2-bromo-2-methylpropanoyl cyanide

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

Procedure: To a room temperature, stirred solution of 1-(4-methoxyphenyl)-2-(4-(quinolin-2-ylmethoxy)phenyl)ethanone (100 mg, 0.26 mmol) in THF (5 mL), t-BuOK (1.0 mL, 1.0 N solution in THF) was added under an inert atmosphere and the resulting mixture was stirred for 30 min. 2-Bromo-2-methylpropanoyl cyanide (90 mg, 0.5 mmol) was then added to the reaction mixture and stirring was continued for an additional 16 h. The reaction mixture was quenched with cold water (10 mL) and extracted with EtOAc (2×50 mL). The combined organic layers were washed with water (30 mL) and brine (30 mL), dried over Na2SO4, filtered, concentrated and purified by column chromatography (10-15% ethyl acetate in hexanes) to afford 5-(4-methoxyphenyl)-2,2-dimethyl-4-(4-(quinolin-2-ylmethoxy)phenyl)furan-3(2H)-one (10 mg) as a solid. was added under an inert atmosphere stirring was continued for an additional 16 h The reaction mixture was quenched with cold water (10 mL) extracted with EtOAc (2×50 mL) The combined organic layers were washed with water (30 mL) and brine (30 mL) dried over Na2SO4 filtered concentrated purified by column chromatography (10-15% ethyl acetate in hexanes)

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

Procedure: To a pre-cooled 0° C. solution of 1-(4-(benzyloxy)phenyl)-2-(4-methoxyphenyl)-ethanone (2 g, 6.02 mmol) in THF (20 mL) under an inert atmosphere was added t-BuOK (8 mL, 1.0 N solution in THF). The mixture was then stirred for 30 minutes. 2-Bromo-2-methylpropanoyl cyanide (2 g, 12 mmol) was then added to then reaction mixture and stirring was continued for an additional 16 h. The reaction mixture was then quenched with cold water (10 mL) and extracted with EtOAc (2×50 mL). The combined organic layers were washed with water (30 mL) and brine (30 mL), and then dried over Na2SO4 concentrated and purified via silica gel column chromatography (10-15% Ethyl acetate in hexanes) to afford 5-(4-(benzyloxy)phenyl)-4-(4-methoxyphenyl)-2,2-dimethylfuran-3(2H)-one (100 mg) as a white solid. reaction mixture stirring was continued for an additional 16 h The reaction mixture was then quenched with cold water (10 mL) extracted with EtOAc (2×50 mL) The combined organic layers were washed with water (30 mL) and brine (30 mL) dried over Na2SO4 concentrated purified via silica gel column chromatography (10-15% Ethyl acetate in hexanes)

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

Procedure: To a pre-cooled 0° C. solution of 1-(4-(benzyloxy)phenyl)-2-(4-methoxyphenyl)-ethanone (2 g, 6.02 mmol) in THF (20 mL) under an inert atmosphere was added t-BuOK (8 mL, 1.0 N solution in THF). The mixture was then stirred for 30 minutes. 2-Bromo-2-methylpropanoyl cyanide (2 g, 12 mmol) was then added to then reaction mixture and stirring was continued for an additional 16 h. The reaction mixture was then quenched with cold water (10 mL) and extracted with EtOAc (2×50 mL). The combined organic layers were washed with water (30 mL) and brine (30 mL), and then dried over Na2SO4 concentrated and purified via silica gel column chromatography (10-15% Ethyl acetate in hexanes) to afford 5-(4-(benzyloxy)phenyl)-4-(4-methoxyphenyl)-2,2-dimethylfuran-3(2H)-one (100 mg) as a white solid. reaction mixture stirring was continued for an additional 16 h The reaction mixture was then quenched with cold water (10 mL) extracted with EtOAc (2×50 mL) The combined organic layers were washed with water (30 mL) and brine (30 mL) dried over Na2SO4 concentrated purified via silica gel column chromatography (10-15% Ethyl acetate in hexanes)

