Rapid and Efficient Microwave-Assisted Friedländer Quinoline Synthesis

Helen Bailey, Mary Mahon, Nigel Vicker, Barry Potter

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)1113-1122
Number of pages10
JournalChemistryOpen
Volume9
Issue number11
Early online date5 Nov 2020
DOIs
Publication statusPublished - 5 Nov 2020

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