Practical synthetic organic chemistry

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PRACTICAL SYNTHETIC
ORGANIC CHEMISTRY


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PRACTICAL SYNTHETIC
ORGANIC CHEMISTRY
Reactions, Principles, and Techniques

Edited by
STE´PHANE CARON


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Copyright 2011 by John Wiley & Sons, Inc. All rights reserved
Published by John Wiley & Sons, Inc., Hoboken, New Jersey
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Library of Congress Cataloging-in-Publication Data:
Practical synthetic organic chemistry : reactions, principles, and techniques / edited by Stephane Caron.
p. cm.
Includes index.
ISBN 978-0-470-03733-1 (pbk.)
1. Organic compounds–Synthesis. I. Caron, Stephane.
QD262.P688 2011
547’.2–dc22
2011008293
Printed in the United States of America
oBooK ISBN: 978-1-118-09355-9
ePDF ISBN: 978-1-118-09357-3
ePub ISBN: 978-1-118-09356-6
10 9 8 7

6 5 4 3

2 1

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CONTENTS

Foreword

vii

Preface

ix

Contributors

xi

1

Aliphatic Nucleophilic Substitution

1

Jade D. Nelson

2

Addition to Carbon–Heteroatom Multiple Bonds

73

Rajappa Vaidyanathan and Carrie Brockway Wager

3

Addition to Carbon–Carbon Multiple Bonds

167

John A. Ragan

4

Nucleophilic Aromatic Substitution

237

Ste´phane Caron and Arun Ghosh

5

Electrophilic Aromatic Substitution

255

Ste´phane Caron

6

Selected Metal-Mediated Cross-Coupling Reactions

279

Ste´phane Caron, Arun Ghosh, Sally Gut Ruggeri, Nathan D. Ide, Jade D. Nelson,
and John A. Ragan

7

Rearrangements

341

David H.B. Ripin

8

Eliminations

383

Sally Gut Ruggeri

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vi

9

CONTENTS

Reductions

419

Sally Gut Ruggeri, Ste´phane Caron, Pascal Dube´, Nathan D. Ide,
Kristin E. Price, John A. Ragan, and Shu Yu

10

Oxidations

493

David H. Brown Ripin

11

Selected Free Radical Reactions

557

Nathan D. Ide

12

Synthesis of “Nucleophilic” Organometallic Reagents

575

David H. Brown Ripin

13

Synthesis of Common Aromatic Heterocycles

609

Ste´phane Caron

14

Access to Chirality

649

Robert W. Dugger

15

Synthetic Route Development of Selected Contemporary
Pharmaceutical Drugs

661

Ste´phane Caron

16

Green Chemistry

683

Juan C. Colberg

17

Naming Carbocycles and Heterocycles

703

Heather N. Frost and David H. Brown Ripin

18

pKa

771

David H. Brown Ripin

19

General Solvent Properties

805

Ste´phane Caron

20

Practical Chemistry Concepts: Tips for the Practicing Chemist or
Things They Don’t Teach You in School

819

Sally Gut Ruggeri

Functional Group Interconversion Index

837

Index

845


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FOREWORD

While all practitioners in the art recognize that synthetic organic chemistry serves society, it
is not always appreciated the other way around; namely that society does not associate the
phenomenal rewards that are derived from our ability to assemble complex functional
molecules. Indeed, the achievements of the pharmaceutical industry are underpinned by
molecular design and synthesis of virtually all the healing drug substances that are currently
on the market, which benefit mankind and cure human diseases.
There is, in my view, nothing nobler than this worthwhile task. However, synthesis of the

complex functional architectures is not a trivial or routine process. This is always made more
difficult on scaling up of the chemistries to comply with current standards of safety,
robustness, costs, quality, and environmental impact. I, therefore, very much welcome
this new textbook, Practical Synthetic Organic Chemistry: Reactions, Principles, and
Techniques, which gives us an inspiring and pragmatic glimpse at the most commonly
used and effective synthesis procedures on scale. This unique textbook has been written by
experts in the field and provides an insight and critique of the key effective methods for
molecular assembly. It will be a great starting point for anyone developing their career in this
worthy industry.
The organization and chapter titles reflect a refreshing approach to explaining a
complicated science covering all the major bond construction methods and functional
control elements necessary for modern synthetic planning and execution.
The authors have incorporated chapters on important topics such as the effectiveness of
rearrangement processes, radical reactions, access to chirality, and green chemistry, which
are not captured as a group in more traditional texts. Furthermore, the educational
component of this book highlighting nomenclature, pKa knowledge, solvent properties,
and tips of the trade from the practicing chemist again adds value in providing a feast of
information that otherwise is dispersed over many sources or is simply locked up in the
personal database of knowledge of those experienced in the art.

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viii

FOREWORD

The creative spirit of this area of science in bringing new functional molecules in our

world for the first time for the betterment of us all is enduring and will continue to seed new
discoveries for many years to come.
STEVEN V. LEY
Cambridge, UK
2011


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PREFACE

Despite the relative maturity of the field of organic chemistry, molecules continue to present
synthetic chemists with significant challenges, especially as the expectations for synthetic,
material, and energy efficiency continue to intensify. In response to these challenges, organic
chemists have continued to develop innovative new synthetic methods. Many of these
recently developed synthetic methods allow for achievement of ever more impressive
chemo-, enantio-, diastereo-, and regioselectivity. Additionally, new synthetic methods
are providing chemists with novel reactions and enabling synthetic strategies that would
have previously been impractical or impossible.
While we are fascinated by the multitude of powerful synthetic methods that have been
developed in recent years, these methods were not the direct inspiration for this book.
Instead, the impetus for this book was actually an article request for a special issue of
Chemical Reviews on process chemistry (Vol. 106, No. 7, July 2006). A group of Pfizer
process chemists, at the Groton (CT) site, elected to write a review of oxidations performed
on large scale. This review was divided among several authors and served as the basis for
Chapter 10 in this book.1 My personal contribution to the review article was the section
covering C–O oxidations, and I was surprised by what I learned upon further investigation of
this seemingly mundane topic. While a number of effective methods exist for the conversion
of primary alcohols to aldehydes, only two general methods have been used consistently and
successfully on manufacturing scale: Moffatt-type and TEMPO-mediated oxidations.

