2-(3-bromophenyl)-2-methylpropanenitrile

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: 2-Methyl-2-[3-bromophenyl]propionitrile (0.56 g, 2.5 mmol) was refluxed in sulfuric acid (2 ml), water (3 ml) and acetic acid (2.5 ml) overnight. The reaction mixture was poured in water, then extracted with Et2O. The combined organic extracts were dried with magnesium sulfate, filtered, concentrated, and chromatographed (silica gel, 10% EtOAc, 1% HOAc) to give the title compound as a white solid (0.2 g, 36%), which was converted to the methyl ester with diazo methane in Et2O and was used in the next reaction without further purification. extracted with Et2O The combined organic extracts were dried with magnesium sulfate filtered concentrated chromatographed (silica gel, 10% EtOAc, 1% HOAc)

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

Procedure: Ethynyltrimethylsilane (4.0 mL, 28.9 mmol) was added to a mixture of ACN (100 mL), TEA (25 mL), 2-(3-bromophenyl)-2-methylpropionitrile (5.0 g, 22.3 mmol), (Ph3P)2PdCl2 (780 mg, 1.11 mol) and copper(I) iodide (130 mg, 0.68 mmol) under nitrogen atmosphere. The reaction mixture was refluxed for 3 hours, cooled to ambient temperature, concentrated to a black residue and filtered through silica gel with 20% ethyl acetate in hexane. The filtrate was concentrated to a red oil and chromatographed on silica gel with 2% ethyl acetate in hexane. Obtained 2-methyl-2-(3-trimethylsilanylethynylphenyl)-propionitrile (4.00 g, 74%) as an orange oil. 1H NMR (DMSO-d6) δ: 0.24 (s, 9H), 1.69 (s, 6H), 7.43 (m, 2H), 7.56 (m, 2H). The reaction mixture was refluxed for 3 hours concentrated to a black residue filtered through silica gel with 20% ethyl acetate in hexane The filtrate was concentrated to a red oil chromatographed on silica gel with 2% ethyl acetate in hexane

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

Procedure: 257 mg 95% sodium hydride were stirred at room temperature in 25 ml dry DMF under an atmosphere of nitrogen. A solution of 1 g 3-bromophenylacetonitrile and 1.593 g iodomethane in 10 ml dry diethyl ether was added slowly below 30° C. The mixture was stirred over night at room temperature and then quenched by addition of a small amount of water. The solvents were evaporated under vacuum and the residue was purified by chromatography on silica in a heptane/ethyl acetate gradient. quenched by addition of a small amount of water The solvents were evaporated under vacuum the residue was purified by chromatography on silica in a heptane/ethyl acetate gradient

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

Procedure: Ethynyltrimethylsilane (4.0 mL, 28.9 mmol) was added to a mixture of ACN (100 mL), TEA (25 mL), 2-(3-bromophenyl)-2-methylpropionitrile (5.0 g, 22.3 mmol), (Ph3P)2PdCl2 (780 mg, 1.11 mmol) and copper(I) iodide (130 mg, 0.68 mmol) under nitrogen atmosphere. The reaction mixture was refluxed for 3 hours, cooled to ambient temperature, concentrated to a black residue and filtered through silica gel with 20% ethyl acetate in hexane. The filtrate was concentrated to a red oil and chromatographed on silica gel with 2% ethyl acetate in hexane. Obtained 2-methyl-2-(3-trimethylsilanylethynylphenyl)-propionitrile (4.00 g, 74%) as an orange oil. 1H NMR (DMSO-d6) δ: 0.24 (s, 9H), 1.69 (s, 6H), 7.43 (m, 2H), 7.56 (m, 2H). The reaction mixture was refluxed for 3 hours concentrated to a black residue filtered through silica gel with 20% ethyl acetate in hexane The filtrate was concentrated to a red oil chromatographed on silica gel with 2% ethyl acetate in hexane

