Microwave-assisted synthesis of indole-2-carboxylic acid esters in ionic liquid

Article abstract of DOI:10.1590/S0103-50532011001100003

An improved procedure for the synthesis of indole-2-carboxylic acid esters in excellent yields has been achieved by the condensation of 2-halo aryl aldehydes or ketones and ethyl isocyanoacetate using ionic liquid under controlled microwave irradiation (100 W) at 50 °C. This method offers a number of advantages in terms of methodology, high-product yield, short period of conversion, mild reaction conditions and easy workup.

Full text of DOI:10.1590/S0103-50532011001100003

J. Braz. Chem. Soc., Vol. 22, No. 11, 2036-2039, 2011.
Printed in Brazil - ©2011 Sociedade Brasileira de Química
0
103 - 5053 $6.00+0.00
Article
A
Microwave-Assisted Synthesis of Indole-2-Carboxylic Acid Esters in Ionic Liquid
,
a
b
Lijun Gu* and Xiangguang Li
a
Key Laboratory of Ethnic Medicine Resource Chemistry, Yunnan University of Nationalities,
State Ethnic Affairs Commission & Ministry of Education of P. R. China, Kunming, 650031, China
b
Department of Chemistry, Northwest University, Xi’an, China
Um procedimento melhorado para a síntese de ésteres ácido indol-2-acético em rendimentos
excelentes foi obtido pela condensação de 2-halo aril aldeídos ou cetonas e isocianoacetato de
o
etila usando líquido iônico sob irradiação de microondas controlada (100 W) a 50 C. Este método
oferece um número de vantagens em termos de metodologia simples, com rendimento elevado
num tempo de reação curto e em condições de reação amenas.
An improved procedure for the synthesis of indole-2-carboxylic acid esters in excellent yields
has been achieved by the condensation of 2-halo aryl aldehydes or ketones and ethyl isocyanoacetate
using ionic liquid under controlled microwave irradiation (100 W) at 50 °C. This method offers
a number of advantages in terms of methodology, high-product yield, short period of conversion,
mild reaction conditions and easy workup.
Keywords: indole, synthesis, ionic liquid, microwave irradiation
Introduction
time and moderate yields. For the cyclization of 2-chloro
aryl aldehydes/ketones with isocyanoacetate, the yield of
the reaction is unsatisfactory and the temperature of the
reaction is high. Therefore, it is necessary to develop a more
practical method for synthesis of such a significant scaffold.
The research and application of green chemistry
principles have led to the development of cleaner processes.
Since the start of this century an ever-growing number
The indole moiety is a vital structural unit found in
a large array of natural products and pharmaceuticals.
Consequently, synthetic approaches toward indoles have
attracted significant attention. In many cases, the well-
studied Fischer indole synthesis is the method of choice, but
this approach suffers from problems such as low yield and
1-3
4
formation of side products. In our design of new inhibitors
of studies has been published describing the use of ionic
5
,6
12-17
of aspartyl protease, we were interested in differently
substituted indole-2-carboxylic acid esters. Owing to
their structural diversity and remarkable biological
functions, a multitude of methods exist for the synthesis
of these compounds. The conventional method is the
liquids.
Microwave-assisted organic synthesis has
shown to be a valuable tool for reducing reaction times,
getting cleaner reactions, improving yields, simplifying
18,19
workup and designing energy-saving protocols.
Due to their ionic nature, ionic liquids allow highly
effective interactions with microwave energy for the
7
Hemetsberger-Knittel indole synthesis. This method
2
0
involves the condensation between an arylaldehyde and
an azidoacetate to provide a-azidocinnamates which
upon heating give indoles. One problem is associated
with employing high boiling solvents such as mesitylene,
rapid generation of products with generally high yields.
Herein, we developed a fast and practical method for the
synthesis of indole-2-carboxylic acid esters in the presence
of 1-methyl-3-butylimidazolium hydroxide ( [bmim]OH )
under controlled microwave irradiation (100 W) at 50 °C.
The synthetic sequence is depicted in Scheme 1.
8
,9
xylene and toluene. In addition, the yield of the reaction
10
11
is low. Cai and co-workers developed a copper-catalyzed
cascade process from 2-halo aryl aldehydes/ketones with
isocyanoacetate for synthesis of these derivatives. However,
the procedure has some drawbacks such as long reaction
Results and Discussion
Initial studies were carried out using 2-bromo
benzenealdehyde as the substrate and isocyanoacetate as
*
e-mail: gulijun2005@126.com