Upon completion of this review, I asked myself if this would be true for other chemical
transformations. Beyond simple curiosity, this question is relevant because search engines
like SciFinderỊ and ReaxysƠ can rapidly search through the chemical literature and
identify large numbers of potentially relevant reactions/references. For example, a simple
search for the nitration of an arene results in thousands of examples of this transformation.
How does one sort through this incredible wealth of information?

1

Caron, S.; Dugger, R. W.; Ruggeri, S. G.; Ragan, J. A.; Ripin, D. H. B. Chem. Rev. 2006, 106, 2943.

ix


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x

PREFACE

In this age of information overload, we thought that a simple collection of proven
methodologies might be of value to practicing synthetic chemists. While many textbooks
offer a compendium of the many synthetic methods that are available, we set out to create a
guide that would help select the first few conditions to attempt for a given transformation.
This might be of particular value when the substrate of interest is difficult to access in
sufficient quantities for a large screen of reaction conditions. The authors agreed that the
objective would not necessarily be to find the original report or the very best procedure for a
given reaction, but rather to identify reaction conditions that work reliably well over the
broadest possible range of substrates. It was a prerequisite for the references cited in this
textbook that experimental data was provided, preferably on a multi-gram scale, and

preferably using reaction conditions that would be amenable to scale-up. In the rare cases
where such experimental data was not identified, the authors used their discretion to select
reaction conditions that we would expect to scale up reasonably well. Not surprisingly, many
of the examples cited in this textbook come from Organic Syntheses or from journals like
Organic Process Research and Development and The Journal of Organic Chemistry.
We also agreed that patent literature would be avoided, if possible, since it is not always
easily accessed and/or interpreted. Finally, we made an effort to focus on references
published after 1980.
In addition to the compilation of reliable methods for accomplishing various chemical
transformations, we have tried to provide the reader with some information that may not be
common knowledge outside of process chemistry groups. The second portion of this book
focuses on this type of information. How can chiral building blocks be accessed most
efficiently? What are the most reliable methods for preparing and naming common
heterocycles? Why are some solvents favored over others? How does the synthesis of a
drug evolve throughout development? What does it mean to have a green synthesis? We hope
that readers will find some useful and practical information in this section of the book.
The completion of this endeavor would have never been possible without the commitment
of several of my colleagues at Pfizer who agreed to the preparation and collective review of
the chapters. We are also extremely grateful to our management for supporting the project.
I would specifically like to thank Jodi Gaynor, Lisa Lentini, and Kim White for their
administrative support. I would also like to thank Kris N. Jones for her assistance in editing
the book. The commitment and support of our collaborators at Wiley-Interscience are very
much appreciated. We especially appreciated their patience as our deadline came and passed.
Building each chapter of this manuscript served as an excellent chemistry refresher
course for the authors, and we learned a lot of new chemistry in the process. We sincerely
hope you enjoy the same experience as you read this book.


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CONTRIBUTORS

Stephane Caron, Senior Director, Chemical R&D, Pfizer Worldwide R&D, Eastern Point
Road, MS 8118D-4002, Groton CT, 06340,
Juan Colberg, API and Analytics Technology Leader, Technology & Strategic Sourcing,
Pfizer Worldwide R&D, Eastern Point Road, MS 8118D-4025, Groton CT, 06340,

Pascal Dube, Principal Scientist, Chemical R&D, Pfizer Worldwide R&D, Eastern Point
Road, MS 8118D-4060, Groton CT, 06340,
Robert W. Dugger, Research Fellow, Chemical R&D, Pfizer Worldwide R&D, Eastern
Point Road, MS 8118D-4031, Groton CT, 06340,
Heather N. Frost, Chemistry Sourcing Lead, External Research Solutions Center of
Emphasis, Pfizer Worldwide R&D, Eastern Point Rd, MS8200-4001, Groton, CT
06340,
Arun Ghosh, Arch Chemicals, Process Technologies Group, 350 Knotter Drive, Cheshire
CT, 06410,
Nathan D. Ide, Principal Scientist, Chemical R&D, Pfizer Worldwide R&D, Eastern Point
Road, MS 8118D-4058, Groton CT, 06340,
Jade D. Nelson, Associate Research Fellow, Chemical R&D, Pfizer Worldwide R&D,
Eastern Point Road, MS 8118D-4047, Groton, CT 06340,
Kristin E. Price, Senior Scientist, Chemical R&D, Pfizer Worldwide R&D, Eastern Point
Road, MS 8156-066, Groton, CT 06340,
John A. Ragan, Associate Research Fellow, Chemical R&D, Pfizer Worldwide R&D,
Eastern Point Road, MS 8118D-4010, Groton, CT 06340,

xi


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xii

CONTRIBUTORS

David H. Brown Ripin, Scientific Director, Drug Access Team, Clinton Health Access
Initiative, Boston, MA 02127,
Sally Gut Ruggeri, Associate Research Fellow, Research API, Pfizer Worldwide R&D,
Eastern Point Road, MS 8156-078, Groton, CT 06340,
Rajappa Vaidyanathan, Associate Research Fellow, Chemical R&D, Pfizer
Worldwide R&D, Eastern Point Road, MS 8118D-4067, Groton, CT 06340, rajappa.

