Rearrangement in the series of 3-(2-aryl-2-oxoethyl)-3, 4-dihydroquinoxalin-2(1H)-ones

Article abstract of DOI:10.1007/s11172-009-0133-0

4-Acetyl- and 4-succinyl-3-(2-aryl-2-oxoethyl)-3, 4-dihydroquinoxalin-2(H/) -ones undergo the rearrangement into (Z)-2-(3-arylquinoxalin-2-ylidene)acetic acids accompanied by the elimination of the acyl groups. The nitration of 3-(2-oxo-2-phenylethyl)-3,

Full text of DOI:10.1007/s11172-009-0133-0

Russian Chemical Bulletin, International Edition, Vol. 58, No. 5, pp. 1041—1048, May, 2009
1041
Rearrangement in the series of 3ꢀ(2ꢀarylꢀ2ꢀoxoethyl)ꢀ
3,4ꢀdihydroquinoxalinꢀ2(1H)ꢀones
N. N. Kolos, L. Yu. Kovalenko, and A. Yu. Kulikov
V. N. Karazin Kharkov National University,
4 pl. Svobody, 61077 Kharkov, Ukraine.
Eꢀmail: kolos@univer.kharkov.ua
4ꢀAcetylꢀ and 4ꢀsuccinylꢀ3ꢀ(2ꢀarylꢀ2ꢀoxoethyl)ꢀ3,4ꢀdihydroquinoxalinꢀ2(1H)ꢀones
undergo the rearrangement into (Z)ꢀ2ꢀ(3ꢀarylquinoxalinꢀ2ꢀylidene)acetic acids accompanied
by the elimination of the acyl groups. The nitration of 3ꢀ(2ꢀoxoꢀ2ꢀphenylethyl)ꢀ3,4ꢀdihydroꢀ
quinoxalinꢀ2(1H)ꢀone affords 5ꢀnitroꢀ and 7ꢀnitroꢀ2ꢀcarboxymethylidenequinoxalines. The
bromination of quinoxalinꢀ2ꢀones in AcOH gives 3ꢀarylꢀ2ꢀcarboxymethylidenequinoxalines
and the corresponding 7ꢀbromo derivatives, with the former products predominating.
Key words: 3ꢀ(2ꢀarylꢀ2ꢀoxoethyl)ꢀ3,4ꢀdihydroquinoxalinꢀ2(1H)ꢀones, nitration, bromination,
acylation, rearrangement, (Z)ꢀ2ꢀ(3ꢀarylquinoxalinꢀ2ꢀylidene)acetic acids, IR spectroscopy,
1H NMR spectroscopy.
Previously,1 it has been found that 3ꢀ(2ꢀarylꢀ2ꢀoxoꢀ
ethyl)ꢀ3,4ꢀdihydroquinoxalinꢀ2(1H)ꢀones 1 are rearꢀ
ranged into 3ꢀarylꢀ2ꢀcarboxymethylidenequinoxalines 2
in low yields (20—37%) upon heating in acetic acid. The
proposed mechanism of the rearrangement involves
the hydrolysis of the amide bond giving rise to the interꢀ
mediate A, the condensation of the carbonyl and amino
groups accompanied by the C—N bond cleavage yielding
the intermediate B, the nucleophilic addition of the amino
group at the activated C=C bond, and the dehydrogenaꢀ
tion of the intermediate C to form acid 2 (Scheme 1).2
Since the rearrangement is the oxidative process, it
was suggested that this reaction should be performed in
the presence of mild oxidizing agents. Actually, the heatꢀ
ing of quinoxalinones 1 in DMF (or in BuOH) in the
presence of an equimolar amount of sulfur or iodine made
it possible to increase the yield of acids 2 to 80—85% and
to perform the rearrangement of quinoxalinones containing
electronꢀwithdrawing substituents in the оꢀphenyleneꢀ
diamine fragment.2,3 Sulfur is involved in the αꢀthiolation of
the methylene group of quinoxalinones 1,4 thus facilitating
the oxidation of the dihydro structure C due to the rapid
elimination of the hydrogen sulfide molecule (Scheme 2).
However, we detected no other products except H2S,
which could confirm the aboveꢀpresented sequence of
reaction steps.
Scheme 1
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 5, pp. 1014—1021, May, 2009.
1066ꢀ5285/09/5805ꢀ1041 © 2009 Springer Science+Business Media, Inc.

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Russ.Chem.Bull., Int.Ed., Vol. 58, No. 5, May, 2009
Kolos et al.
Scheme 2
Scheme 3
In the present study, we investigated the rearrangeꢀ
methylene groups of the succinyl fragment and a broadꢀ
ened signal at δ 12.0 assigned to the OH group.
ment of 3ꢀ(2ꢀarylꢀ2ꢀoxoethyl)ꢀ3,4ꢀdihydroquinoxalinꢀ
2(1H)ꢀones by considering their 4ꢀacylated derivatives
and also using the nitration and bromination reactions of
the starting quinoxalinꢀ2ꢀones.
4ꢀAcetyl and 4ꢀsuccinyl derivatives of quinoxalinꢀ
2ꢀone 3a—c and 4a,b, respectively, were synthesized
according to a known procedure.5 Under these condiꢀ
tions, we failed to synthesize acyl derivatives of quinoxꢀ
alinones 1 containing electronꢀwithdrawing substituents
(Br and NO2) in the benzene ring.
The fragmentation in the mass spectrum of acetyl
derivative 3a ([M]•+ = 308) is in complete agreement
with the suggested structure. The elimination of the
acetyl group ([M – CH3CO]+), the benzoyl fragment
([M – C6H5CO]+), and the phenyl cation ([M – C6H5]+) are
the most characteristic processes (Scheme 3). An analogous
fragmentation pattern is observed for acyl derivative 4a.
