1-[ethoxy(isocyanomethyl)phosphoryl]oxyethane

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

Procedure: To a solution of diethylisocyanomethylphosphonate in diethyl ether (40 ml) was added butyl lithium (6.9 ml, 1.6M in hexane) dropwise at −60° C. After the reaction mixture was stirred at −60° C. for additional 15 min a solution of 2-acetylthiophene (1.26 g, 10 mmol) in diethyl ether (10 ml) was added at the same temperature. The reaction mixture was warmed up to 0° C. and was stirred for 1.5 h. Concentrated HCl (15 ml) was added at 0° C. and then ice bath was removed. After the resulting mixture was stirred at room temperature overnight it was poured to cold water (20 ml). The organic layer was washed with water, sat. sodium bicarbonate, brine, dried over sodium sulfate and concentrated. The crude product was used in the next step without purification. was added at the same temperature ice bath was removed After the resulting mixture was stirred at room temperature overnight it was poured to cold water (20 ml) The organic layer was washed with water, sat. sodium bicarbonate, brine dried over sodium sulfate concentrated The crude product was used in the next step without purification

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

Procedure: To a solution of diethyl isocyanomethylphosphonate (0.86 mL, 5.3 mmol) in anhydrous ether (45 mL) at −78° C. under nitrogen was added n-butyl lithium (2.13 mL, 2.5 M in hexane) and the resulting mixture was stirred at −78° C. for 1 hr. Then, 3-(4-bromo-phenyl)-cyclobutanone (1 g, 4.4 mmol) in anhydrous ether (15 mL) was added dropwise over 30 minutes. The reaction mixture was allowed to warm to ambient temperature and stirred 16 hours. Concentrated hydrochloric acid (9.5 mL) was added dropwise and the reaction mixture was stirred at room temperature for 5 hrs. The mixture was partitioned between ethyl acetate and water. The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried (MgSO4), filtered, and concentrated. The residue was chromatographed on silica gel eluting with 2-3% ethyl acetate in hexanes to provide 3-(4-bromo-phenyl)-trans-cyclobutanecarbaldehyde (281 mg, 27%) as the faster eluting isomer (A1) and 3-(4-bromo-phenyl)-cis-cyclobutanecarbaldehyde (508 mg, 48%) as the slower eluting isomer (A2). A1: 1H NMR (300 MHz, CDCl3) δ 2.37 (m, 2 H), 2.72 (m, 2 H), 3.16 (m, 1 H), 3.53 (p, J=6 Hz, 1 H), 7.09 (d, J=9 Hz, 2 H), 7.44 (d, J=9Hz, 2 H), 9.95 (s, 1 H),; (DCl/NH3) m/z 239 (M+H)+; A2: 1 H NMR (300 MHz, CDCl3) δ 2.35 (m, 2 H), 2.55 (m, 2 H), 3.21 (m, 1 H), 3.52 (p, J=6 Hz, 1 H), 7.07 (d, J=9 Hz, 2 H), 7.42 (d, J=9 Hz, 2 H), 9.73 (s, 1 H); (DCl/NH3) m/z 239 (M+H)+. to warm to ambient temperature stirred 16 hours the reaction mixture was stirred at room temperature for 5 hrs The mixture was partitioned between ethyl acetate and water The layers were separated the aqueous layer was extracted with ethyl acetate The combined organic layers were washed with brine dried (MgSO4) filtered concentrated The residue was chromatographed on silica gel eluting with 2-3% ethyl acetate in hexanes

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

Procedure: A solution of diethyl(isocyanomethyl)phosphonate (410 μL) in diethyl ether (5 mL) was cooled to −78° C. in nitrogen atmosphere. After addition of 1.54M n-butyl lithium solution in hexane (1.7 mL) to the reaction mixture at −78° C., the temperature was raised to 0° C. and stirred for 15 minutes. To the resulting solution spiro[4.5]decane-6-one (300 mg) was added at 0° C., and the temperature was raised to room temperature under stirring. An hour thereafter, conc. hydrochloric acid (5 mL) was added to the reaction mixture at room temperature, followed by further 10 hours' stirring. The resulting solution was diluted with water and extracted with diethyl ether. The extract was dried over anhydrous magnesium sulfate, and from which the solvent was distilled off to provide the title compound in crude, unpurified form, as a colorless oily substance. the temperature was raised to room temperature under stirring followed by further 10 hours ' stirring extracted with diethyl ether The extract was dried over anhydrous magnesium sulfate from which the solvent was distilled off

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

Procedure: To a solution of diethylisocyanomethylphosphonate in diethyl ether (40 ml) was added butyl lithium (6.9 ml, 1.6M in hexane) dropwise at −60° C. After the reaction mixture was stirred at −60° C. for additional 15 min a solution of 2-acetylthiophene (1.26 g, 10 mmol) in diethyl ether (10 ml) was added at the same temperature. The reaction mixture was warmed up to 0° C. and was stirred for 1.5 h. Concentrated HCl (15 ml) was added at 0° C. and then ice bath was removed. After the resulting mixture was stirred at room temperature overnight it was poured to cold water (20 ml). The organic layer was washed with water, sat. sodium bicarbonate, brine, dried over sodium sulfate and concentrated. The crude product was used in the next step without purification. was added at the same temperature ice bath was removed After the resulting mixture was stirred at room temperature overnight it was poured to cold water (20 ml) The organic layer was washed with water, sat. sodium bicarbonate, brine dried over sodium sulfate concentrated The crude product was used in the next step without purification