An efficient iodine-DMSO catalyzed synthesis of quinoxaline derivatives

Article abstract of DOI:10.1016/j.tet.2015.02.003

An efficient iodine-DMSO catalyzed system for the synthesis of quinoxaline derivatives was developed. The construction of this quinoxaline system went through a one-pot oxidation/cyclization process. The reaction afforded a variety of products in good to excellent yields. This methodology has potential applications in the synthesis of biologically and medicinally relevant compounds.

Full text of DOI:10.1016/j.tet.2015.02.003

Tetrahedron xxx (2015) 1e7
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
An efficient iodineeDMSO catalyzed synthesis of quinoxaline
derivatives
Caixia Xie a, Zeyuan Zhang a, Bingchuan Yang a, Gaolei Song a, He Gao a, Leilin Wen a,
,b,
Chen Ma a
*
a Key Laboratory of Special Functional Aggregated Materials, Ministry of Education, School of Chemistry and Chemical Engineering, Shandong
University, Jinan 250100, PR China
b State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and
Peking Union Medical College, Beijing 100050, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient iodineeDMSO catalyzed system for the synthesis of quinoxaline derivatives was developed.
The construction of this quinoxaline system went through a one-pot oxidation/cyclization process. The
reaction afforded a variety of products in good to excellent yields. This methodology has potential ap-
plications in the synthesis of biologically and medicinally relevant compounds.
Ó 2015 Published by Elsevier Ltd.
Received 28 November 2014
Received in revised form 25 January 2015
Accepted 1 February 2015
Available online xxx
Keywords:
Quinoxaline
One-pot synthesis
Iodine/DMSO
Broad range of substrates
1. Introduction
diaminobenzene and alkynes. Many other methods have also been
reported, for example, Wu and co-workers16 disclosed one-pot
Quinoxaline derivatives are important classes of nitrogen con-
taining heterocycles that are found in various natural products and
biologically active compounds. Their antiviral1 and antibacterial2
activities have been widely reported. And they are also powerful
in antitumor agents.3 In addition, compounds, whose structures
consist of quinoxaline, can be used in phytohormone,4 combination
drugs,5 antipsychotics,6 electroluminescent materials7 and dye.8
Because of these extensive functions, a lot of methods have been
reported for the preparation of this type of compounds. Generally,
the following strategies are mentioned: (1) The condensation of 1,
2-dicarbonyl and o-diaminobenzene catalyzed by iodine, PAST or
Zr.9 (2) Ruthenium-catalyzed or gold-catalyzed synthesis with o-
synthesis of the quinoxaline derivatives from aryl arylmethyl (or
methyl) ketones and 1,2-diaminoarenes catalyzed by CuOeiodi-
neeDMSO in good to excellent yields. However, some of these
methods suffer from several disadvantages, such as unsatisfactory
yields, expensive metal precursors, and excessive reactants.
Moreover, most of these reports could not produce the products
bearing strong electron-withdrawing groups in good yields.
Iodine has been used as catalyst in the synthesis of organic
compounds for a long time due to its low cost and eco-friendli-
ness.17 And it has been discovered to act as an oxidant from many
previous work18,21 and we learned that the hydroxylated carbon
can be oxidized to the corresponding carbonyl with iodine as the
oxidant.17b As well as a polar aprotic solvent, DMSO is a nontoxic,
inexpensive and readily available oxidant for various organic
transformations.19 A one-pot synthetic route would be a very useful
improvement. We have been focusing on the development of direct
synthesis of heterocyclic systems using tandem reactions.20 Herein,
we report a highly efficient and simple one-pot tandem method to
synthesize quinoxaline derivatives with o-diaminobenzene and 2-
hydroxy-2-phenylacetophenone catalyzed by iodine in DMSO
(Scheme 1).
diaminobenzene and vicinal-diols.10 (3) The reaction of
a-bromo-
ketones and 1,2-diamines under HClO4/SiO2.11 (4) The oxidation
and condensation of hydroxyl ketones and 1,2-henylenediamine
catalyzed by Mn.12 (5) Copper-catalyzed synthesis with o-dia-
minobenzene and terminal alkyne in the presence of bases.13 (6)
Au/Ag-catalyzed14 or iodine-catalyzed15 synthesis with o-
* Corresponding author. Tel.: þ86 531 8836 4464; fax: þ86 531 8856 4464;
e-mail address: chenma@sdu.edu.cn (C. Ma).
http://dx.doi.org/10.1016/j.tet.2015.02.003
0040-4020/Ó 2015 Published by Elsevier Ltd.
