Acetone → 4-(1-Hydroxy-1-methyl-ethyl)-3-methyl-benzoic acid

HRID 1405373Notes

Reaction equation

HRID 1405373 reaction equation
Br[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[CH3:11].C([Li])CCC.[CH3:17][C:18]([CH3:20])=[O:19].Cl>O1CCCC1.[OH-].[Na+]>[OH:19][C:18]([C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[CH3:11])([CH3:20])[CH3:17]

Participants

7

Reactant 4

HCID 180AcetoneHCID 313Hydrochloric AcidHCID 821314-Bromo-3-methylbenzoic acidHCID 178418339Butyllithium

Product 1

HCID 681532454-(1-Hydroxy-1-methyl-ethyl)-3-methyl-benzoic acidYield 42.3%

Reagents, catalysts & solvents 2

HCID 8028TetrahydrofuranSolventHCID 14798Sodium HydroxideSolvent

Conditions

Temperature
-78 °C

Procedure

4-Bromo-3-methyl-benzoic acid (3.96 g, 18.4 mmol) was dissolved in tetrahydrofuran (100 mL) and the solution was cooled to −78° C. n-Butyllithium in hexanes (16.2 mL of 2.5 M, 41 mmol) was added dropwise over 20 minutes. The reaction mixture was allowed to stir for 30 minutes at −78° C. and then acetone (1.35 mL, 18.4 mmol) was added in a drop-wise manner. The reaction mixture was allowed to stir for 30 minutes at −78° C., and then it was allowed to warm to room temperature. The reaction mixture was then diluted with 100 mL of 1M aqueous sodium hydroxide. The organic layer was discarded and then the aqueous layer was made acidic with 4M aqueous hydrochloric acid. The aqueous layer was then extracted 3 times with ethyl acetate. The combined extracts were dried over sodium sulfate and then evaporated to dryness. The crude material was further purified on silica gel utilizing a gradient of 0-10% methanol in dichloromethane to give 4-(1-hydroxy-1-methyl-ethyl)-3-methyl-benzoic acid (1.51 g, 42%). 1H NMR (400 MHz, DMSO) δ 12.74 (s, 1H), 7.68 (dd, J=3.9, 2.5 Hz, 2H), 7.55 (d, J=8.7 Hz, 1H), 5.06 (s, 1H), 2.56 (s, 3H), 1.51 (s, 6H).

Workup

  1. additionwas added dropwise over 20 minutes
  2. stirringto stir for 30 minutes at −78° C.
  3. temperatureto warm to room temperature
  4. extractionThe aqueous layer was then extracted 3 times with ethyl acetate
  5. dry with materialThe combined extracts were dried over sodium sulfate
  6. customevaporated to dryness
  7. customThe crude material was further purified on silica gel utilizing a gradient of 0-10% methanol in dichloromethane

Sources & evidence

ORD record
ord-1321e9c13bef4f2e947e7ba23cc52e9d
Source dataset
uspto-grants-2014_12
Patent number
US08916565B2

Reaction notes

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