Carrie B. Wager, Senior Principal Scientist, Chemical R&D, Pfizer Worldwide R&D,
Eastern Point Road, MS 8118D-4017, Groton, CT 06340,
Shu Yu, Associate Research Fellow, Chemical R&D, Pfizer Worldwide R&D, Eastern
Point Road, MS 8118D-4028, Groton, CT 06340,


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1
ALIPHATIC NUCLEOPHILIC
SUBSTITUTION
Jade D. Nelson

1.1 INTRODUCTION
Nucleophilic substitution reactions at an aliphatic center are among the most fundamental
transformations in classical synthetic organic chemistry, and provide the practicing chemist
with proven tools for simple functional group interconversion as well as complex targetoriented synthesis. Conventional SN2 displacement reactions involving simple nucleophiles
and electrophiles are well-studied transformations, are among the first concepts learned by
chemistry students and provide a launching pad for more complex subject matter such as

stereochemistry and physical organic chemistry.
A high level survey of the chemical literature provides an overwhelming mass of
information regarding aliphatic nucleophilic substitution reactions. This chapter attempts
to highlight those methods that stand out from the others in terms of scope, practicality, and
scalability.

1.2 OXYGEN NUCLEOPHILES
1.2.1

Reactions with Water

1.2.1.1 Hydrolysis of Alkyl Halides The reaction of water with an alkyl halide to form
the corresponding alcohol is rarely utilized in target-oriented organic synthesis. Instead,
conversion of alcohols to their corresponding halides is more common since methods for
the synthesis of halides are less abundant. Nonetheless, alkyl halide hydrolysis can provide
simple, efficient access to primary alcohols under certain circumstances. Namely, the
hydrolysis of activated benzylic or allylic halides is a facile reaction, and following
benzylic or allylic halogenation, provides a simple approach to the synthesis of this
Practical Synthetic Organic Chemistry: Reactions, Principles, and Techniques, First Edition.
Edited by Stephane Caron.
Ó 2011 John Wiley & Sons, Inc. Published 2011 by John Wiley & Sons, Inc.

1


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ALIPHATIC NUCLEOPHILIC SUBSTITUTION

subset of alcohols. Typical conditions involve treatment of the alkyl halide with a mild base
in an acetone-water or acetonitrile-water mixed solvent system. Moderate heating will
accelerate the reaction, and is commonly employed.1
Na2 CO 3
1:1 acetone/H 2O

CO2 H

O2 N

60°C, 2 h

Br

CO2H

O2 N
HO

93%

1.2.1.2 Hydrolysis of gem-Dihalides Geminal dihalides can be converted to aldehydes
or ketones via direct hydrolysis. The desired conversion can be markedly accelerated by
heating in the presence of an acid or a base, or by including a nucleophilic amine promoter
such as dimethylamine.2
Br

Me

Me

Br

O

O

40% aq. HNMe2

Me

H

60°C, 2–3 h
86%

O

Me
O
O

In the example below from Snapper and coworkers, a trichloro- intermediate was
prepared from p-methoxystyrene via the Kharasch addition of 1,1,1-trichloroethane.
Contact with silica gel effected elimination of the benzylic chloride as well as hydrolysis
of the geminal dichloride moiety to yield the a,b-unsaturated methyl ketone in good overall
yield.3
Cl PCy3
Ru

Cl
PCy3 Ph
MeO

Cl3CCH3
75°C, 2 h

Cl

Cl

Cl
Me

O
SiO2

MeO

Me
MeO

69%

1.2.1.3 Hydrolysis of 1,1,1-Trihalides 1,1,1-Trihalides are at the appropriate oxidation
state to serve as carboxylic acid precursors. These compounds react readily with water at
acidic pH, providing the corresponding acids in high yield, and often at ambient
temperature.4 Trichloromethyl groups, rather than tribromo- or triiodo- analogs, are
more often utilized due to superior access via nucleophilic displacement reactions by
trichloromethyl anions.

1

Lee, H. B.; Zaccaro, M. C.; Pattarawarapan, M.; Roy, S.; Saragovi, H. U.; Burgess, K. J. Org. Chem. 2004, 69,
701–713.
2
Bankston, D. Synthesis 2004, 283–289.
3
Lee, B. T.; Schrader, T. O.; Martin-Matute, B.; Kauffman, C. R.; Zhang, P.; Snapper, M. L. Tetrahedron 2004, 60,
7391–7396.
4
Martins, M. A. P.; Pereira, C. M. P.; Zimmermann, N. E. K.; Moura, S.; Sinhorin, A. P.; Cunico, W.; Zanatta, N.;
Bonacorso, H. G.; Flores, A. C. F. Synthesis 2003, 2353–2357.


