Ready access to 7,8-dihydroindolo[2,3-d][1]benzazepine-6(5H)-one scaffold and analogues via early-stage Fischer ring-closure reaction.

Irina Kuznetcova,Hsiang-Yu Chuang,Vladimir B Arion,Felix Bacher,Daniel Vegh

doi:10.3762/bjoc.18.15

Abstract

Paullone isomers are known as inhibitors of tubulin polymerase and cyclin dependent kinases (Cdks), which are potential targets for cancer chemotherapy. Herein we report an efficient and clean pathway to the fourth isomer, which remained elusive so far, namely 7,8-dihydroindolo[2,3-d][1]benzazepin-6(5H)-one. Moreover, we demonstrate the generality of our pathway by synthesizing two closely related analogues, one containing a bromo substituent and the other one incorporating an 8-membered instead of a 7-membered ring. The key transformation in this four-step synthesis, with an overall yield of 29%, is the Fischer indole reaction of 2-nitrophenylacetyl acetoacetate with 1-benzyl-1-phenylhydrazine in acetic acid that delivers methyl 2-(1-benzyl-3-(2-nitrophenyl)-1H-indol-2-yl)acetate in 55% yield.

Highlights

Indolobenzazepines are fused heterocyclic scaffolds with versatile medicinal properties, including anti-Alzheimer, anti-inflammatory, anticancer, antidiabetic, and antileishmanial activity [1]
Paullone isomers are known as inhibitors of tubulin polymerase and cyclin dependent kinases (Cdks), which are potential targets for cancer chemotherapy
The third pathway (c) was centered around a ring-closure reaction via lactam-bond formation from a precursor that contains a carboxylic ester in position 2 and an o-aniline moiety in position 3 of the indole ring by Fischer indole synthesis from methyl 4-(2-nitrophenyl)-3-oxobutanoate (Scheme 1)

Summary

Introduction

Indolobenzazepines are fused heterocyclic scaffolds with versatile medicinal properties, including anti-Alzheimer, anti-inflammatory, anticancer, antidiabetic, and antileishmanial activity [1]. The first retrosynthetic route (a) started with an alkyl halide precursor, which was expected to afford scaffold C after ringclosure reaction at position 2 of the indole ring [23]. The third pathway (c) was centered around a ring-closure reaction via lactam-bond formation from a precursor that contains a carboxylic ester in position 2 and an o-aniline moiety in position 3 of the indole ring by Fischer indole synthesis from methyl 4-(2-nitrophenyl)-3-oxobutanoate (Scheme 1).

Results

Conclusion