Palladium- and Copper-Catalyzed Aryl Halide Amination ...

REVIEW 1
Palladium- and Copper-Catalyzed Aryl Halide Amination, Etherification and
Thioetherification Reactions in the Synthesis of Aromatic Heterocycles
Palladium- Jessie and Copper-Catalyzed Heterocycle Synthesis E. R. Sadig, Michael C. Willis*
Department of Chemistry, University of Oxford, Chemistry Research Laboratory, Mansfield Road, Oxford, OX1 3TA, UK
Fax +44(1865)285002; E-mail: michael.willis@chem.ox.ac.uk
Received 4 August 2010; revised 13 August 2010
Abstract: This article reviews the use of palladium- and coppercatalyzed
aryl halide amination, etherification and thioetherification
processes in the synthesis of heteroaromatic molecules. The review
is structured by the nature of the key C–X bond being formed,
and then by heterocycle type. Where applicable individual heterocycles
are further divided into syntheses based on intermolecular,
intramolecular and cascade processes. In order to limit the length of
the article, processes that do not deliver an aromatic heterocycle
from the key C–X bond-forming event are excluded. Processes for
the functionalization of intact heteroaromatics are also not included.
1 Introduction
2 Carbon–Nitrogen Bond Formation
2.1 Indoles
2.2 Carbazoles
2.3 Benzimidazoles and Benzimidazolones
2.4 Indazoles and Indazolones
2.5 Pyrroles
2.6 Pyrazoles
2.7 Oxazoles
2.8 Quinolones
2.9 Quinazolines, Quinazolinones and Quinazolinediones
2.10 Phenazines
2.11 Cinnolines
3 Carbon–Oxygen Bond Formation
3.1 Benzofurans
3.2 Benzoxazoles
3.3 Isocoumarins
4 Carbon–Sulfur Bond Formation
4.1 Benzothiophenes
4.2 Benzothiazoles
4.3 Oxathioles
5 Conclusion
Key words: palladium catalysis, copper catalysis, aromatic heterocycles,
amination, etherification
1 Introduction
Given the numerous applications of aromatic heterocycles
in medicine, agriculture and materials, it is not surprising
that a whole host of methods have been developed for
their preparation. Prominent amongst these are routes
based on transition metal catalyzed transformations. 1–8 Indeed,
many transition metal catalyzed processes have
been developed with the explicit goal of delivering new
synthetic routes to heteroaromatics. This forging of new
SYNTHESIS 2011, No. 1, pp 0001–0022xx.xx.2010
Advanced online publication: 12.10.2010
DOI: 10.1055/s-0030-1258294; Art ID: E27810SS
© Georg Thieme Verlag Stuttgart · New York
routes, allowing the introduction of new classes of starting
materials, or access to alternative substitution patterns, is
one of the key advantages offered by transition metal catalysis.
The last fifteen years has seen the development of
efficient and user-friendly methods, based on both palladium
and copper catalysis, for the formation of carbon–
nitrogen, carbon–oxygen and carbon–sulfur bonds using
aryl halide substrates. Collectively, these processes
present almost ideal tools for aromatic heterocycle synthesis,
as witnessed by the rapidly increasing number of
applications that have been published during this time.
For example, reference to the first edition of Li and
Gribble’s excellent treatise on the use of palladium catalysis
in heterocyclic chemistry, 1 published in 2000, shows
only a handful of examples of palladium-catalyzed aryl
amination reactions being employed in the synthesis of aromatic
heterocycles. This is certainly not the case today.
Migita described the palladium-catalyzed coupling of
aminostannanes with aryl halides as early as 1983; 9 however,
it was not until the report of tin-free catalytic amination
reactions, by Buchwald10 and Hartwig, 11 that the
synthetic potential of these processes began to be realized.
Copper-based aryl halide amination (and amidation)
chemistry has an even longer history, dating back to the
original reports by Ullmann12 and Goldberg, 13 but again,
it was not until the development of mild catalytic variants
of these reactions that the majority of applications began
to be developed. In recent years both processes have undergone
enormous development and now encompass a
myriad of different nitrogen nucleophiles and aryl halide
(and equivalent) coupling partners. Advances to carbon–
oxygen and carbon–sulfur bond-forming variants have
also been achieved. It is beyond the scope of this review
to examine the development and mechanistic details of
these underpinning catalytic methods, but extensive reviews
of both the palladium14–17 and copper18–23 chemistries
exist. The following discussion is divided by the key
catalytic bond construction – carbon–nitrogen, carbon–
oxygen or carbon–sulfur – and then by heterocycle type.
Where appropriate, individual heterocycles are then subdivided
into intermolecular, intramolecular or cascade
processes. The review is focused on the formation of aromatic
heterocyles, and accordingly we have not included
reports of the functionalization of intact heterocyclic
cores, nor processes that lead to non-aromatic systems.

2 J. E. R. Sadig, M. C. Willis REVIEW
2 Carbon–Nitrogen Bond Formation
2.1 Indoles
A number of new indole syntheses based on aryl halide
amination have been developed; however, one of the first
heterocycle syntheses to be reported using palladiumcatalyzed
amination chemistry was concerned with intercepting
reaction intermediates from a very well established
route to indoles. 24 In 1998 Buchwald demonstrated
that a variety of aryl halides could be combined with benzophenone
hydrazone using intermolecular palladiumcatalyzed
amination reactions to generate the corresponding
N-arylhydrazones (1, Scheme 1). 25 A palladium(II)
acetate/XantPhos (2) catalyst system, in combination with
sodium tert-butoxide, was found to be optimal. The Narylhydrazones
could either be isolated or, after simple
filtration through a silica plug, treated directly with an
enolizable ketone under acid hydrolysis conditions. The
ensuing Fischer cyclization provided the corresponding
indoles in good to excellent yields. Variations to access either
N-alkyl- or N-arylindoles were also developed, although
in these cases functionalization of the isolated Narylhydrazones
was necessary.
A limitation of the benzophenone hydrazone methodology
is the difficulty in removing benzophenone from the
final indole products, particularly in large-scale
applications. Cho and Lim reported a related procedure, in
which N-Boc arylhydrazines were employed in Fischer
cyclizations. 26 The required N-Boc arylhydrazines were
prepared using palladium-catalyzed amination chemistry,
but in these cases were isolated before indole formation.
The use of intramolecular carbon–nitrogen bond formation
onto an aryl halide has proved to be a popular method
to achieve indole synthesis. In one of the first routes based
Biographical Sketches
Jessie Sadig received her
MChem degree from the
University of Oxford in July
2008, where she carried out
her final year project under
Michael Willis received his
undergraduate education at
Imperial College London,
and his PhD from the University
of Cambridge working
with Prof. Steven V.
Ley, FRS. After a postdoctoral
stay with Prof. David
A. Evans at Harvard University,
as a NATO/Royal
Synthesis 2011, No. 1, 1–22 © Thieme Stuttgart · New York
on this approach, Watanabe et al. demonstrated that N,Ndimethylhydrazones
derived from o-chloroarylacetaldehydes
(4) underwent cyclization under the action of palladium
catalysis to provide the corresponding N-aminoindoles
(Scheme 2). 27 Tri(tert-butyl)phosphine and the
ferrocene derivative 5 were found to be the optimal
ligands. The authors went on to demonstrate that if an appropriately
functionalized substrate was employed, then a
second palladium-catalyzed transformation could be
achieved in the reactions. For example, dichloride 6 could
N
Ph Ph
NH2
+
MeO
MeO
Scheme 1
65%
Br
Me
N
H
Me Me
PPh 2
the supervision of Dr. Jeremy
Robertson. She then
joined the Willis group and
is currently working towards
her DPhil degree. Her
Society Research Fellow, he
was appointed to a lectureship
at the University of
Bath in November 1997. In
January 2007 he moved to
the University of Oxford,
where he is a University
Lecturer and Fellow of
Lincoln College. He was
awarded an EPSRC Ad-
O
i) Pd(OAc) 2 (0.1 mol%)
XantPhos (0.11 mol%)
NaOt-Bu, toluene, 80 °C
ii) TsOH.
H2O, EtOH
reflux
O
Me
Me
Pent
Ph
Ph
N
HN
Me
1
PPh 2
N
H
Ph Ph
79%
Pent
N
H
Pent
N
H
Me
Me
70% 70%
(BINAP used as ligand)
XantPhos (2) (rac)-BINAP (3)
PPh2
PPh2
research focuses on palladium-
and copper-catalyzed
cascade processes for heterocycle
synthesis.
vanced Research Fellowship
in 2005 and the 2008
AstraZeneca Research
Award for Organic Chemistry.
His group’s research interests
are based on the
development and application
of new catalytic processes
for organic synthesis.

REVIEW Palladium- and Copper-Catalyzed Heterocycle Synthesis 3
be reacted under the standard conditions but with the addition
of phenyl boronic acid, to provide 4-phenylindole
7, resulting from tandem carbon–carbon and carbon–
nitrogen bond formation. In addition to aryl boronic acids
being introduced by Suzuki couplings, a range of azoles
and amines could also be effectively incorporated via a
second carbon–nitrogen bond-forming process.
F
Cl
4
6
Scheme 2
Doye and co-workers demonstrated that N-alkyl imines
corresponding to hydrazones 4 can also be effectively cyclized
under the action of palladium catalysis to provide
N-alkylindoles. 28 In their approach, the imine substrates
were prepared from the corresponding alkynes using a
titanium-catalyzed hydroamination process. In this onepot
protocol, the imines were then subjected to palladium
catalysis to deliver the indole products. Scheme 3 shows
an example in which alkyne 8 was converted in a one-pot
process into indole 9. N-Heterocyclic carbene (NHC)
ligand 10 was most effective. Substrates containing a tethered
amine nucleophile could also be included, leading to
the formation of N–C2 annulated indoles.
Scheme 3
H
N
Cl NMe2
H
N
Cl NMe2
Pd(dba) 2 (3 mol%)
5 (4.5 mol%)
NaOt-Bu
o-xylene, 120 °C
PhB(OH) 2
Pd(dba)2 (5 mol%)
5 (7.5 mol%)
Cs 2CO 3
o-xylene, 120 °C
Fe
NMe2 Pt-Bu2
5
N
60% NMe2 N
NMe2 7, 56%
10
8
MeO
Pr i) [Cp2TiMe2] (5 mol%)
toluene
110 °C, 24 h
MeO
+ H2N Me
ii) Pd2(dba)3 (5 mol%)
Cl Me
Me
(10 mol%)
KOt-Bu, dioxane 9, 65%
N
Pr
Me
110 °C
Me Me
Me
Me
Isolated dehydrohalophenylalinate derivatives have been
converted into indoles using related cyclizations. For example,
Brown was the first to report the cyclization of
enamines such as 11 (Scheme 4) into the corresponding
indole-2-carboxylates. In this report from 2000, a simple
dppf-derived catalyst was employed in combination with
F
Ph
Me Me Me
Cl
N N
Me
–
10
+
potassium acetate as base. 29 Kondo and co-workers subsequently
showed that polymer-supported substrates corresponding
to 11 can also be cyclized effectively. 30
O 2N
Scheme 4
11
HN
I
Br
CO2Et
PdCl 2(dppf)
(5 mol%)
KOAc, DMF
90 °C
PPh 2
Fe dppf (12)
PPh2
O2N 83%
Br
Lautens and co-workers established gem-dihalovinylanilines
as versatile substrates for indole synthesis based
on a series of tandem metal-catalyzed processes. The substrates
were readily accessed from the relevant o-nitrobenzaldehyde
derivatives via Ramirez olefinations
followed by reduction of the nitro group. The early chemistry
focused on tandem palladium-catalyzed intramolecular
amination reactions and intermolecular Suzuki
couplings to deliver a series of variously substituted indoles.
31a,b For example, reaction of gem-dibromoaniline
13 with thienyl-3-boronic acid delivered the expected
indole in 86% yield (Scheme 5). The electron-rich
biphenyl-based phosphine SPhos (14), developed by
Buchwald, proved to be optimal. Significant variation in
the substitution pattern of the substrates and in the type of
organoboron coupling partner was possible. For example,
it was possible to prepare indoles with individual substituents
at positions C2–C7; N-aryl substrates could also be
employed. Aryl, alkenyl and alkyl boron reagents were all
used successfully. For many of the examples it was possible
to use palladium loadings of only 1 mol%. Although
no reaction intermediates were detected, a brief mechanistic
investigation suggested that the intramolecular amination
reaction preceded the intermolecular Suzuki
coupling. It is interesting to note that the amination reactions
took place on alkenyl halides, 32 as opposed to the
usual aryl halide substrates. To demonstrate the synthetic
utility of the method, indole 15, prepared in 86% yield
from the corresponding gem-dibromovinylaniline and 2methoxyquinoline
boronic acid, was utilized in a short
synthesis of KDR kinase inhibitors. 31c Bisseret and coworkers
also reported a single example of the synthesis of
a 2-arylindole using a similar strategy. 33
In an elegant extension of this chemistry the same group
was able to demonstrate that the corresponding pyridinederived
substrates could be utilized to access azaindoles.
31d The example shown in Scheme 6 illustrates the
preparation of a 7-azaindole using reaction conditions almost
identical to those for the parent indole series. An important
modification from the parent system, needed to
achieve high yields, was the use of a nitrogen-protecting
group. It was also possible to extend the chemistry to the
preparation of 6-azaindoles; however, the synthesis of the
Synthesis 2011, No. 1, 1–22 © Thieme Stuttgart · New York
N
CO2Et

