Cyclisation reaction between 3-methylquinoxaline-2-thione and benzaldehydes into 3-benzyl-2-aryl-thieno[2,3-b] quinoxaline promoted by Br?nsted acids

Article abstract of DOI:10.1016/j.crci.2015.06.003

2,3-Disubstituted thieno[2,3-b]quinoxaline derivatives have been synthetized through the condensation of commercially available benzaldehydes with 3-methylquinoxaline-2-thione in EtOH using Br?nsted acids, namely sulfuric or hydrochloric acids. A wide range of substituted benzaldehydes has been used, allowing the formation of 3-(substituted)benzyl-2-arylthieno[2,3-b]quinoxalines in high yields in only one step.

Full text of DOI:10.1016/j.crci.2015.06.003

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Preliminary communication/Communication
Cyclisation reaction between 3-methylquinoxaline-2-thione
and benzaldehydes into 3-benzyl-2-aryl-thieno[2,3-b]
quinoxaline promoted by Brønsted acids
Formation de 3-benzyl-2-arylthieno[2,3-b]quinoxaline via la cyclisation
entre le 3-methylquinoxaline-2-thione et des benzaldehydes induite par
des acides de Brønsted
Besma Saoudi a,b, Abderrahmane Teniou b, Adbelmadjid Debache b,
,
*
a
a,
a,
*
*
´
Thierry Roisnel , Jean-Franc¸ois Soule , Henri Doucet
a Institut des sciences chimiques de Rennes, UMR 6226 CNRS-Universite´ de Rennes-1 « Organome´talliques, mate´riaux et catalyse », campus
´
´
de Beaulieu, 263, avenue du General-Leclerc, 35042 Rennes, France
b
`
´
`
´ ˆ
´
Laboratoire de synthese des molecules a interet biologique, Universite Mentouri-Constantine, 25000 Constantine, Algeria
A R T I C L E I N F O
A B S T R A C T
Article history:
2,3-Disubstituted thieno[2,3-b]quinoxaline derivatives have been synthetized through the
condensation of commercially available benzaldehydes with 3-methylquinoxaline-2-
thione in EtOH using Brønsted acids, namely sulfuric or hydrochloric acids. A wide range of
substituted benzaldehydes has been used, allowing the formation of 3-(substituted)ben-
zyl-2-arylthieno[2,3-b]quinoxalines in high yields in only one step.
Received 31 March 2015
Accepted after revision 2 June 2015
Available online xxx
Keywords:
ß 2015 Acade´mie des sciences. Published by Elsevier Masson SAS. All rights reserved.
Benzaldehydes
Brønsted Acid
Cyclisation
Heterocycles
Quinoxalines
´
´
R E S U M E
´
´
´
´
´ ´
´
´
Mots cle´s :
Des derives thieno[2,3-b]quinoxaline substitues en positions 2 et 3 ont ete synthetises par
Acide de Brønsted
Benzaldehydes
Cyclisation
la condensation de benzalde´hydes avec du 3-me´thylquinoxaline-2-thione dans l’EtOH en
`
utilisant des acides de Brønsted, a savoir l’acide sulfurique ou chlorhydrique. Une large
´
´
´ ´
´
gamme de benzaldehydes substitues a ete utilisee, permettant la formation de benzyl-2-
Heterocycles
Quinoxalines
arylthieno[2,3-b]quinoxalines substitue´es en position 3 avec des rendements e´leve´s en
´
une seule etape.
´
´
´
´
ß 2015 Academie des sciences. Publie par Elsevier Masson SAS. Tous droits reserves.
1. Introduction
Heterocycle synthesis is a very important field in
organic chemistry, because such derivatives play a major
role in medicinal chemistry. In addition, such motifs are
*
Corresponding authors.
present in many natural products. Indeed, the discovery of
E-mail address: jean-francois.soule@univ-rennes1.fr (J.-F. Soule´).
http://dx.doi.org/10.1016/j.crci.2015.06.003
1631-0748/ß 2015 Acade´mie des sciences. Published by Elsevier Masson SAS. All rights reserved.
Please cite this article in press as: Saoudi B, et al. Cyclisation reaction between 3-methylquinoxaline-2-thione and
benzaldehydes into 3-benzyl-2-aryl-thieno[2,3-b]quinoxaline promoted by Brønsted acids. C. R. Chimie (2015), http://
dx.doi.org/10.1016/j.crci.2015.06.003

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Fig. 1. Relevant thieno[2,3-b]quinoxaline structures.
new synthetic methods and/or new heterocyclic com-
pounds has always attracted much attention [1].
