Rapid Three-Step One-Pot Microwave-Assisted Synthesis of 2,5-Dioxo-1,2,5,6,7,8-hexahydro-3-quinolinecarbonitrile Library

Abstract

Many well-known drugs contain 2-pyridone and 2-quinolone scaffolds. In the current paper, a one-pot three-step microwave-assisted method for the synthesis of N1-substituted 2,5-dioxo-1,2,5,6,7,8-hexahydro-3-quinolinecarbonitrile derivatives was developed. Employing this protocol, we quickly generated 105 compounds library from 1,3-cyclohexanediones, dimethylformamide dimethylacetal, and various cyanacetamides.

TWO-STAGE ONE-POT INTERACTION OF ACYCLIC Β-Ketoesters, DMFDMA AND 2-Cyanomethylbenzimidazole

“…The use of piperidine as catalyst in i-PrOH under microwave irradiation at 100 ºC during 5 min [8] resulted in formation of pure expected product 8a, but the isolated yield was again very low (12%, Entry 9). Further experiments with catalytic amounts of piperidine, its stoichiometric quantities and excess at higher temperatures (Entries [10][11][12][13][14] showed that under such conditions increasing amounts of the undesired by-product 10a appeared in the isolated material. The reaction carried out at 160 °С during 20 min under microwave irradiation gave the pure by-product (10a, Entry 15).…”

“…However, the formation of two different structures in the course of the above described reactions is possible following two alternative reaction mechanisms (Paths A and B, Scheme 4). In the earlier papers of our group [8,10] enamines 21 were shown to react with N-substituted cyanoacetamides 22 via intermediate formation of resonance-stabilized enolates 23 (Scheme 5) similarly to Path B (Scheme 4). The intermediates 23 were isolated as precipitates and their structure was defined in X-ray diffraction study [9].…”

“…Working in this field we studied previously several variations of a one-pot reaction between α-CH 2 -carbonyl compounds, dimethylformamide dimethylacetal (DMFDMA) and active methylene nitriles giving a great diversity of heterocyclic compounds of different classes [8][9][10][11][12][13]. Selectivity and pathways of such transformations depend on both the reaction conditions and the structure of initial compounds.…”

Reactions of diethyl 2-(ethoxymethylene)malonate with 2-cyanoacetanilides: unexpected transfer of the ethoxymethylene moiety

“…5 additional diversity point into the final 2-pyridone molecule via the amide group 10 or, depending on the reaction conditions, leads to N1-substituted 3-cyano-2-pyridones. 11 In this work we aimed to investigate a novel interaction of N-substituted cyanoacetamides 1a-f with diethyl 2-(ethoxymethylene)malonate 12 (DEEMM) 2.…”

An annulation method for the synthesis of alkyl-substituted 6-carbomethoxy-2-pyridones

“…1 As a result, numerous annulation methods have been designed for its construction. 2,3 In this regard, we were attracted to the structure of lyconadin A (1, Fig. 1), a Lycopodium alkaloid with a unique pentacyclic skeleton that contains a 2-pyridone moiety.…”