Ligand-free iron/copper-cocatalyzed amination of aryl iodides

Article abstract of DOI:10.1002/ejoc.200900588

The Fe₂O₃/CuI system efficiently catalyzes the direct animation of aryl iodides with aqueous ammonia in ethanol at 90 °C under aerobic conditions, No ligand was used to perform such reaction. A very wide variety of functional groups was tolerated on the aryl iodide partner. This procedure is economically and. environmentally attractive as a result of the use of aqueous ammonia and ethanol.

Full text of DOI:10.1002/ejoc.200900588

SHORT COMMUNICATION
DOI: 10.1002/ejoc.200900588
Ligand-Free Iron/Copper-Cocatalyzed Amination of Aryl Iodides
Xiao-Feng Wu[a] and Christophe Darcel*[a]
Keywords: Homogeneous catalysis / Iron / Copper / Amination / Green chemistry
The Fe2O3/CuI system efficiently catalyzes the direct amin- economically and environmentally attractive as a result of
ation of aryl iodides with aqueous ammonia in ethanol at
90 °C under aerobic conditions. No ligand was used to per-
form such reaction. A very wide variety of functional groups
was tolerated on the aryl iodide partner. This procedure is
the use of aqueous ammonia and ethanol.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2009)
iodides by using NH4Cl or aqueous ammonia as a nitrogen
source. The use of 4-hydroxy--proline as a ligand improved
this reaction, as it worked with aryl bromides at 50 °C in
DMSO.[7] Quite simultaneously, Taillefer reported a dike-
tone/copper catalytic system [10 mol-% of Cu(acac)2 and
40 mol-% of 2,4-pentadione] for the direct amination of
both aryl iodides and bromides in the presence of aqueous
ammonia.[5b] Lately, Wolf used Cu2O as a catalyst to per-
form the amination of aryl halides in NMP/water media.[5c]
In our continuing work to develop new methodologies
using iron as catalyst,[8,9] herein, we now report a green,
general, and practical ligand-free, iron/copper-cocatalyzed
synthesis of anilines from aryl iodides and aqueous ammo-
nia at 90 °C in ethanol. The use of ethanol as a solvent,
cheap iron and copper salts as cocatalysts, and inexpensive
and easy-to-handle aqueous ammonia make this method
attractive (Scheme 1).
Introduction
The development of synthetic strategies towards anilines
has attracted the interest of chemists for more than 100
years as a result of the significance and omnipresence of
these compounds in the field of natural products, pharma-
ceuticals, and medicinal compounds.[1] The traditional
strategy for the preparation of primary arylamines usually
involves the use of masked ammonia substitutes to make
the C–N bond and an additional deprotection step, which
make those methodologies less attractive.[2] Consequently,
development of new methodologies for the preparation of
aniline derivatives starting from a more abundant and less
expensive nitrogen source, ammonia, is a goal that attracts
more and more attention. Over the last decades, impressive
progress in transition-metal-catalyzed C–N bond formation
has been made, in particular in palladium-catalyzed[3]
Buchwald–Hartwig reactions and copper-catalyzed[4] Ull-
man-type transformations. More precisely, amination of
aryl halides with the use of ammonia as a nitrogen source
are rare. Lately, some examples of copper-[5] and palladium-
catalyzed[6] amination of aryl halides were reported. Usu-
ally, those methodologies had some drawbacks: the use of Scheme 1. Fe2O3/CuI-cocatalyzed amination of aryl iodides.
DMF or DMSO as solvent, or the need of 3–4 bar of am-
monia pressure.
Recently, during the course of our studies, the copper-
Results and Discussion
catalyzed amination of aromatic halides with the use of
aqueous ammonia or ammonium chloride as a nitrogen
source were reported. For example, Chang[5d] described an
efficient catalytic system based on copper iodide (20 mol-
%) and -proline (40 mol-%) for the amination of aryl
For our initial experiments, we chose to study the amina-
tion reaction of iodobenzene (1a) and aqueous ammonia.
As illustrated in Table 1, the preliminary survey was carried
out in N,N-dimethylformamide (which is one of the usual
solvents for this reaction) at 90 °C with the use of cesium
carbonate as a base, under an argon atmosphere. In the
presence of Fe(acac)3 (30 mol-%), the amination reaction
gave only 5% of the desired aniline product (Table 1, En-
try 1). In contrast, this reaction provided promising results
in the presence of catalytic amounts of both CuI and Fe-
(acac)3, as aniline 2a was obtained in good GC yield (90%;
[a] UMR 6226 CNRS-Université de Rennes 1 “Sciences Chimiques
de Rennes”, Equipe “Catalyse et Organométalliques”, Campus
de Beaulieu, Bat 10C,
Avenue du Général Leclerc, 35042 Rennes Cedex, France
Fax: +33-2-23236939
E-mail: christophe.darcel@univ-rennes1.fr
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.200900588.
Eur. J. Org. Chem. 2009, 4753–4756
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4753

