Chemoselective synthesis of quinoxalines and benzimidazoles by silica gel catalysis

Article abstract of DOI:10.1016/j.tetlet.2014.08.022

Treatment of nitroolefins and o-phenylenediamine with silica gel catalyst produced quinoxalines mainly in THF, but gave benzimidazoles efficiently in water. Such a solvent-dependent chemoselective reaction has prominent features of affording two cyclized products selectively with the same substrate, short reaction time, operational simplicity, as well as available starting materials and nontoxic catalysts. In addition, the scope and limitations were explored and a plausible reaction mechanism is proposed.

Full text of DOI:10.1016/j.tetlet.2014.08.022

Tetrahedron Letters 55 (2014) 5430–5433
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Chemoselective synthesis of quinoxalines and benzimidazoles
by silica gel catalysis
⇑
⇑
Chunmei Li, Furen Zhang , Zhen Yang, Chenze Qi
Zhejiang Key Laboratory of Alternative Technologies for Fine Chemicals Process, Shaoxing University, Shaoxing, Zhejiang Province 312000, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Treatment of nitroolefins and o-phenylenediamine with silica gel catalyst produced quinoxalines mainly
in THF, but gave benzimidazoles efficiently in water. Such a solvent-dependent chemoselective reaction
has prominent features of affording two cyclized products selectively with the same substrate, short
reaction time, operational simplicity, as well as available starting materials and nontoxic catalysts. In
addition, the scope and limitations were explored and a plausible reaction mechanism is proposed.
Ó 2014 Elsevier Ltd. All rights reserved.
Received 17 April 2014
Revised 29 July 2014
Accepted 8 August 2014
Available online 14 August 2014
Keywords:
Nitroolefins
Solvent-dependent reaction
Silica gel
Quinoxaline
Benzimidazole
Introduction
Silica gel, which is a mild acid, easily available, inexpensive, and
nontoxic, can act as a catalyst in the condensation reaction.12 The
Quinoxaline is an important class of benzo-heterocyclic pyra-
zine compound and has been widely used as a key building block
in pharmaceutical agents and functional materials. Its derivatives
exhibit various biological activities, such as anti-inflammatory,1
anticancer,2 antiviral,3 antibacterial,4 antibiotic, and kinase inhibi-
tion.5 They have also been applied in dyes,6 organic semiconduc-
tors,7 electroluminescent materials, and dehydroannulenes.8 Due
to the wide usefulness and growing importance, many powerful
methodologies for assembling these heterocycles have been devel-
oped. The condensation of aryl-1,2-diamine with two-carbon syn-
thons under a variety of conditions is a conventional approach to
construct quinoxalines.9,10 Other strategies for the synthesis of
quinoxaline derivatives were also developed. For example, Chen
and co-workers described the synthesis of quinoxalines from
o-phenylenediamine and nitroolefins in the presence of 10 mol %
of CuBr2 in EtOH at 110 °C.11 Despite the advances of these meth-
odologies, in some cases, most of the reported methods suffer from
one or more limitations such as the use of expensive reagents/
additives, metal catalysts, special apparatus, or harsh reaction
conditions, as well as the tedious work-up procedures. Thus, the
development of a mild and eco-friendly synthetic protocol for
these highly significant classes of compounds is still desirable.
usage of such a heterogeneous catalyst instead of traditional
homogeneous base and metal catalysts offers several advantages,
such as the ease of crude product separation, potential catalyst
reuse, and environmentally friendly alternative. In addition, the
solvent-dependent chemoselective reactions are of obvious value
because it gives one of several products selectively from the same
substrate without the need to separate the product(s) from the
product mixture. Therefore, the development of solvent-dependent
chemoselective reactions is a worthy goal.
Recently, we developed an efficient and mild method for the
synthesis of tetrahydro-4H-indol-4-one derivatives with cyclohex-
ane-1,3-dione, amines, and nitroolefins.13 During the continuation
of this project, we found that when o-phenylenediamine was
employed as amine substrate, the reaction afforded quinoxalines
or benzimidazoles by varying the reaction media, respectively.
