Room-temperature copper-catalyzed synthesis of primary arylamines from aryl halides and aqueous ammonia

Article abstract of DOI:10.1055/s-0029-1219922

Primary arylamines can be prepared via a copper-catalyzed cross-coupling between aryl halides and aqueous ammonia using K₃PO₄ as a base and DMF as a solvent at room temperature.

Full text of DOI:10.1055/s-0029-1219922

LETTER
1355
Room-Temperature Copper-Catalyzed Synthesis of Primary Arylamines from
Aryl Halides and Aqueous Ammonia
a
a
b
a
a
a
b
S
C
ynthesisof Prim
h
a
ry
A
rylami
u
nes anzhou Tao,* Weiwei Liu, Aifeng Lv, Mingming Sun, Ying Tian, Qi Wang, Jing Zhao*
a
School of Chemical Engineering, Huaihai Institute of Technology, Lianyungang 222005, P. R. of China
Fax +86(518)85895121; E-mail: cztao@mail.ustc.edu.cn
b
State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210093, P. R. of China
Fax +86(25)83592672; E-mail: jingzhao@nju.edu.cn
Received 11 February 2010
In the meantime, Fu et al. reported a mild copper-cata-
lyzed coupling of aryl boronic acids and aqueous ammo-
nia (Scheme 1).6 The reaction proceeds at room
temperature without ligands, bases, or other additives, and
many functional groups are tolerated under mild condi-
tions. However, the cost and availability of the aryl boron-
ic acids, particularly the highly functionalized ones,
hampers their applications. Usually aryl halides are pre-
ferred substrates because these electrophiles tend to be
cheaper and easier to prepare. Thus, we set out to develop
more economical, practical, and efficient protocols for the
synthesis of primary arylamines from aryl halides under
mild conditions.
Abstract: Primary arylamines can be prepared via a copper-cata-
lyzed cross-coupling between aryl halides and aqueous ammonia
using K PO as a base and DMF as a solvent at room temperature.
3
4
Key words: copper, catalysis, cross-coupling, room temperature,
aqueous ammonia, primary arylamine
Primary arylamines are important intermediates in the
manufacture of agrochemicals, pharmaceuticals, dyes,
1
pigments, and rubber. Their preparation has attracted in-
creasing attention. These compounds were traditionally
synthesized through the amination of aryl halides using
2
ammonia as the nucleophile, but high pressure and high
As part of our studies on the copper-catalyzed arylation of
nucleophiles,3 we now report that the synthesis of pri-
mary arylamines can be achieved by the copper-catalyzed
cross-coupling between aryl halides and aqueous ammo-
nia at room temperature (Scheme 1).
temperature are necessary to achieve good yields. Several
groups have recently studied the possibility of using tran-
sition metals to catalyze the synthesis of primary aryl-
amines from aryl halides. For instance, palladium- and
copper-catalyzed synthesis has been achieved with
ammonia surrogates. The nitrogen sources include
j,7
3
a
3b,c
Fu's work
allylamines, benzophenone imines,
tert-butyl car-
Zn[N(SiMe3)2]2,
3
d,e
3f,g
3h
bamates,
Li[N(SiMe ) ],
3
2
2
Cu O, MeOH
3
i
3j
Ar B(OH)2
3 2
+ NH ⋅H O
amidines, 2,2,2-trifluoroacetamide. However, the use
of masked ammonia suffers from low atom economy and
needs an additional cleavage step to liberate the primary
r.t.
Ar NH2
CuI, DMF, K PO4
3
4
a,b
4c
Ar X + NH3⋅H2O
arylamine. Recently, Hartwig and Buchwald reported
palladium-catalyzed coupling reactions of aryl halides
and free ammonia, in which bulky ferrocene or electron-
rich phosphine ligands were used. These methods provide
a highly efficient route to anilines and can be carried out
without the ammonia surrogates. More recently, progress
this work
X = I, Br
Scheme 1 Room-temperature copper-catalyzed synthesis of prima-
ry arylamines
has also been achieved in the copper-catalyzed coupling 1-Chloro-4-iodobenzene was selected as a model sub-
5
5b
ammonia with aryl halides , such as CuI/L-proline,
strate for optimization of the reaction conditions at room
CuI/2,4-pentanedione, CuI/N,N-dimethylglycine/organ- temperature. As shown in Table 1, using CuI as a catalyst
5
c
5
d
5e
ic base, CuBr/2-pyridinyl b-ketone, and CuI/4- under ligand-free and base-free conditions, different sol-
hydroxy-L-proline catalytic systems. Wolf and Xu also vents were screened for arylation of ammonia (entries 1–
introduced a copper-catalyzed amination protocol in the 5). Low yields of the desired products were obtained in al-
5
f
5
g
solvent of H O/NMP at 80 °C. The efficiency of all the cohol, acetone, toluene, and dioxane, while the use of
2
above catalytic reactions using ammonia as the nucleo- DMF led to a fair yield (40%) of the cross-coupling prod-
phile is highly dependent on the involvement of suitable uct (entry 5). Generally, in the copper-catalyzed carbon–
4
,5
ligands and elevated temperatures (80–110 °C).
