. The crude was purified by prep-HPLC (TFA, CH.sub.3CNH.sub.2O) to afford ethyl 3-(3,5-difluorophenyl)-1-methyl-2-oxo-cyclopent-3-ene-1-carboxylate (XXXIII) (900 mg, 48%) as a yellow amorphous solid. .sup.1H-NMR (400 MHz, CDCl.sub.3): ?=7.92 (t, J=3.0 Hz, 1H), 7.66 (d, J=1.9 Hz, 2H), 7.35 (t, J=1.8 Hz, 1H), 4.18 (q, J=7.2 Hz, 2H), 3.30 (dd, J=19.8, 3.0 Hz, 1H), 2.60 (dd, J=19.7, 3.0 Hz, 1H), 1.49 (s, 3H), 1.24 (t, J=7.2 Hz, 3H).

##STR00364##

[0641] According to the general procedure for saponification, to a solution of compound XXXIII (553 mg, 1.90 mmol) in a 1:1 mixture of THF (3 mL) and water (3 mL) was added lithium hydroxide (91 mg, 3.8 mmol) at room temperature. After stirring for 2 h, the mixture was quenched with H.sub.2O, acidified with aq. HCl (2 M) until pH=3 and extracted with EtOAc (3?20 mL). The combined organics were washed with brine, dried over Na.sub.2SO.sub.4 and concentrated to give Inter F (900 mg, 77%) as an amorphous yellow solid. The crude (200 mg, 42%) was used in the next step without further purification.

Example 11

Synthesis of methyl (1S,4R)-4-[[3-(3,5-difluorophenyl)-1-methyl-2-oxo-cyclopent-3-ene-1-carbonyl]amino]cyclopent-2-ene-1-carboxylate (Cpd 111.1)

[0642] ##STR00365##

[0643] According to the general procedure for HATU-mediated amide coupling (see example 4), to a solution of Inter F (23.6 mg, 9.36 ?mol) in DMF (4 mL) was added the HCl salt of amine X (16.6 mg, 9.36 ?mol), diisopropylethylamine (0.048 mL, 0.28 mmol) and HATU (CAS: 148893-10-1) (49 mg, 0.12 mmol). After stirring for 16 h at room temperature, the mixture was diluted with water (5 mL) and extracted with EtOAc (3?10 mL). The combined extracts were washed with brine, dried over Na.sub.2SO.sub.4 and concentrated. The residue was purified by flash column chromatography (hexane/EtOAc=9:1) to afford Cpd 111.1 (20 mg, 57%) as a 1:1-mixture of diastereomers. .sup.1H-NMR (400 MHz, CDCl.sub.3): ?=7.93 (t, J=3.0 Hz, 2H), 7.37-7.24 (m, 4H), 7.21 (s, 2H), 6.84-6.72 (m, 2H), 6.05-5.73 (m, 4H), 5.06-5.01 (m, 2H), 3.78 (s, 3H), 3.76 (s, 3H), 3.72-3.67 (m, 1H), 3.64 (dd, J=3.1, 1.5 Hz, 1H), 3.58-3.47 (m, 2H), 2.66-2.40 (m, 4H), 1.96 (dt, J=13.9, 3.7 Hz, 1H), 1.86 (dt, J=13.9, 3.9 Hz, 1H), 1.53 (s, 3H), 1.51 (s, 3H).

Example 12

Synthesis of methyl 4-[(1-methyl-3-phenyl-cyclopent-3-ene-1-carbonyl)amino]cyclopent-2-ene-1-carboxylate (Cpd IV2)

[0644] ##STR00366##

[0645] According to the general procedure for HATU-mediated amide coupling (see example 4), to a solution of literature-known, Angew. Chem. Int. Ed. 2018, 57, 2721-2725., carboxylic acid XXXIV (35 mg, 0.17 mmol) in DMF was added the HCl salt of amine X (30 mg, 0.17 mmol), diisopropylethylamine (0.76 mL, 0.52 mmol) and HATU (CAS: 148893-10-1) (83 mg, 0.21 mmol). After stirring for 18 h at room temperature, the mixture was concentrated and the residue was purified by prep-HPLC (water/acetonitrile) to afford Cpd IV.2 (39 mg, 69%) as a 1:1-mixture of diastereomers. .sup.1H-NMR (400 MHz, CDCl.sub.3): ?=7.46-7.39 (m, 2H), 7.29-7.20 (m, 2H), 7.19-7.12 (m, 1H), 6.79-6.74 (m, 1H), 6.07-6.03 (m, 1H), 5.90-5.74 (m, 3H), 5.07-4.94 (m, 1H), 3.66-3.61 (m, 3H), 3.52-3.47 (m, 1H), 3.30-3.22 (m, 1H), 3.10-3.00 (m, 1H), 2.55-2.47 (m, 1H), 2.36-2.28 (m, 1H), 1.85-1.75 (m, 1H), 1.32-1.29 (m, 3H).

