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Hetarenes
(Vols 9–17)

4/3 C-X bonds
(Vols 18–24)

2 C-X bonds
(Vols 25–33)

1 C-X bond
(Vols 34–42)

All C bonds
(Vols 43–48)

2

3

4

5

6

Classification is based on the product, with all products
belonging to one of six broad-ranging categories. All

products occupy a strict hierarchical position in Science of
Synthesis, defined according to the classification principles*. Products in Categories 3–6 are organized according to
oxidation state, with products containing the greatest
number of carbon–heteroatom (C-X) or C-C p-bonds to a
single carbon occupying the highest positions (e.g.,
carboxylates, enolates, and alcoholates are covered in
Categories 3, 4, and 5, respectively).

Products
of Organic
Synthesis

Organometallics
(Vols 1–8)

1

CATEGORY

Organizational Structure of Science of Synthesis*

… etc.

9.1.2

9.1.1

PRODUCT
SUBCLASS


Each category is subdivided into volumes (see opposing page),
each of which is devoted to discrete groupings of compounds
called product classes (e.g., “Thiophenes” is Product Class 10 of
Volume 9). Product classes may be further subdivided into
product subclasses, (e.g., “Thiophene 1,1-Dioxides” is Product
Subclass 3 of Product Class 10 of Volume 9). Consequently, the
relationship between heading name and heading number varies
below product class level within individual volumes.

… etc.

9.2

9.1

Vol. 10
… etc.

PRODUCT
CLASS

Vol. 9

VOLUME

… etc.

9.1.1.1.2

9.1.1.1.1


VARIATION
Selected
Products
and
Reactions

For each product class or subclass, a number of methods are
described for synthesizing the general product type. Often
there are variations on a method given. Both methods and
variations contain experimental procedures with relevant
background information and literature references. Selected
products and reactions display the scope and limitations of
the methods.

… etc.

9.1.1.2

9.1.1.1

METHOD

* A complete description of the full classification principles can be found in the
Science of Synthesis Guidebook.

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Applications


Transformations

Techniques

Organic
Synthesis

Classical

Structures

Advances

The Science of Synthesis Reference Library comprises volumes covering special topics of organic chemistry in a modular fashion,
with six main classifications: (1) Classical, (2) Advances, (3) Transformations, (4) Applications, (5) Structures, and (6)
Techniques. Volumes in the Science of Synthesis Reference Library focus on subjects of particular current interest with
content that is evaluated by experts in their field. Science of Synthesis, including the Knowledge Updates and the Reference
Library, is the complete information source for the modern synthetic chemist.

Science of Synthesis Reference Library

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Science of Synthesis

Science of Synthesis is the authoritative and

comprehensive reference work for the entire
field of organic and organometallic synthesis.
Science of Synthesis presents the important
synthetic methods for all classes of compounds
and includes:
– Methods critically evaluated
by leading scientists
– Background information and detailed
experimental procedures
– Schemes and tables which illustrate
the reaction scope


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Science of Synthesis
Editorial Board

E. M. Carreira
C. P. Decicco
A. Fuerstner
G. Koch
G. A. Molander

Managing Editor

M. F. Shortt de Hernandez

Senior
Scientific Editors


K. M. Muirhead-Hofmann
T. B. Reeve
A. G. Russell

Scientific Editors

E. L. Hughes
J. S. ODonnell
E. Smeaton

b

E. Schaumann
M. Shibasaki
E. J. Thomas
B. M. Trost

M. J. White
F. Wuggenig

Georg Thieme Verlag KG
Stuttgart · New York


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Science of Synthesis
Applications of Domino Transformations in
Organic Synthesis 1

Volume Editor

S. A. Snyder

Responsible Member E. Schaumann
of the Editorial Board
Authors

D. Adu-Ampratwum
E. A. Anderson
K. W. Armbrust
J. J. Devery, III
J. J. Douglas
M. P. Doyle
K. M. Engle
C. J. Forsyth
F. Gille
T. Halkina
X. Hu
T. F. Jamison

b

E. H. Kelley
A. Kirschning
D. Lee
T. J. Maimone
E. Merino
C. Nevado
M. OConnor

T. Ohshima
K. A. Parker
H. Renata
A. Salvador
R. A. Shenvi

2016
Georg Thieme Verlag KG
Stuttgart · New York

L. Shi
S. Sittihan
C. R. J. Stephenson
M. Tang
P. Truong
Y.-Q. Tu
K. K. Wan
S.-H. Wang
M. Wolling
X. Xu
Z. Yang


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IV
 2016 Georg Thieme Verlag KG
Rüdigerstrasse 14
D-70469 Stuttgart
Printed in Germany
Typesetting: Ziegler + Müller, Kirchentellinsfurt

