Dimethylformamide → 4-Fluoro-2,6-dimethoxybenzaldehyde
Reaction equation
[F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([O:10][CH3:11])[CH:3]=1.CN([CH:15]=[O:16])C.O=P(Cl)(Cl)Cl.[OH-].[Na+]>>[F:1][C:2]1[CH:3]=[C:4]([O:10][CH3:11])[C:5]([CH:15]=[O:16])=[C:6]([O:8][CH3:9])[CH:7]=1Participants
Procedure
A cooled (−5° C.) mixture of commercially available 1-fluoro-3,5-dimethoxybenzene (500 mg; 3.20 mmol; 1.0 equiv.) and DMF (4.680 g; 64.03 mmol; 20.0 equiv.) was treated dropwise with POCl3 (2.454 g; 16.01 mmol; 5.0 equiv.). This mixture was further stirred at rt for 1.5 h, and was then heated to 60° C. for 3 h. After cooling to rt, ice-water (50 ml) and a solution of 2.5 M aq. NaOH (24 ml) were successively added. After extractions with AcOEt (3×30 ml), the mixed organic layers were dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure. Purification by FC (heptane/AcOEt=1/1) afforded 4-fluoro-2,6-dimethoxybenzaldehyde as a yellow solid. LC-MS (conditions A): tR=0.50 min.; [M+H]+: 185.10 g/mol. According to 1H-NMR (CDCl3; 400 MHz), this product also contained 19% of the regioisomer 2-fluoro-4,6-dimethoxybenzaldehyde. This minor regioisomer could be advantageously removed after further chemical transformations of the isomeric mixture.
Workup
- temperatureA cooled
- temperaturewas then heated to 60° C. for 3 h
- temperatureAfter cooling to rt
- extractionAfter extractions with AcOEt (3×30 ml)
- dry with materialthe mixed organic layers were dried over anh. MgSO4
- filtrationfiltered
- concentrationconcentrated to dryness under reduced pressure
- customPurification by FC (heptane/AcOEt=1/1)
Sources & evidence
- ORD record
- ord-ad65805a274448ef8cd8787ff36d9657
- Source dataset
- uspto-grants-2016_01
- Patent number
- US09242970B2
Reaction notes
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