[0646] High Performance Liquid Chromatography: HPLC-column Kinetex XB C18 1.7? (50?2.1 mm); eluent: acetonitrile/water+0.1% trifluoroacetic acid (gradient from 5:95 to 100:0 in 1.5 min at 60? C., flow gradient from 0.8 to 1.0 ml/min in 1.5 min).

[0647] In analogy to the examples described above, the following compounds of formula (I), wherein W.sup.1 is O, W.sup.2 is CH.sub.2 and R.sup.1, R.sup.8 are hydrogen, were prepared using commercially available amines:

TABLE-US-00002 TABLE 2 [00367] Cpd. R.sup.2 R.sup.3 R.sup.4 R.sup.5 R.sup.6 R.sup.7 N*XY HPLC/MS I1# H F H F H (R)-CH.sub.3 [00368] 340.1 I2# H F H F H (S)-CH.sub.3 [00369] 340.1 I3# H Cl H Cl H (R)-CH.sub.3 [00370] 372.1 I4# H Cl H Cl H (S)-CH.sub.3 [00371] 372.1 I5 H F H F H CH.sub.3 [00372] 364.3 I6 H Cl H Cl H CH.sub.3 [00373] 395.7 I7 H F H F H CF.sub.3 [00374] 394.1 I8 H F H F H CF.sub.3 [00375] 418.2 I9 H F H F H CH.sub.3 [00376] 368.2 I10 H F H F H CH.sub.3 [00377] 366.3 I11 H F H F H CH.sub.3 [00378] 352.3 I12 H F H F H CH.sub.3 [00379] 354.2 I13 H F H F H CH.sub.3 [00380] 354.2 I14 H Cl H Cl H CH.sub.3 [00381] 398.2 I15 H F H F H CF.sub.3 [00382] 405.9 I16 H F H F H CH.sub.3 [00383] 359.9 I17 H F H F H CH.sub.3 [00384] 433.9 I18# H F H F H (R)-CH.sub.3 [00385] 395.7 I19# H F H F H (S)-CH.sub.3 [00386] 395.7 #: compounds I1-I4, I18-19 are single isomers, prepared from enantiopure (S)- or (R)- Inter B and C. [00387]HPLC/MS = MassChargeRatio

[0648] In analogy to the examples described above, the following compounds of formula (I), wherein W.sup.1 is C(O), W.sup.2 is CH.sub.2 and R.sup.1, R.sup.8 are hydrogen, were prepared using commercially available amines:

##STR00388##

TABLE-US-00003 TABLE 3 Cpd. R.sup.2 R.sup.3 R.sup.4 R.sup.5 R.sup.6 R.sup.7 N*XY HPLC/MS II1 H F H F H CH.sub.3 [00389] n.d. [00390]HPLC/MS = MassChargeRatio

[0649] In analogy to the examples described above, the following compounds of formula (I), wherein W.sup.1 is CH.sub.2, W.sup.2 is C(O) and R.sup.1, R.sup.8 are hydrogen, were prepared using commercially available amines:

##STR00391##

TABLE-US-00004 TABLE 4 HPLC/ Cpd. R.sup.2 R.sup.3 R.sup.4 R.sup.5 R.sup.6 R.sup.7 N*XY MS III1 H F H F H CH.sub.3 [00392] 375.9 III2 H F H F H CH.sub.3 [00393] 351.9 III3 H F H F H CH.sub.3 [00394] 365.9 [00395]HPLC/MS = MassChargeRatio

[0650] In analogy to the examples described above, the following compounds of formula (I), wherein W.sup.1 is CH.sub.2, W.sup.2 is CH.sub.2 and R.sup.1, R.sup.8 are hydrogen, were prepared using commercially available amines:

##STR00396##

TABLE-US-00005 TABLE 5 HPLC/ Cpd. R.sup.2 R.sup.3 R.sup.4 R.sup.5 R.sup.6 R.sup.7 N*XY MS IV1 H H H H H H [00397] 312.2 IV2 H H H H H CH.sub.3 [00398] 326.2 [00399]HPLC/MS = MassChargeRatio

B USE EXAMPLES

[0651] The herbicidal activity of the compounds of formula (I) was demonstrated by the following greenhouse experiments:

[0652] The culture containers used were plastic flowerpots containing loamy sand with approximately 3.0% of humus as the substrate. The seeds of the test plants were sown separately for each species.

