Rapid and Efficient Microwave-Assisted Friedländer Quinoline Synthesis.

Helen V Bailey,Mary F Mahon,Nigel Vicker,Barry V L Potter

doi:10.1002/open.202000247

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, he unassisted reaction proceeds effectively at room temperature, albeit much more slowly.

Highlights

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
Introduction synthesis can, be either acid- or base-catalysed or it can even proceed without catalysis, uncatalyzed reactions require very high temperatures, up to 220° C.[1]
The straightforward synthesis of two initial amide-linked targets in this series is shown in Scheme 1

Summary

Introduction

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. Synthesis of the quinoline ring system is very important to the synthetic organic chemist and methodology has been widely discussed,[1,2] with more recent work focusing considerably on green and clean methodologies.[3] The structural core of quinolines can be made by many different methods, one of which is the Friedländer synthesis, originally published in 1882,[4] a versatile and reliable reaction It is traditionally a reaction in which an o-aminobenzaldehyde is cyclised by reaction with an α-methyleneketone in the presence of a base.[5] The Friedländer [a] Prof.

Methods

Results

Conclusion