Thieno[2,3-b]quinoxaline derivatives are polycyclic het-
erocycles, which have a thiophene ring fused with a
quinoxaline motif. Such compounds have found many
applications in medicinal as well as in electronic devices
(Fig. 1) [2]. For example, N,N-dimethyl-4-(thieno[2,3-
b]quinoxalin-2-yl)aniline (I) can be used as a fluorescent
presence of an aldehyde. It is important to note that under
basic conditions, 3-methylquinoxaline-2-thione normally
reacts at the methyl position via alkylation-, or aldoliza-
tion-type reactions [12–14].
Initially, we prepared the required starting material, i.e.
3. As described in the literature, 3 could be easily prepared
from the condensation of 2-aminoaniline (1) with ethyl 2-
oxopropanoate under acidic conditions to get 3-methyl-
quinoxalin-2-one (2) in 78% yield [15], then 2 is converted
probe for amyloid-b-fibrils [3], thieno[2,3-b:4,5-
b0]diquinoxaline (II) exhibits fluorescence and phospho-
rescence properties [4], urothion (III) is a yellowish
pteridine pigment isolated from human urine [5], and
ethyl 2-((5-(3-(pyrrol-1-yl)thieno[2,3-b]quinoxalin-2-yl)-
1,3,4-oxadiazol-2-yl)thio)acetate (IV) exhibits antimicro-
bial and fungicide activities [6].
to 3 by a thiation in 87% yield, using phosphorus
pentasulfide in pyridine under reflux conditions during
6 h (Scheme 1) [16].
With compound 3 in our hands, we investigated its
reactivity in the presence of sulfuric acid and one
equivalent of 4-bromobenzaldehyde in EtOH under reflux
conditions for 12 h (Scheme 2). Initially, we expected to
obtain the 2-substitued-2,3-dihydrothieno[2,3-b]quinoxa-
line derivative 5a, resulting from the monocondensation
between aldehyde 4a and compound 3. To our surprise, we
obtained the unexpected 2,3-disubstituted thieno[2,3-
b]quinoxaline 6a, which results from the condensation
of 3 with two molecules of 4-bromobenzaldehyde (4a), in
The synthesis of thieno[2,3-b]quinoxaline derivatives
has been less studied than that of their benzothiophene
analogues, and these heterocycles are rather uncommon in
the literature [7]. One of the first syntheses of thieno[2,3-
b]quinoxaline derivatives was achieved from (3-substitut-
ed styryl)-2-quinoxalinone in the presence of stoichio-
metric amounts of phosphorus pentasulfide via a thiation,
a cyclization and aromatization process [8,9]. 2,3-Disub-
stitued thieno[2,3-b]quinoxaline can be synthesized via
the condensation of 2-aminoaniline with thiophene-2,3-
dione derivatives [10]. More recently, these derivatives
were obtained by the action of NaSH on 3-alkynyl-2-
chloroquinoxalines [11]. To date, there is no simple and
general method for the synthesis of 2,3-disubstitued
thieno[2,3-b]quinoxaline starting from simple chemicals.
Here, we report on the synthesis of 3-(substituted)-
benzyl-2-arylthieno[2,3-b]quinoxalines via a simple con-
densation between 3-methylquinoxaline-2-thione and
benzaldehydes under acidic conditions.
32% yield. We confirmed the structure of 6a by 1H and 13
C
NMR studies. In addition, in order to secure unambiguous-
ly the structure of the product, the X-ray crystallographic
analysis of 6a was carried out and the result is delineated
in Fig. 2.
Then, we investigated the influence of the nature and
the amount of the acid for this reaction. We first increased
the number of equivalents of aldehyde 4a to 2 equivalents
in the presence of 1 equivalent of sulfuric acid. As a result,
the desired product 6a was obtained in higher yield (48%,
Table 1, entry 2). A slight excess of aldehyde (2.2 equiva-
lents) increased again the yield to 52% (Table 1, entry 3).
Only trace amounts of the desired product 6a were
observed using only a catalytic amount of sulfuric acid
(i.e. 20 mol%) (Table 1, entry 4). This low yield in 6a was
explained by a poor conversion, and large amounts of the
starting materials were recovered at the end of the
2. Results
We decided to investigate the reactivity of 3-methyl-
quinoxaline-2-thione (3) under acidic conditions in the
H
N
H
NH2
i)
ii)
O
N
S
78%
NH2
87%
N
N
1
2
3
i) ethyl 2-oxopropanoate (1 equiv.), H2SO4 (pH = 2), water, rt, 3 h.
ii) P2S5 (1.5 equiv.), pyridine, reflux, 6 h.
Scheme 1. Preparation of 3-methylquinoxaline-2-thione (3).
Please cite this article in press as: Saoudi B, et al. Cyclisation reaction between 3-methylquinoxaline-2-thione and
benzaldehydes into 3-benzyl-2-aryl-thieno[2,3-b]quinoxaline promoted by Brønsted acids. C. R. Chimie (2015), http://
dx.doi.org/10.1016/j.crci.2015.06.003

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3
Scheme 2. H2SO4-promoted cyclization reaction between 3-methylquinoxaline-2-thione (3) and 4-bromobenzaldehyde (4a).
