The regioselective catalyst-free synthesis of bis-quinoxalines and bis-pyrido[2,3-b]pyrazines by double condensation of 1,4-phenylene-bis-glyoxal with 1,2-diamines

Article abstract of DOI:10.1515/hc-2018-0039

The oxidation of 1,4-diacetylbenzene using several oxidizing agents gave 1,4-phenylene-bis-glyoxal in 61-85% yields. A convenient and efficient synthesis of bis-quinoxaline and bis-pyrido[2,3-b]pyrazine derivatives involves the double condensation of 1,2-diamines with 1,4-phenylene-bis-glyoxal in ethanol under reflux conditions. The structures of the new products were defined by proton nuclear magnetic resonance (¹H NMR), carbon-13 nuclear magnetic resonance (¹³C NMR), Fourier-transform infrared spectroscopy (FT-IR) and mass spectrometry (MS).

Full text of DOI:10.1515/hc-2018-0039

Heterocycl. Commun. 2018; aop
MThehedirAehgmiaodsi eSalbeecgthi*vaendcaJatbablayr sKht-aflarfeye synthesis of bis-quinoxalines
and bis-pyrido[2,3-b]pyrazines by double condensation
of 1,4-phenylene-bis-glyoxal with 1,2-diamines
https://doi.org/10.1515/hc-2018-0039
routes to heterocyclic compounds using arylglyoxals,
Received March 17, 2018; accepted May 18, 2018
herein we report the synthesis of new bis-quinoxaline
derivatives 3a–f in a 68–94% yield via condensation
of 1,4-phenylene-bis-glyoxal as its hydrate 1 (structure
in Scheme 1) and 1,2-diamines 2a–f in ethanol under
reflux conditions.
Abstract: The oxidation of 1,4-diacetylbenzene using sev-
eral oxidizing agents gave 1,4-phenylene-bis-glyoxal in
61–85% yields. A convenient and efficient synthesis of
bis-quinoxaline and bis-pyrido[2,3-b]pyrazine derivatives
involves the double condensation of 1,2-diamines with
1,4-phenylene-bis-glyoxal in ethanol under reflux condi-
tions. The structures of the new products were defined by Results and discussion
proton nuclear magnetic resonance (1H NMR), carbon-13
nuclear magnetic resonance (13C NMR), Fourier-transform The glyoxal hydrate 1 was synthesized by oxidation of
infrared spectroscopy (FT-IR) and mass spectrometry (MS). 1,4-diacetylbenzene using different oxidizing agents in a
61–85% yield. The SeO2/dioxane/H2O system is preferred
Keywords: 1,2-diamines; 1,4-phenylene-bis-glyoxal; bis-
to other oxidizing agents as its use provides product 1
pyrido[2,3-b]pyrazines bis-quinoxalines; regioselectivity;
in an 85% yield after crystallization from water. The use
selenium dioxide.
of other oxidizing systems described in the literature,
namely HBr/DMSO/H2O, CuCl2/DMSO/H2O and I2/CuO/
DMSO, furnished compound 1 in the respective yields of
Introduction
73%, 65% and 61%.
The condensation of compound 1 with 1,2-diamines
Glyoxals are important building blocks in organic 2a–f in ethanol under reflux gave the desired bis-qui-
synthesis, particularly in the synthesis of biologically noxalines and bis-pyrido[2,3-b]pyrazines under catalyst-
active heterocyclic compounds [1–9] including quinoxa- free conditions in a 68–89% yield (Scheme 1). The use
line derivatives [10–26]. Synthesis of a quinoxaline by of unsymmetrical aromatic diamines 2b, 2e and 2f could
the reaction of a glyoxal with a 1,2-diamine is part of the in principle lead to isomeric products, but the formation
general strategy involving the reaction of 1,2-dicarbo- of a single product in each case shows that the reactions
nyl compounds with 1,2-diamines [27–30]. In continua- are regioselective. As can be seen, in the condensation of
tion of our studies on the development of new synthetic bis-glyoxal 1 with 4-nitro-1,2-diaminobenzene (2b) and
X
Z
X
Z
H2N
H2N
O
O
Y
N
N
Y
X
Y
EtOH
HO
OH
Z
N
N
∆
OH
HO
1
2a–f
3a–f
a: X = Y = Z = CH
b: X = Z = CH; Y = C-NO2
c: X = Z = CH; Y = C-OMe
d: X = Y = C-Cl; Z = CH
e: X = Y = CH; Z = N
f: X = Z = CH; Y = N
Scheme 1ꢀ
*Corresponding author: Mehdi Ahmadi Sabegh, Department of Organic
Chemistry, Faculty of Chemistry, Urmia University, Urmia 57154, Iran,
e-mail: mahmadis88@yahoo.com, m-ahmadi@iau-ahar.ac.ir
Jabbar Khalafy: Department of Organic Chemistry, Faculty of Chemistry,
Urmia University, Urmia 57154, Iran
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2ꢀ ꢀM.A. Sabegh and J. Khalafy: Synthesis of bis-quinoxalines and bis-pyrido[2,3-b]pyrazines
General procedure for the synthesis of bis-quinoxalines
aminopyridines 2e or 2f, the more nucleophilic 1-amino
group attacks the formyl group in the first step, and the
condensation of the less reactive 2-amino group with the
keto groups occurs in the second step, leading to the for-
mation of bis-quinoxaline 3b. The reactions of aminopyri-
dines 2e and 2f with 1 follow a similar pattern and furnish
regioselectively the respective bis-pyrido[2,3-b]pyrazines
3e and 3f. This reactivity pattern is in full agreement with
previous mechanistic studies on the construction of fused
pyrazines [27–30].
