Synthesis of [2,3-b]thieno- and furoquinoxalines by the SN H and SNipso reactions of 2-substituted quinoxalines with acetophenones

Article abstract of DOI:10.1070/MC2006v016n01ABEH002208

The treatment of quinoxalin-2-one with acetophenones in the presence of boron trifluoride gives 3-(2-hydroxy-2-R-vinyl)-quinoxalin-2-ones, which can be transformed into [2,3-b]thienoquinoxalines by reactions with P₂S ₅.

Full text of DOI:10.1070/MC2006v016n01ABEH002208

Mendeleev
Communications
Mendeleev Commun., 2006, 16(1), 16–18
Synthesis of [2,3-b]thieno- and furoquinoxalines by the SNH and SNipso reactions of
2-substituted quinoxalines with acetophenones
Anna Yu. Ponomareva, Dmitry G. Beresnev, Nadezhda A. Itsikson, Oleg N. Chupakhin* and
Gennady L. Rusinov
I. Ya. Postovsky Institute of Organic Synthesis, Ural Branch of the Russian Academy of Sciences, 620219 Ekaterinburg,
Russian Federation. Fax: +7 3433 74 1189; e-mail: chupakhin@ios.uran.ru
DOI: 10.1070/MC2006v016n01ABEH002208
The treatment of quinoxalin-2-one with acetophenones in the presence of boron trifluoride gives 3-(2-hydroxy-2-R-vinyl)-
quinoxalin-2-ones, which can be transformed into [2,3-b]thienoquinoxalines by reactions with P2S5.
Quinoxalines are of interest because some natural compounds
bearing the quinoxaline skeleton exhibit high biological activity,
e.g., echinomycine and triostine. Condensed quinoxalines are
important quinoxaline derivatives by virtue of their structural,1
biological2–4 and medical5 specialties. The main stage of the two-
step synthesis of such compounds is condensation of 1,2-phenyl-
enediamine with 1,2,4-tricarbonyl compounds, which can be
transformed into furo- and thienoquinoxalines.6,7 Here we con-
sider the nucleophilic substitution of hydrogen (SNH),8,9 which
was successfully used for the synthesis of condensed heterocyclic
systems.10–12 It was applied to the modification of 2-substituted
quinoxalines by acetophenones and the design of [2,3-b]thieno-
and furoquinoxalines.
(2 equiv.) of quinoxaline 1 was put into the reaction mixture.
Oxidation of σH adducts occurred most likely by the action
of oxygen dissolved in solvents. This fact was confirmed by
the experiment under anaerobic conditions (argon atmosphere)
using a degassed solvent. The presence of two characteristic
absorption bands at 415 and 440 nm in the UV spectrum of
product 4a makes it possible to perform the UV determination of
absorbance depending on the duration of oxidation. An attempt
to detect the formation of 4a by UV spectroscopy using a
degassed solvent failed. The introduction of another oxidant
O
R
H
N
N
BF3·Et2O
Reactions of quinoxalin-2-one 1 with acetophenones afford
the direct C–C coupling of heterocyclic and acetophenone frag-
ments. Boron trifluoride is a perfect activating agent in the
reaction. On the one hand, it promoted enol formation and, on
the other hand, enhanced quinoxaline ring electrophilicity owing
to complex formation. According to modern concepts in the
SNH chemistry, the first stage of reaction is the formation of σH
adducts 3a–f. However, our attempts to detect them by both
TLC and UV spectroscopy failed but the reaction resulted in the
products of nucleophilic substitution of hydrogen in a quinoxaline
ring obtained by the smooth aromatization of adducts 3a–f
(Scheme 1). This points to the fact that intermediates 3 are
unstable and/or exist in a small concentration due to the fast
conversion of 3 into 4.† To our mind, the ready oxidation of σH
adducts 3a–f is due to the tendency to fix a preferred
conformation for oxidation in which the oxidized bond tends to
be located in the ring plane, as shown in Scheme 1. In this case,
the oxidizing aromatization of this intermediate proceeds either
with the starting quinoxalinone or with air oxygen assistance.
