Gallium(III) triflate-catalyzed synthesis of quinoxaline derivatives

Article abstract of DOI:10.1016/j.tetlet.2008.10.058

Gallium(III) triflate-catalyzed reactions of phenylene-1,2-diamines and 1,2-diketones produce quinoxalines in excellent to quantitative yields. The reactions proceed with 1 mol % catalyst in ethanol at room temperature. The catalyst can be recycled for at

Full text of DOI:10.1016/j.tetlet.2008.10.058

Tetrahedron Letters 49 (2008) 7386–7390
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Tetrahedron Letters
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Gallium(III) triflate-catalyzed synthesis of quinoxaline derivatives
a
b,
Jing-Jing Cai a, Jian-Ping Zou a, , Xiang-Qiang Pan , Wei Zhang
*
*
a Key Laboratory of Organic Synthesis of Jiangsu Province, College of Chemistry and Chemical Engineering, Suzhou University, 1 Renai Street, Suzhou, Jiangsu 215123, China
b Department of Chemistry, University of Massachusetts Boston, 100 Morrissey Boulevard, Boston, MA 02125, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Gallium(III) triflate-catalyzed reactions of phenylene-1,2-diamines and 1,2-diketones produce quinoxa-
lines in excellent to quantitative yields. The reactions proceed with 1 mol % catalyst in ethanol at room
temperature. The catalyst can be recycled for at least 10 times.
Received 29 September 2008
Revised 11 October 2008
Accepted 13 October 2008
Available online 18 October 2008
Ó 2008 Elsevier Ltd. All rights reserved.
Quinoxaline is a privileged ring system. Its derivatives have
broad biological activities, and have been used as anticancer,1 anti-
viral,2 antibacterial agents,3 and kinase inhibition agents.4 In addi-
tion to the medicinal applications, quinoxalines have been used as
dyes5 and key intermediates in the synthesis of organic
semiconductors.6
Over the years, numerous synthetic methods for preparation of
quinoxalines have been reported in the literature.7 Among them,
the condensation of 1,2-aryldiamine with 1,2-diketone in refluxing
ethanol or acetic acid is a general approach.8 Research effort has
been focused on finding new catalysts to improve the yield of this
condensation reaction. In addition to common Lewis acids, many
other catalysts including I2,9a,9b SA,9c Montmorillonite K-10,9d
room temperature. Three polar solvents acetonitrile, methanol,
and ethanol were evaluated under the same reaction conditions
(Scheme 1). It was surprising to find that the reactions in these po-
lar solvents could be completed in as short as 5 min to give quan-
titative yield of product 3a (Table 1, entries 1–3). It was also found
that reaction in ethyl acetate required a longer time (90 min) and
only gave 80% yield of product (Table 1, entry 4). The reaction in
water for 30 min resulted product in 85% yield (Table 1, entry 5).
Because of high product yield, low toxicity, and good availability,
ethanol was chosen as a solvent for further reaction optimization.
In the study of catalyst loading, 0.1%, 1%, and 5 mol % of Ga(OTf)3
were tested. Reactions with both 1% and 5 mol % catalysts both
gave quantitative yields in 5 min (Table 1, entries 3 and 6),
SSA,9e H6P2W18O62Á24H2O,9f InCl3,9g MnCl2,9h CuSO4Á5H20,9i Zn/
L-
Proline,9j and CAN9k have been explored. Oxidative couplings of
epoxides and ene-1,2-diamines10 catalyzed by Bi(0), Pd(OAc)2,
RuCl2-(PPh3)3-TEMPO, and MnO2 have been reported.11 The con-
densation has also been accomplished under catalyst-free condi-
tions, but needs microwave heating.12 We report here a new
method which is catalyzed by Ga(OTf)3, and has advantages of
room temperature reaction, extremely high product yields, simple
product isolation, and catalyst recovery.
O
O
NH2
NH2
N
N
5 mol% Ga(OTf)3
+
solvent
1a
2a
3a
Scheme 1.
Ga(OTf)3 is a water-tolerant strong Lewis acid, which has broad
applications in organic reactions.13 Recently, we reported
a
Ga(OTf)3-promoted condensation of 1,2-aryldiamine or 2-amino-
thiophene with ketones or chalkones to form 1,5-benzodiazepines
and 1,5-benzothiazepines.14 We envisioned that this chemistry
could be extended for condensation of 1,2-aryldiamines and 1,2-
diketones to form quinoxalines.15
Table 1
Ga(OTf)3-catalyzed cycloadditions of o-phenylenediamine 1a and benzyl 2a
Entrya
Solvent
Ga(OTf)3 (mol %)
Time (min)
Yieldb (%)
1
2
3
4
5
6
7
CH3CN
MeOH
EtOH
CH3COOEt
H2O
5
5
5
5
5
1
0.1
5
5
5
90
30
5
>99
>99
>99
80
85
>99
85
The condensation reaction of 1,2-phenylenediamine 1a and
benzil 2a was carried out in the presence of 5 mol % Ga(OTf)3 at
EtOH
EtOH
* Corresponding authors. Tel./fax: +86 512 65880336 (J.-P.Z.); tel.: +1 617 287
6147; fax: +1 617 287 6030 (W.Z.).
E-mail addresses: jpzou@suda.edu.cn (J.-P. Zou), wei2.zhang@umb.edu (W.
Zhang).
30
a
The reaction was performed at rt.
Isolated yield.
b
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.10.058

