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Direct amination of aryl halides with ammonia

Yoann Aubin,a Cédric Fischmeister,*b Christophe M. Thomas*c and
Jean-Luc Renaud*a
Received 22nd April 2010
DOI: 10.1039/c003692g

The traditional homogeneous access to aromatic amine derivatives is a nucleophilic aromatic

substitution of the corresponding aryl halides. The halogen atom is usually relatively inert to
amination reaction unless it is activated by the presence of electron withdrawing groups.
Published on 28 September 2010 on http://pubs.rsc.org | doi:10.1039/C003692G

Consequently, there has been particular emphasis over the past decade on the synthesis of metal
complexes that are active catalysts for the preparation of aromatic amines. This tutorial review
focuses on the use of metal-based complexes for the direct amination of aryl halides with
ammonia.
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Introduction for arylamines is the catalytic nucleophilic amination of

Aromatic amines are highly useful and valuable compounds
that have numerous applications in the pharmaceutical,
agrochemical and polymer industries.1 The most important
manufacturing processes for arylamines are based on the
continuous catalytic hydrogenation of nitro compounds,
employing heterogeneous copper, nickel or platinum-group
metals.2 For more complex amines produced on a smaller
scale, homogeneous catalysis with its greater possibilities for
chemo- and regioselective hydrogenation is the method of
choice. A newer alternative process of increasing importance
a
Laboratoire de Chimie Mole´culaire et Thioorganique, UMR 6507,
INC3M, FR 3038, ENSICAEN-Universite´ de Caen, 14050 Caen,
France. E-mail: jean-luc.renaud@ensicaen.fr; Fax: 33(0)231452877
b the more reactive aniline product and remaining ammonia
Sciences Chimiques de Rennes, Catalyse et Organome´talliques,
UMR 6226, CNRS-Universite´ de Rennes 1, Campus de Beaulieu,
35042 Rennes Cedex, France.
E-mail: cedric.fischmeister@univ-rennes1.fr; Fax: 33(0)223236939
c
Chimie ParisTech, UMR CNRS 7223, 11 rue Pierre et Marie Curie,
75231 Paris Cedex 05, France.
E-mail: christophe-thomas@chimie-paristech.fr; Fax: 33(0)223236939
haloarenes or phenols. Amination processes also find applica-
tion in the production of pyridines and pyrroles. The most
common way to access these compounds is by using ammonia
(NH3) or ammonium hydroxide as the nucleophile under high
temperature and pressure.3–5
Due to its great abundance and extremely low cost, ammonia
has been considered as one of the most interesting commodity
chemicals.6 Therefore, it would be highly desirable for down-
stream amines to be directly synthesized from NH3. However,
using ammonia directly in these reactions is complicated by
several issues: first a facile displacement of ancillary ligands
from the transition metal by ammonia can occur generating
catalytically inactive species and also a lack of reaction control
is possible under basic conditions due to competition between
which results in the formation of considerable amounts of
diaryl and triaryl amines.7
Recently, the copper- and palladium-catalyzed amination
of aryl halides has gained increasing attention.7–12 Buchwald
and Hartwig were the first to study the high potential of Pd

Yoann Aubin was born in Ce´dric Fischmeister received

Sisteron, France, in 1980. He
received his PhD on the total
synthesis of terpenes and
enantioselective synthesis of
carbanucleosides at Paul
Cezanne University in Marseille
(France) in 2007 under the
guidance of Pr Gérard
Audran. After his postdoctoral
work in medicinal chemistry
(2008–2009) with Pr Arun
K. Ghosh at Purdue University
in Indiana, he joined the
Yoann Aubin team of Pr Jean-Luc Renaud
as a postdoctoral researcher
(ATER) to work on the amination reaction of halohetero-
aromatic compounds catalyzed by copper complexes.
his PhD degree in 1998 from
the University of Montpellier
working under the supervision
of Profs. R. Corriu and
G. Cerveau. After spending
1 year in Rennes working with
Prof. R. Re´au and 16 months
in Prof. A. B. Holmes’
Melville laboratories in
Cambridge, he was appointed
in 2001 as a CNRS research
engineer in the group of Dr
C. Bruneau and Prof.
Cédric Fischmeister P. Dixneuf. He obtained his
‘‘Habilitation à Diriger les
Recherches’’ in 2008. His current research interests concern
homogeneous catalysis in particular olefin metathesis and more
recently C–H bond functionalisation and amination reactions,
with an emphasis on green processes and solvents.

4130 Chem. Soc. Rev., 2010, 39, 4130–4145 This journal is c The Royal Society of Chemistry 2010
 View Article Online

complexes for C–N cross-coupling reactions of aryl halides

with various N-nucleophiles, demonstrating mild conditions
and tolerance for a wide range of functional groups.13 Inspired
by these seminal contributions, a large number of investi-
gations have been directed towards synthesizing efficient
metal-based catalysts and studying their reactivities. Although
palladium complexes proved to be quite convenient in the
production of secondary and tertiary amines,14–18 the number
of palladium catalysts for the amination of aryl halides to
produce primary aryl amines are scarce. Efforts to obviate
these limitations focused on the use of synthetic equivalents of
ammonia including imines,19 amides,20 and also allyl-,21
benzyl-,22 or silyl-amines.23 However, the use of ammonia
Published on 28 September 2010 on http://pubs.rsc.org | doi:10.1039/C003692G

surrogates suffers either from low atom economy, the need

for an additional cleavage step to liberate the primary aryl
amine, the formation of waste, or high cost.24 Therefore,
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ammonia is still by far the most interesting N-nucleophile.5

In the following tutorial review, we will describe selected
published efforts to achieve these research goals using metal-
based complexes. We will focus primarily on direct amination
of aryl halides with ammonia by palladium and copper
complexes, but also include some discussion of work for the
amination reaction of heterocycles.

