N-substituted pyrrole synthesis by Paal-Knorr condensation using recyclable cationic exchange resin in water

Article abstract of DOI:10.1002/jhet.317

(Chemical Equation Presented) Cationic exchange resin has been utilized for the first time as a novel and recyclable heterogeneous catalyst for the synthesis of N-substituted pyrroles from variety of 1,4-diketones and aniline. This simple synthesis has been accomplished with excellent yields. The recovered catalyst can be reused for subsequent runs with only a gradual decrease in activity.

Full text of DOI:10.1002/jhet.317

486
N-Substituted Pyrrole Synthesis by Paal–Knorr Condensation
Using Recyclable Cationic Exchange Resin in Water
Vol 47
Yan-Hong He, Gang-Qiang Wang, and Zhi Guan*
School of Chemistry and Chemical Engineering, Southwest University, Chongqing 400715, China
*E-mail: guanzhi@swu.edu.cn
Received April 24, 2009
DOI 10.1002/jhet.317
Published online 2 March 2010 in Wiley InterScience (www.interscience.wiley.com).
Cationic exchange resin has been utilized for the first time as a novel and recyclable heterogeneous
catalyst for the synthesis of N-substituted pyrroles from variety of 1,4-diketones and aniline. This simple
synthesis has been accomplished with excellent yields. The recovered catalyst can be reused for subse-
quent runs with only a gradual decrease in activity.
J. Heterocyclic Chem., 47, 486 (2010).
INTRODUCTION
be efficiently mediated by heterogeneous catalysts that
can be recycled and reused, the result will be nearly
ideal processes in terms of both greeness and simplicity
[13]. Therefore, we wish to report a high-yielding and
straightforward synthesis of N-substituted pyrroles using
water as solvent and a cationic exchange resin as a recy-
clable heterogeneous catalyst.
Pyrrole rings have great importance in organic chem-
istry as they can be found in several natural products
[1], organic materials [2], and bioactive molecules [3].
Especially, substituted pyrroles present antibacterial [4],
antiviral [5], anti-inflammatory, and antioxidant activ-
ities [6]. One of the most important approaches to pyr-
role synthesis is the Paal–Knorr reaction, which involves
the reaction of 1,4-dicarbonyl compounds and their
masked equivalents with primary amines. Generally, the
most used conditions include p-TsOH in toluene or ben-
zene [7], AcOH/methanol [8], TiCl4 in toluene [5a],
Ti(OPr)4 in benzene [9], Bi(OTf)3/[bmim]BF4 [10],
Bi(NO3)3 in CH2Cl2 [11]. However, some of these
methods often suffer from certain drawbacks, such as
hazardous organic solvents, metals, and high costs. As
the increase environmental consciousness in chemical
research and industry, the challenge for a sustainable
environment calls for clean procedures that can avoid
using harmful organic solvents and metals. Therefore,
the development of green and facile methods for the
synthesis of pyrroles is desirable. Besides, on the other
hand, reactions in water have recently attracted signifi-
cant attention because water is a cheap, safe, and non-
toxic solvent [12]. In addition, if aqueous reactions can
RESULTS AND DISCUSSION
In our initial investigation, the condensation of aro-
matic 1,4-dione (5a) with two equivalents of aniline was
carried out in 1 M HCl aqueous at reflux for 24 h. To
our surprise, it gave furan 5d in 100% yield instead of
Scheme 1. Condensation of 5a with 2 equivalents of aniline under dif-
ferent reaction conditions.
C
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N-Substituted Pyrrole Synthesis by Paal–Knorr Condensation Using
Recyclable Cationic Exchange Resin in Water
487
Table 1
Condensation of 1,4-diketones and aniline into pyrroles using cationic exchange resin in water.a
Entry
1
1,4-Diketone
Pyrrole
Time (h)
5
Yield (%)b
Ref.
[14]
85
2
8
95
[15]
3
4
6
6
96
95
[16]
[16]
5
6
6
6
96
94
[16]
[16]
7
8
9
5
6
6
87
97
[14]
[17]
9b: 56, 7b: 34
[14,18]
a For a typical experimental procedure see Ref. [19].
b Refers to yield of isolated product after flash chromatography.
pyrrole 5b (Scheme 1). Then, the reaction was performed
in acidic Dowex 50 W Â 8-200 (1.7 meq mLÀ1) cationic
exchange resin in water at reflux for 16 h, which pro-
vided pyrrole 5b in 36% yield accompanied by furan 5d
in 62% yield. It suggested that the presence of cationic
exchange resin can facilitate the pyrrole condensation,
while 1 M HCl aqueous only catalyzed the formation of
furan. To improve the reaction rate and to observe the
effect of temperature on the condensation, the reaction
was carried out in a sealed tube at increased temperature.
Higher temperatures than 140ꢀC led to thermal decompo-
sition of the resin. We therefore set the reaction at
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

