De

Clercq

(Ed.)

C. Oliver Kappe, Alexander Stadler,and Doris Dallinger

50 Methods and Principles in Medicinal Chemistry

Microwaves in Organicand Medicinal Chemistry

AntiviralD

rugStrategies

Volume 52

Series Editors:R. Mannhold,H. Kubinyi,G. Folkers

www.wiley-vch.de

New viruses can arise very quickly and, if unchecked, result in majorpandemics. Obvious examples being the AIDS and SARS virus. In orderto deal with such imminent threats, drug development times need to becut short. This is only possible by relying on proven strategies andadapting them to the specific features of any new virus or virus variant.

By focusing on general molecular mechanisms of antiviral drugsrather than therapies for individual viruses, this ready reference providesthe critical knowledge needed to develop entirely novel therapeutics andto target new viruses. It is edited by Erik de Clercq, a world authority onantiviral drug discovery.

The volume covers a general discussion of antiviral strategies,followed by a broad survey of known viral targets, such as reversetranscriptases, proteases, neuraminidases, RNA polymerases, helicases,and primases, as well as their known inhibitors. The book also containsseveral case studies of recent successful antiviral drug development.

As a result, medicinal and pharmaceutical chemists, as well asvirologists will be able to pinpoint strategies for combating future viralpandemics.

Erik De Clercq, M.D., PhD, is currently President of the RegaFoundation, a member of the Belgian (Flemish) Royal Academyof Medicine and of the Academia Europaea, and a Fellow of theAmerican Association for the Advancement of Science. He is anactive Emeritus Professor of the Katholieke Universiteit Leuven(K.U.Leuven), Belgium. He is honorary doctor of the Universitiesof Ghent, Belgium, Athens, Greece, Ferrara, Italy, Jinan(Shandong), China, Charles (Prague), Czech Republic, andJihoceska (Ceské Budejovice), Czech Republic, and Tours, France.

For his pioneering efforts in antiviral research, Professor DeClercq received in 1996 the Aventis award from the AmericanSociety for Microbiology, and in 2000 the Maisin Prize forBiomedical Sciences from the Belgian National ScienceFoundation. In 2008 he was elected Inventor of the Year by theEuropean Union. Jointly with Dr. Anthony Fauci, Prof. De Clercqreceived the Dr. Paul Janssen Award for Biomedical Research in2010.

He is the (co)inventor of a number of antiviral drugs, used forthe treatment of HSV (valaciclovir, Valtrex , Zelitrex ), VZV(brivudin, Zostex , Brivirac , Zerpex ), CMV (cidofovir, Vistide ),HBV (adefovir dipivoxil, Hepsera ), and HIV infections (AIDS)(tenofovir disoproxil fumarate, Viread ).

® ®

® ® ® ®

®

®

Second, Completely Revised andEnlarged Edition

57268File AttachmentCover.jpg

C. Oliver Kappe, Alexander

Stadler, and Doris Dallinger

Microwaves in Organic and

Medicinal Chemistry

Methods and Principles in Medicinal ChemistryEdited by R. Mannhold, H. Kubinyi, G. Folkers

Editorial Board

H. Buschmann, H. Timmerman, H. van de Waterbeemd, T. Wieland

Previous Volumes of this Series:

Smith, Dennis A. / Allerton, Charlotte /Kalgutkar, Amit S. / van de Waterbeemd,Han / Walker, Don K.

Pharmacokinetics andMetabolism in Drug DesignThird, Revised and Updated Edition

2012

ISBN: 978-3-527-32954-0

Vol. 51

De Clercq, Erik (Ed.)

Antiviral Drug Strategies2011

ISBN: 978-3-527-32696-9

Vol. 50

Klebl, Bert / Müller, Gerhard / Hamacher,Michael (Eds.)

Protein Kinases as Drug Targets2011

ISBN: 978-3-527-31790-5

Vol. 49

Sotriffer, Christoph (Ed.)

Virtual ScreeningPrinciples, Challenges, and Practical

Guidelines

2011

ISBN: 978-3-527-32636-5

Vol. 48

Rautio, Jarkko (Ed.)

Prodrugs and Targeted DeliveryTowards Better ADME Properties

2011

ISBN: 978-3-527-32603-7

Vol. 47

Smit, Martine J. / Lira, Sergio A. / Leurs,Rob (Eds.)

Chemokine Receptors as DrugTargets2011

ISBN: 978-3-527-32118-6

Vol. 46

Ghosh, Arun K. (Ed.)

Aspartic Acid Proteases asTherapeutic Targets2010

ISBN: 978-3-527-31811-7

Vol. 45

Ecker, Gerhard F. / Chiba, Peter (Eds.)

Transporters as Drug CarriersStructure, Function, Substrates

2009

ISBN: 978-3-527-31661-8

Vol. 44

Faller, Bernhard / Urban, Laszlo (Eds.)

Hit and Lead ProfilingIdentification and Optimization of

Drug-like Molecules

2009

ISBN: 978-3-527-32331-9

Vol. 43

Sippl, Wolfgang / Jung, Manfred (Eds.)

Epigenetic Targets in DrugDiscovery2009

ISBN: 978-3-527-32355-5

Vol. 42

C. Oliver Kappe, Alexander

Stadler, and Doris Dallinger

Microwaves in Organic andMedicinal Chemistry

Second, Completely Revised and Enlarged Edition

Series Editors

Prof. Dr. Raimund MannholdMolecular Drug Research GroupHeinrich-Heine-UniversitätUniversitätsstrasse 140225 DüsseldorfGermanymannhold@uni-duesseldorf.de

Prof. Dr. Hugo KubinyiDonnersbergstrasse 967256 Weisenheim am SandGermanykubinyi@t-online.de

Prof. Dr. Gerd FolkersCollegium HelveticumSTW/ETH Zurich8092 ZurichSwitzerlandfolkers@collegium.ethz.ch

The Authors

Prof. Dr. C. Oliver KappeKarl-Franzens-Universität GrazChristian Doppler LaboratoryHeinrichstrasse 288010 GrazAustria

Dr. Alexander StadlerAnton Paar GmbHAnton-Paar Str. 208054 GrazAustria

Dr. Doris DallingerKarl-Franzens-University GrazChristian Doppler LaboratoryHeinrichstrasse 288010 GrazAustria

All books published by Wiley-VCH are carefully produced.Nevertheless, authors, editors, and publisher do not warrantthe information contained in these books, including this book,to be free of errors. Readers are advised to keep in mind thatstatements, data, illustrations, procedural details or otheritems may inadvertently be inaccurate.

