Chelate-Assisted Arene C-H Bond Functionalization

Abstract

Recent discoveries in the area of transition metal-catalyzed, chelate-assisted arene C–H bond activation and functionalization enable efficient syntheses of substituted aromatic rings. Due to their catalytic nature, these new protocols serve as more direct, typically one-step alternatives to established, multistep synthetic methodologies. Herein, we summarize recent advances in chelate-assisted, often called ligand-directed C–H bond functionalization methods that introduce functional groups into aromatic compounds. We provide detailed examples from the literature for a variety of highly useful C–C and C–X bond forming reactions as well as a short discussion of relevant mechanisms and selectivity.

Full text

Arene Chemistry: Reaction Mechanisms and Methods for Aromatic Compounds,
First Edition. Edited by Jacques Mortier.
© 2016 John Wiley & Sons, Inc. Published 2016 by John Wiley & Sons, Inc.
23.1 INTRODUCTION
During the last two decades, transition metalcatalyzed, direct C–H functionalizations have become a
widely used strategy for the synthesis of arenes bearing substituents. The strategy of using directing
groups has been of particular use for the synthesis of complex molecules; these groups coordinate to
the catalyst during the reaction and thus enable C–H cleavage as well as new bond formations in
proximity to the catalyst coordination site. Since most of these reactions are believed to proceed
through cyclometalated chelate complexes as intermediates, the term “chelate assisted” has been
introduced to describe the relevant reactivity pattern [1]. Other researchers refer to this type of
reactivity as “directed” or “liganddirected” C–H functionalizations [2]; however, this terminology
might be misleading for substrates in which directing substituent effects on site selectivity—similar to
effects in electrophilic substitution [3]—as well catalyst directing effects are possible. Similarly,
several authors refer to functionalizations at C–H bonds in αpositions of heteroaromatics such as
pyridine as heteroatomdirected reactions [4]. In order to avoid confusion, this review will primarily
use the terminology “chelateassisted” instead of “directed” C–H functionalizations (Scheme23.1).
The strategy of using directing groups for C–H activation and subsequent functionalization has
enabled the introduction of many different functional groups on arenes without intermediate steps,
which has the potential to be particularly useful for the diversification of complex molecules at late
stages of syntheses and thus drug discovery applications [5–7]. Conceptual challenges of this approach
are the introduction and/or removal of the used directing group, which is not always desired in
the target molecule. Various creative approaches have been taken to overcome this limitation
(addressed in Sections 23.1.2 and 23.1.3). Nondirected C–H functionalizations of arenes have also
been realized and are addressed in the next chapter of this book. Due to page limitations and
CHELATE‐ASSISTED ARENE C–H BOND
FUNCTIONALIZATION
M H. E  C J. L
Department of Chemistry and Biochemistry, Worcester Polytechnic Institute, Worcester, MA, USA
23
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648 CHELATEASSISTED ARENE C–H BOND FUNCTIONALIZATION
inorder to stay within the scope of this book, this chapter exclusively reviews chelateassisted
functionalizations of nonheteroaromatic C–H bonds.
23.1.1 Mechanisms of Chelate‐Assisted C–H Bond Functionalization
andActivation
C–H functionalizations can generally proceed through three types of mechanisms [5, 8]: (i) radical
rebound mechanisms, which proceed through radical intermediates; (ii) direct insertions into C–H
bonds; and (iii) mechanisms through an organometallic intermediate with a metal–carbon bond.
These three different pathways are outlined in Scheme23.2.
Radical rebound mechanisms (1) are typically proposed for metaloxo catalysts, which are
common in enzyme catalysis and beyond [9]. Due to the high bond dissociation energy of aromatic
C–H bonds [10], radical rebound pathways are rarely proposed for the herein reviewed chelate
assisted C–H bond functionalizations. In analogy, direct insertion mechanisms (2) are most often
proposed for functionalizations of weak C–H bonds, as these pathways also require a complete
breaking of the C–H bond during the rate determining step. Thus, among the three possible
functionalization mechanisms, C–H functionalization through organometallic intermediates (3) is
the most commonly proposed and investigated mechanism for chelateassisted modes of reactivity
[2, 11–13] and will be reviewed in detail in the following paragraphs.
Chelateassisted C–H bond functionalizations through C–H activation are typically initiated by
catalyst precoordination, which situates the aromatic C–H bond in the proximity of the catalyst
(Scheme23.3). The C–H bond is then cleaved, which results in formation of an organometallic
intermediate 1.
MX HCR3
+MXHCR3M + HX CR3
+n+(n–1) +(n–2)
1. Radical rebound mechanism
2. CH insertion
3. Organometallic
MXM+
R3CX
H
M
Oxidant
X=CR1R2, NR
+n
HMCR3
CR3
+n
X
XCH3
HCR3
+
X=O, NR
H functionalizationC
SCHEME23.2 General mechanisms of C–H bond functionalization.
DG
H
DG
X
This review:
Chelate-assisted H functionalizationC
DG = Directing group
HX
H
OMe OMe
X
+
Substituent directing effect in
electrophilic aromatic substitution
NHNX
OMe
α
-C H functionalization of
pyridines
SCHEME23.1 Illustration of different “directed” reactivity in organic chemistry.
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INTRODUCTION 649
Various reactivity modes for this first step of chelateassisted C–H functionalization—transition
metalmediated C–H activation—are reported in the literature [8, 14]. The exact mechanism for C–H
activation in a particular system depends on the identity of the metal and its oxidation state as well as
the ancillary ligands around the metal center. For example, in the presence of carboxylate or carbonate
ligands at the metal center, C–H cleavage through a 6membered transition state is often proposed
(concerted metalation–deprotonation; Scheme23.4, 1A). Furthermore, both heteroatom and carbon
bound ligands such as methoxy or methyl can be involved, which is referred to as concerted
metalation–deprotonation through a 4membered transition state (1B) or sigma bond metathesis (2).
Computations suggest that these two mechanisms are distinctly different with respect to the involved
orbitals: In CMD through a 4membered transition state, the forming X–H bond is not based on the
same orbital as the breaking M–X bond; therefore, these steps are not necessarily happening in a
concerted fashion. In contrast, M–R bond breaking and R–H bond formation are concerted processes
in the SBM mechanism. An additional difference between these mechanisms is the nature of the
involved ligands on the metal center: X is typically a heteroatom with a lone pair (O, N), while R in
the SBM mechanism stands for a Cbased group (alkyl, aryl). Finally, oxidative addition mechanisms
(3) are possible for various transition metal complexes of the third period (IrIII [15], PtII [16]).
M
DG
MDG
H
DG
H
M+
+n
+n
+n
1
SCHEME23.3 Chelateassisted C–H activation. DG, directing group.
1. Concerted metalation deprotonation (CMD)/ambiphilic metal ligand activation (AMLA)
1A.CMD through 6-membered transition states
1B. CMD through 4-membered transition states
2. Sigma bond metathesis (SBM)
3. Oxidative addition
O
M
O
X
H
O
M
R3
CH
O
X
X=alkyl, OH, O–
O
M
O
X
H
X
M
X=OR, NR2
H
X
MCR3
CR3
CR3
CR3
CR3
H XH
MCR3
CR3
CR3
CR3
R
MHCR3
R
M
HR
M
H
R
M
H
or +
Oxidatively added
transition state
R
MHCR3
R
M
H
R
MCR3
H+
Intermediate
+n
+(n+2)
+n
+n
+n
+n
+n
+n
+n
SCHEME23.4 Potential mechanistic manifolds of C–H activation.
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650 CHELATEASSISTED ARENE C–H BOND FUNCTIONALIZATION
Once C–H activation has been achieved and the organometallic intermediate 1 is formed,
different pathways can be taken that all result in C–H functionalization, depending on the used
metal catalyst (Cu, Pd, Rh, Ir, Ru), oxidant (oneelectron vs. twoelectron oxidants, soluble vs.
gaseous vs. saltbased oxidants), the formed bond (C–C vs. C–X), and the reaction conditions (pH,
temperature, solvent). Two potential pathways for the steps following C–H activation are shown in
Scheme23.5: Path A proceeds through initial oxidation of intermediate 1 with subsequent bond
formation, while path B forms the new bond first before the catalyst is regenerated by oxidation.
Polarized bonds (e.g., C–O) are frequently proposed to be formed through initial oxidation, when
product formation by reductive elimination is challenging from a catalyst with a lower oxidation
state [12, 17]. On the other hand, thermodynamically favorable C–C bond reductive eliminations
tend to occur readily before catalyst oxidation [18].
The mechanism of chelateassisted C–H activation has fundamentally important consequences
for the site selectivity of substitution. Since C–H activation takes place in ortho position to the site
of the directing group in order to form energetically favorable 5 or 6membered chelate complexes
as intermediates, formation of a new C–C or C–X bond takes place at the same site. Thus, meta and
paraproducts can typically not be obtained. However, a modification of this strategy with longer
tethers as directing group allows exclusive metaC–H functionalizations through metaC–H
activation (Scheme23.6) [19, 20].
M
DG
X
Oxidant
Path B
Path A
+(n+2)
1
M
+(n–2)
M
DG
X
+n
M
+n
Oxidant
X=CR3, Het
DG
X
DG
X
SCHEME23.5 C–H functionalization of organometallic intermediate 1.
ODG
EtO2C
R
R
R
H
HO
OSi
C
N
sBu sBu
iPr
iPr
C
N
iBu
iBu
SCHEME23.6 Directing groups (DGs) for metaC–H functionalization.
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INTRODUCTION 651
23.1.2 Weakly and Strongly Coordinating Directing Groups
Potential directing groups can possess a large variety of structure, with coordinating atoms being O,
N, S, C, and P (see Scheme23.7). Since commonly used late transition metals tend to form weaker
bonds with Odonor atoms than with N or Pdonor atoms, carboxylatederived directing groups
have been referred to as weakly coordinating groups in the literature. However, the strength of the
formed coordination bond is dependent on the identity and the oxidation state of the transition metal
catalyst [21], and as such, a general classification of directing groups as strong or weak might be
somewhat misleading. Interestingly, recent results with Pd catalysts suggest that the strength of the
coordinative bond may influence the rate of catalytic C–H functionalization [22].
23.1.3 Common Directing Groups
Scheme23.7 depicts various common directing groups for chelateassisted C–H functionalizations.
Directing groups that coordinate through their Natom such as pyridines and other heterocycles
(1a–r) have been most widely used [2, 4, 23].
Carboxylate-derived DGs
Oxime and imine DGs
Ketone DGs Hydroxy DGs
Amine DGs
Heterocyclic DGs
N
R
ON
N
N
N
N
R
N
N
HN N
N
N
NN
N
N
RN
NN
N
MeN
N
RN
NNNNN
N
Bu
N
N
N
Bu/Hex
N
O
R
R
tBu N
O
R
N
ON
O
R/H
R/H
NS
HO O
HN S
Ph
N
HO
O
HN
OMe
HN
tBu/Me
OHN O
NMe2H
N
O
H
N
O
N
R2NOEtO OH
NO
MeO
N
N
H/alkyl
OMe
aryl N
NHTs
H/alkyl N
Me/H NPh
Ph NH
HNN
NtBu
Me/H N
OMe
R
RO
R=H, Me, Et, iPr,
Ph, adamantyl OHOH
Si OH
iPr
iPr
NMe2
NHPr H
NPh RN
N
NN
Ph
NHTf aryl NHTs NH2/NHiPr
POH
OMe
O
S-based DGs
O
SNHC6F5
O
O( )1,2,3
S
Tol
O
1a 1b 1c 1d 1e 1f 1g 1h 1i 1j
1k 1l 1m 1n 1o 1p 1q 1r
2a 2b 2c 2d
2e 2f 2g 2h
2i
2j
2k
3a 3b 3c 3d 3e
3f 3g 3h
4a 4b 4c 4d 4e 4f 4g 4h
56a 6b 6c 6d 7a 7b
DG
H
DG
X/CR3
SCHEME23.7 Directing groups (DGs) for chelateassisted C–H functionalization.
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652 CHELATEASSISTED ARENE C–H BOND FUNCTIONALIZATION
Carboxylates and carboxylic amides are another important class of directing groups (2a–k) [24].
These functional groups are perceived to be more synthetically useful, due to the ease of converting
them into other substructures. Based on carboxylic amide functionalities, chelating directing groups
(2i, 2k) have been developed, which presumably occupy two coordination sites at the metal center
of the catalyst. These structures have enabled a broad range of applications, in particular in
diastereoselective C–H functionalization [25, 26]. Furthermore, imines and oximes (3a–h) have
been widely used as directing groups, both of which coordinate through their Natom to the
transition metal catalyst. Furthermore, various reactions are known to proceed through coordination
