2-cyclopropylethynyl(trimethyl)silane

Conditions: temp:0.00; pressure:0.00; stir:

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

Procedure: A Smith process vial was charged (S)-ethyl 2-(6-bromo-3-methyl-1-(triethylsilyloxy)naphthalen-2-yl)-2-tert-butoxyacetate (151 mg, 0.287 mmol), (cyclopropylethynyl)trimethylsilane (195 mg, 0.316 mmol), Pd(PPh3)4 (33 mg, 0.03 mmol), CuI (55 mg, 0.28 mmol), triethylamine (0.12 mL, 0.86 mmol), cesium fluoride (144 mg, 0.95 mmol) and flushed with nitrogen. THF (3 mL) was added and mixture sparged with nitrogen for 10 minutes and then heated in microwave at 110° C. for 1 hour. Reaction mixture was diluted with ethyl acetate and washed with brine, dried (MgSO4), filtered, concentrated and purified by flash column chromatography (silica gel, 0 to 100% ethyl acetate/hexanes) to give (S)-ethyl 2-tert-butoxy-2-(6-(cyclopropylethynyl)-1-hydroxy-3-methylnaphthalen-2-yl)acetate. LCMS-ESI− (m/z): [M−H]− calcd for C24H27O4: 379.48. Found: 379.20. flushed with nitrogen THF (3 mL) was added mixture sparged with nitrogen for 10 minutes Reaction mixture washed with brine dried (MgSO4) filtered concentrated purified by flash column chromatography (silica gel, 0 to 100% ethyl acetate/hexanes)

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

Procedure: A Smith process vial was charged (S)-ethyl 2-(6-bromo-3-methyl-1-(triethylsilyloxy)naphthalen-2-yl)-2-tert-butoxyacetate (151 mg, 0.287 mmol), (cyclopropylethynyl)trimethylsilane (195 mg, 0.316 mmol), Pd(PPh3)4 (33 mg, 0.03 mmol), CuI (55 mg, 0.28 mmol), triethylamine (0.12 mL, 0.86 mmol), cesium fluoride (144 mg, 0.95 mmol) and flushed with nitrogen. THF (3 mL) was added and mixture sparged with nitrogen for 10 minutes and then heated in microwave at 110° C. for 1 hour. Reaction mixture was diluted with ethyl acetate and washed with brine, dried (MgSO4), filtered, concentrated and purified by flash column chromatography (silica gel, 0 to 100% ethyl acetate/hexanes) to give (S)-ethyl 2-tert-butoxy-2-(6-(cyclopropylethynyl)-1-hydroxy-3-methylnaphthalen-2-yl)acetate. LCMS-ESI− (m/z): [M−H]− calcd for C24H27O4: 379.48. Found: 379.20. flushed with nitrogen THF (3 mL) was added mixture sparged with nitrogen for 10 minutes Reaction mixture washed with brine dried (MgSO4) filtered concentrated purified by flash column chromatography (silica gel, 0 to 100% ethyl acetate/hexanes)

Conditions: temp:10.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of cyclopropylethynyl-trimethyl-silane (3.0 g, 22 mmol) in ether (20 mL) was added dropwise n-BuLi (8.6 mL, 21.7 mol, 2.5 M solution in hexane) at 0° C. The reaction mixture was stirred at ambient temperature for 24 h before dimethyl sulfate (6.85 g, 54.3 mmol) was added dropwise at −10° C. The resulting solution was stirred at 10° C. and then at 20° C. for 30 min each. The reaction was quenched by adding a mixture of sat. aq. NH4Cl and 25% aq. ammonia (1:3, 100 mL). The mixture was then stirred at ambient temperature for 1 h. The aqueous phase was extracted with diethyl ether (3×50 mL) and the combined organic layers were washed successively with 5% aqueous hydrochloric acid (100 mL), 5% aq. NaHCO3 solution (100 mL), and water (100 mL). The organics were dried over anhydrous NaSO4 and concentrated at ambient pressure. After fractional distillation under reduced pressure, trimethyl-(1-methyl-cyclopropylethynyl)-silane (1.7 g, 52%) was obtained as a colorless liquid. 1H NMR (400 MHz, CDCl3) δ 1.25 (s, 3H), 0.92-0.86 (m, 2H), 0.58-0.56 (m, 2H), 0.15 (s, 9H). was added dropwise at −10° C The reaction was quenched by adding a mixture of sat. aq. NH4Cl and 25% aq. ammonia (1:3, 100 mL) The mixture was then stirred at ambient temperature for 1 h The aqueous phase was extracted with diethyl ether (3×50 mL) the combined organic layers were washed successively with 5% aqueous hydrochloric acid (100 mL), 5% aq. NaHCO3 solution (100 mL), and water (100 mL) The organics were dried over anhydrous NaSO4 concentrated at ambient pressure After fractional distillation under reduced pressure

