Indole Syntheses Utilizing <i>o</i>-Methylphenyl Isocyanides

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  • Yoshihiko Ito
    Department of Synthetic Chemistry, Faculty of Engineering, Kyoto University
  • Kazuhiro Kobayashi
    Department of Synthetic Chemistry, Faculty of Engineering, Kyoto University
  • Norihiko Seko
    Department of Synthetic Chemistry, Faculty of Engineering, Kyoto University
  • Takeo Saegusa
    Department of Synthetic Chemistry, Faculty of Engineering, Kyoto University

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<jats:title>Abstract</jats:title> <jats:p>New indole synthesis starting with o-methylphenyl isocyanides such as o-tolyl, 2,4-xylyl, and 2,6-xylyl isocyanide is described in full detail. Treatment of o-tolyl isocyanide with LDA in diglyme at −78 °C generated selectively o-(lithiomethyl)phenyl isocyanide in an almost quantitative yield, which on warming up to room temperature was cyclized to indole after aqueous workup. Similary, 2,4-xylyl and 2,6-xylyl isocyanides were cyclized to 5-methylindole and 7-methylindole quantitatively. The o-(lithiomethyl)phenyl isocyanides reacted with electrophiles such as alkyl halides and alkylene oxides to give o-alkylphenyl isocyanides, which were cyclized via the lithiation at the orthobenzylic carbon to afford 3-substituted indoles. On the other hand, the o-(lithiomethyl)phenyl isocyanides generated in situ at −78 °C was first warmed up to room temperature and then treated with electrophiles to furnish 1-substituted indoles. The o-(lithiomethyl)phenyl isocyanides were acylated in a fairly good yield with N-acylaziridines to give o-(acylmethyl)phenyl isocyanides, which were readily alkylated in the presence of sodium hydride to produce o-(1-acylalkyl)phenyl isocyanides. On acid hydrolysis followed by neutralization, o-(1-acylalkyl)phenyl isocyanides were converted to 2,3-disubstituted indoles.</jats:p>

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