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With pyridine; pyridine N-oxide; copper diacetate; In dichloromethane; at 20℃; for 48h;Molecular sieve;
Example 11-(2.4-Difluoro-3-phenoxy-phenyl)-2-methyl-propylamine. hydrochlorideStep 1 A mixture of <strong>[192927-69-8]2,4-difluoro-3-hydroxybenzaldehyde</strong> (1.67 g, 10.5 mmol), phenyl boronic acid (3.2 g, 26.4 mmol), copper (II) acetate (2.4 g, 13.7 mmol), pyridine (1.0 g, 10.5 mmol), pyridine-/V-oxide (4.25 ml, 52.5 mmol) and 4A molecular sieves (2.5 g) in DCM (50 ml) was stirred at room temperature for 48 hours. The reaction was quenched with sat. sodium hydrogen carbonate and the resulting suspension filtered through celite. The layers were separated and the aqueous fraction further extracted with DCM. The combined organic fractions were dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography. Eluting with 20% DCM in petrol afforded 2,4-Difluoro-3- phenoxybenzaldehyde (2.26 g) as an impure, colourless oil, which was used without further purification.
(2Z,4E)-5-(2,4-difluoro-3-hydroxyphenyl)-3-hydroxy-1-phenylpenta-2,4-dien-1-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
36%
1-Phenylbutane-1,3-dione (15 mmol) and boric anhydride (10.5 mmol) were mixed in dry ethyl acetate (11.25 mL) at 50 C for 30 min. After that, a mixture of <strong>[192927-69-8]2,4-difluoro-3-hydroxybenzaldehyde</strong> (15 mmol) and tributyl borate (22.5 mmol) in dry ethyl acetate (7.5 mL) was added, with stirring for 30 min at 50 C. A solution of butylamine (15 mmol) in dry ethyl acetate (7.5 mL) was added slowly over 15 min. The reaction mixture was stirred at 50 C for 90 min and then overnight at room temperature. Hydrochloric acid (1 M, 30 mL) was then added to the solution at 50 C, and the system was stirred for 1 h. After cooling, the organic layer was separated from the aqueous layer and extracted with 3 9 15 mL of ethyl acetate. The organic layer was washed with water (10 mL, 2 times) and dried (Na2SO4), and the solvent was evaporated unde rvacuum. The crude product was purified by column chromatography with dichloromethane as eluent, m.p. 195.0 C (ethanol/dichloromethane) (1.64 g, yield 36 %).
(3Z,5E)-6-(2,4-difluoro-3-hydroxyphenyl)-1,1,1-trifluoro-4-hydroxyhexa-3,5-dien-2-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
17%
1,1,1-Trifluoropentane-2,4-dione (15 mmol) and boric anhydride (10.5 mmol) were mixed in dry ethyl acetate (11.25 mL) at 50 C for 30 min. After that, a mixture of<strong>[192927-69-8]2,4-difluoro-3-hydroxybenzaldehyde</strong> (15 mmol) and tributyl borate (22.5 mmol) in dry ethyl acetate (7.5 mL) was added, with stirring for 30 min at 50 C. A solution of butylamine (15 mmol) in dry ethyl acetate (7.5 mL) was added slowly over 15 min. The reaction mixture was stirred at 50 C for 90 min and then overnight at room temperature. Hydrochloric acid (1 M, 30 mL) was then added to the solution at 50 C, and the system was stirred for 1 h. After cooling, the organic layer was separated from the aqueous layer and extracted with 3 9 15 mL of ethyl acetate. The organic layer was washed with water (10 mL, 2 times) and dried (Na2SO4), and the solvent was evaporated under vacuum. The crude product was purified by column chromatography with dichloromethane/ethanol (95:5) as eluent, m.p. 129.1 C (ethanol/dichloromethane) (733.12 mg, yield 17 %). C12H7F5O3 (294.18): calcd. C48.99, H 2.40; found C 49.28, H 2.66.
tert-butyl 6-benzyloxy-7-methoxy-1-[(1-phenyltetrazol-5-yl)sulfonylmethyl]-3,4-dihydro-1H-isoquinoline-2-carboxylate[ No CAS ]
[ 192927-69-8 ]
3-[(E)-2-(6-benzyloxy-7-methoxy-1,2,3,4-tetrahydroisoquinolin-1-yl)vinyl]-2,6-difluoro-phenol[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
A solution of tert-Butyl 6-benzyloxy-7-methoxy-1-[(1-phenyltetrazol-5-yl)sulfonylmethyl]-3,4-dihydro-1H-isoquinoline-2-carboxylate (100 mg, 0.169 mmol) and <strong>[192927-69-8]2,4-difluoro-3-hydroxy-benzaldehyde</strong> (133 mg, 0.84 mmol) in THF (10 mL) was cooled to -35 C. with stirring under argon. To this mixture was added a solution of lithium bis(trimethylsilyl)amide (0.68 mL, 0.68 mmol, 1M in THF) and the reaction mixture was stirred for 1 hour at -35 C. The reaction was allowed to warm up to room temperature and the organic solvent was evaporated to give a residue. The residue was dissolved (or suspended) in 4M HCl dioxane (5 mL) and stirred at room temperature until the reaction was completed. The organic layer was evaporated to leave a residue, which was purified by flash or reverse phase preparatory chromatography. LC-MS; M+1=424.
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