Printing and Binding: AZ Druck und Datentechnik
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Bibliographic Information published by
Die Deutsche Bibliothek
Die Deutsche Bibliothek lists this publication in the
Deutsche Nationalbibliografie; detailed bibliographic
data is available on the internet at <>

Library of Congress Card No.: applied for

British Library Cataloguing in Publication Data
A catalogue record for this book is available from the
British Library

ISBN 978-3-13-173141-8

eISBN 978-3-13-202851-7

Date of publication: May 11, 2016

Copyright and all related rights reserved, especially
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This reference work mentions numerous commercial
and proprietary trade names, registered trademarks
and the like (not necessarily marked as such), patents,

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designs, and designations. The editors and publishers
wish to point out very clearly that the present legal situation in respect of these names or designations or
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not imply that any such selection of exclusion has
been based on quality criteria or quality considerations.
Warning! Read carefully the following: Although
this reference work has been written by experts, the
user must be advised that the handling of chemicals,
microorganisms, and chemical apparatus carries potentially life-threatening risks. For example, serious
dangers could occur through quantities being incorrectly given. The authors took the utmost care that
the quantities and experimental details described
herein reflected the current state of the art of science
when the work was published. However, the authors,
editors, and publishers take no responsibility as to the
correctness of the content. Further, scientific knowledge is constantly changing. As new information becomes available, the user must consult it. Although
the authors, publishers, and editors took great care in
publishing this work, it is possible that typographical
errors exist, including errors in the formulas given
herein. Therefore, it is imperative that and the responsibility of every user to carefully check
whether quantities, experimental details, or other information given herein are correct based on
the users own understanding as a scientist. Scaleup of experimental procedures published in Science
of Synthesis carries additional risks. In cases of doubt,
the user is strongly advised to seek the opinion of an
expert in the field, the publishers, the editors, or the
authors. When using the information described herein, the user is ultimately responsible for his or her
own actions, as well as the actions of subordinates
and assistants, and the consequences arising therefrom.



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V

Preface

As the pace and breadth of research intensifies, organic synthesis is playing an increasingly central role in the discovery process within all imaginable areas of science: from pharmaceuticals, agrochemicals, and materials science to areas of biology and physics, the
most impactful investigations are becoming more and more molecular. As an enabling
science, synthetic organic chemistry is uniquely poised to provide access to compounds
with exciting and valuable new properties. Organic molecules of extreme complexity can,
given expert knowledge, be prepared with exquisite efficiency and selectivity, allowing
virtually any phenomenon to be probed at levels never before imagined. With ready access to materials of remarkable structural diversity, critical studies can be conducted that
reveal the intimate workings of chemical, biological, or physical processes with stunning
detail.
The sheer variety of chemical structural space required for these investigations and
the design elements necessary to assemble molecular targets of increasing intricacy place
extraordinary demands on the individual synthetic methods used. They must be robust
and provide reliably high yields on both small and large scales, have broad applicability,
and exhibit high selectivity. Increasingly, synthetic approaches to organic molecules
must take into account environmental sustainability. Thus, atom economy and the overall environmental impact of the transformations are taking on increased importance.
The need to provide a dependable source of information on evaluated synthetic
methods in organic chemistry embracing these characteristics was first acknowledged
over 100 years ago, when the highly regarded reference source Houben–Weyl Methoden
der Organischen Chemie was first introduced. Recognizing the necessity to provide a
modernized, comprehensive, and critical assessment of synthetic organic chemistry, in
2000 Thieme launched Science of Synthesis, Houben–Weyl Methods of Molecular
Transformations. This effort, assembled by almost 1000 leading experts from both industry and academia, provides a balanced and critical analysis of the entire literature
from the early 1800s until the year of publication. The accompanying online version of
Science of Synthesis provides text, structure, substructure, and reaction searching capabilities by a powerful, yet easy-to-use, intuitive interface.
From 2010 onward, Science of Synthesis is being updated quarterly with high-quality content via Science of Synthesis Knowledge Updates. The goal of the Science of

