Multi-component Reactions in Molecular Diversity E-Book

• Herausgeber: John Wiley & Sons
• Kategorie: Wissenschaft und neue Technologien
• Sprache: Englisch

Seitenzahl: 226

Veröffentlichungsjahr: 2019

Beschreibung

While very useful for studying syntheses of molecular diversity, multi-component reactions also offer rapid access to a variety of complex molecules that are relevant for biological applications. Multi-component Reactions in Molecular Diversity analyzes these reactions, whether they are realized by organometallic, ionic or even radical processes. It highlights popular methods based on monotype reactions (cascade, tandem, domino) and their efficiency and academic industrial domain are illustrated. This book also investigates the most efficient ways to prepare complex molecules. Multi-component reactions are in tune with the concepts of atom and steps economy, which are of prior importance in all the reported processes ? from the laboratory to the pilot scale. The essential criteria for green chemistry are also examined in the book in detail.

Leseprobe

Table of Contents

Cover

1 Organometallic Multicomponent Reactions

1.1. Introduction

1.2. Multicomponent reactions: concept and applications

1.3. Merging multicomponent and organometallic transformations

1.4. Conclusion

1.5. References

2 Use of 1,3-Dicarbonyl Derivatives in Stereoselective Domino and Multicomponent Reactions

2.1. Introduction

2.2. Domino reactions

2.3. Multicomponent reactions

2.4. Conclusion

2.5. References

3 Multicomponent Radical Processes: Recent Developments

3.1. Polar effects: electrophilic and nucleophilic radical scales

3.2. Multicomponent radical reactions

3.3. Multi-component radical-ionic reactions

3.4. Sequential multicomponent radical reactions

3.5. Multicomponent reactions by photoredox catalysis

3.6. Conclusion

3.7. References

List of Authors

Index

End User License Agreement

Guide

Cover

Table of Contents

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Eco-compatibility of Organic Synthesis Set

coordinated by

Max Malacria

Volume 1

Multi-component Reactions in Molecular Diversity

Edited by

Jean-Philippe Goddard

Max Malacria

Cyril Ollivier

First published 2019 in Great Britain and the United States by ISTE Ltd and John Wiley & Sons, Inc.

Apart from any fair dealing for the purposes of research or private study, or criticism or review, as permitted under the Copyright, Designs and Patents Act 1988, this publication may only be reproduced, stored or transmitted, in any form or by any means, with the prior permission in writing of the publishers, or in the case of reprographic reproduction in accordance with the terms and licenses issued by the CLA. Enquiries concerning reproduction outside these terms should be sent to the publishers at the undermentioned address:

ISTE Ltd27-37 St George’s RoadLondon SW19 4EUUK

www.iste.co.uk

John Wiley & Sons, Inc.111 River StreetHoboken, NJ 07030USA

www.wiley.com

© ISTE Ltd 2019

The rights of Jean-Philippe Goddard, Max Malacria and Cyril Ollivier to be identified as the authors of this work have been asserted by them in accordance with the Copyright, Designs and Patents Act 1988.

Library of Congress Control Number: 2019947445

British Library Cataloguing-in-Publication Data

A CIP record for this book is available from the British Library

ISBN 978-1-78630-511-4

1Organometallic Multicomponent Reactions

1.1. Introduction

The first multicomponent reactions were discovered in the second half of the 19th Century. Long considered as laboratory curiosities, these reactions, which allow the assembly of several reactants in a single process and hence the synthesis of complex molecules with high added value, prospered at the end of the 20th Century with the advent of combinatorial chemistry. This new tool, used mainly by pharmaceutical and agrochemical companies, aims to quickly and efficiently produce large libraries of small, often heterocyclic, molecules for high throughput screening tests in order to increase the chances of identifying new bioactive compounds. The enthusiasm generated by these reactions has been greatly amplified by the emergence of the concept of green chemistry, through which researchers have committed themselves to minimizing the impact that the chemical sector can have on the environment. These new approaches are well adapted to meet this type of challenge, particularly in terms of saving time, energy or atoms, reducing waste and safety risks, and converging and simplifying processes. Catalysis is essentially one of the pillars of green chemistry because of its ability to accelerate and facilitate chemical reactions. Transition metal complexes are among the most widely used in the design of catalytic multicomponent reactions because of the multitude of transformations they are capable of catalyzing with often high selectivities. This chapter, which is not intended to be exhaustive, aims to illustrate, through selected examples, how multicomponent reactions, merged with metal catalysis, can meet the requirements of green chemistry.