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OXYGEN NUCLEOPHILES

CCl3

EtO

CO 2 H

20% HCl, 12 h

N
N
H

3

95%
EtO

N
N
H

The trifluoromethyl group has seen increased application in the pharmaceutical industry
in recent years due to its relative metabolic stability. Although trifluoromethyl groups are
susceptible to vigorous hydrolytic conditions,5 they are not frequently utilized as carboxylic
acid precursors due to the relative expense of incorporating fluorine into building blocks.
However, an increasingly common synthetic application of the CF3 function is highlighted
by the example below. Alkaline hydrolysis of a trifluoromethyl ketone provides the
corresponding carboxylic acid in good yield. Here, the CF3 group is not the point of
nucleophilic attack by water. Instead, the strong inductive effect of the three highly
electronegative fluorine atoms makes the trifluoromethyl anion an excellent leaving group,
and attack occurs at the carbonyl carbon.6
O

O
KOH, H2 O, EtOH

CF3

OH

rt, 3 h

O

O

OEt

60%

1.2.1.4 Hydrolysis of Alkyl Esters of Inorganic Acids Alkaline hydrolysis of inorganic
esters may proceed through competing mechanisms, as illustrated by the mesylate and boric
acid monoester in the following scheme. Sulfonate hydrolysis favors the product of
stereochemical inversion, via direct SN2 attack at the carbon bearing the sulfonate. In
contrast, the corresponding boron derivative is hydrolyzed under identical reaction
conditions with retention of configuration, which is the result of formal attack by
hydroxide at boron.7
Me

cat. CaCO3, H2 O

MsO

Me

Me
HO

+

85°C, 4 h
O

HO
O

O

95%

94 : 6
Me
(HO) 2BO

Me

Me

cat. CaCO 3 , H 2O
HO

+

85°C, 4 h
O

99%

HO
O

O

2 : 98

Enders and coworkers demonstrated that g-sultone hydrolysis occurs exclusively via
attack at carbon to provide g-hydroxy sulfonates with a high degree of stereochemical
5

Butler, D. E.; Poschel, B. P. H.; Marriott, J. G. J. Med. Chem. 1981, 24, 346–350.
Hojo, M.; Masuda, R.; Sakaguchi, S.; Takagawa, M. Synthesis 1986, 1016–1017.
7
Danda, H.; Maehara, A.; Umemura, T. Tetrahedron Lett. 1991, 32, 5119–5122.
6


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ALIPHATIC NUCLEOPHILIC SUBSTITUTION

control.8 In order to verify stereochemistry, the crude sulfonic acid was converted into the
corresponding methyl sulfonate by treatment with diazomethane (see Section 1.2.3.5).
Me
H

H 2O, Acetone

HO3 S

H Me

O
S
O
O

MeO3 S

CH 2N 2, Et 2 O

OH

H Me
OH

Reflux, 3 d
89%

de >98%, ee >98%

de >98%, ee >98%

1.2.1.5 Hydrolysis of Diazo Ketones Treatment of simple a-diazo ketones with
hydrochloric acid in aqueous acetone provides direct access to the corresponding
alcohols.9 In their 1968 paper, Tillett and Aziz describe an investigation into the kinetics
of this transformation that utilized a number of diazoketones and mineral acids.10 Although
the reaction can be run under mild conditions, and is often high yielding, the preparation and
handling of diazo compounds is a safety concern that may preclude their use on large scale.
O

N2

rt, 30 min

F

MeS

O

1M HCl, Acetone

OH
F

MeS

62%

1.2.1.6 Hydrolysis of Acetals, Enol Ethers, and Related Compounds Acetals are highly
susceptible to acid-catalyzed hydrolysis, typically providing the corresponding aldehydes
under very mild conditions. Almost any acid catalyst can be employed, so the choice is
usually dependent upon substrate compatibility. Solid-supported sulfonic acid catalysts such
as Amberlyst-1511 are an especially attractive option due to the relative ease of catalyst
removal by simple filtration.12
MeO
BocO

OMe

Amberlyst-15

acetone,H2O

Me
rt, 20 h

O
BocO

H
Me

100%

Enol ethers of simple ketones may be similarly hydrolyzed by treatment with aqueous
acid. A water-miscible organic cosolvent such as acetone or acetonitrile is often included to
improve substrate solubility.13 Moderate heating increases the rate of hydrolysis, but high
temperatures are seldom required.
8

Enders, D.; Harnying, W.; Raabe, G. Synthesis 2004, 590–594.
Pirrung, M. C.; Rowley, E. G.; Holmes, C. P. J. Org. Chem. 1993, 58, 5683–5689.
10
Aziz, S.; Tillett, J. G. J. Chem. Soc. B 1968, 1302–1307.
11
Kunin, R.; Meitzner, E.; Bortnick, N. J. Am. Chem. Soc. 1962, 84, 305–306.
12
Coppola, G. M. Synthesis 1984, 1021–1023.
13
Fuenfschilling, P. C.; Zaugg, W.; Beutler, U.; Kaufmann, D.; Lohse, O.; Mutz, J.-P.; Onken, U.; Reber, J.-L.;
Shenton, D. Org. Process Res. Dev. 2005, 9, 272–277.

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OXYGEN NUCLEOPHILES

OMe

O

36% HCl, H 2O
acetone
40°C, 2 h

N
O

N

90%

NH 2

5

O

NH 2

Dithioketene acetals may be hydrolyzed to thioesters under very mild conditions. Note
that the strongly acidic reaction conditions employed in the example below resulted in
concomitant b-dehydration and loss of the acid labile N-trityl protecting group.9

OH

SMe

N

O

36% HCl, H2 O

N

SMe
Acetone, rt

F

N
Tr

SMe
F

Cl H 2 N

61%

Orthoesters may also be hydrolyzed through treatment with aqueous acid, as exemplified
in the scheme below.14 Methanol is often included as a nucleophilic cosolvent that
participates in the hydrolysis.
O
MeO2 C

MeO2 C

O

Me
O

H
H

OMe

O

10% aq. HCl, MeOH
H

Me
rt, 1 h

H

95%

HO

Me

Me

O

H

H
HO

Under mildly acidic conditions, a terminal orthoester will provide the carboxylic acid
ester.15 However, prolonged exposure to aqueous acid will yield the carboxylic acid.
TESO

