Synthesis of quinoxalines through iodine-catalyzed one-pot annulation of alkynes with o-phenylenediamines

Article abstract of DOI:10.1080/00397911.2018.1428752

The synthesis of N-heterocycles of quinoxalines has been developed by an efficient protocol of one-pot annulation of alkynes with o-phenylenediamines. A variety of quinoxalines were prepared in good to high yields in the presence of catalytic amount of iodine as a catalyst.

Full text of DOI:10.1080/00397911.2018.1428752

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
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Synthesis of quinoxalines through iodine-
catalyzed one-pot annulation of alkynes with o-
phenylenediamines
Jing Zi, Da-Wei Gu, Yan Zhang, Zhe-Yao Hu, Xing-Quan Zhang & Xun-Xiang
Guo
To cite this article: Jing Zi, Da-Wei Gu, Yan Zhang, Zhe-Yao Hu, Xing-Quan Zhang & Xun-Xiang
Guo (2018): Synthesis of quinoxalines through iodine-catalyzed one-pot annulation of alkynes with
o-phenylenediamines, Synthetic Communications, DOI: 10.1080/00397911.2018.1428752
To link to this article: https://doi.org/10.1080/00397911.2018.1428752
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https://doi.org/10.1080/00397911.2018.1428752
Synthesis of quinoxalines through iodine-catalyzed one-pot
annulation of alkynes with o-phenylenediamines
Jing Zia, Da-Wei Gua, Yan Zhanga, Zhe-Yao Hua, Xing-Quan Zhangb, and Xun-Xiang Guoa
aShanghai Center for Systems Biomedicine, Ministry of Education Key Laboratory of Systems Biomedicine,
Shanghai Jiao Tong University, Shanghai, China; bTopsense Safety Technology Consulting Co. Ltd, Shanghai,
China
ABSTRACT
ARTICLE HISTORY
Received 9 August 2017
The synthesis of N-heterocycles of quinoxalines has been developed
by an efficient protocol of one-pot annulation of alkynes with
o-phenylenediamines. A variety of quinoxalines were prepared in
good to high yields in the presence of catalytic amount of iodine as a
catalyst.
KEYWORDS
Alkynes; iodine-catalyzed;
o-phenylenediamines;
organic reaction;
quinoxalines
GRAPHICAL ABSTRACT
Introduction
The development of efficient protocols for the synthesis of heterocycles has received much
attention because of the great biological activity of heterocycles.[1] As one of the important
N-heterocycles, quinoxalines show some significant biological activities. For example,
quinoxalines are known to be antitumors,[2] antibacterials,[3] anti-inflammatories,[4]
antivirals,[5] and kinase inhibitors.[6]
Several synthetic methods have been developed for the synthesis of quinoxalines.[7] The
use of commercially available o-phenylenediamines and alkynes as starting materials
should be one of the most efficient and economic strategies toward the formation of
quinoxalines. Using this strategy, some examples of both transition metal-catalyzed[8]
and metal-free mediated[9] reactions have been developed. However, most of them suffered
the disadvantages of using expensive metal catalysts or equivalents of metal-free mediators.
These results led us to focus on the development of a new catalyst system for the synthesis
of quinoxalines owing to their diverse biological activities.
Recently, iodine, with the advantages of inexpensive, nontoxic, and readily available,
has been used as a good mediator and a catalyst in organic synthesis.[10,11] Herein, we
report an efficient method for the synthesis of quinoxalines through a one-pot reaction.
Using this reaction protocol, the quinoxalines were obtained in good to high yields in the
CONTACT Xun-Xiang Guo
xunxiang_guo@sjtu.edu.cn
Shanghai Center for Systems Biomedicine, Ministry of
Education Key Laboratory of Systems Biomedicine, Shanghai Jiao Tong University, Shanghai 200240, China.
Supplemental data for this article can be accessed on the publisher’s website.
© 2018 Taylor & Francis

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J. ZI ET AL.
presence of a catalytic amount of iodine as a catalyst from easily available alkynes and
o-phenylenediamine.
Results and discussion
Initially, we choose 1,2-diphenylethyne (1a) and o-phenylenediamine (2a) as the starting
materials to investigate the formation of quinoxalines. The reaction was performed through
one-pot procedure of iodine-catalyzed oxidation of 1a followed by addition of 2a. In
preliminary experiments, we tested the effect of amount of iodine on this reaction. As
shown in Table 1, when 1 equiv. of iodine was used, the one-pot reaction gave the
corresponding quinoxaline 3aa in 42% yield (Table 1, entry 1). The use of 50 mol% of
iodine improved the yield of 3aa to 72% (Table 1, entry 2). To our pleasure, employment
of 20 mol% of iodine in the reaction afforded 3aa in 92% yield (Table 1, entry 3). However,
the reaction provided 3aa in 52% yield when 10 mol% of iodine was used (Table 1, entry 4).
We used 20 mol% of iodine as the optimal catalyst to test the reaction temperature. It was
found that the desired 3aa was formed in 90% yield when the reaction temperature was
increased to 140 °C (Table 1, entry 5), while decreasing the reaction temperature afforded
3aa in lower yields (Table 1, entries 6–7).
Under the optimal reaction conditions (Table 1, entry 3), we tested the scope of internal
alkynes. As shown in Table 2, a variety of 1,2-disubstituted alkynes were suitable for the
reaction to provide the corresponding quinoxalines in high yields. For example, the
reaction of 1a in the presence of 20 mol% of iodine as the catalyst in DMSO at 130 °C
for 24 h followed by addition of 1.5 equiv. of 2a at room temperature for 1 h afforded
the product 3aa in 92% yield (Table 2, entry 1). It was found that both electron-donating
and electron-withdrawing substituted internal alkynes gave the corresponding products in
high yields (Table 2, entries 2–9). Some functional groups, such as fluoro, ester, and nitrile
groups, were tolerated in the reaction to provide the corresponding quinoxalines in high
yields (Table 2, entries 4–6 and entry 9).
The scope of o-phenylenediamines was also examined. As shown in Table 3, several of
o-phenylenediamines can be used for the reaction to afford the corresponding quinoxalines
Table 1. Iodine-catalyzed one-pot synthesis of quinoxaline (3aa): Optimization of the reaction
conditions.a
Entry
I2 (x mol%)
Temperature (°C)
Yield (%)b
1
2
3
4
5
6
7
100
50
20
10
20
20
20
130
130
130
130
140
120
110
42
72
92
52
90
79
62
aThe reactions were performed in a tube with 1,2-diphenylethyne 1a (0.2 mmol), I2 (� mol%) in DMSO (2.0 mL) at
designated temperature for 24 h in air, then cooled to room temperature, o-phenylenediamine 2a (0.3 mmol) was added
to the solution and stirred at room temperature for 1 h.
bIsolated yield.

