comprehensive organic synthesis ii || 3.23 carbon–carbon σ-bond formation via ch bond...

3.23 Carbon–Carbon r-Bond Formation via C–H Bond FunctionalizationY-H Zhang and G-F Shi, Tongji University, Shanghai, ChinaJ-Q Yu, The Scripps Research Institute, San Diego, CA, USA

r 2014 Elsevier Ltd. All rights reserved.

3.23.1 Introduction 1102
3.23.2 Reactions with C�C/C�X Multiple Bonds 1103 3.23.2.1 Reactions with C�C Multiple Bonds 1103 3.23.2.1.1 Palladium-catalyzed reactions with C�C multiple bonds 1103 3.23.2.1.1.1 Palladium-catalyzed reactions of simple (hetero)arenes with alkenes 1103 3.23.2.1.1.2 Palladium-catalyzed directing group-assisted reactions with alkenes 1107 3.23.2.1.1.3 Palladium-catalyzed reactions of C�H bonds with alkynes 1111 3.23.2.1.2 Rhodium-catalyzed reactions with C�C multiple bonds 1112 3.23.2.1.2.1 Rh(I)-catalyzed C�H alkylation with alkenes 1112 3.23.2.1.2.2 Rh(III)-catalyzed C�H alkenylation with alkenes 1115 3.23.2.1.2.3 Rh-catalyzed reactions of C�H bonds with alkynes 1116 3.23.2.1.3 Ruthenium-catalyzed reactions with C�C multiple bonds 1119 3.23.2.1.4 Other transition-metal-catalyzed reactions with C�C multiple bonds 1123 3.23.2.1.4.1 Nickel-catalyzed reactions of C�H bonds with C�C multiple bonds 1123 3.23.2.1.4.2 Iridium, platinum, and rhenium-catalyzed reactions of C�H bonds with C�C multiple bonds 1125 3.23.2.2 Reactions with CQO and CQN Bonds 1127 3.23.2.2.1 Palladium-catalyzed reactions of C�H bonds with aldehydes and imines 1127 3.23.2.2.2 Other-transition-metal-catalyzed reactions of C�H bonds with CQO and CQN bonds 1129 3.23.2.2.3 Carboxylation of C�H bonds with CO2 1131 3.23.2.2.4 Reactions of C�H bonds with nitriles 1132 3.23.2.3 Reactions with CO 1133 3.23.2.3.1 Palladium-catalyzed reactions of C�H bonds with CO 1133 3.23.2.3.2 Rhodium-catalyzed reactions of C�H bonds with CO 1135 3.23.2.3.3 Ruthenium-catalyzed reactions of C�H bonds with CO 1136 3.23.3 Reactions with (Pseudo)halides 1139 3.23.3.1 Pd-Catalyzed Reactions with (Pseudo)halides 1140 3.23.3.1.1 Pd-catalyzed nondirected reactions of (hetero)arenes with (pseudo)halides 1140 3.23.3.1.1.1 Pd-catalyzed nondirected reactions of (hetero)arenes with (pseudo)halides via Pd(0)/Pd(II) catalytic cycle 1141 3.23.3.1.1.2 Pd-catalyzed nondirected reactions of (hetero)arenes with (pseudo)halides via Pd(II)/Pd(IV) catalytic cycle 1148 3.23.3.1.2 Pd-catalyzed-directed reactions of (hetero)arenes with (pseudo)halides 1148 3.23.3.1.2.1 Pd-catalyzed-directed reactions of (hetero)arenes with (pseudo)halides via Pd(0)/Pd(II) catalytic cycle 1148 3.23.3.1.2.2 Pd-catalyzed-directed reactions of (hetero)arenes with (pseudo)halides via Pd(II)/Pd(IV) catalytic cycle 1150 3.23.3.1.3 Pd-catalyzed arylation of C(sp3)-H bonds with aryl (pseudo)halides 1152 3.23.3.2 Rhodium-Catalyzed Reactions with (Pseudo)halides 1156 3.23.3.2.1 Rhodium-catalyzed nondirected reactions with (pseudo)halides 1156 3.23.3.2.2 Rhodium-catalyzed-directed reactions with (pseudo)halides 1158 3.23.3.3 Ruthenium-Catalyzed Reactions with (Pseudo)halides 1159 3.23.3.4 Other Transition-Metal-Catalyzed Reactions with (Pseudo)halides 1162 3.23.3.4.1 Copper-catalyzed reactions with (pseudo)halides 1162 3.23.3.4.2 Nickel-catalyzed reactions with (pseudo)halides 1163 3.23.3.4.3 Iron/cobalt/iridium-catalyzed reactions with (pseudo)halides 1166 3.23.4 Reactions with Organometallic Reagents 1168 3.23.4.1 Palladium-Catalyzed Reactions with Organometallic Reagents 1168 3.23.4.1.1 Palladium-catalyzed coupling of C(sp2)-H bonds with organometallic reagents 1168 3.23.4.1.2 Palladium-catalyzed coupling of C(sp3)-H bonds with organometallic reagents 1173 3.23.4.2 Rhodium-Catalyzed Reactions with Organometallic Reagents 1175 3.23.4.3 Ruthenium-Catalyzed Reactions with Organometallic Reagents 1176 3.23.4.4 Iron, Cobalt, and Nickel-Catalyzed Reactions with Organometallic Reagents 1178 3.23.5 Reactions with C�H Bonds 1181 3.23.5.1 Palladium-Catalyzed Reactions with C�H Bonds 1181 3.23.5.1.1 Palladium-catalyzed homocoupling of two C�H bonds 1181 3.23.5.1.2 Palladium-catalyzed coupling of two different C�H bonds 1182 3.23.5.1.3 Palladium-catalyzed intramolecular coupling of two C�H bonds 1186
Comprehensive Organic Synthesis II, Volume 3 doi:10.1016/B978-0-08-097742-3.00329-3 1101

dx.doi.org/10.1016/B978-0-08-097742-3.00329-3

1102 Carbon–Carbon r-Bond Formation via C–H Bond Functionalization

3.23.5.1.4 Palladium-catalyzed-directed coupling of two C�H bonds
1188 3.23.5.2 Other Transition-Metal-Catalyzed Reactions with C�H Bonds 1190 3.23.6 Miscellaneous C�H Functionalization Reactions 1192 3.23.6.1 C�H Alkynylation with Terminal Alkynes 1192 3.23.6.2 Decarboxylative C�H Arylation with Aromatic Acids 1195 3.23.6.3 C�H Trifluoromethylation 1197 3.23.6.4 C�H Alkylation with a C�H Bonds of Carbonyl Groups 1199 3.23.7 Summary and Outlook 1202 References 1203
3.23.1 Introduction

Organic synthesis relies mainly on the manipulation of functional groups, chemical moieties exhibiting relatively high reactivity.

Owing to their inertness, carbon–hydrogen (C–H) bonds are not generally viewed as functional groups in this context.1 Not only

is the introduction of functional groups often laborious and time-consuming, but quite often, the synthetic sequences to

manipulate these functional groups often generate unnecessary chemical waste. Direct functionalization of C–H bonds, which are

ubiquitous in organic molecules, would allow unproductive functional groups manipulations to be avoided and would reduce

chemical waste because theoretically, this technology would not produce any byproducts except molecular hydrogen. Moreover,

since C–H functionalization can introduce new functionalities directly through the transformation of C–H bonds, this class of

reactions also provides opportunities for markedly different synthetic strategies, offering distinct retrosynthetic approaches to the

synthesis of complex molecules, while at the same time, increasing overall efficiency and reducing step-count.

Although it is challenging to activate C–H bonds because of their high bond strength and low polarity, a number of C–H

functionalization reactions have nonetheless been developed.2 Nature functionalizes C–H bonds using enzymes highly efficiently and

selectively, and it has inspired chemists to successfully develop enzymatic C–H functionalization reactions.3 Moreover, C–H func-

tionalization via radicals was discovered a long time ago and has been extensively exploited.4 It is important to note that although

there are a number of other classic reactions involving C–H bond disconnection, such as electrophilic aromatic substitution, directed

ortholithiation, and enolate chemistry, these reactions normally are not categorized as C–H functionalization reactions.

In recent decades, transition-metal catalysis has emerged as an effective means for effecting C–H insertion, and as a con-

sequence, a number of new C–H bond transformations have been developed, and a variety of chemical bonds can be formed in an

efficient manner, including carbon–carbon bond and carbon–heteroatom,5 C–O,6 C–N,7 C–B,8 C–Si, C–S, and C–X (X¼F, Cl, Br,

I) bond formation. Remarkably, although in its infancy, transition-metal-catalyzed C–H functionalization has proved applicable

in the total synthesis of complex organic molecules.9,10

Because C–H bonds are ubiquitous in organic molecules, the desired C–H bonds must be activated selectively to develop

synthetically useful reactions. Although regioselective C–H functionalization can be achieved by taking advantage of differentiated

electronic properties or steric effects of different C–H bonds, it is usually a challenge to functionalize C–H bonds selectively.

Currently, a directing group is often employed in a number of transition-metal-catalyzed C–H functionalization reactions. The

directing groups are usually functional groups containing heteroatoms such as oxygen and nitrogen, which can coordinate with

transition metals and force transition metals to cleave proximal C–H bonds selectively. Furthermore, the directing groups facilitate

C–H activation by delivering transition metals to C–H bonds.11

A variety of carbon–heteroatom bond-forming reactions have been developed based on C–H activation. However, in light of

the great advantages of transition metals in organic synthesis for constructing carbon–carbon bonds (primarily s-bonds), tran-

sition-metal-catalyzed carbon–carbon bond-forming reactions via C–H activation are very attractive. A wide range of

carbon–carbon s-bonds, including C(sp2)-C(sp2), C(sp2)-C(sp3), C(sp2)-C(sp), and C(sp3)-C(sp3), can be formed via C–H

activation.12–14 In addition, a wide range of transition metals have been found to be able to promote C–C bond formation via

C–H activation. As their role in the regular transition-metal-catalyzed reactions, palladium,15 rhodium,16 and ruthenium17 are the

most-investigated transition metals in this research field. However, other transition metals have also been found to catalyze C–H

functionalization reactions. The first-row transition metals are very attractive as catalysts because of their abundance and low cost,

and have been extensively utilized to catalyze C–H functionalization reaction.18 The reactions catalyzed by the third-row tran-

sition metals, such as Au, Pt, Ir, and Re, have also been reported.

This chapter aims to provide a comprehensive survey of transition-metal-catalyzed carbon–carbon s-bond formation reactions

via C–H activation. It is noted that the reactions involving radical pathways or transition-metal-carbenoids19 are not covered here.

However, some examples will be described in some sections. Au-catalyzed C–H functionalization20 and Catellani reaction,21

which involves norbornene-mediated C–H functionalization, have been reviewed, so these reactions are beyond the scope of this

chapter. Furthermore, numerous C–H functionalization reactions have been developed, it is impossible to cover all of them. We

apologize for not being able to include every reaction, although they are very important.

This chapter is organized based on the reaction partners of C–H bonds, and it consists of five sections: (1) multiple

carbon–carbon/heteroatom bonds; (2) aryl/alkyl (pseudo)halides; (3) organometallic reagents; (4) C–H bonds; and (5) other

Carbon–Carbon r-Bond Formation via C–H Bond Functionalization 1103

miscellaneous reactions. Some sections are further divided into several subsections if more than one type of reaction partners is

available in the sections. The reactions in each section are organized based on the transition-metal catalysts used in the reactions,

normally starting from palladium, followed by rhodium and ruthenium, and ended with other transition metals. For each type of

reactions, a general mechanism, if available, will be discussed.

3.23.2 Reactions with C–C/C–X Multiple Bonds

In the presence of transition-metal catalysts, C–H bonds can react with a variety of multibonds, including C–C multibonds

(alkenes and alkynes) and polar C–X multibonds (aldehydes, carbonyls, imines, and carbon monoxide), providing an atom-

economical strategy to form C–C bonds.22 A wide range of transition metals have been developed as efficient catalysts to promote

such reactions, and numerous examples are available. In addition, the reactions of C–H bonds with carbon dioxide and cyanides

have also been reported.

3.23.2.1 Reactions with C–C Multiple Bonds

The addition of C–H bond to C–C multibonds is one of the most-investigated C–H activation reactions. The reactions with

alkenes can form either alkenylated or alkylated products, depending on catalysts and reaction conditions. On the contrary, the

addition to alkynes only leads to alkenylation products.

3.23.2.1.1 Palladium-catalyzed reactions with C–C multiple bondsAs one of the most widely used transition metals in organic synthesis, Pd is an attractive catalyst for C–H functionalization.

Although Pd(0) is used as the primary catalyst in traditional cross-coupling reactions involving oxidative addition of aryl/alkyl

(pseudo)halides, Pd(II) is active for C–H cleavage. As Pd has versatile reactivity in traditional Pd(0)-catalyzed cross-coupling

reactions, a variety of Pd(II)-catalyzed C–H functionalization reactions have been developed that emulate this reactivity; and

currently, most modes of bond construction that can be achieved with traditional Pd(0)-catalyzed cross-coupling reactions have

been realized through C–H activation. The coupling partners for Pd-catalyzed C–H functionalization reactions mainly include

C–C multiple bonds, CO, (pseudo) halides, organometallics, and other C–H bonds.

3.23.2.1.1.1 Palladium-catalyzed reactions of simple (hetero)arenes with alkenesIn 1967, Fujiwara and Moritani disclosed the first example of stoichiometric oxidative coupling of arenes with olefins

(Scheme 1).23 A styrene-palladium chloride dimer reacted with benzene to give trans-stilbene by refluxing in a mixture of benzene

and acetic acid. The reactivities of different arenes and the regioselectivities found with substituted benzenes were similar to those

of electrophilic aromatic substitution. Moreover, the use of acids was required. Hence, the authors proposed that the first step of

the reaction involved electrophilic aromatic substitution to form an aromatic Pd s complex, which was followed by its addition to

the olefin and elimination of a Pd-H unit to give olefination products.24

Ph

PdCl

Cl

ClPd

Cl

Ph

+HOAc

Reflux PhPh

Solvent24% Yield

Scheme 1 Pd-mediated stoichiometric olefination of benzene with styrene (Fujiwara et al., 1967).

Fujiwara’s pioneering work was the starting point of direct arylation of olefins, and a number of reactions of this type have

been developed.25 Much effort was made to develop catalytic reactions, and a variety of oxidation systems were successfully

developed. One of the efficient examples is the olefination of arenes using peroxide as the oxidant (Scheme 2).26

Ar HR1

H R2

H Ar

R1 R2

H+

10 mol% Pd(OAc)21 equivalent benzoquinone

1.3 equivalents ButOOH

AcOH/Ac2O(3/1)50−90 °C, 12−15 h

Ar−H : benzenoid and nonbenzenoidR1 = H, CH3, Ph; R2 = Ph, CO2Et, COMe, CHO, CO2H, CN.

10−75% Yield

3 equivalents

Scheme 2 Pd-catalyzed olefination of benzene with tert-butyl hydroperoxide as oxidant (Fujiwara et al., 1999).

MAC_ALT_TEXT Scheme 1



A typical mechanism for Pd-catalyzed reactions of C–H bonds with alkenes is shown in Figure 1.15 Therefore, Pd(II) catalysts

cleave C–H bonds to form arylpalladium(II) species. The subsequent reaction steps are analogous to those in Heck reaction,

which include migratory insertion and b-H elimination, affording alkenylation products and releasing Pd(0). The generated Pd(0)

needs to reoxidize to Pd(II) catalyst to continue catalytic cycles.

RAr

Pd(II)

Pd(II)–Ar

Pd(II)Ar–H

RRAr

C–H activation

Migratory insertion

Pd(0)

Oxidant

Reoxidation

�–H elimination

Figure 1 A general mechanism for Pd-catalyzed reactions of C–H bonds with alkenes.

However, there are still two major drawbacks which hampered the application of the olefination of simple arenes. The first one

was a lack of the control of regioselectivity when substituted benzene was used as the substrate, and the reaction often gave a

mixture with ortho-, para-, meta-isomers, as shown in Scheme 3.27 The second was that a large excess of arenes was required.

R1

+

1 mol% Pd(OAc)2Additive

O2 (0.8 MPa), 90 °C

R1 = H, Me, OMe; R2 = H, Ph; R3 = OBu, OEt, Me.Additive: Mn(acac)2, Co(OAc)2.4H2O, Mn(OAc)3.2H2O, PhCOOH.

R2

O

R3

R2

O

R3

R1

32 equivalents 75−99% Yield

Scheme 3 Pd-catalyzed direct olefination of monosubstituted benzenes (Jacobs et al., 2003).

Intramolecular reactions have also been reported. In 2004, Stoltz and coworkers developed an intramolecular C–H olefination

reaction using highly electron-rich arenes, which contained multiple methoxy substituents on the arene moiety (Scheme 4).28

This protocol provides access to highly substituted benzofuran and dihydrobenzofuran derivatives. Notably, mechanistic studies

in this work provided strong evidence that the reaction proceeded by C–H cleavage and the subsequent Heck-type olefination,

instead of Pd-catalyzed nucleophilic attack of arenes.

MeO

OMe

O R

10 mol% Pd(OAc)220 mol% ethyl nicotinate

20 mol% NaOAc

1 equivalent benzoquinonet-AmylOH/HOAc (4/1)

100 °C, 12−30 h

MeO

OMe

OR

R = alkyl 72−77% Yield

Scheme 4 Pd(II)-catalyzed intramolecular olefination of electron-rich arenes for the synthesis of benzofuran and dihydrobenzofuran (Stoltz et al.,2004).

Since the above C–H activation was an electrophilic process, electron-deficient arenes were unreactive in these reactions. An

unprecedented olefination of electron-deficient arenes has been described by Yu and coworkers (Scheme 5).29 A wide range of

arenes possessing electron-withdrawing groups can react with olefins using 1 atm O2 as the oxidant and 2,6-disubstituted pyridine

as the ligand. Notably, the reactions gave meta-olefinated arenes as the major products because of the ligand, which is remarkable

considering that the reactions of simple arenes gave a mixture of isomers and the use of directing groups leads to ortho-products.

Recently, an elegant example of direct C–H olefination of highly electron-deficient arenes has been reported by Zhang

and coworkers (Scheme 6).30 Thus, perfluoro arenes were olefinated with a variety of olefins including activated and

nonactivated ones.

MAC_ALT_TEXT Figure 1



R1

+ R2

R110 mol% Pd(OAc)2

20 mol% ligand1 equivalent Ac2O

O2 (1 atm)90 °C, 2−56 h

R1 = CF3, CO2Et, NO2, COMe;R2 = CO2Me, P(O)(OEt)2

R2

N

Bun Et BunEt

Ligand52−81% Yield

Scheme 5 Pd-catalyzed meta-selective olefination of electron-deficient arenes (Yu et al., 2009).

R2

R1

+

10 mol% Pd(OAc)22 equivalents Ag2CO3

DMF/DMSO (95/5)120 °C, 10−12 h2−3 equivalents

R1 = H, Me; R2 = alkyl, Ph, electron-withdrawing group

Fn Fn R2R1

n = 3, 4, 5

Scheme 6 Pd(II)-catalyzed direct olefination of perfluoroarenes (Zhang et al., 2010).


Interestingly, although with low enantiomeric excess, asymmetric C–H olefination of benzene has been demonstrated with a

chiral sulfonylamino-oxazoline ligand (Scheme 7).31 The creation of a chiral center was made possible by using cyclic alkenes as

the substrate, which forced b-hydride elimination to occur from the opposite position to the entering phenyl group.

CN CN10 mol% Pd(OAc)210 mol% ligand

100 °C, 9 h+

Solvent

CF3SO2HN N

O

PriLigand24% Yield44% ee

Scheme 7 Pd-catalyzed asymmetric olefination of benzene (Terada et al., 1999).

Not surprisingly, heteroarenes can undergo similar Pd(II)-catalyzed C–H olefination to simple arenes. The stoichiometric

reactions were reported as early as 1972.32,33 Since then, a number of catalytic C–H olefination reactions of heteroarenes have

been developed, and a wide range of heteroarenes, mainly electron-rich heteroarenes including furan, benzofuran, benzothio-

phene, pyrrole, and indole, have been found to be reactive.25 Although the olefination reactions of monosubstituted arenes

usually gave a mixture of regioisomers, heteroarenes were often olefinated regioselectively by taking advantage of differentiated

electronic properties of C–H bonds on heteroarenes.

Pd-catalyzed C–H olefination of furans largely took place at the a-position, and 2,5-difuncationalized product was often

formed. One of the elegant examples is shown in Scheme 8.34

O

6.5 mol% Pd(OAc)26.5 mol% acetylacetone

ca. 1.3 mol% H7PMo8V4O40

0.5 equivalent NaOAcO2 (1 atm)

Propionic acid, 90 °C, 3 h

+

2 equivalents

CO2EtO

CO2EtO

CO2EtEtO2C+

62% 10%

Scheme 8 Pd-catalyzed direct olefination of furan (Ishii et al., 2003).

Many of Pd(II)-catalyzed reaction protocols between furans and olefins have been applied to the C–H olefination of thio-

phenes. An example mainly devoted to thiophenes was recently reported by Zhang and coworkers (Scheme 9).35 A variety of

thiophenes reacted with a wide range of activated alkenes to give monoalkenylated products at the a-positions.

The first Pd-catalyzed C–H olefination of N-arenes was reported as early as in 1983. Thus, Itahara and coworkers disclosed the

olefination of 1-(2,6-dichlorobenzoyl) indole with methyl acrylate to give the 3-substituted product.36 Although most of the

current C–H olefination reactions of indoles mainly led to the 3-substituted product when both 2- and 3-positions are available,

2-substituted products could also be formed. In 2005, Gaunt and coworkers described a general method for the regioselective

functionalization of free indole. Either 2- or 3-olefinated indoles could be synthesized by using different solvents (Scheme 10).37





S

10 mol% Pd(OAc)22 equivalents pyridine

2 equivalents AgOAcDMF, 120 °C, 12 h

+ RX

S

XR

X = H, Me, aryl, OMe, CHO, CF3, etc.R = CO2Bun, CO2But, CONMe2, CN

38−90% Yield

Scheme 9 Pd-catalyzed direct olefination of thiophenes (Zhang et al., 2009).

NHN

H1.8 equivalents Cu(OAc)2

DMF/DMSO (9/1), 70 °C, 18 h

R

10 mol% Pd(OAc)2

R

NH

R

R

20 mol% Pd(OAc)2

0.9 equivalent ButOOBz1,4-dioxane/AcOH(3/1), 70 °C, 18 h

R = electron-withdrawing group, Ph, P(O)(OEt)2, etc.62−91% Yield

34−57% Yield

Scheme 10 Solvent-controlled regioselective Pd-catalyzed olefination of indoles (Gaunt et al., 2005).


Intramolecular C–H olefinations of indoles have also been reported. Both 2- and 3-positions of indoles could be readily

functionalized, even with unactivated double bonds (Schemes 11 and 12).38,39

NMe

MeMe

NMe

Me

10 mol% Pd(OAc)240 mol% ethyl nicotinate

O2 (1 atm)

t-AmylOH/HOAc (4/1)80 °C, 24 h

82% Yield

Scheme 11 Pd-catalyzed intramolecular olefination of indoles using O2 as the oxidant (Stoltz et al., 2003).

NR1NR1

CO2R25 mol% PdCl2(CH3CN)210 equivalents R2OH3 equivalents CuCl2

CO (1 atm)THF, 25 °C, 30 min

R1 = H, Me; R2 = alkyl 73−83% Yield

Scheme 12 Pd-catalyzed intramolecular olefination/carboalkoxylation of indoles (Widenhoefer et al., 2004).

Gaunt and coworkers also reported C–H olefination of pyrroles (Scheme 13).40 Interestingly, depending on the N-substituents

of pyrroles, either 2- or 3-olefinated products could be formed regioselectively.

N

R1

N

TIPS

R2

N

Boc

R2

10 mol% Pd(OAc)2O2 or air or ButOOBz

AcOH/Dioxane/DMSO, 35 °CR2+ or

R1 = Boc or TIPS R2 = electron-withdrawing group38−75% yield 45−81% Yield

Scheme 13 Protecting group-controlled regioselective Pd-catalyzed olefination of pyrroles (Gaunt et al., 2006).

Pd-catalyzed C–H functionalization of pyridine has been a challenge because of the poor electron density of the pyridine ring.

This problem has been solved by employing pyridine N-oxide as the reactant. In 2008, the C2-selective olefination of pyridine

N-oxide was described by Chang and coworkers (Scheme 14).41 Remarkably, the C–H olefination of simple pyridines has also






N

O

N

O

R

10 mol% Pd(OAc)21.5 equivalents Ag2CO3

1,4-dioxane, 100 °C, 12 hR+

53−91% YieldR = CO2But, CONMe2, COMe, P(O)(OEt)2, Ph, But

Scheme 14 Pd-catalyzed olefination of pyridine N-oxides (Chang et al., 2008).


been achieved using 1,10-phenanthroline as the ligand by Yu and coworkers. It is noted that the C-3-positions were selectively

olefinated (Scheme 15).42

N

X + RN

X

R10 mol% Pd(OAc)2

13 mol% 1, 10-phenanthroline

0.5 equivalent Ag2CO3, airDMF, 140 °C, 12 h

16 equivalentsX = Me, OMe, F, CF3, CO2Me, etc.R = electron-withdrawing group, Ph

34−77% Yield

Scheme 15 Pd-catalyzed C-3 selective olefination of pyridines (Yu et al., 2011).

Pd-catalyzed C–H olefination of a variety of other heteroarenes has also been reported, such as thiazoles and oxazoles,43

indolizines,44 1,2,3-triazoles.45

3.23.2.1.1.2 Palladium-catalyzed directing group-assisted reactions with alkenesAs mentioned in Section 3.23.1, a directing group leads to ortho-selectivity in transition-metal-involved C–H activation. A variety

of directing groups have been employed in Pd-catalyzed C–H olefination reactions. The amino group is one of the earliest

directing groups. In 1969, Tsuji and coworkers disclosed the reaction of the cyclopalladation complex of N,N-dimethylbenzy-

lamine with styrene.46 The Pd-catalyzed reaction of aniline with ethane was also reported in 1979 (Scheme 16).47

NH2 NH2

PdCl

NH2PdCl

H2N Pd

H

Cl HN N

PdCl2 H2C CH2

H2C CH2

–HCl

– HPdCl

Scheme 16 Pd-catalyzed amino-directed olefination (Diamond et al., 1979).25

A catalytic C–H olefination of N,N-dimethylbenzylamines was described by Shi and coworkers in 2007 (Scheme 17).

Therefore, a wide range of benzylamines were olefinated by reacting with activated alkenes. It is noted that the amino group could

be removed to make this protocol more useful.48

NMe2X R

5 mol% PdCl21 equivalent Cu(OAc)2

TFEol/AcOH (4/1)85 °C, 48 h

NMe2X+

2 equivalentsR

X = H, Me, OMe, F, Cl, CF3, etc.R = electron-withdrawing group

53−86% Yield

TFEol = 2, 2, 2-trifluoroethanol

Scheme 17 Pd-catalyzed amino-directed olefination of benzylamines (Shi et al., 2007).

An early example involving the stoichiometric vinylation of acetanilides with alkenes in the presence of Pd(OAc)2 was

disclosed by Horino and Inoue in 1981.49 After approximately 20 years, Leeuwen and coworkers described the catalytic C–H

olefination of anilides (Scheme 18).50 Remarkably, the reactions proceeded smoothly at room temperature.





HN

OX CO2Bun+

HN

OX

CO2Bun

2 mol% Pd(OAc)21 equivalent BQ

5 equivalents TsOHHOAc, 20 °C, 24 h1.1 equivalents

X = H, m- or p-Me, OMe, CF3 29−91% Yield

Scheme 18 Pd-catalyzed amide-directed olefination of anilides (de Vries and van Leeuwen et al., 2002).


In 2010, an interesting work regarding C–H olefination of anilides was reported by Lipshutz and coworkers.51 This reaction was

carried out in water as the only medium. Furthermore, a highly active cationic Pd(II) catalyst, [Pd(MeCN)4](BF4)2, was found to

be able to activate aromatic C–H bonds efficiently.

Pd-catalyzed C–H olefination of anilides was also made possible by reacting with haloolefins instead of simple alkenes

(Scheme 19).52 In this reaction, the final b-halo elimination gave the same olefinated products as those in the reaction with

simple alkenes.

N R2

OX COR3+

N R2

OX

CO2R3

5 mol% PdCl21 equivalent AgOTf

DMF, 80−100 °C, 1−3 h1−1.5 equivalents

Br

R1 = H, alkyl; R2 = alkyl; R3 = OMe or Ph33−98% Yield

R1 R1

Scheme 19 Pd-catalyzed amide-directed olefination of anilides with haloolefins (Daugulis et al., 2005).

The urea group was also successfully employed to direct C–H activation by Booker-Milburn and coworkers (Scheme 20).53

Thus, N-methyl-N0-phenyl ureas were found to react with a wide range of dienes, and subsequent cyclization formed indoline

derivatives.

HN

OR+

NMe2 N

R10 mol% Pd(OAc)21 equivalent BQ

R = electron-withdrawing group, Ph 45−82% Yield

OMe2N

0.5 equivalent TsOH.H2O1 equivalent Ac2OTHF, 50 °C, 4 h

Scheme 20 Pd-catalyzed urea-directed 1,2-carboamination of arylureas with dienes (Booker-Milburn et al., 2008).

In 1997, Miura and coworkers reported Pd-catalyzed olefination of 2-phenylphenols (Scheme 21).54 In this reaction, the

hydroxyl of the phenol functions as the directing group by chelating with palladium. Employing a hydroxy group on a saturated

carbon is challenging, because Pd(II) is known to oxidize primary and secondary alcohols and decompose tertiary alcohols.55 This

problem was addressed by Yu and coworkers in 2010 (Scheme 22).55 Therefore, a wide range of phenylethyl alcohols were

olefinated in the presence of a base. Although a tertiary hydroxy was employed as the directing group in most cases, a primary and

secondary alcohol was also compatible albeit with a low yield. Notably, a mono-N-protected amino acid ligand was found to

promote the reaction.

OH

XR+

0.7−3 equivalents

5 mol% Pd(OAc)25 mol% Cu(OAc)2.H2O

MS Å, N2/air (5:1)DMF, 80−120 °C, 5−26 h

OH

X

R

O

X

R

or

R = Ph R = electron-withdrawing group

Scheme 21 Pd-catalyzed hydroxyl-directed olefination of 2-phenylphenols (Miura et al., 1997).

The carboxyl group is an ideal directing group because it occurs widely in natural organic molecules, and can be readily

transformed to other desired functional groups. As early as 1998, Miura and coworkers reported the carboxyl-directed reactions of

benzoic acids with alkenes via C–H activation (Scheme 23).56 In this reaction, the immediate cyclization gave a lactonate.





X R3

10 mol% PdCl220 mol% ligand

4 equivalents AgOAc

1 equivalent Li2CO3C6F6, 85 °C, 48 h

X+

2 equivalents

OH

R1

R2 O

R3

R1

R2

X = mono- or di- Me, OMe, F, Cl, Br, CF3

R1, R2 = H, alkyl Ligand: (+)-Menthyl(O2C)-Leu-OH

30−98% Yield

Scheme 22 Pd-catalyzed hydroxyl-directed olefination of arenes (Yu et al., 2010).

COOHO

O

COOBun

CO2Bun

10 mol% Pd(OAc)210 mol% Cu(OAc)2

DMF, 120 °C, 7 h

+

42% Yield

Scheme 23 Pd-catalyzed carboxyl-directed olefination of benzoic acid (Miura et al., 1998).


Pd-catalyzed C–H olefination of phenylacetic acids and 3-phenylpropionic acids has also been achieved by Yu and coworkers

in 2010 (Scheme 24).57 Remarkably, the two ortho-positions of the acids could be differentiated by introducing amino acid

derivatives as the ligands, so the reactions gave high positional selectivities. The versatility and utility of the method were

demonstrated through direct elaboration of commercial drug scaffolds and efficient syntheses of 2-tetralone and naphthoic acid

natural product cores. This work has illustrated the importance of ligand development for enabling unique reactivity and

selectivity in C–H activation.57

CO2HX

CO2Et

5 mol% Pd(OAc)210 mol% ligand

5 mol% BQ

2 equivalents KHCO3t-AmylOH, 85 °CO2 (1 atm) 48 h

X+

2 equivalents

CO2H

CO2Et

X = alkyl, OMe, F, Cl, etc. 73−98% Yield

Scheme 24 Pd-catalyzed carboxyl-directed olefination of phenylacetic acids (Yu et al., 2010).

Inspired by this discovery, Yu and coworkers developed sequential C–H olefination of phenylacetic acids (Scheme 25).58 Thus,

different olefins were introduced to a desired position of phenyl group by tuning reactivity with amino acid-based ligands, which

offered an efficient way to synthesize multiple-olefinated arenes.

CO2H

R

CO2H

CO2Bn

R

MeO

5 mol% Pd(OAc)25 mol% BQ, 2 equivalents KHCO3

t-AmylOH, 1 atm O290 °C, 48 h

2 equivalents CO2Bn

CO2H

MeO CO2Bn

5 mol% Pd(OAc)210 mol% Ac-Val-OH2 equivalents KHCO3

2 equivalents

t-AmylOH, 1 atm O290 °C, 6 h

23−94% YieldR = CO2Et, CO2But, Ph, Prn

MeO

Scheme 25 Pd-catalyzed carboxyl-directed diolefination of phenylacetic acids (Yu et al., 2010).

To investigate the dramatic effects of the amino acid derivatives on the Pd-catalyzed C–H activation, Yu and coworkers has

conducted extensive mechanistic studies.59 The experimental results implied that the observed rate increases were a result of

acceleration in the C–H cleavage step. Furthermore, the authors suggested that the origin of this phenomenon was a change in the

mechanism of C–H cleavage from electrophilic palladation to proton abstraction.59

As direct C–H functionalization has emerged as promising synthetic tools, it is attractive to develop enantioselective C–H

activation. However, enantioselectvie C–H activation has been a longstanding challenge. As far as Pd-catalyzed C–H activation is

concerned, there are at least two problems imposing obstacles to achieve high enantioselectivities. First, the relatively high

temperature required in C–H activation reactions make chiral recognition challenging; second, chiral ligands may outcompete the

substrate for binding to the Pd center or deactivate Pd for cleavage of the desired C–H bond.15






In 2008, Yu and coworkers achieved enantioselective C–H arylation by successfully desymmetrizing prochiral C–H bonds on

geminal groups, which will be discussed in Section 3.23.4.1.1. This protocol was successfully extended to enantioselective C–H

olefination of diphenylacetic acids (Scheme 26).60 Therefore, one of the arenes in diphenylacetic acids could be olefinated with

excellent enantioselectivity using chiral amino acid derivatives as the ligands.

COONa

R

X X

COOH∗

R

X X

Ar

+ Ar


5 mol% BQ

0.5 equivalent KHCO3t-AmylOH, 90 °CO2 (1 atm) 48 h

X = H, alkyl, alkoxyl, Cl, etc.R = H, alkyl

35−74% Yield58−97% eeLigand : Boc-IIe-OH.0.5 H2O

Scheme 26 Pd-catalyzed enantioselective olefination of diphenylacetic acids (Yu et al., 2010).

Triflamide-directed C–H olefination was reported by Yu and coworkers in 2008 (Scheme 27).61 Thus, arenes substituted by a

triflamidoethyl group were olefinated with alkenes. It is noted that the subsequent cyclization offered an efficient method to

synthesize tetrahydroisoquinolines from arylethylamines.

NHTfR2+

4 equivalents

NHTf

R2

R1R1

10 mol% Pd(OAc)22.5 equivalents AgOAc

DMF/dichloroethane (1/20)130 °C, 72 h

XX

X = Me, Cl, I, OTf; R1 = H, CO2Me; R2 = CO2Me, Ph 51−87%

Scheme 27 Pd-catalyzed trifluoromethanesulfonamide-directed olefination of arenes (Yu et al., 2008).

The Pd-mediated functionalization of C(sp3)-H bonds is much more challenging than that of C(sp2)-H bonds because of not

only competing b-hydride elimination, but also less facile cleavage of C(sp3)-H bonds.62 In 2010, the first C(sp3)-H olefination was

achieved by Yu and coworkers (Scheme 28).63 In this landmark report, an acidic N-arylamido group containing an electron-

deficient phenyl substituent was employed as the directing group. Therefore, a wide range of methylene C–H bonds including

those in cyclopropanes were found to react with alkenes, and the resulting amide products underwent 1,4-conjugate addition to

give the corresponding lactam compounds. Remarkably, the substrates containing b-hydrogen atoms were also compatible.

O

NH

Ar

MeR2 N

O

R2Ar

CO2Bn

+ CO2Bn

10 mol% Pd(OAc)21.1 equivalents Cu(OAc)2

1.1 equivalents AgOAc

51−94% YieldAr = C6F5 or 4-CF3-C6F4

R1R1

2 equivalents LiClDMF, 120 °C

N2, 12 h

Scheme 28 Pd-catalyzed highly acidic amide-directed olefination of C(sp3)-H bonds (Yu et al., 2010).

Another example of Pd-catalyzed unactivated C(sp3)-H olefination was disclosed by the Sanford and coworkers (Scheme 29).64

The b-C(sp3)-H bond of pyridines underwent olefination reaction with a range of activated alkenes, and the subsequent intra-

molecular Michael addition to the olefin products formed cyclic pyridinium salts.

NR1

MeR2

+ R3

10 mol% Pd(MeCN)4(BF4)23 mol% H4[PMo11VO40]

1 equivalent NaOTfor 10 mol% NaOAc, thensaturated aqueous NaBF4

AcOH, 110 °C, 18 h

N

R3

R1

R2X

X

X = Me, OMe, CF3; R1, R2 = H, MeR3 = electron-withdrawing group

36−90% Yield

Scheme 29 Pd-catalyzed pyridine-directed olefination of C(sp3)-H bonds (Sanford et al., 2011).






3.23.2.1.1.3 Palladium-catalyzed reactions of C–H bonds with alkynesThe reactions of C–H bonds and alkynes have been also extensively investigated, and a wide range of transition metal proved

applicable in the hydroarylation of alkynes.65,66 The reactions primarily yielded alkenylated products, which provided an alter-

native method to synthesize alkenyl arenes.

In 2000, Fujiwara and coworkers reported Pd(OAc)2-catalyzed hydroarylation of alkynes (Scheme 30).67,68 A variety of

electron-rich arenes were reactive to give alkenylated products. In addition, various aryl alkynoates and alkynanilides underwent

intramolecular hydroarylation to afford coumarins and quinolinones, respectively. The reactions proceeded in a mixed solvent

containing trifluoroacetic acid (TFA) at room temperature. Both internal and terminal alkynes were compatible in this reaction. It

is noted that the intermolecular reactions were trans-selective to give thermodynamically unfavorable cis-alkenes. The proposed

mechanism suggested that the aryl C–H bond was cleaved via electrophilic metalation, which is analogous to that in the Pd(II)-

catalyzed arylation of alkenes. However, another mechanism proposed that the cationic Pd(II) species attacked the alkynes to

form an alkenyl carbocation intermediate in the first step, which then could cleave the C–H bonds of the arenes.

X R1 R2 X

R1

R2

1−5 mol% Pd(OAc)2

TFA, CH2Cl2, 25 °C, 1−46 h+

R1, R2 = H, alkyl, Ph, CO2Et

O O

R

X1−3 mol% Pd(OAc)2

TFA, CH2Cl2, 25 °C, 0.5−5 h

O O

X

R

46−96% Yield

25−91% YieldR = alkyl, PhX = Me, OH, But, Br, alkenyl, OMe, etc.

Scheme 30 Pd(II)-catalyzed alkenylation of arenes with alkynes (Fujiwara et al., 2000).

The analogous hydroarylation of alkynes with heteroarenes has also been realized by Fujiwara and coworkers (Scheme 31).69

The arene scope was still limited to electron-rich heteroarenes, including pyrroles, furans, and indoles. The reactions occurred at

the a-position for pyrroles and furans and the b-position for indoles regioselectively. However, the a-alkenylated product was

produced for b-methylated indoles. The cis-heteroalkenes were obtained in most case as a result of trans-selectivity.

Y

XR CO2Et

5 mol% Pd(OAc)2

HOAc, r.t., 2−48 h+

Y

X

X = H, Me, alkenyl; Y = NH, NMe, O; R = H, alkyl, Ph

2 equivalents18−83% Yield

R

EtO2C

Scheme 31 Pd-catalyzed alkenylation of heteroarenes with alkynes (Fujiwara et al., 2000).

Gevorgyan and coworkers described the novel intramolecular 5-exo-dig hydroarylation of a variety of o-alkynyl biaryls

(Scheme 32).70 The biaryls possessing electron-neutral and electron-deficient aryl rings underwent cyclization to generate the

geometrically pure fluorenes in a cis-selective fashion. On the basis of the high efficiency of the cyclization of substrates bearing

electron-deficient aryl rings, the observed high values of kinetic isotope effects, as well as on the exclusive cis-selectivity of

cyclization, the author excluded a Friedel–Crafts mechanism and the C–H activation was proposed to account for the

transformation.70

R

X5 mol% Pd(OAc)27 mol% d-i-Prpf

Toluene, 120 °C, 0.5−6 h

R = alkyl, aryl, EtO2C; X = H, Me, OMe, F, CF3, CO2Me; d-i-Prpf=1, 1′-bis(diisopropylphosphino)ferrocene

30−98% Yield

R

X

Scheme 32 Pd-catalyzed intramolecular alkenylation (Gevorgyan et al., 2008).





3.23.2.1.2 Rhodium-catalyzed reactions with C–C multiple bondsOver the course of the past decade, Rh-catalyzed C–H functionalization was also extensively investigated, and a wide range of

reactions have been developed.71 Rhodium can cleave C–H bonds mainly via two distinct pathways. In Rh(I)-catalyzed alkylation,

C–H bonds are cleaved via an oxidative addition pathway to afford Ar-Rh(III)-H species. Subsequent migratory insertion and

reductive elimination furnish the alkylation products and release Rh(I) catalyst (Figure 2).71

Ar−Rh(III)−H

Rh(I)Ar–H

RRh(III)Ar

R

RAr

HOxidative additionReductive elimination

Migratory insertion

Rh(III)

R

Ar

H

Figure 2 A general mechanism of Rh(I)-catalyzed C–H alkylation with alkenes.

A second mechanism involves a Rh(III)/Rh(I) catalytic cycle, which is analogous to the Pd(II)/Pd(0) pathway. In this

mechanism, a Rh(III) species acts as the active catalyst to cleave C–H bonds, affording arylrhodium(III) intermediates. The

subsequent alkene insertion and b-hydride elimination give the alkenylation products and Rh(I) species. Finally, the resulting

Rh(I) species are oxidized to Rh(III) catalysts to close the catalytic cycle (Figure 3).72

Ar−Rh(III)

Rh(III)Ar–H

RAr

RRAr

Rh(III)�-hydride elimination Migratory insertion

Rh(I)

Oxidation

Oxidant −HX

Figure 3 A general mechanism of Rh(III)-catalyzed C–H alkenylation.

Both Rh(III) and Rh(I) have been demonstrated to be able to catalyze the reaction of C–H bonds with alkenes.71,72 Although

the reactions catalyzed by Rh(III) species often form olefinated products, the alkylation generally takes place in the Rh(I)-

catalyzed reactions.

