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DMSO/I2 Oxidation to Produce Heteroaromatic Aldehydes

The oxidation methods using DMSO/I2 continue to grow. (For recent examples, see Synthesis Corner posts from January 6, 2020, October 31, 2019, and October 1, 2019.) These methods generally proceed through iodine-catalyzed C–H functionalization followed by a Kornblum-type oxidation at the same site. Along these lines, recent work by Chen et al. demonstrates the first example of a radical-free, metal-free oxidation of heteroaromatic methanes to produce heteroaromatic aldehydes using DMSO/I2.1

Under optimized conditions, the reaction of a variety of heteroaromatic methanes produced heteroaromatic aldehydes with good to excellent yields, regardless of the presence of electron-withdrawing or electron-donating groups or the ring position of the heteroatom (Table 1).

Table 1: Generation of aldehydes through oxidation of heteroaromatic methanes.

Studies were also undertaken to better understand the mechanistic pathway for this reaction, leading to the proposed mechanism show in Scheme 1. The reaction proceeds in the presence of TEMPO or BHT, indicating that the mechanism does not follow a radical pathway. Additionally, subjecting benzyl iodide 4 to the standard reaction conditions (sans I2) shown in Table 1 leads to high yield of the aldehyde product 2, suggesting that compound 4 is indeed formed during the reaction.

In this mechanism, the tautomer 3 reacts with I2 to produce the benzyl iodide 4. This intermediate 4 is susceptible to Kornblum oxidation by DMSO which leads to the aldehyde product 2. It is believed that intermediate 4 might also undergo hydrolysis, leading to diminished yields. Of note, DMSO oxidizes any iodide ion produced during the reaction back to the active iodine molecule, allowing for the use of substoichiometric amounts of iodine in the reaction.

Scheme 1: Proposed mechanism.

In conclusion, this work outlines another example of DMSO and I2 partnering in a mild and selective oxidative method, without the need for metal catalysts or harsh conditions.

Debra D. Dolliver, Ph.D.

1Ye, R; Cao, Y.; Xi, X.; Liu, L; Chen, T Org. Biomo. Chem., 2019, 17, 4220.

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