Vol. 22, No. 11, 2011
Gu and Li
2037
O
X
R1
R1
Ar or
Het
CuI, [bmim]OH
Ar or
Het
+
CNCH CO Et
2 2
DMSO-free, MW
N
H
CO Et
2
1
2
1
R = H or Me
X = I, Br or Cl
Scheme 1. Sequence for the synthesis of indole-2-carboxylic acid esters in the presence of 1-methyl-3-butylimidazolium hydroxide ([bmim]OH ) under
controlled microwave irradiation.
the nitrogen source in [bmim]OH under the catalysis of CuI
12 mol%) for 8 h, the desired product ethyl 1H-indole-
-carboxylate was obtained in moderate yield (57%). When
irradiation for assembly of indole-2-carboxylic acid esters in
high yields. The experimental procedure is very simple and
the reaction time is short. The synthetic protocols described
above have proven amenable to scale-up to over 10-g
quantities.
(
2
the reaction was irradiated under controlled microwave
o
(
100 W) for 10 min at 50 C, 91% of the desired product
was reached. Encouraged by the result, other Cu reagents,
such as CuBr or CuCl, were investigated in the presence
of [bmim]OH under microwave irradiation. The results
showed that replacement of CuI with CuBr slightly affected
the outcome of this reaction (entry 1 and entry 9, Table 1).
CuCl was less active (entries 9-10, Table 1). When other
copper sources such as Cu O and Cu(OAc) were used, no
Experimental
General
Reagents were obtained commercially and used as
received. Solvents were purified and dried by standard
methods. [bmim]OH was synthesized according to
2
2
desired product was detected.
2
1
Next, the reaction time and the temperature were
investigated in order to find the optimal reaction conditions.
It was found that 10 min was long enough to run the reaction.
Raising the reaction temperature did not obviously improve
the reaction yield (entries 11-12, Table 1). Also an extended
reaction time has no effect on the conversion. Finally, the
optimal conditions for parallel synthesis were determined to
the method described in the literature. Microwave
reactions were performed on a CEM Explorer Hybrid 12
Discover, with built in temperature/pressure probes
and associated software. The melting points (mp) were
determined on an XT-4 micro melting point apparatus and
uncorrected. Infrared (IR) spectra were recorded on an
1
EQUINOX-55 spectrometer on a KBr matrix. H nuclear
o
be 12 mol% CuI at 50 C for 10 min. The substrate variation
magnetic resonance (NMR) spectra were recorded on an
INOVA-400 NMR spectrometer using TMS as an internal
standard. Chemical shift values (d) are given in ppm.
Elemental analyses were performed on a Vario EL III
CHNS analyzer. Electrospray mass spectra were obtained
with an MALDI-TOF Mass spectrometer. 200-300 mesh
silica gel was used for column chromatography.
was then investigated. To our satisfaction, the reaction shows
a wide scope for the structural variations of aryl aldehydes
or ketones under the optimized reaction conditions. Both
electron-donating and electron-withdrawing groups allowed
smooth transformation of aryl aldehydes or ketones into
the corresponding products with high yields. Performing
the reaction with 2-chloro aryl aldehydes or ketones gave
good yields (entries 13-16, Table 1). It was noteworthy that
hetero-aryl aldehydes or ketones with varied substitutions
were found to undergo the reaction (entries 17-20, Table 1). It
was found that DMSO-free condition gave the corresponding
product in excellent yield (entries 21-24, Table 1). To
illustrate the preparative utility, our procedure was performed
on a large scale (entry 25, Table 1). A 60-mmol-scale
synthesis gave the desired product in 88% yield.
Representative procedure for the synthesis of 2
An oven-dried 10-mL microwave vial was charged
with copper(I) iodide (0.24 mmol), [bmim]OH (2 mL),
aldehydes or ketones (1 mmol), ethyl isocyanoacetate
(1.1 mmol), DMSO (1 mL), or DMSO-free with the
addition of a stirred bar. The reaction vessel was sealed,
evacuated and flushed with argon three times. The mixture
o
was irradiated by 100 W microwave at 50 C for 10 min.
Conclusions
The reaction mixture was partitioned between ethyl acetate
and water. The organic layers were washed with water and
In summary, in this study we have successfully extended
the use of ionic liquid [bmim]OH under microwave
brine, dried over anhydrous MgSO and concentrated under
vacuum to yield the crude product. The crude product
4

