A concise Friedländer/Buchwald-Hartwig approach to the total synthesis of quindoline, a bioactive natural indoloquinoline alkaloid, and toward the unnatural 10-methylquindoline

Abstract

A new approach toward the synthesis of quindoline, a recognized indoloquinoline alkaloid, is reported. The sequence comprises the synthesis of 2-(2-nitrophenyl)quinoline through an optimized Friedländer condensation of 2-amino benzaldehyde with 2-nitroacetophenone, followed by the selective C-3 bromination of the quinoline moiety to direct the cyclization, reduction of the nitro group and a final Buchwald-Hartwig cyclization. In addition, quindoline was also converted to the unnatural 10-methylquindoline by reaction with dimethyl carbonate under DBU promotion. It was found that the non-directed reductive cyclization of 2-(2-nitrophenyl)quinoline results in indazolo[2,3-a]quinoline, instead of yielding quindoline. DFT calculations were employed to explain this reaction outcome; this finding suggested that the result of a previously reported total synthesis of quindoline should be revised.