DOI: 10.1002/cctc.

200900074

Palladium-Catalyzed C3 or C4 Direct Arylation of

Heteroaromatic Compounds with Aryl Halides by C H
Bond Activation
Julien Roger, Aditya L. Gottumukkala, and Henri Doucet*[a]

20  2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim ChemCatChem 2010, 2, 20 – 40
In recent years, palladium-catalyzed direct C2 or C5 arylation of
heteroaromatic compounds with aryl halides by C H bond ac-
tivation has become a popular method for generating carbon–
carbon bonds. For this reaction, a wide variety of heteroaro-
matics, such as furans, thiophenes, pyrroles, thiazoles, oxazoles,
imidazoles, pyrazoles, indoles, triazoles, or even pyridines, can
be employed. C3 and C4 arylations of heteroaromatics by C H
bond activation have also been described. Such reactions ini-
tially attracted much less attention than the C2 or C5 arylations
due to the lower reactivity of the C3 and C4 positions. How-
ever, in more recent years, several results from using modified
and improved catalysts and reaction conditions have been
reported, which permit C3 and C4 arylations in synthetically
useful yields. Several intramolecular cyclizations of 2-substitut-
ed heterocycles have been described, with formation of a C C
bond on C3 resulting in the formation of five- to nine-mem-
1. Introduction
There exists a variety of routes for the construction of aryl–aryl
bonds. Some of the most common methods are through the
use of transition metal-mediated reactions. Among these
methods, the Suzuki–Miyaura, Stille, and Negishi couplings
represent some of the most important procedures.[1] However,
these reactions require the preliminary preparation of organo-
metallic or organoboron aryl derivatives, and provide an
organometallic salt (MX) as a byproduct.
If aryl C H bonds can be used as functional groups, they
provide a valuable and straightforward technique for the
synthesis of biaryls. In recent years, direct C2 or C5 arylation of
heteroaromatic compounds with aryl halides by C H bond
activation provides simple access to the corresponding aryl–
heteroaryl derivatives.[2–9] The concept of using a directing
group to control the regioselectivity of the subsequent transi-
tion metal insertion into a C H bond is often employed for the
intermolecular direct arylation of aromatic carbocycles. Con-
versely, this concept is rarely employed in the presence of
aromatic heterocycles. Unlike the intermolecular direct aryla-
tion of carbocyclic arene systems, the inherent electronic bias
of the heterocycle itself is often sufficient to control the regio-
selectivity of direct arylation reactions. Using 2-substituted thi-
ophenes, furans, thiazoles, oxazoles, or imidazoles, the 5-arylat-
ed products were selectively obtained in most cases,[2, 10–16]
whereas 5-substituted thiazoles or oxazoles gave the 2-arylated
derivatives.[2, 17, 18] The selective 2-arylation of unsubstituted
oxazoles or imidazoles has also been reported.[2, 15, 19] With ben-
zoxazoles or benzothiazoles as the substrate, 2-arylbenzoxa-
zoles or 2-arylbenzothiazoles were obtained in good yields.[2, 20]
The arylation of unsubstituted triazoles preferentially gave the
5-arylated compounds. The 2-arylation of pyridine or diazine
derivatives also proceeded in high yields.[2] For selected hetero-
aromatic compounds, the high reactivity of some of the cata-
lysts employed in these reactions allowed the use of as little as
0.01 mol % catalyst loadings, making such arylation reactions
industrially attractive.[10, 12, 13, 16] The most favorable positions for
ChemCatChem 2010, 2, 20 – 40  2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
bered rings incorporating pyrroles, indoles, thiophenes, furans,
isoxazoles, or pyridines. Intermolecular C3 or C4 direct aryla-
tions are still quite rare for some heteroaromatics and are in
several cases not highly regioselective. For such reactions, the
best results have been obtained using pyrroles, thiophenes, or
furans. For selected substrates, regioselective arylation at C3 or
C4 of the heteroaromatic compounds took place under appro-
priate reaction conditions. Only a few examples of intermolec-
ular couplings using oxazoles, thiazoles, imidazoles, isoxazoles,
pyrazoles, triazoles, or pyridines have been reported. For most
of these reactions, aryl iodides or bromides have been used as
coupling partners, although a few examples with aryl chlorides
are also known. This method allows the synthesis of complex
molecules in only a few steps, and will provide access to a
very wide variety of new heteroaryl derivatives in the next
years.
direct arylation of various heteroaromatics are represented in
Figure 1.
Although palladium-catalyzed direct C2 and C5 arylations of
heteroaromatic compounds are strongly favored in general,
the regioselectivity in intermolecular direct arylation reactions
Figure 1. Most favorable positions for direct arylation of heteroaromatic sub-
strates.
is also influenced by the substituents present on the hetero-
cycle and the nature of the catalyst, base, solvent, or additives
employed. Until recently, relatively little effort had been ex-
pended towards developing such direct arylation reactions for
the synthesis of 3- or 4-arylated pyrroles, thiophenes, furans,
thiazoles, oxazoles, imidazoles, isoxazoles, triazoles or pyridines
(Figure 2), as reactions with such substrates are generally con-
[a] J. Roger, A. L. Gottumukkala,+ Dr. H. Doucet
Institut Sciences Chimiques de Rennes
UMR 6226 CNRS-Universit de Rennes 1
Campus de Beaulieu, 35042 Rennes (France)
Fax: (+ 33) 0223236939
E-mail: henri.doucet@univ-rennes1.fr
[+] Present address:
Stratingh Institute for Chemistry, University of Groningen
Nijenborgh 4, 9747 AG Groningen (The Netherlands)
www.chemcatchem.org 21
 H. Doucet et al.

sidered to be much slower and gave mixtures of isomers

during initial attempts. However, such arylations on C3 or C4
are possible, especially in the presence of 2,5-disubstituted
pyrroles, furans, or thiophenes, and of 5-substituted isoxazoles,
pyrazoles, or triazoles. Several catalysts, such as novel palladi-
um–phosphane complexes, and new reaction conditions have
been employed to give such coupling products in moderate to
high yields.
This procedure is of particular interest as relatively few C3/
C4-arylated heteroaromatic compounds are readily available
commercially at an affordable cost. A chief advantage of this
procedure is that the major byproducts are HX associated to a
Figure 2. Less favorable positions for direct arylation of heteroaromatic sub- base, rather than metallic salts (as with classical coupling pro-
strates. cedures). Moreover, no prior preparation of an organometallic
derivative is required, reducing the number of steps to prepare
these compounds. For these reasons, such procedures should
Henri Doucet received his PhD in
give economically viable and environmentally attractive access
chemistry working with Prof. P. H.
to C3 or C4 arylated heterocycles.
Dixneuf and Dr. C. Bruneau at the
Although mechanistic studies have not been performed for
University of Rennes 1 in 1994. After
most of the reactions discussed in this review, some mecha-
post-doctoral appointments at Oxford
nisms have been proposed (Scheme 1). The first step of the
University (J. M. Brown) and Nagoya
University, Japan (R. Noyori), he moved
to the University of Marseille as CNRS
researcher. In 2006 he returned to the
University of Rennes 1. His research
interests include organic synthesis by
metal-catalyzed processes, ligand
synthesis and green chemistry.

Julien Roger received his graduate

education in chemistry at the Universi-
ty of Rennes 1. Currently, he is working
towards his PhD on palladium-cata-
lyzed C H activation for the direct ary-
lation of heteroaromatic compounds
at the University of Rennes 1, under Scheme 1. Three potential pathways for the arylation of aromatic
heterocycles. Y = heteroatom.
the supervision of Dr. Henri Doucet.

catalytic cycle is certainly the oxidative addition of palladium

into the aryl halide bond. Then, the reaction might proceed by
several pathways. One proposed mechanism for of p-excessive
aromatic substrates, such as indoles, is the electrophilic aro-
Aditya L. Gottumukkala was born in matic substitution (SEAr).[3, 21] In SEAr reactions, the attack of the
Tirupati, India. He received his under- ArPdX intermediate may occur at the most reactive position of
graduate education in chemistry at the heteroaromatic substrate. The Heck-type process[2] and,
Loyola College, Chennai. Upon receiv- more recently, the concerted metalation–deprotonation (CMD)
ing a grant from EGIDE, he joined the pathway[22] have also been suggested. Fagnou and co-workers
University of Rennes 1 for his masters reported that the experimental and computational data
program, during which he investigated support the involvement of a CMD pathway for p-excessive
palladium-catalyzed C H activation, aromatics. They found a remarkable similarity between the
under the guidance of Dr. Henri computationally predicted and experimentally observed
Doucet. Currently, he is working
reaction outcomes.
towards his PhD, in the research group The palladium-catalyzed direct arylation of heteroaromatic
of Prof. Adriaan J. Minnaard, at the substrates has been discussed in recent years in several rele-
University of Groningen, the Nether- vant review articles and accounts.[4–8] However, these articles
lands. were mostly concerned with C2 or C5 arylation reactions of
five-membered heteroaromatics or direct intramolecular or

22 www.chemcatchem.org  2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim ChemCatChem 2010, 2, 20 – 40
Palladium-Catalyzed C3 or C4 Direct Arylation of Heteroaromatic Compounds

bimolecular arylation of benzene derivatives, or strongly em-

phasized the author’s own work. Herein we focus on palladi-
um-catalyzed direct C3 or C4 arylation of heteroaromatic com-
pounds with aryl halides, outlining the developments and ad-
vances in both the intramolecular and intermolecular reactions.
Aryl–heteroaryl bond formations using stoichiometric amounts
of metals or by oxidative coupling reactions are not discussed.
Firstly, we will discuss the C3 or C4 arylation of pyrroles and C3
arylation of indole derivatives, followed by C3 or C4 arylation
of furans and of thiophenes. The subsequent sections are con-
cerned with coupling reactions of aryl halides with thiazoles,
oxazoles, imidazoles, isoxazoles, and pyrazoles and the recently
reported C4 arylation of triazoles, before we present several ex-
amples of C3 or C4 arylations of pyridines and, to conclude,
describe the remaining challenges in the field.

