Ionic liquid promoted multicomponent reaction: A good strategy for the eco-compatible synthesis of functionalized pyrroles

Article abstract of DOI:10.1002/jhet.1085

Task specific [bmim]BF₄ was found to be reusable, alternative, and effective reaction media for multicomponent synthesis of highly functionalized pyrroles. Generality of the procedure was established by synthesizing various pyrroles from wide range of aromatic/aliphatic amine, phenacyl bromide, and electrophilic alkynes by utilizing this protocol without any acid or metal catalyst. Ecocompatibility, short reaction time, excellent yield, recyclability of [bmim]BF₄, low cost, easy work-up, and mild reaction conditions are additional advantages of the procedure in the context of sustainable and green chemistry.

Full text of DOI:10.1002/jhet.1085

February 2013
Ionic Liquid Promoted Multicomponent Reaction: A Good
Strategy for the Eco‐Compatible Synthesis of
Functionalized Pyrroles
E111
*
I. R. Siddiqui, Devesh Kumar, and Shayna Shamim
Laboratory of Green Synthesis, Department of Chemistry, University of Allahabad,
Allahabad 211002, India
*
E-mail: irsiddiquiau@rediffmail.com
Received May 24, 2011
DOI 10.1002/jhet.1085
Published online 11 February 2013 in Wiley Online Library (wileyonlinelibrary.com).
Task specific [bmim]BF4 was found to be reusable, alternative, and effective reaction media for
multicomponent synthesis of highly functionalized pyrroles. Generality of the procedure was established
by synthesizing various pyrroles from wide range of aromatic/aliphatic amine, phenacyl bromide, and
electrophilic alkynes by utilizing this protocol without any acid or metal catalyst. Ecocompatibility, short
reaction time, excellent yield, recyclability of [bmim]BF4, low cost, easy work‐up, and mild reaction
conditions are additional advantages of the procedure in the context of sustainable and green chemistry.
J. Heterocyclic Chem., 50, E111 (2013).
INTRODUCTION
capability and ability to carry out reaction involving toxic
intermediates without exposure of these intermediates to
environment has been proved without doubt. Recently,
much attention have been devoted toward ionic liquid
due to their inherent features such as nonvolatility, low
inflammability, high thermal stability, ability to dissolve
large number of organic and inorganic compounds, easy
reusability [15], etc. Capacity of the ionic environment
to generate internal pressure and to promote the associa-
tion of reactant in solvent cavities renders them excellent
media for multicomponent one‐pot reactions. Recently,
various organic transformations have been reported using
[bmim]BF4 as a catalyst as well as reaction media [16].
As part of our endeavors for the design and develop-
ment of simple and green methodology for the synthesis
of biodynamic heterocycle [17], we wish to describe
herein a multicomponent, one‐pot, pyrrole synthesis by
using [bmim]BF4 as reaction medium without any catalyst
(Scheme 1).
Pyrroles are common structural motif in variety of natural
products [1], biologically active compounds [2], and several
drugs [3]. They also play major role in the synthetic building
blocks [4], pharmacophore [5], and various kind of func-
tional material [6]. In addition, pyrroles find application
as promising organic semiconductor [7] and valuable
intermediates [8] in organic synthesis. Consequently, they
appear to be molecular scaffolds of considerable interest
for synthetic organic chemist. Syntheses of pyrroles include
classical Hantzsch reaction [9], Knorr reaction [10], and
Paal–Knorr condensation reaction [11]]. Recently, new
approaches based on the multicomponent coupling [12]
and cycloisomerization of alkyne and allene containing
substrates catalyzed by a transition metal [13] have been
developed and have drawn extensive and enduring attention.
Despite numerous diverse approaches toward the synthesis
of polysubstituted pyrroles development of an easy, efficient,
environmentally benign synthetic method still remains an
attractive goal.
The quality and efficiency of organic synthesis now‐a‐days
is measured not only by the parameters like yields and
selectivity but also by the parameters like reaction time,
cost, and availability of the starting material as well as
source of energy. Multicomponent, one‐pot reactions
[14] have emerged as an efficient and powerful tool in
advance synthetic organic chemistry. Multicomponent
reactions leading to the preparation of the libraries of
the small organic molecules is a rapidly evolving area of
research. MCRs have ability of formation of complex
molecule in single operation, multiple bonds forming
RESULT AND DISCUSSION
To optimize the reaction condition and to study the
scope of the reaction were tried using different traditional
solvents ethanol, THF, CH3CN, DCM, and ionic liquid,
without any catalyst. Another factor was the reaction
temperature. The experiments were run from r.t. to reflux.