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2
C. Xie et al. / Tetrahedron xxx (2015) 1e7
improve this protocol, but neither of them gave better yields.
Finally, we tried to investigate the possibility of direct synthesis of
quinoxaline derivatives under an air atmosphere. To our delight,
a higher yield of 92% was obtained. This probably owed to the ox-
idation of oxygen in the air. The optimized conditions were sum-
marized as follows: 25 mol % of iodine catalyst, 2 mL DMSO as the
reaction solvent, at 100 ꢀC in the first step and room temperature in
the second step without inert gas protection (Table 1, entry 19).
With the optimized reaction in hand, a variety of reactants were
tested to determine the generality and limitation of the method.
Firstly the reactions of compounds 1 and 2 with different sub-
stituent groups were examined. As shown in Table 2, all the re-
actions with different o-diaminobenzene derivatives furnished
desired products in good yields (Table 2, entries 1e5). Compounds
with electron-withdrawing groups (eCl) obtained better yields
than those with electron-donating groups (Table 2, entries 2, 3 and
5). Even compounds 2 bearing a strong electron-withdrawing
group (eNO2) gave higher yield (Table 2, entries 4, 8 and 14),
which was a major breakthrough compared with the previous
work.9 We were delighted to discover that the desired yields were
obtained from the cyclization of o-diaminobenzene and different
benzoin derivatives catalyzed by iodine in DMSO (compounds 1).
Compounds 1 with electron-donating groups gave good yields
(Table 2, entries 1, 6 and 10).
Similarly, heterocyclic hydroxy ketones proceeded well for the
present procedure. As shown in Table 3, the desired products in
good to excellent yields could also be obtained by the reaction of 4a
and 4b. Interestingly, both electron-donating and electron-
withdrawing groups are apparently well-tolerated. Electron-with-
drawing substituents in the hydroxyl ketone part led to a shorter
time in the process of oxidation (Table 3, entries 1e4). On the other
hand, the presence of electron-donating groups in hydroxyl ke-
tones might retard the nucleophilic attack on the in situ formed
dicarbonyl leading to a lower yield (Table 3, entries 5e9).
Scheme 1. Proposed procedure for the synthesis of quinoxaline derivatives.
2. Results and discussion
Our initial efforts were directed towards the best reaction con-
ditions to synthesize quinoxaline derivatives. The reaction was
initially conducted in
a one-pot manner. O-diaminobenzene
(1 mmol) and 2-hydroxy-2-phenylacetophenone (1 mmol) was
heated in DMSO at 100 ꢀC for 12 h in the presence of iodine with N2
protection. We found that the product was obtained with a 22%
yield (Table 1, entry 1). Then we attempted to do this experiment in
a one-pot two-step manner. Gratifyingly, the product was obtained
with a 59% yield (Table 1, entry 4). Inspired by this result, the re-
action
of
o-diaminobenzene
and
2-hydroxy-2-
phenylacetophenone was optimized and the results are summa-
rized in Table 1.
Table 1
Optimization of reaction conditions for the synthesis of quininoxaline in one pota
Entry
Catalyst (mmol %)
I2 (10)
Solvent
T1 (ꢀC)
T2 (ꢀC)
Yield (%)b
1c
2
3
4
5
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
Toluene
DMF
CH3CN
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
100
60
80
d
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
22
Trace
41
59
58
68
83
65
81
Trace
24
23
10
27
45
50
61
52
I
I
I
I
I
I
2 (10)
2 (10)
2 (10)
2 (10)
2 (20)
2 (25)
On the basis of the conventional quinoxalines syntheses,16,21
a plausible mechanism for the generation of quinoxalines from o-
diaminobenzenes and hydroxy ketones is depicted in Scheme 2. To
start, the hydroxyl ketones 4 were oxidized to the corresponding
dicarbonyl M1 with iodine as the oxidant. Then the iodine acted as
a mild Lewis acid and promoted the cyclization of 2 and M1 to
obtain the quinoxaline derivatives 5. Finally, with the DMSO as
oxidant, HI was oxidized into iodine, and iodine was regenerated to
make the system operate in recycle.
100
110
100
100
100
100
100
100
100
Reflux
100
100
100
100
100
100
6
7
8d
9
I2 (25)
2 (30)
d
I
10
11
12
13
14
15
16
17
18
19e
I
I
I
2 (25)
2 (25)
2 (25)
NIS (25)
NBS (25)
TBAI (25)
I
I
2 (25)/K2CO3
2 (25)/AcOH
I2 (25)
92
a
Reaction conditions: 1a (1 mmol), catalyst (25 mol %) and solvent (2 mL) were
heated for 10 h in protection of nitrogen. Then 2 were added to the mixture and
stirred at room temperature for 12 h.
b
Yield of isolated product after column chromatography based on 1a.
All the reactants were added together.
DMSO (4 mL) was used.
The reaction proceeded under an air atmosphere.
c
d
e
Firstly, several temperatures were tested under N2 atmosphere,
and the highest yield (3a) was obtained at 100 ꢀC (Table 1, entries
2e5). Based on this result, the dosages of I2 were also tested and it
was found that 25 mol % I2 gave the highest yield of 83% (Table 1,
entries 4 and 6e10). To get a better yield, several catalysts were
then tested and we failed to get any product without iodine (Table
1, entry 10). Compared with other catalysts, the reaction catalyzed
by iodine obtained a better yield (Table 1, entries 7 and 14e16).
Using iodine as catalyst, several kinds of other solvents were tested
and DMSO was showed to be the best one (Table 1, entries 8 and
11e13). In addition, we attempted to add some base or acid to
Scheme 2. Plausible mechanism for formation of 5.
3. Conclusion
In summary, we have presented a straight forward and efficient
one-pot two-step approach for the synthesis of quinoxalines from
the cyclization of o-diaminobenzenes with hydroxy ketones, using
iodine as catalyst and DMSO as solvent and oxidant. A variety of
quinoxaline derivatives were synthesized in good to excellent
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C. Xie et al. / Tetrahedron xxx (2015) 1e7
3
Table 2
Synthesis of quininoxalinesa
Entry
1
1
2
Time1 (h)
10
Time2 (h)
12
3
Yield (%)b
92
R1¼H
R2¼R3¼H
2
3
R1¼H
R1¼H
R2¼CH3
R3¼H
10
10
12
10
84
92
R2¼Cl
R3¼H
4
5
R1¼H
R1¼H
R2¼NO2
R3¼H
10
10
12
12
94
78
R2¼CH3
R3¼CH3
6
7
R1¼CH3
R1¼CH3
R2¼R3¼H
10
10
12
12
90
84
R2¼CH3
R3¼H
8
R1¼CH3
R2¼NO2
R3¼H
10
12
94
81
9
R1¼CH3
R2¼R3¼CH3
R2¼R3¼H
10
12
12
12
10
R1¼OCH3
87
(continued on next page)
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4
C. Xie et al. / Tetrahedron xxx (2015) 1e7
Table 2 (continued )
Entry
1
2
Time1 (h)
12
Time2 (h)
12
3
Yield (%)b
82
11
12
R1¼OCH3
R2¼CH3
R3¼H
R1¼OCH3
R2¼Cl
R3¼H
12
12
88
13
R1¼OCH3
R1¼OCH3
R2¼R3¼CH3
12
12
12
12
80
92
14
R2¼NO2
R3¼H
a
Reaction conditions: 1 (1 mmol), iodine (25 mol %), DMSO (2 mL) were heated to 100 ꢀC (TLC monitored), then 2 (1 mmol) was added.