Library of Congress Card No.: applied for

British Library Cataloguing-in-Publication DataA catalogue record for this book is available from the BritishLibrary.

Bibliographic information published bythe Deutsche NationalbibliothekThe Deutsche Nationalbibliothek lists this publication in theDeutsche Nationalbibliografie; detailed bibliographic data areavailable on the Internet at http://dnb.d-nb.de.

# 2012 Wiley-VCH Verlag & Co. KGaA,Boschstr. 12, 69469 Weinheim, Germany

All rights reserved (including those of translationinto other languages). No part of this book may be reproducedin any form – by photoprinting, microfilm, or any othermeans– nor transmitted or translated into a machine languagewithout written permission from the publishers. Registerednames, trademarks, etc. used in this book, even when notspecifically marked as such, are not to be consideredunprotected by law.

Print ISBN: 978-3-527-33185-7ePDF ISBN: 978-3-527-64785-9ePub ISBN: 978-3-527-64784-2mobi ISBN: 978-3-527-64783-5oBook ISBN: 978-3-527-64782-8

Cover Design Grafik-Design, Schulz FußgönheimTypesetting Thomson Digital, Noida, IndiaPrinting and Binding betz-druck GmbH, Darmstadt,Germany

Printed on acid-free paper.

Contents

Preface XIPersonal Foreword to the First Edition XIIIPersonal Foreword to the Second Edition XV

1 Introduction: Microwave Synthesis in Perspective 11.1 Microwave Synthesis and Medicinal Chemistry 11.2 Microwave-Assisted Organic Synthesis (MAOS): A Brief History 31.3 Scope and Organization of the Book 6

References 7

2 Microwave Theory 92.1 Microwave Radiation 92.2 Microwave Dielectric Heating 112.3 Dielectric Properties 132.4 Microwave versus Conventional Thermal Heating 162.5 Microwave Effects 182.5.1 Temperature Monitoring in Microwave Chemistry 202.5.2 Thermal Effects (Kinetics) 262.5.3 Specific Microwave Effects 292.5.4 Nonthermal (Athermal) Microwave Effects 34

References 36

3 Equipment Review 413.1 Introduction 413.2 Domestic Microwave Ovens 423.3 Dedicated Microwave Reactors for Organic Synthesis 433.4 Single-Mode Instruments 463.4.1 Anton Paar GmbH 463.4.1.1 Monowave 300 463.4.2 Biotage AB 493.4.2.1 Initiator Platform 493.4.2.2 Chemspeed SWAVE 51

V

3.4.2.3 Peptide Synthesizers 523.4.3 CEM Corporation 543.4.3.1 Discover Platform 543.4.3.2 Explorer Systems 563.4.3.3 Voyager System 573.4.3.4 Peptide Synthesizers 583.5 Multimode Instruments 593.5.1 Anton Paar GmbH 593.5.1.1 Synthos 3000 593.5.1.2 Masterwave Benchtop Reactor 633.5.2 Biotage AB 653.5.3 CEM Corporation 663.5.3.1 MARS Scale-Up System Accessories 683.5.3.2 MARS Parallel System Accessories 693.5.4 Milestone s.r.l 703.5.4.1 MultiSYNTH System 703.5.4.2 MicroSYNTH Labstation 723.5.4.3 StartSYNTH 763.5.4.4 Scale-Up Systems 773.5.4.5 Microwave-Heated Autoclave Systems 79

References 80

4 Microwave Processing Techniques 834.1 Solvent-Free Reactions 834.2 Phase-Transfer Catalysis 854.3 Open- versus Closed-Vessel Conditions 874.4 Pre-pressurized Reaction Vessels 914.5 Nonclassical Solvents 964.5.1 Water as Solvent 964.5.2 Ionic Liquids 984.6 Passive Heating Elements 1044.7 Processing Techniques in Drug Discovery and High-Throughput

Synthesis 1074.7.1 Automated Sequential versus Parallel Processing 1084.7.2 High-Throughput Synthesis Methods 1204.7.2.1 Solid-Phase Synthesis 1214.7.2.2 Soluble Polymer-Supported Synthesis 1244.7.2.3 Fluorous-Phase Organic Synthesis 1254.7.2.4 Polymer-Supported Reagents, Catalysts, and Scavengers 1264.8 Scale-Up in Batch and Continuous Flow 1314.8.1 Scale-Up in Batch and Parallel 1324.8.2 Scale-Up Using Continuous Flow Techniques 1354.8.3 Scale-Up Using Stop-Flow Techniques 1374.8.4 Microwave Reactor Systems for Production Scale 139

References 141

VI Contents

5 Literature Survey Part A: Transition Metal-Catalyzed Reactions 1515.1 General Comments 1515.2 Carbon–Carbon Bond Formations 1515.2.1 Heck Reactions 1535.2.2 Suzuki–Miyaura Reactions 1625.2.3 Sonogashira Reactions 1845.2.4 Stille Reactions 1985.2.5 Negishi, Kumada, and Related Reactions 1985.2.6 Carbonylation Reactions 2035.2.7 Asymmetric Allylic Alkylations 2125.2.8 Miscellaneous Carbon–Carbon Bond-Forming Reactions 2205.3 Carbon–Heteroatom Bond Formations 2325.3.1 Buchwald–Hartwig Reactions 2325.3.2 Ullmann Condensation Reactions 2405.3.3 Miscellaneous Carbon–Heteroatom Bond-Forming Reactions 2455.4 Other Transition Metal-Mediated Processes 2515.4.1 Ring-Closing Metathesis and Cross-Metathesis 2515.4.2 Pauson–Khand Reactions 2605.4.3 Carbon–Hydrogen Bond Activation 2615.4.4 Copper-Catalyzed Azide–Acetylene Cycloaddition (CuAAC) 2675.4.5 Miscellaneous Reactions 269

