Mol Divers (2009) 13:519528
DOI 10.1007/s11030-009-9146-8
FULL LENGTH PAPER
Efficient and green synthesis of tetrasubstituted pyrroles promoted
by task-specific basic ionic liquids as catalyst in aqueous media
Issa Yavari Elaheh Kowsari
Received: 8 December 2008 / Accepted: 20 March 2009 / Published online: 21 April 2009
Springer Science+Business Media B.V. 2009
Abstract Synthesis of tetrasubstituted pyrroles by the three-
component condensation reaction of acid chlorides, dialkyl
acetylenedicarboxylates, and amino acids in the presence
of various room-temperature ionic liquids (RTILs) as cat-
alysts in water is reported. Among the ionic liquids used,
the basic functionalized ionic liquid, butyl methyl imidazoli-
um hydroxide [bmim]OH, was the most effective catalyst.
The influence of reaction temperature, reaction time, and
amount of ionic liquid on the reaction was investigated. The
[bmim]OH/H2 O catalyst system could be reused for at least
five recycles without appreciable loss of efficiency.
Keywords Basic ionic liquid Pyrrole Green synthesis
Multi-component reaction Aqueous media
Introduction
Pyrrole is one of the most important heterocyclic compounds,
having become increasingly important in medicinal chemis-
try and organic synthesis [1,2]. Consequently, numerous pro-
cedures have been developed for the construction of pyrroles
[38]. However, some of these methods often suffer from cer-
tain drawbacks such as hazardous organic solvents, high cost,
long reaction time, use of stoichiometric and even excess
amounts of acids because they can be trapped by amine in
this condensation, and drastic reaction conditions. Therefore,
the development of facile and environmentally benign meth-
ods for synthesis of pyrroles is a necessary part of organic
synthesis.
I. Yavari (B) E. Kowsari
Chemistry Department, Tarbiat Modares University,
P.O. Box 14115-175, Tehran, Iran
e-mail: yavarisa@modares.ac.ir
Due to the increase in environmental consciousness in
chemical research and industry, the challenge for a sustain-
able environment calls for clean procedures that avoid the
use of harmful organic solvents. One of the important prin-
ciples of this green chemistry is the elimination of hazard-
ous solvents in chemical synthesis, through which the use
of expensive toxic solvents and the generation of waste can
be avoided. Ionic liquids (ILs) have received considerable
attention due to their interesting chemical and physical prop-
erties, such as wide liquid range with melting point around
room temperature, good stability in air and moisture, high
solubility including inorganic, organic, and even polymeric
materials, and negligible vapor pressure [911].
Reactions in aqueous media offer many advantages such
as simple operation and high efficiency in many organic trans-
formations that involve water-soluble substrates and reagents.
These advantages become even more attractive if such reac-
tions can be conducted using ILs in aqueous media. Recently,
basic ionic liquids (BILs) were reported, offering a new pos-
sibility for developing environmentally friendly basic cata-
lysts due to the combination of the advantages of inorganic
bases, stability in water and air, easy separation, and reus-
ability [12]. These strong BILs exhibited great potential for
the replacement of conventional basic catalysts because they
are flexible, nonvolatile, noncorrosive, and immiscible with
many organic solvents [13,14].
Our recent interest has been in the development of new
routes in heterocyclic synthesis [1519]. Herein, as a part
of our program to investigate the different organic reactions
feasible in ILs, we report a simple and fast reaction of acid
chlorides, amino acids, and dialkyl acetylenedicarboxylates
by BIL in water to afford tetrasubstituted pyrroles [20]. The
presented protocol not only is simple and high yielding, but
also greatly decreases environmental pollution. At the onset
of this work, we investigated a variety of conditions. Due to
123
520
the good results obtained, we applied the optimal protocol to
a variety of amino acids and acid chloride. In all cases, the
basic IL-catalyzed one-pot reaction proceeded smoothly and
gave the corresponding products in excellent yield.
Experimental section
General remarks
Compounds 13 were obtained from Merck and were used
without further purification. Melting points (m.p.) were
recorded with an Electrothermal-9100 apparatus. Infrared
(IR) spectra were recorded with a Shimadzu IR-460 spec-
trometer. 1 H- and 13 C-nuclear magnetic resonance (NMR)
spectra were recorded on a Bruker DRX-500 AVANCE
instrument, in dimethyl sulfoxide (DMSO)-d6 at 500.1 and
125.7 MHz, respectively; is reported in parts per million
(ppm) and J in Hz. Elemental (C, H, N) analyses were per-
formed with a Heraeus CHN-O-Rapid analyzer.
Preparation of room-temperature ionic liquids
All ILs were prepared and purified in accordance with the
procedure described previously [11,21].
Reaction procedure
A mixture of amino acid 1 (1 mmol), 0.078 g acetyl chlo-
ride 2 (1 mmol), and 1.52 g [bmim]OH (10 mmol) in 2 mL
H2 O was stirred at room temperature (rt) for 10 min. Then,
dialkyl acetylenedicarboxylate 3 (1 mmol) was added slowly.
The reaction mixture was refluxed [monitored by thin-layer
chromatography (TLC)] for 1 h, and cooled to rt; the solid
was filtered and washed with ether. The crude products were
purified by recrystallization from n-hexane/EtOAc to give
compounds 4.
Dimethyl 2,5-diphenyl-1H -pyrrole-3,4-dicarboxylate (4a)
Colorless crystals; m.p. 150151 C; yield: 0.31 g (95%) IR
