One-pot synthesis of pyrrolo[1,2-a]pyrazines via three component reaction of ethylenediamine, acetylenic esters and nitrostyrene derivatives

Article abstract of DOI:10.1016/j.cclet.2013.04.038

An effective route to pyrrolo[1,2-a]pyrazines is described via reaction of ethylenediamine, acetylenic esters and nitrostyrene derivatives in the presence of 20 mol% of sulfamic acid.

Full text of DOI:10.1016/j.cclet.2013.04.038

Chinese Chemical Letters 24 (2013) 740–742
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Chinese Chemical Letters
journal homepage: www.elsevier.com/locate/cclet
Original article
One-pot synthesis of pyrrolo[1,2-a]pyrazines via three component reaction of
ethylenediamine, acetylenic esters and nitrostyrene derivatives
b
a
a
Loghman Moradi a, , Mohammad Piltan , Hedieh Rostami , Golaleh Abasi
*
a Department of Chemistry, Faculty of Science, University of Kurdistan, P.O. Box 416, Sanandaj, Iran
b Young Researches Club, Sanandaj Branch, Islamic Azad University, Sanandaj, Iran
A R T I C L E I N F O
A B S T R A C T
Article history:
An effective route to pyrrolo[1,2-a]pyrazines is described via reaction of ethylenediamine, acetylenic
esters and nitrostyrene derivatives in the presence of 20 mol% of sulfamic acid.
ß 2013 Loghman Moradi. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights
reserved.
Received 5 February 2013
Received in revised form 15 April 2013
Accepted 17 April 2013
Available online 31 May 2013
Keywords:
Pyrrolo[1,2-a]pyrazines
Ethylenediamine
Acetylenic esters
Nitrostyrene
1. Introduction
2. Experimental
One of the main challenges in medicinal chemistry is the design
and synthesis of biologically active molecules. Multi-component
reactions (MCRs), because of their productivity, simple procedures,
convergence, facile execution, and atomeconomy, are one of the
best tools in the synthesis of diverse and complex compounds as
well as small and drug like heterocycles [1–3]. Sulfamic acid
(H2NSO3H, SA), a common inorganic acid, is nonvolatile, noncor-
rosive, stable, water resistance and incapable of forming com-
plexes, making it an outstanding alternative to metal catalysts, in
different areas of organic synthesis, as an efficient and green
reagent [4–6]. In recent years, pharmacological evaluation and
structure–activity relationships of some of pyrrolo[1,2-a]pyrazines
have been reported [7,8].
The reagents and solvents used in this work were obtained from
Merck and were used without further purification. Mp: Electro-
thermal-9100 apparatus; uncorrected. IR spectra: Shimadzu IR-
460 spectrometer; in cmꢀ1. 1H NMR and 13C NMR spectra: Bruker
DRX-250.1 AVANCE instrument; in DMSO-d6 at 250.1 MHz and
62.9 MHz, respectively;
d in ppm, J in Hz. EI-MS: Agilent-5975 C
inert XL MSD mass spectrometer, at 70 eV; in m/z. Elemental
analyses: Heraeus CHN-O-Rapid analyzer.
General procedure for the synthesis of compounds 3: In a round
bottom flask equipped with a magnetic stirrer, diethyl acetylene-
dicarboxylate (1.0 mmol) and ethylenediamine (1.2 mmol) in
CH3CN (3 mL) were charged and the mixture was stirred
vigorously at room temperature. Then, b-nitrostyrene (1.0 mmol)
As part of our study on the development of new routes to
heterocyclic and carbocyclic systems [9–13], we now report a
simple one-pot synthesis of functionalized pyrrolo[1,2-a]pyra-
zines 3. Thus, reaction of ethylenediamine, acetylenic esters 1 and
and SA (20 mol%) were added to the mixture and then refluxed for
24 h. Upon completion, the reaction mixture was cooled to room
temperature and then poured into 3 mL water. The solid product
was removed by filtration and purified by recrystallization from
95% ethanol to afford the pure title compounds.
b
-nitro styrene derivatives 2 in the presence of sulfamic acid (SA)
leads to the corresponding functionalized pyrrolo[1,2-a]pyrazines
3a–3h (Scheme 1).
