Ultrasound-assisted N-arylation of indoles without any catalyst

Article abstract of DOI:10.3987/COM-07-S(N)1

An efficient method for the ultrasound-assisted N-arylation of indoles with haloarenes in an air atmosphere mediated by Cs₂CO₃ without any catalyst is reported. N-arylindoles are obtained in moderate to good yields while indoles cross-coupling with activated aryl halides (X = F or Cl). The Japan Institute of Heterocyclic Chemistry.

Full text of DOI:10.3987/COM-07-S(N)1

HETEROCYCLES, Vol. 76, No. 1, 2008
249
HETEROCYCLES, Vol. 76, No. 1, 2008, pp. 249 - 256. © The Japan Institute of Heterocyclic Chemistry
Received, 24th October, 2007, Accepted, 20th December, 2007, Published online, 21st December, 2007. COM-07-S(N)1
ULTRASOUND-ASSISTED N-ARYLATION OF INDOLES WITHOUT
ANY CATALYST
Hui Xu,* Lei Lv, Ling-ling Fan, and Xiao-qiang He
Lab of Pharmaceutical Synthesis, College of Sciences, Northwest A&F
University, Yangling 712100, P. R. China
E-mail: orgxuhui@nwsuaf.edu.cn
Dedicated to Professor Dr. Ryoji Noyori on the occasion of his 70th birthday
Abstract – An efficient method for the ultrasound-assisted N-arylation of indoles
with haloarenes in an air atmosphere mediated by Cs2CO3 without any catalyst is
reported. N-arylindoles are obtained in moderate to good yields while indoles
cross-coupling with activated aryl halides (X = F or Cl).
INTRODUCTION
The synthesis of compounds bearing the N-arylindole subunit has gained widespread interest due to their
key role in medically important species, such as those displaying antiestrogen,1 analgesic,2
antimicrobial,3 neuroleptic,4 antiallergy,5 5-HT6 receptor antagonists,6 and FTase inhibitors (FTIs)
activity.7 Although the copper-catalyzed coupling of an aryl halide with a heteroatom-based nucleophile,
the Ullmann type coupling reaction, has remained a standard method for the construction of N-arylindoles,
it involves use of expensive chemicals, tedious work-up, and sensitive catalysts/ligands. Recently, the
8
9
methods of palladium- and copper- catalyzed N-arylation of indoles have been reported. Meanwhile,
the nucleophilic aromatic substitution (SNAr) of aryl halides, activated by electron-withdrawing
substituents, with indoles represent an alternate route to N-arylindoles for some substrate combinations.
For example, Smith has described the N-arylation of indole by aromatic nucleophilic substitution
reaction, which was catalyzed by 18-crown-6 at high temperature (120 oC), and non-substituted indole
was investigated.10 Maiorana described N-arylation of indoles by aromatic nucleophilic substitution on
haloarene, using chromium tricarbonyl complexes.11 While all of these methods are useful in its own right,

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HETEROCYCLES, Vol. 76, No. 1, 2008
each suffers from one or more disadvantages including a lack of generality, the use of inert atmosphere
and stoichiometric quantities of toxic and expensive reagents, or the need to employ harsh reaction
conditions. Therefore, there is still a need for mild methods for the preparation of N-arylindoles.
Ultrasound has been increasingly used in organic synthesis in last two decades. A large number of organic
reactions can be carried out to result in higher yield, shorter reaction time and milder conditions under
ultrasonic irradiation.12 However, to the best of our knowledge, the ultrasound-assisted N-arylation of a
wide range of indoles with aryl halides by SNAr reactions without using any catalyst has not yet been
reported. In continuation of our research interest in the use of ultrasonic irradiation,13 herein, we firstly
present our studies toward the coupling of different types of substituted indoles with haloarenes (X = F,
Cl or Br) by SNAr reactions under ultrasonic irradiation in an air atmosphere, which overcome a number
of the above disadvantages (Scheme 1).
X
2
R
3
Cs CO / DMSO
2
2
3
R
R
o
3
1
ultrasound, 40 C
+
R
N
R
N
14 examples
14 - 98 %
H
1
R
1
2
3
1
2
3
R = NO , CN; X = F, Cl, Br; R = Me; R = Me, NO
2
2
Scheme 1
Table 1 Optimization studiesa
F
Cs2CO3 / DMSO
+
N
N
H
NO2
2a
1a
3a
NO2
Entry
Temp. (oC)
Time (h)
Conditions
ultrasound
ultrasound
ultrasound
ultrasound
silent
Isolated yield (%)
1
2
3
4
5
20
30
40
50
40
8
2
49
94
98
99
86
1.5
1.5
2
a All reactions were carried out with 1a (1.0 mmol), 2a (1.2 mmol) and Cs2CO3 (2.0 mmol) in DMSO (2
mL).

