DABCO-promoted facile and convenient synthesis of novel isoxazolyl-1H-2,3-pyrrole dicarboxylates

Article abstract of DOI:10.1016/j.cclet.2013.01.002

Synthesis of isoxazolyl-1H-2,3-pyrrole dicarboxylate (4) was simply achieved by one-pot three component reaction of isoxazole amine (1) with diethyl acetylenedicarboxylate (DEAD) (2), and glyoxal (3), in acetonitrile catalyzed by diazabicyclo octane (DABC

Full text of DOI:10.1016/j.cclet.2013.01.002

Chinese Chemical Letters 24 (2013) 134–136
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Chinese Chemical Letters
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Original article
DABCO-promoted facile and convenient synthesis of novel
isoxazolyl-1H-2,3-pyrrole dicarboxylates
*
Rajanarendar Eligeti , Kishore Baireddy, Ramakrishna Saini
Department of Chemistry, Kakatiya University, Warangal 500009, A.P, India
A R T I C L E I N F O
A B S T R A C T
Article history:
Synthesis of isoxazolyl-1H-2,3-pyrrole dicarboxylate (4) was simply achieved by one-pot three
component reaction of isoxazole amine (1) with diethyl acetylenedicarboxylate (DEAD) (2), and glyoxal
(3), in acetonitrile catalyzed by diazabicyclo octane (DABCO).
ß 2013 Rajanarendar Eligeti. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights
reserved.
Received 14 September 2012
Received in revised form 5 December 2012
Accepted 14 December 2012
Available online 28 January 2013
Keywords:
Isoxazolyl-1H-2,3-pyrroledicarboxylates
DABCO
One-pot three component reaction
1. Introduction
Although several protocols have been developed for the
synthesis of pyrrole derivatives, many of these methods are
Pyrrole is one of the most important simple heterocycles, which
is found in a broad range of natural products [1] and drug
molecules, and is also of growing relevance in materials science [2].
Pyrrole derivatives have been given special emphasis due to a wide
variety of medicinal and biological properties such as antitumor [3]
and immunosuppresants [4] activity. They have also been
recognized as versatile synthetic intermediates in organic synthe-
sis [5]. These derivatives are used as organic conducting materials
[6]. Biological activity of substituted isoxazoles has made them a
focus of medicinal chemistry over the years. Isoxazole derivatives
have been reported with diverse structural features and versatile
biological properties such as antitumor [7], analgesic [8],
antimicrobial [9], and for the treatment of hyper cholsteremia
and hyperlipidemia [10], and as chemotherapeutic agents [11].
Synthesis of pyrrole derivatives has been achieved by the
associated with various drawbacks, such as harsh reaction
conditions, tedious experimental procedures, unsatisfactory
yields, and long reaction times. Hence, there is a need for a rapid
and efficient method for the heterocyclic synthesis of pyrrole
derivatives. As
a part of our continuing effort toward the
development of new methods [17], of expeditiously synthesizing
bioactive compounds carrying isoxazole moiety, we here report a
mild and efficient method for isoxazolyl-1H-2,3-pyrrole dicarbox-
ylate scaffold using DABCO as a catalyst. This is a simple, rapid,
one-pot and eco-friendly protocol for the synthesis of title
compounds.
2. Experimental
oxidative cyclization of
b
-enamino ketones and alkynoates using
All the melting points were determined on a Cintex melting
point apparatus and are uncorrected. Analytical TLC was
performed on Merck precoated 60 F254 silica gel plates. Visualiza-
tion was done by exposing to iodine vapour. IR spectra (KBr pellet)
were recorded on a PerkinElmer BX series FT-IR spectrometer. 1H-
CuI in the presence of oxygen [12], coupling of phenyliodonium
ylides and enamine esters using BF3ÁEt2O [13] silver catalyzed
reaction between aldehydes and amines in a one pot condensation
[14], intermolecular addition of oximes to activated alkynes and
subsequent thermal rearrangement of in situ generated O-vinyl
oximes [15], [4C+1N] cyclization of 4-acetylenic ketones with
primary amines using FeCl3 [16].
