Carbon Dioxide → 4-Chloronicotinic acid

HRID 1521813Notes

Reaction equation

HRID 1521813 reaction equation
C(NC(C)C)(C)C.C([Li])CCC.[Cl:13][C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1.[C:20](=[O:22])=[O:21]>C1COCC1>[Cl:13][C:14]1[C:19]([C:20]([OH:22])=[O:21])=[CH:18][N:17]=[CH:16][CH:15]=1

Participants

6

Reactant 4

HCID 280Carbon DioxideHCID 7912DiisopropylamineHCID 122884-ChloropyridineHCID 178418339Butyllithium

Product 1

HCID 8182294-Chloronicotinic acidYield 57%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Procedure

4-Chloropyridine hydrochloride (25 g) is neutralized with aq. Na2CO3 (10%) and extracted with DCM. The organic layer is separated, dried over Na2SO4 and concentrated under reduced pressure to afford 4-chloropyridine (19 g). To a solution of diisopropylamine (31 mL, 217.6 mmol) in dry THF is added n-butyllithium (115 mL, 184.1 mmol) dropwise at −78° C. under nitrogen. After 30 min, a solution of 4-chloropyridine (19 g, 167.4 mmol) in dry THF is slowly added under nitrogen. The reaction mixture is further stirred for 1 h at −78° C. before addition of solid CO2, let warmed to RT and stirred at RT for 12 h under nitrogen. After this time, reaction mixture is concentrated under reduced pressure and acidified with aq. HC1 solution (1.5 N) under ice-cooled condition. Precipitate is filtered under reduced pressure and dried overnight under vacuum to afford 15 g (57%) of the title compound. 1H NMR (DMSO-d6, 400 MHz): δ 6 13.83 (bs, 1H), 8.92 (s, 1H), 8.64-8.63 (d, J=5.4 Hz, 1H), 7.66-7.65 (d, J=5.4 Hz, 1H).

Workup

  1. customAfter this time, reaction mixture
  2. concentrationis concentrated under reduced pressure
  3. temperaturecooled condition
  4. filtrationPrecipitate is filtered under reduced pressure
  5. customdried overnight under vacuum

Sources & evidence

ORD record
ord-2a1bf9bef15a404298e8205cddcdc50c
Source dataset
uspto-grants-2015_07
Patent number
US09073940B2

Reaction notes

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