Fig. 2. ORTEP figure for 6a.
Table 1
Optimization of the reaction conditions for the synthesis of 3-(4-bromobenzyl)-2-(4-bromophenyl)thieno[2,3-b]quinoxaline (6a).
Entry
4a (x equiv)
Acid (y equiv)
6a yield (%)a
1
2
3
4
5
6
7
8
9
10
1
H2SO4 (1)
32
2
H2SO4 (1)
48
2.2
2.2
2.2
2.2
2.2
2.2
2.2
2.2
H2SO4 (1)
52
H2SO4 (0.2)
H2SO4 (1.5)
H2SO4 (2)
Trace
77
84
H2SO4 (2.5)
CH3CO2H (2)
HCl (2)
82
ND
79
FeCl3.6H2O (2)
ND
ND: not detected.
a
Isolated yield.
Please cite this article in press as: Saoudi B, et al. Cyclisation reaction between 3-methylquinoxaline-2-thione and
benzaldehydes into 3-benzyl-2-aryl-thieno[2,3-b]quinoxaline promoted by Brønsted acids. C. R. Chimie (2015), http://
dx.doi.org/10.1016/j.crci.2015.06.003

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reaction. Then, we decided to increase the number of
equivalents of sulfuric acid. When the reaction was
performed in the presence of 1.5 or 2 equivalents of
sulfuric acid, thienoquinoxaline 6a was isolated in 77% and
84% yields, respectively (Table 1, entries 5 and 6)[17]. Larger
amounts of sulfuric acid (2.5 equivalents) did not offer any
improvement (Table 1, entry 7). Then, we tested other acids
for this reaction. The use of 2 equivalents of acetic acid did
not afford the desired 2,3-disubstituted thienoquinoxaline
6a and only the starting materials were recovered at the end
of the reaction (Table 1, entry 8). Hydrochloric acid allows
the formation of the expected product 6a, albeit in a slightly
lower yield than sulfuric acid (Table 1, entry 9). Iron salts
have recently attracted considerable attention as inexpen-
siveand environmentallyfriendlyLewis acid ina widerange
of selective processes in organic synthesis [17,18]. However,
noreactionoccurred inthepresenceofthisLewis acid(Table
1, entry 10).
2.2 equivalents of aldehydes in the presence of 2 equiva-
lents of sulfuric acid in EtOH at reflux during 12 h—we
turned our attention to the aldehyde scope for such
transformation (Scheme 3). Benzaldehyde also allows the
formation of 3-benzyl-2-phenylthieno[2,3-b]quinoxaline
6b in high yield. Other 4-halogenated benzaldehydes such
as 4-fluorobenzaldehyde or 4-chlorobenzaldehyde that
were reacted with 3 lead to compounds 6c and 6d in 84%
and 86% yields, respectively. Electron-donating groups at
para-position such as the methyl, ethyl, methylthio,
methoxy ones are also tolerated by the optimized reaction
conditions, as the corresponding 2,3-disubstituted
thieno[2,3-b]quinoxalines 6e–6h were isolated in a range
of yields from 84 to 91%. However, with a benzaldehyde
bearing a very strong electron-donating group at para-
position such as the dimethylamino group, only trace
amounts of the desired product 6i were observed. This lack
of reactivity could be explained by a poor solubility of the
materials and/or of the product. 4-Phenylbenzaldehyde
displays a moderate activity, as 2-([1,10-biphenyl]-4-yl)-3-
([1,10-biphenyl]-4-ylmethyl)thieno[2,3-b]quinoxaline (6j)
Having determined the best conditions for the forma-
tion of 2,3-disubstituted thieno[2,3-b]quinoxaline deriva-
tives from 3-methylquinoxaline-2-thione (3)—namely,
Scheme 3. Scope of the benzaldehydes for H2SO4-promoted cyclization with 3-methylquinoxaline-2-thione (3).
Please cite this article in press as: Saoudi B, et al. Cyclisation reaction between 3-methylquinoxaline-2-thione and
benzaldehydes into 3-benzyl-2-aryl-thieno[2,3-b]quinoxaline promoted by Brønsted acids. C. R. Chimie (2015), http://
dx.doi.org/10.1016/j.crci.2015.06.003

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5
Scheme 4. H2SO4-promoted cyclization of 3-methylquinoxaline-2-thione (3) with benzaldehyde: probable sequence leading to 2,3-disubstituted
thieno[2,3-b]quinoxaline (6).
was obtained in only 48% yield. However, 4-nitrobenzal-
dehyde was completely unreactive under these reaction
conditions and the formation of the product 6k was not
detected. The reaction is slightly sensitive to the steric
hindrance of the benzaldehyde, as 2-bromobenzaldehyde
or 2-anisaldehyde displays lower reactivity than their
para-substituted homologues. It is also important to note
that the reaction was not efficient using aliphatic
aldehydes or paraformaldehyde.
should present an interest for biological and/or physical
properties.
