One-pot synthesis of pyrrolo[1,2-a]quinoxaline and pyrrolo[1,2-a]pyrazine derivatives via the three-component reaction of 1,2-diamines, ethyl pyruvate and α-bromo ketones

Article abstract of DOI:10.1016/j.cclet.2014.06.013

A simple synthetic protocol has been developed involving the three-component reaction between 1,2-diamines, ethyl pyruvate and α-bromo ketones in the presence of FeCl₃ as a catalyst. A number of pyrrolo[1,2-a]quinoxaline and pyrrolo[1,2-a]pyrazine derivatives were synthesized in excellent yields using this protocol.

Full text of DOI:10.1016/j.cclet.2014.06.013

Accepted Manuscript
Title: One-pot synthesis of pyrrolo[1,2-a]quinoxaline and
pyrrolo[1,2-a]pyrazine derivatives via the three-component
reaction of 1,2-diamines, ethyl pyruvate and α-bromo ketones
Author: Mohammad Piltan
PII:
S1001-8417(14)00277-0
DOI:
Reference:
http://dx.doi.org/doi:10.1016/j.cclet.2014.06.013
CCLET 3046
To appear in:
Chinese Chemical Letters
Received date:
Revised date:
Accepted date:
19-2-2014
28-5-2014
30-5-2014
Please cite this article as: M. Piltan, One-pot synthesis of pyrrolo[1,2-a]quinoxaline
and pyrrolo[1,2-a]pyrazine derivatives via the three-component reaction of 1,2-
diamines, ethyl pyruvate and rmalpha-bromo ketones, Chinese Chemical Letters
(2014), http://dx.doi.org/10.1016/j.cclet.2014.06.013
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Graphical Abstract
One-pot synthesis of pyrrolo[1,2-a]quinoxaline and pyrrolo[1,2-a]pyrazine
derivatives via the three-component reaction of 1,2-diamines, ethyl pyruvate and α-
bromo ketones
Mohammad Piltan
Department of Chemistry, Sanandaj Branch, Islamic Azad University, Sanandaj, P.O. Box 618, Iran
H
N
O
O
R'
NH2
R'
O
FeCl3 (20 mol%)
OEt
Br
+
+
R
CH3CN, reflux, 5 h
R''
NH2
R''
N
O
2
3
1
4a-h
R', R'' = H, Me
R = CO2Et, Ph, 4-Me-C6H4, 4-Br-C6H4;
R
A simple synthetic protocol has been developed involving the one-pot three-component reaction between 1,2-diamines, ethyl pyruvate and α-
bromo ketones in the presence of FeCl3 as a catalyst. A number of pyrrolo[1,2-a]quinoxaline and pyrrolo[1,2-a]pyrazine derivatives were
synthesized in excellent yields using this protocol.
———
E-mail addresses: mohammadpiltan@yahoo.com, mpiltan@iausdj.ac.ir.
Page 1 of 5

Original article
One-pot synthesis of pyrrolo[1,2-a]quinoxaline and pyrrolo[1,2-a]pyrazine derivatives
via the three-component reaction of 1,2-diamines, ethyl pyruvate and α-bromo ketones
Mohammad Piltan
Department of Chemistry, Sanandaj Branch, Islamic Azad University, Sanandaj, P.O. Box 618, Iran
ARTICLE INFO
ABSTRACT
A simple synthetic protocol has been developed involving the three-component reaction
between 1,2-diamines, ethyl pyruvate and α-bromo ketones in the presence of FeCl3 as a
catalyst. A number of pyrrolo[1,2-a]quinoxaline and pyrrolo[1,2-a]pyrazine derivatives were
synthesized in excellent yields using this protocol.
Article history:
Received 19 February 2014
Received in revised form 28 May 2014
Accepted 30 May 2014
Available online
Keywords:
Pyrrolo[1,2-a]quinoxaline
α-Bromo ketones
1,2-Diamines
Ethyl pyruvate
1. Introduction
Multicomponent reactions (MCRs) are economically and environmentally advantageous as three or more starting materials can be
reacted in a one-pot procedure to give a single product [1-3].