Synthesis Knowledge Updates is to provide a continuous review of the field of synthetic
organic chemistry, with an eye toward evaluating and analyzing significant new developments in synthetic methods. A list of stringent criteria for inclusion of each synthetic
transformation ensures that only the best and most reliable synthetic methods are incorporated. These efforts guarantee that Science of Synthesis will continue to be the most
up-to-date electronic database available for the documentation of validated synthetic
methods.
Also from 2010, Science of Synthesis includes the Science of Synthesis Reference
Library, comprising volumes covering special topics of organic chemistry in a modular
fashion, with six main classifications: (1) Classical, (2) Advances, (3) Transformations, (4)
Applications, (5) Structures, and (6) Techniques. Titles will include Stereoselective Synthesis,
Water in Organic Synthesis, and Asymmetric Organocatalysis, among others. With expertevaluated content focusing on subjects of particular current interest, the Science of Synthesis Reference Library complements the Science of Synthesis Knowledge Updates,
to make Science of Synthesis the complete information source for the modern synthetic
chemist.


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VI

Preface

The overarching goal of the Science of Synthesis Editorial Board is to make the suite
of Science of Synthesis resources the first and foremost focal point for critically evaluated information on chemical transformations for those individuals involved in the design
and construction of organic molecules.
Throughout the years, the chemical community has benefited tremendously from
the outstanding contribution of hundreds of highly dedicated expert authors who have
devoted their energies and intellectual capital to these projects. We thank all of these individuals for the heroic efforts they have made throughout the entire publication process
to make Science of Synthesis a reference work of the highest integrity and quality.

The Editorial Board

E. M. Carreira (Zurich, Switzerland)

C. P. Decicco (Princeton, USA)
A. Fuerstner (Muelheim, Germany)
G. A. Molander (Philadelphia, USA)
P. J. Reider (Princeton, USA)

July 2010
E. Schaumann (Clausthal-Zellerfeld, Germany)
M. Shibasaki (Tokyo, Japan)
E. J. Thomas (Manchester, UK)
B. M. Trost (Stanford, USA)


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Science of Synthesis Reference Library

Science of Synthesis Reference Library

Applications of Domino Transformations in Organic Synthesis (2 Vols.)
Catalytic Transformations via C—H Activation (2 Vols.)
Biocatalysis in Organic Synthesis (3 Vols.)
C-1 Building Blocks in Organic Synthesis (2 Vols.)
Multicomponent Reactions (2 Vols.)
Cross Coupling and Heck-Type Reactions (3 Vols.)
Water in Organic Synthesis
Asymmetric Organocatalysis (2 Vols.)
Stereoselective Synthesis (3 Vols.)

VII



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IX

Volume Editors Preface

Domino reactions have been a mainstay of synthetic chemistry for much of its history.
Domino chemistrys roots trace to achievements such as the one-pot synthesis of tropinone in 1917 by Robinson and the generation of steroidal frameworks through polyene
cyclizations, as originally predicted by the Stork–Eschenmoser hypothesis. In the ensuing
decades, chemists have used these, and other inspiring precedents, to develop even more
complicated domino sequences that rapidly and efficiently build molecular complexity,
whether in the form of natural products, novel pharmaceuticals, or materials such as
buckminsterfullerene.
Despite this body of achievements, however, the development of such processes remains a deeply challenging endeavor. Indeed, effective domino chemistry at the highest
levels requires not only creativity and mechanistic acumen, but also careful planning at
all stages of a typical experiment, from substrate design, to reagent and solvent choice, to
timing of additions, and even the quench. Thus, if the frontiers are to be pushed even further, there is certainly much to master.
It was with these parameters in mind that the Editorial Board of Science of Synthesis decided to focus one of its Reference Library works on domino chemistry, covering the
myriad ways that these sequences can be achieved with the full array of reactivity available, whether in the form of pericyclic reactions, radical transformations, anionic and
cationic chemistry, metal-based cross couplings, and combinations thereof. In an effort
to provide a unique approach in organizing and presenting such transformations relative
to other texts and reviews on the subject, the sections within this book have been organized principally by the type of reaction that initiates the sequence. Importantly, only key
and representative examples have been provided to highlight the best practices and procedures that have broad applicability. The hope is that this structure will afford a clear
sense of current capabilities as well as highlight areas for future development and research.
A work on such a vibrant area of science would not have been possible, first and foremost, without a talented and distinguished author team. Each is mentioned in the introductory chapter, and I wish to thank all of them for their professionalism, dedication, and
expertise. I am also grateful to all of the coaching, advice, and assistance provided by
Ernst Schaumann, member of the Editorial Board of Science of Synthesis. Deep thanks
also go, of course, to the entire editorial team at Thieme, particularly to Robin Padilla and

