DOI: 10.1002/asia.

201403224 Focus Review

Homogeneous Catalysis

Transition-Metal-Catalyzed p-Bond-Assisted C H Bond

Functionalization: An Emerging Trend in Organic Synthesis
Parthasarathy Gandeepan and Chien-Hong Cheng*[a]

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Abstract: Transition-metal-catalyzed C H activation is con- ortho-selective C H bond cleavage. However, recent work
sidered to be an important tool in organic synthesis and has has demonstrated that p-coordinating functional groups can
been accepted and widely used by chemists because it is also assist in guiding metal complexes for site-selective C H
straightforward, cost-effective, and environmentally friendly. bond activation. This emerging approach significantly ex-
A variety of functional groups have been used to direct pands the scope of C H activation reactions in organic syn-
metal complexes and achieve regioselective C H activation. thesis. Herein, recent developments in this field are summar-
Most directing is achieved through the s-bond coordination ized.
of functional groups to the metal catalyst, followed by

1. Introduction et al. in 1993,[5a] many functional groups, including ketones,[5]

aldehydes,[6] carboxylic acids,[7] hydroxyls,[8] imines,[9] oximes,[10]
Carbon–carbon (C C) and carbon–heteroatom (C X) bonds are amides,[11] anilides,[12] and nitrogen heterocycle[13] functional
the basis of organic molecules. Therefore, synthetic organic groups, among others,[14] have been used in this regard.
chemists have always been interested in the development of In most cases, an oxygen or nitrogen atom in the functional
new and convenient methods for the construction of these group interacts with the metal complex through s coordination
bonds, leading to substantial advances in metal-mediated/-cat- of electron lone pairs. This coordination can be interpreted as
alyzed cross-coupling reactions for their formation in the last Lewis acid–base adduct formation, in which the metal complex
few decades.[1] In particular, the representative reactions of this acts as the Lewis acid by accepting electrons from the Lewis
class of transformations, namely, the Mizoroki–Heck reaction, base directing group (DG; Scheme 1). Complex formation is af-
Negishi coupling, and Suzuki coupling, were recognized with fected by several factors, such as the metal complex, functional
the 2010 Nobel Prize in Chemistry. However, these reactions group, solvent, and temperature.
traditionally require functionalized starting compounds, such
as organic halides or pseudo halides, and organometallic re-
agents, which often limit their application in late-stage func-
tionalization in complex organic synthesis. In addition, these
coupling reactions produce significant salt waste as a byprod-
uct.
Recently, transition-metal-catalyzed C H bond activation has
emerged as an effective strategy in C C and C X bond forma-
tion that avoids the need for prefunctionalized starting materi-
als, reduces or eliminates salt waste, and reduces production
time and costs by improving step and atom economy. Owing Scheme 1. s-Bond coordination-assisted ortho-metalation. MO = molecular
orbital.
to these attractive features, C H activation reactions have
been heavily studied and many reviews have appeared in the
literature.[2–4] Therefore, this review only covers p-bond-assisted Because several metal complexes with unsaturated p-bond-
C H activation reactions. ing ligands are known in the literature (Scheme 2), it is unsur-
prising that such ligands can also be used as DGs in these re-

2. Coordination-Assisted C H Bond Activation

Selective functionalization of the C H bond is highly challeng-
ing because of its inert nature and abundance in organic mole-
cules. However, advances in metal-complex-mediated reactions
over the past decade have overcome many of these difficulties,
with directing-group-assisted C H activation having become
particularly common. After the breakthrough report of rutheni-
um-catalyzed ketone-directed ortho-C H activation by Murai

[a] Dr. P. Gandeepan, Prof. Dr. C.-H. Cheng

Department of Chemistry
National Tsing Hua University
Hsinchu 30013 (Taiwan)
Fax: (+ 886) 3572-4698
Web:
E-mail: chcheng@mx.nthu.edu.tw Scheme 2. Metal complexes with p-donor ligands. cod = 1,5-cyclooctadiene,
Homepage: http://mx.nthu.edu.tw/ ~ chcheng/ dba = dibenzylideneacetone, Cp* = pentamethylcyclopentadienyl.

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 Focus Review

of maleimide yields A3, and consecutive insertion into the Ir H

bond gives A4. This is followed by intramolecular migration,
resulting in A5. Coordination and insertion of the second male-
imide eventually leads to the seven-membered iridacycle A7,
then reductive elimination leaves product 3 and regenerates
the catalyst.