2
038
Microwave-Assisted Synthesis of Indole-2-Carboxylic Acid Esters in Ionic Liquid
J. Braz. Chem. Soc.
a
Table 1. Reactions of 2-halo aryl aldehydes or ketones with ethyl isocyanoacetate
b
b
entry
1
Substrate
CHO
Product
Yield / %
entry
Substrate
Product
Yield / %
91
CO2Et
14
g
O
74
78
N
H
Br
N
H
CO2Et
Cl
2
3
O
95
93
N
N
CHO
Cl
N
H
CO2Et
g
Br
15
N
H
CO Et
2
O N
2
O N
CHO
Br
2
N
CO2Et
S
H
S
N
S
g
O
1
6
81
N
H
CO Et
2
Cl
O
4
5
6
92
91
95
O
N
CO2Et
O
Br
H
N
CHO
Br
1
1
7
8
88
90
N
H
CO Et
2
Cl
Cl
CHO
I
N
H
CO2Et
S
CHO
Br
N
H
CO Et
2
CHO
Br
S
N
H
CO2Et
CO2Et
CO2Et
S
1
9
O
93
N
H
CO Et
2
Br
7
8
O
93
91
Cl
N
H
O N
2
S
Cl
Br
O N
2
S
CHO
2
2
2
0
1
2
91
90
93
CHO
Br
N
CO Et
2
Br
H
N
H
O
O
CHO
Br
h
h
N
H
CO2Et
CHO
Br
c
9
90
58
N
H
CO2Et
O
CHO
Br
N
H
CO2Et
d
1
1
0
1
Br
N
H
CO2Et
N
N
CHO
Br
h
2
2
3
4
90
e
O
95
N
H
CO Et
2
N
H
CO2Et
Br
S
S
h
O
89
88
f
1
2
3
O
97
71
N
H
CO Et
CO2Et
2
N
H
Br
Br
CHO
Br
CHO
Cl
i
g
25
1
N
H
CO2Et
N
H
CO2Et
a
Reaction conditions: CuI (0.24 mmol), [bmim]OH (2 mL), aryl bromides (1 mmol), ethyl isocyanoacetate (1.1 mmol), DMSO (1 mL), Ar atmosphere,
o
b
c
d
e
o
f
o
microwave irradiation, 50 C, 10 min; isolated yields; CuBr as catalyst; CuCl as catalyst; reaction temperature of 60 C; reaction temperature of 70 C;
g
o
h
i
reaction temperature of 60 C; without DMSO; CuI (15 mmol), [bmim]OH (35 mL), aryl bromides (60 mmol), ethyl isocyanoacetate (66 mmol), Ar
o
atmosphere, microwave irradiation, 50 C.

