Microwave-assisted catalyst-free and solvent-free method for the synthesis of quinoxalines

Article abstract of DOI:10.1080/00397910902838862

A green and efficient procedure for the synthesis of quinoxalines is reported starting from benzil and 1,2-diaminobenzene. The reactions were carried out under catalyst-free, solvent-free, and microwave-irradiation conditions, affording the corresponding quinoxalines. This method had many dramatic advantages, such as the short reaction time (2-6min), high yields (71-98%), and environmental friendliness, as well as convenient operation.

Full text of DOI:10.1080/00397910902838862

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Microwave-Assisted Catalyst-
Free and Solvent-Free
Method for the Synthesis of
Quinoxalines
Jian-Feng Zhou a b , Gui-Xia Gong b , San-Jun Zhi a &
Xiu-Li Duan a
a Department of Chemistry, Huaiyin Teachers
College, Jiangsu Key Laboratory for Chemistry of
Low-Dimensional Materials, Huaian, China
b School of Chemistry and Chemical Engineering, Key
Laboratory of Organic Synthesis of Jiangsu Province,
Suzhou University, Suzhou, China
Published online: 08 Sep 2009.
To cite this article: Jian-Feng Zhou , Gui-Xia Gong , San-Jun Zhi & Xiu-Li Duan
(2009) Microwave-Assisted Catalyst-Free and Solvent-Free Method for the
Synthesis of Quinoxalines, Synthetic Communications: An International Journal
for Rapid Communication of Synthetic Organic Chemistry, 39:20, 3743-3754, DOI:
10.1080/00397910902838862
To link to this article: http://dx.doi.org/10.1080/00397910902838862
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Synthetic Communications1, 39: 3743–3754, 2009
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910902838862
Microwave-Assisted Catalyst-Free and
Solvent-Free Method for the Synthesis
of Quinoxalines
Jian-Feng Zhou,1,2 Gui-Xia Gong,2 San-Jun Zhi,1 and Xiu-Li Duan1
1Department of Chemistry, Huaiyin Teachers College, Jiangsu Key
Laboratory for Chemistry of Low-Dimensional Materials, Huaian, China
2School of Chemistry and Chemical Engineering, Key Laboratory of
Organic Synthesis of Jiangsu Province, Suzhou University,
Suzhou, China
Abstract: A green and efficient procedure for the synthesis of quinoxalines is
reported starting from benzil and 1,2-diaminobenzene. The reactions were carried
out under catalyst-free, solvent-free, and microwave-irradiation conditions,
affording the corresponding quinoxalines. This method had many dramatic
advantages, such as the short reaction time (2–6 min), high yields (71–98%),
and environmental friendliness, as well as convenient operation.
Keywords: Benzil, catalyst-free, 1,2-diaminobenzene, microwave irradiation,
quinoxaline, solvent-free
In today’s world, synthetic chemists in both academia and industry are
constantly challenged to consider more environmentally benign methods
for generation of the desired target molecules. It is known that micro-
wave irradiation has been utilized as one of the most convenient and
efficient ways to promote organic reactions.[1] In particular, the use of
microwave energy to directly heat chemical reactions has become an
increasingly popular technique in the scientific community. Therefore,
in recent years the combination of these several prominent green
Received November 14, 2008.
Address correspondence to Jian-Feng Zhou, Department of Chemistry,
Huaiyin Teachers College, 223300 Huaian, China. E-mail: orgjfzhou@yahoo.
com.cn
3743