Yield of isolated product after column chromatography based on 1.
b
Table 3
Synthesis of heterocyclic quininoxalinesa
Entry
1
4
2
Time1 (h)
Time2 (h)
5
Yield (%)b
R2¼R3¼H
6
12
94
2
3
4a
4a
R2¼H
6
6
12
12
92
99
R3¼CH3
R2¼H
R3¼Cl
4
5
4a
R2¼H
6
12
12
96
88
R3¼NO2
R2¼R3¼H
10
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C. Xie et al. / Tetrahedron xxx (2015) 1e7
5
Table 3 (continued )
Entry
4
2
Time1 (h)
Time2 (h)
5
Yield (%)b
6
4b
R2¼H
10
12
12
85
R3¼CH3
7
8
4b
R2¼H
R3¼Cl
10
95
4b
4b
R2¼R3¼CH3
10
10
12
12
81
97
9
R2¼H
R3¼NO2
a
Reaction conditions: 4 (1 mmol), iodine (25 mol %), DMSO (2 mL) were heated to 100 ꢀC (TLC monitored), then 2 (1 mmol) was added.
Yield of isolated product after column chromatography based on 4.
b
yields. This one-pot metal-free approach for the construction of
quinoxaline has potential applications in biological chemistry and
medicinal chemistry.
129.55, 129.47, 128.78, 128.73, 128.01; HRMS calcd for C20H14N2
(MþH)þ 283.1230; found: 283.1232.
4.2.2. 6-Methyl-2,3-diphenylquinoxaline (3b). White solid. Mp
115.7e116.9 ꢀC. 1H NMR (300 MHz, DMSO-d6):
d
8.04 (1H, J¼8.4 Hz,
4. Experimental section
4.1. General
d), 7.94 (1H, s), 7.71 (2H, J¼8.4, 1.8 Hz, dd), 7.48e7.45 (4H, m),
7.43e7.32 (6H, m), 2.59 (3H, s); 13C NMR (75 MHz, DMSO-d6):
d
152.82, 152.08, 140.52, 140.50, 138.92, 138.85, 132.52, 129.63,
128.64, 128.57, 128.32, 127.98, 127.47, 21.32; HRMS calcd for
C
All the reagents were commercially available and were used
without further purification. All reactions were monitored by thin-
layer chromatography (TLC). 1H NMR spectra were recorded on
a Bruker Avance 400 or 300 spectrometer 400 or 300 MHz, using
CDCl3 or DMSO-d6 as solvent and tetramethylsilane (TMS) as in-
ternal standard. 13C NMR spectra were run in the same instrument
75 MHz. HRMS spectra were determined on a Q-TOF6510 spectro-
graph (Agilent).
21H16N2 (MþH)þ 297.1386; found: 297.1391.
4.2.3. 6-Chloro-2,3-diphenylquinoxaline (3c). White solid. Mp
122.0e122.7 ꢀC. 1H NMR (300 MHz, DMSO-d6):
8.25 (1H, J¼2.1 Hz,
d), 8.19 (1H, J¼9.0 Hz), 7.92 (1H, J¼2.1, 9.0 Hz, dd), 7.50e7.35 (10H,
m); 13C NMR (75 MHz, DMSO-d6):
154.04, 153.45, 140.76, 139.10,
d
d
138.39, 138.33, 134.60, 130.94, 129.68, 129.65, 129.00, 128.04,
127.48; HRMS calcd for C20H13ClN2 (MþH)þ 317.0840; found:
317.0851.
