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With boron trichloride; tetra-(n-butyl)ammonium iodide In dichloromethane at -78 - 20℃;
In a 100 mL round bottom flask, 3- methoxy-5-methyl-benzonitrile (500 mg, 3.39 mmol) was dissolved in 15 mL dry DCM, and tetrabutylammonium iodide (1.38 g, 3.73 mmol, 3.5 eq.) was added. The flask was cooled to -78 0C. BCk (1 M in DCM, 11.87 mL, 33.16 mmol) was added to the reaction dropwise. The reaction mixture was stirred at -78 0C and warmed up to room temperature overnight. The reaction mixture was quenched with ice and neutralized with saturated NaHCCh solution. DCM was added to extract the <n="425"/>reaction mixture. The organic layer was concentrated down and purified (silica gel, 0-10percent MeOH/DCM) to give a light yellow solid (408 g, 90percent). LC-MS shows 132.0 (M-I). 1H NMR (300 MHz, CDCb): δ 7.20 (s, 1 H), 6.96 (s, 1 H), 6.91 (s, 1 H), 2.37 (s, 3 H).
77%
Stage #1: With boron trichloride; tetra-(n-butyl)ammonium iodide In dichloromethane at 20℃; for 0.5 h; Stage #2: With water In dichloromethane at 0℃; for 0.333333 h;
BC13 (50 ml, 50 mmol, 1 M in DCM) was added dropwise to a solution of 3-methoxy- 5-methylbenzonitrile (Example 2) (2.101 g, 14.27 mmol) and Bu4NI (5.80 g, 15.7 mmol) in dry DCM (50 ml) AT-78 °C. The cold bath was removed and the mixture stirred at ambient temperature for 30 min. Ice was added and the mixture stirred 20 min, and neutralized with sat. NAHCO3. ORGANIC layer separated and product isolated by flash chromatography using 1- 2percent MeOH in DCM. Yield 1.465 g (77percent), white SOLID,-80percent pure by NMR. IN NMR (400 MHz, CDCl3) 8 2.33 (s, 3 H), 6.89 (s, 1 H), 6.92 (s, 1 H), 7.03 (s, 1 H). 13 NMR (100 MHZ, CDCL3) 8 21.12, 112. 79, 115. 85, 118. 70,121. 19,125. 27,141. 20, 155.81.
With copper(I) cyanide In DMF (N,N-dimethyl-formamide) at 60℃; for 20 h;
Three parallels of L-BROMO-3-METHOXY-5-METHYLBENZENE (Chan et al., supra) (2.00 g, 9.94 mmol) and CUCN (1.34 g, 15.0 mmol) in DMF (25 ml) was heated at 160 °C in sealed "Stemblock tubes"for 20 h. The parallels were combined, EtOAc was added and the mixture was filtered through a short plug of silica. The filtrate was purified by flash chromatography using 2-10percent EtOAc in hexanes. Yield 2.88 g (66percent); white solid. 'H NMR (400 MHz, CDC13) 8 2.33 (s, 3 H) 3.79 (s, 3 H) 6.92 (s, 2 H) 7.03 (s, 1 H). 13C NMR (100 MHZ, CDCL3) 8 21. 19,55. 40,112. 74,113. 88,118. 88,120. 01,125. 08,140. 75, 159.53. GC-MS: 100percent; 147 (M.
In a 100 mL round bottom flask, 1-bromo- 3-methoxy-5-methyl-berιzene (2.17 g, 10.79 mmol), Zn(CN)2 (1.9 g, 16.19 mmol, 1.5 eq.) and Pd(PPro)4 ( 1.24 g, 1.08 mmol, 0.1 eq.) was charged with DMF (20 mL). The reaction mixture was heated at 90 0C under Ar for 7 hours. Ethyl acetate was added, followed by washing with brine. The organic layer was concentrated and purified (silica gel, 0-50percent EtOAC/hexane) to give a white solid (1.31 g, 83percent). 1H NMR (300 MHz, CDCb): δ 7.05(s, 1 H), 6.97 (s, 2 H), 3.81 (s, 3 H), 2.39 (s, 3 H).