Scheme 3. p-Bond coordination-assisted ortho-metalation. 3.1.2. Palladium-Catalyzed Carbonylation of Styrenes

In 2007, Ishii et al. described a palladium-catalyzed carbonyla-
actions (Scheme 3). The p-bond coordination is generally tion reaction of styrenes and carbon monoxide that yielded ar-
weaker than s-bond coordination with regard to metals be- ylnaphthalene-1(4H)-ones 5 (Scheme 6).[17] The reaction pro-
cause p-bonding electron pairs tend to be lower in energy ceeds in the presence of a catalytic amount of Pd(OAc)2 and
than lone pairs. HPMoV under a 1:1 ratio of oxygen and carbon monoxide at
a pressure of 1.0 atm. Styrenes substituted with electron-with-
drawing groups failed to give the product. The reaction is
3. p-Bond Coordination-Assisted C H Activa- likely to proceed in two stages, beginning with the palladium-
tion catalyzed head-to-tail dimerization of 1 to form but-1-ene-1,3-
3.1 Alkene-Assisted C H Activation diyldibenzene 6, and ending with carbonylation.
A possible mechanism for this transformation is depicted in
3.1.1 [4+2] Cycloaddition of Styrene with N-Benzyl- Scheme 7.[17] First, compound 6, the production of which is al-
maleimide lowed given the reaction conditions, coordinates to Pd(OAc)2
The first metal olefin complex, Zeise’s salt (Scheme 2), was dis- at two of the C=C double bonds and facilitates ortho-C H acti-
covered in 1827.[15] Many organometallic complexes containing vation of the aryl group to give intermediate B2. Insertion of
p-donor ligands were synthesized thereafter, and have been CO into the Pd C bond, followed by reductive elimination, af-
used in organic and inorganic synthesis. For example, Kiyooka fords product 5 and palladium(0). The palladium(0) species is
and co-workers demonstrated p-bond coordination-assisted then oxidized back to the active palladium(II) species by
C H bond activation by using iridium complexes.[16] They re- HPMoV/O2.
ported the reaction of styrene (1) and N-benzylmaleimide (2)
in the presence of [{IrCl(cod)}2] and 2,2’-bipyridine (bpy) in tolu-
ene at 150 8C for 3 days to give product 3 in 63 % yield, in ad- Chien-Hong Cheng, former Director General of
dition to various byproducts (Scheme 4). The reaction proceeds the Department of Natural Sciences, National
through the in situ formation of the cationic iridium complex Science Council, President of Chemical Society,
4. Taiwan, and Vice President for Academic
Affairs of National Tsing Hua University
(NTHU), currently serves as a Chair Professor
at the Department of Chemistry, NTHU, and
has also held a National Chair in chemistry
since 2009. His research interests include the
development of new synthetic methods that
use organometallic compounds as catalysts
and the synthesis of organic materials and the
fabrication of devices with these materials for
organic light-emitting diodes.

Parthasarathy Gandeepan was born in Seeya-

mangalam village, Thiruvannamalai district,
Tamil Nadu, India, in 1985. He completed his
B.Sc. in chemistry at Arignar Anna Government
Arts College, Cheyyar, and his M.Sc. in organic
chemistry at the Department of Organic
Scheme 4. Iridium-catalyzed p-bond-assisted C H activation. Chemistry, University of Madras, Chennai,
India. He obtained his Ph.D. in 2012 from
National Tsing Hua University, Hsinchu, Tai-
wan, under the supervision of Professor Chien-
A possible catalytic cycle for this reaction is shown in Hong Cheng. Currently, he is working as a
Scheme 5.[16] The reaction is likely to be initiated by the coordi- postdoctoral fellow in the same group. His
nation of 1 to 4 to form the coordinatively unsaturated inter- research interests include transition-metal-
catalyzed C H bond activation, cross-cou-
mediate A1. Then, intermediate A1 undergoes oxidative addi- pling, and multicomponent reactions.
tion to the ortho-C H bond to give A2. Next, the coordination

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3.1.3. Rhodium-Catalyzed Di-

merization of Styrenes Involv-
ing ortho-C H Bond Activation

Tobisu and co-workers were the

first to report the rhodium-cata-
lyzed dimerization of styrenes in-
volving ortho-C H bond cleav-
age.[18] In contrast to the conven-
tional head-to-tail, tail-to-tail, or
head-to-head dimers, they ob-
served the unusual dimerization
product 7 in moderate yields
after reacting various styrenes in
the presence of 10 mol %
[{RhCl(cod)}2], 20 mol % tBuOH,
and 40 mol % Na2CO3 in 1,4-diox-
ane at 160 8C for 15 h
(Scheme 8). The reaction does
not proceed with other metal
complexes, including [Ru3(CO)12],
Scheme 5. A possible mechanism for iridium-catalyzed p-bond-assisted C H activation. [Ni(cod)2], and [Pd(PPh3)4]. Styr-

Scheme 6. Palladium-catalyzed carbonylation of styrenes.

