Elsevier

Tetrahedron

Volume 65, Issue 14, 4 April 2009, Pages 2721-2750
Tetrahedron

Tetrahedron report number 868
Recent synthetic developments in a powerful imino Diels–Alder reaction (Povarov reaction): application to the synthesis of N-polyheterocycles and related alkaloids

https://doi.org/10.1016/j.tet.2008.12.059Get rights and content

Graphical abstract

This review is devoted to the development in Povarov reaction and focuses on new efficient approaches based on this reaction to construct simple substituted (tetrahydro)quinolines and diverse N-polyheterocycles, including some alkaloids, which contain pyrroloquinoline or cyclopentaquinoline ring systems.

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Introduction

The Diels–Alder (DA) reaction, with its rich synthetic diversity, is recognized as a powerful reaction in the synthetic strategies of natural and unnatural polycarbocycles and polyheterocycles.1 From the memorable publication by Diels and Alder2 to our days ‘diene synthesis’ is used as a standard method employed frequently for the formation of six-membered ring systems with excellent regio-, diastereo-, and enantio-selective controls. Because the use of DA reactions covers compounds of academic, industrial or medicinal interest, research work in this area has been discussed in several reviews and monographs from time to time.3, 4, 5, 6, 7, 8, 9, 10 The DA reaction methodology contains two basic variants of reaction, which can be classified as carbo-DA reaction (CDA) and hetero-DA reaction (HDA), which could be also subdivided as like oxa-DA reaction (HDA of carbonyl compounds) and imino (aza)-DA reaction (HDA of imines) (Fig. 1).

This latter variant is becoming a mainstay of heterocycles and natural product synthesis.11, 12, 13, 13(a), 13(b), 14 To complete the proposed classification, it is well to bear in mind that the imines can react in these reactions as either dienophiles or azadienes. The [4+2] cycloaddition reaction of N-aryl imines (Schiff's bases) with nucleophilic olefins is one of the most convenient methods of quinoline preparation, which is usually catalyzed by Lewis acids. BF3·OEt2 has been mainly used for this purpose since the pioneering works of Povarov.15, 16, 17, 18, 19 Acid-mediated cycloaddition between the Cdouble bondC–Ndouble bondC azadiene moieties of N-aryl imines and dienophiles also has become an established route to various tetrahydroquinolines and consequently, quinolines, the major class of heterocycles. Thus, this interaction between N-aryl imines and electron-rich dienophiles should be named the Povarov reaction.20

The DA reaction can also take place intramolecularly when a molecule contains both the diene and dienophile moieties, which are connected by a chain at position C-1 of the diene (type 1 intramolecular DA reaction) or at position C-2 of the diene (type 2 intramolecular DA reaction).21, 21(a), 21(b), 21(c) As a result of these interactions, fused bicyclic adducts and bridged bicyclic compounds are obtained (Fig. 2). The type 2 intramolecular acyl imino DA reaction was utilized as an entry to a class of complex compounds that possess both a bridgehead alkene and bridgehead lactam unit.21c

Nowadays, these types of DA reactions are valuable tools in contemporary organic synthesis, generating heterocyclic rings where the size of the second ring depends on chain broadening. Indeed, multi-component inter- and intramolecular Povarov reactions have gained popularity in both diversity-oriented synthesis (DOS) and target-oriented synthesis (TOS). This review is devoted to the development of the Povarov reaction and focuses on new efficient approaches based on this process to construct simple substituted (tetrahydro)quinolines and diverse N-polyheterocycles, including some alkaloids, which contain pyrroloquinoline or cyclopentaquinoline ring systems. The review covers the literature up to September 2008, but does not mean to be strictly comprehensive, although its goal is to highlight the improvements in the synthesis of quinoline derivatives via the Povarov reaction. Also included are various applications, specially, the multi-component coupling strategy, which allows a quick access to these compounds, giving a special attention to environmentally friendly methodologies and to their synthetic potential in the structural diversification of new heterocyclic entities. However, to provide a good understanding of the quinoline derivatives preparation scope via the Povarov reaction, older reactions were included as well.

