Nitrogen → tert-Butyl 4-hydroxy-2-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-1-oxo-2,8-diazaspiro[4.5]decane-8-carboxylate

HRID 1848481Notes

Reaction equation

HRID 1848481 reaction equation
[OH:1][CH:2]1[C:6]2([CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]2)[C:5](=[O:19])[NH:4][CH2:3]1.FC(F)(F)S(O[C:26]1[CH2:27][O:28][C:29](=[O:32])[C:30]=1[CH3:31])(=O)=O.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+].N#N>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[OH:1][CH:2]1[C:6]2([CH2:7][CH2:8][N:9]([C:12]([O:14][C:15]([CH3:16])([CH3:18])[CH3:17])=[O:13])[CH2:10][CH2:11]2)[C:5](=[O:19])[N:4]([C:26]2[CH2:27][O:28][C:29](=[O:32])[C:30]=2[CH3:31])[CH2:3]1

Participants

8

Reactant 5

HCID 947NitrogenHCID 10796Cesium carbonateHCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)HCID 108901884-Methyl-5-oxo-2,5-dihydrofuran-3-yl trifluoromethanesulfonateHCID 86709491tert-Butyl 4-hydroxy-1-oxo-2,8-diazaspiro[4.5]decane-8-carboxylate

Product 1

HCID 86709492tert-Butyl 4-hydroxy-2-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-1-oxo-2,8-diazaspiro[4.5]decane-8-carboxylate

Reagents, catalysts & solvents 2

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 312751,4-DioxaneSolvent

Conditions

Temperature
90 °C

Procedure

To a round bottom flask was charged tert-butyl 4-hydroxy-1-oxo-2,8-diazaspiro[4.5]decane-8-carboxylate (400 mg, 1.48 mmol), 4-methyl-5-oxo-2,5-dihydrofuran-3-yl trifluoromethanesulfonate (546 mg, 2.22 mmol), Pd2(dba)3 (33.9 mg, 0.037 mmol), Xantphos (64.2 mg, 0.111 mmol), and cesium carbonate (964 mg, 2.96 mmol). The flask was equipped with a condenser, vacuumed and back filled with N2 and filled with dioxane (6 mL). The reaction mixture was heated at 90° C. overnight, and filtered through CELITE®. The filtrate was evaporated to give the crude product, which was purified by column chromatography (0-10% MeOH/DCM) to give the title compound as a racemate. LC/MS: [(M+1)]+=367. The racemic mixture was separated by SFC-HPLC, using the following conditions: chiralcel OJ, 21×250 mm, 10% MeOH+0.2 DEA, 50 mL/min to afford Isomer A (faster eluting enantiomer) LC/MS: [(M+1)]+=367, and Isomer B (slower eluting enantiomer) LC/MS: [(M+1)]+=367.

Workup

  1. customThe flask was equipped with a condenser
  2. filtrationfiltered through CELITE®
  3. customThe filtrate was evaporated
  4. customto give the crude product, which
  5. customwas purified by column chromatography (0-10% MeOH/DCM)

Sources & evidence

ORD record
ord-561bfa312c6c47d5afc7bb2aaede7c16
Source dataset
uspto-grants-2015_02
Patent number
US08952166B2

Reaction notes

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