ethyl 3-oxocyclobutane-1-carboxylate

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 solution of ethyl 3-oxocyclobutanecarboxylate (3.0 g, 21.1 mmol) in anhydrous Et2O (60 mL), cooled to −80° C., was added dropwise a solution of (4-methoxyphenyl)magnesium bromide (50.6 mL, 25.3 mmol, 2M in THF). The reaction mixture was allowed to warm to RT and stir for 2 h. The reaction mixture was quenched with a saturated aq. solution of NH4Cl (20 mL) and then extracted with EtOAc (3×30 mL) The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The crude product was purified by silica gel chromatography (40 g REDISEP® column, eluting with 15% EtOAc in hexanes). Fractions containing the product were combined and evaporated to afford Intermediate 279A as a colorless liquid (3 g, 57%). 1H NMR (300 MHz, DMSO-d6) δ ppm 7.42 (d, J=8.7 Hz, 2H), 6.89 (d, J=8.7 Hz, 2H), 5.58 (s, 1H), 4.08 (d, J=7.2 Hz, 2H), 3.75 (s, 3H), 2.76-2.67 (m, 1H), 2.60 (s, 2H), 2.47 (s, 2H), 1.22-1.16 (m, 3H). The reaction mixture was quenched with a saturated aq. solution of NH4Cl (20 mL) extracted with EtOAc (3×30 mL) The combined organic layers were washed with brine dried over Na2SO4 filtered concentrated The crude product was purified by silica gel chromatography (40 g REDISEP® column, eluting with 15% EtOAc in hexanes) Fractions containing the product evaporated

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

Procedure: To a solution of ethyl 3-oxocyclobutanecarboxylate (3.0 g, 21.1 mmol) in anhydrous Et2O (60 mL), cooled to −80° C., was added dropwise a solution of (4-methoxyphenyl)magnesium bromide (50.6 mL, 25.3 mmol, 2M in THF). The reaction mixture was allowed to warm to RT and stir for 2 h. The reaction mixture was quenched with a saturated aq. solution of NH4Cl (20 mL) and then extracted with EtOAc (3×30 mL) The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The crude product was purified by silica gel chromatography (40 g REDISEP® column, eluting with 15% EtOAc in hexanes). Fractions containing the product were combined and evaporated to afford Intermediate 279A as a colorless liquid (3 g, 57%). 1H NMR (300 MHz, DMSO-d6) δ ppm 7.42 (d, J=8.7 Hz, 2H), 6.89 (d, J=8.7 Hz, 2H), 5.58 (s, 1H), 4.08 (d, J=7.2 Hz, 2H), 3.75 (s, 3H), 2.76-2.67 (m, 1H), 2.60 (s, 2H), 2.47 (s, 2H), 1.22-1.16 (m, 3H). The reaction mixture was quenched with a saturated aq. solution of NH4Cl (20 mL) extracted with EtOAc (3×30 mL) The combined organic layers were washed with brine dried over Na2SO4 filtered concentrated The crude product was purified by silica gel chromatography (40 g REDISEP® column, eluting with 15% EtOAc in hexanes) Fractions containing the product evaporated

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

Procedure: To a stirred solution of ethyl 3-oxocyclobutanecarboxylate (2 g, 14.07 mmol) in dry Et2O (30 mL), cooled to −80° C., was added 4-fluorophenyl magnesium bromide (16.88 mL, 16.88 mmol, 1 M in THF) dropwise. The reaction mixture was then allowed to warm to RT and stir for an additional 2 h. The reaction mixture was quenched with a saturated aq. solution of NH4Cl (50 mL) and extracted with EtOAc (3×30 mL). The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated. The crude reaction mixture was purified by silica gel chromatography (24 g REDISEP® column, eluting with 15% EtOAc in hexanes). Fractions containing the product were combined and evaporated to afford Intermediate 276A as a colorless liquid (1.7 g, 51%). 1H NMR (400 MHz, DMSO-d6) δ ppm 7.54 (dd, J=5.5, 9.0 Hz, 2H), 7.15 (t, J=8.8 Hz, 2H), 4.09 (q, J=7.4 Hz, 2H), 2.83-2.71 (m, 1H), 2.61 (s, 2H), 2.55-2.51 (m, 2H), 1.24-1.12 (t, 3H). The reaction mixture was quenched with a saturated aq. solution of NH4Cl (50 mL) extracted with EtOAc (3×30 mL) The combined organic layer was washed with brine dried over Na2SO4 filtered concentrated The crude reaction mixture was purified by silica gel chromatography (24 g REDISEP® column, eluting with 15% EtOAc in hexanes) Fractions containing the product evaporated