Section snippets

Construction of simple tetrahydroquinoline and/or quinoline ring systems via [4+2] cycloadditions between N-aryl aldimines and alicyclic dienophiles

Among the nitrogen heterocycles, quinolines and their derivatives represent an important class of organic molecules attracting the interest of both synthetic and medicinal chemists. Functionalized quinolines have found applications as pharmaceuticals and agrochemicals as well as useful synthetic blocks in the preparation of several alkaloids. Many syntheses of quinoline derivatives are known, but due to their importance, the development of new synthetic approaches remains an active research

Intramolecular Povarov reaction

The type 1 intramolecular Povarov reaction (Fig. 2) and its multi-component version have gained popularity in both diversity-oriented synthesis and target-oriented synthesis. This intramolecular implementation of the imino Diels–Alder reaction has the added advantages including better control over the formation of stereoisomers and the creation of an additional ring.99 To accomplish the type 1 intramolecular Povarov reaction, all one need to do is to have functionalized anilines and

Intramolecular imino Diels–Alder approach to the synthesis of indolizino[1,2-b]quinolin-9(11H)-one alkaloids

The quinoline derivatives discussed above are closely related to several quinoline alkaloids. Despite the large number of the quinoline derivatives synthesis based on the intramolecular imino DA reaction, there have been only a few examples of the use of this reaction in total synthesis. However, the growing interest for the development of an intramolecular cycloaddition began to produce initial, but remarkable results, specifically in constructing pyrrolo[3,4-b]quinoline-based alkaloids. The

[4+2] Cycloadditions between N-aryl aldimines and cyclic dienophiles

This part of the review deals with the [4+2] cycloadditions between N-aryl aldimines and cyclic dienophiles (Fig. 10), which offer different structural quinoline derivatives. Earlier numerous works on their interactions were discussed in several reviews,13, 13(a), 13(b), 14, 23 an in-depth analysis on the interesting process of polycyclic quinolines construction will not be taken up. This part will focus on the generation of new polyfunctionalized quinoline derivatives, including pyrrolo[3,2-c

Conclusions

The major developments of both intra- and intermolecular imino DA reactions (Povarov reactions) of N-aryl imines and diverse electron-rich alkenes have been presented. Povarov reaction, a simple variant of venerable DA cycloadditions provides a direct route to different N-heterocycles in a single step from available precursors, Schiff's bases. In more recent developments, this reaction has served as a key step in the construction of complex polycyclic rings that make up the core of a number of

Acknowledgements

This work was financially supported by the grants of the Colombian Institute for Science and Research. Author thanks Industrial University of Santander (UIS) for providing sabbatical year (2005–2006) and Prof. José Barluenga and Prof. Miguel Tomas (Instituto Universitario de Química Organometálica ‘Enrique Moles’, Universidad de Oviedo) for their warm receive during the realization of this sabbatical year.

Vladimir V. Kouznetsov was born and raised in Murmansk, Russia, in 1957. He studied Chemistry at the Russian Peoples Friendship University, Moscow where he received his Laurea M.Sc. (1981), Ph.D. (1986), and D.Sc. (1994) degrees in Chemistry, working with Professor Nikolai S. Prostakov and Associate Professor Ludmila A. Gayvoronskaya. He spent postdoctoral fellowship (1990–1992) with Professor José Barluenga and Professor Miguel Tomas at the University of Oviedo (Spain), working on synthetic

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    Vladimir V. Kouznetsov was born and raised in Murmansk, Russia, in 1957. He studied Chemistry at the Russian Peoples Friendship University, Moscow where he received his Laurea M.Sc. (1981), Ph.D. (1986), and D.Sc. (1994) degrees in Chemistry, working with Professor Nikolai S. Prostakov and Associate Professor Ludmila A. Gayvoronskaya. He spent postdoctoral fellowship (1990–1992) with Professor José Barluenga and Professor Miguel Tomas at the University of Oviedo (Spain), working on synthetic approach to hetaryl substituted polyamines and tetraponerine alkaloids. He became Associate Professor in 1993 at the Russian Peoples Friendship University. In 1994 he moved to Colombia through a Colciencias' program of scientific mobilization. Very soon he became Professor Titular at the Industrial University of Santander (Bucaramanga, Colombia), where he founded the Laboratory of Organic Chemistry. Now he is director of the Laboratory of Organic and Biomolecular Chemistry. He was principal tutor of 19 graduated and 17 under graduated students, both in Russia and Colombia. He authored and co-authored over 130 papers, 5 patents, 3 books, and 1 book chapter. Actually, he is editorial board member of organic journals: Letters in Organic Chemistry, Current Organic Synthesis and the Open Organic Chemistry Journal. Kouznetsov's research interest focus on heterocyclic diversity-oriented, including natural product synthesis, interface between chemistry and biology.

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