A novel synthesis of imidazo[1,2-a]quinoxalines

Article abstract of DOI:10.1007/s10593-012-1079-y

Several new derivatives of imidazo[1,2-a]quinoxalines have been synthesized in good to excellent yields starting from arylaminoisoxazol-5(2H)-ones and 2,3-dichloroquinoxaline through a rearrangement under mild base-catalyzed conditions.

Full text of DOI:10.1007/s10593-012-1079-y

Chemistry of Heterocyclic Compounds, Vol. 48, No. 6, September, 2012 (Russian Original Vol. 48, No. 6, June, 2012)
A NOVEL SYNTHESIS OF IMIDAZO[1,2-a]QUINOXALINES
A. Poursattar Marjani1, J. Khalafy1*, and R. H. Prager2
Several new derivatives of imidazo[1,2-a]quinoxalines have been synthesized in good to excellent yields
starting from arylaminoisoxazol-5(2H)-ones and 2,3-dichloroquinoxaline through a rearrangement
under mild base-catalyzed conditions.
Keywords: arylaminoisoxazol-5(2H)-ones, 2,3-dichloroquinoxaline, imidazo[1,2-a]quinoxalines, N-quin-
oxalinylisoxazolones, basic catalysis.
Quinoxaline derivatives are an important class of benzoheterocycles, which have received much
attention in recent years owing both to their biological properties and pharmaceutical applications. These
derivatives are particularly interesting since some of them have shown antimicrobial [1, 2], anticancer [3–5],
antimalarial [6], anti-inflammatory [7], antinociceptive [8], antitubercular [9], anthelmintic [10], antidiabetic
[11], and antiepileptic [12] properties.
We reported earlier the syntheses of imidazoles [13], imidazopyridines [14-17], imidazobenzothiazoles
[18], indoles [19], imidazopyrimidine [20], and pyrimidoquinolines [21-23] starting from isoxazol-5(2H)-ones.
Here we report the synthesis of a series of novel imidazo[1,2-a]quinoxalines in good to excellent yields by
rearrangement of new N-quinoxalinylisoxazolones under mild base-catalyzed conditions.
The N-quinoxalinylisoxazolones 2a-c were prepared by the reaction of the corresponding
arylaminoisoxazolone 1a-c with 2,3-dichloroquinoxaline in good yields in EtOH under reflux for 24 h. The
obtained compounds 2a-c were rearranged to the new imidazo[1,2-a]quinoxaline derivatives 3a-c in good yields
by refluxing with triethylamine in THF.
N
N
Cl
N
N
N
Cl
O
Et3N–THF
O
N
N
Cl
Cl
HN
O
EtOH
O

N
+

–CO2
70–76%
Ar
N
H
CO2Et
62–71%
Ar
2a–c
N
EtO2C
3a–c
1a–c
CO2Et
N
Ar
H
H
a Ar = 3-MeC6H4, b X = 4-BrC6H4, c X = 4-O2NC6H4
_______
*To whom correspondence should be addressed, e-mail: j.khalafi@urmia.ac.ir, jkhalafi@yahoo.com.
1Department of Chemistry, Faculty of Science, Urmia University, University Boulevard, Urmia 57154, Iran.
2School of Chemistry, Physics and Earth Sciences, Flinders University,GPO Box 2100, Adelaide SA 5001,
Australia; e-mail: rolf.prager@flinders.edu.au.
_________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 6, pp. 1001-1005, June, 2012. Original
article submitted April 5, 2011.
0009-3122/12/4806-0931©2012 Springer Science+Business Media New York
931

