Ligand-free CuSO4-catalyzed C-N coupling reaction of aryl halides with alkylamines or N-heterocycles in aqueous solution system

Article abstract of DOI:10.14233/ajchem.2013.oh47

C-N coupling can be achieved successfully under 80°C in aqueous nBu4NOH using CuSO₄ as a catalyst. The study of substrate applicability demonstrated that the C-N coupling reaction of aryl iodides and bromides with alkylamines or N-heterocycles could be completed smoothly in this catalytic system.

Full text of DOI:10.14233/ajchem.2013.oh47

Asian Journal of Chemistry; Vol. 25, No. 10 (2013), 5647-5648
http://dx.doi.org/10.14233/ajchem.2013.OH47
Ligand-free CuSO -Catalyzed C-N Coupling Reaction of Aryl Halides with
4
Alkylamines or N-heterocycles in Aqueous Solution System†
1
1
2,*
HUA YANG , XIULI ZHANG and JINGYU SI
1
2
Department of Applied Chemistry, School of Science, Anhui Agricultural University, Hefei 230036, P.R. China
Chemistry and Materials Engineering Department, Hefei University, Hefei 230601, P.R. China
*
Corresponding author: E-mail: sijyo@hfuu.edu.cn
AJC-13291
C-N coupling can be achieved successfully under 80 ºC in aqueous nBu
4
NOH using CuSO
4
as a catalyst. The study of substrate applicability
demonstrated that the C-N coupling reaction of aryl iodides and bromides with alkylamines or N-heterocycles could be completed
smoothly in this catalytic system.
Key Words: C-N coupling, Transition metal catalysis, Tetrabutylammonium hydroxide.
stirrers. The sealed reaction tube was aerated Ar atmosphere
after vaccumization for three times. Following that, nBu4NOH
INTRODUCTION
Transition metal-catalyzed C-N cross-coupling reaction
Buchwald-Hartwig Reaction) is an important research direction
(
40 % aq, 1.0 mL) was injected into the reaction tube. All the
(
in modern organic synthesis field . Copper catalyst was reported
to be a cheaper and more environmentally friendly catalyst than
1
reagents were stirred for reaction for 24 h under 80 ºC. The
reactive mixture was diluted with ethyl acetate and then further
2
3,4
2 3
isolated by the basic Al O (200-300 mesh) column chroma-
palladium .As various new ligands were discovered, C-N coup-
ling can be performed under moderate conditions in Cu/ligand
catalytic system. However, the ligands often became inactivated
during the repetitive use of these catalyst systems. Therefore,
catalytic systems without ligands are of special interest. Cu(I)-
catalyzed C-N cross-coupling reaction was reported using organic
anion bases, such as quaternary ammonium hydroxide, which
tography. The products were obtained after the elimination of
solvent and drying under vacuum for 0.5 h. Characterization
of products was performed using MattsonAlpha-Centauri FT-
IR, Bruker Avance 300 nuclear magnetic resonance and
Finnigan LCQ high-resolution mass spectrometer.
RESULTS AND DISCUSSION
5
can contribute to form a homogeneous catalytic system . In present
work, we report that C-N coupling reaction of aryl iodides and
bromides with alkyl amines or N-heterocycles could be completed
Substrate adaptability to the C-N coupling of aryl iodides:
Adaptability of this reaction system to the substrate has been
deducted through different aryl iodides reacting with
alkylamines, arylamines and N-heterocycles. As shown in
Table-1, either of iodobenzenes substituted by an electron-
withdrawing group or electron-donating group can couple with
alkylamines successfully with relatively high productivity (3a-
3f). However, ortho-substituted iodobenzene can only yield a
rather low productivity (3i). Although the low reactivity of
4 4
smoothly under 80 ºC in aqueous nBu NOH using cheap CuSO
as catalyst. (Scheme-I)
CuSO (5 mol%)
4
X
N-R R
2 3
nBu
4
NOH (40% aq. 1 mL)
R1
X= I, Br
+ R R -NH
3
2
R
1
Ar, 80oC, 24h
2
-iodine pyridine, the target products can be achieved with a
Scheme-I
high productivity (80 %) (3 h). It can be deduced that the steric
effect of substitutional groups attached to iodobenzenes has
more remarkable influence on coupling reactivity than the
electronic effect of them. In addition, the couplings of aryl
iodides with different N-heterocycles showed the different
reactivity under this system. The coupling of 4-chloro-
EXPERIMENTAL
4
(8.0 mg, 0.05 mmol, solid state), aryl iodide or
CuSO
bromide (1.0 mmol in solid state or 0.5 mmol in liquid state)
and corresponding amine (1.5 mmol in solid state or 0.75 mmol
in liquid state) were added into a Schlenk reaction tube with
†
Presented to the 6th China-Korea International Conference on Multi-functional Materials and Application, 22-24 November 2012, Daejeon, Korea

