Room temperature facile synthesis of quinoxalines catalyzed by amidosulfonic acid

Article abstract of DOI:10.1002/jhet.5570450135

(Chemical Equation Presented) Amidosulfonic acid NH₂-SO ₃H catalyzed direct condensations of o-phenylenediamines with α-diketones at room temperature in organic solvents to afford quinoxalines in excellent yields. The amidosulfonic acid as a solid acid catalyst in this preparation was efficient and recoverable.

Full text of DOI:10.1002/jhet.5570450135

Jan-Feb 2008
285
Room Temperature Facile Synthesis of Quinoxalines Catalyzed by
Amidosulfonic Acid
Zhenjiang Li,* Weisi Li, Yingjie Sun, He Huang and Pingkai Ouyang
College of Life Science and Pharmaceutical Engineering, Nanjing University of Technology, Nanjing 210009,
China. E-mail: zjli@njut.edu.cn
Received December 5, 2006
H3N SO3
R1
NH2
NH2
R1
N
N
R2
R2
O
O
R2
R2
(solid, 5 mol%)
solvent, rt
+
Amidosulfonic acid NH2–SO3H catalyzed direct condensations of o-phenylenediamines with ꢀ-
diketones at room temperature in organic solvents to afford quinoxalines in excellent yields. The
amidosulfonic acid as a solid acid catalyst in this preparation was efficient and recoverable.
J. Heterocyclic Chem., 45, 285 (2008).
INTRODUCTION
such as, it has outstanding physical stability, is insoluble
in common organic solvent, is inexpensive, and readily
available [26]. As part of our on going interest in using of
economical reagents for organic transformations, we had
the opportunity to look into the synthesis of quinoxalines
by using NH2SO3H as solid catalyst in proper solvent.
In aromatic multi-nuclear N-containing heterocyclic
compounds, quinoxaline derivatives exhibit special and
wide range of functions in biological active compounds
[1], electroluminescent materials [2], dyes [3], and anion
sensors [4]. Their extraordinary potentials in pharma-
cological research and practice have attracted much
attention. Although rarely recorded in nature, synthetic
quinoxaline derivatives showed variety of pharmaceutical
activities encompassed major types of drug target families
and effective in many clinical applications such as anti-
tumor agents [5], kinase inhibitors [6], HIV drugs [7],
antibiotics [8], ion channel regulators [9], and anti-
protozoal agents [10]. Several synthetic routes to
quinoxaline have been developed [11] and the well
established preparation method is the direct condensation
[12] of o-phenylenediamines with ꢀ-diketones in
refluxing ethanol [13] or in boiling acetic acid [14]. Most
recently, several preparative methods through direct
condensations to quinoxalines have been reported which
using Yb(OTf)3 [15], molecular iodine [16], or
Ce(NH4)2(NO3)6 [17] as catalysts. Indirect alternative
routes through tandem oxidation-condensation [18] are
useful diversity oriented approaches. In comparison with
the variety use of quinoxalines in many fields, their
preparation methods are limited in number. Some of the
established methods suffered in one or more drawbacks,
such as drastic reaction conditions, special apparatus,
expensive reagents or catalyst, or complicated work-up.
In continuation of our preliminary investigation on the
condensations afford ꢀ-amidosulfones by using NH2SO3H
as efficient catalyst [19–23], we envisioned broader
applications of this solid acid in some condensations
formerly carried out in moisture-free conditions or by
dehydrating measures. NH2SO3H as a powerful solid
catalyst has been used in many organic preparations [24].
It has unique structure [25] and prominent properties,
Scheme I
NH2SO3H
(5 mol%)
solvent, rt
R1
NH2
NH2
R1
N
N
R2
R2
O
O
R2
R2
+
1
2
3
RESULTS AND DISCUSSION
In the beginning, NH2SO3H was tested for the catalytic
activity in the condensation of o-phenylenediamine 1a
with benzil 2a in dichloromethane at room temperature
and showed good performance (entry 3, Table 1). On the
contrary, without catalyst, similar condensations in
alcohols and other protic or polar solvents are not
observed at room temperature [12–14], which was
reconfirmed by blank contrasts (entries 1 and 2, Table 1).
Encouraged by these promising results, we decided to
expand the reactions in array of diketones in various
solvents at room temperature by using NH2SO3H as
catalyst (Scheme I).
Initially, condensations of o-phenylenediamine 1a (2
mmol) with benzil 2a (2 mmol) mediated by NH2SO3H in
different solvents (5 mL) at room temperature were
conducted (Table 1). The optimization on the loading of
the catalyst and reaction time was carried out (entries 3–5,
Table 1), 5 mol % of NH2SO3H and 2 h showed to be an
optimal condition for preparation of quinoxaline 3aa.
Next, the reactions of 1a (2 mmol) with 2a (2 mmol)
catalyzed by NH2SO3H (5 mol %) were tested in common
organic solvents (entries 6–13) at room temperature and
showed polar solvents were preferred. Since NH2SO3H is
slightly soluble in alcohols, DMF, and CH3CN, but

286
Z. Li, W. Li, X, Ren, Y. Sun, H. Huang and P. Ouyang
Vol 45
withdrawing (R1 = Cl, entries 11–15) substitutions were
employed to expand the scope of this protocol. As
indicated in Table 2, substitutions (R1 = Me, Cl) on the
phenyl group of o-phenylenediamine exerted minor
influence on the reactions (take entries 2, 7 and 12 as
examples), and similar yields resulted. On the other hand,
electron-donating groups on the aryl of the diketones
made the reactions slower and it took longer time to
obtain comparable yields (see entries 11–13 as examples).
The reactions proceeded smoothly at ambient
temperature, after completion of the condensation, the
solid catalyst and the product 3 was separated by simple
work-up.
Table 1
Condensation of o-phenylenediamine with benzil as model reaction
at room temperature.
Entry Solvent
NH2SO3H / mol%
Time / h
Yield / %
1
EtOH
0
0
48
48
4
—
6
2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
MeOH
EtOH
3
10
15
5
91
96
92
84
78
81
85
77
71
72
58
4
5
6
2
6
5
2
7
5
5
2
2
8
DMF
9
CH3CN
EtOAc
Et2O
5
2
10
11
12
13
5
5
4
4
Although the structures of NH2SO3H were investi-
gated in gas phase [25] and in molecular clusters
(condensed phase) [27] as zwitterionic units in the
Toluene
Hexane
5
6
5
8
+
–
form of NH3SO3 (see Scheme 2, compound 4), the
structures of the catalyst in crystalline and in solution
were not explored further to our knowledge. Since
NH2SO3H is not soluble in common organic solvents,
the catalysis should take place heterogeneously at the
interface of the solid catalyst and the solution. A
tentative mechanism was proposed in Scheme 2. Due to
the zwitterionic nature of the catalyst, it may work as
bi-functional catalyst by the simultaneous coordination
of the negatively charged O atom on the sulfonic
insoluble in dichloromethane, we decided to use CH2Cl2
in the expanded experiments for its good performance and
the simple separation and recovery of the solid acid
catalyst. Further, the procedure was extended to
substituted aromatic (entries 2 and 3, Table 2), hetero-
cyclic (entry 4), and aliphatic (entry 5) ꢀ-diketones with
excellent yields. o-Phenylenediamines with electron-
donating (R1
=
Me, entries 6–10) and electron-
Table 2
Synthesis of quinoxalines using o-phenylenediamines and symmetrical ꢀ-diketones
Entry
o-Phenylenediamine 1
1,2-Diketone 2
Quinoxaline 3
Time / h
Yield / %
Ref
1
2
1a
1a
1a
1a
1a
1b
1b
1b
1b
1b
1c
1c
1c
1c
1c
2a
2b
2c
2d
2e
2a
2b
2c
2d
2e
2a
2b
2c
2d
2e
3aa
3ab
3ac
3ad
3ae
3ba
3bb
3bc
3bd
3be
3ca
3cb
3cc
3cd
3ce
2
2
2
2
2
2
4
6
3
2
3
5
6
3
2
92
85
82
89
88
91
89
84
87
86
92
87
79
90
89
[15]
[16]
[15]
[18]
[17]
[15]
[15]
[15]
[16]
[16]
[15]
[16]
[16]
[18]
[18]
3
4
5
6
7
8
9
10
11
12
13
14
15
R2
R2
R1
NH2
NH2
O
O
O
O
R1
N
O
O
R1
N
N
R1
N
N
O
O
O
O
N
R2
R2
1a-c
1a R1 = H
1b R1 = Me
1c R1 = Cl
2a-c
2d
2e
3aa-ac; 3ba-bc; 3ca-cc
3ad-cd
3ae-ce
3ae-ce R1 = H, Me, Cl
2a R2 = H
2b R2 = Me
2c R2 = OMe
3aa-ac R1 = H; R2 = H, Me, OMe
3ba-bc R1 = Me; R2 = H, Me, OMe
3ca-cc R1 = Cl; R2 = H, Me, OMe
3ad-cd R1 = H, Me, Cl

