A green approach for efficient synthesis of N-substituted pyrroles in ionic liquid under microwave irradiation

Article abstract of DOI:10.1016/j.tetlet.2010.03.036

A rapid synthesis of N-substituted pyrroles has been described by the reaction of 4-hydroxyproline with isatins in ionic liquid under microwave irradiation. The recovered ionic liquid was reused for six cycles. The reaction proceeds without the addition o

Full text of DOI:10.1016/j.tetlet.2010.03.036

Tetrahedron Letters 51 (2010) 3477–3480
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A green approach for efficient synthesis of N-substituted pyrroles in ionic
liquid under microwave irradiation
*
H. M. Meshram , B. R. V. Prasad, D. Aravind Kumar
Discovery Laboratory, Organic Chemistry Division—I, Indian Institute of Chemical Technology, Hyderabad 500 007, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A rapid synthesis of N-substituted pyrroles has been described by the reaction of 4-hydroxyproline with
isatins in ionic liquid under microwave irradiation. The recovered ionic liquid was reused for six cycles.
The reaction proceeds without addition of any acid promoter
Received 10 February 2010
Revised 10 March 2010
Accepted 11 March 2010
Available online 15 March 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Pyrroles
Quinoxalines
Ionic liquid
Microwave
Pyrroles are important heterocyclic compounds displaying
remarkable pharmacological properties such as antibacterial, anti-
viral, anti-inflammatory, antitumoural, and antioxidant activities.1
has been proven recently that microwave heating improves the
preparative efficiency and reduces the reaction time for several or-
ganic transformations.16 Our interest in the development of new
methodologies17 in the area of green chemistry18 prompted us to
synthesize N-substituted pyrroles in ionic liquid in conjugation
with microwave irradiation (Scheme 1).
The pyrrole moiety is found in many naturally occurring com-
2
pounds such as heme, chlorophyll, and vitamin B12
.
Pyrroles are
also present in various bioactive drug molecules such as atrovast-
atin, anti-inflammatory and antitumor agents, and immunosup-
pressants.3 Quinoxaline4 derivatives are important classes of
nitrogen-containing heterocycles which are useful intermediates
in organic synthesis. In view of their high significance, many meth-
odologies have been developed for the construction of the pyrrole
skeleton.5 Among them, the Paal–Knorr6 synthesis remains the
most useful preparative method for generating pyrroles. In recent
years, a variety of reagents such as K10 clay,7 bismuth nitrate,8
Dy(OTf)3,9 PMA/SiO2,10 b-CD,11 under reflux conditions have been
utilized for the synthesis of N-substituted pyrroles. Many of these
procedures involve the use of expensive reagents, metal triflates,
extended reaction times and produce a huge amount of toxic
waste. So it is desirable to discover ecofriendly procedures for
the synthesis of pyrrole derivatives. Recently, ionic liquids have
emerged as a set of green solvents with unique properties such
as tunable polarity, high thermal stability and immiscibility with
a number of organic solvents, negligible vapor pressure and recy-
clability.12 Among various ionic liquids, 1-butyl-3-methylimidazo-
liumtetrafluoroborate ([Bmim]BF4) has been used in the synthesis
of vicinal diamines,13 one-pot syntheses of 2H-indazolo[2,1-b]-
phthalazine-triones,14 and hydrative cyclization of 1,6-diynes.15 It
Our initial effort was focused on the conventional thermal heat-
ing reaction of 5-bromoisatin (entry 3) with 4-hydroxyproline in
2 ml of [Bmim]BF4. The reaction remained incomplete even after
heating the reaction mixture at 110 °C for 24 h. Considering the re-
cent advances of microwave irradiation for rapid reactions, we car-
ried out the same reaction in the microwave. Surprisingly, the
reaction was completed in 10 min with complete conversion of
5-bromoisatin. This success encouraged us to extend this method
to a wide range of isatins (entries 1–10). The microwave reactions
were performed in a CEM19 discover model microwave apparatus.
Having optimized conditions20 for the rapid synthesis of these pyr-
role derivatives, various 5-substituted isatins and 1-substituted
isatins were condensed with 4-hydroxyproline to afford the corre-
sponding 3-(1H-pyrrol-1-yl)indolin-2-ones (entries 1–10) in good
to excellent yields (Table 1). It was also observed that (ethylide-
neamino)-2,3-dihydroindene-1-ones underwent condensation
with 4-hydroxyproline under similar conditions to produce the
corresponding 11-(1H-pyrrol-1-yl)-11H-indeno[1,2-b]quinoxalin-
11-ones in good yield (Table 1, entries 11 and 12). It is worthy to
mention that there is no byproduct formation in the reaction.
The formation of the desired products may be explained by the for-
mation of an azomethine ylide via decarboxylation and subsequent
1,5-proton shift to give the more stable zwitterion, which can eas-
ily transform to the more stable product to gain aromatic character
* Corresponding author. Tel.: +91 (40) 27160123x2642; fax: +91 (40) 27160512.
E-mail address: hmmeshram@yahoo.com (H.M. Meshram).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.03.036