(KBr): 3260 (NH), 1720 (C=O) cm1 . 1 H NMR (500.1 MHz,
CDCl3 ): = 3.60 (s, 6H, 2CO2 Me), 7.327.35 (m, 6H, CH),
7.507.52 (m, 4H, CH), 8.85 (s, 1H, NH). 13 C NMR (125.7
MHz, CDCl3 ): = 51.80 (2OMe), 114.1 (2C), 128.1 (2CH),
128.5 (4CH), 128.6 (4CH), 130.8 (2C), 137.8 (2C), 165.8
(2C=O). Anal. Calcd. for C20 H17 NO4 (335.35): C, 71.56;
H, 5.11; N, 4.18%. Found: C, 71.65; H, 5.13; N, 4.20%.
123
Mol Divers (2009) 13:519528
Dimethyl 2-(4-methylphenyl)-5-phenyl-1H -pyrrole-3,4-
dicarboxylate (4b)
Colorless crystals; m.p. 198200 C; yield: 0.31 g (91%) IR
(KBr): 3260 (NH), 1702 (C=O) cm1 . 1 H NMR (500.1 MHz,
CDCl3 ): = 2.36 (s, 3H, Me), 3.73 (s, 3H, OMe), 3.75 (s,
3H, OMe), 7.327.35 (m, 5H, CH), 7.18 (d, 3 J = 7.5, 2H,
CH), 7.51 (d, 3 J = 7.5, 2H, CH), 8.70 (s, 1H, NH). 13 C NMR
(125.7 MHz, CDCl3 ): = 21.3 (Me), 51.7 (OMe), 51.8 (OMe),
113.8 (C), 114.1 (C), 127.9 (2CH), 128.0 (CH), 128.1 (2CH),
128.5 (2CH), 128.6 (2CH), 129.2 (C), 130.8 (C), 134.2 (2C),
134.8 (C), 165.7 (C=O) 165.8 (C=O). Anal. Calcd. for C21 H19
NO4 (349.38): C, 72.10; H, 5.48; N, 4.01%. Found: C, 72.19;
H, 5.46; N, 4.04%.
Dimethyl 2-(4-chlorophenyl)-5-phenyl-1H -pyrrole-3,4-
dicarboxylate (4c)
Pale yellow crystals; m.p. 134135 C; yield: 0.34 g (93%) IR
(KBr): 3255 (NH), 1720 (C=O) cm1 . 1 H-NMR (500.1 MHz,
CDCl3 ): = 3.76 (s, 3H, OMe), 3.77 (s, 3H, OMe),7.267.37
(m, 5H, CH), 7.47 (d, 3 J = 8.0, 2H, CH), 7.52 (d, 3 J = 8.0,
2H, CH), 8.72 (s, 1H, NH). 13 C NMR (125.7 MHz, CDCl3 ):
= 51.8 (OMe), 51.9 (OMe), 114.4 (C), 114.5 (C), 128.0
(2CH), 128.6 (CH), 128.7 (CH), 128.8 (2CH), 129.2 (CH),
129.5 (2CH), 130.5 (2C), 133.4 (C), 134.6 (C), 134.7 (C),
165.4 (C=O) 165.7 (C=O). Anal. Calcd. for C20 H16 ClNO4
(369.80): C, 64.96; H, 4.36; N, 3.79%. Found: C, 64.83; H,
4.32; N, 3.84%.
Dimethyl 2-(4-nitrophenyl)-5-phenyl-1H -pyrrole-3,4-
dicarboxylate (4d)
Pale yellow crystals; m.p. 203204 C; yield: 0.36 g (96%)
IR (KBr): 3240 (NH), 1710 (C=O) cm1 . 1 H NMR (500.1
MHz, CDCl3 ): = 3.76 (s, 3H, OMe), 3.80 (s, 3H, OMe),
7.387.44 (m, 3H, CH), 7.53 (dd, 3 J = 7.2, 4 J = 1.0, 2H, CH),
7.69 (d, 3 J = 8.5, 2H, CH), 8.21 (d, 3 J = 8.5, 2H, CH), 8.92 (s,
1H, NH). 13 C NMR (125.7 MHz, CDCl3 ): = 51.9 (OMe),
52.1 (OMe), 114.9 (C), 116.3 (C), 123.9 (2CH), 128.1 (2CH),
128.5 (2CH), 128.7 (2CH), 129.0 (CH), 130.1 (C), 131.4 (C),
136.0 (C), 136.8 (C), 146.4 (C), 165.3 (C=O), 165.4 (C=O).
Anal. Calcd. for C20 H16 N2 O6 (380.35): C, 63.16; H, 4.24;
N, 7.37 %. Found: C, 63.24; H, 4.26; N, 7.39%.
Dimethyl 2-methyl-5-phenyl-1H -pyrrole-3,4-dicarboxylate
(4e)
Colorless crystals; m.p. 8182 C; yield: 0.24 g (87%) IR
(KBr): 3262 (NH), 1724 (C=O) cm1 . 1 H NMR (500.1 MHz,
CDCl3 ): = 2.45 (s, 3H, Me), 3.75 (s, 3H, COOMe), 3.76 (s,
3H, COOMe),7.307.40 (m, 5H, CH), 8.70 (s, 1H, NH). 13 C
NMR (125.7 MHz, CDCl3 ): = 12.8 (CH3 ), 51.2 (OMe), 52.0
Mol Divers (2009) 13:519528
(OMe), 112.3 (C), 114.4 (C), 127.0 (CH), 128.0 (2CH), 128.7
(2CH), 130.9 (C), 131.0 (C), 135.2 (C), 165.0 (C=O) 167.3
(C=O). Anal. Calcd. for C15 H15 NO4 (273.28): C, 65.93; H,
5.53; N, 5.13%. Found: C, 65.80; H, 5.55; N, 5.17%.
Dimethyl 2-benzyl-5-phenyl-1H -pyrrole-3,4-dicarboxylate
(4f)
Colorless crystals; m.p. 8485 C; yield: 0.33 g (95%) IR
(KBr): 3252 (NH), 1728 (C=O) cm1 . 1 H NMR (500.1 MHz,
CDCl3 ): = 3.80 (s, 3H, COOMe), 3.81(s, 3H, CO2 Me), 4.30
(s, 2H, CH2 ), 7.247.37 (m, 10H, CH), 8.38 (s, 1H, NH). 13 C
NMR (125.7 MHz, CDCl3 ): = 32.9 (CH2 ), 51.32 (OMe),
52.0 (OMe), 112.5 (C), 114.5 (C), 127.0 (CH), 127.1 (2CH),
128.1 (CH), 128.7 (2CH), 128.8 (2CH), 128.9 (2CH), 130.7
(C), 131.5 (C), 137.2 (C), 137.4 (C), 164.8 (C=O), 166.9
(C=O). Anal. Calcd. for C21 H19 NO4 (349.38): C, 72.19;
H, 5.48; N, 4.01%. Found: C, 72.13; H, 5.50; N, 4.06%.
Dimethyl 2-benzyl-5-(4-methylphenyl)-1H -pyrrole-3,4-
dicarboxylate (4g)
Colorless crystals; m.p. 132134 C; yield: 0.34 g (94%); IR
(KBr): 3252 (NH), 1728 (C=O) cm1 . 1 H NMR (500.1 MHz,
CDCl3 ): = 2.33 (s, 3H, CH3 ), 3.77 (s, 3H, OMe), 3.80 (s,
3H, OMe), 4.27 (s, 2H, CH2 ), 7.12 (d, 3 J = 8.5, 2H, CH), 7.24
(m, 5H, CH), 7.32 (t, 3 J = 8.5, 2H, CH), 8.32 (s, 1H, NH).
13 C NMR (125.7 MHz, CDCl ): = 21.2 (CH ), 32.9 (CH ),
3 3 2
51.30 (OMe), 52.0 (OMe), 112.4 (C), 114.1 (C), 127.0 (CH),
127.1 (2CH), 128.0 (2CH), 128.9 (2CH), 129.3 (2CH), 131.9
(2C), 137.0 (C), 137.5 (C), 138.1 (C), 164.9 (C=O), 167.0
(C=O). Anal. Calcd. for C22 H21 NO4 (363.41): C, 72.71; H,
5.82; N, 3.85%. Found: C, 72.80; H, 5.85; N, 3.89%.
Dimethyl 2-benzyl-5-(4-chlorophenyl)-1H -pyrrole-3,4-
dicarboxylate (4h)
Pale yellow crystals; m.p. 129130 C; yield: 0.33 g (87%) IR
(KBr): 3240 (NH), 1692 (C=O) cm1 . 1 H NMR (500.1 MHz,
CDCl3 ): = 3.78 (s, 3H, OCH3 ), 3.81 (s, 3H, OCH3 ), 4.28 (s,
2H, CH2 ), 7.137.26 (m, 5H, CH), 7.287.39 (m, 4H, CH),
8.30 (s, 1H, NH). 13 C NMR (125.7 MHz, CDCl3 ): = 32.9
(CH2 ), 51.4 (OMe), 52.2 (OMe), 112.8 (C), 114.9 (C), 127.1
(CH), 128.5 (2CH), 128.9 (2CH), 129.0 (2CH), 129.2 (CH),
129.4 (CH), 130.5 (C), 131.8 (C), 134.2 (C), 137.2 (C), 137.4
(C), 164.7 (C=O), 166.7 (C=O). Anal. Calcd. for C21 H18
ClNO4 (383.82): C, 65.71; H, 4.73; N, 3.63%. Found: C,
65.80; H, 4.75; N, 3.67%.
521
Dimethyl 2-benzyl-5-(4-nitrophenyl)-1H -pyrrole-3,4-
dicarboxylate (4i)
Pale yellow crystals; m.p. 187188 C; yield: 0.37 g (95%) IR
(KBr): 3252 (NH), 1728 (C=O) cm1 . 1 H NMR (500.1 MHz,
CDCl3 ): = 3.80 (s, 3H, CO2 Me), 3.81(s, 3H, CO2 Me), 4.30
(s, 2H, CH2 ), 7.22 (d, 3 J = 6.5, 2H, CH), 7.27 (d, 3 J = 7.0,
1H, CH), 7.31 (t, 3 J = 7.5, 2H, CH), 7.41 (t, 3 J = 8.5, 2H,
CH), 8.13 (t, 3 J = 9.0, 2H, CH), 8.38 (s, 1H, NH). 13 C NMR
(125.7 MHz, CDCl3 ): = 33.0 (CH2 ), 51.6 (OMe), 52.4
(OMe), 113.5 (C), 117.0 (C), 124.0 (CH), 127.3 (2CH), 127.4
