MICROBIOCIDALLY ACTIVE BENZOXABOROLES
20190040087 ยท 2019-02-07
Assignee
Inventors
Cpc classification
International classification
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. (canceled)
2. Compounds of formula (I) according to claim 1 R.sup.a and R.sup.b and R.sup.c independently are H, fluorine, chlorine, bromine, nitro, unsubstituted or substituted C.sub.1-C.sub.6alkyl or unsubstituted or substituted C.sub.1-C.sub.6haloalkyl, unsubstituted or substituted C.sub.1-C.sub.6alkoxy; R is H, unsubstituted or substituted C.sub.1-C.sub.6alkyl, unsubstituted or substituted C.sub.1-C.sub.6haloalkyl, unsubstituted or substituted with five to ten ring membered aryl-A-, unsubstituted or substituted heteroaryl with 5 to 7 ring members comprising heteroatoms selected form O, S and N, C.sub.2-C.sub.6alkenyl, C.sub.2-C.sub.6alkynyl, C(O)R, C(O)OR, S(O).sub.nR R is H, unsubstituted or substituted C.sub.1-C.sub.6alkyl, unsubstituted or substituted C.sub.1-C.sub.6haloalkyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl n is an integer 0 to 2; A is a bridging element selected from C.sub.1-4alkylene, C(O), C.sub.1-4alkylene-C(O), C(O)C.sub.1-4 alkylene wherein the alkylene bridges may be unsubstituted or substituted like an alkyl group; wherein the substituents for the aryl, heteroaryl, are independently selected from the group consisting of halogen, hydroxy, cyano, nitro, C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6alkoxy, C.sub.1-C.sub.6alkoxy-C.sub.1-C.sub.6alkyl, and wherein the substituents for the cycloalkyl, heterocycloalkyl, alkyl, alkenyl and alkynyl moieties are independently selected from OH, CN, NO.sub.2, F, Cl, Br, C.sub.1-4alkyl, C.sub.1-4 alkoxy, S(O).sub.2OH, S(O).sub.2C.sub.1-4alkyl, C(O)(C.sub.1-4 alkoxy), OC(O)(C.sub.1-4 alkyl), C(O)(C.sub.1-4 alkyl), C(O) (C.sub.1-4 alkyl) (C.sub.1-4 alkoxy), unsubstituted or substituted C.sub.3-C.sub.6heterocycloalkyl ring members comprising heteroatoms selected form O, S and N;
3. Compounds of formula (I) according to claim 1 R.sup.a and R.sup.b and R.sup.c independently are H, fluorine, chlorine, bromine, nitro, unsubstituted or substituted C.sub.1-6 alkyl or unsubstituted or substituted C.sub.1-C.sub.6 haloalkyl, unsubstituted or substituted C.sub.1-C.sub.6 alkoxy; R is H, unsubstituted or substituted C.sub.1-C.sub.6 alkyl, unsubstituted or substituted C.sub.1-C.sub.6 haloalkyl, unsubstituted or substituted with five to ten ring membered aryl-A-, unsubstituted or substituted heteroaryl with 5 to 7 ring members comprising heteroatoms selected form O, S and N, C.sub.2-C.sub.6alkenyl, C.sub.2-C.sub.6alkynyl, C(O)R, C(O)OR, S(O)R R is H, unsubstituted or substituted C.sub.1-C.sub.6 alkyl, unsubstituted or substituted C.sub.1-C.sub.6 haloalkyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl n is an integer 0 to 2; A is a bridging element selected from C.sub.1-4 alkylene, C(O), C(O)C.sub.1-4 alkylene wherein the alkylene bridges may be unsubstituted or substituted like an alkyl group; wherein the substituents for the aryl, heteroaryl, are independently selected from the group consisting of halogen, hydroxy, cyano, nitro, C.sub.1-C.sub.6 alkyl, C.sub.1-6 haloalkyl, C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6 alkoxy-C.sub.1-C.sub.6 alkyl, and wherein the substituents for the cycloalkyl, heterocycloalkyl, alkyl, alkenyl and alkynyl moieties are independently selected from OH, CN, NO.sub.2, F, Cl, Br, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, S(O).sub.2OH, S(O).sub.2C.sub.1-4 alkyl, C(O)(C.sub.1-4 alkoxy), OC(O)(C.sub.1-4 alkyl), C(O)(C.sub.1-4 alkyl), C(O)(C.sub.1-4 alkyl)(C.sub.1-4 alkoxy), unsubstituted or substituted C.sub.3-C.sub.6heterocycloalkyl ring members comprising heteroatoms selected form O, S and N; In a preferred embodiment aryl-A- is unsubstituted or substituted benzyl, unsubstituted or substituted phenylcarbonyl, unsubstituted or substituted phenyl-C(O)C.sub.1-4 alkylene, preferably benzyl, phenylcarbonyl, C(O)-methylene.
4. (canceled)
5. Compounds of formula (I) according to claim 1 characterized in that compounds of formula (I) have the formula I-a ##STR00172## and all the substituents R.sup.a, R.sup.b, R.sup.c, R and R are as defined above
6-10. (canceled)
Description
PREPARATION EXAMPLES
[0192] The following non-limiting examples illustrate the above-described invention in greater detail without limiting it.
