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K. Ramesh et al. / Chinese Chemical Letters 23 (2012) 1331–1334
O
H
N
O
CH3
N
N
HO
HO
N
H
O
COOH
H3C
Cl
Bufotenin
Zomepirac
Tolmetin
Fig. 1. Some marketed drugs with pyrrole skeleton.
General experimental procedure for the synthesis of pyrroles using b-cyclodextrin (1a–1o): b-cyclodextrin
(10 mol%) was dissolved in water (15 mL), and to this clear solution, aniline (1.0 mmol) was added, stirred for 15 min,
and followed by the addition of dimethyl/diethyl acetylenedicarboxylate (DMAD/DEAD 1.0 mmol) and phenacyl
bromide (1.0 mmol). The reaction mixture was heated at 50–60 8C until completion of the reaction as indicated by
TLC. The reaction mixture was cooled to 5 8C and b-cyclodextrin was filtered. The aqueous layer was extracted with
ethyl acetate (3 mL Â 10 mL). The combined organic layers were washed with water, saturated brine solution, and
dried over anhydrous Na2SO4. The combined organic layers were evaporated under reduced pressure and the resulting
crude product was purified by column chromatography by using ethyl acetate and hexane (2:8) as eluent. The identity
1
and purity of the product were confirmed by H, 13C NMR, and mass spectra.
2. Results and discussion
In continuation of our efforts towards the development of novel environ friendly methodologies [23–33] herein, we
report a mild and efficient one-pot protocol for the synthesis of highly substituted pyrrole derivatives for the first time
by a three-component reaction, involving amino compounds, DMAD/DEAD and phenacyl bromide promoted by
recyclable b-CD in water (Scheme 1). Presently organic reactions in aqueous phase have attracted the attention of
researchers because of the added advantages of water, as an environmentally benign and economically affordable
solvent. However, the fundamental problem in performing the reactions in water is that many organic substrates are
hydrophobic and are insoluble in water. Cyclodextrins, possessing hydrophobic cavities, are well known
supramolecular catalysts, which by reversible formation of host–guest complexes, activate the organic molecules and
catalyze the reactions. As part of our ongoing program toward the development of greener chemical approaches for the
synthesis of novel reaction intermediates and heterocyclic moieties, we report herein the synthesis of N-substituted
pyrroles by the reaction of amines, DMAD/DEAD, with phenacyl bromides using b-cyclodextrin, a recyclable
supramolecular catalyst, for the first time in aqueous medium.
In this study, a model reaction was conducted by reacting aromatic amines, DMAD/DEAD with phenacyl bromide in
water medium at room temperature to obtain the corresponding N-substituted pyrrole in low yields (42%). The poor
solubility of aniline in water at elevated temperature resulted in the formation of undesired products. When the same
reaction was conducted using b-CD at room temperature the product was obtained in moderate yield (61%). However by
acontrolledexperimentusingb-CD, asasupramolecularcatalyst,at50–60 8Ctheproductwasobtainedinexcellentyield
(88%) (Scheme 1). In general, all the reactions were clean, and the N-substituted pyrroles were obtained in excellent
yields (80–89%) (Table 2). All the products were characterized by 1H, 13C NMR, IR, and mass spectrometry [34]. The
catalytic activity of the b-CD was established by the fact that pyrrole formation was not observed in satisfactory yield in
the absence of b-cyclodextrin. The evidence for the formation of N-aryl substituted pyrrole in the presence of b-CD was
supported by 1H NMR studies of inclusion complex between aniline and b-CD [24].
O
OR2
O
O
OR2
O
OR2
β−CD/water
50-60oC
Br
Ar
Ar
N
R
R-NH2
O
R2O
4-FC H
H
,
R=Ph, 4-MeC6
Ar=Ph, 4-BrC H4 4-NO2C6H4
,
R2 =Me, Et
6
4
4
6
Scheme 1. Synthesis of highly substituted pyrroles.
Ramesh