Vol. 22, No. 11, 2011
Gu and Li
2039
was purified by flash chromatography with ethyl acetate/
petroleum ether as eluent on silica gel to afford the desired
product.
9. Secchi, M.; Derudas, M.; Dallochio, R.; Dessi, A.; Bacchi,
A.; Sannia, L.; Carta, F.; Palomba, M.; Ragab, O.; Chan, C.;
Shoemaker, R.; Sei, S.; Dayam, R.; Neamati, N.; J. Med. Chem.
2
004, 47, 5298.
Supplementary Information
10. Venable, J. D.; Cai, H.; Chai, W.; Dvorak, C. A.; Grice, C. A.;
Jablonowski, J.A.; Shah, C. R.; Kwok,A. K.; Ly, K. S.; Pio, B.;
Wei, J.; Desai, P. J.; Jiang, W.; Nguyen, S.; Ling, P.;Wilson, S. J.;
Dunford, P. J.; Thurmond, R. L.; Lovenberg, T. W.; Karlsson, L.;
Carruthers, N. I.; Edwards, J. P.; J. Med. Chem. 2004, 48, 8289.
11. Cai, Q.; Li, Z. Q.; Wei, J. J.; Ha, C. Y.; Pei, D. Q.; Ding, K.;
Chem. Commun. 2009, 46, 7581.
Supplementary data are available free of charge at
http://jbcs.sbq.org.br as PDF file.
Acknowledgments
The authors thank theYouth Fund ofYunnan University
of Nationalities (No. 09QN04) for finacial support. We
thank Mr. Ahmad for reproducing the results presented in
entries 1 and 19 of Table 1.
12. Lovelock, K. R.; Villar-Garcia, I. J.; Maier, F.; Steinrück, H.;
Licence, P.; Chem. Rev. 2010, 111, 5158.
13. Pilissão, C.; Carvalho, P. O.; Nascimento, M. G.; J. Braz. Chem.
Soc. 2010, 21, 973.
1
4. Polshettiwar, V.; Varma, R. S.; Acc. Chem. Res. 2008, 41, 629.
References
15. Pastre, J. C.; Génisson, Y.; Saffon, N.; Dandurand, J.; Correia,
C. R. D.; J. Braz. Chem. Soc. 2010, 21, 821.
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. Humphrey, G. R.; Kuethe, J. T.; Chem. Rev. 2006, 106, 2875.
. Bandini, M.; Eichholzer, A.; Angew. Chem., Int. Ed. 2009, 48,
16. Dupont, J.; J. Braz. Chem. Soc. 2004, 15, 341.
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M. T.; Alves, D.; Jacob, R. J.; Perin, G.; J. Braz. Chem. Soc.
2010, 21, 2093.
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608.
. Sharma, V.; Kumar, P.; Pathak, D.; J. Heterocycl. Chem. 2010,
7, 491.
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4
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18. Souza, R. O. M. A.; Quim. Nova 2011, 34, 497.
19. Wang, X. Q.; Zhao, Z. G.; Li, W. J.; Liu, X. L.; Han, T.; Chin.
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Tetrahedron Lett. 1999, 40, 3601.
. Gu, L. J.; Liu, F. L.; Li, X. G.; Gao, B.; Yang, B. Q.; Synth.
Commun. 2010, 40, 242.
20. Hoffmann, H.; Nuchter, M.; Ondruschka, B.; Wasserscheid, P.;
Green Chem. 2003, 5, 296.
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8.
7
8
. Knittel, D.; Synthesis 1985, 2, 186.
Submitted: May 17, 2011
. Hickey, D. M. B.; MacKenzie,A. R.; Moody, C. J.; Rees, C. W.;
J. Chem. Soc., Perkin Trans. 1 1987, 921.
Published online: August 25, 2011

