Synthesis of Heterocycles via Multicomponent Reactions II (Topics in Heterocyclic Chemistry, Volume 25)

25 Topics in Heterocyclic Chemistry Series Editor: Bert U. W. Maes Editorial Board: D. Enders S.V. Ley G. Mehta K.C. N...

Author: Romano V. A. Orru | Eelco Ruijter

68 downloads 1286 Views 4MB Size Report

This content was uploaded by our users and we assume good faith they have the permission to share this book. If you own the copyright to this book and it is wrongfully on our website, we offer a simple DMCA procedure to remove your content from our site. Start by pressing the button below!

Report copyright / DMCA form

DOWNLOAD PDF

25 Topics in Heterocyclic Chemistry Series Editor: Bert U. W. Maes

Editorial Board: D. Enders S.V. Ley G. Mehta K.C. Nicolaou R. Noyori L.E. Overman A. Padwa S. Polanc l

l

l

l

l

l

l

Topics in Heterocyclic Chemistry Series Editor: Bert U.W. Maes Recently Published and Forthcoming Volumes

Synthesis of Heterocycles via Multicomponent Reactions II Volume Editors: R.V.A. Orru, E. Ruijter Volume 25, 2010

Synthesis of Heterocycles via Cycloadditions II Volume Editor: A. Hassner Volume 13, 2008

Anion Recognition in Supramolecular Chemistry Volume Editors: P.A. Gale, W. Dehaen Volume 24, 2010

Synthesis of Heterocycles via Cycloadditions I Volume Editor: A. Hassner Volume 12, 2008

Synthesis of Heterocycles via Multicomponent Reactions I Volume Editors: R.V.A. Orru, E. Ruijter Volume 23, 2010 Heterocyclic Scaffolds I: b-Lactams Volume Editor: B. Banik Volume 22, 2010 Phosphorous Heterocycles II Volume Editor: R.K. Bansal Volume 21, 2009 Phosphorous Heterocycles I Volume Editor: R.K. Bansal Volume 20, 2009 Aromaticity in Heterocyclic Compounds Volume Editors: T. Krygowski, M. Cyran´ski Volume 19, 2009 Heterocyclic Supramolecules I Volume Editor: K. Matsumoto Volume 17, 2008 Bioactive Heterocycles VI Flavonoids and Anthocyanins in Plants, and Latest Bioactive Heterocycles I Volume Editor: N. Motohashi Volume 15, 2008 Heterocyclic Polymethine Dyes Synthesis, Properties and Applications Volume Editor: L. Strekowski Volume 14, 2008

Bioactive Heterocycles V Volume Editor: M.T.H. Khan Volume 11, 2007 Bioactive Heterocycles IV Volume Editor: M.T.H. Khan Volume 10, 2007 Bioactive Heterocycles III Volume Editor: M.T.H. Khan Volume 9, 2007 Bioactive Heterocycles II Volume Editor: S. Eguchi Volume 8, 2007 Heterocycles from Carbohydrate Precursors Volume Editor: E.S.H. ElAshry Volume 7, 2007 Bioactive Heterocycles I Volume Editor: S. Eguchi Volume 6, 2006 Marine Natural Products Volume Editor: H. Kiyota Volume 5, 2006 QSAR and Molecular Modeling Studies in Heterocyclic Drugs II Volume Editor: S.P. Gupta Volume 4, 2006 QSAR and Molecular Modeling Studies in Heterocyclic Drugs I Volume Editor: S.P. Gupta Volume 3, 2006

Synthesis of Heterocycles via Multicomponent Reactions II Volume Editors: R.V.A. Orru, E. Ruijter

With contributions by I. Akritopoulou-Zanze J.B. Bariwal C. Bughin S.W. Djuric A. Fayol N. Kielland R. Lavilla G. Masson T.J.J. Mu¨ller L. Neuville R.V.A. Orru E. Ruijter R. Scheffelaar J.C. Trivedi E.V. Van der Eycken J. Zhu

The series Topics in Heterocyclic Chemistry presents critical reviews on “Heterocyclic Compounds” within topic-related volumes dealing with all aspects such as synthesis, reaction mechanisms, structure complexity, properties, reactivity, stability, fundamental and theoretical studies, biology, biomedical studies, pharmacological aspects, applications in material sciences, etc. Metabolism will also be included which will provide information useful in designing pharmacologically active agents. Pathways involving destruction of heterocyclic rings will also be dealt with so that synthesis of specifically functionalized non-heterocyclic molecules can be designed. The overall scope is to cover topics dealing with most of the areas of current trends in heterocyclic chemistry which will suit to a larger heterocyclic community. As a rule, contributions are specially commissioned. The editors and publishers will, however, always be pleased to receive suggestions and supplementary information. Papers are accepted for Topics in Heterocyclic Chemistry in English. In references, Topics in Heterocyclic Chemistry is abbreviated Top Heterocycl Chem and is cited as a journal. Springer www home page: springer.com Visit the THC content at springerlink.com

Topics in Heterocyclic Chemistry ISSN 1861-9282 ISBN 978-3-642-15454-6 e-ISBN 978-3-642-15455-3 DOI 10.1007/978-3-642-15455-3 Springer Heidelberg Dordrecht London New York Library of Congress Control Number: 2010926026 # Springer-Verlag Berlin Heidelberg 2010 This work is subject to copyright. All rights are reserved, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilm or in any other way, and storage in data banks. Duplication of this publication or parts thereof is permitted only under the provisions of the German Copyright Law of September 9, 1965, in its current version, and permission for use must always be obtained from Springer. Violations are liable to prosecution under the German Copyright Law. The use of general descriptive names, registered names, trademarks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. Cover design: WMXDesign GmbH, Heidelberg, Germany Printed on acid-free paper Springer is part of Springer Science+Business Media (www.springer.com)

Series Editor Prof. Dr. Bert U.W. Maes Organic Synthesis Department of Chemistry University of Antwerp Groenenborgerlaan 171 B-2020 Antwerp Belgium

Volume Editors Prof. Dr. Romano V.A. Orru

Dr. Eelco Ruijter

VU University Amsterdam Faculty of Sciences Department of Chemistry and Pharmaceutical Sciences De Boelelaan 1083 1081 HV Amsterdam Netherlands [email protected]

VU University Amsterdam Faculty of Sciences Section of Synthetic & Bioorganic Chemistry 1081 HV Amsterdam Netherlands [email protected]

Editorial Board Prof. D. Enders

Prof. K.C. Nicolaou

RWTH Aachen Institut fu¨r Organische Chemie 52074, Aachen, Germany [email protected]

Chairman Department of Chemistry The Scripps Research Institute 10550 N. Torrey Pines Rd. La Jolla, CA 92037, USA [email protected] and Professor of Chemistry Department of Chemistry and Biochemistry University of CA San Diego, 9500 Gilman Drive La Jolla, CA 92093, USA

Prof. Steven V. Ley FRS BP 1702 Professor and Head of Organic Chemistry University of Cambridge Department of Chemistry Lensfield Road Cambridge, CB2 1EW, UK [email protected] Prof. G. Mehta FRS Director Department of Organic Chemistry Indian Institute of Science Bangalore 560 012, India [email protected]

vi

Editorial Board

Prof. Ryoji Noyori NL

Prof. Albert Padwa

President RIKEN (The Institute of Physical and Chemical Research) 2-1 Hirosawa, Wako Saitama 351-0198, Japan and University Professor Department of Chemistry Nagoya University Chikusa, Nagoya 464-8602, Japan [email protected]

William P. Timmie Professor of Chemistry Department of Chemistry Emory University Atlanta, GA 30322, USA [email protected]

Prof. Larry E. Overman Distinguished Professor Department of Chemistry 516 Rowland Hall University of California, Irvine Irvine, CA 92697-2025 [email protected]

Prof. Slovenko Polanc Professor of Organic Chemistry Faculty of Chemistry and Chemical Technology University of Ljubljana Askerceva 5 SI-1000 Ljubljana Slovenia [email protected]

Topics in Heterocyclic Chemistry Also Available Electronically

Topics in Heterocyclic Chemistry is included in Springer’s eBook package Chemistry and Materials Science. If a library does not opt for the whole package the book series may be bought on a subscription basis. Also, all back volumes are available electronically. For all customers who have a standing order to the print version of Topics in Heterocyclic Chemistry, we offer the electronic version via SpringerLink free of charge. If you do not have access, you can still view the table of contents of each volume and the abstract of each article by going to the SpringerLink homepage, clicking on “Chemistry and Materials Science,” under Subject Collection, then “Book Series,” under Content Type and finally by selecting Topics in Heterocyclic Chemistry. You will find information about the – Editorial Board – Aims and Scope – Instructions for Authors – Sample Contribution at springer.com using the search function by typing in Topics in Heterocyclic Chemistry. Color figures are published in full color in the electronic version on SpringerLink.

Aims and Scope The series Topics in Heterocyclic Chemistry presents critical reviews on “Heterocyclic Compounds” within topic related volumes dealing with all aspects such as synthesis, reaction mechanisms, structure complexity, properties, reactivity, stability, fundamental and theoretical studies, biology, biomedical studies, pharmacological aspects, applications in material sciences etc. Metabolism is also included which provides information useful in designing pharmacologically active agents. Pathways involving destruction of heterocyclic ring are also dealt with so that synthesis of specifically functionalized non-heterocyclic molecules can be designed. Overall scope is to cover topics dealing with most of the areas of current trends in heterocyclic chemistry which suits a larger heterocyclic community. The individual volumes of Topics in Heterocyclic Chemistry are thematic. Review articles are generally invited by the volume editors. In references Topics in Heterocyclic Chemistry is abbreviated Top Heterocycl Chem and is cited as a journal. vii

.

Preface

Synthetic sophistication has increased to an impressive level in the past two centuries. Ongoing development of novel synthetic concepts and methodologies has opened up the way to the construction of many complex and challenging synthetic targets. However, in spite of its scientific merits and its profound influence on the progress of organic chemistry, it has become clear that much of the present synthetic methodology does not meet the conditions set to future purposes. Increasingly, severe economic and environmental constraints force the synthetic community to think about novel procedures and synthetic concepts to optimize efficiency. Robotics and combinatorial techniques allow chemists to synthesize single libraries that contain more compounds than ever before. Especially, medicinal chemists but also chemists active in the catalysis area have embraced this efficient new synthesis tool. Moreover, advances in molecular biology and genomics continue to improve our understanding of biological processes and to suggest new approaches to deal with inadequately or untreated diseases that afflict mankind. Despite all the progress in both molecular biology/genomics and combinatorial chemistry methods, it is generally recognized that the number of pharmaceutically relevant hits is not directly proportional to the number of compounds screened. Both structural diversity and complexity in a collection of molecules are essential to address. Ideally, a synthesis starts from readily available building blocks and proceeds fast and in one simple, safe, environmentally acceptable, and resource-effective operation in quantitative yield. Inspired by Nature, the construction of complex molecules by performing multiple steps in a single operation is receiving considerable attention. Such processes, in which several bonds are formed in one sequence without isolating the intermediates, are commonly referred to as tandem reactions. An important subclass of tandem reactions is the multicomponent reactions (MCRs). These are defined as one-pot processes that combine at least three easily accessible components to form a single product, which incorporates essentially all the atoms of the starting materials. MCRs are highly flexible,

ix

x

Preface

(chemo)-selective, convergent, and atom-efficient processes of high exploratory power (EN) that minimize solvent consumption and maximize atom efficiency. Many MCRs are well suited for the construction of heterocyclic cores. MCR-based processes therefore contribute to a sustainable use of resources and form the perfect basis for modular reaction sequences composed of simple reactions that achieve in a minimal number of steps a high degree of both complexity and diversity for a targeted set of scaffolds. As a consequence, the design of novel MCRs and their exploration as tools in especially heterocyclic chemistry receive growing international attention. Novel MCRs are applied in combinatorial and medicinal chemistry but also in catalysis and more traditional natural product syntheses. These and other topics are at the heart of this Volume of Topics in Heterocyclic Chemistry, which is entirely devoted to MCRs in the synthesis of heterocycles. This collection of major contributions from established scientists will certainly stimulate discussions and further development in this field of chemistry. I hope that you enjoy it. VU University, Amsterdam July 2010

Romano V.A. Orru & Eelco Ruijter

Contents

Multicomponent Syntheses of Macrocycles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 Ge´raldine Masson, Luc Neuville, Carine Bughin, Aude Fayol, and Jieping Zhu Palladium-Copper Catalyzed Alkyne Activation as an Entry to Multicomponent Syntheses of Heterocycles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25 Thomas J.J. Mu¨ller Multicomponent Reaction Design Strategies: Towards Scaffold and Stereochemical Diversity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 95 Rachel Scheffelaar, Eelco Ruijter, and Romano V.A. Orru Recent Developments in Reissert-Type Multicomponent Reactions . . . . . 127 Nicola Kielland and Rodolfo Lavilla Microwave Irradiation and Multicomponent Reactions . . . . . . . . . . . . . . . . . . 169 Jitender B. Bariwal, Jalpa C. Trivedi, and Erik V. Van der Eycken Applications of MCR-Derived Heterocycles in Drug Discovery . . . . . . . . . . 231 Irini Akritopoulou-Zanze and Stevan W. Djuric Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 289

xi

Top Heterocycl Chem (2010) 25: 1–24 DOI: 10.1007/7081_2010_47 # Springer-Verlag Berlin Heidelberg 2010 Published online: 9 July 2010

Multicomponent Syntheses of Macrocycles Ge´raldine Masson, Luc Neuville, Carine Bughin, Aude Fayol, and Jieping Zhu

Abstract How to access efficiently the macrocyclic structure remained to be a challenging synthetic topic. Although many elegant approaches/reactions have been developed, construction of diverse collection of macrocycles is still elusive. This chapter summarized the recently emerged research area dealing with multicomponent synthesis of macrocycles, with particular emphasis on the approach named “multiple multicomponent reaction using two bifunctional building blocks”. Keywords Isocyanide Macrocycle Macrocyclization Macrocylopeptide Multicomponent reaction Multicomponent reaction Oxazole Passerin-3CR Staudinger reaction Ugi 4CR Contents 1 2 3

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 Macrocyclization Involving In Situ Generated (Activated) Functional Groups . . . . . . . . . . . . . . 5 Multiple Multicomponent Macrocyclization Using Two Bifunctional Building Blocks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11 4 Sequential Multiple Multicomponent Macrocyclization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19 5 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22

1 Introduction Macrocycles, by virtue of their widespread occurrence in nature and their intrinsic three-dimensional structures, play an important role in chemistry and biology and are medicinally relevant [1–4]. Indeed various important drugs, such as G. Masson, L. Neuville, C. Bughin, A. Fayol, and J. Zhu (*) Centre de Recherche de Gif, Institut de Chimie des Substances Naturelles, CNRS, 91198 Gif-sur-Yvette Cedex, France e-mail: [email protected]

2

G. Masson et al.

cyclosporine, macrolides (erythromycin) and the vancomycin family glycopeptides, contain macrocyclic element. For example, vancomycin (1, Fig. 1), a trismacrocyclic natural product, has been used for more than quarter a century as an antibiotic of last resort for the treatment of infections due to methicillin-resistant Staphylococcus aureus and other gram-positive organisms in patients allergic to b-lactam antibiotics [5–8]. Furthermore, turning linear molecules into macrocyclic structures is an important tool to manipulate the properties of compounds. Indeed, bioactive linear peptides can exist in a myriad of different conformations, very few of which are able to bind to their receptor [9–12]. Cyclization is a common approach to force peptides adopting bioactive conformations and to assess the important structural and dynamic properties of peptides [13]. In addition, cyclopeptides are much more resistant to in vivo enzymatic degradation than their linear counterpart. Apart from pharmaceutical applications, macrocycles have also found wide application in polymers [14], supramolecular chemistry [15–17], and nanomaterials [18]. Macrocycles and their formation, in general, have been the subjects of a manifold of publications and books (selected references: [19–25]). To address the synthesis of macrocyclic natural products or any designed macrocycles with specific purpose, ring closure is naturally the key step that will determine the efficacy of the overall synthetic strategy. Not surprisingly, the challenging problem of macrocyclization has attracted attention of synthetic chemists and provided impetus for the development of new technologies. Traditionally, two classes of reactions, namely, uni-molecular reaction ((1), Scheme 1) and cyclodimerization of two bifunctional monomers ((2), Scheme 1) have been successfully developed and applied in the synthesis of natural products as well as non-natural molecules (for examples of cyclodimerization, see: [26–28]). As oligomerization is one of the major side reactions that influence the efficiency of any given macrocyclization OH Me

OH OH

NH2

OH

O O

Me

O O O

O C H O N

O

O

H N O

NH

A

OOC

E

D

Cl

HO

Cl

N H O

OH O

H N O

NH2 B

HO

OHOH

Fig. 1 Structure of vancomycin

1 Vancomycin

N H

NH2CH3 CH3 CH3

Multicomponent Syntheses of Macrocycles Scheme 1 Cyclization and cyclodimerization

3

X

eq 1

Y

FG 3

2 X Y

+

Y

X*

Y*

X

Y*

X*

eq 2

2

Scheme 2 Linear sequence to cyclodimers X

2

4

a

X

b

Y

Y

5

YP

c

XP*

X*

YP

Y*

XP′

6 d,e

X*

Y

Y*

X 8

f

7 X*

Y*

Y*

X* 4

reaction; high-dilution conditions are generally applied to achieve the desired ring closure. Although the head-to-tail dimerization of bifunctional monomers is applicable only to C2-symmetric macrocyclic core and is very sensitive to substrate structures and reaction conditions because of the competitive oligomerization/polymerization, it is nevertheless inherently more efficient than the alternative stepwise process. Thus, to synthesize macrocycle 4 from monomer 2 by stepwise process, the functional groups in monomer 2 are required to be selectively protected to afford 5 and 6 before cross-coupling (Scheme 2). Macrocyclization of 8, obtained by the removal of the protecting group P and P0 from 7, would then provide the cyclodimer 4. The advantage of this stepwise process is that oligomerization is impossible in the initial coupling reaction (5þ6) and could potentially be avoided in the macrocyclization step by performing the cyclization under high-dilution conditions. Nevertheless, five linear steps are required to elaborate the macrocycle 4 from 2, in contrast to the one-step cyclodimerization strategy. A third, though far less studied possibility, is the one-step synthesis of macrocycles by a multicomponent reaction (MCR). MCR is a process in which three or more reactants are combined in a single reaction vessel to produce a product that incorporates substantial portions of all the components [29]. They have, by definition, sustainable chemistry and are inherently (a) chemo- and regioselective, a prerequisite for a successful MCR since at least three reactive functional groups are involved and they have to react in an ordered and selective fashion; (b) atomeconomic [30] since most of them involve addition rather than substitution reactions.

4

G. Masson et al.

Indeed, addition reactions are susceptible to generate new reactive functionalities essential for the multicomponent domino process, whereas substitution reactions consume the functional groups; (c) step-efficient and cost-effective since they create at least two chemical bonds in one operation [31]; (d) convergent and efficient in generating molecular complexity and diversity [32]; (e) cost-effective since they reduce significantly waste production by minimizing the number of costly endof-pipe treatment by decreasing the number of synthetic steps; (f) operationally simple since most of the MCRs are performed under mild reaction conditions and in some cases even proceed spontaneously in the absence of external reagent. The past 15 years have witnessed the development of many elegant MCRs allowing the facile access to a diverse collection of chemical compounds, with particular attention being paid to heterocycles (for reviews, see: [33–52]). In contrast to the formidable development on the multicomponent synthesis of heterocycles, there were only sporadic reports on the multicomponent synthesis of macrocycles before 2005. There are roughly three options to synthesize macrocycles by way of MCRs as illustrated in Scheme 3 using four-component reaction: (a) assembly of all components to produce a given scaffold with the concurrent generation of two new cross-reactive functional groups that subsequently cyclize to a macrocycle (1); (b) two components are polyfunctionalized such that after assembly of all the inputs (A, B, C, and D), the remaining two functional groups X and Y can interact to produce a macrocycle (2); (c) Multiple multicomponent macrocyclization using two bifunctional building blocks proposed by Wessjohann (3) (for excellent reviews, see: [53, 54]). The development of multicomponent synthesis of macrocycles is highly challenging. To facilitate the discussion, we use the transformation shown in (1) of Scheme 3 to illustrate the inherent difficulties associated with this approach. To make this approach successful, the fate of intermediate 9 ((1), Scheme 3) is a X A + B + C +D

*X ABCD

ABCD Y 9

X

Y

A + B + C + D

10 X

*X

ABCD

ABCD Y

+

A+B Y

+

X

X*

A+B

A*B*

Y

Y*

eq 2 Y*

9 X

eq 1 Y*

10 X

Y

X*

X*

A*B*

A*B*

Y*

Y*

Scheme 3 Synthesis of macrocycles by multicomponent reactions

eq 3

Multicomponent Syntheses of Macrocycles

5

key issue. Indeed, in addition to the desired macrocyclization leading to 10, the intermediate 9 can undergo the dimerization leading to 11, which in turn can either cyclize to afford cyclodimer 12 or continuing the intermoleculaire process to produce trimer 13 and higher oligomers. Consequently, the constraints on the multicomponent synthesis of 10 from four inputs A, B, C, and D are as follows: (a) concentration dilemma. The desired macrocycle 10 is produced by an initial multicomponent, followed by a subsequent unimolecular, events. The former process (MCRs) is accelerated (and often a prerequisite) when the reaction is performed at high concentration (usually higher than 0.5 M), while the macrocyclization generally needed to be carried out under high-dilution conditions in order to disfavor the dimerization/oligomerization process. Consequently, concentration has to be carefully balanced such that it will allow the formation of multicomponent adduct 9 with reasonable kinetics and at the same time discourage any intermolecular processes from 9. In an ideal case, kc [9] should also be faster than km[A][B][C] [D] in order to avoid the accumulation of the intermediate 9, reducing therefore the rate of the dimerization process (kd [9][9]); (b) entropic factor. The activation energy for a ring closure can be lowered by the preorganization of the two reacting termini into close proximity before the actual cyclization step. Naturally, the energy for bringing the reaction centers together and restraining their motion has to be paid for in the preorganizing steps. The forces responsible for favoring one conformation over another are namely covalent bonds, hydrogen bonding, and steric and electronic interactions of different nature – such as electrostatic interactions, repulsive forces, and polarization or charge transfer [55]. The interplay of these factors of different strengths and to different degrees contributes to the conformation of molecules and, hence as well, to preorganize reactive centers (conformationdirected macrocyclization, see: [56]). In target-oriented synthesis, more subtle structural elements have to be considered in order to preorganize the linear substrate into a folded conformer conducive to ring closure. However, in diversityoriented synthesis wherein the molecular framework is not imperatively fixed on a certain structure, matching building blocks can then be designed to assemble a macrocycle (Scheme 4).

2 Macrocyclization Involving In Situ Generated (Activated) Functional Groups The Ugi four-component reaction (4CR) produced a-acetamidoamide by simply stirring a methanol solution of an aldehyde, an amine, a carboxylic acid and an isocyanide [57, 58]. The Mumm rearrangement (step 5, Scheme 5), being irreversible, drives the reaction towards the formation of the Ugi adduct in good to excellent yield under extremely mild conditions. The Ugi 4CR provides a linear peptide-like adduct. However, it provides an ideal starting point to reach cyclic compound. A conceptually simple approach consisted of

6

G. Masson et al. A + B + C + D Km *X

X

Kc

Y*

ABCD

ABCD Y

10

X Y 11

Kc′

9

Ko

Y*

*X

Y*

*X

Kd

ABCD

ABCD

ABCD

ABCD

*X

X*

*Y

Y* ABCD

ABCD

12

*Y

X

Oligomers X* ABCD Y 13

Scheme 4 Multicomponent synthesis of macrocycles: potential competitive reaction pathways O

MeOH R1CHO + R2NH2 + R3COOH + R4NC step 1

H2O O

R1

R3

N

R2

step 2

R3

H O R1

N

HN

R2 H

step 3

R1

R1 N R2

NHR4 O step 5

R2

R2

R3COO N

step 4 R4

R1

R4

O NH O

N R4 H+

Scheme 5 The Ugi four-component reaction O HOOC

COOBn + NH2 15

CHO NO2 +

MeOH NC 0-65°C

COOBn O

COOBn O N

12 h, 85%

NH NO2

16

O O2 N

N

N H

14

Scheme 6 Three-component four-center Ugi reaction to b-lactam

tethering two out of four inputs and to perform the Ugi three-component/four-center condensation. In Scheme 6 is shown a one-pot three-component synthesis of the medicinally important b-lactame 14 by simply mixing a b-amino acid 15, an aldehyde and an isonitrile. In this example, amine and carboxylic acid were tethered together in the form of b-amino acid. The reaction proceeded according to Ugi mechanism leading to a cyclic imidate intermediate 16, which upon an intramolecular

Multicomponent Syntheses of Macrocycles

7 peptide

H2N

peptide

peptide

O NH

COOH + R1CHO + R4NC

N

O

R1

17

O O

R1 R4HN

N R H+ 4 18

19

Scheme 7 Synthesis of macrocycles by Ugi reaction using peptidic amino acid as a key component H N H N

+

H3N O

–

CF3COO

O N H Ph

O

H N

N H

O

20

H N O

Et3N, DMF 65h, rt

O OH SMe

33% (dr = 1/1)

+

O

O

N MeS HN

NC H

H N

*

O OO O O O

Ph NH

NH

N H 21

Scheme 8 Synthesis of cyclohexapeptide by Ugi reaction

transacylation, afforded the observed cyclic product ([59]; for earlier works, see [60, 61]). Applying the same principle using peptidic amino acid 17 as starting material, one might expect the formation of macrocyclic peptide 19 via the intermediate 18 (Scheme 7). Indeed, the first example of macrocyclization based on Ugi reaction was reported in 1979 from the group of Failli et al. [62]. Reaction of a TFA salt of H-Ala-Phe-ValGly-Leu-Met-OH (20), isobutyraldehyde and cyclohexyl isocyanide afforded the cyclohexapeptide 21 as a mixture of two separable diastereoisomers in 33% overall yield. Slow addition of 20 to the reaction mixture was applied to achieve the pseudodilution in order to minimize the oligomerization (Scheme 8). The utility of this elegant macrocyclization technology remained unexploited for more than 20 years probably due to the low yield and limited application scope of this reaction described in this seminal paper. In fact, when a tripeptide H-gly-glygly-OH was submitted to the same reaction conditions, a cyclohexapeptide resulting from the cyclodimerization was formed instead of the expected cyclotripeptide. Wessjohann and coworkers reported in 2008, a concise synthesis of cyclic RGD pentapeptoids by three consecutive Ugi-4CR including one for macrocyclization [63]. Thus, reaction of 23, obtained from 22 in two steps, with formaldehyde and tert-butyl isocyanide in methanol afforded, after global deprotection under acidic conditions, the pentapeptoid 24 in 33% yield in four steps (Scheme 9). Yudin and coworkers reported in 2010, a variation of this reaction using a secondary amine-terminated peptide 25 and an amphoteric amino aldehyde 26 as

8

G. Masson et al. O

HO O

O

NH

N O N HN

22

H N

O

N O

O CbzHN

O

H N

MeO

O a) LiOH, THF-H2O, 0°C

H2N

O

Dmb N NHpmc

23 O

a) tBuNC, HCHO, MeOH

H N

N

NHpmc

O

O

NH

N

b) TAF, CH2Cl2, rt

HN

Dmb

OH

N O

O

O

O

NH

N

b) 10% Pd/C, H2, MeOH

H N

O

N O

O

O

33% over 4 steps from 22

Dmb = 2,4-dimethoxybenzyl pmc = 2,2,5,7,8-Pentamethyl-chromane-6-sulfonyl

NH HN

24

NH2

Scheme 9 Synthesis of cyclopentapeptide by Ugi reaction

peptide peptide

RHN

NR

25

+ R2NC

O

N R H+ 2

R1

26

NR

O

HN

HN R1

peptide

O

COOH

R2HN

eq 1

O

N O

27

28

R1

NHR R3COOH R1-CHO RHN

+ n

O NR

MeOH, rt

R4NC NHR2

R1

n

R1

R3 O

R N

R3 O

n

N R2

H N

R4 eq 2

O

N R H+ 2

Scheme 10 Synthesis of macrocycles using amphoteric amino aldehyde

reaction partners [64]. The basic principle is outlined in Scheme 10. Thus, the reaction of 25, aziridine aldehyde 26 and tert-butyl isocyanide should afford, via intermediate 27, the cyclopeptide 28. In Failli’s original contribution, the macrocyclization is a transannular process. However, in Yudin’s proposal the key ring forming process is trigged by nucleophilic addition of the aziridine nitrogen, which is positioned exocyclic to the electrophilic imidate function ((1), Scheme 10). This latter process was thought to be kinetically favored because of the less encumbered trajectory of attack, increasing consequently the efficiency of the macrocyclization. The rational behind this approach is reminiscent of the “Split-Ugi” reaction developed for the selective functionalization of 1,n-diamines ((2), Scheme 10) [65].

Multicomponent Syntheses of Macrocycles

9

O

O H N + TBSO

HO

NH O

HN

O

NC

+

29

TFE, rt C 0.2 M 4h, 83% dr > 20/1

TBSO t

H BuHNOC

30

N

NH *

O

N

31 S S

H N

BocHN HN

O O

H N

+

TBSO 29

O

NH O

t

O O

O Bu

HN

TFE, rt C 0.2 M

HN

NC

O O

9h, 77% dr > 20/1

NH +

OH 32

H N

BocHN

NH O

t

O

O Bu

O

NH

N N

TBSO H

t

CONH Bu

33

Scheme 11 Synthesis of macrocycles using amphoteric amino aldehyde: examples

Indeed, this MCR worked extremely well by simply stirring the three components in trifluoroethanol (TFE) at room temperature. Interestingly, no high-dilution conditions were required for the above transformation. Authors prepared 12-, 15and 18-membered macrocycles and even nine-membered medium-sized cycles in excellent yields with diastereoselectivities. Two examples were depicted in Scheme 11. Thus, stirring a TFE solution of aziridine aldehyde 29, dipeptide 30 and tert-butyl isocyanide at room temperature for 4 h afforded a nine-membered cycle 31 in 83% yield. Similarly, a 18-membered cyclopeptide 33 was obtained in 77% yield by the reaction of 29, pentapeptide 32 and tert-butyl isocyanide. In both examples, the cyclic compounds 31 and 33 were formed with high diastereoselectivities (dr > 20/1). This is intriguing, as Ugi reaction provided generally low to moderate stereoselection when chiral substrates was used as inputs ([66–72]; for enantioselective isocyanide-based MCRs, see: [73–80]). The presence of an aziridine in a macrocyclic ring system provided a handle for further functionalization via facile nucleophilic ring opening of the strained three-membered ring. Authors demonstrated this possibility by a late-stage, sitespecific attachment of a fluorescent tag onto a macrocyclopeptide (Scheme 12). Thus coupling of 7-mercapto-4-methylcoumarin with cyclopeptide 36, obtained by three-component reaction of serine-derived aziridine aldehyde 34, tert-butyl isocyanide and pentapeptide 35, afforded the conjugate 37 in 77% yield. Other nucleophiles such as thiols, thioacids and imides worked equally well for this ringopening reaction. In all above examples, macrocyclization of peptidic amino acids by Ugi reaction is the expected transformation, while cyclodimerization is considered to be undesired. Against this notion, Wessjohann and coworkers designed a tethered amino acid having such a backbone that head-to-tail cyclization was impossible because of the conformational constraint [81]. Thus, a twofold Ugi reaction of C-3 amino

10

G. Masson et al.

H N

H N

H N + 34 O

HN

O O

Ph

NH O

OH

NC

O O

TFE, rt C 0.2 M

HN

8h, 76% dr > 20 / 1

NH

N

HN H N

Ph O

NH

N

NH

O HS

O O

H CONHt Bu 36

35

O

O

O O

Ph

NH O

HN

S

t BuHNOC

CH2Cl2, NEt3, rt, C 0.3 M, 77%

O

N

O O O O

NH

N H 37

Scheme 12 Ring opening of aziridine O COOH 38 NH2

NC

N MeOH

+

t

NHt Bu

O O

BuHN

rt

NH

HCHO O

39, 33%

Scheme 13 Synthesis of cyclodimers by a double Ugi reaction

substituted lithocholic acid derivative 38, formaldehyde and tert-butyl isocyanide in methanol afforded the cyclodimer 39 in 33% yield. The reaction has to be performed under high-dilution conditions (syringe pump addition). Under these conditions, a cyclotrimer was also isolated in 12% yield, together with a trace amount of tetramer. Note that the extended, rigid steroid backbone inhibited folding of the molecule and thus making the head-to-tail cyclization of 38 impossible. This design principle fit into the concept of unidirectional multiple multicomponent macrocyclization using two bifunctional building blocks (MiBs) as proposed by Wessjohann (vide supra) (Scheme 13). An MCR allows build up of a scaffold with multitude of substituents. One highly rewarding approach in devising novel MCRs involved the incorporation of paired functional groups into the starting materials that can subsequently react intramolecularly after all components have been assembled. In this context, Paulvannan and coworkers reported an elegant synthesis of bridged tricyclic compounds by the combination of Ugi 4CR and intramolecular Diels–Alder reaction (IMDA) [82]. Key to this process is the incorporation of a diene and a dienophile in two of the four

Multicomponent Syntheses of Macrocycles

11 COOEt O

H2N O 40

CHO

NC +

+

+ 41

42

COOEt

HOOC

MeOH, 36 h, r.t.

O N

H N

43

O COOEt O H N

N

44, 89% (dr = 92 / 8)

O

O 45

Scheme 14 Synthesis of heterocycles by Ugi reaction

components of the Ugi reaction. As shown in Scheme 14, stirring a methanol solution of furaldehyde (40), benzylamine (41), benzyl isonitrile (42) and ethyl fumarate (43) at room temperature for 36 h provided the cycloadduct (44) in 89% yield (dr = 92/8). The initially formed Ugi adduct 45, though isolable, underwent intramolecular [4+2] cycloaddition to afford the observed heterocycle [83]. On the basis of the same principle, we developed a three-component synthesis of macrocycles starting from azido amide (46), aldehyde (47) and a-isocyanoacetamide (48) (the a-isocyanoacetamides are easily available, see: [84–86]) bearing a terminal triple bond (Scheme 11) [87]. The sequence is initiated by a nucleophilic addition of isonitrile carbon to the in situ generated imine 50 led to the nitrilium intermediate 51, which was in turn trapped by the amide oxygen to afford oxazole 52 (selected examples: [88–94]). The oxazole 52, although isolable, was in situ converted to macrocycle 51 by an intramolecular [3+2] cycloaddition upon addition of CuI and diisopropylethylamine (DIPEA). In this MCR, the azido and alkyne functions were not directly involved in the three-component construction of oxazole, but reacted intramolecularly leading to macrocycle once the oxazole (52) was built up. The reaction created five chemical bonds with concurrent formation of one macrocycle, one oxazole and one triazole (Scheme 15). By simply changing the position of the azido and the alkyne functions, macrocycles with different ring connectivity can be obtained by the same three-component reaction. Thus, the reaction of hept-6-ynal (53), morpholine and N-(4-azidobutyl)N-benzyl-2-isocyano-3-phenylpropanamide (54) afforded macrocycle 55 in 40% yield. Structurally, 55 differ from 52 by the presence of an exo-substituted amino function (Scheme 16).

3 Multiple Multicomponent Macrocyclization Using Two Bifunctional Building Blocks The Ugi four-component reaction is currently the most investigated MCRs in both target-oriented [95] as well as diversity-oriented synthesis of compound libraries (for reviews, see: [33–52]). As one of the rare truly and highly versatile

12

G. Masson et al. Ph O

n-C6H13CHO H N

O

Ph +

N 46

47

N3

R

49 O

O n-C6H13

N +

O

n-C6H13

48

N

n-C6H13

Ph N

R N3

O

N

O

Ph

N

N3

N

N3

O

n-C6H13

MeN

N

N

51

50

N

N

Ph

Ph

+ N

N

N

then THF, CuI, DIPEA, rt 45%

N Me

N

N

toluene, NH4Cl, 80°C

O

CN

N

52

Ph

Scheme 15 Tandem Ugi-[3þ2] cycloaddition to macrocycle N N OHC

NH O

N3

53 +

O CN Ph

then THF, CuI DIPEA, rt 40%

N 54

Ph

N

toluene, NH4Cl 80°C O

N O

N 55

N Ph Ph

Scheme 16 Structural diversity of macrocycles by tandem Ugi-[3þ2] cycloaddition process

four-component reaction, it is also the most exploited one in developing multicomponent macrocyclizations. As outlined in the Sect. 2, it is possible to synthesize macrocycles by a single Ugi-based reaction when two out of four inputs are tethered into a single, conformationally biased building block. A drawback of this approach is that one of the diversity elements is lost as a consequence of using a bifunctional building block. To overcome this drawback, Wessjohann advanced a concept of “multiple multicomponent macrocyclization using two bifunctional building blocks”. The basic principle rely on the use of bifunctional building blocks with the same functionality on either side that, after multiple MCRs, leads to bidirectional macrocycles. These “symmetric” bifunctional building blocks can be synthesized in a more straightforward manner than the unsymmetrical ones and problems of functional group incompatibility are avoided (for uni-directional MiBs, see Scheme 13). In his approach, two different symmetric bifunctional building blocks are required and the minimum number of MCRs forming the macrocycle is two.

Multicomponent Syntheses of Macrocycles

2nd Ugi

58

56

FG3

U gi

gi U

3rd Ugi

FG1 FG2 4th Ugi 61

Ugi

FG3

FG3 Ugi

Ugi

FG1 FG2

FG4

gi U

FG4

FG3

i

Ug

FG4

FG1 FG2

eq 2 U gi

FG3

59

U gi

57

60

eq 1

FG4

FG4

2nd Ugi

Ugi

FG1 FG2

Ugi

FG4

FG3 Ugi

FG1 FG3 FG3 56 FG2 1st Ugi

13

62

Scheme 17 Synthesis of macrocycles by multiple multicomponent reactions including bifunctional building blocks (MiBs)

Using Ugi-4CR as prototypical reaction, a possible reaction leading to twofold and fourfold cyclic adduct is shown in Scheme 17. The first Ugi adduct 58 could react further with FG1 and FG2 to afford the cyclic product 59 ((1), Scheme 17). Alternatively, the adduct 58 can react with a second equivalent of a bifunctional substrate 56, FG1 and FG2 to provide twofold linear Ugi adduct 60, which could be further transformed to fourfold Ugi cyclic adduct 62 via intermediate 61. The formation of higher-order oligomers/cyclic oligomers could be competitive making this reaction quite difficult to control. However, it is expected that the overall reaction outcome could in principle be governed by the three-dimensional structure of the bifunctional inputs 56 and 57. To favor the one desired macrocycle, the use of relatively rigid, umbrella-shaped or kinked bifunctional building blocks results often the conformational preorganization of cyclization precursor, generated in situ by the first MCR, leading preferentially to one particular macrocycle. The length of the spacers that link the two bifunctional inputs play also the decisive role on whether cyclodimer, cyclotrimers or higher cyclooligomers to be produced. In practice, high-dilution or pseudodilution conditions achieved by slow addition of at least one input is generally used to disfavor the nonproductive oligomerization process. A unique feature of the MiBs is that the macrocycles produced in this way has no C2-symmetry axis if an asymmetric linker was used in one (or both) of the bifunctional substrate(s). Thus, although the MiBs product looks, at the first glance, like repetitive homodimeric macrocycles, they are in fact non-repetitive, in sharp contrast to the cyclodimerization discussed in (2) of Scheme 1. A complication of using asymmetric bifunctional substrates as reaction partners in MiBs is the high tendency to generate both the head-to-head (H-H) and head-to-tail (H-T) macrocycles (Scheme18). Thus, first MCR could produce two regioisomeric cyclization precursor 63 and 64, which could then undergo a second ring-closing MCR to

14

X

G. Masson et al.

X

X

X

1st MCR +A+B

Y

Y

Y

Y 63

64 2nd MCR

A+B

A+B

65

66

Scheme 18 Formation of possible head-to head and head-to-tail cyclodimers

a R1CHO R2NH2 R3COOH R4NC

OHC

CHO

R3COOH

R3COOH

R4NC

Bifunctional substrates

d

b

R4NC

H2N

NH2

H2N

NH2

CHO

OHC

CHO

R2NH2

R2NH2

R2NH2

R2NH2

R4NC

R4NC

R3COOH

R3COOH

HOOC

e

c

OHC

H2N

CN

COOH

NH2

f

HOOC

NC

COOH

R1CHO

R1CHO

R1CHO

R1CHO

R1CHO

R1CHO

R4NC

R4NC

R3COOH

R3COOH

R2NH2

R2NH2

NC

CN

HOOC

COOH

CN

NC

Scheme 19 Ugi-4CR in MiBs: six random combinations

provide the H-H and H-T cyclodimers 65 and 66, respectively. Unless there were significant steric and electronic biases, both 65 and 66 would be produced in a nonselective manner. Another characteristic feature of MiBs is that the number of the components remained the same when any given MCR was “transformed” into a multiple MCR. Using Ugi-4CR as an example, there are six different random combinations to perform the MiBs, each of them will produce a macrocycle with different ring connectivities (Scheme 19). Using steroid as supporting scaffold, the reaction of diamine 67, diisocyanide 68 (both being derived from lithocholic acid), acetic acid and formaldehyde afforded the macrocycle 69a in 58% yield as a mixture of head-to-tail and head-to head cyclic dimers ((1), Scheme 20; for the sake of clarity, only the head-to-tail regioisomer was shown) [96–98]. On the other hand, the reaction of diacid 70, diisocyanide 68, isopropylamine and formaldehyde afforded the steroid-peptoid conjugate

Multicomponent Syntheses of Macrocycles

NH2

H H H2N

H

H

O

+

H H

MeOH, 25°C

O

NC

H N

O H

R

O

R

H

O H

H

H NH2 MeOH, 25°C + O NC

N

H

H 70

H

H

69a R = H, 58% 69b R = i Pr, 28% O

OH

H

CN

O NH

H

H

HO

O

H

HN

68

H

R H

H

H

O

N O

N

H OH

67 H

CN

15

H

R

N O

68

H

O NH

H H

N O

R H

H

H

O

R H

H

HN 71a R = H, 50% 71b R = i Pr, 14%

Scheme 20 Double Ugi-4CR to cyclic dimer

71a in 50% yield ((2), Scheme 20). It is interesting to note that the diamine/ diisocyanide combination provide a macrocycle with an exo-amide bond, while the diacid/diisocyanide combination afforded a macrocycle with an additional endo-amide bond. These two examples demonstrated nicely the power of MiB approach in the generation of molecular diversities. Aldehydes other than formaldehyde can also be used leading to macrocycles as a mixture of all four possible diastereomers (69b, 71b, Scheme 20). The intrinsic lack of diastereoselectivity of Ugi reaction provided nevertheless an opportunity for chemists to generate libraries of all diastereoisomers by one single operation, a factor that could be exploited in medicinal chemistry. By carefully designing the structure of bifunctional substrates, Wessjohann developed a fourfold Ugi-4CR for the syntheses of large ring-size macrocycles. Thus, the reaction of diamine 67, cyclopropane-1,1-dicarboxylic acid (72), isopropylamine and formaldehyde afforded 48-membered macrocycle 73 in 49% yield (Scheme 21). It is appropriate to note herein that a yield of 49% corresponds to an approximately 96% calculated yield for each individual bond-forming process, including the macrocyclization step. An impressive threefold Ugi reaction using carefully designed trifunctional building blocks has been subsequently developed by Wessjohann (Scheme 22). This reaction unified eight components (74, 75, three equivalents each of formaldehyde and isopropylamine) via twelve reactions including two macrocyclization steps in a one-pot fashion to produce hemicryptophane 76 in 44% yield [99, 100].

16

G. Masson et al. O N H

H

N H NH2

H H H2N

HN

H

MeOH, 25°C

67

H O

NH2

+

O

HO

N

H

H

O

O O

49%

N O H

O

NH

H

O OH

O

H

H

N H

H O

72

N H

73

H

Scheme 21 Four-fold Ugi-4CR to macrocycles

MeO +

O

O

OMe MeO

–

CN

75

O O

44%

O

+

NH2

H

NC

O

N

O

N

+

H N

CO2–NBu4+

74

OMe MeO

O

MeOH

Bu4N O2C + Bu4N–O2C NC

O

MeO

O

N

O O

HN

O

HN N

NH

76

Scheme 22 Synthesis of hemicryptophane by threefold Ugi

This approach should be highly useful in the rapid synthesis of supramolecular receptors because of its efficient and diversity-oriented nature. Passerini 3CR (P-3CR )has also been used for the syntheses of macrocycles using the same MiBs concept. Shown in Scheme 23 was an example of oxidative double P-3CR using diacid and diol as bifunctional substrates. Simply heating a THF solution of N-Boc glutamic acid (77), triethylene glycol (78) and tert-butyl isocyanide in the presence of IBX afforded the macrolide 79 in 59% yield (1) [101]. In this reaction, triethylene glycol (78) was oxidized in situ to the unstable dialdehyde 80 which then participated in the double P-3CR [102]. By applying the same oxidative conditions, the diisocyanide/latent dialdehyde combination afforded the macrocycle 82 in 33% yield (2). Once again, it is interesting to note that the reaction shown in (1) afforded a macrocycle with two exo-amide bonds, while that shown in (2) provided a macrocycle with two endo-amide bonds. We have published, in 2003, a twofold four-component (ABC2) synthesis of m-cyclophane 85 based on the three-component synthesis of 5-aminooxazole developed earlier in this laboratory (for selected examples,see: [88–94]). Thus, the reaction of a diamine (83), a bis a-isocyanoacetamide (84) and two equivalents

Multicomponent Syntheses of Macrocycles HOOC

17 BocHN

COOH NC

77 NHBoc

+

O

HO

IBX, THF

O

O eq 1

O O O O

NH *

OH

O

O

O

40°C, 59%

*

HN

79

78 O

O

O

O 80

N CN

N

N NC

81 O

HO

NH O

O

40°C, 33% O

78 BocHN

HN

IBX, THF

OH

O

N

O

O

*

O

BocHN

COOH

eq 2

O

*

O NHBoc

82

Scheme 23 Oxidative double P-3CR to macrolides

NH2

83

C6H13CHO

+

NH2 MeOH, Reflux

C6H13CHO

* NH

HN *

N

N

O

O

0.1 M, 52% O

NC

NC N

O

O

O

O

O

84

N

N

N

O

N

85 two diastereomers

N

NH2

H

C6H13CHO

N

O

NC

N

N N

N O

O

N

H

O

O

N

N A

O

O

B

Scheme 24 Four-component (ABC2) synthesis of m-cyclophane

of heptaldehyde afforded the cyclophane 85 in 52% yield (Scheme 24) [103]. In this MCR, one macrocycle imbedded with two heterocycles was produced via the creation of six chemical bonds and water was the only by-product generated. The

18

G. Masson et al.

reaction proceeded through a three-component construction of oxazole A followed by its subsequent reaction with a second equivalent of aldehyde to provide the observed product. Amazingly, the reaction performed at 0.1 M furnished cyclophane 85 in higher yield than that carried out at 0.01 M under otherwise identical conditions. That the multicomponent macrocyclization can be performed at such a high concentration is unique. Several factors could account for this observation: (a) the actual concentration of cyclization precusor A, generated by three-component reaction, is much lower than the concentration of the starting materials (0.1 M); (b) the in situ build-in oxazole ring in the cyclization precursor could potentially reduce the conformational mobility of the molecule, facilitating thus the desired head-totail cyclization [104–107]. Control experiment indicated that template effect (in the presence of different metal salts) [108] was not operating for this transformation. The presence of NH function in 86 that could potentially form a H-bond with oxazole ring, thus preorganizing the cyclization precursor [109], was not an obligation. Indeed, compound 86 (R = H) and 87 (R = Et, Fig. 2) was obtained in essentially identical yield. Aliphatic diamines are suitable substrates, as cyclophane 88 and 89 can be prepared in reasonable yield. It is interesting to note that a 47% yield of 89 meant 88% yield per chemical bond created, including the macrocyclization step. The cyclophanes having two oxazoles could also serve as a useful chemical platform for the generation of new structures by taking advantage of the rich chemistry of oxazole. One such example is shown in Scheme 2. Hydrolysis of 85 under mild acidic conditions (THF-H2O, TFA) afforded the corresponding macrocyclic amide in over 85% yield (Scheme 25). All the six possible diastereomers were readily separated and identified by LC/MS. It is interesting to note that the retention time of these diastereomers was significantly different ranging from 2.2 to 26.3 min (column: Symmetry C-18, gradient H2O/MeCN = 2/3, then MeCN) indicating the different hydrophobicity of these diastereoisomers. The Mibs concept is, of course, not restricted to isocyanide-based MCRs. Wessjohann recently demonstrated that multiple Staudinger reaction is highly effective for the construction of marcocycles [110]. Thus, the reaction of diamine 83, dialdehyde 91 and acylchloride 92 in the presence of triethylamine afforded macrocycle 93 incorporating four b-lactam units in 82% yield. The cis-stereochemistry of all the four-membered rings was established based on the coupling S

S COOMe

MeOOC N O

N

R

R

N

NH O

O

N

N O

O

N

86 R = H, 45% 87 R = Et, 42%

HN

N

N

O

O

O

88 43%

N

HN N

O

O

O

Fig. 2 Examples of Four-component (ABC2) synthesis of m-cyclophanes

O N

N

N

N O

NH

89 47%

Multicomponent Syntheses of Macrocycles

NH

19

HN THF-TFA-H2O (8/2 /1)

O

N

N

85%

O

O

O

NH

HN

O O

N O

85

HN

O

N

N

NH

O

N 90

O

Scheme 25 Revealing the peptidic backbone by the hydrolysis of 5-aminooxazole unit

MeO O

N

N

O

O

N

N

O

O

O 91 NH2

NH2

Et3N

O

+

OMe

O

Cl 92

83

MeO

93, 82%

OMe

Scheme 26 Multiple Staudinger reaction

constant of the two vicinal protons (around 4.6 Hz). This is not unexpected assuming that the four-membered lactam ring was produced by a [2þ2] cycloaddition. Experimentally, acyl chloride was added after the macrocyclic oligoimine was preformed, so the staudinger reaction was actually not involved in the ring-closure step. Nevertheless, the formation of cyclic oligoimine is a dynamic process and usually macrocycles with different ring sizes coexisted. Wessjohann and coworkers have provided convincing evidence to show that the subsequent [2þ2] cycloaddition could shift the equilibrium of these oligoimines to provide one major stable macrocycle after the Staudinger reaction. Using Ugi reaction to freeze imine exchange in dynamic libraries as a tool to access templated macrocycles has also been developed from the same group [111] (Scheme 26).

4 Sequential Multiple Multicomponent Macrocyclization Most of the known synthetic receptors, such as cryptands, cyclophanes, and cages, are homo-oligomeric structures, although more complex and unconventional topologies, such as interlocked and knotted molecules have recently proved their

20

G. Masson et al.

potential as prototypical molecular devices. It is fair to say that the conceptual advance in supramolecular chemistry is closely related to our ability to synthesize tailor-made macrocycles. Indeed, to further exploit the potential of these threedimensional large molecules in molecular recognition processes, an even more efficient approach capable of producing genuine nonsymmetric cryptands and other types of macromulticycles with varied molecular topologies is highly demanding. Towards this end, an elegant synthetic strategy named sequential MiBs has been advanced and developed by the group of Wessjohann [112]. A generic presentation of double MiBs for the synthesis of cryptand is shown in Scheme 27. Thus, the first MiB followed by deprotection would produce a bisfunctionalized macrocycle 94 that would be engaged in a second MiB with another bis-functionalized substrate to afford the nonsymmetric cryptand 95. With the combination shown in scheme 27, the bridgehead core of the cryptands are tertiary amides arising from the first double Ugi-4CR-based macrocyclization. Since there were four components taking part in the Ugi reaction, six different combinations of bifunctional building blocks are possible (cf scheme 19). Accordingly, up to 36 permutations leading to 36 topologically different macrocycles could be realized by repeating just two macrocyclization steps in a sequential manner. Thus, the accessible diversity of nonsymmetric cryptands is truly remarkable by applying this approach. One such example is depicted in Scheme 28. Thus, the reaction of diacid 96, diisocyanide 97, formaldehyde and tert-butyl glycine (98) afforded, after removal of tert-butyl ester, the macrocycle 99. The second MiB of macrocyclic

H2N

COOP COOH

RCHO COOH CN

a) Ugi-MiB

step 1

b) N-deprotection COOH CN RCHO COOH H2N

COOP 94 RNH2

COOH RCHO

CN Ugi-MiB step 2

RNH2 COOH RCHO

CN 95

Scheme 27 Synthesis of nonsymmetric cryptand by two consecutive MiBs

Multicomponent Syntheses of Macrocycles

21 O

HO

N

O

O O 96

O

HN

O

OH a) MeOH, rt

+

HCHO NC

CN

O

COOH O

O

b) TFA O

H2N

OBut

O

HN N

98

97

O O

N O NH2

99

O NH O

N

HCHO

O COOH

HN

O

N CN

N

N

NC

81

O N O

HN N

O O HN

O N

O

100

Scheme 28 Sequential MiBs to nonsymmetric cryptands

diacid 99, diisocyanide 81, isopropylamine and formaldehyde provided the nonsymmetric cryptand 100. No purification of intermediate was required for this three-step sequence and macrocycle 100 was obtained in 36% yield form diacid 96. This is impressive, considering that 16 chemical bonds were formed in these reactions including two macrocyclizations. The synthesis of clam-shaped macrobicycles and Igloo-shaped macrotetracycles were also detailed in this full paper.

5 Conclusion Recent years have witnessed the remarkable progress in the development of MCRs and their applications in the total synthesis of natural products and designed molecules with specific biological properties. However, multicomponent synthesis of macrocycles is still in its infancy because of the intrinsic difficulties associated with the development of such an approach. Although total synthesis of macrocyclic

22

G. Masson et al.

natural products featuring a key multicomponent macrocyclization step has yet to be developed, the utilities and the power of this approach, especially the MiBs approach developed by the group of Wessjohann, for the synthesis of designed macrocyclic libraries have already been amply demonstrated. Only those methods leading to macrocycles via covalent bond formation were discussed in this chapter, it is nevertheless appropriate to point out that the multicomponent synthesis of macrocycles via the reversible interactions such as imine formation, boronate formation, metal–ligand interaction etc, can also be successfully used for the construction of macrocycles and cages (for recent examples, see: [113, 114]). It is expected that research in this field could be highly rewarding and could play a pivatol role in the future development of functional macrocycles for applications in medicine, in supramolecular chemistry and as nanomaterials.

References 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30. 31.

Shu Y-Z (1998) J Nat Prod 61:1053–1071 Newman DJ, Cragg GM, Snader KM (2000) Nat Prod Rep 17:215–234 Feliu L, Planas M (2005) Int J Pept Res Ther 11:53–97 Wessjohann LA, Ruijter E, Garcia-Rivera D, Brandt W (2005) Mol Divers 9:171–186 Williams DH (1996) Nat Prod Rep 13:469–477 Zhu J (1999) Expert Opin Ther Pat 9:1005–1019 Nicolaou KC, Boddy CNC, Bra¨se S, Winssinger N (1999) Angew Chem Int Ed 38:2096–2152 Su¨ssmuth RD (2002) Chembiochem 3:295–298 Kessler H (1982) Angew Chem Int Ed Engl 21:512–523 Toniolo C (1990) Int J Pept Protein Res 35:287–300 Lambert JN, Mitchell JP, Roberts KD (2001) J Chem Soc Perkin Trans 1:471–484 Hu HT, Xu CR, Song X, Siahaan TJ (2003) J Pept Res 61:331–342 Fairlie DP, Abbenante G, March DR (1995) Curr Med Chem 2:654–686 Winnik MA (1985) Acc Chem Res 18:73–79 Lehn J-M (1995) Supramolecular chemstry: concepts and perspectives. Wiley-VCH, Weinheim Raymo FM, Stoddart JF (1999) Chem Rev 99:1643–1663 Wang M-X (2008) Chem Commun:4541–4551 Ghadiri MR, Granja JR, Milligan RA, McRee DE, Khazanovich N (1993) Nature 366:324–327 Meng Q, Hesse M (1991) In: Topics in current chemistry, vol 161, pp 107–175 Wipf P (1995) Chem Rev 95:2115–2134 Zhu J (1997) Synlett:133–144 Fu¨rstner A (2000) Angew Chem Int Ed Engl 39:3012–3043 Yeung K-S, Paterson I (2002) Angew Chem Int Chem 41:4632–4653 Wessjohann LA, Ruijter E (2005) Top Curr Chem 243:137–184 Nicolaou KC, Bulger PG, Sarlah D (2005) Angew Chem Int Ed Engl 44:4490–4527 Hoye TR, Humpal PE, Moon B (2000) J Am Chem Soc 122:4982–4983 Smith AB III, Kozmin SA, Adams CM, Paone DV (2000) J Am Chem Soc 122:4984–4985 Singh Y, Sokolenko N, Kelso MJ, Gahan LR, Abbenante G, Fairlie DP (2001) J Am Chem Soc 123:333–334 Zhu J, Bienayme´ H (eds) (2005) Multicomponent reaction. Wiley-VCH, Weinheim Trost BM (1995) Angew Chem Int Ed 34:259–281 Wender PA, Handy S, Wright DL (1997) Chem Ind:765–769

Multicomponent Syntheses of Macrocycles

23

32. Bienayme´ H, Hulme C, Oddon G, Schmitt P (2000) Chem Eur J 6:3321–3329 33. Posner GH (1986) Chem Rev 86:831–844 34. Armstrong RW, Combs AP, Tempest PA, Brown SD, Keating TA (1996) Acc Chem Res 29:123–131 35. Hulme C, Gore V (2003) Curr Med Chem 10:51–80 36. Orru RVA, De Greef M (2003) Synthesis:1471–1499 37. Jacobi von Wangelin A, Neumann H, Go¨rdes D, Klaus S, Stru¨bing D, Beller M (2003) Chem Eur J 9:4286–4294 38. Balme G, Bossharth E, Monteiro N (2003) Eur J Org Chem:4101–4111 39. Zhu J (2003) Eur J Org Chem:1133–1144 40. Simon C, Constantieux T, Rodriguez J (2004) Eur J Org Chem:4957–4980 41. Tempest P (2005) Curr Opin Drug Discov Devel 8:776–788 42. Wessjohann LA, Ru¨ijter E (2005) Top Curr Chem 243:137–184 43. Do¨mling A (2006) Chem Rev 106:17–89 44. D’Souza DM, Mu¨ller TJJ (2007) Chem Soc Rev 36:1095–1108 45. Tejedor D, Garcia-Tellado F (2007) Chem Soc Rev 36:484–491 46. Akritopoulou-Zane I, Djuric SW (2007) Heterocycles 73:125–147 47. Isambert N, Lavilla R (2008) Chem Eur J 14:8444–8454 48. El Kaim L, Grimaud L (2009) Tetrahedron 65:2153–2171 49. Ganem B (2009) Acc Chem Res 42:463–472 50. Arndtsen BA (2009) Chem Eur J 15:302–313 51. Sunderhaus JD, Martin SF (2009) Chem Eur J 15:1300–1308 52. Godineau E, Landais Y (2009) Chem Eur J 15:3044–3055 53. Wessjohann LA, Ruijter E (2005) Mol Divers 9:159–169 54. Wessjohann LA, Rivera DG, Vercillo OE (2009) Chem Rev 109:796–814 55. Morokuma K (1977) Acc Chem Res 10:294–300 56. Blankenstein J, Zhu J (2005) Eur J Org Chem:1949–1964 57. Do¨mling A, Ugi I (2000) Angew Chem Int Ed Engl 39:3168–3210 58. Marcaccini S, Torroba T (2007) Nat Protoc 2:632–639 59. Kehagia K, Ugi I (1995) Tetrahedron 51:9523–9530 60. Ugi I, Steinbru¨ckner C (1961) Chem Ber 94:2802–2814 61. Isenring HP, Hofheinz W (1981) Synthesis:385–387 62. Failli A, Immer H, Go¨tz M (1979) Can J Chem 57:3257–3261 63. Vercillo OE, Andrade CKZ, Wessjohann LA (2008) Org Lett 10:205–208 64. Hili R, Rai V, Yudin AK (2010) J Am Chem Soc 132:2889–2891 65. Giovenzana GB, Tron GC, Di Paola S, Menegotto IG, Pirali T (2006) Angew Chem Int Ed 45:1099–1102 66. Kunz H, Pfrengle W (1988) J Am Chem Soc 110:651–652 67. Linderman RJ, Binet S, Petrich SR (1999) J Org Chem 64:336–337 68. Ross GF, Herdtweck E, Ugi I (2002) Tetrahedron 58:6127–6133 69. Cuny G, Gamez-Montano R, Zhu J (2004) Tetrahedron 60:4879–4885 70. Basso A, Banfi L, Riva R, Guanti G (2005) J Org Chem 70:576–580 71. Banfi L, Basso A, Guanti G, Merlo S, Repetto C, Riva R (2008) Tetrahedron 64:1114–1134 72. Bonger KM, Wennekes T, Filippov DV, Lodder G, van de Marel GA, Overkleeft HS (2008) Eur J Org Chem:3678–3688 73. Denmark S, Fan Y (2003) J Am Chem Soc 125:7824–7825 74. Kusebauch U, Beck B, Messer K, Herdtweck E, Do¨mling A (2003) Org Lett 5:4021–4024 75. Andreana PR, Liu CC, Schreiber SL (2004) Org Lett 6:4231–4234 76. Wang S-X, Wang M-X, Wang D-X, Zhu J (2007) Eur J Org Chem:4076–4080 77. Wang S-X, Wang M-X, Wang D-X, Zhu J (2007) Org Lett 9:3615–3618 78. Wang S-X, Wang M-X, Wang D-X, Zhu J (2008) Angew Chem Int Ed 47:388–391 79. Yue T, Wang M-X, Wang D-X, Zhu J (2008) Angew Chem Int Ed 47:9454–9457 80. Yue T, Wang M-X, Wang D-X, Masson G, Zhu J (2009) Angew Chem Int Ed 48:6717–6721

24 81. 82. 83. 84. 85. 86. 87. 88. 89. 90. 91. 92. 93. 94. 95. 96. 97. 98. 99. 100. 101. 102. 103. 104. 105. 106. 107. 108. 109. 110. 111. 112. 113. 114.

G. Masson et al. Rivera DG, Wessjohann LA (2007) Molecules 12:1890–1899 Pauvannan K (1999) Tetrahedron Lett 40:1851–1854 Lee D, Sello JK, Schreiber SL (2000) Org Lett 2:709–712 Fayol A, Housseman C, Sun X, Janvier P, Bienayme´ H, Zhu J (2005) Synthesis:161–165 Housseman C, Zhu J (2006) Synlett:1777–1779 Do¨mling A, Beck B, Fuchs T, Yazbak A (2006) J Comb Chem 8:872–880 Pirali T, Tron GC, Zhu J (2006) Org Lett 8:4145–4148 Sun X, Janvier P, Zhao G, Bienayme´ H, Zhu J (2001) Org Lett 3:877–880 Janvier P, Sun X, Bienayme´ H, Zhu J (2002) J Am Chem Soc 124:2560–2567 Fayol A, Zhu J (2002) Angew Chem Int Ed 41:3633–3635 Janvier P, Bienayme´ H, Zhu J (2002) Angew Chem Int Ed 41:4291–4294 Ga´mez-Montan˜o R, Gonza´lez-Zamora E, Potier P, Zhu J (2002) Tetrahedron 58:6351–6358 Fayol A, Zhu J (2005) Org Lett 7:239–242 Bonne D, Dekhane M, Zhu J (2007) Angew Chem Int Ed 46:2485–2488 Toure´ BB, Hall DG (2009) Chem Rev 109:4439–4486 Wessjohann LA, Voigt B, Rivera DG (2005) Angew Chem Int Ed 44:4785–4790 Wessjohann LA, Rivera DG, Coll F (2006) J Org Chem 71:7521–7526 Kreye O, Westermann B, Rivera DG, Johnson DV, Orru RVA (2006) QSAR Comb Sci 25:461–464 Rivera DG, Wessjohann LA (2006) J Am Chem Soc 128:7122–7123 Rivera DG, Vercillo OE, Wessjohann LA (2007) Synlett:308–312 Leon F, Rivera DG, Wessjohann LA (2008) J Org Chem 73:1762–1767 Ngouansavanh T, Zhu J (2006) Angew Chem Int Ed 45:3495–3497 Janvier P, Bois-Choussy M, Bienayme´ H, Zhu J (2003) Angew Chem Int Ed 42:811–814 Zhao G, Sun X, Bienayme´ H, Zhu J (2001) J Am Chem Soc 123:6700–6701 Bughin C, Zhao G, Bienayme´ H, Zhu J (2006) Chem Eur J 12:1174–1184 Bughin C, Masson G, Zhu J (2007) J Org Chem 72:1826–1829 Pirali T, Tron G, Masson G, Zhu J (2007) Org Lett 9:5275–5278 Seel C, Vogtle F (2000) Chem Eur J 6:21–24 Carver FJ, Hunter CA, Shannon RJ (1994) J Chem Soc Chem Commun:1277–1280 Leo´n F, Rivera DG, Wessjohann LA (2008) J Org Chem 73:1762–1767 Wessjohann LA, Rivera DG, Leo´n F (2007) Org Lett 9:4733–4736 Rivera DG, Wessjohann LA (2009) J Am Chem Soc 131:3721–3732 Christinat N, Scopelliti R, Severin K (2007) J Org Chem 72:2192–2200 Christinat N, Scopelliti R, Severin K (2008) Angew Chem Int Ed 47:1848–1852

Top Heterocycl Chem (2010) 25: 25–94 DOI: 10.1007/7081_2010_43 # Springer-Verlag Berlin Heidelberg 2010 Published online: 24 June 2010

Palladium-Copper Catalyzed Alkyne Activation as an Entry to Multicomponent Syntheses of Heterocycles Thomas J.J. Mu¨ller

Abstract Alkynones and chalcones are of paramount importance in heterocyclic chemistry as three-carbon building blocks. In a very efficient manner, they can be easily generated by palladium-copper catalyzed reactions: ynones are formed from acid chlorides and terminal alkynes, and chalcones are synthesized in the sense of a coupling-isomerization (CI) sequence from (hetero)aryl halides and propargyl alcohols. Mild reaction conditions now open entries to sequential and consecutive transformations to heterocycles, such as furans, 3-halo furans, pyrroles, pyrazoles, substituted and annelated pyridines, annelated thiopyranones, pyridimines, meridianins, benzoheteroazepines and tetrahydro-b-carbolines, by consecutive couplingcyclocondensation or CI-cyclocondensation sequences, as new diversity oriented routes to heterocycles. Domino reactions based upon the coupling-isomerization reaction (CIR) have been probed in the synthesis of antiparasital 2-substituted quinoline derivatives and highly luminescent spiro-benzofuranones and spiro-indolones. Keywords Alkenones Alkynones Allenes Cross-coupling Domino Reactions Multicomponent Reactions Palladium Catalysis Contents 1 2

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Alkyne Activation by Cross-Coupling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1 The Coupling-Addition Sequence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2 The Coupling-Isomerization Sequence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

28 30 31 34

T.J.J. Mu¨ller Institut fu¨r Organische Chemie und Makromolekulare Chemie der Heinrich-Heine-Universita¨t Du¨sseldorf, Universita¨tsstrasse 1, D-40225 Du¨sseldorf, Germany e-mail: [email protected]

26 3

T.J.J. Mu¨ller

Multicomponent Synthesis of Heterocycles by Coupling-Cycloaddition Sequences . . . . . . 38 3.1 Isoxazoles by a Consecutive 3CR of Acid Chlorides, Alkynes, and Nitrile Oxides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39 3.2 Indolizines by a Consecutive 3CR of Acid Chlorides, Alkynes, and Pyridinium Ylids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41 4 Multicomponent Synthesis of Heterocycles by Coupling-Addition-Cyclocondensation Sequences Concluded by Michael Addition in Basic Media . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43 4.1 Pyrazoles by a Consecutive 3CR of Acid Chlorides, Alkynes, and Hydrazines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44 4.2 Pyrimidines by a Consecutive 3CR of Acid Chlorides, Alkynes, and Amidinium Salts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46 4.3 Pyrimidines by a Consecutive 4CR of (Hetero)aryl Iodides, Carbon Monoxide, Alkynes, and Amidinium Salts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47 4.4 Pyrimidines by a Two-Step Sequence of Consecutive 3CR of (Hetero)Arenes, Oxalyl Chloride, Alkynes, and Cyclocondensation with Guanidinium Salts . . . . . . . . 48 4.5 Benzo[b][1,4]Diazepines by a Consecutive 3CR of Acid Chlorides, Alkynes, and Ortho-Phenylene Diamines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51 4.6 Benzo[b][1,5]Thiazepines by a Consecutive 3CR of Acid Chlorides, Alkynes, and Ortho-Amino Thiophenols . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53 5 Multicomponent Synthesis of Heterocycles by Coupling-Addition-Cyclocondensation Sequences Concluded by Michael Addition and Steps in Acidic Media . . . . . . . . . . . . . . . . . . . 53 5.1 3-Halo Furans by a Consecutive 3CR of Acid Chlorides, Propargyl Ethers, and Halides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 54 5.2 Oxazoles by a Consecutive 3CR of Acid Chlorides, Propargyl Amine, and Acid Chlorides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 57 5.3 3-Iodo Pyrroles by a Consecutive 3CR of Acid Chlorides, Propargyl Amides, and Iodide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 58 5.4 Tetrahydro-b-carbolines by a Consecutive 4CR of Acid Chlorides, Alkynes, Tryptamines, and Acroyl Chlorides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 59 6 Multicomponent Synthesis of Annelated Thiopyranones by Coupling-Addition-Nucleophilic Aromatic Substitution Sequence . . . . . . . . . . . . . . . . . . . . . 62 7 Multicomponent Synthesis of Heterocycles by Coupling– Isomerization–Cyclocondensation Sequences . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 64 7.1 Pyrazoles by a Consecutive 3CR of (Hetero)aryl Halides, Propargyl Alcohols, and Hydrazines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 64 7.2 Pyrimidines by a Consecutive 3CR of (Hetero)aryl Halides, Propargyl Alcohols, and Amidinium Salts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 65 7.3 Benzoheteroazepine by a Consecutive 3CR of (Hetero)aryl Halides, Propargyl Alcohols, and Ortho-Amino or Ortho-Thio Substituted Anilines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 66 7.4 1,4-Diketones by a Consecutive 3CR of (Hetero)aryl Halides, Propargyl Alcohols, and Aldehydes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 66 7.5 Annelated and Substituted Pyridines by a Consecutive 4CR of (Hetero)aryl Halides, Propargyl Alcohols, Enamines, and Ammonium Chloride . . . . . . . . . . . . . . . . . 69 7.6 Annelated and Substituted Pyridines by a Consecutive 4CR of (Hetero)aryl Halides, Propargyl Amides, Ketene Acetals or S,N-Aminals, and Ammonium Chloride . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 72 8 Domino Syntheses of Heterocycles by CouplingIsomerization Sequences . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 75 8.1 Domino Synthesis of 2-Substituted Quinolines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 75 8.2 Domino Synthesis of Spiro-Benzofuranones and Spiro-Benzoindolones . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 76 9 Conclusion and Outlook . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 79 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 80

Palladium-Copper Catalyzed Alkyne Activation as an Entry

Abbreviations Ac AcO atm Boc Bu CNS COX-2 D DBU DFT DMF DME equiv EWG Et GC-MS Hal HIV HMG-CoA kobs L LUMO MCR Me MW nCR NMP Nu OLED p Ph Pr PTSA R r.t. THF THP TLC TBDMS Tos TMS UV vis

Acetyl Acetyloxy Atmosphere [bar] Tert-butyloxycarbonyl Butyl Central nervous system Cyclooxygenase-2 Heating Diazabicyclo[5.4.0]undecene Density functional theory N,N-dimethylformamide 1,2-Dimethoxyethane Equivalent(s) Electron-withdrawing group Ethyl Gas chromatography-mass spectrometry Halogen Human immunodeficiency virus 3-Hydroxy-3-methyl-glutaryl-CoA Observed rate constant Ligand Lowest unoccupied molecular orbital Multicomponent reaction Methyl (Heated in a) microwave (oven) n-Component reaction N-Methylpyrrolidone Nucleophile Organic light emitting diode Conjugated p-electron system Phenyl Propyl p-Toluenesulfonic acid Organic substituent Room temperature (20 C) Tetrahydrofuran Tetrahydropyranyl Thin layer chromatography Tert-butyldimethylsilyl p-Tolylsulfonyl Trimethylsilyl Ultraviolet Visible

27

T.J.J. Mu¨ller

28

1 Introduction Heterocycles are ubiquitous in all aspects of modern chemistry, such as medicinal chemistry, bioorganic and bioinorganic chemistry, and materials sciences. Their facile preparation has remained among of the most challenging goals for synthetic chemistry. However, addressing issues like simplicity, safety, brevity, selectivity, yield, environmental demands, availability of starting materials, and diversity all at the same time in the sense of an ideal synthesis [1] is an endeavor almost like squaring the circle (Fig. 1). Consequently, synthetic chemists have sought and devised fruitful strategies that inevitably tackle the very fundamental principles of efficiency and efficacy. Besides the criteria of selectivity, i.e., chemo-, regio- and stereoselectivity, they encompass also, and with increasing importance, economical and ecological aspects. Concise, elegant and conceptually novel syntheses have become an inspiring and steadily accelerating driving force both in academia and industry. Besides combinatorial and parallel synthetic strategies [2, 3] in the past two decades the productive concepts of multicomponent processes, domino reactions and sequential transformations have considerably stimulated the synthetic scientific community [4–15]. In particular, combination of diversity and creation of functionality has merged into the field of diversity oriented syntheses [16–20] that have found broad application in the discovery and development of pharmaceutical lead structures, and quite recently and steadily increasing also in the conception of functional p-electron systems, such as chromophores, fluorophores, and electrophores [21, 22]. Generally, domino reactions [23–26] are regarded as sequences of uni- or bimolecular elementary reactions that proceed without intermediate isolation or workup as a consequence of the reactive functionality that has been formed in the previous step (Fig. 2). Besides uni- and bimolecular domino reactions that are generally referred to as “domino reactions,” the third class is called multimolecular domino reactions or multicomponent reactions (MCRs).

simple

safe

preserving resources

in one step

Ideal Synthesis 100 % yield

Fig. 1 The ideal synthesis – squaring the circle?

readily available starting materials

environmentally benign diverse, but selective

Palladium-Copper Catalyzed Alkyne Activation as an Entry

29

Domino Reactions unimolecular

bimolecular

multimolecular

Perspective: High Complexity Goals: High Diversity, Functionality

Multi-component Reactions Domino All components are initially present, intermediates are not isolable

Sequential Addition in a defined order, constant conditions, intermediates are isolable

Consecutive Conditions are changed stepwise, intermediates are isolable

Perspective: High Diversity Goals: Structural Complexity, Functionality

Fig. 2 Multicomponent and domino reactions – enhancing synthetic efficiency

Whereas uni- and bimolecular domino reactions inevitably cause a significant increase in the degree of molecular complexity, MCR inherently lead to an increase in molecular diversity. Therefore, MCR bear some significant advantages over uniand bimolecular domino reactions. Besides the facile accessibility and high diversity of starting materials multicomponent syntheses promise high convergence and enormous exploratory potential. In addition to a purist standpoint where all ingredients of MCR have to be present from the very beginning of the process (MCR in a domino fashion), nowadays sequential (subsequent addition of reagents in a welldefined order without changing the conditions) and consecutive (subsequent addition of reagents with changing the conditions) one-pot reactions are as well counted to the class of MCR [4, 6, 11]. Transition metal catalyzed cross-coupling reactions [27] have considerably revolutionized the conceptual construction of molecular frameworks. For devising consecutive multicomponent, most advantageously the cross-coupling methodology displays an excellent compatibility with numerous polar functional groups as a consequence of the mild reaction conditions. Therefore, polar functionalities, which are most favorably for performing one-pot sequences, can be easily introduced and conveyed for subsequent transformations. Mastering unusual combinations of elementary organic reactions under similar conditions is the major conceptual defiance in engineering novel types of sequences for the synthesis of heterocycles in a concise one-pot fashion. Thus, the prospect of transition metal catalysis in MCR syntheses of heterocycles [28–30] and also sequentially palladium catalyzed processes [31] promise multiple opportunities for developing novel lead structures of pharmaceuticals, catalysts and even novel molecule based materials. The following account summarizes in a comprehensive fashion the concept of catalytic alkyne

T.J.J. Mu¨ller

30

activation as an entry to multicomponent and domino syntheses of heterocycles that has been developed over the past decade in our group.

2 Alkyne Activation by Cross-Coupling Reactive three-carbon building blocks such as alkynones [32] and 1,3-diaryl propenones (chalcones) (for a review on the chemistry of 1,3-diaryl propenones, see e.g. [33]) which can react with bifunctional nucleophiles in a sequence of Michael addition and cyclocondensation open a facile access to five-, six-, and sevenmembered heterocycles (Scheme 1). As a consequence, this general strategy has found broad application. However, standard syntheses of alkynones [34] and chalcones [33] are often harsh and require either strongly basic or strongly Lewis or Brønsted acidic conditions. Therefore, the application in one-pot methodology, where delicately balanced reaction conditions are a prerequisite, is largely excluded. Therefore, mild reaction conditions for the catalytic generation of ynones and enones, which are compatible with following transformations, are highly desirable. In particular, transition metal catalysis opens many opportunities for functional group tolerant product formations. Therefore, a catalytic access to ynones and enones turns out to be a versatile entry to consecutive multicomponent syntheses of heterocycles. Taking into account the excellent compatibility of polar functional groups that often dispenses with tedious protection–deprotection steps, the Sonogashira coupling [35–40], a straightforward alkyne-to-alkyne transformation, is a highly favorable tool for devising novel synthetic strategies to functional p-electron systems. Conceptually, the installation of a reactive functional group such as an alkyne with an electron-withdrawing substituent predictably could result in an in situ activation of alkynes towards Michael-type addition, i.e., an entry to a coupling-addition sequence (Scheme 2).

O HNu

R1 Alkynone

Catalytic Accesses?

Nu

XH2

R2

X R2

R1

Oxidation O R2

R1 Alkenone

HNu

XH2

Nu

X

R1

Scheme 1 Ynones and enones as three-carbon building blocks in heterocycle synthesis

R2

Palladium-Copper Catalyzed Alkyne Activation as an Entry

31

[Pd0, CuI], base R

1

π

Hal + R2

Sonogashira Reaction

electron withdrawing group (EWG)

R1

π R2

triple bond activation (Michael acceptor)

Scheme 2 Alkyne activation by Sonogashira coupling of an electron-poor halide as an entry to coupling–Michael addition sequences

2.1 2.1.1

The Coupling-Addition Sequence Sonogashira Coupling of Highly Electron-Deficient Heterocycles to Activated Alkynes and Subsequent Amine Addition

Applying fairly electron-deficient heteroaromatic halides in Sonogashira couplings with terminal alkynes lead to a transposition of the electron-withdrawal onto the coupled alkynyl moiety and result in activation towards nucleophile addition. As a consequence this concept was illustrated as an entry to intensely colored, highly solvochromic b-amino vinyl nitrothiophenes (Scheme 3) [41]. Simultaneously, Lin [42] has also reported that 2-alkynyl 5-nitrothiophenes 1 react very smoothly with secondary amines 2 to furnish b-amino vinyl nitrothiophenes 3. We have closely investigated these novel types of push-pull chromophores with respect to their NLO and thermal properties [41]. Hyper Rayleigh scattering measurements at a fundamental of 1,500 nm have revealed that b-values are surprisingly large for such short dipoles (3a: b0333 ¼ 31 1030 esu; 3b: b0333 ¼ 29 1030 esu). With respect to the relatively low molecular mass, these chromophores display a rather favorable molecular figures of merit, b0m/Mw, where Mw is the molar mass. Furthermore, selected push–pull chromophores 3 were investigated by differential scanning calorimetry revealing relatively low Tg, i.e., glass transitions, a favorable property for composites in photo refractive materials. Based upon the peculiar reactivity of nitrothienyl substituted alkynes a one-pot three-component coupling-aminovinylation sequence to push-pull chromophores was readily developed [43]. Terminal alkynes 4 and sufficiently electron-deficient heteroaryl halides 5 were transformed under Sonogashira conditions into the expected coupling products, which were subsequently reacted in a one-pot fashion with secondary amines 2 to furnish the push-pull systems 6 in good yields (Scheme 4). The critical step in this consecutive reaction is the addition of the amine to the intermediate internal acceptor substituted alkyne. According to semiempirical and DFT calculations, the crucial parameters for the success of the amine addition are the relative LUMO energies and the charge distribution at the b-alkynyl carbon atom. Therefore, only very electron deficient substrates with high

T.J.J. Mu¨ller

32 R′ R″ NO2

S

N H 2

R′ N R″

MeOH, Δ or THF, r.t.

1

NO2

S

3 (7 examples, 43-99%)

N

N NO2

S

NO2

S 3b

3a λmax (pentane) = 450 nm λmax (CHCl3) = 520 nm b0 = 31 × 10–30 esu b0μ /Mw = 1.34

λmax (pentane) = 443 nm λmax (CHCl3) = 513 nm b0 = 29 × 10–30 esu b0μ /Mw = 1.23

Scheme 3 Michael-type addition of secondary amines to nitrothienyl substituted alkynes and NLO data of selected b-amino vinyl nitrothiophenes

R1

+

Br heteroaryl

4

R1

2% (Ph3P)2PdCl2, 4% CuI NEt3 / THF (1:10), r.t.

NO2

R2R3N

heteroaryl

then: R2R3NH (2), MeOH, Δ

5

NO2

6 (10 examples, 31-76%)

O Ph

Ph N S

NO2

Ph O

Et2N S

Ph

N

NO2

S

NO2

N S

6a (57%)

6b (67%)

6c (76%)

NO2 Ph

n

Bu N

N S

Ph N

NO2

O S

NO2 S

S

N

NO2

NO2 N S

Et2N 6e (71%)

6f (42%)

NO2

6d (52%)

6g (69%)

NEt2

6h (67%)

Scheme 4 A coupling–aminovinylation sequence to b-amino vinyl hetero arenes 6

polarizability of the p-electron system are suited to participate in this couplingaddition sequence.

2.1.2

Modified Sonogashira Coupling of Acid Chlorides to Alkynones

A carbonyl group in conjugation with the triple bond exerts a strong polarization of the alkyne. Thus, Sonogashira coupling of acid chlorides 7 and terminal alkynes

Palladium-Copper Catalyzed Alkyne Activation as an Entry

33

4 furnishes alkynones 8 in a catalytic fashion [44–46]. Scrutinizing the reaction conditions revealed that virtually only one equivalent of triethylamine is stoichiometrically necessary for scavenging hydrochloric acid, and as a consequence, to achieve complete conversion (Scheme 5) [47, 48]. This not only reduces the amount of base but also leads to an essentially base-free reaction medium after the crosscoupling event. Furthermore, it is also possible to reduce reaction times by dielectric heating (microwave irradiation, MW) instead of conductive heating (oil bath). Prior to our studies trimethylsilyl (TMS) acetylene (4a) has turned out to be a notorious problem in standard acid chloride couplings and there was no report on its successful transformation. We have optimized the coupling conditions and we exemplified them for several (hetero)aroyl chlorides 7 as coupling partners (Scheme 6). It is noteworthy to mention that the yields for the corresponding Stille couplings with tributylstannyl TMS acetylene as alkyne coupling partner give with 70% (8a) [49], 51% (8b) [50], and 45% (8c) [51] substantially lower yields. Alkynones are reactive synthetic equivalents of 1,3-dicarbonyl compounds, and thus TMS alkynones can be considered to be surrogates of b-ketoaldehydes [52] which are very important and well-established three-carbon building blocks for cyclocondensations in heterocyclic chemistry [53, 54]. Furthermore, a common synthetic pathway to other synthetic equivalents of 1,3-dicarbonyl compounds, such as b-ketoacetals [55, 56], b-ketoenolethers [57, 58], and enaminones [59–64] is the Michael addition of alcohols or amines to alkynones (ketovinylation) [65–68]. Since alkynones are even more electrophilic than all other synthetic equivalents of b-ketoaldehydes a mild catalytic generation of alkynones 8 sets the stage for consecutive transformations to heterocycles in a one-pot fashion. Therefore, the generation of alkynones under mild reaction conditions and in suitable reaction media to allow subsequent transformations represents a major methodological improvement for modular heterocycle synthesis by cyclocondensation strategies. [Pd0, CuI] NEt3, (1.0 equiv), THF, 1 h, r.t.

O + R1

R2

Cl 7

4

O R1

or [Pd0, CuI] NEt3, (1.0 equiv), THF 10 min, 90°C, MW

R2 8

Scheme 5 Alkynones 8 by modified Sonogashira cross coupling of acid chlorides 7 and alkynes 4 O 2% Pd(PPh3)2Cl2, 4% CuI

7 + SiMe3 4a

NEt3 (1.0 equiv), THF, 1 h, r.t.

R1 SiMe3

8a (R1 = p -MeOC6H4, 82%) 8b (R1 = p -O2NC6H4, 65%) 8c (R1 = o -BrC6H4, 61%) 8d (R1 = o -AcOC6H4, 73%) 8e (R1 = 2-thienyl, 82%)

Scheme 6 Trimethylsilyl alkynones 8a–e by modified Sonogashira cross coupling

T.J.J. Mu¨ller

34

2.1.3

Coupling-Addition Sequence to Enaminones

The concept of alkyne activation by Sonogashira coupling was then successfully extended to the consecutive one-pot reaction principle of the coupling-addition sequences leading to an enaminone synthesis [48, 69, 70]. Besides their enormous synthetic potential as well-established three-carbon building blocks for cyclocondensations in heterocyclic chemistry [53, 54] enaminones [59–64] in their own right are highly pharmacologically active and reveal a pronounced anticonvulsant [71–74] and nonsteroidal anti-inflammatory activity [75]. In the sense of a consecutive three-component one-pot reaction, after reacting various acid chlorides 7 with terminal alkynes 4 under modified Sonogashira conditions to furnish the desired alkynones 8 and subsequent addition of primary and secondary amines 9, heating for several hours furnishes the enaminones 10 in good to excellent yields (Scheme 7). Primary amines 9 with R4 ¼ H exclusively give rise to the formation Z-configured enaminones (see e.g., 10h), whereas secondary amines 9 with R4 6¼ H furnish E-enaminones in good E/Z-selectivity. This one-pot coupling-addition enaminone synthesis is of a fairly broad scope and of excellent chemoselectivity. For example, tryptamine (e.g., 10h) neither needs to be protected at the indole nitrogen nor any enamine side reaction can be detected.

