Acid- and metal-free synthesis of annulated pyrroles in a deep eutectic solvent

Article abstract of DOI:10.1039/c4ra14379e

An environmentally benign, one-pot, three component synthesis of annulated pyrroles by coupling free sugars with enamines, generated in situ from aryl amines and 1,3-diketones, has been achieved by using a deep eutectic solvent (DES). The reaction conditions are mild and do not require additional Bronsted or Lewis acid catalysts.

Full text of DOI:10.1039/c4ra14379e

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Acid- and metal-free synthesis of annulated pyrroles in
deep eutectic solvent
Cite this: DOI: 10.1039/x0xx00000x
Sunil M. Rokadea, Ashok M. Garandea, Nazim A. A. Ahmada and Prakash M. Bhate*
Received 00th January 2012,
Accepted 00th January 2012
DOI: 10.1039/x0xx00000x
www.rsc.org/
Abstract: An environmentally benign, oneꢀpot, three component synthesis of annulated pyrroles by coupling free sugars with enamines,
generated in situ from aryl amines and 1,3ꢀdiketones, has been achieved by using deep eutectic solvent (DES). The reaction conditions are
mild and do not require additional Bronsted or Lewis acid catalyst.
Introduction
Deep eutectic solvents (DES) have attracted considerable attention as green alternatives to conventional solvents. These not only reduce the
burden of disposal of organic solvents but also enhance the rate of many organic reactions. In addition to advantages such as chemical
stability and low vapour pressure,1 deep eutectic solvents are diverse, inexpensive, readily available and have emerged as alternatives to
organic solvents.2–4
Multiꢀcomponent reactions (MCRs) in view of their ability to construct complex molecules have become a widely explored area. MCRs
are faster and more efficient than classical reactions, since reactions are completed by mere mixing of compounds in one vessel without
isolating any intermediates. Additional benefits include readily available starting materials, operational simplicity and ease of automation.5
The combination of MCR with DES is therefore one of the most suitable strategies for developing libraries of useful scaffolds.6
Substituted pyrroles occur in bioactive molecules7 and also in a wide range of natural products.8 They also find broad applications in
supramolecular chemistry and material science.9 Hence, several useful strategies have been developed for the construction of the pyrrole
moiety.10 Thus, the development of streamlined methods for their synthesis starting from easily available materials is desirable.
Glycosylation of heterocyclic compounds is also a field of increasing interest, in view of various guanidine derived glycosides showing antiꢀ
inflammatory and antiꢀHIV activity.11 To the best of our knowledge, only two reports12 for the synthesis of sugar annulated pyrrole
derivatives are available. The main disadvantages of these methods are the cost of catalyst,12a time required for reaction completion and yield
obtained.12b Hence, the development of a more practical and economical method for the synthesis of annulated pyrroles is of interest.
In this paper, we disclose a oneꢀpot synthesis of optically pure annulated pyrroles via the cyclization of enamines with free sugars by
Knoevenagel condensation under acidꢀ and solventꢀfree conditions in presence of DES made from choline chloride and urea (see Scheme).
Scheme
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Table 1 Synthesis of annulated pyrroles in choline chloride: urea (CC/U)
Aryl
amine
1,3-
dione
Acylated
product
Time
(min)
Yield
(%)
Entry
Sugar
R1
R2
R3
R4
R5
R6
R7
R8
R4’
R5’
R6’
3a
3b
5a
5b
30
30
94
92
CH3
OEt
1
2
H
2a
3c
3a
7a
5c
45
30
84
92
ꢀ
3
4
H
OH
H
H
OH
CH2OH
H
OAc
CH2OAc
1a
CH3
2b
2a
CH3
3b
5d
30
90
OEt
5
3a
3b
3c
3a
3b
3a
5e
5f
30
40
45
30
35
45
94
92
84
90
92
84
CH3
OEt
ꢀ
6
7
H
H
OH
H
OH
H
CH2OH
OAc
H
CH2OAc
7b
5g
5h
8
1b
CH3
OEt
CH3
9
CH3
2b
2a
10
11
H
5i
5j
CH2OH
H
H
H
OH
OH
H
H
OH
OH
H
H
H
H
OAc
OAc
H
H
1c
2b
2a
3b
3a
CH3
45
30
85
94
OEt
CH3
12
13
1d
H
5k
5a-5k: Yield after acetylation followed by column chromatography
7a-7b: Reaction of 1a, 1b and 2a with dimedone 3c
Results and discussion
Initially we attempted the reaction of Dꢀglucose (1a) with aniline (2a) and acetylacetone (3a) in presence of DES at room temperature.
ο
However, TLC analysis did not indicate formation of any product. When the reaction was carried out at 80 C for 30 min, we were able to
1
isolate (4a) which was identified based on H NMR data of its acetylated derivative (5a) (entry 1 in Table 1). When we carried out the
reaction at 100 οC we observed the formation of several polar side products along with traces of (4a). Similar results were obtained when we
used DES prepared from choline chloride : malonic acid, choline chloride : ethylene glycol, choline chloride : oxalic acid and choline
chloride : TsOH (entries 2ꢀ5 Table 2). Further reactions were carried out with DES prepared from choline chloride : urea as it is the least
expensive option.
Table 2 Optimization of catalyst in reaction of (1a) and (2a) with (3a)
Entry
Catalyst
Time (h)
Temperature (oC)
Yield (%)
8.0
4.0
0.5
2.0
8.0
4.0
0.8
2.0
8.0
4.0
0.5
2.0
8.0
4.0
0.5
2.0
8.0
4.0
0.5
2.0
RT
50
80
100
RT
