1-(hydroxymethyl)cyclopropane-1-carbonitrile

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

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

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

Procedure: A stirred mixture of 1-(hydroxymethyl)cyclopropanecarbonitrile (24.30 mmol, 2.36 g) in dichloromethane (30 mL) was treated with triethylamine (48.6 mmol, 6.83 mL, 4.92 g) and portionwise with methanesulfonyl chloride (31.6 mmol, 2.445 mL, 3.62 g) keeping the reaction mixture at 0° C. The solution was allowed to stir for 1 hour then diluted with saturated sodium hydrogencarbonate and extracted with 10% methanol/dichloromethane (×3). The organic layers were combined and concentrated under reduced pressure to give the intermediate (1-cyanocyclopropyl)methyl methanesulfonate (3.77 g). at 0° C extracted with 10% methanol/dichloromethane (×3) concentrated under reduced pressure

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

Procedure: A mixture of 1-cyanocycloprop-1-ylmethanol (4.31 g, 44.4 mmol), obtained as in the proceeding paragraph, triethylamine (9.04 mL, 64.8 mmol) and methylene chloride (78 mL) was cooled under argon to between 0° and 5° C. and methanesulfonyl chloride (4.67 mL, 59.9 mmol) was added slowly. The mixture was cooled 3 hours with stirring at 0° to 5° C., then diluted with water and extracted with methylene chloride. The extract was washed with 5% sodium bicarbonate, dried (MgSO4) and concentrated to dryness to give 1-cyano-cycloprop-1-ylmethyl methanesulfonate. was cooled under argon to between 0° and 5° C. The mixture was cooled 3 hours extracted with methylene chloride The extract was washed with 5% sodium bicarbonate dried (MgSO4) concentrated to dryness

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

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

Procedure: A solution of 1-(hydroxymethyl)-cyclopropanecarbonitrile (5.52 g, 56.8 mmol), phthalimide (9.20 g, 62.5 mmol), and triphenylphosphine (16.4 g, 62.5 mmol) in THF (550 mL) was treated with DEAD (9.90 mL, 62.5 mmol) and stirred at room temperature for 17 hours. The reaction mixture was then concentrated and the resulting solids were triturated in diethyl ether (150 mL), and collected by filtration. Purification by flash chromatography (SiO2, 0-20% EtOAc in DCM) afforded 1-((1,3-dioxoisoindolin-2-yl)methyl)-cyclopropanecarbonitrile (8.8 g, 38.8 mmol, 68%) as a white solid: LCMS (m/z) 227.0 (MH+), tR=0.66 minute; 1H NMR (300 MHz, CDCl3) δ 7.90 (dd, J=5.4, 3.1 Hz, 2H), 7.77 (dd, J=5.4, 3.1 Hz, 2H), 3.81 (s, 2H), 1.30-1.44 (m, 2H), 1.28 (d, J=3.8 Hz, 2H). The reaction mixture was then concentrated the resulting solids were triturated in diethyl ether (150 mL) collected by filtration Purification by flash chromatography (SiO2, 0-20% EtOAc in DCM)

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

Procedure: A solution of 1-(hydroxymethyl)-cyclopropanecarbonitrile (5.52 g, 56.8 mmol), phthalimide (9.20 g, 62.5 mmol), and triphenylphosphine (16.4 g, 62.5 mmol) in THF (550 mL) was treated with DEAD (9.90 mL, 62.5 mmol) and stirred at room temperature for 17 hours. The reaction mixture was then concentrated and the resulting solids were triturated in diethyl ether (150 mL), and collected by filtration. Purification by flash chromatography (SiO2, 0-20% EtOAc in DCM) afforded 1-((1,3-dioxoisoindolin-2-yl)methyl)-cyclopropanecarbonitrile (8.8 g, 38.8 mmol, 68%) as a white solid: LCMS(m/z) 227.0 (MH+), tR=0.66 minute; 1H NMR (300 MHz, CDCl3) δ 7.90 (dd, J=5.4, 3.1 Hz, 2H), 7.77 (dd, J=5.4, 3.1 Hz, 2H), 3.81 (s, 2H), 1.30-1.44 (m, 2H), 1.28 (d, J=3.8 Hz, 2H). The reaction mixture was then concentrated the resulting solids were triturated in diethyl ether (150 mL) collected by filtration Purification by flash chromatography (SiO2, 0-20% EtOAc in DCM)