Ph

O
O
O

TESO

Me

HO

Ph

PPTS, acetone
H2 O, rt, 5 h

O
O

OH
Me

HO

HO

95%
OTES

OH

1.2.1.7 Hydrolysis of Silyl Enol Ethers Silyl enol ethers are prone to hydrolysis at a
rate generally consistent with their relative steric bulk. Trimethylsilyl (TMS) enol ethers
are particularly labile, and may by hydrolyzed in the absence of an acid catalyst in some

14
Kato, K.; Nouchi, H.; Ishikura, K.; Takaishi, S.; Motodate, S.; Tanaka, H.; Okudaira, K.; Mochida, T.; Nishigaki,
R.; Shigenobu, K.; Akita, H. Tetrahedron 2006, 62, 2545–2554.
15
Martynow, J. G.; Jozwik, J.; Szelejewski, W.; Achmatowicz, O.; Kutner, A.; Wisniewski, K.; Winiarski, J.;
Zegrocka-Stendel, O.; Golebiewski, P. Eur. J. Org. Chem. 2007, 689–703.

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ALIPHATIC NUCLEOPHILIC SUBSTITUTION

instances.16 In contrast, bulky triisopropylsilyl (TIPS) enol ethers are generally stable
enough to withstand an acidic aqueous workup and may even be purified via silica gel
chromatography. In the scheme below, the TMS, tert-butyl dimethylsilyl (TBS) and TIPS
enol ethers of cyclohexanone are desilylated by treatment with aqueous hydrochloric acid in
tetrahydrofuran. The variation in reaction rate under these conditions is noteworthy.17
Me 3SiO
1N HCl, THF (1:20)
rt, 0.25 h
O

t-BuMe 2SiO
1N HCl, THF (1:20)
rt, 1 h
i-Pr 3SiO
1N HCl, THF (1:20)
rt, 2 h

1.2.1.8 Hydrolysis of Silyl Ethers Silyl ethers are generally less susceptible to acidcatalyzed hydrolysis than their enol ether counterparts. However, increasing the reaction
time, reaction temperature or acid concentration can provide a simple, high-yielding method
for the removal of silicon-based hydroxyl protecting groups, provided that the rest of the
molecule is stable to such treatment.18
TBSO

H

H
N

3N HCl, H 2O

HO

H

H
N

100°C, 1 h
TBSO

100%

HO

In the example below, the removal of two silyl ethers and one silyl enol ether was
accomplished with aqueous acetic acid in THF at room temperature.19 These milder
conditions necessitated a longer reaction time, but conserved the acid sensitive methyl
ester and tertiary alcohol functional groups.
TBSO

O
Me

TESO

16

Me 3SiO

CO2Me

HOAc, THF, H 2O

Me

rt, 24 h

Me
HO

60%

CO2Me
Me

HO

Keana, J. F. W.; Eckler, P. E. J. Org. Chem. 1976, 41, 2850–2854.
Manis, P. A.; Rathke, M. W. J. Org. Chem. 1981, 46, 5348–5351.
18
Sun, H.; Abboud, K. A.; Horenstein, N. A. Tetrahedron 2005, 61, 10462–10469.
19

Collins, P. W.; Gasiecki, A. F.; Jones, P. H.; Bauer, R. F.; Gullikson, G. W.; Woods, E. M.; Bianchi, R. G. J. Med.
Chem. 1986, 29, 1195–1201.
17


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OXYGEN NUCLEOPHILES

7

For acid-sensitive substrates, the use of fluoride ion (e.g., tetra-n-butylammonium
fluoride, TBAF) provides an attractive alternative (see Section 1.5.1.7) and is increasingly
employed as a first choice reagent.
Silyl ethers may be cleaved under aqueous alkaline conditions when the silicon center is
less electron-rich. For example, tert-butyl diphenylsilyl (TBDPS or TPS) ethers are
susceptible to base-promoted cleavage, despite their relative stability to acid. This reactivity
is complementary to that of TBS ethers, allowing for selective silyl protection of similar
functional groups.20
OPMB

OPMB
10% aq. NaOH, MeOH
TBSO

TBSO
Reflux, 3h
OTPS

OH

87%

Silyl ethers may also be cleaved by nucleophilic alcohols in the presence of strong acid
catalysts (see Section 1.2.2.6).
1.2.1.9 Hydrolysis of Epoxides Epoxides can be efficiently ring-opened under acid
catalysis in an aqueous environment to afford 1,2-diol products. In cases where the
regiochemistry of attack by water is inconsequential, or is directed by steric and/or
electronic bias within the substrate, simple Brønsted acid catalysts are utilized. In the
example below, hydrolysis is promoted by the sulfonated tetrafluoroethylene copolymer
Nafion-H to provide the racemic 1,2-anti-diol product via backside attack on the epoxide.21
Nafion-H, THF, H2O

O

OH

rt, 2 h

OH

80%

1.2.2

Reactions with Alcohols

1.2.2.1 Preparation of Ethers from Alkyl Halides The preparation of ethers from
alcohols may be accomplished via treatment with an alkyl halide in the presence of a
suitable base (the Williamson ether synthesis). For relatively acidic alcohols such as phenol

derivatives, the use of potassium carbonate in acetone is a simple, low cost option.22
OMe
OH

K2CO3 , C 5H 9Br

OMe
O

Acetone, reflux, 24 h
NO2

98%

NO 2

The rate of ether formation can be accelerated by increasing the reaction temperature, or
more commonly by employing a more reactive alkyl halide. This is accomplished in the
20

Hatakeyama, S.; Irie, H.; Shintani, T.; Noguchi, Y.; Yamada, H.; Nishizawa, M. Tetrahedron 1994, 50,
13369–13376.
21
Olah, G. A.; Fung, A. P.; Meidar, D. Synthesis 1981, 280–282.
22
Garcia, A. L. L.; Carpes, M. J. S.; de Oca, A. C. B. M.; dos Santos, M. A. G.; Santana, C. C.; Correia, C. R. D. J.
Org. Chem. 2005, 70, 1050–1053.