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

Procedure: 3.05 g of 1-{2-chloro-4-(methylthio)phenyl}-2-phenyl-ethanone in 60 ml dry THF was stirred at 0° C. for 20 minutes in the presence of 95% oil dispersion of sodium hydride (1.0 g), which was followed by dropwise addition of α-bromoisobutyryl cyanide (2.5 ml) diluted in 50 ml THF. The reaction solution was allowed to warm slowly to room temperature and was stirred overnight. Then the solvent was removed in vacuo, which was followed by extraction with 30 ml water and diethylether (50 ml×3). The organic layer was concentrated under reduced pressure and was purified by column chromatography (hexane/ethylacetate=8:1) to yield 2.73 g of 5-{2-chloro-4-(methylthio)phenyl}-2,2-dimethyl-4-phenyl-3(2H)-furanone. NMR: δ1.56 (s, 6H), 2.48 (s, 3H), 7.10 (dd, J=8.4, 1.5 Hz, 1H), 7.24 (m, 3H), 7.26 (m, 3H), 7.37 (d, J=1.5 Hz, 1H). IR (cm−1): 1698, 1620, 1394, 1235, 1176, 1144. Then the solvent was removed in vacuo, which was followed by extraction with 30 ml water and diethylether (50 ml×3) The organic layer was concentrated under reduced pressure was purified by column chromatography (hexane/ethylacetate=8:1)

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

Procedure: 3.05 g of 1-{2-chloro-4-(methylthio)phenyl}-2-phenyl-ethanone in 60 ml dry THF was stirred at 0° C. for 20 minutes in the presence of 95% oil dispersion of sodium hydride (1.0 g), which was followed by dropwise addition of α-bromoisobutyryl cyanide (2.5 ml) diluted in 50 ml THF. The reaction solution was allowed to warm slowly to room temperature and was stirred overnight. Then the solvent was removed in vacuo, which was followed by extraction with 30 ml water and diethylether (50 ml×3). The organic layer was concentrated under reduced pressure and was purified by column chromatography (hexane/ethylacetate=8:1) to yield 2.73 g of 5-{2-chloro-4-(methylthio)phenyl}-2,2-dimethyl-4-phenyl-3(2H)-furanone. NMR: δ1.56 (s, 6H), 2.48 (s, 3H), 7.10 (dd, J=8.4, 1.5 Hz, 1H), 7.24 (m, 3H), 7.26 (m, 3H), 7.37 (d, J=1.5 Hz, 1H). IR (cm−1): 1698, 1620, 1394, 1235, 1176, 1144. Then the solvent was removed in vacuo, which was followed by extraction with 30 ml water and diethylether (50 ml×3) The organic layer was concentrated under reduced pressure was purified by column chromatography (hexane/ethylacetate=8:1)

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

Procedure: 437 mg of 1-{3-methyl-4-(methylthio)phenyl}-2-(3-fluorophenyl)-ethanone in 50 ml dry THF was stirred with 67 mg of 60% oil dispersion of sodium hydride for an hour at 0° C., which was followed by dropwise addition of 0.8 ml α-bromoisobutyryl cyanide diluted with 25 ml THF. The reaction solution was slowly warmed to room temperature and was stirred overnight. Then the solvent was removed in vacuo and the resulting residue was extracted with 50 ml water and dichloromethane (50 ml×3). The organic layer was concentrated in vacuo and was purified by column chromatography (hexane/ethylacetate=6:1) to yield 312 mg of 2,2-dimethyl-4-(3-fluorophenyl)-5-{3-methyl-4-(methylthio)phenyl}-3(2H)-furanone. NMR: δ1.55 (s, 6H), 2.27 (s, 3H), 2.48 (s, 3H), 7.36 (m, 4H), 7.32 (m, 1H), 7.45 (m, 2H). IR 1694, 1601, 1385, 1260, 1192. Then the solvent was removed in vacuo the resulting residue was extracted with 50 ml water and dichloromethane (50 ml×3) The organic layer was concentrated in vacuo was purified by column chromatography (hexane/ethylacetate=6:1)

