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Stage #1: With boron trichloride; tetra-(n-butyl)ammonium iodide In dichloromethane at -78 - 20℃; for 3.25 h; Stage #2: With water In dichloromethane for 0.5 h;
Preparation 74: 3-Hydroxy-2-methylbenzonitrile A solution of 3-methoxy-2-methylbenzonitrile [(1 g, 6.79 mmol) U.S. Pat. No. 5,965,766, p6] and tetra nbutyl ammonium iodide (4.12 g, 17 mmol) in dichloromethane (15 mL) was cooled to -78° C. and purged with nitrogen. Boron trichloride (1M in dichloromethane, 17 mL, 17 mmol) was added dropwise and the mixture was stirred for 15 minutes at -78° C. and at room temperature for 3 hours. The reaction mixture was quenched with water, stirred for 30 minutes and concentrated in vacuo. The aqueous residue was extracted with diethyl ether and the organic solution was washed with water (.x.5), dried over magnesium sulfate and concentrated in vacuo to afford the title compound as a brown solid in 91percent yield, 826 mg. 1H NMR(400 MHz, CDCl3) δ: 2.20 (s, 3H), 7.10 (m, 1H), 7.20 (d, 1H), 10.10 (s, 1H); LRMS APCI m/z 132 [M-H]-
With tetrakis(triphenylphosphine) palladium(0) In N,N-dimethyl-formamide at 120℃; for 16 h; Inert atmosphere
A) 3-hydroxy-2-methylbenzonitrile To a solution of 3-bromo-2-methylphenol (20.0 g) in DMF (250 mL) were added copper (I) cyanide (19.0 g) and tetrakis (triphenylphosphine) palladium(O) (3.70 g) , and the mixture was heated with stirring at 120°C for 16 hr under nitrogen atmosphere. The reaction mixture was poured into water, and the mixture was filtered. The filtrate was extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was washed with tert- butyl methyl ether to give the title compound (7.00 g) . 1H NMR (400 MHz, CDC13) δ 2.28 (3H, s) , 7.00-7.15 (1H, m) , 7.14-7.24 (2H, m) , 10.11 (1H, brs) .
Preparation 74: 3-Hydroxy-2-methylbenzonitrile A solution of 3-methoxy-2-methylbenzonitrile [(1 g, 6.79 mmol) U.S. Pat. No. 5,965,766, p6] and tetra nbutyl ammonium iodide (4.12 g, 17 mmol) in dichloromethane (15 mL) was cooled to -78 C. and purged with nitrogen. Boron trichloride (1M in dichloromethane, 17 mL, 17 mmol) was added dropwise and the mixture was stirred for 15 minutes at -78 C. and at room temperature for 3 hours. The reaction mixture was quenched with water, stirred for 30 minutes and concentrated in vacuo. The aqueous residue was extracted with diethyl ether and the organic solution was washed with water (×5), dried over magnesium sulfate and concentrated in vacuo to afford the title compound as a brown solid in 91% yield, 826 mg. 1H NMR(400 MHz, CDCl3) delta: 2.20 (s, 3H), 7.10 (m, 1H), 7.20 (d, 1H), 10.10 (s, 1H); LRMS APCI m/z 132 [M-H]-
With potassium carbonate; In dichloromethane; acetone;
A mixture of <strong>[55289-04-8]3-hydroxy-2-methylbenzonitrile</strong> [23.38 g described by S. Gabriel and A. Thieme, Ber., 52, 1079 (1919)] anhydrous potassium carbonate (26.7 g) and methyl iodide (16.43 ml) in acetone (255 ml) is refluxed for 4 hr, cooled and filtered. The filtrate is evaporated and dissolved in dichloromethane. The solution is washed with water, dried and evaporated. The residue is chromatographed on silica gel using dichloromethane-hexane(1:1) and the eluates are evaporated and crystallized from hexane to obtain 2-methyl-3-methoxybenzonitrile: (II: R1 =2-Me and Y=CN): mp 47-48 C.; ir 2,220, 1,265 and 1,100 cm-1; and nmr (CDCl3) delta2.42 (s, 3H), 3.85 (s, 3H) and 7.15 (m, 3H).
With hydroxylamine hydrochloride; sodium hydrogencarbonate; In ethanol;Reflux;
Description for D50 W,3-dihydroxy-2-methylbenzenecarboximidamide (D50)A mixture of <strong>[55289-04-8]3-hydroxy-2-methylbenzonitrile</strong> (0.9 g), sodium bicarbonate (0.78 g) and hydroxylamine hydrochloride (0.64 g) in ethanol (40 ml) was heated at reflux for overnight. The inorganic precipitate was filtered off. The solid was washed thoroughly with ethanol. The filtrate was concentrated. The obtained solid was dried in vacuo to afford Lambda/,3-dihydroxy-2-methylbenzenecarboximidamide (0.71 g). MS (ES): Ci0H12N2O3 requires 208; found 209.1 (M+H+).
With triethylamine; magnesium chloride; In tetrahydrofuran; for 16h;Inert atmosphere; Reflux;
B) 4-formyl-<strong>[55289-04-8]3-hydroxy-2-methylbenzonitrile</strong> To a solution of <strong>[55289-04-8]3-hydroxy-2-methylbenzonitrile</strong> (7.00 g) in THF (100 mL) were added triethylamine (13.1 g) , magnesium chloride (12.4 g) and paraformaldehyde (6.60 g) , and the mixture was heated with reflux for 16 hr under nitrogen atmosphere. The reaction mixture was poured into IN hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by flash silica gel column chromatography (ethyl acetate/petroleum ether) to give the title compound (1.30 g) . XH NMR (400 MHz, CDC13) delta 2.50 (3H, s) , 7.24-7.28 (2H, m, overlapped with CDC13 signal),. 7.53 (1H, d, J = 8.0 Hz), 9.98 (1H, s) , 11.42 (1H, brs) .
With tetrakis(triphenylphosphine) palladium(0); In N,N-dimethyl-formamide; at 120℃; for 16h;Inert atmosphere;
A) 3-hydroxy-2-methylbenzonitrile To a solution of 3-bromo-2-methylphenol (20.0 g) in DMF (250 mL) were added copper (I) cyanide (19.0 g) and tetrakis (triphenylphosphine) palladium(O) (3.70 g) , and the mixture was heated with stirring at 120C for 16 hr under nitrogen atmosphere. The reaction mixture was poured into water, and the mixture was filtered. The filtrate was extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was washed with tert- butyl methyl ether to give the title compound (7.00 g) . 1H NMR (400 MHz, CDC13) delta 2.28 (3H, s) , 7.00-7.15 (1H, m) , 7.14-7.24 (2H, m) , 10.11 (1H, brs) .
methyl 3-(3-cyano-2-methylphenoxy)-2,2-dimethylpropanoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
58%
With caesium carbonate; In N,N-dimethyl-formamide; at 100℃;
A mixture of methyl 2,2-dimethyl-3-(tosyloxy)propanoate (0.300 g, 1.05 mmol), 3- hydroxy-2-methylbenzonitrile (0.209 g, 1.57 mmol) and CS2CO3 (0.512 g, 1.57 mmol) in DMF (4 mL) was heated at lOOC overnight. The reaction mixture was then cooled, diluted with water (20 mL) and extracted with EtOAc. The combined organics were dried over MgS04, filtered, and concentrated under reduced pressure. The residue was purified by automated flash silica column chromatography, eluting with a gradient of 0-70% EtOAc in heptanes to give the title compound as a clear oil (0.15 g, 58%). ESI-MS [M+H]+ calc?d for CI4HI7N03, 248.13; found, 248.2.