4. Experimental
EtOH (ethanol) (95%), H2SO4 (98%) were purchased from
Acros. Aldehyde compounds were not purified before use.
1H NMR spectra were recorded on Bruker GPX (400 MHz)
or Bruker GPX (300 MHz) spectrometer. Chemical shifts (d)
We propose a possible sequence for this Brønsted acid-
promoted condensation of two equivalent of the benzal-
dehyde derivative with 3-methylquinoxaline-2-thione
(3) (Scheme 4). First, the thiol function of intermediate
A—which is a tautomer of 1—reacts with a molecule of
benzaldehyde under acidic conditions to afford interme-
diate B. Under these acidic conditions, B would be
dehydrated to allow the formation of thiol-carbenium
C, which could cyclize to give 2-aryl-2,3-dihy-
drothieno[2,3-b]quinoxaline D. Then, a Knoevenagel-type
condensation under acidic conditions of the intermediate
D with another molecule of benzaldehyde leads to
compound F [19], which is transformed into the desired
2,3-disubstituted thieno[2,3-b]quinoxaline (6) via a rear-
omatization process.
were reported in parts per million relative to residual
chloroform (7.26 ppm for 1H; 77.0 ppm for 13C), coupling
constants (J) were reported in hertz. 1H NMR assignment
abbreviations were the following: singlet (s), doublet (d),
triplet (t), quartet (q), doublet of doublets (dd), doublet of
triplets (dt), and multiplet (m). 13C NMR spectra were
recorded at 100 MHz or 75 MHz on the same spectrometer
and reported in ppm. All reagents were weighed and
handled in air.
General procedure: to a 5-mL oven-dried Schlenk tube,
3-methylquinoxaline-2-thione (3) (176 mg, 1 mmol),
benzaldehyde (2.2 mmol), H2SO4 (106 mL, 2 mmol), EtOH
(4 mL) were successively added. The reaction mixture
was stirred at 70 8C (oil bath temperature) for 12 h. After
cooling the reaction at room temperature and concentra-
tion, the crude mixture was poured into ice and the solid
was collected by filtration. The crude mixture was purified
using flash chromatography (SiO2, Pentane–Et2O) and
recrystallized in hot EtOH to give the desired product.
3. Conclusion
In summary, we developed a new method for the
synthesis of new 2,3-disubstituted thieno[2,3-b]quinox-
alines via the condensation of 3-methylquinoxaline-2-
thion with a wide range of benzaldehydes. Simple Brønsted
acids, such as sulfuric or hydrochloric acid, have been used
to promote such a reaction, which was performed in EtOH
4.1. 3-(4-Bromobenzyl)-2-(4-bromophenyl)thieno[2,3-
b]quinoxaline (6a)
Following the general procedure using 3-methylqui-
noxaline-2-thione (3) (176 mg, 1 mmol) and 4-bromoben-
zaldehyde (407 mg, 2.2 mmol), the residue was purified
as
a green and renewable solvent. Using this new
methodology, we synthetized 11 new compounds, which
Please cite this article in press as: Saoudi B, et al. Cyclisation reaction between 3-methylquinoxaline-2-thione and
benzaldehydes into 3-benzyl-2-aryl-thieno[2,3-b]quinoxaline promoted by Brønsted acids. C. R. Chimie (2015), http://
dx.doi.org/10.1016/j.crci.2015.06.003

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using flashchromatography(SiO2, pentane–Et2O 90:10) and
recrystallized in hot EtOH to give the desired product 6a as a
yellow solid (84%, 429 mg). mp = 192–197 8C.
and recrystallized in hot EtOH to give the desired product
6d as a yellow solid (86%, 362 mg). mp = 181–185 8C.
1H NMR (300 MHz, CDCl3)
d (ppm) 8.24–8.16 (m, 2H),
1H NMR (400 MHz, CDCl3)
d
(ppm) 8.23–8.15 (m, 2H),
7.84–7.77 (m, 2H), 7.53–7.46 (m, 4H), 7.23–7.16 (m, 2H),
4.44 (s, 2H).
7.82–7.77 (m, 2H), 7.62 (d, J = 8.4 Hz, 2H), 7.43 (d, J = 8.4 Hz,
2H), 7.34 (d, J = 8.4 Hz, 2H), 7.09 (d, J = 8.4 Hz, 2H), 4.40
(s, 2H).
13C NMR (75 MHz, CDCl3)
d (ppm) 156.2, 151.0, 146.6,
141.5, 140.9, 138.5, 136.1, 132.3, 132.2, 130.7, 129.9, 129.7,
129.5, 129.4, 128.8, 128.7, 31.3.
13C NMR (100 MHz, CDCl3)
d (ppm) 156.0, 150.8, 146.4,
141.3, 140.6, 138.7, 132.4, 132.2, 131.6, 130.7, 130.1, 129.7,
129.5, 129.2, 129.0, 128.5, 124.1, 120.1, 31.1.
Elemental analysis: calcd (%) C23H14Cl2N2S for (421.34):
C 65.57, H 3.35; found: C 65.82, H 3.59.
Elemental analysis: calcd (%) C23H14Br2N2S for
(510.25): C 54.14, H 2.77; found: C 54.37, H 3.01.
MS (EI): calcd for C23H14Br2N2S [M+] 510, found: 510.
MS (EI): calcd for C23H14Cl2N2S [M+] 421, found: 421.
4.5. 3-(4-Ethylbenzyl)-2-(4-ethylphenyl)thieno[2,3-
b]quinoxaline (6e)
4.2. 3-(Benzyl)-2-(phenyl)thieno[2,3-b]quinoxaline (6b)
Following the general procedure using 3-methylqui-
Following the general procedure using 3-methylqui-
noxaline-2-thione (3) (176 mg, 1 mmol) and 4-ethylben-
noxaline-2-thione (3) (176 mg, 1 mmol) and benzaldehyde
zaldehyde (303 mL, 2.2 mmol), the residue was purified
(225
m
L, 2.2 mmol), the residue was purified using flash
using flash chromatography (SiO2, pentane–Et2O 85:15)
and recrystallized in hot EtOH to give the desired
product 6e as a yellow solid (91%, 372 mg). mp = 152–
156 8C.
chromatography (SiO2, pentane–Et2O 90:10) and recrys-
tallized in hot EtOH to give the desired product 6b as a
yellow solid (80%, 282 mg). mp = 158–162 8C.
1H NMR (400 MHz, CDCl3)
d
(ppm) 8.22–8.16 (m, 2H),
1H NMR (300 MHz, CDCl3)
d (ppm) 8.14–8.06 (m, 2H),
7.77 (t, J = 8.2 Hz, 2H), 7.62–7.59 (m, 2H), 7.49–7.47 (m,
7.70–7.65 (m, 2H), 7.47 (d, J = 8.2 Hz, 2H), 7.23 (d, J = 8.2 Hz,
2H), 7.10 (d, J = 8.2 Hz, 2H), 6.99 (d, J = 8.2 Hz, 2H), 4.40 (s,
2H), 2.65 (q, J = 7.6 Hz, 2H), 2.51 (q, J = 7.6 Hz, 2H), 1.22 (t,
J = 7.6 Hz, 3H), 1.22 (t, J = 7.6 Hz, 3H).
2H), 7.26–7.22 (m, 3H), 4.50 (s, 2H).
13C NMR (100 MHz, CDCl3)
d (ppm) 156.3, 151.3, 147.6,
141.3, 140.5, 140.1, 133.7, 129.8, 129.5, 129.3, 129.2, 128.9,
128.9, 128.4, 128.2, 128.0, 127.4, 126.1, 31.7.
Elemental analysis: calcd (%) C23H16N2S for (352.46): C
78.38, H 4.58; found: C 78.71, H 4.48.
13C NMR (75 MHz, CDCl3)
d (ppm) 156.4, 151.5, 147.7,
145.9, 141.9, 141.3, 140.4, 131.1, 129.8, 129.3, 129.0, 128.7,
128.5, 128.4, 128.3, 127.9, 31.4, 28.7, 28.4, 15.5, 15.4.
Elemental analysis: calcd (%) C27H24N2S for (408.56): C
79.38, H 5.92; found: C 79.51, H 6.12.
MS (EI): calcd for C23H16N2S [M+] 352, found: 352.
4.3. 3-(4-Fluorobenzyl)-2-(4-fluorophenyl)thieno[2,3-
MS (EI): calcd for C27H24N2S [M+] 408, found: 408.
b]quinoxaline (6c)
4.6. 3-(4-Methylbenzyl)-2-(4-methylphenyl)thieno[2,3-
Following the general procedure using 3-methylqui-
b]quinoxaline (6f)
noxaline-2-thione (3) (176 mg, 1 mmol) and 4-fluoro-
benzaldehyde (236
m
L, 2.2 mmol), the residue was
Following the general procedure using 3-methylqui-
purified using flash chromatography (SiO2, pentane–
Et2O 95:5) and recrystallized in hot EtOH to give the
desired product 6c as a yellow solid (84%, 326 mg).
mp = 150–154 8C.
noxaline-2-thione (3) (176 mg, 1 mmol) and 4-methyl-
benzaldehyde (260
mL, 2.2 mmol), the residue was
purified using flash chromatography (SiO2, pentane–
Et2O 85:15) and recrystallized in hot EtOH to give the
desired product 6f as a yellow solid (89%, 339 mg).
mp = 191–195 8C.
