cyclobutanecarbonitrile

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

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

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

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

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

Procedure: Solid KHMDS (3.48 g, 17.5 mmol) is dissolved in THF (20.0 mL) and cooled to 0° C. Cyclobutanecarbonitrile (1.42 g, 17.5 mmol) is added, and the resulting solution stirred for 40 minutes. A solution of 4-fluorobenzonitrile (2.12 g, 17.5 mmol) in THF (10.0 mL) is added, and the mixture stirred for 2 hours at 0° C. 1N HCl (50.0 mL) is added to the reaction mixture and the aqueous phase extracted with EtOAc (4×40.0 mL). The combined organic phases are dried over MgSO4, filtered and concentrated on the rotovaporator. The product is purified by flash chromatography (CombiFlash), eluting with mixtures of heptanes and EtOAc (0% EtOAc to 40% EtOAc) to yield the desired product (1.76 g, 9.67 mmol, 55%). 1H NMR (400 MHz, DMSO-D6) δ ppm 1.92-2.12 (m, 1H) 2.19-2.37 (m, 1H) 2.57-2.69 (m, 2H) 2.71-2.82 (m, 2H) 7.67 (d, J=8.59 Hz, 2H) 7.91 (d, J=8.79 Hz, 2H). the mixture stirred for 2 hours at 0° C the aqueous phase extracted with EtOAc (4×40.0 mL) The combined organic phases are dried over MgSO4 filtered concentrated on the rotovaporator The product is purified by flash chromatography (CombiFlash) eluting with mixtures of heptanes and EtOAc (0% EtOAc to 40% EtOAc)

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

Procedure: In a dry flask under Ar, 2-fluoropyridine (3.18 ml, 37 mmol) and cyclobutanecarbonitrile (3.0 g, 37 mmol) were dissolved in toluene (55 mL). The solution was cooled to 0° C. A 1M solution of sodium bis(trimethylsilyl)amide in THF (40.7 mL, 40.7 mmol) was added slowly over 5 min. After 1 h, the solution was warmed to room temperature. After another 19 h, the reaction was diluted with NH4Cl (aq) and DCM. The layers were separated. The aqueous layer was extracted with DCM. The combined organic layers were dried over MgSO4, filtered and concentrated to yield 4.68 g (80%) of 1-pyridin-2-yl-cyclobutanecarbonitrile as a pale yellow oil, m/z=159.7 [M+1]+. the solution was warmed to room temperature After another 19 h The layers were separated The aqueous layer was extracted with DCM The combined organic layers were dried over MgSO4 filtered concentrated

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

Procedure: In a dry flask under Ar, 2-fluoropyridine (3.18 ml, 37 mmol) and cyclobutanecarbonitrile (3.0 g, 37 mmol) were dissolved in toluene (55 mL). The solution was cooled to 0° C. A 1M solution of sodium bis(trimethylsilyl)amide in THF (40.7 mL, 40.7 mmol) was added slowly over 5 min. After 1 h, the solution was warmed to room temperature. After another 19 h, the reaction was diluted with NH4Cl (aq) and DCM. The layers were separated. The aqueous layer was extracted with DCM. The combined organic layers were dried over MgSO4, filtered and concentrated to yield 4.68 g (80%) of 1-pyridin-2-yl-cyclobutanecarbonitrile as a pale yellow oil, m/z=159.7 [M+1]+. the solution was warmed to room temperature After another 19 h The layers were separated The aqueous layer was extracted with DCM The combined organic layers were dried over MgSO4 filtered concentrated

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

Procedure: Solid KHMDS (3.48 g, 17.5 mmol) is dissolved in THF (20.0 mL) and cooled to 0° C. Cyclobutanecarbonitrile (1.42 g, 17.5 mmol) is added, and the resulting solution stirred for 40 minutes. A solution of 4-fluorobenzonitrile (2.12 g, 17.5 mmol) in THF (10.0 mL) is added, and the mixture stirred for 2 hours at 0° C. 1N HCl (50.0 mL) is added to the reaction mixture and the aqueous phase extracted with EtOAc (4×40.0 mL). The combined organic phases are dried over MgSO4, filtered and concentrated on the rotovaporator. The product is purified by flash chromatography (CombiFlash), eluting with mixtures of heptanes and EtOAc (0% EtOAc to 40% EtOAc) to yield the desired product (1.76 g, 9.67 mmol, 55%). 1H NMR (400 MHz, DMSO-D6) ε ppm 1.92-2.12 (m, 1H) 2.19-2.37 (m, 1H) 2.57-2.69 (m, 2H) 2.71-2.82 (m, 2H) 7.67 (d, J=8.59 Hz, 2H) 7.91 (d, J=8.79 Hz, 2H). the mixture stirred for 2 hours at 0° C the aqueous phase extracted with EtOAc (4×40.0 mL) The combined organic phases are dried over MgSO4 filtered concentrated on the rotovaporator The product is purified by flash chromatography (CombiFlash) eluting with mixtures of heptanes and EtOAc (0% EtOAc to 40% EtOAc)