Example P1: Preparation of 5-chloro-2-hydroxy-4-methoxy-benzaldehyde
[0193] ##STR00074##
[0194] To a stirred solution of 2-hydroxy-4-methoxy-benzaldehyde (10 g, 65.725 mmol) in dichloromethane (50 ml) was added p-toluene sulfonic acid (5.65 g, 32.8625 mmol) at room temperature. Resulting mixture was stirred at ambient temperature for 30 minutes. Reaction mixture was cooled to 0 C. and 1-chloropyrrolidine-2,5-dione (9.21 g., 69.0113 mmol) was added and then allowed to stir at ambient temperature for 5 h. Reaction mixture was diluted with dichloromethane (50 ml). Combined organic layer was washed with sodium bicarbonate solution (420 ml), and then with water (250 mL) followed by brine (50 mL). Organic layer was dried over Na.sub.2SO.sub.4, filtered and evaporated completely to afford the product 5-chloro-2-hydroxy-4-methoxy-benzaldehyde (12 g, 97.8482% of theoretical yield) as a gummy liquid.
[0195] .sup.1H NMR (400 MHz, DMSO-d6) ppm 3.91 (s, 3H) 6.68 (s, 1H) 7.67 (s, 1H) 10.03 (s, 1H) 11.15 (s, 1H)
Example P2: Preparation of (4-chloro-2-formyl-5-methoxy-phenyl) trifluoromethanesulfonate
[0196] ##STR00075##
[0197] To a stirred solution of 5-chloro-2-hydroxy-4-methoxy-benzaldehyde (12 g, 64.3107 mmol) and pyridine (14.13 g., 192.9323 mmol) in dichloromethane (50 ml) was added trifilic anhydride (20.4 g., 96.4661 mmol) at 0 C. Resulting mixture was stirred at ambient temperature for 3 hrs. Reaction mixture was diluted with dichloromethane (50 ml). Combined organic layer was washed with water (250 mL) followed by brine (50 mL), dried over Na.sub.2SO.sub.4, filtered and evaporated completely to afford the product (4-chloro-2-formyl-5-methoxy-phenyl) trifluoromethanesulfonate (17 g, 82.957% of theoretical yield) as a viscous brownish oil.
[0198] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 3.98-4.06 (m, 3H) 5.74 (s, 1H) 7.36 (s, 1H) 8.19 (s, 1H) 9.91 (s, J=7.83 Hz, 1H)
Example P3: Preparation of 5-chloro-4-methoxy-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde
[0199] ##STR00076##
[0200] A mixture of (4-chloro-2-formyl-5-methoxy-phenyl) trifluoromethanesulfonate (5 g, 15.691 mmol), bis(pinacolato)diboron (7.56 g., 94.147 mmol), KOAc (1.38 g., 47.074 mmol, and Pd(dppf)Cl.sub.2.DCM complex (0.192 g., 0.78456 mmol) in toluene (25 mL, 16V) was degassed for 5 minutes. The reaction mixture was then stirred at 95 C. for 2 hrs. TLC confirmed the completion of the reaction. The reaction mixture was poured in water (40 ml), aqueous layer was extracted with EtOAc (330 ml)
[0201] Combined organic layer was washed with water (2250 mL) followed by brine (250 mL) and dried over Na.sub.2SO.sub.4, filtered and evaporated completely to give crude mass. The crude compound was purified by flash chromatography using 10% ethyl acetate in hexane as eluent to afford pure 5-chloro-4-methoxy-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (3.6 g, 60% of theoretical yield) as white solid.
[0202] .sup.1H NMR (400 MHz, DMSO-d6) ppm (s, 2H) 1.20-1.28 (m, 15H) 3.7 (m, 3H) 7.11 (s, 1H) 7.20 (s, 1H) 7.83 (s, 1H) 10.06 (s, 1H)
Example P4: Preparation of 5-chloro-1-hydroxy-6-methoxy-3H-2,1-benzoxaborole
[0203] ##STR00077##
[0204] To a stirred solution of 5-chloro-4-methoxy-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzaldehyde (5.5 g, 13 mmol) in methanol (25 mL), was added sodium borohydride in portions (0.6 g, 16 mmol) over a period of 15 mins at 0-5 C. Reaction mass was then stirred at ambient temperature. TLC confirmed the completion of the reaction. The reaction mixture was poured in water:Acetone mixture (40 ml) and methanol was evaporated off under vacuum. The aqueous layer was acidified with 6N HCl and stirred at ambient temperature overnight. The desired compound precipitated and the solid mass was filtered, washed with cyclohexane and dried under high vacuum to afford 5-chloro-1-hydroxy-6-methoxy-3H-2,1-benzoxaborole (2.9 g, 78% of theory) as a white solid.
[0205] .sup.1H NMR (400 MHz, DMSO-d6) ppm 3.88 (s, 3H) 4.92 (s, 2H) 7.41 (s, 1H) 7.51 (s, 1H) 9.26 (s, 1H) LC-MSMH 196.9 (RT; 1.56-1.59)
Example P5: Preparation of 5-chloro-1-hydroxy-3H-2,1-benzoxaborol-6-ol
[0206] ##STR00078##
[0207] To a stirred solution of 5-chloro-1-hydroxy-6-methoxy-3H-2,1-benzoxaborole (1.6 g, 8.1 mmol) in dichloromethane (20 mL) at 78 C. was added BBr.sub.3 (35 mL of 1M solution in dichloromethane) drop wise over 10 mins. Reaction mixture was stirred at RT for 2 hrs. When the TLC confirmed the completion of the reaction, reaction mass was quenched by drop wise addition of water.