1H NMR (400 MHz, CDCl3)
d (ppm) 8.17–8.07 (m, 2H),
7.74–6.64 (m, 2H), 7.47 (dd, J = 5.2 and 8.7 Hz, 2H), 7.15–
7.07 (m, 4H), 6.83 (t, J = 8.7 Hz, 2H), 4.35 (s, 2H).
1H NMR (300 MHz, CDCl3)
d (ppm) 8.24–8.16 (m, 2H),
13C NMR (100 MHz, CDCl3)
d
(ppm) 166.4 (d,
7.81–7.74 (m, 2H), 7.53 (d, J = 8.1 Hz, 2H), 7.31 (d, J = 8.1 Hz,
2H), 7.17 (d, J = 8.1 Hz, 2H), 7.17 (d, J = 8.1 Hz, 2H), 4.47 (s,
2H), 2.45 (s, 3H), 2.40 (s, 3H).
J = 254.8 Hz), 161.4 (d, J = 245.8 Hz), 156.1, 150.9, 146.5,
141.2, 140.6, 135.5 (d, J = 3.0 Hz), 131.2, 131.1, 129.8 (d,
J = 7.6 Hz), 129.7, 129.4, 129.3, 129.1, 128.5, 116.2 (d,
J = 16.7 Hz), 115.3 (d, J = 21.3 Hz), 30.9.
Elemental analysis: calcd (%) C23H14F2N2S for (388.44):
C 71.12, H 3.63; found: C 71.36, H 3.55.
13C NMR (75 MHz, CDCl3)
d (ppm) 156.6, 151.7, 147.9,
141.5, 140.7, 139.8, 137.3, 135.7, 131.1, 130.0, 129.9, 129.4,
129.3, 129.2, 129.1, 128.9, 128.6, 128.5, 31.6, 21.6, 21.2.
Elemental analysis: calcd (%) C25H20N2S for (380.51): C
78.91, H 5.30; found: C 79.18, H 5.47.
MS (EI): calcd for C23H14F2N2S [M+] 388, found: 388.
MS (EI): calcd for C25H20N2S [M+] 380, found: 380.
4.4. 3-(4-Chlorobenzyl)-2-(4-chlorophenyl)thieno[2,3-
b]quinoxaline (6d)
4.7. 3-(4-(Methylthio)benzyl)-2-(4-
(methylthio)phenyl)thieno[2,3-b]quinoxaline (6g)
Following the general procedure using 3-methylqui-
noxaline-2-thione (3) (176 mg, 1 mmol) and 4-chloroben-
zaldehyde (309 mg, 2.2 mmol), the residue was purified
using flash chromatography (SiO2, pentane–Et2O 85:15)
Following the general procedure using 3-methylqui-
noxaline-2-thione (3) (176 mg, 1 mmol) and 4-
(methylthio)benzaldehyde (293 mL, 2.2 mmol), the residue
Please cite this article in press as: Saoudi B, et al. Cyclisation reaction between 3-methylquinoxaline-2-thione and
benzaldehydes into 3-benzyl-2-aryl-thieno[2,3-b]quinoxaline promoted by Brønsted acids. C. R. Chimie (2015), http://
dx.doi.org/10.1016/j.crci.2015.06.003

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B. Saoudi et al. / C. R. Chimie xxx (2015) xxx–xxx
7
was purified using flash chromatography (SiO2, pentane–
Et2O 75:25) and recrystallized in hot EtOH to give the
desired product 6g as a yellow solid (87%, 387 mg).
mp = 183–187 8C.
zaldehyde (257
m
L, 2.2 mmol), the residue was purified
using flash chromatography (SiO2, pentane–Et2O 80:20)
and recrystallized in hot EtOH to give the desired product
6l as a yellow solid (62%, 316 mg). mp = 175–179 8C.
1H NMR (300 MHz, CDCl3)
d
(ppm) 8.37–8.18 (m, 2H),
1H NMR (300 MHz, CDCl3)
d (ppm) 8.27–8.20 (m, 2H),
7.99–7.79 (m, 2H), 7.62 (d, J = 8.0 Hz), 7.40 (d, J = 8.0 Hz),
7.84–7.79 (m, 2H), 7.68–7.64 (m, 1H), 7.44 (dd, J = 1.6 and
7.7 Hz, 1H), 7.30–7.24 (m, 3H), 7.08 (dd, J = 2.2 and 7.5 Hz,
1H), 7.03–6.93 (m, 2H), 4.47 (s, 2H).
7.31–7.23 (m, 4H), 4.55 (s, 2H), 2.67 (s, 3H), 2.55 (s, 3H).
13C NMR (75 MHz, CDCl3)
d (ppm) 147.3, 141.4, 141.2,
140.6, 137.1, 135.9, 130.0, 129.8, 129.6, 129.3, 129.1, 128.6,
128.5, 127.1, 126.2, 31.3, 16.2, 15.3.