2.2

The Coupling-Isomerization Sequence

Besides activating the triple bond towards Michael addition the electron-withdrawing group (EWG) introduced by Sonogashira coupling can also exert an activation of the remote propargyl position (Scheme 8). This propargyl activation could for

7 + 4

R2

O

2% Pd(PPh3)2Cl2, 4% CuI NEt3 (1.0-1.25 equiv), THF, 1 h, r.t. Then: R3R4NH 9, methanol, Δ

R1

N R4

R3

10 (11 examples, 74-99%) O Ph

Ph

O N

Et

Ph

Ph

Cl

t

Bu

10b (99%, E:Z = 4:1)

Ph

O N

N O

10a (97%, E:Z = 30:1)

Et

Et 10e (76%, E:Z = 100:0)

Ph

O

Ph

N

Et

O

O

Et

Ph N

S

Et

Et

Et

10c (96%, E:Z = 100:0) 10d (95%, E:Z = 14:1) H

n

Bu N

O Et

Et 10f (97%, E:Z = 100:0)

Ph

N

H N Et

O

Et S

10g (74%, E:Z = 100:0)

N Ph

10h (78%, E:Z = 0:100)

Scheme 7 Coupling-addition three-component one-pot synthesis of enaminones 10

Palladium-Copper Catalyzed Alkyne Activation as an Entry

R1

π

[Pd0, CuI], base Hal +

electron withdrawing group (EWG)

R2

Sonogashira Reaction

35

R1 π R2

propargyl activation (towards isomerization)

Scheme 8 Propargyl activation by Sonogashira coupling of an electron-poor halide as an entry to coupling–isomerization (CI) sequences

instance trigger an alkyne-allene isomerization, over the complete sequence a coupling-isomerization (CI) reaction would be the consequence. As mentioned before enones and, in particular, chalcones (1,3-diaryl propenones) are predominantly synthesized under aldol conditions, which are relatively harsh and not always suitable for establishing multicomponent synthesis. The major short comings in the aldol condensation approach are strongly basic or acidic additives and reagents and the sometimes vigorous conditions in the condensation step. Therefore, mild reaction conditions as in transition metal catalyzed cross-coupling reactions are particularly favorable and promise a high level of functional group tolerance. Generating the enone functionality in a domino fashion en route [26, 28, 76] could pave the route to manifold opportunities for developing novel lead structures of pharmaceuticals, catalysts and even novel molecule based materials in a one-pot scenario. A couple of years ago we have disclosed a new mode of alkyne activation towards isomerization as a detouring outcome of the Sonogashira coupling. As a result of coupling electron deficient (hetero)aryl halides (or a,b-unsaturated b-halo carbonyl compounds) 11 and aryl propargyl alcohols 12 a new access to 1,3-di (hetero)aryl propenones 13, i.e., chalcones, was established (Scheme 9) [77, 78]. The scope for electron deficient (hetero)aromatic halides 11 is fairly broad and even organometallic complexes like 13c can be synthesized by this sequence. Prior to our studies this unusual reaction has only been observed and discussed by Minn [79] and Kundu [80, 81] for the coupling of 2-halogen substituted pyrimidines with 1-phenyl propargyl alcohol. Therefore, Kundu speculated on the mechanism by assuming coordination of an intermediate during a hydropalladation– dehydropalladation catalytic cycle to the heterocyclic nitrogen atom [81]. However, due to a lack of heteroatom coordination in many cases this explanation fails in most instances. Based upon detailed mechanistic studies, such as performing the coupling-isomerization reaction (CIR) in deuterated protic solvents or with a selectively deuterated propargyl alcohol and by 19F NMR kinetic measurements on the isomerization step of a para-fluoro phenyl substituted propargyl alcohol, the CIR can be rationalized as a sequence of a rapid Pd-Cu catalyzed alkynylation followed by a slow (kobs (75 C) ¼ 1.66 · 104 mol L1s1 for a pseudo first order rate law) amine base catalyzed propargyl alcohol-enone isomerization [78].

T.J.J. Mu¨ller

36

Analysis of the activation parameters from temperature dependent kinetics has revealed a significant decrease of the activation entropy indicating a high degree of organization in the rate determining transition state. Therefore, the general mechanistic picture of the CIR rationalizes as follows (Scheme 10). After the Sonogashira coupling of the halide 14 with propargyl alcohol 15 the presumed and actual intermediate is the internal propargyl alcohol 17. Now the isomerization

OH

5% PdCl2(PPh3)2, 1% CuI

+

EWG–π–Hal

O EWG π

NEt3, THF, Δ, 6−24 h

(hetero)aryl 12

11

(hetero)aryl

13 (28 examples, 41-98%)

EWG: electron withdrawing group O O

O Ph

O2N

O

OHC

Ph

Ph OC

13a (80%)

S

S

13b (85%)

Ph

Cr

N

13c (79%)

13d (75%)

CO CO

O

O

O

O

F

NC

NC

MeO2C S

NC

Br 13f (83%)

13e (90%)

13g (93%)

13h (66%)

Scheme 9 Chalcones 13 by coupling–isomerization reaction (CIR)

O OH π

R1

Hal +

[Pd0,

H

NEt3

R1

Coupling Isomerization Sequence

R2 14

CuI],

15

π

R2

16

Coupling

Tautomerization Alkyne-Allene Isomerization OH

R1

π

H

NEt3

R1

π

H

R2

R2 HN+Et3 17

OH

OH

18

Scheme 10 The mechanistic scenario of the CIR

•

π

R2

R1 19

Palladium-Copper Catalyzed Alkyne Activation as an Entry

37

commences by deprotonation at the propargylic position giving rise to a resonance stabilized propargyl-allenyl anion as a contact ion pair 18 in a solvent cage. Protonation either returns to the propargyl alcohol 17 or proceeds to the allenol 19. The later enol is elusive and will immediately tautomerize towards the thermodynamic sink on the energy hypersurface delivering the ultimate enone product 16 of the sequence. Encouraged by the mechanistic insight it became apparent that the CIR could be generalized to electro neutral and even electron rich halide substrates and also to aliphatic propargyl alcohols by overcoming the activation barrier either by increasing the temperature, by increasing the strength of the catalytic base in the isomerization step, or by both approaches. Indeed, the practical solution for a general CIR turned out to be the microwaveassisted version of the CIR (MACIR) (Scheme 11) [82]. In comparison to conductive heating in an oil bath under comparable conditions, dielectric heating furnished higher yields in the model reaction at shorter reaction times. Whereas electron deficient (hetero)aryl halides are rapidly coupled and isomerized with triethylamine as a base, for electro neutral and electron rich aryl halides DBU has to be applied to achieve comparable reaction times and yields. Most remarkably the alkyl substituted propargyl alcohol 15 with R2 ¼ nPr can be successfully transformed giving rise to the enone 16f in moderate isolated yield. In addition the reaction scope of the CIR was extended to sequential catalysis [31]. A designed substrate bearing an aryl bromide functionality in an nonactivated stage, such as a p-bromo phenyl substituted propargyl alcohol, was selectively coupled with an electron deficient halide furnishing the coupled p-bromo phenyl propargyl alcohol. Upon slow base catalyzed isomerization the chalcone is generated, which now display an activated p-bromo substituent ready for rapid oxidative addition of a Pd(0) species. Indeed, the CIR literally switches on the activated halide functionality for a subsequent coupling, e.g., Sonogashira coupling, Suzuki coupling, Heck reaction or CIR, in the same reaction vessel without further addition of catalysts [83]. Likewise, also the aryl halide functionality can be designed to

OH 1

R

Hal

+

H R2

14

15

O

2% PdCl2(PPh3)2, 1% CuI, 20% PPh3 THF, NEt3 (5 equiv) or DBU (2 equiv) MW (120-150°C) 15-30 min

R1

R2 1

2 16a (R = p-NCC6H4, R = Ph, 96%) 1 2 16b (R = 2-pyrimidyl, R = Ph, 84%) 1 2 16c (R = 2-pyridyl, R = Ph, 78%) 16d (R1 = p-H2NSO2C6H4, R2 = Ph, 62%) 16e (R1 = p-NCC6H4, R2 = 3-thienyl, 70%) 16f (R1 = p-NCC6H4, R2 = nPr, 62%) 1 2 16g (R = Ph, R = Ph, 92%) 16h (R1 = p-MeC6H4, R2 = Ph, 92%) 1 2 16i (R = p-MeOC6H4, R = Ph, 85%) 16i (R1 = m-H2NC6H4, R2 = Ph, 73%)

Scheme 11 Microwave-assisted CIR (MACIR) of (hetero)aryl halides 14 and propargyl alcohols 15 to give (hetero)aryl enones 16

T.J.J. Mu¨ller

38 HNTos 11 +

N Tos 2% Pd(PPh3)4, 1% CuI

(hetero)aryl

NEt3, THF, Δ

(hetero)aryl

21 (7 examples, 40-100%)

20 N Tos NC

R

1

N Tos

N Tos

N Tos

S F3C

O2N

N OPh 21a (94%)

OMe 21b (49%)

21c (100%)

OMe 21d (100%)

Scheme 12 Enimines 31 by coupling-isomerization reaction (CIR)

express an electron withdrawing functionality, which simultaneously is a dormant organometallic functionality. Indeed, bromo aryl pinacolyl boronates trigger the CIR with a propargyl alcohol on one hand as electron withdrawing groups. On the other hand by addition of potassium carbonate and another aryl halide the boronates are activated after CIR towards subsequent Suzuki coupling in the same reaction vessel without further addition of catalysts [84]. Finally, in analogy to the chalcone formation by CIR, the use of N-tosyl propargyl amines 20 leads to the formation of N-tosyl enimines 21 in moderate to excellent yields (Scheme 12) [85]. The mild reaction conditions (relatively weak amine bases, short reaction times) of the CIR of (hetero)aryl halides and 1-(hetero)aryl propargyl alcohols opens a modular entry to chalcones, which are as Michael acceptors suitable starting points for consecutive multicomponent syntheses of heterocycles in a one-pot fashion [28, 86]. Both catalytic generations of ynones and enones have set stages for diversity-oriented multicomponent syntheses of heterocycles in a consecutive one-pot fashion.

3 Multicomponent Synthesis of Heterocycles by Coupling-Cycloaddition Sequences Besides their pronounced Michael reactivity (vide supra and infra) alkynones are perfectly suited as highly polarized and reactive dipolarophiles for (3 þ 2)-cycloadditions giving rise to five-membered heterocycles. Taking into account the mild and catalytic access to ynones, the implementation of coupling-cycloaddition sequences as a three-component approach to five-ring heterocycles lies at hand (Scheme 13). According to this concept the three-component syntheses of isoxazoles and indolizines have been realized to date.

Palladium-Copper Catalyzed Alkyne Activation as an Entry O

O

Catalytic Access

39

(3 +2)-Cycloaddition

R1 Z

R1 R2

R2

Y X

Scheme 13 Catalytic generation of alkynones and (3 þ 2)-cycloaddition

3.1

Isoxazoles by a Consecutive 3CR of Acid Chlorides, Alkynes, and Nitrile Oxides

The pronounced biological activity has rendered many substituted isoxazoles an important motif in medicinal chemistry. For instance, isoxazoles are potent and selective agonists of human cloned dopamine D4 receptors [87], they exhibit GABAA antagonist [88] analgesic, antiinflammatory, ulcerogenic [89] COX-2 inhibitory [90, 91] antinociceptive [92], and anticancer [93] activity. Besides carbonyl and alkynone condensation [94, 95] of hydroxylamine, the (2+3)-cycloaddition of aromatic nitrile oxides, a class of propargyl type 1,3-dipoles, is a very general access to isoxazoles [96, 97]. Since aromatic nitrile oxides tend to be very unstable, it is favorable to generate them in situ by dehydrochlorination of the corresponding hydroximinoyl chlorides with a suitable base. If triethylamine is the base, this step can be expected to be fully compatible with a preceding alkynone formation. Therefore, after reacting acid chlorides 7 with terminal alkynes 4 for 1 h at room temperature under modified Sonogashira conditions, subsequently, hydroximinoyl chlorides 22 and triethylamine are added. After dielectric heating for 30 min, the isoxazoles 23 are obtained in moderate to excellent yields and with excellent regioselectivity, often as crystalline solids (Scheme 14) [98]. This coupling-cycloaddition sequence commences with the coupling of acid chloride 7 and alkyne 4 furnishing the alkynone 8, which now can act as a dipolarophile (Scheme 15). The suitable nitrile oxide dipole 24 is generated from 22 by dehydrochlorination with an additional equivalent of triethylamine. As a consequence of the inherent high reactivity of nitrile oxides, the concluding 1,3-dipolar cycloaddition to give the desired isoxazoles 23 is preferentially performed by dielectric heating. Performing the concluding cycloaddition step under conductive heating has proven to be timeconsuming and often not efficient. The major drawback of extended reaction times is a side reaction of the in situ generated nitrile oxides giving rise to the formation of furoxan oxides. Besides the mild conditions and excellent chemo- and regioselectivity the scope of this one-pot coupling–cycloaddition isoxazole synthesis is fairly broad. Due to acid chlorides as halide coupling partners, amines and hydroxy groups inevitably need to be protected prior to the reaction. Therefore, the use of acid chlorides 7 is principally limited to (hetero)aromatic compounds and derivatives without a-hydrogen atoms. As an exception, the cyclopropyl group is tolerated as a

T.J.J. Mu¨ller

40 R1 2% PdCl2(PPh3)2, 4% CuI NEt3(1.05 equiv), THF, 1 h, r.t.

O +

R1

2

R

Cl 7

OH

Then: Cl N

4

R3

O

2

R3

R

O N 22 (1.0 equiv) 23 (24 examples, 12-78 %)

NEt3 (1.0 equiv), 90°C, 30 min, MW O2N S

O NO2

n

Bu

S

S

O OMe

N

O OMe

Cl

Me O N

O N

23a (67%)

S

O N 23c (78%)

23b (55%) t

Bu

O

O

O

OMe

OCH3

OMe Me3Si

Me3Si O N 23d (77%)

Me3Si O N 23f (54%)

O N 23e (56%) MeO

O

S

O n

n

Pr

Bu

S O N

O N 23g (68%)

23h (66%)

Scheme 14 Coupling-cycloaddition three-component synthesis of isoxazoles 23

22

Scheme 15 Mechanistic rationalization of the coupling–cycloaddition sequence to isoxazoles 23

NEt3 R3 7 + 4

[Pd0,

CuI],

NEt3

Coupling

[8]

N+ O– 24

1,3-Dipolar Cycloaddition

23

substituent in both steps of the sequence (see compound 23f). Aliphatic as well as electron rich and electron poor aromatic alkynes can be employed. Even heterocyclic alkynes can be efficiently used as starting materials. TMS acetylene also easily undergoes the coupling procedure. With respect to the 1,3-dipole nitrile oxide, electron rich, polycyclic, electron deficient and heterocyclic substituents are all tolerated and react readily with the alkynone intermediates 8.

Palladium-Copper Catalyzed Alkyne Activation as an Entry

7

+ 4

2% PdCl2(PPh3)2, 4% CuI NEt3 (1.05 equiv), THF, 1 h, r.t. Then: Cl

41

23 (7 examples, 29-79%)

OH 22 (1.0 equiv) N

R3 NEt3 (1.0 equiv), 4 h, r.t.

Fe

Fe

Fe O

O

O

OMe

OMe Me3Si

Me3Si O N

O N

23i (79%)

23j (62%)

Fe

O N 23k (47%)

Scheme 16 Coupling-cycloaddition three-component synthesis of ferrocenyl substituted isoxazoles 23

In addition, testing scope and limitations of this sequence and the conditions, ferrocenyl substituted isoxazoles 23 were synthesized from ferrocenyl carbonyl chloride (R1 ¼ ferrocenyl) and/or ethynyl ferrocene (R2 ¼ ferrocenyl), and were often obtained as red crystals [99]. Unfortunately, standard conditions of the cycloaddition step failed, which had to be conducted at room temperature (Scheme 16). Cyclic voltammetry revealed that all ferrocene derivatives can be reversibly oxidized. The number of reversible waves in the cyclic voltammograms corresponds to the number of the redox sensitive moieties in the molecule. With respect to ferrocene the half-wave potentials of the compounds are shifted anodically. Furoxanes were isolated in minor amounts as the expected byproducts resulting from dimerization of the nitrile oxides.

3.2

Indolizines by a Consecutive 3CR of Acid Chlorides, Alkynes, and Pyridinium Ylids

Indolizine is an aromatic 10p-electron system and constitutional isomer of 1-H indole and, consequently, has received a considerable theoretical and practical interest [100]. Considering the well-established fluorescence properties of indolizines [101–103] and biindolizines [102], and the steadily increasing importance of fluorophores in biolabeling and environmental trace analysis, we have been seeking for a new, efficient synthesis of fluorescent indolizines. Two general ways of indolizine syntheses have been known so far [100]. The first route is based on the intramolecular formation of the indolizine by cyclocondensation of suitable pyridinium precursors. However, the second approach takes advantage of a [3 þ 2]

T.J.J. Mu¨ller

42

cycloaddition of pyridinium ylides with various double or triple bond Michael systems [104–107]. Therefore, the catalytic access to alkynones is well suited for devising a coupling-cycloaddition access to indolizines in a consecutive multicomponent fashion. Thus, submitting (hetero)aroyl chlorides 7 and terminal alkynes 4 to the reaction conditions of the modified Sonogashira coupling in a mixture of THF and triethylamine at ambient temperature and after adding 1-(2-oxoethyl) pyridinium bromides 25 and stirring for 14 h at room temperature the indolizines 26 were obtained in 41–59% yield as pale yellow to yellow green crystalline solids (Scheme 17) [108]. Mechanistically, this sequence can be rationalized by initial alkynone formation upon coupling of acid chloride 7 and alkyne 4 furnishing the alkynone 8, which now can act as a dipolarophile (Scheme 18). The amount of triethylamine is sufficient to deprotonate the 1-(2-oxoethyl)pyridinium bromide 25 giving rise to the zwitterionic pyridinium ylide 27, an allyl-type dipole suitable for the subsequent 1,3-dipolar cycloaddition to give the dihydroindolizine 28. Under either aerobic or anaerobic conditions in the final cycloaddition step oxidative aromatization directly furnishes the desired indolizines 26. The just discussed sequence is another methodological showcase for the combination of cross-coupling and cycloaddition in the same reaction vessel, giving rise to a broad variety of indolizines 26. In particular, 7-(pyridin-4-yl)-substituted R4 2% PdCl2(PPh3)2, 4% CuI NEt3 (20 equiv), THF, 2 h, r.t.

O + R1

R2

Cl 7

O

R4

Then:

N

R1

4

R2 Br–

N+

25

O R3

26 (11 examples, 41-59%)

O

R3 14 h, r.t. N N O N

O

O

Ph N

Ph

Ph

O

N

O O

O

Ph

MeO

EtO

N Ph

TBDMSO

O

Ph

MeO

EtO OMe

26a (55%)

26b (51%)

26c (53%)

Scheme 17 Coupling-cycloaddition three-component synthesis of indolizines 26

26d (59%)

Palladium-Copper Catalyzed Alkyne Activation as an Entry

43

25 NEt3 R4

N+

[Pd0, CuI], NEt3 7 + 4

Coupling

R3 [8]

R4

O

–

27 1,3-Dipolar Cycloaddition

O H N

R1

O

R2 H

Oxidative Aromatization

26

R3 28

Scheme 18 Mechanistic rationalization of the coupling–cycloaddition sequence to indolizines 26

representatives display pronounced fluorescence and even strong day-light fluorescence upon protonation. The reversible protonation as well as the protochromicity of the fluorescence response in weakly acidic media render 7-(pyridin-4-yl)indolizines ideal candidates for fluorescence labels and for studying pH-dependent and pH-alternating cellular processes.

4 Multicomponent Synthesis of Heterocycles by Coupling-Addition-Cyclocondensation Sequences Concluded by Michael Addition in Basic Media Alkynones are potent Michael acceptors in heterocyclic chemistry and many five-, six-, and seven-membered heterocycles can be synthesized from reactive, bifunctional three-carbon building blocks such as alkynones by classical heterocyclic chemistry [32]. Taking into account the mild, catalytic access to alkynones the coupling-addition-cyclocondensation sequence for multicomponent approaches to five-, six-, and seven-ring heterocycles lies at hand (Scheme 19). As a consequence, this synthetic concept of the following MCRs is based on a Sonogashira coupling and the subsequent reaction with binucleophilic substrates. First a Michael addition furnishes an enone which reacts by intramolecular nucleophilic attack and subsequent condensation concludes the sequence with the formation of the heterocycle (Scheme 20). Compared to 1,3-diketone condensations this modus operandi implements a huge advantage, since selectively only one of two possible regioisomers is formed. In most cases, the reaction conditions for the second addition-cyclocondensation step are neutral to slightly basic, i.e., more or less identical to those of the preceding Sonogashira coupling.

T.J.J. Mu¨ller

44 O

Catalytic Access

1 Addition-Cyclocondensation R

R1 2

R

R2 X

Z

5–, 6–, and 7– Membered Rings

(Y)

Scheme 19 Catalytic generation of alkynones and subsequent addition–cyclocondensation

O

H2Nu Nu

+

R1

HNu

R2

R1

Nu R2

–H2O

H2Nu O

HNu Nu HO

R1 R2

R1

Nu R2

Scheme 20 General mechanistic rationale of the reaction of a binucleophile and an alkynone

4.1

Pyrazoles by a Consecutive 3CR of Acid Chlorides, Alkynes, and Hydrazines

The direct conversion of hydrazines with alkynones 8 to pyrazoles by Michael addition-cyclocondensation has been known for more than a century [49, 109–111]. However, neither the regioselectivity issue was studied in detail nor the occurrence of regioisomers was reported [110]. Despite of very few examples [112] the regioselective formation of N-substituted pyrazoles by the alkynone pathway has remained unexplored prior to our studies. With respect to the interesting pharmacological and electronic properties of pyrazoles, in particular as fluorophores, and the increasing quest for tailor-made functional p-electron systems by diversity-oriented strategies, we have developed a regioselective one-pot synthesis of substituted pyrazoles. After coupling of (hetero)aroyl chlorides 7 and terminal alkynes 4, hydrazines 29, and acetic acid are added and reacted in the same reaction vessel. Best results for the formation of pyrazoles 30 are obtained by dielectric heating in the microwave oven at 150 C for 10 min in the presence of methanol. Pyrazoles 30 are obtained in good to excellent yields, predominantly as colorless crystalline solids (Scheme 21) [113]. This concept has also been applied to the nonregioselective synthesis of 3,5-disubstituted pyrazoles 30 (R3 ¼ H) upon conductive heating in the cyclocondensation step [114].

Palladium-Copper Catalyzed Alkyne Activation as an Entry 2% PdCl2(PPh3)2, 4% CuI NEt3 (1.05 equiv), THF, 1 h, r.t.

O +

R1

45

R2

Cl 7

R1

Then: H2N–NH 29 (1.10 equiv) 3 R

4

N N

Cl

N N H 30a (94%)

MeO

n

Bu

Ph

S

R3

30 (25 examples, 13-95 %)

CH3OH, CH3COOH, 10 min, 150°C (MW)

Me

R2

Ph N N

N N

N N

H

H 30b (82%)

Me

30c (83%)

30d (93%)

MeO Cl Cl

CN

CN

N N

S S

Me 30e (87%)

N

N N Me 30g (87%)

N N Me 30f (59%)

n

hexyl

OMe MeO

NC

OMe MeO

CN N N

N N

N N Me

Me

30h (77%)

Me

30i (58%)

MeO

30j (44%)

OMe

Cl n

Cl

butyl

N N

Ph N N N

N N

N Me

Ph Br

Me 30k (68%)

30l (81%)

30m (70%)

Scheme 21 Coupling–addition–cyclocondensation three-component synthesis of pyrazoles 30

Three types of hydrazines have investigated in these methodological studies, i.e., hydrazine (R3 ¼ H), methyl hydrazine (R3 ¼ Me), and aryl hydrazines (R3 ¼ aryl). In agreement with theory in every case only one of the two possible regioisomers, depending on the nature of the hydrazine substituent R3, was preferentially formed. Only trace amounts of the other regioisomer could be detected (regioselectivity >97: <3). Therefore, it is possible to access 1,3,5-trisubstituted pyrazoles almost in a specific fashion (see compounds 30i and 30j). With diynes bridged dipyrazoles can be quite efficiently prepared in the sense of a pseudo five-component reaction (see compound 30k). The rapid, diversity-oriented synthetic approach to fine-tunable fluorophores (with fluorescence quantum yields up to 0.78) is particularly interesting for the development of tailor-made emitters in organic light emitting diode (OLED) applications and fluorescence labeling of biomolecules, surfaces or mesoporous materials.

T.J.J. Mu¨ller

46 2% PdCl2(PPh3)2, 4% CuI NEt3 (1.05 equiv), THF, 1 h, r.t.

O + Cl S

Br

Then: MeNHNH2 (29b) (1.10 equiv) CH3OH, CH3COOH, 10 min, 150°C (MW) Then: p-MeC6H4B(OH)2, K2CO3, (3 equiv) 0.20 eq PPh3 (0.2 equiv), H2O 20 min, 150°C, MW

S Me

N N Me 31 (52%)

Scheme 22 Coupling–addition–cyclocondensation–coupling four-component synthesis of pyrazole 31

As another show case of a sequentially Pd-catalyzed process [31] a one-pot four-component synthesis of pyrazole 31 encompasses a coupling-addition-cyclocondensation-coupling sequence where, without further catalyst addition, the Pd catalyst of the Sonogashira coupling is exploited in the terminal Suzuki coupling step (Scheme 22) [113].

4.2

Pyrimidines by a Consecutive 3CR of Acid Chlorides, Alkynes, and Amidinium Salts

Pyrimidines represent an important class of heterocycles [115–120] and their structural framework not only is a key constituent of nucleic bases, alkaloids, and numerous pharmacophores with antibacterial [121], antimicrobial, antifungal [122], antimycotic [123], antiviral, and antitumor activity [124, 125], but also as a central unit in grid-forming ligands for supramolecular scaffolds [126–130]. As a consequence many pyrimidine syntheses are known, the most efficient of them applying cyclocondensations of 1,3-dicarbonyl compounds or their synthetic equivalents with amidines as a key step [53, 54, 131]. Among these approaches the reaction of alkynones and amidinium salts [132–137] represents an intriguing entry to pyrimidines, and, thus, the catalytic alkynone generation by Sonogashira coupling should be perfectly suited for accessing pyrimidines by multicomponent syntheses. Therefore, a consecutive three-component synthesis of 2,4-disubstituted and 2,4,6-trisubstituted pyrimidines 33 is readily achieved via modified Sonogashira coupling of (hetero)aroyl chlorides 7 and terminal alkynes 4, and the subsequent cyclocondensation with amidinium salts 32 (Scheme 23) [47, 69]. 4-Substituted 2-amino pyrimidines represent highly potent tyrosine kinase inhibitors [124], and representatives like 33a are readily formed upon applying guanidine as a binucleophile in the addition-cyclocondensation step. Interestingly, this one-pot reaction can also be applied to furnish complex ligand type pyrimidines such as 33h or 33i. At first sight the yields do not seem to be too breathtaking, however, if one considers that six CC and CN bonds are formed in this consecutive process it becomes apparent that the average yield for each bond forming step is 74%. In a multistep synthesis by Lehn the overall yield of a ligand with comparable complexity as compound 33h was 15% [138].

Palladium-Copper Catalyzed Alkyne Activation as an Entry 2% PdCl2(PPh3)2, 4% CuI NEt3 (1.05 equiv), THF, 1 h, r.t.

O +

R1

47

Then: H2N

R

Cl 7

R1

Cl–

4

NH2 32 (1.10 equiv)

N

R3

S N

N

N

N

nBu

33c (84%)

nBu

S 33f (60%)

N

33d (56%)

nBu

N N

N

S

OMe

33b (81%)

nBuTosN

N

N SMe

OMe

N

N

OTBDMS

S

N

33a (51%)

nBu

Ph

NH2

HN

33 (17 examples, 17-84%)

nBu

S N

N

N R3

Na2CO3 · 10 H2O (2.5-3.0 equiv), 12-14 h, rfl.

S

R2

+

2

N

N

S

S

N

N

33e (67%)

CO2Et S

S N

N EtO2C

N

S

S

N

S 33g (61%)

33h (17%)

33i (21%)

Scheme 23 Coupling–addition–cyclocondensation three-component synthesis of pyrimidines 33

4.3

Pyrimidines by a Consecutive 4CR of (Hetero)aryl Iodides, Carbon Monoxide, Alkynes, and Amidinium Salts

An alternative catalytic three-component access to alkynones 8 can be conceived by carbonylative alkynylation of aryl iodides 34, terminal alkynes 4, and carbon monoxide [139, 140] or Mo(CO)6 [141, 142] (Scheme 24). After carbonylative alkynylation of aryl iodides 34 with terminal alkynes 4 and in the presence of carbon monoxide under ambient pressure the subsequent addition of an amidinium salt 32 gives rise to the formation of 2,4,6-trisubstituted pyrimidines 33 in the sense of a four-component reaction (Scheme 25) [143]. Additionally, this approach, albeit as a two step carbonylative alkynylation– cyclocondensation sequence, is applicable to concise syntheses of naturally occurring and highly biologically active meridianins and variolin analogs 36. Carbonylative alkynylation of suitable Boc-protected 3-iodo indoles, also with bromo substituents on the benzo core, or Boc-protected 3-iodo 7-aza indoles first furnish the corresponding TMS alkynones 35 in good yields. Then, in a separate step an aqueous guanidine solution concludes the syntheses by addition-cyclocondensation and concomitant desilylation and Boc-deprotection in good yields (Scheme 26) [143]. Meridianins and variolin analogs 36 were found to inhibit “metabolic syndrome” and oncologically relevant protein kinases at a low micromolar and even nanomolar level.

T.J.J. Mu¨ller

48 O R1

[Pd0, CuI], Base

I

+

34

R1

CO(1 atm) or Mo(CO)6

R2

R2 8

4

Scheme 24 Alkynones 8 by carbonylative alkynylation R1

2% PdCl2(PPh3)2, 4% CuI NEt3 (2.0 equiv), CO (1 atm), THF, 48 h, r.t.

34 + 4

Then: H2N Cl –

R2 N

N

NH2 32

R3

R3

Na2CO3 · 10 H2O (2.5-3.0 equiv), 12-14 h, rfl.

33j-n Me

MeO2C

n

Ph

S N

Ph

N

N

N

N

N NH

O2N

Me

Bu

Me Me

33j (56%)

33k (43%)

NC

33l (29%)

MeO n

N

N S

33m (28%)

n

Bu

Bu N

N S

33n (51%)

Scheme 25 Carbonylation–coupling–addition–cyclocondensation four-component synthesis of pyrimidines 33

4.4

Pyrimidines by a Two-Step Sequence of Consecutive 3CR of (Hetero)Arenes, Oxalyl Chloride, Alkynes, and Cyclocondensation with Guanidinium Salts

Based on mechanistic reasoning, the use of carbon monoxide or molybdenum hexacarbonyl as suitable CO sources necessitates of application of aryl halides. In addition, the effective concentration of CO in the reaction medium plays a crucial

Palladium-Copper Catalyzed Alkyne Activation as an Entry

49 N

O

NH2

SiMe3

N

guanidine (2.5 equiv) Na2CO3 (1.0 equiv) R′ X

CH3CN, t BuOH 80°C, 40 h

N

R′ N

X

Boc

H

35 (X = CH, N)

36 (X = CH, N, 59-78%) N

N N

N

N

Br

H

H 36a (Meridianin G) (66%)

NH2

NH2

N

N N

N

N NH2

NH2

36b (Meridianin C) (73%)

Br

N H

36c (Meridianin D) (78%)

N

N H

36d (Variolin analog) (59%)

Scheme 26 Synthesis of meridanins G, C, D, and a variolin analog

role for the outcome of carbonylative alkynylation. An alternative mode, which additionally avoids the use of aryl halides, could be a decarbonylation of an a-dicarbonyl compound. Rhodium mediated decarbonylations of aldehydes (Tsuji–Wilkinson reaction) are well precedented [144–146], however, the process becomes catalytic only at temperatures over 200 C. Decarbonylations of acid chlorides are rare [147] and palladium complexes are not commonly used for decarbonylations. Besides decarbonylative carbostannylations [148], decarbonylative Heck reactions with reaction times of 16 h at 160 C in NMP as a solvent were reported [149, 150]. Just recently, Pd/Cu-catalyzed decarboxylative cross-couplings of a-oxocarboxylates with aromatic bromides [151] and chlorides [152] at high temperatures and long reaction times have been introduced. Interestingly, although oxalyl chloride has been applied in the presence of aluminium chloride as a phosgene surrogate for Friedel–Crafts acylations [153] or as a source of carbon monoxide in stoichiometric copper mediated synthesis of cyclopentadienones from organolithium and organozirconium compounds [154], its use in any catalytic application has remained unexplored prior to our studies. Therefore, we have developed a novel mild carbonylative coupling method without the use of toxic carbon monoxide. Our first findings on the consecutive three-component synthesis of 3-indolyl alkynones 37 by decarbonylative Sonogashira coupling start from electron rich heterocycles and oxalyl chloride as a source of carbon monoxide via intermediary glyoxylyl chlorides [155]. Conceptually, this methodology complements the carbonylative alkynylation of heterocyclic halides with diminished electron density [143]. The glyoxylative-decarbonylative coupling rationalizes as follows (Scheme 27). After the oxidative addition of indole-3-glyoxylyl chloride 38, adduct 39 undergoes a migratory de-insertion and elimination of carbon monoxide furnishing the acyl-Pd

T.J.J. Mu¨ller

50 O

O

O Cl R2

O

Cl

Cl O

N

38

R1

N R1

PdLn

N R1

oxidative addition

37

O O

reductive elimination

PdLn Cl

O

PdLn –1

N 1

R N

39

decarbonylative elimination

R2

R1 41 transmetalation

CO O

PdLn–1 Cl

ClCuLm N 1

40

R

NEt3 + R

2

LmCu R2

4 HN+Et3Cl–

Scheme 27 Mechanistic rationale of the decarbonylative Sonogashira coupling of indole-3glyoxylyl chlorides 38 and terminal alkynes 2

species 40. The driving force of this reaction is the apparent relative instability of the dicarbonyl species 39 in comparison to the acyl species 40. Then, transmetallation of the in situ generated copper acetylide to 40 gives rise to the formation of the acyl-alkynyl-Pd complex 41, which undergoes reductive elimination to give the 3-indolyl alkynone 37 and the catalytically active Pd0 species is regenerated to start a new catalytic cycle. Besides indoles 42 this novel reaction can be extended to 7-aza indoles 43 and substituted pyrroles 44 giving rise to the formation of 3-indolyl alkynones 37, 3-(7-aza indolyl) alkynones 45, and 2-pyrrolyl alkynones 46 (Scheme 28). With this versatile alkynone synthesis in hand, the application to the pyrimidine synthesis was tested as well. As previously shown, 4-(indol-3-yl)- and 4-(7-aza-indol3-yl)-2-amino pyrimidines 36, which are structurally related to the marine natural products class of meridianins, have displayed a considerable potential as kinase inhibitors [143]. Therefore, upon reacting indolyl (37, X ¼ CH) and 7-aza-indolyl (45, X ¼ N) substituted alkynones or the pyrrolyl ynones 46 with an excess of guanidinium hydrochloride and potassium carbonate in 2-methoxy ethanol at 120 C for 12–24 h the heteroaryl substituted 2-amino pyrimidines 47, 48, and 49 were obtained in good to excellent yields (Scheme 29).

Palladium-Copper Catalyzed Alkyne Activation as an Entry

37a (X = CH, R1 = H, R2 = nBu, 43%) 37b (X = CH, R1 = CH2Ph, R2 = nBu, 74%) 37c (X = CH, R1 = CH2Ph, R2 = CH2OMe, 66%) R2 37d(X = CH, R1 = CH2Ph, R2 = Ph, 85%) 37e (X = CH, R1 = CH2Ph, R2 = SiMe3, 76%) 37f (X = CH, R1 = Me, R2 = SiMe3, 76%) 37g (X = CH, R1 = SiiPr3, R2 = nBu, 45%) 45a (X = N, R1 = CH2Ph, R2 = nBu, 63%) 45b(X = N, R1 = Me, R2 = Ph, 61%)

O

N R1 42 (X = CH) 43 (X = N) X

(COCl)2 (1.0 equiv) THF, 4 h, 0°C to r.t. or DME, 2 h, 0 to 105-110°C

or

Then: 1% PdCl2(PPh3)2, 1% CuI, alkyne 4 (1.0 equiv) NEt3 (2.0 equiv) 1 h to 2 d, r.t.

or

N R1 44

N R1

X

51

R2 1 2 n 46a (R = Me, R = Bu, 61%) 1 2 n 46b (R = CH2Ph, R = Bu, 43%)

N O

R1

Scheme 28 Three-component glyoxylative-decarbonylative alkynylation synthesis of alkynones 37, 45, and 46

R2

47a (X = CH, R1 = H, R2 = nBu, 81%) 47b (X = CH, R1 = CH2Ph, R2 = nBu, 86%) 1 2 NH2 47c (X = CH, R = CH2Ph, R = CH2OMe, 88%) 47d (X = CH, R1 = CH2Ph, R2 = Ph, 82%) 47e (X = CH, R1 = CH2Ph, R2 = H, 88%) 47f (X = CH, R1 = Me, R2 = H, 68%) 47g (X = CH, R1 = H, R2 = nBu, 68%) 48a (X = N, R1 = CH2Ph, R2 = nBu, 81%) 48b (X = N, R1 = Me, R2 = Ph, 86%)

N N

H2N+ Cl– 37, 45 or 46

NH2 (2.5 equiv) NH2

X

N R1 or

Na2CO3 · 10 H2O (2.5 equiv) 2-methoxyethanol 12-24 h, 120°C

R2 N R1

N

N

1 2 n 49a (R = Me, R = Bu, 92%) 49b (R1 = CH2Ph, R2 = nBu, 94%)

NH2

Scheme 29 Cyclocondensation of alkynones 37, 45, and 46 to 4-(indol-3-yl)-(47), 4-(7-aza-indol3-yl)-(48), and 4-(pyrrol-2-yl)-2-amino pyrimidines 49

Glyoxylative–decarbonylative alkynylations proceed considerably faster than carbonylative alkynylations of (hetero)aryl iodides with carbon monoxide and a lower catalyst loading is needed [143]. The mild conditions for decarbonylations are unprecedented, and the reagents are applied only in equimolar quantities with a high tolerance for various substituents. In addition, the application of alkynones 37, 45, and 46 in a subsequent transformation into heteroaryl 2-amino pyrimidines also illustrates the vast potential to diversity-oriented syntheses of heterocycles.

4.5

Benzo[b][1,4]Diazepines by a Consecutive 3CR of Acid Chlorides, Alkynes, and Ortho-Phenylene Diamines

Benzodiazepines and their dihydro derivatives constitute an important class of psychopharmaca [156–161]. In particular, derivatives of benzo[b][1,4]diazepines have aroused considerable interest as CNS active anticonvulsant drugs [162–164],

T.J.J. Mu¨ller

52

antianxiety, analgesic, sedative, antidepressive, and hypnotic agents [165–168]. Among the most frequently used methods for the synthesis of benzo[b][1,4]diazepines is the cyclocondensation of ortho-phenylene diamines with 1,3-dicarbonyl compounds [169] or equivalent 1,3 biselectrophiles such as epoxy ketones, a,b-unsaturated carbonyl compounds, or b-haloketones [170–172]. Therefore, the one-pot three-component approach to benzo[b][1,4]diazepines 51 by virtue of alkynones as key intermediates commences with the coupling of (hetero)aroyl chlorides 7 and terminal alkynes 4, and concludes by subsequent addition-cyclocondensation of ortho-phenylene diamines 50 under dielectric or conductive heating to furnish the desired seven-membered heterocycles (Scheme 30) [173]. A related three-component synthesis according to our concept enabled the synthesis of benzo[b][1,4]diazepines 51 in water under conductive heating [174]. In addition, all representatives are highly fluorescent in the solid state, but essentially nonfluorescent in solution at room temperature. Upon cooling the solutions of benzo[b][1,4]diazepines 51 cryo-fluorescence is observed, which can be attributed to a freezing of the ring interconversion and aggregation. This thermo responsive behavior of fluorophores as a consequence of restricted conformational

R1

R1

2% PdCl2(PPh3)2, 4% CuI NEt3 (1.05 equiv), THF, 1 h, r.t.

O Cl

+

R2 Then:

7

4

H2N

R3

H2N

R4

50 (1.10 equiv)

R2

N

R3

N

R3

51 (15 examples, 40-88%)

CH3COOH, 16 h, 80°C (oil bath) or 1 h, 120°C (MW) MeO N

Cl

N

Cl

S

MeO N

Cl

N

Cl

N N N MeO

Ph

MeO O

N

O 51a (81%)

MeO

51b (64%)

51c (88%)

51d (63%)

O2N S

N

S

Cl

N

N

Cl

N

Cl

N

Cl

N

Cl

N N 51e (54%)

n

N

Bu

51f (58%)

n

Bu

51g (86%)

n

Bu 51h (59%)

Scheme 30 Coupling–addition–cyclocondensation three-component synthesis of benzo[b][1,4] diazepines 51

Palladium-Copper Catalyzed Alkyne Activation as an Entry

53

changes opens new avenues for the development of tailor-made emitters in thermo sensors and the fluorescence labeling of biomolecules, surfaces or mesoporous materials.

4.6

Benzo[b][1,5]Thiazepines by a Consecutive 3CR of Acid Chlorides, Alkynes, and Ortho-Amino Thiophenols

The 1,5-benzothiazepine framework has been identified as a pluripotent pharmacophore with derivatives encompassing CNS acting agents, anti-HIV and anticancer drugs, angiotensin converting enzyme inhibitors, antimicrobial and antifungal compounds, calmodulin antagonists, bradykinin receptor agonists, as well as Ca2+ blockers [175]. In addition, dihydro 1,5-benzothiazepines have become increasingly interesting since many derivatives exhibit antifungal, antibacterial [176–178], antifeedant [179], anti-inflammatory, analgesic [180], and anticonvulsant [181] activity. Likewise, the related 1,5-benzothiazepines display a comparable spectrum of biological activity [182, 183]. Syntheses of 1,5-benzothiazepines can be achieved through various routes starting from 2-aminothiophenol and 1,3-difunctional three-carbon building blocks [184, 185]. Among them, a,b-unsaturated carbonyl compounds such as enones [186–188] and ynones [189–192] are suited best for Michael addition and subsequent cyclocondensation. After coupling of (hetero)aroyl chlorides 7 and terminal alkynes 4, ortho-amino thiophenols 52 and acetic acid are added and reacted in the same reaction vessel under dielectric heating for 30 min at 60 C to furnish 2,4-disubstituted benzo[b][1, 5] thiazepines 53 via a coupling-addition-cyclocondensation sequence (Scheme 31) [193]. In the concluding heterocyclization step, dielectric heating is clearly superior over conductive heating. Although the Michael addition and cyclocondensation are essentially completed after 10 min at 60 C in the microwave cavity for electronically diverse substitution a reaction time of 30 min at 60 C has proven to be optimal. In contrast to 2,4-disubstituted benzo[b][1,4]diazepines 51 (vide supra), benzo[b] [1, 5]thiazepines 53 are essentially nonfluorescent.

5 Multicomponent Synthesis of Heterocycles by Coupling-Addition-Cyclocondensation Sequences Concluded by Michael Addition and Steps in Acidic Media The distinctive feature of the catalytic generation of alkynones under modified Sonogashira conditions is the usage of one stoichiometrically necessary equivalent of triethylamine per bond forming reaction [47, 48]. Since the base is inevitably consumed in binding the liberated hydrogen halide the reaction medium is

T.J.J. Mu¨ller

54

R1

Cl

+

2

R

Then: 7

R1

2% PdCl2(PPh3)2, 4% CuI NEt3 (1.05 equiv), THF, 1 h, r.t.

O

H2N

R3 52 (1.10 equiv)

4

HS

R2

N

X

S

53 (14 examples, 45-77 %)

CH3COOH, 30 min, 60°C (MW) NC

MeO Me N N

S

N

N

S S

S

S Me3Si MeO

53a (68%) Cl

53b (65%)

53c (77%)

53d (45%)

MeO

Cl

N

N

S

S

N

S

S

N

Cl

S

Fe N

53e (57%)

NC

53f (57%)

53g (59%)

53h (61%)

Scheme 31 Coupling–addition–cyclocondensation three-component synthesis of 2,4-disubstituted benzo[b][1,5]thiazepines 53

essentially base-free. As a consequence not only subsequent reactions under neutral conditions can be readily performed but also the medium can be immediately converted into an acidic environment without neutralization. Therefore, the coupling can be followed by a sequential transformation under Brønsted or Lewis acidic conditions facilitating unusual combinations of elementary processes.

5.1

3-Halo Furans by a Consecutive 3CR of Acid Chlorides, Propargyl Ethers, and Halides

The peculiar circumstance of an essentially base free reaction medium now allows an entry to Lewis or Brønsted acidic conditions, still in a one-pot fashion. In the presence of hydrogen halide acids g-hydroxy alkynones can be successfully cyclized to give 3-chloro-, 3-bromo-, and 3-iodofurans [194]. Therefore, a sequence

Palladium-Copper Catalyzed Alkyne Activation as an Entry

55

of a Sonogashira coupling of (hetero)aroyl chlorides 7 and THP-protected propargyl alcohols 54, followed by an acid-mediated Michael addition of sodium chloride or sodium iodide in the presence of p-toluene sulfonic acid (PTSA) furnishes by concomitant deprotection and cyclocondensation 3-halo furans 55 in moderate to good yields (Scheme 32) [195, 196]. Mechanistically, it is very likely that the acid not only catalyzes the deprotection of the THP-protected alkynone 56 by transacetalization to liberate the g-hydroxy alkynone 57 but also mediates the Michael addition of the halide to the alkynone intermediate 57 (Scheme 33). Subsequently, the E-configured b-halo hydroxy O R1

Cl

OTHP

+ R2

7

54

2 % PdCl2(PPh3)2, 4 % CuI NEt3 (1.05 equiv), THF, 2 h, r.t. Then: NaCl (2.0 equiv), PTSA · H2O (1.1 equiv) CH3OH, 20 h, 60 °C or NaI (5.0 equiv), PTSA · H2O (1.1 equiv) CH3OH, 2 h, r.t.

THP = tetrahydropyran-2-yl PTSA = p-tolylsulfonic acid

Hal R1

R2

O

55a (Hal = Cl, R1 = Ph, R2 = H, 63 %) 55b (Hal = Cl, R1 = p-MeOC6H4, R2 = H, 71 %) 55c (Hal = Cl, R1 = p-O2NC6H4, R 2 = H, 24 %) 55d (Hal = Cl, R1 = o-FC6H4, R2 = H, 47 %) 55e (Hal = Cl, R1 = 1-cyclohexenyl, R2 = H, 64 %) 55f (Hal = Cl, R 1 = Ph, R2 = Et, 70 %) 55g (Hal = Cl, R1 = 2-thienyl, R2 = Et, 59 %) 55h (Hal = Cl, R1 = Ph-CH=CH, R2 = Et, 73 %) 55i (Hal = I, R1 = Ph, R2 = H, 63 %) 55j (Hal = I, R1 = p-MeOC6H4, R2 = H, 63 %) 55k (Hal = I, R1 = p-O2NC6H4, R2 = H, 40 %) 55l (Hal = I, R1 = Ph-CH=CH, R2 = H, 61 %) 55m (Hal = I, R1 = Ph, R2 = Et, 72 %) 55n (Hal = I, R1 = 2-thienyl, R2 = Et, 49 %) 55o (Hal = I, R 1 = Ph, R2 = p-MeOC6H4, 39 %) 55p (Hal = I, R1 = i Pr, R2 = p-MeOC6H4, 29 %)

Scheme 32 Coupling–transacetalization–addition–cyclocondensation three-component synthesis of 3-halo furans 55

O 7 + 54

[Pd0, CuI], NEt3

R1

OTHP

Coupling 2

R 56

[PTSA], CH3OH

Transacetalization

–THPOCH3

O PTSA, NaHal

R1

OH R2 57

Michael addition

Hal 1

R2

R

O

HO

– H2O Cyclocondensation

55

58

Scheme 33 Mechanistic rationalization of the coupling–deprotection–addition–cyclocondensation sequence to 3-halo furans 55

T.J.J. Mu¨ller

56

enone E-58 undergoes a cyclocondensation to furnish the 3-halo furan 55. The Z-configured b-halo hydroxy enone Z-58, which does not undergo cyclocondensation at comparable rate, is only detected in trace amounts according to TLC (as a highly polar byproduct) and GC-MS (the mass corresponds to a halo hydroxy enone isomer). Furthermore, the concept of a sequential nucleophilic addition in acidic medium can be transposed to the conversion of the ynone intermediates with iodine monochloride [197] and subsequent cyclization [198] into chloro iodo furans in a one-pot fashion. Therefore, after coupling of (hetero)aroyl chlorides 7 and THP-protected propargyl alcohols 54, NaCl, iodine monochloride, and PTSA were added to give after 4 h of stirring at room temperature the substituted 3-chloro-4-iodo furans 59 in moderate to decent yields (Scheme 34) [196]. 5.1.1

Trisubstituted Furans by Coupling-Transacetalization-AdditionCyclocondensation-Coupling Sequence

As a consequence of the mild reaction conditions in the sequence to 3-halo furans 55 the palladium catalyst should be still intact to trigger another Pd-catalyzed coupling in the sense of a sequentially Pd-catalyzed process [31]. As a consequence, a sequential Sonogashira–deprotection–addition–cyclocondensation– Suzuki reaction, where the same catalyst system is applied in two consecutive significantly different cross-coupling reactions in the same reaction vessel should be feasible. Therefore, upon consecutive reactions of (hetero)aroyl chlorides 7 and THP-protected propargyl alcohols 54, NaI and PTSA, and finally, addition of 1.05 equiv of boronic acids 60 and sodium carbonate, the substituted 3-aryl furans 61 can be obtained in decent yields (Scheme 35).

7 + 54

I

2% PdCl2(PPh3)2, 4% CuI NEt3 (1.05 equiv), THF, 2 h, r.t. Then: ICl (1.5 equiv), NaCl (2.5-5 equiv) PTSA · H2O (1.1 equiv) MeOH, r.t. 4 h

Cl

R1

R2

O

59a (R1 = Ph, R2 = H, 52%) 1 2 59b (R = p-MeOC6H4, R = H, 42%) 1 2 59c (R = p-O2NC6H4, R = H, 31%) 1 2 59d (R = 2-thienyl, R = H, 31%) 1 2 59e (R = p-MeOC6H4, R = Et, 64%) 1 2 59f (R = Ph-CH = CH, R = Et, 57%) 1 2 59g (R = p-MeOC6H4, R = p-MeOC6H4, 51%)

Scheme 34 Coupling–transacetalization–addition–cyclocondensation three-component synthesis of 3-chloro-4-iodo furans 59

7 + 54

R3

5% PdCl2(PPh3)2, 4% CuI NEt3 (1.05 equiv), THF, 2 h, r.t. 1

R Then: NaI (5.0 equiv), PTSA · H2O (1.1 equiv) CH3OH, 2 h, r.t. Then: 3 R B(OH)2 60 (1.05 equiv ) Na2CO3 (8.0 equiv), 90°C, 16-46 h

O

R2

61a (R1 = p-MeOC6H4, R2 = H, R3 = Ph, 50%) 1 2 3 61b (R = 2-thienyl, R = p-MeOC6H4, R = Ph, 52%) 61c (R1 = Ph-CH=CH, R2 = Et, R3 = 2-thienyl, 42%) 1 i 2 3 61d (R = Pr, R = H, R = 1-naphthyl, 52%)

Scheme 35 Coupling–transacetalization–addition–cyclocondensation–Suzuki coupling fourcomponent synthesis of 3-aryl furans 61

Palladium-Copper Catalyzed Alkyne Activation as an Entry

57

MeO

59g

5 mol% Pd(PPh3)2Cl2, p-CH3OC6H4B(OH)2 (60d) (1.05 equiv) Na2CO3 (8 equiv), H2O, THF/MeOH, 24 h, 90°C

Cl

O MeO

OMe 62 (59%)

Scheme 36 Suzuki coupling of the 3-chloro-4-iodo furan 59g

3-Chloro-4-iodo furans 59 can be valuable building blocks for the synthesis of highly substituted furans as illustrated by the Suzuki coupling of chloro iodo furan 59g with boronic acid 60d (R3 ¼ p-MeOC6H4) furnishing trisubstituted chloro furan 62 in 59% yield (Scheme 36). Expectedly, the coupling selectively occurs at the carbon–iodine bond.

5.2

Oxazoles by a Consecutive 3CR of Acid Chlorides, Propargyl Amine, and Acid Chlorides

Mechanistically, altering the intermediate propargyl alcohols 57 to the corresponding propargyl amines should facilitate suitable access to pyrroles in the same manner. However, with most of the generated amides this is not the case. Yet, propargyl amine (63) is readily amidated with acid chlorides 7 under mild reaction conditions to furnish propargyl amides. Without isolation these propargyl amides are reacted with acid chlorides 7’ under modified Sonogashira conditions to give rise to functionalized oxazoles 64 in good yields, but not to pyrroles (Scheme 37) [199, 200]. Indeed, Sonogashira coupling in this case is not the initial step but it is placed within the sequence. The interesting aspect of this sequence is the regiospecific introduction of substituents on the oxazole core by determining the order of amidation and coupling. The mechanism of this consecutive amidation–coupling–cycloisomerization sequence can be rationalized as follows (Scheme 38). The first acid chloride 7 and propargyl amine (63) are coupled by amidation to give the terminal alkyne 65, which is a propargyl amide. Upon addition of the second acid chloride 7’, palladium and copper catalysts and triethylamine, the Sonogashira coupling furnishes the alkynone 66. Although the terminal cycloisomerization with concomitant aromatization to give the oxazoles already proceeds under the coupling conditions, optimal rates were achieved by adding PTSA and tert-butanol and gentle heating after the Sonogashira step. As already discussed for the pyrimidine syntheses, this process can also be conducted in the sense of a four-component amidation–carbonylative alkynylation– cycloisomerization sequence [199].

T.J.J. Mu¨ller

58 1.0 equiv. NEt3, THF, 1 h, 0°C to r.t.

O 1

R

+

Cl 7

R2 R O Then: 64 (18 examples, 42-75%) 2% PdCl2(PPh3)2, 4% CuI R2COCl 7¢ (1.0 equiv), NEt3 (1.0 equiv) THF, 2 h, r.t. Then: PTSA · H2O (1.0 equiv) t BuOH, 1 h, 60°C O O N N S Ph Ph O O S

63

O

N

Ph

O Cl 64a (75%)

F3C

64c (53%)

64b (70%)

O

N

O

N

OMe

Cl

64e (50%)

64f (74%)

O

N

O

N Ph

O O2N

Me

Br

O

N

O

Me

64d (46%)

O

N

O

O

O

N 1

NH2

O

O

S

Me

Me

64h (57%)

64g (56%)

64i (66%)

Scheme 37 Amidation–coupling–cycloisomerization three-component synthesis of oxazoles 64

7 + 63

NEt3

H N

Amidation

R1

7¢ [Pd0, CuI], NEt3

O R2

Coupling

O 65

[PTSA] t BuOH

H N

R1

64

Cycloisomerization

O 66

Scheme 38 Mechanistic rationalization of the amidation-coupling-cycloisomerization sequence to oxazoles 64

5.3

3-Iodo Pyrroles by a Consecutive 3CR of Acid Chlorides, Propargyl Amides, and Iodide

Nevertheless, halo pyrroles are valuable synthetic building blocks for various transformations, and therefore a multicomponent access would be highly desirable. For the three component synthesis of the 4-iodo pyrroles with a nitrogen protecting group, propargyl amides still appear to be the most suitable starting materials. As shown, the cycloisomerization to oxazoles 64 under acidic conditions jeopardizes this endeavor. So the choice of the right nitrogen protecting group plays a crucial role. The Boc group is a versatile carbamate protecting group for the pyrrole nitrogen atom, useful for many transformations on the pyrrole core and easily removable. Therefore, upon reacting (hetero)aroyl chlorides 7 and N-Boc-protected propargyl amine (67) under modified Sonogashira conditions, the intermediate

Palladium-Copper Catalyzed Alkyne Activation as an Entry

R1

I

H

O Cl

7

N

+

67

59

Boc

2% PdCl2(PPh3)2, 4% CuI NEt3 (1.05 equiv), THF, 2 h, r.t. Then: NaI (5.0 equiv), PTSA · H2O (2.0 equiv) t BuOH, 1 h, r.t.

R1

N Boc

68a (R1 = p-MeC6H4, 73%) 68b (R1 = m-MeC6H4, 74%) 68c (R1 = o-MeC6H4, 72%) 68d (R1 = p-MeOC6H4, 73%) 68e (R1 = Ph, 72%) 1 68f (R = p-ClC6H4, 62%) 68g (R1 = p-FC6H4, 75%) 68h (R1 = 2-thienyl, 63%) 68i (R1 = β-styryl, 70%) 68j (R1 = cyclopropyl, 69%) 68k (R1 = 1-adamantyl, 61%)

Scheme 39 Coupling–addition–cyclocondensation three-component synthesis of 4-iodo pyrroles 68

alkynone 8 is generated [201]. Without isolation, the concluding addition-cyclocondensation with sodium iodide and PTSA furnishes the N-Boc-4-iodo-2-substituted pyrroles 68 in good yields (Scheme 39). The sequence starts with easily accessible starting materials and gives good yields of 4-iodo pyrroles 68. The reaction is quite general with respect to the underlying acid chlorides 7. Aromatic substituents bearing electron neutral, electron withdrawing, and electron donating substituents even in the ortho-position are tolerated. Furthermore, heteroaryl, alkenyl, cyclopropyl and sterically demanding adamantyl substituents can be effectively carried through the sequence. Boc as an electron withdrawing group allows handling 4-iodo pyrroles 68, which are notoriously unstable towards oxidation with electron donating groups at the pyrrole nitrogen. 5.3.1

3-Alkynylated Pyrroles by Coupling-Addition-CyclocondensationCoupling Sequence

The synthesized N-Boc-protected 4-iodo pyrroles 68 are highly useful synthetic building blocks, and the first scouting experiments were performed in the sense of a sequential Pd/Cu-catalyzed process [31], assuming that the catalyst system is still active after the coupling-addition-cyclocondensation sequence. Therefore, just upon addition of another terminal alkyne 4 to the reaction mixture, N-Boc-2-aryl-4-alkynyl pyrroles 69 can be obtained in good yields (Scheme 40) [201]. The conditions are sufficiently mild to leave the Boc group uncleaved.

5.4

Tetrahydro-b-carbolines by a Consecutive 4CR of Acid Chlorides, Alkynes, Tryptamines, and Acroyl Chlorides

The fundamental principles of MCRs demand that products of consecutive transformations are expected to contain substantial fragments of all starting materials, thus providing a high degree of atom-efficiency. As a consequence for heterocyclic synthesis, b-enaminones should be considered to be more than just synthetic equivalents of 1,3-dicarbonyl compounds. This aspect can be easily envisioned

T.J.J. Mu¨ller

60 R2 H

O 1

R

Cl

N

+

7

Boc

67

2% PdCl2(PPh3)2, 4% CuI NEt3 (1.05 equiv), THF, 2 h, r.t. R1 Then: N NaI (5.0 equiv), PTSA · H2O (2.0 equiv) Boc t BuOH, 1 h, r.t. 1 2 n 69a (R = p-tolyl, R = Bu, 58%) Then: 1 2 69b (R = p-MeOC6H4, R2 = TIPS, 53%) R CCH (4)(2 equiv) 1 69c (R = p-MeOC6H4, R2 = Ph, 67%) Cs2CO3 (4 equiv), 70°C, 1 h

Scheme 40 Coupling–addition–cyclocondensation–coupling four-component synthesis of 4-alkynyl N-Boc pyrroles 69 O O R1

Cl 7

n

+

4c

Bu

2% PdCl2(PPh3)2, 4% CuI NEt3 (1.05 equiv), THF, 2 h, r.t. Then: R2NH2 70, Δ Then: O

R1 n

Bu

N O R2 72a (R1 = 2-thienyl, R2 = CH2Ph, 31%) (71a), Δ 72b (R1 = p-MeOC6H4, R2 = CH2Ph, 63%) Cl 72c (R1 = 2-thienyl , R2 = 3,4-(MeO)2C6H3CH2CH2, 69%)

Scheme 41 Coupling–amination–aza–annulation four-component synthesis of 5-acyl dihydropyrid-2-ones 72

taking advantage of the unique electronically amphoteric reactivity of b-enaminones. Therefore, trying to conserve all atoms in the final product the enamino nitrogen atom should reside in the target molecule. The aza-annulation reaction [202, 203] of enamino carbonyl compounds and a,b-unsaturated acid chlorides is known to furnish 5-acyl dihydropyrid-2-ones 72. Therefore, after coupling of (hetero)aroyl chlorides 7 and 1-hexyne 4c, primary amines 70 are added to furnish enaminones 10. Without isolation acroyl chloride (71a) is added and reacted in the same reaction vessel to give after aza-annulation reaction the 5-acyl dihydropyrid2-ones 72 in moderate to good yields (Scheme 41) [70, 204]. In particular, the consecutive one-pot four-component reaction of (hetero)aroyl chlorides 7, alkynes 4, tryptamine derivatives 73 as primary amines and a,b-unsaturated acid chlorides 71 to form tetrahydro-b-carbolines 74 most clearly demonstrates the potential of this concept and methodology for the rapid construction of highlysubstituted, complex heterocycles. Five new s-bonds and four new stereocenters can be installed in a sequence of consecutive one-pot transformations (Scheme 42). Mechanistically, the sequence commences by coupling of the (hetero)aroyl chloride 7 and the alkyne 4 to give the alkynone 8 (Scheme 43). Upon addition of the tryptamine derivative 73 the enaminone 75 is obtained. Finally, the addition of the a,b-unsaturated acid chloride 71 triggers the aza-annulation reaction to furnish the acyliminium ion 76 which terminates the sequence by a Pictet-Spengler cyclization. Interesting is the excellent diastereoselectivity of the sequence where the R2, acyl-R1, and R5 substituents are exclusively placed in a syn-syn arrangement, whereas with a substituent R4 other than hydrogen, epimers are formed with

Palladium-Copper Catalyzed Alkyne Activation as an Entry

61 R3

2% PdCl2(PPh3)2, 4% CuI NEt3 (1.05 equiv), THF, 2 h, r.t.

O 1

R

Cl

7

+

R2

Then:

4

R3

N 2 H R

NH2

O

N H 73, 24 h, 70°C R4

Then: R5

O N

Cl O

71, 3 h, 70°C

R4 R1

R5

1 2 n 3 4 5 74a (R = 2-thienyl, R = Bu , R = R = R = H, 52%) 74b (R1= p-O2NC6H4, R2 = nBu , R3 = R4 = R5 = H, 43%) 74c (R1= p-MeOC6H4, R2 = nBu , R3 = R4 = R5 = H, 59%) 1 2 3 4 5 74d (R = 2-thienyl, R = Ph, R = R = R = H, 41%) 74e (R1 = 2-thienyl, R2 = nBu, R3 = R4 = H, R5 = CH3, 50%) 74f (R1 = 2-thienyl, R2 = nBu, R3 = R5 = H, R4 = CH3, 54%, syn-syn / syn-anti = 4.5:1) 1 2 3 4 5 74g (R = 2-thienyl, R = R = R = R = H, 32%) 74h (R1 = 2-thienyl, R2 = nBu , R3 = CO2Me, R4 = R5 = H, 45%) 1 2 3 4 5 74i (R = 2-thienyl, R = CH2OTBS, R = R = R = H, 30%) 74j (R1 = N-(phenylsulfonyl)-3-indolyl, R2 = nBu, R3 = R4 = R5 = H, 36%) 1 i 2 n 3 4 5 74k (R = Pr, R = Bu , R = R = R = H, 36%)

Scheme 42 Coupling–amination–aza–annulation–Pictet–Spengler four-component synthesis of tetrahydro-b-carbolines 74 R3

7 + 4

[Pd0, CuI], NEt3 Coupling

[8]

NH

73 Addition

O

2

R

N H

R1

75

Aza-Annulation

71

R3

Cl–

O R4

N 2

N H

R

5

R O

R

–HCl Pictet-Spengler cyclization

74

1

76

Scheme 43 Mechanistic rationalization of the coupling–amination–aza–annulation–Pictet– Spengler sequence to tetrahydro-b-carbolines 74

moderate selectivity (compound 74f, d.r. ¼ 4.5: 1). Most surprisingly, with (S)-(-)tryptophane methyl ester (73b, R3 ¼ CO2Me) as a tryptamine derivative the only cyclization product isolated in 45% yield is tetrahydro-b-carboline 74h that is formed as a single diastereomer. In order to rationalize the exclusive diastereoselectivity of the sequence, two mechanistic pathways can be proposed for the stereogenic aza-annulation step

T.J.J. Mu¨ller

62

O

H R′ N+

R2

R1

[3,3]

–

Path A

75

O R4

H

Cl H

Aza-Cope

R O

O

R5

O

Aza-Ene 1

R

Cl R' R

H N

N H

R4

R2

R5 O

R H O

R

1

76 1

R

2

H

H 79

O

+N

5

R H O

R2

R3

Cl–

R4

5

H Cl R′ N

H

Cl H

R4 78

R4

Path B

2

R

–

R5 77

71

H R′ N+

O 1

80

74

Scheme 44 Mechanistic rationalization of the coupling–amination–aza–annulation–Pictet– Spengler sequence to tetrahydro-b-carbolines 74

(Scheme 44). First, the (Z)-configured b-enaminone 75, arising from the addition of tryptamine 73 to ynones 8, reacts with an a,b-unsaturated acid chloride 71 either via a cationic aza-Cope-type rearrangement (path A) or via an aza-ene reaction (path B) [205]. In the pathway A, the chair-like transition state 77 is preferred, while in the latter pathway B the transition state 79 adopts an envelope conformation with an endo-electron withdrawing group lying over the fold of the envelope [206]. Both mechanistic scenarios rationalize the mutual syn-orientation of the R5 and the carbonyl substituents. Finally, for the resulting acyliminium species 76 an intramolecular nucleophilic attack by the indole can be expected to occur predominantly anti with respect to the more bulky carbonyl group, leading mainly to the syn diastereomer of 74 (with respect to R2 and carbonyl substituents). Two diastereomers observed in the reaction with methacryloyl chloride (R7 ¼ CH3) were formed most probably via epimerization. The overall yields for the stepwise reaction with intermediate isolation of the enaminone 75 after the coupling-addition sequence and its subsequent aza-annulation-Pictet-Spengler transformation lie in the same range as for the coupling-amination-aza-annulation-Pictet-Spengler sequence. However, avoiding the isolation and purification of the intermediate b-enaminone favors the application of the one-pot approach.

6 Multicomponent Synthesis of Annelated Thiopyranones by Coupling-Addition-Nucleophilic Aromatic Substitution Sequence Thiopyranone is the thio homologue of pyranone, a core constituent of many natural products. In their own right, thiochromenones, benzo annelated thiopyranones that are related to the class of flavones, are as well potent drug candidates and

Palladium-Copper Catalyzed Alkyne Activation as an Entry

63

serve as key intermediates for the synthesis of biological active compounds. As a consequence many thiochromenones are known to exhibit antimicrobial and antifungal [207], antibacterial [208], antibiotic [209], and anticarcinogenic [210] activity. Some derivatives are used as antimalaria agents [211], oxidized representatives reversibly inhibit the human cytomegalovirus protease [212]. In general, 4H-thiochromen-4-ones are synthesized either by condensation of b-keto esters and thiophenols with polyphosphoric acid [213–215] or by cyclization of b-substituted cinnamates derived from thiophenols and appropriate propiolates [211, 216, 217]. Conceptually, the alkynone entry to annelated 4H-thiochromen-4-ones can be conceived by a cyclization based upon a Michael addition and a nucleophilic aromatic substitution [218, 219]. Therefore, upon chemoselective coupling of ortho-halogenated (hetero)aromatic acid chlorides 81 and electron rich terminal alkynes 4, and subsequent reaction with sodium sulfide nonahydrate upon dielectric heating furnishes 4H-thiochromen-4-ones 82, 4H-thiopyrano[2,3-b]pyridin-4-ones 83, 2-chloro-4H-thieno[2,3-b]thiopyran-4-ones 84, or 7H-benzo-[b]thieno[3,2-b] thiopyran-7-ones 85 in the sense of a consecutive coupling-addition-substitution one-pot sequence (Scheme 45) [220, 221]. In comparison, the existing protocols for the synthesis of 4H-thiochromen-4-ones 82 generally require several steps, sometimes harsh reaction conditions, longer reaction times, and give significantly lower overall yields. This sequence represents a straightforward and rapid access to annelated 4H-thiochromen-4-ones in a one-pot fashion and with a broad scope in the starting materials in acceptable yields. X

2% PdCl2(PPh3)2, 4% CuI NEt3 (1.05 equiv), THF, 2 h, r.t.

Hal +

2

Cl

R

O

X

S

R2

Then: Na2S · 9 H2O (1.5 eqiuv) EtOH, 90 min, 90°C, MW O

4

81 (Hal = F, Cl) R1

S

R2

82-85 (28 examples, 15-79%) S

N

R2

S

S

R2

Cl O 82a (R1 = R2 = H, 39%) 1

2

82b (R = H, R = Ph, 73%) 82c (R1 = H, R2 = p -tBuC6H4, 76%) 82d (R1 = H, R2 = p -MeOC6H4, 77%) 82e (R1 = H, R2 = 3, 4-(MeO)2C6H3, 73%) 82f (R1 = H, R2 = p -ClC6H4, 52%) 82g (R1 = H, R2 = nBu, 59%) 1 2 82h (R = H, R = ferrocenyl, 63%) 82i (R1 = H, R2 = 6-methoxynaphthalen-2-yl, 51%) 1 2 82j (R = Cl, R = p -MeC6H4 48%) 82k (R1 = Cl, R2 = p -FC6H4, 47%) 1 2 82l (R = Cl, R = 3, 4-(MeO)2C6H3, 59%)

O 83a (R2 = H, 62%) 2

83b (R = C6H5, 55%) 83c (R2 = p -MeC6H4, 23%) 83d (R2 = p -tBuC6H4, 15%) 83e (R2 = p -ClC6H4, 31%) 2 83f (R = ferrocenyl, 19%) 83g (R2 = nBu, 17%) 2 83h (R = cyclopropyl, 53%)

O 84a (R2 = Ph, 40%)

84b (R2 = p -tBuC6H4, 63%) 84c (R2 = 3,4-(MeO)2C6H3, 51%) 84d (R2 = nBu, 36%) S

R2

S O 2 85a (R = Ph, 46%) 2 85b (R = p -tBuC6H4, 41%) 2 85c (R = p -FC6H4, 27%) 85d (R2 = cyclopropyl, 32%)

Scheme 45 Coupling–addition–nucleophilic aromatic substitution three-component synthesis of 4H-thiochromen-4-ones 82, 4H-thiopyrano[2,3-b]pyridin-4-ones 83, 2-chloro-4H-thieno[2,3-b] thiopyran-4-ones 84, or 7H-benzo-[b]thieno[3,2-b]thiopyran-7-ones 85

T.J.J. Mu¨ller

64

X 81 + 4

Hal

[Pd0, CuI], NEt3

R2

Na2S

X

Hal S– R2

Addition

Coupling O 86

O

–Hal – Nucleophilic Aromatic Substitution

82-85

87

Scheme 46 Mechanistic rationalization of the coupling–addition–nucleophilic aromatic substitution sequence to annelated 4H-thiochromen-4-ones 82–85

Mechanistically, the one-pot transformation can be rationalized by a sequence of chemoselective coupling of ortho-halogenated (hetero)aromatic acid chlorides 81 and electron rich terminal alkynes 4, followed by nucleophilic addition of the sulfide ion to the a,b-unsaturated system 86 to furnish the anionic Michael adduct 87, and finally an intramolecular nucleophilic aromatic substitution in the sense of an addition–elimination process concludes the sequence (Scheme 46). Furthermore, as a consequence of pronounced zwitterionic character of the computed electronic ground state, intense bathochromic halochromicity of the longest wavelength absorption bands with concomitant weak orange fluorescence can be observed upon protonation [221].

7 Multicomponent Synthesis of Heterocycles by Coupling– Isomerization–Cyclocondensation Sequences The CI sequence introduced in Chap. 2.2 represents a mild and catalytic access to chalcones. 1,3-Diarylprop-2-en-1-ones are bifunctional electrophilic Michaelsystems and per se important three-carbon building blocks in synthetic heterocyclic chemistry [33]. Among many classes of five-, six-, and seven-membered heterocycles the underlying principle is always the Michael-addition-cyclocondensation sequence of chalcones and bifunctional nucleophiles [176–181, 222–229]. Furthermore, chalcones can also participate in cycloadditions , as dienophiles and dipolarophiles and furnish in the case of 1,3-dipolar cycloadditions with diazo alkanes pyrazolines [230, 231], with azides triazolines [232], with nitrones isoxazolidines [233] with azomethinylides pyrrolidines [234], or with nitriloxides isoxazolines [235]. Therefore, the mild, catalytic access to chalcones by the CIR excellently sets the stage for the development of consecutive MCRs based upon cyclocondensation strategies.

7.1

Pyrazoles by a Consecutive 3CR of (Hetero)aryl Halides, Propargyl Alcohols, and Hydrazines

Thus, upon CIR of electron-deficient (hetero)aryl halides 11 and phenyl propargyl alcohol 12a, and subsequent addition of a hydrazine (29b) (R3 ¼ Me) 3,5-disubstituted

Palladium-Copper Catalyzed Alkyne Activation as an Entry

+

EWG

Then: N-methyl hydrazine (29b)(4 eqiuv) Δ, 5 h

Ph 11

CH3

2% PdCl2(PPh3)2, 1% CuI NEt3, THF, Δ, 10 h

OH EWG π Hal

65

12a

N N

π

Ph 88 (4 examples, 63-90%)

CH3 N N

CH3 N N O2N

Ph Cr

Ph OC 88a (90%)

CH3

CH3 N N

S

N N

N Ph

CO CO

N

88c (77%)

88b (63%)

Ph

88d (69%)

Scheme 47 CI–cyclocondensation three-component synthesis of pyrazolines 88

OH EWG π Hal 11

+

2% PdCl2(PPh3)2, 1% CuI NEt3, THF, Δ, 10 h

12

(hetero)aryl N

+

(hetero)aryl Then: H2N Cl–

EWG π

NH2 32 (1.0 equiv) R

N

R 89 (8 examples, 41-70 %)

89a (EWG– π = p-O2NC6H4, (hetero)aryl = Ph, R = 2-thienyl, 57%) 89b (EWG– π = p-O2NC6H4, (hetero)aryl = Ph, R = p-BrC6H4, 56%) 89c (EWG– π = p-O2NC6H4, (hetero)aryl = Ph, R = p-O2NC6H4, 46%) 89d (EWG– π = p-O2NC6H4, (hetero)aryl = Ph, R = 4-pyridyl, 51%) 89e (EWG– π = p-O2NC6H4, (hetero)aryl = p-MeOC6H4, R = m-BrC6H4, 50%) 89f (EWG– π = p-O2NC6H4, (hetero)aryl = p -BrC6H4, R = 2-thienyl, 56%) 89g (EWG– π = p-O2NC6H4, (hetero)aryl = 3-thienyl, R = 2-thienyl, 70%) 89h (EWG– π = 4-pyridyl, (hetero)aryl = Ph, R = m-BrC6H4, 41%)

Scheme 48 CI–cyclocondensation three-component synthesis of 2,4,6-trisubstituted pyrimidines 89

2-pyrazolines 88 can be obtained in a consecutive three-component reaction in good to excellent yields (Scheme 47) [77]. Considering the pharmacological activity of 3,5-diaryl-2-pyrazolines [236–240] this facile approach to 3,5-disubstituted 2-pyrazolines offers also the possibility to combinatorial lead finding.

7.2

Pyrimidines by a Consecutive 3CR of (Hetero)aryl Halides, Propargyl Alcohols, and Amidinium Salts

Likewise, upon CIR of electron-deficient (hetero)aryl halides 11 and (hetero)aryl propargyl alcohols 12, and subsequent addition of amidinium salts 32, 2,4,6-trisubstituted pyrimidines 89 can be obtained in a consecutive three-component reaction in good yields (Scheme 48) [241]. Interestingly, in all cases the aromatic products 89 are found and not the expected dihydropyrimidines, regardless whether the reaction has been performed under an anaerobic or an aerobic atmosphere. Therefore, it can be assumed that the presence of the transition metal catalysts is beneficial for a terminal aromatizing dehydrogenation.

T.J.J. Mu¨ller

66

7.3

Benzoheteroazepine by a Consecutive 3CR of (Hetero)aryl Halides, Propargyl Alcohols, and Ortho-Amino or Ortho-Thio Substituted Anilines

Following the same rationale, the CI sequence can also be applied to the synthesis of seven-membered heteroazepines. Thus, upon CIR of electron-deficient (hetero) aryl halides 11 and (hetero)aryl propargyl alcohols 12, and subsequent addition of ortho-phenylene diamines 50 or ortho-amino thiophenols 52, 2,4-di(hetero)aryl substituted 2,3-dihydro benzo[b][1,4]diazepines 90 or di(hetero)aryl substituted 2,3-dihydro benzo[b][1,4]thiazepines 91 can be obtained in a consecutive threecomponent reaction in moderate to good yields (Scheme 49) [242, 243].

7.4

1,4-Diketones by a Consecutive 3CR of (Hetero)aryl Halides, Propargyl Alcohols, and Aldehydes

Besides the Michael addition of heteroatomic nucleophiles initiating cyclocondensations, acceptor substituted unsaturated systems can also be reacted with carbon nucleophiles stemming from aldehydes in the sense of an umpolung, generally referred to as the Stetter reaction [244–246]. This process is organocatalytic and furnishes in turn 1,4-dicarbonyl compounds, intermediates that are well suited for Paal–Knorr cyclocondensations giving rise to furans or pyrroles. Among numerous heterocycles furans and pyrroles have always been the most prominent ones since they constitute important classes of natural products [247–249], of synthetic OH EWG π Hal

+ (hetero)aryl

11

2% PdCl2(PPh3)2, 1% CuI NEt3, THF, Δ, 10 h Then: HX

NH2

EWG

π

(hetero)aryl X

32 (1.0 equiv)

N

12 R 90 (X = NH) and 91 (X = S) (13 examples, 38-85%)

R acetic acid (for X = S), Δ, 8-36 h

EWG

π HN

(hetero)aryl N

90a (EWG – π = p -O2NC6H4, (hetero)aryl = Ph, 52%) 90b (EWG – π = p-O2NC6H4, (hetero)aryl = p-MeOC6H4, 44%) 90c (EWG – π = p-NCC6H4, (hetero)aryl = Ph, 79%) 90d (EWG – π = o-NCC6H4, (hetero)aryl = Ph, 39%) 90e (EWG – π = 4-thiazolyl, (hetero)aryl = Ph, 58%)

EWG

π

Ph S

N

R 91a (EWG – π = p-O2NC6H4, R = H, 67%) 91b (EWG – π = p-O2NC6H4, R = CF3, 50%) 91c (EWG – π = p-NCC6H4, R = H, 71%) 91d (EWG – π = p-NCC6H4, R = CF3, 75%) 91e (EWG – π = o-NCC6H4, R = H, 85%) 91f (EWG – π = 4-pyridyl, R = H, 38%)

Scheme 49 CI–cyclocondensation three-component synthesis of 2,3-dihydro benzo[b][1, 4] heteroazepines 90 and 91

Palladium-Copper Catalyzed Alkyne Activation as an Entry

67

pharmaceuticals [247] and also of electrically conducting materials such as polypyrroles [250]. In particular, 2,3,5-trisubstituted furans and 1,2,3,5-tetrasubstituted pyrroles are highly biologically active and have proven to display antibacterial [251] antiviral (also anti-HIV-1) [252, 253] anti-inflammatory [254, 255], and antioxidant [256] activity as well as to inhibit cytokine mediated diseases [257, 258]. Interestingly, the mild reaction conditions of the CIR are fully compatible with the Stetter reaction. As a result a sequence of transition metal, base and organocatalysis can be easily conceived. Upon CIR of electron-deficient (hetero)aryl halides 11 and (hetero)aryl propargyl alcohols 12, and after subsequent addition of aliphatic or aromatic aldehydes 92 and catalytic amounts of thiazolium salt 93 1,4-diketones 94 are obtained in moderate to excellent yields in a one-pot procedure (Scheme 50) [259, 260]. For aromatic aldehydes the catalyst precursor of choice is 3,4-dimethyl5-(2-hydroxyethyl) thiazolium iodide (93a) (R’ ¼ Me), and for aliphatic aldehydes 3-benzyl-4-methyl-5-(2-hydroxyethyl)-thiazolium chloride (93b) (R’ ¼ CH2Ph) is applied. 2% PdCl2(PPh3)2, 1% CuI NEt3, THF, Δ, 10 h

OH EWG–π–Hal +

EWG

π

(hetero)aryl

1

Then: R -CHO 92 (1.0 equiv)

(hetero)aryl 11

HO

12

O O R1 94 (12 examples, 34-88%)

S 93 N+ – I R′

20%

R′ = Me (93a), CH2Ph (93b) NEt3, Δ, 8-24 h NC NC

N O O

O

O

O

O

O O

O

O

MeO CN

94a (81%)

94b (70%)

94c (69%)

NC

NC

n

pentyl

O

94d (76%)

O

NC

O

94e (66%)

O

HO

O 94f (59%)

Scheme 50 CI–Stetter addition three-component synthesis of 1,4-diketones 94

O

T.J.J. Mu¨ller

68

This straightforward three-component approach to 1,4-diketones can readily expanded to a CIR–Stetter–Paal–Knorr synthesis of furans 24 and pyrroles 25 in the sense of a consecutive three-component or four-component reaction in a one-pot fashion. 7.4.1

Furans by a Consecutive 3CR of (Hetero)aryl Halides, Propargyl Alcohols, and Aldehydes

Thus, upon CIR of electron-deficient (hetero)aryl halides 11 and phenyl propargyl alcohol 12a, after subsequent Stetter reaction with aldehydes 92 in presence of catalytic amounts of thiazolium salt 93, and after addition of glacial acetic acid and concentrated HCl, the 2,3,5-trisubstituted furans 95 are obtained in moderate to good yields in a one-pot procedure (Scheme 51) [260]. 7.4.2

Pyrroles by a Consecutive 4CR of (Hetero)aryl Halides, Propargyl Alcohols, Aldehydes, and Amines

Likewise, pyrroles are accessible if in the last cyclocondensation step a primary amine is applied. Therefore, upon CIR of electron-deficient (hetero)aryl halides 11 and (hetero)aryl propargyl alcohols 12, after subsequent Stetter reaction with aldehydes 92 in presence of catalytic amounts of thiazolium salt 93, and after addition of primary amines 96 or ammonium chloride and glacial acetic acid, the 1,2,3,5-tetrasubstituted or 2,3,5-trisubstituted pyrroles 97 are obtained in good yields in a one-pot procedure (Scheme 52) [259, 260]. Most conspicuously, all furans 95 and pyrroles 97 display an intense blue luminescence upon irradiation with UV light (Scheme 53). The fluorescence behavior of both heterocycle classes are fairly similar as illustrated by furan 95a and pyrrole 97a, having the same substitution pattern and a difference of Stokes shifts of only 200 cm1. The phenomenon of large Stokes shifts arises from significant structural changes upon excitation from singlet ground state S0 and subsequent relaxation to the lowest vibrational level of the first excited singlet

OH

2 % PdCl2(PPh3)2, 1 % CuI NEt3, THF, Δ, 10 h

Ph

Then: R1-CHO 92 (1.0 equiv)

EWG–π–Hal + 11

12a

HO 20%

S

93

N+ – I R′

EWG π R1

O

95a (EWG–π = p-NCC6H4, R1 = Ph,79%) 95b (EWG–π = p-NCC6H4, R1 = 2-furyl, 74%) 95c (EWG–π = 4-pyridyl, R1 = p-FC6H4, 46%) 95d (EWG–π = 4-thiazolyl, R1 = Ph, 42%) 95e (EWG–π = p-NCC6H4, R1 = npentyl, 64%)

R′ = Me (93a), CH2Ph (93b) NEt3, Δ, 8-24h Then: conc. HCl, HOAc, Δ, 6-12h

Scheme 51 CI–Stetter addition–Paal–Knorr three-component synthesis of 2,3,5-trisubstituted furans 95

Palladium-Copper Catalyzed Alkyne Activation as an Entry

OH EWG–π–Hal +

2 % PdCl2(PPh3)2, 1 % CuI NEt3, THF, Δ, 10 h

EWG π

1

Ph

Then: R -CHO 92 (1.0 equiv) R1 HO

11

69

12a

S

N R2

93 N+ – I R′ 97a (EWG–π = p-NCC6H4, R1 = Ph, R2 = H, 70%) R′ = Me (93a), CH2Ph (93b) 97b (EWG–π = p-NCC6H4, R1 = p-MeOC6H4, NEt3, Δ, 8-24 h R2 = H, 60%) Then: R2-NH2(96) or NH4Cl 97c (EWG–π = 4-pyridyl, R1 = p-FC6H4, HOAc, Δ, 22-120h R2 = H, 54%) 97d (EWG–π = p-NCC6H4, R1 = npentyl, R2 = H, 59%) 97e (EWG–π = p-NCC6H4, R1 = (CH2)5OH, R2 = H, 53%) 97f (EWG–π = p-NCC6H4, R1 = Ph, R2 = CH2Ph, 60%) 97g (EWG–π = p-NCC6H4, R1 = 2-furyl, R2 = CH2Ph, 55%) 97h (EWG–π = p-NCC6H4, R1 = Ph, R2 = CH2CO2Et, 54%) 97i (EWG–π = p-NCC6H4, R1 = 2,6-dimethylhept-5-enyl, R2 = CH2CONH2, 56%) 97j (EWG–π = p-NCC6H4, R1 = Ph, R2 = CH2CH2OAc, 57%) 97k (EWG–π = p-NCC6H4, R1 = npentyl, R2 = i Pr, 59%) 20%

Scheme 52 CI–Stetter addition–Paal–Knorr four-component synthesis of 1,2,3,5-tetrasubstituted and 2,3,5-trisubstituted pyrroles 97

state S1 [261]. In particular, since all furans 95 and pyrroles 97 are acceptor substituted, a considerable charge transfer character of the excited state can be expected. However, the interpretation is complicated since these systems are highly substituted. Therefore, additional subchromophores as in the pair 97a/97b have to be taken into account where the electron-rich anisyl group (97b) causes a bathochromic shift only of the emission maximum. The same situation is found in the pair 97f/97g where the furyl substituent (97g) acts as a donor and enhances the push–pull character and its influence in the stabilization of the S1 state. Fluorescent compounds are of significant interest in molecular photonics and biophysical analytics.