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

Procedure: A solution of 1-(hydroxymethyl)-cyclopropanecarbonitrile (5.52 g, 56.8 mmol), phthalimide (9.20 g, 62.5 mmol), and triphenylphosphine (16.4 g, 62.5 mmol) in THF (550 mL) was treated with DEAD (9.90 mL, 62.5 mmol) and stirred at room temperature for 17 hours. The reaction mixture was then concentrated and the resulting solids were triturated in diethyl ether (150 mL), and collected by filtration. Purification by flash chromatography (SiO2, 0-20% EtOAc in DCM) afforded 1-((1,3-dioxoisoindolin-2-yl)methyl)-cyclopropanecarbonitrile (8.8 g, 38.8 mmol, 68%) as a white solid: LCMS(m/z) 227.0 (MH+), tR=0.66 minute; 1H NMR (300 MHz, CDCl3) δ 7.90 (dd, J=5.4, 3.1 Hz, 2H), 7.77 (dd, J=5.4, 3.1 Hz, 2H), 3.81 (s, 2H), 1.30-1.44 (m, 2H), 1.28 (d, J=3.8 Hz, 2H). The reaction mixture was then concentrated the resulting solids were triturated in diethyl ether (150 mL) collected by filtration Purification by flash chromatography (SiO2, 0-20% EtOAc in DCM)

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

Procedure: TsCl (7.25 g, 38 mmol) was added in one portion to a stirred solution of 1-(hydroxymethyl)cyclopropanecarbonitrile (3.1 h, 32 mmol) in dichloromethane (75 mL) at 0° C. Et3N (4.1 g, 40 mmol) was added. The reaction mixture was stirred at rt over night. The mixture was diluted with dichloromethane, washed with water, 0.5 N NaOH, brine. The organic extract was dried over MgSO4, filtered and concentrated in vacuo. The crude product was purified by flash chromatography to give 18A (6.43 g, 81% yield) as a white solid. washed with water, 0.5 N NaOH, brine The organic extract was dried over MgSO4 filtered concentrated in vacuo The crude product was purified by flash chromatography

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

Procedure: TsCl (7.25 g, 38 mmol) was added in one portion to a stirred solution of 1-(hydroxymethyl)cyclopropanecarbonitrile (3.1 h, 32 mmol) in dichloromethane (75 mL) at 0° C. Et3N (4.1 g, 40 mmol) was added. The reaction mixture was stirred at rt over night. The mixture was diluted with dichloromethane, washed with water, 0.5 N NaOH, brine. The organic extract was dried over MgSO4, filtered and concentrated in vacuo. The crude product was purified by flash chromatography to give 18A (6.43 g, 81% yield) as a white solid. washed with water, 0.5 N NaOH, brine The organic extract was dried over MgSO4 filtered concentrated in vacuo The crude product was purified by flash chromatography

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

Procedure: A solution of 1-(hydroxymethyl)-cyclopropanecarbonitrile (5.52 g, 56.8 mmol), phthalimide (9.20 g, 62.5 mmol), and triphenylphosphine (16.4 g, 62.5 mmol) in THF (550 mL) was treated with DEAD (9.90 mL, 62.5 mmol) and stirred at room temperature for 17 hours. The reaction mixture was then concentrated and the resulting solids were triturated in diethyl ether (150 mL), and collected by filtration. Purification by flash chromatography (SiO2, 0-20% EtOAc in DCM) afforded 1-((1,3-dioxoisoindolin-2-yl)methyl)-cyclopropanecarbonitrile (8.8 g, 38.8 mmol, 68%) as a white solid: LCMS (m/z) 227.0 (MH+), tR=0.66 minute; 1H NMR (300 MHz, CDCl3) δ 7.90 (dd, J=5.4, 3.1 Hz, 2H), 7.77 (dd, J=5.4, 3.1 Hz, 2H), 3.81 (s, 2H), 1.30-1.44 (m, 2H), 1.28 (d, J=3.8 Hz, 2H). The reaction mixture was then concentrated the resulting solids were triturated in diethyl ether (150 mL) collected by filtration Purification by flash chromatography (SiO2, 0-20% EtOAc in DCM)

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

Procedure: A solution of 1-(hydroxymethyl)-cyclopropanecarbonitrile (5.52 g, 56.8 mmol), phthalimide (9.20 g, 62.5 mmol), and triphenylphosphine (16.4 g, 62.5 mmol) in THF (550 mL) was treated with DEAD (9.90 mL, 62.5 mmol) and stirred at room temperature for 17 hours. The reaction mixture was then concentrated and the resulting solids were triturated in diethyl ether (150 mL), and collected by filtration. Purification by flash chromatography (SiO2, 0-20% EtOAc in DCM) afforded 1-((1,3-dioxoisoindolin-2-yl)methyl)-cyclopropanecarbonitrile (8.8 g, 38.8 mmol, 68%) as a white solid: LCMS (m/z) 227.0 (MH+), tR=0.66 minute; 1H NMR (300 MHz, CDCl3) δ 7.90 (dd, J=5.4, 3.1 Hz, 2H), 7.77 (dd, J=5.4, 3.1 Hz, 2H), 3.81 (s, 2H), 1.30-1.44 (m, 2H), 1.28 (d, J=3.8 Hz, 2H). The reaction mixture was then concentrated the resulting solids were triturated in diethyl ether (150 mL) collected by filtration Purification by flash chromatography (SiO2, 0-20% EtOAc in DCM)