CeCl3·7H2O-catalyzed synthesis of quinoxaline derivatives in liquid PEG-400

Article abstract of DOI:10.3987/COM-11-12278

A mild and efficient route for the synthesis of quinoxaline derivatives utilizing cerium chloride heptahydrate (CeCl₃·7H₂O) as a novel catalyst in poly(ethylene glycol) (PEG-400) under mild conditions was described.

Full text of DOI:10.3987/COM-11-12278

HETEROCYCLES, Vol. 83, No. 10, 2011
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HETEROCYCLES, Vol. 83, No. 10, 2011, pp. 2313 - 2320. © 2011 The Japan Institute of Heterocyclic Chemistry
Received, 9th June, 2011, Accepted, 21st July, 2011, Published online, 28th July, 2011
DOI: 10.3987/COM-11-12278
CeCl3·7H2O-CATALYZED
SYNTHESIS
OF
QUINOXALINE
DERIVATIVES IN LIQUID PEG-400
Fang-Wen Wu,a Rei-Sheu Hou,b* Huey-Min Wang,b Iou-Jiun Kang,c and
Ling-Ching Chena*
a Graduate Institute of Pharmaceutical Sciences, College of Pharmacy, Kaohsiung
Medical University, Kaohsiung 807, Taiwan, R.O.C.
E-mail: m715003@cc.kmu.edu.tw
b Chung Hwa University of Medical Technology, Tainan 717, Taiwan, R.O.C.
c
Research and Development Department, Yung Shin Pharmaceutical, Taichung
city, Taiwan, R.O.C.
Abstract - A mild and efficient route for the synthesis of quinoxaline derivatives
utilizing cerium chloride heptahydrate (CeCl3·7H2O) as a novel catalyst in
poly(ethylene glycol) (PEG-400) under mild conditions was described.
Nitrogen-containing heteroaromatic and heterocyclic compounds are indispensable structural units for
both the chemist and the biochemist. Quinoxalines constitute the basis of many insecticides, fungicides,
herbicides and anthelmintics, as well as being important in human health and as receptor antagonists.1,2
A number of methods have been developed for the synthesis of substituted quinoxalines involving
condensation of 1,2-diamines with α-diketones,3 1,4-addition of 1,2-diamines to diazenylbutenes,4
oxidation-trapping of α-hydroxy ketones with 1,2-diamine.5 Other recently, reported methods
accomplished the synthesis of quinoxaline by the reaction of 1,2-amines with phenacyl bromides in
solid-phase,6 or using heterogenous catalyst like HClO4·SiO2.7 Nevertheless, most of these methods
suffer from unsatisfactory yields, difficult experimental procedures, expensive and detrimental metal
precursors and harsh reaction conditions. Therefore, the development of improved methods for the
synthesis of quinoxaline derivatives has acquired relevance to current research.
Poly(ethylene glycol) (PEG),8 a biologically acceptable polymer used extensively in drug delivery and in

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HETEROCYCLES, Vol. 83, No. 10, 2011
bioconjugates as tools for diagnostics has been used as a solvent medium support for various
transformations.9 In recent times ionic liquids have been in the forefront of research, and several
publications and reviews have already appeared.10 Even though ionic liquids offer some advantages, the
tedious preparation of ionic liquids (and raw materials for ionic liquids) and their environmental safety is
still debated. Compared with PEG, however, toxicity and environmental burden data of ionic liquids are
for the most part unknown. Furthermore, the cost of ionic liquids is often more expensive than that of
PEG.11
Cerium chloride heptahydrate (CeCl3·7H2O) has emerged as a potentially useful Lewis acid imparting
high regio- and chemoselectivity in various chemical transformations. It is also a cheap, nontoxic and
water-tolerant catalyst.12
As part of our efforts to develop greener organic reaction procedures, we now report PEG-400 mediated
facile and efficient synthesis of quinoxaline derivatives by the reaction of o-phenylenediamines with
phenacyl bromides in the presence of catalytic amounts of CeCl3·7H2O under mild reaction conditions
(Scheme 1).
Treatment of phenacyl bromide (1a) and o-phenylenediamine (2a) with CeCl3·7H2O as catalyst in
PEG-400 at room temperature for 30 min caused cyclodehydration to give 2-phenylquinoxaline (3a) in
92% yield. The results are given in Table 1. An array of phenacyl bromides having electron-donating
and -withdrawing substituents on the aromatic ring attached to carbonyl carbon reacted with
o-phenylenediamine (2a) to afford 2-aryl substituted quinoxalines (3b-3g) in good yields.
The method is equally effective for -bromo cyclic ketone and -bromo--keto ester such as -bromo
cyclohexanone (4) and-bromo ethyl acetoacetate (6) reacted efficiently with o-phenylenediamine (2a)
to give the corresponding substituted quinoxalines (5, 7) (Scheme 2).
O
R1
NH2
NH2
CeCl3·7H2O
PEG-400
R1
N
N
R
Br
Ar
R
Ar
1
3
2
a, R = H
a, R1 = H
b, R1 = Me
b, R = Me
c, R = C6H5
Scheme 1