We found that the reaction does not proceed at all. Although
the FeCl3 catalyzed reaction of aniline and phenacyl bromide
in halogenated solvent is reported [18] to give the desired
product with longer reaction time (16–20 h). But when the
© 2013 HeteroCorporation

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I. R. Siddiqui, D. Kumar, and S. Shamim
Vol 50
Scheme 1. Synthesis of functionalized pyrroles using [bmim]BF4 at r.t.
reaction was carried out in ionic liquid [bmim]BF4 proceeds
smoothly, quantitatively and completed within 0.5–1.0 h at
room temperature. This observation clearly indicated that
in the present reaction conditions the ionic liquid plays the
dual role of solvent and promoter. Ionic environment gener-
ated internal pressure which promoted the association of
reactants in ionic liquid cavities as well as enhance the bond
forming transformations. Thus, the reaction in [bmim]BF4 is
advantageous, because of its operational simplicity, and it
can be reused in subsequent reactions. After the completion
of the reaction, the reaction mixture was extracted with ethyl
acetate (3 × 20 mL) and residual ionic liquid were activated
at 85°C under vacuum for an hour. The recycled ionic liquid
was used for four times for the same reaction, and we found
no substantial loss in activity.
afforded highly functionalized pyrroles. Presence of
electron releasing group on 1 and/or 2 accelerated the
nucleophilic addition as well as nucleophilic substitution
and hence promoted the formation of product and enhance
yield of the product. But the electron withdrawing group
in 1 and/or 2 retarded the overall rate of formation of product
and yield of the product.
CONCLUSION
In summary, ionic liquid are used as efficient and useful
reaction medium for the synthesis of polysubstituted pyr-
roles. Compared with the conventional method, above pro-
tocols offer several advantages like higher yield, shorter
reaction time, ecocompatible reaction condition, opera-
tional simplicity, efficient recovery, and recyclability of
[bmim]BF4.
With the optimized condition in hand various deriva-
tives of phenacyl bromide, aliphatic/aromatic amine, and
DEAD/DMAD were used to explore the generality and
reproducibility of this protocol; results are summarized
in Table 1.
EXPERIMENTAL
Melting points were determined into an open glass capillary
method and are uncorrected. All chemicals used were of reagent
grade and used without further purification. 1H NMR spectra
were recorded at 400 MHz and 13C NMR spectra at 100 MHz
on a Broker AVANCE DPX FT spectrometer in CDCl3 using
TMS as an internal reference. Mass spectra were determined on
a JEOL sx‐102 (FAB) mass spectrometer at 70 eV. Elemental
On the basis of the results obtained above, a plausible
mechanism of this reaction is illustrated in Scheme 2.
α,β‐unsaturated N‐arylamine formed in situ from aromatic/
aliphatic amine and DEAD/DMAD, was not isolated
but it on nucleophilic substitution with α‐bromoketone
and subsequent intramolecular dehydrative cycloaddition
Table 1
Synthesis of functionalized pyrrolesa using ionic liquid [bmim]BF4.
Entry
Product
R1
R2
R3
Time (min)
Yieldb (%)
1
2
3
4
5
6
7
8
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
H
H
C6H5
C6H5
C6H5
C2H5
CH3
C2H5
CH3
C2H5
CH3
C2H5
CH3
C2H5
CH3
C2H5
CH3
CH3
CH3
60
70
65
60
75
70
80
65
75
75
65
63
55
50
87
86
90
93
92
92
85
85
86
86
92
92
90
90
CH3
CH3
OCH3
OCH3
NO2
NO2
NO2
NO2
CH3
CH3
H
C6H5
ClC6H4
ClC6H4
C6H5
C6H5
9
CH3C6H4
CH3C6H5
ClC6H4
ClC6H4
C2H5
10
11
12
13
14
H
CH3
aReaction condition: α‐halo‐ketone (1.05 mmol), aniline (1 mmol), and DEAD/DMAD (1 mmol) in [bmim]BF4 at rt.
bIsolated yield.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

February 2013
Ionic Liquid Promoted Multicomponent Reaction: A Good Strategy for the
E113
Eco‐Compatible Synthesis of Functionalized Pyrroles
Scheme 2. Plausible mechanism for ionic liquid promoted synthesis of functionalized pyrroles.
analysis was executed using a Coleman automatic C, H, and N
analyzer. The progress of the reaction was monitored by TLC
(Merk silica gel).