4 J. E. R. Sadig, M. C. Willis REVIEW
BnO
13
+
(HO) 2B
MeO
O
Scheme 5
N
Scheme 6
Br
NH2
S
Br
Pd(OAc) 2 (1 mol%)
SPhos (2 mol%) S
N
H
Ph
NH
Me
Me
N
86% 73%
77%
15, 86%
(2 mol% Pd)
Br
NH
Bn
Br
+
N
H
MeO
(HO) 2B Ph
K3PO .
4 H2O toluene, 90 °C
regioisomeric 5- and 4-azaindoles was more challenging
and required the use of N-oxide substrates. Thienopyrroles
could also be prepared starting from the corresponding
thiophene-derived substrates.
The same gem-dihalovinylaniline substrates have been
utilized in a number of different tandem processes. For example,
as Scheme 7 illustrates, the initial intramolecular
amination reactions have been partnered with a number of
alternative reactions, including Heck olefinations (16 →
17), 31e carbonylations (16 → 18) 34 and Sonogashira couplings
(16 → 19), 31f to deliver acrylate-, ester- and alkynesubstituted
indoles, respectively. Bisseret and co-workers
used the same substrates in tandem palladium-catalyzed
amination/phosphonation sequences to deliver 2-phosphonate-substituted
indoles. 33 Tethered substrates were
used in the Heck chemistry to provide polycyclic products
via an intramolecular second step. 31e Related tethered substrates,
invoking a second intramolecular amination reaction,
31g or an intramolecular direct arylation reaction, 31h
were also developed to access alternative polycyclic scaffolds.
It is interesting to note that the double amination
processes were achieved using copper catalysis. Lautens
and co-workers also demonstrated that the reactivity of
gem-dibromovinylanilines can be controlled to allow access
to 2-bromoindoles by a single (as opposed to a tandem)
palladium-catalyzed intramolecular amination
reaction. 31i
The Willis research group has developed cascade catalytic
amination strategies to access a range of indole deriva-
Synthesis 2011, No. 1, 1–22 © Thieme Stuttgart · New York
N
Me
Pd(OAc) 2 (3 mol%)
SPhos (14) (6 mol%)
K3PO .
4 H2O toluene, 100 °C
N
H
Me
86%
(dichloro substrate)
Cy2P OMe
MeO
SPhos (14)
N
N
Bn
74%
Ph
t-BuO 2C
Scheme 7
Br
NH
16
R
SiMe 3
Pd(OAc) 2 (4 mol%)
Me4NCl (100 mol%)
K3PO4 .
H2O, Et3N
toluene, reflux
Br
PdCl2(PPh3) 2
Ph3P (10 mol%)
CO (10 atm)
DIPEA, THF
MeOH, 110 °C
P(p-MeOC6H4)3 (8 mol%)
Pd/C (2 mol%)
CuI (4 mol%)
i-Pr2NH, toluene, 100 °C
tives. They focused on the use of 2-(2-haloalkenyl)aryl
halides, together with the corresponding alkenyl triflates,
as indole substrates. 35a,b Scheme 8 shows examples of
both the aryl halide/alkenyl triflate (20) and the aryl halide/alkenyl
halide (21) substrates in palladium-catalyzed
indole-forming reactions. Both reactions feature an initial
intermolecular amination reaction followed by an intramolecular
amination as the second step of the cascade,
to deliver N-functionalized indole products. The authors
noted that it was possible to employ either Z- or E-configured
alkene isomers in the process, a consequence of the
initial amination reaction taking place at the alkenyl halide
and generating a configurationally unstable enamine
intermediate. Reactions employing the triflate substrates
were best achieved using DPEPhos (22) or XantPhos (2)
ligands, while the dihalide substrates delivered best yields
with the Buchwald diphenyl ligands, such as SPhos (14).
By selecting the appropriate class of substrate it was possible
to access a number of indole substitution patterns.
Significant variation of the nitrogen coupling partner was
possible, with examples of aniline, amine, amide, hydrazine
and sulfonamide nucleophiles all being reported.
Sterically demanding nitrogen nucleophiles, such as tertbutylamine,
could also be introduced; 35c the ability to access
indoles bearing bulky N-substituents was exploited
in a synthesis of the natural product demethylasterriquinone
A, in which N-(reverse prenyl)indole 23 was utilized as
a key intermediate. A recent extension of the chemistry
has seen trihalogenated substrates employed, allowing access
to 4-, 5-, 6- and 7-chloroindoles. 35d The Li research
group has adapted the method to encompass trifluoromethyl-substituted
substrates in order to prepare a series
of N-aryl-2-trifluoromethyl-substituted indoles. 36 A related
intramolecular amination reaction between an aniline and
an alkenyl triflate was employed by Smith and co-workers
in their synthesis of the nodulisporic acids tetracycle. 37
The Willis research group also demonstrated that similar
palladium-catalyzed cascade processes can be achieved
using pyridine-derived substrates to provide access to the
corresponding azaindole products. 35e For example, reaction
of dihalopyridine substrate 24 with p-anisidine, using
a DPEPhos-derived catalyst, delivered the corresponding
N
Bn
17, 79%
CO2t-Bu
CO2Me N
18, 70%
Bn
N
H
SiMe3
19, 57%

REVIEW Palladium- and Copper-Catalyzed Heterocycle Synthesis 5
Br OTf
Cl
+
20 H2N
N
71%
Ph
Scheme 8
7-azaindole in good yield (Scheme 9). The process was
shown to work well for 7-azaindoles; however, access to
the remaining regioisomers was less successful.
Scheme 9
The 2-(2-haloalkenyl)aryl halide substrates have also
been shown to undergo cascade copper-catalyzed amination
reactions to deliver N-functionalized indoles. 35f An
example featuring a carbamate coupling partner is shown
in Scheme 10. Although some overlap in scope with the
palladium-catalyzed version of the process was established,
there were also significant differences in reactivity.
In general, the copper-catalyzed variant was more
limited, with chloro-substituted substrates performing
poorly; however, greater success was achieved with
amide nucleophiles, relative to the palladium system.
Scheme 10
Pd2(dba)3 (2.5 mol%)
DPEPhos (6 mol%)
Cs2CO3 toluene, 100 °C
Br Cl
Ph
21, E/Z 2:7
+ H2N
Ph
Pd2(dba)3 (2.5 mol%)
SPhos (14) (7.5 mol%)
NaOt-Bu
toluene, 80 °C
N Cl Br
+
O
OEt
24
H2N OMe
O
PPh2 PPh2
DPEPhos (22)
N
Ph 81%
OMe
Pd2(dba) 3 (5 mol%)
DPEPhos (22) (12 mol%)
Cs2CO3 toluene, 110 °C
Br Br
25
MeO
CuOAc (10 mol%)
MeO
MeO
H2N
+
Ot-Bu
(20 mol%)
Cs2CO3
toluene, 110 °C
MeO
O
MeN NMe
H H 25
75%
94%
N
N
Ph
N
23, 77%
Me Me
N
83%
N
t-BuO
82%
OEt
O
OMe
N
O
Cl
Ackermann and co-workers developed efficient indole
syntheses based on a cascade amination process starting
from o-alkynylhaloarenes. 38 In his original report,
Ackermann described both palladium- and copper-catalyzed
variants of the process (Scheme 11). 38a For example,
the combination of o-alkynylchloroarene 26 with
benzylamine under the action of an NHC-derived palladium
catalyst delivered indole 27 in 66% yield. The original
copper-catalyzed protocol simply employed copper(I) iodide
to combine o-alkynylchoroarenes with anilines furnishing
the corresponding N-arylindoles in good yields.
The reactions proceed via initial intermolecular N-arylation,
followed by cyclization onto the alkyne. The two
different metal systems were shown to display differing,
and complementary, reactivities; for example, the palladium-catalyzed
methods were effective for N-alkyl and Naryl
nucleophiles, while the copper system tolerated Naryl
and N-acyl substrates. 38b The N-acyl systems required
the use of diamine ligand 25. Scheme 11 shows several
examples of products obtained using the copper methodology,
including an N-acyl indole, as well as an azaindole.
An indole corresponding to the Chek1/KDR kinase inhibitor
pharmacophore was also prepared. The palladiumcatalyzed
version of the chemistry was shown to be effective
for the preparation of indoles bearing sterically demanding
substituents; for example, the adamantylsubstituted
indole 28 was obtained in 94% yield. 38c,d The
Hu 39 and Sanz 40 research groups have reported related
indole-forming chemistries.
F3C
Scheme 11
29
26
Hex
Pd(OAc)2 (5 mol%)
(5 mol%)
+
H2N
Cl
Ph
K3PO4
toluene, 105 °C
Bu
i-Pr i-Pr
Cl
+
N N
–
F 3C
N
27, 66% Bn
Hex
H2N
Cl
+ OMe
CuI (10 mol%)
KOt-Bu
toluene, 105 °C
N
Bu
OMe
69%
t-BuO
61%
N
O
S
N
N
t-BuO
86%
O
i-Pr i-Pr
29
Ph
Synthesis 2011, No. 1, 1–22 © Thieme Stuttgart · New York
N
28, 94%
F

