Task-specific basic ionic liquid: A reusable and green catalyst for one-pot synthesis of highly functionalized pyrroles in aqueous media

Article abstract of DOI:10.1055/s-2008-1042912

A basic functionalized ionic liquid, 1-butyl-3-methylimidazolium hydroxide ([bmim]OH), catalyzed the three-component condensation reaction of acid chlorides, amino acids, and dialkyl acetylenedicarboxylates in water to afford functionalized pyrroles in high yields. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2008-1042912

LETTER
897
Task-Specific Basic Ionic Liquid: A Reusable and Green Catalyst for One-Pot
Synthesis of Highly Functionalized Pyrroles in Aqueous Media
Catalyst
s
for
O
ne-P
s
ot Synthe
a
sis of
H
ighly Func
Y
tionalized Pyrrole
a
s
vari,* Elaheh Kowsari
Chemistry Department, Tarbiat Modares University, PO Box 14115-175, Tehran, Iran
Fax +98(21)88006544; E-mail: yavarisa@modares.ac.ir
Received 27 December 2007
pounds
(Paal-Knorr
synthesis),7
and
various
Abstract: A basic functionalized ionic liquid, 1-butyl-3-methylim-
idazolium hydroxide ([bmim]OH), catalyzed the three-component
condensation reaction of acid chlorides, amino acids, and dialkyl
acetylenedicarboxylates in water to afford functionalized pyrroles
in high yields.
cycloaddition strategies.8 Multicomponent strategies offer
significant advantages over classical linear syntheses by
combining a series of reactions from easily available and
simple precursors without the need for isolation of the in-
termediates. Such reactions are thus economically and en-
vironmentally attractive and have become an important
area of research in organic chemistry. Herein we report an
efficient reaction of acid chlorides 1, amino acids 2, and
dialkyl acetylenedicarboxylates 3 in aqueous medium in
the presence of a task-specific basic IL, [bmim]OH,9 as a
catalyst (Table 1).10 The catalyst can be recycled for sub-
sequent reactions without appreciable loss of efficiency.
Key words: functional ionic liquid, pyrrole synthesis, aqueous me-
dia, green catalyst
Room-temperature ionic liquids (IL) have attracted inten-
sive interests in recent years due to their wide applications
in synthesis, catalysis, and chemical separations.1,2 In
comparison with conventional molecular solvents, the IL
are advantageous because they are nonvolatile, thermally
stable over a wide temperature range, and recyclable. Re-
actions in aqueous media offer many advantages such as
simple operation and high efficiency in many organic re-
actions that involve water-soluble substrates and re-
agents.3 These advantages become even more attractive if
such reactions can be conducted using IL in aqueous me-
dia.
The three-component, one-pot condensation of 1, 2, and 3
proceeded smoothly in [bmim]OH–H2O system to give
the functionalized pyrroles 4 in high yields. When ben-
zoyl chlorides with electron-withdrawing groups (such as
NO2) are employed, the reaction time is shorter than those
with electron-donating groups. Results obtained under op-
timized conditions were compared with those using inor-
ganic or organic alkali catalysts. The [bmim]OH-H2O
system was found to be a much better catalytic medium
for this reaction. Non-imidazolium-based ILs such as [Et-
Py][BF4] or [bmim][BF4] were found to be less effective
catalysts for reaction of 1, L-phenylalanine, and 3. These
results confirm the vital role of the hydroxy counterion of
the [bmim]OH-H2O system.
Pyrroles represent an important class of N-heterocycles
that display remarkable pharmacological activities.4
Many synthetic methods are known for the construction of
the pyrrole structure.5 The most frequently used methods
include the classical Hantzsch procedure,6 the cyclocon-
densation of primary amines with 1,4-dicarbonyl com-
Ar
O
Ar
O
O
+ 3
– CO2
[bmim] OH
HN
HN
1
+
2
+
[bmim]
O
– H2O
R1
R1
5
6
7
CO2R2
CO2R2
CO2R2
R1
R2O2C
O
– [bmim] OH
– H2O
+
HO
Ar
[bmim]
4
Ar
N
R1
N
H
9
H
8
6
Scheme 1 Plausible mechanism for the formation of functionalized pyrroles 4
SYNLETT 2008, No. 6, pp 0897–0899
x
x.
x
x.
2
0
0
8
Advanced online publication: 11.03.2008
DOI: 10.1055/s-2008-1042912; Art ID: D41007ST
© Georg Thieme Verlag Stuttgart · New York