3.23.2.1.2.1 Rh(I)-catalyzed C–H alkylation with alkenesLim and Kang reported pioneering work in the field of Rh(I)-catalyzed reactions of C–H bonds with alkenes. A pyridine group was

employed as the directing group to enable the alkylation of arenes. In addition to the pyridine group, a wide range of func-

tionalities have been developed as the directing group in the Rh(I)-catalyzed C–H alkylation reactions. In 1999, Brookhart

reported the alkylation of aromatic ketones by using the rhodium bis-olefin complex [C5Me5Rh(C2H3SiMe3)2] (Scheme 33).73

R1

O

R25 mol% [C5Me5Rh (C2H3SiMe3)2]

+

R1 = Me, Ph; R2 = SiMe3, alkyl, OEt; X = H, Cl, CF3, OMe

XR1

X

O

R2Cyclohexane, 120 °C

10−99% Yield

Scheme 33 Rh(I)-catalyzed carbonyl-directed alkylation (Brookhart et al., 1999).

The imine functionality has also been utilized as the directing group in the Rh(I)-catalyzed C–H alkylation by Jun and

coworkers (Scheme 34).74 Therefore, in the presence of Wilkinson’s catalyst, the ketimines reacted with a broad range of alkenes,

including simple unactivated and even internal alkenes that isomerize to the terminal alkenes before coupling, to give the ortho-

alkylated products. Aldimines were also reactive with the aid of 2-amino-3-picoline as a cocatalyst. In these reactions, the

aldimines, which were generated in situ from aldehydes and benzylamine, underwent transimination with 2-amino-3-picoline to




R1

NCH2Ph

R2R1

O

R2

1.2 mol% Rh(PPh3)3Cltoluene, 150 °C, 2 h

2. H+/H2O+

R1 = alkyl; R2 = alkyl, Cy, C6F5, TMS

H

O

R

O

R

10 mol% Rh(PPh3)3Cl20 mol% 2-amino-3-picoline

100 mol% PhCH2NH2toluene, 170 °C, 12 h

+

R = alkyl

R

35−97% Yield

35−94% Yield

Scheme 34 Rh(I)-catalyzed imino-directed alkylation (Jun et al., 2000).


give N-pyridyl imines, which were the actual directing group. Interestingly, the reactions started with the hydroacylation of the

imine to the alkenes, and the subsequent imino-directed alkylation provided the hydroacylated and alkylated products.

Rh(I)-catalyzed imino-directed alkylation of aldimines and ketimines was also enabled using Rh(Cl(coe)2)]2 and Cy3P cat-

alytic system by Lim and coworkers (Scheme 35).75 Although the aldimines mainly gave the double ortho-alkylated products, the

ketimines provided the mono-alkylated products predominantly.

R1

NCH2Ph

R2

1. 5 mol% [Rh(Cl(coe)2)]23 mol% Cy3P

THF, 140 °C, 24 h

2. H+/H2O+

R1 = H, alkyl; R2 = alkyl

XR1

X

O

R2

R2

R1

X

O

R2

+

19−99% Total yieldcoe = cyclooctene

Scheme 35 Rh(I)-catalyzed imino-directed alkylation of aldimines and ketimines (Lim et al., 2001).

Interestingly, the imine-directing group can be introduced through the oxidation of primary amines (Scheme 36).76 The

benzylamines gave hydroacylated and alkylated products. However, the hydroacylation occurred exclusively for the

phenylethylamines.

( )nNH2 R1

R1

5 mol% Rh(PPh3)3Cl50 mol% 2-amino-3-picoline

Toluene, 170 °C, 12 h+

R1

n = 1R1

O

Phor

n = 2R = Cy, alkyl14−82% Yield 70−96% Yield

H2N R2

NHR2

H

NR2

H

R2NN

R2 H

NN

R2 R1

N

R2 R1

O

N Ph

[Rh]

H

N Ph

R1

R1

R1−

H2N R2

− NH3 H2N R2−

Rh(PPh3)3Cl

R1 R1

O

Ph

R1

R1

O

R2H2N R2 H+/H2O

R2 = PhCH2

R1 H+/H2O

R2 = Ph

N

R2 R1

R2[Rh]

R1 R1

2-amino-3-picoline

−2-amino-3-picoline

Scheme 36 Rh(I)-catalyzed alkylation assisted by in situ generated imines (Jun et al., 2001).





The intramolecular alkylation directed by an imino group was achieved by Bergman and Ellman (Scheme 37).77 Using

Wilkinson’s catalyst, aryl ketimines could cyclize efficiently with a broad range of simple olefins tethered to the meta-position,

which provided a novel method to synthesize indane, tetralane, dihydrobenzofuran, and dihydroindole derivatives.

R1BnN

X

R2

R3 R1BnN

X

R2

R3

R1BnN

X

R2

R31. 5 mol% Rh(PPh3)3ClToluene, 125−150 °C, 1−48 h

2. H+/H2Oor

X = CH2, O, NR; R1, R2, R3 = H, Me; n = 0, 1.

( )n( )n ( )n

24−85% Yield

Scheme 37 Rh(I)-catalyzed imino-directed intramolecular alkylation (Bergman and Ellman et al., 2001).

The introduction of new chiral centers in the Rh(I)-catalyzed C–H alkylation opened the possibility of developing asymmetric

version of the reactions. The first enantioselective C–H alkylation catalyzed by Rh(I) species was reported as early as 1997.78 In the

presence of ferrocenyl-based phosphine as the chiral ligand, the intramolecular alkylation of imidazoyl dienes was achieved to

give moderate ees (Scheme 38).

N

N

N

N

∗

FePPh2

OMe

30 mol%

5 mol% [RhCl(coe)2]2THF, 50 °C, 20 h

75% Yield, 82% ee

Scheme 38 Rh(I)-catalyzed enantioselective alkylation of olefins (Murai et al., 1997).

The highly enantioselective version of this reaction was achieved using monodentate chiral phosphoramidite ligands by

Ellman and Bergman in 2004 (Scheme 39).79 Therefore, the aryl ketimines underwent intramolecular cyclization with a broad

range of olefins in a highly efficient and enantioselective manner. Notably, in the case of trisubstituted olefins, the reactions set

two stereocenters with high enantioselectivities.

N

X

R1

X

10 mol% [RhCl(coe)2]220 mol% ligand

1,4-dioxane, 50−125 °C

X = CH2, O; R1 = H, alkyl, Ph;R2 = Me, Ph.

R2R2

R1

Bn

N

Bn

O

OP NR2

Ligand90−100% Yield70−96% ee

Scheme 39 Rh(I)-catalyzed imino-directed ligand-enabled enantioselective alkylation (Bergman and Ellman et al., 2004).

The Rh(I)-catalyzed intramolecular C–H alkylation has been successfully applied to the synthesis of some natural products.71

One of the examples is synthesis of (þ)-lithospermic acid, which is a key constituent of a popular traditional herbal medicine with

a variety of biological activities (Scheme 40).80 The key step in the exciting total synthesis is the Rh(I)-catalyzed asymmetric

cyclization. It is worth noting that the chirality was incorporated into the cyclized product by using a chiral amine auxiliary, which

represents an alternative method to achieve asymmetric Rh(I)-catalyzed C–H alkylation.

Rh(I)-catalyzed C–H alkylation reactions of olefins were also developed, although underdeveloped if compared to arenes.

Early examples involve the use of heterocyclic directing groups such as pyridine, imidazole, and oxazoline to afford inter- and

intramolecular alkylation.71 The first Rh (I)-catalyzed alkylation of an a,b-unsaturated carbonyl derivative was disclosed by Jun

and coworkers in 2002.81 In 2006, Bergman and Ellman described the C–H alkylation of a,b-unsaturated imines (Scheme 41).82

Remarkably, the reaction proceeded at mild temperature in the presence of the electron-donating (dicyclohexylphos-

phinyl)ferrocene ligand. Moreover, the Z isomers were produced predominantly, and the reactions had broad substrate scope.

Alkynes were also compatible in this reaction.




N

OMe

OMe

OMeOMe

O

CO2Me

OMe

OMe

H O1. 10 mol% Rh(PPh3)3Cl30 mol% FcPCy2

toluene, 75 °C, 20 h

2. H3O+

88% yield, 73% ee(56% yield, 99% ee after recrystallization)

OH

O

CO2Me

OH

OH

OO

CO2H

OH

HO

O

MeO2C

(+)-lithospermic acid5.9% overall yieldFcPCy2 = ferrocenyl-PCy2

Scheme 40 Rh(I)-catalyzed imino-directed stereoselective alkylation using a chiral auxiliary in the total synthesis of (þ)-lithospermic acid(Bergman and Ellman et al., 2005).

NBn

+ R

O

R

O

R

1. 2.5 mol% [RhCl(coe)2]210 mol% FcPCy2

toluene, 50 °C

2. Chromatography

R = alkyl, Ph, CO2Me Z:E > 90:1073−96% total yield

Scheme 41 Rh(I)-catalyzed imino-directed alkylation of olefins (Bergman and Ellman et al., 2006).


In 2007, Furstner developed a very interesting protocol for the formation of seven-membered rings initiated by the pyridine-

directed C–H activation of olefins (Scheme 42).83 Therefore, following initial C–H activation, the resulting vinylmetal hydride

species underwent hydrometalation of an alkylidenecyclopropane in vicinity to give a metallacycle, which cleaved the C–C bond

of the adjacent cyclopropane to give the ring enlarged complex. The following reductive elimination formed the seven-

membered ring.

R

R

NN

R

R

5 mol% [RhCl(coe)2]27.5 mol% AgSbF6

THF, 120 °C

R

R

N

Rh

H

N

Rh

R

R

N

Rh

R

R

R = alkyl, alkenyl53−77% yield

Scheme 42 Rh(I)-catalyzed pyridine-directed alkylation of olefins followed by cycloisomerization (Furstner et al., 2007).

Rh(I)-catalyzed undirected C–H alkylation was reported by Zhao and coworkers (Scheme 43).84 Thus, electron-deficient

perfluoroarenes underwent hydroarylation reaction with a variety of a,b-unsaturated carbonyl derivatives by using [(cod)-

Rh(OH)]2 as the catalyst and DPP Benzene as the ligand. It is worth noting that olefination products were formed in the absence

of water.

3.23.2.1.2.2 Rh(III)-catalyzed C–H alkenylation with alkenesAs discussed in Section 3.23.2.1.2, Rh(III) can catalyze the oxidative coupling reactions of C–H bonds with alkenes. The reaction

proceeds in an analogous way to that involving Pd(II)/Pd(0) process, and generally gives the similar arylation products. However,




Fn

R

O+

Fn

O

R

1.5 mol% [(cod)Rh(OH)]23.3 mol% DPPBenzene

dioxane/H2O (10/1), 120 °C, 24 h

R = alkyl, alkoxyl, NH2, NMe2 43−91% yield

DPPBenzene = 1,2-bis(diphenylphosphino)benzene

Scheme 43 Rh(I)-catalyzed alkylation of electron-deficient perfluoroarenes (Zhao et al., 2010).


the Rh(III)-catalyzed reactions were less explored than those with palladium. In 2000, Matsumoto and Yoshida reported the

reaction of benzene and ethylene-catalyzed Rh(acac)(CO)2 in the presence of acetylacetone and O2 (Scheme 44). The actual

catalyst was proposed to be an Rh(III) species, which was possibly formed by in situ oxidation.85

H2C CH2

Rh(acac)(CO)2 (1.0 mM)/O2 (20 bar)

AcOH, acacH, 180 °C+

Excess 15 bars TON = 23

Scheme 44 Rh(III)-catalyzed alkenylation of benzene (Yoshida et al., 2000).

Over the past 5 years, Rh(III)-catalyzed coupling reactions of aryl C–H bonds with alkenes and alkynes have been extensively

investigated, and most of them rely on the use of a directing group. Among the discovered reactions to date, [Cp�RhCl2]2 is the

dominant catalyst. The carboxyl functionality is one of the early examples as the directing group in Rh(III)-catalyzed C–H

arylation of olefins. In 2007, Miura and Satoh reported the reaction of benzoic acid with acrylate by the use of catalyst

[Cp�RhCl2]2 (Scheme 45).86 Both of the two ortho-positions were functionalized, and the subsequent cyclization gave a phthalide

and a minor amount of its dehydrogenative derivative. The Rh(I) species occurring in the reaction was reoxidized in the presence

of the copper catalyst under air to regenerate the active Rh(III) catalyst.

COOR O

O

COOR

O

O

COOR

ROOC ROOC

0.5 mol% [Cp*RhCl2]20.5 equivalent Cu(OAc)2.H2O

o-xylene, 120 °C, 10 h+ +

R = Et, Bun

66−76% yield 15−18% yield

OH

O

Scheme 45 Rh(III)-catalyzed carboxyl-directed alkylation/alkenylation (Miura and Satoh et al., 2007).

Miura and Satoh also utilized N-containing heteroaryl groups as the directing group in the Rh(III)-catalyzed arylation of

alkenes (Scheme 46).87 Under similar reaction conditions, 1-phenyl-1H-pyrazole were olefinated with alkenes. Notably, two

different vinyl groups could be installed in a simple one-pot manner. 2-Phenylpyridine and 2-phenyl-1H-imidazole were also

reactive.

A wide range of carbonyl-containing functional groups have also been successfully developed as the directing group. The

reactive substrates include acetophenones, benzamides (Scheme 47),88 benzoates, and benzaldehydes (Scheme 48).89

Glorius and coworkers reported the C–H olefination of N-methoxybenzamides (Scheme 49).90 Interestingly, the directing

group CONH(OMe) functioned as the oxidant as well to oxidize Rh(I) species to regenerate Rh(III) catalyst, so the use of an

external oxidant was avoided.

3.23.2.1.2.3 Rh-catalyzed reactions of C–H bonds with alkynesAlthough the Rh(I)-catalyzed hydroarylation of olefins has seen broad success, the analogous reactions with alkynes were less

exploited. Lim and Kang successfully extended the catalyst system in the alkylation reaction with alkenes to the hydroarylation of

alkynes (Scheme 50).91 Therefore, 2-phenylpyridines reacted primarily with internal, symmetrical alkynes in the presence of

Wilkinson’s catalyst to yield ortho-vinylated products.

In addition to the pyridyl group, a range of directing groups could assist vinylation of arenes under similar reaction conditions

when triisopropylacetylene was used as the coupling partner. The directing groups included imidazole, benzimidazole, ketimine,

and ketoxime.92 Notable, the alkenylation of aryl ketimines with terminal alkynes has been reported by Jun and coworkers.93




NN

NN

NN

R1R1R2

2.4 mol% [(Cp*RhCl2)2]4.8 equivalents Cu(OAc)2.H2O

DMF, N2, 60 °C, 2−7 h

2.4 mol% [(Cp*RhCl2)2]4.8 equivalents Cu(OAc)2.H2O

DMF, N2, 100 °C, 2 h

1.2 equivalents

R1R24 equivalents

N 1 mol% [Cp*RhCl2]22 or 4 equivalents Cu(OAc)2.H2O

DMF, N2, 60 °C

+

N

R

N

RR

R

R1, R2 = aryl, ester55−74% yield

64−89%

1 mol% [Cp*RhCl2]22 or 4 equivalents Cu(OAc)2.H2O

DMF, N2, 100 °C

+ R

2 equivalents

2.4 equivalents

N

NN

N

N

62−81% yield

R = aryl, ester

Scheme 46 Rh(III)-catalyzed heteroarene-directed alkenylation (Miura and Satoh et al., 2009).

R1

R2

0.5 mol% [Cp*RhCl2]22 mol% AgSbF6

2.1 equivalents Cu(OAc)2

t-AmylOH, 120 °C, 16 h+

R1

R2X X

O O

R1 = Me, NH2, NEt2; R2 = aryl, CO2Bun

X = H, CH3, CF3, etc.

1.5 equivalents

40−99% yield

Scheme 47 Rh(III)-catalyzed carbonyl-directed alkenylation (Glorius et al., 2011).

OEt

O

R


0.2 equivalent Cu(OAc)2

1,2-DCE, 110 °C, 12 h+

OEt

O

RX X

X = H, Me, OMe, OH, Cl, Br, I, CO2EtR = CO2Et, CO2Me, CO2H, aryl

30−80% yield

Scheme 48 Rh(III)-catalyzed ester-directed alkenylation of benzoates (Chang et al., 2011).

NH

O

R

1.0 mol% [Cp*RhCl2]230 mol% CsOAc

MeOH, 60 °C, 3−16 h+

NH2

O

RX X

OMe

1.5 equivalents

X = H, Me, OMe, CF3, halo, NO2, CO2Me, Ac, Ph, alkenylR = H, aryl, alkyl, CO2Bun

40−95% yield

Scheme 49 Rh(III)-catalyzed CONH(OMe)-directed alkenylation (Glorius et al., 2011).






N+ RR

N

R

R

N

R

R

R

R

R = alkyl, phenyl

10 mol% [RhCl(coe)2]210 mol% PPh3


33−99% total yield

Scheme 50 Rh(I)-catalyzed pyridine-directed alkenylation with alkynes (Lim and Kang et al., 2001).


Interestingly, Bergman and Ellman reported a convenient one-pot procedure for the synthesis of highly substituted pyridines

from a,b-unsaturated imines and alkynes (Scheme 51).94 The synthesis was initiated by the imino-directed C–H alkenylation of

the alkenes. The subsequent electrocyclization/aromatization formed highly substituted pyridines. It is notable that a new class of

ligands was found to expand the scope the C–H alkenylation reaction greatly.

NBn

N

R1

R2

Bn

N

R1R2

Bn

R2R1

2.5 mol% [RhCl(coe)2]25 mol% ligand

Toluene, 100 °C

20 wt% Pd/Ctoluene/TFE (3/1)

H2 (1 atm), 16 h

+

N PEt2

Ligand

R1, R2 = alkyl, TMS, Ph, CO2Me

50−99% yield

32−86% overall yield

Scheme 51 Rh(I)-catalyzed imino-directed alkenylation of olefins in the synthesis of pyridines (Bergman and Ellman et al., 2008).

As mentioned in Section 3.23.2.1.2.2, Rh(III)-catalyzed C–H alkenylation with alkynes has been extensively investigated, and

the majority of the reactions used [Cp�RhCl2]2 as the catalyst. In the paper regarding Rh(III)-catalyzed olefination of benzoic acids

with alkenes, which has been discussed in Section 3.23.2.1.2.2, Miura and Satoh also reported the alkenylation reactions of

benzoic acids with alkynes under similar conditions (Scheme 52).86 Therefore, a range of benzoic acids were ortho-alkenylated

with internal alkynes, and the subsequent reductive elimination provided isocoumarins. Besides benzoic acids, heteroarene

carboxylic acids also underwent analogous reactions with diphenylacetylene to form heteroaryl analogs of isocoumarins.95 The

employed heteroarenes included indole, pyrrole, benzothiophene, thiophene, and furan.

OH

O

R1 R2XO

O

X

0.5 mol% [Cp*RhCl2]20.5 equivalent Cu(OAc)2.H2O

DMF, 50 °C, 2 h+

R1

R2

R1, R2 = alkyl, Ph; X = H, Me, OMe, Cl

1.2 equivalents

75−94% yield

Scheme 52 Rh(III)-catalyzed carboxyl-directed alkenylation with alkynes (Miura and Satoh et al., 2009).

The C–H bonds of alkenes were also allowed to react with alkynes. A straightforward and efficient synthesis of a-pyrone

derivatives has been achieved by the rhodium-catalyzed oxidative coupling reactions of substituted acrylic acids with alkynes

(Scheme 53). Alkenes were also reactive to give butenolide derivatives.96

R1OH

O

R2

R3 R3

1 mol% [Cp*RhCl2]21 equivalent Ag2CO3

DMF, N2, 120 °C, 4−10 h+

1 equivalentO

O

R1

R2

R3

R3

R1 = H, Me, aryl; R2 = H, Me, Ph; R3 = Ph, alkyl. 22−93% yield

Scheme 53 Rh(III)-catalyzed carboxyl-directed alkenylation of alkenes (Miura and Satoh et al., 2009).






A range of directing groups have been applied to assist the Rh(III)-catalyzed alkenylation of arenes with alkynes. Miura and

Satoh reported the direct coupling of phenylazoles with internal alkynes in the presence of [Cp�RhCl2]2 and Cu(OAc)2

(Scheme 54).97 Interestingly, the rhodacycle intermediate resulted from the C–H alkenylation of heteroarenes underwent a

second C–H activation and alkyne insertion, which provided an efficient way to construct polyarylated naphthyl- and anthrylazole

derivatives. Pyrazole, imidazole, and benzoxazole proved effective as the directing group in the reactions.

NN

Ar Ar

1 mol% [Cp*RhCl2]24 mol% C5H2Ph4

1 equivalent Cu(OAc)2.H2O

DMF, N2, 80 °C, 1 h+

NN

Ar

Ar

Ar

ArC5H2Ph4: 1,2,3,4-tetraphenylcyclopentadiene

76−93% yield

Scheme 54 Rh(III)-catalyzed heteroarene-directed alkenylation with alkynes (Miura and Satoh et al., 2008).

The Rh(III)-catalyzed oxidative coupling of N-acetyl anilines and alkynes was realized by Fagnou and coworkers

(Scheme 55).98 Following C–H alkenylation, the cyclization via reductive elimination occurred to form indole derivatives.

Interestingly, nonsymmetrical anilines underwent indolization at the more sterically accessible ortho-position, and high regio-

selectivities were achieved for unsymmetrical alkynes.

NH

X

O

R1 R2


2.1 equivalents Cu(OAc)2.H2O

t-AmOH, 120 °C, 1 h+

XN

R2

R1

O

R1 = aryl; R2 = alkyl; X = F, Cl, OMe, etc. 47−83% yield

Scheme 55 Rh(III)-catalyzed acetamido-directed alkenylation with alkynes (Fagnou et al., 2008).

A different Rh(III) catalyst was employed by Fagnou and coworkers to catalyze imino-directed alkenylation of arenes with

alkynes (Scheme 56).99 In the presence of [Cp�Rh(MeCN)3][SbF6]2, aryl aldimines underwent C–H alkenylation and C(sp2)-

N(sp2) bond reductive elimination to provide isoquinoline.

NX R1 R2

2.5 mol% [Cp*Rh(MeCN)3][SbF6]22.1 equivalents Cu(OAc)2.H2O

DCE, 83 °C, 16 h+X

N

R2R1

X = H, F, Br, OH, OMe, CF3, NO2; R1, R2 = alkyl 30−81% yield

Scheme 56 Rh(III)-catalyzed imino-directed alkenylation (Fagnou et al., 2009).

The hydroxyl group without a-hydrogen also proved viable in Rh(III)-involved C–H alkenylation with alkynes (Scheme 57).

The peri C–H bond of 1-naphthols and analogs including 4-hydroxycoumarin and -quinolinone and 9-phenylxanthen-9-ol were

cleaved, and the analogous reaction sequence produced fused pyran derivatives.100

Glorious and Chen disclosed the reactions of aryl ketones and alkynes almost at the same time.101,102 The intramolecular

insertion of the carbonyl group into the formed rhodium–alkenyl bond afforded substituted indenols. In the Glorious’ work,

electron-neutral and electron-rich phenones bearing protons in dehydrative positions (a or g) generally led to the corresponding

fulvene derivatives (Scheme 58).

The coupling reaction of N-methoxybenzamides with alkynes was achieved by Guimond and coworkers to yield isoquinolines

(Scheme 59).103 As the reactions with alkenes discussed in Section 3.23.2.1.2.2, the CONH(OMe) oxidized Rh(I) species formed

in the reaction to active Rh(III) catalyst.

3.23.2.1.3 Ruthenium-catalyzed reactions with C–C multiple bondsRu-catalyzed C–H functionalization has also been extensively explored, and a range of C–C bond forming reactions has been

discovered. The reaction partners include alkenes, alkynes, (pseudo)halides, and organometallic reagents. An initial work involved




OH

R R

1 mol% [Cp*RhCl2]25 mol% Cu(OAc)2.H2O

o-xylene, air+

OR

R

X O

OH

Ph Ph

1 mol% [Cp*RhCl2]22 equivalents Cu(OAc)2.H2O

DMF, N2

+

X

OPh

Ph

OX = O, NMe

R = alkyl, Ph49−74% yield

70−92% yield

Scheme 57 Rh(III)-catalyzed hydroxyl-directed alkenylation with alkynes (Miura and Satoh et al., 2010).

R1


2.1 equivalents Cu(OAc)2

PhCl, 120 °C, 16 h+X X

O

1.5 equivalents

R2 Ph Ph

R2

R1OH

R1, R2 = alkyl, Ph; X = H, Br, CF3 49−99% yield

Scheme 58 Rh(III)-catalyzed keto-directed alkenylation with alkynes (Glorius et al., 2011).

NH

O2.5 mol% [Cp*RhCl2]2

30 mol% CsOAc

MeOH, 60 °C, 16 h+

NH

O

X XOMe

1.1 equivalentsR2

R1R1 R2

R1, R2 = alkyl, aryl; X = H, Br, I, OMe, CF3, NO2, AcNH 48−90% yield

Scheme 59 Rh(III)-catalyzed CONH(OMe)-directed alkenylation with alkynes (Guimond et al., 2010).


the reaction of phenol with ethylene to give mono and double ortho-alkylation products by using a cyclometalated ruthenium

phosphite complex (Scheme 60).104

OH

+ H2C CH2

OH OH

+

[Ru]KOPh

THF, 177 °C

13% yield 75% yield

O

(PhO)2P

Ru

(PhO)2P

P(OPh)3

P(OPh)3

O[Ru]

Scheme 60 Ru-catalyzed ethylation of phenol with ethylene (Lewis et al., 1986).

A decisive breakthrough in Ru-catalyzed C–H functionalization was reported by Murai and coworkers in 1993 (Scheme 61).105

Therefore, a range of aromatic and heteroaromatic ketones were alkylated by reacting with olefins in the presence of the complex

R1

O

R2 R1

O

R2

2 mol% RuH2(CO)(PPh3)3

Toluene, 135 °C, 0.2−33 h+

R1 = alkyl; R2 = H, alkyl, aryl, SiMe3, Si(OEt)3; X = H, Me, alkenyl

X X

66−100% yield

Scheme 61 Ru-catalyzed carbonyl-directed alkylation (Murai et al., 1993).







RuH2(CO)(PPh3)3. The seminal reaction is a pioneering work in chelation-assisted C–H activation. It was proposed that the

actual active catalyst was Ru(0) species, which was generated in situ through the reaction of the complex RuH2(CO)(PPh3)3 with

alkene.106 The C–H cleavage occurs via an agostic interaction instead of the usual oxidative addition mechanism. The subsequent

olefin insertion and reductive elimination formed the alkylated products (Figure 4).22

Ru(0)(PPh3)3L

R2

O

R1

H

Ru(PPh3)3

O

R1

Ru(PPh3)3

H

O

R1

Ru(PPh3)3

R2

O

R1

R2

O

R1

RuH2(CO)(PPh3)3

R2 + L

R2 + CO

L L

Figure 4 The mechanism of Ru(0)-catalyzed carbonyl-directed alkylation.

The related complex Ru3(CO)2-catalyzed reactions with imidates or imines as the directing group gave a mixture of alkylated

and olefinated products (Scheme 62).107,108 The olefination products were believed to be formed by b-hydride elimination from a

carbometalation intermediate. The intermediate was produced through olefin insertion into the Ru–C bond, which was formed by

the oxidative addition of C–H bond to the Ru catalyst.22

DGSi(OEt)3

2 mol% Ru3(CO)2

Toluene, 135 °C+

DG

Si(OEt)3

DG

Si(OEt)3

+

81% 10%H

NBut

O

N

( )n

DG =

DG = n = 2 35% 30%

n = 1 10% 87%

Scheme 62 Ru-catalyzed-directed alkylation/alkenylation (Murai et al., 1999).

A commercially available and stable complex [Ru(p-cymene)Cl2]2 was elegantly exploited by Darses and Genet for the C–H

alkylation of arenes (Scheme 63).109 [Ru(p-cymene)Cl2]2 generated an active catalyst species, likely to be {RuH2}, in the presence

of a formate salt and triphenylphosphine ligand. This in situ-generated catalyst had a similar or higher activity than the above

Murai catalyst in the alkylation reaction of aromatic ketones.

O

R

O

R

2.5 mol% [Ru(p-cymene)Cl2]215 mol% PPh3, cat. NaHCO3

Toluene, 140 °C, 0.2−20 h+

R = Si(OEt)3, SiMe3, Ph; X = Me, OMe, F, Br, etc.

X X

70−100% yield

Scheme 63 Ru-catalyzed carbonyl-directed alkylation (Darses and Genet et al., 2006).





The above complex was also successfully extended to the functionalization of Michael acceptors (Scheme 64).110 In the

presence of electron-deficient P(4-CF3Ph)3 instead of PPh3, a range of a,b-unsaturated amides and esters reacted with vinylsilanes

to give alkylated products. Interestingly, on some particular substrates, mainly crotonic acid derivative, stereodefined trisubstituted

allylsilanes were formed. The formation of such compounds was believed to be the result of b-hydride elimination followed by

reductive elimination.

R1 EWG

R2

Si(R3)3

2.5 mol% [Ru(p-cymene)Cl2]215 mol% P(4-CF3Ph)3

cat. NaHCO2

Dioxane, 100 °C, 20 h+

R1 EWG

R2 Si(R3)3

EWG = ester, amide; R1 = H, alkyl; R2 = alkyl, Ph; R3 = alkoxyl

Si(R3)3

32−99% yield

50−70% yield

EWGEWG

Scheme 64 Ru-catalyzed carbonyl-directed alkylation of alkenes (Darses et al., 2009).

Although the above Ru(0)-catalyzed reactions normally gave alkylated products, the RuCl3-catalyzed C–H alkenylation of

simple arenes was disclosed by Milstein and coworkers (Scheme 65).111 The reactions required a CO atmosphere, and mono-

substituted arenes formed a mixture of regioisomers. The proposed mechanism was similar to that involved in the Pd(II)-

catalyzed C–H alkenylation of arenes. Therefore, the C–H bond cleavage resulted from electrophilic attack of the metal on a C–H

bond. The resulting Ar-[Ru] species underwent olefin insertion and b-H elimination to yield the aromatic alkene and a ruthenium

hydride, which was oxidized by olefins or oxygen to regenerate the electrophilic species.

R1

R2

0.4 mol% RuCl3.H2OO2 (2 atm), CO(6.1 atm)

180 °C, 48 h+

18 equivalents

R1

R2

R1 = H, Cl, Me, MeO; R2 = H, CO2Me, C4F9 3−47% yield

Scheme 65 Ru-catalyzed direct alkenylation of simple arenes (Milstein et al., 2001).

The catalytic system in the RuH2(CO)(PPh3)3-catalyzed alkylation reaction with alkenes also proved applicable to the reaction

of aromatic ketones with alkynes (Scheme 66).112 Under similar conditions, aromatic ketones reacted with alkynes with two

identical substitutions to provide alkenylated products as a mixture of two E/Z isomers.

O


Toluene, 135 °C+ PrPr

OPr

Pr

2 equivalents72% yieldE/Z = 16/1

Scheme 66 Ru-catalyzed carbonyl-directed alkenylation with alkynes (Murai et al., 1995).

Plietker and coworkers reported hydrovinylation reaction of alkynes (Scheme 67).113 The reactions were catalyzed by an air

and moisture-stable ruthenium hydride complex that was prepared in one step starting from RuCl3 and activated by addition of

NaOMe before use. A broad range of terminal alkynes were hydrovinylated with electron-deficient olefins to give highly sub-

stituted 1,3-dienes.

RuCl3-catalyzed C–H alkenylation of arylpyridines with alkynes was disclosed by Zhang and coworkers (Scheme 68).114

Therefore, a variety of arylpyridines underwent regio- and/or stereoselective alkenylation reactions efficiently with terminal

alkynes to give (E)-alkenylated products. Benzoyl peroxide or benzoic acid was required to achieve high yield.




5 mol% [(Ph3P)3Ru(CO)HCl](10 mol% NaOMe in some cases)

DMF, 100 °C, 24 h+ R4R3

O

R1R2

O

R1R2

R3

R4O

R1R2

R4

R3

+

R1 = H, Me; R2 = alkoxyl, amine, Me; R3, R4 = H, alkyl, aryl, CO2Et 39−96% total yield

Scheme 67 Ru-catalyzed carbonyl-directed alkenylation of alkenes with alkynes (Plietker et al., 2009).

NX

5 mol% RuCl31 equivalent benzoyl peroxide

2 equivalents K2CO3

NMP, 150 °C, 6 h+ R

1.2 equivalents

NX

RX = H, Me, CF3, Cl, OMe, alkenyl; R = alkyl, aryl 61−96% yield

Scheme 68 Ru-catalyzed pyridine-directed alkenylation with alkynes (Zhang et al., 2008).


3.23.2.1.4 Other transition-metal-catalyzed reactions with C–C multiple bondsBesides the Ru, Rh, Pd triad, a range of other transition metals also proved viable to catalyze the direct reaction of C–H bonds and

alkenes or alkynes.

3.23.2.1.4.1 Nickel-catalyzed reactions of C–H bonds with C–C multiple bondsIn 2006, Nakao, Hiyama and coworkers reported Ni-catalyzed hydroheteroarylation of alkynes (Scheme 69).115 Therefore, a wide

range of heteroarenes were allowed to react with alkynes in the presence of the catalyst Ni(cod)2 and the ligand PCyp3 to afford

alkenylated products under mild conditions. A variety of functionalities were tolerated and a range of internal alkynes were

reactive in this reaction. The authors suggested the reaction started with alkyne-coordinating Ni(0) species, which then underwent

oxidative addition of an Ar–H bond to give alkyne-coordinating Ar-Ni(II)-H intermediate. The subsequent hydronickelation and

reductive elimination to afford a cis-hydroarylation product and regenerate Ni(0) species (Figure 5).115

NR2

R1

NR2

R1

Pr

Pr10 mol% Ni(cod)210 mol% PCyp3

Toluene, 35 °C, 6−120 hPr Pr+

R1 = CN, CO2Me, C(O)Me, CHO, (E)-CH = CHCO2Me, PhR2 = Me, CH2Ph, CH2OMe

10 mol% Ni(cod)210 mol% PCyp3

Toluene, 35 °C, 6−40 hPr Pr+

Z

Y

Z

Y

Pr

Pr

1 equivalent

1 equivalent

X = alkyl, alkenyl, etc.; Y = CH, N; Z = O, S, NMe

X X

57−91% yield

47−97% yield

Scheme 69 Ni-catalyzed alkenylation of heteroarenes with alkynes (Hiyama and Nakao et al., 2006).

Inspired by this elegant reaction, the authors investigated the Ni-catalyzed reactions of C–H bonds with C–C multiple bonds

extensively, and discovered a series of novel reactions.116 Under the almost same reaction conditions, a diverse range of pyridine-

N-oxides reacted with internal alkynes to afford (E)-2-alkenylpyridine-N-oxides regioselectively and stereoselectively. In the case of

asymmetrical alkynes, the reaction took place at the carbon with the smaller substituent selectively (Scheme 70).117

The alkenylation of simple pyridines was realized in the presence of a Lewis acid, which coordinated with the nitrogen on the

pyridine ring and made the nitrogen electron-deficient that enhanced the acidity of the C(2)–H bond (Scheme 71).118 By using

diorganozincs such as ZnMe2 and ZnPh2 as the Lewis acid, a broad range of pyridines were alkenylated with internal alkynes.

Interestingly, the use of AlMe3 as the Lewis acid generated a C2-dienylated pyridine as a result of double insertion of alkynes.

Although the direct C–H functionalization of pyridine usually occurs at C-2 position, the selective C-3 or C-4 functionalization

has been a challenge in the absence of a directing group. Remarkably, Hiyama and Nakao disclosed Ni(cod)2-catalyzed efficient C-

4 alkylation of simple pyridines with alkenes in the presence of N-heterocyclic carbene (NHC) and AlMe3 as ligand and LA

catalyst, respectively (Scheme 72).119 In most cases, the reaction occurred at the terminal position of alkenes dominantly, and a

very minor amount of internal product was observed. The reaction of pyridine with alkynes gave a mixture of C-3 and C-4




Ni(0)

Ni(0)

Pr Pr

NR

Ni(II)

H

Pr

Pr

NR

Ni(II) H

Pr Pr

NR

Pr

PrPr

Pr

NR

Figure 5 Mechanism of Ni-catalyzed alkenylation.

N

O

X


Toluene, 35 °C, 15−40 hR1 R2+

1.5 equivalents N

O

X

R1R2

X = H, Me, alkenyl, CO2Me; R1, R2 = Me, Pr, But (R1 ≤ R2) 54−81% yield

Scheme 70 Ni-catalyzed alkenylation of pyridine-N-oxides with alkynes (Hiyama and Nakao et al., 2007).

NX

3 mol% Ni(cod)212 mol% P(Pri)3

6 mol% ZnMe2 or ZnPh2

Toluene, 50−100 °C, 3−24 hR1 R2+

3 equivalentsN

X

R1R2

R1, R2 = alkyl, Ph, SiMe3 (R1 ≤ R2)

X = alkyl, alkenyl, OMe, NMe2, CF3, Ph, B(pin), CO2Me 30−96% yield

N

3 mol% Ni(cod)212 mol% P(Pri)36 mol% AlMe3

toluene, 80 °C, 24 hPr Pr+

3 equivalents

N

Pr

Pr

17% yield

N

Pr

Pr

Pr

Pr

+

56% yield

Scheme 71 Ni-catalyzed alkenylation of pyridine with alkynes (Hiyama and Nakao et al., 2008).

N

X

N

XR

N

XR

5 mol% Ni(cod)25 mol% IPr

20 mol% MAD

Toluene, 130 °C, 5−23 h+

1.5 equivalents

R +

IPr:1,3-(2,6-diisopropylphenyl)imidazol-2-ylidene); MAD: (2,6-But2-4-Me-C6H2O)2AlMe

Major Minor

X = H, 2-Me, 2, 6-Me2, 3-CO2Me; R = alkyl, SiMe3, Ph 12−91% yield (major/minor ≥ 88/12)

Scheme 72 Ni-catalyzed C-4 alkenylation of pyridine with alkenes (Hiyama and Nakao et al., 2010).


alkenylated products. The novel regioselectivity was attributed to the Z2-coordination of the C(3)–C(4) double bond of pyridine

to the Ni(0)/NHC complex.

The idea of employing Lewis acids to increase the activity of pyridines was also successfully extended to the alkenylation/

alkylation of 2-pyridone derivatives by Hiyama and Nakao (Scheme 73).120 The Lewis acid coordinated with the carbonyl oxygen

of 2-pyridones and the C(6)–H bond was selectively functionalized in a manner similar to that of pyridines. Therefore, a variety of





X

N

ZY

O

R1

R2 R3X

N

ZY

O

R1 R3R2

5 mol% Ni(cod)210 mol% P(Pri)320 mol% AlMe3

Toluene, 80 °C, 2−44 h+

X = C, NMe; Y = C, C=O; Z = C, NR1 = Me, Bn; R2 = alkyl, Ph; R3 = alkyl, Si(Me)3

1.2 equivalents

62−99% yield

Scheme 73 Ni-catalyzed alkenylation/alkylation of pyridone with alkynes (Hiyama and Nakao et al., 2009).


substituted 2-pyridones reacted with 4-octyne to afford alkenylated products in the presence of the Ni(cod)2, P(Pri)3, and AlMe3.

As a representative, N,N-dimethyluracil was demonstrated to undergo reactions with a range of alkynes.

Ni-catalyzed alkenylation of electron-deficient fluoroarenes was also developed by Hiyama and Nakao (Scheme 74).121 Thus,

fluoroarenes containing different number of fluorines underwent alkenylation reactions with a range of internal alkynes to afford

cis-adducts. It was observed that fluoroarenes with a lower number of fluorines gave a lower yield. In the case of the substrates with

more than one possible reaction site, the reactions occurred at the position ortho to an F substituent selectively. The alkylation of

perfluoroarenes with alkenes also proved viable under similar reaction conditions.


Toluene, 80−100 °C, 1−20 hR1 R2+

1.5−3.0 equivalentsR1

R2

R1, R2 = alkyl, Ph, SiMe3, CH2SiMe3n = 1, 2, 3, 4, 5


Toluene, 100 °C, 5−8 h+

1 equivalent

F F

F

F F

F F

F

F F

RR

R = 2-Np, Ph

Fn Fn

8−99% yield

67−83% yield

Scheme 74 Ni-catalyzed alkenylation/alkylation of fluoroarenes with alkynes/alkenes (Hiyama and Nakao et al., 2008).

3.23.2.1.4.2 Iridium, platinum, and rhenium-catalyzed reactions of C–H bonds with C–C multiple bondsIn 1999, Ir-catalyzed C–H alkenylation with alkynes was disclosed (Scheme 75).122 In the presence of catalyst [IrCl(cod)]2 and

ligand PBut3, 1-hydroxynaphthalene was allowed to react with oct-4-yne to afford the cis-adduct.

OH

+ PrPrOH

Pr

Pr[IrCl(cod)]2PBut

3, Na2CO3

Toluene, reflux, 5 h

Scheme 75 Ir(I)-catalyzed hydroxyl-directed alkenylation with alkynes (Miura et al., 1999).

Periana and coworkers developed Ir(III) systems for the alkylation of benzene (Scheme 76).123 The reactions formed linear

alkyl arenes as the major products, which indicated a Friedel–Crafts mechanism was not operative. Detailed mechanistic studies

suggested that the reaction involved phenyl C–H activation that occurred through a novel concerted oxidative hydrogen transfer

mechanism.124

RR

R

Ir(III):[Ir(�-acac-O,O,C3)-(acac-O,O)(acac-C3)]2

Ir(III)

180 °C+ +

R = H, alkyl, COOMeTN: 2−455

Scheme 76 Ir(III)-catalyzed alkylation of benzene with alkenes (Matsumoto and Periana et al., 2000).






Ir-catalyzed alkenylation of benzoic acids was described by Miura and Satoh (Scheme 77).125 Interestingly, the iridocycle

formed by the alkyne insertion underwent decarboxylation to give a five-membered iridocycle rather than reductive elimination.

Subsequently, a second alkyne insertion and the intramolecular reductive elimination afforded naphthalene products. A range of

benzoic acids were reactive with internal aryl alkynes in the presence of catalyst [Cp�IrCl2]2. Ag2CO3 was required as the

oxidant.

OH

O

X Ar Ar X

Ar

Ar

Ar

Ar

2 mol% [Cp*IrCl2]22 equivalents Ag2CO3

+

X = H, Me, O(Pri), Cl, Cy; Ar = Ph, 4-MeOC6H4, 4-ClC6H4 60−89% yield

o-xylene, 180 °CN2, 2−10 h

Scheme 77 Ir(III)-catalyzed carboxyl-directed alkenylation with alkynes (Miura and Satoh et al., 2007).

A few examples of Pt-catalyzed reactions of arenes with alkenes have been reported.126 The reactions yielded alkylated arenes,

and branched alkyl arenes were formed predominantly, however, linear products were also observed. Currently, the substrate

scopes were primarily limited to simple arenes and alkenes. A representative example is the alkylation reaction of simple arenes

reported by Goldberg and coworkers (Scheme 78).127 In the presence of the catalyst [(dmpp)PtMe3] or [(dmpp)Pt-(SMe2)Ph],

simple arenes were successfully alkylated with alkenes. In the case of propene, both branched and linear alkyl arenes were formed

in a ratio of approximately 85:15. For the substituted arenes, the reactions yielded a mixture of o/p/m alkylated products with the

isomeric distribution meta4para4ortho.

R R R1−3 mol% catalyst

100−110 °C, 17−50 h+ +

Catalyst: [(dmpp)PtMe3] or [(dmpp)Pt-(SMe2)Ph]; [dmpp = 3,5-dimethyl-2-(2-pyridyl)pyrrolide]

R = H, Me, CF3 MajorMinor

Scheme 78 Pt-catalyzed alkylation of simple arenes with alkenes (Goldberg et al., 2008).