Jan-Feb 2008
Synthesis of Quinoxalines at Room Temperature
287
(95:5, v/v), the fractions of product was combined and solvents
were evaporated in vacuo to afford the product 3aa. All the
products gave mp in good accordance with the reported data
moiety with the amine proton NH on 1 and the
coordination of the positively charged H atom on the
amido- moiety with ketone O on 2. Thus the reaction in
the first step was facilitated in two ways; one was the
double activation of the nucleophile 1 and the
electrophile 2, another was the proximity of 1 and 2.
The latter part of the schematic approach from freed 6
to 3 was proposed and confirmed [28].
1
[15–17]. Each H NMR spectrum of 3 agreed with the assigned
structure. Representative compounds were given below.
2,3-Diphenylquinoxaline (3aa). White crystal (EtOH), 1.3 g
(92 %), mp 124–125 (lit. [15] 123–125) °C; 1H nmr (CDCl3): ꢁ
7.35 (m, 6H), 7.56 (m, 4H), 7.76 (m, 2H), 8.20 (m, 2H); HRMS
(ESI): m/z [M + Na]+ calcd. for C20H14N2Na+ 305.1055, found
305.1058.
Scheme II
2,3-Di(furan-2-yl)-6-methylquinoxaline (3bd). Light brown
crystal (EtOH), 1.2 g (87 %), 119–120 (lit. [16] 118–119) °C; 1H
nmr (CDCl3): ꢁ 2.56 (s, 3H), 6.47 (m, 2H), 6.62 (d, 2H, J = 3.6
Hz), 7.56 (dd, 1H, J = 8.6, 1.3 Hz), 7.93 (s, 1H), 8.06 (d, 1H, J =
proton shift
zwitterionic form
8.6 Hz,); HRMS (ESI): m/z [M + H]+ calcd. for C17H13N2O2
+
amidosulfonic form
O
H
O
277.0977, found 277.0972.
6-Chloro-2,3-dimethylquinoxaline (3ce). Light orange
crystal (EtOH), 0.86 g (89%), 85–86 (lit. [18] 83–84) °C; H
nmr (CDCl3): ꢁ 2.77 (s, 6H), 7.64 (dd, 1H, J = 9.0, 2.2 Hz), 8.01
(d, 1H, J = 9.0 Hz), 8.09 (d, 1H, J = 2.2 Hz); HRMS (ESI): m/z
[M + H]+ calcd. for C10H10ClN2+ 193.0533, found 193.0529.
O
H
O
4
S
N
5
H
S
N
1
O
H
H
O
H
H
O
H
N
O
R
N
R
H
H
O
R
Acknowledgement. We are grateful to the Hi-tech R & D
Program of China (No. 2007CB714305) for financial support.
R
R
O
NH2
NH2
2
1
6
REFERENCES AND NOTES
R
N
N
R
[1] Nasr, M. N. A. Arch. Pharm., 2002, 335, 389.
[2] Thomas, K. R. J.; Lin, J. T.; Tao, Y. T.; Chuen, C. H. J.
Mater. Chem., 2002, 12, 3516.
O
R
NH2
N
H
N
R
R
OH
H OH
N
[3] Hirayama, T.; Yamasaki, S.; Ameku, H.; Ishi-i, T.;
Thiemann, T.; Mataka, S. Dyes Pigment, 2005, 67, 105.
[4] Aldakov, D.; Anzenbacher, P. Chem. Commun., 2003, 1394 .
[5] Torre, M. H.; Gambino, D.; Araujo, J.; Cerecetto, H.;
Gonzalez, B.; Lavaggi, M. L.; Azqueta, A.; de Cerain, A. L.; Vega, A.
M.; Abram, U.; Costa, A. J. Eur. J. Med. Chem., 2005, 40, 473.
[6] Szekelyhidi, Z.; Pato, J.; Waczek, F.; Banhegyi, P.;
Hegymegi-Barakonyi, B.; Eros, D.; Meszaros, G.; Hollosy, F.;
Hafenbradl, D.; Obert, S.; Klebl, B.; Keri, G.; Orfi, L. Bioorg. Med.
Chem. Lett., 2005, 15, 3241.
H OH
N
N
R
R
R
R
3
N
N
H OH
In summary, we have developed an efficient approach
to quinoxalines by direct condensations of o-phenyl-
enediamines with ꢀ-diketones catalyzed by NH2SO3H in
dichloromethane at room temperature. The protocols
featured with mild reaction conditions, easy work-up, and
excellent yields.
[7] Cheon, H. G.; Lee, C. M.; Kim, B. T.; Hwang, K. J. Bioorg.
Med. Chem. Lett., 2004, 14, 2661.
[8] Refaat, H. M.; Moneer, A. A.; Khalil, O. M. Arch. Pharm.
Res., 2004, 27, 1093.
[9] Bonde, C.; Noraberg, J.; Noer, H.; Zimmer, J. Neurosci.,
2005, 136, 779.
EXPERIMENTAL
[10] Hui, X.; Desrivot, J.; Bories, C.; Loiseau, P. M.; Franck, X.;
Hocquemiller, R.; Figadere, B. Bioorg. Med. Chem. Lett., 2006, 16, 815.
[11] Brown, D. J. Quinoxalines: Supplement II, in The Chemistry
of Heterocyclic Compounds, Taylor, E. C.; Wipf, P. eds., John Wiley &
Sons, New Jersey, 2004.
All reactants and solvents are commercially available and
were used as received without purification. Melting points were
determined using a microscope hot stage type apparatus without
correction. 1H NMR spectra were recorded at 500 MHz in
CDCl3 on a Bruker DRX-500 instrument. Chemical shifts were
expressed in ppm using TMS as internal standard for H NMR.
High-resolution electrospray mass spectra were obtained on a
Mariner ESI-TOF spectrometer.
General Procedure for the Preparation of Quinoxalines 3.
A mixture of o-phenylenediamine 1a (0.54 g, 5.0 mmol), 1,2-
diketone 2a (1.41 g, 5.0 mmol), and sulfamic acid (24 mg, 5 mol
%) in CH2Cl2 (25 mL) was stirred for appropriate time (Table 2)
at ambient temperature. After completion of the reaction, the
solid catalyst NH2SO3H was filtered off, the solution was
subject to silica column directly and eluted with CH2Cl2–MeOH
[12] Bost, R. W.; Towell, E. E. J. Am. Chem. Soc., 1948, 70, 903.
[13] Cheeseman, G. W. H. in Advances in Heterocyclic
Chemistry, Vol. 1, Katritzky, A. R. ed., Academic Press, London,
1963.
1
[14] Furniss, B. S.; Hannaford, A. J.; Smith, P. W. G.; Tatchell, A.
R. VOGEL’s Textbook of Practical Organic Chemistry, 5th ed., Pearson
Education Ltd., Edinburgh, 1989, pp. 1189–1190.
[15] Wang, L. M.; Liu, J. J.; Tian, H.; Qian, C. T. Synth.
Commun., 2004, 34, 1349.
[16] Bhosale, R. S.; Sarda, S. R.; Ardhapure, S. S.; Jadhav, W. N.;
Bhusare, S. R.; Pawar, R. P. Tetrahedron Lett., 2005, 46, 7183.
[17] More, S. V.; Sastry, M. N. V.; Yao, C. F. Green Chem.,

