Isocyanide-based three-component synthesis of pyrano-pyrido-quinoxalines

Article abstract of DOI:10.1002/hlca.201100019

Pyrano-pyrido-quinoxaline derivatives were synthesized in good yields by a three-component reaction of isocyanides, dialkyl acetylenedicarboxylates, and pyrido[1,2-a]quinoxaline-triones in DMF at 100°. Copyright

Full text of DOI:10.1002/hlca.201100019

Helvetica Chimica Acta – Vol. 94 (2011)
1527
Isocyanide-Based Three-Component Synthesis of Pyrano-pyrido-quinoxalines
by Roya Akbarzadeh, Tayebeh Amanpour, Peiman Mirzaei, and Ayoob Bazgir*
Department of Chemistry, Shahid Beheshti University, G. C. Tehran, 1983963113, Iran
(e-mail: a_bazgir@sbu.ac.ir)
Pyrano-pyrido-quinoxaline derivatives were synthesized in good yields by a three-component
reaction of isocyanides, dialkyl acetylenedicarboxylates, and pyrido[1,2-a]quinoxaline-triones in DMF at
1008.
Introduction. – Within the past decade, the resurgence of interest in multi-
component reactions (MCRs) has been driven, not only due to their convergent nature,
superior atom economy, and straightforward experimental procedures, but also
because of their value to the pharmaceutical industry for construction of low-
molecular-weight compound libraries through combinatorial strategies and parallel
synthesis [1 – 3]. Isocyanide-based multicomponent reactions (IMCRs) are particularly
interesting as they are more versatile and diverse than other MCRs [4][5]. The great
potential of isocyanides for the development of multicomponent reactions lies in the
diversity of bond forming processes available, functional-group tolerance, and the high
levels of chemo-, regio-, and stereoselectivity often observed. Moreover, there is
virtually no restriction on the nature of the nucleophiles and electrophiles in IMCRs.
MCRs involving isocyanides have emerged as valuable tools for the preparation of
structurally diverse chemical libraries of drug-like heterocyclic compounds [6 – 12].
It has been shown that isocyanides add to activated alkynes to generate zwitterionic
species, which have been captured by CH acids to produce various heterocycles [13 –
24]. Although three-component reaction of isocyanide, activated alkynes, and CH
acid has been applied to the synthesis of various heterocycles, to the best of our
knowledge, this synthetic strategy has not been applied to the synthesis of substituted
pyrano-pyrido-quinoxalines.
Quinoxaline and its derivatives are important heterocyclic compounds with wide
applications in medicinal chemistry, as antidiabetic, anticancer, antibacterial, antiviral,
and antifungal agents [25 – 28]. Quinoxalines play an important role as a basic skeleton
for the design of a number of antibiotics, such as echinomycin, actinomycin, and
leromycin, compounds with reported inhibition of the growth of Gram-positive
bacteria and activity against various tumors [29][30]. A number of fused (or
substituted) quinoxalines, I – III, have been demonstrated to possess antidepressant,
excitatory amino acid antagonistic, and antiglaucoma activities [31 – 33], respectively.
Imidazo-quinoxaline IV [34] and isoindolo-quinoxalies V [35] have turned out to be a
highly selective and potent inhibitor of IKK-2, and to exhibit antiproliferative activity,
respectively (Fig.).
ꢀ 2011 Verlag Helvetica Chimica Acta AG, Zꢁrich

1528
Helvetica Chimica Acta – Vol. 94 (2011)
Figure. Structures of some quinoxalines with biological activities
As continuation of our studies of isocyanide-based multicomponent reactions [36 –
38] and synthesis of biologically active heterocyclic compounds [39 – 43], herein, we
report an efficient isocyanide-based three-component reaction for the synthesis of
pyrano-pyrido-quinoxaline.
Results and Discussion. – The three-component condensation reactions of
pyrido[1,2-a]quinoxaline-4-carboxylate 1 with dialkyl acetylenedicarboxylates 2 in
the presence of isocyanides 3 proceeded rapidly in DMF at 1008 and were complete
after 24 h. Corresponding pyrano[2’,3’:4,5]pyrido[1,2-a]quinoxalines 4 were synthe-
sized via the formation of three new bonds by a [CCO þ CC þ C] condensation strategy
in good yields (Scheme 1).
Scheme 1. Synthesis of Pyrano-pyrido-quinoxaline 4