7.5

Annelated and Substituted Pyridines by a Consecutive 4CR of (Hetero)aryl Halides, Propargyl Alcohols, Enamines, and Ammonium Chloride

Among six-membered aromatic heterocycles the pyridyl core [262] adopts a central role. In nature, pyridine is the constituting structural unit in the coenzyme vitamin

T.J.J. Mu¨ller

70 NC

NC

NC

N S

Ph

O

Ph

Ph

O

Ph

NC

95d λmax, abs 312 nm λmax, em 407 nm Δn 7500 cm–1

NC

N

Ph

N

CH2Ph

97a λmax, abs 317 nm λmax, em 436 nm Δn 8600 cm–1

N O

Ph

CH2Ph

97g λmax, abs 320 nm λmax, em 446 nm Δn 8900 cm–1

Ph

H 97b λmax, abs 319 nm λmax, em 451 nm Δn 9100 cm–1

NC

NC

Ph

97f λmax, abs 318 nm λmax, em 428 nm Δn 8000 cm–1

N MeO

H

95a λmax, abs 313 nm λmax, em 432 nm Δn 8800 cm–1

Ph

Ph

N

Ph

N

Ph

CH2CONH2 97i λmax, abs 312 nm λmax, em 401 nm Δn 7200 cm–1

97k λmax, abs 327 nm λmax, em 425 nm Δn 7100 cm–1

Scheme 53 Selected UV absorptions (lmax,abs), luminescence (lmax,em), and Stokes shifts D~ v of furans 95 and pyrroles 97 (recorded in CHCl3, excitation at lmax,ex = lmax,abs + 20 nm)

B6 family (pyridoxal, pyridoxol, pyridoxamine) and an important subunit in numerous alkaloids [263, 264]. Also as versatile building blocks in the syntheses of natural products and as ligands in supramolecular coordination chemistry, pyridine derivatives find broad applications. In pharmaceutical chemistry, highly substituted [265–267] and annelated [268, 269] pyridines, like 6,7-dihydro-5H-[1]pyrindines and 5,6,7,8-tetrahydroquinolines, recently have gained a considerable interest as antiarteriosclerotics since they efficiently inhibit HMG-CoA reductase and cholesterol transport proteins. Besides, the classes of pyrindine, tetrahydroquinoline and naphthyridine derivatives additionally display antimycobacterial [270], fungicidal and bactericidal [271], antiulcer [272, 273], antivertigo [274], antiviral [275–277], and anti-inflammatory activities [278]. There are numerous synthetic approaches to highly substituted pyridines, however, novel multicomponent strategies, comparable to the powerful, classical Hantzsch dihydropyridine synthesis [53, 54] remain particularly challenging. Besides Michael additions the mild reaction conditions of CIR are also compatible with cycloadditions. Since chalcones can also be considered as heterodienes, Diels-Alder reactions with inverse electron demand are suitable elementary steps that are applicable for heterocycle synthesis. Therefore, after CIR of electrondeficient (hetero)aryl halides 11 and (hetero)aryl propargyl alcohols 12, (hetero) cyclic and acyclic morpholino enamines 98 are added and, finally, after adding

Palladium-Copper Catalyzed Alkyne Activation as an Entry

71

ammonium chloride in the presence of acetic acid, dihydropyrindines 99, tetrahydroquinolines 100, naphthyridines 101, or substituted pyridines 102 are formed in moderate to good yields (Scheme 54) [279, 280]. Mechanistically, after the CI of electron-deficient (hetero)aryl halides 11 and (hetero)aryl propargyl alcohols 12 furnishing the chalcone 13, indeed a (4+2)-cycloaddition with inverse electron demand of the chalcone 13 as heterodiene and the enamine 98 as dienophile gives rise to the formation of the cycloadduct 103 (Scheme 55). In one case, this

EWG π 2% PdCl2(PPh3)2, 4% CuI NEt3, THF, Δ, 10h

OH EWG–π–Hal

+

O

(hetero)aryl

N (hetero)aryl 99-102 (18 examples, 31-70%)

Then: 11

N

12

98 (1.25-1.5 equiv)

Δ, 16h Then: NH4Cl, HOAc, Δ, 24-48h EWG π

N

(hetero)aryl

99a (EWG–π = p-NCC6H4, (hetero)aryl = Ph, 48%) 99b (EWG–π = p-EtO2CC6H4, (hetero)aryl = Ph, 42%) 99c (EWG–π = 2-pyridyl, (hetero)aryl = Ph, 62%) 99d (EWG–π = 2-pyrimidyl, (hetero)aryl = Ph, 59%) 99e (EWG–π = p-F3CC6H4, (hetero)aryl = Ph, 54%) 99f (EWG–π = p-NCC6H4, (hetero)aryl = p-MeOC6H4, 31%)

EWG π

100a (EWG–π = p-NCC6H4, (hetero)aryl = Ph, 70%) 100b (EWG–π = 2-pyridyl, (hetero)aryl = Ph, 64%) 100b (EWG–π = 2-pyrimidyl, (hetero)aryl = Ph, 50%) 100d (EWG–π = p-NCC6H4, (hetero)aryl = p-MeOC6H4, 48%)

N

(hetero)aryl EWG 101a (EWG–π = p-NCC6H4, 61%) 101b (EWG–π = 2-pyridyl, 41%) 101c (EWG–π = 2-pyrimidyl, 57%) 101d (EWG–π = p-F3CC6H4, 58%)

π EtO2C

N N

Ph

EWG 102a (EWG–π = p-NCC6H4, R = p-MeOC6H4, 54%) 102b (EWG–π = p-NCC6H4, R = 2-thienyl, 46%) 102c (EWG–π = 2-pyrimidyl, R = Ph, 68%) 102d (EWG–π = 2-pyrimidyl, R = p-MeOC6H4, 39%)

π

R

N

Ph

Scheme 54 CI–cycloaddition–cyclocondensation four-component synthesis of dihydropyrindines 99, tetrahydroquinolines 100, naphthyridines 101, and substituted pyridines 102

T.J.J. Mu¨ller

72 EWG

0

11 + 12

H

I

[Pd , Cu ], NEt3 CouplingIsomerization

[13]

π

98

NH4Cl

(4 +2)– Cycloaddition

EliminationCyclocondensation Dehydrogenative Aromatization

N

O

(hetero)aryl

O

99-102

103

Scheme 55 Mechanistic rationalization of the CI–cycloaddition–cyclocondensation sequence to annelated and substituted pyridines 99–102

cycloadduct was isolated and its structure was unambiguously elucidated by an X-ray structure analysis [280]. If the reaction mixture is hydrolyzed after the cycloaddition step then the expected 1,5-dicarbonyl compounds can be isolated and unambiguously characterized. Then, the sequence concludes by cyclocondensation of ammonium chloride and adduct 103 with concomitant aromatization giving rise to the annelated and substituted pyridines 99–102. Only with 3-amino crotonate as an enamine component and strongly electron deficient substituted aryl halides the expected dihydropyridines, i.e., the unsymmetrical Hantzsch products, were isolated as byproducts. Presumably, the presence of the transition metal catalysts supports the aromatization by dehydrogenation. Interestingly, with primary and secondary b-amino crotonamides or butenones as enamine components and dielectric heating the outcome of the cycloaddition-cyclocondensation step is different and furnishes 1-acetyl-2amino-cyclohexa-1,3-dienes 104 or 6-N,N-dimethyl carbamoyl-cyclohexenones 105 in moderate to good yields as a consequence of a concluding intramolecular aldol condensation (Schemes 56 and 57) [281].

7.6

Annelated and Substituted Pyridines by a Consecutive 4CR of (Hetero)aryl Halides, Propargyl Amides, Ketene Acetals or S,N-Aminals, and Ammonium Chloride

The CI sequence, as already disclosed in Chap. 2.2, can be successfully transposed to electron-deficient (hetero)aryl halides 11 and N-tosyl propargyl amines 20 giving rise to the formation of N-tosyl enimines 21. As previously shown for chalcones, N-tosyl enimines are also heterodienes suitable for Diels–Alder reactions with inverse electron demand [282–284] for the generation of pyridines. However, in this case the pyridyl nitrogen is already present in the enimine substrate and the tosyl group is a suitable leaving group in elimination processes. In addition, the dienophiles have to be electron-rich alkenes such as ketene acetals or N,S-ketene acetals. Thus, upon CIR of electron-deficient (hetero)aryl halides 11 and N-tosyl p-anisyl propargyl amine 20a, and subsequent addition of diethyl ketene acetal (106)

Palladium-Copper Catalyzed Alkyne Activation as an Entry

73 EWG

2% PdCl2(PPh3)2, 1% CuI THF, NEt3, MW (150°C), 15 min

OH EWG–π–Hal +

(hetero)aryl Then:

O

HN

π

O

R HN

11

12

HOAc (3 equiv) MW (150°C), 10 min

CN

(hetero)aryl

R 104 (10 examples, 30-74%)

CN N

O

CN CN

N

O

O

O O

Ph

HN HN

HN

Ph

Ph

HN S Ph

HN n

Bu

HN HN

104a (68%)

HN

104b (74%)

OMe

104c (64%)

104e (30%)

104d (54%)

Scheme 56 CI–cycloaddition–cyclocondensation three-component synthesis of 1-acetyl-2amino-cyclohexa-1,3-dienes 104 EWG OH EWG–π–Hal + Ph

2% PdCl2(PPh3)2, 1% CuI THF, NEt3, MW (150°C), 15 min Then:

O

HN

R

O Me2N O

11

12a

Me2N HOAc (3 equiv) MW (150°C), 10 min

π

Ph

105a (EWG–π = p -NCC6H4, 66%) 105b (EWG–π = p -F3CC6H4, 70%) 105c (EWG–π = 2-pyridyl, 68%) 105d (EWG–π = 2-pyrimidyl, 48%)

Scheme 57 CI–cycloaddition–cyclocondensation three-component synthesis of 6-N,N-dimethyl carbamoyl-cyclohexenones 105

2-ethoxy substituted pyridines 107 can be obtained in a consecutive three-component reaction in moderate to good yields (Scheme 58) [85]. After the CIR N-tosyl enimines 21 are generated, which now can serve as electron-deficient dienes in Diels–Alder reactions with inverse electron demand. With diethyl ketene acetal (106) as electron-rich dienophile the (4+2)-cycloaddition proceeds to furnish the tetrahydro pyridine core that bears two potential leaving groups. The sequence is concluded by elimination of ethanol and p-tolyl sulfinate and thereby yielding the aromatic pyridine.

T.J.J. Mu¨ller

74 EWG HN EWG π Hal

Ts

+

π

2% PdCl2(PPh3)2, 1% CuI THF or CH3CN / NEt3, Δ, 24 h OEt

Then:

106 (4 equiv)

EtO

N

OEt OMe 11

OMe

THF, Δ, 24 h

107a (EWG–π = p -NCC6H4, 57%) 107b (EWG–π = p -EtO2CC6H4, 25%) 107c (EWG–π = p -F3CC6H4, 30%) 107d (EWG–π = 2-pyridyl, 65%) 107e (EWG–π = 2-pyrimidyl, 46%)

20a

Scheme 58 CI–cycloaddition–elimination three-component synthesis of 2-ethoxy substituted pyridines 107 EWG HN Ts EWG π Hal

+ (hetero)aryl

11

20

π

2% PdCl2(PPh3)2, 1% CuI THF or CH3CN / NEt3, Δ, 24 h n Then:

n

N

MeS

108 (5 equiv) n = 1, 2, 3

Me

N

N

(hetero)aryl

Me 109-111 (10 examples, 31-66%)

THF, Δ, 12 h

N

EWG

EWG

EWG

π

π

π

N

N

Me OMe 109a (EWG-π = p -NCC6H4, 64%) 109b (EWG-π = 2-pyridyl, 49%) 109c (EWG-π = 2-pyrimidyl, 66%)

N

(hetero)aryl

Me 110a (EWG-π = p -NCC6H4, (hetero)aryl = p -MeOC6H4, 31%) 110b (EWG-π = p -NCC6H4, (hetero)aryl = p -PhOC6H4, 43%) 110c (EWG-π = 2-pyridyl, (hetero)aryl = p -MeOC6H4, 48%)

N

N

(hetero)aryl

Me 111a (EWG-π = p -NCC6H4, (hetero)aryl = p -MeOC6H4, 52%) 111b (EWG-π = p -NCC6H4, (hetero)aryl = p -PhOC6H4, 43%) 111c (EWG-π = 2-pyridyl, (hetero)aryl = p -MeOC6H4, 52%) 111d (EWG-π = 2-pyrimidyl, (hetero)aryl = p -MeOC6H4, 56%)

Scheme 59 CI–cycloaddition–elimination three-component synthesis of pyrrolo(2,3-b)pyridines 109, 1,8-naphthyridines 110, and pyrido(2,3-b)azepines 111

Likewise, this in situ generation of enimines can also be applied in a consecutive CIR-cycloaddition-aromatization sequence with highly reactive cyclic N,S-ketene acetals to furnish annelated pyridines. Thus, upon reaction of electron poor (hetero) aryl halides 11, terminal propargyl N-tosyl amines 20, and cyclic N,S-ketene acetals 108, annelated 2-amino pyridines such as pyrrolo(2,3-b)pyridines 109, 1,8-naphthyridines 110, and pyrido(2,3-b)azepines 111 can be synthesized in moderate to good yields (Scheme 59) [285]. The sequence to annelated 2-aminopyridines 109–111 can be rationalized as previously discussed for the one-pot synthesis of 2-ethoxypyridines (Scheme 60). After the CI of 11 and 20 the enimine 21 undergoes a (4+2)-cycloaddition with cyclic N,S-ketene acetal 108 to give the bicyclic

Palladium-Copper Catalyzed Alkyne Activation as an Entry

75

EWG π 11 + 20

[Pd0, CuI], NEt3 CouplingIsomerization

[21]

(4 + 2)– Cycloaddition

– MeSH – Ts – HN+Et3

H

108 n

N N Me SMe Ts

(hetero)aryl

109-111

Aromatization By Twofold Elimination

112

Scheme 60 Mechanistic rationalization of the CI–cycloaddition–elimination sequence to annelated 2-aminopyridines 109–111

cycloadduct 112. In the presence of triethylamine as a base a twofold elimination of methyl mercaptane and p-tolyl sulfinate yields the aromatic pyridine core in the bicyclic product 109–111. Interestingly, all annelated 2-aminopyridines 109–111 are highly fluorescent and the luminescence color of the pyrido(2,3-b)azepines 111 is highly protochromic in a small pH range and can be shifted from blue (alkaline) to green (acidic) [285].

8 Domino Syntheses of Heterocycles by CouplingIsomerization Sequences The mechanistic rationale of the CI sequence provides reactive intermediates such as enones and elusive allenols (vide supra) that can be exploited even in a domino sense, if a suitable trapping functionality is present. For the synthesis of heterocycles two bimolecular sequences have been elaborated. One is terminated by an intramolecular cyclocondensation with an amino group, which is unprotected and carried through the sequence to trap the evolving enone functionality. The other exploits the generation of a vinyl allene intermediate, which is captured by an intramolecularly tether dienophile in the sense of a (4þ2)-cycloaddition.

8.1

Domino Synthesis of 2-Substituted Quinolines

Quinolines represent an important class of heterocycles, and the quinoline skeleton is present in various natural products, especially in alkaloids. Among them quinine is an active ingredient for the treatment of malaria [286]. Despite its relatively low efficacy and tolerability, quinine still plays an important role in the treatment of multiresistant malaria, one of the world’s most devastating infectious diseases [287]. Therefore, the design of many drugs and affordable chemotherapies are based upon synthetic quinoline derivatives, such as chloroquine, mefloquine or quinacrine [288–292]. In addition, chimanine alkaloids, are also effective against parasitic diseases such as leishmaniasis and trypanosomiasis [293–295]. Besides,

T.J.J. Mu¨ller

76

R1

OH

I

2% PdCl2(PPh3)2, 1% CuI THF, DBU (2 equiv) microwave (120-150°C), 30 min

R1

+ R2

NH2 113

15

114 (9 examples, 40-92%)

Me N 114a (81%)

Ph

N 114b (40%)

R2

N

N N

N

114c (79%)

Ph

N

Ph

114d (78%)

Ph

N

N

Ph

114e (64%)

Scheme 61 CI domino synthesis of 2-substituted quinolines 114

leishmania-HIV coinfection has been regarded as an emerging infectious disease. Several two-substituted quinolines [296] have been shown to possess in vitro activity against causal agents of cutaneous leishmaniasis, visceral leishmaniasis, African trypanosomiasis and Chaga’s disease as well as against HIV-1 replication. Thus, substituted quinolines are generally attractive as antimalarials, antibacterials, protein kinase inhibitors, NADH models, and as agrochemicals. Applying dielectric heating and stronger bases such as DBU facilitates the CI of electroneutral and even electron-rich aryl halides as substrates as discussed in Chap. 2.2. Ortho-iodo anilines and their pyridyl analogs contain an amino group, which can be carried through the sequence without protection. Then, this amino functionality is able to cyclocondense intramolecularly with the adjacent enone carbonyl group to complete the annelating heterocyclization. Therefore, reacting ortho-iodo aniline derivatives 113 and propargyl alcohols 15 under microwaveassisted CI conditions with DBU as a base furnishes the two-substituted quinolines 114 in good to excellent yields (Scheme 61) [297]. This domino methodology not only allows to access naturally occurring quinolines such as 114a and 114b (chimanine B), but also a rapid access to the antimalarial active 1,8-naphthyridine 114c, which inhibits the growth plasmodium falciparum at a lower micromolar level [297].

8.2

Domino Synthesis of Spiro-Benzofuranones and Spiro-Benzoindolones

Based upon the studies on the mechanism of the CI sequence we rationalized that the elusive allenol intermediate 19 (Chap. 2.2) could participate in intramolecular trapping reactions as an allenyl ether. Furthermore, vinyl allenes are perfectly suited as dienes in Diels–Alder reactions. Considering both reactive functionalities, allenyl ethers and vinyl allenes, which are perfectly suited for domino processes, we designed an insertion sequence based upon cyclizing carbopalladation [76], where the vinyl allene results from an isomerization of an alkynylation of a vinyl

Palladium-Copper Catalyzed Alkyne Activation as an Entry R2

Ph

O

1

R I + O 115

O

77

O (hetero)aryl 116

5% PdCl2(PPh3)2 2.5% CuI toluene, NEt3, 72 h

(hetero)aryl

R2 R1 Ph O O 117a (R1 = R2 = H, (hetero)aryl = p -NCC6H4, 51%) 117b (R1 = R2 = H, (hetero)aryl = o -FC6H4 (50%) 117c (R1 = R2 = H, (hetero)aryl = p -MeOC6H4 (66%) 117d (R1 = R2 = H, (hetero)aryl = p -EtOC6H4 (46%) 117e (R1 = R2 = H, (hetero)aryl = p -Me2NC6H4 (32%) 1 2 117f (R = CH3, R = H, (hetero)aryl = p -EtOC6H4 (29%) 117g (R1 = CH3, R2 = H, (hetero)aryl = 2-thienyl (49%) 117h (R1 = R2 = CH3, (hetero)aryl = p -MeOC6H4 (33%)

Scheme 62 Insertion–CI–Diels–Alder domino reaction to spiro-benzofuranones 117

palladium species. Therefore, reacting alkynoyl ortho-iodo phenolester 115 and propargylallyl ethers 116 under CI conditions with triethylamine as a base furnishes (tetrahydroisobenzofuran) spiro-benzofuranones 117 in moderate yields (Scheme 62) [298, 299]. Likewise, upon reacting alkynoyl ortho-iodo anilides 118 and propargylallyl ethers 116 under CI conditions in a boiling mixture of butyronitrile and triethylamine (tetrahydroisobenzofuran) spiro-indolones 119 can be isolated in moderate to excellent yields (Scheme 63). Based upon the product analysis the hetero domino sequence can be interpreted as a combination of a transition metal catalyzed insertion cascade that concludes in a pericyclic final step. Intramolecular Heck reactions [300] have been developed to a broad methodology and have culminated in impressive domino sequences like Negishi’s zippers [76], however, the termination of insertion cascades by Sonogashira alkynylation has received only little attention [301, 302]. As a consequence, the hetero domino sequence can be described as an insertion-alkynylation followed by a base catalyzed isomerization of an electron-poor vinylpropargyl allyl ether to give an electron poor vinyl allene that reacts in an intramolecular (4+2)-cycloaddition through an anti-exo transition state to conclude the sequence by formation of the spirocycles 117 or 119. Methodologically, upon formation of four new carbon– carbon bonds with concomitant generation of a complex tetracyclic framework in high efficiency, this insertion–CI–Diels–Alder domino reaction furnishes spirocyclic benzofuranones 117 and dihydroindolones 119 in moderate to excellent yields. Mechanistically, this new insertion–CI–Diels–Alder hetero domino sequence can be rationalized as follows (Scheme 64): After the oxidative addition of the aryl halide 115 or 118 to the in situ generated Pd(0) species the arylpalladium halide 120 intramolecularly coordinates and inserts into the tethered triple bond via a syncarbopalladation to furnish cyclized vinylpalladium species 121 with a b-acceptor substitution in a stereospecific fashion. Transmetallation of the in situ generated copper acetylide 122 gives rise to the diorganylpalladium complex 123 that readily undergoes a reductive elimination and liberates the electron poor vinylpropargylallyl ether 124. The triethylamine catalyzed propargyl-allene isomerization furnishes the

T.J.J. Mu¨ller

78 O

R2

R4

5% PdCl2(PPh3)2 2.5 % CuI butyronitrile, NEt3, 72 h

R1 I +

R2 R1

R4 O

O

N R3 118

O (hetero)aryl

116

(hetero)aryl

N R3 119

119a (R1 = R2 = H, (hetero)aryl = p -MeOC6H4, R3 = Ts, R4 = Ph, 81%) 119b (R1 = CH3, R2 = H (hetero)aryl = 2-thienyl, R3 = Ts, R4 = Ph, 72%) 119c (R1 = R2 = CH3, (hetero)aryl = p -OHCC6H4, R3 = Ts, R4 = Ph, 71%) 119d (R1 = R2 = CH3, (hetero)aryl = p -ClC6H4, R3 = Ts, R4 = Ph, 86%) 119e (R1 = R2 = CH3, (hetero)aryl = Ph, R3 = Ts, R4 = Ph, 86%) 119f (R1 = R2 = CH3, (hetero)aryl = 2-thienyl, R3 = Ts, R4 = Ph, 72%) 119g (R1 = R2 = CH3, (hetero)aryl = p -MeOC6H4, R3 = Ts, R4 = Ph, 79%) 119h (R1 = R2 = CH3 (hetero)aryl = p -ClC6H4, R3 = Ts, R4 = nBu, 81%) 119i (R1 = R2 = CH3, (hetero)aryl = Ph, R3 = Ts, R4 = nBu, 79%) 119j (R1 = R2 = CH3, (hetero)aryl = p -MeOC6H4, R3 = Ts, R4 = nBu, 77%) 119k (R1 = R2 = CH3, (hetero)aryl = p -ClC6H4, R3 = Ts, R4 = iPr3Si, 79%) 119l (R1 = R2 = CH3, (hetero)aryl = Ph, R3 = Ts, R4 = iPr3Si, 85%) 119m (R1 = R2 = CH3, (hetero)aryl = p -MeOC6H4, R3 = Ts, R4 = iPr3Si, 77%) 119n (R1 = R2 = CH3, (hetero)aryl = p -ClC6H4, R3 = Ms, R4 = p -MeOC6H4, 53%) 119o (R1 = R2 = CH3, (hetero)aryl = Ph, R3 = Ms, R4 = p -MeOC6H4, 63%) 119p (R1 = R2 = CH3, (hetero)aryl = p -MeOC6H4, R3 = Ms, R4 = p -MeOC6H4, 63%) 119q (R1 = R2 = CH3, (hetero)aryl = p -OHCC6H4, R3 = Ts, R4 = p -MeOC6H4, 66%) 119r (R1 = R2 = CH3, (hetero)aryl = p -ClC6H4, R3 = Ts, R4 = p -MeOC6H4, 87%) 119s (R1 = R2 = CH3, (hetero)aryl = Ph, R3 = Ts, R4 = p -MeOC6H4, 88%) 119t (R1 = R2 = CH3, (hetero)aryl = p -ClC6H4, R3 = Ts, R4 = 10-methylphenothiazin-3-yl, 58%) 119u (R1 = R2 = CH3, (hetero)aryl = Ph, R3 = p -(AcOCH2CH2OC6H4SO2, R4 = Ph, 73%) 119v (R1 = R2 = CH3, (hetero)aryl = Ph, R3 = Ac, R4 = Ph, 46%) 119w (R1 = R2 = CH3, (hetero)aryl = Ph, R3 = Me, R4 = Ph, 38%)

Scheme 63 Insertion–CI–Diels–Alder domino reaction to spiro-indolones 119

electron poor enallene 125 that reacts in an intramolecular (4+2)-cycloaddition to conclude the sequence with the formation of the spirocycle 117 or 119 via an anti-exo transition state in the Diels–Alder step. Most interestingly, upon irradiation with UV light all members of this class of pale yellow to yellow absorbing spirocycles display a pronounced and intense blue over green to yellow orange fluorescence with large Stokes shifts in solution (4,300–9,600 cm–1) and in the solid state. UV/vis and emission spectroscopic studies reveal that both absorption and emission properties are strongly affected by minute substituent variations or conformational biases. All chromophores absorb between near UV and the edge to visible where the longest wavelength absorption maxima are between 327 and 398 nm. In the fluorescence spectra, the shortest wavelength emission maxima range from 433 to 545 nm and are always accompanied by either a blue or red shifted shoulder. The large Stokes shift is most probably caused by a distortion of the molecular

Palladium-Copper Catalyzed Alkyne Activation as an Entry 115 or 118

79

Reductive Elimination

Oxidative Addition

(hetero)aryl

PdLn

O

toluene or butyronitrile NEt3, Δ, 3 d

R2

R4

R1

O L

I

R2

4

R

X

R1

Pd

Pd X

124

Ln O

O

120

I

Pd

R

X

R4

•

O

R2

(hetero)aryl

O

R1

123

R4

[NEt3]

4

O

(hetero)aryl Ln

Isomerization

X 125

Alkyne Insertion (Carbopalladation)

O X

Transmetallation R2

121

(4 + 2 ) Cycloaddition R1

O CuLn (hetero)aryl 122

117 or 119

Scheme 64 Mechanistic rationale of the insertion–CI–Diels–Alder domino sequence to spirobenzofurans 117 and spiro-dihydroindolones 119

framework in the excited state as reported for coumarin derivatives [303]. The latter notion arises because the model trans-cis 1,4-diphenyl butadiene does not fluoresce at all upon photo excitation, but rather undergoes a conformational twisting and an efficient internal conversion back to the ground state [304]. This deviating peculiar behavior of the spirocyclic 1-(hetero)aryl-4-(hetero)aryl butadienes 117 and 119 can be unequivocally attributed to structurally fixed conformations in the excited state. The ongoing quest for high performance fluorophores in OLED with peculiar properties is a stimulating challenge [305], which can be addressed with spirocyclic lumophores.

9 Conclusion and Outlook The catalytic generation of alkynones and chalcones by palladium catalyzed reactions is an entry to sequential, consecutive, and domino transformations and opens new routes to heterocycles by consecutive coupling-cyclocondensation or CI-cyclocondensation sequences. The advantages are not only the compatibility of similar reaction conditions but also the tunable reaction design that allows the combination of several organic and organometallic elementary reactions to new diversity oriented syntheses. Future developments will address also sequentially catalyzed processes

80

T.J.J. Mu¨ller

and the extension to hetero domino reactions for the rapid construction of complex molecular frameworks. Transition metal catalysis has considerably fertilized the development of diversity-oriented synthesis of heterocycles, namely by disclosing new transition metal catalyzed MCRs. Besides purely insertion based domino processes, sequential and consecutive one-pot reactions have significantly expanded the playground for reaction design. Conceptually, many applications such as in natural product synthesis, in medicinal chemistry, for the design of functional fluorescent and redox active molecular materials, or in ligand syntheses for catalysis and coordination chemistry can be tackled by this methodological approach. Still many other transition metal complexes, that are known to catalyze uni- and bimolecular transformations, are waiting to be discovered for inventing new sequences. Undoubtedly, the future holds surprising sequences in store. Acknowledgments The work summarized in this account was continuously supported by the Deutsche Forschungsgemeinschaft, the MORPHOCHEM AG, Merck Serono GmbH, the Fonds der Chemischen Industrie, and the Dr.-Otto-Ro¨hm Geda¨chtnisstiftung. The dedication, the intellectual input and the skill of the group members and students who actually carried out the research in the laboratories is gratefully acknowledged.

References 1. Wender PA, Handy ST, Wright DL (1997) Towards the ideal synthesis. Chem Ind 765: 767–769 2. Jung G (ed) (1999) Combinatorial chemistry – synthesis, analysis, screening. Wiley-VCH, Weinheim 3. Balkenhohl F, von dem Bussche-Hu¨nnefeld C, Lansky A, Zechel C (1996) Combinatorial synthesis of small organic molecules. Angew Chem Int Ed Engl 35:2288–2337 4. Zhu J, Bienayme´ H (eds) (2005) Multicomponent reactions. Wiley-VCH, Weinheim 5. Sunderhaus JD, Martin SF (2009) Applications of multicomponent reactions to the synthesis of diverse heterocyclic scaffolds. Chem Eur J 15:1300–1308 6. Isambert N, Lavilla R (2008) Heterocycles as key substrates in multicomponent reactions: the fast lane towards molecular complexity. Chem Eur J 14:8444–8454 7. Do¨mling A (2006) Recent developments in isocyanide based multicomponent reactions in applied chemistry. Chem Rev 106:17–89 8. Orru RVA, de Greef M (2003) Recent advances in solution-phase multicomponent methodology for the synthesis of heterocycles. Synthesis 10:1471–1499 9. Bienayme´ H, Hulme C, Oddon G, Schmitt P (2000) Maximizing synthetic efficiency: multi-component transformations lead the way. Chem Eur J 6:3321–3329 10. Do¨mling A, Ugi I (2000) Multicomponent reactions with isocyanides. Angew Chem Int Ed Engl 39:3168–3210 11. Ugi I, Do¨mling A, Werner B (2000) Since 1995 the new chemistry of multicomponent reactions and their libraries, including their heterocyclic chemistry. J Heterocycl Chem 37:647–658 12. Weber L, Illgen K, Almstetter M (1999) Discovery of New Multi Component Reactions with Combinatorial Methods. Synlett 366–374 13. Armstrong RW, Combs AP, Tempest PA, Brown SD, Keating TA (1996) Multiple-component condensation strategies for combinatorial library synthesis. Acc Chem Res 29:123–131

Palladium-Copper Catalyzed Alkyne Activation as an Entry

81

14. Ugi I, Do¨mling A, Ho¨rl W (1994) Multicomponent reactions in organic chemistry. Endeavour 18:115–122 15. Posner GH (1986) Multicomponent one-pot annulations forming 3 to 6 bonds. Chem Rev 86:831–844 16. Schreiber SL, Burke MD (2004) A planning strategy for diversity-oriented synthesis. Angew Chem Int Ed 43:46–58 17. Burke MD, Berger EM, Schreiber SL (2003) Generating diverse skeletons of small molecules combinatorially. Science 302:613–618 18. Arya P, Chou DTH, Baek MG (2001) Diversity-based organic synthesis in the era of genomics and proteomics. Angew Chem Int Ed 40:339–346 19. Cox B, Denyer JC, Binnie A, Donnelly MC, Evans B, Green DVS, Lewis JA, Mander TH, Merritt AT, Valler MJ, Watson SP (2000) Application of high-throughput screening techniques to drug discovery. Prog Med Chem 37:83–133 20. Schreiber SL (2000) Target-oriented and diversity-oriented organic synthesis in drug discovery. Science 287:1964–1969 21. Mu¨ller TJJ (2007) Diversity-oriented synthesis of chromophores by combinatorial strategies and multi-component reactions. In: Mu¨ller TJJ, Bunz UHF (eds) Functional organic materials. Syntheses, strategies, and applications. Wiley-VCH GmbH & KGaA, Weinheim, pp 179–223 22. Mu¨ller TJJ, D’Souza DM (2008) Diversity oriented syntheses of functional p-systems by multi-component and domino reactions. Pure Appl Chem 80:609–620 23. Tietze LF, Brasche G, Gericke KM (2006) Domino reactions in organic synthesis. Wiley-VCH, Weinheim 24. Tietze LF (1990) Domino-reactions – the Tandem-Knoevenagel-Hetero-Diels-Alder reaction and its application in natural product synthesis. J Heterocycl Chem 27:47–69 25. Tietze LF, Beifuss U (1993) Sequential transformations in organic chemistry: a synthetic strategy with a future. Angew Chem Int Ed Engl 32:131–163 26. Tietze LF (1996) Domino reactions in organic synthesis. Chem Rev 96:115–136 27. de Meijere A, Diederich F (eds) (2004) Metal-catalyzed cross-coupling reactions, metal catalyzed cross-coupling reactions. Wiley-VCH, Weinheim 28. D’Souza DM, Mu¨ller TJJ (2007) Multi-component syntheses of heterocycles by transition metal catalysis. Chem Soc Rev 36:1095–1108 29. Balme G, Bossharth E, Monteiro N (2003) Pd-assisted multicomponent synthesis of heterocycles. Eur J Org Chem 4101–4111 30. Battistuzzi G, Cacchi S, Fabrizi G (2002) The aminopalladation/reductive elimination domino reaction in the construction of functionalized indole rings. Eur J Org Chem 2671–2681 31. Mu¨ller TJJ (2006) Sequentially palladium-catalyzed processes. In: Mu¨ller TJJ (ed) Metal catalyzed cascade reactions. Topics in Organometallic Chemistry, vol 19. Springer, Berlin/ Heidelberg, pp 149–205 32. Bol’shedvorskaya RA, Vereshchagin LI (1973) Advanced chemistry of a-acetylenic ketones. Russ Chem Rev 42:225–240 33. Thebtaranonth C, Thebtaranonth Y (1989) Synthesis of enones. In: Patai S, Rappoport Z (eds) The chemistry of enones, vol 29. Wiley, Chichester, pp 199–280 34. Nelson A (2005) Product class 7: ynones. In: Cossy J (ed) Science of synthesis, vol 26. Georg Thieme, Stuttgart, pp 971–988 35. Takahashi S, Kuroyama Y, Sonogashira K, Hagihara N (1980) A convenient synthesis of ethynylarenes and diethynylarenes. Synthesis 627–630 36. Sonogashira K (2002) Development of Pd-Cu catalyzed cross-coupling of terminal acetylenes with sp2-carbon halides. J Organomet Chem 653(1–2):46–49 37. Negishi EI, Anastasia L (2003) Palladium-catalyzed alkynylation. Chem Rev 103:1979–2018 38. Marsden JA, Haley MM (2004) Cross-coupling reactions to sp carbon atoms. In: de Meijere A, Diederich F (eds) Metal-catalyzed cross-coupling reactions. Wiley-VCH, Weinheim, pp 319–345

82

T.J.J. Mu¨ller

39. Doucet H, Hierso JC (2007) Palladium-based catalytic systems for the synthesis of conjugated enynes by sonogashira reactions and related alkynylations. Angew Chem Int Ed 46:834–871 40. Yin L, Liebscher J (2007) Carboncarbon coupling reactions catalyzed by heterogeneous palladium catalysts. Chem Rev 107:133–173 41. Mu¨ller TJJ, Robert JP, Schma¨lzlin E, Bra¨uchle C, Meerholz K (2000) A straightforward modular approach to NLO-active b-amino vinyl nitrothiophenes. Org Lett 2:2419–2422 42. Wu IY, Lin JT, Li CS, Wang WC, Huang TH, Wen YS, Chow T, Tsai C (1999) Preparation of push-pull type chromophores via nitrothiophene induced Michael type reaction of alkynes. Tetrahedron 55:13973–13982 43. Karpov AS, Rominger F, Mu¨ller TJJ (2003) Facile one-pot coupling-aminovinylation approach to push-pull chromophores – alkyne activation by sonogashira-coupling. J Org Chem 68:1503–1511 44. Tohda Y, Sonogashira K, Hagihara N (1977) A convenient synthesis of 1-alkynyl ketones and 2-alkynamides. Synthesis 777–778 45. Nielsen TE, Cubillo de Dios MA, Tanner D (2002) Highly stereoselective addition of stannylcuprates to alkynones. J Org Chem 67:7309–7313 46. Alonso DA, Najera C, Pacheco MC (2004) Synthesis of ynones by palladium-catalyzed acylation of terminal alkynes with acid chlorides. J Org Chem 69:1615–1619 47. D’Souza DM, Mu¨ller TJJ (2008) Catalytic alkynone generation by Sonogashira reaction and its application in three-component pyrimidine synthesis. Nat Protoc 3:1660–1665 48. Karpov AS, Mu¨ller TJJ (2003) A new entry to a three component pyrimidine synthesis by TMS-ynones via sonogashira-coupling. Org Lett 5:3451–3454 49. Miller RD, Reiser O (1993) The synthesis of electron donor-acceptor-substituted pyrazoles. J Heterocycl Chem 30:755–763 50. Logue MW, Teng K (1982) Palladium-catalyzed reactions of acyl chlorides with (1-alkynyl)tributylstannanes. A convenient synthesis for 1-alkynyl ketones. J Org Chem 47:2549–2553 51. Sashida H (1998) An alternative facile preparation of telluro- and selenochromones from o-bromophenyl ethynyl ketones. Synthesis 745–748 52. Quintanilla-Licea R, Teuber HJ (2001) Review on reactions of acetylacetaldehyde with aromatic and biogenic amines and indoles-synthesis of heterocycles via hydroxymethylene ketones. Heterocycles 55:1365–1397 53. Eicher T, Hauptmann S (1994) Chemie der Heterocyclen. Georg Thieme, Stuttgart 54. Gilchrist TL (1992) Heterocyclic chemistry. Longman Scientific and Technical, Essex 55. Takazawa O, Mukaiyama T (1982) New synthesis of b-keto acetals. Chem Lett 1307–1308 56. Mukaiyama T, Hayashi M (1974) New syntheses of b-alkoxy ketones and b-keto acetals. Chem Lett 15 57. Clerici A, Pastori N, Porta O (2001) Mild acetalisation of mono and dicarbonyl compounds catalysed by titanium tetrachloride. Facile synthesis of b-keto enol ethers. Tetrahedron 57:217–225 58. Effenberger F, Maier R, Schoenwaelder KH, Ziegler T (1982) Enolether, XIII. Die Acylierung von Enolethern mit reaktiven Carbonsa¨urechloriden. Chem Ber 115:2766 59. Smirnova YV, Krasnaya ZA (2000) Methods of the synthesis of conjugated omega-amino ketone. Russ Chem Rev 69:1021–1036 60. Michael JP, De Koning CB, Gravestock D, Hosken GD, Howard AS, Jungmann CM, Krause RWM, Parsons AS, Pelly SC, Stanbury TV (1999) Enaminones: versatile intermediates for natural product synthesis. Pure Appl Chem 71:979–988 61. Lue P, Greenhill JV (1997) Enaminones in heterocyclic synthesis. Adv Heterocycl Chem 67:207–343 62. Michael JP, Gravestock D (1997) Enaminones as intermediates in the synthesis of indolizidine alkaloids. Pure Appl Chem 69:583–588

Palladium-Copper Catalyzed Alkyne Activation as an Entry

83

63. Kuckla¨nder U (1994) Enaminones as synthones. In: Rappoport Z (ed) Chemistry of enamines. In: Patai S, Rappoport Z (series eds) The chemistry of functional groups. Wiley, Chichester, pp 523–636 64. Greenhill JV (1977) Enaminones. Chem Soc Rev 6:277–294 65. Bromidge SM, Entwistle DA, Goldstein J, Orlek BS (1993) A convenient synthesis of masked b-ketoaldehydes by the controlled addition of nucleophiles to (trimethylsilyl)ethynyl ketones. Synth Commun 23:487–494 66. Tripathi VK, Venkataramani PS, Mehta G (1979) Addition of nitrogen-containing, oxygencontaining, and sulfur-containing nucleophiles to aryl ethynyl ketones. J Chem Soc Perkin Trans 1:36–41 67. Venkataramani PS, Saxena NK, Tripathi VK, Mehta G (1975) Nucleophilic addition to ethynyl aryl ketones – stereospecific route to disubstituted enol ethers. Indian J Chem 13:852–854 68. Gais HJ, Hafner K, Neuenschwander M (1969) Acetylene mit Elektronendonator und Elektronenakzeptorgruppen. Helv Chim Acta 52:2641–2657 69. Karpov AS, Mu¨ller TJJ (2003) Straightforward novel one-pot enaminone and pyrimidine syntheses by coupling-addition-cyclocondensation sequences. Synthesis 2815–2826 70. Karpov AS, Oeser T, Mu¨ller TJJ (2004) A novel one-pot four-component access to tetrahydro-b-carbolines by a coupling-amination-aza-annulation-Pictet-Spengler sequence (CAAPS). Chem Commun 1502–1503 71. Eddington ND, Cox DS, Roberts RR, Butcher RJ, Edafiogho IO, Stables JP, Cooke N, Goodwin AM, Smith CA, Scott KR (2002) Synthesis and anticonvulsant activity of enaminones. 4. Investigations on isoxazole derivatives. Eur J Med Chem 37:635–648 72. Eddington ND, Cox DS, Roberts RR, Stables JP, Powell CB, Scott KR (2000) Enaminonesversatile therapeutic pharmacophores. Further advances. Curr Med Chem 7:417–436 73. Scott KR, Rankin GO, Stables JP, Alexander MS, Edafiogho IO, Farrar VA, Kolen KR, Moore JA, Sims LD, Tonnut AD (1995) Synthesis and anticonvulsant activity of enaminones 3. Investigations on 40 -substituted, 30 -substituted, and 20 -substituted and polysubstituted anilino compounds, sodium channel binding studies, and toxicity evaluations. J Med Chem 38:4033–4043 74. Edafiogho IO, Alexander MS, Moore JA, Farrar VA, Scott KR (1994) Anticonvulsant enaminones: with emphasis on methyl 4-[(p-chlorophenyl)amino]-6-methyl-2-oxocyclohex-3-en-1-oate (ADD 196022). Curr Med Chem 1:159–175 75. Dannhardt G, Bauer A, Nowe U (1997) Non-steroidal anti-inflammatory agents.24. Pyrrolidino enaminones as models to mimic arachidonic acid. Arch Pharm 330:74–82 76. Negishi EI, Cope´ret C, Ma S, Liou SY, Liu F (1996) Cyclic carbopalladation. A versatile synthetic methodology for the construction of cyclic organic compounds. Chem Rev 96:365–393 77. Mu¨ller TJJ, Ansorge M, Aktah D (2000) An unexpected coupling-isomerization. Sequence as an entry to novel three-component-pyrazoline syntheses. Angew Chem Int Ed 39: 1253–1256 78. Braun RU, Ansorge M, Mu¨ller TJJ (2006) The coupling-isomerization synthesis of chalcones. Chem Eur J 12:9081–9094 79. Minn, K (1991) Chalcones via a palladium-catalyzed coupling of iodoheterocycles to 1-phenyl-2-propyn-1-ol. Synlett 115–116 80. Kundu NG, Das P (1995) Palladium-catalysed synthesis of 6-(2-acylvinyl)uracils, a group of novel 6-substituted uracils of biological significance. J Chem Soc Chem Commun 99–100 81. Das P, Kundu NG (1996) Preparation of 6-iodo-N1,N3-dimethyluracil and 6-(2-acylvinyl)N1,N3-dimethyluracils: the correction of a mistake and an improved synthesis. J Chem Res (S) 298–299 82. Schramm ne´e Dediu OG, Mu¨ller TJJ (2006) Microwave-accelerated coupling-isomerization reaction (MACIR) – a general coupling-isomerization synthesis of 1,3-diarylprop-2-en1-ones. Adv Synth Cat 348:2565–2570

84

T.J.J. Mu¨ller

83. Braun RU, Mu¨ller TJJM (2003) Coupling-isomerization-coupling sequences switched on by propargyl alcohol-enone-isomerization. Mol Divers 6:251–259 84. Liao WW, Mu¨ller TJJ (2006) Sequential coupling-isomerization-coupling reactions – a novel three-component synthesis of aryl-chalcones. Synlett 3469–3473 85. Dediu OG, Yehia NAM, Mu¨ller TJJ (2004) The coupling-isomerization approach to enimines and the first sequential three-component access to 2-ethoxy pyridines. Z Naturforsch 59b:443–450 86. Mu¨ller TJJ (2006) Multi-component syntheses of heterocycles by virtue of palladium catalyzed generation of alkynones and chalcones. Targets Heterocycl Syst 10:54–65 87. Rowley M, Broughton HB, Collins I, Baker R, Emms F, Marwood R, Patel S, Ragan CI (1996) 5-(4-Chlorophenyl)-4-methyl-3-(1-(2-phenylethyl)piperidin-4-yl)isoxazole: a potent, selective antagonist at human cloned dopamine D4 receptors. J Med Chem 39:1943–1945 88. Frolund B, Jorgensen AT, Tagmose L, Stensbol TB, Vestergaard HT, Engblom C, Kristiansen U, Sanchez C, Krogsgaard-Larsen P, Liljefors T (2002) Novel class of potent 4-arylalkyl substituted 3-isoxazolol GABA(A) antagonists: synthesis, pharmacology, and molecular modeling. J Med Chem 45:2454–2468 89. Daidone G, Raffa D, Maggio B, Plescia F, Cutuli VMC, Mangano NG, Caruso A (1999) Synthesis and pharmacological activities of novel 3-(isoxazol-3-yl)-quinazolin-4(3H)-one derivatives. Arch Pharm Pharm Med Chem 332:50–54 90. Talley JJ (1999) Selective inhibitors of cyclooxygenase-2 (COX-2). Prog Med Chem 13:201–234 91. Talley JJ, Brown DL, Carter JS, Graneto MJ, Koboldt CM, Masferrer JL, Perkins WE, Rogers RS, Shaffer AF, Zhang YY, Zweifel BS, Seibert K (2000) 4-[5-methyl-3-phenylisoxazol-4-yl]-benzenesulfonamide, valdecoxib: a potent and selective inhibitor of COX-2. J Med Chem 43:775–777 92. Giovannoni MP, Vergelli C, Ghelardini C, Galeotti N, Bartolini A, Kal Piaz V (2003) (3-Chlorophenyl)piperazinylpropyl]pyridazinones and analogues as potent antinociceptive agents. J Med Chem 46:1055–1059 93. Li WT, Hwang DR, Chen CP, Shen CW, Huang CL, Chen TW, Lin CH, Chang YL, Chang YY, Lo YK, Tseng HY, Lin CC, Song JS, Chen HC, Chen SJ, Wu SH, Chen CT (2003) Synthesis and biological evaluation of N-heterocyclic indolyl glyoxylamides as orally active anticancer agents. J Med Chem 46:1706–1715 94. Bowden K, Jones ERH (1946) Acetylenic compounds. IX. Heterocyclic compounds derived from ethynyl ketones. J Chem Soc 25:953–954 95. Adlington RM, Baldwin JE, Catterick D, Pritchard GJ, Tang LT (2000) The synthesis of novel heterocyclic substituted alpha-amino acids; further exploitation of alpha-amino acid alkynyl ketones. J Chem Soc Perkin Trans 1:303–305 96. Denmark SE, Kallemeyn JM (2005) Synthesis of 3,4,5-trisubstituted isoxazoles via sequential [3þ2] cycloaddition/silicon-based cross-coupling reactions. J Org Chem 70:2839–2842 97. Ja¨ger V, Colinas PA (2002) Nitrile oxides. In: Padwa A, Pearson WH (eds) Synthetic applications of 1,3-dipolar cycloaddition chemistry toward heterocycles and natural products; chemistry of heterocyclic compounds, vol 59. Wiley, Hoboken, pp 361–472 98. Willy B, Rominger F, Mu¨ller TJJ (2008) Novel microwave-assisted one-pot synthesis of isoxazoles by a three-component coupling-cycloaddition sequence. Synthesis 293–303 99. Willy B, Frank W, Rominger F, Mu¨ller TJJ (2009) One-pot three-component synthesis, structure and redox properties of ferrocenyl isoxazoles. J Organomet Chem 694:942–949 100. Swinbourne FJ, Hunt JH, Klinker G (1978) Advances in indolizine chemistry. In: Katritzky AR, Boulton AJ (eds) Advances in Heterocyclic Chemistry, vol 23. Academic, New York, pp 103–170 101. Vlahovici A, Andrei M, Druta I (2002) A study of the dimethyl 3-benzoyl-5(2’-pyridyl)indolisine-1,2-dicarboxylate exciplexes with alcohols. J Lumin 96:279–285 102. Vlahovici A, Druta I, Andrei M, Cotlet M, Dinica R (1999) Photophysics of some indolizines, derivatives from bipyridyl, in various media. J Lumin 82:155–162

Palladium-Copper Catalyzed Alkyne Activation as an Entry

85

103. Sonnenschein H, Hennrich G, Resch-Genger U, Schulz B (2000) Fluorescence and UV/Vis spectroscopic behaviour of novel biindolizines. Dyes Pigm 46:23–27 104. Padwa A (1984) 1,3-dipolar cycloaddition chemistry. Wiley, New York 105. Broggini G, Zecchi G (1999) Pyrrolizidine and indolizidine syntheses involving 1,3-dipolar cycloadditions. Synthesis 905–917 106. Na´jera C, Sansano JM (2003) Azomethine ylides in organic synthesis. Curr Org Chem 7:1105–1150 107. Padwa A, Austin DJ, Precedo L, Zhi L (1993) Cycloaddition reactions of pyridinium and related azomethine ylides. J Org Chem 58:1144–1150 108. Rotaru AV, Druta ID, Oeser T, Mu¨ller TJJ (2005) A novel coupling 1, 3-dipolar cycloaddition sequence as a three-component approach to highly fluorescent indolizines. Helv Chim Acta 88:1798–1812 109. Claisen L (1903) To the knowledge of the propargylaldehydes and the phenylpropargylaldehydes. Ber Dtsch Chem Ges 36:3664–3673 110. Moureu C, Delange R (1901) Over some Acetylenketone and over a new method to the synthesis of b-Diketones. Bull Soc Chim Fr 25:302–313 111. Grotjahn DB, Van S, Combs D, Lev DA, Schneider C, Rideout M, Meyer C, Hernandez G, Mejorado L (2002) New flexible synthesis of pyrazoles with different, functionalized substituents at C3 and C5. J Org Chem 67:9200–9209 112. Bishop BC, Brands KMJ, Gibb AD, Kennedy DJ (2004) Regioselective synthesis of 1,3,5substituted pyrazoles from acetylenic ketones and hydrazines. Synthesis 43–52 113. Willy B, Mu¨ller TJJ (2008) Regioselective three-component synthesis of highly fluorescent 1,3,5-trisubstituted pyrazoles. Eur J Org Chem 4157–4168 114. Liu HL, Jiang HF, Zhang M, Yao WJ, Zhu QH, Tang Z (2008) One-pot three-component synthesis of pyrazoles through a tandem coupling-cyclocondensation sequence. Tetrahedron Lett 49:3805–3809 115. Brown DJ (1970) The pyrimidines, supplement 1. In: Weissberger A (ed) The chemistry of heterocyclic compounds, vol 16. Wiley-Interscience, New York 116. Lister JH (1971) Fused pyrimidines, Pt. 2: purines. In: Weissberger A, Taylor EC (eds) The chemistry of heterocyclic compounds, vol 24. Wiley-Interscience, New York 117. Hoffmann MG, Nowak A, Mu¨ller M (1996) Pyrimidines. In: Schaumann E (ed) HoubenWeyl, Methoden der Organischen Chemie; Hetarenes IV, Six-Membered and Larger HeteroRings with Maximum Unsaturation, vol E9b Part 1, 4th edn. G Thieme, Stuttgart, pp 1–249 118. Hurst DT (1980) An introduction to the chemistry and biochemistry of pyrimidines, purines and pteridines. Wiley, Chichester 119. Bojarski JT, Mokrosz JL, Barto´n HJ, Paluchowska MH (1985) Recent progress in barbituricacid chemistry. Adv Heterocycl Chem 38:229–297 120. Brown DJ (1984) Pyrimidines and their benzo derivatives. In: Katritzky AR, Rees CW (eds) Comprehensive heterocyclic chemistry, vol 3. Pergamon, Oxford, pp 57–155 121. Ahluwalia VK, Kaila N, Bala S (1987) Synthesis and antifungal and antibacterial activities of some 2-amino-4, 6-substituted-pyrimidines and 4-styryl-6, 7-pyranocoumarins. Indian J Chem Sect B 26B:700–702 122. El-Hashash MA, Mahmoud MR, Madboli SA (1993) A facile one-pot conversion of chalcones to pyrimidine-derivatives and their antimicrobial and antifungal activities. Indian J Chem Sect B 32B:449–452 123. Keutzberger A, Gillessen J (1985) Antimycotic agents 18. Aromatically substituted 2-(4-toluidino)pyrimidines. Arch Pharm (Weinheim, Ger) 318:370–374 124. Traxler P, Bold G, Buchdunger E, Caravatti G, Furet P, Manley P, O’Reilly T, Wood J, Zimmermann J (2001) Tyrosine kinase inhibitors: from rational design to clinical trials. Med Res Rev 21:499–512 125. Zimmermann J, Buchdunger E, Mett H, Meyer T, Lydon NB (1997) Potent and selective inhibitors of the Abl-kinase: phenylamino-pyrimidine (PAP) derivatives. Bioorg Med Chem Lett 7:187–192

86

T.J.J. Mu¨ller

126. Lehn JM (1995) Supramolecular chemistry – concepts and perspectives (Chapter 9). VCH, Weinheim 127. Hanan GS, Volkmer D, Schubert US, Lehn JM, Baum G, Fenske D (1997) Coordination arrays: tetranuclear cobalt(II) complexes with [22]-grid structure. Angew Chem Int Ed Engl 36:1842–1844 128. Semenov A, Spatz JP, Mo¨ller M, Lehn JM, Sell B, Schubert D, Weidl CH, Schubert US (1999) Controlled arrangement of supramolecular metal coordination arrays on surfaces. Angew Chem Int Ed 38:2547–2550 129. Harriman A, Ziessel R (1998) Building photoactive molecular-scale wires. Coord Chem Rev 171:331–339 130. Harriman A, Ziessel R (1996) Making photoactive molecular-scale wires. Chem Commun 1707–1716 131. Gompper R, Mair HJ, Polborn K (1997) Synthesis of oligo(diazaphenyls). tailor-made fluorescent heteroaromatics and pathways to nanostructures. Synthesis 696–718 132. Adlington RM, Baldwin JE, Catterick D, Pritchard GJ (1997) A versatile approach to pyrimidin-4-yl substituted alpha-amino acids from alkynyl ketones; the total synthesis of L-lathyrine. Chem Commun 1757–1758 133. Bagley MC, Hughes DD, Taylor PH, Xiong X (2003) Highly efficient synthesis of pyrimidines under microwave-assisted conditions. Synlett 259–261 134. Bagley MC, Hughes DD, Sabo HM, Taylor PH, Xiong X (2003) One-pot synthesis of pyridines or pyrimidines by tandem oxidation-heteroannulation of propargylic alcohols. Synlett 1443–1446 135. Baddar FG, Al-Hajjar FH, El-Rayyes NR (1976) Acetylenic ketones 2. Reaction of acetlyenic ketones with nucleophilic nitrogen-compounds. J Heterocycl Chem 13:257–268 136. Adlington RM, Baldwin JE, Catterick D, Pritchard GJ (1999) The synthesis of pyrimidin4-yl substituted alpha-amino acids. A versatile approach from alkynyl ketones. J Chem Soc Perk Trans 1:855–866 137. Bagley MC, Hughes DD, Lubinu MC, Merritt EA, Taylor PH, Tomkinson NCO (2004) Microwave-assisted synthesis of pyrimidine libraries. QSAR Comb Sci 23:859–867 138. Breuning E, Ziener U, Lehn JM, Wegelius E, Rissanen K (2001) Two-level self-organisation of arrays of [22] grid-type tetranuclear metal complexes by hydrogen bonding. Eur J Inorg Chem 1515–1521 139. Ahmed MSM, Mori A (2003) Carbonylative sonogashira coupling of terminal alkynes with aqueous ammonia. Org Lett 5:3057–3060 140. Ahmed MSM, Kobayashi K, Mori A (2005) One-pot construction of pyrazoles and isoxazoles with palladium-catalyzed four-component coupling. Org Lett 7:4487–4489 141. Stonehouse JP, Chekmarev DS, Ivanova NV, Lang S, Pairaudeau G, Smith N, Stocks MJ, Sviridov SI, Utkina LM (2008) One-pot four-component reaction for the generation of pyrazoles and pyrimidines. Synlett 100–104 142. Ma W, Li X, Yang J, Liu Z, Chen B, Pan X (2006) A convenient synthesis of aryl ferrocenylethynyl ketones and 2-ferrocenyl-4H-chromen-4-ones via palladium-catalyzed carbonylation coupling. Synthesis 2489–2492 143. Karpov AS, Merkul E, Rominger F, Mu¨ller TJJ (2005) Concise syntheses of meridianins by carbonylative alkynylation and a four-component pyrimidine synthesis. Angew Chem Int Ed 44:6951–6956 144. Tsuji J, Ohno K (1965) Organic syntheses by means of noble metal compounds XXI. Decarbonylation of aldehydes using rhodium complex. Tetrahedron Lett 6:3969–3971 145. Tsuji J, Ohno K (1967) Organic syntheses by means of noble metal compounds part XXXII selective decarbonylation of a,b-unsaturated aldehydes using rhodium complexes. Tetrahedron Lett 8:2173–2176 146. Fristrup P, Kreis M, Palmelund A, Norrby PO, Madsen R (2008) The mechanism for the rhodium-catalyzed decarbonylation of aldehydes: a combined experimental and theoretical study. J Am Chem Soc 130:5206–5215

Palladium-Copper Catalyzed Alkyne Activation as an Entry

87

147. Tsuji J, Ohno K (1968) Organic synthesis by means of noble metal compounds. XXXV. Novel decarbonylation reactions of aldehydes and acyl halides using rhodium complexes. J Am Chem Soc 90:99–107 148. Nakao Y, Satoh J, Shirakawa E, Hiyama T (2006) Regio- and stereoselective decarbonylative carbostannylation of alkynes catalyzed by Pd/C. Angew Chem Int Ed 45:2271–2274 149. Gooßen LJ, Paetzold J (2002) Pd-catalyzed decarbonylative olefination of aryl esters: towards a waste-free heck reaction. Angew Chem Int Ed 41:1237–1241 150. Gooßen LJ, Paetzold J (2004) Decarbonylative heck olefination of enol esters: salt-free and environmentally friendly access to vinyl arenes. Angew Chem Int Ed 43:1095–1098 151. Gooßen LJ, Rudolphi F, Oppel C, Rodrı´guez N (2008) Synthesis of ketones from a-oxocarboxylates and aryl bromides by Cu/Pd-catalyzed decarboxylative cross-coupling. Angew Chem Int Ed 47:3043–3045 152. Gooßen LJ, Zimmermann B, Knauber T (2008) Palladium/copper-catalyzed decarboxylative cross-coupling of aryl chlorides with potassium carboxylates. Angew Chem Int Ed 47:7103–7106 153. Ketcha DM, Gribble GW (1985) A convenient synthesis of 3-acylindoles via Friedel Crafts acylation of 1-(phenylsulfonyl)indole. A new route to pyridocarbazole-5, 11-quinones and ellipticine. J Org Chem 50:5451–5457 154. Chen C, Xi C, Jiang Y, Hong X (2005) 1,1-cycloaddition of oxalyl dichloride with dialkenylmetal compounds: formation of cyclopentadienone derivatives by the reaction of 1,4,-dilithio-1,3-dienes or zirconacyclopentadienes with oxalyl chloride in the presence of CuCl. J Am Chem Soc 127:8024–8025 155. Merkul E, Oeser T, Mu¨ller TJJ (2009) Consecutive three-component synthesis of ynones by decarbonylative sonogashira coupling. Chem Eur J 15:5006–5011 156. Archer GA, Sternbach LH (1968) Chemistry of benzodiazepines. Chem Rev 68:747–784 157. Popp FD, Noble AC (1967) Chemistry of diazepines. Adv Heterocycl Chem 8:21–82 158. Sternbach LH (1971) 1,4-benzodiazepines. Chemistry and some aspects of the structureactivity relationship. Angew Chem Int Ed Engl 10:34–43 159. Vanderheyden JL, Vanderheyden JE (1981) Pharmacology and mechanism of action of benzodiazepines: recent literature. J Pharm Belg 36:354–364 160. Jones GR, Singer PP (1989) The newer benzodiazepines. Adv Anal Toxicol 2:1–69 161. Bremner JB (1996) 1,2-oxazepines and 1, 2-thiazepines. In: Katritzky AR, Rees CW, Scriven EFV (eds) Comprehensive heterocyclic chemistry II, vol 9. Pergamon, Oxford, pp 183–198 162. Zellou A, Cherrah Y, Hassar M, Essassi EM (1998) Synthesis and pharmacological study of 1,5-benzodiazepine-2,4-diones and alkyl derivatives. Ann Pharm Fr 56:169–174 163. Savelli F, Boido A, Mule A, Piu L, Alamanni MC, Pirisino G, Satta M, Peana A (1989) 1, 4-disubstituted 1,3-dihydro-H-2–1,5-benzodiazepin-and chlorobenzodiazepin-2-ones with activity on the central nervous system (CNS). Farmaco 44:125–140 164. Srivastava VK, Satsangi RK, Kishore K (1982) 2-(20 -hydroxyphenyl)-4-aryl-1, 5-benzodiazepines as CNS active agents. Arzneim Forsch 32:1512–1514 165. Schutz H (1982) Benzodiazepines. Springer, Heidelberg 166. Landquist JK (1984) Application as pharmaceuticals. In: Katritzky AR, Rees CW (eds) Comprehensive heterocyclic chemistry, vol 1. Pergamon, Oxford, pp 143–183 167. Fryer RI (1991) Bicyclic diazepines. In: Taylor EC (ed) Comprehensive heterocyclic chemistry (Chapter ), vol 50. Wiley, New York 168. Randall LO, Kappel B (1973) Pharmacological activity of some benzodiazepines and their metabolites. In: Garattini S, Musini E, Randall LO (eds) Benzodiazepines. Raven, New York, pp 27–51 ¨ ber heterocyclische Siebenringsysteme, X. Synthesen 169. Ried W, Torinus E (1959) U kondensierter 5-,7- und 8-gliedriger Heterocyclen mit 2 Stickstoffatomen. Chem Ber 92:2902–2916 ¨ ber heterocyclische Siebenringsysteme, V. Umsetzung von 170. Stahlhofen P, Ried W (1957) U o-Phenylendiamin mit a,b-ungesa¨ttigten Carbonylverbindungen. Chem Ber 90:815–824

88

T.J.J. Mu¨ller

171. Nagaraja GK, Vaidya VP, Rai KS, Mahadevan KM (2006) An efficient synthesis of 1, 5-thiadiazepines and 1,5-benzodiazepines by microwave-assisted heterocyclization. Phosphorus Sulfur Silicon Relat Elem 181:2797–2806 172. Mu¨ller TJJ, Karpov AS (2005) Synthesis of substituted heterocycles by means of a new onepot reaction. Ger Offen. CODEN: GWXXBX DE 10328400 A1 20050113, p 8 173. Willy B, Dallos T, Rominger F, Scho¨nhaber J, Mu¨ller TJJ (2008) Three-component synthesis of cryofluorescent 2,4-disubstituted 3H-1,5-2 benzodiazepines – conformational control of emission properties. Eur J Org Chem 4796–4805 174. Palimkar SS, Lahoti RJ, Srinivasan KV (2007) A novel one-pot three-component synthesis of 2, 4-disubstituted-3H-benzo[b][1, 4]diazepines in water. Green Chem 9:146–152 175. Bariwal JB, Upadhyay KD, Manvar AT, Trivedi JC, Singh JS, Jain KS, Shah AK (2008) 1,5-Benzothiazepine, a versatile pharmacophore: a review. Eur J Med Chem 43:2279–2290 176. Mane RA, Ingle DB (1982) Synthesis and biological activity of some new 1, 5-benzothiazepines containing thiazole moiety: 2-aryl-4-(4-methyl-2-substituted-aminothiazol-5-yl)-2, 3-dihydro-1,5-benzothiazepines. Indian J Chem Sect B 21B:973–974 177. Jadhav KP, Ingle DB (1982) Synthesis of 2,4-diaryl-2,3-dihydro-1,5-benzothiazepines and their 1,1-dioxides as antibacterial agents. Indian J Chem Sect B 22B:180–182 178. Attia A, Abdel-Salam OI, Abo-Ghalia MH, Amr AE (1995) Chemical and biological reactivity of newly synthesized 2-chloro-6-ethoxy-4-acetylpyridine. Egypt J Chem 38:543–554 179. Reddy RJ, Ashok D, Sarma PN (1993) Synthesis of 4, 6-bis(20 -substituted-20 ,30 -dihydro-1, 5benzothiazepin-40 -yl)resorcinols as potential antifeedants. Indian J Chem Sect B 32B: 404–406 180. Satyanarayana K, Rao MNA (1993) Synthesis of 3-[4-[2, 3-dihydro-2-(substituted aryl)-1, 5benzothiazepin-4-yl]phenyl]sydnones as potential antiinflammatory agents. Indian J Pharm Sci 55:230–233 181. De Sarro G, Chimirri A, De Sarro A, Gitto R, Grasso S, Zappala M (1995) 5H-[1,2,4] oxadiazolo[5, 4-d][1,5]benzothiazepines as anticonvulsant agents in DBA/2 mice. Eur J Med Chem 30:925–929 182. Swellem RH, Allam YA, Nawwar GAM (1999) Cinnamoylacetonitrile in heterocyclic synthesis, part 7. Simple synthesis of benzothiazepines, pyrones and oxazolopyridine. Z Naturforsch B 54:1197–1201 183. Dubey PK, Naidu A, Kumar CR, Reddy PVVP (2003) Preparation of 4-(1-alkylbenz[d] imidazol-2-yl)-2-phenyl-2,3-dihydrobenzo[b][1, 4]thiazepines. Indian J Chem Sect B 42:1701–1705 184. Le´vai A (1986) Synthesis of benzothiazepines (review). Chem Heterocycl Comp 22:1161– 1170 185. Le´vai A (2000) Synthesis and chemical transformation of 1, 5-benzothiazepines. J Heterocycl Chem 37:199–214 ¨ ber heterocyclische Siebenringsysteme, VIII. Synthesen Kon186. Ried W, Marx W (1957) U densierter 7-Gliedriger Heterocyclen mit 1 Stickstoff- und 1 Schwefelatom. Chem Ber 90:2683–2687 187. Stephens WD, Field L (1959) A seven-membered heterocycle from o-aminobenzenethiol and chalcone. J Org Chem 24:1576 188. Aryaa K, Dandia A (2008) The expedient synthesis of 1,5-benzothiazepines as a family of cytotoxic drugs. Bioorg Med Chem Lett 18:114–119 189. Ried W, Ko¨nig E (1972) Reaktionen von Acetylenketonen mit nucleophilen Agenzien vom Typ des o-Phenylendiamins, o-Amino-thiophenols und N1-disubstituierten Hydrazins. Liebigs Ann Chem 755:24–31 190. Blitzke T, Sicker D, Wilde H (1995) Diethyl 2-oxopent-3-ynedioate: synthesis and first cyclizations of a novel, reactive alkyne. Synthesis 236–238 191. Cabarrocas G, Rafel S, Ventura M, Villalgordo JM (2000) A new approach toward the stereoselective synthesis of novel quinolyl glycines: synthesis of the enantiomerically pure quinolyl-b-amino alcohol precursors. Synlett 595–598

Palladium-Copper Catalyzed Alkyne Activation as an Entry

89

192. Cabarrocas G, Ventura M, Maestro M, Mahia J, Villalgordo JM (2001) Synthesis of novel optically pure quinolyl-b-amino alcohol derivatives from 2-amino thiophenol and chiral a-acetylenic ketones and their IBX-mediated oxidative cleavage to N-Boc quinolyl carboxamides. Tetrahedron Asymmetry 12:1851–1863 193. Willy B, Mu¨ller TJJ (2010) Three-component synthesis of benzo[b][1,5]thiazepines via coupling-addition-cyclocondensation sequence. Mol Diversity 13:DOI: 10.1007/ s11030-009-9223-z 194. Obrecht D (1989) Acid-catalyzed cyclization reactions of substituted acetylenic ketones: a new approach for the synthesis of 3-halofurans, flavones, and styrylchromones. Helv Chim Acta 72:447–456 195. Karpov AS, Merkul E, Oeser T, Mu¨ller TJJ (2005) A novel one-pot three-component synthesis of 3-halofurans and sequential Suzuki coupling. Chem Commun 2581–2583 196. Karpov AS, Merkul E, Oeser T, Mu¨ller TJJ (2006) One-pot three-component synthesis of 3-halofurans and 3-chloro-4-iodofurans. Eur J Org Chem 2991–3000 197. Heasley VL, Buczala DM, Chappell AE, Hill DJ, Whisenand JM, Shellhamer DF (2002) Addition of bromine chloride and iodine monochloride to carbonyl-conjugated, acetylenic ketones: synthesis and mechanisms. J Org Chem 67:2183–2187 198. Ma S, Wu B, Shi Z (2004) An efficient synthesis of 4-halo-5-hydroxyfuran-2(5H)-ones via the sequential halolactonization and g-hydroxylation of 4-aryl-2, 3-alkadienoic acids. J Org Chem 69:1429–1431 199. Merkul E, Mu¨ller TJJ (2006) A new consecutive three-component oxazole synthesis by an amidation-coupling-cycloisomerization (ACCI) sequence. Chem Commun 4817–4819 200. Merkul E, Grotkopp O, Mu¨ller TJJ (2009) 2-oxazol-5-ylethanones by consecutive threecomponent amidation-coupling-cycloisomerization (ACCI) sequence. Synthesis 502–507 201. Merkul E, Boersch C, Frank W, Mu¨ller TJJ (2009) Three-component synthesis of N-Boc4-iodopyrroles and sequential one-pot alkynylation. Org Lett 11:2269–2272 202. Benovsky P, Stephenson GA, Stille JR (1998) Asymmetric formation of quaternary centers through aza-annulation of chiral b-enamino amides with acrylate derivatives. J Am Chem Soc 120:2493–2500 203. Paulvannan K, Chen T (2000) Solid-phase synthesis of 1,2,3,4-tetrahydro-2-pyridones via aza-annulation of enamines. J Org Chem 65:6160–6166 204. Karpov AS, Rominger F, Mu¨ller TJJ (2005) A diversity oriented four-component approach to tetrahydro-b-carbolines initiated by Sonogashira coupling. Org Biomol Chem 4382–4391 205. Barta NS, Brode A, Stille JR (1994) Asymmetric formation of quaternary centers through aza-annulation of chiral b-enamino esters with acrylate derivatives. J Am Chem Soc 116:6201–6206 206. Fleming I (2002) Pericyclic reactions. Oxford University, New York, pp 78–85 207. Nakazumi H, Ueyama T, Kitao T (1985) Antimicrobial activity of 3-(substituted methyl)2-phenyl-4H-1-benzothiopyran-4-ones. J Heterocycl Chem 22:1593–1596 208. Nakazumi H, Ueyama T, Kitao T (1984) Synthesis and antibacterial activity of 2-phenyl-4Hbenzo[b]thiopyran-4-ones (thioflavones) and related compounds. J Heterocycl Chem 21:193–196 209. Couquelet J, Tronche P, Niviere P, Andraud G (1963) Antibiotic activity of an isomer of patulin and of a homolog. Trav Soc Pharm Montpellier 23:214–219 210. Holshouser MH, Loeffler LJ, Hall IH (1981) Synthesis and anti-tumor activity of a series of sulfone analogs of 1,4-naphthoquinone. J Med Chem 24:853–858 211. Razdan RK, Bruni RJ, Mehta AC, Weinhardt KK, Papanastassiou ZB (1978) New class of anti-malarial drugs – derivatives of benzothiopyrans. J Med Chem 21:643–649 212. Dhanak D, Keenan RM, Burton G, Kaura A, Darcy MG, Shah DH, Ridgers LH, Breen A, Lavery P, Tew DG, West A (1998) Benzothiopyran-4-one based reversible inhibitors of the human cytomegalovirus (HCMV) protease. Bioorg Med Chem Lett 8:3677–3682 213. Bossert F (1964) New thiochromone synthesis. Liebigs Ann Chem 680:40–51

90

T.J.J. Mu¨ller

214. Schneller SW (1975) Thiochromanones and related Compounds. Adv Heterocycl Chem 18:59–97 215. Nakazumi H, Wanatabe S, Kitaguchi T, Kitao T (1990) Intermediates formed in the reaction of benzenethiol or tert-butythio benzene with ethyl benzoylacetate in polyphosphoric acid. Bull Chem Soc Jpn 63:847–851 216. Truce WE, Goldhamer DL (1959) The stereochemistry of the base-catalyzed addition of p-toluenethiol to sodium and ethyl phenylpropiolate. J Am Chem Soc 81:5795–5798 217. Buggle K, Delahunty JJ, Philbin EM, Ryan ND (1971) Preparation and cyclization of alphasubstituted b-(phenylthio)cinnamic acids. J Chem Soc C:3168–3170 218. Shvartsberg MS, Ivanchikova ID (2003) Synthesis of sulfur-containing heterocyclic compounds by cyclocondensation of acetylenic derivatives of anthraquinone with sodium sulfide. ARKIVOC 13:87–100 219. Ivanchikova ID, Shvartsberg MS (2004) Synthesis of anthrathiopyrantriones by heterocyclization of alkynoyl derivatives of chloroanthraquinones. Russ Chem Bull 53:2303–2307 220. Willy B, Mu¨ller TJJ (2009) A novel consecutive three-component coupling-addition-SNAr (CASNAR) synthesis of 4H-thiochromen-4-ones. Synlett 1255–1260 221. Willy B, Frank W, Mu¨ller TJJ (2010) Microwave assisted three-component coupling-addition-SNAr (CASNAR) sequences to annelated 4H-thiopyran-4-ones. Org Biomol Chem 8:90–95 222. Powers DG, Casebier DS, Fokas D, Ryan WJ, Troth JR, Coffen DL (1998) Automated parallel synthesis of chalcone-based screening libraries. Tetrahedron 54:4085–4096 223. Shibata K, Katsuyama I, Izoe H, Matsui M, Muramatsu H (1993) Synthesis of 4, 6-disubstituted 2-methylpyridines and their 3-carboxamides. J Heterocycl Chem 30:277–281 224. Matsui M, Oji A, Hiramatsu K, Shibata K, Muramatsu H (1992) Synthesis and characterization of fluorescent 4,6-disubstituted-3-cyano-2-methylpyridines. J Chem Soc Perkin Trans 2:201–206 225. Dodson RM, Seyler JK (1951) The reaction of amidines with a, b-unsaturated ketones. J Org Chem 16:461–465 226. Al-Hajjar FH, Sabri SS (1982) Reaction of a,b-unsaturated ketones with guanidine – substituent effects on the protonation constants of 2-amino-4,6-diarylpyrimidines. J Heterocycl Chem 19:1087–1092 227. Simon D, Lafont O, Farnoux CC, Miocque M (1985) Obtaining of diaza binucleophiles on chalcones – influence of the substituent in position-2. J Heterocycl Chem 22:1551–1557 228. Boykin DW, Kumar A, Bajic M, Xiao G, Wilson WD, Bender BC, McCurdy DR, Hall JE, Tidwell RR (1997) Anti-pneumocystis carinii pneumonia activity of dicationic diaryl methylpyrimidines. Eur J Med Chem 32:965–972 229. Lloyd D, McNab H (1998) 1,5-benzodiazepines and 1,5-benzodiazepinium salts. Adv Heterocycl Chem 71:1–56 230. Stanovnik B, Jelen B, Turk C, Zlicar M, Svete J (1998) 1,3-dipolar cycloadditions of diazoalkanes to pyridazines. Asymmetric 1,3-dipolar cycloaddition of azomethine imines derived from diazoalkane-pyridazine cycloadducts. J Heterocycl Chem 35:1187–1204 231. Stanovnik B (1991) 1,3-dipolar cycloadditions of diazoalkanes to some nitrogen containing heteroaromatic systems. Tetrahedron 47:2925–2945 232. Katritzky AR, Zhang Y, Yuming S, Sandeep K (2003) 1,2,3-triazole formation under mild conditions via 1,3-dipolar cycloaddition of acetylenes with azides. Heterocycles 60:1225–1239 233. Osborn HMI, Gemmell N, Harwood LM (2002) 1,3-dipolar cycloaddition reactions of carbohydrate derived nitrones and oximes. J Chem Soc Perkin Trans 1:2419–2438 234. Lo¨ber S, Rodriguez-Loaiza P, Gmeiner P (2003) Click linker: efficient and high-yielding synthesis of a new family of SPOS resins by 1,3-dipolar cycloaddition. Org Lett 5: 1753–1755 235. Grundmann C (1970) Synthesis of heterocyclic compounds with the aid of nitrile oxides. Synthesis 344–359

Palladium-Copper Catalyzed Alkyne Activation as an Entry

91

236. Bilgin AA, Palaska E, Sunal R, Guemuesel B (1994) Some 1,3,5-triphenyl-2-pyrazolines with antidepressant activities. Pharmazie 49:67–69 237. Abbady MA, Hebbachy R (1993) Synthesis and application of some symmetrical and unsymmetrical diaryl sulfides and diaryl sulfones containing pyrazolinyl and isoxazolinyl moieties. Indian J Chem Sect B 32:1119–1124 238. Descacq P, Nuhrich A, Varache-Beranger M, Capdepuy M, Devaux G (1990) Nitrofuranylarylpyrazolines: synthesis and antibacterial properties. Eur J Med Chem Chim Ther 25: 285–290 239. Ankhiwala MD (1990) Studies on pyrazolines. Part 2. Preparation and antimicrobial activity of 1H-3-(200 -hydroxy-300 -bromo-400 -n-butoxy-5-nitrophen-100 -yl)-5-substituted-phenyl-2-pyrazolines and related compounds. J Indian Chem Soc 67:514–516 240. Fahmy AM, Hassan KM, Khalaf AA, Ahmed RA (1987) Synthesis of some new b-lactams, 4-thiazolidinones and pyrazolines. Indian J Chem Sect B 26:884–887 241. Mu¨ller TJJ, Braun R, Ansorge M (2000) A novel three component one-pot pyrimidine synthesis based upon a coupling-isomerization sequence. Org Lett 2:1967–1970 242. Braun RU, Zeitler K, Mu¨ller TJJ (2000) A novel 1,5-benzoheteroazepine synthesis via a onepot coupling-isomerization-cyclocondensation sequence. Org Lett 2:4181–4184 243. Braun RU, Mu¨ller TJJ (2004) One-pot syntheses of dihydro benzo[b][1, 4]thiazepines and -diazepines via coupling-isomerization-cyclocondensation sequences. Tetrahedron 60: 9463–9469 244. Stetter H, Kuhlmann H, Haese W (1987) The Stetter reaction: 3-methyl-2-pentyl-2-cyclopenten-1-one (dihydrojasmone) (2-cyclopenten-1-one, 3-methyl-2-pentyl-). Org Synth 65:26–31 245. Stetter H, Kuhlmann H (1991) The catalyzed nucleophilic addition of aldehydes to electrophilic double bonds. Org React 40:407–496 246. Stetter H (1976) Catalyzed addition of aldehydes to activated double bonds – a new synthetic approach. Angew Chem Int Ed Engl 15:639 247. Gribble GW (1996) Pyrroles and their benzo derivatives: applications. In: Katritzky AR, Rees CW, Scriven EFV (eds) Comprehensive heterocyclic chemistry II, vol 2. Pergamon, Oxford, pp 207–257 248. Sundberg RJ (1996) Pyrroles and their benzo derivatives: synthesis. In: Katritzky AR, Rees CW, Scriven EFV (eds) Comprehensive heterocyclic chemistry II, vol 2. Pergamon, Oxford, pp 119–206 249. Fu¨rstner A (1999) Venturing into catalysis based natural product synthesis. Synlett 1523–1533 250. MacDiarmid AG (1997) Polyaniline and polypyrrole: where are we headed? Synth Met 84:27–34 251. Daidone G, Maggio B, Schillaci D (1990) Salicylanilide and its heterocyclic analogs. A comparative study of their antimicrobial activity. Pharmazie 45:441–442 252. Almerico AM, Diana P, Barraja P, Dattolo G, Mingoia F, Loi AG, Scintu F, Milia C, Puddu I, La Colla P (1998) Glycosidopyrroles – Part 1. Acyclic derivatives: 1-(2-hydroxyethoxy) methylpyrroles as potential anti-viral agents. Farmaco 53:33–40 253. Almerico AM, Diana P, Barraja P, Dattolo G, Mingoia F, Putzolu M, Perra G, Milia C, Musiu C, Marongiu ME (1997) Glycosidopyrroles. Part 2. Acyclic derivatives: 1(1, 3-dihydroxy-2-propoxy)methylpyrroles as potential antiviral agents. Farmaco 52:667–672 254. Kimura T, Kawara A, Nakao A, Ushiyama S, Shimozato T, Suzuki K (2000) Preparation of five-membered heteroaryl compounds as antiinflammatory agents. PCT Int Appl. CODEN: PIXXD2 WO 2000001688 A1 20000113, p 173 255. Kaiser DG, Glenn EM (1972) Correlation of plasma 4,5-bis(p-methoxyphenyl)-2-phenylpyrrole-3-acetonitrile levels with biological activity. J Pharm Sci 61:1908–1911 256. Lehuede J, Fauconneau B, Barrier L, Ourakow M, Piriou A, Vierfond JM (1999) Synthesis and antioxidant activity of new tetraarylpyrroles. Eur J Med Chem 34:991–996 257. Kawai A, Kawai M, Murata Y, Takada J, Sakakibara M (1998) Preparation of pyridylpyrroles as interleukin and tumor necrosis factor antagonists. PCT Int Appl. CODEN: PIXXD2 WO 9802430 A1 19980122, p 95

92

T.J.J. Mu¨ller

258. De Laszlo SE, Chang LL, Kim D, Mantlo NB (1997) Preparation of pyridylpyrroles and analogs as cytokine inhibitors and glucagon antagonists. PCT Int Appl. CODEN: PIXXD2 WO 9716442 A1 19970509, p 178 259. Braun RU, Zeitler K, Mu¨ller TJJ (2001) A novel one-pot pyrrole synthesis via a couplingisomerization-stetter-paal-knorr sequence. Org Lett 3:3297–3300 260. Braun RU, Mu¨ller TJJ (2004) Coupling-isomerization-stetter and coupling-isomerizationstetter-paal-knorr sequences – a multicomponent approach to furans and pyrroles. Synthesis 2391–2406 261. Valeur B (2002) Molecular fluorescence. Wiley-VCH, Weinheim, p 34 262. Toomey JE, Murugan R (1994) Six-membered ring systems: pyridine and benzo derivatives. In: Suschitzky H, Scriven EFV (eds) Progress in heterocyclic chemistry, vol 6. Pergamon, Oxford, pp 206–230 263. Plunkett AO (1994) Pyrrole, pyrrolidine, pyridine, piperidine, and azepine alkaloids. Nat Prod Rep 11:581–590 264. Pinder AR (1992) Azetidine, pyrrole, pyrrolidine, piperidine, and pyridine alkaloids. Nat Prod Rep 9:491–504 265. Robl JA, Duncan LA, Pluscec J, Karanewsky DS, Gordon EM, Ciosek CP Jr, Rich LC, Dehmel VC, Slusarchyk DA (1991) Phosphorus-containing inhibitors of HMG-CoA reductase. 2. Synthesis and biological activities of a series of substituted pyridines containing a hydroxyphosphinyl moiety. J Med Chem 34:2804–2815 266. Roth BD, Bocan TMA, Blankley CJ, Chucholowski AW, Creger PL, Creswell MW, Ferguson E, Newton RS, O’Brien P (1991) Relationship between tissue selectivity and lipophilicity for inhibitors of HMG-CoA reductase. J Med Chem 34:463–466 267. Beck G, Kesseler K, Baader E, Bartmann W, Bergmann A, Granzer E, Jendralla H, von Kerekjarto B, Krause R (1990) Synthesis and biological activity of new HMG-CoA reductase inhibitors. 1. Lactones of pyridine- and pyrimidine-substituted 3, 5-dihydroxy-6-heptenoic (-heptanoic) acids. J Med Chem 33:52–60 268. Stoltefuss J, Lo¨gers M, Schmidt G, Brandes A, Schmeck C, Bremm KD, Bischoff H, Schmidt D (1999) 4-heteroaryl-tetrahydroquinolines and their use as inhibitors of the cholesterin-ester transfer protein. PCT Int Appl. CODEN: PIXXD2 WO 9914215 A1 19990325, p 107 269. Smith HW (1985) 5,6,7,8-Tetrahydroquinolines and 5,6-dihydropyrindines and their therapeutic use. Eur Pat Appl. CODEN: EPXXDW EP 161867 A2 19851121, p 35 270. Klimesova V, Churacek K, Sova J, Odlerova Z (1997) Antimycobacterial derivatives of 5,6,7,8-tetrahydroquinolines. Conf Org Chem Adv Org Chem 160–161 271. Knorr H, Mildenberger H, Salbeck G, Sachse B, Hartz P (1980) 4-Substituted 5,6,7,8tetrahydroquinolines. Ger Offen. CODEN: GWXXBX DE 2918591 19801120. Ger Offen DE 2918590, p 44 272. Beattie DE, Crossley R, Curran ACW, Hill DG, Lawrence AE (1977) 5,6,7,8-Tetrahydroquinolines. 5. Antiulcer and antisecretory activity of 5,6,7,8-tetrahydroquinolinethioureas and related heterocycles. J Med Chem 20:718–721 273. Beattie DE, Crossley R, Curran ACW, Dixon GT, Hill DG, Lawrence AE, Shepherd RG (1977) 5,6,7,8-tetrahydroquinolines. 4. Antiulcer and antisecretory activity of 5,6,7,8-tetrahydroquinolinenitriles and thioamides. J Med Chem 20:714–718 274. Shiozawa A, Ichikawa Y, Komuro C, Ishikawa M, Furuta Y, Kurashige S, Miyazaki H, Yamanaka H, Sakamoto T (1984) Antivertigo agents. IV. Synthesis and antivertigo activity of 6-[o-(4-aryl-1-piperazinyl)alkyl]-5,6,7,8-tetrahydro-1, 6-naphthyridines. Chem Pharm Bull 32:3981–3993 275. Hazuda DJ, Anthony NJ, Gomez RP, Jolly SM, Wai JS, Zhuang L, Fisher TE, Embrey M, Guare JP, Egbertson MS, Vacca JP, Huff JR, Felock PJ, Witmer MV, Stillmock KA, Danovich R, Grobler J, Miller MD, Espeseth AS, Jin L, Chen IW, Lin JH, Kassahun K, Ellis JD, Wong BK, Xu W, Pearson PG, Schleif WA, Cortese R, Emini E, Summa V, Holloway MK, Young SD (2004) A naphthyridine carboxamide provides evidence for

Palladium-Copper Catalyzed Alkyne Activation as an Entry

276.

277.

278.

279.

280.

281.

282. 283. 284.

285.

286. 287. 288.

289.

290.

291. 292.