The quinoxaline nucleus is present in many biologically and pharmaceutically active compounds. Quinoxalines show anti-
inflammatory [4], antiviral [5], antiglucoma [6], herbicidal [7], and anticancer [8] activities. Furthermore, the synthesis of quinoxalines
and their derivatives has received much attention from organic and medicinal chemists. Nevertheless, most of the reported methods for
the synthesis of pyrrolo[1,2-a]quinoxalines suffer from one or more disadvantages which limit their use, such as: difficulties in product
isolation, the use of highly expensive and detrimental metal precursors, unsatisfactory yields, and longer reaction times [9-12].
Iron(III) chloride has been used as an efficient catalyst for the manufacture of carbon-heteroatom and heteroatom-heteroatom bonds
with considerable advantages [13]. It has been used previously by us for the synthesis of pyrrolo[2,1-c]benzoxazines [14]. As part of
our current studies on the development of new routes to synthesize heterocyclic systems [15-17], the syntheses of pyrrolo[1,2-
a]quinoxaline and pyrrolo[1,2-a] pyrazine derivatives from 1,2-diamines (1), ethyl pyruvate (2) and α-bromo ketones (3) in the
presence of FeCl3 as a catalyst are reported herein (Scheme 1).
2. Experimental
Melting point (mp) was measured on a microscopic melting point apparatus. The IR spectra were recorded on a Shimadzu 460 FT-
IR spectrometer with a KBr disk. 1H NMR and 13C NMR spectra were taken on a Bruker DRX-250 Avance spectrometer at 250 MHz
and 62.5 MHz in DMSO-d6, chemical shift are given in part per million (ppm) relative to TMS as an internal standard. Mass spectra
and high resolution mass spectra were performed on Finnigan-MAT-8430 mass spectrometer with electron spray ionization (ESI) as
the ionization mode. Elemental analyses were obtained using Heraeus CHN-O-Rapid analyzer.
Typical procedure for the preparation of compounds 4a-h, exemplified by 4a: In a round-bottom flask equipped with a magnetic
stirrer, 1,2 phenylenediamine (2 mmol) and ethyl pyruvate (2 mmol) in MeCN (3 mL) were added, and the mixture was stirred
vigorously at room temperature. Ethyl bromopyruvate (2 mmol) in MeCN (2 mL) and FeCl3 (20 mol%) were added to the mixture,
which was refluxed for 5 h. After completion of the reaction, as indicated by TLC (EtOAC/hexane = 1/3, v/v), the mixture was cooled
to room temperature. The solvent was evaporated and the residue was purified by column chromatography using n-hexane/EtOAc (3/1,
v/v) as the eluent. The solvent was removed and the product was obtained.
o
Ethyl 4-oxo-4,5-dihydropyrrolo[1,2-a]quinoxaline-2-carboxylate (4a): Yield (0.20 g, 78%), grey crystals; mp 240-242 C. IR (KBr,
cm-1): νmax 3419 (NH), 1721 (C=O), 1669 (C=O). 1H NMR (250.1 MHz, DMSO-d6): δ 1.30 (t, 3H, 3J = 7.0 Hz, CH3), 4.27 (q, 2H, 3J =
7.0 Hz, OCH2), 7.19-7.35 (m, 4H, 4CH ), 8.22 (d, 1H, 3J = 8.0 Hz, CH), 8.75 (s, 1H, CH), 11.45 (br s, 1H, NH). 13C NMR (62.9 MHz,
———
E-mail addresses: mohammadpiltan@yahoo.com, mpiltan@iausdj.ac.ir.