Helvetica Chimica Acta – Vol. 94 (2011)
1529
The structures of the isolated products 4a – 4f were deduced from their elemental
analyses, IR, and 1H- and 13C-NMR spectra. The nature of these compounds as 1:1:1
adducts was apparent from their mass spectra, which displayed, in each case, the
molecular-ion peak at appropriate m/z value.
The mass spectrum of 4a showed the molecular-ion peak at m/z 537. The IR
spectrum of 4a exhibited absorption bands due to C¼O groups at 1738, 1706, 1700,
1650, and 1622 cmꢀ1, and a broad absorption band for the NH groups was observed at
1
3338 and 3325 cmꢀ1. The H-NMR spectrum of 4a consisted of multiplets for the
cyclohexyl rings (d(H) 1.28 – 2.07) and the HꢀCꢀN resonance (d(H) 3.40), four sharp
singlets for the three MeO groups (d(H) 3.48, 3.57 and 3.86), and an allylic CH signal
(d(H) 4.64). A broad resonance (d(H) 12.09) was observed for the amide NH group,
along with a doublet (d(H) 9.21, J ¼ 8.8) for the NH of isocyanide moiety. The NH of
isocyanide moiety at d(H) 9.21 was strongly deshielded as a result of extensive
intramolecular H-bonding as shown in Scheme 1. The aromatic H-atoms give rise to
characteristic signals in the aromatic region of the spectrum. Due to the very low
solubility of product 4a, we were unable to obtain the 13C-NMR spectrum.
Although the mechanism of the reaction has not yet been established experimen-
tally, a proposal is presented in Scheme 2. The 1:1 zwitterionic ionic intermediate 5,
formed from the isocyanide and the acetylenic ester, is protonated by 1 to furnish
intermediate 6, which is attacked by the anion of the CH-acidic 7 in a Michael fashion to
produce ketenimine 8. The latter then can undergo cyclization under the reaction
conditions to afford the pyrano-pyrido-quinoxalines 4 (Scheme 2) [20 – 24].
Scheme 2. Proposed Mechanism
In conclusion, an efficient, atom-economical, and simple method for the prepara-
tion of pyrano-pyrido-quinoxalines of potential synthetic and biological interest is
reported. The method is performed under neutral conditions, and the starting material
can be used without any activation or modification. Moreover, it is worth noting that
two CꢀC and one CꢀO bonds were formed with concomitant creation of a fused
pyrano-pyrido-quinoxalines ring in this three-component process.