J. Braz. Chem. Soc., Vol. 22, No. 11, S1-S14, 2011.
Printed in Brazil - ©2011 Sociedade Brasileira de Química
0
103 - 5053 $6.00+0.00
Supplementary Information
SI
Microwave-Assisted Synthesis of Indole-2-Carboxylic Acid Esters in Ionic Liquid
,
a
b
Lijun Gu* and Xiangguang Li
a
Key Laboratory of Ethnic Medicine Resource Chemistry, Yunnan University of Nationalities,
State Ethnic Affairs Commission & Ministry of Education of P. R. China, Kunming, 650031, China
b
Department of Chemistry, Northwest University, Xi’an, China
1
Ethyl 1H-indole-2-carboxylate
H NMR (CDCl , 400 MHz) d 1.40 (t, 3H, J 7.2 Hz), 2.59
3
o
1
o
White solid; mp 120-122 C (lit. mp 121-123 C); IR
(s, 3H), 3.81 (s, 3H), 4.42 (q, 2H, J 7.2 Hz), 6.83 (d, 1H,
J 2.4 Hz), 6.91-7.03 (m, 1H), 7.49 (d, 1H, J 8.0 Hz), 9.06
(br s, 1H); C NMR (CDCl , 75 MHz) d 160.8, 144.1,
-1
1
(
KBr) nmax/cm 3463, 3431, 2929, 1711 and 1695; H NMR
13
(
CDCl , 400 MHz) d 1.41 (t, 3H, J 6.8 Hz), 4.39 (q, 2H,
3
3
J 6.8 Hz), 7.23-7.16 (m, 1H), 7.29-7.33 (m, 2H), 7.49-7.56
130.6, 128.4, 127.0, 121.3, 118.5 109.7, 105.2, 61.7, 56.2,
14.1, 11.6; MALDI-TOF MS m/z 233 (M ); Anal. calcd.
1
3
+
(
(
m, 1H), 7.69 (d, 1H, J 9.6 Hz), 9.41 (br s, 1H); C NMR
CDCl , 75 MHz) d 161.7, 135.4, 128.2, 126.5, 122.6,
for C H NO : C 66.94, H 6.48, N 6.00; found: C 66.81,
3
13 15
3
1
21.7, 121.1, 110.6, 109.2, 62.3, 14.7; MALDI-TOF MS
H 6.44, N 6.03.
+
m/z 189 (M );Anal. calcd. for C H NO : C 69.83, H 5.86,
11
11
2
N 7.40; found: C 70.01, H 5.69, N 7.21.
Ethyl 5-chloro-1H-indole-2-carboxylate
o
1
o
White solid; mp 169-171 C (lit. mp 167-169 C);
-
1
Ethyl 3-methyl-1H-indole-2-carboxylate
IR (KBr) n /cm 3461, 3343, 2928, 1715 and 1693;
max
o
2
o
1
White solid; mp 132-134 C (lit. mp 134-136 C);
H NMR (CDCl , 400 MHz) d 1.39 (t, 3H, J 4.8 Hz), 4.41
3
-
1
IR (KBr) n /cm 3466, 3429, 2928, 1716 and 1691;
(q, 2H, J 4.8 Hz), 7.31 (s, 1H), 7.41-7.44 (m, 1H), 7.53
(d, 1H, J 3.2 Hz), 7.67 (s, 1H), 9.89 (br s, 1H); C NMR
max
1
13
H NMR (CDCl , 400 MHz) d 1.43 (t, 3H, J 9.6 Hz), 2.61
3
(
(
(
s, 3H), 4.33 (q, 2H, J 9.6 Hz), 7.21-7.25 (m, 1H), 7.31-7.39
