Application of DMSO as "oxidant" in organic synthesis!

The oxidation process of Dimethyl Sulfoxide (DMSO) Reagent Grade follows the classic path of "electrophilic activation–nucleophilic addition–elimination": First, electrophilic reagents (such as oxalyl chloride, DCC, sulfur trioxide-pyridine complex) bind to the sulfur-oxygen double bond of dimethyl sulfoxide DMSO, activate the oxygen atom to make it easier to leave, and generate the key intermediate sulfonium cation. Subsequently, the substrate (such as alcohol hydroxyl group or halogenated hydrocarbon) attacks the sulfur atom to form an alkoxysulfonium ion. Finally, deprotonation occurs under the action of the base to generate a sulfur ylide intermediate, which releases dimethyl sulfide through a five-membered ring transition state, and the substrate is oxidized to carbonyl compounds such as aldehydes and ketones.

This process avoids the strong corrosiveness of traditional oxidants (such as Cr⁶+, MnO₂) and provides a mild reaction environment for sensitive functional groups. It enables oxidation reactions of alcohols, halides, and heavy bonds, such as Swern oxidation, Kornblum oxidation, Parikh-Doering oxidation, Pfitzner–Moffatt oxidation, etc. These reactions greatly benefit from the use of DMSO for Organic Oxidation Reactions, offering better selectivity and compatibility for complex organic substrates.

1. Swern Oxidation

The low-temperature oxidation system (Dimethyl Sulfoxide (DMSO) Reagent Grade/oxalyl chloride/triethylamine) developed by Daniel Swern and his colleagues in 1978 can be called the "guardian" of sensitive substrates.

The reaction is usually carried out at -78°C. First, dimethyl sulfoxide DMSO reacts with oxalyl chloride to form dimethyl chlorosulfonium chloride, which then reacts with alcohol to form alkoxysulfonium ions. After alkaline treatment, the sulfonium ylide decomposes to yield aldehydes and ketones. The advantage of this reaction is that the conditions are mild and peroxide formation can be avoided. It is especially suitable for the oxidation of alcohols containing acid-sensitive or heat-sensitive groups, such as the transformation of complex cyclic alcohols in natural product synthesis.

2. Pfitzner–Moffatt Oxidation

In 1963, Moffatt and his student Pfitzner discovered that the Pharmaceutical-Grade DMSO Solvent/DCC combination can be used for the oxidation of alcohols under weakly acidic conditions. The reaction pathway is as follows: First, protonated DCC activates dimethyl sulfoxide DMSO to generate an active intermediate; second, the intermediate reacts with alcohol to form an alkoxysulfonium ylide, and finally releases N,N-dicyclohexylurea (DCU) as a byproduct.

The reaction conditions are mild and suitable for sensitive alcohol substrates. It has the characteristics of high yield, simple operation, low cost, and compatibility with most functional groups. However, unprotected tertiary alcohols are prone to elimination. Another disadvantage is that the byproduct dialkyl urea and excess DCC are difficult to completely remove.

Tips | How to remove the byproduct dicyclohexyl urea (DCU) generated by the reaction of DCC?

3. Albright–Goldman Oxidation

The reaction of oxidizing alcohols to aldehydes and ketones with anhydrous acetic acid (acetic anhydride) and Dimethyl Sulfoxide (DMSO) Reagent Grade as activators was first systematically introduced by Albright and Goldman in 1965. Due to the weak activation ability of acetic anhydride, the reaction time is generally long.

The advantage of this reaction is that it can be carried out at room temperature and is easy to post-process, especially for the oxidation of alcohols with large steric hindrance. The disadvantage is that for hydroxyl groups with small steric hindrance, acetylation and the formation of methylthiomethyl ether may occur as side reactions.

4. Parikh–Doering Oxidation

The reaction of converting primary and secondary alcohols into corresponding aldehydes and ketones using DMSO for Organic Oxidation Reactions, solid sulfur trioxide-pyridine complex as the activator, and triethylamine as the base was first reported by Parikh and Doering in 1967.

Reaction pathway: First, dimethyl sulfoxide DMSO and sulfur trioxide are added at 0°C or room temperature; then it is attacked by alcohol to form a key alkoxysulfonium ion intermediate. The intermediate is then deprotonated by the base to obtain the corresponding sulfur ylide, which passes through a five-membered ring transition state and releases dimethyl sulfide, yielding aldehydes and ketones.