Synthesis of Heterocycles via Multicomponent Reactions II (Topics in Heterocyclic Chemistry, 25) 3642154549, 9783642154546

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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

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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

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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

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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

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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.

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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: