Simple and efficient CuI/PEG-400 system for amination of aryl halides with aqueous ammonia

Article abstract of DOI:10.1016/j.tetlet.2011.02.096

The cross-coupling reaction between aryl halides with aqueous ammonia was efficiently catalyzed in CuI/PEG-400 System with high yield. A range of electron-withdrawing or electron-donating aryl iodides and bromides were found to be applicable to the environmentally benign system. The process allows assembly of primary arylamines in great diversity which bear a wide range of functional groups including cyano, nitro, acetyl, ether, or amino moiety.

Full text of DOI:10.1016/j.tetlet.2011.02.096

Tetrahedron Letters 52 (2011) 3710–3713
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Tetrahedron Letters
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Simple and efficient CuI/PEG-400 system for amination of aryl halides
with aqueous ammonia
⇑
Junmin Chen , Tangjun Yuan, Wenyan Hao, Mingzhong Cai
Department of Chemistry, Jiangxi Normal University, Nanchang 330022, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
The cross-coupling reaction between aryl halides with aqueous ammonia was efficiently catalyzed in CuI/
PEG-400 System with high yield. A range of electron-withdrawing or electron-donating aryl iodides and
bromides were found to be applicable to the environmentally benign system. The process allows assem-
bly of primary arylamines in great diversity which bear a wide range of functional groups including
cyano, nitro, acetyl, ether, or amino moiety.
Received 6 December 2010
Revised 27 January 2011
Accepted 22 February 2011
Available online 26 February 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Amination
Cross-coupling
Copper
PEG-400
1
. Introduction
Transition metal-catalyzed carbon–nitrogen bond formation
progress in the development of primary aniline synthesis, it is
note-worthy that these protocols are generally performed in toxic
organic solvent and/or with efficient supporting ligand. Thus, a
more simple and efficient catalytic system for amination of aryl ha-
lides is desired in view of green and sustainable chemistry.
Recently, PEG and its solutions have been introduced as inter-
with aryl halides and aliphatic or aromatic amines is a powerful
tool to prepare N-containing compounds which have high utilities
in synthetic, biological, pharmaceutical, and materials science.
Over the last decades, impressive progress in transition-metal-cat-
alyzed carbon–nitrogen bond formation has been made, in partic-
ular in palladium-catalyzed Buchwald–Hartwig reactions and
1
9
esting green solvent systems. Low cost, reduced flammability, re-
duced toxicity, recyclability, easily degradable, and miscibility with
wide variety of organic solvents are some of the properties that
render PEG a benign alternative solvent in organic synthesis, such
2
3
copper-catalyzed Ullman-type transformations. However, the
1
0
11
12
13,9c
synthesis of the parent aniline compounds from the direct amina-
tion of aryl halides with ammonia has proved to be a great chal-
lenge due to competition between ammonia and the more
reactive aniline products, which results in the formation of consid-
erable amounts of diaryl and triaryl amines,4 the most common
synthetic method is the well-known classical Ullmann or Goldberg
as in coupling,
substitution,
oxidation,
addition,
and
1
4
reduction reactions. To the best of our knowledge, the copper-
catalyzed amination of aryl halides and ammonia in PEG-400 as
solvent medium has not so far been reported. Here, we report an
efficient copper-mediated amination of aryl iodides and bromides
with aqueous ammonia in PEG-400 to produce primary aryl
amines.
5
cross-coupling reaction. However, these reactions usually require
harsh conditions, such as high temperatures, extended reaction
time, and in some cases stoichiometric amounts of copper. To cir-
cumvent these problems, Hartwig and Buchwald and co-workers
recently reported the catalyzed selective coupling reactions of aryl
2
. Result and discussion
We initially selected iodobenzene as a model substrate for opti-
6,4b
halides with ammonia by palladium catalysts,
following these
mization of the reaction conditions. Selected results from our
screening experiments are summarized in Table 1. As expected,
no target product could be detected in the absence of a copper cat-
alyst (Table 1, entry 1). Furthermore, only trace amounts of prod-
ucts were obtained when the reaction was preformed in the
presence of CuI as catalyst and KOH as base (Table 1, entry 2),
pioneering works, several Cu-catalyzed coupling reactions of aryl
7
halides with ammonia have been reported. Very recently, simple
and practical protocols for coupling aryl halides with aqueous
8
ammonia in water has been developed by Zhou and co-workers.
Although the examples mentioned above have led to remarkable
1
plenty of phenol was detected by H NMR. It means that a strong
base is unfavorable to the reaction system, because iodobenzene
was firstly reacted with a strong base such as KOH to obtain phenol
⇑
Corresponding author.
E-mail address: jxnuchenjm@163.com (J. Chen).
0
040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.02.096