We therefore describe here a new solvent-controlled method for
the chemoselective synthesis of quinoxalines and benzimidazoles
(Scheme 1).
Results and discussion
In the initial experiment, the nitroolefin 1a which was derived
from the reaction of nitroethane with benzaldehyde was subjected
to the reaction with o-phenylenediamine (2a) in the presence of
silica gel at 50 °C in different solvents, such as THF, EtOH, i-PrOH,
DCM, H2O, DMF, and toluene. The results of the screening of
⇑
Corresponding authors. Tel./fax: +86 575 88345682.
E-mail addresses: frzhang@usx.edu.cn (F. Zhang), qichenze@usx.edu.cn (C. Qi).
http://dx.doi.org/10.1016/j.tetlet.2014.08.022
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.

C. Li et al. / Tetrahedron Letters 55 (2014) 5430–5433
5431
Table 2
R3
N
N
R1
R2
R3
N
N
R2
R1
Silica gel
Synthesis of quinoxalines 3 with o-phenylenediamine 2aa
+
THF, 50oC
R3
NH2
NH2
NO2
R2
R1
+
NH2
N
R
3
NO2
Silica gel
3'
R
+
R3
N
Silica gel
1
THF, 50oC
2
N
NH2
2a
R1
H2O, 50oC
N
H
1
3
4
Entry
3
R
Time (h)
Yieldb (%)
Scheme 1. Solvent-dependent chemoselective synthesis of quinoxalines and
1
2
3
4
5
6
7
8
9
3a
3b
3c
3d
3e
3f
3g
3h
3i
C6H5 (1a)
5
5
5
5
5
5
5
6
6
5
6
5
8911
8710j
9211
8611
8811
8711
7111
6511
6910t
7811
7511
8610t
benzimidazoles.
4-F–C6H4 (1b)
4-Cl–C6H4 (1c)
4-Br–C6H4 (1d)
4-Me–C6H4 (1e)
4-OMe–C6H4 (1f)
4-NO2–C6H4 (1g)
2-NO2–C6H4 (1h)
3-NO2–C6H4 (1i)
2,4-Cl–C6H3 (1j)
2-Furyl (1k)
solvents are presented in Table 1 (entries 1–7). When ethanol and
i-PrOH were employed as reaction media, the reaction gave a
mixture of 3a and 4a. While four aprotic solvents (THF, DCM,
DMF, and toluene) were used as the solvent, only quinoxaline 3a
was obtained with 89%, 81%, 18%, and 52% yields, respectively
(entries 1–4), whereas the reaction in water gave benzimidazole
in 83% yield. Thus, the reaction could be directed cleanly to form
two different products, quinoxaline 3a and benzimidazole 4a, by
changing the reaction medium. Clearly, the nature of solvent
greatly influenced the reaction.
10
11
12
3j
3k
3l
2-Thienyl (1l)
a
Reaction conditions: 1 (0.50 mmol), 2a (0.50 mmol), silica gel (200 mg), and
THF (3.0 mL).
b
Isolated yields.
For further screening of the reaction conditions for the chemo-
selective reaction, several other bases or acid catalysts were evalu-
ated for their catalytic efficiency in the reaction (Table 1, entries
8–13). In all case 10% of the catalyst was used and the reaction
was carried out at 50 °C in THF. However, none of the tested cata-
lysts proved better than silica gel. To identify the optimum reaction
temperature, the reaction was carried out with silica gel at room
temperature, 40, and 80 °C in THF, respectively. The results indi-
cated that the yield of 3a improved and the reaction time was
shortened as the temperature increased from rt to 50 °C (Table 1,
entries 1, 14, and 15). When further increasing the temperature
to 80 °C, no significant improvement in yield was observed (Table 1,
entry 16).
fluoro, chloro, bromo, and nitro groups. It is worth noting that
strong electron-withdrawing substituted groups of nitroolefins
such as nitro had a noticeable impact on yield (entries 7–9).