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

Procedure: Ethynyltrimethylsilane (4.0 mL, 28.9 mmol) was added to a mixture of ACN (100 mL), TEA (25 mL), 2-(3-bromophenyl)-2-methylpropionitrile (5.0 g, 22.3 mmol), (Ph3P)2PdCl2 (780 mg, 1.11 mmol) and copper(I) iodide (130 mg, 0.68 mmol) under nitrogen atmosphere. The reaction mixture was refluxed for 3 hours, cooled to ambient temperature, concentrated to a black residue and filtered through silica gel with 20% ethyl acetate in hexane. The filtrate was concentrated to a red oil and chromatographed on silica gel with 2% ethyl acetate in hexane. Obtained 2-methyl-2-(3-trimethylsilanylethynylphenyl)-propionitrile (4.00 g, 74%) as an orange oil. 1H NMR (DMSO-d6) δ: 0.24 (s, 9H), 1.69 (s, 6H), 7.43 (m, 2H), 7.56 (m, 2H). The reaction mixture was refluxed for 3 hours concentrated to a black residue filtered through silica gel with 20% ethyl acetate in hexane The filtrate was concentrated to a red oil chromatographed on silica gel with 2% ethyl acetate in hexane

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 2-(3-bromo-phenyl)-2-methyl-propionitrile [0.5 g, 2.2 mmol, Intermediate (65)] in toluene (8 mL) and THF (2 mL) is added triisopropyl borate (0.61 mL, 2.68 mmol) at −78° C. tert-Butyl lithium (1.7 M in pentane, 1.55 mL, 2.68 mmol) is added dropwise during 15 min. Reaction mixture is stirred at −78° C. for additional 1 hour, warmed up to −20° C. and quenched with 2N hydrochloric acid (10 mL). The reaction mixture is extracted with ether, combined ether layers are washed with brine, dried and concentrated to obtain 3-(cyano-dimethyl-methyl)-phenyl boronic acid (0.5 g) [Intermediate (66)] as an oil. is added dropwise during 15 min Reaction mixture warmed up to −20° C. quenched with 2N hydrochloric acid (10 mL) The reaction mixture is extracted with ether are washed with brine dried concentrated

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 2-(3-bromo-phenyl)-2-methyl-propionitrile [0.5 g, 2.2 mmol, Intermediate (65)] in toluene (8 mL) and THF (2 mL) is added triisopropyl borate (0.61 mL, 2.68 mmol) at −78° C. tert-Butyl lithium (1.7 M in pentane, 1.55 mL, 2.68 mmol) is added dropwise during 15 min. Reaction mixture is stirred at −78° C. for additional 1 hour, warmed up to −20° C. and quenched with 2N hydrochloric acid (10 mL). The reaction mixture is extracted with ether, combined ether layers are washed with brine, dried and concentrated to obtain 3-(cyano-dimethyl-methyl)-phenyl boronic acid (0.5 g) [Intermediate (66)] as an oil. is added dropwise during 15 min Reaction mixture warmed up to −20° C. quenched with 2N hydrochloric acid (10 mL) The reaction mixture is extracted with ether are washed with brine dried concentrated

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 2-(3-bromo-phenyl)-2-methyl-propionitrile (prepared as described by Barlaam et al. J. Med. Chem., 1999, 42, 23, 4890-4908 incorporated herein by reference; 1.4 g, 6.24 mmol) was dissolved in ethanol (40 mL), treated with concentrated sulfuric acid (1 mL) and the resulting reaction mixture was refluxed for 36 h. The reaction mixture was cooled to ambient temperature, diluted with water and extracted with ethyl acetate. The organic phase was washed with water and brine, dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to a residue that was subjected to flash column chromatography over silica gel (230-400 mesh) using 5% ethyl acetate in hexane as the eluent to afford the title product as an orange oil (0.77 g, 46%). the resulting reaction mixture was refluxed for 36 h extracted with ethyl acetate The organic phase was washed with water and brine dried over anhydrous magnesium sulfate filtered evaporated in vacuo to a residue that