Highly efficient and mild copper-catalyzed N- and C-arylations with aryl bromides and iodides

Article abstract of DOI:10.1002/chem.200400582

Mild, efficient, copper-catalyzed N-arylation procedures for nitrogen heterocycles, amides, carbamates, and C-arylation procedures for malonic acid derivatives have been developed that afford high yields of arylated products with excellent selectivity. The N-arylation of imidazole with aryl bromides or iodides was found to be greatly accelerated by inexpensive, air-stable catalyst systems, combining catalytic copper salts or oxides with a set of structurally simple chelating ligands. The reaction was shown to be compatible with a broad range of aryl halides, encompassing sterically hindered, electron-poor, and electron-rich ones, providing the arylated products under particularly mild conditions (50-82°C). The lower limit in ligand and catalyst loading and the scope of Ullmann-type condensations catalyzed by complexes bearing those ligands with respect to the nucleophile class have also been investigated. Chelating Schiff base Chxn-Py-Al (1c) generates a remarkably general copper catalyst for N-arylation of pyrrole, indole, 1,2,4-triazole, amides, and carbamates; and C-arylation of diethyl malonate, ethyl cyanoacetate, and malononitrile with aryl iodides under mild conditions (50-82°C). The new method reported here is the most successful to date with regard to Ullmann-type arylation of some of these nucleophiles.

Full text of DOI:10.1002/chem.200400582

FULL PAPER
Highly Efficient and Mild Copper-Catalyzed N- and C-Arylations with Aryl
Bromides and Iodides
[
a]
[a, c]
[b]
[a]
Henri-Jean Cristau,* Pascal P. Cellier,
Jean-Francis Spindler, and Marc Taillefer*
Abstract: Mild, efficient, copper-cata-
lyzed N-arylation procedures for nitro-
gen heterocycles, amides, carbamates,
and C-arylation procedures for malonic
acid derivatives have been developed
that afford high yields of arylated prod-
ucts with excellent selectivity. The N-
arylation of imidazole with aryl bro-
mides or iodides was found to be great-
ly accelerated by inexpensive, air-stable
catalyst systems, combining catalytic
copper salts or oxides with a set of
structurally simple chelating ligands.
The reaction was shown to be compati-
ble with a broad range of aryl halides,
encompassing sterically hindered, elec-
tron-poor, and electron-rich ones, pro-
viding the arylated products under par-
ticularly mild conditions (50–828C).
The lower limit in ligand and catalyst
loading and the scope of Ullmann-type
condensations catalyzed by complexes
bearing those ligands with respect to
the nucleophile class have also been in-
vestigated. Chelating Schiff base Chxn-
Py-Al (1c) generates a remarkably
general copper catalyst for N-arylation
of pyrrole, indole, 1,2,4-triazole,
amides, and carbamates; and C-aryla-
tion of diethyl malonate, ethyl cyano-
acetate, and malononitrile with aryl io-
dides under mild conditions (50–828C).
The new method reported here is the
most successful to date with regard to
Ullmann-type arylation of some of
these nucleophiles.
Keywords: arylation
homogeneous catalysis · N,O ligands
nucleophilic substitution
·
copper
·
·
Introduction
ucts. Crucial requirements for development of an industrial
process giving access to the aforementioned compounds are
reliability, experimental ease, and, most important, low cata-
lyst cost. Nucleophilic aromatic substitution with aryl halides
Transition-metal-catalyzed arylation of nucleophilic com-
pounds with aryl halides is a key tool for carbon–hetero-
atom or carbon–carbon bond formation in organic synthesis.
Certain classes of compounds available through these pro-
[5]
[6]
can be mediated by palladium, nickel, or copper cata-
[7,8]
lysts.
The lower cost of copper-based catalytic systems
[1]
cesses, such as N-arylated azoles, N-arylated oxazolidin-2-
makes them particularly attractive for large-scale industrial
applications.
[2,3]
[4]
ones,
or C-arylated malonic acid derivatives, are indus-
trially important synthetic targets. These motifs are found in
a range of pharmaceuticals, agrochemicals, and natural prod-
Copper-catalyzed arylation of amines (Ullmann condensa-
[9]
tion), amides and carbamates (Ullmann–Goldberg conden-
[
10]
sation)
or activated methylene compounds (Ullmann–
[11]
Hurtley condensation)
are well-documented methodolo-
[
a] Prof. Dr. H.-J. Cristau, Dr. P. P. Cellier, Dr. M. Taillefer
Laboratoire de Chimie Organique
gies that were discovered several decades before the palladi-
um and nickel-catalyzed methodologies. However, these
transformations have not been employed to their full poten-
tial for a long time. Until recently, they suffered from re-
duced synthetic scope as a result of the harsh reaction con-
ditions often required, a limited substrate scope, and the
UMR CNRS 5076 et Ecole Nationale SupØrieure de Chimie de
Montpellier
8
rue de LꢀEcole Normale, 34296 Montpellier Cedex 5 (France)
Fax : (+33)467-144-319
E-mail: cristau@cit.enscm.fr
taillefe@cit.enscm.fr
[7c–e]
moderate yields obtained.
Condensations were tradition-
[
b] Dr. J.-F. Spindler
ally conducted in high-boiling-point polar solvents such as
N-methylpyrrolidone (NMP), nitrobenzene, or dimethylform-
amide (DMF), at temperatures as high as 2108C, sometimes
in the presence of stoichiometric amounts of copper re-
agents and preferentially with aryl halides activated by elec-
Rhodia Organique Fine, Centre de Recherches de Lyon (CRL)
8
6
5 avenue des Fr›res Perret, BP 62
9192 Saint-Fons Cedex (France)
[
c] Dr. P. P. Cellier
Current address:
Laboratoire de Chimie Organique et GØnØrale
UMR CNRS 8525 et FacultØ de Pharmacie
[12,13]
tron-withdrawing or o-carboxylic acid groups.
The eco-
nomic attractiveness of copper has led to a resurgence of
interest in Ullmann-type reactions in recent years and has
3
5
rue du Professeur Laguesse, BP 83
9006 Lille Cedex (France)
Chem. Eur. J. 2004, 10, 5607 – 5622
DOI: 10.1002/chem.200400582
ꢁ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
5607

FULL PAPER
challenged synthetic chemists to devise milder synthetic
methods. The development of new ligand structures for
copper-catalyzed cross-coupling protocols constitutes an
area of considerable interest. Indeed, pioneering work by
required to effect pyrazole and phenol arylations (25–828C),
while affording coupling products with excellent yields and
selectivity regardless the electronic nature of substituents on
aryl halides. Copper(i) oxide (Cu O; 5 mol%), an inexpen-
2
[14]
[15]
[16]
[17]
Weingarten, Takenaka, Buchwald, and Goodbrand
sive ligand 1 (20 mol%) and two equivalents of Cs CO in
2
3
revealed rate accelerations when arylations were conducted
in the presence of certain copper ligands. These additional
compounds are thought to increase catalyst solubility, stabil-
ity, and/or to prevent aggregation of the metal. This and the
observation that some coupling partners with a supplemen-
tary copper-chelating group, such as 2-halogenobenzoic
acetonitrile were identified as highly efficient systems to
perform the couplings and brought notable improvement
over previously disclosed methods.
Thus, it was a natural extension for us to investigate the
generality of the coupling reaction with respect to nucleo-
philes, such as the other azoles (imidazoles, pyrroles, indoles,
triazoles, and tetrazoles), amides, carbamates, or malonic
acid derivatives. In this paper, we report a full account of
our efforts toward the synthesis of arylated derivatives of
these compounds and we demonstrate that Chxn-Py-Al (1c)
is a remarkably general ligand for Ullmann-type condensa-
[18]
[19]
[20]
acids, a- and b-amino acids, or b-amino alcohols, in-
duced rate accelerations of Ullmann-type arylations relative
to unfunctionalized parent substrates have led to a growing
number of papers focusing on the deliberate use of addition-
[7a–b]
al ligands to facilitate the cross-coupling reactions.
Care-
[25]
ful choice of the promoter allows condensations to be run at
relatively low temperatures, contrasting with the rather dras-
tic experimental conditions necessitated by the traditional
Ullmann-type arylations.
tion reactions. While being not commercially available, 1c
is a stable, crystalline solid, which is very easily synthesized
from cheap starting materials, with high yield and on a mul-
[22]
tigram scale.
Starting from the idea that the presence of ancillary li-
gands coordinating the metal center is the most important
factor in determining the efficiency of the catalyst system,
we initiated a research program aimed at identifying appro-
priate new ligands with high binding propensity, to improve
copper-catalyzed cross-couplings. A screening of forty new
potential ligands led us to the discovery that simple biden-
tate oxime-containing compounds generate extremely effec-
tive catalysts for CÀN and CÀO bond formation involving
Results and Discussion
Copper-catalyzed N-arylation of azoles with aryl bromides
and iodides: We first focused on the N-arylation of imida-
zole, since 1-arylimidazoles, which in addition to being re-
[26]
current templates in medicinal chemistry, are exploited as
important building blocks for the synthesis of N-heterocyclic
carbenes, a powerful class of ligands for transition-metal
catalysis and for room-temperature ionic liquids,
have been attracting a great deal of interest as environmen-
tally benign solvents for organic
synthesis.
[21]
[22]
[27]
pyrazoles
and phenols, respectively. These compounds
[28]
include the mixed donor salicylaldoxime 1i and the vicinal
dioxime dimethylglyoxime 1k. Although oximes have often
which
It was determined during a
preliminary survey of reaction
conditions using bromobenzene
as a model arylating agent that:
1
) cuprous oxide is slightly
more efficient than cuprous
bromide as a precatalyst, 2)
acetonitrile is a better solvent
than DMF, and 3) cesium car-
bonate is far more efficient
than any other inorganic base
investigated. These are the
same findings as those we have
obtained for pyrazole N-aryla-
[21]
tion.
Copper(i) oxide is par-
[
23]
been used to complex copper salts, there have been no re-
ports of the use of such ligands in Cu-catalyzed aromatic
substitution chemistry. Next, we tried to devise second-gen-
eration ligands and pursued our investigations on a broader
structural range. We succeeded in identifying new multiden-
tate donor compounds with nitrogen- or oxygen-binding
sites, and alternatively a mixture thereof. An example is the
ticularly interesting as a copper source owing to its low cost
and insensitivity to light and air. In comparison, cuprous
bromide is slightly air-sensitive, while cuprous iodide is light
[29]
sensitive, and both are more expensive than Cu O. The
2
search for suitable ligands for imidazole N-arylation with
bromobenzene was undertaken in acetonitrile at a relatively
low temperature (828C), with cesium carbonate as a base
(2 equiv), a catalytic amount of cuprous oxide (5 mol%),
and 20 mol% of each ligand (based on the limiting reagent),
with a reaction time fixed to 24 h. Table 1shows the most
[24]
chelating Schiff base 1c,
hereafter named Chxn-Py-Al,
which allowed expanding the reaction scope in a few cases.
The ligands depicted here dramatically reduce temperatures
5608
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Chem. Eur. J. 2004, 10, 5607 – 5622

