JOURNAL OF CHEMICAL RESEARCH 2014 181
Table 2 Copper-catalysed N-arylation of pyrroles with aryl halides under ligand-free conditionsa
N-Het
X
5 mol% CuSO4.5H2O
Het-NH
R1
R1
NaOH, DMSO
110 °C, 12 h
4a 4n
-
5a 5d
-
6a 6p
-
N
N
N
H
N
H
N
H
N
H
5a
5b
5c
5d
M.p./°C
Entry
Aryl halides (R, X)
Het-NH
Product
Yield/%b
Found
Reported
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
4-OMe, I (4a)
3-OMe, I (4b)
4-OEt, I (4c)
3,5-di-Me, I (4d)
4-Me, I (4e)
H, I (4f)
4-OH, I (4g)
2-Me, I (4h)
2-OMe, I (4i)
4-Ph, I (4j)
4-F, I (4k)
4-Cl, I (4l)
4-Br, I (4m)
4-Cl, Br (4n)
3,5-di-Me, I (4d)
3,5-di-Me, I (4d)
3,5-di-Me, I (4d)
5a
5a
5a
5a
5a
5a
5a
5a
5a
5a
5a
5a
5a
5a
5b
5c
5d
6a
6b
6c
6d
6e
6f
6g
6h
6i
6j
6k
6l
6m
6l
6n
6o
6p
84
65
88
90
80
75
58
37
66
86
40
60
47
10
66
32
17
110–111
57–58
69–70
Colourless oil
82–83
111–11216
56–5717
70–7116
Colourless oil18
82–8416
60–62
60–6116
111–113
Yellow oil
Yellow oil
186–188
50–51
87–88
92–93
86–87
113–11519
Oil16
Oil16
183–18820
51–5216
87–8816
93–9416
87–8816
Viscous oil
Colourless oil
Yellow oil
Viscous oil18
Colourless oil18
Yellow oil21
aReaction conditions: aryl halides (1.0 mmol), Het-NH (1.5 mmol), CuSO4·5H2O (0.05 mmol), NaOH (2.0 mmol), DMSO (2 mL), 110 °C, 12 h.
bIsolated yield.
in no product (entry 6). The results of the effect of the solvent
indicated that DMSO was superior to other solvents (entries
7–10). The target product was obtained by 80% yield in DMSO,
and low yields were generated in DMF, DMA and 1,4-dioxane,
and no product was detected in water. Investigation into the
bases with different basicities revealed that NaOH showed
the highest efficiency, KOH was fair, Cs2CO3 gave moderate
activity, and K3PO4 and K2CO3 were not suitable as the bases
(entries 11–14). Increasing the catalyst loading from 5 mol% to
10 mol% only led to a slight improvement of the yield (entry 15).
However, decreasing the copper loading from 5 to 2.5 mol%
or lowering the temperature from 110 °C to 100 °C gave
markedly lower yields (entries 16 and 17). It must be noted that
the hydrate of CuSO4 can accelerate the arylation of pyrrole,
possibly because of the hydrate increased the solubility of the
catalyst in DMSO (entry 18). Considering the efficiency and the
price, CuSO4·5H2O was finally chosen as the copper source.
After optimising the reaction conditions, we attempted the
coupling reactions with various aryl halides and nitrogen-
containing heterocycles under our standard conditions. The
substrates which were examined gave the corresponding
products in moderate to excellent yields (see Table 2). In general,
aryl iodides, containing electron-donating groups possessed
a higher activity than those containing electron-withdrawing
groups. It was noteworthy that the reaction exhibited high
selectivity in the amination of 4-iodophenol, and no diaryl ether
products were found (entry 7). More interesting, the system
tolerated ortho-substituted halides, which afforded the target
product in moderate yields (entries 8 and 9). We found that the
arylation of imidazole also gave moderate yield, but the yields
of arylation of indole and benzimidazole were not satisfactory
(entries 15–17). Unfortunately, the N-arylation product was
obtained only in 10% yield, when 4-bromo-1-chlorobenzene
was used as the substrate (entry 14).
Conclusion
In summary, we have developed a new catalyst system for the
N-arylation of pyrrole with different substituted aryl iodides
under ligand-free conditions without the protection of an inert
atmosphere. The low loading (5 mol%), cheap and commercial
available copper catalyst (CuSO4·5H2O) is expected to be useful
in a variety of synthesis.
Experimental
All reagents were purchased from commercial suppliers and used
without further purification. H NMR spectra were recorded at room
temperature on a Varian Inova-400 instrument at 400 MHz for H
NMR, and the chemical shifts were recorded in ppm (δ) with TMS as
internal standard. Mass spectra were recorded on GC-MS (Agilent
7890A/5975C) instrument under EI model.
1
1
N-arylation of pyrrole; general procedure
CuSO4·5H2O (12.50 mg, 0.05 mmol), the aryl iodide or bromide
(1.0 mmol), pyrrole (1.5 mmol), NaOH (80 mg, 2 mmol), and DMSO
(2 mL) were placed in a 10 mL sealed tube. The mixture was heated
at 110 °C in a preheated oil bath for 12 h. It was then cooled to room
temperature, diluted with 20 mL H2O, and the mixture was extracted
with ethyl acetate (3×20 mL). The combined organic phases was
washed with water and brine, dried over anhydrous Na2SO4, and
concentrated in vacuo. The residue was purified by flash column
chromatography on silica gel (ethyl acetate/petroleum ether, 1:100)
to afford the target products. All C–N coupling products reported here
are known products and were characterised by GC-MS and 1H NMR,
which were compared with the previously reported dates.
We acknowledge the Outstanding Youth Project of Shihezi
University (2012ZRKXYQ-YD02), the Opening Project of the
Key Laboratory for Green Processing of Chemical Engineering
of Xinjiang Bingtuan (KF201303) and the Ministry of Education
Innovation Team (No.IRT1161) for their financial support.
JCR1402380_FINAL.indd 181
04/03/2014 10:08:48
Liu, Lili