HETEROCYCLES, Vol. 76, No. 1, 2008
251
RESULTS AND DISCUSSION
At the beginning of our work we investigated the ultrasound-assisted coupling of 4-fluoronitrobenzene
(1a) with indole (2a) for optimizing the reaction conditions, and the results were summarized in Table 1.
In our previous paper, Cs2CO3 as the base and DMSO as the solvent under ultrasonic irradiation were
found to be the most effective conditions for the cross-coupling of various phenols with activated
fluoroarenes,13 therefore in this paper Cs2CO3 and DMSO were used as the base and the solvent,
o
o
o
respectively. Subsequently, we investigated the influence of temperature (such as at 20 C, 30 C, 40 C
o
and 50 C) to this reactions under ultrasonic irradiation at an output power of 200 W, and found that the
reaction temperature seems crucial. For example, the yield of 1-(4-nitrophenyl)indole （3a）was only
49 % after reaction at 20 oC even for 8 h (entry 1), but the yield was increased to 94 % after reaction at 30
o
oC for 2 h (entry 2), and the yield was increased to 98 % after reaction at 40 C only for 1.5 h (entry 3).
o
However, when the reaction temperature was above 40 C, e.g. 50 oC , there was no obvious different
o
between the yield and reaction time as compared to those of 40 C (entry 4). On the contrary, while 1a
o
was reacted with 2a at 40 C for 2 h without any ultrasonic irradiation, 3a was obtained in 86 % yield
o
(entry 5). Evidently, Cs2CO3 as the base and DMSO as the solvent at 40 C under ultrasonic irradiation
were found to be the most effective conditions for this N-arylation of indoles.
Based on the above findings, we further studied the coupling reaction of various indoles (2a-d) and
haloarenes (1a-e) (X = F, Cl or Br) in the presence of Cs2CO3 under ultrasonic irradiation. From the
results shown in Table 2, firstly, it can be seen in our reaction that a variety of indoles, having
electron-deficient and electron-rich group, were effective for this C(aryl)-N cross-coupling SNAr reaction
with activated fluoroarenes. Good to excellent yields (55-98 %) were obtained. For example, when indole
(2a) was coupled with 4-fluoronitrobenzene (1a) or 2-fluorobenzonitrile (1c) under ultrasonic irradiation
at 40 oC in the presence of Cs2CO3 without any catalyst, the corresponding compounds
1-(4-nitrophenyl)indole （3a） and 1-(2-cyanophenyl)indole (3c) were obtained in 98 % yield for 1.5 h
and 97 % yield for 2 h, respectively (entries 1, 3). But under the usual heating conditions, the
o
KF-Al2O3/18-crown-6-catalyzed coupling indole with 1a or 1c needed long reaction time at 120 C to
give the same results.10 Moreover, it is noteworthy in our reaction that the electron-poor indole (e.g.
o
5-nitroindole) could smoothly be coupled with 1a or 1b at 40 C only for 1.5 h, and the corresponding
yields were 82 % (3d) and 77 % (3e), respectively (entries 4, 5).
Distinct steric effect of aryl halides was observed in this cross-coupling SNAr reaction. For instance, when
5-nitroindole was reacted with 1a or 1b, the corresponding yields of 3d and 3e were 82 % and 77 %,
respectively (entries 4 vs. 5). Especially when 7-methylindole (2c) was coupled with 1a or 1b, the
corresponding compounds 1-(4-nitrophenyl)-7-methylindole (3f) and 1-(2-nitrophenyl)-7-methylindole
(3g) were obtained in 78 % and 55 % yields, respectively (entries 6 vs. 7). On the other hand, the steric

