Unexpected cyclization of 2-(2-aminophenyl)indoles with nitroalkenes to furnish indolo[3,2-c]quinolines.

The polyphosphoric acid-mediated reaction of 2-(2-aminophenyl)indenes with nitroalkenes was tested in the frame of synthetic studies towards CDK inhibitors with the paullone core. Unexpectedly, this reaction proceeded via a different mechanistic pathway affording derivatives of the natural alkaloid isocryptolepine. The scope of this unusual transformation was investigated and a mechanistic rationale explaining this outcome is offered.

A nitroalkane-based approach to one-pot three-component synthesis of isocryptolepine and its analogs with potent anti-cancer activities.

A second generation polyphosphoric acid-mediated one-pot three-component synthesis of indoloquinoline scaffold is developed. This improved version of the process involves electrophilically activated nitroalkanes for the installation of strategic C-C and C-N bonds and ring C assembly. This modification allows the elimination of unnecessary solvent change operations and all steps are carried out in a true, uninterrupted one-pot manner. A further improvement involves the possibility to install an ortho-amino group in situ. A synthetic application of this method is showcased by the concise synthesis of an isocryptolepine alkaloid and its synthetic analogs with potent anticancer activities.

One-Pot, Three-Component Assembly of Indoloquinolines: Total Synthesis of Isocryptolepine.

Indolo[3,2-c]quinolones have been efficiently synthesized via an acid-mediated, one-pot, three-component condensation of arylhydrazines, o-aminoacetophenones, and triazines or nitriles. The synthetic application of this method is showcased by the concise synthesis of isocryptolepine alkaloid and a series of its synthetic analogues with demonstrated cancer cell antiproliferative activities.