HPMoV = H5PMo10V2O40·26 H2O.
Scheme 8. Rhodium-catalyzed dimerization of styrenes through ortho-C H
bond cleavage.

enes substituted with electron-withdrawing groups displayed

better reactivity than those with electron-donating groups.
Two possible mechanisms are considered for this reaction
(Scheme 9).[18] In path A, the reaction is initiated by the coordi-
nation of styrene to the rhodium center to form p-complex
C1, which undergoes oxidative cyclization to give intermediate
C2 and a consecutive 1,2-hydride shift to give rhodium(III) hy-
dride complex C3. Insertion of the second styrene molecule
into the Rh C bond, followed by intramolecular hydrometala-
tion, gives C5. Sequential b-hydride elimination and reductive
elimination gives 7 and regenerates the rhodium(I) species.
Path B in Scheme 9, meanwhile, begins with the in situ for-
mation of a rhodium hydride complex from tert-butyl alcohol
Scheme 7. Mechanism for the carbonylation of styrenes.
and [{RhCl(cod)}2]. Hydrometalation of this species into the sty-
rene gives the alkyl rhodium intermediate C7, which then un-
dergoes 1,4-migration to provide the arylrhodium intermediate
C8. Insertion of the second styrene into the Rh C bond, fol-

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takes place prior to C H pallada-

tion because similar values
should be observed otherwise.

3.1.5. Palladium-Catalyzed An-

nulation of Allylarenes with In-
ternal Alkynes through C H
Activation
Cheng and Gandeepan reported
the synthesis of highly substitut-
ed naphthalenes from substitut-
ed allylarenes and internal al-
kynes by using a catalytic
amount of Pd(OAc)2.[20] The reac-
tion of allylarene 6 with an
alkyne, by using 10 mol %
Pd(OAc)2, 20 mol % Cu(OAc)2,
and 10 equivalents of TFA in o-
Scheme 9. Possible mechanisms for rhodium-catalyzed styrene dimerization. xylene under an oxygen atmos-

lowed by b-hydride elimination, leaves 7 and regenerates the

rhodium hydride. Path B in Scheme 9 is unlikely, however, be-
cause the formation of intermediate C7 would be unfavorable
compared with the formation of C10.

3.1.4. Palladium-Catalyzed Allylic Olefin Assisted C H Bond

Alkenylation
In 2012, Cheng and Gandeepan demonstrated a palladium-cat-
alyzed C H olefination of arenes containing a substituted allyl
group.[19] The reaction proceeded under mild conditions and
used oxygen as an oxidant. Reaction of 6 and activated olefins
in the presence of 10 mol % Pd(OAc)2 and 8 equivalents of tri-
fluoroacetic acid (TFA) in dichloromethane (DCM) at room tem-
perature for 36 h gave ortho-olefinated allylarenes 8 in good to
excellent yields (Scheme 10). TFA was essential for efficient
conversion. The reaction is very selective and effectively
cleaves the C H bond of the arene attached to the allylic C=C
bond at the ortho position. No C H activation was observed
when using vinylic or butenylic C=C bonds as DGs.
Scheme 10. Palladium-catalyzed allylic double-bond-assisted C H olefina-
A possible mechanism for this reaction is shown in tion.
Scheme 11.[19] First, a cationic palladium complex is formed in
situ and coordinates to the allylic olefin, yielding p-complex
D1. This complex undergoes ortho-C H palladation to form phere at 80 8C for 30 h, gave substituted naphthalenes 9 in
the palladacycle D2, which then allows for insertion of the good yields (Scheme 12). This reaction also worked in the ab-
other olefin into the Pd C bond, forming 8 and H Pd X after sence of Cu(OAc)2, but was less effective. No reaction was ob-
b-hydride elimination. Reductive elimination of HX from H served without TFA. Unsymmetrical alkynes produced two re-
Pd X results in palladium(0), which is oxidized to the active gioisomeric products. Substrates with meta substituents selec-
palladium(II) catalyst with oxygen and TFA. Performing this re- tively underwent C H activation at less hindered sites owing
action with CF3CO2D gave no deuterium scrambling, which to steric hindrance.
suggested that the cyclopalladation step was irreversible. Fur- A plausible catalytic cycle for this reaction is presented in
thermore, inter- and intramolecular kinetic isotopic effects Scheme 13.[20] Again, it is believed that a cationic palladium
(KIEs) of kH/kD = 1.63 and 3.7, respectively, were observed. The complex is formed in the presence of excess TFA.[21] Facile co-
large difference in these values indicates that C=C coordination ordination of the electrophilic catalyst to the allylic double

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10 to produce 9-benzylidene-9H-fluorines 11
(Scheme 14).[22] The reaction proceeds through
alkyne-assisted C H activation instead of the more
common Friedel–Crafts-type electrophilic aromatic
substitution, which predominantly follows 6-endo-dig
carbocyclization.[23] The electronics of the substitu-
ents minimally affected the reaction, which gave
good to excellent yields. In addition, the cyclization
proceeded with high cis selectivity. Significant inter-
and intramolecular KIE effects were observed, with
kH/kD = 2.6 and 3.5, respectively, which suggested
that the reaction proceeded through palladium-cata-
lyzed C H activation.
The mechanistic studies suggest the possible cata-
lytic cycle outlined in Scheme 15. Coordination of the
alkyne to the palladium complex, followed by activa-
tion of the aromatic C H bond, affords intermediate
F1. Intramolecular migratory insertion of the alkyne
into the Pd C bond provides the vinylpalladium spe-
cies F2, which gives the final product upon protonol-
Scheme 11. Proposed mechanism for palladium-catalyzed allylic double-bond-assisted
C H olefination. ysis. This reaction can also be applied to the synthe-
sis of fluorenes that are fully substituted at C-10 by

Scheme 12. Synthesis of naphthalenes through palladium-catalyzed olefin-

assisted C H activation. Scheme 13. Mechanism for the synthesis of substituted naphthalene
through palladium-catalyzed olefin-assisted C H activation.

bond followed by ortho-C H bond activation gives E2. Subse- adding an aryl bromide and slightly modifying the reaction
quent coordination of the alkyne and insertion into the Pd C conditions (Scheme 16).[24]
bond forms the vinyl palladium intermediate E3, which under- Chernyak et al. further extended this strategy to synthesize
goes insertion into the allylic C=C bond to afford intermediate alkylidene indanones 14 as single E stereoisomers in good to
E4. Finally, b-hydride elimination, followed by aromatization, excellent yields from ortho-alkynyl ketones 13 through a carbo-
gives the final product. palladation pathway (Scheme 17).[25] The starting material was
combined with 5 mol % Pd(OAc)2 and 6 mol % d-i-Prpf in tolu-
3.2 Alkyne-Assisted C H Activation ene at 120 8C and the reaction provided excellent yields. Nota-
bly, the ligand is crucial to the success of this reaction; other
3.2.1. Palladium-Catalyzed Alkyne-Assisted Intramolecular
common phosphine ligands, including PPh3, 2,2’-bis(diphenyl-
C H Bond Activation
phosphino)-1,1’-binaphthyl (BINAP), and 1,1’-bis(diphenylphos-
In 2008, Gevorgyan and Chernyak discovered the palladium- phino)ferrocene (dppf), offered lower yields, although no reac-
catalyzed, exclusive 5-exo-dig cyclization of ortho-alkynyl biaryls tion occurred without one. More detailed mechanistic studies

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kynes were effectively transformed in the presence of

10 mol % PdCl2, 10 equivalents of pivalic acid (PivOH),
and 3 equivalents of MnO2 in dimethylacetamide
(DMAc) at 80 8C over 12 h (Scheme 18).
The mechanism for this reaction is provided in
Scheme 19. Coordination of the alkynyl moiety of 15
to PdCl2 initiates the cycle by forming palladium p-
complex H1. Subsequently, PivOH-assisted C H acti-
vation of the adjacent aryl ring affords arylpalladium
intermediate H3, which then undergoes a second
PivOH-assisted C H activation to provide biarylpalla-
dium complex H5. Finally, intramolecular carbopalla-
dation of 19 e affords six-membered palladacycle H5,
which undergoes reductive elimination to give the
final product and palladium(0). The active palla-
dium(II) is regenerated by oxidation with MnO2.[26]
Recently, Hiyama and co-workers demonstrated
Scheme 14. Palladium-catalyzed intramolecular C H activation and cyclization of o-alkyn- the intramolecular C H activation of 2-(silylethynyl-
yl biaryls. d-i-Prpf = 1,1’-bis(diisopropylphosphino)ferrocene.

Scheme 15. Mechanism for the palladium-catalyzed intramolecular C H acti-

vation and cyclization of o-alkynyl biaryls.

Scheme 16. Palladium-catalyzed arylative cyclization of o-alkynylbiaryls.

