3-trimethylsilylprop-2-ynoic acid

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

Procedure: Dibromo(triphenyl)phosphorane (1.208 g, 2.862 mmol) was added to a suspension of 3-trimethylsilylprop-2-ynoic acid (84.8 mg, 0.60 mmol) and 3-amino-6-(4-(isopropylsulfonyl)phenyl)pyrazine-2-carbohydrazide (200 mg, 0.60 mmol) in acetonitrile (3.000 mL) at room temperature and the resulting solution stirred for 30 min. DIPEA (385.4 mg, 519.4 μL, 2.982 mmol) was then added and a precipitate quickly formed. The resulting mixture was stirred at room temperature for 1 h and was then filtered. The reaction mixture was concentrated in vacuo and the residue taken up in methanol (5 mL) and potassium carbonate (131.9 mg, 0.9541 mmol) added and the resulting solution stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate (5 mL) and water (5 mL) and the layers separated. The aqueous layer was extracted further with ethyl acetate (2×5 mL), dried over MgSO4 and concentrated in vacuo. The material was purified by reverse phase preparative HPLC [Waters Sunfire C18, 10 μM, 100 Å column, gradient 10%-95% B (solvent A: 0.05% TFA in water; solvent B: CH3CN) over 16 minutes at 25 mL/min]. Product fractions were freeze dried to leave the product as a yellow solid (56.1 mg, 27% yield); 1H NMR (400 MHz, DMSO) d 1.18 (m, 6H), 3.44 (m, 1H), 5.48 (s, 1H), 7.96 (m, 2H), 8.32 (m, 2H) and 9.08 (s, 1H) ppm; MS (ES+) 370.14 a precipitate quickly formed The resulting mixture was stirred at room temperature for 1 h was then filtered The reaction mixture was concentrated in vacuo the resulting solution stirred at room temperature overnight the layers separated The aqueous layer was extracted further with ethyl acetate (2×5 mL) dried over MgSO4 concentrated in vacuo The material was purified by reverse phase preparative HPLC [Waters Sunfire C18, 10 μM, 100 Å column, gradient 10%-95% B (solvent A: 0.05% TFA in water; solvent B: CH3CN) over 16 minutes at 25 mL/min] dried

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

Procedure: Dibromo(triphenyl)phosphorane (1.208 g, 2.862 mmol) was added to a suspension of 3-trimethylsilylprop-2-ynoic acid (84.8 mg, 0.60 mmol) and 3-amino-6-(4-(isopropylsulfonyl)phenyl)pyrazine-2-carbohydrazide (200 mg, 0.60 mmol) in acetonitrile (3.000 mL) at room temperature and the resulting solution stirred for 30 min. DIPEA (385.4 mg, 519.4 μL, 2.982 mmol) was then added and a precipitate quickly formed. The resulting mixture was stirred at room temperature for 1 h and was then filtered. The reaction mixture was concentrated in vacuo and the residue taken up in methanol (5 mL) and potassium carbonate (131.9 mg, 0.9541 mmol) added and the resulting solution stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate (5 mL) and water (5 mL) and the layers separated. The aqueous layer was extracted further with ethyl acetate (2×5 mL), dried over MgSO4 and concentrated in vacuo. The material was purified by reverse phase preparative HPLC [Waters Sunfire C18, 10 μM, 100 Å column, gradient 10%-95% B (solvent A: 0.05% TFA in water; solvent B: CH3CN) over 16 minutes at 25 mL/min]. Product fractions were freeze dried to leave the product as a yellow solid (56.1 mg, 27% yield); 1H NMR (400 MHz, DMSO) d 1.18 (m, 6H), 3.44 (m, 1H), 5.48 (s, 1H), 7.96 (m, 2H), 8.32 (m, 2H) and 9.08 (s, 1H) ppm; MS (ES+) 370.14 a precipitate quickly formed The resulting mixture was stirred at room temperature for 1 h was then filtered The reaction mixture was concentrated in vacuo the resulting solution stirred at room temperature overnight the layers separated The aqueous layer was extracted further with ethyl acetate (2×5 mL) dried over MgSO4 concentrated in vacuo The material was purified by reverse phase preparative HPLC [Waters Sunfire C18, 10 μM, 100 Å column, gradient 10%-95% B (solvent A: 0.05% TFA in water; solvent B: CH3CN) over 16 minutes at 25 mL/min] dried