(CH), 128.5 (CH), 128.9 (2CH), 129.1 (2CH), 136.7 (C),
136.8 (2C), 138.7 (C), 147.0 (C), 164.3 (C=O) 166.5 (C=O).
Anal. Calcd. for C21 H18 N2 O4 (394.38): C, 63.96; H, 4.60;
N, 7.10%. Found: C, 63.91; H, 4.53; N, 7.12%.
Dimethyl 2-isobutyl-5-phenyl-1H -pyrrole-3,4-
dicarboxylate (4j)
Colorless crystals; m.p. 141143 C; yield: 0.26 g (83%); IR
(KBr): 3225 (NH), 1681 (C=O) cm1 . 1 H NMR (500.1 MHz,
CDCl3 ): = 0.88 (d, 3 J = 7.5, 6H, CHMe2 ), 1.911.96 (m,
1H, CH), 2.68 (d, 3 J = 7.5, 2H, CH2 ), 3.74 (s, 3H, OMe),
3.77 (s, 3H, OMe), 7.237.30 (m, 3H, CH), 7.39 (d, 3 J = 7.5,
2H, CH), 9.1 (s, 1H, NH). 13 C NMR (125.7 MHz, CDCl3 ):
= 22.3 (2Me), 29.2 (CH), 35.7 (CH2 ), 51.2 (OMe), 52.0
(OMe), 112.4 (C), 114.2 (C), 127.1 (2CH), 127.9 (CH), 128.5
(2CH), 130.9 (C), 131.2 (C), 138.9 (C), 165.2 (C=O), 167.5
(C=O). Anal. Calcd. for C18 H21 NO4 (315.36): C, 68.55; H,
6.71; N, 4.44%. Found: C, 68.49; H, 6.73; N, 4.47%.
Dimethyl 2-isobutyl-5-(4-methylphenyl)-1H -pyrrole-3,4-
dicarboxylate (4k)
Colorless crystals; m.p. 106107 C; yield: 0.29 g (89%); IR
(KBr): 3236 (NH), 1678 (C=O) cm1 . 1 H NMR (500.1 MHz,
CDCl3 ): = 0.89 (d, 3 J = 6.5, 6H, CHMe2 ), 1.921.98 (m,
1H, CH), 2.32 (s, 3H, CH3 ), 2.69 (d, 3 J = 6.5, 2H, CH2 ),
3.76 (s, 3H, OCH3 ), 3.77 (s, 3H, OCH3 ), 7.10 (d, 3 J = 7.0,
2H, CH), 7.30 (d, 3 J = 7.0, 2H, CH), 8.50 (s, 1H, NH). 13 C
NMR (125.7 MHz, CDCl3 ): = 21.0 (2Me), 22.2 (Me), 29.0
(CH), 35.6 (CH2 ), 51.0 (OMe), 51.8 (OMe), 112.2 (C), 113.6
(C), 127.0 (2CH), 128.0 (CH), 129.2 (2CH), 131.4 (C), 137.7
(C), 138.5 (C), 165.1 (C=O), 167.4 (C=O). Anal. Calcd. for
C19 H23 NO4 (329.40): C, 69.28; H, 7.04; N, 4.25%. Found:
C, 69.20; H, 7.08; N, 4.29%.
Dimethyl 2-isobutyl-5-(4-chlorophenyl)-1H -pyrrole-3,4-
dicarboxylate (4l)
Pale yellow crystals; m.p. 141143 C; yield: 0.29 g (84%);
IR (KBr): 3238 (NH), 1668 (C=O) cm1 . 1 H NMR (500.1
MHz, CDCl3 ): = 0.88 (d, 3 J = 7.0, 6H, CHMe2 ), 1.931.98
123
522
(m, 1H, CH), 2.71 (d, 3 J = 7.5, 2H, CH2 ), 3.74 (s, 3H, OMe),
3.78 (s, 3H, OMe), 7.29 (d, 3 J = 8.5, 2H, CH), 7.40 (d, 3 J =
8.5, 2H, CH), 8.66 (s, 1H, NH). 13 C NMR (125.7 MHz,
CDCl3 ): = 22.3 (2Me), 29.2 (CH), 35.7 (CH2 ), 51.2 (OMe),
52.0 (OMe), 112.8 (C), 114.6 (C), 128.5 (2CH), 128.9 (CH),
129.4 (CH), 130.0 (C), 131.8 (C), 134.0 (C), 138.9 (C),
164.9 (C=O), 167.0 (C=O). Anal. Calcd. for C18 H2o ClNO4
(349.81): C, 61.80; H, 5.76; N, 4.00%. Found: C, 61.70; H,
5.78; N, 4.04%.
Dimethyl 2-isobutyl-5-(4-nitrophenyl)-1H -pyrrole-3,4-
dicarboxylate (4m)
Pale yellow crystals; m.p. 130132 C; yield: 0.31 g (88%);
IR (KBr): 3285 (NH), 1697 (C=O) cm1 . 1 H NMR (500.1
MHz, CDCl3 ): = 0.88 (d, 3 J = 7.0, 6H, CHMe2 ), 1.921.97
(m, 1H, CH), 2.68 (d, 3 J = 7.5, 2H, CH2 ), 3.68 (s, 3H, OMe),
3.81 (s, 3H, OMe), 7.49 (d, 3 J = 8.5, 2H, CH), 8.00 (d, 3 J =
8.5, 2H, CH), 9.50 (s, 1H, NH). 13 C NMR (125.7 MHz,
CDCl3 ): = 22.3 (2Me), 29.2 (CH), 35.7 (CH2 ), 51.4 (OMe),
52.5 (OMe), 113.2 (C), 116.7 (C), 123.9 (2CH), 127.1(2CH),
128.1 (C), 136.9 (C), 140.7 (C), 146.6 (C), 164.7 (C=O),
167.4 (C=O). Anal. Calcd. for C18 H20 N2 O6 (360.36): C,
59.99; H, 5.59; N, 7.77%. Found: C, 59.92; H, 5.56; N,
7.80%.
Diethyl 2,5-diphenyl-1H -pyrrole-3,4-dicarboxylate (4n)
Colorless crystals; m.p. 151153 C; yield: 0.33 g (91%) IR
(KBr): 3250 (NH), 1708 (C=O) cm1 . 1 H NMR (500.1 MHz,
CDCl3 ): = 1.20 (t, 3 J = 7.0, 6H, Me), 4.17 (q, 3 J = 7.0, 4H,
OCH2 ), 7.317.37 (m, 6H, CH), 7.517.53 (m, 4H, CH),
8.90 (s, 1H, NH). 13 C NMR (125.7 MHz, CDCl3 ): = 14.0
(2Me), 60.7 (2OMe), 114.4 (2C), 128.2 (2CH), 128.4 (4CH),
128.6 (4CH), 130.9 (2C), 134.4 (2C), 165.3 (2C=O). Anal.
Calcd. for C22 H21 NO4 (363.40): C, 72.11; H, 5.82; N, 3.85
%. Found: C, 72.20; H, 5.84; N, 3.88%.
Diethyl 2-(4-methylphenyl)-5-phenyl-1H -pyrrole-3,4-
dicarboxylate (4o)
Colorless crystals; m.p. 181182 C; yield: 0.33 g (90%) IR
(KBr): 3275 (NH), 1695 (C=O) cm1 . 1 H NMR (500.1 MHz,
CDCl3 ): = 1.23 (t, 3 J = 7.5, 3H, Me), 1.25 (t, 3 J = 7.5, 3H,
Me), 1.23 (s,3H, Me), 4.20 (q, 3 J = 7.5, 2H, OCH2 ), 4.22 (q,
3 J = 7.5, 2H, OCH ), 7.18 (d, 3 J = 8.0, 2H, CH), 7.337.40
2
(m, 3H, CH), 7.18 (d, 3 J = 8.0, 2H, CH), 7.53 (d, 3 J = 8.0,
2H, CH), 8.64 (s, 1H, NH). 13 C NMR (125.7 MHz, CDCl3 ):
= 14.0 (Me), 14.1 (Me), 21.30 (Me), 60.6 (OCH2 ), 60.7
(OCH2 ), 114.1 (C), 114.5 (C), 128.0 (CH), 128.1 (2CH),
128.2 (CH), 128.4 (2CH), 128.5 (2CH), 129.1 (CH), 131.1
(C), 134.0 (C), 134.6 (C), 138.5 (2C), 165.2 (C=O) 165.3
123
Mol Divers (2009) 13:519528
(C=O). Anal. Calcd. for C23 H23 NO4 (377.43): C, 73.19; H,
6.14; N, 3.71%. Found: C, 73.28; H, 6.16; N, 3.74%.
Diethyl 2-(4-chlorophenyl)-5-phenyl-1-H-pyrrole-3,4-
dicarboxylate (4p)
Colorless crystals; m.p. 191193 C; yield: 0.35 g (89%) IR
(KBr): 3270 (NH), 1695 (C=O) cm1 . 1 H NMR (500.1 MHz,
CDCl3 ): = 1.20 (t, 3 J = 7.0, 3H, Me), 1.22 (t, 3 J = 7.0, 3H,
Me), 4.17 (q, 3 J = 7.0, 2H, OCH2 ), 4.20 (q, 3 J = 7.0, 2H,
OCH2 ), 7.267.37 (m, 5H, CH), 7.45 (d, 3 J = 7.5, 2H, CH),
7.50 (d, 3 J = 7.5, 2H, CH), 8.90 (s, 1H, NH). 13 C NMR
(125.7 MHz, CDCl3 ): = 14.0 (Me), 14.1 (Me), 60.8 (OMe),
60.9 (OMe), 114.6 (C), 114.7 (C), 128.1 (2CH), 128.5 (2CH),
128.6 (CH), 128.7 (2CH), 129.3 (C), 129.5 (2CH), 130.7 (C),
133.2 (C), 134.4 (C 134.5 (C), 165.0 (C=O) 165.3 (C=O).
Anal. Calcd. for C22 H20 Cl NO4 (397.85): C, 66.42; H, 5.07;
N, 3.52 %. Found: 66.30; H, 5.04; N, 3.55%.
Diethyl 2-(4-nitrophenyl)-5-phenyl-1H -pyrrole-3,4-
dicarboxylate (4q)
Pale yellow crystals; m.p. 214216 C; yield: 0.32 g (80%) IR
(KBr): 3260 (NH), 1709 (C=O) cm1 . 1 H NMR (500.1 MHz,
CDCl3 ): = 1.21 (t, 3 J = 7.0, 3H, Me), 1.24 (t, 3 J = 7.0, 3H,
Me), 4.18 (q, 3 J = 7.0, 2H, OCH2 ), 4.23 (q, 3 J = 7.0, 2H,