3478
H. M. Meshram et al. / Tetrahedron Letters 51 (2010) 3477–3480
O
R2
HO
N
[Bmim]BF4
R2
O
+
CO2H
N
H
O
N
MW, 110 OC
10-15 min
N
R1
R1
R1= H, Bn, Ph, Me
R2= H, F, Br, CN, NO2, Me
O
HO
N
[Bmim]BF4
N
+
N
CO2H
N
MW, 110 O C
15min
N
H
N
X
X
X= C, N
Scheme 1.
Table 1
Synthesis of N-substituted pyrroles using ionic liquid [Bmim]BF4
Entry
Isatin
4-Hydroxy proline
Producta
Time (min)
Yieldb (%)
O
HO
N
O
CO2H
N
1
10
10
10
15
15
10
93
N
H
H
O
N
H
O
HO
F
N
O
CO2H
N
F
2
3
4
5
6
96
95
93
92
97
N
H
H
O
N
H
O
HO
Br
N
O
CO2H
N
Br
N
H
H
O
N
H
O
HO
NC
O2N
H3C
N
O
CO2H
N
NC
O2N
H3C
N
H
H
O
N
H
O
HO
N
O
CO2H
N
N
H
H
O
N
H
O
HO
N
O
CO2H
N
N
H
H
O
N
H
O
HO
N
N
O
CO2H
N
7
10
94
N
H
O
CH2Ph
CH2Ph

H. M. Meshram et al. / Tetrahedron Letters 51 (2010) 3477–3480
3479
Table 1 (continued)
Entry
Isatin
4-Hydroxy proline
Producta
Time (min)
Yieldb (%)
O
HO
O2N
N
O
CO2H
N
O2N
8
9
10
95
93
96
N
H
O
CH2Ph
N
CH2Ph
O
HO
N
O
CO2H
N
15
10
N
Ph
H
O
N
Ph
O
HO
N
O
N
N
CO2H
N
N
CH3
10
H
O
N
N
CH3
O
HO
N
CO2H
N
11
15
15
93
94
H
N
O
N
N
HO
CO2H
N
12
H
N
N
N
N
N
a
All products were identified by IR, NMR, mass spectroscopy and elemental analysis.
Yields of products isolated after column chromatography.
b
(Scheme 2). After completion of the reaction (entry 3), the reaction
mixture was extracted with ether (two or three times) and the
residual ionic liquid was dried at 80 °C under vacuum and reused
for six cycles. We have observed consistent yield (95%) for four cy-
cles and there was gradual decrease in yields (87% and 79%) for 5th
and 6th cycles, respectively. Thus the present method provides an
useful alternative over conventional methods for the same trans-
formation, since our method can avoid the use organic solvents
and metallic reagents, moreover it reduces the reaction time
significantly.
In conclusion, we have demonstrated a rapid, efficient and
ecofriendly method for the synthesis of 3-(1H-pyrrol-1-yl)indo-
lin-2-ones and 11-(1H-pyrrol-1-yl)-11H-indeno[1,2-b]quinoxalin-
11-ones by the condensation of 4-hydroxyproline with substituted
HO
HO
O
+
_
O
HO
[Bmim]BF4
-H2O
N
N
-CO2
O
O
+
O
CO2H
O
N
H
N
H
N
H
N
H
H
+
N
_
+
N
H+
-H2O
N
H
O
O
O
N
N
H
N
H
H
Scheme 2.

