DABCO-promoted three-component reaction between amines, dialkyl acetylenedicarboxylates, and glyoxal

Article abstract of DOI:10.1016/j.tetlet.2011.05.100

A simple and efficient three-component protocol for the synthesis of highly substituted pyrroles has been developed by using amines, DEAD/DMAD, and glyoxal, with the formation of products in good to excellent yields.

Full text of DOI:10.1016/j.tetlet.2011.05.100

Tetrahedron Letters 52 (2011) 3937–3941
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Tetrahedron Letters
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DABCO-promoted three-component reaction between amines, dialkyl
acetylenedicarboxylates, and glyoxal
⇑
K. Ramesh, S. Narayana Murthy, K. Karnakar, Y. V. D. Nageswar
Organic Chemistry Division-I, Indian Institute of Chemical Technology, Hyderabad 500 607, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A simple and efficient three-component protocol for the synthesis of highly substituted pyrroles has been
developed by using amines, DEAD/DMAD, and glyoxal, with the formation of products in good to excel-
lent yields.
Received 5 March 2011
Revised 20 May 2011
Accepted 22 May 2011
Available online 30 May 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Amines
Dimethyl/diethyl acetylenedicarboxylate
Glyoxal
DABCO
Acetonitrile
Pyrroles play a crucial role in the context of synthetic organic
chemistry, hetero cyclic chemistry, as well as medicinal chemis-
try.1 Their derivatives are used as important intermediates in the
preparation of drug molecules, as well as natural products. These
have been given special emphasis due to a wide variety of medic-
inal and biological properties associated with them2 (Fig. 1). Sev-
eral methods are developed for the synthesis of pyrroles such as
for the synthesis of polysubstituted pyrroles via the coupling of
phenyliodonium ylides and enamine esters using BF3ÁEt2O. Shi
and co-workers17 used a low-valent Titanium reagent (TiCl4) to ac-
cess polysubstituted pyrroles using a highly regioselective three-
component reaction. Jia and co-workers18 reported a silver ace-
tate-catalyzed reaction between aldehydes and amines for the
preparation of 3,4-disubstituted pyrroles in a one-pot condensa-
tion strategy under mild conditions. Ngwerume and Camp19 de-
scribed a concise synthesis of highly substituted pyrroles via
intermolecular addition of oximes to activated alkynes and subse-
quent thermal rearrangement of in situ generated O-vinyl oximes
to form pyrroles via nucleophilic catalysis. Recently, Liu and co-
workers20a described an efficient method for the synthesis of
polysubstituted pyrroles via [4C+1N] cyclization of 4-acetylenic
ketones with primary amines using FeCl3. M. A. Abbasinejad et
al.20b reported the synthesis of highly functionalized pyrroles by
using amines, dialkylacetylenedicarboxylates, and aryl glyoxals
Knorr reaction3 which involves the reaction between
tones derived from -haloketones, ammonia and b-ketoesters;
and Paal–Knorr condensation reaction.4–14 However Paal–Knorr
reaction, a prominent condensation strategy, between -ketones
a-aminoke-
a
c
and primary amines gained importance for the synthesis of
pyrroles.
Liang and co-workers15 developed a methodology for the syn-
thesis of pyrrole derivatives by the oxidative cyclization of b-ena-
mino ketones and alkynoates using CuI in the presence of
oxygen. Yu and co-workers16 demonstrated an efficient method
O
HO
HO
O
H
N
OH
HO
O
N
N
HO
NH
O
N
H
Cl
F
Zomepirac
Atorvastatin
Bufotenin
Figure 1. Biologically active molecules with pyrrole as core skeleton.
⇑
Corresponding author. Tel.: +91 40 27191654; fax: +91 40 27160512.
E-mail address: dryvdnageswar@gmail.com (Y.V.D. Nageswar).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.05.100

