NOVEL MICROBIOCIDES

Abstract

Compounds of formula (I) are as defined in the claims, and their use in compositions and methods for the control and/or prevention of microbial infection, particularly fungal infection, in plants and to processes for the preparation of these compounds.

##STR00001##

Claims

1. A method for controlling or preventing for infestation of plants or plant propagation material and/or harvested food crops susceptible to microbial attack by treating plants or plant propagation material and/or harvested food crops with an effective amount of a benzoxaborole derivative according to formula (I) ##STR00068## wherein R.sub.1 is selected from H, fluorine, chlorine, bromine, cyano, nitro, C.sub.1-C.sub.4alkyl which can be substituted by one to five R.sub.9, C.sub.1-C.sub.4alkoxy which can be substituted by one to five R.sup.9, and C.sub.1-C.sub.4haloalkyl which can be substituted by one to five R.sub.9a; R.sub.2, R.sub.3, R.sub.4, R.sub.5 and R.sub.6 are independently selected from H, fluorine, chlorine, bromine, cyano, nitro, amino, hydroxyl, C.sub.1-C.sub.6alkyl which can be substituted by one to five R.sub.9, C.sub.1-C.sub.6haloalkyl which can be substituted by one to five R.sub.9a, C.sub.3-C.sub.5cycloalky which can be substituted by one to five R.sub.9, C.sub.2-C.sub.6alkenyl which can be substituted by one to five R.sub.9, C.sub.2-C.sub.6alkynyl which can be substituted by one to five R.sub.9, C.sub.1-C.sub.6alkoxy which can be substituted by one to five R.sub.9, and C.sub.1-C.sub.6haloalkoxy which can be substituted by one to five R.sub.9a; or R.sub.2, R.sub.3, R.sub.4, R.sub.5 and R.sub.6 are independently selected from —NR.sub.7R.sub.8, C.sub.3-C.sub.6cycloalkyl, —C(O)(OH), —C(O)(C.sub.1-4 alkoxy), —C(O)(C.sub.1-4 alkyl), —C(O)—NH—(C.sub.1-4 alkyl), —C(O)—N(C.sub.1-4 alkyl).sub.2, C.sub.1-C.sub.4alkyl, C.sub.1-C.sub.4haloalkyl, C.sub.1-C.sub.4alkoxy, C.sub.1-C.sub.4alkylthio, C.sub.1-C.sub.4alkoxy-C.sub.1-C.sub.4alkyl, C.sub.1-C.sub.4haloalkoxy, C.sub.1-C.sub.4alkoximino, —C(O)NH(C.sub.1-4 alkyl), —C(O)N(C.sub.1-4 alkyl)(C.sub.1-4 alkyl), —OC(O)NH(C.sub.1-4 alkyl), —OC(O)N(C.sub.1-4 alkyl)(C.sub.1-4 alkyl), —NHC(O)(C.sub.1-4 alkyl), —NHC(O)(C.sub.1-4 alkoxy), —N(C.sub.1-4 alkyl)C(O)(C.sub.1-4 alkyl), —N(C.sub.1-4 alkyl)C(O)(C.sub.1-4 alkoxy), —OC(O)(C.sub.1-4 alkyl), —C(═N—O—(C.sub.1-4 alkyl)-H, and —C(═N—O—(C.sub.1-4 alkyl)-C.sub.1-C.sub.4alkyl; or R.sub.2, R.sub.3, R.sub.4, R.sub.5 and R.sub.6 are independently selected from a -X-(6 to 10 membered-aryl) group which can be substituted by one to five substituents selected halogen, C.sub.1-C.sub.4alkyl, C.sub.1-C.sub.4haloalkyl, C.sub.1-C.sub.4alkoxy, —CN, —NO.sub.2, —NR.sup.6R.sup.7, C.sub.3-C.sub.6cycloalkyl; or R.sub.2, R.sub.3, R.sub.4, R.sub.5 and R.sub.6 are independently selected from a -X-linked-5- or 6-membered heteroaryl group which comprises one or two or three heteroatoms selected from or two N, O and S which can be substituted by one to five substituents selected from halogen, C.sub.1-C.sub.4alkyl, C.sub.1-C.sub.4haloalkyl, C.sub.1-C.sub.4alkoxy, —CN, —NO.sub.2, —NR.sup.6R.sup.7, C.sub.3-C.sub.6cycloalkyl; or R.sub.2 and R.sub.3, R.sub.3 and R.sub.4, R.sub.4 and R.sub.5, R.sub.5 and R.sub.6 can form a five- or six-membered annellated ring which comprises one or two or three heteroatoms selected from N, O and S and this heterocyclic ring can be substituted by one to five substituents selected from halogen, C.sub.1-C.sub.4alkyl, C.sub.1-C.sub.4haloalkyl, C.sub.1-C.sub.4alkoxy, —CN, —NO.sub.2, —NR.sup.6R.sup.7, C.sub.3-C.sub.6cycloalkyl; R.sup.7 and R.sup.8 are independently selected from H, —C.sub.1-4alkyl —C.sub.2-4alkenyl, —C.sub.2-4alkynyl or combine with the interjacent nitrogen to form a five- or six-membered ring which may comprise one or two or three heteroatoms selected from N, O or S atoms in addition to the interjacent nitrogen atom this heterocyclic ring can be substituted by one to five substituents selected from halogen, C.sub.1-C.sub.4alkyl, C.sub.1-C.sub.4haloalkyl, C.sub.1-C.sub.4alkoxy, —CN, —NO.sub.2, —NR.sup.6R.sup.7, C.sub.3-C.sub.6cycloalkyl; R.sub.9 is independently selected from halogen, C.sub.1-C.sub.4alkyl, C.sub.1-C.sub.4haloalkyl, C.sub.1-C.sub.4alkoxy, C.sub.1-C.sub.4haloalkoxy, —OH, —CN, —NO.sub.2; R.sub.9a is independently selected from C.sub.1-C.sub.4alkyl, C.sub.1-C.sub.4haloalkyl, C.sub.1-C.sub.4alkoxy, C.sub.1-C.sub.4haloalkoxy, —OH, —CN, —NO.sub.2; X is a direct bond or a bridge selected from —O—, —S(O).sub.m— or —NH—; m is 0, 1 or 2; or an agronomically acceptable salt or N-oxide thereof.

