Reaction of 2-[(2-Oxo-2-arylethyl)anilino]-1-aryl-1-ethanones with o-phenylenediamine: Formation of quinoxalines

Article abstract of DOI:10.1002/jhet.73

Unexpected quinoxalines (3) have been obtained from a one-pot reaction of 2-[(2-oxo-2-arylethyl)ani- lino]-1-aryl-1-ethanones (1) with o-phenylenediamine (2) in the presence of a catalytic amount of p-toluene sulfonic acid. The reaction presumably involve

Full text of DOI:10.1002/jhet.73

332
Reaction of 2-[(2-Oxo-2-arylethyl)anilino]-1-aryl-1-ethanones
with o-Phenylenediamine: Formation of Quinoxalines
Vol 46
Gurusamy Ravindran, Shanmugam Muthusubramanian,* and Subbu Perumal
Department of Organic Chemistry, School of Chemistry, Madurai Kamaraj University,
Madurai 625 021, India
*E-mail: muthumanian2001@yahoo.com
Received February 26, 2008
DOI 10.1002/jhet.73
Published online 13 April 2009 in Wiley InterScience (www.interscience.wiley.com).
Unexpected quinoxalines (3) have been obtained from a one-pot reaction of 2-[(2-oxo-2-arylethyl)ani-
lino]-1-aryl-1-ethanones (1) with o-phenylenediamine (2) in the presence of a catalytic amount of p-tol-
uene sulfonic acid. The reaction presumably involves a tandem carbonyl addition—eliminative
cyclization—air oxidation sequence.
J. Heterocyclic Chem., 46, 332 (2009).
INTRODUCTION
in this reaction and the details are presented in this
article.
Solvent-free approach using microwave irradiation
opens numerous possibilities for conducting rapid heter-
ocyclic synthesis via cyclocondensation reactions using
a variety of supported reagents [1]. Generally, cyclocon-
densation reactions, where light polar molecules as
water and alcohol are eliminated, constitute good candi-
dates for microwaves. Furthermore, there are advantages
of these solvent-free protocols with reduced reaction
time and generally improved yields.
RESULTS AND DISCUSSION
Hinsberg [5] reported that 2-bromoacetophenone gave
directly 2-arylquinoxalines when reacted with o-phenyl-
enediamine or m-tolylenediamine in boiling alcohol. He
suggested that dihydroquinoxaline was an intermediate
product which was readily oxidized by air to the corre-
sponding quinoxaline. Buu-Hoi and Khoi [6] reported
quantitative yields of 2-arylquinoxalines directly from
the reaction of 2-bromo-30-nitroacetophenone and 2-
bromo-40-nitroacetophenone with o-phenylenediamine in
the presence of sodium acetate.
Nitrogen-containing heterocyclic compounds are in-
dispensable structural units for both the chemist and the
biochemist. In continuation of our work [2] on the
chemistry of bis(aroylmethyl)anilines, which is relatively
unexplored [3], herein, we report the condensation reac-
tion of bis(aroylmethyl)anilines with 1,2-diaminoben-
zene. The reaction of diphenacyl aniline with 2-amino-
phenol and 2-aminothiophenol has led to diazine-fused
benzheteroazole derivatives [4] (Fig. 1). In the same
angle, the reaction of diphenacyl aniline with o-phenyl-
enediamine is expected to give a related product. But
unexpected quinoxaline is obtained as the major product
Quinoxalines constitute the basis of many insecti-
cides, fungicides, herbicides, and anthelmintics, as well
