Microwave-assisted nucleophilic aromatic substitution on aryl halides with different indoles is described. Moderate to good yields are obtained in short reaction time (25 -40 min) when coupling indoles with fluoro-and chloro-substituted aryl halides under catalyst-free conditions

Hui Xu

Ling-Ling Fan

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Microwave-assisted N-Arylation of Indoles via C(sp2)–N(sp2) Bond
Formation by Aromatic Nucleophilic Substitution Reactions
Hui Xu and Ling-Ling Fan
Lab of Pharmaceutical Synthesis, College of Science, Northwest A & F University, Yangling 712100,
Shaanxi Province, China
Reprint requests to Prof. Dr. Hui Xu. Fax : +86(0)29/87091952. E-mail: orgxuhui@nwsuaf.edu.cn
Z. Naturforsch. 2008, 63b, 298 – 302; received October 7, 2007
Microwave-assisted nucleophilic aromatic substitution on aryl halides with different indoles is de-
scribed. Moderate to good yields are obtained in short reaction time (25 – 40 min) when coupling
indoles with fluoro- and chloro-substituted aryl halides under catalyst-free conditions.
Key words: N-Arylindoles, Aryl Halides, Microwave, SNAr Reaction, Cross-coupling
Introduction
The N-arylindole subunit is an important species in
many biologically active and pharmaceutically impor-
tant compounds, which display antiestrogen [1], anal-
gesic [2], antiallergy [3], antimicrobial [4], and neu-
roleptic activity [5]. Although the traditional copper-
catalyzed coupling of an aryl halide with a heteroatom-
based nucleophile, the Ullmann-type coupling reac-
tion, has remained a standard method for the construc-
tion of N-arylindoles, it requires high temperatures,
generally 140 ◦C or more, and often the use of two or
more equivalents of the aryl halide to obtain optimal
yields. Buchwald reported some improved N-arylation
of indoles, but still using expensive palladium or cop-
per [6]. Another reaction of the CuOAc catalyzed N-
arylation of indoles has been reported recently [7].
On the other hand, the nucleophilic aromatic substitu-
tion of aryl halides, activated by electron-withdrawing
substituents, with indoles represents yet another route
to N-arylindoles for certain substrate combinations.
Smith has described the N-arylation of indole by aro-
matic nucleophilic substitution, however, this SNAr re-
action was catalyzed by 18-crown-6 at high temper-
ature (120 ◦C), and no examples of reactions of sub-
stituted indoles were reported [8]. Maiorana described
N-arylation of indoles by aromatic nucleophilic sub-
stitution on haloarenes, but using chromium tricar-
bonyl complexes [9]. Therefore, a simple and general
method for SNAr reactions, including easy work-up
and a wide scope of substrates, for the preparation of
N-arylindoles is highly desirable.
0932–0776 / 08 / 0300–0298 $ 06.00 c© 2008 Verlag der Zeitschrift für Naturforschung, Tübingen · http://znaturforsch.com
Fig. 1. Microwave-assisted synthesis of N-arylindoles via
C(sp2)–N(sp2) bond formation.
Compared to traditional processing of organic syn-
thesis, microwave-enhanced chemistry saves signifi-
cant time, very often improves yields and has attracted
considerable attention in the past decade [10, 11]. To
the best of our knowledge, however, the catalyst-free
N-arylation of a variety of 3-, 5- and 7-substituted in-
doles with aryl halides by SNAr reaction using high-
speed microwave techniques has not been reported.
In continuation of our research interest in the use of
microwave irradiation [11], herein, we wish to de-
scribe our studies on the microwave-assisted construc-
tion of N-arylindoles via C(sp2)–N(sp2) bond forma-
tion by SNAr reaction at an irradiation power of 420 W
(Fig. 1).
Results and Discussion
From the results shown in Table 1 it can be seen