NMR spectra were recorded on
spectrometer. 13C NMR spectra were recorded on a Bruker
75 MHz spectrometer. Chemical shift values are given in with
a Varian Gemini 300 MHz
d
tetramethyl silane as an internal standard. Mass spectral
measurements were carried out by EI method on a JEOL JMC-
300 spectrometer at 70 eV. Elemental analyses were performed on
a Carlo Erba 106 and Perkin-Elmer model 240 analyzers.
* Corresponding author.
E-mail address: rajanarendareligeti@gmail.com (R. Eligeti).
1001-8417/$ – see front matter ß 2013 Rajanarendar Eligeti. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
http://dx.doi.org/10.1016/j.cclet.2013.01.002

R. Eligeti et al. / Chinese Chemical Letters 24 (2013) 134–136
135
COOEt
OH
EtOOC
H3C
O
OEt
O
H3C
NH2
O
H
H
O
DABCO
55 oC
CH3CN,
N
+
+
N
O
N
O
EtO
Ar
Ar
4
3
1
2
4a
4b
4c
4d
4e
4f
Ar = C6H5 4-ClC6H4 4-CH3C6H4 4-CH3OC6H4 2-OHC6H4 2-CH3C6H4
4g
4h
4i
4j
4k
4l
2-ClC6H4 4-BrC6H4 2-BrC6H4 4-N(CH3)2C6H4 4-NO2C6H4 3,4-OCH2OC6H3
Scheme 1. One-Pot synthesis of isoxazolyl pyrroles.
OEt
O
COOEt
OH
O
..
NH2
OEt
OH
EtOOC
H3C
OEt
+
O
H3C
H
O
O
H
H
N
+
H3C
NH
+
..
N
4
O
H
O
N
N
..
O
O
EtO
O
N
Ar
Ar
Ar
N
3
A
2
1
B
Scheme 2. Plausible mechanism for pyrrole ring formation.
Synthesis of diethyl-4-hydroxy-1-3-methyl-5-[(E)-2-aryl-1-ethe-
nyl]-4-isoxazolyl-1H-2,3-pyrrole dicarboxylate 4: To a stirred solu-
tion of 4-amino-3-methyl-5-styrylisoxazole (1) (1 mmol), in
CH3CN (15 mL) DABCO 10 mol% were added. The reaction mixture
was refluxed with stirring at 55 8C for 30 min to this diethyl
acetylenedicarboxylate (DEAD) (2) (1 mmol), glyoxal (3) (1 mmol)
was added, and the reaction continued for another 4 h at 55 8C.
After completion of the reaction (monitored by TLC), the solvent
was removed under reduced pressure, and 30 mL water was added
to the residue, which was then extracted with ethyl acetate and the
residue was purified by recrystallization in methanol to produce 4
in high yield (Scheme 1).
4. Conclusion
In conclusion, we have developed an efficient and facile method
for the synthesis of isoxazolyl pyrrole derivatives by a one-pot
three-component protocol involving isoxazole amine, DEAD and
glyoxal using DABCO as a catalyst. This synthesis offers the benefit
of a simple method of purification, which does require chroma-
tography. The mild reaction conditions, operational simplicity, and
high yields are the advantages of the protocol.
Acknowledgments
The authors are thankful to the Head, Department of Chemistry,
Kakatiya University, Warangal for facilities and to the Director,
Indian Institute of Chemical Technology, Hyderabad for recording
1H NMR and Mass Spectra. One of the authors (B. Kishore) thanks
UGC, New Delhi for financial assistance (JRF).
3. Results and discussion
4-Amino-3-methyl-5-styrylisoxazoles 1, required for synthesis
of target compounds was obtained by Knoevenagel condensation
of 3,5-dimethyl-4-nitroisoxazole with aromatic aldehydes in the
presence of piperidine in ethanol [18] followed by reduction with
SnCl2–HCl [19]. The reaction of 1 with diethyl acetylenedicarbox-
ylate 2 and glyoxal 3 in presence of DABCO in acetonitrile at 50 8C
gave diethyl-4-hydroxy-1-3-methyl-5-[(E)-2-aryl-1-ethenyl]-4-
isoxazolyl-1H-2,3-pyrrole dicarboxylate 4 by a one-pot three
components reaction.