Page 2 of 5

DMSO-d6): δ 14.7 (CH3), 60.5 (OCH2), 111.9 (CH), 116.3 (CH), 117.1 (CH), 119.4 (C), 121.8 (CH), 122.5 (C), 123.4 (CH), 124.7 (C),
127.3 (C), 129.4 (CH), 155.2 (C=O), 163.6 (C=O). MS: m/z (%): 256 (M+, 100), 241 (8), 228 (44), 211 (100), 183 (47), 155 (42), 77
(15). Anal. Calcd. for C14H12N2O3 (256.26): C, 65.62; H, 4.72; N, 10.93; found: C, 65.57; H, 4.69; N, 10.96.
2-Phenylpyrrolo[1,2-a]quinoxaline-4(5H)-one (4b): Yield (0.18 g, 70%), yellow oil. IR (KBr, cm-1): νmax 3423 (NH), 1662 (C=O),
3
1H NMR (250.1 MHz, DMSO-d6): δ 7.21-7.53 (m, 9H, 9CH), 8.12 (d, 1H, J = 8.0 Hz, CH), 8.62 (s, 1H, CH), 11.47 (br s, 1H, NH).
13C NMR (62.9 MHz, DMSO-d6): δ 111.9 (CH), 116.0 (C), 117.1 (CH), 117.2 (C), 121.6 (C), 122.2 (CH), 123.4 (CH), 126.5 (CH),
126.9 (CH), 127.3 (2CH), 127.8 (CH), 129.0 (C), 129.3 (2CH), 133.1 (C), 154.3 (C=O). MS: m/z (%): 260 (M+, 100), 232 (13), 218
(24), 183 (86), 77 (35). Anal. Calcd. for C17H12N2O (260.30): C, 78.44; H, 4.65; N, 10.76; found: C, 78.57; H, 4.61; N, 10.79.
2-(4-Bromophenyl)pyrrolo[1,2-a]quinoxalin-4(5H)-one (4c): Yield (0.25 g, 73%), pink crystals; mp 119-121 oC. IR (KBr, cm-1): νmax
1
3
3315 (NH), 1667 (C=O). H NMR (250.1 MHz, DMSO-d6): δ 7.17-7.48 (m, 8 H, 8 CH), 8.09 (d, 1H, J = 8.1 Hz, CH), 8.65 (s, 1H,
CH), 11.42 (br s, 1H, NH). 13C NMR (62.9 MHz, DMSO-d6): δ 116.8 (CH), 118.2 (CH), 123.1 (C), 123.8 (CH), 124.4 (CH), 125.1
(CH), 125.8 (2CH), 126.3 (C), 129.8 (C), 132.2 (2CH), 132.9 (C), 135.4 (CH), 136.6 (C), 139.2 (C), 154.1 (C=O). MS: m/z (%): 339
(M+, 9), 297 (28), 218 (91), 183 (96), 157 (38), 76 (62), 57 (100). Anal. Calcd. for C17H11BrN2O (339.19): C, 60.20; H, 3.27; N, 8.26;
found: C, 60.27; H, 3.21; N, 8.32.
1-Methyl-2-p-tolylpyrrolo[1,2-a]quinoxalin-4(5H)-one (4d): Yield (0.20 g, 72%), yellow powder; mp 60-61 oC. IR (KBr, cm-1): νmax
3200 (NH), 1663 (C=O). 1H NMR (250.1 MHz, DMSO-d6): δ 2.29 (s, 3H, CH3), 7.21-7.39 (m, 5H, 5CH), 7.64-7.67(m, 3H, 3CH), 8.07
(s, 1H, CH), 8.64 (s, 1H, CH), 11.23 (br s, 1H, NH). 13C NMR (62.9 MHz, DMSO-d6): δ 22.3 (CH3), 116.1 (CH), 116.6 (CH), 118.1
(CH), 124.0 (C), 124.4 (CH), 125.8 (CH), 126.9 (2CH), 127.3 (C), 129.4 (C), 130.1 (CH), 130.5 (C), 131.0 (2CH), 132.5 (C), 137.5
(C), 156.5 (C=O). MS: m/z (%): 274 (M+, 100), 246 (6), 232 (41), 183 (81), 91 (32), 76 (18). Anal. Calcd. for C18H14N2O (274.33): C,
78.81; H, 5.14; N, 7.63; found: C, 78.94; H, 5.19; N, 7.69.