Methyl 1-oxo-7-phenyl-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-
8-carboxylate (3a): Gray crystals; 0.24 g, 88%, mp 182–185 8C. IR
(KBr, cmꢀ1):
n
max 3215 (NH broad), 1712 (C55O), 1655 (C55O), 1555,
1405, 1462. 1H NMR (250 MHz, CDCl3): 3.44 (t, 2H, 3JHH = 3.5 Hz,
CH2), 3.51 (t, 2H, 3JHH = 3.5 Hz, CH2), 3.69 (s, 3H, OCH3), 6.59–7.26
(m, 6H, 6H), 8.28 (s, 1H, NH). 13C NMR (62.9 MHz, CDCl3):
40.1
d
d
(CH2), 44.3 (CH2), 52.4 (OCH3), 118.8 (N–CH55C), 120.8 (C), 123.1
* Corresponding author.
(C), 125.4 (CH of Ar), 126.9 (C of Ar), 127.4 (2CH of Ar), 128.5 (2CH
E-mail address: l.moradi@uok.ac.ir (L. Moradi).
1001-8417/$ – see front matter ß 2013 Loghman Moradi. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
http://dx.doi.org/10.1016/j.cclet.2013.04.038

[
L. Moradi et al. / Chinese Chemical Letters 24 (2013) 740–742
741
H
N
CO2R
O
NH2
NH2
NO2
SA
+
+
N
R'
CH3CN, reflux
CO2R
CO2R
1
2
R'
3
R= Me, Et
R'=C H5, p-CH3-C6H4, p-Cl-C6H4, p-NO -C6H4
6
2
Scheme 1. Synthesis of pyrrolo[1,2-a]pyrazines.
of Ar), 133.4 (N–CH55C) 161.0 (C55O), 170.9 (C55O). Anal. calcd. for
15H14N2O3 (270.29); C, 66.66; H, 5.22; N, 10.36%; Found: C, 66.58;
H, 5.19; N, 10.48.
1402, 1460. 1H NMR (250 MHz, CDCl3):
d
1.41 (t, 3H, 3JHH = 7.2 Hz,
C
CH3), 3.42 (t, 2H, 3JHH = 3.5 Hz, CH2), 3.50 (t, 2H, 3JHH = 3.5 Hz, CH2),
4.28 (q, 2H, 3JHH = 7.2 Hz, CH2), 6.56–7.24 (m, 6H, 6H), 8.26 (s, 1H,
Ethyl 1-oxo-7-p-tolyl-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-
8-carboxylate (3b): Gray crystals, yield 0.27 g (90%), mp 186–
190 8C (decomp). IR (KBr, cmꢀ1): nmax 3305 (NH broad), 1714
NH). 13C NMR (62.9 MHz, CDCl3):
d 13.2 (CH3), 40.2 (CH2), 44.4
(CH2), 62.3 (OCH2), 118.4 (N–CH55C), 120.8 (C), 123.1 (C), 125.4 (CH
of Ar), 126.7 (C of Ar), 127.2 (2CH of Ar), 128.7 (2CH of Ar), 133.3
(N–CH55C) 161.1 (C55O), 170.8 (C55O). Anal. calcd. For C16H16N2O3
(284.32) C, 67.59; H, 5.67; N, 9.85%; Found: C, 67.58; H, 5.79; N,
9.74.
(C55O), 1653 (C55O), 1604, 1552, 1495. 1H NMR (250 MHz, CDCl3):
d
3
1.44 (t, 3H, JHH = 7.2 Hz, CH3), 2.34 (s, 3H, CH3),3.48 (t, 2H,
3
3JHH = 3.5 Hz, CH2), 3.46 (t, 2H, JHH = 3.5 Hz, CH2), 4.29 (q, 2H,
3JHH = 7.2 Hz, CH2), 6.59–7.26 (m, 5H, 5H), 8.26 (s, 1H, NH). 13C
Ethyl
a]pyrazine-8-carboxylate (3g): Gray crystals; 0.26 g (80%). mp
188–190 8C (decomp). IR (KBr, cmꢀ1):
max 3210 (NH broad), 1716
7-(4-nitrophenyl)-1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-
NMR (62.9 MHz, CDCl3):
d 13.1 (CH3), 22.3 (CH3), 40.2 (CH2), 45.3
(CH2), 62.4 (OCH2), 117.7 (N–CH55C), 121.8 (C), 122.8 (C of Ar),
125.1 (C of Ar), 128.6 (2CH of Ph), 129.8 (2CH of Ph), 131.2 (C),
131.8 (N–CH55C), 158.7 (C55O), 165.3 (C55O). MS: m/z (%) 298 (M+,
98), 269 (10), 253(100), 239(12), 226(30). Anal. calcd. for
n
(C55O), 1651 (C55O), 1563, 1520, 1417. 1H NMR (250 MHz, CDCl3):
d
1.23 (t, 3H, 3JHH = 7.1 Hz, CH3), 3.70 (t, 2H, 3JHH = 4.0 Hz, CH2), 4.11
(t, 2H, 3JHH = 4.0 Hz, CH2), 4.20 (q, 2H, 3JHH = 7.1 Hz, CH2), 7.72–7.85
C17H18N2O3 (298.34) C, 68.44; H, 6.08; N, 9.39%; Found: C,
(m, 5H, 5H), 8.74 (s, 1H, NH). 13C NMR (62.9 MHz, CDCl3):
d 14.3
68.36; H, 5.87; N, 10.12.
