Dimethylformamide → 5-Bromo-2-fluoro-3-methylbenzaldehyde

HRID 1502900Notes

Reaction equation

HRID 1502900 reaction equation
C(NC(C)C)(C)C.C([Li])CCC.[Br:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[C:16]([CH3:21])[CH:15]=1.CN([CH:25]=[O:26])C>C1COCC1>[Br:13][C:14]1[CH:15]=[C:16]([CH3:21])[C:17]([F:20])=[C:18]([CH:19]=1)[CH:25]=[O:26]

Participants

6

Reactant 4

HCID 6228DimethylformamideHCID 7912DiisopropylamineHCID 1235275-Bromo-2-fluorotolueneHCID 178418339Butyllithium

Product 1

HCID 532168945-Bromo-2-fluoro-3-methylbenzaldehydeYield 64%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
-78 °C

Procedure

To a stirred solution of di-isopropyl amine (4.01 g, 39.88 mmol) in THF (20 mL) was added n-butyl lithium (1.6 M in hexane) (19.9 mL, 31.91 mmol) at −78° C. slowly dropwise over the period of 10 min, the reaction mixture was stirred at −78° C. for 30 min. A solution of 4-bromo-1-fluoro-2-methylbenzene (5.0 g, 26.6 mmol) in THF (30.0 mL) was added at −78° C., and the reaction mixture was stirred for 1 h at the same temperature. DMF (5.0 mL) was added and stirred at −78° C. for another 30 min. The reaction was monitored by TLC; then the reaction mixture was quenched with 1N HCl solution (aq) at 0° C. The aqueous layer was extracted with diethyl ether, washed with water and saturated brine solution. The combined organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain the crude compound purified by flash column chromatography (SiO2, 100-200 mesh; eluting with 5% ethyl acetate/pet ether) to afford the title compound as a white solid (3.6 g, 64%); mp 48-50° C.: 1H NMR (400 MHz, CDCl3) δ 8.33 (s, 1H), 8.22 (s, 1H), 7.67 (s, 1H), 7.60 (s, 1H), 6.75 (dd, J=17.6, 10.8 Hz, 1H), 5.92 (dd, J=17.6, 10.8 Hz, 1H), 5.52 (d, J=17.6 Hz, 1H), 2.21 (s, 3H); ESIMS m/z 211.35 ([M−H]−).

Workup

  1. stirringthe reaction mixture was stirred for 1 h at the same temperature
  2. stirringstirred at −78° C. for another 30 min
  3. customthen the reaction mixture was quenched with 1N HCl solution (aq) at 0° C
  4. extractionThe aqueous layer was extracted with diethyl ether
  5. washwashed with water and saturated brine solution
  6. dry with materialThe combined organic layer was dried over anhydrous Na2SO4
  7. concentrationconcentrated under reduced pressure
  8. customto obtain the crude compound
  9. custompurified by flash column chromatography (SiO2, 100-200 mesh; eluting with 5% ethyl acetate/pet ether)

Sources & evidence

ORD record
ord-fb5562cc60d6485395b3274350b1e173
Source dataset
uspto-grants-2015_12
Patent number
US09211280B2

Reaction notes

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