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Me2S/NCS Corey – Kim oxidation

Mechanism + Description

A non-catalytic, non- metal catalysed oxidation mechanistically related to the Swern oxidation, albeit with N-Chlorosuccinimide

Activating the DMS to attack from the alcohol. Chlorinated by-products can result in some instances.

General comments

Often used with complex, multi-functional natural products. A range of ‘greener’ options have been proposed for Swern and Corey-Kim type oxidations. These tend to focus on the use of reagents than remove the odour issues with using/generating Me2S. These alternative S reagents, often solid-supported, are effective at removing issues with volatile sulphides and can facilitate work-up, but add considerably to PMI for a process. It also needs to be borne in mind that making these reagents involves multi-stage synthesis utilising solvents, reagents, energy etc. In mitigation, some can be regenerated and reused.

Key references

Org. Process Res. Dev., 2010, 14 (3), pp 504–510 – 50L scale up of complex macrolide
Green Chemistry (2004), 6(3), 142-146 – A practical improvement of odorless Corey –Kim and Swern oxidations
Tetrahedron (2003), 59(42), 8393-8398 – odorless method for the Corey –Kim utilizing dodecyl methyl sulfide (Dod-S-Me)
Tetrahedron (2002), 58(20), 3865-3870 – fluorous Swern and Corey-Kim reactions: scope and mechanism

Relevant scale up example

300L scale oxidation

Org. Process Res. Dev., 2012, 16 (5), pp 788–797

Green Review

  1. Atom efficiency (by-products Mwt)
    For removal of H2, the Cory-Kim oxidation produces DMSO (78), Succinimide (99) and HCl (37) as by-products.
  2. Safety Concerns
    Me2S reagent and any off gas from the reaction needs to be controlled. The addition of NCS to Me2S and the resultant oxidation step can be highly exothermic.
  3. Toxicity and environmental/aquatic impact
    DMS, whilst occurring naturally in the environment, is an irritant, volatile compound with a disagreeable smell. Succinimide is fairly benign.
  4. Cost, availability & sustainable feedstocks
    Readily available at reasonable cost.
  5. Sustainable implications
    NCS is produced via the chlorination of succinimide with Cl2. Succinimide is produced from succinic acid and ammonia.