(CH3), 41.0 (CH2), 45.2 (CH2), 62.3 (OCH2), 118.8 (N–CH55C), 120.5
(C), 123.2 (C of Ar), 123.3 (C of Ar), 127.4 (2CH of Ph), 128.9 (2CH of
Ph), 130.9 (C), 132.6 (N–CH55C), 158.3 (C55O), 166.1 (C55O). Anal.
calcd. for C16H15N3O5 (329.32) C, 58.36; H, 4.59; N, 12.76%; Found:
C, 58.40; H, 4.40; N, 12.52.
Methyl 1-oxo-7-p-tolyl-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-
8-carboxylate (3c): Gray crystals, yield 0.27 g (95%), mp 190–192 8C
(decomp.). IR (KBr, cmꢀ1):
nmax 3304 (NH broad), 1713 (C55O), 1651
(C55O), 1600, 1553, 1499. 1H NMR (250 MHz, CDCl3):
d 2.30 (s, 3H,
CH3), 3.48 (t, 2H, 3JHH = 3.5 Hz, CH2), 3.46 (t, 2H, 3JHH = 3.5 Hz, CH2),
Methyl 7-(4-nitrophenyl)-1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-
a]pyrazine-8-carboxylate (3h): Gray crystals; 0.25 g (82%). mp
3.80 (s, 3H, OCH3), 6.59–7.26 (m, 5H, 5H), 8.26 (s, 1H, NH). 13C NMR
(62.9 MHz, CDCl3):
d
22.3 (CH3), 40.2 (CH2), 45.3 (CH2), 52.4
192–194 8C (decomp). IR (KBr, cmꢀ1):
nmax 3213 (NH broad), 1714
(OCH3), 117.7 (N–CH55C), 121.8 (C), 122.8 (C of Ar), 125.1 (C of Ar),
128.6 (2CH of Ph), 129.8 (2CH of Ph), 131.2 (C), 131.8 (N–CH55C),
158.7 (C55O), 165.3 (C55O). Anal. calcd. for C16H16N2O3 (284.32) C,
67.59; H, 5.67; N, 9.85%; Found: C, 67.50; H, 5.87; N, 9.92.
Ethyl 7-(4-cholorophenyl)-1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-
a]pyrazine-8-carboxylate (3d): Gray crystals; 0.28 g (88%), mp
(C55O), 1650 (C55O), 1561, 1522, 1414. 1H NMR (250 MHz, CDCl3):
3.66 (s, 3H, OCH3), 3.73 (t, 2H, JHH = 4.0 Hz, CH2), 4.14 (t, 2H,
3JHH = 4.0 Hz, CH2), 7.75–7.87 (m, 5H, 5H), 8.73 (s, 1H, NH). 13C
d
3
NMR (62.9 MHz, CDCl3):
d 41.2 (CH2), 45.1 (CH2), 52.5 (OCH3),
118.4 (N–CH55C), 122.5 (C), 123.3 (C of Ar), 124.3 (C of Ar), 127.2
(2CH of Ph), 128.8 (2CH of Ph), 130.6 (C), 132.2 (N–CH55C), 157.3
(C55O), 166.2 (C55O). Anal. calcd. for C15H13N3O5 (315.29) C, 57.14;
H, 4.16; N, 13.33%; Found: C, 57.32; H, 4.10; N, 13.22.