2. 3- or 4-Arylation of Pyrrole or Indole

Derivatives
The palladium-catalyzed direct arylation of furans or thio-
phenes generally gives the 2- or 5-arylated products with high stead of the desired benzocyclazinone derivative [Eq. (4)].[27]
regioselectivity. Conversely, the electronic properties of Again, PdACHTUNGRE(OAc)2/PPh3 was employed as the catalyst and
pyrroles or indoles appear to be much less favorable to regio- Ag2CO3 as the base.
selective 2-arylations. As a consequence, when appropriate
reaction conditions are employed, the direct regioselective
3-arylation of indoles or pyrroles is possible. Several examples
of direct arylations on C3 of indoles using either intra- or inter-
molecular reactions have been reported. Some examples of
intramolecular cyclizations on C3 of pyrroles have also been
described. On the other hand, the bimolecular coupling on C3
using pyrroles has attracted less attention.
Intramolecular palladium-catalyzed direct 3-arylation reac-
tions of pyrroles or indoles have been utilized in organic syn-
thesis as a simple route for the synthesis of complex polycyclic
ring systems. The first part of this section focuses on the
developments of this important reaction. In 1991, Ma and
Kozikowski reported the intramolecular cyclization of an indole
substituted by 2-bromobenzoyl at C2 [Eq. (1)].[23] This reaction Several intramolecular cyclizations of 2-substituted pyrroles
was performed in the presence of [PdACHTUNGRE(PPh3)4] as catalyst and have also been reported [Eq. (5)–(10)]. For example, intramo-
KOAc as base at 130 8C in N,N-dimethylacetamide (DMAc). The lecular cyclization of 1,5-dichloroanthracene substituted at C9
tetracyclic product was obtained in 95 % yield. In the course of and C10 by two 1-methylpyrrol-2-yl substituents allowed the
this reaction, a five-membered ring was formed. Using the synthesis of substituted rubicenes [Eq. (5)].[28] However, a rela-
same catalyst, a six-membered ring was formed by Mrour and tively low yield was obtained, probably due to some polymer
co-worker, in the course of the palladium-catalyzed cyclization formation or decomposition.
of an indole substituted on C2 by a 2-bromophenyl ester.[24]
Similar intramolecular cyclizations of 2-substituted indoles re-
sulting in the formation of seven-membered rings have also
been described [Eq. (2) and (3)]. Indoles bearing a 2-iodoben-
zylcarbamate substituent at C2 gave the expected cyclization
products in 90–96 % yield using a catalyst system of 5 mol %
PdACHTUNGRE(OAc)2 and 10 mol % PPh3 with Ag2CO3 as a base.[25] Using a
similar catalyst and CsOAc as base, an indole with a (2-bromo-
benzyl)butylamine derivative as 2-substituent gave the 1-Methylpyrroles with 2-iodobenzylcarbamate substituents
dihydrobenzoazepine-fused indole in high yield.[26] at C2 have also been cyclized using conventional or microwave
Intramolecular cyclization of an indolizine substituted by a heating [Eq. (6)].[29] With conventional heating, satisfactory
2-bromobenzoyl group at C2 gave a tetracyclic compound yields could only be obtained from aryl iodides. A significant
with the formation of a five-membered ring in 43 % yield, in- amount of unreacted starting material was recovered, even

ChemCatChem 2010, 2, 20 – 40  2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim www.chemcatchem.org 23

after 72 h, from a substrate with a bromopyridine substituent.
However, with this more challenging substrate, an impressive
yield of 90 % was obtained after only 30 min using microwave
heating. Using a similar reactant, Cavell and co-workers did not
succeed to obtain the desired cyclized product [Eq. (7)].[30] De-
spite several attempts, they were unable to detect the product
by either GC-MS or NMR spectroscopy.
The cyclization of 2-substituted pyrroles is not limited to the
formation of five- or six-membered rings. Seven- and nine-
membered rings have also been formed in such reactions
[Eq. (8) and (9)].[31, 32] In both cases, the catalysts systems were
10 mol % PdACHTUNGRE(OAc)2 with monophosphine ligands. The forma-
tion of the nine-membered lactam in 47 % yield, by cyclization
of a pyrrole bearing an alkyl chain terminated by 2-iodopheny-
lacetamide, was the key step for the synthesis of biologically
active rhazinilam. A pentacyclic compound was obtained by a
double C H bond activation/arylation of a trisubstituted
pyrrole [Eq. (10)].[33] During the course of this reaction, two six-
membered rings were formed. However, the yield of the
target product was quite low.
24 www.chemcatchem.org  2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
H. Doucet et al.
Although intramolecular palladium-catalyzed C3 direct aryla-
tion of pyrroles has been described in several publications, the
intermolecular version of this reaction has attracted much less
attention, probably owing to the more challenging control of
the regioselectivity of such arylations. In 1992, Filippini and co-
workers reported the direct arylation of pyrrolyl anions with
bromobenzene [Eq. (11)].[34] Pyrrol-1-ylzinc bromide or chloride
underwent coupling with bromobenzene in the presence of
[PdCl2ACHTUNGRE(PPh3)2]/PPh3 in N-methylpyrrolidone (NMP) to give a
mixture of 2- and 3-phenylpyrrole. The nature of the cation on
the pyrrole ring had an important effect on the regioselectivity
of the reaction. However, the highest reported yield of the
C3-arylated product was only 10 %
Also in 1992, Ohta and co-workers reported the direct 3-
arylation of N-phenylsulfonylpyrrole with 3,6-dialkyl-2-chloro-
pyrazines [Eq. (12)].[35] A mixture of 2- and 3-arylated pyrroles
was obtained, which could not be separated. The presence of
bulky groups on the pyrazine ring favored the production of 3-
substituted pyrroles. The reaction with 2-chloro-3,6-dimethyl-
pyrazine gave an equimolar mixture of 2- and 3-arylated
pyrroles, whereas that with 2-chloro-3,6-diisobutylpyrazine
gave the 2- and 3-arylated pyrroles in a 2:5 ratio.
Recently, the direct C3 arylations of 1,2,5-trimethylpyrrole,
2,5-dimethyl-1-phenylpyrrole, and 2,5-dimethylpyrrole using
PdACHTUNGRE(OAc)2 as catalyst were reported [Eq. (13) and (14)].[36] The
ChemCatChem 2010, 2, 20 – 40
Palladium-Catalyzed C3 or C4 Direct Arylation of Heteroaromatic Compounds
coupling of para-substituted electron-deficient aryl bromides,
such as 4-bromoacetophenone, 4-bromopropiophenone,
4-bromobenzaldehyde, or 4-trifluoromethylbromobenzene, to
1,2,5-trimethylpyrrole afforded the expected products in
55–61 % yields. Slightly lower yields were obtained using the
meta-substituted aryl bromides, 3-bromoacetophenone or 3-
bromonitrobenzene. The electron-poor heteroaryl bromides, 3-
bromopyridine, 3-bromoquinoline, and 4-bromoisoquinoline,
gave the 3-arylated pyrroles in 53, 54, and 65 % yields, respec-
tively. Quite similar results to those for the coupling with 1,2,5-
trimethylpyrrole, were obtained using 2,5-dimethyl-1-phenyl-
pyrrole [Eq. (14)]. With 4-bromobenzophenone or 4-bromoben-
zonitrile, the C3-arylated products were obtained in 41 and
50 % yields, respectively. The reactivity of free (NH) 2,5-dime-
thylpyrrole was also examined [Eq. (14)]. With this substrate,
the target compounds were formed in moderate yields using
4-bromobenzonitrile or 4-trifluoromethylbromobenzene. The
formation of 2,5-dimethyl-1-arylpyrroles was not detected.
This group has also demonstrated that, using an unsymmet-
rically 2,5-disubstituted pyrrole, control of the regioselectivity
of the arylation is possible. By coupling 1,5-dimethyl-2-pyrrole-
carbonitrile with 4-bromoacetophenone, they initially obtained
a mixture of C3- and C4-arylated products [Eq. (15)].[36] Howev-
er, the ratio of regioisomers and the yield strongly depended
on the reaction conditions. The use of KOAc as base, DMAc as
solvent and PdACHTUNGRE(OAc)2 as catalyst led to a complete conversion
of the aryl bromide. Moreover, these reaction conditions gave
a high selectivity in favor of the C4 arylation product (C3/C4
ratio = 1:4). Other palladium sources, such as PdCl2, [Pd2ACHTUNGRE(dba)3]
(dba = trans,trans-dibenzylideneacetone), and [{PdClACHTUNGRE(C3H5)}2],
gave moderate conversions and selectivities. The presence of
the phosphine ligands PPh3 or dppe was not found to be
advantageous. Under these reaction conditions, 4-bromoben-
zophenone, 4-bromonitrobenzene, and 4-bromobenzaldehyde
ChemCatChem 2010, 2, 20 – 40  2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
were coupled with 1,5-dimethyl-2-pyrrolylcarbonitrile to give
the desired 4-arylated products in 46–60 % yields. Conversely,
when the electron-rich aryl bromide 4-bromoanisole was used
as a coupling partner, no arylation product was detected. In
the presence of sterically congested bromobenzene deriva-
tives, the coupling products were obtained. Ortho-substituted
2-bromobenzonitrile reacted with 1,5-dimethyl-2-pyrrolylcarbo-
nitrile to give the C4-arylated pyrrole in 64 % yield. The reactiv-
ity of heteroaryl bromides has also been explored. A selective
reaction also took place with 4-bromoisoquinoline. With this
substrate the C4 arylation product was obtained in 64 % yield.
A great deal of attention has been given in recent years to
the Pd-catalyzed intermolecular direct 3-arylation of indoles
[Eqs. (16)–(26)]. N-Phenylsulfonylindole reacted with 3,6-dialkyl-
2-chloropyrazines to give, very regioselectively, the 3-arylated
indoles [Eq. (16)].[37, 38] Again, more bulky groups on the chloro-
pyrazine ring led to higher regioselectivities in favor of 3-aryla-
tion. In the presence of isopropyl or isobutyl substituents on
pyrazines, 3-arylindoles were obtained highly regioselectively
(C2/C3 ratio = 1:50). Substitution at the nitrogen atom of the
indole also had a determining effect on the regioselectivity of
this coupling reaction. Under the same reaction conditions, the
coupling of 1-methylindole or 1-benzylindole with chloropyra-
zines led regioselectively to the 2-arylated indoles.
Sames and co-workers studied the regioselectivity of this re-
action using aryl iodides. They initially reported that the aryla-
tion of 1-methylindole using PdACHTUNGRE(OAc)2/PPh3 as catalyst and
CsOAc as base in DMAc led highly selectively to the 2-arylated
indoles when using para-substituted aryl iodides, whereas, an
ortho-substituted aryl iodide gave a mixture of 2- and 3-arylat-
ed indoles in 29:38 ratio [Eq. (17)].[39] The formation of mixtures
of 2- and 3-arylated indoles using congested haloarenes was
explained by a slower migration of palladium from C3 of the
indole to C2 with such substrates. The deprotonation of the
C3-metalated indole produces the 3-arylindole.[21, 40] Consider-
ing that the regioselectivity of such arylations can be influ-
enced by several factors, Sames and co-workers explored the
influence of the nature of the magnesium salt on indoles on
the regioselectivity in the presence of iodobenzene. Congested
MeMgCl/tmeda or [MgACHTUNGRE(HMDS)2] gave 57 and 74 % yields of
3-phenylindole, respectively [Eq. (18); tmeda = N,N,N’,N’-tetra-
methylethylenediamine, HMDS = hexamethyldisilazide].
www.chemcatchem.org 25

