Efficient synthesis of dialkyl (2Z)-2-[(E)-1-aryl-2-(3-arylquinoxalin-2-yl) ethenyl]but-2-enedioates

Article abstract of DOI:10.1002/hlca.200690253

The reaction of dialkyl acetylenedicarboxylates 4 with 1-aryl-2-[(3- arylquinoxalin-2(1H)-ylidene)-ethanones 3 in the presence of Ph₃P leads to dialkyl (2Z)-2-[(E)-1-aryl-2-(3-arylquinoxalin-2-yl)ethenyl]-but-2- enedioates 1 in good yields.

Full text of DOI:10.1002/hlca.200690253

Helvetica Chimica Acta – Vol. 89 (2006)
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Efficient Synthesis of Dialkyl (2Z)-2-[(E)-1-Aryl-2-(3-arylquinoxalin-2-
yl)ethenyl]but-2-enedioates
by Issa Yavari*, Anvar Mirzaei, and Loghman Moradi
Chemistry Department, Tarbiat Modarres University, P. O. Box 14115-175, Tehran, Iran
(phone: +98-21-88006631; fax: +98-21-88006544; e-mail: yavarisa@modares.ac.ir)
The reaction of dialkyl acetylenedicarboxylates 4 with 1-aryl-2-[(3-arylquinoxalin-2(1H)-ylidene)-
ethanones 3 in the presence of Ph
A
but-2-enedioates 1 in good yields.
Introduction. – The quinoxaline ring system [1] is present in many natural and syn-
thetic products exhibiting antitumor activity [2]. Quinoxalines have also been used for
the synthesis of poly(phenylquinoxalines), which possess excellent thermal stabilities,
low dielectric constants, high glass-transition temperatures, and good mechanical prop-
erties [3]. New living polymerization of 1,2-di(isocyano)arenes via (quinoxalinyl)palla-
dium complexes have been reported [4]. The majority of quinoxaline derivatives are
prepared by the reaction of benzene-1,2-diamine or an equivalent reagent with a 1,2-
dicarbonyl compound [5][6].
As part of our current studies on the development of new routes in the synthesis of
heterocyclic systems [7], we now report a convenient one-pot synthesis of dialkyl (2Z)-
2-[(E)-1-aryl-2-(3-arylquinoxalin-2-yl)ethenyl]but-2-enedioates of type 1.
Results and Discussion. – Reaction of benzene-1,2-diamine with the corresponding
1,4-diarylbut-2-yne-1,4-dione 2 gave rise to the 1-aryl-2-[(3-arylquinoxalin-2(1H)-ylide-
ne)ethanones 3. The latter were then reacted with acetylenic esters of type 4 in the pres-
ence of Ph3P in refluxing toluene to afford the target compounds 1 in good yields
G
(Scheme 1). No products other than 1 were detected by NMR spectroscopy. The struc-
1
tures of 1a–1f were deduced by elemental analysis, MS, IR, H-NMR, and 13C-NMR
spectroscopy.
The 1H-NMR spectrum of, e.g., 1a exhibited two singlets at d(H) 3.68 and 3.82 due to
two MeO groups. The olefinic resonances were observed at d(H) 5.68 and 7.01, along
1
with characteristic multiplets for the aromatic H-atoms. The H-decoupled 13C-NMR
spectrum of 1a showed 24 distinct signals, in agreement with the proposed structure.
Unambiguous evidence for the proposed structure of 1a was finally obtained by sin-
gle-crystal X-ray-diffraction analysis. An ORTEP [8] diagram of 1a is shown in the Fig-
ure. For details of the structure determination and refinement, see the Exper. Part.