6 J. E. R. Sadig, M. C. Willis REVIEW
The Hsung research group employed related cascade processes
for the synthesis of 2-aminoindoles. 41 Scheme 12
shows an example in which ynamide 30 was combined
with p-toluamine to deliver indole 31 in 85% yield. An
XPhos-derived palladium catalyst was found to be optimal,
and a variety of 2-carbamate-substituted indoles
were prepared in good yields. The ynamide substrates
were prepared, in a separate operation, by a copper-catalyzed
amidation of the corresponding bromo-alkynes.
30
Br
Scheme 12
Ackermann and colleagues were able to extend their original
methodology to a three-component system, featuring
the in situ formation of the key o-alkynylhaloarenes. 38a,e
The process involved the initial combination of an ochloroiodobenzene
with an alkyne in the presence of a
mixed palladium/copper catalyst system (Scheme 13); after
two hours the required nitrogen nucleophile was introduced
along with additional base, resulting in arylamination
followed by a 5-endo ring closure. A variety of
1,2-disubstituted indoles were obtained in good yields. A
possible limitation of the method is the poor commercial
availability of alternative o-chloroiodobenzene derivatives.
Scheme 13
O
N
O Pd2(dba) 3 (2.5 mol%)
XPhos (5 mol%)
Cs2CO3 +
Ph toluene, 110 °C
H2N p-Tol
Cy2P i-Pr
i-Pr
XPhos (32)
N N
p-Tol
Ph
31, 85%
The Barluenga research group developed a successful cascade
process, based on palladium-catalyzed aza-enolate
a-arylation followed by intramolecular N-arylation, for
the synthesis of a variety of indole derivatives. 42 The process
is outlined in Scheme 14: Initial palladium-catalyzed
aza-enolate arylation joins N-phenylimine 33 with 1,2-dibromobenzene,
to provide imine 34. Palladium-catalyzed
intramolecular amination, presumably via enamine intermediate
35, then delivers the expected indole in an excel-
i-Pr
29
I i) Pd(OAc) 2 (10 mol%)
CuI (10 mol%), (10 mol%)
Cs2CO3 Cl toluene, 105 °C
H
+
Ph
ii) KOt-Bu
H2N p-Tol
Ph
65%
Cl
Ph
N
p-Tol
Synthesis 2011, No. 1, 1–22 © Thieme Stuttgart · New York
O
O
lent 86% yield. The same XPhos-derived catalyst proved
optimal for both steps of the cascade. A wide range of
imine derivatives could be incorporated. The use of mixed
halogen systems, such as 1-bromo-2-iodobenzenes, allowed
the regioselective synthesis of substituted indoles
by exploiting the greater reactivity of the aryl iodide substituent.
The authors were also able to show that mixed
halide/sulfonate substrates were efficient reaction components,
with both triflate and nonaflate systems being successfully
employed. The ability to generate the required
sulfonate derivatives from the parent o-chlorophenols significantly
widened the scope of the process and allowed
unusual substitution patterns to be accessed, such as the
2,4,6-trisubstituted example 36. 42b Although an N-aryl or
N-alkyl substituent was a requirement of the imine components,
the authors demonstrated that N-tert-butylsubstituted
indoles could be deprotected under a variety of
conditions. For example, the N-H indole derived from Ntert-butylindole
37 was obtained in 97% yield for the indole
formation and deprotection (AlCl 3) sequence. The
group also reported a three-component variant of the
methodology, in which an initial palladium-catalyzed alkenyl
halide amination was used to prepare the imine reaction
components.
Scheme 14
33 86%
Br
+
Br Me
N
Ph
Ph
Pd2(dba)3 (2 mol%)
XPhos (32) (4 mol%)
NaOt-Bu, dioxane
110 °C
N
Ph
N
86% Ph
Br Ph
N
2.2 Carbazoles
Ph
Br Ph
HN
34 35
OMe
Catalytic amination chemistry has a number of applications
in carbazole synthesis. Nozaki was one of the first to
exploit cascade amination processes for the preparation of
a wide range of carbazole architectures. 43 An example of
the general process developed by the Nozaki research
group is shown in Scheme 15; the key heterocycle-forming
reaction is a coupling between a nitrogen nucleophile
and a doubly activated biphenyl. In this particular example,
ditriflate 37 was coupled with tert-butylcarbamate using
a XantPhos-derived catalyst to deliver carbazole 38 in
70% yield. 43b Deprotection of the Boc group from carbazole
38 revealed the natural product mukinone. The same
group has exploited their methodology in the synthesis of
heteroacenes, 43d,e chiral carbazole variants, 43a as well as
Ph
Ph
36, 74%
N
Ph
Ph
N
37, 91%
Me
Ph
Me
Me
(from Cl/ONf substrate) (from I/Cl substrate)
Cl

REVIEW Palladium- and Copper-Catalyzed Heterocycle Synthesis 7
helicenes. 43b The second example shown in Scheme 15
was reported by Chida and colleagues, and shows that related
strategies developed using dibromobiphenyls are
also effective in carbazole synthesis. 44a The example
shows the preparation of a key intermediate in the synthesis
of the natural product murrayazoline. 44b In order to
achieve an efficient transformation using the sterically demanding
amine 39, it was necessary to employ a high catalyst
loading (20 mol%). A copper-catalyzed version of
these transformations has also been reported. 45 The cascade
coupling of nitrogen nucleophiles with doubly activated
bi-aromatics has proven to be a powerful method for
carbazole synthesis and has been exploited by several other
groups. For example, Samyn and co-workers utilized
dibromo-2,2¢-bithiophene substrates to prepare
dithienopyrroles, 46 as did the Barlow research group. 47
MeO
Me
O
37
OMOM
Scheme 15
O
OMe
OTf
OTf
Pd2(dba)3.CHCl3
(5 mol%)
XantPhos (2) (10 mol%)
K3PO4
o-xylene, 100 °C
Br
Pd2(dba) 3 (20 mol%)
XPhos (32) (60 mol%)
Br
H2N +
Me
Me
NaOt-Bu
toluene, 130 °C
O
+
t-BuO
NH2
39
O
MeO2C
Bedford et al. developed a cascade sequence based on intermolecular
aryl-amination followed by intramolecular
direct C–H arylation as a route to carbazole derivatives;
several examples are shown in Scheme 16. 48 The process
combines o-chloroanilines with aryl bromides using palladium
catalysis. Use of the bulky electron-rich tri(tertbutyl)phosphine
ligand in combination with palladium(II)
acetate was the optimal catalyst system and allowed the
preparation of a range of carbazoles in good yields. Significant
substitution could be tolerated on the coupling
partners, as illustrated by the preparation of the natural
product clausine P (40).
Ackermann et al. developed a related aryl-amination and
direct C–H arylation sequence for carbazole synthesis. 49
In the Ackermann approach, 1,2-dihaloaromatics were
combined with anilines to deliver carbazole products
(Scheme 17). A combination of palladium(II) acetate and
Me
N
OMe
Boc
70%
N-Boc mukonine (38)
MOMO
murrayazoline
59%
O O
Me
N
Me
F 3C
Me
Scheme 16
tricyclohexylphosphine was found to be optimal and allowed
a wide range of carbazoles to be prepared. Using
this catalyst system it was possible to employ inexpensive
1,2-dichloroarenes as coupling partners, as well as heterocyclic
derivatives, illustrated by the preparation of pyrazine
and pyridine derivatives 41 and 42. The authors
exploited the methodology in a synthesis of the natural
product murrayafoline A (43). 49b Although less accessible,
1,2-dihaloalkenes could also be employed as substrates,
allowing the same cascade sequence to be applied
to indole synthesis.
+
+
N
H
43%
Cl
H
N
N
Cl
Scheme 17
Ph
N
Ph
41, 93%
Bn
NH
Cl
Br
N
Pd(OAc)2 (4 mol%)
t-Bu3P (5 mol%)
NaOt-Bu
toluene, reflux
OMe
Pd(OAc)2 (5 mol%)
Cy3P (10 mol%)
NaOt-Bu
NMP, 130 °C
N
Ph
42, 93%
N
69% Bn
Kan and co-workers reported a palladium-catalyzed cascade
route to carbazoles based on initial intermolecular
Suzuki coupling followed by an intramolecular aryl amination.
A small scoping study was described, although a
possible limitation is the availability of suitably functionalized
boronic acids. 50 Fujii and Ohno have also described
a cascade route to carbazoles. In their approach, an intermolecular
aryl amination between an aryl triflate and an
aniline was used to construct a diphenylamine which then
underwent an oxidative coupling to generate a carbazole
product. The efficiency of the oxidative step was shown to
be dependent on the substitution pattern of the diphenylamine
intermediates. 51
N
F 3C
MeO
N
H
69%
clausine P (40)
CF 3
Synthesis 2011, No. 1, 1–22 © Thieme Stuttgart · New York
Me
Me
N
Ph
85%
OMe
N
MeO H
murrayafoline A (43)
74% from Br/Cl-Ar
72% from Cl/Cl-Ar
Me
Me