2. A compound of formula (I) ##STR00069## wherein R.sub.1 is selected from fluorine, chlorine, bromine, cyano, nitro, C.sub.1-C.sub.4alkyl which can be substituted by one to five R.sub.9, C.sub.1-C.sub.4alkoxy which can be substituted by one to five R.sup.9, and C.sub.1-C.sub.4haloalkyl which can be substituted by one to five R.sub.9a; R.sub.2, R.sub.3, R.sub.4, R.sub.5 and R.sub.6 are independently selected from H, fluorine, chlorine, bromine, cyano, nitro, amino, hydroxyl, C.sub.1-C.sub.6alkyl which can be substituted by one to five R.sub.9, C.sub.1-C.sub.6haloalkyl which can be substituted by one to five R.sub.9a, C.sub.3-C.sub.5cycloalky which can be substituted by one to five R.sub.9, C.sub.2-C.sub.6alkenyl which can be substituted by one to five R.sub.9, C.sub.2-C.sub.6alkynyl which can be substituted by one to five R.sub.9, C.sub.1-C.sub.6alkoxy which can be substituted by one to five R.sub.9, and C.sub.1-C.sub.6haloalkoxy which can be substituted by one to five R.sub.9a; or R.sub.2, R.sub.3, R.sub.4, R.sub.5 and R.sub.6 are independently selected from —NR.sub.7R.sub.8, C.sub.3-C.sub.6cycloalkyl, —C(O)(OH), —C(O)(C.sub.1-4 alkoxy), —C(O)(C.sub.1-4 alkyl), —C(O)—NH—(C.sub.1-4 alkyl), —C(O)—N(C.sub.1-4 alkyl).sub.2, C.sub.1-C.sub.4alkyl, C.sub.1-C.sub.4haloalkyl, C.sub.1-C.sub.4alkoxy, C.sub.1-C.sub.4alkylthio, C.sub.1-C.sub.4alkoxy-C.sub.1-C.sub.4alkyl, C.sub.1-C.sub.4haloalkoxy, C.sub.1-C.sub.4alkoximino, —C(O)NH(C.sub.1-4 alkyl), —C(O)N(C.sub.1-4 alkyl)(C.sub.1-4 alkyl), —OC(O)NH(C.sub.1-4 alkyl), —OC(O)N(C.sub.1-4 alkyl)(C.sub.1-4 alkyl), —NHC(O)(C.sub.1-4 alkyl), —NHC(O)(C.sub.1-4 alkoxy), —N(C.sub.1-4 alkyl)C(O)(C.sub.1-4 alkyl), —N(C.sub.1-4 alkyl)C(O)(C.sub.1-4 alkoxy), —OC(O) (C.sub.1-4 alkyl), —C(═N—O—(C.sub.1-4 alkyl)-H, and —C(═N—O—(C.sub.1-4 alkyl)-C.sub.1-C.sub.4alkyl; or R.sub.2, R.sub.3, R.sub.4, R.sub.5 and R.sub.6 are independently selected from a -X-(6 to 10 membered-aryl) group which can be substituted by one to five substituents selected halogen, C.sub.1-C.sub.4alkyl, C.sub.1-C.sub.4haloalkyl, C.sub.1-C.sub.4alkoxy, —CN, —NO.sub.2, —NR.sup.6R.sup.7, C.sub.3-C.sub.6cycloalkyl; or R.sub.2, R.sub.3, R.sub.4, R.sub.5 and R.sub.6 are independently selected from a -X-linked-5- or 6-membered heteroaryl group which comprises one or two or three heteroatoms selected from or two N, O and S which can be substituted by one to five substituents selected from halogen, C.sub.1-C.sub.4alkyl, C.sub.1-C.sub.4haloalkyl, C.sub.1-C.sub.4alkoxy, —CN, —NO.sub.2, —NR.sup.6R.sup.7, C.sub.3-C.sub.6cycloalkyl; or R.sub.2 and R.sub.3, R.sub.3 and R.sub.4, R.sub.4 and R.sub.5, R.sub.5 and R.sub.6 can form a five- or six-membered annellated ring which comprises one or two or three heteroatoms selected from N, O and S and this heterocyclic ring can be substituted by one to five substituents selected from halogen, C.sub.1-C.sub.4alkyl, C.sub.1-C.sub.4haloalkyl, C.sub.1-C.sub.4alkoxy, —CN, —NO.sub.2, —NR.sup.6R.sup.7, C.sub.3-C.sub.6cycloalkyl; R.sup.7 and R.sup.8 are independently selected from H, —C.sub.1-4alkyl —C.sub.2-4alkenyl, —C.sub.2-4alkynyl or combine with the interjacent nitrogen to form a five- or six-membered ring which may comprise one or two or three heteroatoms selected from N, O or S atoms in addition to the interjacent nitrogen atom this heterocyclic ring can be substituted by one to five substituents selected from halogen, C.sub.1-C.sub.4alkyl, C.sub.1-C.sub.4haloalkyl, C.sub.1-C.sub.4alkoxy, —CN, —NO.sub.2, —NR.sup.6R.sup.7, C.sub.3-C.sub.6cycloalkyl; R.sub.9 is independently selected from halogen, C.sub.1-C.sub.4alkyl, C.sub.1-C.sub.4haloalkyl, C.sub.1-C.sub.4alkoxy, C.sub.1-C.sub.4haloalkoxy, —OH, —CN, —NO.sub.2; R.sub.9a is independently selected from C.sub.1-C.sub.4alkyl, C.sub.1-C.sub.4haloalkyl, C.sub.1-C.sub.4alkoxy, C.sub.1-C.sub.4haloalkoxy, —OH, —CN, —NO.sub.2; X is a direct bond or a bridge selected from —O—, —S(O).sub.m— or —NH—; m is 0, 1 or 2; or an agronomically acceptable salt or N-oxide thereof.

3. The compound of formula (I) according to claim 2 characterized in that R.sub.1 is fluorine, chlorine, bromine, cyano, nitro, or C.sub.1-C.sub.4alkyl.

4. The compound of formula (I) according to claim 2 characterized in that R.sub.2, R.sub.3, R.sub.4, R.sub.5 and R.sub.6 independently are H, fluorine, chlorine, bromine, cyano, nitro, amino, or R.sub.2, R.sub.3, R.sub.4, R.sub.5 and R.sub.6 independently are a -X-phenyl can be substituted by one to five substituents selected from F, Cl, Br, or R.sub.2, R.sub.3, R.sub.4, R.sub.5 and R.sub.6 independently are a -X-linked-5- or 6-membered heteroaryl group which comprises one or two or three heteroatoms selected from or two N, O and S, can be substituted by one to five substituents selected from halogen, C.sub.1-C.sub.4alkyl, C.sub.3-C.sub.6cycloalkyl, or R.sub.2 and R.sub.3, R.sub.3 and R.sub.4, R.sub.4 and R.sub.5, R.sub.5 and R.sub.6 can form a five- or six-membered annellated ring which comprises one or two or three heteroatoms selected from or two N, O and S and this heterocyclic ring can be substituted by one to five substituents selected from C.sub.1-C.sub.4alkyl, C.sub.3-C.sub.6cycloalkyl.

5. The compound of formula (I) according to claim 2 characterized in that R.sub.2, R.sub.3, R.sub.4, R.sub.5 and R.sub.6 are independently selected from H, fluorine, chlorine, cyano, or R.sub.2, R.sub.3, R.sub.4, R.sub.5 and R.sub.6 independently are a -X-linked-5- or 6-membered heteroaryl group which comprises one or two or three heteroatoms selected from or two N, O and S can be substituted by one to five substituents selected from C.sub.1-C.sub.4alkyl, C.sub.3-C.sub.6cycloalkyl, or R.sub.2 and R.sub.3, R.sub.3 and R.sub.4, R.sub.4 and R.sub.5, R.sub.5 and R.sub.6 can form a five- or six-membered annellated ring which comprises one or two or three heteroatoms selected from or two N, O and S can be substituted by one to five substituents selected from C.sub.3-C.sub.6cycloalkyl.

6. The compound of formula (I) according to claim 2 characterized in that X designates a direct bond or —NH—.

7. A compound Compounds of formula (VIII) ##STR00070## wherein HAL is halogen; and R.sub.1 is H, fluorine, chlorine, bromine, cyano, nitro, C.sub.1-C.sub.4alkyl, C.sub.1-C.sub.4alkoxy, or C.sub.1-C.sub.4haloalkyl.

8. The method of claim 1, wherein controlling further includes controlling at least one of infestation of useful plants by phytopathogenic microorganisms and controlling phytopathogenic diseases on useful plants or plant propagation material thereof, the method comprising applying a compound of formula (I) as defined in claim 3 to the plants, to parts thereof or the locus thereof.

9. A composition for controlling and protecting against phytopathogenic microorganisms, comprising a compound of formula (I) as defined in claim 2 and at least one addition inert ingredient.

10. (canceled)

11. The composition of claim 9 further comprising at least one additional active ingredient.

12. The method of claim 1, wherein R.sub.1 is fluorine, chlorine, bromine, cyano, nitro, or C.sub.1-C.sub.4alkyl; R.sub.2, R.sub.3, R.sub.4, R.sub.5 and R.sub.6 independently are H, fluorine, chlorine, bromine, cyano, nitro, amino, or R.sub.2, R.sub.3, R.sub.4, R.sub.5 and R.sub.6 independently are a -X-phenyl can be substituted by one to five substituents selected from F, Cl, Br, or R.sub.2, R.sub.3, R.sub.4, R.sub.5 and R.sub.6 independently are a -X-linked-5- or 6-membered heteroaryl group which comprises one or two or three heteroatoms selected from or two N, O and S, can be substituted by one to five substituents selected from halogen, C.sub.1-C.sub.4alkyl, C.sub.3-C.sub.6cycloalkyl, or R.sub.2 and R.sub.3, R.sub.3 and R.sub.4, R.sub.4 and R.sub.5, R.sub.5 and R.sub.6 can form a five- or six-membered annellated ring which comprises one or two or three heteroatoms selected from or two N, O and S and this heterocyclic ring can be substituted by one to five substituents selected from C.sub.1-C.sub.4alkyl, C.sub.3-C.sub.6cycloalkyl.