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HETEROCYCLES, Vol. 76, No. 1, 2008
Table 2 Ultrasound-assisted synthesis of N-arylindoles
X
R2
R3
R2
Cs2CO3 / DMSO
ultrasound / 40 oC
R3
N
R1
+
N
H
R1
1
2
3
Entry
1
Aryl halides (1)
Indoles (2)
Time (h)
1.5
Isolated yield of 3 (%)
F
3a (98)
NO2
N
H
2a
1a
F
NO2
2
3
2
2
2a
2a
3b (91)
3c (97)
1b
F
CN
1c
O N
2
4
5
1.5
1.5
1a
3d (82)
3e (77)
N
H
2b
1b
2b
6
2.5
1a
3f (78)
N
H
Me
2c
7
8
9
3
2.5
3
1b
1a
1b
2c
3g (55)
3h (86)
3i (93)
Me
N
H
2d
2d
Cl
NO2
10
2
2a
3b (55)
1d
11
12
13
8
5
1d
2b
2c
3c (50)
3g (23)
3i (41)
1d
1d
2d
5.5
Br
2a
11
14
3a (14)
NO
2
1e

HETEROCYCLES, Vol. 76, No. 1, 2008
253
effect among indoles was also obvious. when 4-fluoronitrobenzene was reacted with 2a or 2c, the
corresponding yields of 3a and 3f were 98 % and 78 %, respectively (entries 1 vs. 6). Particularly when
2-fluoronitrobenzene was reacted with 2a or 2c, the corresponding compounds 3b and 3g were obtained
in 91 % and 55 % yields, respectively (entries 2 vs. 7).
Later on, other haloarenes (X = Cl or Br, entries 10-14) have also been studied under our reaction
conditions. As shown in Table 2, the fluoroarenes underwent SNAr reactions with indoles much easier
than those chloro and bromo analogues. For example, when 2a was reacted with 1b or 1d, the
corresponding yields were 91 % (entry 2) and 55 % (entry 10), respectively. Similarly, when
3-methylindole (2d) was reacted with 1b or 1d, the corresponding yields were 93 % for 3 h (entry 9)
and 41 % for 5.5 h (entry 13), respectively. Especially when indole was reacted with
4-bromonitrobenzene (1e) (entry 14), even if the reaction time was prolonged to 11 h, the corresponding
yield of 3a was only 14 %.
In summary, we have described nucleophilic aromatic substitutions of some haloarenes (X = F, Cl or Br)
with a wide range of indoles under ultrasonic irradiation without any catalyst in an air atmosphere.
Especially when various indoles were reacted with activated fluoroarenes using sonication by SNAr
reactions, N-arylation indoles were achieved in good to excellent yields (55-98 %). Compared to the
reported results,10 advantages of the present procedure are as follows: (1) very lower reaction temperature
(40 oC); (2) easy work-up and without inert atmosphere; (3) catalyst-free.
EXPERIMENTAL
The materials were used as purchased. Melting points were determined on a digital melting-point
1
13
apparatus and uncorrected. H NMR spectra and C NMR spectra were recorded on a Bruker Avance
DMX 400 MHz and 100 MHz instruments using TMS as internal standard and CDCl3 as solvent. HR-MS
and EI-MS were carried out with APEX II Bruker 4.7T AS and Thermo DSQ GC/MS instruments,
respectively. Elemental analysis was executed on Carlo-Erba 1106 CHN microanalyzer. Sonication was
performed in Ningbo SB-5200DT ultrasonic cleaner with the frequency of 40 KHz and an output power
of 200 W. The size of the bath of the ultrasonic cleaner is 25 × 31 × 15 cm.
General Procedure for the preparation of N-arylindoles:
The mixture of the appropriate haloarene (1.0 mmol), the indole (1.2 mmol), anhydrous Cs2CO3 (2.0
mmol), and DMSO (2 mL) in 25 mL rockered flask in an air atmosphere, checked by TLC, was reacted
using sonication at an output power of 200 W at 40 oC for an appropriate time as shown in Table 2. Then
40 mL ice water was added to the above mixture, and the latter was extracted by EtOAc (60 mL × 3).
Subsequently the combined organic phase was washed by brine (40 mL), dried over anhydrous Na2SO4,

