Green multicomponent reaction for synthesis of trisubstituted pyrroles in ionic liquid [bmim]BF4

Article abstract of DOI:10.1007/s11164-016-2501-3

2,4,5-Trisubstituted pyrrole derivatives were efficiently synthesized by one-pot condensation of 1,3-diones, α-bromoacetophenones, and ammonium acetate in ionic liquid [bmim]BF₄. The new synthetic method offers multisubstituted pyrroles with th

Full text of DOI:10.1007/s11164-016-2501-3

Res Chem Intermed
DOI 10.1007/s11164-016-2501-3
Green multicomponent reaction for synthesis
of trisubstituted pyrroles in ionic liquid [bmim]BF4
G. Narshimha Reddy1 Pravin R. Likhar1
•
Received: 10 January 2016 / Accepted: 29 February 2016
Ó Springer Science+Business Media Dordrecht 2016
Abstract 2,4,5-Trisubstituted pyrrole derivatives were efficiently synthesized by
one-pot condensation of 1,3-diones, a-bromoacetophenones, and ammonium acetate
in ionic liquid [bmim]BF4. The new synthetic method offers multisubstituted pyr-
roles with the advantages of mild reaction conditions, operational simplicity, higher
yield, and environmental friendliness.
Keywords 1,3-Diones Á a-Bromoacetophenones Á Ammonium acetate Á Ionic
liquid [bmim]BF4
Pyrroles represent an important class of heterocycles in organic chemistry. They are
structural units in many natural products and pharmaceuticals and key intermediates
for synthesis of a variety of biologically active molecules and functional materials
[1, 2]. They are also the key structural fragment of heme and chlorophyll, two
pigments essential for life [3, 4]. Examples of pyrrole-derived drugs include the
nonsteroidal antiinflammatory compound tolmetin, the anticancer drug candidate
tallimustine, and the cholesterol-lowering agent atorvastatin calcium (Lipitor), one
of the top-selling drugs worldwide (Fig. 1) [5–7].
While many classical methods including Knorr [8], Paal–Knorr [9], and Hantzsch
syntheses [10] are known for synthesis of pyrrole derivatives, some of them involve
tedious multistep synthetic operations and explosive starting materials. On the other
hand, several catalytic methodologies have been established for synthesis of
trisubstituted pyrroles, including N-substituted pyrroles. Among the transition
metals used in synthesis of trisubstituted pyrroles, copper [11–17] and palladium
[18, 19] metals have been extensively investigated, as well as other metals including
&
Pravin R. Likhar
plikhar@yahoo.com; plikhar@iict.res.in
1
Organometallic Gp., Inorganic and Physical Chemistry Division, CSIR-Indian Institute of
Chemical Technology, Hyderabad 500007, India
123

G. N. Reddy, P. R. Likhar
Fig. 1 Top-selling pyrrole-core drugs
Ag [20–22], Au [23], Rh [24], Ir [25], Zr [26], Bi [27], In [28], Co [29], Zn [30], and
Yb [31]. Though some metal catalysts have proven to be efficient and inexpensive,
others have limitations regarding cost, involving multiple steps, and moderate yield.
In spite of these outstanding efforts, it is still challenging to prepare polysubstituted
pyrroles possessing diverse substituents directly from commercially available
starting materials in a one-pot simple synthetic operation. Multicomponent reactions
(MCRs), in which a number of multiple reactions are combined into a one-pot
synthetic operation, have been widely used to prepare bioactive heterocyclic
compounds [16, 32–34]. Recently, ionic liquids have attracted extensive interest as
benign reaction media for use in organic synthesis because of their unique properties
of nonvolatility, nonflammability, recyclability, and ability to dissolve a wide range
of materials [35]. Ionic liquid-promoted synthesis of pyrroles was recently
accomplished by Siddiqui et al. [36]. Therefore, development of an environmentally
benign, simple, and efficient protocol for synthesis of substituted pyrrole derivatives
is in great demand.
Inspired by previous literature on development of environmentally benign
methodologies for synthesis of heterocyclic compounds [37–39], we turned our
attention to three-component condensation of 1,3-diketones, a-bromoacetophe-
nones, and ammonium acetate in ionic liquid [bmim]BF4. Herein, we report a novel,
efficient, and green procedure for synthesis of 2,4,5-trisubstituted pyrroles via three-
component condensation. To the best of our knowledge, this methodology has not
been reported in literature.
The three-component condensation reaction was initiated with acetylacetone, a-
bromoacetophenone, and ammonium acetate (1 equiv) in presence of ionic liquid
[bmim]BF4 at 70 °C to target synthesis of substituted pyrrole. To our surprise, in
this three-component condensation, the cyclization product 3a was obtained in
moderate yield. Screening of solvents using different temperatures and times was
carried out to achieve high yield of desired pyrrole (Table 1).
First, we investigated the effect of temperature on reaction rate and product yield.
This showed that desired product was not formed at room temperature even after
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Green multicomponent reaction for synthesis of…
Table 1 Screening of solvents using different temperatures and times in synthesis of 2,4,5-trisubstituted
pyrroles from 1,3-diketones, a-bromoacetophenones, and ammonium acetate
Entry
Solventa
Temp. (°C)
Time (h)
Yield (%)b
a
b
c
d
e
f
[bmin]BF4
[bmim]BF4
[bmin]BF4
DMF
35
50
12
12
3
–
10
85
40
35
30
45
20
53
70
100
100
90
6
DMSO
6
Toluene
CH3CN
DCE
6
g
h
i
80
6
80
6
PEG-400
100
6
a
The reaction was performed at 0.5 mmol scale ar reflux
Isolated Yield
b
12 h (Table 1, entry a). The yield of product 3a was improved and the reaction time
was shortened as the temperature was increased from 35 to 70 °C (Table 1, entry c),
so the most appropriate reaction temperature was 70 °C. When we employed the
same reaction condition using other solvents (DMF, DMSO, toluene, CH3CN, and
DCE) and ecofriendly solvent (PEG), product 3a was formed in low yields after a
long time (Table 1, entries d–i). These results show that 2 equiv NH4OAc was
essential to the reaction, and the best result was obtained when the reaction was
carried out with 2 equiv NH4OAc in ionic liquid [bmim]BF4 at 70 °C.
The base NH4OAc acts as proton transporter as well as reactant. Furthermore, we
found that the yields were clearly affected by the quantity of NH4OAc used in the
reaction. The greater the quantity of NH4OAc used from 1 to 2 equiv, the higher the
obtained product yield (up to 85 %) (Table 1, entry c).
With the set of optimized reaction conditions, we extended this method to other
a-bromoacetophenones such as 4-methyl-, 3-methyl-, and 3,4,5-trimethoxy-substi-
tuted a-bromoacetophenones. In all cases, corresponding pyrrole derivatives were
obtained in good yields (Table 2, entries a, b, e, h, and i). Furthermore, we
examined the reactivity of different 1,3-diones. Interestingly, other 1,3-diones such
as ethyl acetoacetate, methyl acetoacetate, and heptane-3,5-dione afforded corre-
sponding pyrroles in good yields as well (Table 2, entries c, d, f, and g). In addition,
this method works not only with linear 1,3-diones but also with cyclic 1,3-diones
such as dimedone and cyclohexane-1,3-dione. In the case of cyclic diketones,
corresponding pyrroles were obtained in lower yields (Table 2, entries j and k) than
123