Ethyl 7,8-diamethy1-4-oxo-4,5-dihydroptrrolo[1,2-a]quinoxaline-1-carboxylate (4e): Yield (0.24 g, 84%), grey crystals; mp 237-239
oC. IR (KBr, cm-1): νmax 3305 (NH), 1731 (C=O), 1623 (C=O). 1H NMR (250.1 MHz, DMSO-d6): δ 1.23 (t, 3H, 3J = 7.1 Hz, CH3), 2.24
(s, 3H, CH3) , 2.47 (s, 3H, CH3), 4.27 (q, 2H, 3J = 7.0 Hz, OCH2), 7.08 (s, 1H, CH ), 7.32 (s, 1H, CH ), 7.75 (s, 1H, CH), 8.33 (s, 1H,
CH) , 11.45 (br s, 1H, NH). 13C NMR (62.9 MHz, DMSO-d6): δ 14.3 (CH3), 21.2 (CH3), 22.4(CH3), 61.8 (OCH2), 115.6 (CH), 118.5
(C), 121.0 (CH), 123.8 (CH), 125.2 (C), 128.3 (C), 129.4 (CH), 133.6 (C), 135.3 (CH), 136.2 (CH), 155.2 (C=O), 162.4 (C=O). MS:
m/z (%): 284 (M+, 100), 269 (10), 256 (45), 239 (100), 211 (45), 183 (38), 169 (25). Anal. Calcd. for C14H16N2O3 (284.32): C, 67.59;
H, 5.67; N, 9.85; found: C, 67.62; H, 5.69; N, 9.81.
o
2-(4-Bromophenyl)-7,8-dimethylpyrrolo[1,2-a]quinoxalin-4(5H)-one (4f): Yield (0.27 g, 74%), grey crystals; mp 235-237 C. IR
(KBr, cm-1): νmax 3335 (NH), 1653 (C=O). 1H NMR (250.1 MHz, DMSO-d6): δ 2.29 (s, 3H, CH3), 2.38 (s, 3H, CH3), 6.85(s, 1H, CH ),
7.23-7.39 (m, 3H, 3CH), 7.48-7.59 (m, 2H, 2CH), 7.71-7.75 (m, 1H, CH), 8.22 (s, 1H, CH), 11.45 (br s, 1H, NH). 13C NMR (62.9
MHz, DMSO-d6): δ 22.3 (CH3), 22.8 (CH3), 109.9 (CH), 116.4 (CH), 117.1 (C), 118.6 (CH), 122.8 (C), 124.1 (C), 124.3 (C), 126.1
(2CH), 127.2 (CH), 129.3 (C), 132.9 (C), 130.0 (C), 131.1 (2CH), 136.4 (C), 155.6 (C=O). MS: m/z (%): 367 (M+, 12), 325 (28), 246
(94), 76 (63), 57 (100). Anal. Calcd. for C19CH15BrN2O (367.25): C, 62.14; H, 4.12; N, 7.63; found: C, 62.11; H, 4.15; N, 7.59.
