Diethyl Malonate → Diethyl (3-fluoro-2-pyridyl)malonate

HRID 523264Notes

Reaction equation

HRID 523264 reaction equation
F[C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][N:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[C:15]([O:23][CH2:24][CH3:25])(=[O:22])[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18]>CS(C)=O.CCOC(C)=O>[F:8][C:7]1[C:2]([CH:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:15]([O:23][CH2:24][CH3:25])=[O:22])=[N:3][CH:4]=[CH:5][CH:6]=1

Participants

6

Reactant 3

HCID 7761Diethyl MalonateHCID 10796Cesium carbonateHCID 27831762,3-Difluoropyridine

Product 1

HCID 57950221Diethyl (3-fluoro-2-pyridyl)malonateYield 60.3%

Reagents, catalysts & solvents 2

HCID 679Dimethyl SulfoxideSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
100 °C

Procedure

A mixture of 2,3-difluoropyridine (2.00 g, 17.4 mmol), Cs2CO3 (13.59 g, 41.7 mmol) and diethyl malonate (6.68 g, 41.7 mmol) in DMSO (19 mL) was heated at 100° C. for 4.5 h. The mixture was poured onto ice, diluted with EtOAc, and the organic phase was separated, washed sequentially with water and brine, and dried and concentrated. The residue was purified by column chromatography on silica gel (80 g), eluting with EtOAc-hexanes (sequentially 10%, 20% and 30%), to provide diethyl 2-(3-fluoropyridin-2-yl)malonate as a pale colored oil (2.68 g, 60% yield). 1H NMR (400 MHz, chloroform-d) δ 8.42 (dt, J=4.6, 1.3 Hz, 1H), 7.43 (ddd, J=9.4, 8.3, 1.4 Hz, 1H), 7.30 (dt, J=8.5, 4.3 Hz, 1H), 5.09 (d, J=1.1 Hz, 1H), 4.30 (q, J=7.0 Hz, 4H), 1.33-1.26 (m, 6H).

Workup

  1. additionThe mixture was poured onto ice
  2. customthe organic phase was separated
  3. washwashed sequentially with water and brine
  4. customdried
  5. concentrationconcentrated
  6. customThe residue was purified by column chromatography on silica gel (80 g)
  7. washeluting with EtOAc-hexanes (sequentially 10%, 20% and 30%),

Sources & evidence

ORD record
ord-142b7053e592453ab1b6e8df89dd5274
Source dataset
uspto-grants-2016_05
Patent number
US09334290B2

Reaction notes

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