The first way should be excluded because the yields of products
4a–f are higher than 50%. Moreover, the rate of the reaction
and the yields of products did not increase while an excess
Me
R
N
H
O
O
N
H
3a–f
O
1
2a–f
N
R
N
P2S5
Air
R
OH
S
N
H
4a–f
O
N
5d–f
e R =
a R = Ph
O
O
b R = 4-MeOC6H4
c R = 4-FC6H4
O
O
O
S
d R =
O
f R =
Scheme 1
16 Mendeleev Commun. 2006

Mendeleev Commun., 2006, 16(1), 16–18
As for furo[2,3-b]quinoxalines, they can be obtained from
N
N
ButOK
Me
R
compounds 4 according to the well-known reaction.6 We propose
another way to 7, which consists in the reactions of 2-chloro-
quinoxaline with acetophenones (Scheme 2).§
Cl
O
O
Taking into account the tendency of 1,4-diazines to a double
nucleophilic attack on two neighbouring carbons,5,10 2-chloro-
quinoxaline 6 is a good starting material for the synthesis of
condensed heterocyclic systems. Note that its chemistry was
presented essentially to ipso-substitution of halogens. For example,
replacement of the chlorine atom by treatment of 6 by enols
was described previously.14,15 We found that the reaction of
2-chloroquinoxaline with enols generated from acetophenones
appears in the presence of ButOK to be a tandem of SNH and
SNipso processes leading to furoquinoxalines 7 with moderate yields
(Scheme 2). In addition to the main product, 1,2-phenylenedi-
amine was isolated in 10–21% yield. In our opinion, o-phenylene-
diamine forms as a result of destruction of an intermediate pro-
duct of a nucleophilic attack of two acetophenone molecules
on the C(2) and C(3) atoms of quinoxaline. In order to confirm
6
2a–e
N
N
NH2
NH2
(10–21%)
R
7a–e (38–82%)
a R = Ph
d R =
e R =
O
b R = 4-MeOC6H4
c R = 4-FC6H4
O
S
Scheme 2
‡
General procedure for the preparation of 2-arylthieno[2,3-b]quinoxalines
5d–f. A mixture of 4d–f (0.5 mmol), phosphorus pentasulfide (1 mmol),
and pyridine (2 ml) was refluxed for 8 h. After cooling to room tem-
perature, the reaction mixture was diluted with water (4 ml) and the
precipitate obtained was filtered off. The crude product was subjected to
column chromatography (silica gel 40/60) using CH2Cl2 as an eluent
to give pure 5d–f.
(e.g., FeCl3) increases the reaction rate and does not affect the
yield of the product.
Products 4a–f were converted into corresponding thieno-
quinoxalines 5 according to a commonly used procedure13 by
treatment with phosphorous pentasulfide in pyridine (Scheme 1).‡
2-(2-Thienyl)thieno[2,3-b]quinoxaline 5d: yield 82 mg (61%), mp 200–
201 °C. 1H NMR ([2H6]DMSO) d: 8.14–8.19 (m, 2H), 7.94 (s, 1H),
7.84–7.92 (m, 4H), 7.29 (dd, 1H, J 3.7 Hz, J' 5 Hz). Found (%):
C, 62.48; H, 2.95; N, 10.20. Calc. C14H8N2S2 (%): C, 62.69; H, 3.00;
N, 10.45.
†
Column and flash chromatography was performed using Lancaster
silica gel (230–400 mesh) and CH2Cl2–MeOH as an eluent. All melting
points were measured on a Boetius melting point apparatus. Elemental
analyses were performed on a Carlo Erba 1108 CHNO Analyzer. The
1H NMR spectra were recorded on a Bruker DRX 400 spectrometer
with TMS as an internal standard. Starting quinoxalin-2-one 1 and
2-chloroquinoxaline 6 were obtained according to published proce-
dures.16,17
General procedure for the preparation of 3-(2-hydroxy-2-arylvinyl)-1H-
quinoxalin-2-ones 4a–f. Acetophenone 2a–f (0.68 mmol) was added to a
suspension of quinoxalin-2-one 1 (100 mg, 0.68 mmol) in the mixture
of methanol (3 ml) and boron trifluoride etherate (1 ml), and resulted
mixture was stirred for 3 h at room temperature. Next, it was diluted
with water (2 ml) and neutralised with saturated NaHCO3. The precipitate
obtained was filtered off and recrystallised from EtOH.
