Diversification of Indoles via Microwave-assisted Ligand-free Copper-catalyzed N-Arylation

Article abstract of DOI:10.1002/bkcs.10995

A simple, efficient Cu₂O catalyst system under microwave irradiation was developed for N-arylation of various indoles without ligands and additives. Diverse N-heteroarylated indoles were prepared by coupling indoles with various heteroaryl hali

Full text of DOI:10.1002/bkcs.10995

Article
DOI: 10.1002/bkcs.10995
BULLETIN OF THE
J.-K. Kwon et al.
KOREAN CHEMICAL SOCIETY
Diversification of Indoles via Microwave-assisted Ligand-free
Copper-catalyzed N-Arylation
‡
Jae-Kwan Kwon,† Jin -Hee Lee,† Tae Sung Kim,† Eul Kgun Yum,†, and Hee Jung Park
*
†Department of Chemistry, Chungnam National University, Daejon 34134, Korea.
*E-mail: ekyum@cnu.ac.kr
‡Western Seoul Center Korea Basic Science Institute, Seoul 120-750, Korea
Received September 2, 2016, Accepted September 29, 2016
A simple, efficient Cu2O catalyst system under microwave irradiation was developed for N-arylation of
various indoles without ligands and additives. Diverse N-heteroarylated indoles were prepared by coupling
indoles with various heteroaryl halides within 1 h. The selective reactivity of bromoindole with aryl iodide
provided N-aryl bromoindoles, which could be useful intermediates for palladium-catalyzed Heck and
Suzuki coupling reactions.
Keywords: Microwave, Ligand-free, Cu2O, Indole, N-arylation
Introduction
ligand, with long reaction times (12–48 h) under conven-
tional heating.
The indole moieties are the most important class of hetero-
cyclic compounds in natural products and pharmaceutical
agents. The identification and structural characterization of
serotonin and tryptophan in living organisms have inspired
chemists to design and synthesize thousands of indole-
containing pharmaceuticals, which exhibit activities as
5-HT3 receptor antagonists, HIV-1 reverse transcriptase
inhibitors, HMG-CoA reductase inhibitors, and growth
hormone inhibitors, among others.1 Considerable effort has
been expended on the development of versatile, efficient,
and economical synthetic routes to synthesize indole deri-
vatives.2,3 In particular, many synthetic approaches are
based on palladium-catalyzed coupling reactions, which
have been extensively investigated and can provide highly
selective routes to variously substituted indoles.4
In organic chemistry, microwave-mediated organic reac-
tions have attracted considerable attention because they can
accelerate slow thermal reactions with significant energy
savings, high chemical yields, and cleaner reactions.16 Our
study also showed that microwave-mediated copper- or
palladium-catalyzed diversification of heterocycles17 has
significant advantages over conventional heating in hetero-
cycle diversification. In the course of establishing a chemi-
cal compound library of biologically active indoles, we
required a convenient and rapid synthetic procedure to
obtain diverse N-arylated indoles. In this report, we exam-
ined the microwave-assisted ligand-free copper-catalyzed
direct N-arylation of indoles as part of our ongoing efforts
to develop organometallic approaches for the diversification
of indoles.18
Mild and efficient N-arylation of indoles has been
reported for the development of new, inexpensive, and effi-
cient catalytic systems with palladium and copper. Despite
the mild palladium-catalyzed reaction conditions,5 the
palladium-catalyzed N-arylation of indoles has some limita-
tions due to the high cost of the catalyst and the ligand
specificity to indole substrates. The traditional method of
synthesizing N-arylated indoles consists of copper-mediated
Ullmann-type reactions of indoles with aryl halides,6 but
this has a number of limitations, such as the need for high-
temperature reaction conditions and stoichiometric amounts
of the catalyst. Recently, significant progress has been
achieved in the copper-catalyzed N-arylation of indoles
with various organic ligands, such as diamine,7 diimine,8
benzotriazole,9 surfactant/copper-based ionic liquid,10,11
oxazolidin-2-one,12 1,10-phenanthroline,13 and (diphenyl-
phosphine)propanoic acid,14 among others.15 The copper-
catalyzed N-arylation of indoles has shown that the yield of
these indoles depends on the catalyst species and the
Results and Discussion
Initially, the reaction of 2-bromopyridine and indole was
selected as a preliminary model reaction to overcome the
long reaction time with conventional heating. The reaction
conditions were optimized by varying the copper source,
additive, base, and solvent. The results are summarized in
Table 1.
