Pyrrole synthesis in ionic liquids by Paal-Knorr condensation under mild conditions

Article abstract of DOI:10.1016/j.tetlet.2004.03.012

Paal-Knorr condensation of 2,5-hexandione with primary amines was successfully carried out in ionic liquids. Through investigating different ionic liquids, different reaction times, the reaction, using ionic liquids as solvent, exhibited simple product isolation procedure, improved yields and exclusive selectivity and the mild conditions and the avoidance of using toxic catalysts are also its special features. Recovery and reuse of ionic liquid are also satisfactory.

Full text of DOI:10.1016/j.tetlet.2004.03.012

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 3417–3419
Pyrrole synthesis in ionic liquids by Paal–Knorr condensation
under mild conditions
*
Bo Wang, Yanlong Gu, Cheng Luo, Tao Yang, Liming Yang and Jishuan Suo
State Key Laboratory for Oxo Synthesis and Selective Oxidation, Lanzhou Institute of Chemical Physics,
Chinese Academy of Sciences, Lanzhou 730000, China
Received 11 February 2004; revised 2 March 2004; accepted 4 March 2004
Abstract—Paal–Knorr condensation of 2,5-hexandione with primary amines was successfully carried out in ionic liquids. Through
investigating different ionic liquids, different reaction times, the reaction, using ionic liquids as solvent, exhibited simple product
isolation procedure, improved yields and exclusive selectivity and the mild conditions and the avoidance of using toxic catalysts are
also its special features. Recovery and reuse of ionic liquid are also satisfactory.
Ó 2004 Elsevier Ltd. All rights reserved.
6
Room temperature ionic liquids, especially those based
on the 1-alkyl-3-methylimidazolium cation, have given a
promise as attractive alternative to conventional sol-
vents, tedious workup, large amounts of solid catalysts,
may not be the preferred choices in view of green
chemistry. Hence, an efficient and mild Paal–Knorr
condensation is needed for contemporary chemical
synthesis. Herein, we wish to report our preliminary
results on the synthesis of pyrroles from c-diketone and
primary amines in ionic liquids at ambient temperature.
1
vents. Besides their special characteristics, they can
2
even not only promote some organic reactions, but also
3
provide the chemoselectivity to some reaction processes
and simple and convenient isolation of product in cat-
4
alytic reactions. In our continuing effort to utilize ionic
liquids as an environmentally attractive media, for the
synthesis and catalysis processes, we have some interests
in the organic reactions participated by some nitrogen-
containing compounds because their rate could be evi-
Initial experimentation was undertaken in [BMIm]BF
4
ionic liquid. Two conditions were used: one in which the
reaction had gone to completion, was to obtain the
yields as far as it can achieve; the other was terminated
before completion, so that the conversion of aniline after
a certain period was observed. When using diethyl ether
as extractant, the pyrrole product and unreacted aniline
could be recovered with thoroughly mass balances
as assessed using nitrobenzene as external standard,
however, cyclohexane and hexane were failed.
5
dently accelerated by ionic liquids.
Most recently, Paal–Knorr condensation has experi-
enced a rekindled interest in the synthetic chemistry for
the preparation of pyrrole, pyrazoles and their deriv-
atives, as naturally occurring organic compounds and
intermediates for pharmaceutical industry. Various
6
i
7
8
acidic materials, such as zeolite, Ti(OPr ) , Al O ,
4
In conventional systems, an excess of amine usually has
10
to be used in order to promote the condensation. From
2
3
9
p-TSA, layered zirconium phosphate and zirconium
sulfophenyl phosphonate, as well as the microwave
technology have been used to promote these conden-
sations. However, some of them often involve the use of
excess amounts of acids because they can be trapped by
nitrogen in this condensation, or hazard organic sol-
10
a recent atom-economical standpoint, the use of nearly
equimolar amounts of substrates is strongly required.
Thus we have initially treated aniline with equimolar
2,5-hexandione in ionic liquids as well as in organic
solvents to compare their efficiency and the results are
presented in Figure 1.
11
In these ionic liquids, it can be seen that the initial rate
of these reactions is very high as 70–91% aniline con-
version was obtained in the 1 h, especially in [BMIm]I,
86% of aniline was consumed within 30 min and the
Keywords: Paal–Knorr; Ionic liquid; 2,5-Hexandione; Primary amine;
Pyrrole.
*
Corresponding author. Tel.: +86-9318277635; fax: +86-9318277088;
e-mail: limy@ns.lzb.ac.cn
0
040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.03.012