DABCO = 1,4-diazabicyclo[2.2.2]octane, NMP = N-methylpyrrolidone.
Scheme 17. Palladium-catalyzed carbocyclization of ortho-alkynyl ketones. d-
i-Prpf = 1,1’-bis(diisopropylphosphino)ferrocene.
and DFT calculations revealed that alkyne-coordinated palladi-
um enolate G3 formed as part of the reaction, after which mi- oxy)biphenyls 17 in the presence of 5 mol % Pd(OAc)2 and
gratory insertion of the alkyne into the Pd C bond formed 20 mol % PCy3 (Cy = cyclohexyl) in toluene to give 6-methyl-
vinyl palladium intermediate G4. The E–Z isomerization, fol- ene-6H-dibenzo[b,d]pyrans 18.[27] Under similar reaction condi-
lowed by proto-depalladation, gave the final product tions, bis(silylethynyloxy)terphenyl 19 underwent dual C H ac-
(Scheme 17).[25] tivation and carbocyclization to give pentacycle product 20 in
Recently, Jin and co-workers reported novel palladium-cata- excellent yield. However, alkyne-assisted C H activation of 2,2’-
lyzed alkyne-assisted dual C H activation and intramolecular bis(alkynoxy)biphenyl 21 only gave the single C H bond acti-
annulation of bis-biaryl alkynes 15 to form 9,9’-bifluorenylidene vation product 22 in 38 % yield, without providing the double
derivatives 16 in good yields.[26] Unusually, MnO2 was the most C H activation product 23 at all (Scheme 20). Mechanistic
suitable oxidant for this reaction. A variety of bis-biphenyl al- studies suggested that the alkyne served as a DG to palladium.

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3.2.2. Palladium-Catalyzed ortho-C H Bond Activation and

Annulation of Alkynyl Aryl Ethers with Internal Alkynes

Hiyama and co-workers reported a palladium(0)-catalyzed C H

activation assisted by alkynyl coordination; this allowed the
synthesis of 2-methylidene-2H-chromenes 25 from alkynyl aryl
ethers 24 and internal alkynes.[28] The reaction conditions of
5 mol % Pd(OAc)2, 10 mol % PCy3, and 5 mol % zinc in toluene
at 90 8C for 6 h gave moderate to good yields (Scheme 21).
Scheme 18. Palladium-catalyzed synthesis of 9,9’-bifluorenylidenes from bis-
Other phosphine ligands, such as PPh3 and PBu3, were less ef-
biphenyl alkynes.
fective, whereas the presence of bulky silyl substituents on the
alkynyl groups was essential. A variety of alkynes were compat-
ible with the reaction conditions, whereas unsymmetrical al-
kynes afforded single regioisomer products.

Scheme 19. Mechanism for the palladium-catalyzed synthesis of 9,9’-bifluor-

enylidenes from bis-biphenyl alkynes.

Scheme 21. Palladium-catalyzed cycloaddition of alkynyl aryl ethers with al-

kynes through C H activation. TBDMS = tert-butyldimethylsilyl, TIPS = 1,1,3,3-
tetraisopropyl-1,3-disiloxan-1,3-diyl.

A plausible mechanism for this reaction is provided in

Scheme 22.[28] The reaction is initiated by coordination of the
CC bond to palladium(0) to form h2-palladium complex I1,
which transforms into the zwitterionic palladium complex I2.
Subsequent ortho-C H bond activation through oxidative addi-
tion gives the palladium hydride complex I4. Coordination, fol-
lowed by insertion of the external alkyne into the aryl–palladi-
um bond, gives I5. Next, intramolecular carbopalladation with
the alkynyl group affords vinyl palladium hydride intermediate
I6, which, after reductive elimination, yields both the final
product 25 and palladium(0). Alternatively, intramolecular in-
sertion of the CC bond into the Pd H bond in I4 gives the
five-membered palladacycle I7. Coordination of the external
Scheme 20. Palladium-catalyzed intramolecular C H activation and annula-
alkyne to this species, followed by insertion into the Pd C
tion of disubstituted silylethynyloxybiaryls.
bond, gives the seven-membered palladacycle I8. Finally, re-
ductive elimination of this species affords the final product
and palladium(0).

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Scheme 24. Proposed mechanism for the palladium-catalyzed hydrobenzyla-

tion of ortho-tolyl alkynyl ethers.

Scheme 22. Mechanism of palladium-catalyzed cycloaddition of alkynyl aryl

ethers with alkynes.
pound plays dual roles as a Lewis acid and an acetate ion
donor in the possible mechanism for this reaction, as provided
3.2.3. Palladium-Catalyzed Alkyne-Assisted Intramolecular in Scheme 24. First, the alkyne coordinates to palladium(0) to
sp3-C H Bond Activation form h2-palladium complex J1, which is transformed into J2 by
intramolecular nucleophilic attack of the palladium species on
Hiyama and co-workers extended their alkynyl-assisted C H ac- the a-carbon atom of the alkynoxy group. This zwitterionic in-
tivation for the synthesis of functionalized benzofurans termediate is neutralized by Zn(OAc)2 to give the vinyl palladi-
through intramolecular sp3-C H activation.[29] The reaction of um acetate intermediate J3. Notably, this intermediate may
silyl-substituted, ortho-tolyl alkynyl ethers 26 in the presence also be formed via J2’. Next, the six-membered palladacycle J4
of 1 mol % Pd(OAc)2, 2 mol % PCy3, and 1 mol % zinc metal in is formed by sp3-C H cleavage by the acetate base through an
toluene at 90 8C for 30 min gave the Z-exocyclic alkylidene 27 assisted concerted metalation–deprotonation pathway. After-
in 97 % yield, according to NMR spectroscopic analysis; this wards, rapid protonation of the vinyl zinc moiety and C C
product was transformed into benzofuran 28 upon treatment bond formation through reductive elimination at the palladium
with acetic acid (Scheme 23). The reaction does not occur if center afforded product 27 and palladium(0).