OCH2 ), 7.377.41 (m, 3H, CH), 7.51 (dd, 3 J = 7.0, 4 J = 1.5,
2H, CH), 7.67 (d, 3 J = 8.5, 2H, CH), 8.17 (d, 3 J = 8.5, 2H,
CH), 8.92 (s, 1H, NH). 13 C NMR (125.7 MHz, CDCl3 ):
= 13.9 (Me), 14.0 (Me), 60.9 (OCH2 ), 61.2 (OCH2 ), 115.2
(C), 116.6 (C), 123.8 (2CH), 128.2 (2CH), 128.5 (2CH),
128.6 (2CH), 129.0 (CH), 130.3 (C), 131.2 (C), 136.0 (C),
137.0(C) 147.2 (C), 164.8 (C=O) 164.9 (C=O). Anal. Calcd.
for C22 H20 N2 O6 (408.40): C, 64.70; H, 4.94; N, 6.86 %.
Found: 64.61; H, 4.97; N, 6.89%.
Diethyl 2-isobutyl-5-phenyl-1H -pyrrole-3,4-dicarboxylate
(4r)
Colorless crystals; m.p. 128130 C; yield: 0.33 g (96%); IR
(KBr): 3225 (NH), 1693 (C=O) cm1 . 1 H NMR (500.1 MHz,
CDCl3 ): = 0.87 (d, 3 J = 7.0, 6H, CMe2 ), 1.23 (t, 3 J = 7.0,
3H, Me), 1.25 (t, 3 J = 7.0, 3H, Me), 1.911.97 (m, 1H, CH),
2.68 (d, 3 J = 7.0, 2H, CH2 ), 4.18 (q, 3 J = 7.0, 2H, OCH2 ),
4.21(q, 3 J = 7.0, 2H, OCH2 ), 7.217.28 (m, 3H, CH), 7.39
7.42 (m, 2H, CH), 9.1 (s, 1H, NH). 13 C NMR (125.7 MHz,
CDCl3 ): = 14.0 (Me), 14.3 (Me), 22.3 (2Me), 29.1 (CH),
35.7 (CH2 ), 59.9 (OCH2 ), 60.9 (OCH2 ), 112.4 (C), 114.5
(C), 127.2 (2CH), 127.7 (CH), 128.5 (2CH), 131.0 (C), 131.1
(C), 138.9 (C), 164.8 (C=O), 167.1 (C=O); Anal. Calcd. for
C20 H25 NO4 (343.42): C, 69.95; H, 7.34; N, 4.08%. Found:
C, 69.84; H, 7.31; N, 4.11%.
Mol Divers (2009) 13:519528
Diethyl 2-isobutyl-5-(4-methylphenyl)-1H -pyrrole-3,4-
dicarboxylate (4s)
Colorless crystals; m.p. 146.6-147.5 C; yield: 0.32 g (90 %);
IR (KBr): 3238 (NH), 1676 (C=O) cm1 . 1 H NMR (500.1
MHz, CDCl3 ): = 0.88 (d, 3 J = 6.5, 6H, CHMe2 ), 1.21 (t,
3 J = 7.1, 3H, CH ), 1.23 (t, 3 J = 7.5, 3H, CH ), 1.911.96 (m,
3 3
1H, CH), 2.28 (s, 3H, CH3 ), 2.68 (d, 3 J = 6.5, 2H, CH2 ), 3.74
(q, 3 J = 7.5, 2H, OCH2 ), 3.78 (q, 3 J = 7.5, 2H, OCH2 ), 7.09 (d,
3 J = 7.0, 2H, CH), 7.23 (d, 3 J = 7.0, 2H, CH), 8.60 (s, 1H, NH).
13 C NMR (125.7 MHz, CDCl ): = 13.9. (CH ), 14.1 (CH ),
3 3 3
21.1 (2Me), 22.3 (Me), 29.2 (CH), 35.7 (CH2 ), 59.8 (OCH2 ),
60.8 (OCH2 ), 112.5 (C), 114.2 (C), 127.0 (2CH), 128.2 (C),
129.2 (2CH), 131.0 (C), 137.7 (C), 138.2 (CH), 164.6 (C=O),
166.8 (C=O); Anal. Calcd. for C21 H27 NO4 (357.44): C, 70.56;
H, 7.61; N, 3.92%. Found: 70.65; H, 7.64; N, 3.95%.
Diethyl 2-isobutyl-5-(4-nitrophenyl)-1H -pyrrole-3,4-
dicarboxylate (4t)
Yellow crystals; m.p. 130132 C; yield: 0.37 g (97%); IR
(KBr): 3225 (NH), 1697 (C=O) cm1 . 1 H NMR (500.1 MHz,
CDCl3 ): = 0.88 (d, 3 J = 7.0, 6H, CHMe2 ), 1.28 (t, 3 J = 7.0,
3H, Me), 1.30(t, 3 J = 7.0, 3H, Me), 1.931.99 (m, 1H, CH),
2.69 (d, 3 J = 7.5, 2H, CH2 ), 4.21 (q, 3 J = 7.0, 2H, OCH2 ),
4.27 (q, 3 J = 7.0, 2H, OCH2 ), 7.53 (d, 3 J = 8.5, 2H, CH),
8.07 (d, 3 J = 8.5, 2H, CH), 9.30 (s, 1H, NH). 13 C NMR
(125.7 MHz, CDCl3 ): = 14.0 (Me), 14.1 (Me), 22.3 (2Me),
29.2 (CH), 35.8 (CH2 ), 60.2 (OCH2 ), 61.5 (OCH2 ), 113.5
(C), 117.2 (C), 123.9 (2CH), 127.0(2CH), 127.7 (C), 137.0
(CH), 140.3 (C), 146.6 (C), 164.2 (C=O), 166.7 (C=O); Anal.
Calcd. for C20 H24 N2 O6 (388.41): C, 61.85; H, 6.23;
N, 7.21%. Found: C, 61.92; H, 6.26; N, 7.25%.
Diethyl 2-benzyl-5-phenyl-1H -pyrrole-3,4-dicarboxylate
(4u)
Colorless crystals; m.p. 131132 C; yield: 0.37 g (98%); IR
(KBr): 3260 (NH), 1720 (C=O) cm1 . 1 H NMR (500.1 MHz,
CDCl3 ): = 1.27 (t, 3H, 3 J = 7.0, Me), = 1.33 (t, 3H, 3 J =
7.0, Me), 4.27 (q, 2H, 3 J = 7.0, OCH2 ), 4.30 (q, 2H, 3 J = 7.0,
OCH2 ), 4.32 (s, 2H, CH2 ), 7.267.30 (m, 5H, CH), 7.32
7.38 (m, 5H, CH), 8.09 (s, 1H, NH). 13 C NMR (125.7 MHz,
CDCl3 ): 13 C NMR (125.7 MHz, CDCl3 ): = 14.0 (Me), 14.3
(Me), 33.0 (CH2 ), 60.1 (OCH2 ), 61.0 (OCH2 ), 112.7 (C),
115.0 (C), 127.0 (CH), 127.2 (2CH), 128.1 (CH), 128.6
(2CH), 129.0 (2CH), 129.1 (2CH), 130.9 (C), 131.2 (C),
136.9 (C), 137.4 (C), 164.4 (C=O), 166.4 (C=O). Anal. Calcd.
for C23 H23 NO4 (377.43): C, 73.19; H, 6.14; N, 3.71%.
Found: C, 73.28; H, 6.10; N, 3.74%.
523
Diethyl 2-benzyl-5-(4-methylphenyl)-1H -pyrrole-3,4-
dicarboxylate (4v)
Colorless crystals; m.p. 132134 C; yield: 0.34 g (94%); IR
(KBr): 3252 (NH), 1728 (C=O) cm1 . 1 H NMR (500.1 MHz,
CDCl3 ): = 1.25 (t, 3H, 3 J = 7.0, Me), = 1.33 (t, 3H, 3 J = 7.0,
Me), 2.28 (s, 3H, Me), 4.22 (q, 2H, 3 J = 7.0, OCH2 ), 4.24
(q, 2H, 3 J = 7.0, OCH2 ), 4.26 (s, 2H, CH2 ), 7.12 (d, 3 J = 8.5,
2H, CH), 7.23 (m, 5H, CH), 7.30 (t, 3 J = 8.5, 2H, CH), 8.42
(s, 1H, NH). 13 C NMR (125.7 MHz, CDCl3 ): = 14.2 (CH3 ),
14.5 (CH3 ), 21.2 (CH3 ), 31.0 (CH2 ), 60.8 (OCH2 ), 61.5
(OCH2 ), 112.6 (C), 114.8 (C), 127.2 (CH), 127.5 (2CH),
128.4 (2CH), 128.9 (2CH), 129.5 (2CH), 131.8 (2C), 137.4
(C), 137.6 (C), 138.6 (C), 164.8 (C=O), 167.5 (C=O). Anal.
Calcd. for C24 H25 NO4 (391.46): C, 73.64; H, 6.44; N, 3.58%.
Found: C, 73.69; H, 6.46; N, 3.61%.
Diethyl 2-benzyl-5-(4-chlorophenyl)-1H -pyrrole-3,4-
dicarboxylate (4w)
Pale yellow crystals; m.p. 123125 C; yield: 0.38 g (92%);
IR (KBr): 3230 (NH), 1692 (C=O) cm1 . 1 H NMR (500.1
MHz, CDCl3 ): = 1.25 (t, 3 J = 7.0, 3H, Me), 1.28 (t, 3 J = 7.0,
3H, Me), 4.22 (q, 3 J = 7.0, 2H, OCH2 ), 4.25 (q, 3 J = 7.0 2H,
OCH2 ), 4.27 (s, 2H, CH2 ), 7.227.26 (m, 5H, CH), 7.28
7.32 (m, 4H, CH), 8.50 (s, 1H, NH). 13 C NMR (125.7 MHz,
CDCl3 ): = 14.0 (Me), 14.2 (Me), 32.8 (CH2 ), 60.2 (OCH2 ),
61.1 (OCH2 ), 112.9 (C), 115.1 (C), 126.9 (CH), 128.5 (2CH),
128.7 (2CH), 128.9 (2CH), 129.3 (2CH), 130.2 (C), 134.0
(C), 137.2 (2C), 137.4 (C), 164.3 (C=O), 166.4 (C=O). Anal.
Calcd. for C23 H22 ClNO4 (411.88): C, 67.07; H, 5.38; N,
3.40%. Found: C, 67.01; H, 5.36; N, 3.43%.
Diethyl 2-benzyl-5-(4-nitrophenyl)-1H -pyrrole-3,4-
dicarboxylate (4x)
Yellow crystals; m.p. 156157 C; yield: 0.39 g (95%); IR
(KBr): 3252 (NH), 1728 (C=O) cm1 . 1 H NMR (500.1 MHz,