1. Amination reactions catalyzed by palladium complexes

The first example of palladium catalyzed amination of aryl
halides with ammonia was reported in 2006 by Hartwig et al.25
With the aim to prepare a catalyst with an ancillary ligand
stable towards displacement by ammonia, preventing bridging
structures, facilitating reductive elimination and favoring
the formation of primary amines, a catalyst was prepared
from Pd(CH3CN)2Cl2 and the bulky and electron donating
bidentate ligand (CyPF-t-Bu) based on the Josiphos archi-
tecture disclosed by Togni and Spindler et al. in 1994.26 This
catalyst-(CyPF-t-Bu)PdCl2 was found to be very active for the
amination of various aryl halides providing in all cases high
selectivities for primary amines in DME at 90 1C under 80 psi
Scheme 1 (CyPF-t-Bu)PdCl2 catalyzed amination reactions.
(5.5 bar) of NH3 (Scheme 1). Several experimental parameters
in particular concentration and ammonia pressure were crucial
to ensure high conversions and selectivity for the primary
amines (P) vs. secondary amine (S). Best results were obtained
with a strong base, sodium tert-butoxide, whereas weaker
carbonates or phosphates afforded poor conversions. Various
monophosphines (including X-phos)27 and diphosphines as

Christophe Thomas obtained After graduating from the

his PhD degree in 2002
working under the supervision
of Prof. Süss-Fink. He then
joined Prof. Coates’ group at
Cornell University as a post-
doctoral fellow supported by
the Swiss National Science
Foundation. After one year in
Prof. Ward’s laboratories, he
became Assistant Professor at
the University of Rennes in
2004. In 2008 he was promoted
to full professor at the Ecole
Christophe M. Thomas Nationale Supe´rieure de
Chimie de Paris. His research
interests comprise the study of fundamental processes in organo-
metallic chemistry with an emphasis on catalytic transforma-
tions and the control of stereochemistry.
Ecole Nationale Supe´rieure
de Chimie de Paris in 1995,
Jean-Luc Renaud obtained his
PhD degree in 1998 under the
supervision of Dr Aubert and
Prof. Malacria. He was a
Lavoisier Postdoctoral fellow
in 1999 with Prof. Lautens,
Research Assistant in the
group of Prof. Riant in 2000.
He was appointed Assistant
Professor at the University of
Rennes in 2000 and Associate
Jean-Luc Renaud Professor in 2006. He moved
to the Ecole Nationale
Supe´rieure de Chimie de Rennes in 2007 and was promoted full
Professor at the University of Caen in 2008. His research
interests comprise development of new methods for organic
synthesis with an emphasis on (enantioselective) catalytic
transformation.

This journal is c The Royal Society of Chemistry 2010 Chem. Soc. Rev., 2010, 39, 4130–4145 4131
 View Article Online

well as a NHC ligands were also evaluated but failed to

provide any conversion thus validating the importance of the
steric hindrance and strong chelation of the Josiphos-derived
ligand. As depicted in Scheme 1, several electron-rich
halo-arenes and heteroarenes provided the amino products
in high yields and with high selectivity for primary amines.
Interestingly, the reaction seemed unaffected by sterically
hindered ortho-substituents that led to the highest selectivity
for the primary amine. One example with a chloro-derivative
provided the expected product in good yield but with a
significantly reduced selectivity for the primary amine. This
catalyst was also efficiently transposed to amination reactions
involving lithium amide instead of NH3/t-BuONa although
Published on 28 September 2010 on http://pubs.rsc.org | doi:10.1039/C003692G

slightly lower selectivities for primary amines were obtained

(8/1 to 50/1).
In order to get more insight into the reaction mechanism, in
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particular the involvement of an arylpalladium amido inter-

mediate, the same group prepared two Pd(II) complexes
(Scheme 2). First the complex (CyPF-t-Bu)Pd(4-MeOPh)Br28
likely to be formed by oxidative addition of the aryl halide to a
Pd(0) species was prepared. Treatment of this complex with
5 equiv. of NH3, t-BuONa and deuterated triphenylphophine
at 90 1C provided a mixture of primary and secondary amines
in a 3/1 ratio with an overall yield of 80%. A second
amido complex (CyPF-t-Bu)Pd(4-MeOPh)(NH2) potentially
resulting from halide substitution by NH3/t-BuONa was
prepared. Thermal treatment of this complex at 90 1C in the Scheme 3 Pd2dba3/L catalyzed coupling of ammonia with aryl
halides.
presence of deuterated triphenyl phosphine again provided a
mixture of primary and secondary amines but in a different
to be a key parameter for a selective transformation. Several
ratio (1/1) than previously observed. These two examples
electron-rich and electron-deficient aryl bromides as well as
set the basis for further development and understanding of
chlorobenzene were converted to the corresponding primary
Pd-catalyzed amination mechanism.
amines (Scheme 3).
In 2007, Buchwald et al. reported on a series of phosphine
The lower selectivity for primary amines provided by L2 was
ligands for the amination of aryl halides using Pd2dba3 as the
advantageously used for the efficient synthesis of di- and
Pd source, sodium t-butoxide as the base and a user friendly
triarylamines, the latter being of interest as hole transporting
ammonia solution in 1,4-dioxane.29 Efficient and selective
materials in optoelectronics and in devices such as LEDs.30
amination were thus realized with the biaryl phosphine ligand
Thus a modified procedure utilizing a higher aryl halide con-
L1 (Scheme 3) whereas the selectivity for the primary amine
centration and reduced excess of NH3 enabled the synthesis of
dropped upon using the X-Phos ligand L2. Of note, the latter
several functionalized di- and triarylamines (Fig. 1).
ligand was found totally inefficient in the catalytic system
A judicious sequential addition of various aryl halides to the
previously described by Hartwig,25 hence showing the impor-
same reaction mixture allowed the synthesis of unsymmetrical
tance of experimental conditions and Pd source. In agreement
with Hartwig’s results, the reactant concentration was found

Scheme 2 Possible intermediates in the Pd-catalyzed coupling of

ammonia with aryl halides. Fig. 1 Di- and triarylamines by amination reactions.

