Easy copper-catalyzed synthesis of primary aromatic amines by coupling aromatic boronic acids with aqueous ammonia at room temperature

Article abstract of DOI:10.1002/anie.200805424

(Chemical Equation Presented) A reaction without the added extras: Aromatic boronic acids have been coupled using inexpensive aqueous ammonia to give primary aromatic amines under copper catalysis. This simple and highly efficient approach can be carried

Full text of DOI:10.1002/anie.200805424

Communications
DOI: 10.1002/anie.200805424
Heterogeneous Catalysis
Easy Copper-Catalyzed Synthesis of Primary Aromatic Amines by
Coupling Aromatic Boronic Acids with Aqueous Ammonia at Room
Temperature**
Honghua Rao, Hua Fu,* Yuyang Jiang, and Yufen Zhao
Primary aromatic amines are widely used in the synthesis of
natural products, pharmaceutical and medicinal compounds,
as well as polymers and materials,[1] and their preparation has
attracted increasing attention. Ammonia is an abundant and
inexpensive chemical reagent, so it is an attractive amino
source in organic synthesis.[2] Traditional synthesis of primary
amines has been performed through couplings of aryl halides
with ammonia, but high pressure, high temperature, and
sealed reaction vessels were necessary[3]—these procedures
do not seem to be operationally simple or safe. To overcome
the drawbacks, ammonia surrogates have been used as
suitably masked forms (of ammonia) in cross-coupling
amination reactions; they include allylamine,[4a] benzophe-
none imine,[4b,c] tert-butyl carbamate,[4d,e] Li[N(SiMe3)2],[4f,g]
Zn[N(SiMe3)2],[4h] solid-supported ammonia surrogates,[5]
the fluoroalkyl benzophenone imine reagent,[6a–c] N-substi-
tuted-FBoc carbamate (Boc = tert-butoxycarbonyl),[6d] and
amidines (developed by our research group)[6e]. Obviously,
the direct use of free ammonia is more economical and
practical than using the ammonia surrogates. Recently, the
highly efficient palladium-catalyzed synthesis of primary
aromatic amines has been developed through couplings of
aryl halides with ammonia under pressure.[7] In the last decade
great progress has been made in the copper-catalyzed
Ullmann N-arylation reactions,[8] but the efficiency of these
reactions is highly depended on the involvement of suitable
ligands. For example, the CuI/l-proline system was used to
catalyze the couplings of aryl iodides with aqueous ammonia
or ammonium chloride to prepare primary arylamines at
room temperature.[9] Similarly, the CuI/2,4-pentanedione
system was used to catalyze the couplings of aryl iodides or
bromides with aqueous ammonia at 908C to also give primary
arylamines.[10] Although the previous methods are effective, a
more convenient and efficient approach to primary aromatic
amines is desired. Aromatic boronic acids and their deriva-
tives are common reagents, and they have been used in
N-arylation of arylamines through the amination strategies
developed by the research groups of Chan and Lam.[11]
However, to the best of our knowledge, there is no example
for the preparation of primary aromatic amines by coupling
reactions of aromatic boronic acids with aqueous ammonia.