1530
Helvetica Chimica Acta – Vol. 94 (2011)
Experimental Part
General. The chemicals were obtained from Fluka and Merck, and were used without purification.
Pyrido[1,2-a]quinoxalines 1 were prepared according to a literature procedure [44]. M.p.: Electrothermal
9100 apparatus; uncorrected. IR Spectra: BOMEM MB-series FT-IR apparatus; in cmꢀ1 1H-NMR
.
Spectra: BRUKER DRX-300 AVANCE spectrometer recorded at 300.13 MHz; in (D6)DMSO; d in ppm
rel. to Me4Si (¼0 ppm), J in Hz. EI-MS (70 eV): FINNIGAN-MAT 8430 mass spectrometer; in m/z.
Elemental analyses: Heraeus CHN-O-Rapid analyzer.
General Procedure for the Preparation of Compounds 4a – 4f. To a magnetically stirred soln. of 1
(1 mmol) and 2 (1 mmol) in DMF (4 ml) was added, dropwise, a soln. of 3 (1 mmol) in DMF (2 ml) at r.t.
over 10 min. The mixture was stirred for 24 h at 1008 (as indicated by TLC). Then, the mixture was
filtered off and washed with EtOH (10 ml) to afford the pure product 4.
Trimethyl 9-(Cyclohexylamino)-6,12-dihydro-6,12-dioxo-5H,11H-pyrano[2’,3’:4,5]pyrido[1,2-a]qui-
noxaline-7,10,11-tricarboxylate (4a). Yield 82%. Yellow powder. M.p. 155 – 1578. IR (KBr): 3338, 3325
1
(NH), 1738, 1706, 1700, 1650, 1622 (C¼O). H-NMR: 1.28 – 2.07 (m, 5 CH2 of cyclohexyl); 3.40 (m,
CHꢀN); 3.48 (s, MeO); 3.57 (s, MeO); 3.86 (s, MeO); 4.64 (s, CH); 7.15 – 7.39 (m, 3 arom. H); 8.54 (br. s,
1 arom. H); 9.21 (d, J ¼ 8.8, NH); 12.09 (s, NH). EI-MS: 537 (Mþ). Anal. calc. for C27H27N3O9 (537.52): C
60.33, H 5.06, N 7.82; found: C 60.23, H 5.13, N 7.75.
Trimethyl 9-[(2,6-Dimethylphenyl)amino]-6,12-dihydro-6,12-dioxo-5H,11H-pyrano[2’,3’:4,5]pyri-
do[1,2-a]quinoxaline-7,10,11-tricarboxylate (4b). Yield 78%. Yellow powder. M.p. 179 – 1818. IR
1
(KBr): 3350, 3314 (NH), 1750, 1740, 1682, 1664 (C¼O). H-NMR: 2.10 (br. s, 2 Me); 3.55 (s, MeO);
3.67 (br. s, 2 MeO); 4.70 (s, CH); 6.88 – 7.62 (m, 6 arom. H); 9.10 (br. s, 1 arom. H); 9.68 (br. s, NH); 11.93
(br. s, NH). EI-MS: 559 (Mþ). Anal. calc. for C29H25N3O9 (559.52): C 62.25, H 4.50, N 7.51; found: C
62.13, H 4.42, N 7.43.
10,11-Diethyl 7-Methyl 9-(Cyclohexylamino)-6,12-dihydro-6,12-dioxo-5H,11H-pyrano[2’,3’:4,5]pyr-
ido[1,2-a]quinoxaline-7,10,11-tricarboxylate (4c). Yield 75%. Cream powder. M.p. 195 – 1978. IR (KBr):
