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STRATEGIES FOR
PALLADIUM-
CATALYZED
NON-DIRECTED AND
DIRECTED C H BOND
FUNCTIONALIZATION
STRATEGIES FOR
PALLADIUM-
CATALYZED
NON-DIRECTED AND
DIRECTED C H BOND
FUNCTIONALIZATION
Edited by
ANANT R. KAPDI
Institute of Chemical Technology, Mumbai, India
DEBABRATA MAITI
Indian Institute of Technology, Mumbai, India
Elsevier
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LIST OF CONTRIBUTORS
Bhalchandra M. Bhanage
Institute of Chemical Technology, Mumbai, Maharashtra, India
Aniruddha Dey
Indian Institute of Technology Bombay, Mumbai, Maharashtra, India
Uttam Dhawa
Ian J.S. Fairlamb
University of York, York, United Kingdom
Prashant Gautam
Vijay Gayakhe
Aniket Gholap
Ye-Qiang Han
Zhejiang University, Hangzhou, China
Fang Hu
Lin-Yu Jiao
Northwest University, Xi’an, Shaanxi, PR China
Anant R. Kapdi
Fuk-Yee Kwong
The Hong Kong Polytechnic University, Kowloon, Hong Kong; The Chinese
University of Hong Kong, Shatin, New Territories, Hong Kong
Gabriele Laudadio
Eindhoven University of Technology, Eindhoven, The Netherlands
Gang Li
Fujian Institute of Research on the Structure of Matter, Chinese Academy of
Sciences, Fuzhou, Fujian, China
Bin Liu
Debabrata Maiti
ix
x List of Contributors
Timothy Noël
Eindhoven University of Technology, Eindhoven, The Netherlands
Martin Oestreich
Technical University of Berlin, Berlin, Germany
Benudhar Punji
CSIR-National Chemical Laboratory (CSIR-NCL), Pune, Maharashtra, India
Bing-Feng Shi
Vineeta Soni
CSIR-National Chemical Laboratory (CSIR-NCL), Pune, Maharashtra, India
Neetipalli Thrimurtulu
Chandra M.R. Volla
Shun-Man Wong
The Hong Kong Polytechnic University, Kowloon, Hong Kong
FOREWORD
Methods for the functionalization of otherwise unreactive CaH bonds

have emerged as an increasingly viable platform in molecular synthesis,
with enabling applications in various research areas ranging from material
sciences and natural product chemistry to crop protection and pharma-
ceutical industries. While various transition metals have been identified as
viable catalysts for step-economical CaH activations, palladium catalysis
has arguably thus far proven among the most versatile tools. Thus, pio-
neering studies by Chatt on stoichiometric cyclopalladation reactions
indicated, among others, the potential of this approach for the positional
selective cleavage of inert CaH bonds. Hence, Lewis-basic functionalities
proved instrumental for the site-selective CaH palladation on arenes by
chelation assistance. The strategy of proximity-induced CaH activation
set the stage for a plethora of protocols for directing group-guided CaH
functionalizations. However, from a historical perspective it is interesting
to note that the first palladium-catalyzed CaH functionalizations were
actually accomplished in the absence of directing groups—an observation
that holds true for most of the initial catalyzed CaH functionalizations,
irrespective of the transition metal. Specifically, the oxidative alkenylation
of simple benzene derivatives proved viable by the action of palladium
(II/0) catalysis in a nondirected fashion. The practical importance of the
cross-dehydrogenative olefination was quickly realized and is, for instance,
reflected by this chemical transformation being recognized as a named
reaction. Yet, the synthetic utility of palladium catalysis in CaH activa-
tion chemistry is not limited to the palladium(II/0)-catalyzed
Fujiwara 2 Moritani reaction. Indeed, the palladium(II/IV) reaction man-
ifold was viable through oxidation-induced reductive eliminations as the
key elementary step. Arguably, the most powerful approach continues to
be represented by the palladium(0/II) catalysis regime. Here, the oxidative
addition of organic electrophiles onto catalytically competent palladium
(0) complexes set the stage for various CaH transformations, including
CaH arylations and difficult CaH alkylations. The unique power of the
palladium(0) catalysis approach became evident by ligand-accelerated
CaH functionalizations employing challenging organic chlorides,
xi
xii Foreword
tosylates, and even mesylates. Since the substrates of interest in palladium-

catalyzed CaH functionalizations usually display various CaH bonds
with close dissociation energies, achieving positional selectivity in inter-
molecular reactions continues to be the key challenge. While the early
studies by Chatt and Fujiwara/Moritani (vide supra) highlighted the power
of directed and nondirected CaH transformations, respectively, more
recent advances exploited strategies to control site-selectivity by means of
remote arene functionalizations. However, the palladium-catalyzed CaH
activation approach was not restricted to the functionalizations of
C(sp2)aH bonds, but also allowed for proximity-induced functionaliza-
tions of aliphatic C(sp3)aH bonds. Particularly, in the arena of
challenging C(sp3)aH activation, palladium catalysis displayed a yet
unparalleled broad substrate scope.
With a remarkable toolbox for palladium-catalyzed CaH functionali-
zation protocols at hand, it does not come as a surprise that transforma-
tive applications to the preparation of structurally complex target
molecules have appeared in the past few years. Thus, the power of
palladium-catalyzed CaH activation was illustrated by efficient syntheses
of natural products, novel polymerization techniques, and the late-stage
modification of bioactive compounds, such as nucleobases or peptides in
a bioorthogonal fashion.
This book summarizes all facets of palladium-catalyzed CaH activa-
tion of relevance to the assembly of organic molecules and the design of
molecular architectures, which should prove invaluable for scientists in
academia, as well as practitioners in applied areas, such as chemical and
pharmaceutical industries. In consideration of the increasing practical
importance of CaH functionalizations, along with the outstanding versa-
tility of palladium catalysis, further exciting applications are expected.
The full potential of catalytic CaH activation chemistry will only be
unleashed through the transition from academic research to industrial
applications on scale.
Lutz Ackermann
Göttingen, August 2016
Traditionally, the assembly of heterocycles largely involved the

interconversion of preexisting functional groups, the installation of which
often required lengthy synthetic operations. Since these approaches, thus,
produce major amounts of undesired by-products and waste, the focus has
shifted during the past decade towards the development of methods that
Foreword xiii
capitalize upon the activation of otherwise inert CaH bonds. Hence,

metal-catalyzed CaH functionalizations have revolutionized the effi-
ciency of heterocycle syntheses, leading to an overall streamlining of the
construction of increasingly complex target structures. Particularly, oxida-
tive transformations were identified as versatile tools for the effective de
novo synthesis of, among others, oxygen-, nitrogen-, and phosphorous-
containing heterocycles.
The synthetic utility of the CaH activation approach is, however, not
limited to the assembly of heterocycles. Indeed, the past decade has
gained enormous momentum in establishing tools for the step-
economical functionalization of heterocycles. Furthermore, in a more
general context, heterocycles are not only of relevance as substrates for
CaH functionalizations, but are also mandatory as ligands and/or as site-
selectivity-ensuring directing groups in CaH activation chemistry.
Organic substrates of interest for direct functionalizations usually bear
numerous CaH bonds of comparable dissociation energies. Therefore, a
major obstacle in achieving synthetically useful CaH functionalizations is
constituted by fully controlling the site-selectivity in intermolecular trans-
formations. While this represents a formidable challenge in direct arene
functionalizations, heteroarenes often display CaH bonds with increased
kinetic acidity, mostly proximal to an electronegative heteroatom.
Hence, recent years have witnessed a major growth in protocols for
metal-catalyzed CaH functionalizations that proceed in a (concerted
metalation) deprotonation fashion. For instance, earth abundant base
metals, such as copper, nickel, or cobalt catalysts, allow for site-selective
CaH functionalizations of various five-membered heteroarenes, provided
rather strong bases were utilized. Since the functional group tolerance of
such reactions is often compromised, a powerful alternative was estab-
lished by carboxylate-assisted CaH metalations, largely with the aid of
4d transition metal catalysts based on palladium, rhodium, or ruthenium.
Thereby, challenging heteroarene functionalizations proved ultimately via-
ble under exceedingly mild reaction conditions.
From a historical perspective, it is noteworthy that several CaH func-
tionalization protocols were in fact initially developed for heterocyclic sub-
strates. For instance, one of the arguably most powerful tools in CaH
functionalization chemistry, palladium(0)-catalyzed direct arylation with
organic electrophiles, was originally devised for the site-selective diversifi-
cation of indoles. This pioneering report nicely illustrated the power of
controlling the site-selectivity in heteroarene CaH functionalizations.
xiv Foreword
Thus far, most of the advances in heterocyclic CaH activation were

accomplished through the cleavage of C(sp2)aH bonds. However, major
recent progress was constituted by the functionalization of thermodynami-
cally less stable, but frequently more difficult to activate, C(sp3)aH bonds.
CHAPTER 1
Introduction
Aniruddha
1
Dey1, Anant R. Kapdi2 and Debabrata Maiti1
2
Organic chemistry has often been nominated as collateral to a celestial

divinity bestowing Earth with the art of creation of life. Since the
realization of a tangible cognizance about the prowess of this wonderful
repository, mankind began their venture into developing deeper compre-
hension about the same. Theories akin to “Vitalism” were dubbed as out-
moded clichés, as burgeoning scientific tendencies separated abstract
convictions into perceptible rationale. Credulous minds gradually evolved
into inquisitive intellects, and the convergence between beliefs and truth
was thus laid, resulting in the foundation of unfettered knowledge and
newfound discoveries. This had been proactive in carving the existence
and subsequent development of the human race since its genesis. This
saga remained persistent throughout centuries, leading to the creation of
rewarding inventions time and again whenever cogent queries hit covert
speculations. This is what defines science in its purest form, and organic
chemistry, being an inseparable and indispensable subset, fulfills the crite-
ria in more ways than are actually expected. Organic chemistry serves to
be an omnipotent benefactor for human civilization beside other
subsidiaries of chemical science. Beginning with the discovery of the first
organic compound, i.e., urea in 1828, chemists continued to seek startling
revelations about the chemical structure of organic components, and
develop synthetic procedures to mimic the formation of natural products,
produce life-saving pharmaceuticals, and address solutions to product
manufacture in complex industrial settings. The late 19th century wit-
nessed the first ever synthesis of aspirin and since then, the pharmaceuti-
cal industry has undergone a boom in drug production and development,
thereby emerging to occupy a voluminous portion of the world’s econ-
omy in recent times. Classical organic synthetic procedures paved the way
for chemists to find a path for the creation of important bio-relevant
components that were otherwise preeminent in their occurrence through
natural chemical processes. Importantly, cross-coupling reactions, typical
Strategies for Palladium-Catalyzed Non-Directed and Directed C H Bond Functionalization © 2017 Elsevier Inc.
DOI: http://dx.doi.org/10.1016/B978-0-12-805254-9.00001-3 All rights reserved. 1
2 Strategies for Palladium-Catalyzed Non-Directed and Directed C H Bond Functionalization
of the Wurtz reaction, appealed to the minds of erudite chemists.