J.-J. Cai et al. / Tetrahedron Letters 49 (2008) 7386–7390
7387
Table 2
R1
NH2
NH2
O
O
a
R1
N
N
R2
R2
1 mol% Ga(OTf)3
EtOH, 25 o
The catalytic activity of recycled Ga(OTf)3
+
Entry
Time (min)
Yieldb (%)
C
R2
R2
2
1
2
3
4
5
6
7
8
9
5
8
>99
>99
>99
>99
99
99
>99
97
1
3
10
10
10
10
10
10
10
10
Scheme 2.
whereas 0.1 mol % catalyst loading only gave 85% yield even after a
longer reaction time of 30 min (Table 1, entry 7).
The optimized condition for the condensation reaction is as fol-
lows: An equimolar amount of 1 and 2 is mixed with 1 mol %
Ga(OTf)3 of catalyst in ethanol as a solvent. The reaction is finished
in 5 min at room temperature. This general condition was used for
other experiment described below.
98
>99
10
a
The reaction was performed at 25 °C.
b
Isolated yields.
Table 3
Quinoxaline derivatives from the reaction of 1,2-diamines and 1,2-diketones catalyzed by 1 mol % Ga(OTf)3
Entry
1,2-Diamine
1,2-Diketone
Producta
Time (min)
Yieldb (%)
O
O
NH2
N
1
5
>99
NH2
N
1a
2a
O
O
H3C
NH2
NH2
H3C
N
N
2
5
>99
1b
3b
2a
O
O
N
N
NH2
NH2
3
5
>99
1c
2a
O
O
O
O
N
N
NH2
NH2
4
5
6
20
10
10
95
1d
3d
2a
O
O
Cl
N
N
Cl
NH2
NH2
94
1e
3e
2a
O
O
Br
NH2
NH2
Br
N
N
95
1f
3f
2a
(continued on next page)

7388
J.-J. Cai et al. / Tetrahedron Letters 49 (2008) 7386–7390
Table 3 (continued)
Entry
1,2-Diamine
1,2-Diketone
Producta
Time (min)
Yieldb (%)
O2N
N
N
O2N
NH2
NH2
O
O
7
360
90
1g
2a
3g
Cl
Cl
Cl
NH2
N
O
O
8
10
>99
>99
>99
>99
97
NH2
N
1a
Cl
2b
3h
O
O
O
O
N
N
NH2
9
10
O
O
NH2
1a
3i
2c
O
O
O
N
N
3j
NH2
NH2
O
10
11
12
13
14
10
O
O
1b
2c
O
O
O
N
N
O
NH2
NH2
10
O
O
1c
2c
3k
O
O
O
N
O
Cl
NH2
NH2
10
O
O
Cl
N
1c
2c
3l
O
O
N
N
O2N
NH2
NH2
O
240
90
O
O
O2N
O
1g
2c
3m
O
O
O
O
N
O
NH2
NH2
10
98
O
O
N
O
1d
2c
3n

