* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
With 1,1'-carbonyldiimidazole In tetrahydrofuran for 2 h; Reflux
(12) A solution of ,Γ-earbonyidiimidazoie (2.0 eq) in THF (0,1 M) was added dropwise to a rcfluxing solution of 4-bromo~2~hydroxy~be:nzertecari ohydfoxar)iie acid (1.0 eq) in THF (0.15 M) and then stirred for 2h at reihrxing conditions. The THF was removed under vacuum and the residue was suspended ia water. HO (2 ) was added dropwise at rt. A precipitate formed and was collected by filtration, washed with water and dried overnight ia a vacuum ovea to afford 6-bromo- 1 ,2-benzoxazol- 3-0.1 (95percent yield).
89%
With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 20℃; for 0.533333 h; Inert atmosphere
General procedure: Salicylhydroxamic acid 1a (77 mg, 0.5 mmol, 1 equiv) was dissolved in anhydrous THF (7 mL) under an inert (N2) atmosphere. Triphenylphosphine (164 mg, 0.625 mmol, 1.25 equiv) was then added. After 2 min, DIAD (123 lL, 0.625 mmol, 1.25 equiv) was added dropwise. TLC (Hex/EtOAc, 1:3) after 30 min revealed the reaction was complete. The THF was removed in vacuo. The residue was partitioned between 0.1 M NaOH (50 mL)and CH2Cl2 (100 mL). The organic layer was separated, then the aqueous layerwas washed a further three times with CH2Cl2 (100 mL). The aqueous layer was acidified with 1 M HCl (10 mL), then extracted into CH2Cl2 (2 100 mL),washed with brine (50 mL), dried (Na2SO4), filtered and concentrated to yield the 3-hydroxybenzisoxazole 2a.
Stage #1: With potassium <i>tert</i>-butylate In N,N-dimethyl-formamide for 0.5 h; Stage #2: at 20℃; for 240 h;
Step A: 6-bromobenzo[d]isoxazol-3-ol: N-hydroxyacetamide (0.99 g, 12.9 mmol) was dissolved in DMF (20 mL). To this was added KOt-Bu (1.44 g, 12.9 mmol) and the reaction was stirred for 30 minutes before addition of methyl 4-bromo-2-fluorobenzoate (2.0 g, 8.58 mmol). The reaction mixture was stirred at ambient temperature for 10 days, then diluted with ethyl acetate (50 mL) and 1N NaOH (50 mL). The aqueous layer was washed with ethyl acetate, then acidified with 2N HCl (30 mL). The desired product was collected by filtration (570 mg, 31percent).
With 1,1'-carbonyldiimidazole; In tetrahydrofuran; for 2h;Reflux;
(12) A solution of ,Gamma-earbonyidiimidazoie (2.0 eq) in THF (0,1 M) was added dropwise to a rcfluxing solution of 4-bromo~2~hydroxy~be:nzertecari ohydfoxar)iie acid (1.0 eq) in THF (0.15 M) and then stirred for 2h at reihrxing conditions. The THF was removed under vacuum and the residue was suspended ia water. HO (2 ) was added dropwise at rt. A precipitate formed and was collected by filtration, washed with water and dried overnight ia a vacuum ovea to afford 6-bromo- 1 ,2-benzoxazol- 3-0.1 (95% yield).
89%
With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 20℃; for 0.533333h;Inert atmosphere;
General procedure: Salicylhydroxamic acid 1a (77 mg, 0.5 mmol, 1 equiv) was dissolved in anhydrous THF (7 mL) under an inert (N2) atmosphere. Triphenylphosphine (164 mg, 0.625 mmol, 1.25 equiv) was then added. After 2 min, DIAD (123 lL, 0.625 mmol, 1.25 equiv) was added dropwise. TLC (Hex/EtOAc, 1:3) after 30 min revealed the reaction was complete. The THF was removed in vacuo. The residue was partitioned between 0.1 M NaOH (50 mL)and CH2Cl2 (100 mL). The organic layer was separated, then the aqueous layerwas washed a further three times with CH2Cl2 (100 mL). The aqueous layer was acidified with 1 M HCl (10 mL), then extracted into CH2Cl2 (2 100 mL),washed with brine (50 mL), dried (Na2SO4), filtered and concentrated to yield the 3-hydroxybenzisoxazole 2a.
A solution of carbonyldiimidazole (0.75g) in dry tetrahydrofuran (15ml) was added to a refluxing solution of 4-bromo-N, 2-dihydroxybenzamide (Intermediate 23) (0.56g) in dry tetrahydrofuran (10ml) then stirred for 2h. The solvent was removed under vacuum, the residue was suspended in water and 2N hydrochloric acid (10ml) was added. The resulting precipitate was collected by filtration, washed with water then cyclohexane and dried to give the title compound as a cream solid (0.37g). LCMS: Rt 3. 30min.