Karen Muirhead-Hofmann who served as the scientific editors in charge of coordinating
this reference work; Robin started the project, and Karen saw it through to the end. Their
attention to detail and passion to produce an excellent final product made this project a
true pleasure. Last, but not least, I also wish to thank my wife Cathy and my son Sebastian
for their support of this project over the past two years.
Finally, I wish to dedicate this work, on behalf of the chapter authors and myself, to
our scientific mentors. It was through their training that we learned how to better understand reactivity, propose novel chemistry, and identify the means to actually bring those
ideas to fruition. Hopefully this text will serve the same role to those who study its contents, with even greater wisdom achieved as a result.

Scott A. Snyder

Chicago, October 2015


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XI

Abstracts

p 13
1.1

Polyene Cyclizations
R. A. Shenvi and K. K. Wan

A domino transformation consists of a first chemical reaction enabling a second reaction,
which can then effect a third reaction, and so on, all under the same reaction conditions.

A polyene cyclization is defined as a reaction between two or more double bonds contained within the same molecule to form one or more rings via one or more C-C bondforming events. Herein, domino polyene cyclizations are discussed, with an emphasis on
operationally simple methods of broad utility. From the perspective of synthesis theory,
polyene cyclizations are a powerful approach for the efficient generation of both complexity and diversity, with the potential for a single synthetic route to generate a series
of both constitutional and stereochemical isomers. However, with some noteworthy exceptions, the ability to controllably cyclize a linear chain to multiple products with high
selectivity still generally eludes synthetic chemists and represents a significant chemical
frontier for further development.
domino polyene cyclizations

Keywords: polyenes • cyclization • carbocations • radicals • polycycles

p 43
1.2

Cation–ð Cyclizations of Epoxides and Polyepoxides
K. W. Armbrust, T. Halkina, E. H. Kelley, S. Sittihan, and T. F. Jamison

This chapter describes the formation of complex polycyclic fragments from linear epoxide and polyepoxide precursors via domino reactions. Depending on the reaction conditions employed, either exo or endo epoxide opening can be selectively achieved. Applications of these domino reactions toward the synthesis of complex natural products are discussed.
H+

OBn O

O

O

HO

O

O


HO

H

O

H2O

O

O

BnO

HO

HO

O

H

H

H H
H

O


H

O

O

H H

O

H

H

O

Keywords: oxiranes • cascades • natural products • marine ladder polyethers • ionophores • ethers • oxygen heterocycles • tetrahydrofurans • tetrahydropyrans • oxepanes


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XII

Abstracts

p 67
Enyne-Metathesis-Based Domino Reactions in Natural Product Synthesis

1.3.1

D. Lee and M. OConnor


Enyne-metathesis-based domino processes are highlighted in the context of natural product synthesis; these include domino double ring-closing metathesis, enyne metathesis/
metallotropic [1,3]-shifts, enyne metathesis/Diels–Alder reaction, and other variations of
their domino combinations. Issues regarding selectivity and mechanism are also discussed.
R1
R1
R4

R1

R2

Ru

R3

R3

R2

natural products
2

R
R1
R3

R2

Keywords: enyne metathesis • ð-bond exchange • domino transformations • natural

products • total synthesis

p 135
Domino Metathesis Reactions Involving Carbonyls

1.3.2

H. Renata and K. M. Engle

This review describes different methods to perform net carbonyl–alkene metathesis. Reactions of this type generally involve domino transformations employing organometallic
reagents. Different conditions and procedures are surveyed and strategic applications of
carbonyl–alkene metathesis in the synthesis of natural products are highlighted.
Cp

