Dimethylformamide → 5-(tert-Butoxy)picolinonitrile

HRID 713053Notes

Reaction equation

HRID 713053 reaction equation
[CH3:1][C:2]([O-:5])([CH3:4])[CH3:3].[Na+].CN(C=O)C.F[C:13]1[CH:14]=[CH:15][C:16]([C:19]#[N:20])=[N:17][CH:18]=1>CN(P(N(C)C)(N(C)C)=O)C.O>[C:2]([O:5][C:13]1[CH:14]=[CH:15][C:16]([C:19]#[N:20])=[N:17][CH:18]=1)([CH3:4])([CH3:3])[CH3:1]

Participants

6

Reactant 3

HCID 6228DimethylformamideHCID 113324532-Cyano-5-fluoropyridineHCID 23676156Sodium t-butoxide

Product 1

HCID 681535125-(tert-Butoxy)picolinonitrileYield 62.4%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 12679HexamethylphosphoramideSolvent

Procedure

To NaOtBu (1.57 g, 16.4 mmol) in HMPA (6 mL) was added DMF (6 mL), followed by 5-fluoropyridine-2-carbonitrile (1 g, 8.19 mmol) and the reaction mixture was stirred for 16 hours under an atmosphere of nitrogen. The reaction mixture was diluted with water (100 mL) and extracted with DCM (3×50 mL) and layers were separated. The organics were washed sequentially with water (50 mL) and sat. aq. NaHCO3 solution (50 mL) and the organic layer was separated, dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with 0-50% EtOAc/hexanes to give 5-tert-butoxypyridine-2-carbonitrile (0.90 g, 62%) as a yellow solid. ESI-MS m/z calc. 176.0. found 177.5 (M+1)+; Retention time: 1.3 minutes (3 min run). 1H NMR (400 MHz, CDCl3) δ 8.38 (dd, J=2.7, 0.5 Hz, 1H), 7.67-7.56 (m, 1H), 7.41-7.31 (m, 1H), 1.52-1.38 (m, 10H). To 5-tert-butoxypyridine-2-carbonitrile (0.75 g, 4.26 mmol) in ethanol (10 mL) was added NaOH (4.3 mL of 5 M, 21.3 mmol) and the reaction mixture was heated at 85° C. for 1 hour. The reaction mixture was cooled, concentrated in vacuo and diluted with ethyl acetate (50 mL). The organic layer was washed with mixture of brine solution (10 mL) and 6N HCl (3 mL). The organic layer was separated, dried over MgSO4 and concentrated in vacuo to give 5-tert-butoxypyridine-2-carboxylic acid (0.82 g, 99%) as a yellow solid. ESI-MS m/z calc. 195.1. found 196.1 (M+1)+; Retention time: 0.62 minutes (3 min run).

Workup

  1. extractionextracted with DCM (3×50 mL) and layers
  2. customwere separated
  3. washThe organics were washed sequentially with water (50 mL) and sat. aq. NaHCO3 solution (50 mL)
  4. customthe organic layer was separated
  5. dry with materialdried over MgSO4
  6. concentrationconcentrated in vacuo
  7. customThe residue was purified by silica gel column chromatography
  8. washeluting with 0-50% EtOAc/hexanes

Sources & evidence

ORD record
ord-40f042dbcdc646aba9d82571f03c4c4b
Source dataset
uspto-grants-2015_11
Patent number
US09181273B2

Reaction notes

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