Imino Diels-Alder/transition metal catalyzed reactions to synthesise fused ring heterocycles

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Highlights

  • Imino Diels-Alder reactions were tactically combined with transition metal catalysed cycloaddition reactions.

  • Creating molecular complexity using simple starting materials.

  • Highly atom economical process.

Abstract

Imino Diels-Alder reactions were tactically combined with various transition metal catalysed [2 + 2], [3 + 2] and [4 + 2] cycloaddition reactions to form novel syntheses for biologically relevant fused-ring heterocycles with molecular complexity in good yields.

Introduction

[2,3]-Dihydropyridone and tetrahydroquinoline heterocycles are important structural skeletons as they can provide the structural backbone to many bioactive molecules (Fig. 1) [[1], [2], [3], [4]].

There are several methods of constructing these six membered nitrogen-containing heterocycles, although one of the most powerful tools is the imino Diels-Alder reaction. This reaction allows the synthesis of various pyridines and quinolines using dienes and dienophiles, whilst maintaining functionality of attached functional groups. The remaining functionality of the imino Diels-Alder adducts can then be exploited to achieve further structural complexity, and hence have more potential for bioactivity.

These imino Diels-Alder reactions are often catalysed by either Brønsted acids or Lewis acids such as BF3·OEt2 or lanthanide triflates (Scheme 1) [[5], [6], [7]].

Tactical pre-selection of starting materials prior to imino Diels-Alder synthesis then results in heterocycles that can be functionalised at specific points within the resulting molecule. The use of transition metal catalysed reactions is then an attractive methodology for this functionalisation. The ability to construct complicated molecules from readily accessible starting materials, whilst using mild conditions is very appealing, especially in the formation of C–C bonds [8,9]. There are many examples of using transition metals for different organometallic transformations, with notable examples and reviews reported on palladium [[10], [11], [12], [13], [14]], rhodium [[15], [16], [17], [18]], copper [[19], [20], [21]] and many more [[22], [23], [24]].

In this article we wish to report tactical combinations of the imino Diels-Alder reaction with transition metal catalysed processes. The examples presented show multiple ways in which further molecular complexity can be attained, by decorating the heterocyclic scaffolds using various transition metal catalysed processes.

Section snippets

Results and discussion

Imino Diels-Alder adducts were combined with: (i) rhodium catalysed [2 + 2+2] cycloaddition reaction [25] or copper catalysed click reaction [26] and (ii) palladium catalysed strained alkene/aryne/alkyne insertion [[27], [28], [29], [30], [31], [32], [33]], (iii) intramolecular Heck reaction [34] and (iv) palladium catalysed carbonylation [35] reaction to form novel fused-ring heterocycles analogues to the Estrogen receptor agonist shown in Fig. 1.

Initially we carried out the reactions of the

General experimental information

Unless otherwise stated all chemicals were obtained commercially with no additional purification. Chromatography columns were prepared using Geduran Silicagel 60 (40–63 μm) silica powder. Nuclear magnetic resonance spectra were recorded using 500 MHz (1H) and 125 MHz (13C) upon a Bruker Avance 500 spectrometer in each case. Unless otherwise stated all NMR were obtained in deuterated chloroform at room temperature (25 °C). NMR chemical shifts are reported in parts per million (ppm) (δ) compared

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgements

We would like to thank the University of Leeds for their support.

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