Description

PREPARATION EXAMPLES

[0132] The following examples illustrate the above-described invention in greater detail without limiting it.

Example 1: Synthesis of (2-formyl-5-phenyl-phenyl) trifluoromethanesulfonate

[0133] ##STR00014##

[0134] To a stirred solution of 2-hydroxy-4-phenyl-benzaldehyde (4.80 g, 23.0 mmol, 95 mass %) and pyridine (2.0 equiv., 46.0 mmol, 99.8 mass %) in dichloromethane (15 mL/mmol, 99.9 mass %) at 0° C. under argon, was added triflic anhydride (1.50 equiv., 34.5 mmol, 98 mass %). The mixture was stirred for 30 min at 0° C. and 1 h at 20° C. Water was added to the mixture which was transferred in an extracting funnel. Organics were washed again with water and brine, dried and evaporated to afford (2-formyl-5-phenyl-phenyl) trifluoromethanesulfonate (8.0 g, 22 mmol, 90 mass %, 95% Yield) as a brown solid.

[0135] LC-MS: rt 1.12 min −

Example 2: Synthesis of 4-phenyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde

[0136] ##STR00015##

[0137] To a solution of (2-formyl-5-phenyl-phenyl) trifluoromethanesulfonate (8.0 g, 22 mmol, 90 mass %) in dioxane (12 mL/mmol, 99.5 mass %), was added bis(pinacolato)diboron (Pin.sub.2B2) (1.10 equiv., 24 mmol, 98 mass %), potassium acetate (1.50 equiv., 33 mmol, 99.0 mass %) and [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (0.050 equiv., 1.1 mmol, 98 mass %) under nitrogen. The solution was stirred at 80° C. for 18 h. Most of the solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate and the organic phase was washed with water, water (pH 3), water and brine. It was then dried over sodium sulfate, filtered over celite pad and evaporated to afford the crude which was subject to flash chromatography over silicagel (80 g prepacked column) with cyclohexane/ethyl acetate 95:5 to 8:2 as eluent. After evaporation of fractions the solid obtained was recrystallized in cyclohexane. 4-phenyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (5.6 g, 18 mmol, 95 mass %, 83% Yield) was obtained as a white solid.

[0138] LC-MS: rt 0.79 min −

Example 3: Synthesis of 1-hydroxy-6-phenyl-3H-2,1-benzoxaborole compound No 1

[0139] ##STR00016##

[0140] 4-phenyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (2.10 g, 6.68 mmol, 98 mass %) was dissolved in methanol (7.0 mL/mmol, 99.5 mass %) and sodium borohydride (7.0 equiv., 46.7 mmol, 96 mass %) was added portionwise (9×200 mg). Strong gas bubbling and exothermic (up to 15° C.) was observed. The mixture was stirred 1 h at 5° C. and let stirred overnight at 23° C. The mixture was cooled down to 5° C. and 20 mL 4M hydrochloric acid was added carefully. A white solid precipitated in the mixture which was stirred 1 h at 23° C. Water was added. The white solid was filtered off, washed with water and dried. 1-hydroxy-6-phenyl-3H-2,1-benzoxaborole (1.38 g, 6.57 mmol, 97 mass %, 98.4% Yield) was obtained as a white solid.

[0141] LC-MS: rt 0.91 min −

[0142] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 5.04 (s, 2H), 7.32-7.43 (m, 1H), 7.44-7.56 (m, 3H), 7.65 (d, J=7.70 Hz, 2H), 7.76 (dd, J=7.89, 1.65 Hz, 1H), 7.99 (s, 1H), 9.22 (s, 1H).

Example 4: Synthesis of 5-chloro-1-hydroxy-6-iodo-3H-2,1-benzoxaborole

[0143] ##STR00017##

[0144] To a solution of PTSA monohydrate (2.5 equiv., 200 mmol, 99 mass %) in acetonitrile (5.0 mL/mmol, 99.5 mass %) was added 5-chloro-1-hydroxy-3H-2,1-benzoxaborol-6-amine (15.0 g, 80.2 mmol, 98 mass %) and the grey suspension obtained was stirred for 10 min at 20° C. The mixture was cooled to 17-20° C. and a solution of sodium nitrite (2.0 equiv., 160 mmol, 99 mass %) and potassium iodide (2.1 equiv., 168 mmol, 99 mass %) in water (0.60 mL/mmol, 100 mass %) was added drop wise (1 h) via dropping funnel. During addition the mixture turned dark brown quickly, gas release was observed and mixture became thicker (stirring to be increased a lot). The mixture was stirred 1 h at 20° C. Water (350 mL), sat. sodium hydrogen carbonate (50 mL), 2M sodium thiosulfate (50 mL) was added to the stirred mixture. The crude was extracted three times with ethyl acetate. Combined organics were washed with water, dried over sodium sulfate, evaporated under reduced pressure to afford the crude as red solid. The crude was triturated in isopropanol/water, filtered again and dried in the vacuum oven. 5-chloro-1-hydroxy-6-iodo-3H-2,1-benzoxaborole (18.2 g, 59 mmol, 95 mass %, 73% Yield) was obtained as a yellow solid.

[0145] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 4.93 (s, 2H), 7.70 (s, 1H), 8.28 (s, 1H), 9.29-9.46 (m, 1H).

Example 5: Synthesis of 2-(5-chloro-1-hydroxy-3H-2,1-benzoxaborol-6-yl)ethynyl-trimethyl-silane

[0146] ##STR00018##

[0147] 5-chloro-1-hydroxy-6-iodo-3H-2,1-benzoxaborole (2.50 g, 8.07 mmol, 95 mass %) was dissolved in degased dimethylformamide (8.0 mL/mmol, 830 mmol, 99.7 mass %) and were added respectively ethynyl(trimethyl)silane (4.0 equiv., 32.3 mmol, 98 mass %), copper iodide (0.050 equiv., 0.404 mmol, 98 mass %), PdCl2(PPh3)2 (0.10 equiv., 0.807 mmol, 99 mass %) and triethylamine (6.0 equiv., 48.4 mmol, 98 mass %). The mixture was stirred for 2 h at 23° C. under argon. The crude was poured in ammonium chloride solution (300 mL) and extracted with ethyl acetate (3×100 mL). Organics were washed with water (2×100 mL−pH 4), and brine (100 mL) dried over sodium sulfate and evaporated under reduced pressure. The crude was subject to flash chromatography over silica gel with dichloromethane/methanol 99:1 to 95:5 as eluant. 2-(5-chloro-1-hydroxy-3H-2,1-benzoxaborol-6-yl)ethynyl-trimethyl-silane (2.8 g, 5.7 mmol, 54 mass %, 71% Yield) was obtained as a solid.

[0148] LC-MS: rt 1.12 min −

[0149] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 0.24 (s, 9H), 5.00 (s, 2H), 7.64 (s, 1H), 7.89 (s, 1H), 9.34 (s, 1H).

