Three-component tandem reactions of (2-arylsulfanyl-3-aryl-2-oxiranyl)(aryl)methanones and o-phenylenediamine: formation of quinoxalines

Article abstract of DOI:10.1016/j.tetlet.2007.01.106

A series of new quinoxalines has been obtained from a one pot, three-component reaction of (2-arylsulfanyl-3-aryl-2-oxiranyl)(aryl)methanones with o-phenylenediamine in the presence of a catalytic amount of acetic acid. This reaction presumably involves a

Full text of DOI:10.1016/j.tetlet.2007.01.106

Tetrahedron Letters 48 (2007) 2155–2158
Three-component tandem reactions
of (2-arylsulfanyl-3-aryl-2-oxiranyl)(aryl)methanones
and o-phenylenediamine: formation of quinoxalines
M. Kamal Nasar, Raju Ranjith Kumar and Subbu Perumal*
Department of Organic Chemistry, School of Chemistry, Madurai Kamaraj University, Madurai 625 021, India
Received 19 December 2006; revised 8 January 2007; accepted 18 January 2007
Available online 24 January 2007
Abstract—A series of new quinoxalines has been obtained from a one pot, three-component reaction of (2-arylsulfanyl-3-aryl-2-
oxiranyl)(aryl)methanones with o-phenylenediamine in the presence of a catalytic amount of acetic acid. This reaction presumably
involves a tandem oxirane aminolysis–cyclisation–elimination–air oxidation–condensation sequence.
Ó 2007 Published by Elsevier Ltd.
One-pot tandem reactions1 by virtue of their conver-
gence, elegance, economy of cost, labour and time and
ease of execution are powerful for the rapid construction
of diverse organic molecules. These reactions fall under
the fold of green chemistry,2 as they obviate the isola-
tion and purification of intermediates leading to dimin-
ished pollution of the environment.
In the present work, the starting materials for the syn-
thesis of quinoxalines, namely, (2-arylsulfanyl-3-aryl-2-
oxiranyl)(aryl)methanones 2 were obtained by the reac-
tion of 1,3-diaryl-2-(arylsulfanyl)-2-propen-1-ones
1
with alkaline hydrogen peroxide in ethanol in excellent
yields (95–98%) at room temperature (Scheme 1).11 Pre-
viously, only one oxirane of type 2 had been prepared by
Kroehnke et al.12 from the same reaction in acetone–
methanol mixture in a lower yield (87%) and longer
reaction time. The yields and melting points of (2-aryl-
sulfanyl-3-aryl-2-oxiranyl)(aryl)methanones 2 prepared
are given in Table 1. The structures of 2 were deduced
from NMR spectroscopic data. The 1,3-diaryl-2-(aryl-
sulfanyl)-2-propen-1-ones 1, in turn, were synthesized
in 70–75% yields by the condensation of substituted benz-
aldehydes with 1-aryl-2-(arylsulfanyl)-1-ethanones using
piperidinium acetate as catalyst.12
In continuation of our research programme on the syn-
thesis of novel organic molecules employing tandem
reactions,3 it was planned to synthesise a series of hith-
erto unreported 2,4-diaryl-3-(arylsulfanyl)-1H-1,5-benzo-
diazepines 6 (Scheme 1) from the tandem reactions
of (2-arylsulfanyl-3-aryl-2-oxiranyl)(aryl)methanones 2
with o-phenylenediamine 3, as benzodiazepines are of
paramount biological importance4 and reports on benzo-
diazepines bearing sulfur functionality are scarce.
Interestingly, this reaction, in the presence of a catalytic
amount of acetic acid, led to the formation of new quin-
oxalines 4 and the results are presented in this Letter.