Mechanistically, it is conceivable that the reaction leading to 1 involves the initial
formation of a zwitterionic 1:1 intermediate 5 of Ph3P and the acetylenic compound
A
(Scheme 2) [9–11]. The intermediate 5 is then protonated by the NH-acidic 3 to afford
ꢀ 2006 Verlag Helvetica Chimica Acta AG, Zürich

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Helvetica Chimica Acta – Vol. 89 (2006)
Scheme 1
Figure. X-Ray crystal structure of 1a. ORTEP-III Plot [8]; arbitrary atom numbering.

Helvetica Chimica Acta – Vol. 89 (2006)
2827
Scheme 2
6. The latter might be attacked by the C-atom of the bidentate anion 7 to afford the
ylide 8, which undergoes an intramolecular Wittig reaction to yield the cyclobutene
derivative 9. Compound 1 would then result from electrocyclic ring opening of 9.
The advantage of the present procedure for the synthesis of the title compounds 1 is
that the reaction can be performed under neutral conditions by simply mixing the start-
ing materials.
Experimental Part
General. Benzene-1,2-diamine, Ph3P, and the dialkyl acetylenedicarboxylates 4 were obtained from
G
Fluka and used without further purification. M.p.: Electrothermal-9100 apparatus; uncorrected. IR Spec-
1
tra: Shimadzu IR-460 spectrometer; in cmÀ1. H- and 13C-NMR Spectra: Bruker DRX-500 AVANCE
instrument; in CDCl3 at 500.1 and 125.7MHz, resp.; d in ppm, J in Hz. EI-MS: Finnigan-MAT-8430
mass spectrometer, at 70 eV; in m/z. Elemental analyses: Heraeus CHN-O-Rapid analyzer.
General Procedure for the Preparation of Compounds 3. To a stirred soln. of benzene-1,2-diamine
(0.22 g, 2 mmol) in MeOH (10 ml) was added dropwise 2 (2 mmol) in MeOH, and the mixture was stirred
for 4 h. The solvent was removed under reduced pressure, and the residue was purified by column chro-
matography (CC) (SiO2; hexane/AcOEt 5 :1) to afford the pure title compounds.
1-Phenyl-2-(3-phenylquinoxalin-2(1H)-ylidene)ethanone (3a). Yield: 0.62 g (95%). Pale-yellow pow-
der. M.p. 75–778. IR (KBr): 3050 (NH), 1578 (C=O), 1528, 1278, 750. 1H-NMR: 6.50 (s, CH); 7.50–7.51
(m, 4 CH); 7.65–7.66 (m, 5 CH); 7.86–7.91 (m, 4 CH); 8.00 (d, 3J=7.5, CH); 15.94 (s, NH). 13C-NMR:
91.2 (CH); 119.7(CH); 126.0 (CH); 126.6 (2 CH); 128.3 (2 CH); 128.8 (2 CH); 128.9 (2 CH); 129.3 (CH);
129.8 (CH); 130.8 (CH); 130.9 (CH); 132.2 (C); 137.3 (C); 137.4 (C); 138.2 (C); 147.7 (C); 156.8 (C);
181.2 (C=O). EI-MS: 324 (6, M+), 247 (58), 219 (71), 218 (70), 105 (100), 77 (65), 76 (22). Anal. calc.
for C22
A
G
N
1-(4-Methylphenyl)-2-[3-(4-methylphenyl)quinoxalin-2(1H)-ylidene]ethanone (3b). Yield: 0.48 g
(70%). Pale-yellow powder. M.p. 80–828. IR (KBr): 3050 (NH), 1578 (C=O), 1528, 1278, 750. 1H-
NMR: 2.38, 2.47(2 s, 2 Me); 6.41 (s, CH); 7.25 (d, 3J=7.8, 2 CH); 7.36 (d, 3J=7.8, 2 CH); 7.39 (d,
3
3
3
3
3J=7.7, CH); 7.50 (t, J=7.2, CH); 7.51 (d, J=7.1, CH); 7.54 (t, J=7.4, CH); 7.66 (d, J=7.6, 2 CH);
7.71 (d, J=7.6, 2 CH); 15.90 (s, NH). 13C-NMR: 21.4, 22.7(2 Me); 90.9, 119.2, 125.6 (3 CH); 126.7(2
3
CH); 128.8 (2 CH); 129.2 (2 CH); 129.3 (CH); 129.4 (2 CH); 130.5 (CH); 131.8 (C); 133.3 (CH);
134.6, 135.7, 137.1, 139.9, 141.3, 147.4, 157.0 (7 C); 182.3 (C=O). EI-MS: 352 (8, M+), 260 (5), 232
(68), 220 (30), 160 (10), (100), 105 (87), 77 (80), 65 (10). Anal. calc. for C
H 5.72, N 7.95; found: C 81.86, H 7.68, N 8.01.