4.2. General procedure for the synthesis of 3-
diphenylquinoxaline 3a
4.2.4. 6-Nitro-2,3-diphenylquinoxaline (3d). Yellow solid. Mp
184.7e185.5 ꢀC. 1H NMR (300 MHz, DMSO-d6):
d
8.95 (1H, J¼1.8 Hz,
d), 8.57 (1H, J¼1.8, 9.0 Hz, dd), 8.38 (1H, J¼9.3 Hz, d), 7.54e7.52 (4H,
m), 7.48e7.37 (6H, m); 13C NMR (75 MHz, DMSO-d6):
156.04,
A mixture of 2-hydroxy-1, 2-diphenylethanone (1.0 mmol) and
iodine (25 mol %) in DMSO (2 mL) was stirred at 100 ꢀC under an air
atmosphere. TLC monitored the end of the reaction. Then the
mixture was cooled to room temperature, and benzene-1,2-
diamine (1.0 mmol) was added into the mixture and stirred for
several hours. TLC monitored the end of the reaction. Then H2O
(100 mL) was added and the mixture was filtered and extracted
with ethyl acetate. The combined organic layer was washed by
chilled water, dried by Mg2SO4 for 10 min, filtered, and evaporated
in vacuo. The product was purified by flash column chromatogra-
phy on silica gel by petroleum ether and ethyl acetate (20:1). White
solid was obtained as 3a (0.25 g).
d
155.38, 147.64, 142.98, 139.21, 137.97, 137.94, 130.94, 129.79, 129.71,
129.5, 129.36, 128.13, 124.83, 123.57; HRMS calcd for C20H13N3O2
(MþH)þ 328.1081; found: 328.1083.
4.2.5. 6,7-Dimethyl-2,3-diphenylquinoxalin (3e). White solid. Mp
175.5e176.6 ꢀC. 1H NMR (300 MHz, CDCl3):
d
7.92 (2H, s), 7.511e7.47
(4H, m), 7.35e7.26 (6H, m), 2.52 (6H, s); 13C NMR (75 MHz, CDCl3):
d
152.50, 140.53, 140.22, 139.38, 129.86, 128.53, 128.22, 128.19,
20.42; HRMS calcd for C22H18N2 (MþH)þ 311.1543; found: 311.1550.
4.2.6. 2,3-Di-p-tolylquinoxaline
148.5e149.7 ꢀC. 1H NMR (300 MHz, DMSO-d6):
7.89e7.83 (2H, m), 7.39 (4H, J¼8.1 Hz, d), 7.18 (4H, J¼7.8 Hz, d), 2.33
(6H, s); 13C NMR (75 MHz, DMSO-d6):
152.93, 140.34, 138.27,
(3f). White
solid.
8.16e8.10 (2H, m),
Mp
4.2.1. 2,3-Diphenylquinoxaline
116.5e117.7 ꢀC. 1H NMR (300 MHz, DMSO-d6):
7.95e7.81 (2H, m), 7.50e7.47 (4H, m), 7.45e7.33 (6H, m); 13C NMR
(75 MHz, DMSO-d6): 153.04, 140.43, 138.75, 130.38, 129.66,
(3a). White
solid.
8.19e8.14 (2H, m),
Mp
d
d
d
d
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6
C. Xie et al. / Tetrahedron xxx (2015) 1e7
136.04, 130.14, 129.56, 128.68, 128.64, 20.81; HRMS calcd for
C
139.75, 131.50, 131.34, 130.64, 130.39, 125.39, 122.87, 113.98, 55.37;
22H18N2 (MþH)þ 311.1543; found: 311.1542.
HRMS calcd for C22H17N3O4 (MþH)þ 388.1292; found: 388.1393.
4.2.7. 6-Methyl-2,3-di-p-tolylquinoxaline (3g). White solid. Mp
130.7e132.0 ꢀC. 1H NMR (300 MHz, CDCl3):
4.2.15. 2,3-Di(pyridin-2-yl)quinoxaline (5a). Yellow solid. Mp
d
8.04 (1H, J¼8.4 Hz,
179.4e181.1 ꢀC. 1H NMR (300 MHz, DMSO-d6):
d
8.29e8.20 (4H, m),
d), 7.93 (1H, s), 7.57 (1H, J¼8.4, 1.8 Hz, dd), 7.41 (4H, J¼1.2, 7.8 Hz,
8.03e7.93 (6H, m), 7.38e7.34 (2H, m); 13C NMR (75 MHz, DMSO-
dd), 7.13 (4H, J¼7.8 Hz, d), 2.60 (3H, s), 2.36 (6H, s); 13C NMR
d6):
d 158.09, 153.54, 149.20, 141.37, 137.94, 132.14, 130.08, 125.01,
(75 MHz, CDCl3):
d
153.30, 152.59, 141.14, 140.18, 139.59, 138.65,
124.39; HRMS calcd for
285.1135.