Copper Catalysts
5607 – 5622
Table 1. Screening of ligands for the N-arylation of imidazole with bro-
mobenzene or iodobenzene at 828C.
tion of an imidazole with a haloaromatic, whatever the
metal catalyst.
[a]
The scope of the process with respect to aryl halide struc-
ture was investigated next. The catalyst systems composed
of cuprous oxide and commercially available ligands 1d or
1i efficiently catalyzed the arylations of imidazole with elec-
tronically diverse aryl bromides at 828C and iodides at 50–
[c]
Entry
X
T [8C]
t [h]
Ligand
GC Yield [%]
1
2
3
4
5
6
7
8
9
Br
82
Br
24
82
82
82
82
82
82
82
82
Br
82
Br
Br
82
1a
1b
1c
1d
1d
10 d0
1e
1 f
1g
12 h4
1i
12 k4
12 l4
1j
1i
1i
55
49
48
48
91
>99
45
45
40
39
38
23
12
100
100
100
8
28C (Table 2, reaction times are not optimized). Thus, elec-
24
24
24
72
1
24
24
24
Br
Br
Br
Br
Br
Br
Br
tron-poor (entries 3,4,6,8), electron-neutral (entries 1,2), and
even electron-rich (entries 5) aryl halides afforded the N-
arylated products in excellent yields (generally greater than
9
0%). This weak sensitivity to electronic effects is very in-
teresting with regard to electron-rich substrates, since transi-
tion-metal-catalyzed reactions involving these arylating
agents are traditionally less straightforward, particularly if
1
1
1
1
1
1
1
0
Br
82
1
24
[32]
the metal is palladium. Lastly, the reaction was sensitive
2
3
I
I
I
82
82
to steric hindrance near halogen atom, as usually stated in
Ullmann-type condensations, being slower when starting
from an ortho-substituted aryl iodide (entry 7).
[
[
[
b]
b]
b]
4
5
6
24
24
24
82
50
Particularly noteworthy are the reactivity differences ex-
hibited by aryl halides toward oxidative addition. The reac-
tion of imidazole with 4-bromoiodobenzene 4 took place on
the iodine moiety with complete regioselectivity at 508C,
when starting from a stoichiometric mixture of coupling
partners (Table 2, entry 6; GC yield: 96%). This selectivity
in favor of the monosubstitution product thus allows retain-
ing an active halide site for further functionalization. It was
exploited to perform the two-step, one-pot synthesis of 1-
[(4-imidazol-1-yl)phenyl]pyrazole (3 f) starting from 4-bro-
moiodobenzene (4; Scheme 1). Compound 3 f was obtained
with a remarkable 98% GC yield (based on the default re-
agent, pyrazole).
[
(
a] Reaction conditions: imidazole (0.75 mmol), bromobenzene
0.5 mmol), Cs CO (1.0 mmol), Cu (5 mol%), ligand (20 mol%),
MeCN (300 mL), under N . [b] Iodobenzene (0.75 mmol) and imidazole
0.5 mmol) were used. [c] Selectivity was >99% in all cases.
2
3
2
O
2
(
significant results and reveals that many of the new ligands
we recently reported for pyrazole N-arylation allowed the
present Ullmann-type condensation to be efficiently per-
formed at the lowest temperature reported to date for an
aryl bromide. Our results are noteworthy compared with the
1
258C required using Cu(OTf) ·PhH/1,10-phenanthroline
2
[16b]
catalytic system.
Hydrazone- (entries 1,4,8) and Schiff-
base-type supporting ligands (entries 2,3,7) with at least one
[30]
additional phenol- or pyridine-type binding site proved to
be superior to oxime-type bidentate ligands (entries 9–12).
It can be observed that salen-type ligand 1e is much more
efficient than parent compound 1l in promoting Ullmann-
type condensation. This result could be explained in terms
of the geometry induced by the ligand around the copper
catalyst. Actually, the dismutation equilibrium of the active
copper(i) species into copper metal and copper(ii) can be
I
shifted toward Cu thanks to the use of ligands that favor a
tetrahedral structure rather than a square planar one, more
Scheme 1. One-pot synthesis of compound 3 f starting from 4-bromoiodo-
benzene.
[31]
common with copper(ii) species.
Moreover, rotation
around the CÀC bond in 1l is expected to reduce its binding
efficiency, which is restricted in 1e. Reactions using ligands
1
a–l were totally selective with respect to imidazole and
In an endeavor to expand the scope of the methodology,
protocols based on the use of our new catalytic systems
were applied to a variety of other azoles. N-Arylation of
pyrrole and indole with iodobenzene in acetonitrile was un-
eventful and could be driven to completion within 24 h at
828C by using ligands 1c or 1i (Table 3, entries 1,4). Both
arylated products were isolated in 92–94% yield. Condensa-
tions were also quantitative at 508C albeit the reaction time
required was longer (74–96 h, entries 2,5). It should be
pointed out that no byproduct arising from C-3 arylation of
indole was observed under our reaction conditions. Such
side reactions have been observed in the literature with pal-
almost totally selective with respect to bromobenzene. They
were never accompanied by formation of biaryl byproducts,
while affording less than one percent of hydrodehalogenated
arene byproduct. Moreover, bromobenzene proved to be
unreactive toward NH- or OH-group-containing ligands.
With commercially available and cheap ligand 1d, a yield
higher than 90% could be obtained after 72 h heating
(
entry 5). The more reactive iodobenzene allowed condensa-
tion to be driven to completion in less than 24 h at tempera-
tures ranging from 50 to 828C (entries 14–16). Those reac-
tion conditions are the mildest yet reported for the N-aryla-
Chem. Eur. J. 2004, 10, 5607 – 5622
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ꢁ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
5609

M. Taillefer, H.-J. Cristau et al.
FULL PAPER
[
a]
Table 2. Copper-catalyzed N-arylation of imidazole with functionalized aryl bromides or iodides under mild conditions.
Entry
Aryl
halide
Coupling
product
T
[8C]
t
Ligand
Yield
[%]
[l]
[b]
[h]
[
d]
[k]
1
2
50
82
24
100
1i
1d
100
95
3
3
a
[i]
[
[
d]
h]
[k]
3
4
50
82
24
72
1i
1d
100
94
b
[
[
f]
5
6
3c
3d
50
50
24
36
1d
1i
97
89
c]
[j]
7
3e
3 f
82
36
1i
92
[
[
e]
g]
[k]
8
9
82
82
24
48
1i
1i
100
3g
90
[
[
[
a] Reaction conditions: imidazole (3 mmol), ArX (2 mmol), Cs
b] Yield of isolated product unless otherwise noted. [c] With imidazole (2 mmol) and ArX (2 mmol). [d] With imidazole (2 mmol) and ArX (3 mmol).
e] With imidazole (2 mmol) and ArX (2.4 mmol). [f] With imidazole (2 mmol) and ArX (2.6 mmol). [g] With imidazole (5 mmol), ArX (2 mmol), and
2
CO
3
2 2
(4 mmol), Cu O (5 mol%), ligand 1d or 1i (20 mol%), MeCN (1.2 mL), under N .
2 3 2 3
Cs CO (6 mmol). [h] With Cs CO (3.6 mmol). [i] GC yield was 91% after 72 h heating. [j] GC yield was 93% after 24 h heating. [k] GC yield. [l] Reac-
tion times are unoptimized; no reaction was stopped before 24 h.
[
a]
Table 3. Copper-catalyzed N-arylation of azoles with iodobenzene under mild conditions.
[
c]
Entry
Azole
Coupling
product
T
[8C]
t
Ligand
Solvent
Yield
[%]
Selectivity
[
b]
[h]
[
[
d]
d]
1
2
82
50
24
96
1i
1c
MeCN
MeCN
100 (94)
100
97
97
6
a
[
[
[
e]
e]
e]
3
4
5
82
82
50
24
24
74
1i
1c
1c
MeCN
MeCN
MeCN
82
>99 (92)
99
96
99
99
6b
[
[
[
f]
f]
f]
6
7
8
82
82
82
24
24
48
1i
1c
1c
DMF
DMF
DMF
80
79
100 (91)
79
99
98
6c
9
–
1
1
0 1c
24
DMF
0
–
[
a] Reaction conditions: azole (1equiv), iodobenzene ( 1. 5 equiv), Cs
under N . [b] Yields refer to GC yields and yields in parentheses refer to isolated yields with >95% purity as determined by GC and H NMR spectros-
copy. [c] Selectivity relative to PhI. [d] With azole (1equiv) and iodobenzene ( 1. 2 equiv), [PhI] =2m. [e] With azole (1.5 equiv) and iodobenzene
1equiv), [PhI] =1.67m. [f] With Cs CO (1.6 equiv).
2
CO (2 equiv), Cu O (5 mol%), ligand 1c or 1i (20 mol%), solvent, [PhI]=2.5m,
3
2
1
2
(
2
3
[
5j]
ladium catalysis with aryl halides or with copper cataly-
sis
sponding anion. Reactions had to be performed in DMF
due to poor solubility of cesium salt of 1,2,4-triazole
[
33]
with triarylbismuthanes as arylating agents. 1,2,4-Tri-
[37a]
azole coupled smoothly to iodobenzene to yield a single re-
gioisomer. N-Arylation occurred regiospecifically at the
N1(2) atom, because of its enhanced nucleophilicity relative
to the N4 atom, resulting from an a-effect in the corre-
(pKHA =14.75 in DMSO) in acetonitrile,
which led to in-
complete conversion of iodobenzene even after prolonged
heating. Ligand 1c was found more suitable than Salox 1i,
because the latter was not fully unreactive toward arylating
5610
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Chem. Eur. J. 2004, 10, 5607 – 5622

Copper Catalysts
5607 – 5622
agent. Due to the weaker nucleophilicity of 1,2,4-triazole
compared to pyrazole or imidazole, reaction of iodobenzene
with Salox could actually compete with N-arylation of the
substrate (Table 3, entry 6: 79% selectivity to product). Use
of ligand 1c, which cannot undergo any copper-catalyzed
cross-coupling, cleanly led to a quantitative condensation
within 48 h at 828C and 1-phenyl-1,2,4-triazole 6c was iso-
lated in 91% yield (entry 8). Attempts to N-arylate 5-phe-
nyltetrazole with iodobenzene in DMF or acetonitrile at
pyrazole and imidazole could be attributed to an overall de-
crease in nucleophilicity when going from diazole to triazole
family. As a result, two of the three elementary steps of the
possible catalytic cycles depicted in Scheme 5 (see below)
would be significantly slowed down: 1) nucleophilic substitu-
tion of copper-bound halide by triazolate anion and 2) CÀN
[40]
bond-forming reductive elimination.
Thus, reactivity of
azoles appears to be the result of a complex balance be-
tween several parameters, including nucleophilicity, catalyst
[12g]
828C failed, regardless of the precatalyst and nature of the
complexing ability, and acidity.
supporting ligands. The arylating agent was recovered un-
changed after 24 h heating. The use of more forcing reaction
conditions (1108C, DMF) was also unsuccessful (entry 9)
and led to decomposition of iodobenzene to benzene
Taking into account the future large-scale industrial appli-
cations of our cross-coupling methodology, we decided to
study the lower limit in ligand and catalyst loading compati-
ble with both satisfactory reaction rates and high yields for
the N-arylation of pyrazole. Though a 2:1ligand-to-copper
ratio has been used in all couplings described in our previ-
ous article, it should be noted that reducing the amount
of either 1i or 1c to a 1:1 ligand-to-copper ratio afforded
almost the same yield within 24 h for condensation with bro-
mobenzene (Table 4, entries 1–4). The exact nature of the
(
12%), phenol (8%), and diphenyl ether (38%). The two
last reaction products probably arise from mono- and di-O-
arylation, respectively, of cesium hydroxide generated from
[21]
[34]
thermal decomposition of cesium hydrogen carbonate.
Analogous byproduct formation has already been observed
[22,35]
[20a]
in the literature, with carbonate
or hydroxide bases.
The formation of a CÀN bond is here a difficult problem to
address, probably because of poor nucleophilicity of 5-phe-
nyltetrazole anion. To our knowledge, metal-catalyzed N-ar-
ylation of tetrazole derivatives with aryl halides has never
Table 4. N-arylation of pyrazole at reduced catalyst and/or ligand load-
ing.
[36]
been described in the literature.
The order of reactivity in the azole series for Ullmann-
type N-arylation emerging from this study is as follows:
Entry
X
Ligand Amount Amount
of Cu of ligand of Cs
mol%]
Amount
t
GC
Yield
2
O
2
CO
3
[
d]
[
[mol%]
[equiv]
[h] [%]
[
[
[
[
[
[
a,c]
a]
1
2
3
4
5
6
7
8
9
0
Br 1i
Br 1i
Br 1c
Br 1c
5
5
5
5
0.2
0.2
0.55
0.55
0.05
0.05
20
10
20
10
0.8
4.0
2.2
11
1.0
0.2
2
2
2
2
1.4
1.4
1.4
1.4
1.4
1.4
24
24
24
24
48
48
48
48
96
96
96
95
93
85
71
100
>99
>99
77
a,c]
a]
b]
I
I
I
I
I
I
1i
1i
1i
1i
1i
1i
First, we observed that imidazole proved to be less reac-
tive than pyrazole. N-Arylation of the latter with bromoben-
b]
[b]
[b]
[21]
zene was almost quantitative within 24 h at 828C, while
the same level of yield was only reached after 72 h with the
former under the same reaction conditions. The weaker re-
activity of imidazole does not appear to be the result of a
difference in the ease of deprotonation by the base, since
[
[
b]
b]
1
61
[a] Reactions conditions: Cu
0.5 mmol), Cs CO (1mmol), MeCN (300 mL), under N
conditions: Cu O, Salox, pyrazole (12.5 mmol), PhI (8.3 mmol), Cs
11.7 mmol), MeCN (5 mL), under N . [c] This entry is taken from refer-
ence [21]. [d] Selectivity was >99%.
2
O, ligand, pyrazole (0.75 mmol), PhBr
. [b] Reaction
CO
(
2
3
2
[37,38b]
2
2
3
both substrates have comparable pKHA values.
We be-
(
2
lieve that the a-effect in pyrazolate anion is responsible for
nucleophilicity enhancement, and consequently for such a
rate-acceleration. Considering their better nucleophilicity
and their superior ability to undergo CÀN bond-forming re-
catalytically active species is not known, albeit these results
support an active species bearing one 1i or 1c ligand. The
model reaction chosen for study of the coupling efficiency at
low catalyst loading was the N-arylation of pyrazole with
the more reactive iodobenzene in the presence of Cu O and
1i in acetonitrile at 828C (Table 4). Lowering the amount of
ductive elimination, one would have expected indole and
[40a]
pyrrole to be more reactive than imidazole.
The opposite
result that we obtained can be explained by the higher acidi-
ty of imidazole and the subsequent greater ease of ioniza-
2
[37a]
tion (pKHA =18.6 in DMSO).
It can also be rationalized
by invoking the high copper-binding propensity of diazoles
through the lone pair of their pyridine-type nitrogen atom
Cu O to 0.2 mol% led to incomplete consumption of iodo-
2
benzene after 48 h heating (71%, entry 5, L/Cu =2:1). How-
ever, raising the ratio of L/Cu to 10:1 was of great benefit,
since a quantitative yield of 6d was obtained within the
same time period (entry 6). When low catalyst loadings are
employed (Figure 1), a higher ligand/catalyst ratio is thought
to statistically favor formation of the active catalyst species
and to disfavor competitive complexation of compounds
other than the coordination of 1i to copper. By contrast, no
[38]
(
s binding interaction), when indole and pyrrole cannot
efficiently chelate copper salts due to the electron-deficient
[
39]
nature of their nitrogen atoms.
DMSO)
Pyrrole (pKHA =23.0 in
[37a]
[37a]
and indole (pKHA =20.95 in DMSO)
exhibit-
ed similar reactivity. The latter is more sterically encum-
bered, which is apparently counterbalanced by its greater
ease of ionization. That 1,2,4-triazole was less reactive than
Chem. Eur. J. 2004, 10, 5607 – 5622
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ꢁ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
5611