[0208] The aqueous layer was extracted with EtOAc (330 ml). Combined organic layer was washed with water (2250 mL), followed by brine (250 mL) and dried over Na.sub.2SO.sub.4, filtered and evaporated completely to afford the desired product 5-chloro-1-hydroxy-3H-2,1-benzoxaborol-6-ol (1.3 g, 87% of theoretical yield) as a white solid .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 4.86 (s, 2H), 7.29 (s, 1H) 7.39 (s, 1H) 9.20 (br. s., 1H) 10.10 (s, 1H) LC-MSM+H 185 (RT; 1.28-1.34)
Example P6: Preparation of 5-chloro-1-hydroxy-6-prop-2-ynoxy-3H-2,1-benzoxaborole
[0209] ##STR00079##
[0210] To a stirred solution of 5-chloro-1-hydroxy-3H-2,1-benzoxaborol-6-ol (0.1 g, 0.5 mmol) in DMF (2 ml), was added NaH (0.04 g., 2 mmol) at 0-5 C. and stirred for 20 mins. 3-BROMO-1-PROPYNE (0.2 g 0.6 mmol) was added to the reaction mass and stirred at ambient temperature for 2 hrs. When the TLC confirmed the completion of the reaction, 1N HCl solution was added in drops till reaction mass turned acidic and aqueous layer was extracted with DCM (225 ml), which was evaporated off to get the crude product. The crude mass was purified by comb flash using 10-30% ethyl acetate in hexane to afford the desired product 5-chloro-1-hydroxy-6-prop-2-ynoxy-3H-2, 1-benzoxaborole (0.08 g, 70% of theoretical yield) as a gummy solid
[0211] 1H NMR (400 MHz, DMSO-d6) ppm 3.33 (s, 1H)) 4.93 (s, 4H) 7.50 (s, 1H) 7.54 (s, 1H) 9.31 (s, 1H) LC-MSMH 221 (RT; 1.67-1.71)
Example P7: Preparation of 4-ethoxy-2-hydroxy-benzaldehyde
[0212] ##STR00080##
[0213] To a stirred solution of 2,4-dihydroxybenzaldehyde (1 g, 7.24 mmol) and K.sub.2CO.sub.3 (0.8 og., 5.792 mmol) in acetone (25 ml) was added bromoethane (1.78 g, 13.032 mmol) in drops over a period of 10 minutes and refluxed overnight. When the TLC confirmed the completion of the reaction, reaction mass was acidified with 1N HCl. The aqueous layer was extracted with EtOAc (320 ml). Combined organic layer was washed with water (220 mL), followed by brine (20 mL) and dried over Na.sub.2SO.sub.4, filtered and evaporated completely to afford the desired product 4-ethoxy-2-hydroxy-benzaldehyde (1.1 g, 94% of theoretical yield) 1H NMR (400 MHz, DMSO-d6) b ppm 1.41-1.49 (m, 3H), 4.05-4.15 (m, 2H), 6.40-6.43 (m, 1H), 6.53 (dd, J=8.78, 2.26 Hz, H), 7.42 (d, J=8.53 Hz, 1H), 9.71 (s, 1H) 11.49 (s, 1H)
Example P8: Preparation of 5-chloro-4-ethoxy-2-hydroxy-benzaldehyde
[0214] ##STR00081##
[0215] To a stirred solution of 4-ethoxy-2-hydroxy-benzaldehyde (1 g, 6.0177 mmol) in dichloromethane (20 ml) was added p-toluene sulfonic acid (0.51 g, 3.0089 mmol) at room temperature. Resulting mixture was stirred at ambient temperature for 30 minutes. Reaction mixture was cooled to 0 C. and 1-chloropyrrolidine-2,5-dione (0.82 g., 6.3186 mmol) was added and then allowed to stir at ambient temperature for 5 h. Reaction mixture was diluted with dichloromethane (20 ml). Combined organic layer was washed with sodium bicarbonate solution (410 ml), and then with water (220 mL) followed by brine (20 mL). Organic layer was dried over Na2SO4, filtered and evaporated completely to afford the product 5-chloro-4-ethoxy-2-hydroxy-benzaldehyde (0.82 g, 60% of theoretical yield) as a gummy liquid.
[0216] 1H NMR (400 MHz, CDCl.sub.3) ppm 1.41-1.46 (m, 3H) 4.05-4.12 (m, 2H) 6.40 (s, 1H) 7.44 (s, 1H) 9.61 (s, 1H) 11.35 (s, 1H)
Example P9: Preparation of (4-chloro-5-ethoxy-2-formyl-phenyl) trifluoromethanesulfonate
[0217] ##STR00082##
[0218] To a stirred solution of 5-chloro-4-ethoxy-2-hydroxy-benzaldehyde (7.6 g, 38 mmol) and pyridine (9.1 g., 110 mmol) in dichloromethane (30 ml) was added trifilic anhydride (13 g, 45 mmol) at 0 C. Resulting mixture was stirred at ambient temperature for 3 hrs. Reaction mixture was diluted with dichloromethane (50 ml). Combined organic layer was washed with water (250 mL) followed by brine (50 mL), dried over Na.sub.2SO.sub.4, filtered and evaporated completely to afford the product (4-chloro-5-ethoxy-2-formyl-phenyl) trifluoromethanesulfonate (11 g 87% of theoretical yield) as a viscous brownish oil.