3385, 3335 (NH), 1727, 1706, 1678, 1664, 1620 (C¼O). 1H-NMR: 1.14 (t, J ¼ 8.6, Me); 1.22 (t, J ¼ 8.1, Me);
1.23 – 1.88 (m, 5 CH2 of cyclohexyl); 3.46 (m, CHꢀN); 3.86 (s, MeO); 4.02 – 4.23 (m, 2 CH2O); 4.62 (s,
CH); 7.16 – 7.40 (m, 3 arom. H); 8.55 (d, J ¼ 7.2, 1 arom. H); 9.19 (d, J ¼ 8.9, NH); 12.08 (s, NH). EI-MS:
565 (Mþ). Anal. calc. for C29H31N3O9 (565.57): C 61.59, H 5.52, N 7.43; found: C 61.65, H 5.46, N 7.57.
10,11-Diethyl 7-Methyl 9-[(2,6-Dimethylphenyl)amino]-6,12-dihydro-6,12-dioxo-5H,11H-pyra-
no[2’,3’:4,5]pyrido[1,2-a]quinoxaline-7,10,11-tricarboxylate (4d). Yield 74%. Cream powder. M.p. 176 –
1
1788. IR (KBr): 3433, 3343 (NH), 1742, 1730, 1702, 1672 (C¼O). H-NMR: 1.17 (t, J ¼ 7.1, Me); 1.29
(t, J ¼ 8.4, Me); 2.10 (s, Me); 2.20 (s, Me); 3.15 (s, MeO); 4.04 – 4.26 (m, 2 CH2O); 4.71 (s, CH); 7.11 – 7.38
(m, 6 arom. H); 9.16 (d, J ¼ 9.0, 1 arom. H); 9.80 (br. s, NH); 11.98 (br. s, NH). EI-MS: 587 (Mþ). Anal.
calc. for C31H29N3O9 (587.58): C 63.37, H 4.97, N 7.15; found: C 63.30, H 4.92, N 7.06.
7-Ethyl 10,11-Dimethyl 9-(Cyclohexylamino)-6,12-dihydro-6,12-dioxo-5H,11H-pyrano[2’,3’:4,5]pyr-
ido[1,2-a]quinoxaline-7,10,11-tricarboxylate (4e). Yield 80%. Yellow powder. M.p. 209 – 2108. IR (KBr):
3440, 3385 (NH), 1735, 1690, 1681 (C¼O). 1H-NMR: 1.20 – 1.87 (m, 5 CH2 of cyclohexyl, Me); 3.48 (br. s,
CHꢀN); 3.58 (s, MeO); 3.73 (s, MeO); 4.34 – 4.36 (m, CH2O); 4.64 (s, CH); 7.17 – 7.68 (m, 3 arom. H);
8.54 (d, J ¼ 8.3, 1 arom. H); 9.20 (d, J ¼ 8.8, NH); 12.09 (s, NH). EI-MS: 551 (Mþ). Anal. calc. for
C28H29N3O9 (551.54): C 60.97, H 5.30, N 7.62; found: C 60.88, H 5.21, N 7.67.
Triethyl 9-[(2,6-Dimethylphenyl)amino]-6,12-dihydro-6,12-dioxo-5H,11H-pyrano[2’,3’:4,5]pyri-
do[1,2-a]quinoxaline-7,10,11-tricarboxylate (4f). Yield 76%. Yellow powder. M.p. 124 – 1268. IR
1
(KBr): 3337, 3289 (NH), 1735, 1700, 1677, 1650 (C¼O). H-NMR: 1.12 – 1.28 (m, 3 Me); 2.07 (s, Me);
2.19 (s, Me); 4.06 – 4.38 (m, 3 CH2O); 4.70 (s, CH); 6.91 – 7.35 (m, 6 arom. H); 9.16 (d, J ¼ 7.5, 1 arom. H);
9.77 (d, J ¼ 9.7 NH); 11.97 (br. s, NH). EI-MS: 601 (Mþ). Anal. calc. for C32H31N3O9 (601.60): C 63.89, H
5.19, N 6.98; found: C 63.95, H 5.11, N 7.07.
We gratefully acknowledge financial support from the Research Council of Shahid Beheshti
University.