J. Chen et al. / Tetrahedron Letters 52 (2011) 3710–3713
3711
Table 1
Table 2
CuI-catalyzed coupling of amination of iodobenzene with aqueous ammonia in PEG-
CuI-catalyzed coupling of amination of aryl iodides with aqueous ammonia in PEG-
400
4
00
CuI, base
CuI(10%mol)
NH
2
Na
3
PO
4
(1.0equiv)
I
+
3
NH (aq)
solvent, 100°C, 15h
Ar
I
+
NH
3
(aq)
Ar
NH
2
PEG/H
2
O(2:1)
Entrya
b
100°C, 15h
Solvent PEG (ml): NH
3 2
ÁH O (ml)
Base
Yield (%)
1c
2
3
4
5
6
7
8
2:1
2:1
2:1
2:1
2:1
2:1
2:1
2:1
2:1
1:1
3:1
4:1
0:1
KOH
KOH
0
Entry a
Yieldb (%)
Aryl halide
Product
Trace d
40
Na
CO
CO
NaOAc
2
CO
3
1
2
3
4
I
NH2
96
91
81
85
K
2
3
27
30
32
72
24
96
76
82
Cs
2
3
Br
I
Br
F
NH
NH
NH2
2
Na
3
PO
4
K
3
PO
4
F
I
2
e
9
Na
3
Na
3
Na
3
Na
3
Na
3
PO
4
4
4
4
4
1
1
1
1
0e
PO
PO
PO
PO
e
e
e
NC
I
I
NC
1
2
3
81
Trace
NH2
a
Unless otherwise noted, the reactions were carried out with iodobenzene
0.5 mmol), 25–28% aqueous ammonia (1 mL), CuI (0.05 mmol), base (2.0 equiv) in
5
81
(
NO2
PEG-400 (0–4 mL) at 100 °C, 15 h.
NO
2
b
Isolated yield.
In absence of CuI.
Phenol was obtained.
3 4
Na PO for 1.0 equiv.
c
6
H
CO
C
I
HO
F3C
H COC
C
NH
NH2
NH2
NH2
NH2
NH2
2
77
67
75
90
92
75
3
2
2
d
e
7
F
3
C
I
8
H
H
3
COC
CO
I
3
2 3
instead of with ammonia to obtain aniline. To our delight, Na CO
as a base afforded 40% yield of the desired aniline product at 100 °C
for 15 h (Table 1, entry 3). Other bases were tested; we found that
yield of aniline decreased to 27%, 30%, and 32% (Table 1, entries 4–
9
3
I
H CO
3
10
11
Me
I
Me
6
) using K
2
CO
3
, Cs
2
CO
3
and NaOAc as bases, respectively.
PO as a base, iodoben-
We were pleased to find that using Na
3
4
2
H N
I
H N
2
zene could be selectively coupled with aqueous ammonia at 100 °C
to give the desired aniline product in good yield (72%, Table 1, en-
try 7), while the similar base such as K PO afforded only 24% yield
3 4
of aniline. The amounts of base were screened; gratifyingly, we
found that the yield of aniline was increased to 96% when the
I
NH
2
OCH
I
3
OCH
3
1
1
2
3
81
50
amounts of Na
3
PO
4
were decreased to 1 equiv, while phenol was
S
S
NH2
formed in negligible amounts (Table 1, entry 9). Therefore, the
choice of base was pivotal to obtain the target product with high
yield; a strong base such as KOH mostly afforded phenol product,
a
Unless otherwise noted, the reactions were carried out with aryl iodides
0.5 mmol), 25–28% aqueous ammonia (1 mL), CuI (0.05 mmol), Na PO (0.5 mmol)
(
3
4
in PEG-400 (2 mL) at 100 °C, 15 h.
b
while weak bases such as K
uct in low yield. Thus, we selected Na
lowing studies. The influences of ratio of mixed solvent PEG-400/
O on reaction activity were screened, we found that the lower
or higher ratio of PEG/H O was unfavorable to the reaction system
Table 1, entry 10–12). Finally, in order to evaluate the role of PEG-
2
CO
3
, Na
2
CO
3
afforded the aniline prod-
Isolated yield.
3
PO as the base in the fol-
4
H
2
function groups such as cyano, nitro, acetyl, trifluoromethyl affor-
ded relatively low yield (Table 2, entries 4–7), while substrate with
electron-donating functional groups such as methyl, methoxyl
gave the desired product in excellent yield (Table 2, entries 9 and
10). Moreover, the reactions show interesting chemoselectivity
(Table 2, entry 2), the coupling takes place selectively at an iodo
part in the presence of a bromo group. In contrast to Zhou’s report,8
substrate with ester moiety was hydrolyzed to corresponding acid
(Table 2, entry 6). Significantly, the reactions between 4-iodo-
phenylamine and aqueous ammonia afforded corresponding 1,2-
diaminobenzene product in good yield, not diaryl amine byproduct
2
(
4
00 in the reaction system, the reaction was performed in the ab-
sence of PEG-400 with the same reaction conditions, only trace
amounts of products were obtained (Table 1, entry 13). We
thought that PEG-400 was served not only as a solvent, but also
as a phase transfer catalyst in the present reaction system based
on the result of the above screening experiment. By a systematic
variation of the reaction parameters we finally established CuI/
PEG-400 as an effective catalytic system for amination of aryl ha-
lides with aqueous ammonia.
1
was detected by H NMR. In addition to iodobenzenes, heterocyclic
With the optimized conditions in hand, we explored cross-cou-
pling reactions between a range of commercially available aryl io-
dides and aqueous ammonia. The results are summarized in Table
iodide such as thiophene could also be utilized as efficient sub-
strate under the present mild N-arylation protocol (Table 2, entry
13). It was worth mentioning that the reaction was tolerant with
a range of functional groups including cyano, nitro, acetyl, ether
or amino moiety.
Although the aryl iodides are interesting substrates, we focused
our attention on N-arylation with aryl bromides, which are less
reactive electrophiles but of much greater interest for industrial
applications. However, low yields were found under the previously
2. The present coupling protocol with different aryl iodide was suc-
cessful, leading to the desired products in good to excellent yields.
The protocol is tolerant to electron-withdrawing and electron-
donating functional groups and also to the presence of a functional
group in the ortho-position of the aryl iodide (Table 2, entry 12). In
the present protocol, substrate with strong electron-withdrawing