The same group also reported that the coupling using a
SEM-protected indole [SEM = 2-(trimethylsilyl)ethoxymethyl], in
the presence of a palladium complex containing a carbene
ligand and triphenylphosphine generally gave the 2-arylated
indole, except when using 2-iodotoluene [Eq. (19)].[41] With this
congested substrate, 11 % of the 3-arylated product was also
formed. The reactivity of a 2-substituted free (NH) indole was
also described by this group [Eq. (20)].[42] The arylation of
2-phenylindole with 4-trifluoromethylbromobenzene using
1 mol % PdACHTUNGRE(OAc)2 as catalyst gave the C3-arylated product in
46 % yield. However, this unreactive substrate required the
presence of a stoichiometric amount of Bu4NCl in the reaction
mixture. This additive presumably stabilizes the Pd species.
Djakovitch and co-workers also studied the 3-arylation of in-
doles using PdACHTUNGRE(OAc)2 as catalyst. The selectivity of the reaction
(N1 vs. C3 arylation) using free (NH) 2-phenylindole was mostly
directed by electronic factors [Eq. (21)].[43, 44] Tuning of the reac-
tion conditions allowed either a selective N1 or C3 arylation. In
the presence of 4-iodonitrobenzene, the N1-arylated product
was exclusively obtained; whereas 4-bromonitrobenzene gave
only C3 arylation in 50 % yield. The use of AgBF4 as an additive
improved the yield of C3 arylation to 74 %. Very different be-
26 www.chemcatchem.org  2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
H. Doucet et al.
havior was observed using methyl indole-2-carboxylate. With
this substrate, the arylation using 4-iodo- or 4-bromonitroben-
zene led selectively in both cases to the C3-arylated indole.
This procedure is limited to activated aryl bromides. Neither
bromo- nor iodobenzene gave arylation product under these
reaction conditions.
This group also reported the 3-arylation of free (NH) indoles
using a heterogeneous palladium catalyst [Eq. (22)].[45] Employ-
ing K2CO3 as base, only 1 mol % of [PdACHTUNGRE(NH3)4]2 + supported on
zeolite NaY as catalyst in refluxing dioxane, unsubstituted and
C2-substituted indoles gave up to 92 % conversion and up to
85 % yield of the C3-arylated indoles. However, the yield
strongly depended on the substituents on the aryl bromide
and on the indole. For example, 40 % yield of coupling product
was obtained using indole and 4-bromoanisole, whereas no
product was formed with the same aryl bromide and 2-methyl-
indole or 2-phenylindole.
The direct 3-arylation of free (NH) indoles was also reported
recently by He and co-workers [Eq. (23)].[46] Using a palladium–
phosphinous acid complex, K2CO3 or KOH, and dioxane, they
obtained selectively the 3-arylated indoles in moderate to
good yields. Both electron-rich and electron-poor aryl bro-
mides were employed as reaction partners. The highest yield
ChemCatChem 2010, 2, 20 – 40
Palladium-Catalyzed C3 or C4 Direct Arylation of Heteroaromatic Compounds

Table 1. Effect on regioselectivity of phosphine ligands in the coupling

of 4-bromoanisole with indoles.[47]

Ligand or additive R1 R2 SC3 [%][a] Yield (C3) [%][b]

PPh3 H OMe 97 60
PCy3 H OMe 95 57
dppf H OMe 93 53
dppp H OMe 98 56
binap H OMe 96 54
BnBu3NCl H OMe – 56
(71 %) was obtained using bromobenzene. Electron-deficient BnBu3NCl H CF3 – 80
aryl bromides, such as 4-bromobenzonitrile or 4-bromonitro- BnBu3NCl H NO2 – 0
BnBu3NCl Me OMe – 62
benzene, led to the target compounds in lowers yields of 52 BnBu3NCl Ph OMe – 74
and 48 % respectively. Indoles substituted at C5 with methoxy
[a] SC3 = selectivity towards C3 regioselectivity; [b] yield of C3-regioselec-
or cyano groups were also found to be useful reactants for this
tive product; dppf = 1,1-bis(diphenylphosphanyl)ferrocene; dppp = 1,3-
reaction. However, 2-acetylindole and 5-nitroindole both failed bis(diphenylphosphanyl)propane; binap = 2,2’-bis(diphenylphosphanyl)-
to couple with bromobenzene. 1,1’-binaphthyl.

was recovered unreacted. This ligand-free palladium procedure

also tolerated some functionalized aryl bromides. The authors
proposed a catalytic cycle based on an electrophilic palladation
pathway at the C3 position of 1-indolylpotassium salts.
Using an air-stable heteroatom-substituted secondary phos-
phine oxide (HASPO) preligand and 5 mol % PdACHTUNGRE(OAc)2 as the
catalytic system, Ackermann and Barfsser were also able to
arylate free (NH) indole regioselectively at C3 [Eq. (24)].[48]
Diversely functionalized aryl bromides were employed as
coupling partners.