Elemental analysis: calcd (%) C25H20N2S3 for (444.63): C
67.53, H 4.53; found: C 67.89, H 4.87.
13C NMR (100 MHz, CDCl3)
d (ppm) 156.4, 150.1, 146.7,
141.2, 140.6, 138.5, 134.2, 133.1, 132.4, 131.5, 130.8, 130.6,
130.5, 129.8, 129.5, 129.0, 128.5, 127.6, 127.3, 127.0, 124.5,
123.9, 32.4.
MS (EI): calcd for C25H20N2S3 [M+] 444, found: 444.
Elemental analysis: calcd (%) C23H14Br2N2S for
(510.25): C 54.14, H 2.77; found: C 54.33, H 3.02.
MS (EI): calcd for C23H14Br2N2S [M+] 510, found: 510.
4.8. 3-(4-(Methoxy)benzyl)-2-(4-
(methoxy)phenyl)thieno[2,3-b]quinoxaline (6h)
4.11. 3-(2-methoxybenzyl)-2-(2-methoxyphenyl)thieno[2,3-
Following the general procedure using 3-methylqui-
b]quinoxaline (6m)
noxaline-2-thione (3) (176 mg, 1 mmol) and p-anisalde-
hyde (268
m
L, 2.2 mmol), the residue was purified using
Following the general procedure using 3-methylqui-
flash chromatography (SiO2, pentane–Et2O 80:20) and
recrystallized in hot EtOH to give the desired product 6h as
a yellow solid (84%, 347 mg). mp = 161–165 8C.
noxaline-2-thione (3) (176 mg, 1 mmol) and o-anisalde-
hyde (266
mL, 2.2 mmol), the residue was purified
using flash chromatography (SiO2, pentane–Et2O
80:20) and recrystallized in hot EtOH to give the desired
product 6m as a yellow solid (59%, 243 mg). mp = 181–
185 8C.
1H NMR (300 MHz, CDCl3)
d (ppm) 8.24–8.16 (m, 2H),
7.80–7.76 (m, 2H), 7.58 (d, J = 8.8 Hz, 2H), 7.20 (d, J = 8.8 Hz,
2H), 7.02 (d, J = 8.8 Hz, 2H), 6.80 (d, J = 8.8 Hz, 2H), 4.45 (s,
2H), 3.90 (s, 3H), 3.77 (s, 3H).
1H NMR (400 MHz, CDCl3)
d (ppm) 8.24–8.17 (m, 2H),
13C NMR (75 MHz, CDCl3)
d
(ppm) 160.6, 157.9, 156.4,
7.79–7.73 (m, 2H), 7.44–7.37 (m, 2H), 7.14–7.08 (m, 2H),
7.04–6.98 (m, 2H), 6.78 (d, J = 8.3 Hz, 1H), 6.73 (t, J = 7.5 Hz,
1H), 4.36 (s, 2H), 3.74 (s, 3H), 3.69 (s, 3H).
151.6, 147.4, 141.3, 140.4, 132.2, 130.7, 129.7, 129.4, 129.0,
128.8, 128.5, 128.4, 126.1, 114.4, 113.9, 55.5, 55.2, 30.9.
Elemental analysis: calcd (%) C25H20N2O2S for (412.51):
C 72.79, H 4.89; found: C 72.81, H 4.77.
13C NMR (100 MHz, CDCl3)
d (ppm) 157.4, 157.2, 151.2,
144.7, 141.3, 140.4, 131.6, 130.9, 130.8, 130.0, 129.0, 128.7,
128.5, 128.3, 127.0, 122.8, 120.7, 120.2, 111.4, 110.0, 55.6,
55.3, 26.4.
MS (EI): calcd for C25H20N2O2S [M+] 412, found: 412.
4.9. 2-([1,1’-Biphenyl]-4-yl)-3-([1,1’-biphenyl]-4-
Elemental analysis: calcd (%) C25H20N2O2S for (412.51):
C 72.79, H 4.89; found: C 73.06, H 5.08.
ylmethyl)thieno[2,3-b]quinoxaline (6j)
MS (EI): calcd for C25H20N2O2S [M+] 412, found: 412.
Following the general procedure using 3-methylqui-
noxaline-2-thione (3) (176 mg, 1 mmol) and biphenyl-4-
carboxaldehyde (401 mg, 2.2 mmol), the residue was
purified using flash chromatography (SiO2, pentane–Et2O
80:20) and recrystallized in hot EtOH to give the desired
product 6j as a yellow solid (48%, 242 mg). mp = 176–
180 8C.
Acknowledgments
We thank the ‘‘Centre national de la recherche
scientifique’’, ‘‘Rennes Metropole’’ for providing financial
support. We also thank the university of Constantine for
the fellowship granted to B.S.