Me
Ti

R1

Cp

n

Al
Cl

Me

R1


n

O
R2

O

R2

O

R3

R3

Keywords: metathesis • alkenylation • carbonyl compounds • alkenes • ring closure •
transition metals • titanium complexes • organometallic reagents • organocatalysts

p 157
1.4.1

Peroxy Radical Additions
X. Hu and T. J. Maimone

In this chapter, radical addition reactions involving peroxy radical intermediates are reviewed. These transformations typically generate a carbon radical intermediate which
then reacts with molecular oxygen forming a peroxy radical species. Following peroxy
radical cyclization, various endoperoxide rings are constructed. Two major classes of reactions are discussed: (1) radical additions to alkenes and quenching with molecular oxygen, and (2) radical formation from the opening of cyclopropanes and incorporation of
molecular oxygen. Various methods for radical initiation that are compatible with the
presence of molecular oxygen are described.



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XIII

Abstracts

OOH

air, CDCl3
6-exo cyclization

rt, 1 week

O
O
OOH

OO
44%
PhSSPh (cat.)
AIBN, O2

Ph

Ph

O O

O O


hν, MeCN, 0 oC

Ph

Ph

38%

O O

Keywords: peroxide synthesis • endoperoxides • cyclic peroxides • radical addition • peroxy radicals • thiyl radicals • hydroperoxidation • cyclopropane cleavage • 1,2-dioxolanes •
1,2-dioxanes • 1,2-dioxepanes

p 187
1.4.2

Radical Cyclizations
J. J. Devery, III, J. J. Douglas, and C. R. J. Stephenson

This chapter details recent examples of domino radical reactions that are initiated via an
intramolecular radical cyclization.

X

H

radical cyclization

n


X

Y

further reaction(s)

n

product(s)
Y
Z

Z

Keywords: radicals • domino reactions • cyclization • tin • samarium • organo-SOMO •
ammonium cerium(IV) nitrate (CAN) • visible light

p 217
1.4.3

Tandem Radical Processes
K. A. Parker

This review presents selected examples of regio- and stereospecific domino radical reactions developed in the context of total synthesis studies. The underlying strategies demonstrate the variety of connectivity patterns that can be generated by cascades of intraand intermolecular bond-forming steps.
H
O

OAc

OAc


TBDMSO
O
O

O

O
O

TBDPSO

SnBu3

Keywords: tandem radical cyclization • radical domino cyclization • radical cascade cyclization • intermolecular reactions • radical trapping • manganese(III) acetate • titanocene
dichloride • tris(trimethylsilyl)silane • triethylborane • tri-sec-butylborane • TEMPO •
1,1,3,3-tetramethylguanidine • samarium(II) iodide • cobaloxime


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XIV

Abstracts

p 243
1.5.1

Protic Acid/Base Induced Reactions
D. Adu-Ampratwum and C. J. Forsyth


This chapter covers synthetic domino processes that are induced by protic acid or base.
They are broadly classified into those that capitalize upon the release of oxirane ring
strain under acidic or basic conditions, and carbocyclic ring expansions and contractions
under protic acid or basic conditions. The focus here is upon single substrate, monocomponent domino processes, rather than multicomponent variants.
O
O
HO

OH

OH
HO

CSA, CH2Cl2

H
H

44%

HO

OH
O

O
O

H
H


O
O

HO
OH

O

Keywords: carbocyclic compounds • cyclization • epoxy compounds • ethers • Favorskii
rearrangement • intramolecular reactions • Nazarov cyclization • pinacol rearrangement •
ring contraction • ring expansion • tandem reactions • Wagner–Meerwein rearrangement

p 269
1.5.2

Lewis Acid/Base Induced Reactions
S.-H. Wang, Y.-Q. Tu, and M. Tang

The efficient construction of complex molecular skeletons is always a hot topic in organic
synthesis, especially in the field of natural product synthesis, where many cyclic structural motifs can be found. Under the assiduous efforts of synthetic chemists, more and more
methodologies are being developed to achieve the construction of cyclic skeletons. In particular, the beauty and high efficiency of organic synthesis are expressed vividly among
those transformations realized through a domino strategy. Based on these important
methodologies, selected Lewis acid/base induced domino reactions leading to ring expansions, contractions, and closures are presented in this chapter.
TiCl4, CH2Cl2
−78 to 0 oC