898
I. Yavari, E. Kowsari
LETTER
Table 1 Synthesis of Compounds 4a-q10
OR3
O
OH
CO2R3
OR3
R1
O
O
N
N
O
R2
OH
+
R2
+
R1
Cl
in aqueous media
N
H
NH2
CO2R3
1
2
3
4
Entry
1
Product
4a
R1
R2
R3
Yield (%)
Ph
Ph
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Et
95
91
93
96
92
94
87
95
87
89
84
88
91
90
89
87
96
2
4b
4c
4-MeC6H4
4-ClC6H4
4-O2NC6H4
Ph
Ph
3
Ph
4
4d
4e
Ph
5
Bn
6
4f
4-MeC6H4
4-ClC6H4
4-O2NC6H4
Ph
Bn
7
4g
Bn
8
4h
4i
Bn
9
i-Bu
i-Bu
i-Bu
i-Bu
Ph
10
11
12
13
14
15
16
17
4j
4-MeC6H4
4-ClC6H4
4-O2NC6H4
Ph
4k
4l
4m
4n
4o
4-MeC6H4
4-ClC6H4
4-O2NC6H4
Ph
Ph
Et
Ph
Et
4p
4q
Ph
Et
i-Bu
Et
The structures of 4a-q were deduced from their high-
References and Notes
field 1H NMR and 13C NMR spectra, and IR spectral data.
(1) (a) Rantwijk, F.; Sheldon, R. A. Chem. Rev. 2007, 107,
2757. (b) Pârvulescu, V. I.; Hardacre, C. Chem. Rev. 2007,
107, 2615. (c) Chowdhury, S.; Mohan, R. S.; Scott, J. L.
Tetrahedron 2007, 63, 2363.
(2) (a) Binnemans, K. Chem. Rev. 2007, 107, 2592. (b) Yavari,
I.; Kowsari, E. Tetrahedron Lett. 2007, 48, 3753.
(3) (a) Grieco, P. A. Organic Synthesis in Water; Blackie:
London, 1998. (b) Wei, W.; Li, C. J.; Varma, R. S. Clean
Tech. Environ. Policy 2005, 7, 62. (c) Narayan, S.;
Muldoon, J.; Finn, M. G. Angew. Chem. Int. Ed. 2005, 44,
3275.
(4) Jacobi, P. A.; Coults, L. D.; Guo, J. S.; Leung, S. I. J. Org.
Chem. 2000, 65, 205.
(5) For reviews on pyrrole synthesis, see: Sundberg, R. J. In
Comprehensive Heterocyclic Chemistry, Vol. 2; Katritzky,
A. R.; Rees, C. W.; Scriven, E. F. V., Eds.; Pergamon:
Oxford, 1996, 119.
Although the mechanistic details of the reaction are not
clearly known, it is reasonable to assume that intermediate
5 results from the reaction of acid chloride 1 with amino
acid 2. Subsequent decarboxylation of 5 in the presence of
[bmim]OH leads to intermediate 7, which is attacked by 3
to produce 8. Cyclization of 8 leads to 9, which is convert-
ed to 4 by elimination of H2O (Scheme 1).
In conclusion, we have described a convenient route to
functionalized pyrroles from the three-component reac-
tion of benzoyl chlorides, amino acids, and dialkyl acety-
lenedicarboxylates in a [bmim]OH–H2O system. The
attractive features of this protocol are: simple procedure,
short reaction time, use of cheap and benign solvent, the
reuse of the reaction medium, and its adaptability for syn-
thesis of a diverse set of pyrroles.
(6) For examples of the Hantzsch synthesis, see: Trautwein, A.
W.; Süßmuth, R. D.; Jung, G. Bioorg. Med. Chem. Lett.
1998, 8, 2381.
Synlett 2008, No. 6, 897–899 © Thieme Stuttgart · New York