of a ketone functionality on the substrate (5) [4, 23, 27]. A more unusual example is directing
groups that coordinate to the catalyst through hydroxy groups (6a–d), and a few examples of this
type have been reported [28–31]. Amine directing groups are slightly more common and are found
as primary, secondary, and tertiary amines (4a–d, f), as well as aminederived functional groups (4e,
h) [2, 23, 32]. Additionally, tailored sulfonamide (7a) and sulfoxide functionalities (7b) have been
shown to act as directing groups for aromatic C–H functionalizations [6, 33].
23.1.4 Transformable and In Situ Generated Directing Groups
From a synthetic perspective, direct and intermolecular C–H functionalizations are more favorable
than sequential functional group conversions, as the former approaches approach can minimize the
number of linear steps in a synthetic sequence [7, 34]. However, if additional steps like the installa-
tion and removal of directing groups have to be added to the sequence, the overall step count might
not decrease, which often reduces the usefulness of C–H functionalization protocols. Several
directing groups can address this challenge: Groups based on carboxylate structures fall into this
category, as the further modification of carboxylic acids and amides is well established; one
example is shown in Scheme23.8 [35].
Furthermore, several functional groups have been developed specifically for the purpose of
subsequent synthetic modification. These directing groups are prepared in prior reactions and are
readily converted into other functional groups after C–H functionalization. One example of this
strategy is the use of Nacetyl oximes as directing groups by Neufeldt and Sanford (Scheme23.9)
[36]. After C–H acetoxylation, halogenation, or arylation, Nacetyl oximes can be transformed into
a variety of functional groups that are useful for subsequent synthesis. Scheme23.10 depicts an
example of a transformable directing group developed by Kornienko and coworkers. The directing
group used is a transformable heterocycle that can be reacted with alkynes after C–H functionaliza-
tion to form two new C–C bonds and eliminate N2 through an inverse electron demand Diels–Alder
sequence [37].
A slightly different strategy takes advantage of labile Si–O or Si–N bonds that can be formed
quantitatively by initial reaction of NH and OH groups with tBu2SiClH, tBu2SiBr2, or Et2SiH2. This
H
R1
R1
R1
R1
R1
TsHN O
I
R2
R2
R2
R2
+
TsHN O
X
X= CO2H, CO2Me,
CH2OH, CONH2
or
or
O
H
N
O
8
R2
SCHEME23.8 Carboxylic amide 8 as substrate transformable directing group.
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INTRODUCTION 653
leads to the quantitative formation of a directing group that then catalyzes the highly selective
subsequent C–H functionalization [28, 38–40]. One example of this kind is provided later in this
chapter (Scheme23.31), depicting a silanedirected C–H borylation protocol.
Another approach toward traceless directing groups prepares them in the same pot in which C–H
functionalization occurs. This strategy is commonly referred to as the use of in situ generated direct-
ing groups. Work by Bedford and Limmert (Scheme23.11) is an elegant example of this approach,
as it exploits the power of both organocatalysis and transition metal catalysis [41, 42]. In the shown
reaction, C–H arylation takes place in ortho position to a hydroxy group on the arene 11. However,
this functional group is not acting as a directing group; instead, a phosphonate group that can be
transferred in situ between phenol moieties of different molecules directs the Rh catalyst to the
functionalization site. Another good example for the use of this strategy is Catellanitype reactions,
in which norbornene insertion into metal–C bonds generates a directing group for orthoC–H func-
tionalization in situ (Scheme23.12). This type of reactivity has found manifold applications such as
in Suzuki–Miyaura couplings and direct arylations and has been reviewed elsewhere [43, 44].
H
N
N
X
N
N
or
X=OH, OAc
OH OO
R
10
or
SCHEME23.10 Transformable heterocycle strategy.
OH
H
OH
Ar
11
R5 mol% (Rh)
15 mol% ArʹOPiPr2
Rvia [Rh]
P
O
iPr
iPr
Hal Ar
+
SCHEME23.11 Rhodiumcatalyzed orthoarylation with an in situ generated DG.
HaI
H
R2
R1
12
R, [Pd] Rvia
XR1
+YR2
+[Pd]
R1= alkyl, aryl
R2= aryl, alkenyl, H, CN
SCHEME23.12 In situ generated DGs in Catellanitype reactions.
H
RN
X
RN
or
OAc
OAc
X= Cl, I, Ph, OAc
OH
RO
OH
ROH
or or
OH
R NH
2
O
N
9
SCHEME23.9 Nacetyl oximes 9 as precursors to difunctionalized arenes.
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654 CHELATEASSISTED ARENE C–H BOND FUNCTIONALIZATION
In summary, the use of directing groups has been highly successful in enabling chelateassisted
C–H cleavage and functionalization. The selectivity of these reactions is determined by the structure
of the employed groups, with orthoC–H functionalization being the most common reactivity
pattern observed. In order to lower the step count for these reactions, transformable and in situ
generated directing groups have been developed. The following chapters will provide an overview
of the types of C–C and C–X bonds that can be formed using the previously outlined strategies and
will highlight examples of common catalyst systems and reaction conditions.
23.2 CARBON–CARBON (C–C) BOND FORMATIONS
23.2.1 C–CAryl Bond Formations
Biaryl moieties are ubiquitous in natural products and pharmaceuticals [45]. Consequentially,
efficient and direct synthetic protocols for the formation of biaryl molecules are highly desirable.
The earliest report of chelateassisted C–H arylation from 1998 describes the use of Wilkinson’s
catalyst [RhCl(PPh3)3] for the orthoC–H functionalization of 2arylpyridines with tetraphenylstan-
nane (Scheme23.13) [46]. Monoarylated products can be obtained by using a blocking group on
one of the ortho positions on the pyridine moiety of the substrate (13) that prevents arylation of the
second orthoC–H bond. In the absence of a blocking substituent in the substrate 14, diarylated
products are formed.
Since this first report, a large variety of catalysts (e.g., Pd(OAc)2, RhCl(PPh3)3, RuCl2(η6C6H6)2,
Ni(cod)2), directing groups (heterocycles, carboxylate based, phenols), and aryl transfer reagents
(ArHal, ArOR, ArB(OR)2, ArH) has been employed to achieve direct arylations [47–51]. Many
of these reactions have been reviewed elsewhere [52–55], and only few representative examples
will be discussed in detail in this chapter.
As one example of this large body of literature, we depict in Scheme23.14 the redoxneutral
orthoC–H arylation of anilides with simple Pd(OAc)2 as efficient catalyst. Daugulis and coworkers
reported very high yields for this reaction, forming both mono and diarylated products under mild
reaction conditions [56]. Interestingly, the protocol tolerates various functional groups on the
anilide including halogens.
HPh
5 mol% RhCl(PPh
3
)
3
5 mol% RhCl(PPh
3
)
3
+SnPh
4
SnPh
4
N
13
N
HPh
+
N
14
N+
Ph
N
Ph
60%
65% 20%
CCl
4
, N
2
, 120°C, 24 h
CCl
4
, N
2
, 120°C, 24 h
SCHEME23.13 Rhcatalyzed orthoarylation of 2aryl pyridines.
NHCOR
HPd(OAc)2or
IAr
+
AgOAc, TFA
90–120°C, 1–12 h
up to 96%
FG
NHCOR
Ar
FG
NHCOR
Ar
FG
Ar
FG=H, Me, Br, I
SCHEME23.14 Pdcatalyzed orthoarylation of anilides.
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CARBON–CARBON (C–C) BOND FORMATIONS 655
In an effort to move away from precious metal catalysts, various reports in recent years have
focused on the use of firstrow metal catalysts for direct arylations [57–60]. As a representative
example of these new developments, we illustrate in Scheme23.15 the chelateassisted orthoC–H
arylation of arenes with Fe catalysts [61]. With iron being cheap, nontoxic, and ubiquitous, this
protocol is highly attractive for pharmaceutical syntheses. Using the catalyst precursor Fe(acac)3 in
conjunction with bidentate pyridine ligands, Znaryl reagents as aryl transfer reagents and 1,2
dichloroisobutane as the oxidant, excellent yields of the arylated product were obtained. An
interesting feature of this reaction is the hydrolysis of the imine moiety after workup. The reaction
conditions tolerate additional functionalities such as cyanides, chlorides, triflates, tosylates, and
thiophenes.
23.2.2 C–CAlkenyl Bond Formations
Aromatics with alkenyl substituents are central substructures in synthetic chemistry and can be
found in vast numbers of materials such as dyes [62] and optical and electronic polymers [63].
Transition metal catalysis has played an invaluable role in the direct synthesis of these important
materials [64].
Even though not (yet) among the typically employed reactions for the production of materials,
C–H olefinations of arenes are a valuable, more sustainable alternative for the synthesis of olefin
substituted arenes. C–H olefinations are among the first C–H functionalizations ever reported [65],
and the originally stoichiometric modifications of simple arenes with olefins in the presence of PdII
have initiated broad research efforts. To this day, C–H alkenylations are more common using
aromatic substrates without directing groups [18], and these reactions will be addressed in the next
chapter of this book. However, several examples of chelateassisted C–H olefinations are known
[30, 66–74], which exhibit excellent orthoselectivity.
Ru complexes catalyze the reaction between 2aryl pyridines and alkenyl esters (Scheme23.16)
[75]. These types of olefins are often only slowly reacting substrates in oxidative Heck (Fujiwara–
Moritani) reactions [18]; thus, their use in Rucatalyzed C–H olefinations is a remarkable advance.
The shown reaction is overall redox neutral and produces 1 equivalent of alcohol or acid as side
product. A variety of heterocyclic directing groups can be employed, and many functional groups
are tolerated. However, the olefin scope of the reaction is somewhat limited to alkyl and aryl
substituted alkenes.
H
Fe(acac)3, 15
HBrMg Ar
+
TMEDA, THF, 0°C
ZnCl2
FG
Ar
FG
FG=H, Ar, heteroaryl, Cl,
Br, TfO, TsO, MeO, CF3, CN
NN
tBu tBu
Cl Cl
2 eq 15
N
O
Ar
SCHEME23.15 Fecatalyzed orthoarylation of aromatic imines.
DG
HRu(cod)(cot)
+
Toluene, 120°C
FG
DG
FG
FG = OMe, CF3, Ac, Me,
CN, thiophene, pyrrole
RʹRʹ
RO
R=Ac, Ph
R′= Ph, alkyl
DG=pyridine, tetrazole,
oxazoline, pyrazole, thiazole
SCHEME23.16 Rucatalyzed C–H alkenylation with alkenyl ethers and esters.
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656 CHELATEASSISTED ARENE C–H BOND FUNCTIONALIZATION
Phosphine oxide directing groups enable both redoxneutral and oxidative C–H olefinations
(Scheme23.17) [76, 77]. In combination with [Ru(pcymene)Cl2]2, cisselective hydroarylations of
alkynes can be achieved. Furthermore, in the presence of [Cp*RhCl2]2/AgSbF6, Cu(OAc)2, and
Ag2CO3, oxidative C–H olefinations are possible with electronpoor olefins as coupling partners.
The latter reactions proceed with complete selectivity for the transproduct.
23.2.3 C–CAlkyl Bond Formations
In contrast to C–H arylations and olefinations, C–H alkylations are a rather recent development.
Interestingly, these reactions can proceed under oxidative or redoxneutral conditions and use
different alkyl precursors [78–80]. One of the earliest examples for this reaction was published by
Murai and coworkers, using olefins as reactants [81]. The overall hydroarylation of the olefin with
a Ru catalyst leads to orthoalkylsubstituted aryl ketones, which are difficult to synthesize
selectively with classical methods (Scheme23.18).
A more recent example from the Yu group uses alkylboronic acids as alkyl precursors, which
enables a broader product scope and even the introduction of strained cyclopropyl groups [82].
Pyridine directing groups enable the complete orthoselectivity in the presence of AgI salts,
benzoquinone, and air as oxidants (Scheme23.19). Interestingly, the protocol can be employed for
C–H alkylations of both sp2 and sp3 C–H bonds.
P
H
[Ru( p-cymene)Cl2]2
AgSbF6
+
AcOH/dioxane, 100°C
FG
P
FG
FG=OMe, CF3, Cl, F
Ar
O
Ph
Ph
Ar
Ar
O
Ph
Ph Ar
P
H
[Cp*RhCl2]2
AgSbF6
+
Cu(OAc)2, Ag2CO3
dioxane, 90–120°C
FG
P
FG
FG=OMe, CF3, Cl, F
R
O
Me
Me O
Me
Me
R
69–88%
90–98%
R=aryl, CO2R
SCHEME23.17 C–H olenations with phosphine oxide directing groups.
HRuH2(CO)(PPh3)3
+
Toluene, 135°C
FG FG
FG=alkyl, heteroaryl
R′R′
R′= alkyl, aryl, SiR3
RO O
R
66–100%
SCHEME23.18 Rucatalyzed hydroarylation of olens.
H
Pd(OAc)2
+
Ag2O, benzoquinone, 6 h
tamyl alcohol, air, 100°C
Calkyl =Me, Et, nBu, nHex,
Ph(CH2)2, cyclopropyl
N
48–75%
(HO)2B–Calkyl Calkyl
N
SCHEME23.19 Pdcatalyzed oxidative alkylation with alkylboronic acids.
0002567366.INDD 656 10/24/2015 1:13:46 PM