The generality of the reaction was investigated for the synthesis
of various isoxazolyl pyrrole derivatives by reacting several
substituted amino styrylisoxazoles having electron donating as
well as electron attracting groups with glyoxal and DEAD in the
presence of DABCO. In general, all the reactions were clean and
isoxazolyl pyrrole derivatives were obtained in high yields. All the
products were characterized by IR, 1H NMR, 13C NMR and mass
spectra [20].
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The plausible mechanism for the synthesis of isoxazole
substituted pyrroles in the presence of DABCO as catalyst involves
is the nucleophilic addition of isoxazole amine with DEAD followed
by the attack of the acetylenic bond with glyoxal 3 to give an
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isolated. Proton abstraction by DABCO finally gives the title
compound 4 (Scheme 2).
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NMR (75 MHz, CDCl3): d 12.11, 16.28, 71.41, 101.58, 114.74, 116.31, 123.45,
123.81, 124.45, 127.30, 127.62, 128.55, 128.87, 129.41, 134.18, 136.42, 156.73,
159.70, 160.28, 168.45. Anal. Calcd. for C22H21ClN2O6: C, 59.40; H, 4.76; N, 6.30.
Found C, 59.37; H, 4.80; N, 6.24. 4c: Pale yellow; yield 88%, m.p. 153–155 8C; IR
(KBr, cmÀ1): n 3442 (OH), 1745 (CO); 1H NMR (300 MHz, CDCl3): d 1.70 (t, 6H,
J = 7.2 Hz, 2CH3), 2.30 (s, 3H, CH3), 2.64 (s, 3H, ArCH3), 3.48 (q, 4H, J = 7.2 Hz,
2CH2), 6.58 (s, 1H, pyrrole–CH), 6.67 (d, 1H, J = 12 Hz, CH5CH), 6.83 (d, 1H,
J = 12 Hz, CH5CH), 6.98–7.66 (m, 4H, ArH), 8.15 (s, 1H, OH, D2O exchangeable).
EI-MS [M]+ m/z 424. 13C NMR (75 MHz, CDCl3): d 12.16, 16.15, 28.43,71.38,
101.58, 114.70, 116.43, 123.56, 123.82, 124.57, 127.28, 127.64, 128.47, 128.88,
129.61, 134.14, 136.40, 156.69, 159.77, 160.28, 168.24. Anal. Calcd. for
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927–930;
C
23H24N2O6: C, 65.08; H, 5.70; N, 6.60. Found. C, 65.03; H, 5.73; N, 6.66. 4d:
Pale yellow; yield 90%, mp 148–150 8C; IR (KBr, cmÀ1): n 3440 (OH), 1742 (CO); 1
H
NMR (300 MHz, CDCl3): d 1.66 (t, 6H, J = 7.2 Hz, 2CH3), 2.26 (s, 3H, CH3), 3.51 (q,
4H, J = 7.2 Hz, 2CH2), 3.62 (s, 3H, OCH3), 6.61 (s, 1H, pyrrole–CH), 6.71 (d, 1H,
J = 12 Hz, CH5CH), 6.87 (d, 1H, J = 12 Hz, CH5CH), 7.00–7.73 (m, 4H, ArH), 8.20 (s,
1H, OH, D2O exchangeable). EI-MS [M]+ m/z 440. 13C NMR (75 MHz, CDCl3): d
12.10, 16.19, 63.44,71.26, 101.45, 114.78, 116.45, 123.56, 123.71, 124.38, 127.42,
127.77, 128.59, 128.62, 129.79, 134.26, 136.57, 156.61, 159.75, 160.36, 168.39.