Example 6: Synthesis of 5-chloro-6-ethynyl-1-hydroxy-3H-2,1-benzoxaborole

[0150] ##STR00019##

[0151] 2-(5-chloro-1-hydroxy-3H-2,1-benzoxaborol-6-yl)ethynyl-trimethyl-silane (2.10 g, 4.29 mmol, 54 mass %) was dissolved in tetrahydrofuran (5.0 mL/mmol, 100 mass %) and TBAF (2.0 equiv., 8.57 mmol, 1.0 mol/L) was added to the stirred mixture which was stirred for 2 h at 23° C. The mixture was poured in sodium hydrogen carbonate solution and brine and extracted with ethyl acetate three times. Combined organics were evaporated and dissolved again in ethyl acetate. This organic phase was washed with water (pH 4) then dried over sodium sulfate and evaporated under reduced pressure to afford the crude as a red solid. The crude was subject to reverse phase column chromatography. 5-chloro-6-ethynyl-1-hydroxy-3H-2,1-benzoxaborole (334 mg, 1.736 mmol, 98 mass %, 40% Yield) was obtained as a solid.

[0152] LC-MS: rt 0.82 min −

Example 7: Synthesis of 5-chloro-6-cyclohexa-1,4-dien-1-yl-1-hydroxy-3H-2,1-benzoxaborole

[0153] ##STR00020##

[0154] To a stirred suspension of CoBr2(dppe) (0.10 equiv., 0.104 mmol, 97 mass %), Zn powder (0.10 equiv., 0.104 mmol, 99.99 mass %) and Znl.sub.2 (0.20 equiv., 0.208 mmol, 99.99 mass %) in dichloromethane (5 mL/mmol, 99.9 mass %) at 23° C. under argon atmosphere, 5-chloro-6-ethynyl-1-hydroxy-3H-2,1-benzoxaborole (0.200 g, 1.04 mmol, 98 mass %) was added and buta-1,3-diene (99.5 mass %) was let bubbling slowly directly to the solution for 5 h. Gas bomb of butadiene was closed and the mixture was stirred overnight at 23° C. The mixture was filtered over celite (washed with DCM and DCM/methanol), evaporated and the green residue subject to flash chromatography over silica gel (24 g prepacked column) with dichloromethane/methanol 99:1 to 95:5 as eluent. 5-chloro-6-cyclohexa-1,4-dien-1-yl-1-hydroxy-3H-2,1-benzoxaborole (115 mg, 0.467 mmol, 98 mass %, 45% Yield) was obtained as a white solid.

[0155] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 2.78-2.95 (m, 4H), 4.97 (s, 2H), 5.65 (d, J=1.47 Hz, 1H), 5.73-5.85 (m, 2H), 7.51 (s, 1H), 7.57 (s, 1H), 9.21-9.29 (m, 1H).

Example 8: Synthesis of 5-chloro-1-hydroxy-6-phenyl-3H-2, 1-benzoxaborole compound No 3

[0156] ##STR00021##

[0157] 5-chloro-6-cyclohexa-1,4-dien-1-yl-1-hydroxy-3H-2,1-benzoxaborole (0.090 g, 0.37 mmol, 98 mass %) was dissolved in toluene (10 mL/mmol, 99.9 mass %) and DDQ (1.10 equiv., 0.40 mmol, 98 mass %) was added. The mixture was stirred 1 h30 at 23° C. The mixture was evaporated under reduced pressure and subject to flash chromatography over silicagel (40 g prepacked column) with dichloromethane/methanol 100:0 to 95:5 as eluant. Fraction were combined and evaporated to afford 5-chloro-1-hydroxy-6-phenyl-3H-2,1-benzoxaborole (84 mg, 0.3264 mmol, 95 mass %, 89% Yield) was recovered as a light yellow solid.

[0158] LC-MS: rt 0.98 min

[0159] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 5.03 (s, 2H) 7.39-7.44 (m, 3H) 7.45-7.50 (m, 2H) 7.65 (s, 1H) 7.71 (s, 1H) 9.32 (s, 1H).

Example 9: Synthesis of 5-chloro-1-hydroxy-6-(2-methoxyphenyl)-3H-2,1-benzoxaborole compound No 7 and 5-chloro-1-hydroxy-6-(4-methoxyphenyl)-3H-2,1-benzoxaborole compound No 8

[0160] ##STR00022##

[0161] Under argon, 5-chloro-1-hydroxy-3H-2,1-benzoxaborol-6-amine (0.95 g, 5.00 mmol, 97 mass %) was suspended in anisole (3.0 mL/mmol, 136 mmol, 99 mass %). One drop of trifluoro acetic acid (0.050 equiv., 0.250 mmol, 99.5 mass %) was added, temperature of the mixture was increased to 45° C. and tert-butyl nitrite (1.5 equiv., 7.50 mmol, 90 mass %) was added dropwise. The colour of the suspension turned from grey to red/brown, solubilisation occurred and bubbling was observed. It was stirred for 40 min at 45° C. Anisole was removed by concentration under reduced pressure. The red oily residue was dissolved in ethyl acetate and the organic phase was washed with water (pH 2) and then water. The phase was dried and evaporated under reduced pressure to afford the crude as red oil (1.50 g). The crude was purified by reverse phase column chromatography.

[0162] 5-chloro-1-hydroxy-6-(2-methoxyphenyl)-3H-2,1-benzoxaborole (348 mg, 1.204 mmol, 95 mass %, 24% Yield) was recovered as a brown solid.

[0163] LC-MS: rt 0.95 min −

[0164] .sup.1H NMR (400 MHz, chloroform-d) δ ppm 3.78 (s, 3H), 5.11 (s, 2H), 5.49 (br. s., 1H), 6.93-7.07 (m, 2H), 7.18 (dd, J=7.34, 1.47 Hz, 1H), 7.34-7.43 (m, 1H), 7.45 (s, 1H), 7.66 (s, 1H) 5-chloro-1-hydroxy-6-(4-methoxyphenyl)-3H-2,1-benzoxaborole (249 mg, 0.8164 mmol, 90 mass %, 16% Yield) was recovered as a brown solid.

[0165] LC-MS: rt 0.97 min −

[0166] .sup.1H NMR (400 MHz, chloroform-d) 6 ppm 3.86 (s, 3H), 5.11 (s, 2H), 5.46 (br. s., 1H), 6.94-6.99 (d, J=8.80 Hz, 2H), 7.37 (d, J=8.44 Hz, 2H), 7.46 (s, 1H), 7.69 (s, 1H)

Example 10: Synthesis of N-[2-(5-chloro-1-hydroxy-3H-2,1-benzoxaborol-6-yl)-4-fluoro-phenyl]acetamide compound No 19 and N-[3-(5-chloro-1-hydroxy-3H-2,1-benzoxaborol-6-yl)-4-fluoro-phenyl]acetamide compound No 20

[0167] ##STR00023##

[0168] 5-chloro-1-hydroxy-3H-2,1-benzoxaborol-6-amine (0.19 g, 1.0 mmol, 97 mass %) was suspended in acetonitrile (5.0 mL/mmol, 95 mmol, 99.9 mass %) and N-(4-fluorophenyl)acetamide (8.0 equiv., 8.0 mmol, 95 mass %) was added. Temperature of the mixture was increased to 45° C. and hydrobromic acid, 48% in water (0.05 equiv., 0.050 mmol, 48 mass %) was added followed by tert-butyl nitrite (1.50 equiv., 1.5 mmol, 90 mass %) at once. The mixture was stirred for 2 h at 45° C. The mixture was fully evaporated to afford the crude which was subject to reverse phase column chromatography.

[0169] N-[2-(5-chloro-1-hydroxy-3H-2,1-benzoxaborol-6-yl)-4-fluoro-phenyl]acetamide (27 mg, 0.081 mmol, 95 mass %, 8% Yield) was recovered as a solid.

[0170] LC-MS: rt 0.81 min 320/322 ES+[M+H]+

[0171] .sup.19F NMR (377 MHz, DMSO-d.sub.6) δ ppm −117.94 (s, 1F)

[0172] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 1.82 (s, 3H), 5.04 (s, 2H), 7.08 (dd, J=9.17, 2.93 Hz, 1H), 7.24 (td, J=8.62, 2.93 Hz, 1H), 7.54-7.68 (m, 3H), 9.01 (s, 1H), 9.35 (br. s., 1H)

[0173] N-[3-(5-chloro-1-hydroxy-3H-2,1-benzoxaborol-6-yl)-4-fluoro-phenyl]acetamide (6.7 mg, 0.016 mmol, 75 mass %, 2% Yield) was recovered as a solid.