CDCl3 ): = 1.30 (t, 3 J = 7.0, 3H, Me), 1.32 (t, 3 J = 7.0, 3H,
Me), 4.27 (q, 3 J = 7.0, 2H, OCH2 ), 4.30 (q, 2H, OCH2 ), 4.32
(s, 2H, CH2 ), 7.25 (d, 3 J = 8.5, 2H, CH), 7.28 (d, 3 J = 8.5,
1H, CH), 7.31 (t, 3 J = 7.5, 2H, CH), 7.50 (d, 3 J = 8.5, 2H,
CH), 8.14 (d, 3 J = 8.5, 2H, CH), 8.45 (s, 1H, NH). 13 C NMR
(125.7 MHz, CDCl3 ): = 14.0 (Me), 14.2 (Me), 33.0 (CH2 ),
60.4 (OCH2 ), 61.5 (OCH2 ), 113.6 (C), 117.5 (C), 124.0
(CH), 127.3 (2CH), 128.2 (2CH), 128.9 (2CH), 129.1 (2CH),
136.8(C), 136.9 (2C), 138.7 (C), 146.9 (C), 163.9 (C=O),
166.1 (C=O). Anal. Calcd. for C23 H22 N2 O6 (422.43): C,
65.40; H, 5.25; N, 6.63%. Found: C, 65.30; H, 5.27; N, 6.66%.
123
524
Diethyl 2-(sec-butyl)-5-phenyl-1H -pyrrole-3,4-
dicarboxylate (4y)
Colorless crystals; m.p. 110111 C; yield: 0.33 g (98%); IR
(KBr): 3205 (NH), 1676 (C=O) cm1 . 1 H NMR (500.1 MHz,
CDCl3 ): = 0.89 (t, 3 J = 7.0, 3H, CH3 ), 1.24 (t, 3 J = 7.0,
3H, CH3 ), 1.26 (t, 3 J = 7.0, 3H, CH3 ), 1.31 (d, 3 J = 7.0, 3H,
CH3 ), 1.571.69 (m, 2H, CH2 ), 3.483.53 (m, H, CH), 4.21
(q, 3 J = 7.0, 2H, OCH2 ), 4.24 (q, 3 J = 7.0, 2H, OCH2 ), 7.30
(t, 3 J = 6.0, 1H, CH), 7.32 (t, 3 J = 6.0, 2H, CH), 7.397.42 (d,
3 J = 6.0, 2H, CH), 8.4 (s, 1H, NH). 13 C NMR (125.7 MHz,
CDCl3 ): = 12.0 (Me), 14.0 (Me), 14.2 (Me), 19.5 (CHCH3 ),
29.6 (CH2 ), 32.5 (CH), 60.0 (OCH2 ), 60.8 (OCH2 ), 112.1
(C), 114.5 (C), 127.4 (2CH), 128.0 (CH), 128.6 (2CH), 131.0
(C), 131.2 (C), 143.2 (C), 164.7 (C=O), 166.5 (C=O). Anal.
Calcd. for C20 H25 NO4 (343.42): C, 69.95; H, 7.34; N, 4.08%.
Found: C, 69.90; H, 7.36; N, 4.10%.
Diethyl 2-(sec-butyl)-5-(4-methylphenyl)-1-H -pyrrole-3,4-
dicarboxylate (4z)
Colorless crystals; m.p. 146147 C; yield: 0.32 g (91%). IR
(KBr): 3215 (NH), 1681 (C=O) cm1 . 1 H NMR (500.1 MHz,
CDCl3 ): = 0.80 (t, 3 J = 7.5, 3H, Me), 1.23 (t, 3 J = 7.5, 3H,
CH3 ), 1.27 (t, 3 J = 7.5, 3H, CH3 ), 1.32 (d, 3 J = 7.5, 3H, CH3 ),
1.581.69 (m, 2H, CH2 ), 2.37 (s, 3H, CH3 ), 3.473.54 (m,
H, CH), 4.22 (q, 3 J = 7.5, 2H, OCH2 ), 4.26 (q, 3 J = 7.5, 2H,
CH2 ), 7.16 (d, 3 J = 8.0, 2H, CH), 7.33 (d, 3 J = 8.0, 2H, CH),
8.20 (s, 1H, NH). 13 C NMR (125.7 MHz, CDCl3 ): = 11.9
(Me), 14.0 (Me), 14.3 (Me), 19.5 (CHCH3 ), 21.2 (Me), 29.6
(CH2 ), 32.5 (CH), 60.0 (OCH2 ), 60.7 (OCH2 ), 112.1 (C),
114.1 (C), 127.3 (2CH), 128.4 (CH), 129.3 (2CH), 131.1
(C), 138.0(C), 142.8 (C), 164.7 (C=O), 166.5 (C=O); Anal.
Calcd. for C21 H27 NO4 (357.44): C, 70.56; H, 7.61; N, 3.92%.
Found: C, 70.44; H, 7.63; N, 3.95%.
Diethyl 2-(sec-butyl)-5-(4-chlorophenyl)-1H -pyrrole-3,4-
dicarboxylate (4aa)
Pale yellow crystals; m.p. 190191 C; yield: 0.32 g (85%);
IR (KBr): 3215 (NH), 1681 (C=O) cm1 . 1 H NMR (500.1
MHz, CDCl3 ): = 0.89 (t, 3 J = 7.5, 3H, Me), 1.23 (t, 3 J = 7.5,
3H, Me), 1.26 (t, 3 J = 7.5, 3H, Me), 1.33 (d, 3 J = 7.5, 3H,
Me), 1.581.69 (m, 2H, CH2 ), 3.453.52 (m, H, CH), 4.19
(q, 3 J = 7.5, 2H, OCH2 ), 4.26 (q, 3 J = 7.5, 2H, CH2 ), 7.33 (d,
3 J = 8.0, 2H, CH), 7.40 (d, 3 J = 8.0, 2H, CH), 8.35 (s, 1H,
NH). 13 C NMR (125.7 MHz, CDCl3 ): = 11.9 (Me), 14.0
(Me), 14.2 (Me), 19.5 (Me), 29.6 (CH2 ), 32.5 (CH), 60.1
(OCH2 ), 60.9 (OCH2 ), 112.5 (C), 114.9 (C), 128.7 (2CH),
128.8 (CH), 129.6 (CH), 129.9.1 (C), 134.0(2C), 143.2 (C),
164.5 (C=O), 166.3 (C=O); Anal. Calcd. for C20 H24 ClNO4
(377.86): C, 63.57; H, 6.40; N, 3.71%. Found: C, 63.45; H,
6.43; N, 3.73%.
123
Mol Divers (2009) 13:519528
Diethyl 2-methyl-5-phenyl-1H -pyrrole-3,4-dicarboxylate
(4bb)
Colorless crystals; m.p. 151153 C; yield: 0.26 g (86%); IR
(KBr): 3262 (NH), 1724 (C=O) cm1 . 1 H NMR (500.1 MHz,
CDCl3 ): = 1.24 (t, 3 J = 7.0, 3H, Me), 1.29 (t, 3 J = 7.0, 3H,
Me), 2.44 (s,3H, Me), 4.22 (q, 3 J = 7.0, 2H, OCH2 ), 4.25
(q, 3 J = 7.0, 2H, OCH2 ), 7.307.40 (m, 3H, CH), 7.30-7.40
(dd, 3 J = 7.0, 4 J = 1.0, 2H, CH), 8.70 (s, 1H, NH). 13 C
NMR (125.7 MHz, CDCl3 ): = 12.8 (Me), 14.0 (Me), 14.3
(Me), 59.9 (OCH2 ), 60.9 (OCH2 ), 112.4 (C), 114.7 (C), 127.0
(CH), 127.8 (2CH), 128.6 (2CH), 130.6 (C), 131.0 (C), 135.1
(C), 164.6 (C=O) 166.8 (C=O). Anal. Calcd. for C17 H19 NO4
(301.34): C, 67.76; H, 6.35; N, 4.65%. Found: C, 67.65; H,
6.37; N, 4.68%.
Dimethyl 2-phenyl-5-propyl-1H -pyrrole-3,4-
dicarboxylate (4cc)
Colorless crystals; m.p. 8182 C; yield: 0.26 g (87%) IR
(KBr): 3262 (NH), 1724 (C=O) cm1 . 1 H NMR (500.1 MHz,
CDCl3 ): = 0.90 (t, 3 J = 7.0, 3H, Me), 1.62 (sext, 2H, 3 J = 7.0,
2H, CH2 ), 2.78 (t, 3 J = 7.0, 2H, CH2 N), 3.74 (s, 3H, OMe),
3.75 (s, 3H, OMe), 7.247.30 (m, 3H, CH), 7.397.40 (d,
3 J = 5.0, 2H, CH), 9.10 (s, 1H, NH). 13 C NMR (125.7 MHz,
CDCl3 ): = 13.8 (Me), 22.8 (CH2 ), 28.7 (CH2 ), 51.2 (OMe),
52.0 (OMe), 112.0 (C), 114.2 (C), 127.0 (CH), 127.9 (CH),
128.6 (2CH), 130.9 (C), 131.0 (C), 139.9 (C), 165.1 (C=O),
167.6 (C=O). Anal. Calcd. for C17 H19 NO4 (301.43): C,
67.76; H, 6.35; N, 4.65%. Found: C, 67.64; H, 6.38; N,
4.68%.
Dimethyl 2-(tert-butyl)-5-phenyl-1H -pyrrole-3,4-
dicarboxylate (4dd)
Colorless crystals; m.p. 8182 C; yield: 0.28 g (90%) IR
(KBr): 3262 (NH), 1724 (C=O) cm1 . 1 H NMR (500.1 MHz,
CDCl3 ): = 1.40 (s, 9H, CMe3 ), 3.70 (s, 3H, OMe), 3.71 (s,
3H, OMe), 7.337.41 (m, 3H, CH), 7.497.51 (m, 2H, CH)
8.50 (s, 1H, NH). 13 C NMR (125.7 MHz, CDCl3 ): = 19.4
(CMe3), 37.0 (C) 51.40 (OMe), 51.9 (OMe), 112.8 (C), 113.5
(C), 128.3 (CH), 128.5 (2CH), 131.3 (C), 132.6 (C), 150 (C)
165.1 (C=O), 167.4 (C=O). Anal. Calcd. for C18 H21 NO4
(315.36): C, 68.55; H, 6.71; N, 4.44%. Found: C, 68.50; H,
6.74; N, 4.47%.
Results and discussion
The yield of functionalized pyrroles (4) depended on type
and amount of IL, reaction temperature, and reaction time.
The condensation of acid chloride 1 with amino acid 2 in
Mol Divers (2009) 13:519528 525