Conditions: temp:-70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: This compound was prepared according to a procedure similar to that described in Procedure A. To a 100-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed bromo(ethynyl)magnesium (0.5M in THF, 50 mL, 1.20 equiv). This was followed by the addition of a solution of ethyl 3-oxocyclobutane-1-carboxylate (3.0 g, 21.10 mmol, 1.00 equiv) in tetrahydrofuran (3 mL) dropwise with stirring at −70° C. in 15 min. The resulting solution was stirred for 30 min at −70° C. The reaction was then quenched by the addition of 10 mL of sat. aq. ammonium chloride. The resulting solution was extracted with 3×20 mL of ethyl acetate and the organic layers combined and dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:10). This resulted in 2.6 g (66%) of ethyl 3-ethynyl-3-hydroxycyclobutane-1-carboxylate as light yellow oil (single undetermined diastereomer). This compound was prepared To a 100-mL 3-necked round-bottom flask purged maintained with an inert atmosphere of nitrogen The resulting solution was stirred for 30 min at −70° C The reaction was then quenched by the addition of 10 mL of sat. aq. ammonium chloride The resulting solution was extracted with 3×20 mL of ethyl acetate dried over anhydrous sodium sulfate concentrated under vacuum This resulted in 2.6 g (66%) of ethyl 3-ethynyl-3-hydroxycyclobutane-1-carboxylate as light yellow oil (single undetermined diastereomer)

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

Procedure: To a solution of 5-methyl-4H-1,2,4-triazol-3-amine (16.35 g) and ethyl 3-oxocyclobutanecarboxylate (12.41 g) in acetic acid (150 mL) was added sodium triacetoxyborohydride (36.56 g), and the mixture was stirred at room temperature for 5 days. The solvent was evaporated under reduced pressure, the residue was diluted with saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate-isopropyl alcohol (3:1). The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography [eluent: methanol/ethyl acetate=0/100→10/90 (volume ratio)], and crystallized from diethyl ether to give the title compound as a colorless solid (15.93 g, 62%). The solvent was evaporated under reduced pressure the residue was diluted with saturated aqueous sodium hydrogen carbonate solution the mixture was extracted with ethyl acetate-isopropyl alcohol (3:1) The extract was washed with saturated brine dried over anhydrous magnesium sulfate The solvent was evaporated under reduced pressure the residue was purified by silica gel chromatography [eluent: methanol/ethyl acetate=0/100→10/90 (volume ratio)] crystallized from diethyl ether

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

Procedure: To a solution of 5-methyl-4H-1,2,4-triazol-3-amine (16.35 g) and ethyl 3-oxocyclobutanecarboxylate (12.41 g) in acetic acid (150 mL) was added sodium triacetoxyborohydride (36.56 g), and the mixture was stirred at room temperature for 5 days. The solvent was evaporated under reduced pressure, the residue was diluted with saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate-isopropyl alcohol (3:1). The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography [eluent: methanol/ethyl acetate=0/100→10/90 (volume ratio)], and crystallized from diethyl ether to give the title compound as a colorless solid (15.93 g, 62%). The solvent was evaporated under reduced pressure the residue was diluted with saturated aqueous sodium hydrogen carbonate solution the mixture was extracted with ethyl acetate-isopropyl alcohol (3:1) The extract was washed with saturated brine dried over anhydrous magnesium sulfate The solvent was evaporated under reduced pressure the residue was purified by silica gel chromatography [eluent: methanol/ethyl acetate=0/100→10/90 (volume ratio)] crystallized from diethyl ether

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 solution of 5-methyl-4H-1,2,4-triazol-3-amine (16.35 g) and ethyl 3-oxocyclobutanecarboxylate (12.41 g) in acetic acid (150 mL) was added sodium triacetoxyborohydride (36.56 g), and the mixture was stirred at room temperature for 5 days. The solvent was evaporated under reduced pressure, the residue was diluted with saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate-isopropyl alcohol (3:1). The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography [eluent: methanol/ethyl acetate=0/100→10/90 (volume ratio)], and crystallized from diethyl ether to give the title compound as a colorless solid (15.93 g, 62%). The solvent was evaporated under reduced pressure the residue was diluted with saturated aqueous sodium hydrogen carbonate solution the mixture was extracted with ethyl acetate-isopropyl alcohol (3:1) The extract was washed with saturated brine dried over anhydrous magnesium sulfate The solvent was evaporated under reduced pressure the residue was purified by silica gel chromatography [eluent: methanol/ethyl acetate=0/100→10/90 (volume ratio)] crystallized from diethyl ether

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

Procedure: To a solution of 5-methyl-4H-1,2,4-triazol-3-amine (16.35 g) and ethyl 3-oxocyclobutanecarboxylate (12.41 g) in acetic acid (150 mL) was added sodium triacetoxyborohydride (36.56 g), and the mixture was stirred at room temperature for 5 days. The solvent was evaporated under reduced pressure, the residue was diluted with saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate-isopropyl alcohol (3:1). The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography [eluent: methanol/ethyl acetate=0/100→10/90 (volume ratio)], and crystallized from diethyl ether to give the title compound as a colorless solid (15.93 g, 62%). The solvent was evaporated under reduced pressure the residue was diluted with saturated aqueous sodium hydrogen carbonate solution the mixture was extracted with ethyl acetate-isopropyl alcohol (3:1) The extract was washed with saturated brine dried over anhydrous magnesium sulfate The solvent was evaporated under reduced pressure the residue was purified by silica gel chromatography [eluent: methanol/ethyl acetate=0/100→10/90 (volume ratio)] crystallized from diethyl ether