3744
J.-F. Zhou et al.
chemistry principles—microwaves, lack of solvent, and lack of catalyst–
has become very popular and received substantial interest because of the
work of chemists[2] who demonstrated that a great variety of synthetic
organic transformations can be carried out very efficiently and rapidly
under these environmentally benign conditions.
Quinoxaline derivatives are an important class of benzoheterocycles,
which have a wide range of pharmacologically active compounds that
have anticancer,[3] antimicrobial,[4] and antibacterial[5] activities. Some
quinoxaline derivatives serve as DNA photo-cleavers,[6] antagonists of
the 5-HT3 receptor,[7] inhibitors of HCV NS5B RNA-dependent RNA
polymerase,[8] and fluorescent dyes.[9] Furthermore, they also serve as
useful rigid subunits in macrocyclic receptors for molecular recogni-
tion[10] and chemically controllable switches,[11] and they constitute the
building blocks of some organic semiconductors.[12]
Numerous synthetic routes have been developed for the synthesis of
quinoxaline derivatives involve involving condensation of 1,2-diamines
with a-diketones,[13] 1,4-addition of 1,2-diamines to diazenylbutenes,[14]
and cyclization–oxidation of phenacyl bromides and o-phenylenediamines
through solid-phase synthesis.[15] 2,3-Disubstituted quinoxalines have also
been prepared via the Suzuki–Miyaura coupling reaction,[16] condensa-
tion of o-phenylenediamines with 1,2-dicarbonyl compounds under
microwave irradiation,[17] and iodine-catalyzed cyclocondensation of
1,2-dicarbonyl compounds with substituted o-phenylenediamines.[18]
Also, a-hydroxy ketones react with o-phenylenediamines in the presence
of transition metals such as Mn, Pd, Ru, Cu, Pb, and Bi to give quinox-
alines.[19,20] The most common method is the condensation of an aryl
1,2-diamine with a 1,2-dicarbonyl compound by heating it in a solvent
for 2–12h. The yields of products are 34–85%. Improved methods
have been reported for the synthesis of quinoxaline derivatives including
the use of RuCl2(PPh3)3-2,20,6,60-tetramethylpiperidine N-oxyl (TEMPO),[19a]
MnO2,[19b] POCl3,[19c] cerium ammonium nitrate,[19d] SA=MeOH,[19e]
CuSO4 ꢀ 5H2O,[19f] Montmorillonite K-10,[19g] HClO4 ꢀ SiO2,[19h] H6P2
W18O62 ꢀ 24H2O,[19i] KHSO4,[19j] Ni-nanoparticles,[19k] Zn[(l)proline],[19l]
and p-toluenesulfonic acid[19m] as catalyst. However, most of the exist-
ing methodologies sufer from disadvantages such as use of volatile
organic solvents, critical product isolation procedures, expensive and
detrimental metal precursors, and harsh reaction conditions, which limit
their environmental friendliness.
Continuing our interest in the synthesis of organic compounds by
microwave irradiation,[21] we report herein a novel method to synthesize
differently substituted quinoxalines from benzils and 1,2-diamino-
benzenes under catalyst-free, solvent-free, and microwave-irradiation
conditions (Scheme 1).

Synthesis of Quinoxalines
3745
Scheme 1. Ar¼C6H5, 4-CH3C6H4, 4-ClC6H4, funyl; R1¼H, CH3; R2¼H, CH3,
OCH3, NO2.
RESULTS AND DISCUSSION
When a mixture of benzil 1 (Ar¼C6H5) and 1,2-diaminobenzene 2 were
irradiated at 100ꢁC in catalyst-free and solvent-free conditions, the
reaction was completed after 4 min. The crude product was purified by
recrystallization from 95% ethanol to afford product 3a with excellent
yield (96%). Subsequently, to examine the efficiency and applicability
of this protocol, the reaction was extended to other substituted benzils
1 (Ar¼4-CH3C6H4, 4-ClC6H4, furyl) and substituted 1,2-diaminoben-
zenes 2 (R1¼H, CH3; R2¼H, CH3, OCH3, Br, NO2) under catalyst-free,
catalyst-free, and microwave-irradiation conditions. To our delight, these
actions proceeded smoothly to afford a series of quinoxaline derivatives 3
in excellent yields (entries 2–16 of Table 1). The results showed that the
scope of the reaction is quite broad in regard to the benzils 1 and 1,2-
diaminobenzenes 2. The structures of these compounds are established
1
by infrared (IR), H NMR, 13C NMR, and mass spectrometry (MS).
In conclusion, we have developed a novel, efficient method for
synthesis of quinoxalines of potential synthetic and pharmacological
interest. Catalyst-free, solvent-free, and microwave-irradiation conditions,
the short reaction time, excellent yields of the products, environmental
friendliness, and convenient workup are the advantages of this method.
EXPERIMENTAL
The reactions under microwaves were performed in a CEM Discover
monomode microwave reactor. Melting points were determined with a
WRS-1B digital melting-point apparatus and are uncorrected. 1H
NMR and 13C NMR were measured on a Burke 400-MHz spectrometer
in CDCl3 using tetramethylsilane (TMS) as an internal standard. IR spec-
tra were recorded on a Nicolet Avatar 360 FT-IR instrument. MS spectra
were recorded on a LCQ Advantage instrument. Elemental analyses were
determined using a Perkin-Elmer 240C elemental analyzer. All the
reagents are commercially available.