Ethyl 4-oxo-4,5,5a,6,7,8,9,9a-octahydropyrrolo[1,2-a]quinoxalin-1-carboxylate (4g): Yield (0.18 g, 68%), yellow oil. IR (KBr, cm-
1): νmax 3280 (NH), 1725 (C=O), 1656 (C=O). 1H NMR (250.1 MHz, DMSO-d6): δ 1.22-1.46 (m, 7H, 2CH2 and CH3), 1.75-1.94 (m,
3
4
4
4H, 2CH2), 3.38-3.54 (m, 2H, 2CH), 4.23 (q, 2H, J = 7.1 Hz, OCH2), 6.76 (d, 1H, J = 1.5 Hz, CH), 7.69 (d, 1H, J = 1.5 Hz, CH),
11.28 (1H, br s, NH). 13C NMR (62.9 MHz, DMSO-d6): δ 14.3 (CH3), 23.2 (CH2), 24.8 (CH2), 31.2 (CH2), 31.8 (CH2), 54.7 (CH), 60.5
(CH2), 61.2 (OCH2), 111.3 (C), 118.6 (CH), 126.3 (C), 132.2 (CH) 158.4, 164.7 (2 C=O). MS: m/z (%): 262 (M+, 100), 247 (15), 217
(51), 189 (100), 161 (39). Anal. Calcd. for C14H18N2O3 (262.31): C, 64.11; H, 6.92; N, 10.68; found: C, 64.05; H, 6.88; N, 10.76.
o
Ethyl 1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-7-carboxylate (4h): Yield (0.15 g, 72%), yellow crystals; mp 236-238 C. IR
(KBr, cm-1): νmax 3330 (NH), 1727 (C=O), 1647 (C=O). 1H NMR (250.1 MHz, DMSO-d6): δ 1.27 (t, 3H, 3J = 7.1 Hz, CH3), 3.46-3.51
(m, 2H, CH2), 4.11-4.13 (m, 2H, CH2), 4.21 (q, 2H, 3J = 7.0 Hz, OCH2), 6.90 (d, 1H, 4J = 1.4 Hz, CH), 7.62 (d, 1H, 4J = 1.4 Hz, CH),
11.21 (s, 1H, NH).13C NMR (62.9 MHz, DMSO-d6): δ 14.8 (CH3), 43.1 (CH2), 43.9 (CH2), 60.9 (OCH2), 114.2 (CH), 116.7 (C), 118.3
(C), 134.6 (CH), 156.0 (C=O ), 163.7 (C=O). MS: m/z (%): 208 (M+, 100), 193 (82), 180 (27), 163 (100), 135 (20), 120 (57), 107 (26),
77 (27). Anal. Calcd. for C10H12N2O3 (208.22): C, 57.69; H, 5.8; N, 13.45; found: C, 57.73; H, 5.78; N, 13.41.
3. Results and discussion
The reaction of 1, 2 phenylenediamine, ethyl pyruvate, and ethyl bromopyruvate in the presence of FeCl3 (20 mol%) was selected as
a model system (Scheme 2).
Initially, we thought of varying the nature of solvent to increase the product yield, so we carried out the reactions in dichloromethane,
dichloroethane, ethanol, ethyl acetate, acetonitrile, and methanol at reflux temperature (Table 1). When the reaction mixture was
refluxed for 5 h in acetonitrile, the yield of 4a was improved significantly (78%), Next the catalytic amount of the Iron (III) chloride
catalyst was examined in the model reaction. In the presence of 10, 15, 20, and 25 mol% of FeCl3, the yields of pyrrolo[1,2-
a]quinoxaline 4a obtained were 42%, 55%, 78%, and 78%, respectively. This shows the important role of FeCl3 in this reaction. Thus,
to verify that this is generally the case, we optimized the conditions for the other reactions. The results are presented in Table 2.
The 1H NMR, 13C NMR, IR spectra and MS of the products clearly indicated the formation of compounds 4a-h. For example, the 1H
NMR spectrum of 4a exhibited a triplet at 1.21 ppm and a quartet at 4.20 ppm for the ethoxy group, along with multiplets (7.19–8.75
Page 3 of 5

1
ppm) for the aromatic region, and a broad singlet at 11.45 ppm due to the NH group. The H-decoupled 13C NMR spectrum of 4a
showed 14 distinct resonances in agreement with the proposed structure. The IR spectrum of 4a exhibited absorption bands due to
carbonyl groups at 1721 and 1669 cm-1. The 1H NMR and 13C NMR spectra of products 4b-h were similar to those of 4a, except for the
ester moieties, which exhibited characteristic resonances in the appropriate parts of the spectrum.