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Lithium diisopropylamide (3.34 mL, 6.68 mmol), was added dropwise to a solution of cyclobutanecarbonitrile (0.417 g, 5.14 mmol) in THF (20 mL) at −78° C. under an argon atmosphere. The reaction mixture was stirred at −78° C. for 30 min, then was a solution of 4-bromo-1-(bromomethyl)-2-iodobenzene (see Caruso, A.; Tovar, J., D. J. Org. Chem. 2011, 76, 2227-2239, 2.51 g, 6.68 mmol) in THF (8 mL) slowly added dropwise and the reaction was allowed to reach r.t. The mixture was stirred for another 3 h and then quenched with water. The reaction mixture was partitioned between water and EtOAc, the organic layer was dried over MgSO4 and concentrated to give a crude product which was purified by flash chromatography (eluent: heptane/ethylacetae 12:1) to afford the title compound (1.71 g, 89% yield): 1H NMR (500 MHz, CDCl3) δ ppm 2.08-2.34 (m, 4 H), 2.47-2.58 (m, 2 H), 3.18-3.23 (m, 2 H), 7.29 (s, 1 H), 7.49 (dd, 1 H), 8.03 (d, 1 H); GC MS (EI) m/z 375 M+. to reach r.t The mixture was stirred for another 3 h quenched with water The reaction mixture was partitioned between water and EtOAc the organic layer was dried over MgSO4 concentrated to give a crude product which was purified by flash chromatography (eluent: heptane/ethylacetae 12:1)

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

Procedure: LiHMDS (1M in toluene, 17.7 mL, 17.7 mmol, 3.1 eq) is added dropwise to a cold (−5° C.) solution of 4-bromo-2-fluoro-pyridine [Marsais, F. et al, Journal of Organic Chemistry, (1992), 57, 565-573] (1 g, 5.7 mmol) and cyclobutanecarbonitrile (1.39 g, 17.1 mmol, 3 eq) in toluene (20 mL). The reaction mixture is allowed to warm to rt, stirred for 5 h, quenched by addition of a saturated solution of NaHCO3 (50 mL) and filtered through a pad of celite. The filtrate is extracted with EtOAc (3×75 mL). The organic phase is washed with a saturated solution of NaHCO3 (2×50 mL), dried (Na2SO4), filtered and concentrated. The residue is purified by silica gel column chromatography (Hex/EtOAc, 1:0→95:5) to afford 933 mg of the title compound as a yellow oil: ESI-MS: 237.0/239.0 [M+H]+; tR=4.27 min (System 1); TLC: Rf=0.30 (Hex/EtOAc, 9:1). quenched by addition of a saturated solution of NaHCO3 (50 mL) filtered through a pad of celite The filtrate is extracted with EtOAc (3×75 mL) The organic phase is washed with a saturated solution of NaHCO3 (2×50 mL) dried (Na2SO4) filtered concentrated The residue is purified by silica gel column chromatography (Hex/EtOAc, 1:0→95:5)

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

Procedure: LiHMDS (1M in toluene, 17.7 mL, 17.7 mmol, 3.1 eq) is added dropwise to a cold (−5° C.) solution of 4-bromo-2-fluoro-pyridine [Marsais, F. et al, Journal of Organic Chemistry, (1992), 57, 565-573] (1 g, 5.7 mmol) and cyclobutanecarbonitrile (1.39 g, 17.1 mmol, 3 eq) in toluene (20 mL). The reaction mixture is allowed to warm to rt, stirred for 5 h, quenched by addition of a saturated solution of NaHCO3 (50 mL) and filtered through a pad of celite. The filtrate is extracted with EtOAc (3×75 mL). The organic phase is washed with a saturated solution of NaHCO3 (2×50 mL), dried (Na2SO4), filtered and concentrated. The residue is purified by silica gel column chromatography (Hex/EtOAc, 1:0→95:5) to afford 933 mg of the title compound as a yellow oil: ESI-MS: 237.0/239.0 [M+H]+; tR=4.27 min (System 1); TLC: Rf=0.30 (Hex/EtOAc, 9:1). quenched by addition of a saturated solution of NaHCO3 (50 mL) filtered through a pad of celite The filtrate is extracted with EtOAc (3×75 mL) The organic phase is washed with a saturated solution of NaHCO3 (2×50 mL) dried (Na2SO4) filtered concentrated The residue is purified by silica gel column chromatography (Hex/EtOAc, 1:0→95:5)

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

Procedure: Solid KHMDS (3.48 g, 17.5 mmol) is dissolved in THF (20.0 mL) and cooled to 0° C. Cyclobutanecarbonitrile (1.42 g, 17.5 mmol) is added, and the resulting solution stirred for 40 minutes. A solution of 4-fluorobenzonitrile (2.12 g, 17.5 mmol) in THF (10.0 mL) is added, and the mixture stirred for 2 hours at 0° C. 1N HCl (50.0 mL) is added to the reaction mixture and the aqueous phase extracted with EtOAc (4×40.0 mL). The combined organic phases are dried over MgSO4, filtered and concentrated on the rotovaporator. The product is purified by flash chromatography (CombiFlash), eluting with mixtures of heptanes and EtOAc (0% EtOAc to 40% EtOAc) to yield the desired product (1.76 g, 9.67 mmol, 55%). 1H NMR (400 MHz, DMSO-D6) δ ppm 1.92-2.12 (m, 1H) 2.19-2.37 (m, 1H) 2.57-2.69 (m, 2H) 2.71-2.82 (m, 2H) 7.67 (d, J=8.59 Hz, 2H) 7.91 (d, J=8.79 Hz, 2H). the mixture stirred for 2 hours at 0° C the aqueous phase extracted with EtOAc (4×40.0 mL) The combined organic phases are dried over MgSO4 filtered concentrated on the rotovaporator The product is purified by flash chromatography (CombiFlash) eluting with mixtures of heptanes and EtOAc (0% EtOAc to 40% EtOAc)