O

O


OTMS

N3

N3

O

n

O

n

OH

O

O TiCl2
N3

TiCl2

n

O
N

TiCl2


− N2

N
n

n

N2

O


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XV

Abstracts

SnCl4
CH2Cl2

R1
n

−70 to 23 C

O
R

R1


R1

OH

HO

o

2

O

n

O

R2

R2

O

n

O

R1
R2
O


n

H

Keywords: tandem reactions • Lewis acid • Lewis base • ring expansion • ring contraction •
ring closure

p 355
Brook Rearrangement as the Key Step in Domino Reactions

1.5.3

A. Kirschning, F. Gille, and M. Wolling

The Brook rearrangement has lost its Cinderella status over the past twenty years since
being embedded into cascade reaction sequences. The powerful formation of carbanions
through silyl migration has been exploited for the development of many new methodologies and has been used as a key transformation in complex natural product syntheses.
Now, the Brook rearrangement belongs to the common repertoire of synthetic organic
chemists.
SiR13
R13Si

OH

base

R13Si

O

n

n

O
n

E+

SiR13
E

O
n

Keywords: Brook rearrangement • domino reactions • migration • organosilicon chemistry • total synthesis

p 449
1.6.1

Palladium-Mediated Domino Reactions
E. A. Anderson

Palladium catalysis offers excellent opportunities to engineer domino reactions, due to
the ability of this transition metal to engage with a variety of electrophiles and to effect
stereocontrolled bond formations in complex settings. This review covers palladium-catalyzed domino processes, categorized according to the initiating species (alkenyl-, aryl-,
allyl-, allenyl-, or alkylpalladium complexes), with a particular focus on applications in
natural product synthesis that exemplify more general methodology.



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XVI

Abstracts

Pd(OAc)2 (30 mol%)
Ag2CO3 (2.2 equiv)
toluene, rt, 40 h

O
BnO
N
TBDMS

O

I

+
NC

O
HO

Et

O
O
TBDMS


O

N

O

N

TBDMS [Pd]

O
HO

N

[Pd]

O

Et
HO

N

Et

BnO
BnO

O

TBDMS

N

O
O

N

HO

Et

BnO
70%

Keywords: palladium • domino • cascade • total synthesis

p 511
Dirhodium-Catalyzed Domino Reactions

1.6.2

X. Xu, P. Truong, and M. P. Doyle

With dirhodium carbenes generated from diazocarbonyl compounds, 1-sulfonyl-1,2,3-triazoles, or cyclopropenes, a subsequent intramolecular cyclization forms a reactive intermediate that undergoes a further transformation that usually terminates the reaction
process. Commonly, the electrophilic dirhodium carbene adds intramolecularly to a
C”C bond to provide a second rhodium carbene. Catalytically generated dirhodiumbound nitrenes initiate domino reactions analogously, and recent examples (nitrene to
carbene to product) have also been documented.
Rh2L4

A=B

C=D

Rh2L4

E=F

C=D
−Rh2L4
E=F

Rh2L4

E=F

Rh2L4

A=B = C=N2, triazolyl, cyclopropenyl; C=D = C=C, C≡C; E=F = C—H
= newly formed bond


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XVII

Abstracts

Keywords: ặ-carbonyl carbenes ã (azavinyl)carbenes ã cyclopropenes ã [3 + 2] annulation •
cyclopropenation • carbene/alkyne metathesis • carbonyl ylide reactions • Claisen/Cope
rearrangement • C-H insertion • oxonium ylides • dipolar cycloaddition • aromatic substitution


p 535
Gold-Mediated Reactions

1.6.3

E. Merino, A. Salvador, and C. Nevado

In this review, a selection of the most relevant examples featuring gold-catalyzed domino
transformations are presented. Processes catalyzed by both gold(I) and gold(III) complexes
are described, including multicomponent reactions, annulations, cycloisomerizations,
and cycloadditions. The scope, limitations, and mechanistic rationalization of these
transformations are also provided.
But
But

P

Au

NCMe

SbF6− (5 mol%)