CARBON–CARBON (C–C) BOND FORMATIONS 657
Redoxneutral orthoC–H alkylations of phenols can be achieved with simple alcohols in the
presence of a Ru catalyst (Scheme23.20) [83]. Using this method, several complex molecules
(e.g., 16, 17, and 18) have been synthesized. Mechanistic experiments show the loss of deuterium
labeling in αposition to the phenol functionality and no primary kinetic isotope effect
(kH/kD = 1.1 ± 0.1). Both findings are consistent with rapid and reversible C–H bond activation
before C–C bond formation. However, the mechanism of the reaction has not been studied in detail,
and the source of the unusual directing group effect of the phenol moiety is unclear.
23.2.4 C–CAcyl Bond Formations
C–H bond acylations are a relatively new area of C–H functionalizations. These reactions have the
potential to provide alternatives to Friedel–Crafts acylations, which are used to produce aryl ketones
on a multiton scale per year [84]. Using directing groups, only orthoC–H acylations are possible,
which might limit their usefulness on a large scale.
C–H acylations can proceed using various acyl precursors and most reactions proceed under
oxidative conditions. The Rhcatalyzed protocol in Scheme23.21 is an exemption from this trend,
as the carboxylic anhydride reagent acts as oxidant and acyl source at once.
When using aldehydes as acyl synthons, C–H bond acylations require the presence of an oxidant.
Commonly employed oxidants are Ag salts (Scheme23.22) [85] in Rhcatalyzed protocols or tert
butyl hydroperoxide for Pdcatalyzed methodologies [86].
Another approach to achieve C–H acylations relies on synthesizing the carbonyl group in situ
from seemingly unrelated precursors. Following this strategy, tertbutyl hydroperoxide can be used
to oxidize benzylic methyl groups, which leads to C–H acylation of acetanilides in the presence of
a Pd catalyst (Scheme23.23). Remarkably, these reactions tolerate the presence of other benzylic
methyl groups as well as aryl bromides [87].
OH
H[HRu(C6H6)(PCy3)(CO)]BF4
+
Toluene, 100°C
FG
OH
FG
FG=H, OMe, CN, Cl,
alkyl, aryl
Calkyl
HO
Calkyl = cycloalkyl, Me,
Et, iPr, PhCH(CH3)OH
Calkyl
81–95%
10 mol%
O
OH
O
Ph O
OH
HN
Ph
H
H
OH
OH
H H
16 17 18
SCHEME23.20 Dehydrative C–H alkylation of phenols with alcohols.
H[Rh(cod)Cl]2
+Base
Mesitylene, 145–155°C
FG FG
FG=acyl, alkyl, Me2N, MeO,
CF3, F, Cl, Br
R=alkyl, aryl
R
HO O
O
HO
45–92%
ROR
OO O
SCHEME23.21 Rhcatalyzed orthoC–H acylation of aromatic carboxylic acids.
0002567366.INDD 657 10/24/2015 1:13:47 PM