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HETEROCYCLES, Vol. 76, No. 1, 2008
concentrated in vacuo, and purified by preparation TLC to give the pure N-arylation indoles.
o
1
Compound 3a: yellow solid, mp109-109.5 C; H–NMR (400 MHz, CDCl3): δ 6.77 (1H, d, J = 3.2 Hz),
13
7.21(2H, m), 7.37 (1H, d, J = 3.6 Hz), 7.64 (4H, m), 8.39 (2H, d, J = 8.8 Hz); C–NMR (100 MHz,
CDCl3 ): δ 130.4, 127.0, 125.4, 123.3, 121.6, 121.5, 110.4, 110.1, 106.1; GC/MS (EI, 70 eV): m/z (%) =
238 (100) [M]+; HRMS (ESI): m/z = 239.0818 (calcd. 239.0815 for C14H10N2O2, [M+H]+).
o
Compound 3b: orange solid, mp 69-70 C; 1H–NMR (400 MHz, CDCl3): δ 6.72 (1H, d, J = 3.2 Hz),
7.11(4H, m), 7.53 (2H, m), 7.68 (2H, m), 8.01 (1H, d, J = 8.4 Hz); 13C–NMR (100 MHz, CDCl3): δ 136.6,
133.6, 132.8, 129.7, 128.9, 128.3, 127.9, 125.4, 122.9, 121.3, 120.9, 109.4, 105.0; GC/MS (EI, 70 eV):
m/z (%) = 238 (100) [M]+. HRMS (ESI): m/z = 239.0818 (calcd. 239.0815 for C14H10N2O2, [M+H]+).
Compound 3c: white solid, mp 96-96.5 oC; 1H–NMR (400 MHz, CDCl3): δ 6.76 (1H, d, J = 3.6 Hz), 7.18
(2H, m), 7.33 (1H, d, J = 8.4 Hz), 7.40 (1H, d, J = 3.2 Hz), 7.46 (1H, m), 7.60 (1H, d, J = 8.4 Hz), 7.69
13
(2H, m), 7.83 (1H, d, J = 7.6 Hz); C–NMR (100 MHz, CDCl3): δ 134.5, 133.8, 129.3, 128.1, 127.4,
127.3, 122.8, 121.3, 121.1, 116.4, 110.2, 109.7, 105.0; GC/MS (EI, 70 eV): m/z (%) = 218 (100) [M]+.
HRMS (ESI): m/z = 219.0919 (calcd. 219.0917 for C15H10N2, [M+H]+).
o
1
Compound 3d: yellow solid, mp 220-221 C; H–NMR (400 MHz, CDCl3): δ 6.95 (1H, d, J = 3.6 Hz),
7.53 (1H, d, J = 3.2 Hz), 7.61 (1H, d, J = 8.8 Hz), 7.70 (2H, d, J = 8.4 Hz), 8.18 (1H, dd, J = 8.8 Hz, J =
2.0 Hz), 8.46 (2H, d, J = 8.8 Hz), 8.66 (1H, d, J = 2.0 Hz); 13C–NMR (100 MHz, CDCl3): δ 144.0, 130.4,
129.4, 125.7, 124.4, 118.8, 118.5, 110.4, 107.5; GC/MS (EI, 70 eV): m/z (%) = 283 (28) [M]+; Anal.
Calcd. for C14H9N3O4 (283): C 59.36, H 3.18, N 14.84; found C 59.71, H 3.42, N 14.48.
Compound 3e: orange solid, mp 104.5-106 oC; 1H–NMR (400 MHz, CDCl3): δ 6.90 (1H, d, J = 3.2 Hz),
7.10 (1H, d, J = 9.2 Hz), 7.32 (1H, d, J = 3.2 Hz), 7.59 (1H, dd, J = 8.0 Hz, J = 0.8 Hz), 7.68 (1H, m),
7.81 (1H, m), 8.08 (2H, m), 8.63 (1H, d, J = 1.6 Hz); 13C–NMR (100 MHz, CDCl3): δ 142.7, 139.6, 134.1,
131.3, 130.0, 129.8, 128.2, 125.8, 118.5, 118.3, 109.6, 106.6; GC/MS (EI, 70 eV): m/z (%) = 283 (100)
[M]+; HRMS (ESI): m/z = 284.0592 (calcd. 284.0588 for C14H9N3O4, [M+H]+).
Compound 3f: yellow solid, mp 121-122 oC; 1H–NMR (400 MHz, CDCl3): δ 2.09 (3H, s), 6.71 (1 H, d, J
= 3.2 Hz), 7.01 (1 H, d, J = 7.2 Hz), 7.11 (2H, m), 7.49 (2H, dd, J = 6.8 Hz, J = 1.6 Hz), 7.54 (1 H, d, J =
8.0 Hz), 8.33 (2H, dd, J = 6.4 Hz, J = 1.6 Hz); 13C–NMR (100 MHz, CDCl3): δ 146.8, 130.3, 130.1, 127.3,
125.8, 124.2, 121.4, 119.3, 105.2, 20.4; GC/MS (EI, 70 eV): m/z (%) = 252 (100) [M]+; Anal. Calcd. for
.
C15H12N2O2 0.5H2O (261): C 68.96, H 4.98, N 10.73; found C 69.28, H 4.57, N 11.20.
Compound 3g: orange solid, mp 96.5-97 oC; 1H–NMR (400 MHz, CDCl3): δ 1.94 (3H, s), 6.67 (1 H, d, J
= 3.2 Hz), 6.92 (1 H, d, J = 6.8 Hz), 7.05 (2H, m), 7.49 (2H, m), 7.66 (2H, m), 7.97 (1H, dd, J = 8.0 Hz, J
= 1.2 Hz); 13C–NMR (100 MHz, CDCl3): δ 134.8, 132.6, 131.7, 130.0, 129.2, 125.2, 124.4, 120.8, 119.3,
104.4, 18.5; GC/MS (EI, 70 eV): m/z (%) = 252 (95) [M]+; HRMS (ESI): m/z = 253.0973 (calcd.
253.0972 for C15H12N2O2, [M+H]+).