The rearrangement of acyl derivatives 3 and 4 was
performed by refluxing in DMF in the presence of sulfur.
It was expected that the presence of Nꢀacyl groups in
molecules 3 and 4 would allow us to isolate either the
cleavage products of the dihydropyrazine ring in 5 or
2ꢀRꢀbenzimidazole derivatives 6 (as a result of the
intramolecular condensation of the acyl and amino
groups6) and the corresponding βꢀaroylacrylic acids 7
(Scheme 4), which could be formed in the course of the
rearrangement.
The structures of compounds 3 and 4 were confirmed
by IR and 1H NMR spectroscopy. The IR spectra (in KBr
pellets) of the reaction products show no stretching bands
of the secondary amino group at 3340—3380 cm–1 charꢀ
acteristic of quinoxalinones 1 and contain a broadened
band at 3430—3440 cm–1, which is indicative of the
retention of the amide NH group.
1
The H NMR spectra of compounds 3a—c show the
following signals for the protons of the ABX system:
doublets of doublets for the methylene protons A and B, a
doublet of doublets for the methine proton, a singlet for
the NH proton (amide) at δ 10.74—10.84, and multiplets
for aromatic protons. At the same time, the singlet for the
proton of the amino group at δ 6.0—6.5 disappears, and a
singlet for the methyl protons of the acetyl fragment is
Acids 2a—c proved to be identical to the products
prepared previously by the rearrangement of unacylated
quinoxalinones 1 (Scheme 5). An analysis of the mother
liquors obtained in the synthesis of acetyl derivatives 3a—c
showed that 2ꢀmethylbenzimidazole 6 and βꢀaroylacrylic
acids 7 were absent in these mixtures (TLC analysis
with authentic samples), which is indicative of the rapid
deacylation under the experimental conditions (see
Scheme 5). It should be noted that the yields of comꢀ
1
observed at δ ~2.10. In addition, the H NMR spectra of
compounds 4a,b show triplets for the protons of two

3ꢀ(Aryloxoethyl)ꢀ3,4ꢀdihydroquinoxalinꢀ2(1H)ꢀones
Russ.Chem.Bull., Int.Ed., Vol. 58, No. 5, May, 2009
1043
To study the mechanism of the rearrangement in more
detail, we performed the nitration of quinoxalinone 1a
according to a known procedure used for the nitration of
arenes.7 This reaction afforded a mixture of colored nitraꢀ
tion products, which was studied by HPLC. The starting
quinoxalinone 1a, a mixture of 6(7)ꢀnitroꢀ(2ꢀoxoꢀ2ꢀ
phenylethyl)ꢀ3,4ꢀdihydroquinoxalinꢀ2(1H)ꢀones 1e + 1f
(possible nitration products of compound 1a prepared
by the reaction of 4ꢀnitroꢀоꢀphenylenediamine with
βꢀbenzoylacrylic acid8), and 2ꢀcarboxymethylideneꢀ
6ꢀnitroꢀ3ꢀphenylquinoxaline (2e) (the individual regioꢀ
isomer isolated after the rearrangement of a mixture of
quinoxalinones 1e + 1f)2 served as the reference comꢀ
pounds. An analysis of the results showed that a mixture
contained the starting quinoxalinone 1a and two
products, whose signals correspond to none of the aboveꢀ
mentioned reference samples. The mixture of the nitraꢀ
tion products was separated by fractional crystallization
from MeOH.
Scheme 4
pounds 2a—c were 53—58%, whereas the corresponding
reactions of the unacylated derivatives afforded the
products in 85—87% yields.2
The IR spectra of compounds 2f,g contain bands
νs(NO2) and νas(NO2) at 1340—1350 and 1510—1512 cm–1,
respectively. The structures of products 2f,g were deterꢀ
Scheme 5
1
mined by analyzing the H NMR spectra. Thus, the
spectrum of compound 2f shows a doublet at δ 7.12
(J = 2.4 Hz) assigned to the proton H(8) of the annulated
benzene ring, a doublet for the proton H(5) at δ 7.75
(J = 7.0 Hz), and a doublet of doublets for the proton
H(6) (J = 6.8 Hz) at δ 7.90. The protons of the phenyl
group at position 3 appear as a doublet at δ 8.00 and a
multiplet at δ 7.51—7.62 with integrated intensities equal
to two and three protons, respectively. In addition, the
spectrum shows oneꢀproton singlets at δ 6.94, 12.05, and
13.28 assigned to the vinyl, enamine, and carboxyl proꢀ
tons, respectively. The above results suggest that product
2f has the structure of 2ꢀ(7ꢀnitroꢀ3ꢀphenylquinoxalinꢀ
2(1H)ꢀylidene)acetic acid. Compound 2g was assigned to
the 5ꢀnitro isomer. The physicochemical characteristics
of 2g appeared to be similar to those of 2ꢀ(5ꢀnitroꢀ
3ꢀphenylquinoxalinꢀ2(1H)ꢀylidene)acetic acid, which has
been synthesized previously9 by the reaction of 3ꢀnitroꢀ
оꢀphenylenediamine with 2,3ꢀdibromoꢀ4ꢀoxoꢀ4ꢀphenylꢀ
butanoic acid. The configuration of compounds 2f,g was
established by 1H NMR and NOE studies. The saturation
of the signal for the vinyl proton at δ 6.94 in the spectrum
of compound 2f leads to the response of the protons of the
phenyl substituent in the ortho position, which is indicaꢀ
tive of the Z configuration of the rearrangement products.
We failed to nitrate acid 2a under the conditions used
in the known procedure7 (see the Experimental section).
Hence, we suggest the most probable pathway giving rise
to nitroquinoxalines 2f,g under the reaction conditions.
