Saegusa indole synthesis

What is Saegusa indole synthesis?

Saegusa et al. first reported the Saegusa indole synthesis in 1977, which is a synthetic method for the preparation of indole and 2- or 3-substituted indole derivatives through lithiation of ortho-alkyl phenyl isocyanides followed by intramolecular cyclization. The reaction is named after Saegusa due to its significant contribution to the field, and is also referred as the Saegusa cyclization.

Saegusa indole synthesis - Saegusa cyclization - general reaction scheme
Saegusa indole synthesis

Saegusa indole synthesis involves the treatment of ortho-alkyl phenyl isocyanide with two equivalents of base, such as LDA or LiTMP, in diglyme at low temperature, leading to the formation of simple indole by intramolecular cyclization. On the other hand, the reaction between o-lithomethylphenyl isocyanide and an electrophile, such as an alkyl halide or an epoxide, followed by lithiation and ring closure, produces 3-substituted indoles.

This reaction is highly dependent on the solvent and can produce indoles in quantitative yields. The reaction between o-tolyl isocyanide and LDA in ether or THF results in low yield of indole, along with the formation of a considerable amount of N,N-diisopropyl-N-(o-tolyl)-formamidine. This is probably due to the strong coordination from the two oxygen atoms in diglyme to the lithium cation, whereas only one oxygen atom exists in ether, THF, or monoglyme. Moreover, o-(acylmethyl)phenyl isocyanides, prepared from the acylation of o-lithomethylphenyl isocyanide with allyl carboxylates, can yield 3-acyl indoles or 2-alkyl indoles upon treatment with cuprous oxide or acid.

References

  • Ito, Y.; Kobayashi, K. and Saegusa, T., J. Am. Chem. Soc., 1977, 99, 3532
  • Ito, Y.; Kobayashi, K. and Saegusa, T., J. Org. Chem., 1979, 44, 2030
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