References 275

6 Literature Survey Part B: Miscellaneous OrganicTransformations 297

6.1 Rearrangement Reactions 2976.1.1 Claisen Rearrangements 2976.1.2 Domino/Tandem Claisen Rearrangements 2996.1.3 Squaric Acid–Vinylketene Rearrangements 3036.1.4 Vinylcyclobutane–Cyclohexene Rearrangements 3036.1.5 Miscellaneous Rearrangements 3046.2 Cycloaddition Reactions 3096.2.1 Diels–Alder Reactions 3096.2.2 Miscellaneous Cycloadditions 3196.3 Oxidations 3226.4 Reductions and Hydrogenations 3256.5 Mitsunobu Reactions 3326.6 Glycosylation Reactions and Related Carbohydrate-Based

Transformations 3336.7 Organocatalytic Transformations 3416.8 Organometallic Transformations (Mg, Zn, and Ti) 3436.9 Multicomponent Reactions 3476.10 Alkylation Reactions 3686.11 Nucleophilic Aromatic Substitutions 3736.12 Ring-Opening Reactions 381

Contents VII

6.12.1 Cyclopropane and Cyclobutene Ring Openings 3816.12.2 Aziridine Ring Openings 3826.12.3 Epoxide Ring Openings 3836.13 Addition and Elimination Reactions 3876.13.1 Michael Additions 3876.13.2 Addition to Alkynes 3896.13.3 Addition to Alkenes 3916.13.4 Addition to Nitriles 3926.13.5 Elimination Reactions 3936.14 Substitution Reactions 3946.15 Enamine and Imine Formations 4016.16 Reductive Aminations 4036.17 Ester and Amide Formation 4066.18 Decarboxylation Reactions 4126.19 Free Radical Reactions 4146.20 Protection/Deprotection Chemistry 4186.21 Preparation of Isotopically Labeled Compounds 4226.22 Miscellaneous Transformations 425

References 433

7 Literature Survey Part C: Heterocycle Synthesis 4497.1 Three-Membered Heterocycles with One Heteroatom 4497.2 Four-Membered Heterocycles with One Heteroatom 4497.3 Five-Membered Heterocycles with One Heteroatom 4507.3.1 Pyrroles 4507.3.2 Furans 4597.3.3 Thiophenes 4617.4 Five-Membered Heterocycles with Two Heteroatoms 4617.4.1 Pyrazoles 4617.4.2 Imidazoles 4657.4.3 Isoxazoles 4717.4.4 Oxazoles 4747.4.5 Thiazoles 4787.5 Five-Membered Heterocycles with Three Heteroatoms 4837.5.1 1,2,3-Triazoles 4837.5.2 1,2,4-Triazoles 4847.5.3 1,2,4-Oxadiazoles 4857.5.4 1,3,4-Oxadiazoles 4867.5.5 1,3,2-Diazaphospholidines 4867.6 Five-Membered Heterocycles with Four Heteroatoms 4877.7 Six-Membered Heterocycles with One Heteroatom 4887.7.1 Piperidines 4887.7.2 Pyridines 4897.7.3 Pyrans 5017.8 Six-Membered Heterocycles with Two Heteroatoms 505

VIII Contents

7.8.1 Pyrimidines 5057.8.2 Pyrazines 5157.8.3 Pyridazines 5207.8.4 Oxazines 5207.8.5 Thiazines 5237.9 Six-Membered Heterocycles with Three Heteroatoms 5247.10 Larger Heterocyclic and Polycyclic Ring Systems 527

References 534

8 Literature Survey Part D: Combinatorial Chemistryand High-Throughput Organic Synthesis 543

8.1 Solid-Phase Organic Synthesis 5438.1.1 Peptide Synthesis and Related Examples 5438.1.2 Resin Functionalization 5498.1.3 Transition Metal Catalysis 5568.1.4 Substitution Reactions 5638.1.5 Multicomponent Chemistry 5708.1.6 Condensation Reactions 5728.1.7 Rearrangements 5748.1.8 Cleavage Reactions 5768.1.9 Miscellaneous 5818.2 Soluble Polymer-Supported Synthesis 5878.3 Fluorous-Phase Organic Synthesis 5998.4 Grafted Ionic Liquid-Phase-Supported Synthesis 6098.5 Polymer-Supported Reagents 6138.6 Polymer-Supported Catalysts 6268.6.1 Catalysts on Polymeric Support 6278.6.2 Silica-Grafted Catalysts 6348.6.3 Catalysts Immobilized on Glass 6348.6.4 Catalysts Immobilized on Carbon 6368.6.5 Miscellaneous 6378.7 Polymer-Supported Scavengers 639

References 642

Index 649

Contents IX

Preface

The application of microwaves marks a real revolution in synthetic organicchemistry. Although it was more or less a curiosity, only a few decades ago, therapid development within this field made it necessary to come up with a second,completely revised edition of the standard monograph, Microwaves in Organic andMedicinal Chemistry, by Oliver Kappe and Alexander Stadler, published in this bookseries in 2005. Indeed, the current edition is not just an updated version, but acompletely newmonograph as one can see from the increase in size, from originally409 pages to almost 700 pages! An enormous amount of recent literature has beenconsidered and included, making these two volumes now the new ‘‘gold standard’’ ofmicrowave chemistry.

Especially in medicinal chemistry, yield and elegance of the synthesis of a newcompound are no issue – only a minor amount of pure material is needed to screenfor biological properties. Only later and only for a negligibly small number ofpotential candidates, better synthetic strategies have to be developed. Thus, micro-wave-supported synthesis is the first choice to quickly (and simply) create a multi-tude of test compounds.

We, the editors of the book seriesMethods and Principles inMedicinal Chemistry,are very grateful to Oliver Kappe, Alexander Stadler, and Doris Dallinger for havingundertaken this enormous effort. We are also grateful to Frank Weinreich for hisongoing engagement in our book series and to Heike Noethe, both at Wiley-VCHVerlag GmbH, for her editorial support.