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8

ALIPHATIC NUCLEOPHILIC SUBSTITUTION

example below via conversion of benzyl chloride to benzyl iodide in situ by including
potassium iodide in the reaction mixture (Finkelstein reaction; see Section 1.5.1.1).23 Since
the iodide ions are regenerated over the course of the reaction, a sub-stoichiometric quantity
can often be used. However, a stoichiometric excess of iodide increases the concentration of
the more reactive alkylating agent, and thus improves the kinetics of the alkylation reaction.
Note that under the conditions utilized, the carboxylic acid is also converted to the
corresponding benzyl ester. For more on the preparation of esters from carboxylic acids
see Sections 1.2.3 and 2.29.
CO2 H
MeO

BnCl, K2 CO 3, KI
Acetone, ref lux, 18 h

OH

CO2 Bn
MeO

OBn

79%

Henegar and coworkers reported the use of potassium isopropoxide in dimethyl carbonate
for the large scale preparation of an ether intermediate in the synthesis of the commercial

antidepressant (Ỉ)-reboxetine mesylate.24
EtO
O
HO

EtO

H

H

Cl

N

H

i-PrOK
i-PrOH, t-BuOH

O

(MeO)2 CO

O

H

H

> 62%

O

N

H

O

1.2.2.2 Preparation of Methyl Ethers from Dimethyl Carbonate or Dimethyl
Sulfate Dimethyl carbonate is an ambident electrophile that typically reacts with soft
nucleophiles at a methyl carbon and with hard nucleophiles at the central carbonyl. Via the
former mechanism, dimethyl carbonate has been used for the methylation of phenols,
leading to the formation of arylmethyl ethers. This is an especially attractive reagent for large
scale applications, owing to the low cost, low toxicity and neglegible environmental impact
of dimethyl carbonate,25 however scope is limited due to the modest reactivity of the reagent.
In the example below, Thiebaud and coworkers illustrate the selective methylation of a
bis-phenol compound with dimethyl carbonate and potassium carbonate in the absence of
solvent.26
OH

O

OH

(MeO) 2CO, K2 CO 3

O
Ph

Ph
160ºC, 10 h
MeO

HO
80%

23

Bourke, D. G.; Collins, D. J. Tetrahedron 1997, 53, 3863–3878.
Henegar, K. E.; Ball, C. T.; Horvath, C. M.; Maisto, K. D.; Mancini, S. E. Org. Process Res. Dev. 2007, 11,
346–353.
25
Tundo, P.; Rossi, L.; Loris, A. J. Org. Chem. 2005, 70, 2219–2224.
26
Ouk, S.; Thiebaud, S.; Borredon, E.; Le Gars, P. Green Chem. 2002, 4, 431–435.
24


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OXYGEN NUCLEOPHILES

9

Shen and coworkers discussed the “greenness” of their protocol for the preparation of
arylmethyl ethers from their phenol precursors.27 Thus, treatment of various phenols with
dimethyl carbonate at 120 C in the recyclable ionic liquid 1-n-butyl-3-methylimidazoliumchloride [(BMIm)Cl] provides quantitative yields of aryl methyl ethers. The use of ionic
liquids has been heavily debated in recent years, as these materials are relatively expensive

and current methods for their manufacture pose a significant environmental impact.
Nevertheless, opportunities for reuse and recycle make continued development in this area
a worthwhile venture.
OMe

OH
(MeO)2 CO, (BMIm)Cl

Me

Me

120°C, 2.3 h

Me

Me

100%

The preferred method for the preparation of methyl ethers via alkylation of alcohol
precursors generally utilizes dimethyl sulfate (MeO)2SO2, rather than methyl iodide, due to
the decreased worker-exposure risk that accompanies its lower volatility. Typically, the
alcohol is treated with dimethyl sulfate and a suitable base in a polar aprotic solvent. Yields
are generally high and product isolation relatively straightforward. The examples below are
illustrative, and were both carried out on a large scale.28,29 It should be noted that most
alkylating agents—dimethylsulfate included—pose serious toxicological hazards and thus
require cautious handling and environmental controls.

Br

(MeO)2 SO2
K2 CO 3, Acetone
Reflux, 8 h

HO

Br
MeO

95%

Br
HO

(MeO)2 SO2
K2 CO 3, H2 O
Acetone
15–45ºC, 4 h

Br
MeO

85%

1.2.2.3 Preparation of Ethers from Alkyl Sulfonates A widespread and practical
strategy for the synthesis of ethers, especially on large scale, is through the intermediacy
of alkyl sulfonates. Broad access to alcohol precursors, coupled with the low cost and high
efficiency in converting these alcohols to electrophilic sulfonates has contributed to the
popularity of this method. Mesylates or tosylates are used most often, as MsCl and TsCl are

considerably less expensive than other sulfonyl halides. However, for demanding nucleophilic
substitution reactions, the 4-bromobenzenesulfonate (brosylate) or 4-nitrobenzenesulfonate
27

