azidomethyl(trimethyl)silane

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

Procedure: To a solution of pyridin-2-yl-propynoic acid ethyl ester (1.25 g, 7.14 mmol) in benzene (22 mL) was added azidomethyl-trimethyl-silane (1.11 g, 8.56 mmol) and the reaction mixture was refluxed under nitrogen for 72 h. The mixture was then evaporated and purification by chromatography [silica, 0 to 50% ethyl acetate in heptane then HPLC (Chiralpak AD, ethanol in heptane)] afforded the title compound (477 mg, 23%) as a yellow oil. MS: m/e=305.2 [M+H]+. the reaction mixture was refluxed under nitrogen for 72 h The mixture was then evaporated purification by chromatography [silica, 0 to 50% ethyl acetate in heptane

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

Procedure: To a solution of (4-fluoro-phenyl)-propynoic acid ethyl ester (1.45 g, 7.55 mmol) in benzene (25 mL) was added azidomethyl-trimethyl-silane (1.17 g, 9.05 mmol) and the reaction mixture was refluxed under nitrogen for 72 h. A subsequent batch of azidomethyl-trimethyl-silane (0.29 g, 2.26 mmol) was added and refluxing was continued for 5 h. The mixture was then evaporated and purification by chromatography (silica, 0 to 50% ethyl acetate in heptane) afforded the title compound (1.0 g, 41%) as a yellow oil. MS: m/e=322.2 [M+H]+. the reaction mixture was refluxed under nitrogen for 72 h refluxing The mixture was then evaporated purification by chromatography (silica, 0 to 50% ethyl acetate in heptane)

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

Procedure: 5-Ethynyl-2-{[6-(morpholin-4-ylmethyl)pyridin-2-yl]amino}thiophene-3-carboxamide (Example 599, Step 4) (75 mg, 0.22 mmol) and trimethylsilylmethyl azide (0.65 ml, 0.44 mmol) were combined in DMF (1.0 mL). CuSO4.5H2O (5.5 mg, 0.022 mmol) in water (0.2 mL) and sodium ascorbate (17 mg, 0.088 mmol) in water (0.2 ml) were added, and the reaction mixture was stirred at room temperature overnight. The reaction was evaporated to dryness, combined with MeOH and silica gel, and evaporated. Flash chromatography (dry load, 0-10% MeOH/EtOAc) afforded the title compound a yellow solid. The reaction was evaporated to dryness evaporated Flash chromatography (dry load, 0-10% MeOH/EtOAc)

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

Procedure: 2-Bromo-6-(1-fluoroprop-2-yn-1-yl)pyridine (520 mg, 2.43 mmol) and trimethylsilylmethyl azide (377 mg, 2.92 mmol) were combined in t-BuOH (5.0 mL) and water (3.0 mL). CuSO4.5H2O (30 mg, 0.12 mmol) in water (1.0 mL) was added, followed by sodium ascorbate (96 mg, 0.49 mmol) in water (1.0 mL). The reaction was stirred at room temperature overnight, diluted with saturated NaHCO3, and extracted with EtOAc (2×). The combined organic layers were washed with brine, dried (MgSO4), filtered, and evaporated to a brown residue that was purified by flash chromatography (0-30% EtOAc/hexanes) to afford the title compound as a colorless solid. extracted with EtOAc (2×) The combined organic layers were washed with brine dried (MgSO4) filtered evaporated to a brown residue that was purified by flash chromatography (0-30% EtOAc/hexanes)

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

Procedure: 2-Bromo-6-ethynylpyridine (Example 465, Step 1) (350 mg, 1.92 mmol) and trimethylsilylmethyl azide (323 mg, 2.50 mmol) were combined in t-BuOH (4.0 mL) and water (3.0 mL). CuSO4.5H2O (24 mg, 0.096 mmol) in water (0.50 mL) was added, followed by sodium ascorbate (76 mg, 0.39 mmol) in water (0.50 mL). The reaction was stirred at room temperature overnight, diluted with saturated NaHCO3, and extracted with EtOAc (2×). The combined organic layers were washed with brine, dried (MgSO4), filtered, and evaporated to a yellow residue that was purified by flash chromatography (0-50% EtOAc/hexanes) to afford the title compound as a colorless solid. extracted with EtOAc (2×) The combined organic layers were washed with brine dried (MgSO4) filtered evaporated to a yellow residue that was purified by flash chromatography (0-50% EtOAc/hexanes)

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

Procedure: To a degassed solution of methyl 3-ethynyl-5-(5-methylpyridin-2-yl)benzoate (124 mg, 0.493 mmol) in benzene (12 mL) were added trimethylsilylmethylazide (96 mg, 0.740 mmol) and pentamethylcyclopentadienylbis(triphenylphosphine)ruthenium(II) chloride (59 mg, 0.074 mmol) and the mixture heated to 80° C. in a sealed tube. After 16 h, the title compound was showed as the major isomer (10:1 isomeric ratio) in the reaction. The reaction was concentrated and purified by reverse-phase HPLC gave the title compound (120 mg). MS 381.1 (M+1).