January 2012Düsseldorf Raimund MannholdWeisenheim am Sand Hugo KubinyiZurich Gerd Folkers

XI

Personal Foreword to the First Edition

We are currently witnessing an explosive growth in the general field of microwavechemistry. The increase of interest in this technology stems from the realization thatmicrowave-assisted synthesis, apart frommany other enabling technologies, actuallyprovides significant practical and economic advantages. Although microwavechemistry is currently used in both academic and industrial contexts, the impacton the pharmaceutical industry especially has developedmicrowave-assisted organicsynthesis (MAOS) from a laboratory curiosity in the 1980s and 1990s to a fullyaccepted technology today. Thefield has grown such that nearly every pharmaceuticalcompany and more and more academic laboratories now actively utilize thistechnology for their research.

One of the main barriers facing a synthetic chemist contemplating to usemicrowave synthesis today is – apart from access to suitable equipment – obtainingeducation and information on the fundamental principles and possible applicationsof this new technology. Thus, the aim of this book is to give the reader a well-structured, up-to-date, and exhaustive overview of known synthetic proceduresinvolving the use of microwave technology and to illuminate the black box stigmathat microwave chemistry still has.

Our main motivation for writing Microwaves in Organic and Medicinal Chemistryderived from our experience in teaching microwave chemistry in the form of shortcourses and workshops to researchers from the pharmaceutical industry. In fact, thestructure of this book closely follows a course developed for the American ChemicalSociety and can be seen as a compendium for this course. It is hoped that some of thechapters of this book are sufficiently convincing as to encourage scientists not only tousemicrowave synthesis in their research but also to offer training for their studentsor coworkers.

We would like to thank Hugo Kubinyi for his encouragement and motivation towrite this book. Thanks are also due toMats Larhed, Nicholas E. Leadbeater, Erik Vander Eycken, and scientists from Anton Paar GmbH, Biotage AB, CEM Corp., andMilestone srl, who have been kind enough to read various sections of this book and toprovide valuable suggestions. First and foremost, we would like to thank DorisDallinger, Bimbisar Desai, Toma Glasnov, Jenny Kremsner, and other members ofthe Kappe research group for spending their time searching the microwave

jXIII

literature and for tolerating this distraction. We are particularly indebted to DorisDallinger for carefully proofreading the complete text and to Jenny Wheedby forproviding the cover art. We are very grateful to Dr. FrankWeinreich and other editorsat Wiley-VCH Verlag GmbH for their assistance in bringing out this book.

This book is dedicated to Rajender S. Varma, a pioneer in the field of microwavesynthesis, who inspired us to enter this exciting research area in the 1990s.

Graz, Austria C. Oliver KappeDecember 2004 Alexander Stadler

XIVj Personal Foreword to the First Edition

Personal Foreword to the Second Edition

In more than 6 years since the manuscript submission for the first edition ofMicrowaves in Organic and Medicinal Chemistry, many things have changed. Incontrast to 2004, microwave chemistry now is truly an established technology,especially in the pharmaceutical industry. Most medicinal chemists are now soaccustomed to this nonclassical form of heating that taking their microwave reactorsaway from them would probably cause significant chaos in the laboratory. To asomewhat smaller extent, dedicated microwave instruments are however slowlyreplacing oil baths and heating mantles in many academic labs. Importantly, thespeculation and confusion about microwave effects that persisted for many yearshave now subsided and most scientists today accept the fact that microwavechemistry is a great way to heat reaction mixtures in sealed tubes with very accuratecontrol of the reaction parameters and to do synthesis in general.

Based on these facts, we now present the second, extensively updated, edition ofMicrowaves in Organic and Medicinal Chemistry. This edition covers the literature tillearly 2011, which has led to a significant increase in the number of references andexamples inmost chapters.We have tried not to greatly increase the page numbers ofthe introductory Chapters 1–4, but rather to selectively update the fundamental andmore technical information on the concept of microwave chemistry containedtherein (removing some outdated content). Having the practicing organic andmedicinal chemist in mind, most of the changes and additions have occurred inthe chapters (now Chapters 5–8) describing the examples of microwave chemistry.Close to 1000 additional references have been included in these chapters. We hopethat this revised versionwill become an indispensable referencework for all chemistsinterested in microwave chemistry.

Graz, Austria C. Oliver KappeJuly 2011 Alexander Stadler

Doris Dallinger

jXV

1Introduction: Microwave Synthesis in Perspective

1.1Microwave Synthesis and Medicinal Chemistry

Improving research and development (R&D) productivity is one of the biggesttasks facing the pharmaceutical industry. In a few years, the pharmaceutical industrywill see many patents of drugs expire. In order to remain competitive, pharmacompanies need to pursue strategies that will offset the sales decline and seerobust growth and improved shareholder value. The impact of genomics andproteomics is creating an explosion in the number of drug targets. Todays drugtherapies are solely based on approximately 500 biological targets; in a few yearstime, it is expected that the number of targets will well reach 10 000. In order toidentify more potential drug candidates for all these targets, pharmaceutical com-panies have made major investments in high-throughput technologies for genomicand proteomic research, automated/parallel chemistry, and biological screening.However, lead compound optimization and medicinal chemistry remain one of thebottlenecks in the drug discovery process. Developing chemical compounds with thedesired biological properties is time-consuming and expensive. Consequently,increasing interest is being directed toward technologies that allow more rapidsynthesis and screening of chemical substances to identify compounds with func-tional qualities.

Medicinal chemistry has benefited tremendously from the technologicaladvances in the field of combinatorial chemistry and high-throughput synthesis.This discipline has been an innovative machine for the development of methods andtechnologies that accelerate the design, synthesis, purification, and analysis ofcompound libraries. These new tools have had a significant impact on both leadidentification and lead optimization in the pharmaceutical industry. Large compoundlibraries can now be designed and synthesized to provide valuable leads for newtherapeutic targets.Once a chemist develops a suitable high-speed synthesis of a lead,it becomes possible to synthesize and purify hundreds of molecules in parallel

Microwaves in Organic and Medicinal Chemistry, Second Edition.C. Oliver Kappe, Alexander Stadler, and Doris Dallinger.� 2012 Wiley-VCH Verlag GmbH & Co. KGaA. Published 2012 by Wiley-VCH Verlag GmbH & Co. KGaA.

j1

to discover new leads and/or derive structure–activity relationships (SAR) inunprecedented timeframes.

