A rapid synthesis of quinoxalines starting from ketones

Article abstract of DOI:10.1016/j.tetlet.2010.11.116

A fast and general synthesis of quinoxalines, performed in two stages or as a one-pot reaction, starting from ketones via their α-hydroxylimino ketone derivatives, and condensation of the latter with 1,2-diaminobenzene under microwave irradiation, is described.

Full text of DOI:10.1016/j.tetlet.2010.11.116

Tetrahedron Letters 52 (2011) 544–547
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Tetrahedron Letters
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A rapid synthesis of quinoxalines starting from ketones
⇑
K. Padmavathy, Gopalpur Nagendrappa , K. V. Geetha
Department of Medicinal Chemistry, Sri Ramachandra University, Porur, Chennai 600 116, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A fast and general synthesis of quinoxalines, performed in two stages or as a one-pot reaction, starting
Received 4 November 2010
Revised 20 November 2010
Accepted 23 November 2010
Available online 26 November 2010
from ketones via their
diaminobenzene under microwave irradiation, is described.
a-hydroxylimino ketone derivatives, and condensation of the latter with 1,2-
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
1,2-Diaminobenzene
Diketomonoxime
a-Hydroxylimino ketone
Microwave
Quinoxaline
1. Introduction
NH2
R1
4
R1
N
R1
RONO - ClSiMe3
Heterocycles containing the quinoxaline1 unit find numerous
applications. They show biological properties, such as anticancer,2
antiviral,3 antibacterial,4 anti-inflammatory,5 and kinase inhibitor6
activities. Quinoxalines are used as antibiotics,7 dyes,8 electron-
luminescent materials,9 semiconductors,10 pesticides,11 DNA
cleaving agents,12 corrosion inhibitors,13 and many others. Because
of their importance, a number of methods have been developed for
the synthesis of quinoxalines. The most common of them is the
condensation of 1,2-diaminobenzenes with 1,2-dicarbonyl com-
pounds14 under a variety of conditions, including the use of differ-
ent solvents and catalysts. Quinoxalines are also prepared by the
O
O
NH2
OR
MW
30 sec-12 min
R2
2a -j
NaNO2 - HCl
R2
R2
NOH
-15 oC, 45 min
N
N
1a - j
3a - i
CH3
R2
R1
NOH
CH3
1a, 2a, 3a :
C6H5
H
H
N
: p-Cl-C H
1b, 2b, 3b
1c, 2c, 3c
1d, 2d, 3d
6
4
5
:
2-furyl
H
:
CH3
CH3
CH3
C6H5
1e, 2e, 3e p-Cl-C H
:
6
4
reaction of 1,2-diaminobenzenes with, (a)
a
-hydroxy ketones,15
1f, 2f, 3f : p-F-C6H4
(b) epoxides,16 (c) -haloketones,17 (d) -tosyloxy ketones,18 (e)
a
a
_(CH2)6
_
1g, 2g, 3g :
a
-keto carboxylic acids,19 (f) oxalic acid,20 (g) diazenyl butenes,21
:
CH3
1h, 2h, 3h
CH3
and (e) hydroxyacetylenes.22 There are other synthetic strate-
gies23–25 that do not involve 1,2-diaminobenzenes. All these re-
ported procedures are multistep reactions that employ the not
1i, 2i, 3i
:
:
CO2Et
CH3
CH3
1j, 2j
CH3-CO
easily available two-carbon synthons like 1,2-diketones or
substituted ketones and environmentally undesirable solvents, re-
a-
Scheme 1. Synthesis of quinoxalines from ketones.
agents, and reaction conditions.
A recent report26 describes the direct reaction of 1,2-diamino-
benzenes with ketones in the presence of potassium hydroxide in
PEG-400, which, however, requires heating at 60 °C for as long as
60 h.
We considered using simple ketones as starting compounds for
quinoxaline synthesis via their a-hydroxylimino derivatives, which
can be easily prepared by our anhydrous method27 or the literature
procedure using concd HCl–NaNO2 combination.28 We found that
a-hydroxylimino ketones condense with 1,2-diaminobenzene in
very short times (in seconds in one method), when exposed to
microwaves (MWs). The two step reaction can be conducted in
two separate stages or in one-pot. The results are reported here.
⇑
Corresponding author at present address: Department of Chemistry, Jain
University, Bangalore 560 004, India. Tel.: +91 80 26670899.