4132 Chem. Soc. Rev., 2010, 39, 4130–4145 This journal is c The Royal Society of Chemistry 2010
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Scheme 4 [Pd]/L6 coupling of ammonia with aryl halides.

results. Other bases provided high conversions but low yields

for the expected compound. Notably, the Pd source had little
influence on the reaction outcome. For instance Pd(OAc)2 and
[Pd(dba)2] afforded very good and similar results. Finally, the
pressure applied to the reaction was also an important para-
Published on 28 September 2010 on http://pubs.rsc.org | doi:10.1039/C003692G

meter and the best results were obtained under 10 bar (145 psi)
of nitrogen. However, the effect of the nitrogen pressure was
not clearly established.
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Fig. 2 Unsymmetrical triarylamines by sequential amination

reactions.

diarylamines and triarylamines. The key point to achieve such

transformation was to remove the excess of ammonia following
the first amination promoted by Pd2dba3/L1 and to sub-
sequently increase the reactant concentration before adding L2
to the reaction mixture. With this procedure, several di- and
triarylamines including TPD derivatives were prepared in good
yields (Fig. 2).31
In 2009, Beller et al. reported on the use of various
phosphino ligands tethered to N-heterocycles in palladium
catalyzed amination of aryl halides (Fig. 3).32
An initial screening of the reaction parameters was performed
with the amination of 1-bromonaphtalene at 140 1C with a
catalyst in situ generated from L6 and [Pd(CH3CN)2Cl2] using
a solution of NH3 in 1,4-dioxane (Scheme 4). These tests
revealed some trends already noted by Hartwig and Buchwald,
in particular t-BuONa was again the base providing the best

Fig. 3 N-heterocycle tethered phosphines. Scheme 5 Pd(OAc)2/L6 coupling of ammonia with aryl halides.

This journal is c The Royal Society of Chemistry 2010 Chem. Soc. Rev., 2010, 39, 4130–4145 4133
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With these optimized experimental conditions, other ligands
such as 2-phosphino-N-aryl-pyrroles L3 and L4, 2-phosphino-
N-arylindole L5 and dialkyl-2-(N-arylimidazolyl)phosphines
L7 have been evaluated. All these ligands provided similar
results than L6. Of note, bulky trialkyl phosphines such as
P(Ad)2(n-Bu) or P(t-Bu)3 promoted the reaction in very low
yields of 2% and 13%, respectively. The scope of the reaction
was further extended to various aryl halides using slightly
different experimental conditions. The reaction were then
conducted at 120 1C using a fourfold excess of ligand and
Pd(OAc)2. Diverse aryl chlorides were thus aminated with
similar efficiency than the corresponding aryl bromides and
several deactivated bromoarenes as well as heteroaryl compounds
Published on 28 September 2010 on http://pubs.rsc.org | doi:10.1039/C003692G
the base, 5 equiv. of ammonia (1,4-dioxane solution) in 1,4-
dioxane at 80–100 1C. Of note, the catalyst generated in situ
provided higher selectivity for the primary amine than
(CyPF-t-Bu)PdCl2 previously used by the same group.25 Two
sets of experimental conditions were identified for meta- and
para- substituted aryl halides, on the one hand, and for ortho-
substituted aryl halides on the other hand. In both cases,
the substrate concentration was still a key parameter.
Thus, several ortho-substituted aryl bromides were efficiently
aminated with high selectivity for primary amines using low
catalyst loadings (0.1–0.5 mol%) and substrate concentrations
in the range 0.038–0.1 M (Table 1).
Under similar conditions, the reaction of meta- and para-

were also transformed into the corresponding amines in good substituted aryl bromides led to very high yields and higher
yields. Best results are summarized in Scheme 5 regardless of selectivities for primary amines than those obtained with
the reaction conditions used. It must be mentioned at this (CyPF-t-Bu)PdCl2.25 Various substrates possessing electron-
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stage that the selectivity for primary amine was not reported in donating and electron-withdrawing substituents were
this study. efficiently coupled with ammonia (Table 2).
In 2009, Hartwig extended also the scope of an efficient
catalyst for the room temperature amination of aryl tosylates33 Table 2 Coupling of meta- and para- substituted aryl bromides with
ammoniaa
to the coupling of aryl halides with ammonia with the aim to
address the limitations of the previously reported studies.34
The main concern was to disclose catalysts with enhanced
activity able to transform efficiently aryl chlorides, aryl sulfonates
and base sensitive substrates. Initial screening clearly demon-
strated the superiority of catalytic systems generated from
Loading Conc./mol Yield
Pd(0) rather than Pd(II) complexes. Indeed, Pd([(P(o-toly)3]2 (%) l 1 Product (%) P/S
was identified as the best Pd source when associated to the
Josiphos-derived ligand (see Scheme 1) using t-BuONa as
0.5 0.038 88 19 : 1
Table 1 Coupling of ortho-substituted aryl bromides with ammonia

0.5 0.038 78 —

Conc./
Cat. (%) mol l 1 T/1C t/h Product Y (%) P/S
0.5 0.038 61 12 : 1

0.5 0.038 80 4 83 450 : 1

0.5 0.038 77 —
0.5 0.07 80 4 93 450 : 1
0.1 0.1 100 12 84 450 : 1

1 0.05 91 450 : 1
0.5 0.07 80 4 89 450 : 1
0.1 0.1 100 12 82 450 : 1

0.5 0.05 64 —

0.5 0.1 100 15 88 450 : 1

2.0 0.05 79 450 : 1

0.5 0.038 80 5 66 —

a
A 1/1 ratio of Pd([(P(o-toly)3]2 and ligand was used.

4134 Chem. Soc. Rev., 2010, 39, 4130–4145 This journal is c The Royal Society of Chemistry 2010
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The challenging coupling of ammonia with aryl chlorides Table 4 Coupling of ammonia with reactants containing base
and aryl sulfonates was investigated with this catalytic system. sensitive functional groups
In the first case, low catalyst loading could be used. However,
all the reactions were performed at 100 1C, and the yields were
generally lower than those obtained from aryl bromides
(Table 3). In the second case, based on recent results on
coupling of aryl tosylates with alkyl- and arylamines,28,33
the authors conducted the transformations at relatively low X Loading (%) Product Yield (%) P/S
temperature (50 1C) in order to prevent S–O bond cleavage
leading to phenol derivatives. However, at this temperature
higher catalyst loading (2 mol%) was required to ensure good Br 0.5 94 30 : 1
yields (Table 3). OTs 0.5 73 6:1
The scope of this Pd catalyst was then extended to the
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coupling of ammonia with aryl halides containing base Br 0.5 83 430 : 1