NMR (100 MHz, CDCl3): δ 14.5, 14.7, 21.1, 61.9, 62.4, 122.4,
123.7, 125.1, 126.7, 127.2, 128.5, 133.2, 140, 160.1, 167.2. MS
(ESI): m/z = 378 [M + H]+. Anal. Calcd for C23H23NO4: C,
73.19; H, 6.14; N, 3.71. Found: C, 73.14; H, 5.62; N, 3.94.
1‐Phenyl‐5‐tolyl‐1H‐pyrrole‐2,3‐dicarboxilic acid dimethyl
General procedure. A mixture of aniline (1 mmol) and
α‐halo‐ketone (1.05 mmol) in [bmim]BF4 (2 mL) was added
DEAD (1 mmol) dropwise and stirred at room temperature for
the appropriate time (Table 1). After completion of the
reaction, as indicated by TLC, the reaction mixture was
extracted with ethyl acetate (3 × 10 mL). The combined
organic extracts were washed with saturated brine solution and
dried (anhyd. Na2SO4) and concentrated under vacuum and the
resulting crude product was directly charged on a silica gel
(Merck, 60–120 mesh) column and eluted with 5–10% ethyl
acetate/n‐hexane to afford the corresponding pure product. The
residual ionic liquid was dried under vacuum and reused. All
the products were prepared by following the same procedure
and characterized mass and NMR.
1
ester (4d). H NMR (400 MHz, CDCl3): δ 2.37 (s, 3H), 3.77
(s, 3 H), 3.89 (s, 3 H), 7.14 (s, 1 H), 7.25–7.55 (m, 9 H). 13C
NMR (50 MHz, CDCl3): δ 21.8, 53.2, 54.1, 124.6, 126.1,
127.4, 127.9, 128.6, 129, 133, 161.7, 167.5. MS (ESI): m/z = 336
[M + H]+. Anal. Calcd for C21H19NO4: C, 72.19; H, 5.48; N,
4.01. Found: C, 72.27; H, 5.32; N, 4.09.
1‐(4‐Chloro‐phenyl)‐5‐(4‐methoxy‐phenyl)‐1H‐pyrrole‐2,3‐
dicarboxylic acid diethyl ester (4e). 1H NMR (400 MHz,
CDCl3): δ 1.25 (t, J = 8, 3H), 1.31 (t, J = 8, 3H), 3.75 (s, 3H),
4.24 (q, J = 8, 2H), 4.32 (q, J = 8, 2H), 6.88–6.90 (d, J = 6Hz,
2H), 7.16 (s, 1H), 7.22–7.37 (m, 6H). 13C NMR (50 MHz,
CDCl3): δ 13.5, 13.2, 57.1, 61.5, 61.2, 112.3, 112.9, 116.7,
118.4, 121.3, 124.2, 124.8, 128.7, 129.1, 129.8, 130.1, 140.1,
158, 163, 167.9. MS (ESI): m/z = 428 [M + H]+. Anal. Calcd
for C23H22ClNO5: C, 64.56; H, 5.18; N, 3.27. Found: C,
64.68; H, 5.25; N, 6.48.
1‐(4‐Chloro‐phenyl)‐5‐(4‐methoxy‐phenyl)‐1H‐pyrrole‐2,3‐
dicarboxylic acid dimethyl ester (4f). 1H NMR (400 MHz,
CDCl3): δ 3.77 (s, 3H), 3.95 (s, 2H), 4.12 (s, 2H), 6.86–6.89
(d, J = 6Hz, 2H), 7.18 (s, 1H), 7.21–7.35 (m, 6H). 13C NMR
(100 MHz, CDCl3): δ 51.6, 57.1, 58.6, 112.5, 112.2, 116.5,
118.1, 121.8, 124.5, 124.4, 128.1, 129.3, 130, 130.7, 140.1,
159.2, 163.4, 170. MS (ESI): m/z = 400 [M + H]+. Anal.
Calcd for C21H18ClNO5: C, 63.08; H, 4.54; N, 3.50. Found: C,
63.15; H, 4.38; N, 3.55.
Spectral data compounds 3a‐n.