5
648 Yang et al.
Asian J. Chem.
iodobenzene with morpholine can achieve relatively high
productivity (3 g), while the reactions between iodobenzene
and pyrazol, imidazole or triazole are in relatively lower yields
TABLE-2
SUBSTRATE ADAPTABILITY TO THE C-N
a-b
COUPLING OF ARYL BROMIDE
(
3j-3l). Furthermore, aryl iodides cannot react with arylamines
CuSO4 (5 mol%)
Br
NR R
2 3
nBu4NOH (40% aq. 1 mL)
in this catalytic system.
+
HNR R3
2
R1
R1
o
Ar, 80 C, 24h
5
4
2
TABLE-1
SUBSTRATE ADAPTABILITY TO THE C-N
a-b
COUPLING OF ARYL IODIDES
O
NHBn
NHBn
NBn
Ph
I
CuSO4 (5 mol%)
HNR R3 nBu4NOH (40% aq.)（1.0 mL）
NR R
2
NHBn
3
5a (76%)
5b (84%)
5c
(67%)
+
2
R1
R
o
2
4h, Ar, 80 C
NHBn
NHBn
1
2
3
TsO
N
NHBn
NHBn
NHBn
O
5d (88%)
5
e (71%)
5
f (71%)
Br
Cl
NHn-Hex
NHn-Hex
H
N
3
a (95%)
3c (76%)
O
O
3
b (84%)
NHBn
H
N
Ph
NHBn
Cl
5
g (70%)
5
h (72%)
5l (65%)
O2N
F3C
Cl
3
d (74%)
3e (77%)
3
f (74%)
NHBn
a
Reaction conditions: aryl bromide (1 mmol), alkyl amine or N-hetero-
cyclic (1.5 mmol), nBu NOH (40 % aq.) (1 mL) and CuSO (0.05
O
NBn
N
4
4
N
b
mmol) are at 80 ºC under Ar atmosphere for 24 h. Yields are given for
isolated products
Cl
3
i (34%)
3g (86%)
3h (80%)
N-Phenyl-benzylamine (5a): White solid. m.p.: 37.1-
1
7.9 ºC. H NMR (300 MHz, CDCl
N
N
N
N
N
3
4
7
3
): δ (ppm): 7.31-7.37 (m,
H), 7.28 (m,1H), 7.16 (dt, J = 12.4, 1.6 Hz, 2H), 6.70 (t, J =
.2 Hz, 1H), 6.62 (d, J = 8.0 Hz, 2H), 4.31 (s, 2H), 4.01 (s,
N
N
3
j (61%)
3k (60%)
3l (58%)
a
13
3
1H). C NMR (75 MHz, CDCl ): δ (ppm): 148.2, 139.5, 129.3,
-1
128.8, 127.6, 127.3, 117.8, 113.0, 48.5. IR (neat): (λmax/cm ):
Reaction conditions: aryl iodide (1 mmol), alkyl amine or N-heteroc-
n
yclic (1.5 mmol), Bu NOH (40 % aq.) (1 mL) and CuSO (0.05 mmol)
4
4
b
are at 80 ºC under Ar atmosphere for 24 h. Yields are given for
isolated products
3
7
419, 3026, 2924, 2853, 1949, 1602, 1505, 1324, 11267, 989,
+
49. EI-MS: m/z = 182 (M ).
Conclusion
Ligand-free C-N cross-coupling reaction has been realized
successfully using economic and environmentally-friendly
CuSO catalyst in aqueous nBu NOH. Either aryl iodide or
Substrate adaptability to the C-N coupling of aryl
bromides: Under the same catalytic system, further study on
the C-N coupling of aryl bromides with alkylamines,
arylamines and N-heterocycles has been carried out (Table-2).
Either of bromobenzenes substituted by an electron-withdrawing
group or electron-donating group can react with alkylamines
with medium yields (5a-5l). However, aryl bromides cannot
react with arylamines or N-heterocycles for C-N coupling,
which showed aryl bromides possessing the generally lower
reactivity than aryl iodides.
4
4
aryl bromide can react with alkylamine well. More importantly,
C-N coupling can also be achieved between aryl iodide and
low-active pyrazol, imidazole or triazole. This reaction system
showed the advantages of moderate reaction condition, simple
experimental operation and relative low amount of CuSO
4
catalyst which can be decreased to 5 mol %, which must have
large industrial application value.
Structural characterization of some products
ACKNOWLEDGEMENTS
Benzyl-(4-chloro-phenyl)-amine (3b):Yellow solid. m.p.:
1
8.3-49.2 ºC. H NMR (300 MHz, CDCl
4
3
): δ (ppm): 7.32-7.22
This work was supported by the Foundation for Outstand-
ingYoung Teachers in Higher Education Institutions ofAnhui
Province, China (Grant No.2011SQRL132) to Jingyu Si.
(
m, 5H), 7.10-7.05 (m, 2H), 6.52-6.48 (m, 2H), 4.24 (s, 2H),
1
3
3
.89 (s, 1H); C NMR (75 MHz, CDCl
3
): δ (ppm): 146.5, 138.8,
129.0, 128.6, 127.4, 127.3, 122.1, 114.1, 48.3. IR (neat): (λmax
cm ): 3671, 3418, 2922, 2851, 1898, 1603, 1508, 1430, 1324,
/
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+
271, 1092, 1014, 814,750, 692. EI-MS: m/z = 217 (M ).
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