658 CHELATEASSISTED ARENE C–H BOND FUNCTIONALIZATION
23.2.5 C–CN Bond Formations
In contrast to all the C–C bond formations described previously, C–H cyanations are much rarer.
This might be due to the possible strong coordination of free CN ligands to transition metal centers,
which would preclude C–H activation as the first step of the catalytic cycle for C–H functionaliza-
tion. The first C–CN bond formation was reported in 2006 by Yu and coworkers along with a series
of Cucatalyzed and Cumediated C–H functionalizations of 2phenyl pyridine (Scheme23.24)
[88]. C–CN bond formations can thus be achieved with Me3SiCN or CH3NO2 as cyanating reagents
in the presence of 1 equivalent of Cu(OAc)2 and air.
Since then, more recent developments have focused on using less toxic reagents (Scheme23.25)
[89], on broadening the scope of the used directing group (Scheme23.26) [90], and on estab-
lishing functional group tolerant protocols. A great example for the use of cyanide sources
with low toxicity is the example shown in Scheme23.25, which employs K3Fe(CN)6 as reagent
of choice. A variety of functional groups are tolerated under these conditions and pyrazole
directing groups are effective for this transformation in addition to pyridinebased directing
groups, [89].
A Rhcatalyzed protocol with PhTsN(CN) as cyanide source exhibits a remarkably broad scope
of functionalized substrates, leaving even unprotected phenol groups, boronates, epoxides, and
reactive aliphatic C–Cl bonds untouched under the reaction conditions (Scheme23.26) [90].
NH
HPd(OAc)2
+
tBuOOH
DMSO, 100°C
FG
NH
FG
FG=Me, OMe,
Cl, Br, NO2
53–90%
H3C
O
RR
O O
R=Me, Cl, Br,
OMe
SCHEME23.23 Pdcatalyzed C–H acylation by benzylic oxidation.
H
1 eq Cu(OAc)2
+
Air, 130°C CN
N
42–67%
N
H3C-NO2
or
Me3SiCN
SCHEME23.24 Cumediated C–H cyanation.
H[Cp*RhCl2]2/AgSbF6
+
Ag2CO3
THF, 110°C
FG FG
FG=Me, Ph, OMe,
OAc, F, Cl, Br
Et2N
Et
2
N
OO
33–72%
H
OO
RR
SCHEME23.22 Rhcatalyzed oxidative orthoC–H acylation with aldehydes.
0002567366.INDD 658 10/24/2015 1:13:47 PM