[0174] LC-MS: rt 0.82 min 320/322 ES+[M+H]+

[0175] .sup.19F NMR (377 MHz, DMSO-d.sub.6) δ ppm −121.24 (s, 1F)

[0176] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 2.04 (s, 3H), 5.05 (s, 2H), 7.26 (t, J=9.17 Hz, 1H), 7.39 (d, J=7.70 Hz, 1H), 7.56-7.65 (m, 2H), 7.69 (d, J=7.34 Hz, 1H), 9.29 (s, 1H), 9.34 (s, 1H)

Example 11: Synthesis of 5-chloro-1-hydroxy-6-phenyl-3H-2,1-benzoxaborole compound No 3

[0177] ##STR00024##

[0178] 5-chloro-1-hydroxy-3H-2,1-benzoxaborol-6-amine (9.45 g, 50.0 mmol, 97 mass %) was suspended in benzene (125 mL, 2.5 mL/mmol, 99.5 mass %) and ethanol (10 mL). TFA (0.20 mL, 0.050 equiv., 99.5 mass %) was added, temperature of the mixture was increased to 45° C. and tert-butyl nitrite (10.0 mL, 1.50 equiv., 90 mass %) dissolved in ethanol (15 mL) was added dropwise via the dropping funnel (40 min). Gas release and exothermic (to 50° C.) observed. It was stirred for 1 h at 45° C. Solvent was removed by concentration under reduced pressure and the crude was subject to flash chromatography over silicagel (110 g prepacked column) with dichloromethane/methanol 99.5:0.5 to 97:3 as eluant. The yellow solid obtained was recrystallized in cyclohexane. 5-chloro-1-hydroxy-6-phenyl-3H-2,1-benzoxaborole (4.07 g, 98 mass %, 35% Yield) was recovered as a white crystalline solid.

[0179] LC-MS: rt 1.00 min −

[0180] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 5.03 (s, 2H), 7.38-7.44 (m, 3H), 7.45-7.52 (m, 2H), 7.65 (s, 1H), 7.71 (s, 1H), 9.31 (s, 1H)

Example 12: Synthesis of 5-fluoro-1-hydroxy-6-iodo-3H-2,1-benzoxaborole

[0181] ##STR00025##

[0182] To a solution of p-toluenesulfonic acid (PTSA) monohydrate (3 equiv., 35.9396 mmol, 100 mass %) in acetonitrile (25.0 mL, 99.5 mass %) was added 5-fluoro-1-hydroxy-3H-2,1-benzoxaborol-6-amine (2.0 g, 11.9798 mmol, 100 mass %) and the grey suspension obtained was stirred for 10 min at 20° C. The mixture was cooled to 0° C. and a solution of sodium nitrite (2.0 equiv., 23.9597 mmol, 99 mass %) and potassium iodide (2.5 equiv., 29.9496 mmol, 99 mass %) in water (5 mL, 100 mass %) was added drop wise (1 h) via dropping funnel. During addition the mixture turned dark brown quickly, gas release was observed and mixture became thicker (stirring to be increased a lot). The mixture was stirred 1 h at 20° C. Water (50 mL), sat. Sodium hydrogen carbonate (25 mL), 2M sodium thiosulfate (25 mL) was added to the stirred mixture. The crude was extracted three times with ethyl acetate. Combined organics were washed with water, dried over sodium sulfate, evaporated under reduced pressure to afford the crude as red solid. The crude was subject to flash chromatography over silica gel (12 g pre packed column) with Cyclohexane/Ethylacetate 99.5:0.5 to 20:80 as eluent to obtain 5-fluoro-1-hydroxy-6-iodo-3H-2,1-benzoxaborole (1.4 g, 5 mmol, 100 mass %, 42% Yield) was obtained as a white solid.

[0183] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 4.94 (s, 2H), 7.36 (s, 1H), 8.16 (s, 1H), 9.32 (s, 1H)

[0184] LCMS: rt 1.72 min 276.8−ESI

Example 13: Synthesis of N8-(5-fluoro-6-iodo-3H-2,1-benzoxaborol-1-yl)-N1,N1,N8-trimethyl-naphthalene-1,8-diamine

[0185] ##STR00026##

[0186] To a stirred solution of 5-fluoro-1-hydroxy-6-iodo-3H-2,1-benzoxaborole (1.38 g 4.9 mmol, 95 mass %) in toluene (100 mL, 99.9 mass %) was added N1,N1,N8-trimethylnaphthalene-1,8-diamine (1.0 equiv., 4.9 mmol, 99.8 mass %) at 23° C. under argon. The reaction mass was stirred for 1 h at 120° C. accompanied by azeotropic removal of water. Toluene was distilled to obtain the crude. The crude mass was washed with ethyl acetate to afford (N8-(5-fluoro-6-iodo-3H-2,1-benzoxaborol-1-yl)-N1,N1,N8-trimethyl-naphthalene-1,8-diamine (1.6 g, 3.5 mmol, 95 mass %, 70% Yield) as a pale yellow solid.

[0187] .sup.1H NMR (400 MHz, DMSO-d6) δ ppm 2.68-2.75 (m, 6H) 2.80 (s, 3H) 5.01 (s, 2H) 6.18 (br. s., 1H) 6.53 (d, J=7.78 Hz, 1H) 7.07 (d, J=8.78 Hz, 1H) 7.16 (d, J=7.53 Hz, 1H) 7.40-7.56 (m, 3H) 7.85 (dd, J=7.78, 1.25 Hz, 1H)

[0188] LC-MS: rt 2.19-2.32 min −460.9

Example 14: Synthesis of N8-[5-fluoro-6-(3-methoxyphenyl)-3H-2,1-benzoxaborol-1-yl]-N1,N1,N8-trimethyl-naphthalene-1,8-diamine

[0189] ##STR00027##

[0190] To a solution of N8-(5-fluoro-6-iodo-3H-2,1-benzoxaborol-1-yl)-N1,N1,N8-trimethyl-naphthalene-1,8-diamine (0.3 g, 0.7 mmol, 95 mass %) in tetrahydrofuran (5 mL, 99.5 mass %), was added (3-methoxyphenyl)boronic acid (1.10 equiv., 0.77 mmol, 98 mass %), cesium carbonate (2 equiv., 1 mmol, 99.0 mass %) and Bis(tri-t-butyl-phosphine)palladium(0) (0.050 equiv., 0.03 mmol, 98 mass %) under nitrogen. The solution was stirred at 60° C. for 18 h. The solvent was removed by concentration under reduced pressure. The residue was dissolved in ethyl acetate and the organic phase was washed with water and brine. It was then dried over sodium sulfate, filtered over celite pad and evaporated to dryness to obtain the crude mass. The crude was subject to flash chromatography over silica gel (4 g pre-packed column) with Cyclohexane/Ethylacetate 99.5:0.5 to 80:20 as eluent to obtain N8-[5-fluoro-6-(3-methoxyphenyl)-3H-2,1-benzoxaborol-1-yl]-N1,N1,N8-trimethyl-naphthalene-1,8-diamine (0.2 g, 0.5 mmol, 95 mass %, 70% Yield) as a off white solid.