Helvetica Chimica Acta – Vol. 94 (2011)
1531
REFERENCES
[1] L. F. Tietze, A. Modi, Med. Res. Rev. 2000, 20, 304.
[2] A. Dçmling, I. Ugi, Angew. Chem., Int. Ed. 2000, 39, 3168.
[3] J. Zhu, Eur. J. Org. Chem. 2003, 1133.
[4] P. Hoffmann, G. Gokel, D. Marquarding, I. Ugi, in ꢂIsonitrile Chemistryꢃ, Ed. I. Ugi, Academic, New
York, 1971.
[5] A. Dçmling, Chem. Rev. 2006, 106, 17.
[6] I. Ugi, B. Werner, A. Dçmling, Molecules 2003, 8, 53.
[7] C. Hulme, V. Gore, Curr. Med. Chem. 2003, 10, 51.
[8] J. Li, Y. Liu, C. Li, X. Jia, Tetrahedron Lett. 2009, 50, 6502.
[9] M. M. Heravi, B. Baghernejad, H. A. Oskooie, Tetrahedron Lett. 2009, 50, 767.
[10] A. Shaabani, A. Maleki, H. Mofakham, H. R. Khavasi, J. Comb. Chem. 2008, 10, 323.
[11] S. Fujiwara, Y. Asanuma, T. Shin-Ike, N. Kambe, J. Org. Chem. 2007, 72, 8087.
[12] A. Shaabani, E. Soleimani, A. Maleki, Tetrahedron Lett. 2006, 47, 3031.
[13] I. Yavari, M. Esnaashari, Synthesis 2005, 1049.
[14] I. Yavari, M. Adib, M. H. Sayahi, J. Chem. Soc., Perkin Trans. 1 2002, 2343.
[15] I. Yavari, L. Moradi, Helv. Chim. Acta 2006, 89, 1942.
[16] V. Nair, A. U. Vinod, R. Ramesh, R. S. Menon, L. Varma, S. Mathew, A. Chiaroni, Heterocycles
2002, 58, 147.
[17] M. B. Teimouri, F. Mansouri, J. Comb. Chem. 2008, 10, 507.
[18] M. B. Teimouri, H. R. Khavasi, Tetrahedron 2007, 63, 10269.
[19] M. B. Teimouri, R. Bazhrang, V. Eslamimanesh, A. Nouri, Tetrahedron 2006, 62, 3016.
[20] A. Shaabani, E. Soleimani, H. R. Khavasi, R.-D. Hoffmann, U. C. Rodewald, R. Pçttgen,
Tetrahedron Lett. 2006, 47, 5493.
[21] A. Shaabani, E. Soleimani, A. Sarvary, A. H. Rezayan, Bioorg. Med. Chem. Lett. 2008, 18,
3968.
[22] A. Shaabani, A. Sarvary, A. H. Rezayan, S. Keshipour, Tetrahedron 2009, 65, 3492.
[23] M. Adib, E. Sheikhi, A. Kavoosi, H. R. Bijanzadeh, Tetrahedron 2010, 66, 9263.
[24] S. Asghari, L. Mohammadi, Tetrahedron Lett. 2006, 47, 4297.
[25] D. Gupta, N. N. Ghosh, R. Chandra, Bioorg. Med. Chem. Lett. 2005, 15, 1019.
[26] M. A. Naylor, M. A. Stephen, J. Nolan, B. Sutton, J. H. Tocher, E. M. Fielden, G. E. Adams, I.
Strafford, Anticancer Drug Des. 1993, 8, 439.
[27] G. W. H. Cheeseman, R. F. Cookson, in ꢂThe Chemistry of Heterocyclic Compoundsꢃ, 2nd edn., Eds.
A. Weissberger, E. C. Taylor, Wiley, New York, NY, 1979, Vol. 35, pp. 1 – 27.
[28] A. E. Porter, in ꢂComprehensive Heterocyclic Chemistryꢃ, Eds. A. R. Katrizky, C. W. Rees,
Pergamon, New York, NY, 1984, Vol. 3, p. 157.
[29] C. Bailly, S. Echepare, F. Gago, M. Waring, Anticancer Drug Des. 1999, 14, 291.
[30] S. A. Raw, C. D. Wilfred, R. J. K. Taylor, Chem. Commun. 2003, 2286.
[31] B. K. Trivedi, R. F. Bruns, J. Med. Chem. 1988, 31, 1011.
[32] L. A. McQuaid, E. C. R. Smith, K. K. South, C. H. Mitch, D. D. Schoepp, R. A. True, D. O.
Calligaro, P. J. OꢃMalley, D. Lodge, P. L. Ornstein, J. Med. Chem. 1992, 35, 3319.
[33] J. J. Li, J. Org. Chem. 1999, 64, 8425.
[34] J. R. Burke, M. A. Pattoli, K. R. Gregor, P. J. Brassil, J. F. MacMaster, K. W. McIntyre, X. Yang, V. S.
Iotzova, W. Clarke, J. Strnad, Y. Qiu, F. C. Zusi, J. Biol. Chem. 2003, 278, 1450.
[35] P. Diana, A. Martorana, P. Barraja, A. Montalbano, G. Dattolo, G. Cirrincione, F. DallꢃAcqua, A.
Salvador, D. Vedaldi, G. Basso, G. Viola, J. Med. Chem. 2008, 51, 2387.
[36] R. Akbarzadeh, P. Mirzaei, A. Bazgir, J. Organomet. Chem. 2010, 695, 2320.
[37] R. Akbarzadeh, G. Imani Shakibaei, A. Bazgir, Monatsh. Chem. 2010, 141, 1077.
[38] A. Shaabani, M. B. Teimouri, A. Bazgir, H. R. Bijanzadeh, Mol. Diversity 2003, 6, 199.
[39] R. Ghahremanzadeh, S. Ahadi, G. Imani Shakibaei, A. Bazgir, Tetrahedron Lett. 2010, 51,
499.
[40] R. Ghahremanzadeh, G. Imani Shakibaei, S. Ahadi, A. Bazgir, J. Comb. Chem. 2010, 12, 191.

1532
Helvetica Chimica Acta – Vol. 94 (2011)
[41] S. Ahadi, R. Ghahremanzadeh, P. Mirzaei, A. Bazgir, Tetrahedron 2009, 65, 9316.
[42] K. Jadidi, R. Ghahremanzadeh, A. Bazgir, J. Comb. Chem. 2009, 11, 341.
[43] R. Ghahremanzadeh, M. Sayyafi, S. Ahadi, A. Bazgir, J. Comb. Chem. 2009, 11, 393.
[44] I. Yavari, S. Souri, M. Sirouspour, M. J. Bayat, Synlett 2009, 1921.
Received January 13, 2011