3746
J.-F. Zhou et al.
Table 1. Synthesis of quinoxalines 3a–p under catalyst-free, solvent-free, and
microwave-irradiation conditions
Temp.
(ꢁC)
Time
(min)
Yielda
(%)
Entry
1
Ar
R1, R2
Products
C6H5
R1¼R2¼H
100
100
4
4
96
93
R1¼H
2
C6H5
R2¼CH3
3
4
C6H5
C6H5
R1¼R2¼CH3 100
3
97
98
R1¼H
120
3.5
R2¼NO2
R1¼H
110
5
C6H5
4
71
R2¼OCH3
6
7
4-CH3C6H4 R1¼R2¼H
120
120
3
4
97
95
R1¼H
4-CH3C6H4
R2¼CH3
8
9
4-CH3C6H4 R1¼R2¼CH3 120
3
3
95
4-ClC6H4 R1¼R2¼H
120
93
(Continued )

Synthesis of Quinoxalines
3747
Table 1. Continued
Temp.
(ꢁC)
Time
(min)
Yielda
(%)
Entry
10
Ar
R1, R2
Products
R1¼H
4-ClC6H4
120
6
97
R2¼CH3
11
12
4-ClC6H4 R1¼R2¼CH3 120
5
3
97
94
R1¼H
4-ClC6H4
120
R2¼NO2
13
14
Furyl
Furyl
R1¼R2¼H
120
120
3
3
98
96
R1¼H
R2¼CH3
15
16
Furyl
Furyl
R1¼R2¼CH3 120
2
3
90
98
R1¼H
120
R2¼NO2
aYields of the isolated product.
General Procedure for Synthesize of Quinoxalines Under Catalyst-Free,
Solvent-Free, and Microwave-Irradiation Conditions
Benzils 1 (1 mmol) and 1,2-diaminobenzenes 2 (1 mmol) were mixed
and sealed with a cap containing a septum. The loaded vial was then
placed into the cavity of the microwave reactor and heated at
100–130ꢁC for 2–6 min (as indicated by thin-layer chromatography,
TLC). After completion of the reaction, the reaction mixture was then
allowed to cool to room temperature, resulting in the precipitation of

3748
J.-F. Zhou et al.
the solid product. The product was were filtered off and dried. The
crude products were recrystallized from 95% ethanol to afford the pure
product 3a–p.
Data
Compound 3a
Mp 126.2–126.8ꢁC (126–127ꢁC).[19h] 1H NMR (400 MHz, CDCl3)
d ¼ 8.21–8.23 (m, 2H), 7.82–7.80 (m, 2H), 7.56–7.54 (m, 4H), 7.40–7.35
(m, 6H). MS m=z (%): (M þ H)þ ¼ 283.6 (100).
Compound 3b
Mp 115.1ꢁC (116–117ꢁC).[19h] 1H NMR (400 MHz, CDCl3) d ¼ 8.09 (d,
1H, J ¼ 8.8 Hz), 7.98 (s, 1H), 7.64–7.62 (m, 1H), 7.54 (t, 4H, J ¼ 7.6 Hz),
7.40–7.35 (m, 6H), 2.65 (s, 3H). MS m=z (%): (M þ H)þ ¼ 297.6 (100).
Compound 3c
Mp 150.7–150.9ꢁC. IR (KBr): 3058, 2919, 1636, 1341, 1094, 967, 696 cmꢂ1
.
1H NMR (400 MHz, CDCl3) d ¼ 7.96 (d, 1H, J ¼ 8.4 Hz), 7.62 (t, 3H,
J ¼ 8.8 Hz), 7.55 (t, 2H, J ¼ 7.6 Hz), 7.40–7.35 (m, 6H), 2.83 (s, 3H),
2.58 (s, 3H). 13C NMR (100 MHz, CDCl3) d ¼ 151.6, 140.2 139.6,
137.7, 134.6, 132.9, 130.1, 129.8, 128.5, 128.1, 125.9, 20.5, 12.9. MS
m=z (%): (M þ H)þ ¼ 311.7 (100). Anal. calcd. for C22H18N2: C, 85.13;
H, 5.85; N, 9.03; found: C, 84.81; H, 5.87; N, 8.97.
Compound 3d
Mp 188.9ꢁC (187ꢁC).[22] 1H NMR (400 MHz, CDCl3) d ¼ 9.11 (s, 1H),
8.58–8.55 (m, 1H), 8.33 (d, 1H, J ¼ 9.2 Hz), 7.60–7.58 (m, 4H),
7.47–7.38 (m, 6H). MS m=z (%): (M þ H)þ ¼ 328.6 (100).
Compound 3e
Mp 156.4–156.5ꢁC (155–156ꢁC).[23] 1H NMR (400 MHz, CDCl3) d ¼ 8.09
(d, 1H, J ¼ 9.2 Hz), 7.51–7.54 (m, 5H), 7.44–7.49 (m, 1H), 7.34–7.40 (m,
6H), 4.02 (s, 3H). MS: m=e (M þ H)þ ¼ 313.7 (100).