as being important in human health and as receptor
antagonists [7]. There are numerous methods of prepar-
ing quinoxalines, but the double condensation of a 1,2-
dicarbonyl compound and a 1,2-diaminoaromatic is
commonly used [8]. This article describes the first report
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Reaction of 2-[(2-Oxo-2-arylethyl)anilino]-1-aryl-1-ethanones with
o-Phenylenediamine: formation of quinoxalines
333
Scheme 2
Figure 1. Benzheteroazoles.
of the formation of quinoxalines from 3-aza-1,5-
diketones.
A mixture of o-phenylenediamine 2 with appropri-
ately substituted diphenacyl aniline 1 was taken in a 1:1
molar ratio along with a catalytic amount of p-toluene
sulfonic acid and ground well to ensure thorough mixing
with no solvent. This mixture was placed in an open
glass tube over a silica bath in a domestic microwave
oven and irradiated for 10 min at 540 W. The major
product 3 (Scheme 1) was isolated from the remaining
mass of the reaction mixture by column chromatography
and the product eluted first. Compound 3 was obtained
in considerable yield and all the compounds were char-
acterized by their NMR spectral data. The 1H NMR
spectrum of a representative compound, 2-(4-methylphe-
nyl)quinoxaline (3, X ¼ Me) showed the presence of
one singlet at 2.38 ppm accounting for three hydrogen
atoms. A two proton doublet is visible at 7.30 ppm (J ¼
8.4 Hz) and a six proton multiplet appears in the region
7.65–8.18 ppm. There is a singlet appearing downfield,
9.24 ppm. The 13C NMR spectrum of this compound
has signals at 20.4, 126.4, 128.0, 128.2, 128.5, 128.8,
129.2, 133.0, 139.5, 140.4, 141.3, 142.3, and 150.8 ppm.
The data are very much consistence with 2-arylquinoxa-
line. Thus the major compound 3 formed in the reaction
is unexpected 2-arylquinoxalines, which has been con-
firmed by comparing with an authentic sample of 2-
phenylquinoxaline.
Scheme 1
The quinoxalines 3 presumably arise from a tandem
sequence of reactions and the mechanism (Scheme 2)
envisages an acid catalyzed imine formation followed
by the attack of amino group on the methylene car-
bon—not
on
the
imino
carbon—displacing
NPhCH2COPh group. This is contrary to the case of the
reaction 1 with 2-aminophenol and 2-aminothiophenol.
There the initial attack by the nucleophilic center SH or
OH on the electrophilic carbonyl gives a tertiary alcohol
and the nitrogen of the amino group attacks this carbon
center, displacing hydroxyl group (probably via the ini-
tially formed carbocation with the help of p-toluene sul-
phonic acid). But in the present case, the initially
formed tertiary alcohol undergoes 1,2-elimination form-
ing an imine. Now the second nitrogen of the amino
group does not attack this imino carbon rather attacks
the methylene carbon displacing NPhCH2COPh group
(again aided by p-toluene sulphonic acid through proto-
nation of the leaving group, thus increasing its leaving
group ability).
With the successful optimization results in hand, we
investigated the scope of this process to another substi-
tuted diamine, N-(1-phenylethyl)-1,2-diaminobenzene.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