Scheme 1 The O CO2R"

three-component, one-pot O "RO2C CO2R"
condensation of acid chlorides R' ILs
1, amino acids 2, and dialkyl R Cl + OH +
acetylenedicarboxylates 3 in the In aqueous media R' R
NH2 N
presence of different ILs CO2R" H
1 2 3 4

OH OH
N N Table 1 Optimization of the reaction condition for the synthesis of 4f
N N
Entry IL Temperature ( C) Yield (%)a,b Time (h)
[bmim]OH [hmim]OH
6 1 [EtPy]BF4 25 Trace 24
5
2 [EtPy]BF4 50 Trace 24
BF4
BF4 3 [EtPy]BF4 80 30 24
N
N N 4 [bmim]BF4 25 Trace 24
[EtPy]BF4 5 [bmim]BF4 50 Trace 24
[bmim]BF4 6 [bmim]BF4 80 25 10
8
7 7 [bmim]BF4 80 35 24
Br Cl 8 [bmim]Br 25 None 24
N N N N
9 [bmim]Br 50 None 24
10 [bmim]Br 80 None 24
[bmim]Cl
[bmim]Br 11 [bmim]Cl 25 None 24
9 10 12 [bmim]Cl 50 None 24
Scheme 2 The structures of ILs used in this study 13 [bmim]Cl 80 None 24
14 [bmim]OH 25 40 24
15 [bmim]OH 50 65 24
16 [bmim]OH 80 95 3
the presence of dialkyl acetylenedicarboxylates 3 was first 17 [hmim]OH 25 35 24
carried out with different ILs (Scheme 1). 18 [hmim]OH 50 55 24
19 [hmim]OH 80 75 24
a Isolated
yield
b Reaction
conditions: acid chloride (1 mmol), amino acid (1 mmol),
Comparison of ILs DMAD (1 mmol), IL (10 mmol), H2 O (2 mL)