With sodium hydroxide; In tetrahydrofuran; water; at 20℃; for 72h;
Step B: tert-butyl 6-bromo-3-oxobenzo[d]isoxazole-2(3H)-carboxylate: To a suspension of <strong>[65685-51-0]6-bromobenzo[d]isoxazol-3-ol</strong> (0.183 g, 0.86 mmol) in THF (8.0 mL) was added 1N NaOH (4.28 mL, 4.28 mmol), followed by (Boc)2 (0.93 g, 4.28 mmol). The reaction material was stirred at ambient temperature for 72 hours before quenching with water (10 mL). The aqueous layer was separated and extracted with ethyl acetate. The combined organics were dried, filtered and concentrated. The crude material was purified by flash column chromatography, eluting with hexanes/ethyl acetate (20:1) to give the desired product (265 mg, 99%).
6-bromo-3-(4-morpholinyl)-1,2-benzisoxazole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
An ice-bath cooled solution of 6-brom-1, 2-benzisoxazol-3 (2H)-one (Intermediate 24) (0. 15g) and dry pyridine (0. 15ml) in dry dichloromethane (12ml) was stirred under nitrogen and treated with triflic anhydride (18011L). The solution was stirred at room temp. for 90min, diluted with cyclohexane then applied to a Varian Bond-Elut SPE cartridge (silica, 5g) and eluted with cyclohexane and dichloromethane to give a colourless oil. The oil was dissolved in acetonitrile (4ml) treated with morpholine (61 , ut) and diisopropylethylamine (0. 15ml) then stirred at 70 under nitrogen for 16h. The cooled reaction mixture was purified on a Varian Bond-Elut SPE cartridge (silica, 5g) using dichloromethane: ethanol : 0. 88ammonia to give the title compound as a white solid (0.03g). LCMS: Rt 3. 01min.
An ice-bath cooled solution of 6-brom-1, 2-benzisoxazol-3 (2H)-one (Intermediate 24) (0.05g) and dry pyridine (0. 05ml) in dry dichloromethane (4ml) was stirred under nitrogen and treated with triflic anhydride (60pal). The solution was stirred at room temp. for 4h, diluted with cyclohexane then applied to a Varian Bond-Elut SPE cartridge (silica, lg) and eluted with dichloromethane to give a yellow oil. The oil was dissolved in acetonitrile (2ml) treated with 1,1-dimethylethyl 1-piperazinecarboxylate (0.04g) and diisopropylethylamine (0. 05ml) then stirred at 70 under nitrogen for 20h. The cooled reaction mixture was purified on a Varian Bond-Elut SPE cartridge (silica, 5g) using dichloromethane: methanol to give the title compound as a white solid (0.016g). LCMS: Rt 3. 62min.
Step A: 6-bromobenzo[d]isoxazol-3-ol: N-hydroxyacetamide (0.99 g, 12.9 mmol) was dissolved in DMF (20 mL). To this was added KOt-Bu (1.44 g, 12.9 mmol) and the reaction was stirred for 30 minutes before addition of methyl 4-bromo-2-fluorobenzoate (2.0 g, 8.58 mmol). The reaction mixture was stirred at ambient temperature for 10 days, then diluted with ethyl acetate (50 mL) and 1N NaOH (50 mL). The aqueous layer was washed with ethyl acetate, then acidified with 2N HCl (30 mL). The desired product was collected by filtration (570 mg, 31%).
6-bromo-3-[(4-methoxyphenyl)methoxy]-1,2-benzoxazole[ No CAS ]
6-bromo-2-[(4-methoxyphenyl)methyl]-1,2-benzoxazol-3-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
39%; 15%
With potassium carbonate; In N,N-dimethyl-formamide; at 20℃;
(13) 6-bron .li2-benzoxazoi-3-ol (L0 eq), potassium carbonate f 1.5 eq) were added to a bf, followed by DMF (0.2 M). 4-Methoxybeayl chloride ( i.l eq) was added and the rxn was stirred overnight at rt. LCMS shows both product regioisoraers, Rxn is added to water (0.1 M) and extracted with EtO Ac (2x). The combined extracts are washed with water (3x), brine, and dried over MgSO.*. Solvent was removed in vacuo and the residue was purified by normal phase chromatography ( 15-30%EiOAciiexaoes). The two regioisomers were collected separately. The major product, 6-bronio-3-{(4- methoxyphenyl }methoxy] 1 ,2-benzoxazo e (39% yield)and the minor product 6~bromo-2-i(4~methoxyphenyl)methyl'j-l,2-benzoxazol-3-one (.15% yield).
(6-bromo-1,2-benzoxazol-3-yl)trifluoromethanesulfonate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With pyridine; In dichloromethane; at 0 - 20℃; for 0.916667h;Inert atmosphere;
(17) To a suspension of pyridine (3.0 eq) and 6-brorao-l 2-benzoxaaol-3-ol (1.0 eq) in DCM (0,05 M) at 0"C under nitrogen was added triflooromethanesoifonic anndride (1 ,5 eq, 1 M in DCM), dropwise. After 10 rain, the ice bath was removed, it was stirred for an additional 45 rain at rt.Rxti was added to DCM: Water (1 : i ), The organic layer was separated with the hydrophobic phase separator, solvent was removed and the product (6-brorao-i ,2-benzoxazol-3-yl ) trifluororaedianesulfonate was carried forward without further purification.