Rhenium has also been found to be able to catalyze the reactions of C(sp2)–H bonds with alkynes/alkenes. In 2005, Takai and

Kuninobu reported the alkenylation of aromatic aldimines with acetylenes (Scheme 79).128 In the presence of the catalyst

[{ReBr(CO)3(thf)}2], the aldimines with a diversity of substituents on the aromatic ring were allowed to react with internal

alkynes to form various indene derivatives. The proposed mechanism involved Re(I)-catalyzed C–H bond activation, insertion of

an acetylene to the resulting rhenium–carbon bond, intramolecular nucleophilic attack of the formed alkenyl–rhenium moiety to

a carbon atom of the imine, reductive elimination and 1,3-rearrangement of hydrogen atoms (or vice versa) (Figure 6).128

H

NBut

R1 R23 mol% [{ReBr(CO)3(thf)}2]

Toluene, reflux, 24 h+

HN But

R2

R1X

X

HN But

R1

R2X+

X = H, o-Me, p-Me, MeO, PhR2, R2 = Ph, alkyl, SiMe3

40−96% total yield

Scheme 79 Re-catalyzed imino directed alkenylation with alkynes (Takai and Kuninobu et al., 2005).

The above catalyst system was extended to the reaction of aromatic ketones with alkenes (Scheme 80).129 The ketones were

in situ transformed into the imines, which then underwent analogous reactions with a, b-unsaturated esters and the final

elimination of aniline to form indene derivatives.

Re-catalyzed reactions of olefinic C–H bonds with alkenes also proved viable (Scheme 81).130 By using Re2(CO)10, a wide

range of a,b-unsaturated ketimines reacted with diverse a,b-unsaturated carbonyl compounds to form cyclopentadiene via an

analogous reaction pathway. Interestingly, the resulted cyclopentadienes formed Cp-Re complex with catalyst Re2(CO)10.




N

H

But

N

H

But

Re H

N

HBut

R2

Re

R1

N

R1

R2

ReButH

HN

R1

R2

But

Re(I)

R1

R2

Figure 6 Mechanism of Re-catalyzed alkenylation of aldimines with alkynes.

Me

O 3 mol% [{ReBr(CO)3(thf)}2]15 mol% p-anisidine

Toluene, 180 °C, 24 h+ CO2R

XXCO2R

X = H, Me, OMe, CF3, alkenyl; R = Me, Et, Ph 11−93% yield

Scheme 80 Re-catalyzed imino-directed annulation via C–H alkenylation (Takai et al., 2006).

R2

R3

N

R1

PhR4

O

+ 1/2 Re2(CO)10Xylene, 150 °C, 72 h

+

O

R4R2

R3

R1

ReOC

COCO

R1, R2, R3 = alkyl, alkoxyl; R4 = alkoxyl, n-C5H11, NMe2 36−94% yield

Scheme 81 Re-catalyzed imino-catalyzed olefinic C–H alkylation (Takai and Kuninobu et al., 2008).


3.23.2.2 Reactions with CQO and CQN Bonds

Recently, the reaction of C–H bonds with polar multibonds has attracted considerable attention, and quite a number of reactions

have been developed. A range of transition metals were found to catalyze the addition of C–H bonds to CQO and CQN bonds

effectively. Just as the reactions with CQC double bonds, the reactions with polar CQX bonds may also form arylation/

alkylation or hydroarylation/alkylation products, depending on the transition metals used in the reactions. The first catalytic

example of such an addition reaction was reported by Hong and coworkers in 1978 (Scheme 82).131 Therefore, benzene was

allowed to react with a range of aryl isocyanates in the presence of catalyst Rh4(CO)12 and CO, yielding the corresponding

benzanilides.

PhN=C=O +

Rh4(CO)12CO (25 atm)

220 °C, 6 h

HN

O

Ph

Scheme 82 Rh-catalyzed C–H addition of benzene to isocyanates (Hong et al., 1978).

3.23.2.2.1 Palladium-catalyzed reactions of C–H bonds with aldehydes and iminesPd has been successfully utilized to catalyze the addition of C(sp2)–H bonds to carbonyl groups. The substrates are still limited to

aldehydes, and the reactions give arylated products. An early example is the heteroarene-directed acylation of C(sp2)–H bonds






reported by Cheng and coworkers (Scheme 83).132 Therefore, arenes with nitrogen-containing heteroarenes were acylated with

aryl aldehydes to give diaryl ketones regioselectively. Air was utilized as the terminal oxidant. A wide range of functional groups

were tolerated under the reactions conditions. The proposed mechanism was similar to that involved in the arylation of alkenes,

including Pd-mediated C–H cleavage, the insertion of the carbonyl group into the formed carbopalladium bond, b-hydride

elimination to release the ketones and Pd(II) species, the reductive elimination of the Pd(II) to produce Pd(0) species, which was

reoxidized to Pd(II) to close the catalytic cycle (Figure 7).132

DG 10 mol% Pd(OAc)2air

Xylene, 120 °C, 24 h

O

HX2+X1

DG

X1

O

X2

1.5 equivalents

DG (Directing group):N O

N O N NN

X1 = H, Me, OMe, F, Br, CO2Me, alkenyl; X2 = H, Me, Cl, Br, NO2, CN, CO2Me, alkenyl

45−90% yield

Scheme 83 Pd-catalyzed heteroarene-directed acylation with benzaldehydes (Cheng et al., 2009).

N

N

Pd(II)

N

H

O Pd(II)

Ar

Ar

O

Pd(II)

Pd(0)

H Ar

O

airOxidation

C=O insertion�−H eliminationthen reductive elimination

C−HActivation

Figure 7 Proposed mechanism of Pd-catalyzed acylation with aldehydes.

Subsequently, Li and coworkers disclosed unprecedented acylation reactions with aliphatic aldehydes (Scheme 84).133 Thus, in

the absence of solvents, 2-phenylpyridine and benzo[h]quinoline underwent the solvent-free acylation with a variety of aliphatic

aldehydes using t-butylhydroperoxide (TBHP) as the oxidant. The catalytic systems proved applicable to the acylation of aromatic

aldehydes. Palladium (IV) complexes, which were formed through the oxidation of the aryl-Pd(II)-COR intermediates by TBHP,

were proposed as key intermediates in this C–H acylation reaction. Therefore, the formed aryl-Pd(IV)-COR intermediates

underwent reductive elimination to furnish the acylated products and regenerate Pd(II) catalyst.

N

R

O

H

5 mol% Pd(OAc)21.5 equivalents TBHP

Neat, 120 °C, 16 h+

N

R

O

2 equivalents

TBHP: tert-butyl hydroperoxideR = alkyl, Ph

42−89% yield

Scheme 84 Pd-catalyzed pyridine-directed acylation with alkyl aldehydes (Li et al., 2010).

The similar acylation were also enabled by using other directing groups. Yu and coworkers realized the oxime-directed

coupling of aryl ketone oximes and aldehydes (Scheme 85).134 The use of 0.5 equivalent acetic acid gave a slightly higher yield.




N

Y

OMe

R

O

H

5 mol% Pd(OAc)22 equivalents TBHP

0.5 equivalent AcOHToluene, 100 °C, 2 h

+ N

Y

OMe

R

OX X

X = H, OMe, AcNH, SO2Me, OCH2CONH; Y = H, CH2, CH(CH3), OR = alkyl, aryl, heteroaryl 40−95% yield

Scheme 85 Pd-catalyzed oxime-directed acylation with aldehydes (Yu et al., 2010).


Both aromatic and aliphalic aldehydes were compatible under the reaction conditions. Mechanistically, on the contrary to the

direct reaction of palladacycles with aldehydes in the above reactions, the authors proposed that acyl radicals, which were

generated in situ by hydrogen atom abstraction of the aldehydes, were the actual reaction partners. The acyl radicals reacted with

the palladacycles to afford the product ketones via either reactive Pd(IV) or dimeric Pd(III) intermediates. Subsequently, such an

acylation of acetanilides was demonstrated by Li and Kwong using Pd(TFA)2 as the catalyst (Scheme 86). A mechanism involving

radicals was also proposed.135

X

5 mol% Pd(TFA)24 equivalents TBHP

Toluene, 90 °C, 24 hR2

O

H+

2 equivalents

HN O

R1

X

NH

O

R1 O

X = H, Me, OMe, Cl, Br, ester, alkenylR1 = Me, Pri, But, Ph; R2 = alkyl, aryl.

R2

38−88% yield

Scheme 86 Pd-catalyzed amide-directed acylation with aldehydes (Kwong and Li et al., 2011).

The carbopalladium bond formed via C–H cleavage has also been demonstrated to undergo the nucleophilc attack to imines

in a similar manner to that to carbonyl groups. Remarkably, Xia and Huang discovered the addition reaction of benzylic C–H

bonds to aldimines (Scheme 87).136 Therefore, a range of 2-methyl azaarenes reacted with N-sulfonyl aldimines in the presence of

catalyst Pd(OAc)2 and ligand 1,10-phenanthroline. It is noted that protolysis took place instead of b-hydride elimination in the

reaction, affording amines as the final product and release Pd(II) species. Hence, the formation of Pd(0) was avoided and no

oxidants were required.

N

X

Ar

NR

N

X

Ar

HNR5 mol% Pd(OAc)2

5 mol% 1,10-phenanthroline

THF, 120 °C, 24−30 h+

X = H, Me, 6-Bn, alkenyl; R = tosyl, p-nitrobenzenesulfonyl 40−92% yield

Scheme 87 Pd-catalyzed reactions of benzylic C–H bonds with N-sulfonyl aldimines (Xia and Huang et al., 2010).

3.23.2.2.2 Other-transition-metal-catalyzed reactions of C–H bonds with CQO and CQN bondsRh-enabled addition of organometallic reagents to carbonyls and imines has been extensively explored and provided chemists

with attractive alternatives to the Grignard-type additions.137 Such an addition reaction via C–H activation is intriguing and

gained attention recently. The first Rh-catalyzed addition of C–H bonds to imines was reported by Bergamn and Ellman

(Scheme 88).138 Therefore, catalyst [Cp�RhCl2]2 was found to catalyze the addition of 2-arylpyridines to N-Boc- and N-sulfonyl-

aldimines via C–H bond functionalization to give branched amine products in the presence of oxidant AgSbF6. A wide range of

N N

R

NHBocNBoc

R

10 mol% [Cp*RhCl2]240 mol% AgSbF6

CH2Cl2, 75 °C, 20 h

+

R = Alkyl, aryl 27−95% yield

Scheme 88 Rh-catalyzed pyridine-directed reactions of C–H bonds with Boc-imine (Bergman and Ellman et al., 2011).






functional groups were compatible with the reaction. Mechanistically, the C–H cleavage involved electrophilic deprotonation

caused by the Rh(III) catalyst. The formed Ar-Rh(III) added to the imines, followed by protonolysis to afford the final products

and regenerate the Rh(III) catalyst (Figure 8).138

N

N

N

Rh(III)

Rh(III)

H Ph

NBoc

Rh(III)

NBoc

Ph

NN

Ph

Rh (III)

Boc

NNHBoc

Ph

H+H+

Figure 8 Proposed mechanism of Rh-catalyzed reaction of C–H bonds with imines.

Concurrently, Shi and coworkers reported a similar addition reaction of 2-arylpyridines with N-sulfonyl aldimines using

catalyst [Cp�Rh(CH3CN)3][SbF6]2.139

The Rh-catalyzed addition of C–H bonds to carbonyls also proved viable. In 2011, Jung and Kim reported that a wide range of

benzamides underwent acylation reactions with (hetero)aryl aldehydes to form diaryl ketones in the presence of [Cp�RhCl2]2 and

AgSbF6, and Ag2CO3 as the oxidant (Scheme 89). It is noted that reductive elimination products were obtained instead of

protonolysis products, which were produced in the above reactions with imines.140

(Et)2N O

X1

O

HX2

5 mol% [Cp*RhCl2]220 mol% AgSbF6

2 equivalents Ag2CO3THF, 110 °C, 20 h

(Et)2N O

X1

O

X2+

X1 = H, Me, OMe, OCH2O, OAc, Ph, halo, alkenylX2 = H, Me, OMe, OCH2O, F, Br, NO2, alkenyl

25−72% yield

Scheme 89 Rh-catalyzed amide-directed acylation with benzaldehydes (Jung and Kim et al., 2011).

For all the above reactions, the substrate scopes were limited to aldehydes. By using catalyst [Ir(cod)2]BARF/rac-BINAP, Shibata

and coworkers realized the addition of C–H bonds to ketones with elegantly-designed substrates (Scheme 90).141 The substrates

were so designed that the reacting carbonyl group was attached to the arenes through a linker and a directing group was installed

at the meta-position. As a result, a bidentate chelating group consisting of the directing group and the carbonyl group enabled

C–H activation at the more congested ortho-position regioselectively. Subsequently, intramolecular 1,2-addition to the carbonyl

moiety and dehydration formed benzoheteroles including indoles and benzofurans. A range of directing groups were found to be

effective in the reaction.

X

O R2

R35 mol% [Ir(cod)2]BARF

5 mol% rac-BINAP

PhCl, 135 °C, 24 h

XR3

R2

X = O, NHR1 = Ac, MeO2C, AcHN; R2 = alkyl, Ph; R3 = H, Me, p-anisyl

R1 R1

72−100% yield

Scheme 90 Ir-catalyzed intramolecular reactions of C–H bonds with carbonyl groups (Shibata et al., 2009).





Rhenium has lower electronegativity than rhodium and ruthenium, so the carbon–rhenium bond is more polarized than the

carbon–ruthenium and –rhodium bonds, and the organorhenium species will hopefully react with aldehydes such as Grignard

reagents.142 Inspired by this conjecture, Takai and Kuninobu disclosed the insertion of aldehydes into a C–H bond of aromatic

ketimines by using a rhenium complex [ReBr(CO)3(thf)]2, as a catalyst. The reactions provided isobenzofuran derivatives via C–H

bond activation, insertion of the aldehyde, intramolecular nucleophilic cyclization, reductive elimination, and elimination of

aniline (Scheme 91).142

R2

NR1

O

HX

2.5 mol% [ReBr(CO)3(thf)]2

MS (4 Å)Toluene, 115 °C, 24 h

+

O

R2

X

X = H, o-Me, p-Me, p-OMe, p-CF3R1 = Ph, PhCH2; R2 = Ph, PhCH=CH 70−93% yield

Scheme 91 Re-catalyzed imino-directed reactions of C–H bonds with benzaldehydes (Takai and Kuninobu et al., 2006).

Subsequently, Takai and Kuninobu reported analogous insertion reaction catalyzed with manganese (Scheme 92).143 In the

presence of [MnBr(CO)5], 2-phenylimidazoles underwent a Grignard-type reaction with aromatic and aliphalic aldehydes via

C–H activation. The mechanism was similar to that involved in Re-catalyzed insertion reaction, except that Mn-catalyzed reactions

ended up with silyl protection with HSiEt3, which provided silyl ethers as the final products and released dihydrogen. Notably, the

use of chiral imidazoles led to asymmetric reactions with moderate diatereoselectivities.

NNMe

R

O

H

5 mol% [MnBr(CO)5]2 equivalents HSiEt3


2 equivalents

NNMe OSiEt3

R

NNMe

R2

O

H

5 mol% [MnBr(CO)5]2 equivalents HSiEt3


2 equivalents

NNMe OSiEt3

R2

R1 R1

R = aryl, heteroaryl, alkyl 48−87% yield

R1 = Ph, PhCH2, Pri; R2 = Ph, n-C8H1760−80% yield30−95% de

Scheme 92 Mn-catalyzed imidazole-directed reactions of C–H bonds with aldehydes (Takai et al., 2007).

3.23.2.2.3 Carboxylation of C–H bonds with CO2

The use of carbon dioxide for chemical synthesis has been intriguing, because it is an abundant, cheap, and nontoxic renewable

source. Although the carboxylation with CO2 has seen broad applications for a long time, the reactions via C–H activation are very

rare. An elegant example is the gold-catalyzed carboxylation reported by Nolan and Boogaerts in 2010 (Scheme 93).144 By using

Au(IPr)OH as the catalyst, a variety of acidic (hetero)arenes were carboxylated with CO2 in the presence of KOH. The reactions

occurred selectively at the most acidic C–H bonds, which can be rationalized in terms of simple acid/base theory. Mechanistic

NN

IPr

Y

NX 1. 3 mol% Au(IPr)OH

1.05 equivalents KOHTHF, 20 °C, 12 h

2. Aqueous HCl+ CO2

1.5 barFn FnCO2H

or

Y

NX CO2H

or

X = H, alkenyl; Y = O, S, NMe; n = 2, 3, 4

61−94% yield

84−93% yield

Scheme 93 Au-catalyzed carboxylation of acidic C–H bonds with CO2 (Nolan et al., 2010).





studies, along with the necessary use of a strong base and basic Au(IPr)OH complex, supported that the reactions proceeded via a

deprotonative reaction mechanism. Therefore, protonolysis of [IRr]AuOH] by the oxazole gave the gold(I) oxazole intermediate.

The subsequent nucleophilic addition of the oxazole ligand to the carbon atom of CO2 afforded Au(I)–carboxylate complex,

which underwent metathesis with KOH furnished the carboxylation product and regenerate [IRr]AuOH] (Figure 9).144

Au

OH

IPr

O

NH

Au

IPr

N O

Au

O

IPr

CO

N

O

OK

CO

N

O

H2O

CO2

KOH

Figure 9 Proposed mechanism of Au-catalyzed carboxylation with CO2.

Subsequently, Nolan and Cazin reported similar carboxylation reactions catalyzed by copper (Scheme 94).145 Acidic het-

eroarenes and polyfluorinated arenes underwent similar carboxylation using catalyst Cu(IPr)OH and base CsOH. The proposed

mechanism was similar to that proposed in the above gold-catalyzed carboxylation reaction.

1. 3 mol% Cu(IPr)OH1.1 equivalents CsOHTHF, 65 °C, 8 h

2. Aqueous HCl+ CO2

1.5 bar

Fn FnCO2H

Y

Nor

Y

Nor

H CO2H

X = H, Br, alkenyl; Y = N, O; n = 3,4 85−93% yield 80−93% yield

X X

Scheme 94 Cu-catalyzed carboxylation of electron-deficient arenes with CO2 (Nolan and Cazin et al., 2010).

Independently, Hou and coworkers disclosed the Cu(IPr)Cl-catalyzed C–H carboxylation of acidic heteroarenes with CO2 in

the presence of KOBut (Scheme 95). The formed carboxylic acids were transformed into esters because of the slow uncatalyzed

decomposition.146

Y

NX

Y

NX CO2C6H13

1. 5 mol% Cu(IPr)Cl1.1 equivalents KOBut

THF, 80 °C

2. 2 equivalents C6H13I,DMF, 80 °C

+ CO2

1 atm

Y = O, NMe 14−89% yield

Scheme 95 Cu-catalyzed carboxylation of heterocycles with CO2 (Hou et al., 2010).

All of the above carboxylation reactions relied on the use of the substrates with acidic C–H bonds and proceeded via a

deprotonation mechanism, which severely limited their application in chemical synthesis. In 2011, Iwasawa and coworkers

successfully realized the C–H carboxylation of less acidic arenes (Scheme 96).147 Therefore, arenes-containing directing groups,

including pyridine and pyrazole, underwent carboxylation with CO2 in the presence of [Rh(coe)2Cl]2 and PCy3. Methylaluminum

alkoxides were found to promote the carboxylation efficiently, mainly because they underwent transmetallation to regenerate

active catalyst methylrhoduim(I) species. A wide range of functional groups were tolerated under the reaction conditions.

3.23.2.2.4 Reactions of C–H bonds with nitrilesAnother intriguing polar multiple bond is nitrile. The first Pd-catalyzed C–H addition to nitriles was demonstrated by Larock and

coworkers (Scheme 97).148,149 In the presence of Pd(OAc)2, a wide range of simple arenes with electron-donating substituents




+ R2 C N

2 equivalents

10 mol% Pd(OAc)2

DMSO/TFA (1/25)75−100 °C, 24 h

R1R1 O(NH)

R2

X = H, Me, OMe, But; R1 = Me, OMe, OH; R2 = Me, arene

X X

55−90% yield

Scheme 97 Pd-catalyzed acylation of simple arenes with nitriles (Larock et al., 2004).

DG

X

DG

X

CO2Me+ CO2

5 mol% [Rh(coe)2Cl]212 mol% PCy3

2 equivalents AlMe2(OMe)DMA, 70 °C, 8 h

TMSCHN2

Et2O-MeOH, 0 °C1 atm

DG (Directing group):

NN

N

X = H, Me, OMe, CO2Me, alkenyl 44−88% yield

Scheme 96 Rh-catalyzed heteroarene-directed carboxylation with CO2 (Iwasawa et al., 2011).


reacted with benzonitriles to afford ketimines, which were converted into corresponding ketones very readily. The reactions were

conducted in TFA, and the addition of a small amount of dimethyl sulfoxide (DMSO) increased the yields dramatically. In the case

of substrates with one substituent, the mixtures of o/p/m isomers were formed, with para-isomer as the major product. The

proposed mechanism involved Pd-catalyzed C–H activation, intermolecular carbopalladation of a nitrile, and the protonation to

give ketimines.

3.23.2.3 Reactions with CO

Transition-metal-catalyzed carbonylation of aryl (pseudo)halides with carbon monoxide provides an efficient method to access

carboxylic acid derivatives. Direct carbonylation of C–H bonds are advantageous, and have been extensively exploited and a range

of transition metals can catalyze such a carbonylation with carbon monoxide effectively.

3.23.2.3.1 Palladium-catalyzed reactions of C–H bonds with COThe first Pd-mediated carboxylation of arenes with CO was reported by Fujiwara and coworkers in 1980 in the presence of

stoichiometric amount of Pd(OAc)2.150 The catalytic reactions proved viable in the presence of oxidants such as O2, ButOOH,

alkyl halides, or K2S2O8. Both arenes and heteroarenes such as furan and thiophene were reactive to give the corresponding aryl

carboxylic acids.151

Pd-catalyzed carbonylation with CO was achieved by Orito and coworkers in 2004 (Scheme 98).152 Therefore, with the aid of

a directing group, a range of benzylic amines and phenethyl amines were carbonylated in the presence of 1 atm CO and a catalytic

amount of Pd(OAc)2 to give five- or six-membered benzolactams, respectively. The oxidant Cu(OAc)2 was required to regenerate

Pd(II) to make the reaction catalytic. The authors proposed that the carbonylation involved ortho-palladation with Pd(OAc)2, the

insertion of CO, and the nucleophilic attack of the internal amino group on the carbonyl group to generate benzolactams and

Pd(0) (Figure 10).152 This mechanism represents a general pathway for palladium-catalyzed arene carbonylation with CO.

X NHR( )n

XNR( )n

O

5 mol% Pd(OAc)20.5 equivalent Cu(OAc)2

Toluene, 120 °C, 2 or 24 h+ CO

1 atm

X = H, Me, OMe, OCH2O, Cl, Br, CN, NO2; R = Pr, Bn 18−95% yield

Scheme 98 Pd-catalyzed amino-directed carbonylation (Orito et al., 2004).

Yu and coworkers described the carboxyl-directed carboxylation with CO (Scheme 99).153 Both benzoic acids and phenyl

acetic acids were allowed to react with CO in the presence of an inorganic base to afford dicarboxylic acid derivatives. It is noted

that b-vinyl C–H bond in a,b-unsaturated carboxylic acid was also carboxylated selectively to give cis-1,2-dicarboxylic acid.

The analogous carboxylation of anilides was also realized by Yu and coworkers (Scheme 100).154 The formed N-acyl

anthranilic acids in the reaction could be readily transformed into biologically and pharmaceutically significant molecules, such

as benzoxazinones and quinazolinones, making the reaction synthetically useful. The use of p-TsOH �H2O proved crucial to

achieve high yields.

Concurrently, Lloyd-Jones and Booker-Milburn disclosed the urea-directed carbonylation (Scheme 101).155 Remarkably, the

precatalyst [(MeCN)2Pd(OTs)2] proved highly effective and the reaction proceeded smoothly at room temperature.




Pd(II)

Pd(0)

Oxidant

Oxidation

CO insertion

C−Hactivation

NPd(II)

Pd(II)NO

N O

NR H

H

CO

R

R

R

Figure 10 Proposed mechanism of Pd-catalyzed carbonylation with CO.

OH

O

XOH

O

X

CO2H+ CO

1 atm


2 equivalents NaOAc1,4-dioxane, 130 °C, 18 h

X + CO

1 atm


2 equivalents NaOAc1,4-dioxane, 130 °C, 18 h

O

OHX

O

OHCO2H

X

O

O

O

R R R R R R

+

R = alkyl

Ph

O

OH + CO

1 atm


1 equivalent K2HPO41,4-dioxane, 110 °C, 12 h Ph

O

OH

HO2C

X = H, Me, OMe, OCH2CH2O, Bn, F, Cl

40−93% yield

50−88% Total yield

68% yield

Scheme 99 Pd-catalyzed carboxyl-directed carbonylation (Yu et al., 2008).

HN

X + CO

1 atm

10 mol% Pd(OAc)21 equivalent benzoquinone0.5 equivalent p-TsOH.H2O

60−80 °C, 18−36 hO

RHN

XO

R

CO2HX = Me, Bn, alkoxyl; R = Me, aryl 53−97% Yield

Conditions: HOAc/1,4-dioxane (2/1) or HOAc/toluene (2/1) or 1,4-dioxane;0.5 equivalent NaOAc in some cases

Scheme 100 Pd-catalyzed amide-directed carbonylation of acetylanilines (Yu et al., 2010).

HN N

O

R2

R1

X

HN N

O

R2

R1

X

CO2Me

5 mol% [(MeCN)2Pd(OTs)2]2 equivalents benzoquinone

2 equivalents TEMPO

0.5 equivalent TsOHTHF/MeOH (1/1), 18 °C, 3−5 h

+ CO

1 atm

X = H, Me, OMe, Br, CF3, CO2Me; R1, R2 = H, alkyl 5−90% Yield

Scheme 101 Pd-catalyzed urea-directed carbonylation of phenylureas (Booker-Milburn and Lloyd-Jones et al., 2009).







Yu and coworkers also reported the alkyl hydroxyl-directed carbonylation with CO (Scheme 102).156 Thus, phenylethanol was

carbonylated to afford 1-isochromanones in the presence of a catalytic amount of Pd(OAc)2 and one equivalent of Li2CO3. An

amino acid ligand was beneficial to the reaction, and a wide range of functionalities were tolerated. However, the substrate scope

was still limited to tertiary alcohols.

X + CO

1 atm


3 equivalents Ag2CO3

1 equivalent Li2CO3DCM, 110 °C, 48 h

OHX

O

O

R RRR

O NH

O

CO2H

Me

MeMe

MeMeLigandX = H, Me, OMe, F, Cl, Br; R1, R2 = alkyl 51−94% Yield

Scheme 102 Pd-catalyzed hydroxyl-directed carbonylation (Yu et al., 2011).

The reaction of C(sp3)–H bonds with CO also proved viable. In 1989, Fujiwara and coworkers reported the carboxylation of

cyclohexane with CO (20–40 atm) using Pd(II)/Cu(II) catalytic systems in TFA, which is the first example of transition metal-

catalyzed alkane carboxylation (Scheme 103).157 Other alkanes such as methane, ethane, and propane were also carboxylated to

give the corresponding carboxylic acids.158

+ CO

Pd(OAc)2Cu(OAc)2

K2S2O8/TFA80 °C, 20 h

CO2H

20−40 atmTON = 19.8

Scheme 103 Pd-catalyzed carboxylation of alkanes with CO (Fujiwara et al., 1989).

By using an acidic amide group as the directing group, the efficient carbonylation of C (sp3)–H bonds was achieved by Yu and

coworkers (Scheme 104).159 The amide group was made acidic by introducing a highly electron-withdrawing perfluorophenyl

group. The b–C(sp3)–H bonds of N-arylamides were carbonylated with 1 atm CO to form succinimides in the presence of TEMPO

and KH2PO4. It is noted that substrates with an a-H were compatible under the reaction conditions. The C–H bonds of

cyclopropanes were also reactive. Interestingly, n-hexane, has rarely been an effective solvent in C–H functionalization reactions,

was found to be the optimal solvent.

F

F

F

F

CF3

NH

OR1

R2

N

O

O

R1

R2

F F

CF3

F F

10 mol% Pd(OAc)22 equivalents AgOAc2 equivalents TEMPO

2 equivalents KH2PO4hexane, 130 °C, 18 h

+ CO

R1 = H, Me; R2 = alkyl

1 atm

52−99% Yield

Scheme 104 Pd-catalyzed acidic amide-directed carbonylation of C(sp3)-H bonds (Yu et al., 2010).

3.23.2.3.2 Rhodium-catalyzed reactions of C–H bonds with COIn 1983, Eisenberg and coworkers described the first example of the carbonylation of benzene using IrH3(CO)(dppe) complex

(dppe¼Ph2PCH2CH2PPh2) in the presence of CO.160 The reaction was conducted under photo-irradiation conditions and

formed benzaldehyde as the major product. RhCl(CO)(PPh3)2 was also found to catalyze such a carbonylation.161 Inspired by the

pioneering works, Tanaka and coworkers investigated the RhCl(CO)(PMe3)2-catalyzed carbonylation of C–H bonds under irra-

diation extensively. They successfully realized carbonylation of simple arenes and alkanes in the presence of RhCl(CO)(PMe3)2 to

afford the corresponding aldehydes (Scheme 105).162 The reaction proceeded at an ambient temperature under an atmospheric

pressure of CO. In the reactions of monosubstituted benzenes, meta-substituted benzaldehydes were formed as the major pro-

ducts. In the case of n-alkanes, the carbonylation took place preferentially at the terminal methyl group to give a linear aldehyde.

The analogous carbonylation with the aid of a directing group was also disclosed. Zhang and Liang reported the Rh-catalyzed

oxidative carbonylation of arenes and heteroarenes with CO (Scheme 106).163 A variety of N-containing heteroarenes or an amide

group was the effective directing group. The reactions afforded esters as the final products because of the presence of an alcohol.

Oxone was found to play an important role in the reactions.




DG

+ CO + ROH

2 atm

2 mol% [Rh(COD)Cl]2oxone

Toluene, 110 °C, 8 h

DG

OR

O5 equivalents

XX

X = H, Me, OMe, CF3, F, CO2Me, alkenyl; R = alkyl

DG (Directing group):

N

N

NN

N

HN Me

O

5−96% Yield

Scheme 106 Rh-catalyzed heteroarene-directed carbonylation (Zhang and Liang et al., 2009).

+ CO

RhCl(CO)(PMe3)2h�

r.t., 16.5 h

CHO

CHO

+

R

RhCl(CO)(PMe3)2h�

r.t., 16.5 h+ CO R

CHO

R

CH2OH

+

1 atm

1 atm

Major

Major

Scheme 105 Rh-catalyzed carbonylation of simple arenes and alkanes with CO (Tanaka et al., 1990).


Although the above Rh/Ir-catalyzed carbonylation involves the insertion of CO into C–H bonds leading to aldehydes, a three-

component coupling acylation of C–H bonds, CO, and alkenes may take place to give ketones.12 As early as 1979, Hong and

coworkers observed Rh4(CO)12-catalyzed acylation of benzene with CO and ethylene.164 Another example of such an acylation is

the Rh4(CO)12-catalyzed reaction of N-acylpiperazines with CO and ethylene discovered by Murai and coworkers

(Scheme 107).165 The reactions started with the amide group-directed olefinic C–H activation of N-acyl-1,2,3,4-tetra-

hydropyrazines, which were generated through Rh-catalyzed hydrogen transfer from the piperazines to ethylene. The next reaction

steps involved the insertion of ethylene into the Rh–H bond in the formed rhodocycle complex, the subsequent CO insertion to

form acyl Rh complex, and the reductive elimination to afford the final acylated products (Figure 11).165

N

N

O

Me

+ CO+4 mol% Rh4(CO)12

Toluene, 160 °C, 20 h N

N

O

Me

N

N

OR

Me

O15 atm

RR = Me, Ph, 4-Me2NC6H4, 2-pyridyl 71−89% Yield

R

Scheme 107 Rh-catalyzed amide-directed three-component coupling acylation of N-acylpiperazines (Murai et al., 1997).

The direct Rh-catalyzed three-component coupling acylation of C(sp3)–H bonds was realized by Murai and coworkers in 2000

(Scheme 108).166 Therefore, the C(sp3)–H bonds adjacent to a nitrogen atom in alkylamines were acylated by reaction with CO

and ethylene in the presence of catalyst [RhCl(cod)]2. The reactions relied on the use of pyridine or pyrimidine as the directing

groups. The scope of substrates and alkenes was still quite limited.

3.23.2.3.3 Ruthenium-catalyzed reactions of C–H bonds with CORuthenium was also successfully used to catalyze the reaction of C–H bonds with CO, and both carbonylation and acylation have

been demonstrated. An elegant example is the carbonylation of aromatic amides reported by Chatani and coworkers

(Scheme 109).167 Remarkably, a N,N-bidentate directing group consisting of an amide and a pyridine group was designed. This

novel directing group strongly coordinated to the Ru catalyst even under high-pressure CO. In the presence of catalyst Ru3(CO)12

and 10 atm CO, a range of aromatic amides bearing a pyridin-2-ylmethylamine moiety underwent ortho-carbonylation of C–H

bonds and the nucleophilic attack of the nitrogen of the amide group to afford phthalimides. Interestingly, the acylation products

were not observed even in the presence of 10 atm ethylene.

The bidentate directing group was successfully extended to the carbonylation of C(sp3)–H bonds with CO (Scheme 110).168

Thus, the C(sp3)–H bonds of alkyl amides containing a 2-pyridinylmethylamino moiety were effectively carbonylated under the




N

MeN

OR

N

MeN

OR

Rh H

N

MeN

OR

N

MeN

OR

Rh Et

H2C=CH2

CH3CH3N

MeN

OR

Rh H

Rh

Rh

H2C=CH2

CO

N

MeN

ORO

Et

Figure 11 Proposed mechanism of Rh-catalyzed amide-directed acylation of N-acylpiperazines.

N

N( )n

+ CO+4 mol% [RhCl(cod)]2

PriOH, 160 °C, 40−60 h10 atm

N

N( )n

O

X X

X = H, Me, CF3; n = 1, 2

5 atm

12−84% Yield

Scheme 108 Rh-catalyzed pyridine-directed three-component coupling acylation of C(sp3)-H bonds (Murai et al., 2000).

NH

O

N

N

O

O N

+ CO

10 atm

5 mol% Ru3(CO)122 equivalents H2O

Ethylene (7 atm)toluene, 160 °C, 24 h

XX

X = H, m- or p- Me, OMe, OCF3, NMe2, CO2Me, COCH3, CN, Cl, Br 60−92% Yield

Scheme 109 Ru-catalyzed N,N-bidentate directing group-assisted carbonylation (Chatani et al., 2009).

NH

O

N

R2

R1 N

O

O N

R2

R1

+ CO

10 atm

5 mol% Ru3(CO)122 equivalents H2O

Ethylene (7 atm)toluene, 160 °C, 120 h

R1 = H, alkyl, R2 = alkyl 14−87% Yield

Scheme 110 Ru-catalyzed bidentate directing group-assisted carbonylation of C(sp3)-H bonds (Chatani et al., 2011).


same reaction conditions to afford the corresponding succinimides. A variety of functional groups were tolerated and the reactions

took place selectively at a methyl C–H bond over a methylene C–H bond. Although the substrates with an a-tertiary carbon

showed the best reactivity, those with one a-H were also reactive. Mechanistically, the authors proposed that the reaction was

initiated by the formation of a ruthenium hydride complex arising from N–H bond activation. The subsequent ethylene insertion

followed by C–H bond activation gave the metallacycle with the concomitant generation of ethane. It is interesting that no direct

C–H bond cleavage took place in the hydride complex. Finally, the insertion of CO and subsequent reductive elimination

furnished the final product and regenerated the ruthemiun catalyst (Figure 12).168





H2C=CH2CO

N

N

O

Ru H

N

N

O

Ru Et

N

N

O

Ru

N

N

O

RuO

CH3CH3

NNHON

N

O

O

Ru

Figure 12 Proposed mechanism of Ru-catalyzed carbonylation of C(sp3)-H bonds.


Ruthenium was also found to catalyze the three-component coupling acylation of C–H bonds effectively. In 1992, Moore and

coworkers described the acylation reactions of pyridines with CO and olefins using catalyst Ru3(CO)12 (Scheme 111).169 The

reaction occurred at the a-position of the pyridine selectively. A range of terminal olefins underwent the acylation to give the linear

pyridyl ketone as the major product. Remarkably, cis/trans internal olefins were also reactive and yielded the same linear/branched

product ratio as the terminal olefins, indicating that a rapid olefin isomerization occurred in the reaction.

NR + CO

1.3 mol% Ru3(CO)12

150 °C150 psiN

O

RN R

O

+ +

Solvent R = alkylMajor Minor

Scheme 111 Ru-catalyzed three-component coupling acylation of pyridine (Moore et al., 1992).

The Ru3(CO)12-catalyzed three-component coupling acylation of imidazoles was also reported (Scheme 112).170 A range of

imidazoles reacted with alkenes and CO to afford 5-acyl imidazoles selectively. The linear products were formed predominantly.

R3 + CO

4 mol% Ru3(CO)12

Toluene, 160 °C, 20 h20 atm

+N

N

R1

R2

N

N

R1

R2

O

R3

R1, R2 = alkyl, Ph; R3 = alkyl, Ph, SiMe3 42−95% Yield

Scheme 112 Ru-catalyzed three-component coupling acylation of imidazoles (Murai et al., 1996).

The above catalytic systems proved applicable to the acylation of arenes with the aid of pyridine directing groups. Therefore,

pyridylbenzenes were allowed to react with CO and ethylene to yield propionylated products under similar conditions

(Scheme 113).171 In addition to pyridine, pyrimidine was also found to be an effective directing group. Moreover, some hetero-

arenes, such as thiophene derivatives, were also reactive.

Murai and coworkers developed a range of the sp2 nitrogen-directed three-component coupling acylation using catalyst

Ru3(CO)12. In 1997, they reported the analogous acylation of aromatic aldimines with the aid of imine directing groups

(Scheme 114).172 The formed acylated products were labile and underwent the rapid cyclization to form indenone derivatives via

intramolecular aldol condensation.

Notably, Murai and coworkers successfully achieved the similar acylation at the C–H bonds b to a directing nitrogen atom

(Scheme 115).173 A wide range of azo-heteroarenes underwent the acylation to afford aryl ketones under the similar conditions.




R + CO4 mol% Ru3(CO)12


+N

NN

N

O

R

N N

NO

NS

N NNN

R + CO4 mol% Ru3(CO)12


+ N N

O

R

25−78% Yield

36−80% Yield

O

But

O

But

O

But

O

But

7% Yield 15% Yield 46% Yield0% Yield

Scheme 115 Ru-catalyzed three-component coupling acylation of aza-heterocycles (Murai et al., 1998).

+ CO2.5 mol% Ru3(CO)12

Toluene, 160 °C, 20 h20 atm+N

7 atm

N

O51% Yield

Scheme 113 Ru-catalyzed pyridine-directed three-component coupling acylation of pyridylbenzenes (Murai et al., 1997).

N

H

But

X R + CO5 mol% Ru3(CO)12

Toluene, 160 °C, 8−40 h7 atm

+

X

O

X

O

HN But

Silica gel

25 °C, 24 h

X = Me, OMe, CF3, F, alkenyl; R = H, alkyl, SiMe3

22−85% Yield

R

R

Scheme 114 Ru-catalyzed imino-directed three-component coupling acylation (Murai et al., 1997).


This reaction is remarkable, because the C–H activation relying on directing groups usually takes place at the position g or d to a

chelating atom because of the facile formation of five or six-membered metalacycles. The unusual reactivity was attributed to the

formation of a carboruthenium complex consisting of a trimetalic Ru3(CO)12 cluster. One of the Ru atoms was chelated by the

directing nitrogen atom, and another Ru atom was bonded to the b carbon, which formed a stable five-membered ruthenocycle

complex. For the substrates without 2-substituents, the acylation occurred at the 2-postion preferentially.

3.23.3 Reactions with (Pseudo)halides

Aryl (pseudo)halides play crucial roles in transition-metal-catalyzed reactions. Many classical reactions, such as Heck coupling and

cross-coupling reactions, are initiated by an oxidative addition of aryl (pseudo)halides with transition metals. Aryl (pseudo)-

halides have also been extensively exploited in the transition-metal-catalyzed direct arylation via C–H activation in the last three





decades. A great number of reactions have been developed, and a diversity of transition metals have seen applications in the direct

aryl–aryl bond formation reactions involving aryl (pseudo)halides.13,14

3.23.3.1 Pd-Catalyzed Reactions with (Pseudo)halides

In Pd-mediated C–H arylation reactions with aryl (pseudo)halides, there are two principal mechanistic manifolds. One involves

Pd(II)/Pd(IV) catalysis, and the other one proceeds via a Pd(0)/Pd(II) catalytic cycle. In the Pd(II)/Pd(IV) mechanism, the

reactions usually start with Pd(II)-mediated C–H cleavage. Next, the newly formed organopalladium species undergoes oxidative

addition of the aryl (pseudo)halide (normally aryl iodides or aryl iodonium species, such as [Ph2I]BF4) to form a Pd(IV) species.

Finally, reductive elimination from the Pd(IV) species generates the new aryl–aryl bond and releases the Pd(II) catalyst to continue

the catalytic cycle. For reactions involving a Pd(0)/Pd(II) mechanism, however, the initial step is oxidative addition of the aryl

(pseudo)halide to the Pd(0) catalyst to form a Pd(II) species. This arylpalladium species then cleaves a C–H bond and forms an

aryl-Pd(II)-aryl complex. Finally, reductive elimination generates the arylated product and regenerates the Pd(0) catalyst

(Figure 13).15

Ar1–XPd(0)

Ar1–Pd(II)–X

Ar2–H

Ar1–Pd(II)–Ar2

Ar1–Ar2

Oxidativeaddition

C−Hactivation

Reductiveelimination

Ar1–H

Ar1–Pd(II)–X

Ar2–X

Pd(IV)–Ar1

Ar1–Ar2

Oxidativeaddition

C−Hactivation


Pd(II)

Ar2

X

Pd(0)/Pd(II) catalytic cycle Pd(II)/Pd(IV) catalytic cycle

Figure 13 Two general mechanisms in Pd-catalyzed arylation of C–H bonds with (pseudo)halides.

3.23.3.1.1 Pd-catalyzed nondirected reactions of (hetero)arenes with (pseudo)halidesAs discussed in Section 3.23.1, regioselectivity is one of the major issues in nondirected C–H functionalization of (hetero)arenes.

The presence of multiple sites for C–H functionalization can lead to a mixture of isomeric products. However, unlike inter-

molecular direct arylation of carbocyclic arene systems, the inherent electronic bias of the heterocycle itself is often sufficient to

control the regioselectivity of direct arylation reactions.174 The body of literature on Pd-catalyzed C–H functionalization reactions

of heteroarenes reveals a general tendency for preferential reactivity at the position a- to the heteroatom, as represented in

Figure 14.13,174 However, the nature of the catalyst, base, solvent, and additives can influence the regioselectivity to a great extent.

N O S

ON

R

NN

R

N

N

O

N

S

N

R

N

NN

R

N N

N

N

N N

NN

N N

N

NR

O S

N

N

N

O

N

S

R

N

O

NN

O

N

N

O

Figure 14 The preferred reaction sites for the C–H functionalization of heteroarenes.