CARBON–CARBON (C–C) BOND FORMATIONS 659
23.2.6 C–CF3 Bond Formations
Trifluoromethyl (CF3) groups are electronwithdrawing substituents that increase the lipophilicity
of molecules at the same time. Furthermore, CF3 substitution can enhance the bioavailability of a
drug by increasing its metabolic stability. Therefore, the selective installation of CF3 groups is of
substantial interest for pharmaceutical applications [91].
Chelateassisted C–H bond trifluoromethylations are rare, and so far, only two reagents have
been used successfully in these reactions. The first reagent 19 is an electrophilic source of CF3
+,
which reacts under Pd catalysis with substrates bearing directing groups (Scheme23.27) [92, 93].
The reaction also requires the presence of Cu(OAc)2 and trifluoroacetic acid as promoters; both
amidebased and heterocyclic directing groups can be employed.
Interestingly, the rather unusual triazene directing group also promotes chelateassisted C–H bond
trifluoromethylations in combination with superstoichiometric amounts of AgF (Scheme23.28) [94].
The reagent used in this process, Me3SiCF3 (20), is considerably less expensive than reagent 19,
which makes the protocol highly attractive. However, no other directing groups have been shown to
promote analogous C–H trifluoromethylations. Interestingly, very similar conditions to those shown
in Scheme23.28 also promote orthoC–H pentafluoroethylation, heptafluoropropylation, and ethoxy-
carbonyldifluoromethylation of aromatic triazenes using the respective Me3SiRf reagents [95].
O
DG
H
[Cp*Rh(MeCN)3]
(SbF6)2
+
Ag2CO3, dioxane,
Ar, 120°C
FG
DG
FG
DG=oxime, pyridine,
dihydroimidazole,
dihydrooxazole, pyrazole
CN
Ph NTs
CN
FG=Me, MeO, CO2Me, F, Cl, Br,
I, OH, OTs, NHAc, Cl
O( )3
B
N
O
OO
O
O
OAc
OAc
AcO
AcO OO
SCHEME23.26 C–H cyanation with broad functional group tolerance.
DG
H
Pd(OAc)2
+
Cu(OAc)2, CF3CO2H
DCE, 110–130°C
FG
DG
FG
DG= pyridine,
pyrimidine, imidazole,
amide, thiazole
CF3
FG=alkyl, F, Cl, Br, MeO,
CF3, CO2Me, naphthyl
32–88%
S
CF3
OTf–
19
SCHEME23.27 Pdcatalyzed orthoC–H triuoromethylation.
DG
HPd(OAc)2
+CuBr2, DMF
130°C
FG
DG
FG
DG=pyridine, pyrazole
FG=alkyl, MeO, F, Cl,
CN, CO2Me
CN
K2Fe(CN)6
SCHEME23.25 Pdcatalyzed C–H cyanation with nontoxic K3Fe(CN)6 as cyanide source.
0002567366.INDD 659 10/24/2015 1:13:48 PM

660 CHELATEASSISTED ARENE C–H BOND FUNCTIONALIZATION
In summary, a wide variety of chelateassisted C–C bond formations is possible using var-
ious transition metal catalysts. These protocols introduce C–Caryl, C–Calkenyl, C–Calkyl, C–Cacyl,
C–CN, and C–CF3 bonds in ortho positions of suitable directing groups. As such, these methods
can be employed in order to build carbon frameworks. With their increasing popularity in the
synthetic community, many more applications of these protocols can be expected in the years
to come.
23.3 CARBON–HETEROATOM (C–X) BOND FORMATIONS
23.3.1 C–B Bond Formations
C–H borylations as methods to prepare synthetically valuable aryl boronic acids and esters have
been intensively studied for substrates without directing groups since their discovery by Smith and
coworkers in 1999 [96, 97]. Continuing this work, several groups have pursued ways to control the
selectivity of these reactions. Among the applied strategies, the use of directing groups to achieve
orthoselective C–H borylations has been realized with late transition metal catalysts such as Pd,
Rh, and Ir. Interestingly, some of the created protocols proceed under oxidative conditions
(Scheme23.29), resulting in stoichiometric byproducts derived from the used oxidant [98]. The
presence of the ligand 21 is crucial for high yields in the shown protocol. In contrast, early examples
of C–H borylations as well as most Rh and Ircatalyzed protocols proceed under mild conditions
in the absence of added oxidants [96, 97, 99, 100].
In order to make the developed catalysts more synthetically useful, anchoring the ligands to
surfaces has been a successful strategy, resulting in a protocol with significant tolerance of steric
hindrance around the cleaved C–H bond (Scheme23.30) [101, 102]. An additional feature of this
protocol is its capability to employ various and unusual directing groups, including esters, amides,
sulfonic esters, and even Cl.
A second interesting development uses traceless, silylbased directing groups as shown in
Scheme23.31. This strategy allows orthoC–H borylation of phenols, arylamines, and alkylarenes
H
Pd(OAc)2/21
+
K2S2O8, TsONa
MeCN, 80°C
FG
FG
B
HN O
O
ArHN
46–85%
CF3
F
F
F
F
O
B
O
B
O
O
O
O
FG=Me, MeO,
AcO, F, Cl, NO2
O
R
R
21
R=(4-CF3)C6H4
SCHEME23.29 Pdcatalyzed oxidative orthoC–H borylation.
N
H
AgF
+
C6F14, 100°C, 4 h
FG
N
FG
CF3
FG=F, Cl, Br, I, CN,
MeO, alkyl, CO2Et
39–74%
N
CF3
N
NiPr2
NiPr2
20
Me3Si
SCHEME23.28 Triazene/Agmediated C–H bond triuoromethylation.
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CARBON–HETEROATOM (C–X) BOND FORMATIONS 661
in one pot without additional steps, which are often required to install and remove directing
groups [103].
23.3.2 C–Si Bond Formations
Similar to C–H borylations, C–H silylations form new C–X bonds with small electronegativity
differences between the bonding partners (ΔEN[C–B] = 0.51; ΔEN[C–Si] = 0.65). This leads to
organosilicon and organoboron reagents possessing a relatively lower reactivity compared with
other organometallic compounds (e.g., for organolithium reagents, ΔEN[C–Li] = 1.57) and a better
functional group tolerance [104]. Therefore, both C–H borylations and silylations lead to valuable
and versatile organometallic intermediates, which have been used for very diverse subsequent
transformations [105].
C–H silylations are possible without an intramolecularly tethered directing group using Pt, Ru,
or Ir catalysts [106–108]. In these cases, the site selectivity of C–Si bond formation is mainly con-
trolled by the electronic and steric properties of the substrates. Silylations using a directing group
circumvent this inherent substrate control of selectivity and enforce orthoC–H silylation. Directing
groups promoting these reactions include silanes (Scheme23.32) [108, 109] and transformable
protecting–directing groups (PG/DGs) of arylboronic acids (Scheme23.33) [110, 111]. In the latter
case, the directing group enables C–H functionalizations in the ortho position of a Caryl–B bond,
which can be used for further transformations after reaction with pinacol under acidic conditions
[110]. Both directing–protecting groups shown in Scheme23.33 can be recovered from the reaction
mixtures and are thus reusable.
OH
H
3.KHF2(aq), THF
FG
OH
FG FG
FG=alkyl, ether
BF3K
1. Et2SiH2, [Ir(cod)Cl]2
2. B2pin2, HBpin, (Ir(cod)Cl)2,
dtbpy, THF, 80°C OSiEt2H
Bpin N
N
tBu
tBu
dtbpy
via
SCHEME23.31 Onepot orthoC–H borylation of phenols.
X
H[Pt] or [Ir]
FG FG
X=-CH2-CH2-, -CR2-O-,
-CHR-O-
SiR
2
H
SiR2
X
–H-H
FG=Me, Cl, Br, NMe2, OTBS,
OPiv, heteroaryl, alkene
SCHEME23.32 Silyldirected intramolecular C–H bond silylations.
DG
HIr/SiO2
+
25–80°C
FG
DG
FG
DG = ester, amide,
sulfonic ester, Cl
B
FG=alkyl, MeO, CF3
OB
O
B
O
O
O
O
Ir(cod)OMe
P
Si
Si
OO
O
O
SiO2
Si
Si
OO
O
O
Ir/SiO2=
SCHEME23.30 Directed orthoC–H borylation with supported Ir catalyst.
0002567366.INDD 661 10/24/2015 1:13:49 PM

