tert-butyl 4-oxo-1-oxa-9-azaspiro[5.5]undec-2-ene-9-carboxylate

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

Procedure: To a solution of tert-butyl 8-oxo-11-oxa-3-azaspiro[5.5]undec-9-ene-3-carboxylate (200 mg, 0.748 mmol) in CH2Cl2 (2.4 mL) was added TFA (0.6 mL, 7.8 mmol). The mixture was stirred at room temperature for 15 min. Solvent was removed. The crude material was evaporated again from toluene (2×) and dried under high vacuum overnight to provide 11-oxa-3-azaspiro[5.5]undec-9-en-8-one (300 mg). 1H NMR (400 MHz, CDCl3) δ 7.34 (d, J=6.1 Hz, 1H), 5.57 (d, J=6.1 Hz, 1H), 3.45 (d, J=11.7 Hz, 2H), 3.34 (dd, J=24.1, 12.7 Hz, 2H), 2.67 (s, 2H), 2.38 (d, J=14.6 Hz, 2H), 1.98 (td, J=14.8, 4.8 Hz, 2H). ESI-MS m/z calc. 167.09, found 168.2 (M+1)+; Retention time: 0.17 minutes (3 minute run). Solvent was removed The crude material was evaporated again from toluene (2×) dried under high vacuum overnight

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

Procedure: To an oven-dried flask under argon gas was added copper iodide (1.28 g, 6.73 mmol) followed by anhydrous THF (125 mL). The suspension was cooled to −78° C. prior to the dropwise addition of (4-fluorophenyl)magnesium bromide (33.7 mL of 2 M in diethyl ether, 67.3 mmol). The resulting mixture was stirred at −78° C. for 20 minutes. HMPA (23.4 mL, 135 mmol) was added, and the reaction mixture was allowed to further stir at −78° C. for 30 minutes. In a separate flask, TMSCl (17.1 mL, 135 mmol) was slowly added to a solution of tert-butyl 8-oxo-11-oxa-3-azaspiro[5.5]undec-9-ene-3-carboxylate (3.00 g, 11.2 mmol) in THF (10 mL). This solution was then slowly transferred to the reaction mixture at −78° C. The resulting thick opaque white mixture was then allowed to slowly warm to room temperature and stirred overnight. To the obtained grey reaction mixture was added a saturated ammonium chloride (75 mL). The mixture was allowed to stir at room temperature for 5 minutes, and volatiles were removed under reduced pressure. To the remaining ⅓ volume was mixed with ethyl acetate (100 mL) and water (25 mL). The aqueous layer was further extracted with ethyl acetate (2×50 mL). Organic layers were combined, dried over sodium sulfate, filtered and concentrated under reduced pressure. The obtained yellow oil was purified by column chromatography (20-40% ethyl acetate/hexane) to provide tert-butyl 10-(4-fluorophenyl)-8-oxo-11-oxa-3-azaspiro[5.5]undecane-3-carboxylate (3.81 g). 1H NMR (400 MHz, CDCl3) δ 7.41-7.33 (m, 2H), 7.11-7.03 (m, 2H), 4.83 (dd, J=11.2, 3.1 Hz, 1H), 3.87-3.72 (m, 2H), 3.32 (ddd, J=13.4, 11.5, 3.3 Hz, 1H), 3.09-2.98 (m, 1H), 2.61 (ddd, J=14.0, 3.1, 1.7 Hz, 1H), 2.57-2.47 (m, 2H), 2.39 (dd, J=13.9, 1.8 Hz, 1H), 2.02-1.95 (m, 1H), 1.85 (ddd, J=13.4, 5.8, 3.2 Hz, 1H), 1.68 (ddd, J=13.4, 11.5, 4.8 Hz, 1H), 1.54-1.47 (m, 1H), 1.45 (d, J=6.0 Hz, 9H). ESI-MS m/z calc. 363.18, found 364.0 (M+1)+; Retention time: 1.81 minutes (3 minute run). to further stir at −78° C. for 30 minutes was then slowly transferred to the reaction mixture at −78° C to slowly warm to room temperature stirred overnight to stir at room temperature for 5 minutes volatiles were removed under reduced pressure To the remaining ⅓ volume was mixed with ethyl acetate (100 mL) and water (25 mL) The aqueous layer was further extracted with ethyl acetate (2×50 mL) dried over sodium sulfate filtered concentrated under reduced pressure The obtained yellow oil was purified by column chromatography (20-40% ethyl acetate/hexane)