2-(3,4-Methylenedioxyphenyl)thieno[2,3-b]quinoxaline 5e: yield 98 mg
(64%), mp 252–254 °C. 1H NMR ([2H6]DMSO) d: 8.13–8.18 (m, 2H), 8.1
(s, 1H), 7.85–7.90 (m, 2H), 7.71 (d, 1H, J 1.8 Hz), 7.48 (dd, 1H, J 8 and
1.8 Hz), 7.12 (d, 1H, J 8 Hz), 6.17 (s, 2H). Found (%): C, 66.65; H, 3.23;
N, 8.76. Calc. for C17H10N2O2S (%): C, 66.66; H, 3.29; N, 9.15.
3-(Thieno[2,3-b]quinoxalin-2-yl)benzo-12-crown-4 5f: yield 77 mg (38%),
1
mp 172–174 °C. H NMR ([2H6]DMSO) d: 8.14–8.19 (m, 2H), 8.13 (s,
1H), 7.86–7.89 (m, 2H), 7.74 (d, 1H, J 2.3 Hz), 7.58 (dd, 1H, J 2.3 and
8.4 Hz), 7.23 (d, 1H, J 8.4 Hz), 4.21–4.29 (m, 4H), 3.73–3.77 (s, 4H), 3.63
(s, 4H). Found (%): C, 64.22; H, 4.61; N, 6.71. Calc. for C22H20N2O4S
(%): C, 64.71; H, 4.94; N, 6.86.
§
3-(2-Hydroxy-2-phenylvinyl)-1H-quinoxalin-2-one 4a: yield 108 mg
(60%), mp 260 °C. 1H NMR ([2H6]DMSO) d: 13.67 (s, 1H, NH), 12.05
(s, 1H, OH), 7.98–8.00 (m, 2H, Ar), 7.52–7.61 (m, 4H, Ar), 7.13–7.16
(m, 3H, Ar), 6.83 (s, 1H, CH). Found (%): C, 72.36; H, 4.44; N, 10.37.
Calc. for C16H12N2O2 (%): C, 72.71; H, 4.58; N, 10.60.
General procedure for the preparation of 2-arylfuro[2,3-b]quinoxaline
7a–e. A solution of acetophenone (0.61 mmol) in THF and ButOK (205 mg,
1.8 mmol) was added portionwise to a solution of 2-chloroquinoxaline
(100 mg, 0.61 mmol) in THF (20 ml) for three days with vigorously
stirring. After addition of reagents, stirring was continued for a day at
room temperature. The solvent was evaporated to dryness. The residue
was dissolved in water. The obtained solution was neutralised with dilute
HCl and extracted with CHCl3 (3×5 ml). The combined extracts were
dried over CaCl2, and the solvent was evaporated to give a crude product.
Recrystallization from ethanol gave analytically pure 7a–e.
3-[2-Hydroxy-2-(4-methoxyphenyl)vinyl]-1H-quinoxalin-2-one 4b:
yield 102 mg (51%), mp 277–280 °C. H NMR ([2H6]DMSO) d: 13.60
1
(s, 1H, NH), 11.99 (s, 1H, OH), 7.97–7.99 (m, 2H), 7.47–7.48 (m, 1H),
7.05–7.15 (m, 5H), 6.79 (s, 1H, CH), 3.85 (s, 3H, OMe). Found (%):
C, 68.97; H, 4.84; N, 9.37. Calc. for C17H14N2O3 (%): C, 69.39; H, 4.76;
N, 9.52.