93

discordant resistance between mechanistically identical inhibitors of HIV-1 integrase. Proc Natl Acad Sci USA 101:11233–11238 Zhuang L, Wai JS, Embrey MW, Fisher TE, Egbertson MS, Payne LS, Guare JP, Vacca JP, Hazuda DJ, Felock PJ, Wolfe AL, Stillmock KA, Witmer MV, Moyer G, Schleif WA, Gabryelski LJ, Leonard YM, Lynch JJ, Michelson SR, Young SD (2003) Design and synthesis of 8-hydroxy-[1, 6]naphthyridines as novel inhibitors of HIV-1 integrase in vitro and in infected cells. J Med Chem 46:453–456 El-Subbagh HI, Abu-Zaid SM, Mahran MA, Badria FA, Al-Obaid AM (2000) Synthesis and biological evaluation of certain alpha, beta-unsaturated ketones and their corresponding fused pyridines as antiviral and cytotoxic agents. J Med Chem 43:2915–2921 Calhoun W, Carlson RP, Crossley R, Datko LJ, Dietrich S, Heatherington K, Marshall LA, Meade PJ, Opalko A, Shepherd RG (1995) Synthesis and antiinflammatory activity of certain 5, 6, 7, 8-tetrahydroquinolines and related compounds. J Med Chem 383:1473–1481 Yehia NAM, Polborn K, Mu¨ller TJJ (2002) A novel four component one-pot access to pyrindines and tetrahydroquinolines based upon a coupling-isomerization sequence. Tetrahedron Lett 43:6907–6910 Dediu OG, Yehia NAM, Oeser T, Polborn K, Mu¨ller TJJ (2005) Coupling-isomerizationenamine-addition-cyclocondensation sequences – a multicomponent approach to substituted and annealed pyridines. Eur J Org Chem 1834–1858 Schramm ne´e Dediu OG, Mu¨ller TJJ (2006) Microwave-accelerated coupling-isomerizationenamine addition-aldol condensation sequences to 1-acetyl-2-amino-cyclohexa-1,3-dienes. Synlett 1841–1845 Sauer J, Wiest H (1962) Diels-Alder additions with “inverse” electron demand. Angew Chem Int Ed Engl 1:269 Sauer J, Sustmann R (1980) Mechanistic aspects of Diels-Alder reactions: a critical survey. Angew Chem Int Ed Engl 19:779–807 Boger DL, Patel M (1989) Recent applications of the inverse electron demand Diels-Alder reaction. In: Suschitzky H, Scriven EFV (eds) Progress in heterocyclic chemistry, vol 1. Pergamon, Oxford, pp 30–64 Schramm ne´e Dediu OG, Oeser T, Mu¨ller TJJ (2006) Coupling-isomerization-N,S-ketene acetal-addition sequences – a three-component approach to highly fluorescent pyrrolo[2,3-b] pyridines, [1,8]naphthyridines, and pyrido[2,3-b]azepines. J Org Chem 71:3494–3500 Wiesner J, Ortmann R, Jomaa H, Schlitzer M (2003) New Antimalarial Drugs. Angew Chem Int Ed 43:5274–5293 Gilles MH (2000) Management of severe malaria: a practical handbook, 2nd edn. World Health Organization, Geneva O’Neill PM, Mukhtar A, Stocks PA, Randle LE, Hindley WS, Storr SARC, Bickley JF, O’Neil IA, Maggs JL, Hughes RH, Winstanley PA, Bray PG, Park BK (2003) Isoquine and related amodiaquine analogues: a new generation of improved 4-aminoquinoline antimalarials. J Med Chem 46:4933–4945 Ridley RG, Hofheinz W, Matile H, Jaquet C, Dorn A, Masciadri R, Jolidon S, Richter WF, Guenzi A, Girometta MA, Urwyler H, Huber W, Thaithong S, Peters W (1996) 4-aminoquinoline analogs of chloroquine with shortened side chains retain activity against chloroquine-resistant Plasmodium falciparum. Antimicrob Agents Chemother 40:1846–1854 Stocks PA, Raynes KJ, Bray PG, Park BK, O’Neill PM, Ward SA (2002) Novel short chain chloroquine analogues retain activity against chloroquine resistant K1 Plasmodium falciparum. J Med Chem 45:4975–4983 Vlakhov R, Parushev S, Vlakhov I, Nickel P, Snatzke G (1990) Synthesis of some new quinoline derivatives – potential antimalarial drugs. Pure Appl Chem 62:1303–1306 Madrid PB, Sherrill J, Liou AP, Weisman JL, DeRisi JL, Kipling GR (2005) Synthesis of ring-substituted 4-aminoquinolines and evaluation of their antimalarial activities. Bioorg Med Chem Lett 15:1015–1018

94

T.J.J. Mu¨ller

293. Fournet A, Vagneur B, Richomme P, Bruneton J (1989) New 2-aryl and 2-alkyl quinoline alkaloids isolated from Bolivian Rutaceae: Galipea longiflora. Can J Chem 67:2116–2118 294. Fournet A, Hocquemiller R, Roblot F, Cave´ A, Richomme P, Bruneton J (1993) The chimanines, new 2-substituted quinolines, antiparasitics isolated from the Bolivian plant: Galipea longiflora. J Nat Prod 56:1547–1552 295. Fournet A, Barrios AA, Mun˜oz V, Hocquemiller R, Cave´ A, Richomme P, Bruneton J (1993) 2-substituted quinoline alkaloids as potential antileishmanial drugs. Antimicrob Agents Chemother 37:859–863 296. Fakhfakh MA, Fournet A, Prina E, Mouscadet JF, Franck X, Hocquemiller R, Figadere B (2003) Synthesis and biological evaluation of substituted quinolines: Potential treatment of protozoal and retroviral co-infections. Bioorg Med Chem 11:5013–5023 297. Schramm OG, Oeser T, Kaiser M, Brun R, Mu¨ller TJJ (2008) Rapid one-pot synthesis of anti-parasitic quinolines based upon the microwave–assisted coupling-isomerization reaction (MACIR). Synlett 359–362 298. D’Souza DM, Rominger F, Mu¨ller TJJ (2005) A domino sequence consisting of insertion, coupling, isomerization, and Diels-Alder steps yields highly fluorescent spirocycles. Angew Chem Int Ed 44:153–158 299. D’Souza DM, Kiel A, Herten DP, Mu¨ller TJJ (2008) Synthesis, structure and emission properties of spirocyclic benzofuranones and dihydroindolones – a domino insertioncoupling-isomerization-Diels-Alder approach to rigid fluorophores. Chem Eur J 14:529–547 300. Link JT, Overman LE (1998) Intramolecular Heck reactions in natural product chemistry. In: Diederich F, Stang PJ (eds) Metal catalyzed cross-coupling reactions. Wiley-VCH, Weinheim, pp 231–269 301. Pal M, Parasuraman K, Subramanian V, Dakarapu R, Yeleswarapu RK (2004) Palladium mediated stereospecific synthesis of 3-enynyl substituted thioflavones/flavones. Tetrahedron Lett 45:2305–2309 302. Pottier LR, Peyrat JF, Alami M, Brion JD (2004) Unexpected tandem sonogashira-carbopalladation-sonogashira coupling reaction of benzyl halides with terminal alkynes: a novel four-component domino sequence to highly substituted enynes. Synlett 1503–1508 303. Volmer F, Rettig W, Birckner E (1994) Photochemical mechanisms producing large fluorescence Stokes shifts. J Fluorescence 4:65–69 304. Yee WA, Hug SJ, Kliger DS (1988) Direct and sensitized photoisomerization of 1, 4-diphenylbutadienes. J Am Chem Soc 110:2164–2169 305. Mu¨llen K, Scherf U (eds) (2006) Organic light-emitting diodes – synthesis, properties, and applications. Wiley-VCH, Weinheim

Top Heterocycl Chem (2010) 25: 95–126 DOI: 10.1007/7081_2010_44 # Springer-Verlag Berlin Heidelberg 2010 Published online: 24 June 2010

Multicomponent Reaction Design Strategies: Towards Scaffold and Stereochemical Diversity Rachel Scheffelaar, Eelco Ruijter, and Romano V.A. Orru

Abstract In the past decade, it has been extensively demonstrated that multicomponent chemistry is an ideal tool to create molecular complexity. Furthermore, combination of these complexity-generating reactions with follow-up cyclization reactions led to scaffold diversity, which is one of the most important features of diversity oriented synthesis. Scaffold diversity has also been created by the development of novel multicomponent strategies. Four different approaches will be discussed [single reactant replacement, modular reaction sequences, condition based divergence, and union of multicomponent reactions (MCRs)], which all led to the development of new MCRs and higher order MCRs, thereby addressing both molecular diversity and complexity. Keywords Complexity Diversity oriented synthesis Multicomponent reactions Scaffold diversity Synthesis Contents 1

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 97 1.1 Complexity and Diversity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 97 1.2 Multicomponent Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 100 2 Molecular Diversity Involving MCRs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 102 3 Novel Multicomponent Strategies Towards Scaffold Diversity . . . . . . . . . . . . . . . . . . . . . . . . . . . 107 3.1 Single Reactant Replacement (SRR) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 108 3.2 Modular Reaction Sequences . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 111 3.3 Condition-Based Divergence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 115 3.4 Union of MCRs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 120 4 Concluding Remarks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 123 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 124

R. Scheffelaar, E. Ruijter, and R.V.A. Orru (*) Department of Chemistry and Pharmaceutical Sciences, Vrije Universiteit Amsterdam, De Boelelaan 1083, 1081 HV, Amsterdam, The Netherlands e-mail: [email protected]

96

R. Scheffelaar et al.

Abbreviations Ac Ar BINAP Bn Bu tBu CBD Cp CR 3D DA DCM de DIPEA DMAD DMF DMSO DOS dppf dr ee Et EWG FG HWE IMCR mCPBA MCR Me MeCN min. MRS MS MTBE MW n.d. Nu P-3CR Ph PMP rt SRR

Acetyl Aryl 2,20 -bis(diphenylphosphino)-1,10 -binaphthyl Benzyl Butyl Tert-butyl Condition-based divergence Cyclopentadienyl Component reaction Three dimensional Diels-Alder Dichloromethane Diastereomer excess N,N-diisopropylethylamine Dimethyl acetylenedicarboxylate Dimethylformamide Dimethyl sulfoxide Diversity oriented synthesis 1,10 -bis(diphenylphosphino)ferrocene Diastereomer ratio Enantiomer excess Ethyl Electron withdrawing group Functional group Horner-Wadsworth-Emmons Isocyanide based multicomponent reaction m-chloroperoxybenzoic acid Multicomponent reaction Methyl Acetonitrile Minute(s) Modular reaction sequences Molecular sieves Methyl tert-butyl ether Microwave Not determined Nucleophile Passerini 3-component reaction Phenyl p-methoxyphenyl Room temperature Single reactant replacement

Multicomponent Reaction Design Strategies

Tf TFA THF TMS Ts U-4CR

97

Trifluoromethanesulfonyl (triflyl) Trifluoroacetic acid Tetrahydrofuran Trimethylsilyl Tosyl, 4-toluenesulfonyl Ugi 4-component reaction

1 Introduction 1.1

Complexity and Diversity

The importance of small molecules1 in contemporary chemical biology and medicinal research is undisputed. Studying the interaction of small molecules with biological systems is crucial for understanding all fundamental processes of life, both in health and disease [2]. Synthetic organic chemists enable access to structurally complex and functionally diverse sets of small molecules and thus supply the feedstock for advanced chemical biology and medicinal research studies. Current drug discovery involves the screening of small molecules for their ability to bind to a preselected protein target (found by biological methods) [3]. This is rather time-consuming and leads to the development of drugs for only a small selection of protein targets. The ultimate goal, however, is to identify molecular modulators for all cellular processes, which emerge from growing insights in genome biology, including nonclassical biological targets that are currently considered “undruggable”.2 This can be done by screening small molecules for their ability to modulate a biological pathway in cells or organisms, without considering a specific protein target. This will result in the simultaneous identification of the therapeutic protein target and its chemical modulator [3]. Since the protein target and the chemical modulator are unknown, for this drug development strategy methodologies are required that lead to structurally complex and diverse small molecules covering a broad region of the so-called “chemical space”3 [2, 6]. This is one of the main focuses of diversity-oriented 1

Small molecules are typically compounds with a molecular weight less than 500 Da: [1]. Molecules/interactions that are considered to be “undruggable”, comprise transcription factors, regulatory RNAs, interactions between proteins (especially intracellular) and between proteins and DNA. There are only about 500 “druggable” targets: [4]. 3 The chemical space is a multidimensional area with each dimension defined by a descriptor which can be molecular weight, polarity, solubility, membrane permeability, binding constant. H-bonding properties etc. and encompasses all small carbon-based molecules that could in principle be created: [5]. 2

98

R. Scheffelaar et al.

Fig. 1 Representation of (a) target oriented synthesis (TOS), (b) combinatorial chemistry and (c) diversity oriented synthesis (DOS) in chemical space [2]

synthesis (DOS, Fig. 1c) [2, 7–9]. The aim of DOS, i.e., to access as many points in the chemical space, differs very much from target oriented synthesis (TOS, Fig. 1a) and combinatorial chemistry (Fig. 1b), which access just a single point or dense region in chemical space. TOS is especially used in drug discovery involving preselected protein targets and makes use of retro-synthetic analysis [3]. TOS primarily relies on nature to discover small bioactive compounds. After isolation and characterization of a natural product, it can become a target for chemical synthesis. Closely related to this approach is combinatorial chemistry, which often uses these natural products or other known drugs, as a starting point to obtain a collection of molecules derived from the parent skeleton (focused libraries), for example, by changing substituents around a common skeleton. In contrast to retrosynthetic analysis used for TOS and combinatorial chemistry, DOS requires “forward synthetic planning” that enables the conversion of simple starting materials into complex and diverse products. Molecular complexity (generally found in natural products) seems to be extremely important to obtain an optimal perturbation function and specificity of action of the chemical modulators on their protein targets [2, 9]. The goal of achieving molecular diversity can be divided in three different diversity elements: (a) appendage diversity (combinatorial chemistry), (b) stereochemical diversity, and most importantly (c) scaffold diversity (Fig. 2) [2]. Appendage diversity (Fig. 2a) is the central feature of combinatorial chemistry and involves the introduction of different appendages to a common molecular skeleton. Although diversity is generated, these compounds all have a common molecular skeleton, thereby displaying related chemical information in the 3D space (same molecular shape) resulting in a limited amount of potential binding partners. For DOS, it is especially important to create compounds that display diverse 3D information. This can be realized by developing synthetic pathways that incorporate the two other diversity elements, stereochemical and scaffold diversity. Stereochemical diversity (Fig. 2b) involves the generation of as many stereoisomers of the same molecule, however, not as mixtures, but selectively.

Multicomponent Reaction Design Strategies

a Appendage diversity

99

b Stereochemical diversity B

B

B

B

c Scaffold diversity

Fig. 2 The three different elements of molecular diversity

Fig. 3 Schematic illustration of a multicomponent reaction toward a complex product

For this, stereospecific reactions are required that allow selective access to different stereoisomers by, for example, changing the stereochemistry of the catalyst or the chiral substrates. Finally, scaffold diversity (Fig. 2c), probably the most important element of diversity, is the generation of a collection of products with different molecular skeletons (scaffolds). This can, for example, be realized by changing the reagents added to a common substrate (reagent-based approach) or by transforming a collection of substrates having suitable preencoded skeletal information with similar reaction conditions (substrate-based approach) [2, 10]. For DOS to succeed, highly efficient (max. 3–5 reaction steps), versatile, and robust synthetic methodologies are needed. This requires new concepts and novel design approaches that focus on complexity- and diversity generation and do not require protective group manipulations: a clear challenge for the synthetic organic chemist. A powerful strategy to address these challenges involves the use of multicomponent reactions (MCRs), which are reactions of at least three different simple reagents reacting in a well-defined manner to form a single product (Fig. 3) [11–17]. This highly convergent methodology allows molecular complexity to be created by the facile formation of several new covalent bonds in a one-pot transformation. At the same time MCRs proceed with remarkably high atom economy [18]

100

R. Scheffelaar et al.

and low E factors4 minimizing the number of functional group (FG) manipulations towards a given complex molecular target, thus avoiding the use of protective groups. As such, syntheses involving MCRs save time and energy (step efficiency) and quite closely approach the concept of the ideal synthesis, making them very useful to apply in DOS [13].

1.2

Multicomponent Reactions

The first important MCR was developed by Strecker in 1850 (Scheme 1) [20]. In this reaction ammonia, an aldehyde and hydrogen cyanide combine to form a-cyano amines 1, which upon hydrolysis form a-amino acids 2. Also, heterocyclic compounds were obtained using MCRs. An example of this is the Hantzsch reaction, discovered in 1882 [21]. This reaction is a condensation of an aldehyde with two equivalents of a b-ketoester in the presence of ammonia resulting in the formation of dihydropyridines 3. A comparable reaction is the Biginelli reaction, founded in 1893 ([22] and see for review: [23]). This reaction is a 3-component reaction (3CR) between an aldehyde, a b-ketoester and urea to afford dihydropyrimidines 4. O Strecker reaction 1 H+ (1850) R

R1 NH3

HCN

+

– H2O

H2N

R1

H+ CN

H2N

H2O

1 O

O Hantzsch 1 reaction R (1882)

O H+

NH3

+ 2

R3

O

R2

O

O O O Biginelli + + 2 reaction 1 H2N NH2 R H (1893) R

R

3

O R3 –2 H O O 2

R3

R2

N H 3

O

R1

O

R – NH R3

+ R

R6 5

R2 –H2O

R

R2

O

N H 4 R1

O 4

R3

NH R

2

O O

2

Mannich O reaction + 1 H (1912) R

R1

O

–3 H2O

COOH 2

O

N R6 5 R3 R 4 R 5

Scheme 1 Overview of one of the first reported MCRs

4

The E factor is defined as the mass ratio of waste (everything but the desired product) to desired product. For a recent overview, see: [19].

Multicomponent Reaction Design Strategies

101

Another well-known 3CR is the Mannich reaction, developed in 1912, in which formaldehyde or a nonenolizable aldehyde and an amine form an intermediate Schiff base which subsequently reacts with an a-acidic compound, to afford b-amino carbonyl 5 [24]. A few years later Passerini, developed a new 3CR towards a-acyloxy amides 9 which are formed by reacting an aldehyde or ketone 6, a carboxylic acid 8 and an isocyanide 7 (Scheme 2) ([25] and see for review: [26]). Since the first synthesis of isocyanides (formerly known as isonitriles [27]) in 1858, the Passerini 3-component reaction (P-3CR) was the first MCR involving these reactive species. It has become one of the renowned examples of an important subclass of MCRs, the isocyanidebased MCRs (IMCRs). Especially important for the Passerini reaction, but also for a lot of other IMCRs, is the ability of isocyanides to form a-adducts, by reacting with nucleophiles and electrophiles (at the carbon atom). The nucleophilic

O R1

R3–N

+

R3 R4

R2 6

O

O

+

C

7

N H

OH 8

R4

O R1 R2 O 9

Passerini reaction (1921) R4 H

O

C

O +

R1 O

R2

4

R

O

N

R3

R3

H O R1 R2

7

10

O

N

11

O + R1

R2

R5– NH2 +

6

12

Ugi reaction (1959)

R3–N

C

O

O

+

3

R4 7

–H2O

OH

R

R5 R4

N

N H

R1 R2 O 13

8

–H2O O H

N

R5

C +

R1 14

R2

N R 7

3

R5

R

O 16

NH

R1 R2

4

C

N

R5

NH

R1 R2 R3

15

Scheme 2 The Passerini and Ugi MCRs and their proposed mechanisms

R3

C

R4

O O

N 17

102 Fig. 4 Frontier orbitals of the isocyanide, explaining the reactivity of this important functional group in multicomponent chemistry

R. Scheffelaar et al.

R N C filled non-bonding σ-orbital

R N C empty π∗-orbital

character of the isocyanide carbon can be explained by the filled nonbonding s-orbital. The electrophilic character is explained by the empty p*-orbital possessing a high orbital coefficient on carbon (Fig. 4) [13]. Even though the isocyanide carbon is nucleophilic, good electrophiles such as protonated carbonyl or iminium ions are typically required for a reaction to occur [28]. The Passerini reaction is typically carried out at high concentrations of starting materials in aprotic solvents (generally DCM), at or below room temperature. The reaction shows a high substrate scope and variation of all three components is extensively possible. Since the Passerini reaction is accelerated in aprotic solvents, it is assumed that the reaction follows a nonionic pathway. The most plausible mechanism of the reaction is depicted in Scheme 2 ([25] and see for review: [26]; [13]). Initially, a loosely bound hydrogen bonded adduct 10 is formed, from the carboxylic acid 8 and the carbonyl compound 6. The next step is the formation of the a-adduct 11 by reaction of the isocyanide with the nucleophilic carboxylate and the electrophilic protonated carbonyl compound. a-Adduct 11 then rearranges to give a-acyloxy amide 9. About 40 years later, in 1959, Ugi developed a four-component variant of this reaction that involves an aldehyde or ketone 6, carboxylic acid 8, an amine 12 and an isocyanide 7 yielding a-acylamino amide 13 (Ugi 4-component reaction [U-4CR], Scheme 2) [29]. Like the Passerini reaction, the Ugi reaction shows a high substrate scope. The reaction is favored in polar protic solvents and is usually performed in methanol, though several other solvents have been reported [13, 30]. Although different mechanisms have been reported [17], the Ugi reaction will presumably proceed via nitrilium ion intermediate 15, formed by a reaction of the isocyanide 7 with the in situ generated iminium ion 14. Subsequent trapping of 15 with the carboxylate 16 generates the instable a-adduct 17, which undergoes an intramolecular acylation called the Mumm rearrangement to afford a-acylamino amide 13 [28, 31].

2 Molecular Diversity Involving MCRs As already became clear from the previous examples, MCRs are ideal to obtain complex products in an easy way. However, DOS also requires molecular diversity (appendage, stereochemical and scaffold diversity), which can also be accomplished using MCRs.

Multicomponent Reaction Design Strategies

103

MCRs are ideal to achieve appendage diversity, because all individual components can be varied to create a large library of products that have the same skeleton but differ in the substituents around it. If, for example, a 4-component reaction (4CR) is considered and 40 inputs of all four components are combined, this will result in 404 ¼ 2,560,000 reaction products [32]. To create stereochemical diversity within MCRs there is need for stereoselective (or -specific) reactions. Since many MCRs involve flat intermediates, like imines and a,b-unsaturated ketones, they result in the formation of racemic products. Moreover, often mixtures of diastereomers are obtained if more than one stereogenic centre is formed. However, there are several examples known of asymmetric induction, by the use of chiral building blocks (diastereoselective reactions). For example, it has been successfully applied to the Strecker, Mannich, Biginelli, Petasis, Passerini, Ugi, and many other MCRs, which has been excellently reviewed by Yus and coworkers [33]. Enantioselective MCRs, which generally proved to be much harder, have been performed with organometallic chiral catalysts and organocatalysts [33, 34]. An interesting example that shows the possibility of stereochemical diversity, is the Mannich reaction involving organocatalysis (Scheme 3) [35–37]. By changing the nature of the organocatalyst (L-proline (20) vs. (3R,5R)-5-methyl-3-pyrrolidinecarboxylic acid (25)) the (2S,3S)-syn and (2S,3R)-anti diastereomers 21 and 26 could be formed selectively in high diastereo- and enantioselectivities. The difference in stereochemical outcome of the two reactions can be explained by the different steric influence of the pyrrolidine ring. For L-proline (Pathway A), enamine conformation 24 is favored over 23 due to steric hindrance of the carboxylic acid and the double bond in conformation 23. The facial selection (the re face of the enamine reacts with the si face of the imine) is controlled by the carboxylic acid, which activates the imine (transition state I). For organocatalyst 25 the steric bulk is on the five-position of the pyrrolidine ring instead of the two-position. This results in a favored enamine conformation 29, with the carboxylic acid and the PMP O HN R H R CO2Et R 22 PMP O HN S H S CO2Et

PMP O HN S H CO R 2Et COOH R COOH 27 Me N N PMP H O PMP O HN H 25 20 5 mol% 1-5 mol% N R + H H S CO Et DMSO 2 CO2Et dioxane, rt R R 26 anti 18 19 Pathway B

O

Pathway A COOH

COOH O

Me N H Me PMP N N H H H H H CO2Et R R II 29

R 21 syn

Me H

H R 28

COOH

N

N

H

H R 23

N H R 24

COOH PMP N N H O H H H H CO2Et R

O

I

Scheme 3 Introduction of stereochemical diversity in the Mannich reaction applying organocatalysis

104

R. Scheffelaar et al.

enamine double bond to the same side. The carboxylic acid will direct the approach of the enamine to the imine (transition state II) similarly as described for L-proline, resulting in the formation of anti-diastereomer 26. Evidently, by taking the enantiomers of the organocatalyst the two enantiomeric products 22 and 27 (depicted in grey) are accessible, making it possible to access all four possible stereoisomers for this MCR [36].5 Regarding scaffold diversity it is evident that any single MCR does not lead to multiple scaffolds, since ideally, three or more components combine to form a single product (one of the criteria for MCRs). As a result several research groups have introduced scaffold diversity by combining MCRs with cyclization reactions, as illustrated in Fig. 5 [40, 41]. This concept of introducing scaffold diversity by intramolecular cyclizations is nowadays commonly referred to as the build/couple/pair strategy, introduced by Schreiber in 2008 [42]. The build phase involves the (asymmetric) synthesis of (chiral) building blocks containing orthogonal sets of functionalities that can be used for the coupling and subsequent pairing reactions. In this stage, smart selection of building blocks will lead to a large number of different scaffolds in the pairing (cyclization) stage. The couple phase involves intermolecular coupling reactions that combine the different building blocks, resulting in densely functionalized substrates ready for use in the pairing phase. Considering MCRs as coupling reactions, there is a need for versatile MCRs that are able to use a lot of different substrates (high FG tolerance/broad

Fg2

Fg1 build

+

Fg3

MCR

cyclize

couple

pair

Fg4

Fig. 5 The generation of scaffold diversity, by combining MCRs with cyclization reactions6

5

Although the authors used a pre-formed imine, there are several examples known of proline catalyzed one-pot three component Mannich reactions. However, if aromatic aldehydes are used in this one-pot procedure, the obtained Mannich products had to be reduced (by NaBH4) to the corresponding alcohols to avoid epimerization: [38, 39]. 6 This figure is a slightly modified figure as published in [40].

Multicomponent Reaction Design Strategies

105

substrate scope). Furthermore, it would be ideal that the MCR can provide every possible stereoisomer, to obtain stereochemical diversity. The pair phase involves intramolecular coupling reactions (FG pairing reactions [43]) that join the FGs that were strategically planned in the build phase. Carefully adapting the reaction conditions in this pairing phase leads to pairing of different FGs, resulting in the formation of a variety of different scaffolds. Since the build/couple/pair strategy requires versatile MCRs it is not surprising that the Ugi reaction is often used for this purpose as coupling reaction. A wide variety of Ugi (couple) postcyclization reactions (pair) is reported [40, 44]. A small selection of these sequencing reactions is depicted in Scheme 4 [45–50]. As is clear from the scheme, by variation of the Ugi building blocks and applying the proper cyclization reaction, different scaffolds are accessible in only two to three steps. For example, if 4-bromo-1H-indole-3-carbaldehyde, allylamine, 3-butenoic acid and isopropyl isocyanide are used as Ugi inputs, the two retained alkene functionalities in Ugi product 33 allow ring-closing metathesis to afford 34. This product possesses an aryl bromide and an alkene functionality that can undergo a second cyclization by a subsequent intramolecular Heck reaction occurring with excellent diastereoselectivity to afford 35 in 59% overall yield (product is racemic) [45]. MeO O NH O

N

N

MeO

CO2Et

30 53%

H H O

41 70% dr = 92:8 stereochemistry C9 n.d. Spontaneous Ugi / Diels-Alder

32 87% dr = 3:2

N N

O N

O 40 92%

Cl Ugi / Arylation

N

HN O

Cl

O

N

O

OMe H N O 39 88%

I

H

N

R

2

1

3

R

R +

NC

R

NH2

O NH

O 5

O

O 37 91% Ugi / N-arylation

N

Br

O 33 73% N H

OH

R

H N

N I

N

N H

O

O

4

XPhos

hv MeOH O

H N

O

Cl

N

NH

O

MeO

O 31 41% Pd(OAc)2, dppf OMe n -Bu4NBr, K2CO3 H N DMF, 80°C

N

O Ugi / [2+2] Ene-Enone Photocycloadditions

TFA

O

O

O

H N

MeO CO2Et

N

Cl

Ugi / Pictet-Spengler

O H N

O

N

O

O NH

Grubbs II DCM

N

Br

O 34 N 94% H Pd(PPh3)2Cl2 Et3N, DMF 110°C, MW O

O

O 36 85%

O

BINAP Pd(dba)2 Cs2CO3 dioxane / MeCN (85 / 15) MW, 150°C

O N

N

H N H 35 N 86% H dr = >98:2 Ugi / RCM / Heck

O NH 38 80% dr = 1:1 Ugi / a -CH arylation

Scheme 4 The introduction of scaffold diversity by the Ugi-4CR (couple) and follow-up cyclization reactions (pair)

106

R. Scheffelaar et al.

In some of the examples, i.e., Ugi/Diels-Alder and Ugi/Pictet-Spengler, the reactions were performed in a single pot (although step-wise), but in the majority of the examples the Ugi intermediate was first isolated. A second, very elegant, example of build/couple/pair strategy in DOS is performed by Schreiber and co-workers (Scheme 5) [51]. This example uses the Petasis reaction of (S)-lactol 42, L-phenylalanine methyl ester (43), and (E)-2cyclopropylvinylboronic acid (44) as coupling reaction, which is followed by a OH

Ph

Ph

O

O

H2N

Build 42

+

Ph Couple Petasis 3-CR

CO2Me 43

HN

EtOH

Pair Au-cat MeOH

Pair Ru-cat II

Ph

Ph

H OH

N

Ph

HH OH

N N

MeO2C

Ph CO2Me N

N

H OH H

O

Ph

N

N

MeO

O

Ph

H OH

N

Ph

B (89%)

Ph

O H

G (87%) Pair Ru-cat I

Ph

CO2Me

O

Ph OH

O

Diels-Alder

46 (86%)

Pair mCPBA

E (85%)

Ph

O

OH

Pair NaH

MeO2C

N

C (85%)

A (81%)

O

45 (85%)

CO2Me

Ph

Ph

MeO2C

N

Ph

DMF NaHCO3

Pair [Co2(CO)8]

Ph

MeO2C

N

44

Pair Ru-cat I

Pair Pd-cat

Couple

Ph OH

(HO) 2B

Ph

Br

CO2Me

CO2Me

H Ph

D (80%)

N

F (88%)

O

Ph MeO2C Ph

H OH O

Pair [Co2(CO)8]

Pair Pd-cat

Pair Ru-cat II

Pair Ru-cat I

N

Ph

H (90%)

OH

N N Ph N

Ph

O

I (72%)

O

N O

N N

O

Diels-Alder

N

Ph

Ph J (87%)

Ph

O

M (65%)

N K (70%)

Ph

N

Ph N (91%)

N

O

N

O

N O

O HH

O

N

N O

N N

Ph OH

O

O

O H

CO2Me

H

Ph

N

Diels-Alder Ph

O

Ph O

O

N

H O

N

O

N N

O

L (80%) HH

Ph

O

O (85%)

Pd-cat = [Pd(PPh3)2(OAc)2] : cycloisomerization Ru-cat I = Hoveyda-Grubbs II : Enyne metathesis Ru-cat II = [CpRu(CH3CN)3PF6] : cycloisomerization ([5 + 2]-reaction) Au-cat = NaAuCl4 : cycloketalization [Co2(CO)8] : Pauson-Khand reaction NaH : lactonization m CPBA : Meisenheimer rearrangement

Scheme 5 The use of the Petasis 3CR as coupling reaction and several pairing reactions to afford 15 distinct scaffolds

Multicomponent Reaction Design Strategies

107

propargylation to obtain the densely functionalized substrate 46 in >99% de. Although the Petasis reaction was not sufficient to introduce all required functionalities, making an additional coupling step necessary, it can easily introduce stereochemical diversity. This is because the anti-diastereomer is exclusively formed, directed by the a-hydroxy functionality of the intermediate imine. By combining both enantiomers of the lactol and the amino acid, four stereoisomers are accessible. As is common for the build/couple/pair strategy, the scaffold diversity is created in the pairing phase. Remarkably, Schreiber was able to use every single functionality of 46. Seven different highly selective pairing reactions were performed, to obtain seven different scaffolds (A–G), which is quite remarkable since they are all obtained from one single substrate. To come back to a term earlier introduced, this is an example of a reagent-based approach since a single substrate is converted by different reaction conditions, producing a diversity of scaffolds [42]. Products F and G were in turn substrates for subsequent pairing reactions to obtain multicyclic compounds J, N, K, O, and H. Finally, products B, J, and H, which all comprise a diene functionality could be further converted by a subsequent Diels-Alder (DA) reaction with 4-methyl-1,2,4-triazolin-3,5-dione to obtain the highly complex products I, M, and L. This example shows that by applying the build/couple/pair strategy a collection of 15 highly diverse (and complex) scaffolds can be obtained in only three to five steps.7

3 Novel Multicomponent Strategies Towards Scaffold Diversity From the previous examples it is clear that scaffold diversity can be achieved using MCRs and post condensation cyclizations. However, during the last decade much work has also been devoted to obtain scaffold diversity by using MCR strategies exclusively. Besides scaffold diversity, this has also lead to the development of a number of novel MCRs. These new multicomponent design strategies, to achieve scaffold diversity, can be divided into four main approaches: l l l l

Single reactant replacement (SRR) Modular reaction sequences (MRS) Condition-based divergence (CBD) Union of MCRs (MCR2)

As will be clear from the following examples, many of these are illustrations of rationally designed MCRs that could generally only succeed because of chemists’ insight into mechanisms and FG reactivities, although some MCRs are still found serendipitously.

7

For more examples of the Build/Couple/Pair principle applied in DOS: [52–54].

108

3.1

R. Scheffelaar et al.

Single Reactant Replacement (SRR)

The SRR strategy (Fig. 6), a phrase first introduced by Ganem, involves the development of new MCRs by systematic assessment of the mechanistic or functional role of each component in a known MCR [55]. In this method one reactant (C) is substituted for reactant (D) that displays a similar chemical reactivity mode required for condensation with A and B. By incorporation of an additional reactivity or functionality into D, the resulting MCR might be directed to a different outcome, leading to scaffold diversity [55]. Probably one of the first examples of SRR is performed by Ugi and co-workers, who replaced the carbonyl component 6 of the Passerini reaction by a different electrophile, i.e., imine 47, which resulted in the well-known Ugi reaction affording 13 (Scheme 6) [29]. Ugi furthermore replaced the carboxylic acid (8) input of the Ugi reaction by different acidic components 48 to afford various different scaffolds (Scheme 6) [56]. It is required that the selected components are acidic enough (to activate the imine) but their conjugated bases should moreover be able to attack the intermediate nitrilium ion as a nucleophile. Consequently, Ugi was able to use HNCO and HNCS to afford hydantoin- (49a) and thiohydantoinimides (49b), respectively. These are formed from the corresponding a-adducts, by an intramolecular acylation. Also, hydrazoic acid was used, resulting in the formation of tetrazole 50 by spontaneous cyclization of the a-adduct. By applying water or hydrogen selenide the corresponding a-adducts are transformed by tautomerization, to obtain the final products 51a and b, respectively. Ganem and coworkers changed the carboxylic acid in the Passerini reaction for a Lewis acid (TMSOTf, 53) to activate the carbonyl compound 6. Reaction of several carbonyls, morpholinoethylisonitrile 52 and Zn(OTf)2/TMSCl (which forms TMSOTf in situ) resulted in the formation of a-hydroxyamide 56 (Scheme 7). Ganem realized that a neighboring stabilizing group like in this example the morpholine ring, was required to stabilize the nitrilium ion 54 (formed by attack of the isonitrile to the activated carbonyl), since simple isonitriles did not result in

A

+

B

+

C

A

C

B

SRR

B

A A

+

B

+

D D

Fig. 6 Schematic representation of the single reactant replacement (SRR) strategy to scaffold diversity

Multicomponent Reaction Design Strategies

R3

109

Y H N 5 N R H R1 R2

N N

Y = O (51a), Se (51b)

H N

N N

HX = H2O, H2Se R5

O R1

+ R

2

5

R – NH2 12

6

HX = HN3 R5

N

3

+ R –N

2 R1 R 47

C

+ HX

7

HX = HSCN, HOCN

48

R5

2 R1 R 50

R3

R1 R2 N N H

Y

R3 N U-variant 4CR

Y = O (49a), S (49b) SRR2

O R

R2

1

6

+ R5– NH2

R5 R

12

O N

1

3 + R –N C +

R

2

47

O R4

7

R3 OH

8

R5 N

N H R1 R2 O 13

R4

U-4CR

SRR1

O 1

2

R

+ R3 N C

6

4

R

R

7

O

O

+

R3 OH

8

N H

O

R4

P-3CR

2

R1 R O 9

Scheme 6 One of the first examples of SRR performed by Ugi and co-workers

any reaction [57]. These mechanistic insights lead Ganem to study other donating groups at the isocyanide component, applying, for example, isocyano esters or amides (57). Indeed, the esters and amides were able to function as stabilizing group, leading to the formation of ethoxy- and morpholinooxazoles 60 [57]. Further SRR could be achieved by replacing carbonyl 6 to imine 61, which resulted in the formation of bis-amino oxazoles 65 (catalyzed by a Brønsted acid).8 Finally, our research group serendipitously discovered the formation of N-(cyanomethyl)amides 70 when primary a-isocyanoamide 67 was used as an input (Scheme 7, SRR4, Brønsted acid was applied only with primary amines) [60]. The mechanism of this reaction will be discussed further in Sect. 3.3. Another nice example of SRR is depicted in Scheme 8. The original reaction was developed by Diels and Harms in 1936 [61]. Reaction of isoquinoline 71 with dimethyl acetylenedicarboxylate (DMAD, 72) initially forms zwitterionic intermediate 73, which is reacted with a second equivalent of DMAD to form benzoquinolizine 74. This is, however, not a true 3CR reaction, since two components are identical. In 1967, Huisgen reported three variations of this reaction in which

8

It has to be noted that this reaction was first developed by Zhu and coworkers in 2001, even before the previous mentioned carbonyl variant of Ganem and co-workers: [58]. Later on, Ganem published a similar reaction with unsubstituted isocyanoamides: [59].

110

R. Scheffelaar et al.

O R

1

R

+ R3 N C

2

O

+

OH

R 7

6

O 4 R O N H R1 R2 O 9

3

R 4

8

P-3CR

1

SRR

TMS

C

N

O Zn(OTf )2 / TMSCl + lewis acid 53

O +

2

1

R

R

N O

6

52

1

R

O

O

H2O

N

OH

N H

2

N

R N

54

2

SRR

O

1

R

2

N

N

TMS

O

R

O

2

1

R

R

56

55 TMS O

O

O +

2

1

R

R

N

X

C

X = OEt, 57 morpholino

6

Zn(OTf)2 / TMSCl + lewis acid 53

R

1

R O

O

N

O

1

R R

2

58

1

R

2

O

R N

X

N

X X

TMS

TMS O

2

60

59

3

SRR

R

4

3 R N 3

R

N

R

R

O +

R

2

R 6

+ bronsted acid

5

4

O

C

R X = NMe2, 62 morpholino

61

1

N

X

2

1

R

R

1

R + HN R3

O

3

R

4

R N

2

4 3

R N

1

R

2

O

N

R

N

X

4 1

R

2

O

R

R

R N

X

X

5

63

R 65

64

4

SRR

66

2

1

R 4

3

R

N

1

+ 2

R

R 61

O

R

H2N

N 5

R 67

C

+ bronsted acid

C O H NH

N

R

4

R N 3 R

1

R

2

R

O N H

5

R 68

N N

R

4

R

3

1

H R N

N

R

5

R

5

O

2

R

N 3 R

4

R

H 69

Scheme 7 Four successive SRRs, resulting in four new scaffolds

intermediate 73, a 1,4-dipole, is trapped with several different dipolarophiles, such as dimethyl azocarboxylate 75, diethyl mesoxalate 77 and phenylisocyanate 79 to form tricyclic scaffolds 76, 78 and 80, respectively [62]. Other examples of replacement of the second equivalent of DMAD have been published by Nair et al. who applied 2,5-dimethyl-1,4-benzoquinone 81 to obtain spiro[1, 3]oxazino [2,3-a]isoquinoline derivative 82, N-tosylimines 83 to afford 2H-pyrimido-[2,1-a] isoquinolines 84 and arylidinemalononitriles 85 to yield tetrahydrobenzoquinolizine derivatives 86 [63–65]. Recently, Yavari et al. reported a 3CR to pyrrolo[2,1-a] isoquinolines 88, by reacting 71, 72, and aroylnitromethanes 87 in good yields [66]. The reactions reported here, obtained by SRR, are all one-pot 3CRs. For additional MCRs involving intermediate 73, see [67–74]. From the reported examples in this paragraph9 it is clear that SRR is a fast way of developing new MCRs and extremely useful for application in DOS, since it can quickly afford many different scaffolds.

9

In addition to the examples reported here there are several other publications that apply SRR to achieve new scaffolds, thereby discovering new MCRs: [55, 75, 76].

Multicomponent Reaction Design Strategies

111

CO2Me

N

N MeOOC 74

MeO2C

CO2Me

N

N CO2Me CO2Me

N

76

CO2Me COOMe

N N

MeO2C

CO2Me

EtO2C CO2Et 78

O

MeO2C DMAD, 72

O

EtO2C 77

CO2Et N

75

PhNCO 79

O

CO2Me

73

81

N H

O 2N CN

COAr 87

Ar 85

Ts

ArOC

CO2Me CO2Me

CN Ar

82 N

CO2Me

88 CO2Me

O

N 83

N

CO2Me O

80 O

DMAD, 72

CO2Me

CO2Me

N

+ CO2Me

71

N

Ph

CO2Me N

CO2Me

N

CO2Me Ts

NC NC

CO2Me Ar

N

O

CO2Me CO2Me

Ar 84

86

Scheme 8 Replacement of DMAD in the original reaction to 74, by different third components yielding several new isoquinoline based MCRs

3.2

Modular Reaction Sequences

The second MCR development strategy leading to scaffold diversity involves MRS (Fig. 7), which is closely related to SRR but involves a versatile reactive intermediate that is generated from substrates A, B, and C by an initial MCR. This intermediate is then reacted in situ with a range of final differentiating components (D, E and F) to yield a diverse set of scaffolds. One striking example is the use of 1-azadiene 92 as intermediate to scaffold diversity which is generated in situ from a phosphonate 89, a nitrile 90 and an aldehyde 91 via a 3CR involving a Horner–Wadsworth–Emmons (HWE) reaction (Scheme 9) [77, 78]. In 1995, Kiselyov reported the first MCR involving this 1-azadiene which he reacted with sodium or potassium salts of aryl-substituted acetonitriles 93 to afford 2-amino pyridines 94 in 61–72% yields (three examples, R1 ¼ H, R2 ¼ R3 ¼ Ar) [79]. Furthermore, he reacted the 1-azadiene with sodium enolates of methyl aryl ketones 95 to afford 2,4,6-substituted pyridines 96 in 63–67% yield (three examples, R1 ¼ H, R2 ¼ R3 ¼ Ar) [79].

112

R. Scheffelaar et al.

B A

D C

D B

B B

A + C

E E

A

A

C

F

C versatile reactive intermediate

B

F

A

F

C

Fig. 7 Schematic representation of the modular reaction sequence (MRS) strategy to scaffold diversity

Ten years later, Kiselyov published an extension of this work, by reacting the 1-azadiene 92 with amidines (97, R4 ¼ alkyl, aryl) and guanidines (97, R4 ¼ NHR) to afford the polysubstituted pyrimidines 98 in 22–73% yield. This MCR proved to have a rather high substrate scope since all components could be varied to some extent (19 examples, R1 ¼ H, alkyl, Ph, R2 ¼ R3 ¼ Ar)10 [80]. Furthermore, the one-pot reaction of 92 with 5-amino pyrazoles (99, X ¼ N, Y ¼ C) and 2amino imidazoles (99, X ¼ C, Y ¼ N) resulted in the formation of bicyclic compounds 100 and 101 (12 examples, 52–77%, R1 ¼ H, R2 ¼ R3 ¼ Ar) [81]. In another one-pot procedure, Kiselyov reacted 92 with the dianion of methyl imidazolyl acetates 102 to yield imidazo[1,2-a]pyridines 103 (12 examples, 54–75%, R1 ¼ H, R2 ¼ R3 ¼ Ar) [82]. Our group has also contributed to these 1-azadiene derived MCRs by reacting 92 with isocyanates 104 to selectively afford functionalized 3,4-dihydropyrimidine2-ones 105 (29 examples, 15–90% yield) [83, 84] and triazinane diones 106 (17 examples, 25–91% yield) [85, 86] depending on the nature of the isocyanate (Scheme 9). The use of isocyanates with strongly electron-withdrawing groups (Ts, p-NO2Ph, CO2Me, C(O)Ph) resulted in the exclusive formation of the dihydropyrimidones 105, while isocyanates with less electron-withdrawing (Ph, PMP) or donating substituents (Et, benzyl) resulted in the formation of triazinane diones 106. Dihydropyrimidones are most likely formed by nucleophilic attack of the 1-azadiene nitrogen to the isocyanate (with electron-withdrawing substituent), 10

The use of phosphonates with large R1 substituents resulted in a significant decrease in yield, 22– 39% for R1 ¼ Ph and i-pentyl.

Multicomponent Reaction Design Strategies

113 O EtO P EtO 89 +

R3

R3 4

R1 R2

N N H 109

R

R1

MW

R2CN

1

R4 N H 108 R4 = alkyl, aryl

R3

R3CHO

R4

R1

91

90

S

R2

S

R

R2

N

R4

n BuLi R4NCS 107

R5

N

4 5 94 R = Ar, R = NH2 4 5

96 R = H, R = Ar

CN 93 R

O

4

R

5

95

R4 N R2

R

O

4

N

4

R

R NCO 104

R3

N O H R1 106 R4 = alkyl, aryl

3

R2

R3

NH2

R1

R

4

NH HCl 97

NH

N

N

N

R4

98

92

4 R NCO 104

N

R2

DIPEA R

R1

4

Y

NH2 X N H 99

R4 = alkyl, aryl, NH-alkyl, NH-aryl

R3 3

EWG

R R1 R2

N

R

4

N O H 4 105 R = Ts, p -NO2Ph, CO2Me, C(O)Ph

R1

N

102 R

3

R1 R2

R2 EWG

N

N

N X

Y R4

100 X = N, Y = C 101 X = C, Y = N

103

Scheme 9 Modular reaction sequence involving the 1-azadiene 3CR as initial MCR, to which several fourth components were added

followed by cyclization. On the other hand, when isocyanates with less electronwithdrawing or donating substituents are used, the initial condensation product (of the 1-azadiene to the isocyanate) can act as a nucleophile and react with a second equivalent of isocyanate, which can then ring-close to afford the thermodynamically favored six-membered triazinane diones. Both reactions showed to have a broad substrate scope (appendage diversity) and the R2 and R3 substituents could be varied extensively. However, variation of the R1 substituent was limited (only H and Me). A modification of the dihydropyrimidone MCR was performed by applying isothiocyanates 107 as the fourth component, which resulted in the formation of 2-aminothiazines 108 which upon microwave heating could rearrange (Dimroth rearrangement) to dihydropyrimidine-2-thiones 109 [87]. A second example that uses MRS was reported by Zhu and coworkers. They combined the bis-amino oxazole (113) MCR with primary amines, discussed earlier

114

R. Scheffelaar et al.

in the SRR paragraph, with a subsequent N-acylation using a,b-unsaturated acyl chloride 114 (fourth component) affording polysubstituted pyrrolopyridinones 119 (Scheme 10) [58, 88]. After acylation and upon heating, the formation of 119 can be explained by an intramolecular DA reaction affording the bridged tricyclic intermediate 116. Subsequent base-catalyzed retro-Michael cycloreversion, with loss of morpholine (117) and final tautomerization gives 119. A variation of this reaction (Scheme 10), which involves the same intermediate oxazole MCR product 113, uses activated alkynoic acid derivatives 120 as the acylating agent (fourth component) [89]. The resulting intermediate again undergoes an intramolecular DA reaction, followed by a retro-Diels Alder, resulting in the loss of nitrile 123 and giving dihydrofuropyrrolone 124. This product itself is a diene that can react with dienophile 125 (fifth component) in a second DA reaction, to give hexasubstituted benzenes 127 after loss of water. Since these steps all occurs in one pot, this reaction has evolved from a three- to a 5-component reaction by applying a very elegant modular reaction sequence. All together, three different highly functionalized scaffolds have been developed, originating from a single 3CR towards bis-amino oxazoles (Scheme 10). In summary, MRS have proven to be extremely useful for the fast generation of scaffold diversity. It can be argued that these example belong to the SRR strategy. However, since the intermediate is formed by a MCR, we have divided this as a

O

R

R1

2

R

R4

N O

R1

N

O

aza-DA

H

R3

O R +

2

111

O NC

N

R

NH2

R

toluene, 60°C

N

N 113

O

O

R4

N

R3

O

N

O

R1

–H2O

R

O

2

R4

N

N

R1 R

126

R5

R6

R5

R6

toluene, 110°C, 12h

5

R6

O

127

O Et3N toluene, 110°C, 12h

O

X R4

125 DA

O

2

N O

R4 N

N 121

O R4 119

118

2

X = Cl, OC6F5 120

R1

2

O 114

O

R1

112

R

HO

R

R4

Cl

NH NH4Cl

N

N R3

O R4

O

2

R3

O

O

2

117

Et3N toluene, 110°C, 12h

R1 110

R3

HN

116 O

R

N

N

NEt3

R4

N

R3

115

O

R1

R1

retroMicheal

N

O

N

2

N

R3

aza-DA

R

R4

2

N

R1 122

N

retro-DA N

O R1

O

–R3CN 123

R

O

2

R4

N

R1 124

O

N O

Scheme 10 Modular reaction sequences reported by Zhu and co-workers, involving an initial bis-amino oxazole MCR

Multicomponent Reaction Design Strategies

115

separate strategy. The generation of the intermediate via a MCR gives the possibility for easy appendage diversity, since generally all the components can be varied.

3.3

Condition-Based Divergence

CBD in MCRs (Fig. 8) generates multiple molecular scaffolds from the same starting materials by merely applying different conditions. It is evident that for reactions involving simultaneous molecular interactions of three or more components, different potential reaction pathways leading to different products are accessible. A good MCR follows one pathway selectively. However, it is certainly of great interest to modulate the selectively to a different pathway by changing the reaction conditions, which is the major goal of CBD [90]. For example, depending on the catalyst, solvent or temperature that is used, a set of inputs A, B and C may react via different pathways to produce distinct scaffolds. As can be understood this is not a simple task, which is expressed by the limited amount of reported examples. In 2008 Liu et al. demonstrated this concept by the organocatalytic asymmetric one-pot 3CR of aldehydes 128 (generally aromatic), diethyl a-aminomalonate 129 and nitroalkenes 130 (Scheme 11) [91]. By altering the organocatalyst they could selectively obtain either Michael addition product 132 or [3 þ 2] dipolar cycloaddition product 134. In the absence of a catalyst, reaction control generally proved to be poor. Initially, for both reaction pathways, a-imino esters are formed in situ by reaction of the aldehyde with the a-aminomalonate. The use of organocatalyst 131, which activates both the a-imino ester (producing an azomethine ylide) and the nitroalkene (via a doubly hydrogen-bonded interaction), resulted in the selective formation of Michael adduct 132 with high enantioselectivity (16 examples,

B A nd .1

C

co

B

B

A +

C

A

3 d.

n co

C

cond.2

Fig. 8 Schematic representation of the Condition Based Divergence (CBD) strategy to scaffold diversity

B

A C

116

R. Scheffelaar et al. CF3 O

N

N N CF3 H H 131 10 mol%

toluene, 4Å MS, 0°C

R

O2N Ar

N

CO2Et CO2Et

132 EtO2C

O Ar

H 128

EtO2C

+

NO2 R

CF3

NH2

130

S

129 Ar

N

N H Ar 133

CF3 N H Ar = 3,5-F2Ph

R

O2N

20 mol% Ar

MTBE, 4Å MS, –20°C

CO2Et N H

CO2Et

134

Scheme 11 Reaction control in the 3CR of aldehydes diethyl a-aminomalonate and nitroalkenes

48–95%, 94–98% ee). This product is stable and does not react further to form the cycloaddition product 134. When, on the other hand, organocatalyst 133 (possessing a bulky 2,5-diaryl-pyrrole moiety) is applied, product 134 was selectively formed by a highly diastereo- and enantioselective 1,3-dipolar cycloaddition (11 examples, 56–90%, 60–91% ee). This reaction most likely involves activation of the nitroalkene by the thiourea, via the earlier mentioned doubly hydrogen-bonded interaction, followed by a concerted attack of the in situ formed azomethine ylide (this ylide is not activated by nor coordinated to the organocatalyst, because of the bulky, nonbasic pyrrole group, but is most likely formed via a 1,2-prototropic rearrangement [92]). Although Liu et al. established the formation of two different reaction products starting from the same three components, the degree of structural diversity is rather limited, since Michael product 132 is formally an intermediate to 134 (although this product is presumably not formed step-wise but concerted). Nevertheless, both products are formed under high stereocontrol, and the enantiomeric products are theoretically accessible by taking the enantiomeric organocatalysts giving rise to stereochemical diversity. In 2008, Chebanov et al. reported an excellent example of condition base divergence by the MCR of 5-amino pyrazoles 135, cyclic 1,3 diketones 136 and aromatic aldehydes 137 (Scheme 12) [90].11 5-Amino pyrazoles 135 have at least 11

Several other research groups have been involved in MCRs with aminoazoles, 1,3-diketones and aldehydes. For a recent overview see: [93].

Multicomponent Reaction Design Strategies Ar

Ph

Ar

O

N N H

Ph

R R

N H 139

144

R R

N H OH

NH2

N N H 135

EtOH, sonication rt, 30 min. –H2O

R 136 R

O

Ph

O

N N H

Ph Ar

H 137

O

N N N H OH 143

R R

EtOH, t BuOK 150 °C (MW or conventional) 15 min.

NuAr O Nu

OH

Ar N N H

Ar

O

+

138

Ph

R R

Biginelli-type

EtOH, Et3N 150 °C (MW or conventional) 15 min. O

–H2O

Ar

O

N N N H

Hantzsch-type

Ph

117

R R

N H OH

R R

N N NH

140

O 142

–Nu–

Ar O Nu

Ph N N H

N H OH 141

R R

Scheme 12 Tuning the 3CR to three different scaffolds by adapting the reaction conditions

three nonequivalent nucleophilic centers (N1, C4, NH2), but the authors were able to drive the reaction to three distinct scaffolds 139, 142, and 144 by changing the reaction conditions. Under reflux conditions in ethanol, a mixture of 139 and 144 was always obtained. However, performing the reaction at 150 C in a sealed vessel (MW or conventional heating) in the presence of NEt3 led to the exclusive formation of Hantzsch product 139 (eight examples, 70–91% yield). This indicates that the Hantzsch product is most likely the thermodynamic product in this transformation. Although a thorough mechanistic study was not performed, the reaction likely proceeds via intermediate 138, which upon loss of water provides Hantzsch product 139.

118

R. Scheffelaar et al.

In their search for the optimal base for the selective formation of 139, the authors unexpectedly found a different reaction product, namely 142 (nine examples, 38–75% yield). This product is formed when a nucleophilic base such as sodium ethoxide or potassium tert-butoxide was used instead of NEt3 (under otherwise identical reaction conditions as for the formation of 139). The formation of 142 is explained by nucleophilic attack of ethoxide or tert-butoxide to intermediate 138 followed by a ring-opening/recyclization. Conversely, neutral and ambient conditions lead to the formation of the kinetically controlled Biginelli product 144 (eight examples, 51–70%). The authors found that sonication was required to obtain the final product, since simple stirring of the three components at rt did not result in any desired reaction. They explained this observation by the improved mass transfer through cavitation phenomena.12 This reaction presumably involves intermediate 143. Recently, our group also contributed to CBD as a tool for DOS. By judicious selection of the reaction conditions, the 3CR between a-acidic isocyanides 145 (isocyano amides13 and isocyano esters14), carbonyl components 6 and primary amines 146 could be directed towards either 2H-2-imidazolines 150 or trisubstituted oxazoles 152 (Scheme 13) [98]. By applying 2 mol% AgOAc as the catalyst 2-imidazolines 150 were obtained selectively, while the use of a Brønsted acid (for R4 ¼ NR2) or a polar aprotic solvent (for R4 ¼ OR) selectively provided the corresponding oxazoles 152. The formation of 2-imidazolines 150 can be mechanistically explained by coordination of the isonitrile carbon to Ag+, which enhances the a-acidity of the isocyanide (Pathway A), and blocks the nucleophilicity of the isonitrile (preventing pathway B). Upon loss of a proton the isocyano anion 147 can perform a Mannich type addition to the iminium ion 148, which subsequently cyclizes to form the 2-imidazoline 150 after a final proton shift. When, on the other hand, a Brønsted acid is applied (Pathway B), the slight decrease in pH will lower the concentration of the isocyanide a-anion, thereby making the imidazoline pathway less favorable (Pathway A). Since the imine is activated by the Brønsted acid, the isonitrile carbon of 145 can attack the iminium ion 148 as a nucleophile, leading to nitrilium intermediate 151. After proton abstraction and ring closure oxazole 152 is formed. For isocyano esters, however, the use of methanol and Brønsted acid was not 12

Propagation of ultra sound waves into the liquid medium results in a series of high-pressure (compression) and low-pressure (rarefaction) cycles, with rates depending on the frequency. During the low-pressure cycle, high-intensity ultrasonic waves generate small vacuum bubbles in the liquid, which can reach a volume at which they are not stable anymore resulting in a violent collapse. This phenomenon is termed cavitation: [94, 95]. 13 It has to be noted that the formation of oxazoles using isocyano amides has been well studied by Zhu and co-workers (see [58, 59]). With the work of Elders et al. the oxazole MCR has been expanded with a wide range of isocyano esters. The MCR with isocyano amides can now also be directed to the 2-imidazolines. 14 The directing properties of the MCR involving isocyano esters could exclusively be performed using a-aryl isocyano esters, since the use of a-alkyl isocyano esters always resulted in the formation of 2-imidazolines, in various solvents, even without AgOAc, see [96] and [97].

Multicomponent Reaction Design Strategies R2 R1 R5 R4

R3 N H N C

O 149

Ag

O H N 3 R

Ag

R2 +

119

N

R4

C

R5 147

148

+ Ag Pathway A

–Ag

R2 R1 R5 R4

R3 N

MgSO4 AgOAc

N

O 150 2-Imidazoline

MeOH, rt 4

6 7

R = OMe, NR R

– H2O O C N O R4 MgSO4 145 R5 + R1 R2 6 3 R MeOH, Et3N•HCl (R4 = NR6R7), 60°C NH2 or DMF (R4 = OMe), rt 146 +H –H2O

R4

1 2 O R R

HN R3

N

R5

152 Oxazole

Pathway B

–H R1 R2

O N

R4 R5 145

C R2 +

H N R1 148

O R3

R4

N

C

N H

R3

5 H R 151

Scheme 13 Directing the MCR of a-acidic isocyanides, carbonyl components and primary amines towards 2H-2-imidazolines 150 and trisubstituted oxazoles 152 and their proposed mechanisms

sufficient to exclusively form the oxazole, since polar protic solvents turned out to promote the formation of 2-imidazolines [96]. The use of aprotic solvents seemed to be the best choice for directing the 3CR with isocyano esters to the trisubstituted oxazoles (best results were obtained with DMF). An elaboration of this work involves the 3CR between primary a-isocyanoamides 67, carbonyl components 6 and primary amines 146, which could be directed towards either 2H-2-imidazolines 153 or N-(cyanomethyl)amides 156 by Ag+-catalysis vs. Brønsted acid mediated reaction, respectively (Scheme 14) [60]. The selective formation of N-(cyanomethyl)amides 156 (also earlier mentioned in the SRR approach, Scheme 7) can be rationalized by the same criteria as the formation of trisubstituted oxazoles 152 (Scheme 13), since the use of a Brønsted acid, prevents the formation of 2-imidazolines 153 by the decreased pH. By applying a Brønsted acid, the reaction initially proceeds via the same mechanism as for the oxazole MCR. However, when intermediate 155 is formed, it does not tautomerize to form the 5-aminooxazole 157. Instead, proton abstraction at the exocyclic imine nitrogen and subsequent ring opening gave the corresponding N-(cyanomethyl)amides 156. Again Ag+ catalysis promotes the formation of 2-imidazolines 153, for the same reasons as discussed before. In conclusion, the CBD approach makes it possible to obtain scaffold diversity starting from the same reaction inputs by adapting the temperature, reaction promoter or solvent.

120

R. Scheffelaar et al.

3 O O MgSO4 C R2 R MgSO4 N N Et3N•HCl 1 AgOAc H2N R1 R2 R 4 4 67 R R 6 + N MeOH, rt MeOH, 60°C 1 2 H2N R = R = Me R3 O 3 = Bn R 153 146 NH2 2-Imidazoline 4 39% R = H 48% R4 = Ph +H –H2O 2

R O H2N

N R4 67

C + HN

R1 3

R 148

O H

N H

N

156 N-(cyanomethyl)amide

R1 R2 3 R N N H C

R4 154

H R1 R2 N R3 N 4 R O H

21-97%, 13 examples –H

H

N 4

R

1 O R

N H 155

R2 HN R3

H2N

1 O R

R2 3

N HN R 157 5-aminooxazole

R4

Scheme 14 Directing the MCR towards 2H-2-imidazolines 153 and N-(cyanomethyl)amides 156 and the suggested mechanism for the formation of N-(cyanomethyl)amides 156

3.4

Union of MCRs

The Union of MCRs (MCR2, Fig. 9) is a fourth strategy for the rational design of novel MCRs that combines two (or more) different types of MCRs in a one-pot process. The presence of orthogonal reactive groups in the product of the primary MCR (which is either formed during the primary MCR or present in one of the inputs) allows the union with the secondary MCR [17, 99]. By varying the secondary MCR (e.g., by addition of inputs E/F or G/H), diverse (and complex) scaffolds will be available, making this strategy excellent for application in DOS. The combination of MCRs in one pot is not new. It was first introduced by Do¨mling and Ugi who developed a 7-component reaction (7CR), that was basically a one-pot combination of a modified Asinger 4CR and U-4CR (Scheme 15) [100, 101]. In this 7CR, an a- or b-bromo/chloro aldehyde 158, NaSH/NaOH, NH3, another aldehyde 161, an isocyanide 166, CO2, and a primary alcohol (solvent) are combined to afford 167 efficiently. However, NaSH/NaOH, NH3 and CO2 are invariable components in this reaction which limits the substitutional diversity (appendage diversity) and thereby the scope of the MCR. Another example, also reported by Ugi and co-workers, is the combination of an Ugi five center 4-component reaction (U-5C-4CR) with a Passerini-3CR (Scheme 16) [102]. This one-pot procedure uses an a-amino acid (L-aspartic acid, 168) as a 2-center-1-component input, which explains the origin of the U-5C-4CR. The reaction mechanism most likely involves an initial condensation of the amino functionality of the a-amino acid 168 with the aldehyde 169 to form iminium ion 171. After a-addition, intermediate 172 is formed which is attacked by the solvent methanol, to form derivative 174 after rearrangement. This compound still has a free carboxylic acid, which can undergo a P-3CR in the same pot to afford 175. The drawback of this procedure is that two equivalents of the aldehyde and isonitrile inputs are used, which also limits the substituent variability.

Multicomponent Reaction Design Strategies

121 F B

A

F

E

D

E

C B

A

D

+

MCR1

C

B

A

MCR2

D

G

C

H

G A

H

D

B C

Fig. 9 Schematic representation of the union of MCRs (MCR2) to scaffold diversity

CO2

R3OH

163

164 R4 O

n

NaXH 159 Y = O, S

O

Y

H R1 158 Y = Cl, Br n = 0, 1

+ NH3 160

1

HO

R O H R2 161

N

Asinger 4CR n

X

O

R3 + R4NC

165 R2

Ugi reaction

162

HN R

O

O

1

N

166 n

X

O

R3

R2

167

Scheme 15 Asinger 4CR-Ugi 4CR, a one-pot 7-component reaction

In 2009, our group demonstrated that the MCR2 strategy can also be used to obtain complexity as well as scaffold diversity (Scheme 17) [103]. The strategy is based on the abovementioned 3CR to 2H-2-imidazolines (reacting an isocyano ester, aldehyde or ketone and an amine) that shows extraordinary FG and solvent compatibility [96]. By incorporation of a second orthogonally reactive group in one of the starting materials, this MCR can be coupled to a second MCR. This concept has been demonstrated by the use of diisocyanide 176 in the 2-imidazoline MCR. These two isocyanide functionalities show intrinsic different reactivities, resulting in the chemoselective formation of 2-imidazoline 177.15 The retention of the isocyanide moiety in 177 provides an handle for subsequent isocyanide based MCRs. The goal of obtaining different final scaffolds has been demonstrated by varying the secondary isocyanide based MCR. Since the 2-imidazoline MCR can be performed in a wide range of solvents, the solvent of the one-pot procedure will The a-isocyanide is a-acidic and will react in the 3CR to yield 2H-2-imidazolines, while the other isocyanide is an aliphatic isocyanide and remains unaffected.

15

122

R. Scheffelaar et al.

O

O O + 2 OH

H2N

O

CH3OH

OH

173

H + 2

H N

NC

N H

O

168 O

169

NH

170

O O O

175 O

–H2O

+

P-3CR

U-5C-4CR

H 169

HN

OH

HO O

HN O

O

H O 173

N N

170

O

OH

171 O O

NC

172

H N O

N H

O O O

174

170

Scheme 16 Mechanism of the Ugi-5C-4CR [ Passerini-3CR

be selected based on the optimal solvent for the secondary MCR. For example, the 2-imidazoline MCR has been combined with the Passerini MCR to give 180 and 181. This one-pot MCR2 reaction has been performed in CH2Cl2, since this is the best solvent for the Passerini reaction. The initial MCR could also be combined with the U-4CR (in MeOH) to give 184, an Ugi variant [104] (in MeOH) using the tethered keto acid, levulinic acid (188), to give 189 and with a recently reported 3CR towards highly substituted 1,6-dihydropyrazine-2,3-dicarbonitrile derivatives 186 [105] (in EtOH), to yield 187. The possibility of obtaining scaffold diversity by the MCR2 strategy has been further demonstrated using the N-(cyanomethyl)amide 3CR [60] (discussed earlier) as the primary MCR [103]. By applying the primary a-isocyano amide derivative of 176, this MCR could be connected to the Passerini, the Ugi and the Ugi Smiles [106, 107] MCRs resulting in various new scaffolds. Interestingly, it was even possible to combine the 2-imidazoline and the N-(cyanomethyl)amide 3CRs with the U-4CR to afford a novel 8-component reaction, which is a landmark in this field [103]. In conclusion, the MCR2 strategy has proven to be a useful tool to achieve complex scaffolds in a simple one-pot procedure. Furthermore our group has demonstrated that by choosing MCRs that show unique solvent and FG tolerance as the primary MCR, these can be easily coupled to various secondary MCRs to produce several new scaffolds.

Multicomponent Reaction Design Strategies

123

N

O O

O

O

5

R

R

6

+ HO R 179

178

H N MeO

O

7

N O

180, 69%, dr = 1:1

DCM, rt

N

O

P-3CR

H N

O

N MeO

O

O

181, 41%, dr = 1:1 O

O

Ph +

+ HO

H

182

169

NH2 183

N

O

H N

N MeOH, rt U-4CR

O

N MeO

O

184, 69%, dr = 48:52 O O 4

R O

+ 176

6

R

3

R

NH2 NC

CN

2

1

R

NC

R

R

MgSO4 solvent, rt

2

1

3

N

4

R O 177

R N

O

146 Ph

185

NH2

NC

O

R = Me, Et

+ NC NH2 186

TsOH (2 equiv.) EtOH, rt

N NC

N

NC

N H

H N

N EtO

O

187, 53%, dr = 1:1 O

Ph + NH 2

HO 188

O

MeOH, rt Ugi variant

183

O

N

N

H N

N

O

O MeO 189, 78%, dr = 47:53

Scheme 17 MCR2 using diisocyanide 176 in the initial 2-imidazoline MCR

4 Concluding Remarks Diversity-oriented synthesis of small molecules is a great challenge for synthetic organic chemists. DOS requires the development of new methodologies that generate scaffold diversity in addition to appendage and stereochemical diversity. MCRs have been demonstrated to be extremely useful for DOS, since these complexity-generating reactions can easily be combined with several follow-up cyclization reactions resulting in the rapid synthesis of diverse (heterocyclic) scaffolds. Furthermore, novel MCR design strategies have emerged as important tools to generate scaffold diversity. Four different approaches (SRR, MRS, CBD and MCR2) have been applied, which all led to the development of new MCRs and higher order MCRs, thereby addressing both molecular diversity and complexity.

124

R. Scheffelaar et al.

Most examples described in paragraph 3, however, did not address the concept of stereoselectivity, since nearly all products products obtained were isolated as racemic mixtures and/or mixtures of diastereomers. The development of stereoselective MCRs (to be able to introduce stereochemical diversity) remains a major challenge for the future. Acknowledgment This work was performed with financial support of the Dutch Science Foundation (NWO, VICI grant).

References 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30. 31. 32. 33. 34. 35.

Lipinski C, Hopkins A (2004) Nature 432:855–861 Burke MD, Schreiber SL (2004) Angew Chem Int Ed 43:46–58 Schreiber SL (2000) Science 287:1964–1969 Schreiber SL (2009) Nature 457:153–154 Dobson CM (2004) Nature 432:824–828 Tan DS (2005) Nat Chem Biol 1:74–84 Galloway WRJD, Bender A, Welch M, Spring DR (2009) Chem Commun:2446–2462 Morton D, Leach S, Cordier C, Warriner S, Nelson A (2009) Angew Chem Int Ed 48:104–109 Spandl RJ, Bender A, Spring DR (2008) Org Biomol Chem 6:1149–1158 Burke MD, Berger EM, Schreiber SL (2004) J Am Chem Soc 126:14095–14104 Orru RVA, de Greef M (2003) Synthesis:1471–1499 Do¨mling A (2006) Chem Rev 106:17–89 Do¨mling A, Ugi I (2000) Angew Chem Int Ed 39:3168–3210 Zhu JP (2003) Eur J Org Chem 7:1133–1144 Jacobi von Wangelin A, Neumann H, Go¨rdes D, Klaus S, Stru¨bing D, Beller M (2003) Chem Eur J 9:4286–4294 Simon C, Constantieux T, Rodriguez J (2004) Eur J Org Chem:4957–4980 Zhu J, Bienayme´ H (2005) Multicomponent reactions. Wiley-VCH, Weinheim Trost BM (1995) Angew Chem Int Ed Engl 34:259–281 Sheldon RA (2007) Green Chem 9:1273–1283 Strecker A (1850) Justus Liebigs Ann Chem:27–51 Hantzsch A (1882) Justus Liebigs Ann Chem 215:1–82 Biginelli P (1893) Gazz Chim Ital 23:360–416 Kappe CO (1993) Tetrahedron 49:6937–6963 Mannich C, Kro¨sche I (1912) Arch Pharm 250:647–667 Passerini M (1921) Gazz Chim Ital 51:126–129 Banfi L, Riva R (2005) Org React 65:1–140 Lieke W (1859) Justus Liebigs Ann Chem 112:316 El Kaim L, Grimaud L (2009) Tetrahedron 65:2153–2171 Ugi I, Meyr R, Fetzer U, Steinbrucker C (1959) Angew Chem 71:386 Marcaccini S, Torroba T (2007) Nat Protoc 2:632–639 Pan SC, List B (2008) Angew Chem Int Ed 47:3622–3625 Ugi I (1971) Isonitrile chemistry. Academic, New York Ramo´n DJ, Yus M (2005) Angew Chem Int Ed 44:1602–1634 Guillena G, Ramo´n DJ, Yus M (2007) Tetrahedron Asymmetry 18:693–700 Mitsumori S, Zhang H, Cheong PH-Y, Houk KN, Tanaka F, Barbas CF III (2006) J Am Chem Soc 128:1040–1041

Multicomponent Reaction Design Strategies

125

36. Co´rdova A, Watanabe S, Tanaka F, Notz W, Barbas CFIII (2002) J Am Chem Soc 124:1866–1867 37. Notz W, Tanaka F, Watanabe S, Chowdari NS, Turner JM, Thayumanuvan R, Barbas CFIII (2003) J Org Chem 68:9624–9634 38. Hayashi Y, Tsuboi W, Ashimine I, Urushima T, Shoji M, Sakai K (2003) Angew Chem Int Ed 42:3677–3680 39. Co´rdova A (2003) Synlett:1651–1654 40. Sunderhaus JD, Martin SF (2009) Chem Eur J 15:1300–1308, and references therein 41. Sunderhaus JD, Dockendorff C, Martin SF (2009) Tetrahedron 65:6454–6469, and references therein 42. Nielsen TE, Schreiber SL (2008) Angew Chem Int Ed 47:48–56 43. Comer E, Rohan E, Deng L, Porco JA Jr (2007) Org Lett 9:2123–2126 44. Banfi L, Riva R, Basso A (2010) Synlett:23–41 45. El Kaim L, Gageat M, Gaultier L, Grimaud L (2007) Synlett:500–502 46. Akritopoulou-Zanze I, Whitehead A, Waters JE, Henry RF, Djuric SW (2007) Org Lett 9:1299–1302 47. Ribelin TP, Judd AS, Akritopoulou-Zanze I, Henry RF, Cross JL, Whittern DN, Djuric SW (2007) Org Lett 9:5119–5122 48. Erb W, Neuville L, Zhu J (2009) J Org Chem 74:3109–3115 49. Ma Z, Xiang Z, Luo T, Lu K, Xu Z, Chen J, Yang Z (2006) J Comb Chem 8:696–704 50. Paulvannan K (1999) Tetrahedron Lett 40:1851–1854 51. Kumagai N, Muncipinto G, Schreiber SL (2006) Angew Chem Int Ed 45:3635–3638 52. Galloway WRJD, Dia´z-Gavila´n M, Isidro-Llobet A, Spring DR (2009) Angew Chem Int Ed 48:1194–1196, and references therein 53. Luo T, Schreiber SL (2009) J Am Chem Soc 131:5667–5674 54. Uchida T, Rodriquez M, Schreiber SL (2009) Org Lett 11:1559–1562 55. Ganem B (2009) Acc Chem Res 42:463–472 56. Ugi I (1962) Angew Chem Int Ed 1:8–21 57. Xia Q, Ganem B (2002) Org Lett 4:1631–1634 58. Sun X, Janvier P, Zhao G, Bienayme´ H, Zhu J (2001) Org Lett 3:877–880 59. Wang Q, Xia Q, Ganem B (2003) Tetrahedron Lett 44:6825–6827 60. Elders N, Ruijter E, de Kanter FJJ, Janssen E, Lutz M, Spek AL, Orru RVA (2009) Chem Eur J 15:6096–6099 61. Diels O, Harms J (1936) Justus Liebigs Ann Chem 525:73–94 62. Huisgen R, Morikawa M, Herbig K, Brunn E (1967) Chem Ber 100:1094–1106 63. Nair V, Sreekanth AR, Abhilash N, Bhadbhade MM, Gonnade RC (2002) Org Lett 4:3575–3577 64. Nair V, Sreekanth AR, Biju AT, Rath NP (2003) Tetrahedron Lett 44:729–731 65. Nair V, Devi BR, Varma LR (2005) Tetrahedron Lett 46:5333–5335 66. Yavari I, Piltan M, Moradi L (2009) Tetrahedron 65:2067–2071 67. Yavari I, Hossaini Z, Sabbaghan M (2006) Tetrahedron Lett 47:6037–6040 68. Yavari I, Hossaini Z, Sabbaghan M, Ghazanfarpour-Darjani M (2007) Monatsh Chem 138:677–681 69. Yavari I, Ghazanfarpour-Darjani M, Sabbaghan M, Hossaini Z (2007) Tetrahedron Lett 48:3749–3751 70. Yadav JS, Subba Reddy BV, Yadav NN, Gupta MK, Sridhar B (2008) J Org Chem 73: 6857–6859 71. Alizadeh A, Zohreh N (2008) Helv Chim Acta 91:844–849 72. Yadav JS, Subba Reddy BV, Yadav NN, Gupta MK (2008) Tetrahedron Lett 49:2815–2819 73. Ghahremanzadeh R, Ahadi S, Sayyafi M, Bazgir A (2008) Tetrahedron Lett 49:4479–4482 74. Yavari I, Karimi E (2008) Tetrahedron Lett 49:6433–6436 75. Weber L (2005) In: Zhu J, Bienayme´ H (eds) Multicomponent reactions. Weinheim, Wiley-VCH, Chapter 10 and references therein 76. Mironov MA (2006) QSAR Comb Sci 25:423–431, and references therein

126

R. Scheffelaar et al.

77. 78. 79. 80. 81. 82. 83.

Shin WS, Lee K, Oh DY (1995) Tetrahedron Lett 36:281–282 Lee K, Oh DY (1991) Synthesis:213–214 Kiselyov AS (1995) Tetrahedron Lett 36:9297–9300 Kiselyov AS (2005) Tetrahedron Lett 46:1663–1665 Kiselyov AS, Smith LII (2006) Tetrahedron Lett 47:2611–2614 Kiselyov AS (2006) Tetrahedron Lett 47:2941–2944 Vugts DJ, Jansen H, Schmitz RF, de Kanter FJJ, Orru RVA (2003) Chem Commun: 2594–2595 Vugts DJ, Koningstein MM, Schmitz RF, de Kanter FJJ, Groen MB, Orru RVA (2006) Chem Eur J 12:7178–7189 Groenendaal B, Vugts DJ, Schmitz RF, de Kanter FJJ, Ruijter E, Groen MB, Orru RVA (2008) J Org Chem 73:719–722 Groenendaal B, Ruijter E, de Kanter FJJ, Lutz M, Spek AL, Orru RVA (2008) Org Biomol Chem 6:3158–3165 Glasnov TN, Vugts DJ, Koningstein MM, Desai B, Fabian WMF, Orru RVA, Kappe CO (2006) QSAR Comb Sci 25:509–518 Janvier P, Sun X, Bienayme´ H, Zhu J (2002) J Am Chem Soc 124:2560–2567 Janvier P, Bienayme´ H, Zhu J (2002) Angew Chem Int Ed 41:4291–4294 Chebanov VA, Saraev VE, Desenko SM, Chernenko VN, Knyazeva IV, Groth U, Glasnov TN, Kappe CO (2008) J Org Chem 73:5110–5118 Liu Y-K, Liu H, Du W, Yue L, Chen Y-C (2008) Chem Eur J 14:9873–9877 Grigg R (1987) Chem Soc Rev 16:89–121 Chebanov VA, Gura KA, Desenkol SM (2010) Top Heterocycl Chem 23:41–84 (and references cited therein) Mason T (1997) J Chem Soc Rev 26:443–451 Cravotto G, Cintas PJ (2006) Chem Soc Rev 35:180–196 Elders N, Schmitz RF, de Kanter FJJ, Ruijter E, Groen MB, Orru RVA (2007) J Org Chem 72:6135–6142 Elders N (2010) PhD thesis, Vrije Universiteit, Amsterdam Elders N, Ruijter E, de Kanter FJJ, Groen MB, Orru RVA (2008) Chem Eur J 14:4961–4973 Do¨mling A (2000) Curr Opin Chem Biol 4:318–323 Do¨mling A, Ugi I (1993) Angew Chem Int Ed 32:563–564 Do¨mling A, Herdtweck E, Ugi I (1998) Acta Chem Scan 52:107–113 Ugi I, Demharter A, Ho¨rl W, Schmid T (1996) Tetrahedron 52:11657–11664 Elders N, van der Born D, Hendrickx LJD, Timmer BJJ, Krause A, Janssen E, de Kanter FJJ, Ruijter E, Orru RVA (2009) Angew Chem Int Ed 48:5856–5859 Harriman GCB (1997) Tetrahedron Lett 38:5591–5594 Shaabani A, Maleki A, Moghimi-Rad J (2007) J Org Chem 72:6309–6311 El Kaı¨m L, Grimaud L, Oble J (2005) Angew Chem Int Ed 44:7961–7964 El Kaı¨m L, Gizolme M, Grimaud L, Oble J (2007) J Org Chem 72:4169–4180

84. 85. 86. 87. 88. 89. 90. 91. 92. 93. 94. 95. 96. 97. 98. 99. 100. 101. 102. 103. 104. 105. 106. 107.

Top Heterocycl Chem (2010) 25: 127–168 DOI: 10.1007/7081_2010_42 # Springer-Verlag Berlin Heidelberg 2010 Published online: 24 June 2010

Recent Developments in Reissert-Type Multicomponent Reactions Nicola Kielland and Rodolfo Lavilla

Abstract The chapter reviews the classic Reissert reaction, the keystone of a broad family of multicomponent reactions involving azines, electrophilic reagents and nucleophiles to yield N,a-disubstituted dihydroazine adducts. The first sections deal with the standard nucleophilic attack upon activated azines, including asymmetric transformations. Section 5 focuses on the generation of dipolar intermediates by azine activation, and on their subsequent transformation; chiefly in cycloadditions. Lastly, Sect. 6 is primarily devoted to a special branch of this chemistry involving isocyanides. It also covers the reactivity of dihydroazines and reviews the mechanistic proposals for related reactions.

Keywords Azines Isocyanides Multicomponent reactions Reissert reaction Contents 1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 128 2 Range of Activating Agents in Reissert-Type Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 132 3 Range of Nucleophiles in Reissert-Type Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 134 4 Asymmetric Reissert-Type Processes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 142 5 Dipole Formation and Domino Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 147 6 MCRs Involving Azines and Isocyanides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 152 7 Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 163 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 163

N. Kielland and R. Lavilla ð*Þ Barcelona Science Park, University of Barcelona, Baldiri Reixac 10-12, 08028 Barcelona, Spain e-mail: [email protected]

128

N. Kielland and R. Lavilla

Abbreviations 3CR 4CR Al2O3 Boc Boc2O Cbz CO2 DDQ DHP E FMOC HF IBX ICl KOH LDA MC m-CPBA MCR NMDA Nu O3 PINAP POCl3 TCAA Tf2O TFAA THF TMS-CN TMS-N3 TOSMIC

Three component reaction Four component reaction Alumina tert-Butoxycarbonyl Di-tert-butyl dicarbonate Carbobenzyloxy Carbon dioxide 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone Dihydropyridine Electrophile 9H-fluoren-9-ylmethoxycarbonyl Hydrogen fluoride 2-Iodoxybenzoic acid Iodine monochloride Potassium hydroxide Lithium diisopropylamide Multicomponent m-Chloroperoxybenzoic acid Multicomponent reaction N-methyl D-aspartate Nucleophile Ozone N-(alkyl(phenyl)methyl)-4-(2-(diphenylphosphino)naphthalen-1-yl) phthalazin-1-amine Phosphorus (V) oxychloride Trichloroacetic anhydride Triflic anhydride Trifluoroacetic anhydride Tetrahydrofuran Trimethylsilyl cyanide Trimethylsilyl azide p-Toluenesulfonylmethyl isocyanide

1 Introduction Multicomponent reactions (MCRs) have recently become a fruitful route to synthesizing diverse scaffolds in single-step operations [1, 2]. Perhaps the most attractive strategy in this field, and one which is widely employed, is the use of reactants bearing functional groups featuring complementary (ambivalent) reactivity: those

Recent Developments in Reissert-Type Multicomponent Reactions

129

which can interact with two or more distinct species. Isocyanides are the paradigmatic example of Type I MCR reagents (see Type I in Scheme 1). Their carbene-like electronic structure enables formal addition of nucleophilic and electrophilic partners, thereby leading to MCRs. Other functional groups display this behavior, and combinations of these constitute the core of a family of MCRs marked by high bond-forming efficiency and structural diversity [3]. Electron-deficient alkenes and alkynes have often been employed with this purpose in MCRs. Arynes, in which the nucleophile and the electrophile react at two contiguous positions, are another relevant group (Type II in Scheme 1). Imines, which have a nucleophilic nitrogen linked to an electrophilic carbon atom, are among the most used components in many classic MCRs and also participate in processes of this type. As such, azines could be regarded as heterocyclic surrogates of imines and thus, are a useful source of reactive inputs for this chemistry (Type III in Scheme 1, Reissert reactions in a broad sense). This is especially relevant, since nitrogen heterocycles are ubiquitous common motifs in natural products, drugs, and bioactive compounds; involving these species in MCRs has, therefore, important consequences in organic synthesis [4]. The interaction of the azine nitrogen with electrophiles is normally fast and could display a reversible nature, while the addition of a nucleophile at the position a of the activated heterocyclic system B implies the loss of aromaticity and is often the rate determining step of the reaction. The resulting substituted dihydroazines C display a rich reactivity, and may be subsequently transformed into a variety of heterocyclic systems D with diverse oxidation degrees [5, 6]. Alternatively, reaction of azines with several activating agents can generate azinium ylides E, species which can undergo [3þ2] cycloadditions with dipolarophiles (Scheme 2). In some cases the result of these combinations produces reactive intermediates, triggering complex cascade reactions [7]. This chemistry has enabled practical syntheses of alkaloids and heterocyclic structures as well as pilot scale production of major drugs and synthetic intermediates. Type Ι

Type ΙΙ

Nu +

Nu

–

R

R Nu

Carbene

R N E

E

E

R

R

Nu

Nu

E

E

Type ΙΙΙ E

R

N

N R Nu

N

E Nu

E Nu

Scheme 1 Examples of common complementary reactants used in MCRs

130

N. Kielland and R. Lavilla

In 1905, Arnold Reissert described the addition of cyanide to the a-position of a quinoline (1, Scheme 3) activated by an acylating agent [8–14]. The resulting substituted dihydroquinoline 2, generally called a Reissert compound, can be hydrolyzed with aqueous HCl to afford the quinoline-2-carboxylic acid 3 and an equivalent of the aldehyde, after spontaneous dismutation of the intermediate dihydroazine derivative. Reissert originally performed the reaction in aqueous media; however, under these conditions, the acid chlorides hydrolyze quickly. To overcome this limitation, in 1940, Woodward explored the reaction in sulfur dioxide, using several aromatic acyl chlorides [15, 16]. Later, Fischer extended the acyl chloride range to include aliphatic derivatives using benzene as solvent, demonstrating that hydrolysis of these adducts was a useful way to convert the acid chlorides used as activating agents into aldehydes [17–19]. Interestingly, reactions of Reissert compounds with aldehydes or ketones bring new synthetic possibilities (see Scheme 3). For instance, the nucleophilic a-amidonitrile moiety of the

+

R

E N

N

E+ Nu

N

+

base

B Cationic intermediates E N

–

E+

A

E Dipolar intermadiates R R N

Nu

R′′

Dihydroazine reactivity

C

R′

D R′′′

N Dihydroazine reactivity

X Y

C¢

Scheme 2 Azine activation modes

N O + R

N

1

+

Cl

2

O

R

+ R–CHO

H+ red

N

CN R1– CHO

3

R1 N

KCN Reissert Compound

CO2H

O O

R

4 H2 / Cat.

O

H N 5

Scheme 3 Reissert reactions and post-condensation transformations

N H

R

Recent Developments in Reissert-Type Multicomponent Reactions

131

dihydroquinoline 2 can attack the carbonyl of aldehydes or ketones to afford the substituted quinoline ester 4 (after an acyl shift and subsequent cyanide elimination) [20–23]. Alternatively, the catalytic hydrogenation of the Reissert adduct afforded the tetrahydroquinoline 5 with concomitant migration of the acyl group to the primary amine moiety [24]. Indeed, the chemistry and synthetic uses of the Reissert adducts have been covered in several reviews [25, 26]. Apart from quinolines, isoquinolines (Scheme 4a, b) are also excellent substrates, even when substituted at position 1 [27–29]. The group of Popp extensively explored the azine range of the Reissert reaction: 1-azapyrene, 2-azafluoranthene, diazaaromatic systems, benzimidazoles, quinazolines, and even the analogous oxygen system of 2-benzopyrylium salts, all of which made suitable substrates for this process [30–35]. More recently, Reissert compounds of imidazolium and imidazolinium salts have been employed to synthesize new carbene complexes [36]. Although pyridines do not afford the expected adduct under classic Reissert conditions, N-alkylpyridinium salts do work [37]. Similarly, carbonyl derivatives such as acetophenone 11 have been used as nucleophiles in a regioselective addition through the N-acylpyridinium salt intermediate, demonstrating that non-cyanide nucleophiles could be employed in Reissert-type reactions (Scheme 4c) [38].

a

CN O

N + R

6

b

+

O

N

KCN

Cl

R 7

R

R CN O N

O +

N

KCN

+ R

Cl

8

6a

c

R

O + Cl

N

O

10

O

+

N

O

4 months

12

25%

9

11

d +

N

O Cl

R

9

O

O 13 + Si

N

AlCl3

CN

15

Yields: 3-50%

N 14

O

R

Scheme 4 Isoquinolines and pyridines in Reissert reactions and related processes

132

N. Kielland and R. Lavilla R2

R R

R

+

N + 6b TMS-CN 14 Cl +

LDA N 16

NO2 PhNCO in situ Et3N (Cat.)

