Org Prep Daily

October 8, 2006

2-(2′,6′-dichlorophenyl)-2,2-difluoroacetyl chloride

Filed under: procedures — milkshake @ 9:41 pm

difac.gif

In an oven-dried flask filled with Ar gas, 6.822g of 2,6-dichloro-iodobenzene  (25.0mmol, Transworld) together with copper “activated nanopowder” 4.626g (72.8mmol, Aldrich) was suspended in anhydrous DMSO 150mL and the mixture was sparged with Ar gas for 10 min. Ethylester of bromodifluoroacetic acid 6.090g (30mmol, TCI-US) was added and the mixture was stirred under Ar at 60C for 11 hours (overnight). The reaction mixture was diluted with toluene 350mL, stirred for 15 min, filtered through a large medium-porosity glass Buchner funnel and the solids were washed with toluene. The filtrates were quickly washed with saturated ammonium chloride solution 400mL and then with sat. NaCl 200mL, the aqueous phases were re-extracted with toluene 150mL. The combined  extracts were dried (MgSO4) and evaporated on rotavap with help of oil pump. The residue was dried on higvac. [The ethyl ester intermediate is moisture-sensitive – it should not be allowed to sit in a sep funnel because the resulting acid is quite water-soluble].

The obtained crude Et-ester 6.67g (containing some iodo starting material) was dissolved in THF 100mL, water 60mL and LiOH-monohydrate 2.10g (50 mmol, Aldrich) was added and the mixture was stirred for 1 hour. The mixture was diluted with water 20mL and concentrated on rotavap to remove all THF. The residue was diluted with water 60mL, the precipitated unreacted iodo- starting material was removed by filtration. The filtrates were acidified with 4M HCl 50mL. The resulting emulsion was extracted three times with dichloromethane (3x150mL), the combined extracts were dried by adding activated 4A mol sieves powder, stirred for 10 min, filtered through Celite and evaporated. The residue was dried on higvac. Y=3.731g (62%) of a hygroscopic white crystalline solid

1H(CDCl3, 400MHz): 10.123(br s, 1H), 7.381(dAA’B, 7.8Hz, 2H), 7.305(dd, 9.0Hz, 7.0Hz, 1H); 13C(CDCl3, 100MHz): 166.94(t, 33Hz), 134.77, 131.87(2C), 130.55(2C), 127.73(t, 23Hz), 113.10(br t, 258Hz); 19F(CDCl3, 376.5MHz): -97.794(s, 2F)

The difluoroacid 3.696g (15.33 mmol) with added 2 drops of DMF was dissolved in dichloromethane 15mL with a gentle reflux. The mixture was placed on ambient bath and oxalyl chloride 2.7mL (30.9 mmol) was added (gas evolution). The flask was equipped with a Drierite-filled outlet tube and the mixture was stirred for 18 hours (overnight). The reaction mixture was concentrated on rotavap and then briefly dried at RT at 0.5 Torr. The residue was distilled on Kugelrohr apparatus on higvac (0.5 Torr) with air bath temperature set to 100C. Y=3.724g (93.5%) of a colorless, nasty-smelling liquid

1H(CDCl3, 400MHz): 7.418(m, 2H), 7.391(m, 1H); 19F(CDCl3, 376.5MHz): -93.668(s, 2F)

The Ulman coupling of BrCF2CO2Et with aryl iodides is a good, quite general method for making these alpha-difluorinated phenylacetic acids. The reaction proceeds through CuCF2CO2Et. The organocopper reagent is best made in situ from the bromoester. [The reagent could be pre-made as a stock solution if ICF2CO2Et is used at RT but this is inconvenient because the iododifluoroester has to be made – from the commercial bromodifluoroester by Zn matallation/I2 quench (and the yield of the prep is underwhelming). Finkelstein direct halogen exchange does not work in this case.]

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