50
Traces
42
94
68
Traces
36
90
65
Traces
42
92
67
Traces
41
90
67
Traces
40
93
1
ChCl : Urea
2
3
4
5
ChCl : Ethylene glycol
ChCl : Malonic acid
80
100
RT
50
80
100
RT
50
ChCl : Oxalic acid
ChCl : TsOH
80
100
RT
50
80
100
66
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In order to evaluate the scope of this protocol we studied the reaction of Dꢀglucose, Dꢀgalactose, Dꢀfructose and Dꢀxylose with aniline and
pꢀtoluidine and 1,3ꢀdicarbonyl compounds such as acetylacetone (3a), ethyl acetoacetate (3b) and dimedone (3c). In general, all reactions
were clean and the corresponding annulated pyrroles, characterized by conversion into diꢀOꢀacetyl derivatives, were obtained in short
reaction times in moderate to high yield (see Table 1). DꢀGlucose (1a) on reaction with aniline (2a) and acetylacetone (3a) in the presence of
DES at 80 °C for 30 min rapidly produced annulated pyrrole derivative (4a) in 94% yield. Reaction with pꢀtoluidine (2b) resulted in the
formation of annulated pyrrole (4c) in 93% yield (entries 4 in Table 1). Use of a cyclic 1,3ꢀdiketone such as dimedone (3c) with Dꢀglucose
(1a) and aniline (2a) afforded annulated pyrroles (6a) and (6b) in lesser yield (84ꢀ88%) (entry 3 and 8 in Table 1). DꢀGalactose (1b) and Dꢀ
fructose (1c) on reaction with anilines (2a, 2b) and 1,3ꢀdicarbonyl compounds (3a, 3b, 3c) under the same reaction condition afforded the
corresponding annulated pyrroles in good yield (entries 6ꢀ12 in Table 1). A pentose such as xylose on reaction with aniline (2a) and
acetylacetone (3a) afforded the corresponding annulated pyrrole (4k) in good yield (94%, entry 13 in Table 1). In all cases, only a single
product was obtained the 1H NMR spectrum of which was identical to that previously reported.12
Table 3 Recyclability studies of DES
Entrya
Recycling
Yield (%)
1
2
3
4
5
Fresh
94
92
90
88
84
1
2
3
4
aThese reactions were allowed to run for 30 min and were isolated via extraction with ethyl acetate.
We chose the preparation of pyrrole (4a) for studying the recyclability of DES. Thus the DES residue obtained after extraction of (4a)
with ethyl acetate (see General experimental procedure) was dehydrated under vacuum on a rotary evaporator for 15 min and directly used
for repeating the reaction. Table 3 presents data obtained after five such recycles. The results indicate that DES can be recycled at least
three times without significant loss in activity.
Probable mechanism
Figure 1 depicts a plausible mechanism for this reaction. It is based on a mechanism reported12a previously and on the proposed13
hydrogen bonding capability of urea. Thus condensation of the enaminoketone (2a') formed by reaction of aniline (2a) with 1,3ꢀdiketone
(3a) with Dꢀglucose is facilitated by hydrogen bonding of urea with the anomeric hydroxyl group. The resulting aldol product (3a') on
subsequent cyclodehydration followed by aromatization affords the annulated pyrrole (4a).
Figure 1
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Conclusion
In summary, we have demonstrated a remarkably simple three component reaction between free sugars, amines and 1,3ꢀdicarbonyl
compounds in DES that results in the formation of annulated pyrroles in good yields. This protocol offers additional advantages such as
simple workup and general applicability for the synthesis of biologically active pyrrole derivatives.
Acknowledgments
SMR thanks the Council of Scientific and Industrial Research (CSIR), New Delhi, India and AMG and NAAA thank the University Grant
Commission (UGC), New Delhi, India for providing research fellowships.
References
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14. General experimental procedure:
A mixture of free sugar (1a, b, c, d) (5.5 mmol), aryl amine (2a, b) (6.11 mmol), 2,4ꢀdione (3a, b, c) (6.11 mmol) and CC/U (10 ml) was stirred at 80 °C
for 30 min (see Table 1). When the reaction was complete (TLC), the mixture was extracted with ethyl acetate (2×15 mL). The combined organic extracts
were washed with H2O and dried (anhyd Na2SO4). Removal of solvent followed by purification by column chromatography (silica gel, EtOAc–nꢀhexane,
7:3) afforded pure dihydroxy product (4a-4k), which was acetylated by using Ac2O (7.3 mmol) and DMAP (catalytic amount) in CH2Cl2 (5 mL). The
reaction mixture was stirred at r.t. for 30 min, then poured into iceꢀwater (50 mL) and extracted with CH2Cl2 (2 ×25 mL). The combined organic layer was
washed with H2O (2×25mL), dried (anhyd Na2SO4) and evaporated to yield pure acetylated products (5a-5k) in 84–94% yield.
Notes and references
a These authors contributed equally to this work
a Department of Dyestuff Technology,
.
Institute of Chemical Technology (formerly UDCT),
N. P. Marg, Matunga, Mumbai ꢀ 400 019. Maharashtra, India.
*Corresponding author:
Department of Dyestuff Technology,
Institute of Chemical Technology (formerly UDCT),
N. P. Marg, Matunga, Mumbai ꢀ 400 019. Maharashtra, India.
pm.bhate@ictmumbai.edu.in, pmbhate@gmail.com Tel: +91ꢀ22ꢀ3361 1111/2222/2706.
Electronic Supplementary Information (ESI) available: [details of any supplementary information available should be included here]. See
DOI: 10.1039/c000000x/
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