Tuning of the reaction conditions has been used to alter the regioselectivity to achieve the desired product. Furthermore, C–H

functionalization at other positions can be achieved if the favorable a-position is blocked.

3.23.3.1.1.1 Pd-catalyzed nondirected reactions of (hetero)arenes with (pseudo)halides via Pd(0)/Pd(II) catalytic cycleOne of the first examples for Pd-catalyzed reactions of C–H bonds with aryl halides was the arylation of isoxazoles

(Scheme 116).175 Therefore, the 3,5-disubstituted isoxazoles were phenylated with iodobenzene at the 4-position using Pd/C as

the catalyst.

ONMe

OTs

I+

ONMe

OTs10 mol% Pd/C1.5 equivalents NaHCO3

HMPA, 100 °C, 9 h

44% Yield

Scheme 116 Pd-catalyzed arylation of isoxazole with aryl iodide (Nakamura et al., 1982).

Currently, a variety of heteroarenes have been found to undergo Pd-catalyzed arylation with aryl halides, including aryl

chloride, -bromides and -iodides.176,177 A large number of reactions have been disclosed, making it impossible to cover all of

them. This section presents representative reactions for each type of heteroarene.

An elegant example of arylation of pyrroles with aryl iodide was reported by Gryko and coworkers (Scheme 117).178 By using

Pd(PPh3)2Cl2 as the catalyst, N-protected pyrroles were arylated with a wide range of aryl iodides in the presence of AgOAc and KF.

The arylation occurred at the C-2 position selectively.

N

R

+ ArI

5 mol% Pd(PPh3)2Cl21 equivalent AgOAc (batchwise)

2 equivalents KFDMSO, 100 °C, 5 h

N

R

Ar

R = Me, Ph, Bn 14−80% Yield

Scheme 117 Pd-catalyzed C2-arylation of pyrroles with aryl iodides (Gryko et al., 2009).

The arylation of indole was reported as early as 1989 by Ohta and coworkers (Scheme 118).179 1-Substituted indoles

underwent coupling reaction with 2-chloro-3,6-dialkylpyrazines using Pd(PPh3)3 and KOAc. Interestingly, while 1-tosylindole

formed 3-arylated indoles as the major products, the reactions occurred at the 2-position for 1-methyl or 1-benzylindole.

N+

4 mol% Pd(PPh3)4

1.2 equivalents KOAcDMA, reflux, 12 hR1 N

N

R2

R2

ClNR1

N

NR2

R2

R1 = Me, Bn

N+

4 mol% Pd(PPh3)4

1.2 equivalents KOAcDMA, reflux, 12 hTs

N

N

R

R

Cl NTs

R = alkylN

N

R

R1.2 equivalents

1.2 equivalents

R2 = alkyl 18−70% Yield

40−68% Yield

Scheme 118 Pd-catalyzed regioselective arylation of indoles with chloropyrazines (Ohta et al., 1989).

Regioselective arylation of indoles was described by Sames and coworkers. The authors first discovered the C2-arylation

reactions of N-substituted indoles with a wide range of aryl iodides.180 The mechanistic studies suggested that the reactions

involved an electrophilic palladation of indole, accompanied by a 1,2-migration of an intermediate palladium species. Based on

the mechanism, the authors designed new catalytic conditions for the C3-arylation of indole. Therefore, in case of free (NH)-

indole, regioselectivity of the arylation reaction (C-2 vs. C-3) was achieved by the choice of magnesium base (Scheme 119).181

In 1990, Aoyagi described C2-arylation of furans and thiophenes (Scheme 120).182 In the presence of Pd(PPh3)4 and KOAc,

the arylation was enabled by treating with aryl iodides. Benzofuran and benzothiophene were also reactive under the chemical




N + ArI

0.5 mol% Pd(OAc)22 mol% PPh3

2 equivalents CsOAcDMA, 125 °C, 24 h1.2 equivalentsMe

NMe

ArX X

NH

+ PhI2. 2.5 mol% Pd(OAc)2

10 mol% PPh3125 °C, 24 h

0.5 equivalentNH

1. MeMgCl/TMEDAdioxane, 65 °C

PhX = H, Me, OMe, NO2, CO2Me, PhSO2NH, CN 24−88% Yield

61% Yield

Scheme 119 Pd-catalyzed regioselective arylation of indoles with aryl iodides (Sames et al., 2005).

X+ ArI

5 mol% Pd(PPh3)4KOAc

DMA, 150 °C, 12 h X Ar

X = O, S

Scheme 120 Pd-catalyzed C2-arylation of furans and thiophenes with aryl iodides (Aoyagi et al., 1990).


conditions. Remarkably, aryl chlorides were also found to react with benzothiophene to yield 2-arylated products

(Scheme 121).183

S+ ArCl

2 mol% Pd(PBut3)2

3 equivalents LiOBut

DMF, 100 °C, 15 h SAr

62−92% Yield

Scheme 121 Pd-catalyzed C2-arylation of benzothiophene with aryl chlorides (Mori et al., 2010).

Notably, C3-arylation of thiophenes was achieved by Itami and coworkers (Scheme 122).184 The arylation occurred at the

3-position with 499% selectivity by using PdCl2/P(OCH(CF3)2)3/Ag2CO3 catalytic system. The electron-withdrawing ligand

P(OCH(CF3)2)3 was a necessity to achieve the high 3-selectivity. A wide range of functional groups on the benzene rings of aryl

iodides were tolerated in the reactions.

S+ ArI

5 mol% PdCl210 mol% P[OCH(CF3)2]3

1 equivalent Ag2CO3m-xylene, 130 °C, 12 h S

ArX X

X = H, Me, OMe, Ph, OPh, Cl, Br, alkenyl 40−86% Yield

Scheme 122 Pd-catalyzed C3-arylation of thiophenes with aryl iodides (Itami et al., 2010).

Pyridine was found to undergo 2-phenylation on a heterogenous palladium catalyst on carbon in the presence of zinc and

water (Scheme 123).185 Besides phenyl bromide and iodide, phenyl chloride was also reactive.

N+ PhX

1−2 mol% Pd/C

Zn, H2O, 110 °C N PhX = Cl, Br, I

27−69% Yield

Scheme 123 Pd-catalyzed C2-phenylation of pyridine with phenyl halides (Sasson et al., 2000).

Fagnou and coworkers reported C2-arylation of pyridine N-oxides (Scheme 124).186 The reactions occurred in high yields with

a wide range of aryl bromides in the presence of Pd(OAc)2/(But)3P-HBF4 and K2CO3.






N

O

5 mol% Pd(OAc)215 mol% PBut

3-HBF4

2 equivalents K2CO3Toluene, 110 °C, overnight

+ ArBr

4 equivalents

XN

O

XAr

X = H, 4-OMe, 4-NO2

45−97% Yield

Scheme 124 Pd-catalyzed C2-arylation of pyridine N-oxides with aryl bromides (Fagnou et al., 2005).


Miura and coworkers conducted extensive studies toward the palladium-catalyzed arylation of a variety of azoles.187 The

representative examples are the reactions of N-methylimidazole and thiozole with iodobenzene (Scheme 125). Interestingly,

the arylation could be controlled depending on the catalyst used. In the absence of CuI, the arylations occurred preferentially at

the C-5 position, followed by C2-arylation. On the contrary, in the presence of CuI, 2- and 2,5-diarylated imidazoles were the only

products for N-methylimidazole, and only 2,5-diarylated thiozole was observed for thiazole. Notably, in the absence of palladium

catalyst, CuI-catalyzed arylation occurred to give the C-2 products, albeit in low yields.

N

X+ PhI

10 mol% Pd(OAc)2PPh3

Cs2CO3DMF, 140 °C

N

X

X = NMe, S

N

X

N

XPh Ph Ph Ph

+ +

Without CuI 54% 24% 0%

2 equivalents CuI 0% 37% 40%X = NMe

Without CuI 17% 35% 0%

2 equivalents CuI 0% 66% 0%X = S

Scheme 125 Pd-catalyzed phenylation of azoles with iodobenzene (Miura et al., 1998).

Selective C-2 arylation of imidazoles was reported by Bellina and Rossi (Scheme 126).188 A variety of azoles, including

N-methylimidazole, N-arylimidazoles, free (NH)-imidazole, thiazole, and oxazole, underwent arylation with aryl iodides in the

presence of Pd(OAc)2 and CuI. Subsequently, the same authors disclosed C5-arylation of imidazoles (Scheme 127).189 Therefore,

1-methyl-1H-imidazoles was arylated with a wide variety of aryl bromides using Pd(OAc)2/P(2-furyl)3 catalyst system.

N

N+ ArI

5 mol% Pd(OAc)22 equivalents CuI

DMF, 140 °C, 25−48 h

N

N Ar

R R

R = H, Me, aryl 47−99% Yield

Scheme 126 Pd-catalyzed C2-arylation of imidazoles with aryl iodides (Bellina and Rossi et al., 2006).

N

N+ ArBr

5 mol% Pd(OAc)210 mol% P(2-furyl)3

2 equivalents K2CO3DMF, 110 °C, 24−90 h

N

N Ar

Me Me24−80% Yield

Scheme 127 Pd-catalyzed C5-arylation of imidazoles with aryl bromides (Bellina and Rossi et al., 2008).

Both C2 and C5-arylation of thiazoles have also been proved viable. Mori reported Pd/Cu-catalyzed C2-arylation of thiazole

with a wide range of aryl iodides (Scheme 128).190 In this reaction, tetra-n-butylammonium fluoride (TBAF) serves a novel and

excellent activator. It is noted that the formed 2-arylated thiazoles may undergo a second Pd-catalyzed arylation at C-5 position

with aryl iodide, which provided an efficient method to synthesize 2,5-diarylated thiazole. Subsequently, Fagnou and coworkers

disclosed selective C5-arylation of simple thiazole by using Pearlman’s catalyst (palladium hydroxide on carbon)

(Scheme 129).191 The catalyst system also proved applicable to the intramolecular arylation of a variety of arenes tethered with

aryl iodide/bromides. Furthermore, regioselective arylation of imidazo[1,2-a] pyrimidines and furan was also enabled under the





N

S+ Ar1I

3 mol% PdCl2(Ph3)22 mol% CuI

TBAFDMSO, 60 °C, 24 h

N

S Ar1

2 equivalents Ar2X (X = Br, I)10 mol% Pd(OAc)2

20 mol% PPh3

2 equivalents Cs2CO3DMSO, 140 °C, 24−70 h

N

S Ar1Ar2

26−94% YieldAr1 = 4-OMeC6H4, 4-NMe2C6H4

Scheme 128 Pd-catalyzed regioselective arylation of thiazole with aryl iodide (Mori et al., 2003).

N

S+ ArX

10 mol% Pd(OH)2/C2 equivalents KOAc

DMA, 140 °C, 12−24 h

N

S ArX = Br, I 71−82% Yield

Scheme 129 Pd-catalyzed C5-arylation of thiazole with aryl bromides/iodides (Fagnou et al., 2005).


same reaction conditions. The reactions occurred at 3-position for imidazo[1,2-a]pyrimidines and at 2-position for furan,

respectively.

Regioselective C2- or C5-arylation of oxazole can be controlled by employing different ligand (Scheme 130).192 Therefore, in

the presence of ligand C and nonpolar solvent such as toluene, oxazole was arylated predominantly at the C-2 position, whereas

C5-arylation is preferred in polar solvent as N,N-dimethylacetamide (DMA) with ligand A or B, which represents the first general

method for C5-arylation of oxazole. Remarkably, the methods were applicable to diverse (pseudo)halides, including chlorides,

bromides, and tosylates. Based on the mechanistic studies, the author proposed that C5-arylation took place through concerted-

metalation-deprotonation (CMD) pathways, whereas deprotonation mechanisms accounted for C2-arylation.

N

O+ ArX

5 mol% Pd(OAc)210 mol% ligand C

0.4 equivalent pivalic acid

3 equivalents K2CO3Toluene, 110 °C, 16 h

N

O Ar

P(But)2

Me

Me

Me

Me

Pri

PriPri

P

PCy2

OPri

OPri

N

OAr

Ligand A Ligand B

5 mol% Pd(OAc)210 mol% ligand A or B

0.4 equivalent pivalic acid

3 equivalents K2CO3DMA, 110 °C, 16 h

Ligand C

X = Cl, Br, OTf 34−78% Yield

Scheme 130 Pd-catalyzed C2/C5-arylation of oxazole with aryl halides/triflates (Strotman and Chobanian et al., 2010).

Compared to aryl (pseudo)halides, alkyl (pseudo)halides are much less explored in the transition-metal-catalyzed organic

reactions. Recently, Hirano and Miura reported the direct alkylation of benzoxazoles with alkyl halides (Scheme 131).193 Thus, in

the presence of strong base LiO-But, benzoxazoles underwent C2-alkylation using catalyst [{PdCl(C3H5)}2] and ligand P(Bun)3.

Both alkyl chlorides and bromides were compatible in the reactions.

O

N+ RY

3.75 mol% [{PdCl(C3H5)}2]30 mol% P(Bun)3

3.0 equivalents LiOBut

diglyme, 120 °C, 4 h

XO

NX R

R = alkylY = Cl, BrX = H, Me, aryl, etc. 33−75% Yield

Scheme 131 Pd-catalyzed C2-alkylation of benzoxazole with alkyl halides (Hirano and Miura et al., 2010).

The Pd(OAc)2/Ph3P-catalyzed direct arylation of oxazole[1,2-b] pyridine occurred regioselectively at the C-2 position of the

oxazole (Scheme 132).194

Sames and coworkers undertook systematic studies in an effort to achieve the C–H arylation of pyrazoles. They identified

a palladium-pivalate catalytic system as the most effective protocol and mapped the reactivity of all three C–H bonds of the

2-trimethylsilylethoxymethoxy (SEM)-protected pyrazole (C-54C-4cC-3) (Scheme 133).195 Interestingly, to circumvent the low

reactivity of the C-3 position, the authors developed a smart method to transpose the SEM-protecting group from one nitrogen to

the other in one step, which transformed the unreactive C-3 position to the reactive C-5 position. Therefore, the C-4 arylated





N N

O+ ArBr

5 mol% Pd(OAc)220 mol% Ph3P

2 equivalents Cs2CO3acetone, 30 °C, 24 h

N N

OAr

2 equivalents33−74% Yield

Scheme 132 Pd-catalyzed C2-arylation of oxazole [1,2-b] pyridine with aryl bromides (Zhuravlev, 2006).

NN

SEM

5 mol% Pd(OAc)27.5 mol% P(Bun)Ad2

25 mol% HOPiv

3 equivalents K2CO3

DMA, 140 °C, 12 h

+ PhBrN

N

SEM

Ph NN

SEM

Ph

Ph

NN

SEM

Ph

+ +

10 : 2.5 : 7.5 80% Total yield

NN

SEM

+

Ph

NN

SEM

Ph

N

NN

Ph

N

SEM

NN

Ph

N

SEM

F3C

NNH

Ph

N

F3C

N

Br

1.5 equivalents

1.5 equivalents

1.5 equivalents

10 mol% SEMCl

MeCN, 95 °C, 24 h

The same conditionsas above

The same conditionsas above

HCl (3 N)

EtOH, reflux, 3 h

84%

77% 75%

F3C Br

65%

Scheme 133 Pd-catalyzed arylation of pyrazole with aryl bromides (Sames et al., 2009).


substrates were arylated at C-5 position regioselectively in the first step. Subsequently, the SEM-protecting group was transposed to

the other nitrogen atom. As a result, the initial unreactive C-3 was switched to reactive C-5, which could be readily arylated under

the same conditions. This protocol enabled sequential arylation of C-5 and C-3 position of pyrazole, providing rapid access to

protected or free 3,4,5-triarylpyrazoles (the C-4 arene ring was readily introduced by bromination and Suzuki coupling).

In the Pd(OAc)2-catalyzed arylation of Bn-protected 1,2,3-triazole reported by Gevorgyan, the reactions occurred at the C-5

position regioselectively (Scheme 134).196 However, C-4 arylation may take place under similar conditions when the C-5

positions were blocked with substituents, albeit in moderate yields.

NN

N

Bn

5 mol% Pd(OAc)22 equivalents Bu4NOAc

NMP, 100 °C+ ArBr

NN

N

Bn

Ar

64−83% Yield

Scheme 134 Pd-catalyzed C5-arylation of 1,2,3-triazole with aryl bromides (Gevorgyan et al., 2007).

Gevorgyan and coworkers also developed a highly effective method for selective arylation and heteroarylation of indolizines at

the C-3 position (Scheme 135).197 A variety of aryl and heteroaryl bromides were compatible in the reactions. Mechanistic studies

unambiguously supported an electrophilic substitution pathway for this transformation.

NR + ArBr

5 mol% PdCl2(PPh3)22 equivalents KOAc

2 equivalents H2ONMP, 100 °C, 1−3 h

NR

Ar1.2 equivalents

R = H, Me, CN, CO2Et, Ac 51−96% yield

Scheme 135 Pd-catalyzed C3-arylation of indolizines with aryl bromides (Gevorgyan et al., 2004).

The direct arylation of imidazo[1,2-a]pyrimidine was also investigated by Li and coworkers (Scheme 136).198 The authors

found that imidazo[1,2-a]pyrimidine can be arylated at the 3-position with aryl bromides in the presence of Cs2CO3 and





N

N N+ ArBr

2 mol% Pd(OAc)24 mol% Ph3P

2 equivalents Cs2CO3dioxane, 100 °C, 18 h

N

N N

Ar• HBr39−96% yield

Scheme 136 Pd-catalyzed C3-arylation of imidazo[1,2-a]pyrimidine with aryl bromides (Li et al., 2003).


Pd(OAc)2/Ph3P. A variety of substituents on the aryl bromides were tolerated under the reaction conditions. The proposed

mechanism involved an electrophilic metalation in the C–H activation step, consistent with the observed outcome that the

arylation took place at the electron-rich imidazole ring instead of the electron-deficient pyrimidine ring.

Sames and coworkers described a general protocol for the arylation of azoles palladium complexes containing imidazolyl

carbene ligand (Scheme 137).199 Therefore, a wide range of SEM-protected azoles were arylated with aryl iodides or bromides

using the palladium complex (shown in scheme) as the catalyst. The reactive azoles included pyrroles, indoles, imidazoles, and

imidazo[1,2-a]pyridines. In most cases, the arylation occurred at the position a to SEM-protected nitrogen. However, a mixture of

isomers or diarylated products was also observed for some substrates.

Z

N + ArX

0.15−5 mol% catalyst2 equivalents CsOAc

DMA, 125 °C, 24 h

1.2−3 equivalentsSEM

Y

Z

NSEM

Y

Ar

Y, Z = C, N

X = Br, IN N

Pd(I)2PPh3

Me

MeO

N

catalyst

NSEM

N

SEMN N

SEM

N

N

SEM

N

N

SEM

Ph

Ph

Ph PhPh

22−82% yield

82% yield 57% yield 81% yield 93% yield

NC

59% yield

NC

Scheme 137 Pd-catalyzed arylation of heteroarenes with aryl halides (Sames et al., 2006).

Another general catalytic system was developed for the arylation of heterorenes N-oxide by Ackermann and coworkers

(Scheme 138).200 In the presence of catalyst Pd(OAc)2/X-Phos and base CsF, pyridine N-oxide and its analogs underwent

a-arylation with aryl tosylates or mesylates. Alkenyl tosylates and electron-deficient fluorinated arenes were also reactive under the

reaction conditions.

XN

X

O

5 mol% Pd(OAc)210 mol% X-Phos

Toluene/ButOH (2/1),CsF, 110 °C, 20 h

Ts/MsOY

XN

X

OY

+

X = CH2, N

N

O

NN

ON

N

O

N

N

O

N

O

Y = alkyl, OMe, OCH2O, carbonyl, alkenyl, NMe2, F 46−82% yield

Scheme 138 Pd-catalyzed arylation of heteroarenes with aryl tosylates/mesylates (Ackermann et al., 2011).

The Pd-catalyzed direct arylation of arenes lacking directing groups was discovered much later than that of heteroarenes. In

2006, Fagnou and coworkers reported the first nondirected catalytic benzene arylation (Scheme 139).201 Thus, electron-deficient

polyfluorobenzenes underwent arylation reaction with a wide range of aryl bromide in the presence of catalyst Pd(OAc)2/

PBut2Me–HBF4 and K2CO3. Aryl chlorides and iodides can also be used. In the reactions, the more electron-deficient arenes

showed higher reactivities, and the arylation occurred preferentially at the most acidic conditions for the substrates with two

distinct C–H bonds.

Subsequently, Fagnou and coworkers also achieved the arylation of simple arenes (Scheme 140).202 Notably, pivalate anion

played a key role in this C–H bond cleavage. It acted as a catalytic proton shuttle from benzene to the stoichiometric carbonate

base and lowered the energy of C–H bond cleavage. By using palladium-pivalic acid cocatalyst combination, benzene was arylated




ArBr

Fn

+


2Me-HBF4

1.1 equivalents K2CO3DMA, 120 °C

Fn

Ar

1.1−3 equivalents 76−98% yield

Scheme 139 Pd-catalyzed arylation of perfluorobenzenes with aryl bromides (Fagnou et al., 2006).

+ Ar

2−3 mol% Pd(OAc)22−3 mol% DavePhos30 mol% ButCO2H

2.5 equivalents K2CO3PhH/DMA (1/1.2)120 °C, 10−15 h

PCy2

Me2N

DavePhos

ArBr

55−85% yield

Scheme 140 Pd-catalyzed arylation of benzene with aryl bromides (Fagnou et al., 2006).


with aryl bromides in the presence of DavePhos and K2CO3. A variety of substituents of aryl bromides were compatible in the

reaction, and the monosubstituted benzenes, including anisole and fluorobenzene, gave a mixture of o/p/m regioisomers.

Pd-catalyzed intramolecular reactions of arenes with halides have also been developed. The reactions are remarkable, because

they provide efficient methods to synthesize complex polycycles. In these reactions, the substrates contain an arene tethered with a

halide, including aryl, alkenyl, and alkyl halides. As the intermolecular reactions, the intramolecular reactions were also initiated

with the oxidative addition of the halides to Pd(0). The subsequent intramolecular Pd(II)-mediated C–H cleavage and reductive

elimination formed new C–C bonds.

As early as 1983, Ames and coworkers disclosed intramolecular dehydrobromination of 2-bromophenyl phenyl ethers by

using a catalytic amount of Pd(OAc)2, which provided a convenient, general process for the synthesis of substituted dibenzofurans

(Scheme 141).203 The reactions tolerated electron-withdrawing and electron-releasing group.

O

Br

X

O

X

10 mol% Pd(OAc)2Na2CO3

DMA, 170 °C

X = H, 3-Me, 4-CH2OH, 4-CN, 4-CO2H, NO2 9−99% yield

Scheme 141 Pd-catalyzed intramolecular arylation of arenes (Ames et al., 1983).

The intramolecular alkenylation of arenes was described by Willis and coworkers (Scheme 142).204 Therefore, a catalyst

generated from Pd(OAc)2 and dppp was found to effectively catalyze the direct intramolecular arylation of alkenyl triflates,

yielding conjugated alkene-arene-containing carbocycles in good yield.

TfO

X

R

XR

( )n

( )n

2 mol% Pd(OAc)22 mol% dppp

3 equivalents NBu3,NMP, 80 °C, 6−60 h

R = H, alkyl; n = 1,2X = H, OMe, OTIPS, CN, CO2Me, F, Cl

51−93% yield

dppp = 1,3-bis(diphenylphosphino)propane

Scheme 142 Pd-catalyzed intramolecular alkenylation of arenes (Willis et al., 2007).

Buchwald and coworkers developed intramolecular alkylation of arenes with alkyl chlorides (Scheme 143).205 In the presence

of a bulky phosphine ligand, the reactions proceeded under quite mild conditions to form substituted oxindoles. A wide range of

functional groups were tolerated under the reaction conditions.

Notably, a diverse variety of tethers have proved applicable to the intramolecular aryl–aryl bond formation by Pd-catalyzed

direct arylation, and various (pseudo)halides, including Cl, Br, I, and OTf, were used to initiate the C–H activation (Scheme 144).13

Moreover, the intramolecular direct arylation of heteroaryl C–H bonds have been extensively investigated, and a great number

of reactions have been reported. A wide range of heteroarenes may undergo C–H activation and subsequent arylation by reacting

with carbopalladium, which are generated by the oxidative addition of aryl halides to Pd(0). The reactions formed aryl–heteroaryl

bonds.174





N

O

Cl

R

XX

NO

R

1−3 mol% Pd(OAc)22−6 mol% ligand

1.5 equivalents NEt3,Toluene, 80 °C, 2.5−6 h

PBut2

Ligand

R = Me, Et, Bn, Ph, PMBX = H, Me, OMe, OTBS, TMS, Cl, CF3, NO2

76−99% yield

Scheme 143 Pd-catalyzed intramolecular alkylation of arenes (Buchwald et al., 2003).

Y

X

Y

X = Cl, Br, I, OTf

ORN

H2C C

O

OO

NO R

HNO

N SOOS

H2C OH2C CH2 H2C N

R

H2C O

H2C

HC CH NN

Y =

Ph O

O

Pd

Scheme 144 Pd-catalyzed intramolecular C–H arylation.


3.23.3.1.1.2 Pd-catalyzed nondirected reactions of (hetero)arenes with (pseudo)halides via Pd(II)/Pd(IV) catalytic cycleAlthough all of the above Pd-catalyzed direct arylation reactions involve Pd(0)/Pd(II) mechanisms, the Pd(II)/Pd(IV) catalytic

process has also been utilized to enable arylation of heteroarenes. In 2006, Sanford and coworkers reported such an arylation of

indoles and pyrroles, using [Ph-I-Ph]BF4 as the arylation reagent (Scheme 145).206 The reactions proceeded under remarkably

mild conditions (often at room temperature), and occurred at C-2 position regioselectively. However, appreciable amounts of

phenylation at the C-3 position were also observed when C-2 was blocked. A diverse variety of substituents of indoles were well

tolerated.

NR

X Ar I Ar

BF4–

+5 mol% IMesPd(OAc)2

AcOH, 25 °C, 15−24 h NR

X Ar

R = H, MeX = H, OMe, OAc, morpholinyl, Br, NO2

1−3 equivalents

29−90% yield

IMes = 1,3-bis(2,4,6-trimethylphenyl)imidazol-2-ylidene

Scheme 145 Pd-catalyzed C2-arylation of indoles with [Ph-I-Ph]BF4 (Sanford et al., 2006).

As discussed in Section 3.23.2.1.1.1, the direct C–H functionalization of pyridine has been a challenge. Among the rare

reported examples, the reactions usually occurred at C-2 position. Recently, Yu and coworkers described the first example of Pd-

catalyzed, C3-arylation of unprotected pyridines (Scheme 146).207 Therefore, by employing a catalytic system consisting of

Pd(OAc)2 and 1,10-phenanthroline, pyridine and its derivatives were 3-arylated with a wide range of aryl bromides or iodides. The

Pd(II)/(IV) mechanism was also proposed to be responsible for the novel procedure.

3.23.3.1.2 Pd-catalyzed-directed reactions of (hetero)arenes with (pseudo)halides3.23.3.1.2.1 Pd-catalyzed-directed reactions of (hetero)arenes with (pseudo)halides via Pd(0)/Pd(II) catalytic cycleA diversity of directing groups has been utilized to assist the direct arylation of arenes with aryl halides, forming ortho-arylated

products regioselectively. In 1997, Miura and coworkers reported the hydroxyl-assisted arylation of 2-phenylphenols

(Scheme 147).208 Thus, 2-phenylphenols were ortho-arylated with aryl iodides in the presence of Pd(OAc)2 with Cs2CO3 as base.

Cs2CO3 was crucial to the success of the reaction because of its relatively high solubility in dimethylformamide (DMF), facilitating

the deprotonation and the subsequent transmetalation. Furthermore, the mono- or diarylated product could be selectively

obtained by controlling the amount of aryl iodide and Cs2CO3.




ArX

N

Y +

N

Y

Ar5 mol% Pd(OAc)2

15 mol% Phen

3 equivalents Cs2CO3140 °C, 48 h

X = Br, IY = H, Me, OMe, CF3, alkenyl

N N

Phen:

54−90% yield

Scheme 146 Pd-catalyzed C3-arylation of pyridines with aryl bromides/iodides (Yu et al., 2011).

OHX + ArI

5 mol% Pd(OAc)21.2 equivalents Cs2CO3

4 Å MSDMF, 100 °C, 7−44 h

OHX

ArX = H, Me, OMe, NO2 56−73% yield

Scheme 147 Pd-catalyzed hydroxyl-directed arylation with aryl iodides (Miura et al., 1997).


The amide group was also found to be an efficient directing group in the C–H arylation reactions (Scheme 148).209 Therefore,

benzanilides underwent diarylation with aryl triflates using catalyst Pd(OAc)2/PPh3 and base Cs2CO3. Notably, the arylation

occurred on the benzoyl moiety selectively, and neither the N-arylated product nor the arylated anilide was observed.

NHPh

O

+ ArOTf

5 mol% Pd(OAc)230 mol% PPh3

4 equivalents Cs2CO3Toluene, 110 °C

NHPh

OAr

Ar

74−96% yield

Scheme 148 Pd-catalyzed amide-directed arylation with aryl triflates (Miura et al., 2000).

The arylation of benzaldehydes was also reported (Scheme 149).210 By using Pd(OAc)2 and a bulky electron-rich N-hetero-

cyclic carbene ligand, a variety of benzaldehydes were allowed to react with a wide range of aryl chlorides, forming the arylated

products in good to excellent yields. The diarylated products were produced when aryl bromides were used.

O

H + ArCl

1 mol% Pd(OAc)22 mol% [L-H]Cl

2 equivalents Cs2CO3,dioxane, 80 °C, 16 h

2−3 equivalentsX

O

HX

Ar

N NR R

L =

X = H, 4-CHO, 4-NMe2, 4-But, 4-OMe, 3,4,5-(OMe)356−97% yield

Scheme 149 Pd-catalyzed aldehyde-directed arylation with aryl chlorides (C- etinkaya et al., 2005).

Ethers have been seldom used as the directing group in the transition-metal-catalyzed C–H functionalization reactions because

of their weak coordination with metals. Remarkably, Fagnou and coworkers achieved the first ether-directed arylation in 2006

(Scheme 150).211 1,3-benzodixole was arylated with a range of aryl bromides and chlorides in the presence of Pd(OAc)2,

PBut2Me �HBF4, AgOTf, and K2CO3.

+ ArX


2Me.HBF41 equivalent AgOTf

2 equivalents K2CO3,DMA, 145 °C, 8−16 h

10 equivalentsAr

OO

OO

X = Cl, Br62−86% yield

Scheme 150 Pd-catalyzed arylation of 1, 3-benzodioxles with aryl chlorides/bromides (Fagnou et al., 2006).







Daugulis and coworkers described the direct arylation of benzoic acids with aryl chlorides by using ligand BuAd2P

(Scheme 151).212 The reaction required the presence of molecular sieves. Benzoic acids of any properties were reactive. Isotope

effect studies pointed to heterolytic C–H bond cleavage as the turnover-limiting step.

O

OH + ArCl

5 mol% Pd(OAc)210 mol% BuAd2P

2.2 equivalents Cs2CO3,3 Å MS

DMF, 145 °C, 24 h

2−3 equivalentsX

O

OHX

ArX = H, Me, Ph, OMe, F,CF3, CO2Me, NO2

65−91% yield

Scheme 151 Pd-catalyzed carboxyl-directed arylation with aryl chlorides (Daugulis et al., 2007).

The C–H arylation of electron-deficient arenes have been less extensively investigated, because they are less reactive. As such,

the arylation with a electron-withdrawing directing group, such as nitro, should be more challenging. However, the reactions

would benefit from electron-deficiency if they occurred through a concerted metalation-deprotonation (CMD) pathway. The

arylation of electron-poor arenes have been reported, and the CMD mechanisms were proposed to be operative in these reactions.

Inspired by the successes, Fagnou and coworkers reported the arylation of nitrobenzenes with a variety of aryl bromides

(Scheme 152).213 The reactions could be performed on gram scale. The competition experiments revealed that the arylation of

nitrobenzene was highly favored over those of electron-richer arenes, including methylbenzoate and anisole.

+ ArBr


2Me.HBF430 mol% PivOH

1.3 equivalents K2CO3,mesitylene, 125 °C, 16 h5 equivalents

X

NO2

X

NO2

Ar

X = H, Me, OMe, Ph, alkenyl, CO2Me, CN, benzoyl 40−77% yield

Scheme 152 Pd-catalyzed nitro-directed arylation with aryl bromides (Fagnou et al., 2008).

It is not surprising that the C–H arylation of pyridines is a challenge. Recently, Yu and coworkers reported a Pd(0)/PR3-

catalyzed arylation procedure for N-phenylnicotinamides and N-phenylisonicotinamides with the acidic amides as directing

groups (Scheme 153). This reaction constituted the first example of directed transition-metal-catalyzed C–H functionalization of a

pyridine ring at the 3- or 4-positions. The reactions of N-phenylisonicotinamides formed a mixture of mono- and diarylated

products when the two meta-C–H bonds were available. However, the use of 3,5-dimethylphenyl as the protecting group sig-

nificantly improved the monoselectivity. For the substrate N-phenylisonicotinamides, para-arylation occurred preferentially.214

N

NHAr

O

+ Ar1Br

10 mol% Pd(OAc)210 mol% PCy2But.HBF4

1.5 equivalents N

NHAr

OAr1

N

NHAr

OAr1

Ar1+

X X X

X = H, F, Me, alkenyl 62−94% Total yield

3 equivalents Cs2CO3, 3 Å MSToluene, N2, 130 °C, 48 h

Scheme 153 Pd-catalyzed amide-directed arylation of nicotinic and isonicotinic acid derivatives with aryl bromides (Yu et al., 2010).

3.23.3.1.2.2 Pd-catalyzed-directed reactions of (hetero)arenes with (pseudo)halides via Pd(II)/Pd(IV) catalytic cycleAll of the above directed C–H arylation reactions were proposed to proceed through a Pd(0)/Pd(II) mechanism. Pd(II)/Pd(IV)

catalysis have also been extensively exploited for the Pd-catalyzed reactions of C–H bonds with aryl halides with the assistance of

directing groups. The pioneering work is the C–H methylation of anilides with MeI reported by Tremont and coworkers in 1984

(Scheme 154).215 The use of AgOAc and TFA was required to make the reactions catalytic. The alkylation of the cyclopalladated

intermediates was proposed to involve either an electrophilic attack of MeI on the Pd–carbon bond or a Pd(IV) intermediate.

Ethyl and allyl iodide were also reactive to give the corresponding ethylated and allylated products.

Twenty years later, Daugulis and coworkers reported the arylation of anilides under similar conditions (Scheme 155).216

Although the monoarylated products were formed for the meta- or ortho-substituted anilides, the reactions yielded diarylated

anilides in the absence of meta- or ortho-substituents. The reactions were highly tolerant to functional groups including bromide

and iodide. It is noted that up to 1000 turnovers were demonstrated for this method.




HN

X

HN

X

R+ RI

Pd(OAc)2AgOAc

TFA

O

Me

R = Me, Et, allyl

O

Me

X = H, Me, OMe, CF3

71−86% yield

Scheme 154 Pd-catalyzed amide-directed alkylation with alkyl iodides (Tremont et al., 1984).

HN

X

NH

X

Ar+

O

R

R = Me, But

X = H, 4-Me, 4-Br, 4-I, 3-I

O

R

0.2−5 mol% Pd(OAc)2AgOAc (1 equivalent per

coupled Ar)

TFA, 90−130 °C2−9 equivalents

or

NH

X

Ar

O

R

ArArI

55−96% Total yield

Scheme 155 Pd-catalyzed amide-directed arylation with aryl iodides (Daugulis et al., 2005).


The similar protocol was also successfully extended to the arylation of benzoic acids (Scheme 156).212 A range of benzoic acids

were ortho-arylated in the presence of Pd(OAc)2 and AgOAc. Acetic acid was used as the solvent instead of TFA. Mechanistic studies

supported that a Pd(II)/Pd(IV) mechanism was operative.

OH

O 5 mol% Pd(OAc)21.3 equivalents AgOAc

AcOH, 100−130 °C, 4.5−7 hX

OH

O

X

Ar

+ ArI3 equivalents

X = Me, OMe, OPri, Br, alkenyl 53−69% yield

Scheme 156 Pd-catalyzed carboxyl-directed arylation with aryl iodides (Daugulis et al., 2007).

Remarkably, Lipshutz described the room temperature arylation of anilides with aryl iodides, using urea as the directing group

(Scheme 157).217 A range of aryl ureas were arylated with various aryl iodides. The reactions were conducted in water, and the use

of HBF4 and the surfactants was crucial for the novel reactivity. The surfactant Brij proved to give the best yield.

HN

X

NH

X

Ar+

O

NMe2

O

NMe2

10 mol% Pd(OAc)22 equivalents AgOAc

5 equivalents HBF42 wt% Brij35/water, r.t., 20 h2 equivalents

Brij35: a surfactant

ArI

X = OMe, OBn, alkyl, H 42−97% yield

Scheme 157 Pd-catalyzed urea-directed arylation with aryl iodides (Lipshutz et al., 2010).

Interestingly, the cyano group also proved to be an effective directing group in the arylation of aryl nitriles (Scheme 158).218

Ag2O was found to give good yields, whereas a trace amount of products were formed in the presence of AgOAc, which was used

in the other similar arylation reactions with aryl iodides.

CN 10 mol% Pd(OAc)2

1.0 equivalent Ag2O

TFA, 110 °C, 9 h

CX

Ar

+ ArI2 equivalents

N

X

X = p-Me, OMe, Cl or m-Me 50−91% yield

Scheme 158 Pd-catalyzed cyano-directed arylation with aryl iodides (Sun et al., 2011).







The purine219 and N-methoxyamide groups220 were also successfully employed to assist the C–H arylation of the corre-

sponding arenes with aryl iodides. The reactions were conducted under the conditions similar to those for the other arylation

reactions.

Although aryl iodides were the most common arylation reagents in the Pd-catalyzed arylation of C–H bonds, Sanford and

Daugulis independently developed a general approach using iodine(III) reagent [Ph2I]BF4 and [Ph2I]PF6 for C–H arylation

(Scheme 159).221 In Sanford’s reactions, 2-phenylpyridines were arylated by using catalyst IMesPd(OAc)2 in the presence of AcOH

and Ac2O. In addition to pyridine, diverse heterocycles, including quinolines, pyrrolidinones, and oxazolidinones, were effective

directing groups, and a wide variety of functionalities were well tolerated. Intriguingly, the benzylic C–H bonds were also arylated

under the reaction conditions. Preliminary mechanistic experiments provided evidence in support of a Pd(II)/(IV) catalytic cycle

for this reaction. In Daugulis’ method, N-p-tolylpivalamide underwent arylation reaction with [Ph2I]PF6 in the presence of catalyst

Pd(OAc)2 and solvent AcOH.

NPh I Ph

BF4–


AcOH/Ac2OBenzene or toluene

100 °C, 8−24 h1.1−2.5 equivalents

N

PhX X

Ph I Ph

BF4–


AcOH/Ac2OBenzene or toluene

100 °C, 8−24 h1.1−2.5 equivalents

N N

Ph

Note: Arylation reagent [Mes-I-Ar]BF4 is also reactiveX = Me, Ac, CHO, etc. 51−91% yield

72%

Scheme 159 Pd-catalyzed pyridine-directed arylation with [Ph2I]BF4 (Sanford et al., 2005).

An analogous iodine(III) reagent Ph2IþOTf� was employed for the arylation of phenol esters by Liu and coworkers

(Scheme 160).222 The use of HOTf was required to achieve the high yields, and Ac2O was added so that the reaction would not be

sensitive to moisture. It is noted that the first cyclopalladation complex formed from a simple phenol ester was characterized by

X-ray crystallography.

O O

R

X Ar I Ar

TfO–

+

10 mol% Pd(OAc)210 mol% HOTf

0.5 equivalent Ac2ODCE, 25 °C, 3 h1.2 equivalents

O O

R

X

Ar

R = alkyl, aryl, NMe2X = alkyl, OMe, halo, alkenyl, Ph, NO2, CF3, etc.

24−96% yield

Scheme 160 Pd-catalyzed ester-directed arylation with Ph2IþOTf- (Liu et al., 2010).

Intriguingly, Yu and coworkers reported a simple method for the alkylation of benzoic acids (Scheme 161).223 A range of

benzoic acids underwent ortho-C–H alkylation reaction with ClCH2CH2Cl and CH2Br2 in the presence of Pd(OAc)2 and bases.

The subsequent cyclization afforded five- or six-membered benzolactones. Remarkably, the reactions avoided the use of expensive

Agþ salt, which is required in the arylation reactions with aryl iodides. 2-Chloroethyl or bromomethyl benzoate did not form the

corresponding benzolactones under the same conditions. This fact provided evidence that the reaction was initiated by C–H

activation instead of Friedel–Crafts-type reactions. Either a Pd(II)/Pd(IV) mechanism or direct s-bond metathesis between the

aryl–Pd bond and the alkyl halide was proposed to account for the transformation.

3.23.3.1.3 Pd-catalyzed arylation of C(sp3)-H bonds with aryl (pseudo)halidesIn 2006, Hu and coworkers reported the intramolecular arylation of benzylic C–H bonds (Scheme 162).224 In this work, the

Pd(0)/Pd(II) chemistry was elegantly combined with a Kumada coupling reaction to enable the arylation of C(sp3)-H bonds with

aryl halides. Therefore, by using catalyst Pd2(dba)3/But3P, 1,2-dihalobenzenes first reacted with 2,6-dimethylphenylmagenisium

bromides to form the intermediate biaryls. The use of hindered Grignard reagents was crucial to suppress a second cross-coupling

reaction. The oxidative addition of the remaining C–Cl bond to Pd(0) generated another Pd(II) species, which cleaved the

benzylic C–H bonds to form a palladacycle complex. The subsequent reductive elimination yielded substituted fluorenes as the

final products.



OH

O10 mol% Pd(OAc)2

Base

115−140 °C, 36 hX

O

O

X+ ClCH2CH2Cl

OH

O10 mol% Pd(OAc)2

Base

115−140 °C, 36 hX X+ CH2Br2 O

O

X = H, Me, OMe, COPh, CF3 42−81% yield

X = H, Me, OMe, COPh, CF3, halo, CO2Me, alkenyl 47−92% yield

Scheme 161 Pd-catalyzed alkylation of benzoic acids with alkyl halides (Yu et al., 2009).

X1

X2

Y BrMgZ

Y Z

1.5 mol% Pd2(dba)36 mol% But

3P

THF, r.t., 20 h+

X1 = Br, Cl; X2 = Br, I 2.5 equivalentsY = H, Me, OMe; Z = H, mono- or tri-Me

2−99% yield

Scheme 162 Pd-catalyzed intramolecular arylation of benzylic C–H bonds (Hu et al., 2006).


Another intramolecular arylation of benzylic C–H bonds was described by Knochel and coworkers (Scheme 163).225 The C–H

bond of the methyl group at position 2 of a pyrrole ring was cleaved. This reaction provided an efficient route to construct tricyclic

heterocycles. Alkenylbromides were also reactive under the reaction conditions.

X

N NY

Y5 mol% Pd(OAc)210 mol% p-Tol3P

1.2 equivalents Cs2CO3

Toluene, 110 °C, 12 hX = Br, I

N

O

Y

O

N

Br

( )n

n = 1, 2, 3

N

O

( )n

N

O

Y

Br

Y = CO2Et, CN, NO2, CF3

33−83% yield

Y = H, OMe 75−81% yield 74−85% yield

Scheme 163 Pd-catalyzed intramolecular arylation of benzylic C–H bonds (Knochel et al., 2006).