E-mail address: gnagendrappa@gmail.com (G. Nagendrappa).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.11.116

K. Padmavathy et al. / Tetrahedron Letters 52 (2011) 544–547
545
Table 1
MW-assisted condensation of 1,2-diaminobenzene with
a
-hydroxylimino ketones
Reaction timed
Product
Yielde (%)
PEG-400b
Mp (Lit mp) °C
Neata (min)
PEG-400b (min)
AcOHc (s)
Neata
96
AcOHc
85
N
3a
6.5
5.0
40
90
79.0 (79–80)15b,32
N
N
Cl
3b
3c
3d
7
8
4
6
7
30
50
60
90
89
93
84
87
89
82
83
84
133.0 (134.0)18b
98.0 (99–100)18b
55.0 (55.0)14a,18b
N
N
O
N
N
10
N
N
CH3
CH3
Cl
3e
3f
7.5
6
9
40
80
92
95
82
85
80
79
102.5 (103.0)33
N
N
F
12
79.5 (Ref.9b)f
N
N
CH3
CH3
3g
3h
8
6
6
4
50
30
85
90
70
89
64
80
123.0 (122.0)26
N
N
105.0 (105– 106)32,33
67.5 (63–65)34
N
N
CH3
CH3
3i
4
3
20
88
83
77
N
CO2Et
a
b
c
d
e
f
Neat, 300 w, 140 °C.
PEG-400 paste, 300 w, 125 °C.
AcOH paste, 160 w, 125 °C.
The time (2 min) needed to reach the target temperature is not included in the reaction time.
Isolated yields.
Mp is not reported, but spectral data are given in the cited paper.
reaction was complete as shown by TLC analysis. In the second
method, we irradiated with MWs a well mixed paste of equivalent
amounts of the reactants in PEG-400, which is known to promote
certain types of reactions.18b,30 In the third method, a mixture of
equivalent amounts of the two reactants as a paste in acetic acid
was exposed to MWs. In the last case, the reactions were complete
in seconds even though the MW wattage was much lower than in
the other two cases. The isolated yields were excellent, though
there were some differences among the three methods. The yields
in the neat reaction were the best, while they were slightly less in
the reactions run in PEG-400, followed by those from the acetic
2. Results and discussion
We first converted the ketones 1a–j into
a-hydroxylimino ke-
tones 2a–j by oximation employing chlorotrimethylsilane and
iso-amyl nitrite27 or sodium nitrite and conc. HCl,28 after making
some changes in the reaction conditions (see Ref. 29). The
a-
hydroxylimino ketones 2a–j were then condensed with 1,2-diami-
nobenzene (4) under microwave irradiation (Scheme 1) in three
ways.
The first method consisted of exposing a well ground neat mix-
ture of equivalent amounts of the two reactants to MWs until the

546
K. Padmavathy et al. / Tetrahedron Letters 52 (2011) 544–547
1. Br2 /AlCl3 /ether / 0 oC
F
F
2. Reflux / N2 / 21 h
3. MeONa / MeOH
4
3f
(Ref. 9b)
I2 / MeCN
O
10 min (Toatal: ~24 h)
6
O
1f
O
4
F
PEG-400 / -15 o
C
(One-pot)
(Present work)
(Toatal: <2 h)
1f
NaNO2 -Conc. HCl
45 min
MW
9 min
NOH
O
2f
Scheme 2. Advantage of the present synthesis over a literature method.9b
OH
H2
NHOH
R2
+
R2
R1
N
NH2
N
NH2
NH2
HON
NH
R2
+
-NH2OH
+
3a - i
O
R1
R1
N
2a - i
4
Scheme 3. Mechanism of quinoxaline formation in the presence of AcOH.
acid paste method. This is perhaps due to some loss of products
during work-up. The reaction conditions and the results are
recorded in Table 1.
and in the shortest possible time. It is a convenient and environ-
ment-friendly general procedure for the preparation of
quinoxalines.
Compounds 3a–j are well known in the literature and the iden-
tity of the products obtained in our reactions was established by
comparing their melting points and spectral properties with those
reported in the literature (Table 1). Recently 2-(4-fluorophenyl)-3-
methylquinoxaline (3f), which is used in making light emitting
diodes, has been synthesized starting from 4-fluoropropiophenone
by an elaborate three-step process9b using several solvents and re-
agents, under not so simple reaction conditions and taking alto-
gether about 24 h (Scheme 2). In contrast, we were able to
prepare 3f using our present atom-economic green procedure that
took a little less than 2 h for the whole process (see brief experi-
mental procedure29 in References and Notes section).
Acknowledgments
The authors are grateful to the authorities of Sri Ramachandra
University, Chennai, for generous financial support. They wish to
thank Professor H.S.P. Rao, University of Pondicherry, Pondicherry
and Dr. B. Gopalan, Orchid Research Laboratories, Chennai, for
NMR spectra, and Dr. G. Rangarao, IIT-Madras, Chennai, for provid-
ing microwave reactor facilities.