3.2.4. Palladium-Catalyzed An-

nulation of Alkynyl Aryl Ethers
and Allenes
Palladium-catalyzed alkyne-as-
sisted C H activation reaction
conditions can generally also be
used with allenes as the cou-
pling partner. Recently, Hiyama
and co-workers demonstrated
the palladium(0)-catalyzed cyclo-
addition of alkynyl aryl ethers 24
and allenes 29 to form 2,3-bis-
Scheme 23. Palladium-catalyzed hydrobenzylation of ortho-tolyl alkynyl ethers. methylidene-2,3-dihydro-4H-1-
benzopyrans 30 in good yields
by using the Pd(OAc)2/PCy3/zinc
only Pd(OAc)2, PdCl2, or PtCl2 are used. It is apparent that the catalyst system in toluene at 100 8C (Scheme 25).[30] Experi-
reaction is not a Lewis acid catalyzed transformation. Similarly, ments suggested that the reaction proceeded through an in-
either Zn(OAc)2 or PCy3 alone do not catalyze the reaction in termediate similar to I4 in Scheme 22. Insertion of the allene
the absence of palladium. Furthermore, the presence of the into the Pd C bond followed by intramolecular migratory in-
bulky silyl group at the alkyne moiety is crucial for the success sertion to the alkynyl moiety offered the final product.
of the reaction.
Detailed mechanistic studies revealed that Zn(OAc)2 formed
in situ from the reaction of Pd(OAc)2 and zinc metal. This com-

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 Focus Review

Scheme 25. Palladium-catalyzed cycloaddition of alkynyl aryl ethers and al-

Scheme 27. Possible catalytic cycle for the palladium-catalyzed cycloaddition
lenes.
of silylethynyl aryl ethers with isocyanates.

3.2.5. Palladium-Catalyzed Annulation of Aryl Alkynyl Ethers

with Isocyanates The p coordination of the alkynyl group of the starting sub-
strate to Pd(OAc)2 is particularly important.
Palladium-catalyzed p-assisted C H functionalization can be
further explored by using isocyanates as the coupling part-
3.2.6. Palladium-Catalyzed Annulation of Aryl Acetylenes
ner.[31] The palladium-catalyzed reaction of alkynyl aryl ethers
through ortho-C H Activation
with isocyanates proceeds through ortho-C H bond activation
to give methylidene-2H-1,4-benzoxazin-3(4H)-one derivatives In 2013, Segawa et al. reported an interesting C H activation
32 in moderate to good yields (Scheme 26). A possible catalyt- and annulation for the synthesis of dibenzo[a,e]pentalenes 33
ic cycle to account for this reaction is shown in Scheme 27.[31] from diarylacetylenes by using 15 mol % PdCl2, 1 equivalent of
AgOTf (OTf = triflate), and 1 equivalent o-chloranil
(Scheme 28).[32] A mechanistic study indicated that the reaction
proceeded through alkyne-directed ortho-C H activation. The
reaction was compatible with both symmetrical and unsym-
metrical alkynes.
A possible mechanism for this reaction is shown in
Scheme 29. Coordination of the alkyne to palladium(II), fol-
lowed by ortho-selective C H palladation, gives aryl-palladium
s-complex L2. Insertion of the second alkyne moiety into the
resulting Pd C bond affords L3, which subsequently under-
goes intramolecular carbopalladation to provide vinyl palladi-
um intermediate L4. This intermediate further undergoes C H
activation at the adjacent aryl ring to form the six-membered
palladacycle L5. The final product is then formed by reductive
elimination.