Very recently, Rossi and co-workers examined the influence

on arylation regioselectivity of a wide variety of phosphine
ligands associated to PdACHTUNGRE(OAc)2 for the coupling of 4-bromoani-
sole with free (NH) indole (Table 1).[47] The monophosphines
PPh3 and PCy3 gave the 3-arylated indole in 60 and 57 % yields,
respectively. Sterically very congested and electron-rich ligands
PACHTUNGRE(tBu)3 and PBuACHTUNGRE(1-Ad)2 gave only N1 arylation. Bidentate
phosphine ligands 1,1-bis(diphenylphosphanyl)ferrocene
(dppf), 1,3-bis(diphenylphosphanyl)propane (dppp), and 2,2’-
bis(diphenylphosphanyl)-1,1’-binaphthyl (binap) gave selective-
ly the 3-arylated indole, albeit in moderate yields. However, on
studying the scope and limitations of this procedure, they es-
tablished that the reaction conditions (PdACHTUNGRE(OAc)2/PCy3, toluene, Beletskaya and co-workers also studied the arylation of in-
K2CO3 with 2-phenyl- or 2-methylindole as a coupling partner) doles (Scheme 2).[49] In the presence of a magnesium salt of
did not produce satisfactory results. Ligand-free reaction condi- indole, they obtained quite selectively the 3-arylated indole,
tions with added BnBu3NCl, in several cases greatly improved with [Pd{PACHTUNGRE(tBu)3}2] as catalyst. Lower selectivities were detected
the yields. Under these conditions, the arylation of 2-methyl- for the coupling of other indole salts (Scheme 2 a). They also
or 2-phenylindole with 4-bromoanisole gave the 3-arylated in- explored the regioselectivity of the reaction in the presence of
doles in 62 and 74 % yields, respectively. On the other hand, a variety of ligands, using [PdACHTUNGRE(dba)2] as the palladium source,
ethyl indole-2-carboxylate in the presence of 4-bromoanisole and, in contrast to the results obtained by Rossi, the nature of

ChemCatChem 2010, 2, 20 – 40  2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim www.chemcatchem.org 27

Scheme 2. Arylation of indoles by Beletskaya and co-workers.[49] dba =
trans,trans-dibenzylideneacetone; dppp = 1,2-bis(diphenylphosphanyl)-
ethane.
the ligand was found to dramatically influence the regioselec-
tivity of the arylation (Scheme 2 b). The highest selectivity in
3-phenylindole was obtained using PACHTUNGRE(tBu)3 as the ligand,
whereas Xantphos gave almost exclusively 2-phenylindole.
The indole direct 3-arylation methodology was applied
recently for the synthesis of fluorescent rhodamine dyes.[50]
N-Methylindole was arylated at C3 in 61 % yield using 4-
bromo-3-nitroanisole as coupling partner and PdACHTUNGRE(OAc)2/PPh3 as
catalyst.
In summary, the palladium-catalyzed direct arylation of in-
doles is now a powerful method for the synthesis of 3-arylin-
doles. For bimolecular reactions, the regioselectivity (C2 vs. C3
arylation) seems to be very sensitive to the reaction conditions.
In the presence of free (NH) indoles, the addition of congested
magnesium salts to the indoles improved the regioselectivity
in favor of C3 arylation. However, simpler procedures, employ-
ing either a palladium–phosphinous acid complex, K2CO3, and
dioxane, or PdACHTUNGRE(OAc)2, toluene, BnBu3NCl, and K2CO3, also gave
this regioisomer in high selectivity. A heterogeneous palladium
catalyst [PdACHTUNGRE(NH3)4]/NaY, with K2CO3 and dioxane was also found
to produce this regioisomer.
2-Substituted pyrrole derivatives have also been relatively
widely used for intramolecular 3-arylation, and five-, six-,
seven-, and even nine-membered rings have been formed suc-
cessfully. Pyrroles have been only rarely used for intermolecular
arylation reactions. Moreover, the selectivities in favor of 3-ary-
lation and yields of these reactions have been quite low. Good
results have been described for the 3-arylation of 2,5-dimethyl-
pyrrole derivatives. In the presence of 1,5-dimethyl-2-pyrrolyl-
carbonitrile, a regioselective 4-arylation was obtained under
the appropriate reaction conditions.
28 www.chemcatchem.org  2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
H. Doucet et al.
Several palladium catalysts bearing mono-, or bidentate
ligands or even ligand-free methods have been employed for
the arylation of indoles or pyrroles. With the most efficient cat-
alysts, the reaction was effective with as little as 1 mol % palla-
dium. These catalysts allowed the coupling of electron-defi-
cient or excessive aryl bromides and iodides. So far, the cou-
pling with aryl chlorides has attracted less attention. Only a
few examples using chloropyrazines have been reported.
Several sets of reaction conditions have been investigated.
However, in most cases, K2CO3, or acetates were used as the
bases, and toluene, dioxane, DMAc, or DMF were used as the
solvents. In the presence of pyrrolyl anions, the reaction could
be performed in the absence of additional base. In general, rel-
atively elevated reaction temperatures (100–150 8C) have been
employed.
3. 3- or 4-Arylation of Furan Derivatives
Despite the fact that C2 or C5 direct arylation of furans is
strongly favored,[2, 10] several examples of successful C3 or C4
direct arylations using palladium have also been reported.
Both intra- and intermolecular versions of these reactions have
been explored. In 1995, Grigg and co-workers employed a pal-
ladium catalyzed cyclization process, resulting in a C3-arylated
furan motif, as a viable route to bicyclic b-lactams
(Scheme 3).[51] However, this reaction required the use of toxic
Scheme 3. Synthesis of bicyclic b-lactams by Grigg and co-workers.[51]
Tl2CO3 as the base, along with 10 mol % PdACHTUNGRE(OAc)2 and
20 mol % PPh3. In the course of these cyclizations, seven-mem-
bered rings were formed. The formation of six-membered
rings from furans, substituted at C2 by a 2-iodobenzylamine,
has been described more recently. Using 33 mol % of PdACHTUNGRE(OAc)2,
the expected product was obtained in 57 % yield [Eq. (25)].[52, 53]
A very similar furan derivative was successfully cyclized by Bec-
calli and co-workers, using 10 mol % PdACHTUNGRE(OAc)2 with PPh3 as a
ligand.[54] With conventional heating, the target compound
was obtained in only 35 % yield after 24 h, whereas, under
microwave irradiation, the cyclized product was obtained in
80 % yield after only 1 h [Eq. (26)].
Such cyclizations are not limited to aryl iodides or bromides.
A furoquinolinone was prepared in high yield by Fagnou and
co-workers using a furan substituted at C2 by a N-(2-chloro-
phenyl)amide [Eq. (27)].[55] As the oxidative addition of aryl
ChemCatChem 2010, 2, 20 – 40
Palladium-Catalyzed C3 or C4 Direct Arylation of Heteroaromatic Compounds
chlorides to palladium is generally quite slow with ligand-free
palladium, this reaction was carried out using PdACHTUNGRE(OAc)2 with
PCy3, an electron-rich and bulky phosphine ligand. The
expected tricyclic compound was obtained in 83 % yield.
Using a 3-substituted furan, Larock and co-workers obtained
a tetracyclic compound by C H bond activation at C4 of the
furan derivative [Eq. (28)]. For this reaction, 5 mol % of a
palladacyclic catalyst was required to bring about the desired
transformation.[56]
Palladium migration in catalyzed reactions is a fairly general
rearrangement that has been observed to occur in a wide vari-
ety of systems. Such migration is synthetically useful because
it provides an alternative way to introduce a palladium moiety
at a specific position on an organic molecule, which may not
be readily accessible by conventional methods. Larock and co-
workers recently detected a 1,4-migration of Pd from an aryl
position to an imidoyl position.[57] Presumably, Pd0 first under-
goes oxidative addition to the aryl iodide. The palladium
moiety may then undergo further oxidative addition of the
imidoyl C H bond to afford a palladacycle(IV) intermediate,
which can undergo reductive elimination to form an imidoyl
palladium complex. Then an intramolecular arylation followed
by a reductive elimination forms the imine. Using this method,
a 3-substituted furan, was converted to a cyclized compound
by C H bond activation (Scheme 4). Interestingly, with this
ChemCatChem 2010, 2, 20 – 40  2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Scheme 4. Palladium-catalyzed intramolecular arylation by Larock and co-
workers.[57] dppm = bis(diphenylphosphanyl)methane.
substrate, the C4 position on the furan was activated, instead
of C2, which is usually more reactive for palladium-catalyzed
direct arylation reactions.
Intermolecular C3 or C4 arylation of furans by C H bond ac-
tivation has remained largely unexplored. In 2006, 2,3-diphe-
nylfuran was detected as a side-product, formed in low yield in
the course of the coupling of bromobenzene with 2-furancar-
boxylic acid (Scheme 5).[58] The authors postulated that the
Scheme 5. Formation of 2,3-diphenylfuran as a side-product in the coupling
of bromobenzene with 2-furancarboxylic acid.[58]
electrophilic PdII intermediate generated from the oxidative ad-
dition is first coordinated by the carboxylate moiety prior to an
electrophilic palladation at the C3 position of furan. At this
stage, two pathways are possible. A 3,2-migration of Pd and
extrusion of CO2 can occur, followed by reductive elimination
to yield the 2-substituted furan. Alternatively, deprotonation to
regenerate the aromatic furan can take place, after which re-
ductive elimination will generate 3-phenyl-2-furancarboxylic
acid. This product can in turn re-enter the catalytic cycle and
www.chemcatchem.org 29
 H. Doucet et al.

afford 2,3-diphenylfuran. When 2-phenylfuran was subjected to

the reaction conditions, only 2,5-diphenylfuran was formed,
ruling out 2-phenylfuran as an intermediate for the formation
of 2,3-diphenylfuran under these conditions.
In 2007, Daugulis and Chiong generated 2,3-diphenylbenzo-
furan in 68 % yield from benzofuran and chlorobenzene
[Eq. (29)].[59] For this reaction, the catalyst system was PdACHTUNGRE(OAc)2
with n-butyldi-1-adamantylphosphine.

