An efficient copper-catalyzed synthesis of anilines by employing aqueous ammonia

Article abstract of DOI:10.1039/c1ob06208e

Under the catalysis of CuI/2-carboxylic acid-quinoline-N-oxide, the cross coupling reactions between aryl iodides or bromides and aqueous ammonia proceed very well to afford N-unprotected aniline derivatives in excellent yields. This inexpensive catalytic system shows great functional group tolerance and excellent reaction selectivity. The Royal Society of Chemistry 2011.

Full text of DOI:10.1039/c1ob06208e

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An efficient copper-catalyzed synthesis of anilines by employing aqueous
ammonia†
Xin Zeng,a,b Wenming Huang,b Yatao Qiub and Sheng Jiang*b
Received 20th July 2011, Accepted 20th September 2011
DOI: 10.1039/c1ob06208e
Table 1 Amination of iodobenzene under different conditionsa
Under the catalysis of CuI/2-carboxylic acid-quinoline-N-
oxide, the cross coupling reactions between aryl iodides or
bromides and aqueous ammonia proceed very well to afford
N-unprotected aniline derivatives in excellent yields. This
inexpensive catalytic system shows great functional group
tolerance and excellent reaction selectivity.
Aryl amines in general are useful intermediates in pharmaceu-
ticals, agrochemicals, and polymers.1 The traditional method
for the preparation of primary aryl amines is by amination of
the corresponding aryl halides using ammonia or ammonium
hydroxide as the nucleophile under high temperature and pressure.
Recently, the palladium-catalyzed amination of aryl halides with
ammonia or ammonia surrogates has been reported.2,3 However,
the drawbacks of these methods are the use of strong bases, a
toxic and expensive metal, and sophisticated supporting ligands.
Only a few examples of the copper-catalyzed amination of aryl
halides with aqueous ammonia under mild conditions have been
reported.4,5 It is highly desirable to develop more efficient, versatile,
and facile ligands to further improve the efficiency and generality
of the copper-catalyzed amination of aryl halides with aqueous
ammonia under relatively mild conditions.
More recently, we developed a series of new ligands for the
copper-catalyzed C–N coupling reaction under relatively mild
conditions (Fig. 1).6,7 In this paper, we report an efficient amination
of both aryl iodides and bromides under very mild conditions by
using aqueous ammonia in a catalytic system, which uses a less
toxic and inexpensive metal, of 20% CuI and 40% 2-carboxylic
acid-quinoline-N-oxide ligand.
Entry
Ligand
Base
Copper source
Solvent
Yield (%)b
1
2
3
4
6
7
8
9
L1
L2
L3
L4
L2
L2
L2
L2
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K3PO4
Cs2CO3
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
DMSO
DMSO
DMSO
DMSO
DMF
toluene
DMSO
DMSO
52
93
84
87
57
13
Trace
90%
a 1a (1.0 mmol), commercial 28% aqueous NH3 (5 equiv), 20 mol% CuI, 40
mol% ligand, base (2.0 mmol), solvent (2 mL), Ar, 50 ◦C, 12 h. b Isolated
yield.
We initially chose the coupling of iodobenzene and aqueous
ammonia as the model reaction for optimization of the reaction
conditions. We were pleased to find that, with DMSO as the
solvent, this reaction proceeded at 50 ◦C to give aniline in 52% yield
in the presence of catalytic amounts of CuI and the ligand picolinic
acid-N-oxide (L1) (Table 1, entry 1). The catalytic activity of the
other ligands (L2–L4) was also evaluated in the same reaction
system, and L2 gave the highest yield (93%, entry 2). This might
be due to the fact that there is a compromise between the solubility
of the ligand in the water phase and its chelating with the copper
ion ability, which may explain the similar yields observed in the
presence of L2 and L4 (the former is more soluble in water but less
electron-donating than the latter). Other solvents such as DMF
and toluene were investigated, using CuI as the catalyst and L2 as
the ligand, and the results showed that DMSO was the best solvent
(entries 2, 6, 7). Several bases were screened using the same model
substrate and supporting ligand L2. K2CO3 was most effective in
DMSO solvent (entries 2, 8, 9). By a systematic variation of the
reaction parameters, the optimal condition was the 20 mol% CuI
as the catalyst, 40 mol% L2 as the ligand, DMSO as the solvent,
and K2CO3 as the base at 50 ◦C.
Fig. 1 Structure of designed ligands.