sensitive functional groups. Since the difficulty to trans- Cl 0.5 79 430 : 1
form such substrates was attributed to the use of a strong
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base (t-BuONa), weaker bases were evaluated under

the previously described reaction conditions (0.5 mol% Br 0.5 76 —
Pd([(P(o-tolyl)3]2, 0.5 mol% CyPF-t-Bu, 5 equiv. NH3 from I 1 78 —
1,4-dioxane solution). A first test revealed that K3PO4
(5 equiv.) could provide full conversion of ethyl 4-bromo- Br 0.5 71 —
benzoate, but only the diarylamine was obtained. This Cl 0.5 44 —
problem was solved by switching the ammonia source from OTs 0.5 77 —
ammonia in 1,4-dioxane to ammonia gas (200 psi B14 bar).
With these new conditions, several arylbromides, aryl-
chlorides and aryltosylates containing base sensitive
functional groups were efficiently coupled with ammonia at
70 1C using low catalyst loadings (Table 4). However, the same
Table 3 Coupling of aryl-chlorides and tosylates with ammoniaa
conditions applied to electron rich aryl halides and sulfonates
containing base sensitive functional groups provided low
yields of arylamines.
Two one pot procedures based on the initial coupling of
ammonia were developed. First, an unsymmetrical diaryl
amine was prepared in a sequential manner using a coupling
with ammonia followed by the coupling of the generated
Loading Conc./ Yield arylamine with an aryltosylate (Scheme 6). The removal of
X (%) mol l 1 T/1C Product (%) P/S
ammonia and dioxane was necessary between the two steps. In
contrast to the similar method reported by Buchwald, the
Cl 0.5 0.07 100 64 17 : 1 reaction proceeded with a single catalyst without need for
OTs 2 0.1 50 65 17 : 1 ligand exchange between the two steps (Scheme 6).
In another one pot sequence, the intermediate arylamine
was reacted in a stoichiometric way with acid chlorides,
cyclic anhydride and Boc-anhydride to furnish the corres-
Cl 1 0.1 100 89 450 : 1 ponding N-arylamides, imides and carbamates in good to high
yields.

OTs 2 0.1 50 86 450 : 1

Cl 0.1 0.1 100 84 —

Cl 0.5 0.038 100 89 —

OTs 2 0.05 50 67 450 : 1

a Scheme 6 Unsymmetrical diarylamine by sequential amination

A 1/1 ratio of Pd([(P(o-tol)3]2 and ligand was used.
reaction.

This journal is c The Royal Society of Chemistry 2010 Chem. Soc. Rev., 2010, 39, 4130–4145 4135

Fig. 4 P,N ligands used by Stradiotto et al.
More recently, Stradiotto et al. reported the use of P,N
ligands for the Pd-catalyzed coupling of aryl chlorides with
amines and ammonia.35,36 An initial screening of the reaction
conditions based on the coupling of chlorobenzene with
aniline or ammonia showed the superiority of the system
Published on 28 September 2010 on http://pubs.rsc.org | doi:10.1039/C003692G
composed of [Pd(allyl)Cl]2 and ligands L8 and L9 (Fig. 4)
using t-BuONa as the base in toluene or 1,4-dioxane at
100–110 1C. Other Pd sources including Pd2dba3 used by
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Buchwald gave only modest conversions.
The scope of the coupling reaction with ammonia was
further extended to various aryl- and heteroaryl chlorides
using L9 and a 0.5 M solution of ammonia in 1,4-dioxane at
120 1C. As depicted in Table 5 very high conversions were
reached but the selectivity for primary amines was poor in
some cases in particular with meta- and para- substituted
phenyl chloride.
Mechanism. Hartwig et al. provided several mechanistic
experiments allowing the proposal of a rational mechanism
for the coupling of aryl halides with ammonia. First,
they demonstrated the superiority of the Pd(0) source
Table 5 Coupling of aryl and heteroaryl chlorides with ammonia
Loading cat/L9(mol%) Product Conv. (%)
1/8 99
1/8 99
1/8 98
1/8 88
1/2 96
4/8 99
4136 Chem. Soc. Rev., 2010, 39, 4130–4145
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Fig. 5 Postulated mechanism for the Pd-catalyzed coupling of
ammonia with aryl halides.
[Pd(P(o-tolyl)3)2] vs. Pd(II) sources such as Pd(OAc)2/
CyPF-t-Bu or (CyPF-t-Bu)PdCl2. It was shown that under
the reaction conditions the Pd(II) sources failed to furnish
efficiently the Pd(0) complex (CyPF-t-Bu)Pd. To the contrary,
a mixture of Pd(P(o-tolyl)3) and CyPF-t-Bu furnished
P(o-tolyl)3 and (CyPF-t-Bu)Pd(P(o-tolyl)3) a complex which
adds aryl halides such as 4-chloromethylbenzene quantita-
tively in less than 15 min. at room temperature.33 The
combination of these results with those previously mentioned
on the involvement of aryl-Pd (A) and Pd-amido (B) species
(Scheme 2)25 and with the extensive study on the mechanism
of Pd(BINAP)2-catalyzed amination of aryl halides37 allow to
postulate the mechanism depicted in Fig. 5 for the coupling
of ammonia with aryl-halides. It is assumed that coordination
of ammonia to the Pd increases the proton acidity thus making
P/S
possible the deprotonation by t-BuONa to generate the
Pd-amide bond.
2.9/1 2. Amination reactions catalyzed by ligand-free copper
complexes
Copper salts are well known and attractive not only because
420 : 1 copper is one of the cheapest, most abundant and relatively,
a less toxic metal, but also because copper salts can act as a
catalytic cross-coupling agent, Lewis acid and oxidizing
420 : 1 agent.38 Mechanistically, the copper may be involved in
catalytic cycles through several oxidation states (0–3). Two-
electron, as well as one-electron transfer processes are thus
conceivable.39 Moreover, Copper salts have a high affinity
— for polar functional groups, such as amines, and thus may
facilitate the addition of ammonia to aryl halides. Copper
mediated amination reactions with ammonia have been
known for a long time, but the reaction conditions were
420 : 1 quite harsh and catalyst loading very high before 2000.39,40
Thus, a general copper-catalyzed method suitable for
1.1/1 the amination reaction between ammonia and a wide range
of aryl halides including aryl chloride is an important
challenge.
This journal is c The Royal Society of Chemistry 2010