[0191] 1H NMR (400 MHz, DMSO-d6) δ ppm 2.71-2.79 (m, 6H) 2.81-2.84 (m, 3H) 3.65 (s, 3H) 5.02-5.09 (m, 2H) 5.87-5.99 (m, 1H) 6.42-6.55 (m, 2H) 6.60-6.65 (m, 1H) 6.74-6.82 (m, 1H) 7.03-7.13 (m, 2H) 7.16-7.22 (m, 1H) 7.34-7.40 (m, 1H) 7.44-7.50 (m, 1H) 7.52-7.58 (m, 1H) 7.79-7.86 (m, 1H)

Example 15: Synthesis of 5-fluoro-6-(3-methoxy-phenyl)-3H-benzo[c][1,2] oxaborol-1-ol compound No 27

[0192] ##STR00028##

[0193] To a stirred solution of N8-[5-fluoro-6-(3-methoxyphenyl)-3H-2,1-benzoxaborol-1-yl]-N1,N1,N8-trimethyl-naphthalene-1,8-diamine (0.12 g, 0.27 mmol, 95 mass %) in tetrahydrofuran (2 mL, 99.5 mass %), Hydrochloric acid (4 mL 36 mass %) and 2 drop of TFA was added at 25° C. The reaction mixture was stirred 25° C. for 18 h. The mixture was extracted with ethyl acetate and the organic phase was washed with water and brine. Organic layer was then dried over sodium sulfate, filtered over celite pad and evaporated to afford the crude. The crude was subject to flash chromatography over silica gel (4 g pre packed column) with Cyclohexane/Ethylacetate 99.5:0.5 to 80:20 as eluent to obtain 5-fluoro-1-hydroxy-6-(3-methoxyphenyl)-3H-2,1-benzoxaborole (0.05 g, 0.2 mmol, 97 mass %, 70% Yield) as a white solid.

[0194] LC-MS: rt 1.3 min −259.2 (Method-M2)

[0195] .sup.1H NMR (400 MHz, DMSO-d6) δ ppm 3.82 (s, 3H) 5.00-5.07 (m, 2H) 6.97-7.02 (m, 1H) 7.03-7.12 (m, 2H) 7.32-7.44 (m, 2H) 7.76-7.89 (m, 1H) 9.09-9.42 (m, 1H)

Example 16: Synthesis of 4-(5-chloro-1-hydroxy-3H-2,1-benzoxaborol-6-yl)-2-methyl-1,3-benzothiazole (Compound No. 13), 5-(5-chloro-1-hydroxy-3H-2,1-benzoxaborol-6-yl)-2-methyl-1,3-benzothiazole Compound No. 14), 7-(5-chloro-1-hydroxy-3H-2,1-benzoxaborol-6-yl)-2-methyl-1,3-benzothiazole Compound No. 15)

[0196] ##STR00029##

[0197] Under argon, 5-chloro-1-hydroxy-3H-2,1-benzoxaborol-6-amine (0.19 g, 1.0 mmol, 97 mass %) was suspended in acetonitrile (5.0 mL, 99.9 mass %) and 2-methyl-1,3-benzothiazole (1.0 mL, 8.0 equiv., 98 mass %) was added. Temperature of the mixture was increased to 45° C. and hydrobromic acid, 48% (0.0060 mL, 0.05 equiv., 48 mass % in water) was added followed by tert-butyl nitrite (0.20 mL, 1.50 equiv., 90 mass %) at once. The mixture was stirred for 2 h at 45° C. The mixture was fully evaporated to afford the crude which was subject to reverse phase column chromatography. Three products were obtained:

[0198] Compound No. 13: 4-(5-chloro-1-hydroxy-3H-2,1-benzoxaborol-6-yl)-2-methyl-1,3-benzothiazole (11 mg, 0.028 mmol, 80 mass %, 2.9% Yield) as resin.

[0199] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 2.78 (s, 3H), 5.08 (s, 2H), 7.36 (d, J=7.34 Hz, 1H), 7.60 (t, J=7.70 Hz, 1H), 7.73 (s, 1H), 7.80 (s, 1H), 7.97 (d, J=8.07 Hz, 1H), 9.35 (s, 1H)

[0200] LC-MS: RT 0.94 Min 316/318 [M+H]+

[0201] Compound No. 14: 5-(5-chloro-1-hydroxy-3H-2,1-benzoxaborol-6-yl)-2-methyl-1,3-benzothiazole (8.6 mg, 0.022 mmol, 80 mass %, 2.2% Yield) as resin.

[0202] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 2.83 (s, 3H), 5.05 (s, 2H), 7.51 (dd, J=8.44, 1.83 Hz, 1H), 7.68 (s, 1H), 7.78 (s, 1H), 7.98 (d, J=8.07 Hz, 1H), 8.10 (d, J=1.83 Hz, 1H), 9.33 (br. s., 1H)

[0203] LC-MS: RT 0.95 Min 316/318 [M+H]+

[0204] Compound No. 15: 7-(5-chloro-1-hydroxy-3H-2,1-benzoxaborol-6-yl)-2-methyl-1,3-benzothiazole (17 mg, 0.032 mmol, 60 mass %, 3.2% Yield) as resin.

[0205] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 2.73 (s, 3H), 5.07 (s, 2H), 7.38 (dd, J=7.34, 0.80 Hz, 1H), 7.48 (t, J=7.70 Hz, 1H), 7.66 (s, 1H), 7.74 (s, 1H), 8.09 (dd, J=8.07, 0.80 Hz, 1H), 9.30 (s, 1H)

[0206] LC-MS: RT 0.97 Min 316/318 [M+H]+

TABLE-US-00010 TABLE T1 Melting point data and/or retention times of selected compounds: Cpd No Chemical structure LC/MS Method melting point 1 [00030] RT 0.91 Min — M2 140-150 2 [00031] RT 1.08 Min — M2 155-165 3 [00032] RT 1.00 Min — M2 135-145 4 [00033] RT 1.02 Min — M2 solid 5 [00034] RT 1.04 Min — M2 solid 6 [00035] RT 1.04 Min — M2 solid 7 [00036] RT 0.95 Min — M2  90-105 8 [00037] RT 0.97 Min — M2 105-115 9 [00038] RT 0.93 Min 229 ES+ [M + H]+ M2 142-152 10 [00039] RT 1.19 Min 245 ES+ [M + H]− M2 161-163 11 [00040] RT 0.97 Min 261 ES+ [M + H]+ M2 — 12 [00041] RT 0.94 Min — M2  95-115 13 [00042] RT 0.94 Min 316/318 ES+ [M + H]+ M2 solid 14 [00043] RT 0.97 Min 316/318 ES+ [M + H]+ M2 solid 15 [00044] RT 0.95 Min 316/318 ES+ [M + H]+ M2 solid 16 [00045] RT 0.94 Min 286/288 ES+ [M + H]+ M2 solid 17 [00046] RT 1.09 Min 389/391/393 ES+ [M + H]+ M2 solid 18 [00047] RT 1.00 Min 389/391/393 ES+ [M + H]+ M2 solid 19 [00048] RT 0.81 Min 320/322 ES+ [M + H]+ M2 solid 20 [00049] RT 0.82 Min 320/322 ES+ [M + H]+ M2 solid 21 [00050] RT 0.79 Min 368/370 ES+ [M + H]+ M2 solid 22 [00051] RT 1.13 Min 392/394 ES+ [M + H]+ M2 solid 23 [00052] RT 1.18 Min — M2 solid 24 [00053] RT 1.18 Min — M2 solid 25 [00054] RT 0.90 Min 259 ES+ [M + H]+ M2 50-65 26 [00055] RT 0.93 Min 259 ES+ [M + H]+ M2 solid 27 [00056] RT 1.31 Min 259 ES+ [M + H]+ M2 118-120 28 [00057] RT 1.49 Min 297 ES+ [M + H]+ M2 Gummy mass 29 [00058] RT 1.27 Min 253 ES+ [M + H]+ M2 270-272 30 [00059] RT 1.40 Min 331.1 [M − H]+ M1 — 31 [00060] RT 1.59 Min 307 [M − H]+ M1 — 32 [00061] RT 1.76 Min 253 [M − H]+ M2 Gummy mass 33 [00062] RT 1.71 Min 253 [M − H]+ M2 253-255 34 [00063] RT 2.14 Min 297 [M − H]+ M2 243-245 35 [00064] RT 1.54 Min 286 [M − H]+ M2 199-201 36 [00065] RT 2.05 Min 297 [M − H]+ M2 Gummy mass 37 [00066] RT 1.89 Min 246 [M − H]+ M2 144-146 38 [00067] RT 1.89 Min 262 [M − H]+ M2 135-137

[0207] Table T1 shows all the prepared examples with selected melting point and selected NMR data for prepared compounds. CDCl.sub.3/D.sub.2O and DMSO are used as solvents for NMR 400 MHz measurements. No attempt is made to list all characterising data in all cases.