Manipulating the structure of ILs with respect to the organic

cation, the length of side-chains attached to the organic cat-
ion and inorganic anion gives us the ability to adjust their
properties (Scheme 2).
The effect of anions and cations of the ILs on the yield of
pyrroles 4 is shown in Table 1.
Although most of the investigated ILs had the same cation
of [bmim]+ , high catalytic activities were obtained when the
anion was OH . This shows the vital role of the hydroxyl
counterion for this IL. It can be seen that anions had a much
greater effect than the side-chain of the imidazolium cation
on the activities of ILs. When the anion was BF4 , which is an
anion of low basic strength, the catalytic activity was much
lower. Low yield of pyrrole 4 was obtained when non-imi-
dazolium-based ILs such as [EtPy][BF4 ] were used in water.
The difference in the side-chain attached to the imidazolium
cation may be responsible for the differences in the activity
of ILs 5 and 6 (Table 1).
Effects of the solvents on three-component condensations
reaction
Compared with NaOH, [bmim]OH not only gives higher
yield, but also takes much less time. The results are sum-
marized in Table 2.
It can be seen that [bmim]OH, as environmentally benign
basic IL, catalyzed the reaction of amino acids and a wide
range of aromatic acid chlorides at 80 C. To optimize the
reaction conditions, the condensation reaction of benzoyl
chloride, L-phenylalanine, and dimethyl acetylenedicarbox-
ylate (DMAD) was employed as the model reaction to screen
a suitable solvent (Table 2). As shown in Table 2, condensa-
tion reaction in BIL5/H2 O gave an isolated yield of 95%
(entry 1), which is much higher than those obtained in BIL5/
C2 H5 OH and BIL5/CH3 OH (entries 2 and 3).

123
526 Mol Divers (2009) 13:519528

Table 2 Different catalytic systems in various solvents used for the Table 3 Effect of the amount of BIL in synthesis of compound 4f
synthesis of compound 4f
Entry Basic IL (mmol) Yield (%)a,b
Entry IL or base Solvent Temperature Yield Time
( C) (%)a,b (h) 1 0 0
2 [bmim]OH (2) 35
1 [bmim]OH H2 O 80 95 3
2 [bmim]OH C2 H5 OH 80 36 24 3 [bmim]OH (4) 45
3 [bmim]OH CH3 OH 80 30 24 4 [bmim]OH (6) 67
4 NaOH H2 O 80 30 24 5 [bmim]OH (8) 70
5 NaOH C2 H5 OH 80 25 24 6 [bmim]OH (10) 95
6 NaOH CH3 OH 80 20 24 7 [hmim]OH (4) 35
7 TEAc H2 O 80 40 24 8 [hmim]OH (6) 45
8 TEA C2 H5 OH 80 30 24 9 [hmim]OH (10) 78
9 TEA CH3 OH 80 25 24 10 [bmim]BF4 (4)
10 [bmim]BF4 H2 O 80 32 24 11 [bmim]BF4 (6) 20
11 [bmim]BF4 CH3 OH 80 27 24 12 [bmim]BF4 (10) 35
12 [bmim]BF4 C2 H5 OH 80 20 24 a Isolated
yield
b Reaction
conditions: acid chloride (1 mmol), amino acid (1 mmol),
13 [hmim]OH H2 O 80 78 24
DMAD (1 mmol), H2 O (2 mL), at 80 C for 3 h
14 [hmim]OH C2 H5 OH 80 45 24
15 [hmim]OH CH3 OH 80 40 24
a Isolated yield
b Reaction conditions: acid chloride (1 mmol), amino acid (1 mmol), Preparation of pyrrole derivatives
DMAD (1 mmol), BIL or base (10 mmol), Solvent (2 mL)
c Triethylamine
To investigate the general validity of this procedure, differ-
ent acid chlorides 1 were also used to react with the various
amino acids 2. As shown in Table 4, in all cases the reaction
Effect of reaction temperature and time
gave the product in good yields.
When benzoyl chlorides with electron-withdrawing
The reaction temperature had significant effect on the con-
groups were employed, the reaction time was shorter than that
densation, when the amount of BIL (10 mmol) and the reac-
with electron-donating groups. Aliphatic acid chloride such
tion time (3 h) were kept constant. At 25 C, 50 C, and
as acetyl chloride or pivaloyl chloride reacted with amino
80 C, pyrrole 4f was obtained in 40%, 65%, and 95% iso-
acids 2 to give the corresponding pyrroles 4 in high yields. It
lated yields, respectively (entries 1416 in Table 1). At a fixed
can be observed that the condensation of a series of acid chlo-
amount of BIL (10 mmol), the effect of reaction time on iso-
rides 1, amino acids 2, and dialkyl acetylenedicarboxylates
lated yield was studied. Increasing the reaction time led to
3 in the presence of BIL5 at 80 C was completed within 3 h.
an increase in the yield of pyrrole 4f. The isolated yields for
Aromatic acid chlorides carrying either electron-donating or
the reactions corresponding to 0.5, 1 and 3 h were 80%, 90%,
electron-withdrawing substituents afforded good yields of
and 95%, respectively.
pyrroles 4. Another important feature of this procedure is the
survival of a variety of functional groups such as esters, nitro,
Effect of amount of BIL on the reaction and halides under the reaction conditions.

The efficiency of the BIL catalysts was tested for the reac-
tion of benzoyl chloride, L-phenylalanine, and DMAD under
different conditions (Table 3).
No product could be detected when the reaction was con-
ducted at 80 C for 24 h in the absence of BIL5 (entry 1).
Then, the three-component condensation of benzoyl chlo-
ride, L-phenylalanine, and DMAD in stoichiometric ratio
was investigated with different amounts of BILs (entries 2
11). It is clear that the yield increased with addition of BILs,
and the optimal amount of BILs was 10 mmol (entry 6).
Greater amount of catalyst did not improve the result to a
greater extent.
Reusability of BIL5
The recycling performance of BIL5 was investigated in the
reaction of benzoyl chloride, L-phenylalanine, and DMAD
(Fig. 1).
After separation of the products, the filtrate containing
the BIL and water was reused in the next run without further
purification. A 1:1:1 mixture of benzoyl chloride, L-phen-
ylalanine, and DMAD was added to the filtrate and stirred
under the same conditions. The BIL5 could be reused five
times without appreciable lowering of its catalytic activity.