We investigated the effects of different solvents and
additives under the same temperature conditions (Table 1,
entries 1–5). The reaction using N,N-dimethylacetamide
(DMA) or N-methylpyrrolidone (NMP) as solvent produced
80% yields of the desired product, but DMA was selected
as the solvent for the microwave reaction due to its low
cost and use as an industrial solvent, in contrast to NMP
(entries 1–5). The same reaction had slow and poor yields
under a low temperature with a short reaction time. Yields
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Table 1. Optimization of conditions for microwave-assisted Cu-catalyzed N-arylation of indoles.
Entrya
Cu source
Additive
Base
Solvent
Yield (%)
1
2
3
4
5
6
7
8
Cu2O
–
–
Cs2CO3
DMF
DMA
DMA
NMP
NMP
DMA
DMA
DMA
DMA
DMA
DMA
DMA
DMA
59
80
50
80
49
58
40
<10
51
61
52
45
65
00
00
00
00
00
00
00
00
00
00
00
00
LiCl
–
LiCl
–
CuI
Cu(OAc)2
CuO
–
–
9
CuBr
–
10
11
12
13
a
Cu2O
00
00
00
–
K3PO4
K2CO3
Na2CO3
Rb2CO3
–
–
–
All reactions were conducted at a 1.0 mmol scale under 3 mL of solvent in a Biotage 5-mL vial sealed with a crimp cap using an initiator
instrument (400 W, 2450 MHz, EXP EU, Biotage). DMF: N,N-dimethylformamide , DMA: N-N-dimethylacetamide, NMP:
N-methylpyrrolidone
were higher when no chloride source was used than when
LiCl was added (Table 1, entries 2–5). We also examined
the effects of several commercial copper species that are
frequently used for copper-coupling reactions. N-Arylation
of indoles using Cu2O produced higher yields of the
desired product than reactions using CuI, Cu(OAc)2, CuBr,
and CuO under Cs2CO3 (Table 1, 6–9). Reactions using
Cs2CO3 as a base produced good yields of the desired
product. However, reactions using K2CO3, K3PO4,
Na2CO3, and Rb2CO3 as bases only produced moderate
yields of the desired product (Table 1, entries 10–13). The
vapor pressure of the reaction mixture in the vial was moni-
tored to keep it at 3–5 bar using an online programmed
Biotage microwave reactor at 200ꢀC. The results showed
that the optimal conditions for N-arylation of indoles were
1 equiv Cs2CO3, 10 mol % Cu2O in DMA at 200ꢀC.
N-arylation was examined using various aryl iodides or
bromides under optimal reaction conditions to diversify the
N-arylated indole products. The results are summarized in
Table 2. The reaction using iodobenzene instead of bromo-
benzene produced high yields of N-phenylindole with short
reaction times (Table 2, entries 1 and 2). Additionally, reac-
tions using substituted iodobenzene produced excellent
yields of N-phenyl indoles (Table 2, entries 3–6). These
results indicate that reactions using ortho, meta, para sub-
stituted phenyl halides produced almost the same yield of
the desired product. The reaction using heteroaryl bro-
mides, such as thiophene, and thiazole, produced good
yields of N-heteroarylated indoles (Table 2, entries 7 and
8). These results indicate that reactions using nitrogen- or
sulfur-containing heteroaryl halides produced the same
reactivity as with carboaryl halides. The optimized reaction
conditions were applied for 3-acetylindole and 3-
formylindole using aryl bromides. N-arylated 3-substituted
indoles were obtained with different aryl variations at good
to excellent yields (Table 2, entries 9–14). The reactions
using 5-benzyloxyindole and 5-bromoindole were exam-
ined with various aryl halides. The reactions also provided
N-arylated indoles with excellent yields.
