Hydrochloric Acid → 6-Bromo-2,3-difluorobenzaldehyde

HRID 2414210Notes

Reaction equation

HRID 2414210 reaction equation
CC1(C)CCCC(C)(C)N1.C([Li])CCC.[Br:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[C:19]([F:24])[CH:18]=1.CN([CH:28]=[O:29])C.Cl>O1CCCC1.O>[Br:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[C:19]([F:24])[C:18]=1[CH:28]=[O:29]

Participants

8

Reactant 5

HCID 313Hydrochloric AcidHCID 6228DimethylformamideHCID 130352,2,6,6-TetramethylpiperidineHCID 676754-Bromo-1,2-difluorobenzeneHCID 178418339Butyllithium

Product 1

HCID 98778516-Bromo-2,3-difluorobenzaldehydeYield 56.2%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 8028TetrahydrofuranSolvent

Procedure

A solution of 152 mmol of 2,2,6,6-tetramethylpiperidine and 152 mmol of n-butyllithium (1.6 M solution in n-hexane) in 280 ml of dry tetrahydrofuran is admixed with 145 mmol of 1-bromo-3,4-difluorobenzene at −75° C. This temperature is maintained for 4 hours, and then 174 mmol of DMF are added dropwise. The reaction mixture is then slowly thawed, hydrolyzed with water at −20° C., acidified using hydrochloric acid and extracted with tert-butyl methyl ether. The combined organic extracts are washed with saturated sodium chloride solution and dried using sodium sulfate. The solvent is removed under reduced pressure, and the raw product is purified by chromatography over silica gel (eluent: dichloromethane/n-heptane 1:1) and recrystallization from n-heptane, yielding 18 g (56%) of 2-bromo-5,6-difluorobenzaldehyde in the form of slightly yellow crystals.—M.p.: 40-43.5° C.—1H-NMR (400 MHz, CDCl3/TMS): δ=10.31 (dd, 4J(HF)=2 Hz, 5J(HF)=1.5 Hz, 1 H, CHO), 7.45 (ddd, 3J(HH)=9 Hz, 4J(HF)=4 Hz, 5J(HF)=2 Hz, 1 H, Har), 7.28 (ddd, 3J(HH)=9 Hz, 3J(HF)=9 Hz, 4J(HF)=8 Hz, 1 H, Har).—19F-NMR (376.5 MHz, 1H broad-band decoupled, CDCl3/CFCl3): δ=−136.4 (d, 3J=19.2 Hz), −139.2 (d, 3J=19.2 Hz).

Workup

  1. temperatureThis temperature is maintained for 4 hours
  2. extractionextracted with tert-butyl methyl ether
  3. washThe combined organic extracts are washed with saturated sodium chloride solution
  4. customdried
  5. customThe solvent is removed under reduced pressure
  6. customthe raw product is purified by chromatography over silica gel (eluent: dichloromethane/n-heptane 1:1) and recrystallization from n-heptane

Sources & evidence

ORD record
ord-608c07a583044f139214e34ffd3b6d43
Source dataset
uspto-grants-2004_11
Patent number
US06811832B2

Reaction notes

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