m, 2H), 7.61 (d, 1H, J 8.0 Hz), 9.01 (br s, 1H); C NMR
(CDCl , 75 MHz) d 160.9, 137.1, 129.4, 128.6, 127.2,
3
1
3
122.8, 120.7, 111.5, 109.3, 62.4, 14.5; MALDI-TOF MS
+
CDCl , 75 MHz) d 162.3, 136.1, 128.7, 125.6, 123.7, 121.3,
m/z 223 (M ); Anal. calcd. for C H ClNO : C 59.07,
3
11 10
2
1
2
20.4, 119.2, 110.5, 61.2, 14.8, 10.3; MALDI-TOF MS m/z
H 4.51, N 6.26; found: C 59.16, H 4.57, N 6.32.
+
03 (M ); Anal. calcd. for C H NO : C 70.92, H 6.45,
12
13
2
N 6.89; found: C 71.14, H 6.49, N 6.92.
Ethyl 3H-benz[e]indole-2-carboxylate
o
5
o
Brown solid; mp 164-166 C (lit. mp 164-165 C);
-
1
Ethyl 5-nitrol-1H-indole-2-carboxylate
IR (KBr) n /cm 3464, 3340, 2929, 1710 and 1691;
max
o
3
o
1
Yellow solid; mp 221-223 C (lit. mp 220-222 C);
H NMR (CDCl , 400 MHz) d 1.42 (t, 3H, J 6.0 Hz),
3
-
1
IR (KBr) n /cm 3460, 3431, 2931, 1506 and 1341;
4.43 (q, 2H, J 6.0 Hz), 7.33-7.51 (m, 4H), 7.66-7.79 (m,
2H), 8.03 (d, 1H, J 8.0 Hz), 9.92 (br s, 1H); C NMR
max
1
13
H NMR (CDCl , 400 MHz) d 1.39 (t, 3H, J 4.0 Hz), 4.38
3
(
(
(
q, 2H, J 4.0 Hz), 7.41 (s, 1H), 7.59 (d, 1H, J 4.0 Hz), 8.11
d, 1H, J 8.0 Hz), 8.63 (s, 1H), 10.11 (br s, 1H); C NMR
(CDCl , 75 MHz) d 161.4, 135.2, 130.1, 129.0, 128.6,
3
13
127.7, 126.5, 124.8,124.1, 122.9, 121.6, 112.3, 109.1,
+
CDCl , 75 MHz) d 161.4, 146.3, 138.9, 131.1, 125.8,
61.8, 14.2; MALDI-TOF MS m/z 239 (M ); Anal. calcd.
3
1
20.7, 119.5, 112.2, 110.6, 61.7, 14.3; MALDI-TOF MS
for C H NO : C 75.30, H 5.48, N 5.85; found: C 75.42,
H 5.51, N 5.83.
15
13
2
+
m/z 234 (M );Anal. calcd. for C H N O : C 56.41, H 4.30,
11
10
2
4
N 11.96; found: C 56.53, H 4.39, N 11.74.
Ethyl 6-chloro-3-methyl-1H-indole-2-carboxylate
o
6
o
Ethyl 6-methoxyl-3-methyl-1H-indole-2-carboxylate
White solid; mp 159-161 C (lit. mp 159-160 C);
o
4
o
-1
Brown solid; mp 121-123 C (lit. mp 122-124 C);
IR (KBr) n /cm 3460, 3339, 2929, 1710 and 1691;
max
-
1
1
IR (KBr) nmax/cm 3467, 3336, 2990, 1706 and 1681;
H NMR (CDCl , 400 MHz) d 1.41 (t, 3H, J 8.0 Hz),
3
2
.59 (s, 3H), 4.31 (q, 2H, J 8.0 Hz), 7.11-713 (m, 1H),
*e-mail: gulijun2005@126.com
7.31-7.35 (d, 1H, J 1.8 Hz), 7.59 (d, 1H, J 9.6 Hz), 9.09

