Functionalized quinolines are an important group of heterocyclic molecules with diverse, different, and interesting biological and pharmacological activities. Traditionally, several methods have been developed for the construction of this N-heterocyclic ring, but nowadays the functionalization of the quinoline scaffold has gained great interest and it is highly demand for the synthesis of quinoline derivatives. In this context, quinoline N-oxides have attracted considerable attention as a starting material for different transformations in organic chemistry, such as oxidations, deoxygenations, nucleophilic reactions, cycloadditions, aminations, etc. However, with the current need to extend the quinoline framework through the formation of new C–C bonds, in this review we will survey the recent developments in the direct alkenylation of quinoline N-oxides via the C(sp²)–H bond activation process, discussing metal-free and transition-metal catalysed protocols, and the regioselectivity during the synthesis of promising antiparasitic drugs.

The synthesis of 6H-benzo[c]chromenes from unactivated 2-bromo aryl benzyl ethers was studied through two approaches: (i) the transition-metal-free intramolecular dehydrohalide coupling via intramolecular homolytic aromatic substitution; and (ii) the intramolecular cyclization via direct C–H arylation catalysed by PdCl₂(MeCN)₂. Having developed the most efficient method, a 17-membered chromene library was prepared in good yields and in shorter reaction times starting from commercially available phenol derivatives and phenol-rich essential oils (Eugenia caryophyllys and Plectranthus amboinicus) as raw materials, proving how sustainable and eco-friendly our protocol is. Additionally, the ruggedness of the optimized reaction conditions was evaluated with N-benzylanilines, giving the respective phenanthridone as an unexpected product, while the metal-free oxidation of the obtained 6H-benzo[c]chromenes was also performed to furnish the benzocoumarins.

Ligands promoting copper-catalysed coupling reactions have received increasing attention because of their ability to enhance the catalytic activity of copper, making these reactions applicable in different fields such as drugs, pharmaceutically interesting molecules, and organic materials. Herein, we reported the synthesis and characterization of different selective 2-arylquinoline-based acyl hydrazones toward copper(I) salts. We explored the scope of the catalytic system based on copper/acyl hydrazones in the catalysis of C–N bond formation between N-heterocycles, specifically indoles, pyrroles and carbazoles, and aryl iodides as well as redox-A³ coupling of tetrahydroisoquinolines, terminal alkynes, and aldehydes.

Considering the current challenges of the A³ redox-neutral C1-alkynylation of tetrahydroisoquinolines (THIQs), we studied this synthetic tool under visible light photocatalysis and transition-metal catalysis in order to describe alternative reaction conditions and discuss possible improvements to this process. We demonstrated that 1-alkynylated THIQs can be readily obtained by three different approaches: iridium-based photocatalysis and copper ([CuBr(PPh₃)₃]) and silver (AgNO₃) catalysis under mild, selective and accessible reaction conditions. Among these approaches, the copper(I)-based methodology resulted in the most robust, optimal reaction conditions for the synthesis of a series of 18 1-alkynylated THIQs in moderate to excellent yields and with high selectivity for the endo-alkynylated products. Moreover, this reaction can be accelerated by microwave irradiation (120 °C, 15 min) affording a novel library of diverse THIQs with alkyne and N-substituent moieties, from unreactive and uncommon substrates, that could be further transformed into new compounds of interest. Received: 02 June 2020 Accepted after revision: 03 August 2020 Publication Date: 21 September 2020 (online) © 2020. Thieme. All rights reserved Georg Thieme Verlag KG Rüdigerstraße 14, 70469 Stuttgart, Germany

A rapid, efficient, and original synthesis of novel pyrido[3,2,1-de]phenanthridin-6-ones is reported. First, the key cinnamamide intermediates 8a–f were easily prepared from commercial substituted anilines, cinnamic acid, and 2-bromobenzylbromide in a tandem amidation and N-alkylation protocol. Then, these N-aryl-N-(2-bromobenzyl) cinnamamides 8a–f were subjected to a TFA-mediated intramolecular Friedel-Crafts alkylation followed by a Pd-catalyzed direct C–H arylation to obtain a series of potentially bioactive 4-phenyl-4,5-dihydro-6H,8H-pyrido[3,2,1-de]phenanthridin-6-one derivatives 4a–f in good yields. Finally, the toxicological profile of the prepared final compounds, including their corresponding intermediates, was explored through in silico computational methods, while the acute toxicity toward zebrafish embryos (96 hpf-LC₅₀, 50% lethal concentration) was also determined in the present study.

The quinoline derivative, N-(7-chloro-4-morpholinoquinolin-2-yl)benzamide, was synthesized in a conventional three-step procedure from 4,7-dichloroquinoline using a N-oxidation reaction/C2-amide formation reaction/C4 S_NAr reaction sequence. The structure of the compound was fully characterized by FT-IR, ¹H-, ¹³C-NMR, DEPT-135°, and ESI-MS techniques. Its physicochemical parameters (Lipinski’s descriptors) were also calculated using the online SwissADME database. Such derivatives are relevant therapeutic agents exhibiting potent anticancer, antibacterial, antifungal, and antiparasitic properties.