G. N. Reddy, P. R. Likhar
Table 2 Reaction screening with different 1,3-diketones and bromoacetophenones
General experimental procedure: A mixture of 1,3-diones 1 (1 mmol), a-bromoacetophenones (1 mmol),
and ammonium acetate (2 mmol) was stirred at 70 °C in ionic liquid [bmim]BF4 (3 mL). After reaction
completion as indicated by thin-layer chromatography (TLC), water (6 mL) was added and the product
filtered off and washed with water. The remaining aqueous layer containing the ionic liquid was extracted
with diethyl ether (10 mL) for three times to remove remaining organic compound, then dried under
vacuum at 90 °C for about 13 h to afford ionic liquid, which was used in subsequent runs without further
purification. The combined organic ether layer with filtrate product and solvent was removed in vacuo, and
the crude compound was purified by column chromatography from petroleum ether and ethyl acetate to
give compound 3
a
All products characterized by nuclear magnetic resonance (NMR), infrared (IR), and mass spectroscopy
b
Yield refers to pure product after chromatography
123

Green multicomponent reaction for synthesis of…
Fig. 2 Recyclability of ionic
liquid
acyclic counterpart. In all cases, the reactions proceeded efficiently in ionic liquid
[bmim]BF4 at 70 °C and products were obtained in good yields.
Recovery and reusability of [bmim]BF4
After the reaction, the reaction mass was cooled to room temperature (RT) and the
crude product extracted with ether (2–3 times). The combined ether layers were
subjected to flash chromatography to obtain pure product, and trace amount of ether
was removed from the ionic liquid using vacuum pump at 90 °C for about 13 h,
followed by use in subsequent runs without further purification.
The recovered ionic liquid was further used as solvent in the second cycle of the
condensation reaction. As shown in Fig. 2, though the activity of the ionic liquid
diminished in terms of product yield from 85 to 55 % in the fifth cycle, the yields of
substituted pyrroles were almost the same during two recycles.
Scheme 1 Possible mechanism for formation of 3
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G. N. Reddy, P. R. Likhar
Based on the experimental results, a plausible mechanism for the ammonium
acetate-catalyzed condensation for formation of derivatives 3 is proposed in
Scheme 1. Initially, ammonium acetate condensation between 1,3-dione 1 and a-
bromoacetophenones 2 would give intermediate 4. Later, displacement of bromine
would furnish intermediate 5, which underwent aromatization to give product 3.
In conclusion, an efficient, environmentally friendly, and simple procedure for
condensation of 1,3-diketones, a-bromoacetophenones, and ammonium acetate to
synthesize trisubstituted pyrroles in ionic liquid is reported. Mild reaction
conditions, operational simplicity, higher yields (55–85 %), short reaction time,
cheap starting materials, and environmental friendliness are notable features of this
procedure. Meanwhile, ionic liquid [bmim]BF4 could be reused in up to five cycles
without much loss of activity. The methodology opens a new green route to
synthesis of trisubstituted pyrrole derivatives with simple workup.
Supplementary data
Experimental details, characterization data, and 1H and 13C NMR spectra of
products can be found in the online version at http://dx.doi.org/10.1007/s11164-
016-2501-3.
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