The protonation of the amine nitrogen atom N(4) folꢀ
lowed by the cleavage of the quinoxalinone ring affords
the protonated form A, whose nitration gives the interꢀ
mediates B and C (the para and ortho orientations with
Reagents and conditions: i. DMF, S. ii. (CH2CO)2O. iii. Ac2O.
1
R
Ar
2
R
Ar
3
R
Ar
a
b
c
d
H
H
H
Ph
4ꢀMeC6H4
4ꢀBrC6H4
a
b
c
d
H
H
H
Ph
4ꢀMeC6H4
4ꢀBrC6H4
a
b
c
H
H
H
Ph
4ꢀMeC6H4
4ꢀBrC6H4
7ꢀMe 4ꢀClC6H4
6ꢀMe 4ꢀClC6H4
4: R = H, Ar = Ph (a); R = 7ꢀMe, Ar = 4ꢀClC6H4 (b)

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Kolos et al.
Scheme 6
denced by our attempt to perform the bromination of
quinoxalinone 1a. Thus, acid 2a and 2ꢀ(7ꢀbromoꢀ
3ꢀphenylquinoxalinꢀ2(1H)ꢀylidene)acetic acid 2j were
isolated from the reaction mixture in a ratio of 3 : 1.
The fact that the bromination affords 6ꢀnitro isomers
as the major products (like in the rearrangement of mixꢀ
tures of 6(7)ꢀnitroquinoxalinones upon heating in DMF
in the presence of sulfur2) can be explained as follows
(Scheme 7).
respect to the free amino group). The latter compounds
undergo cyclization to acids 2f,g, which were isolated in a
ratio of 5 : 1 (Scheme 6). The formation of regioisomer 2f
as the major product is well consistent with the known
data on the nitration of activated arenes.10
It should be noted that acid 2g could be formed also
through the rearrangement of 8ꢀnitro isomer 1g as the
nitration product of quinoxalinone 1a. However, this is
unlikely because it is known1 that 6(7)ꢀnitroquinoxalinꢀ
ones remain intact even upon prolonged refluxing in
AcOH. These compounds do not undergo the rearrangeꢀ
ment upon the treatment with a nitrating mixture at ~5 °C
as well. At the same time, the thermodynamic stability
of quinoxalinone 1a is low. Thus, acid 2a was detected
chromatographically even upon refluxing in methanol for
2—3 h, i.e., the opening of the pyrazine ring in quinoxꢀ
alinones containing no electronꢀwithdrawing substituents
in the annulated moiety proceeds rapidly.
The rearrangement occurs also in the case of the broꢀ
mination of a 1 : 4 mixture of 6(7)ꢀnitroꢀ3ꢀ(2ꢀoxoꢀ
2ꢀtolylethyl)ꢀ3,4ꢀdihydroquinoxalinꢀ2(1H)ꢀones 1h + 1i
in AcOH (1H NMR data). After washing off of the
unconsumed regioisomer 1i, the mixture of the reaction
products was studied by HPLC. 2ꢀCarboxymethylideneꢀ
3ꢀ(pꢀmethylphenyl)ꢀ6ꢀnitroquinoxaline (2h), which was
synthesized according to a known procedure,2 served as
the reference compound. An analysis of the chromatoꢀ
grams showed that the isolated mixture contained acid 2h
and a new compound in a ratio of 3 : 2. The minor prodꢀ
uct (1H NMR data) proved to be 7ꢀbromoꢀ2ꢀcarboxyꢀ
methylideneꢀ6ꢀnitroquinoxaline (2i).
The bromination occurs through the enol form to give
the intermediate D. The protonation of the latter folꢀ
lowed by the ring opening affords the intermediate E. It is
known that the acidꢀcatalyzed hydrolysis of amides is
more sensitive to the steric effect of the substituents than
to the electronic effect. Thus, only slight changes in the
hydrolysis rate were observed for the mꢀ and pꢀnitroꢀ
substituted benzamides, whereas the hydrolysis rate for
the oꢀnitro isomer is substantially lower.11 Consequently,
the hydrolysis rates for 6(7)ꢀnitro isomers 1i and 1h are
virtually equal. The elimination of the HBr molecule from
the intermediate D giving rise to phenacylidene derivaꢀ
tives 8 is theoretically possible. However, according to
the available data,12 these compounds are not prone
to the rearrangement. The 7ꢀnitro group of quinoxalinones
1 facilitates the formation of the intermediates F or G.
This group accelerates the C—N bond cleavage in the
intermediate E and assists in the formation of the azoꢀ
methine bond (the nucleophilicity of the amino group in
the meta position with respect to the 7ꢀnitro group is
higher). However, the cyclization of the intermediates F
and G should occur more slowly (the nucleophilicity of
the amino group in the para position with respect to the
nitro group is lower). Evidently, this step is not rateꢀ
The fact that the rearrangement occurs more rapidly
than the electrophilic aromatic substitution is also eviꢀ

3ꢀ(Aryloxoethyl)ꢀ3,4ꢀdihydroquinoxalinꢀ2(1H)ꢀones
Russ.Chem.Bull., Int.Ed., Vol. 58, No. 5, May, 2009
1045
Scheme 7
R = H, Ar = Ph (1a, 2a,j); R = NO2, Ar = 4ꢀMeC6H4 (1h, 2h,i)
determining, which accounts for the lower activity of
6ꢀnitro isomer 1i in the rearrangements and the predomiꢀ
nant formation of the 6ꢀnitro isomers of quinoxalines
2h,i. The synthesis of acid 2i involves the bromination of
the intermediate E and correlates well with the results
of nitration of quinoxalinone 1a.
stabilized by the conjugation with the electronꢀwithꢀ
drawing carboxy group was <20%.16 Interestingly, the
reaction of morpholide of this acid with oꢀphenylenediꢀ
amine produces quinoxaline 9 rather than dihydro derivaꢀ
tive 2 (Scheme 8). This fact can be attributed to the
πꢀelectron density delocalization in the amide fragment.
