TiCl₄-Catalyzed Synthesis of Pyrimido[1,6-a]indol-1-ones

Significance

Reported is the TiCl₄-catalyzed ­cyclization of N-ethoxycarbonyl-2-alkynylindoles with aniline derivatives to give pyrimido[1,6-a]indol-1-ones in good to excellent yield. The TiCl₄/t-BuNH₂ system was chosen because it is known to facilitate anti-Markovnikov addition to alkynes. Hence, the proposed mechanism involves first the addition of amine to the alkyne, followed by ­intramolecular cyclization to give the products shown. This is supported by the isolation of the ­intermediate ketone A in 52% yield (together with the expected pyrimido[1,6-a]indol-1-one in 38% yield) from the reaction of n-hexylalkyne and 4-chloroaniline at room temperature in only four hours. Ketone A is proposed to arise by hydrolysis of the corresponding intermediate enamine.