2-Phenylfuro[2,3-b]quinoxaline 7a: yield 123 mg (82%), mp 261–263 °C.
1H NMR ([2H6]DMSO) d: 8.16–8.20 (m, 3H), 8.10–8.12 (m, 1H), 7.93
(s, 1H), 7.83–7.85 (m, 2H), 7.61–7.66 (m, 3H). Found (%): C, 77.88;
H, 4.03; N, 11.21. Calc. for C16H10N2O (%): C, 78.01; H, 4.12; N, 11.40.
2-(4-Methoxyphenyl)furo[2,3-b]quinoxaline 7b: yield 90 mg (53%),
mp 204 °C. 1H NMR ([2H6]DMSO) d: 8.10 (d, 2H, J 9.0 Hz), 8.06–8.18
(m, 2H), 7.79–7.82 (m, 2H), 7.74 (s, 1H), 7.19 (d, 2H), 3.88 (s, 3H).
Found (%): C, 73.98; H, 4.43; N, 10.01. Calc. C17H12N2O2 (%): C, 73.91;
H, 4.32; N, 10.10.
3-[2-Hydroxy-2-(4-fluorophenyl)vinyl]-1H-quinoxalin-2-one 4c: yield
85 mg (44%), mp 251–252 °C. H NMR ([2H6]DMSO) d: 13.62 (s, 1H,
1
NH), 12.05 (s, 1H, OH), 8.05–8.08 (m, 2H, Ar), 7.52–7.54 (m, 1H,
Ar), 7.34–7.37 (m, 2H, Ar), 7.13–7.15 (m, 3H, Ar), 6.80 (s, 1H, CH).
Found (%): C, 67.98; H, 3.94; N, 9.52. Calc. for C16H11N2O2F (%):
C, 68.09; H, 3.92; N, 9.92.
3-[2-Hydroxy-2-(thien-2-yl)vinyl]-1H-quinoxalin-2-one 4d: yield 120 mg
(65%), mp 270–272 °C. H NMR ([2H6]DMSO) d: 13.26 (s, 1H, NH),
1
12.02 (s, 1H, OH), 7.89–7.91 (m, 2H), 7.47–7.48 (m, 1H), 7.22–7.24
(m, 1H), 7.11–7.14 (m, 3H), 6.68 (s, 1H, CH). Found (%): C, 61.97;
H, 3.84; N, 10.17. Calc. for C14H10N2O2S (%): C, 62.22; H, 3.73; N, 10.37.
3-[2-Hydroxy-2-(3,4-methylenedioxyphenyl)vinyl]-1H-quinoxalin-2-one
4e: yield 136 mg (66%), mp 281–283 °C. 1H NMR ([2H6]DMSO) d:
13.55 (s, 1H, NH), 12.00 (br. s, 1H, OH), 7.60–7.62 (m, 1H), 7.46–7.50
(m, 2H), 7.30–7.32 (m, 1H), 7.11–7.13 (m, 2H), 7.03–7.05 (m, 1H), 6.74
(s, 1H, CH), 6.14 (s, 2H, CH2). Found (%): C, 65.93; H, 3.84; N, 8.87.
Calc. for C17H12N2O4 (%): C, 66.23; H, 3.92; N, 9.09.
3-[1-Hydroxy-2-(2-oxoquinoxalin-3-yl)vinyl]benzo-12-crown-4 4f:
yield 148 mg (53%), mp 241–242 °C. 1H NMR ([2H6]DMSO): 13.63
(s, 1H, NH), 11.99 (br. s, 1H, OH), 7.68–7.65 (m, 1H), 7.62–7.63 (m, 1H),
7.47–7.48 (m, 1H), 7.13–7.17 (m, 4H), 6.78 (s, 1H, CH), 4.13 (s, 4H,
CH2), 3.71–3.75 (m, 4H, CH2), 3.61–3.63 (m, 4H, CH2). Found (%):
C, 63.89; H, 5.61; N, 6.65. Calc. for C22H22N2O6 (%): C, 64.39; H, 5.37;
N, 6.82.