Conditions: temp:75.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a dried 40 mL scintillation vial fitted with a Teflon coated cap is added 3-methoxycinnamyl acetate (619 mg, 3.0 mmol), toluene (20 mL), 3-(trimethylsilyl)propiolic acid (512 mg, 3.6 mmol), cesium carbonate (1.17 g, 3.6 mmol), and tetrakis(triphenylphosphine)palladium (0) (346 mg, 0.3 mmol, 10 mol %). The vessel is evacuated and back-filled with Argon and then heated to 75° C. for 18 h. Upon cooling to room temperature, the reaction mixture is quenched with H2O (5 mL) and extracted with diethyl ether (2×10 mL). The combined organics are washed with brine, dried over MgSO4, filtered, and concentrated. The crude oil is purified by flash chromatography (12 g RediSep flash cartridge, hexanes to 1.5% ethyl acetate/hexanes) to give 307 mg (42%) of ((E)-5-(3-methoxyphenyl)pent-4-en-1-ynyl)trimethylsilane as an oil. 1H NMR (acetone-d6, 400 MHz) δ 7.23 (d, J=8.1 Hz, 1H), 6.99-6.97 (m, 2H), 6.80 (m, 1H), 6.65 (dt, J=15.7, 1.7 Hz, 1H), 6.26 (dt, J=15.7, 5.7 Hz, 1H), 3.8 (s, 3H), 3.19 (dd, J=5.7, 1.8 Hz, 2H), 0.16 (s, 9H). Reference: Tunge, J. A.; rayabarapu, D. K. J. Am. Chem. Soc. 2005, 127, 13510-13511. cap The vessel is evacuated back-filled with Argon Upon cooling to room temperature the reaction mixture is quenched with H2O (5 mL) extracted with diethyl ether (2×10 mL) The combined organics are washed with brine dried over MgSO4 filtered concentrated The crude oil is purified by flash chromatography (12 g RediSep flash cartridge, hexanes to 1.5% ethyl acetate/hexanes)

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

Procedure: Dibromo(triphenyl)phosphorane (1.208 g, 2.862 mmol) was added to a suspension of 3-trimethylsilylprop-2-ynoic acid (84.8 mg, 0.60 mmol) and 3-amino-6-(4-(isopropylsulfonyl)phenyl)pyrazine-2-carbohydrazide (200 mg, 0.60 mmol) in acetonitrile (3.000 mL) at room temperature and the resulting solution stirred for 30 min. DIPEA (385.4 mg, 519.4 μL, 2.982 mmol) was then added and a precipitate quickly formed. The resulting mixture was stirred at room temperature for 1 h and was then filtered. The reaction mixture was concentrated in vacuo and the residue taken up in methanol (5 mL) and potassium carbonate (131.9 mg, 0.9541 mmol) added and the resulting solution stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate (5 mL) and water (5 mL) and the layers separated. The aqueous layer was extracted further with ethyl acetate (2×5 mL), dried over MgSO4 and concentrated in vacuo. The material was purified by reverse phase preparative HPLC [Waters Sunfire C18, 10 μM, 100 Å column, gradient 10%-95% B (solvent A: 0.05% TFA in water; solvent B: CH3 CN) over 16 minutes at 25 mL/min]. Product fractions were freeze dried to leave the product as a yellow solid (56.1 mg, 27% yield); 1H NMR (400 MHz, DMSO) d 1.18 (m, 6H), 3.44 (m, 1H), 5.48 (s, 1H), 7.96 (m, 2H), 8.32 (m, 2H) and 9.08 (s, 1H) ppm; MS (ES+) 370.14 a precipitate quickly formed The resulting mixture was stirred at room temperature for 1 h was then filtered The reaction mixture was concentrated in vacuo the resulting solution stirred at room temperature overnight the layers separated The aqueous layer was extracted further with ethyl acetate (2×5 mL) dried over MgSO4 concentrated in vacuo The material was purified by reverse phase preparative HPLC [Waters Sunfire C18, 10 μM, 100 Å column, gradient 10%-95% B (solvent A: 0.05% TFA in water; solvent B: CH3 CN) over 16 minutes at 25 mL/min] dried