nitrogen bond formation of aryl halides, additional bases
were essential. Although ammonia itself could play the
8
role of a base in the catalyst system, we speculated that the
basicity of reaction system was not strong enough. Then,
SYNLETT 2010, No. 9, pp 1355–1358
Advanced online publication: 06.05.2010
DOI: 10.1055/s-0029-1219922; Art ID: W02410ST
x
x.
x
x.
2
0
1
0
with DMF as solvent, several bases such as Na
2 3
CO ,
K CO , K PO , Cs CO , and NaOH were introduced into
2
3
3
4
2
3
the reaction mixture. We were delighted to find that the
©
Georg Thieme Verlag Stuttgart · New York

1
356
C. Tao et al.
LETTER
Table 1 Copper-Catalyzed Coupling of 1-Chloro-4-halobenzenea
of CuI as the catalyst and aqueous ammonia (6.5 equiv) as
the amino source, relative to the aryl halide, DMF as the
with Aqueous Ammonia: Optimization of the Reaction Conditions
9
solvent and K PO as the base at room temperature.
X
NH2
3
4
CuI, base
+
NH3⋅H2O
Having identified the catalytic system of CuI, K PO and
3
4
Cl
Cl
DMF, we next examined whether the same catalytic sys-
tem could be applied to the coupling of aqueous ammonia
with various aryl iodides and bromides with different
electronic and steric properties (Table 2). It was found
that the coupling of aryl iodides containing electron-
donating groups with ammonia afforded anilines in mod-
erate yields (entries 1–3). Aryl iodide carrying electron-
withdrawing groups could be smoothly converted to the
desired products with good to excellent isolated yields
(83–98%, entries 4–13). It is noteworthy that many func-
tional groups including ether, cyano, nitro, keto, ester, and
free carboxylic acid moiety were tolerated under these
mild conditions. However, aryl iodide carrying an ortho
substituent was not found to be a good substrate in the re-
action (entry 14, 15). Only when a neighboring carboxylic
acid group was present, aryl iodide could be readily con-
verted to aniline in 84% yield (entry 16). This finding was
consistent with the well-known accelerating effect of the
carboxylate group on copper-catalyzed aryl halide ex-
change reactions.10 Although nonactivated aryl bromide
reacted sluggishly with ammonia (entry 17), satisfactory
yields (40–89%) of primary arylamines were obtained
when the electron-deficient aryl bromides (entries 18–23)
were utilized.
Temp Yield (%)b
Entry
X
I
I
I
I
I
I
I
I
I
I
I
I
I
I
I
I
Cat.
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
Free
CuCl
CuBr
Base
Solvent
MeOH
acetone
toluene
dioxane
DMF
1
2
3
4
5
6
7
8
9
–
–
–
–
–
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
6
7
5
10
40
57
66
80 (87c)
69
62
0
Na CO
DMF
2
3
K CO
DMF
2
3
K PO
DMF
3
4
Cs CO
DMF
2
3
1
1
1
1
1
1
1
0
1
2
3
4
5
6
7
NaOH
K PO
DMF
DMF
3
4
4
4
4
4
4
4
K PO
DMF
45
33
15
0
3
K PO
DMF
3
Cu O
K PO
DMF
2
3
CuO
K PO
DMF
3
Table 2 Copper(I) Iodide Catalyzed Cross-Coupling of Aryl Ha-
lides 1 with Aqueous Ammonia at Room Temperaturea
Cu SO4 K PO
DMF
0
2
3
R
R
c
d
CuI
1
Br CuI
K PO
DMF
29 (40 , 5 )
3
X
+
NH ⋅H O
NH2
3
2
K3PO4, DMF
a
Reaction conditions: 1-chloro-4-halobenzene (1.0 mmol), 25% aq
NH (6.5 mmol, 0.5 mL), catalyst (10 mol%), base (2.0 mmol), sol-
1
2
3
vent (1 mL), nitrogen atmosphere, 24 h.