M. Taillefer, H.-J. Cristau et al.
FULL PAPER
with yields ranging from 80 to 100%. It should also be men-
tioned that Buchwaldꢀs system was reported to be unsuc-
[47]
[44b]
cessful
or low-yielding (18%)
for the N-arylation of
imidazole with aryl bromides at 110–1128C. The CuI–l-pro-
[48]
line catalytic system recently described by Ma et al.
quires much longer reaction times than ours, temperatures
0–408C higher, and was not reported to allow the use of
re-
1
aryl bromides. As a comparison, this group has performed
the arylation of imidazole with 4-iodoanisole at 908C within
3
6 h (91% yield), while we have succeeded to complete the
same reaction at 508C in less than 24 h (Table 2, entry 5,
7% yield).
9
Copper-catalyzed N-arylation of amides and amide deriva-
tives: In the hope of broadening the scope of our arylation
protocol, we decided to check the efficiency of our catalyst–
ligand systems on reactions that involve nitrogen nucleo-
philes with an a-carbonyl or an a-sulfonyl group, known as
Goldberg condensations. We first focused on the N-arylation
of acetamide and benzamide, which can be considered as
cheap aniline precursors. A preliminary study involving both
substrates has shown that condensations have to be conduct-
ed in DMF rather than in acetonitrile, in which amides are
less soluble. Salicylaldoxime (1i) was found efficient for pro-
moting Goldberg condensations, although substituting with
1c improved reaction yields. We observed that acetamide,
benzamide, and their N-arylated products were slightly sen-
sitive under the basic reaction conditions employed. Small
amounts of aniline and diphenylamine were detected by
GC/MS (<5%). The observed hydrolysis might be caused
by cesium hydroxide or water, arising from thermal decom-
Figure 1. Beneficial use of a higher L/Cu ratio at low catalyst loading.
significant effect on reactivity was observed when shifting
from a 2:1to a 10 :1L/Cu ratio from 0.55 mol% Cu 2O load-
ing (Table 4, entries 7,8 and Figure 1). We also checked that
the catalyst suffered no deactivation after prolonged heating
at 828C: feeding a reaction mixture with additional pyra-
zole, iodobenzene, and cesium carbonate (0.5 equiv each)
after complete conversion of starting material immediately
got the reaction started again. Catalytic arylation still oper-
ates with 0.05 mol% Cu O and retains its complete selectivi-
2
ty albeit the reaction rate is very slow (entries 9,10). It is
worth noting that this study, which was carried out on an
8
mmol scale, also demonstrates that this reaction has the
[34]
potential to scale up to gram quantity.
position of cesium hydrogen carbonate produced by de-
protonation of amides with Cs CO [Eq. (1)].
It is worth noting that we have devised a general and
high-yielding method for the N-arylation of monoazoles, di-
azoles, and triazoles. Copper-catalyzed methods with orga-
nometal or organometalloid reagents (arylbismuthanes, aryl-
plumbanes, arylboronic acids, etc.) are generally not very
successful for the N-arylation of monoazoles like indole or
2
3
[33,41]
pyrrole,
while palladium is virtually inefficient for medi-
ating the N-arylation of diazoles with unactivated aryl hal-
We were pleased to find that addition of small amounts of
powdered and activated 3 Š molecular sieves to the reaction
mixture had the synthetic advantage of reducing formation
of these byproducts to less than 1%. Molecular sieves also
limit the competitive arylation of water by iodoaromatics,
producing phenols and diarylethers, to less than 2%.
Arylation of acetamide with iodobenzene occurred slug-
gishly at 828C and delivered two coupling products, in spite
of the use of excess amide (1.5 equiv). The expected N-phe-
nylacetamide (7a) was obtained with 85% selectivity, along
with N,N-diphenylacetamide (7b) from competitive diaryla-
tion with 8% selectivity (Table 5, entry 1). Raising the
amount of amide to 2.5 equivalents did not result in an in-
teresting increase in selectivity. As Ullmann–Goldberg ary-
lations are sensitive to steric hindrance effects, a better se-
lectivity for the monoarylation product was expected if
starting from the more hindered benzamide. Indeed, diaryla-
tion of this substrate was not observed and N-phenylbenz-
amide (7c) was obtained in 96% selectivity and 91% yield
within 48 h (Table 5, entry 3). The better reactivity of benza-
[42]
ides. Besides, the present methodology is a cheap alterna-
tive to the use of sophisticated palladium–phosphine systems
[5j,43]
for the N-arylation of monoazoles.
With regard to Ull-
mann condensations, the experimental conditions presented
here are milder than those reported in the literature. Buch-
wald et al. found that CuI-catalyzed coupling reactions of
aryl iodides and various azoles occurred at 110–1258C using
ligands such as 1,10-phenanthroline, N,N’-dimethyl-1,2-ethyl-
enediamine, racemic trans-1,2-diaminocyclohexane, or its
N,N’-dimethyl analogue (only three N-arylations of indole
and one N-arylation of pyrazole with aryl iodides were run
[16b,24,44,45]
at 808C).
Kang et al. obtained similar results for
the N-arylation of indole and pyrrole with 1,2-ethylenedia-
[46]
mine as a promoter at 1108C. As a comparison, Buchwald
et al. have performed the N-arylation of pyrazole (808C),
imidazole (1108C), and 1,2,4-triazole (1108C) within 24 h
[
44c]
with iodobenzene or 5-iodo-m-xylene in 89–93% yield,
[21]
while we have run the corresponding reactions at 50, 50,
and 828C, respectively, within the same reaction time and
5612
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Copper Catalysts
5607 – 5622
[
a]
Table 5. Copper-catalyzed N-arylation of amides or amide derivatives with aryl iodides under mild conditions.
Entry
Aryl
halide
Nucleophile
Coupling
product
T
[8C]
t
Ligand
Solvent
DMF
Yield
[%]
[
b]
[h]
7
7
a
b
7a: 81(85)
7b: 7 (8)
[
c]
1
82
75
1c
2
3
82
82
24
48
1c
1c
DMF
DMF
(81)
91(96)
7
c
8
8
2
2
24
48
1c
1c
DMF
DMF
(86)
88 (94)
[
[
c,d]
e]
4
5
7d
7e
82
82
82
40
24
48
1c
1c
1c
DMF
92 (100)
7
7
f
g
7 f: 90 (98)
7 g: 2 (2)
[
e]
6
MeCN
MeCN
[
e,f]
7
7h
82
[
[
[
[
[
[
g]
g]
g]
g]
c]
c]
8
9
0
1
2
3
82
82
82
82
82
50
24
24
24
24
24
96
1i
1c
1i
1c
1c
1c
MeCN
MeCN
DMF
DMF
DMF
DMF
(59)
(74)
(86)
(94)
97 (>99)
(>99)
1
1
1
1
7
i
[
d,e,g]
1
4
7j
82
100
1i
MeCN
89
[
(
a] Reaction conditions: nucleophile (3 mmol), ArI (2 mmol), Cs
600 mg), solvent (1.2 mL), under N
parentheses refer to GC yields. [c] With Cs
2
CO
3
2
(4 mmol), Cu O (5 mol%), ligand 1c or 1i (20 mol%), 3 Š molecular sieves
1
2
. [b] Yields refer to isolated yields with >95% purity as determined by GC and H NMR spectroscopy and yields in
CO (3.2 mmol). [d] With MeCN (1.6 mL). [e] With nucleophile (2 mmol) and ArI (3 mmol). [f] With ligand
c (10 mol%). [g] Without molecular sieves.
2
3
1
[
37a]
mide (pKHA =23.35 in DMSO)
relative to acetamide
[37a]
(
pKHA =25.5 in DMSO)
might result from its greater
ease of deprotonation. N-Arylation of benzenesulfonamide
was uneventful. Only a small amount (0.5%) of benzenesul-
fonamide diarylation product was detected by GC/MS and
identified by coaddition of a pure sample.
Given the full selectivity of the reaction with respect to
pyrrolidin-2-one, the use of a moderate excess of iodoben-
zene allowed the coupling to be driven to completion and
the corresponding N-phenylamide (7e) to be isolated in
N-Arylation of this substrate with iodobenzene was found
to strongly predominate over O-arylation, in acetonitrile at
828C (N-/O-arylation=98:2), and the reaction turned out to
be quantitative within 24 h (Table 5, entry 6). Such a ratio is
consistent with literature data related to Goldberg conden-
92% yield (entry 5). Arylation of ambidentate pyridin-2-one
[12f,50]
(
8) was also investigated. According to the literature, the
sations.
We took advantage of this selectivity in favor
more polar lactam form 8, which is in tautomeric equilibri-
um with the lactim form 9 (2-hydroxypyridine) [Eq. (2)], is
of the N-arylation product and exemplified the method de-
veloped by the synthesis of a medicinally active molecule,
[49]
[51]
favored in polar solvents. We only observed the polar oxo
the sedative Amphenidone (7h; Scheme 2).
Compound
1
form by H NMR spectroscopy in deuterated acetonitrile at
7h was obtained in 82% isolated yield (N-/O-arylation
>99:1), from pyridin-2-one (8) and 3-iodoaniline (10; Table 5,
258C.
Chem. Eur. J. 2004, 10, 5607 – 5622
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5613

