Hydrochloric Acid → 4-((3,4-Difluorophenyl)ethynyl)benzoic acid

HRID 533711Notes

Reaction equation

HRID 533711 reaction equation
I[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8]CC)=[O:7])=[CH:4][CH:3]=1.[F:13][C:14]1[CH:15]=[C:16]([C:21]#[CH:22])[CH:17]=[CH:18][C:19]=1[F:20].C(NCC)C.[Li+].[OH-].Cl>CN(C=O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[F:13][C:14]1[CH:15]=[C:16]([C:21]#[C:22][C:2]2[CH:3]=[CH:4][C:5]([C:6]([OH:8])=[O:7])=[CH:11][CH:12]=2)[CH:17]=[CH:18][C:19]=1[F:20]

Participants

10

Reactant 5

HCID 313Hydrochloric AcidHCID 3939Lithium HydroxideHCID 8021DiethylamineHCID 142891Ethyl 4-iodobenzoateHCID 138784543,4-Difluorophenylacetylene

Product 1

HCID 575752964-((3,4-Difluorophenyl)ethynyl)benzoic acid

Reagents, catalysts & solvents 4

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)CatalystHCID 178418397HCID 178418397, compoundCatalystHCID 962WaterSolventHCID 6228DimethylformamideSolvent

Conditions

Temperature
60 °C

Procedure

To a solution of ethyl 4-iodobenzoate (5.0 g, 18.1 mmol) in DMF (15 mL) was added 3,4-difluorophenylacetylene (2.99 g, 21.7 mmol), Pd(Ph3P)4 (520 mg, 0.45 mmol), CuI (173 mg, 0.90 mmol) and diethylamine (3 mL). The reaction vessel was sealed and heated at 60° C. for 1 h in a microwave reactor. The reaction was cooled to room temperature, diluted with EtOAc:hexanes (2:1, 150 mL) and washed with water (2×100 mL) and brine (100 mL). The organic phase was dried over MgSO4, filtered and concentrated under vacuum. The crude product was dissolved in THF (60 mL) added MeOH (14 mL) and a solution of LiOH (1.52 g, 36.2 mmol) in water (14 mL). The reaction was stirred at room temperature and for 4 h. The reaction was acidified with 1 N HCl (60 mL) and 4-((3,4-difluorophenyl)ethynyl)benzoic acid was isolated (2.45 g, 57%) as a white solid; 1H-nmr (400 MHz, d6-DMSO) δ 7.96 (d, J=8.5 Hz, 2H), 7.73 (td, J=8.5, 2.0 Hz, 1H), 7.67 (d, J=8.5 Hz, 2H), 7.55-7.43 (m, 2H); LC (290 nM) 5.08 min (>98%); MS (ESI) m/z=258.7.

Workup

  1. customThe reaction vessel was sealed
  2. temperatureThe reaction was cooled to room temperature
  3. washwashed with water (2×100 mL) and brine (100 mL)
  4. dry with materialThe organic phase was dried over MgSO4
  5. filtrationfiltered
  6. concentrationconcentrated under vacuum
  7. dissolutionThe crude product was dissolved in THF (60 mL)
  8. additionadded MeOH (14 mL)

Sources & evidence

ORD record
ord-0e5902ee0d834454b7a95f595ae6e73c
Source dataset
uspto-grants-2014_10
Patent number
US08853392B2

Reaction notes

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