[0208] In Table T1 and throughout the description that follows, temperatures are given in degrees Celsius; “NMR” means nuclear magnetic resonance spectrum; MS stands for mass spectrum; “%” is percent by weight, unless corresponding concentrations are indicated in other units. The following abbreviations are used throughout this description:

TABLE-US-00011 m.p. = melting point b.p. = boiling point. S = singlet br = broad d = doublet dd = doublet of doublets t = triplet q = quartet m = multiplet ppm = parts per million

[0209] The characteristic values obtained for each compound were the retention time (“R.sub.t”, recorded in minutes) and the molecular ion as listed in Table 1.

[0210] The following LC-MS methods were used to characterize the compounds:

Method: M 1

[0211] ACQUITY SQD Mass Spectrometer from Waters (Single quadrupole mass spectrometer)
Ionisation method: Electrospray
Polarity: positive ions

Capillary (kV) 3.00, Cone (V) 20.00, Extractor (V) 3.00, Source Temperature (° C.) 150, Desolvation

Temperature (° C.) 400, Cone Gas Flow (L/Hr) 60, Desolvation Gas Flow (L/Hr) 700

[0212] Mass range: 100 to 800 Da
DAD Wavelength range (nm): 210 to 400
Method Waters ACQUITY UPLC with the following HPLC gradient conditions
(Solvent A: Water/Methanol 9:1, 0.1% formic acid and Solvent B: Acetonitrile, 0.1% formic acid)

TABLE-US-00012 Time (minutes) A (%) B (%) Flow rate (ml/min) 0 100 0 0.75 2.5 0 100 0.75 2.8 0 100 0.75 3.0 100 0 0.75
Type of column: Waters ACQUITY UPLC HSS T3; Column length: 30 mm; Internal diameter of column: 2.1 mm; Particle Size: 1.8 micron; Temperature: 60° C.

Method: M2

Instrumentation:—

[0213] Mass Spectrometer: 6410 Triple quadrupole Mass Spectrometer from Agilent Technologies

HPLC: Agilent 1200 Series HPLC

Optimized Mass Parameter

[0214] Ionisation method: Electrospray (ESI)
Polarity: positive and Negative Polarity Switch

Scan Type: MS2 Scan

Capillary (kV): 4.00

Fragmentor (V): 100.00

Gas Temperature (° C.): 350

Gas Flow (L/min): 11

[0215] Nebulizer Gas (psi): 35
Mass range: 110 to 1000 Da
DAD Wavelength range (nm): 190 to 400
Optimized Chromatographic parameter:—

Gradient Conditions

[0216] (Solvent A: Water, 0.1% formic acid and Solvent B: Acetonitrile, 0.1% formic acid)

TABLE-US-00013 Time (minutes) A (%) B (%) Flow rate (ml/min) 0 90 10 1.8 2.0 0 100 1.8 3.0 0 100 1.8 3.2 90 10 1.8 4.0 90 10 1.8
Type of column: Waters Xterra MS C18; Column length: 30 mm; Internal diameter of column: 4.6 mm; Particle Size: 3.5μ; Temperature: 30° C.

BIOLOGICAL EXAMPLES: FUNGICIDAL ACTION

[0217] 1 Phytophthora infestans/Tomato/Leaf Disc Preventative (Late Blight)

[0218] Tomato leaf disks were placed on water agar in multiwell plates (24-well format) and sprayed with the formulated test compound diluted in water at an application rate of 200 ppm. The leaf disks were inoculated with a spore suspension of the fungus 1 day after application. The inoculated leaf disks were incubated at 16° C. and 75% relative humidity under a light regime of 24 h darkness followed by 12/12 h (light/dark) in a climate cabinet and the activity of a compound was assessed as percent disease control compared to untreated when an appropriate level of disease damage appears in untreated check leaf disks (5-7 days after application). The compounds 9 and 13 (from Table T1) at 200 ppm give at least 80% disease control in this test when compared to untreated control leaf disks under the same conditions, which show extensive disease development.

[0219] 2 Plasmopara viticola/Grape/Leaf Disc Preventative (Late Blight)

[0220] Grape vine leaf disks were placed on water agar in multiwell plates (24-well format) and sprayed with the formulated test compound diluted in water. The leaf disks were inoculated with a spore suspension of the fungus 1 day after application. The inoculated leaf disks were incubated at 19° C. and 80% relative humidity under a light regime of 12/12 h (light/dark) in a climate cabinet and the activity of a compound was assessed as percent disease control compared to untreated when an appropriate level of disease damage appears in untreated check leaf disks (6-8 days after application). The compounds 1, 3, 4, 7, 9, 10, 11, 12, 14, 15, 25 and 27 (from Table T1) at 200 ppm give at least 80% disease control in this test when compared to untreated control leaf disks under the same conditions, which show extensive disease development.

[0221] 3 Puccinia recondita f. Sp. Tritici/Wheat/Leaf Disc Preventative (Brown Rust):

[0222] Wheat leaf segments cultivated variety (cv) Kanzler were placed on agar in 24-well plates and sprayed with formulated test compound diluted in water at an application rate of 200 ppm. The leaf disks were inoculated with a spore suspension of the fungus 1 day after application. The inoculated leaf segments were incubated at 19° C. and 75% relative humidity under a light regime of 12/12 h (light/dark) in a climate cabinet and the activity of a compound was assessed as percent disease control compared to untreated when an appropriate level of disease damage appears in untreated check leaf segments (7-9 days after application). The compounds 3, 4, 7, 8, 10 and 28 (from Table T1) at 200 ppm give at least 80% disease control in this test when compared to untreated control leaf disks under the same conditions, which show extensive disease development.

[0223] 4 Phaeosphaeria Nodorum (Septoria nodorum)/Wheat/Leaf Disc Preventative (Glume Blotch):

[0224] Wheat leaf segments cv Kanzler were placed on agar in a 24-well plate and sprayed with formulated test compound diluted in water at an application rate of 200 ppm. The leaf disks were inoculated with a spore suspension of the fungus 2 days after application. The inoculated test leaf disks were incubated at 20° C. and 75% relative humidity under a light regime of 12/12 h (light/dark) in a climate cabinet and the activity of a compound was assessed as percent disease control compared to untreated when an appropriate level of disease damage appears in untreated check leaf disks (5-7 days after application). The compounds 1, 3, 5, 6, 7, 9 and 10 (from Table T1) at 200 ppm give at least 80% disease control in this test when compared to untreated control leaf disks under the same conditions, which show extensive disease development.

[0225] 5 Pyrenophora teres/Barley/Leaf Disc Preventative (Net Blotch):

[0226] Barley leaf segments cv Hasso were placed on agar in a 24-well plate and sprayed with formulated test compound diluted in water at an application rate of 200 ppm. The leaf segments were inoculated with a spore suspension of the fungus two days after application of the test solution. The inoculated leaf segments were incubated at 20° C. and 65% relative humidity under a light regime of 12/12 h (light/dark) in a climate cabinet and the activity of a compound was assessed as disease control compared to untreated when an appropriate level of disease damage appears in untreated check leaf segments (5-7 days after application). The compound 10 (from Table T1) at 200 ppm give at least 80% disease control in this test when compared to untreated control leaf disks under the same conditions, which show extensive disease development.

[0227] 6 Alternaria solani/Tomato/Leaf Disc (Early Blight)

[0228] Tomato leaf disks cultivated variety (cv.) Baby were placed on agar in multiwell plates (24-well format) and sprayed with the formulated test compound diluted in water at an application rate of 200 ppm. The leaf disks were inoculated with a spore suspension of the fungus 2 days after application. The inoculated leaf disks were incubated at 23° C./21° C. (day/night) and 80% relative humidity under a light regime of 12/12 h (light/dark) in a climate cabinet and the activity of a compound was assessed as percent disease control compared to untreated when an appropriate level of disease damage appears on untreated check disk leaf disks (5-7 days after application). The compound 1 (from Table T1) at 200 ppm give at least 80% disease control in this test when compared to untreated control leaf disks under the same conditions, which show extensive disease development.

