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Synthesis 2006(20): 3467-3477  
DOI: 10.1055/s-2006-950223
PAPER
© Georg Thieme Verlag Stuttgart · New York

Synthesis of Indoles: Efficient Functionalisation of the 7-Position

Nicolas Charrier, Emmanuel Demont*, Rachel Dunsdon, Graham Maile, Alan Naylor, Alistair O’Brien, Sally Redshaw, Pam Theobald, David Vesey, Daryl Walter
Neurology and Gastrointestinal Center of Excellence for Drug Discovery, GlaxoSmithKline, New Frontiers Science Park, Third Avenue, Harlow, CM19 5AW, Essex, UK
Fax: +44(1279)627685; e-Mail: emmanuel.h.demont@gsk.com;
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Received 8 June 2006
Publikationsdatum:
04. September 2006 (online)

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Abstract

Traditional strategies in indole chemistry do not allow high-yielding access to some substitution patterns such as 3,5,7-trisubstituted indoles. We report in this article the efficient synthesis of this type of indole. The Heck cyclisation strategy we used allows the synthesis of 7-iodo-, 7-alkoxy-, 7-amino-, and 7-nitroindoles bearing other functionalities at the 3- and 5-positions. We believe that the mild conditions used should allow the preparation of indoles with a wide range of substituents in these two positions as shown by the synthesis of a 5-bromo-7-iodoindole. However, this strategy has some limitations in the case of very electron-deficient indoles such as a 7-nitroindole where the aromatisation of the 7-nitrodihydroindole intermediate is not complete. In this case, Larock’s indole synthesis from disubstituted acetylenes proved to be more appropriate.

Key words

indoles - Heck reaction - palladium - 2-vinylanilines - Larock’s cyclisation

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2

A search for the indole core in the WDI database retrieved more than 3700 hits. See also ref. 12a.

21

The synthesis of the 7-substituted indoles will be described with ethyl or n-propyl at the 3-position. The synthetic routes described in this paper are applicable to both substituents.

30

An NOE experiment proved that the stereochemistry of the exocyclic double bond is as shown in Scheme [7] .

33

See references 133d and 136a-e cited in ref. 7b.

34

Compounds 28a and 28b are drawn as acids for convenience, but are isolated as trimers. See ref. 20a.

37

The structure of 30 was assigned by an NOE experiment.

38

We ensured that we were able to reproduce Larock’s results on 2-iodoaniline. Under the same conditions, methyl 4-amino-3-iodo-benzoate gave a 94:6 mixture of isomers. Within this set of examples, the selectivity appears related to the electron deficiency of the aromatic ring.

39

We did not attempt to increase the yield of the ring formation by using substituents more stable than trimethylsilyl to the reaction conditions, since the yield obtained was adequate for our purposes.

40

Removal of the trifluoroacetamido group proved easier for 25 (deprotection takes 45 minutes at room temperature) than for 14 (deprotection not complete after two days under similar conditions).