M. Taillefer, H.-J. Cristau et al.
FULL PAPER
[11]
could be promoted by catalytic amounts of copper salts.
His protocol necessitates the use of a strong base (NaH,
MeONa) and is limited to aryl halides bearing ortho- or
[13]
pseudo-ortho-carboxylic acid groups.
Extension of the
method to aryl halides lacking substituents capable of coor-
dinating to the active Cu species is hampered by numerous
restrictions, including modest yields, the requirement of at
Scheme 2. Synthesis of the sedative Amphenidone 7h (Dornwall).
[56a,57]
least stoichiometric amounts of copper,
strate scope, or a high reaction temperature (1208C), at
limited sub-
[58]
[59]
entry 7). This new mild and efficient synthetic route to Am-
phenidone is noteworthy compared with its previous prepa-
ration, which was carried out under traditional Goldberg
conditions (heating at 1808C in refluxing 1,2-dichloroben-
which malonate esters tend to decompose. Only recently
was a variant of this transformation performed under mild
conditions, in the presence of simultaneously catalytic
copper and a weak base, allowing high functional-group tol-
erance. Buchwald et al. employed CuI as a precatalyst and
2-phenylphenol as ligand to mediate the C-arylation of di-
ethyl malonate with aryl iodides in the presence of cesium
[51]
zene).
We next attempted to subject oxazolidin-2-one to aryla-
tion with iodobenzene. N-Aryloxazolidin-2-ones constitute
an important class of therapeutic agents; this is illustrated
[8]
carbonate at 708C. However, this method suffers from a
few drawbacks. The nature of the ligand 2-phenylphenol is
problematic, since O-arylation of this compound competes
with C-arylation of the substrate in a few cases. Yields are
also diminished by hydrolysis followed by decarboxylation
of the coupling products, affording ethyl a-arylacetates as
side products (up to 10%). Keeping these limitations in
mind, we decided to devise new conditions allowing efficient
Ullmann-type arylation of three malonic derivatives bearing
an activated methylene group, diethyl malonate, ethyl cya-
noacetate, and malononitrile, without preparation of the
anions prior to coupling.
[2]
by the drugs Linezolid (Zyvox) and (R)-Toloxatone (Hu-
[3]
moryl), with antibiotic and antidepressant activity, respec-
tively. N-Aryloxazolidin-2-ones are also precursors to vic-ar-
[
52]
ylaminoalcohols,
another template in medicinal chemis-
[
53]
try. The reaction catalyzed by Cu O/1c was quantitative
2
in DMF in less than 24 h at 828C, provided that molecular
sieves were used and the amount of Cs CO was reduced to
2
3
1.6 equiv (entry 12). The GC yield was still excellent without
molecular sieves and with two equivalents of base (7i: 94%,
entry 11), albeit slightly lowered by Cs CO -promoted hy-
2
3
[52]
drolysis of the coupling product to 2-anilinoethanol. Con-
densations proved to be more troublesome and sluggish in
acetonitrile or when using Salox (1i) as supporting ligand
Our initial exploration of reaction conditions focused on
the coupling of diethyl malonate (2 equiv) with iodobenzene
(1equiv). The results are compiled in Table 6. Chxn-Py-Al
1c was preferred to Salox 1i as a ligand, since previous
work in our laboratory has shown that the latter, due to its
nucleophilic nature, was not fully unreactive toward base-
(
entries 8–10). We suspect that Salox or the Salox anion are
not to be fully unreactive toward oxazolidin-2-one moieties
and to contribute a few percent to their decomposition.
Moreover, it is believed that deprotonations of Salox and
[21]
oxazolidin-2-one produce some CsHCO , which thermally
sensitive functional groups.
The beneficial use of 1c in
3
decomposes into cesium hydroxide, as mentioned earlier.
This species might also be responsible for the observed de-
composition. Condensations can also be carried out in a
quantitative fashion at 508C, if reaction time is not an issue
this case probably arose from its aprotic nature and chemi-
cal inertness toward ester moieties. Cuprous iodide as a pre-
catalyst afforded an excellent yield (95%) of cross-coupling
product 11a in THF or acetonitrile at 708C, using Cs CO as
2
3
(
entry 13). Lastly, N-arylation of 2H-pyridazin-3-one was
a base, and proved to be more efficient than cuprous oxide
(Table 6, entries 1–3). Ethyl a-phenylacetate (11b) was also
obtained with 3–4% GC yield through decarboxylation of
the product. Since water or cesium hydroxide generated
performed in 89% yield (entry 14); reactions employing
Salox and acetonitrile were somewhat faster than those with
Chxn-Py-Al and DMF. To the best of our knowledge, this is
the first time an Ullmann-type N-arylation of pyridazin-2-
one has been described. This provides a new protocol to
synthesize a class of compounds with reported herbicide, in-
from CsHCO [Eq. (1)] probably contribute to decomposi-
3
tion through ester hydrolysis, water removal could deliver
an even cleaner condensation. Indeed, we found that addi-
tion of small amounts of finely ground and activated 3 Š
molecular sieves almost completely inhibited this side reac-
tion (<0.5%), while leading to only a slight decrease in the
reaction rate. In the presence of this additive, acetonitrile
was superior to THF as solvent (entries 4,5). Quantitative
consumption of iodobenzene was attained by employing a
slightly longer reaction time, which provided diethyl a-phe-
nylmalonate (11a) in 93% isolated yield (entry 6). It is im-
portant to note that no iodobenzene was consumed by reac-
tion with 1c, contrary to the literature with 2-phenylphenol
[54]
[55]
secticide, or anti-inflammatory activity.
Copper-catalyzed C-arylation of malonic acid derivatives:
The synthesis of a-arylated malonic acid derivatives contin-
ues to attract much attention, as they represent useful pre-
cursors to two commercially important classes of nonsteroi-
dal anti-inflammatory drugs, a-arylacetic acids (Diclofenac,
Indomethacin, etc.) and a-arylpropionic acids (Ibuprofen,
Naproxen, Flurbiprofen, etc.). They are also used in mate-
rial sciences, as precursors to electron-acceptors of the
7
[4]
[56]
[8]
,7,8,8-tetracyano-p-quinodimethane (TCNQ) class. Hurt-
as ligand. Although 11a is more acidic than diethylmalo-
ley discovered in 1929 that C-arylation of several families of
stabilized carbanions, including malonic acid derivatives,
nate, no diarylated byproduct arising from phenylation of
11a was formed under our conditions. We also observed
5614
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Chem. Eur. J. 2004, 10, 5607 – 5622

Copper Catalysts
5607 – 5622
[
a]
Table 6. Copper-catalyzed C-arylation of malonic acid derivatives with iodobenzene under mild conditions.
Entry
Cu
Cu
CuI
CuI
CuI
CuI
CuI
Nucleophile
Coupling
product
T
[8C]
t
Additive
Solvent
Yield
[%]
[
b]
[h]
1
2
3
4
5
6
2
O
24
24
24
24
24
30
–
–
–
THF
THF
MeCN
THF
MeCN
MeCN
11a: 59/11b: 3
11a: 95/11b: 4
11a: 95/11b: 3
11a: 88
11a: 95
1
1b
70
[
c]
MS 3 Š
MS 3 Š
MS 3 Š
[
c]
[c]
11a: 98 (93)
7
8
9
CuI
CuI
CuI
11c
11d
11e
70
70
50
24
28
72
MS 3 Š
MS 3 Š
–
MeCN
MeCN
MeCN
<1
98 (92)
[d]
69 (62)
[
a] Reaction conditions: nucleophile (4 mmol), PhI (2 mmol), Cs
needed), solvent (1.2 mL), under N . [b] Yields refer to GC yields and yields in parentheses refer to isolated yields with >95% purity as determined by
GC and H NMR spectroscopy. [c] GC yield in 1b was <0.5%. [d] Conversion of PhI was 88% and GC yield of benzene was 15%.
2 3
CO (3 mmol), Cu (10 mol%), ligand 1c (20 mol%), 3 Š molecular sieves (600 mg, if
2
1
that a reversal of the stoichiometry of the reaction, that
means using a twofold excess of iodobenzene relative to di-
ethyl malonate, was detrimental to the yield, which de-
creased to about 70%.
of iodobenzene. We found that reducing temperature to
508C had a beneficial impact on selectivity in favor of the
desired reaction and that the use of molecular sieves was
unnecessary. Condensation proceeded to 88% conversion of
iodobenzene within 72 h at this relatively low temperature.
Compound 11e was obtained with 79% selectivity and was
isolated in decent yield (62%, entry 9). This yield is note-
With optimized conditions in hand, the scope of this cata-
lytic process was examined with various malonic derivatives,
and the results are summarized in Table 6. Diethyl 2-methyl-
malonate did not participate in the copper-catalyzed aryla-
tion process under conditions permitting a quantitative ary-
lation of the unsubstituted parent compound (entry 7). It is
unclear whether this lack of reactivity arises because of
steric hindrance or is due to decreased acidity of the sub-
[59]
worthy compared with the 55% reported by Miura
for
the same coupling performed at 1208C without additional
ligand, and with the 42–61% yields obtained using stoichio-
[56a,57g–57h]
metric amounts of copper salts.
Malononitrile is
prone to decomposition under our coupling conditions,
which leads to formation of benzonitrile in small amounts,
from cyanide ion arylation (4%). Such a side reaction has
already been observed in the literature in the course of a
[
60]
strate (pKHA =18.7 in DMSO)
nate (pKHA =16.4 in DMSO).
relative to diethyl malo-
Poor results were also ob-
[
37a]
tained in the literature for that kind of coupling using cop-
[
57i,58b]
[5e]
[57e]
per
or palladium catalysts. In fact, catalytic intermo-
copper-catalyzed dicyanomethyl anion arylation.
lecular arylation of 2-alkyl-substituted diethylmalonates
with aryl halides was only reported to be successful under
Thus, the three targeted malonic acid derivatives have
been monoarylated with iodobenzene under mild conditions
(50–708C, 62–93% yield), by using the same catalytic
system, CuI/1c. The experimental conditions employed have
no equivalent in the literature from the standpoint of cost
and performance with regard to ethyl cyanoacetate aryla-
tion.
[61]
Hurtleyꢀs conditions.
However, diethyl 2-methyl-2-aryl-
malonates, precursors to profen drugs, could be accessed
easily by sequential one-pot arylation and alkylation of di-
[5e]
ethyl malonate. Arylation of ethyl cyanoacetate with io-
dobenzene proceeded in a chemoselective fashion and 11d
was isolated in a remarkable 92% yield (entry 8). The reac-
tion time required was similar to that of diethyl malonate.
Again, molecular sieves reduced the extent of decarboxyla-
tion to less than 0.5% and diarylation was not observed.
Careful choice of reaction conditions proved of value in
the synthesis of 2-phenylmalononitrile (11e), the formation
of which is significantly hampered by hydrodehalogenation
Mechanism of the copper-catalyzed nucleophilic aromatic
substitution with aryl halides: The results we obtained pro-
vided valuable information with respect to the mechanism
[62]
of the reaction. Uncatalyzed pathways, such as S Ar
or
(thermal or photochemical) could be discarded,
since control experiments involving either bromobenzene or
N
[63]
SRN1
Chem. Eur. J. 2004, 10, 5607 – 5622
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5615

M. Taillefer, H.-J. Cristau et al.
FULL PAPER
iodobenzene conducted without the copper source did not
allow the cross-coupling products to be formed. Elimina-
[62]
tion–addition via aryne intermediates was also ruled out
considering the regioselectivity of the reaction with respect
to substituted aryl halides. As a consequence, arylations de-
scribed in this article proceed according to a copper-cata-
lyzed pathway. Among the classes of mechanisms that have
[7c]
been proposed in the literature
for such Ullmann-type
condensations, two conceivable ones are those involving 1)
radical intermediates and 2) oxidative addition/reductive
elimination.
Intervention of radicals or radical anions is contradicted
by several experiments that we have carried out. Nucleo-
philic aromatic substitutions were inhibited neither by elec-
tron-acceptors (nitroarenes) nor by radical scavengers such
Scheme 4. Expected behavior of 1,4-diodobenzene if mechanism would
involve radical anion intermediates.
[64]
as THF or BHT. Supplementary evidence excluding the
participation of radical anion intermediates under our reac-
tion conditions was obtained by using a classical diagnostic
technique, the study of the behavior of a dihalobenzene and
its substitution products during a nucleophilic substitution
reaction. Pyrazole was chosen as the model nucleophile
for that experiment. We observed that coupling of 1,4-diio-
dobenzene (12) to excess pyrazole initially gave rise to mon-
osubstituted product 13, which underwent subsequent sub-
stitution to afford 14 (Scheme 3). Mechanisms involving for-
The intervention of the oxidative addition/reductive elimi-
nation mechanism in Ullmann condensations was first pro-
[68]
posed by Cohen in 1974. This mechanism was next sub-
[
64,66b,69]
I
stantiated by several literature reports
indicating Cu
[65]
III
and Cu intermediates. It appears to be a possible explana-
tion for the Ullmann condensations described here, since it
[21]
accommodates the following experimental facts: 1) the re-
activity sequence in such processes (ArI>ArBr@ArCl) par-
allels the leaving-group ability of the halide ions, 2) cou-
plings are slightly favored by electron-withdrawing groups
on aryl halides and slightly disfavored by electron-releasing
ones, 3) steric hindrance on either coupling partner is rate-
depressing, and 4) unactivated aryl halides do not react in
the absence of the copper catalyst. A copper(i)-catalyzed
nucleophilic substitution mechanism would thus parallel that
of the corresponding palladium(0) and nickel(0) reactions;
this would not be surprising, since copper(i) is a d10 transi-
tion metal, isoelectronic to the two aforementioned species.
This mechanism involves the three following elementary
steps: oxidative addition of the aryl halide to copper(i) gen-
Scheme 3. Test for intermediacy of radical anion intermediates in Ull-
mann-type condensations.
III
erating a transient Cu species, nucleophilic substitution of
copper-bound halide by pyrazole anion, and reductive elimi-
nation of the coupling product, thereby regenerating the
active catalyst. Although we have assumed that copper com-
plexes are monomeric and undergo oxidative addition to a
single metal center, a dinuclear oxidative addition process
could also occur. Uncertainty remains as to whether nucleo-
philic substitution step precedes or follows the oxidative ad-
dition step. Both possibilities are depicted on Scheme 5.
A possible role played by the additional ligands in the
present Ullmann condensation is to promote oxidative addi-
mation of radical anion intermediates would lead to the di-
substitution product 14 without significant intermediacy of
[66]
monosubstitution product 13. According to the literature,
the aforementioned processes lead to quasi-exclusive disub-
stitution, even at short reaction times, because radical anion
1
5, generated by reaction of the nucleophile with halo-aryl
radical 16, does not undergo bimolecular electron transfer
to copper(ii) or 1,4-diiodobenzene) to give monosubstitu-
(
tion product 13, but instead loses the second iodide ion to
form aryl radical 17. This unimolecular pathway is indeed
much faster (Scheme 4). Additionally, a radical pathway
would not have led to a ratio of E/Z=99:1for the configu-
ration of the double-bond geometry in the 1-styrylpyrazole
that we have recently synthesized through alkenylation of
[21]
pyrazole with b-bromostyrene using the present method.
Since vinyl radicals are known to undergo rapid inversion of
[67]
configuration, a substantial loss of stereochemistry would
have been observed. This result seems to rule out interven-
tion of radicals, even briefly, free, or tightly held in a solvent
cage or in the form of undissociated complex with cop-
Scheme 5. The two alternative oxidative addition/reductive elimination
mechanistic pathways for copper-catalyzed nucleophilic aromatic substi-
tutions with aryl halides.
[
18,66b]
per.
5616
ꢁ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
Chem. Eur. J. 2004, 10, 5607 – 5622

