1-methylimidazole-catalyzed reaction between tosylmethyl isocyanide and dialkyl acetylenedicarboxylates: An efficient synthesis of functionalized pyrroles

Article abstract of DOI:10.1016/j.cclet.2010.10.032

An efficient 1-methylimidazole-catalyzed synthesis of dialkyl 2-[(4-methylphenyl)sulfonyl]-1H-pyrrole-3,4-dicarboxylates is described. The reactive 1:1 zwitterionic intermediate formed by the addition of 1-methylimidazole to dialkyl acetylenedicarboxylate

Full text of DOI:10.1016/j.cclet.2010.10.032

Available online at www.sciencedirect.com
Chinese Chemical Letters 22 (2011) 314–317
www.elsevier.com/locate/cclet
1-Methylimidazole-catalyzed reaction between tosylmethyl
isocyanide and dialkyl acetylenedicarboxylates: An efficient
synthesis of functionalized pyrroles
a
a
b
Mehdi Adib a, , Bagher Mohammadi , Ehsan Sheikhi , Hamid Reza Bijanzadeh
*
a School of Chemistry, University College of Science, University of Tehran, PO Box 14155-6455, Tehran, Iran
b Department of Chemistry, Tarbiat Modarres University, PO Box 14115-175, Tehran, Iran
Received 29 June 2010
Available online 22 December 2010
Abstract
An efficient 1-methylimidazole-catalyzed synthesis of dialkyl 2-[(4-methylphenyl)sulfonyl]-1H-pyrrole-3,4-dicarboxylates is
described. The reactive 1:1 zwitterionic intermediate formed by the addition of 1-methylimidazole to dialkyl acetylenedicarbox-
ylates is trapped by tosylmethyl isocyanide (TOSMIC) to afford the title compounds in excellent yields.
# 2010 Mehdi Adib. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
Keywords: 1-Methylimidazole; Tosylmethyl isocyanide; Acetylenic esters; Pyrrole synthesis
Pyrroles, an important class of heterocyclic compounds, have attracted much synthetic attention. Some pyrroles are
basic constituents of numerous natural products such as heme, chlorophyll, vitamin B12, and various cytochrome
enzymes. Some pyrroles have been reported to possess antioxidant, antibacterial, ionotropic, antitumor, anti-
inflammatory and antifungal activities. Furthermore, some pyrrole derivatives have been shown to be P38 kinase
inhibitors, prolyl-4-hydroxylase inhibitors, poly (ADP-ribose) polymerase inhibitors, estrogen receptor b selective
ligands, AT1-selective angiotensin II receptor antagonists, and minor groove recognition elements [1,2].
Classical methods including Knorr reaction, Paal–Knorr synthesis and Hantzsh synthesis [3] are still widely used
for the preparation of substituted pyrroles [4]. There are several pyrrole syntheses from alkenes and isocyanides via
pyrrolines. For example, a pyrrole synthesis has been reported based on the reaction between TOSMIC and electron-
deficient alkenes [5]. Base-catalyzed reaction of nitroalkenes or b-nitroacetates with alkyl isocyanoacetates or
TOSMIC afforded pyrrole-2-carboxylates [6] or 2-sulfonylpyrroles [7], respectively. However, only a few pyrrole
syntheses are found in literature starting from acetylenes. In 1979, a pyrrole synthesis was reported via reaction
between acetylenic esters and TOSMIC in the presence of DBU [8]. A direct synthesis of substituted pyrroles has been
reported via cycloaddition of a-metalated isocyanides to acetylenic compounds [9]. Another synthesis of substituted
pyrroles was reported via reaction of acetylenedicarboxylates with TOSMIC in the presence of triphenylphosphine
[10]. However, most of these procedures have significant drawbacks such as long reaction times, low yields of the
* Corresponding author.
E-mail address: madib@khayam.ut.ac.ir (M. Adib).
1001-8417/$ – see front matter # 2010 Mehdi Adib. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
doi:10.1016/j.cclet.2010.10.032