8 J. E. R. Sadig, M. C. Willis REVIEW
2.3 Benzimidazoles and Benzimidazolones
A host of approaches to benzimidazoles and related derivatives,
featuring inter- and intramolecular and cascade reactions,
as well as both palladium and copper catalysts,
have been reported. Ma and co-workers developed a number
of copper-catalyzed routes to these important heterocycles.
52 In 2007, they demonstrated that o-haloacetanilides
could be combined with primary amines to deliver
benzimidazoles (Scheme 18). For example, a copper(I)
iodide/proline catalyst system was effective for the union
of aryl iodide 44 with allylamine, to furnish benzimidazole
45 in 94% yield. 52a When more sterically demanding
amines, or less activated aryl units, were employed it was
necessary to use either heat or an acid/heat combination to
achieve cyclization to the aromatic system; for example,
the formation of cyclohexyl-substituted benzimidazole 46
required the addition of acid. A broad range of amines and
aryl units, including pyridine derivatives, could be included
in the method, delivering benzimidazoles in good to
excellent yields. Although Scheme 18 shows only aryl iodide
substrates, aryl bromides were also used. When the
starting substrates were changed to o-iodoarylcarbamates,
the same reaction system was used to access benzimidazolones
(47 → 48). 52b Aqueous ammonia could also be
employed as the nitrogen nucleophile in both reaction
pathways, leading to the corresponding N–H derivatives.
52c
44
+
H2N +
H2N 47
+
H2N
H
N
Scheme 18
I
H
N
I
H
N
I
O
O
O
CF3
O
OMe
N Boc
CuI (10 mol%)
L-proline (20 mol%)
K 2CO 3, DMSO, r.t.
i) CuI (10 mol%)
L-proline (20 mol%)
K2CO3, DMSO, 40 °C
ii) AcOH, 140 °C
CuI (10 mol%)
L-proline (20 mol%)
K 2CO 3, DMSO
50 °C then 130 °C
OH
N
H H
O
L-proline
N
45, 94%
46, 73%
48, 74%
Buchwald and co-workers developed a related palladiumcatalyzed
route to aryl-substituted benzimidazoles. For
example, the coupling of o-bromacetanilide 49 with otoluamine
using an XPhos-derived catalyst provided the
corresponding N-arylbenzimidazole in 94% yield
Synthesis 2011, No. 1, 1–22 © Thieme Stuttgart · New York
N
N
N
H
N
N
N
CF3
O
Boc
O
(Scheme 19). 53a A good range of anilines and aryl substrates
(both Br and Cl) were described; Scheme 19 also
shows an aza-example, derived from the corresponding
pyridine substrate, as well as a cyclopropyl-substituted
product. Some variation of ligand between XPhos (32)
and RuPhos (50) was needed for certain substrates. In
2006, Scott reported a palladium-catalyzed synthesis of
imidazopyridinones (aza-benzimadazolones) in a process
analogous to the conversion of 47 into 48 shown in
Scheme 18. 54
Me
N
H2N
Me
Scheme 19
Buchwald and Zheng also described a complementary
copper-catalyzed protocol, based on aryl halide amidation
(as opposed to amination), for benzimidazole synthesis. 53b
The basic process is shown in Scheme 20; copper(I)
iodide/diamine-catalyzed coupling of hexamide with oiodo-N-alkylaniline
51, followed by base-promoted cyclization,
delivered the desired N-alkylbenzimidazole 52
in 87% yield. Alkyl, alkenyl and aryl amides could all be
incorporated effectively.
Scheme 20
N
N
(from ArCl using ligand 50)
F 3C
49
Br
H
N Me
Pd2(dba) 3 (1 mol%)
+
O
Br
XPhos (32) (8 mol%)
K3PO4 t-BuOH, 110 °C
88%
H2N
51
+
O
H
N
I
Pent
N
Me
Me
Me
N
Me
Me
83%
(using ligand 50)
i) CuI (5 mol%)
25 (20 mol%)
Cs2CO3, dioxane, 90 °C
ii) K3PO4
t-BuOH, 110 °C
F3C
94%
Intramolecular aryl amidation using urea substrates has
been achieved using both palladium and copper catalysis
and provides a further route to benzimidazolones
(Scheme 21). The cyclization of urea 53, using a palladium(II)
acetate/XPhos catalyst system, was described by
the process group at Merck. 55 Chloro-, bromo- and iodoaryl
derivatives could all be employed as substrates, as
could chloropyridines. Copper-catalyzed variants of similar
cyclizations have also been reported, 56 including a
polymer-supported example; 57 the second reaction shown
in Scheme 21, reported by SanMartin, Domínguez and co-
Me
Br
N
N
Cy 2P Oi-Pr
i-PrO
RuPhos (50)
52, 87%
N
N
Pent
Me
Me
Me

REVIEW Palladium- and Copper-Catalyzed Heterocycle Synthesis 9
MeO
Scheme 21
workers, 58 illustrates a copper(I) iodide catalyzed cyclization
using water as the solvent.
Intramolecular reactions to access benzimidazoles can be
achieved using amidines as substrates. An example, reported
by Brain et al., 59 is shown in Scheme 22 in which
amidine 54 was converted into the corresponding benzimidazole
under the action of a Pd2(dba) 3/triphenylphosphine
catalyst. The authors were also able to show that use
of a ‘catch-and-release’ purification strategy, 59b involving
Amberlyst resin, allowed the benzimidazoles to be obtained
in pure form without recourse to chromatography.
Related cyclizations in which the amidine is embedded
within a heterocycle have also been described. 60,61
De Meijere and Lygin reported that amidines, generated
in situ from an isocyanide and a primary amine, can also
be cyclized using copper(I) conditions to access N-alkylbenzimidazoles.
62
Me
53
54
Scheme 22
PMB PMB
Pd(OAc) 2 (1 mol%)
N O XPhos (32) (3 mol%)
N
NH2
Cl
Bn
N
O
NH2 Br
NaHCO3
i-PrOH, 83 °C
CuI (8.5 mol%)
TMEDA (3.5 equiv)
H 2O, 120 °C
MeO
92%
92%
Batey and Evindar used related cyclizations employing
guanidine substrates to access 2-aminobenzimidazoles. 63
Efficient reactions were achieved using either palladium
or copper catalysis; Scheme 23 gives an example of the
reaction conditions needed for each metal. In general, the
copper conditions were found to be superior, providing
higher yields and more selective reactions. Both aryl iodides
and aryl bromides could be employed as substrates,
allowing a broad range of 2-aminobenzimidazoles to be
Me
Br
HN
Bn
N
Scheme 23
N
N Me
NHMe
Br
Pd2(dba)3, (1.5 mol%)
Ph3P (12 mol%)
NaOH, H 2O–DME
160 °C, MW
Pd(PPh3)4 (10 mol%)
Cs2CO3, DME, 80 °C
or
CuI (5 mol%)
1,10-Phen (10 mol%)
Cs2CO3, DME, 80 °C
Me
Me
82%
N
N
Bn N
Pd: 66%
Cu: 90%
N
N
N
H
Bn
N
N
H
Me
O
O
Me
prepared in good yields. Szczepankiewicz et al. applied
this type of copper-catalyzed cyclization to substrates
based on uracil templates to prepare purine and related
fused imidazole systems. 64 2-Mercaptobenzimidazoles
can similarly be accessed using copper-catalyzed cyclization
of in situ generated isothioureas. 65
The research groups of both Zhang66and Wu67 showed
that o-halophenylimidoyl chlorides are effective substrates
for copper-catalyzed benzimidazole synthesis.
Scheme 24 presents an example from the Zhang group,
and shows how imidoyl chloride 55 can be combined with
benzylamine using a copper(I) iodide catalyst, to deliver
the expected benzimidazole in excellent yield. Both alkyland
arylamines could be employed. In both reports it was
necessary to include an electron-withdrawing substituent
on the imidoyl chloride substrate; for example, the trifluoromethyl
substituent on imidoyl chloride 55.
N
Scheme 24
Maes and co-workers explored a range of cascade amination
strategies to access a variety of benzo-fused benzimidazole
systems. 68 In their lead publication, they were able
to combine 2-chloro-3-iodopyridine with 2-picoline to
generate dipyridoimidazole 56 in 96% yield (Scheme 25).
The example shown employs a palladium(II) acetate/
BINAP catalyst, although XantPhos (2) was also shown to
be an effective ligand. 68a The chemistry has been extended
to the preparation of a number of benzo-fused and aza analogues,
68a–c,69 and in an interesting application a temperature/halide
dependent regioselectivity switch was
developed. 68d
Scheme 25
I
H2N Ph
N
55
+
I
Cl
+
CF3
Cl N NH 2
CuI (10 mol%)
TMEDA (20 mol%)
Cs 2CO 3
toluene, 110 °C
Pd(OAc) 2 (3 mol%)
BINAP (3) (3 mol%)
Cs2CO3
toluene, reflux
98%
Batey and co-workers described a copper-catalyzed cascade
route to benzimidazoles from the combination of a
1,2-dihalobenzene with an amidine, although only a single
example was reported. 70 Deng et al. reported a related
cascade in which amidines were exchanged for
guanidines, leading to the synthesis of 2-aminobenzimidazoles
(Scheme 26). The majority of examples delivered
N–H products, although N-substitution could also be introduced.
71
Synthesis 2011, No. 1, 1–22 © Thieme Stuttgart · New York
N
N
N
CF3
Ph
N
N
56, 96%

10 J. E. R. Sadig, M. C. Willis REVIEW
Me
HN
H2N
+
N
Scheme 26
2.4 Indazoles and Indazolones
Indazoles have proven to be popular targets for amination
chemistry. A number of groups have described the cyclization
of appropriately substituted arylhydrazones.
Scheme 27 illustrates an intramolecular coupling of bromo-substituted
arylhydrazone 57 to deliver 1H-indazole
58 in 85% yield. 72 The DPEPhos-derived catalyst system
was effective for a wide range of substrates, although aryl
chloride substrates performed poorly. Analogous N-tosylhydrazones
were also established as effective indazole
precursors, 73a and were utilized in a synthesis of the natural
product nigellicine. 73b 3-Amino-1H-indazoles were
also prepared by similar palladium-catalyzed cyclizations.
74 Song and Yee demonstrated that appropriately
substituted hydrazines are also useful indazole precursors.
For example, palladium-catalyzed ring closure using hydrazine
59 delivered the corresponding aromatic 1H-indazole
directly in 87% yield, following intramolecular
amination and spontaneous aromatization. 75 The mechanism
of aromatization was not established. The authors
noted the instability of certain hydrazine substrates to
long-term storage, and as alternatives established that the
corresponding N-triphenylphosphonium bromide salts
provided convenient stable precursors that could be cyclized
under identical reaction conditions.
MeO
57
Scheme 27
Br
I
Br
N
O
CuI (15 mol%)
25 (30 mol%)
Cs2CO3
DMA, 165 °C
N
N O
N
H
53%
There are a number of reports of halo-substituted hydrazones
being formed in situ and then cyclized to yield 1Hindazoles;
Scheme 28 presents examples using both palladium
and copper catalysis. Cho et al. were able to show
that o-bromobenzaldehydes could be combined with phenylhydrazine
using a palladium(II) chloride/dppp catalyst
system to furnish the corresponding indazoles in good
yields (60 → 61). 76 The copper example, reported by
Synthesis 2011, No. 1, 1–22 © Thieme Stuttgart · New York
Me
Me
H
N
Pd(dba)2 (2 mol%
N
DPEPhos (22) (2 mol%)
N
Me
NH
K 3PO 4
toluene, 110 °C
MeO
Pd(OAc) 2 (5 mol%)
dppf (12) (7.5 mol%)
Me
58, 85%
Br HN
NaOt-Bu
toluene, 90 59 °C
87%
N
N
Me
Pabba et al., required a two-step one-pot approach in
which a ten-minute microwave reaction was used to form
the hydrazone before a copper(I)/diamine catalyst was
added to the system (62 → 63). 77 Del Olmo and co-workers
reported a related copper-catalyzed process which also
allowed the use of aryl carboxylic acid substrates to deliver
1-hydroxy-1H-indazoles. 78
MeO
MeO
F
Scheme 28
Guillaumet and co-workers reported an intermolecular
copper-catalyzed amination method for the preparation of
pyrazolopyridines (azaindazoles). 79 3-Cyano-2-chloropyridine
was combined with a range of hydrazines using a
copper(I) iodide/phenanthroline catalyst to deliver 3-amino-1H-azaindazoles
in good yields (Scheme 29). The 3amino
products were converted into the corresponding 3iodo
derivatives by way of their diazonium salts, and were
employed in a range of palladium-catalyzed coupling processes
including Stille, Heck and Suzuki reactions.
N
CN
Cl
Scheme 29
O
60
O
+
62
H
+ H2N
Br
H
+ H2N
Br
Et
H
N NH2
NH
Ph
NH
Ph
PdCl 2 (2 mol%)
dppp (3 mol%) MeO
NaOt-Bu
toluene, 100 °C
i) NMP, 160 °C
10 min, MW
ii) CuI (5 mol%)
64 (10 mol%)
K2CO 3, 160 °C
10 min, MW
NHMe
NHMe
MeO
61, 65%
N
N
N
N
The less thermodynamically stable 2H-indazole isomers
can also be accessed using amination chemistry. In an approach
mirroring their route to the 1H-isomers (see
Scheme 27), Song and Yee employed a palladium-catalyzed
cyclization of appropriately substituted hydrazines.
80 For example, N-alkyl-N-arylhydrazine 65 was
converted into 2-aryl-2H-indazole 66 in 60% yield
(Scheme 30). Katayama and co-workers showed that N2–
C3-fused examples can also be prepared using similar
chemistry. 81
64
CuI (5 mol%)
1,10-phenanthroline
(10 mol%)
Cs 2CO 3
DMF, 60 °C
N N
1,10-phenanthroline
F
63, 84%
NH 2
N
N N
86% Et

