ethenylcyclopropane

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

Procedure: To a stirred mixture containing 3.8 g. of isonicotinoyl chloride, oxime hydrochloride and 1.4 g. of vinylcyclopropane in 100 ml. of ethanol is added dropwise over a 1 hour period, a solution 4.1 g. of triethylamine in 40 ml. of ethanol. The reaction is stirred for 1 hour and then the solvent is removed under reduced pressure. The residue is extracted with ether and the ether solution is dried over sodium sulfate. The solution is filtered and then the solvent is removed giving a yellow solid. The solid is recrystallized from ethanol giving white crystals, melting point 102°-108°C. To a stirred mixture containing 3.8 g the solvent is removed under reduced pressure The residue is extracted with ether the ether solution is dried over sodium sulfate The solution is filtered the solvent is removed giving a yellow solid The solid is recrystallized from ethanol giving white crystals, melting point 102°-108°C.

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

Procedure: 1-Cyano-1-phenyl-2-ethylcyclopropane was prepared by carrying out a reduction on the corresponding 2-vinylcyclopropane derivative, prepared in accordance with the procedure of Example I, employing tosyl hydrazine. The 1-cyano-1-phenyl-2-vinylcyclopropane (10.14 g) was combined with 22.32 g tosyl hydrazine in 70 cc diglyme and the mixture refluxed with stirring for 1 hour. The reaction mixture was extracted with petroleum ether and, upon distillation, 5.23 g 1-cyano-1-phenyl-2-ethylcyclopropane was obtained. Reduction of the vinyl group was confirmed by the nuclear magnetic resonance spectrum in that there was no absorption at δ5.3. Absence of vinyl absorption was also confirmed by infrared analysis. 1-Cyano-1-phenyl-2-ethylcyclopropane was prepared prepared in accordance with the procedure of Example I the mixture refluxed The reaction mixture was extracted with petroleum ether and, upon distillation

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

Conditions: temp:40.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 3-fluoro-4-[5-methoxy-4-oxo-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-1(4H)-yl]phenyl trifluoromethanesulfonate (255 mg, 0.5 mmol), cyclopropylethylene (0.0846 mL, 1.0 mmol), i-Pr2NEt (0.348 mL, 2.0 mmol), CuI (9.5 mg, 0.05 mmol), Pd(PPh3)2Cl2 (17.5 mg, 0.025 mmol) and PPh3 (6.6 mg, 0.025 mmol) in DMF (1 mL) was heated to 40° C. for 90 min under Ar. The mixture was diluted with NaHCO3 aqueous solution, extracted with AcOEt, dried over Na2SO4, filtered, concentrated in vacuo, purified by column chromatography on basic silica gel (hexane/AcOEt=50/50 to 0/100) and recrystallized with AcOEt/hexane to yield the title compound (181 mg, 85% yield) as a yellow solid: mp 145-146° C. 1H NMR (DMSO-d6, 300 MHz): δ ppm 0.74-0.82 (2H, m), 0.88-0.98 (2H, m), 1.58 (1H, tt, J=8.2, 5.1 Hz), 3.77 (3H, s), 6.91-7.01 (2H, m), 7.20 (1H, dd, J=8.3, 1.1 Hz), 7.28-7.51 (6H, m), 7.78 (1H, d, J=1.9 Hz), 8.47 (1H, d, J=1.9 Hz). Anal. Calcd for C25H19FN4O2: C, 70.41; H, 4.49; N, 13.14. Found: C, 70.33; H, 4.60; N, 13.08. extracted with AcOEt dried over Na2SO4 filtered concentrated in vacuo purified by column chromatography on basic silica gel (hexane/AcOEt=50/50 to 0/100) recrystallized with AcOEt/hexane

Conditions: temp:40.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 3-fluoro-4-[5-methoxy-4-oxo-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-1(4H)-yl]phenyl trifluoromethanesulfonate (255 mg, 0.5 mmol), cyclopropylethylene (0.0846 mL, 1.0 mmol), i-Pr2NEt (0.348 mL, 2.0 mmol), CuI (9.5 mg, 0.05 mmol), Pd(PPh3)2Cl2 (17.5 mg, 0.025 mmol) and PPh3 (6.6 mg, 0.025 mmol) in DMF (1 mL) was heated to 40° C. for 90 min under Ar. The mixture was diluted with NaHCO3 aqueous solution, extracted with AcOEt, dried over Na2SO4, filtered, concentrated in vacuo, purified by column chromatography on basic silica gel (hexane/AcOEt=50/50 to 0/100) and recrystallized with AcOEt/hexane to yield the title compound (181 mg, 85% yield) as a yellow solid: mp 145-146° C. 1H NMR (DMSO-d6, 300 MHz): δ ppm 0.74-0.82 (2H, m), 0.88-0.98 (2H, m), 1.58 (1H, tt, J=8.2, 5.1 Hz), 3.77 (3H, s), 6.91-7.01 (2H, m), 7.20 (1H, dd, J=8.3, 1.1 Hz), 7.28-7.51 (6H, m), 7.78 (1H, d, J=1.9 Hz), 8.47 (1H, d, J=1.9 Hz). Anal. Calcd for C25H19FN4O2: C, 70.41; H, 4.49; N, 13.14. Found: C, 70.33; H, 4.60; N, 13.08. extracted with AcOEt dried over Na2SO4 filtered concentrated in vacuo purified by column chromatography on basic silica gel (hexane/AcOEt=50/50 to 0/100) recrystallized with AcOEt/hexane