However, expectations rose further in the search for strategies that would
render high yields of final products while utilizing raw materials at
low cost. Implementation of transition metal-based catalytic procedures
were determined as perfunctory measures to address this conjecture.
Consequently, famous reactions like those devised by Fujiwara 2 Moritani,
Heck, Suzuki, and others rose to the zenith of popularity, as these seemed
to assure cost-effective and productive routes for synthesis of complex
moieties from simpler ones. Advances were made in transforming various
types of carbon bonds into the desired ones, using an assortment of func-
tionalization techniques. The advent of catalysis imbued synthetic chemis-
try with the right panache to provide remedies for several limitations that
had been prevalent since preexisting times. The most vibrant of these was
the modification of a target site in a molecule beside the concurrent pres-
ence of several competitive sites with identical reactivities. This has been
addressed through a plethora of metal-mediated transformations that
ensured accentuated levels of site-selectivity within a complex molecular
cluster containing bonds with innately similar chemical properties. This
has been found to be prevalent during functionalization of heterocycles,
aromatic-rings, and several other members of the aliphatic class.
Recognition of directing groups in performing remote functionalization
was another feather in the crown that rose to attain distinctive stature at
the turn of the 21st century. Leading the fleet of innovations and ushering
in interest in the betterment of science and research, directing group
assisted CaH activation was established as the modus operandi for compli-
cated functionalization in organic molecules. This has enabled transforma-
tions to be executed at remote sites, be it in aromatic or in long aliphatic
chains. Discovery of detachable nucleophilic anchors for directing remote
sp2 CaH activation in recent years has further advanced the chain of
development in regioselective functionalization. Additionally, curious
quests to blend computational tools with synthetic methodology have
unlocked a new field of inquiry and élan.
This book summarizes the recent advances in synthetic chemistry
through the eyes of CaH functionalization-based strategies. Renowned
research scholars have penned a collective treatise from their distinctive
fields of interest, and pooled a coherent discussion about the fundamental
concepts. Insightful and detailed address of the intricacies for the various
methodologies further mark the cogent and analytical comprehension of
the ideal mindsets of the 21st century chemists. However, the variety of
Introduction 3
metals used for catalytic conversions stands legion, and a vivid discourse
encompassing all of them is beyond a corporeal attempt. Undoubtedly,
the countable occasions in which palladium was used to perform such
historical transformations are innumerable. This could be attributed to
its greater catalytic efficiency, ease of procurement, and a multitude of
advantages, coupled with the cost-effectiveness. Subsequent chapters
in this book therefore revolve around chemical strategies which discern
palladium as a catalyst, and thus rightfully recognize it as the protagonist
in the book’s context (Fig. 1.1).
The opening chapter introduces readers to the fascinating diorama of
ligand supported functionalization of CaH bonds in aromatic cores.
Owing to the synthetic significance of metal-mediated CaH activation
strategies, the benefit of using ligands are well-precedented in the literature
Figure 1.1 Schematic representation of the various aspects of palladium-catalyzed

protocols covered in this book.
of organometallic chemistry. With respect to the modes of coordination,

ligands can either form a strong or weak coordination bond to the metal
precatalyst. This in turn compensates for lowering the energy of inter-
mediates formed in the chemical transformation. A low energy requiring
pathway is thereby established which renders the transformation effective
on a catalytic scale. Strongly coordinating ligands are believed to yield a
more stable intermediate compared to the weakly binding ligands. In this
chapter, Fairlamb and Kapdi present a vivid exemplar of CaH activation-
based transformation based on the effective and logical use of ligand
control-based strategies.
In the chapter about nondirected CaH bond functionalization, Wong
et al. discuss viable strategies undertaken for synthesis of biheteroarenes.
The latter class of compounds enjoy a celebrated mention among a multi-
tude of applicative fields like biological and pharmaceutical materials, and
natural products, as well as in synthetic research. Correspondingly, a deep
insight into the contemporary synthetic procedures which allow their
production is significant. Wong et al. underline nondirected catalytic
routes used in the last decade for effectuating the synthesis of bihetero-
arenes from simple starting precursors. These ensure cost-effective and
greener alternatives to the directing group-based functionalization phe-
nomenon. The chapter talks about strategies for palladium-catalyzed
cross-coupling reactions between arenes/heteroarenes and arylhalides.
Owing to the harsh synthetic procedures required for preparation of
non-commercially available arylhalides, application of pseudohalides for
biheteroarene synthesis is discussed as well.
The discussion on biheteroarene synthesis is then succeeded by an
account of the activation of sp3 CaH bonds. The high bond dissociation
energy of an aliphatic sp3 CaH bond renders these types of systems
extremely inert. Moreover, an absolute absence of an easily polarizable
electron cloud renders them unreactive. In this chapter, Liu et al. talk
about a highly challenging aspect of incorporating arene rings at these
unactivated centres. An assortment of novel strategies encompassing the
efficacy of using directing groups and other chelation assisted strategies
to perform a highly selective arylation in aliphatic carbon motifs have
been explored. These include a lucid imagery of the benign directing
groups which have been designed by Daugulis, Carratero, Ma, and
others. More about this and about other types of functionalizations at
unactivated sp3 CaH centers have been discussed by Dey et al. in a later
chapter of this book.
Introduction 5
In the following chapter, Jiao et al. concentrate on the synthetic

approaches for CaH bond functionalization at the benzene core of het-
erocycles, namely indole and indolines. The prominent importance of the
indole motif in natural products and biologically significant materials
recognizes the divulgence of their synthetic strategies. Jiao and Oestreich
conscientiously portray recent advances in functionalization at the C-4
and C-7 positions of indole, and C-6 and C-7 positions of indolines
under the broad umbrella of palladium catalysis. Preferable reactivity at
the C-2 and C-3 positions of indoles render selective functionalization at
the other positions challenging. The chapter describes measures that cir-
cumvent such a possibility to ensure the desired functionalization.
Drawing analogies from the traditional Fujiwara 2 Moritani reaction,
selective functionalization at the C-4 position of indole has been
effected. Interestingly, chemists have employed indolines as plausible pre-
cursors for C-7 transformation in indoles. Execution of such phenome-
non through the use of directing groups is also tangible. Numerous
reports on palladium-catalyzed CaC bond formation reactions are
detailed in this chapter.
Subsequently, Gautam et al. present highlights on carbonylative and
carboxylative reactions in CaH functionalization. The latter two catego-
ries of functionalization are recognized to be some of the oldest examples
of chemical transformations to be executed. In this chapter, the authors
describe an account of palladium-catalyzed carbonylative and carboxyla-
tive methodologies. Additionally, the importance of directing groups like
those of amidines, oximes, sulfonamides, etc., in attaining sp2 CaH
carbonylation has been emphasized. Further, the same stretches over a
discussion on carbonylation reactions with heterocyclic systems contain-
ing single or multiple heteroatoms. Carboxylative reactions which typify
the use of CO2 as a reacting agent are also mentioned towards the close
of the chapter.
While the sojourn through the metal-catalyzed organic transforma-
tions continues, Laudadio et al. introduce us to the riveting applications
of “Flow Chemistry” in organic synthesis. A boon for the chemists of the
modern era, flow chemistry has created a completely new dimension for
synthetic processes by allowing faster reaction rates at cheaper production
costs. Laudadio and Noël draw a contour emphasizing the potential of
microflow reactors in performing catalytic transformations in microliter
scale. The hardware setup for flow chemistry is meticulously designed to
cause self-degeneration of the hazardous chemical wastes that are formed
as by-products in a reaction mixture. Eminent research groups like those

of Davies, Jones, Lapkin, and Noël have showcased the efficiency of this
technique in performing transition metal-catalyzed CaH activation reac-
tions that proceed with shorter time scales and precise selectivity.
Integrated multistep synthesis coupled with effective scalability augment
the attractiveness of this approach in a practical laboratory setup.
As Noël builds the stage for presenting the new-fangled advances of
recent eons, Gang Li presents the subsequent chapter describing a phe-
nomenon occurring in the area of directed CaH functionalization chem-
istry: meta-CaH functionalization of aromatic cores. In this chapter,
Li summarizes the significant reports on sp2 CaH functionalization at the
distal meta- position of an arene. Pioneered by Yu in 2012, directed meta-
CaH activation has emerged currently as a hot area of research in the
arena of organometallic catalysis. Regioselective formation of CaC/
CaO bonds continues to make way at the meta-position of unactivated
arenes, thereby overcoming a problem persistent since the onset of metal-
mediated CaH bond activation in an arene core. Gang Li pens a chrono-
logical sequence of the gradual evolution of meta-functionalization. The
latter popularizes an emerging class of cleavable directors which were sub-
sequently brought to operational existence by the Yu, Tan, Maiti, and
Li groups to perform distinguished meta-CaH olefination, acetoxylation,
arylation, hydroxylation, and iodination.
In the succeeding chapter, Dey et al. discuss transformation of sp3
CaH bonds catalyzed by palladium precatalysts. As discussed in
Chapter 4, activation of an sp3 CaH bond is quite challenging, owing to
its low reactivity and relative inertness compared to the sp2 and sp conge-
ners. In such cases, complexity is further amplified by the attempts at
functionalization at remote positions with respect to the preinstalled func-
tional groups. Functionalization at sites which are close to the preinstalled
functionality (say, at α/β position) has been addressed mostly through
classical or in some cases, by application of traditional cross-coupling
methods. Functionalization at sites remote to these positions requires
skilled construction of the catalytic operations. A suitable requirement of
directing groups in promoting such remote aliphatic CaH activation was
realized. This chapter therefore highlights some recent advances made in
the field of aliphatic distal CaH functionalization which have been made
possible through the employment of an assortment of strategies.
In Chapter 10, Palladacycles for Directed and Nondirected CaH
Bond Functionalization of (Hetero)arenes, Soni et al. focus on the use of
Introduction 7
palladacycle precatalysts in CaH bond functionalization, as well as pro-

viding an overview of palladacycle intermediates in directed CaH bond
functionalization reactions. The described palladacycle precatalysts are
more efficient and more selective than the traditional palladium com-
plexes for the CaH bond functionalization processes. The second half of
the chapter summarizes the involvement of palladacycle intermediates in
various directed CaH bond functionalizations that are proposed with
experimental evidence. Some of the described palladacycle intermediates
are shown to be competent as catalyst precursors, coupled with their sta-
bility during the functionalization phenomenon.
The penultimate chapter deals with the mechanistic aspects of metal-
mediated CaH bond functionalization as part of its context. Gayakhe
et al. present an account of the fundamental and key concepts behind the
operation of organometallic catalysis. With the earlier reports about oxi-
dative addition to H2, the authors discuss the basic mechanistic pathways
involving electrophilic aromatic substitution and oxidative additions.
Further, owing to the recent reports on the popularity of cyclometalla-
tion 2 demetallation (CMD)-based reaction schemes, an insight into the
CMD mechanism is provided. Finally, the discussion concludes with
mention of the Heck-type carbometallation pathways that lessen the
requirement for any preactivation step. The latter is particularly popular
in the case of palladium-catalyzed cross-coupling reactions.
In the closing chapter, Thrimurtulu et al. collectively summarize the
application of CaH functionalization in the total synthesis of organic
molecules. This chapter discusses the synthetic routes to form a host of
natural products and other complex substrates, starting from simple and
readily available starting precursors. All of these involve CaH activation
as a key step in achieving the desired transformation. The applicability of
sp3 and sp2 CaH functionalization has been showcased as an effective
method of ensuring functional group installation in a highly site-selective
manner. Examples from recent literature reports are detailed with substan-
tial analysis of the reaction pathways. This chapter is therefore important
from the point of view of developing a sound concept about simplifying
retrosynthetic disconnections in the course of synthesizing any complex
molecules as the target motif.
An intuitive mind is always a sacred gift for humanity, and the curios-
ity to know opens up boundless possibilities for evolution and advance-
ment. This has been the sole truth behind every piece of advancement
made throughout history since bygone ages, which continues to be in
existence and shall remain the same for eternity. Attempts to bring mod-
ernization into chemistry led to the development of CaH activation-
based protocols which have significantly reshaped scientific temperament
and created a novel dimension for rethinking synthetic transformations.
This book, besides summarizing the notion of scientific progress made in
the field of palladium-catalyzed CaH functionalization in recent times,
aims to inculcate cognizance among the scientific fraternity about the
same, and wishes to encourage chemists of both the present and future
generations to contribute their ideas towards the welfare of the scientific
community, as well as for all and sundry.
CHAPTER 2
Directed CaH Bond

Functionalization Strategies
for Synthesis
Ian
1
J.S. Fairlamb1 and Anant R. Kapdi2
University of York, York, United Kingdom
2
Contents
2.1 Introduction 9
2.2 Ortho-Palladated CaH Bond Functionalization via Directing Group Effect 11
2.2.1 Effect of Coordination Capacity on Functionalization 11
2.3 Conclusion 45
References 46
2.1 INTRODUCTION
Organic synthesis in recent decades has undergone a tremendous change
with the advent of catalytic processes providing an efficient alternative to
non-catalyzed reactions. The unparalleled success obtained by these cata-
lytic processes was based on the rapid development of newer and more
efficient catalytic systems functioning under milder reaction conditions.
Selective functionalization of a variety of unactivated bonds having appli-
cations across a wide spectrum of fields has contributed further to the
popularity of these processes. The prerequisite for achieving the required
success involves the pre-functionalization of the substrate leading to fur-
ther activation of other bonds. Although the installation of CaO, CaX,
CaN, and CaC bonds could be achieved via these processes, cost escala-
tion for the multi-step reactions renders the overall process commercially
less attractive. Circumventing this problem would involve the possibility
of employing an unfunctionalized substrate that could be directly functio-
nalized without the requirement for a prefunctionalization step.
Direct functionalization via the activation of unreactive CaH bonds
could provide researchers with the required sustainable solution that could
Strategies for Palladium-Catalyzed Non-Directed and Directed C H Bond Functionalization © 2017 Elsevier Inc.
DOI: http://dx.doi.org/10.1016/B978-0-12-805254-9.00002-5 All rights reserved. 9
also be cost-effective.1 This is achieved via the insertion of transition

metals into the unreactive CaH bond, resulting in a chemically more
reactive Ca[TM] bond being available for further functionalization.
Although an attractive alternative to the multi-step coupling processes,2
selective functionalization of chemically equivalent CaH bonds presents
researchers with a unique synthetic challenge. Initial reports on the stoi-
chiometric activation of CaH bonds have now been replaced in recent
years with efficient catalytic activation processes employing transition
metals such as Ru, Cu, Fe, Ni, Rh, and Pd.3 Palladium, with its unique
reactivity, has been at the forefront in these processes, allowing the func-
tionalizations to be performed under milder conditions.
To address the problem of selective CaH activation in substrates,
researchers have strategized several methods based on factors that could
assist metal insertion into a solitary CaH bond. One of the strategies that
has found extensive application in palladium-catalyzed CaH bond activa-
tion takes advantage of the coordinating ability of ligands (functional
groups) on substrates that can direct the metal into CaH bonds allowing
selective functionalization (Fig. 2.1). Such a strategy would not just allow
a cost-effective method for functionalization, but also would make it possi-
ble to install a variety of bonds such as carbonaoxygen, carbonanitrogen,
carbonasulfur, and carbonacarbon, etc.
The focus of this chapter involves the classification of the coordinating
ligands based on their coordinating ability and the type of bond formation
they have been employed for. Some discussion on the effect of base for
the abstraction of proton, as well as the role of acids (as solvents) for pro-
moting the directed CaH functionalization, is also undertaken. Most of
the examples discussed herein are related to ortho-functionalization of aro-
matic substrates proceeding commonly via a cyclopalladated intermediate
that governs the selectivity in these reactions. Functionalization of other
sites on the benzene ring or on aliphatic substrates falls outside the scope
[DG] [DG] [DG]

