4-formyl-2-methoxybenzonitrile

Conditions: temp:110.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 4-formyl-2-methoxyphenyl trifluoromethanesulfonate (37.0 g, 130 mmol), zinc cyanide (61.0 g, 521 mmol) and tetrakis triphenylphosphine palladium (0) (22.6 g, 19.5 mmol) in DMF (300 mL) were stirred at 110° C. for 8 h. EtOAc was added to the reaction mixture and the organic layer was washed two times with water, dried, filtered and concentrated. The crude product was then purified by column chromatography (silica gel, ethylacetate/hexanes 3:7) which afforded 4-formyl-2-methoxybenzonitrile. the organic layer was washed two times with water dried filtered concentrated The crude product was then purified by column chromatography (silica gel, ethylacetate/hexanes 3:7) which

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a cool solution of NaH (0.16 g, 3.9 mmol) in THF (40 mL) was added dropwise a solution of trimethylsulfonium iodide (0.91 g, 4.5 mmol) in DMSO (20 mL). The resulting mixture was stirred at 0° C. under N2 for 20 min. A solution of 4-formyl-2-methoxybenzonitrile (0.60 g, 3.72 mmol) in THF (20 mL) was added. The resulting reaction mixture was stirred at 0° C. under N2 for 1 hr, and then it was warmed gradually to room temperature and stirred at that temperature for 12 hr. The starting material was consumed as indicated by TLC (25% ethyl acetate/hexanes). The reaction mixture was cooled to 0° C. and quenched with dropwise addition of water. The mixture was extracted with ethyl acetate (2×70 mL). The combined organic layers were washed with water, brine, then dried (MgSO4) and filtered. The filtrate was concentrated in vacuo. The residue was purified via column chromatography (silica gel, 10-30% EtOAc-hexanes) to afford 2-methoxy-4-(oxiran-2-yl)benzonitrile: 1H NMR (CDCl3, 500 MHz) δ 7.57 (d, J=8 Hz, 1H), 6.99 (dd, J=1.1 Hz, J=1.2 Hz, 1H), 6.89 (s, 1H), 3.97 (s, 3H), 3.94-3.92 (m, 1H), 3.22 (dd, J=5.2, Hz, J=4.1 Hz, 1H), 2.77 (d, J=2.5 Hz, 1H); LC/MS: (IE, m/z) [M+1]+=176.33. The resulting reaction mixture was stirred at 0° C. under N2 for 1 hr it was warmed gradually to room temperature stirred at that temperature for 12 hr The starting material was consumed The reaction mixture was cooled to 0° C. quenched with dropwise addition of water The mixture was extracted with ethyl acetate (2×70 mL) The combined organic layers were washed with water, brine dried (MgSO4) filtered The filtrate was concentrated in vacuo The residue was purified via column chromatography (silica gel, 10-30% EtOAc-hexanes)

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

Procedure: A mixture of 4-formyl-2-methoxybenzonitrile (383 mg, 2.38 mmol) and chloroacetic acid ethyl ester (291 mg, 2.38 mmol) were dissolved in 10 mL of dry benzene. Freshly prepared EtONa (3.09 mmol) in 2.5 mL of ethanol was added, and the mixture were stirred at room temperature for 2 hours. The mixture was added water, then extracted with EtOAc. The organic layers were dried over Na2SO4 and concentrated to afford ethyl 3-(4-cyano-3-methoxyphenyl)oxirane-2-carboxylate. MS m/z: 248 (M+1)+. extracted with EtOAc The organic layers were dried over Na2SO4 concentrated

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

Procedure: To a stirred solution of 4-bromo-2-methoxybenzonitrile (1.0 g, 4.7 mmol) in 30 mL of anhydrous THF was added BuLi (1.6 M, 3.3 mL, 5.2 mmol) dropwise at −78° C. under nitrogen atmosphere. After the addition, the pale red solution was stirred for 5 min at −78° C. and dry DMF (0.6 mL) then added dropwise. After 20 min, the reaction mixture was poured onto a saturated solution of sodium chloride (50 mL). The organic phase was separated, extracted with diethyl ether (100 mL), dried over Na2SO4 and distilled off the solvent to afford 4-formyl-2-methoxybenzonitrile. MS m/z: 162 (M+1)+. After the addition After 20 min The organic phase was separated extracted with diethyl ether (100 mL) dried over Na2SO4 distilled off the solvent