that a range of indoles, including those with electron-
deficient and electron-rich substitutents, can be used in
this C(sp2)–N(sp2) cross-coupling SNAr reaction with
activated aryl halides (X = F, Cl, Br) in the presence of
K2CO3 or Cs2CO3 under microwave irradiation. For
H. Xu – L.-L. Fan · Microwave-assisted N-Arylation of Indoles 299
Table 1. Microwave-assisted synthesis of N-arylated indolesa.
Entry Aryl halides (1) Indoles (2) N-Arylindoles (3) Base Timeb (min) Yield (%)
a K2CO3 6×5 79
b K2CO3 6×5 71
c K2CO3 7×5 52
d K2CO3 6×5 94
e K2CO3 5×5 91
f K2CO3 6×5 NRc
example, 4-fluoronitrobenzene (0.5 mmol) was cou-
pled with indole (0.55 mmol) in DMSO (2 mL) at
an irradiation power of 420 W mediated by K2CO3
(1.5 mmol) for 6×5 min, N-(4-nitrophenyl)indole be-
ing obtained in 79 % yield (entry a). It is notewor-
thy that in our reaction the electron-poor 5-nitroindole
could smoothly be coupled with 4-fluoronitrobenzene
and 2-fluoronitrobenzene (entries d and e), the corre-
sponding yields being 94 % and 91 %, respectively. A
steric effect was observed for this reaction. Although
K2CO3 was a good base for combining the activated
fluoroarenes with indole, 5-nitroindole or 3-methyl-
indole (entries a – e, i, j), it was ineffective in the cou-
pling reaction with 7-methylindole. For example, when
300 H. Xu – L.-L. Fan · Microwave-assisted N-Arylation of Indoles
Table 1 (continued).
Entry Aryl halides (1) Indoles (2) N-Arylindoles (3) Base Timeb (min) Yield (%)
g Cs2CO3 8×5 62
h Cs2CO3 8×5 46
i K2CO3 7×5 83
j K2CO3 7×5 94
k K2CO3 8×5 NR
l Cs2CO3 5×5 47
m Cs2CO3 5×5 18
a All reactions were carried out with compounds 1 (0.5 mmol), 2 (0.55 mmol), and K2CO3 (1.5 mmol) or Cs2CO3 (1.0 mmol) in DMSO
(2 mL) under microwave irradiation; b 6× 5 means 6 times 5 min as reaction time; the progress of the reaction was checked by TLC at the
end of each irradiation period; c NR = no reaction.
7-methylindole was coupled with 4-fluoronitrobenz-
ene in the presence of K2CO3 for 6× 5 min, no tar-
get compound was monitored by TLC as the nitrogen
atom of 7-methylindole is strongly hindered (entry f).
H. Xu – L.-L. Fan · Microwave-assisted N-Arylation of Indoles 301
However, when we chose Cs2CO3 as the base for the
N-arylation of 7-methylindole with 4-fluoronitrobenz-
ene and 2-fluoronitrobenzene, the corresponding yields
were 62 % and 46 %, respectively (entries g and h).
Finally we investigated the microwave-assisted cou-
pling of 2-chloronitrobenzene or 4-bromonitrobenz-
ene with indole at an irradiation power of 420 W.
Unfortunately, conditions employing K2CO3 as the
base were inefficient for the cross-coupling reaction
(entry k). However, N-(2-nitrophenyl)indole and N-
(4-nitrophenyl)indole were obtained in 47 and 18 %
yields, respectively, in the presence of Cs2CO3 (en-
tries l and m).
Conclusion
In summary, we have described an efficient SNAr re-
action to synthesize N-arylindoles via C(sp2)–N(sp2)
bond formation in the presence of K2CO3 or Cs2CO3
under a microwave irradiation power of 420 W. The
reaction time was very short (25 – 40 min), and mod-
erate to good yields (46 – 94 %) were achieved without
any catalyst, when a wide substrate range of indoles
were reacted with fluoro- and chloro-substituted aryl
halides.
Experimental Section
The materials were used as purchased. Melting points
were determined on a digital melting-point apparatus and
are uncorrected. NMR spectra were recorded on a Bruker
Avance DMX instrument (1H: 400 MHz; 13C: 100 MHz) us-
ing TMS as internal standard and CDCl3 as solvent. HRMS
and EIMS measurements were carried out with APEX II
Bruker 4.7T AS and Thermo DSQ GC/MS instruments,
respectively. Elemental analyses were determined with a
Carlo-Erba 1106 CHN microanalyzer. Microwave irradiation