[0219] 1H NMR (400 MHz, CDCl.sub.3) ppm 1.48 (t, J=7.03 Hz, 3H) 4.15 (d, J=7.03 Hz, 2H) 6.80 (s, 1H) 7.93 (s, 1H) 10.02 (s, 1H)
Example P10: Preparation of 5-chloro-4-ethoxy-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde
[0220] ##STR00083##
[0221] A mixture of (4-chloro-5-ethoxy-2-formyl-phenyl) trifluoromethanesulfonate (0.5 g, 2 mmol) in toluene (10 mL) was degassed for 5 minutes. Then were added bis(pinacolato)diboron (1 g, 5 mmol), KOAc (0.4 g, 5 mmol, and Pd(dppf)Cl.sub.2.DCM complex (0.06 g., 0.08 mmol,). The reaction mixture was then stirred at 95 C. for 2 hrs. TLC confirmed the completion of the reaction. The reaction mixture was poured in water (10 ml), aqueous layer was extracted with EtOAc (310 ml). Combined organic layer was washed with water (210 mL) followed by brine (10 mL) and dried over Na.sub.2SO.sub.4, filtered and evaporated completely to give crude mass.
[0222] The crude compound was purified by flash chromatography using 10% ethyl acetate in hexane as eluent to afford pure 5-chloro-4-ethoxy-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (0.4 g, 90% of theoretical yield) as white solid.
[0223] 1H NMR (400 MHz, CDCl.sub.3) ppm 1.36-1.45 (s, 12H), 1.53 (t, J=7.03 Hz, 3H), 4.26 (d, J=7.03 Hz, 2H), 7.34 (s, 1H) 8.03 (s, 1H), 10.46 (s, 1H)
Example P11: Preparation of 5-chloro-6-ethoxy-1-hydroxy-3H-2,1-benzoxaborole
[0224] ##STR00084##
[0225] To a stirred solution of 5-chloro-4-ethoxy-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (0.4 g, 1 mmol) in methanol (10 mL), was added sodium borohydride (0.06 g, 2 mmol) at 0-5 C. Reaction mass was then stirred at ambient temperature. TLC confirmed the completion of the reaction. The reaction mixture was poured in water:Acetone mixture (2 ml) and methanol was evaporated off under vacuum. The aqueous layer was acidified with 6N HCl and stirred at ambient temperature overnight. The desired compound precipitated and the solid mass was filtered, washed with cyclohexane and dried under high vacuum to afford 5-chloro-1-hydroxy-6-methoxy-3H-2,1-benzoxaborole (0.21 g, 80% of theory) as a white solid.
[0226] 1H NMR (400 MHz, DMSO-d6) ppm 1.38 (t, J=6.90 Hz, 3H) 4.12 (q, J=7.03 Hz, 2H) 4.91 (s, 2H) 7.39 (s, 1H) 7.51 (s, 1H) 9.24 (s, 1H)
[0227] MS [M+H]+: 211.1 (rt 6.2-6.3 min)
Example P12: Preparation of methyl 2-chloro-4-hydroxy-5-iodo-benzoate
[0228] ##STR00085##
[0229] To a stirred solution of methyl 2-chloro-4-hydroxy-benzoate (12.5 g, 67.0 mmol) in ethanol (300 mL) were added at 0 C. iodine (17.0 g, 67.0 mmol) followed by silver sulfate (20.9 g, 67.0 mmol) by portions. The reaction mixture was stirred at 0-5 C. for 4 hrs. The reaction mixture was filtered. The cake was rinsed with ethyl acetate. The filtrate was washed twice with water. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude compound was purified by flash chromatography using 10% ethyl acetate in cyclohexane as eluent to afford pure methyl 2-chloro-4-hydroxy-5-iodo-benzoate (7.02 g, 33.5% of theoretical yield) as a white solid.
[0230] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 3.90 (s, 3H) 5.69 (s, 1H) 7.08 (s, 1H) 8.26 (s, 1H)
Example P13: Preparation of methyl 2-chloro-4-hydroxy-5-methyl-benzoate
[0231] ##STR00086##
[0232] To a solution of methyl 2-chloro-4-hydroxy-5-iodo-benzoate (5.57 g, 17.8 mmol) in dioxane (54 mL) were added potassium carbonate (2.96 g, 21.4 mmol), trimethylboroxine (3.36 g, 3.74 ml, 26.7 mmol) and Pd(ddpf)Cl.sub.2.DCM complex (0.522 g, 0.713 mmol). The mixture was irradiated in microwave 10 minutes at 150 C.
[0233] Then the mixture was cooled at room temperature, filtered over celite, the cake was rinsed with ethyl acetate. The filtrate was concentrated under reduced pressure. The crude was purified by flash chromatography using 10% ethyl acetate in cyclohexane as eluent to afford pure methyl 2-chloro-4-hydroxy-5-methyl-benzoate (2.264 g, 63.3% of theoretical yield) as a white solid.