C
18H12N4 (MþH)þ 285.1135; found:
138.57,136.47, 132.02, 129.74, 129.71, 128.94, 128.60, 127.92, 21.87,
21.83; HRMS calcd for
325.1699.
C
23H20N2 (MþH)þ 325.1699; found:
4.2.16. 6-Methyl-2,3-di (pyridin-2-yl)quinoxaline (5b). Yellow solid.
Mp 136.8e137.9 ꢀC. 1H NMR (300 MHz, CDCl3):
8.39e8.37 (2H, m),
d
4.2.8. 6-Nitro-2,3-di-p-tolylquinoxaline (3h). Yellow solid. Mp
169.3e170.1 ꢀC. 1H NMR (300 MHz, CDCl3):
8.12 (1H, J¼8.7 Hz, d), 8.00e7.94 (3H, m), 7.85e7.78 (2H, m), 7.66
d
9.40 (1H, J¼2.7 Hz,
(1H, J¼8.7, 2.1 Hz, dd), 7.26e7.22 (2H, m); 13C NMR (75 MHz,
d), 8.49 (1H, J¼2.4, 9.0 Hz, dd), 8.25 (1H, J¼9.0 Hz, d), 7.49e7.45
CDCl3): d 157.46, 152.18, 148.43, 141.27, 142.19, 139.69, 136.73,
(4H, m), 7.26e7.17 (4H, m), 2.39 (6H, s); 13C NMR (75 MHz,
132.90,128.90,124.32, 124.30,122.95,122.89, 21.95; HRMS calcd for
CDCl3):
d
156.32, 155.70, 147,71, 143.56, 140.02, 139.88, 139.83,
C
19H14N4 (MþH)þ 299.1291; found: 299.1294.
135.44, 135.38, 130.61, 129.84, 129.74, 129.18, 125.54, 123.03,
21.42; HRMS calcd for C22H17N3O2 (MþH)þ 356.1394; found:
356.1390.
4.2.17. 6-Chloro-2,3-di(pyridin-2-yl)quinoxaline (5c). Yellow solid.
Mp 109.9e110.3 ꢀC. Mp 116.5e117.7 ꢀC. 1H NMR (300 MHz, DMSO-
d6):
NMR (75 MHz, DMSO-d6):
d C
8.32e8.24 (4H, m), 8.03e7.93 (5H, m), 7.40e7.34 (2H, m); 13
4.2.9. 6,7-Dimethyl-2,3-di-p-tolylquinoxaline (3i). White solid. Mp
d 156.94, 156.90, 153.63, 153.04, 148.46,
130.6e131.4 ꢀC. 1H NMR (300 MHz, CDCl3):
d
7.89 (2H, s), 7.40 (4H,
140.95, 139.28, 137.22, 135.65, 131.94, 128.04, 124.29, 124.24, 123.82,
123.76; HRMS calcd for C18H11ClN4 (MþH)þ 319.0745; found:
319.0745.
J¼8.1 Hz, d), 7.13 (4H, J¼8.1 Hz, d), 2.50 (6H, s), 2.36 (6H, s); 13C NMR
(75 MHz, CDCl3):
d 152.49, 140.19, 140.09, 138.43, 136.63, 129.73,
128.90, 128.13, 21.32, 20.37; HRMS calcd for C24H22N2 (MþH)þ
339.1856; found: 339.1874.
4.2.18. 6-Nitro-2,3-di(pyridin-2-yl)quinoxaline (5d). Yellow solid.