Additionally, it should be noted that good results were also
obtained by using other aromatic systems, such as 2-thienyl-1-
nitroethene and 2-furyl-1-nitroethene (entries 11 and 12).
However, when (E)-(2-nitroprop-1-en-1-yl)benzene was replaced
with (Z)-bromonitrostyrene, (E)-(2-nitrovinyl)benzene, and (E)-
(2-nitrobut-1-en-1-yl)benzene, respectively, none of target
product was obtained at similar conditions, probably because of
the action of the strong inductive effect of the bromine atom and
Under the above optimized reaction conditions, we then exam-
ined the scope of the reaction for the construction of various quin-
oxaline derivatives by alternating the substituted nitroolefin 1 and
o-phenylenediamine 2a (Table 2). As shown in Table 2, a wide
range of substituted groups of nitroolefins gave the desired prod-
ucts in good to excellent yields, which include methyl, methoxy,
the
r–p hyperconjugation between CAH bond and double bond,
which influence the stability of the substrates.
To further expand the scope of diamine substrates, we
employed different nitroolefins as model substrates and examined
different diamines, including 4-methylbenzene-1,2-diamine, 4-
chlorobenzene-1,2-diamine, and (R/S)-cyclohexane-1,2-diamine.
When 4-methylbenzene-1,2-diamine and 4-chlorobenzene-1,
2-diamine were used under the optimized conditions, the reactions
proceeded smoothly to provide moderate to good yields and differ-
ent ratios of isomers 3 and 30 were observed, confirmed by 1H NMR
(Table 3). However, (R/S)-cyclohexane-1,2-diamine failed to give
the desired products.
Subsequently, we found that the desired product 3 can be
obtained, but with poor yield by the one-pot, three-component
reaction, while modifying the conditions slightly. In an attempt
to enhance further, the reaction of o-phenylenediamine, benzalde-
hyde, and nitroethane was tested under a variety of different con-
ditions. Unfortunately, only 35% yield of 3a was obtained in the
presence of silica gel at 100 °C in 24 h. The method could also be
successfully extended to substituted-benzaldehydes 5 for synthe-
sizing corresponding quinoxaline derivatives with low to moderate
yields (Table 4, entries 2–13).
In addition, the scope of the reaction of using silica gel catalyst
in water to give benzimidazoles was validated with similar condi-
tions. To our delight, a wide range of substituted groups of nitro-
olefins can give benzimidazole products in good to excellent
yields (Table 5).
Although the effect of solvent to direct the subsequent pro-
cesses to quinoxaline and benzimidazole systems, respectively,
remains to be fully clarified, the nature of solvent must play a role
in determining the product distribution. To probe the mechanism
of the reaction, several control experiments were performed. The
reactions were carried out with 1a (0.5 mmol) and 2a (0.5 mmol),
Table 1
Optimization of reaction conditions for the synthesis of 3a and 4aa
NH2
NH2
NO2
N
N
+
+
N
H
N
3a
1a
2a
4a
Entry
Solvent
Cat.b
T (°C)
Yieldc (%)
3a
4a
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
THF
Silica gel
Silica gel
Silica gel
Silica gel
Silica gel
Silica gel
Silica gel
Et3N
DMAP
HCl
TFA
HOAc
50
50
50
50
50
50
50
50
50
50
50
50
50
rt
89
81
18
52
75
65
Trace
45
40
31
77
63
37
0
0
0
CH2Cl2
DMF
Toluene
EtOH
iPrOH
H2O
THF
THF
THF
THF
0
20
25
83
0
0
0
0
0
0
0
THF
THF
THF
THF
Y(OTf)3
Silica gel
Silica gel
Silica gel
42
58
90
40
80
0
0
THF
a
b
c
Reaction conditions: 1a (0.50 mmol), 2a (0.50 mmol), and solvent (3.0 mL), 5 h.
Catalysts (10 mol %) or silica gel (200 mg).
Isolated yields.