CN

R1 O

17

O

N

R

1

R

N

2. KOH

CN O

I

–

1.R2 C N O 19

18

20 O N

R1

R2

Overall yields 25-27%

Scheme 5 Solid-phase Reissert reaction

In 1987, Popp et al. described the first Reissert reaction with pyridine as substrate using TMS-CN (14), in the presence of a catalytic amount of aluminum chloride [39]. Further modifications included the use of diethylaluminiumcyanide and tri-n-butyltin cyanide as alternative cyanide sources (Scheme 4d) [29, 40, 41]. In 1996 the Kurth group described the first sold-phase Reissert reaction (Scheme 5) [42, 43]. Activation of a carboxylic acid functionalized resin to the corresponding acyl chloride, followed by treatment with isoquinoline and TMS-CN (14) afforded the resin-linked Reissert adduct 16. This intermediate was subsequently alkylated at the a-position by treatment with LDA and alkyl iodides 17. Some of these adducts were further manipulated, and finally the substituted isoquinolines 20 were conveniently released using a traceless cleavage with KOH/THF. This account reviews recent advances in Reissert-type transformations, focusing on the use of different reactants, asymmetric versions of the process, and also on dipole-related reactivity and on the participation of activated azines in isocyanideMCRs.

2 Range of Activating Agents in Reissert-Type Reactions Besides the classic Reissert process, a wide range of modifications have been described. Structural variations on each component have been extensively screened, and several approaches have been designed based on the interaction of azines, activating agents, and nucleophiles to yield substituted dihydroazines or related compounds. This chapter does not provide an exhaustive list of these many transformations; rather, it offers a general overview of the field (Scheme 6). Different types of activating agents have been employed in Reissert-related reactions (Scheme 6). In many cases, it is mandatory to generate, or even isolate, the corresponding azinium salt intermediate, and sequentially proceed with the nucleophilic addition. Moreover, since the former step often takes place selectively and at a fast rate, the transformation can be performed in a multicomponent manner without any functional group interference.

Recent Developments in Reissert-Type Multicomponent Reactions 22

R1 = Alk, Ar, silyl etc. N N

CO2Me

R

39

Nu

N

H R1

H

CO2Me

21 Cl

R

38

H

O R

CO2Me

9

N Si R R R

OMe

Tf2O 33

or

R

N 1

R

NC O

N Cl R 25 KCN

KCN

(RO)2P X

29 O R

Cl

32

30 Nu

N

N N

N P(OR)2 28 NC X

27

F

34 Tf

26

R N

+ Nu

N

31 i RSO2Cl ii base

Me2N

23 Cl

O

or N

6 36

O

KCN

CO2Me

R3SiOTf 35

O

O

N

CO2Me

Nu

Nu

N R

O

CO2Me

R1

24

O

CO2Me 37

133

CN

R

O

Scheme 6 Range of activating agents used in Reissert processes

Acid chlorides 21 and chloroformates 23 are the most commonly used activating agents and the preferred reagents for evaluating the reactivity of other components in new Reissert-type processes. For example, in studies on the total synthesis of the indolopyridine alkaloids 42, acetyl chloride was used in the key step to prepare the common synthetic intermediate 41. In this case, an enamide moiety intramolecularly attacks the in situ generated N-acylazinium salt, and the Reissert adduct is spontaneously oxidized and hydrolyzed to regain aromaticity in the last step (Scheme 7) [44, 45]. N,N-dialkyl- or diaryl-carbamoyl chlorides 25 are far less frequently used in this chemistry, although they were successfully employed by Popp in a Reissert-related process [28]. This group also investigated the use of chlorophosphates and chlorothiophosphates 27 as activating agents. The resulting Reissert analogs can be converted by base treatment into anions that can be alkylated or undergo elimination to isoquinaldonitrile [46]. Interestingly, acid fluorides have also been used [47]. Reissert compounds arising from sulfonyl chlorides are often unstable; however, the corresponding 2-substituted azines 32 can be obtained by treating the crude product of these reactions with a mild base [48]. Triflic anhydride (33) has been successfully used for promoting the incorporation of less reactive nucleophiles. The Corey group

134

N. Kielland and R. Lavilla

N

O

O

O

N

N AcCl

N H

N DCM 40

N H

N H

N Ac O

N H

84%

Pd chemistry

N Indolopyridine Alkaloids

41

Br

Br

Br

N

N

42

R

Scheme 7 Synthesis of indolopyridine alkaloids based on a Reissert-type process

O Cl Cl O +

CO2Me H2N

9 +

43

N

O

N

MW N

O

O

O

NH

N O

N

44

CO2Me

O

Scheme 8 Reissert-type cascade promoted by an activated double bond

used this activating agent in a direct arylation of pyridines that did not require an organometallic species [49]. The bulky trialkylsilyloxytriflates 35 have been used to activate pyridines in the presence of Grignard reagents: they protect the a-position of the azine, thereby leading to g-regioselective nucleophilic attack. Additional examples of these activating agents are discussed in the following sections of this chapter. Substituted alkynes such as 38 (normally with electronwithdrawing groups) constitute a common class of activating agents. They interact with azines to form dipoles that can react in cycloadditions (see Sect. 5). However, in some cases, the anion moiety can trap a proton, generating an azinium species, which then enables subsequent nucleophilic addition. For instance, adducts 37 and 39 (Scheme 6) have been obtained by using a terminal alkyne as the nucleophile, in reactions catalyzed by copper or gold chlorides [50, 51]. Appropriately substituted p-acceptors such as 43 can also activate azines, through addition–elimination processes, consequently promoting cascade reactions based on Reissert chemistry (Scheme 8)[52].

3 Range of Nucleophiles in Reissert-Type Reactions The range of nucleophiles used in these processes is very wide (Scheme 9). Although alcohols and amines cannot be directly used – as they would quickly trap the electrophilic partner, and therefore, bypass the intervention of the azine – the literature does contain a few examples of sequential use of these compounds.

Recent Developments in Reissert-Type Multicomponent Reactions

N

N Tf 60

45

CO2t-Bu

CO2R

Ot-Bu

N

O

(Boc)2O RO2C

Tf2O 33

O

Ph 47

CO2R

Ph 46 NH

57

O

O

Bu

X

O

O

9

Bu

58

or N

N

33 Tf2O

N

1

Tf

EtOOC CO2R R4

NH

ROCOCl

CO2R N 54 EtOOC

48 49 H

N

P(OR)2

R1

O

R2 = CO2R, CO2R

CO2R

COOEt

O

R1 = Tf, CO2R

51

56 R4 = H, CO2R

R

N

50

ROCOCl or CO2R

RO2C N

O (RO)2P

N

53 EtOOC

N

ROCOCl or 33 Tf2O

6 R4

N RCOX

9

or 55 MeNO2

O2N

N

CO2R

CO2

59

MeS

MeS

135

N 52

R2

RO2C NH

Scheme 9 Range of nucleophiles used in Reissert-type reactions

This entails preformation of the activated azinium ion and subsequent reaction of the nucleophile to generate the desired adduct [53–56]. In this regard, an interesting possibility is the use of symmetric carbonates. For example, the dihydroisoquinoline 45 (Scheme 9) was synthesized using this strategy. The nucleophilic alkoxide is released during the interaction between the azine and Boc2O with loss of CO2. Adduct 45 is an efficient tert-butoxycarbonylation reagent for phenols, aromatic and aliphatic amines in the absence of bases under mild conditions [57, 58]. Even poor nucleophiles such as the amides 46 can react with azines in the presence of alkynes as activating agents [59, 60]. Various nucleophiles (including alkoxides, thiols, amines and nitrogen heterocycles) were recently employed in a related process with N-oxide azaindoles (Reissert–Henze reaction, Scheme 10). In the process, the oxygen is alkylated with dimethyl sulfate and, after the nucleophilic attack, methanol is released to aromatize the initial adduct [61, 62]. Following similar mechanistic trends, N-heteroatom-activated azines afford the corresponding substituted adducts. Likewise, N-tosylated isoquinoline [63, 64] and N-fluoropyridinium salts [65] are also reactive substrates in Reissert–Henze type processes.

136

N. Kielland and R. Lavilla

Cl (MeO)2SO2 +

O

N O–

O

N H

Nu

Nu, Base (MeO)2SO2

H

Nu +

N O

Nu

N H

H

N H

N O

Nu: cyanide alkoxydes thiolates azoles ammonia –MeOH primary amines secondary amines amino acids Yields: 50-90% aminoalcohols N H

N

Scheme 10 Nucleophiles used in the Reissert–Henze reaction

a

CN

CN Ar

CN ClCH2CN + Ar-CHO + 61

b

+

+ CN 62

N

Ar

9

N N

64 Ar

+

N+

Cl–

9

Ar

NH2 CN 63

61 ClCH2CN N

CN

Ar

CN

NC

N+ Pyr Pyr+H

NC

N

CN

–

Ar

CN

65

Ar-CHO +

NC

CN

NC

CN CN

NC Ar –

66

Pyr

CN

Pyr+H

CN 62 CN

CN Ar

CN

CN

Ar

Ar CN

Ar

–

Ar

N

CN CN

NC

–

Ar

NC CN

Ar

–

CN

N

NC

Ar

Ar

CN

Ar

N–

CN NH2 CN 63

NC N+

CN

CN

CN Ar

CN CN

NC CN Pyr

CN

–

Reissert-type process

Ar

NC

N N

CN

Ar

CN

Ar

–HCN –2H

Ar

N N

64

67

Scheme 11 Cascade process terminating with a with Reissert-type reaction

In a chemodifferentiating ABB’ process [66], King and coworkers characterized the adduct 48, arising from the nucleophilic attack by pyridine upon an N-acylpyridinium intermediate (Scheme 9) [67]. The Yan group described an impressive cascade reaction involving chloroacetonitrile (61), malononitrile (62), aromatic aldehydes and pyridine (9, Scheme 11a). Alkylation and Knoevenagel-type reactions are suitably engaged with conjugate additions, cyclopropane ring formation and subsequent ring-opening to finish with an intramolecular Reissert-type reaction, leading to the complex heterocyclic system 64 (Scheme 11b). The different roles played by pyridine in this sequence are noteworthy [68].

Recent Developments in Reissert-Type Multicomponent Reactions

137

a R

R1COCl

R N

P(OMe)3

1

68

N PO(OMe)2 COR1

1 O3 2 Base

R

CHO N COR1

69

b O + 1

N 51 H

N

c

+ Me

O 71

O

N H

N 70

N

N +

R

N+ O R

N H

O

Ph Ph O 73 OH

RHNOC MeOC

COPh 72

PhOC

NH

N Me

6

+ +

H2N

POCl3 Me

–

H COPh

N

COPh Me

74

R

H N

COPh COPh Me 75

O

O

Scheme 12 Phospho- and carbo-Reissert-type processes

Dialkyl phosphites such as 49 (Scheme 9) have been reacted as nucleophiles with activated pyridines [69, 70]. The first examples of this chemistry involved either N-alkyl-pyridinium salts in the presence of DDQ, or pyridine and terminal alkynes as activating agents in a one-step protocol. The reaction proceeds under mild conditions that include Al2O3 catalysis. Quinolines 1 and chloroformates afford the expected adducts 68. The latter structures can be easily oxidized with O3 to provide the substituted indoles 69 (Scheme 12a). Isoquinolinephosphonates obtained this way have been used in Wittig–Horner chemistry. The whole sequence offers ready access to alkyl substituted isoquinolines [71]. Analogously, silyl substituents have been introduced into N-acylated pyridines by using silylcuprates [72]. Several classes of carbon nucleophiles have been successfully used in these systems, reflecting the utility of Reissert chemistry for derivatizing azines via carbon–carbon bond formation. Apart from cyanide anion, other classes of carbon nucleophiles have been explored. For instance, addition of indole (51) to N-acylazinium salts proceeds selectively at the a-position (Scheme 9). Pyrrole, quinolines and isoquinolines all behave similarly [73–76]. A related reaction, yielding adduct 70 (Scheme 12b) has also been described. In this case, azine activation is promoted by Vilsmeier reagents (generated by reaction of amides with POCl3) [77]. b-Dicarbonyls are reactive inputs in this chemistry, and dialkyl malonates 53

138

N. Kielland and R. Lavilla

have been added to quinolines and isoquinolines in the presence of chloroformates [78]. In a related 4CR (Scheme 12c), the dicarbonyl 74 is first generated in situ by interaction of diketene 71 and a primary amine, then reacts with an isoquinoline dipole (presumably via proton transfer and nucleophilic addition) to give intermediate 75, which by intramolecular addition of the acidic methine, provides the final adduct 73 [79, 80]. Nitroalkanes 55, (Scheme 9) are also reactive as carbon nucleophiles in Reissert-type processes [81, 82]. Use of stronger activating agents such as triflic anhydride (33) enables functionalization of pyridines with electronrich aromatic rings, as well as azulene derivatives (59), pyrroles, allylstannanes, and even substituted ketones 57 [49, 83, 84]. Allyl groups can be easily attached to azines through the standard activationnucleophilic attack approach. Quinoline (or isoquinoline) smoothly reacts with chloroformate and allylsilanes (76) in the presence of iodine or triflate catalysts (Scheme 13). Using two equivalents of silane reagent in the isoquinoline reaction, gives adduct 79 [85–87]. Triallylborane 80 reacts both as activating agent and nucleophile. Interestingly, due to the lability of the N–B bond, the process leads to N–H derivatives, ready for further derivatization. A noteworthy transformation is the double allylation of pyridines by triallylboron 80 leading to the tetrahydropyridine derivative 81.

77 N 94

92

N E R

R R

N

MeO2C

R

O

81

80 3B

O O

ROCOCl

Me 93

Et

CO2R

SiMe3

ROCOCl

O

N

or 76

Me3Si

79

CO2R

76

O

Me3Si

N

SiMe3

Et

Me

78

N CO2R

N H

or OTBS 91

N

1 N

9

R l or COC N 1. RO 89 OMe 6 SiMe3 2. O OMe ROCOCl ROCOCl O R187 3. DDQ (i-PrO)3Ti OSiMe3 90 R2 O EtO O 85 R2 Me3SiO R1 OH CO2R N OEt 88 N CO2R

O

1. RLi 2. (All)3B 80 83 ROCOCl

82 N H

SnBu3 84 N CO2R

86

Scheme 13 Activated alkenes and related species as nucleophiles in Reissert chemistry

R

Recent Developments in Reissert-Type Multicomponent Reactions

139

a 80 N

3B

3B

N

80

B 9

95

b

N H

81

N H

H2O, OH –, Δ

96

3B

80

RLi N

N 9

R

Li

N

R one pot

All3B

N H

R 97

Scheme 14 Allylboration of pyridine

After coordination with the azine nitrogen, the activated complex 95 (Scheme 14a) undergoes a stereoselective diallylation to afford the trans-2,6-diallyl-tetrahydropyridine (81). Furthermore, 81 can be transformed into its cis-isomer (96) by heating. Isomerization can also occur at a dihydropyridine (DHP) intermediate following incorporation of an alkyl group via organometallic attack upon a pyridine in a one-pot transformation (Scheme 14b) [88–90]. An alternative method for allylating pyridines entails use of the corresponding organometallic reagents. For example, allyltin derivatives (83, Scheme 13) offer good yields and regioselectivity [91]. Moreover, interaction of chiral ligands of bisoxazoline type with allylzinc derivatives and N-acylpyridinium salts enables selective transformations, although with poor enantiomeric excesses [92]. A variety of enol derivatives have been used as functionalized nucleophiles in these processes, including titanium- and silicon-enolates 85 [93]. Addition of the ketene silyl acetal 89 to quaternized methyl nicotinate, followed by oxidation with DDQ, yields the g-substituted pyridine 90, an advanced intermediate in the total synthesis of ()-sesbanine (Scheme 13) [94, 95]. Reaction of isoquinolines, silyloxyfurans 91 and activating agents have yielded diverse isoquinolinobutyrolactones with excellent diastereoselectivity, even for a-substituted azine substrates (Scheme 13). Furthermore, use of a chiral auxiliary has enabled formation of single stereoisomers in excellent yields [96]. The Rudler and Langer groups have developed this approach by using 1,1-bis(trimethylsilyloxy)ketene acetals 87 [97]. This versatile reactant can promote further bond-forming events, as the resulting carboxylic acid moiety may react as a nucleophile, trapping the iminium ion generated from the dihydroazine upon interaction with an external electrophile. The sequential addition–lactonization process can be induced by halogens or epoxidizing agents (Scheme 15a). Several azines (e.g., pyrazines and isoquinoline) react under these conditions to afford d- or g-lactones, thereby reflecting the generality of the methodology (Scheme 15b, c) [98–106]. Charette recently described an innovative activation protocol in which lactams, in the presence of triflic anhydride (33), react with pyridines to afford the pyridinium imidate 107 in good yield. Subsequent addition of metal enolates to this species leads to 2-substituted tricyclic dihydropyridines, advanced intermediates for the total synthesis of the natural alkaloid ()-tetraponerine T4 (109, Scheme 16) [107].

140

N. Kielland and R. Lavilla

a R1

R2 O I

R1 R2

O

OSiMe3 R2

87 OSiMe3

R1

+ ClCOOMe +

O

I2 OH

R 88 N COOMe

R

N

N COOMe

b

R1

HO

Ph N COOMe

87 OSiMe3 + ClCOOMe

+ n-Bu

6

R1

N

O

O

O

N+ Ph COOMe

N Ph 100 COOMe

103 +

R2 O

102

N

Me Me O

O

OSiMe3 2

101

c

Me

HO

H+

O

R

N

Me O

MeOOC

+

N

Me

Me

m-CPBA

R = Ph R1 = R2 = Me

98

99

R=H

O N COOMe

OSiMe3

I

OSiMe3

R

H N H 104 n-Bu

ClCOOMe

I2

COOMe

N

O

H

COOH

105 O

R = CO2Me

n-Bu

Scheme 15 Sequential Reissert–lactonization processes O OMet NH + 9

N

106 + 33

TfO– +

N Tf2O

–

108

TfO

N +

N

N 107 one pot

OH

1. hydrogenation 2. reduction

H H

N

H N 109 tetraponerine T4

Scheme 16 Charette’s activation protocol

Besides lithium, zinc and tin derivatives (see Scheme 13), other types of organometallic reagents have been used as nucleophiles in related processes (Scheme 17). Yoon described a 3CR, resembling a Petasis process, in which isoquinolines or quinolines are reacted with activating agents and boronic acids to yield the expected a-arylated dihydroazines 111 [108]. Azines have been benzylated via the corresponding organostannanes [91, 109, 110], and alkylated or arylated via the organocuprate precursors [111–113]. Vinylation of isoquinolines or quinolines with alkenylzirconocene chlorides 116 proceeds in excellent yields. Interestingly, an analogous reaction of a reduced derivative, catalyzed by a copper (I) salt in the presence of a chiral amine ligand, furnishes the corresponding adduct 117 in an enantioselective manner. (Scheme 17) [114].

Recent Developments in Reissert-Type Multicomponent Reactions

Si(i -Pr)3 N [A] =

O

N

Si(i -Pr)3 N

+

111

141

CO2R B(OH)2

TfO– Ph

(i -Pr)3SiOTf 128 BnMgBr 129

Bn Ph 130

N

O 110

A ROCOCl

R 125 t-BuMe2SiOTf 126 RMgBr / O2

127

112

Ph

115 N R(CH2)nCu(CN) ZnI S8

1. 2.

or N

123 MgCl

N

1

9

ROCOCl

6

N

RLi

[B] preformed

119 Et2Zn CuCN·2LiBr ROCOCl

CO2R

ZrCp2 Cl

N

124

114

116

Ph or

E

(CH2)nR

R

N

N

113

EtO2C

R

SnMe3

Ph

ROCOCl SnMe3

CO2Et

CO2R

117

PhCOCl Ph [B] =

N

N 122

CO2R R

ratio 30:70

CO2R R 121

Bu

N

Et Ph 120

O

118

N+ i-Bu

Al–

i-Bu

Bu

N CO2R

Scheme 17 Organometallic addition to activated azines

In a related process, pyridines, vinyl alanes, and acid chlorides are reacted to afford the MC adduct 118 [115]. Also, reaction of pyridines, chloroformates, and organozinc reagents proceeds with high yields and regioselectivity in position g [116]. Organolithium compounds are also useful nucleophiles, reacting with activated azine derivatives under standard conditions. In this respect, Clayden has developed remarkably elegant cyclizations of N-benzylpyridine- and quinolinecarboxamides, promoting the in situ formation of the carbanion (by deprotonation with a base) with subsequent azine activation with chloroformates (Scheme 18a) [117]. This route provides ready access to the spiro b-lactam system 133. Sequential reaction of azines with alkyl lithium compounds and chloroformates usually affords the expected Reissert-type products 136, together with minor amounts of doubly acylated compounds 135 (Scheme 18b). Isoquinoline is likely to react directly with the alkyl-lithium compound to generate the alkylated lithioenamine intermediate E, and this species may account for the formation of dihydroisoquinolines 135 and 136, through interaction with the electrophilic partner. Mamane recently expanded this concept by replacing the acylating agent with different electrophiles. These combinations lead exclusively to isomers 134 (Scheme 18) [118–120].

142

N. Kielland and R. Lavilla

a

O

O N N

b

t Bu Ph

N LDA

131

N

O

O

Li

tBu

ClCO2Me

Ph

–

Cl

MeO2C

N N +

Li

tBu

MeO2C N

N

Ph 133

132

t Bu

Ph

E RLi

EX

NLi

N

N R

6

CO2Me

N R

C-Acylation

134

E

R

N-Acylation CO2Me

ClCO2Me

N 135 R

+

N

CO2Me ratio 30:70

R

CO2Me

136

Scheme 18 Reaction of organolithium compounds with azines and electrophiles

Grignard reagents also have been explored as nucleophiles in these types of processes. The regioselectivity of the addition of these reagents to acylated pyridines strongly depends on the substrates [121]. However, the nucleophilic attack can be directed to the g-position by using a stoichiometric organocuprate derivative or catalytically, with small amounts of copper iodide. Alternatively, the attack can be guided to the a-position by blocking the g-site with a bulky substituent, regioselectively providing adduct 124 (Scheme 17) [122, 123]. To improve the poor regioselectivity often observed in nucleophilic additions of organometallics to pyridinium salts, the Akira group employed tert-butyldimethylsilyl triflate 125 as activating agent (Scheme 17). This bulky reagent efficiently protects the a-positions of the pyridine ring, and consequently, the Grignard reagent selectively attacks the g-position. Furthermore, the silyl group can be easily removed, and oxidation of the dihydropyridine adduct smoothly regenerates the aromatic azine nucleus. Directed substitution has also been investigated in quinolines. Although this reaction is considerably more challenging, Mani achieved a 60:40 ratio of g-substituted to a-substituted product [124]. More recently, Wanner had success with g-substituted pyridines, obtaining even in these cases the corresponding adducts with excellent g-regioselectivity [125].

4 Asymmetric Reissert-Type Processes The need of enantiopure compounds has fuelled the development of asymmetric transformations in this field. This is especially challenging due to the mechanistic complexity of MCRs and to the lability of the dihydroazine moieties of the final adducts. Nevertheless, significant progress has been reported in the area. Shibasaki

Recent Developments in Reissert-Type Multicomponent Reactions

143

a Z O

137

O

+ RCOCl

Ar Ar P

Al Cl

O N O

Z

N

+

2

N 1

Si

O R

O Al

CN O

+

R

Cl P(O)Ar2

Z = PO(Ar)2

N

Si CN

Yield: 74-91% ee: 85-89%

14

b

Me

+ RCO2Cl

1

R

Chiral ligand

1

5% CuCI 5.5% chiral L

N

139

N

+ N

3

R

i Pr2NEt

H

N CO2R

2

R

3

Ph

HN

R

MeO

PPh2

138 Yield: 72-92% ee: 70-84%

c

Catalyst 10% mol

t Bu S

1.TrocCl N 6

2.

OTBS

140

OMe 3. NaOMe (quench)

NTroc 141 Yield: 55% ee: 85% CO2Me

i-Bu2N O 142

N H

N H Me

N

Ph

Scheme 19 Catalytic enantioselective Reissert-type processes

recently described the first catalytic enantioselective Reissert reactions of quinolines (and isoquinolines) using the bifunctional aluminum catalyst 137 (Scheme 19a). The Lewis acidic and basic sites of the catalyst are critical for its coordination to the N-acylazinium salt and for directing the nucleophile with facial selectivity. In this manner, excellent yields and enantioselectivities of the desired Reissert adducts were obtained [126–129]. This process allowed the preparation of a potent NMDA receptor antagonist [130]. A few years later, an analogous catalyst was used to promote the first enantioselective Reissert reaction of pyridine derivatives [131]. Arndtsen recently described the copper catalyzed reaction of pyridines or quinolines with terminal alkynes and acylating agents to yield the dihydroazine adducts 138. Several chiral ligands were analyzed, and the best results were obtained with the PINAP derivative 139, reaching enantiomeric excesses greater than 80% with excellent chemical yields (Scheme 19b) [132]. In this context, Feringa et al. recently described the catalytic enantioselective addition of dialkylzinc reagents to 4-methoxypyridine [133]. Moreover, thiourea organocatalyst 142 has enabled enantioselective addition of silyl enol esters to activated N-acylisoquinolinum salts, conveniently providing the corresponding adduct 141 (Scheme 19c) [134]. In a different approach, chiral auxiliaries have been widely used in Reissert-type chemistry to provide practical access to enantiopure addition adducts. For example, the stereoselective addition of cyanide to isoquinoline or quinoline with a modified

144

N. Kielland and R. Lavilla

a TfO–

TfO– ON

Re N+

PPh3

ON R

RMgCl

Re N

Re

PPh3 R′OTf

NaBH4 R′

–

R′ 143

+ CN

145

144 Yield: 77-96% de: 70-88%

Yield: 72-83 % de: 88 %

Re PPh3 ON recyclable CN

b H

Chiral Auxiliary

O 147

X 148

N

O

N CO2Me 151

Yield: 90% de: 84%

H

Et

Et

150

Chiral Auxiliary

N CO2Me

O

SnBu3

146 Yield: 91% de: 88%

HCl 5% O

X

149 N Yield: 80-90% CO Me 2 de: 80-90%

N

c R

X

ClCO2Me Et2CuLi

X

H N

R

ON N PPh3 R +

H N

Ph

N H

Ph

O Br N

83 152

N

O

Bn

ClCO2Me

R

153 In

N CO2Me 154

Yield: 82% de: 84%

Scheme 20 Chiral auxiliaries linked to the azine moiety

Evan’s-type chiral oxazolidinone as the activating agent has been described [135]. Gladysz reported coordination of the azine nitrogen to a chiral metal complex as an efficient tool for activating the azine and promoting the diastereoselective addition of a Grignard reagent (Scheme 20a) [136, 137]. Pyridine carboxyaldehyde (147) has been used as the azine input in asymmetric processes; its condensation with chiral diols or diamines affords the chirally modified pyridine derivatives 148, which can be activated for stereoselective addition. The synthetic sequence ends with hydrolytic removal of the auxiliary (Scheme 20b) [111]. Yamada reported a regio- and diastereo-selective process to prepare enantiopure a- and g-substituted addition adducts based on the use of a chiral oxazolidine linked to the nicotinic moiety involving either the allyl tin derivative 83 (which leads to attack at the more reactive a-sites) or an allyl indium reagent (which affords the g-substituted isomers 154), both of which offer good diastereomeric excess (Scheme 20c) [138, 139]. In a different context, chiral reagents have been implemented in this chemistry. For instance, Liebscher and Itho developed the use of chiral acylating agents such as amino acid-fluorides 158 and -chlorides 156, respectively, (Scheme 21). The outcome of the reaction of isoquinoline (6), TMS-CN (14) and N-protected a-amino acid fluorides is dictated by the nature of the protecting group: whereas Cbz- and

Recent Developments in Reissert-Type Multicomponent Reactions

145

NO2 NO2

HN N O2S

Me N O

O

N H

SO2

R

156 NH O

Me

O

NH

F

Alk

F–

158

Cl

155

HN N

N OSiMe3

MeO OMe

CN

MeO OMe

157

6

14 AlCl3

N

159

Alk O

160 Yield: 44-89% de: 70-95%

1

R

+

Si

R

Cbz

O N H ArO2S Yield: 47% de: 95%

O

N Alk 161

Scheme 21 Acid fluorides and chlorides in asymmetric Reissert-type processes

FMOC-protected amino acid fluorides afford the expected Reissert adducts 160 with a good stereoselectivities, the a-sulfonylamino acid fluorides undergo cyclization to adduct 161 [47, 140, 141]. Itho’s protocol is amenable to using silyl enol ethers 157 as nucleophiles [142]. Gibson has used bulky asymmetric acid chlorides as substrates in a Reissert reaction with TMS-CN; the corresponding Reissert compound was then treated with aldehydes and sodium hydride to obtain the enantiopure adducts 4 (Scheme 3) [143]. An area that deserves special attention is the Comins methodology, which exploits the reactivity of p-methoxypyridine (162) in Reissert-type reactions (Scheme 22). This powerful and versatile synthetic approach represents an important tool for the preparation of natural products [144, 145]. The activation-nucleophilic addition protocol generates N-substituted-tetrahydropyridones, arising from the hydrolysis of the enol ether moiety of the initial adduct. This strategy was employed to prepare ()-lasubine II (163) in three steps, using a Grignard reagent as nucleophile in the Reissert-type reaction (Scheme 22a) [146]. Chiral chloroformates provide the corresponding enantiopure adducts, which are versatile building blocks for the synthesis of alkaloids belonging to different groups. In this way, p-methoxypyridines can be further functionalized; the use of activating agents such as (+)-trans-2-(R-cumyl)cyclohexyl chloroformate can direct the attack of organometallic species to afford the expected adducts with good diastereomeric excesses. (+)-Hyperaspine (165) was obtained in six steps using this strategy (Scheme 22b) [147]. Charette recently published an asymmetric version of a protocol using a chiral amide-derived activating group (Scheme 22c). First, 4-methoxypyridine (162) was reacted with triflic anhydride (33) and the chiral amide 166 to generate in situ the salt 167. Subsequent addition of a Grignard reagent yielded the tetrahydropyridone 168, which is an advanced intermediate in the total synthesis of (-)-barrenazines A and B (169) [148, 149]. Incidentally, although in a different context, this Reissert-type chemistry has also been done on solid phase. In this regard, Munoz loaded a 4-hydroxypyridine

146

N. Kielland and R. Lavilla

a

OH

O

OMe

3 steps

PhCH2OCOCl OMe 3, 4-(MeO)2PhMgBr

N

CO2Bz

75%

162

b

OZnCl

OMe

H+

164 CO R* 2

OMe

O

OMe

+ 33 Tf2O N N + 162 O DCM N –78°C to rt Ph Ph NH OMe

166

O

N

(+)-hyperaspine 165 21% overall yield

Bu

O –

OTf

Yield: 65-85% de: 83-95% 1. RMgX 2. H3O+

N Ph

OMe 168

R NH

N

R

N

OMe

167

N

HN

R

169 (-)-barrenazine A and B

d

O ClCOR

+

N

O

O

1. RMgX

R

2. H2O

N

O

170

e

H N

O

H

N

R* = (+)-trans-2-(R-cumyl)cyclohexyl

c

Me

Yield: 72% CO2R* de: 93%

Me

OMe

5 steps

SiR3

O

Cl

163

O

–

+

N

OMe

OMe

SiR3

(+/–)-lasubine II 28% overall yield

N

N

Cl–

171 R

O

+

N O

OMe

1. RMgX 2. H3O+

HN

O

R

172

N

R O

Scheme 22 Use of 4-methoxypyridines in activation–addition protocols

onto a Wang resin, and then reacted the resulting solid-supported pyridine 170 with acid chlorides and Grignard reagents to obtain the N-acyl-2-substituted-tetrahydro4-pyridones 171, which were isolated after cleavage under mild acidic conditions (Scheme 22d). A synthetic variant in which the 4-methoxypyridine is activated by the resin, produces the final adduct 172, released as the corresponding N–H pyridone derivative (Scheme 22e) [150–154]. Coordinating groups have been introduced in the chiral activating agent, to direct the attack of the organometallic reagents. Charette has shown that the ether moiety in adduct 175 can coordinate with the Mg atom of a Grignard compound, and thereby guide the nucleophilic attack to one face of the azine (Scheme 23a) [155, 156]. Finally, the chirality can be directly transmitted from the nucleophile. Yamaguchi successfully employed this approach, using the chiral allylsilane 176 to prepare enantioenriched dihydroisoquinoline 178 (Scheme 23b) [157].

Recent Developments in Reissert-Type Multicomponent Reactions

147

a Aux

1. Tf2O, 2-ClPyr 2. R1MgX

H N

MeO

N

R1

N O 173

174

NAux

Tf2O, 2-ClPyr TfO– TfO–

N+

R1 N Mg X O Me

N

MeO 175

b

ClCO2Ph +

AgOTf

H , Pd / C * N CO Ph 2 2

N 6

+ Ph

SiMe3

+

N

177

Ph

H 176

* N CO Ph 2 178

Ph

yield 83% ee 59%

Scheme 23 Use of coordinating chiral auxiliaries and chiral nucleophiles

In summary, a wide variety of methods are available to prepare enantiopure Reissert-type adducts. Depending on the synthetic requirements, the use of chiral auxiliaries, enantioselective catalysis or chiral reagents may be the most suitable option.

5 Dipole Formation and Domino Reactions Dipoles enable a rich variety of transformations, with a considerable impact in organic synthesis; among them dipolar cycloadditions are especially productive. In some cases, complex domino reactions, processes in which the product of one elemental step is the reactant of the next one, are the result of apparently simple combinations. When the reaction of an azine with activating agents involves the conjugate addition of a Michael acceptor or related species, a dipole is generated. Huisgen’s systematic studies on dipolar cycloadditions include several reactions of this kind [158, 159]. The dipolar intermediates can react with other complementary partners, typically in concerted processes, or can trigger complex domino reactions. The most widely used activating agents for this chemistry are substituted alkynes (Scheme 24).

148

N. Kielland and R. Lavilla

Nu N

+ R

E N Nu

N

R

+

R

R

Nu

–

R

E

R

E

Scheme 24 Dipole formation from reactions of azines and substituted alkynes

N

O

MeO2C N MeO2C 196

CO2Me

MeO2C

CO2Me CO2Me MeO2C

N

CF3

180

MeOOC MeOOC S

O 38

182

CO2Me

O

CO2Me

CF3

N N MeO2C CO2Me 195 CO Me 2

or N

1 N or +

N

N N

181 O

S

MeO2C N N 193 CO2Me CO2Me

9

N

6

RO2C

NC

O

S

179 N

S

O

N MeOOC MeOOC O 184 O N H 183

NH

O 185

O

N

NC

Ph N 189 C O

191 CN

CN CN CN MeO2C CN 192 CO2Me

O

CO2R

CN

MeO2C CO2Me 194 CO2Me

O

187

O

COOMe

N Ts

COOMe

186 O

N

N N MeO2C

N

Ph

Ts

N

COOMe COOMe

O

190 CO2Me

188

Scheme 25 MCRs involving dipolar intermediates

Scheme 25 shows representative examples of various chemotypes that can be generated with this simple and efficient strategy. Practically, all common azines and Michael acceptors react in these processes, and the range of the third component is also extremely wide. Aldehydes (such as 179), ketones and a-dicarbonyls (such as 181) afford the expected products in good yields; moreover, the cyclic carbonyl derivatives 183 and 185 lead to spiro-polyheterocycles 184 and 186, respectively [160]. Interestingly, activated imines (such as 187) are also reactive, which naturally

Recent Developments in Reissert-Type Multicomponent Reactions

149

leads to 4CRs involving azines, alkynes, aldehydes, and amines. Isocyanates 189 yield the cyclic amides 190. Tetracyanoethylene 191 is another good substrate, affording the highly substituted quinolizine 192 in a single step [161–170]. The reaction with azodicarboxylates 193 has been described by Huisgen in his comprehensive review [158, 159]. In the absence of a third component, two equivalents of alkyne can react to form adduct 196 in a chemodifferentiating ABB’ process [66]. This historically relevant reaction was reported in a review by Krohnke in 1953 [171]. The Mironov group recently described an innovative approach for a combinatorial search for new MCRs based on this rationale, which enabled then to discover novel mechanistically related processes [172]. In this context, the Ma group described interesting related reactions involving other kinds of N-heterocycles [173, 174]. Modified versions of these reactions also have been described. Particularly attractive are the processes in which some of the components are linked. For instance, 4-hydroxybut-2-ynenitrile (197, Scheme 26a) contains both the activating alkyne moiety and the nucleophilic alcohol: thus, once the dipole is generated, a proton shift gives raise to the alkoxide anion ready to trap the azinium ion in an intramolecular manner to yield adduct 198 [175–178]. Similarly, an enolate (derived from the reaction of Michael acceptor 199 and pyridine) can trap the intermediate azinium moiety, to afford the quinolizidine ring system 200. Interestingly, subtle changes in the substitution pattern of the reactive inputs can completely modify the reaction pathway. For instance, a tosyl group at the nitrogen

a

R2 R1 OH

+

CN 197

+

+

N

N R1

NC –

1 N

N R

H N

9 CO2t-Bu

+

R1

R2

H N

Boc

200 R

or

a R: Boc

b R: Ts

a +

C

CO2t-Bu

N

b –O

Scheme 26 Dipolar processes with bifunctional substrates

N Ts 201

CO2t-Bu

NH

R NH

–O

CO2t-Bu

O

O

N+

R1 198

O

N 199

O R2

NC

2 HO R

b

N

–

O

NC

CO2t-Bu

150

N. Kielland and R. Lavilla

a 1 N + MeO2C +

R

38

CO2Me

R

OEt

O –

O 202

O

H

MeO2C

MeO2C

MeO2C

OEt O

O

COR

CO2Me

MeO2C R OEt

O

OEt

N

CO2Me

–

R H

CO2Me

CO2Et

N+

N+

N+

CO2Me 203 55%

O –

O

b O

N

CO2R

O CO2R +

N + RO2C 6

204

O

O

CO2R 205 80%

Scheme 27 b-Dicarbonyls in dipolar processes

+ Br 206 O

CO2Et

N +

Br– COR

6

N

+

ROC

–

COR + O2N 208 O

+

EtO2C

COR

COR

EtO2C

COR N

N

–H2

COR O

O

207

COR

Ph

N

N

CO2Me –HNO2

Ph

NO2 CO2Me

–H2

O

Ph 209

O

CO2Me CO2Me

Scheme 28 Access to pyrroloisoquinolines via dipolar MCRs of azines

of the aminoalkyne 199 leads to the azepinone 201 (i.e., pyridine acts as leaving group in the dipole), whereas a Boc substituent in this reagent, leads to the normal dipolar process, affording the quinolizine 200 (Scheme 26b) [179]. Likewise, b-dicarbonyls 202 [180] react with quinolines and the acetylene dicarboxylates 38 to produce the pyrroloquinolines derivatives 203 in a single step (Scheme 27a), whereas the cyclic derivatives 204 lead to the corresponding spiro-compound 205 (Scheme 27b) [181, 182]. Distinct functional groups with acidic hydrogens can also promote these transformations. For instance, benzoylnitromethane (208) or ethyl bromopyruvate (206) react with isoquinoline (6) and acetylenedicarboxylates via the same dipolar mechanism to generate a pyrrolo[2,1-a]isoquinoline scaffold. However, in these cases, after closure of the 5-membered ring, a double-bond formation via dehydrogenation or nitrous acid elimination yields the fully aromatic ring systems 207 and 209 (Scheme 28) [82, 183].

Recent Developments in Reissert-Type Multicomponent Reactions

151

O N O

R2

N R R

1

TMS

R

1

N

213

1

215

O

R

Cl

O

Ph-C NOH 218 O

O

N

N O

OTf

R

212

216

N

O

O

N

Ph

R

O

O

O 214 R

O R

R

X R

R

2

211

–HX

+ N

N 210

–

O

X

R2 H N

R4 222

R

N

R

O

O

N

2

O

R2

N R

R2

O 217

O N R

O

219

Cl

4

Ph-C NOH 218

N O

N O

Ph-C NOH O 218

CO2Me 3

Ph

Cl

O

214

+N –

N

O R

R3

O

MeO2C

R2

Ph N

N O

220 R2

MeO2C

N

221

O O

R

2

Scheme 29 Azine-based dipolar [3þ2] cycloadditions

Alkylation of the azine input with a-haloketones 211 or related compounds yields a different type of dipole (Scheme 29). Thus, the initially generated azinium salt, having highly acidic methylene hydrogens, can provide species suitable for undergoing [3þ2] cycloadditions with a variety dipolarophiles. Interestingly, the resulting adducts (215, 217, and 220), featuring a dihydroazine moiety, may be engaged in a second cycloaddition with a nitrile oxide (218), leading to the final polycyclic products (216, 219, and 221, respectively) with high diastereoselectivity. The Huang group successfully introduced arynes (generated from the corresponding o-silylaryltriflates 212) as dipolarophiles in this chemistry. Using this method, they obtained benzoindolizine 213, which displays a scaffold frequently found in highly fluorescent materials, and is also a structural analog of the antitumor agent batracyclin [184]. These [3þ2] cycloadditions occur also with other common dipolarophiles such as maleimides and substituted alkenes. Solid-supported versions of these processes have also been described [185–187]. The structural variety obtained through the methodologies listed in this section is quite remarkable. The high bond-forming efficiency displayed in these transformations is also noteworthy. Most likely, the above mentioned features would be crucial to extend the use of this family of reactions in diversity oriented synthesis.

152

N. Kielland and R. Lavilla

6 MCRs Involving Azines and Isocyanides Use of isocyanides in Reissert-type MCRs greatly amplifies the complexity that can be generated in a single step. Indeed, the well-known carbene-like reactivity of isocyanides, combined with the rich chemistry of azines enables a wealth of transformations and cascade processes (Scheme 30). The synthetic outcome of these reactions is often controlled by the electronic effects of the substituents on the respective inputs. In Reissert-type chemistry, isocyanides typically react as nucleophiles, affording products of the general structure G. The carbon atom of the isocyanide normally ends up directly connected to the a-carbon of the azine. Alternatively, the isocyanide may attack the carbonyl of the acylazinium salt. In this case, an “imine-type” intermediate would be generated, and its nucleophilic nitrogen could promote a cyclization yielding adducts H. The same kind of structure can arise if the isocyanide reacts first with the activating agent and then with the azine nitrogen. Also, the intermediate formed by interaction of an isocyanide with an electrophilic partner can lead to undesired (in this context) polymerization processes (Scheme 30). The mechanism leading to adduct G presents clear analogies with that of the well established Ugi MCR, in which the isocyanide attacks the electrophilic carbon of an iminium ion; for this reason, this process could be called the Ugi–Reissert reaction (Scheme 31). However, in this transformation, the adduct arises after a final hydration of the nitrilium ion, instead of undergoing the Mumm rearrangement as in the traditional Ugi reaction [188]. The novelty here lies in the use of N-acylazinium salts as a new source of reactive iminium ions for Ugi-type processes. The Ugi–Reissert reaction is quite general [188]; it accepts a wide array of isocyanides, azines (excluding pyridine and derivatives lacking unsubstituted a-positions) and activating agents (chloroformates, acid chlorides, anhydrides,

+

N+ B

N E +

–

R N

C

+

A

F –

C– + E+

C

–

C

+N

N+ R

+N

R

R

N N

N HN

E

O G

R

Scheme 30 Azine-isocyanide MCRs

C E

R N

R

N H

E

A

Isocyanide polymerization processes

Recent Developments in Reissert-Type Multicomponent Reactions

Reissert type reaction + Nu +

Ugi reaction

N+

N E

153

N

E

Nu R1 + N H

R3NC

RCHO + R1NH2 + R3NC + R2COOH

E

Nu R1

O R R2COOH quenching + rearrangement

R

3

N

N H

R2

R

Cl – Ugi-Reissert reaction

N

N R3NC

+ R3NC + RCOCI

+

R

O

N H2O quenching

R3

N H

O

R O

Scheme 31 Analogies between Reissert and Ugi MCRs

R 1

R2 N

i) R -COCl + R3–N=C ii) H2O quenching

R N R

2

N CO-R1

3

N H

O

t-BuHN

225

t-Bu

R

NH

N

O

Me-O R2

224

N Yields: 60-90% R3

O

O O 226 Me O

O

227

Scheme 32 The Ugi–Reissert reaction and representative adducts

and tosyl chlorides), affording the corresponding adducts in good to moderate yields (Scheme 32). In these reactions, the intermediate nitrilium ion is assumed to be stabilized via coordination with the nucleophilic species (either the carbonyl group or the chloride counter ion) and to be hydrolyzed via quenching during aqueous work up. A solid-phase Ugi–Reissert reaction on chloroformate resin, has been reported. The product, the a-carbamoylated isoquinoline 230, is released by oxidative cleavage (Scheme 33a). Interestingly, the enamide moiety in the adduct can be exploited to perform this process in tandem with a Povarov MCR [189, 190]. In this way, by interaction of dihydroisoquinoline 231 with aldehydes, anilines and a suitable Lewis acid catalyst, the polyheterocyclic system 232 was prepared (Scheme 33b). The Zhu group devised an innovative approach for the synthesis of this class of compounds. They employed the heterocyclic amine 233, which was oxidized in situ to the dihydroisoquinoline 234 with IBX, to undergo the classic Ugi reaction. Remarkably, all the components are chemically compatible, allowing the sequence to proceed as a true MCR (Scheme 33c) [191].

154

N. Kielland and R. Lavilla

a O O 228

O

i) N Cl

N

6 tert-Bu-NC CH2Cl2 ii) H2O

N

DDQ

O O NH t-Bu

229

t-Bu N H 230

1, 4-Dioxane O 70%

b i) Me-OCOCl tert-Bu-NC N 6

CH2Cl2 ii) H2O

Me O O

c

OHCCO2Et

N O

NHtBu 231

H N

NH2

Me

Me Me

Sc(OTf)3 CH3CN

O

H O

CO2Et H

N O

NH-tBu 232 60%

+ R–NC HN

+ R1–COOH 233

R1

IBX N

N O

234

O

R 235 N H Yields: 50-97%

Scheme 33 Ugi–Reissert MCRs: a solid-phase version, post-synthetic transformations, and analogous processes

Zhu and coworkers implemented a family of Ugi-type MCRs, based on intramolecular trapping of the intermediate nitrilium ion by a carboxamido group, to prepare diversely substituted oxazoles as versatile synthetic intermediates [192–194]. They later reported an interesting example of the Ugi–Reissert process using this feature (237, Scheme 34a) [195]. This strategy enabled the direct addition of isocyanides to the N-alkyl nicotinamide salts 239. However, the different substitution pattern of the carboxamido group, led to a different outcome: isomerization of the putative bis-iminofurane intermediate to the cyano-carbamoyl derivative 240. Remarkably, the process is also efficient in a Reissert-type reaction (Scheme 34b, c) [196]. In a similar context Arndtsen developed a new pyrrole synthesis from alkynes, acid chlorides either imines or isoquinolines, based on the reactivity of isocyanides (Scheme 35a) [197]. Although all atoms from the isocyanide are excluded from the final structure, its role in the reaction mechanism is crucial. The process takes place through the activation of the imine (isoquinoline) by the acid chloride to generate the reactive N-acyliminium salt, which is then attacked by the isocyanide to furnish a nitrilium ion. This cationic intermediate coordinates with the neighboring carbonyl group to form a mu¨nchnone derivative, which undergoes a [3þ2] cycloaddition followed by subsequent cycloelimination of the isocyanate unit, to afford the pentasubstituted pyrrole adducts 243 and 244 (Scheme 35a, b).

Recent Developments in Reissert-Type Multicomponent Reactions

a

155

CO2Me N + O

6

N

NC

ClCO2Me

N

O

38 CO2Me

O

Bn N

Bn 237 76%

236 O

O CO2Me

O

COOR2 N

N 2

ClCOOR H2N

NC O

239

N

238 35%

c

Bn N

CO2Me

O

MeO2C

O

HN O

MeO2C

N

– Bn Br N

C6H11NC

N

CO2Me CO2Me

Bn

O

B

H 2N

N

3+2 cycloaddition

N

b Bn – + N Br

N

OMe

NC6H5 B-H

R1NC

NC

O

HN O C6H11 240

HN R1

241

O 242

Scheme 34 Internal trapping of the nitrilium intermediate by carboxamido groups

a

R

1

R

R NC

O

N

+

+

5

R

H

Cl

R

4

R

R

R

3

N

5

R

2

i

2

NEt Pr2 R

b

1

4

R

3

243

O C6H11–NC

Cl N +

MeO2C

OMe

6

38

OMe

N

CO2Me

244

MeO2C

CO2Me

CO2Me

MeO2C 38 Cl N

+

O

–

OMe C6H11–NC

N

C6H11–N

OMe

– N +

+

H

C6H11

N

O

C O

OMe

O

i

NEt Pr2

N C6H11

Scheme 35 Arndtsen pyrrole synthesis

In many of the precedent reactions, pyridines are inert, and activation of this fundamental heterocycle remains problematic. To overcome this problem, more powerful activating agents have been tested. For instance, Corey explored the use of triflic anhydride (35) as an efficient method to link a variety of nucleophiles to the pyridine g-position (see 34, Scheme 6) [49]. This reaction in the presence of isocyanides affords a mixture of the a-and g-carbamoylated dihydropyridines 245 and 246 together with the corresponding oxidized products 2450 and 2460 , respectively, in low overall yield (Scheme 36a). A major problem here is the massive degradation of the isocyanide under these rather drastic conditions. Trifluoroacetic

156

N. Kielland and R. Lavilla

a

Tf

N

N

C6H11 NC

9

Tf2O 33

b C6H11 NC

F

Tf

N

H N

C6H11 O 246

O

O

O 9

F3C

O

N

C6H11

6

F3C

O O

H N

O

CF3

N

O

N 247 54%

C6H11 NC O

C6H11

C6H11

CF3

c N

N

H N

O 246¢ Low overall yield

+

–

C6H11

245¢ O

O

O N

H N

C6H11

245

C6H11

N

H N

Not detected O F

N N+

CF3

–

O

248 85%

Scheme 36 Tf2O- and TFAA-promoted isocyanide-azine MCRs

anhydride (TFAA) was then evaluated as a milder surrogate. Surprisingly, the reaction did not yield the expected Ugi–Reissert product, but instead gave the mesoionic acid fluoride 247 (Scheme 36b). Isoquinoline behaves similarly affording the analogous product 248, although in higher yields (Scheme 36c) [198]. The unusual connectivity pattern of the dipoles 247 and 248, whereby the isocyanide nitrogen is linked to the a-carbon of the azine, suggests a markedly distinct reaction mechanism (Scheme 37) to that of the Ugi–Reissert reaction. A reasonable mechanistic proposal may involve the formation of the N-acylazinium salt I, which would then be attacked at its a-position by the isocyanide, then leading to the Arndtsen-type dipoles 249 (which have been isolated in some cases). Alternatively, the isocyanide can attack the activated carbonyl group in I, triggering a cascade leading to the generation and subsequent transformation of intermediate L. This species can undergo cyclization, followed by ring closure to epoxide M, rearrangement, formal elimination of HF, and aromatization, to yield dipole 248. Yet another possibility is that the isocyanide attacks the anhydride to form the intermediate K, a direct precursor of the dipolar species L. This mode of activation for isocyanides has been investigated by El Kaim, who promoted a series of useful transformations based on this reactivity, leading to products such as trifluoropyruvamides 250 (R ¼ F) [199–201].

Recent Developments in Reissert-Type Multicomponent Reactions N

O +

+

–

R2–N C

6 O + O R1 R1 C O F F + F F 2

157

O

N+

F F

O C

or

R2

R1

–

O

R1

N+

F

F I

–

R2 N

1

R F F

O C

O

F F

C N O +

O N R2

K

–

N 6 -F

H2O F F

O

R N H HO OH 250

N

+

L 249 R1=

O

N

C

R1

O R1 C– C N F2

F F

–

R2 N H 2

R1

R2 OOCF2R1 R1

C F2

J

R –N C

R1

C

N

R2 N H

R1 F O

+

R

C

O

R2 N

O

N

–

-F, -H, -Ph, -CF3, -CF2CF3

1

+

N

C–

O

O

-F M

N

R1

248

Scheme 37 Mechanistic proposals for the MCR of azines, isocyanides, and TFAA

O Cl Cl Cl

N

O Cl

O

O N

6

+

Cl Cl

–

N

C6H11–NC

N CCl3

O

251 30%

–CO2 CCl3–CO2– N

O N +

–

N

O O

O

c-Hex Cl

6

N +

N

–

N +

O

P

Scheme 38 Cascade reaction of azines and isocyanides promoted by TCAA

The scope of the reaction is quite general, allowing reasonable variation for each component. Apart from TFAA, substituted difluoroanhydrides also react, yielding the expected derivatives with diverse groups attached to the exocyclic carbonyl moiety. Chlorinated anhydrides are less reactive: and only trichloroacetic anhydride (TCAA) leads to dipole 251 in moderate yield (Scheme 38). A new

158

N. Kielland and R. Lavilla

a

NHR2

Cl –

NR1

2

R –NC + N Cl MeS 252 9

NR1

N+

+

N Cl –

SMe

NHR2

SMe

+

N

CN

Ph

255 CN +

N –

Ar

c

+

N O

N

CN CN

CN CN 256 Yield: 40-90%

Ar–N

N

+

S–

R1

NHR2

NHAr

258 Yield: 60-90%

2

+

N–R2

N

R1 = 4–Br–C6H4–CO–

Br

Ph

R2 –NC

ArNCS Br – PS-NEt2

257

N

Ph

+

Ar–NC

6

NR1

N+ Cl –

SMe 254 Yield: 50-90%

253 Yield: 60-100%

b

NR2

N R1 +

R1

S–

N

N R1

R

R1

S

NHAr

259 Yield: 20-50%

NHAr

NHAr

N

d N 9

F–

Ar-NC

F2

+

N+ F

F–

N F

N–Ar

H2O

N 260 O 66%

Ar NH

TMS-N3

N

Ar N N N N 261 84%

Scheme 39 Isocyanide-azine MCRs promoted by various activating agents

domino reaction derives, in this case, from the higher reactivity of the putative acid chloride adduct O, which can interact with another isoquinoline unit to generate a new N-acylisoquinolinium cation P, which in turn may undergo an a-trichloromethylation [198, 202]. Other electrophilic reagents have been used to activate azines in isocyanidepromoted reactions. For example, reaction of the methyl chlorothioimidates 252 with pyridines and isocyanides provides convenient access to the fused imidazolium salts 253 (Scheme 39a). The isocyanide attacks the a-carbon of the activated pyridinium salt, and the resulting intermediate is then trapped by the nitrogen of the activating agent to yield the product. The competing reaction of double isocyanide insertion to give 254 has also been described [203]. Substituted alkenes also react efficiently in analogous processes. For example, pyrroloisoquinoline derivative 256 was obtained in a straightforward manner by interaction of isoquinoline, Michael

Recent Developments in Reissert-Type Multicomponent Reactions

159

acceptor 255 and aromatic isocyanides (Scheme 39b) [172, 204, 205]. Similarly, Ley reported that reaction of an isocyanide with the isoquinolinium dipole 258 (generated from the interaction of the salt 257 with isothiocyanate) initiates a sequence yielding amino-substituted pyrroloisoquinolines (259), pyrroloquinolines and indolizines (Scheme 39c) [206]. Fluorine has also been used as activating agent in a bicomponent processes in which pyridine and isocyanides react to form the picolinamides 260 or the tetrazoles 261, whereby the intermediate nitrilium ion is hydrolyzed or trapped with TMS-N3, respectively (Scheme 39d) [207, 208]. Alternative activating pathways are based on the coordination of the isocyanide to the electrophilic reagent to furnish a nitrilium intermediate, which is the actual reactive species attacked by the azine (see intermediate K in Scheme 37) [201]. In this regard, Berthet described the reaction of azines and isocyanides with triflic acid to obtain the imidazopyridinium salts 262, presumably through a cascade involving double isocyanide incorporation. Interestingly, one equivalent of the isocyanide generates the initial electrophilic intermediate, which goes on to be attacked by the azine, and subsequently, the second equivalent of the isocyanide acts as the next nucleophile; the sequence terminates upon nucleophilic ring closure promoted by the amidine nitrogen (Scheme 40a) [209]. Related processes, in which the isocyanide is activated by acidic species, have been described by Shaabani [210–212]. Similar connectivity patterns arise from the interaction of azines with TOSMIC or isocyanoacetate [213, 214]. This reactivity (isocyanide activation) was further exploited by Mironov et al., who reacted isocyanides with isothiocyanates and azines (isoquinolines or phtalazines) to prepare compounds 264 (Scheme 40b). Mechanistically related processes include the reaction of isocyanides with aldehydes for in situ generation of the activated species, which is then attacked by the azine (Scheme 41a). This strategy has been harnessed in a convenient synthesis of

a R + R–NC + TfOH TfO – N+ N 9

H

+

H

N

b +

+ R–NC N + X R1–NCS 263 X = CH or N

TfO –

TfO –

R N

N

+

N

N–R N R

N R N R

H

N

N H R 262 Yield: 50-70% HN R –S

S N X

–

NHR

N

N R N X

N S

TfO –

+

R1

R1

+

N X N

R1 264 Yield: 40-90%

Scheme 40 MCRs involving isocyanide activation mechanisms

160

N. Kielland and R. Lavilla

a

+ R–NC + N H O

+

NF

R N

N –

N

O

H

R N

R NH

H

F

Q

O

O F

266

b

N N

N

F 265

N

267 R

N

R–NC + NH2 R′– CHO H+ or LA

268

N C N

R CHR′ N +

H

H R N

+

N N

(LA)

C

CHR′ N

N

R′ N

H R

269

Scheme 41 Additional isocyanide-activation processes

the fused dihydrooxazoles 267: the dipolar intermediate Q activates the azine, whereas the alkoxide attacks as the nucleophile; the final product is obtained after a proton shift [215]. The Bienayme´-Blackburn-Groebcke MCR – in which an a-amino-azine, an aldehyde and an isocyanide react to yield the fused imidazoazine systems 269 (Scheme 41b) – could be considered in this section, as the heterocyclic nitrogen of the azine intramolecularly attacks the activated nitrilium species R, which is formed by addition of the isocyanide to the in situ generated imine. In fact, this MCR constitutes the most reliable access to these products. The process has been widely modified in each component, and has enabled the preparation of a wide range of bioactive compounds [216–222]. Alternative reaction pathways exploring different synthetic possibilities have been studied. For instance, electron-rich dihydroazines also react with isocyanides in the presence of an electrophile, generating reactive iminium species that can then be trapped by the isocyanide. In this case, coordination of the electrophile with the isocyanide must be kinetically bypassed or reversible, to enable productive processes. Examples of this chemistry include the hydro-, halo- and seleno-carbamoylation of the DHPs 270, as well as analogous reactions of cyclic enol ethers (Scheme 42a) [223, 224]. p-Toluenesulfonic acid (as proton source), bromine and phenylselenyl chloride have reacted as electrophilic inputs, with DHPs and isocyanides to prepare the corresponding a-carbamoyl-b-substituted tetrahydropyridines 272–274 (Scheme 42b). Wanner has recently, implemented a related and useful process that exploits N-silyl DHPs (275) to promote interesting MCRs. These substrates are reacted with a carboxylic acid and an isocyanide in an Ugi–Reissert-type reaction, that forms the polysubstituted tetrahydropyridines 276 with good diasteroselectivity (Scheme 42c) [225]. The mechanism involves initial protiodesilylation to form the dihydropyridinum salt S, which is then attacked by the isocyanide, en route to the final adducts. Suprisingly, the use of iodine in an attempted iodocarbamoylation of a DHP led instead to the benzimidazolium salt 279; in contrast, iodine monochloride (ICl)

Recent Developments in Reissert-Type Multicomponent Reactions

a

E+ + R-NC

Me N EWG

Me N+ EWG

E

O N H

R

E

EWG 271

R–N C–E

b

Me N EWG

+ C6H11 – NC 270

Br2

RSO3H Me N

O N H

C6H11

272 iPr iPriPr Si

N

Ph

Me N

i Pr

Ph-SeCl Me N

O N H

EWG

EWG

c

Me N

+

270

161

C6H11 EWG

Br 273

R1COOH + R2NC

275

C H N 6 11 H Se–Ph

274

R1

O N

Ph

O

O

O N H

i Pr

H

R2

N+

via :

276 Yield: 30-80%

Ph

– O

i Pr

R1

S

Scheme 42 Hydro-, halo- and seleno-carbamoylation of dihydropyridines

afforded the expected iodo-carbamoylated tetrahydropyridine 277 (Scheme 43) [226]. The scope of this unprecedented transformation was studied through systematic variation of the substituents and was found to be quite general: aliphatic, aromatic, and benzylic isocyanides have been reacted with a variety of DHPs bearing several electron-withdrawing groups (Scheme 43). The use of labeled precursors (2H-DHPs and 13C-isocyanides) provided meaningful data for establishing a mechanistic rationale. Although isolated in small amounts, the pyridinium salts 282 (arising from the iodine-mediated oxidation of DHPs 281) do not afford benzimidazolium salts 279 in the presence of isocyanides. A likely pathway may start with the iodo-dihydropyridinium intermediate 280, which can be formed by interaction of iodine with the reactive double bond of the DHPs (Scheme 44). The isocyanide may subsequently attack these species to generate the nitrilium ion T, which interacts with a second equivalent of isocyanide to form cation U. This intermediate undergoes an intramolecular trapping by the enamine unit to close the bicyclic system V

162

N. Kielland and R. Lavilla

R N

C6H11

N H

ICl

+

C6H11 + C6H11 – NC

MeOOC

I 277

MeOOC

I–

R N

O

C6H11 278

N

N

I2

R

R = Alk, Ar, Bn

HN

279

MeOOC

Scheme 43 Reactions of isocyanides, DHPs and different iodonium sources

R1 N

R–N +

I2

+

R2

280

R R1 N

N

281

1

R2

H N

N N + R1 I–

2

R

+

277 From ICl reactions

R R

R N

N R

R–NC

282 Detected

R–NC –IH

H2O

I

1 I– R N

R2

R2

I

T

RHNOC

R1 N

I2

+

R–NC R2

I

1 I– R N

I

R2

U

+

1

R N

R N+

N I–

R–N

279

R1

Formed bonds

R–N R–N

R2 V

2 X R

Scheme 44 Mechanistic proposal for the formation of benzimidazolium salts 279

(Scheme 44). Iodoiminium X may then be formed by iodide-mediated fragmentation, possibly evolving through ring closure and subsequent aromatization to yield the final product 279. In the presence of ICl, the halocarbamoylated tetrahydropyridine 277 is formed by the standard hydrolysis of nitrilium ion T. Therefore, the nature of the free anion in the mixture appears to be critical for stabilizing the nitrilium species and consequently promoting the formation of either 279 or 277. Furthermore benzimidazolium salts 279 were tested in screening assays, looking for new inhibitors for human Prolyl Oligopeptidase, (an enzyme expressed in the central nervous system and involved in mental disorders), and some derivatives displayed potent and selective inhibitory activities [227]. As a final remark for this section, it is evident that the complexity of some processes together with the strikingly different synthetic outcomes, originated by slight changes in the reactants, reflects our low capacity of prediction for these MCRs. Therefore, more experimental work is needed to generate enough data that may enable a future rationalization for these fascinating cascades.

Recent Developments in Reissert-Type Multicomponent Reactions

163

7 Conclusions Reissert’s initial discovery sparked research that continues to provide ever-growing combinations of azines, activating agents, and nucleophiles for countless synthetic applications. The structure of azines enables reactions with at least two other components, thus making them a privileged class of reactants for the development of new MCRs. The combination of azines with other types of bidentate compounds, such as alkenes and isocyanides, can trigger complex cascade reactions, elegantly leading to the corresponding MC-adducts in a single step. These products often feature intricate connectivities and structural motifs, that are nearly impossible to construct through classical stepwise approaches. The Reissert reaction and mechanistic variations thereof provide ready access to several types of N-heterocyclic systems, including the most common scaffolds found in natural products and bioactive compounds. Furthermore, the modularity of this chemistry makes it very attractive for generating the structural diversity sought in drug discovery. Future work in this area should expand the already great impact of these methodologies on organic synthesis. Acknowledgments We warmly thank all the members of our research group involved in this project for their enthusiasm and dedication. Financial support from the DGICYT (Spain, projects CTQ 2003-00089, 2006-03794 and 2009-07758) is acknowledged. N. K. thanks the Spanish Ministry of Science and Education for a grant. We are especially thankful to Laboratorios Almirall and Grupo Ferrer (Barcelona) for their support.

References 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19.

Zhu J, Bienayme´ H (2005) Multicomponent reactions. Wiley-VCH, Weinheim Domling A (2006) Chem Rev 106:17 Nair V, Bindu S, Sreekumar V (2004) Angew Chem Int Ed Engl 43:5130 Isambert N, Lavilla R (2008) Chem Eur J 14:8444 Lavilla R (2002) J Chem Soc Perkin Trans 1:1141 Stout DM, Meyers AI (1982) Chem Rev 82:223 Tietze LF, Brasche G, Gericke K (2006) Domino reactions in organic synthesis. Wiley-VCH, Weinheim Reissert A (1905) Berichte der deutschen chemischen Gesellschaft 38:1603 Sugasawa S, Tsuda T (1936) J Pharm Soc Jpn 56:557 Mosettig E (1954) Org React:218 McEwen WE, Cobb RL (1955) Chem Rev 55:511 Popp FD (1979) Adv Heterocycl Chem 24:187 Popp FD (1982) Chem Heterocycl Comp 32:353 Cooney JV (1983) J Heterocycl Chem 20:823 Woodward RB (1940) J Am Chem Soc 62:1626 Popp FD, Soto A (1963) J Chem Soc:1760 Grosheintz JM, Fischer HOL (1941) J Am Chem Soc 63:2021 Schwartz A (1982) J Org Chem 47:2213 McEwen WE, Hazlett RN (1949) J Am Chem Soc 71:1949

164

N. Kielland and R. Lavilla

20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30. 31. 32. 33.

Walters LR, Iyer NT, McEwen WE (1958) J Am Chem Soc 80:1177 McEwen WE, Kindall JV, Hazlett RN, Glazier RH (1951) J Am Chem Soc 73:4591 Popp FD, Katz LE, Klinowski CW, Wefer J (1968) J Org Chem 33:4447 Popp FD, Wefer J (1966) Chem Commun 7:207 Rupe H, Paltzer R, Engel K (1937) Helv Chim Acta 20:209 Popp FD (1973) Heterocycles 1:165 Blasko G, Kerekes P, Makleit S (1987) Alkaloids 31:1 Berg MAG, Gibson HW (1992) J Org Chem 57:748 Popp FD, Duarte FF, Uff BC (1987) J Heterocycl Chem 24:1353 Duarte FF, Popp FD (1991) Heterocycles 32:723 Popp FD, Blount W (1962) J Org Chem 27:297 Popp FD, Blount W, Melvin P (1961) J Org Chem 26:4930 Popp FD (1980) Heterocycles 14:1033 Balaban AT, Gheorghiu MD, Shcherbakova IV, Kuznetsov EV, Yudilevich IA (1987) Tetrahedron 43:409 Uff BC, Ho YP, Burford DLW, Popp FD (1987) J Heterocycl Chem 24:1349 Uff BC, Joshi BL, Popp FD (1986) Perkin Trans 1 12:2295 Bittermann A, Baskakov D, Herrmann WA (2009) Organometallics 28:5107 Reuss RH, Smith NG, Winters LJ (1974) J Org Chem 39:2027 Doering W, McEwen WE (1951) J Am Chem Soc 73:2104 Popp FD, Takeuchi I, Kant J, Hamada Y (1987) J Chem Soc Chem Commun:1765 Popp FD, Kant J (1985) Heterocycles 23:2193 Duarte FF, Popp FD, Holder AJ (1993) J Heterocycl Chem 30:893 Lorsbach BA, Miller RB, Kurth MJ (1996) J Org Chem 61:8716 Lorsbach BA, Bagdanoff JT, Miller RB, Kurth MJ (1998) J Org Chem 63:2244 Lavilla R, Gullon F, Bosch J (1999) Eur J Org Chem:373 Naito T, Miyata O, Ninomiya I (1979) J Chem Soc Chem Commun:517 Spatz DM, Popp FD (1968) J Heterocycl Chem 5:497 Sieck O, Ehwald M, Liebscher J (2005) Eur J Org Chem 2005:663 Boger DL, Brotherton CE, Panek JS, Yohannes D (1984) J Org Chem 49:4056 Corey EJ, Tian Y (2005) Org Lett 7:5535 Kumaraswamy G, Rambabu D, Jayaprakash N, Rao GV, Sridhar B (2009) Eur J Org Chem 2009:4158 Yadav JS, Reddy BVS, Yadav NN, Gupta MK, Sridhar B (2008) J Org Chem 73:6857 Defant A, Guella G, Mancini I (2008) Synth Commun 38:3003 Valeur E, Bradley M (2005) Chem Commun:1164 Valeur E, Bradley M (2007) Tetrahedron 63:8855 Kakarla R, Li G, Gerritz W (2007) J Comb Chem 9:745 Pathirana C, Shukla R, Castoro J, Weaver D, Byrne L, Pennarun-Thomas G, Palaniswamy V (2009) Tetrahedron Lett 50:1586 Ouchi H, Saito Y, Yamamoto Y, Takahata H (2002) Org Lett 4:585 Saito Y, Ouchi H, Takahata H (2006) Tetrahedron 62:11599 Ghahremanzadehl R, Ahadi S, Sayyafi M, Bazgir A (2008) Tetrahedron Lett 49:4479 Yavari I, Ghazanfarpour-Darjani M, Sabbaghan M, Hossaini Z (2007) Tetrahedron Lett 48:3749 Stroz T, Bartberger MD, Sukits S, Wilde C, Soukup T (2008) Synthesis 2:201 Fife WK, Scriven EFV (1984) Heterocycles 22:2375 Yu X, Yang X, Wu J (2009) Org Biol Chem 7:4526 Su S, Porco JA (2007) Org Lett 9:4983 Kiselyov AS, Strekowski L (1993) J Heterocycl Chem 30:1361 Tejedor D, Garcia-Tellado F (2007) Chem Soc Rev 36:484 King JA (1988) J Am Chem Soc 110:5764 Yan CG, Wang QF, Song XK, Sun J (2009) J Org Chem 74:710

34. 35. 36. 37. 38. 39. 40. 41. 42. 43. 44. 45. 46. 47. 48. 49. 50. 51. 52. 53. 54. 55. 56. 57. 58. 59. 60. 61. 62. 63. 64. 65. 66. 67. 68.

Recent Developments in Reissert-Type Multicomponent Reactions 69. 70. 71. 72. 73. 74. 75. 76. 77. 78. 79. 80. 81. 82. 83. 84. 85. 86. 87. 88. 89. 90. 91. 92. 93. 94. 95. 96. 97. 98. 99. 100. 101. 102. 103. 104. 105. 106. 107. 108. 109. 110. 111. 112. 113.

165

Van der Jeught S, Stevens CV (2009) Chem Rev 109:2672 Albouy D, Lasptras M, Etemad-Moghadam G, Koenig M (1999) Tetrahedron Lett 40:2311 Akiba K, Negishi Y, Kurumaya K, Ueyama N, Inamoto N (1981) Tetrahedron Lett 22:4977 Hosl CE, Wanner KT (1998) Heterocycles 48:2653 Yadav JS, Reddy BVS, Yadav NN, Gupta MK (2008) Tetrahedron Lett 49:2815 Yadav JS, Reddy BVS, Vishnumurthy P, Premalatha K (2008) Synthesis 5:719 Lavilla R, Gotsens T, Guerrero M, Bosch J (1995) Synthesis:382 Lavilla R, Gotsens T, Guerrero M, Masdeu C, Santano MC, Minguillo´n C, Bosch J (1997) Tetrahedron 53:13959 Ryan RP, Hamby RA, Wu YH (1975) J Org Chem 40:724 Yadav JS, Reddy BVS, Sathaiah K, Narayana Reddy P (2006) Chem Lett 35:448 Alizadeh A, Zohreh N (2008) Helv Chim Acta 91:844 Alizadeh A, Zohreh N (2008) Synthesis 3:429 Yadav JS, Reddy BVS, Yadav NN, Gupta MK (2009) Synthesis 7:1131 Yavari I, Piltan M, Moradi L (2009) Tetrahedron 65:2067 Higashi J, Shoji T, Ito S, Toyota K, Yasunami M, Morita N (2008) Eur J Org Chem 2008:5823 Katritzky AR, Zhang S, Kurz T, Wang M, Steel PJ (2001) Org Lett 3:2807 Yamaguchi R, Hatano B, Nakayasu T, Kozima S (1997) Tetrahedron Lett 38:403 Yamaguchi R, Nakayasu T, Hatano B, Nagura T, Kozima S, Fujita K-I (2001) Tetrahedron 57:109 Yadav JS, Reddy BVS, Srinivas M, Sathaiah K (2005) Tetrahedron Lett 46:3489 Bubnov YN, Klimkina EV, Ignatenko AV, Gridnev ID (1996) Tetrahedron Lett 37:1317 Kuznetsov NY, Khrustalev VN, Godovikov IA, Bubnov YN (2006) Eur J Org Chem:113 Kuznetsov NY, Khrustalev VN, Godovikov IA, Bubnov YN (2007) Eur J Org Chem:2015 Yamaguchi R, Moriyasu M, Yoshioka M, Kawanisi M (1988) J Org Chem 53:3507 Nakamura M, Hirai A, Nakamura E (1996) J Am Chem Soc 118:8489 Comins DL, Brown JD (1984) Tetrahedron Lett 25:3297 Wada M, Nishihara Y, Akiba K-Y (1985) Tetrahedron Lett 26:3267 Akiba K-Y, Nishihara Y, Wada M (1983) Tetrahedron Lett 24:5269 Hermange P, Tran Huu Dau ME, Retailleau P, Dodd RH (2009) Org Lett 11:4044 Langer P (2007) Eur J Org Chem 14:2233 Ullah E, Rotzoll S, Schmidt A, Michalik D, Langer P (2005) Tetrahedron Lett 46:8997 Rudler H, Denise B, Parlier A, Daran J-C (2002) Chem Commun:940 Rudler H, Denise B, Xu YJ, Parlier A, Vaissermann J (2005) Eur J Org Chem:3724 Garduno-Alva A, Xu Y, Gualo-Soberanes N, Lopez-Cortes J, Rudler H, Parlier A, OrtegaAlfaro MC, Alvarez-Toledano C, Toscano RA (2008) Eur J Org Chem:3714 Rudler H, Denise B, Xu Y, Vaissermann J (2005) Tetrahedron Lett 46:3449 Xu Y, Rudler H, Denise B, Parlier A, Chaquin P, Herson P (2006) Tetrahedron Lett 47:4541 Xu Y, Aldeco-Pe´rez E, Rudler H, Parlier A, Alvarez C (2006) Tetrahedron Lett 47:4553 Garduno-Alva A, Xu Y, Gualo-Soberanes N, Lopez-Cortes J, Rudler H, Parlier A, OrtegaAlfaro MC, Alvarez-Toledano C, Toscano RA (2008) Eur J Org Chem 2008:3714 Parlier A, Kadouri-Puchot C, Beaupierre S, Jarosz N, Rudler H, Hamon L, Herson P, Daran J-C (2009) Tetrahedron Lett 50:7274 Charette AB, Mathieu S, Martel J (2005) Org Lett 7:5401 Chang YM, Lee SH, Nam MH, Cho MY, Park YS, Yoon CM (2005) Tetrahedron Lett 46:3053 Deline JE, Miller RB (1998) Tetrahedron Lett 39:1721 Colandrea VJ, Naylor EM (2000) Tetrahedron Lett 41:8053 Mangeney P, Gosmini R, Raussou S, Commercon M, Alexakis A (1994) J Org Chem 59:1877 Bennasar ML, Juan C, Bosch J (1998) Tetrahedron Lett 39:9275 Shiao M-J, Chia WL, Peng C-J, Shen C-C (1993) J Org Chem 58:3162

166

N. Kielland and R. Lavilla

114. 115. 116. 117. 118. 119. 120. 121. 122. 123. 124. 125. 126. 127. 128. 129. 130. 131.

Saito A, Iimura K, Hayashi M, Hanzawa Y (2009) Tetrahedron Lett 50:587 Signore G, Malanga C, Menicagli R (2008) Tetrahedron 64:197 Wang X, Kauppi AM, Olsson R, Almqvist F (2003) Eur J Org Chem:4586 Clayden J, Hamilton SD, Mohammed T (2005) Org Lett 7:3673 Giam CS, Knaus EE (1971) Tetrahedron Lett 12:4961 Alexakis A, Amiot F (2002) Tetrahedron Asymmetry 13:2117 Loue¨rat F, Fort Y, Mamane V (2009) Tetrahedron Lett 50:5716 Yamaguchi R, Nakazono Y, Matsuki T, Hata E (1986) Bull Chem Soc Jpn 60:215 Comins DL, Abdullah AH, Mantlo NB (1984) Tetrahedron Lett 25:4867 Comins DL, Abdullah AH (1982) J Org Chem 47:4315 Mani NS, Chen P, Jones TK (1999) J Org Chem 64:6911 Bra¨ckow J, Wanner KT (2006) Tetrahedron 62:2395 Takamura M, Funabashi K, Kanai M, Shibasaki M (2000) J Am Chem Soc 122:6327 Funabashi K, Ratni H, Kanai M, Shibasaki M (2001) J Am Chem Soc 123:10784 Shibasaki M, Kanai M, Mita T (2008) Org React 70:1 Groger H (2003) Chem Rev 103:2795 Takamura M, Funabashi K, Kanai M, Shibasaki M (2001) J Am Chem Soc 123:6801 Ichikawa E, Suzuki M, Yabu K, Albert M, Kanai M, Shibasaki M (2004) J Am Chem Soc 126:11808 Black DA, Beveridge RE, Arndtsen BA (2008) J Org Chem 73:1906 ´ , Macia´ B, Pizzuti MG, Minnaard AJ, Feringa BL (2009) Angew Ferna´ndez-Iba´n˜ez MA Chem Int Ed Engl 48:9339 Taylor MS, Tokunaga N, Jacobsen EJ (2005) Angew Chem Int Ed Engl 44:6700 Pauvert M, Collet SC, Bertrand MJ, Guingant AY, Evain M (2005) Tetrahedron Lett 46:2983 Richter-Addo GB, Knight DA, Dewey MA, Arif AM, Gladysz JA (1993) J Am Chem Soc 115:11863 Tomon T, Ooyama D, Wada T, Shirenb K, Tanaka K (2001) Chem. Commun. 1100. Yamada S, Inoue M (2007) Org Lett 9:1477 Yamada S, Morita C (2002) J Am Chem Soc 124:8184 Sieck O, Schaller S, Grimme S, Liebscher J (2003) Synlett 3:337 Surygina O, Ehwald M, Liebscher J (2000) Tetrahedron Lett 41:5479 Itoh T, Matsuya Y, Enomoto Y, Nagata K, Miyazaki M, Ohsawa A (1999) Synlett 7:1154 Gibson HW, Berg MAG, Dickson JC, Lecavalier PR, Wang H, Merola JS (2007) J Org Chem 72:5759 Comins DL, Joseph SP, Goehring RR (1994) J Am Chem Soc 116:4719 Bharathi P, Comins DL (2008) Org Lett 10:221 Brown JD, Foley MA, Comins DL (1988) J Am Chem Soc 110:7445 Comins DL, Sahn JJ (2005) Org Lett 7:5227 Focken T, Charette AB (2006) Org Lett 8:2985 Pabel J, Hosl CE, Maurus M, Ege M, Wanner KT (2000) J Org Chem 65:9272 Chen C, Munoz B (1998) Tetrahedron Lett 39:6781 Chen C, McDonald IA, Munoz B (1998) Tetrahedron Lett 39:217 Chen C, Munoz B (1999) Tetrahedron Lett 40:3491 Chen C, Munoz B (1998) Tetrahedron Lett 39:3401 Munoz B, Chen C, McDonald IA (2000) Biotechnol Bioeng 71:78 Barbe G, Pelletier G, Charette AB (2009) Org Lett 11:3398 Barbier D, Marazano C, Riche C, Das BC, Potier P (1998) J Org Chem 63:1767 Yamaguchi R, Tanaka M, Matsuda T, Fujita KI (1999) Chem. Commun. 2213. Huisgen R, Morikawa M, Herbig K, Brunn E (1967) Chem Ber 100:1094 Huisgen R, Herbig K, Morikawa M (1967) Chem Ber 100:1107 Esmaeili AA, Nazer M (2009) Synlett 13:2119 Yavari I, Hossaini Z, Sabbaghan M, Ghazanfarpour-Darjani M (2007) Monatsh Chem 138:677

132. 133. 134. 135. 136. 137. 138. 139. 140. 141. 142. 143. 144. 145. 146. 147. 148. 149. 150. 151. 152. 153. 154. 155. 156. 157. 158. 159. 160. 161.

Recent Developments in Reissert-Type Multicomponent Reactions

167

162. Nair V, Devipriya S, Suresh E (2008) Tetrahedron 64:3567 163. Nair V, Sreekanth AR, Abhilash N, Bhadbhade MM, Gonnade RC (2002) Org Lett 4:3575 164. Teimouri BM, Abbasi T, Ahmadian S, Heravi MRP, Bazhrang R (2009) Tetrahedron 65:8120 165. Nair V, Sreekanth AR, Abhilash NP, Biju ATN, Varma L, Viji S, Mathew S (2005) Arkivoc 178. 166. Shaabani A, Rezayan AH, Sarvary A, Khavasi HR (2008) Tetrahedron Lett 49:1469 167. Nair V, Devipriya S, Eringathodi S (2007) Tetrahedron Lett 48:3667 168. Nair V, Sreekanth AR, Biju AT, Rath NP (2003) Tetrahedron Lett 44:729 169. Adib M, Yavari H, Mollahosseini M (2004) Tetrahedron Lett 45:1803 170. Pillai AN, Rema Devi B, Suresh E, Nair V (2007) Tetrahedron Lett. 48:4391. 171. Krohnke F (1953) Angew Chem 24:605 172. Mironov MA (2006) QSAR Comb Sci 25:423 173. Ma C, Ding H, Wang Y (2006) Org Lett 8:3133 174. Ma C, Ding H, Wu G, Yang Y (2005) J Org Chem 70:8919 175. Andriyankova LV, Mal’kina AG, Afonin AV, Trofimov BA (2003) Mendeleev Commun 13:186 176. Trofimov BA, Andriyankova LV, Zhivet’ev SA, Mal’kina AG, Voronov VK (2002) Tetrahedron Lett 43:1093 177. Andriyankova LV, Mal’kina AG, Nikitina LP, Belayaeva KV, Ushakov IA, Afonin AV, Nikitin MV, Trofimov BA (2005) Tetrahedron 61:8031 178. Trofimov BA, Andriyankova LV, Tlegenov RT, Mal’kina AG, Afonin AV, Il’icheva L, Nikitina LP (2005) Mendeleev Commun 15:33 179. Grant TN, Benson CL, West FG (2008) Org Lett 10:3985 180. Simon C, Constantieux T, Rodriguez J (2004) Eur J Org Chem:4957 181. Yavari I, Mirzaei A, Moradi L, Hosseini N (2008) Tetrahedron Lett 49:2355 182. Nair V, Devipriya S, Eringathodi S (2008) Synthesis 7:1065 183. Yavari I, Hossaini Z, Sabbaghan M (2006) Tetrahedron Lett 47:6037 184. Huang X, Zhang T (2009) Tetrahedron Lett 50:208 185. Bicknell AJ, Hird NW, Readshaw SA (1998) Tetrahedron Lett 39:5869 186. Tsuge O, Kanemasa S, Takenaka S (1986) Bull Chem Soc Jpn 59:3631 187. Goff DA (1999) Tetrahedron Lett 40:8741 188. Diaz JL, Miguel M, Lavilla R (2004) J Org Chem 69:3550 189. Lavilla R, Carranco I, Daz JL, Bernabeu MC, De la Rosa G (2003) Mol Divers 6:171 190. For a review on the Povarov reaction, see:Kouznetsov VV (2009) Tetrahedron 65:2721. 191. Ngouansavanh T, Zhu J (2007) Angew. Chem., Int. Ed. 46:5775. 192. Janvier P, Sun X, Bienayme H, Zhu J (2002) J Am Chem Soc 124:2560 193. Gamez-Montano R, Gonzalez-Zamora E, Potier P, Zhu J (2002) Tetrahedron 58:6351 194. Gonzalez-Zamora E, Fayol A, Bois Choussy M, Chiaroni A, Zhu J (2001) Chem. Commun. 1684. 195. Tron GC, Zhu J (2005) Synlett 532. 196. Williams NAO, Masdeu C, Diaz JL, Lavilla R (2006) Org Lett 8:5789 197. St. Cyr DJ, Martin N, Arndtsen BA (2007) Org. Lett. 9:449 198. Are´valo MJ, Kielland N, Masdeu C, Miguel M, Isambert N, Lavilla R (2009) Eur J Org Chem:617 199. El Kaim L (1994) Tetrahedron Lett. 35:6669. 200. El Kaim L, Pinot-Perigord E (1998) Tetrahedron 54:3799. 201. El Kaim L, Grimaud L (2009) Tetrahedron 65:2153. 202. For a precedent of the trichloromethylation step, see:Grignon-Dubois M, Diaba F, GrellierMarly M-C (1994) Synthesis 800. 203. Marchand E, Morel G (1993) Tetrahedron Lett 34:2319 204. Mironov MA, Maltsev SS, Mokrushin VS, Bakulev VA (2005) Mol Divers 9:221 205. Mironov MA, Mokrushin VS, Maltsev SS (2003) Synlett 7:943 206. Hopkin MD, Baxendale IR, Ley SV (2008) Synthesis 1688–1702.