1,5‐Diphenyl‐1H‐pyrrole‐2,3‐dicarboxilic acid diethyl ester
1
(4a). H NMR (400 MHz, CDCl3): δ 1.14 (t, J = 8 Hz, 3 H),
1.27 (t, J = 8 Hz, 3 H), 4.18 (q, J = 8 Hz, 2 H), 4.31 (q, J = 8 Hz,
2 H), 7.02 (s, 1 H), 7.22–7.54 (m, 10 H). 13C NMR (100 MHz,
CDCl3): δ 14.1, 14.4, 61.7, 62.1, 122.6, 123.5, 124.8, 126.4,
127.5, 128.3, 133.6, 140.3, 160.4, 167. MS (ESI): m/z = 364
[M + H]+. Anal. Calcd for C22H21NO4: C, 72.71; H, 5.82; N,
3.85. Found: C, 72.78; H, 5.65; N, 3.93.
1,5‐Diphenyl‐1H‐pyrrole‐2,3‐dicarboxilic acid dimethyl ester
(4b). 1H NMR (400 MHz, CDCl3): δ 3.75 (s, 3 H), 3.84 (s, 3 H),
6.98 (s, 1 H), 7.57–7.24 (m, 10 H). 13C NMR (50 MHz, CDCl3):
δ 53.2, 55.4, 124.1, 125.8, 126.9, 127.2, 128.1, 128.8, 132.8,
161.5, 167.7. MS (ESI): m/z = 336 [M + H]+. Anal. Calcd for
C20H17NO4: C, 71.63; H, 5.11; N, 4.18. Found: C, 71.52; H,
5.22; N, 4.24.
5‐(4‐Nitrophenyl)‐1‐phenyl‐1H‐pyrrole‐2,3‐dicarboxylic acid
diethyl ester (4g). 1H NMR (400 MHz, CDCl3): δ 1.18 (t, J = 8,
3H), 1.27 (t, J = 8, 3H), 4.21 (q, J = 8, 2H), 4.32 (q, J = 8, 2H),
7.11 (s, 1H), 7.36–7.41 (m, 2H), 7.45 (m, 2H), 7.63 (d, J = 9, 2H),
8.24 (d, J = 9, 2H). 13C NMR (100 MHz, CDCl3): δ 13.3, 13.7,
60.9, 61.1, 121.2, 122, 122.8, 123.7, 126.5, 128.4, 129.1, 129.5,
138.9, 140, 157.4, 160.2, 166.6. MS (ESI): m/z = 409 [M + H]+.
1‐Phenyl‐5‐tolyl‐1H‐pyrrole‐2,3‐dicarboxilic acid diethyl ester
(4c). 1H NMR (400 MHz, CDCl3): δ 1.23, (t, J = 8 Hz, 3 H), 1.33
(t, J = 8 Hz, 3 H), 2.32 (s, 3H), 4.22 (q, J = 8 Hz, 2 H), 4.34
(q, J = 8 Hz, 2 H), 7.1 (s, 1 H), 7.25–7.58 (m, 9 H). 13C
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

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I. R. Siddiqui, D. Kumar, and S. Shamim
Vol 50
Anal. Calcd for C22H20N2O6: C, 64.70; H, 4.94; N, 6.86. Found: C,
64.64; H, 4.83; N, 6.94.
Acknowledgments. The authors thank CSIR, New Delhi, for
financial support and SAIF Chandigarh for spectral analysis.
5‐(4‐Nitrophenyl)‐1‐phenyl‐1H‐pyrrole‐2,3‐dicarboxylic
1
acid dimethyl ester (4h). H NMR (400 MHz, CDCl3): δ 3.74
(s, 3 H), 3.86 (s, 3 H), 7.05 (s, 1 H), 7.33–7.38 (m, 2 H),
7.42–7.52 (m, 3 H), 7.61 (d, J = 9 Hz, 2 H), 8.26 (d, J = 9 Hz,
2 H). 13C NMR (100 MHz, CDCl3): δ 52.3, 51.4, 120.7,
122.3, 124.1, 125.5, 126.3, 128.2, 128.7, 129.1, 138.4, 140.2,
146.7, 160.12, 166.5. MS (ESI): m/z = 381 [M + H]+. Anal.
Calcd for C20H16N2O6: C, 63.16; H, 4.24; N, 7.37. Found: C,
63.11; H, 4.32; N, 7.35.