[M] [M]
[M] = Pd - HL
H
L
[DG] = Directing group
Figure 2.1 Schematic representation of directing group effect on CaH bond
activation.
Directed CaH Bond Functionalization Strategies for Synthesis 11
of this chapter, and readers are advised to refer to some of the recent liter-
ature on this topic,4 as well as the further chapters of this book where
these topics are discussed in depth by Li and Maiti.
2.2 ORTHO-PALLADATED CaH BOND FUNCTIONALIZATION

VIA DIRECTING GROUP EFFECT
The innate nature of the CaH bond makes the process of selective acti-
vation all the more challenging. Researchers have developed various
methods to circumvent this problem, with the use of directing groups
(coordinating ligands) on the substrate to be functionalized the most pop-
ular of all. Depending on the coordinating capacity of the directing
groups a lot of chemistry has been developed in the past decade that uti-
lizes palladium precursors for catalyzing these transformations. These
coordinating ligands could be divided into two types (only for those func-
tional groups that have been employed in this chemistry) as strongly coor-
dinating or weakly coordinating with regards to their interaction with the
palladium center. Some of the commonly employed coordinating ligands
in palladium-catalyzed CaH bond functionalization are listed below:
(a) Strongly coordinating ligands: pyridine, anilide, urea, etc.
(b) Weakly coordinating ligands: ketone, hydroxyl, amides, phosphate,
esters, sulfonamides, carbamates, formate esters, alkynes, alkenes,
carboxylic acids, etc.
There are many other functionalities that have also found applications
in selective CaH bond functionalization reactions; however, based on
the number of examples in literature, only the most applicable ligand sys-
tems (listed above) will be discussed in detail in this chapter.
2.2.1 Effect of Coordination Capacity on Functionalization

At the outset it is important to understand the effect of the coordinating
power of ligand on the effectiveness of selective CaH bond activation,
and the functionalization possibility presented by such types of coordina-
tion. A glance through the literature suggests that the number of examples
based on the employment of strongly coordinating ligands as directing
groups far exceeds that of their weakly coordinating counterparts. On a
fundamental level, this difference in coordination with the metal center
directly affects the stability of the resultant cyclopalladated intermediate
that would translate into a more stable intermediate for the strongly coor-
dinating ligands, and conversely a weaker intermediate for the weaker
O Me NH
O C—H activation R
Me NH
Me NH
[Pd]
More stable intermediate Lower energy barrier
HO O
C—H activation
R
Pd precursor
XO O
[Pd]
XO O
Less stable intermediate Higher energy barrier
Figure 2.2 Energy representation for strong and weakly coordinating ligands in CaH
bond activation processes.
ligands. In terms of the energetics of the reactions, it could be observed

that complexation of the metal precursor with strongly coordinating
ligands could lead to a lowering of energy, thus making the resultant
intermediate more stable (Fig. 2.2). Conversely, binding the metal with a
weakly coordinating ligand increases the energy of the intermediate,
which is less stable and has a higher possibility of dissociation.
Based on these details, it would be fair to say that the effectiveness of
selective CaH bond functionalization could be achieved in the presence
of strongly coordinating ligands on the substrate. However, pioneering
work by Yu and co-workers5 in recent years demonstrating the potential
of weakly coordinating ligands for the functionalization of a diverse range
of substrates also holds a lot of promise, and could help promote further
development in this area. From the myriad of functional groups that have
found major applications in palladium-catalyzed CaH bond functionali-
zation, we will discuss in detail examples involving heterocyclic rings,
amides, anilides, and carboxylic acids as the directing groups.
2.2.1.1 Heterocycles as Directing Groups for Palladium-Catalyzed

CaH Bond Functionalization
One of the most common and applicable heterocyclic directing groups
coordinating with the palladium center through the lone pairs available
on the nitrogen atom is pyridine.6 Although recent examples have also
incorporated other heterocyclic ring systems (quinolines, benzoquino-

lines, pyrrolidinones, oxazolidinones, etc.), pyridine has led the way due
to its better coordinating capacity, and the ease of synthesis of the
required substrates for carrying out such transformations.
One of the earliest examples for the employment of pyridine as a
directing group in palladium-catalyzed CaH bond functionalization
was reported by Sanford in 20057 (Scheme 2.1A), with diphenyliodo-
nium trifluoroborate used as the coupling reagent. Subsequently, an
oxidative homocoupling protocol was also reported by the same group8
(Scheme 2.1B).
The possibility of using simple aryl iodides as coupling partners was
first put forth by Daugulis and co-workers,9 making the process syntheti-
cally more attractive. This was further extended to benzylic substrates
rather than the general arenes, allowing the generalization of substrate
combination for effective CaH bond functionalization (Scheme 2.2A).
Despite all the advances involving the development of highly active cata-
lytic systems for efficient CaX activation (especially CaBr or CaCl
bond activation) in cross-coupling processes, their application in directed
arylations has been limited. A major synthetic challenge therefore remains
to be addressed for using commercially viable aryl bromides, or preferably
chlorides, as the arylating reagents. However, recently Sun and co-
workers10 have reported on aryltrimethoxysilanes as coupling partners for
the arylation of phenylpyridines (Scheme 2.2B).
N N
Pd(OAc) 2 (5.0 mol%)
(A) + [Ph 2 I]BF4 Ph
AcOH/Ac 2 O,
100ºC, 8 h
Me
Me
Oxone (2.0 equiv.) N
(B) N
N i PrOH, 25ºC, 17 h
Me
Scheme 2.1 (A) Functionalization using diphenyliodonium salt; (B) oxidative homo-
coupling of phenylpyridines using oxone as the oxidant.
I
Pd(OAc) 2 (5.0 mol%) N R2
AgOAc (3.0 equiv.)
(A)
AcOH, 100°C
R2 longer reaction times R1
N
+
Si(OMe) 3
Pd(OAc) 2, N R3
Benzoquinone
R1 (B)
AgF, 1,4-dioxane
R3 100°C R1
Scheme 2.2 (A) Aryl iodides as the arylating agents; (B) aryltrimethoxysilanes as cou-
pling partners.
BF 3 K Pd(OAc) 2 (10 mol%)

Cu(OAc) 2 (3.0 equiv.) N R2
Benzoquinone (2.0 equiv.)
(A)
1,4-Dioxane, 120°C, 24 h
R2 R1
N
+ Pd(OAc) 2 (10 mol%)
B(OH) 2
Cu(OTf) 2 (20 mol%) N R3
TBHP (2.0 equiv.)
R1 (B)
60°C, 24 h
R3 R1
Scheme 2.3 Boron reagents for arylation: (A) potassium aryltrifluoroborates; (B) aryl-
boronic acids.
The employment of boron compounds as arylating reagents has also

been explored, with the first example reported in 2009 for the arylation
of phenylpyridine using potassium aryltrifluoroborates, although the cata-
lyst loading of Pd(OAc)2 was found to be very high (Scheme 2.3A).11
Arylboronic acids were also tried as a possible cheaper coupling partner,
but this failed to furnish the arylated product in good yields. A few years
later, Cai and co-workers, in 2013, employed the economical arylboronic
acids for the directed arylation reactions in the presence of TBHP and
catalytic copper salt as oxidants, with the amount of copper restricted to
20 mol% as compared to a large excess used in the earlier protocol
(Scheme 2.3B).12
Besides the examples mentioned above for the arylation of phenylpyr-

idines, another protocol involving a lesser known arylating agent, acyl
peroxides, was also demonstrated to provide the ortho-arylated product in
good yields.
In comparison to the directed arylation protocols involving the use of a
variety of arylating reagents (vide infra), alkenylation or alkylation of pyri-
dines yielding molecules of synthetic importance due to the possibility of
further manipulation are less pronounced. Pyridine as a directing group
allowed the olefination to take place in the presence of a Pd(II) catalyst and
a catalytic amount of a heteropolyacid in the presence of air as the oxi-
dant.13 Such a synthetic strategy allows easy access to 6,5-N-fused bicyclic
cores of further biological relevance (Scheme 2.4). The protocol, however,
suffers from a limited reaction scope attributed to the dependence of cata-
lytic activity on the reactivity of the olefin with activated olefins being pre-
ferred over the unactivated. Surprisingly, this is the only report for
olefination being carried out utilizing the directing property of pyridine.
Another synthetic challenge that has intrigued researchers in the past
decade has been the alkylation of substrates using highly reactive alkylboron
reagents that are known to dissociate rapidly under the conditions via the
deboronation pathway. The employment of these alkylboron reagents as
alkylating agents in palladium-catalyzed CaH bond functionalization of
phenylpyridines was first reported by Yu and co-workers14 (Scheme 2.5).
Given the reactive nature of the alkylboron reagents, rather than using
methylboronic acid (for methylation) that is known to deboronate at a rapid
rate, its cyclic analogue methylboroxine (stable over a longer period of time)
was employed, providing good yields of the methylated product. Based on
these results, the authors developed an asymmetric variant involving the use
of butylboronic acid in the presence of Pd(OAc)2/chiral amino acid ligand.
Methylation of phenylpyridine could also be carried out by the employ-
ment of a unique methylating agent in the form of tert-butyl peroxides.
Pd(MeCN) 4 (BF4 )2 (10 mol%) OAc

N N
H 4[PMo 11 VO40] (3.0 mol%)
+ CO 2 Et CO 2 Et
NaOTf (1.1 equiv.)
AcOH, Air, 110°C
Scheme 2.4 Pyridine as directing group for olefination leading to 6,5-N-fused bicyclic
cores.
Me Pd(OAc) 2 (10 mol%)

N Cu(OAc) 2 (1.0 equiv.) N
B
O O Benzoquinone (1.0 equiv.)
+ Me
B B CH 2 Cl 2, Air
Me O Me
100°C, 24 h
Scheme 2.5 Methylation of phenylpyridine using boroxine as an alkylating agent.
N N N
R Pd(OAc) 2 (10 mol%)
+ O
O Me Me Me
R 130°C, 12 h, N2
R = H or Ph
2-Phenylpyridine:peroxide = 1 : 1 50% 0%
2-Phenylpyridine:peroxide = 1 : 4 10% 70%
Scheme 2.6 Methylation of phenylpyridine using peroxide as methylating agent.
This unusual methylation protocol was recently disclosed by Li and co-

workers,15,16 with the peroxide serving as the possible methylating agent
(Scheme 2.6). An interesting aspect of the ortho-arylation process is the
selectivity achieved for the mono-methylated product over di-methylation.
Support for the selectivity observed, as well as the possible pathway
followed, was provided by Sunoj and co-workers,17 based on computational
studies that were performed. A combination of radical and non-radical
pathways involving a palladiumamethyl intermediate was found to be
operative.
Trifluoromethylation of phenylpyridine under palladium-catalyzed
CaH bond functionalization conditions was performed using 5-(trifluor-
omethyl)-dibenzothiophenium tetrafluoroborate as the trifluoromethylat-
ing agent by Yu and co-workers18 (Scheme 2.7). It is the only literature
report on phenylpyridines with trifluoroacetic acid as the solvent. The
protocol showed remarkable functional group tolerance, with a variety of
functional groups showing compatibility to the conditions employed.
Aryl nitriles are important synthetic intermediates that have found
wide application due to their ease of conversion to other functional
groups. The introduction of a cyanide group via palladium-catalyzed
CaH bond functionalization would therefore provide synthetic chemists
with a handle for further manipulation, leading to molecules of synthetic
N Pd(OAc) 2 (10 mol%) N

Cu(OAc) 2 (1.0 equiv.)
+ CF3
S DCE-TFA (10 equiv.)
CF 3 BF 4 110°C, 48 h
Scheme 2.7 Trifluoromethylation via ortho-CaH bond functionalization of

phenylpyridine.
Pd(OAc) 2 (10 mol%)

N
CuBr 2 (40 mol%)
(A) CuCN
DMF,130°C CN
N
R
Pd(II)/Mg–La (5.5 mol% Pd)

N H4 HCO3 Cu(NO ) 3H O (2.0 equiv.) N
3 2. 2
R (B) (2.1 equiv.)
140°C, 18 h CN
O
S
H 3C CH3 R
(2.0 mL)
Scheme 2.8 Palladium-catalyzed CaH cyanation of phenylpyridines using cyanating
agent: (A) copper cyanide; (B) a combination of ammonium hydrogen carbonate and
dimethyl sulfoxide.
relevance. The first example of CaH cyanation using CuCN as the cya-
nide source was reported in 2009 by Cheng and co-workers19
(Scheme 2.8A). The cyanation protocol thus developed was applied to
the synthesis of a key intermediate of an alkaloid, Menispermum dauri-
cum DC, which is known to exhibit promising analgesic and antipyretic
properties. An important advanceinvolving a palladium(II)/magne-
siumalanthanum mixed oxide as a heterogeneous catalyst for palladium-
catalyzed CaH cyanation of phenylpyridines was put forth by Kantam
and co-workers in 2015 (Scheme 2.8B).17 In situ generation of CN2 was
made possible from the combination of NH4HCO3 and DMSO, rather
than the commonly applicable inorganic cyanide sources. Besides achiev-
ing excellent regioselectivity for cyanation, the catalytic solution was also
found to be recyclable for up to three cycles. The active nature of the
heterogeneous catalyst allowed a tandem Suzuki coupling/CaH cyana-
tion reaction of 2-halopyridines.
Another biologically and chemically important process that is known

to define numerous cellular processes is acylation. A functional group that
has defined a large number of industrial processes due to its unique reac-
tivity demands a special place in the synthetic chemist’s arsenal. To access
these important structural motifs, a cross-dehydrogenative coupling strat-
egy between phenylpyridine and arylaldehyde (electron-rich or electron-
deficient) in air as an oxidant was envisaged by Cheng and co-workers
(Scheme 2.9A).20 This transformation was made possible through the
coordination-assistance provided by the pyridine nitrogen. The protocol
was further extended to other heterocyclic ring systems such as quino-
lines. On similar lines, Li and co-workers21 also reported an efficient acyl-
ation protocol for such heterocyclic ring systems allowing aliphatic,
alicyclic aldehydes to be used as acylating agents (Scheme 2.9B).
O
N
H Pd(OAc) 2 (10 mol%) O
(A)
Xylene, air (1 atm),
R2 120°C, 24 h
R 2 = 4-Me, 4-CN, R1 R2
3-NO2, 4-MeO
24 examples, 40%–90%
O Pd(OAc) 2 (5.0 mol%)

N
TBHP (1.5 equiv.) O
(B) 3
R H Air (1 atm), 120°C, 16 h
R3
R 3 = Me, Cy, n-Bu,
(S)-citronellal
16 examples, 29%–89% R1
N OH PdCl 2 (5.0 mol%)

N
(C) 4
TBHP (3.0 equiv.) O
R H
PhCl, Air (1 atm) R4
140°C, 24 h
R1 R1
R4 = Ar, alkyl
OH Pd(II)/Mg–La (13.5 mol% Pd)

N
TBHP O
(D) R5 H
PhCl, 120°C, 8 h R5
R4 = Ar, alkyl
20 examples, 53%–82% R1
Scheme 2.9 Acylation strategies via palladium-catalyzed CaH bond functionalization.

A) Arylaldehyde as acylating reagents B) Alkyl aldehydes as acylating reagents
C) Alcohols as acylating reagents D) Alcohols as acylating reagents with heteroge-
neous catalyst.
Further developments in this area allowed the CaH bond functionali-

zation to be performed with primary alcohols rather than aldehydes as
the acylating reagents, which was shown independently by Deng and Li
to be efficiently oxidized in situ using TBHP as the oxidant
(Scheme 2.9C).22 Recently, a heterogeneous catalytic version (mixed
metal catalyst) developed by Kantam and co-workers,23 allowed the trans-
formation to be carried out with good selectivity and with some level of
recyclability also achieved (Scheme 2.9D). Besides using aldehydes or
alcohols as the acylating agents, Yang, Fu, and co-workers,24 recently
revealed the possibility of utilizing a cheap and readily available acylating
reagent in the form of arylmethyl amines. In the presence of a palladium
precursor, PdCl2, and with TBHP as the oxidant, benzylamines were effi-
ciently converted into acyl functionalities via the chelation-assisted CaH
activation protocol.
Halogenation of substrates in a selective manner has important syn-
thetic applications, as it could provide researchers with a useful handle for
further manipulation. Pioneering work by Sanford and co-workers
deserves special mention in this regard, with a large variety of functional
groups including halogens (I, Cl, Br, and F) as well as pseudohalides
(OAc) being introduced on the aryl moiety of the phenylpyridine via the
directing capabilities of the pyridine nitrogen. These types of functionali-
zations could be brought about by the employment of mild and selective
halogenating reagents. One of the earliest examples of the functionaliza-
tion of phenylpyridine and related structural features was reported by
Sanford and co-workers in 200425 for the acetoxylation using PhI(OAc)2
as a stoichiometric oxidant (Scheme 2.10).
The resultant ortho-acetoxylated product was obtained with very good
yields. The protocol was further extended towards the functionalization
of other heterocycles in an efficient way.26 Mechanistic studies performed
on the catalytic acetoxylation reaction revealed the initiation of such
transformations taking place via a chelation-assisted cyclometalation path-
way resulting in a possible Pd(IV) intermediate [A], although no direct
evidence for such a proposal has been provided.27 Given the synthetic
utility of this procedure, Ritter and co-workers conducted a thorough
investigation into the scope of the acetoxylation reaction, and were suc-
cessful in extending the protocol to a vast variety of heterocycles and
other substrates.28 Rather than employing the hypervalent PhI(OAc)2
reagent for acetoxylation, Yu and co-workers, revealed the capability of
IOAc for effecting the same transformation also in good yields.29

PhI(OAc)2 (2.3 equiv.)
R N MeCN, 100°C, 12 h R N
OAc
[PdII] Chelation-assisted
C—H activation Reductive
elimination
OAc
N L N L
PhI(OAc) 2
PdII PdIV
Oxidation L
L
OAc
R R [A]
OAc X
N N
OAc OAc (ref 26)
(78%, ref=25) X= F 59% X = CF3 81%
X = Br 83% X = OMe 78%
Scheme 2.10 Selective acetoxylation of phenylpyridines.
Directed halogenation of substrates has been known in the literature

since 1970,30 however, the problems associated with this transformation in
terms of the selectivity, reactivity, and the employment of substoichio-
metric amounts of the palladium catalyst, were addressed more recently. In
2004, a catalytic version was first reported by Sanford and co-workers as
part of their study into the functionalization of heteroarenes (vide infra).25
N-Halosuccinimides for the first time were demonstrated to promote the
selective halogenation of benzo[h]quinoline,25 which was later extended to
phenylpyridines28c (Scheme 2.11). These results triggered a flurry of activ-
ity leading to the identification of a large variety of halogenating (bro-
mination or chlorination) reagents that have now found application in the
palladium-catalyzed CaH activation of heteroarenes. Some of the com-
monly applicable reagents are copper halides (CuX2; X 5 Cl, Br),31
PhICl2,28c and electrochemical oxidation using HX (X 5 Cl or Br).32
Iodination of heteroarenes in a selective manner was also achieved by
Martin-Matute and co-workers,33 using a heterogeneous (Pd@MIL-88B-
NH2(Fe)) catalyst and NIS as the iodinating agent (Scheme 2.12). Selectivity
was switched between mono-ortho-iodination to di-ortho-iodination by sim-
ply varying the solvent from AcOH (providing majority mono-selectivity)
Pd(OAc) 2 (1–2mol%)
Halogenating reagent
R N R N
X
Halogenating reagents = NXS (X = Cl or Br) Ref. [25]
= CuX2 (X = Cl or Br) Ref. [31]
= PhICl2 Ref. [28c]
= HX (X = Cl or Br) Ref. [32]
Scheme 2.11 Palladium-catalyzed CaH halogenation of phenylpyridines.
R1 N R2
Pd@MOF (4.0 mol%) Pd@MOF (4.0 mol%)

NIS (3.0 equiv.) NIS (2.3 equiv.)
PTSA (0.5 equiv.) AcOH, 40–50°C, 8–16 h

THF, 80°C, 8–16 h
R1 N R2 R1 N R2
I I
4 examples (97–97%) 4 examples (59–92%)
Scheme 2.12 Selective iodination of heteroarenes using Pd@MOF heterogeneous

catalyst.
to THF (complete di-iodination). The addition of PTSA was helpful in pro-

moting the di-iodination to take place in a quantitative manner, and no
traces of mono-iodination were observed.
Finally, selective fluorination of phenylpyridines has also been
performed using N-fluoro-2,4,6-trimethylpyridinium tetrafluoroborate as
an electrophilic fluorinating reagent (Scheme 2.13).34 Although a variety
of fluorinating reagents (Selectfluor, N-fluoro-2,4,6-trimethylpyridinium
tetrafluoroborate, N-fluoropyridinium tetrafluoroborate, 4-
iodotoluenedifluoride, and N-fluorodisulfonamide) have been reported in
literature35 and have shown excellent selectivity for the fluorination of
organic substrates, the best selectivity in the case of phenylpyridines was
achieved with N-fluoro-2,4,6-trimethylpyridinium tetrafluoroborate.
N BF4 N
Pd(OAc)2 (10 mol%)
+ N F F
0.5 mL MeCNin CF3C 6H 5
microwave, 150°C, 1.5 h
R 5 examples, 33–75% R
Scheme 2.13 Selective fluorination of phenylpyridines using electrophilic fluorinat-

ing agents.
Beside the examples discussed so far highlighting the directing influ-

ence of pyridine as an important heteroarene for palladium-catalyzed
CaH functionalization, several other examples including those for other
heteroarenes are known, and readers are encouraged to refer to the recent
reviews that have given a comprehensive account of these types of
transformations.
2.2.1.2 Anilides and Ureas as Directing Group for

Palladium-Catalyzed CaH Bond Functionalization
Another example of strongly coordinating ligands on organic substrates
exhibiting superior directing influences and assisting efficient palladium-
catalyzed CaH bond functionalization of innumerable substrates are the
anilides or ureas. The versatility of anilides as a functional group could be
understood from the myriad of catalytic functionalizations, ranging from
olefination, arylation, acylation, amination, halogenation, trifluoromethy-
lation, alkynylation, and many more. In this section, we will be discussing
some of these examples in further detail.
CaH bond functionalization reactions performed on substrates with
anilides as the directing group have been well documented over the past
decades; however, the possibility of utilizing the strong coordinating power
of the anilide group was first put forth by Leeuwen and co-workers36 in
2002 (Scheme 2.14). Olefination of acetanilides via palladium-catalyzed
CaH bond activation with the employment of benzoquinone as the
stoichiometric oxidant was performed with high ortho-selectivity for the
first time.
The above transformation was recently revisited by Brown and co-
workers37a to understand the pathway followed, and to ascertain the role
of the added p-toluenesulfonic acid (TsOH). The reaction was found to
be catalyzed by an electrophilic palladium species that is generated from
the combination of Pd(OAc)2 and TsOH.37b The process proceeded
Pd(OAc)2 (2.0 mol%)