The bottleneck of conventional parallel/combinatorial synthesis is typicallyoptimization of reaction conditions to afford the desired products in high yieldsand with suitable purities. Since many reaction sequences require at least one ormore heating steps for extended time periods, these optimizations are often difficultand time-consuming. Microwave-assisted heating under controlled conditions hasbeen shown to be an invaluable technology for medicinal chemistry and drugdiscovery applications since it often dramatically reduces reaction times, typicallyfrom days or hours to minutes or even seconds. Many reaction parameters can beevaluated in a few hours to optimize the desired chemistry. Compound libraries canthen be rapidly synthesized in either a parallel or (automated) sequential formatusing this new, enabling technology. In addition, microwave synthesis allows thediscovery of novel reaction pathways that serve to expand chemical space in generaland biologically relevant, medicinal chemistry space in particular.

Specifically, microwave synthesis has the potential to impact upon medicinalchemistry efforts in at least three major phases of the drug discovery process: leadgeneration, hit-to-lead efforts, and lead optimization. Medicinal chemistry addresseswhat are fundamentally biological and clinical problems. Focusing first on thepreparation of suitable molecular tools for mechanistic validation, efforts ultimatelyturn to the optimization of biochemical, pharmacokinetic, pharmacological, clinical,and competitive properties of drug candidates. A common theme throughout thisdrug discovery and development process is speed. Speed equals competitive advan-tage, more efficient use of expensive and limited resources, faster exploration ofstructure–activity relationship, enhanced delineation of intellectual property, moretimely delivery of critically neededmedicines, and ultimately determines positioningin the marketplace. To the pharmaceutical industry and the medicinal chemist, timetruly does equal money, and microwave chemistry has become a central tool in thisfast-paced, time-sensitive field.

Chemistry, like all sciences, consists of never-ending iterations of hypotheses andexperiments, with results guiding the progress and development of projects. Theshort reaction times provided bymicrowave synthesismake it ideal for rapid reactionscouting and optimization, allowing very rapid progress through the hypotheses–experiment–results iterations, resulting in more decision points per time unit. Inorder to fully benefit from microwave synthesis, one has to be prepared to fail inorder to succeed. While failure could cost a few minutes, success would gain manyhours or even days. The speed at whichmultiple variations of reaction conditions canbe performed allows a morning discussion of What should we try? to become anafter lunch discussion of What were the results? (the lets talk after lunchmantra) [1]. Not surprisingly, therefore, most pharmaceutical, agrochemical, andbiotechnology companies are already heavily using microwave synthesis as frontlinemethodology in their chemistry programs, both for library synthesis and for leadoptimization, as they realize the ability of this enabling technology to speed chemicalreactions and therefore the drug discovery process.

2j 1 Introduction: Microwave Synthesis in Perspective

1.2Microwave-Assisted Organic Synthesis (MAOS): A Brief History

While fire is now rarely used in synthetic chemistry, it was not until Robert Bunseninvented the burner in 1855 that the energy from this heat source could be applied to areaction vessel in a focusedmanner. The Bunsen burner was later superseded by theisomantle, the oil bath, or the hot plate as a means of applying heat to a chemicalreaction. In the past few years, heating and driving chemical reactions by microwaveenergy has been an increasingly popular theme in the scientific community [1, 2].

Microwave energy, originally applied for heating foodstuff by Percy Spencer in the1940s, has found a variety of technical applications in the chemical and relatedindustries since the 1950s, in particular in food processing, drying, and polymerindustries. Other applications range from analytical chemistry (microwave digestion,ashing, and extraction) [3] to biochemistry (protein hydrolysis and sterilization)[3], pathology (histoprocessing and tissue fixation) [4], to medical treatments(diathermy) [5]. Somewhat surprisingly, microwave heating has only been implemen-ted in organic synthesis since themid-1980s. Thefirst reports on theuse ofmicrowaveheating to accelerate organic chemical transformations (MAOS) were published 25years ago by the groups ofGedye et al. (Scheme 1.1) [6] andGiguere et al. [7] in 1986. Inthose early days, experimentswere typically carried out in sealedTeflonor glass vesselsin a domestic household microwave oven without any temperature or pressuremeasurements. The results were often violent explosions due to the rapid uncon-trolled heating of organic solvents under closed-vessel conditions. In the 1990s,several groups started to experimentwith solvent-freemicrowave chemistry (so-calleddry media reactions), which eliminated the danger of explosions [8]. Here, thereagents were preadsorbed onto either a more or less microwave-transparent (i.e.,silica, alumina, or clay) or strongly absorbing (i.e., graphite) inorganic support thatadditionally may have been doped with a catalyst or reagent. Particularly in the earlydays ofMAOS, the solvent-free approachwas very popular since it allowed the safe useof domestic microwave ovens and standard open-vessel technology. While a largenumber of interesting transformations using dry media reactions have beenpublished in the literature [8], technical difficulties relating to nonuniform heating,mixing, and the precise determination of the reaction temperature remainedunsolved, in particular when scale-up issues needed to be addressed.

O

NH220% H2SO4

MW or thermal

O

OH

thermal: 1 h, 90 % (reflux)MW: 10 min, 99 % (sealed vessel)

Scheme 1.1 Hydrolysis of benzamide. The first published example (1986) of microwave-assistedorganic synthesis.