OAc
R1

R2
OAc


R2

CH2Cl2, rt, 30 min

R3

+
R1

R3

R4

H
OAc
R3

R4
1. AuCl(PPh3) (1 mol%)
AgSbF6 (1 mol%)

O

CH2Cl2, 25 oC
2. K2CO3, MeOH, 30 min

R3
R2

R1


R1

R2

Keywords: domino transformations • multicomponent reactions • cycloisomerizations •
cycloadditions • rearrangements • gold

p 577
1.6.4

Rare Earth Metal Mediated Domino Reactions
T. Ohshima

Rare earth metals, comprising 17 chemical elements in the periodic table, are relatively
abundant in the Earths crust despite their name. In the series of lanthanides, a systematic contraction of the ionic radii is observed when going from lanthanum to lutetium (often referred to as the lanthanide contraction), but this variation is so smooth and limited,
with ca. 1% contraction between two successive lanthanides, that it is possible to finetune the ionic radii, Lewis acidity, and Brønsted basicity of rare earth complexes. As a result of the large size of the lanthanide ions compared to other metal ions, lanthanide ions
have high coordination numbers, varying from 6 to 12. Due to the strong oxophilicity of
rare earth elements, their metal ions have a hard Lewis acidic nature. Most particularly,
rare earth metal trifluoromethanesulfonates [M(OTf)3] have been regarded as new types of
Lewis acids and are stable and active in the presence of many Lewis bases. Another important type of rare earth metal species, the rare earth metal alkoxides [M(OR)3], exhibit both
Lewis acidity and Brønsted basicity. These collated characteristic features of rare earth
based complexes, such as high coordination numbers, a hard Lewis acidic nature, high
compatibility with various functional groups, ease of fine-tuning, and multifunctionality,
have led to the development of a variety of domino reactions catalyzed largely by rare
earth metal trifluoromethanesulfonates and alkoxides.


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XVIII


Abstracts

MX3 (cat.)
BINOL (cat.)

A

+

B

+

C

D

+

C

E

M = rare earth metal; X = OTf, OR1

Keywords: lanthanide contraction • rare earth metal trifluoromethanesulfonates • rare
earth metal alkoxides • Lewis acidity • Brønsted basicity • high coordination numbers •
multifunctionality


p 601
1.6.5

Cobalt and Other Metal Mediated Domino Reactions: The Pauson–Khand Reaction
and Its Use in Natural Product Total Synthesis
L. Shi and Z. Yang

The Pauson–Khand reaction constitutes one of the most formidable additions to the repertoire of synthetically useful reactions. It rapidly affords a cyclopentenone skeleton from
an alkene, an alkyne, and carbon monoxide, based on a domino sequence of bond constructions. In this chapter, the prowess of the Pauson–Khand reaction is illustrated by judicious selection of complex target molecules, the total syntheses of which are cleverly
orchestrated by the key Pauson–Khand reaction sequence. Emphasis is placed on cobaltmediated processes to exemplify the applicability of this classical reaction.
R1

Co2(CO)8

R1

heat

O

Keywords: Pauson–Khand reaction • alkenes • carbon monoxide • alkynes • cyclopentenones • natural product synthesis • octacarbonyldicobalt • thioureas • allenic alkynes •
asymmetric synthesis


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XIX

Applications of Domino Transformations in
Organic Synthesis 1


1.1

1.2

1.3

1.3.1

1.3.2

1.4

Preface . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

V

Volume Editors Preface . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

IX

Abstracts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

XI

Table of Contents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

XXI

Introduction
S. A. Snyder . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .


1

Polyene Cyclizations
R. A. Shenvi and K. K. Wan . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

13

Cation–ð Cyclizations of Epoxides and Polyepoxides
K. W. Armbrust, T. Halkina, E. H. Kelley, S. Sittihan, and T. F. Jamison . . . . . . . .