On the basis of these results, a possible mechanism for the formation of pyrrolo[1,2-a]quinoxaline 4a is shown in Scheme 3. The
reaction between 1,2-diaminobenzene (1a) and ethyl pyruvate (2) affords quinoxaline 5, then ethyl bromopyruvate (3) could be
activated by FeCl3 and undergo the nucleophilic addition. The subsequent intermediate 6 by the elimination of the HBr leads to
intermediate 7, which undergoes a series of cyclization and elimination reactions to generate product 4a.
4. Conclusion
In conclusion, we have described a simple and efficient method for the synthesis of pyrrolo[1,2-a]quinoxaline and pyrrolo[1,2-
a]pyrazine derivatives of potential synthetic and pharmacological interest. This method is characterized by several unique advantages,
such as simplicity in operation under neutral conditions, high yields of products, and relatively short reaction time.
Acknowledgment
We are grateful to Sanandaj Branch, Islamic Azad University Research Council for the financial support of this research.
References
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[14] M. Piltan, L. Moradi, S.A. Zarei, H. Rostami, One-pot multicomponent synthesis of novel tricyclic pyrrolo[2,1-c][1,4]benzoxazines, Chin. Chem. Lett. 25
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Page 4 of 5

H
N
O
O
R'
O
R
R'
NH2
NH2
FeCl3
OEt
Br
+
+
R
CH3CN
R''
N
R''
O
3
4a-h
2
1
R = CO2Et, Ph, 4-Me-C6H4, 4-Br-C6H4;
R', R'' = H, Me
Scheme 1. Three-component synthesis of pyrrolo[1,2-a]quinoxaline and pyrrolo[1,2-a]pyrazine derivatives.
H
N
O
O
NH2
NH2
O
FeCl3 (20 mol%)
OEt
Br
+
EtO2C
+
CH3CN, reflux, 5 h
N
O
1a
3
4a
2
CO2Et
Scheme 2. The model system for the synthesis of 4a.
Table 1
The effect of solvent on the reaction time and yield.a
Entry
1
2
3
4
5
6
7
Solvent
Time (h)
Yield (%)b
DCM
8
64
EtOAC DCE
MeCN
5
78
MeCN
8
77
EtOH MeOH
8
8
8
8
60
61
68
65
a Reaction conditions: 1,2-phenylenediamine (2 mmol), ethyl pyruvate (2 mmol), ethyl bromopyruvate (2 mmol), and FeCl3 (20 mol %).
b Isolated yield.
Table 2
Synthesis of pyrrolo[1,2-a]quinoxaline and pyrrolo[1,2-a]pyrazine derivatives 4.
H
O
O
R'
N
O
R'
NH2
FeCl3
OEt
Br
+
+
R
CH3CN
R''
N
R''
NH2
O
3
4a
2
1
R
Entry
Diamine
R
Product
Yield
(%)a
78
70
73
1
2
3
4
5
benzene-1,2-diamine
benzene-1,2-diamine
benzene-1,2-diamine
benzene-1,2-diamine
4,5-dimethylbenzene-
1,2-diamine
CO2Et
Ph
4-Br-C6H4
4-Me-C6H4
CO2Et
4a
4b
4c
4d
4e
72
84
6
4,5-dimethylbenzene-
1,2-diamine
4-Br-C6H4
4f
74
7
8
cyclohexyl diamine
ethylenediamine
CO2Et
CO2Et
4g
4h
68
72
a Isolated yield.
H
N
H
N
O
O
NH2
O
3
_
Br
OEt
H3C
Br
FeCl3
+
N
+
CH3
NH2
N
CH3
O
CO2Et
1a
O
2
5
Cl3Fe
EtO2C
O
6
H
H
N
O
N
O
cyclization
4a
- HBr
-H2O
N
CH2
CO2Et
7
N
CO2Et
HO
Cl3Fe
8
O
Scheme 3. Possible mechanism for the synthesis of pyrrolo[1,2-a]quinoxaline 4a.
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