1.2. Multicomponent reactions: concept and applications

1.2.1. Concept and correlation with the principles of green chemistry

Synthetic organic chemists have a wide range of methods at their disposal to develop new functionalized target molecules on which future progress in medicine, biotechnology, crop protection and materials depend. Traditionally, over the last century, these molecules have been essentially developed through successive steps allowing the incorporation of the various fragments that make up the final structure. The desired structural and functional complexity is thus only accessible through a linear sequence of independent chemical reactions. Multicomponent reactions, on the other hand, are processes that condense at least three reactants (components) into a single synthetic operation to produce a final molecule that incorporates the majority of the initial atoms. In general, an initial transformation combining two initial components will generate a reactive intermediate that will then undergo further transformations in the reaction medium by combining with other components. All these transformations take place in a single reactor; we will refer to this as a one-pot reaction (Figure 1.1). Ideally, and from a puristic point of view, all components, reagents and possible catalytic systems should be present in the reaction medium from the beginning of the reaction. The various components must then be successively assembled in a predetermined order under the same reaction conditions to synthesize a single product. This therefore raises the problem of the compatibility of the various reactants involved, and therefore the formation of secondary products. However, in practice, the development of such reactions is very difficult, and it may be appropriate, when possible, to delay the addition of one or more components, reagents, catalysts or ligands. It may also be possible to modulate the reaction parameters during the reaction. Thus, in some extreme cases, the design of a multicomponent reaction will involve successively carrying out several independent steps in the same pot (Herrera and Marques-López 2015a; Zhu et al. 2015).

Figure 1.1.Linear approach compared to a multicomponent approach involving three reactants (components) A, B and C. For color versions of the figures in this book, see www.iste.co.uk/malacria/reactions.zip

Multicomponent reactions are very effective in terms of atom economy and selectivity; they allow complex and varied structures to be reached in a single synthetic operation, that is without isolating the intermediate products formed during the reaction. Synthesis therefore requires fewer steps than a linear approach, saving time, equipment and consumables (solvents and reagents) and thus significantly reduces its impact on the environment, in particular by producing less waste (Cioc et al. 2014). This also reduces safety risks. Multicomponent reactions thus satisfy many of the principles of green chemistry (Anastas and Warner 1998).

1.2.1.1. Step economy

In general, conventional chemical synthesis pathways can only create one bond per step. This approach is very costly in terms of solvents, reagents, auxiliaries, energy and time. Multicomponent reactions, on the other hand, create several bonds in a single operation in the same reaction medium, without purification of the intermediates. They are therefore clean reactions insofar as the use of solvents is limited to the reaction itself. As the intermediate products are not isolated, the purification steps, which consume large amounts of organic solvents, are therefore limited, which also reduces the cost of producing the desired molecules. One-pot reactions also aim to reduce the production of toxic waste that is difficult to dispose of or recycle. These are reactions that take place in a single reactor, resulting in energy savings and lower equipment costs. This strategy also saves a significant amount of time, which is also an economic advantage.

1.2.1.2. Atom economy

Multicomponent reactions are a perfect answer to the concept of atom economy since they capitalize on the functionalities of each reactant in the final product. Indeed, these reactions offer the possibility of reaching very complex molecular systems in a single step where most of the functionalities of the starting products are found in the finished product. Reduced energy consumption is therefore required to create these structures compared to the requirements claimed in multistage synthesis.

1.2.1.3. Convergence and selectivity

Multicomponent reactions are often compatible with many functional groups, which do not participate in the main reaction but can then be involved, in situ where possible, in derivatization reactions – also called post-condensation reactions. The latter make it possible to increase the structural complexity and/or functional diversity of the targeted products. These reactions, which take place in a single reactor, are very efficient, generating fewer by-products that are difficult to separate and eliminate. Tedious steps such as protection/deprotection of functional groups are avoided.

1.2.1.4. Process safety

Some solvents are dangerous. They can be toxic, flammable, polluting, explosive. Multicomponent reactions considerably reduce these risks by reducing the quantities of solvents used to prepare the required compounds. Multicomponent reactions also avoid isolating the reaction intermediates. These can be unstable or toxic. Such reactions therefore have the advantage of performing transformations that would not be feasible in several, independent steps, as well as minimizing some risks of chemical accidents.