Synthesis of Quinoxalines
3749
Compound 3f
1
Mp 149.4–149.7ꢁC. H NMR (400 MHz, CDCl3) d ¼ 8.19–8.17 (m, 2H),
7.80–7.75 (m, 2H), 7.46 (d, 4H, J ¼ 7.6 Hz), 7.18 (d, 4H, J ¼ 7.6 Hz). MS
m=z (%): (M þ H)þ ¼ 311.5 (100). Anal. calcd. for C22H18N2: C, 85.13; H,
5.85; N, 9.03; found: C, 84.80; H, 5.87; N, 8.96.
Compound 3g
Mp 130.2–130.6ꢁC (137ꢁC).[19d] 1H NMR (400 MHz, CDCl3) d ¼ 8.07 (d,
1H, J ¼ 8.4 Hz), 7.97 (s, 1H), 7.60 (d, 1H, J ¼ 8.0 Hz), 7.43 (t, 4H,
J ¼ 7.6 Hz), 7.16 (d, 4H, J ¼ 7.6 Hz), 2.63 (s, 3H), 2.39 (s, 6H). MS m=z
(%): (M þ H)þ ¼ 325.4 (100).
Compound 3h
Mp 173.4–73.6ꢁC. IR (KBr): 3022, 2920, 1609, 1512, 1340, 1089, 823,
797 cmꢂ1
.
1H NMR (400 MHz, CDCl3) d ¼ 8.00 (d, 1H, J ¼ 8.4 Hz),
7.59 (d, 1H, J ¼ 8.8 Hz), 7.52–7.46 (m, 4H), 7.19–7.16 (m, 4H), 2.81 (s,
3H), 2.57 (s, 3H), 2.39 (s, 6H). 13C NMR (100 MHz, CDCl3) d ¼ 151.6,
140.1, 139.4, 138.5, 137.5, 136.8, 134.5, 132.6, 130.0, 129.7, 128.9, 125.7,
21.3, 20.5, 12.9. MS m=z (%): (M þ H)þ ¼ 339.4 (100). Anal. calcd. for
C24H22N2: C, 85.17; H, 6.55; N, 8.28; found: C, 84.85; H, 6.57; N, 8.22.
Compound 3i
Mp 174.9ꢁC (187–188ꢁC).[24] 1H NMR (400 MHz, CDCl3) d ¼ 8.21–8.18 (m,
2H), 7.94 (d, 1H, J¼ 8.4 Hz), 7.84–7.81 (m, 2H), 7.54 (s, 1H), 7.50 (d, 3H,
J¼ 8.4 Hz), 7.37 (d, 3H, J¼ 8.0 Hz). MS m=z (%): (M)þ ¼ 351.6 (100).
Compound 3j
Mp 170.6–172.5ꢁC (180ꢁC).[19l] 1H NMR (400 MHz, CDCl3) d ¼ 8.08 (d, 1H,
J¼ 8.4 Hz), 7.97–7.93 (m, 2H), 7.65 (d, 1H, J¼ 8.4 Hz), 7.54–7.47 (m, 4H),
7.36 (d, 3H, J¼ 8.4 Hz), 2.65 (s, 3H). MS m=z (%): (M)þ ¼ 365.6 (100).
Compound 3k
1
Mp 184.8–184.9ꢁC. IR (KBr): 3052, 1661, 1586, 1091, 836, 732 cmꢂ1. H
NMR (400MHz, CDCl3) d ¼ 8.01 (d, 1H, J ¼ 8.4 Hz), 7.94 (d, 2H,