and bis-pyrido[2,3-b]pyrazines (3a–f)
A mixture of 1,4-phenylene-bis-glyoxal (1, 1 mmol) and a 1,2-diamine
(2a–f, 2 mmol) in absolute ethanol (10 mL) was heated under reflux
for 10–15 h, then cooled and the resultant precipitate of 3a–f was fil-
tered, washed with ethanol and crystallized from ethanol.
1,4-Bis-(quinoxalin-2-yl)benzene (3a)ꢁReaction time 12 h; yield
82% of light yellow powder; mp 264–266°C; IR: νmax 3054, 1678, 1609,
1574, 1545, 1490, 1462, 1426, 1370, 1320, 1262, 1231, 1208, 1130, 1054,
1
1014, 956, 847, 756, 674, 630, 601, 566 cm−1; H NMR (CDCl3): δ 9.45
(s, 2H), 8.45 (s, 4H), 8.24–8.16 (m, 4H), 7.85–7.80 (m, 4H); 13C NMR
(CDCl3): δ 150.9, 142.4, 141.8, 138.3, 130.5, 129.9, 129.7, 129.2, 128.2;
Conclusion
+
+
EI-MS: m/z (%) 335 ([Mꢀ+ꢀ1] , 28), 334 [M] (100), 307 (11), 306 (17),
+
204 (12), 76 (19). ESI-HRMS. Calcd. for C22H14N4, [M] : 334.1218. Found:
m/z 334.1205.
A double condensation of 1,4-phenylene-bis-glyoxal with
various 1,2-diamines furnished bis-quinoxaline deriva-
tives 3a–f in high to excellent yields. The simplicity of
operation, high yields and regioselectivity are the key
advantages of this method.
1,4-Bis(6-nitroquinoxalin-2-yl)benzene (3b)ꢁReaction time 15 h;
yield 68% of orange powder; mp 235–236°C; IR: νmax 3047, 1578, 1554,
1348, 1320, 1280, 1193, 1078, 1050, 964, 844, 831, 792, 742 cm−1; 1H NMR
(C6D6): δ 9.16 (s, 1H), 9.13 (s, 1H), 8.20 (s, 4H), 8.10 (d, Jꢀ=ꢀ9 Hz, 2H), 7.98
(d, Jꢀ=ꢀ9 Hz, 2H), 7.10 (bs, 2H); 13C NMR (C6D6): δ 138.5, 137.7, 136.1, 135.7,
+
133.7, 127.6, 126.9, 124.6, 124.0, 123.8; EI-MS: m/z (%) 425 ([Mꢀ+ꢀ1] , 27),
+
424 ([M] , 100), 394 (25), 382 (11), 351 (14), 75 (13). ESI-HRMS. Calcd.
Experimental
+
for C22H12N6O4, [M] : m/z 424.0920. Found: m/z 424.0907.
Melting points were measured on an Electrothermal 9200 apparatus
and are uncorrected. Infrared spectra were measured on a Spectrum
RXI, Perkin Elmer, UK Fourier-transform infrared (FT-IR) instrument
using KBr disks. The 1H (300 MHz) and 13C (75 MHz) nuclear magnetic
resonance (NMR) spectra were recorded on a Bruker DRX-300 Avance
spectrometer in DMSO-d6, CDCl3 and C6D6 relative to tetramethyl-
silane (TMS) as the internal reference. Thin layer chromatography
(TLC) was carried out on a pre-coated aluminum sheet with silica gel
60F 254 obtained from Merck, and detection was made with the help
of an ultraviolet (UV) lamp (λ 254 nm). Mass analysis was performed
on an Agilent Technology (HP) 5973 Network Mass Selective Detec-
tor and high-resolution mass spectra were recorded on a Kratos mass
spectrometry (MS) 25RF spectrometer.
1,4-Bis(6-methoxyquinolin-2-yl)benzene (3c)ꢁReaction time
10 h; yield 89% of brown powder; mp 267–268°C; IR: νmax 3047, 1616,
1498, 1374, 1321, 1261, 1217, 1201, 1173, 1122, 1060, 1026, 958, 846,
830, 779 cm−1; 1H NMR (DMSO-d6): δ 9.52 (s, 2H), 8.55(s, 4H), 8.03 (d,
Jꢀ=ꢀ8.7 Hz, 2H), 7.54 (s, 2H), 7.51 (d, Jꢀ=ꢀ8.7 Hz, 2H), 3.86 (s, 6H); 13C NMR
spectrum could not be recorded due to low solubility of the sample;
+
+
EI-MS: m/z (%) 395 ([Mꢀ+ꢀ1] , 29), 394 ([M] , 100), 262 (10), 197 (7),
+
106 (12), 63 (10). ESI-HRMS. Calcd. for C24H18N4O2, [M] : m/z 394.1430.