1.2.1.5. Eco-compatible solvents

The use of water as a solvent has many advantages. Due to its physico-chemical properties, it makes it possible to increase the reactivity and selectivity of many reactions and to operate under milder conditions, as well as to avoid in some cases the protection/deprotection steps (Gawande et al. 2013). It also simplifies the isolation of products, which are generally not very soluble in this medium. It is therefore interesting from an economic point of view (reduced costs), but also ecological (total absence of toxicity). These beneficial effects of water have also been observed in some multicomponent reactions (Gu 2012). The use of other eco-compatible media, such as ionic liquids and deep eutectic solvents, polyethylene glycol, biosourced solvents, or simply solvent-free reactions, has also been documented (Isambert et al. 2011; Shankar Singh and Chowdhury 2012; Liu et al. 2015).

Multicomponent reactions have also benefitted from many non-conventional reaction techniques particularly adapted to the principles of green chemistry. These include sonication techniques, but above all microwave technology, the main advantage of which is to drastically reduce reaction times, thus reducing the energy cost of processes while often improving the efficiency and purity of reaction products (Hügel 2009). Likewise, continuous reactor technologies have developed considerably in recent years and are also gradually adapting to multicomponent synthesis. Among their many advantages, these continuous flow chemical production methods (flow chemistry) allow, through automation, reactions to proceed under optimal conditions of efficiency and safety, on a small or large scale, and in a reproducible manner (Newman and Jensen 2013). These technologies, particularly well adapted to the synthesis of chemical libraries, are used in pharmaceutical research and development departments.

1.2.2. Origins and areas of application

The first multicomponent reaction was developed in the mid-19th Century (1850) by Strecker; it allows the synthesis of α-amino acids from aldehydes, ammonia and hydrocyanic acid, after hydrolysis of the α-aminonitriles formed (Strecker 1880). However, it should be noted that a few years earlier, in 1837, the French chemists Auguste Laurent and Charles Gerhardt studied the reaction of bitter almond oil, containing benzaldehyde and hydrocyanic acid, with ammonia and proposed the formation of aminonitriles (Laurent and Gerhardt 1837, 1838). The first reaction to achieve heterocyclic compounds was developed in 1882 by Hantzsch during the synthesis of functionalized dihydropyridines, by reacting ammonia on various aldehydes in the presence of two equivalents of β-ketoesters (Hantzsch 1882). This was followed by Biginelli’s reaction to synthesize dehydropyrimidones (1891) (Kappe 1993) and Mannich’s reaction to β-aminoketones (1912) (Figure 1.2a) (Mannich and Krösche 1912). New reactions emerged later, based on the reactivity of isonitriles. These include the Passerini reaction (1921) and more particularly that of Ugi (1959) involving four components (Figure 1.2b) (Ugi et al. 1991).

Figure 1.2.History of multicomponent reactions

Among the first notable applications of these reactions was the synthesis of nifedipine by Bayer in 1981. This molecule used in the treatment of hypertension and angina pectoris is directly synthesize via the Hantzsch reaction (Figure 1.3a) (Bossert et al. 1981). It should also be noted that tropinone, a precursor of atropine used as an antidote to certain intoxications, was also synthesized in 1917 by Robinson (Nobel Prize 1947). It represents the first multicomponent synthesis of a natural product and involves successive inter- and intramolecular Mannich reactions (Figure 1.3b) (Robinson 1917).

Figure 1.3.Syntheses of Nifedipine and Tropinone based on the Hantzsch and Mannich reactions, respectively

