9,12-dioxa-4-azadispiro[4.2.48.25]tetradecan-3-one

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: A stirred mixture of 1-azaspiro[4.5]decane-2,8-dione (P1, 2.00 g, 12.0 mmol), ethylene glycol (2.96 g, 47.7 mmol), and 4-methylbenzenesulfonic acid (100 mg, 0.735 mmol) in toluene (100 mL) was refluxed for 20 h with Dean-Stark apparatus to remove water. After this time, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The resulting residue was mixed with saturated aqueous sodium bicarbonate (100 mL) and the resulting aqueous mixture was extracted with 5% methanol/ethyl acetate (4×150 mL). The combined organic extracts were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford compound P2 as an off-white solid (2.41 g, 95%): 1H NMR (300 MHz, DMSO-d6) δ 5.82 (bs, 1H), 3.95 (s, 4H), 2.41 (t, J=8.0 Hz, 2H), 1.99 (t, J=8.0 Hz, 2H), 1.80-1.65 (m, 8H). MS (M+H) 212. was refluxed for 20 h with Dean-Stark apparatus to remove water concentrated under reduced pressure The resulting residue was mixed with saturated aqueous sodium bicarbonate (100 mL) the resulting aqueous mixture was extracted with 5% methanol/ethyl acetate (4×150 mL) The combined organic extracts were dried over anhydrous sodium sulfate filtered concentrated under reduced pressure

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

Procedure: A suspension of 1,4-dioxa-9-aza-dispiro[4.2.4.2]tetradecan-10-one (prepared according to J. Org. Chem. 2004, 69, 2755) (500 mg, 2.4 mmol) in THF (7 mL) was treated with 1M aqueous HCl (7 mL) and the resulting mixture stirred at ambient temperature for 20 hours. The reaction mixture was quenched with 1M aqueous NaOH (7 mL) and the mixture concentrated under vacuum. The resulting solid was purified by column chromatography on silica gel (gradient: DCM then 2 to 10% methanol in ethyl acetate) to afford 398 mg (quant.) of 1-aza-spiro[4.5]decane-2,8-dione. LCMS (Method B, ESI): RT=1.63 min, 168; 1H NMR (400 MHz, CDCl3) δ: 3.95 (s, 1H), 3.77-3.71 (m, 1H), 2.46-2.44 (m, 3H), 2.05-2.03 (m, 3H), 1.81-1.65 (m, 4H). The reaction mixture was quenched with 1M aqueous NaOH (7 mL) the mixture concentrated under vacuum The resulting solid was purified by column chromatography on silica gel (gradient

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