A
G
N

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Helvetica Chimica Acta – Vol. 89 (2006)
General Procedure for the Preparation of Compounds 1. To a stirred soln. of Ph3P (0.57g, 2.2 mmol)
A
and 3 (0.65 g, 2 mmol) in toluene (10 ml), compound 4 (0.31 g, 2.2 mmol) in toluene (2 ml) was added
dropwise, and the mixture was heated at reflux for 24 h. The solvent was removed under reduced pres-
sure, and the residue was separated by CC (SiO2; hexane/AcOEt 4 :1) to afford the pure title compounds.
Dimethyl (2Z)-2-[(E)-1-Phenyl-2-(3-phenylquinoxalin-2-yl)ethenyl]but-2-enedioate (1a). Yield: 0.80 g
1
(90%). Pale-brown powder. M.p. 126–1288. IR (KBr): 1726, 1724 (C=O); 1593; 1264; 1161; 757. H-
3
NMR: 3.68, 3.82 (2s, 2 MeO); 5.68 (s, CH); 6.97–6.98 (t, J=7.6, 2 CH); 7.01 (s, CH); 7.20–7.27 (m, 3
3
CH); 747–7.48 (m, 3 CH); 7.59–7.67 (m, 5 CH); 8.0 (d, J=8.2, CH). 13C-NMR: 52.0, 52.6 (2 MeO);
121.4 (CH); 127.8 (C); 128.2 (2 CH); 128.4 (2 CH); 129.0 (CH); 129.1 (CH); 129.3 (CH); 129.6 (2
CH); 129.8 (CH); 129.9 (2 CH); 130.3 (CH); 132.3 (CH); 135.5, 137.8, 140.6, 140.7, 142.3, 148.6 (6 C);
151.0, 154.1 (2 C=N); 165.5, 168.0 (2 C=O). EI-MS: 450 (9, M+), (3), 391 (8), 332 (34), 296 (86), 268
(28), 252 (83), 211 (84), 171 (100), 156 (42), 115 (18), 105 (14), 59 (85), 57 (87). Anal. calc. for C
O4 (450.49): C 74.65, H 4.92, N 6.22; found: C 74.72, H 4.98, N 6.29.
Diethyl (2Z)-2-[(E)-1-Phenyl-2-(3-phenylquinoxalin-2-yl)ethenyl]but-2-enedioate (1b). Yield: 0.70 g
A
G
ACHTREUNG
1
(75%). Pale-brown powder. M.p. 130–1328. IR (KBr): 1717, 1715 (C=O); 1591; 1261; 1168; 760. H-
NMR: 1.22 (t, 3J=7.2, Me); 1.26 (t, 3J=7.2, Me); 4.15 (q, 3J=7.2, CH2O); 4.27( q, 3J=7.2, CH2
O);
5.66 (s, CH); 6.99 (d, 3J=7.0, 2 CH); 7.12 (s, CH); 7.19–7.29 (m, 3 CH); 7.47–7.49 (m, 3 CH);
7.60–7.68 (m, 5 CH); 8.01 (d, 3J=8.2, CH). 13C-NMR: 13.9, 14.1 (2 Me); 60.9, 61.8 (2 CH2
O); 121.9
A
ACHTREUNG
AHCTREUNG
(CH); 127.7 (C); 128.2 (2 CH); 128.5 (2 CH); 129.0, 129.1, 129.3 (3 CH); 129.6 (2 CH); 129.8 (CH);
129.9 (2 CH); 130.3, 132.0 (2 CH); 135.7, 137.9, 140.7, 142.7, 148.8 (5 C); 150.8, 154.1 (2 C=N); 165.0,
167.6 (2 C=O). EI-MS: 478 (6, M+), 405 (30), 332 (19), 262 (16), 171 (64), 165 (31), 119 (100), 91 (22),
59 (30). Anal. calc. for C
A
G
N
Bis(1-Methylethyl) (2Z)-2-[(E)-1-Phenyl-2-(3-phenylquinoxalin-2-yl)ethenyl]but-2-enedioate (1c).
