Rapid and Efficient Microwave‐Assisted Friedländer Quinoline Synthesis

Abstract

A microwave‐based methodology facilitates reaction of 2‐aminophenylketones with cyclic ketones to form a quinoline scaffold. Syntheses of amido‐ and amino‐linked 17β‐hydroxysteroid dehydrogenase type 3 inhibitors with a benzophenone‐linked motif were pursued using 2‐aminobenzophenone as building block. Two amido‐linked targets were achieved in modest yield, but when using microwave‐assisted reductive amination for the amino‐linked counterparts an unexpected product was observed. X‐ray crystallography revealed it as a quinoline derivative, leading to optimisation of a simple and efficient modification of Friedländer methodology. Using reagents and acetic acid catalyst in organic solvent the unassisted reaction proceeds only over several days and in very poor yield. However, by employing neat acetic acid as both solvent and acid catalyst with microwave irradiation at 160 °C quinoline synthesis is achieved in 5 minutes in excellent yield. This has advantages over the previously reported high temperatures or strong acids required, not least given the green credentials of acetic acid, and examples using diverse ketones illustrate applicability. Additionally, the unassisted reaction proceeds effectively at room temperature, albeit much more slowly.

Quinoline‐derivatives as privileged scaffolds for medicinal and pharmaceutical chemists: A comprehensive review

“…Helen and coworkers optimized the Friedlander condition using 2‐aminophenyl ketone and other cyclic ketone in the acetic acid, acting as solvent and catalyst at 160°C temperature for 5 min under microwave conditions (Scheme 4), the results were obtained with good to excellent yields (Bailey et al, 2020).…”

Environmentally Benign Approaches towards the Synthesis of Quinolines

“…Another Friedländer quinoline synthesis via rapid condensation of 2-aminophenylketones (116) with cyclic ketones (117, 1.5 equiv) to synthesize quinolines (118) under microwave irradiation in good yields at 160 °C has been accomplished by Potter et al (Scheme 39). [118] 3.5. Meatal catalysts…”

Recent Advances in Green Synthesis of Functionalized Quinolines of Medicinal Impact (2018‐Present)

“…Bailey et al in year 2020, reported microwave-assisted synthesis of Quinolines 260 following Friedlander pathway (Scheme 71). [111] This reaction was performed between 2-aminoaryl ketones 57 and cyclic/acyclic ketone molecules 259 while neat acetic acid played the role of solvent and catalyst at 160 °C under microwave condition for 5 minutes and the products were obtained in good yields.…”