Herein, we report an easy and highly efficient copper-
catalyzed method for the synthesis of primary aromatic
amines in air at room temperature without the addition of a
base, a ligand, or an additive.
Initially, phenylboronic acid was chosen as the model
substrate to optimize the reaction conditions at room temper-
ature. Catalysts, solvents, amino sources, and bases were
investigated. As shown in Table 1, various copper catalysts
were tested using aqueous ammonia (5 equiv relative to the
amount of phenylboronic acid) in methanol as the amino
source (Table 1, entries 1–9). The best activity was shown with
Cu2O (Table 1, entry 8). Under copper(0) catalysis, no aniline
was formed and the major product was biphenyl, which was
formed from the homocoupling of phenylboronic acid
(Table 1, entry 9). The coupling reaction did not occur in
the absence of copper catalyst (Table 1, entry 10). The effect
of solvents was also investigated (compare Table 1, entry 8
with Table 1, entries 11–15), and methanol was the best
choice. Several amino sources were screened (compare
Table 1, entry 8 with Table 1, entries 16–19), and aqueous
ammonia was the best substrate. The addition of base
(K2CO3) inhibited the reactivity of the substrates (Table 1,
entry 20). An extended reaction time lowered the yield
because of the formation of a small amount of diphenylamine
by-product (Table 1, entry 21). The reaction provided a lower
yield when the temperature increased to 408C because the
higher temperature decreased the solubility of NH3 in the
solvent (Table 1, entry 22). No desired product was observed
in the absence of air (in a nitrogen atmosphere; Table 1,
entry 23), which indicated that an oxidative process was
involved in the formation of primary aromatic amines. The
amount of catalyst required was investigated, and the results
showed that 10 mol% of Cu2O (relative to the aromatic
boronic acid) was the best choice (compare Table 1, entry 8
with Table 1, entries 24 and 25). Therefore, our optimal
[*] H. Rao, Prof. Dr. H. Fu, Prof. Dr. Y. Jiang, Prof. Dr. Y. Zhao
Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical
Biology (Ministry of Education), Department of Chemistry
Tsinghua University, Beijing 100084 (PR China)
Fax: (+86)10-6278-1695
E-mail: fuhua@mail.tsinghua.edu.cn
Prof. Dr. Y. Jiang
Key Laboratory of Chemical Biology (Guangdong Province)
Graduate School of Shenzhen, Tsinghua University (PR China)
[**] Financial support was provided by the National Natural Science
Foundation of China (grant nos. 20672065, 20732004), the Ministry
of Science and Technology of China (grant nos. 2007AA02Z160,
2006DFA43030). Programs for New Century Excellent Talents in
University (grant no. NCET-05-0062) and Changjiang Scholars and
Innovative Research Team in University (PCSIRT) (grant
no. IRT0404) in China, and the Key Subject Foundation from the
Beijing Department of Education (grant no. XK100030514) are
acknowledged.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200805424.
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Angew. Chem. Int. Ed. 2009, 48, 1114 –1116