[()TD$FIG]
M. Adib et al. / Chinese Chemical Letters 22 (2011) 314–317
315
N
R
m.p. (°C) (lit) [11]
108–109 (107–108)
159 (157–159)
% Yield
95
4
a
b
c
RO2C
S
CO2R
H3C
H3C
N
(3, cat.)
Me
Et
CH3
93
+
NC
C
C
CO2R
RO2C
S
N
H
r.t., 2 h
O
O
O
O
iPr
tBu
133–134 (132–134)
143–144 (144–146)
91
1
2
4
d
90
Scheme 1.
products, use of highly basic conditions, use of expensive reagents or catalysts and low atom economy. Hence,
development of simple and efficient methods for the preparation of substituted pyrroles is much desirable.
As part of our current studies on the development of efficient routes in heterocyclic synthesis [11], we would like to
report herein a simple and mild method with higher atom economy for the preparation of highly functionalized
pyrroles.
We found that a mixture of TOSMIC 1, and a dialkyl acetylenedicarboxylate 2, in the presence of a catalytic amount
of 1-methylimidazole 3 undergo a smooth addition reaction in anhydrous CH2Cl2 at ambient temperature to afford
2,3,4-trisubstituted pyrroles 4 in 90–95% (Scheme 1).
The reactions were carried out by first mixing 1 and a catalytic amount of 3 in anhydrous CH2Cl2. Then, a solution
of 2 in anhydrous CH2Cl2 was slowly added. The reaction proceeded smoothly at ambient temperature and was
complete within a few hours to afford the functionalized pyrrole 4. The 1H NMR spectra of the crude products clearly
indicated formation of pyrrole 4. Any product other than 4 could not be detected by NMR spectroscopy.
1
The structure of compounds 4a–d was deduced from their elemental analysis, and high-field H- and 13C NMR
spectra. The mass spectrum of 4a displayed the molecular ion (M+) peak at m/z = 337, which was consistent with the
1:1 adduct of TOSMIC and dimethyl acetylenedicarboxylate. The 1H NMR spectrum of 4a exhibited four single sharp
lines due to the methyl group (d 2.36), two MeO functions (d 3.77 and 3.91), and the pyrrole C5–H (d 7.46). A fairly
broad signal at d 10.90 was observed for the pyrrole NH, along with characteristic signals for four aromatic H atoms.
1
The H-decoupled 13C NMR spectrum of 4a showed 13 distinct resonances in agreement with the structure of the
product.
The mp values, elemental analyses, and spectral data of compounds 4b–d, were also in good agreement with those
of authentic samples [10].
A mechanistic rationalization of the reaction is provided in Scheme 2. The initially formed zwitterionic
intermediate 5, from nucleophilic addition of 1-methylimidazole on the acetylenic ester 2 [12], is protonated by
TOSMIC. Then, the positively charged ion 6 and the conjugate base of TOSMIC 7 may undergo 1,3-dipolar
cycloaddition to yield 1:1:1 adduct 8. Alternatively, conjugate addition of 7 to 6 may form ylide 9, which can cyclize to
the adduct 8 under the reaction conditions. Then the catalyst, 1-methylimidazole 3, may be removed from 8 to produce
2H-pyrrole intermediate 10, which tautomerizes to afford the isolated 1H-pyrrole 4.
In summary, we have found a simple and 1-methylimidazole-catalyzed reaction for the preparation of
functionalized pyrroles. Excellent yields of the products, fairly fast reaction times, mild reaction conditions, use of
simple and inexpensive catalyst, and high atom economy characterize this method. The present method carries the
advantage that, not only is the reaction performed under neutral conditions, but the substances have reacted without
any activation or modification. The simplicity of the present procedure makes it an interesting alternative to complex
multistep approaches.
1. Experimental
Dimethyl-, diethyl- and di(tert-butyl) acetylenedicarboxylates, 1-methylimidazole and tosylmethyl isocyanide
were obtained from Merck and Fluka, and were used without further purification. Diisopropyl acetylenedicarboxylate
was prepared according to the literature procedure [13]. Melting points were measured on an Electrothermal 9100
apparatus. Elemental analyses for C, H and N were performed using a Heraeus CHN-O-Rapid analyzer. Mass spectra
were recorded on an Agilent Technologies (HP) 5973 mass spectrometer operating at an ionization potential of 20 eV.
1H and 13C NMR spectra were measured with Bruker DRX-500 AVANCE (at 500.1 and 125.8 MHz) spectrometer
using CDCl3 solvent with TMS as an internal standard. Chromatography columns were prepared from Merck silica gel
60 mesh.

[()TD$FIG]
316
M. Adib et al. / Chinese Chemical Letters 22 (2011) 314–317
H3C
RO2C
RO2C
N
CO2R
CHCO2R
CO2R
C
S
NC
_
CH3
+
+
N
N
O
O
_
.
+
.
C
N
N
N
C
N
S
CH3
CH3
CH3
O
O
CO2R
5
6
7
N
_
N
RO2C
CO2R
CH3
1,3-Dipolar
cycloaddition
CO R
CO2R
H
2
CH3
+
4
H
S
N
N
H3C
H
_
CH3
.
.
N
S
N
O
O
O
O
8
10
CO2R
Conjugate
addition
+
_
N
CO2R
N
H3C
.
.
CH3
C
N
S
O
O
9
Scheme 2.
1.1. General procedure for the preparation of 4
To a magnetically stirred solution of 1 (1 mmol) and 3 (0.2 mmol) in anhydrous CH2Cl2 (3 mL) was added
dropwise a solution of 2 (1 mmol) in anhydrous CH2Cl2 (1 mL) at r.t. over 10 min. The mixture was stirred for 2 h. The
solvent was removed and the residue was purified by column chromatography using n-hexane–EtOAc (3:1) as eluent.
The solvent was removed and the product was recrystallized from 1:1 n-hexane–EtOAc.
1.2. Dimethyl 2-[(4-methylphenyl)sulfonyl]-1H-pyrrole-3,4-dicarboxylate (4a)
Yield: 0.32 g (95%). Colorless crystals. Mp 108–109; 1H NMR (CDCl3, 500.1 MHz): d 2.36 (s, 3H, CH3), 3.76 (s,
3H, OCH3), 3.91 (s, 3H, OCH3), 7.26 (d, 2H, J = 8.2 Hz, 2CH), 7.44 (s, 1H, CH), 7.82 (d, 2H, J = 8.2 Hz, 2CH), 10.96
(br., 1H, NH). 13C NMR (CDCl3, 125.8 MHz): d 23.12 (CH3), 53.41 and 54.49 (2OCH3), 117.88 and 123.24 (2C),
128.73 and 129.16 (2CH), 130.06 (C), 131.44 (CH), 139.04 and 146.54 (2C), 164.41 and 165.97 (2C O). EI-MS m/z:
337 (20, M+). Anal. Calcd. for C15H15NO6S (337.34): C 53.41, H 4.48, N 4.15; found: C 53.37, H 4.52, N 4.01.
Acknowledgments
This research was supported by the Research Council of the University of Tehran as research project (No. 6102036/
1/03).
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