Incidentally, it is pertinent to note that quinoxaline is
also an important pharmacophore which displays a wide
range of biological activities such as anticancer,5 antifo-
lic,6 human dihydrofoliate reductase,7 antibacterial,8
antiprotozoal,8 antiviral9 and antiproliferative.10
The reactions of (2-arylsulfanyl-3-aryl-2-oxiranyl)-
(aryl)methanones 2 with o-phenylenediamine in a molar
ratio of 1:1 in the presence of a catalytic amount of ace-
tic acid in ethanol failed to furnish the expected benzo-
diazepine 6 even in traces. Instead, this reaction led to
the formation of N-[aryl(3-aryl-2-quinoxalinyl)methyl-
idene]-1,2-benzenediamines 4 (Table 2). These reactions,
as expected, did not go to completion as 4 requires a 1:2
stoichiometry of the reactants and hence unreacted 2
was present in the reaction mixture. Consequently, sub-
sequent reactions were performed with a 1:2 molar ratio
of 2 and 3 which led to products 4 in a pure state after
column chromatography as viscous liquids in good
Keywords: Oxiranes; o-Phenylenediamine; Tandem; Quinoxaline;
X-ray.
*
Corresponding author. Tel.: +91 452 2458246; fax: +91 452
2459845; e-mail: subbu.perum@gmail.com
0040-4039/$ - see front matter Ó 2007 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2007.01.106

2156
M. Kamal Nasar et al. / Tetrahedron Letters 48 (2007) 2155–2158
Cl
S
Cl
NH2
NH2
2
O
O
N
1
1
NH2
1
2
3
2
N
N
4
2
S
3
H2O2/NaOH
EtOH
O
cat. AcOH
EtOH (reflux)
or
Xcat. AcOH, MW
R1
3
3
R1
R1
R2
R2
R2
1
2
Ac2O
O
R1
NH
Cl
N
1
4
N
2
N
3
S
R1
N
H
2
N
3
1
R2
R1 = R2 = Me
R2
6
5a
Scheme 1. Synthesis of quinoxalines.
Table 1. Physical data of oxiranes 2
solid acetyl derivative 5a14 and its structure deduced
from an X-ray crystallographic study of a single crystal
(Fig. 1), which, in turn, confirmed the structure of 4a as
well.
2
R1
R2
Yield (%)
Mp (°C)
a
b
c
d
e
f
p-Me
H
H
p-Me
p-Me
H
p-Me
p-Cl
p-Me
H
p-Cl
H
96
95
95
97
95
97
98
95
95
88–90
79–81
81–83
78–80
87–89
73–75
91–93
90–92
85–87
Quinoxalines 4 presumably arise from tandem reactions
and the mechanism (Scheme 2) envisages an acid catal-
ysed oxirane aminolysis–cyclisation–elimination–air oxi-
dation–condensation sequence. The elimination of
benzenethiol from 8, requiring the phenylthio group to
function as a nucleofuge, can probably be ascribed to
the stabilising conjugative interactions shown in 9 as
well as catalysis by acid (Scheme 2). That this reaction
gives quinoxalines 4 even when a 1:1 molar ratio of 2
g
h
i
p-Cl
p-Cl
p-Cl
H
p-Cl
p-Me
Table 2. Physical data of quinoxalinesa
4
4
R1
R2
Yieldb (%)
Reflux
MW
a
b
c
d
e
f
p-Me
H
H
p-Me
p-Me
H
p-Cl
p-Cl
p-Cl
p-Me
p-Cl
p-Me
H
p-Cl
H
H
p-Cl
p-Me
57
57
60
61
60
58
60
56
55
67
65
66
68
67
68
70
66
67
g
h
i
a All the products are viscous liquids.
b After purification by column chromatography.
yields (55–61%), considering the number of steps
involved.13 Presumably, the aromatic stability of 4
provides the impetus for the tandem transformation.