Yield: 0.68 g (70%). Pale-brown powder. M.p. 140–1428. IR (KBr): 1720, 1717 (C=O); 1593; 1268;
1097; 758. 1H-NMR: 1.29 (d, 3J=7.0, 2 Me); 1.31 (d, 3J=6.8, 2 Me); 5.13 (sept., 3J=6.8, CH); 5.28
(sept., 3J=7.0, CH); 5.74 (s, CH); 7.10–7.11 (d, 3J=7.1, 2 CH ); 7.24 (s, CH); 7.30–7.38 (m, 3 CH);
7.58–7.60 (m, 3 CH); 7.71–7.79 (m, 5 CH); 8.11 (d, 3J=8.2, CH). 13C-NMR: 21.4, 21.7(4 Me); 68.4,
69.6, 122.4 (3 CH); 127.6 (C); 128.1 (2 CH); 128.6 (2 CH); 128.9, 129.0, 129.3 (3 CH); 129.5 (2 CH);
129.7 (CH); 130.0 (2 CH); 130.2, 131.5 (2 CH); 135.9, 137.9, 140.6, 140.7, 143.0, 148.9 (6 C); 150.5,
154.1 (2 C=N); 164.4, 167.0 (2 C=O). EI-MS: 506 (7, M+), 463 (15), 419 (48), 322 (80), 268 (28), 252
(83), 211 (84), 171 (100), 156 (34), 115 (18), 105 (44), 59 (44), 57 (57). Anal. calc. for C32
(506.59): C 75.87, H 5.97, N 5.53; found: C 75.92, H 5.93, N 5.60.
Bis(1,1-Dimethylethyl) (2Z)-2-[(E)-1-Phenyl-2-(3-phenylquinoxalin-2-yl)ethenyl]but-2-enedioate
A
N2
A
ACHTREUNG
(1d). Yield: 0.72 g (72%). Pale-brown powder. M.p. 169–1718. IR (KBr): 1709, 1707 (C=O); 1594;
1273; 1135; 757. 1H-NMR: 1.40, 1.42 (2s, 2 tBu ); 5.57( s, CH); 7.0 (d, 3J=7.0, 2 CH); 7.12 (s, CH);
3
7.19–7.26 (m, 3 CH); 7.46–7.50 (m, 3 CH); 7.58–7.67 (m, 5 CH); 8.0 (d, J=8.2, CH). 13C-NMR: 27.8,
28.1 (2 Me3C); 81.0, 82.7(2 M e3C); 123.5 (CH); 127.5 (C); 128.1 (2 CH); 128.6 (2 CH); 129.0, 129.1,
R
129.2 (3 CH); 129.6 (2 CH); 129.7(CH); 130.1 (2 CH); 130.2, 131.0 (2 CH); 136.3, 138.0, 140.6, 140.7,
143.4, 149.2 (6 C); 150.0, 154.2 (2 C=N); 164.4, 166.6 (2 C=O). EI-MS: 534 (5, M+), 477 (10), 433
(27), 332 (39), 331 (30), 255 (5), 178 (3), 152 (3), 58 (100), 41 (28). Anal. calc. for C
C 76.38, H 6.41, N 5.24; found: C 76.45, H 6.32, N 6.48.
