2,2,6,6-Tetramethylpiperidine → Methyl 1-(5-cyanopyridin-2-yl)pyrrolidine-3-carboxylate

HRID 874955Notes

Reaction equation

[CH3:1][O:2][C:3]([CH:5]1[CH2:9][CH2:8][NH:7][CH2:6]1)=[O:4].Br[C:11]1[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][N:12]=1.CC1(C)CCCC(C)(C)N1>CN(C=O)C.CCOC(C)=O>[C:15]([C:14]1[CH:17]=[CH:18][C:11]([N:7]2[CH2:8][CH2:9][CH:5]([C:3]([O:2][CH3:1])=[O:4])[CH2:6]2)=[N:12][CH:13]=1)#[N:16]

Participants

Conditions

Temperature: 130 °C

Procedure

Pyrrolidine-3-carboxylic acid methyl ester (100 mg, 0.77 mmol) was dissolved in dry DMF (0.5 MI) in a shield tube. 6-Bromonicotinonitrile (140 mg, 077 mmol) was added to the reaction mixture, followed by 2,2,6,6-tetramethylpiperadine (110 mg, 0.77 mmol) and the mixture was heated to 130° C. for 3 h, cooled to room temperature, and diluted with EtOAc. The organic layer was washed with H2O and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel 60-120 mesh, eluent 15-18% EtOAc in petroleum ether) to afford methyl 1-(5-cyanopyridin-2-yl)pyrrolidine-3-carboxylate (90 mg, yield 70%). 1H NMR (300 MHz, CDCl3) δ 8.42 (d, J=2.2 Hz, 1H), 7.62-7.59 (dd, J=8.9 Hz, J=2.3 Hz, 1H), 6.36 (d, J=9.0 Hz, 1H), 3.78-3.77 (m, 2H), 3.75 (s, 3H), 3.67 (m, 1H), 3.56-3.52 (m, 1H), 3.28-3.23 (t, J=7.1 Hz, 1H), 2.37-2.30 (q, J=7.1 Hz, 2H). MS (ESI) m/z: Calculated for C12H13N3O2: 231.10. found: 232.2 (M+H)+

Workup

temperaturecooled to room temperature
washThe organic layer was washed with H2O and brine
dry with materialdried over anhydrous sodium sulfate
concentrationconcentrated under reduced pressure
customThe crude product was purified by column chromatography (silica gel 60-120 mesh, eluent 15-18% EtOAc in petroleum ether)

Sources & evidence

ORD record: ord-7e3e5488135d4c2d96780228a887e44c
Source dataset: uspto-grants-2015_03
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US08981084B2

Reaction notes

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