HETEROCYCLES, Vol. 83, No. 10, 2011
2315
O
NH2
N
N
·
CeCl3 7H2O
Br
PEG-400
NH2
5
2a
(82 %)
4
O
O
N
N
CO2Et
Me
NH2
NH2
·
CeCl3 7H2O
OEt
PEG-400
Br
7 (87 %)
6
Scheme 2
The formation of product may be explained by the reaction of phenacyl bromide (1) with
o-phenylenediamine (2) and subsequent cyclization to produce A which leads to product 3 by oxidation
(Scheme 3).
H
O
R1
N
R
R1
N
N
R
·
CeCl3 7H2O
R
NH2
NH2
Br
Ar
(O)
-HBr
-H2O
R1
N
Ar
Ar
3
1
A
2
Scheme 3
In conclusion, the PEG-400 was shown to be an effective and useful alternative reaction medium for the
preparation of quinoxaline derivatives using CeCl3·7H2O as a catalyst. The important features of this
procedure are enhanced reaction rate, mild reaction condition, high yields and green aspects such as
avoiding hazardous organic solvents and toxic catalysts.

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HETEROCYCLES, Vol. 83, No. 10, 2011
Table 1. Synthesis of quinoxalines 3a-n
Entry
1
Ar
R
H
R1
H
H
H
H
H
H
H
H
H
Me
H
H
H
H
Product
3a
Yield (%)
92
C6H5
2
4-MeC6H4
4-MeOC6H4
4-FC6H4
4-ClC6H4
4-BrC6H4
3,4-Cl2C6H3
C6H5
H
3b
3c
88
3
H
87
4
H
3d
3e
90
5
H
86
6
H
3f
87
7
H
3g
90
8
Me
C6H5
C6H5
H
3h
3i
84
9
C6H5
91
10
11
12
13
14
C6H5
3j
93
2-Pyridyl
2-Furyl
3k
3l
90
H
85
2-Thienyl
2-Naphthyl
H
3m
3n
92
H
89
ACKNOWLEDGEMENT
We gratefully acknowledge the National Council Science of Republic of China for financial support of
this work.
EXPERIMENTAL
All melting points are uncorrected. The IR spectra were recorded on a Shimadzu IR-27 G
13
spectrophotometer. 1H NMR and C NMR spectra were recorded on a Varian Unity Plus 400 MHz.
Chemical shifts () were measured in ppm with respect to TMS. MS were obtained on a JEOL JMS
D-300 instrument.
General procedure for the synthesis of quinoxalines (3)