was performed in a Galanz microwave oven, WG700CTL.
General procedure
To a mixture of activated aryl halide (X = F, Cl, Br,
0.5 mmol), indole (0.55 mmol) and K2CO3 (1.5 mmol) or
Cs2CO3 (1.0 mmol) was added DMSO (2 mL). The reac-
tion was found not to be sensitive to air and moisture, hence
DMSO was used directly without any additional purifica-
tion, and there was no need for inert atmosphere. The mix-
ture was placed in a microwave oven and irradiated at a
power of 420 W for the appropriate time as shown in Ta-
ble 1. The progress of the reaction was monitored by thin-
layer chromatography (TLC). After completion of the reac-
tion, the mixture was cooled to r. t. and poured into ice water
(20 mL). Then 40 mL of EtOAc was added to the mixture,
the organic layer was separated, and the aqueous layer was
extracted with EtOAc (2× 40 mL). The combined organic
extracts were washed with 4 mol/L HCl (3× 20 mL), brine
(1 × 40 mL) and dried over anhydrous MgSO4. After re-
moval of the solvent under reduced pressure, the residue was
purified by preparative thin-layer chromatography (PTLC)
or silica gel column chromatography to give the pure N-
arylindoles. All compounds were characterized by 1H NMR
(400 MHz), 13C NMR (100 MHz), HRMS or elemental anal-
ysis, EIMS, and melting points.
Compounds 3a and 3m: Yellow solid, m. p. 109 –
109.5 ◦C. – 1H NMR (400 MHz, CDCl3): δ = 6.77 (1H, d,
J = 3.2 Hz), 7.21 (2H, m), 7.37 (1H, d, J = 3.6 Hz), 7.64
(4H, m), 8.39 (2H, d, J = 8.8 Hz). – 13C 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]+).
Compounds 3b and 3l: Orange solid, m. p. 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, m. p. 96 – 96.5 ◦C. – 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 (2H, m), 7.83
(1H, d, J =7.6 Hz). – 13C NMR (100 MHz, CDCl3): δ =
142.0, 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]+).
Compound 3d: Yellow solid, m. p. 220 – 221 ◦C. –
1H 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]+. – C14H9N3O4 (283): calcd. C 59.36, H 3.18,
N 14.84; found C 59.71, H 3.42, N 14.48.
Compound 3e: Orange solid, m. p. 104.5 – 106 ◦C. –
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]+).
302 H. Xu – L.-L. Fan · Microwave-assisted N-Arylation of Indoles
Compound 3g: Yellow solid, m. p. 121 – 122 ◦C. –
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]+. – C15H12N2O2 · 0.5H2O (261): calcd. C 68.96,
H 4.98, N 10.73; found C 69.28, H 4.57, N 11.20.
Compound 3h: Orange solid, m. p. 96.5 – 97 ◦C. –
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]+).
Compound 3i: Yellow solid, m. p. 137 – 139 ◦C. –
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]+. – C15H12N2O2 (252): calcd. C 71.42, H 4.76,
N 11.11; found C 71.54, H 4.52, N 10.98.
Compound 3j: Red liquid. – 1H NMR (400 MHz, CDCl3):
δ = 2.35 (3H, s), 6.90 (1H, s), 7.11 (3H, m), 7.43 (2H,
m), 7.61 (2H, m), 7.94 (1H, dd, J = 8.0 Hz, J = 1.2 Hz).
– 13C 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 was supported by the Program for New Cen-
tury Excellent Talents in University (NCET-06-0868), State
Education Ministry, China, and the Scientific Research Foun-
dation for the Returned Overseas Chinese Scholars, State
Education Ministry (No.14110101). We also acknowledge
Northwest A&F University for the financial assistance within
the program for excellent young talents.
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Microwave-assisted N-Arylation of Indoles via C(sp 2 )-N(sp 2 ) Bond Formation by Aromatic Nucleophilic Substitution Reactions

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Microwave-assisted N-Arylation of Indoles via C(sp 2 )-N(sp 2 ) Bond Formation by Aromatic Nucleophilic Substitution Reactions

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