43

Metathesis Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

67

Enyne-Metathesis-Based Domino Reactions in Natural Product Synthesis
D. Lee and M. OConnor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

67

Domino Metathesis Reactions Involving Carbonyls
H. Renata and K. M. Engle . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 135
Radical Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 157

1.4.1

Peroxy Radical Additions
X. Hu and T. J. Maimone . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 157


1.4.2

Radical Cyclizations
J. J. Devery, III, J. J. Douglas, and C. R. J. Stephenson . . . . . . . . . . . . . . . . . . . . . . . . . 187

1.4.3

Tandem Radical Processes
K. A. Parker . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1.5

217

Non-Radical Skeletal Rearrangements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 243

1.5.1

Protic Acid/Base Induced Reactions
D. Adu-Ampratwum and C. J. Forsyth . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 243

1.5.2

Lewis Acid/Base Induced Reactions
S.-H. Wang, Y.-Q. Tu, and M. Tang . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 269


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XX


Overview

1.5.3

Brook Rearrangement as the Key Step in Domino Reactions
A. Kirschning, F. Gille, and M. Wolling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 355

1.6

Metal-Mediated Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 449

1.6.1

Palladium-Mediated Domino Reactions
E. A. Anderson . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 449

1.6.2

Dirhodium-Catalyzed Domino Reactions
X. Xu, P. Truong, and M. P. Doyle . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

511

1.6.3

Gold-Mediated Reactions
E. Merino, A. Salvador, and C. Nevado . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 535

1.6.4


Rare Earth Metal Mediated Domino Reactions
T. Ohshima . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 577

1.6.5

Cobalt and Other Metal Mediated Domino Reactions:
The Pauson–Khand Reaction and Its Use in Natural Product Total Synthesis
L. Shi and Z. Yang . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 601

Keyword Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 633
Author Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 669
Abbreviations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 693


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XXI

Table of Contents
Introduction
S. A. Snyder
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1.1

1

Polyene Cyclizations
R. A. Shenvi and K. K. Wan


1.1

Polyene Cyclizations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

13

1.1.1

Cationic Polyene Cyclizations Mediated by Brønsted or Lewis Acids . . . . . . . . . . .

14

1.1.1.1

Most Used Cationic Polyene Cyclization Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . .

15

Polyene Cyclization via Biomimetic Heterolytic Opening of
Epoxides by Alkylaluminum Lewis Acids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

15

1.1.1.1.2

Polyene Cyclization Mediated by Carbophilic Lewis Acids . . . . . . . . . . . . . . . . . . . .

17

1.1.1.2


Recent Advances in Cationic Polycyclization: Halonium-Initiated Polycyclization

17

1.1.1.3

Other Common Cationic Polyene Cyclization Methods . . . . . . . . . . . . . . . . . . . . . . .

19

1.1.1.3.1

Catalytic, Enantioselective, Protonative Polycyclization . . . . . . . . . . . . . . . . . . . . . .

19

1.1.1.3.1.1

Chiral Transfer from a Brønsted Acid . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

19

Chiral Transfer from (R)-2,2¢-Dichloro-1,1¢-bi-2-naphthol–Antimony(V)
Chloride Complex . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

19

1.1.1.1.1


1.1.1.3.1.2

1.1.1.3.1.3
1.1.1.3.2

Chiral Transfer via Nucleophilic Phosphoramidites . . . . . . . . . . . . . . . . . . . . . . . . . . . 20
Polyene Cyclization Initiated by Unsaturated Ketones and
Mediated by Aluminum Lewis Acids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

21

1.1.1.3.3

Gold-Mediated Enantioselective Polycyclization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22

1.1.1.3.4

Polycyclization Initiated by an Episulfonium Ion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23

1.1.1.3.5

Polycyclization Initiated by a ð-Lewis Acidic Metal . . . . . . . . . . . . . . . . . . . . . . . . . . . 23
Enantioselective Polyene Cyclization Mediated by Chiral
Scalemic Iridium Complexes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

24

1.1.1.3.7

Acyliminium-Initiated Polyene Cyclization Mediated by Thioureas . . . . . . . . . . . .


24

1.1.1.3.8

Tail-to-Head Polycyclization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25

1.1.2

Radical Polyene Cyclizations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26

1.1.2.1

Most Used Radical Polycyclization Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26

1.1.1.3.6

1.1.2.1.1

Cyclization of Mono-and Polyunsaturated â-Oxo Esters Mediated
by Manganese(III) Acetate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26

1.1.2.1.2

Titanocene-Catalyzed Polycyclization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1.1.2.2

Recent Advances in Radical Polycyclization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28


1.1.2.2.1

Manganese- and Cobalt-Catalyzed Cyclization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28

27