1
The structures of 4 were deduced from the H and 13C
NMR spectroscopic data. As all the quinoxalines were
Figure 1. X-ray structure of 5a.
viscous liquids, quinoxaline 4a was converted into its

M. Kamal Nasar et al. / Tetrahedron Letters 48 (2007) 2155–2158
2157
O
H
O
O
Ar
Ar
O
Ar
S
S
S
Ar
H2N
H2N
H2N
+
Ar
Oxirane
aminolysis
CH3COOH
Ar
Ar
HO
H2O
Ar
H
HN
H
Ar
7
2
3
Cyclization
Ar
O
O
N
H+
Ar
O
NH2
NH2
Air oxidation
S
NH
N
Ar
Elimination
-PhSH
+
Ar
Ar
Ar
N
N
H
Ar
N
H
3
10
Condensation
8
NH2
N
O-
N
N
Ar
Ar
Ar
Ar
+
N
N
H
4
9
Scheme 2. Mechanism for formation of quinoxalines via tandem reactions.
and 3 was employed shows that quinoxaline 10 is prob-
ably very reactive towards further condensation with o-
phenylenediamine to afford imine 4. This is probably
due to the protonation of the carbonyl oxygen and/or
nitrogen(s) of quinoxaline 10 by acetic acid, which could
enhance the electrophilicity of the carbonyl functionality
expediting the last step in the sequence.
Supplementary data
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.
2007.01.106.
Reaction between 2 and 3 under solvent-free microwave
irradiation in the presence of a catalytic amount of
acetic acid also furnished 4 in slightly higher yields of
65–70% compared to the thermal reaction in ethanol.13
References and notes
1. (a) Posner, G. H. Chem. Rev. 1986, 86, 831; (b) Tietze, L.
F.; Beifuss, U. Angew. Chem., Int. Ed. Engl. 1993, 32, 131;
(c) Bunce, R. A. Tetrahedron 1995, 48, 13103; (d) Ho, T.
L. Tandem Organic Reactions; John Wiley & Sons: New
York, 1992.
2. Anastas, P. T.; Warner, J. C. Green Chemistry: Theory and
Practice; Oxford University Press: New York, 2000.
3. (a) Alex Raja, V. P.; Perumal, S. Tetrahedron 2006, 62,
4892; (b) Savitha Devi, N.; Perumal, S. Tetrahedron 2006,
62, 5931; (c) Srinivasan, M.; Perumal, S. Tetrahedron
2006, 62, 7726; (d) Indumathi, S.; Ranjith Kumar, R.;
Perumal, S. Tetrahedron 2007, 63, 1411; (e) Srinivasan,
M.; Perumal, S. Tetrahedron, in press.
To the best of the knowledge of the authors, this is the
first synthesis of quinoxalines from the direct reaction
of epoxyketones with o-phenylenediamine. Previously,
syntheses of quinoxalines have been reported from
epoxyketones by converting (i) the latter to 1,2-diones
by treatment with either alcoholic sodium hydroxide
or boron trifluoride, and (ii) reacting the resulting
1,2-diones with o-phenylenediamine or its dihydro-
chloride.15
4. (a) Evans, B. E.; Rittle, K. E.; Bock, M. G.; DiPardo, R.
M.; Freidinger, R. M.; Whitter, W. L.; Lundell, G. F.;
Veber, D. F.; Anderson, P. S.; Chang, R. S. L.; Lotti, V.
J.; Cerino, D. J.; Chen, T. B.; Kling, P. J.; Kunkel, K. A.;
Springer, J. P.; Hirshfield, J. J. Med. Chem. 1988, 31, 2235;
(b) Kariakomi, M.; Watanabe, S.; Kimura, Y.; Uyehara,
T. Tetrahedron Lett. 2002, 43, 1495.
The present work describes a facile, acid catalysed,
one-pot three-component tandem protocol for the syn-
thesis of novel quinoxalines from readily accessible
oxiranes.
5. Stratford, I. J.; Stephens, M. A.; Naylor, M. A.; Fielden,
E. M.; Adams, G. E. Br. J. Cancer 1992, 65, 17.
6. Loriga, M.; Fiore, M.; Sanna, P.; Paglietti, G. Farmaco
1997, 50, 289.
7. Loriga, M.; Piras, S.; Paglietti, G.; Costi, M. P.; Ventu-
relli, A. Farmaco 2003, 58, 51.