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a cool solution of NaH (0.16 g, 3.9 mmol) in THF (40 mL) was added dropwise a solution of trimethylsulfonium iodide (0.91 g, 4.5 mmol) in DMSO (20 mL). The resulting mixture was stirred at 0° C. under N2 for 20 min. A solution of 4-formyl-2-methoxybenzonitrile (0.60 g, 3.72 mmol) in THF (20 mL) was added. The resulting reaction mixture was stirred at 0° C. under N2 for 1 hr, and then it was warmed gradually to room temperature and stirred at that temperature for 12 hr. The starting material was consumed as indicated by TLC (25% ethyl acetate/hexanes). The reaction mixture was cooled to 0° C. and quenched with dropwise addition of water. The mixture was extracted with ethyl acetate (2×70 mL). The combined organic layers were washed with water, brine, then dried (MgSO4) and filtered. The filtrate was concentrated in vacuo. The residue was purified via column chromatography (silica gel, 10-30% EtOAc-hexanes) to afford 2-methoxy-4-(oxiran-2-yl)benzonitrile: 1H NMR (CDCl3, 500 MHz) δ 7.57 (d, J=8 Hz, 1H), 6.99 (dd, J=1.1 Hz, J=1.2 Hz, 1H), 6.89 (s, 1H), 3.97 (s, 3H), 3.94-3.92 (m, 1H), 3.22 (dd, J=5.2, Hz, J=4.1 Hz, 1H), 2.77 (d, J=2.5 Hz, 1H); LC/MS: (IE, m/z) [M+1]+=176.33. The resulting reaction mixture was stirred at 0° C. under N2 for 1 hr it was warmed gradually to room temperature stirred at that temperature for 12 hr The starting material was consumed The reaction mixture was cooled to 0° C. quenched with dropwise addition of water The mixture was extracted with ethyl acetate (2×70 mL) The combined organic layers were washed with water, brine dried (MgSO4) filtered The filtrate was concentrated in vacuo The residue was purified via column chromatography (silica gel, 10-30% EtOAc-hexanes)

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

Procedure: To a solution of 1-vinyl-4-cyano-3-methoxybenzene (0.343 g, 2.16 mmol, 1.0 eq) in dioxane (7 mL) was added 2,6-lutidine (0.461 g, 0.50 mL, 4.31 mmol, 2.0 eq) followed by osmium tetroxide (1.37 g, 1.32 mL of a 4% solution in water, 0.22 mmol, 0.1 eq). A brown/black solution resulted after 1→2 minutes. Sodium periodate (1.847 g, 8.63 mmol as a solution in 7 mL of water, 4.0 eq) was added forming a white precipitate. The mixture was stirred at room temperature for 35 minutes before partitioning between EtOAc (100 mL) and HCl (1M, 100 mL). The organics were washed with brine (100 mL), dried (Na2SO4) and concentrated under reduced pressure. MPLC (10→50% EtOAc-hexane) yielded the title compound as a white solid; 1H nmr (CDCl3) d 9.89 (1H, s, CHO), 8.09 (2H, m, ArH-2, H-6), 7.12 (1H, d, J 9.5 Hz, ArH-3), 4.04 (3H, s, OCH3); m/z 162 [M+H]+. A brown/black solution resulted after 1→2 minutes forming a white precipitate before partitioning between EtOAc (100 mL) and HCl (1M, 100 mL) The organics were washed with brine (100 mL) dried (Na2SO4) concentrated under reduced pressure

Conditions: temp:110.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 4-formyl-2-methoxyphenyl trifluoromethanesulfonate (37.0 g, 130 mmol), zinc cyanide (61.0 g, 521 mmol) and tetrakis triphenylphosphine palladium (0) (22.6 g, 19.5 mmol) in DMF (300 mL) were stirred at 110° C. for 8 h. EtOAc was added to the reaction mixture and the organic layer was washed two times with water, dried, filtered and concentrated. The crude product was then purified by column chromatography (silica gel, ethylacetate/hexanes 3:7) which afforded 4-formyl-2-methoxybenzonitrile. the organic layer was washed two times with water dried filtered concentrated The crude product was then purified by column chromatography (silica gel, ethylacetate/hexanes 3:7) which