In 2008, Doucet and Gottumukkala reported a method for Table 2. Direct 4-arylation of 2,5-diaryl-3-fluorofurans.[61]
the C3 or C4 arylation of 2,5-disubstituted furans. The reaction
of 2,5-dimethylfuran with electron-deficient aryl bromides gave
the 3-arylated furans in moderate yields [Eq. (30)].[60] An elec-
tron-withdrawing substituent on the furan ring favored the re-
action. When using 2-acetyl-5-methylfuran, higher yields were
recorded than in the presence of 2,5-dimethylfuran. Moreover,
the reaction was regioselective in favor of the 4-arylated com- R1 R2 R2 Yield [%]
pound [Eq. (31)]. This regioselectivity suggested that coordina- Ph Ph H 51
tion of the metal species to the carbonyl group of the furan is Ph Ph 2-MeC6H4 64
Ph Ph 4-FC6H4 73
not an essential step of the catalytic cycle. In the course of this
Ph Ph 2-ClC6H4 70
reaction, 3-arylation and 3,4-diarylation products were also 4-MeC6H4 Ph 2-MeC6H4 60
formed. The ratio of these products was strongly dependent 3-FC6H4 Ph 4-ClC6H4 60
on the reaction conditions and catalyst. Under the optimized Et Ph 4-ClC6H4 57
Ph n-pentyl 4-ClC6H4 61
coupling conditions, [{PdClACHTUNGRE(C3H5)}2], KOAc, DMAc at 120 8C, the
C4-arylated product was formed with high regioselectivity (C3/
C4 ratio = 13:87). This procedure was tolerant to a variety of
functional groups on the aryl bromide, such as ester, formyl, phenyl ring exerted any considerable influence on the yields.
acetyl, nitrile, nitro, fluoro, or trifluoromethyl groups. The presence of the fluorine atom on furan seemed to
2-Formyl-5-methylfuran and 2-propionyl-5-methylfuran were facilitate the arylation. After subjecting 2,5-diphenylfuran and
also suitable reactants. 4-chlorobromobenzene to similar reaction conditions, no cross-
coupled product was detected.
Finally, Miura and co-workers recently reported the peraryla-
tion of 3-furancarboxylic acid. Using an excess of aryl bromide,
the cleavage of three C H bonds and decarboxylation in the
presence of 10 mol % of PdACHTUNGRE(OAc)2 and 40 mol % of PCy3, gave
the tetraarylated furans in 33–77 % yields [Eq. (32)].[62] The
highest yield was obtained using the electron-deficient aryl
bromide, 4-trifluoromethylbromobenzene.
In summary, the intramolecular C3 or C4 arylation of 2- or 3-
substituted furans proceeds using aryl chlorides, bromides or

The direct C4 arylation of 2,5-diaryl-3-fluorofurans, exploiting

the effect of the neighboring fluorine atom, was reported by
Zhu and co-workers (Table 2).[61] This reaction afforded 2,4,5-tri-
aryl-3-fluorofurans in moderate to good yields. Several reaction
conditions were tested and the best yields were obtained
with KOAc as the base, NMP or DMF as the solvent, and
[PdCl2ACHTUNGRE(PPh3)2] as the catalyst. Several aryl bromides were suc-
cessfully coupled by this method and, interestingly, neither the
electronic nature nor the position of the substituents on the

30 www.chemcatchem.org  2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim ChemCatChem 2010, 2, 20 – 40
Palladium-Catalyzed C3 or C4 Direct Arylation of Heteroaromatic Compounds

iodides. The formation of five-, six-, and seven-mem-

bered rings by such cyclization reactions has been re-
ported. In general, relatively high catalyst loadings
were employed (3–33 mol %). Carbonates or acetates
were used as bases and DMAc, DMF, or even toluene
were employed as
solvents.
The control of the intermolecular C3 or C4 aryla-
tion of furans by C H activation appears to be more
sensitive. However, in the presence of a symmetrical-
ly 2,5-disubstituted furan, the 3-arylated compounds
were obtained in moderate yields. Unsymmetrically Scheme 7. Preparation of rubicene analogues.[40]
2,5-disubstituted furans, such as 2-acetyl-5-methylfur-
an, allowed selective access to the 4-arylated furans.
2,5-Diaryl-3-fluorofurans were also useful reactants and provid- heating, the desired product was obtained in only 49 % yield
ed the 2,4,5-triaryl-3-fluorofurans in good yields. However, after 24 h, whereas, with microwave heating, an excellent yield
studies on the influence of the nature of the substituents on of 92 % was obtained after only 12 min. Fagnou and co-work-
furans need to be greatly extended to enable prediction of the ers reported a very similar reaction using a thiophene bearing
yields and regioselectivities of such arylations. a N-(2-chlorophenyl)amide as substituent in position C2
[Eq. (34)].[55] As the oxidative addition of aryl chlorides is gener-
ally quite slow when catalyzed by ligand-free palladium, this
4. 3- or 4-Arylation of Thiophene Derivatives reaction was performed using PdACHTUNGRE(OAc)2 alongside the electron-
The palladium-catalyzed direct arylation of unsubstituted thio- rich and bulky phosphine ligand, PCy3. Beccalli and co-workers
phenes with aryl halides occurs at C2 and, in the presence of have also employed the microwave heating for the cyclization
2-substituted thiophenes, generally at C5.[2, 10, 13] However, of a (2-iodobenzyl)-thiophen-2-yl-carbamate [Eq. (35)]. Again,
several examples of direct arylations at C3 or C4, either by in- the use of microwave irradiation gave a higher yield of cyclized
tramolecular cyclizations, mostly using 2-substituted thio- product than conventional heating.[54] This method is not limit-
phenes, or intermolecular reactions have also been described. ed to the formation of five- or six-membered rings. A seven-
In the course of intramolecular cyclization reactions, 5-, 6-, or membered ring has also been formed by cyclization of a 2-sub-
7-membered rings were formed. For example, two thiophenes stituted benzothiophene [Eq. (36)].[24, 30]
substituted at C2 by b-lactams (Scheme 6) cyclized to give the

Scheme 6. Formation of bicyclic b-lactams from C2-substituted thiophenes

by C H bond activation at C3.[51]

bicyclic b-lactams in 65 and 66 % yields, respectively, after a C

H bond activation at C3.[51] Rubicene analogues have also been
prepared by cyclization of thienyl- or dithienyl-1,5-dichloroan-
thracenes (Scheme 7).[27] However, the yields of target products
are quite low (20 and 30 %), due to some polymerization and
decomposition.
Recently, Beccalli and co-workers reported the formation of
a tricyclic compound by intramolecular cyclization of a thio-
phene substituted at C2 by N-(3-bromopyridin-2-yl)-N-methyl-
ACHTUNGREamide using [PdACHTUNGRE(PPh3)4] as catalyst [Eq. (33)].[28] Under classical

ChemCatChem 2010, 2, 20 – 40  2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim www.chemcatchem.org 31
 H. Doucet et al.