The selective reactivity of aryl iodide with 5-
bromoindole provided N-arylated 5-bromoindole, which
could be a useful intermediate for diversifying indole com-
pounds with palladium-catalyzed Heck and Suzuki
reactions.
Conclusions
The N-arylation of indoles using microwave irradiation
could be a valuable synthetic method to prepare various
indole compounds in a short reaction time. This catalyst
system offered N-arylated haloindoles by the selective reac-
tivity of aryl iodide with bromoindole. The catalyst system
also showed the valuable development of green chemistry
and simple diversification of the indole chemical library for
drug development.
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Diversification of Indoles via mircowave assisted N-arylation
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Table 2. Preparation of N-arylated indoles with arylhalides
Entrya
1
Indole
ArX
Product
Time (min)
20
Yield (%)
97
2b
2b
I
N
H
N
2
60
75
Br
N
H
N
I
3
4
2c
30
20
87
94
CH3
N
H
N
CH3
OCH3
2d
N
H
I
N
OCH3
F
5
6
2e
2f
20
60
92
73
N
H
I
F
N
F
F
I
NH2
N
H
N
NH2
S
7
8
9
2g
2h
2i
60
60
60
85
60
76
Br
Br
N
H
N
S
S
N
N
H
N
S
O
N
O
I
N
H
N
(continued overleaf )
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Diversification of Indoles via mircowave assisted N-arylation
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Table 2 (continued)
Entrya
Indole
ArX
Product
Time (min)
40
Yield (%)
86
O
O
N
O
10
2j
Br
N
H
N
N
Br
O
11
2k
60
72
N
N
N
H
N
O
S
O
12
13
2l
60
60
83
87
Br
N
N
N
N
H
S
O
O
2m
Br
H
H
H
H
N
H
N
O
N
O
14
2n
60
56
Br
N
H
N
N
BnO
BnO
BnO
15
16
2o
2p
20
60
87
67
I
N
N
H
BnO
N
Br
N
H
N
N
N
S
BnO
Br
S
BnO
Br
17
18
2q
2r
60
20
71
90
Br
N
H
I
N
H
N
Br
Br
19
2s
20
84
I
Cl
N
H
N
Cl
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Diversification of Indoles via mircowave assisted N-arylation
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Table 2 (continued)
Entrya
Indole
ArX
Product
Time (min)
20
Yield (%)
76
Br
OCH3
Br
20
2t
I
N
N
H
OCH3
a
All reactions were conducted at a 1.0 mmol scale under 3 mL of solvent in a Biotage 5-mL vial sealed with a crimp cap using an initiator
instrument (400 W, 2450 MHz, EXP EU, Biotage).
Experimental
Ar–H), 7.30–7.34 (m, 2H, Ar–H), 7.13–7.22 (m, 2H, Ar–
H), 6.66 (d, 1H, J = 7.8 Hz, Ar–H); 13C NMR (CDCl3,
100 MHz) δ 139.59, 135.62, 129.39, 139.11, 127.73,
126.21, 124.15, 122.15, 120.92, 120.15, 110.32, 103.39;
MS (m/z) 193 (M+, 100), 192 (21), 165 (33), 124 (51),
116 (20), 89 (20).20
Instrumentation and Analysis. All 1H and 13C NMR
spectra were recorded on a JEOL 400 MHz spectrometer,
and chemical shifts were referenced to tetramethylsilane
(TMS) as an internal standard. The GC-MS spectra were
obtained using a Shimadzu QP 1000 GC-MS (Kyoto,
Japan). Microwave-assisted reactions were performed with
an initiator instrument (400 W, 2450 MHz, EXP EU, Bio-
tage, Uppsala, Sweden). Each reaction was carried out in a
5-mm-thickness Biotage 5-mL vial sealed with a crimp cap.