Conditions: temp:10.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of cyclopropylethynyl-trimethyl-silane (3.0 g, 22 mmol) in ether (20 mL) was added dropwise n-BuLi (8.6 mL, 21.7 mol, 2.5 M solution in hexane) at 0° C. The reaction mixture was stirred at ambient temperature for 24 h before dimethyl sulfate (6.85 g, 54.3 mmol) was added dropwise at −10° C. The resulting solution was stirred at 10° C. and then at 20° C. for 30 min each. The reaction was quenched by adding a mixture of sat. aq. NH4Cl and 25% aq. ammonia (1:3, 100 mL). The mixture was then stirred at ambient temperature for 1 h. The aqueous phase was extracted with diethyl ether (3×50 mL) and the combined organic layers were washed successively with 5% aqueous hydrochloric acid (100 mL), 5% aq. NaHCO3 solution (100 mL), and water (100 mL). The organics were dried over anhydrous NaSO4 and concentrated at ambient pressure. After fractional distillation under reduced pressure, trimethyl-(1-methyl-cyclopropylethynyl)-silane (1.7 g, 52%) was obtained as a colorless liquid. 1H NMR (400 MHz, CDCl3) δ 1.25 (s, 3H), 0.92-0.86 (m, 2H), 0.58-0.56 (m, 2H), 0.15 (s, 9H). was added dropwise at −10° C The reaction was quenched by adding a mixture of sat. aq. NH4Cl and 25% aq. ammonia (1:3, 100 mL) The mixture was then stirred at ambient temperature for 1 h The aqueous phase was extracted with diethyl ether (3×50 mL) the combined organic layers were washed successively with 5% aqueous hydrochloric acid (100 mL), 5% aq. NaHCO3 solution (100 mL), and water (100 mL) The organics were dried over anhydrous NaSO4 concentrated at ambient pressure After fractional distillation under reduced pressure

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

Procedure: To a solution of cyclopropylethynyl-trimethyl-silane (3.0 g, 22 mmol) in ether (20 mL) was added dropwise n-BuLi (8.6 mL, 21.7 mol, 2.5 M solution in hexane) at 0 CC. The reaction mixture was stirred at ambient temperature for 24 h before dimethyl sulfate (6.85 g, 54.3 mmol) was added dropwise at −10° C. The resulting solution was stirred at 10 CC and then at 20° C. for 30 min each. The reaction was quenched by adding a mixture of sat. aq. NH4Cl and 25% aq. ammonia (1:3, 100 mL). The mixture was then stirred at ambient temperature for 1 h. The aqueous phase was extracted with diethyl ether (3×50 mL) and the combined organic layers were washed successively with 5% aqueous hydrochloric acid (100 mL), 5% aq. NaHCO3 solution (100 mL), and water (100 mL). The organics were dried over anhydrous NaSO4 and concentrated at ambient pressure. After fractional distillation under reduced pressure, trimethyl-(1-methyl-cyclopropylethynyl)-silane (1.7 g, 52%) was obtained as a colorless liquid. 1H NMR (400 MHz, CDCl3) δ 1.25 (s, 3H), 0.92-0.86 (m, 2H), 0.58-0.56 (m, 2H), 0.15 (s, 9H). was added dropwise at −10° C The reaction was quenched by adding a mixture of sat. aq. NH4Cl and 25% aq. ammonia (1:3, 100 mL) The mixture was then stirred at ambient temperature for 1 h The aqueous phase was extracted with diethyl ether (3×50 mL) the combined organic layers were washed successively with 5% aqueous hydrochloric acid (100 mL), 5% aq. NaHCO3 solution (100 mL), and water (100 mL) The organics were dried over anhydrous NaSO4 concentrated at ambient pressure After fractional distillation under reduced pressure