With copper(II) nitrate trihydrate; cesium fluoride In methanol; water at 100℃; Sealed vessel
To a sealable vessel was added 2-(3- methoxy-5-methylphenyl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (15.23 g, 61.4 mmol), copper(II)nitrate trihydrate (29.7 g, 123 mmol), zinc cyanide (21.62 g, 184 mmol), cesium fluoride (9.32 g, 61.4 mmol), 107 mL methanol, and 43 mL water. The vessel was sealed and heated to 100 °C overnight. The reaction mixture was cooled and an insoluble tan solid was filtered and washed with ethyl acetate. Water was added to the filtrate and the layers were separated. The aqueous layer was extracted with ethyl acetate. The organic layers were washed with water, brine, dried over magnesium sulfate, filtered and evaporated. The residue was purified by column chromatography eluting with 0 to 10percent ethyl acetate/hexane (3.7 g, 41percent)
Reference：
[1] Patent: WO2012/116231, 2012, A2, . Location in patent: Page/Page column 125
[2] Journal of the American Chemical Society, 2010, vol. 132, # 33, p. 11389 - 11391
With copper(I) cyanide; In DMF (N,N-dimethyl-formamide); at 60℃; for 20h;
Three parallels of L-BROMO-3-METHOXY-5-METHYLBENZENE (Chan et al., supra) (2.00 g, 9.94 mmol) and CUCN (1.34 g, 15.0 mmol) in DMF (25 ml) was heated at 160 C in sealed "Stemblock tubes"for 20 h. The parallels were combined, EtOAc was added and the mixture was filtered through a short plug of silica. The filtrate was purified by flash chromatography using 2-10% EtOAc in hexanes. Yield 2.88 g (66%); white solid. 'H NMR (400 MHz, CDC13) 8 2.33 (s, 3 H) 3.79 (s, 3 H) 6.92 (s, 2 H) 7.03 (s, 1 H). 13C NMR (100 MHZ, CDCL3) 8 21. 19,55. 40,112. 74,113. 88,118. 88,120. 01,125. 08,140. 75, 159.53. GC-MS: 100%; 147 (M.
With boron trichloride; tetra-(n-butyl)ammonium iodide; In dichloromethane; at -78 - 20℃;
In a 100 mL round bottom flask, 3- methoxy-5-methyl-benzonitrile (500 mg, 3.39 mmol) was dissolved in 15 mL dry DCM, and tetrabutylammonium iodide (1.38 g, 3.73 mmol, 3.5 eq.) was added. The flask was cooled to -78 0C. BCk (1 M in DCM, 11.87 mL, 33.16 mmol) was added to the reaction dropwise. The reaction mixture was stirred at -78 0C and warmed up to room temperature overnight. The reaction mixture was quenched with ice and neutralized with saturated NaHCCh solution. DCM was added to extract the <n="425"/>reaction mixture. The organic layer was concentrated down and purified (silica gel, 0-10% MeOH/DCM) to give a light yellow solid (408 g, 90%). LC-MS shows 132.0 (M-I). 1H NMR (300 MHz, CDCb): delta 7.20 (s, 1 H), 6.96 (s, 1 H), 6.91 (s, 1 H), 2.37 (s, 3 H).
77%
BC13 (50 ml, 50 mmol, 1 M in DCM) was added dropwise to a solution of 3-methoxy- 5-methylbenzonitrile (Example 2) (2.101 g, 14.27 mmol) and Bu4NI (5.80 g, 15.7 mmol) in dry DCM (50 ml) AT-78 C. The cold bath was removed and the mixture stirred at ambient temperature for 30 min. Ice was added and the mixture stirred 20 min, and neutralized with sat. NAHCO3. ORGANIC layer separated and product isolated by flash chromatography using 1- 2% MeOH in DCM. Yield 1.465 g (77%), white SOLID,-80% pure by NMR. IN NMR (400 MHz, CDCl3) 8 2.33 (s, 3 H), 6.89 (s, 1 H), 6.92 (s, 1 H), 7.03 (s, 1 H). 13 NMR (100 MHZ, CDCL3) 8 21.12, 112. 79, 115. 85, 118. 70,121. 19,125. 27,141. 20, 155.81.
Preparation 42 3-Hydroxy-5-methylbenzonitrile Boron trichloride (17.6 ml of a 1.0M solution in dichloromethane, 17.6 mmol) was added dropwise to a stirred solution of the nitrile of Preparation 41 (866 mg, 5.88 mmol) and tetrabutylammonium iodide (2.61 g, 7.05 mmol) in dichloromethane (50 ml) at -78 C. The reaction was allowed to warm to room temperature and stirred for 20 minutes. The reaction was cooled to 0 C., cautiously quenched with ice and diluted with dichloromethane (100 ml). The organic phase was separated, dried over magnesium sulphate, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel eluding with pentane:ethyl acetate (50:50, by volume) to provide the title compound (677 mg) as a white solid. 1H-NMR (400 MHz, CDCl3): delta=2.32 (s, 3H), 5.05 (s, 1H), 6.88 (s, 1H), 6.90 (s, 1H), 7.04 (s, 1H).
4
[ 29578-83-4 ]
[ 557-21-1 ]
[ 473923-98-7 ]
Yield
Reaction Conditions
Operation in experiment
83%
tetrakis(triphenylphosphine) palladium(0); In N,N-dimethyl-formamide; at 90℃; for 7h;
In a 100 mL round bottom flask, 1-bromo- 3-methoxy-5-methyl-beriotazene (2.17 g, 10.79 mmol), Zn(CN)2 (1.9 g, 16.19 mmol, 1.5 eq.) and Pd(PPro)4 ( 1.24 g, 1.08 mmol, 0.1 eq.) was charged with DMF (20 mL). The reaction mixture was heated at 90 0C under Ar for 7 hours. Ethyl acetate was added, followed by washing with brine. The organic layer was concentrated and purified (silica gel, 0-50% EtOAC/hexane) to give a white solid (1.31 g, 83%). 1H NMR (300 MHz, CDCb): delta 7.05(s, 1 H), 6.97 (s, 2 H), 3.81 (s, 3 H), 2.39 (s, 3 H).
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