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a cool solution of NaH (0.16 g, 3.9 mmol) in THF (40 ml) was added dropwise a solution of trimethylsulfonium iodide (0.91 g, 4.5 mmol) in DMSO (20 ml). The resulting mixture was stirred at 0° C. under N2 for 20 min. The solution of 4-formyl-2-methoxybenzonitrile (0.60 g, 3.7 mmol) in THF (20 ml) was added. The resulting reaction mixture was stirred at 0° C. under N2 for 1 hr, and then it was warmed gradually to room temperature and stirred at that temperature for 12 hr. The starting material was consumed as indicated by TLC (25% ethyl acetate/hexanes). The reaction mixture was cooled to 0° C. and quenched by drop-wise addition of water. The mixture was extracted with ethyl acetate (2×70 mL). The combined organic layers were washed with water, brine, then dried (MgSO4) and filtered. The filtrate was concentrated in vacuo. The residue was purified via column chromatography (silica gel, 10-30% EtOAc-hexanes) to afford 2-methoxy-4-(oxiran-2-yl)benzonitrile. 1H NMR (CDCl3, 500 MHz) δ 7.57 (d, J=8 Hz, 1H), 6.99 (dd, J=1.1 Hz, J=1.2 Hz, 1H), 6.89 (s, 1H), 3.97 (s, 3H), 3.94-3.92 (m, 1H), 3.22 (dd, J=5.2, Hz, J=4.1 Hz, 1H), 2.77 (J=2.5 Hz, 1H); LC/MS (IE, m/z) 176.33 [M+1]+; tR=2.55 min. The resulting reaction mixture was stirred at 0° C. under N2 for 1 hr it was warmed gradually to room temperature stirred at that temperature for 12 hr The starting material was consumed The reaction mixture was cooled to 0° C. quenched by drop-wise addition of water The mixture was extracted with ethyl acetate (2×70 mL) The combined organic layers were washed with water, brine dried (MgSO4) filtered The filtrate was concentrated in vacuo The residue was purified via column chromatography (silica gel, 10-30% EtOAc-hexanes)

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a cool solution of NaH (0.16 g, 3.9 mmol) in THF (40 ml) was added dropwise a solution of trimethylsulfonium iodide (0.91 g, 4.5 mmol) in DMSO (20 ml). The resulting mixture was stirred at 0° C. under N2 for 20 min. The solution of 4-formyl-2-methoxybenzonitrile (0.60 g, 3.7 mmol) in THF (20 ml) was added. The resulting reaction mixture was stirred at 0° C. under N2 for 1 hr, and then it was warmed gradually to room temperature and stirred at that temperature for 12 hr. The starting material was consumed as indicated by TLC (25% ethyl acetate/hexanes). The reaction mixture was cooled to 0° C. and quenched by drop-wise addition of water. The mixture was extracted with ethyl acetate (2×70 mL). The combined organic layers were washed with water, brine, then dried (MgSO4) and filtered. The filtrate was concentrated in vacuo. The residue was purified via column chromatography (silica gel, 10-30% EtOAc-hexanes) to afford 2-methoxy-4-(oxiran-2-yl)benzonitrile. 1H NMR (CDCl3, 500 MHz) δ 7.57 (d, J=8 Hz, 1H), 6.99 (dd, J=1.1 Hz, J=1.2 Hz, 1H), 6.89 (s, 1H), 3.97 (s, 3H), 3.94-3.92 (m, 1H), 3.22 (dd, J=5.2, Hz, J=4.1 Hz, 1H), 2.77 (J=2.5 Hz, 1H); LC/MS (IE, m/z) 176.33 [M+1]+; tR=2.55 min. The resulting reaction mixture was stirred at 0° C. under N2 for 1 hr it was warmed gradually to room temperature stirred at that temperature for 12 hr The starting material was consumed The reaction mixture was cooled to 0° C. quenched by drop-wise addition of water The mixture was extracted with ethyl acetate (2×70 mL) The combined organic layers were washed with water, brine dried (MgSO4) filtered The filtrate was concentrated in vacuo The residue was purified via column chromatography (silica gel, 10-30% EtOAc-hexanes)