The intramolecular arylation of unactivated C(sp3)-H bonds was also achieved by Fagnou and coworkers (Scheme 164).226

Thus, in the presence of Pd(OAc)2, PCy3–HBF4, ButCO2H and Cs2CO3, alkyl bromides and chlorides were alkylated via intra-

molecular C(sp3)-H bond activation, leading to the formation of 2,2-dialkyldihydrobenzofurans. A variety of functional groups

were well tolerated. However, the substrate scope was still limited to compounds without hydrogen atoms at the position a to the

reactive methyl groups.

Br

O

Me

R1

R2 O R1

R2

3 mol% Pd(OAc)26 mol% PCy3-HBF430 mol% ButCO2H

1.1 equivalents Cs2CO3mesitylene, 135 °C, 10−15 h

X X

R1 = alkyl;R2 = alkyl, CF3, benzylX = H, Me,OMe, alkenyl, F, CN, NO2

57−97% yield

Scheme 164 Pd-catalyzed intramolecular arylation of C(sp3)-H bonds (Fagnou et al., 2007).

Subsequently, Baudoin (Scheme 165)227 and Ohno (Scheme 166)228 reported the analogous intramolecular arylation under

similar conditions. It is noted that a four-membered ring was formed in Baudoin’s reactions.





Me

Br

R1 R2R1

R2

X X

10 mol% Pd(OAc)220 mol% But

3P-HBF4

1.4 equivalents K2CO3DMF, 140 °C, 45−90 min

R1 = Me, CO2Me; R2 = alkyl, ester, CN, CH2OSi(Pri)3, CH2N(Me)TsX = H, Me, OMe, CO2Me, F, Cl, CF3, OTr, NHNs, etc.

44−92% yield

Scheme 165 Pd-catalyzed intramolecular arylation of C(sp3)-H bonds (Baudoin et al., 2008).

Br

NR1

R2 N R1

R2

3 mol% Pd(OAc)26 mol% PCy3-HBF430 mol% ButCO2H

1.4 equivalents Cs2CO3Xylene, 140 °C, 1−4 h

X X

R1, R2, R3 = H, alkyl

MeO2C

R3

R3

CO2Me

X = Me, F, CO2Me, CF3, NO222−100% yield

Scheme 166 Pd-catalyzed intramolecular arylation of C(sp3)-H bonds (Ohno and Fujii et al., 2008).


Pd-catalyzed intermolecular arylation of C(sp3)-H bonds have also been realized. In 2008, Fagnou reported benzylic C–H

arylation with aryl chlorides and bromides (Scheme 167).229 Therefore, the 2-methyl groups of pyridine N-oxides were arylated

using catalyst Pd2dba3/X-Phos and base NaOBut. The azine and diazine N-oxides were also reactive under the reaction conditions.

It is noted that the secondary C(sp3)-H bonds were also compatible in the reactions, forming the corresponding arylated products,

albeit in lower yields. Interestingly, the a-C(sp2)-H bonds can be arylated site-selectively when the reactions were carried out under

different conditions.

N

O

2.5 mol% Pd2dba35 mol% X-Phos

3 equivalents NaOBut

Toluene, 110 °C, 45 min

+

R = H, alkyl, arylY = Me, CN, alkenyl, etc.

Y

N

O

YAr

X = Cl, BrR

1.5 equivalents

R

ArX

51−98% yield

Scheme 167 Pd-catalyzed arylation of benzylic C–H bonds of pyridine N-oxides with aryl chlorides/bromides (Fagnou et al., 2008).

Charette and coworkers described an analogous benzylic C–H arylation of 2-alkyl substituted N-iminopyridinium ylides with

various aryl chlorides (Scheme 168).230 2-ethyl pyridinium ylides were also reactive and underwent arylation at the benzylic

position in good yields. Furthermore, the diarylated products may be obtained when 2.2 equivalents of chlorobenzene was added.

N

BzN

N

BzN

X5 mol% Pd(OAc)2

12 mol% DavePHOS

3 equivalents Cs2CO3DMF, 70 °C, 16 h

+

1.1 equivalents

R R

R = H, Me

ArCl

X = H, Me, OMe, CO2Me, NHBoc, Bz, F, CF3

43−94% yield

Scheme 168 Pd-catalyzed arylation of benzylic C–H bonds of 2-substituted N-iminopyridinium ylides with aryl chlorides (Charette et al., 2008).

The arylation of 2-methyl group of unprotected pyridines was disclosed by Morris and coworkers (Scheme 169).231 A variety of

(pseudo)halides, including iodides, bromides and triflates, were found to effectively arylate the methyl groups of pyridines and

their analogs. However, chlorobenzene did not yield any desired product. A wide range of functional groups of aryl halides were

well tolerated.

Remarkably, Yu and coworkers realized the intermolecular arylation of unactivated C(sp3)-H bonds by employing a highly

acidic amide group as the directing group (Scheme 170).232 Thus, the a-methyl groups of N-pentafluorophenyl amides were

arylated with aryl iodides in the presence of Pd(OAc)2, Buchwald’s cyclohexyl JohnPhos ligand, and CsF. It is noted that a wide

range of substrates with one a-hydrogen were compatible in the reactions. The directing group can be removed readily and

transformed into carboxylic acids. Therefore, this reaction provides a simple method for b-arylation of carboxylic acids.





N

2.5 mol% Pd(dba-3,5,3′,5′-OMe)22.5 mol% Xantphos

2 equivalents Cs2CO3dioxane, 100 °C, 16 h

N NNAr

X = Cl, Br, OTf

+ ArX

35−92% yield

Scheme 169 Pd-catalyzed benzylic arylation of 2-methyl azaarenes (Morris et al., 2010).

NHC6F5

O

+


3 equivalents CsFMS (3 Å), N2

Toluene, 100 °C, 24 hR1 = H, Me;R2 = H, alkyl, aryl

Me

R1

R2 NHC6F5

O

R1

R2

Ar3 equivalentsPCy2

.HBF4

Ligand:

ArI

30−84% yield

Scheme 170 Pd-catalyzed acidic amide-directed arylation of C(sp3)-H bonds with aryl iodides (Yu et al., 2009).


All of the above arylation reactions of C(sp3)-H bonds were proposed to proceed via Pd(0)/Pd(II) mechanisms. The Pd(II)/

Pd(IV) catalysis also proved viable to arylate C(sp3)-H bonds. By using a well-designed bidentate directing group, Daugulis and

coworkers successfully achieved the arylation of simple alkanes (Scheme 171).233 Thus, in the presence of Pd(OAc)2 and AgOAc,

carboxylic amides possessing a directing aminoquinoline group were b-arylated with aryl iodides regioselectively. The g-arylation

of amine derivatives with 2-picolinic acid as an auxiliary also took place effectively under the similar conditions. Subsequently, the

protocol was successfully extended to the b-arylation of amino acids.234

N

NHO

R

+

0.1−5 mol% Pd(OAc)21.1−4.1 equivalents AgOAc

70−130 °C, 5 min−16 h4−6 equivalents

N

NHO

R

Ar

R = H, alkyl, aryl

N

NH

O

R

+

5 mol% Pd(OAc)21.1 equivalents AgOAc

130−150 °C, 1−12 h4 equivalents

N

NH

O

R

Ar

ArX

ArX

60−92% yield

54−81% yield

Scheme 171 Pd-catalyzed bidentate directing group-assisted arylation of C(sp3)-H bonds with aryl iodides (Daugulis et al., 2005).

Yu and coworkers described the b-arylation of simple aliphatic acids with aryl iodides, which was the first example of Pd-

insertion into b C(sp3)-H bonds in simple aliphatic acids (Scheme 172).235 The reactions formed a mixture of mono- and

diarylated products, and only the acids without a-hydrogens were compatible.

OH

O

R

Me Me+ ArI


1 equivalent K2HPO4

2 equivalents NaOAcButOH, 130 °C, 3 h

OH

O

R

MeAr

OH

O

R

ArAr

+

R = Alkyl, (CH2)3OBn,(CH2)2CO2Me 42−72% Total yield

(mono-/di- ≥ 5/2)

Scheme 172 Pd-catalyzed carboxyl-directed arylation of C(sp3)-H bonds with aryl iodides (Yu et al., 2007).






3.23.3.2 Rhodium-Catalyzed Reactions with (Pseudo)halides

Rh-enabled reactions of C–H bonds with halides have also been exploited, and a variety of arylation reactions have been reported,

albeit a fewer number of examples in comparison with those catalyzed by palladium.16,71

3.23.3.2.1 Rhodium-catalyzed nondirected reactions with (pseudo)halidesIn 2007, Kempe and coworkers disclosed the Rh(I)-catalyzed direct arylation of benzene by employing a novel bimetallic rhodium

complex derived from [{Rh(COD)Cl}2] and a P, N-ligand (Scheme 173).236 The bimetallic complex was necessary for catalysis

and was found to catalyze the arylation of benzene efficiently. In addition to aryl iodides, aryl bromides, and chlorides were found

to be effective arylation reagents, and a diversity of functional groups of aryl halides was well tolerated. The mechanism involved

in the reactions and superior catalytic activity of the bimetallic catalyst remained to be clarified.

+ ArX

5 mol%[{Rh(COD)Cl}2]10 mol% ligand

3.3 equivalents KOBut

70 °C, 24 h

ArN

N P

N

Ligand

X = Cl, Br, I 46−96% yield

Scheme 173 Rh-catalyzed arylation of benzene (Kempe et al., 2007).

A variety of heteroarenes have been found to undergo Rh-catalyzed arylation reactions with aryl halides. One of the repre-

sentative examples is the arylation of azoles with aryl iodides described by Bergman and Ellman in 2004 (Scheme 174).237

Therefore, a wide range of azoles and their analogs, including benzimidazole, benzoxazole, 3,4-dihydroquinazoline, and

oxazolines, were arylated in the presence of [Rh(coe)2Cl]2, PCy3, and Et3N. The arylation occurred at the 2-positions of the azoles

selectively. In addition to the desired arylated products, a large amount of benzene was formed because of the hydrodehalogenation

of PhI. Based on the mechanistic studies, the reactions were believed to proceed via key rhodium-N-heterocyclic-carbene (NHC)

intermediates. Therefore, the carbene complex was formed via a C–H activation/tautomerizaion process. The low-valent Rh complex

underwent oxidative addition of aryl iodides to generate the (aryl)(carbene)rhodium complex. The subsequent HBr elimination

from the complex and reductive elimination furnished the final arylated products and regenerated the Rh catalyst (Figure 15).237

X

N+ ArI

5 mol% [Rh(coe)2Cl]240 mol% PCy3

4 equivalents Et3NTHF, 150 °C, 6 h

X

NAr

X = NH, NMe, O 30−79% yield

Scheme 174 Rh-catalyzed C2-arylation of azoles with aryl iodides (Bergman and Ellman et al., 2004).

X

N

X

HN

Rh Cl

PCy3

PCy3

X

HN

Rh I

Ar

ClPCy3

X

HN

Rh Cl

ArPCy3

PCy3

ArIPCy3

X

NAr

+ I−

RhCy3P

ClCy3P

+ HI

PCy3

Rhcoe

coe

Cl

ClRh

coe

coe

Figure 15 Proposed mechanism of Rh-catalyzed C2-arylation of azoles.





Inspired by this initial discovery, Bergman and Ellman continued their efforts to optimize the original procedure for the

arylation of heterocycles with aryl halides. After gaining a deeper understanding of the reaction mechanism, the authors improved

the procedure to successfully overcome the shortcomings of the initial methodology. By using a more hindered amine base, a

bulky bicyclic trialkylphosphine ligand, and microwave irradiation, the substrate scope was expanded to include a broader range

of heterocycles and aryl bromides.238,239

Subsequently, Bergman and Ellman disclosed Rh-catalyzed direct arylation of pyridines and quinolines (Scheme 175).240

Thus, pyridines and quinolines underwent 2-arylation with a diversity of aryl bromides in the presence of [RhCl(CO)2]2 and Et3N.

Interestingly, a phosphine ligand, which was required in the arylation reactions of other heterocycles, was found to suppress the

catalytic activity. Although no mechanism was provided for these arylation reactions, Itami and Bouffard proposed that the

reactions were likely to share a common mechanism, which involves the formation of a Rh(I)-NHC complex, with the above

heterocycle arylation processes.16

N

X + ArBr

5 mol% [RhCl(CO)2]24 equivalents Et3N

Dioxane, 190 °C, 24 h

6 equivalents

N

X

ArN N ArX = Alkyl


Scheme 175 Rh-catalyzed C2-arylation of pyridines and quinolines with aryl bromides (Bergman and Ellman et al., 2008).

Although the above Rh(I)-catalyzed arylation reactions proceeded through NHC mechanisms, the arylation of electron-rich

heteroarenes were realized by using electron-deficient Rh(III) complexes. One of the representative examples is the 2-arylation of

free (NH)-indoles and pyrroles with aryl iodides reported by Sames and coworkers (Scheme 176).241 Notably, the C-arylation

occurred selectively even in the presence of the acidic NH bonds. The proposed mechanism involved a Rh(I)/Rh(III) catalytic

cycle, which is analogous to the Pd(0)/Pd(II) mechanism for Pd-catalyzed arylation of C–H bonds with (pseudo)halides.

Therefore, the catalytically active Rh(III) was generated through the oxidative addition of aryl iodides to the Rh(I) precatalyst. The

formed Rh(III) complex then participated in the electrophilic metalation to insert the C–H bonds. The subsequent reductive

elimination generated the coupling products and released Rh(I) species (Figure 16).241 The electrophilicity of Rh(III) was

augmented by using a electron-deficient phosphine ligand. Furthermore, the pivalate ligand from CsOPiv was also crucial for the

remarkable reactivity. The use of the phosphine and pivalate ligand accounted for the novel selective C-arylation.

NH

Y

X

+ ArI

2.5 mol% [Rh(coe)2Cl]215 mol% [p-(CF3)-C6H4]3P

1.4 equivalents CsOPivDioxane, 120 °C, 18−56 h

NH

Y

X

Ar

Y = CH, NX = H, NHPiv, NHBoc, NHTosyl, etc.

1.2 equivalents

59−82% yield

Scheme 176 Rh-catalyzed arylation of indoles and pyrroles with aryl iodides (Sames et al., 2005).

Ar–Rh(III)–INH

Ar–I

Oxidativeaddition

C−Hactivation


Rh(III) Ar

NH

NH

ArRh(I)

Figure 16 Proposed mechanism of Rh-catalyzed arylation of indoles and pyrroles with aryl iodides.

Itami and coworkers developed a general protocol for the arylation of a variety of heterocycles (Scheme 177).242 In this

reaction, a rhodium complex bearing a strongly p-accepting ligand, P[OCH(CF3)2]3, was developed. Therefore, in the presence of

Rh(CO)Cl{P[OCH(CF3)2]3}2 and Ag2CO3, a diverse variety of electron-rich heteocycles, including furans, thiophenes, pyrroles,




+ ArI

3 mol% Rh(CO)Cl{P[OCH(CF3)2]3}21 equivalent Ag2CO3

m-xylene, 150−200 °C,0.5 h (microwave)

Yor

OMe

X

Yor

OMe

X ArAr

Y = O, S, NRX = OMe, Me, Et, Ph, alkenyl

S Ar

73–94%

OMe

S ArEt S ArS

O Ar

Me

Me N

Ar

PhNMe

Ar

(C2/C3 = 57/23)

OMe

Ar

(ortho/para = 71/29)

1.5 equivalents50−94% yield 51%

(Ar=p-NO2C6H4)

50−79% 64% 64−66% 58%

Scheme 177 Rh-catalyzed arylation of (hetero)arenes with aryl iodides (Itami et al., 2006).


and indoles, underwent arylation reaction with (hetero)aryl iodides. Although the reactions took place at 2-positions selectively

for furans and thiophenes, the 3-arylated product was produced for 1-phenylpyrrole and the arylation of 1-methylindole resulted

in a mixture of regioisomers. This protocol also proved applicable to the arylation of simple arenes. A mixture of ortho- and para-

isomers was yielded for anisole in a ratio of 29:71, which was consistent with an electrophilic metalation manifold. A similar

Rh(I)/Rh(III) mechanism was also proposed to be operative in the reaction.

3.23.3.2.2 Rhodium-catalyzed-directed reactions with (pseudo)halidesThe Rh-catalyzed arylation relying on a directing group has also been reported. Earlier than the direct arylation of heteroarenes,

Bedford and coworkers described that phenols were ortho-arylated with aryl halides in the presence of Wilkinson’s catalyst

(RhCl(PPh3)3) and a catalytic amount of an aryl dialkylphosphinite as cocatalyst (Scheme 178).243 The phosphinite, which was

transferred to the phenols by transesterification, functioned as the actual directing group. The presence of one ortho-substituent on

the reactive phenols was required to enable the arylation reaction, and bulkier substituents gave higher yields. Bromoarenes with

electron-withdrawing or donating groups were reactive, whereas chloroarenes gave much lower yields. The proposed mechanism

was similar to those for the above Rh(III)-catalyzed arylation of electron-rich heterocycles.

OH

R5 mol% [RhCl(PPh3)3]

5 mol% co-catalyst

1.7 equivalents Cs2CO3Toluene, N2, 130 °C, 48 h

+ ArX

1.5 equivalents

OP(Pri)2

R

Co-catalystOH

R Ar

X = Cl, Br

R = Me, Et, Pri, But15−100% yield

Scheme 178 Rh-catalyzed ortho-arylation of phenols with aryl chlorides/bromides (Bedford et al., 2003).

A major drawback of the above catalytic system is that an aryl diisopropylphosphinite cocatalyst has to be prepared. To avoid

the formation of by-products derived from the cocatalyst, the aryl group of the cocatalyst should match the phenolic substrates. To

circumvent this drawback, Bedford and coworkers developed a new catalytic system chlorodialkylphosphines/[Rh(cod)Cl]2,

which gave the identical results to RhCl(PPh3)3/ArOPPri2.244 Furthermore, Oi and coworkers independently disclosed an ana-

logous rhodium-catalyzed ortho-arylation of phenols with aryl bromides by using hexamethylphosphotriamide (HMPT) as the

phosphinyl group transfer agent.245

In 2009, Chang and coworkers reported basic nitrogen-directed arylation (Scheme 179).246 In this procedure, a wide range of

basic nitrogen-containing heteroarenes and imine were found to effectively direct the metalation of arenes in Rh-catalyzed C–H

N N

Ar

+ ArBr

1.5 mol% [Rh2(OAc)4]

3 mol% IMes.HCl

1.5 equivalents ButONaToluene, 80 °C, 2−4 h

1.5 equivalents

N

Ph

Ph

N

Ph

Ph

N

Ph

Ph

N

O

N

Ph Ph

N

Ph

NMe

Ph

Ph RR

56−99% yield

96% 98% 99% 90% 68%

5 mol% PCy3

Scheme 179 Rh-catalyzed-directed arylation of C(sp2)/sp3)-H bonds with aryl bromides (Chang et al., 2009).





arylation. [Rh2(OAc)4] was used as the catalyst, and the simultaneous employment of electron-rich N-heterocyclic carbene and

PCy3 ligands dramatically increased the reactivity of the rhodium catalyst. Diarylated products were formed in the reactions.

Mechanistic studies revealed that the C–H activation occurred by a proton abstraction pathway with the aid of ButONa. The

formed carborhodiums underwent oxidative addition to aryl bromides and reductive elimination, yielding the final arylated

products. Notable, benzylic and vinylic C–H bonds were also arylated under the reaction conditions.

This protocol also proved applicable to the arylation of quinolines (Scheme 180).247 By using the identical catalytic system, a

wide range of quinolines were arylated with aryl bromides at 8-position regioselectively. The formation of a bimetallic Rh species

bound to an NHC ligand was proposed to be the active catalyst species and be responsible for the regioselectivity.

N

X + ArBr

3 mol% [Rh2(OAc)4]6 mol% IMes.HCl

2.5 equivalents ButONaToluene, 90 °C, 24 h

1.5 equivalents N

X

ArX = H, Me, OMe, OPh, OBn,OCH2OMe, OSi(Pri)3, amine, etc.

61−94% yield

5 mol% PCy3

Scheme 180 Rh-catalyzed C8-arylation of quinolines with aryl bromides (Chang et al., 2011).

Interestingly, the similar arylation can be realized by using acid chlorides as coupling partners. In 2008, Yu and coworkers

reported pyridine-directed C–H arylation with benzoic chlorides (Scheme 181).248 Therefore, 2-phenylpyridines and their analogs

were arylated in the presence of [Rh(COD)Cl]2, Na2CO3, and molecular sieves. The proposed mechanism consisted of oxidative

addition of benzoic chlorides to Rh(I), decarbonylation, cyclometalation, and subsequent reductive elimination to form the final

arylated products. Anhydrides have also been used as the arylation reagents to achieve the similar results.249

NX

NX

Ar

+ ArCOCl

5−10 mol% [Rh(COD)Cl]22−3 equivalents Na2CO3

MS (4 Å)Xylene, 145 °C, 16 h

X = H, Me, OMe, etc. 60−76% yield

Scheme 181 Rh-catalyzed pyridine-directed arylation with benzoic chlorides (Yu et al., 2008).

3.23.3.3 Ruthenium-Catalyzed Reactions with (Pseudo)halides

In 2005, Sames and coworkers disclosed Ru3(CO)12-catalyzed 2-phenylation of pyridine with iodobenzene. This novel protocol

set the precedent for the development of new methodologies for direct arylation of p-deficient heteroarenes (Scheme 182).250

Mechanistic studies demonstrated that a bimetallic complex was the catalytically active species.

N+ PhI

2 mol% Ru3(CO)12

4 mol% PPh3

1.2 equivalents Cs2CO3ButOH, 150 °C, 18 h

N Ph36% yield

Scheme 182 Ru-catalyzed C2-phenylation of pyridine with iodobenzene (Sames et al., 2005).

Directed C–H arylation with aryl halides was achieved by Oi, Inoue and coworkers in 2001 (Scheme 183).251 In the presence

of the catalyst [RuCl2(C6H6)]2 and the ligand PPh3, 2-phenylpyridines were ortho-arylated with a broad range of aryl bromides

with the aid of K2CO3. A mixture of mono- and diarylated products was produced for 2-phenylpyridine without any substituents,

whereas the substrates with substituents on either phenyl or pyridyl group gave the sole monoarylated products. Alkenylation also

proceeded effectively under the reaction conditions by using alkenyl bromides. In addition, other (pseudo)halides, including

iodobenzene, chlorobenzene, and phenyltriflate, were also found to be reactive, albeit in lower efficiency. The proposed

mechanism involved a Ru(II)/Ru(IV) catalytic cycle. A Ru(IV) species was suggested to be the key intermediate, which was

generated by the oxidative addition of aryl bromides to the Ru(II) complex. The Ru(IV) complex cleaved the C–H bonds of

2-phenylpyridines electrophilically with the aid of the chelation of the pyridyl group, to form ruthenocycles. The subsequent

reductive elimination afforded the final arylated products (Figure 17).251




N + ArX

2.5 mol% [RuCl2(C6H6)]210 mol% PPh3

2 equivalents K2CO3NMP, N2, 120 °C, 20 h

1 equivalentAr = arylor alkenyl

YN

Y

Ar

and/or NY

Ar

Ar

X = Cl, Br, I, OTf; Y = H, Me, CF3, alkenyl32−95% yield 0−18% yield

Scheme 183 Ru-catalyzed pyridine-directed arylation/alkenylation of arenes (Oi and Inoue et al., 2001).

Ar–Ru(IV)–Br

Ar–Br

Oxidativeaddition

N

N

Ru(IV)

Ar

N

Ar

N

Ru(IV)

BrH

Ar

Ru(II)

HBr

Figure 17 Proposed mechanism of Ru-catalyzed pyridine-directed arylation/alkenylation of arenes.


The Oi and Inoue also demonstrated that the protocol may be applicable to the directed arylation of a wide range of

substituted arenes, which include aromatic imines,252 imidazolines, oxazolines,253,254 and azoles.255 Interestingly, this protocol

was also extended to purine- and deoxyribonucleoside-directed arylation by Lakshman and coworkers.256

Furthermore, the arylation of vinylic C–H bonds also proved viable under the identical reactions (Scheme 184).257 Thus, 2-

alkenylpyridines underwent arylation with aryl bromides, affording b-arylated (Z)-2-alkenylpyridines in a regio- and stereo-

selective manner. It is noteworthy that the aryl moiety was introduced cis to the pyridyl group. This geometrical selectivity is in

sharp contrast to the Mizoroki–Heck reaction. Mechanistically, four possible pathways were proposed, and Ru(0), Ru(II) or

Ru(IV) catalyst might be responsible for the C–H cleavage.

NR1

R2Ar

NR1

R2H

R1 = H, alkyl, 2-Me-C6H4R2 = H, alkyl

2.5 mol% [RuCl2(C6H6)]210 mol% PPh3

2 equivalents K2CO3

NMP, N2, 120 °C, 20 h

+ ArBr

33−100% yield

Scheme 184 Ru-catalyzed pyridine-directed arylation of alkenes with aryl bromides (Oi and Inoue et al., 2005).

Ackermann developed another Ru-catalyzed arylation protocol (Scheme 185).258 This protocol relied on the use of a sterically

hindered adamantly-substituted phosphine oxide as the preligand, which allowed for diarylation of aryl pyridines and mono-

arylation of aryl imines with diversely substituted aryl chlorides. A wide range of functional groups were well tolerated.

By using an analogous bulky phosphine oxide preligand, Ackermann and coworkers successfully achieved Ru-catalyzed C–H

arylation with aryl tosylates (Scheme 186).259 Under the similar conditions, arenes with different directing groups, including

oxazoline, pyridine, and pyrazole, underwent arylation reaction with a wide range of aryl tosylates to afford monoarylated

products. It is noted that aryl chlorides were also reactive to give diarylated products predominantly. Hence, this protocol allowed

for selective arylation through the judicious choice of arylation reagents. Interestingly, the catalytic system enabled direct arylation

with phenols in the presence of sulfonyl chloride.260

The high catalytic efficacy of phosphine oxide preligands inspired Ackermann and coworkers to conjecture that an assisted

intramolecular proton abstraction mechanism might be operative in the above Ru-catalyzed arylation reactions (Scheme 187).261

Based on this conjecture, the authors envisioned that the similar reactivities should be accessible through the use of sub-

stoichiometric amounts of carboxylates, which may enable C–H activation via a concerted cyclometalation-deprotonation




N

+ Ar2Cl

2.5 mol% [RuCl2(p-cymene)]210 mol% (1-Ad)2PHO

2−3 equivalents K2CO3NMP, 120 °C, 5 h

N

Ar2

Ar2

2−3 equivalentsNAr1

Me

R

O

Me

R Ar2

(After treatmentwith 1 N HCl)

or or81−95% yield

R = H, Me, OMe 54−79% yield

Scheme 185 Ru-catalyzed-directed arylation of arenes with aryl chlorides (Ackermann, 2005).

+ ArOTs

2.5 mol% [RuCl2(p-cymene)]210 mol% ligand

1.5 equivalents K2CO3

NMP, 120 °C, 23 h1.2 equivalentsAr

N

O

N

OMe Me

NP

N

H OPri PriLigand

NN

N

Ar Ar

Pri Pri50−96% yield

54% yield(Ar = C6H4COPh)

55−57% yield(Ar = C6H4COMe, C6H4CO2Me)

Scheme 186 Ru-catalyzed-directed arylation of arenes with aryl tosylates (Ackermann et al., 2006).

DG+ ArX

2.5 mol% [RuCl2(p-cymene)]230 mol% MesCO3

2.0 equivalents K2CO3Toluene, 120 °C, 16−20 h

1.5 equivalents

DG

Ar

Me Me

DG:

NN

NN

NN

N

O

X = Cl, Br, OTs

51−99% yield

Scheme 187 Ru-catalyzed-directed arylation of arenes (Ackermann et al., 2008).


process. Gratingly, by replacing the phosphine oxide with MesCO2H, the similar arylation proceeded effectively in toluene. This

reaction displayed a broad substrate scope and allowed for efficient-directed arylations of 1,2,3-triazoles, pyridines, pyrazoles, or

oxazolines. Aryl bromides, chlorides and tosylates were compatible under the reaction conditions.

Interestingly, ruthenium(IV) carbene complexes have also been found to enable direct arylation with aryl (pseudo)halides

(Scheme 188).262 Therefore, the use of precatalyst [Ru¼CHCl2(PCy3)2] allowed for the pyridine-directed arylation of arenes and

alkenes with a wide range of aryl chlorides in the presence of K2CO3. Pyrazole and oxazoline also functioned as directing groups

effectively.

N

H

+ ArCl

5 mol% [Ru=CHCl2(PCy3)2]2 equivalents K2CO3

NMP, 120 °C, 22 h1.2−2 equivalents

N

Ar48−92% yield

Scheme 188 Ru-catalyzed pyridine-directed arylation of arenes with aryl chlorides (Ackermann et al., 2007).






3.23.3.4 Other Transition-Metal-Catalyzed Reactions with (Pseudo)halides

3.23.3.4.1 Copper-catalyzed reactions with (pseudo)halidesCopper was the first transition metal to promote C–H bond arylation. As early as 1941, substantial amounts of trithienyl was

observed in the Ullmann reaction of 2-iodothiophene, which was generated via C–H bond arylation.263 Although underexploited

in comparison with those catalyzed by palladium, quite a number of copper-promoted C–H arylation reactions have been

reported, especially in the past 5 years.

In 2007, Daugulis reported CuI-catalyzed arylation of heteroarenes with aryl iodides with the assistance of LiOBut

(Scheme 189).264 A variety of heteroarenes with acidic C–H bonds, including imidazole, thiazole, and pyridine N-oxide, were

reactive. Mechanistic studies suggested that the heterocycles were first deprotonated by LiOBut, which may be assisted by copper

precoordination to the heterocycle. The subsequent lithium–copper transmetalation formed the organocopper species, which

reacted with aryl iodide to afford the final arylation products. For less acidic imidazole, 1,2,4-triazole, and caffeine derivatives, the

use of a stronger base KOBut is required. It is noteworthy that a copper-assisted benzyne-type mechanism was believed to be

operative for the strong base-promoted arylation.

O

N

O

NAr+ ArI

10 mol% CuI2 equivalents LiOBut

DMF, 140 °C, 10 min3 equivalents

O

NPh

S

NPh

NMe

NPh

N

NMe

NPh

N

O

PhPh

KOBut KOBut

55−91% yield

59% 59% 57% 89% 66%

Ph

Scheme 189 Cu-catalyzed arylation of heteroarenes with aryl iodides (Daugulis et al., 2007).

Daugulis and coworkers optimized the protocol by employing the ligand 1,10-phenanthroline. The optimized reaction con-

ditions allowed for the arylation of a broader range of heteroarenes, including the less acidic ones that were not reactive under the

initial conditions (Scheme 190).265 For comparatively acidic heterocycles with DMSO pKas below 27, K3PO4 was basic enough to

promote the arylation reactions. If the substrates were less acidic (pKa 27–35), a stronger lithium alkoxide base ButOLi or Et3COLi

may be employed. The unnecessity of ButOK shut down the benzyne mechanism, ensuring arylation regioselectivity. Furthermore,

the use of hindered base Et3COLi may suppress the nucleophilic substitution of aryl iodide by alkoxide.

+ ArI

10 mol% CuI10 mol% 1,10-phenanthroline

base

DMF or DMPU100−125 °C, 5−12 h

NMe

NPh

S

N N

NMe

NPh

N

O

Ph

LiOBut

N

K3PO4, ArBr used

SPh Ph

NN Ph

Ph

SPh

OPh

Et3COLiEt3COLi

Et3COLi

Et3COLi

Et3COLi LiOBut

NN

N

N

PhPh

Et3COLi Et3COLi

Heterocycle-H Heterocycle-Ar

89% 88% 82%

85%

52%

86% 60%

58%

60% 31%

Scheme 190 Cu-catalyzed arylation of heteroarenes with aryl iodides with the aid of a ligand (Daugulis et al., 2008).

The similar arylation reactions of heteroarenes have also been reported by other groups independently.266,267 The protocol also

proved applicable to the arylation of 1,2,3-triazole268 and benzotriazepines,269 affording 5-arylated products in all cases.

Since the above C–H bond cleavage involved a deprotonation mechanism, it was reasonable to assume that acidic poly-

fluorobenzenes may be arylated in a similar manner. Daugulis and coworkers demonstrated that pentafluorobenzene was arylated

with a wide range of aryl bromides under the similar conditions, with K3PO4 as base (Scheme 191).270 The arylation of other

polyfluorobenzenes with various numbers of fluorines had also been exemplified by using 4-iodotoluene as the coupling partner.

Other electron-deficient arenes with acidic C–H bonds were also arylated efficiently. The reactivity paralleled the acidity of C–H



Fn

+ ArX

10 mol% CuIphenanthroline

2 equivalents K3PO4DMF/xylene, 120−140 °C

1.5 equivalents

Fn

Ar

n = 3, 4, 5 X = Br, I10−95% yield

Scheme 191 Cu-catalyzed arylation of polyfluoroarenes aryl iodides (Daugulis et al., 2008).


bonds, and the most acidic C–H bonds were arylated preferentially. The reactive arenes included polychlorobenzenes, 1, 3-

dinitrobenzene, and 3-nitrobenzonitrile, and the reactions afforded the arylation products in moderate yields. For less acidic

arenes possessing only one electron-withdrawing group, such as nitro-, chloro-, fluoro-, and cyanobenzene, o5% conversion to

products was observed.265

Interestingly, Miuro, Hirano and coworkers reported the allylation of polyfluoroarenes with allyl phosphates following the

similar catalytic system (Scheme 192).271 It is noteworthy that the stereochemical information of the allyl phosphates was

retained in the reaction. The E/Z olefin stereochemistry of the starting material was translated to the product in a highly

stereospecific manner.

Fn

+

10 mol% [Cu(acac)2]

10 mol% 1,10-phenanthroline


1,4-dioxane, r.t., 4 h1.2 equivalents

Fn

n = 3, 4, 5

OP

O

OEt

EtO

R

R

R = alkyl, aryl37−82% yield(E/Z ≥ 97/3)

Scheme 192 Cu-catalyzed allylation of polyfluoroarenes with allyl phosphates (Hirano and Miura et al., 2011).

Although the above Cu(I)-catalyzed arylation protocol takes advantage of acidic C–H bonds to facilitate C–H cleavage, the

Gaunt and coworkers put forward a second concept to realize Cu-promoted C–H arylation. Considering that electrophilic

metalation is one of the major pathways in transition-metal-enabled C–H activation and that Cu(III) should be highly electro-

philic, Gaunt reasoned that Cu(III) could cleave C–H bonds under mild conditions. This hypothesis proved viable in the arylation

of electron-rich indoles (Scheme 193).272 Therefore, both NH- and N-substituted indoles were arylated with diaryl-iodine(III)

reagents in the presence of Cu(OTf)2 and 2,6-di-tert-butylpyridine (dtbpy). It is noted that the regioselectivities were dependent

on the substituents on the nitrogen of indoles. Although N-methyl and 1-H indoles afforded C3-arylated products, the arylation

occurred at 2-position selectively for N-acylindoles.

NR

X 10 mol% Cu(OTf)2dtbpy

DCE, 35 or 70 °C NR

X Ar

or

NR

X

Ar

R = H, Me R = Ac

Pri

Pri

Pri I ArOTf−

+

X = H, OMe, CHO, CO2Me, NO2, Br 38−86% yield 49−83% yield

Scheme 193 Cu-catalyzed site-selective arylation of indoles with diaryl-iodine(III) reagents (Gaunt et al., 2008).

The reaction was proposed to proceed via a Cu(III)-aryl species that underwent electrophilic addition at the C-3 position of the

indole motif. The Cu(III)-aryl species were generated through the oxidation of Cu(I) by diaryl-iodine(III) reagents. The formation

of the C2-arylated products arose through migration of the Cu(III)-aryl group from C3 to C2 (Figure 18).272

Interestingly, when a similar protocol was applied to the arylation of acetanilides, meta-arylated products were observed

(Scheme 194).273 This discovery is remarkable because transition-metal-catalyzed C–H functionalization usually occurs at ortho-

position and classical electrophilic aromatic substitution reactions yield para- and ortho-products predominantly for electron-rich

arenes. The unusual site selectivity was proposed to arise through antioxy-cupration of the carbonyl group of an acetamide across

the 2,3-positions on the arene ring, which placed the Cu(III)-aryl species at the meta position (Figure 19).273

Subsequently, Gaunt and coworkers demonstrated that the protocol was applicable to the arylation of anilines and phenols

(Scheme 195).274 It is noted that the reactions occurred at para-position selectively, which represented the first highly para-

selective arylation of aniline and phenol derivatives. For para-substituted anilines, ortho-arylated products were formed.

3.23.3.4.2 Nickel-catalyzed reactions with (pseudo)halidesIn 2009, Itami and coworkers reported Ni-catalyzed arylation of acidic heteroarenes under conditions similar to those for the Cu-

promoted arylation (Scheme 196).275 A variety of heteroarenes with acidic C–H bonds, such as imidazoles, oxazoles, and




Cu(I)OTf

[Ar–Cu(III)–OTf]OTf

NR

NR

HCu(III)

Ar

OTf

NR

Cu(III)

Ar

OTf

NR

Ar

Base

Base-TfOH

[TRIP–I–Ar]OTf

TRIP–I

Figure 18 Proposed mechanism of Cu-catalyzed site-selective arylation of indoles.

NH

O

CMe3

Y

10 mol% Cu(OTf)2

DCE, 50−70 °C, 24−48 h+ Ph2IX

(X = OTf or BF4)

NH

O

CMe3

X

PhY = H, alkyl, OMe, Ph, halo, CO2Et, SO2Me 11−93% yield

Scheme 194 Cu-catalyzed meta-selective arylation of acetanilides with diaryl-iodine(III) reagents (Gaunt et al., 2009).

NH

O

R

NH

O

R

H

Cu(III)H

Ar

OTf

NH

O

R

Cu(III)Ar

OTf

NH

O

R

Ar

Cu(OTf)2

Ph2IOTf

Figure 19 Proposed mechanism of Cu-catalyzed meta-selective arylation of arenes.

ROX

10 mol% Cu(OTf)2

DCE, 50−70 °C, 22−72 h+ Ar1Ar2IOTf or BF4

ROX

Ar1R = H, Me; X = H, alkyl, alkenyl, OMe, NHPiv

NX 10 mol% Cu(OTf)2

dtbpy

DCE, r.t., −70 °C+ Ar2IOTfR2

R1

NX

R2

R1

Ar

50−95% yield

R1, R2 = H, Bn, 1-phenylethylX = H, alkyl, Cl, Br, NO2, CO2Et 29−77% yield

Scheme 195 Cu-catalyzed para-selective aryltion of aniline and phenol derivatives with diaryl-iodine(III) reagents (Gaunt et al., 2011).


thiazoles were arylated at the most acidic positions in the presence catalyst Ni(OAc)2, ligand 2,20-bipyridyl (bipy) or 4,40-

(But)2bipy, and base LiOBut. Aryl iodide, bromide and chloride were shown to be effective coupling partners. Aryl triflate was also

reactive, albeit in modest yields. A diverse variety of functional groups on the aryl halides were well tolerated. The proposed

mechanism involved Ni(0)/Ni(II) redox catalysis, which included the oxidative addition of aryl (pseudo)halide to Ni(0) (in situ





Y

N+ ArX

10 mol% Ni(OAc)210 mol% bipy or dppf

1.5 equivalents LiOBut, dioxane85 or 140 °C, 36 or 40 h

Y

NAr

Y = O, S, NMeX = Cl,Br, I, OTf

1.5 equivalents41−91% yield

Scheme 196 Ni-catalyzed arylation of heteroarenes (Itami et al., 2009).


generated), metalation of heteroarenes (Het-H) generating Ar-Ni(II)-Het, and reductive elimination affording the coupling

products and regenerating Ni(0) species (Figure 20).275

Ar–Ni(II)–X

Ar–X

Oxidativeaddition


Z

N

Ni(0)

H

Z

NNi(II)–Ar

Z

NAr

MOBut

MXHOBut

Azolenickelation

Figure 20 Proposed mechanism of Ni-catalyzed arylation of heteroarenes.

Concurrently, Miura and coworkers disclosed analogous arylation of heteroarenes independently (Scheme 197).276 The

catalytic system including NiBr2, 1,10-phenanthroline and LiOBut was found to be the most effective for the arylation of

benzothiazoles. However, for benzoxazoles, the reactions gave the highest yields in the presence of NiBr2�diglyme, 2,9-dimethyl-

1,10-phenanthroline, LiOBut and Zn powder.

O

N+ ArBr

10 mol% NiBr2.diglyme12 mol% 2,9-dimethyl-1,10-

phenanthroline

0.5 equivalent Zn powder4 equivalents LiOBut

o-xylene, 150 °C, 4 h

O

NAr

2 equivalents

S

N+ ArBr

10 mol% NiBr212 mol% 1,10-phenanthroline


diglyme, 150 °C, 4−6 hS

NAr

1.2 equivalents44−76% yield

50−83% yield

Scheme 197 Ni-catalyzed arylation of heteroarenes with aryl bromides (Miura et al., 2009).

Interestingly, a similar protocol was developed to enable the alkynylation of azoles with alkynyl bromides by using catalyst

Ni(cod)2 and ligand 1,2-bis(diphenylphosphino)benzene (dppbz) (Scheme 198).277 In some cases, a catalytic amount of CuI

was employed to enhance the reaction yields.

Y

X

N5 mol% Ni(cod)25 mol% dppbz


Toluene, reflux, 1−3 h

Y

X

N

X = O, S, NPh; Y = CH, NR = aryl, 1-cyclohexenyl, n-C6H13, Si(Pri)3

Br R+ R

28−91% yield

Scheme 198 Ni-catalyzed alkynylation of azoles with alkynyl bromides (Miura et al., 2009).

Ni-catalyzed direct C–H arylation of simple arenes using aryl halides was achieved by the Yamakawa and coworkers

(Scheme 199).278 For the first time, the arylation of benzene and naphthalene was successfully catalyzed by Cp2Ni in the presence





+ ArX

5 mol% NiCp25 mol% BEt3

3 equivalents KOBut

80 °C, 12 hX = Cl, Br, IAr

Solvent

+ ArBr

5 mol% NiCp25 mol% PPh3

1 equivalent KOBut

100 °C, 12 hN N

Ar

Solvent

21−76% yield

50−73% yield

Scheme 199 Ni-catalyzed arylation of benzene, naphthalene, and pyridine (Yamakawa et al., 2009).


of KOBut and BEt3. A mixture of 1- and 2-arylated products was produced for naphthalenes. This Ni catalyst system was also

successfully applied to direct C–H arylation of pyridine. PPh3 was found to be superior to BEt3, and a mixture of 2-, 3-, and

4-substituted arylated derivatives was formed.

In 2010, Miura and coworkers described NiBr2�diglyme-catalyzed alkylation of benzothiazole with alkyl bromides

(Scheme 200).193 The reactions were proposed to proceed by a radical mechanism.

S

N+ R−Br

5 mol% NiBr2.diglyme5 mol% terpyridine


Diglyme, 120 °C, 6 hS

NR

25−46% yieldR = alkyl

Scheme 200 Ni-catalyzed alkylation of benzothiazole with alkyl bromides (Miura and Hirano et al., 2010).