1.2 Microwave-Assisted Organic Synthesis (MAOS): A Brief History j3

Alternatively, microwave-assisted synthesis has been carried out using standardorganic solvents under open-vessel conditions. If solvents are heated by microwaveirradiation at atmospheric pressure in an open vessel, the boiling point of the solventtypically limits the reaction temperature that can be achieved. Nonetheless, in orderto achieve high reaction rates, high-boiling microwave-absorbing solvents have beenfrequently used in an open-vessel microwave synthesis [9]. However, the use of thesesolvents presented serious challenges in relation to product isolation and recycling ofthe solvent. Because of the recent availability of modern microwave reactors withonline monitoring of both temperature and pressure, MAOS in dedicated sealedvessels using standard solvents – a technique pioneered by Christopher R. Strauss inthe mid-1990s [10] – has been celebrating a comeback in recent years. This is clearlyevident surveying the recently published (since 2001) literature in the area ofcontrolled microwave-assisted organic synthesis (Figure 1.1). In addition to theprimary and patent literature, many review articles, several books, special issues ofjournals, feature articles, online databases, information on theWorldWideWeb, andeducational publications provide extensive coverage of the subject (see Section 5.1 fora comprehensive survey). Among the approximately 1000 original publications thatappeared in 2010 describing microwave-assisted reactions under controlled condi-tions, a careful analysis demonstrates that in about 90% of all cases, sealed-vesselprocessing (autoclave technology) in dedicated single-mode microwave instrumentshas been employed. A 2007 survey has however found that as many as 30% of allpublished MAOS papers still employ kitchen microwave ovens [11], a practice

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Figure 1.1 Publications on microwave-assisted organic synthesis (1986–2010). Graygraphs: Number of articles involving MAOS forseven selected synthetic organic chemistryjournals (Journal of Organic Chemistry, OrganicLetters, Tetrahedron, Tetrahedron Letters,Synthetic Communications, Synthesis, andSynlett; SciFinder scholar search, keyword:

microwave). The black graphs representthe number of publications (2001–2008)reporting MAOS experiments in dedicatedreactors with adequate process control(about 50 journals, full text search: microwave).Data for 2009 and 2010 are not available, butare estimated to be in the 1000–1200publications per year range.

4j 1 Introduction: Microwave Synthesis in Perspective

banned bymost of the respected scientific journals today. For example, the AmericanChemical Society (ACS) organic chemistry journals will typically not considermanuscripts describing the use of kitchen microwave ovens or the absence of areaction temperature as specified in the relevant author guidelines [12].

Since the early days of microwave synthesis, the observed rate accelerations andsometimes altered product distributions compared to oil bath experiments have ledto speculation on the existence of so-called specific or nonthermal microwaveeffects [13]. Historically, such effects were claimed when the outcome of a synthesisperformedundermicrowave conditionswas different from that of the conventionallyheated counterpart at the same apparent temperature. Reviewing the presentliterature [14, 15], it appears that today most scientists agree that in the majorityof cases the observed rate enhancement is a purely thermal/kinetic effect, that is, aconsequence of the high reaction temperatures that can rapidly be attained whenirradiating polar materials in a microwave field, although effects that are caused bythe unique nature of the microwave dielectric heating mechanism (specific micro-wave effects) also need to be considered.While for themedicinal chemist in industry,this discussion may seem futile, the debate on microwave effects is undoubtedlygoing to continue for a few years in the academic world. Regardless of the nature ofthe observed rate enhancements (for further details on microwave effects, seeSection 2.5), microwave synthesis has now truly matured and has moved from alaboratory curiosity in the late 1980s to an established technique in organic synthesis,heavily used in both academia and industry.

The initially slow uptake of the technology in the late 1980s and 1990s has beenattributed to its lack of controllability and reproducibility, coupled with a general lackof understanding of the basics of microwave dielectric heating. The risks associatedwith theflammability of organic solvents in amicrowavefield and the lack of availablededicated microwave reactors allowing adequate temperature and pressure controlweremajor concerns. Important instrument innovations (see Chapter 3) now allow acareful control of time, temperature, and pressure profiles, paving the way forreproducible protocol development, scale-up, and transfer from laboratory to labo-ratory and scientist to scientist. Today, microwave chemistry is as reliable as the vastarsenal of synthetic methods that preceded it. Since 2001, therefore, the number ofpublications related to MAOS has increased dramatically (Figure 1.1) to such a levelthat it might be assumed that in a few years, many more chemists than today willprobably usemicrowave energy to heat chemical reactions on a laboratory scale [1, 2].However, it should be emphasized that the potential for growth is still very large as arecent survey has found that less than 10% of all publications in synthetic organicchemistry currently make use of microwave technology [15].

Recent innovations in microwave reactor technology now allow controlled paralleland automated sequential processing under sealed-vessel conditions and the use ofcontinuous or stop-flow reactors for scale-up purposes. In addition, dedicated vesselsfor solid-phase synthesis, for performing transformations using pre-pressurizedconditions and for a variety of other special applications, have been developed. Today,there are four major instrument vendors that produce microwave instrumentationdedicated toward organic synthesis. All those instruments offer temperature and

1.2 Microwave-Assisted Organic Synthesis (MAOS): A Brief History j5

pressure sensors, built-in magnetic stirring, power control, software operation, andsophisticated safety controls. The number of users of dedicatedmicrowave reactors istherefore growing at a rapid rate, and it appears only to be a question of time untilmost laboratories will be equipped with suitable microwave instrumentation.

In the past, microwave chemistry was often used only when all other options toperform a particular reaction failed or when exceedingly long reaction times or hightemperatures were required to complete a reaction. This practice is now slowlychanging and due to the growing availability of microwave reactors in manylaboratories, routine synthetic transformations are also now being carried out bymicrowave heating. One of themajor drawbacks of this relatively new technology stillis equipment cost. While prices for dedicated microwave reactors for organicsynthesis have come down considerably since their first introduction in the late1990s, the current price range for microwave reactors is still many times higher thanthat of conventional heating equipment. As with any new technology, the currentsituation is bound to change over the next several years and less expensive equipmentshould become available. By then, microwave reactors will have truly become theBunsen burners of the twenty first century and will be a standard equipment inevery chemical laboratory.