Yield (%)b
Entry Aryl halide
Product
b
Isolated yields.
Reaction time: 48 h.
c
d
At 80 °C.
1
2
3
4
5
6
I
NH2
69
1
1
a
2a
coupling yields can be increased to 60% (entries 6–10).
Gratifyingly, the use of K PO , an inexpensive base, re-
I
3
4
NH2
61
50
87
83
84
sulted in the coupled product in 80% yield. At this point
we screened the copper sources including CuCl, CuBr,
Cu O, CuO, and CuSO (entries 11–16). The yields indi-
b
2b
MeO
2c
2
4
MeO
I
NH2
cated that CuI was the best catalyst.
1
c
When 1-chloro-4-iodobenzene was replaced by 1-bromo-
4
-chlorobenzene, however, the reaction was less effective
Cl
I
I
Cl
NH2
providing 4-chloroaniline in 29% yield (entries 17). Sur-
prisingly, when the reaction temperature was raised to 80
1
d
2d
°
C for the aryl bromide, only 5% yield was obtained. It is
Br
Br
NH2
noteworthy that in previous reports, an elevated tempera-
ture (up to 80 °C) was usually necessary for aryl bro-
mides. However, in our catalytic system, elevating the
reaction temperature results in a reduction of the product
yield. We presumed that the low reactivity results from
the decreased solubility of ammonia in the solvent. There-
fore, our optimal reaction condition for room-temperature
synthesis of primary arylamines was as follows: 10 mol%
1
e
2e
MeOC
I
MeOC
2f
NH2
1f
Synlett 2010, No. 9, 1355–1358 © Thieme Stuttgart · New York

LETTER
Synthesis of Primary Arylamines
1357
Table 2 Copper(I) Iodide Catalyzed Cross-Coupling of Aryl Ha-
lides 1 with Aqueous Ammonia at Room Temperature (continued)
Table 2 Copper(I) Iodide Catalyzed Cross-Coupling of Aryl Ha-
lides 1 with Aqueous Ammonia at Room Temperature (continued)
a
a
R
R
R
R
CuI
CuI
X
+
NH ⋅H O
NH2
X
+
NH ⋅H O
NH2
3
2
3
2
K3PO4, DMF
K3PO4, DMF
1
2
1
2
Entry Aryl halide
Product
Yield (%)b
Entry Aryl halide
Product
Yield (%)b
EtOOC
I
EtOOC
2g
NH2
NC
Br
NC
NH2
7
90
20
76
1
g
1t
2h
NC
I
NC
NH2
21
O2N
Br
O2N
NH2
89
50
8
9
0
92
88
98
1
h
2h
1u
NC
2j
NC
HOOC
I
HOOC
2i
NH2
2
2
3
Br
NH2
1
i
1
v
2r
O N
2
O2N
I
2
O N
NH2
1
2
O N
2j
2
66
1
j
Br
NH2
Cl
Cl
1
w
2m
1
1
2
85
93
I
NH2
a
Reaction conditions: aryl halide (1.0 mmol), 25% aq NH (6.5
3
mmol, 0.5 mL), CuI (10 mol%), K PO (2.0 mmol), DMF (1 mL), r.t.,
3
4
1
k
2k
MeOOC
nitrogen atmosphere, 36–48 h.
MeOOC
b
Isolated yields.
1
I
NH2
A possible mechanism for the present catalytic reaction
was proposed. It has been proposed that the function of
the base in the copper-catalyzed C–N couplings is to re-
move the proton from the NH group in the amine-coordi-
1
O2N
l
2l
O N
2
1
1
1
1
3
4
5
6
90
11
20
84
I
NH2
8
nated Cu intermediate. We can reasonably assume that
1
1
m
n
2m
2n
when the coupling reaction was carried out at room tem-
perature, the basicity of aqueous ammonia was not strong
enough. Therefore, addition of a base can drastically pro-
mote the reaction. However, the difference between the
I
NH2
effect of K PO and of other bases suggested that K PO
3
4
3
4
may not only act as a base, but also played a role as a
ligand in the catalysis. This phenomenon was consistent
NO2
NO2
NH2
7b
I
with our earlier report on copper-catalyzed, ligand-free
cross-couplings.