5432
C. Li et al. / Tetrahedron Letters 55 (2014) 5430–5433
Table 3
Table 5
Synthesis of quinoxalines 3/30 with 4-substituted o-phenylenediamine 2a
Synthesis of benzimidazoles 4 in watera
R2
N
N
NH2
NH2
R2
NH2
NH2
R2
N
R1
NO2
R2
NO2
Silica gel
Silica gel
H2O, 50oC
R1
R1
R1
+
+
R2CH2NO2
+
THF, 50oC
N
N
3
R1
N
3'
H
1
2
1
2a
4
Entry
3/30
R1
R2
Yieldb (%) (3/30)c
Entry
4
R1
C6H5
4-Cl–C6H4
4-Br–C6H4
4-Me–C6H4
4-OMe–C6H4
C6H5
4-Cl–C6H4
4-Br–C6H4
4-Me–C6H4
4-OMe–C6H4
R2
Time (h)
Yieldb (%)
1
2
3
4
5
6
7
8
9
3ab/30ab
3bb/30bb
3cb/30cb
3eb/30eb
3fb/30fb
3ac/30ac
3bc/30bc
3cc/30cc
3dc/30dc
C6H5 (1a)
Me(2b)
Me(2b)
Me(2b)
Me(2b)
Me(2b)
Cl(2c)
Cl(2c)
Cl(2c)
Cl(2c)
80 (3/2)11
79 (3/2)
81 (3/2)
76 (1/1)
81 (7/3)
78 (3/2)11
72 (4/1)14
80 (3/2)
69 (3/2)
1
2
3
4
5
6
7
8
9
4a
4b
4c
4d
4f
4g
4h
4i
Me
Me
Me
Me
Me
H
H
H
H
H
5
5
5
5
5
4
4
4
4
4
8315b
8215b
7715a
7715b
7915b
8515b
8715b
8015a
8315b
8515b
4-F–C6H4 (1b)
4-Cl–C6H4 (1c)
4-Me–C6H4 (1e)
4-OMe–C6H4 (1f)
C6H5 (1a)
4-F–C6H4 (1b)
4-Cl–C6H4 (1c)
4-Br–C6H4 (1d)
4j
4k
10
a
Reaction conditions: 1 (0.50 mmol), 2 (0.50 mmol), silica gel (200 mg), and THF
(3.0 mL), 5 h.
a
Reaction conditions: 1 (0.50 mmol), 2a (0.50 mmol), silica gel (200 mg), and
water (3.0 mL).
b
Total isolated yields of compounds 3 and 30.
Determined by 1H NMR of the crude mixture.
c
b
Isolated yields.
Table 4
H
Three-component synthesis of quinoxalines 3a
H
N
H
N
Ph
N
Ph
OH -H2O
OH
Ph
N
N
3
Ph
-HNO
air
-H2O
H+
N
R
NH2
NH2
N
H
N
N O
OH
N
H
D
Silica gel
RCHO
C2H5NO2
100oC, 24-40h
N
3
A
NH2
2a
C
6
5
r
o
u
t
e
r
i
T
NH2
H
H
F
b
Ph
N
Entry
3
R
Time (h)
Yield (%)
NH2
NH2
NO2
N
Ph
NO2
1
2
3
4
5
6
7
8
9
3a
3b
3c
3d
3e
3f
3g
3h
3i
C6H5 (5a)
24
24
24
24
24
24
24
36
36
36
24
24
3511
4310j
4411
2311
3511
2611
3411
3011
2610t
1811
2311
3910t
B
e
t
a
4-F–C6H4 (5b)
4-Cl–C6H4 (5c)
4-Br–C6H4 (5d)
4-Me–C6H4 (5e)
4-OMe–C6H4 (5f)
4-NO2–C6H4 (5g)
2-NO2–C6H4 (5h)
3-NO2–C6H4 (5i)
2,4-Cl–C6H3 (5j)
2-Furyl (5k)
w
ii
1
2a
e
t
u
o
r
H
N
H
N
Ph
Ph
H+
air
-H2O
N
-CH3CH2NO2
Ph
H
Ph
N
H
NH2
NH2
N
H
N O
OH
E
4
A
F
Scheme 2. The plausible mechanism for the formation of 3 and 4.