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

Procedure: To a solution of cyclopropylethynyl-trimethyl-silane (3.0 g, 22 mmol) in ether (20 mL) was added dropwise n-BuLi (8.6 mL, 21.7 mol, 2.5 M solution in hexane) at 0 CC. The reaction mixture was stirred at ambient temperature for 24 h before dimethyl sulfate (6.85 g, 54.3 mmol) was added dropwise at −10° C. The resulting solution was stirred at 10 CC and then at 20° C. for 30 min each. The reaction was quenched by adding a mixture of sat. aq. NH4Cl and 25% aq. ammonia (1:3, 100 mL). The mixture was then stirred at ambient temperature for 1 h. The aqueous phase was extracted with diethyl ether (3×50 mL) and the combined organic layers were washed successively with 5% aqueous hydrochloric acid (100 mL), 5% aq. NaHCO3 solution (100 mL), and water (100 mL). The organics were dried over anhydrous NaSO4 and concentrated at ambient pressure. After fractional distillation under reduced pressure, trimethyl-(1-methyl-cyclopropylethynyl)-silane (1.7 g, 52%) was obtained as a colorless liquid. 1H NMR (400 MHz, CDCl3) δ 1.25 (s, 3H), 0.92-0.86 (m, 2H), 0.58-0.56 (m, 2H), 0.15 (s, 9H). was added dropwise at −10° C The reaction was quenched by adding a mixture of sat. aq. NH4Cl and 25% aq. ammonia (1:3, 100 mL) The mixture was then stirred at ambient temperature for 1 h The aqueous phase was extracted with diethyl ether (3×50 mL) the combined organic layers were washed successively with 5% aqueous hydrochloric acid (100 mL), 5% aq. NaHCO3 solution (100 mL), and water (100 mL) The organics were dried over anhydrous NaSO4 concentrated at ambient pressure After fractional distillation under reduced pressure

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To the product of Example 20, Step 1, 3-methyl-4-trifluoromethanesulfonyloxy-benzofuran-2-carboxylic acid ethyl ester (1.8 g, 5.1 mmol, 1 eq), in 2 mL of DMF under nitrogen was added 200 mg of PdCl2(PPh3)2 (0.28 mmol, 0.05 eq), Et3N (2.85 mL, 20.4 mmol, 4 eq), cyclopropylethynyl-trimethylsilane (1 g, 7.2 mmol, 1.4 eq), and tetrabutylammonium fluoride (5.1 mL, 1.0 M in THF, 5.1 mmol, 1 eq). The reaction mixture was sealed and heated to 80° C. for 12 h. After workup and column chromatography (2% ethyl acetate/hexane), 4-cyclopropylethynyl-3-methyl-benzofuran-2-carboxylic acid ethyl ester was obtained in 15% yield (202.6 mg). 1H NMR (400 MHz, CD3OD) δ ppm 0.7 (m, 2 H) 0.9 (m, 2 H) 1.3 (t, J=7.1 Hz, 3 H) 1.5 (m, 1 H) 2.7 (s, 3 H) 4.3 (q, J=7.2 Hz, 2 H) 7.2 (m, 1 H) 7.3 (dd, J=8.3, 7.3 Hz, 1 H) 7.4 (m, 1 H). The reaction mixture was sealed

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To the product of Example 20, Step 1, 3-methyl-4-trifluoromethanesulfonyloxy-benzofuran-2-carboxylic acid ethyl ester (1.8 g, 5.1 mmol, 1 eq), in 2 mL of DMF under nitrogen was added 200 mg of PdCl2(PPh3)2 (0.28 mmol, 0.05 eq), Et3N (2.85 mL, 20.4 mmol, 4 eq), cyclopropylethynyl-trimethylsilane (1 g, 7.2 mmol, 1.4 eq), and tetrabutylammonium fluoride (5.1 mL, 1.0 M in THF, 5.1 mmol, 1 eq). The reaction mixture was sealed and heated to 80° C. for 12 h. After workup and column chromatography (2% ethyl acetate/hexane), 4-cyclopropylethynyl-3-methyl-benzofuran-2-carboxylic acid ethyl ester was obtained in 15% yield (202.6 mg). 1H NMR (400 MHz, CD3OD) δ ppm 0.7 (m, 2 H) 0.9 (m, 2 H) 1.3 (t, J=7.1 Hz, 3 H) 1.5 (m, 1 H) 2.7 (s, 3 H) 4.3 (q, J=7.2 Hz, 2 H) 7.2 (m, 1 H) 7.3 (dd, J=8.3, 7.3 Hz, 1 H) 7.4 (m, 1 H). The reaction mixture was sealed