REVIEW Palladium- and Copper-Catalyzed Heterocycle Synthesis 11
N Ph
MeO
Pd(OAc) 2 (5 mol%)
MeO
dppf (12) (7.5 mol%)
NH2 Br
NaOt-Bu
toluene, 90 °C
65
Scheme 30
Halland, Lindenschmidt and co-workers reported an alternative
route to the 2H-indazole isomers employing the
same o-alkynylhaloarene substrates used successfully by
others to access indoles (see Schemes 11 and 12). The reactions
proceeded via an initial regioselective amination
reaction using a monosubstituted hydrazine to generate an
N,N¢-disubstituted hydrazine, which then underwent intramolecular
hydroamination to form a dihydroindazole
intermediate (67, Scheme 31). 82 Isomerization from these
intermediates to the aromatic 2H-indazoles occurred
spontaneously under the reaction conditions of palladium(II)
chloride/tri(tert-butyl)phosphine with cesium carbonate
in N,N-dimethylformamide. Good functional
group tolerance was demonstrated and an extensive range
of substituted products was described; three examples are
shown in Scheme 31.
67
Scheme 31
Indazolones can be prepared by the copper-catalyzed cyclization
of o-halobenzohydrazides. For example, treatment
of hydrazide 68 with a copper(I) iodide/proline
catalyst system delivered indazolone 69 in 60% yield
(Scheme 32). 83 Iodo substrates delivered the most efficient
reactions; the bromo and chloro substrates were also
shown to deliver the desired products, albeit in reduced
yields.
Scheme 32
Ph
+ H2N
Cl
O
I
Ph
N Ph
N
H
N
H
H
N
2.5 Pyrroles
PdCl2 (5 mol%)
Pt-Bu3 HBF4 (10 mol%)
NH
Cs2CO
Ph
3
DMF, 110–130 °C
.
93%
CO2t-Bu
N Ph
N
CuI (10 mol%)
L-proline (20 mol%)
K 2CO 3, DMSO
r.t. to 70 °C
68 69, 60%
N Ph
N
66, 60%
N Ph
N
79%
OEt
The Buchwald and Li research groups both reported cascade
copper-catalyzed alkenyl amidation routes to pyr-
Ph
N Ph
N
55%
O
OEt
NH
N
roles. The Buchwald group utilized a copper(I) iodide/
diamine 25 catalyst system to combine carbamates (and a
limited number of amides) with 1,4-diiodo-1,3-dienes to
generate highly substituted pyrrole products (70 → 71,
Scheme 33). 84 The methodology displayed excellent
functional group tolerance and was applied to the synthesis
of a wide range of pyrroles, including tetrasubstituted
examples. The method was also applicable to the synthesis
of heteroarylpyrroles, such as thienopyrrole 72. The Li
approach exploited similar diene substrates in combination
with a range of amide coupling partners. 45,85 For example,
diiododiene 73 was combined with phenylacetamide
using a copper(I) iodide/diamine 64 catalyst to
deliver the expected pyrrole in 86% yield (Scheme 33).
Pr
S
Bu
Bu
SiMe3
Pr
70
73
Scheme 33
I O
I
+
H2N Ot-Bu
Me
Pr
CuI (5 mol%)
25 (20 mol%)
Cs 2CO 3
THF, 80 °C
CuI (20 mol%)
64 (20 mol%)
Cs 2CO 3
dioxane, 100 °C
Pr
N
Boc
71, 86%
N
SiMe3
Pr
N
SiMe3
N
Boc
Boc
Boc
98% 80%
72, 83%
I O
+
I
H2N Ph
Buchwald and colleagues reported a complementary stepwise
approach to pyrroles also based on copper-catalyzed
alkenylation reactions. 86 N,N¢-Di(Boc)-protected alkenylhydrazides
74, themselves prepared by copper-catalyzed
alkenylation reactions, were coupled with a second alkenyl
iodide to generate bis(ene)hydrazide 75 (Scheme 34).
Thermolysis triggered a [3,3] rearrangement to generate
bis-imine 76, cyclization of which provided the pyrrole
Pr
Pr
Pr
Boc
Oct
N
Boc
N
N
H
Boc
74
+
Boc
N
Pr Oct
I
[3,3]
Bu
(i) CuI (10 mol%)
1,10-phenanthroline
(20 mol%)
Cs2CO3, DMF
80 °C, 30 h
ii) o-xylene, 140 °C, 30 h
iii) p-TsOH, r.t.
Boc Boc
N N
Pr
Pr Oct
Synthesis 2011, No. 1, 1–22 © Thieme Stuttgart · New York
Pr
S
Bu
N
Bu
O
86% Ph
75 76 77
Scheme 34
Pr
Pr
Pr Oct
N
68% Boc
Boc
N
Pr Oct
SiMe3
H
NBoc

12 J. E. R. Sadig, M. C. Willis REVIEW
via intermediate 77. For certain substrates it was necessary
to add acid to achieve complete conversion into the
aromatic system. The bis(ene)hydrazides could be isolated,
or more conveniently used directly in the next step of
the sequence with no purification. The overall method
represents a modified Piloty–Robinson reaction.
The final pyrrole synthesis considered here comprises a
copper-catalyzed cascade alkenyl amidation/hydroamination
sequence. The process is essentially a pyrroleforming
version of the indole synthesis described in
Scheme 11. In this approach, described by Buchwald and
co-workers, haloenynes such as 78 replace the alkynylhaloarenes
used for indole synthesis, and, when combined
with tert-butyl carbamate and a copper(I) iodide/diamine
catalyst, provide the corresponding pyrroles in good
yields (Scheme 35). 87 A broad range of di- and trisubstituted
pyrroles were prepared, and although the study focused
on the use of iodoenynes, it was also possible to
employ bromoenynes. A brief mechanistic study established
that the reactions likely proceed via initial intermolecular
aryl carbon–nitrogen bond formation followed by
a 5-endo-dig intramolecular hydroamination.
Pent
78
OTIPS
I
+
t-BuO NH2
Scheme 35
O
2.6 Pyrazoles
25
CuI (5 mol%)
(20 mol%) OTIPS
Cs2CO3 THF, 80 °C
Pent
N
Boc
83%
Buchwald and co-workers utilized haloenyne substrates
in a tandem copper-catalyzed pyrazole synthesis. 87 For
example, combination of iodoenyne 78 with bis(Boc)hydrazine
using a copper(I) iodide/diamine catalyst provided
pyrazole 79 in 78% yield after Boc-deprotection with
trifluoroacetic acid (Scheme 36). As in the related pyrrole
syntheses, a good range of di- and trisubstituted aromatics
were prepared. The mechanism was again established as
proceeding via intermolecular aryl carbon–nitrogen bond
formation followed by intramolecular hydroamination, although
the cyclizations were in this case 5-exo-dig processes.
Cho and Patel reported a pyrazole synthesis based on the
palladium-catalyzed combination of b-bromovinyl aldehydes
with hydrazines. 88 For example, treatment of
Pent
25 78
(i) CuI (5 mol%)
(20 mol%)
Pent
I
+
H
N
Boc NH
Boc
OTIPS
Cs2CO3 THF, 80 °C
ii) TFA, CH2Cl2, r.t.
Scheme 36
N
N
H
79, 78%
Synthesis 2011, No. 1, 1–22 © Thieme Stuttgart · New York
OTIPS
bromo-enal 80 with phenylhydrazine in the presence of a
dppf-derived catalyst yielded pyrazole 81 in 77%
(Scheme 37). Both cyclic and acyclic substrates could be
employed, although no ketone-derived substrates were reported.
Haddad and co-workers developed a pyrazole synthesis
in which aryl benzophenone hydrazones, prepared
by the palladium-catalyzed coupling of benzophenone hydrazone
with aryl halides, were treated with a range of
1,3-bifunctional substrates under acidic conditions. 89 1,3-
Diketones, keto esters and ester/acid chlorides could be
combined with the hydrazones to provide a range of substituted
pyrazole products.
80
O
H
+
Br
Scheme 37
H2N Pd(OAc) 2 (5 mol%)
dppf (12) (7.5 mol%)
NH NaOt-Bu, toluene
Ph 125 °C
N
N
Ph
81, 77%
2.7 Oxazoles
Buchwald and co-workers utilized copper-catalyzed alkenyl
iodide amidation reactions as the key step in a route to
oxazoles. 90 For example, enamides such as 82 could be
treated with iodine and base to provide the expected
trisubstituted oxazoles in good yields (Scheme 38). The
required enamides were prepared from the corresponding
alkenyl bromides using a copper(I) iodide/diamine-catalyzed
coupling with the appropriate amide; both aryl and
alkyl amides could be used. Depending on the substitution
pattern of the oxazole product, certain examples required
the addition of p-toluenesulfonic acid to achieve complete
conversion into the aromatic molecule. Attempts to prepare
mono- and disubstituted oxazoles using this method
resulted in complex reaction mixtures, and an alternative
process, based on the use of 1,2-dihaloalkene substrates,
was developed.
Ph Br
+
O
Ph
H2N Ph
Scheme 38
Ph
Ph
H
N
82
O
2.8 Quinolones
i) CuI (5 mol%)
(20 mol%)
25
Cs2CO3, THF, 80 °C
ii) I2, DBU
r.t. to 80 °C
Ph
Ph
Ph
Manley and Bilodeau used palladium-catalyzed intermolecular
aryl halide amidation followed by an in situ aldol
condensation to prepare 2-quinolones. 91 In this way o-bromobenzaldehydes
were combined with a range of enolizable
amides to deliver the quinolone products. Scheme 39
I
H
N
O
Ph
Ph
Ph
N
O
77%
Ph

