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Dilip Kumar T. Yadav et al. / Tetrahedron Letters 55 (2014) 931–935
R3
R3
X
R2
Cu I (10 mol% )
R2
DMSO (1 mmol)
N
+
N
K2CO3 (2 equiv.)
glycerol, 120 oC
R1
H
R1
R2 = OCH3, Br, NO2
R3 = CH3
X = I, Br
24h
R1 = CH3, OCH3,
Br, F, NO2
Scheme 1. Copper catalyzed N-arylation of indoles with aryl halides.
temperature (Table 1, entry 17). While decreasing the time from
24 h to 20 h, low yield of 3a was observed indicating that 24 h
was an optimum time required for completion of the reaction
(Table 1, entry 18).
Table 1
Screening reaction conditions for N-arylation of indole with iodobenzenea
I
CuI (10 mol%)
DMSO (1 mmol)
N
With these optimized reaction conditions in hand, we have
studied the scope and limitation of developed protocol for N-
arylation of various heterocycles. As illustrated in Table 2, the
reaction of N-heterocycles with various halides proceeds
efficiently to furnish a wide range of N-aryl heterocycles in
good to excellent yield.20 Firstly, we have screened various in-
dole derivatives and it was observed that 3-methyl-1H-indole
gave excellent yield of 3-methyl-1-phenyl-1H-indole (Table 2,
entry 2), whereas 5-methoxy-, 5-bromo-1H-indole on coupling
with iodobenzene afforded good yield of corresponding
products (Table 2, entries 3 and 4). The prominent feature of
developed protocol is that the bromo substituent at C-5 position
of indole remained intact.
The indole with electron withdrawing substituent such as 5-
nitro-1H-indole also provided acceptable yield (65%) of 5-nitro-
1-phenyl-1H-indole (Table 2, entry 5). Interestingly, less reactive
aryl halide such as bromobenzene also couples with indole
derivatives furnishing N-aryl indoles in good to appreciable
yields (Table 2, entries 6 and 7). The reaction of indole with
1-bromo-2-iodobenzene afforded the selective mono coupling
1-(2-bromophenyl)-1H-indole in good yield under optimized
reaction condition (Table 2, entry 8). Next, electronically
different halo derivatives with indole were also studied. The
ortho-substituted 1-iodo-2-methoxybenzene afforded the 1-(2-
methoxyphenyl)-1H-indole in 73% yield indicating no steric
effect in the coupling reaction (Table 2, entry 9). Furthermore,
good to excellent yields were achieved regardless of the
electronic nature of the substituents on the aryl iodide, and no
considerable electronic effects were observed for both meta-
and para-substituted aryl iodides (Table 2, entries 10–12). We
extended the substrate scope of the present protocol by replac-
ing the indoles with other heterocycles. The treatment of pyrrole
with aryl iodide afforded the corresponding 1-phenyl-1H-pyrrole
in 52% yield (Table 2, entry 13). Further, various imidazole and
pyrazole derivatives such as 1H-imidazole, 2-phenyl-1H-imidaz-
ole, and 3-phenyl-1H-pyrazole were coupled with aryl iodide
furnishing the corresponding 3l, 3m, and 3n in 67%, 64%, and
62% yields respectively (Table 2, entries 14–16).
+
N
K2CO3 (2 equiv.)
H
glycerol, 120 o
24h
C
3a
1a
2a
Entry
Catalyst
Base
Time (h)
Temp (°C)
Yieldb (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16d
17
18
CuI
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
—
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
20
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
110
120
91, 47c
79
75
50
70
53
43
49
—
Trace
74
64
62
43
49
63
72
80
CuCl
CuBr
CuCl2
Cu2O
Cu(OAc)2Á5H2O
CuO
CuSO4Á5H2O
—
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
KOH
Cs2CO3
KOtBu
Na3PO4
Et3N
K2CO3
K2CO3
K2CO3
CuI
a
Reaction conditions: iodobenzene (1 mmol), indole (1.5 mmol), Cu catalyst
(0.1 mmol), base (2 mmol), DMSO (1 mmol), glycerol (2 ml), 120 °C, 24 h.
b
GC yield.
c
Reaction carried out without DMSO.
CuI (0.05 mmol).
d
indole (3a) was obtained in 91% yield (Table 1, entry 1). Encour-
aged by this result, we screened various copper catalysts and bases
for the model reaction (Table 1). It was observed that among the
various screened copper catalysts, CuI gave the best yield of the
desired product and hence was used for further studies (Table 1,
entries 1–8), whereas no product formation was observed in the
absence of copper catalyst (Table 1, entry 9). Subsequently, we
screened various bases for this transformation and it was observed
that the base plays an important role; in the absence of base very
less product was formed (Table 1, entry 10). Among screened
bases, K2CO3 exhibited higher activity (Table 1, entries 1 and 11–
15). We have also screened various solvents such as DMSO, DMF,
toluene, and water for this transformation. It was found that DMSO
and DMF provided trace amount of the desired product and
solvents like toluene and water were ineffective for N-arylation
of indole. However, decreasing the catalyst loading from 10 mol %
to 5 mol %, decreases yield of 3a (Table 1, entry 16). In addition,
the effect of reaction temperature and time was also investigated.
It was observed that the yield of 3a decreases with a decrease in
In consideration of economical view of the developed method-
ology, reusability of the catalytic system was examined for N-ary-
lation of (2a) with (1a) as model reaction after the extraction of
product with diethyl ether. 1 mmol of fresh DMSO should have
been complemented to the reaction system before the next run,
as very less product was observed for next run without fresh addi-
tion of DMSO. The recovered glycerol layer containing copper
catalyst accomplishes the respective transformation up to four
times with iodobenzene and indole as a substrate (Table 3). In this