Scheme 7 Copper(I) oxide catalyzed aniline synthesis.
Vedejs reported the enantioselective synthesis of substituted
isoquinolines, via, as a key step, a ligand-free copper mediated
amination of an aryl bromide in liquid ammonia.40 Although a
high yield was obtained (82%) under mild conditions (70 1C),
Published on 28 September 2010 on http://pubs.rsc.org | doi:10.1039/C003692G
the reaction time was too long (5 days), the copper loading
(75 mol% of Cu) was not useful on large scale synthesis and
the pressure was too high. In 2001, Lang et al. introduced
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copper(I) oxide as catalyst in the amination reaction of aryl
iodides under ammonia pressure in ethylene glycol as solvent
(Scheme 7).7 Then, in the presence of 5 mol% of Cu2O, aniline
derivatives were obtained in 65–72% yields, accompanied by
some ethylene glycol monoaryl ether as by product. Even
if the side product was the main drawback in this procedure,
the alcoholic solvent was essential for the success of this
coupling reaction. Although worthy to note is the slight effect
of the ammonia concentration on the yield (86% at 2 M and
91% at 8 M).
To overcome the second drawback of the Lang procedure,
namely the use of ammonia, one solution may be the use of
easy to handle sources of NH3 such as ammonium chloride or
aqueous ammonia. Thus, Zou and coworkers disclosed a
copper mediated amination of various aryl iodides or bromides
in low to moderate yields (7–85%) in a mixture of aqueous
ammonia/ammonia ethylene glycol solution at 50–85 1C.41
The main drawback in this procedure, as in the Vedejs
synthesis,40b is the use of stoichiometric amount of copper
salts or copper metal. Following these pioneering works,
Darcel et al. reported a green and economical general methodo-
logy introducing Fe2O3–CuI as cocatalysts (10 mol% of each)
in the synthesis of aniline derivatives at 90 1C from aryl iodides
(Scheme 8).42 The main advantage is that this procedure was
carried out under aerobic conditions with aqueous ammonia
as a nitrogen source in ethanol. The investigations revealed
that a polar protic solvent was necessary for the reaction.
The nature of the base has also a significant effect on the
reaction rate. Indeed, NaOH led to total conversion whereas
KOH or K2CO3 provided low conversion rates, 35 and
48%, respectively. The scope of this iron/copper-cocatalyzed
amination reaction was not hampered by electronic effects
(electron-donating or electron-withdrawing groups) and ortho-
substituents but was limited to aryl iodide compounds.
Scheme 8 Copper/iron catalyzed amination reaction.
This journal is c The Royal Society of Chemistry 2010
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Also, by contrast with Zou works, no deiodination was
mentioned.
In order to use a wide range of aryl halides, and notably the
less expensive aryl chlorides, Wolf et al. developed an attrac-
tive methodology using aqueous ammonia and lower Cu2O
catalyst loading (5 mol%) in a water-NMP (1 : 1) solvent
mixture at 80 1C (Scheme 9).43 This procedure avoided again
an inert atmosphere, anhydrous solvents and additional
base. The optimized protocol tolerates a wide range of aryl
bromides or iodides bearing electron-rich or electron-deficient
groups. But the reaction time depends on the steric hindrance
on the ortho position. For example, 1-bromo-2-isopropyl-
benzene required a longer reaction time (48 h) and higher
temperatures (90 1C) than bromobenzene (15 h and 80 1C) or
1-bromo-2-methylbenzene (20 h, 80 1C). On the other hand,
electronic effects on the aryl moiety have little influence. A
successful regioselective amination occurred with 1-bromo-
3-chlorobenzene leading to the corresponding 3-amino-1-
chlorobenzene in 15 h and 93% yield.
Wolf also demonstrated that an amination reaction could
be achieved with several aryl chlorides at 110 1C under
microwave irradiation (Scheme 10). Electron withdrawing
groups or electron donating groups can be introduced without
decreasing the yields. Thus 1-chloro-2-methylbenzene led
to 1-amino-2-methylbenzene in 83% yield, whereas methyl
3-chloro benzoate provided the corresponding methyl
3-aminobenzoate in 82% yields. Surprisingly, compared to
Taillefer results,48 in this later case, no amide formation was
mentioned.
Recently, Zhang and Cheng reported a direct access to
symmetric diarylamines in one-pot process via copper
(II)-catalyzed oxidative coupling of aqueous ammonia under
atmospheric pressure with arylboronic acids (Scheme 11).44
During this study, the authors observed that the distribution
of the in situ formed copper species depended on the basicity of
the reaction media. Thus, after a screening of additional acids,
they showed that benzoic acid had an important dual positive
effect on the reaction. On the one hand, it allowed to tune the
Scheme 9 Copper(I) oxide catalyzed aniline synthesis in aqueous
solvent.
Chem. Soc. Rev., 2010, 39, 4130–4145 4137