Several examples of direct C3 or C4 arylations of

thiophenes by intermolecular couplings have also
been described. Bi-, tri-, and even tetraarylations of
thiophenes have been reported. In 1998, Lemaire
and co-workers described the direct arylations of
3-formylthiophene and 3-cyanothiophene, which
resulted in a mixtures of 2-arylthiophenes and 2,4-
diarylthiophenes (Scheme 8).[63] In most cases, the 2-
arylated thiophenes were obtained with high selec-
tivities and 2,4-diarylthiophenes were only obtained
in low yields. The coupling of 3-cyanothiophene and
1-iodonaphthalene led to a drastic change in selectiv-
ity and 2,4-dinaphthyl-3-cyanothiophene was formed
in 47 % yield (Scheme 8 b). The selectivity seems to
be largely related to the steric hindrance of the
iodoaryl moiety.
The di- or triarylation of 2-thiophenecarboxamides
has been reported by Miura and co-workers
(Scheme 9).[64] Several 2-thiophenecarboxamides have
been arylated using an excess of aryl bromide (up to
six equivalents). In the course of these reactions, de-
carbamoylation took place and the 2,3,5-triarylated
Scheme 9. Di- and triarylation of 2-thiophenecarboxamides by Miura and co-workers.[64]
thiophenes were obtained in 52–83 % yields using a

the major route for the formation of 2,3,5-triphenylthiophenes

does not proceed via the formation of 2-phenylthiophene or
2,5-diphenylthiophene (Scheme 10 a). The 3-arylation of N-
phenyl-2-thiophenecarboxamide probably proceeds by a coor-
dination-assisted mechanism, whereas 5-arylation would pro-
ceed electrophilically. The arylation of 3-substituted thiophenes

Scheme 8. Direct arylation of (a) 3-formylthiophene and (b) 3-cyanothio-

phene by Lemaire and co-workers.[63]

catalyst system of 10 mol % PdACHTUNGRE(OAc)2 and 20 mol % P(o-

biphenyl)ACHTUNGRE(tBu)2 (Scheme 9 a). The 2-thiophenecarboxamide ap-
peared to be phenylated first at the C3 and C5 positions
(Scheme 9 b). Then, the mono- and diarylated compounds un-
derwent decarbamoylation to give the triarylated thiophenes.
To obtain some
insight into the mechanism of decarbamoylation, Miura and
co-workers heated the 3,5-diphenyl-2-thiophenecarboxamide
in the presence of PdACHTUNGRE(OAc)2, P(o-biphenyl) (tBu)2, and Cs2CO3
(Scheme 9 c). 2,4-Diphenylthiophene was produced quantita-
tively, together with aniline. By using N-phenyl-2-thiophenecar-
boxamide, the 3,5-diphenylated thiophene was obtained in
62 % yield. However, when 2-phenylthiophene was used, 2,5- Scheme 10. Arylation of (a) 2-substituted and (b) 3-substituted thiophenes
diphenylthiophene was obtained in 90 % yield, indicating that by Miura and co-workers.[64]

32 www.chemcatchem.org  2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim ChemCatChem 2010, 2, 20 – 40
Palladium-Catalyzed C3 or C4 Direct Arylation of Heteroaromatic Compounds
was also examined by this group. In the presence of 3-cyano-
thiophene, they obtained mixtures of 2,5-diarylated thiophenes
and 2,4,5-triarylated thiophenes (Scheme 10 b). The triarylated
thiophenes were obtained in relatively high yields. With the
electron-deficient 3-trifluoromethylbromobenzene, the triary-
lated thiophene was the only product. Phenylation of 3-ben-
zoylthiophene gave 3-benzoyl-2,5-diphenylthiophene in 44 %
yield and 3-benzoyl-2,4,5-triphenylthiophene in 33 % yield.
Conversely, 3-phenylthiophene was only diarylated, at C2 and
C5. These results seem to confirm a coordination-assisted
mechanism for the 4-arylation of 3-substituted thiophenes.
Recently, Miura and co-workers have extended these perary-
lation reactions to 3-thiophenecarboxylic acid (Scheme 11 a).[62]
Using this reactant and PdACHTUNGRE(OAc)2/PCy3 as catalyst, the tetraary-
Scheme 11. Perarylation of (a) 3-thiophenecarboxylic acid and (b) 2,5-diaryl-
3-thiophenecarboxylic acid by Miura and co-workers.[62]
lated thiophenes were obtained in 30–90 % yields. In the
course of this reaction, three C H bonds were cleaved and a
decarboxylation occurred. The reaction using electron-neutral
and electron-deficient aryl bromides afforded the perarylated
thiophenes in 60–90 % yields. However, the use of 4-bromoani-
sole gave the expected compound in a lower yield of 30 %.
They also examined the preparation of tetraarylthiophenes
with two pairs of different aryl groups at the 2- and 5-posi-
tions, and at the 3- and 4-positions (Scheme 11 b). 2,5-Di-
phenyl- and 2,5-bis(4-methoxyphenyl)-3-thiophenecarboxylates
were coupled with bromobenzene, 4-bromoanisole, or 4-tri-
fluoromethylbromobenzene to give the perarylated thiophenes
in 47–69 % yields. In each case, the formation of a minor
amount of triarylthiophene was detected. The success of the
tetraarylation appears to be due to the fact that the carbonyl
function acts as a directing group before it is substituted.
ChemCatChem 2010, 2, 20 – 40  2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Doucet and co-workers demonstrated that, by using
PdACHTUNGRE(OAc)2 as the catalyst precursor, direct 3- or 4-arylation by
C H bond activation of 2,5-disubstituted thiophenes with aryl
bromides proceeds in moderate to good yields.[65] 3-arylated
thiophenes were obtained by arylation of 2,5-dimethylthio-
phene. In the presence of 2-acetyl-5-methylthiophene, regiose-
lective arylation took place at C4 [Eq. (37)]. This procedure was
limited to activated aryl bromides. However, a wide range of
functions, such as propionyl, benzoyl, formyl, nitro, nitrile,
fluoro, and trifluoromethyl, are tolerated on the aryl bromide.
Several examples of 3-arylation of 2-substituted benzothio-
phenes have been reported by Pellet-Rostaing and co-workers
[Eq. (38)].[66] Arylation at C3 of 2-substituted benzothiophenes
afforded the corresponding coupling products in lower yields
than arylation at C2, despite longer reaction times. However,
the coupling of 4-(trifluoromethyl)bromobenzene or 2-bromo-
benzonitrile with benzothiophene-2-carbonitrile or 2-(2,2,2-tri-
fluoroethoxy)benzothiophene gave the 3-arylated compounds
in 67 and 69 % yields, respectively.
Lautens and co-workers have developed a route to a variety
of polycyclic sulfur-containing heterocycles, based on a palladi-
um-catalyzed alkylation/direct arylation reaction sequence.[67]
The method works well with 3-substituted thiophene
substrates (Scheme 12 a). The authors suggest that, for these
intramolecular direct arylations of thiophenes, an electrophilic
metalation mechanism may occur. However, for 2-substituted
thiophene substrates, the expected cyclized product was not
detected (Scheme 12 b). With this procedure, there was no acti-
vation of the C H bond in position 3.
In summary, several interesting results have been reported
for the palladium-catalyzed direct arylation of thiophenes at
C3 or C4. Both intra- and intermolecular reactions have been
explored and developed into synthetically viable protocols.
Concerning intramolecular reaction, the formation of five-, six-,
or seven-membered rings is possible. Aryl iodides, bromides,
or chlorides were employed successfully as coupling partners.
www.chemcatchem.org 33
 H. Doucet et al.

Scheme 13. Arylation of (a) 2-phenyl-5-oxazolecarboxanilide and (b) 2-

phenyl-5-thiazolecarboxanilide by Miura and co-workers.[67]

Scheme 12. Synthesis of polycyclic sulfur-containing heterocycles from (a) 3-

substituted and (b) 2-substituted thiophenes by Lautens and co-workers.[67]

In general, the intramolecular cyclizations proceeded with high Fagnou and co-workers have also reported the 4-arylation of
yields. Bimolecular couplings of thiophene or benzothiophene thiazole derivatives (Table 3).[70] Conversion of thiazole to thia-
derivatives have also been investigated. For these reactions, zole N-oxide considerably increases the reactivity of the thia-
some regioselective arylations have been reported. In the pres- zole ring system, and also alters the reactivity profile in terms
ence of amide substituents on thiophene, a regioselective C3
arylation was possible. The C3 arylation of benzothiophene
proceeded in high yields with some electron-deficient aryl Table 3. 4-arylation of thiazole derivatives.[70]
bromides. The synthesis of triarylthiophenes has also been
described. However, in several cases, only the perarylations of
thiophenes were possible.

R1 R2 Ar Yield [%]
5. 4-Arylation of Thiazole, Oxazole, or Imida-
zole Derivatives Ph 4-CF3C6H4 4-MeC6H4 79
Ph 4-MeOC6H4 3,5-(CF3)2C6H3 99
The palladium-catalyzed direct arylations of unsubstituted thia- 4-MeC6H4 Ph 1-naphthyl 65
zoles, oxazoles, and imidazoles occurs preferentially at C2 or Ph 4-OMeC6H4 3,5-Me2C6H3 59
4-MeOC6H4 Ph 3,5-Me2C6H3 64
C5.[2, 15–18] When these positions are blocked, C4 arylation at is 3,5-Me2C6H3 Ph 4-MeOC6H4 84
possible. However, only a few examples of such arylations
have been reported to date.[68–71] The C4 arylation of a 2-
phenyl-5-oxazolecarboxanilide using bromobenzene has been
described by Miura and co-workers (Scheme 13 a).[68] In the of the order of arylation. Arylation of thiazole N-oxides ob-
course of this reaction the decarbamoylation of the oxazole oc- serves a strict order, occurring at C2, then at C5, and finally at
curred, and the diarylation took place at C4 and C5 to give C4. Moreover, the use of thiazole N-oxide substrates led to a
2,4,5-triphenyloxazole in 33 % yield. For the coupling of 2- dramatic increase in reactivity, in comparison to thiazoles, for
phenyl-5-thiazolecarboxanilide with various aryl bromides, a direct arylation at all positions of the azole ring, and the reac-
similar reactivity was detected. The 2,4,5-triarylthiazoles were tion conditions were milder than those usually required for
formed in 52–85 % yields (Scheme 13 b). The highest yield was direct arylation of thiazoles. This permitted high-yielding aryla-
obtained in the presence of 4-chlorobromobenzene. The C4 ar- tions at C4, providing a unique opportunity for exhaustive
ylation of 2,5-diphenyloxazole was reported very recently by functionalization of the thiazole core. 2,5-diarylthiazole N-
Fagnou and co-workers, using PdACHTUNGRE(OAc)2/PCy3 as the catalyst oxides or 2-tolyl-5-methylthiazole N-oxide and a variety of aryl
[Eq. (39)]. The desired compound was obtained in 83 % bromides were used as reactants. With a catalyst system com-
yield.[69] prising 5 mol % PdACHTUNGRE(OAc)2 and 15 mol % PPh3, the 4-arylated