168

N. Kielland and R. Lavilla

207. 208. 209. 210. 211. 212. 213.

Kiselyov AS (2005) Tetrahedron Lett 46:2279 Kiselyov AS (2005) Tetrahedron Lett 46:4851 Berthet JC, Nierlich M, Ephritikhine M (2002) Eur J Org Chem:375 Shaabani A, Soleimani E, Moghimi-Rad J (2008) Tetrahedron Lett 49:1277 Shaabani A, Soleimani E, Khavasi HR (2008) J Comb Chem 10:442 Shaabani A, Soleimani E, Khavasi HR (2007) Tetrahedron Lett 48:4743 Murashima T, Nishi K, Nakamoto K, Kato A, Tamai R, Uno H, Ono N (2002) Heterocycles 58:301 Van Nispen SPJM, Mensink C, Van Leusen AM (1980) Tetrahedron Lett 21:3723 Maghsoodlou MT, Marandi G, Hazeri N, Aminkhanib A, Kabiri R (2007) Tetrahedron Lett 48:3197 Bienayme´ H, Bouzid K (1998) Angew Chem Int Ed Engl 37:2234 Blackburn C, Guan B, Fleming P, Shiosaki K, Tsai S (1998) Tetrahedron Lett 39:3635 Groebcke K, Weber L, Mehlin F (1998) Synlett 661. Umkehrer M, Ross G, Ja¨ger N, Burdack C, Kolb J, Hu H, Alvim-Gaston M, Hulme C (2007) Tetrahedron Lett 48:2213 DiMauro EF, Kennedy JM (2007) J Org Chem 72:1013 Carballares S, Espinosa JF (2005) Org Lett 7:2329 Lyon MA, Kercher TS (2004) Org Lett 6:4989 Masdeu C, Gomez E, Williams NA, Lavilla R (2006) QSAR Comb Sci 25:465 Masdeu C, Diaz JL, Miguel M, Jimenez O, Lavilla R (2004) Tetrahedron Lett 45:7907 Sperger CA, Mayer P, Wanner KT (2009) Tetrahedron 65:10463 Masdeu C, Gomez E, Williams NAO, Lavilla R (2007) Angew. Chem., Int. Ed. 46:3043. Tarrago T, Masdeu C, Gomez E, Isambert N, Lavilla R, Giralt E (2008) ChemMedChem 3:1558

214. 215. 216. 217. 218. 219. 220. 221. 222. 223. 224. 225. 226. 227.

Top Heterocycl Chem (2010) 25: 169–230 DOI: 10.1007/7081_2010_45 # Springer-Verlag Berlin Heidelberg 2010 Published online: 27 July 2010

Microwave Irradiation and Multicomponent Reactions Jitender B. Bariwal, Jalpa C. Trivedi, and Erik V. Van der Eycken

Abstract A common theme throughout drug discovery and process development is speed. With the emergence of combinatorial chemistry and high-speed parallel synthesis, multicomponent reactions (MCRs) have seen a resurgence of interest. MCRs are therefore becoming increasingly popular since they provide the possibility to introduce a large degree of chemical diversity in only one step! Microwave irradiation under controlled conditions has been shown to be an invaluable technology since it often allows to dramatically reduce reaction times from days or hours to minutes or even seconds. Compound libraries can be rapidly synthesized in either a parallel or sequential way using this new, enabling technology. The current chapter highlights the application of microwave irradiation for MCRs during the last 4 years. More than 110 recent literature reports have been covered. Keywords Microwave-assisted organic synthesis (MAOS) Multicomponent reaction (MCR)

Contents 1 2

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Recent Literature Reports . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1 Pyridines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2 Pyrimidines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3 Quinolines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.4 Imidazoles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.5 Thiazolines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.6 Pyrazoles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.7 Acridines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

170 171 171 183 191 203 206 206 207

J.B. Bariwal, J.C. Trivedi, and E.V. Van der Eycken (*) Department of Chemistry, Laboratory for Organic & Microwave-Assisted Chemistry (LOMAC), Katholieke Universiteit Leuven, Celestijnenlaan 200F, 3001, Leuven, Belgium e-mail: [email protected]

170

J.B. Bariwal et al.

2.8 Oxazepines, Thiazapines and Benzodiazepines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.9 Chromens . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.10 Pyrans and Furans . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.11 Propargylamines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.12 Miscellaneous . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 Conclusions and Outlook . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

209 211 212 213 215 221 222

1 Introduction One of the major tasks facing the pharmaceutical industry is improving the efficiency of its explorative research. The development of chemical compounds with desired biological properties is time-consuming and expensive. Therefore there is an ever-growing interest in the development of high-throughput techniques that allow for the fast synthesis and screening of chemical substances to identify compounds with the required characteristics. The application of combinatorial compound libraries plays nowadays an important role for reaching this goal and multicomponent reactions (MCRs) are viewed as ideal tools to assemble large compound libraries for medicinal purposes [1–4]. By minimizing the number of synthetic operations while maximizing the buildup of structural and functional complexity, these reactions are particularly appealing in this context. Since the development of what we commonly know as the ur-MCRs as the Strecker amino acid synthesis [5, 6], the Hantsch dihydropyridine synthesis [7, 8], the Biginelli dihydropyrimidine synthesis [9, 10], the Mannich reaction [11, 12] and the isocyanide-based Passerini reactions [13–15] and Ugi four-component reactions [16–18], a rich arsenal of novel MCRs has been developed in recent years. The fact that most MCRs are highly suited for automation makes them extremely valuable for high-throughput synthesis. According to Ugi, MCRs are one-pot procedures in which at least three easily accessible starting materials react to give a single reaction product, in which all of the atoms of the starting materials are incorporated [15]. However, considering the wealth of existing literature nowadays concerning MCRs, we have to introduce the concept of tandem reactions. Generalizing the definition given by Denmark, tandem reactions are best described as one-pot sequences of two or more reactions [19]. In this regard, MCRs can be regarded as a subclass of either tandem sequential or higher order tandem domino reactions. Tandem sequential reactions require the addition of a supplementary reactant after completion of the first reaction step enabling the propagation of the sequence [20]. Tandem domino reactions [21] are processes in which every reaction step brings about the structural change required for the following reaction step. The reaction proceeds without modification of the conditions or addition of supplementary reagents. Ideally, at least the last reaction step of a MCR should be irreversible in order to avoid the formation of a mixture of products.

Microwave Irradiation and Multicomponent Reactions

171

The main concern for the development of high-throughput procedures is the rate of the applied reactions. In this regard, the application of microwave irradiation has been proven to be very useful. Since its dawn in 1986 with the first seminal publications of the groups of Gedye [22] and Giguere [23] the application of microwave irradiation in organic synthesis has gained increasing popularity in the organic synthetic lab. Started as a curiosity, this way of transferring energy to a reaction mixture is steadily becoming the Bunsen burner of the present day [24]. Controlled microwave irradiation under sealed vessel conditions has been shown to dramatically reduce reaction times, increase product yields and to enhance product purity by reducing unwanted side reactions compared to conventional synthetic methods [25–28]. Microwave chemistry generally relies on the ability of the reaction mixture to efficiently absorb microwave energy, taking advantage of “microwave dielectric heating” phenomena such as dipolar polarization or ionic conduction mechanisms [25]. The very efficient internal heat transfer results in minimized wall effects which may lead to for example diminished catalyst deactivation [25]. Besides the generally accepted thermal effects, one believes that there are some specific (but also thermal) microwave effects, as e.g., the formation of “hot spots.” There is still some controversy about the existence of nonthermal (athermal) microwave effects. At the present time, new techniques as “cooling while heating” are being investigated and the problem of upscaling for industrial purposes has been tackled with the introduction of continuous and stop-flow microwave systems, although certainly still a long way has to be gone. Therefore, it is no surprise that the application of microwave irradiation has found its way to multicomponent chemistry as several of these MCRs suffer from long reaction times [4, 29]. The present chapter is organized according to the class of scaffold that is accessed via a MCR covering the literature from 2006 until present. A clear distinction is made between the application of dedicated microwave instruments and domestic microwave ovens. Although application of the last does not allow full control of the parameters, we reasoned that it was nevertheless worthwhile to include few of these examples. For more precise information about the conditions the reader is referred to the appropriate literature. Taking into account the current explosive developments in the field of MCRs, the present overview cannot be regarded as being exhaustive but is rather meant to provide a useful introduction.

2 Recent Literature Reports 2.1 2.1.1

Pyridines Dihydropyridines

1,4-Dihydropyridines, are very attractive targets because of their wide range of pharmacological activities; they have been reported for their vasodilating, antihypertensive, bronchodilating, anti-atherosclerotic, antioxidant, hepatoprotective,

172

J.B. Bariwal et al.

antitumor, antimutagenic, antidiabetic, geroprotective, and photosensitizing effects [30–34]. They are also important reducing agents for nicotinamide adenine dinucleotide coenzyme [NAD(P)H] models [35, 36]. Many drugs possess the 1,4-dihydropyridine nucleus, such as nifedipine, [37, 38] which has been used in clinical medicine since 1975, benidipine and lacidipine which are novel second generation calcium channel antagonists [39] and BAY K 8644 which is a calcium channel agonist [40]. Although numerous procedures have been developed for the synthesis of 1,4-dihydropyridines, the application of MCRs has been proven to be an excellent strategy to prepare libraries of these compounds. Li and co-workers [41] reported a facile one-pot two-step, MCR of a b-aroyl thioamide, an aldehyde, an acetonitrile and an alkyl halide using microwave irradiation to access highly functionalized hexa-substituted 1,4-dihydropyridines 1 in high yield in mere 18–25 min. The protocol was applied to aryl aldehydes bearing electron-withdrawing as well as electron-donating groups and also to aliphatic aldehydes. The nature of the substituents of the aryl aldehydes has no significant impact on the conversion (Scheme 1). A new series of some spiro-1,4-dihydropyridines 2 has been synthesized by Hatamjafari [42] in good yields using a four-component, solvent-free process by the condensation of isatin, a primary amine, ethyl cyanoacetate and cyclohexanone absorbed on different solid supports under microwave irradiation applying a domestic oven. The report reveals that the application of montmorillonite K10 led to higher yields as compared to other solid supports (Scheme 2).

O

R2

S

NC NHPh

R1

+ R2

R1 H2N

MW, 78°C, 18-25 min

O

O

R3

R3 1. Et3N 2. KI, KOH, R4X

N

SR

4

H 1 33 examples, 41-84%

Scheme 1 R2 R2 N

NC O +

R1

+ R3–NH2

O

Scheme 2

COOEt +

N

O

O Montmorillonite K10 MW, 4 min

R1 COOEt

N NH2 R3 2 7 examples, 78-97%

Microwave Irradiation and Multicomponent Reactions

2.1.2

173

Pyridines

The pyridine nucleus is a key constituent of many synthetic and naturally occurring bioactive compounds [43–46]. Streptonigrin, streptonigrone, and lavendamycin are described as anticancer drugs and cerivastatin is reported as a HMG-CoA enzyme inhibitor [47]. Substituted pyridines are used as leukotriene B-4 antagonists [48]. Pyridines have been invoked as functional modules within the domain of supramolecular chemistry, coordination chemistry, and material science [49–51]. They are employed as chelating ligands in coordination chemistry, as building blocks in supramolecular chemistry, as metal-containing polymers and in molecular electronics, optoelectronic devices, light-emitting diodes, solar cells and photoactivated species [52, 53]. Therefore, it is no surprise that much attention has been paid to the development of efficient procedures for the synthesis of functionalized pyridines. Yen and co-workers [54] have reported an efficient one-pot procedure for the synthesis of 4,6-diaryl-2-pyridinones 3 based on a cyclocondensation reaction of N-ethoxycarbonyl-methylpyridinium chloride or N-carbamoylmethyl pyridinium chloride with an aromatic aldehyde and a substituted acetophenone. The MCR was performed under microwave irradiation (domestic oven) with NH4OAc/AcOH as the reaction medium. The nature of the substituents on the aromatic aldehyde and ketone seem to have little influence on the obtained yields. The highlights of this approach include a convenient and simple experimental procedure with easy product isolation (Scheme 3). Recently, Tu and co workers [55] reported a green and facile synthesis of 2,6-diaryl-4-styrylpyridines 4 via a microwave-assisted MCR of an 3-arylacrylaldehyde oxime, a 1-arylethanone and ammonium acetate under solvent-free conditions. Electron-donating groups on the 3-arylacrylaldehyde oxime seem to prolong the reaction time. This protocol offers a broad scope of applicability (Scheme 4). Tu and co-workers [56] have developed a facile and selective synthesis of N-substituted 2-aminopyridines 5 via a microwave-assisted MCR which is controlled by the basicity of the amine and the nature of the solvent. When reacted in a solvent mixture of DMF/HOAc (1:1), the desired aminopyridine 5 was formed next to 2,6-dicyanoanilines in nearly equal amounts. However, when the volume ratio was increased to 1:4, compound 5 was obtained as the main product. The elaborated

Ar1 Ar1CHO Cl –

+

N

E O E = NH2, OEt

Scheme 3

Ar2COCH3

NH4OAc/AcOH MW, 2-4 min

Ar2

N

OH

3 7 examples, 65-82%

174

J.B. Bariwal et al. Ar1 H O Ar1–CH=CH–CH=N–OH

+ Ar2

+ NH4OAc

H

solvent free MW, 110°C, 6-18 min

Ar2

N

Ar2

4 12 examples, 76-87%

Scheme 4

Ar1

Ar1 CN DMF/AcOH (1:4)

NC + O

Ar2

R1–NH2

MW, 100°C, 3-9 min

NC R1

N H

N

Ar2

5 29 examples, 76-90%

Scheme 5

Ar NC ArCHO

CN

NC

O

Glycol/AcOH

+ NH2 O O

MW, 120°C, 6-10 min

H2N

O

N

6 11 examples, 82-89%

Scheme 6

method is superior to the existing ones in view of the simplicity of the purification (recrystallization) and the good yields that are obtained (Scheme 5). The same group also published a facile one-step synthesis of methyl 4-substituted6-amino-5-cyano-2-methylpyridine-3-carboxylates 6 via a three-component reaction of an aromatic aldehyde, malononitrile and methyl 3-aminobut-2-enoate under microwave irradiation. A mixture of glycol/HOAc (2:1) was used at a ceiling temperature of 120 C delivering the compounds very rapidly in excellent yields. Aromatic aldehydes, bearing electron-donating or electron-withdrawing functional groups and heterocyclic aldehydes have been proven to show excellent reactivity under these conditions [57] (Scheme 6). Sridhar and co-workers [58] investigated the synthesis of 2-amino-3,5-dicarbonitrile-6-thio-pyridines 7 via a MCR of a suitable aldehyde with malononitrile and thiophenol, using a variety of Lewis acid catalysts such as ZnCl2, AlCl3, FeCl3, I2, Cu(OTf)3, InCl3 and BF3·Et2O under microwave irradiation at a ceiling temperature of 100 C in ethanol. ZnCl2 was found to be highly efficient yielding the derived compounds in 46–77% yield in mere 2–3 min. Applying the optimized protocol, a

Microwave Irradiation and Multicomponent Reactions

175

variety of substituted pyridines was synthesized using aliphatic and (hetero)aromatic aldehydes (Scheme 7). A series of 4-aryl-3,5-dicyano-2,6-di(30 -indolyl)pyridines 8 was synthesized by Ji and co-workers [59] via a one-pot MCR of an aromatic aldehyde, a 3-cyanoacetyl indole and ammonium acetate under microwave irradiation. The optimum ceiling temperature was found to be 140 C with AcOH/glycol (1:2) mixture as the solvent of choice. This protocol can be applied to aromatic aldehydes bearing electronwithdrawing as well as electron-donating groups and also to heterocyclic aldehydes. This MCR allows the incorporation of both the indole and the 3,5-dicyanopyridine moiety into a single molecule (Scheme 8). A series of 4-aryl-6-(1H-indol-3-yl)-2,2-bipyridine-5-carbonitriles 9 was synthesized by Perumal and co-workers [60] via a one-pot MCR of an aromatic aldehyde, a 3-(cyanoacetyl)indole, 2-acetyl pyridine and ammonium acetate by microwave irradiation under solvent-free conditions. The compounds were obtained in high yields and in a very short period of time as compared to conventional heating. Remarkably, when 2,4-dichlorobenzaldehyde was used in this reaction, only the Hantzsch 1,4-dihydropyridine was isolated which had to be separately dehydrogenated to get the targeted pyridine (Scheme 9). R1 2NC

O R

1

CN ZnCl2, Ethanol

+

H

Ph–SH

MW, 100°C, 2-3 min

NC

CN

S Ph

NH2

N

7 9 examples, 46-77%

Scheme 7 Ar O

CN NH4OAc, AcOH/glycol + ArCHO

2R1 N H

R1

MW, 140°C, 12-16 min

CN

NC

R1

N HN

NH

8

16 examples, 71-86%

Scheme 8 O

N O

Scheme 9

NC + ArCHO

+ N H

Ar

CN NH4OAc MW, 120°C, 13-18 min

N N 9 10 examples, 77-90%

HN

176

J.B. Bariwal et al.

Patel and co-workers [61] have reported the microwave-assisted synthesis of a series of 3-(2,6-diphenyl-4-pyridyl)hydroquinolin-2-ones 10 by a one-pot cyclocondensation reaction under Krohnke’s reaction conditions using 2-chloro-3-formyl quinoline, an acetophenone and N-phenacylpyridinum chloride in a mixture of ammonium acetate and acetic acid. Different kinds of substituents on the quinoline and acetophenone are well tolerated and most compounds 10 are obtained in high yield. This method allows the easy introduction of various substituents in the 2-, 4- and 6-positions of the pyridine 10 (Scheme 10). Zhou and co-workers [62] have reported a series of 2-amino-6-(2-oxo-2Hchromen-3-yl)-4-pyridine-3-carbonitriles 11 by a one-pot, MCR of 3-acetylcoumarin, an aromatic aldehyde, malononitrile, and ammonium acetate in acetic acid using a domestic microwave oven. Aromatic aldehydes bearing electronwithdrawing groups gave rather low yields of 11 (Scheme 11). The microwave-assisted synthesis of indeno[1,2-b]pyridines 12 and 13 have been reported by Tu and co-workers [63]. The 5H-indeno[1,2-b]pyridin-5-one framework is present in the alkaloids from Annonaceae species that represent a small but biologically intriguing group of compounds [64, 65]. Applying a microwave-assisted MCR with a suitable aldehyde, an acetophenone, a 1,3-indanedione or a 1-indenone and ammonium acetate in DMF, a small library of compounds 12

R1 NH

O N

O

+

Cl– +

R1

NH4OAc, AcOH

COCH3

CHO

MW, 118°C, 3-5 min R2

Cl

N

N 10 24 examples, 82-92%

R2

Scheme 10

Ar CN

O ArCHO + O

CN

O CN

Scheme 11

NH4OAc/AcOH MW, 10-13 min

N O

O

11 9 examples, 61-86%

NH2

Microwave Irradiation and Multicomponent Reactions

O

Ar1

Ar1CHO

O

NH4OAc /DMF

+ O

177

Ar2COCH3

MW, 120°C 6-15 min

Ar2

N 12

26 examples, 57-89%

Scheme 12

O

Ar1

Ar1CHO +

NH4OAc/DMF

Ar2COCH3

MW, 120°C 8-15 min

Ar2

N

13 9 examples, 57-83%

Scheme 13

NC

Ar

O

CN Ar +

+ R1SH or R1NH2 O

DMF MW, 120°C, 4-12 min

O

NC R1

X N X = S, NH 14 31 examples, 78-91%

Scheme 14

and 13 was synthesized in good yields. Aromatic aldehydes bearing electron-rich group require longer reaction time (Schemes 12 and 13). The same group has also developed a novel microwave-assisted three-component reaction between an arylidenemalononitrile, a 1,3-indanedione and a mercaptoacetic acid or a 4-methyl-benzenethiol or a substituted amine to afford a series of new polysubstituted indeno[1,2-b]pyridines 14 bearing a mercapto group or an amino group in the 2-position (Scheme 14). Arylamines containing either electron-donating groups or electron-withdrawing groups gave excellent results [66]. DiMauro and co-workers [67] have developed a rapid and efficient synthesis of 3-amino-imidazopyridines 16 using a microwave-assisted one-pot cyclization. The intermediate 15 was further reacted with various aryl bromides in the presence of a catalytic amount of Pd(dppf)Cl2 to yield the target compounds 16. The reaction scope is quite broad with respect to the aldehyde and aryl bromide components which might be electron-rich, electron-poor, aromatic, aliphatic, or sterically encumbered (Scheme 15).

178

J.B. Bariwal et al. NH2 N

O

B

O

R1CHO, CNR2 MgCl2 (4 Mol%), MeOH

N O

MW, 160°C, 10 min

R1

N

B O

R2

NH

R3Br, aq K2CO3 Pd(dppf)Cl2 (10 Mol%) R3 MW, 90°C, 30 min

N R1

N R2

NH

16 15 examples, 0-68%

15

Scheme 15

N NH2 N

+

R1CHO

+

CNR2

ZnCl2 (5 mol %) MW, 60 min

N

R1

NH R2 17 8 examples, 14-78%

Scheme 16

The synthesis of the same nucleus (imidazo[1,2-a]pyridines) 17 has been described by Rousseau and co-workers [68] applying zinc chloride. In a domestic microwave oven, in one-pot fashion, a number of imidazo[1,2-a]pyridines has been synthesized in reasonable yields and with short reaction times. The reaction with nicotinaldehyde did not proceed to completion, as zinc chloride form a stable complex with the imine. However, when Montmorillonite clay K10 was used as catalyst, the desired product was obtained in good yield (Scheme 16). Similarly, a novel one-pot microwave-assisted reaction has been described by Hulme and co-workers that enables the selective formation of 3-iminoarylimidazo[1,2-a]pyridines 19 and imidazo[1,2-a]pyridyn-3-ylamino-2-acetonitriles 20, in good yields. Reactions were performed in methanol by mixing a suitable a-aminopyridine, an aldehyde and trimethylsilylcyanide (TMSCN) with polymerbound scandium triflate, to afford either product 19 or 20 (Scheme 16). Initially, the 3-iminoaryl-imidazo[1,2-a]pyridine 19, was observed as a minor side product (0– 10%) during the pseudo-Ugi reaction affording the 3-aminoimidazo[1,2-a]pyridine 18. However, by increasing the aldehyde input to 2.2 equiv the reaction could be directed to the formation of 19 in moderate yields. Interestingly, low yields of 20 were detected with aromatic aldehydes, whereas nonaromatic aldehydes were easily undergoing the second Strecker reaction in high yields [69] (Scheme 17). Yadav and co-workers [70] described two very efficient and unprecedented one-pot high-yielding synthetic approaches to imidazo[1,2-a]pyridine scaffolds 21 starting from carbohydrates. The first approach involves a microwave-assisted acid-catalyzed domino reaction of unprotected D-glucose or D-xylose with ammonium acetate and a benzoin to afford a polyhydroxy iminosugar-bearing tetrahydroimidazo[1,2-a]pyridine 21a or 21b. In the second approach, polyhydroxy iminosugar-bearing tetrahydrobenzimidazo[1,2-a]pyridines 21c and 21d

Microwave Irradiation and Multicomponent Reactions

179 R2

R2

1

R

PS-Sc(OTf)3 R2CHO (5 mol %) N + MeOH NH2 Si CN MW, 140°C, 5-20 min

NH2 1

R

N

HN

N 2

1

R N

18

R

N

R2

N 19 6 examples, 31-51%

CN

N

R1

R2

N 20 6 examples, 62-77%

Scheme 17

OH HO

OH HO

OH

OH N N

OH Ar2

Ar1 21a

HO

OH N

n=4 oxalic acid

OH

N

MW, 80°C, n=3 9-13 min Ar 2 O 1

Ar Ar2

Ar1 21b

8 examples, 80-96%

N

OH

N

OH +

NH2OAc

CHO (CHOH)n CH2OH D-glucose, n=4 D-xylose, n=3

n=4 oxalic acid MW, 80°C, 8-14 min NH2

21c OH

n=3

HO

OH N

N

NH2 21d 8 examples, 79-81%

Scheme 18

were synthesized by reacting D-glucose or D-xylose and 1,2-diamines in the presence of 10 mol% of oxalic acid under solvent-free microwave irradiation conditions. The protocol is generally high yielding and offers an easy access to chemically and pharmaceutically relevant products (Scheme 18). Li and co-workers [71] have presented a green and efficient reaction using KF/neutral Al2O3 cooperating with PEG 6000 an environmentally friendly, highly active catalyst. Under microwave irradiation the reaction leads to the unusual thiochromeno[2,3-b]pyridines 22 via a sequence of Knoevenagel condensation, Michael addition, cyclization, and intramolecular nucleophilic substitution. In this one-pot, three-component reaction, seven different active sites are involved and two C–C bonds, one C–S bond, one C–N bond, and two new rings are constructed. The nature of the solvent is significantly affecting the yield of the reaction. In general the application of protic or polar solvents such as ethanol, results in high yields while, non polar solvents like dichloromethane afford low yields due to the formation of many byproducts. Interestingly, the reaction is also working better with aromatic aldehydes (Scheme 19). Chebanov and co-workers [72] studied the microwave-assisted three-component reaction of a 3-substituted 5-aminopyrazole with pyruvic acid and an aromatic aldehyde yielding a pyrazolo[3,4-b]pyridine-4-carboxylic acid 23 as the major

180

J.B. Bariwal et al.

NC

CN

KF/neutral Al2O3 cat. PEG 6000 EtOH R1 MW, 80°C, 20-35 min

R2CHO +

O

S NHPh

R1

O

R2 CN

S

NH2

N Ph

22

Cl

29 examples, 62-88%

Scheme 19

R1 N

R1

O N R2

+ NH2

O

OH

Ethanol, HCl OH + ArCHO

O

N MW, 150°C 10 min

N R2

N

Ar

23 8 examples, 35-45%

Scheme 20

O

R2

CN

CN

R1 + N H

R2CHO

Glycol + N

N Ph

NH2 MW, 150°C, 6-15min

N N Ph

R1

N

NH 24 20 examples, 67-88%

Scheme 21

product. They found that this condensation could be carried out very efficiently either in acetic acid or in ethanol in the presence of HCl as catalyst. Yields for both protocols were similar and also comparable to the yields obtained under conventional reflux conditions, although the microwave-assisted reactions were much faster (Scheme 20). Ji and co-workers [73] have elaborated a simple and efficient approach for the synthesis of highly functionalized pyridines 24 via a one-pot, three-component reaction under microwave irradiation. This method enables the incorporation of a pyrazolo[3,4-b]pyridine and an indole moiety into the same molecule. The synthesis was achieved by reaction of a suitable aldehyde and 3-cyanoacetyl indole with 5-aminopyrazol. Particularly valuable features of this method include high yields, broad substrate scope, and short reaction times. It has been observed that when there are electron-withdrawing groups on the aryl aldehyde this results in a faster and higher yielding reaction (Scheme 21). Tu and co-workers [74] have synthesized a series of new polycyclic-fused isoxazolo[5,4-b]pyridines 25–29 by a one-pot tandem reaction under microwave

Microwave Irradiation and Multicomponent Reactions

181 Ar

O

O Water ArCHO + H2N

O

N + O

O

N

MW, 120°C, 3-7 min

O

N

O

25 8 examples, 84-91%

ArCHO + H2N

O

N

Ar

O

O Water

+

N

MW, 120°C, 5-8 min

O

O

O

O

N

26 10 examples, 88-94% Ar

O

Ar

Water ArCHO + H2N

O

N

N or

+ O N H 27-28

MW, 120°C, O

27 = 12 examples, 6-9 min, 87-95% 28 = 6 examples, 4-6 min, 84-95% O O O

O

N N

O

29 8 examples, 3-6 min, 83-89%

O = O O

for 27

O

O for 28

for 29

O

Scheme 22

irradiation in water. Interestingly, the reaction proceeds without any catalyst but the aliphatic aldehydes did not work under this protocol. It is noteworthy that with cyclohexane-1,3-dione, 1,4-dihydropyridines 28 are obtained. This method represents a green protocol and is highly suitable for library synthesis in drug discovery programs (Scheme 22). A one-pot, multicomponent, microwave procedure was efficiently applied for the synthesis of a series of diaza- and dibenzofluorenediones. The synthetic sequence starts by reacting 6,7-dichloroquinoline-5,8-dione or its metal complex with pyridine or 4-methyl pyridine and ethyl acetoacetate to get two regioisomers, N,N-syn 30 or 32 and N,N-anti 31 or 33. It has been found that DMSO is the solvent of choice resulting in high regioselectivity and good yields. However, when a catalytic amount of MgCl2 was used, a different regioselectivity was observed yielding 30/31 in the ratio of 8:92 [75] (Scheme 23). Similarly, pentacyclic ring systems were accessible when isoquinoline was used instead of pyridine, resulting in the formation of diaza-dibenzofluorenediones 34

182

J.B. Bariwal et al.

O

O

O

O

Cl N O or O

O +

O

DMSO

+ O

N

MW,110-140°C 4-6 min

Cl N Mn+

N R1 O 30 R1 = H, 32 R1 = CH3 + O R1 N N

R1

Cl

Cl

N

R1 = H, CH3

O

O O 31 R1 = H, 33 R1 = CH3 O

30 /31 (80:20), Yield 94% 32 / 33 (80:20), Yield 85%

Scheme 23

O

O O + Cl O

N+

O

O

DMSO O

O

N

N Cl

N

O

34

MW,110-140°C 4-6 min

O

+ N

N O

O

O

35 34/35 (72:28), Yield 87%

Scheme 24

and 35. A high selectivity of 72:28 was observed when DMSO was used as the solvent. Applying a catalytic amount of MgCl2, the ratio of 34/35 shifted to 15:85 [75] (Scheme 24). Shu-Jiang and co-workers [76] have developed a green approach for the synthesis of biologically important indeno[2,1-e]pyrazolo[5,4-b]pyridines 36 via a MCR of a suitable aldehyde, 3-methyl-1-phenyl-1H-pyrazol-5-amine and 1,3-indanedione in water under microwave irradiation without the aid of any catalyst. This protocol has the prominent advantages of being environmentally benign and having

Microwave Irradiation and Multicomponent Reactions

183 Ar

O N ArCHO + N Ph

O

Water

+

N MW, 100°C, O 5-9 min

NH2

N Ph

N 36

10 examples, 92-97%

Scheme 25

Ar OH O NH4OAc ArCHO

Catalyst =

H3C N

O

Catalyst

+

MW, 150°C, 50 min Cl– N +

Ar + 4H2O

N OH 37 14 examples, 40-71%

OSO3H

Scheme 26

a broad scope delivering the compounds in a short reaction time, with excellent yields (Scheme 25). Wu and co-workers [77] have developed a novel, simple and efficient method for the synthesis of 2,4,5-triaryl-5H-chromeno[4,3-b]pyridines 37 under microwave radiation via a three-component cascade reaction of 2-hydroxyacetophenone, an aromatic aldehyde and ammonium acetate catalyzed by 2-10 -methylimidazolium3-yl-1-ethyl sulfate. When an insufficient amount of (or no) catalyst was used, solely the corresponding chalcone was formed. Nine new bonds and two new rings are generated in a one-pot process with water as the only byproduct (Scheme 26).

2.2 2.2.1

Pyrimidines Dihydropyrimidines

Dihydropyrimidines (DHPMs) and their derivatives have received significant attention owing to their wide range of pharmacological properties such as antiviral [78], antimitotic [79], anticarcinogenic [80], antihypertensive [81], calcium channel modulator [82], a1-antagonist [83] and neuropeptide Y (NPY) antagonist activity [84]. Additionally, the marine alkaloids batzelladine A and B containing the DHPMs core, have been used to inhibit the binding of HIV gp-120 to CD4 cells [85]. Therefore, efforts for the development of simple, convenient, rapid and

184

J.B. Bariwal et al.

environmentally benign procedures for the synthesis of DHPMs based on the idea of green chemistry were elaborated in recent years. Sulfated zirconia (ZrO2/SO42) solid superacid has been proven by Gopalakrishnan and co-workers [86] to be an efficient reusable heterogeneous catalyst for the three-component one-pot cyclocondensation reaction of a b-dicarbonyl compound and (thio)urea with an aromatic aldehyde under solvent-free conditions furnishing the corresponding 3,4-dihydropyrimidin-2(1H)-ones and -thiones 38 in good to excellent yields. A substantial improvement of the yields was established when the reactions were run under microwave irradiation instead of conventional heating. The yields were practically unaffected upon recycling the ZrO2/SO42 solid superacid up to five times (Scheme 27). The Biginelli reaction has been investigated by Chang, Ahn and co-workers [87] under solvent-free conditions, catalyzed by porous material or Lewis acid supported porous material, such as MCM-41, SBA-15, VSB-5, Nanopore Silica, FeCl3/MCM41, FeCl3/Nanopore Silica, CeCl3/Nanopore Silica and InCl3/Nanopore Silica. Aromatic aldehydes carrying either electron-donating or electron-withdrawing substituents afforded good yields of the products 39 using MCM-41 as the catalyst. When FeCl3/Nanopore Silica was employed as heterogeneous catalyst, the yield of the Biginelli products 39 was found to increase dramatically. This reaction represents a very cost efficient procedure (Scheme 28). A new microwave-assisted protocol for the generation of diversely substituted 3,4-dihydropyrimidine-5-carboxylic acid esters 40 has been developed by Kappe and co-workers [88, 89] using trimethylsilyl chloride (TMSCl) as a mediator for the Biginelli MCR. This involved the reaction of S-ethyl acetothioacetate or ethyl acetoacetate, an aromatic aldehyde and (monosubstituted) urea or thiourea as building blocks. Also sterically hindered aromatic and heterocyclic aldehydes

O R1

+

O

NH2 H2N

O

Ar

O

ArCHO

X

ZrO2 /SO42–

R1

O

NH

H3C

MW, 53-69°C 30-60 s

N H

X

38

X = O, S

20 examples, 87-98%

Scheme 27

O

+ EtO O H2N

Scheme 28

O

ArCHO NH2 O

FeCl3 / Nanopore Silica MW, 180°C, 12 min

Ar

EtO

NH N H

O

39 7 examples, 36-73%

Microwave Irradiation and Multicomponent Reactions

185

performed well in this reaction. Compared to the use of other Lewis acids, the desired DHPMs were obtained in short reaction times and high yields (Scheme 29). The microwave-assisted Biginelli reaction was also optimized by the same authors under continuous flow conditions [90]. An equimolar reaction mixture of benzaldehyde, ethyl acetoacetate and urea was injected at a flow rate of 2 mL/min at a ceiling temperature of 120 C providing 52% of the desired DHPM 41 in 13 min of total processing time (5 min residence time in the cell). This flow rate allows the preparation of compound 41 on a 25 g/h scale (Scheme 30). Nanosized sulfated tin oxide (STO) particles dispersed in the micropores of Al-pillared clay (STO/Al-P), were used by Mishra and co-workers [91] as an environmentally benign, recyclable and efficient catalyst for the solvent-free synthesis of 3,4-dihydropyrimidin-2(1H)-ones 42 using a domestic microwave oven. The protocol offers advantages in terms of simple experimentation, reusable catalyst, excellent yields, short reaction times, and preclusion of toxic solvents (Scheme 31). O

ArCHO

O

TMSCl, MeCN +

EtX

NH2 HN R1

O

O/S

NH

EtX

MW,120°C, 10 min

R1 = H, CH3,C2H5

X = O, S

Ar

O/S

N R1

40 13 examples, 53-94%

Scheme 29 O

Ar

ArCHO

O

EtOH/AcOH/HCl +

EtO

NH2

O H2N

O

NH

EtO

Batch: MW,120°C, 5 min residence time (2 mL /min flow rate)

N H 41

O

52%

Scheme 30

O

ArCHO O R1

Scheme 31

O

O

+

R2

STO/Al-P, solvent free

H2N

MW, 60-120 s NH2

Ar

R1

NH R2

N H

O

42 13 examples, 83-94%

186

J.B. Bariwal et al.

A novel and efficient ionic liquid synthesis of DHPMs has been developed by Bazureau and co-workers [92] in which ionic liquid-phase bound acetoacetate was reacted with (thio)urea and a suitable aldehyde in the presence of HCl affording ionic liquid-phase supported 3,4-dihydropyrimidine-2-(thi)ones 43. The desired 3,4-dihydropyrimidine-2-(thi)one was easily cleaved from the ionic liquid-phase by transesterification under mild conditions in good yield and with high purity. Advantageously, the ionic liquid-phase linked DHPM could be crystallized from the excess of (thio)urea (Scheme 32). A simple, efficient and modified Biginelli procedure was developed by Shah and co-workers [93] for the synthesis of tetrahydropyrimidines 44 by a solvent and catalyst-free condensation of a 1,3-dicarbonyl compound, an aryl aldehyde and (thio)urea applying microwave irradiation. The desired compounds 44 were obtained in short reaction times and in better yields compared to conventional heating (Scheme 33). An efficient and high-yielding protocol was established by Wang and co-workers [94] for the synthesis of 5-unsubstituted-3,4-dihydropyrimidin-(1H)-ones 45 involving a three-component, one-pot solvent-free condensation of an aromatic aldehyde, acetophenone and urea using ZnI2 as the catalyst applying a domestic microwave oven. Aliphatic aldehydes did not deliver the expected products 45 using this protocol (Scheme 34). Sheibani and co-workers [95] reported the synthesis of 4-amino-5-pyrimidinecarbonitriles 46 via a three-component reaction of malononitrile, an aldehyde and a N-unsubstituted amidine in water, in the presence of sodium acetate applying a domestic microwave oven. This method provides a new route to produce pyrimidine derivatives in good to excellent yields (Scheme 35). +

N

O

N

O – O .PF6

O + O

X

O H N 2

O

HCl (cat.) MW, 10 min

HN X

N

O

N

+

O

N H

.PF6–

O

NH2 43

X = O, S

2 examples, 96-98%

Scheme 32

O

O ArCHO NH2

+ O

Scheme 33

F3C

O

H

H2N

Solvent free

X MW, 110-120°C, 1.5-6.5 min X = O, S

Ar

HO O

F3C

N H

H NH X

44 15 examples, 78-85%

Microwave Irradiation and Multicomponent Reactions

187

O H2N

O NH2

Znl2, solvent-free

+ ArCHO

PhCOCH3

MW, 8 min

HN

NH

Ph

Ar 45 16 examples, 71-96%

Scheme 34 Ar

NH R1

NH2 · HCl +

NC

ArCHO

CN

H2O CH3CO2Na MW, 25-120 s

N

CN

R1

N NH2 46 11 examples, 67-96%

Scheme 35

2.2.2

Fused Pyrimidines

Moving to fused pyrimidines, Tu and co-workers [96] elaborated a microwaveassisted three-component reaction for the synthesis of 2-amino pyrido[2,3-d]pyrimidines 47–50. 2,6-Diaminopyrimidin-4-one was reacted without any catalyst with an aldehyde and malononitrile, ethyl cyanoacetate, 2-cyanoacetamide or Meldrum’s acid. Importantly, aromatic and aliphatic aldehydes perform equally well in the reaction to give the desired products in good yields (Scheme 36). A new procedure has been developed by Prajapati and co-workers [97] for the synthesis of pyrimido[4,5-d]pyrimidines 51. The condensation was carried out in the solid state under microwave irradiations by reacting electron-rich 6-[(dimethylamino)methylene]amino uracil that undergoes a [4+2] cycloaddition reaction with in situ generated glyoxylate imine to provide novel pyrimido[4,5-d]pyrimidines 51 in excellent yields (Scheme 37). A series of 1,2,4-triazolo[4,3-a]pyrimidines 52 was synthesized in excellent yield by Dandia and co-workers [98] via a microwave-assisted reaction of the 1H-1,2,4-triazol-5-amine, a suitable carbonyl compound and malononitrile in aqueous medium. A variety of aromatic aldehydes and cyclic and aliphatic ketones was successfully used to give the desired compounds 52 in good to excellent yields. The reactions were carried out in a domestic microwave oven (Scheme 38). Boruah and co-workers [99] developed an efficient procedure for the synthesis of ring-A fused [3,2-b]pyrimidines 53 in a steroidal moiety. The novel steroidal pyrimidines were prepared via a solid phase three-component reaction of a 2-hydroxymethylene-3-keto steroid, an arylaldehyde and ammonium acetate under microwave irradiation. This protocol has been applied successfully to the cyclization of bicyclic, monocyclic and acyclic 2-hydroxymethylene ketones with diversely substituted aromatic aldehydes (Scheme 39).

188

J.B. Bariwal et al. R1

O

CN

HN N

H2N

O

N H

49 8 examples, 73-94%

NC

O

R1

O

CN

HN H2N

N

N

MW, 120°C 6-8 min

CONH2

NH2

MW, 120°C

O

H2N

NH2

N

O

MW, 120°C 7-10 min

+

6-8 min

47 8 examples, 74-99%

O

HN

CN

NC

O O

R1

N

N H

HN H2N

50

R1CHO

8 examples, 78-93% MW, 120°C 6-8 min

COOEt

NC

R1

O

CN

HN

N O H 48 8 examples, 73-94%

H2N

N

Scheme 36 O N O

N

N

NMe2

O

COOEt Ar N

N

N

N

Neat conditions O

MW, 110°C, 3.5-4.5 min

COOEt + ArNH2 CHO

51 6 examples, 80-95 %

Scheme 37 N N N NH N

O + NC NH2

CN +

aq. medium

N

NH

MW, 7-13 min Substituted aromatic aldehyde or cyclic ketone

Scheme 38

O

NH2 CN 52 10 examples, 78-94%

Microwave Irradiation and Multicomponent Reactions

189

A efficient three-component solution-phase condensation of a 3-amino-5alkylthio-1,2,4-triazoles with an aromatic aldehyde and an acetoacetamide was developed by Chebanov and co-workers [100] for the rapid synthesis of 7-aryl2-alkylthio-4,7-dihydro-1,2,4- triazolo[1,5-a]pyrimidine-6-carboxamides 54. All reactions were completed within 5 min of microwave irradiation at 120 C and provided the desired dihydroazolopyrimidines 54 in high yields and with excellent purities. The cyclocondensation reactions were performed in ethanol and a significant decrease of the product yield was observed when switching the solvent to acetic acid or DMF or when an acidic catalysts was added (Scheme 40). Tu and co-workers [101] reported the synthesis of a series of novel pyrimido [5,4-b][4, 7]phenanthroline-9,11(7H,8H,10H,12H)-diones 55 via a microwaveassisted three-component reaction of barbituric acid, an aldehyde and quinolin6-amine in DMF without any catalyst. The results suggest that aldehydes bearing electron-withdrawing groups have higher reactivity providing higher yields in shorter reaction times (Scheme 41). R1

HO

MW, 120°C

A O

ArCHO

R1

H +

N

6-9 min

Ar

A N

H

53 7 examples, 79-88%

NH4OAc

Scheme 39

ArCHO +

N NH S

N

Ar

R2 NH

O O

EtOH S MW, 120°C, 5 min

R1

O

N N N

N H

R2

N H

NH2

54 15 examples, 75-95%

R1

Scheme 40 O HN O

O H2N +

N H

O

DMF + ArCHO N

MW, 110°C, 6-15 min

Ar N

HN O

N H

N H

55 9 examples, 72-92%

Scheme 41

190

J.B. Bariwal et al.

An interesting approach for the synthesis of some fused pyrimidines has been reported by Shaaban [102] via reaction of 4,4,4-trifluoro-1-(thien-2-yl)butane1,3-dione in the presence of triethylorthoformate with 5-aminopyrazole or 1,2,4aminotriazole or 2-aminobenzimidazole under microwave irradiation. The resulting trifluoromethyl derivatives of pyrazolo[1,5-a]pyrimidine 56, 1,2,4-triazolo[1,5-a] pyrimidine 57 and pyrimido[1,2-a]benzimidazoles 58 were obtained in excellent yields and purity (Scheme 42). Tu and co-workers [103] have elaborated an efficient microwave-assisted synthesis of 4,5-bis-phenyl substituted benzo[4,5]imidazo[1,2-a]pyrimidines 59 through a MCR of an aromatic aldehyde with 1,2-diphenylethanone and 2-aminobenzimidazole. PEG-300 was used as an inexpensive, nontoxic, and recyclable reaction medium which can be reused up to three times without reduction of the product yield although a weight loss of 10% PEG was observed per cycle (Scheme 43). O

R2

CF3 N

S

R1 R2

N N R1

56

NH2

N N

NH N

MW, 100°C 5 min

CF3

S O

5 examples, 75-89%

O

NH2

O

N H

CF3 N

MW, 100°C 5 min

S

N

+

57

CH(OEt)3

91% N

MW, 100°C 5 min

NH2 N H CF3

O

N S

N

N

58 83%

Scheme 42

Ph

PEG-300, K2CO3

N

MW, 120°C, 10-18 min

O + H2N

ArCHO + Ph

Ar

H N

Ph

N N H

N

Ph

59 11 examples, 75-87%

Scheme 43

N N

Microwave Irradiation and Multicomponent Reactions

191 Ar

O N N Ph

ArCHO +

N + NH2

O NH O

O

H2O MW, 110°C 5-10 min

N

N N Ph

N N O H 60 12 examples, 80-88%

Scheme 44 O R1 N + ArCHO O

N

R1 H2N + O

O N

AcOH/Glycol (1:1)

R1

S

MW, 130°C, 5 min

O

Ar

N S

N N N H R1 61

10 examples, 90-93%

Scheme 45

A green approach for the synthesis of polyfunctionalized pyrazolo[40 ,30 :5,6]pyrido [2,3-d]-pyrimidines 60 was elaborated by Tu and co workers [104] via a MCR of an aromatic aldehyde, a 3-methyl-1-phenyl-1H-pyrazol-5-amine and 1-methylbarbituric acid in water under microwave irradiation without catalyst. The yield of this reaction was affected by the volume of water. This protocol could be applied to aromatic aldehydes with either electron-withdrawing or electron-donating groups and also to heterocyclic aldehydes giving excellent yields (Scheme 44). The same group [105] has synthesized a series of new pyrido[2,3-d]pyrimidines 61 via a MCR of an aromatic aldehyde, a barbituric acid, and 5-amino-2-methylbenzo[d]thiazol applying a solvent mixture of acetic acid and ethylene glycol (1:1) under microwave irradiation (Scheme 45). Tu and co-workers [106] also reported a novel and highly stereoselective fourcomponent protocol reacting 2,6-diaminopyrimidine-4-one with an aryl aldehyde and a barbituric acid, resulting in the generation of new 6-spirosubstituted pyrido [2,3-d]pyrimidines 62 as a mixture of two diastereoisomers in which the 5,7-cis isomer prevails. Water was used as the solvent and the reaction was run under microwave irradiation. The reaction did not proceed with aliphatic or heteroaryl aldehydes (Scheme 46).

2.3

Quinolines

2.3.1

Quinolines

The quinoline moiety is an important core structure of several natural and synthetic heterocyclic compounds that show remarkable medicinal activities [107]. In particular, quinolines have played a unique role in the design and synthesis of

192

J.B. Bariwal et al. O

O R1

HN H2N

R1

O N

NH2

N

+

N R2

O O

2ArCHO

H2O MW, 100°C, 6-9 min

N

O N

O Ar O

R2

R1

O Ar + NH

HN

N

N

O Ar O

N

R2 O Ar

NH

HN

N

NH2

NH2 62 up to 99:1 19 examples, 79-90%

Scheme 46

O

R1 + R2

ArCHO + O

O

O

O

O + O

R3–NH2

Ar

EtOH MW, 100°C 4-9 min

R1 R2

N R3

O

63 R1

= H, CH3 R2 = CH3, Cyclopropyl, p -tolyl 18 examples, 82-96%

Scheme 47

novel biologically active compounds serving as anti-inflammatory, antiasthmatic, antituberculosis, antibacterial, antihypertensive, antitumor, and antimalarial agents [108, 109]. A series of N-substituted 4-aryl-4,6,7,8-tetrahydroquinoline-2,5(1H,3H)-diones 63 has been synthesized by Tu and co-workers [110] through a rapid one-pot fourcomponent reaction of an aldehyde, Meldrum’s acid, a 1,3-cyclohexanedione and an amine in ethanol under microwave irradiation. This method allows the introduction of substituents at the nitrogen of octahydroquinolones 63. The reaction has a wide scope as different aromatic aldehydes and a variety of amines (including aliphatic and aromatic) are well tolerated in this four-component condensation (Scheme 47). A new series of polyhydroquinolines 64 has been prepared by Shingare and co-workers [111] using nanosized Ni as a heterogeneous catalyst in a one-pot synthesis via Hantzsch condensation by reacting an aldehyde, dimedone, ethyl acetoacetate and ammonium acetate in a domestic microwave oven. Ni (80 0.5 nm), having a higher surface to volume ratio, has given the best results in terms of short reaction times and excellent product yields. This method has demonstrated that Ni, in the form of nanoparticles, is a potential alternative catalyst for the Hantzsch

Microwave Irradiation and Multicomponent Reactions

193

condensation. It was demonstrated that the catalyst can easily be recovered and reused up to four times without noticeable loss of activity (Scheme 48). Tu and co-workers [112] have elaborated a simple and efficient microwaveassisted one-pot three-component synthesis of polysubstituted quinoline-3-carbonitriles 65 in excellent yields. An aldehyde, malononitrile and an enaminone were reacted in acidic medium using microwave irradiation. When the reaction was performed at high temperature, compound 65 was observed as the main product (Scheme 49). An efficient one-pot procedure for the synthesis of 4-aryl-8-arylidene-5,6,7,8tetrahydro-2-quinolinones 66 has been developed by Yen and co-workers [54] based on a cyclocondensation reaction of N-ethoxycarbonylmethylpyridinium chloride with an aromatic aldehyde and cyclohexanone. The microwave-assisted (domestic microwave oven) MCR resulted in the formation of compound 66 in high yields (Scheme 50).

Ar

O

O O ArCHO +

O

COOC2H5

NH4OAc / Ni-Nanoparticles

+ OC2H5

N H

MW, 1-1.5 min

O

64 15 examples, 85-96%

Scheme 48

NC

CN

Ar1 O AcOH

Ar1CHO

+ Ar2HN

R1 R2

MW, 120°C, 5-8 min

O

NC H2N

N Ar2

R1 R2

65 6 examples, 86-92%

Scheme 49

O Ar +

+

N Cl – O O

Scheme 50

2ArCHO

NH4OAc/AcOH MW, 2-4 min

O

N H

Ar 66 5 examples, 53-83%

194

J.B. Bariwal et al.

Sheng and co-workers [113] described an efficient Hantzsch reaction for the synthesis of polyhydroquinolines 67 applying a solvent-free microwave-assisted one-pot four-component reaction of PEG-bound acetoacetate, 1,3-cyclohexanedione, an aromatic aldehyde and ammonium acetate in the presence of a catalytic amount of PPA. The target compounds 67 were obtained in excellent yields and purities, after cleavage from the PEG support using NaOEt in EtOH. The reactions were carried out in domestic microwave oven (Scheme 51). Tu and co workers [114] reported a series of new pyrazolo[4,3-f]quinolin-7-ones 68 synthesized by a MCR of an aromatic aldehyde with Meldrum’s acid and 1H-indazol-5-amine in ethylene glycol without any catalyst under microwave irradiation. Among various polar solvents tested, ethylene glycol gave the highest yields. Various (hetero)aromatic aldehydes could be used (Scheme 52). Tu and co-workers [112, 115] elaborated a green protocol for the synthesis of polysubstituted indeno[1,2-b]-quinolines 69 via condensation of an aldehyde, 1,3-indanedione and an enaminone using p-toluene sulfonic acid as the catalyst in water under microwave irradiation. A series of 23 indeno[1,2-b]quinolines 69 was generated in excellent yields. The same authors have also described the microwaveassisted synthesis of these compounds in acetic acid as solvent (Scheme 53). Ferrocene derivatives coupled with heterocyclic systems have attracted special attention in recent years because of their interesting organic and inorganic properties. Recently, an efficient and rapid route for the synthesis of 4-aryl-2ferrocenyl-quinolines 70 has been described by Tu and co-workers [116] through a microwave-assisted MCR of acetylferrocene with an aromatic aldehyde and dimedone in the presence of ammonium acetate in DMF. This novel procedure provides the target hetero-metallic compounds in excellent yields without the need of any purification (Scheme 54). O

Ar

O

ArCHO O

O

+

O

O

NH4OAc, PPA

OEt

MW, 3-4 min

N H

O

67 9 examples, 95-97%

Scheme 51

O NH2 Ethylene glycol

O ArCHO +

+ N O O

Scheme 52

N H

MW, 130°C 9-12 min

N HN

Ar

O N H 68 9 examples, 80-88%

Microwave Irradiation and Multicomponent Reactions Ar1CHO

195 Ar1

O

O

O

O

H2O, p-TsOH

+ R2 R2

Ar2HN O

MW, 150°C, 2-7 min

R2 N R2 Ar2 69 23 examples, 86-94%

Scheme 53 Ar O

O

ArCHO O

Fe

N H

DMF

+ NH4OAc

MW, 100°C, 9-15 min

O

Fe 70 9 examples,75-93%

Scheme 54 O

O

O

Ar

O

AcOH

ArCHO +

+ O

O

R1 R1

NHR2

MW, 100°C, 5-9 min

O N R2 71 28 examples, 90-98%

R1 R1

Scheme 55

Moving to some complex quinoline derivatives, Tu and coworkers [117] have developed a sequential three-component reaction of an aldehyde, tetronic acid and an enaminone using a small amount of glacial acetic acid under microwave irradiation to obtain N-substituted furo[3,4-b]quinolines 71 in excellent yields and purities. In this way a series of aza-analogs of the antitumor compound podophyllotoxin was synthesized (Scheme 55). A number of unusually fused heterocyclic compounds have been reported by Tu and co-workers [118]. The three-component domino reaction of an aldehyde, an enaminone 72 and malononitrile resulted in the formation of polysubstituted imidazo[1,2-a]quinazolines 73 and pyrimido[1,2-a]quinolines 74. (Scheme 56) When enaminone 75 was reacted using the same reaction conditions, this resulted in the formation of quinolino[1,2-a]quinazolines 76 in good yields. In this one-pot reaction, up to five new bonds were formed accompanied by the generation of the lactam group. Interestingly, the volume of ethylene glycol used seems to influence the yield of the product (Scheme 57).

196

J.B. Bariwal et al. O CN

ArCHO

CN Ethylene glycol

+ CN

Ar

O MW, 120°C, 4-8 min

R1

R2HN

R1

R1 R1

R2 = CH2COOH or CH3CHCOOH or CH2CH2COOH

N

NH

R3

n

O

3

R = H or CH3 73, n = 0 74, n = 1 33 examples, 81-89%

72

Scheme 56 O

R1

O

R1CHO

CN

CN

Ethylene glycol

+ CN

HN

N

MW, 120°C, 5-8 min

HOOC

NH O

R2

R2 75

76 9 examples, 80-88%

Scheme 57

R1 R

1

OH + NH2

ArCHO

+ O

OH

TFA (0.13 equiv.) CH3CN n

MW, 60°C, 15 min

NH Ar

O n

77 10 examples, 39-59%

Scheme 58

The synthesis of functionalized 8-hydroxy-1,2,3,4-tetrahydroquinolines 77 has been reported by Dai and co-workers [119] in moderate to good yields via an azaDiels–Alder reaction of an 2-aminophenol, a substituted benzaldehyde and a cyclic alkene catalyzed by TFA under controlled microwave irradiation in acetonitrile. In general, when electron deficient aromatic aldehydes were used, the adducts could be isolated in 39–59% yields with a predominance of the trans isomer (Scheme 58). Ji and co-workers [73] have reported a new series of polysubstituted (30 -indolyl) benzo[h]quinoline 78, synthesized via a one-pot MCR of an aldehyde, 3-cyanoacetyl indole, and naphthylamine under microwave irradiations in good yields (Scheme 59).

Microwave Irradiation and Multicomponent Reactions

197 Ar

CN

O

NC

NH2 Glycol

N

+ MW, 150°C, 12-15 min

N H ArCHO

HN 78 5 examples, 67-72%

Scheme 59

O ArCHO + O

Ar

DMSO, Flow reactor

+ HN N

NH2 MW, 29 min

O

HN N

N H

79 7 examples, 55-94%

Scheme 60

Organ and co-workers [120] described a unique approach to MCRs using a microwave-assisted, continuous flow process for the synthesis of new series of tetrahydro-pyrazolo[3,4-b]quinolin-5(6H)-ones 79. An aldehyde, dimedone, and 5-amino-3-methyl-1H-pyrazole were reacted, yielding the desired compound 79 in moderate to excellent yields. It was proved that the electronic properties of the substituted benzaldehydes have an important impact on the conversions as with electron-donating groups rather low yields were obtained (Scheme 60). A microwave-assisted three-component coupling reaction of 5-amino-3-phenylpyrazole, a cyclic 1,3-dicarbonyl compound and an aromatic aldehyde has been described by Chebanov and co-workers [121]. Depending on the applied reaction conditions a series of 4-aryl-3-phenyl-1,4,6,7,8,9-hexahydro-1H pyrazolo[3,4-b] quinolin-5-ones 80, 9-p-tolyl-6,6-dimethyl-2-phenyl 5,6,7,9-tetrahydro-pyrazolo [5,1-b]quinazolin-8-ones 81, or 4-aryl-5a-hydroxy-4,5,5a,6,7,8-hexahydropyrazolo[4,3-c]quinolizin-9-ones 82 can be formed (Scheme 61). Tu and co-workers [122] have reported the synthesis of a series of new bifunctional compounds 83 containing a bisfuro[3,4-b]quinoline and a bisacridinedione skeleton through a rapid one-pot three-component reaction of a dialdehyde with an N-aryl enaminone and a cyclic-1,3-dicarbonyl compound (tetronic acid or cyclohexane-1,3-dione) in a solvent mixture of AcOH/DMF (2:1) using microwave irradiation. The described compounds 83 were obtained in good to excellent yields. N-Aryl enaminones bearing electron-withdrawing groups on the aryl substituent require longer reaction times (Scheme 62). Ji and co-workers [123] have reported a simple and efficient synthesis of spiro [indoline-3,40 -quinolines] 84 by a one-pot reaction of an isatin, malononitrile, and

198

J.B. Bariwal et al.

O Me3SiCl, MeCN

N N

Ph MW, 170°C, 30 min

R1

N H

R1

81 1 example, > 98% Ar

Ph Ph

EtOH, Et3N

+ N

N H

NH2

O

O

ArCHO

R1

O

N N H

MW, 150°C, 15 min

R1

R1 R1

N H 80

8 examples, 70-91% H

OH

Ar EtOH, KOtBu

N

Ph N NH

MW, 150°C, 15 min

R1 R1

O

82 9 examples, 38-75%

Scheme 61

H

O

O

O

O AcOH/DMF (2:1)

+

+

O H O

O =

O

Scheme 62

MW, 120°C, 7-16 min

NH O Ar

O

O or O

O

O

Ar N OO

83 11 examples, 82-92%

N

Ar

Microwave Irradiation and Multicomponent Reactions

199

an enaminone under microwave irradiation. The merits of the procedure include a broad substrate scope, short reaction times and high yields (Scheme 63). Fulop and co-workers [124] have reported the synthesis of some new (aminoalkyl) naphthols and (aminoalkyl) quinolinols 85 in good yields through a onepot, microwave-assisted three-component modified Mannich reaction of naphthol or quinolinol with two equivalents of an aldehyde using ammonium carbamate or ammonium hydrogen carbonate as solid ammonia sources. It was observed that aliphatic aldehydes did not lead to the formation of the desired (aminoalkyl) quinolinols 85 (Scheme 64).

2.3.2

Isoquinolines

An efficient, solid-supported reaction catalyzed by TiO2–silica gel has been investigated for the synthesis of a series of novel dispiroheterocyclic systems 86–89 by Raghunathan and coworkers [125]. An azomethine ylide generated from tetrahydroisoquinoline-3-carboxylic acid and acenaphthenequinone or isatin were reacted with various 2-arylidene-1,3-indanediones or (E)-2-oxoindolino-3-ylidene acetophenones in a one-pot three-component tandem reaction to give the products in high yields applying a domestic microwave oven. From the various solid supports that were evaluated, the combination of TiO2 with silica gel (1:1) was found to be the best, resulting in the rapid formation of the compounds in high yields. The reaction afforded a series of novel dispiroheterocycles 86–89 containing the acenaphthenone 3 R3 R

R4

O

O

N

CN R2

O + N R1

+ CN

O

EtOH R4

R3 R3

N H

MW, 80°C, 7-10 min

NH2

R2 N R1

O

CN

84 15 examples, 66-85%

Scheme 63

R1 OH R2

X

O Solid NH3 Source

+ 2R1CHO

Scheme 64

MW, 70-130°C, 30-45 min

R2

X

OH

NH R1

10% aq. HCl

R2

NH2.HCl

X

85 8 examples, 68-87%

R1

200

J.B. Bariwal et al. R1 O R1 HO

H

H O

N

TiO2-Silica gel MW, 2-7 min O

R1

O

COOH NH

+

H

O

O 86 5 examples, 82-95% R1 O

O O

H

N H TiO2-Silica gel MW, 2-7 min

H N

NH O

O 87 4 examples, 84-92%

Scheme 65

and oxindole ring systems by a regio- and stereocontrolled cycloaddition of the azomethine ylide to the exocyclic double bond of 2-arylidene-1,3-indanedione in all cases (Schemes 65 and 66). In a recent article by Beifuss and co-workers [126], the synthesis of pyrido [20 ,10 :2,3]imidazo[4,5-c]isoquinolin-5(6H)-ones 90 has been described in good yields by means of a microwave-assisted three-component reaction of a 2-aminopyridine, an isocyanide and a 2-carboxybenzaldehyde under acidic conditions. The reactions are easy to perform, robust, and highly efficient. This process allows the formation of two heterocyclic rings and four new bonds in a single synthetic operation (Scheme 67)!

2.3.3

Quinazolines

Kaur and co-workers [127] investigated the acid catalyzed condensation of tetralone, thiourea and a substituted benzaldehyde in acetonitrile under microwave irradiation to obtain 4-phenyl-3,4,5,6-tetrahydrobenzo[h]quinazoline-2(1H)thiones 91. A domestic microwave oven was used and the targeted compounds were obtained in moderate yields (Scheme 68). A microwave-assisted one-pot three-component reaction of a (un)substituted anthranilic acid, ribosylamine and an (un)substituted benzoic acid has been

Microwave Irradiation and Multicomponent Reactions

201 R1

O R1 H

HO

H

O N

TiO2-Silica gel MW, 2-7 min

N H

R1

NH

88

O

COOH

O

O

10 examples, 80-95% O

+

N H

H R1

O

O

O N H

H NH O

H N

TiO2-Silica gel MW, 2-7 min

O N H 89 5 examples, 82-88%

Scheme 66

R3 R3

NH2 R1

R4

N

OHC R2NC

N

MsOH, Toluene

+ COOH

MW, 160°C 7 min

R4

R1

N N R2

O

90 16 examples, 38-68%

Scheme 67

S S H2N O

NH2 HCl (conc.), CH3CN

+ ArCHO

HN

NH Ar

MW, 3.3-6.3 min 91

7 examples, 35-53%

Scheme 68

202

J.B. Bariwal et al.

investigated by Siddiqui and co-workers [128] using a domestic microwave oven to rapidly access a new series of 2-aryl-3-(b-D-ribofuranosyl)-3H-quinazolin-4-ones 92 as novel N-nucleosides. Montmorillonite K10 clay was used as solid support. Interestingly this method can be used for glycosylation without protecting the sugar moiety (Scheme 69). Li, Tu and co-workers [129] have elaborated a novel four-component domino reaction of an aromatic aldehyde, a cyclic ketone and a cyanoamide to give highly functionalized quinazolines 93 under microwave irradiation using K2CO3 as the base and ethylene glycol as the solvent. The reaction proceeded in mere 10–24 min with water as the sole byproduct. Four stereogenic centers are generated and the reaction is highly diastereoselective. The reaction did not seem to work with acyclic ketones (Scheme 70).

2.3.4

Quinolizines

Chebanov and co-workers [130] described an efficient synthetic route for the synthesis of some novel derivatives of 5a-hydroxy-4,5,5a,6,7,8-hexahydropyrazolo[4,3-c]quinolizin-9-ones 94 which is based on a multicomponent condensation of a 5-aminopyrazole with a cyclic 1,3-diketone and an aromatic aldehyde under microwave irradiation. The reaction runs via an unusual base-mediated ring-opening/recyclization of the cyclic 1,3-diketone moiety (Scheme 71).

R1 1

R O HO HO

2

NH2 H2N + OH HO O

R

+ 3

HO

R

Ar

N

O MW, 6-10 min

HO

R4

OH O

HO

R2

N

Ar

Montmorillonite K10 clay

O

R3 R4

92 10 examples, 81-88%

Scheme 69

H O ArCHO +

CN + 2 H2N

O

K2CO3 Ethylene glycol MW,120°C, 12-24 min

Ar

HN O

N H 93

CN

H O

NH2

26 examples, 74-90%

Scheme 70

Microwave Irradiation and Multicomponent Reactions

ArCHO

R1

R1 Ar

O KOH, EtOH

+

N N H

O

NH2

203

R2 R2 R2 = CH3, H

MW, 100-150°C, 25 min

H

N

OH N H

N R2 R2

O

94 11 examples, 32-75%

Scheme 71

O

NC

NC

CN

OH + OH

CN

H2N

R1

DMSO (cat.)

N

R1

H2N

R2

MW, 125-130°C 3 min

N

R2

O

95 3 examples, 77-85%

Scheme 72 NC

O

O

R1

NC

CN +

K2CO3, DMSO (cat.)

O O N H

O

N H

MW, 125-130°C, 3 min

CN

R1

N N O 96 3 examples, 68-78%

Scheme 73

2.3.5

Quinoxalines

A microwave-assisted one-pot three-component procedure for the condensation of ninhydrin with a phenylenediamine and malononitrile under solvent-free conditions using a catalytic amount of DMSO has been reported by Mohammadizadeh and co-workers [131] to obtain the corresponding 2-(indenoquinoxalin-11-ylidene)malononitriles 95. (Scheme 72) Further, this one-pot procedure has been extended for the preparation in good yields of dicyanomethylene derivatives 96 of tryptanthrin when potassium carbonate was used as a base (Scheme 73).

2.4

Imidazoles

Imidazoles have received significant attention due to their biological and pharmaceutical importance [132]. Several substituted imdazoles are known as potent P38

204

J.B. Bariwal et al.

kinase inhibitors [133], as angiotensin II receptor antagonist [134] and as platelet aggregation inhibitors in several animal species. Some of them show cytotoxicity against specific human cancer cell lines. Nagarapu and co-workers [135] have reported a new synthetic approach for 1,2,4,5-tetrasubstituted imidazoles 97 through a four-component condensation of benzil, an aldehyde, an amine, and ammonium acetate using potassium dodeca tungstocobaltate trihydrate (K5CoW12O40·3H2O) as catalyst. The reaction proceeds under solvent-free conditions in a domestic microwave oven. This method can be applied to large-scale processes with high efficiency and the catalyst can be reused for several runs without significant loss of catalytic activity. Under the same reaction conditions, benzoin (replacing benzil) gave low yields (15–30%) even after long irradiation times (Scheme 74). The synthesis of a series of pyrimido[1,2-a]benzimidazoles 98 has been reported by Dandia and co-workers [136] through a MCR of 2-aminobenzimidazole, malononitrile or ethylcyanoacetate and a carbonyl compound in water. Cyclic as well as acyclic carbonyl compounds could be used. The reaction highly benefits from microwave (domestic oven) irradiation in terms of rate and the compounds 98 were obtained in good yields (Scheme 75). Liu and co-workers have elaborated [137] a highly efficient method for the synthesis of spiroimidazolinones 99 via a microwave-assisted three-component one-pot domino reaction of a protected amine, an amino acid ester and a carboxylic acid in the presence of triphenylphosphite in pyridine, providing the desired

O

O

R1–NH2 K5CoW12O40.3H2O NH4OAc

+

ArCHO

N Ar

N R1

MW, 2 min

97 20 examples, 85-97%

Scheme 74

N

N NH2

R1 O R2

N H +

NH H2O

CN

MW, 3.5-11 min X

X= CN, COOEt R1 = H, CH3 R2 = Ar R1= R2 = –(CH2)4–

Scheme 75

N H2N

R1 R2

X

98 8 examples, 78-88%

Microwave Irradiation and Multicomponent Reactions

205

compound 99 in excellent yields. The efficiency and utility of the method have been demonstrated with the synthesis of the antihypertensive drug Irbesartan (Scheme 76). Mohammadizadeh and co-workers [138] applied for the synthesis of tetrasubstituted imidazoles 100, a four-component condensation of benzil, an aldehyde, an amine and ammonium acetate under solvent-free conditions using a domestic microwave oven. The condensation is catalyzed by TFA and the desired compounds 100 are obtained in mere 4 min in good to excellent yields. Both aliphatic and aromatic amines could be successfully used (Scheme 77). A highly flexible and efficient microwave-assisted Ugi-type reaction was described by Guchhait and co-workers [139] for the generation of a library of N-fused aminoimidazoles 101 in excellent yields. A heterocyclic amidine or 2aminopyridine was reacted with an aldehyde and an isocyanide using zirconium (IV)chloride as the catalyst and PEG-400 as the solvent. The reaction is very tolerant to the nature of the substituents of the aldehyde (Scheme 78).

O O n

HO

O

R2

P(OPh)3, pyridine

OR1 + NH2 BocHN–R3

MW, 250°C, 10 min

n

3 N R

N R2 99 17 examples, 36-78%

Scheme 76

Ph Ph Ph

O ArCHO + NH4OAc O R1–NH2

N TFA (20 mol%)

Ph

MW, 4 min

N R1

Ar

100 14 examples, 79-94%

Scheme 77

NH2 R2– NC Het Ar + N R1– CHO

ZrCl4 (10 mol%) PEG-400 MW, 140°C, 7 min

N Het Ar

N

R1

HN R2 101 28 examples, 72-97%

Scheme 78

206

J.B. Bariwal et al.

2.5

Thiazolines

4-Thiazolidinones are an important group of heterocycles found in numerous natural products and pharmaceuticals known for their antitumor, COX-2 inhibition, anti-HIV and antibacterial activities [140]. Saidi and co-workers [141] have reported a three-component reaction of different thiosemicarbazides with dimethyl or diethyl acetylenedicarboxylate and an aldehyde under solvent-free conditions applying a domestic microwave oven. Thiazolines 102 were obtained in good to excellent yields. Interestingly, the presence of electron-donating groups on the aromatic aldehyde resulted in faster reactions and higher product yields (Scheme 79). Mahler and co-workers [140] reported a tandem procedure for the synthesis of 2-hydrazolyl-4-thiazolidinones 103 from a three-component reaction of an aldehyde, a thiosemicarbazide and maleic anhydride, efficiently assisted by microwave irradiation in a solvent mixture of toluene/DMF (1:1). Short reaction times and high product yields were obtained as compared to conventional heating. This process could be generally applied for aromatic as well as for aliphatic aldehydes, although for aliphatic aldehydes a slightly lower temperature of 100 C should be used (Scheme 80).

2.6

Pyrazoles

The class of pyrazoles bears a broad spectrum of biological activity, e.g., antihyperglycemic, analgesic, anti-inflammatory, antipyretic, antibacterial and Et / MeOOC

COOMe / Et +

H2N

H N

R1CHO

R1

N

S O

N H

MW, 3 min

NH2

N

solvent free

O

Me /Et

O

102

S

9 examples, 83-92%

Scheme 79

O

S R1HN

N H

NH2 +

O + R2CHO O

R2 p -TsOH (cat.) Toluene/DMF (1:1) MW, 100-120°C, 5-12 min

OH

O N N

S N R1

O

103 10 examples, 33-82%

Scheme 80

Microwave Irradiation and Multicomponent Reactions

207

sedative-hypnotic activity [142, 143]. In addition, several 3,5-diaryl-substituted pyrazoles reversibly inhibit monoamine oxidase-A and monoamine oxidase-B [144]. Recently, Mu¨ller and co-workers [145] have reported a series of 3,5-disubstituted and 1,3,5-trisubstituted pyrazoles 104 and 105 by reacting an acyl chloride, a terminal alkyne and a hydrazine via a consecutive one-pot three-component Sonogashira coupling/Michael addition/cyclocondensation sequence under microwave irradiation. The desired products were obtained in good to excellent yields. These obtained pyrazoles are highly fluorescent, both in solution and in the solid state (Scheme 81). Botta and co-workers [146] described an efficient microwave-assisted organocatalytic domino Knoevenagel/hetero-Diels–Alder reaction (DKHDA) protocol for the synthesis of 2,3-dihydropyran[2,3-c]pyrazoles 106 using diaryl-prolinol as catalyst and t-BuOH as the solvent. A diastereomeric mixture of compounds 106a and 106b was isolated with a diastereomeric ratio of (4:1). The procedure can be used to synthesize quickly, novel rigid analogs of potential antitubercular agents (Scheme 82).

2.7

Acridines

Acridine derivatives have been known since the nineteenth century when they were first used as pigments and dyes [147]. Their antiseptic activity has been discovered O R1

Cl +

R2

PdCl2(PPh3)2 (2% ), CuI (4%) Et3N (1.05), THF, 1h, r.t.

R1

R2 N N

then R3NHNH2 CH3OH, AcOH MW, 150°C, 10 min

R3 104, =H 105, R3 = CH3, Ph R3

21 examples, 53-95%

Scheme 81 Cl

N

N

O

Cl

+

+ CHO

OEt

diaryl-prolinol (cat.), t-BuOH MW, 110°C, 30 min

N

OEt N

O

Cl Cl 106a (cis) 56% 106b (trans) 12%

Scheme 82

208

J.B. Bariwal et al.

in the early 1900s and some derivatives were extensively used during the First World War for their antibacterial and antimalarial activities. In the 1920s, their potential in the fight against cancer was noticed. The synthetic research on acridines experienced a renaissance during the mid 1960s when wide ranges of this class of compounds were tested for antimalarial activity [148]. Among them benzo analogs have received considerable attention [149, 150]. Acridines are also known therapeutic agent as inhibitors of monoamine oxidases, NADH-dehydrogenases etc. [151, 152]. Numerous studies regarding these applications have been described [153, 154]. Therefore, the synthesis of new tetracyclic acridine compounds has increased rapidly in the last few years. Yen and co-workers [155] have described a one-pot MCR for the synthesis of 4,5-dibenzylidene octahydroacridines 107 in high yields. A tandem reaction was performed with three equivalents of an aromatic aldehyde and two equivalents of 4-alkylcyclohexanone in NH4OAc/AcOH applying a domestic microwave oven. Except for one example, most of the reported compounds were obtained in moderate to good yields (Scheme 83). Some new substituted tetrahydroacridin-8-ones 108 have been synthesized by Selvi and co-workers [156]. They applied a MCR to dimedone or cyclohexan-1,3dione, a-naphthylamine and a substituted benzaldehyde, without the aid of any catalyst using a domestic microwave oven. Compounds 108 exhibit interesting antimicrobial activities (Scheme 84). Following the same strategy, Tu and co-workers [112] have reported a rapid and direct method for the synthesis of highly functionalized acridine-1,8(2H,5H)diones 109 in excellent yields. They employed a multicomponent protocol to a 5-substituted-cyclohexane-1,3-dione, an aldehyde and an enaminone to get the Ar O 2

R1 + 3 ArCHO

R1

NH4OAc/AcOH N

MW, 3-4.5 min Ar

Ar 107 11 examples, 42-79%

R1

Scheme 83

O

NH2

O

Ar

Neat conditions + R1 O 1 R R1 = R1 = H R1 = R1 = CH3

+ ArCHO MW, 2-5 min

R1 R1

N H 108

14 examples, 92-98%

Scheme 84

Microwave Irradiation and Multicomponent Reactions

209

targeted compound 109. A wide range of aldehydes can be used. A comparison between the application of microwave irradiation and conventional heating was performed and it was concluded that, except for the reaction times, the results were comparable (Scheme 85).

2.8

Oxazepines, Thiazapines and Benzodiazepines

Several functionalized benzothiazepinones and their fused analogs possess interesting biological properties and many of them have been tested and applied as drugs [157]. Some pyrimido-oxazepines are potent inhibitors of the epidermal growth factor receptor (EGFR) [158] which is the biological target of cancer therapeutics as Iressa and Tarceva [159]. A synthetic approach towards pyrimido[4,5-b][1,4]benzoxazepin-4-amines 111 has been developed by Gustafson and co-workers [160] through the use of microwave irradiation by reaction of 2,4-dichloro-3-amino pyrimidine, a substituted salicylic acid and an amine using cesium carbonate as the base. The obtained imines 110 were reduced with NaBH4 leading to the desired compounds 111 in moderate to good yields. Primary and secondary aliphatic amines could be used, although aryl amines gave low yields (Scheme 86). An efficient multicomponent tandem reaction has been described by Tu and co-workers [161] to access benzothiazepinones 112 in excellent yields in aqueous media. The reaction is easy to perform using inexpensive starting materials such as

O R1 R1

Ar1HN

O

O + Ar2CHO

+ R2 O

Ar2 O

AcOH R1 N R1 Ar1 109 6 examples, 89-95%

MW, 120°C 2-4 min

R2

Scheme 85 O HO

Cl

HO

NH2

N

Cs2CO3, i-PrOH

+ N

Cl 1

R

Scheme 86

R1

R3

H N

2

R

MW, 150°C 10 min

N

R1

R2 N

N N

O 110

NaBH4 r.t. R3

N

N N

R2 H N O

111 12 examples, 30-98%

R3

210

J.B. Bariwal et al.

an aromatic aldehyde, an amine and mercaptoacetic acid and the desired products 112 are generated in high yields in a short time. Surprisingly, aldehydes bearing electron-withdrawing groups gave only thiazolidinones in excellent yields. This environmentally friendly protocol is highly attractive to access compounds which are potentially biologically active (Scheme 87). Dai and co-workers [162] have described an Ugi-type four-component reaction applying a 2-aminophenol, a 2-alknylbenzaldehyde, benzyl isocyanide and 2-chloro-5-nitrobenzoic acid in methanol under microwave irradiation. The resulting Ugi product 113 was subsequently treated with aqueous K2CO3 to promote an intramolecular nucleophilic aromatic substitution, leading to the formation of highly functionalized dibenz[b, f][1,4]oxazepin-11(10H)-ones 114. This protocol tolerates a diverse substitution pattern of the 2-aminophenol and affords highly functionalized products 114 in good yields (Scheme 88). 3H-1,4-Benzodiazepines and 3H-1,5-benzodiazepines are important classes of compounds because of their interesting pharmacological properties. They show anticonvulsant, antianxiety, analgesic, sedative, antidepressive, hypnotic, antiinflammatory activity and also potent inhibitor of HIV-1 reverse transcriptase. Besides their biological relevance, benzodiazepines have also found application as dyes for acrylic fibers [163].

Ar

NH2 R1

SH + HO

water + ArCHO MW, 110°C, O 7-11 min

S R1 N H

O

112 30 examples, 89-96%

Scheme 87

R1 2

R

OH R3

3

R

+

+

CN–Bn MeOH MW, 80°C, NO2 20 min CHO

4

R

Scheme 88

R1 R Cl

R1

N OH O NH Bn 4 R 113

O

aq. K2CO3 (1.2 eq.) MW, 100°C, 10 min

NO2

O

2

R

NH2

Cl HOOC

O2N

2

R3

N Bn

O

H N O 4

R

114 7 examples, 57-81%

Microwave Irradiation and Multicomponent Reactions

O R1

+ Cl

R2

PdCl2(PPh3)2, CuI, Et3N, THF,1h, r.t. Then: AcOH MW, 120°C, 60min R3

NH2

R4

NH2

211 R1

R2

N

R3

N

R4

115 12 examples, 40-88%

Scheme 89

A novel one-pot approach for the synthesis of 2,4-disubstituted 3H-benzo[b] [1, 5]diazepines 115 has been disclosed by Muller and co-workers [163]. The compounds were obtained in good yields by the reaction of an acyl chloride, a terminal alkyne and a benzene-1,2-diamine via a consecutive one-pot, three-component Sonogashira coupling/Michael addition/cyclocondensation sequence, under microwave irradiation (Scheme 89). Andreana and co-workers [164] have developed a novel one-pot, two-step reaction protocol for the synthesis of regiochemically differentiated 1,2,4,5tetrahydro-1,4-benzodiazepin-3-ones 116 and 117. Using protic solvents and controlled microwave irradiation, the Ugi product was synthesized by reacting an aldehyde, an aromatic amine, an isocyanide and a carboxylic acid. The obtained Ugi product was then reduced with Fe(0)/NH4Cl to give the target compound in good yields and high diastereoselectivity. Two pathways were accessible; both routes utilized bifunctional, o-nitro-substituted arenes leading to either C2, N4, C5 substitution in compound 116 or C2, N4 substitution in compound 117. Interestingly, when acrylic acid was used as a coupling component, an eight membered ring was not observed and only the acyclic Ugi product was isolated. These biologically relevant small molecules can be prepared efficiently and are highly amenable for further derivatization (Scheme 90).

2.9

Chromens

Chromens and their derivatives are an important class of compounds possessing antiestrogenic, [165] potassium channel agonist, hypotensive [166], vasodilator, antihypertensive, b-adrenolytic [167] and antimicrobial activity [168]. Moreover, some derivatives show high antagonistic affinity for the retinoic acid receptor [169]. Mg/Al hydrotalcite as a heterogeneous base catalyst has been used by Samant and co-workers [170] in combination with microwave irradiation for the synthesis of 2-aminochromenes 118 via a multicomponent condensation of an aromatic aldehyde, malononitrile and 1-naphthol. The hydrotalcite is a heterogeneous basic catalyst and could easily be separated from the reaction mixture by simple filtration. The recovered catalyst was used for successive runs to investigate its reusability,

212

J.B. Bariwal et al. H N

R2NH2 NO2 R1 CHO

Fe(0) and NH4Cl EtOH / H2O, (3:1)

R1 5

MW, 150°C, 30-45 min

O

O

4

N

R2

NH

R3 (±)-116 5 examples, 70-78%

O R4

R4 2

OH + R3–NC NO2 R2

NH2 + R1CHO

Fe(0) and NH4Cl EtOH / H2O, (3:1) MW, 150°C, 30-45 min

H N R2

R4 2

O 4

N R1

O HN–R3

(±)-117 2 examples, 85-90%

Scheme 90

OH CN +

+ ArCHO CN

Mg/Al hydrotalcite Solvent free MW, 140°C, 5-24 min

O

NH2 CN

Ar 118 12 examples, 71-90%

Scheme 91

however, an important reduction of the product yields was observed. The reaction was rapid, clean and gave the desired products 118 in high yields (Scheme 91). A short and simple synthesis of chromeno[3,4-b][4,7]phenanthrolines 119 has been investigated by Tu and co-workers [167] using a three-component reaction of an aromatic aldehyde, 6-aminoquinoline and 4-hydroxycoumarine in water, under microwave irradiation without any catalyst. This method has the advantage of short reaction time, high yields, low cost and being environment-friendly (Scheme 92).

2.10

Pyrans and Furans

2,3-Dihydropyrans represent an attractive and challenging class of compounds as many of them are key intermediates for the synthesis of several natural products [171]. In particular, their olefin function has great synthetic value for the further functionalization to obtain polysubstituted tetrahydropyrans [172] that constitute

Microwave Irradiation and Multicomponent Reactions

213 O

OH

N +

+ O

O

Ar N

O

H2O ArCHO

N H

MW, 140°C, 5-6 min

H2N

119 5 examples, 93-95%

Scheme 92 R1 + O

O

MW, 80°C, 20 min R1

EtOOC

COOEt

COOEt

Grubbs’ cat. 2nd gen. OEt toluene

O

+ OEt

120 trans

ZnCl2

R1

DCM OEt R1 120 cis

COOEt O OEt

120 trans 8 examples, 40-75%

Scheme 93

the structural core of most carbohydrates as well as of many biologically important natural products and pharmaceutical agents [173]. Botta and co-workers [174, 175] have described the synthesis of 2,3-dihydropyrans that were obtained as a mixture of cis/trans diastereoisomers 120 through a microwave-assisted multicomponent enyne cross metathesis/hetero-Diels–Alder reaction of an acetylene, ethylvinyl ether and ethyl glyoxalate using Grubbs’ catalyst under microwave irradiation at 80 C. (Scheme 93) The obtained diastereoisomeric mixture could be equilibrated applying ZnCl2 leading to the unique formation of the all 120 trans isomer. This MCR was applied for the synthesis of C-linked furanosedihydropyranes 122 as a mixture of four diastereoisomers, upon reaction of the acetylene precursor 121 with ethylvinyl ether and ethylglyoxalate under the same reaction conditions. Equilibration of this mixture upon treatment with ZnCl2 led to a 1:1 mixture of two diastereoisomers 122a and 122b (Scheme 94). Organ and co-workers [120] elaborated a synthesis of aminofurans 123 applying a microwave-assisted continuous flow organic synthesis (MACOS) by reacting dimethyl acetylenedicarboxylate, cyclohexyl isocyanide and a substituted benzaldehyde. The obtained conversions were equal or even higher compared to conventional batch conditions and reactions required only seconds to reach full completion. Benzaldehydes bearing electron-withdrawing groups gave the highest conversions (Scheme 95).

2.11

Propargylamines

Propargylamines are versatile synthetic intermediates in organic synthesis and are also key structural elements in natural products and therapeutic drug molecules [176].