10
11
12
3j
3k
3l
2-Thienyl (5l)
different solvents were used. The reaction gave the desired prod-
ucts 3 and 4 with good to excellent yields and chemo- and regiose-
lectivity that avoided tedious workup and purification steps. More
importantly, the use of silica gel as catalyst in water or THF at 50 °C
makes it quite simple, more convenient, and environmentally
benign.
a
Reaction conditions: 5 (0.50 mmol), 2a (0.50 mmol), C2H5NO2 (3.0 mL), silica
gel (200 mg), and THF (3.0 mL).
b
Isolated yields.
in the presence of silica gel in THF and water, respectively, at 50 °C
with TLC monitoring for the formation of intermediates. We found
that THF and water afforded the same intermediate B, which was
separated and identified by various spectral data. Based on the
above observations and the analogous mechanisms discussed in
the literature,15 a plausible mechanism for this reaction was pro-
posed as shown in Scheme 2. Firstly, the intermediate A, which fur-
ther isomerized to B, was obtained from the Michael addition of
nitroolefins 1 to o-phenylenediamine 2a. Then, it is our supposition
that the intermediate A was more stable in aprotic solvent THF and
provided a route i to give desired product 3. With silica gel serving
as mild acid, the intermediate C was produced via intramolecular
cyclization. Subsequently, the intermediate C underwent elimina-
tion of H2O and HNO followed by aromatization under aerial
oxidation to the desired product 3. In protic solvent water, the
Acknowledgments
We are grateful for the financial support from the Science Tech-
nology Department of Zhejiang Province (No. 2010R50014-17),
Natural Science Foundation of China (No. 21302129), Science
Foundation of Zhejiang Province (No. LQ13B020002) and the
Research Funds of Shaoxing University (No. 2013LG1005).
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2014.
08.022.
intermediate
A was unstable and underwent elimination of
References and notes
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resulting in the formation of the intermediate F, which further
aromatized under aerial oxidation to give benzimidazole 4.
In conclusion, we have demonstrated an efficient and practical
approach for the chemo- and regioselective synthesis of quinoxa-
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14. General procedure for the synthesis of quinoxalines 3bc and 30bc: In a 10-mL
reaction vial, (E)-1-fluoro-4-(2-nitroprop-1-en-1-yl)benzene 1b (90.5 mg,
0.50 mmol), 4-chlorobenzene-1,2-diamine 2c (71.0 mg, 0.50 mmol), silica gel
(200 mg), and solvents (3.0 mL) were mixed and then capped. The mixture was
stirred for 5 h at 50 °C. Upon completion as shown by TLC monitoring, the
reaction mixture was cooled to room temperature and exacted with ethyl
acetate (5.0 mL ꢀ 3). The combined organic layer was dried over Na2SO4, and
concentrated in vacuum. The resulting residue was purified by column
chromatography on silica gel with the eluent (ethyl acetate/petroleum
ether = 1:20–1:4) to give the pure product. 6-Chloro-2-(4-fluorophenyl)-3-
methylquinoxaline (3bc) and 6-chloro-3-(4-fluorophenyl)-2-methylquinoxaline
(30bc): yellow solid; mp 110–116 °C; 1H NMR (400 MHz, CDCl3): d = 8.10 (d,
1H, J = 2.0 Hz, ArH), 7.98–8.01 (m, 1H, ArH), 7.65–7.71 (m, 3H, ArH), 7.22–7.27
(m, 2H, ArH), 2.86 (s, 0.6H, CH3), 2.78 (s, 2.4H, CH3); 13C NMR (100 MHz,
CDCl3): d = 162.1, 154.6, 152.6, 141.2, 139.7, 135.0, 134.6, 131.0, 130.9, 130.8,
129.6, 128.0, 115.9, 115.6, 24.4; HRMS (ESI): m/z [M+H]+ calcd for C15H10ClFN2:
273.0589; found: 273.0592.
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