1
1
o
2o
To summarize, herein we report a convenient, practical,
and efficient copper-catalyzed method for the synthesis of
primary arylamines from couplings of aryl halides and in-
expensive aqueous ammonia. It was found that by using
K PO as the base, DMF as the solvent, the cross-coupling
COOH
I
COOH
NH2
p
2p
Ph
2q
Cl
3
4
could proceed successfully at room temperature for aryl
iodides and bromides. The present procedure is mild and
tolerant of a variety of functional groups, thus allowing
for a practical route to primary aryl amines. The conve-
nience of aqueous ammonia and low cost of the catalytic
copper system make this method readily adaptable to pro-
duction on an industrial scale.
Ph
Br
Br
NH2
1
1
1
7
8
9
24
40
61
1
q
Cl
NH2
1
r
2a
MeOC
Br MeOC
NH2
1
s
2f
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
Synlett 2010, No. 9, 1355–1358 © Thieme Stuttgart · New York

1
358
C. Tao et al.
LETTER
(7) (a) Tao, C.-Z.; Cui, X.; Li, J.; Liu, A.-X.; Liu, L.; Guo,
Acknowledgment
Q.-X. Tetrahedron Lett. 2007, 48, 3525. (b) Tao, C.-Z.; Li,
J.; Cui, X.; Fu, Y.; Guo, Q.-X. Chin. Chem. Lett. 2007, 18,
This work was supported by Open-end Funds of Jiangsu Key Labo-
ratory of Marine Biotechnology (No. 2009HS02), the Six Kinds of
Professional Elite Foundation of Jiangsu Province (No. 07-A-024),
the Natural Science Foundation (No. Z2008024), and the Initial
Fund (No. KQ09030) of Huaihai Institute of Technology.
1199. (c) Tao, C.-Z.; Liu, W.-W.; Sun, J.-Y. Chin. Chem.
Lett. 2009, 20, 1170. (d) Tao, C.-Z.; Liu, W.-W.; Sun, J.-Y.;
Cao, Z.-L.; Li, H.; Zhang, Y.-F. Synthesis 2010, 1280.
8) (a) Strieter, E. R.; Blackmond, D. G.; Buchwald, S. L.
J. Am.Chem. Soc. 2005, 127, 4120. (b) Ouali, A.; Spindler,
J.-F.; Jutand, A.; Taillefer, M. Adv. Synth. Catal. 2007, 349,
(
References and Notes
1906. (c) Zhang, S.-L.; Liu, L.; Fu, Y.; Guo, Q.-X.
Organometallics 2007, 26, 4546. (d) Ouali, A.; Taillefer,
M.; Spindler, J.-F.; Jutand, A. Organometallics 2007, 26,
(
(
(
1) Lawrence, S. A. Amines: Synthesis, Properties, and
Application; Cambridge University Press: Cambridge, 2004.
2) Larock, R. C. In Comprehensive Organic Transformations;
VCH: New York, 1989, 399–400.
3) (a) Jaime-Figueroa, S.; Liu, Y.; Muchowski, J. M.; Putman,
D. G. Tetrahedron Lett. 1998, 39, 1313. (b) Wolfe, J. P.;
Ahman, J.; Sadighi, J. P.; Singer, R. A.; Buchwald, S. L.
Tetrahedron Lett. 1997, 38, 6367. (c) Grasa, G. A.; Viciu,
M. S.; Huang, J.; Nolan, S. P. J. Org. Chem. 2001, 66, 7729.
65. (e) Altman, R. A.; Koval, E. D.; Buchwald, S. L. J. Org.
Chem. 2007, 72, 6190. (f) Altman, R. A.; Hyde, A. M.;
Huang, X.; Buchwald, S. L. J. Am. Chem. Soc. 2008, 130,
9613. (g) Huffman, L. M.; Stahl, S. S. J. Am. Chem. Soc.
2
008, 130, 9196. (h) Mansopur, M.; Giacovazzi, R.; Ouali,
A.; Jutand, A.; Taillefer, M. Chem. Commun. 2008, 6051.
