2416▌
LETTER
letter
Transition-Metal-Free Synthesis of Quinoxalines from o-Phenylenediamines
and Arylacetaldehydes under Basic Conditions
Synthesis of Quinoxalines
Jinli Song,a,b Xiaolong Li,a,b Yongxin Chen,a,b Mingming Zhao,a,b Yani Dou,a,b Baohua Chen*a,b
a
State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Gansu, Lanzhou 730000, P. R. of China
b
Key Laboratory of Nonferrous Metal Chemistry and Resources Utilization of Gansu Province, Lanzhou 730000, P. R. of China
Fax +86(931)8912582; E-mail: chbh@lzu.edu.cn
Received date: 24.05.2012; Accepted after revision: 23.06.2012
action times, elevated temperature, and poor scope of
Abstract: A novel method for the synthesis of quinoxalines via
substrates. As a part of our ongoing studies on N-hetero-
transition-metal-free cyclization of o-phenylenediamine and aryl-
cyclization, we also reported a copper-catalyzed approach
acetaldehyde in a one-pot procedure has been developed. In this
process, an inorganic base (K2CO3) is the only reagent required, and
to quinoxalines with o-phenylenediamine and terminal al-
it proceeds smoothly in the absence of adding transition metal cata- kyne in the presence of bases.16 Encouraged by these
lysts. The reaction appears to be very general and suitable for the
construction of a variety of quinoxalines.
transformations, we conceived that the reaction between
o-phenylenediamine and phenylacetaldehyde may be pos-
Key words: quinoxalines, o-phenylenediamine, arylacetaldehyde,
oxidation, condensation, transition-metal-free
sible. In addition, many methods that utilized metal-free
and basic conditions have been reported for synthesizing
other organic compounds.17,18
Herein, we report a novel approach for the synthesis of
quinoxalines in good to excellent yields by the direct oxi-
dative condensation of o-phenylenediamine with aryl-
acetaldehyde. The process involves a one-pot procedure
and proceeds smoothly in air without adding any
transition-metal catalyst. An inorganic base (K2CO3) is
the only reagent required. The method is highly efficient
and provides a novel, convenient, economical, and envi-
ronmentally friendly practical route to quinoxalines.
Quinoxalines are one of the most important nitrogen-
containing heterocycles since they are useful as biologi-
cally active compounds,1 antibiotics,2 electroluminescent
materials,3 and dyes.4 Furthermore, they can serve as pre-
cursors for a variety of pharmacological active com-
pounds.5 Consequently, various synthetic strategies6 were
developed for the preparation of substituted quinoxalines,
and the most common methods relied on the direct con-
densation o-phenylenediamines with α-dicarbonyls.7 In
addition, several new methods that utilized metal-
catalytic systems for synthesizing quinoxalines have been
At the beginning of our study, o-phenylenediamine (1a)
and phenylacetaldehyde (2a) were chosen as the test sub-
strates for this cyclization using CuI in toluene at 90 °C in
air to achieve the transformation. Gratifyingly, the desired
2-phenylquinoxaline (3aa) was obtained in 67% yield af-
ter eight hours (Table 1, entry 1). Compared with CuBr2
and other catalysts, the reaction in the absence of catalyst
showed the highest activity and resulted in 83% yield (see,
Table 1, entries 2 and 3, and Supporting Information).
When the reaction was carried out in the absence of cata-
lysts and bases, a lower yield was obtained (Table 1, entry
4). Therefore, the presence of K2CO3 was essential for the
effective formation of 3aa. Similar methodologies by add-
ing K2CO3 in the absence of transition-metal catalysts for
the synthesis of 3-carboxylated indoles have been report-
ed.18 However, there was a lower yield, both increasing
and decreasing temperatures, or prolonging and shorten-
ing reaction times, or a nitrogen atmosphere (Table 1, en-
tries 5–7). When oxygen was employed as the oxidant,
only 81% of 3aa was isolated (Table 1, entry 8). Thus, air
was chosen as one of the best conditions for its low cost
and convenience. What’s more, different bases including
organic and inorganic bases were also evaluated, but no
better results were obtained (see, Table 1, entries 3, 9, 10,
and Supporting Information). Further inspection of the re-
action conditions revealed that the reaction proceeded
more efficiently in toluene, while other solvents such as
developed:
PdI2,8
Yb(OTf)3,9
Bi(OTf)3,10
Ce(NH4)2(NO3)6,11 RuCl2(PPh3)3,12 and Ga(OTf)3.13 In
spite of the wide applicability of these methodologies in
modern organic synthesis, a limitation of the general ap-
proach is the requirement of metals, either as catalysts or
in stoichiometric amounts, which in many cases can make
these preparative procedures environmentally unfriendly
and expensive.
Recently, some examples have been discovered in the de-
velopment of metal-free transformations to form quin-
oxalines. In general, there are two routes. The first route
is the direct reaction of 1,2-diaminobenzenes with ketones
in the presence of potassium hydroxide in PEG-400 for 60
hours.14 The second route is the condensation of 1,2-di-
aminobenzene with ketones via their α-hydroxylimino ke-
tone derivatives under microwave irradiation at 125 °C or
140 °C.15 Although they are efficient processes, there are
very few general methods that convert commercially
available or readily accessible materials in one step into
quinoxalines, and they suffer from one or more limita-
tions, for example, the use of expensive reagents, long re-
SYNLETT 2012, 23, 2416–2420
Advanced online publication: 17.09.2012
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DOI: 10.1055/s-0031-1290450; Art ID: ST-2012-W0450-L
© Georg Thieme Verlag Stuttgart · New York
Song, Jinli