3.3. Arene p-Bond Coordination-Assisted C H Bond Activa-

tion
Various transition-metal catalysts have accomplished direct C
H activation of arenes.[2–4] It is believed that arenes initially
ligate to transition-metal complexes through p-bond coordina-
tion prior to forming h2-metal–arene complexes.[33] This is fol-
lowed by C H bond cleavage to form the aryl–metal s com-
Scheme 26. Palladium-catalyzed alkyne-assisted C H activation and annula- plex, which can then react with various coupling partners to
tion of silylethynyl aryl ethers with isocyanates. produce a diverse range of products. In this context, Miura

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3.4. Cyano-Assisted C H Activa-

tion
3.4.1. Ruthenium-Catalyzed
ortho-C H Bond Activation of
Aryl Nitriles
The cyano (CN) group is known
to bond to metal complexes
either through s-bond coordina-
tion[35] or, less commonly, p-
bond coordination.[36] However,
p-bonded nitrile intermediates
have been proposed for the C
Scheme 28. Palladium-catalyzed annulation of arylacetylenes. H bond cleavage of ruthenium-

Scheme 29. Mechanism of the palladium-catalyzed annulation of arylacety- Scheme 30. Rhodium(III)-catalyzed annulation of 3-arylthiophenes with al-
lenes. kynes.

et al. showed an interesting rhodium(III)-catalyzed C H activa-

tion reaction by using the thiophene p bond as a DG.[34] This
strategy can be used to synthesize substituted naphthothio-
phenes 35 through annulation of 3-phenylthiophenes 34 with
alkynes by double C H bond cleavage (Scheme 30). Alkenyla-
tion of 3-phenylthiophene can also proceed through the same
procedure (Scheme 31). Scheme 31. Rhodium(III)-catalyzed thiophene-assisted C H olefination.
A possible catalytic pathway for the formation of products
35 and 36 is outlined in Scheme 32.[34] Intermediate M1 is catalyzed acrylonitrile dimerization.[37] In 1999, Murai et al. re-
a common intermediate formed by thiophene p-bond coordi- ported a ruthenium-catalyzed alkylation through cyano-group-
nation-assisted rhodium-mediated C H bond cleavage. Se- directed ortho-C H bond activation.[38] In this reaction, substi-
quential alkyne insertion into the Rh C bond forms the seven- tuted aryl nitriles reacted with excess triethoxyvinylsilane in
membered rhodacycle M2, and is followed by reductive elimi- the presence of 10 mol % [Ru(H)2(CO)(PPh3)3] in toluene at
nation to give product 35. Similarly, alkene insertion into the 135 8C for 18–216 h to afford dialkyl-substituted aryl nitriles.
Rh C bond of M1, followed by b-hydride elimination, affords The ortho-substituted benzonitriles produced monoalkyl-sub-
product 36. stituted products (Scheme 33). The exclusive ortho selectivity
suggests that the nitrile group directs the ruthenium complex
to the ortho-C H bond through p bonding.[38]

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Scheme 32. Mechanism for rhodium(III)-catalyzed thiophene-assisted C H

functionalization. Scheme 34. Palladium-catalyzed reaction of benzonitriles with aryl iodides.

dium(II) catalyst. The exact role of Ag2O in this reac-

tion is not very clear, although it is likely to act as
a halogen scavenger.[40]

3.4.3. Palladium-Catalyzed Synthesis of Fluore-

nones from Aryl Nitriles and Aryl Iodides
The one-pot synthesis of fluorenones 39 from aryl ni-
triles and aryl iodides can be achieved through
cyano-group-directed palladium-catalyzed multiple
C H bond activation.[41] The reaction of substituted
benzonitriles with aryl iodides in the presence of
10 mol % Pd(CH3CN)2Cl2, 1.1 equivalents of Ag2O, and
1 equivalent of H2O in a solvent mixture of TFA and
DMAc at 140 8C for 96 h afforded the target mole-
cules in moderate to good yields (Scheme 36).
Scheme 33. Ruthenium-catalyzed ortho-alkylation of aryl nitriles with alkenes.
A possible mechanism for this reaction is present-
ed in Scheme 37. The catalytic cycle begins with p-
bond coordination of the nitrile group to Pd(TFA)2,
3.4.2. Palladium-Catalyzed ortho-C H Arylation of Aromatic
which forms in situ; this affords O1, which then
Nitriles
forms the aryl–palladium intermediate O2 through ortho-C H
bond activation. Oxidative addition of an aryl iodide then gives
The synthesis of biphenyl-2-carbonitrile is conveniently ach-
the palladium(IV) intermediate O3, after which facile reductive
ieved through the palladium-catalyzed ortho-C H bond aryla-
elimination provides an ortho-arylated benzonitrile and regen-
tion of benzonitriles by using aryl iodides.[39] The reaction
erates the active catalyst. Further coordination of palladium(II)
smoothly proceeds in the presence of 10 mol % Pd(OAc)2 and
1 equivalent of Ag2O in TFA at 110 8C for 9 h. The reaction se-
lectively gives monoarylated products 38 (Scheme 34). Chang-
ing the solvent prevents any reaction from occurring, and
Ag2O proved to be highly effective when compared with other
silver salts. Aryl iodides substituted with electron-withdrawing
groups gave higher yields.[39]
A possible mechanism that accounts for this reaction is de-
picted in Scheme 35. Owing to the linear structure of the ni-
trile group, end-on coordination does not favor the formation
of five-membered metallacycles.[40] Instead, side-on p-bond co-
ordination is more likely to allow access to the ortho-C H
bond, leading to C H cleavage and the formation of inter-
mediate N2. Oxidative addition of the aryl iodide to N2 leads
to the palladium(IV) intermediate N3, followed by reductive Scheme 35. Mechanism for the palladium-catalyzed C H arylation of benzo-
elimination to the ortho-arylated benzonitrile and the palla- nitriles.