LETTER
Catalyst for One-Pot Synthesis of Highly Functionalized Pyrroles
5.09; N, 4.21.
899
(7) For recent examples of the Paal–Knorr synthesis, see:
(a) Trost, B. M.; Doherty, G. A. J. Am. Chem. Soc. 2000,
122, 3801. (b) Quiclet-Sire, B.; Quintero, L.; Sanchez-
Jimenez, G.; Zard, S. Z. Synlett 2003, 75. (c) Tracey, M. R.;
Hsung, R. P.; Lambeth, R. H. Synthesis 2004, 918.
Dimethyl 2-Benzyl-5-phenyl-1H-pyrrole-3,4-dicarbox-
ylate (4e)
Colorless crystals; mp 134–135 °C; yield 0.32 g (92%). IR
(KBr): 3252 (NH), 1728 (C=O) cm–1. 1H NMR (500.1 MHz,
CDCl3): d = 3.80 (s, 3 H, OMe), 3.81 (s, 3 H, OMe), 4.30 (s,
2 H, CH2), 7.24–7.37 (m, 10 H, 2 C6H5), 8.38 (s, 1 H, NH).
13C NMR (125.7 MHz, CDCl3): d = 32.9 (CH2), 51.3 (OMe),
52.0 (OMe), 112.5 (C), 114.5 (C), 127.0 (CH), 127.1 (CH),
128.1 (2 CH), 128.7 (2 CH), 128.8 (2 CH), 128.9 (2 CH),
130.7 (C), 131.5 (C), 137.2 (C), 137.4 (C), 164.8 (C=O),
166.9 (C=O). Anal. Calcd (%) for C21H19NO4 (349.38): C,
72.19; H, 5.48; N, 4.01. Found: C, 72.13; H, 5.51; N, 4.05.
Dimethyl 2-Isobutyl-5-(4-methylphenyl)-1H-pyrrole-
3,4-dicarboxylate (4j)
Colorless crystals; mp 141–143 °C; yield 0.29 g (89%). IR
(KBr): 3225 (NH), 1681 (C=O) cm–1. 1H NMR (500.1 MHz,
CDCl3): d = 0.90 (d, 3J = 7.2, 6 H, CHMe2), 1.92–1.97 (m, 1
H, CH), 2.32 (s, 3 H, Me), 2.70 (d, 3J = 7.2 Hz, 2 H, CH2),
3.77 (s, 3 H, OMe), 3.79 (s, 3 H, OMe), 7.11 (d, 3J = 8.1 Hz,
2 H, 2 CH), 7.31 (d, 3J = 8.1 Hz, 2 H, 2 CH), 8.87 (s, 1 H,
NH). 13C NMR (125.7 MHz, CDCl3): d = 21.0 (Me), 22.2 (2
Me), 29.0 (CH), 35.6 (CH2), 51.0 (OMe), 51.9 (OMe), 112.3
(C), 113.6 (C), 127.0 (2 CH), 128.0 (C), 129.2 (2 CH), 131.4
(C), 137.8 (C), 138.6 (C), 165.1 (C=O), 167.4 (C=O). Anal.
Calcd (%) for C19H23NO4 (329.39): C, 69.22; H, 7.00; N,
4.25. Found: C, 69.41; H, 7.03; N, 4.28.
(8) (a) Katritzky, A. R.; Zhang, S.; Wang, M.; Kolb, H. C.;
Steel, P. J. J. Heterocycl. Chem. 2002, 39, 759.
(b) Bullington, J. L.; Wolff, R. R.; Jackson, P. F. J. Org.
Chem. 2002, 67, 9439. (c) Washizuka, K. I.; Minakata, S.;
Ryu, I.; Komatsu, M. Tetrahedron 1999, 55, 1296.
(9) [bmim]OH was prepared according to literature, see: Ranu,
B. C.; Banerjee, S. Org. Lett. 2005, 7, 3049.
(10) Dimethyl 2,5-Diphenyl-1H-pyrrole-3,4-dicarbox-
ylate (4a); Typical Procedure
A solution of the benzoyl chloride (1a, 0.14 g, 1 mmol),
phenyl glycine (2a, 0.15 g, 1 mmol), and [bmim]OH (1.40 g,
0.01 mol) in H2O (2 mL) was stirred at r.t. for 15 min. Then,
3 (0.14 g, 1 mmol) was added and the reaction mixture was
refluxed for 3 h (monitored by TLC). The reaction mixture
was cooled to r.t. and the solid mass was filtered, washed
with Et2O, and crystallized from n-hexane-EtOAc to give
4a as colorless crystals; mp 150-151 °C; yield: 0.31 g
(95%). IR (KBr): 3260 (NH), 1720 (C=O) cm–1. 1H NMR
(500.1 MHz, CDCl3): d = 3.60 (s, 6 H, 2 OMe), 7.32–7.35
(m, 6 H, 6 CH), 7.50–7.52 (m, 4 H, 4CH), 8.85 (s, 1 H, NH).
13C NMR (125.7 MHz, CDCl3): d = 51.8 (2 OMe), 114.1 (2
C), 128.1 (2 CH), 128.5 (4 CH), 128.6 (4 CH), 130.8 (2 C),
137.8 (2 C), 165.8 (2 C=O). Anal. Calcd (%) for C20H17NO4
(335.35): C, 71.56; H, 5.11; N, 4.18. Found: C, 71.70; H,
All other compounds isolated possessed spectroscopic and
analytical data in agreement with their proposed structures.
Synlett 2008, No. 6, 897–899 © Thieme Stuttgart · New York