Reaction temperatures were measured using infrared sen-
sors on the outer surface of the reaction vial. Products were
purified by flash chromatography on 230–400-mesh ASTM
60 silica gel. All base and Cu species were purchased from
Sigma-Aldrich Chemical Co (St. Louis, MO, USA). Che-
micals were used directly as obtained from commercial
sources unless otherwise noted.
General Procedure for Microwave-assisted Copper-
catalyzed N-Arylation of Indoles. Indole (1.0 mmol),
Cs2CO3 (1.0 mmol), 2-bromopyridine (1.5 mmol), Cu2O
(0.1 mmol), and DMA (3 mL) were added to a 5-mL vial.
The vial was sealed with a crimp cap and placed in a Bio-
tage initiator microwave cavity. After irradiation at 200ꢀC
for the appropriate time and subsequent cooling, the reac-
tion mixture was diluted with saturated aqueous ammonium
chloride. Products were isolated by extraction into ethyl
acetate. The organic layer was dried over anhydrous mag-
nesium sulfate, filtered, and concentrated. Products were
purified by silica gel column chromatography using a hex-
ane: ethyl acetate solvent. N-2-pyridylindole (2a)19 was
1-(2-Methylphenyl)-1H-indole (2c). Yield (180 mg, 87%),
1
red oil; H NMR (CDCl3, 400 MHz) δ 7.70 (d, J = 6.4 Hz,
1H, Ar–H), 7.30–7.45 (m, 4H, Ar–H), 7.15–7.28 (m, 4H,
Ar–H), 6.68 (d, J = 3.2 Hz, Ar–H), 2.08 (s, 3H, CH3); 13C
NMR ( CDCl3, 100 MHz) δ 138.23, 136.92, 135.82,
131.85, 128.61, 128.25, 127.59 ,125.40, 122.03, 120.82,
120.52, 110.18, 102.48, 17.6; MS (m/z) 207 (M+, 100).21
1-(3-Methoxy-phenyl)-1H-indole (2d). Yield (210 mg,
1
94%), yellow oil; H NMR (CDCl3, 400 MHz) δ 7.68 (d,
1H, J = 7.2 Hz, Ar–H), 7.41–7.66 (m, 3H, Ar–H),
7.11–7.22 (m, 5H, Ar–H), 6.64 (d, 1H, J = 3.2 Hz, Ar–H)
3.87 (s, 3H, −OCH3); 13C NMR (CDCl3, 100 MHz) δ
154.14, 140.26, 136.67, 129.12, 128.28, 127.89, 121.67,
120.65, 119.70, 112.28, 110.81, 102.34, 55.62; MS (m/z)
224 (M + 1, 16), 223 (M+, 100), 208 (50), 180 (21),
152 (12).20
1-(3,4-Difluoro-phenyl)-1H-indole (2e). Yield (210 mg,
1
92%), brown oil; H NMR (CDCl3, 400 MHz) δ 7.67 (d,
1H, J = 7.6 Hz, Ar–H), 7.48 (d, 1H, J = 7.6 Hz, Ar–H),
7.15–7.34 (m, 6H, Ar–H), 6.67 (d, 1H, J = 3.2 Hz, Ar–H);
13C NMR (CDCl3, 100 MHz) δ 136.01, 128.82, 128.79,
128.72, 128.68, 128.59, 128.42, 128.71, 122.46, 121.00,
120.45, 111.91, 111.87, 111.69, 111.65, 110.13, 110.11,
105.56, 105.33, 105.31, 105.07, 103.86; MS (m/z)
230 (M + 1, 15), 229 (100), 201 (13), 113 (37),
101 (23), 90 (40).
1
obtained (80% yield) as yellow oil; H NMR (400 MHz,
CDCl3) δ 8.55 (m, 1H, Ar–H), 8.22 (d, 1H, Ar–H), 7.74 (
m, 1H, Ar–H), 7.71 (d, 1H, J = 3.6 Hz, Ar–H), 7.68 (m,
1H, Ar–H), 7.44 (d, 1H, J = 6.8 Hz, Ar–H), 7.30 (m, 1H,
Ar–H), 7.22 (t, 2H, J = 7.6 Hz, Ar–H), 7.14 (m, 1H, Ar–
H), 6.71 (d, 1H, J = 3.6 Hz, Ar–H); 13C NMR (CDCl3,
100 MHz) δ 152.7, 149.2, 138.6, 130.6, 126.2, 123.3,
121.5, 121.3, 120.2, 113.2, 105.7; MS (m/z) 195 (M + 1,
15), 193 (57), 167 (12).
