-
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
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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
Dü[email protected]
Prof. Dr. Hugo KubinyiDonnersbergstrasse 967256 Weisenheim am
[email protected]
Prof. Dr. Gerd FolkersCollegium HelveticumSTW/ETH Zurich8092
[email protected]
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
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# 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
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Print ISBN: 978-3-527-33185-7ePDF ISBN: 978-3-527-64785-9ePub
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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
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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
0100
200300400500
600700800
9001000
198619
8719
8819
8919
9019
9119
9219
9319
9419
9519
9619
9719
9819
9920
0020
0120
0220
0320
0420
0520
0620
0720
0820
0920
10
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
���
electric component
������������������������������������
C
H
magneticcomponent
2.45 GHz = 12.25 cm
= electric fieldH = magnetic fieldc = speed of light
= wavelength
λ
λ
εε
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