A
N2
G
N
Dimethyl (2Z)-2-{(E)-1-(4-Methylphenyl)-2-[3-(4-methylphenyl)quinoxalin-2-yl]ethenyl}but-2-ene-
dioate (1e). Yield: 0.56 (60%). Colorless powder. M.p. 126–1288. IR: 1722, 1720 (C=O); 1601; 1265;
3
1164; 755. 1H-NMR: 2.42, 2.54 (2s, 2 Me); 3.80, 3.94 (2s, 2 MeO); 5.80 (s, CH); 6.93 (d, J=7.7, 2 CH);
3
3
3
3
7.10 (d, J=7.7, 2 CH); 7.19 (s, CH); 7.37 (d, J=7.8, 2 CH); 7.60 (d, J=7.8, 2 CH); 7.72 (t, J=7.1,
CH); 7.77 (t, J=7.8, CH); 7.80 (d, J=8.0, CH); 8.10 (d, J=8.2, CH). 13C-NMR: 21.2, 21.4 (2 Me);
51.9, 52.6 (2 MeO); 121.2 (CH); 128.8 (2 CH); 128.9, 129.0 (2 CH); 129.1 (2 CH); 129.4 (C); 129.5 (2
CH); 129.8 (2 CH); 130.1 (CH); 132.3, 132.4, 134.9, 137.5, 139.3, 140.5 (6 C); 140.7, 142.2, 149.0 (3 C);
151.2, 154.0 (2 C=N); 165.5, 168.2 (2 C=O). EI-MS: 478 (5, M+), 420 (30), 419 (100), 359 (16), 243
3
3
3
(4), 165 (3), 119 (24), 91 (22), 59 (30). Anal. calc. for C
found: C 75.41, H 5.53, N 5.88.
A
N2
G
N
Diethyl
(2Z)-2-{(E)-1-(4-Methylphenyl)-2-[3-(4-methylphenyl)quinoxalin-2-yl]ethenyl}but-2-ene-
dioate (1f). Yield: 0.64 g (65%). Colorless powder. M.p. 119–1218. IR (KBr): 1714, 1712 (C=O); 1600;

Helvetica Chimica Acta – Vol. 89 (2006)
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1262; 1177; 755. 1H-NMR: 1.22 (t, 3J=7.2, Me); 1.28 (t, 3J=7.2, Me); 2.30, 2.43 (2s, 2 Me); 4.14 (q, 3J=7.2,
3
3
3
CH2
CH); 7.27 (d, J=7.8, 2 CH); 7.50 (d, J=7.8, 2 CH); 7.60 (t, J=7.2, CH); 7.65 (t, J=7.9, CH); 7.69
(d, 3J=8.1, CH); 8.0 (d, 3J=8.1, CH). 13C-NMR: 13.8, 14.1, 21.2, 21.4 (4 Me); 60.9, 61.8 (2 CH2
O);
O); 4.30 (q, J=7.2, CH2
U
3
3
3
3
121.7(CH); 128.8 (2 CH); 129.0, 129.1 (2 CH); 129.2 (2 CH); 129.4 (CH); 129.5 (2 CH); 129.9 (2 CH);
130.1, 132.1, 132.5 (3 CH); 135.1, 137.4, 139.3, 140.7, 140.9, 142.5, 149.2 (7 C); 151.1, 154.1 (2 C=N);
165.6, 167.9 (2 C=O). EI-MS: 506 (4, M+), 433 (21), 360 (19), 296 (46), 268 (31), 252 (53), 211 (74),
171 (100), 156 (42), 115 (18), 105 (14), 59 (54), 57 (65). Anal. calc. for C
5.97, N 5.53; found: C 75.62, H 5.88, N 5.59.