Also, when 2 equivalents of the isoxazolone 1a was reacted with 2,3-dichloroquinoxaline under the
above-described conditions in the absence of base, the rearranged bisimidazoquinoxaline product 4 was
precipitated from the reaction mixture in 10% yield. Reaction of compounds 1b,c with 2,3-dichloroquinoxaline
under the same conditions failed to produce the corresponding bis-imidazoquinoxalines, which may reflect
relatively low susceptibility of the quinoxaline ring to nucleophilic substitution.
H
N
EtO2C
Me
Me
N
N
N
N
Cl
Cl
N
N
2 equiv. 1a
EtOH, 
10%
EtO2C
N
H
4
The structure of the obtained products was confirmed by the appropriate spectroscopic methods. The
ring system of the derivatives 3a-c and 4 appears to be novel and the synthesis reported here has the advantage of
being straightforward.
In conclusion, the work reported herein provides a facile and highly effective method for the synthesis
of imidazoquinoxalines with functional groups capable of further elaboration, potentially being of interest in
medicinal chemistry.
EXPERIMENTAL
FT-IR spectra were recorded in KBr disks on a Thermo Nicolet (Nexus 670) FT-IR spectrometer.
1H and 13C NMR spectra were recorded on a Bruker Avance 300 FT-NMR spectrometer (300 and 75 MHz,
respectively) in DMSO-d6 (compound 4) or in CDCl3 (remaining compounds) using TMS as internal standard.
Mass spectra (EI, 70 eV) were recorded on a Varian Matt 311 spectrometer. Elemental analyses were performed
on a Leco Analyzer 932. Melting points were determined on a digital melting point apparatus (Electrothermal)
and remain uncorrected. Freshly distilled solvents were used throughout, anhydrous solvents were obtained
according to Perrin and Armarego [24]. Starting isoxazoles 1a-c were prepared according to literature methods
[16] (for compounds 1a,c) and [19] (for compound 1b).
Ethyl 3-(arylamino)-2-(3-chloroquinoxalin-2-yl)-5-oxo-2,5-dihydroisoxazole-4-carboxylates 2a-c
(General Method). Ethyl 3-(arylamino)-5-oxo-2,5-dihydroisoxazole-4-carboxylates 1a-c (0.38 mmol) and
2,3-dichloroquinoxaline (76 mg, 0.38 mmol) were refluxed in EtOH (20 ml) for 24 h. Removal of the solvent
and recrystallization of the precipitate from EtOH gave the desired compound.
Ethyl 2-(3-chloroquinoxalin-2-yl)-5-oxo-3-(m-tolylamino)-2,5-dihydroisoxazole-4-carboxylate (2a).
Yield 110 mg (68%). Yellow crystals, mp 174-176°C. FT-IR spectrum, , cm-1: 3291 (NH), 2981, 1777, 1678,
1616, 1604, 1584, 1487, 1291, 1102, 963, 798. 1H NMR spectrum, δ, ppm (J, Hz): 1.46 (3H, t, J = 6.9, CH2CH3);
2.02 (3H, s, ArCH3); 4.47 (2H, q, J = 6.9, CH2CH3); 6.57 (1H, d, J = 6.6, H Ar); 6.78-6.83 (2H, m, H Ar); 6.93
(1H, s, H Ar); 7.72-7.86 (3H, m, H Ar); 7.93 (1H, d, J = 7.8, H Ar); 9.81 (1H, s, NH, exchanged by D2O
addition). 13C NMR spectrum, δ, ppm: 14.5; 20.8; 60.9; 120.1; 123.6; 127.5; 128.1; 128.8; 129.1; 131.2; 131.5;
132.6; 135.4; 139.0; 139.5; 141.6; 142.7; 144.5; 164.4; 165.4; 166.0. Mass spectrum, m/z (Irel, %): 426 [M+2]+
(4), 424 [M]+ (12), 390 (11), 380 (62), 334 (94), 305 (18), 271 (25), 256 (32), 230 (100), 158 (80), 102 (60), 91
(94), 65 (40), 44 (20). Found, %: C 59.47; H 3.98; N 13.22. C21H17ClN4O4. Calculated, %: C 59.37; H 4.03;
N 13.19.
932

