Boron trifluoride etherate → 3-Bromo-4-cyanobenzoic acid

HRID 1455133Notes

Reaction equation

HRID 1455133 reaction equation
N[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8]CC)=[O:7])=[CH:4][C:3]=1[Br:13].N(OC(C)(C)C)=O.B(F)(F)F.CCOCC.[Cu][C:31]#[N:32].[C-]#N.[Na+]>C(Cl)Cl.C(OCC)C.O.CCOC(C)=O>[Br:13][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:2]=1[C:31]#[N:32])[C:6]([OH:8])=[O:7]

Participants

10

Reactant 5

HCID 8000Boron trifluoride etherateHCID 8929Sodium CyanideHCID 10906Tert-Butyl nitriteHCID 242793ethyl 4-amino-3-bromobenzoateHCID 178418546HCID 178418546, compound

Product 1

HCID 534255203-Bromo-4-cyanobenzoic acidYield 76%

Reagents, catalysts & solvents 4

HCID 962WaterSolvent2×HCID 3283Diethyl EtherSolventHCID 6344DichloromethaneSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
0 °C

Procedure

A solution of ethyl 4-amino-3-bromobenzoate (23.5 g, 96.3 mmol) in methylene chloride at −10° C. is treated dropwise with tert-butyl nitrite (14.0 mL, 118.4 mmol), followed by boron trifluoride diethyl etherate (18.4 mL, 146.5 mmol). The reaction mixture is allowed to come to room temperature, stirred for 4 h, diluted with ethyl ether and filtered. The filtercake is dried, dispersed in toluene, cooled to 0° C., treated with a solution of copper (I) cyanide (11.5 g, 129.2 mmol) and sodium cyanide (15.8 g, 323.1 mmol) in water, stirred at 0° C. for 30 min., warmed to 60° C., stirred for 1 h, cooled to room temperature and diluted with EtOAc and water. The organic phase is separated, dried over MgSO4 and concentrated in vacuo. The resultant residue is crystallized from ethyl ether/hexanes to give the ethyl ester of the title compound as an off-white solid, 18.6 g (76% yield). A solution of this ester (8.5 g, 33.6 mmol) in THF is treated with a solution of NaOH (30 mL, 2.5 N) and ethanol, stirred for 20 h, acidified with 2N HCl and extracted with ethyl ether. The ether extracts are combined, dried over MgSO4 and concentrated in vacuo. The resultant residue is crystallized from ethyl ether/hexanes to afford the title compound as a beige solid, 6.81 g (90% yield), identified by HNMR and mass spectral analyses. MS m/e 223 (M−H)+; 1H NMR (400 MHz, DMSO-d6) δ 8.05 (dd, J=9.76, 1.37 Hz 1H), 8.09 (d, J=8.08 Hz, 1H), 8.29 (d, J=1.37 Hz, 1H).

Workup

  1. customto come to room temperature
  2. filtrationfiltered
  3. customThe filtercake is dried
  4. additiondispersed in toluene
  5. stirringstirred at 0° C. for 30 min.
  6. temperaturewarmed to 60° C.
  7. stirringstirred for 1 h
  8. temperaturecooled to room temperature
  9. customThe organic phase is separated
  10. dry with materialdried over MgSO4
  11. concentrationconcentrated in vacuo
  12. customThe resultant residue is crystallized from ethyl ether/hexanes

Sources & evidence

ORD record
ord-6f498ee89785469cb11bfe7a34240430
Source dataset
uspto-grants-2009_01
Patent number
US07482349B2

Reaction notes

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