662 CHELATEASSISTED ARENE C–H BOND FUNCTIONALIZATION
23.3.3 C–O Bond Formations
Transition metalcatalyzed hydroxylations, acetoxylations, and analogous C–H oxygenations of
simple arenes have been studied by the catalysis community for several decades [112–114].
However, orthoselective C–H oxygenations are a more recent development with the first example
being reported by Sanford and coworkers in 2004 [115]. Since then, a large variety of directing
groups (heterocycles, carboxylates, carboxylic amides, oximes) and catalysts (Pd(OAc)2, PdCl2,
[RuCl2(pcymene)2]2, Cu(OAc)2) enabling C–H oxygenations has been established [2, 11, 40, 116–
125]. Typically, these reactions require the presence of a strong oxidant (O2, IIII reagents, oxone,
K2S2O8), which is likely needed to promote C–O reductive elimination through oxidation of the
catalyst [12, 17].
An interesting recent development in the field is the use of directing groups that are not predicted
to coordinate strongly to the catalyst, for example, phosphoric and phosphonic acids as shown in
Scheme23.34 [126].
Other remarkable developments include the use of oxygen as the terminal oxidant to directly
form Caryl–OH functionalities without the intermediacy of phenolic ester structures. Several types of
directing groups, among them pyridyl and carboxylate groups (Scheme23.35), have been reported
to enable these reactions. Notably, each of these protocols requires the presence of a cocatalyst
(benzoquinone or Nhydroxyphthalimide) [127, 128].
23.3.4 C–N Bond Formations
Chelateassisted C–H bond aminations often require the presence of an oxidant in analogy to the
previously discussed C–H oxygenations. Therefore, many protocols use a mixture of amine source
and oxidant as reagents in order to achieve C–N bond formation. Intermolecular directed C–H
aminations have been realized with this approach by Che and coworkers (Scheme 23.36).
Remarkably, this methodology is capable of employing a variety of different directing groups as
well as primary amides as amine sources [129].
X
H
Pd(OAc)2
FG FG
X=CH2, O
P
Dioxane, 110°C, 15 h
FG=alkyl, MeO, Bn,
Ph, MeO, Cl, CO2Me
O
OH
OMe
+PhI(OAc)2
XP
O
OH
OMe
OAc
SCHEME23.34 C–H bond acetoxylation of phosphonic and phosphoric acids.
B
H
1. RuH2(CO)(PPh3)
2. p-TsOH ,
FG
B
FG
FG=F, Cl, CF3, Me, MeO,
CO2Me, heteroaryl
SiR
3
HSiR3
H
FG
or +
NHHN BN
HN
O
N
R=Me, Et, Ph
OO
OH
OH
40–91%
SCHEME23.33 OrthoC–H silylation of arylboronic acids with transformable PG/DGs.
0002567366.INDD 662 10/24/2015 1:13:50 PM