Ethyl 3-(4-bromophenylamino)-2-(3-chloroquinoxalin-2-yl)-5-oxo-2,5-dihydroisoxazole-4-carboxy-
late (2b). Yield 133 mg (71%). White crystals, mp 170-172°C. FT-IR spectrum, , cm-1: 3290 (NH), 3090, 2987,
1778, 1660, 1621, 1485, 1296, 794, 762. 1H NMR spectrum, δ, ppm (J, Hz): 1.46 (3H, t, J = 7.2, CH2CH3); 4.47
(2H, q, J = 7.2, CH2CH3); 7.00 (2H, d, J = 8.7, H Ar); 7.12 (2H, d, J = 8.7, H Ar); 7.75-7.89 (3H, m, H Ar);
7.99 (1H, d, J = 8.7, H Ar); 9.86 (1H, s, NH, exchanged by D2O addition). 13C NMR spectrum, δ, ppm: 14.5;
61.2; 120.0; 124.0; 124.2; 128.3; 128.6; 131.5; 132.1; 132.4; 132.9; 134.8; 138.9; 141.7; 142.4; 144.1; 165.3;
165.7. Mass spectrum, m/z (Irel, %): 492 [M+4]+ (1), 490 [M+2]+ (4), 488 [M]+ (3), 446 [M+2-CO2]+ (27), 444
[M-CO2]+ (22), 319 (92), 294 (24), 224 (20), 222 (20), 163 (29), 129 (20), 103 (100), 90 (29), 76 (43), 63 (19), 45
(28). Found, %: C 49.15; H 2.71; N 11.51. C20H14BrClN4O4. Calculated, %: C 49.05; H 2.88; N 11.44.
Ethyl 2-(3-chloroquinoxalin-2-yl)-3-(4-nitrophenylamino)-5-oxo-2,5-dihydroisoxazole-4-carboxy-
late (2c). Yield 107 mg (62%). Yellow crystals, mp 178-180°C. FT-IR spectrum, , cm-1: 3227, 2935, 1782,
1673, 1626, 1588, 1345, 1298, 960. 1H NMR spectrum, δ, ppm (J, Hz): 1.47 (3H, t, J = 7.2, CH2CH3); 4.49 (2H,
q, J = 7.2, CH2CH3); 7.30 (2H, d, J = 9.0, H Ar); 7.76–7.86 (3H, m, H Ar); 7.94 (2H, d, J = 9.0, H Ar); 8.00
(1H, d, J = 8.4, H Ar); 10.28 (1H, s, NH, exchanged by D2O addition). 13C NMR spectrum, δ, ppm: 14.4; 61.6;
121.1; 121.2; 124.9; 125.1; 128.5; 131.8; 133.1; 138.7; 141.5; 141.8; 142.4; 143.7; 144.7; 163.6; 165.0; 165.1.
Mass spectrum, m/z (Irel, %): 457 [M+2]+ (2), 455 [M]+ (6), 411 [M-CO2]+ (25), 380 (14), 365 (10), 334 (22),
319 (32), 293 (63), 256 (88), 247 (100), 189 (55), 171 (65), 102 (84), 90 (60), 76 (68), 63 (66), 44 (58). Found,
%: C 52.88; H 3.01; N 15.22. C20H14ClN5O6. Calculated, %: C 52.70; H 3.10; N 15.36.
Ethyl 2-(arylamino)-4-chloroimidazo[1,2-a]quinoxaline-1-carboxylates 3a–c (General Method). The
isoxazolone 2a–c (0.24 mmol) was refluxed in THF (20 ml) with Et3N (0.5 ml, 0.36 g, 3.56 mmol) for 6 h. The
solvent was removed under reduced pressure to give a yellow oil, which was crystallized from EtOH.
Ethyl 4-chloro-2-(m-tolylamino)imidazo[1,2-a]quinoxaline-1-carboxylate (3a). Yield 64 mg (71%).
Yellow needles, mp 154-155°C. FT-IR spectrum, , cm-1: 3410, 3131, 2983, 1705, 1606, 1573, 1495, 1457, 756.
1H NMR spectrum, δ, ppm (J, Hz): 1.54 (3H, t, J = 7.2, CH2CH3); 2.41 (3H, s, ArCH3); 4.57 (2H, q, J = 7.2,
CH2CH3); 6.89 (1H, d, J = 7.5, H Ar); 7.26-7.31 (1H, m, H Ar); 7.55 (1H, s, H Ar); 7.58-7.68 (3H, m, H Ar);
8.04 (1H, dd, J = 9.0, J = 1.8, H Ar); 8.55 (1H, s, NH, exchanged by D2O addition); 8.64 (1H, d, J = 8.4, H Ar).
13C NMR spectrum, δ, ppm: 14.5; 21.7; 61.6; 103.8; 115.2; 118.8; 118.9; 119.3; 123.2; 126.9; 127.6; 128.5;
129.1; 129.8; 136.1; 139.0; 139.8; 141.6; 154.7; 160.7. Mass spectrum, m/z (Irel, %): 382 [M+2]+ (21), 380 [M]+
(80), 337 (10), 336 (42), 335 (33), 334 (100), 305 (20), 271 (18), 102 (40), 91 (26), 77 (12), 65 (18). Found, %:
C 63.25; H 4.39; N 14.62. C20H17ClN4O2. Calculated, %: C 63.08; H 4.50; N 14.71.
Ethyl 2-(4-bromophenylamino)-4-chloroimidazo[1,2-a]quinoxaline-1-carboxylate (3b). Yield 69 mg
1
(76%). Pale-yellow solid, mp 180-182°C. FT-IR spectrum, , cm : 3404, 3064, 2975, 1799, 1695, 1647, 1594,
1492, 1455, 1178, 764. 1H NMR spectrum, δ, ppm (J, Hz): 1.07 (3H, t, J = 7.2, CH2CH3); 4.04 (2H, q, J = 7.2,
CH2CH3); 7.48 (2H, d, J = 8.4, H Ar); 7.47-7.62 (1H, m, H Ar); 7.78 (2H, d, J = 8.4, H Ar); 8.00 (1H, d,
J = 8.4, H Ar); 8.11 (1H, d, J = 8.4, H Ar); 8.13 (1H, s, NH, exchanged by D2O addition); 8.64 (1H, d, J = 7.5,
H Ar). 13C NMR spectrum, δ, ppm: 14.0; 60.7; 119.3; 119.7; 127.1; 128.3; 128.5; 128.6; 129.2; 129.9; 132.1;
132.6; 138.4; 138.8; 153.3; 159.9; 164.6. Mass spectrum, m/z (Irel, %): 448 [M+4]+ (10), 446 [M+2]+ (40), 444
[M]+ (32), 319 (100), 291 (24), 257 (22), 128 (22), 102 (86), 90 (29), 75 (36), 63 (14), 50 (16). Found, %:
C 51.29; H 3.01; N 12.66. C19H14BrClN4O2. Calculated, %: C 51.20; H 3.17; N 12.57.
Ethyl 4-chloro-2-(4-nitrophenylamino)imidazo[1,2-a]quinoxaline-1-carboxylate (3c). Yield 63 mg
(70%). Pale-yellow solid, mp 201°C (decomp.). FT-IR spectrum, , cm-1: 3392, 2929, 1677, 1604, 1575, 1506,
1329, 1264, 1187, 1110, 750. 1H NMR spectrum, δ, ppm (J, Hz): 1.53 (3H, t, J = 7.2, CH2CH3); 4.62 (2H, q, J =
7.2, CH2CH3); 7.61-7.69 (2H, m, H Ar); 7.96 (2H, d, J = 8.7, H Ar); 8.10 (1H, d, J = 7.0, H Ar); 8.30 (2H, d,
J = 8.7, H Ar); 8.66 (1H, d, J = 7.5, H Ar); 9.12 (1H, s, NH, exchanged by D2O addition). 13C NMR spectrum,
δ, ppm: 14.5; 62.2; 105.1; 117.2; 119.2; 124.9; 125.4; 125.6; 127.5; 128.3; 128.8; 130.0; 136.3; 141.9; 145.7;
153.1; 160.6. Mass spectrum, m/z (Irel, %): 413 [M+2]+ (39), 412 [M+1]+ (36), 411 [M]+ (100), 365 (34), 319
(78), 291 (24), 256 (10), 163 (10), 102 (30), 76 (13). Found, %: C 55.52; H 3.31; N 17.18. C19H14ClN5O4.
Calculated, %: C 55.42; H 3.43; N 17.01.
933

