Chapter One - The application of the Fischer indole synthesis in medicinal chemistry

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Abstract

The indole ring system is an important scaffold in a great number of biologically significant molecules and hence there are numerous methods to access this heterocyclic ring system. The Fischer indole reaction is one of the oldest methods, and due to its versatility, it is a widely employed method of preparing substituted indoles. This review will cover the period from 2016 to June 2022 and will focus on the application of the method in the area of medicinal chemistry.

Introduction

The indole ring system is widely distributed in biological systems and known as a privileged heterocycle in medicinal chemistry.1 It is therefore not surprising that many synthetic methods exist to prepare the ring system,2 but one of the most versatile methods is the Fischer indole synthesis. The synthesis was discovered in 1883 by Emil Fischer and involves the conversion of enolizable N-arylhydrazones into indoles.3 The original synthesis employed alcoholic hydrogen chloride as catalyst, but the reaction has now been extended to include an extensive range of catalysts and there are also examples of uncatalyzed thermal reactions. There are many advantages to the Fischer indole synthesis, but the most important attributes are the range of functional groups that are tolerated; the ready accessibility of the starting materials and no requirement to isolate the hydrazone intermediate. There are many excellent reviews4, 5, 6, 7, 8 and the current review will cover the period 2016 to 2022 and focus on applications to medicinal chemistry.

Section snippets

Mechanism of the Fischer indole synthesis

The mechanistic details of the Fischer indole synthesis were established over several years and the currently accepted mechanism is that outlined in Scheme 1 and originally proposed by R. Robinson.9 Following formation of the hydrazone 1, the imine nitrogen is protonated and tautomerization generates an ene-hydrazine 2, which then undergoes a [3,3]-sigmatropic rearrangement (diaza-Cope rearrangement).10 The dimide 3 produced rearomatizes, followed by cyclisation to generate intermediate 4 which

Aryl hydrazines and hydrazones

The classical approach to obtaining phenyl hydrazines is via treatment of the corresponding diazonium salt (in turn accessed from the requisite aniline via treatment with NaNO2/acid) with an appropriate reducing agent. The resulting hydrazines are frequently protected either as the hydrochloride salt, or boc-protected form,25 given their inherent instability.

In a recent paper from Schmidt and coworkers26 they explored the effect of alkylation of the phenyl hydrazine component on the nature of

Cancer

Cancer has been characterized as the main public health problem around the world. One of the key treatment for cancers is chemotherapy. However, side effects and drug resistance to the current treatments necessitates the development of new drugs.

The indole ring has long been used as a scaffold in this area and work by Gaikwad and coworkers utilized 2-phenylindole is an effective scaffold for the treatment of cancers, such as breast cancer, lung cancer and melanoma. Molecular modeling studies

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