214

J.B. Bariwal et al. COOEt O

BzO

O

+ OBz

BzO

Grubbs’ cat. 2nd gen. COOEt toluene

O O BzO

121

OEt

OBz

BzO

MW, 80°C, 20 min

OEt

122, 64% ZnCl2 DCM COOEt

COOEt +

O

O

O

O

BzO BzO

OBz

BzO

OEt

BzO

122a

OBz 122b

OEt

Scheme 94

MeOOC

COOMe +

NC

flow process

Ar

MW

MeOOC

ArCHO

O

H N

COOMe 123 7 examples, 30-83%

Scheme 95

R1-NH2

+

R2

+

R3– CHO

CuBr (20 mol %) Toluene MW, 100°C, 25 min

R3 R2 HN–R1 124

26 examples, 41-94%

Scheme 96

Recently, Van der Eycken and co-workers [177] have elaborated an effective protocol for the synthesis of secondary alkylpropargylamines 124 via a microwaveassisted A3-coupling reaction. The resulting propargylamines were obtained by a MCR of a primary aliphatic amine, a terminal alkyne and an aldehyde (aliphatic or aromatic) using CuBr as the catalyst in high yields. Primary aliphatic amines which were considered as difficult substrates for A3-coupling reactions, react very efficiently under these reaction conditions. Heterocyclic and aliphatic acetylenes were also explored and gave moderate yields (Scheme 96). An effective MCR has been developed by Organ and Li and co-workers [178] for the synthesis of tertiary propargylamines 125 by reacting an aldehyde, an amine

Microwave Irradiation and Multicomponent Reactions

215

and a terminal alkyne using MACOS. The process is catalyzed by a thin film of either copper or gold that achieves temperatures exceeding the 900 C when irradiated with microwaves. The process works equally well for premixed solutions of the three starting materials, or as for three separate streams of reagent solutions that were introduced. The process can be used for a wide variety of aldehydes and acetylenes (Scheme 97). Van der Eycken and co-workers [179] have reported a microwave-assisted A3-MCR of an aniline, an alkyne and biaryl aldehyde to generate a small library of propargylamines 126 using CuBr as the catalyst. The resulting compounds 126 were isolated in good to excellent yields except when n-butylamine was used as amine counterpart and were further converted into Steganacin aza-analogs (Scheme 98).

2.12

Miscellaneous

Shaterian and co-workers [180] have described an efficient and expeditious route towards the synthesis of 1-amidoalkyl-2-naphthols 127 via a three-component reaction of an aryl aldehyde, 2-naphthol and acetamide in the presence of Fe(HSO4)3 using a domestic microwave oven. The reaction of 2-naphthol with an aromatic aldehyde in the presence of an acid catalyst gives an o-quinone methide that is subsequently reacted with acetamide to give the desired product 127. This solvent-free microwave-assisted green procedure offers the advantages of short

R1

H N

R2 +

Ar

R3CHO

Metal film flow process Toluene MW Temp of film = 950°C

R1

N

R2

R3

Ar 125 18 examples, 55-84%

Scheme 97 R2

R2 R3NH2 CHO + TBSO

R1

R4

R4

Neat conditions CuBr MW, 90-120°C 15 min

TBSO

HN 3 R R1

126 12 examples, 42-89%

Scheme 98

216

J.B. Bariwal et al.

reaction time, simple work-up, excellent yields, and reusability of the catalyst (Scheme 99). A new microwave-assisted three-component Knoevenagel-nucleophilic aromatic substitution reaction of 4-halobenzaldehyde, cyanoacetic acid ester or cyanoacetamide and a cyclic secondary amine was reported by Yu, Shen, Wang and co-workers [181] to give the compounds of type 128. Via this one-pot domino process a carbon– carbon double bond and a carbon–nitrogen bond were formed. Taking advantage of microwave irradiation, the reaction times could be reduced significantly resulting in high yields even with less reactive benzaldehydes (Scheme 100). The proline-catalyzed asymmetric Mannich reaction between cyclohexanone, formaldehyde and an aniline has been described by Bolm and co-workers [182]. With only 0.5 mol% of homochiral catalyst, the Mannich products have been obtained with excellent ee’s up to 98% after a short irradiation time using a constant low power of 10–15 W in conjunction with simultaneous cooling with compressed air. These reaction conditions allow achieving a high reaction rate and an excellent enantioselectivity. In situ reduction of the resulting ketones 129 afford the N-aryl amino alcohols 130 in high yield (syn/anti in ratio 1:5) (Scheme 101). Dai and co-workers [183] have reported a one-pot U-4CR followed by an intramolecular O-alkylation sequence starting from a 2-aminophenol in combination with an a-bromoalkanoic acid, an aromatic aldehyde and an isocyanide under controlled microwave irradiation. The U-4CR was carried out in MeOH and the resulting acyclic intermediate 131 was turned into the 3,4-dihydro-3-oxo-2H1,4-benzoxazines 132, without isolation, upon treatment with an aqueous solution of K2CO3 to promote the intramolecular O-alkylation in high yields (Scheme 102).

OH Fe(HSO4)3

+ ArCHO + CH3CONH2 MW, 5-14 min OH

Ar

NH

O 127 18 examples, 84-97%

Scheme 99 Y Y

X + CHO X = F, Cl, Br

CN

EtOH

Z

MW, 80°C, 5-30 min

n=0–1

N

CN

+ N H

n=0 –1

Z 128 Z = COOEt, COOMe, CONH2 Y = CH2 and O, NR1 14 examples, 72-90%

Scheme 100

Microwave Irradiation and Multicomponent Reactions O

O +

ArNH2

OH

O

(s)-proline (cat.) DMSO

H

H

217

N H

MW, 41-63°C, 1-4 h

NaBH4

Ar

N H

Ar

130 syn/anti 1:5 3 examples, 70-96%

129 94-98% ee

Scheme 101

Br

R2

HO

O

OH OH R1

+

CN–R3

NH2

U-4CR MeOH MW, 80-100°C, 20 min

ArCHO

R1 N Ar HN 131

R2 Br O

O

R2

R1 N

aq. K2CO3

O MW, 120-150°C, 15 min R3

Ar

O O

HN 3 R 132 14 examples, 52-90%

Scheme 102

O

COOH R3

R1– CHO

NH + O NC

O

R2– NH2

O

NH

R1

O

H N

MeOH MW, 80°C, 5 min

R3

N R2

O

133 7 examples, 50-93%

Scheme 103

Similarly, Hulme and co-workers [184] have described an U-4CR under microwave-assisted conditions of an N-Boc-anthranilic acid, n-butylisonitrile, an aldehyde, and an amine resulting in the formation of the Ugi products 133 that were further used in the UDC-protocol (Ugi reaction–Deprotection–Cyclization) for lead finding (Scheme 103). Beller and co-workers [185] have developed a solvent-free MCR of crotonaldehyde, acetamide and N-methylmaleimide. The described methodology is one of the most simple and direct approaches for the synthesis of 4-N-acetylamino-2-methylcis-3a,4,7,7a-tetrahydroisoindole-1,3-dione 134. The application of microwave irradiation resulted in significantly reduced reaction times and increased yields. Aliphatic and aromatic amides, as well as sulfonamides gave excellent results with excellent stereoselectivity. However, the application of maleic anhydride, diethyl

218

J.B. Bariwal et al. O NH

O O

+

O

Solvent-free

O

+ H

NH2

N O

N MW, 150°C, 20 min 134

O

90%

Scheme 104

O R1

O O(CH2)3C8F17

NH2

+ ArCHO

O 1. Et3N, DMF, 25°C, 30 min

N O

2. MW, 150°C, 30 min 3. F-SPE

H R1

O

N

O(CH2)3C8F17 NH

O H Ar 135 4 examples, 48-94%

Scheme 105

but-2-ynedioate and acrylonitrile as dienophiles resulted in low yields. Advantageously, there is no need for employing additional solvents and the reaction times are drastically reduced compared to similar thermal reactions (Scheme 104). Zhang and co-workers [186] reported a microwave-assisted one-pot, threecomponent [3þ2] cycloaddition reaction of a fluorous amino ester, an aldehyde and a maleimide to afford bicyclic prolines 135 in yields up to 94%. Fluorous solid phase extraction (F-SPE) has been used effectively to separate the product from the reaction mixture (Scheme 105). Muthusubramanian and co-workers [187] disclosed a new approach towards the synthesis of asymmetrical diarylamines 136 by a novel MCR between an aryl aldehyde, an N-arylhydroxylamine and maleic anhydride using a domestic microwave oven. Interestingly, the role of the methoxy group in the migration of the aryl group from carbon to nitrogen is very important as it leads to the enone intermediate 136b via another intermediate 136a. The nucleophilic attack of water on intermediate 136b, gave the diarylamine 136 via another intermediate 136c. The diarylamines were obtained in high yields within 2–3 min (Scheme 106). Andreana and co-workers [188] developed a one-pot method for generating molecular diversity via a multicomponent coupling reaction under microwave irradiation. The initially formed Ugi four-component coupling products gave rise to three structurally distinct scaffolds depending on the solvent effects and sterics: the 2,5-diketopiperazines 137, the 2-azaspiro[4.5]deca-6,9-diene-3,8-diones 138, and the thiophene-derived Diels–Alder tricyclic lactams 139 (Scheme 107). Tu and co-workers [189] described a series of new 3-pyrimidin-5-ylpropanamides 140, spiro[5.5] undecane-1,5,9-triones 141 and pyrimidin-5-ylpropanoic acids 142

Microwave Irradiation and Multicomponent Reactions CHO

NHOH

O

OCH3 X

219

toluene O

Y +

+

136 16 examples, 60-76%

O

N

Y

O

HO HO

H 2O

O O H+ OCH3

O

HO

O

X

Y MW, 2-3 min

O

–

OCH3

H N

O

O

N

Y

N

Y

O H3CO

OH H3CO

X

X

X 136a

136c

136b

Scheme 106

O

R3 = OMe MeOH via Aza-Michael

R4

R1

N N

R2

R3

11 examples, 81-98% dr < 20:1 137

O O

O R2

R3 = OH

R1CHO

+ R3NH2

MW, 200°C, 20 min

MeOH via Michael

R4NC

R3 = DCM via Diels-Alder

OH O

N

HN R4

R1

O

O R3 R4 N N OMe H S

R2

6 examples, R2 60-82% dr < 3:1 138

2 examples, O 23-25% dr < 10:1 H 139 H

Scheme 107

which were selectively synthesized via a microwave-assisted, chemoselective reaction of arylidene-Meldrum’s acid, 6-hydroxypyrimidin-4(3H)-one and an amine. The outcome of the reaction depends on the nature of the applied solvent.

220

J.B. Bariwal et al.

Arylidene–Meldrum’s acids bearing electron-withdrawing groups on the aromatic substituent reacted rapidly under these conditions (Scheme 108). Hulme and co-workers [190] have reported a novel two-step solution-phase protocol for the synthesis of an array of triazadibenzoazulenones 144 via a U-4CR of a mono-Boc-protected-phenylene diamine, a Boc-protected anthranilic acid, an isonitrile, and an aldehyde. Further, the acid treatment of the Ugi products 143 leads to a tandem ring closing reaction. This two-step protocol is strongly facilitated by microwave irradiation. Careful selection of the isonitrile enables the correct order of ring forming events (Scheme 109). An efficient and environmental friendly multicomponent synthesis of substituted 1,8-naphthyridines 145 has been described by Naik and co-workers applying a

O AcOH

Ar

O

HN

R1

N H

MW, 100°C 12-22 min

OH N 140 34 examples, 69-91%

R1NH2 O

+

Ar

O

Ar

O

N

O

H2O

HN O

O

O

O

MW, 100°C 16-22 min

OH

O

Ar

O

141 7 examples, 31-42% O HCOOH

Ar

O

HN

MW, 100°C 16-22 min

OH OH

N

142 6 examples, 74-89%

Scheme 108

NH2 R2 NHBoc 1

4

R –CHO + R – NC

MW,100°C, COOH 5 min

O

H N

N O

BocHN

R2

R3

TFA R4

R

MW, 130°C, 20 min

N NH

1

R

O 144

NHBoc 143

Scheme 109

2

R1

BocHN MeOH

R3

N

R3

12 examples, < 5-72%

Microwave Irradiation and Multicomponent Reactions

221 Ar

R1

ArCHO

Bi(NO3)3 .5H2O

+ N

NH2

NC

R1

MW, 4-5 min

CN

CN N

N

NH2

145 8 examples, 92-96%

Scheme 110

R1

R1 O

X + S

+ R2

CN

X

KF-Alumina MW, 100°C, 3.5-8 min

X = CN, COOEt

R2

S

NH2

146 16 examples, 55-92%

Scheme 111

domestic microwave oven [191]. A 2-aminopyridine, an aryl aldehyde and malononitrile were reacted in the presence of Bi(III)nitrate as the catalyst under solvent-free conditions yielding the desired compounds 145 in 92–96% yields. The catalyst could be reused several times (Scheme 110). Sridhar and co-workers [192] have described a microwave-promoted synthesis of 2-aminothiophenes 146 by reaction of a ketone with a nitrile and elemental sulfur using KF-alumina as a base via multicomponent condensation reaction. This method offers an efficient and convenient modification to the Gewald reaction replacing organic base with KF-alumina (Scheme 111).

3 Conclusions and Outlook In this contribution, we have tried to present an overview of the application of microwave irradiation for MCRs in the last 4 years. As these reactions are highly suited for automation, making them extremely valuable for high-throughput synthesis, the application of microwave irradiation has been intensively investigated to speed up these reactions, reducing the reaction times from hours or days, to mere minutes or even seconds and delivering the compounds mostly in higher yields, as compared to conventional heating. In several cases, MCRs are performed under solvent-free conditions, e.g., with the components absorbed on a solid support. Although these conditions allow the safe performance of the reactions in a domestic oven, it should be emphasized that these methods usually suffer from technical difficulties related to nonuniform heating and mixing and precise determination of the reaction temperature. However, with the current dedicated microwave instruments available, one might expect that multicomponent chemistry will shift away

222

J.B. Bariwal et al.

from these techniques. Of interest is also the recent combination of flow chemistry with microwave irradiation (microwave-assisted continuous flow organic synthesis – MACOS) which looks very promising for generating compounds on a larger scale without having the need of optimizing the conditions for scale-up. For all these reasons we are convinced that we will see many more exciting examples of the application of microwave irradiation to multicomponent chemistry in the near future.

References 1. Domling A (1998) Isocyanide based multi component reactions in combinatorial chemistry. Comb Chem High Throughput Screen 1:1–22 2. Hulme C, Gore V (2003) Multi-component reactions: emerging chemistry in drug discovery ‘from xylocain to crixivan’. Curr Med Chem 10:51–80 3. Ulaczyk-Lesanko A, Hall DG (2005) Wanted: new multi-component reactions for generating libraries of polycyclic natural products. Curr Opin Chem Biol 9:266–276 4. Zhu J, Bienayme H (2005) Multi-component reactions. Wiley-VCH, New York 5. Strecker A (1850) Strecker amino acid synthesis. Liebigs Ann Chem 75:27–45 6. Miller SL (1986) Current status of the prebiotic synthesis of small molecules. Chem Scripta 26B:5–11 7. Hantzsch A (1882) Ueber die Synthese pyridinartiger Verbindungen aus Acetessiga¨ther und Aldehydammoniak (Hantzsch dihydropyridine synthesis). Justus Liebegs Ann Chem 215:1–82 8. Sausins A, Duburs G (1988) Synthesis of 1,4-dihydropyridines by cyclocondensation reactions. Heterocycles 27:269–289 9. Biginelli P (1893) Aldehyde-urea derivatives of aceto- and oxaloacetic acids. Gazz Chim Ital 23:360–413 10. Kappe CO, Stadler A (2004) The Biginelli dihydropyrimidinone synthesis. Org React 63:1–117 11. Mannich C, Krosche W (1912) Ueber ein Kondensationsprodukt aus Formaldehyd, Ammoniak und Antipyrin. Arch Pharm 250:647–667 12. Thompson BB (1968) The Mannich reaction. Mechanistic and technological considerations. J Pharm Sci 57:715–733 13. Passerini M (1921) Isonitriles. I. Compound of p-isonitrileazobenzene with acetone and acetic acid. Gazz Chim Ital 51:126–129 14. Domling A (2002) Recent advances in isocyanide-based multi-component chemistry. Curr Opin Chem Biol 6:306–313 15. Domling A, Ugi I (2000) Multi-component reactions with isocyanides. Angew Chem Int Ed 39:3168–3210 16. Ugi I (1962) The a-addition of immonium ions and anions to isonitriles accompanied by secondary reactions. Angew Chem Int Ed 1:8–21 17. Ugi I, Steinbruckner C (1961) Isonitrile, IX. a-Addition von immonium-ionen und carbonsa¨ure-anionen an isonitrile. Chem Ber 94:2802–2814 18. Ugi I, Domling A, Horl W (1994) Multi-component reactions in organic chemistry. Endeavour 18:115–122 19. Denmark SE, Thorarensen A (1996) Tandem [4+2]/[3+2] cycloadditions of nitroalkenes. Chem Rev 96:137–165 20. Organ MG, Winkle DD, Huffman J (1997) Tandem transformations involving allylic silanes. 2. Highly diastereoselective substitutions involving [(trialkylsilyl) methyl]cyclohexene

Microwave Irradiation and Multicomponent Reactions

21. 22. 23. 24. 25. 26. 27. 28.

29. 30.

31.

32. 33. 34.

35.

36.

37.

38. 39.

40. 41.

223

derivatives with aldehydes. Synthetic studies on the problem of Lewis acid-promoted protodesilylation and enolization. J Org Chem 62:5254–5266 Bravo PA, Carrero MCP, Galan ER et al (2000) Synthesis of polycyclic systems via Diels– Alder reactions of sugar derived dienes. Heterocycles 1:81–92 Gedye RN, Smith FE, Westaway KG et al (1986) The use of microwave ovens for rapid organic synthesis. Tetrahedron Lett 27:279–283 Giguere RJ, Bray TL, Duncan SM et al (1986) Application of commercial microwave ovens to organic synthesis. Tetrahedron Lett 27:4945–4948 Kappe CO, Dallinger D, Murphree S (2009) Practical microwave synthesis for organic chemists. Strategies, instruments and protocols. Angew Chem Int Ed 48:2828–2829 Kappe CO (2008) Microwave dielectric heating in synthetic organic chemistry. Chem Soc Rev 37:1127–1139 Kappe CO, Dallinger D (2009) Controlled microwave heating in modern organic synthesis: highlights from the 2004–2008 literature. Mol Divers 13:71–193 and references therein Caddick S, Fitzmaurice R (2009) Microwave enhanced synthesis. Tetrahedron 65:3325–3355 and references therein Appukkuttan P, Van der Eycken E (2008) Recent developments in microwave-assisted, transition-metal-catalysed C–C and C–N bond-forming reactions. Eur J Org Chem 7:1133–1155 and references therein Loupy A (ed) (2002) Microwaves in organic synthesis, 2nd edn. Wiley-VCH, Weinheim Shah A, Bariwal J, Molnar J et al (2008) Advanced dihydropyridines as novel multidrug resistance modifiers and reversing agents. In: Motohashi N (ed) Bioactive heterocycles VI: flavonoids and anthocyanins in plants, and latest bioactive heterocycles 1, vol 15. Springer, Berlin Alker D, Campbell SF, Cross PE et al (1990) Long-acting dihydropyridine calcium antagonists. 4. Synthesis and structure-activity relationships for a series of basic and non basic derivatives of 2[(2-aminoethoxy)methyl]-1, 4-dihydropyridine calcium antagonists. J Med Chem 33:585–591 Godfraind T, Miller R, Wibo M (1986) Calcium antagonism and calcium entry blockade. Pharmacol Rev 38:321–416 Fasani E, Fagnoni M, Dondi D et al (2006) Intramolecular electron transfer in the photochemistry of some nitrophenyldihydropyridines. J Org Chem 71:2037–2045 Ragno G, Vetuschi C, Risoli A et al (2003) Application of a classical least-squares regression method to the assay of 1, 4-dihydropyridine antihypertensives and their photoproducts. Talanta 59:375–382 Zhu XQ, Zhao BJ, Cheng JP (2000) Mechanisms of the oxidations of NAD(P)H model Hantzsch 1, 4-dihydropyridines by nitric oxide and its donor N-methyl-N-nitrosotolueneP-sulfonamide. J Org Chem 65:8158–8163 Zhu XQ, Wang HY, Wang JS et al (2001) Application of NAD(P)H model Hantzsch 1, 4-dihydropyridine as a mild reducing agent in preparation of cyclo compounds. J Org Chem 66:344–347 Iqbal N, Akula MR, Vo D et al (1998) Synthesis, rotamer orientation, and calcium channel modulation activities of alkyl and 2-phenethyl 1, 4-dihydro-2, 6-dimethyl-3-nitro-4-(3- or 6-substituted-2-pyridyl)-5-pyridinecarboxylates. J Med Chem 41:1827–1837 Li RWS, Tse CM, Man RYK et al (2007) Inhibition of human equilibrative nucleoside transporters by dihydropyridine-type calcium channel antagonists. Eur J Pharmacol 568:75–82 Cosconati S, Marinelli L, Lavecchia A et al (2007) Characterizing the 1, 4-dihydropyridines binding interactions in the L-type Ca2+ channel: model construction and docking calculations. J Med Chem 50:1504–1513 Schramm M, Thomas G, Towart R et al (1983) Novel dihydropyridines with positive inotropic action through activation of Ca2+ channels. Nature 303:535–537 Li M, Zuo Z, Wen L et al (2008) Microwave-assisted combinatorial synthesis of hexasubstituted 1, 4-dihydropyridines scaffolds using one-pot two-step multi-component reaction followed by a S-alkylation. J Comb Chem 10:436–441

224

J.B. Bariwal et al.

42. Hatamjafari F (2006) New protocol to synthesize spiro-1, 4-dihydropyridines by using a multi-component reaction of cyclohexanone, ethyl cyanoacetate, isatin and primary amines under microwave irradiation. Synth Commun 36:3563–3570 43. Ranu BC, Jana R, Sowmiah S (2007) An improved procedure for the three-component synthesis of highly substituted pyridines using ionic liquid. J Org Chem 72:3152–3154 44. Boger DL, Nakahara S (1991) Diels–Alder reactions of N-sulfonyl-1-aza-1, 3-butadienes: development of a synthetic approach to the streptonigrone C ring. J Org Chem 56:880–884 45. Boger DL, Kasper AM (1989) A general solution to implementing the 4.pi. participation of 1-aza-1, 3-butadienes in Diels–Alder reactions: inverse electron demand Diels-Alder reactions of alpha, beta-unsaturated N-benzenesulfonyl imines. J Am Chem Soc 111:1517–1519 46. Ma X, Gang DR (2004) The lycopodium alkaloids. Nat Prod Rep 21:752–772 47. Bringmann G, Reichert Y, Kane VV (2004) The total synthesis of streptonigrin and related antitumor antibiotic natural products. Tetrahedron 60:3539–3574 48. Zhou Y, Kijima T, Kuwahara S et al (2008) Synthesis of ethyl 5-cyano-6-hydroxy-2-methyl4-(1-naphthyl)-nicotinate. Tetrahedron Lett 49:3757–3761 49. Cooke MW, Hanan GS (2007) Luminescent polynuclear assemblies. Chem Soc Rev 36:1466–1476 50. Constable EC (2007) 2, 20 :60 , 200 -Terpyridines: from chemical obscurity to common supramolecular motifs. Chem Soc Rev 36:246–253 51. Medlycott EA, Hanan GS (2005) Designing tridentate ligands for ruthenium (II) complexes with prolonged room temperature luminescence lifetimes. Chem Soc Rev 34:133–142 52. Kaes C, Katz A, Hosseini M et al (2000) The most widely used ligand. A review of molecules comprising at least two 2, 20 -bipyridine units. Chem Rev 100:3553–3590 53. Gribble GW (2000) Recent developments in indole ring synthesis-methodology and applications. J Chem Soc Perkin Trans 1:1045–1075 54. Yan C-G, Cai X-M, Wang Q-F et al (2008) A novel four component one-pot access to 4, 6-diaryl-2-pyridinone and 4-aryl-5, 6, 7, 8-tetrahydro-2-quinolinones. Lett Org Chem 5:282–285 55. Shi F, Zhang G, Zhou D et al (2009) An unexpected green and facile synthesis of 2, 6-diaryl4-styrylpyridines via multi-component reactions in microwave-assisted solvent-free conditions. Chin J Chem 27:1569–1574 56. Tu S, Jiang B, Zhang Y et al (2007) An efficient and chemoselective synthesis of N-substituted 2-aminopyridines via a microwave-assisted multi-component reaction. Org Biomol Chem 5:355–359 57. Tu S, Zhou D, Cao L et al (2009) A simple three-component condensation: highly efficient microwave-assisted one-pot synthesis of polyfunctional pyridine derivatives. J Heterocycl Chem 46:54–57 58. Sridhar M, Ramanaiah BC, Narsaiah C et al (2009) Novel ZnCl2-catalyzed one-pot multicomponent synthesis of 2-amino-3, 5-dicarbonitrile-6-thio-pyridines. Tetrahedron Lett 50:3897–3900 59. Zhu SL, Ji SJ, Su XM et al (2008) Facile and efficient synthesis of a new class of bis(30 indolyl) pyridine derivatives via one-pot multi-component reactions. Tetrahedron Lett 49:1777–1781 60. Thirumurugan P, Perumal PT (2009) A simple one-pot synthesis of functionalised 6-(indol3-yl)-2, 20 -bipyridine derivatives via multi-component reaction under neat condition. Tetrahedron Lett 50:4145–4150 61. Ladani NK, Patel MP, Patel RG et al (2009) A convenient one pot synthesis of series of 3-(2, 6-diphenyl-4-pyridyl)hydroquinolin-2-one under microwave irradiation and their antimicrobial activities. Indian J Chem 48B:261–266 62. Zhou J-F, Song Y-Z, Lv J-S et al (2009) Facile one-pot, multi-component synthesis of pyridines under microwave irradiation. Synth Commun 39:1443–1450 63. Tu S, Jiang B, Jia R et al (2007) An efficient and expeditious microwave-assisted synthesis of 4-azafluorenones via a multi-component reaction. Tetrahedron Lett 48:1369–1374

Microwave Irradiation and Multicomponent Reactions

225

64. Arango GJ, Cortes D, Cassels BK et al (1987) Alkaloids of the Annonaceae. Part 80. Azafluorenones from Oxandra cf. major and biogenetic considerations. Phytochemistry 26:2093–2098 65. Goulart MOF, Sant’ana AEG, de Oliveira AB et al (1986) Azafluorenones and azaanthraquinone from Guatteria dielsiana. Phytochemistry 25:1691–1695 66. Tu S, Jiang B, Jiang H et al (2007) A novel three-component reaction for the synthesis of new 4-azafluorenone derivatives. Tetrahedron 63:5406–5414 67. DiMauro EF, Kennedy JM (2007) Rapid synthesis of 3-amino-imidazopyridines by a microwave-assisted four-component coupling in one pot. J Org Chem 72:1013–1016 68. Rousseau AL, Matlaba P, Parkinson CJ (2007) Multi-component synthesis of imidazo[1, 2-a] pyridines using catalytic zinc chloride. Tetrahedron Lett 48:4079–4082 69. Masquelin T, Bui H, Brickley B et al (2006) Sequential Ugi/Strecker reactions via microwave assisted organic synthesis: novel 3-center-4-component and 3-center-5-component multi-component reactions. Tetrahedron Lett 47:2989–2991 70. Yadav LS, Awasthi C (2010) Efficient one-pot synthetic protocols for iminosugar-bearing imidazo[1, 2-a]pyridines from carbohydrates. Carbohydr Res 345:318–323 71. Wen L, Ji C, Li Y et al (2009) Application of b(2-chloroaroyl)thioacetanilide in synthesis (III): an efficient three-component synthesis of thiochromeno[2, 3-b]pyridines catalyzed by KF/neutral Al2O3 co-operated with PEG 6000 under microwave irradiation. J Comb Chem 11:799–805 72. Chebanov VA, Sakhno YI, Desenko SM et al (2007) Cyclocondensation reactions of 5-aminopyrazoles, pyruvic acids and aldehydes. Multi-component approaches to pyrazolopyridines and related products. Tetrahedron 63:1229–1242 73. Zhu SL, Ji SJ, Zhao K et al (2008) Multi-component reactions for the synthesis of new 30-indolyl substituted heterocycles under microwave irradiation. Tetrahedron Lett 49:2578– 2582 74. Tu SJ, Zhang XH, Han ZG et al (2009) Synthesis of isoxazolo[5, 4-b]pyridines by microwave-assisted multi-component reactions in water. J Comb Chem 11:428–432 75. Defant A, Guella G, Mancini I (2008) Microwave-assisted multi-component synthesis of aza-, diaza-, benzo-, and dibenzofluorenedione derivatives. Synth Commun 38:3003–3016 76. Feng S, Yan Z, Shu-Jiang T et al (2008) A green approach to the synthesis of biologically important indeno[2, 1-e]pyrazolo[5, 4-b]pyridines via microwave-assisted multi-component reactions in water. Chin J Chem 26:1262–1266 77. Wu H, Wan Y, Chen X-M et al (2009) Synthesis of 2, 4, 5-triaryl-5H-chromeno[4, 3-b] pyridines under microwave radiation. J Heterocycl Chem 46:702–707 78. Kappe CO (2000) Biologically active dihydropyrimidones of the Biginelli-type-A literature survey. Eur J Med Chem 35:1043–1052 79. Mayer TU, Kapoor TM, Haggarty SJ et al (1999) Small molecule inhibitor of mitotic spindle bipolarity identified in a phenotype-based screen. Science 286:971–974 80. Tetsuzou K, Takao C, Yoshihito A (1984) Production of 5-carbamoyl-6-methyl-4substituted-1,2,3,4-tetrahydro-2-thioxopyrimidine. PCT Int Appl JP59190974 81. Rovnyak GC, Atwal KS, Hedberg A et al (1992) Dihydropyrimidine calcium channel blockers. 4. Basic 3-substituted-4-aryl-1, 4-dihydropyrimidine-5-carboxylic acid esters. Potent antihypertensive agents. J Med Chem 35:3254–3263 82. Jauk B, Pernat T, Kappe CO (2000) Design and synthesis of a conformationally rigid mimic of the dihydropyrimidine calcium channel modulator SQ 32, 926. Molecules 5:227–239 83. Sidler DR, Larsen RD, Chartrain M et al (1999) Alpha 1a adrenergic receptor antagonist. PCT Int Appl WO 99 07695 84. Bruce MA, Pointdexter GS, Johnson G (1998) Dihydropyrimidone derivatives as NPY antagonists. PCT Int Appl WO 98 033 791 85. Patil AD, Kumar NV, Kokke WC et al (1995) Novel alkaloids from the sponge Batzella sp.: inhibitors of HIV gp120-human CD4 binding. J Org Chem 60:1182–1188 86. Gopalakrishnan M, Sureshkumar P, Kanagarajan V et al (2006) Microwave-promoted facile and rapid solvent-free synthesis procedure for the efficient synthesis of 3, 4-dihydropyrimidin-2(1H)-ones and–thiones using ZrO2/SO42 as a reusable heterogeneous catalyst. Lett Org Chem 3:484–488

226

J.B. Bariwal et al.

87. Ahn BJ, Gang MS, Chae K et al (2008) A microwave-assisted synthesis of 3, 4-dihydropyrimidin-2-(1H)-ones catalyzed by FeCl3-supported nanopore silica under solvent-free conditions. J Ind Eng Chem 14:401–405 88. Pisani L, Prokopcova H, Kremsner JM et al (2007) 5-Aroyl-3, 4-dihydropyrimidin-2-one library generation via automated sequential and parallel microwave-assisted synthesis techniques. J Comb Chem 9:415–421 89. Matloobi M, Kappe OC (2007) Microwave-assisted solution- and solid-phase synthesis of 2-amino-4-arylpyrimidine derivatives. J Comb Chem 9:275–284 90. Glasnov TN, Vugts DJ, Koningstein MM et al (2006) Microwave-assisted dimroth rearrangement of thiazines to dihydropyrimidinethiones: synthetic and mechanistic aspects. QSAR Comb Sci 25:509–518 91. Sowmiya M, Sharma A, Parsodkar S et al (2007) Nanosized sulfated SnO2 dispersed in the micropores of Al-pillared clay as an efficient catalyst for the synthesis of some biologically important molecules. Appl Catal A Gen 333:272–280 92. Legeay JC, Eynde JJV, Toupet L et al (2007) A three-component condensation protocol based on ionic liquid phase bound acetoacetate for the synthesis of Biginelli 3,4-dihydropyrimidine-2(1H)-ones. Arkivoc (iii):13–28 93. Khunt RC, Akbari JD, Manvar AT et al (2008) Green chemistry approach to synthesis of some new trifluoromethyl containing tetrahydropyrimidines under solvent free conditions. Arkivoc (xi):277–284 94. Liang B, Wang X, Wang JX et al (2007) New three component cyclocondensation: microwave assisted one-pot synthesis of 5-unsubistutited-3, 4-dihydropyrimidin-2(1H)-ones under solvent-free conditions. Tetrahedron 63:1981–1986 95. Sheibani H, Saljoogi AS, Bazgir A (2008) Three-component process for the synthesis of 4-amino-5-pyrimidine carbonitriles under thermal aqueous conditions or microwave irradiation. Arkivoc (ii):115–123 96. Tu S, Zhang J, Zhu X et al (2006) New potential inhibitors of cyclin-dependent kinase 4: design and synthesis of pyrido[2, 3-d]pyrimidine derivatives under microwave irradiation. Bioorg Med Chem Lett 16:3578–3581 97. Prajapati D, Gohaina M, Thakur AJ (2006) Regiospecific one-pot synthesis of pyrimido[4, 5-d]pyrimidine derivatives in the solid state under microwave irradiations. Bioorg Med Chem Lett 16:3537–3540 98. Dandia A, Sarawgi P, Aryab K et al (2006) Mild and ecofriendly tandem synthesis of 1,2,4-triazolo [4,3-a]pyrimidines in aqueous medium. Arkivoc (xvi):83–92 99. Barthakur MG, Gogoi S, Dutta M et al (2009) A facile three-component solid phase synthesis of steroidal A-ring fused pyrimidines under microwave irradiation. Steroids 74:730–734 100. Chebanov VA, Muravyova EA, Desenko SM et al (2006) Microwave-assisted threecomponent synthesis of 7-aryl-2-alkylthio-4, 7-dihydro-1, 2, 4-triazolo[1, 5-a]pyrimidine6-carboxamides and their elective reduction. J Comb Chem 8:427–434 101. Shi F, Yan S, Zhou D et al (2009) A facile and efficient synthesis of novel pyrimido[5, 4-b] [4, 7]-phenanthroline-9, 11(7H, 8H, 10H, 12H)-dione derivatives via microwave-assisted multi-component reactions. J Heterocycl Chem 46:563–566 102. Shaaban MR (2008) Microwave-assisted synthesis of fused heterocycles incorporating trifluoromethyl moiety. J Fluorine Chem 129:1156–1161 103. Wang S-L, Hao W-J, Tu S-J et al (2009) Poly(ethyleneglycol): a versatile and recyclable reaction medium in gaining access to Benzo[4, 5]imidazo[1, 2-a]pyrimidines under microwave heating. J Heterocycl Chem 46:664–668 104. Shi F, Ma N, Zhou D et al (2010) Green approach to the synthesis of polyfunctionalized pyrazolo[40 , 30 :5, 6] pyrido[2, 3-d]pyrimidines via microwave-assisted multi-component reactions in water without catalyst. Synth Commun 40:135–143 105. Tu S, Wu S, Han Z et al (2009) An efficient microwave-assisted synthesis of pyrido[2, 3-d] pyrimidine derivatives. Chin J Chem 27:1148–1152 106. Jiang B, Cao L-J, Tu S-J et al (2009) Highly diastereoselective domino synthesis of 6-spirosubstituted pyrido[2, 3-d]pyrimidine derivatives in water. J Comb Chem 11:612–616

Microwave Irradiation and Multicomponent Reactions

227

107. Michael JP (2007) Quinoline, quinazoline and acridone alkaloids. Nat Prod Rep 24:223–246 108. Gabriele B, Mancuso R, Salerno G et al (2007) Novel and convenient synthesis of substituted quinolines by copper- or palladium-catalyzed cyclodehydration of 1-(2-aminoaryl)-2-yn1-ols. J Org Chem 72:6873–6877 109. Roma G, Braccio MD, Grossi G et al (2000) 1, 8-Naphthyridines IV. 9-Substituted N, N-dialkyl-5-(alkylamino or cycloalkylamino) [1, 2, 4]triazolo[4, 3-a][1, 8]naphthyridine-6carboxamides, new compounds with anti-aggressive and potent anti-inflammatory activities. Eur J Med Chem 35:1021–1035 110. Tu S, Zhu X, Zhang J et al (2006) New potential biologically active compounds: design and an efficient synthesis of N-substituted 4-aryl-4, 6, 7, 8-tetrahydroquinoline-2, 5(1H, 3H)diones under microwave irradiation. Bioorg Med Chem Lett 16:2925–2928 111. Sapkal SB, Shelke KF, Shingate BB et al (2009) Nickel nanoparticle-catalyzed facile and efficient one-pot synthesis of polyhydroquinoline derivatives via Hantzsch condensation under solvent-free conditions. Tetrahedron Lett 50:1754–1756 112. Tu SJ, Jiang B, Jia RH (2006) An efficient one-pot, three-component synthesis of indeno [1, 2-b]quinoline-9, 11(6H, 10H)-dione, acridine-1, 8(2H, 5H)-dione and quinoline-3-carbonitrile derivatives from enaminones. Org Biomol Chem 4:3664–3668 113. Zhang X-L, Sheng S-R, Liu X-L (2007) Solvent-free liquid-phase synthesis of polyhydroquinoline derivatives under microwave irradiation. Arkivoc (xiii):79–86 114. Peng J, Hao W, Wang X et al (2009) Microwave-assisted synthesis of pyrazolo[4, 3-f] quinolin-7-one derivatives via multi-component reactions. Chin J Chem 27:1707–1710 115. Tu S-J, Jiang B, Zhang J-Y et al (2006) Efficient and direct synthesis of poly-substituted indeno[1, 2-b]quinolines assisted by p-toluene sulfonic acid using high-temperature water and microwave heating via one-pot, three-component reaction. Org Biomol Chem 4:3980–3985 116. Tu S-J, Yan S, Cao X-D et al (2009) A facile and expeditious microwave-assisted synthesis of 4-aryl-2-ferrocenyl-quinoline derivatives via multi-component reaction. J Organomet Chem 694:91–96 117. Tu S, Zhang Y, Jia R et al (2006) A multi-component reaction for the synthesis of N-substituted furo[3, 4-b]quinoline derivatives under microwave irradiation. Tetrahedron Lett 47:6521–6525 118. Tu S, Li C, Li G et al (2007) Microwave-assisted combinatorial synthesis of polysubstituent imidazo[1, 2-a]quinoline, pyrimido[1, 2-a]quinoline and quinolino[1, 2-a]quinazoline derivatives. J Comb Chem 9:1144–1148 119. Xing X, Wua J, Dai W-M (2006) Acid-mediated three-component aza-Diels–Alder reactions of 2-aminophenols under controlled microwave heating for synthesis of highly functionalized tetrahydroquinolines. Part 9: Chemistry of aminophenols. Tetrahedron 62: 11200–11206 120. Bremner WS, Organ MG (2007) Multi-component reactions to form heterocycles by microwave-assisted continuous flow organic synthesis. J Comb Chem 9:14–16 121. Chebanov VA, Saraev VE, Desenko SM et al (2008) Tuning of chemo- and regioselectivities in multi-component condensations of 5-aminopyrazoles, dimedone, and aldehydes. J Org Chem 73:5110–5118 122. Wang X-H, Hao W-J, Tu S-J et al (2009) Microwave-assisted multi-component reaction for the synthesis of new and significative bisfunctional compounds containing two furo[3, 4-b] quinoline and acridinedione skeletons. J Heterocycl Chem 46:742–747 123. Zhu S-L, Zhao K, Su X-M et al (2009) Microwave-assisted synthesis of new spiro[indoline3, 40 -quinoline] derivatives via a one-pot multi-component reaction. Synth Commun 39:1355–1366 124. Szatmari I, Fulop F (2009) Microwave-assisted one-pot synthesis of (aminoalkyl) naphthols and aminoalkyl) quinolinols by using ammonium carbamate or ammonium hydrogen carbonate as solid ammonia source. Synthesis 5:775–778 125. Babu ARS, Raghunathan R (2007) TiO2-silica mediated one pot three component 1, 3-dipolar cycloaddition reaction: a facile and rapid synthesis of dispiro acenaphthenone/oxindole [indanedione/oxindole] pyrroloisoquinoline ring systems. Tetrahedron 63:8010–8016

228

J.B. Bariwal et al.

126. Mert-Balci F, Conrad J, Meindl K et al (2008) Microwave-assisted three-component reaction for the synthesis of pyrido[20 , 10 :2, 3]imidazo[4, 5-c]isoquinolin-5(6H)-ones. Synthesis 22:3649–3656 127. Kaur B, Kaur R (2007) Synthesis of fused quinazolinethiones and their S-alkyl/aryl derivatives. Arkivoc (xv):315–323 128. Siddiqui IR, Siddique SA, Srivastava V et al (2008) A novel anthranilic acid based multicomponent strategy for expeditious synthesis of 4(3H)-quinazolinone N-nucleosides. Arkivoc (xii):277–285 129. Jiang B, Tu SJ, Kaur P et al (2009) Four-component domino reaction leading to multifunctionalized quinazolines. J Am Chem Soc 131:11660–11661 130. Chebanov VA, Saraev VE, Desenko SM et al (2007) One-pot, multi-component route to pyrazolo-quinolizinones. Org Lett 9:1691–1694 131. Azizian J, Mohammadizadeh MR, Zomorodbakhsh S et al (2007) Microwave-assisted onepot synthesis of some dicyano-methylene derivatives of indenoquinoxaline and tryptanthrin under solvent free conditions. Arkivoc (xv):24–30 132. Claiborne CF, Liverton NJ, Nguyen KT (1998) An efficient synthesis of tetrasubstituted imidazoles from N-(2-oxo)-amides. Tetrahedron Lett 39:8939–8942 133. Lee JC, Laydon JT, McDonnell PC et al (1994) A protein kinase involved in the regulation of inflammatory cytokine biosynthesis. Nature 372:739–746 134. Pierce ME, Carini DJ, Huhn G et al (1993) Practical synthesis and regioselective alkylation of methyl 4(5)-(pentafluoroethyl)-2-propylimidazole-5(4)-carboxylate to give DuP 532, a potent angiotensin II antagonist. J Org Chem 58:4642–4645 135. Nagarapu L, Apuri S, Kantevari S (2007) Potassium dodecatugstocobaltate trihydrate (K5CoW12O40·3H2O): a mild and efficient reusable catalyst for the one-pot synthesis of 1, 2, 4, 5-tetrasubstituted imidazoles under conventional heating and microwave irradiation. J Mol Catal A Chem 266:104–108 136. Dandia A, Singh R, Jain AK et al (2008) Versatility of alternative reaction media: watermediated domino and green chemical synthesis of pyrimido[1, 2-a]benzimidazole under nonconventional conditions. Synth Commun 38:3543–3555 137. Ye P, Sargent K, Stewart E et al (2006) Novel and expeditious microwave-assisted threecomponent reactions for the synthesis of spiroimidazolin-4-ones. J Org Chem 71:3137–3140 138. Mohammadizadeh MR, Hasaninejad A, Bahramzadeh M (2009) Trifluoroacetic acid as an efficient catalyst for one-pot, four-component synthesis of 1, 2, 4, 5-tetrasubstituted imidazoles under microwave-assisted, solvent-free conditions. Synth Commun 39:3232–3242 139. Guchhait SK, Madaan C, Thakkar BS (2009) A highly flexible and efficient Ugi-type multicomponent synthesis of versatile N-fused aminoimidazoles. Synthesis 19:3293–3300 140. Saiz C, Pizzo C, Manta E et al (2009) Microwave-assisted tandem reactions for the synthesis of 2-hydrazolyl-4-thiazolidinones. Tetrahedron Lett 50:901–904 141. Darehkordi A, Saidi K, Islami MR (2007) Preparation of heterocyclic compounds by reaction of dimethyl and diethyl acetylene dicarboxylate (DMAD, DEAD) with thiosemicarbazone derivatives. Arkivoc (i):180–188 142. Wustrow DJ, Capiris T, Rubin R et al (1998) Pyrazolo[1, 5-a]pyrimidine CRF-1 receptor antagonists. Bioorg Med Chem Lett 8:2067–2070 143. Menozzi G, Mosti L, Fossa P et al (1997) Synthesis and structural study of novel 5-aryl substituted 2-amino-4, 7-dioxopyrido[2, 3-d]pyrimidines. J Heterocycl Chem 34:963–968 144. Chimenti F, Fioravanti R, Bolasco A et al (2007) Monoamine oxidase isoform-dependent tautomeric influence in the recognition of 3, 5-diaryl pyrazole inhibitors. J Med Chem 50:425–428 145. Willy B, Mu¨ller TJJ (2008) Regioselective three-component synthesis of highly fluorescent 1, 3, 5-trisubstituted pyrazoles. Eur J Org Chem 24:4157–4168 146. Radi M, Bernardo V, Bechi B et al (2009) Microwave-assisted organocatalytic multicomponent Knoevenagel/hetero Diels–Alder reaction for the synthesis of 2, 3-dihydropyran[2, 3-c]pyrazoles. Tetrahedron Lett 50:6572–6575 147. Albert A (1996) The acridines, 2nd edn. Edward Arnold Ltd, London

Microwave Irradiation and Multicomponent Reactions

229

148. Spalding DP, Chapin EC, Mosher HS (1954) Heterocyclic basic compounds. XV. Benzacridine derivatives. J Org Chem 19:357–364 149. Bachman GB, Picha GM (1946) Synthesis of substituted aminobenzacridines. J Am Chem Soc 68:1599–1602 150. Dobson J, Hutchison WC, Kermac WO (1948) Attempts to find new antimalarials. Part XXVII. Derivatives of various benzacridines and pyridoacridines. J Chem Soc:123–126 151. Thull U, Testa B (1994) Screening of unsubstituted cyclic compounds as inhibitors of monoamine oxidases. Biochem Pharmacol 47:2307–2310 152. Reil E, Scoll M, Masson K et al (1994) Synthesis of quinolones and acridones and their inhibitory activity in NADH-dehydrogenases and cytochrome b/c1-complexes. Biochem Soc Trans 22:62S 153. Berg SL, Balis FM, McCully CL et al (1991) Pharmacokinetics of pyrazoloacridine in the Rhesus monkey. Cancer Res 51:5467–5470 154. Metha G, Sambaiah T, Maiya BG et al (1993) Synthesis and nuclease activity of some ‘porphyrin–acridone’ hybrid molecules. J Chem Soc Perkin Trans 1:2667–2670 155. Wang Q-F, Yen GC (2008) Efficient synthesis of diarylidene octahydroacridines by one-pot multi-component tandem reactions. Cent Eur J Chem 6:404–409 156. Nadaraj V, Selvi ST, Mohan S (2009) Microwave-induced synthesis and anti-microbial activities of 7, 10, 11, 12-tetrahydrobenzo[c]acridin-8(9H)-one derivatives. Eur J Med Chem 44:976–980 157. Rizzuto R, Bernardi P, Pozzan T (2000) Mitochondria as all-round players of the calcium game. J Physiol 529:37–47 158. Pan W, Liu H, Xu Y-J et al (2005) Pyrimido-oxazepine as a versatile template for the development of inhibitors of specific kinases. Bioorg Med Chem Lett 15:5474–5477 159. Tamura K, Fukuoka M (2005) Gefitinib in non-small cell lung cancer. Expert Opin Pharmacol 6:985–993 160. Hudson C, Murthy VS, Estep KG et al (2007) Microwave-assisted three component one-pot synthesis of pyrimido-oxazepines. Tetrahedron Lett 48:1489–1492 161. Tu SJ, Cao XD, Hao WJ et al (2009) An efficient and chemoselective synthesis of benzo[e] [1, 4]thiazepin-2-(1H, 3H, 5H)-ones via a microwave-assisted multi-component reaction in water. Org Biomol Chem 7:557–563 162. Wu J, Jiang Y, Dai W-M (2009) Assembly of 1, 3-dihydro-2H–3-benzazepin-2-one conjugates via Ugi four-component reaction and palladium-catalyzed hydroamidation. Synlett 7:1162–1166 163. Willy B, Dallos T, Rominger F et al (2008) Three-component synthesis of cryofluorescent 2, 4-disubstituted 3H-1, 5-benzodiazepines-conformational control of emission properties. Eur J Org Chem 2008:4796–4805 164. De Silva RA, Santra S, Andreana PR (2008) A tandem one-pot, microwave-assisted synthesis of regiochemically differentiated 1, 2, 4, 5-tetrahydro-1, 4-benzodiazepin-3-ones. Org Lett 10:4541–4544 165. Hajela K, Kapil RS (1997) Synthesis and post-coital contraceptive activity of a new series of substituted 2, 3-diaryl-2H-1-benzopyrans. Eur J Med Chem 32:135–142 166. Mannhold R, Cruciani G, Weber H et al (1999) 6-Substituted benzopyrans as potassium channel activators: Synthesis, vasodilator properties, and multivariate analysis. J Med Chem 42:981–991 167. Zhuang Q, Zhou D, Tu S et al (2008) A highly efficient microwave-assisted synthesis of chromeno[3, 4-b][4, 7]phenanthroline derivatives through multi-component reactions in water. J Heterocycl Chem 45:831–835 168. El-Shaaer HM, Foltinova P, Lacova M et al (1998) Synthesis, antimicrobial activity and bleaching effect of some reaction products of 4-oxo-4H-benzopyran-3-carboxaldehydes with aminobenzothiazoles and hydrazides. Farmaco 53:224–232 169. Johnson AT, Wang L, Standeven AM et al (1999) Synthesis and biological activity of highaffinity retinoic acid receptor antagonists. Bioorg Med Chem 7:1321–1338

230

J.B. Bariwal et al.

170. Surpur MP, Kshirsagar S, Samant SD (2009) Exploitation of the catalytic efficacy of Mg/Al hydrotalcite for the rapid synthesis of 2-aminochromene derivatives via a multi-component strategy in the presence of microwaves. Tetrahedron Lett 50:719–722 171. Yet L (2000) Metal-mediated synthesis of medium-sized rings. Chem Rev 100:2963–3007 172. Schmidt B, Westhus M (2000) Diastereoselectivity in a ring closing metathesis reaction with a remote stereogenic centre leading to quaternary dihydropyrans. Tetrahedron 56:2421–2426 173. Class YJ, DeShong P (1995) The pseudomonic acids. Chem Rev 95:1843–1857 174. Castagnolo D, Botta L, Botta M (2009) Stereoselective protecting group free synthesis of D, L-gulose ethyl glycoside via multi-component enyne cross metathesis-hetero Diels-Alder reaction. Carbohydr Res 344:1285–1288 175. Castagnolo D, Botta L, Botta M (2009) One-pot multi-component synthesis of 2, 3-dihydropyrans: new access to furanose-pyranose 1, 3-C–C-linked-disaccharides. Tetrahedron Lett 50:1526–1528 176. Wei C, Li Z, Li CJ (2004) The development of A3-coupling (aldehyde-alkyne-amine) and AA3-coupling (asymmetric aldehyde-alkyne-amine). Synlett:1472–1483 177. Bariwal JB, Ermolat’ev DS, Van der Eycken EV (2010) Efficient microwave-assisted synthesis of secondary alkyl propargylamines via A3-coupling with primary aliphatic amines. Chem Eur J 16:3281–3284 178. Shore G, Yoo W-J, Li C-J et al (2009) Propargyl amine synthesis catalysed by gold and copper thin films by using microwave-assisted continuous-flow organic synthesis (MACOS). Chem Eur J 16:126–133 179. Mont N, Mehta VP, Appukkuttan P et al (2008) Diversity oriented microwave-assisted synthesis of (-) -Steganacin aza-analogues. J Org Chem 73:7509–7516 180. Shaterian HR, Yarahmadi H, Ghashang M (2008) An efficient, simple and expedition synthesis of 1-amidoalkyl-2-naphthols as ‘drug like’ molecules for biological screening. Bioorg Med Chem Lett 18:788–792 181. Xu H, Yu X, Sun L et al (2008) Microwave-assisted three-component Knoevenagel-nucleophilic aromatic substitution reactions. Tetrahedron Lett 49:4687–4689 182. Rodriguez B, Bolm C (2006) Thermal effects in the organocatalytic asymmetric Mannich reaction. J Org Chem 71:2888–2891 183. Xing X, Wu J, Feng G et al (2006) Microwave-assisted one-pot U-4CR and intramolecular O-alkylation toward heterocyclic scaffolds. Tetrahedron 62:6774–6781 184. Hulme C, Chappeta S, Dietrich J (2009) A simple, cheap alternative to ‘designer convertible isonitriles’ expedited with microwaves. Tetrahedron Lett 50:4054–4057 185. Strubing D, Neumann H, Jacobi von Wangelin A et al (2006) An easy and general protocol for multi-component coupling reactions of aldehydes, amides, and dienophiles. Tetrahedron 62:10962–10967 186. Werner S, Nielsen SD, Wipf P et al (2009) Fluorous parallel synthesis of a piperazinedionefused tricyclic compound library. J Comb Chem 11:452–459 187. Sridharan V, Karthikeyan K, Muthusubramanian S (2006) Unexpected multi-component reaction of 2/4-methoxyaryl aldehydes with arylhydroxylamines and maleic anhydride: a novel synthesis of unsymmetrical diarylamines. Tetrahedron Lett 47:4221–4223 188. Santra S, Andreana PR (2007) A one-pot, microwave-influenced synthesis of diverse small molecules by multi-component reaction cascades. Org Lett 9:5035–5038 189. Hao W-J, Jiang B, Tu S-J et al (2009) Microwave-assisted combinatorial synthesis of new 3-pyrimidin-5-ylpropanamides via a solvent-dependent chemoselective reaction. J Comb Chem 11:310–314 190. Hulme C, Chappeta S, Griffith C et al (2009) An efficient solution phase synthesis of triazadibenzoazulenones: ‘designer isonitrile free’ methodology enabled by microwaves. Tetrahedron Lett 50:1939–1942 191. Naik T, Naik H (2008) An efficient Bi(NO3)3·5H2O catalyzed multi component one-pot synthesis of novel naphthyridines. Mol Divers 12:139–142 192. Sridhar M, Rao RM, Baba NHK et al (2007) Microwave accelerated Gewald reaction: synthesis of 2-aminothiophenes. Tetrahedron Lett 48:3171–3172

Top Heterocycl Chem (2010) 25: 231–287 DOI: 10.1007/7081_2010_46 # Springer-Verlag Berlin Heidelberg 2010 Published online: 9 July 2010

Applications of MCR-Derived Heterocycles in Drug Discovery Irini Akritopoulou-Zanze and Stevan W. Djuric

Abstract Heterocyclic structures are an integral part of numerous drugs and natural products and there is a considerable interest in efficient methods for their synthesis. A variety of multicomponent reactions (MCRs) provide access to heterocyclic structures such as isocyanide based MCRs, dicarbonyl derivative and cycloaddition MCRs. MCR-derived heterocycles are typically prepared in few, versatile and atom efficient synthetic steps and exhibit anticancer, antioxidant and antimicrobial properties. Keywords Multicomponent reactions Heterocyles Drug discovery Antimicrobial Anticancer Antioxidant Antibacterial Antifungal Antimycobacterial Dicarbonyl based MCRs Isocyanide based MCRs Knoevenagel based MCR Contents 1 2

3

4

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Isocyanide-Based MCRs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1 Ugi Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2 Bienayme´–Blackburn–Groebke Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Dicarbonyl, Cyanomalonate and Malononitrile Based MCRs . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1 The Biginelli Condensation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2 The Hantzsch Reaction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3 The Gewald Reaction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.4 Knoevenagel/Diels–Alder Sequences . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.5 Knoevenagel/Michael-Type Sequences . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.6 Knoevenagel/Krohnke Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.7 Other Knoevenagel-Based MCRs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Cycloadditions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1 Hetero-Diels–Alder Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

I. Akritopoulou-Zanze (*) and S.W. Djuric Medicinal Chemistry Technologies, Abbott Laboratories, Abbott Park, IL 60064, USA e-mail: [email protected]

233 233 233 235 237 237 245 253 256 260 263 264 268 268

232

I. Akritopoulou-Zanze and S.W. Djuric

4.2 1,3-Dipolar Cycloadditions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Miscellaneous . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.1 The Do¨bner Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.2 The Bucherer–Bergs Reaction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.3 Other Multicomponent Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6 Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

5

Abbreviations ATP BACE Boc Cdc cGMP DBP DDQ DEAD DIC DIEA DMAP DMF DOS DPPH EDCI EDDA F HOBt Hsp HTS MCR MDR MIC MMP MSO MtGS NMP PDE Pgp PPT PTSA RCM

Adenosine 50 -triphosphate b-Secretase t-Butoxy carbonyl Cyclin-dependent kinase Cyclic guanosine monophosphate Diastolic blood pressure 2,3-Dichloro-5,6-dicyano-p-benzoquinone Diethyl azodicarboxylate N,N0 -Diisopropylcarbodiimide Diisopropylethylamine 4-Di(methylamino)pyridine Dimethylformamide Diversity-oriented synthesis 2,2-Diphenyl-1-picrylhydrazyl N-ethyl-N0 -(3-dimethylaminopropyl)carbodiimide Ethylenediammonium diacetate Bioavailability 1-Hydroxybenzotriazole Heat shock protein High-throughput screening Multicomponent reaction Multidrug resistance Minimum inhibitory concentration Matrix metalloproteinase L-Methionine-SR-sulfoximine Mycobacterium tuberculosis glutamine synthase 1-Methyl-2-pyrrolidinone Phosphodiesterase P-glycoprotein Phospinothricin p-Toluenesulfonic acid Ring-closing metathesis

271 272 272 273 276 282 282

Applications of MCR-Derived Heterocycles in Drug Discovery

Red-Al ROC ROS RSA SBP TFA THF

233

Sodium bis(2-methoxyethoxy)aluminum hydride Ring-opening metathesis Reactive oxygen species Radical scavenging activity Systolic blood pressure Trifluoroacetic acid Tetrahydrofuran

1 Introduction Heterocyclic structures are an integral part of numerous drugs and natural products [1] and there is a considerable interest in efficient methods for their syntheses [2]. Multicomponent reactions (MCRs) are powerful tools in creating heterocycles in an atom- and time-efficient manner [3, 4]. MCRs involve the use of multiple reaction inputs to generate products in a single step. For a reaction to be considered a multicomponent reaction, most atom parts of each component need to be incorporated into the final product. The more interesting and highly utilized MCRs have invariably been the ones that allow for the generation of large numbers of products by combining highly diverse components. Large libraries of MCR heterocyclic products are particularly attractive for drug discovery efforts because they provide rapid access to complex molecules for biological testing. Furthermore, once biological activity is found, optimization exercises are relatively straightforward and expedient. In addition, compounds of interest can be easily scaled-up for advanced in vivo studies.

2 Isocyanide-Based MCRs One of the most prominent class of multicomponent reactions involves the use of isocyanides [5] and many synthetic methods have been developed to access heterocycles from isocyanide-based chemistry [6, 7]. There are a number of reviews covering the applications of isocyanide-based MCRs in drug discovery [8, 9]. In this review, we will focus on the most recent developments in the field.

2.1

Ugi Reactions

A high-throughput screening (HTS) campaign to identify b-secretase (BACE-1) inhibitors provided compound 1 (Fig. 1) as a promising new hit which was quickly optimized to compound 2 with the aid of an Ugi MCR [10]. Although compound

234

I. Akritopoulou-Zanze and S.W. Djuric O

O

N

N N

N H

F N

N H

N

N

1

2 BACE 1 IC50 = 0.11 μM sAPPβ IC50 = 5.2 μM (cell)

BACE 1 IC50 = 22 μM

Fig. 1 Initial BACE 1 HTS hit and optimized analog O

O R1

N+

KOCN

C–

a

NH2 R2 N R3

N

R1 N H

N

O R2

b, c

N R3

R1

N N H

N

R2

N R4

Scheme 1 a MeOH, H2O: b HCl (R3 = Boc): c R4CHO, Na(CN)BH3

2 did not show in vivo efficacy because of its weak cellular potency, it was not a substrate for (P-glycoprotein) Pgp and had high plasma and brain levels validating this class of compounds for further consideration. The synthesis of 2 and related analogs proceeded as shown in Scheme 1. The spiropiperidine iminohydantoin core was obtained in a one-step, four-component Ugi coupling of piperidones, isocyanides, amines and KOCN, and proceeded in moderate yields. Deprotection of the piperidine nitrogen and further elaboration provided the final products. Numerous heterocyclic structures can be accessed by combining the Ugi reaction with subsequent transformations [11, 12]. In an elegant diversity-oriented synthesis (DOS) approach, a library of highly complex molecular scaffolds was prepared and evaluated for its binding affinity against Bcl-xL [13]. Most of the scaffolds were accessed in few synthetic steps as shown in Scheme 2 by initially forming versatile intermediates 3 via Ugi-5-center-4-component reactions. When R1 and/or R4 possessed a double or triple bond, subsequent ring-opening/ringclosing metatheses (ROM/RCM) of compounds 3 provided compounds 4–6. When R2 contained an amino group, compounds 7 were prepared. Compounds 6 and 7 can be further elaborated to compounds 8 and 9 via Diels–Alder and ROM/RCM transformations, respectively. All compounds were evaluated for their binding affinity against Bcl-xL by performing docking exercises and by 1H NMR binding assays and several potential inhibitor core structures were identified for further evaluation.

Applications of MCR-Derived Heterocycles in Drug Discovery

O

R3 NH

N

R2 CO2R4

O 4 O

O R2

H N

235

O

R3 NH

O

R3 NH

N

R2

N

R2

CO2R4 R1

O

R2 N

H

6

O

R4 OH H N R 3

O N

O 8

R1

CO2R4 3

R3 N+ C–

R6

N R3 H

O

CO2H

CO2R4

R5

O

O

R1 O N N R3 H R 7 N H 7

O N O NH O

N H R7

R3

9

R2 O O

O

5

Scheme 2 Diversity-oriented synthesis of highly complex scaffolds via Ugi-5C-4CR followed by ROM/RCM cyclizations and Diels–Alder reactions

R1

O

N NH2

R2

H

R3 N+ C –

HN R3

a R1

N

R2 N

Scheme 3 a MgCl2, EtOH, 160 C, Microwave, 20–30 min

2.2

Bienayme´–Blackburn–Groebke Reactions

The Bienayme´–Blackburn–Groebke reaction [14–16] provides access to a variety of fused heterocyclic ring systems in one, atom-economical, synthetic step. The reaction has been recently utilized to prepare functionalized 3-aminoimidazo[1,2-a]pyridines from aldehydes, 2-aminopyridines and isocyanides, as shown in Scheme 3 [17]. The compounds prepared were tested for their inhibitory activity against Mycobacterium tuberculosis glutamine synthetase (MtGS), an enzyme that plays a key role in mycobacterial cell-wall biosynthesis and nitrogen metabolism. Compound

236

I. Akritopoulou-Zanze and S.W. Djuric

10 was identified as a potent inhibitor of the enzyme with favorable inhibitory activity compared to the most potent inhibitors known, L-methionine-SR-sulfoximine (MSO) and phosphinothricin (PPT) (Fig. 2). An interesting variation of the Bienayme´–Blackburn–Groebke reaction employing 2-formylbenzoic acid, 2-aminopyridines and isocyanides (Scheme 4) resulted in the production of fused isoquinolinones 11 [18]. The reaction proceeded better without the presence of a Lewis acid and worked with a variety of different isocyanides and 2-aminopyridines. Phenyl isocyanide, however, did not give a satisfactory result. The products were tested against the non-small-cell lung cancer cell line A549 and three exhibited potent activity (Fig. 3). It was found that the presence of the 4-methoxybenzyl group was necessary for activity.

Br

HN

O S

HO2C

N

O P OH

HO2C NH

N

NH2

NH2

CO2H 10

MSO

PPT

Mt GS IC50 = 0.38 μM

Mt GS IC50 = 51 μM

Mt GS IC50 = 1.9 μM

Fig. 2 MtGS inhibitors

O

R1

R1

N

H CO2H

N

R2 N+ C – NH2

N

a N

R2

O

11

Scheme 4 a MeOH, 55 C, 39–82%

N

N

N

N

N

O

12

N

N

N

N

O

O

A549 IC50 = 1.82 μM

13

Cl

O

14

O

A549 IC50 = 6.61 μM

O

A549 IC50 = 10.692 μM

Fig. 3 Cytotoxic activity of compounds 12–14 against the A549 cell line

Applications of MCR-Derived Heterocycles in Drug Discovery

237

3 Dicarbonyl, Cyanomalonate and Malononitrile Based MCRs In addition to isocyanide-based MCRs, a wealth of highly functionalized heterocycles can be obtained from 1,3-dicarbonyl, cyanomalonate and malononitrile based MCRs [19]. These easily accessible starting materials participate in a variety of multicomponent reactions and have found numerous applications in drug discovery.

3.1

The Biginelli Condensation

The classic Biginelli reaction features the cyclocondensation of an aldehyde, a urea and an active methylene compound to form dihydropyrimidinones (Fig. 4). The reaction has been extensively utilized and reviewed [20] and its applications to drug discovery have also been highlighted [21]. This chapter will focus on some of the most recent developments and applications of Biginelli reactions to the discovery of biologically active molecules. A straightforward synthesis of Biginelli products using p-toluenesulfonic acid (PTSA) was developed (Scheme 5) [22]. The methodology did not require anhydrous conditions and proceeded in high yields at room temperature, although some reaction mixtures required reflux to go to completion. The compounds obtained from these reactions were tested for their cytotoxic and antioxidant activities. It was found that compounds, deriving from cinnamoyl aldehydes such as 15 and 16 (Fig. 5), had significant cytotoxic activity against MCF-7 human breast cancer cells. Furan and pyridine moieties in the same position also imparted potent cytotoxicity, while 3-nitrophenyl substitutions resulted in compounds 17 and 18 with good antioxidant activity. These were the only compounds with antioxidant activity up to 100 mg. Several groups have used the Biginelli reaction to search for heat shock protein 70 (Hsp70) modulators. Hsp70 performs essential cell functions such as protein R H

E

R O

H+ NH2

O

R

Fig. 4 The Biginelli condensation

H2N

O

NH2

R2

R1 N H

H O

R1 = Me, 2-ClPh

O

HN Y

X

E

heat

R

X O a

R1

NH N H

X

R2

N H

NH N H

X

X = O, S, NH Y = H, CN

Scheme 5 a PTSA, EtOH, room temperature or reflux, 24–30 h, 67–81%, for R1 = 2-ClPh, R2 = Ph, Y = H, X = NH 12%

238

I. Akritopoulou-Zanze and S.W. Djuric

O2N O

Cl

O

N H

NH N H

X

Cl

% Cytotoxicity at 10 μg

N H

NH N H

X

DPPH antioxidant activity

15 X = S

71%

17 X = S

IC50 = 58 μg

16 X = O

79%

18 X = O

IC50 = 63 μg

Fig. 5 Cytotoxic and antioxidant activities of compounds 15–18

folding and trafficking and protects cells from thermal and oxidative stresses. Although the many roles and mechanisms by which Hsp70 operates are not fully elucidated, overexpression of Hsp70 in various cancers has made this protein an interesting target for anticancer therapies. Hybrid peptoid–dihydropyrimidinones libraries 20 have been prepared by combining the Biginelli and Ugi reactions (Scheme 6) [23]. Dihydropyrimidone acids 19 have also been used for direct couplings to provide amides 21 [24]. Alternatively, solid-phase synthesis of dipeptides on Wang resin, followed by coupling of the resin bound amines with 19 and subsequent cleavage from the resin, furnished peptoid-type amides 21 [25]. Several compounds derived from these libraries were identified as Hsp70 modulators and were further evaluated in cell proliferation assays such as the SK-BR-3 and MCF-7 breast cancer cell lines and the HT29 colon cancer cell line (Fig. 6) [26]. Compounds 22–24 were potent against all three cell lines. The dihydropyrimidinone libraries were also tested for replication inhibition of the malarial parasite, Plasmodium falciparum, where Hsp70 chaperones are believed to play an important role in the parasite’s homeostasis [24]. Nine compounds that inhibit replication of the parasite were identified. Among them, compounds 25 and 26 were the most potent (Fig. 7) and were prepared by direct couplings of dihydropyrimidone acids 19 with a pyrrolo amine. The activity of numerous peptoid-amides 21 (Scheme 6), deriving from solidphase syntheses [25], against two evolutionary distant members of the Hsp70 family, DnaK from Escherichia coli (E. coli) and bovine Hsc70, was also reported. Several compounds were found to be active against mammalian Hsp70 and some compounds such as 27 and 28 were found to be active against both Hsp70 isoforms (Fig. 8). Copper (II) chloride proved to be a very efficient catalyst for the Biginelli reaction in the absence of solvent [27]. When ethyl acetoacetate, aldehydes and urea or thiourea were heated neat in the presence of copper (II) chloride, the Biginelli products were isolated, after recrystallization from hot ethanol, in high yields and purities (Scheme 7).

Applications of MCR-Derived Heterocycles in Drug Discovery

239 O R1

R3

O

R4 NH2

NH R2

O

N

R5 CHO R6 N+ C –

n O

c R3

O R1

O

O O

H

a or b

R1

O

NH2 R2

NH R2

O HN

R3

N

O

N

HN R6

O

R4 20

R4 NH2

n n

O

R5

O

O

d R1

O OH

19

R3

O

OH

NH R2

n = 1, 3

N

O

n O R4

NH

21

Scheme 6 a THF, cat HCl, rt, 48 h; b DMF, cat HCl, 55 C, 38 h; c MeOH, Microwave, 70 C, 21–63%; d EDCI, DMAP, CH2Cl2, rt or when R4 is a dipeptide attached to Wang resin, DIC, HOBt, 60 C, microwave then 1:1 TFA/CH2Cl2

The compounds produced were tested for their antifungal activity against Trichoderma hammatum, Trichoderma koningii and Aspergillus niger. Radial growths of the corresponding fungus at 24-, 48- and 72-h time intervals, at various concentrations of compound, were recorded and inhibition rates over control were calculated. Most of the compounds exhibited modest antifungal activity. Compound 29 was the most potent against T. hammatum with an MIC of 0.35 mM, compound 31 against T. koningii (radial growth after 24 and 48 h was completely inhibited) and compounds 30–33 against A. niger with MIC values of 0.35 mM each (Table 1). Fused dihydropyrimidinones of general structure 35, deriving from the combination of the Biginelli reaction with another one-pot multicomponent reaction as shown in Scheme 8, exhibited good antifungal as well as antibacterial properties [28]. The Biginelli product 34 was prepared by a tin dichloride-mediated condensation followed by recrystallization from hot ethanol in 91% yield. It was then subjected to a one-pot reaction with monochloroacetic acid and an arylaldehyde or arylfurfuraldehyde in the presence of anhydrous sodium acetate in acetic acid/acetic anhydride. All the products were tested for antifungal activity against Aspergillus fumigatus (NCIM No. 524), Aspergillus flavus (NCIM No. 902), Candida albicans (NCIM No. 3100) and Penicillium marneffei. They were also

240

I. Akritopoulou-Zanze and S.W. Djuric

O

NH

O N

O

O O

O

R3

N

O

O

O

O

O O

O

O

O

O

O

N HN

NH

O

N

O

HN

O

O

22 R3 = Phenyl

23 R3 = c-Propyl

24

SK-BR-3 GI50 = 6.5 μM

SK-BR-3 GI50 = 6.2 μM

SK-BR-3 GI50 = 8.8 μM

MCF7 GI50 = 2.4 μM

MCF7 GI50 = 6.3 μM

MCF7 GI50 = 7.8 μM

HT29 GI50 = 4.8 μM

HT29 GI50 = 5.3 μM

HT29 GI50 = 3.1 μM

Fig. 6 Antiproliferative activity of hybrid peptoid-dihydropyrimidinones

evaluated for antibacterial properties against E. coli (ATCC 25922), Staphylococcus aureus (S. aureus) (ATCC 25923), Pseudomonas aeruginosa (ATCC 27853) and Klebsiella pneumoniae. Compounds 36–39 were some of the most potent compounds with good broad antifungal and antibacterial activities (Table 2). A variation of the Biginelli condensation in which aldehydes and guanidine hydrochloride were reacted with ethylcyanoacetate (Scheme 9) under basic conditions provided 2-aminopyrimidines in a one-step synthesis [29]. The products were tested against E. coli and S. aureus bacteria. Compound 40 was selectively active against S. aureus. Another variation of the Biginelli condensation involved the reaction of aldehyde 42, guanidine hydrochloride with various pyrazolones 41 to provide pyrazolopyrimidines 43 (Scheme 10) [30]. All the products obtained were tested against the M. tuberculosis H37 Rv strain and found to be active. In particular, compounds 44–46 had comparable activity (MIC = 1.2 mg/mL) to first-line drugs such as rifampicin (RIP) (MIC = 1 mg/mL). The reaction of o-methylisourea hydrogen sulfate with ethyl acetoacetate and aldehydes provided dihydropyrimidines 47 (Scheme 11) which underwent

Applications of MCR-Derived Heterocycles in Drug Discovery

241

NO2

O O NH

O O

NH O

N N

O O NH

O

O N

NH O

O

N

O 25

26

P. falsiparum IC50 = 0.05 μM

P. falsiparum IC50 = 0.03 μM

Fig. 7 Antimalarial activity of peptoid-dihydropyrimidinones

Br

Br

O

O NH

O

O

N

N

O H N

HO O

H N O

NH

O

O

O NH

H N

HO

O

O

NH O

27

28

NH2 Hsc70 Ec50 = 105 μM

Hsc70 Ec50 = 179 μM

Dnak Ec50 = 107 μM

Dnak Ec50 = 190 μM

Fig. 8 Hsp70 activity of peptoid-dihydropyrimidinones

242

I. Akritopoulou-Zanze and S.W. Djuric R1

O

O NH2

R1

O H O

a

O

NH

X

H2N

O

N H

X = O, S

X

Scheme 7 a 20 mol% CuCl2·2H2O, 100 C, 20 min to 1 h, 85–96% Table 1 Percentage inhibition of radial growth over control (mm) of dihydropyrimidinones N

O

OH

O NH

O N H

NH

O

X

N H

29 X = O

O O

NH

X

N H

31 X = O

32 X = O

30 X = S

33 X = S

T. hammatum 24 h 48 h 100 100 100 100 100 100 100 96 100 100

Compound 7% conc. 29 30 31 32 33

X

72 h 100 96 97 94 98

T. koningii 24 h 48 h 100 100 91 91 100 100 100 87 100 95

72 h 96 84 97 80 91

A. niger 24 h 100 100 100 100 100

S

48 h 79 100 100 100 100

72 h 77 100 93 100 100

S

S

O

NH2 O H 2N O H

O

a

b

O

O

S NH

O N H 34

S

O

O

N S

N

R

35

Scheme 8 a SnCl2·2H2O, EtOH, reflux, 6 h, 91%; b ClCH2CO2H, NaOAc, RCHO, AcOH/Ac2O, reflux, 3 h, 74–86%

nucleophilic substitution reaction with various phenacyl bromides to provide tetrahydropyrimidines 48 [31]. These compounds were evaluated for their antihypertensive, anti-inflammatory, analgesic and acute ulcerogenesis activity. The antihypertensive activity was measured in Norwegian inbred albino rats (i.p. dosing, hypertension was induced with deoxycorticosterone acetate salt), first, by

Applications of MCR-Derived Heterocycles in Drug Discovery

243

Table 2 Antifungal and antibacterial activity (MIC values in mg/mL) of fused dihydropyrimidinones S

S

O

O

O

O

O

O

N

N

S

N

S

N

O

R1

R2

36 R1 = 4-OMe

38 R2 = 4-Br

37 R1 = 4-OH, 3-OMe

39 R2 = 2, 4-diCl

Compound 36 37 38 39

Antifungal activity MIC (mg/mL) A. fum A. flav C. alb P. marn 6 12.5 6 12.5 6 25 12.5 6 12.5 12.5 6 6 12.5 12.5 6 6

Antibacterial activity MIC (mg/mL) S. aur P. aer K. pneu E. coli 25 6 6 25 12.5 6 12.5 12.5 12.5 6 6 12.5 12.5 6 6 25

N NH2.HCl

Ar O

O

H2N

O

H

Ar NC

a

N

NC

NH HO

N

NH2

N

HO

N

NH2

40

Scheme 9 a NaOH, EtOH, reflux, 1–3 h, 79–95%

Mycobacterium tuberculosis

N N N N

R

H 41

Cl

NH2.HCl a

O N N

Cl H N 2

MIC (μg/mL)

NH

N N

O 42

Scheme 10 a EtOH, reflux, 5 h, 68–100%

R

N N 43

NH2

44 R = 2-Cl

1.2

45 R = 3-Cl

1.2

46 R = 4-Me 1.2

244

I. Akritopoulou-Zanze and S.W. Djuric R1

R1

R1 O

NH

O H

N

O

N H

R2

O

b

O

O

H2N O

O

a

N

O O

N H

47

O

O

48

R1 = Cl, OMe, OH, Me

R2 = Cl, OMe

Scheme 11 a NaHCO3, DMF, 70 C, 12 h, 64–76%; b Substituted phenyl acetyl bromides, CH2Cl2, pyridine, reflux, 7 h, 45–81% Table 3 Antihypertensive and anti-inflammatory activity of tetrahydropyrimidines R1 R2

O N

O N H

Compound (10 mg/kg) 49 50 51 52 Control Nifedipine Iodomethacin

R1

R2

H Me OMe OMe OMe OMe OMe

Cl H H Cl Cl Cl Cl

O

O

Average SBP (mmHg) at 460 min 122 155 121 110 225 120 –

Average DBP (mmHg) at 240 min 102 100 101 102 196 101 –

Average paw volume at 5 h 1.10 1.16 0.9 1.10 1.86 – 0.93

a noninvasive tail-cuff method to measure the systolic blood pressure (SBP). The diastolic blood pressure (DBP) was then measured by direct cannulation of the carotid artery. Most of the compounds exhibited antihypertensive activity comparable to that of nifedipine (Table 3). The compounds were further tested for their anti-inflammatory activity in the carrageenan-induced rat-paw oedema model (p.o dosing). Compound 51 was the most efficacious in this model (Table 3). This compound had also the highest analgesic activity in Swiss albino mice (59.76% protection) comparable with ibuprofen’s 62.55% at 20 mg/kg p.o. None of the compounds showed significant ulcerogenic activity. The antioxidant activity of dihydropyrimidinones was also evaluated. In one study [32], the compounds were prepared by ultrasound irradiation in the presence of NH4Cl in good yields. The antioxidant activities were measured in liver homogenates from male adult albino Winstar rats. The compounds were tested for their activity against Fe- and EDTA-induced lipid peroxidation at various

Applications of MCR-Derived Heterocycles in Drug Discovery

245

R O

O N

O

O

NH

NH N H

O

N H 53 R = H

O

55 ROS levels in 15 min at 400 μM = 11.86 fluorescence emission units (UAF)

54 R = NO2

Control = 64.14 (UAF)

Fig. 9 Antioxidant activity of dihydropyrimidines R1 R1

O

NH2

O

Cl O

H

O

HN R2

X

R1

Cl O

a

b NH

O

NH

O

R2

N R2

56

57

N X = O, S

HN

X

X

Scheme 12 a H3BO3, AcOH, reflux, 3 h, 60–90%; b NH3, 10 bar, 250 C, 16 h, 65–90%

concentrations. Compounds 53 and 54 exhibited the best activity with a maximal effect at 200 mM. Compounds 53 and 55 were the most effective in reducing reactive oxygen species (ROS) levels in rat liver (Fig. 9). The free radical scavenging effects of compounds 57 derived from dihydropyrimidines 56 (Scheme 12) was also examined by the DPPH method and by measuring hydroxyl radical scavenging activity (RSA) [33]. It was found that compounds derived from the thioureas had the best antioxidant activities. Compounds 58 and 59 were the most potent and had comparable activity to quercetol (Table 4).

3.2

The Hantzsch Reaction

The Hantzsch MCR is a well-established tool in the arsenal of contemporary synthetic organic and medicinal chemists and has, along with many of its variants, been a subject of past review articles [34]. The material of this chapter briefly summarizes past contributions and focuses on recent examples of the Hantzsch reaction in the synthesis of potential medicinal agents. In its original incarnation,

246

I. Akritopoulou-Zanze and S.W. Djuric Table 4 Decreasing absorbance DPPH and fluorescence of fused dihydropyrimidines Cl

HN

HN

O

NH

O

NH N

Cl

S

N

58

59

Compound (50 mmol/L) 58 59 Ascorbic acid Quercetol

% DPPH 9.5 7.7 36.9 –

O NH3 R2

% Fluorescence 76.5 82.7 – 87.9

R1

O R1

R3O O

H

S

O

OR3 O

R2

a R3O2C R2

CO2R3 N H 60

R2

Nifedipine R1 = 2-NO2, R2, R3 = Me

Scheme 13 a AcOH or EtOH, heat

the reaction utilized 1,3 dicarbonyl compounds, aldehydes and amines to provide ready access to symmetrically substituted 1,4-dihydropyridines 60 through a fourcomponent reaction that featured two acetoacetic ester inputs (Scheme 13). A wellknown example of this reaction is the synthesis of Nifedipine, a calcium antagonist, by Bayer AG in 1977 (Scheme 13) [35]. Cyclic 1,3 diketones could also participate in this MCR allowing for a fourcomponent Hantzsch synthesis of unsymmetrically substituted 1, 4-dihydropyridines or pyridines depending upon reaction conditions [36, 37] (Scheme 14). There are numerous variations in the Hantzsch protocol deriving from variations in the aldehydes, ammonia derivatives and active methylene compounds employed. The final products are 1,4-dihydropyridine and pyridine derivatives as well as pyrroles. Some new substituted tetrahydroacridin-8-ones and diverse derivatives were synthesized by uncatalyzed multicomponent reaction of dimedone or cyclohexan1, 3-dione, a-naphthylamine and various (o, p, m)-substituted benzaldehydes (Scheme 15) [38]. The in vitro antimicrobial activities of the prepared compounds

Applications of MCR-Derived Heterocycles in Drug Discovery

247 O

O

O

a

N H

O

O

R

R O H

O O

O

O

b

R

O

O N

Scheme 14 a NH4OH/H2O, 110 C; b microwave, NH4NO3, bentonite R O O O NH 61 NH2

R a CHO

R

O O O

NH 62

Scheme 15 a Microwave, 160 W, neat, 2–5 h, 92–98%

were evaluated against some bacteria and fungi strains. The results suggested that the products 61 and 62 exhibited good inhibitory effect against most of the tested organisms. Especially, 63–66 were shown to be most effective against E. coli, Rhodotorula rubra and Aspergillus parasiticus (Table 5). A one-pot efficient method for the synthesis of derivatives 67 and 68 by condensation reaction of barbituric acids, 1H-pyrazol-5-amines and aldehydes under solvent-free conditions has been reported (Scheme 16) [39]. These products were evaluated in vitro for their antibacterial activities against E. coli (ATCC 25922), P. aeruginosa (ATCC 85327), Enterococcus faecalis (ATCC 29737), Bacillus subtilis (ATCC 465), Bacillus pumilus (PTCC 1114), Micrococcus luteus

248

I. Akritopoulou-Zanze and S.W. Djuric

Table 5 Antibacterial and antifungal activities of tetrahydrobenzo-acridinone derivatives OH

OH

NO2 O

O

O

O

OH

NH

NH

NH

NH

63

64

65

66

Compound

Antibacterial activity MIC (mg/mL) E. coli B. cereus 125 62.5 31.2 31.2 3.9 15.6 125 –

63 64 65 66

Antifungal activity R. rubra 7.8 3.9 7.8 7.8

Ph

O HN

A. parasiticus 3.9 7.8 3.9 15.6

Ar

NH

NH

O

N

O

N H

Ph N

N

O

a

NH2

O CHO X

N H

67

X

R

O

NH O

N H

Ar

Ph

O NH

S

N

X=H

N H

N H

S

X = NO2 X

68

Scheme 16 a PTSA, neat, 100 C, 4 h, 80–95%

(PTCC 1110), S. aureus (ATCC 25923), Staphylococcus epidermis (ATCC 12228) and Streptococcus mutans (PTCC 1601). Good antibacterial activity was observed for most of the compounds against all species of gram-positive and gram-negative bacteria used in the study (Table 6). Compounds 67 were more potent than compounds 68. The majority of the compounds were found to be more active than

Applications of MCR-Derived Heterocycles in Drug Discovery

249

Table 6 Antibacterial activities of select pyrazolo-pyrido-pyrimidine-diones NO2 O

Ph

O

Ph NH

N

N H

N H

O

O

Ph NH

N

N H

N H

O

O

Ph NH

N

N H

N H

NH N

O

N H

N H

69

70

71

72

MIC (μg/mL)

MIC (μg/mL)

MIC (μg/mL)

MIC (μg/mL)

2 <2 2 2 2 <2 <2 2 2

2 2 2 2 2 <2 <2 2 2

4 4 8 8 4 <2 4 4 32

B. subtilis B. pumilus M. luteus S. aureus S. epidermis S. mytans E. coli E. faecalis P. aeruginosa

2 <2 <2 2 2 <2 <2 2 2

O

Fig. 10 Cytotoxic activity of compound 73

S

O

N H 73 HSC-2 IC50 = 7 μM

Gentamicin against all tested strains and compounds 67 were more potent than Tetracycline against B. pumilus, M. luteus, S. mutans, E. coli, and P. aeruginosa. The anticancer properties of a series of dibenzoyl dihydropyrimidines have recently been reported [40]. In particular, compound 73 (Fig. 10) showed cytotoxic activity against human oral squamous carcinoma (HSC-2) cells and also inhibited the Pgp-mediated drug efflux in (multidrug resistant) MDR cells. The Hantzsch pyrrole synthesis found application in the preparation of a series of Cdc7 kinase inhibitors (Scheme 17) [41, 42]. Cdc7 is a key regulator of the S-phase of the cell cycle and its inhibition can cause tumor cell death. SAR studies of a series of 2-heteroaryl-pyrrolopyridinones 74 identified compound 75 (Fig. 11) as a potent ATP-competitive inhibitor of Cdc7. This compound had a Ki of 0.5 nM,

250

I. Akritopoulou-Zanze and S.W. Djuric O O

NR1

Br

Het

O

O

a, b

NR1

Het N H

R

R

74

Scheme 17 a NH4OAc, EtOH, rt; b TFA where R1 = Boc

(ovarian) A2780 (mammary) MCF7 (AML) L363 (myeloma) NCI-H929 (myeloma) OPM2 (human fibroblasts) NHDF (human fibroblasts) NIH-3T3 (colon) COL0205 (colon) HCT116 (colon) HT29 (colon) SW403 (colon) SW48

O NH

N N H2N

N H F

75

Ic50 = 0.5 μM Ic50 = 1.1 μM Ic50 = 1.3 μM Ic50 = 1.2 μM Ic50 = 3.7 μM Ic50 = 1.6 μM Ic50 = 2.5 μM Ic50 = 0.5 μM Ic50 = 0.4 μM Ic50 = 4.1 μM Ic50 = 0.6 μM Ic50 = 0.9 μM

Fig. 11 Antiproliferative activity against various cancer cell lines of compound 74

OMe

OMe OMe R2

MeO

MeO OMe

a N N R1

O NH2

O H

OMe

MeO

OMe

O

O

R2

O

N N R1

O N H 76

O N

O N H

N H 77

Scheme 18 a Et3N, EtOH, reflux, 45–80%

inhibited cell proliferation in numerous tumor cell lines with an IC50 in the singledigit micromolar or submicromolar range and exhibited in vivo ovarian tumor growth inhibition in an A2780 female mice xenograft model. Other efforts in the anticancer area have focused on the use of heterocyclic podophyllotoxin analogs 76 as antiproliferative and apoptosis inducing agents [43, 44] Libraries of analogs were prepared by a one-step multicomponent Hantzsch-type protocol employing aminopyrazoles (Scheme 18). Apoptosis

Applications of MCR-Derived Heterocycles in Drug Discovery

251 OMe

OMe O R NH2

H

a O

O

O

O

O

HN N H

O

78

N H

N H

79

Scheme 19 a AcOH/glycol, 120 C, 4 h, 61–72%

induction was observed with some analogs in Jurkat cells. In particular, analog 77 showed greater than 50% apoptosis induction at 5 mM. The same group has also reported a multicomponent Hantzsch protocol which provided access to polycyclic indenoheterocycles 78 utilizing a variety of aromatic and heterocyclic amines (Scheme 19) [45]. Some of the compounds disclosed showed apoptosis-inducing activity in a human T-cell leukemia cell line similar to etoposide. One of the most potent analogs was compound 79 (Scheme 19) which showed greater than 30% induction of apoptosis at 25 mM, as assessed in a flow cytometric annexin V/propidium iodide assay in Jurkat cells. Several papers have been published that highlight the use of the Hantzsch reaction for the synthesis of compounds that exhibit ion channel modulating activity. The majority of protocols invoke dihydropyridine synthesis as outlined in Schemes 13 and 14. For example, recently new, condensed 1,4-dihydropyridines with variations at the ester site were synthesized and their calcium channel antagonistic activities were examined on isolated rabbit sigmoid colon strips[46]. Compounds 80 containing 2-methoxyethyl esters were found to be the most active (Fig. 12). Myorelaxant activity in isolated rabbit gastric fundal smooth muscle strips was also reported for 7-substituted hexahydroquinoline derivatives such as compounds 81 [47] and 82 [48] (Fig. 12). Imidazolyl dihydropyridines such as 83 exhibited calcium channel antagonist activity in guinea pig ileal longitudinal smooth muscle [49]. A series of substituted dihydropyridines was also examined for its KATP channel functional activity in isolated pig bladder strips and compound 84 (Fig. 12) was found to be a potent potassium channel opener [50]. Compound 84 also showed efficacy in vivo inhibiting myogenic bladder contractions in the partial outlet obstructed rat model. Dihydropyridines were tested for their ability to modulate activity of the heat- and ligand-gated cation channel vanilloid receptor 1 TRPV1[51]. Compound 85 was the most efficacious enhancer of this ion channel which has been implicated in pain sensation. A variant of the Hantzsch reaction catalyzed by molecular iodine (Scheme 20) provided N-Aryl dihydropyridine derivatives 86, which were evaluated for their antidyslipidemic and antioxidant potencies [52]. Several compounds exhibited promising antidyslipidemic and antioxidant activities (Table 7).