HETEROCYCLES, Vol. 76, No. 1, 2008
255
Compound 3h: yellow solid, mp 137-139 oC; 1H–NMR (400 MHz, CDCl3): δ 2.39 (3H, s), 7.18 (1H, s),
7.24 (2H, m), 7.63 (2 H, d, J = 8.4 Hz), 7.64 (2H, d, J = 8.8 Hz), 8.36 (2H, d, J = 8.8 Hz); 13C–NMR (100
MHz, CDCl3): δ 145.0, 125.4, 124.4, 123.4, 122.6, 121.1, 119.7, 116.0, 110.4, 9.5; GC/MS (EI, 70 eV):
m/z (%) = 252 (100) [M]+; Anal. Calcd. for C15H12N2O2 (252): C 71.42, H 4.76, N 11.11; found C 71.54,
H 4.52, N 10.98.
1
Compound 3i: red liquid, H–NMR (400 MHz, CDCl3): δ 2.35 (3H, s), 6.90 (1H, s), 7.11 (3H, m), 7.43
13
(2H, m), 7.61 (2H, m), 7.94 (1H, dd, J = 8.0 Hz, J = 1.2 Hz); C–NMR (100 MHz, CDCl3): δ 145.9,
136.6, 133.5, 132.9, 129.6, 129.3, 127.6, 125.4, 125.1, 122.8, 120.3, 119.3, 114.3, 109.3, 9.5; GC/MS (EI,
70 eV): m/z (%) = 252 (80) [M]+; HRMS (ESI): m/z = 253.0971 (calcd. 253.0972 for C15H12N2O2,
[M+H]+).
ACKNOWLEDGEMENTS
This work has been supported by the program for New Century Excellent University Talents
(NCET-06-0868), State Education Ministry of China, the Scientific Research Foundation for the Returned
Overseas Chinese Scholars, State Education Ministry (No.14110101), and Science & Technology
Research Plan in Shaanxi Province of China (No.2006K01-G31-04). We also thank Northwest A&F
University for the financial support by program for excellent talents.
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