H H
N Me OR 2 Benzoquinone (1.0 equiv.) N Me
TsOH (0.5 equiv.)
O O AcOH/PhMe, r.t. O
R1 R1
O
OR 2
Pd(OAc) 2
/TsOH β -hydride
elimination
H H H
N Me N Me N Me
-TsOH
O O
O
R1 1 OR 2 R1
H Pd R Pd
S OTs OR 2
TsO TsO 2 Pd
O
OTs O
Palladacycle intermediate
Scheme 2.14 Olefination of acetanilides via palladium-catalyzed CaH bond

activation.
through the formation of a palladacyclic intermediate that was isolated

and shown to perform the catalytic functionalization efficiently. Using
NMR, single crystal X-ray diffraction, and kinetic studies, conclusive evi-
dence on the pathway for such a transformation was put forth. This has
laid the foundation for the rapid development of CaH bond activation
processes for the functionalization of a vast variety of substrates.
One of the synthetically useful catalytic reactions involving the selec-
tive introduction of an aryl group on different substrates has commonly
been achieved via the cross-coupling pathway which suffers from a num-
ber of drawbacks, including the requirement for pre-functionalized sub-
strates. A more efficient and sustainable solution to this problem was
provided in the form of a useful directed ortho-arylation protocol, first
developed by Daugulis and co-workers38 in 2005 (Scheme 2.15A).
The potential of an anilide functionality as a strongly directing group
for effecting selective ortho-arylation was achieved for the first time using a
combination of aryl iodides and silver acetate. Daugulis also demonstrated
the effectiveness of the developed protocol with diphenyliodonium salts.
Daugulis, later in 2007, followed up this result with a useful synthetic pro-
cedure for the preparation of phenanthridine derivatives via a palladium-
catalyzed anilide directed-arylation/cyclization strategy in the presence of
trifluoroacetic anhydride (Scheme 2.15B).39 A similar strategy, taking into
account the directing capability of protected N-methylbenzylamines (with
R2
Me O
H I Pd(OAc)2(0.2–5.0 mol%)
H
N Me AgOAc (1.0 equiv.) NH N
COMe
(A)
O 2 TFA, 90–130°C
1 1 1
R R R R
2
R R2
O
H I Pd(OAc)2(5.0 mol%) MeO
Br N AgOAc (1.3–2.3 equiv.) Br NH
OMe
(B)
O TFA, 110–120°C
R
R
TFAA
(2.0-3.0 equiv.)
110°C, 0.5–3.0 h
Br N
OMe
Scheme 2.15 Directed arylations using anilide as directing group. A) ortho-arylation

or diarylation B) ortho-arylation/cyclization
trifluoroacetic anhydride), was shown to provide ortho-arylated product via

palladium-catalyzed CaH bond activation.40
One more method for the arylation of aromatic ring systems with aryl-
boronic acids as organometallic coupling reagents via the directing group
effect of the anilide functionality was first explored by Shi and co-workers
(Scheme 2.16A).41 The insertion of the palladium species into the ortho-
position of the arene is facilitated by the strongly coordinating power of the
anilide group bringing about the desired oxidative arylation, with the aryl-
boronic acid acting as the nucleophilic reagent. Further developments in
this area have been restricted due to the lower reactivity of palladium species
in effecting such transformations compared to its counterpart, ruthenium,
that has shown promising results for a wide variety of functionalization reac-
tions. Another class of organometallic reagents that was demonstrated to
provide the ortho-arylation product in good yields is the arylsilanes42
(Scheme 2.16B), however, this is the only example present in literature for
palladium-catalyzed ortho-arylation employing such reagents.43
In 2014, Wang and co-workers44 reported a unique palladium-
catalyzed decarboxylative, anilide-assisted, ortho-arylation with acyl perox-
ides as the arylating agent (Scheme 2.17A). The reaction proceeded
through the release of CO2 to afford the orth-arylated products; however,
Pd(OAc) 2 (5.0 mol%) Me O

(A) B(OH)2
Cu(OTf) 2 (1.0 equiv.)
N
Ag2 O (1.0 equiv.) R2
PhMe, 120°C, 24 h
R2 R3 R1
N Me
R3
O Me O
R1 (B) Si(OR) 3 Pd(OAc) 2 (5.0 mol%)
Cu(OTf) 2 (2.0 equiv.) N
AgF (2.0 equiv.) R2
1,4-Dioxane, 110°C, 48 h
R3 R1
R3
Scheme 2.16 Ortho-arylation via anilide-assistance using organometallic reagents.

A) Aryl boronic acids for arylation B) Arylsilanes for arylation
Me O
O
H Pd(OAc) 2 (7.5 mol%)
N Me O NH
O TfOH (2.0 equiv.)
(A)
O O 3 A MS, MeCN, 80°C, 32 h
R1 R1
O O Pd(OAc)2 (7.5 mol%) O

OMe O OMe
(B) N O TfOH (2.0 equiv.) N
H
O 3 A MS, MeCN, 80°C, 32 h
R1 R1
Scheme 2.17 Acylperoxides as arylating agents A) ortho-arylation via C-H activation

B) ortho-arylation/cyclization via C-H/N-H activation
when the anilide functionality was replaced by an amide the reaction

resulted in a simultaneous decarboxylation followed by cyclization to
afford phenanthridinones in good yields (Scheme 2.17B).
An affordable and more desirable way of arylating substrates would be
the employment of simple unfunctionalized arenes as coupling partners.
The attractiveness of such a methodology is dwarfed by the unreactive
nature of the arenes and problems related to the selective activation of a
CaH bond over others. Development of efficient dehydrogenative cou-
pling protocols are therefore highly desirable, and given this possibility
Shi and co-workers45 first reported a double CaH bond activation strat-
egy involving directed-assistance from the anilide group providing excel-
lent regioselectivity for the arylation reaction (Scheme 2.18A). Due to
Pd(OAc) 2 (10 mol%)

Cu(OTf)2 (20 mol%)
H
O2 (1 atm) N
(A)
EtCO 2 H, 120°C, 7 h COMe
N R
H COMe R
Pd(OAc) 2 (10 mol%) H

H DMSO (10–20 mol%) N
N H Piv
(B) Piv O2 (1 atm)
TFA, 80–100°C, 10–18 h R1 R2
R1 R2
Scheme 2.18 Unsubstituted arenes as arylating agents for dehydrogenative

coupling.
the lower reactivity of the arenes, an excess amount was commonly

required to drive the reaction in the forward direction.
Advances in this regard were reported by Buchwald and co-workers,46
allowing the requirement for 4 2 11 equivalents of the arene rather than
excess of it (Scheme 2.18B). This was brought about by the subtle modi-
fication in the protocol by incorporating TFA as the solvent under an
atmosphere of pure oxygen as the oxidant. An unprecedented result for
the arylation of anilides at room temperature was achieved by You and
co-workers,47 demonstrating the power of a highly electrophilic palla-
dium species (Pd[TFA]1) obtained from the reaction of Pd(OAc)2 and
TFA to efficiently insert into the ortho-position assisted by the anilide at
ambient temperature.
Acylation strategies for the functionalization of aromatic compounds
have undergone rapid development, given the synthetic and commercial
importance of these substrates. Directing-group assisted CaH bond acti-
vation strategies for the installation of acyl functionality would be a
promising and more effective alternative to other uncatalyzed and cata-
lyzed processes. Kwong and co-workers first reported the strategy for
ortho-acylation by employing aldehydes as the acylating agents in the pres-
ence of TBHP for oxidation.48 Around the same time, Yu49 and Wang50
also published similar strategies for acylation with aldehydes
(Scheme 2.19B). However, a synthetically attractive strategy for acylation
was later reported by Yu and co-workers,49 allowing the in situ oxidation
of primary alcohols and further activation to provide the ortho-acylated
products in good yields (Scheme 2.19B). Benzylic alcohols have
also found applications as acylating agents in aqueous media under
R2 O
H
N R2 O NH
(A) Pd precursor
O R3 H R3
TBHP as the oxidant
R1 R1
O
R2 O
H 2 OH
N R NH
(B) Pd precursor
R3 H
O TBHP as the oxidant R3
R1 R1
O
Scheme 2.19 Aldehydes and alcohols as acylating agents for anilide-directed acyla-
tion strategy. A) Aldehydes as acylating reagents B) Alcohols as acylating reagents
O R2 O
H
NH 2 Ac O N R2 NH 2
2 R3 H NH
H2O, SDS O Pd(OAc) 2, TFA, HCl, 125°C R3
R1 r.t. 0.5 h R1 TBHP, r.t. 24 h R3 R1
R1 3h O
O
Scheme 2.20 One-pot step-economic acylation strategy for anilides.
palladium-catalyzed conditions by Zhou and co-workers in 2015 for

obtaining substituted benzophenones.51
In continuation of the discussion on the employment of aldehydes as
acylating agents, it is worth mentioning a mild, practical, and selective
method reported by Novak and co-workers in 2014 for the one-pot syn-
thesis of ortho-aminobenzophenones (Scheme 2.20).52 The process involves
the protection of anilines as acetanilide, followed by ortho-selective
palladium-catalyzed CaH bond activation with TBHP as the oxidizing
agent. The acylated product was finally hydrolyzed to afford ortho-amino-
benzophenone, providing a step-economic alternative to such molecules.
Taking advantage of the strong coordination possibility of the anilide
group, Ge and co-workers53 also developed a decarboxylative ortho-selective
acylation protocol using α-oxocarboxylic acid as the acylating reagent. One
of the unique features of the protocol was the replacement of TBHP as the
oxidizing agent with ammonium thiosulfate, commonly employed in most
of the earlier protocols (Scheme 2.21). The attractiveness of the protocol
developed was further enhanced by the possibility of performing the cata-
lytic functionalization at ambient temperature. A similar synthetic strategy
O O
HN Me O Pd(TFA) 2 (10 mol%) Me NH O

HO (NH 4) 2S 2 O8 (2.0 equiv.)
R2 R2
Diglyme, r.t.
O
R1 R1
O O O
Me NH O Me NH O Me NH O
Br Cl Br
80% 91% 60%
Scheme 2.21 Acylation strategy using α-oxocarboxylic acid.
O H O
H H
HN Me C Me NH O
Pd(OAc) 2 /TBHP
R2
2
R1 R R1
Scheme 2.22 Toluene as acylating reagent for substituted benzophenone synthesis.
was recently employed by Kim and co-workers for palladium-catalyzed dec-

arboxylative acylation of phenylacetamides.54
Toluene, when employed as a substrate, provides researchers with an
economic and synthetically useful alternative to alcohols and aldehydes, as
it could be readily oxidized in situ with suitable oxidizing agents. Sun and
co-workers,55 first introduced this strategy towards the acylation of aceta-
nilides with toluene as the direct acylating reagent using TBHP as the oxi-
dizing agent, providing a highly regioselective protocol for ortho-acylation.
Subsequently, Kwong and co-workers,56 in 2013, further extended the
scope of the reaction allowing easy access to functionalized benzophenones
under mild reaction conditions (Scheme 2.22).
Regioselective halogenation of substrates presents researchers with a chal-
lenge that also provides a useful handle for further functionalization. Taking
into consideration the directing ability of anilides, Shi and co-workers57
reported a highly regioselective and efficient protocol for ortho-halogenation
using Cu(II)halide (halides 5 Cl or Br) salts with Cu(OAc)2 as the oxidizing
agent (Scheme 2.23A). Mechanistic studies performed on the catalytic system
revealed the presence of a cyclopalladated complex that was proposed to be
O O
HN R2 Pd(OAc) 2 (10 mol%) R2 NH

(A) Cu(OAc) 2 (2.0 equiv.) X
CuX 2 (2.0 equiv.)
R1 DCE, 90°C, 48 h R1
X = Br or Cl
O O
HN R2 R2 NH
(B) Pd(OAc) 2 (5.0 mol%) Cl
CuCl 2 (2.0 Equiv.)
R1 Solvent-free, 120°C, 24 h R1
10 mmol scale, 13 mm diameter tube, 66%
10 mmol scale, 13 mm diameter tube, Cu(OAc) 2 (2.0 equiv.), 89%
10 mmol scale, 55 mm diameter beaker, 84%
100 mmol scale, 70 mm diameter beaker, 89%
O O
HN R2 R2 NH
(C) NXS (2.0 equiv.) X
PTSA (0.5 equiv.)
PhMe, r.t., 1–4 h R1
R1
X = Br or Cl
H
N R
O
Pd
L L
[B]
Scheme 2.23 Ortho-selective halogenation of substrates via palladium-catalyzed

anilide-chelation-assisted CaH activation. A) Copper halides as halogenating
reagents with Cu(OAc)2 as oxidant B) CuCl2 as chlorinating reagent C) N-
halosuccinimides as halogenating reagents
the active species involved in the catalytic cycle for the functionalization.
Bedford and co-workers followed this up with a solvent-free palladium-cata-
lyzed CaH bond activation 2 halogenation protocol for scale-up possibilities
(Scheme 2.23B).58 The reaction conditions were the same as those devel-
oped by Shi, although the solvent was completely removed as part of the
scale-up procedure, with the catalytic reaction performed with and without
Cu(OAc)2 still resulting in good-to-excellent yields.
Based on the initial assumptions for the presence of palladacyclic inter-
mediates as a part of the functionalization process, Bedford and co-workers
developed a mild and selective ortho-halogenation protocol, with
N-halosuccinimide as the halogenating reagent and p-toluenesulfonic acid

as the additive (Scheme 2.23C).59 The functionalization was found to pro-
ceed effectively under aerobic conditions at ambient temperature via an ortho-
palladated PTSA complex [B] that was proposed to catalyze the reaction.
Anilide-directed CaH bond activation has been explored extensively
in the past several years, and many more functionalization protocols
involving CaC and Caheteroatom bond formation have been reported.
Recent reviews3 have elegantly highlighted these examples in more detail,
and the reader is advised to refer to these for further reading.
Structurally identical functional groups to anilides, urea, and forma-
mides are also known for their strong coordinating properties, which
were recently exploited for the development of a variety of functionaliza-
tion strategies such as arylation, alkenylation, carbonylation, etc. Most
notable contributions in this regard comes from Xu and Huang’s group60
for developing a palladium-catalyzed ortho-arylation of formanilides
(Scheme 2.24). These substructures in the past have allowed their easy
conversion to important heterocyclic molecules.
Urea as a directing group has also provided promising results for the
ortho-arylation of substrates. Ease of removal of the urea functionality also
makes it highly desirable as a directing group in palladium-catalyzed CaH
bond functionalization reactions. An excellent example employing urea as
the directing group for direct olefination with n-butyl acrylate was recently
disclosed by Yu and co-workers (Scheme 2.25A).61 The unique feature of
the protocol was the achievement of efficient olefination at ambient tem-
perature, made possible by the Pd(OAc)2/p-TsOH/AcOH combination.
Another useful protocol for palladium-catalyzed fluoroalkylation of aro-
matic ureas was reported for the first time by Novak and co-workers62 in
2017 (Scheme 2.25B). The fluoroalkylation was facilitated by the applica-
tion of a novel trifluoroethyl(mesityl)iodonium salt that enabled the
O O
HN H I Pd(OAc) 2 (5.0 mol%) H NH