Supplementary data
There are a few reports that briefly deal with the condensation
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2010.11.116.
of
a
-oximino ketones with aryl 1,2-diamines.6c,31 However, they
are multistep reactions involving conventional heating in solvents
for several (2–24) hours. The present method is the simplest,
quickest, and perhaps the most environment-friendly general syn-
thesis of quinoxalines starting from simple ketones.
References and notes
1. For recent reviews on quinoxalines see: (a) Brown, D. J. Qinoxalines:
Supplement II. In The Chemistry of Heterocyclic Compounds; Taylor, E. C., Wipf,
P., Eds.; John Wiley and Sons: New Jersey, 2004; (b) Gobec, S.; Urleb, U. In
Science of Synthesis Houben Weyl Methods of Molecular Transformations 2;
Yamamoto, Y., Ed.; Georg Thieme: Stuttgart, 2004; Vol. 16, pp 845–911; (c)
Kamal, A.; Reddy, K. L.; Devaiah, V.; Shankaraiah, N.; Rao, M. V. Mini-Rev. Med.
Chem. 2006, 6, 71–89; (d) Saifina, D. F.; Mamedov, V. A. Russ. Chem. Rev. 2010,
79, 351–370.
2. (a) Baffert, F.; Regnier, C. H.; De Pover, A.; Pissot-Soldermann, C.; Taveres, G. A.;
Blasco, F.; Brueggen, J.; Chene, P.; Drueckes, P.; Erdmann, D.; Furet, P.;
Gerspacher, M.; Lang, M.; Ledieu, D.; Nolan, L.; Ruetz, S.; Trappe, J.;
Vanghrevelinghe, E.; Wartmann, M.; Wyder, L.; Hofmann, F.; Mol.Radimerski,
T. Cancer Ther. 2010, 9, 1945–1955; (b) Lee, S.-B.; Park, Y. I.; Dong, M.-S.; Gong,
Y.-D. Bioorg. Med. Chem. Lett. 2010, 20, 5900–5904.
The condensation of 1,2-diaminobenzene with 3-hydroxylimi-
no-2,4-pentanedione (2j), obtained by the oximation of acetylace-
tone (1j), did not yield the expected 2-acetyl-3-methylquinoxaline,
but instead gave 3-hydroxylimino-2,4-dimethyl-1,5-bezodiaze-
pine (5). The formation of 5 by the condensation of 1,2-diamino-
benzene with 3-oximinopentan-2,4-dione (2j) is reported
earlier.32 This shows that keto carbonyl is more reactive than the
oxime function. However, the ester carbonyl of ethyl 2-hydroxyli-
mino-3-oxobutanoate (2i) seems to be not as reactive, since quin-
oxaline 3i was formed as the only product of condensation of 2i
and 1,2-diaminobenzene.
3. El-Ashry, E. S. H.; Abdel-Rahman, A. A. H.; Rashed, N.; Rasheed, H. A. Pharmazie
1999, 54, 893–897.
4. (a) Badran, M. M.; Abonzid, K. A.; Hussein, M. H. Arch. Pharm. Res. 2003, 26,
107–113; (b) Seitz, L. E.; Suling, W. J.; Reynolds, R. C. J. Med. Chem. 2002, 45,
5604–5606.
The almost instantaneous condensation of a-hydroxylimino ke-
tones (2a–j) in the presence of acetic acid, as compared to the neat
and the PEG-400 paste reactions, is attributable to the oxime car-
bon becoming more amenable to nucleophilic attack as a result
of protonation of the oxime group (Scheme 3).
5. Abu-Hashem, A. A.; Gouda, M. A.; Badria, F. A. Eur. J. Med. Chem. 2010, 45, 1976–
1981.
6. (a) Khattab, S. N.; Hassan, S. Y.; Bekhit, A. A.; El Massry, A. M.; Langer, V. Eur. J.
Med. Chem. 2010, 45, 4479–4489; (b) Srinivas, C.; Kumar, C. N. S. S. P.; Rao, V. J.;
Palaniappan, S. J. Mol. Catal. A: Chem. 2007, 26, 227–230; (c) Fröhlich, L. G.;
Kotsonis, P.; Traub, H.; Taghavi-Moghadam, S.; Al-Masoudi, N.; Hofmann, H.;
Strobel, H.; Matter, H.; Pfleiderer, W.; Schmid, H. H. H. W. J. Med. Chem. 1999,
42, 4108–4121.