3.23.3.4.3 Iron/cobalt/iridium-catalyzed reactions with (pseudo)halidesIn 2010, Lei and coworkers reported Fe-catalyzed direct arylation of benzene with aryl halides (Scheme 201).279 A wide range of

aryl iodides and bromides were effective coupling partners in the presence of FeCl3, DMEDA (N1,N2-dimethylethane-1,2-dia-

mine), and LiHMDS or KOBut. Aryl chlorides were also reactive, albeit in lower yields.

+ ArX

15 mol% FeCl330 mol% DMEDA

2.0 equivalents LiHMDSor KOBut

80 °C, 48 h

Solvent

Ar

X = Cl, Br, I

HMDS = hexamethyldisilazane

34−82% yield

Scheme 201 Fe-catalyzed arylation of benzene (Lei et al., 2010).

Concurrently, an analogous arylation was disclosed by the Charette and coworkers (Scheme 202).280 By using catalyst

Fe(OAc)2 and ligand bathophenanthroline, benzene was arylated with a variety of aryl iodides with the aid of KOBut. The

arylation of substituted arenes also proceeded effectively under the reaction conditions, and a mixture of regioisomers were

produced in the cases that more than one reactive position were available. Mechanistic evidence suggested that the transformation

proceeded through a Fe-catalyzed radical process giving a metal-catalyzed radical living direct arylation.

+ ArI

5 mol% Fe(OAc)210 mol% bathophenanthroline

2 equivalents KOBut

90 °C, 20 hSolvent

X XAr

28−93% yieldX = Me, OMe, TMS

Scheme 202 Fe-catalyzed arylation of simple arenes with aryl iodides (Charette et al., 2010).

In a continuous effort to develop direct coupling reactions, Lei and coworkers demonstrated that Co can act as a similar

catalyst to iron in the direct arylation of simple arenes (Scheme 203).281 By using catalyst [Co(acac)3], benzene was allowed to

react with a wide range of aryl bromides and iodides in the presence of LiHMDS. Remarkably, the chloro substituent was

well tolerated under the reaction conditions. However, the use of a different catalyst system consisting of CoBr2 and DMEDA





+ ArX

15 mol% [Co(acac)3]3.0 equivalents LiHMDS

80 °C, 48 hAr

X = Br, ISolvent

+ ArCl

30 mol% CoBr260 mol% DMEDA

3.0 equivalents LiHMDS80 °C, 48 h

Ar

Solvent

10−94% yield

37−57% yield

HMDS = bis(trimethylsilyl)amide

Scheme 203 Cocatalyzed arylation of benzene (Lei et al., 2011).


(N1,N2-dimethylethane-1,2-diamine) enabled aryl chlorides as reactive coupling partners, albeit in lower yields. Preliminary

mechanistic studies suggested that the reactions operated by a radical mechanism.

Independently, Chan and coworkers reported an analogous arylation of simple arenes (Scheme 204).282 Thus, benzene was

effectively arylated with either aryl bromides or iodides in the presence of Co(t4-OMePP), KOH and ButOH. The arylation of

substituted arenes were also examined with para-iodotoluene. Arenes with methyl or methoxy groups were found to be reactive

under the identical reaction conditions, and a mixture of regioisomers was formed. A radical mechanism was also proposed.

+ ArX5 mol% Co(t4-OMePP)

10 equivalents KOH

10 equivalents ButOH200 °C, N2, dark, 2−6 h

Ar

Solvent

X = Br, I

Y I

+

Y

15−85% yield

Y = mono- or di-Me, OMe20−53% yield

t4-OMePP = tetrakis-4-methoxyphenylporphyrinato dianion

Scheme 204 Cocatalyzed arylation of simple arenes (Chan et al., 2011).

Concurrently, the Nakamura and coworkers disclosed cobalt-catalyzed ortho-alkylation of benzamide with alkyl chloride

(Scheme 205).283 Therefore, secondary benzamides underwent alkylation with a range of alkyl chloride including ButCl using

Co(acac)2, CyMgCl, and DMPU. The Grignard reagent formally acted to remove hydrogen atoms from the amide nitrogen and

from the ortho-position and to generate the active cobalt species.

NH

O

Me

X

10 mol% Co(acac)23 equivalents CyMgCl

12 equivalents DMPUEt2O, r.t., 30 h

+ RClNH

O

Me

XR

X = H, Ph, OMe, alkenyl, etc.R = alkyl, Cy, TMSCH2

15−83% yield

DMPU = 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone

Scheme 205 Co-catalyzed amide-directed alkylation of benzamides with alkyl chlorides (Nakamura et al., 2011).

Iridium has also been utilized to enable the direct arylation of simple arenes. In 2004, the Fujita, Yamaguchi and coworkers

reported [Cp�IrHCl]2-catalyzed arylation of benzene with aryl iodides (Scheme 206).284 The use of KOBut was required, and other

bases were ineffective. The arylation of toluene and anisole with iodobenzene was also demonstrated, affording ortho-, meta- and

para-arylated products. An aryl radical, which was formed via an electron transfer from Cp�Ir(II) species to aryl iodide, was

proposed to react with benzene to give the biaryl products. The Cp�Ir(II) species were generated by the reduction of Cp�Ir(III)

species with base.

The Ir-catalyzed direct arylation of heteroarenes has also been achieved by Itami and coworkers (Scheme 207).285 Therefore, a

variety of electron-rich heteroarenes were arylated with aryl iodides in the presence of [Ir(cod)PCy3]PF6 and Ag2CO3. The

reactions occurred at the a-positions selectively for pyrroles, furans, and thiophenes, whereas 3-arylated products were formed for

indoles. Furthermore, the diarylated thiophene was yielded when the reaction was treated with an excess amount of iodobenzene.

A diversity of functionalities including bromo group were well tolerated. An electrophilic metalation mechanism was proposed to

be responsible for the C–H cleavage.




+ ArI5 or 10 mol% [Cp*IrHCl]2


80 °C, 30 h

Ar

OMe

Ph

Me

Ph

20−72% yield

55% yield(2-/3-/4- = 72:16:12)

16% yield(2-/3-/4- = 58/27/15)

Scheme 206 Ir-catalyzed arylation of simple arenes with aryl iodides (Fujita and Yamaguchi et al., 2004).

Y

X+ ArI

5 mol% [Ir(cod)PCy3]PF61 equivalent Ag2CO3

m-xylene, 160 °C, 18 h Y

X

Ar

SR ArOMe Ar

R

NTs

Ph

N Ar

MeS Ar

SAr Ar

MeO

R = Me, Et, OMe R = Me, SMe

X = H, alkyl, OMe, SMe, Br, alkenylY = O, S, NMe, NTs

31−80% yield

10−87% 31% 54−72%

61% 63% 66%

Scheme 207 Ir-catalyzed aryltion of heteroarene (Itami et al., 2009).


3.23.4 Reactions with Organometallic Reagents

Given that the cross-coupling of aryl (pseudo)halides and organometallic reagents serves as a powerful tool for C–C bond

formation (primarily for aryl–aryl bond formation), the C–H activation version of this reaction, which substitutes a C–H bond for

the C–X bond of the aryl halide, has received considerable interest, and a number of reactions of this type have been reported.

Among the developed reactions, Pd has predominantly been the catalyst of choice. However, other metals, including Rh, Ru, Fe,

Co, and Ni, have also found success in promoting the cross-coupling of C–H bonds with organometallic reagents. Moreover,

while organoboron reagents are the reaction partners in most of the reported Pd-catalyzed reactions, reactions involving other

organometallic reagents, such as organotin, organosilane, and organozinc reagents have also been developed.

3.23.4.1 Palladium-Catalyzed Reactions with Organometallic Reagents

Although Pd(0) species is used as the catalyst in cross-coupling reactions of aryl or alkyl (pseudo)halides with organometallic

reagents, Pd(II) species in C–H activation would cause big troubles in coupling reactions of C–H bonds with organometallic

reagents. Pd(II) tends to react preferentially with organometallic reagents rather than the more inert C–H bonds, which leads to

the homocoupling of organometallic reagents and the precipitation of palladium black.

A typical Pd-catalyzed direct coupling of C–H bonds with organometallic reagents commences with Pd-mediated C–H acti-

vation. Transmetallation with organometallic reagents and subsequent reductive elimination gives coupling products and Pd(0).

Pd(0) needs to be reoxidized to Pd(II) to complete the catalytic cycle (Figure 21).15

3.23.4.1.1 Palladium-catalyzed coupling of C(sp2)-H bonds with organometallic reagentsIn 2006, Yu and coworkers reported Pd-catalyzed coupling of C–H bonds with organometallic reagents (Scheme 208).286 In this

remarkable protocol, aromatic C–H bonds were alkylated with alkyltin reagents by using oxazoline as the directing group. To slow

down the homocoupling of organotin reagents, the organotin reagent was added batchwise. It is noteworthy that benzoquinone

plays crucial roles in these reactions. Benzoquinone may not only be involved in the reoxidation of Pd(0) to Pd(II), but also

promote C–H activation.



Ar1–H

Ar1–Pd(II)

Ar2–M

Ar1–Pd(II)–Ar2

Ar1–Ar2

C-Hactivation


Pd(II)

Pd(0)

Oxidant

Reoxidation

Transmetallation

Figure 21 A general mechanism of Pd-catalyzed coupling of C–H bonds with organometallic reagents.

N

O

R1 R2

N

O

R1 R2

R

5 mol% Pd(OAc)220 x 0.037 equivalent R4Sn

1 equivalent Cu(OAc)21 equivalent BQ

MeCN, 100 °C, 60 h

R1, R2 = alkyl; R = Me, Et, Prn, Bun, Octn60−90% yield

Scheme 208 Pd-catalyzed oxazoline-directed coupling reaction with organotin reagents (Yu et al., 2006).


Although Pd-catalyzed alkylation of C–H bonds with organotin reagents opened an avenue for Pd-catalyzed coupling of C–H

bonds with organometallic reagents, the batchwise addition of organotin reagents and their toxicity diminishes this protocol

practicality. Organoboron reagents are the most widely used coupling partners because of their ready availability, stability, and

functional group tolerance,287 so it is attractive to develop the coupling reactions of C–H bonds with organoboron reagents. Pd-

catalyzed coupling reaction of C–H bonds was also developed by Yu and coworkers (Scheme 209).288 A variety of aromatic rings

can be alkylated with alkylboronic acids or methylboroxine in the presence of pyridine as the directing group, and arylboronic

acids could also be used in spite of poor yields.

NX

10 mol% Pd(OAc)21 equivalent Ag2O

0.5 equivalent BQt-amyl alcohol, 100 °C, 6 h

NX

R

X = H, Me, OMe, alkenyl, CHO, CF3; R = alkyl, aryl R = alkyl, 40−93% yieldR = aryl, 20−30% yield

Methylboroxine (2 equivalents)RB(OH)2 (3 equivalents)

+

Scheme 209 Pd-catalyzed pyridine-directed coupling reaction of pyridylbenzenes with organoboron reagents (Yu et al., 2006).

Pyridine and oxazoline are strong coordinating groups for palladium to insert C–H bonds. However, the substrates with such a

group have limited applications because of the lack of versatility for further synthetic manipulations and the required pre-

installation of oxazolines. Yu and coworkers continued their effort to develop more practical coupling reactions of C–H bonds

with organometallic reagents. They achieved carboxyl-directed coupling reaction of C–H bonds with methylboronic acid or

arylboronate in 2007 (Scheme 210).235 It should be noted that the presence of a cationic counter ion-promoted Pd insertion into

C–H bonds of carboxylic acid substrates because it can prevent Pd from coordinating with the carboxyl group in a k2 fashion,

which keeps Pd far away from C–H bonds and makes C–H insertion impossible.

The versatility and practicality of the above coupling protocol, which suffered from narrow substrate scope and poor yields,

was then substantially improved by using potassium aryltrifluoroborates as the coupling partners (Scheme 211).289 Remarkably,

inexpensive and environmentally benign air or O2 was used as the oxidant instead of expensive Ag2CO3 in this new protocol. A

wide range of benzoic acids including those containing electron-withdrawing groups were tolerated under these new conditions.

This protocol was also applicable to the coupling of C–H bonds of phenylacetic acids, which is synthetically useful because the

broadly useful lithiation/iodination/arylation sequence is incompatible with this type of substrates because of the presence of

acidic a-hydrogen atom.

Shi and coworkers reported Pd-catalyzed arylation of C–H bonds of anilides with arylboronic acids by using N-alkyl acetamino

group as the directing group (Scheme 212).290 The coupling of C–H bonds of anilides with trialkyloxyarylsilanes has also been

developed (Scheme 213).291 The unprotected acetamino group had to be used as the directing group as compared N-alkylated

acetamino group in the coupling with arylboronic acids. Electron-withdrawing groups on the phenyl ring of the anilides decreased

the efficiency of the coupling reactions.




CO2H

X10 mol% Pd(OAc)2

1 equivalent Ag2CO3

0.5 equivalent BQ1.5 equivalents K2HPO4

ButOH, 100 °C, 3 h

CO2H

X

Me

CO2H

X10 mol% Pd(OAc)2

1 equivalent Ag2CO30.5 equivalent BQ

1.5 equivalents K2HPO4ButOH, 120 °C, 3 h

CO2H

X

Ph

MeB(OH)22 equivalents

OB

OPh

Me

Me+

1 equivalent

+

X = Me, OMe, CO2Me

63−75% yield

40−50% yield

O

O K+

O

OK

Pd(II)

Pd(II)O

O Pd(II)

κ2 coordination

O

O K+

Pd(II)

κ1coordination

Scheme 210 Pd-catalyzed carboxyl-directed coupling reaction of benzoic acids with organoboron reagents (Yu et al., 2007).

CO2H

X10 mol% Pd(OAc)2

O2/air, 20 atm0.5 equivalent BQ


CO2H

X

Ar

X

ArBF3K1.2–1.5 equivalents

+

+

CO2H

R1 R2

ArBF3K1.2–1.5 equivalents

10 mol% Pd(OAc)2

O2/air, 20 atm0.5 equivalent BQ


XCO2H

R1 R2

ArX = H, alkyl, OMe, Cl, NO2R1, R2 = H or alkyl

X = Me, OMe, NMe2, Cl, Br,I, CN, CF3, acyl group, etc.

36−98% yield

67−98% yield

Scheme 211 Pd-catalyzed carboxyl-directed coupling reaction with organoboron reagents (Yu et al., 2008).

X5 mol% Pd(OAc)2

1 equivalent Cu(OTf)21 equivalent Ag2O

Toluene, 120 °C, 24 h

N

X

Ar

ArB(OH)22 equivalents

+

N

R

Ac

R

Ac

X = H, Me, Cl; R = alkyl 20−92% yield

Scheme 212 Pd-catalyzed acetamide-directed coupling reaction of acetanilides with boronic acids (Shi et al., 2007).

X5 mol% Pd(OAc)2

2 equivalents Cu(OTf)22 equivalents AgF

Dioxane, 110 °C, 48 h

NHAc

X

Ar

ArSi(OMe)32 equivalents

+

NHAc

X = H, Me, OMe, Ac, OAc, OBz, Cl 42−80% yield

Scheme 213 Pd-catalyzed acetamide-directed coupling reaction of acetanilides with organosilyl reagents (Shi et al., 2007).


The Pd-catalyzed direct arylation of vinylic C–H bonds has also been reported by Loh and coworkers (Scheme 214).292

Therefore, the vinylic C–H bonds of cyclic enamides were arylated by reacting with trialkyloxyarylsilanes. Various functional

groups including chloro and bromo were tolerated to afford coupling products in moderate to excellent yields.

Most of Pd-catalyzed C–H coupling reactions have to rely on high temperatures, which severely limits their potential for

synthetic applications. Intriguingly, Lipshutz and coworkers reported Pd-catalyzed coupling reactions of aryl C–H bonds with

arylboronic acids at room temperature (Scheme 215).293 This approach employed cationic palladium ([Pd(MeCN)4](BF4)2) as





O

10 mol% Pd(OAc)2

3 equivalents AgFDioxane, 80 °C, 16 h

ArSi(OMe)33 equivalents

+

NHAc

X

O

NHAc

X

Ar

X = H, Me, F, Cl 47−95% yield

Scheme 214 Pd-catalyzed vinyl C–H coupling reaction of cyclic enamides with organosilicon reagents (Loh et al., 2009).

HN

X

10 mol% [Pd(MeCN)4](BF4)2

2–5 equivalents BQEtOAc, r.t., 20 h

65−98% yield

ArB(OH)21.5–3 equivalents

+NMe2

OHN

XNMe2

O

Ar

X = alkyl, alkoxyl, Bn

Scheme 215 Cationic Pd(II)–catalyzed urea-directed coupling reaction of arylureas with arylboronic acids at room temperature (Lipshutz et al.,2010).


catalyst and dimethyl urea as directing group, which can be removed by hydrolysis to produce the corresponding amine quan-

titatively. A wide range of arylboronic acids were reactive under these mild conditions.

Another Pd-catalyzed coupling reaction of C–H bonds at room temperature was reported by Gaunt and coworkers

(Scheme 216).294 It is noteworthy that an electron-withdrawing imine directing group was used in this protocol, and the low

temperature enabled arylation of benzaldimines containing sensitive functional groups.

X

10 mol% Pd(OAc)2

BQ, ButO2HAc2O, 4 Å M.S.

ArBF3K1.5–3 equivalents

+

N

H

Pri

Pri

X

N

H

Pri

Pri

Ar

X = alkyl, Ph, alkenyl, TMS, F, Br, CO2Me, TsO 38−93% yieldCH2Cl2/PriOH, r.t.

Scheme 216 Pd-catalyzed imine-directed coupling reaction of electron-deficient arenes with organoboron reagents at room temperature (Gauntet al., 2011).

Although all the above C–H coupling reactions rely on the use of directing groups, nondirected coupling reactions of C–H

bonds with organometallic reagents have also been achieved. Thus, electron-rich arenes and heteroarenes could be arylated via

coupling of their C–H bonds with arylboronic acids (Scheme 217).295 In the couplings of arenes, Cu(OAc)2 and 1 atm O2 were

employed as the oxidants, and the sole O2 was able to oxidize Pd(0) to Pd(II) in the coupling reactions of heteroarenes. In

addition, the coupling of indoles selectively occurred at 2-position.

N

R

5 mol% Pd(OAc)2

O2, 1 atmAcOH, r.t.

ArB(OH)21.5–2 equivalents

+NR

Ar

R = H, Me, Bn

5 mol% Pd(OAc)2

1 equivalent Cu(OAc)2O2, 1 atmTFA, r.t.

ArB(OH)20.5 equivalent

+Ar

50−87% yield

83% yield

Scheme 217 Pd-catalyzed coupling reaction of electron–rich arenes with arylboronic acids (Shi et al. 2008).

In Shi’s approach, the coupling reactions of all of the heteroarenes, including indole, pyrrole, 2,3-benzofuran, and 2,3-

benzothiophene, occurred at 2-position regioselectively. Conversely, Itami and Studer and coworkers described the Pd-catalyzed






C-4 selective C–H arylation of thiophenes and thiozoles with arylboronic acids (Scheme 218),296 which was also contrary to the

C–H arylation of thiophenes with haloarenes occurring preferentially at the positions a to the sulfur atom (Section 3.23.3.1.1).

The use of 2,20-bipyridine as the ligand was necessary for the reactions to occur. Mechanistic studies revealed that the presence of

excess boronic acids was necessary for the C-4 selectivities. The authors proposed that the C-4 selectivities arose from aryl group

migration to C-4-position after the initial C–H insertion at the C-5 position. Intriguingly, the authors also proposed that the

transmetalation of [(bipy)Pd(OAc)2] with ArB(OH)2 occurred before the C–H insertion of palladium, which is different from the

widely proposed mechanism involving the C–H activation of Pd(OAc)2.

S

10 mol% Pd(OAc)210 mol% bipy

4 equivalents TEMPOPhCF3, 80 °C, 12 h

ArB(OH)24 equivalents

+S

Ar

X Xbipy

N N

X = alkyl, Ph, OMe, Cl, etc. 93−99% yield

.

Scheme 218 Pd-catalyzed C4-coupling reaction of thiophenes/thiazoles with arylboronic acids (Itami et al., 2011).

Interestingly, direct coupling reactions of enaminones have also been demonstrated by Georg and coworkers (Scheme 219).297

N-protected enaminones with electron-pushing protecting groups could be arylated by the coupling reactions of their C–H bonds

with aryltrifluoroborates, and a wide variety of aryltrifluoroborates were compatible in these coupling reactions. Notably, this

approach provides a direct method for the construction of 3-arylpiperidine scaffolds, a privileged structure and prevalent motif in

many natural products.

N

O 30 mol% Pd(OAc)2

3 equivalents Cu(OAc)22 equivalents K2CO3

ButOH/AcOH/DMSO, 60 °C, 3−24 h

N

O

Ar

ArBF3K2–3 equivalents

+R R

R = Bn, alkyl 27−98% yield

Scheme 219 Pd-catalyzed coupling reaction of enaminones with aryltrifluoroborates (Georg et al., 2008).

It should be mentioned that only electron-rich substrates have been demonstrated to undergo Pd-catalyzed C–H coupling

reactions with organometallic reagents in the above approaches, which indicates that the C–H activation of these coupling

reactions may involve an electrophilic process. Continued efforts are expected to study the direct coupling reactions of unactivated

arenes, especially electron-deficient ones. Furthermore, as other C–H functionalizations of monosubstituted benzenes, the

regioselective arylation with organometallic reagents remains to be a challenge.

As mentioned in Section 3.23.2.1.1.2, Yu and coworkers developed Pd-catalyzed C–H activation by successfully desymme-

trizing prochiral C–H bonds on geminal groups (Scheme 220).298 Therefore, one of the C–H bonds on the two geminal aryl

groups was enantioselectively alkylated by coupling with alkylboronic acids in the presence of a pyridine as the directing group.

Remarkably, cheap and readily prepared monoprotected amino acids were used as the chiral ligand, and a wide range of amino

acids were effective for these enantioselective C–H coupling reaction.

N

R1

R1

N∗

R1

R1

R

10 mol% Pd(OAc)210–20 mol% ligand

0.5 equivalent BQ1 equivalent Ag2O

THF, 60–80 °C, 20 h

RB(OH)23 equivalents

+

R = Alkyl; R1 = H, Me, OMe, OAc

Me

Me

HN

CO2H

OMe

O

ligand

43−96% yield54−95% ee

Scheme 220 Enantioselective C(sp2)–H coupling with alkylboronic acids (Yu et al., 2008).

Based on the mechanistic studies, Yu and coworkers proposed a stereomodel for the asymmetric C–H insertion (Figure 22).298

The enantioselective C–H insertion is caused by the steric interaction between the protecting group on the chiral ligand and the

aryl group of the substrate. It should be noted that the chirality on the a carbon of the ligand is relayed to the nitrogen atom

attached to the palladium center, which is crucial for the chiral recognition.




PdOHN

NO

H

Me

Me Boc

H

o-TolH

MeOAc

PdOHN

NO

H

Me

Me Boc

o-Tol

HH

MeOAc

Disfavored Favored

Figure 22 A simplified stereomodel for Yu’s asymmetric C–H insertion.


3.23.4.1.2 Palladium-catalyzed coupling of C(sp3)-H bonds with organometallic reagentsAlthough impressive progress has been made in the coupling reaction of C(sp3)-H bond with halides, efforts to couple C(sp3)-H

with organometallic reagents have met numerous problems. On the basis of the progress in the coupling reactions of C(sp2)-H

bond, Yu and coworkers have also achieved successes in the coupling reactions of C(sp3)-H bond with organometallic reagents.

Thus, they developed the first protocol for Pd-catalyzed alkylations of C(sp3)-H bonds b to pyridine with either methylboroxine or

alkylboronic acids (Scheme 221).288

N

cat. Pd(OAc)2RB(OH)2

or methylboroxine

Cu(OAc)2 or Ag2O, BQSolvent, 100 °C, 6 or 24 h

R1

R2

NR1

R2 R

R1, R2 = alkyl or aryl;R = Me, Et, Bun, Hexn, Ph(CH2)2, cyclopropylSolvent: CH2Cl2 or HOAc or t-amyl alcohol

33−80% yield

Scheme 221 Pd-catalyzed pyridine-directed coupling reaction of C(sp3)–H bond with organoboron reagents (Yu et al., 2006).

The coupling of simple aliphatic carboxylic acids with organoboron reagents was also observed (Scheme 222).235 However,

this approach suffered from poor yields and limited substrate scope. Only arylboronic esters and methylboronic acid were reactive

under the reaction conditions, likely because of undesired homocoupling or b-hydride elimination from the alkyl fragments of

the sp3 boronic acids. Yu and coworkers successfully solved these problems by substituting the CONHOMe group with the CO2H

group, because the CONHOMe group may exhibit similar but stronger binding to palladium (Scheme 223).299 Thus, b-C(sp3)-H

10 mol% Pd(OAc)2

1 equivalent Ag2CO30.5 equivalent BQ

1.5 equivalents K2HPO4

ButOH, 100 °C, 3 h

OB

OPh

Me

Me+

O

OHR

Me Me

O

OHR

Me

Ph

R = alkyl20−38% yield

Scheme 222 Pd-catalyzed carboxyl-directed coupling reaction of C(sp3)–H bond with organoboron reagents (Yu et al., 2007).

10 mol% Pd(OAc)2Ag2O or air 20 atm0.5 equivalent BQ

2 equivalents K2CO3Solvent, 70−80 °C, 18 or 48 h

+

1.5 equivalents

O

NH

Me

R1 R2

OMe ArB(OH)2

R1, R2 = alkyl

10 mol% Pd(OAc)2Ag2O or air 20 atm0.5 equivalent BQ

2 equivalents K2CO3Solvent, 70−80 °C, 18 or 48 h

+

1.5 equivalents

O

NH

Me

R1 R2

OMe RB(OH)2

R1, R2 = alkyl R = alkyl

O

NHR1 R2

OMe

O

NHR1 R2

OMe

Ar

R

Solvent: ButOH or ButOH/DMF (4/1)

41−94% yield

Solvent: 2,2,5,5-tetramethyl THF

54−72% yield

Scheme 223 Pd-catalyzed CONHOMe-directed coupling reaction of C(sp3)–H bond with aryl/alkylboronic acids (Yu et al., 2008).






bonds of O-methyl hydroxamic acids can couple with a wide range of aryl/alkylboronic acids. Remarkably, in these coupling

reactions, air could also be used as the oxidant instead of expensive silver reagents. Furthermore, the CONHOMe groups can be

readily converted into esters and amides or reduced to alkane fragments, making this approach synthetically useful.

The utility of this coupling reaction was further demonstrated by the derivatization of dehydroabietic acid (Figure 23),299 a

natural product identified as an efficient BK channel opener. Typically, it is difficult to diversify such structures because of the

absence of reactive chemical functional groups aside from the carboxylic acid moiety. The methyl C–H bond could be readily

alkylated with a range of alkylboronic acids by converting the carboxylic acid into the hydroxamic acid as the directing group,

affording a novel class of analogs that may display improved pharmacokinetic properties.

Me

Me

Me

Me OHO

Me

Me

Me

OHN

OMe

Me

Me

Me

Me

OHN

OMe

Me

Me

Me

OHN

OMe

40% 52% 41%

Dehydroabietic acid

Figure 23 Functionalization of dehydroabietic acid via C(sp3)–H activation.

Notably, Yu and coworker also extended the protocol of enantioselective C(sp2)-H activation to the direct alkylation of C(sp3)-

H bond (Scheme 224).298 Intriguingly, the use of a rigid ligand gave the highest enantioselectivity (37% ee), whereas other

monoprotected amino acid ligands yielded poorer enantioselectivities. Although the enantioselectivities obtained so far are still

poor, it opened an avenue for enantioselective C(sp3)-H functionalization. Furthermore, the sensitive response of enantioselec-

tivity to the ligand structures suggested that there were great potentials of improving enantioselectivity by tuning the existing

ligand structures or designing entirely new ligands.

N N∗

Me


0.5 equivalent BQ1 equivalent Ag2O

t-amyl alcohol, 100 °C, 6 h

BunB(OH)23 equivalents

+

38% yield37% ee

LigandBun

Ph CO2H

NHBoc

Scheme 224 Enantioselective C(sp3)–H coupling reaction with alkylboronic acid (Yu et al., 2008).

During the investigation of Suzuki–Miyaura coupling reaction of sterically hindered aryl bromides, Buchwald observed the

products resulting from the arylation of C(sp3)–H bonds with phenylboronic acids, instead of the desired biaryls

(Scheme 225).300 Therefore, in the presence of Pd2(dba)3 and the bulky ligand, the reaction of 2,4,6-tri-tert-butylbromobenzene

with phenylboronic acid yielded the a,a-dimethyl-b-aryl hydrostyrene derivatives. The proposed mechanism involved: the oxi-

dative addition of the aryl bromide to Pd(0), cyclometalation by the formed Pd(II) species via abstraction of one of the hydrogen

atoms from the tert-butyl group, selective protonation of the C(sp3)-Pd bond to afford the alkyl Pd(II) species, the subsequent

transmetalation with the boronic acid, and the reductive elimination to form the C(sp3)–C(sp2) bond and release Pd(0).

But

Br

But

But (HO)2B

R

R

+

But

But

MeMe

1 mol% Pd2(dba)34 mol% ligand

3 equivalents K3PO4Toluene, 100 °C, 18 h

R = H, Me, phenyl

PCy2

OMeMeO

Ligand

95−99% yield

Scheme 225 Pd-catalyzed arylation of C(sp3)-H bonds (Buchwald et al., 2005).





3.23.4.2 Rhodium-Catalyzed Reactions with Organometallic Reagents

Although in total more examples using palladium have been reported, rhodium was the metal employed in the first successful

cross-coupling reaction between aromatic C–H bonds and organometallic reagents. In 1998, Oi and coworkers disclosed

RhCl(PPh3)3-catalyzed arylation of 2-phenylpyridine with tetraphenylstannane in 1,1,2,2-tetrachloroethane (Scheme 226).301

The reaction afforded mono- and diarylated products, whereas only monophenylated products were observed for the other

pyridine-substituted arene substrates. The use of 1,1,2,2-tetrachloroethane as the solvent was crucial for the transformation. The

possible mechanism involved the directed oxidative addition of the low-valent Rh complex to the ortho-C–H bond of the phenyl

ring followed by phenylation with tetraphenylstannane.

N5 mol% RhCl(PPh3)3

Cl2CHCHCl2120 °C, 20 h

N

Ph

N

Ph

Ph

+ Ph4Sn +

65% yield 20% yield

1 equivalent

Scheme 226 Rh-catalyzed pyridine-directed arylation of 2-phenylpyridine with tetraphenylstannane (Oi et al., 1998).

The use of less toxic organoboron reagents as the coupling partners was achieved by the Miura, Satoh and coworkers

(Scheme 227).302 By using the same catalyst, diphenylmethanimine underwent arylation with sodium tetraphenylborate in the

presence of ammonium chloride. Unfortunately, the reaction gave a relatively low yield because of the formation of diphe-

nylmethanamine. Mechanistically, the C–H bond was proposed to be cleaved by an in situ generated phenylrhodium(I) species,

forming the rhodacycle intermediate. The subsequent reductive elimination afforded the arylated products and released rhodium

hydride, which consumed another molecule of diphenylmethanimine to form diphenylmethanimine and to regenerate Rh(I)Cl

(Figure 24).302

NH NH Ph NH PhPh

+ NaBPh4

1 mol% RhCl(PPh3)3

1 equivalent NH4Clo-xylene, 120 °C, 44 h

+

26% yield 20% yield

+

NH2

51% yield

Scheme 227 Rh-catalyzed imine-directed arylation with tetraphenylborate (Miura and Satoh et al., 2005).

Rh(I)–Cl

Rh(I)–Ph

N

Ph

Rh(III)

H

PhH

Rh(I)–H

NH

RhH

PhPh

Ph4BNa

Ph3B, NaCl

NHPh

Ph

N

Ph

H

Ph

NHPh

Ph

NH4Cl

Ph2CHNH2NH3

Figure 24 Proposed mechanism of Rh-catalyzed arylation with tetraphenylborate.

The yields were improved by the addition of ethyl chloroacetate and potassium fluoride as a hydrogen acceptor and a

promoter, respectively (Scheme 228).303 A wide range of heteroarenes, including imidazoles, oxazolines, and pyridines, were

found to act as effective directing groups for the arylation. Notably, boronic acids were used as the arylating reagents in the

arylation of azobenzene. The reactions were rendered catalytic by the oxidative addition of ethyl chloroacetate to the formed

rhodium hydride in reaction and the subsequent reductive elimination.




+ NaBPh4

2 mol% RhCl(PPh3)34 equivalents KF

4 equivalents ClCH2CO2Eto-xylene, 140 °C, 6 h

Het Het

Phor

Het

PhPh

Het =

+ ArB(OH)2

2 mol% [Rh(OMe)(cod)]28 equivalents KF

4 equivalents ClCH2CO2Eto-xylene, 140 °C, 4 h

NN

Ph NN

Ph

Ar

47−98% yield

22−44% yield

NN NO NR

R = alkyl

Scheme 228 Rh-catalyzed-directed arylation with organoboron reagents (Miura and Satoh et al., 2008).


Studer and coworkers reported another efficient protocol for Rh-catalyzed C–H arylation with boronic acids (Scheme 229).304

The catalytic system consisted of [RhCl(C2H4)2]2 and P[p-(CF3)C6H4]3, and TEMPO was used as the terminal oxidant. Various

boronic acids were found to be effective arylating reagents. A 2-pyridyl group and an imine functional group served as ortho-

directing groups. In addition, the direct arylation of thiophenes also proceeded effectively under the reaction conditions. A

Rh(III)/Rh(I) catalysis was proposed to be operative for this transformation. Therefore, the transmetalation of aryl boronic acids

with Rh(I) catalyst formed aryl rhodium(I) species. The subsequent oxidation with TEMPO gave rise to Rh(III) species, which

cleaved C–H bonds to afford the key cyclometalated complex. The reductive elimination afforded the final arylated products and

regenerated Rh(I) catalyst (Figure 25).304

N

5 mol% [RhCl(C2H4)2)320 mol% P[p-(CF3)C6H4]3

4 equivalents TEMPODioxane/ButOH (10/1)

130 °C, 9 h

N

Ph

N

Ph

Ph

+ PhB(OH)2 +

50% yield 18% yield

4 equivalents

Scheme 229 Rh-catalyzed pyridine-directed arylation of 2-phenylpyridine with boronic acids (Studer et al., 2008).

Rh(I)TEMPO

Rh(I)–Ar

N

(TEMPO)2Rh(III)–Ar

ArB(OH)2

N

Rh(III)TEMPO

Ar

(TEMPO)B(OH)2

2 TEMPO

NAr

Figure 25 Proposed mechanism of Rh-catalyzed arylation with boronic acids.

3.23.4.3 Ruthenium-Catalyzed Reactions with Organometallic Reagents

The first Ru-catalyzed C–H arylation with organometallic compounds was achieved by Kakiuchi and coworkers in 2003

(Scheme 230).305 In the presence of the catalyst RuH2(CO)(PPh3)3, aromatic ketones were ortho-arylated with a variety of

arylboronates. Diarylated products were formed preferentially for some of the starting ketones. The use of two equivalents of aryl

ketones was required to achieve high yields, and a nearly equivalent amount of alcohol derived from the reduction of the starting




R

O

XR

O

X

Ar

Ar BO

O+


0.5 equivalent

Toluene, reflux, 1−20 h

X = H, OMe, F, CF3, alkenyl; R = alkyl

R

O

X

Ar

Ar

or/and

56−95% yield

Scheme 230 Ru-catalyzed carbonyl-directed arylation with arylboronates (Kakiuchi et al., 2003).


ketone was obtained as a byproduct. The proposed mechanism suggested that the C–H bond was cleaved by Ru(0) complex to

give the ortho-metalated intermediate. The formed Rh–H bond added to the ketone carbonyl group to produce an (alkoxy)-

ruthenium intermediate, which accounted for the consumption of one equivalent of the aryl ketones. The subsequent trans-

metalation with phenylboronate and reductive elimination afforded the final arylation products and regenerate the active Ru(0)

catalyst (Figure 26).305

Ru

Me

O

Me

O

Ru

HMe

O

Ru

Me

O

Ru

Ph

Ph BO

O

O

Me Ph

BO

O

Me

O

Ph

Ph

Me

O

O

Ph

Me

Figure 26 Proposed mechanism of Ru-catalyzed arylation with organoboron reagents.

A major drawback for the above novel arylation method is that one equivalent of starting ketones was consumed in the

reaction. Remarkably, this problem was elegantly addressed by the addition of aliphatic ketones as a scavenger.306 Therefore, the

use of pinacolone as the solvent dramatically suppressed the reduction of the ketone starting material, and as a result, high yields

were obtained. The arylation protocol has been further optimized. For instance, the authors found that the use of styrene as an

additive led to selective formation of monoarylated product using acetophenone starting materials bearing two potentially

reactive ortho-C–H bonds.307

The method was successfully extended to the arylation of anthraquinone308 and perylene bisimide (PBI).309 Tetraarylated

products were produced for both of the substrates, which set a stage for the efficient multiarylation of complex arenes.

The arylation protocol also proved applicable to the arylation of benzoates (Scheme 231).310 Isopropyl esters were found to

give particularly high yields, and the introduction of electron-withdrawing CF3 group also increased the product yield.

O

O

O

O

Ar

Ar BO

O

+


2 equivalents

2 equivalents

Pinacolone, reflux, 3 h

R = Me, CF3

O

O

Ar

Ar

19−27% yield

R

O

OR

Ar

O

O

Ar BO

O+


Pinacolone, reflux, 3 h+

37−58% yield

Scheme 231 Ru-catalyzed ester-directed arylation of benzoates with arylboronates (Kakiuchi et al., 2010).





Inspired by the above work, Sames and coworkers developed Ru-catalyzed C(sp3)-H arylation with arylboronates

(Scheme 232).311 Thus, in the presence of Ru3(CO)12 and ButCOMe, 2-substituted pyrrolidines bearing cyclic imine-directing

groups were a-arylated with a wide range of arylboronates. The reactions gave mixtures of trans/cis diastereomers with ratios

ranging from 3:1 to 6:1. The arylation of piperidines was also demonstrated, and pyridine and pyrimidine were also found to be

effective directing groups. The mechanism was analogous to that proposed in the above RuH2(CO)(PPh3)3-promoted C(sp2)-H

arylation, which involved the C(sp3)-H cleavage by the oxidative addition to a Ru(0) species and pinacolone as a scavenger of

a-hydrogens of the pyrrolidines.

N

NRAr B

O

O

1.2 equivalentsN

NR Ar+

3.3 mol% Ru3(CO)12

5 equivalents ButCOMe150 °C, 4−19 h

R = Ph, TBSOCH2 45−76% yield

Scheme 232 Ru-catalyzed imine-directed C(sp3)-H arylation with arylboronates (Sames et al., 2006).

In Sames’ work, the arylation of piperdines gave moderate yields because of their chair conformation. Maes and coworkers

demonstrated that the yields could be improved by using 3-ethyl-3-pentanol in place of pinacolone as the scavenger

(Scheme 233).312 The idea of using 3-ethyl-3-pentanol was based on the assumption that pinacolborane, which is generated

during transmetalation of the [Ru(II)-H] intermediate with the arylboronate, could poison the catalyst and needed to be

sequestered to achieve high yields. As such, the role of 3-ethyl-3-pentanol was to scavenge the pinacolborane species, with

formation of the corresponding 3-ethyl-3-pentylborate and H2. The hypothesis was supported by the fact that the conversion

could be further increased by carrying out the reaction in an open vial under reflux conditions.

Ar BO

O

3 equivalents

+6 mol% Ru3(CO)12

1 equivalent 3-ethyl-3-pentanolN

N

N

N Ar

reflux, 24 h

35−48% yield

Scheme 233 Ru-catalyzed pyridine-directed C(sp3)-H arylation with arylboronates (Maes et al., 2010).

3.23.4.4 Iron, Cobalt, and Nickel-Catalyzed Reactions with Organometallic Reagents

In 2008, the Nakamura and coworkers disclosed Fe-catalyzed C–H arylation with arylzinc reagents under the conditions shown in

Scheme 234.313 The combination of the employed reagents was important for the success of the reactions. The arylzinc reagents

were generated in situ from the corresponding Grignard reagents and zinc chloride. The use of an excess amount of arylzinc

reagents was required. Although 1st equivalent was required for the desired arylation reaction, a 2nd equivalent was required to

remove the hydrogen. In addition, a certain amount of the phenylzinc reagent was also consumed because of the biphenyl

N+ ArMgBr

6 equivalents

10 mol% Fe(acac)310 mol% 1,10-phenanthroline3 equivalents ZnCl2.TMEDA

2 equivalents 1,2-dichloro-2-methylpropaneTHF, 0 °C, 6−48 h

N

Ar

N

Ar

Ar

R = H, Me, OMe, CO2Me 12−21% yield

R R R

+

N+ ArMgBr

6 equivalents

10 mol% Fe(acac)310 mol% 1,10-phenanthroline3 equivalents ZnCl2.TMEDA

2 equivalents 1,2-dichloro-2-methylpropaneTHF, 0 °C, 16−48 h

N

Ar

17−89% yield

X X

X = 3-Me, 2-Me, 2-Ph

65−82% yield

Scheme 234 Fe-catalyzed pyridine-directed arylation of pyridylarenes with arylzinc reagents (Nakamura et al., 2008).





forming side reaction. The reaction might involve a redox cycle of iron with the dichloride acting as an electron acceptor. It is

remarkable that the reactions proceeded smoothly at 0 1, whereas the majority of C–H functionalization reactions were run at

high temperature. In addition to pyridine, pyrimidine, and pyrazole also acted as the effective directing groups for this

transformation.

This method was also successfully extended to the arylation of aryl imines (Scheme 235).314 4,40-Di-tert-butyl-2,20-bipyridine

(dtbpy) was found to be superior to 1,10-phenanthroline. Although the imines derived from acetophenones gave the sole

monoarylated products, the aldehyde-derived imines delivered a mixture of mono- and diarylated products. The resulted arylated

imines were converted into the corresponding ketones via in situ hydrolysis. Notably, this reaction showed an excellent tolerance

for functional groups. A wide range of substituents of aryl imines, including iodide, bromide, chloride, sulfonate, and triflate, were

well tolerated in the reaction.

NAr1

X + Ar2MgBr

12 equivalents

15 mol% Fe(acac)315 mol% dtbpy

6 equivalents ZnCl2•TMEDA

4 equivalents 1,2-dichloroisobutaneTHF, 0 °C, 3−72 h

OX

Ar2

X = H, alkyl, OMe, Cl, Br, I, TfO, TsO, CN, CF314−100% yield

Scheme 235 Fe-catalyzed imine-directed arylation with arylzinc reagents (Nakamura et al., 2009).

Subsequently, the Nakamura and coworkers discovered the C–H arylation with Grignard reagents (Scheme 236).315 When the

authors tried to apply the above method to the arylation of vinylic C–H bonds, no desired products were obtained under the

identical conditions. However, the reactions occurred effectively after the removal of zinc chloride and a further condition

optimization. Therefore, a variety of olefinic C–H bonds were arylated with Grignard reagents, with pyridine as the directing

group. The arylation reaction took place only at the 2-position of the olefin, notably, in a syn-specific manner. The preliminary

mechanistic studies suggested that a five-membered metallacycle was formed via pyridine-directed C–H activation. Subsequently,

the intermediate underwent reductive elimination, perhaps after interaction with 1,2-dichloro-2-methylpropane, to afford the syn-

substituted olefins (Figure 27).315

NR1

R2

+ ArMgBr

3.2 equivalents

10 mol% Fe(acac)315 mol% dtbpy

2 equivalents 1,2-dichloro-2-methylpropanePhCl/Et2O, 0 °C, 5 min

NR1

R2 Ar

R1, R2 = H, alkyl, Ph40−99% yield

Scheme 236 Fe-catalyzed pyridine-directed arylation of vinylic C–H bonds with Grignard reagents (Nakamura et al., 2011).