2-(4-Fluorophenyl)furo[2,3-b]quinoxaline 7c: yield 77 mg (48%),
mp 209 °C. 1H NMR ([2H6]DMSO) d: 8.22 (dd, 2H, JHH 9.0 Hz, JHF
5.4 Hz), 8.16–8.18 (m, 1H), 8.01–8.11 (m, 1H), 7.90 (s, 1H), 7.81–7.86
(m, 2H), 7.50 (dd, 2H, JHH 9.0 Hz, JHF 11.8 Hz). Found (%): C, 72.58;
H, 3.33; N, 10.01. Calc. for C16H9N2OF (%): C, 72.71; H, 3.42; N, 10.60.
2-(3,4-Methylenedioxyphenyl)furo[2,3-b]quinoxaline 7d: yield 100 mg
(57%), mp 217 °C. 1H NMR ([2H6]DMSO) d: 8.16–8.18 (m, 1H), 8.10–
8.13 (m, 1H), 7.71–7.77 (m, 2H), 7.63 (dd, 1H, J 8.1 and 1.6 Hz), 7.47
(d, 1H, J 1.6 Hz), 7.14 (s, 1H), 6.98 (d, 1H, J 8.1 Hz), 6.10 (s, 2H).
Found (%): C, 70.18; H, 3.43; N, 9.41. Calc. for C17H10N2O3 (%): C,
70.31; H, 3.52; N, 9.72.
2-(Thien-2-yl)furo[2,3-b]quinoxaline 7e: yield 58 mg (38%), mp 219 °C.
1H NMR ([2H6]DMSO) d: 8.14–8.18 (m, 1H), 8.05–8.09 (m, 1H), 8.04
(dd, 1H, J 1.1 and 3.8 Hz), 8.00 (dd, 1H, J 1.1 and 5.0 Hz), 7.79–7.85
(m, 2H), 7.67 (s, 1H), 7.37 (dd, 1H, J 3.8 and 5.0 Hz). Found (%): C, 66.68;
H, 3.13; N, 11.01. Calc. C14H8N2OS (%): C, 66.71; H, 3.22; N, 11.10.
Mendeleev Commun. 2006 17

Mendeleev Commun., 2006, 16(1), 16–18
7
8
9
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M. Makosza and K. Wojciechowski, Chem. Rev., 2004, 104, 2631.
this reaction pathway, we carried out a blank test. The stirring
of a THF solution of 2-chloroquinoxaline and an excess of
ButOK for two days did not result in the destruction of the
quinoxaline ring.
Thus, readily available 2-substituted quinoxalines can be used
for the synthesis of fused quinoxalines by the combination of
SNH and SNipso reactions.
10 O. N. Chupakhin and D. G. Beresnev, Usp. Khim., 2002, 71, 803
(Russ. Chem. Rev., 2002, 71, 707).
11 V. N. Charushin, N. N. Mochulskaya, A. A. Andreiko, V. I. Filyakova,
M. I. Kodess and O. N. Chupakhin, Tetrahedron Lett., 2003, 44, 2421.
12 S. K. Kotovskaya, V. N. Charushin, N. M. Perova, M. I. Kodess and
O. N. Chupakhin, Synth. Commun., 2004, 34, 2531.
13 Y. A. Ibrahim, M. A. Badawy and S. El-Bahaie, J. Heterocycl. Chem.,
1982, 19, 699.
14 C. Iijima and E. Hayashi, Yakugaku Zasshi, 1988, 108, 586 (Chem.
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15 C. Iijima and E. Hayashi, Yakugaku Zasshi, 1977, 97, 712 (Chem.
Abstr., 1977, 100, 88434).
This work was supported in part by the US Civilian Research
and Development Foundation, the Russian Ministry of Education
(REC-005), the Programme for Supporting Leading Scientific
Schools (grant no. NSh-1766.2003.3) and ISTC (project no. 2117).
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Received: 30th June 2005; Com. 05/2539
18 Mendeleev Commun. 2006