[0229] 7 Magnaporthe grisea (Pyricularia oryzae)/Rice/Leaf Disc Preventative (Rice Blast):

[0230] Rice leaf segments cv. Ballila were placed on agar in multiwell plate (24-well format) and sprayed with the formulated test compound diluted in water at an application rate of 200 ppm. The leaf segments were inoculated with a spore suspension of the fungus 2 days after application. The inoculated leaf segments were incubated at 22° C. and 80% rh under a light regime of 24 h darkness followed by 12/12 h (light/dark) in a climate cabinet and the activity of a compound was assessed as percent disease control compared to untreated when an appropriate level of disease damage appears in untreated check leaf segments (5-7 days after application). The compound 9 (from Table T1) at 200 ppm give at least 80% disease control in this test when compared to untreated control leaf disks under the same conditions, which show extensive disease development.

[0231] 8 Pythium ultimum/Liquid Culture (Seedling Damping Off)

[0232] Mycelia fragments and oospores of a newly grown liquid culture of the fungus were directly mixed into nutrient broth (potato dextrose broth). After placing a DMSO solution of test compound into a 96-well format microtiter plate at an application rate of 200 ppm, the nutrient broth containing the fungal mycelia/spore mixture was added. The test plates were incubated at 24° C. and the inhibition of growth was determined photometrically 2-3 days after application. The compounds 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 25, 26, 27, 29, 30 and 31 (from Table T1) at 200 ppm give at least 80% disease control in this test when compared to untreated control leaf disks under the same conditions, which show extensive disease development.

[0233] 9 Botryotinia fuckeliana (Botrytis cinerea)/liquid culture (Gray mould):

[0234] Conidia of the fungus from cryogenic storage were directly mixed into nutrient broth (Vogels broth). After placing a DMSO solution of test compound into a 96-well microtiter plate at an application rate of 200 ppm, the nutrient broth containing the fungal spores was added. The test plates were incubated at 24° C. and the inhibition of growth was determined photometrically 3-4 days after application. The compounds 1, 3, 9, 10, 20, 21, 22, 28 and 31 (from Table T1) at 200 ppm give at least 80% disease control in this test when compared to untreated control leaf disks under the same conditions, which show extensive disease development.

[0235] 10 Glomerella lagenarium (Colletotrichum Lagenarium)/Liquid Culture (Anthracnose):

[0236] Conidia of the fungus from cryogenic storage were directly mixed into nutrient broth (PDB potato dextrose broth). After placing a DMSO solution of test compound into a 96-well microtiter plate at an application rate of 200 ppm, the nutrient broth containing the fungal spores was added. The test plates were incubated at 24° C. and the inhibition of growth was measured photometrically 3-4 days after application. The compounds 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 13, 16, 17, 18, 20, 25, 26, 27 and 31 (from Table T1) at 200 ppm give at least 80% disease control in this test when compared to untreated control leaf disks under the same conditions, which show extensive disease development.

[0237] 11 Mycosphaerella arachidis (Cercospora arachidicola)/Liquid Culture (Early Leaf Spot):

[0238] Conidia of the fungus from cryogenic storage were directly mixed into nutrient broth (PDB potato dextrose broth). After placing a DMSO solution of test compound into a 96-well microtiter plate at an application rate of 200 ppm, the nutrient broth containing the fungal spores was added. The test plates were incubated at 24° C. and the inhibition of growth was determined photometrically 4-5 days after application. The compounds 1, 3, 9, 10, 20, 21, 25, 27, 28 and 31 (from Table T1) at 200 ppm give at least 80% disease control in this test when compared to untreated control leaf disks under the same conditions, which show extensive disease development.

[0239] 12 Mycosphaerella graminicola (Septoria tritici)/Liquid Culture (Septoria Blotch):

[0240] Conidia of the fungus from cryogenic storage were directly mixed into nutrient broth (PDB potato dextrose broth). After placing a DMSO solution of test compound into a 96-well microtiter plate at an application rate of 200 ppm, the nutrient broth containing the fungal spores was added. The test plates were incubated at 24° C. and the inhibition of growth was determined photometrically 4-5 days after application. The compounds 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 13, 16, 17, 18, 19, 20, 25, 26, 27, 28 and 31 (from Table T1) at 200 ppm give at least 80% disease control in this test when compared to untreated control leaf disks under the same conditions, which show extensive disease development.

[0241] 13 Gaeumannomyces Graminis/Liquid Culture (Take-all of Cereals):

[0242] Mycelial fragments of the fungus from cryogenic storage were directly mixed into nutrient broth (PDB potato dextrose broth). After placing a DMSO solution of test compound into a 96-well microtiter plate at an application rate of 200 ppm, the nutrient broth Cp.33, containing the fungal spores is added. The test plates were incubated at 24° C. and the inhibition of growth was determined photometrically 4-5 days after application. The compounds 1, 2, 3, 8, 9, 10, 12, 13, 16, 17, 18, 20 and 28 (from Table T1) at 200 ppm give at least 80% disease control in this test when compared to untreated control leaf disks under the same conditions, which show extensive disease development.

[0243] 14 Monographella nivalis (Microdochium nivale)/liquid culture (foot rot cereals):

[0244] Conidia of the fungus from cryogenic storage were directly mixed into nutrient broth (PDB potato dextrose broth). After placing a DMSO solution of test compound into a 96-well microtiter plate at an application rate of 200 ppm, the nutrient broth containing the fungal spores was added. The test plates were incubated at 24° C. and the inhibition of growth was determined photometrically 4-5 days after application. The compounds 1, 3, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 20, 22, 23, 24, 25, 26, 27, 29, 30, and 31 (from Table T1) at 200 ppm give at least 80% disease control in this test when compared to untreated control leaf disks under the same conditions, which show extensive disease development.

[0245] 15 Fusarium culmorum/liquid culture (Head blight):

[0246] Conidia of the fungus from cryogenic storage were directly mixed into nutrient broth (PDB potato dextrose broth). After placing a (DMSO) solution of the test compounds into a microtiter plate (96-well format), the nutrient broth containing the fungal spores was added. The test plates were incubated at 24° C. and the inhibition of growth was determined visually 3-4 days after application. The compounds 3, 5, 6, 7, 9, 10, 19, 20, 25, 26, 27 and 31 (from Table T1) at 200 ppm give at least 80% disease control in this test when compared to untreated control leaf disks under the same conditions, which show extensive disease development.

[0247] 16 Thanatephorus cucumeris (Rhizoctonia solani)/liquid culture (foot rot, damping-off):

[0248] Mycelia fragments of a newly grown liquid culture of the fungus were directly mixed into nutrient broth (PDB potato dextrose broth). After placing a DMSO solution of the test compounds into a 96-well microtiter plate at an application rate of 200 ppm, the nutrient broth containing the fungal material was added. The test plates were incubated at 24° C. and the inhibition of growth was determined photometrically 3-4 days after application. The compounds 3, 4, 5, 6, 7, 8, 28 and 31 (from Table T1) at 200 ppm give at least 80% disease control in this test when compared to untreated control leaf disks under the same conditions, which show extensive disease development.

[0249] 17 Sclerotinia sclerotiorum/liquid culture (cottony rot):

[0250] Mycelia fragments of a newly grown liquid culture of the fungus were directly mixed into nutrient broth (PDB potato dextrose broth). After placing a (DMSO) solution of the test compounds into a microtiter plate (96-well format) the nutrient broth containing the fungal material was added. The test plates were incubated at 24° C. and the inhibition of growth was determined visually 3-4 days after application. The compounds 1, 3, 9, 10, 20, 25, 27, 28 and 31 (from Table T1) at 200 ppm give at least 80% disease control in this test when compared to untreated control leaf disks under the same conditions, which show extensive disease development.