8. Hannon, M.; Rodger, A.; Mann, N. H. Patent No. WO
2005033119, 2005; Chem. Abstr. 2005, 142, 402929h.
9. Carona, P.; Vitale, G.; Loriga, M.; Paglietti, G.; Colla, P.
L.; Collu, G.; Sanna, G.; Loddo, R. Eur. J. Med. Chem.
2006, 41, 1102.
Acknowledgements
S.P. thanks the Department of Science and Technology,
New Delhi for, (i) a major research project, (ii) funds
under the IRHPA programme for the purchase of a high
resolution NMR spectrometer and (iii) funds under the
FIST programme and the University Grants Commis-
sion, New Delhi, for funds under the DRS and ASIST
programmes.

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M. Kamal Nasar et al. / Tetrahedron Letters 48 (2007) 2155–2158
10. Alleca, S.; Corona, P.; Loriga, M.; Paglietti, G.; Loddo,
R.; Mascia, V.; Busonera, B.; Colla, P. L. Farmaco 2003,
58, 639.
irradiation, the reaction mixture was cooled to room
temperature and thoroughly mixed. The maximum tem-
perature of the silica bath, measured immediately after
irradiation by stirring the silica bath with the thermom-
eter, was found to be 78 °C. After completion of the
reaction (TLC), the product was obtained in a pure state
as described under thermal conditions (0.28 g, 67% yield).
Compound 4a: viscous liquid. Anal. Calcd for C29H24N4:
C, 81.28; H, 5.65; N, 13.07. Found: C, 81.18; H, 5.72; N,
13.15; IR (KBr) m 3320, 1590 cmÀ1; dH (300 MHz, CDCl3)
2.25 (s, 3H), 2.35 (s, 3H), 2.96 (s, 2H), 5.69 (d, J = 7.8 Hz,
1H), 6.01 (t, J = 7.5 Hz, 1H), 6.28 (d, J = 7.8 Hz, 1H),
6.59 (t, J = 7.5 Hz, 1H), 6.95–8.11 (m, 12H); dC (75 MHz,
CDCl3) 21.8, 22.0, 115.6, 117.7, 120.9, 126.2, 129.1, 129.2,
129.5, 129.7, 129.8, 130.3, 131.2, 135.1, 135.7, 136.3, 139.9,
140.5, 141.3, 141.9, 142.0, 152.2, 153.7, 163.7.
11. Experimental procedure: Synthesis of [2-[(4-chlorophen-
yl)sulfanyl]-3-(4-methyl-phenyl)-2-oxiranyl](4-methylphen-
yl)methanone (2a). In a typical reaction, hydrogen perox-
ide (1.6 mL, 30%) was added in one lot to a stirred
solution of 2-[(4-chlorophenyl)sulfanyl]-1,3-bis(4-methyl-
phenyl)-2-propen-1-one (1a) (0.76 g, 2 mmol) in ethanol
(6 mL), followed by dropwise addition of sodium hydrox-
ide solution (2 mL, 10%). After completion of the reaction
(1 h), the product was washed with water to afford a
colourless solid (0.76 g, in 96% yield), which was recrys-
tallised from alcohol. Compound 2a: white solid, mp 88–
90 °C. Anal. Calcd for C23H19ClO2S: C, 69.95; H, 4.85.
Found: C, 70.07; H, 4.77; IR (KBr) m 3020, 1650,
1210 cmÀ1; dH (300 MHz, CDCl3) 2.42 (s, 6H), 4.39 (s,
1H), 7.16–7.84 (m, 12H); dC (75 MHz, CDCl3) 21.4, 21.8,
62.3, 75.0, 127.3, 127.9, 128.8, 129.0, 129.2, 129.5, 131.2,
134.6, 134.8, 139.2, 144.8, 190.4.