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Scheme 36. Palladium-catalyzed synthesis of fluorenones from benzonitriles Scheme 38. Palladium-catalyzed ortho-alkoxylation of aryl nitriles.
and aryl iodides.

methods for their production

have been developed. In this
regard, the synthesis of ortho-
substituted halo aryl nitriles can
be conveniently attained by the
palladium-catalyzed halogena-
tion of aryl nitriles, with N-halo-
succinimides commonly used as
the halogenating agent.
The reaction of aryl nitriles
with an N-halosuccinimide in the
presence of 10 mol % Pd(OAc)2
and 1 equivalent of p-toluenesul-
Scheme 37. Mechanism for palladium-catalyzed fluorenone formation from benzonitrile and aryl iodide.
fonic acid (PTSA) in 1,2-dichloro-
ethane (DCE) at 70 8C for 12 h af-

to the biaryl nitrile, followed by C H activation, gives inter-

mediate O4. Finally, intramolecular insertion of the cyano
group into the Pd C bond forms O5, which yields the final
product upon hydrolysis.

3.4.4. Palladium-Catalyzed ortho-C H Bond Alkoxylation of

Aryl Nitriles
Selective ortho-alkoxylation of aryl nitriles has also been ac-
complished by directed palladium-catalyzed C H bond activa-
tion by utilizing cyano p-bond coordination. Aryl nitriles in the
presence of 10 mol % Pd(OAc)2 and 5 equivalents of Na2S2O8 in
methanol at 70 8C undergo alkoxylation to yield 2-alkoxy aryl
nitriles 40 and 40’ (Scheme 38).[42] An inexpensive oxidant and
Scheme 39. Possible mechanism for the palladium-catalyzed ortho-alkoxyla-
mild reaction conditions make this transformation particularly tion of aryl nitriles.
attractive. A possible reaction pathway for this transformation
is depicted in Scheme 39. In the presence of Na2S2O8, the aryl–
palladium intermediate oxidizes to form a palladium(IV) spe- forded ortho-halogenated products in good yields
cies; this is a key factor in the success of this reaction. (Scheme 40).[43] This method is compatible with a variety of
substituents.
A possible catalytic cycle for this reaction is presented in
3.4.5. Palladium-Catalyzed ortho-C H Bond Halogenation of
Scheme 41. Side-on coordination of the cyano group of the
Aryl Nitriles
aryl nitrile to the palladium(II) species, followed by ortho-C H
Aryl halides are important starting materials for many organic bond cleavage, affords the aryl–palladium intermediate Q2.
syntheses that rely on cross-coupling; as such, numerous Oxidative addition of the selected N-halosuccinimide gives the

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 Focus Review

Acknowledgements

We thank the Ministry of Science and Technology of the Re-

public of China (MOST-102-2633M-007-002) for support of this
research.

Keywords: annulation · C H activation · directing groups ·

homogeneous catalysis · transition metals

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Angew. Chem. Int. Ed. 2013, 52, 1245 – 1247; Angew. Chem. 2013, 125, Published online on && &&, 0000

Chem. Asian J. 2015, 00, 0 – 0 www.chemasianj.org 15  2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim & &

These are not the final page numbers! ÞÞ

 Focus Review

FOCUS REVIEW
Homogeneous Catalysis

Parthasarathy Gandeepan,
Chien-Hong Cheng*
&& – &&
Piece of pi: Transition-metal-catalyzed dination of their lone pairs, yet p-bond
Transition-Metal-Catalyzed p-Bond- directing-group-assisted C H activation directing groups also exist (see figure).
Assisted C H Bond Functionalization: reactions play an indispensable role in The p-coordination-assisted C H bond
An Emerging Trend in Organic organic synthesis. Most directing groups functionalization reactions are summar-
Synthesis interact with metals through the s coor- ized.

&&

& & Chem. Asian J. 2015, 00, 0 – 0 www.chemasianj.org 16  2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

ÝÝ These are not the final page numbers!