3750
J.-F. Zhou et al.
J ¼ 8.4 Hz), 7.65 (d, 1H, J ¼ 8.8 Hz), 7.55–7.31 (m, 6H), 2.81 (s, 3H), 2.65
(s, 3H). 13C NMR (100MHz, CDCl3) d ¼ 150.1, 141.8, 140.3, 139.6, 138.3,
137.6, 135.1, 134.6, 133.4, 131.4, 131.2, 129.5, 128.6, 125.8, 20.5, 12.9. MS
m=z (%): (M)þ ¼ 379.7 (100). Anal. calcd. for C22H16Cl2N2: C, 69.67; H,
4.25; N, 7.39; found: C, 69.41; H, 4.27; N, 7.34.
Compound 3l
Mp 163.7–164.4ꢁC (176ꢁC).[19l] 1H NMR (400 MHz, CDCl3) d ¼ 9.07 (s,
1H), 8.58–8.55 (m, 1H), 8.30 (d, 1H, J ¼ 9.2 Hz), 7.56–7.52 (m, 4H), 7.41
(d, 4H, J ¼ 8.0 Hz). MS m=z (%): (M)þ ¼ 396.5 (100).
Compound 3m
Mp 133.9–134.1ꢁC (131–132ꢁC).[25] 1H NMR (400 MHz, CDCl3)
d ¼ 8.18–8.16 (m, 2H), 7.79–7.76 (m, 2H), 7.65 (s, 2H), 6.69 (d, 2H,
J ¼ 3.2 Hz), 6.60–6.58 (m, 2H). MS m=z (%): (M þ H)þ ¼ 263.7 (100).
Compound 3n
Mp 116–116.2ꢁC (119–120ꢁC).[26] 1H NMR (400MHz, CDCl3) d ¼ 8.06
(d, 2H, J ¼ 8.4 Hz), 7.96 (s, 1H), 7.64–7.60 (m, 3H), 7.67 (d, 2H, J ¼ 3.2 Hz),
), 6.58 (s, 2H), 2.62 (s, 3H). MS m=z (%): (Mþ H)þ ¼ 277.5 (100).
Compound 3o
Mp 125–125.1ꢁC. IR (KBr): 3111, 2920, 1591, 1560, 1492, 1328, 1147,
1008, 879, 759 cmꢂ1
.
1H NMR (400 MHz, CDCl3) d ¼ 7.91 (d, 1H,
J ¼ 8.8 Hz), 7.63 (s, 1H), 7.59 (d, 2H, J ¼ 9.2 Hz), 6.82 (s, 1H, J ¼ 3.2 Hz),
6.60 (d, 2H, J ¼ 3.2 Hz), 6.56 (t, 1H, J ¼ 4.8 Hz), 2.78 (s, 3H), 2.55 (s, 3H).
13C NMR (400 MHz, CDCl3) d ¼ 151.9, 151.2, 143.9, 143.6, 141.1, 139.7,
139.3, 138.3, 134.5, 133.3, 125.9, 112.3, 111.8, 20.5, 12.9. MS m=z (%):
(M þ H)þ ¼ 291.6 (100). Anal. calcd. for C18H14N2O2: C, 74.47; H,
4.86; N, 9.65; found: C, 74.19; H, 4.88; N, 9.58.
Compound 3p
Mp 169.2–169.4ꢁC. IR (KBr): 3094, 1566, 1522, 1241, 1059, 826, 741 cmꢂ1
.
1H NMR (400MHz, CDCl3) d ¼ 9.03 (d, 1H, J ¼ 2.4 Hz), 8.52–8.50 (m,

Synthesis of Quinoxalines
3751
1H), 8.25 (d, 2H, J ¼ 9.2 Hz), 7.69 (d, 1H, J ¼ 6.0 Hz), 6.91 (d, 1H,
J ¼ 3.2 Hz), 8.86 (d, 1H, J ¼ 3.2 Hz), 6.65–6.63 (m, 2H). 13C NMR
(400 MHz, CDCl3) d ¼ 150.2, 148.0, 145.4, 144. 8, 144.2, 143.0, 139.2,
130.4, 125.3, 123.6, 115.3, 114.4, 112.3. MS m=z (%): (M þ H)þ ¼ 308.3
(100). C16H9N3O4: C, 62.54; H, 2.95; N, 13.68; found: C, 65.31; H, 2.97;
N, 13.58.
ACKNOWLEDGMENT
We thank the Jiangsu Key Laboratory for Chemistry of Low-
Dimensional Materials for financial support.
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