Angewandte
Chemie
Table 1: Copper-catalyzed coupling of phenylboronic acid with various
Table 2: Copper-catalyzed synthesis of primary aromatic amines.[a]
amino sources: optimization of the reaction conditions.[a]
Entry
1
ArB(OH)2
t [h]
1a 15
Product
Yield [%][b]
80
Entry
Catalyst
Solvent
Source of NH2
Yield [%][b]
2a
2b
1
2
3
4
5
6
7
8
CuCl2
Cu(OAc)2
CuSO4
CuO
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
CHCl3
NH3·H2O
NH3·H2O
NH3·H2O
NH3·H2O
NH3·H2O
NH3·H2O
NH3·H2O
NH3·H2O
NH3·H2O
NH3·H2O
NH3·H2O
NH3·H2O
NH3·H2O
NH3·H2O
NH3·H2O
NH4Cl
31
42
0[c]
8
22
31
0[c]
76
0[c]
0
43
57
74
52
58
0[c]
0[c]
8
31
42
65[d]
41[e]
0[f]
57[g]
75[h]
2
3
1b 16
1c 20
87
89
CuI
2c
CuBr
CuCl
Cu2O
Cu
4
5
6
1d 18
1e 20
1 f 16
2d
2e
2 f
74
72
87
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
–
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
EtOH
CH3CN
DMF
H2O
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
NH4OAc
7
8
1g 12
1h 12
2g
2h
93
88
(NH4)2CO3
NH4OAc + K2CO3
NH3·H2O + K2CO3
NH3·H2O
NH3·H2O
NH3·H2O
NH3·H2O
NH3·H2O
9
1i 12
2i
92
10
11
12
1j 12
1k 15
1l 16
2j
2k
2l
92
90
92
[a] Reaction condition: room temperature (ca. 208C), reaction time
(15 h), catalyst (0.1 mmol), phenylboronic acid (1 mmol), amino source
(5 mmol), solvent (2 mL). [b] Yield of isolated product. [c] No aniline was
observed, biphenyl was the major product. [d] Reaction time (20 h).
[e] Reaction temperature (408C). [f] In a nitrogen atmosphere. [g] Cu2O
(0.05 mmol). [h] Cu2O (0.2 mmol).
13
1m 16
2m
86
reaction condition for the synthesis of primary aromatic
amines is as follows: 10 mol% of Cu2O as the catalyst,
aqueous ammonia as the amino source, methanol as the
solvent, and the reaction was carried out in air at room
temperature (ca. 208C).
14
15
1n 18
1o 18
2n
2o
89
83
16
17
18
1p 15
1q 20
1r 24
2p
2q
2r
88
78
65
Next, we investigated the scope of the copper-catalyzed
reaction with respect to the aromatic boronic acid. As shown
in Table 2, all the substrates examined under the standard
reaction condition provided good to excellent yields at room
temperature. The substituted aromatic boronic acids contain-
ing electron-deficient groups showed slightly lower reactivity
than those containing electron-rich or neutral groups.
For example 3-nitrophenylboronic acid, with an electron-
withdrawing group, provided a lower yield than aromatic
boronic acids with an electron-donating groups (compare
Table 2, entry 5 with entries 6–10). Higher reactivity was
observed for 4-phenylbenzeneboronic acid and 1- or 2-
naphthylboronic acid (Table 2, entries 11–13). The reaction
tolerated a range of functional groups on the aryl ring with
coupling occurring in the presence of carbon–halogen bonds
(Table 2, entries 2–4), an hydroxy group (Table 2, entry 14),
an aldehyde group (Table 2, entries 15 and 16), an ester group
(Table 2, entry 17), a carboxyl group (Table 2, entry 18), an
19
1s 12
2s
89
20
21
1t 15
1u 16
2t
92
84
2u
[a] Reaction condition: temperature (ca. 208C), ArB(OH)2 (1 mmol), NH3·H2O
(25% aqueous solution, 5 mmol), Cu2O (0.1 mmol), MeOH (2 mL). [b] Yield of
isolated product.
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Communications
amino group (Table 2, entry 19), and oxygen- or sulfur-
Keywords: ammonia · arylamines · copper ·
heterogeneous catalysis · synthetic methods
.
containing heterocycles (Table 2, entries 20 and 21). The
reaction with aryl boronic acids containing electron-donating
and neutral groups yielded trace amount of diarylamine by-
products, as arising from the reaction of aromatic boronic
acids with primary arylamines. However, 2,6-dimethylphe-
nylboronic acid and 2,4,6-trimethylphenylboronic acid did not
produce the corresponding diarylamine by-products because
of steric hindrance (Table 2, entries 9 and 10). Also, the
diarylamine by-products were not observed for the substrates
containing electron-withdrawing groups for the reaction
times as shown in Table 2. To broaden the scope of substrates
used, we carried out reactions of arylboric acid esters with
aqueous ammonia under the standard condition as shown in
Scheme 1, and the corresponding primary arylamines were
afforded in good yields.
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Scheme 1. Reactions of arylboronic acid esters with aqueous ammonia
under the standard reaction condition.
When methanol was used as the solvent, it could form
hydrogen bonds with ammonia and thereby prevent the
release of ammonia from solution. In addition, the use of
methanol was favorable for the workup procedure because
high-boiling-point solvents such as N,N-dimethylformamide
(DMF) and dimethyl sulfoxide are avoided. To the best of our
knowledge, the present method is the simplest approach to
primary aromatic amines.
In summary, we have developed a simple and highly
efficient copper-catalyzed method for the synthesis of primary
aromatic amines by couplings of aromatic boronic acids with
inexpensive aqueous ammonia. The coupling reactions were
performed in air at room temperature without the need for
sealed reaction vessels and, importantly, a base, a ligand, or an
additive was not necessary. The remarkable functional group
tolerance means that this reaction will find wide applications
in various fields.
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Received: November 6, 2008
Published online: December 29, 2008
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