Therefore, the data on the nitration and bromination
reactions of quinoxalinones 1 confirm the fact that the
quinoxalinoneꢀquinoxaline rearrangement occurs through
the cleavage of the amide bond, which is characteristic of
quinoxalinꢀ2ꢀone derivatives.13 We failed to isolate the
cleavage products, but the related αꢀamino adducts of
βꢀaroylacrylic acids have been long known.14,15 The latter
compounds are thermodynamically unstable and are
easily decomposed into the starting components upon
heating.8 The transformation of the αꢀamino adduct into
the azomethine intermediate is apparently the rateꢀdeterꢀ
mining step and occurs intramolecularly, as evidenced by
the fact that only acids 2a,j were isolated after the rearꢀ
rangement of a mixture of quinoxalinones 1a,j (see the
Experimental section). The rapid elimination of the HBr
molecule (or the H2S molecule in the reaction in DMF in
the presence of sulfur) in the course of the cyclization
reaction is the decisive factor in the formation of acids 2
in high yields. In the reaction of 3ꢀbromoꢀ4ꢀoxoꢀ
4ꢀphenylbutanoic acid with oꢀphenylenediamine, in which
the oxidation occurs slowly, the yield of enamine 2a
Scheme 8
X = OH (2a), N(CH2)4O (9)

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Kolos et al.
It is known17 that amides undergo hydrolysis in an
alkaline medium as well. Hence, we performed the rearꢀ
rangement of 7ꢀnitroquinoxalinone 1j by heating in DMF
with the addition of a concentrated NaOH solution, as
well as in the presence of sulfur. As a result, we isolated
6ꢀnitroquinoxaline 2k in 25 and 50% yields, respectively
(Scheme 9). However, these procedures have drawbacks
from the experimental point of view, because these reacꢀ
tions are accompanied by resinification, which hinders
the isolation and purification of the target products.
Silufol UVꢀ254 plates using a 1 : 1 toluene—ethyl acetate
mixture as the eluent. The melting points were measured on a
Kofler hot stage.
Chromatographic measurements were carried out on a
Hewlett Packard chromatograph (Agilent Technologies, Walborn,
Germany) consisting of a Series 1050 pump, a variableꢀwaveꢀ
length Series 1050 spectrophotometric detector, and a Series
3395 integrator. A Kromasil C18 250Ѕ4.6 mm analytical column
(Hichrom Limited, Theale, UK) was packed with a sorbent with
a particle size of 5 μm; an acetonitrile (for HPLC)—water
mixture (40 : 60, v/v) was used as the mobile phase at a flow rate
of 1.0 mL min–1; the temperature of the column thermostat was
30.0 0.1 °C; the detection wavelength was 254 nm; the sample
volume was 10 μL. The analytes were prepared by dissolving
weighed samples in a 1 : 1 methanol—acetonitrile mixture until
the solution at a concentration of ~1 mg mL–1 was obtained.
Some analytes were dissolved in DMSO (1—2 mL) to improve
the solubility, and then the solutions were brought to the desired
volume with a 1 : 1 methanol—acetonitrile mixture.
Scheme 9
Quinoxalinones 1a—d,j and mixtures of 6(7)ꢀnitroquinoxꢀ
alinones 1f + 1e and 1i + 1h were synthesized according to a
known procedure2 by refluxing 4ꢀRꢀsubstituted оꢀphenyleneꢀ
diamines and the corresponding βꢀaroylacrylic acids in ethanol
for 1 h.
4ꢀAcetylꢀ3ꢀ(2ꢀoxoꢀ2ꢀphenylethyl)ꢀ3,4ꢀdihydroquinoxalinꢀ
2(1H)ꢀone (3a). A solution of 3ꢀ(2ꢀoxoꢀ2ꢀphenylethyl)ꢀ
3,4ꢀdihydroquinoxalinꢀ2(1H)ꢀone (1a) (0.27 g, 1 mmol) in
acetic anhydride (10 mmol) was heated (60—70 °C) with
magnetic stirring until the quinoxalinone was completely disꢀ
solved. Then oneꢀtwo drops of concentrated H2SO4 were added.
The reaction mixture was kept at this temperature for 5—10 min
and then cooled. The precipitate that formed was filtered off and
washed with water. Product 3a was obtained in a yield of 0.23 g
(75%), m.p. 184—185 °C (from EtOH). Found (%): C, 70.10;
H, 5.27; N, 9.11. C18H16N2O3. Calculated (%): C, 70.12;
H, 5.23; N, 9.09. 1H NMR, δ: 2.12 (s, 3 H, Me); 3.27 (dd, 1 H,
HA, J = 17.2 Hz, J = 6.8 Hz); 3.49 (dd, 1 H, HB, J = 17.2 Hz,
J = 6.8 Hz); 5.62 (t, 1 H, HХ, J = 6.8 Hz, J = 4.2 Hz); 7.01—7.89
The quinoxalinoneꢀquinoxaline rearrangement under
study is similar to the Pfitzinger reaction. It is known18,19
that the prolonged boiling of isatins with αꢀmethyleneꢀ
carbonyl compounds in the presence of an alkali (in some
cases, in the presence of an acid) is accompanied by the
formation of quinolineꢀ4ꢀcarboxylic acids. The mechaꢀ
nism of the Pfitzinger reaction with aryl methyl ketones
involves the formation of the phenacylidene derivative of
isatin, the amide bond cleavage, and the cyclization to
the quinoline ring.
Therefore, the formation of thermodynamically stable
aromatic compounds, such as quinoxalineꢀ or quinolineꢀ
carboxylic acids, is the driving force for both the quinoxꢀ
alinoneꢀquinoxaline rearrangement and the Pfitzinger
rearrangement.