488
Y.-H. He, G.-Q. Wang, and Z. Guan
Vol 47
Scheme 2. Recovery of the cationic exchange resin for recycling and use in subsequent Paal–Knorr pyrrole synthesis.
130ꢀC; the starting material 5a was consumed in 6 h. We
pleasurably found that the reaction exclusively provided
the N-substituted pyrrole 5b in excellent yield of 96%. It
seems that the higher temperature favors the formation of
pyrrole in the presence of resin in water.
CONCLUSION
In summary, a new catalytic protocol to synthesize
pyrroles by Paal–Knorr condensation in water has been
developed. Compared to previous reported methods, the
present procedure avoids the use of metals and organic
solvents, and instead employs cationic exchange resin as
a cheap and readily available heterogeneous catalyst that
is easily removed from the product mixture, which can
be recycled and reused. This method has great potential
for future application.
Encouraged by this new finding, we further investi-
gated the reaction by using wide range of diketone com-
pounds. The condensation of substituted 1,4-diketones
and aniline proceeded smoothly and gave the correspond-
ing pyrroles in good to excellent yields in water in the
presence of cationic exchange resin (Table 1). The reac-
tions were carried out in sealed tubes at 130ꢀC. In this
manner, the reactions can be run as a batch in sealed
tubes within an oven without stirring. The reactions were
complete in 5–8 h, and the two equivalents of amine
were used to afford a valuable increase of the yields. To
assess the generality of the method, variety of 1,4-dicar-
bonyl compounds including aromatic and aliphatic, di-
and tri-substituted 1,4-dicarbonyl compounds were sub-
jected to the condensation with aniline to give the corre-
sponding pyrrole derivatives. When the 1,4-diphenyl-1,4-
diones (3–6a, entries 3–6) were used, The excellent yields
of 94–96% were obtained. Triphenyl 1,4-dione (8a, entry
8) gave the best yield of 97%. Nevertheless, methyl sub-
stituted 1,4-diones (1a and 7a, entries 1 and 7) provided
the products in slightly decreased yields (85 and 87%,
respectively). Although 1,4-di(thienyl)butane-1,4-dione
(2a, entry 2) required longer reaction time, the product
was received in excellent yield of 95%. Interestingly,
when ethyl 2-acetyl-4-oxo-4-phenylbutanoate (9a, entry
9) was submitted to the reaction conditions described ear-
lier, the corresponding ester substituted pyrrole 9b was
obtain in 56% yield, accompanied by decarboxylated
product pyrrole 7b in 34% yield.
Acknowledgments. Financial support from 2007 Select
Project in Scientific and Technological Activities for
Returned Scholars of The State Personnel Ministry and the
High-Tech Training Fund of Southwest University
(XSGX0601) is gratefully acknowledged.
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N-Substituted Pyrrole Synthesis by Paal–Knorr Condensation Using
Recyclable Cationic Exchange Resin in Water
489
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet