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DMSO – Pyridine-SO3 (Parikh-Doering)

Mechanism + Description

This widely used Swern variant uses pyridine-sulfur trioxide complex as an activating agent in a mechanism analogous to the Swern and Pfitzner-Moffat mechanisms.

General comments

These reagents are common in scale-up examples.

HSO4 is a common impurity in a commercial pyridine-SO3 complex. This can catalyze undesired side reactions, but can be effectively neutralized by the addition of extra pyridine to give 2 C5H5NH SO4.

Key references

Zanka, A.; Itoh, N.; Kuroda, S. Process Improvements in the Production of a Novel Non-Xanthine Adenosine A1 Receptor Antagonist. A “One-Pot” Horner-Emmons Isomerization Reaction. Org. Process Res. Dev. 1999, 3 (6), 394–399.

Waser, M.; Moher, E. D.; Borders, S. S. K.; Hansen, M. M.; Hoard, D. W.; Laurila, M. E.; LeTourneau, M. E.; Miller, R.D.; Phillips, M. L.; Sullivan, K. A.; et al. Process Development for a Key Synthetic Intermediate of LY2140023, a Clinical Candidate for the Treatment of Schizophrenia. Org. Process Res. Dev. 2011, 15 (6), 1266–1274.

Haycock-Lewandowski, S. J.; Wilder, A.; Åhman, J. Development of a Bulk Enabling Route to Maraviroc (UK-427,857), a CCR-5 Receptor Antagonist. Org. Process Res. Dev. 2008, 12 (6), 1094–1103.

Relevant scale-up example

Org. Process Res. Dev. 2006, 10 (1), 163-164.

Green Review

  1. Atom efficiency (by-products)
    Sulphur trioxide is oxidized to sulfate. Pyridine is recovered from the reaction unchanged, but never reused. The organic base is converted to the corresponding sulfate salt.
  2. Safety concerns
    This oxidation can be very exothermic. Me2S may off-gas from the reaction mixture.
  3. Toxicity and environmental/aquatic impact
    Pyridine is toxic to humans and the environment. SO3 is an acidic gas and contributes to acid rain. The DMS by-product occurs naturally in the environment, but it is an irritant, volatile, and has a disagreeable smell.
  4. Cost, availability & sustainable feedstocks
    Relatively cheap and available on-scale. Pyridine can also be purchased in polymer bound form, though at a cost premium.
  5. Sustainable implications
    Pyridine used to be made from coal tar and coal gasification, but greener routes from acetaldehyde and ammonia are now extensively used.