REVIEW Palladium- and Copper-Catalyzed Heterocycle Synthesis 13
illustrates the combination of the parent aldehyde (83)
with phenylacetamide using a XantPhos-derived catalyst
in combination with cesium carbonate as base. A variety
of substituted amides could be employed, as could ketonebased
substrates, allowing the synthesis of 4-substituted
products such as quinolone 84. Pyridine derivatives could
also be employed, thus providing a route to naphthyridinones.
Ester- and nitrile-substituted aryl bromides were
also examined and allowed access to hydroxy- and aminosubstituted
products, respectively. For a small number of
amide coupling partners, the researchers were able to employ
a copper(I) iodide/diamine catalyst system.
83
Scheme 39
O
O
H
+ H2N
Br
N
H
94%
O
N
Ph
Pd 2(dba)3 (1 mol%)
XantPhos (2) (3 mol%)
Cs2CO3
toluene, 100 °C
N
H
84, 55%
N
H
94%
Huang et al. utilized the related o-acetylbromoarenes as
substrates in a palladium-catalyzed synthesis of 4-quinolones.
The simplest version of the process employed formamide
as the nitrogen nucleophile and, when coupled
with bromide 85, delivered quinolone product 86 in 77%
yield (Scheme 40). 92 The reactions proceeded via initial
palladium-catalyzed amidation followed by a base-promoted
intramolecular condensation step. A XantPhosderived
catalyst in combination with cesium carbonate as
base was optimal for the amidation step, and the addition
of sodium tert-butoxide as a second base was found to be
necessary to achieve high yields for the combined process.
As can be seen from the examples presented in
Scheme 40, a range of substituted amides could be employed,
including lactams, which allowed the synthesis of
N-fused products such as quinolone 87. The Buchwald research
group reported a related process based on coppercatalyzed
amidation, although in their case it was neces-
MeO
N
H
Scheme 40
85
O
Ph
Ph
O
Me
Br H O
Pd2(dba) 3 (1 mol%)
XantPhos (2) (2.5 mol%)
+
2N H
Cs2CO3, dioxane
100 °C, 2–48 h then
NaOt-Bu, 100 °C
MeO
O
N
H
O
N
N
H
75%
Ph
O
Ph
O
O
N
H
86, 77%
S
82% 91% 87, 85%
Me
O
N
sary to isolate the initial amidation products before cyclization.
93
A tandem Heck/intramolecular amidation strategy was reported
by Cacchi and co-workers as a route to 4-aryl-2quinolones.
94 Using molten tetrabutylammonium acetate/
tetrabutylammonium bromide as the reaction medium and
a simple palladium(II) acetate catalyst, the combination of
o-bromophenylacrylamides (88) and aryl iodides provided
the quinolone products in moderate to good yields
(Scheme 41). Although only a single acrylamide substrate
was employed, a good range of aryl iodide coupling partners
could be incorporated. A brief mechanistic investigation
supported the Heck followed by intramolecular
amidation pathway.
88
+
Br
Scheme 41
Willis and co-workers exploited 2-(2-haloalkenyl)aryl halide
substrates, previously employed in indole syntheses
(see Scheme 8), in the preparation of 2-quinolones. 95 A
cascade palladium-catalyzed carbonylation/intramolecular
amidation sequence was employed to access a range of
quinolone products. For example, combination of the simple
dibromide 89 and p-methoxybenzylamine under a balloon
pressure of carbon monoxide delivered quinolone 90
in 80% yield (Scheme 42). Although all of the products
shown in Scheme 42 were obtained using a dppp-derived
catalyst, the researchers found that ligand variation was
needed for particular substrate/amine combinations. In
addition, purging the reaction of carbon monoxide was
shown to benefit the efficiency of certain amidation reactions.
By delaying the introduction of the carbon monoxide
and running the reaction in a two-stage process, it was
also possible access the regioisomeric isoquinolone products,
although in these cases competing indole formation
was problematic.
O
Scheme 42
O
I
NH 2
+
H2N
Br
Br
89
Pd(OAc)2 (5 mol%)
n-Bu4NOAc, n-Bu4NBr
120 °C
CO (balloon)
Pd2(dba)3 (3 mol%)
dppp (6 mol%)
Cs2CO3, toluene
100 °C
OMe
N
H
75%
Synthesis 2011, No. 1, 1–22 © Thieme Stuttgart · New York
O
N O
PMB
90, 80%
O N O
MeO
N O N N O
Oct
O Oct
Oct
69% 65% 73%

14 J. E. R. Sadig, M. C. Willis REVIEW
2.9 Quinazolines, Quinazolinones and
Quinazolindiones
In 2006 Willis and co-workers reported the palladiumcatalyzed
coupling of o-bromobenzoate esters with
monosubstituted ureas as a route to 3-alkylated quinazolinediones.
96 The reactions proceeded via initial intermolecular
carbon–nitrogen bond formation followed by
intramolecular, base-promoted, amidation. A XantPhosderived
catalyst in combination with cesium carbonate allowed
efficient and regioselective processes; for example,
bromobenzoate 91 was combined with N-butyl urea to
provide quinazolinedione 92 in 77% yield as a single regioisomer
(Scheme 43). A variety of substituents were
tolerated on both the aryl bromide and urea coupling partners.
The observed regiocontrol originates from the initial
aryl carbon–nitrogen bond formation taking place at the
least hindered nitrogen of the urea nucleophile.
Cl
91
Scheme 43
O
OMe
Br
+
Bu
N
H
O
Pd 2(dba) 3 (2.5 mol%)
XantPhos (2) (5 mol%)
NH2
Cs 2CO 3
dioxane, 100 °C
N
H
92, 77%
The Fu research group reported a related strategy for the
synthesis of quinazolinones and quinazolines. In their
original report, they exploited a copper-catalyzed coupling
of amidines with o-bromobenzoic acids to access
quinazolinones. For example, acid 93 was combined with
acetimidamide 94 to provide quinazolinone 95 in 81%
yield (Scheme 44). 97a The reaction conditions consisted of
copper(I) iodide without any added ligand, in N,N-dimethylformamide
at room temperature. The ability to use
such low-temperature conditions was attributed to the formation
of a chelated intermediate involving the oxygen
atom of the ortho-positioned carboxylic acid. The reaction
was applicable to a broad range of amidines and benzoic
acids. The researchers next extended the chemistry to include
guanidines as the nitrogen nucleophiles, resulting in
the formation of 3-aminoquinazolinone products such as
96. 97b The carboxylic acid substrates could also be replaced;
the use of the related ketones in combination with
guanidines resulted in the synthesis of 3-aminoquinazolines
such as 97. Ding and co-workers reported an alternative
copper-catalyzed route to quinazolinones based on
the use of o-iodobenzamide substrates. 98 A typical reaction
is shown in Scheme 44: coupling of benzamide 98
with formimidamide, using copper(I) iodide as catalyst,
provided quinazolinone 99 in 77% yield. The method was
shown to tolerate reasonable variation of both reaction
components.
Li and co-workers reported a cascade process involving in
situ amidine formation followed by palladium-catalyzed
Synthesis 2011, No. 1, 1–22 © Thieme Stuttgart · New York
Cl
O
N
Bu
O
O
93 95, 81%
94
OH
CuI (20 mol%)
NH
+
H2N
Br
NH.HCl Cs2CO3 DMF, r.t. N Me
Me
75%
O
N
cyclization as an entry into ring-fused quinazolinone derivatives.
The key amidine intermediates were generated
from intramolecular amide addition to a nitrile; the nitrile
group also being introduced by a palladium-catalyzed
process. 99 Scheme 45 outlines the overall conversion,
with aryl iodide 100 being transformed into quinazolinone
101 in 91% yield. A DPEPhos-derived catalyst was effective
for both the initial cyanation reaction to generate nitrile
102, and then to achieve the final ring closure from
the proposed amidine intermediate to give quinazolinone
101. Using a bromoquinoline-derived substrate, the authors
were able to apply the methodology to a synthesis of
the natural product luotonin (103).
Scheme 45
NH
2.10 Phenazines
O
N
96, 81%
NH
The Kamikawa and Beifuss groups have both reported intramolecular
palladium-catalyzed aryl-amination routes
to phenazines. Both explored the ring-closure of 2-amino-
2¢-bromodiphenylamines to access the target systems.
Scheme 46 shows an example from Beifuss and co-workers,
in which a JohnPhos-derived catalyst was used to convert
aniline 104 into phenazine 105 in 76% yield. 100 The
Kamikawa research group utilized BINAP-derived cata-
N
O
O
Ph
N
97, 56%
98
O
O
I
Scheme 44
Ph
N
H
+ H2N NH
AcOH
CuI (10 mol%)
K2CO3 DMF, 80 °C
N
99, 77%
N
Ph
O
NH
Pd(OAc)2 (5 mol%)
DPEPhos (22) (10 mol%)
O
I
Br
+ KCN
dioxane, reflux
then dppf (10 mol%)
K2CO3
N
N
100 101, 91%
N
H
O
CN Br
102
N
N
O
N
N
91%
luotonin (103)
N

REVIEW Palladium- and Copper-Catalyzed Heterocycle Synthesis 15
MeO
Scheme 46
lysts. 101 In both cases the phenazine ring system was isolated
directly from the amination reactions.
2.11 Cinnolines
An intermolecular copper-catalyzed aryl amination was
used by Nishida and co-workers to access cinnoline derivatives.
In the example shown in Scheme 47, hydrazonesubstituted
aryl iodide 107 was converted into N-acyldihydrocinnoline
108 using a copper(I) iodide/diamine
catalyst. 102 The use of superstoichiometric amounts of catalyst
led to mixtures of N-acyl product 108 together with
smaller amounts (up to 40%) of the aromatic cinnoline being
obtained. Cyclization of hydrazines derived from hydrazone
107 allowed access to 1-aminoindoles.
I
NH2
107
Scheme 47
H
N
Br
104
OTBS
CO2t-Bu HN
Ac
N
3 Carbon–Oxygen Bond Formation
Initially, the development of catalytic carbon–oxygen
bond-forming processes using aryl halide substrates
lagged behind the corresponding carbon–nitrogen forming
reactions; however, efficient methods, using both palladium
and copper catalysts, are now well established.
3.1 Benzofurans
Pd 2(dba) 3 (3 mol%)
JohnPhos (6 mol%)
NaOt-Bu
toluene, 100 °C MeO
P(t-Bu)2
JohnPhos (106)
CuI (10 mol%)
25 (10 mol%)
Cs 2CO 3
DMSO, r.t.
N N
Ac
108, 89%
Few examples of benzofuran syntheses that proceed via a
metal-catalyzed intermolecular (aryl)carbon–oxygen
bond-forming reaction exist. In one example, Buchwald
and co-workers were able to apply their palladium-catalyzed
phenol synthesis to the preparation of benzofurans.
103 The chemistry was based on the use of
potassium hydroxide as a nucleophile in the palladiumcatalyzed
hydroxylation of aryl halides to provide phenols.
When applied to benzofuran synthesis, o-chloroarylalkyne
substrates reacted with potassium hydroxide in the
presence of t-Bu-XPhos as catalyst, to give o-hydroxyalkynylarenes,
which, as previously shown, 104 undergo
N
N
105, 76%
OTBS
CO2t-Bu cyclization to the required benzofurans (109 → 110,
Scheme 48). You’s research group went on to develop a
copper-catalyzed version of the hydroxylation reaction
and also demonstrated its use in benzofuran synthesis, in
this case from an o-iodoarylalkyne to generate benzofuran
112. 105
F 3C
Cl
109
Scheme 48
A greater number of research groups have utilized intramolecular
carbon–oxygen bond formation as the key
step in benzofuran syntheses. In 2004 Willis et al. demonstrated
the use of a-(o-haloaryl) ketones as precursors to
the required oxygen heterocycles via an enolization/palladium-catalyzed
intramolecular O-arylation reaction, with
a Pd 2(dba) 3/DPEPhos catalyst system proving optimum
for the process (Scheme 49). 106 The starting ketones were
themselves formed by a palladium-catalyzed ketone arylation;
however, attempts to achieve a one-pot combination
of these processes was not straightforward, and after
optimization only a single high-yielding example of the
cascade could be achieved. Kotschy and co-workers
showed that the same cyclization of o-bromobenzyl ketones,
which they accessed from aromatic aldehydes and
2-bromobenzyl bromide using dithiane chemistry, is possible
using a palladium–NHC catalyst system. 107
O
Scheme 49
Cl
I
O
Br
Me
86%
(NaOt-Bu)
Ph
S
KOH
F3C
Pd2(dba) 3 (2 mol%)
t-BuXPhos (8 mol%)
H2O, dioxane
100 °C
KOH
Ph CuI (10 mol%)
1,10-phenathroline
(20 mol%)
H 2O, DMSO
100 °C
t-Bu2P i-Pr
i-Pr
t-BuXPhos (111)
Cs2CO3
toluene, 100 °C
Synthesis 2011, No. 1, 1–22 © Thieme Stuttgart · New York
Cl
i-Pr
Pd 2(dba) 3 (2.5 mol%)
DPEPhos (22) (6 mol%)
N
O
86%
(NaOt-Bu)
(chloro substrate)
F
O
110, 87%
O
112, 86%
O
95%
O
74%
(NaOt-Bu)
Ph
S

