2-Chloropyridine → Tert-butyl 10-ethyl-8-(2-pyridyl)-11-oxa-3,8-diazaspiro[5.5]undecane-3-carboxylate

HRID 712986Notes

Reaction equation

HRID 712986 reaction equation
[CH2:1]([CH:3]1[O:8][C:7]2([CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)[CH2:6][NH:5][CH2:4]1)[CH3:2].Cl[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1.CC(C)([O-])C.[Na+].C(OCC)(=O)C.CCCCCC>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([CH:3]1[O:8][C:7]2([CH2:9][CH2:10][N:11]([C:14]([O:16][C:17]([CH3:19])([CH3:18])[CH3:20])=[O:15])[CH2:12][CH2:13]2)[CH2:6][N:5]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=2)[CH2:4]1)[CH3:2]

Participants

8

Reactant 4

HCID 79772-ChloropyridineHCID 21226206Ethyl acetate hexaneHCID 23676156Sodium t-butoxideHCID 68291802HCID 68291802, compound

Product 1

HCID 70872778Tert-butyl 10-ethyl-8-(2-pyridyl)-11-oxa-3,8-diazaspiro[5.5]undecane-3-carboxylateYield 76.1%

Reagents, catalysts & solvents 3

HCID 634876Binap, (A+-)-CatalystHCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 1140TolueneSolvent2×

Conditions

Temperature
40 °C

Procedure

A solution of rac-BINAP (43.8 mg, 0.070 mmol) and Pd2(dba)3 (32.2 mg, 0.0352 mmol) in toluene (1 mL) was stirred under nitrogen atmosphere in a sealed vial at 90° C. for 10 min, then cooled to 40° C. and cannulated into a stirring solution of tert-butyl 4-ethyl-5-oxa-2,9-diazaspiro[5.5]undecane-9-carboxylate (500 mg, 1.76 mmol) and 2-chloropyridine (200 mg, 165 μL, 1.76 mmol) in toluene (6 mL). The solution was treated with sodium tert-butoxide (275 mg, 2.87 mmol), flushed with nitrogen and stirred for 3 h at 90° C. The reaction mixture was cooled, diluted with ethyl acetate (100 mL), filtered through Celite and concentrated in vacuo. Silica gel chromatography (120 g silica, 10-70% ethyl acetate/hexane) provided tert-butyl 10-ethyl-8-(2-pyridyl)-11-oxa-3,8-diazaspiro[5.5]undecane-3-carboxylate (486 mg, 1.34 mmol, 76%) as an orange-colored oil. ESI-MS m/z calc. 361.2. found 362.3 (M+1)+; Retention time: 1.25 minutes (3 min run). 1H NMR (400 MHz, DMSO-d6) δ 8.08 (dd, J=4.9, 1.4 Hz, 1H), 7.51 (ddd, J=8.8, 7.1, 2.0 Hz, 1H), 6.85 (d, J=8.7 Hz, 1H), 6.61 (dd, J=6.7, 4.9 Hz, 1H), 4.24 (d, J=12.0 Hz, 1H), 4.11 (d, J=12.9 Hz, 1H), 3.75-3.51 (m, 3H), 3.15 (br s, 1H), 2.91 (br s, 1H), 2.59 (d, J=13.0 Hz, 1H), 2.40 (dd, J=12.6, 10.9 Hz, 1H), 2.02 (d, J=13.3 Hz, 1H), 1.60-1.42 (m, 4H), 1.39 (s, 9H), 1.36-1.26 (m, 1H), 0.95 (t, J=7.5 Hz, 3H).

Workup

  1. customflushed with nitrogen
  2. temperatureThe reaction mixture was cooled
  3. additiondiluted with ethyl acetate (100 mL)
  4. filtrationfiltered through Celite
  5. concentrationconcentrated in vacuo

Sources & evidence

ORD record
ord-278b8eff508841ccb75fd93e89bde991
Source dataset
uspto-grants-2015_11
Patent number
US09181273B2

Reaction notes

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