Copper(I)‐Catalyzed Coupling Cyclization of Methyl Perfluoroalk‐2‐ynoates with 2‐Aminobenzonitriles: Synthesis of 2‐Perfluoroalkylated Quinolines

Abstract

An efficient route to 2-perfluoroalkylated quinoline derivatives through the copper(I)-mediated coupling-cyclization of 2-aminobenzonitriles with methyl perfluoroalk-2-ynoates is described. Moderate to excellent yields have been achieved under mild conditions. The reaction mechanism is also discussed.

CuII‐Promoted Aerobic Cascade Reactions of 2‐Alkynylanilines with Methyl Perfluoroalk‐2‐ynoates: En Route to 4‐Carbonyl‐2‐perfluoroalkylquinolines

“…[13] X-ray crystallography of 3b revealed the ester group attached to the quinoline 3-position and the R F group attached to the quinoline 2-position. Based on the above observations and the previous literature, [11j,11l] together with our recent work on the synthesis of 2-perfluoroalkylquinolines, [12] a plausible mechanism is shown in Scheme 2. The formation of the sole product 3 could be explained by the highly regioselective coordination of the base-activated amino group in 1 with the more electrophilic carbon atom of the triple bond in 2.…”

“…Such findings can be easily explained by the increased nucleophilicity of the -NH 2 group due to the presence of a p-EDG (-OMe), thus affecting the efficiency of the first Michael addition step in this two-step heterocyclization by improving the reaction yields. [12] The investigation of the electronic nature of substituent R 2 also showed that substrates with an electron-rich group such as p-OMe in the aryl group of the alkyne moiety gave better yields (Table 2, Entry 11 vs. 13).…”

“…[12] As a continuation of our interest in the design and discovery of new methods for the synthesis of these types of fluorinated heterocycles, herein, we report a Cu II -promoted cascade reaction of 2-alkynylanilines with unsymmetrical internal alkynes exemplified by methyl perfluoroalk-2-ynoates in methanol at room temperature under air to synthesize 4-carbonyl-2-perfluoroalkylquinolines. …”

Synthesis of Organofluoro Compounds Using Methyl Perfluoroalk-2-ynoates as Building Blocks

“…[29] The reaction commences with a Michael addition of the amino group of compound 41 to alkynoate 1 to generate 43, which undergoes successive deprotonation by piperidine, Analogously, through the treatment of o-aminophenyl ketones 48 and methyl perfluoroalk-2-ynoates 1 in the presence of a catalytic amount of Cu 2 O, a series of 2-perfluoroalkylated quinolines 49 were obtained with excellent regioselectivity (Scheme 17). [30] Most o-aminophenyl ketones, whether with electron-withdrawing or electron-donating groups, were suitable for this protocol.…”

“…A facile CuBr‐catalyzed one‐pot procedure was developed by us to synthesize 2‐perfluoroalkylquinolines from 2‐aminobenzonitriles 41 and methyl perfluoroalk‐2‐ynoates 1 (Scheme ) 29…”