2,3-Substituted Indole synthesis by Regioselective Electrophilic Trapping


The selective synthesis of indoles is an important area of organic chemistry, largely due to their prevalence in countless natural products, medicines, materials etc. Numerous methods have been described for the synthesis of substituted indoles, with many requiring the pre-instillation of functional groups by incorporating them within the initial starting material. Late stage functionalisation is also possible, but in order for this to be achieved additional steps are often required, with some involving harsh conditions or the use of expensive transition metal catalysts. With this in mind, the report described by Eiichi Nakamura from the University of Tokyo could be of interest to people wishing to make a small library of substituted indoles from one common building block.1

mark-1

Scheme 1

Within this communication, Nakamura describes the synthesis of indoles via dimetalated intermediates – although the synthesis via 2,3-dimetalloindoles has previously been reported, the selective introduction of electrophiles has, to the best of my knowledge, not previously been achieved. The problem of obtaining such selectively is shown in Scheme 2 – the dimetalated intermediates A and B react without selectivity, and so a mixture of isomers are obtained. In comparison to other dimetalated indoles,2 the Authors show that dizincioindoles are stable and relatively easily formed, suggesting a dimeric structure (shown in Figure 1) to rationalise this stability.

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Scheme 2

 

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Figure 1

The Authors show that when using of ZnCl2, electrophiles can be introduced at C-3 when simple electrophiles are used, but this can be switched C-2 when transition metals are introduced. When ZnPhBr is used, reactivity is generally more selective for C-3, unless a stannane is used, with differing reactivity probably due to a change in mechanism from simple nucleophilic reactions to that occurring through charge transfer (please see reference 1 for detailed substrate scope).

Although the above chemistry is not completely selective, it is certainly a good starting point for further investigation, as the selective synthesis of indoles remains and important task within many disciplines. I suppose the next question is – what other heterocyclic systems can this chemistry be applied to next?

Blog by Mark Honey

All Schemes and Figures were taken from J. Am. Chem. Soc. 2017, 139, 23-26

References

  1. J. Am. Chem. Soc. 2017, 139, 23-26
  2. Organometallics, 1998, 17, 2906

 

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