CARBON–HETEROATOM (C–X) BOND FORMATIONS 663
However, the approach of using mixtures of oxidant and amine source in C–H amination
protocols poses the challenge of reagent compatibility, in particular with easily oxidized amine
sources. In order to address this issue, several protocols have been developed, which combine the
oxidant and amine source in one reagent. Both organic azides and protected hydroxylamine
derivatives have been used with this approach in mind to result in high yields of aminated products
(Scheme23.37) [130–134].
A second strategy to broaden the functional group tolerance of C–H aminations consists of
employing inert amine sources [27] or relatively inert oxidants [135]. Using the latter approach in
the protocol shown in Scheme23.38, the presence of various heterocyclic and functionalized struc-
tures in arene substrates can be tolerated with Cu(OAc)2 and O2 as oxidants. The elaborate directing
group that is required for high reactivities can be readily cleaved from the product and recovered
for reuse.
H
PdCl2
FG
FG
FG=alkyl, Ph, F, CF3, OR
Toluene, O2, 100°C
+
OH
NN
OO
OH
HPd(OAc)2
FG
FG=alkyl, MeO, NHAc, F, Cl,
CF3, Ac, CN, NO2
DMA, KOAc, O2, 115°C
+
CO2HO
O
DG
SCHEME23.35 Pdcatalyzed aerobic C–H hydroxylations.
DG
H[Cp*RhCl2]2
FG FG
DG=pyridine,
pyrimidine,
CONH-OMe
1,2-DCE, AgSbF6, 80°C, 12 h
or MeCN, KOAc, 50°C, 16 h FG = Me, OR, alkene, F,
Cl, Ac, CO2R, CHO, CF3
+
DG
NHR
R=SO2R
R′= 2,4,6-Cl3C6H2
RN3 or
R′CO2-NHBoc
SCHEME23.37 Rhcatalyzed C–H aminations with electrophilic amination reagents.
DG
HPd(OAc)2
FG FG
DG=oxime,
pyridine
K2S2O8, DCE, 80°C
14–20 h
68–95%
FG=Me, I, Br, Cl, MeO
+RNH2
DG
NHR
R=COCF3,
CO2Me,
CO2
tBu, SO2R
SCHEME23.36 Intermolecular, Pdcatalyzed C–H amination with K2S2O8 as oxidant.
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664 CHELATEASSISTED ARENE C–H BOND FUNCTIONALIZATION
23.3.5 C–P Bond Formations
Functional groups containing phosphorous in the oxidation state +III are typically very easily
oxidized, even by relatively inert oxidants such as O2. Therefore, strategies for oxidative C–H bond
phosphorylations typically avoid the presence of PIII in the presence of other oxidants.
Intramolecularly, this issue can be addressed by using PV reagents [136] or by performing the
reaction without external oxidants (Scheme 23.39) [137]. The latter example possibly proceeds
through C–P bond activation as well as C–H bond activation. Since the reaction products are
susceptible to air oxidation, they are isolated as oxides 22 after treatment with H2O2.
Intermolecular, chelateassisted phosphorylations of arene C–H bonds have focused so far on
reagents with PV substructures. The two known protocols both avoid an excess of strongly
coordinating phosphonating reagent in order to prevent catalyst deactivation. The example in
Scheme23.40 achieves this goal by slow addition of the phosphite reagent 23 over a period of 13 h
[138]. The modified phosphorylation reagent 24 (Scheme23.41) achieves a similar effect: the
active phosphite reactant (HP(═O)Bu2 or [P(═O)Bu2]−) is slowly liberated from the masked reagent
24 under the reaction conditions by basepromoted elimination of acetone [139].
H[Pt] or [Ir]
FG
FG
FG= alkyl, OMe, NMe2,
Ac, CO2Me, CN, F, Cl,
Br, pyridine, pyrrole, furan
PPh2
PPh
O
FG FG
22
54–94%
SCHEME23.39 Pdcatalyzed intramolecular C–H bond phosphorylation.
DG
HPd(OAc)2
FG FG
DG=pyridine,
pyrimidine, oxazoline,
pyrazole
NaOAc, AgOAc, benzoquinone
120°C, 13 h 15–80%
FG=alkyl, MeO, F, Cl,
CF3, CN, NHAc, CO2Me
+
DG
PR2
23
HPR2
OO
R=aryl, OR′
SCHEME23.40 Pdcatalyzed C–H bond phosphorylation.
H
Cu(OAc)2
FG
FG
FG = Me, F, Cl, Br,
CF3, Ac, alkene
Na2CO3, DMSO
air/O2, 80°C, 6 h
+
DG
NHR
R=CH3, CF3, aryl
R′=CF3, aryl, pyridyl
RSO2NH2
or
R′CONH2
ONH N
O
SCHEME23.38 Cumediated, aerobic C–H amination of arenes.
0002567366.INDD 664 10/24/2015 1:13:52 PM

CARBON–HETEROATOM (C–X) BOND FORMATIONS 665
23.3.6 C–S Bond Formations
Together with C–H phosphorylations, C–H sulfenylations are rather rare among the large body of
literature covering chelateassisted C–H functionalizations. An initial example of this type of reac-
tivity was reported by Yu and coworkers, using PhSH or MeSSMe as reagents for the sulfenylation
of 2phenyl pyridine (Scheme23.42) [88].
The general concept shown in Scheme23.42 has later been extended by Daugulis and coworkers
to arrive at a general auxiliarypromoted Cucatalyzed C–H sulfenylation protocol for benzoic
acids (Scheme23.43). The reaction exclusively affords disulfenylated products when both ortho
C–H bonds are available; otherwise, monosulfenylated products can be obtained [140].
Notably, a C–H sulfonylation protocol by Dong and coworkers provides a quite different approach
to forming C–S bonds (Scheme23.44) [141]. Using pyridine or oximebased directing groups, ortho
C–H bonds can be directly sulfonylated through Pdcatalyzed reaction with arylsulfonyl chlorides.
H
Pd(OAc)2, tBuOH
FG
FG
AgOAc, K2HPO4, 120°C, 48 h
15–80%
FG = alkyl, MeO, Cl,
heteroaryl, alkene
+
DG
O
N
P(OnBu)2
P(OnBu)2
O
HO
24
N
Me
OO
SCHEME23.41 Pdcatalyzed C–H bond phosphorylation with masked reagent 24.
H
Cu(OAc)2, air
DMSO, 130°C, 24 h
40% (R=Ph)
51% (R=Me)
+
DG
SR
NPhSH or
MeSSMe
SCHEME23.42 First chelateassisted Cucatalyzed C–H sulfenylation.
H
Cu(OAc)2, air
DMSO, 100–110°C
43–90%
FG=alkyl, OMe, Cl, F, Br,
CO2Me, heteroaryl
+
DG
SR
H
ONH
N
RSSR
R=CF3, iPr,
tBu, Bn, aryl
FG
FG
SCHEME23.43 Auxiliarypromoted, Cucatalyzed C–H sulfenylation.
DG
HPd(MeCN)2Cl2
FG FG
DG=pyridine,
pyrazole, oxime
K2CO3, dioxane, 4Å MS
120°C, 6h
+
41–88%
FG = alkyl, MeO, CF3
DG
R=Me, F,
NO2, naphthyl
Cl SR
OO
SR
OO
SCHEME23.44 Pdcatalyzed, chelateassisted C–H sulfonylation.
0002567366.INDD 665 10/24/2015 1:13:53 PM

666 CHELATEASSISTED ARENE C–H BOND FUNCTIONALIZATION
23.3.7 C–Halogen Bond Formations
Chelateassisted C–H bond halogenations are among the more developed C–H bond functionaliza-
tions and can generally employ a large variety of directing groups such as pyridines, pyrimidines,
oximes, carboxylates, and amides [88, 142, 143]. Some protocols use electrophilic halogen sources
such as NCS, NBS, or NIS (Scheme23.45) [143–147]; furthermore, C–I bonds can be introduced
by reacting the substrates with elementary I2 [88] or IOAc [148].
Furthermore, both C–H iodinations and brominations can be achieved using the respective
halide salts in combination with oxidants [148]. Scheme23.46 shows one example of this approach,
in which calcium halides act as halide sources for C–H bond halogenations with Cu(O2CCF3)2 as
stoichiometric oxidant [142].
Clearly, various methods are available to achieve C–I, C–Br, and C–Cl bond formations follow-
ing chelateassisted C–H activation. However, none of these methods are applicable to C–H fluori-
nations. Several possible challenges for establishing this reaction have been described in the
literature: (i) The C–F coupling step through reductive elimination from transition metal aryl
complexes is challenging. As such, relatively few examples of this reaction have been reported so
far [149, 150]. (ii) C–H bond fluorination protocols are sensitive to the directing groups used in the
transformation [151]. (iii) Only few electrophilic F+ sources are available, which can be used con-
veniently in methodology development. The alternative pathway, fluoride salts in combination with
an oxidant has shown to be successful for C–F bond formation, but so far only for the fluorination
of benzylic C–H bonds [152].
Despite these challenges, several groups have developed chelateassisted fluorinations of C–H
bonds. The earliest example from 2006 uses 25 as F+ source and oxidant in combination with
microwave irradiation (Scheme23.47) [149]. Using a pyridine directing group, difluorination is
observed when the arene has no additional substituents in ortho or meta position.
Similar selectivity issues can be found in triflamidedirected reactions (Scheme23.48) [153].
Using a modified fluorinating reagent 26, mono and difluorinated products can be obtained.
Amore recent development focuses on addressing this selectivity issue with an auxiliarybased
approach [154]. Finally, quinoxalinebased directing groups are also able to promote monoselective
C–H bond fluorinations in combination with Nfluorobenzenesulfonimide as F+ source [151].
DG
H
Pd(OAc)2
FG FG
DG=pyridine,
amide, oxime
AcOH or MeCN
100°C, 12 h 53–82%
FG=alkyl, CHO, C=O,
CF3, Br, OAc, F
+
DG
HaI
N
O
O
Hal
Hal=Cl, Br, I
SCHEME23.45 Pdcatalyzed C–H bond halogenations with NXS (X = Cl, Br, I).
HPd(OAc)2, Cu(O2CCF3)
AcOH, 130°C, air
74–95%
+Hal
NN
CaHal2
NN
FG FG
FG=alkyl, MeO,
Ph, naphthyl
Hal
NN
FG
+
0–9%
Hal
SCHEME23.46 Pdcatalyzed selective monohalogenation of aryl pyrimidines.
0002567366.INDD 666 10/24/2015 1:13:54 PM