Mp 184.4e185.6 ꢀC. 1H NMR (300 MHz, DMSO-d6):
d 9.04 (1H,
4.2.10. 2,3-Bis(4-methoxyphenyl) quinoxaline (3j). White solid. Mp
J¼2.7 Hz, d), 8.49 (1H, J¼2.4, 9.0 Hz, dd), 8.25 (1H, J¼9.0 Hz, d),
131.6e132.8 ꢀC. 1H NMR (300 MHz, CDCl3):
d
8.17e8.12 (2H, m),
7.76e7.70 (2H, m), 7.52e7.48 (4H, m), 7.26e6.85 (4H, m), 3.84 (6H,
s); 13C NMR (75 MHz, CDCl3):
160.24, 152.99, 140.96, 131.57,
7.49e7.45 (4H, m), 7.26e7.17 (4H, t); 13C NMR (75 MHz, DMSO-d6):
d
156.08, 154.93, 154.34, 148.18, 148.10, 142.75, 139.10, 137.01,
d
130.89, 124.95, 124.19, 124.08, 123.96, 123.81, 123.71; HRMS calcd
131.28, 129.61, 128.94, 113.81, 55.31; HRMS calcd for C22H18N202
for C18H11N5O2 (MþH)þ 330.0986; found: 330.0981.
(MþH)þ 343.1441; found: 343.1442.
4.2.19. 2,3-Di(furan-2-yl)quinoxaline
131.3e131.6 ꢀC. 1H NMR (300 MHz, DMSO-d6):
7.92e7.86 (4H, m), 6.74e6.72 (4H, m); 13C NMR (75 MHz, DMSO-
(5e). Grey
solid.
Mp
4.2.11. 2,3-Bis(4-methoxyphenyl)-6-methylquinoxaline (3k). White
d
8.14e8.08 (1H, m),
solid. Mp 99.5e100.7 ꢀC. 1H NMR (300 MHz, CDCl3):
d 8.02 (1H,
J¼8.4 Hz, d), 7.92 (1H, s), 7.56 (1H, J¼1.8, 8.7 Hz, dd), 7.51e7.45
d6): d 150.31, 144.91, 142.07, 139.92, 130.90, 128.68, 112.85, 112.15;
(4H, m), 6.89e6.85 (4H, m), 3.83 (6H, s), 2.60 (3H, s); 13C NMR
HRMS calcd for C16H10N2O2 (MþH)þ 263.0815; found: 263.0827.
(75 MHz, CDCl3):
d 160.16, 160.09, 152.81, 152.12, 140.99, 140.11,
139.46, 131.93, 131.75, 131.70, 131.27, 131.22, 128.47, 127.78, 113.76,
55.30; HRMS calcd for C23H20N2O2 (MþH)þ 357.1598; found:
357.1587.
4.2.20. 2,3-Di(furan-2-yl)-6-methylquinoxaline (5f). Grey solid. Mp
113.2e114.9 ꢀC. 1H NMR (300 MHz, CDCl3):
d
8.05 (2H, J¼8.4 Hz, d),
7.95 (1H, s), 7.62e7.57 (3H, t), 6.67e6.55 (4H, m), 2.60 (3H, s); 13C
NMR (75 MHz, CDCl3): 150.89, 144.18, 144.04, 142.56, 141.85,
d
4.2.12. 6-Chloro-2,3-bis(4-methoxyphenyl)quinoxaline (3l). White
141.20, 140.68, 139.10, 132.84, 128.62, 127.94, 112.92, 112.64, 111.90,
111.87, 21.94; HRMS calcd for C17H12N2O2 (MþH)þ 277.0972; found:
277.0970.
solid. Mp 148.6e149.5 ꢀC. 1H NMR (300 MHz, CDCl3):
d 8.13 (1H,
J¼2.1 Hz, d), 8.07 (1H, J¼9.0 Hz, d), 7.66 (1H, J¼2.4, 9.0 Hz, dd),
7.51e7.47 (4H, m), 6.90e6.85 (4H, m), 3.84 (6H, s); 13C NMR
(75 MHz, CDCl3):
d
160.49, 160.42, 153.79,153.11,141.24, 139.42,
4.2.21. 6-Chloro-2,3-di(furan-2-yl)quinoxaline (5g). Grey solid. 1H
135.24, 131.32, 131.25, 131.20,131.13, 130.55, 130.13, 127.82,
113.86,55.33; HRMS calcd for C22H17ClN2O2 (MþH)þ 377.1051;
found: 377.1050.