183–185 8C (decomp). IR (KBr, cmꢀ1):
nmax 3212 (NH broad), 1718
(C55O), 1650 (C55O), 1560, 1526, 1419. 1H NMR (250 MHz, CDCl3):
d
1.20 (t, 3H, 3JHH = 7.1 Hz, CH3), 3.72 (t, 2H, 3JHH = 4.0 Hz, CH2), 4.14
(t, 2H, 3JHH = 4.0 Hz, CH2), 4.21 (q, 2H, 3JHH = 7.1 Hz, CH2), 7.20–7.32
(m, 5H, 5H), 8.70 (s, 1H, NH). 13C NMR (62.9 MHz, CDCl3):
d 14.1
3. Results and discussion
(CH3), 41.1 (CH2), 45.2 (CH2), 62.4 (OCH2), 118.7 (N–CH55C), 120.7
(C), 123.2 (C of Ar), 123.3 (C of Ar), 127.6 (2CH of Ph), 128.9 (2CH of
Ph), 130.9 (C), 132.6 (N–CH55C), 158.4 (C55O), 166.1 (C55O). Anal.
calcd. for C16H15ClN2O3 (318.76) C, 60.25; H, 4.74; N, 8.79%; Found:
C, 60.40; H, 4.23; N, 8.52.
The reaction of ethylenediamine and acetylenic esters 1 with
nitrostyrene derivatives 2 in the presence of 20 mol% of SA
proceeded in CH3CN at reflux condition, and was finished after
24 h. Any product other than 3 could not be detected by NMR
spectroscopy. Satisfactorily, the reactions displayed high function-
al group tolerance and afforded the corresponding pyrazines with
great efficiency (Table 1). The structure of 3a–3h was determined
Methyl 7-(4-cholorophenyl)-1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-
a]pyrazine-8-carboxylate (3e): Gray crystals; 0.27 g (89%), mp 193–
195 8C (decomp). IR (KBr, cmꢀ1): nmax 3210 (NH broad), 1720
(C55O), 1654 (C55O), 1568, 1529, 1429. 1H NMR (250 MHz, CDCl3):
d
3
3.70 (t, 2H, JHH = 4.0 Hz, CH2), 3.84 (s, 3H, OCH3), 4.11 (t, 2H,
3JHH = 4.0 Hz, CH2), 6.69 (s, 1H, CH), 6.83 (s, 1H, NH), 7.22–7.31 (m,
4H, 4H of Ph). 13C NMR (62.9 MHz, CDCl3):
d 40.1 (CH2), 44.3 (CH2),
Table 1
Substituted pyrrolo[1,2-a]pyrazines.
Compounds
R
R0
Yield (%)
52.4 (OCH3), 118.7 (N–CH55C), 120.8 (C), 123.3 (C of Ar), 124.3 (C of
Ar), 128.7 (2CH of Ph), 128.8 (2CH of Ph), 131.9 (C), 132.8 (N–
CH55C), 159.4 (C55O), 166.4 (C55O). Anal. calcd. for C15H13ClN2O3
(304.74) C, 59.12; H, 4.30; N, 9.19%; Found: C, 59.10; H, 4.23; N,
9.22.
3a
3b
3c
3d
3e
3f
CH3
C6H5
88
90
95
92
90
87
82
80
CH3CH2
CH3
p-CH3–C6H4
p-CH3–C6H4
p-Cl–C6H4
p-Cl–C6H4
C6H5
CH3CH2
CH3
CH3CH2
CH3
Ethyl 1-oxo-7-phenyl-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-
8-carboxylate (3f): Gray crystals; 0.24 g, 87%, mp 180–182 8C. IR
3g
3h
p-NO2–C6H4
p-NO2–C6H4
CH3CH2
(KBr, cmꢀ1):
nmax 3215 (NH broad), 1711 (C55O), 1653 (C55O), 1555,

[
L. Moradi et al. / Chinese Chemical Letters 24 (2013) 740–742
O
H
N
H
N
HO S NH2
O
H
N
H
N
O
H
O
N
O
CO2R
O
O
NH2
NH2
CO2R2
Ar
Oxidation
Aromatization
O
+
+
CO2R2
N
H
N
CO2R2
N
N
H
Ar
CO2R
1
CO2R
Ar
Ar
3
4
2
N
O
H
O
6
5
Scheme 2. Possible mechanism for the synthesis of pyrrolo[1,2-a]pyrazines derivatives 3a–h.
on the basis of its elemental analyses, 1H and 13C NMR and IR
spectroscopic data. The 1H NMR spectrum of 3a exhibited two
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4. Conclusion
In summary, the reaction of ethylenediamine, acetylenic esters
and nitrostyrenes in the presence of SA as catalyst provides a
simple one-pot synthesis of pyrrolo[1,2-a]pyrazines of potential
synthetic and pharmaceutical interest. The method carries present
the advantage of being performed under the one-pot multicom-
ponent conditions, and requiring no modification of the educts. The
simplicity of the present procedure makes it an interesting
alternative to other approaches.