Shen, Z. L.; Jiang, X. Z.; Mo, W. M.; Hu, B. X.; Sun, N. Green Chem. 2005, 7, 97–99.
Liu, Z.; Xiang, J. Org. Process Res. Dev. 2006, 10, 285–288.
29
Prabhakar, C.; Reddy, G. B.; Reddy, C. M.; Nageshwar, D.; Devi, A. S.; Babu, J. M.; Vyas, K.; Sarma, M. R.;
Reddy, G. O. Org. Process Res. Dev. 1999, 3, 121–125.
28


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10

ALIPHATIC NUCLEOPHILIC SUBSTITUTION

(nosylate, ONs) offer increased reactivity. In the following example, a substituted phenol was
alkylated with a primary mesylate in good yield under representative conditions.30
Me

Me
EtO2 C
Me

i) t -BuOK, THF, 0–5°C, 1 h
N

ii) MsO

Me

EtO2 C
Me

OH

Me

S N

N

O

CF 3

CF3

S N

5–18°C, 16h
75%

In a second example, alkylation was shown to proceed through an epoxide intermediate
formed via intramolecular displacement of the tosylate by the adjacent hydroxyl. The zinc
alkoxide was superior to the lithium derivative in terms of yield and reaction rate.31
OBn
TsO

OH
H

OBn
F

OZnBr

O

OH
H

F
N

N

THF, 65°C, 12 h

O

O

67%
F

F

1.2.2.4 Iodoetherification Treatment of olefins with iodine provides an electrophilic
iodonium species that can be trapped with oxygen nucleophiles to provide ethers. A base is
included to quench the HI that gets generated during the reaction. The intramolecular
nucleophilic displacement occurs at a much higher rate than intermolecular trapping, so
cyclic ethers are formed in high yield. In the example below, two additional stereocenters are
created with high selectivity through treatment of an unsaturated cis-1,3-diol with iodine and
sodium bicarbonate in aqueous ether at 0 C.32
Ph

Me
OH

OH

I2, NaHCO3
H2 O, Et2 O
0°C 10 h
79%

OH
H
Ph

O

Me
I
H

OH

+

H
Ph

O

Me
I
H

93 : 7

1.2.2.5 Preparation of Silyl Ethers Despite the relatively high molar expense of
substituted silicon compounds such as TBSCl, silyl ethers are often utilized as alcoholprotecting groups in synthesis because of their excellent compatibility with a broad range of
common processing conditions, coupled with their relative ease of removal. Vanderplas and
coworkers prepared the TBS ether below in high yield as part of a multi-kilogram synthesis
of a b-3 adrenergic receptor agonist.33 The preferred conditions for TBS protection of this
secondary alcohol included imidazole base in dimethylformamide.
30
Reuman, M.; Hu, Z.; Kuo, G.-H.; Li, X.; Russell, R. K.; Shen, L.; Youells, S.; Zhang, Y. Org. Process Res. Dev.
2007, 11, 1010–1014.
31
Wu, G. G. Org. Process Res. Dev. 2000, 4, 298–300.
32
Tamaru, Y.; Hojo, M.; Kawamura, S.; Sawada, S.; Yoshida, Z. J. Org. Chem. 1987, 52, 4062–4072.
33
Vanderplas, B. C.; DeVries, K. M.; Fox, D. E.; Raggon, J. W.; Snyder, M. W.; Urban, F. J. Org. Process Res. Dev.
2004, 8, 583–586.

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OXYGEN NUCLEOPHILES

OH
O
Me

N

OTBS
OTs

TBSCl, imidazole

OTs

O
DMF, 25°C, 14 h

N

H

Me

11

N

N

H

95%

The example below highlights the strong steric bias of TBSCl toward reaction with the
unhindered secondary alcohol over the more hindered secondary and tertiary alcohols.34
Me
Me

Me
Me
HO

Me TBSCl, imidazole
Me OH
DMF, rt

Me

100%

HO

HO

Me
Me OH

Me

TBSO

1.2.2.6 Cleavage of Silyl Ethers with Alcohols Although the most common methods
utilize fluoride ion (see Section 1.5.1.7), silyl ethers can be cleaved with alcohols promoted
by strong acids. Watson and coworkers reported a high-yielding example of the use of
ethanolic hydrogen chloride in their large scale synthesis of the tumor necrosis factor-a
inhibitor candidate MDL 201449A.35
NH 2

NH 2
N

N
N

6N HCl, EtOH, rt

N

94%

• HCl
N

N

N

N

OH

OTBS

Selective cleavage of a TMS ether in the presence of the more sterically encumbered TBS
derivative has been accomplished via treatment with a methanolic solution of oxalic acid
dihydrate.36
HO
Me
Me

OH

TBSO

SO2 Ph
H

Me

H

H

(CO2H)2 • 2H2O, MeOH
Me
98%

Me OTMS

HO
Me
Me

OH

TBSO

SO2 Ph
H

Me

H

Me
Me OH

H

34
Van Arnum, S. D.; Carpenter, B. K.; Moffet, H.; Parrish, D. R.; MacIntrye, A.; Cleary, T. P.; Fritch, P. Org. Process
Res. Dev. 2005, 9, 306–310.
35
Watson, T. J. N.; Curran, T. T.; Hay, D. A.; Shah, R. S.; Wenstrup, D. L.; Webster, M. E. Org. Process Res. Dev.
1998, 2, 357–365.
36
Maehr, H.; Uskokovic, M. R.; Adorini, L.; Reddy, G. S. J. Med. Chem. 2004, 47, 6476–6484.