HETEROCYCLES, Vol. 83, No. 10, 2011
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A mixture of phenacyl bromide (1) (1.0 mmol) and o-phenylenediamine (2) (1.0 mmol) in PEG-400 (2 g)
was added CeCl3·7H2O (0.05 mmol) and the resultant mixture was stirred at room temperature for 0.5 h
to complete the reaction. Subsequently, AcOEt (3×5 mL) was added and the organic phase was
separated from PEG-400/catalyst mixture, dried over MgSO4, and evaporated under reduced pressure.
The resulting residue was chromatographed on silica gel using ethyl acetate as eluent to give 3.
2-Phenylquinoxaline (3a)
Mp 74-75 °C (Lit.,13 75-76 °C). IR (KBr)  :3119, 1614, 1560, 1076 cm-1; 1H NMR (CDCl3)  : 7.55-7.58
(m, 3H), 7.74-7.82 (m, 2H), 8.11-8.22 (m, 4H), 9.34 (s, 1H); 13C NMR (CDCl3, 100 MHz)  :127.5, 128.5,
129.1, 129.5, 129.6, 130.1, 130.2, 136.8, 141.5, 142.3, 143.3, 151.8; EI-MS m/z (relative intensity) 206
(M+), 179, 152.
2-(4-Methylphenyl)quinoxaline (3b)
Mp 92-93 °C (Lit.,13 90-91 °C). IR (KBr)  :3053, 952, 748 cm-1; 1H NMR (CDCl3)  : 2.46 (s, 3H), 7.38
13
(dd, J = 0.8, 8.8 Hz, 2H), 7.71-7.80 (m, 2H), 8.09-8.16 (m, 4H), 9.32 (s, 1H); C NMR (CDCl3, 100
MHz)  : 21.4, 127.4, 129.0, 129.3, 129.5, 129.8, 130.2, 133.9, 140.5, 141.4, 142.3, 143.3, 151.8; EI-MS
m/z (relative intensity) 220 (M+), 193, 192.
2-(4-Methoxyphenyl)quinoxaline (3c)
1
Mp 97-98 °C (Lit.,13 99-100 °C). IR (KBr)  : 3057, 2360, 954, 759 cm-1; H NMR (CDCl3)  : 3.90 (s,
3H), 7.07 (dd, J = 2.0, 6.8 Hz, 2H), 7.68-7.77 (m, 2H), 8.09 (t, J = 8.0 Hz, 2H), 8.15-8.18 (m, 2H), 9.28 (s,
1H); 13C NMR (CDCl3, 100 MHz)  : 55.3, 114.5, 128.9, 129.0, 129.1, 129.3, 130.1, 141.1, 142.2, 143.0,
151.4, 161.4; EI-MS m/z (relative intensity) 236 (M+), 221, 209, 193, 166.
2-(4-Fluorophenyl)quinoxaline (3d)
1
Mp 119-120 °C (Lit.,13 120-121 °C). IR (KBr)  : 3048, 2361, 956, 755 cm-1; H NMR (CDCl3)  :
13
7.22-7.28 (m, 2H), 7.72-7.81 (m, 2H), 8.11-8.14 (m, 2H), 8.18-8.22 (m, 2H), 9.29 (s, 1H); C NMR
(CDCl3, 100 MHz)  : 116.3, 129.1, 129.4, 129.5, 130.3, 132.8, 132.9, 141.4, 142.1, 142.8, 150.7, 165.4;
EI-MS m/z (relative intensity) 225, 224 (M+), 197, 196.
2-(4-Chlorophenyl)quinoxaline (3e)
1
Mp 134 °C IR (KBr)  : 3056, 2360, 955, 760 cm-1; H NMR (CDCl3)  : 7.52-7.55 (m, 2H), 7.74-7.82
(m, 2H), 8.11-8.17 (m, 4H), 9.30 (s, 1H); 13C NMR (CDCl3, 100 MHz)  : 128.7, 129.1, 129.3, 129.5,
129.7, 130.4, 135.1, 136.5, 141.6, 142.1, 142.8, 150.5; EI-MS m/z (relative intensity) 242, 240 (M+), 213,
205, 178, 151; Anal. Calcd for C14H9ClN2: C, 69.86; H, 3.77; N, 11.64. Found: C, 69.75; H, 3.68; N,
11.78.