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Table 2. Iodine-catalyzed one-pot synthesis of quinoxalines: Scope of alkynes 1.a
Entry
1
Alkyne 1
Product 3
Yield (%)b
92
2
78
92
92
71
3c
4
5c
6
86
93
7c
8c
85
90
9c
aThe reactions were performed in a tube with alkyne 1 (0.2 mmol), I2 (0.04 mmol) in DMSO (2.0 mL) at 130 °C for 24 h in air,
then cooled to room temperature, o-phenylenediamine 2a (0.3 mmol) was added to the solution and stirred at room
temperature for 1 h.
bIsolated yield.
cThe reaction time is 10 h in the first step.

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J. ZI ET AL.
Table 3. Iodine-catalyzed one-pot synthesis of quinoxalines: Scope of o-phenylenediamines 2.a
Entry
1
Amine 2
Product 3
Yield (%)b
96
2
93
96
91
93
86
3
4c
5c
6d
7e
88
66
8f
aThe reactions were performed in a tube with alkyne 1a (0.2 mmol), I2 (0.04 mmol) in DMSO (2.0 mL) at 130 °C for 24 h in air,
then cooled to room temperature, o-phenylenediamines 2 (0.3 mmol) were added to the solution and stirred at room
temperature for 1 h.
bIsolated yield.
crt for 2 h in the second step.
d50 °C for 4 h in the second step.
e50 °C for 5 h in the second step.
f50 °C for 8 h in the second step.
in good to high yields. Although both electron-donating and electron-withdrawing
substituted o-phenylenediamines are suitable for the reaction, the reactions of
o-phenylenediamines with a bromo, chloro, trifluoromethyl, nitrile, or nitro group on

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Scheme 1. Plausible mechanism.
the 4-position of benzene ring are much slower than those of electron-donating partners
(Table 3, entries 4–8 vs entries 1–3).
A plausible mechanism for present reaction is outlined in Scheme 1. 1,2-Diphenylethyne
(1a) is oxidized to benzil in the presence of I2/DMSO.[9b,11a] Subsequently, the
condensation reaction of benzil with o-phenylenediamine (2a) affords the desired
quinoxaline (3aa).
Experimental
DMSO was distilled over CaH2 under N2. Compounds 1a and 2a–2i were purchased
without further purification. Compounds 1b–1i were prepared according to the reported
procedure.[12] All commercial reagents were used without further purification. NMR
1
spectra were recorded on a 400 spectrometer (400 MHz for H, 100 MHz for 13C) with
deuterated chloroform (CDCl3) as a solvent at 298 K. Chemical shifts are reported in δ
1
ppm referenced to an internal SiMe4 standard for H NMR, chloroform-d (δ 77.16) for
13C NMR: the following abbreviations are used; s: singlet, d: doublet, t: triplet, q: quartet,
m: multiplet. HRMS were obtained on an ESI-TOF mass spectrometer. Flash column
chromatography was performed on silica gel (300–400 mesh).
General procedure for iodine-catalyzed one-pot annulation of alkynes and
o-phenylenediamines
To a stirred solution of alkyne (0.2 mmol) in DMSO (2.0 mL) was added I2 (10.1 mg, 0.04 mmol).
The solution was stirred at 130 °C for 24 h in air. Then the mixture was cooled to room
temperature, and o-phenylenediamine (0.3 mmol) was added. The solution was stirred at
room temperature for 1 h. After completion, the solution was diluted with ethyl acetate,
washed with H2O, dried over MgSO4, and concentrated under vacuum. The residue was
purified by preparative thin-layer chromatography on silica gel with PE/EtOAc (15/1) as
an eluent to give quinoxaline 3.
Complete experimental details are available online in the Supplemental Material.
Conclusion
In conclusion, we developed an efficient iodine-catalyzed one-pot reaction for the synthesis
of quinoxalines. Using of a catalytic amount of iodine as a catalyst, a variety of quinoxalines
were prepared in good to high yields from easily available alkynes and o-phenylenediamines.
This one-pot protocol provided an efficient synthetic method for the construction of
six-membered N-heterocycles.

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J. ZI ET AL.
Funding
This work was supported by the Natural Science Foundation of China (No. 21172142).
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