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12

ALIPHATIC NUCLEOPHILIC SUBSTITUTION

1.2.2.7 Transetherification The direct interconversion of ethers is not typically a
practical transformation, and is thus rarely employed. The reaction can be
accomplished, however, by treating the starting ether with an alcohol under the
promotion of a strong mineral acid. The interconversion is an equilibrium process, so
the alcohol is typically used as a cosolvent or in significant molar excess. A thorough study of
the thermodynamics of interconversion of electronically diverse 1-phenylethyl ethers with
aliphatic alcohols was reported by Jencks and coworkers.37
The following example from Pittman and coworkers highlights the efficiency of acetal
exchange under Brønsted acid catalysis.38 This reaction is formally a double transetherification, although it has the advantage of proceeding via an intermediate oxonium ion. In this
instance, the reaction is rendered irreversible by running at a temperature where the liberated
methanol is removed by distillation.
Ph

OH

Dowex-X8 (H+) resin

MeO

Ph

O

+
Ph

MeO

OH

80°C, 36 h

Br

O

Ph

Br

97%

A wide variety of vinyl ethers can be prepared from ethyl vinyl ether via palladiumcatalyzed transetherification, as exemplified below.39 Additional substitution on the olefin,
however, severely diminishes the efficiency of the transformation and limits scope. This
reaction is not a nucleophilic aliphatic substitution, but is included here to illustrate this
complementary, albeit limited methodology.
Me OH

Me O

Pd(OAc)2
1,10-phenanthroline

Me

Me
Ethyl vinyl ether
DCM, rt, 4 d

O

O

87%

1.2.2.8 Preparation of Epoxides Epoxides can be prepared in high yield through
intramolecular nucleophilic displacement of halides by vicinal hydroxyls. In the example
below, concentrated aqueous sodium hydroxide is used as the base in dichloromethane.40
This solvent choice, when used in combination with highly concentrated NaOH solution,
minimizes water content within the organic phase to prevent competitive epoxide hydrolysis
to the corresponding 1,2-diol. The addition of a phase transfer catalyst, as well as aggressive
agitation, facilitates movement of hydroxide ions into the dichloromethane.
Me

Me

Me

Me

O

O

O

O

i) 50% aq. NaOH
TBAHSO4,DCM
rt, 8 h

Me

Me

O

O

O
O

+
TBSO
HO

37

NHTs
Br

NHTs ii) Piperonyl bromide
rt,7 h

TBSO
Br

OH

91%

TBSO

N
Ts
O

Rothenberg, M. E.; Richard, J. P.; Jencks, W. P. J. Am. Chem. Soc. 1985, 107, 1340–1346.
Zhu, P. C.; Lin, J.; Pittman, C. U., Jr., J. Org. Chem. 1995, 60, 5729–5731.
39
Weintraub, P. M.; King, C.-H. R. J. Org. Chem. 1997, 62, 1560–1562.
40
Elango, S.; Yan, T.-H. Tetrahedron 2002, 58, 7335–7338.
38


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13

OXYGEN NUCLEOPHILES

Epoxides are often prepared from olefin precursors by sequential reaction with
N-bromosuccinimide (NBS) and hydroxide in an aqueous environment. The NBS initially
forms an electrophilic bromonium species, which is quickly converted to a bromohydrin via
nucleophilic attack by water. As described in the following example, the bromohydrin can
be converted to an epoxide in the same reaction vessel by addition of sodium hydroxide.41 In
this instance, the epoxide was not purified, but was further reacted to the azidohydrin by
reaction with sodium azide at an elevated temperature. The opening of epoxides with
nitrogen nucleophiles is also discussed in Section 1.4.1.6. More on the preparation of
epoxides from carbon-carbon double bonds can be found in Section 3.10.4.
H

i) NBS, THF-H 2O
0°C to rt, 2 h

O

NaN3
CH 3 O(CH 2)2 OH

H

O

O

O
O

H

O

N3
HO

H
O

O

Me
Me

ii) 1N NaOH, THF
reflux, 1 h

O

H

O

Me
Me

O

130°C, 2 h

O

48% – 3 steps

H

O

Me
Me

1.2.2.9 Reaction of Alcohols with Epoxides Epoxides can be opened with nucleophilic
alcohols in the presence of various activating agents. Despite a low degree of atom economy,
N-bromosuccinimide (NBS) proved to be a very effective promoter in the example below.42
A catalytic quantity of an acid catalyst is often sufficient, however.
NBS, EtOH
O

OH

Reflux, 30 h

OEt

93%

In the example below from Loh and coworkers, a late stage intramolecular epoxide
opening by an alcohol is catalyzed by camphorsulfonic acid in dichloromethane to provide
the desired furan as a single diastereomer in good yield.43 The g-lactone resulting from
intramolecular transesterification was observed as a minor byproduct.

OTs

OTs

TsO
OBz

OBz
O

0°C to rt, 16 h
HO
CO2 Me
TFA
N
CO2 Me
Me
Ph

OBz

CSA, DCM

85%

HO H

O

O

CO2 Me +

CO 2Me

TFA
N

TFA
CO 2Me

Me
Ph

Me

O

N
Ph

O

95 : 5

41
Loiseleur, O.; Schneider, H.; Huang, G.; Machaalani, R.; Selles, P.; Crowley, P.; Hanessian, S. Org. Process Res.
Dev. 2006, 10, 518–524.
42
Iranpoor, N.; Firouzabadi, H.; Chitsazi, M.; Ali Jafari, A. Tetrahedron 2002, 58, 7037–7042.

43
Huang, J.-M.; Xu, K.-C.; Loh, T.-P. Synthesis 2003, 755–764.