16 J. E. R. Sadig, M. C. Willis REVIEW
Chen and Dormer reported a copper(I) iodide catalyzed,
ligand-free modification of this benzofuran synthesis using
o-iodo- or o-bromoaromatic ketones. 108 A range of
substituents at the resulting 2- and 3-positions of the product
benzofuran were tolerated, and the first use of an aldehyde
substrate was demonstrated, yielding 3benzylbenzo[b]furan
113 in 92% yield (Scheme 50). An
on-water variant of this protocol was described by the
SanMartin and Domínguez group, with the use of a diamine
ligand being required. 109 Ackermann and Kaspar
also utilized a related copper-catalyzed cyclization in
combination with alkyne hydration chemistry to access
benzofurans. 110
O
Br
Scheme 50
Willis and co-workers developed a second strategy to
access benzofurans, again based on an intramolecular
carbon–oxygen bond-forming reaction. Scheme 8 highlighted
the use of aryl halide/alkenyl triflate substrates in
the synthesis of indole derivatives; the research group was
able to further demonstrate the utility of these substrates
as general heterocycle precursors, through their use in a
copper-catalyzed benzofuran synthesis. 111 Coupling of the
same substrates with potassium hydroxide yielded benzofurans
via presumed enolate intermediates.
Lautens and co-workers reported an approach to 2-bromobenzofurans
using an intramolecular carbon–oxygen
coupling of gem-dibromovinyl phenols. 31i As in the related
indole chemistry (see Scheme 5), the dibromovinyl
phenol substrates were synthesized using a Ramirez olefination
process. As shown in Scheme 51, a ligand-free
copper(I) iodide catalyst was found to be effective, providing
the benzofurans in excellent yields.
Br
Scheme 51
H
Br
OH
Br
Cl
CuI (10 mol%)
K3PO4 DMF, 105 °C
CuI (5 mol%)
K3PO4
THF, 80 °C
H
O
113, 92%
In 1999 Miura and co-workers developed a tandem palladium-catalyzed
intermolecular carbon–carbon/intramolecular
carbon–oxygen bond-forming reaction of benzyl
phenyl ketones with o-dibromoarenes to yield benzofurans.
112 A palladium(II) acetate/triphenylphosphine catalyzed
system was found to be optimal, with high reaction
temperatures also being used (Scheme 52). The reactions
proceeded via initial palladium-catalyzed enolate C-arylation,
followed by palladium-catalyzed O-arylation. The
protocol was extended to the use of phenol coupling part-
Synthesis 2011, No. 1, 1–22 © Thieme Stuttgart · New York
Br
O
96%
Br
Cl
ners in place of ketones, to give dibenzofuran products
(114 → 115). SanMartin, Domínguez and co-workers reported
a similar method for the synthesis of benzofurans;
113 in their account they compared the use of
homogeneous and heterogeneous polymer-supported palladium
catalysis, with the latter affording the heterocycles
in slightly inferior yields.
MeO
MeO
t-Bu
OH
114
Scheme 52
Ma and co-workers reported a related copper-catalyzed
cascade route to benzofurans. In the optimized system, bketo
esters were combined with 1-bromo-2-iodobenzenes
to provide benzofurans via initial intermolecular carbon–
carbon bond formation followed by intramolecular formation
of the carbon–oxygen bond (Scheme 53). 114 Substitution
on both the aryl halide and keto ester was well
tolerated, providing benzofurans in good yields.
Ph
Cl
O
Scheme 53
+
+
Br
Br
O
Ph
3.2 Benzoxazoles
+
O
I
Br
OEt
Pd(OAc) 2 (5 mol%)
Ph3P (20 mol%)
Cs2CO3 o-xylene, 160 °C
Br
Pd(OAc)2–4Ph3P
(5 mol%)
O
78%
CsCO3
Br o-xylene, 160 °C
O
t-Bu
115, 66%
CuI (10 mol%)
K2CO3 THF, 100 °C
The use of catalytic intramolecular carbon–oxygen bondforming
reactions has proved to be a popular route to
benzoxazoles. In 2006 Batey and Evindar developed a
copper-catalyzed cyclization of o-halobenzanilides to
generate a variety of alkyl, aryl, benzyl, alkenyl, dienyl
and heterocyclic 2-substituted benzoxazoles (as well as a
handful of benzothiazoles – see section 4.2). As shown in
Scheme 54 the optimal catalyst was a copper(I) iodide/
phenanthroline combination. 115 The majority of examples
employed aryl bromide substrates, although the iodo derivatives
also performed well. A single aryl chloride example
was included. SanMartin, Domínguez and coworkers
reported a similar copper-catalyzed cyclization to
access benzoxazoles. They developed two catalyst systems,
using either copper(I) chloride or copper(II) triflate
in combination with N,N,N¢,N¢-tetramethylethylenediamine
(TMEDA), on water, to yield the desired heterocy-
Cl
O
78%
Ph
CO2Et
OMe
OMe
Ph

REVIEW Palladium- and Copper-Catalyzed Heterocycle Synthesis 17
cles in good yields from either the o-iodo, o-bromo- or ochlorobenzanilides.
116 Similar cyclizations have also been
reported by Jiang and Ma 117 and Kantam and co-workers.
118
H
N
Br
N
Scheme 54
In 2009 Sun and co-workers extended this type of cyclization
to the synthesis of 2-substituted oxazolopyridines. 119
As shown in Scheme 55, a copper(I) iodide/diamine or
copper(I) iodide/phenanthroline catalyst system proved to
be optimal, yielding the desired heterocycles from the cyclization
of o-chloro- or o-bromopyridylamides, respectively.
Me
N
Scheme 55
CuI (5 mol%)
1,10-phenanthroline
(10 mol%)
O OMe Cs 2CO 3
DME, relfux
O Ph
89%
N N
O
90%
Cbz
25
H
N
CuI (5 mol%)
(10 mol%)
N
O
Cl
K2CO3 toluene, reflux
N O
91%
N
H
N
O
Br
Ph
Cl
CuI (5 mol%)
1,10-phenanthroline
(10 mol%)
Cs2CO3
THF, reflux
MeO
N
The Batey research group developed a further synthesis of
benzoxazoles involving intramolecular carbon–oxygen
bond formation. The substrates were again o-halobenzanilides;
however, these were formed in situ from the reaction
of o-bromoanilines and acyl chlorides. 70 A copper(I)
iodide/1,10-phenanthroline combination was found to be
the optimal catalyst system for this one-pot strategy. In
addition, the use of microwave irradiation gave substantially
better results than conventional heating. A library of
24 benzoxazoles was prepared, examples of which are
shown in Scheme 56.
A tandem approach to benzoxazoles was reported by
Glorius and Altenhoff, in which reaction of o-dihalobenzenes
with amides underwent copper(I) iodide/diamine
catalyzed carbon–nitrogen followed by carbon–oxygen
cross-couplings to yield the desired heterocycles. 120 Examples
of diiodo-, dibromo- and mixed dihalobenzenes,
as well as dihalopyridines (Br and Cl) were successfully
coupled to benzamide affording 2-phenylbenzoxazoles
(Scheme 57). The dibromobenzene substrate was utilized
to demonstrate variation of the amide partner, giving aryl,
Me
N
O
99%
N
O
90%
97%
N
O
Ph
Ph
Cl
Me
S
O
+
Scheme 56
alkyl, vinyl and heterocyclic 2-substituted benzoxazoles.
The use of o-bromochlorobenzenes allowed the regioselective
synthesis of substituted benzoxazoles, with the reaction
proceeding via initial amidation at the aryl bromide
position. Batey and co-workers had previously reported
on investigations of related processes, but had not
achieved an efficient system. 70
Scheme 57
Cl
O
NH 2
Br
N
3.3 Isocoumarins
CuI (10 mol%)
1,10-phenanthroline
(20 mol%)
Cs 2CO3, MeCN
210 °C, 15 min, MW
O
91%
In 1999 Shen and Wang described the synthesis of isocoumarins
from a palladium-catalyzed reaction of gem-dibromovinyl
benzoates with an organostannane. 121 For
example, reaction of benzoate 114 with phenyltrimethylstannane
using a trifurylphosphine-derived palladium catalyst
delivered isocoumarin 115 in 92% yield (Scheme
58). The tandem process is believed to proceed via an initial
Stille reaction of the ‘E’ bromide with the stannane,
which is followed by an intramolecular carbon–oxygen
bond-forming cyclization and ensuing elimination of methyl
bromide. Examples using phenyl, furyl, thienyl and
vinyl tin reagents gave the 3-substituted isocoumarins in
mostly excellent yields, and both esters and methoxy
groups could be tolerated on the aromatic ring. Willis and
co-workers reported a palladium-catalyzed carbonylative
isocoumarin synthesis, commencing from the same a-(o-
Synthesis 2011, No. 1, 1–22 © Thieme Stuttgart · New York
Me
O O Ph
F3C
O
66%
85%
Br
+
Br
O OMe
114
85% O
Scheme 58
O
H 2N Ph
Br
Br
+
PhSnMe3 O
O
CuI (5 mol%)
25 (10 mol%)
K2CO 3
toluene, 110 °C
80%
Pd2(dba)3 (2.5 mol%)
P(2-furyl)3 (15 mol%)
toluene, 100 °C
O
O
S
MeO
N
MeO
N
N
O
90%
115, 92%
81%
O
O
S
Ph
O
O
Ph
Ph