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Scheme 10 Copper(I) oxide catalyzed amination of aromatic
chloride.
Scheme 11 Oxidative coupling with boronic acids.
basicity of the reaction system and on the other hand, it
formed a buffering system (NH4+/NH3) to avoid dramatic
variation of basicity during the reaction. Diamination reac-
tions with the combination of Cu(OAc)2
H2O (20 mol%),
aqueous ammonia (3 equiv.) and benzoic acid were carried
out in ethyl propanoate at 80 1C from aryl boronic acids
having electron-donating groups. However, the amination
reaction with aryl boronic acids substituted by electron-
withdrawing groups led to low yields and furnished a mixture
of the corresponding primary- and secondary aromatic
amines. Fortunately, replacing Cu(OAc)2
H2O (20 mol%)
by Cu(OTf)2 (10 mol%) led to the desired symmetric
diarylamines.
Simultaneously, Fu et al. reported a related oxidative
process leading only to monoarylation of ammonia
(Scheme 12).45 The best catalytic activity for the amination
process was obtained with Cu2O (10 mol%), at room tempera-
ture in methanol under air atmosphere. Remarkably, the
absence of air inhibited the amination reaction. Aqueous
ammonia was found to be the best NH3 source. Surprisingly,
when K2CO3 was added as a base to the reaction mixture, the
yield decreased significantly (from 65% to 42%). Increasing
4138 Chem. Soc. Rev., 2010, 39, 4130–4145
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Scheme 12 Oxidative coupling of ammonia with boronic acids.
the temperature lowered the solubility of ammonia in the
solvent and so the yield. The scope of the copper-catalyzed
reaction under mild conditions provided high to excellent
yields. Various functional groups are tolerated and coupling
reactions occurred in the presence of carbon–halogen bonds
(chloride and bromide). Substrates with steric hindrance in
ortho-position reacted well. The substituted aryl boronic acids
containing electron-withdrawing functional groups showed
lower reactivity than those containing electron-donating
groups. Traces of diarylamine by-products were detected with
aromatic boronic acids bearing electron-donating groups.
Futhermore, neither substrate containing electron-withdrawing
groups nor ortho-substituted substrates provided side reactions
(Scheme 12).
Then, depending on the reaction conditions (copper(II) in
hot ethylpropionate, Scheme 11,44 or copper(I) in methanol at
room temperature,45 Scheme 12), mono- or diarylamines can
be selectively isolated. This trend might be explained by the
use of a more Lewis acid copper source and a higher reaction
temperature, which then decrease the ammonia concentration
in the medium, in the Zhang and Cheng protocol.
All of these studies indicate that the ligand free copper
catalyzed amination reaction with aqueous ammonia is broadly
applicable to a large variety of substrates (with different
functional groups) under relatively mild conditions. More-
over, these procedures obviate the use of expensive, air-and/or
moisture-sensitive ligands. It is worth noting that polar protic
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 View Article Online

solvents such as alcohols and pressure have generally positive

effects on the conversion rate. However, in spite of the recent
advances, copper-catalyzed coupling with ammonia required
high copper loadings, generally greater than 10 mol%. Another
key point is that, in some reactions, applying pressure
was required to avoid competitive C–O arylation by alcoholic
solvents or hydroxide anion arising from aqueous ammonia.
Finally although the synthesis of primary aromatic amines
from aromatic boronic acids was efficient for several aryl
derivatives, additional steps were necessary to prepare these
precursors. Finally, aryl chlorides remained less studied
due to their lower reactivity. To address some of these
drawbacks, several groups studied the influence of ligands
Published on 28 September 2010 on http://pubs.rsc.org | doi:10.1039/C003692G

in order to decrease copper loading and/or to develop

more convenient and efficient approaches under milder
conditions. Scheme 13 Amination of aniline derivatives using copper iodide/
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proline catalyst.

3. Amination reactions catalyzed by copper complexes

Ligands allow fine tuning of the coordination properties
(such as electron density on the metal and steric hindrance
around the metal) and therefore the modulation of the metal
activity. Thus to gain better activities (higher yields, lower
reaction temperatures, lower catalyst loading. . .), one solution
is to coordinate ligands to metals.
In 2008 Chang et al. first reported on the use of a
copper/ligand catalytic system in the amination reaction of
aryl halides by aqueous ammonia solution.46 Based on the
work of D. Ma in C–C, C–O, and C–S coupling reactions,47
this group demonstrated that the association of copper
iodide with amino acids, such as N-methyl glycine or L-proline,
led to a quite efficient system in the synthesis of primary
aryl amines (Scheme 13). Then in the presence of 20 mol%
of CuI, 40 mol% of L-proline, 1.5 equiv. of aqueous ammonia
and 3 equiv. of potassium carbonate in DMSO at room
temperature, aniline derivatives were isolated in yields
ranging from 34 to 97%. This catalytic system worked
well with electron deficient aryl halides (iodide or bromide)
but, with more challenging non-activated aryl bromides
or sterically hindered aryl halides, lower reactivities were
shown even at 80 1C (34% yield from 2-methyl iodo-
benzene, 44% yield from 4-bromomethoxybenzene, see
Scheme 13).
To overcome these lower reactivities, and almost
simultaneously, Taillefer reported in 2009 results patented
in 2007 in which the amination of both activated and
non-activated aryl iodides and bromides using aqueous
ammonia, a copper salt and a diketone ligand in DMF at
60–90 1C.48 With 4-bromobiphenyl as model substrate,
a screening of diketones and copper salts showed that the
best combination was obtained between copper(II) acetyl-
acetonate (Cu(acac)2 (10 mol%)) and 2,4-pentanedione
(acetylacetone, 40 mol%). Then, several aniline derivatives
were isolated in moderate to excellent yields (Scheme 14).
However, no reaction with aryl chlorides was reported.
One of the key points in this procedure is that a biphasic
system is required. In pure water or in neat DMF saturated
with ammonia, no reaction took place. Taillefer suggested Scheme 14 Copper(II) acetylacetonate catalyzed amination of
that water is necessary as NH3 and [Cu(NH3)4]2+ reservoir aromatic halides.

This journal is c The Royal Society of Chemistry 2010 Chem. Soc. Rev., 2010, 39, 4130–4145 4139