[0234] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 2.23 (s, 3H) 3.89 (s, 3H) 5.36 (s, 1H) 6.87 (s, 1H) 7.73 (s, 1H)
Example P14: Preparation of methyl 4-hydroxy-5-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate
[0235] ##STR00087##
[0236] A solution of methyl 2-chloro-4-hydroxy-5-methyl-benzoate (750 mg, 3.74 mmol) in dioxane (23 mL) was degassed for 5 minutes. Then were added tricyclohexylphosphine (168 mg, 0.598 mmol), bis(pinacolato)diboron (4.75 g, 18.7 mmol), potassium acetate (550 mg, 5.61 mmol) and Pd.sub.2(dba).sub.3 (137 mg, 0.150 mmol). The mixture was irradiated in microwave for 40 minutes at 150 C. The mixture was filtered over celite. The filtrate was concentrated under reduced pressure. The crude was purified by flash chromatography using 15% ethyl acetate in cyclohexane as eluent to afford pure methyl 4-hydroxy-5-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (560 mg, 51.3% of theoretical yield) as a white solid.
[0237] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 1.41 (s, 12H) 2.23 (s, 3H) 3.87 (s, 3H) 5.22 (br. s., 1H) 6.82 (s, 1H) 7.75 (s, 1H)
Example P15: Preparation of methyl 4-ethoxy-5-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate
[0238] ##STR00088##
[0239] To a solution of methyl 4-hydroxy-5-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (440 mg, 1.056 mmol) in dimethylformamide (10 mL) was added at 0 C. potassium carbonate (333.1 mg, 2.410 mmol) then bromoethane (197 mg, 0.135 mL, 1.808 mmol). The mixture was stirred 10 minutes at 0 C. then 18 hrs at room temperature and then poured onto a mixture of ethyl acetate and water. The 2 layers were separated. The aqueous layer was extracted twice with ethyl acetate. The organic layers were combined, washed twice with water, once with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to afford methyl 4-ethoxy-5-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (458.2 mg, 95% of theoretical yield) as a beige solid.
[0240] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 1.43 (t, J=6.97 Hz, 3H) 1.45 (s, 12H), 2.21 (s, 3H), 3.87 (s, 3H), 4.10 (q, J=6.97 Hz, 2H), 6.82 (s, 1H), 7.74 (s, 1H)
Example P16: Preparation of 6-ethoxy-1-hydroxy-5-methyl-3H-2,1-benzoxaborole
[0241] ##STR00089##
[0242] To a solution of methyl 4-ethoxy-5-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (233 mg, 0.7277 mmol) in ethanol (10 mL) was added by portions sodium borohydride (41.3 mg, 1.092 mmol) at 0 C. The reaction mixture was stirred 20 hrs at ambient temperature. Then water was added. Ethanol was evaporated under reduced pressure. HCl 6N (6 mL) was added. The reaction mixture was stirred 8 Hrs at ambient temperature.
[0243] The precipitated was filtered, rinsed with water and dried over reduced pressure to give a solid. Then, it was triturated in a mixture cyclohexane/Et.sub.2O, filtered and dried under high vacuum to afford pure 6-ethoxy-1-hydroxy-5-methyl-3H-2,1-benzoxaborole (114.1 mg, 81.7% of theoretical yield) as a white solid (mp: 97-100 C.).
Example P17: Preparation of (4-chloro-2-formyl-6-methoxy-phenyl)trifluoromethanesulfonate
[0244] ##STR00090##
[0245] To a stirred solution of 5-chloro-2-hydroxy-3-methoxy-benzaldehyde (2.5 g, 13 mmol) and pyridine (3.2 g., 40 mmol) in dichloromethane (25 ml) was added trifilic anhydride (5.8 g, 20 mmol) at 00 C. Resulting mixture was stirred at ambient temperature for 3 hrs. Reaction mixture was diluted with dichloromethane (50 ml). Combined organic layer was washed with water (250 mL) followed by brine (50 mL), dried over Na2SO4, filtered and evaporated completely to afford the product (4-chloro-2-formyl-6-methoxy-phenyl) trifluoromethanesulfonate (1.6 g 37% of theoretical yield) as a viscous oil.
[0246] .sup.1H NMR (400 MHz, DMSO-d6) ppm 10.20 (s, 1H), 7.51 (s, 1H), 7.27 (s, 2H), 3.98 (s, 3H)
Example P18: Preparation of 5-chloro-3-methoxy-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde
[0247] ##STR00091##
[0248] A solution of 4-chloro-2-formyl-6-methoxy-phenyl) trifluoromethanesulfonate (1.6 g, 5 mmol) in toluene (20 mL) was degassed for 5 minutes. Then were added bis(pinacolato)diboron (2 g, 7.5 mmol), KOAc (1.5 g, 15 mmol, and Pd(dppf)Cl2.DCM complex (0.21 g., 0.25 mmol). The mixture was refluxed for 2 hrs at 110 C. The reaction mixture was diluted with water (10 ml), aqueous layer was extracted with EtOAc (310 ml). Combined organic layer was washed with water (210 mL) followed by brine (10 mL) and dried over Na2SO4, filtered and evaporated completely to give crude mass. The crude was purified by flash chromatography using 15% ethyl acetate in cyclohexane as eluent to afford pure methyl product 5-chloro-3-methoxy-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (1.4 g, 94% of theoretical yield) as a white solid.