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H. M. Meshram et al. / Tetrahedron Letters 51 (2010) 3477–3480
12. Reviews on ionic liquids: (a) Welton, T. Chem. Rev. 1999, 99, 2071; (b)
Wasserscheid, P.; Keim, W. Angew. Chem., Int. Ed. 2000, 39, 3772.
13. Yadav, J. S.; Reddy, B. V. S.; Premalatha, K. Adv. Synth. Catal. 2003, 345, 948.
14. Khurana, J. M.; Magoo, D. Tetrahedron Lett. 2009, 50, 7300.
15. Cui, D. M.; Ke, Y. K.; Zhuang, D. W.; Wang, Q.; Zhang, C. Tetrahedron Lett. 2010,
52, 980.
isatins and (ethyldeneamino)-2,3-dihydroindene-1-ones by using
an ionic liquid. Rapid reactions, operational simplicity, high yields,
and reusability of ionic liquids are notable features of the present
protocol.
16. (a) Appukkuttan, P.; Eycken, E. V. D. Eur. J. Org. Chem. 2008, 1133; (b) Kappe, C.
O. Angew. Chem., Int. Ed. 2004, 43, 6250.
Acknowledgments
17. (a) Meshram, H. M.; Kumar, G. S.; Ramesh, P.; Reddy, B. C. K. Tetrahedron Lett.
2010; (b) Varma, R. S.; Saini, R. K.; Meshram, H. M. Tetrahedron Lett. 1997, 38,
6525; (c) Meshram, H. M.; Srinivas, D.; Yadav, J. S. Tetrahedron Lett. 1997, 38,
8743; (d) Meshram, H. M.; Reddy, G. S.; Reddy, M. M.; Yadav, J. S. Tetrahedron
Lett. 1998, 39, 4103.
B.R.V.P and D.A.K. thank CSIR for the award of a fellowship and
to Dr. J. S. Yadav, Director IICT, for his support and encouragement.
18. (a) Meshram, H. M.; Reddy, B. C.; Goud, P. R. Synth. Commun. 2009, 39, 2297; (b)
Meshram, H. M.; Reddy, P. N.; Vishnu, P.; Sadashiv, K.; Yadav, J. S. Tetrahedron
Lett. 2006, 47, 991; (c) Meshram, H. M.; Kumar, D. A.; Prasad, B. R. V. Synth.
Commun. 2009, 29, 2317; (d) Meshram, H. M.; Kumar, D. A.; Prasad, B. R. V.;
Goud, P. R. Helv. Chim. Acta 2010, 93, 648.
References and notes
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B.; Mynott, R. J. Am. Chem. Soc. 1998, 120, 8305.
19. CEM Corporation, PO Box 200, Matthews, NC 28106.
20. General procedure for the synthesis of N-substituted pyrroles: Isatin (1 mmol), 4-
hydroxyproline(1 mmol) and 1-butyl-3-methylimidazolium tetrafluoroborate
([bmim]BF4) (2 ml) were placed in a 10 ml crimp-sealed thick walled glass
tube equipped with a pressure sensor and magnetic stirrer. The reaction tube
was placed inside the cavity of a CEM Discover benchmate, operated at 110 °C
(temperature monitored by built-in infrared sensor), power 150 W and
pressure 25–30 psi for 10–15 min. After completion of the reaction, the
reaction mixture brought to room temperature and extracted with ether
(2 Â 5 ml). The organic layer was washed with brine solution and dried over
Na2SO4. The combined organic layers were evaporated and purified through
