Synthesis: Sulfonylated Pyridines

Sulfonyl pyridines have utility both as constituents of bioactive molecules and as synthetic intermediates.  Typical methods for their preparation have suffered from the use of odiferous thiols, capricious oxidation steps, poor atom economy, and production of significant amounts of hazardous waste.  Scientists in process research at Merck recently published a nice, straightforward, and one-pot approach which addresses all of these issues.Their method involves direct displacement of chloropyridines (they do also demonstrate that the methodology applies equally to other halides and triflates) with sulfinic acid salts in the presence of tetrabutylammonium chloride (TBACl).  [The TBACl is postulated to enhance the solubility of the sulfinic acid salt in the solvent used (Dimethylacetamide, DMAc)].  The method works equally well for electron-deficient, electron-neutral, and electron-rich chloropyridines and is operationally straightforward (See examples above – an equivalent of HCl is required to protonate, and hence activate, the pyridine in the case of the latter two classes of substrate).  The products are isolated in high yield simply by quenching with water and filtration of the resulting slurry.

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2 Responses to Synthesis: Sulfonylated Pyridines

  1. milkshake says:

    I would be reluctant to use 2-sulfonyl subst pyridines in a drug because they are just as good electrophiles as 2-chloropyridines, if not better. I remember using 4-chloro-2-sulfonyl substituted pyrimidine with additonal chlorine in 4 postion for ArN substitutions with thiols and it the displacement of sulfone with thiol/NEt3 went at 0 C, and chlorine in the 4-position remained intact. (Normally the chlorine in the 4 position of 2,4-dichloropyrimidine is the more reactive one)

  2. mcb says:

    That’s a good point milkshake and they actually comment in the paper on the fact that some of the 2- and 4-substituted sulfonylated adducts they looked at were more reactive than the parent chloropyridines (they suggest this as a potential way of switching in alternative sulfonyl groups and give one example). I guess it will depend on the overall substitution pattern and the nature of the sulfonyl group as well but definitely a concern to consider. It’d be interesting to know what they applied this methodology to.

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