In conclusion, we have shown that
a-hydroxylimino ketones,
obtained by the oximation of the readily available ketones, very
rapidly condense with 1,2-diaminobenzene, under microwave irra-
diation, to deliver the highly useful quinoxalines. The reaction is
carried out in solvent-free media using simple and inexpensive
reagents, either in two separate stages or as one-pot reaction,
7. (a) Myers, M. R.; He, W.; Hanney, B.; Setzer, N.; Maguire, M. P.; Zulli, A.; Bilder,
G.; Galzciniski, H.; Amin, D.; Needle, S.; Spada, A. P. Bioorg. Med. Chem. Lett.

K. Padmavathy et al. / Tetrahedron Letters 52 (2011) 544–547
547
2003, 13, 3091–3095; (b) Dietrich, B.; Diederchsen, U. Eur. J. Org. Chem. 2005,
147–153.
22. Barluenga, J.; Aznar, F.; Liz, R.; Cabal, M.-P. Synthesis 1985, 313–314.
23. Roy, P.; Ghorai, B. K. Beilstein J. Org. Chem. 2010, 6, 52.
8. (a) Brock, E. D.; Lewis, D. M.; Yousaf, T. I.; Harper, H. H. U. S. Patent No. WO
9951688, 1999 to The Proctor and Gamble Company, U.S.A. (b) Shankarling, G.
S.; Sonawane, Y. A. Indian Patent No. 150/MUM/2010 (International
classification: CO 9B23/14).
9. (a) Duan, J. P.; Sun, P. P.; Cheng, C. H. Adv. Mater. 2004, 15, 224–228; (b)
Schneidenbach, D.; Ammermann, S.; Debeaux, M.; Freund, A.; Zöllner, M.;
Daniliuc, C.; Jones, P.; Kowalsky, W.; Johannes, H.-H. Inorg. Chem. 2010, 49,
397–406.
10. Dailey, S.; Feast, J. W.; Peace, R. J.; Sage, I. C.; Till, S.; Wood, E. L. J. Mater. Chem.
2001, 11, 2238–2243.
11. Sakata, G.; Makino, K.; Kurasawa, Y. Heterocycles 1988, 27, 2481–2515.
12. Sasmal, P. K.; Majumdar, R.; Dighe, R. R.; Chakravorty, A. R. Dalton Trans. 2010,
39, 7104–7113.
24. Xekoukoulotakis, N. P.; Hadjiantoniou-Maroulis, S. P.; Maroulis, A. J.
Tetrahedron Lett. 2000, 41, 10299–10302.
25. Tung, C.-L.; Sun, C.-M. Tetrahedron Lett. 2004, 45, 1159–1162.
26. Cho, C. S.; Ren, W. X.; Shin, S. C. Tetrahedron Lett. 2007, 48, 4665–4667.
27. Mohammed, A. H. A.; Nagendrappa, G. Tetrahedron Lett. 2003, 44, 2753–2755.
28. Rüedi, G.; Oberli, M. A.; Nagel, M.; Weymuth, C.; Hansen, H.-J. Synlett 2004,
2315–2318.
29. Experimental procedure: A CEM Discover microwave (MW) reactor was used.
The reactions were followed by TLC. The reaction time was determined based
on several trials in each case. Two stage synthesis: Each a-oximino ketone was
prepared from the corresponding ketone.27,28 (a) Neat: 1,2-Diaminobenzene
(0.37 g, 3.4 mmol) and the oximino ketone (3.4 mmol) were mixed well by
grinding. The mixture was taken in
a sealed vial and subjected to MW
13. Zarrouk, A.; Dafali, A.; Hammouti, B.; Zarrok, H.; Boukhris, S.; Zertoubi, M. Int. J.
Electrochem. Sci. 2010, 5, 46–55.
irradiation. After the reaction was complete, the product was purified by
passing through a short silica gel column (eluant, hexane/EtOAc = 9:1). (b) In
PEG-400: A well ground mixture of 1,2-diaminobenzene (0.37 g, 3.4 mmol),
14. (a) Zhao, Z.; Wisnoski, D. D.; Wolkenberg, S. E.; Leister, W. H.; Wang, Y.;
Lindsley, C. W. Tetrahedron Lett. 2004, 45, 4873–4876; (b) Ajaikumar, S.;
Pandurangan, A. Appl. Catal. A: Gen. 2009, 357, 184–192; (c) Heravi, M. M.;
Bakhtiari, K.; Oskooie, H.; Taheri, S. Heteroatom Chem. 2008, 19, 218–220; (d)
Adlington, R. M.; Baldwin, J. E.; Catterick, D.; Pritchard, G. J. J. Chem. Soc., Perkin
Trans. 1 2001, 668–679; (e) China Raju, B.; Dharma Theja, N.; Ashok Kumar, J.