whereas the amination reaction occurred in the organic phase.
Other hypothesis for this biphasic reaction might be the
following ones:
(i) the catalyst (Cu(II)/L) is not soluble in aqueous phase.
(ii) ammonia is sparingly soluble in DMF.
The problem of catalyst solubility in water was recently
questioned by Zhou et al.50 In order to develop an amination
reaction using ammonia in ‘‘non toxic, cheap and readily
available green solvent’’ (namely in water), a sulfonato-
copper(salen) complex was prepared (Scheme 15). The
amination reaction was carried out in pure water at 120 1C
in the presence of sodium hydroxide as base, aqueous
ammonia and 5–10 mol% of catalyst. In these reaction
Published on 28 September 2010 on http://pubs.rsc.org | doi:10.1039/C003692G
conditions, anilines were obtained in yields ranging from
71 to 95%, starting from aryl iodides, or between 64 and
95% starting from aryl bromides. Interestingly, whatever the
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halide (I or Br), the corresponding amine was isolated in
similar yields (Scheme 15). Similarly, electron withdrawing
groups or electron donating groups can be present without
any loss of reactivity. Moreover, the steric hindrance seems to
be well tolerated. Indeed, from 1-iodo-2-methylbenzene,
1-amino-2-methylbenzene was isolated in 71% yield (70%
from 1-bromo-2-methylbenzene) and from the 1-iodo-2,6-
dimethylbenzene the aniline was obtained in a gratifying
64% yield.
Scheme 15 Sulfonato-copper(salen), a water soluble catalyst.
4140 Chem. Soc. Rev., 2010, 39, 4130–4145
View Article Online
These results clearly demonstrated that water could be a
suitable solvent in this coupling reaction, as soon as a water-
soluble complex is engaged.
Other copper complexes were also generated in situ in order
to improve the activity of the catalyst and to expand the scope
of this reaction. In 2009, Ding et al. described the association
of copper salts with 2-pyridyl-b-ketone ligands.51 In the
presence of CuBr (5 mol% with aryl iodides, 10 mol% with aryl
bromides) and 1-(5,6,7,8-tetrahydroquinolin-8-yl)-2-methyl-
propan-1-one (10 mol% with aryl iodides, 20 mol% with
aryl bromides), potassium carbonate as a base, aqueous
ammonia (5 equiv.) in DMSO at room temperature or at
110 1C, the aniline compounds were obtained in excellent
yields (56–96%). Aryl halides containing electron donating
or electron withdrawing substituents can be used without
decreasing the yields. Sterically hindered halides led to the
amines in moderate yields (60% from 2,4,6-trimethyliodo-
benzene, Scheme 16).
In 2010, D. Ma et al. reported the amination of aryl halides
with aqueous ammonia using 20 mol% copper iodide and
40 mol% of L-proline or 4-hydroxyproline as a ligand at 50 1C
in DMSO.52 The aniline derivatives were isolated in 55 to 91%
yield from activated or non activated aryl bromides. Sterically
hindered aryl halides required higher temperatures (70 1C)
to ensure high conversions. It is worth mentioning that
this reaction is chemoselective at 50 1C (Scheme 17). From
1,4-dibromo-2-methylbenzene, only the less hindered bromide
reacted to provide 4-amino-1-bromo-2-methylbenzene in
63% yield.
Extension of this work to 2-iodoacetanilides or 2-iodophenyl-
carbamates led to the synthesis of 1H-benzimidazoles or 1,3-
dihydrobenzimidazol-2-ones at room temperature in 61–86%
yield (Scheme 18).53 Again, a wide range of functional
groups can be tolerated under these reaction conditions
(ketones, nitro). When diodoaryl were engaged in the coupling
reaction, a bis amination occurred. However, only a chemo-
selective monoamination was observed when a bromo-, or a
chloro substituted iodoacetanilide was introduced in this
process at room temperature.
The recent works on amination of aryl halides demonstrate
the potential of copper catalysts. Even if the catalyst loading
remain higher than the one in palladium chemistry, the yields
and the reaction conditions are usually acceptable. At
this stage, only monoarylations were reported. This higher
selectivity, compared to palladium chemistry, might be due to
a lower reactivity of the copper complexes. Moreover, no
convincing copper complexes allow the synthesis of primary
anilines from aryl chlorides, and no detailed mechanism has
been given in literature until now.
4. Copper catalyzed amination of heterocyclic derivatives
As a subclass of aromatic compounds, heteroaromatic
derivatives are important building blocks in pharmacology
and material sciences.1 For example, pyrimidine derivatives
are of potential interest for the treatment of diseases associated
with histamine H4 receptor activity. Two non-catalyzed ami-
nation reactions of electron deficient derivatives (pyridine,
pyrimidine) are known in the literature: (i) the Chichibabin
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Scheme 16 C–N coupling reaction.
reaction, and (ii) the SNAr reaction. The former, a direct
addition of sodium or potassium amides, is a process of great
practical value for the production of 2-amino-pyridines or
quinolines. The latter is a direct addition of nucleophiles on
This journal is c The Royal Society of Chemistry 2010
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Scheme 17 Copper(I)/hydroxyproline catalyzed amination of aromatic
bromide.
Scheme 18 Synthesis of 1H-benzimidazoles or 1,3-dihydrobenz-
imidazol-2-ones.
electron deficient aryl halides. 2,4,6-halogenated pyridines are
known to undergo nucleophilic aromatic substitution.54 In
uncatalyzed SNAr reactions, the ability of the leaving group
is generally the opposite to the ones in metal-catalyzed
reactions,39 i.e., the iodide atom is the best halides for copper
assisted nucleophilic displacement of aryl halide whereas the
fluoride atom will favor the SNAr pathway. The better leaving
group is then the fluorine and electron withdrawing group,
such as F, Cl, CF3 or NO2, accelerated this process.55
However, for less activated or more functionalized derivatives,
synthetic methods affording the efficient formation of C–N
bonds are strongly desired. Lang et al. reported that copper
salts were able to catalyze the amination of halopyridine and
heterocyclic bromides (Scheme 19).7 Among polar protic
solvents such as aqueous or alcoholic solvents, ethylene glycol
was found to give the best results. Corresponding pyridine
ethers or hydroxides were usually observed as by-products. An
increase of the ammonia pressure to 100 psi (7 bar) slightly
improved the selectivity thanks to a higher concentration of
ammonia in ethylene glycol. Cu2O and Cu/CuCl provided full
conversions at low catalyst loading (0.5 mol%) in ethylene
glycol at 100 1C. Due to the practical simplicity of the reaction
and cleanliness of the reaction profile, Cu2O was used to
explore the scope of the amination. Chloropyridines reacted
in these conditions only when an electron withdrawing
substituent was on the pyridine ring. However the SNAr
process can not be completely ruled out. The amination
reactions proceeded in high yields and selectivities with a series
of 2-bromopyridine. Amination reactions also occurred in
high yields and with quite good selectivities with several other
heterocyclic bromides (Scheme 19).
Chem. Soc. Rev., 2010, 39, 4130–4145 4141