X.-F. Wu, C. Darcel
SHORT COMMUNICATION
Table 1, Entry 2). It must be pointed out that in the absence amination reaction (Table 1, Entry 20). Conversely, upon
of an iron source, catalytic amounts of CuI afforded a mod- employment of iron halide salts such as FeCl3, FeF3, FeCl2,
erate GC yield of aniline (30%; Table 1, Entry 3).
FeBr2, or FeF2, GC yields up to 79% were obtained
(Table 1, Entries 14–18). Interestingly, with the use of
FeCl3·7H2O, aniline was obtained in 95% GC yield
(Table 1, Entry 19). Remarkably, the GC yield afforded by
using Fe2O3 as catalyst was also excellent (100%; Table 1,
Entry 21). It must be pointed out that in the absence of
copper iodide, with the use of Fe2O3 as catalyst, no aniline
derivative was obtained (Table 1, Entry 22).
Next, we explored the scope of this iron/copper-cocata-
lyzed amination reaction. By using the optimized condi-
tions (10 mol-% of Fe2O3, 10 mol-% of CuI in ethanol at
90 °C for 16 h in the presence of 5 equiv. of aqueous ammo-
nia and 2 equiv. of solid NaOH) on the model reaction, we
accomplished this transformation with respect to the aryl
iodide substrates.
Table 1. Iron/CuI-cocatalyzed coupling of iodobenzene with aque-
ous ammonia.[a]
Entry
Fe salt
Solvent
Base
Atm. GC yield [%]
[c]
1[b]
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22[b]
23
Fe(acac)3[c]
Fe(acac)3
–
DMF
DMF
DMF
EtOH
EtOH
DMF
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
argon
argon
argon
argon
air
air
air
air
air
air
air
air
air
air
air
air
air
air
air
5
90
30
35
90
0
Fe(acac)3
Fe(acac)3
Fe(acac)3
Fe(acac)3
Fe(acac)3
Fe(acac)3
Fe(acac)3
Fe(acac)3
Fe(acac)3
Fe(acac)3
FeCl3
CH3CN Cs2CO3
0
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
NaOH
KOH
98
35
1
48
1
21
70
71
71
69
79
95
5
Na2CO3
K2CO3
NaOAc
KOAc
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH
The electronic effects on the reactivity were limited. Aryl
iodides substituted with electron-withdrawing groups such
as acyl or nitro led to the corresponding para-substituted
anilines in isolated yields up to 87% (Table 2, Entries 6 and
7). Furthermore, it must be pointed out that the yield ob-
tained for the reaction of p-nitroiodobenzene with aqueous
FeF3
FeCl2
FeBr2
FeF2
FeCl3·6H2O
Fe(acac)2
Fe2O3
air
air
air
100
0
85
Fe2O3
Table 2. Fe2O3/CuI-cocatalyzed coupling of aryl iodides with aque-
ous ammonia.[a]
FeSO4·7H2O
air
[a] Reaction conditions: iodobenzene (1 mmol), aqueous ammo-
niac solution (5 mmol), iron salt (10 mol-%), CuI (10 mol-%), and
base (2 mmol) at 90 °C for 16 h. [b] The CuI cocatalyst was not
added. [c] 30 mol-% of catalyst was used.
Remarkably, when the reaction was performed in ethanol
with the use of both Fe(acac)3 and CuI as cocatalysts and
Cs2CO3 as base in air, aniline was obtained with a very
good GC yield of 90% after 16 h at 90 °C, whereas only
35% GC yield was observed when the reaction was con-
ducted under an argon atmosphere (Table 1, Entries 4 and
5). However, no reaction was observed in DMF or acetoni-
trile by using the same conditions in air.
To get more information on the optimal catalyst condi-
tions, we also carried out investigations to define the best
base. Seven different bases (2 equiv.) were tested at 90 °C
for 16 h with the use of Fe(acac)3 (10 mol-%) and CuI
(10 mol-%) as cocatalysts in the presence of aqueous am-
monia (5 equiv.). Carbonate bases such as sodium or potas-
sium carbonate gave lower GC yields than that obtained
with cesium carbonate (1 and 48%, respectively, compared
to 90%; (Table 1, Entries 10 and 11 vs. 5). Potassium and
sodium acetate led to moderate GC yields (1 and 21% GC
yield, respectively; Table 1, Entries 12 and 13). In fact,
NaOH was found to be a far better base than the other
classic ones tested, as aniline was obtained in quantitative
GC yield (98%; Table 1, Entry 8).
Finally, we carried out extensive investigations to define
the best iron catalyst (10 mol-%) for the amination of iodo-
benzene in the presence of CuI (10 mol-%), NaOH