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2-(4-Bromophenyl)quinoxaline (3f)
1
Mp 128 °C IR (KBr)  : 3057, 2359, 955, 760 cm-1; H NMR (CDCl3)  : 7.68-7.71 (m, 2H), 7.74-7.82
(m, 2H), 8.07-8.15 (m, 4H), 9.29 (s, 1H); 13C NMR (CDCl3, 100 MHz)  : 124.9, 128.9, 129.1, 129.5,
129.7, 130.4, 132.3, 135.6, 141.6, 142.7, 150.6; EI-MS m/z (relative intensity) 287, 286, 285 (M+), 284,
205, 178, 151; Anal. Calcd for C14H9BrN2: C, 58.97; H, 3.18; N, 9.82. Found: C, 59.23; H, 3.26; N, 9.74.
2-(3,4-Dichlorophenyl)quinoxaline (3g)
1
Mp 150-151 °C IR (KBr)  : 3054, 2360, 963, 757 cm-1; H NMR (CDCl3)  : 7.64 (d, J=8.4 Hz, 1H),
7.76-7.84 (m, 2H), 8.04 (dd, J = 2.4, 8.4 Hz, 1H), 8.14 (ddd, J = 1.6, 7.0, 7.2 Hz, 2H), 8.35 (d, J = 2.0 Hz,
1H), 9.29 (s, 1H); 13C NMR (CDCl3, 100 MHz)  : 128.3, 129.1, 129.3, 129.6, 130.1, 130.6, 131.0, 133.6,
134.6, 136.6, 141.8, 142.5, 149.2; EI-MS m/z (relative intensity) 279, 277, 275 (M+), 239, 212, 177, 150;
Anal. Calcd for C14H8Cl2N2: C, 61.12; H, 2.92; N, 10.18. Found: C, 61.23; H, 2.73; N,10.26.
2-Methyl-3-phenylquinoxaline (3h)
Mp 55 °C (Lit.,14 56 °C). IR (KBr)  : 3058, 2359, 1558, 1342, 816, 764 cm-1; 1H NMR (CDCl3)  : 2.78
(s, 3H), 7.46-7.54 (m, 3H), 7.63-7.75 (m, 4H), , 8.04-8.12 (m, 2H); 13C NMR (CDCl3, 100 MHz)  :24.3,
128.2, 128.4, 128.8, 128.9, 129.1, 129.6, 138.9, 140.8, 141.1, 152.4, 154.8; EI-MS m/z (relative intensity)
220 (M+), 219, 179, 151.
2,3-Diphenylquinoxaline (3i)
1
Mp 123-124 °C (Lit.,15 126-127 °C). IR (KBr)  : 3054, 2922, 1539, 1344, 768, 729 cm-1; H NMR
(CDCl3)  : 7.32-7.40 (m, 6H), 7.52-7.54 (m, 4H), 7.75 (m, dd, J = 2.4, 9.2 Hz, 2H), 8.20 (dd, J = 2.4, 8.8
Hz, 2H); 13C NMR (CDCl3, 100 MHz)  : 128.2, 128.7, 129.1, 129.7, 129.9, 139.0, 141.1, 153.4; EI-MS
m/z (relative intensity) 282 (M+), 178, 152, 140, 77.
6-Methyl-2,3-diphenylquinoxaline (3j)
1
Mp 118-119 °C (Lit.,15 116-117 °C). IR (KBr)  : 3055, 2940, 1617, 1199, 1020, 699 cm-1; H NMR
(CDCl3)  : 2.60 (s, 3H), 7.30-7.33 (m, 6H), 7.49-7.52 (m, 4H), 7.58 (dd, J = 2.4, 11.2 Hz, 1H), 8.06 (d, J
13
= 11.2 Hz, 1H); C NMR (CDCl3, 100 MHz)  : 21.8, 127.9, 128.1, 128.5, 128.6, 129.7, 129.7, 132.2,
139.1, 140.3, 142.2, 152.4, 153.2; EI-MS m/z (relative intensity) 296 (M+), 192, 165, 89.
2-(2-Pyridyl)quinoxaline (3k)
1
Mp 110-111 °C (Lit.,16 113-114 °C). IR (KBr)  : 3048, 2923, 1589, 1401, 805, 770 cm-1; H NMR
(CDCl3)  : 7.38-7.41 (m, 1H), 7.74-7.81 (m, 2H), 7.86-7.91 (m, 1H), 8.13-8.17 (m, 2H), 8.57-8.60 (m,
1H), 8.77-8.78 (m, 1H), 9.96 (s, 1H); 13C NMR (CDCl3, 100 MHz)  : 121.9, 124.5, 139.2, 129.6, 129.9,
130.0, 137.0, 141.7, 142.4, 144.0, 149.3, 150.0, 154.4; EI-MS m/z (relative intensity) 207 (M+), 179, 105,