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

Procedure: 3.6 g of 1-{3-chloro-4-(methylthio)phenyl}-2-phenyl-ethanone in 100 ml dry THF was stirred at 0° C. for 20 minutes in the presence of 60% oil dispersion of sodium hydride (1.5 g), which was followed by dropwise addition of α-bromoisobutyryl cyanide (3.0 ml) diluted in 50 ml THF. The reaction solution was allowed to warm slowly to room temperature and was stirred overnight. Then the solvent was removed in vacuo, which was followed by extraction with 30 ml water and diethylether (50 ml×3). The organic layer was concentrated under reduced pressure and was purified by column chromatography (hexane/ethylacetate=8:1) to yield 3.2 g of 5-{3-chloro-4-(methylthio)phenyl}-2,2-dimethyl-4-phenyl-3(2H)-furanone. NMR: δ1.52 (s, 6H), 2.45 (s, 3H), 7.17 (d, J=8.4 Hz, 1H), 7.25 (m, 3H), 7.32 (m, 2H), 7.87 (dd, J=8.4, 1.8 Hz, 1H), 7.97 (d, J=1.8 Hz, 1H). IR (cm−1): 1694, 1613, 1592, 1389, 1252, 1145, 1128. Then the solvent was removed in vacuo, which was followed by extraction with 30 ml water and diethylether (50 ml×3) The organic layer was concentrated under reduced pressure was purified by column chromatography (hexane/ethylacetate=8:1)

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

Procedure: To a stirred solution of 1-{3-bromo4(methylthio)phenyl}-2-phenyl-ethan-1-one (1.54 g) in 50 ml THF, was added 232 mg of 60% oil dispersion of sodium hydride. The mixture was stirred for 1 hour at 0° C., which was followed by dropwise addition of 1.1 ml α-bromoisobutyryl cyanide diluted in 20 ml THF. The reaction mixture was then slowly warmed to room temperature and was stirred overnight. The solvent was removed in vacuo and the resulting residue was extracted with 50 ml water and dichloromethane (30 ml×3). The organic layer was concentrated under reduced pressure and was purified by column chromatography (hexane/ethylacetate=6:1) to yield 1.1 g of 5-{3-bromo-4-(methylthio)phenyl}-2,2-dimethyl-4-phenyl-3(2H)-furanone. NMR: δ1.55 (s, 6H), 2.47 (s, 3H), 6.99 (d, J=8.7 Hz, 1H), 7.32 (m, 5H), 7.48 (dd, J=8.7, 2.1 Hz, 1H), 7.88 (d, J=1.8 Hz, 1H). The reaction mixture was then slowly warmed to room temperature was stirred overnight The solvent was removed in vacuo the resulting residue was extracted with 50 ml water and dichloromethane (30 ml×3) The organic layer was concentrated under reduced pressure was purified by column chromatography (hexane/ethylacetate=6:1)

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

Procedure: To a stirred solution of 1-{3-fluoro-4-(methylthio)phenyl}-2-phenyl-ethan-1-one (1.68 g) in 100 ml dry THF, was added portion-wise at 0° C. 60% oil dispersion of sodium hydride (270 mg). The reaction solution was stirred at the same temperature for 1 hour. Then 1.2 ml of α-bromo-isobutyryl cyanide diluted in 25 ml dry THF was added dropwise to the stirred solution at 0° C. The reaction mixture was stirred overnight while warming gradually to room temperature. The solution was concentrated in vacuo, to which was added 50 ml water. The aqueous solution was extracted with dichloromethane (50 ml×3). The organic layer was concentrated in vacuo and purified by column chromatography (hexane/ethylacetate=6:1) to give 1.21 g of 2,2-dimethyl-5-{3-fluoro-4-(methylthio)phenyl}-4-phenyl-3(2H)-furanone. NMR: δ1.55 (s, 6H), 2.48 (s, 3H), 7.26-7.39 (m, 7H), 7.67 (m, 1H), 7.81 (m, 1H). IR (cm−1): 1696, 1421, 1388, 1238. was added dropwise to the stirred solution at 0° C The reaction mixture was stirred overnight The solution was concentrated in vacuo, to which was added 50 ml water The aqueous solution was extracted with dichloromethane (50 ml×3) The organic layer was concentrated in vacuo purified by column chromatography (hexane/ethylacetate=6:1)

