Indole Syntheses Utilizing o-Methylphenyl Isocyanides

• Published in: Bulletin of the Chemical Society of Japan Vol. 57; no. 1; pp. 73 - 84
• Main Authors: Ito, Yoshihiko, Kobayashi, Kazuhiro, Seko, Norihiko, Saegusa, Takeo
• Format: Journal Article
• Language: English
• Published: Tokyo The Chemical Society of Japan 01.01.1984; Chemical Society of Japan
• Subjects: Chemistry; Exact sciences and technology; Heterocyclic compounds; Heterocyclic compounds with only one n hetero atom and condensed derivatives; Organic chemistry; Preparations and properties; Bicyclic compound; Benzenic compound; Aromatic compound; Nitrogen heterocycle; Heterocyclization; Alkylation
• ISSN: 0009-2673; 1348-0634
• DOI: 10.1246/bcsj.57.73

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.