Copper Catalysts
5607 – 5622
I
tion to the Cu complex. Indeed, oxidative addition of cupr-
process, reported by Buchwald and co-workers, using 1,2-di-
[73]
ous halides to aryl halides would be a reversible process ac-
cording to the literature.
catalyzed halogen exchange in aryl halides is a further indi-
cation of this reversibility,
tion is equivalent to reductive elimination of aryl halide
from Cu . Our best ligands are hard donor ligands
Lewis bases with nitrogen or oxygen binding sites), which
amines as ligands. Compared to other Ullmann-type nu-
cleophilic aromatic substitution methods described in the lit-
erature, the present one is unique in terms of versatility,
since a single catalyst, generated from ligand 1c, can be
used for the first time in CÀN, CÀO, and CÀC bond-forming
[64]
The well-documented copper-
[64,70]
seeing that the reverse reac-
III
reactions. The attractiveness of this general and reliable syn-
thetic tool is further enhanced by its absence of reactivity
toward aryl halides. This is an advantage over some of the li-
gands recently reported by others for analogous copper-cat-
(
display a higher affinity toward hard copper(iii) than soft
[
31b,71]
copper(i).
Due to their suitable s-donor and p-acceptor
[8,20b,24,44a,48,73,74]
properties, as well as their chelating nature, they might ex-
hibit a superior ability to stabilize the oxidative addition
product 20, thus shifting to the right the position of the equi-
librium in Scheme 6.
alyzed reactions.
Mildness, low-cost, experi-
mental simplicity, and the ability to work at low catalyst
loading are features of our methodology that make it partic-
ularly well suited for industrial-scale syntheses, for which fi-
nancial and environmental issues are of greater concern.
[75]
Consequently, it should find applications very soon.
Ef-
forts to expand the utility of our new catalyst systems to
other cross-coupling and related reactions, along with mech-
anistic studies, are in progress in our laboratory and will be
reported in due course.
Experimental Section
III
General: Flash column chromatography was performed with SDS
Scheme 6. Hypothesis of stabilization of the Cu oxidative addition
6
0 ACC silica gel (35–70 mm or 70–200 mm). Thin-layer chromatography
product by the use of an appropriate supporting ligand L.
was carried out with Merck silica gel 60F254 plates. All products were
1
13
characterized by H NMR and C NMR spectroscopy and GC/MS. IR
spectra were recorded on a Nicolet 210 FT-IR instrument (neat or thin
film for liquid products, and KBr pellets or in dichloromethane for solid
Conclusion
1
13
1
products). H NMR and C{ H} NMR spectra were recorded at room
temperature on a Bruker AC 200 MHz or a Bruker Avance 250 MHz in-
strument with chemical shifts reported in ppm relative to the residual
In conclusion, we have shown that the catalytic systems we
have recently described for Ullmann-type arylation of pyra-
zoles and phenols offer a straightforward entryway into a
variety of other copper-catalyzed reactions. Catalysts gener-
ated from catalytic cuprous oxide or iodide and a catalytic
amount of a multidentate donor compound 1, combining
oxygen- and/or nitrogen-binding sites, such as potentially bi-
dentate oxime ligand Salox 1i, hydrazone ligand 1d or po-
tentially tetradentate Schiff base ligand 1c, allowed the
high-yielding arylation of a broad spectrum of nitrogen and
carbon nucleophiles at relatively low temperatures (50–
1
9
1
deuterated solvent peak. F{ H} NMR spectra were recorded at room
temperature on a Bruker Avance 250 MHz instrument with chemical
3
shifts reported in ppm relative to CFCl . The peak patterns are indicated
as s, singlet; d, doublet; t, triplet; q, quadruplet; dd, doublet of doublets;
m, multiplet. Gas chromatographic analysis were performed on a Delsi
Nermag DI-200 instrument with an FID detector, a Delsi Nermag Enica
3
1integrator and a SGE BPX5 25 m”0.53 mm semicapillary apolar
column (stationary phase: 5% phenylpolysil-phenylenesiloxane film,
mm). Gas chromatography/mass spectra (GC/MS) were recorded on an
1
Agilent Technologies 6890 N instrument with an Agilent 5973 N mass de-
tector (EI) and a HP5-MS 30 m”0.25 mm capillary apolar column (sta-
tionary phase: 5% diphenyldimethylpolysiloxane film, 0.25 mm). GC and
8
28C), in acetonitrile or DMF, in the presence of the mild
GC/MS method: initial temperature: 508C; initial time: 3 min; ramp:
base cesium carbonate. A variety of substituted aryl bro-
mides and iodides were readily coupled with a number of
azoles (with the exception of tetrazoles), amides, carba-
mates, pyridazin-2-one, diethyl malonate, ethyl cyanoace-
tate, and malononitrile. The experimental conditions descri-
bed in this work represent a new landmark in the field of
Ullmann-type arylation of imidazole, 1,2,4-triazole, pyrrole,
and ethyl cyanoacetate. Our conditions proved to be just as
À1
1
08Cmin ; final temperature: 2508C; final time: 10 min. FAB+ mass
spectra were recorded on a JEOL JMS-DX300 spectrometer (3 Kev,
xenon) in a m-nitrobenzylalcohol (NBA) matrix. Melting points were de-
termined using a Büchi B-540 apparatus and are uncorrected.
Materials: All reactions were carried out under a pure and dry nitrogen
atmosphere with standard Schlenk techniques. All solvents were distilled
and stored under a nitrogen atmosphere. Acetonitrile was distilled from
[76]
2 5
P O and stored on 3 Š activated molecular sieves. DMF was distilled
under vacuum from MgSO
vated molecular sieves. All solid materials were stored in the presence of
in a bench-top desiccator under vacuum at room temperature and
weighed in the air. Of special note is that Cs CO (Aldrich) was ground
to a fine powder prior to drying. Copper(i) iodide was purified according
4
and stored protected from light on 4 Š acti-
[44a]
efficient as those already reported for indole,
diethyl
[8]
[59]
2 5
P O
malonate, and malononitrile
arylation. With regard to
amides and carbamates, our catalytic systems were particu-
larly efficient for condensations with oxazolidin-2-one and
pyridin-2-one. The synthetic use of the method was dem-
onstrated by an efficient preparation of the sedative Am-
phenidone. Reactions were somewhat slower with sulfona-
mides and other carboxylic amides investigated. Their scope
did not exceed that of the best Ullmann–Goldberg-type
2
3
[
77]
to a reported procedure
and stored protected from light. Copper(i)
[72]
oxide was used without further purification. Ligands 1a,b,e–h were syn-
[
21]
thesized as we have previously reported.
Ligands 1d,i–l were pur-
chased from commercial sources. Salicylaldoxime (1i) was recrystallized
in petroleum ether before use. The synthesis of ligand Chxn-Py-Al (1c) is
described below. All aryl halides and nucleophiles were purchased from
commercial sources (Aldrich, Acros, Avocado, Fluka, Lancaster). If
Chem. Eur. J. 2004, 10, 5607 – 5622
www.chemeurj.org
ꢁ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
5617