34 www.chemcatchem.org  2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim ChemCatChem 2010, 2, 20 – 40
Palladium-Catalyzed C3 or C4 Direct Arylation of Heteroaromatic Compounds
thiazoles were obtained in 59–99 % yields. This reaction
method was tested on imidazole N-oxide [Eq. (40)]. The 4-ary-
lated imidazole was obtained in 66 % yield with methyl 4-bro-
mobenzoate as a coupling partner. The reactivity of the thia-
zole arylation may be explained by considering the distribution
of the molecular orbitals on the thiazole ring. In thiazole, the
nearly equal distribution of the HOMO on all of the carbon
atoms (C2/C4/C5 ratio = 25.2:30.5:29.9) led to little bias. Con-
versely, on thiazole N-oxide, the HOMO is localized on C2, with
very little density on C4 or C5. Following C2 arylation, the
HOMO density on C5 is much larger than that on C4, leading
to regioselective arylations.
The direct arylation of 1-methylimidazole was also reported
recently by Rossi and co-workers [Eq. (41)].[71] As expected, the
major product was 5-aryl-1-methylimidazole. However, by
using PACHTUNGRE(2-furyl)3, instead of PPh3, as a ligand, 4-aryl-1-methyl-
imidazole was also formed in 11 % yield.
Although successful C4 arylation of some thiazoles, oxazoles,
and imidazoles has been reported, the substrate scope in
these reactions remains largely unexplored and limited. To
date, no examples of such couplings to aryl chlorides or of in-
tramolecular cyclizations have been reported. Moreover, these
reactions were all performed with 5 mol % catalyst. Therefore,
more efficient procedures, permitting a broader scope of sub-
strates and lower catalyst loadings, need to be developed to
provide synthetically useful access to such compounds.
6. 3- or 4-Arylation of Isoxazole or Pyrazole
Derivatives
To date, very few examples of 4-arylation of isoxazoles or
pyrazoles have been reported. In 1982, the intramolecular
cyclization of a 3-substituted isoxazole was described by the
Nakamura and co-workers (Scheme 14 a).[72] Employing
ChemCatChem 2010, 2, 20 – 40  2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
PdACHTUNGRE(OAc)2/PPh3 as catalyst and the carcinogenic solvent hexam-
ethylphosphoramide (HMPA), the desired tricyclic compound
was formed in 45 % yield. 5-subtituted isoxazoles have also
been cyclized to give tricyclic compounds (Scheme 14 b).[73]
The cyclization process led to the fused heterocycles in 9–60 %
yield, with ligand-free PdACHTUNGRE(OAc)2 as catalyst and microwave
heating.
The bimolecular 4-arylation of isoxazoles was also found to
be possible, although it required higher temperatures and
longer reaction times. The coupling of iodobenzene or 4-iodo-
toluene with 3,5-disubstituted isoxazoles, afforded the 4-arylat-
ed isoxazoles in 30-48 % yields (Scheme 15).[72] These reactions
were performed using 10 mol % of either 5 % Pd/C or
PdACHTUNGRE(OAc)2 as catalyst and hexamethylphosphoric tria-
mide (HMPT) as a solvent. Recently, the scope of this
reaction was extended to include aryl chlorides,
when 1-chloronaphthalene was used as a coupling
partner [Eq. (42)].[59] T To facilitate the oxidative addi-
tion of 1-chloronaphthalene to palladium, PdACHTUNGRE(OAc)2
was associated to the bulky and electron-rich ligand,
butyldi-1-adamantylphosphine to act as catalyst. The
expected product, 3,5-dimethyl-4-naphthalen-1-yli-
soxazole, was obtained in 76 % yield.
Only a few examples of palladium-catalyzed direct C3 aryla-
tion of a pyrazole using aryl halides have been described.
Brnardic et al. utilized this reaction as the key step for ring
closure in the synthesis of pyrazoloquinolinone Chk1 kinase in-
hibitors.[74] Using a 4-substituted pyrazole, and ligand-free
Scheme 14. Intramolecular cyclization of (a) 3-substituted[72] and (b) 5-substi-
tuted[73] isoxazoles to give tricyclic products.
www.chemcatchem.org 35
 H. Doucet et al.

Scheme 15. Bimolecular 4-arylation of 3,5-disubstituted isoxazoles.[72]

PdACHTUNGRE(OAc)2 as catalyst, the intramolecular cyclization produced

the desired tetracyclic compound in 75 % yield [Eq. (43); CBz = Scheme 16. Effect on regioselectivity of substituents on the catalytic
benzyloxycarbonyl THP = tetrahydropyranyl]. arylation of pyrazoles.[67] SEM = CH2OCH2CH2SiMe3 ; PivOH = pivalic acid.

the most acidic C H bond which can be selectively deproton-

ated by strong bases.
The potential of Pd-catalyzed C3/C4 arylation of isoxazoles
or pyrazoles remains largely unexplored. To our knowledge,
the C3 arylation of isoxazoles has not, to date, been reported
and the regioselectivity of the arylation (C3 vs. C4) of 5-substi-
tuted isoxazoles has not been examined. The scope and limita-
tions of various aryl halide coupling partners also need to be
explored.

Sames and co-workers recently established the regioselectiv-

ity of the catalytic C H arylation of pyrazoles (Scheme 16).[75]
7. 4-Arylation of Triazole Derivatives
SEM-pyrazole (SEM = 2-(trimethylsilyl)ethoxymethyl) was cou-
pled with bromobenzene to give a mixture of products, which The earliest report of Pd-catalyzed direct arylation of 1,2,3-tria-
indicated the higher reactivity of the 5-position relative to the zoles was from the Gevorgyan and co-workers,[76] who detect-
4-position, and very low reactivity of the 3-position ed a strong preference for C5 arylation, regardless of variations
(Scheme 16 a). This trend was confirmed by examining the in the electron density on the aryl halide (Scheme 17 a). When
reaction of 1-SEM-3-phenylpyrazole, which gave a 5:2 ratio of the C5 position was blocked, arylation took place at C4, al-
1-SEM-3,5-diphenylpyrazole and 1-SEM-3,4,5-triphenylpyrazole
(Scheme 16 b). In contrast, 1-SEM-4-phenylpyrazole was arylat-
ed at C5 with high selectivity to provide 1-SEM-4,5-diphenyl-
pyrazole in 80 % yield (Scheme 16 c). The regioisomer resulting
from arylation at the C3 was not detected, and only a small
amount of the bisarylation product, 1-SEM-3,4,5-triphenylpyra-
zole, was formed. Arylation of 1-SEM-5-phenylpyrazole was
also selective, taking place at the C4 to afford 1-SEM-4,5-diphe-
nylpyrazole as the major product (Scheme 16 d). These results
demonstrate that arylation at the C3 is inefficient, which is
consistent with the low reactivity of this site, whereas arylation
occurs at both C4 and C5, with preference for the latter. Ac-
cording to Sames and co-workers, it is well established that C4
of pyrazole is the most nucleophilic position and readily under- Scheme 17. Palladium-catalyzed arylation of 1,2,3-triazoles by Gevorgyan
goes electrophilic substitution, whereas the 5-position carries and co-workers.[76]

