Diethyl Malonate → 2-(6-Cyano-2,3-difluorophenyl)malonic acid diethyl ester
Reaction equation
[H-].[Na+].[C:3]([O:11][CH2:12][CH3:13])(=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].F[C:15]1[C:22]([F:23])=[C:21]([F:24])[CH:20]=[CH:19][C:16]=1[C:17]#[N:18]>C1COCC1.Cl>[CH2:12]([O:11][C:3](=[O:10])[CH:4]([C:15]1[C:16]([C:17]#[N:18])=[CH:19][CH:20]=[C:21]([F:24])[C:22]=1[F:23])[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH3:13]Participants
Conditions
- Temperature
- 2.5 °C
Procedure
To a mixture of NaH (16.6 g, 657 mmol, dry) in THF (150 mL) was added dropwise over 30 min with stirring at 0-5° C. a solution of diethyl malonate (104.7 g, 654 mmol) in THF (120 mL). To this translucent mixture was then immediately added a solution of 2,3,4-trifluorobenzonitrile (47.7 g, 304 mmol) in THF (50 mL) dropwise with stirring at 0-5° C. The ice bath was then removed and the mixture allowed to stir at room temperature for 4 days. The clear yellow reaction was then diluted with 1 M HCl (350 mL), 4 N HCl was added to pH ˜2 (paper), and the mixture was extracted with 1:1 ether/hexanes (1×350 mL, 1×200 mL). The combined organic layers were washed with brine (1×300 mL), dried (Na2SO4), and concentrated to afford the title compound (88.1 g, 98%) as a 1.35:1 mixture of regioisomers. 1H NMR of major (desired) regioisomer (300 MHz, CDCl3) δ 7.51 (ddd, J=8.7 Hz, 4.6 Hz, 1.8 Hz, 1H), 7.29 (dt, J=8.9 Hz, 7.2 Hz, 1H), 5.12 (s, 1H), 4.35-4.20 (m, 4H), 1.31 (t, 7.2 J=Hz, 6H).
Workup
- additionwas added dropwise over 30 min
- customThe ice bath was then removed
- stirringto stir at room temperature for 4 days
- customThe clear yellow reaction
- additionwas added to pH ˜2 (paper)
- extractionthe mixture was extracted with 1:1 ether/hexanes (1×350 mL, 1×200 mL)
- washThe combined organic layers were washed with brine (1×300 mL)
- dry with materialdried (Na2SO4)
- concentrationconcentrated
Sources & evidence
- ORD record
- ord-f10ebcaa552c4afda62e1fd84fcb6279
- Source dataset
- uspto-grants-2009_06
- Patent number
- US07550474B2
Reaction notes
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