123
Mol Divers (2009) 13:519528 527

Table 4 Preparation of pyrrole

derivatives 4 Entry Product R R R Yield(%)a,b

1 4a C6 H5 C6 H5 Me 95
2 4b 4-MeC6 H4 C6 H5 Me 91
3 4c 4-ClC6 H4 C6 H5 Me 93
4 4d 4-NO2 C6 H4 C6 H5 Me 96
5 4e Me C6 H5 Me 87
6 4f C6 H5 Bn Me 95
7 4g 4-MeC6 H4 Bn Me 94
8 4h 4-ClC6 H4 Bn Me 87
9 4i 4-NO2 C6 H4 Bn Me 95
10 4j C6 H5 i-Bu Me 83
11 4k 4-MeC6 H4 i-Bu Me 89
12 4l 4-ClC6 H4 i-Bu Me 84
13 4m 4-NO2 C6 H4 i-Bu Me 88
14 4n C6 H5 C6 H5 Et 91
15 4o 4-MeC6 H4 C6 H5 Et 90
16 4p 4-ClC6 H4 C6 H5 Et 89
17 4q 4-NO2 C6 H4 C6 H5 Et 80
18 4r C6 H5 i-Bu Et 96
19 4s 4-MeC6 H4 i-Bu Et 90
20 4t 4-NO2 C6 H4 i-Bu Et 97
21 4u C6 H5 Bn Et 98
22 4v 4-MeC6 H4 Bn Et 94
23 4w 4-ClC6 H4 Bn Et 92
24 4x 4-NO2 C6 H4 Bn Et 95
25 4y C6 H5 sec-Bu Et 98
26 4z 4-MeC6 H4 sec-Bu Et 91
a Isolated yield
b Reaction 27 4aa 4-ClC6 H4 sec-Bu Et 85
conditions: acid
chloride (1 mmol), amino acid 28 4bb Me C6 H5 Et 86
(1 mmol), DMAD (1 mmol), IL 29 4cc n-Pr C6 H5 Me 87
(10 mmol), H2 O (2 mL), at
30 4dd t-Bu C6 H5 Me 90
80 C for 3 h

Mechanistic aspects

Although the mechanistic details of the reaction are not

clearly known, it is reasonable to assume that intermediate 11
results from the reaction of acid chloride 1 with amino acid 2.
Subsequent deprotonation of 11 leads to di-anion 13, which
attacks on the acetylenic ester 3 to generate 14. Intermediate
14 undergoes a cyclization reaction to furnish the dihydro-
pyrrole derivative 15, which is converted to 4 by elimination
of CO2 and H2 O (Scheme 3).

Conclusions

An efficient three-component, one-pot synthesis of function-

alized pyrroles, catalyzed by basic ILs in aqueous media, has
Fig. 1 Reusability of the catalyst (BIL5)/H2 O in the synthesis of 4f been described. The attractive features of this protocol are:

123
528
Scheme 3 Plausible mechanism R R
for the formation of
functionalized pyrroles 4 [bmim] OH
1 + 2 HN
_ H O
2
CO2R"
CO2R"
O _ [bmim] OH
+3
R'
R N
H O
O H
14
simple procedure, short reaction time, use of cheap and envi-
ronmentally benign solvent, and reuse of the aqueous media.
References
1. Robertson J, Hatley RJD, Watkin DJ (2000) Preparation of the tri-
cyclic ketopyrrole core of roseophilin by radical macrocyclisation
and PaalKnorr condensation. J Chem Soc Perkin Trans 1:3389
3396. doi:10.1039/b005351l
2. Robinson RS, Dovey MC, Gravestock D (2004) Silver-catalysed
hydroamination: synthesis of functionalized pyrroles. Tetrahedron
Lett 45:67876789. doi:10.1016/j.tetlet.2004.07.019
3. Raghavan S, Anuradha K (2003) Solid-phase synthesis of hetero-
cycles from 1,4-diketone synthons. Synlett 711713. doi:10.1055/
s-2003-38369
4. Banik BK, Samajdar S, Banik I (2004) Simple synthesis of substi-
tuted pyrroles. J Org Chem 69:213216. doi:10.1021/jo035200i
5. Balme G (2004) Pyrrole syntheses by multicomponent coupling
reactions. Angew Chem Int Ed Engl 43:62386241. doi:10.1002/
anie.200461073
6. Bharadwaj AR, Scheidt KA (2004) Catalytic multicomponent
synthesis of highly substituted pyrroles utilizing a one-pot sila-
stetter/PaalKnorr strategy. Org Lett 6:24652568. doi:10.1021/
ol049044t
7. Minetto G, Raveglia LF, Sega A, Taddei M (2005) Microwave-
assisted PaalKnorr reaction-three-step regiocontrolled synthesis
of polysubstituted furans, pyrroles and thiophenes. Eur J Org Chem
52775288. doi:10.1002/ejoc.200500387
8. Banik BK, Banik I, Renteria M, Dasgupta SK (2005) A straightfor-
ward highly efficient PaalKnorr synthesis of pyrroles. Tetrahedron
Lett 46:26432645. doi:10.1016/j.tetlet.2005.02.103
9. Binnemans K (2007) Lanthanides and actinides in lonic liquids.
Chem Rev 107:25922614. doi:10.1021/cr050979c
10. Rantwijk F, Sheldon RA (2007) Biocatalysis in ionic liquids. Chem
Rev 107:27572785. doi:10.1021/cr050946x
11. Yavari I, Kowsari E (2007) Ionic liquids as novel and recyclable
reaction media for N -alkylation of amino-9,10-anthraquinones by
trialkyl phosphites. Tetrahedron Lett 48:37533756. doi:10.1016/
j.tetlet.2007.03.077
123
Mol Divers (2009) 13:519528
O O
O O
+ [bmim] HN
O O
R' R'
11 12 13
"RO2C CO2R"
_ CO
R' 2
HO O 4
-H2O
R N
O
15
12. Welton T (1999) Room-temperature ionic liquids. Solvents for
synthesis and catalysis. Chem Rev 99:20712084. doi:10.1021/
cr980032t
13. Rogers R, Seddon K (eds) (2002) Ionic liquids: industrial applica-
tions for green chemistry; ACS symposium series 818. American
Chemical Society, Washington, DC
14. Wasserscheid P, Welton T (eds) (2003) Ionic liquids in synthesis.
Wiley-VCH, Weinheim
15. Yavari I, Hossaini Z, Sabbaghan M (2008) Efficient synthesis of
tetrasubstituted thiophenes by reaction of benzoyl isothiocyanates,
ethyl bromopyruvate and enaminones. Tetrahedron Lett 49:844
846. doi:10.1016/j.tetlet.2007.11.174
16. Yavari I, Sabbaghan M, Hossaini Z (2008) Proline-promoted
efficient synthesis of 4-aryl-3,4-dihydro-2h,5h-pyrano[3,2-c]chro-
mene-2,5-diones in aqueous media. Synlett 11531154. doi:10.
1055/s-2008-1072656
17. Yavari I, Hossaini Z, Sabbaghan M (2006) Synthesis of functional-
ized 5-imino-2,5-dihydro-furans through the reaction. Mol Divers
10:479482. doi:10.1007/s11030-006-9034-4
18. Yavari I, Sabbaghan M, Hossaini Z (2007) Reaction between alkyl
isocyanides and isopropylidene Meldrums acid in the presence of
bidentate nucleophiles. Mol Divers 11:15. doi:10.1007/s11030-
006-9052-2
19. Yavari I, Sabbaghan M, Porshamsian K, Bagheri M, Ali-Asgari S,
Hossaini Z (2007) Efficient synthesis of alkyl 2-[2-(arylcarbonyli-
mino)-3-aryl-4-oxo-1,3-thiazolan-5-ylidene]-acetates. Mol Divers
11:8185. doi:10.1007/s11030-007-9061-9
20. Yavari I, Kowsari E (2008) Task-specific basic ionic liquid: a
reusable and green catalyst for one-pot synthesis of highly function-
alized pyrroles in aqueous media. Synlett 897899. doi:10.1055/
s-2008-1042912
21. Ranu BC, Banerjee S (2005) Ionic liquid as catalyst and reaction
medium. The dramatic influence of a task-specific ionic liquid,
[bmim]OH, in Michael addition of active methylene compounds
to conjugated ketones, carboxylic esters, and nitriles. Org Lett
7:30493051. doi:10.1021/ol051004h