36 www.chemcatchem.org  2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim ChemCatChem 2010, 2, 20 – 40
Palladium-Catalyzed C3 or C4 Direct Arylation of Heteroaromatic Compounds
though the reaction was much more sluggish, requiring longer
reaction time and higher catalyst loading (Scheme 17 b). A ra-
tionalization for this trend was provided by density functional
(DFT) calculations of the electrostatic potential charge at C4
and C5 for a model triazole. Based on these calculations, an
electrophilic substitution mechanism was proposed.
Similar results were obtained by Oshima and Yorimitsu,[77]
when they attempted the arylation of 1,2,3-triazoles with aryl
chlorides under microwave irradiation [Eq. (44)]. This approach
drastically reduced the reaction time (15 min), although higher
reaction temperatures (250 8C) were employed during the
course of the reaction. For 1-substituted triazoles, selective 5-
arylation took place. Arylation of a 1,5-disubstituted triazole re-
sulted in the formation of the 4-arylated triazole in low yield
(19 %). Arylation at C4 would be unfavorable because of the
more localized stabilization of the cationic charge formed after
the addition of the triazole to [ArPdCl].
Recently, Ackermann and co-workers reported the 4-aryla-
tion of 1,5-disubstituted 1,2,3-triazoles with aryl chlorides, at
much lower temperatures and employing conventional heat-
ing techniques (Scheme 18 a).[78] Again, the transformation was
difficult to perform, whereas corresponding 5-arylation took
place with much greater ease (Scheme 18 b).
In summary, the 4-arylation of triazoles is possible when the
5-position is blocked. To date, the reported procedures have
used catalyst loadings of 4–10 mol %, but, in this case, aryl
chlorides have been employed as coupling partners. The
reported yields (13–60 %) have been relatively low and the
substrate scope has been quite limited.
Scheme 18. Palladium-catalyzed arylation of 1,2,3-triazoles by Ackermann
and co-workers.[78]
ChemCatChem 2010, 2, 20 – 40  2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
8. 3- or 4-Arylation of Pyridine Derivatives
The direct palladium-catalyzed arylation of pyridines generally
provides 2-arylpyridines.[2] However, several examples of direct
3- or 4-arylations of substituted pyridines have also been
described. Again, intramolecular cyclization reactions have
been employed for the preparation of a variety of pyridine
derivatives. In 1984, Ames and Opalko employed 2-(2-bromo-
phenoxy)pyridine, as a tether for directing arylation to C3, re-
sulting in the synthesis of a benzofuropyridine [Eq. (45)].[79] De-
spite a high reaction temperature and a relatively high catalyst
loading, the target compound was only obtained in 10 % yield,
and 25 % of the starting material was recovered unreacted.
Alternatively, several C4-substituted tethers have been used
for directing arylation at C3 position. Both five- and six-mem-
bered rings have been formed using this reaction. LaVoie and
co-workers used this method to prepare biologically active
compounds.[80–85] The cyclized products were generally
obtained in moderate yields (22–55 %; Scheme 19).
Maes and co-workers prepared cryptolepine derivatives
using (2-chlorophenyl)quinolin-4-ylamine or (3-chloropyridin-2-
yl)pyridin-4-ylamine as reactants (Scheme 20).[86, 87] For these
cyclizations, the electron-rich phosphine ligand PACHTUNGRE(tBu)3 was
used alongside [Pd2ACHTUNGRE(dba)3] as catalyst. The quinoline derivative
was more reactive than the pyridine. The reaction of (2-chloro-
phenyl)quinolin-4-yl-amine gave the expected product with
formation of a five-membered ring in 95 % yield, with only
2.5 mol % catalyst. However, cyclization of (3-chloropyridin-2-
yl)pyridin-4-ylamine gave the desired compound in only 52 %
yield, with 10 mol % catalyst. In the presence of a pyridine sub-
stituted at C4 by a 2-bromoaniline, the cyclization proceeded
in 72 % yield, with 5 mol % ligand-free PdACHTUNGRE(OAc)2 as catalyst
[Eq. (46)]. This improvement in yield is due to the easier oxida-
tive addition of aryl bromides to palladium.[88] Intramolecular
cyclization of a pyridine substituted at C4 by a 2-bromophenol
gave the desired cyclized product in only 21 % yield
[Eq. (47)].[89] This low yield is probably due to the formation of
side products. Notably, the higher yields were obtained only if
air was allowed into the reaction mixture.
www.chemcatchem.org 37

Scheme 19. Preparation of biologically active compounds by 3-arylation by LaVoie and
co-workers.[80–85]
Scheme 20. Synthesis of cryptolepine derivatives from (a) (2-chlorophenyl)-
quinolin-4-ylamine or (b) (3-chloropyridin-2-yl)-pyridin-4-ylamine by Maes
and co-workers.[86, 87]
Maes and co-workers also studied the cyclization of 3-substi-
tuted quinolines [Eq. (48)].[90, 91] During the course of this reac-
tion, the formation of two products was possible, resulting
from C H activation of the pyridine moiety either at C2 or C4.
However, the C4 arylation occurred selectively. Several reac-
tions conditions were tested and microwave heating was
found to improve the yield. The use of various catalyst load-
ings for this cyclization was also studied and a higher yield
was obtained with 0.2 mol % catalyst, rather than 23 mol %,
probably due to a faster aggregation of the palladium into in-
active “palladium black”, at higher palladium concentration. To
have a more general protocol for the synthesis of indoloquino-
lines, they also studied the reactivity of a few other substrates.
38 www.chemcatchem.org  2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
H. Doucet et al.
Echavarren and co-workers studied the cyclization
of another interesting substrate [Eq. (49)].[92, 93] The
cyclization of a 5-methyl-5-indenopyridine derivative,
substituted by a 2-bromobenzyl group at C5, in the
presence of PdACHTUNGRE(OAc)2 associated to a phosphine
ligand, proceeded with relative selectivity to the para
position of the pyridine ring. However, the other re-
gioisomer, that cyclized on the phenyl ring, was also
obtained in 30 % yield. They also studied the reactivi-
ty of substituted bromobenzyldiarylmethanes and es-
tablished that electron-withdrawing substituents fa-
vored reaction on the substituted ring. These results
are incompatible with an electrophilic aromatic sub-
stitution mechanism. The key step would be the ab-
straction of a proton from the pyridyl ring by carbon-
ate.
There have, to date, been very few examples of palladium-
catalyzed intermolecular C3 or C4 arylation of pyridines with
aryl halides. One of the rare cases, described by Cetinkaya and
co-workers in 2005, involved the coupling of pyridine-2-carbal-
dehyde and 4-chloroacetophenone in the presence of PdACHTUNGRE(OAc)2
with a N-heterocyclic carbene ligand. The 3-arylated pyridine
product was obtained in 88 % yield [Eq. (50)].[94] Recently, the
4-arylation of 2,3,5,6-tetrafluoropyridine with challenging 2-
chlorotoluene or 4-bromotoluene reactants was reported by
Fagnou and co-workers (Scheme 21).[95, 96] The coupling
products were obtained in 97 % and 86 % yields, respectively.
In summary, the direct arylation of pyridines at C3 or C4 pro-
vides simple access to 3- or 4-arylpyridines. However, to date,
the reaction has been limited to specific substrates. Intramo-
lecular cyclization of 4-substituted pyridines generally gave the
cyclized products with the formation of five- or six-membered
rings in good yields. Some 3-substituted pyridines cyclized at
C4 of pyridine, with the formation of five- or six-membered
rings. Again, intermolecular couplings have attracted less
attention, as only pyridine-2-carbaldehyde and 2,3,5,6-tetra-
fluoropyridine have been employed as reactants.
9. Conclusion and Perspectives
During the last five years, the scope and limitations of the pal-
ladium-catalyzed direct C3 and C4 arylations of heteroaromatic
compounds have been greatly extended. Recent investigations
ChemCatChem 2010, 2, 20 – 40
Palladium-Catalyzed C3 or C4 Direct Arylation of Heteroaromatic Compounds
Scheme 21. 4-arylation of 2,3,5,6-tetrafluoropyridine with (a) 2-chlorotoluene
or (b) 4-bromotoluene by Fagnou and co-workers.[95, 96]
into coupling partners for this simple and elegant reaction
have demonstrated that it is actually one of the most straight-
forward and powerful catalytic processes to prepare 3- or 4-
arylated aromatic heterocycles. Although the highest yields
were generally obtained using intramolecular cyclizations, in-
termolecular couplings have also provided, in some cases, a
very simple access to useful heteroaromatic derivatives. Several
catalysts are available for the direct arylation of heteroaromat-
ics. In most cases, aryl iodides or bromides were employed as
coupling partners. However, aryl chlorides have also been used
alongside the most efficient catalysts. Undoubtedly, this meth-
odology will help both synthetic and materials chemists a
great deal, making direct C3 or C4 arylation a valuable tool for
diverse academic and industrial applications.
However, a number of challenges remain. If satisfactory re-
sults were generally obtained for intramolecular cyclizations,
the bimolecular reactions led in several cases to mixtures of re-
gioisomers and to low yields. Moreover, the substrate scope
needs to be greatly extended, and the influence of functional
groups on heteroaromatic substrates and of the reaction con-
ditions on the yields and selectivities need to be explored in
greater details. Although several catalytic systems are active
for the direct 3- or 4-arylation of readily available and low-cost
aryl chlorides, more efficient catalysts, permitting lower catalyst
loadings, need to be prepared in order to provide more
economically attractive procedures.
Regarding the mechanism involved in these reactions, con-
cerning both catalytic cycles and elementary steps, many ave-
nues of investigation have not been addressed. The exact
mechanism for any given example seems to largely depend on
the substrates and reaction conditions employed. Determining
ChemCatChem 2010, 2, 20 – 40  2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
the reasons for the various regioselectivities for these reactions
could allow further improvement in terms of selectivity,
efficiency, mildness, and reaction scope.
Keywords: arylation · C H bond activation · heterocycles ·
homogeneous catalysis · palladium
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