252

I. Akritopoulou-Zanze and S.W. Djuric

F3C

Cl

O

F

Cl

Cl

NO2

O

CO2CH2CH2 OMe

O

Cl

CO2Me

CO2Me

N H

N H

N H 80

81

82

pD2 = 5.11

pD2 = 5.23

pD2 = 6.87

Emax = 44.99 %

Emax = 57.71 %

Emax = 96.76 %

F Br O

NH O

N

O

CH3 CO2Me

O

O

O

O

S

O

O

O

N H

N H

N H

HN

83

84

85

Ca Channel IC50 = 0.031 μM

(–) enantiomer

TRPV1 EC50 = 21.3 μM

KATP pEC50 (% efficacy) = 6.29

Emax = 626%

Fig. 12 Ion channel activities of dihydropyrimidines

R R NH2

O

R3

R6

R1 R2

R4 R5

O

O

a

R1 R2

O C

R6

N R3

H R4 R5

86

Scheme 20 a I2, MeOH, rt, 1 h, 80–92%

Another application of the Hantzsch reaction involved the identification of pyridopyrimidine derivatives such as 91 as inhibitors of stable toxin a (STA) induced cGMP synthesis (Fig. 13) [53].

Applications of MCR-Derived Heterocycles in Drug Discovery

253

Table 7 Antidyslipidemic and antioxidant activity of compounds 86

O C

O C

O

O C

O

O C

O

N

N

N

N

87

88

89

90

Compound plus triton 87 88 89 90 Gemfibrozil Mannitol

Total cholesterollowering activity (%) 21.9 24.8 24.1 15.5 3.71 –

Phospholipidlowering activity (%) 28.5 21.3 23.9 12.8 39.1 –

Triglyceridelowering activity (%) 25.3 10.5 25.7 11.0 36.1 –

O

Generation of hydroxyl radicals at 200 mg/mL 60.92 53.35 58.57 56.05 – 50.24

F3 C

CF3

O

O

N O

Fig. 13 Inhibition of cGMP accumulation in T84 cells

3.3

N

N H

91 IC50 = 2.5 μM

The Gewald Reaction

The Gewald reaction [54] is one of the most facile methods of preparing 2-aminothiophenes from activated nitriles, active methylene compounds and elemental sulfur (Fig. 14). Several groups have used this reaction in recent years to prepare biologically active molecules. Benzothiophene derivatives 93, prepared from Gewald products 92 in three steps via a palladium-mediated aromatization reaction, (Scheme 21) were tested for their antiproliferative activity and inhibition of tubulin polymerization [55]. Several compounds showed inhibitory effects against murine leukemia (L1210), murine mammary carcinoma (FM3A) and human T-lymphoblastoid (Molt/4 and CEM) cells. For most of the compounds, there was a positive

254

I. Akritopoulou-Zanze and S.W. Djuric R2

R3 O S8

R3

R4

R4

R2

b, c, d O

O

R1

NH2

S

R3

R4

R2

a

R2

R1

S8

E

R2

amine CN

R1

Fig. 14 The Gewald reaction

E

O

R1

CN

S

O R1

NH2

S

92

NH2

93

Scheme 21 a Morpholine, EtOH, 70 C 1 h then rt 18 h; b Ac2O, pyridine, reflux, 2 h; c 10%Pd/C (50% wet with water), 130 C, 20 h; d 1 N NaOH, EtOH, reflux, 5 h

O

O

O

O

O O O S

NH2

94

HO Combretastatin A-4

L1210

IC50 = 0.76 nM

IC50 = 2.8 nM

FM3A

IC50 = 0.09 nM

IC50 = 42 nM

Molt4 /C8

IC50 = 0.69 nM

IC50 = 1.6 nM

CEM

IC50 = 0.52 nM

IC50 = 1.9 nM

tubuline assembly

IC50 = 0.76 μM

IC50 = 1.2 μM

colchicine

binding at 1 μM = 91%

binding at 1 μM = 86%

Fig. 15 Antiproliferative activity and inhibition of tubulin polymerization of thiophene 94 and combretastatin A-4

correlation between the inhibition of tubulin polymerization and the antiproliferative effects. Compound 92 stood out as a potent subnanomolar inhibitor of cancer cell growth and nanomolar inhibitor of tubulin polymerization by binding to the colchicine site (Fig. 15).

Applications of MCR-Derived Heterocycles in Drug Discovery

255 O

R2

O

R3

S8

a

CN

R1

R3

R2 R1

S

O NH2

NH2

S

95 GluR6 IC50 = 0.75 μM

Scheme 22 a Diethylamine or morpholine, EtOH, 50 C, 1–3 h, 60–77% Table 8 A1AR allosteric and antagonistic activity

Cl O

N N

O

N N O

O O

O S

96

NH2

S

NH2

97

Compound EC50 (mM)a % Inhibitionb pA2c 96 9.75 23 Inactive 97 5.7 100 8.7 a Concentration of compound producing half-maximal allosteric effect on [125I]-ABA dissociation b Percentage inhibition of specific [3H]CPX binding at 50 mM c Negative logarithm of concentration of antagonist needed to double the concentration of agonist necessary to achieve the same response as in the absence of antagonist

The Gewald reaction was also utilized to rapidly assemble 2-aminothiophenederived libraries of compounds (Scheme 22) to be evaluated for binding against the glutamate receptor GluR6 [56]. A calcium influx functional assay was used to measure antagonistic activity. Compound 95 was identified as a submicromolar antagonist of GluR6. Compound 96 was identified as a new lead molecule (Table 8) through screening for allosteric modulators of the Adenosine A1 receptor (A1AR). A series of related compounds was prepared and evaluated for activity [57]. It was found that although the compounds appeared to recognize the allosteric binding site of the receptor their behavior in the various assays was more consistent with orthosteric antagonism. Compound 97 was a potent antagonist of A1AR and also exhibited inverse agonism. Fused thiazolopyridazinones such as 96 and 97 were obtained from anilines which were converted to phenyl diazonium salts and reacted with ethyl acetoacetate to prepare phenyl hydrazones 98 (Scheme 23). These compounds participated in a Knoevenagel-type condensation with ethyl cyanoacetate to provide pyridazinones

256

I. Akritopoulou-Zanze and S.W. Djuric R

R

R R a, b H2N

N NH

O

c

O

d

N N O

O

O O 98

CN 99

O

N N O

O S

NH2

100

Scheme 23 a 48% HBF4 in H2O, NaNO2, 67–100%; b NaOAc, ethylacetoacetate, EtOH, 58–100%; c 4-aminobutyric acid, ethyl cyanoacetate, 160 C, 2.5 h, 42–95%; d S8, morpholine, EtOH, reflux, 6–12 h, 55–100% or Microwave, 150 C, 10–20 min, 79–100%

99. Gewald reaction of compounds 99 with sulfur under reflux conditions or with microwave heating yielded the final products 100.

3.4

Knoevenagel/Diels–Alder Sequences

A domino Knoevenagel/Diels–Alder epimerization sequence followed by Suzuki coupling provided a library of biphenyl and terphenyl spirocyclic triones (Scheme 24) [58]. The initial Knoevenagel adducts 103 were formed from either 1,3-indandione or Meldrum’s acid 101 and various bromosubstituted benzaldehydes in the presence of catalytic (L)-5,5-dimethyl thiazolidinium-4-carboxylate (DMTC) in high yields. Diels–Alder cycloaddition of 103 with 104, formed in situ from 102 and (L)-DMTC, provided exclusively the cis-spiro compounds 105 due to epimerization of the minor trans isomer to the thermodynamically more stable cis. Subsequent Suzuki couplings of 105 with various boronic acids afforded the final compounds 106. Compounds of general structure 106 were evaluated for their antiproliferative effects on sensitive acute myelogenous leukemia HL60, Bcr-Abl-expressing K562 cells and normal cells (lymphocytes) [59]. They were also evaluated for their proapoptotic activity against HL60 and K562 cells. Several compounds showed activity as illustrated in Table 9. Although the mechanism of action of these molecules has not been fully understood, it was found that compounds 107 and 109 were able to reduce expression of Bcl-2 in K562 cells. Further mechanistic studies were under way and they were facilitated by the ease of synthesis by which the final products could be obtained. A similar domino sequence in an intramolecular Diels–Alder version of the previous example provided access to pyrano benzo-[60] and naphtho-[61] quinones as shown in Scheme 25. Depending on substitution patterns of the aldehyde 111, para-(112 and 116) or ortho-(113 and 117) adducts or both were obtained. Typically high diastereoselectivity was observed. Libraries 114 and 115 were tested for their ability to reverse the multidrug resistance phenotype resulting from overexpression of drug efflux pumps. The compounds were evaluated in mammalian

Applications of MCR-Derived Heterocycles in Drug Discovery

O

O

257

O

H

S

O a

N

CO2H

O O

R

R

R = Br R = 3-Br-Ph R = 4-Br-Ph

101

102

103

O

104

O b O

O

O

R = Br R = 3-Br-Ph R = 4-Br-Ph

A = Ar A = 3-Ar-Ph A = 4-Ar-Ph

O

R

105

A

106

Scheme 24 a Cat. (L)-DMTC, MeOH, rt, 72 h, 50–90%; b ArB(OH)2, Pd(Ph3P)4, aq Na2CO3, toluene, Et3N

Table 9 Antiproliferative and proapoptotic activities of select spiro-triones

O

O

O

O

O O

O

O

O

OH 107

O

O

O

O

OH

OH 108

O O

O

109

110 OH

K562 IC50 Lymphocytes HL60 IC50 (mM) (mM) IC50 (mM) 107 6 8 215 108 6 14 286 109 8 9 172 110 16 8 185 a Concentration to induce apoptosis in 50% of the cells after 48 h Compound

HL60 (mM) 11 12 16 32

AC50a

K562 AC50 (mM) 25 80 33 >100

258

I. Akritopoulou-Zanze and S.W. Djuric O

O O

O

R O

R

O

112

OH

114

O

O O

O

HO O

O

a

H

R

111

O

R O

O O R

R 115

113

O

O O

R

O

a

OH

O

R

O

118

O

O O

H

R

O

116 O

O

R

O

O

a

R

O

R

O

a 111 O

O R

R 117

119

Scheme 25 a EtOH, EDDA, reflux, 57–100%

cancer cell lines overexpressing Pgp, multidrug resistance-associated protein 1 (MDRP1) or breast cancer resistance protein (BCRP) (Fig. 16) [59]. They were also evaluated in a parasitic Leishmania tropica cell line overexpressing Pgp. From this series, compounds 120 and 121 were found to be the most potent MDR reversal agents in human cancer cell lines, while 122 was the most potent in reversing the MDR phenotype in the parasitic Leismania cells. Libraries 118 and 119 were evaluated against the a isoform of human topoisomerase II (Fig. 17) [60]. Six compounds were found to completely inhibit the enzyme at 100 mM. Substituted tetrahydropyridines 134 have been recently prepared via an interesting one-pot transformation involving the Aza Diels–Alder reaction of imines 132 with enamines 133 (Scheme 26) [62]. The enamine adducts were prepared from the reaction of anilines 129 with the Knoevenagel products of 130 and 131. The compounds were tested against P. falciparum (3D7) and showed good antimalarial activity (Fig. 18). In particular, compounds 136 showed much better potency than chloroquine, a known antimalarial agent (MIC = 0.39 mg/mL).

Applications of MCR-Derived Heterocycles in Drug Discovery

259

O O

O

H

H

O O H

H

O

O

H

O

O

O

H

O

O H

H

H

O

O

H O

O

O

O

O H

H

O

120

121

122

NHI-3T3 MDR1

NHI-3T3 MDR1

MDR L.Tropica

IC50 = 0.09 μM

IC50 = 0.07 μM

inhibition at 10 μM = 100%

Fig. 16 Daunorubicin resistance reversal in NIH-3T3 MDR1 and L. Tropica MDR cells O

O

O

O

O

O

H O

H

H O H

O

Br

O O

H

O

Br

125

O

O

H

O

O

O

O

H Br

O

O O H

H

H

O

124

O

O

O

123

O

H

126

H 128

127

Fig. 17 Inhibitors of hTopoIIa

R1 NH2

R1 NH

CHO

O

R1 129

OR3

R2 130

N R2

131

132

O OR3

OR3

a O

NH

O

N

R2 133

R1

Scheme 26 a L-Proline, TFA, MeCN, 20–30 C, 16–24 h, 55–75%

R2

R2 R1

134

260

I. Akritopoulou-Zanze and S.W. Djuric

O NH

NH

O O

O O

O

N F

NH

O

N

N F

F

F

N

N

O

135

136

137

P. falciparum

P. falciparum

P. falciparum

MIC = 0.39 μg/mL

MIC = 0.09 μg/mL

MIC = 0.39 μg/mL

Fig. 18 Antimalarial activity of substituted tetrahydropyridines

3.5

Knoevenagel/Michael-Type Sequences

Knoevenagel condensation of aldehydes with malononitrile under mechanochemical mixing in the presence of MgO resulted in adducts of general structure 138 (Scheme 27), which were further treated with either ethylacetoacetate or 5,5dimethylcyclohexane-1,3-dione to provide products 139 and 140 [63]. The transformation of 138 and 139 or 140 proceeded via a Michael-type nucleophilic addition of the enolizable ketoester or dione, followed by intramolecular cyclization. Several of the compounds synthesized showed antibacterial activity against E. coli (MTCC 41), S. aureus (MTCC 1144) and the ampicillin-resistant strain Pseudomonas putida (MTCC 1072) (Table 10). Tetrahydrochromones have also found applications as inhibitors of excitatory amino acid transporter Subtype 1(EAAT1) [64]. For example, compound 145 (Fig. 19) was the first reported submicromolar inhibitor of EAAT1 with >400fold selectivity over EAAT2 and EAAT3. The subtype selectivity of 145 made that compound a highly valuable tool to further explore the physiological role of EAAT1. The antiproliferative and antitubulin activities of libraries of pyranopyridones and pyranoquinolones 147 (Scheme 28) derived from aldehydes, malononitrile and pyridones 146 have been examined [65]. The compounds were evaluated for their ability to reduce cell viability by 50% after 48 h of treatment relative to control. The HeLa and MCF-7 cell lines were used as models for human cervical and breast adenocarcinoma, respectively. Numerous compounds exhibited submicromolar antiproliferative activities with the quinolones being more potent than their pyridine counterparts (Fig. 20). Because of the structural similarity of pyranopyridones with chromene scaffolds known to inhibit tubulin polymerization, compounds 149 and 150 were further evaluated in Jurkat cells for their apoptotic

Applications of MCR-Derived Heterocycles in Drug Discovery

261

O O O

CN

Ar H

O

Ar

O

CN

O O

Ar a

CN

b

NH2

139

CN CN

O

Ar CN

138

O

O

NH2

140

O

Scheme 27 a MgO, rt, grinding, 10 min b MgO, rt, grinding, 15 min 73–94%

Table 10 Antibacterial activity of 2-aminopyrans and tetrahydrochromenes O

NO2 OH

O

O

O O

NH2

O

141

Compound 141 142 143 144 Ampicillin

O

O

CN

CN

CN

NH2

O

142

143

E. coli MIC (mg/mL) 64 64 64 128 16

S. aureus MIC (mg/mL) 128 >128 64 >128 16

NH2

CN O

NH2

144

P. putida MIC (mg/mL) 128 128 128 64 >256

O

Fig. 19 Excitatory amino acid transporter activities of compound 145

EAAT1 IC50 = 0.66 μM

O CN O

145

NH2

EAAT2 IC50 = >300 μM EAAT3 IC50 = >300 μM

262

I. Akritopoulou-Zanze and S.W. Djuric O

O CN

Ar

N OH

H

O

Ar CN

N

a

CN

O

146

NH2

147

Scheme 28 a Et3N, EtOH, reflux, 50 min, 64–98%

OH Br

Br

O

O O

Br

O CN

N O

NH2

148

O

Br

O CN

N O

NH2

149

N

O CN

N O 150

NH2

CN

N O

NH2

151

HeLa GI50

0.74 μM

0.047 μM

0.014 μM

0.013 μM

MCF-7 GI50

0.003 μM

0.39 μM

0.38 μM

0.015 μM

Fig. 20 Antiproliferative activity of pyrano-quinolones

properties and displayed cell cycle arrest in the G2/M phase. They were also found to block tubulin polymerization in vitro. A related three-component sequence has been reported, that involved the reaction of N-(arylsulfonamido)-acetophenones 152 with aldehydes and malononitrile [66] and gave access to functionalized pyrrolidines 153 as shown in Scheme 29. The compounds were obtained as mixtures of cis and trans diastereomers and evaluated for their antiproliferative properties in HeLa and MCF-7 cells. Compounds 154 and 155, among others, showed antiproliferative effects in both cells lines and were further evaluated for their apoptotic properties (Fig. 21). It was suggested that the antiproliferative effects of these compounds might originate from different mechanisms of action with that of 154 being due to induction of apoptosis in cancer cells, while for 155 from cancer cell growth inhibition only. When the Knoevenagel adducts formed from aldehydes with dimedone were reacted with dihydropyridazine-dione 156 (Scheme 30), pyridazino indazole triones 157 were obtained under solvent-free conditions in moderate yields [67]. The compounds were tested for their antibacterial properties against E. coli (ATCC 25922), P aeruginusa (ATCC 85327), Bacillus subtilis (ATCC 465) and S. aureus (ATCC 25923) (Table 11). Compounds 158–160 were found to be more active than Amoxicillin against E. coli but less potent than Norfloxacin. None of the reported compounds was active against S. aureus.

Applications of MCR-Derived Heterocycles in Drug Discovery

O

R3

O

R1 HN

O S O H R2

R3

CN

263

a

R1 HN

O CN

O S O

R3

O

CN CN

R1

R2

CN

N NH2 O S O R2

152

153

Scheme 29 a Et3N, EtOH, reflux, 1.5 h, 90%

CN

O N O S O

Br

CN

O N O S O

NH2 Br

154

NH2

155

% Apoptosis in Jurkat cells at 50 μM = 30%

% Apoptosis in Jurkat cells at 50 μM = 56%

% Live Jurkat Cells at 50 μM = 3%

% Live Jurkat Cells at 50 μM = 96%

Fig. 21 Apoptotic and cell-killing properties of pyrrolidines

O NH NH

Ar H

O

O

Ar

O a

O N N

O O

156

O 157

Scheme 30 a PTSA, 20–40 min, 46–55%

3.6

Knoevenagel/Krohnke Synthesis

2-Chloro-3-formylquinolines 161 (Scheme 31) were transformed in the presence of acetic acid to 3-formylquinolones which upon reaction with acetophenones provided the intermediate a,b unsaturated Knoevenagel adducts. Subsequent Krohnke reaction of these adducts with pyridinium salts 162 and ammonium acetate provided the final quinoline-pyridines 163 in excellent yields [68]. All the compounds were tested

264

I. Akritopoulou-Zanze and S.W. Djuric

N

Cl H

R1

O

N+ O

O

161

H N

Cl– R1

162

a

O

N

NH4OAc 163

R2

R2

Scheme 31 a AcOH, Microwave, 180 C, 3–5 min, 80–92%

Table 11 Antibacterial activity of pyridazinoindazole triones O2N Br

O2N

O O

O N

O

158 159 160 Amoxycillin Norfloxacin

N N

158

E. coli MIC (mg/mL) 16 8 16 128 <2

O O

N N

Compound

O

O

N

159

P. aeruginusa MIC (mg/mL) Not active 64 60 – 20

O

B. subtilis MIC (mg/mL) 16 8 8 2 2

160

S. aureus MIC (mg/mL) Not active Not active Not active 16 16

for their antibacterial properties against S. aureus, Bacillus Subtilis, and E. coli and antifungal properties against A. Niger and phizopus (Table 12).

3.7

Other Knoevenagel-Based MCRs

Reactions of chromene 168 (Scheme 32) with Knoevenagel adducts derived from aldehydes and ethyl cyanoacetate or malononitrile and ammonium acetate yielded, after condensation, libraries of general structure 169 and 170, respectively [69]. The products were tested for their anti-inflammatory, analgesic and antipyretic properties. Anti-inflammatory efficacy was measured in vivo in the rat carrageenan-

Applications of MCR-Derived Heterocycles in Drug Discovery

265

Table 12 Antibacterial and antifungal activities of quinolinone-pyridines H N

H N

O

O

O N

N

164

165

Cl H N

H N

O

Cl

O

Cl N

166

Compound (1,000 mg/mL) 164 165 166 167 Ciprofloxacin Griseofulvin

N

167

Antibacterial activity Zone of inhibition in mm S. aureus B. subtilis 21 20 14 21 15 21 10 12 35 37 – –

Cl

Antifungal activity E. coli 25 21 26 23 34 –‘

A. niger 11 18 15 15 – 28

Rhizopus 15 15 18 24 – 21

induced paw edema model. Several compounds such as 172–174 showed antiinflammatory activity (Table 13). Analgesic activity was measured using the acetic acid-induced writhing model in mice. Significant protection against writhing was observed for compound 171. Antipyretic activity was evaluated using the brewer’s yeast-induced hyperpyrexia model in hyperthermic rats. Compounds 172 and 173 were able to decrease the temperature of pyretic rats as compared to control. In all the studies, the compounds were administered at doses 1/10 of their LD50s. The three-component reactions of malononitrile 175, aldehydes 176 and 2-mercaptoacetic acid 177 (Scheme 33), in different molar ratios under microwave heating, in water, provided thiazolopyridine derivatives 178 and 179 in high yields [70]. The compounds were evaluated for their cytotoxic activity against the carcinoma cell line HCT 116 (ATTC CCL 247) and mice lymphocytes (Table 14). Compound 183 was the only one with selective cytotoxic activity towards the HTC 116 cells (Fig. 22). The compounds were also evaluated for their antioxidant

266

I. Akritopoulou-Zanze and S.W. Djuric CN O

Ar CN

OH

O

N H

O

O O

OH O

Ar

O

H

169

a Ar

O

O

CN

OH N H

168

NH

O

CN

O

CN

170

Scheme 32 a Ammonium acetate, EtOH, reflux, 8 h, 55–86%

Table 13 Anti-inflammatory, analgesic and antipyretic activities of chromenone-dihydropyridines Cl

N

HO CN

OH N H

HO CN

OH

O

N H

O

O O

171

Compound

Control Celecoxib Diclofenac sodium Paracetamol 171 172 173 174

CN

OH

O

N H O

O

172

Anti-inflammatory activity, paw size (mm) 29.54 17.82 – – 24.71 28.26 23.97 24.72

CN

OH

NH

N H

NH

O O

173

Analgesic activity, number of writhes after 2 h 43.7 – 10.2 – 41.6 29.4 37.4 38.6

O

174

Antipyretic activity, rectal temperature ( C) after 2 h 39.11 – – 37.2 38.84 38.2 38.17 38.91

Applications of MCR-Derived Heterocycles in Drug Discovery

267 Ar NC

a

CN N

H2N

175:176:177 = 2:1:1.5 CN CN

O

SH

Ar H

O O

178 Ar

OH NC

175

S

176

CN

b

177

N

H2N

175:176:175 = 2:2:2.1

O

S Ar

179

Scheme 33 a Water, microwave, 90 C, 6–9 min, 81–89%; b Water, microwave, 100 C, 6–7 min, 82–89%

Table 14 Cytotoxic and antioxidant properties of thiazolopyridines OH

F

O2N

S CN

NC CN

NC

H 2N H2N

N

S

O 180

Compound

180 181 182 183 L-ASCORBIC ACID

H2N

N

CN

NC

CN

NC

S

N

S H2N S

O 181

Cytotoxic activity % Inhibition on proliferation of HCT-116 (1 mg/mL) 47.77 47.42 63.81 41.22 –

N

O

182

% Inhibition on proliferation of lymphocytes (1 mg/mL) 66.88 63.77 55.42 5.31 –

S

O

NO2 OH

183

Antioxidant activity DPPH % OH % inhibition inhibition of free of free radicals radicals 880.99 654.55 858.77 609.85 717.53 665.91 108.64 204.52 188.12 108.65

properties by measuring their scavenging DPPH and OH capacity as compared to control ascorbic acid. Nearly all the compounds showed strong antioxidant properties, with the most potent being compounds 180–182.

268

I. Akritopoulou-Zanze and S.W. Djuric PDE5 IC50 = 0.3 nM

Cl O

IC50 ratio of PDE1,2,3,4 /PDE5 >10,000 IC50 ratio of PDE6/PDE5 = 150 N

HN

N

ED50 rabbit in vivo model = 100 nmol/kg N

N N

N

F in rats = 29 % F in dogs = 42 %

N NH

t1/2 in rats = 1.2 h t1/2 in dogs = 2 h

O

188

Fig. 22 In vitro and in vivo profile of compound 188

O

R2 O N N

O

a

NH

N R1

184

N

R2 d N N R1

N

b, c

N R1

N R1

N

N Cl

N

185

Cl

N

R2

N

O

N

Cl

NH

R2

N

186 R5 HN

N N R3

R4

N

R2 e N N R1

N

N N R3

R4

187

Scheme 34 a Water or AcOH, rt or 50 C, 24 h, 12–70%; b hydrazine hydrate, EtOH/water, rt, 2 h, 100%; c POCl3, reflux, 3 h, 85%; d R4R5NH, DIEA, NMP, 80 C, 3 h, 40%; e R5NH2, DIEA, NMP, 110 C, 85%

4 Cycloadditions 4.1

Hetero-Diels–Alder Reactions

Hetero-Diels–Alder reactions have been extensively used in organic synthesis. Cycloadditions of imines 184 with maleimide 185 (Scheme 34) generated pyrazolopyridines 186 [71]. These compounds were further elaborated as shown in Scheme 34 to provide pyrazolopyridopyridazines 187 which were potent and selective PDE5 inhibitors [72]. Compound 188 was selected for further evaluation. This compound had superior selectivity towards other PDE isoenzymes and was found to be efficacious in an anesthetized rabbit model of erectile function.

Applications of MCR-Derived Heterocycles in Drug Discovery

N

O

H2N

269

a R

R

H

N

N

O b N

R

c N

HN

N

189

190

R

R

N N

191

Scheme 35 a BF3·OEt2, MeCN, 80 C, 2–10 h, 32–98%; b S8, 220–240 C, 5–10 min, 76–96%; c KMnO4, Na2CO3, acetone, heat, 26–45%

Furthermore, its pharmacokinetic profile in rats and dogs was favorable and there were no major safety concerns. Although the compound was reported to enter Phase I clinical trials and was well tolerated at the highest dose in healthy volunteers, no further information has been disclosed for its development. A three-component Grieco condensation [73] of anilines, aldehydes and indene resulted in libraries of tetrahydroindenoquinolines 189 (Scheme 35), which were heated with powdered sulfur to provide indenoquinolines 190 [74]. Subsequent oxidation with potassium permanganate yielded indeno-quinolinones 191. Compounds 189–191 were evaluated for their cytotoxic properties against the breast MCF-7, lung H-460 and central nervous system SF-268 human cancer cell lines (Table 15). They were also tested for their antifungal activities against a panel of ten pathogenic fungi: C. albicans (ATCC 10231), Candida tropicalis (C 131), Cryptococcus neoformans (ATCC 32264), Saccharomyces cerevisiae (ATCC 9763), A. niger (ATCC 9092), A. flavus (ATCC 9170), A. fumigatus (ATCC 26934), Microsporum gypseum (C115), Trichophyton rubrum (C113), Trichophyton mentagrophytes (ATCC 9972). Almost all the compounds showed cytotoxic activity (GI < 10 mg/mL). None of the compounds was active against the yeast fungi and Aspergillus species. However, several compounds from the 189 and 190 series showed modest activity against dermatophytes. None of compounds 191 had any antifungal activity.

4.1.1

The Povarov Reaction

A subset of imino-Diels–Alder cycloadditions involving reactions between N-aryl imines and electron-rich dienophiles is the Povarov reaction [75].

270

I. Akritopoulou-Zanze and S.W. Djuric

Table 15 Cytotoxic and antifungal activities of select indenoquinoline derivatives O N N

N

N HN

N

192

Compound

192 193 194 195 Adriamycin Terbinafine

N

193

Cl

N

194

Cytotoxic activity H-460 IC50 MCF-7 IC50 (mg/mL) (mg/mL) 2.4 2 4.8 6.5 4.9 4.7 2.3 2.4 0.16 0.18 – –

195

SF-268 IC50 (mg/mL) 4.3 >10 6.7 2.7 0.14 –

Antifungal activity M. gyp T. rub

T. men

>250 31 31 >250 – 0.04

>250 31 31 >250 – 0.04

>250 31 31 >250 – 0.01

R3 N N

R1

R3

HN R2 O H2N

R1 H

196

a R2

O n n = 1, 2

R1

n

O b

HN

n

R1

O c

N R2 197

R2 198

n

R1 N+ I–

O

R2

199

Scheme 36 a Sc(OTf)3, MeCN, rt, 12 h; b DDQ, CH2Cl2, rt, 24–48 h; c MeI, acetone/water, rt, 72 h

The reaction has been used to synthesize libraries of benzonaphthyridines 196, in high diastereoselectivity, from the cycloaddition of 1,4-dihydropyridines with imines formed from aldehydes and anilines. When cyclic enol ethers were used as dienophiles, mixtures of diastereomers 197 were obtained. These compounds were oxidized to the corresponding quinolines 198 and were further transformed to the quinolinium salts 199 as shown in Scheme 36 [76]. Compounds 196 and 198 were tested for their ability to inhibit human propyl oligopeptidase (POP) and were found to have modest potencies. Much better results were obtained when the quinoline nitrogen was methylated to provide adducts 199. The cationic center improved the inhibitory activity of these compounds (Fig. 23).

Applications of MCR-Derived Heterocycles in Drug Discovery

Cl

Cl

O N I–

271

O

+

O

+

N+

N CO2Et

CO2Et

CO2Et

200

201

202

POP IC50 = 75 μM

POP IC50 = 133 μM

POP IC50 = 124 μM

Fig. 23 POP inhibition of quinolinium salts

Cl O N

N

H N

N H

O 203 hAChE IC50 = 14 nM

Inhibition of AChE-induced Aβ1-40 aggregation = 45.7 % Inhibition of self-induced Aβ1–40 aggregation = 47.3 % BACE-1 % inhibition at 2.5 μM = 77.8 %

Fig. 24 In vitro profile of compounds 203

Following similar procedures, compound 203 (Fig. 24) and related analogs were prepared from couplings of Povarov products with 6-chlorotacrine tethered diamines [77]. The hybrid molecules were designed as dual AChE active-site/ peripheral-site binders. In particular, 203 emerged as a promising anti-Alzheimer candidate because of its strong inhibitory potency against human AChE, AChEinduced and self-induced b-amyloid peptide (Ab) aggregation and BACE1. Furthermore, compound 203 was predicted based on the PAMPA-BBB assay to have good CNS penetration.

4.2

1,3-Dipolar Cycloadditions

A highly atom-efficient azomethine ylide 1,3-dipolar cycloaddition of compound 204 (Scheme 37) with ylides formed in situ from either proline, phenylglycine or

272

I. Akritopoulou-Zanze and S.W. Djuric

H N

N

CO2H O N

Ar O 206

Ar

H2N

CO2H

Ar a

O

N

Ar 204

H N

O

O

O N

205

Ar O 207

Ar

H N

N CO2H O N

Ar

Ar O 208

Scheme 37 a MeOH, reflux, 1 h, 95–98%

sarcosine and acenaphthenequinone 205 yielded libraries of spiro pyrrolidines 206–208 [78]. The compounds were tested against M. tuberculosis, MDR M. tuberculosis and M. smegmatis. Most of the compounds exhibited some antimycobacterial activity (Table 16). Compounds 209 and 211 were very potent against the multidrug-resistant M. tuberculosis strain.

5 Miscellaneous 5.1

The Do¨bner Synthesis

The one-step Do¨bner reaction of aldehyde 213, anilines and pyruvic acid (Scheme 38) was used to prepare, after oxidation of the methylthio substituent to

Applications of MCR-Derived Heterocycles in Drug Discovery

273

Table 16 Antimycobacterial activities of spiro pyrrolidines

H N

N

N

N

Cl

Cl

Cl O N

O N

O N

O N

O

O

O

O

Cl

Cl

Cl

Cl

Cl 209

210

211

M. tuberculosis MIC (mg/mL) 0.4 1.56 0.78 0.78 0.05 1.56

Compound 209 210 211 212 Isoniazid Ciprofloxacin

212

MDR M. tuberculosis MIC (mg/mL) 0.4 Not tested 0.4 0.78 1.56 12.5

M. smegmatis MIC (mg/mL) 25 3.13 25 12.5 6.25 0.78

H O 213

HO

S

HO

O

a

R2

N R1

R2

O

b R2

O

HO

O

NH2

N R1

S

S O O

214

R1

Scheme 38 a EtOH, reflux, 12 h, 16–27%; b oxone, THF/water, rt, 12 h, 40–89%

the methyl sulfone, quinoline derivatives 214 as cyclooxygenase-2 (COX-2) inhibitors [79]. Most compounds were potent COX-2 inhibitors and compound 215 had better selectivity over COX-1 than Celecoxib (Fig. 25). Quinolines 216–218, prepared in a similar manner via a microwave-assisted Do¨bner synthesis, were found to have moderate antiparasitic activities (Table 17) [80].

5.2

The Bucherer–Bergs Reaction

The Bucherer–Bergs hydantoin synthesis has been employed to build spiro compounds 221 as 5-HT1A modulators [81]. The compounds were prepared from

274

I. Akritopoulou-Zanze and S.W. Djuric HO

F 3C

O

N N N

S O O

S O O 215

Celecoxib

COX-1 IC50 = 22.1μM COX-2 IC50 = 0.0432 μM

COX-1 IC50 = 24.3 μM COX-2 IC50 = 0.060 μM

Fig. 25 COX-1 and COX-2 inhibitory activity of compound 215 and Celecoxib Table 17 Antiparasitic and cytotoxic activities of 2-phenylquinoline-4-carboxylic acid derivatives HO

O

HO

O

N

N

216

217

HO

F3C

O

N

O

Compound 216 217 218

P. falciparum IC50 (mg/mL) >5 3.1 >20.3

P. cruzi IC50 (mg/mL) 13.8 >30 Not tested

218

P. T. b. rhodesiense IC50 (mg/mL) >90 35.25 2.2

O O

a

L6 cells 35.6 75.6 >20.3

O NH

b, c

N

N

N N H

219

L. infantum IC50 (mg/mL) Not tested Not tested 8.6

220

O

N H

O

R

221

Scheme 39 a KCN, (NH4)2CO3, 50% EtOH/water, reflux, 20 h, 51–66%; b Br(CH2)3Cl, K2CO3, acetone, reflux, 30 min, 70–98%; c 1-phenylpiperazine derivatives, anhydrous EtOH, reflux, 28–30 h, 31–72%

ketones 219 upon reaction with KCN and (NH4)2CO3 in refluxing EtOH/water (Scheme 39). Further derivatization of the Bucherer–Bergs adducts 220 with alkyl tethers and attachment of phenylpiperazines provided the final products 221. These compounds were tested for their 5-HT1A and 5-HT2A activity (Table 18) and compounds 222–224 exhibited antagonistic, partial agonistic and agonistic activity, respectively, towards the 5-HT1A receptor. These compounds were evaluated in a four-plate mouse anxiolytic model and only compound 224 showed efficacy at 10 mpk. This compound was further profiled in the forced swim mouse model for

Applications of MCR-Derived Heterocycles in Drug Discovery

275

Table 18 5-HT1A, 5-HT2A and D2 affinities and 5-HT1A/5-HT2A functional activitiesa of spirohydantoins O

O N

N N H

N

N

Cl

N

N H

O 222

Cl

N O

223 O

N H

O

N

N

N O

224

5-HT2A D2 5-HT1A 5-HT2A 5-HT1A Ki (nM) Ki (nM) Ki (nM) functional activity functional activity antagonist Nd 222 13 78 Ndb 223 38 53 6,200 Partial agonist Antagonist 224 23 284 965 Agonist Nd a Conclusions were based on the following in vivo experiments: hypothermia model in mice, lower lip retraction in rats, heat-twitch response in mice b Not determined Compound

Table 19 Porcine TACE and MMP-1, -2, -9 and -13 activities of hydantoins O O

O

NH NH

N H O

N H

O

O

NH

HN

N H O

O NH

HN

HN

O

O

O

O

N

N N

225

226

227

racemic mixture

(5R,6S)

(5R,6R)

Compound 225 226 227

pTACE IC50 (nM) 64 11 25

MMP-1 IC50 (nM) >4,946 >4,946 >4,946

MMP-2 IC50 (nM) >3,333 >3,333 >3,333

MMP-9 IC50 (nM) >2,128 >2,128 >2,128

MMP-13 IC50 (nM) >5,025 >5,025 >5,025

276

I. Akritopoulou-Zanze and S.W. Djuric

Table 20 M3 and M2 binding affinities and intrinsic clearance (rat and human) of select hydantoin derivatives F

N

O N

N

O N

S

N H

N

O N

S

N H

N H

S

S

232

233

Compounds

M3 Ki (nM)

M2 Ki (nM)

232 233 234

1.9 2.7 2.75

80.1 96.8 187

234

r Clint_L mL/min/g liver 4.7 23.7 13.8

h Clint_L mL/min/g 1.1 2.3 0.95

depression and was found to be efficacious at 10 and 20 mpk doses without an effect on the locomotor activity of mice. Spiro hydantoins such as 225–227 (Table 19) were tested for their inhibitory activity against tumor necrosis factor a (TNF-a) converting enzyme (TACE) [82]. The compounds exhibited strong inhibitory activity against porcine TACE and excellent selectivity over MMPs (Table 11). For compound 226, the (5S, 6R) enantiomer was more than 80-fold less active against pTACE. Boc or isopropylacetyl pyrrolidine derivatives of 227 were also equipotent with 227. Bucherer–Bergs products were also the starting points for the preparation of potent and selective muscarinic M3 receptor antagonists (Table 20) [83]. Hydantoins of general structure 228 (Scheme 40) participated in Mitsunobu reactions with alcohols to provide derivatives 229, which were reduced with sodium bis (2-methoxyethoxy)aluminum hydride (Red-Al) to afford imidazolidinones 230. Removal of the benzyl group allowed for further functionalization of the secondary amines to yield compounds 231.

5.3

Other Multicomponent Reactions

The one-pot, three-component synthesis of 1,2,4-triazoles from primary amines, acyl hydrazines and dimethoxy-N-N-dimethylmethanamine [84] was utilized for the preparation of compounds 235 (Scheme 41), which were evaluated for their anticonvulsant and neurotoxic properties [85]. The anticonvulsant activity was measured in mice by the maximal electroshock test (MES) and the neurotoxicity in mice by the rotarod neurotoxicity test (Tox). The majority of the compounds

Applications of MCR-Derived Heterocycles in Drug Discovery

O

O R1

a R2

O

N

HO

R1

NH

R2

N H

277

b

O

R2

N H

228

O R1 R2

N H

c O

229

O

N d,e

N

N N

R1

N R3

R1

N

R2

N H

230

231

Scheme 40 a KCN, (NH4)2CO3, 50% EtOH/water, 120 C stainless steel sealed tube, 24 h; b PPh3, DEAD, THF, 0 C-rt, 24 h; c Red-Al, THF, 0 C then 85 C, 4 h; d H2, Pd/C, MeOH/water, HCl, 20 psi, 8 h; e R3Cl, K2CO3, CH2Cl2, rt, 5 h

C6H13O

R

a

N

O O

NH2

C6H13O

R

O

NH NH2

N

N N

235

Scheme 41 MeCN, 120 C, 3 h, 69.5–87.5% Table 21 Anticonvulsant and neurotoxic activities of 1,2,4-triazoles in mice

C6H13O

C6H13O N

236

Compounds 236 237 238 239 Phenyltoin

C6H13O N

N N 237

ED50 (mg/kg) 9.8 13.2 5.7 11.4 9.5

C6H13O N

N N

N

N N

238

TD50 (mg/kg) 112.3 62.1 65.7 101.2 65.5

N N

239

PI (TD50/ED50) 11.4 4.7 11.5 8.8 6.9

exhibited strong anticonvulsant potencies (Table 21) and lower neurotoxicity. Compound 238 had better overall profile than the antiepileptic drug phenyltoin. The domino three-component reaction of isatins, aminoacids and cyclic ketones provided novel dispiropyrrolidines 240–243 (Scheme 42) [86]. The compounds were

278

I. Akritopoulou-Zanze and S.W. Djuric O O

n

N

n

R1 n = 1, 2, 3

O N H

R2 O

CO2H HN

240 O

N X X = Me, N = O

R1

X

N N O

a O

R2

R1 O R2

N H

241

O

N H

O Ph Ph

n NH2

b

NH

n

R1 n = 1, 2, 3

O

CO2H

R2 242

O

O Ph

N X X = Me, N = O

N H

R1

X

Ph

N NH O N H R2 243

Scheme 42 a MeOH, reflux, 6–10 h, 37–52%; b MeOH, reflux, 24 h, 32–42%

evaluated for their antimycobacterial activity against M. tuberculosis H37Rv. Several compounds showed good antimycobacterial activity (Fig. 26), with compound 246 having better potency than fluoroquinolone Ciprofloxacin (MIC ¼ 4.71 mM) but is less potent than Isoniazid (MIC = 0.36 mM). A three-component synthesis of di- and tetrahydroisoquinolines via the Ritter reaction yielded compounds 248 and 249 (Scheme 43), which were tested for their anticoagulant properties using citrated dog blood [87]. An increase in coagulation time (CT) for all the tested compounds was observed, with compounds 250–252

Applications of MCR-Derived Heterocycles in Drug Discovery O

O N

Br

O

O Ph Ph

O O NN Br

N

Br

279

N N

O

N H

NH

Br O

N H

O

N H

N H

244

245

246

247

M. tuberculosis MIC = 4.13 μM

M. tuberculosis MIC = 4.29 μM

M. tuberculosis MIC = 1.98 μM

M. tuberculosis MIC = 6.06 μM

Fig. 26 Antimycobacterial activity of dispiropyrrolidines

O

O O

ArCN

O

O

a

b

N

O

NH

O

Ar

Ar

248

249

Scheme 43 a Conc. H2SO4, 5–10 C, 30 min, 33–76%; b LiAlH4, Et2O, 15 h, 35–79%

O

O N

O

O NH

O

NH

O

F NO2 250 % increase in CT over control – 44.9

251

252

– 30.5

– 34.3

Fig. 27 Anticoagulant activity of dihydroisoquinolines and tetrahydroisoquinolines

having percent increases in coagulation times greater than Heparin (% increase in CT = 22.4) (Fig. 27). Dihydroisoquinolines such as 253 were prepared in a similar manner to compounds 248 and were tested for their hypotensive properties in anesthetized cats as shown in Fig. 28 [88]. The four-component reaction of arylthioacetones, arylaldehydes, and methylamine or ammonium acetate resulted in the productions of piperidinones of general structure 254 (Scheme 44) which were evaluated for their antibacterial and antifungal properties [89]. The compounds were tested against gram-positive bacteria S. Aureus, K. pneumoniae, Vibrio cholerae and Salmonella typhi, the gram-negative E. coli and also the fungi C. albicans and A. niger. None of the compounds were active against K. pneumoniae. Several compounds showed strong antibacterial and antifungal properties as shown in Table 22.

280

I. Akritopoulou-Zanze and S.W. Djuric

N Hypotensive activity Extent of effect at 5 mg/Kg = 72.4 mmHg

253

Cl

Fig. 28 Hypotensive activity of 253

R1 O

O

S

O H

R1

R2

O H

R2

a

NH2R

S N R

R = H, Me R2

R2 254

Scheme 44 a EtOH, heat, 32–50%

Table 22 Antibacterial and antifungal activities of piperidinones Cl

Cl

Cl

O

O

S

N H

Cl

Cl

N

Cl

255

255 256 257 Streptomycin Nystatin

S

Cl

N H

Compound (200 mg/mL)

O

S

Antibacterial activity Zone of inhibition in mm S. aureus V. cholerae 11 11 12 12 13 12 13 12 – –

Cl

256

Cl 257

Antifungal activity S. typhi 10 12 11 12 –

E. coli 11 12 13 13 –

C. albicans 11 12 11 – 12

A. niger 10 12 12 – 12

The four-component, two-step synthesis of tetrasubstituted imidazoles 259 is described in Scheme 45 [90]. Initially, all the four components were heated together resulting, however, in lower yields because of the competing formation of

Applications of MCR-Derived Heterocycles in Drug Discovery

281

O R1 NH2

HO

R2

H

N

a O O

CH3CO2NH4 N R1

N R2

N

b

N R1

258

R2 CO2H 260 CTC50 = 94.63 mg/mL

259

Scheme 45 a glacial AcOH, reflux, 6 h or Microwave, activated silica gel, 8 min b reflux, 12–15 h, 58–90% or Microwave, 14–23 min, 81–92%

O O R3 R1

O O

R3 a

NH3

HN

Br

R2

R2 R4

N R1 H

R4

261

HN H 262

N H HO

Cl

Scheme 46 a MeOH, ultrasonic irradiation, 90 min, 75–95%

trisubstituted adducts. When imines 258 were preformed, the final products were obtained in much higher yields particularly using microwave irradiation. The imidazoles were tested for their antibacterial (S. aureus, B. subtilis, E. coli, K. pneumoniae), antimycobacterial (M. tuberculosis H37Rv) and anticancer (Dalton’s lymphoma ascites cells) properties. None of the compounds showed any antibacterial or antimycobacterial properties, with the exception of compound 260 (Scheme 45) which demonstrated moderate activity against S. aureus (MIC = 250 mg/mL). Several compounds exhibited good anticancer activity as measured by the concentration that inhibited 50% growth of total cells, with the most potent being 260. The three component reaction of a,b unsaturated ketones with aldehydes or ketones and ammonia, under ultrasound irradiation, provided tetrahydropyrimidines 261 in high yields (Scheme 46) [91]. The compounds were tested against M. tuberculosis H37Rv (ATCC 27294) at a single concentration of 6.25 mg/mL. Most of the compounds exhibited inhibitory activity between 50 and 80%. The most potent compound was 262 (Scheme 46), with inhibitory activity of 98%. Reactions of amines, aldehydes and mercaptoacetic acid in ionic liquids (Scheme 47) resulted in the formation of thiazolidinones 263 in moderate to high yields [92]. The reaction was used to create a library of nucleoside thiazolidinones

282

I. Akritopoulou-Zanze and S.W. Djuric

AcO

AcO O O

H R1 NH2

OH

R2 O

SH

O

a

R1

R2 N

O

N

NH

Cl

O S

N

S

O 263

264

Scheme 47 a [bmim] [PF6] , 60–80 C, 5–9 h, 47–92% +

employing 5-formyl-20 -deoxyuridine as the aldehyde component. The compounds were tested against Trypanosoma brucei brucei GVR35 and against Leishmania donovani LV9. While none of the compounds was active against the latter, several compounds showed moderate activity against T. brucei brucei. The most potent was compound 264 (Scheme 47) with an IC50 = 25 mM.

6 Conclusions In recent years multicomponent reactions have been extensively utilized to produce libraries of heterocyclic molecules with biological activity against a variety of targets. The majority of these compounds were tested for their anticancer, antioxidant and antimicrobial properties and numerous promising compounds were identified and were further evaluated. With the continuous development of new multicomponent reactions and combinations of MCRs with subsequent transformations, this area of research holds great promise for the discovery of novel therapeutic agents.

References 1. Ertl P, Jelfs S, Mu¨hlbacher J et al (2006) Quest for the rings. In silico exploration of ring universe to identify novel bioactive heteroaromatic scaffolds. J Med Chem 49:4568–4573 2. Nielsen TE, Meldal M (2009) Solid-phase synthesis of complex and pharmacologically interesting heterocycles. Curr Opin Drug Discov Devel 12:798–810 3. Isambert N, Lavilla R (2008) Heterocycles as key substrates in multicomponent reactions: the fast lane towards molecular complexity. Chem Eur J 14:8444–8454 4. Sunderhaus JD, Martin SF (2009) Applications of multicomponent reactions to the synthesis of diverse heterocyclic scaffolds. Chem Eur J 15:1300–1308 5. Do¨mling A (2006) Recent developments in isocyanide based multicomponent reactions in applied chemistry. Chem Rev 106:17–89

Applications of MCR-Derived Heterocycles in Drug Discovery

283

6. Tempest PA (2005) Recent advances in heterocycle generation using the efficient Ugi multiple-component condensation reaction. Curr Opin Drug Discov Devel 8:776–788 7. Zhu J (2003) Recent developments in the isonitrile-based multicomponent synthesis of heterocycles. Eur J Org Chem:1133–1144 8. Hulme C, Dietrich J (2009) Emerging molecular diversity from the intra-molecular Ugi reaction: iterative efficiency in medicinal chemistry. Mol Div 13:195–207 9. Akritopoulou-Zanze I (2008) Isocyanide-based multicomponent reactions in drug discovery. Curr Opin Chem Biol 12:324–331 10. Barrow JC, Stauffer SR, Rittle KE et al (2008) Discovery and X-ray crystallographic analysis of a spiropiperidine iminohydantoin inhibitor of b-secretase. J Med Chem 51:6259–6262 11. Akritopoulou-Zanze I, Djuric SW (2007) Recent advances in the development and applications of post-Ugi transformations. Heterocycles 73:125–147 12. Marcaccini S, Torroba T (2005) Post-condensation modifications of the Passerini and Ugi reactions. In: Zhu J, Bienayme´ H (eds) Multicomponent reactions. Wiley-VCH, Weinheim, pp 33–75 13. Di Micco S, Vitale R, Pellecchia M et al (2009) Identification of lead compounds as antagonists of protein Bcl-xL with a diversity-oriented multidisciplinary approach. J Med Chem 52:7856–7867 14. Bienayme´ H, Bouzid K (1998) A new heterocyclic multicomponent reaction for the combinatorial synthesis of fused 3-aminoimidazoles. Angew Chem Int Ed 37:2234–2237 15. Blackburn C, Guan B, Fleming P et al (1998) Parallel synthesis of 3-aminoimidazo[1, 2-a]pyridines and pyrazines by a new three component condensation. Tetrahedron Lett 39:3635–3638 16. Groebke K, Weber L, Mehlin F (1998) Synthesis of imidazo[1,2-a]annulated pyridines, pyrazines and pyrimidines by a novel three-component condensation. Synlett:661–663 17. Odell LR, Nilsson MT, Gising J et al (2009) Functionalized 3-amino-imidazo[1, 2-a]pyridines: a novel class of drug-like Mycobacterium tuberculosis glutamine synthetase inhibitors. Bioorg Med Chem Lett 19:4790–4793 18. Meng T, Zhang Z, Hu D et al (2007) Three-component combinatorial synthesis of a substituted 6H-pyrido[20 , 10 :2, 3]imidazo-[4, 5-c]isoquinolin-5(6H)-one library with cytotoxic activity. J Comb Chem 9:739–741 19. Simon C, Constantieux T, Rodriguez J (2004) Utilisation of 1, 3-dicarbonyl derivatives in multicomponent reactions. Eur J Org Chem 24:4957–4980 20. Vdovina SV, Mamedov VA (2008) New potential of the classical Biginelli reaction. Russ Chem Rev 77:1017–1053 21. Kappe CO (2000) Biologically active dihydropyrimidones of the Biginelli-type – a literature survey. Eur J Med Chem 35:1043–1052 22. Kumar BRP, Sankar G, Baig RBN, Chandrashekaran S (2009) Novel Biginelli dihydropyrimidines with potential anticancer activity: a parallel synthesis and CoMSIA study. Eur J Med Chem 44:4192–4198 23. Fewell SW, Smith CM, Lyon MA et al (2004) Small molecule modulators of endogenous and co-chaperone-stimulated Hsp70 ATPase activity. J Biol Chem 279:51131–51140 24. Chiang AN, Valderramos J-C, Balachandran R et al (2009) Select pyrimidinones inhibit the propagation of the malarial parasite, Plasmodium falciparum. Bioorg Med Chem 17:1527–1533 25. Wise´n S, Androsavich J, Evans CG et al (2008) Chemical modulators of heat shock protein 70 (Hsp70) by sequential, microwave-accelerated reactions on solid phase. Bioorg Med Chem Lett 18:60–65 26. Wright CM, Chovatiya RJ, Jameson NE et al (2008) Pyrimidinone-peptoid hybrid molecules with distinct effects on molecular chaperone function and cell proliferation. Bioorg Med Chem 16:3291–3301 27. Singh OM, Singh SJ, Devi MB et al (2008) Synthesis and in vitro evaluation of the antifungal activities of dihydropyrimidinones. Bioorg Med Chem Lett 18:6462–6467

284

I. Akritopoulou-Zanze and S.W. Djuric

28. Ashok M, Holla BS, Kumari NS (2007) Convenient one pot synthesis of some novel derivatives of thiazolo[2, 3-b]dihydropyrimidinone possessing 4-methylthiophenyl moiety and evaluation of their antibacterial and antifungal activities. Eur J Med Chem 42:380–385 29. Deshmukh MB, Salunkhe SM, Patil DR, Anbhule PV (2009) A novel and efficient one step synthesis of 2-amino-5-cyano-6-hydroxy-4-aryl pyrimidines and their anti-bacterial activity. Eur J Med Chem 44:2651–2654 30. Trivedi A, Dodiya D, Surani J et al (2008) Facile one-pot synthesis and antimycobacterial evaluation of pyrazolo[3, 4-d]pyrimidines. Arch Pharm Chem Life Sci 341:435–439 31. Chikhale RV, Bhole RP, Khedekar PB, Bhusari KP (2009) Synthesis and pharmacological investigation of 3-(substituted 1-phenylethanone)-4-(substituted phenyl)-1, 2, 3, 4-tetrahydropyrimidine-5-carboxylates. Eur J Med Chem 44:3645–3653 32. Stefani HA, Oliveira CB, Almeida RB et al (2006) Dihydropyrimidin-(2H)-ones obtained by ultrasound irradiation: a new class of potential antioxidant agents. Eur J Med Chem 41:513–518 33. Ismaili L, Nadaradjane A, Nicod L et al (2008) Synthesis and antioxidant activity evaluation of new hexahydropyrimido[5, 4-c]quinoline-5-ones and 2-thioxohexahydropyrimido[5, 4-c] quinoline-5-ones obtained by Biginelli reaction in two steps. Eur J Med Chem 43:1270–1275 34. Saini A, Kumar S, Sandhu JS (2008) Hantzsch reaction: recent advances in Hantzsch 1, 4-dihydropyridines. J Sci Ind Res 67:95–111 35. Bossert VF, Meyer H, Wehinger E (1981) 4-Aryldihydropyridine, a new class of highly active calcium antagonists. Angew Chem 93:755–763 ¨ hberg L, Westman J (2001) An efficient and fast procedure for the Hantzsch dihydropyridine 36. O synthesis under microwave conditions. Synlett:1296–1298 37. Cotterill IC, Usyatinsky AY, Arnold JM et al (1998) Microwave assisted combinatorial chemistry synthesis of substituted pyridines. Tetrahedron Lett 39:1117–1120 38. Nadaraj V, Selvi ST, Mohan S (2009) Microwave-induced synthesis and anti-microbial activities of 7, 10, 11, 12-tetrahydrobenzo[c]acridin-8(9H)-one derivatives. Eur J Med Chem 44:976–980 39. Bazgir A, Khanaposhtani MM, Soorki AA (2008) One-pot synthesis and antibacterial activities of pyrazolo[40 , 30 :5, 6]pyrido[2, 3-] d pyrimidine-dione derivatives. Bioorg Med Chem Lett 18:5800–5803 40. Kawase M, Shah A, Gaveriya H et al (2002) 3, 5-Dibenzoyl-1, 4-dihydropyridines: synthesis and MDR reversal in tumor cells. Bioorg Med Chem 10:1051–1055 41. Menichincheri M, Bargiotti A, Berthelsen J et al (2009) First Cdc7 kinase inhibitors: pyrrolopyridinones as potent and orrally active antitumor agents. 2. Lead discovery. J Med Chem 52:293–307 42. Vanotti E, Amici R, Bargiotti A et al (2008) Cdc7 kinase inhibitors: pyrrolopyridinones as potential antitumor agents. 1. Synthesis and structure–activity relationships. J Med Chem 51:487–501 43. Magedov IV, Manpadi M, Van Slambrouck S et al (2007) Discovery and investigation of antiproliferative and apoptosis-inducing properties of new heterocyclic podophyllotoxin analogues accessible by a one-step multicomponent synthesis. J Med Chem 50:5183–5192 44. Magedov IV, Manpadi M, Rozhkova E et al (2007) Structural simplification of bioactive natural products with multicomponent synthesis: dihydropyridopyrazole analogues of podophyllotoxin. Bioorg Med Chem Lett 17:1381–1385 45. Manpadi M, Uglinskii PY, Rastogi SK et al (2007) Three-component synthesis and anticancer evaluation of polycyclic indenopyridines lead to the discovery of a novel indenoheterocycle with potent apoptosis inducing properties. Org Biomol Chem 5:3865–3872 ¨ ztu¨rk GS, Vural IM et al (2009) Condensed 1, 4-dihydropyridines with various 46. Bu¨lbu¨l B, O esters and their calcium channel antagonist activities. Eur J Med Chem 44:2052–2058 ¨ ztu¨rk GS, Vural M et al (2008) Evaluation of myorelaxant activity of 47. Gu¨ndu¨z MG, O 7-substituted hexahydroquinoline derivatives in isolated rabbit gastric fundus. Eur J Med Chem 43:562–568

Applications of MCR-Derived Heterocycles in Drug Discovery

285

¨ ztu¨rk GS, Vural IM et al (2008) Synthesis and calcium modulatory activity of 48. S¸imS¸ek R, O 3-alkyloxy-carbonyl-4-(disubstituted)aryl-5-oxo-1, 4, 5, 6, 7, 8-hexahydroquinoline derivatives. Arch Pharm Chem Life Sci 341:55–60 49. Davood A, Mansouri N, Dehpour AR et al (2006) Design, synthesis, and calcium channel antagonist activity of new 1, 4-dihydropyridines containing 4-(5)-chrolo-2-ethyl-5-(4)-imidazolyl substituent. Arch Pharm Chem Life Sci 339:299–304 50. Altenbach RJ, Brune ME, Buckner SA et al (2006) Effects of substitution on 9-(3-bromo-4fluorophenyl)-5, 9-dihydro-3H, 4H–2, 6-dioxa-4-azacyclopenta[b]naphthalene-1, 8-dione, a dihydropyridine ATP-sensitive potassium channel opener. J Med Chem 49:6869–6887 51. Roh EJ, Keller JM, Olah Z et al (2008) Structure-activity relationships of 1, 4-dihydropyridines that act as enhancers of the vanilloid receptor 1 (TRPV1). Bioorg Med Chem 16:9349–9358 52. Kumar A, Maurya RA, Sharma S et al (2010) Synthesis and biological evaluation of N-aryl-1, 4-dihydropyridines as novel antidyslipidemic and antioxidant agents. Eur J Med Chem 45:501–509 53. Tanifum EA, Kots AY, Choi B-K et al (2009) Novel pyridopyrimidine derivatives as inhibitors of stable toxin a (STa) induced cGMP synthesis. Bioorg Med Chem Lett 19:3067–3071 54. Sabnis RW, Rangnekar DW, Sonawane ND (1999) 2-Aminothiophenes by the Gewald reaction. J Heterocycl Chem 36:333–345 55. Romagnoli R, Baraldi PG, Carrion MD et al (2007) Synthesis and biological evaluation of 2-and 3-aminobenzo[b]thiophene derivatives as antimitotic agents and inhibitors of tubulin polymerization. J Med Chem 50:2273–2277 56. Briel D, Rybak A, Kronbach C, Unverferth K (2010) Substituted 2-Aminothiopen-derivatives: a potential new class of GluR6-antagonists. Eur J Med Chem 45:69–77 57. Ferguson GN, Valant C, Horne J et al (2008) 2-Aminothienopyridazines as novel adenosine A1 receptor allosteric modulators and antagonists. J Med Chem 51:6165–6172 58. Pizzirani D, Roberti M, Recanatini M (2007) Domino Knoevenagel/Diels–Alder sequence coupled to Suzuki reaction: a valuable synthetic platform for chemical biology. Tetrahedron Lett 48:7120–7124 59. Pizzirani D, Roberti M, Grimaudo S et al (2009) Identification of biphenyl-based hybrid molecules able to decrease the intracellular level of Bcl-2 protein in Bcl-2 overexpressing leukemia cells. J Med Chem 52:6936–6940 60. Jime´nez-Alonso S, Pe´rez-Lomas AL, Este´vez-Braun A et al (2008) Bis-pyranobenzoquinones as a new family of reversal agents of the multidrug resistance phenotype mediated by P-glycoprotein in mammalian cells and the protozoan parasite Leishmania. J Med Chem 51:7132–7143 61. Jime´nez-Alonso S, Orellana HC, Este´vez-Braun A et al (2008) Design and synthesis of a novel series of pyranonaphthoquinones as topoisomerase II Catalytic inhibitors. J Med Chem 51:6761–6772 62. Misra M, Pandey SK, Pandey VP et al (2009) Organocatalyzed highly atom economic one pot synthesis of tetrahydropyridines as antimalarials. Bioorg Med Chem 17:625–633 63. Kumar D, Reddy VB, Sharad S et al (2009) A facile one-pot green synthesis and antibacterial activity of 2-amino-4H-pyrans and 2-amino-5-oxo-5, 6, 7, 8-tetrahydro-4H-chromenes. Eur J Med Chem 44:3805–3809 64. Jensen AA, Erichsen MN, Nielsen CW et al (2009) Discovery of the first selective inhibitor of excitatory amino acid transporter subtype 1. J Med Chem 52:912–915 65. Magedov IV, Manpadi M, Ogasawara MA (2008) Structural simplification of bioactive natural products with multicomponent synthesis. 2. Antiproliferative and antitubulin activities of pyrano[3, 2-c]pyridones and pyrano[3, 2-c]quionolones. J Med Chem 51:2561–2570 66. Magedov IV, Luchetti G, Evdokimov NM et al (2008) Novel three-component synthesis and antiproliferative properties of diversely functionalized pyrrolines. Bioorg Med Chem Lett 18:1392–1396

286

I. Akritopoulou-Zanze and S.W. Djuric

67. Sayyafi M, Soorki AA, Bazgir A (2008) One-pot synthesis and antibacterial activities of novel 1H-pyridazino[1, 2-a]indazole-1, 6, 9(2H, 11H)-triones. Chem Pharm Bull 56:1289–1291 68. Ladani NK, Patel MP, Patel RG (2009) A convenient one-pot synthesis of series of 3-(2, 6diphenyl-4-pyridyl)hydroquinolin-2-one under microwave irradiation and their antimicrobial activities. Indian J Chem 48B:261–266 69. Eissa AAM, Farag NAH, Soliman GAH (2009) Synthesis, biological evaluation and docking studies of novel benzopyranone congeners for their expected activity as anti-inflammatory, analgesic and antipyretic agents. Bioorg Med Chem 17:5059–5070 70. Shi F, Li C, Xia M et al (2009) Green chemoselective synthesis of thiazolo[3, 2-a]pyridine derivatives and evaluation of their antioxidant and cytotoxic activities. Bioorg Med Chem Lett 19:5565–5568 71. Mason HJ, Wu X, Schmitt R et al (2001) Synthesis of fused pyridopyrrolidine dione derivatives using hetero Diels-Alder reactions. Tetrahedron Lett 42:8931–8934 72. Yu G, Mason H, Wu X et al (2003) Substituted pyrazolopyridopyridazines as orally bioactive potent and selective PDE5 inhibitors: potential agents for treatment of erectile dysfunction. J Med Chem 46:457–460 73. Grieco PA, Bahsas A (1988) Role reversal in the cyclocondensation of cyclopentadiene with heterodienophiles derived from aryl amines and aldehydes: synthesis of novel tetrahydroquinolines. Tetrahedron Lett 29:5855–5858 74. Kouznetsov VV, Puentes CO, Boho´rquez APP et al (2006) A straightforward synthetic approach to antitumoral pyridinyl substituted 7H-indeno[2, 1-c]quinoline derivatives via three-component imino Diels-Alder reaction. Lett Org Chem 3:300–304 75. Kouznetsov VV (2009) Recent synthetic developments in a powerful imino Diels-Alder reaction (Povarov reaction): application to the synthesis of N-polyheterocycles and related alkaloids. Tetrahedron 65:2721–2750 76. Tarrago´ T, Masdeu C, Go´mez E et al (2008) Benzimidazolium salts as small, nonpeptidic and BBB-permeable human prolyl oligopeptidase inhibitors. Chem Med Chem 3:1558–1565 77. Camps P, Formosa X, Galdeano C et al (2009) Pyrano[3, 2-c]qionoline-6-chlorotacrine hybrids as a novel family of acetylcholinesterase- and b-amyloid-directed anti-Alzheimer compounds. J Med Chem 52:5365–5379 78. Kumar RR, Perumal S, Senthilkumar P et al (2008) A highly atom economic, chemo-, regioand stereoselective synthesis, and discovery of spiro-pyrido-pyrrolizines and pyrrolidines as antimycobacterial agents. Tetrahedron 64:2962–2971 79. Zarghi A, Ghodsi R, Azizi E et al (2009) Synthesis and biological evaluation of new 4-carboxyl quinoline derivatives as cyclooxygenase-2 inhibitors. Bioorg Med Chem 17:5312–5317 80. Muscia GC, Carnevale JP, Bollini M, Ası´s SE (2008) Microwave-asssisted Do¨bner synthesis of 2-phenylquinoline-4-carboxylic acids and their antiparasitic activities. J Heterocycl Chem 45:611–614 81. Czopek A, Byrtus H, Kołaczkowski M et al (2010) Synthesis and pharmacological evaluation of new 5-(cyclo)alkyl-5-phenyl- and 5-spiroimidazolidine-2, 4-dione derivatives. Novel 5HT1A receptor agonist with potential antidepressant and anxiolytic activity. Eur J Med Chem 45:1295–1303 82. Sheppeck JE, Gilmore JL, Yang A et al (2007) Discovery of novel hydantoins as selcective non-hydroxamate inhibitors of tumor necrosis factor-a converting enzyme (TACE). Bioorg Med Chem Lett 17:1413–1417 83. Peretto I, Forlani R, Fossati C et al (2007) Discovery of diaryl imidazolidin-2-one derivatives, a novel class of muscarinic M3 selective antagonists (Part 1). J Med Chem 50:1571–1583 84. Stocks MJ, Cheshire DR, Reynolds R (2004) Efficient and regiospecific one-pot synthesis of substituted 1, 2, 4-triazoles. Org Lett 6:2969–2971 85. Cui X-S, Chen J, Chai K-Y et al (2009) Synthesis and anticonvulsant evaluation of 3substituted-4-(4-hexyloxyphenyl)-4H–1, 2, 4-triazoles. Med Chem Res 18:49–58 86. Kumar RS, Rajesh SM, Perumal S et al (2010) Novel three-component domino reactions of ketones, isatin and amino acids: synthesis and discovery of antimycobacterial activity of highly functionalised novel dispiropyrrolidines. Eur J Med Chem 45:411–422

Applications of MCR-Derived Heterocycles in Drug Discovery

287

87. Glushkov VA, Arapov KA, Minova ON et al (2006) Synthesis and anticoagulant activity of 1-aryl derivatives of tetrahydroisoquinolines. Pharm Chem J 40:363–366 88. Glushkov VA, Stryapunina OG, Dolzhenko AV et al (2009) Synthesis and antiaggregant and antihypotensive activity of benzo-annelated azabicyclo[m.n.0]alkanes. Pharm Chem J 43:245–248 89. Srinivasan M, Pemural S, Selvaraj S (2006) Synthesis, stereochemistry, and antimicrobial activity of 2, 6-diaryl-3-(arylthio)piperidin-4-ones. Chem Pharm Bull 54:795–801 90. Kumar BRP, Sharma GK, Srinath S et al (2009) Microwave-assisted, solvent-free, parallel syntheses and elucidation of reaction mechanism for the formation of some novel tetraaryl imidazoles of biological interest. J Heterocycl Chem 46:278–284 91. Muravyova EA, Desenko SM, Musatov VI et al (2007) Ultrasonic-promoted threecomponent synthesis of some biologically active 1, 2, 5, 6-tetrahydropyrimidines. J Comb Chem 9:797–803 92. Zhang X, Li X, Li D et al (2009) Ionic liquid mediated and promoted eco-friendly preparation of thiazolidinone and pyrimidine nucleoside-thiazolidinone hybrids and their antiparasitic activities. Bioorg Med Chem Lett 19:6280–6283

Index

A Acenaphthenequinone, 272 Acetamidoamide, 5 4-N-Acetylamino-2-methyl-cis-3a,4,7,7atetrahydroisoindole-1,3-dione, 217 Acridines, 207 Acroyl chlorides, 59 5-Acyl dihydropyrid-2-ones, 60 Alkenones, 25 Alkenylzirconocene chlorides, 140 Alkyne activation, cross-coupling, 30 – Sonogashira coupling, 31 Alkynones, 25, 30, 43 2-Alkynyl 5-nitrothiophenes, 31 Allenes, 25 Allylboration, pyridine, 139 Amidinium salts, 46 1-Amidoalkyl-2-naphthols, 215 b-Amino acid, 6 5-Amino-3-phenylpyrazole, 197 3-Aminoimidazo[1,2-a]pyridines, 235 Aminoimidazoles, N-fused, 205 2-Aminothiophenes, 221 Aminovinylation, 31 b-Aminovinyl nitrothiophenes, 31 Anilines, ortho-thio substituted, 66 Antibacterial activity, 46, 53, 63, 76, 192, 206, 231 Anticancer activity, 39, 173, 231, 250, 281 Antifungal activity, 46, 53, 231, 239, 243, 264 Antimicrobial activity, 46, 53, 63, 208, 231, 246

Antimycobacterial activity, 231 Antioxidant activity, 171, 231, 251, 265 Arndtsen pyrrole synthesis, 156 4-Aryl-8-arylidene-5,6,7,8-tetrahydro2-quinolinones, 193 Aspergillus niger, 239 Aspergillus parasiticus, 247 2-Azafluoranthene, 131 1-Azapyrene, 131 2-Azaspiro[4.5]deca-6,9-diene-3,8diones, 218 N-(4-Azidobutyl)-N-benzyl-2-isocyano3-phenylpropanamide, 11 Azines, 127, 152 Aziridine, 9

B BACE 1 HTS, 233 Barbituric acids, 247 Barrenazines, 145 Benzimidazoles, 131 Benzodiazepines, 51, 209 Benzoheteroazepine, 66 Benzonaphthyridines, 270 Benzothiazepines, 53 Benzothiophenes, 253 Bienayme´–Blackburn–Groebke reactions, 235 Biginelli condensation, 100, 237 Biindolizines, 41 Bis-amino oxazole, 114 Bucherer–Bergs reaction, 273

289

290

C Carbamoylation, 161 Carbo-Reissert-type processes, 137 Cerivastatin, 173 Chalcones, 36, 64 2-Chloro-3-formylquinolines, 263 3-Chloro-4-iodo furans, 57 Chromenone-dihydropyridines, 266 Chromeno[3,4-b][4,7]phenanthrolines, 212 Chromens, 211 Ciprofloxacin, 278 Combinatorial chemistry, 98 Combretastatin, 255 Complexity, 95, 97 Condition-based divergence, 115 Coupling-addition, 31 Coupling-isomerization, 25, 34 Cross-coupling, 25 Cyanomalonate, 237 Cycloadditions, 268 – 1,3-dipolar, 271 Cyclodimerization, 3 Cyclopeptides, 7 Cyclophanes, 18 Cyclopropane-1,1-dicarboxylic acid, 15 Cyclopropylvinylboronic acid, 106

D Daunorubicin, 259 1,3-Diaryl propenones (chalcones), 30 Diarylamines, 218 Dibenzoyl dihydropyrimidines, 249 Dicarbonyl, 231, 237 Diethyl a-aminomalonate, 116 Dihydroazine, N,a-disubstituted, 127 Dihydrofuropyrrolone, 114 Dihydroisoquinolines, 279 3,4-Dihydro-3-oxo-2H-1,4benzoxazines, 216 2,3-Dihydropyrans, 212 Dihydropyridines, 171 Dihydropyrimidines, 183 – ion channel activities, 252 Dihydropyrimidinones, 237 Dihydropyrimidone, 113 Diisopropylethylamine (DIPEA), 11 1,4-Diketones, 66 2,5-Diketopiperazines, 218

Index

Dimethoxy-N,N-dimethylmethanamine, 276 Dimethyl acetylenedicarboxylate, 109 Dipole formation, 147 Dispiropyrrolidines, 277 – antimycobacterial, 279 Diversity oriented synthesis (DOS), 95, 98, 234 Do¨bner synthesis, 272 Domino Knoevenagel/hetero-Diels–Alder reaction (DKHDA), 207 Domino reactions, 25, 28, 147 Drug discovery, 97, 231

E Enaminones, 34 Enimines, 38

F Ferrocene, 194 3-Formylquinolones, 263 Furans, 212 Furo[3,4-b]quinolines, 195

G Gentamicin, 249 Gewald reaction, 253 Guanidinium salts, 48

H Halo furans, 54 Hantzsch reaction, 245 Hemicryptophane, 15 Hept-6-ynal, 11 Heteroarenes, 48 Heteroaryl enones, 37 Heteroaryl halides, 47, 64 2-Heteroaryl-pyrrolopyridinones, 249 Heterocycles, 231 – coupling–addition– cyclocondensation, 43 – coupling–cycloaddition, 38 – coupling–isomerization– cyclocondensation, 64 – domino synthesis, couplingisomerization, 75 Hetero-Diels–Alder reactions, 268

Index

Horner–Wadsworth–Emmons (HWE) reaction, 111 Hydantoin, 273 Hydrazines, 44, 64 2-Hydrazolyl-4-thiazolidinones, 206 Hyperaspine, 145

I Igloo-shaped macrotetracycles, 21 Imidazoles, 203 Imidazolines, 119 Imidazolyl dihydropyridines, 251 Iminium ion, 102 Indenoquinolines, 269 Indole-3-glyoxylyl chlorides, 50 Indolizines, 41 Indolopyridine alkaloids, 134 3-Iodo pyrroles, 58 Irbesartan, 205 Isatins, 277 Isocyanides, 1, 127, 152, 231, 233 Isocyanoacetamides, 11 Isoquinolinephosphonates, 137 Isoquinolines, 131, 199 Isoquinolinobutyrolactones, 139 Isoquinolinones, fused, 236 Isoxazoles, 39

K Knoevenagel, 231 – /Diels–Alder, 256 – /Krohnke synthesis, 263 – /Michael-type sequences, 260

L

b-Lactames, 6 Lasubine II, 145 Lavendamycin, 173 Leishmania donovani, 282 Leishmania tropica, 258 Leukotriene, 173 Levulinic acid, 122

M Macrocyclization, 1, 5, 19 – in situ generated functional groups, 5

291

Macrocylopeptide, 1 Malononitrile, 237 Meridianins, 47 4-Methoxypyridines, 146 Michael addition, 43 Microwave-assisted organic synthesis (MAOS), 152 Modular reaction sequences, 111 Molecular diversity, 102 Morpholine, 11, 254 Multiple multicomponent macrocyclization, 11, 19 Mumm rearrangement, 5 Mycobacterium tuberculosis 240, 272 – glutamine synthetase (MtGS), 235

N Naphthyridines, 220 Nifedipine, 246 Nitrile oxides, 39 Nucleophiles, 135

O Organocatalysis, 103 Ortho-amino thiophenols, 53 Ortho-phenylene diamines, 51 Oxalyl chloride, 48 Oxazepines, 209 Oxazoles, 1, 57

P Palladium catalysis, 25 Passerin-3CR, 1 Passerini 3-component reaction (P-3CR), 101 Penicillium marneffei, 239 Peptoid-dihydropyrimidinones, antimalarial, 241 2-Phenylquinoline-4-carboxylic acids, 274 Phosphinothricin, 236 Phospho-Reissert-type processes, 137 Piperidinones, 279 Piperidones, 234 Plasmodium falciparum, 238, 260, 274 Podophyllotoxin, 250 Polyhydroquinolines, 194 Povarov reaction, 269

292

Propargyl alcohols, 64 Propargyl amides, 58 Propargyl amines, 57, 213 Propargyl ethers, 54 Propyl oligopeptidasen, 270 Pyrans, 212 Pyrazoles, 44, 64, 206 Pyrazolo[4,3-f]quinolin-7-ones, 194 Pyrazolopyridines, 268 Pyrazolopyridopyridazines, 268 Pyrazolo-pyrido-pyrimidine-diones, 249 Pyrazolopyrimidines, 240 Pyridazinoindazole triones, antibacterial, 264 Pyridazinones, 255 Pyridine, allylboration, 139 Pyridines, 171, 173 – annelated/substituted, 4CR 69 Pyridinium ylids, 41 3-Pyrimidin-5-ylpropanamides, 218 Pyrimidines, 46, 65, 183 – fused, 187 Pyrimido[1,2-a]quinolines, 195 Pyrrolidines, 263 Pyrroloisoquinolines, 150

Q Quinazolines, 131, 200 Quinoline-pyridines, 263 Quinolines, 191 – 2-substituted, domino synthesis, 75 Quinolino[1,2-a]quinazolines, 195 Quinolizines, 202 o-Quinone methide, 215 Quinoxalines, 203

R Reissert reaction, 127 – activating agents, 132 – asymmetric, 142 – nucleophiles, 134 Reissert–Henze reaction, nucleophiles, 136 Rhodotorula rubra, 247

Index

Silyloxyfurans, 139 Single reactant replacement (SRR), 108 Spiro hydantoins, 276 Spiro-benzofuranones, domino synthesis, 76 Spiro-benzoindolones, domino synthesis, 76 Spiroimidazolinones, 204 Spiro-triones, 257 Staudinger reaction, 1 Streptonigrin, 173 Streptonigrone, 173

T Target oriented synthesis (TOS), 98 Tetracyanoethylene, 149 Tetrahydro-b-carbolines, 59, 61 Tetrahydrochromones, 261 Tetrahydroindenoquinolines, 269 Tetrahydroisoquinolines, 279 Tetrahydropyridines, antimalarial, 260 Tetrahydropyrimidines, 244 Tetraponerine T4, 139 Thiazapines, 209 Thiazolidinones, 206, 281 Thiazolines, 206 Thiazolopyridazinones, fused, 255 Thiazolopyridines, 265 – cytotoxic/antioxidant, 267 Thiochromenones, 63 Thiopyranones, annelated, 62 Transition metal catalysis, 29 Triazadibenzoazulenones, 220 Triazoles, 276 Trichoderma hammatum, 239 Trichoderma koningii, 239 Trichophyton rubrum, 269 Trimethylsilyl alkynones, 33 Trypanosoma brucei brucei, 282 Tryptamines, 59 Tryptanthrin, 203

U Ugi reactions, 101, 233 – 4CR, 1, 5, 102

S Salmonella typhi, 279 Scaffold diversity, 95, 99, 107 Secretase (BACE-1), 233 Sequential Reissert–lactonization, 140

V Vancomycin, 2 Variolins, 47 Vibrio cholerae, 279

Synthesis of Heterocycles via Multicomponent Reactions II (Topics in Heterocyclic Chemistry, Volume 25)

Synthesis of Heterocycles via Multicomponent Reactions I (Topics in Heterocyclic Chemistry)

Synthesis of Heterocycles via Cycloadditions I (Topics in Heterocyclic Chemistry)

Phosphorus Heterocycles II (Topics in Heterocyclic Chemistry, Volume 21)

Synthesis of Heterocycles via Cycloadditions II

Heterocyclic Scaffolds II: Reactions and Applications of Indoles (Topics in Heterocyclic Chemistry, Volume 26)

Advances in Heterocyclic Chemistry, Volume 25

Heterocycles from Carbohydrate Precursors (Topics in Heterocyclic Chemistry)

Name Reactions in Heterocyclic Chemistry

Multicomponent Reactions

Natural Products via Enzymatic Reactions (Topics in Current Chemistry)

Multicomponent Reactions

Transition-Metal-Catalyzed Reactions in Heterocyclic Synthesis

Topics in current chemistry, 216, Stereoselective Heterocyclic Synthesis III

Progress in Heterocyclic Chemistry, Volume 13 (Progress in Heterocyclic Chemistry)

Progress in Heterocyclic Chemistry, Volume 20 (Progress in Heterocyclic Chemistry)

Progress in Heterocyclic Chemistry, Volume 19 (Progress in Heterocyclic Chemistry)

Progress in Heterocyclic Chemistry, Volume 9 (Progress in Heterocyclic Chemistry)

Aromaticity in Heterocyclic Compounds (Topics in Heterocyclic Chemistry)

Progress in Heterocyclic Chemistry, Volume 18 (Progress in Heterocyclic Chemistry) (Progress in Heterocyclic Chemistry)

Heterocyclic Scaffolds I: ß-Lactams (Topics in Heterocyclic Chemistry)

Heterocyclic Scaffolds I: ß-Lactams (Topics in Heterocyclic Chemistry)

Organolithiums in Enantioselective Synthesis (Topics in Organometallic Chemistry Volume 5)

Metal Catalyzed Cascade Reactions (Topics in Organometallic Chemistry, Volume 19)

Catalytic Carbonylation Reactions (Topics in Organometallic Chemistry, Volume 18)

Heterocyclic Polymethine Dyes: Synthesis, Properties and Applications (Topics in Heterocyclic Chemistry)

QSAR and Molecular Modeling Studies in Heterocyclic Drugs II (Topics in Heterocyclic Chemistry)

Asymmetric Synthesis of Nitrogen Heterocycles

The Chemistry of Heterocycles: Structure, Reactions, Syntheses, and Applications

The Chemistry of Heterocycles: Structure, Reactions, Syntheses, and Applications

Organic Chemistry II (Organic Chemistry Reactions) (SparkCharts)

Synthesis of Heterocycles via Multicomponent Reactions II (Topics in Heterocyclic Chemistry, Volume 25)

Synthesis of Heterocycles via Multicomponent Reactions I (Topics in Heterocyclic Chemistry)

Synthesis of Heterocycles via Cycloadditions I (Topics in Heterocyclic Chemistry)

Phosphorus Heterocycles II (Topics in Heterocyclic Chemistry, Volume 21)

Synthesis of Heterocycles via Cycloadditions II

Heterocyclic Scaffolds II: Reactions and Applications of Indoles (Topics in Heterocyclic Chemistry, Volume 26)

Advances in Heterocyclic Chemistry, Volume 25

Heterocycles from Carbohydrate Precursors (Topics in Heterocyclic Chemistry)

Name Reactions in Heterocyclic Chemistry

Multicomponent Reactions

Natural Products via Enzymatic Reactions (Topics in Current Chemistry)

Multicomponent Reactions

Transition-Metal-Catalyzed Reactions in Heterocyclic Synthesis

Topics in current chemistry, 216, Stereoselective Heterocyclic Synthesis III

Progress in Heterocyclic Chemistry, Volume 13 (Progress in Heterocyclic Chemistry)

Progress in Heterocyclic Chemistry, Volume 20 (Progress in Heterocyclic Chemistry)

Progress in Heterocyclic Chemistry, Volume 19 (Progress in Heterocyclic Chemistry)

Progress in Heterocyclic Chemistry, Volume 9 (Progress in Heterocyclic Chemistry)

Aromaticity in Heterocyclic Compounds (Topics in Heterocyclic Chemistry)

Progress in Heterocyclic Chemistry, Volume 18 (Progress in Heterocyclic Chemistry) (Progress in Heterocyclic Chemistry)

Heterocyclic Scaffolds I: ß-Lactams (Topics in Heterocyclic Chemistry)

Heterocyclic Scaffolds I: ß-Lactams (Topics in Heterocyclic Chemistry)

Organolithiums in Enantioselective Synthesis (Topics in Organometallic Chemistry Volume 5)

Metal Catalyzed Cascade Reactions (Topics in Organometallic Chemistry, Volume 19)

Catalytic Carbonylation Reactions (Topics in Organometallic Chemistry, Volume 18)

Heterocyclic Polymethine Dyes: Synthesis, Properties and Applications (Topics in Heterocyclic Chemistry)

QSAR and Molecular Modeling Studies in Heterocyclic Drugs II (Topics in Heterocyclic Chemistry)

Asymmetric Synthesis of Nitrogen Heterocycles

The Chemistry of Heterocycles: Structure, Reactions, Syntheses, and Applications

The Chemistry of Heterocycles: Structure, Reactions, Syntheses, and Applications

Organic Chemistry II (Organic Chemistry Reactions) (SparkCharts)

Recommend Documents