tert-butyl 1-oxo-2,8-diazaspiro[4.5]decane-8-carboxylate

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

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

Procedure: To a solution of tert-butyl 1-oxo-2,8-diazaspiro[4.5]decane-8-carboxylate (330 mg, 1.298 mmol) and iodomethane (0.085 mL, 1.362 mmol) in THF (10 mL) was cooled in an ice bath. Sodium hydride (78 mg, 1.946 mmol) was added and the ice bath was removed. The reaction was stirred at room temperature for 4 hrs. The reaction mixture was diluted with EtOAc and washed with sat NaHCO3; the aqueous layer was extracted with EtOAc. Then the combined organics were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by chromatography (silica gel, Hexanes/EtOAc gradient 0 to 100% EtOAc) to give tert-butyl 2-methyl-1-oxo-2,8-diazaspiro[4.5]decane-8-carboxylate (315 mg). the ice bath was removed The reaction mixture was diluted with EtOAc washed the aqueous layer was extracted with EtOAc Then the combined organics were washed with brine dried over Na2SO4 filtered concentrated under reduced pressure The crude product was purified by chromatography (silica gel, Hexanes/EtOAc gradient 0 to 100% EtOAc)

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

Procedure: To a solution of tert-butyl 1-oxo-2,8-diazaspiro[4.5]decane-8-carboxylate (330 mg, 1.298 mmol) and iodomethane (0.085 mL, 1.362 mmol) in THF (10 mL) was cooled in an ice bath. Sodium hydride (78 mg, 1.946 mmol) was added and the ice bath was removed. The reaction was stirred at room temperature for 4 hrs. The reaction mixture was diluted with EtOAc and washed with sat NaHCO3; the aqueous layer was extracted with EtOAc. Then the combined organics were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by chromatography (silica gel, Hexanes/EtOAc gradient 0 to 100% EtOAc) to give tert-butyl 2-methyl-1-oxo-2,8-diazaspiro[4.5]decane-8-carboxylate (315 mg). the ice bath was removed The reaction mixture was diluted with EtOAc washed the aqueous layer was extracted with EtOAc Then the combined organics were washed with brine dried over Na2SO4 filtered concentrated under reduced pressure The crude product was purified by chromatography (silica gel, Hexanes/EtOAc gradient 0 to 100% EtOAc)

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

Conditions: temp:110.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 1-oxo-2,8-diaza-spiro[4,5]decane-8-carboxylic acid tert-butyl ester (127 mg, 0.5 mmol, 1 equiv), 4-bromo-1-chloro-2-methoxy-benzene (221 mg, 2equiv), N,N-dimethylethylenediamine (14 mg, 0.3 equiv), CuI (29 mg, 0.3 equiv) and Cs2CO3 (325 mg, 2 equiv) in 1 mL of dioxane were heated at 110° C. overnight and then cooled to room temperature, taken up in a 1:1 mixture of methanol and EtOAc, filtered through a thin pad of celite and concentrated. The crude product was purified by flash column to give 2-(4-Chloro-3-methoxy-phenyl)-1-oxo-2,8-diaza-spiro[4.5]decane-8-carboxylic acid tert-butyl ester. cooled to room temperature filtered through a thin pad of celite concentrated The crude product was purified by flash column

Conditions: temp:110.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 1-oxo-2,8-diaza-spiro[4,5]decane-8-carboxylic acid tert-butyl ester (127 mg, 0.5 mmol, 1 equiv), 4-bromo-1-chloro-2-methoxy-benzene (221 mg, 2equiv), N,N-dimethylethylenediamine (14 mg, 0.3 equiv), CuI (29 mg, 0.3 equiv) and Cs2CO3 (325 mg, 2 equiv) in 1 mL of dioxane were heated at 110° C. overnight and then cooled to room temperature, taken up in a 1:1 mixture of methanol and EtOAc, filtered through a thin pad of celite and concentrated. The crude product was purified by flash column to give 2-(4-Chloro-3-methoxy-phenyl)-1-oxo-2,8-diaza-spiro[4.5]decane-8-carboxylic acid tert-butyl ester. cooled to room temperature filtered through a thin pad of celite concentrated The crude product was purified by flash column