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

Procedure: To a degassed solution of methyl 3-ethynyl-5-(5-methylpyridin-2-yl)benzoate (124 mg, 0.493 mmol) in benzene (12 mL) were added trimethylsilylmethylazide (96 mg, 0.740 mmol) and pentamethylcyclopentadienylbis(triphenylphosphine)ruthenium(II) chloride (59 mg, 0.074 mmol) and the mixture heated to 80° C. in a sealed tube. After 16 h, the title compound was showed as the major isomer (10:1 isomeric ratio) in the reaction. The reaction was concentrated and purified by reverse-phase HPLC gave the title compound (120 mg). MS 381.1 (M+1).

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

Procedure: To a 100 ml round bottom flask equipped with a magnetic stir bar were added (azidomethyl)(trimethyl)silane (1.000 g, 7.740 mmol), 3,3-diethoxyprop-1-yne (0.992 g, 7.740 mmol), freshly made 1.0N sodium asorbate (0.774 ml, 7.740 mmol), and 1.0N Cu2SO4 (0.774 ml, 7.740 mmol) into 30.0 ml of a mixed solvent BuOH/H2O (1:1). The resulting solution was stirred at room temperature for 16 hours. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuum to give the crude title compound as a light yellow liquid (1.620 g, 81% crude). ES-MS [M+1]+: 258.1 (M+H). This intermediate was carried over to the next step without further purifications and characterizations. To a 100 ml round bottom flask equipped with a magnetic stir bar extracted with EtOAc The combined organic layers were washed with brine dried over anhydrous Na2SO4 filtered The filtrate was concentrated in vacuum

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

Procedure: To a solution of 1.5 g (4.8 mmol) N-[(1R)-1-(4-bromophenyl)prop-2-ynyl]-2-methylpropane-2-sulfinamide in 10 mL water and 10 mL t-butanol was added 0.62 g (azidomethyl)(trimethyl)silane, 0.48 mL (0.48 mmol) 1.0M aqueous ascorbic acid solution, and 0.05 mL (0.05 mmol) 1.0M solution of aqueous copper (II) sulfate pentahydrate. After 24 h at room temperature, the reaction mixture was quenched with water, extracted three times with ethyl acetate, and washed with brine. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. Purification by flash chromatography (silica gel, linear gradient 25-100% EtOAc:hexane) afforded N-((S)-(4-bromophenyl){1-[(trimethylsilyl)methyl]-1H-1,2,3-triazol-4-yl}methyl)-2-methylpropane-2-sulfinamide. 1H NMR (CDCl3, 400 MHz) 7.51-7.47 (m, 2H); 7.35-7.30 (m, 2H); 7.06 (s, 1H); 5.68 (d, 1H, J=2.65 Hz); 4.58 (d, 1H, J=2.48 Hz); 3.81 (d, 2H, J=3.84 Hz); 1.24 (s, 9H); 0.12 (s, 9H). ES-MS [M+1]+=444.94. the reaction mixture was quenched with water extracted three times with ethyl acetate washed with brine The organic layer was dried over Na2SO4 filtered concentrated in vacuo Purification by flash chromatography (silica gel, linear gradient 25-100% EtOAc:hexane)

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

Procedure: Ethyl 1-[5-[2-(ethylcarbamoylamino)-7-ethynyl-1,3-benzothiazol-5-yl]pyrimidin-2-yl]-4-methyl-piperidine-4-carboxylate (115 mg, 0.233 mmol), (azidomethyl)trimethylsilane (150 mg, 1.169 mmol), Copper(I)Iodide (8.9 mg, 0.0467 mmol), N-ethyl-N-isopropylpropan-2-amine (30.1 mg, 0.233 mmol) in 2 mL of DMF were stirred at rt for 24 hours. The reaction was diluted with 10 mL of water, filtered and washed with water then dried to yield the desired compound as a beige solid, 95 mg, 65.5 yield %. filtered washed with water then dried

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: In a 50 mL pear-shaped flask, ethyl 3-(4-bromo-2-fluorophenyl)propiolate (1.27 g, 4.68 mmol) and (azidomethyl)trimethylsilane (2.42 g, 2.78 mL, 18.7 mmol, Eq: 4) were combined with benzene (3.5 mL) to give a light yellow solution. The reaction mixture was heated to 90° C. and stirred for 4 h. The reaction mixture was concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 80 g, 0% to 20% EtOAc in heptane) to afford 616 mg (33%) of the desired less polar regio-isomer as a white solid. (M+H)+=400.0/402.0 m/e. to give a light yellow solution The reaction mixture was concentrated in vacuo The crude material was purified by flash chromatography (silica gel, 80 g, 0% to 20% EtOAc in heptane) to afford 616 mg (33%) of the

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

Procedure: To a solution of pyridin-2-yl-propynoic acid ethyl ester (1.25 g, 7.14 mmol) in benzene (22 mL) was added azidomethyl-trimethyl-silane (1.11 g, 8.56 mmol) and the reaction mixture was refluxed under nitrogen for 72 h. The mixture was then evaporated and purification by chromatography [silica, 0 to 50% ethyl acetate in heptane then HPLC (Chiralpak AD, ethanol in heptane)] afforded the title compound (477 mg, 23%) as a yellow oil. MS: m/e=305.2 [M+H]+. the reaction mixture was refluxed under nitrogen for 72 h The mixture was then evaporated purification by chromatography [silica, 0 to 50% ethyl acetate in heptane