1.3Scope and Organization of the Book

Today, a large body of work on microwave-assisted synthesis exists in the publishedand patent literature. Many review articles, several books, and information on theWorld Wide Web already provide extensive coverage of the subject (see Section 5.1).The goal of the present book is to present carefully scrutinized, useful, and practicalinformation for advanced practitioners of microwave-assisted organic synthesis.Special emphasis is placed on concepts and chemical transformations that are ofimportance to medicinal chemists, and that have been reported in the most recentliterature (2002–2010). The extensive literature survey is limited to reactions thathave been performed using controlled microwave heating conditions, that is,where dedicated microwave reactors for synthetic applications with adequatetemperature and pressure measurements have been employed. After a discussionofmicrowave dielectric heating theory andmicrowave effects (Chapter 2), a review ofthe existing equipment for performing MAOS will be presented (Chapter 3). This isfollowed by a chapter outlining the different processing techniques in a microwave-heated experiment (Chapter 4). Finally, a literature survey with more than 1500references will be presented in Chapters 5–8.

Beginners in the field of microwave-assisted organic synthesis are referred to arecent book containing a chapter with useful practical tips (How To Get Started)and an additional section with carefully selected and documented microwaveexperiments that may be used by scientists in academia to design a course onmicrowave-assisted organic synthesis [16].

6j 1 Introduction: Microwave Synthesis in Perspective

References

1 Leadbeater, N. (2004) Chemistry World, 1,38–41.

2 (a) Adam, D. (2003)Nature, 421, 571–572;(b) Marx, V. (2004) Chemical andEngineering News, 82 (50), 14–19;(c) Yarnell, A. (2007) Chemical andEngineering News, 85 (21), 32–33.

3 Kingston, H.M. and Haswell, S.J. (eds)(1997) Microwave-Enhanced Chemistry:Fundamentals, Sample Preparation andApplications, American Chemical Society,Washington.

4 Giberson, R.T. and Demaree, R.S. (eds)(2001)Microwave Techniques and Protocols,Humana Press, Totowa, NJ.

5 Prentice, W.E., (2002) TherapeuticModalities for Physical Therapists, McGraw-Hill, New York.

6 Gedye,R., Smith, F.,Westaway, K., Ali,H.,Baldisera, L., Laberge, L., and Rousell, J.(1986) Tetrahedron Letters, 27, 279–282.

7 Giguere, R.J., Bray, T.L., Duncan, S.M.,and Majetich, G. (1986) TetrahedronLetters, 27, 4945–4958.

8 (a) Loupy, A., Petit, A., Hamelin, J.,Texier-Boullet, F., Jacquault, P., andMath�e, D. (1998) Synthesis, 1213–1234;(b) Varma, R.S. (1999) Green Chemistry,43–55.

9 (a) Bose, A.K., Banik, B.K., Lavlinskaia, N.,Jayaraman, M., and Manhas, M.S. (1997)Chemtech, 27, 18–24; (b) Bose, A.K.,Manhas, M.S., Ganguly, S.N.,Sharma, A.H., and Banik, B.K. (2002)Synthesis, 1578–1591.

10 (a) Strauss, C.R. and Trainor, R.W. (1995)Australian Journal of Chemistry, 48,1665–1692; (b) Strauss, C.R. (1999)Australian Journal of Chemistry, 52,83–96.

11 Moseley, J.D., Lenden, P., Thomson, A.D.,and Gilday, J.P. (2007) Tetrahedron Letters,48, 6084–6087 (Ref. 13).

12 (2011) The Journal of Organic Chemistry,76 (1), Author Guidelines.

13 (a) Perreux, L. and Loupy, A. (2001)Tetrahedron, 57, 9199–9223; (b) Perreux, L.and Loupy, A. (2006) Chapter 4, inMicrowaves in Organic Synthesis,2nd edn (ed. A. Loupy),Wiley-VCHVerlagGmbH, Weinheim, pp. 134–218;(c) de la Hoz, A., D�ıaz-Ortiz, A., andMoreno, A. (2005) Chemical SocietyReviews, 34, 164–178; (d) de la Hoz, A.,Diaz-Ortiz, A., and Moreno, A. (2006)Chapter 5, in Microwaves in OrganicSynthesis, 2nd edn (ed. A. Loupy),Wiley-VCH Verlag GmbH, Weinheim,pp. 219–277.

14 (a) Caddick, S. and Fitzmaurice, R. (2009)Tetrahedron, 65, 3325–3355; (b)Kappe, C.O. and Dallinger, D. (2009)Molecular Diversity, 13, 71–193.

15 Leadbeater, N.E. (ed.) (2011) MicrowaveHeating as a Tool for Sustainable Chemistry,CRC Press, Boca Raton.

16 Kappe, C.O., Dallinger, D., andMurphree, S.S. (2009) Practical MicrowaveSynthesis for Organic Chemists, Wiley-VCHVerlag GmbH, Weinheim.

Referencesj7

2Microwave Theory

The physical principles behind and the factors determining the successful applica-tion of microwaves in organic synthesis are not widely familiar to chemists.Nevertheless, it is essential for the synthetic chemist involved in microwave-assistedorganic synthesis to have at least a basic knowledge of the underlying principles ofmicrowave–matter interactions and of the nature of microwave effects. The basicunderstanding of macroscopic microwave interactions with matter was formulatedby von Hippel in the mid-1950s [1]. In this chapter, a brief summary of the currentunderstanding of microwaves and their interactions with matter is given. For morein-depth discussion on this quite complexfield, the reader is referred to recent reviewarticles [2–5].

2.1Microwave Radiation

Microwave irradiation is an electromagnetic irradiation in the frequency range of0.3–300GHz, corresponding to wavelengths of 1mm–1m. Themicrowave region ofthe electromagnetic spectrum (Figure 2.1) therefore lies between infrared (IR) andradio frequencies. The major use of microwaves is either for transmission ofinformation (telecommunication) or for transmission of energy. Wavelengthsbetween 1mm and 25 cm are extensively used for RADAR transmissions and theremaining wavelength range is used for telecommunications. All domestic kitchenmicrowave ovens and all dedicated microwave reactors for chemical synthesis thatare commercially available today operate at a frequency of 2.45GHz (correspondingto a wavelength of 12.25 cm) in order to avoid interference with telecommunication,wireless networks, and cellular phone frequencies. There are other frequencyallocations for microwave heating applications (ISM (industrial, scientific, andmedical) frequencies (see Table 2.1) [6], but these are generally not employed indedicated reactors for synthetic chemistry. Indeed, published examples of organicsynthesis carried out withmicrowave heating at frequencies other than 2.45GHz areextremely rare [7].