(i) Kaddouri, H.; Vicente, V.; Ouali, A.; Ouazzani, F.;
Taillefer, M. Angew. Chem. Int. Ed. 2009, 48, 333. (j) Tye,
J. W.; Weng, Z.; Johns, A. M.; Incarvito, C. D.; Hartwig,
J. F. J. Am. Chem. Soc. 2008, 130, 9971. (k) Strieter, E. R.;
Bhayana, B.; Buchwald, S. L. J. Am. Chem. Soc. 2009, 131,
(
d) Hartwig, J. F.; Kawatsura, M.; Hauck, S. I.;
Shaughnessy, K. H.; Alcazar-Roman, L. M. J. Org. Chem.
1
2
2
2
7
999, 64, 5575. (e) Yin, J.; Buchwald, S. L. Org. Lett. 2000,
, 1101. (f) Lee, S.; Jorgensen, M.; Hartwig, J. F. Org. Lett.
001, 3, 2729. (g) Huang, X. H.; Buchwald, S. L. Org. Lett.
001, 3, 3417. (h) Lee, D.-Y.; Hartwig, J. F. Org. Lett. 2005,
, 1169. (i) Gao, X.; Fu, H.; Qiao, R.; Jiang, Y.; Zhao, Y.
78.
(
9) Coupling of Aryl Halides with Aqueous Ammonia at
Room Temperature – General Procedure
An oven-dried Schlenk tube was charged with CuI (18 mg,
J. Org. Chem. 2008, 73, 6864. (j) Tao, C.-Z.; Li, J.; Fu, Y.;
Liu, L.; Guo, Q.-X. Tetrahedron Lett. 2008, 49, 70.
1
0 mol%), K PO (424 mg, 2.0 mmol), and aryl halide
3 4
(1.0 mmol). The tube was evacuated and backfilled with
(
4) (a) Shen, Q.; Hartwig, J. F. J. Am. Chem. Soc. 2006, 128,
nitrogen. Then, aq NH (6.5 mmol, 0.5 mL) and DMF (1.0
1
1
0028. (b) Vo, G. D.; Hartwig, J. F. J. Am. Chem. Soc. 2009,
31, 11049. (c) Surry, D. S.; Buchwald, S. L. J. Am. Chem.
3
mL) were added under nitrogen. The tube was sealed, and
the reaction mixture was stirred at r.t. for 36–48 h. The
Soc. 2007, 129, 10354.
reaction mixture was quenched with H O, extracted with
(
5) (a) Lang, F.; Zewge, D.; Houpis, I. N.; Volante, R. P.
Tetrahedron Lett. 2001, 42, 3251. (b) Kim, J.; Chang, S.
Chem. Commun. 2008, 3052. (c) Xia, N.; Taillefer, M.
Angew. Chem. Int. Ed. 2009, 48, 337. (d) Yang, C.-T.; Fu,
Y.; Huang, Y.-B.; Yi, J.; Guo, Q.-X.; Liu, L. Angew. Chem.
Int. Ed. 2009, 48, 7398. (e) Wang, D.-P.; Cai, Q.; Ding, K.
Adv. Synth. Catal. 2009, 351, 1722. (f) Jiang, L.-Q.; Lu, X.;
Zhang, H.; Jiang, Y.-W.; Ma, D.-W. J. Org. Chem. 2009, 74,
2
Et O, and dried over anhyd MgSO . The solvents were
2
4
removed under vacuum, and the residue was purified by
column chromatography (silica gel, EtOAc–PE) to afford
the product.
(
10) (a) Wolf, C.; Mei, X. J. Am. Chem. Soc. 2003, 125, 10651.
b) Docampo Palacios, M. L.; Pellon Comdom, R. F. Synth.
(
Commun. 2003, 33, 1771. (c) Mei, M.; Wolf, C. J. Am.
Chem. Soc. 2004, 126, 14736. (d) Mei, M.; Wolf, C. Chem.
Commun. 2004, 2078. (e) Liu, S.; Pestano, J. P. C.; Wolf, C.
Synlett 2007, 3519.
4
542. (g) Xu, H.-H.; Wolf, C. Chem. Commun. 2009, 3035.
6) Rao, H.; Fu, H.; Jiang, Y.; Zhao, Y. Angew. Chem. Int. Ed.
009, 48, 1114.
(
2
Synlett 2010, No. 9, 1355–1358 © Thieme Stuttgart · New York

Copyright of Synlett is the property of Georg Thieme Verlag Stuttgart and its content may not
be copied or emailed to multiple sites or posted to a listserv without the copyright holder's
express written permission. However, users may print, download, or email articles for
individual use.