Org Prep Daily

October 25, 2006

2-(2′,6′-dichlorophenyl)-2-fluoroacetic acid

Filed under: procedures — milkshake @ 2:17 pm


2,6-dichlorobenzaldehyde 7.000g (40.0mmol) and anhydrous ZnI2 65mg was dissolved in anh dichloromethane 10mL with gentle heating on heat gun under Ar. The solution was placed on ambient water bath and TMSCN 5.60mL (42mmol) was added dropwise over 10 min period. The mixture was stirred at RT for 90 min, then cooled on ice bath. Neat DAST 6.00mL (45 mmol, Aldrich) was carefully added dropwise over 10 min (exothermic!). The mixture was stirred at 0C for 1 hour and then at RT for 2 hours. The reaction mixture was diluted with a common-grade dichloromethane (100mL), cooled to 0C and carefully quenched by addition of ice-cold water 50mL followed by 2M HCl 50mL. The mixture was stirred at RT for 15 min, separated, the aqueous phases were re-extracted with dichloromethane (2x20mL). The extracts were washed with sat. NaHCO3 (100mL), combined, dried (MgSO4) and evaporated. The residue was purified on a column of silica in a mixture hexane-ethyl acetate 40:3. The purified oily product was placed into a freezer overnight and the obtained crystalline mass was then dried on highvac. Y=6.136g (75%) of the fluoronitrile as a sticky, low-melting light tan solid. 1H(CDCl3, 400MHz): 7.428(m, 3H), 6.826(d, 44Hz, 1H); 19F(CDCl3, 376.6MHz): -179.58 (d, 45Hz, 1F)

The fluoronitrile intermediate 6.130g (30.04mmol) was combined with 50% H2SO4 (540g) in a 1L round flask and the heterogennous mixture was stirred on oil bath at 80-90C for 18 hours. The resulting heterogennous mixture was cooled to RT, diluted with water 0.5L and chloroform 300mL, separated, the aqueous phase was re-extracted twice with chloroform (2x100mL). The org extracts were washed with brine 400mL, combined, dried (MgSO4) and evaporated. The obtained yellow semi-solid residue was suspended in ether 100mL, a solution of potassium carbonate 5.0g in water 200mL was added and the mixture was stirred for 30 min. The aqueous phase was separated, the org phase was re-extracted twice with water (2x100mL). The aqueous extracts were washed with ether (100mL), combined and acidified with 4M HCl (gas evolution) . Extraction with chloroform (150 mL, then 2x50mL) followed by washing the org. extracts with brine, drying with MgSO4 and evaporating the extracts provided a pure product that solidified on highvac. Y=3.094g (46%) of a white crystalline solid.

1H(CDCl3, 400MHz): 8.357(very br s, 1H), 7.377(m, 2H), 7.337(m, 1H), 6.582(d, 45Hz, 1H); 19F(CDCl3, 376.5MHz): -183.66(d, 45Hz, 1F)

TMS-CN is very poisonous (generates HCN instantly with moisture). DAST is extremely corrosive, it reacts with water with huge exotherm and also generates HF. Always use good gloves (if using thin disposable gloves, double them), work in the hood, do not spill and add it slowly, to avoid “bumping”.  Having a face shield (or a hood sash down) is a good idea, especialy with larger scales. HF burns are exceptionaly nasty and painful, Ca-gluconate ointment is used as antidote.

TMS-cyanohydrine formation followed by OTMS exchange for F with DAST or Deoxyfluor reagent is a convenient alternative to enolate electrophilic fluorination. The next step – alpha fluoronitrile hydrolysis – has to be done rather carefully: using a more concentrated sulfuric acid or increasing the reaction temperature produces the o,o-dichloromandelic acid due to alpha F hydrolysis.


  1. Do you have any other contributors so far? You’re pretty visible
    in other people’s blogrolls, but maybe some active recruitment
    is in order.

    Comment by Eugen Leitl — October 30, 2006 @ 5:23 am

  2. I don’t know about advertising – I hoped that somebody reading this stuff would volunteer but if not the site will eventualy turn into Org Prep Monthly.

    Comment by milkshake — November 6, 2006 @ 11:06 am

  3. The zinc iodide that you used – did you make it fresh? Zinc iodide is pretty hygroscopic and I have had problems with ZnI2 that has absorbed a ton of water. I used to make my own by just reacting zinc with iodine in THF and completely removing the solvent.

    Comment by Vinod Jairaj — April 9, 2009 @ 5:28 am

    • I used ZnI2 straight from Aldrich bottle. It is little hygroscopic but not terribly so – many common chemicals (for example sodium borohydride or cesium carbonate) are worse. As long as your ZnI2 is still solid I would not worry about it – you need only very little of it to catalyze the reaction and TMSCN is a pretty good dehydrating reagent.

      Comment by milkshake — April 9, 2009 @ 6:32 am

  4. Hi MS,

    I need to convert a benzylic nitrile (attached to a bicyclic pyrimidinone ring system) into the corresponding primary amide.

    Please suggest me conditions which does not affect the ring system..



    Comment by marto — May 4, 2009 @ 9:40 am

  5. If your system can tolerate basic media (pH=13) I think the mildest method is to use H2O2 with some LiOH.H2O in THF-water mix, cooled to 0C.

    The final concentration of peroxide in the react mix needs to be only about 5-10%

    Typically one would dissolve the material in THF, dilute it with about equal volume of 10-15% aqueous peroxide, cool on ice, then add some LiOH.H2O solid (just few equivs is enough) and stir for awhile at 0 C

    Comment by milkshake — May 4, 2009 @ 12:56 pm

  6. Thanks very much..Marto

    Comment by marto — May 6, 2009 @ 9:04 am

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