S2
Microwave-Assisted Synthesis of Indole-2-Carboxylic Acid Esters in Ionic Liquid
J. Braz. Chem. Soc.
1
3
(
1
1
br s, 1H); C NMR (CDCl , 75 MHz) d 161.7, 137.2,
Ethyl 6-methyl-thieno[3,2-b]pyrrole-5-carboxylate
3
o
8
o
30.1, 128.4, 125.6, 122.5, 121.3, 120.5, 110.2, 61.3,
4.9, 9.7; MALDI-TOF MS m/z 237 (M ); Anal. calcd.
White solid; mp 144-146 C (lit. mp 144-145 C);
+
-1
1
IR (KBr) nmax/cm 3430, 3300, 2993 and 1687; H NMR
for C H ClNO : C 60.64, H 5.09, N 5.89; found: C 60.33,
(CDCl , 400 MHz) d 1.35 (t, 3H, J 7.2 Hz), 2.43 (s, 3H),
1
2
12
2
3
H 5.02, N 5.97.
4.31 (q, 2H, J 7.2 Hz), 6.69 (d, 1H, J 5.4 Hz), 7.31 (d, 1H,
13
J 5.4 Hz), 9.42 (br s, 1H); C NMR (CDCl , 75 MHz)
3
Ethyl 7-methoxyl-1H-indole-2-carboxylate
d 161.8, 140.4, 130.6, 127.2, 122.9, 121.3, 109.6, 61.5,
14.8, 11.7; MALDI-TOF MS m/z 209 (M ); Anal. calcd.
o
1
o
+
White solid; mp 159-161 C (lit. mp 160-162 C);
-
1
IR (KBr) n /cm 3465, 3335, 2930, 1711 and 1695;
for C H NO S: C 57.39, H 5.30, N 6.69, S 15.32; found:
max
10 11
2
1
H NMR (CDCl , 400 MHz) d 1.39 (t, J 6.0 Hz, 3H), 3.83
C 57.27, H 5.38, N 6.57, S 15.26.
3
(
1
s, 3H), 4.41 (q, 2H, J 6.0 Hz), 6.87 (s, 1H), 7.01-7.09 (m,
H), 7.25 (d, 1H, J 2.0 Hz), 7.29 (d, 1H, J 7.2 Hz), 9.11
Ethyl 2-nitrothieno[3,2-b]pyrrole-5-carboxylate
1
3
o
9
o
(
br s, 1H); C NMR (CDCl , 75 MHz) d 160.9, 145.2,
Yellow solid; mp 187-189 C (lit. mp 188-189 C);
3
-
1
1
5
30.2, 129.1, 128.8, 122.3, 118.6, 111.0, 105.4, 61.7,
6.2, 14.4; MALDI-TOF MS m/z 219 (M ); Anal. calcd.
IR (KBr) n /cm 3410, 3303, 1689, 1490 and 1370;
max
+
1
H NMR (CDCl , 400 MHz) d 1.40 (t, 3H, J 7.0 Hz), 4.33 (q,
3
for C H NO : C 65.74, H 5.98, N 6.39; found: C 65.69,
H 5.91, N 6.44.
2H, J 7.0 Hz), 7.11 (m, 1H), 7.76 (d, 1H, J 4.8 Hz), 9.39 (br
s, 1H); C NMR (CDCl , 75 MHz) d 162.7, 151.3, 137.4,
3
1
2
13
3
13
1
31.6, 128.1, 122.2, 108.5, 60.6, 14.1; MALDI-TOF MS
+
Ethyl 1H-pyrrolo[3,2-b]pyridine-2-carboxylate
m/z 240 (M );Anal. calcd. for C H N O S: C 45.00, H 3.36,
9
8
2
4
o
7
o
Brown solid; mp 179-181 C (lit. mp 179 C);
N 11.66, S 13.35; found: C 45.06, H 3.38, N 11.59, S 13.29.
-1
1
IR (KBr) nmax/cm 3405, 3300, 2887 and 1685; H NMR
CDCl , 400 MHz) d 1.31 (t, 3H, J 7.2 Hz), 4.35 (q, 2H,
(
References
3
J 7.2 Hz), 7.19 (d, 1H, J 7.2 Hz), 7.27 (dd, 1H, J 4.8,
.1 Hz), 7.79 (d, 1H, J 7.2 Hz), 8.37-8.41 (m, 1H), 9.23 (br
8
1. Sanz, R.; Escribano, J.; Pedrosa, M. R.; Aguado, R.; Arnáiz,
F. J.; Adv. Synth. Catal. 2007, 349, 713.
1
3
s, 1H); C NMR (CDCl , 75 MHz) d 162.3, 142.5, 141.7,
3
1
31.2, 130.1, 121.4, 120.6, 108.5, 61.1, 14.8; MALDI-TOF
2. Acheson, R. M.; Prince, R. J.; Procter, G.; J. Chem. Soc., Perkin
Trans. 1 1979, 3, 595.
+
MS m/z 190 (M ); Anal. calcd. for C H N O : C 63.15, H
10
10
2
2
5
.30, N 14.73; found: C 63.01, H 5.37, N 14.81.
3. Ning, Z. L.;Yang, F. L.; He, L. P.; Guo,Y.; Wang, W.; Li, G.Y.;
Wang, X.; Wang, E. S.; Jilin Daxue Xuebao, Lixueban 2006, 1,
118; CA 2006, 146: 295872.
Ethyl thieno[3,2-b]pyrrole-5-carboxylate
o
8
o
White solid; mp 132-134 C (lit. mp 132.5-133 C);
4. Gan, T.; Liu, R.; Yu, P.; Zhao, S.; Cook, J. M.; J. Org. Chem.
1997, 62, 9298.
-1
1
IR (KBr) nmax/cm 3400, 3315, 2893 and 1693; H NMR
CDCl , 400 MHz) d 1.33 (t, 3H, J 7.1 Hz), 4.30 (q, 2H,
(
5. Goldsmith, E.A.; Lindwall, H. G.; J. Org. Chem. 1953, 18, 507.
6. Kim, Y. A.; Han, S. Y.; Synth. Commun. 2004, 34, 2931.
7. Frydman, B.; Reil, S. J.; Boned, J.; Rapoport, H.; J. Org. Chem.
1968, 33, 3762.
3
J 7.1 Hz), 7.0 (d, 1H, J 2.4 Hz), 7.18 (d, 1H, J 2.4 Hz),
13
7
7
6
.26 (d, 1H, J 3.2 Hz), 9.31 (br s, 1H); C NMR (CDCl ,
5 MHz) d 162.1, 131.7, 130.0, 125.1, 122.4, 118.3, 109.2,
1.7, 14.1; MALDI-TOF MS m/z 195 (M ); Anal. calcd.
3
+
8. Gale, W. W.; Scott, A. N.; Snyder, H. R.; J. Org. Chem. 1964,
29, 2160.
for C H NO S: C 55.37, H 4.65, N 7.17, S 16.42; found:
9
9
2
C 55.41, H 4.57, N 7.21, S 16.33.
9. Gálvez, J. E. C.; García, F.; J. Heterocycl. Chem. 1984, 21, 215.