It was only at the end of the last century that this type of reaction gained renewed interest with the advent of combinatorial chemistry (Jung 1999) and the need to develop new chemical technologies that are more environmentally friendly. As the search for new lead compounds by pharmaceutical and agrochemical companies is mainly based on the evaluation of biological tests of a large number of small molecules, the introduction of high throughput screening techniques in molecular biology has led synthetic chemists to develop methods for the rapid and efficient preparation of large collections of small molecules (libraries), often heterocyclic, with the same skeleton but differing only by the nature of the substituents (Hulme 2005; Rotstein et al. 2014). The main challenge was to improve synthesis strategies by avoiding the isolation of intermediates and time-consuming purifications including extraction, distillation, chromatography and crystallization, and to develop strategies to achieve a set of related molecules in the fewest operations. In this context, multicomponent reactions have proven to be a perfect tool for the rapid synthesis of compound series. The Ugi condensation reaction, in particular, has seen considerable growth as it allows a high degree of molecular diversity to be achieved thanks to its four modular components, while generating only water as a by-product. It enables, from commercial or easily accessible compounds, the quick creation of large libraries of peptide derivatives. Many post-condensation reactions associated with the Ugi reaction have also been developed, including cyclization reactions that lead to “rigidification” of structures, thus broadening their potential properties and applications (Sunderhaus and Martin 2009). Very high levels of diversity and complexity are thus easily accessible (Ruijter et al. 2011). In addition to the new opportunities for the research of bioactive molecules (Dömling 2012), multicomponent reactions have found their application in the optimization of existing synthesis pathways by reducing the number of steps. A very good example is telaprevir, a peptide protease inhibitor recently approved for the treatment of hepatitis C, whose 20 synthetic steps have been halved thanks to the implementation of a new strategy based on two multicomponent reactions (Ugi and Passerini) (Zarganes-Tzitzikas and Dömling 2014). Multicomponent reactions have also been used in the synthesis of natural products and analogues (Toure and Hall 2009), and more recently in the construction of macromolecules, such as polymers, including dendrimers (Rudick 2013), as well as peptidomimetics (Koopmanschap et al. 2014). Some of these applications will be illustrated during this presentation.

Given their remarkable potential for organic synthesis, the search for new multicomponent reactions now occupies a major place in modern organic chemistry. To date, a multitude of processes have been described in the literature, most often combining three to four reactants, but in some rare cases up to five or more reactants (Brauch et al. 2013). In this field, many advances have been made, thanks to the contribution of catalysis by transition metals.

1.3. Merging multicomponent and organometallic transformations

As we have just seen, the first multicomponent reactions were based on condensation reactions of carbonyl derivatives and the use of reactive compounds such as imines and isonitriles; they were therefore mainly adapted to the preparation of a certain type of nitrogen compounds. The use of catalyzed processes, particularly by transition metals, has made it possible to achieve greater diversity and molecular complexity thanks to the wide variety of elementary processes that they are able to catalyze, and all within a reasonable time frame.

1.3.1. History: the predominant role of palladium

Among the first multicomponent organometallic reactions, we can mention the conjugate addition reactions of organometallic nucleophiles on cyclic enones, followed by a trapping of the enolate formed by an electrophilic species. As the alkylating agent approaches the most exposed side of the enolate, the trans diastereomer is preferentially formed (Figure 1.4a).

These reactions, developed in the 1970s by Stork (Stork and Isobe 1975), have been used in particular in the synthesis of prostaglandins, natural products involved in many biological processes. They most often involve the addition of a lithiated organo-copper compound (R2CuLi type) to a cyclopentenone.

A very good illustration of these reactions is shown by the synthesis of an advanced intermediate of prostaglandin E2 (Figure 1.4b). Developed by Noyori in 1984, it enables the introduction of the two side chains in a single step and with perfect control of the formed stereogenic centers (Noyori and Suzuki 1984).

Figure 1.4.Tandem conjugate addition/alkylation reactions: application to the synthesis of prostaglandin E2

Many catalytic multicomponent reactions began to emerge in the 1980s, particularly focusing on alkenes, alkynes, and to a lesser extent allenes as key components, due to the particular affinity of transition metals for unsaturated functional groups. Among the latter, palladium occupies a prominent place. The interest of this metal for the development of multicomponent reactions lies, on the one hand, in its compatibility with a very large number of functional groups and, on the other hand, in the great diversity of fundamental processes that it catalyzes, as well as in its ability to create several carbon-carbon or carbon-heteroatom bonds in a single operation (Balme et al. 2003; D’Souza and Müller 2007). The Heck reaction (Nobel Prize in Chemistry 2010), used since 1968 for the coupling of alkenes with halogenated aromatic derivatives (Figure 1.5a), has significantly contributed to the development of the first multicomponent metal-catalyzed reactions, based in particular on alkene carbopalladation. It has indeed been shown that the syn-addition of an organopalladium complex to a suitably chosen unsaturated bond – so that the catalytic cycle cannot end with the conventional syn-