M. Taillefer, H.-J. Cristau et al.
FULL PAPER
[
78]
2
3
solids, they were recrystallized in an appropriate solvent.
If liquids,
129.5 (q,
J
J
CF =33.2 Hz, C
q
), 127.2 (q,
J
CF =3.8 Hz, 2 CH), 123.6 (q,
1
19
1
they were distilled under vacuum and stored under an atmosphere of ni-
trogen. Pyrrole was distilled immediately before use. Special care was
taken with aryl iodides: liquid samples were regularly distilled over
copper powder to remove iodine and stored protected from light. Solid
samples were stored protected from light. Molecular sieves were activat-
CF =272.1Hz, CF
3
), 121.3 (2CH), 118.3 ppm (CH); F{ H} NMR
(235 MHz, CDCl ): d=À62.9 ppm (s); GC/MS (EI): t =14.82 min; m/z:
3
R
212; R =0.20 (CH Cl ).
f
2
2
1
-(4-Methoxyphenyl)-1H-imidazole (3c): Following the general proce-
dure (508C, 24 h), imidazole (136 mg, 2 mmol) was coupled with 4-iodoa-
nisole (608 mg, 2.6 mmol) by using Cu O (14.4 mg, 0.1 mmol), ligand 1d
54 mg, 0.4 mmol), cesium carbonate (1.303 g, 4 mmol), and acetonitrile
1.2 mL). The crude residue was purified by flash chromatography on
Cl /AcOEt 100:0 to 50:50) to provide 338 mg
97% yield) of the desired product as a pale brown solid. M.p. 60–618C
ed and stored under vacuum at 1008C in the presence of P
2
O
5
. Formation
2
[
79]
of the two byproducts N,N-diphenylbenzamide and N,N-diphenylben-
(
(
[
80]
zenesulfonamide
was determined by GC by coaddition of authentic
samples, synthesized under Schotten–Baumann conditions according to
or by adapting reported procedures. GC yield of compound 3 f (Table 2)
was determined by obtaining the correction factor by using an authentic
silica gel (gradient CH
2
2
(
(
(
[82]
1
Lit.: 61–638C); H NMR (200 MHz, CDCl
m, 2H), 7.18 (m, 2H), 6.96 (m, 2H), 3.82 ppm (s, 3H); C{ H} NMR
3
): d=7.75 (brs, 1H), 7.28
[
21]
sample that we had previously synthesized.
13
1
General procedure for the N- or C-arylation of nucleophiles: After stan-
dard cycles of evacuation and back-fill with dry and pure nitrogen, an
oven-dried Schlenk tube equipped with a magnetic stir bar was charged
3 q q
(50 MHz, CDCl ): d=158.9 (C ), 135.8 (CH), 130.6 (C ), 130.0 (CH),
123.1 (2CH), 118.8 (CH), 114.9 (2CH), 55.6 ppm (CH ); GC/MS (EI):
3
t =17.96 min; m/z: 174; R =0.27 (CH Cl /AcOEt 1:1).
R
f
2
2
with Cu
(
(
2
O (0.1 mmol, 10 mol%) or CuI (0.2 mmol, 10 mol%), ligand 1
0.4 mmol, 20 mol%), the nucleophile (2 mmol), if a solid, Cs CO
4.0 mmol), and the aryl halide (3.0 mmol), if a solid. The tube was evac-
1
(
-(4-Bromophenyl)-1H-imidazole (3d): Following the general procedure
508C, 36 h), imidazole (136 mg, 2 mmol) was coupled with 4-bromoiodo-
benzene (566 mg, 2 mmol) by using Cu O (14.4 mg, 0.1 mmol), ligand 1i
55 mg, 0.4 mmol), cesium carbonate (1.303 g, 4 mmol), and acetonitrile
1.2 mL). The crude residue was purified by flash chromatography on
Cl 1:1) to provide 397 mg (89% yield) of the de-
sired product as a colorless solid. Colorless crystals were obtained follow-
ing recrystallization in aqueous ethanol. M.p. 120–1218C (EtOH/H O)
]DMSO): d=8.27 (brs,
H), 7.74 (t, J=1.3 Hz, J=1.3 Hz, 1H), 7.54–7.70 (m, 4H), 7.12 ppm
2
3
2
uated, back-filled with nitrogen and capped with a rubber septum. If liq-
uids, the nucleophile and the aryl halide were added under a stream of
nitrogen by syringe at room temperature, followed by anhydrous and de-
gassed acetonitrile or DMF (1.2 mL). The septum was removed; the tube
was sealed under a positive pressure of nitrogen and stirred in an oil bath
(
(
silica gel (AcOEt/CH
2
2
2
(
preheated to the required temperature), for the required time period.
[82]
1
(
Lit.:
119–1208C); H NMR (200 MHz, [D
6
The reactions were generally carried out for 24 h for convenience, but do
not necessarily require such extended reaction time. The reaction mixture
was allowed to cool to room temperature, diluted with dichloromethane
and filtered through a plug of Celite, the filter cake being further washed
with dichloromethane (~20 mL). The filtrate was concentrated in vacuo
to yield a residue that was dissolved in dichloromethane (50 mL). The re-
sulting organic layer was washed sequentially with water (2”20 mL) and
3
4
1
13
1
(
(
(
m, 1H); C{ H} NMR (50 MHz, [D
CH), 132.5 (2CH), 130.0 (CH), 122.2 (2CH), 119.2 (C
CH); GC/MS (EI): t =18.35 min; m/z: 222, 224; R =0.30 (AcOEt).
-(2-Tolyl)-1H-imidazole (3e): Following the general procedure (828C,
6 h), imidazole (204 mg, 3 mmol) was coupled with 2-iodotoluene
O (14.4 mg, 0.1 mmol), ligand 1i (55 mg,
.4 mmol), cesium carbonate (1.303 g, 4 mmol), and acetonitrile (1.2 mL).
6
]DMSO): d=136.1 (C
q
), 135.5
q
), 117.8 ppm
R
f
1
3
(
255 mL, 2 mmol) by using Cu
2
4
brine (2”20 mL), and then dried over MgSO . The solvent was removed
0
in vacuo to yield the crude product, which was purified by flash column
chromatography on silica gel. In a few cases (pointed out below), the ex-
traction sequence was skipped and the crude residue was directly adsor-
bed onto silica gel.
The crude yellow oil was purified by flash chromatography on silica gel
gradient AcOEt/CH Cl 0:100 to 25:75) to provide 291 mg (92% yield)
of the desired product as a yellow oil. H NMR (200 MHz, CDCl =
(
2
2
1
[83]
3
): d
.57 (brs, 1H), 7.27–7.34 (m, 2H), 7.21–7.25 (m, 2H), 7.19 (brs, 1H),
7
7
1
1
1
General procedure for reactivity comparisons or screening of reaction
conditions: The above procedure was applied on a 0.5 mmol scale instead
of a 2 mmol scale. After heating for the required time period, the reac-
tion mixture was allowed to cool to room temperature and was diluted
with dichloromethane (5 mL). 1,3-Dimethoxybenzene (65 mL, internal
standard) was added. A small sample of the reaction mixture was taken
and filtered through a plug of Celite, the filter cake being further washed
with dichloromethane. The filtrate was washed three times with water
and analyzed by gas chromatography. The GC yields were determined by
obtaining the correction factors using authentic samples of the expected
products.
1
3
1
.04 (brs, 1H), 2.17 ppm (s, 3H); C{ H} NMR (50 MHz, CDCl
37.5 (CH), 136.6 (C ), 133.8 (C ), 131.3 (CH), 129.4 (CH), 128.8 (CH),
26.9 (CH), 126.5 (CH), 120.5 (CH), 17.6 ppm (CH ); GC/MS (EI): t
4.99 min; m/z: 158; R =0.23 (AcOEt/CH Cl 1:1).
-[4-(1H-Imidazol-1-yl)phenyl]-1H-imidazole (3g): Following the general
3
): d=
q
q
3
R
=
f
2
2
1
procedure (828C, 48 h), imidazole (340 mg, 5 mmol) was coupled with
,4-diiodobenzene (660 mg, 2 mmol) by using Cu O (14.4 mg, 0.1 mmol),
1
2
ligand 1i (55 mg, 0.4 mmol), cesium carbonate (1.95 g, 6.0 mmol), and
acetonitrile (1.2 mL). The extraction sequence was skipped and the crude
yellow solid was directly purified by flash chromatography on silica gel
(
gradient diethyl ether/MeOH 100:0 to 90:10) to provide 378 mg (90%
1
-Phenyl-1H-imidazole (3a): Following the general procedure (828C,
[
84]
yield) of the desired product as a colorless solid. M.p. 216–2178C (Lit.:
1
00 h), imidazole (204 mg, 3 mmol) was coupled with bromobenzene
1
2
02–2048C); H NMR (200 MHz, [D
6
]DMSO): d=8.34 (s, 1H), 7.82 (m,
]DMSO): d=135.5
), 121.4 (CH), 120.0 (2CH), 118.0 ppm (CH); GC/MS
=23.90 min; m/z: 21 0;R =0.23 (AcOEt/MeOH 9:1).
(
211 mL, 2 mmol) by using Cu
2
O (14.4 mg, 0.1 mmol), ligand 1d (54 mg,
1
3
1
3
H), 7.14 ppm (s, 1H); C{ H} NMR (50 MHz, [D
6
0
.4 mmol), cesium carbonate (1.303 g, 4 mmol), and acetonitrile (1.2 mL).
(
(
CH), 135.3 (C
EI): t
q
The crude yellow oil was purified by flash chromatography on silica gel
gradient CH Cl /AcOEt 100:0 to 50:50) to provide 274 mg (95% yield)
of the desired product as a pale yellow oil. H NMR (200 MHz, CDCl
R
f
(
2
2
1
):
=7.84 (dd, J=1.3 Hz, J=1.0 Hz, 1H), 7.43–7.53 (m, 2H), 7.32–7.41
1-Phenyl-1H-pyrrole (6a): Following the general procedure (828C, 24 h),
freshly distilled pyrrole (208 mL, 2 mmol) was coupled with iodobenzene
(269 mL, 2.4 mmol) by using Cu O (14.4 mg, 0.1 mmol), ligand 1i (55 mg,
2
0.4 mmol), cesium carbonate (1.303 g, 4 mmol), and acetonitrile (1.2 mL).
The crude residue was purified by flash chromatography on silica gel
(hexanes) to provide 269 mg (94% yield) of the desired product as a pale
3
[
81]
4
4
d
3
4
3
(
m, 3H), 7.28 (t, J=1.3 Hz, J=1.3 Hz, 1H), 7.19 ppm (dd, J=1.3 Hz,
4
13
1
J=1.0 Hz, 1H); C{ H} NMR (50 MHz, [D
1
1
6
]Acetone): d=138.5 (C
36.4 (CH), 131.2 (CH), 130.8 (2CH), 127.9 (CH), 121.7 (2CH),
2
18.8 ppm (CH); GC/MS (EI): t =14.76 min; m/z: 144; Rf=0.17 (CH Cl /
q
),
R
2
[
85]
1
AcOEt 1:1).
-(4-Trifluoromethylphenyl)-1H-imidazole (3b): Following the general
procedure (828C, 72 h), imidazole (1.02 g, 15 mmol) was coupled with 4-
bromotrifluoromethylbenzene (1.40 mL, 10 mmol) by using Cu O (72 mg,
.5 mmol), ligand 1d (272 mg, 2 mmol), cesium carbonate (5.86 g,
8 mmol), and acetonitrile (6 mL). The crude residue was purified by
Cl 100:0 to
:100) to provide 1.99 g (94% yield) of the desired product as a pale
brown solid. M.p. 628C (Lit.: 628C); H NMR (200 MHz, CDCl
3
): d=
7
.50–7.60 (m, 4H), 7.38 (m, 1H), 7.26 (m, 2H), 6.54 ppm (m, 2H);
1
1
3
1
[86]
C{ H} NMR (50 MHz, CDCl
3 q
): d =141.0 (C ), 129.7 (2CH), 125.7
(
CH), 120.6 (2CH), 119.4 (2CH),
2
1
10.7 ppm (2CH); GC/MS (EI): t
R
=
0
1
1
2.75 min; m/z: 143; =0.33 (hex-
R
f
anes).
flash chromatography on silica gel (gradient hexanes/CH
2
2
0
1-Phenyl-1H-indole (6b): Following
the general procedure (828C, 24 h),
indole (351mg, 3 mmol) was coupled
with iodobenzene (224 mL, 2 mmol) by
1
3
yellow solid. M.p. 708C; H NMR (200 MHz, CDCl ): d=7.90 (brs, 1H),
7
.72 (m, 2H), 7.49 (m, 2H), 7.31 (brs, 1H), 7.22 ppm (s, 1H);
C{ H} NMR (50 MHz, CDCl
1
3
1
3
): d=140.0 (C
q
), 135.5 (CH), 131.2 (CH),
5618
ꢁ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
Chem. Eur. J. 2004, 10, 5607 – 5622