Vol. 22, No. 11, 2011
Gu and Li
S3
1
Figure S1. H NMR spectrum (CDCl , 400 MHz) of ethyl 1H-indole-2-carboxylate.
3
1
Figure S2. H NMR spectrum (CDCl , 400 MHz) of ethyl 3-methyl-1H-indole-2-carboxylate.
3

S4
Microwave-Assisted Synthesis of Indole-2-Carboxylic Acid Esters in Ionic Liquid
J. Braz. Chem. Soc.
1
Figure S3. H NMR spectrum (CDCl , 400 MHz) of ethyl 5-nitrol-1H-indole-2-carboxylate.
3
1
Figure S4. H NMR spectrum (CDCl , 400 MHz) of ethyl 6-methoxyl-3-methyl-1H-indole-2-carboxylate.
3

Vol. 22, No. 11, 2011
Gu and Li
S5
1
Figure S5. H NMR spectrum (CDCl , 400 MHz) of ethyl 5-chloro-1H-indole-2-carboxylate.
3
1
Figure S6. H NMR spectrum (CDCl , 400 MHz) of ethyl 3H-benz[e]indole-2-carboxylate.
3

S6
Microwave-Assisted Synthesis of Indole-2-Carboxylic Acid Esters in Ionic Liquid
J. Braz. Chem. Soc.
1
Figure S7. H NMR spectrum (CDCl , 400 MHz) of ethyl 6-chloro-3-methyl-1H-indole-2-carboxylate.
3
1
Figure S8. H NMR spectrum (CDCl , 400 MHz) of ethyl 7-methoxyl-1H-indole-2-carboxylate.
3

Vol. 22, No. 11, 2011
Gu and Li
S7
1
Figure S9. H NMR spectrum (CDCl , 400 MHz) of ethyl 1H-pyrrolo[3,2-b]pyridine-2-carboxylate.
3
1
Figure S10. H NMR spectrum (CDCl , 400 MHz) of ethyl thieno[3,2-b]pyridine-5-carboxylate.
3

S8
Microwave-Assisted Synthesis of Indole-2-Carboxylic Acid Esters in Ionic Liquid
J. Braz. Chem. Soc.
1
Figure S11. H NMR spectrum (CDCl , 400 MHz) of ethyl 6-methyl-thieno[3,2-b]pyrrole-5-carboxylate.
3
1
Figure S12. H NMR spectrum (CDCl , 400 MHz) of ethyl 2-nitrothieno[3,2-b]pyrrole-5-carboxylate.
3

Vol. 22, No. 11, 2011
Gu and Li
S9
13
Figure S13. C NMR spectrum (CDCl , 75 MHz) of ethyl 1H-indole-2-carboxylate.
3
13
Figure S14. C NMR spectrum (CDCl , 75 MHz) of ethyl 3-methyl-1H-indole-2-carboxylate.
3

S10
Microwave-Assisted Synthesis of Indole-2-Carboxylic Acid Esters in Ionic Liquid
J. Braz. Chem. Soc.
13
Figure S15. C NMR spectrum (CDCl , 75 MHz) of ethyl 5-nitrol-1H-indole-2-carboxylate.
3
13
Figure S16. C NMR spectrum (CDCl , 75 MHz) of ethyl 6-methoxyl-3-methyl-1H-indole-2-carboxylate.
3

Vol. 22, No. 11, 2011
Gu and Li
S11
13
Figure S17. C NMR spectrum (CDCl , 75 MHz) of ethyl 5-chloro-1H-indole-2-carboxylate.
3
13
Figure S18. C NMR spectrum (CDCl , 75 MHz) of ethyl 1H-benz[e]indole-2-carboxylate.
3

S12
Microwave-Assisted Synthesis of Indole-2-Carboxylic Acid Esters in Ionic Liquid
J. Braz. Chem. Soc.
13
Figure S19. C NMR spectrum (CDCl , 75 MHz) of ethyl 6 chloro-3-methyl-1H-indole-2-carboxylate.
3
13
Figure S20. C NMR spectrum (CDCl , 75 MHz) of ethyl 7-methoxyl-1H-indole-2-carboxylate.
3

Vol. 22, No. 11, 2011
Gu and Li
S13
13
Figure S21. C NMR spectrum (CDCl , 75 MHz) of ethyl 1H-pyrrolo[3,2-b]pyridine-2-carboxylate.
3
13
Figure S22. C NMR spectrum (CDCl , 75 MHz) of ethyl thieno[3,2-b]pyrrole-5-carboxylate.
3

S14
Microwave-Assisted Synthesis of Indole-2-Carboxylic Acid Esters in Ionic Liquid
J. Braz. Chem. Soc.
13
Figure S23. C NMR spectrum (CDCl , 75 MHz) of ethyl 6-methyl-thieno[3,2-b]pyrrole-5-carboxylate.
3
13
Figure S24. C NMR spectrum (CDCl , 75 MHz) of ethyl 2-nitrothieno[3,2-b]pyrrole-5-carboxylate.
3