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B. Wang et al. / Tetrahedron Letters 45 (2004) 3417–3419
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1
00
1
[
BMIm]BF4
8
6
0
0
8
6
4
2
0
0
0
0
0
[BMIm]I
[
[
[
[
PMIm]Cl
25˚C
BMIm]PF6
BDMIm]PF6
BPy]PF6
5
7
0˚C
5˚C
40
20
0
[HMIm][PhSO3]
CH2Cl2
100˚C
toluene
0
30
60
90
DMF
Time (min)
0
50
100
150
200
250
300
Figure 2. The effect of temperature on the Paal–Knorr condensation
Time (min)
of aniline with 2,5-hexandione in [BMIm]I ionic liquid.
Figure 1. Paal–Knorr condensation of aniline with 2,5-hexandione to
compare the efficiency of ionic liquids and organic solvents.
Table 1. Pyrroles derivatives produced from Paal–Knorr condensation
in [BMIm]I (via Scheme 1)
a
Entry
R
Time (min)
Yield (%)
1
2
3
4
5
6
7
8
9
n-Propyl
n-Heptyl
30
30
96
95
96
97
95
99
O
O
Ionic Liquid
+
R NH
2
iso-Propyl
t-Butyl
30
60
N
R
Cyclohexyl
Benzyl
Phenyl
60
30
Scheme 1. Synthesis of N-substituted-2,5-dimethylpyrrole in some
ionic liquids.
b
180
180
180
180
180
96 (94)
Tolyl
94
93
95
85
p-Nitrophenyl
p-Methoxyphenyl
2-Pyridinyl
1
1
0
1
product exclusively is N-phenyl-2,5-dimethylpyrrole. It
is noteworthy that Figure 1 shows the maximum con-
versions of aniline, obtained in all the tested ionic liquids
within 5 h, are all greater than 94%. To determine
whether the ionic liquid was an essential factor to realize
the high conversions of this condensation, the same
reaction (Scheme 1) was carried out in traditional sol-
vents. As a result, the Paal–Knorr condensations were
a
GC yield.
Yield of N-phenyl-2,5-dimethylpyrrole obtained in the ionic liquid
of having been reused three times.
b
to several amines. It is well known that the reactivity
of aliphatic amines is more potent compared with that
of aromatic amines, thus aliphatic amines give higher
yields or shorter reaction times that are generally ob-
served in other systems. It is gratifying that labile
functionality such as methoxy and nitro groups are
tolerated under this reaction condition.
2 2
sluggish in CH Cl and toluene, and the conversions
only reached 45% and 39%, respectively, after 5 h reac-
tion. But the result in nitrogen-containing solvents, such
as DMF was better. It is worthy to note that aniline has
a relatively low activity for this reaction, in order to
obtain the yield as high as possible in the traditional
systems, even more than 24 h has to be used, which
reproducibly indicated the effectiveness of ionic liquids
for Paal–Knorr pyrrole synthesis.
6
10
The recycle process was investigated starting with fresh
[BMIm]I and aniline. After the reaction was completed
(monitored by GC), the ionic liquid was recycled and
reused in the next cycle with the same substrate. To our
delight, the ionic liquid could be reused three times
without losing activity.
Having established the best solvent [BMIm]I, we started
to study the effect of temperature on the Paal–Knorr
condensation of aniline with 2,5-hexandione and the
results are presented in Figure 2. When the reaction
temperature was raised, maximum yield was reached
soon: for a 25 °C rise in temperature, the reaction time
can be halved until 75 °C. Because the 1.5 h of reaction
time, which is comparable with the conventional sys-
tems, is sufficient to complete this condensation under
room temperature, the reaction was ultimately carried
out at 25 °C to meet the requirement of minimization of
energy consumption, which is one of the principles of
green chemistry.
In summary, Paal–Knorr condensation of 2,5-hexan-
dione with an amine was successfully achieved in ionic
liquids. Compared with classical methods, the reaction
using ionic liquids as solvent has exhibited simple
product isolation procedure, improved yields and
exclusive selectivity. Other advantages are the acceler-
ated reaction rate, mild conditions and avoidance of
using toxic catalysts. Recovery and reuse of ionic liquids
are also satisfactory, which demonstrates the cost effi-
ciency and green aspect of our methodology.
Having these results in hand, other amines have been
subjected to the above-mentioned optimized conditions,
and the results are listed in Table 1. It is evident that our
methodology is reasonably general and can be applied
A representative procedure as follows: Aniline (1 mmol)
and 2,5-hexandione (1 mmol) were dissolved into 1.5 g
[BMIm]I ionic liquid in a 50 mL round bottom flask
equipped with a magnetic stirer, and the mixture was

B. Wang et al. / Tetrahedron Letters 45 (2004) 3417–3419
3419
heated at room temperature for 3 h with vigorous stir-
ring. After the reaction, the content was extracted with
ethyl ether (5 mL Â 3). The GC/MS analysis of the
combined organic extractant indicated the formation
of N-phenyl-2,5-dimethylpyrrole.
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