4-(1H-indol-1-yl)aniline (2f). Yield (152 mg, 73%), yellow
oil; 1H NMR (CDCl3, 400 MHz)
δ 7.66 (d, 1H,
J = 7.4 Hz, Ar–H), 7.42 (d, 1H, J = 8.0 Hz, Ar–H), 7.17
(m, 5H, Ar–H), 6.67 (dd, 2H, J = 8.0 Hz, Ar–H), 6.61 (d,
1H, J = 3.2 Hz, Ar–H), 4.02 (brs, 2H, NH2); 13C NMR (
CDCl3, 100 MHz) δ 145.28, 136.40, 130.81, 128.79,
128.42, 126.00, 121.93, 121.92, 120.90, 120.89, 119.86,
115.56, 110.45, 102.39; MS (m/z) 208 (M+, 100).
The following compounds (2b–2t) were prepared with
microwave-assisted general experimental procedures.
1-Phenyl-1H-indole (2b). Yield (187 mg, 97%), yellow oil;
1H NMR (CDCl3, 400 MHz) δ 7.67 (d, 1H, J = 7.8 Hz,
Ar–H), 7.54 (d, 1H, J = 7.8 Hz, Ar–H), 7.46–7.48 (m, 4H,
1-Thiophen-2-yl-1H-indole (2g). Yield (170 mg, 85%),
brown oil; 1H NMR (CDCl3, 400 MHz) δ 7.66 (d, 1H,
J = 8.0 Hz, Ar–H), 7.56 (d, 1H, J = 8.0 Hz, Ar–H), 7.43
(dd, 1H, J = 4.8 Hz, 3.2 Hz, Ar–H), 7.14–7.31 (m, 5H,
Ar–H), 6.63 (d, 1H, J = 3.2 Hz, Ar–H); 13C NMR (CDCl3,
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Diversification of Indoles via mircowave assisted N-arylation
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100 MHz) δ 136.84, 127.71, 126.58, 126.47, 125.19,
125.07, 124.36, 121.47, 121.02, 110.68, 103.04; MS (m/z)
200 (M + 1, 7), 119 (100), 171 (13), 166 (10), 118 (17).22
124.82, 124.58, 123.43, 122.21, 119.66, 111.05; MS (m/z)
221 (M+, 100).
1-(Pyridin-3-yl)-1H-indole-3-carbaldehyde (2n). Yield
1
(124 mg, 56%), brown solid; mp = 141–146ꢀC; H NMR
1-Thiazol-2-yl-1H-indole (2h). Yield (120 mg, 60%), yel-
low oil; 1H NMR (CDCl3, 400 MHz) δ 8.29 (d, 1H,
J = 7.6 Hz, Ar–H), 7.57–7.66 (m, 3H, Ar–H), 7.21–7.37
(m, 2H, Ar–H), 7.01(d, 1H, J = 3.6 Hz, Ar–H), 6.69 (d,
1H, J = 3.6 Hz, Ar–H); 13C NMR ( CDCl3, 100 MHz) δ
152.71, 143.28, 135.59, 127.60, 124.18, 121.74, 120.57,
119.45, 118.72, 111.02, 110.97, 102.28; MS (m/z)
201 (M + 1, 18), 200 (40), 174 (6), 143 (5), 128 (5),
116 (5), 101 (5), 89 (8), 57 (100).
(CDCl3, 400 MHz) δ 9.84 (s, 1H, CHO), 8.87 (s, 1H, Ar–
H), 8.76 (d, 1H, J = 4.4 Hz, Ar–H), 8.40 (m, 1H, Ar–H),
7.92 (s, 1H, Ar–H), 7.89 (m, 1H, Ar–H), 7.57 (m, 1H, Ar–
H), 7.45 (m, 1H, Ar–H), 7.38 (m, 2H, Ar–H); 13C NMR
(CDCl3, 100 MHz) δ 184.91, 149.25, 149.22, 145.91,
137.57, 137.24, 132.07, 125.48, 124.97, 123.73, 122.35,
120.33, 110.43; MS (m/z) 221 (M+, 100).
5-(Benzyloxy)-1-phenyl-1H-indole (2o). Yield (260 mg,
87%) yellow solid; mp = 128–130ꢀC; 1H NMR (CDCl3,
400 MHz) δ 7.41 (m, 7H, Ar–H), 7.33 (t, 2H, J = 7.0 Hz,
Ar–H), 7.25 (m, 3H, Ar–H), 7.17 (d, 1H, J = 2.4 Hz, Ar–
H), 5.06 (s, 2H, OCH2); 13C NMR (CDCl3, 100 MHz) δ
153.74, 139.85, 137.61, 131.16, 129.82, 129.56, 128.50,
128.33, 127.75, 127.50, 126.18, 123.93, 113.15, 111.29,
104.23, 103.27, 70.66; MS (m/z) 300 (M + 1, 24),
299 (M+, 100), 224 (18), 124 (8).
1-(1-Phenyl-1H-indol-3-yl)ethanone (2i). Yield (202 mg,
86%), brown solid; mp: 143–145ꢀC; 1H NMR (CDCl3,
400 MHz) δ 8.45 (d, 1H, J = 7.8 Hz, Ar–H), 7.87 (s, 1H,
Ar–H), 7.50 (m, 2H, Ar–H), 7.42 (m, 4H, Ar–H), 7.26 (m,
2H, Ar–H), 2.51 (s, 3H, COCH3); 13C NMR (CDCl3,
100 MHz) δ 193.26, 138.17, 136.83, 134.60, 129.75,
127.85, 126.40, 124.70, 123.77, 122.92, 122.57, 118.40,
110.66, 27.39; MS (m/z) 236 (M + 1, 25), 235 (M+,100).
5-(Benzyloxy)-1-(pyridin-3-yl)-1H-indole
(2p).
Yield
1-(1-(Pyridin-3-yl)-1H-indol-3-yl)ethanone (2j). Yield
1
(201 mg, 67%), brown oil; H NMR (CDCl3, 400 MHz) δ
8.79 (s, 1H, Ar–H), 8.56 (s, 1H, Ar–H), 7.73 (d, 1H,
J = 8.2 Hz, Ar–H), 7.38 (m, 7H, Ar–H), 7.24 (d, 1H,
J = 3.2 Hz, Ar–H), 7.20 (d, 1H, J = 2.0 Hz, Ar–H), 6.90
(d, 1H, J = 2.0 Hz, Ar–H), 6.61(d, 1H, J = 3.2 Hz, Ar–H),
5.09 (s, 2H, OCH2); 13C NMR (CDCl3, 100 MHz) δ
153.97, 147.19, 145.18, 137.35, 130.87, 130.81, 130.01,
128.47, 128.46, 127.78, 127.76, 127.43, 113.51, 110.75,
104.44, 104.37, 70.52; MS (m/z) 303 (M + 1, 10),
302 (M+, 100), 280 (25).
1
(180 mg, 76%), white soild; mp = 156–160ꢀC; H NMR
(CDCl3, 400 MHz) δ 8.80 (s, 1H, Ar–H), 8.73 (d, 1H,
J = 4.4 Hz, Ar–H), 7.93 (s, 1H, Ar–H), 7.89 (m, 1H, Ar–
H), 7.54 (m, 1H, Ar–H), 7.43 (d, 1H, J = 7.4 Hz, Ar–H),
7.36 (m, 2H, Ar–H), 2.60 (s, 3H, COCH3); 13C NMR
(CDCl3, 100 MHz) δ 193.20, 148.98, 146.01, 136.77,
134.00, 132.14, 126.48, 124.26, 123.32, 122.82, 119.28,
110.12; MS (m/z) 236 (M+, 100).
1-(1-(Quinolin-3-yl)-1H-indol-3-yl)ethanone (2k). Yield
1
(207 mg, 72%), yellow solid; mp = 128–130ꢀC; H NMR
5-(Benzyloxy)-1-(thiophen-2-yl)-1H-indole (2q). Yield
1
(CDCl3, 400 MHz) δ 9.04 (s, 1H, Ar–H), 8.44 (d, 1H,
J = 7.8 Hz, Ar–H), 8.18 (m, 2H), 7.96 (s, 1H,Ar–H), 7.85
(d, 1H, J = 8.2 Hz, Ar–H), 7.76 (t, 1H, J = 7.6 Hz, Ar–H),
7.62 (t, 1H, J = 7.6 Hz, Ar–H), 7.38 (d, 1H, J = 7.6 Hz,
Ar–H), 7.26 (m, 2H, Ar–H), 2.53 (s, 3H, COCH3); 13C
NMR (CDCl3, 100 MHz) δ 193.10, 146.97, 146.82,
136.87, 134.20, 131.60, 130.29, 130.08, 129.31, 127.85,
127.65, 127.48, 126.37, 124.17, 123.22, 122.71, 119.21,
110.06, 27.41; MS (m/z) 286 (M+, 100).
(218 mg, 71%), yellow oil; H NMR (CDCl3, 400 MHz) δ
7.43 (t, 3H, J = 7.6 Hz, Ar–H), 7.33 (t, 2H, J = 7.6 Hz,
Ar–H), 7.26 (m, 1H, Ar–H), 7.18 (d, 1H, J = 3.2 Hz, Ar–
H), 7.14 (d, 1H, J = 2.4 Hz, Ar–H), 7.02 (m,1H, Ar–H),
6.94 (m, 3H, Ar–H), 6.51 (d, 1H, J = 3.2 Hz, Ar–H), 5.05
(s, 2H, OCH3); 13C NMR (CDCl3, 100 MHz) δ 154.06,
141.83, 137.51, 132.30, 129.66, 129.53, 128.48, 127.74,
127.45, 125.96, 121.10, 119.66, 113.44, 111.38, 104.37,
103.90, 70.65; MS (m/z) 306 (M + 1, 20), 305 (M+, 100.
5-Bromo-1-phenyl-1H-indole (2r). Yield (245 mg, 90%),
1-(1-(Thiazol-2-yl)-1H-indol-3-yl)ethanone (2l). Yield
(200 mg, 83%), brown solid; mp = 99–104ꢀC; 1H NMR
(CDCl3, 400 MHz) δ 8.40 (d, 1H, J = 7.6 Hz, Ar–H), 8.26
(s, 1H, Ar–H), 8.10 (d, 1H, J = 8.2 Hz, Ar–H), 7.60 (d,
1H, J = 3.6 Hz, Ar–H), 7.35 (m, 2H, Ar–H), 7.15 (d, 1H,
J = 3.6 Hz, Ar–H), 2.55 (s, 3H, COCH3); 13C NMR
(CDCl3, 100 MHz) δ 193.42, 158.92, 140.02, 135.10
132.40, 126.95, 125.06, 124.06, 124.24, 120.03, 114.24,
112.38, 27.56; MS (m/z) 243 (M + 1, 15), 242 (M+, 100).