[0653] For the pre-emergence treatment, the active ingredients, which had been suspended or emulsified in water, were applied directly after sowing by means of finely distributing nozzles. The containers were irrigated gently to promote germination and growth and subsequently covered with transparent plastic hoods until the test plants had rooted. This cover caused uniform germination of the test plants, unless this had been impaired by the active ingredients. For the post-emergence treatment, the test plants were first grown to a height of 3 to 15 cm, depending on the plant habit, and only then treated with the active ingredients which had been suspended or emulsified in water. For this purpose, the test plants were either sown directly and grown in the same containers, or they were first grown separately as seedlings and transplanted into the test containers a few days prior to treatment.

[0654] Depending on the species, the test plants were kept at 10-25? C. or 20-35? C., respectively. The test period extended over 2 to 4 weeks. During this time, the test plants were tended, and their response to the individual treatments was evaluated.

[0655] Evaluation was carried out using a scale from 0 to 100. 100 means no emergence of the test plants, or complete destruction of at least the aerial moieties, and 0 means no damage, or normal course of growth. A good herbicidal activity is given at values of 60 to 90 and a very good herbicidal activity is given at values of 90 to 100.

[0656] The test plants used in the greenhouse experiments were of the following species:

TABLE-US-00006 Bayer code Scientific name ABUTH Abutilon theophrasti ALOMY Alopercurus myosuroides AMARE Amaranthus retroflexus APESV Apera spica-venti AVEFA Avena fatua ECHCG Echinocloa crus-galli SETVI Setaria viridis SETFA Setaria faberi LOLMU Lolium multiflorum

[0657] At an application rate of 1,000 kg/ha, applied by the pre-emergence method: [0658] compounds I1, I2, I3 showed very good herbicidal activity against APESV. [0659] compounds I1, I3 showed very good herbicidal activity against ECHCG. [0660] compound I2 showed good herbicidal activity against ECHCG. [0661] compounds I1, I3 showed very good herbicidal activity against SETFA. [0662] compound I2 showed good herbicidal activity against SETFA.

[0663] At an application rate of 0.250 kg/ha, applied by the pre-emergence method: [0664] compounds I5, I7, I8, I10, I11, I12, I15 showed very good herbicidal activity against APESV. [0665] compounds I9, I14 showed good herbicidal activity against APESV. [0666] compounds I5, I15 showed very good herbicidal activity against ECHCG. [0667] compounds I6, I7, I10, I11, I12 showed good herbicidal activity against ECHCG. [0668] compounds I5, I6, I18 showed very good herbicidal activity against AMARE. [0669] compounds I8 showed good herbicidal activity against AMARE. [0670] compounds I7, I8, I11, I15 showed very good herbicidal activity against SEFTA. [0671] compound I112 showed good herbicidal activity against SEFTA. [0672] compound I18 showed very good herbicidal activity against SETVI. [0673] compound I18 showed very good herbicidal activity against LOLMU.

[0674] At an application rate of 0.125 kg/ha, applied by the pre-emergence method: [0675] compound I113 showed good herbicidal activity against APESV. [0676] compound I113 showed good herbicidal activity against ABUTH. [0677] compound I113 showed good herbicidal activity against AMARE.

[0678] At an application rate of 1.000 kg/ha, applied by the post-emergence method: [0679] compound I1 showed very good herbicidal activity against ALOMY. [0680] compound I2 showed good herbicidal activity against ALOMY. [0681] compound I2, I4 showed very good herbicidal activity against AVEFA. [0682] compound I3 showed very good herbicidal activity against AMARE. [0683] compounds I1, I3 showed very good herbicidal activity against ECHCG. [0684] compounds I1, I2, I3, I4 showed very good herbicidal activity against SETVI.

[0685] At an application rate of 0.250 kg/ha, applied by the post-emergence method: [0686] compounds I5, I6, I8, I9, I10, I11, I12, I15, I16, I17, I18 showed very good herbicidal activity against AMARE. [0687] compound I14 showed good herbicidal activity against AMARE. [0688] compounds I5, I6, I7, I8, I11, I12, I15, I16, I17, I18 showed very good herbicidal activity against ECHCG. [0689] compound I111 showed good herbicidal activity against ECHCG. [0690] compounds I5, I7, I9, I10, I11, I12, I15, I16, I17, I18 showed very good herbicidal activity against AVEFA. [0691] compounds I13, I19 showed good herbicidal activity against AVEFA. [0692] compound I6 showed very good herbicidal activity against ALOMY [0693] compounds I7, I8, I19 showed good herbicidal activity against ALOMY. [0694] compound I14 showed good herbicidal activity against ABUTH. [0695] compounds I9, I10 showed very good herbicidal activity against SETVI.

[0696] At an application rate of 0.125 kg/ha, applied by the post-emergence method: [0697] compound I113 showed very good herbicidal activity against ABUTH.