288
Z. Li, W. Li, X, Ren, Y. Sun, H. Huang and P. Ouyang
Vol 45
2006, 8, 91.
2005, 1321.
[18] Kim, S. Y.; Park, K. H.; Chung, Y. K. Chem. Commun.,
2007, 803.
[24] Wang, B. Synlett, 2005, 1342.
[19] Li, Z.; Ren, X.; Wei, P.; Wan, H.; Shi, Y.; Ouyang, P. Green
Chem., 2006, 8, 433.
[25] Canageratna, M.; Ott, M. E. and Leopold, K. R. Chem. Phys.
Lett., 1997, 281, 63.
[20] Li, Z.; Ren, X.; Shi, Y.; Ouyang, P. Synth. Commun., 2007, 37, 713.
[21] Li, Z.; Sun, Y.; Ren, X.; Shi, Y.; Ouyang, P. Heterocycles,
2007, 71, 453.
[26] NH2SO3H is 31.5 $/kg, see at: http://www.sigmaaldrich.com/
catalog/search/.
[27] Pawlowski, P. M.; Okimoto, S. R. and Tao, F. M. J. Phys.
Chem. A, 2003, 107, 5327.
[28] Anderson, L. M. and Butler, A. R. J. Chem. Soc. Perkin
[22] Li, Z.; Sun, Y.; Ren, X.; Li, W.; Shi, Y. and Ouyang, P.
Synth. Commun., 2007, 37, 1609.
[23] Li, Z.; Sun, Y.; Ren, X.; Wei, P.; Shi, Y.; Ouyang, P. Synlett,
Trans. 2, 1994, 323.