[0249] .sup.1H NMR (400 MHz, DMSO-d6) ppm 9.88 (s, 1H), 7.39 (s, 1H), 7.06 (s, 1H), 3.83 (s, 3H), 1.45 (s, 12H)
Example P19: Preparation of 5-chloro-1-hydroxy-7-methoxy-3H-2,1-benzoxaborole
[0250] ##STR00092##
[0251] To a solution of methyl 5-chloro-3-methoxy-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (400 mg, 0.1 mmol) in ethanol (4 mL) was added by portions sodium borohydride (100 mg, 3 mmol) at 0 C. The reaction mixture was stirred 20 hrs at ambient temperature. Then water was added. Ethanol was evaporated under reduced pressure. HCl 6N (6 mL) was added. The reaction mixture was stirred 8 Hrs at ambient temperature.
[0252] The precipitated was filtered, rinsed with water and dried over reduced pressure to give a solid. Then, it was triturated in a mixture cyclohexane/Et.sub.2O, filtered and dried under high vacuum to afford pure 5-chloro-1-hydroxy-7-methoxy-3H-2,1-benzoxaborole (100 mg, 40% of theoretical yield) as a white solid (mp: C.).
[0253] MS [MH]+: 197.4 (rt 1.55-1.68 min)
[0254] .sup.1H NMR (400 MHz, DMSO-d6) ppm 3.82 (s, 3H) 4.91 (s, 2H) 6.90 (s, 1H) 7.06 (s, 1H) 8.91 (s, 1H)
Example 20: Preparation of 5,7-dichloro-1-hydroxy-3H-2,1-benzoxaborol-6-ol
[0255] ##STR00093##
[0256] To a round bottom flask equipped with a stir bar, dichloromethane (50 mL, 100 mass %), 5-chloro-1-hydroxy-3H-2,1-benzoxaborol-6-ol (0.50 g, 2.7 mmol, 100 mass %) and 4-methylbenzenesulfonic acid (0.23 g, 0.5 equiv., 1.4 mmol) was added. The mixture was stirred for 20 mins at room temperature after which the chlorinating agent, 1-chloropyrrolidine-2,5-dione (0.38 g, 1.05 equiv., 2.8 mmol) was added portionwise at 0 C. Reaction mass was stirred for 4 hrs at room temperature. Reaction mixture was quenched with water, and organic layer was washed with water, dried over sodium sulphate and concentrated to get the desired product as a pale brown solid 5,7-dichloro-1-hydroxy-3H-2,1-benzoxaborol-6-ol (0.55 g, 2.5 mmol, 93% of theoretical yield)
[0257] MS [MH]+: 216.7 (rt 1.35 min)
[0258] .sup.1H NMR (400 MHz, DMSO-d6) ppm 4.91 (s, 2H) 7.45 (s, 1H) 9.25 (s, 1H) 9.90 (s 1H)
Example 21: Preparation of 5,7-dichloro-6-ethoxy-1-hydroxy-3H-2,1-benzoxaborole
[0259] ##STR00094##
[0260] To a stirred solution of 5,7-dichloro-1-hydroxy-3H-2,1-benzoxaborol-6-ol (0.12 g, 0.55 mmol) in DMF (2 ml), NaH (0.07 g, 1.6 mmol) was added at 0-5 C. and stirred for 20 mins, after which bromoethane (0.15 g, 1.1 mmol) was added to the reaction mass and stirred the RM for 2 hrs at ambient temperature. The reaction mixture was then quenched with 1N HCl solution under cold condition, the solid precipitated out was filtered and washed with water. The crude solid thus obtained was purified by flash chromatography using 15% ethylacetate in cyclohexane as eluent to get the desired product as a white solid 5,7-dichloro-6-ethoxy-1-hydroxy-3H-2,1-benzoxaborole (0.055 g, 41% of theoretical yield)
[0261] .sup.1H NMR (400 MHz, DMSO-d6) ppm 1.38 (t, J=7.03 Hz, 3H) 4.03 (q, J=7.11 Hz, 2H) 4.94 (s, 2H) 7.56 (s, 1H) 9.29 (s, 1H)
##STR00095##
TABLE-US-00002 TABLE 2 Table of selected examples and physical data CpdNo. m.p. MS (entry) Formula R.sup.a R.sup.b R R.sup.c ( C.) [M H].sup.+ RT 1 I-a H
[0262] NMR Data for the compound 5 (1H-NMRdata: ppm (multiplicity/number of hydrogens)):
[0263] 1HNMR (400 MHz, DMSO-d6) ppm 3.88 (s., 1H) 4.92 (s, 2H) 7.41 (s, 2H) 7.51 (s, 2H) 9.26 (s, 1H)
[0264] The compound 1 (in the Table 2) has the following structure
##STR00171##
Characterising Data:
[0265] Table 2 shows selected melting point, The selected NMR data for compounds in the description were obtained as follows 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.
[0266] In Table 2 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: [0267] m.p.=melting point b.p.=boiling point. [0268] S=singlet br=broad [0269] d=doublet dd=doublet of doublets [0270] t=triplet q=quartet [0271] m=multiplet ppm=parts per million
[0272] The following LC-MS method was used to characterize the compounds:
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
[0273] 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-00003 Time A B Flow rate (minutes) (%) (%) (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.
[0274] 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 3.