18 J. E. R. Sadig, M. C. Willis REVIEW
haloaryl) ketone substrates previously used in benzofuran
synthesis (see Scheme 49). 122
4 Carbon–Sulfur Bond Formation
Relative to the carbon–nitrogen and carbon–oxygen
bond-forming reactions discussed above, there are far
fewer examples of catalytic aryl carbon–sulfur bondforming
processes in the literature. However, reactions
are beginning to be developed that exploit the highly nucleophilic
character of thiols (and related functional
groups) and synthetically useful methods with very low
catalyst loadings are being reported. 123 The number of applications
of these reactions to the synthesis of heterocycles
is also growing.
4.1 Benzothiophenes
Although a number of metal-catalyzed benzothiophene
syntheses exist, 1,2 few of these involve a key carbon–sulfur
bond formation using an aryl halide substrate. As discussed
in section 3.1, Willis et al. demonstrated the use of
a palladium-catalyzed intramolecular O-enolate arylation
in the synthesis of benzofurans (see Scheme 49). 106 Similarly,
the same group showed that thio ketones, derived
from the same a-(o-haloaryl) ketone substrates using
phosphorus pentasulfide, could also undergo this enolization–cyclization,
again using a DPEPhos catalyst system
to afford benzothiophenes. 106 Scheme 59 shows an aryl
bromide example, although the corresponding aryl chloride
also underwent cyclization, albeit in a reduced 44%
yield.
Br S
Scheme 59
Pd2(dba)3 (2.5 mol%)
DPEPhos (22) (6 mol%)
Cs2CO3 S
toluene, 100 °C 74%
In 2009 Lautens and co-workers extended the use of gemdihalovinylanilines
in indole synthesis (see Scheme 5) to
establish similar thiophenols as precursors for benzothiophenes.
124 The combination of a palladium-catalyzed
carbon–sulfur bond-forming reaction with a second
cross-coupling process, such as a Suzuki–Miyaura, Heck
or Sonogashira reaction, yielded diversely functionalized
benzothiophenes. For example, combination of thiophenol
116 with thiophene-3-boronic acid using an SPhos-derived
catalyst delivered benzothiophene 117 in 99% yield
(Scheme 60). The majority of examples reported involved
Suzuki chemistry; a broad range of boronic acids, as well
as other boron reagents, were readily included and allowed
the introduction of aryl, alkenyl and alkyl C2 substituents.
Application of the methodology to a variety of
thiophenol backbones afforded the required heterocycles
in mostly excellent yields.
Synthesis 2011, No. 1, 1–22 © Thieme Stuttgart · New York
S
Scheme 60
4.2 Benzothiazoles
Two research groups have established benzothiazole syntheses
based on a key catalytic intermolecular carbon–sulfur
bond-forming step. In the first approach, Itoh and
Mase utilized a palladium-catalyzed thioetherification of
o-bromoanilides using a thiol surrogate coupling partner.
125 For example, reaction between aryl bromide 118
and thiol 119, an odorless thiol surrogate, using a
XantPhos-derived catalyst, ultimately delivered benzothiophene
120 in 75% yield (Scheme 61). The reaction
proceeded via intermediate sulfide 121, which was
cleaved under basic conditions and then cyclized in the
presence of acid to generate the aromatic product. p-
Methoxybenzylthiol could also be employed as the thiol
surrogate, allowing sulfide cleavage under acid conditions.
Scheme 61
Br
Br
SH
116
+
B(OH) 2
PdCl2 (3 mol%)
SPhos (14) (3 mol%)
K 3PO4, Et3N
dioxane, 110 °C
S
117, 99%
118
121
F
+
H
N
O
Br
Me
Pd2(dba)3 (5 mol%)
XantPhos (2) (10 mol%)
i-Pr2NEt, dioxane
reflux
F
H
N
S
O
Me
O
SH O
OR
O
119
Me
Me
NaOEt, THF, r.t.
then TFA, reflux
S
120, 75%
Rather than use a thiol surrogate, Ma and co-workers exploited
metal sulfides in copper-catalyzed couplings with
o-haloanilides to generate benzothiazoles. 126 They were
able to show that sodium sulfide nonahydrate could be
coupled with o-iodoanilides, and following acidic workup,
deliver the desired benzothiazole products. For o-bromo
substrates, the use of potassium sulfide was optimal.
Both systems utilized a ligandless copper(I) iodide catalyst;
significant variation of the substrate substituents was
possible, delivering benzothiazoles in good to excellent
yields (Scheme 62).
The use of an intramolecular carbon–sulfur bond-forming
reaction has proved more popular in the synthesis of benzothiazoles.
In 1982, Bowman, Heaney and Smith reported
an intramolecular, copper-catalyzed S-arylation in the
synthesis of 2-alkyl- and 2-aryl-1,3-benzothiazoles from
F
N
S
Me

REVIEW Palladium- and Copper-Catalyzed Heterocycle Synthesis 19
F
H
N
I
O
Me
Na2S
CuI (10 mol%)
DMF, 80 °C
then HCl, r.t. F
N
S
75%
.9H2O
+
Scheme 62
o-halothioacetanilides and o-halothiobenzanilides, respectively.
127 Castillón and co-workers extended this
methodology to a more efficient palladium-catalyzed cyclization
of o-bromothioamides (Scheme 63). 128 It was
also shown that cyclization of o-bromothioureas, prepared
from o-bromophenylisothiocyanates and amines, afforded
2-aminobenzothiazoles under similar reaction conditions
(122 → 123).
H
N
S
Br
122
Scheme 63
Batey and co-workers reported a comparison of the copper-
and palladium-catalyzed syntheses of 2-aminobenzothiazoles
based on this same cyclization of obromothioureas.
129 The use of copper catalysis generally
led to higher yields and conversions. Both metals were
also shown to catalyze an example of a one-pot thiourea
formation–cyclization reaction in the same excellent
yield. Batey’s research group also demonstrated that cyclization
of o-bromothioamides under the same copper(I)
iodide/1,10-phenanthroline catalyst system afforded benzothiazoles
in excellent yields; 115 a representative example
is shown in Scheme 64. Jiang and Ma reported a
related copper-catalyzed cyclization employing oxazolidin-2-one
as the ligand; a number of aryl chloride substrates
were included in their study, and effectively
converted into benzothiazoles. 117 Pan and co-workers reported
a related preparation of 2-aminobenzothiazoles using
a copper(I) iodide/oxazoline catalyst system. 130
Scheme 64
H
N Ph
+
O
Br
Me Me
Me
H
N NMe 2
S
Br
H
N
S
Br
K 2S
CuI (10 mol%)
DMF, 140 °C
then HCl, r.t.
Pd2(dba)3 (5 mol%)
JohnPhos (106)
(5.5 mol%)
Cs2CO 3
dioxane, 80 °C
Pd 2(dba) 3 (5 mol%)
P(t-Bu)3 (5.5 mol%)
OMe
Cs2CO 3
dioxane, 80 °C
CuI (5 mol%)
1,10-phenanthroline
(10 mol%)
Cs 2CO3, reflux
88%
N
S
Me
Ph
N Me
Me
S Me
88%
N
S
123, 92%
N
S
93%
NMe 2
OMe
The Wu research group described the synthesis of 2-aminobenzothiazoles
by the reaction of o-iodobenzamines
with isothiocyanates using a copper(I) iodide/phenanthroline
catalyst system (Scheme 65). 131 The method was useful
as it eliminated the need to generate an ohalobenzothiourea
cyclization precursor in a separate
step, with the addition/carbon–sulfur coupling reaction
occurring in one pot. The authors exploited the method in
the preparation of an 18-membered library.
F
Scheme 65
A number of benzothiazole syntheses that involve tandem
processes have also appeared in the literature. Vera and
Pelletier utilized tandem palladium-catalyzed carbon–
sulfur and carbon–nitrogen arylation reactions to prepare
a series of aminobenzothiazoles. 132 For example, the
combination of dibromothiobenzamide 124 and isopropylamine,
using a JohnPhos catalyst, delivered 4-aminobenzothiazole
125 in 47% yield (Scheme 66). As can be seen
from the remainder of the examples in Scheme 66, it was
possible to alter the position of the second bromine substituent,
to generate 5-, 6-, and 7-amino-substituted products.
Scheme 66
NH 2
I
+
SCN
CuI (10 mol%)
1,10-phenanthroline
(20 mol%)
DABCO
toluene, 50 °C
99%
Br NHi-Pr
124
i-PrHN
H
N Ph
+
H2N(i-Pr)
S
Br
16%
N
S
Ph
Pd 2(dba) 3 (10 mol%)
JohnPhos (106) (20 mol%)
i-PrHN
Patel and co-workers showed that 2-arylthiobenzothiazoles
can be accessed from cascade intra- and intermolecular
carbon–sulfur bond-forming reactions using a single
catalytic system. 133 A combination of o-iodo- or o-bromodithiocarbamates
and iodoarenes were subjected to a
copper(I) iodide/diamine catalyst system yielding the substituted
benzothiazoles in mostly excellent yields
(Scheme 67). The methodology was successfully applied
to the synthesis of a cathespin-D inhibitor analogue.
The same research group developed a cascade protocol for
the synthesis of 2-thio- or 2-oxa-benzothiazoles by the
copper-catalyzed reaction of o-iodo- or o-bromoarylisothiocyanates
with a sulfur or oxygen nucleophile, respectively.
134 The required dithiocarbamates or
Synthesis 2011, No. 1, 1–22 © Thieme Stuttgart · New York
F
Cs 2CO 3, NaOt-Bu
toluene-dioxane
80 °C
50%
N
S
Ph
N
S
NH
N
S
125, 47%
N
S
NHi-Pr 39%
Ph
Ph

20 J. E. R. Sadig, M. C. Willis REVIEW
Me
I
Scheme 67
thiocarbamates, which were formed in situ under basic
conditions, readily underwent copper-catalyzed intramolecular
carbon–sulfur bond formation. Thiophenols and
phenols showed the greatest reactivity; however, the corresponding
alkyl series could also be employed, albeit to
generate the products in reduced yields (Scheme 68).
73%
+
Scheme 68
4.3 Oxathioles
Bao and co-workers reported a novel one-pot synthesis of
2-iminobenzo-1,3-oxathioles using a cascade addition/
intramolecular carbon–sulfur coupling process. 135 o-Iodophenols
and isothiocyanates were combined using a
copper(I) iodide/phenanthroline catalyst system to afford
the desired heterocycles in good to excellent yields. A
representative example is shown in Scheme 69.
Scheme 69
H
N
5 Conclusion
I
S
NCS
+
Br
HS Ph
N
S
OPh
S HNEt3
CuI (5 mol%)
(10 mol%)
126
OMe
K 2CO 3
DMSO, 90 °C
126
NH2
NH2
CuI (5 mol%)
1,10-phenanthroline
(10 mol%)
K2CO 3
dioxane, 90 °C
N
SBn
S
69%
(iodo substrate)
By definition, palladium- and copper-catalyzed aryl amination,
aryl etherification and aryl thioetherification reactions
are transformations designed to fashion bonds
between heteroatoms and aromatic rings. It is perhaps not
surprising that these reactions have enjoyed considerable
success when applied to the synthesis of aromatic heterocycles.
The examples presented above show how these re-
Synthesis 2011, No. 1, 1–22 © Thieme Stuttgart · New York
Me
OH
CuI (10 mol%)
1,10-phenanthroline
O
SCN
+
I
OMe
(20 mol%)
Cs2CO3
toluene, 70–90 °C
S
86%
Cl
72%
N
S
Ar = 4-MeOC 6H 4
N
S
76%
N
S
54%
N
O
SPh
SAr
Ph
OMe
actions have been exploited towards a wide range of
heterocyclic targets. They also show these reactions being
used to provide new entries to existing, classic synthetic
routes, as well as in the formulation of completely new
disconnections. As advances in the underpinning transformations
continue to develop – new coupling partners,
more active catalysts and milder reaction conditions – the
number of applications will undoubtedly continue to
grow. The importance of heteroaromatic molecules virtually
assures it.
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22 J. E. R. Sadig, M. C. Willis REVIEW
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