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

Abstract

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

“…All reagents and solvents were purchased from commercial vendors and used as received. Indoloquinoline products 1aaa, 11 1aab, 12 1aac, 4 1aba, 10 1abb, 11 1abc, 4 1aca, 13 1ada, 3 g 1aea, 3 g 1bba, 4 1bbb, 12 1bbd 6 are known compounds and their physical and spectral properties matched those previously reported in literature.…”

“…We also discovered an alternative protocol involving unusual cyclization with nitroalkenes accompanied by extrusion of HCN (Scheme 2). 6 Still, these previously developed methods did not provide any synthetically meaningful results in reactions of acylating agents bearing functional group as substituent R 5 . In certain cases, these issues rendered synthesis of some types of compounds for our SAR studies impossible or cost prohibitive.…”

An Effective Synthesis of Previously Unknown 7-Aryl Substituted Paullones

“…It was shown, however, that the reaction of the corresponding 2-arylindoles with nitrostyrenes 2 leads to the formation of 2-quinolones 12 instead of desired paullones 7 [19] (Scheme 3a). An attempt to introduce an ortho-amine function into the aryl substituent did not afford the paullones either, resulting in indoloquinolines 13 related to the isocryptolepine alkaloid as the only isolable products (Scheme 3b) [36]. This prompted us to explore alternative approaches based on the classical Fischer indolization reaction.…”

Synthesis and characterization of terbium doped TiO2 nanoparticles and their use as recyclable and reusable heterogeneous catalyst for efficient and environmentally sustainable synthesis of spiroannulated indolo[3,2‐c]quinolines‐ mimetic scaffolds of isocryptolepine

“…[2,3] Indoloquinoline alkaloids [4] including isocryptolepine (I), cryptolepine (II), 11-isopropylcryptolepine (III), neocryptolepine (IV), 11-methylneocryptolepine (V) and isoneocryptolepine (VI), are isolated from the roots of West African plant, Cryptolepis Sanguinolenta (Figure 1). [5] Among them, isocryptolepine has been reported to exhibit promising activity, [6,7] such as antimalarial, [8,9] antiproliferative [9] and anticancer activity. [10] Moreover, the use of isocryptolepine as DNA intercalator [11] for inhibiting DNA replication, transcription and/or topoisomerase activity and selective protein kinase DYRK1A inhibitor [12] has also been reported.…”