Conditions: temp:10.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of cyclopropylethynyl-trimethyl-silane (3.0 g, 22 mmol) in ether (20 mL) was added dropwise n-BuLi (8.6 mL, 21.7 mol, 2.5 M solution in hexane) at 0° C. The reaction mixture was stirred at ambient temperature for 24 h before dimethyl sulfate (6.85 g, 54.3 mmol) was added dropwise at −10° C. The resulting solution was stirred at 10° C. and then at 20° C. for 30 min each. The reaction was quenched by adding a mixture of sat. aq. NH4Cl and 25% aq. ammonia (1:3, 100 mL). The mixture was then stirred at ambient temperature for 1 h. The aqueous phase was extracted with diethyl ether (3×50 mL) and the combined organic layers were washed successively with 5% aqueous hydrochloric acid (100 mL), 5% aq. NaHCO3 solution (100 mL), and water (100 mL). The organics were dried over anhydrous NaSO4 and concentrated at ambient pressure. After fractional distillation under reduced pressure, trimethyl-(1-methyl-cyclopropylethynyl)-silane (1.7 g, 52%) was obtained as a colorless liquid. 1H NMR (400 MHz, CDCl3) δ 1.25 (s, 3 H), 0.92-0.86 (m, 2 H), 0.58-0.56 (m, 2 H), 0.15 (s, 9 H). was added dropwise at −10° C The reaction was quenched by adding a mixture of sat. aq. NH4Cl and 25% aq. ammonia (1:3, 100 mL) The mixture was then stirred at ambient temperature for 1 h The aqueous phase was extracted with diethyl ether (3×50 mL) the combined organic layers were washed successively with 5% aqueous hydrochloric acid (100 mL), 5% aq. NaHCO3 solution (100 mL), and water (100 mL) The organics were dried over anhydrous NaSO4 concentrated at ambient pressure After fractional distillation under reduced pressure

Conditions: temp:10.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of cyclopropylethynyl-trimethyl-silane (3.0 g, 22 mmol) in ether (20 mL) was added dropwise n-BuLi (8.6 mL, 21.7 mol, 2.5 M solution in hexane) at 0° C. The reaction mixture was stirred at ambient temperature for 24 h before dimethyl sulfate (6.85 g, 54.3 mmol) was added dropwise at −10° C. The resulting solution was stirred at 10° C. and then at 20° C. for 30 min each. The reaction was quenched by adding a mixture of sat. aq. NH4Cl and 25% aq. ammonia (1:3, 100 mL). The mixture was then stirred at ambient temperature for 1 h. The aqueous phase was extracted with diethyl ether (3×50 mL) and the combined organic layers were washed successively with 5% aqueous hydrochloric acid (100 mL), 5% aq. NaHCO3 solution (100 mL), and water (100 mL). The organics were dried over anhydrous NaSO4 and concentrated at ambient pressure. After fractional distillation under reduced pressure, trimethyl-(1-methyl-cyclopropylethynyl)-silane (1.7 g, 52%) was obtained as a colorless liquid. 1H NMR (400 MHz, CDCl3) δ 1.25 (s, 3H), 0.92-0.86 (m, 2H), 0.58-0.56 (m, 2H), 0.15 (s, 9H). was added dropwise at −10° C The reaction was quenched by adding a mixture of sat. aq. NH4Cl and 25% aq. ammonia (1:3, 100 mL) The mixture was then stirred at ambient temperature for 1 h The aqueous phase was extracted with diethyl ether (3×50 mL) the combined organic layers were washed successively with 5% aqueous hydrochloric acid (100 mL), 5% aq. NaHCO3 solution (100 mL), and water (100 mL) The organics were dried over anhydrous NaSO4 concentrated at ambient pressure After fractional distillation under reduced pressure

Conditions: temp:10.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of cyclopropylethynyl-trimethyl-silane (3.0 g, 22 mmol) in ether (20 mL) was added dropwise n-BuLi (8.6 mL, 21.7 mol, 2.5 M solution in hexane) at 0° C. The reaction mixture was stirred at ambient temperature for 24 h before dimethyl sulfate (6.85 g, 54.3 mmol) was added dropwise at −10° C. The resulting solution was stirred at 10° C. and then at 20° C. for 30 min each. The reaction was quenched by adding a mixture of sat. aq. NH4Cl and 25% aq. ammonia (1:3, 100 mL). The mixture was then stirred at ambient temperature for 1 h. The aqueous phase was extracted with diethyl ether (3×50 mL) and the combined organic layers were washed successively with 5% aqueous hydrochloric acid (100 mL), 5% aq. NaHCO3 solution (100 mL), and water (100 mL). The organics were dried over anhydrous NaSO4 and concentrated at ambient pressure. After fractional distillation under reduced pressure, trimethyl-(1-methyl-cyclopropylethynyl)-silane (1.7 g, 52%) was obtained as a colorless liquid. 1H NMR (400 MHz, CDCl3) δ 1.25 (s, 3 H), 0.92-0.86 (m, 2 H), 0.58-0.56 (m, 2 H), 0.15 (s, 9 H). was added dropwise at −10° C The reaction was quenched by adding a mixture of sat. aq. NH4Cl and 25% aq. ammonia (1:3, 100 mL) The mixture was then stirred at ambient temperature for 1 h The aqueous phase was extracted with diethyl ether (3×50 mL) the combined organic layers were washed successively with 5% aqueous hydrochloric acid (100 mL), 5% aq. NaHCO3 solution (100 mL), and water (100 mL) The organics were dried over anhydrous NaSO4 concentrated at ambient pressure After fractional distillation under reduced pressure