R2
AgBF 4 (1.5 equiv.)
HFIP, 100°C, 2 h
R 1 R2 R1
Scheme 2.24 Formanilide as a directing group for palladium-catalyzed arylation of

aromatic amines.
O O
R2 R2
HN N N NH O
H Pd(OAc)2/pTsOH H
(A) OBu
OBu
Benzoquinone/AcOH
O
R1 r.t. –60°C R1
O OTf O
CF3 R2
R2 Pd(OAc)2(7.5 mol%)
HN N I N NH
TFA (2.0–3.0 equiv.) H
(B) R3 Me Me
CF3
CH2Cl2, 25°C, 3 h
R1 34 examples, 53%–95% R1
Me
Scheme 2.25 Urea as a directing group for olefination and trifluoroalkylation.
A) Olefination using acrylates B) Trifluoroalkylation using iodonium salt
installation of the trifluoroethyl moiety on the aromatic ureas at ambient

temperature in high yields. Beside these examples for the application of
urea as a directing group for the functionalization of substrates, various
strategies for arylation and carbonylation are also known, and have contrib-
uted immensely in the further development of this area.
2.2.1.3 Amides as a Directing Group for Palladium-Catalyzed

CaH Bond Functionalization
Examples in the earlier sections were representative of functional groups
that exhibit strong coordination (possibly due to the availability of a lone
pair of electrons on the heteroatoms) towards palladium, facilitating a
wide variety of catalytic functionalization processes. In comparison to
these, several functional groups such as ketone, hydroxyl, amides, phos-
phate, esters, sulfonamides, carbamates, formate esters, alkynes, alkenes,
and carboxylic acids are known to be weakly coordinating to the metal
center. Amides are one such example of weakly coordinating directing
groups that have found extensive applications in the palladium-catalyzed
CaH bond functionalization of substrates.
The earliest example for the use of amides (COHNOMe) as a directing
group was reported by Yu and co-workers63 in 2008 for palladium-catalyzed
functionalization of o-methyl hydroxamic acids with organometallic boron
reagents (Scheme 2.26A). The same group subsequently reported64 the aryla-
tion protocol using aryl iodides as coupling partners and CONHC6F5 as the
directing group (Scheme 2.26B).
B(OH) 2 Pd(OAc) 2 (10 mol%)

Ag2 O (2.0 equiv.) R4
Benzoquinone (0.5 equiv.) O
(A) R3 = OMe
K2 CO 3 (2.0 equiv.) R3
R4
tBuOH, 70°C, 18 h R1 R2
H O
R3
N
R1 2
R H Pd(OAc) 2 (10 mol%)
I R4
PR 3 (20 mol%)
CsF (3.0 equiv.) O
(B) R3 = C 6F 5
R4
3 A MS, PhMe, 100°C, 24 h R3
R1 R2
PR3 = Cyclohexyl JohnPhos
Pd(TFA) 2 (10 mol%)

Ligand (20 mol%)
AgOPiv (3.0 equiv.) R4 O
(C) R2 = H R4 I
DCE, 80°C, Air, 20 h R3
R3 = (4-CF 3 )C 6 F5
4
R = Alkyl R1 R2
Ligand = 9-Methylacridine
TIPS
[Pd(allyl)Cl] 2 (5.0 mol%)
R2 = H, R 3 = (4-CF 3)C 6F5 IAd . BF 4 (20 mol%) O
(D)
Cs2 CO 3 (2.0 equiv.) R3
Et 2 O, 85°C, N2,8 h R1 R2
TIPS Br
Scheme 2.26 Early examples of using amides as directing groups. A) Arylboronic

acids as arylating reagents B) Aryl iodides as arylating reagents C) Alkyl iodides as
alkylating reagents D) Alkynylation using halo alkynes
Another notable contribution to the functionalization of simple

amides was presented by Yu and co-workers65 in 2014, with alkyl halides
as alkylating agents. The strategy was similar to that employed in Scheme
2.26B for arylation of amides. Instead of using phosphine as ligand, Yu
and co-workers employed 9-methyl acridine and other pyridine based
ligands to obtain the desired reactivity (Scheme 2.26C). Finally, Yu and
co-workers in 2013 also reported an amide-directed palladium-catalyzed
alkynylation protocol using a Pd(0)/N-heterocyclic carbene catalytic
system (Scheme 2.26D).66
Functionalization of aromatic amides via palladium-catalyzed CaH
bond activation takes place through the chelation-assistance provided by
the weakly coordinating amides, thus allowing selective ortho-arylation.
H H
Pd(OAc)2 (10 mol%) N O
R2
DMF (2.0 equiv.) R3
(A) R2 = (4-CF 3)C6F5
NFSI (1.5 equiv.)
H R3
O N 70°C, 48 h
R2 R1
I Pd(OAc)2 (5.0 mol%) H

R1 N O
Ag2O (2.0 equiv.) R2
(B) 2
R =H R3
AcOH, 120°C
R3
R1
Scheme 2.27 Ortho-CaH functionalization using aromatic amides as directing

groups. A) Arenes as arylating reagents B) Aryl iodides as arylating reagents
Yu and co-workers, in 2011,67 first reported the dehydrogenative aryla-

tion of aromatic amides (although with a protected form of amide) using
simple substituted arenes in the presence of NFSI as the oxidizing agent
(Scheme 2.27A). The incoming aryl functionality showed an exception-
ally high preference for para-coordination that was unprecedented at the
time and readily attributed to the use of NFSI. Later, Wang and co-
workers68 reported in 2012 the arylation of aromatic amides (the first
example of unprotected amide used as a directing group) using aryl
iodides as the coupling partners (Scheme 2.27B). More recently, Srinivasu
and co-workers in 2014 reported the ortho-arylation of benzamides cata-
lyzed by palladium supported over mesoporous silica as a recyclable cata-
lytic system.69 The catalyst was found to retain its activity for up to four
recycles.
Further developments in this area were centered around the ortho-
activation of aromatic amides followed by oxidative cyclization of the
resultant ortho-arylated benzamides, allowing easy access of phenanthridi-
nones, a structural motif of relevance to synthetic organic chemists
pertaining to their occurrence in a large number of naturally occurring
bio-active molecules. The first of these reports highlighting the impor-
tance of the amide directing group towards cyclization was by Wang and
co-workers70 in 2011, with aryl iodides as the arylating agent (Scheme
2.28A). The simultaneous activation of two CaH bonds and one NaH
in a single pot (one-pot) procedure without the isolation of intermediate
ortho-arylated N-methoxybenzamides provides researchers with a
OMe
I
Pd(OAc) 2 (5.0 mol%) O N
H
Ag2O (2.0 equiv.) R3
(A)
H AcOH, 120°C, 24–72 h
R3
O N R1
OMe
H
OMe
H
Pd(OAc) 2 (5.0 mol%) O N
R1 H K2S2O 8 (2.0 equiv.) R3
(B)
R3 TFA (20 equiv.), 25°C, 16 h
R1
Scheme 2.28 Phenanthridinone synthesis via one-pot multi CaH bond activations.
A) Using Aryl iodides B) Using arenes
F F
I PdCl2 (10 mol%)
F CF3 2,5-Lutidine (20 mol%) F CF3
Ag 2CO3 (3.0 equiv.)
HN F tAmylOH, 140°C, 24 h N F
Me F F
O O
Scheme 2.29 Cascade multi-bond activation for 4-aryl-2-quinolinone synthesis.
step-economic alternative for the synthesis of phenanthridinones. Cheng

and co-workers71 later provided an attractive, atom-economic alternative
involving the activation of three CaH and one NaH through the
employment of simple arenes as arylating agents (Scheme 2.28B).
Following on the cascade processes (vide infra) allowing the activation
of multiple bonds in one-pot, Yu and co-workers72 in 2014 reported on
a similar cyclization strategy for obtaining diversely substituted 4-aryl-2-
quinolinones (Scheme 2.29). The uniqueness of this reaction was the
simultaneous C(sp2)aH arylation, dehydrogenative coupling, Heck reac-
tion, followed by amidation in a single synthetic procedure.
Acylation strategies have also been developed that employ amides as
weakly coordinating ligands for palladium-catalyzed functionalization using
different acylating reagents. One such strategy, reported by Kim and co-
workers54 in 2013, discusses a decarboxylative methodology involving
α-oxocarboxylic acids as acylating agents (Scheme 2.30A). Interestingly, the
decarboxylation of the acid was performed at the relatively lower tempera-
ture of 70˚C, with (NH4)2S2O8 as the oxidant. Another useful synthetic
O Pd(TFA)2 (10 mol%)

CONEt2 OH (NH4 )2S2O 8 (1.5–3.0 equiv.) CONEt2
(A) R 1 R2 R1
DCE, 70°C, 20 h R2
O
O
O O
O Pd(OAc) 2 (10 mol%)
OMe
N TBHP (5.0 equiv.)
(B) R 1 H R2 H R1 N OMe
1,4-Dioxane, 100°C, 15 min
HO R2
Scheme 2.30 Acylation strategies in CaH activation using benzamides as a directing

group. A) Oxocarboxylic acids as acylating reagents B) Aldehydes as acylating
reagents
O O Pd(OAc) 2 (10 mol%) O

NXS (1.2 equiv.) Ts
Ts
N TFA (10 equiv.) N
(A) R1 H N X R1 H
MeOH, 25°C, 13–24 h
X
O X = Cl, Br, I
Pd(TFA) 2 (10 mol%)
CONEt 2 (NH 4 )2 S 2O 8 (1.5–3.0 equiv.) CONEt 2
(B) 1
R I2 R1
DCE, 70°C, 20 h I
Scheme 2.31 Benzamide-directed halogenation of arenes. A) N-halosuccinimides as

halogenating reagents B) Iodine as iodinating reagent
methodology using palladium-catalyzed CaH activation (acylation with

benzaldehyde)/annulation for the synthesis of hydroxyl isoindolones was
reported by Zhao and co-workers73 in 2013 (Scheme 2.30B). Besides the
use of a benign oxidant, TBHP, the reaction protocol proceeded with a
short reaction time, excellent atom economy, and good selectivity.
Palladium-catalyzed amide-directed halogenation reactions could pro-
vide useful solutions to the mild functionalization of further exploitation.
With this in mind, Fabis and co-workers74 developed a mild and selective
iodination protocol for arenes (Scheme 2.31A). The N-tosylbenzamide
functional group helps direct the incoming halide (N-halosuccinimide as
the halide source) to the ortho-position at ambient temperature. A cheaper
alternative for iodination was subsequently reported by Yu and co-
workers75 that uses molecular iodine as a readily available and economic
iodination reagent, and also satisfies the oxidizing requirement for the
process (Scheme 2.31B).
All the above examples highlighting the application of amides as
directing groups, suggest the influence of a weakly coordinating ligand
on the CaH activation reactions. In comparison to the strongly coor-

dinating phenylpyridines or anilides as directing groups, it could be
observed that weakly coordinating amides have lesser applicability,
although the conditions are milder and more suitable for further mod-
ification. Several other examples of benzamide-directed functionaliza-
tion are known in literature as well as the ones we have discussed
here.
Sulfonamides are another class of functional groups with structural
similarities to the amides, that have found applications as directing groups
in the CaH bond activation processes. Although the number of protocols
reported in literature is more limited, this could be attributed to the
rather unreactive and rigid nature of sulfonamides.
In spite of all the problems associated with the sulfonamide structural
motif, researchers have successfully applied them as effective directing
groups for palladium-catalyzed CaH bond activation in processes such as
arylation, carbonylation, carboxylation, halogenation, methylation, and
olefination. Pioneering work by Yu and co-workers76 deserves a special
mention for their contribution to the development of sulfonamides as
directing groups in CaH activation reactions (Scheme 2.32). Yu and co-
workers demonstrated the applicability of the developed methodology
towards the late-stage modification of a non-steroidal anti-inflammatory
blockbuster drug celecoxib.
Arylation
Carbonylation
MeO MeO
Ha Carboxylation
O O X
O O
Hc S Hc S
NHC 6 F5 NHC 6 F5
Hb Halogenation Hb
N N
N N
F3C Methylation F3C Celecoxib
X = Ar, CO, COOH, X, Me, CR 2=CR