Conditions: temp:40.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 3-fluoro-4-[5-methoxy-4-oxo-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-1(4H)-yl]phenyl trifluoromethanesulfonate (255 mg, 0.5 mmol), cyclopropylethylene (0.0846 mL, 1.0 mmol), i-Pr2NEt (0.348 mL, 2.0 mmol), CuI (9.5 mg, 0.05 mmol), Pd(PPh3)2Cl2 (17.5 mg, 0.025 mmol) and PPh3 (6.6 mg, 0.025 mmol) in DMF (1 mL) was heated to 40° C. for 90 min under Ar. The mixture was diluted with NaHCO3 aqueous solution, extracted with AcOEt, dried over Na2SO4, filtered, concentrated in vacuo, purified by column chromatography on basic silica gel (hexane/AcOEt=50/50 to 0/100) and recrystallized with AcOEt/hexane to yield the title compound (181 mg, 85% yield) as a yellow solid: mp 145-146° C. 1H NMR (DMSO-d6, 300 MHz): δ ppm 0.74-0.82 (2H, m), 0.88-0.98 (2H, m), 1.58 (1H, tt, J=8.2, 5.1 Hz), 3.77 (3H, s), 6.91-7.01 (2H, m), 7.20 (1H, dd, J=8.3, 1.1 Hz), 7.28-7.51 (6H, m), 7.78 (1H, d, J=1.9 Hz), 8.47 (1H, d, J=1.9 Hz). Anal. Calcd for C25H19FN4O2: C, 70.41; H, 4.49; N, 13.14. Found: C, 70.33; H, 4.60; N, 13.08. extracted with AcOEt dried over Na2SO4 filtered concentrated in vacuo purified by column chromatography on basic silica gel (hexane/AcOEt=50/50 to 0/100) recrystallized with AcOEt/hexane

Conditions: temp:40.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 3-fluoro-4-[5-methoxy-4-oxo-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-1(4H)-yl]phenyl trifluoromethanesulfonate (255 mg, 0.5 mmol), cyclopropylethylene (0.0846 mL, 1.0 mmol), i-Pr2NEt (0.348 mL, 2.0 mmol), CuI (9.5 mg, 0.05 mmol), Pd(PPh3)2Cl2 (17.5 mg, 0.025 mmol) and PPh3 (6.6 mg, 0.025 mmol) in DMF (1 mL) was heated to 40° C. for 90 min under Ar. The mixture was diluted with NaHCO3 aqueous solution, extracted with AcOEt, dried over Na2SO4, filtered, concentrated in vacuo, purified by column chromatography on basic silica gel (hexane/AcOEt=50/50 to 0/100) and recrystallized with AcOEt/hexane to yield the title compound (181 mg, 85% yield) as a yellow solid: mp 145-146° C. 1H NMR (DMSO-d6, 300 MHz): δ ppm 0.74-0.82 (2H, m), 0.88-0.98 (2H, m), 1.58 (1H, tt, J=8.2, 5.1 Hz), 3.77 (3H, s), 6.91-7.01 (2H, m), 7.20 (1H, dd, J=8.3, 1.1 Hz), 7.28-7.51 (6H, m), 7.78 (1H, d, J=1.9 Hz), 8.47 (1H, d, J=1.9 Hz). Anal. Calcd for C25H19FN4O2: C, 70.41; H, 4.49; N, 13.14. Found: C, 70.33; H, 4.60; N, 13.08. extracted with AcOEt dried over Na2SO4 filtered concentrated in vacuo purified by column chromatography on basic silica gel (hexane/AcOEt=50/50 to 0/100) recrystallized with AcOEt/hexane

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

Procedure: To illustrate the preparation of vinylcyclopropane derivatives via malonic ester condensation in an aqueous medium, the following experiment was conducted: To a flask provided with a stirrer and containing 125 g (1.0 mol) trans 1,4-dichlorobutene-2, 94 g (0.50 mol) diisopropyl malonate and 3.2 g (1.63 mol percent based on the malonate ester) tricaprylylmethylammonium chloride were added dropwise over a 30-minute perid with vigorous stirring 168 g 50% aqueous potassium hydroxide solution. Cooling was provided to maintain the reaction temperature at 25°-30° C. After five hours the reaction mixture was poured into water and extracted three times with ethyl ether. The combined etheral layers were dried over magnesium sulfate, filtered and concentrated to afford 184 g (67.2% yield) diisopropyl 2-vinylcyclopropane-1,1-dicarboxylate. Bp 77°-78° C.(0.5 mm); nD24° 1.4482. Infrared and proton nmr spectra were consistent with the desired structure. Similar results were obtained using other quaternary ammonium compounds, however, when the onium compound was omitted the reaction did not proceed. To a flask provided with a stirrer were added dropwise over a 30-minute perid Cooling was provided to maintain the reaction temperature at 25°-30° C extracted three times with ethyl ether The combined etheral layers were dried over magnesium sulfate filtered concentrated