(2 equiv.), and aqueous ammonia (5 equiv.) at 90 °C for
[a] Reaction conditions: aryl iodide (1 mmol), aqueous ammoniac
solution (5 mmol), Fe2O3 (10 mol-%), CuI (10 mol-%), NaOH
(2 mmol) in ethanol (2 mL) at 90 °C for 16 h. [b] Isolated yields.
16 h. First of all, Fe(acac)2 was not able to promote any [c] Isolated yield for reaction performed on 5-mmol scale.
4754 Eur. J. Org. Chem. 2009, 4753–4756
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© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Ligand-Free Iron/Copper Cocatalyzed Amination of Aryl Iodides
ammonia was significantly lower (61%; Table 2, Entry 7).
In contrast, aryl iodides substituted by electron-donating
substituents such as NH2, Me, or OMe afforded the desired
aniline derivatives in good yields (72–92%; Table 2, En-
tries 2–4). Interestingly, when the reaction was performed
with o-methoxyiodobenzene, corresponding o-methoxyani-
line (2e) was obtained in 90% isolated yield, which shows
that ortho substituents did not hamper the reaction
(Table 2, Entry 5). Extending the procedure to heterocyclic
aromatic iodide such as 3-iodopyridine was also possible,
as 94% of 3-aminopyridine (2h) was isolated under our
standard conditions (Table 2, Entry 8). Finally, para- and
meta-substituted bromoaryl iodides led selectively to the
corresponding para- and meta-bromoanilines in good yield
(82 and 89%, respectively), without detection of diami-
nobenzene derivatives (Table 2, Entries 9 and 10). Further-
more, when using aryl bromide derivatives under these con-
ditions, no reaction occurred.
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In summary, we have developed a general, economical,
efficient, and environmentally friendly way to transform
aryl iodides into aniline derivatives by using an iron/copper
cocatalyst system in the presence of NaOH and aqueous
ammonia in ethanol at 90 °C. The easy use of aqueous am-
monia, the use of nontoxic ethanol as solvent, and the low
cost and environmentally benign character of the cocata-
lytic system (Fe2O3/CuI) are great advantages in terms of
green chemistry. It must be pointed out that this reaction
proceeds in air in ethanol as solvent (whereas the usual sol-
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glycol). Studies are currently in progress to elucidate the
mechanism of this reaction.
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Experimental Section
Representative Procedure: Commercially available red iron oxide
Fe2O3 (16 mg, 10 mol-%) and CuI (19.1 mg, 10 mol-%) were added
to a solution of iodobenzene (204 mg, 1 mmol) in ethanol (2 mL).
Aqueous ammonia (5 mmol, 25% in water) and NaOH (2 mmol,
80 mg) were successively added to the reaction mixture. The reac-
tion tube was sealed and then heated at 90 °C for 16 h. The reaction
progress was monitored by GC. The reaction mixture was cooled
to room temperature, extracted with diethyl ether (3ϫ10 mL) and
concentrated in vacuo. The residue was purified by flash column
chromatography on silica gel to provide the corresponding pure
primary arylamine compound.
Supporting Information (see footnote on the first page of this arti-
cle): Experimental procedures and compound characterization, in-
cluding NMR spectra.
Acknowledgments
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This research was financially supported by the Centre National de
la Recherche Scientifique (CNRS) and the French Ministry of Re-
search (Enseignement Supérieur et de la Recherche).
Eur. J. Org. Chem. 2009, 4753–4756
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4755

X.-F. Wu, C. Darcel
SHORT COMMUNICATION
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Received: May 28, 2009
[7] L. Jiang, X. Lu, H. Zhang, Y. Jiang, D. Ma, J. Org. Chem.
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Published Online: August 14, 2009
4756
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Eur. J. Org. Chem. 2009, 4753–4756