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

Procedure: To a stirred solution of 1-{3-fluoro-4-(methylthio)phenyl}-2-phenyl-ethan-1-one (1.68 g) in 100 ml dry THF, was added portion-wise at 0° C. 60% oil dispersion of sodium hydride (270 mg). The reaction solution was stirred at the same temperature for 1 hour. Then 1.2 ml of α-bromo-isobutyryl cyanide diluted in 25 ml dry THF was added dropwise to the stirred solution at 0° C. The reaction mixture was stirred overnight while warming gradually to room temperature. The solution was concentrated in vacuo, to which was added 50 ml water. The aqueous solution was extracted with dichloromethane (50 ml×3). The organic layer was concentrated in vacuo and purified by column chromatography (hexane/ethylacetate=6:1) to give 1.21 g of 2,2-dimethyl-5-{3-fluoro-4-(methylthio)phenyl}-4-phenyl-3(2H)-furanone. NMR: δ1.55 (s, 6H), 2.48 (s, 3H), 7.26-7.39 (m, 7H), 7.67 (m, 1H), 7.81 (m, 1H). IR (cm−1): 1696, 1421, 1388, 1238. was added dropwise to the stirred solution at 0° C The reaction mixture was stirred overnight The solution was concentrated in vacuo, to which was added 50 ml water The aqueous solution was extracted with dichloromethane (50 ml×3) The organic layer was concentrated in vacuo purified by column chromatography (hexane/ethylacetate=6:1)

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

Procedure: To a stirred solution of 2-(3-fluorophenyl)-1-{4-(methylthio)phenyl}-ethan-1-one (100 g) in 1 L dry THF, was added portion-wise 26 g of 95 % sodium hydride at 0° C. The reaction solution was stirred at the same temperature for 1 hour. Then 69 g of α-bromo-isobutyryl cyanide diluted in 25 ml dry THF was added dropwise to the stirred solution at 0° C. The reaction mixture was stirred overnight while allowing to warm gradually to room temperature. The solution was concentrated in vacuo, to which was added 50 ml water. The aqueous solution was extracted with ethylacetate (1 L). The organic layer was concentrated in vacuo and purified by column chromatography (hexane/ethylacetate=6:1) to give 102 g of 2,2-dimethyl-4-(3-fluorophenyl)-5-{4-(methylthio)phenyl}-3(2H)-furanone. mp: 106° C. NMR: δ1.55 (s, 6H), 2.50 (s. 3H), 6.97-7.11 (m, 3H), 7.18 (d, J=9.0 Hz, 2H), 7.26-7.36 (m, 1H), 7.55 (d, J=9.0 Hz, 2H). was added dropwise to the stirred solution at 0° C The reaction mixture was stirred overnight The solution was concentrated in vacuo, to which was added 50 ml water The aqueous solution was extracted with ethylacetate (1 L) The organic layer was concentrated in vacuo purified by column chromatography (hexane/ethylacetate=6:1)

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

Procedure: To a stirred solution of 2-(3-fluorophenyl)-1-{4-(methylthio)phenyl}-ethan-1-one (100 g) in 1 L dry THF, was added portion-wise 26 g of 95 % sodium hydride at 0° C. The reaction solution was stirred at the same temperature for 1 hour. Then 69 g of α-bromo-isobutyryl cyanide diluted in 25 ml dry THF was added dropwise to the stirred solution at 0° C. The reaction mixture was stirred overnight while allowing to warm gradually to room temperature. The solution was concentrated in vacuo, to which was added 50 ml water. The aqueous solution was extracted with ethylacetate (1 L). The organic layer was concentrated in vacuo and purified by column chromatography (hexane/ethylacetate=6:1) to give 102 g of 2,2-dimethyl-4-(3-fluorophenyl)-5-{4-(methylthio)phenyl}-3(2H)-furanone. mp: 106° C. NMR: δ1.55 (s, 6H), 2.50 (s. 3H), 6.97-7.11 (m, 3H), 7.18 (d, J=9.0 Hz, 2H), 7.26-7.36 (m, 1H), 7.55 (d, J=9.0 Hz, 2H). was added dropwise to the stirred solution at 0° C The reaction mixture was stirred overnight The solution was concentrated in vacuo, to which was added 50 ml water The aqueous solution was extracted with ethylacetate (1 L) The organic layer was concentrated in vacuo purified by column chromatography (hexane/ethylacetate=6:1)