Anal. Calcd. for C23H24N2O7: C, 62.72; H, 5.49; N, 6.36. Found C, 62.77; H, 5.44; N,
6.36. 4e: Pale yellow; yield 87%, mp 160–162 8C; IR (KBr, cmÀ1): n 3443 (OH),
1746 (CO); 1H NMR (300 MHz, CDCl3): d 1.63 (t, 6H, J = 7.2 Hz, 2CH3), 2.30 (s, 3H,
CH3), 3.49 (q, 4H, J = 7.2 Hz, 2CH2), 6.60 (s, 1H, pyrrole–CH), 6.72 (d, 1H, J = 12 Hz,
CH5CH), 6.86 (d, 1H, J = 12 Hz, CH5CH), 7.11–7.89 (m, 4H, ArH), 8.10 (s, 1H, OH,
D2O exchangeable), 8.22 (s, 1H, OH, D2O exchangeable). EI-MS [M]+ m/z 426. 13
C
NMR (75 MHz, CDCl3): d 12.19, 16.24, 71.39, 101.27, 114.55, 116.32, 123.45,
123.69, 124.40, 127.21, 127.53, 128.40, 128.73, 129.86, 134.41, 136.30, 156.44,
159.61, 160.29, 168.30. Anal. Calcd. for C22H22N2O7: C, 61.97; H, 5.20; N, 6.57.
Found C, 61.93; H, 5.25; N, 6.52. 4f: Pale yellow; yield 92%, mp 173–175 8C; IR
(KBr, cmÀ1): n 3435 (OH), 1738 (CO); 1H NMR (300 MHz, CDCl3): d 1.67 (t, 6H,
J = 7.2 Hz, 2CH3), 2.24 (s, 3H, CH3), 2.60 (s, 3H, ArCH3), 3.44 (q, 4H, J = 7.2 Hz,
2CH2), 6.51 (s, 1H, pyrrole–CH), 6.59 (d, 1H, J = 12 Hz, CH5CH), 6.70 (d, J = 12 Hz,
1H, CH5CH), 7.00–7.81 (m, 4H, ArH), 8.12 (s, 1H, OH, D2O exchangeable). EI-MS
[M]+ m/z 424. 13C NMR (75 MHz, CDCl3): d 11.98, 16.36, 27.42, 71.45, 101.42,
114.55, 116.52, 123.50, 123.77, 124.42, 127.38, 127.59, 128.41, 128.80, 129.63,
134.22, 136.51, 156.73, 159.81, 160.30, 168.11. Anal. Calcd. for C23H24N2O6: C,
65.08; H, 5.70; N, 6.60. Found C, 65.05; H, 5.68; N, 6.64. 4g: Pale yellow; yield 90%,
mp 157–159 8C; IR (KBr, cmÀ1): n 3432 (OH), 1738 (CO); 1H NMR (300 MHz,
CDCl3): d 1.68 (t, 6H, J = 7.2 Hz, 2CH3), 2.22 (s, 3H, CH3), 3.61 (q, 4H, J = 7.2 Hz,
2CH2), 6.59 (s, 1H, pyrrole–CH), 6.65 (d, 1H, J = 12 Hz, CH5CH), 6.72 (d, 1H,
J = 12 Hz, CH5CH), 7.04–7.77 (m, 4H, ArH), 8.25 (s, 1H, OH, D2O exchangeable).