Synth. Commun. 2009, 39, 175–188; (f) Hou, J. –T.; Liu, Y. H.; Zhang, Z. H. J.
Heterocycl. Chem. 2010, 47, 703–706; (g) Sadjadi, S.; Sadjadi, S.; Hekmatshoar,
R. Ultrason. Sonochem. 2010, 17, 764–767; (h) Mantel, M. L. H.; Lindhardt, A. T.;
Lupp, D.; Skrydstrup, T. Chemistry 2010, 16, 5437–5442.
oximino ketone (3.4 mmol) and PEG-400 was taken in
a sealed vial and
irradiated with MW. After the reaction was over, the product was obtained as
mentioned in the previous case. (c) In AcOH: The same amounts of reactants as
mentioned in the previous cases were ground with 2–3 drops of AcOH, and the
mixture was subjected to the same procedure as mentioned earlier. The one-pot
reaction: Sodium nitrite (0.617 g, 8.9 mmol) in 1 mL of water was taken in a
25 mL flask and cooled to À15 °C. Ketone (7.5 mmol) in 1 mL of PEG-400 was
added, followed by concd HCl (0.33 g) over 5 min. The mixture turned green.
After the colour disappeared (about 45 min), 0.74 g (6.8 mmol) of 1,2-
15. (a) Kim, S. Y.; Park, K. H.; Chung, Y. K. Chem. Commun. 2005, 1321–1323; (b)
Jeena, V.; Robinson, R. S. Beilstein J. Org. Chem. 2009, 5, 24; (c) Shaabani, A.;
Maleki, A. Chem. Pharm. Bull. 2008, 56, 79–81.
16. Kumar, A.; Kumar, S.; Saxana, A.; De, A.; Mojumdar, S. Catal. Commun. 2008, 9,
778–784.
17. (a) Nagarapu, L.; Mallepalli, R.; Arava, G.; Yaramanchi, L. Eur. J. Chem. 2010, 1,
228–231; (b) Kumar, A.; Verma, A.; Chawla, G.; Vaishali Int. J. Chem. Tech. Res.
2009, 1, 1177–1181.
18. (a) Nicolaou, K. C.; Montagnon, T.; Ulven, T.; Baran, P. S.; Zhong, X. L.; Sarabia, F.
J. Am. Chem. Soc. 2002, 124, 5718–5728; (b) Lin, P.-Y.; Hou, R.-S.; Wang, H.-M.;
Kang, I.-J.; Chen, L. C. J. Chin. Chem. Soc. 2009, 56, 683–687.
19. Ali, M. M.; Ismail, M. M. F.; El-Gaby, M. S. A.; Zahran, M. A.; Ammar, Y. A.
Molecules 2000, 5, 864–873.
diaminobenzene was added. The mixture was transferred to a vial and
subjected to MW irradiation (9 min). After the reaction was over, the product
was added to 10 mL of water and worked up in the usual way using
dichloromethane for extraction.
30. Harris, J. M.; Zalipsky, S. Poly(polyethylene glycol): Chemistry and Biological
Applications; ACS Books: Washington, DC, 1997.
31. (a) Tajbaksh, M.; Bakooie, H.; Ghassemzadeh, M.; Beheshtiha, Y. Sh.; Heravi, M.
M. Indian J. Chem., Sect. B 2001, 40, 1232–1233; (b) Camplillo, N.; Garcia, C.;
Goya, P.; Alkorta, I.; Paez, J. A. J. Med. Chem. 2000, 43, 4219–4227.
32. (a) Barltrop, J. A.; Richards, C. G.; Russell, D. M.; Ryback, G. J. Chem. Soc. 1959,
1132–1142; (b) Aly, M. M.; Al-Shatti, N. I. Transition Met. Chem. 1998, 23, 361–
369.
33. Mahajanshetti, C. S. Indian J. Chem., Sect. B 1978, 16, 830–832.
34. (a) Homaidan, F. R.; Issidorides, C. H. Heterocycles 1981, 16, 411–415; (b)
Orazio, A. A.; Grescentini, L. D.; Filippone, P.; Mantellini, F.; Santeusani, S. Helv.
Chim. Acta 2001, 84, 2379–2385.
20. Thakuria, H.; Das, G. J. Chem. Sci. 2006, 118, 425–428.
21. Attanasi, O. A.; De Crascentini, L.; Philippone, P.; Mantellini, F.; Santeusanig, S.
Helv. Chim. Acta 2001, 84, 2379–2386.