NR1

R2

NR1

R2 Ar

NR1

R2 Fe

ArCl

Cl


ArMgBrcat. Fe

Figure 27 Proposed mechanism of Fe-catalyzed arylation of vinylic C–H bonds with Grignard reagents.

Notably, boronic acids were also successfully developed as the arylation reagents in the Fe-promoted C–H arylation. In 2008,

the Yu and coworkers disclosed the Fe2(SO4)3�7 H2O/cyclen-mediated arylation of benzene with arylboronic acids in the pre-

sence of pyrazole and tripotassium phosphate (Scheme 237).316 A wide range of substituents of arylboronic acids were com-

patible including chloro and bromo in the reaction. A diversity of substituted arenes such as bromobenzene and chlorobenzene

were also found to be reactive, affording mixtures of regioisomers. In the cases of monosubstituted benzenes, ortho-, meta-, and

para-arylated products were generated.

Subsequently, Yu and coworkers described analogous protocols for the C–H arylation of nitrogen-containing heteroarenes

(Scheme 238).317 The arylation of both electron-rich pyrroles and electron-deficient pyridine were demonstrated. In the arylation

of pyrroles, the reactions occurred at the 2-positions selectively. For pyridine, 2-arylated product was also formed predominantly,

but 3- and 4-arylation was also observed. Preliminary mechanistic studies suggested that an oxoiron species derived from oxygen

was the catalytically active species, which cleaved C–H bonds via electrophilic metalation with the assistance of the heteroatoms.

Shi and coworkers demonstrated that cobalt was able to enable C–H arylation/alkylation with Grignard reagents catalytically

under the similar conditions to iron (Scheme 239).318 Therefore, benzo[h]quinolines and 2-phenylpyridine reacted with a wide




(HO)2BX

+

Solvent

2 equivalents pyrazole4 equivalents K3PO4

80 °C, 48 h

X1 equivalent Fe2(SO4)3.7H2O

1 equivalent cyclen

X = H, Me, OMe, Cl, Br, NO2, CO2Me 31−83% yield

Scheme 237 Fe-catalyzed arylation of benzene with boronic acids (Yu et al., 2008).

(HO)2BX

+

7.5 equivalents

20 mol% L1

130 °C, 10 hNH

R

NH

R X

N

50 mol% L2

Acetic acid, 110 °C, 10 h(HO)2B

X+ N

XNH

NHHN

HN

N

NH

NHHN

L2

L1

Solvent

X = H, Me, Pri, OMe, Nap-2, F, Cl, Br, NO2, CO2Me; R = H, mono-or di-Me

28−84% yield

26−45% yield

20 mol% FeC2O4.2H2O

50 mol% FeCl3.6H2O

Scheme 238 Fe-catalyzed C2-arylation of pyrroles/pyridine with boronic acids (Yu et al., 2010).

N N

R

+ RMgBr4 equivalents

10 mol% Co(acac)31 equivalent TMEDA

1.5 equivalents 2,3-dichlorobutaneTHF, r.t., 48 h

X X

X = H, alkyl, OMe, Ph, amine; R = aryl, alkyl 26−93% yield

Scheme 239 Co-catalyzed pyridine-directed arylation/alkylation with Grignard reagents (Shi et al., 2011).


range of aryl/alkyl Grignard reagents in the presence of Co(acac)3, TMEDA, and 2,3-dichlorobutane, affording the corresponding

arylated/alkylated products. Based on the mechanism experiments, the authors ruled out a radical mechanism, and proposed that

the C–H bonds were cleaved via the oxidative addition of the aryl/alkylcobalt species to the C–H bonds. 2,3-dichlorobutane acted

as an oxidant in a similar manner to the dichloroalkanes employed in the Fe-catalyzed C–H arylation reactions, and was reduced

to 2-butene.

Subsequently, Nakamura and coworkers reported a different protocol for Co-catalyzed C–H alkylation of benzamides with

Grignard reagents (Scheme 240).319 The use of the ligand DMPU (1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone) was

crucial for the success of this new method. It is noted that dichloroalkanes were not used and air acted as the sole oxidant. For the

alkylation of N-methylbenzamides, dialkylated products were produced preferentially. However, the dialkylation could be sup-

pressed by the choice of a suitable organic substituent on the amide nitrogen atom, such as phenyl and isopropyl groups.

NH

O

+ EtMgBr

5.8 equivalents

10 mol% Co(acac)330 equivalents DMPU

THF, 25 °C, 12 h

R1 = H, OMe, F

NH

O

Et

61−79% yield

NH

O

R2

NH

O

R2

Et

+ EtMgBr

5.8 equivalents

10 mol% Co(acac)330 equivalents DMPU

THF, 25 °C, 12 h

R2 = Pri, Ph 52% yield

R1R1

Scheme 240 Co-catalyzed amide-directed alkylation of benzamides with Grignard reagents (Nakamura et al., 2011).






Moreover, benzo[h]quinolines and 2-phenylpyridines were also ethylated under the similar conditions, largely affording

monoethylated products.

Nickel also proved applicable to promote the C–H arylation with organometallic reagents. In 2010, Miura and coworkers

disclosed nickel-catalyzed arylation of heteroarenes with organosilicon reagents in the presence of NiBr2�diglyme, 2,20-bipyridine,

CsF, and CuF2 (Scheme 241).320 An array of heteroarenes such as 5-aryloxazole, benzothiazole, benzimidazole, and 1,3,4-

oxadiazole underwent the arylation effectively. Alkenylation with alkenylsilane also occurred smoothly under the conditions, with

the concomitant minor E/Z isomerization. The proposed mechanism involved the C–H cleavage by Ni(II) with the assistance of

CsF, the transmetalation with organosilicon reagents, and the subsequent reductive elimination to afford the coupling products

and Ni(0) species. The reoxidation of the formed Ni(0) species with CuF2 regenerated the active Ni(II) catalyst to complete the

catalytic cycle.

Z

Y

N+ (R1O)3Si

NZ

Y

10 mol% NiBr2.diglyme10 mol% 2,2'-bipyridine

3 equivalents CsF, 2 equivalents CuF2N,N-dimethylacetamide, 150 °C, 2−6 h2 equivalentsY = O, NMe, S

Z = C, N

X X

X = alkenyl, aryl; R1 = Me, Et43−86% yield

Scheme 241 Ni-catalyzed coupling reaction of heteroarenes with organosilicon reagents (Miura et al., 2010).

3.23.5 Reactions with C–H Bonds

Although the reactions of C–H bonds with (pseudo)halides and organometallic reagents have great advantages over traditional

cross-coupling reactions, they are not ‘perfect’ considering that one of the reaction partners needs to be preactivated and unwanted

byproducts are still generated in the reactions. As illustrated in many of the reactions in this chapter, [M–R] species, obtained from

the oxidative addition of halides to transition metals or other sources, can react with C–H bonds. However, it has also been

demonstrated that transition-metal-promoted C–H activation may form the C–M intermediates with the similar reactivity. As such, it

is quite obvious to envision that the C–M intermediates produced via C–H activation could react with a second C–H bonds,

providing dehydrogenative coupling products. Such a reaction involving the coupling of two C–H bonds provides a novel C–C bond

forming strategy through double C–H activation. The coupling of two C–H bonds would obviate the need for any preactivation of

substrates and produce a minimum of byproducts, so that it should count as ‘perfect reactions.’ However, this attractive reaction is

very challenging, because a new problem regarding chemoselectivity arises, in addition to those existing in the C–H functionali-

zation reactions with one preactivated substrate. The C–M intermediate generated in the first C–H activation may react with both of

the coupling partners to gave a mixture homocoupling and heterocoupling products. Therefore, for a successful dehydrogenative

coupling reaction, the desired coupling must occur selectively. For synthetically more useful reactions, the catalyst must react with

one substrate selectively first and then invert its reactivity to react with the second C–H bond in the second step. In spite of the

challenge, a number of coupling reactions involving double C–H bond activation have been developed,321 and Pd is the dominant

catalyst used in these reactions. To achieve desired heterocoupling, the coupling partners with distinct C–H bonds were often

employed, and one of the partners was excessive, often as solvent. It should be mentioned because these reactions are categorized as

double C–H activation reactions, both of the reacting C–H bonds are restricted to those with high pKa values.

3.23.5.1 Palladium-Catalyzed Reactions with C–H Bonds

Pd-promoted coupling of two C–H bonds have been extensively investigated, and a number of reactions have been developed,

including homocoupling and heterocoupling reactions Among these reactions, the vast majority of them involve aryl–aryl bond

formation, and a variety of arenes have been demonstrated to undergo the dehydrogenative coupling reaction, providing a novel

method for the synthesis of biaryls.322 To illustrate the mechanism involved in such a reaction, a representative catalytic cycle for

Pd-catalyzed cross-coupling of two arenes illustrated shown in Figure 28.15 Therefore, the reaction is initiated by Pd(II)-enabled

C–H activation. The formed arylpalladium(II) species cleaves the C–H bond of a second arenes. The subsequent reductive

elimination yield the desired biaryl product and generate Pd(0) species. Finally, the Pd(0) species is oxidized by an oxidant to

Pd(II) complex, which then continues a second catalytic cycle.

3.23.5.1.1 Palladium-catalyzed homocoupling of two C–H bondsThe homocoupling of benzene is relative simple compared to the complicated coupling of two different arenes, because biphenyl

is the sole possible coupling product. As early as 1965, Pd-mediated homocoupling of benzene to biphenyl was observed.323

Subsequently, the similar coupling was reported.324,325 Inspired by these early observations, this attractive reaction gained

considerable interest, and a number of effective protocols have been developed and catalytic reactions have been enabled.


Ar1Pd(II)

Pd(II)

Ar1Pd(II)Ar2

Pd(0)

Ar2–HAr1–Ar2

OxidantAr1–H

The first C−Hactivation

The secondC−H activation


reoxidation

Figure 28 A general mechanism of Pd-catalyzed cross-coupling of two arenes.


The homocoupling of heteroarenes have also been extensive investigated, and a wide range of electron-rich heteroarenes were

found to undergo homocoupling reaction to form dimerization products. One of the recent examples is the homocoupling of

thiophene reported by the Mori and coworkers (Scheme 242).326 Therefore, a variety of 2-substituted thiophenes underwent

dimerization to afford homocoupling products in the presence of a catalylic amount of PdCl2(PhCN)2 and 2 equivalents of AgF.

The reaction occurred selectively at the 5-positions. In addition, 2-(4-methoxyphenyl)thiazole was also found to undergo the

similar homocoupling reaction.

X

SR

3 mol% PdCl2(PhCN)22 equivalents AgF

DMSO, 60 °C, 5 h

X

SR

X

S R

X = CH, N 41−85% yieldR = Me, CHO, COMe, CO2Et, aryl

Scheme 242 Pd-catalyzed coupling of thiophene and thiazole (Mori et al., 2004).

The homocoupling with the assistance of a directing group was also achieved. In 2006, Sanford and coworkers described the

Pd(OAc)2-promoted homocoupling of 2-arylpyridines using oxone as the oxidant (Scheme 243).327 The b-selectivity of the

reactions demonstrated that pyridine acted as a directing group. Detailed mechanistic studies suggested that the reactions involved

two different C–H activation mechanism, one at Pd(II) center and one at Pd(IV) center.

NN

N

X

X

X

5−10 mol% Pd(OAc)22 equivalents oxone

Solvent, 25−60 °C

X = H, OMe, CF3, halo 41−82% yield

Scheme 243 Pd-catalyzed homocoupling of 2-arylpyridines (Sanford et al., 2006).

3.23.5.1.2 Palladium-catalyzed coupling of two different C–H bondsThe Pd-mediated cross-couplings of two different arenes were also observed quite early. In 1976, Kozhevnikov isolated the cross-

coupling products of furan and thiophene during the study on the Pd(OAc)2-mediated oxidative homocoupling of furan or

thiophene.328 Subsequently, Itahara observed 2-phenylation products of pyrroles and indoles along with their homocoupling

products when pyrroles or indoles were stirred with a stoichiometric amount of Pd(OAc)2 in a mixture of benzene and acetic

acid.329 Another example is the direct arylation of isoxazole reported by Nakamura and coworkers.175

One of the earliest catalytic cross-coupling of two arenes was the contribution of the Lu and coworkers in 2006

(Scheme 244).330 The authors found that unsymmetrical biaryls were formed preferentially over homocoupling products when a

X 5 mol% Pd(OAc)2

TFA, K2S2O8

r.t., 24 h

+ X

X = H, Me, OMe, Cl 11−50% yield

Scheme 244 Pd-catalyzed cross-coupling of naphthalene and arenes (Lu et al., 2006).






mixture of benzene and anisole/mesitylene was stirred with Pd(OAc)2 in the presence of TFA and K2S2O8 at room temperature.

Under the similar conditions, naphthalene reacted with a wide range of simple arenes to afford arylated products with turnover up

to 22. Preliminary mechanistic studies suggested that two aromatic C–H activation steps were involved in the tandem direct

arylation.

Although the yields of the above reactions were quite low, these early works provided great inspiration for the development of

efficient cross-coupling reactions via double C–H activation. A decisive breakthrough was made by Fagnou and coworkers in 2007,

when the authors reported the arylation of N-acetylindoles with simple arenes in high yield and high regioselectivity under the

conditions shown in Scheme 245.331 The reaction occurred at the 3-position preferentially, and a range of functional groups of the

indoles were compatible in the reactions. In addition to benzene, other substituted arenes such as p-xylene, 1,4-difluorobenzene,

and 1,4-dimethoxybenzene were also reactive. Notably, no arene homocoupling products were detected in the reactions, indi-

cating that a complete inversion in catalyst selectivity occurred at the crucial arene metalation steps of the catalytic cycle.331

10−20 mol% Pd(TFA)210−20 mol% 3-nitropyridine

40 mol% CsOPiv

3 equivalents Cu(OAc)2Pivalic acid

110−140 °C (microwave)30−68 h

+

X = H, Me, OMe, Cl, CO2Me; R = H, Me, OMe, F

R

R

NAc

X

NAc

X

RR

NAc

X R

R

+

30 equivalentsMajor

42−84% yield (major/minor ≥ 2.8/1.0)Minor

Scheme 245 Pd-catalyzed coupling of indoles and simple arenes (Fagnou et al., 2007).

Interestingly, a reversal in regioselectivity was observed when N-pivaloyl indoles were employed and the reaction conditions

were modified to employ Pd(TFA)2, AgOAc, and pivalic acid (Scheme 246).332 The use of the oxidant AgOAc was crucial for the

C2 selectivity, whereas Cu(OAc)2 favored C3-arylation. The new conditions tolerated a variety of substituents, and some sym-

metrically substituted benzenes were also found to be reactive. In addition, the protocol was extended to the arylation of indoles,

and the reactions also gave C2-arylated indoles as the major products. Further experiments revealed that the C2/C3 selectivity was

greatly influenced by Pd concentration and acetate additives. The acetate base, when added as a Ag(I) or Cs(I) salt, increased C2

selectivity. To explain these findings, the authors proposed that the formation of higher-order Pd and/or Pd-Cu clusters accounted

for the favored C3-arylation, whereas acetates may cleave Pd clusters and thus promote cross-coupling at C2-position.

10 mol% Pd(TFA)2AgOAc

Pivalic acid110 °C

+

R1 = H, COMe, CO2Me, CN;R2 = Me, COBut, CH2OMe

N

R2

R1N

R2

R1

5 mol% Pd(TFA)23 equivalents AgOAc

6 equivalents pivalic acid110 °C

+N

X

N

X

O But O But

X = H, Me, OMe, Cl, CO2Me 76−90% yield

64−68% yield

Scheme 246 Pd-catalyzed coupling of indoles/pyrroles and benzene (Fagnou et al., 2007).

Concurrently, DeBoef and coworkers reported the similar oxidative coupling of benzofurans and indoles with simple arenes

(Scheme 247).333 Although the use of the heteropolymolybdovanadic acid H4PMo11VO40 (HPMV) as the cooxidant gave the

optimal outcome for the arylation of benzofurans, both N-acetylindole and N-methylindole decomposed under the reaction

conditions. However, the milder oxidant Cu(OAc)2 proved effective to enable the arylation of N-acetylindole, and the more

electron-rich N-methylindole could only be arylated in the absence of oxygen. The arylation took place at the 2-position

preferentially, but the selectivity for N-methylindole was poor. Moreover, the method also proved viable in the intramolecular

hetero-coupling of N-benzoylindoles via double C–H activation, affording cyclized products.

Subsequently, DeBoef and coworkers improved the arylation of electron-rich indoles primarily by tuning the acidity of the

reaction medium.334 The authors successfully achieved C2-arylation of indoles by using a new catalytic system consisting of

Pd(OAc)2, pivalic acid, and AgOAc. A wide range of electron-rich indoles were arylated with various simple arenes with high C2

selectivity. The reaction mechanism was investigated. Based on the experimental and computational data, the authors believed

that both C–H palladation steps should involve a CMD mechanism.



N

X10 mol% Pd(OAc)2

10 mol% HPMV

O2 (3 atm), AcOH120 °C, 24 min−15 h

+O O

X

RN

R

15 or 20 mol% Pd(OAc)21 equivalent Cu(OAc)2/O2 (3 atm)

or 4 equivalents Cu(OAc)2/argon (1 atm)

AcOH, 120 °C, 3 h

+

20 mol% Pd(OAc)21 equivalent Cu(OAc)2

O2 (3 atm)AcOH, 120 °C

N

O

X

N

O

X

X = H, Me, OMe 49−84% yield

R = Me 69% yieldOAc 45% yield

X = H 29% yieldOMe 82% yield

Scheme 247 Pd-catalyzed coupling of indoles and simple arenes (DeBoef et al., 2007).


Interestingly, Stahl and coworkers found that the C2/C3 selectivity in the cross-couplings of indoles and benzene can be

controlled by using different 4,5-diazafluorene ligands. It is noteworthy that the use of the ligands enabled the aerobic cross-

coupling to proceed efficiently with oxygen as the sole oxidant, and other oxidant such as Ag(I) and Cu(II) salts were not

needed.335

In 2008, the Chang and coworkers described the cross-coupling of pyridine N-oxides and simple arenes (Scheme 248).41

During the course of the studies on the alkenylation of pyridine N-oxides, the authors isolated 2-phenylpyridine N-oxide when

the reaction was carried out in benzene. After extensive condition optimization, it was found that a variety of pyridine N-oxides

could be a-arylated with a range of simple arenes in the presence of Pd(OAc)2 and Ag2CO3. N-Oxides of pyrazine and quinoxaline

also underwent the arylation with benzene at the a-position.

N

Y

O

X1 X210 mol% Pd(OAc)2

2.2 equivalents Ag2CO3

130 °C, 16 h+ N

Y

O

X1

X2

Y = CH, NX1 = H, Ph, alkenylX2 = H, 1,2-dimethyl, 1,3-dimethyl, 1,2-dichloro, 1,2-difluoro

40−79% yield

Scheme 248 Pd-catalyzed regioselective coupling of pyridine N-oxides and simple arenes (Chang et al., 2008).

The C–H bonds of polyfluorobenzenes are relatively acidic and can be cleaved via a different mechanism from those involved

in the C–H activation of simple arenes. As such, it is reasonable to envision that polyfluorobenzenes could undergo dehy-

drogenative cross-coupling with other arenes. In 2010, Su and coworkers developed an efficient protocol for the arylation of

polyfluoroarenes (Scheme 249).336 A range of tetrafluoroarenes and pentafluorobenzene cross-coupled with simple arenes via

double C–H activation. A diversity of simple arenes, including nitrobenzene, chlorobenzene, and trifluoromethylbenzene, were

found to be effective coupling partners. Monosubstituted arenes gave a mixture of para- and meta-isomers with a ratio of

approximately 1–2.5.

Fn X

10 mol% Pd(OAc)22 equivalents Cu(OAc)2

0.75 equivalent Na2CO3

1.5 equivalents pivalic acidDMA, 110 °C, 24 h

+

Fn X

n = 4, 5X = H, Me, Cl, CF3, NO2

33−86% yield

Scheme 249 Pd-catalyzed coupling of polyfluoroarenes and simple arenes (Su et al., 2010).

Different types of heteroarenes often have distinct electronic characteristics and their C–H bonds should be able to be

differentiated and cleaved in a sequential way. In 2010, You and coworkers reported the oxidative cross-coupling of two





heteroarenes (Scheme 250).337 Therefore, in the presence of Pd(dppf)Cl2, Cu(OAc)2 �H2O, and pyridine, xanthines reacted with

diversely substituted furans or thiophenes to afford biheteroaryl products. The reactions occurred at the 2-positions of furans or

thiophenes selectively. It is noted that this new method had a very broad substrate-scope. A wide range of heteroarenes (xanthines,

azoles, indolizines, and pyridine N-oxides) underwent effective heterocoupling with furans or thiophenes.

Y

X

N

NN

N

OR3

R2

R1

O

2.5 mol% Pd(dppf)Cl21.5 equivalents Cu(OAc)2.H2O

1 equivalent pyridine1,4-Dioxane, 105 °C, 20 h

+

Y = O, SY

X

N

NN

N

OR3

R2

R1

O

Y

Y = O, SZ = NMe, O

3 equivalents

Z

NX

Y

Y = O, S

X

N

O

X = Me, OMe, CHO, COMe, CN, alkenylR1, R2 = alkyl, R3 = H, alkyl

25−96% yield


X = CHO, COMe X = Me, CHO, alkenyl

dppf = 1,1'-bis(diphenylphosphino)ferrocene

Scheme 250 Pd-catalyzed coupling of furans/thiophenes and heteroarenes (You et al., 2010).

Subsequently, You and coworkers described an analogous hetero-coupling of indoles and pyrroles with heteroarenes-

containing acidic C–H bonds (Scheme 251).338 Similar to the above reactions, a wide range of heteroarenes reacted with indoles

or pyrroles under a new catalytic system as shown in Scheme 251. In contrast to the C2 selectivities in the above reactions

involving thiophenes and furans, this reaction occurred selectively at the 3-positions of pyrroles and indoles. For the other

coupling partners, the most acidic C–H bonds were the reactive sites and cleaved selectively. Interestingly, 2-substituted thiazole

gave 5-arylated product.

N

NN

N

OMe

Me

Me

ONY

X

R

N

Y

X

RN

NN

N

OMe

Me

Me

O

5 mol% Pd(dppf)Cl25 mol% X-Phos20 mol% CuCl

3 equivalents Cu(OAc)2.H2O

1 equivalent pyridine1,4-dioxane/DMSO

105 °C, 30 h

+

Y = CH, NX = H, Me, OBn, Cl, NO2; R = H, Me, Bn, MOM

N

X

ON R

X

N NR

N

S NMePri

X = CH, NR = Me, Bn

X = O, SR = Me, Bn

49−93% yield

55−84% yield 51−60% yield70% yield

Scheme 251 Pd-catalyzed coupling of indoles/pyrroles and heteroarenes (You et al., 2011).

Concurrently, Zhang and Li reported Pd(II)-catalyzed oxidative coupling between pyridine N-oxides and N-substituted indoles

with using Ag2CO3 as an oxidant and the additive tetrabutylammonium bromide (TBAB).339 The reactions also took place at the

3-position of indoles selectively. In addition, the heterocoupling between xanthines and simple arenes has also been disclosed.340

Although the coupling partners in the above reactions have distinctly differentiated C–H bonds, Ofial and coworkers reported

oxidative cross-coupling of two heteroarenes with similar electronic characteristics: azoles and benzazoles (Scheme 252).341

A broad-scope of azoles, including imidazoles, oxazoles, and thiazoles, coupled with benzazoles selectively to afford 2,20-

bisheteroaryls in high yields. The use of Agþ was mandatory for the highly selective heterocoupling. The C–H bonds of more

electron-rich azoles were believed to be cleaved as the initial step. The formed heteroarylpalladium(II) intermediate promoted a

second C–H cleavage selectively with benzazoles.



Y

N N

Z

5−10 mol% Pd(OAc)22 equivalents Cu(OAc)2

2 equivalents AgF orKF/AgNO3 (3/1.5 equivalents)

DMF, 120 °C, 24−48 h

X1 X2+N

ZX2

N

YX1

Y = O, S, NR1

1.5 equivalentsZ = S, NR2

X1 = H, Me, Cl, 4-Br-C6H4; R1 = Me, vinyl, C6HF4X2 = H, 3,4-dimethyl; R2 = Me, Bn

61−95% yield

Scheme 252 Pd-catalyzed coupling of azoles and benzazoles (Ofial et al., 2011).


3.23.5.1.3 Palladium-catalyzed intramolecular coupling of two C–H bondsAs far as selectivity is concerned, the intramolecular dehydrogenative coupling of two C–H bonds should be less challenging

because of entropically favored intramolecular reaction. As intermolecular reaction, Pd-catalyzed intramolecular coupling of two

arenes have attracted great attention342,343 since the oxidative coupling of benzene to biphenyl reported by van Helden and

Verberg in 1965.323 One of the earliest examples is the Pd(OAc)2-catalyzed coupling of diphenyl ether to dibenzofuran disclosed

by Itanani and coworkers in 1973.344,345 In this reaction, the yield of dibenzofuran was up to 10 400% based on the reacted

Pd(OAc)2. In 1975, Akermark and coworkers reported Pd(OAc)2-mediated intramolecular dehydrogenative coupling of diphenyl

ether, diphenylamine, benzophenone, and benzanilide.346 Subsequently, the catalytic reactions were also achieved by the same

authors.347 Oxygen was the sole oxidant, and a variety of heterocyclic compounds were synthesized via double C–H activation.

Furthermore, the palladium-mediated intramolecular coupling of N-arylindoles and N-arylpyrroles were also demonstrated by

Itahara and coworkers.348–351

In 2008, Fagnou and coworkers developed new reaction conditions to improve intramolecular biaryl coupling

(Scheme 253).352 Under the new conditions, which employed pivalic acid as the solvent, diphenylethers or diphenylamines

underwent intramolecular dehydrogenative coupling with greater reproducibility, higher yields, and broader scope.

Y

X

Y

X

3−10 mol% Pd(OAc)210 mol% K2CO3

Air, pivalic acid110 or 120 °C, 14−48 h

Y = NH, OX = H, Me, OMe, F, Ac, NO2

58−95% yield

Scheme 253 Pd-catalyzed intramolecular coupling of two arenes (Fagnou et al., 2008).

Interestingly, the Fujii, Ohno and coworkers developed an efficient method for construction of various functionalized car-

bazoles by one-pot N-arylation-oxidative biaryl coupling from readily available anilines and phenyl triflates (Scheme 254).353 The

reactions started with Pd(0)-promoted Buchwald–Hartwig amination. The subsequent intramolecular coupling afforded func-

tionalized carbazoles.

OTf

X1H2N

X2

HN

X1 X2

+


1.1 equivalents

AcOH, 80 °C, 22.5 hPri Pri

Pri

PCy2

Ligand

X1 = H, Me, But, OMe, Ph, COMe, F, CF3, CO2Me, CO2BnX2 = H, Ph, CF3, CO2Me

20−99% yield

NH

X1 X2

1 atm O2 or air

1.2 equivalents Cs2CO3toluene, 100 °C, 1.5 h

Scheme 254 Pd-catalyzed intramolecular coupling of two arenes in the one-pot synthesis of carbazoles (Fujii and Ohno et al., 2009).

Six-membered rings can also be constructed through Pd-catalyzed intramolecular dehydrogenative coupling. The first example

is the oxidative cyclization shown in Scheme 255, which was reported by the Fagnou and coworkers.354

Subsequently, Dong and coworkers described the oxidative cyclization of N-phenylbenzamides (Scheme 256).355 In the

presence of Na2S2O8 and TFA, a range of six-membered lactams could be synthesized efficiently.




O

N

MeO2C

Me Me

Me 10 mol% Pd(OAc)220 mol% NaOBut

PivOH, 120 °C, 6 h

O

N

MeO2C

Me MeMe

92% yield

Scheme 255 Pd-catalyzed intramolecular coupling of pyrrole and benzene (Fagnou et al., 2008).

MeNO

X1X2

MeNO

X1X2

10 mol% Pd(OAc)23 equivalents Na2S2O8

5 equivalents TFADCE, 70 °C

X1 = H, alkenyl; X2 = H, mono- or di-OMe, OCH2O 30−77% yield

Scheme 256 Pd-catalyzed intramolecular coupling of N-phenylbenzamides (Dong et al., 2010).


The intramolecular coupling between 1,2,3-triazoles and phenyl groups were demonstrated by Ackermann and coworkers

(Scheme 257).356 The direct arylation of 1,2,3-triazoles provided a facile way for the synthesis of annulated phenanthrenes.

A variety of tethers were compatible with the reaction.

Y

NN

N

RX

Y

X


Toluene/pivalic acid (6/1)140 °C, 20 h

Y = C, OX = H, alkyl, F, Cl; R = alkyl

54−93% yield

NN

N

R

Scheme 257 Pd-catalyzed intramolecular coupling of 1,2,3-triazoles and simple arenes (Ackermann et al., 2010).

Remarkably, Greaney and Pintori disclosed an effective strategy for synthesizing medium-ring compounds via intramolecular

C–H coupling for the first time (Scheme 258).357 In the presence of Cu(OAc)2 and K2CO3, tethered indoles and phenyl groups

underwent dehydrogenative coupling, forming annulated heterocycles. Both seven- and eight-membered rings could be con-

structed efficiently, and a rich array of functional groups was well tolerated. In addition to phenyl groups, heteroarenes such as

indoles, benzimidazoles, and pyrazoles, also underwent coupling reaction with indoles under the reaction conditions.

Mechanistically, the indoles were proposed to be palladated first. The second C–H activation involved a CMD mechanism.

Y N

ZZ1

R

X1

X2 Y N

R

X1

ZZ1

X2


1 equivalent K2CO3

DMA, 90 or 120 °C, 16 h

R = CHO, CN, NO2; X1 = H, OMe, etc.X2 = H, OMe, F, CF3, Me

Y N

R

X1 Y N

R

X1

Z2 X2 Z2

X2

51−62% yield

63−95% yieldY = CH, N; Z = CH2, OZ1 = CH2, NMe, NMs

Y = CH; Z2 = NR

Scheme 258 Pd-catalyzed intramolecular coupling of indoles and arenes to construct medium-rings (Greaney et al., 2011).

Finally, intramolecular C(sp2)-H/C(sp3)-H coupling was reported by Fagnou and coworkers in 2008 (Scheme 259).354 By using

air as the terminal oxidant, the coupling of pyrroles and unactivated methyl groups proceeded smoothly in the presence of Pd(OAc)2





N

OMe

R2 R1

X

N

X

O R2R1

10 mol% Pd(OAc)220 mol% NaOBut

Air, pivalic acid120 °C, 15 h

X = Me, CO2Me, aryl, Ac, COPh; R1, R2 = alkyl12−69% yield

Scheme 259 Pd-catalyzed intramolecular coupling of arenes and unactivated alkane (Fagnou et al., 2008).


and NaOBut. The reactions exhibited high regioselectivity with respect to both the pyrrole and the methyl moieties. The proposed

mechanism involved the palladation of pyrroles as the first step. The subsequent sp3 C–H activation was the rate-limiting step.

3.23.5.1.4 Palladium-catalyzed-directed coupling of two C–H bondsAlthough the intermolecular C–H coupling of two arenes involves regioselectivity for both of the two coupling partners, the

introduction of directing groups can avoid this problem at least for one of the reactants. This strategy gained considerable interests

recently, and a wide range of directing groups has been successfully employed to promote this type of dehydrogenative coupling.

In 2007, Sanford and Hull described oxidative cross-coupling of Benzo[h]quinolines and simple arenes (Scheme 260).358 A

diverse variety of simple arenes were found to be effective coupling partners. The reactions were highly chemoselective and

homocoupling of either benzo[h]quinoline or arene partners was not observed. As usual, the C–H activation for benzo[h]qui-

noline was controlled by the directing group. For most of the reacting simple arenes, their C–H bonds were also cleaved with high

regioselectivity, which was controlled by steric effects. Although 1, 2-disubstitued arenes gave 4-arylated products, the reactions

occurred primarily at the less-hindered 5-positions for 1,3-disubstituted arenes. For monosubstituted arenes, the regioselectivities

were still poor. Furthermore, pyridine, pyrimidine, and pyrazole were also found to be effective directing groups. It is remarkable

that benzylic C(sp3)-H bond underwent the coupling with benzene under the reaction conditions. The mechanism experiments

supported that directing group-assisted C–H activation took place first, followed by a second C–H cleavage of simple arenes via a

dissociative s-bond metathesis mechanism. The use of a substoichiometric quantity of a 1,4-benzoquinone (BQ) derivative was

required to promote the oxidative coupling reaction and the regioselectivity was strongly influenced by the structure of the

quinone for some simple arenes. Subsequently, the authors carried out the detailed mechanistic studies to elucidate the role of

the quinone in this novel coupling reaction.359 It was found that the rate-determining step in the reaction was dependent on the

concentration of the quinone promoter. Therefore, at high concentration, the C–H activation of the simple arenes was the rate-

limiting step. However, benzoquinone-promoted reductive elimination was rate-limiting at low concentration of benzoquinone.

NX

10 mol% Pd(OAc)20.5 equivalent benzoquinone

2 equivalents Ag2CO3

4 equivalents DMSO130 °C, 12 h

+

65−100 equivalents

N

X

NMeO

N

N

Cl

Cl

NN NMe

X = H, Me, OMe, F, Cl, NO2 5−93% yield

46% 69% 48% 26%

Scheme 260 Pd-catalyzed heteroarene-directed coupling of two C–H bonds (Sanford et al., 2007).

Concurrently, the You and coworkers reported a facile method for the arylation of ferrocene via dehydrogenative coupling of

ferrocenes bearing oxazoline as the directing group (Scheme 261).360 Although the catalytic reactions gave moderate yields, the

FeN

O

X1 equivalent Pd(OAc)2

then 2.3 equivalents K2CO3

100 or 120 °C, 8−51 h+ Fe

N

O

Ar FeN

O

Ar

Ar

+

Solvent26−70% total yield (mono-/di- ≥ 32:3)

Scheme 261 Pd-catalyzed oxazoline-directed coupling of ferrocene and simple arenes (You et al., 2007).





use of a stoichiometric amount of Pd(OAc)2 proved more successful. The reactions were tolerant of a wide range of arenes,

including electron-neutral, -rich, and -deficient ones. It is noteworthy that diastereoselectively pure products were obtained when

enantiopure ferrocenyl oxazolines were used.

Another concurrent work was the cross-coupling of N-acetanilides and simple arenes disclosed by Shi and coworkers

(Scheme 262).361 In the reactions, oxygen was used as the oxidants along with a catalytic or stoichiometric amount of Cu(OTf)2.

The reactions displayed a broad substrate scope with respect to both coupling partners. Interestingly, the authors demonstrated

that the formed 2-arylated acetanilides could underwent cyclization via an intramolecular C–H amination, providing an efficient

method for the synthesis of carbazole structures. The practicability of this method was demonstrated by a short synthesis of

4-deoxycarbazomycin B.

NAcR

X1 X2NAc

R

X1 X210 mol% Pd(OAc)2

0.1−1 equivalent Cu(OTf)2

O2 (1 atm)EtCOOH, 120 °C

+

SolventX1 = H, Me, OMe; X2 = H, Me, Ph, OPh, CH2CH2O, F; R = H, alkyl

16−86% yield

Scheme 262 Pd-catalyzed acetamide-directed coupling of N-phenylacetamides and simple arenes (Shi et al., 2008).

Shortly thereafter, Buchwald and coworkers reported a similar arylation of acetanilides with simple arenes.362 By using oxygen

as the sole oxidant and TFA as the solvent, a wide range of N-acetanilides were allowed to couple with various arenes in the

presence of 10 mol% Pd(OAc)2 and 10–20 equivalents DMSO, affording 2-arylated acetanilide products.

O-carbamates were also found to be effective directing groups to assist the coupling of O-phenylcarbamates and simple arenes

(Scheme 263).363 Na2S2O8 was used as the oxidant and the addition TFA was critical for the successful cyclopalladation of

O-phenylcarbamates. In addition to benzene, a variety of ortho-disubstituted benzenes were found to be reactive, and the reactions

took place at the 4-positions selectively for these arenes. Diarylated O-phenylcarbamates were obtained when two ortho-C–H

bonds were available and no meta-substituents were present. The authors carried out detailed mechanistic studies, and the

experimental results supported a mechanism involving cyclopalladation of O-phenylcarbamates as the first C–H activation. The

formed palladacycles underwent electrophilic metalation with simple arenes. However, the authors noted that a CMD could not

be ruled out.

10 mol% Pd(OAc)23 equivalents Na2S2O8

5 equivalents TFA70 °C, 30−68 h

+ R

X = H, alkyl, OMe, Ph, CO2Me, F, Cl;R = H, Me, OMe, F, Cl

40 equivalents

RO

X

OMe2N

OX

OMe2N

R

R

44−98% yield

Scheme 263 Pd-catalyzed carbamate-directed coupling of O-phenylcarbamates and simple arenes (Dong et al., 2010).

The above coupling protocol proved to be versatile. A broad class of arenes, including phenylacetamides, benzamides, and

anilides, underwent cross-coupling reaction efficiently with simple arenes in a similar manner to the reactions of O-phe-

nylcarbamates.355 The intramolecular dehydrogenative coupling of benzanilides also proved viable under the similar conditions,

affording lactam products. It is noted that although the reactions with these substrates yielded the similar outcomes as the

arylation of O-phenylcarbamates, the mechanisms may be different. It was evidenced by the observations that the bimetallic

palladium complex derived from O-phenylcarbamates underwent the ortho-arylation with simple arenes in excellent yields

in the absence of any external oxidant, the addition of Na2S2O8 was required for the arylation of the palladacycles of

N-(m-tolyl)pivalamide and N-phenylpyrrolidine.

Finally, Yu and coworkers reported the cross-coupling of benzamides and monosubstituted arenes (Scheme 264).364 In the

reactions, the acidic amide derived from 4-trifluoromethyl-2,3,5,6-tetrafluoroaniline was used as the directing group, and an Fþ

reagent as the bystanding oxidant. A great breakthrough for this reaction was that excellent para-selectivity was achieved for the

C–H functionalization of monosusbstituted arenes. As discussed in Sections 3.23.2.1.1.1 and 3.23.3.1.1.1, the reactions involving

the C–H activation of monosubstituted simple arenes always gave a mixture of regiomers with poor selectivities, in the alkeny-

lation or cross-coupling reactions. Remarkably, a wide range of monosubstituted arenes were para-arylated with high selectivities.

Only a minor amount of meta-isomers was formed, and no ortho-products were observed. In some of the reactions, the para-

isomers were the sole products. The use of Fþ oxidant was crucial for the para-selectivity, and other oxidants such as Na2S2O8 gave



10 mol% Pd(OAc)21.5 equivalents NFSI

2 equivalents DMF70 °C, 48 h

+ RX

ONHAr

RX

ONHAr

X = H, Me, OMe, OAc, COMe, F, Cl, Br, CN, CF3R = H, Me, Et, Pri, OMe, F, Cl, Br

Solvent48−86% yield

Ar =

F F

F F

CF3

Scheme 264 Pd-catalyzed amide-directed coupling of benzamides and monosubstituted arenes with high regioselectivities (Yu et al., 2011).


a low selectivity. The [ArPd(IV)F] species, which was formed through the oxidation of the palladacycles derived from the ben-

zamides by the Fþ oxidant, was proposed to be partially responsible for selective para-C–H cleavage of monosubstituted arenes.

3.23.5.2 Other Transition-Metal-Catalyzed Reactions with C–H Bonds

Contrary to the availability of a great number of examples for palladium-promoted dehydrogenative reactions, other transition-

metal-catalyzed oxidative coupling of two C–H bonds are quite rare. In 2009, Daugulis and coworkers disclosed copper-catalyzed

homocoupling of arenes with one atmosphere of oxygen as the terminal oxidant (Scheme 265).365 Therefore, a variety of

heteroarenes and polyfluoroarene underwent deprotonative dimerization in the presence of CuCl2 and a strong base, affording

symmetrical biaryl products. The strong base could be hindered magnesium or zinc amides, but the exact composition of the

bases needed to be optimized for each substrate. For polyfluoroarenes, the method was tolerant to functionalities such as ester,

amino, cyano, and nitro group.

Ar H

1−3 mol% CuCl21.2−1.5 equivalents base

O2 (1 atm)THF, 0−50 °C

Ar Ar

Ar =

N

SH

OH

SH

ClN

NH

Bu

N

N

NH

Bu

N

N OMe

HN

Cl Cl

H

HFn

73% 73% 56% 74%

71% 51% 50% 70−91%X = H, OMe, NMe2, CN,CO2Et, NO2; n = 2, 4

X

Scheme 265 Cu-catalyzed homocoupling of (hetero)arenes (Daugulis et al., 2009).

Subsequently, the same authors developed a general method for a highly regioselective copper-catalyzed cross-coupling of two

different aromatic compounds (Scheme 266).366 In the reactions, one of the arenes was initially iodinated with iodine, and the

formed iodides reacted with the most acidic C–H bond of the other coupling component, yielding cross-coupling products.

Several coupling protocols were developed based on the operative iodination mechanisms. As a result, the method displayed

excellent substrate scope, and cross-coupling of electron-rich arenes, electron-poor arenes, and five- and six-membered

Ar H

10 mol% CuI/phenanthroline1.2−1.5 equivalents I2

0−1.0 equivalent pyridine1,2-dichlorobenzene or dioxane

base, 130 °C

Ar Ar1H Ar1+

Compatible coupling partners:

Ar = Electron-rich arenes; Ar1 = Heterocycles and electron-poor arenes;Ar = Electron-deficient arenes; Ar1 = Heterocycles and electron-poor arenes;Ar = Five-membered heterocycles; Ar1 = Heterocycles and electron-poor arenes;Ar = Pyridines; Ar1 = Heterocycles and electron-poor arenes.

Scheme 266 Cu-catalyzed coupling of two different (hetero)arenes (Daugulis et al., 2011).





heterocycles proved viable in many combinations. Although most of the existing dehydrogenative arene cross-coupling reactions

employed one of the arenes as the solvent, a 1/1.5–1/3 ratio of coupling components was used in this remarkable method.

The directing group-assisted dehydrogenative coupling has also been developed by the Hirano, Miura group in 2011

(Scheme 267).367 Therefore, 2-phenylpyridines and benzoquinolines coupled with azoles in the presence of a stoichiometric

amount of Cu(OAc)2 and pivalic acid. The reactive azoles included benzoxazoles, 3-substituted oxazoles, and an imidazole

derivative. Two equivalents of azoles were enough to ensure the heterocoupling reactions to take place efficiently. Based on the

results of the mechanism experiments, the authors proposed the following reaction steps: (1) reversible C–H cupration of the

azoles involving carboxyl-ligand-promoted proton abstraction, (2) C–H metalation of the arylazine, and (3) productive reductive

elimination.365

N

+

N5 equivalents Cu(OAc)21 equivalent PivOH

Mesitylene, N2, 170 °C, 2 hY

NX

Y

N X

Y = O, N2 equivalents

X = alkenyl, aryl, etc. 32−78% yield

Scheme 267 Cu-mediated pyridine-directed coupling of arenes and oxazoles/imidazoles (Hirano and Miura et al., 2011).