(m, 9 H, Ar); 10.82 (s, 1 H, NH). IR (in KBr pellets), ν/cm–1
:
3440 (NH), 3150, 3056 (CH arom.), 2983, 2920 (CH aliph.),
1695, 1680 (C=O). MS, m/z (Irel (%)): 308 [M]+ (10), 265 (9),
105 (64), 77 (100).
4ꢀAcetylꢀ3ꢀ[2ꢀoxoꢀ2ꢀ(pꢀtolyl)ethyl]ꢀ3,4ꢀdihydroquinoxalinꢀ
2(1H)ꢀone (3b). Analogously to compound 3a, compound 3b
was synthesized from quinoxalinone 1b (0.28 g, 1 mmol) in a
yield of 0.2 g (61%), m.p. 216—218 °C (from EtOH). Found (%):
C, 70.75; H, 5.64; N, 8.71. C19H18N2O3. Calculated (%): C, 70.79;
1
H, 5.63; N, 8.69. H NMR, δ: 2.10 and 2.34 (both s, 3 H each,
Me); 2.96 (dd, 1 H, HA, J = 17.5 Hz, J = 6.7 Hz); 3.13 (dd, 1 H,
HB, J = 17.5 Hz, J = 6.7 Hz); 5.61 (t, 1 H, HХ, J = 6.7 Hz,
J = 4.4 Hz); 6.97—7.33 (m, 4 H, H(5), H(6), H(7), H(8)); 7.27
(d, 2 H, mꢀHAr, J = 7.9 Hz); 7.70 (d, 2 H, оꢀHAr, J = 7.9 Hz);
10.84 (s, 1 H, NH). IR (in KBr pellets), ν/cm–1: 3430 (NH),
3150, 3056 (CH arom.), 2980, 2920 (CH aliph.), 1690, 1678 (C=O).
4ꢀAcetylꢀ3ꢀ[2ꢀ(pꢀbromophenyl)ꢀ2ꢀoxoethyl]ꢀ3,4ꢀdihydroꢀ
quinoxalinꢀ2(1H)ꢀone (3c). Analogously to compound 3a, comꢀ
pound 3c was synthesized from quinoxalinone 1c (0.34 g, 1 mmol)
in a yield of 0.3 g (78%), m.p. 215—217 °C (from EtOH).
Found (%): C, 55.81; H, 4.11; N, 7.21. C18H15BrN2O3. Calcuꢀ
lated (%): C, 55.83; H, 3.90; N, 7.23. 1H NMR, δ: 2.11 (s, 3 H,
Me); 2.97 (dd, 1 H, HA, J = 17.6 Hz, J = 6.3 Hz); 3.17 (dd, 1 H,
Experimental
The IR spectra were recorded on a Specordꢀ75 IR specꢀ
trometer (in KBr pellets and in solutions in CCl4). The
1H NMR spectra were measured on a Varian Mercury VXꢀ200
spectrometer (200 MHz) in DMSOꢀd6 with Me4Si as the interꢀ
nal standard. The mass spectra were obtained on a Hewlettꢀ
Packard LC/MSD 1100 instrument (EI, 70 eV). The elemental
analysis was carried out on a LECO CHNSꢀ900 instrument.
The purity of the reaction products was checked by TLC on

3ꢀ(Aryloxoethyl)ꢀ3,4ꢀdihydroquinoxalinꢀ2(1H)ꢀones
Russ.Chem.Bull., Int.Ed., Vol. 58, No. 5, May, 2009
1047
HB, J = 17.6 Hz, J = 6.3 Hz); 5.57 (t, 1 H, HХ, J = 6.3 Hz,
J = 4.4 Hz); 7.10—7.33 (m, 4 H, H(5), H(6), H(7), H(8)); 7.67
(d, 2 H, mꢀHAr, J = 8.9 Hz); 7.75 (d, 2 H, оꢀHAr, J = 8.9 Hz);
10.82 (s, 1 H, NH). IR (in KBr pellets), ν/cm–1: 3440 (NH),
3145, 3060 (CH arom.), 2980, 2920 (CH aliph.), 1692, 1680
(C=O).
3 H, Me); 6.76 (s, 1 H, CH=); 7.55 (d, 2 H, оꢀHAr, J = 9.2 Hz);
7.97 (d, 2 H, mꢀHAr, J = 9.2 Hz); 6.93—7.43 (m, 3 H, H(5),
H(6), H(8)); 12.04 (s, 1 H, NH); 13.67 (s, 1 H, OH). IR (in KBr
pellets), ν/cm–1: 1698 (C=O), 1620 (C=C). IR (CCl4), ν/cm–1
:
3522 (OH), 3400 (NH), 1740, 1702, 1684 (C=O).
Analogously to compound 2a, acid 2a (in a yield of 0.20 g,
76%) and acid 2j (in a yield of 0.24 g, 70%; m.p. >300 °C (from
EtOH); cf. lit. data2: m.p. >300 °C) were isolated from the
mixture containing quinoxalinone 1a (0.27 g, 1 mmol) and
quinoxalinone 1j (0.35 g, 1 mmol).
Nitration of 3ꢀ(2ꢀoxoꢀ2ꢀphenylethyl)ꢀ3,4ꢀdihydroquinoxalinꢀ
2(1H)ꢀone (1a). A 2 : 1 mixture of sulfuric acid (0.125 mL) and
nitric acid (0.2 mL) was added with cooling and constant stirꢀ
ring to a solution of quinoxalinꢀ2ꢀone 1a (0.27 g, 1 mmol) in
sulfuric acid (0.6 mL, 10 mmol). The reaction solution was
stirred at a temperature of no higher than 5 °C for 1 h. Then the
mixture was poured into ice water. The precipitate was filtered
off, washed with water, and recrystallized from methanol. Poorly
soluble 5ꢀnitro isomer 2g was filtered off. 7ꢀNitro isomer 2f
was isolated from the filtrate upon cooling. The starting quinoxꢀ
alinone 1a was detected in the filtrate (Rf 0.6, a toluene—ethyl
acetate mixture as the eluent).