1H NMR (300 MHz, CDCl3)
d (ppm) 8.28–8.20 (m, 2H),
7.83–7.79 (m, 2H), 7.77–7.72 (m, 4H), 7.68 (d, J = 8.2 Hz,
2H), 7.57 (d, J = 7.33 Hz, 2H), 7.54–7.47 (m, 4H), 7.45–7.30
(m, 6H), 4.62 (s, 2H).
References
[1] D.J. Brown, Cumulative Index of Heterocyclic Systems, John Wiley &
Sons, Inc., Hoboken, NJ, USA, 2008.
[2] I. Baranowska, M. Lapkowski, Z. Phys. Chem. (Munich) 142 (1984) 191–
199.
[3] H. Benzeid, E. Mothes, E.M. Essassi, P. Faller, G. Pratviel, C. R. Chimie 15
(2012) 79–85.
[4] I. Baranowska, Monatsh. Chem. 118 (1987) 659–668.
[5] N. Kuboyama, A. Sakurai, Y. Hashimoto, Y. Okumura, Heterocycl. Com-
mun. 1 (1995) 451–454.
13C NMR (75 MHz, CDCl3)
d (ppm) 151.4, 147.4, 142.3,
141.4, 140.9, 140.6, 140.1, 139.2, 139.1, 132.6, 129.8, 129.2,
129.0, 129.0, 129.0, 128.9, 128.7, 128.5, 127.9, 127.6, 127.2,
127.1, 127.1, 127.0, 31.5.
Elemental analysis: calcd (%) C35H24N2S for (504.65): C
83.30, H 4.79; found: C 83.57, H 4.71.
[6] A.A. Geies, Y.A. El-Ossaily, O.S. Moustafa, Russ. J. Bioorg. Chem. 38
(2012) 526–532.
MS (EI): calcd for C35H24N2S [M+] 504, found: 504.
[7] O.S. Moustafa, Y. Yamada, J. Heterocycl. Chem 38 (2001) 809–821.
[8] Y.A. Ibrahim, Chem. Ind. (Lond.) 13 (1980) 536.
[9] Y.A. Ibrahim, M.A. Badawy, S. El-Bahaie, J. Heterocycl. Chem. 19 (1982)
699–700.
4.10. 3-(2-bromobenzyl)-2-(2-bromophenyl)thieno[2,3-
b]quinoxaline (6l)
[10] W. Ott, E. Ziegler, G. Kollenz, Synthesis 1976 (1976) 477–478.
[11] S.K. Kolli, A. Nakhi, R. Medishetti, S. Yellanki, P. Kulkarni, R. Ramesh
Raju, M. Pal, Bioorg. Med. Chem. Lett. 24 (2014) 4460–4465.
Following the general procedure using 3-methylqui-
noxaline-2-thione (3) (176 mg, 1 mmol) and 2-bromoben-
Please cite this article in press as: Saoudi B, et al. Cyclisation reaction between 3-methylquinoxaline-2-thione and
benzaldehydes into 3-benzyl-2-aryl-thieno[2,3-b]quinoxaline promoted by Brønsted acids. C. R. Chimie (2015), http://
dx.doi.org/10.1016/j.crci.2015.06.003

G Model
CRAS2C-4098; No. of Pages 8
8
B. Saoudi et al. / C. R. Chimie xxx (2015) xxx–xxx
[12] C. Amatore, C. Combellas, J. Pinson, J.-M. Save´ant, A. Thie´bault, J. Chem.
Soc., Chem. Commun. (1988) 7–8.
[16] A. Makhloufi, M. Baitiche, M. Merbah, D. Benachour, Synth. Commun.
41 (2011) 3532–3540.
[13] O.S. Moustafa, Y.A. El-Ossaily, J. Chin. Chem. Soc. (Taipei, Taiwan) 49
(2002) 107–112.
[14] G.A. El-Hiti, Synthesis (2003) 2799–2804.
[15] Y. Li, J. Zhang, W. Xu, H. Zhu, X. Li, Bioorg. Med. Chem. 18 (2010)
1516–1525.
[17] C. Bolm, J. Legros, J. Le Paih, L. Zani, Chem. Rev. 104 (2004) 6217–6254.
[18] D.D. Diaz, P.O. Miranda, J.I. Padron, V.S. Martin, Curr. Org. Chem. 10
(2006) 457–476.
[19] M.A. Rani, V. Jeyachandran, M. Muthu, S. Sivakolunthu, R.R. Kumar,
Tetrahedron Lett. 55 (2014) 5805–5807.
Please cite this article in press as: Saoudi B, et al. Cyclisation reaction between 3-methylquinoxaline-2-thione and
benzaldehydes into 3-benzyl-2-aryl-thieno[2,3-b]quinoxaline promoted by Brønsted acids. C. R. Chimie (2015), http://
dx.doi.org/10.1016/j.crci.2015.06.003