NMR (300 MHz, DMSO-d6):
d
8.19 (1H, J¼2.1 Hz, d), 8.16 (1H,
J¼9.0 Hz, d), 7.94e7.87(3H, m), 6.78e6.72 (4H, m); 13C NMR
(75 MHz, DMSO-d6): d 150.03, 149.95, 145.32, 145.15, 142.83, 140.28,
138.59, 135.12, 131.37, 130.50, 127.36, 113.58, 113.28, 112.29, 112.25;
4.2.13. 2,3-Bis(4-methoxyphenyl)-6,7-dimethylquinoxaline
HRMS calcd for C16H9ClN2O2 (MþH)þ 297.0425; found: 297.0427.
(3m). White solid. Mp 123.6e124.7 ꢀC. 1H NMR (300 MHz, CDCl3):
d
7.89 (2H, s), 7.49e7.44 (4H, m), 6.89e6.84 (4H, m), 3.83 (6H, s),
4.2.22. 2,3-Di(furan-2-yl)-6,7-dimethylquinoxaline
(5h). Yellow
d 7.89 (2H, s),
2.50 (6H, s); 13C NMR (75 MHz, CDCl3):
d
159.98, 152.08, 140.06,
solid. Mp 115.6e116.5 ꢀC. 1H NMR (300 MHz, CDCl3):
140.00, 132.09, 131.22, 128.10, 113.72, 55.31; HRMS calcd for
C
7.61e7.60 (2H, t), 6.61e6.54 (4H, m), 2.50 (6H, s); 13C NMR (75 MHz,
24H22N2O2 (MþH)þ 371.1754; found: 371.1756.
CDCl3): d 151.08, 143.88, 141.85, 141.16, 139.64, 128.17, 112.38, 111.79,
20.41; HRMS calcd for C18H14N2O2 (MþH)þ 291.1128; found:
4.2.14. 2,3-Bis(4-methoxyphenyl)-6-nitroquinoxaline (3n). Yellow
solid. Mp 190.5e191.6 ꢀC. 1H NMR (300 MHz, CDCl3):
9.02 (1H,
291.1129.
d
J¼2.4 Hz, d), 8.48 (1H, J¼2.4, 9.0 Hz, dd), 8.24 (1H, J¼9.0 Hz, d),
4.2.23. 2,3-Di(furan-2-yl)-6-nitroquinoxaline (5i). Yellow solid. Mp
7.59e7.52 (4H, m), 6.92e6.89 (4H, t), 3.86 (6H, s); 13C NMR
166.2e167.5 ꢀC. 1H NMR (300 MHz, DMSO-d6):
d
8.83 (1H, J¼2.7 Hz,
(75 MHz, CDCl3):
d 161.02, 160.87, 155.75, 155.17, 147.58, 143.46,
d), 8.51 (1H, J¼2.4, 9.3 Hz, dd), 8.27 (1H, J¼9.0 Hz, d), 8.00e7.98 (2H,
Please cite this article in press as: Xie, C.; et al., Tetrahedron (2015), http://dx.doi.org/10.1016/j.tet.2015.02.003

C. Xie et al. / Tetrahedron xxx (2015) 1e7
7
m), 6.93e6.76 (4H, m); 13C NMR (75 MHz, DMSO-d6):
d 149.74,
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2001, 11, 2238.
9. (a) Kumbhar, A.; Kamble, S.; Barge, M.; Rashinkar, G.; Salunkhe, R. Tetrahedron
Lett. 2012, 53, 2756; (b) More, S. V.; Sastry, M. N. V.; Wang, C.; Yao, C. Tetra-
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16H9N3O4 (MþH)þ 308.0666; found: 308.0677.
Acknowledgements
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We are grateful to the National Science Foundation of China (No.
21172131) and State Key Laboratory of Bioactive Substance and
Function of Natural Medicines, Institute of Materia Medica, Chinese
Academy of Medical Sciences and Peking Union Medical College
(No. GTZK 201405) for financial support of this research.
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Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.tet.2015.02.003.
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Please cite this article in press as: Xie, C.; et al., Tetrahedron (2015), http://dx.doi.org/10.1016/j.tet.2015.02.003