14. Experimental procedure for the synthesis of N-[2-[(4-meth-
ylphenyl)[3-(4-methylphenyl)-2-quinoxalinyl]methylidene]-
aminophenyl]acetamide (5a). Compound 4a (0.09 g,
0.21 mmol) dissolved in acetic anhydride (3 mL) was
stirred at room temperature for 5.5 h. Then the reaction
mixture was poured into water (100 mL), stirred for 4 h
and extracted with dichloromethane. The organic layer
was washed repeatedly with water, dried over anhydrous
sodium sulfate and the solvent removed. The resulting
colourless solid was recrystallised from alcohol (0.094 g,
95% yield; mp 121–122 ° C). Compound 5a: pale yellow
crystal. Anal. Calcd for C31H26N4O: C, 79.12; H, 5.57; N,
11.91. Found: C, 78.98; H, 5.68; N, 12.03, IR (KBr) m
3365, 1690 cmÀ1; dH (300 MHz, CDCl3) 1.82 (s, 1H), 1.92
(s, 3H), 2.35 (s, 3H), 2.50 (s, 3H), 5.81 (d, J = 7.2 Hz, 1H),
6.40 (t, J = 7.5 Hz, 1H), 6.89 (t, J = 7.8 Hz, 1H), 8.11 (d,
J = 7.5 Hz, 1H), 7.00–8.21 (m, 12H). dC (75 MHz, CDCl3)
21.8, 22.1, 25.2, 119.2, 120.3, 122.6, 126.3, 128.8, 129.4,
129.7, 129.8, 129.9, 130.1, 130.6, 131.5, 132.9, 134.7, 136.0,
136.8, 140.3, 140.4, 142.0, 142.8, 151.4, 153.7, 165.8, 167.4.
Crystallographic data (excluding structure factors) for 5a
in this Letter have been deposited with the Cambridge
Crystallographic Data Centre as supplementary publica-
tion number CCDC 628360. Copies of the data can be
obtained, free of charge, on application to CCDC, 12
Union Road, Cambridge CB2 1EZ, UK [fax: +44(0)-
1223-336033 or e-mail: deposit@ccdc.cam.ac.uk].
12. Kroehnke, F.; Ahrenholz, G. W.; Gross, K. F. J. Prakt.
Chem. 1960, 11, 256.
13. Experimental procedure: Synthesis of N-{(4-methylphen-
yl)[3-(4-methylphenyl)-2-quinoxalinyl]methylidene}-1,2-
benzenediamine (4a): 1. Conventional method. A mixture
of [2-[(4-chlorophenyl)sulfanyl]-3-(4-methylphenyl)-2-oxiran-
yl](4-methyl-phenyl)methanone (2a) (0.39 g, 1 mmol), o-
phenylenediamine (3) (0.22 g, 2 mmol) and a catalytic
amount of acetic acid (0.02 mL) was refluxed in ethanol
(1 mL) for 30 min. After completion (TLC), the reaction
mixture was poured into water, extracted with dichloro-
methane, the organic layer separated and the solvent
removed and the residue purified by flash column chro-
matography on silica gel employing petroleum ether–ethyl
acetate [19:1 (v/v)] as eluent to give the desired product as
a viscous liquid (0.24 g, 57% yield).
2. Under microwave irradiation. In a glass tube, [2-[(4-
chlorophenyl)sulfanyl]-3-(4-methylphenyl)-2-oxiranyl](4-
methylphenyl)methanone (2a) (0.39 g, 1 mmol), o-phenyl-
enediamine (3) (0.22 g, 2 mmol) and a catalytic amount of
acetic acid (0.09 mL) were thoroughly mixed and the open
glass tube was kept in a silica bath in a microwave oven
(IFB, model-Electron, 1000 W capacity, microwave fre-
quency of 2450 MHz) and irradiated for 5 min periods for
40 min at power level 4 in a total scale of 5. After each
15. (a) House, H. O.; Reif, D. J. J. Am. Chem. Soc. 1955, 77,
6525; (b) House, H. O. J. Am. Chem. Soc. 1954, 76, 1235.