column (30% ethyl acetate/petroleum ethers). The products (solids) were
recrystallized from appropriate solvents. The residual ionic liquid was dried
under vacuum at 80 °C for 4 h and reused for subsequent cycles. The products
were characterized by IR, NMR and mass spectroscopy. The spectral data of all
compounds are in accordance with those reported in literature. The data for
some selected compounds are given below. 3-(1H-Pyrrol-1-yl)indolin-2-one
(entry 1): Solid. Mp 140–142 °C. 1H NMR (CDCl3, 200 MHz): d (ppm) 5.46 (s,
1H), 6.17 (t, 2H, J = 2.2 Hz), 6.63 (t, 2H, J = 2.2 Hz), 6.85–7.09 (m, 2H), 7.20–7.33
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Nedolya, N. A.; Vvedensky, V. Y.; Brandsma, L.; Trofimov, B. A. Tetrahedron Lett.
1997, 38, 7241; (b) Azizian, J.; Karimi, A. R.; Arefrad, H.; Mohammadi, A. A.;
Mohammadizadeh, M. R. Mol. Div. 2003, 6, 223; (c) Sundberg, R. J.. In
Comprehensive Heterocyclic Chemistry; Katritzky, A. R., Rees, C. W., Scriven, E.
F. V., Eds.; Pergamon: Oxford, 1996; Vol. 2, p 119; (d) Ferreira, V. F.; De Souza,
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3801; (d) Quiclet-Sire, B.; Quintero, L.; Sanchez-Jimenez, G.; Zard, S. Z. Synlett
2003, 75; (e) Tracey, M. R.; Hsung, R. P.; Lambeth, R. H. Synthesis 2004, 918.
7. Azizian, J.; Karimi, A. R.; Kazemizadeh, Z.; Mohammadi, A. A.;
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3295.
(m, 2H), 9.5 (br s, 1H). IR (KBr)
m
= 3306, 3194, 1717, 1618, 1466 cmÀ1. EIMS:
m/z 198 (M+). 5-Nitro-3-(1H-pyrrol-1-yl)indolin-2-one (entry 5): Solid. Mp 135–
136 °C. 1H NMR (CDCl3, 200 MHz): d (ppm) 5.60 (s, 1H), 6.25 (s, 2H), 6.66 (s,
2H), 6.97 (d, 1H, J = 8.5 Hz), 8.09–8.29 (m, 2H), 9.50 (br s, 1H). IR (KBr)
m = 3292,
2925, 1738, 1625, 1524, 1481, 1338 cmÀ1. EIMS: m/z 243 (M+). (6E,9Z)-N1-(1-
(1H-pyrrol-1-yl)-1H-inden-2(3H)-ylidene)-N2-ethylidenebenzene-1,2-diamine
(entry 11): Solid. Mp 180–181 °C. 1H NMR (CDCl3, 300 MHz): d (ppm) 6.19 (s,
1H), 6.22 (t, 2H, J = 2.2 Hz), 6.73 (t, 2H, J = 2.2 Hz), 7.49–7.74 (m, 5H), 8.04–8.26
(m, 3H). IR (KBr)
m
= 3092, 2924, 1479 cmÀ1. EIMS: m/z 283 (M+). 6-(1H-1-
Pyrroyl)-6H-indeno-[1,2-b]-pyrido[3,2-e]pyrazine (entry 12): Solid. Mp: 150–
153 °C. 1H NMR (CDCl3, 200 MHz): d (ppm) 6.15 (s, 1H), 6.18 (t, 2H, J = 1.5 Hz),
6.67 (t, 2H, J = 1.5 Hz), 7.47–7.52 (m, 1H), 7.61–7.70 (m, 4H), 8.38 (m, 1H), 9.12
10. Kumar, M. A.; Krishna, A. B.; Babu, B. H.; Reddy, C. B.; Reddy, C. S. Synth.
Commun. 2008, 3456.
11. Sridhar, R.; Srinivas, B.; Kumar, V. P.; Reddy, V. P.; Kumar, A. V.; Rao, K. R. Adv.
Synth. Catal. 2008, 350, 1489.
(s, 1H). IR (KBr)
MS: m/z 285 (M++1).
m
= 2959, 2927, 2854, 1725, 1577, 1283, 1076, 787 cmÀ1 LC–