1,2,3-trichloro-5-(3,3,3-trifluoroprop-1-en-2-yl)benzene

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of crude (E)-ethyl 8-((hydroxyimino)methyl)indolizine-5-carboxylate (1.15 mmol) in THF (20 mL) was added slowly to a stirred solution of DIB (528 mg, 1.64 mmol) and 1,2,3-trichloro-5-(3,3,3-trifluoroprop-1-en-2-yl)benzene (452 mg, 1.64 mmol) in THF (10 mL) at rt. The mixture was stirred for 1 h at rt. The solvent was removed under reduced pressure and the crude product was purified by prep-TLC and then Combiflash to give ethyl 8-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)indolizine-5-carboxylate (130 mg; yield 22% over 2 steps). MS: m/z=506.7 (M+1, ESI+). The solvent was removed under reduced pressure the crude product was purified by prep-TLC and then Combiflash

Conditions: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 3,4,5-trichlorophenylboronic acid (4.5 g, 20 mmol), 2-bromo-3,3,3-trifluoro-prop-1-ene (4.9 g, 28 mmol), Cs2CO3 (20 mL, 2 M, 40 mmol) and Pd(PPh3)2Cl2 (421 mg) in THF (30 mL) was heated at 70° C. in a sealed tube for 4 h. The mixture was cooled to rt and partitioned between ether and H2O. The aqueous layer was extracted with EA and the combined organic layers were dried over Na2SO4. The solvent was removed under reduced pressure and the crude product was purified by column chromatography over silica gel eluted with hexanes to give 1,2,3-trichloro-5-(3,3,3-trifluoroprop-1-en-2-yl)benzene (4.3 g; yield 80%). 1H NMR (500 MHz, CDCl3): δ 7.40 (s, 2H), 5.99 (s, 1H), 5.76 (s, 1H) ppm. The mixture was cooled to rt partitioned between ether and H2O The aqueous layer was extracted with EA the combined organic layers were dried over Na2SO4 The solvent was removed under reduced pressure the crude product was purified by column chromatography over silica gel eluted with hexanes

Conditions: temp:68.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of crude (E)-methyl 5-((hydroxyimino)methyl)indolizine-8-carboxylate (300 mg, 1.37 mmol) in THF (20 mL) was added to a stirred solution of DIB (882 mg, 2.74 mmol) and 1,2,3-trichloro-5-(3,3,3-trifluoroprop-1-en-2-yl)benzene (750 mg, 2.74 mmol) in THF (15 mL) at rt. The mixture was heated at 68° C. for 2 h. The solvent was removed under reduced pressure and the crude product was purified by prep-TLC and then Combiflash to give methyl 5-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)indolizine-8-carboxylate (70 mg, yield 10%). The solvent was removed under reduced pressure the crude product was purified by prep-TLC and then Combiflash

Conditions: temp:68.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of crude (E)-methyl 5-((hydroxyimino)methyl)indolizine-8-carboxylate (300 mg, 1.37 mmol) in THF (20 mL) was added to a stirred solution of DIB (882 mg, 2.74 mmol) and 1,2,3-trichloro-5-(3,3,3-trifluoroprop-1-en-2-yl)benzene (750 mg, 2.74 mmol) in THF (15 mL) at rt. The mixture was heated at 68° C. for 2 h. The solvent was removed under reduced pressure and the crude product was purified by prep-TLC and then Combiflash to give methyl 5-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)indolizine-8-carboxylate (70 mg, yield 10%). The solvent was removed under reduced pressure the crude product was purified by prep-TLC and then Combiflash

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of methyl 4-(chloro(hydroxyimino)methyl)-2-methylbenzoate (12.6 mmol) in DMF (30 mL) at 0° C. was added 1,2,3-trichloro-5-(3,3,3-trifluoroprop-1-en-2-yl)benzene (4.2 g, 15.1 mmol) followed by Et3N (2.55 g, 25.2 mmol). The reaction mixture was stirred at rt for 18 h, poured into ice-water (30 mL) and extracted with ethyl acetate (50 mL×2). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography over silica gel eluted with PE:EA (10:1) to give methyl 4-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydro-isoxazol-3-yl)-2-methylbenzoate (4.1 g; yield 70% over 3 steps) as a pale yellow oil. 1H NMR (500 MHz, CDCl3): δ 7.98 (d, J=8.5 Hz, 1H), 7.66 (s, 2H), 7.55 (s, 2H), 4.13 (d, J=17.5 Hz, 1H), 3.93 (s, 3H), 3.73 (d, J=17.5 Hz, 1H), 2.64 (s, 3H) ppm; MS: m/z=465.9 (M+1, ESI+). extracted with ethyl acetate (50 mL×2) The combined organic layers were washed with brine dried over Na2SO4 filtered concentrated under reduced pressure The residue was purified by column chromatography over silica gel eluted with PE

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: In a solution of 45 mg of methyl N-[4-hydroxyiminomethyl-2-methylbenzoyl]carbamate in 10 mL of 1,2-dimethoxyethane, 40 mg of N-chlorosuccinimide was added, and stirred at 60° C. for 45 minutes. Then, the reaction mixture was left and cooled to room temperature, and then 68 mg of 3,4,5-trichloro-1-(1-trifluoromethylethenyl)benzene, 40 mg of potassium hydrogen carbonate and 5 drops of water were added, and continued to stir at room temperature further for 15 hour. After the completion of the reaction, the reaction mixture was poured in 10 mL of water, and extracted with ethyl acetate (15 mL×2). The combined organic phases were dehydrated with and dried over saturated sodium chloride aqueous solution and then anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified with silica gel column chromatography that was eluated with ethyl acetate-hexane (gradient of 1:2 to 1:1) to obtain 23 mg of the aimed product as colorless resinous substance. Then, the reaction mixture was left cooled to room temperature to stir at room temperature further for 15 hour After the completion of the reaction extracted with ethyl acetate (15 mL×2) dried over saturated sodium chloride aqueous solution anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure The residue was purified with silica gel column chromatography that

