LETTER
▌495
letter
A Mild and Simple Method for the Synthesis of Substituted Phenazines
Substituted Phenazines
a
a
b
a
Harpreet Kour, Satya Paul,* Parvinder Pal Singh, Rajive Gupta
a
Department of Chemistry, University of Jammu, Jammu 180006, India
Fax +91(191)2431365; E-mail: paul7@rediffmail.com
b
Medicinal Chemistry Division, Indian Institute of Integrative Medicine (CSIR), Canal Road, Jammu 180001, India
Received: 04.09.2013; Accepted after revision: 23.11.2013
reactions of 1,4-naphthoquinone required the presence of
copper(II) acetate as a catalyst.
Abstract: A mild, simple, and general method has been developed
for the synthesis of phenazines by cross-coupling of benzoquinones
with o-phenylenediamines. Benzoquinones and o-phenylenedi- Initially, when we attempt the reaction of 1,4-benzoqui-
amines reacted smoothly to give the corresponding cross-coupled
products in good to excellent yields. 1,4-Naphthoquinone also cou-
pled with o-phenylenediamines in the presence of copper acetate at
none (1a) with benzene-1,2-diamine (2a) in the presence
of copper(II) acetate as catalyst under air at room temper-
ature, coupling occurred rapidly to give phenazin-2-ol
5
0 °C to give the corresponding benzo[a]phenazines. All reactions
(
(
3a) and 5,12-dihydroquinoxalino[2,3-b]phenazine (4a)
Table 1, entry 1). In a control experiment, we found that
could be carried out under air.
Key words: cross-coupling, quinones, amines, heterocycles, cycli-
zation, polycycles, catalysis, copper
coupling occurred even in the absence of copper(II) ace-
tate (entry 2). Further optimization towards the predomi-
nant formation of either product 3a or 4a was studied
(
entries 3–5). At a low temperature and with one equiva-
Phenazines are an important class of compounds with di-
verse biological activities, such as antibacterial, antifun-
gal, antiviral, antiparasitic, antimalarial, neuroprotectant,
lent of diamine 2a, phenazin-2-ol (3a) was obtained as the
major product together with minor amounts of 4a (entry
4
). When 1,4-benzoquinone was coupled with two equiv-
1
and antitumor properties. In addition, phenazines are
alents of diamine 2a at room temperature, quinoxalino-
phenazine 4a was obtained as the major product (entry 5),
together with traces of phenazin-2-ol (3a). The use of oth-
er solvents, such as methanol, ethanol, tetrahydrofuran,
dichloromethane, and N,N′-dimethylformamide was also
examined (entries 6–10). Coupling in polar solvents such
as methanol, ethanol, tetrahydrofuran, or N,N-dimethyl-
formamide occurred with almost equal efficiency to that
observed in acetic acid. The optimal conditions for the
synthesis of phenazine (3a) involve treating 1,4-benzo-
quinone (1a) with one equivalent of diamine 2a in acetic
acid at –10 °C (entry 4), whereas the reaction of 1a with
two equivalents 2a at room temperature in acetic acid
gave 5,12-dihydroquinoxalino[2,3-b]phenazine (4a) (en-
try 5).
used in dyes, as building blocks for the synthesis of or-
ganic semiconductors, and as chemically controllable
switches, cavitands, DNA-cleaving agents, and dehy-
2
droannulenes. In nature, phenazines are generally pro-
3
duced by microorganisms, and their role in the virulence
and competitive fitness of such organisms has been re-
4
viewed by Kerr. In 2004, Laursen and Nielsen reviewed
natural and synthetic phenazines, including their biosyn-
5
thesis and biological activity. Six methods for synthesiz-
ing these systems have been developed (Scheme 1);6
however, most of these methods have severe limitations
with respect to the substrates, and no efficient and general
method for the synthesis of phenazine derivatives has
been reported in the literature.
7
Our interest in the synthesis of bioactive heterocycles, to-
The structure of product 3a (enol-imine) was confirmed
gether with a recent report by Garden and co-workers on
1
13
1
1
by NMR spectroscopy ( H, C DEPT, H– H COSY; see
SI) and by comparison with values reported in the litera-
a copper-catalyzed oxidative coupling of anilines with
8
1
,4-naphthoquinone through C–H activation, prompted
1
c
ture. The possibility of a keto-amine structure of product
us to consider that coupling of quinones with o-phenyl-
enediamines might provide an alternative route for the
synthesis of phenazine scaffolds. We have therefore de-
veloped a general, mild, and efficient method for the syn-
thesis of phenazine derivatives by the direct coupling of
o-phenylenediamines with quinones. We found that
3
a was ruled out based on the 13C NMR signal at =
1
60.94 ppm, which showed the presence of a hydroxyl
1c
group at the 2-position. Moreover, Zendah et al. have
isolated closely related keto-amine phenazine derivatives,
viz. chromophenazines, where the carbonyl-containing
phenazine 7 and 8 showed a chemical shift at = 183.9
1
,4-benzoquinone couples efficiently with o-phenylene-
13
and 181.9 ppm in the C NMR spectra corresponding to
diamines to give good to excellent yields of the correspond-
ing products, whereas the corresponding coupling
1
d
the C=O group (Fig. 1). Gomez et al. studied the tautom-
erism of quinoxalines derivatives 9 and 10, where the hy-
droxyl-containing phenazine 10 showed a signal at =
13
1
51 ppm in the C NMR spectrum corresponding to a car-
bon attached to a hydroxyl group (normally expected in
the range of 160–170 ppm). In the C NMR, there is no
SYNLETT 2014, 25, 0495–0500
Advanced online publication: 20.12.2013
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DOI: 10.1055/s-0033-1340478; Art ID: ST-2013-D0855-L
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