Found: m/z 394.1416.
1,4-Bis(6,7-dichloroquinoxalin-2-yl)benzene (3d)ꢁReaction time
1
12 h; yield 78% of gray powder; mp 190–191°C; the H NMR and 13C
NMR spectra could not be recorded due to low solubility of the sam-
ple; IR: νmax 3066, 3045, 1544, 1459, 1418, 1317, 1274, 1177, 1111, 1058,
1016, 945, 928, 900, 878, 840, 810, 660, 624 cm−1; EI-MS: m/z (%) 478
+
+
+
+
Synthesis of 1,1′-(1,4-phenylene)bis(2,2-dihydroxy-
ethanone) (1)
([Mꢀ+ꢀ6] , 14), 474 ([Mꢀ+ꢀ4] , 52), 472 ([Mꢀ+ꢀ2] , 100), 470 ([M] , 80), 300
(17), 272 (15), 237 (11), 170 (13), 146 (32), 144 (50), 109 (30), 74 (12).
+
ESI-HRMS. Calcd. for C22H10Cl4N4, [M] : m/z 469.9660. Found: m/z
469.9648.
A solution of selenium dioxide (1.55 g, 14 mmol) in 90% aqueous
dioxane (10 mL) was treated at 100°C with a solution of 1,4-dia-
cetylbenzene (1.62 g, 10 mmol) in dioxane (12 mL). The mixture
was heated under reflux for 14 h and the precipitated selenium was
removed by filtration. The solution was cooled and the resultant
pale yellow precipitate of product 1 was collected and crystallized
from water: yield 1.92 g (85%); mp 141–142°C; IR: νmax 3428, 3377,
2975, 1670, 1505, 1446, 1407, 1297, 1121, 1037, 962, 873, 801, 696, 584,
1,4-Bis(pyrido[2,3-b]pyrazine-2-yl)benzene (3e)ꢁReaction time
10 h; yield 80% of brown powder; mp 320–321°C; IR: νmax 3413, 3067,
1
2372, 1546, 1461, 1310, 209, 1125, 1061, 952, 848, 794 cm−1; H NMR
(CDCl3): δ 9.29 (s, 2H), 9.25 (bs, 2H) 8.82 (s, 4H), 8.54 (d, Jꢀ=ꢀ7.8 Hz,
2H), 7.77 (dd, J1ꢀ=ꢀ8.4 Hz, J2ꢀ=ꢀ4.5 Hz, 2H); 13C NMR spectrum could not
be recorded due to low solubility of the sample; EI-MS: m/z (%) 337
+
+
1
([Mꢀ+ꢀ1] , 24), 336 ([M] , 100), 308 (9), 233 (20), 205 (9), 104 (10), 77 (14).
517 cm−1; H NMR (DMSO-d6): δ 8.15 (s, 4H), 6.90 (d, Jꢀ=ꢀ7.2 Hz, 4H,
+
ESI-HRMS. Calcd. for C20H12N6, [M] m/z 336.1123. Found: m/z 336.1111.
4ꢀ×ꢀOH, exchanged by D2O addition), 5.68 (bt, Jꢀ=ꢀ7.2 Hz, 2H, changed
to a singlet after D2O addition); 13C NMR (DMSO-d6): δ 196.5, 137.4,
+
129.7, 89.9; MS: m/z (%) 226 ([M] , 59), 184 (100), 163 (58), 149 (65),
1,4-Bis(pyrido[3,4-b]pyrazine-2-yl)benzene (3f)ꢁReaction time
10 h; yield 78% of creamy powder; mp 248–249°C; IR: νmax 3216, 2373,
133 (76), 105 (59), 91 (52), 77 (56), 55 (75). ESI-HRMS: Calcd. for
+
1
1547, 1419, 1317, 1235, 1054, 960, 854, 837, 584 cm−1; H NMR (CDCl3):
C10H10O6, [M] : m/z 226.0477. Found: m/z 226.0462.
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M.A. Sabegh and J. Khalafy: Synthesis of bis-quinoxalines and bis-pyrido[2,3-b]pyrazinesꢂ ꢂ3
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Jꢀ=ꢀ6 Hz, 2H); 13C NMR (CDCl3ꢀ+ꢀDMSO-d6): δ 154.2, 147.7, 145.2, 144.8,
+
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136.8, 128.9, 128.5, 121.9, 121.5; EI-MS: m/z (%) 337 ([Mꢀ+ꢀ1] , 22), 336
+
([M] , 100), 309 (13), 308 (15), 233 (11), 77 (11), 50 (32). ESI-HRMS.
+
Calcd. for C20H12N6, [M] : m/z 336.1123. Found: m/z 336.111.
Acknowledgments: We are grateful to Urmia University for
the financial support and we also thank Professor R. H.
Prager (Flinders University, Australia) for language edit-
ing and proofreading of this article.
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