CARBON–HETEROATOM (C–X) BOND FORMATIONS 667
23.3.8 C–D Bond Formations
Incorporating deuterium into organic molecules is highly useful for the detection and identification
of metabolites and decomposition products of bioactive molecules. Therefore, deuterating reactions
such as H/D exchange have been used for many environmental and pharmaceutical applications
[155]. Moreover, molecules with C–D bonds are helpful for analyzing transition metalcatalyzed
reactions [156, 157].
In order to achieve selective deuterium incorporation in ortho positions to a directing group,
chelateassisted C–H deuterations can be performed with cationic Ir complexes such as Crabtree’s
catalyst 27 (Scheme23.49) [155, 158, 159]. Moreover, Pd complexes catalyze the same type of
reactivity, even with weakly directing groups (Scheme23.50) [22]. The proposed mechanisms for
HPd(OAc)2
MeCN/CF3Ph, 150°C, µwave
Meta-/ortho-FG
33–75%
+F
NN
FG FG
FG=alkyl, MeO, CF3,
Cl, CO2Et, C=O
F
N
or
60%
F
N
FBF4–
25
SCHEME23.47 Pdcatalyzed C–H uorination of 2phenyl pyridines.
HPd(OTf)2
NMP, DCE, 120°C
Meta-/ortho-FG
58–88%
+F
NH
SNHTf
FG
FG
FG=alkyl, MeO, F,
Cl, Br, OMe, CF3
F
or
53–71%
F
N
FOTf–
26
CF3
O
ONHTf
FG
SCHEME23.48 Pdcatalyzed C–H bond uorination of benzylic triamides.
DG
H[Ir(cod)(PCy3)(C5H5N)] (27)
FG FG
DG=ketone, ester,
amide, oxime, heterocycle
CH2Cl2, D2O, D2
RT 5–100% D incorporation
FG = alkyl, OMe, NO2,
CO2Me, CF3, F, Cl, Br
DG
D
D
SCHEME23.49 C–H deuteration of C–H bonds with Crabtree’s catalyst 27.
HPd(OAc)2
Na2CO3, AcOH-D4,
120°C, 12 h 65 to >99% D incorporation
D
CO2H
CO
2
H
FG FG
FG=alkyl, CF3, OMe, F,
Cl, NO2, naphthyl
D
SCHEME23.50 H/D exchange with weakly coordinating directing groups.
0002567366.INDD 667 10/24/2015 1:13:55 PM

668 CHELATEASSISTED ARENE C–H BOND FUNCTIONALIZATION
these processes essentially consist of C–H activation, followed by the microscopic reverse of C–H
activation to form the new C–D bond [22, 160].
In summary, various functional groups can be introduced in ortho positions of arene substrates
by using suitable directing groups. The scope of directing groups is extremely broad, as documented
in this chapter. The large variety of introducible functional groups promises high versatility of these
protocols for organic syntheses and will very likely find broad applications, in particular for the
latestage modification of complex structures[6, 161, 162].
23.4 STEREOSELECTIVE C–H FUNCTIONALIZATIONS
As aromatic structures are typically planar—and therefore often not the focus of method
development in enantioselective synthesis—this chapter contains only few examples of stereose-
lective arene C–H functionalizations. Despite this restriction, stereoselective syntheses can be per-
formed through chelateassisted C–H functionalizations of arene moieties in specially designed
substrates.
One such example is biaryl substrates with low rotation barriers around the biaryl C–C bond.
Rotation around this bond converts one axial enantiomer into the other [163]. The naphthyl pyridine
28 falls into this class of substrates (Scheme23.51). Chelateassisted C–H alkylation of 28 results
in generation of two enantiomeric products with 49% ee, since the rotation around the biaryl C–C
bond is frozen in the product.
Notably, diastereoselective iodinations of aryl and other substituents can be achieved through an
auxiliarybased approach using enantiomerically pure oxazolines as directing groups (Scheme23.52)
[164]. Diastereomeric ratios as well as yields are high using this protocol, providing monoiodinated
aryl products.
Another class of substrates bearing prochiral arene substituents has been shown to undergo Pd
catalyzed C–C couplings in high yields and enantioselectivities up to 95% ee (Scheme23.53) [165].
Key to this reactivity is a broad screening of carboxylate coligands such as 30 whose design takes
advantage of the chiral pool of amino acids.
H
[RhCl(coe)2]2/29
Toluene
120°C, 20 h
37%, 49% ee
H2
C
N
28
+H2C
CH2
CH2H
N
Fe
OMe
PPh2
29
SCHEME23.51 Rhcatalyzed C–H alkylation inducing axial chirality.
H
Pd(OAc)2
I2, PhI(OAc)2, CH2Cl2
24°C, 13 h
98%, dr
I
N
O
N
OtBu
tBu
*
99:1
SCHEME23.52 Diastereoselective Pdcatalyzed C–H iodination.
0002567366.INDD 668 10/24/2015 1:13:56 PM

REFERENCES 669
Interestingly, none of the stereoselective reactions described previously assembles a new chiral
center; instead, the applied strategies rely on previously existing, special chiral characteristics of the
substrates (prochiral moieties or fluxional axial chirality). In contrast to these approaches, a recently
published report relies solely on catalyst design to generate a new stereocenter in the product through
chelateassisted hydroarylation (Scheme23.54) [166]. The most selective Rh catalyst 31 uses a biaryl
substituted Cp ring as the structural element to induce enantioselectivity. After the reaction, the
hydroarylation product with a new quaternary stereocenter can be isolated in 87% yield and 91% ee.
In conclusion, several approaches have been taken in order to enable stereoselective C–H func-
tionalizations of arene substrates. Most currently known examples take advantage of chiral features
in the substrate, but recent developments aim at establishing catalystcontrolled enantioselectivity.
Overall, the field of chelateassisted C–H bond functionalization has evolved dramatically over
the last 10 years and is expected to contribute even more to streamlining organic synthesis and
enabling efficient synthetic methodologies in the years to come. The following chapter will cover
developments in the area of nonchelateassisted C–H bond functionalizations, some of which have
been mentioned briefly in this chapter.
ABBREVIATIONS
AMLA Ambipilic metal ligand activation
CF3 Trifluoromethyl
CMD Concerted metalation deprotonation
PG/DGs Protectingdirecting groups
SBM Sigma bond metathesis
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