Ru has also been utilized to promote the coupling of two C–H bonds. In 2008, the Oi and Inoue and coworkers reported

directed homocoupling reaction of aromatic compounds catalyzed by a ruthenium complex (Scheme 268).368 The catalytic

system consisted of [RuCl2(cod)]n, PPh3 and methyl allyl acetate as the hydrogen scavenger. Arenes bearing a variety of nitrogen-

containing heteroaryl, including oxazole, imidazole, pyrazole, or thiazole, could be homocoupled regioselectively.

NY

NY

NY 2.5 mol% [RuCl2(cod)]n

10 mol% PPh33.0 equivalents methylallyl acetate

1.0 equivalent K2CO3o-xylene, 120 °C, 20 h

Y = O, NMe, S

XX

X

X = H, Me, OMe, Ph, alkenyl, CF3 30−96% yield

Scheme 268 Ru-catalyzed homocoupling of arylazoles (Oi and Inoue et al., 2008).

Remarkably, Li and coworkers reported Ru-catalyzed C(sp2)-H/C(sp3)-H coupling reactions (Scheme 269).369 Therefore, in the

presence of the catalyst [{Ru(p-cymene)Cl2}2] and oxidant ButOOH, 2-phenylpyridines reacted with simple cycloalkanes to give

alkylated products. Depending on the structures of 2-phenylpyridines, monoalkylated or a mixture of mono- and dialkylated

products were obtained. The proposed mechanism involved the initial chelation-assisted C–H activation of 2-phenylpyridines, the

reaction of the formed ruthenacycles with cycloalkanes and the peroxide, and the final reductive elimination to afford the final

coupling products (Figure 29).369

N+

5 mol% [{Ru(p-cymene)Cl2}2]4 equivalents ButOOH

135 °C, 16 h

1 equivalent

XN

X and/or NX( )n

( )n

( )n

( )nn = 1, 2, 3

SolventX = H, Me, OMe, Ph, F, CO2Et, alkenyl 42−75% total yield

Scheme 269 Ru-catalyzed pyridine-directed alkylation of arenes with cycloalkanes (Li et al., 2008).

Subsequently, the Li and coworkers described the para-selective coupling of substituted arenes and cycloalkanes catalyzed by

Ru3(CO)12/dppb (bis(diphenylphosphino)butane) (Scheme 270).370 The peroxide TBP (di-tert-butyl peroxide) was used as the

oxidant. A wide range of benzenes bearing one substituent were found to undergo dehydrogenative coupling with cycloalkanes.

The arenes with one electron-withdrawing substituent, such as COOMe, COOH, COMe, and CONHMe, were alkylated with high




+

10 mol% Ru3(CO)125 mol% dppb

2 equivalents TBP135 °C, 12 h

R R( )n

n = 1, 2, 3Solvent

R = H, carbonyl, CN, OMe, halo, py

26−95% yield

( )n

Scheme 270 Ru-catalyzed alkylation of simple arenes with cycloalkanes (Li et al., 2011).

Ru

N

Ru HN

Ru

NN

HRO–OR +2 HOR

Figure 29 Proposed mechanism of Ru-catalyzed pyridine-directed alkylation of arenes.


para-selectivity; the substituents F, Cl, Br, OMe, and CN mainly gave para-alkylated products. It is remarkable that para-functio-

nalized products instead of ortho-ones were produced even in the presence of the widely employed directing group in transition-

metal-catalyzed C–H functionalization. In addition, the 1, 2- and 1, 3-disubstituted arenes also gave high para-selectivity.

Finally, although the methylene C–H bond of diphenylmethane is quite acidic, we wish to illustrate the intriguing Fe-catalyzed

cross-coupling of benzylic C–H bonds with arenes disclosed by Shi and coworkers (Scheme 271).371 Thus, diphenylmethanes

underwent ‘cross-dehydrogenative arylation’ (CDA) with a rich array of simple arenes in the presence of FeCl2 and 2, 3-dichloro-5,

6-dicyano-1, 4-benzoquinone (DDQ). The reaction displayed excellent functional group compatibility and gave high regio-

selectivity for the arene-coupling partners. The ortho- and para-alkylated products were formed preferentially for the arenes bearing

electron-donating groups. This proposed mechanism involved single-electron-transfer oxidation and Friedel–Crafts alkylation.

The observed large primary kinetic isotope effect for diphenylmethane (kH/kD¼6.0) indicated that benzylic C–H bond cleavage

was the rate-limiting step.

+

10 mol% FeCl22.5 equivalents DDQ

DCE, 100 °C, 36 h

X Ar1

Ar2

Ar1

Ar2

X

X = Me, OMe, SMe, OAc, halo, CHO, OMe, CO2Me51−96% yield

Scheme 271 Fe-catalyzed coupling of benzylic C–H bonds and arenes (Shi et al., 2009).

3.23.6 Miscellaneous C–H Functionalization Reactions

In addition to the four major categories of reactions presented in Sections 3.23.2, 3.23.3, 3.23.4, and 3.23.5, C–H bonds have also

been demonstrated to be able to react with a variety of other reaction partners to form C–C s-bonds. In this section, four types of

reactions will be discussed, including alkynylation with terminal alkynes, decarboxylative coupling with aromatic acids, tri-

fluoromethylation, and alkylation by reacting with a-C–H bonds of carbonyl groups.

3.23.6.1 C–H Alkynylation with Terminal Alkynes

In Sonogashira reaction, the cross-coupling between a hetero(aryl) halide and a terminal alkyne, serves as a powerful tool for the

functionalization of terminal alkynyl carbons. Recently, an alternative strategy, an ‘inverse Sonogashira coupling,’ has gained





considerable attraction.372 The new strategy involves the direct alkynylation of unreactive C–H bonds with alkynyl halides.

However, the more attractive methods are the direct coupling between C–H bonds and terminal alkynes. The development of such

a reaction has been hampered mainly by the uncontrolled homocoupling of terminal alkynes.

In 2010, Li and coworker reported Pd-catalyzed coupling of indoles and terminal alkynes (Scheme 272).373 Therefore, a variety

of terminal alkynes reacted with 1, 3-dialkylindoles in the presence of a catalytic amount of K2PdCl4 and a buffer system

consisting of Cs2CO3 and PivOH, affording 2-alkynylated indole products. Oxygen was used as the oxidant, and the use of the

buffer system was crucial for high yields. To suppress its homocoupling, acetylene was added slowly using a syringe pump. The

N

R1

Me

X + H R2

10 mol% K2PdCl420 mol% Cs2CO3

2 equivalents PivOH

O2 (1 atm),DMSO, 80 °C, 24 h

NR1

Me

X R2

X = H, Me, OMe, Cl; R1 = Me, Bn; R2 = aryl, Si (Pri)3, C8H17 15−73% yield

Scheme 272 Pd-catalyzed C2-alkynylation of indoles (Li et al., 2010).

proposed mechanism included the following reaction sequences: (1) the alkynes were palladated by reacting with Pd(II) catalyst

with the assistance of CsOPiv; (2) the key C–H cleavage involved the electrophilic attack of the formed alkynylpalladium species

at the 2-position of the indoles and the subsequent deprotonation by CsOPiv; (3) the reductive elimination gave the final

coupling products and Pd(0), which was reoxidized to Pd(II) in the presence of O2 and PivOH (Figure 30).373

Pd(II)

PhPd(II)

PhH

N

Me

Me

Pd(II)H

Ph

+ PivO−N

Me

Me

Pd(II) Ph

Pd(0)

N

Me

Me

PivOH

N

Me

Me

Ph

O2

Figure 30 Proposed mechanism of Pd-catalyzed alkynylation of indoles.

Subsequently, the Chang and coworkers described the alkynylation of azoles using the conditions shown in Scheme 273.374 A

wide range of alkynes were found to be effective coupling partners, and the reactive azoles included benzoxazoles, oxazoles, and

benzothiazoles. The reaction of a partially saturated oxazoline was also demonstrated, albeit in a poor yield. Contrary to the

mechanism proposed in the Li’s reactions, the C–H cleavage of azoles in this reaction was proposed to take place before the

palladation of alkynes. The active Pd(II) species was generated in situ by the oxidation of Pd(0).

Y

NX + H R

5 mol% Pd(PPh3)44 equivalents LiOBut

Toluene, air, 100 °C, 12 h Y

NX R

3 equivalentsY = O, S

X = H, Me, OMe, aryl, Cl; R = aryl, heteroaryl, alkenyl, Cy, TIPS

31−88% yield

Scheme 273 Pd-catalyzed alkynylation of azoles (Chang et al., 2011).

Cu has also been found to enable the coupling of arenes and terminal alkynes. In 2010, Miura and coworkers disclosed copper-

mediated alkynylation of 1,3,4-oxadiazoles and oxazoles in the presence of CuCl2, Na2CO3, and one atmosphere of oxygen

(Scheme 274).375 The presence of oxygen was necessary for the reaction to occur, since the N2 atmosphere did not lead to the

product even in the presence of a stoichiometric amount of CuCl2. A rich array of terminal alkynes bearing substituents such as

aryl, alkenyl, and alkyl groups was compatible under the reaction conditions. The proposed mechanism involved the initial ligand

exchange between Cu(II) species and the terminal alkyne, the subsequent cupration of an oxadiazole or oxazole, and the final




Y

O

N+ H R2

1 equivalent CuCl22.0 equivalents Na2CO3

O2 (1 atm)DMAC, 120 °C, 1 h

2.5 equivalentsY = CH, N

R1

Y

O

N

R1

R2

R1 = aryl, PhCH2CH2; R2 = aryl, 3-thienyl, 1-cyclohexenyl, Cy, alkyl

42−74% yield

Scheme 274 Cu-catalyzed alkynylation of 1, 3, 4-oxadiazoles and oxazoles (Miura et al., 2010).


reductive elimination to yield the coupling products. Oxygen may act as a promoter in the productive reductive elimination by

coordinating to the copper center (Figure 31).375

Cu(II)H R2

Cu(II) R2Cu(II) R2NY

OR1

+ Na2CO3

N Y

O R1

O2

NY

OR1

R2

Figure 31 Proposed mechanism of Cu-catalyzed alkynylation of 1,3,4-oxadiazoles and oxazoles.

Concurrently, the Su and coworkers achieved Cu-catalyzed alkynylation of polyfluoroarenes by using a catalytic system

consisting of CuCl2, 1,10-phenanthroline and DDQ (Scheme 275).376 The use of the strong base LiOBut was required and oxygen

was used as the oxidant. The reactions exhibited a broad substrate scope with respect to alkynes. Although penta- and a range of

tetrafluoroarenes were compatible under the reaction conditions, di- or trifluoroarenes did not yield the desired products,

presumably because of the decreased acidity. The possible mechanism was similar to that proposed by Miura and coworkers.

+ H R

30 mol% CuCl230 mol% 1, 10-phenanthroline

15 mol% DDQ

4 equivalents LiOBut, O2 (1 atm)DMSO, 40 °C, 12 h

Fn Fn

R

2 equivalentsn = 4, 5R = aryl, heteroaryl

30−85% yield

Scheme 275 Cu-catalyzed alkynylation of polyfluoroarenes (Su et al., 2010).

Finally, Miura and coworkers reported Ni-catalyzed coupling of azoles and terminal alkynes under the conditions shown in

Scheme 276.377 The reactive azoles included benzoxazoles, oxazoles, and benzothiazoles, and both of aryl- and alkyl- terminal

alkynes were compatible in the reaction. The mechanism was proposed to parallel that of Cu-promoted azole alkynylation.

Moreover, the catalytic alkynylation of perfluoroarenes using Cu(OTf)2 was also described.

Y

NX + H R

5 mol% NiBr2.diglyme5 mol% dtbpy

3 equivalents LiOBut, O2 (1 atm)Toluene, 100 °C, 1 h

Y

NX R

2 equivalentsY = O, SX = H, Me, aryl, Cl; R = aryl, n-C6H13, Si(Pri)3

37−62% yield

dtbpy = 4,4'-di(tert-butyl)-2,2'-bipyridine

Scheme 276 Ni-catalyzed alkynylation of azoles (Miura et al., 2010).






3.23.6.2 Decarboxylative C–H Arylation with Aromatic Acids

There is a developing interest in decarboxylative coupling reactions and numerous catalytic transformations have been dis-

covered.378 In these decarboxylative transformations, carboxylic acids can function as the synthetic equivalent of either aryl

halides or organometallic reagents. In comparison to the traditional coupling partners, many aromatic acids are easily available,

cheap, stable, and nontoxic.

Recently, combining decarboxylative coupling and C–H activation has gained much attention. One of the earliest examples

was disclosed by Crabtree and coworkers.379 Therefore, under the conditions as shown in Scheme 277, anisole was allowed to

react with 3, 5-dimethoxylbenzoic acid to form the meta- and para-coupling products as well as the protonated byproduct 1,3-

dimethoxybenzene. However, the arenes bearing directing groups were arylated with 4-methoxybenzoic acid at the ortho-positions

selectively. In the reaction, microwave heating was crucial and greatly enhanced yields and shortened reaction time. In addition,

the intramolecular coupling of 2-phenoxybenzoic acid also proved viable under the similar conditions, yielding the annulated

product, dibenzofuran, in a moderate yield.

DG+

O

HO

10 mol% Pd(OAc)220 mol% But-XPhos

1.25 equivalents Ag2CO3

DMF/DMSO (9/1)MS 4 Å

mw 200 °C, 5 min

DG

DG = pyridyl,CH3CONH, CH3CO

1.24 equivalents

+ OMeOMe

OMe

O

HO

OMe

OMe

MeO MeOOMe

OMe

OMe

OMe

+ +

95% (meta-/para-/protonated = 1/3/5)


Scheme 277 Pd-catalyzed decarboxylative coupling reaction with arenes (Crabtree et al., 2008).

The highly efficient intramolecular decarboxylative coupling of 2-phenoxybenzoic acids was achieved using a new catalytic

system consisting of Pd(TFA)2 and Ag2CO3 by Glorius and coworkers (Scheme 278).380 The Ag salt not only assisted the

decarboxylation, but also acted as the oxidant for the C–H activation. The reaction accommodated a range of functionalities such

as F, Cl, and Br. Dibenzofurans were formed in good yields and only a trace amount of protonation products were observed. The

suggested mechanism involved Ag-mediated decarboxylation, transmetalation with Pd(II) catalyst to form arylpalladium species,

and final reductive elimination to afford dibenzofurans as the final products.

O

COOH

X1 X2

15 mol% Pd(TFA)23 equivalents Ag2CO3

1,4-dioxane/DMSO(20/1)150 °C, 14 h O

X1 X2

X1, X2 = H, Me, But, OMe, alkenyl, halo 39−85% yield

Scheme 278 Pd-catalyzed intramolecular decarboxylative coupling reaction (Glorius et al., 2009).

Concurrently, Larrosa and coworkers reported Pd(MeCN)2Cl2-catalyzed coupling of N-pivaloylindole and benzoic acids

(Scheme 279).381 The reactive benzoic acids were limited to those bearing ortho-electron-withdrawing substituents, and the

reaction took place at the 3-positions of the indoles selectively. Mechanistically, the authors proposed that the C–H activation

involved electrophilic palladation of indoles by Pd(II) catalyst, affording arylpalladium species. The Ag(I)-mediated decarbox-

ylation formed arylsilver, which underwent transmetalation to the arylpalladium species to yield aryl-Pd-aryl complex. The

subsequent reductive elimination gave the final coupling products (Figure 32).381

N

X1

+HO

O20 mol% Pd(MeCN)2Cl23.0 equivalents Ag2CO3

2.4 equivalents DMSODMF, 110−120 °C, 3−16 h

2 equivalents

R

O But

N

X1

O But

R

X2

X2

X1 = H, Me, OMe, Cl, Br, CO2Me; X2 = H, Me, OMe, F, NO2

R = F, Cl, NO244−76% yield

Scheme 279 Pd-catalyzed decarboxylative coupling reaction with indoles (Larrosa et al., 2009).




Pd(II)

Pd(0)

RN

Pd(II)

X

RN

Pd(II)

Ar

Ag(I)

Ar–Ag(I)

Ar

O

O Ag

Ar-COOH

CO2

Ag(0)

NR

NR

Ar

C-H arylationcycle

DecarboxylationcycleAg(I)

Figure 32 Proposed mechanism of Pd-catalyzed decarboxylative coupling reaction with indoles.


Subsequently, the Su and coworkers developed a versatile protocol for regioselective arylation of indoles with benzoic acids

(Scheme 280).382 Although the benzoic acids with ortho-electron-donating functionalities gave 2-arylated indole products, the

arylation took place at the 3-positions of indoles selectively for the benzoic acids bearing ortho-electron-withdrawing groups under

similar conditions. Mechanism experiments revealed that Pd(TFA)2 alone could enable the decarboxylation of 2,4-dimethoxybenzoic

acid and the arylation reaction. However, Ag2CO3 was required for the decarboxylation of electron-deficient benzoic acids. Based on

these observations, the authors suggested that two different mechanisms were operative in this novel arylation reaction. In the cases

of electron-rich benzoic acids, the decarboxylation was promoted by Pd(II), and the C2-selectivity resulted from the migration of

aryl–Pd fragment from C3 to C2. As for electron-deficient benzoic acids, Ag(I) was still responsible for the decarboxylation.

NAc

X1 +

HO

O X27.5 mol% Pd(TFA)2

2.0 equivalents Ag2CO30.25 equivalent EtCOOH

1.5 equivalents TMSO1,4-dioxane, 80 °C, 24 h

NAc

X1

5 equivalents

NR1

X1 +

HO

O X2

15 mol% Pd(TFA)23.0 equivalents Ag2CO3

0.25 equivalent EtCOOH

NR1

X1

R1 = Ac, Piv2.5−3 equivalents

X2

X2

1.5 equivalents TMSODMF, 115−120 °C, 24 h

R

R

R

R

X1 = H, Me, OMe, halo, NO2, CO2Me; X2 = H, Me, OMe, F, Br, NO2, etc.R = OMe, F, Cl, NO2

31−78% yield

13−69% yieldTMSO = tetramethylene sulfoxide

Scheme 280 Pd-catalyzed decarboxylative coupling reaction with indoles (Su et al., 2010).

Greaney and coworkers reported decarboxylative C–H cross-coupling of azoles (Scheme 281).383 A range of substituted

oxazole/thiazole-5-carboxylic acids coupled with various 5-substituted oxazoles to afford 2,50-biazole products. The absence of

5-substituents for the oxazoles without carboxylic acids led to the formation of mixtures of products because of the difficulty in

N

X

20 mol% Pd(OAc)25 mol% dcpe

3.0 equivalents CuCO3

Dioxane/DMSO (9/1)MS (4 Å), 140 °C, 16 h

CO2HO

N+

N

X O

N

X = O, S

R3

R4

R3

R4

R1

R2

R1

R2

R1 = Me, aryl; R2 = H, Me, CO2HR3 = alkyl, aryl, CO2Et; R4 = CO2Et, H, SO2Tol

45−82% yield

dcpe = bis(dicyclohexylphosphino)ethane

Scheme 281 Pd-catalyzed decarboxylative coupling reaction for biheteroaryl synthesis (Greaney et al., 2010).





discriminating the 2- and 5-positions. Only the arylation of 2,4-disubstituted oxazole/thiazole-5-carboxylic acids were demon-

strated. The isomeric oxazole-4-carboxylic acids without 5-substituents could give multiarylated products because of C–H/C–H

cross-coupling.

Concurrently, the Tan and coworkers disclosed the arylation of benzoxazoles/benzothiazoles and polyfluoroarenes via de-

carboxylative C–H coupling (Scheme 282).384 The reaction was compatible to a broad range of benzoic acids, including electron-

rich and electron-poor ones. The arylation of 4,5-dimethylthiazole was also effective under the reaction conditions.

Y

NX1 +

HO

O X220 mol% PdCl240 mol% PPh3

3 equivalents Ag2CO3DMSO, 130 °C, 12 h

Y = O, S, NMe 1.5 equivalents

Y

NX1

X2

F

R1

F

FF

orF

R1

F

FF

X2

R1 = F, MeO; R2 = NO2, OMe, FX1 = H, dimethyl; X2 = H, Me, OMe, F, Cl

R2

49−63% yield

42−63% yield or

R2

R2

Scheme 282 Pd-catalyzed decarboxylative coupling reaction with benzoxazoles and polyfluorobenzenes (Tan et al., 2010).

Intriguingly, the Ge and coworkers reported a novel acylation method via decarboxylative C–H coupling with a-oxocarboxylic

acids (Scheme 283).385 Therefore, a broad range of acetanilides were ortho-acylated with various 2-oxo-2-phenylacetic acids using

the catalyst Pd(TFA)2 and the oxidant (NH4)2S2O8. It is noted that no silver salts were required to promote decarboxylation and

the reaction proceeded smoothly at room temperature. The reactions exhibited an excellent substrate scope with respect to both of

the substrates. A diversity of functionalities, including F, Cl, and Br, were well tolerated. In addition, the similar acylation of

2-phenylpyridines was also demonstrated by the same authors.386 The catalytic system consisted of Pd(PhCN)2, Ag2CO3, and

K2S2O8.

10 mol% Pd(TFA)22 equivalents (NH4)2S2O8

Diglyme, r.t., 9−36 h

HN O

Me

+X1

O

O

HO

X2

NH

X1

Me

O O

X2

2−3 equivalentsX1 = H, Me, Pri, Bn, halo, Ac, CO2H, CO2MeX2 = H, Me, OMe, halo, CF3, NO2, alkenyl

43−95% yield

Scheme 283 Pd-catalyzed decarboxylative acylation of acetanilides with a-oxocarboxylic acids (Ge et al., 2010).

3.23.6.3 C–H Trifluoromethylation

The introduction of trifluoromethyl groups into organic molecules can dramatically change their physical properties and bio-

logical activity, and trifluoromethylated aromatic compounds are widely found in pharmaceuticals, agrochemicals, and organic

materials.387 Therefore, the development of new methods for the introduction of trifluoromethyl groups has gained considerable

attention, and a number of protocols for efficient trifluoromethylation have been reported. In particular, transition-

metal-catalyzed cross-coupling has emerged as a powerful tool for the construction of C(sp2)-CF3 bond.388

Recently, direct C–H trifluoromethylation has been the subject of intense research, and a variety of transition metals have been

demonstrated to be able to promote C(sp2)-CF3 bond formation via C–H activation. In 2010, Yu and coworkers reported Pd-

catalyzed-directed trifluoromethylation of arenes using the CF3þ reagent 5-(trifluoromethyl)dibenzothiophenium tetra-

fluoroborate (Scheme 284).389 In this reaction, a wide range of N-containing heteroarenes, including pyridine, pyrimidine,

imidazole, and thiazole could be used as the directing group, and TFA was crucial for the success of this novel trifluoromethylation

method. In addition, Cu(OAc)2 was found to enhance the catalytic turnover effectively.

The above strategy has been successfully extended to the trifluoromethylation of N-arylbenzamides (Scheme 285).390

Therefore, under similar conditions, a range of N-(2,3,5,6-tetrafluoro-4-(trifluoromethyl)phenyl)benzamides were ortho-

trifluoromethylated with 5-(trifluoromethyl)dibenzothiophenium triflate. N-methylformamide was crucial for the effective C–CF3

bond formation.



CONHAr

X


15 equivalents N-methylformamideTFA, DCE, 130 °C, 24 h

+ S

CF3OTf−

CONHAr

X

CF3

Ar = (4−CF3)C6F41.5 equivalents

X = H, Me, But, OMe, Ph, halo, CF3, CO2Me, alkenyl

40−94% yield

Scheme 285 Pd-catalyzed acidic amide-directed trifluoromethylation of N-arylbenzamides (Yu et al., 2012).

N

Y

XN

Y

X

CF3


10 equivalents TFADCE, 110 °C, 48 h

+S

CF3BF4

−

1.5 equivalentsY = CH, N

N

MeN

N

SMe

CF3CF3

N

CF3

X = H, Me, OMe, Cl, alkenyl54−87% yield

53% 74% 88%

Scheme 284 Pd-catalyzed heteroarene-directed trifluoromethylation (Yu et al., 2010).


It is noted that Sanford and coworkers carried out the detailed mechanistic studies of the trifluoromethylation with CF3þ

reagents.391 The authors systematically investigated the formation of the monomeric Pd(IV) aquo complex (bzq)Pd(CF3)-

(OAc)2(OH2) and its reductive elimination to form aryl C–CF3 bond. The experimental data provided evidence that the formation

of a Pd(IV) intermediate, which was produced through the oxidation of the arylpalladium(II) species by the CF3þ reagent, was

responsible for the aryl C–CF3 bond formation. The reductive elimination of the Pd(IV) species can afford the trifluoromethylated

products effectively and generate Pd(II) catalyst. Actually, the major challenge in transition-metal-catalyzed aryl C–CF3 bond

forming reaction is that CF3 ligands are typically inert toward C–C bond-forming reductive elimination. However, it has been

shown that the formation of Pd(IV) species can accelerate reductive elimination which is difficult to occur on the other metal

center.392 As such, the trifluoromethylation protocol involving the formation of Pd(IV) intermediates with CF3þ reagents pro-

vides a novel strategy for the development of trifluoromethylation reactions.

Subsequently, the Liu and coworkers developed another trifluoromethylation method by using the CF3� reagent TMSCF3.393

Therefore, 3-substituted indoles underwent 2-trifluoromethylation smoothly under the conditions shown in Scheme 286.

3-Trifluoromethylation could be enabled by blocking the 2-position with a substituent, and the reaction for indoles without 2 or 3

substituents occurred at the 3-positions selectively, albeit in a low yield. The addition of TEMPO significantly improved the

reaction yields, which was against a possible radical pathway. The reaction may also involve a Pd(II)/Pd(IV) catalytic cycle.

However, the Pd(IV) species were formed through oxidation by PhI(OAc)2 instead of CF3þ reagents.

NR

X

+ TMSCF3


2 equivalents PhI(OAc)2

0.5 equivalent TEMPO4 equivalents CsF

CH3CN, r.t.

NR

X1

4 equivalents

R2

CF3

R2

NMe

X R1

NMe

X R1

CF3

O

N N

O

Ligand

X = H, Me, OMe, Cl, Br, CO2MeR1 = H, Me, Ph; R2 = alkyl, Cy, cyclopentyl, CO2Me

R = alkyl, Bn, Ph, SEM

39−66% yield

33−83% yield

Scheme 286 Pd-catalyzed trifluoromethylation of indoles with TMSCF3 (Liu et al., 2011).

Buchwald described the copper-catalyzed allylic trifluoromethylation of unactivated terminal olefins (Scheme 287).394 In the

presence of the catalyst [(MeCN)4Cu]PF6, terminal olefins reacted with the Togni electrophilic trifluoromethylating reagent to give

linear allylic trifluoromethylation products in good yields. The reactions also displayed high E/Z selectivity with E/Z ratios ranging

from 89:11 to 97:3.




R

15 mol% [(MeCN)4Cu]PF6

MeOH, 0 °C–r.t., 24 hR CF3+

1.25 equivalentsI O

O

F3CR = Ph, Bn, alkyl

54−80% yieldE/Z ≥ 89/11

Scheme 287 Cu-catalyzed allylic trifluoromethylation of terminal alkenes (Buchwald et al., 2011).


Concurrently, the Liu and coworkers reported an analogous Cu-catalyzed allylic trifluoromethylation using 5-(tri-

fluoromethyl)dibenzothiophenium tetrafluoroborate as the trifluoromethyl source (Scheme 288).395 The Cu(I) salts (thiophene-

2-carbonyloxy)copper (CuTc) and the ligand 2,4,6-trimethylpyridine gave the best yields, and the reaction showed good

functional group tolerance. Mechanistically, both experimental and theoretical analyses indicated that the trifluoromethylation

may occur via a Heck-like four-membered-ring transition state.393

R

20 mol% CuTc2 equivalents ligand

DMAc, 40 °C, 48 hR CF3+ S

CF3BF4

−

1.2 equivalents Tc = thiophene-2-carbonyloxy

Ligand =

NR = alkyl

32−78% yield

Scheme 288 Cu-catalyzed allylic trifluoromethylation of terminal alkenes (Liu et al., 2011).

Sanford and coworkers disclosed Ag-mediated trifluoromethylaion of simple arenes with TMSCF3 in the presence of KF

(Scheme 289).396 Various substituted arenes and benzene were trifluoromethylated effectively under the conditions as shown in

the scheme. A mixture of regioisomers was obtained for substituted arenes. In addition, heteroarenes such as N-methylpyrrole,

thiophene, and caffeine also underwent such a reaction. For N-methylpyrrole and thiophene, the reactions took place at the C2

positions preferentially. Although the detailed mechanism remains to be clarified, the authors proposed that the reactions

proceeded via an AgCF3 intermediate, and preliminary mechanistic studies suggested against a free CF3� pathway.

+ TMSCF3

4 equivalents AgOTf4 equivalents KF

DCE, N285 °C, 24 h5−20 equivalents

X X

CF3

NMe S

N

N

N

NO

O

CF3CF3 CF3

X = H, Me, OMe, I, alkenyl46−88% yield

44% 72% 42%

Scheme 289 Ag-mediated trifluoromethylation of (hetero)arenes with TMSCF3 (Sanford et al., 2011).

3.23.6.4 C–H Alkylation with a C–H Bonds of Carbonyl Groups

In 2010, during the course of the investigation of the direct coupling of acetophenones with aryl iodides, Cheng and coworkers

obtained the cyclization product phenanthrones, which arose from the intramolecular reaction of aryl C–H bonds with the a-C–H

bonds of the carbonyl groups following the coupling reaction of the acetophenones and the aryl iodides (Scheme 290).397 The

prepared coupling intermediate ortho-arylated acetophenones also underwent the cyclization reaction under the same conditions,

affording phenanthrone products.

In 2009, Kundig and coworkers developed a novel and efficient method for the synthesis of oxindoles by the Cu-mediated

oxidative coupling of aryl C–H bonds and a-C–H bonds of amides (Scheme 291).398 Therefore, N,2-diphenylacetamide deriv-

atives underwent intramolecular a-arylation reaction effectively in the presence of CuCl2 and ButONa to yield the cyclization

product oxindoles. The reactive substrates were limited to those with one a-hydrogen and N-protected amide groups. In addition,

the presence of the a-aryl groups was crucial for the success of the a-arylation reaction. The proposed mechanism involved a

radical pathway.

Taylor and coworkers reported an analogous Cu-mediated a-arylation via C–H activation for the synthesis of 3,3-disub-

stituted oxindoles (Scheme 292).399 In the reactions, electron-withdrawing groups were introduced to activate the a-C–H bonds

instead of phenyl groups that were used in the Kundig method. The author also preferred a radical mechanism, which




N

O

R1 R2

X1 X2

NX1

R2

R1

O

X22.2 equivalents CuCl25 equivalents ButONa

DMF, 110 °C, 3−24 h

X1 = H, Me, OMe, CF3; X2 = H, Me, OMe, alkenylR1 = Me, Bn, CH2CH2CH2; R2 = alkyl, Bn 32−97% yield

Scheme 291 Cu-mediated intramolecular C(sp2)-H alkylation (Kundig et al., 2009).

NEWG

O

Me RN

EWGR

Me

ODMF, 110 °C, 1 h

R = Me, PhEWG = COOEt, CN, P(O)(OEt)2

1.0 equivalent Cu(OAc)2•H2O

93−98% yield


Scheme 292 Cu-mediated intramolecular C(sp2)-H alkylation (Taylor et al., 2009).

OX1

IX2 10 mol% Pd(OAc)2

1.0 equivalent Ag2O

TFA, 120 °C, 20 hX1

O

X2+

3 equivalents

10 mol% Pd(OAc)21.0 equivalent Ag2O

TFA, 120 °C, 20 h

O

X3O

X3

X1 = H, Me, Cl, Br; X2 = H, OMe, CO2Et, NO2

X3 = H 94%4−F 92%

20−92% yield

Scheme 290 Pd-catalyzed intramolecular C(sp2)-H alkylation (Cheng et al., 2010).


involved the generation of a b-dicarbonyl-flanked radical by Cu(II) and the subsequent intramolecular homolytic aromatic

substitution.

Subsequently, the a-arylation reaction was rendered catalytic by using air as the oxidant (Scheme 293).400 The reaction could

be run in mesitylene or toluene. Interestingly, no additional base was required.

NEWG

O

R1 R2

X

NX

EWGR2

R1

OMesitylene, air, 165 °C, 1−3 h

X = H, OMe, CF3, CO2EtR1 = Me, Bn; R2 = Me, Bn, allyl, etc.EWG = CO2Et, CO2Pri, CO2But, CN

53−92% yield

5 mol% Cu(OAc)2•H2O

Scheme 293 Cu-catalyzed intramolecular C(sp2)-H alkylation (Taylor et al., 2010).

Allylic alkylation provides a powerful tool for the construction of C–C bonds, and has found widespread use in modern

organic synthesis. In such a reaction, a substrate containing a leaving group at the allyl position is generally employed. Just as

other C–H functionalization reactions, allylic C–H alkylation is highly advantageous because it could allow for the direct

functionalization of simple allylic compounds and avoid the prefunctionalization required in the traditional allylic alkylation. As

early as 1978, Trost and coworkers reported two-step allylic C–H alkylation in the presence of stoichiometric amount of

Pd(OAc)2, mainly because the in situ reoxidation of Pd(0) to Pd(II) was difficult.401 The catalytic version of such a reaction was






not achieved until the Shi and coworkers reported the first Pd-catalyzed allylic C–H alkylation in 2008 (Scheme 294).402

Therefore, inter/intramolecular coupling between allylic C–H bonds and a-C–H bonds of 1,3-diketones proceeded smoothly in

the presence of BQ and an atmosphere of oxygen. For the intramolecular reactions, simple aliphatic allylic substrates were reactive

and the internal allylic alkylation products were formed because of the preferential formation of five- or six-membered rings. In

the case of prochiral substrates, two diastereoisomers were isolated in high diastereoselectivities. As for the intermolecular

reactions, the substrates bearing allylic aryl groups were required, and the reactions yielded linear alkylation products. The

proposed mechanism involved the formation of p-allylpalladium via an electrophilic allylic C–H bond cleavage by Pd(II) catalyst.

The subsequent nucleophilic attack by 1,3-dicarbonyl compounds or their enolate forms afforded the final allylic alkylation

product. BQ acted as the oxidant to reoxidize Pd(0) to Pd(II) to fulfill the catalytic cycle (Figure 33).402

R

O O

Ar R1 R2

O O

+

10 mol% Pd(OAc)21.3 equivalents BQ

O2 (balloon)toluene, 60 °C, 48 h

Ar

O

O

R1

R2

( )n ( )n

R

O O15−20 mol% Pd(OAc)21.3 equivalents BQ

O2 (balloon)toluene, 60 °C, 60 h

n = 1, 2 25−53% yield

R1, R2 = Me, Et, Ph 16−82% yield

Scheme 294 Pd-catalyzed allylic alkylation of C(sp3)-H bonds (Shi et al., 2008).

Pd(II)

Ph

Pd(II)Pd(0)

Ph

H

[H]

NuHPh Nu

BQ

[HH] +

Figure 33 Proposed mechanism of Pd-catalyzed allylic alkylation of C(sp3)-H bonds.

Simultaneously, the White and coworkers reported an analogous intermolecular allylic C–H alkylation under the conditions

shown in Scheme 295.403 The p-acceptor ligand DMSO was critical for the reactions to occur. Although the allylic aryl group was

also required to achieve high yields, aliphatic allylic substrates were also reactive, albeit in a very poor yield. In addition to

benzoylnitromethane, methyl nitroacetate and (phenylsulfonyl)nitromethane also afforded alkylated products in excellent yields.

The reaction furnished excellent E/Z selectivity (420:1) and good regioselectivity, with a linear: branched product ratio 43 in

most of the cases.

Ar MeONO2

O

+

10 mol% catalyst1.5 equivalents DMBQ

0.5 equivalent AcOH1,4-dioxane/DMSO (4/1)

45 °C, 24 h

Ar O

OMe

NO23 equivalents

S SPh Ph

O O

Pd(OAc)2

Catalyst

•O

OMe

NO2

Ar

+

Major Minor50−83% total yield

(Major/minor = 1.7/1 to >20/1)

Scheme 295 Pd-catalyzed allylic C–H alkylation (White et al., 2008).

Remarkably, the White and coworkers successfully achieved the intermolecular allylic alkylation of unactivated a-olefins by

using the ligand benzyl bis(sulfoxide) in place of benzyl bis(sulfoxide) (Scheme 296).404 In the allylic C–H alkylation reaction

developed by the White and coworkers, the ligand bis(sulfoxide) was crucial for the C–H activation and the addition of DMSO

was required to promote the subsequent alkylation. However, DMSO also could inhibit the binding of bis(sulfoxide) to the




R PhNO2

O

+

10 mol% catalyst5 mol% 1,2-bis(benzylsulfinyl)ethane

1.5 equivalents DMBQ1,4-dichloroethane/DMSO (7/3)

45 °C, 72 h

R O

Ph

NO24.0 equivalents

S SBn Bn

O O

Pd(OAc)2

Catalyst

•

R = alkyl, alkenyl, aryl, CONEt2, etc.49−73% total yieldL/B = 5/1 to >20/1

E/Z > 20/1

Scheme 296 Pd-catalyzed allylic C–H alkylation of unactivated a-olefins (White et al., 2011).


palladium center and consequently suppress the allylic C–H activation, so the substrate scope of the above alkylation protocol was

limited to activated allylic substrates. The new ligand benzyl bis(sulfoxide) is a stronger s-donor than benzyl bis(sulfoxide) and is

better able to compete with DMSO for binding to the palladium center, which accounted for the success of this novel alkylation

reaction. The reaction proceeded with high regioselectivity (L/B420:1 in most cases) and excellent E/Z selectivity (420:1) and a

variety of functionality at the homoallylic positions were well tolerated. Furthermore, the reaction conditions were also amenable

to allylbenzene substrates and other classes of activated substrates such as amides and enols.

In 2006, the Li and coworkers disclosed the Cu-catalyzed alkylation of cycloalkenes with 1, 3-dicarbonyl compounds, which is

the first catalytic allylic C–H alkylation (Scheme 297).405 Therefore, by using a combination of the catalysts CuBr and CoCl2, a

range of cycloalkenes reacted with 1,3-diketones and acetoacetate derivatives in the presence of the oxidant TBHP to afford allylic

alkylation products. The alkylation of cycloheptatriene and cyclopentadiene also took place under the reaction conditions, albeit

in low yields. Mechanistically, the authors proposed that the reaction started with the formation of a p-allyl copper or allyl cobalt

complex via the allylic H-abstraction. Subsequently, standard allylic alkylation followed by oxidation furnished the alkylation

product and regenerated the catalyst.

R1 R2

O O

R3 H

( )n +

2.5 mol% CuBr10 mol% CoCl2

2 equivalents TBHP80 °C, overnight

R1 R2

O O

R3

( )nn = 1, 2, 3, 4

R1, R2 = alkyl, alkoxyl, aryl, CH2Cl; R3 = H, alkyl5 equivalents

30−71% yield

O O

O

O

41% 18%

Scheme 297 Cu-catalyzed allylic C(sp2)-H alkylation (Li et al., 2006).

3.23.7 Summary and Outlook

Transition-metal-catalyzed C–H functionalization has made explosive growth over the last two decades, and has emerged as a

powerful tool for forming various chemical bonds, including C–C, C–X, C–N, C–O, and C–S. As classical transition-metal-

promoted reactions, reactions via C–H activation have also proved most valuable in the construction of C–C bonds, especially

C–C s-bonds. It has been demonstrated that a variety of C–C s-bonds can be formed through transition-metal-catalyzed C–H

functionalization. Although the formation of aryl–aryl and aryl–alkenyl bonds has proved the most successful, other C–C s-bonds

such as aryl–alkyl, aryl–alkynyl, and alkyl–alkyl have also been constructed effectively. To form these C–C s-bonds, a diverse

variety of reactions via C–H activation have been developed. The major strategy is to substitute C–H bonds for one of the reaction

partners in classical coupling reactions. Therefore, C–H bonds can react with (pseudo)halides, organometallic reagents to form

C–C bonds. Heck-type C–H alkenylation involves the reactions of C–H bonds with alkenes, which also may provide alkylation

products, depending on the catalyst and reaction conditions. The reaction of C–H bonds with carbonyl and imino groups have

also been demonstrated, which afford expedient methods for the synthesis of ketones or amines, respectively. The more attractive

dehydrogenative cross-coupling, wherein two reaction partners are replaced with C–H bonds, offer a waste-free and the most

atom-economic method for C–C bond formation. In addition, many other types of C–H functionalization reactions have been

reported, which include alkynylation with terminal alkynes, arylation with benzoic acids, trifluoromethylation with CF3þ or CF3

�

reagents, and alkylation with activated C(sp3)-H bonds.

Pd is the most-extensively investigated transition metal in C–H activation. It has been successfully utilized to promote almost

all the types of reactions discussed in this chapter. Rh and Ru also proved applicable in various C–H functionalization reactions.




The first-row transition metals, especially Fe, Cu, and Ni, also attract considerable interests because of their low cost and rich

abundance in nature. These metals are also able to act as effective catalysts to enable C–C s-bonds formation, mainly aryl–aryl

bond formation.

It is noted that transition-metal-catalyzed C–H functionalization reactions has proved viable in the synthesis of complex

natural products, and quite a few examples have been reported. However, many major challenges must still be overcome before

the reactions find broad applicability.

1. Most of transition-metal-catalyzed C–H functionalization reactions are run under harsh conditions such as high temperature,

which diminishes their practicality, especially in the synthesis of complex molecules. However, quite a few examples, which

proceed effectively under mild conditions, have been reported. It indicates that C–H activation and the subsequent function-

alization reaction can take place even under mild conditions. Developing new catalysts and ligands may be a solution to

achieve this end.

2. Many C–H functionalization reactions, especially Pd-catalyzed reactions, require 5–10 mol% catalyst, or even higher.

Considering the high cost of these transition metals, it is necessary to lower the catalyst loading and improve turnovers.

3. One of the greatest advantages for C–H activation is that it can reduce the production of chemical wastes. However, in many

cases, the C–H functionalization reactions require the use of stoichiometric amounts of oxidants, which end up with chemical

wastes. It not only increases the cost of the reactions, but also cancel the chemical waste-saving advantage of C–H activation. To

solve this problem, developing reactions using cheap and safe oxidants such as air or avoiding the use of oxidant may be the

long-term goal. Fortunately, many examples using oxygen or air as the oxidant are available, which laid a foundation for

developing chemical-waste-saving C–H activation reactions.

4. Although the existence of ubiquitous C–H bonds in organic molecules offers great opportunities for the development of C–H

activation reactions, it also causes troubles for selective functionalization. Although the use of directing groups can afford high

regioselectivity, selective C–H activation in the absence of directing groups is still a challenge. The introduction and removal/

conversion of directing groups not only cost additional synthetic steps, but also limits the substrate scope. Hence, developing

regioselective C–H activation without the assistance of directing groups is paramount.

5. Although a few examples have been reported, enantioselective C–H functionalization is still a great challenge. The major

hurdle is the lack of effective chiral ligands which can not only facilitate C–H activation, but also furnish high enantio-

selectivities. Furthermore, the use of harsh conditions, which are required in most of the current C–H activation reactions, also

hamper high enantioselectivity.

6. Understanding the detailed reaction mechanisms underlying the C–H activation reactions will lay a foundation for developing

new catalytic systems to solve the above problems. Many mechanism experiments have been carried out to decipher the

mechanism responsible for the C–H activation, and many reasonable mechanism have been proposed. However, more strong

experimental evidences are needed, and more detailed mechanisms have yet been elucidated.

In addition, there still exists a wide variety of C–C bond-forming reactions via C–H bond activation remain to be developed,

and continuous efforts are needed to direct toward more practical methods for the construction of C–C s-bonds.

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