Tandem Nenitzescu reaction/nucleophilic aromatic substitution to form novel pyrido fused indole frameworks

Abstract

Two regioisomeric sets of 5-hydroxy indoles, prepared from Nenitzescu reaction, were transformed to polyfused ring system bearing pyridine, furan and additionally indole as key component through intramolecular nucleophilic substitution. This methodology provides simple access to various linear and angular-shaped pyrido (furo) fused indole frameworks from easily available precursors under mild reaction conditions. 5-Hydroxyindoles are privileged structures that form part of various bioactive compounds. The Nenitzescu reaction of quinones and enamines is one of the most powerful methods to obtain 5-hydroxyindoles. In this work, we have applied the Nenitzescu reaction to 2-(2-chloropyrid-3-yl)benzoquinones. Mixtures of regioisomers were obtained that could be separated in the 4- and 6-substituted analogues, and then cyclized separately in a metal-free base-catalyzed reaction, affording novel tetracyclic indole derivatives. These are indeed the first examples reported in the literature of the linear pyrido[3?,2??:?4,5]furo[3,2-b]indole and angular 1H-pyrido[2?,3??:?4,5]furo[2,3-c]indole systems. The regioselectivity and the yield of the Nenitzescu reaction were found to be dependent on the N-substituent at the enamine. Furthermore, we analyzed the UV-Vis and PL spectra of the new systems, and this was supported by DFT calculations, allowing us to compare the properties of angular compared to linearly shaped compounds.