Diethyl Malonate → Ethyl {3,4-difluoro-5-[(phenylmethyl)oxy]phenyl}acetate
Reaction equation
Br[C:2]1[CH:3]=[C:4]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:5]([F:9])=[C:6]([F:8])[CH:7]=1.C(OCC)(=O)[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21].C([O-])([O-])=O.[Cs+].[Cs+].O1CCOCC1>CC(P(C(C)(C)C)C(C)(C)C)(C)C.CC(P(C(C)(C)C)C(C)(C)C)(C)C.[Pd].CCOC(C)=O.O>[F:8][C:6]1[CH:7]=[C:2]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:3]=[C:4]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:5]=1[F:9]Participants
8
Reactant 4
Product 1
Reagents, catalysts & solvents 3
Conditions
- Temperature
- 80 °C
Procedure
5-bromo-1,2-difluoro-3-[(phenylmethyl)oxy]benzene (10 g, 33.3 mmol), diethyl propanedioate (6.9 g, 43.3 mmol), Cs2CO3 (108 g, 333 mmol), and dioxane (200 mL) were combined in a sealed flask and N2 was bubbled through the solution for 15 minutes. Pd(t-Bu3P)2 (1.7 g, 3.33 mmol) was then added and the flask was sealed. The solution was heated to 80° C. and stirred vigorously. After 8 h, the temperature was increased to 120° C. After 3 days, it was cooled and H2O and EtOAc were added. The aqueous layer washed with EtOAc (3×). The combined organic extracts were concentrated, and purified by Biotage (in two batches) to afford 1.82 g of the title compound (21%).
Workup
- customN2 was bubbled through the solution for 15 minutes
- customthe flask was sealed
- temperaturethe temperature was increased to 120° C
- waitAfter 3 days
- temperatureit was cooled
- washThe aqueous layer washed with EtOAc (3×)
- concentrationThe combined organic extracts were concentrated
- custompurified by Biotage (in two batches)
Sources & evidence
- ORD record
- ord-70dcfc668a134e23b23de828cc399535
- Source dataset
- uspto-grants-2011_03
- Patent number
- US07902394B2
Reaction notes
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