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.