Conditions: temp:40.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: In a solution of 30 mg of N-acetyl-N-(5-chloro-2-pyrimidinyl)-4-hydroxyiminomethyl-2-methyl benzoic acid amide in 5 mL of 1,2-dimethoxyethane, 16 mg of N-chlorosuccinic acid imide was added and stirred at 40° C. for 30 minutes. Then the reaction mixture was left and cooled to room temperature, and 24 mg of 3,4,5-trichloro-1-(1-trifluoromethylethenyl)benzene, 10 mg of potassium hydrogen carbonate and 1 drop of water were added, and continued to stir at room temperature for 1.5 hour. After the completion of the reaction, the reaction mixture was poured in 10 mL of water, and extracted with ethyl acetate (10 mL×2). The combined organic phases were dehydrated with and dried over saturated sodium chloride aqueous solution and then anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified with silica gel column chromatography that was eluated with ethyl acetate-hexane (gradient of 1:3 to 1:1) to obtain 11 mg of the aimed product as colorless resinous substance. Then the reaction mixture was left cooled to room temperature to stir at room temperature for 1.5 hour After the completion of the reaction extracted with ethyl acetate (10 mL×2) dried over saturated sodium chloride aqueous solution anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure The residue was purified with silica gel column chromatography that

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: In a solution of 45 mg of methyl N-[4-hydroxyiminomethyl-2-methylbenzoyl]carbamate in 10 mL of 1,2-dimethoxyethane, 40 mg of N-chlorosuccinimide was added, and stirred at 60° C. for 45 minutes. Then, the reaction mixture was left and cooled to room temperature, and then 68 mg of 3,4,5-trichloro-1-(1-trifluoromethylethenyl)benzene, 40 mg of potassium hydrogen carbonate and 5 drops of water were added, and continued to stir at room temperature further for 15 hour. After the completion of the reaction, the reaction mixture was poured in 10 mL of water, and extracted with ethyl acetate (15 mL×2). The combined organic phases were dehydrated with and dried over saturated sodium chloride aqueous solution and then anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified with silica gel column chromatography that was eluated with ethyl acetate-hexane (gradient of 1:2 to 1:1) to obtain 23 mg of the aimed product as colorless resinous substance. Then, the reaction mixture was left cooled to room temperature to stir at room temperature further for 15 hour After the completion of the reaction extracted with ethyl acetate (15 mL×2) dried over saturated sodium chloride aqueous solution anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure The residue was purified with silica gel column chromatography that

Conditions: temp:40.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: In a solution of 30 mg of N-acetyl-N-(5-chloro-2-pyrimidinyl)-4-hydroxyiminomethyl-2-methyl benzoic acid amide in 5 mL of 1,2-dimethoxyethane, 16 mg of N-chlorosuccinic acid imide was added and stirred at 40° C. for 30 minutes. Then the reaction mixture was left and cooled to room temperature, and 24 mg of 3,4,5-trichloro-1-(1-trifluoromethylethenyl)benzene, 10 mg of potassium hydrogen carbonate and 1 drop of water were added, and continued to stir at room temperature for 1.5 hour. After the completion of the reaction, the reaction mixture was poured in 10 mL of water, and extracted with ethyl acetate (10 mL×2). The combined organic phases were dehydrated with and dried over saturated sodium chloride aqueous solution and then anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified with silica gel column chromatography that was eluated with ethyl acetate-hexane (gradient of 1:3 to 1:1) to obtain 11 mg of the aimed product as colorless resinous substance. Then the reaction mixture was left cooled to room temperature to stir at room temperature for 1.5 hour After the completion of the reaction extracted with ethyl acetate (10 mL×2) dried over saturated sodium chloride aqueous solution anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure The residue was purified with silica gel column chromatography that

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of the crude compound 6-fluoro-N,1-dihydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxaborole-5-carbimidoyl chloride (310 mg, 0.95 mmol) and 1,2,3-trichloro-5-(3,3,3-trifluoroprop-1-en-2-yl)benzene (262 mg, 0.95 mmol) in DMF (5 mL) at rt was added TEA (158 μL, 1.2 mmol). The reaction mixture was stirred for 12 h, poured into ice-water and extracted with DCM (60 mL×3). The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by prep-TLC eluted with PE-EA (3:2) and then purified by combiflash to give the title compound 6-fluoro-3,3-dimethyl-5-(5-(3,4,5-trichloro-phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)benzo[c][1,2]oxaborol-1(3H)-ol (86 mg; yield 16% over 3 steps from the aldehyde) as a white solid. 1H NMR (500 MHz, DMSO-d6): δ 9.352 (s, 1H), 7.875 (s, 2H), 7.826 (d, J=6.0 Hz, 1H), 7.513 (d, J=10.0 Hz, 1H), 4.399 (d, J=18.5 Hz, 1H), 4.274 (d, J=18.5 Hz, 1H), 1.482 (s, 6H) ppm; HPLC purity: 100% at 220 nm and 100% at 254 nm; MS: m/z=495.9 (M+1, ESI+). extracted with DCM (60 mL×3) The organic layer was washed with brine dried over Na2SO4 filtered concentrated under reduced pressure The residue was purified by prep-TLC eluted with PE-EA (3:2) purified by combiflash