An Unexpected Transition-Metal Free Regioselective Cyclization of Alkynyl-Tethered Indoles to Prepare Indole-Fused Azepino[2,1-b]quinazolinones and Spiroindole-pyrrolo[2,1-b]quinazolinones

Abstract

We report an unexpectedly transition-metal free and base-promoted regioselective cyclization of N3-alkynyl-2-indolylquinazolinones for the efficient synthesis of various indole-fused azepino[2,1-b]quinazolinones and spiroindole-pyrrolo[2,1-b]quinazolinones in good to excellent yields under mild reaction conditions. The reaction showed that N-protected N3-alkynyl-2-indolylquinazolinones favoured to afford indole-fused azepino[2,1-b]quinazolinones via selective 7-exo-cyclization of the alkyl carbanion at the C2’-position of the indole moiety whereas N-unprotected N3-alkynyl-2-indolylquinazolinones underwent 5-exo-cyclization of the C3-position of indole moiety to give spiroindole-pyrrolo[2,1-b]quinazolinones. Mechanistic studies revealed that the base promoted not only the isomerization of the unactivated alkynes to the reactive allenyl moiety but also deprotonation of the alkyl groups at the C2’-position of indole to form alkyl carbanions. More importantly, the newly synthesized indole-fused azepino[2,1-b]quinazolinones possessed selective anti-proliferation activity against cancer cells without affecting the growth of normal cells. The present method features transition-metal free and atom economic reaction, broad substrate scope and good functional compatibility, simple purifications without column chromatography, high cyclization selectivity for indoles, and various new types of indole-fused quinazolinone scaffolds.