Diethyl 2,11-bis(m-tolylamino)diimidazo[1,2-a:2',1'-c]quinoxaline-3,10-dicarboxylate (4). Isoxazo-
lone 1a [16] (100 mg, 0.38 mmol) and 2,3-dichloroquinoxaline (38 mg, 0.19 mmol) were refluxed in EtOH
(20 ml) for 48 h. Compound 4 precipitated out during this time as yellow crystals (11 mg, 10%), mp 156°C. FT-
1
IR spectrum, , cm-1: 3408, 2971, 2922, 1689, 1647, 1605, 1471, 1432, 1381, 1079, 764. H NMR spectrum,
δ, ppm (J, Hz): 1.38 (6H, t, J = 6.9, 2CH2CH3); 2.35 (6H, s, 2ArCH3); 4.45 (4H, q, J = 6.9, 2CH2CH3); 6.84
(2H, d, J = 8.4, H Ar); 7.20-7.58 (6H, m, H Ar); 7.77 (2H, s, H Ar); 8.21 (2H, d, J = 9.0, H Ar); 8.73 (2H, s,
2NH, exchanged by D2O addition). 13C NMR spectrum, δ, ppm: 14.7; 21.7; 61.3; 102.0; 116.1; 119.3; 121.4;
123.0; 125.1; 126.1; 129.2; 137.1; 138.5; 140.7; 155.3; 160.6. Found, %: C 68.22; H 5.49; N 14.88. C32H30N6O4.
Calculated, %: C 68.31; H 5.37; N 14.94.
The filtrate was concentrated by removal of ethanol to give a yellow solid (45 mg, 55%) identified as
compound 2a by its spectral data.
We are grateful to Urmia University for financial support.
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