3938
K. Ramesh et al. / Tetrahedron Letters 52 (2011) 3937–3941
HO
COOR2
COOR2
COOR2
N
NH2
DABCO
CHO
CHO
CH3CN, 50-55 °C
COOR2
R1
R1
R1 = -H, -F, -Cl, -Br, -NO2, -CH3, -OCH3, -CH(CH3)2. R2 = -Et, -Me
Scheme 1.
Table 1
Synthesis of highly substituted pyrroles using DABCO as catalysta
Entry
Amine
DEAD/DMAD
Product
Yieldb (%)
91
NH2
COOEt
COOEt
N
EtOOC
1
HO
COOEt
COOEt
NH2
COOEt
N
EtOOC
F
2
3
4
5
89
88
88
92
HO
COOEt
COOEt
F
NH2
COOEt
N
EtOOC
HO
Cl
COOEt
COOEt
Cl
NH2
COOEt
N
EtOOC
HO
Br
COOEt
COOEt
Br
NH2
COOEt
N
EtOOC
HO
CH3
COOEt
COOEt
CH3
NH2
COOEt
N
EtOOC
HO
OCH3
6
93
COOEt
COOEt
OCH3
NH2
COOEt
N
EtOOC
HO
CH3
7
8
91
75
COOEt
COOEt
H3C
NH2
COOEt
NO2
EtOOC
N
HO
NO2
NH2
COOEt
COOEt
COOEt
N
EtOOC
9
10
11
77
90
91
HO
COOEt
COOEt
NH2
COOEt
N
CH3
EtOOC
HO
CH3
H3C
COOEt
COOEt
H3C
NH2
COOEt
OCH3
EtOOC
HO
OCH3
N
H3CO
COOEt
H3CO

K. Ramesh et al. / Tetrahedron Letters 52 (2011) 3937–3941
3939
Table 1 (continued)
Entry
Amine
DEAD/DMAD
Product
Yieldb (%)
NH2
COOEt
COOEt
N
EtOOC
12
89
HO
COOEt
COOEt
NH2
NH2
COOEt
N
EtOOC
HO
13
88
COOEt
COOEt
COOEt
N
EtOOC
HO
F
14
15
16
86
89
86
Cl
COOEt
Cl
F
NH2
COOMe
COOMe
N
MeOOC
HO
COOMe
COOMe
NH2
COOMe
N
MeOOC
F
HO
COOMe
COOMe
F
NH2
COOMe
N
MeOOC
HO
Cl
17
18
19
85
86
86
COOMe
COOMe
Cl
NH2
COOMe
N
MeOOC
HO
Br
COOMe
COOMe
Br
NH2
COOMe
N
MeOOC
HO
CH3
COOMe
COOMe
CH3
NH2
COOMe
N
MeOOC
HO
OCH3
20
89
COOMe
COOMe
OCH3
NH2
COOMe
N
MeOOC
HO
21
22
86
75
COOMe
COOMe
NH2
COOMe
N
MeOOC
HO
O2N
COOMe
NO2
a
Reaction conditions: amine (1.0 mmol), DEAD/DMAD (1.0 mmol), glyoxal (1.5 mmol), catalyst (0.7 mol %), ace-
tonitrile (10 mL).
b
Isolated yield.
promoted by Ph3P in CH2Cl2 at rt. Maiti et al.21 have recently devel-
oped a straightforward synthesis of polysubstituted pyrroles using
FeCl3 as a catalyst under refluxing conditions.
However, the above mentioned methods suffer from one or
more disadvantages such as the use of hazardous organic solvents,
expensive moisture-sensitive catalysts, tedious workup conditions,
longer reaction times, and large volume of catalyst loadings which
in turn result in the generation and release of huge burden of metal
wastes into the environment.
Organic chemical synthesis involving multi-component reac-
tion strategies has great value, as the target molecules are often ob-
tained in a single step rather than multiple steps, minimizing the
elaborate work-up procedures and environmental pollution. In
continuation of our efforts towards the development of novel envi-
ronmentally friendly methodologies22 which include the synthesis
of heterocyclic compounds, herein, we report a mild and efficient
one-pot protocol for the synthesis of highly substituted pyrrole
derivatives for the first time by a three-component reaction involv-

