Ravikumar and coworkers have developed a new chemoselective oxidation method using DMSO as the oxidant.1 Unlike other classical oxidation methods using DMSO, which go through the alkoxysulfonium ion intermediate A (Scheme 1), this work indicates that selective oxidation can occur at active methylenes and benzhydrols through intermediate B (Scheme 2) where the substrate initially bonds to the sulfur of DMSO instead of the oxygen of DMSO.
Scheme 1: Classical DMSO oxidations (Kornblum, Swern) and recent electrochemically-generated carbocation oxidation (Yoshida)2 which proceed through an alkoxysulfonium intermediate A.
Scheme 2: New oxidation with DMSO which proceeds through an intermediate with a bond between the substrate and the sulfur of DMSO.
The Ravikumar group optimized the reaction such that excellent yields were achieved for the oxidized product of compounds containing a methylene group flanked by an aromatic ring and a carbonyl group (Equation 1). Multiple mechanistic studies indicated that the newly installed oxygen atom came from DMSO.
Equation 1: Oxidation of active methylene compounds using DMSO and a mild base.
Attempts at oxidizing methyl groups or methylenes which were flanked by only one of these groups did not result in oxidation. Therefore, this oxidation method could offer a chemoselective method to target specific methylene groups for oxidation while leaving others untouched.
As mentioned previously, mechanistic studies indicated that the oxygen atom in the oxidized product originated from the DMSO molecule. Mechanistic studies also ruled out the possibility of radical intermediates. Therefore, the authors proposed the following ionic mechanistic pathway (Scheme 3).
Scheme 3: Proposed mechanistic pathway.
In this mechanism, the base deprotonates the methylene carbon, producing a delocalized carbanion I. The authors propose that the soft nature of this carbanion interacts with the soft electrophilic sulfur of DMSO to produce intermediate II. Intermediate II undergoes a rearrangement and eliminates dimethylsulfide to produce alkoxide ion III. Alkoxide III attacks the electrophilic sulfur in DMSO and produces intermediate IV. After a proton exchange to produce V, an elimination (E1cb) to produce the product occurs, and the base is regenerated to reenter the cycle.
As the proposed mechanism proceeds through alkoxide III, the authors extended their oxidation protocol to include various activated benzhydrols (Equation 2).
Equation 2: DMSO oxidation of benzhydrols.
In most cases, the reaction was faster with Cs2CO3 as the base, but it also worked well with K2CO3. It was very slow with KHCO3. Again, the reaction was found to only work if the carbon to be oxidized was attached to two aromatic rings. In other words, benzyl alcohol remained unchanged when subjected to these same reaction conditions.
With the observed selectivity noted above, these researchers undertook studies to verify the chemoselectivity of this oxidation method. As seen in Scheme 4, the reaction only produced oxidation at the more activated positions.
Scheme 4: Evaluation of chemoselectivity of the DMSO oxidation.
As seen in the examples illustrated in Scheme 4, excellent control of the oxidation site was achieved.
In summary Ravikumar and coworkers have demonstrated the first-reported use of the electrophilic sulfur center of DMSO to initiate oxidation at active methylenes and benzhydrols through a carbanion mechanism. This method offers good selectivity and excellent yields using readily-available and inexpensive materials.
Debra D. Dolliver, Ph.D.
- Chebolu, R.; Bahuguna, A.; Sharma, R.; Mishra, V. K.; Ravikumar, P. C., An unusual chemoselective oxidation strategy by an unprecedented exploration of an electrophilic center of DMSO: a new facet to classical DMSO oxidation. Chemical Communications 2015, 51 (84), 15438-15441.
- Ashikari, Y.; Nokami, T.; Yoshida, J.-i., Integrated Electrochemical–Chemical Oxidation Mediated by Alkoxysulfonium Ions. Journal of the American Chemical Society 2011, 133 (31), 11840-11843.