aCollege of Chemical and Environmental Engineering, Shanghai Institute of
Technology, Shanghai 210032, China
bLaboratory of Medicinal Chemistry, Guangzhou Institute of Biomedicine
and Health, CAS, Guangzhou, Guangdong 510530, P. R. China. E-mail:
jiang_sheng@gibh.ac.cn; Fax: +86-20-32290439
The optimized reaction conditions were then explored by
varying aryl iodides and the results are summarized in Table 2.
In general, the coupling reactions were performed well for most
† Electronic supplementary information (ESI) available: Detailed experi-
mental section and NMR spectra. See DOI: 10.1039/c1ob06208e
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Table 2 CuI-catalysed amination of aryl iodidesa
of the substrates examined with 83–94% yields. In addition, the
reaction showed a great tolerance to a range of functional groups
including ester, ketone, nitro, or hydroxy moiety (entries 1–4, 8,
11). Remarkably, sterically hindered aryl iodide also afforded the
coupling product in good yield (entry 13). When halide substituted
aryl iodides were used, the coupling takes place selectively at an
iodo part in the presence of other halide group (entries 5–7).
Because of their low cost and ready availability, aryl bromides
are of much greater interest for industrial applications. We further
investigated the potential catalytic efficiency of the CuI/L2 system
for the coupling between aryl bromides and aqueous ammonia.
As shown in Table 3, all the examined aryl bromides coupled with
Entry
1
Product
Yieldb (%)
91
2
3
90
94
◦
aqueous ammonia with excellent yields at 80 C. Both electron-
rich and electron-deficient aryl bromides, no matter whether at the
para- or meta positions, are suitable substrates for this reaction,
and showing similar reactivity. High yields were obtained even
for those aryl bromides with an electron-donating group (entries
2–4 and 11–14). We were pleased to find that the reaction of 4-
bromotoluene with aqueous ammonia, which had been considered
as a difficult case for the copper-catalysed C–N coupling reation,4a
gave the coupling product at 80 ◦C in 90% yield (entry 2). We were
also successful in applying the procedure to heterocyclic aromatic
bromides, which are important pharmaceutical intermediates
(entries 14 and 15).
Furthermore, as described in Fig. 2, we have formulated a
possible mechanism for the copper-catalyzed amination of aryl
halides with aqueous ammonia. We proposed that the chelating
CuI with 2-carboxylic acid-quinoline-N-oxide (L2) formed a six-
member reactive species A, and the subsequent oxidative addition
of the chelating with aryl halides led to the intermediate B. In the
presence of base, aqueous ammonia with intermediate B readily
to afford intermediate C, followed by reductive elimination to
provide the desired product and regenerate active Cu(I) species A.
4
89
92
91
83
90
94
90
5
6
7
8
9
10
11
92
12
13
92
87
a Reaction conditions: ArI (1.0 mmol), 28% aqueous NH3 (5.0 mmol), CuI
(0.20 mmol, 20 mol%), and L2 (0.4 mmol, 40 mol%) in 2.0 mL of DMSO
at 50 ◦C. b Isolated yield.
Fig. 2 Proposed mechanism.
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Table 3 CuI-catalysed amination of aryl bromidesa
Table 3 (Contd.)
Entry
1
Product
Yieldb (%)
98
Entry
15
Product
Yieldb (%)
86
2
3
4
5
90
82
97
93
16
92
a Reaction conditions: ArBr (1.0 mmol), 28% aqueous NH3 (5.0 mmol),
CuI (0.20 mmol, 20 mol%), and L2 (0.4 mmol, 40 mol%) in 2.0 mL of
DMSO at 80 ◦C. b Isolated yield.
In summary, we have developed an efficient, practical, and
economical protocol of Cu-catalyzed coupling of aryl iodides
and bromides with aqueous ammonia. A wide range of aryl
iodides or bromides bearing both electron-donating and electron-
withdrawing substituents were found applicable to this coupling
reaction. In addition, our inexpensive catalytic system shows
great functional group tolerance. Thus our results may provide
a practical new route for the industrial scale synthesis of primary
aryl amines.
6
7
8
96
93
88
9
93
95
Acknowledgements
We thank the National Natural Science Foundation (Grant
No. 20802078, 20972160 and 21172220), Shanghai University
Distinguished Professor (Eastern scholars) Program (DF2009-02),
Pujiang Talent Plan Project (09PJ1409200) and the National Basic
Research Program of China (Grant No. 2009CB940900) for their
financial support.
10
11
12
93
91
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