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

Procedure: To a solution of tert-butyl 1-oxo-2,8-diazaspiro[4.5]decane-8-carboxylate (I-11) (5.0 g, 19.7 mmol) in methylene chloride (10 mL) was added trifluoroacetic acid (15.2 mL, 197 mmol) and the resulting solution was stirred at rt for 1 h. After evaporating the volatiles the residue was basified on ion exchange column washed with methanol followed by 1 N ammonia in methanol to give 2,8-diazaspiro[4.5]decan-1-one. LC/MS: (M+1)+: 155.11 After evaporating the volatiles the residue washed with methanol

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

Procedure: A mixture of tert-butyl 1-oxo-2,8-diazaspiro[4.5]decane-8-carboxylate (150 mg, 0.590 mmol), 4-fluoro-2-methyl-5-oxo-2,5-dihydrofuran-3-yl trifluoromethanesulfonate (148 mg, 0.590 mmol), xantphos (34.1 mg, 0.059 mmol), water (0.032 mL, 1.77 mmol) in toluene (20 mL) was degassed by nitrogen followed by addition of palladium acetate (6.6 mg, 0.029 mmol). was degassed by nitrogen

Conditions: temp:65.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of tert-butyl 1-oxo-2,8-diazaspiro[4.5]decane-8-carboxylate (200 mg, 0.786 mmol), 2,4-dimethyl-5-oxo-2,5-dihydrofuran-3-yl trifluoromethanesulfonate, Xantphos (45.5 mg, 0.079 mmol), water (0.043 mL, 2.4 mmol) and potassium carbonate (217 mg, 1.57 mmol) in toluene (20 mL) was degassed by nitrogen for 20 min followed by addition of palladium acetate (8.8 mg, 0.039 mmol). The resulting mixture was heated at 65° C. for 16 h. After filtration the filtrate was concentrated and the residue was purified on silica gel column eluting with EtOAc/hexane to give the title compound. LC/MS: (M+1)+: 365.20. was degassed by nitrogen for 20 min After filtration the filtrate was concentrated the residue was purified on silica gel column eluting with EtOAc/hexane

Conditions: temp:65.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of tert-butyl 1-oxo-2,8-diazaspiro[4.5]decane-8-carboxylate (200 mg, 0.786 mmol), 2-methyl-5-oxo-2,5-dihydrofuran-3-yl trifluoromethanesulfonate (232 mg, 0.944 mmol), Xantphos (45.5 mg, 0.079 mmol), palladium (II) acetate (8.83 mg, 0.039 mmol), water (0.043 mL, 2.359 mmol), and potassium carbonate (217 mg, 1.573 mmol) in toluene (20 mL) was degassed by nitrogen and heated at 65° C. for 16 h. After filtration through CELITE® the filtrate was concentrated and the residue was purified on silica gel column using ethyl acetate and hexane as eluting solvents to give the title compound. LC/MS: (M+1)+: 351.15. was degassed by nitrogen After filtration through CELITE® the filtrate was concentrated the residue was purified on silica gel column as eluting solvents

Conditions: temp:66.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of tert-butyl 1-oxo-2,8-diazaspiro[4.5]decane-8-carboxylate (I-11) (200 mg, 0.786 mmol), 4-isopropyl-5-oxo-2,5-dihydrofuran-3-yl trifluoromethanesulfonate (259 mg, 0.944 mmol), Xantphos (46 mg, 0.079 mmol), palladium (II) acetate (8.8 mg, 0.039 mmol), water (0.043 mL, 2.4 mmol), and potassium carbonate (217 mg, 1.57 mmol) in toluene (20 mL) was heated at 66° C. for 16 h. After filtration through CELITE®, the filtrate was concentrated and the residue was purified on a silica gel column to give the title compound. LC/MS: (M+1)+: 379.21. After filtration through CELITE® the filtrate was concentrated the residue was purified on a silica gel column

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of tert-butyl 1-oxo-2,8-diazaspiro[4.5]decane-8-carboxylate (200 mg, 0.786 mmol), 4-ethyl-5-oxo-2,5-dihydrofuran-3-yl trifluoromethanesulfonate (246 mg, 0.944 mmol), Xantphos (45.5, 0.079 mmol), palladium (II) acetate (8.8 mg, 0.039 mmol), water (0.043 mL, 2.4 mmol), and potassium carbonate (217 mg, 1.57 mmol) in toluene (20 mL) was heated at 60° C. for 16 h. After filtration through CELITE®, the filtrate was concentrated and the residue was purified on silica gel using ethyl acetate/hexane to give the title compound. LC/MS: (M+1)+: 365.19. After filtration through CELITE® the filtrate was concentrated the residue was purified on silica gel