Olefination
Scheme 2.32 Sulfonamides as directing groups in palladium-catalyzed CaH

activation.
Another random document with
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into the shape of soup. Mouth will not admit of hard
food. This hospital is not far from the Savannah jail,
and when the gate is open we can see it. It is said
that some one was hung there not long ago. Papers
referred to it and I asked a guard and he nodded
“Yes.” Have seen one “hanging bee,” and never want
to see another one. Last of my three pecks of sweet
potatoes almost gone. For a dollar, Confed., bought
two quarts of guber peas (pea-nuts), and now I have
got them can’t eat them. Sell them for a dollar per
quart—two dollars for the lot. It is thus that the
Yankee getteth wealth. Have loaned one cane to
another convalescent and go around with the aid of
one only. Every day a marked improvement. Ain’t so
tall as I “used to was.” Some ladies visited the
hospital to-day to see live Yankees, who crowded
around. They were as much of a curiosity to us as we
were to them.
Oct. 30.—It is said prisoners from main prison are
being removed every day, and the sick will go last.
Quite a batch of the nearest well ones were sent
from here to-day to go with the others. Am to be a
nurse pretty soon. Don’t think I could nurse a sick
cat, still it’s policy to be one. Winn tells me that he
has made money dickering at trade with the rebels
and prisoners. He has trusted me to twelve dollars
worth of things and says he don’t expect or want pay.
The twelve dollars amounts to only one dollar and
twenty cents in our money. The surgeon who has
had charge of us has been sent away to the front. It
seems he had been wounded in battle and was doing
home duty until able to again go to his command.
Shall always remember him for his kind and skillful
treatment. Came round and bid us all good bye, and
sick sorry to lose him. Are now in charge of a hospital
steward, who does very well. The atmosphere here
makes gentlemen of everybody. Papers say that the
city must be fortified, and it is being done.
Considerable activity about the place. Trains run
through at all hours of the night, evidently shifting
their troops to other localities. Later—Since the
surgeon went away the rebels are drinking up our
whiskey, and to-night are having a sort of carnival,
with some of the favorite nurses joining in; singing
songs, telling stories, and a good time generally.
They are welcome to my share.
Oct. 31.—Reported that the well prisoners have all
left this city for Millen and we go to-night or to-
morrow. I am duly installed as nurse, and walk with
only one cane. Legs still slightly drawn up. Hub
Dakin, Land and myself now mess together. Am
feeling very well. Will describe my appearance. Will
interest me to read in after years, if no one else. Am
writing this diary to please myself, now. I weigh one
hundred and seventeen pounds, am dressed in rebel
jacket, blue pants with one leg torn off and fringed
about half way between my knee and good sized
foot, the same old pair of miss matched shoes I wore
in Andersonville, very good pair of stockings, a
“biled” white shirt, and a hat which is a compromise
between a clown’s and the rebel white partially stiff
hat; am poor as a tad-pole, in fact look just about like
an East Tennesseean, of the poor white trash order.
You might say that I am an “honery looking cuss” and
not be far out of the way. My cheeks are sunken,
eyes sunken, sores and blotches both outside and
inside my mouth, and my right leg the whole length of
it, red, black and blue and tender of touch. My eyes,
too, are very weak, and in a bright sun I have to draw
the slouch hat away down over them. Bad as this
picture is, I am a beauty and picture of health in
comparison to my appearance two months ago.
When taken prisoner was fleshy, weighing about one
hundred and seventy or seventy-five, round faced, in
fact an overgrown, ordinary, green looking chap of
twenty. Had never endured any hardships at all and
was a spring chicken. As has been proven however, I
had an iron constitution that has carried me through
and above all a disposition to make the best of
everything no matter how bad, and considerable will
power with the rest. When I think of the thousands
and thousands of thorough-bred soldiers, tough and
hearty and capable of marching thirty, forty, and even
fifty miles in twenty-four hours and think nothing of it,
I wonder and keep wondering that it can be so, that I
am alive and gaining rapidly in health and strength.
Believe now that no matter where we are moved to, I
shall continue to improve, and get well. Succumbed
only at the last in Andersonville, when no one could
possibly keep well. With this general inventory of
myself and the remark that I haven’t a red cent, or
even a Confederate shin-plaster, will put up my diary
and get ready to go where ever they see fit to send
us, as orders have come to get ready. Later—We
are on the Georgia Central Railroad, en-route for
Millen, Ga., which is ninety miles from Savannah,
and I believe north. Are in box cars and very crowded
with sick prisoners. Two nurses, myself being one of
them, have charge of about a hundred sick. There
are, however, over six hundred on the train.
R E M O V E D TO M I L L E N .
ANOTHER CHANGE AND NOT A BAD ONE—ALMOST A HOSTAGE

OF WAR—ELECTION DAY AND A VOTE FOR LITTLE MAC—ONE
YEAR A PRISONER OF WAR, ETC., ETC.
Camp Lawton, Millen, Ga., Nov. 1.—Arrived at our