Microwaves in Organic and Medicinal Chemistry, Second Edition.C. Oliver Kappe, Alexander Stadler, and Doris Dallinger.� 2012 Wiley-VCH Verlag GmbH & Co. KGaA. Published 2012 by Wiley-VCH Verlag GmbH & Co. KGaA.

j9

From comparison of the data presented in Table 2.2 [8], it is obvious thatthe energy of the microwave photon at a frequency of 2.45GHz (about 10�5 eV)is too low to cleave molecular bonds and is also lower than Brownian motion. It istherefore clear that microwaves cannot induce chemical reactions by directabsorption of electromagnetic energy, as opposed to ultraviolet and visible radiation(photochemistry).

Figure 2.1 The electromagnetic spectrum.

Table 2.1 ISM microwave frequencies.

Frequency (MHz) Wavelength (cm)

433.92� 0.2% 69.14915� 13 32.752450� 50 12.245800� 75 5.1724 125� 125 1.36

Data from Ref. [6].

Table 2.2 Comparison of radiation types and bond energies.

Radiation type Frequency(MHz)

Quantumenergy (eV)

Bond type Bondenergy (eV)

Gamma rays 3.0� 1014 1.24� 106 C�C 3.61X-Rays 3.0� 1013 1.24� 105 C¼C 6.35Ultraviolet 1.0� 109 4.1 C�O 3.74Visible light 6.0� 108 2.5 C¼O 7.71Infrared light 3.0� 106 0.012 C�H 4.28Microwaves 2450 1.01� 10�5 O�H 4.80Radio frequencies 1 4.0� 10�9 Hydrogen

bond0.04–0.44

Data from Refs [6, 8].

10j 2 Microwave Theory

2.2Microwave Dielectric Heating

Microwave chemistry is based on the efficient heating of materials by microwavedielectric heating effects [4, 5]. Microwave dielectric heating depends on the abilityof a specific material (e.g., a solvent or reagent) to absorb microwave energy andconvert it into heat. Microwaves are electromagnetic waves that consist of an electricand a magnetic field component (Figure 2.2). For most practical purposes related tomicrowave synthesis, it is the electric component of the electromagnetic field that isof importance for wave–material interactions, although in some instances magneticfield interactions (e.g., with metals or metal oxides) can also be of relevance [9, 10].

The electric component of an electromagnetic field causes heating by two mainmechanisms: dipolar polarization and ionic conduction. The interaction of theelectric field component with thematrix is called the dipolar polarizationmechanism(Figure 2.3a) [4, 5]. For a substance to be able to generate heat when irradiated withmicrowaves, it must possess a dipole moment. When exposed to microwavefrequencies, the dipoles of the sample align with the applied electric field. As thefield oscillates, the dipole field attempts to realign itself with the alternating electricfield and, in the process, energy is lost in the form of heat throughmolecular frictionand dielectric loss. The amount of heat generated by this process is directly related tothe ability of the matrix to align itself with the frequency of the applied field. If thedipole does not have enough time to realign (high-frequency irradiation) or itreorients too quickly (low-frequency irradiation) with the applied field, no heatingoccurs. The allocated frequency of 2.45GHz, used in all commercial systems, liesbetween these two extremes and gives the molecular dipole time to align in the fieldbut not to follow the alternating field precisely. Therefore, as the dipole reorients toalign itself with the electric field, the field is already changing and generates aphase difference between the orientation of the field and that of the dipole. Thisphase difference causes energy to be lost from the dipole by molecular friction andcollisions, giving rise to dielectric heating. In summary, field energy is transferred tothe medium and electrical energy is converted into kinetic or thermal energy andultimately into heat. It should be emphasized that the interaction betweenmicrowave

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electric component

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H

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2.45 GHz = 12.25 cm

= electric fieldH = magnetic fieldc = speed of light

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Figure 2.2 Electric and magnetic field components in microwaves.

2.2 Microwave Dielectric Heating j11

radiation and the polar solvent, which occurs when the frequency of the radiationapproximately matches the frequency of the rotational relaxation process, is not aquantum mechanical resonance phenomenon. Transitions between quantized rota-tional bands are not involved and the energy transfer is not a property of a specificmolecule but the result of a collective phenomenon involving the bulk [4, 5]. The heatis generated by frictional forces occurring between the polar molecules whoserotational velocity has been increased by the couplingwith themicrowave irradiation.It should also be noted that gases cannot be heated under microwave irradiation,since the distance between the rotating molecules is too far. Similarly, ice is also(nearly) microwave transparent, since the water dipoles are constrained in a crystallattice and cannot move as freely as in the liquid state.

The second major heating mechanism is the ionic conduction mechanism(Figure 2.3b) [4, 5]. During ionic conduction, as the dissolved charged particles ina sample (usually ions) oscillate back and forth under the influence of themicrowavefield, they collide with their neighboring molecules or atoms. These collisions causeagitation ormotion, creating heat. Thus, if two samples containing equal amounts ofdistilled water and tap water, respectively, are heated by microwave irradiation at afixed radiation power,more rapid heatingwill occur for the tapwater sample due to itsionic content. Such ionic conduction effects are particularly important when con-sidering the heating behavior of ionic liquids in amicrowave field (see Section 4.5.2).The conductivity principle is a much stronger effect than the dipolar rotationmechanism with regard to the heat-generating capacity.

A related heating mechanism exists for strongly conducting or semiconductingmaterials such asmetals, wheremicrowave irradiation can induce a flow of electronson the surface. This flow of electrons can heat the material through resistance(ohmic) heating mechanisms [11]. In the context of organic synthesis, this becomesimportant for heating strongly microwave-absorbing materials, such as thin metal

Figure 2.3 (a) Dipolar polarization mechanism. Dipolar molecules try to align with an oscillatingelectric field. (b) Ionic conduction mechanism. Ions in solution will move in the electric field.

12j 2 Microwave Theory