Org Prep Daily

November 15, 2006

4-(2′,4′-difluorobenzyl)-piperidine hydrochloride

Filed under: procedures — milkshake @ 6:52 pm


TFA 100mL was added to 1-acetyl-4-(2′,4′-difluorobenzoyl)-piperidine 5.00g (Astatech; 18.7 mmol) slurry in triethylsilane 20mL. The mixture was stirred at RT for 30 min, then cooled to -20C on salt/ice bath under argon. Boron trifluoride etherate 15mL (119 mmol) was added dropwise over 5 min and the mixture was stirred at -20 to -10C for 4 hours, then at -10 to -5C for 1 hour. The reaction mixture was concentrated to a small volume from ambient bath, the residue was diluted with water 50mL and ether 150mL. Saturated NaHCO3 solution 300mL was slowly added (CO2 evolution) and the mixture was stirred at RT overnight (16 hours). The mixture was extracted twice with ether (2x200mL), the extracts were washed with brine 200mL, combined, dried (MgSO4) and evaporated. The residue was purified on a column of silica (80g) in a EtOAc gradient in hexane, 0 to 100%EtOAc, followed by straight EtOAc.

The obtained pure 1-acetyl-4-(2′,4′-difluorobenzyl)-piperidine was dissolved in conc HCl 80mL. Water 80mL was added and the mixture was refluxed on oil bath (140C) for 5 hours. The obtained solution was cooled and evaporated,  the residue was re-evaporated from a 2:1 chloroform-methanol mixture (50mL) and dried on highvac. The residue was suspended in ethyl acetate 10mL, TBME 200mL was added, the slurry was briefly sonicated (5 min), filtered quickly (hygroscopic!), the precipitate washed with TBME and dried on highvac. Y=4.212g (91%Y) of a white solid, pure by HPLC, LC/MS(+cESI): 212(M+1)

BF3 in TFA is much stronger acid than TFA alone. (Without BF3 the reduction stops at benzylic alcohol in this case). Addition of BF3 etherate is also advantageous for easier workup on large scale: TES-F is much easier to evaporate than TES-OH.


  1. I didn’t even know that this reduction is possible. I assume it only works for benzylic ketones (acetophenones/benzophenones).

    Comment by Jordan — November 16, 2006 @ 11:45 am

  2. Et3SiH reduces carbocations. So you need aryl ketones and benzylic/allylic alcohols or electron-rich olefins. The ease of reduction depends on the ease of carbocation formation. This is quite good system also for reducing indoles to indolines.

    Comment by milkshake — November 16, 2006 @ 1:45 pm

  3. I’ve tried those conditions on several substrates with various levels of success; often stops at the benzylic alcohol stage like milkshake observes, or the BF3 chews it up to basline garbage. Indoles can also be reduced to indolines quite nicely with NaCNBH3…

    Comment by Jose — November 16, 2006 @ 5:32 pm

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