1
yellow oil; H NMR (CDCl3, 400 MHz) δ 7.76 (d, 1H,
J = 7.6 Hz, Ar–H), 7.45 (t, 2H, J = 7.6 Hz, Ar–H), 7.37
(dd, 2H, J = 7.8 Hz, 1.2 Hz, Ar–H), 7.31 (m, 2H, Ar–H),
7.24 (m, 2H, Ar–H), 6.56 (d, 1H, J = 3.2 Hz, Ar–H); 13C
NMR (CDCl3, 100 MHz) δ 139.26, 134.50, 130.95,
130.57, 129.69, 129.04, 126.79, 125.11, 124.24, 123.53,
113.48, 111.93, 102.96; MS (m/z) 274 (M + 2, 89),
272 (M+,100), 251 (65).20
1-Phenyl-1H-indole-3-carbaldehyde (2m). Yield (158 mg,
87%) brown oil; H NMR (CDCl3, 400 MHz) δ 9.80 (s,
1H, CHO), 8.38 (dd, 1H, J = 6.6 Hz, 2.0 Hz, Ar–H), 7.89
(s, 1H, Ar–H), 7.57 (m, 2H, Ar–H), 7.48 (m, 4H, Ar–H),
7.34 (m, 2H, Ar–H); 13C NMR (CDCl3, 100 MHz) δ
185.00, 138.18, 138.14, 137.47, 129.97, 128.27, 125.52,
5-Bromo-1-(4-chlorophenyl)-1H-indole
(2s).
Yield
1
(257 mg, 84%), yellow solid; mp = 82–84ꢀC; 1H NMR
(CDCl3, 400 MHz) δ 7.76 (s, 1H, Ar–H), 7.43 (d, 2H,
J = 8.6 Hz, Ar–H), 7.30 (m, 3H, Ar–H), 7.21 (m, 2H, Ar–
H), 6.57 (d, 1H, J = 3.2 Hz, Ar–H); 13C NMR (CDCl3,
100 MHz) δ 137.78, 134.40, 132.34, 130.98, 129.85,
Bull. Korean Chem. Soc. 2016
© 2016 Korean Chemical Society, Seoul & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.bkcs.wiley-vch.de
6

BULLETIN OF THE
Article
Diversification of Indoles via mircowave assisted N-arylation
KOREAN CHEMICAL SOCIETY
8. M. Periasamy, P. Vairaparkash, M. Dalai, Organmetallics
2008, 27, 1963.
9. A. K. Verma, J. Singh, R. C. Larock, Tetrahedron 2009,
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10. F. Heidarizadeh, A. Majdi-nasab, Tetrahedron Lett. 2015,
56, 6360.
11. S. Liu, J. Zhou, New J. Chem. 2013, 37, 2537.
12. H. Ma, S. Wu, Q. Sun, Z. Lei, Lett. Org. Chem. 2010, 7, 212.
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Lett. 2014, 55, 5973; (b) R. Hosseinzadeh, M. Tajbakhsh,
M. Alikarami, M. Mohadjerani, J. Heterocycl. Chem. 2008,
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128.80, 128.44, 125.44, 125.38, 123.67, 113.72, 112.18,
111.68, 103.43, 103.16; MS (m/z) 308 (M + 2, 100),
306 (M+, 100).
5-Bromo-1-(3-methoxy-phenyl)-1H-indole (2t). Yield
1
(230 mg, 76%), yellow oil; H NMR (CDCl3, 400 MHz) δ
7.75 (d, 1H, J = 2.0 Hz, Ar–H), 7.37 (m, 2H, Ar–H), 7.25
(m, 2H, Ar–H), 6.95 (m, 2H, Ar–H), 6.85 (dd, 1H,
J = 8.2 Hz, 2.4 Hz, Ar–H), 6.55 (d, 1H, J = 3.2 Hz, Ar–
H), 3.79 (s, 3H, −CH3); 13C NMR (CDCl3, 100 MHz) δ
160.57, 140.36, 134.42, 130.96, 130.44, 129.02, 125.12,
123.51, 116.37, 113.48, 112.12, 112.07, 110.17, 102.95,
55.3; MS (m/z) 304 (M + 2, 100), 302 (M+, 100).20
Acknowledgement. Financial support from Chung Nam
National University is greatly acknowledged.
14. Y. S. Liu, N. N. Gu, Y. Liu, X. W. Ma, P. Liu, J. W. Xie,
Asian J. Chem. 2015, 27, 1075.
15. B. Sreedhar, D. K. Devi, Y. Sowjanya, J. Appl. Chem. 2013,
2, 573.
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Bull. Korean Chem. Soc. 2016
© 2016 Korean Chemical Society, Seoul & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.bkcs.wiley-vch.de
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