destination not far from midnight, and it was a
tedious journey. Two died in the car I was in. Were
taken from the cars to this prison in what they call
ambulances, but what I call lumber wagons. Are now
congregated in the south-east corner of the stockade
under hastily put up tents. This morning we have
drawn rations, both the sick and the well, which are
good and enough. The stockade is similar to that at
Andersonville, but in a more settled country, the
ground high and grassy, and through the prison runs
a stream of good pure water, with no swamp at all. It
is apparently a pleasant and healthy location. A
portion of the prison is timber land, and the timber
has been cut down and lays where it fell, and the
men who arrived before us have been busily at work
making shanties and places to sleep in. There are
about six thousand prisoners here, and I should
judge there was room for twelve or fifteen thousand.
Men say they are given food twice each day, which
consists of meal and fresh beef in rather small
quantities, but good and wholesome. The rebel
officer in command is a sociable and kindly disposed
man, and the guards are not strict, that is, not cruelly
so. We are told that our stay here will be short. A
number of our men have been detailed to cook the
food for the sick, and their well being is looked to by
the rebel surgeon as well as our own men. The same
surgeon who for the last ten days had charge of us in
Savannah has charge of us now. He does not know
over and above much but on the whole does very
well. Barrels of molasses (nigger toe) have been
rolled inside and it is being issued to the men, about
one-fourth of a pint to each man, possibly a little
more. Some of the men, luxuriantly, put their
allowances together and make molasses candy of it.
One serious drawback is the scarcity of dishes, and
one man I saw draw his portion in his two hands,
which held it until his comrade could find a receptacle
for it.
Nov. 2.—Have seen many of my old comrades of
Andersonville, among whom is my tried friend Sergt.
Wm. B. Rowe; were heartily glad to see one another;
also little Bullock who has improved wonderfully in
appearance. Everyone is pleased with this place and
are cheerful, hoping and expecting to be released
before many weeks; they all report as having been
well treated in Savannah and have pleasant
recollections of that place; from what could be seen
of the city by us prisoners it seems the handsomest
one in America. Should judge it was a very wealthy
place. My duties as nurse are hard, often too much
so for my strength, yet the enforced exercise does
me good and continue to improve all the time. A cane
will be necessary to my locomotion for a long time as
am afraid myself permanently injured; my cane is not
a gold headed one; it is a round picket which has
been pulled off some fence. Very cheering accounts
of the war doings. All who want to can take the oath
of allegiance to the confederacy and be released; am
happy to say though that out of all here, but two or
three has done so, and they are men who are a
detriment to any army. The weather now is beautiful,
air refreshing, water ditto; all happy and contented
and await coming events with interest. Part of the
brook, the lower part, is planked and sides boarded
up for sanitary privileges; water has also been
dammed up and a fall made which carries off the filth
with force. Plenty of wood to do cooking with and the
men putter around with their cooking utensils such as
they have. Sort of prize fight going on now.
Nov. 3.—About a hundred convalescents were
taken outside to-day to be sent away to our lines the
officials told us. At a later hour the commander came
inside and said he wanted twelve men to fall into line
and they did so, myself being one of the twelve; he
proceeded to glance us over and on looking at me
said: “Step back out of the ranks, I want only able-
bodied men.” I stepped down and out considerably
chagrinned, as the general impression was that they
were to go to our lines with the convalescents who
had been taken outside before. He marched off the
twelve men and it then leaked out that they were to
be sent to some prison to be held as hostages until
the end of the war. Then I felt better. It is said all the
sick will be taken outside as soon as they get
quarters fixed up to accommodate them. Think that I
shall resign my position as nurse. Would rather stay
with the “boys.” Land is no longer with the sick but
has been turned into the rank and file, also Dakin.
Dakin, Rowe and Land are all together, and if the
sick are taken outside I shall join my old comrades
and mess with them. But few die now; quite a
number died from the removal, but now all seem to
be on the mend. I am called, contrary to my
expectations, a good nurse; certainly have pity for
the poor unfortunates, but lack the strength to take
care of them. It needs good strong men to act as
nurses.
Nov. 4.—The fine weather still continues. Just
warm enough, and favorable for prisoners. Food now
we get but once a day—not all we want, but three
times as much as issued at Andersonville and of
good quality. The officer in command, as I have said
before, is a kind hearted man, and on his
appearance inside he was besieged by hundreds of
applications for favors and for the privilege of going
outside on parole of honor. He began granting such
favors as he could, but has been besieged too much
and now stays outside. Has, however, put up a letter
box on the inside so that letters will reach him, and
every day it is filled half full. Occasionally he takes to
a letter and sends inside for the writer of it, and that
one answered is the occasion of a fresh batch, until it
is said that the poor man is harrassed about as much
as the President of the United States is for fat offices.
As I have before remarked in my diary, the Yankee is
a queer animal.
Nov. 5.—Hostages taken out. Everything is bright
and pleasant and I see no cause to complain,
therefore won’t. To-morrow is election day at the
North; wish I was there to vote—which I ain’t. Will
here say that I am a War Democrat to the backbone.
Not a very stiff one, as my backbone is weak.
Nov. 6.—One year ago to-day captured.
Presidential election at the North between Lincoln
and McClellan. Some one fastened up a box, and all
requested to vote, for the fun of the thing. Old
prisoners haven’t life enough to go and vote; new
prisoners vote for present administration. I voted for
McClellan with a hurrah, and another hurrah, and still
another. Had this election occurred while we were at
Andersonville, four-fifths would have voted for
McClellan. We think ourselves shamefully treated in
being left so long as prisoners of war. Abe Lincoln is
a good man and a good president, but he is
controlled by others who rule the exchange business
as well as most other things. Of course our likes and
dislikes make no difference to him or any one else.
Yes, one year ago to-day captured. A year is a good
while, even when pleasantly situated, but how much
longer being imprisoned as we have been. It seems
a lifetime, and I am twenty years older than a year
ago. Little thought that I was to remain all this time in
durance vile. Improving in health, disposition and
everything else. If both breeches legs were of the
same length should be supremely happy. Should
make a bon-fire to-night if I wasn’t afraid of
celebrating a defeat. Had lots of fun hurrahing for
“Little Mac.”
Nov. 7.—A rather cold rain wets all who have not
shelter. Many ladies come to see us; don’t come
through the gate, but look at us through that
loophole. Any one with money can buy extras in the
way of food, but, alas, we have no money. Am now
quite a trader—that is, I make up a very thin dish of
soup and sell it for ten cents, or trade it for
something. Am ravenously hungry now and can’t get
enough to eat. The disease has left my system, the
body demands food, and I have to exert my
speculative genius to get it, am quite a hand at such
things and well calculated to take care of myself. A
man belonging to the Masonic order need not stay
here an hour. It seems as if every rebel officer was of
that craft, and a prisoner has but to make himself
known to be taken care of. Pretty strong secret
association that will stand the fortunes of war. That is
another thing I must do when I get home—join the
Masons. No end of things for me to do: visit all the
foreign countries that prisoners told me about, and
not forgetting to take in Boston by the way, wear silk
under clothing, join the masons, and above all
educate myself to keep out of rebel prisons. A person
has plenty of time to think here, more so than in
Andersonville; there it was business to keep alive.
Small alligator killed at lower part of the stream.
Nov. 8.—All eager for news. Seems as if we were
on the eve of something. So quiet here that it must
predict a storm. Once in a while some pesky rebel
takes it upon himself to tell us a lot of lies to the
effect that our armies are getting beaten; that
England joins the Confederacy to whip out the North;
that there is no prospect of ending the war; that we
are not going to be exchanged at all, but remain
prisoners, etc., etc. If he is a good talker and tells his
story well it makes us all blue and down-hearted.
Then, pretty soon, we are told more joyful news
which we are ready to believe, and again take heart
and think of the good times coming. Would like to
hear the election news. Wonder who is elected? Feel
stronger every day, and have a little flesh on my
bones. As the weather gets cool, we are made
painfully aware of the fact that we are sadly deficient
in clothing. Will freeze if compelled to stay through
the winter. Coverlid still does duty although disabled
by past experience, same as all of us. We talk over
the many good traits of Battese and others who are
separated from us by death and otherwise. The
exploits of Hendryx we will never tire of narrating.
What a meeting when we can get together in future
years, and talk over the days we have lived and
suffered together. Exchange rumors fill the air. One
good sign—the rebels are making no more
improvements about this prison; they say we are not
to stay here long. We hear that our troops are
marching all through the South. Guess that is the
reason why they think of moving us all the time. All
right, Johnny Rebels, hope we are an elephant on
your hands. Jeff Davis denounced by the papers,
which is a good sign. Occasionally get one in camp,
and read it all up. No library here. Not a scrap of
anything to read; principal occupation looking for
stray news.
Nov. 9.—This diary would seem to treat of two
things principally, that of food and exchange. Try to
write of something else, but my thoughts invariably
turn to these two subjects. Prisoners of war will know
how to excuse me for thus writing. A dead line has
also been fixed up in Camp Lawton, but thus far no
one has been shot. Rebel doctors inside examining
men who may be troubled with disease prison life
might aggravate. Those selected are taken outside
and either put in hospitals or sent to our lines.
Yankee ingenuity is brought into play to magnify
diseases, and very often a thoroughly well man will
make believe that he is going to die in less than a
week unless taken away. Have laughed for an hour
at the way a fellow by the name of Sawyer fooled
them. The modus operandi will hardly bear writing in
these pages, but will do to tell. Have made a raise of
another pair of pants with both legs of the same
length, and I discard the old ones to a “poor”
prisoner. An advantage in the new pair is that there is
plenty of room, too, from being three or four sizes too
large, and the legs as long as the others were short.
My one suspender has a partner now, and all runs
smoothly. Although Bullock is fleshing up and getting
better in health, he is a wreck and always will be.
Seems to be a complete change in both body and
mind. He was a favorite in our regiment, well known
and well liked. Rowe is the same stiff, stern patrican
as of old, calmly awaiting the next turn in the wheel
of fortune.
Nov. 10.—Pleasant and rather cool. My hair is
playing me pranks. It grows straight up in the air and
only on the topmost part of my head. Where a man is
generally bald, it’s right the other way with me. If
there is anything else that can happen to make me
any more ridiculous, now is the time for it to appear.
About all I lack now is to have an eye gouged out. A
friend says that the reason my hair grows the way it
does is because I have been scared so much, and it
has stuck up straight so much, that it naturally has a
tendency that way. Perhaps that is it. If I thought we
were to stay here for any length of time would open
up a hair cutting shop; but should hate to get nicely
started in business and a trade worked up, then have
an exchange come along and knock the whole thing
in the head. We are not far from the railroad track,
and can listen to the cars going by. Very often
Confederate troops occupy them and they give the
old familiar rebel yell. Once in a while the Yanks get
up steam enough to give a good hurrah back to
them. Seems to be a good deal of transferring troops
now in the South. I watch all the movements of the
rebels and can draw conclusions, and am of the
opinion that Mr. Confederacy is about whipped and
will soon surrender. It certainly looks that way to me.
Rumors that we are to be moved.
Nov. 11.—Very well fed. There it goes again. Had
determined not to say anything more about how we
were fed, and now I have done it. However, I was not
grumbling about it any way. Will merely add that I
have an appetite larger than an elephant. Will also
say that there are rumors of exchange, for a change
—a subject that has been spoken of before. Cannot
possibly refrain from saying that I am feeling
splendidly and worth a hundred dead men yet. Have
two dollars in Confederate money and if I can sell
this half canteen of dish-water soup shall have
another dollar before dark. “Who takes it? Ah, here
ye are! Sold again; business closed for to-night,
gentlemen. Early in the morning shall have a fresh
supply of this delicious soup, with real grease floating
on top.” Shutters put up and we settle down for the
night without depositing in the bank. Shan’t go to
sleep until ten or eleven o’clock, but lay and think,
and build those air castles that always fall with a
crash and bury us in the debris. Often hear the
baying of hounds from a distance, through the night
—and such strange sounds to the Northern ear.
Good night. In rather a sentimental mood. Wonder if
she is married?
Nov. 12.—Everything quiet and running smoothly.
Waiting for something. Have just heard the election
news—Mr. Lincoln again elected, and “Little Mac”
nowhere. Just about as I expected. Returns were
rather slow in coming in, evidently waiting for the
Camp Lawton vote. Well, did what I could for
George; hurrahed until my throat was sore and
stayed so for a week; know that I influenced twenty
or thirty votes, and now can get no office because
the political opponent was elected. ’Tis ever thus.
Believe I would make a good postmaster for this
place. There is none here and should have applied
immediately, if my candidate had been elected. More
sick taken away on the cars; rebels say to be
exchanged. Appears to be a sort of mystery of late,
and can’t make head nor tail of their movements.
Would not be surprised at any hour to receive news
to get ready for our lines. Don’t know that I have felt
so before since my imprisonment. Have lived rather
high to-day on capital made yesterday and early this
morning. Just my way—make a fortune and then
spend it.
Nov. 13.—To-day had an incident happen to me;
hardly an incident, but a sort of an adventure. When I
was nurse on one or two occasions I helped the
hospital steward make out his report to his superiors,
and in that way got a sort of reputation for knowing
how to do these things a little better than the ordinary
run of people, and rebels in particular. A rebel
sergeant came inside at just about nine o’clock this
morning and looked me up and said I was wanted
outside, and so went. Was taken to a house not far
from the stockade, which proved to be the officers
head-quarters. There introduced to three or four
officers, whose names do not occur to me, and
informed that they were in need of some one to do
writing and assist in making out their army papers,
and if I would undertake the job, they would see that I
had plenty to eat, and I should be sent North at the
first opportunity. I respectfully, gently and firmly
declined the honor, and after partaking of quite a
substantial meal, which they gave me thinking I
would reconsider my decision, was escorted back
inside. Many thought me very foolish for not taking
up with the offer. My reasons for not doing so are
these: I would be clearly working for the
Confederacy; can see no real difference in it from
actually entering their army. If I occupied that position
it would relieve some rebel of that duty, and he could
stay in the ranks and fight our men. That is one
reason. Another is the fact that instead of their letting
me go to our lines with the first that went, I would be
the very last to go, as they would need me to do duty
for them until the last moment. Was always willing to
do extra duty for our own men, such as issuing
clothing on Belle Isle, also my nursing the sick or in
any way doing for them, but when it comes to
working in any way for any rebel, I shall beg to be
excused. Might have gone out and worked in the
printing offices in Savannah had I so wished, as they
were short of men all the time, in fact could hardly
issue their papers on account of the scarcity of
printers. And so I am still loyal to the Stars and
Stripes and shall have no fears at looking my friends
in the face when I do go home.
Nov. 14.—The kaleidoscope has taken another
turn. Six hundred taken away this forenoon; don’t
know where to. As I was about the last to come to
Millen, my turn will not come for some days if only six
hundred are taken out each day. Rebels say they go
straight to our lines, but their being heavily guarded
and every possible precaution taken to prevent their
escape, it does not look like our lines to me. Probably
go to Charleston; that seems to be the jumping off
place. Charleston, for some reason or other, seems a
bad place to go to. Any city familiar with the war I
want to avoid. Shall hang back as long as I can,
content to let well enough alone. Some of my friends,
of which Bullock is one, flanked out with those going
off. What I mean by “flanked out” is crowding in when
it is not their turn and going with the crowd. Hendryx
and I did that when we left Belle Isle, and we brought
up in Andersonville. Will let those do the flanking who
want to, I don’t.
Nov. 15.—At about six or seven o’clock last night
six hundred men were taken away, making in all
twelve hundred for the day; another six hundred are
ready to go at a moment’s notice. I don’t know what
to think. Can hardly believe they go to our lines.
Seems almost like a funeral procession to me, as
they go through the gate. Rowe and Hub Dakin talk
of going to-day, if any go, having decided to flank. I
have concluded to wait until it is my turn to go. If it is
an exchange there is no danger but all will go, and if
not an exchange would rather be here than any place
I know of now. Later.—Eight hundred have gone,
with Rowe and Dakin in the crowd, and I am here
alone as regards personal friends. Could not be
induced to go with them. Have a sort of presentiment
that all is not right. Still Later.—Six hundred more
have gone, making 2,600 all together that have
departed, all heavily guarded.
Nov. 16.—A decided thinness in our ranks this
morning. Still house keeping goes right along as
usual. Rebels not knowing how to figure give us just
about the same for the whole prison as when all were
here. Had a talk with a rebel sergeant for about an
hour. Tried to find out our destination and could get
no satisfaction, although he said we were going to
our lines. Told him I was a mason, odd-fellow, had
every kind of religion (in hopes to strike his), and
flattered him until I was ashamed of myself. In a
desultory sort of way he said he “reckoned we war
goin’ nawth.” Well, I will write down the solution I
have at last come to, and we will see how near right I
am after a little. Our troops, Sherman or Kilpatrick or
some of them, are raiding through the South, and we
are not safe in Millen, as we were not safe in
Andersonville, and as was plainly evident we were
not safe in Savannah. There is the whole thing in a
nutshell, and we will see. Six hundred gone to-day.
Nov. 17.—It is now said that the prisoners are
being moved down on the coast near Florida. That
coincides with my own view, and I think it very
probable. Will try and go about to-morrow. Hardly
think I can go to-day. Later.—The to-day’s batch are

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Strategies for Palladium-Catalyzed

Non-Directed and Directed C-H Bond

Copyright r 2017 Elsevier Inc. All rights reserved.

British Library Cataloguing-in-Publication Data

Library of Congress Cataloging-in-Publication Data

For Information on all Elsevier publications

Publisher: John Fedor

Typeset by MPS Limited, Chennai, India

Methods for the functionalization of otherwise unreactive CaH bonds

tosylates, and even mesylates. Since the substrates of interest in palladium-

Traditionally, the assembly of heterocycles largely involved the

capitalize upon the activation of otherwise inert CaH bonds. Hence,

Thus far, most of the advances in heterocyclic CaH activation were

Organic chemistry has often been nominated as collateral to a celestial

of the Wurtz reaction, appealed to the minds of erudite chemists.

Figure 1.1 Schematic representation of the various aspects of palladium-catalyzed

of organometallic chemistry. With respect to the modes of coordination,

In the following chapter, Jiao et al. concentrate on the synthetic

as by-products in a reaction mixture. Eminent research groups like those

palladacycle precatalysts in CaH bond functionalization, as well as pro-

Directed CaH Bond

also be cost-effective.1 This is achieved via the insertion of transition

[DG] [DG] [DG]

2.2 ORTHO-PALLADATED CaH BOND FUNCTIONALIZATION

2.2.1 Effect of Coordination Capacity on Functionalization

More stable intermediate Lower energy barrier

Less stable intermediate Higher energy barrier

ligands. In terms of the energetics of the reactions, it could be observed

2.2.1.1 Heterocycles as Directing Groups for Palladium-Catalyzed

incorporated other heterocyclic ring systems (quinolines, benzoquino-

BF 3 K Pd(OAc) 2 (10 mol%)

The employment of boron compounds as arylating reagents has also

Besides the examples mentioned above for the arylation of phenylpyr-

Pd(MeCN) 4 (BF4 )2 (10 mol%) OAc

Me Pd(OAc) 2 (10 mol%)

Scheme 2.5 Methylation of phenylpyridine using boroxine as an alkylating agent.

2-Phenylpyridine:peroxide = 1 : 4 10% 70%

Scheme 2.6 Methylation of phenylpyridine using peroxide as methylating agent.

This unusual methylation protocol was recently disclosed by Li and co-

N Pd(OAc) 2 (10 mol%) N

Scheme 2.7 Trifluoromethylation via ortho-CaH bond functionalization of

Pd(OAc) 2 (10 mol%)

Pd(II)/Mg–La (5.5 mol% Pd)

Another biologically and chemically important process that is known

O Pd(OAc) 2 (5.0 mol%)

N OH PdCl 2 (5.0 mol%)

OH Pd(II)/Mg–La (13.5 mol% Pd)

Scheme 2.9 Acylation strategies via palladium-catalyzed CaH bond functionalization.

Further developments in this area allowed the CaH bond functionali-

Pd(OAc) 2 (6.0 mol%)

Directed halogenation of substrates has been known in the literature

Scheme 2.11 Palladium-catalyzed CaH halogenation of phenylpyridines.

Pd@MOF (4.0 mol%) Pd@MOF (4.0 mol%)

PTSA (0.5 equiv.) AcOH, 40–50°C, 8–16 h

Scheme 2.12 Selective iodination of heteroarenes using Pd@MOF heterogeneous

to THF (complete di-iodination). The addition of PTSA was helpful in pro-

Scheme 2.13 Selective fluorination of phenylpyridines using electrophilic fluorinat-

Beside the examples discussed so far highlighting the directing influ-

2.2.1.2 Anilides and Ureas as Directing Group for

Pd(OAc)2 (2.0 mol%)

Scheme 2.14 Olefination of acetanilides via palladium-catalyzed CaH bond

through the formation of a palladacyclic intermediate that was isolated

Scheme 2.15 Directed arylations using anilide as directing group. A) ortho-arylation