3ꢀ(2ꢀOxoꢀ2ꢀphenylethyl)ꢀ4ꢀsuccinylꢀ3,4ꢀdihydroquinoxalinꢀ
2(1H)ꢀone (4a). Succinic anhydride (0.1 g, 1 mmol) was added
to a solution of quinoxalinꢀ2ꢀone 1a (0.27 g, 1 mmol) in benꢀ
zene (10 mL). The reaction mixture was refluxed for 3.5 h and
then cooled to room temperature. The precipitate that formed
was filtered off, washed with water, and recrystallized from ethaꢀ
nol. Compound 4a was obtained in a yield of 0.26 g (72%),
m.p. 182—183 °C (from EtOH). Found (%): C, 65.61; H, 4.96;
N, 7.59. C20H18N2O5. Calculated (%): C, 65.57; H, 4.95;
N, 7.65. 1H NMR, δ: 2.40 and 2.80 (both t, 2 H each, J = 7.0 Hz);
2.90 (dd, 1 H, HA, J = 6.8 Hz); 3.19 (dd, 1 H, HB, J = 17.2 Hz,
J = 6.8 Hz); 5.57 (t, 1 H, HХ, J = 6.8 Hz, J = 4.2 Hz);
7.01—7.82 (m, 9 H, Ar); 10.43 (s, 1 H, NH); 12.04 (s, 1 H, OH).
MS, m/z (Irel (%)): 366 [M]+ (10), 265 (44), 105 (100), 77 (83).
IR (in KBr pellets), ν/cm–1: 3435 (NH), 3150, 3065 (CH arom.),
2985, 2925 (CH aliph.), 1715, 1695, 1682 (C=O).
3ꢀ[2ꢀ(pꢀChlorophenyl)ꢀ2ꢀoxoethyl]ꢀ7ꢀmethylꢀ4ꢀsuccinylꢀ
3,4ꢀdihydroquinoxalinꢀ2(1H)ꢀone (4b). Analogously to compound
4a, compound 4b was synthesized from quinoxalinone 1d
(0.31 g, 1 mmol) in a yield of 0.22 g (53%), m.p. 190—192 °C
(EtOH). Found (%): C, 60.75; H, 4.64; N, 6.73. C21H19ClN2O5.
(Z)ꢀ2ꢀ[7ꢀNitroꢀ3ꢀphenylquinoxalinꢀ2(1H)ꢀylidene]acetic acid
(2f). The yield was 0.16 g (52%), m.p. 274—276 °C (from
MeOH). Found (%): C, 62.11; H, 3.64; N, 13.62. C16H11N3O4.
1
Calculated (%): C, 62.14; H, 3.58; N, 13.59. H NMR, δ: 6.94
(s, 1 H, CH=); 7.12 (d, 1 H, H(8), J = 2.4 Hz); 7.75 (d, 1 H,
H(5), J = 7.0 Hz); 7.51—7.62 (m, 3 H, mꢀHPh + pꢀHPh); 8.00
(d, 2 H, oꢀHPh, J = 7.8 Hz); 7.94 (d, 1 H, H(6), J = 6.8 Hz);
12.05 (s, 1 H, NH); 13.28 (s, 1 H, OH). IR (in KBr pellets),
ν/cm–1: 1346, 1512 (NO2), 1620 (C=C), 1698 (C=O).
1
Calculated (%): C, 60.80; H, 4.62; N, 6.75. H NMR, δ: 2.27
(s, 3 H, CH3); 2.39 and 2.80 (both t, 2 H each, J = 7.0 Hz);
2.92 (dd, 1 H, HA, J = 17.2 Hz, J = 6.8 Hz); 3.20 (dd, 1 H, HB,
J = 17.2 Hz, J = 6.8 Hz); 5.59 (t, 1 H, HХ, J = 6.8 Hz, J = 4.2 Hz);
6.81—7.23 (m, 3 H, H(5), H(6), H(8)); 7.59 (d, 2 H, mꢀHAr
,
(Z)ꢀ2ꢀ[5ꢀNitroꢀ3ꢀphenylquinoxalinꢀ2(1H)ꢀylidene]acetic acid
(2g). The yield was 0.03 g (10%), m.p. 259—260 °C (from
MeOH) (cf. lit. data9: m.p. 259—260 °C). 1H NMR, δ: 6.81
(s, 1 H, CH=); 7.35 (d, 1 H, H(8), J = 7.9 Hz); 7.94 (d,
2 H, oꢀHPh, J = 6.8 Hz); 7.51—7.76 (m, 5 H, H(6), H(7),
mꢀHPh + pꢀHPh); 12.14 (s, 1 H, NH); 13.67 (s, 1 H, OH).
A mixture of compound 2g with 2ꢀ[5ꢀnitroꢀ3ꢀphenylꢀ
quinoxalinꢀ2(1H)ꢀylidene]acetic acid described in the study9
showed no melting point depression.
J = 8.4 Hz); 7.81 (d, 2 H, оꢀHAr, J = 8.4 Hz); 10.75 (s, 1 H,
NH); 12.04 (s, 1 H, OH). IR (in KBr pellets), ν/cm–1: 3430
(NH), 3150, 3060 (CH arom.), 2985, 2925 (CH aliph.), 1710,
1690, 1678 (C=O).
The rearrangement of acyl derivatives 3 and 4 was carried
out according to a procedure described previously.3
(Z)ꢀ2ꢀ(3ꢀPhenylquinoxalinꢀ2(1H)ꢀylidene)acetic acid (2a).