3
712
J. Chen et al. / Tetrahedron Letters 52 (2011) 3710–3713
optimized reaction conditions. After careful optimization of the
reaction conditions it was found that prolonging the reaction time
to 24 h resulted in comparable catalytic abilities when aryl bro-
mides were used instead of aryl iodides. Thus, a variety of substi-
tuted aryl bromides were then examined, and the results are
shown in Table 3.
reactivity with aqueous ammonia as shown in the preparation of
2-methoxylaniline (Table 3, entry 7). Remarkably, 1 and 2-bro-
mo-naphthalene also proved to be good substrates in the reaction,
giving the corresponding naphthol in good yields (Table 3, entries
13 and 14). It must be pointed out that the reaction of aryl chlo-
rides was not efficient under the present system.
It was observed that aryl bromides bearing electron-withdraw-
ing or electron-donating groups were viable substrates, most of the
substrates afforded good to excellent yields. Furthermore, reac-
tions of bromide bearing ortho-substituent exhibited still high
3
. Conclusions
In conclusion, we have discovered a simple and environment-
friendly and economical method for transforming aryl iodides
and bromides into aniline derivatives in one step. A wide range
of aryl iodides and aryl bromides were found to be applicable to
the catalytic system. The present procedure is mild and tolerant
of a variety of functional groups, thus allowing for the practical
new route to primary aryl amines. The convenience of aqueous
ammonia, and low cost of the ligand-free catalytic copper system
makes this method readily adaptable to production on an indus-
trial scale, where safety and environmental factors are of particular
concern. Further application of the CuI/PEG-400 catalytic system is
currently under investigation in our laboratory.
Table 3
CuI-catalyzed coupling of amination of bromides with aqueous ammonia in PEG-400
CuI(10%mol)
Na PO (1.0equiv)
3
4
Ar
Br + NH
3
(aq)
NH2
Ar
PEG/H O(2:1)
2
1
00°C, 24h
Entrya
Aryl halide
Product
Yieldb (%)
1
2
Br
NH2
93
88
4. Experimental section
Br
Br
Br
Br
NH2
NH2
Br
Cl
NH2
4
.1. Typical procedure for the catalysis
Cl
3
4
81
89
3 4
CuI (0.05 mmol), aryl halide (0.5 mmol), Na PO (0.5 mmol),
2
5–28% aqueous ammonia (1 mL), and PEG-400 (2 mL) were added
Cl
Br
Cl
to a sealed tube. The reaction mixture was stirred at 100 °C (aryl
iodides for 15 h and aryl bromides for 24 h) and then cooled to
room temperature and extracted with diethyl ether (3 times).
The combined organic phase was then dried with anhydrous
NH2
5
78
F
F
2 4
Na SO and the solvent was removed under reduced pressure.
The remaining residue was purified by column chromatography
on silica gel to provide the desired aryl amines.
6
7
F
Br
F
NH
2
77
76
Br
NH2
NH2
OMe
OMe
OMe
OMe
Acknowledgments
Br
This project was sponsored by the Jiangxi Provincial Natural
Science Foundation (No 2010GQH0064), We also thank the Analy-
sis and Testing Center of Jiangxi Normal University for NMR
measurements.
8
9
80
83
87
90
86
MeO
Br
Br
Br
MeO
NH2
NH
2
References and notes
1
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CH3
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