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K. Ramesh et al. / Tetrahedron Letters 52 (2011) 3937–3941
COOEt
COOEt
COOEt
OH
O
H
O
H
EtOOC
EtOOC
[B]
NH2
NH
COOEt
NH
O
[A]
-H2O
EtOOC
EtOOC
OH
COOEt
EtOOC
OH
H
N
N
N
N
[C]
Scheme 2. Plausible mechanistic pathway for the synthesis of highly substituted pyrroles using DABCO.
Table 2
In conclusion, we have developed a convenient one-pot synthe-
sis of highly substituted pyrroles catalyzed by DABCO in excellent
yields. This method involves mild reaction conditions and cleaner
reaction profiles.
Screening of DABCO-catalyzed synthesis of diethyl 4-hydroxy-1-phenyl-1H-pyrrole-
2,3-dicarboxylatea
Entry
Catalyst
Solvent
Time (h)
T (°C)
Yieldb (%)
1
2
3
4
5
6
7
—
CH3CN
CH3CN
CH3CN
Toluene
Toluene
Toluene
Ethanol
3
3
3
4
4
4
5
80
rt
50–55
100
rt
—
DABCO
DABCO
—
DABCO
DABCO
DABCO
58
91
—
45
50
48
Acknowledgements
We thank CSIR, New Delhi, India, for the fellowships to S.N.M.,
K.K. and UGC for the fellowship to K.R.
60
60
a
Supplementary data
Reaction conditions: amine (1.0 mmol), DEAD (1.0 mmol), glyoxal (1.5 mmol),
catalyst (0.7 mol %), solvent (10 mL).
b
Isolated yield.
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.05.100.
References and notes
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reaction proceeded to completion within 3 h and yielded the corre-
sponding pyrrole derivative in 91% yield.23, 24 While evaluating the
influence of different solvent systems for DABCO-catalyzed synthe-
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peared to be a better choice (Table 2).
To expand the scope of this novel methodology, several di-
versely substituted anilines having electron-donating as well as
electron-withdrawing groups were reacted with glyoxal and
DMAD/DEAD in the presence of DABCO resulting in good yields
in fast reaction times. It was observed that aromatic amines bear-
ing electron-donating groups resulted in higher yields of the prod-
ucts compared to amines with electron-withdrawing groups. The
experimental results are included in Table 1. All the products were
characterized by 1H, 13C NMR, IR, and mass spectra.
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The plausible mechanism for the synthesis of highly substituted
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[A], this enamine part on reaction with glyoxal gives another inter-
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(Scheme 2).

K. Ramesh et al. / Tetrahedron Letters 52 (2011) 3937–3941
3941
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indicated by TLC. The reaction mixture was cooled to room temperature and
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(3 Â 10 mL). The organic layers were washed with water, saturated brine
solution, and dried over anhydrous Na2SO4. The combined organic layers were
evaporated under reduced pressure and the resulting crude product was
purified by column chromatography by using ethylacetate and hexanes
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(75–93%) yield. The identity and purity of the product was confirmed by 1H, 13
NMR, and mass spectra.
C
24. Data for the representative examples of synthesized compounds: Diethyl 4-
hydroxy-1-phenyl-1H-pyrrole-2,3-dicarboxylate: (Table 1, entry1): yellow
liquid; IR(KBr); 3290, 2929, 1780, 1680, 1572, 1452, 1378, 1205, 1151, 1102,
935, 855 cmÀ1 1H NMR (300 MHz, CDCl3, TMS) d = 9.67 (s, 1H, -OH), 7.25 (t,
;
2H, J = 8.3 Hz), 7.06 (t, 1H, J = 7.3 Hz), 6.91 (d, 2H, J = 7.7 Hz), 5.34 (s, 1H), 4.22–
4.09 (m, 4H), 1.32–1.25 (m, 6H); 13C NMR (75 MHz CDCl3, TMS) d = 164.3,
158.9, 140.2, 128.4, 125.3, 123.5, 122.1, 111.9, 58.9, 14.8; Mass (ESI-MS): m/z
326 (M+Na)+. Anal. calcd for C16H17NO5: C, 63.36; H, 5.65; N, 4.62. Found: C,
63.29; H, 5.62; N, 4.58.
23. General experimental procedure for the synthesis of highly substituted pyrrole
derivatives: To a stirred solution of acetonitrile (10 mL), amine (1.0 mmol) and
DABCO (0.7 mol %) were added and stirred for 10 min. To this DEAD/DMAD