tert-butyl N-(2,2-dimethyl-3-oxocyclobutyl)carbamate

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 2,2-dimethyl-3-oxocyclobutanecarboxylic acid (3.9 g, 27.5 mmol) and TEA (5.75 g, 57 mmol) in toluene (160 mL) was added diphenylphosphoryl azide (11.5 mL, 57 mmol) slowly under cooling in an ice-water bath. The mixture was stirred at 100° C. for 4 h. The reaction mixture was cooled down to room temperature, and tert-butanol (82 mL, 925 mmol) was added. The resulting mixture was refluxed overnight. The reaction mixture was treated with aqueous sodium bicarbonate (150 mL) and the aqueous solution was extracted with ethyl acetate (50 mL×3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under vacuum, the residue was purified by silica gel column chromatography (2-7% ethyl acetate in petroleum ether) to afford the title compound (650 mg, 3.05 mmol, 11% yield) as a yellow oil. 1H NMR (300 MHz, CDCl3) δ (ppm) 4.81-4.70 (m, 1H), 4.05-3.93 (m, 1H), 3.37 (dd, J1=18.0 Hz, J2=9.0 Hz, 1H), 2.89 (dd, J1=18.0 Hz, J2=6.9 Hz, 1H), 1.48 (s, 9H), 1.28 (s, 3H), 1.13 (s, 3H). under cooling in an ice-water bath The reaction mixture was cooled down to room temperature The resulting mixture was refluxed overnight the aqueous solution was extracted with ethyl acetate (50 mL×3) The combined organic layers were washed with brine dried over anhydrous sodium sulfate filtered The filtrate was concentrated under vacuum the residue was purified by silica gel column chromatography (2-7% ethyl acetate in petroleum ether)

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

Procedure: To a solution of tert-butyl (2,2-dimethyl-3-oxocyclobutyl)carbamate (1.0 equiv.) in anhydrous THF (0.15 M) under nitrogen was added methyllithium (1.6 M in ether, 4.0 equiv.) drop-wise, keeping the temperature below −70° C. The mixture was stirred at this temperature for 1 h. The mixture was quenched with aqueous solution of ammonium chloride and the mixture was extracted with ethyl acetate, washed with aqueous solution of sodium bicarbonate and brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under vacuum, the residue was purified by silica gel column chromatography (5% to 25% ethyl acetate in petroleum ether) to afford the title product (30% yield). 1H NMR (400 MHz, CDCl3) δ (ppm) 4.65-4.52 (m, 1H), 3.60-3.49 (m, 1H), 2.37-2.28 (m, 1H), 1.84-1.76 (m, 1H), 1.66 (s, 1H), 1.44 (s, 9H), 1.28 (s, 3H), 1.06 (s, 3H), 1.01 (s, 3H); MS (ESI) m/z 230.2 [M+H]+. the temperature below −70° C The mixture was quenched with aqueous solution of ammonium chloride the mixture was extracted with ethyl acetate washed with aqueous solution of sodium bicarbonate and brine dried over anhydrous sodium sulfate filtered The filtrate was concentrated under vacuum the residue was purified by silica gel column chromatography (5% to 25% ethyl acetate in petroleum ether)

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 2,2-dimethyl-3-oxocyclobutanecarboxylic acid (1.0 equiv.) and triethylamine (1.5 equiv.) in toluene (0.2 M) was added diphenylphosphoryl azide (2.0 equiv.) slowly under ice-water bath. Then the mixture was stirred at 100° C. for 4 h. The reaction mixture was cooled down to room temperature, and tert-butanol (2.2 equiv.) was added. The resulting mixture was refluxed for 15 h. After the mixture cooled down, an aqueous solution of sodium bicarbonate and ethyl acetate were added. The organic layer was separated and the aqueous solution was extracted with ethyl acetate. The combined organic layer was washed with aqueous solution of sodium bicarbonate and brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under vacuum, the residue was purified by silica gel column chromatography (7% ethyl acetate in petroleum ether) to afford the title product (16% yield). 1H NMR (300 MHz, CDCl3) δ (ppm) 4.81-4.70 (m, 1H), 4.05-3.93 (m, 1H), 3.37 (dd, J1=18.0 Hz, J2=9.0 Hz, 1H), 2.89 (dd, J1=18.0 Hz, J2=6.9 Hz, 1H), 1.48 (s, 9H), 1.28 (s, 3H), 1.13 (s, 3H). The reaction mixture was cooled down to room temperature The resulting mixture was refluxed for 15 h After the mixture cooled down The organic layer was separated the aqueous solution was extracted with ethyl acetate The combined organic layer was washed with aqueous solution of sodium bicarbonate and brine dried over anhydrous sodium sulfate filtered The filtrate was concentrated under vacuum the residue was purified by silica gel column chromatography (7% ethyl acetate in petroleum ether)

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

Procedure: To a solution of tert-butyl (2,2-dimethyl-3-oxocyclobutyl)carbamate (1.0 equiv.) in MeOH (0.1 M) was added sodium borohydride (1.0 equiv.) in small portions at 0° C. After addition, the mixture was stirred at room temperature for 2 h, then the mixture was quenched with acetone. The solvent was removed under vacuum, the residue was passed through a short silica gel column chromatography (40% ethyl acetate in petroleum ether) to afford the crude title product (85% yield), which was used for the next step without further purification. MS (ESI) m/z 216.2 [M+H]+. After addition the mixture was quenched with acetone The solvent was removed under vacuum

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 2,2-dimethyl-3-oxocyclobutanecarboxylic acid (1.0 equiv.) and triethylamine (1.5 equiv.) in toluene (0.2 M) was added diphenylphosphoryl azide (1.5 equiv.) slowly at 0° C. The mixture was then stirred at 100° C. for 4 h. The reaction mixture was cooled to room temperature, and tert-butanol (2.5 equiv.) was added. The resulting mixture was then refluxed for 15 h. After reaction completion, aqueous solution of sodium bicarbonate was added, and the mixture was extracted with ethyl acetate, the organic layer was washed with aqueous solution of sodium bicarbonate and brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under vacuum, the residue was purified by silica gel column chromatography (7% ethyl acetate in petroleum ether) to afford the title product (16% yield). 1H NMR (300 MHz, CDCl3) δ (ppm) 4.79 (br, 1H), 4.03-4.01 (m, 1H), 3.43 (dd, J1=18.0 Hz, J2=9.0 Hz, 1H), 2.94 (dd, J1=18.0 Hz, J2=6.9 Hz, 1H), 1.48 (s, 9H), 1.28 (s, 3H), 1.13 (s, 3H). The reaction mixture was cooled to room temperature The resulting mixture was then refluxed for 15 h was added the mixture was extracted with ethyl acetate the organic layer was washed with aqueous solution of sodium bicarbonate and brine dried over anhydrous sodium sulfate filtered The filtrate was concentrated under vacuum the residue was purified by silica gel column chromatography (7% ethyl acetate in petroleum ether)