[0275] Formulation examples for compounds of formula (I):
Example F-1.1 to F-1.2: Emulsifiable Concentrates
[0276]
TABLE-US-00004 Components F-2.1 F-2.2 A compound selected from the 25% 50% Tables 1-1 to 1-21 and Table 2 calciumdodecylbenzenesulfonate 5% 6% castoroilpolyethyleneglycolether (36molethylenoxyunits) 5% tributylphenolpolyethyleneglycolether (30molethylenoxyunits) cyclohexanone 20% xylenemixture 65% 20%
[0277] Emulsions of any desired concentration can be prepared by diluting such concentrates with water.
Example F-2: Emulsifiable Concentrate
[0278]
TABLE-US-00005 Components F-2 A compound selected from the 10% Tables 1-1 to 1-21 and Table 2 octylphenolpolyethyleneglycolether 3% (4 to 5 mol ethylenoxy units) Calcium dodecylbenzenesulfonate 3% Castoroilpolyglycolether 4% (36 mol ethylenoxy units) cyclohexanone 30% xylenemixture 50%
[0279] Emulsions of any desired concentration can be prepared by diluting such concentrates with water.
Examples F-3.1 to F-3.4: Solutions
[0280]
TABLE-US-00006 Components F-3.1 F-3.2 F-3.3 F-3.4 A compound selected from the 80% 10% 5% 95% Tables 1-1 to 1-21 and Table 2 propylene glycol monomethyl ether 20% polyethylene glycol 70% (relative molecular mass: 400 atomic mass units) N-methylpyrrolid-2-one 20% epoxidised coconut oil 1% 5% benzin (boiling range: 160-190 ) 94% The solutions are suitable for use in the form of microdrops.
Examples F-4.1 to F-4.4: Granulates
[0281]
TABLE-US-00007 Components F-4.1 F-4.2 F-4.3 F-4.4 A compound selected from the 5% 10% 8% 21% Tables 1-1 to 1-21 and Table 2 Kaolin 94% 79% 54% highly dispersed silicic acid 1% 13% 7% Attapulgite 90% 18%
[0282] The novel compound is dissolved in dichloromethane, the solution is sprayed onto the carrier and the solvent is then removed by distillation under vacuum.
Examples F-5.1 and F-5.2: Dusts
[0283]
TABLE-US-00008 Components F-5.1 F-5.2 A compound selected from the 2% 5% Tables 1-1 to 1-21 and Table 2 highly dispersed silicic acid 1% 5% Talcum 97% Kaolin 90%
[0284] Ready for use dusts are obtained by intimately mixing all components.
Examples F-6.1 to F-6.3: Wettable Powders
[0285]
TABLE-US-00009 Components F-6.1 F-6.2 F-6.3 A compound selected from the 25% 50% 75% Tables 1-1 to 1-21 and Table 2 sodium lignin sulfonate 5% 5% sodium lauryl sulphate 3% 5% sodium diisobutylnaphthalene sulfonate 6% 10% octylphenolpolyethylene glycol ether 2% (7 to 8 mol ethylenoxy units) highly dispersed silicic acid 5% 10% 10% Kaolin 62% 27%
[0286] All components are mixed and the mixture is thoroughly ground in a suitable mill to give wettable powders which can be diluted with water to suspensions of any desired concentration.
Example F7: Flowable Concentrate for Seed Treatment
[0287]
TABLE-US-00010 Components F-7 A compound selected from the 40% Tables 1-1 to 1-21 and Table 2 propylene glycol 5% copolymer butanol PO/EO 2% tristyrenephenole with 10-20 2% moles EO 1,2-benzisothiazolin-3-one 0.5% (in the form of a 20% solution in water) monoazo-pigment calcium salt 5% Silicone oil 0.2% (in the form of a 75% emulsion in water) Water 45.3%
[0288] The finely ground active ingredient is intimately mixed with the adjuvants, giving a suspension concentrate from which suspensions of any desired dilution can be obtained by dilution with water. Using such dilutions, living plants as well as plant propagation material can be treated and protected against infestation by microorganisms, by spraying, pouring or immersion.
Biological Examples: Fungicidal Action
[0289] 1. Phytophthora infestans/Tomato/Leaf Disc Preventative (Late Blight)
[0290] 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 compound 17, 82 and 85 (from Table 2) 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.
[0291] 2. Plasmopara viticola/Grape/Leaf Disc Preventative (Late Blight)
[0292] 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 10, 15, 16, 17, 80, 85, 86, 87, 89, 90, 94, 95, 96 and 98 (from Table 2) 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.
[0293] 3. Puccinia recondita f. sp. Tritici/Wheat/Leaf Disc Preventative (Brown Rust):
[0294] 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 5, 7, 8, 10, 15, 26, 28, 32, 34, 44, 77, 80, 84, 86, 90, 95, 98, 99, 100 and 101 (from Table 2) 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.
[0295] 4. Puccinia recondita f. sp. tritici/Wheat/Leaf Disc Curative (Brown Rust)
[0296] Wheat leaf segments are placed on agar in multiwell plates (24-well format). The leaf disks are then inoculated with a spore suspension of the fungus. One day after inoculation the test solution is applied. After appropriate incubation the activity of a compound is assessed 8 dpi (days after inoculation) as curative fungicidal activity. Dose range: 200-22 ppm. The Compound 17, 39, 43, 80, 84 and 86 (from Table 2) 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.
[0297] 5. Phaeosphaeria nodorum (Septoria nodorum)/Wheat/Leaf Disc Preventative (Glume Blotch):
[0298] 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 7, 8, 15, 17, 32, 44, 100 and 106 (from Table 2) 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.