HETEROCYCLES, Vol. 83, No. 10, 2011
2319
79.
2-(2-Furanyl)quinoxaline (3l)
Mp 99-100 °C (Lit.,13 97-98 °C). IR (KBr) ν : 3117, 2364, 961, 755 cm-1; 1H NMR (CDCl3)  : 6.64 (dd,
J = 2.0, 3.6 Hz, 1H), 7.33 (d, J = 3.2 Hz, 1H), 7.69-7.78 (m, 3H), 8.09 (ddd, J = 1.6, 8.0, 12.8 Hz, 2H),
9.25 (s, 1H); 13C NMR (CDCl3, 100 MHz)  : 111.7, 112.4, 126.9, 130.4, 130.8, 141.2, 142.0, 143.8,
144.2, 145.0, 151.5; EI-MS m/z (relative intensity) 196 (M+), 169, 168, 141, 140, 114.
2-(2-Thienyl)quinoxaline (3m)
1
Mp 118-119 °C (Lit.,16 120-121 °C). IR (KBr)  : 3052, 2360, 927, 756 cm-1; H NMR (CDCl3)  : 7.20
(ddd, J = 0.4, 4.0, 4.8 Hz, 1H), 7.54 (dd, J = 0.4, 4.4 Hz, 1H), 7.67-7.76 (m, 2H), 7.85 (d, J = 3.6 Hz, 1H),
8.05-8.07 (m, 2H), 9.23 (s, 1H); 13C NMR (CDCl3, 100 MHz)  : 126.9, 128.4, 129.0, 129.1, 129.7, 130.3,
141.3, 142.0, 142.1, 142.2, 147.3; EI-MS m/z (relative intensity) 212 (M+), 211, 185, 141.
2-(2-Naphthyl)quinoxaline (3n)
1
Mp 141-142 °C (Lit.,13 140-142 °C). IR (KBr)  : 3054, 2355, 1541, 1358, 825, 743 cm-1; H NMR
(CDCl3)  : 7.55-7.59 (m, 2H), 7.74-7.83 (m, 2H), 7.91-7.93 (m, 1H), 8.01-8.04 (m, 2H), 8.15 (dd, J = 1.2,
8.0 Hz, 1H), 8.20 (d, J = 8.0 Hz, 1H ), 8.37 (d, J = 0.8, 8.4 Hz, 1H), 8.66 (s, 1H), 9.49 (s, 1H); 13C NMR
(CDCl3, 100 MHz)  : 124.4, 126.6, 127.2, 127.4, 127.7, 128.8, 129.0, 129.1, 129.5, 129.5, 130.3, 133.3,
134.0, 134.0, 141.5, 142.3, 143.4, 151.6; EI-MS m/z (relative intensity) 256 (M+), 202, 153, 126.
1,2,3,4-Tetrahydrophenazine (5)
1
Mp 89-90 °C (Lit.,13 91-92 °C). IR (KBr)  : 3057, 2930, 1605, 1492, 1248,736 cm-1; H NMR (CDCl3)
13
 : 2.01-2.08 (m, 4H), 3.13-3.20 (m, 4H), 7.64-7.69 (m, 2H), 7.95-7.80 (m, 2H); C NMR (CDCl3, 100
MHz)  : 23.2, 33.6, 128.7, 129.3, 141.6, 154.5; EI-MS m/z (relative intensity) 184 (M+), 169, 156, 129,
118.
Ethyl 3-methyl-quinoxaline-2-carboxylate (7)
1
Mp 63-64 °C (Lit.,17 65-66 °C). IR (KBr)  : 2971, 2926, 1717, 1314, 1269, 1079, 768 cm-1; H NMR
(CDCl3)  : 1.50 (t, J = 4.8Hz, 3H), 2.96 (s, 3H), 4.57 (q, J = 4.8Hz, 2H), 7.76-8.20 (m, 4H); EI-MS m/z
(relative intensity) 216 (M+), 172, 144, 116, 102, 75.
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