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DMSO/I2 Metal-Free Oxidative α-Nitration of Ketones: A Route to One-Pot Synthesis of Thiohydroximic Acids from Acetophenones

29 Oct 16
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Recently, Batra et al. have reported another new DMSO/I2 metal-free route to functionalize ketones at the α-position.1 Their previous work had demonstrated a DMSO/I2/NaNO2-mediated route to the synthesis of highly substituted isoxazoles.2 Building on this work, they have developed a metal-free route using DMSO/I2/NaNO2 to nitrate the alpha position of ketones.

Optimization indicated that, while the reaction worked with DMSO playing the role of both solvent and co-oxidant (58%), yields were improved using the external oxidant of hydrogen peroxide (35 wt %) (Eq. 1). Unfortunately, if R1 is an electron-withdrawing group, like –CN or –COOR, the reaction results in C-C bond cleavage and produces benzoic acid as the major product.

Interestingly, when performing this DMSO/I2 reaction with methyl aryl ketones, instead of producing the expected α-nitroacetophenone, the alpha carbon was converted into a thiohydroximic acid moiety. Optimization indicated that the highest yields of the thiohydroximic acid were obtained without an external oxidant (Eq. 2).  The reaction tolerated a wide variety of aromatic rings, including nitrogen, sulfur, and oxygen-containing ones, and was not impaired by ortho substituents on the aromatic ring.

Investigations into the mechanism for the transformations shown in Eq. 1 and Eq. 2 indicated the following:

  1. An α-iodoketone intermediate was ruled out, as placing α-iodoacetophenone in the standardized DMSO/I2/NaNO2 conditions only led to negligible formation of the thiohydroximic acid product.
  2. A radical intermediate was suggested, as inclusion of the radical inhibitors TEMPO or BHT severely curtailed thiohydroximic product formation.
  3. An α-nitroketone intermediate was supported, as placing α-nitroacetophenone in the standardized DMSO/I2/NaNO2 conditions resulted in an 82% yield of the thiohydroximic product.
  4. The thiomethyl group of the thiohydroximic acid comes from DMSO, as reaction in deuterated DMSO resulted in the thiohydroximic acid containing a deuterated thiomethyl (–SCD3) group.

With these observations, the mechanism in Scheme 1 was proposed. In this mechanism, molecular iodine decomposes into two iodine radicals that abstract an α-hydrogen from the ketone. This produces HI, and the I is then oxidized back to I2 by DMSO. This produces dimethyl sulfide (DMS) which will serve as the thiomethyl source later in the mechanism. Intermediate A undergoes an oxidative single electron transfer to produce carbocation B that then undergoes nucleophilic attack by the nitrite ion. If R is an alkyl group, the reaction stops at C.

Scheme 1: Plausible mechanism of reaction

If R is a hydrogen, intermediate C undergoes tautomerization to the nitronate D. Dimethyl sulfide then attacks the carbon of the C=N bond to produce intermediate E. A rearrangement of intermediate E produces intermediate F which undergoes elimination of methanol to produce the thiohydroximic acid G.

This reaction was shown to also work with other dialkylsulfoxides. However, with an aryl sulfoxide, the reaction produced 0% of the thiohydroximic acid product.


Since the reaction is run under oxidizing conditions, the authors explored running the reaction with a benzylic alcohol, and found that the medium for the reaction also oxidized the benzylic alcohol to produce the same thiohydroximic acid that would be produced starting from the acetophenone (Eq. 3).

The authors also demonstrated useful synthetic transformations on both the α-nitroketones (Scheme 2) and the thiohydroximic acids (Scheme 3) produced by the DMSO/I2/NaNO2 reactions.

Scheme 2: Synthetic transformations of an α-nitroketone produced by the DMSO/I2/NaNO2 reaction

Scheme 3: Synthetic transformations on the thiohydroximic acids formed from the DMSO/I2/NaNO2 reactions.

These DMSO/I2/NaNO2 reactions again demonstrate the usefulness of DMSO in I2 catalyzed reactions. These types of reactions allow for metal-free functionalization of α-carbons in ketones with a wide variety of functionalities under mild conditions.

Debra D. Dolliver, Ph.D.



(1)            Dighe, S. U.; Mukhopadhyay, S.; Priyanka, K.; Batra, S. Organic Letters 2016, 18, 4190.

(2)            Dighe, S. U.; Mukhopadhyay, S.; Kolle, S.; Kanojiya, S.; Batra, S. Angewandte Chemie International Edition 2015, 54, 10926.

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