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Scheme 19 Ligand free copper(I) oxide catalyzed amination of
heterocyclic aryl halides.
Chemoselective monoamination was rendered possible by
modulating the reaction temperatures. At 60 1C, the 2-amino-
5-bromopyridine was isolated in 62% yield whereas at 80 1C
the corresponding diamino compound was obtained as a
major product (Scheme 20).
Recently, Renaud et al. used Lang’s procedure with success
for the synthesis of some new substituted amino-bispyridyl
derivatives (Scheme 21).49 In some cases, higher amounts of
corresponding alkoxypyridines were produced from addition
of ethylene glycol on bromopyridine derivative. However,
neither bis-aryl formation nor reduction of bromopyridine
was observed. The aminopyridines were isolated in yields
ranging from 54 to 82% (Scheme 21).
The first report on the use of aqueous ammonia for the
amination of heteroaryl compounds was done by Chang
et al. in 2008.46 Iodopyridines and thiophenes led to the corres-
ponding primary amino derivatives in 50 to 90% yields
Scheme 20 Chemoselective formation of aminopyridine.
4142 Chem. Soc. Rev., 2010, 39, 4130–4145
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Scheme 21 Synthesis of functionalized aminopyridine derivatives.
Scheme 22 Amination of iodoheteroaryl derivatives.
(Scheme 22). It is worth mentioning that the chemoselective
monoamination of the 2-chloro-5-iodopyridine led exclusively
to the 5-amino-2-chloropyridine in 90% yields.
Copper(I) oxide with or without ligand catalyzed the amina-
tion of several bromopyridines in the presence of aqueous
ammonia. In 2009, Wolf and Xu described the amination of
4-bromoquinoline and pyridine in the presence of copper(I)
oxide, aqueous ammonia under air in a H2O:NMP mixture as
solvent at 80–90 1C.43 The corresponding amines were isolated
in 81 and 74% yield, respectively (Scheme 23).
We have reported an efficient catalytic system for the amina-
tion of various bromo-pyridine and pyrimidine derivatives.56
This reaction proceeds with high conversions and yields under
mild conditions regardless of the substitution by electron-
donating or withdrawing groups. The interest of the system
is based on the use of a cheap copper complex (Cu2O) and
aqueous ammonia, as a cheap and easy to handle ammonia
source, at 60 1C. It is worth mentioning that both the
unsymetrical and symmetrical DMEDA ligand provided similar
results. The aminopyridines were then obtained in moderate
to high yields (68 to 94%). The efficiency of the reaction was
not sensitive to the steric hindrance of an adjacent methyl
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 View Article Online

Scheme 25

Scheme 23 Ligand free copper(I) oxide.

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group. Similarly, the catalytic system was also found suitable

for the amination of 3-bromopyridine and 2-bromopyrimidine
yielding 3-aminopyridine and 2-aminopyrimidine in high yields.
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It is noteworthy that the diaminaton of 2,6-dibromopyrine

afforded 2,6-diaminopyridine in good yield. However, the use
of 20 equiv. of NH3
H2O (10 equiv./Py-Br) resulted in an
incomplete reaction leading to a mixture of 2,6-diaminopyridine
and 2-bromo-6-aminopyridine. To ensure good conver-
sion and yield, 40 equiv. of NH3
H2O (20 equiv. per Br)
have to be used, then 2,6-diaminopyridine was isolated in
68% yield (Scheme 24). Without copper, no reaction took
place.
Other catalytic systems also showed some interesting
activities. Thus Darcel reported the amination of 3-iodo-
pyridine in 94% yield using a iron/copper cocatalyst system
in refluxing ethanol (Scheme 25).42
In 2009, Taillefer reported two examples of NH3
H2O
heteroarylation using CuI/2,4-pentadione as the catalytic

Scheme 26 Copper(II) catalyzed amination of bromopyridines.

system at 90 1C.48 The 2- and 3-aminopyridines were obtained

in 82 and 84% yield, respectively. These compounds were also
isolated in 92 and 93% yields, respectively, using the water
soluble sulfonatocopper(salen) complex (Scheme 26).50
Finally, copper bromide associated to 1-(5,6,7,8-tetrahydro-
quinolin-8-yl)-2-methylpropan-1-one (L3) promoted the
amination of electron rich iodopyridine at room temperature
or bromopyridine at 110 1C. The corresponding amino-
pyridine were obtained in 79 to 89% yields (Scheme 27).51

Scheme 24 Cu2O/DMEDA as catalyst for the preparation of
functionalized aminopyridine.
Conclusion
In the past decade transition-metal-catalyzed C–N bond-
forming reactions have emerged as a potent tool for the
production of aryl amines. These reactions offer a versatile
strategy and represent one of the key technologies for the
progress of green and sustainable chemistry. However,
although research efforts have been dedicated to catalytic
processes, it is highly desirable to develop new efficient
methods to further improve the efficiency and generality of
the metal-catalyzed preparation of primary aromatic amines.
Indeed, in palladium-catalyzed aminations, a lowering of
the reaction temperature will be beneficial with respect to

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Scheme 27 Copper bromide/L3 catalyzed amination of bromo- or
iodopyridine.
increased chemoselectivity and environmental concerns. In
copper-catalyzed aminations, high catalyst loadings are
employed: alternative approaches capable of decreasing these
loadings are therefore desirable. In summary, despite recent
significant advances in this field, the number of active, produc-
tive and selective catalysts remains limited. This might be
improved most likely by designing new catalytic systems, more
reactive and more robust toward large amounts of substrate.
In addition, for copper- and palladium-catalyzed reactions, a
closer examination of the reaction mechanism would lead to a
deeper understanding of the reaction.
Future work in this area will likely focus on incorporating
high degrees of selectivity into these catalytic systems, and also
in discovering new chemical reactions and reactivities that will
present opportunities for the development of entirely different
catalyst systems. It would be of great interest to develop new
catalysts that allow the conversion of more challenging
substrates such as aminoaryl halides, halostyrenes, or func-
tionalized aryl chlorides. The future of this chemistry might
also probably lie in the combination of the above reactions
with other catalytic reactions in tandem and multi-component
intra- and intermolecular transformations.
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