4ꢀAcetylꢀ3ꢀ(2ꢀoxoꢀ2ꢀphenylethyl)ꢀ3,4ꢀdihydroquinoxalinꢀ
2(1H)ꢀone (3a) (0.31 g, 1 mmol) was added to a solution of
sulfur (0.032 g, 1 mmol) in DMF (10 mL). The reaction mixture
was refluxed for 6 h. The precipitate that formed was filtered off,
washed on the filter with hot ethanol, and dried in air. The yield
was 0.15 g (58%), m.p. 240—241 °C (from EtOH) (cf. lit. data9:
m.p. 240—241 °C).
(Z)ꢀ2ꢀ[3ꢀ(pꢀTolyl)quinoxalinꢀ2(1H)ꢀylidene]acetic acid (2b).
Analogously to compound 2a, compound 2b was synthesized
from quinoxalinone 3b (0.32 g, 1 mmol) in a yield of 0.15 g
(53%), m.p. 245 °C (from EtOH) (cf. lit. data9: m.p. 245 °C).
(Z)ꢀ2ꢀ[3ꢀ(pꢀBromophenyl)quinoxalinꢀ2(1H)ꢀylidene]acetic
acid (2c). Analogously to compound 2a, compound 2c was
synthesized from quinoxalinone 3c (0.39 g, 1 mmol) in a yield
of 0.18 g (54%), m.p. 265 °C (from EtOH) (cf. lit. data9:
m.p. 264—265 °C).
The treatment of compound 2a (0.26 g, 1 mmol) with a
nitrating mixture (analogously to compound 1a) afforded the
starting acid 2a in a yield of 0.24 g (91%).
Bromination of a mixture of quinoxalinones 1h + 1i. A soluꢀ
tion of Br2 (5 mmol) in AcOH (0.3 mL) was added dropwise
with constant stirring to a solution of a mixture of quinoxalinꢀ
2ꢀones 1h + 1i (1.6 g, 5 mmol) in AcOH (15 mL). The reaction
mixture was stirred at room temperature for 1 h and then poured
into ice water. The precipitate was filtered off, washed with
water, and triturated with hot ethanol (in 10 mL portions).
The residue was recrystallized from ethyl acetate. Poorly soluble
7ꢀbromoꢀ6ꢀnitro isomer 2i was filtered off. 6ꢀNitro acid 2h was
isolated from the filtrate on cooling. 6ꢀNitroquinoxalinone 1i
was isolated from the ethanolic solution in a yield of 1.1 g (85%).
6ꢀNitroꢀ3ꢀ[2ꢀoxoꢀ2ꢀ(pꢀtolyl)ethyl]ꢀ3,4ꢀdihydroquinoxalinꢀ
2(1H)ꢀone (1i). The yield was 1.1 g (85%), m.p. 196—198 °C
(from EtOH). Found (%): C, 62.73; H, 4.64; N, 12.79. C17H15N3O4.
(Z)ꢀ2ꢀ[3ꢀ(pꢀChlorophenyl)ꢀ7ꢀmethylquinoxalinꢀ2(1H)ꢀ
ylidene]acetic acid (2d). Analogously to compound 2a, comꢀ
pound 2d was synthesized from quinoxalinone 4b (0.41 g,
1 mmol) in a yield of 0.13 g (41%), m.p. 257—259 °C (from
EtOH). Found (%): C, 65.26; H, 7.21; N, 8.93. C17H13ClN2O2.
Calculated (%): C, 65.29; H, 7.19; N, 8.96. 1H NMR, δ: 2.28 (s,
1
Calculated (%): C, 62.76; H, 4.65; N, 12.92. H NMR, δ: 2.35
(s, 3 H, CH3); 3.36 (dd, 1 H, HA, J = 17.7 Hz, J = 6.7 Hz); 3.52
(dd, 1 H, HB, J = 17.7 Hz, J = 6.7 Hz); 4.53 (t, 1 H, HХ, J = 6.7 Hz,
J = 4.6 Hz); 6.60 (s, 1 H, NH); 7.33 (d, 2 H, mꢀHAr, J = 7.9 Hz);

1048
Russ.Chem.Bull., Int.Ed., Vol. 58, No. 5, May, 2009
Kolos et al.
7.49—7.73 (m, 3 H, H(5), H(7), H(8)); 7.88 (d, 2 H, оꢀHAr
J = 7.9 Hz); 10.93 (s, 1 H, NH).
,
4. K. Gewald, Khim. Geterotsikl. Soedin., 1976, 1299 [Chem.
Heterocycl. Compd. (Engl. Transl.), 1976, 12]; K. Gewald,
S. Bennet, R. Schindler, H. Schafer, J. Prakt. Chem., 1995,
337, 442.
5. WeygandꢀHilgetag, Organischꢀchemische Experimentierkunst,
J. Ambrosius Barth Verlag, Leipzic, 1964.
(Z)ꢀ2ꢀ[7ꢀBromoꢀ6ꢀnitroꢀ3ꢀ(pꢀtolyl)quinoxalinꢀ2(1H)ꢀylidene]ꢀ
acetic acid (2i). The yield was 0.12 g (29%), m.p. 288—290 °C
(from AcOEt). Found (%): C, 70.75; H, 5.64; N, 10.79.
C16H10BrN3O4. Calculated (%): C, 70.79; H, 5.63; N, 10.83.
1H NMR, δ: 2.37 (s, 3 H, Me); 6.98 (s, 1 H, CH=); 7.87 (s,
6. J. A. Joule, K. Mills, Heterocyclic Chemistry, Blackwell Sci.,
Oxford, 2000.
1 H, H(8)); 8.25 (d, 1 H, H(5), J = 2.2 Hz); 7.34 (d, 2 H, mꢀHAr
,
J = 7.6 Hz); 7.92 (d, 2 H, оꢀHAr, J = 7.6 Hz); 12.38 (s, 1 H,
NH); 13.84 (s, 1 H, OH). IR (in KBr pellets), ν/cm–1: 1694
(C=O), 1610 (C=C).