[0299] 6. Magnaporthe grisea (Pyricularia oryzae)/Rice/Leaf Disc Preventative (Rice Blast):
[0300] 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 7, 8, 32 and 104 (from Table 2) 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.
[0301] 7. Pyrenophora teres/Barley/Leaf Disc Preventative (Net Blotch):
[0302] Barley leaf segments cv. Hasso were placed on agar in a multiwell plate (24-well format) and sprayed with the formulated test compound diluted in water. The leaf segments were inoculated with a spore suspension of the fungus 2 days after application. The inoculated leaf segments were incubated at 20 C. and 65% rh under a light regime of 12 h light/12 h darkness 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 8 and 76 (from Table 2) 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.
[0303] 8. Alternaria solani/Tomato/Leaf Disc (Early Blight)
[0304] 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 Compounds (from table T1 and Tx) 31, 76, 104 and 106 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.
[0305] 9. Pythium ultimum/Liquid Culture (Seedling Damping Off)
[0306] 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 20 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, 22, 23, 24, 25, 27, 28, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 48, 49, 50, 51,52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 63, 64, 65, 66, 67, 68, 69, 70, 71,72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 92, 93, 94, 95, 96, 97, 98, 99, 101, 103, 104, 105, 106 and 107 (from Table 2) at 20 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.
[0307] 10. Botryotinia fuckeliana (Botrytis cinerea)/Liquid Culture (Gray Mould):
[0308] 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 20 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, 2, 3, 4, 7, 8, 9, 12, 20, 21 and 103 (from Table 2) at 20 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.
[0309] 11. Glomerella lagenarium (Colletotrichum lagenarium)/Liquid Culture (Anthracnose):
[0310] 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 20 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 1,3, 4, 5, 6, 7, 8, 9, 12, 15, 16, 17, 18, 20, 21,23, 24, 28, 29, 31, 32, 33, 37, 38, 39, 43, 44, 50, 54, 59, 60, 66, 74, 76, 80, 83, 85, 86, 87, 89, 90, 95, 99, 100, 101, 103, 104, 105, 106 and 107 (from Table 2) at 20 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.
[0311] 12. Mycosphaerella arachidis (Cercospora arachidicola)/Liquid Culture (Early Leaf Spot):
[0312] 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 20 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, 11, 12, 13, 15, 16, 17, 18, 20, 21, 22, 27, 31, 32, 35, 37, 38, 39, 44, 49, 50, 59, 66, 74, 75, 76, 77, 80, 83, 85, 86, 87, 90, 94, 95, 96, 97, 99, 101, 103, 104, 105, 106 and 107 (from Table 2) at 20 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.
[0313] 13. Mycosphaerella graminicola (Septoria tritici)/Liquid Culture (Septoria Blotch):
[0314] 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 20 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, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 15, 16, 17, 18, 21, 22, 28, 29, 31, 32, 33, 34, 37, 38, 44, 89, 90, 94, 95, 96, 97, 98, 99, 100, 101, 103, 104, 105 and 107 (from Table 2) at 20 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.
[0315] 14. Gaeumannomyces graminis/Liquid Culture (Take-all of Cereals):
[0316] 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 20 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, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 15, 20, 21, 31, 32, 33, 36, 37, 38, 43, 44, 50, 54, 59, 60, 63, 66, 74, 75, 76, 77, 80, 81, 83, 85, 86, 87, 89, 90, 94, 95, 96, 97, 98, 99, 100, 101 and 103 (from Table 2) at 20 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.
[0317] 15. Monographella nivalis (Microdochium nivale)/Liquid Culture (Foot Rot Cereals):
[0318] 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 20 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, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 31,32, 33, 34, 35, 36, 37, 38, 43, 44, 50, 52, 59, 60, 63, 65, 66, 74, 76, 77, 80, 83, 85, 86, 87, 88, 89, 90, 94, 95, 96, 97, 99, 100, 101, 103, 104, 105, 106 and 107 (from Table 2) at 20 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.
[0319] 16. Fusarium culmorum/Liquid Culture (Head Blight):
[0320] 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 1, 3, 4, 7, 8, 9, 12, 17, 20, 21,22, 28, 31,32, 33, 37, 38, 39, 43, 48, 50, 59, 74, 80, 85, 86, 96, 101, 103, 104, 105, 106 and 107 (from Table 2) at 20 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.
[0321] 17. Thanatephorus cucumeris (Rhizoctonia solani)/Liquid Culture (Foot Rot, Damping-Off):
[0322] 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 20 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 1, 3, 7, 8, 9, 11, 13, 14, 15, 16, 17, 18, 22, 31, 32, 37, 43, 44, 50, 60, 61, 80, 84, 86, 94, 95, 96, 99, 101, 104, 106 and 107 (from Table 2) at 20 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.
[0323] 18. Sclerotinia sclerotiorum/Liquid Culture (Cottony Rot):
[0324] 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, 2, 3, 4, 5, 7, 8, 9, 11, 13, 15, 17, 20, 21, 22, 31, 32, 33, 36, 37, 38, 43, 44, 48, 50, 52, 59, 74, 75, 76, 77, 80, 85, 86, 95, 96, 99, 101, 103, 104, 105, 106 and 107 (from Table 2) at 20 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.