EI-MS [M]+ m/z 444. 13C NMR (75 MHz, CDCl3): d 12.23, 16.18, 71.45, 101.41,
114.53, 116.28, 123.36, 123.78, 124.47, 127.41, 127.82, 128.41, 128.79, 129.32,
134.27, 136.50, 156.62, 159.75, 160.36, 168.26. Anal. Calcd. for C22H21ClN2O6: C,
59.40; H, 4.76; N, 6.30. Found C, 59.38; H, 4.79; N, 6.27. 4h: Pale yellow; yield 92%,
mp 154–156 8C; IR (KBr, cmÀ1): n3425 (OH), 1745 (CO); 1H NMR (300 MHz, CDCl3):
d1.68 (t, 6H, J = 7.2 Hz, 2CH3), 2.30 (s, 3H, CH3), 3.48 (q, 4H, J = 7.2 Hz, 2CH2), 6.55 (s,
1H,pyrrole–CH),6.60(d,1H,J = 12 Hz, CH5CH),6.71(d,1H,J = 12 Hz, CH5CH), 7.00–
7.61 (m, 4H, ArH), 8.09 (s, 1H, OH, D2O exchangeable). EI-MS [M]+ m/z 488. 13C NMR
(75 MHz, CDCl3): d 12.28, 16.41, 71.39, 101.47, 114.60, 116.28, 123.55, 123.68,
124.40, 127.37, 127.55, 128.42, 128.79, 129.29, 134.25, 136.36, 156.44, 159.51,
160.39, 168.51. Anal. Calcd. for C22H21BrN2O6: C, 54.00; H, 4.33; N, 5.73. Found C,
54.03; H, 4.30; N, 5.69. 4i: Pale yellow; yield 91, mp 154–156 8C; Anal. Calcd. for
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in vitro and in vivo anticancer activity of novel arylmethylene bis-isoxazolo[4,5-
b]pyridine-N-oxide, India Eur. J. Med. Chem. Lett. 50 (2012) 274–279;
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Suzuki–Miyaura cross-coupling reaction of organoboronic acids with N-protected
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tion of a,b-unsaturated aromatic acids, Gazz. Chim. Ital. 72 (1942) 399.
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1054.
[20] Analytical data for compounds: 4a: Pale brown; yield 90%, mp 143–145 8C; IR
(KBr, cmÀ1): n 3446 (OH), 1740 (CO); 1H NMR (300 MHz, CDCl3): d 1.59 (t, 6H,
J = 7.2 Hz, 2CH3), 2.28 (s, 3H, CH3), 3.72 (q, 4H, J = 7.2 Hz, 2CH2), 6.68 (s, 1H,
pyrrole–CH), 6.74 (d, 1H, J = 12 Hz, CH5CH), 6.91 (d, 1H, J = 12 Hz, CH5CH), 7.00–
7.75 (m, 5H, ArH), 8.11 (s, 1H, OH, D2O exchangeable). EI-MS [M]+ m/z 410. 13C
NMR (75 MHz, CDCl3): d 12.01, 16.32, 71.32, 101.62, 114.73, 116.34, 123.54,
123.78, 124.52, 127.38, 127.64, 128.20, 128.93, 129.47, 134.25, 136.41, 156.83,
159.72, 160.10, 168.45. Anal. Calcd. for C22H22N2O6: C, 64.38; H, 5.40; N, 6.83.
Found C, 64.33; H, 5.42; N, 6.87. 4b: Pale yellow; yield 93%, mp 161–163 8C; IR
(KBr, cmÀ1): n 3432 (OH), 1738 (CO); 1H NMR (300 MHz, CDCl3): d 1.61 (t, 6H,
J = 7.2 Hz, 2CH3), 2.26 (s, 3H, CH3), 3.59 (q, 4H, J = 7.2 Hz, 2CH2), 6.51 (s, 1H,
pyrrole–CH), 6.69 (d, 1H, J = 12 Hz, CH5CH), 6.90 (d, 1H, J = 12 Hz, CH5CH), 7.10–
7.72 (m, 4H, ArH), 8.18 (s, 1H, OH, D2O exchangeable). EI-MS [M]+ m/z 444. 13C
C22H21BrN2O6: C, 54.00; H, 4.33; N, 5.73. Found C, 53.97; H, 4.38; N, 5.77. 4j: Pale
yellow; yield 91, mp 177–179 8C; Anal. Calcd. for C24H27N3O6: C, 63.56; H, 6.00; N,
9.27. Found C, 63.51; H, 6.04; N, 9.23. 4k: Pale yellow; yield 93, mp 173–175 8C;
Anal. Calcd. for C22H21N3O8: C, 58.02; H, 4.65; N, 9.23. Found C, 58.04; H, 4.63; N,
9.28. 4l:Paleyellow;yield89,mp169–171 8C;Anal. Calcd. forC23H22N2O8: C,60.79;
H, 4.88; N, 6.16. Found C, 60.74; H, 4.93; N, 6.14.