Copper Catalysts
5607 – 5622
using Cu
2
O (14.4 mg, 0.1 mmol), ligand 1c (117 mg, 0.4 mmol), cesium
121.6 ppm (2CH); GC/MS (EI):
(CH Cl ).
R f
t =21.54 min; m/z: 233; R =0.36
carbonate (1.303 g, 4 mmol), and acetonitrile (1.2 mL). The crude red oil
was purified by flash chromatography on silica gel (gradient hexanes/
2
2
1
4
-Phenylpyrrolidin-2-one (7e): Following the general procedure (828C,
0 h), pyrrolidin-2-one (152 mL, 2 mmol) was coupled with iodobenzene
CH
2 2
Cl 100:0 to 50:50) to provide 355 mg (92% yield) of the desired
1
product as a green-yellow oil. H NMR (200 MHz, CDCl
3
): d=7.74–7.80
m, 1H; H5), 7.62–7.68 (m, 1H; H8), 7.51–7.58 (m, 4H; H10–13), 7.34–
(
2
336 mL, 3 mmol) by using Cu O (14.4 mg, 0.1 mmol), ligand 1c (117 mg,
(
0
3
.4 mmol), cesium carbonate (1.303 g, 4 mmol), activated and powdered
Š molecular sieves (600 mg), and DMF (1.2 mL). The crude residue
3
7
.47 (m, 1H; H14), 7.40 (d, J=3.3 Hz, 1H; H2), 7.20–7.33 (m, 2H;
3
5
H6,7), 6.76 ppm (dd, J(H3,H2)=3.3 Hz, J(H3,H8)=0.9 Hz, 1H; H3);
was purified by flash chromatography on silica gel (gradient hexanes/
CH Cl /AcOEt 50:50:0 to 0:100:0, then 0:100:0 to 0:95:5) to provide
97 mg (92% yield) of the desired product as a colorless solid. Alterna-
1
3
1
assignment was based on
a
COSY H-H experiment; C{ H} NMR
): d =139.9 (C1), 135.9 (C9), 129.7 (C10,11), 129.4
C4), 128.0 (C2), 126.5 (C14), 124.4 (2CH), 122.4 (C7), 121.2 (C5), 120.4
C6), 110.6 (C8), 103.7 ppm (C3); GC/MS (EI): t =19.08 min; m/z: 193;
=0.23 (hexanes).
2
2
[
86]
(
(
(
50 MHz, CDCl
3
2
tively, the crude residue can be purified by recrystallisation in ethanol in-
stead of flash column chromatography, to provide 265 mg (82% yield) of
R
R
f
[12f]
the desired product as an off-white solid. M.p. 69–708C (EtOH) (Lit.:
1
1
-Phenyl-1H-[1,2,4]triazole (6c): Following the general procedure (828C,
708C, diisopropyl ether); H NMR (200 MHz, CDCl
3
): d=7.58–7.63 (m,
4
8 h), 1,2,4-triazole (138 mg, 2 mmol) was coupled with iodobenzene
2H), 7.32–7.40 (m, 2H), 7.13–7.18 (m, 1H), 3.87 (m, 2H), 2.61 (m, 2H),
1
3
1
(
336 mL, 3 mmol) by using Cu
2
O (14.4 mg, 0.1 mmol), ligand 1c (117 mg,
2.08–2.23 ppm (m, 2H); C{ H} NMR (50 MHz, CDCl
139.4 (C ), 128.8 (2CH), 124.5 (CH), 120.0 (2CH), 48.8 (CH
), 18.0 ppm (CH ); GC/MS (EI): t =17.38 min; m/z: 161; R
Cl /AcOEt 4:1).
3
): d=174.2 (C
), 32.8
=0.53
q
),
0
.4 mmol), cesium carbonate (1.043 g, 3.2 mmol), and DMF (1.2 mL).
q
2
The crude residue was purified by flash chromatography on silica gel
gradient hexanes/CH Cl 100:0 to 50:50) to provide 264 mg (91% yield)
of the desired product as a dark yellow solid. Pale yellow needles were
obtained following recrystallization in chloroform. M.p. 468C (CHCl
(CH
(CH
2
2
2
R
f
(
2
2
2
1
-Phenyl-1H-pyridin-2-one (7 f) and 2-phenoxypyridine (7g): Following
the general procedure (828C, 24 h), 2-hydroxypyridine (951mg,
0 mmol) was coupled with iodobenzene (1.68 mL, 15 mmol) by using
Cu O (72 mg, 0.5 mmol), ligand 1c (584 mg, 2 mmol), cesium carbonate
6.52 g, 20 mmol), activated and powdered 3 Š molecular sieves (3 g),
and acetonitrile (6 mL). The crude residue was purified by flash chroma-
tography on silica gel (gradient hexanes/CH Cl /AcOEt 100:0:0 to
0:100:0, then 0:100:0 to 0:80:20). Elution with CH Cl /AcOEt 9:1gave
34 mg (2% yield) of 7g as a yellowish oil (which can be crystallized in a
3
)
[
87]
1
(
(
(
1
R
Lit.: 46–478C). H NMR (200 MHz, CDCl
brs, 1H), 7.53–7.65 (m, 2H), 7.26–7.51ppm (m, 3H); C{ H} NMR
50 MHz, CDCl ): d=152.6 (CH), 140.9 (CH), 137.0 (C ), 129.7 (2CH),
28.2 (CH), 120.0 ppm (2CH); GC/MS (EI): t =14.02 min; m/z: 145;
=0.21(CH Cl /AcOEt 9:1).
3
): d=8.52 (brs, 1H), 8.04
1
1
3
1
2
3
q
(
R
f
2
2
2
2
N-Phenylacetamide (7a) and N,N-diphenylacetamide (7b): Following the
general procedure (828C, 75 h), acetamide (177 mg, 3 mmol) was coupled
2
2
with iodobenzene (224 mL, 2 mmol) by using Cu
2
O (14.4 mg, 0.1 mmol),
few hours if left at 08C), and elution with CH
2
Cl
2
/AcOEt 8:2 gave 1.54 g
ligand 1c (117 mg, 0.4 mmol), cesium carbonate (1.043 g, 3.2 mmol), acti-
vated and powdered 3 Š molecular sieves (600 mg), and DMF (1.2 mL).
The crude residue was purified by flash chromatography on silica gel
(90% yield) of 7 f as a yellow solid.
[12f]
1
Data for 7 f: M.p. 1278C (Lit.:
200 MHz, [D
1298C, diisopropyl ether); H NMR
(
6
]DMSO): d=7.59–7.66 (m, 1H), 7.36–7.56 (m, 6H, H),
(
gradient CH
2
Cl
2
/AcOEt 100:0 to 60:40) to provide 219 mg (81% yield)
13
1
6
.48 (m, 1H), 6.31ppm (m, 1H);
3
C{ H} NMR (50 MHz, CDCl ): d=
of 7a as a colorless solid and 15 mg (7% yield) of 7b as a colorless solid.
1
62.4 (C ), 140.97 (C ), 139.9 (CH), 138.0 (CH), 129.3 (2CH), 128.5
q
q
[
88]
1
Data for 7a: M.p. 1158C (Lit.: 1148C); H NMR (200 MHz, CDCl
3
):
(CH), 126.5 (2CH), 121.9 (CH), 105.9 ppm (CH); GC/MS (EI): t
18.11 min; m/z: 171; R =0.14 (CH Cl /AcOEt 9:1).
Data for 7g: M.p. 398C (Lit.:
CDCl ): d=8.19–8.22 (m, 1H, H), 7.63–7.73 (m, 1H, H), 7.36–7.45 (m,
H), 7.12–7.24 (m, 3H), 6.96–7.02 (m, 1H), 6.88–6.92 ppm (m, 1H);
R
=
d=8.35 (brs, 1H, NH), 7.49–7.54 (m, 2H), 7.24–7.32 (m, 2H), 7.04–7.12
f
2
2
1
3
1
[89]
(
(
m, 1H), 2.13 ppm (s, 3H); C{ H} NMR (50 MHz, CDCl
3
): d =169.2
);
[93]
1
41.5–43.58C); H NMR (200 MHz,
C
q
), 138.1 (C ), 128.9 (2CH), 124.3 (CH), 120.3 (2CH), 24.4 ppm (CH
q
3
3
GC/MS (EI): t
R
=14.06 min; m/z: 135; R
f
2 2
=0.30 (CH Cl /AcOEt 3:2).
2
[
90]
1
13
1
Data for 7b: M.p. 1028C (Lit.: 1018C); H NMR (200 MHz, CDCl
3
):
C{ H} NMR (50 MHz, CDCl
139.4 (CH), 129.7 (2CH), 124.7 (CH), 121.2 (2CH), 118.5 (CH),
111.5 ppm (CH); GC/MS (EI): =15.15 min; m/z: 171; =0.43
(CH Cl /AcOEt 9:1).
-(3-Aminophenyl)-1H-pyridin-2-one (Amphenidone, 7h): Following the
general procedure (828C, 48 h), 2-hydroxypyridine (190 mg, 2 mmol) was
coupled with 3-iodoaniline (361 mL, 3 mmol) by using Cu O (14.4 mg,
3 q q
): d=163.8 (C ), 154.2 (C ), 147.8 (CH),
1
3
1
d=7.12–7.45 (m, 10H), 2.07 ppm (s, 3H); C{ H} NMR (50 MHz,
), 143.1 (2C
2CH), 126.7 (2CH), 23.9 ppm (CH
[
89]
CDCl
3
): d =170.4 (C
q
q
), 129.4 (4 CH), 128.3 (2CH), 127.6
); GC/MS (EI): t =19.66 min; m/z:
t
R
R
f
(
3
R
2
2
2
f 2 2
11; R =0.14 (CH Cl ).
1
N-Phenylbenzamide (7c): Following the general procedure (828C, 48 h),
benzamide (363 mg, 3 mmol) was coupled with iodobenzene (224 mL,
2
2
0
3
mmol) by using Cu
.4 mmol), cesium carbonate (1.303 g, 4 mmol), activated and powdered
Š molecular sieves (600 mg), and DMF (1.2 mL). The crude residue
2
O
(14.4 mg, 0.1 mmol), ligand 1c (117 mg,
0.1mmol), ligand 1c (58 mg, 0.2 mmol), cesium carbonate (1.303 g,
4 mmol), activated and powdered 3 Š molecular sieves (600 mg), and
acetonitrile (1.2 mL). The extraction sequence was skipped and the crude
brown oil was directly purified by flash chromatography on alumina gel
was purified by flash chromatography on silica gel (gradient CH
2 2
Cl /hex-
anes 50:50 to 100:0) to provide 359 mg (91% yield) of the desired prod-
(gradient hexanes/CH
0:25:75) to provide 305 mg (82% yield) of the desired product as a color-
2 2
Cl /AcOEt 50:50:0 to 0:100:0, then 0:100:0 to
[
91]
1
uct as a colorless solid. M.p. 1648C (Lit.:
200 MHz, CDCl ): d=7.88 (brs, 1H, NH), 7.86 (m, 2H), 7.64 (m, 2H),
.32–7.58 (m, 5H), 7.15 ppm (m, 1H); C{ H} NMR (50 MHz, CDCl
d=165.8 (C ), 138.0 (C ), 135.0 (C ), 131.8 (CH), 129.1 (2CH), 128.8
2CH), 127.0 (2CH), 124.6 (CH), 120.3 ppm (2CH); GC/MS (EI): t
0.76 min; m/z: 197; R =0.45 (CH Cl ).
N-Phenylbenzenesulfonamide (7d): Following the general procedure
828C, 48 h), benzenesulfonamide (472 mg, 3 mmol) was coupled with io-
dobenzene (224 mL, 2 mmol) by using Cu O (14.4 mg, 0.1 mmol), ligand
c (117 mg, 0.4 mmol), cesium carbonate (1.043 g, 3.2 mmol), activated
and powdered 3 Š molecular sieves (600 mg), and DMF (1.6 mL). The
reaction mixture was diluted with CH Cl /MeOH (25 mL, 1:1) before
being filtered through a plug of Celite. The crude brown oil was purified
by flash chromatography on silica gel (gradient hexanes/CH Cl 9:1to
:95) to provide 411 mg (88% yield) of the desired product as a colorless
1638C, EtOH); H NMR
[
51]
1
(
7
3
less solid. M.p. 1798C (Lit.:
[D ]DMSO): d=7.43–7.56 (m, 2H), 7.11 (m, 1H), 6.60 (m, 1H), 6.41–
6.50 (m, 3H), 6.25 (m, 1H), 5.34 ppm (brs, 2H, NH
(50 MHz, [D ]DMSO): d=161.0 (C ), 149.4 (C ), 141.7 (C
139.0 (CH), 129.3 (CH), 120.4 (CH), 113.4 (2CH), 111.8 (CH), 105.1 ppm
CH); GC/MS (EI): t =22.11 min; m/z: 186; R =0.33 (AcOEt/CH Cl
:1, alumina).
182.5–184.58C); H NMR (200 MHz,
1
3
1
3
):
6
1
3
1
q
q
q
2
); C{ H} NMR
), 140.2 (CH),
(
R
=
6
q
q
q
2
f
2
2
(
R
f
2
2
4
(
2
3-Phenyloxazolidin-2-one (7i): Following the general procedure (828C,
24 h), oxazolidin-2-one (263 mg, 3 mmol) was coupled with iodobenzene
(224 mL, 2 mmol) by using Cu O (14.4 mg, 0.1 mmol), ligand 1c (117 mg,
2
0.4 mmol), cesium carbonate (1.043 g, 3.2 mmol), activated and powdered
3 Š molecular sieves (600 mg), and DMF (1.2 mL). The crude residue
was purified by flash chromatography on silica gel (gradient hexanes/
1
2
2
2
2
5
CH
product as a colorless solid. M.p. 1208C (Lit.: 120–1218C); H NMR
(200 MHz, CDCl ): d=7.48–7.53 (m, 2H), 7.30–7.38 (m, 2H), 7.07–7.15
(m, 1H), 4.40 (m, J=8.0 Hz, 2H), 3.97 ppm (m, J=8.0 Hz, 2H);
2 2
Cl 50:50 to 0:100) to provide 316 mg (97% yield) of the desired
[
92]
1
[94]
1
solid. M.p. 109–1108C (Lit.: 1108C); H NMR (200 MHz, CDCl
3
): d=
7
7
.78–7.88 (m, 2H, H), 7.79 (brs, 1H, NH), 7.35–7.50 (m, 3H), 7.07–
3
1
3
1
3
3
.25 ppm (m, 5H); C{ H} NMR (50 MHz, CDCl
3
): d=138.9 (C
q
), 136.6
1
3
1
(
C
q
), 133.1 (CH), 129.3 (2CH), 129.1 (2CH), 127.3 (2CH), 125.3 (CH),
C{ H} NMR (50 MHz, CDCl
3
): d=155.3 (C
q
), 138.3 (C
q
), 129.0 (2CH),
Chem. Eur. J. 2004, 10, 5607 – 5622
www.chemeurj.org
ꢁ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
5619