C
N2
T
U
mula,
a=11.741(3), b=7.224(2), c=26.500(8) Š, b=94.28(3); space group P21/c; Z=4, V=2241.4(11) Š3,
calc. =1.335 g cmÀ3
C
A
N2
A
D
;
R=0.0433 (for 3800 reflections), Rw =0.0850; À2ꢀhꢀ14; À9ꢀkꢀ9;
À33ꢀlꢀ33; MoKa radiation (l=0.71073 Š); T=293(2) K.
REFERENCES
[1] D. J. Brown, ꢁQuinoxalines: Supplement IIꢂ, John Wiley & Sons, New York, 2004.
[2] S. T. Hazeldine, L. Polin, J. Kushner, J. Paluch, K. White, M. Edelstein, E. Palomino, T. H. Corbett, J.
P. Horwitz, J. Med. Chem. 2001, 44, 1758; D. Gupta, N. Ghosh, R. Chandra, Bioorg. Med. Chem.
Lett. 2005, 15, 1019; S. T. Hazeldine, L. Polin, J. Kushner, K. White, T. H. Corbett, J. Biehl, J. P. Hor-
witz, Bioorg. Med. Chem. Lett. 2005, 13, 1069.
[3] J. Hedrick, R. Twieg, T. Matray, K. Carter, Macromolecules 1993, 26, 4833.
[4] Y. Ito, E. Ihara, M. Murakami, J. Am. Chem. Soc. 1990, 112, 6447.
[5] T. L. Gilchrist, ꢁHeterocyclic Chemistryꢂ, 2nd edn., J. Wiley & Sons, New York, 1992, pp. 272–276.
[6] E. C. Taylor, C. A. Maryanoff, J. S. Skotnickilc, J. Org. Chem. 1980, 45, 2513.
[7] I. Yavari, L. Moradi, Helv. Chim. Acta. 2006, 89, 1942; I. Yavari, H. Djahaniani, Tetrahedron Lett.
2006, 47, 1477; I. Yavari, L. Moradi, Tetrahedron Lett. 2006, 47, 1627; I. Yavari, A. R. Alborzi, B.
Mohtat, Dyes Pigments 2006, 68, 85; I. Yavari, H. Djahaniani, Tetrahedron Lett. 2006, 47, 7 491; I.
Yavari, H. Djahaniani, Tetrahedron Lett. 2005, 46, 7491; I. Yavari, H. Djahaniani, F. Nasiri, Synthesis
2004, 679; I. Yavari, A. Habibi, Synthesis 2004, 989; I. Yavari, F. Nasiri, H. Djahaniani, Mol. Divers.
2004, 8, 431; I. Yavari, I. A. Alizadeh, Synthesis 2004, 237; I. Yavari, F. Nasiri, L. Moradi, H. Djaha-
niani, Tetrahedron Lett. 2004, 45, 7099; I. Yavari, M. Adib, M. Esnaashari, Monatsh. Chem. 2001,
132, 1557; I. Yavari, M. Adib, J. Chem. Res., Synop. 2001, 543.
[8] A. M. N. Burnett, C. K. Johnson, ꢁOak Ridge National Laboratory Report ORNL-6895ꢂ, 1996.
[9] D. E. C. Cobridge, ꢁPhosphorus: An Outline of Chemistry, Biochemistry and Usesꢂ, 5th edn., Elsev-
ier, Amsterdam, 1995.
[10] O. I. Kolodiazhnyi, Russ. Chem. Rev. 1997, 66, 225
[11] V. Nair, C. Rajesh, A. U. Vinod, S. Bindu, A. R. Sreekanth, J. S. Mathess, L. Balagopal, Acc. Chem.
Res. 2003, 36, 899.
Received May 20, 2006
1
)
The crystallographic data of 1a have been deposited with the Cambridge Crystallographic Data Cen-
tre as supplementary publication number CCDC-299057. Copies of the data can be obtained, free of
charge, at http://www.ccdc.cam.ac.uk/data_request/cif.