J.-J. Cai et al. / Tetrahedron Letters 49 (2008) 7386–7390
7389
Table 3 (continued)
Entry
1,2-Diamine
1,2-Diketone
Producta
Time (min)
Yieldb (%)
NH2
N
N
O
O
15
16
17
70
95
90
92
—
NH2
1h
2a
3o
Cl
Cl
Cl
NH2
O
O
N
N
80
NH2
1h
Cl
2b
3p
O
O
NH2
N
N
O
20
O
O
O
NH2
1h
2c
3q
NH2
O
18
n.r.c
360
NH2
O
2d
1a
a
All products were characterized by 1H, 13C NMR and HRMS spectra.
Isolated yields.
No reaction was observed.
b
c
Reducing the amount of catalyst and making it reusable are two
To test if 1 mol % Ga(OTf)3 could effectively catalyze the reac-
tion of 1,2-alkyldiamines, the reactions of 1,2-ethylenediamine
1h with 2a, 2b and 2c were carried out, and they all gave excellent
yields (90–95%) of dihydropyrazines 3o–3q (Table 3, entries 15–
17). Since the reactions were carried out at room temperature, this
condition was not strong enough to oxidize the dihydropyrazines
to pyrazines. In an attempted condensation reaction of 1,2-pheny-
lene diamine 1a with 2,3-butanedione 2d, it was found that the
reaction did not take place in 6 h (Table 3, entry 18). Obviously,
1,2-dialkyldiketone is not suitable for the synthesis of quinoxaline
derivatives under this general reaction condition.
In summary, a Ga(OTf)3-promoted synthesis of quinoxaline
derivatives has been developed. This method has advantages of
very mild reaction conditions, simple manipulation, and high prod-
uct yields. It also has a good aspect of green chemistry since the
Ga(OTf)3 catalyst can be easily recovered and reused for at least
10 times without significant change of activity. This protocol
may also be applicable for large-scale preparation of quinoxalines.
important aspects of green chemistry. We developed a catalyst re-
cycle protocol, and also tested the activity of recovered Ga(OTf)3.
The procedure is as follows: a mixture of 1,2-aryldiamine and
1,2-diketone (1 mmol each) and Ga(OTf)3 (0.01 mmol) in 3 mL of
ethanol was stirred at room temperature for 5–10 min. After com-
pletion of the reaction (monitored by TLC), the product was precip-
itated from the ethanol, and Ga(OTf)3 was left in solvent.15 The
product was collected by filtration, and the filtrate was directly
used for the next round of reaction without additional treatment.
Within ten cycles, the catalyst showed no significant change on
reactivity (Table 2).16
The scope of this condensation reaction was evaluated by using
different 1,2-aryldiamines and benzil (Scheme 2). Results in Table
3 show that electron-donating groups at the phenyl ring of 1,2-dia-
mine favored the formation of product (Table 3, entries 2 and 3) to
give quantitative yields. In contrast, electron-withdrawing groups
such as benzoyl, chloro, and bromo gave slightly lower yields
(94–95%) (Table 3, entries 4–6). The NO2 group further reduced
the yield to 90%, even the reaction time increased to 6 h (Table 3,
entry 7). Reactions of 1,2-di(4-chlorophenyl)ethanedione 2b and
1,2-di(2-furano)ethanedione 2c with different 1,2-aryldiamines
bearing electron-donating groups afforded products in quantita-
tive yields (Table 3, entries 8–11), while the 1,2-aryldiamines bear-
ing electron-withdrawing groups afforded slightly lower yields
(Table 3, entries 12–14). On the other hand, the substituents at
the 1,2-diketones had no significant effect on the yield of products.
Since only symmetric 1,2-diketones were used for the condensa-
tion reactions, no regioisomers were generated as the products.
Acknowledgment
J.P.Z. thanks the financial support from National Natural Science
Foundation of China (No. 20772088).
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2008.10.058.

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J.-J. Cai et al. / Tetrahedron Letters 49 (2008) 7386–7390
Taheri, Sh.; Bakhtiari, Kh.; Oskooie, H. A. Catal. Commun. 2007, 8, 211; (j)
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16. A general procedure for preparation of quinoxaline derivatives 3 and catalyst
Ga(OTf)3 recycle: A mixture of 1,2-diamine (1 mmol), 1,2-diketone (1 mmol),
and Ga(OTf)3 (0.01 mmol) in 3 mL of ethanol was stirred at room temperature.
After completion of the reaction (monitored by TLC), the resultant was cooled
with ice-salt bath, filtered to afford pure products 3, and the filtrate containing
Ga(OTf)3 could be directly used by adding reactants. After ten recycles, the
catalytic activity of Ga(OTf)3 remained unchanged.