M. Taillefer, H.-J. Cristau et al.
FULL PAPER
1
1
24.0 (CH), 118.2 (2CH), 61.4 (CH
8.25 min; m/z: 163; R =0.20 (CH Cl
-Phenyl-2H-pyridazin-3-one (7j): Fol-
2
), 45.1ppm (CH
2 R
); GC/MS (EI): t =
f
2
2
/hexanes 4:1).
2
lowing the general procedure (828C,
1
2
00 h), 2H-pyridazin-3-one (192 mg,
mmol) was coupled with iodoben-
2
zene (336 mL, 3 mmol) by using Cu O
(
14.4 mg, 0.1 mmol), ligand 1i (55 mg,
0
.4 mmol), cesium carbonate (1.303 g, 4 mmol), and acetonitrile (1.6 mL).
sively added to a solution of 2-pyridylaldehyde (6.66 mL, 70.0 mmol) in
absolute EtOH (50 mL). The mixture was stirred for 20 h at room tem-
perature, heated at reflux for 2.5 h, and filtered through a frit while still
hot. The solid was discarded and the filtrate was concentrated in vacuo.
The residue was recrystallized in EtOH to provide 8.2 g (80% yield) of
the desired product as pale yellow crystals. Only the (1S,2S)-stereoisomer
The crude residue was purified by flash chromatography on silica gel
gradient hexanes/CH Cl 50:50 to 0:100) to provide 306 mg (89% yield)
of the desired product as a colorless solid. Colorless crystals were ob-
tained following recrystallization in petroleum ether/CHCl . M.p. 106–
1028C); H NMR (250 MHz,
): d=7.89 (dd, J=1.7 Hz, J=3.8 Hz, 1H; H7), 7.57–7.63 (m, 2H;
(
2
2
3
[
95]
1
1
3
088C (petroleum ether/CHCl ) (Lit.:
4
3
CDCl
3
[96]
of compound 1c is known in the literature. M.p. 140–1418C (EtOH);
3
3
H2,6), 7.35–7.52 (m, 3H; H3–5), 7.24 (dd, J=3.8 Hz, J=9.5 Hz, 1H;
1
3
4
5
H NMR (250 MHz, CDCl
3
): d=8.54 (ddd, J=4.9 Hz, J=1.7 Hz, J=
4
3
13
1
H8), 7.05 ppm (dd, J=1.7 Hz, J=9.5 Hz, 1H; H9); C{ H} NMR
50 MHz, CDCl ): d=160.1 (C10), 141.5 (C1), 136.7 (C7), 131.3 (CH),
31.2 (CH), 128.8 (2CH), 128.4 (C4), 125.3 ppm (2CH); GC/MS (EI):
=17.83 min; m/z: 172; R =0.20 (CH Cl ).
Diethyl phenylmalonate (11a): Following the general procedure (708C,
0 h), diethyl malonate (607 mL, 4 mmol) was coupled with iodobenzene
224 mL, 2 mmol) by using CuI (38 mg, 0.2 mmol), ligand 1c (117 mg,
3
4
1
.0 Hz, 2H; H1,2), 8.30 (s, 2H; H7,14), 7.87 (ddd, J=7.9 Hz, J=1.5 Hz,
J=1.0 Hz, 2H; H5,16), 7.63 (dddd, J=7.9 Hz, J=7.5 Hz, J=1.7 Hz,
J=0.6 Hz, 2H; H4,17), 7.22 (ddd, J=7.5 Hz, J=4.9 Hz, J=1.5 Hz,
H; H3,18), 3.50 (m, 2H; H8,13), 1.83 (m, 6H), 1.40–1.55 ppm (m, 2H);
3
C{ H} NMR (50 MHz, CDCl ): d=161.4 (C7,14), 154.6 (C6,15), 149.2
(
1
3
5
3
3
4
5
3
3
4
t
R
f
2
2
2
1
3
1
3
(
0
3
(C1,2), 136.4 (C4,17), 124.4 (C3,18), 121.3 (C5,16), 73.5 (C8,13), 32.7
(C9,12), 24.3 ppm (C10,11); IR (KBr): n=3273, 3071, 3055, 3050, 2941,
2934, 2925, 2865, 2857, 2850, 1644, 1586, 1566, 1467, 1449, 1433, 1372,
.4 mmol), cesium carbonate (977 mg, 3 mmol), activated and powdered
Š molecular sieves (600 mg), and acetonitrile (1.2 mL). The reaction
À1
1338, 991, 934, 867, 839, 771, 743 cm ; MS (FAB+, NBA): m/z (%): 293
+
+
mixture was neutralized with aqueous hydrochloric acid (6 mL, 1n)
before being filtered through a plug of Celite, extracted with CH
(100) [M +H], 107 (52), 92 (38), 119 (25), 294 (23) [M +2H], 204 (22),
+
Cl
2
79 (21), 187 (20), 585 (1) [2M +H].
2
(
~20 mL) and concentrated in vacuo. The crude residue was directly pu-
rified by flash chromatography on silica gel (gradient hexanes/CH
2
Cl
2
1
00:0 to 80:20) to provide 439 mg (93% yield) of the desired product as
1
a colorless oil. H NMR (200 MHz, CDCl
3
): d=7.32–7.42 (m, 5H), 4.62
s, 1H), 4.22 (m, 4H), 1.26 ppm (t, J=7.1Hz, 6H); the protons of each
methylene group were diastereotopic (second order signal)—consequent-
Acknowledgement
3
(
P.P.C. thanks RHODIA Organique Fine for a Ph.D. grant, and the Labo-
ratoire de Chimie Organique is grateful to the same company for finan-
cial support of this work. Prof. A. Fruchier is gratefully acknowledged for
helpful discussions and assistance with the NMR analyses.
[
8]
ly, multiplicities given in the literature for such proton signals are not
1
3
1
correct; C{ H} NMR (50 MHz, CDCl
3
): d=168.2 (2C
29.3 (2CH), 128.6 (2CH), 128.2 (CH), 61.8 (2CH
4.0 ppm (2CH ); GC/MS (EI): t =16.77 min; m/z: 236; R
Cl 7:3).
-Phenylethylcyanoacetate (11d): Following the general procedure
708C, 28 h), ethyl cyanoacetate (427 mL, 4 mmol) was coupled with iodo-
benzene (224 mL, 2 mmol) by using CuI (38 mg, 0.2 mmol), ligand 1c
117 mg, 0.4 mmol), cesium carbonate (977 mg, 3 mmol), activated and
q
), 132.9 (C
), 58.0 (CH),
=0.27 (hex-
q
),
1
1
2
3
R
f
anes/CH
2
2
2
(
[1] a) I. Sircar, B. L. Duell, G. Bobowski, J. A. Bristol, D. B. Evans, J.
Med. Chem. 1985, 28, 1405–1413; b) T. Güngçr, A. Fouquet, J.-M.
Teulon, D. Provost, M. Cazes, A. Cloarec, J. Med. Chem. 1992, 35,
4
455–4463; c) N.-X. Hu, S. Xie, Z. Popovic, B. Ong, A.-M. Hor, S.
(
Wang, J. Am. Chem. Soc. 1999, 121, 5097–5098; d) K. R. Justin
Thomas, J. T. Lin, Y.-T. Tao, C.-W. Ko, J. Am. Chem. Soc. 2001, 123,
powdered 3 Š molecular sieves (600 mg), and acetonitrile (1.2 mL). The
reaction mixture was neutralized with aqueous hydrochloric acid (6 mL,
9
6
404–9411; e) S. Yu, J. Saenz, J. K. Srirangam, J. Org. Chem. 2002,
7, 1699–1702.
1
(
n) before being filtered through a plug of celite, extracted with CH
~20 mL) and concentrated in vacuo. The crude residue was directly pu-
rified by flash chromatography on silica gel (gradient hexanes/CH Cl
00:0 to 75:25) to provide 348 mg (92% yield) of the desired product as
2 2
Cl
[
2] a) S. J. Brickner, D. K. Hutchinson, M. R. Barbachyn, P. R. Manni-
nen, D. A. Ulanowicz, S. A. Garmon, K. C. Grega, S. K. Hendges,
D. S. Toops, C. W. Ford, G. E. Zurenko, J. Med. Chem. 1996, 39,
673–679; b) J. Gallego, G. Varani, Acc. Chem. Res. 2001, 34, 836–
843.
2
2
1
1
a colorless oil. H NMR (200 MHz, CDCl
3
): d=7.37–7.45 (m, 5H), 4.71
3
3
(
s, 1H), 4.25 (q, J=7.1Hz, 2H), 1. 28 ppm (t,
J=7.1Hz, 3H);
), 130.0 (C ), 129.3 (2CH),
), 43.7 (CH), 13.9 ppm
=0.22 (hexanes/CH Cl
2
1
3
1
C{ H} NMR (50 MHz, CDCl
3
): d=165.0 (C
q
q
[
3] F. Moureau, J. Wouters, D. P. Vercauteren, S. Collin, G. Evrard, F.
Durant, F. Ducrey, J. J. Koenig, F. X. Jarreau, Eur. J. Med. Chem.
1
29.2 (CH), 127.9 (2CH), 115.7 (CN), 63.3 (CH
); GC/MS (EI): t =15.24 min; m/z: 189; R
2
(
CH
3
R
f
2
1
994, 29, 269–277.
3
:1).
[
[
4] G. C. Lloyd-Jones, Angew. Chem. 2002, 114, 995–998; Angew.
Chem. Int. Ed. 2002, 41, 953–956.
5] a) D. Prim, J.-M. Campagne, D. Joseph, B. Andrioletti, Tetrahedron
Phenylmalononitrile (11e): Following the general procedure (508C,
2 h), malononitrile (132 mg, 4 mmol) was coupled with iodobenzene
224 mL, 2 mmol) by using CuI (38 mg, 0.2 mmol), ligand 1c (117 mg,
.4 mmol), cesium carbonate (977 mg, 3 mmol), and acetonitrile
1.2 mL). The reaction mixture was neutralized with aqueous hydrochlo-
ric acid (6 mL, 1n) before being filtered through a plug of celite, extract-
ed with CH Cl (~20 mL) and concentrated in vacuo. The black residue
was directly purified by flash chromatography on silica gel (gradient hex-
anes/CH Cl 100:0 to 60:40) to provide 176 mg (62% yield) of the de-
sired product as a colorless solid. M.p. 64–658C (Lit.:
7
(
0
(
2
002, 58, 2041–2075; b) J. F. Hartwig in Modern Amination Methods
(
Ed.: A. Ricci), Wiley-VCH, Weinheim, 2000, pp. 195–262; c) B. H.
Yang, S. L. Buchwald, J. Organomet. Chem. 1999, 576, 125–146;
d) J. F. Hartwig, Angew. Chem. 1998, 110, 2154–2177; Angew. Chem.
Int. Ed. 1998, 37, 2046–2067; e) N. A. Beare, J. F. Hartwig, J. Org.
Chem. 2002, 67, 541–555; f) Kat N. Kataoka, Q. Shelby, J. P. Stam-
buli, J. F. Hartwig, J. Org. Chem. 2002, 67, 5553–5566; g) J. Yin,
S. L. Buchwald, J. Am. Chem. Soc. 2002, 124, 6043–6048; h) G.
Mann, J. F. Hartwig, M. S. Driver, C. Fernandez-Rivas, J. Am. Chem.
Soc. 1998, 120, 827–828; i) J. F. Hartwig, M. Kawatsura, S. I. Hauck,
K. H. Shaughnessy, L. M. Alcazar-Roman, J. Org. Chem. 1999, 64,
2
2
2
2
[
57g]
66–688C, hex-
): d=7.51(m, 5H),
): d=130.4 (C ), 130.1
2CH), 127.2 (CH), 126.2 (2CH), 111.8 (2CN), 28.1 ppm (CH); GC/MS
EI): t =12.96 min; m/z: 142; R =0.32 (hexanes/CH Cl 1:1).
1
anes/diethyl ether); H NMR (200 MHz, CDCl
3
1
3
1
5
.08 ppm (s, 1H); C{ H} NMR (50 MHz, CDCl
3
q
(
(
R
f
2
2
5
575–5580; j) D. W. Old, M. C. Harris, S. L. Buchwald, Org. Lett.
Chxn-Py-Al (1c): Anhydrous magnesium sulphate (12.65 g, 105.1 mmol)
and rac-trans-1,2-diaminocyclohexane (4.2 mL, 35.0 mmol) were succes-
2000, 2, 1403–1406; k) G. A. Grasa, M. S. Viciu, J. Huang, S. P.
Nolan, J. Org. Chem. 2001, 66, 7729–7737; l) I. P. Beletskaya, D. V.
5620
ꢁ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
Chem. Eur. J. 2004, 10, 5607 – 5622

Copper Catalysts
5607 – 5622
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620; m) M. Watanabe, M. Nishiyama, T. Yamamoto, Y. Koie, Tetra-
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6] a) R. T. Baker, S. S. Kristjansdottir (E. I. DuPont de Nemours), WO
[
[
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