3-azaspiro[5.5]undecane

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

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 solution of 7 ml of 3-azaspiro[5.5]undecane and 9.7 ml of acetic anhydride in 19.5 ml of tetrahydrofuran was refluxed for 3 hours. The volatiles were evaporated to a yellow oil which was distilled in a Kugelrohr still giving a yellow oil, BP 90°-100° C./200-atm. The distillate was purified by chromatography on silica gel using 1:1 ethyl acetate:hexanes giving 7.89 g of the desired product as a colorless oil. The volatiles were evaporated to a yellow oil which was distilled in a Kugelrohr still giving a yellow oil, BP 90°-100° C./200-atm The distillate was purified by chromatography on silica gel using 1:1 ethyl acetate

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

Procedure: A solution of 7 ml of 3-azaspiro[5.5]undecane and 9.7 ml of acetic anhydride in 19.5 ml of tetrahydrofuran was refluxed for 3 hours. The volatiles were evaporated to a yellow oil which was distilled in a Kugelrohr still giving a yellow oil, BP 90°-100° C./200-atm. The distillate was purified by chromatography on silica gel using 1:1 ethyl acetate:hexanes giving 7.89 g of the desired product as a colorless oil. The volatiles were evaporated to a yellow oil which was distilled in a Kugelrohr still giving a yellow oil, BP 90°-100° C./200-atm The distillate was purified by chromatography on silica gel using 1:1 ethyl acetate

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

Procedure: To a solution of 3-azaspiro[5,5]undecane (0.34 g, 2.2 mmol), cyclopropanecarbaldehyde (0.14 g, 2 mmol) and NaBH(OAc)3 (0.64 g, 3 mmol) in dichloroethane (10 mL) were added AcOH (0.12 mL, 2 mmol), the resulting suspension was stirred overnight, quenched with NaHCO3 and extracted with CH2Cl2 twice, the combined organic layer was washed with brine, and dried with MgSO4. The solution was filtered, concentrated in vacuo and purified by flash chromatography. The compound was converted to the hydrochloride by passing HCl gas into the ether solution of 3-(cyclopropylmethyl)-3-azoniaspiro[5,5]undecane at 0° C., followed by decanting the ether supernatant, the final white solid (0.39 g, 80% yield) was dried in vacuo. 1H NMR (360 MHz, CDCl3) δ 2.45 (t, J=5.66 Hz, 4H), 2.23 (d, J=6.51 Hz 2H), 1.49 (t, J=5.66 Hz, 4H), 1.48-1.40 (m, 6H), 1.38-1.30 (m, 4H), 0.92-0.82 (m, 1H), 0.52-0.47 (m, 2H), 0.11-0.17 (m, 2H); 13C NMR (90 MHz, CDCl3) δ 64.55, 49.67, 36.47, 35.46, 31.00, 27.12, 21.73, 8.74, 4.19; ESI-MS: Calculated for C14H25N (M+H)+ 208.4, Found: 208.4. quenched with NaHCO3 extracted with CH2Cl2 twice the combined organic layer was washed with brine dried with MgSO4 The solution was filtered concentrated in vacuo purified by flash chromatography at 0° C. by decanting the ether supernatant

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

Procedure: 3-Azaspiro[5,5]undecane (0.38 g, 2 mmol) and 2-methylthio-2-imidazoline hydroiodide (0.44 g, 1.8 mmol) was refluxing in CH3OH overnight, concentrated in vacuo and purified by flash chromatography to give yellow oil (0.26 g, 65% yield). 1H NMR (360 MHz, CDCl3) δ 8.27 (br s, 2H), 3.72 (s, 4H), 3.39 (t, J=5.83 Hz, 4H), 1.50 (t, J=5.94 Hz, 4H), 1.47-1.44 (m, 10H); 13C NMR (90 MHz, CDCl3) δ 159.48, 43.39, 42.73, 36.02, 35.26, 30.83, 26.65, 21.61. 21.49; ESI-MS: Calculated for C13H24IN3 (M−I)+ 222.3, Found: 222.5. concentrated in vacuo purified by flash chromatography

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

Procedure: 3-Azaspiro[5,5]undecane (0.38 g, 2 mmol) and 2-methylthio-2-imidazoline hydroiodide (0.44 g, 1.8 mmol) was refluxing in CH3OH overnight, concentrated in vacuo and purified by flash chromatography to give yellow oil (0.26 g, 65% yield). 1H NMR (360 MHz, CDCl3) δ 8.27 (br s, 2H), 3.72 (s, 4H), 3.39 (t, J=5.83 Hz, 4H), 1.50 (t, J=5.94 Hz, 4H), 1.47-1.44 (m, 10H); 13C NMR (90 MHz, CDCl3) δ 159.48, 43.39, 42.73, 36.02, 35.26, 30.83, 26.65, 21.61. 21.49; ESI-MS: Calculated for C13H24IN3 (M−I)+ 222.3, Found: 222.5. concentrated in vacuo purified by flash chromatography

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

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: 252 mg (1.3 mmol) of the isocyanate from example 7 were dissolved at 0° C. in 5 ml of THF and admixed with 109 mg (3.25 mmol, 2.5 eq.) of sodium hydrogencarbonate and 209 mg (1.37 mmol, 1.05 eq.) of 3-azaspiro[5.5]undecane. The mixture was stirred overnight, precipitated salts were removed and the reaction mixture was treated directly with 2.5 ml of 1 M LiOH solution (2.5 mmol, 1.9 eq.). The reaction was monitored by HPLC-MS. When the mass peak of the reactant had disappeared completely, the mixture was acidified cautiously with dilute HCl and the product was isolated by extraction with ethyl acetate, drying of the organic phase over sodium sulfate and concentration under reduced pressure. Yield: 440 mg (quantitative). The crude product was used directly in the amide coupling which follows. precipitated salts were removed drying of the organic phase over sodium sulfate and concentration under reduced pressure