7. L. F. Tietze, T. Eicher, Reactionen und Synthesen in organishꢀ
chemischen Praktikum und Forshungslaboratorium, Georg
Thieme Verlag, Stuttgart—New York, 1999.
(Z)ꢀ2ꢀ[6ꢀNitroꢀ3ꢀ(pꢀtolyl)quinoxalinꢀ2(1H)ꢀylidene]acetic
acid (2h). The yield was 0.15 g (45%), m.p. >300 °C (from
AcOEt) (cf. lit. data2: m.p. >300 °C).
8. N. N. Kolos, A. A. Tishchenko, V. D. Orlov, Khim. Geterotsikl.
Soedin., 2001, 1407 [Chem. Heterocycl. Compd. (Engl. Transl.),
2001, 37].
The bromination of compound 1a (0.27 g, 1 mmol) in acetic
acid, like the bromination of a mixture of quinoxalinꢀ2ꢀones
1h + 1i, afforded acid 2a in a yield of 0.14 g (53%) and acid 2j in
a yield of 0.06 g (18%).
9. N. N. Kolos, T. V. Berezkina, V. D. Orlov, Yu. N. Surov,
I. V. Ivanova, Khim. Geterotsikl. Soedin., 2002, 1690 [Chem.
Heterocycl. Compd. (Engl. Transl.), 2002, 38].
10. M. B. Smith, J. March, March´s Advanced Organic Chemꢀ
istry: Reactions, Mechanisms, and Structure, 6th ed., J. Wiley
and Sons, New Jersey, 2007, 670.
11. Comprehensive Organic Chemistry, Eds D. Barton, W. D. Ollis,
Pergamon Press, Oxford—New York, 1979. Vol. 2.
12. Yu. S. Andreichikov, S. G. Pitirimova, R. F. Saraeva, Khim.
Geterotsikl. Soedin., 1978, 407 [Chem. Heterocycl. Compd.
(Engl. Transl.), 1978, 14].
13. V. A. Mamedov, A. A. Kalinin, A. T. Gubaidullin, A. V.
Chernova, I. A. Litvinov, Ya. A. Levin, R. R. Shagidullin,
Izv. Akad. Nauk, Ser. Khim., 2004, 159 [Russ. Chem. Bull.,
Int. Ed., 2004, 53, 164].
14. N. H. Cromwell, K. E. Cook, J. Org. Chem., 1958, 23, 1327.
15. A. Y. Soliman, I. A. Attia, Indian J. Chem., 1997, 36(B), 75.
16. A. A. Lisakovskii, L. M. Potekha, V. A. Kovtunenko, Tez.
dokl., XXI Vseukr. konf. po Organicheskoi Khimii [Abstrs. of
Papers, XXI AllꢀUkrainian Conf. on Organic Chemistry]
(Chernigov, October 1—6, 2007), Chernigov, 2007, p. 218
1C43 (in Ukrainian).
(Z)ꢀ2ꢀ[7ꢀBromoꢀ3ꢀphenylquinoxalinꢀ2(1H)ꢀylidene]acetic
acid (2j). The yield was 0.06 g (18%), m.p. 208—210 °C (from
EtOH). Found (%): C, 54.97; H, 3.24; N, 8.13. C16H11BrN2O2.
1
Calculated (%): C, 56.00; H, 3.23; N, 8.16. H NMR, δ: 6.80
(s, 1 H, CH=); 7.87 (d, 1 H, H(8), J = 2.4 Hz); 7.52—7.60 (m,
5 H, Ar); 8.00 (d, 2 H, оꢀHPh, J = 7.6 Hz); 12.04 (s, 1 H, NH);
13.47 (s, 1 H, OH). IR (in KBr pellets), ν/cm–1: 1692 (C=O),
1618 (C=C). IR (CCl4), ν/cm–1: 3530 (OH), 3400 (NH), 1750,
1700, 1688 (C=O).
(Z)ꢀ2ꢀ[3ꢀ(pꢀChlorophenyl)ꢀ6ꢀnitroquinoxalinꢀ2(1H)ꢀylidene]ꢀ
acetic acid (2k). A 40% aqueous NaOH solution (2ꢀ3 drops) and
quinoxalinone 1j (0.35 g, 1 mmol) were added to a solution of
elemental sulfur (0.05 g) in DMF (5 mL). The reaction mixture
was refluxed for 5 h and cooled. Then water (20 mL) was added,
and the mixture was acidified with 20% HCl. The precipitate
that formed was filtered off and recrystallized from ethanol. The
yield was 0.17 g (50%). In the absence of sulfur, acid 2k was
obtained in 25% yield.
17. F. Carey, R. Sundberg, Advanced Organic Chemistry. Part A:
Structure and Mechanisms, 5th ed., Library of Congress, Conꢀ
trol Number 2006939782, 2007, 1199.
References
18. J. A. Gainor, S. M. Weinreb, J. Org. Chem., 1982, 47, 2833.
19. J. F. M. Da Silva, S. J. Garden, A. C. Pinto, J. Braz. Chem.
Soc., 2001, 12, 273.
1. N. N. Kolos, T. V. Berezkina, V. D. Orlov, Zh. Org. Farm.
Khim. [J. Org. Pharm. Chem.], 2003, 1, 31 (in Ukrainian).
2. N. N. Kolos, L. Yu. Kovalenko, T. V. Berezkina, V. I.
Musatov, Zh. Org. Farm. Khim. [J. Org. Pharm. Chem.], 2007,
5, 49 (in Ukrainian).
3. N. N. Kolos, L. Yu. Kovalenko, Khim. Geterotsikl. Soedin.,
2007, 1588 [Chem. Heterocycl. Compd. (Engl. Transl.), 2007,
43].
Received March 12, 2008;
in revised form August 5, 2008