5‐(4‐Nitrophenyl)‐1‐(4‐tolyl)‐1H‐pyrrole‐2,3‐dicarboxylic
acid diethyl ester (4i). 1H NMR (400 MHz, CDCl3): δ 1.17
(t, J = 8 Hz, 3 H), 1.33 (t, J = 8 Hz, 3 H), 2.42 (s, 3 H), 4.18
(q, J = 8 Hz, 2 H), 4.34 (q, J = 8 Hz, 2 H), 7.04 (s, 1 H),
7.11–7.27 (m, 4 H), 7.60 (d, J = 8.0 Hz, 2 H), 8.22 (d,
J = 8.0 Hz, 2 H). 13C NMR (100 MHz, CDCl3): δ 13.1,
13.6, 22.7, 61.5, 61.8, 123.2, 123.4, 126.2, 126.5, 127.8,
128, 130.2, 139.3, 147.2, 160.2, 166.1. MS (ESI): m/z = 423
[M + H]+. Anal. Calcd for C23H22N2O6: C, 65.39; H, 5.25; N,
6.63. Found: C, 65.47; H, 5.21; N, 6.65.
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1
(s, 3 H), 3.63 (s, 3 H), 3.86 (s, 3 H), 7.04 (s, 1 H), 7.05–7.35
(m, 4 H), 7.61 (d, J = 9 Hz, 2 H), 8.23 (d, J = 9 Hz, 2 H).
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146.7, 161.4, 167.2. MS (ESI): m/z = 395 [M + H]+. Anal.
Calcd for C21H18N2O6: C, 63.96; H, 4.60; N, 7.10. Found: C,
63.85; H, 4.68; N, 7.17.
1‐(4‐Chloro‐phenyl)‐5‐p‐tolyl‐1H‐pyrrole‐2,3‐dicarboxylic
acid diethyl ester (4k). 1H NMR (400 MHz, CDCl3): δ 1.18
(t, J = 8 Hz, 3 H), 1.33 (t, J = 8 Hz, 3 H), 2.42 (s, 3 H), 4.21
(q, J = 8 Hz, 2 H), 4.31 (q, J = 8 Hz, 2 H), 7.06 (s, 1H), 7.12–7.37
(m, 8H). 13C NMR (100 MHz, CDCl3): δ 12.8, 13.7, 21.2, 58.5,
61.1, 112.4, 118.1, 121.7, 124.2, 124.8, 126, 129.4, 130, 133.2,
138.2, 138.9, 159.6, 167. MS (ESI): m/z = 412 [M + H]+. Anal.
Calcd for C23H22ClNO4: C, 67.07; H, 5.38; N, 5.13. Found: C,
67.15; H, 5.45; N, 5.07.
1‐(4‐Chloro‐phenyl)‐5‐p‐tolyl‐1H‐pyrrole‐2,3‐dicarboxylic
acid dimethyl ester (4l). 1H NMR (400 MHz, CDCl3): δ 2.37 (s,
3H), 3.74 (s, 3 H), 3.83 (s, 3 H), 7.01 (s, 1 H), 7.19–7.42 (m, 8 H).
13C NMR (100 MHz, CDCl3): δ 21.1, 50.2, 51.8, 112.5, 118.2,
121.6, 123.4, 124.2, 124.7, 126.9, 127.3, 129.4, 133.5, 138.1,
138.7, 158.9, 166.8. MS (ESI): m/z = 384 [M + H]+. Anal.
Calcd for C21H18ClNO4: C, 65.71; H, 4.73; N, 5.13. Found: C,
65.82; H, 4.67; N, 5.08.
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1
3 H), 3.75 (s, 3H), 3.85 (s, 2H), 3.89 (s, 3H), 6.84 (s, 1H),
7.18–7.37 (m, 5H). 13C NMR (100 MHz, CDCl3): δ 14.7,
33.5, 50.1, 110.2, 126.1, 127.0, 128.7, 129.6, 136.9, 159.4,
167.2. MS (ESI): m/z = 288 [M + H]+. Anal. Calcd for
C16H17NO4: C, 66.89; H, 5.96; N, 4.88. Found: C, 65.82; H,
5.84; N, 4.97.
1‐Methyl‐5‐phenyl‐1H‐pyrrole‐2,3‐dicarboxylic acid
1
dimethyl ester (4n). H NMR (400 MHz, CDCl3): δ 3.54 (s, 3 H),
3.75 (s, 3H), 3.78 (s, 3H), 3.91 (s, 2H), 6.86 (s, 1H), 7.24–7.39
(m, 5H). 13C NMR (100 MHz, CDCl3): δ 25.5, 49.3, 50.1, 110.6,
115.7, 127.1, 128.7, 129.4, 136.8, 159.6, 167.4. MS (ESI):
m/z = 274 [M + H]+. Anal. Calcd for C15H15NO4: C, 65.82;
H, 5.53; N, 5.13. Found: C, 65.71; H, 5.59; N, 5.17.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

February 2013
Ionic Liquid Promoted Multicomponent Reaction: A Good Strategy for the
E115
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet