Indoles are a privileged structure unit in many natural products and medicinal chemistry, this weeks contribution comes from Spain, the Institute of Chemical Research of Catalonia, and is presented by the Muñiz group and deals with indole synthesis. To be found in Angewandte Chemie this paper discusses the metal free preparation of indoles and is based on sterically congested hypervalent iodine (Koser) reagents. When combined with a sulphonic acid the oxidative cyclisation of 2-amino styrenes to indoles proceeds in high yields and mild conditions.

So what are Koser reagents? They are a class of hypervalent iodine compounds where the iodine is substituted with two functional groups, for example;

where the structure has been confirmed by x-ray.

By employing iodosobenzene diacetate with a Cbz protected amino group the indole was obtained in low yields (20%). It was observed that the addition of Brønsted acids, TsOH for example, gave the same yields around 20%. However employing the Koser reagent produced the indole in 55% yield, which could further be increased to 64% by using chloroform as a solvent. In situ formation of the reagent from iodosobenzene and p-toluenesulphonic acid (1.0/1.1 equiv.) gave the same result, 64% yield. A screening of different sterically crowded sulphonic acids, for example 2,4,5-tri-isopropylbenzenesulphonic acid produced the indole in 92% yield after 15 minutes at room temperature.

The reaction is tolerant to a variety of functionalised Cbz protected amino styrenes, for example, aldehydes, halogens, ketones, esters, acetylenes etc. The corresponding indoles are produced in medium to high yield and can be carried out on a 5 g scale.

They also found a catalytic system that was almost as efficient in producing the indole: 4-methoxyiodobenzene 20 mol%/ the sulphonic acid, above (1.1 equiv.) and m-chloroperbenzoic acid (1.1 equiv.). Deuterium labelling experiments revealed deuterium finishing up at both the 2 and 3 positions of the indole:

To explain this the reaction is suggested to proceed via the intermediate 5 which produces  compound 6:

Then formation of the cyclopropyl phenonium ion 7 takes place:

Two possible products can be formed by ring opening by the nitrogen, the 3-substituted indole and the 2-substituted indole, with elimination of the arylsulphonic acid generating the same indole. Ring opening of the cyclopropyl intermediate demonstrates a preference for attack at the methylene carbon due to steric hinderance caused by the sulphonic acid, thus explaining the ratios from the deuterium experiment.

A final interesting experiment involved the use of an aminating reagent designed by this group, PhI(NTs₂)₂ to give the 3-bis-tosylamino substituted indole in 52% yield.

So there we have it, a nice way of generating indoles from simple starting materials in reasonable to high yield. I hope this reaction finds a home in the toolbox of medicinal chemists and other chemists as well. Congratulations on a very nice piece of chemistry.

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