Dimethylformamide → Tert-butyl 4-formyl-2-methylbenzoate

HRID 1522786Notes

Reaction equation

HRID 1522786 reaction equation
[C:1]([O:5][C:6](=[O:15])[C:7]1[CH:12]=[CH:11][C:10](Br)=[CH:9][C:8]=1[CH3:14])([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.CN([CH:24]=[O:25])C>O1CCCC1>[CH:24]([C:10]1[CH:11]=[CH:12][C:7]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:15])=[C:8]([CH3:14])[CH:9]=1)=[O:25]

Participants

5

Reactant 3

HCID 6228DimethylformamideHCID 53432590tert-Butyl 4-bromo-2-methylbenzoateHCID 178418339Butyllithium

Product 1

HCID 59563495Tert-butyl 4-formyl-2-methylbenzoateYield 98.4%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
-100 °C

Procedure

To a solution of 4-bromo-2-methyl-benzoic acid tert-butyl ester (500 g, 1.8 mol) in tetrahydrofuran (5 L) was added n-butyl lithium (1.6 M solution, 1.4 L, 2.2 mol) at such a rate that the reaction temperature is between −95° C. to −100° C. After completion of the addition, the reaction mixture was stirred for 30 min at −100° C. and monitored by quenching the reaction mixture with water and following the product by TLC. After complete conversion, DMF (170 ml, 2.2 mol) was added to the reaction mixture and after 15 min the reaction mixture was quenched with ammonium chloride (sat. solution, 5 L). The organic layers were separated at room temperature and the aqueous layer was extracted with ethyl acetate (3×2 L). The combined organic layer was washed with water (3×5 L), dried over sodium sulphate and concentrated to yield tert-butyl 4-formyl-2-methyl-benzoate (390 g, 96% isolated yield, 75-78% HPLC purity). The crude product was used as such without any further purification for the next step. 1H-NMR (CDCl3, 400 MHz): δ in ppm=1.59 (s, 9 H), 2.61 (s, 3 H), 7.71 (d, 2 H), 7.92 (d, 1 H), 10.01 (s, 1 H).

Workup

  1. customis between −95° C. to −100° C
  2. additionAfter completion of the addition
  3. customby quenching the reaction mixture with water
  4. customwas quenched with ammonium chloride (sat. solution, 5 L)
  5. customThe organic layers were separated at room temperature
  6. extractionthe aqueous layer was extracted with ethyl acetate (3×2 L)
  7. washThe combined organic layer was washed with water (3×5 L)
  8. dry with materialdried over sodium sulphate
  9. concentrationconcentrated

Sources & evidence

ORD record
ord-6e4a548530e742d3b2e859359cd17a6d
Source dataset
uspto-grants-2015_07
Patent number
US09078444B2

Reaction notes

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