334
G. Ravindran, S. Muthusubramanian, and S. Perumal
Vol 46
Scheme 3
General procedure for the preparation of 2-arylquinoxa-
line (3). A mixture of 2-[(2-oxo-2-arylethyl)anilino]-1-aryl-1-etha-
none 1 (0.0015 mol), 1,2-benzenediamine (0.2 g, 0.0015 mol) and
catalytic amount of p-toluenesulfonic acid was irradiated in an
open glass tube over a silica bath in a domestic microwave oven
and irradiated for 10 min at power level 5 (540 W). The reaction
mixture was treated with water and then extracted with dichloro-
methane. The organic layer was washed with water repeatedly
and dried over anhydrous calcium chloride and evaporated to give
the crude product. Purification of the product was performed by
column chromatography on silica gel using petroleum ether-ethyl
acetate [97:3 (v/v)] mixture as eluent. The signal due to NH
hydrogen is so broad that it is not visible in these compounds.
However, when exchanged with D2O, the HOD peak appears con-
firming the presence of NH signal.
2-Phenylquinoxaline (3, X ¼ H). This compound was
1
obtained as colorless solid, mp, 79ꢀC (Lit. m.p. 76–77ꢀC [9]); H
NMR (300 MHz, CDCl3): 7.51–7.56 (m, 3H), 7.73–7.82 (m, 2H),
8.11–8.22 (m, 4H), 9.3 (s, 1H); 13C NMR (75 MHz, CDCl3):
127.5 (d), 129.0 (d), 129.1 (d), 129.5 (d), 129.6 (d), 130.1 (d),
130.3 (d), 136.7 (s), 141.5 (s), 142.2 (s), 143.3 (d), 151.8 (s).
2-(4-Chlorophenyl)quinoxaline (3, X ¼ Cl). This com-
pound was obtained as colorless solid, mp, 128ꢀC (Lit. m.p.
When the reaction is carried out with substituted 1,2-
diaminobenzene, N-(1-phenylethyl)-1,2-diaminobenzene,
prepared from 2-chloronitrobenzene and dl-phenylethyl-
amine, the final oxidation step shown in Scheme 2 is not
possible and the 1,2-dihydroquonoxaline can be expected.
Hence, the proposed reaction of 1b with N-(1-phenyl-
ethyl)-1,2-diaminobenzene was carried out under identical
condition as depicted in Scheme 2. The reaction proceeds
1
137ꢀC [10]); H NMR (300 MHz, CDCl3): 7.53–7.56 (m, 2H),
7.78–7.83 (m, 2H), 8.15–8.18 (m, 4H), 9.3 (s, 1H); 13C NMR
(75 MHz, CDCl3): 129.2 (d), 129.5 (d), 129.8 (d), 129.9 (d),
130.2 (d), 130.8 (d), 135.5 (s), 137.0 (s), 142.0 (s), 142.6 (s),
143.3 (d), 151.0 (s).
2-(4-Methylphenyl)quinoxaline (3, X ¼ Me). This com-
pound was obtained as colorless solid, mp, 92ꢀC (Lit. m.p.
1
94ꢀC [10]); H NMR (300 MHz, CDCl3): 2.38 (s, 3H); 7.30(d,
1
2H, J ¼ 8.4 Hz); 7.65–7.73 (m, 2H); 8.02–8.08 (m, 4H); 9.24
(s, 1H); 13C NMR (75 MHz, CDCl3): 20.4 (q), 126.4 (d),
128.0 (d), 128.2 (d), 128.5 (d), 128.8 (d), 129.2 (d), 133.0 (s),
139.5 (s), 140.4 (s), 141.3 (s), 142.3 (d), 150.8 (d).
3-(4-Chlorophenyl)-1-(1-phenylethyl)-1,4-dihydroquinoxa-
line (4). This compound was obtained as yellow solid, yield
68%, mp, 146ꢀC; 1H NMR (300 MHz, CDCl3): 1.85 (d, J ¼
6.9 Hz, 3H); 4.63 (q, J ¼ 6.9 Hz, 1H); 7.14–8.31 (m, 14H); 13C
NMR (75 MHz, CDCl3): 22.2 (q), 43.9 (d), 126.4 (d), 127.8 (d),
128.4 (d), 128.5 (d), 129.0 (d), 129.1 (d), 129.6 (d), 129.8 (d),
130.3 (d), 135.0 (d), 137.4 (s), 140.4 (s), 141.5 (s), 144.2 (s),
154.2 (s), 157.3 (s); Anal. Calcd. for C22H19ClN2: C, 76.18; H,
5.52; N, 8.08%. Found: C, 76.25, H, 5. 54; N, 8.03%.
smoothly giving a product 4 (Scheme 3). The H NMR
spectrum has a three hydrogen doublet and one hydrogen
multiplet at 1.85 ppm and 4.63 ppm, respectively. In the
aromatic/olefinic region, there are 14 hydrogen resonan-
ces. In the 13C NMR spectrum, there are signals at 22.2
and 43.9 ppm apart from 16 signals in the olefinic/aro-
matic region. There is no methylenic carbon or hydrogen.
1
Thus the H NMR and 13C NMR spectra of the com-
pound 4 clearly suggest the structure to be a 1,4-dihydro-
quinoxazine and not a 1,2-dihydroquinoxazine. It is sur-
prising that the 1,2-dihydro system obtained has rear-
ranged to a 1,4-dihydro system.
Even in the case of 3, it is probable that if the air oxi-
dation is prevented, then the 1,2-dihydro system would
have not been isolated and the 1,4-dihydro system
would have been obtained.
Acknowledgments. The authors thank DST, New Delhi for as-
sistance under the IRHPA program for the NMR facility.
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