Synthesis and functionalization of 3-ethylquinoxalin-2(1H)-one

Article abstract of DOI:10.1007/s11178-005-0210-2

A new and effective procedure was developed for the synthesis of 3-ethylquinoxalin-2(1H)-one from o-phenylenediamine and ethyl 2-oxobutanoate. The latter was prepared by the Grignard reaction of diethyl oxalate with ethylmagnesium bromide or iodide. The ethyl group in 3-ethylquinoxalin-2(1H)-one can readily be converted into various functional groups: α-bromoethyl, α-thiocyanato, α-azidoethyl, α-phenylaminoethyl, acetyl, and bromoacetyl. The reaction of 3-(bromoacetyl)quinoxalin-2(1H)-one with thiourea and hydrazine-1,2-dicarbothioamide gives the corresponding 3-(2-amino-4- thiazolyl) derivatives.

Full text of DOI:10.1007/s11178-005-0210-2

Russian Journal of Organic Chemistry, Vol. 41, No. 4, 2005, pp. 599–606. Translated from Zhurnal Organicheskoi Khimii, Vol. 41, No. 4, 2005,
pp. 609–616.
Original Russian Text Copyright © 2005 by Mamedov, Kalinin, Gubaidullin, Isaikina, Litvinov.
Synthesis and Functionalization of 3-Ethylquinoxalin-2(1H)-one
V. A. Mamedov, A. A. Kalinin, A. T. Gubaidullin, O. G. Isaikina, and I. A. Litvinov
Arbuzov Institute of Organic and Physical Chemistry, Kazan Research Center, Russian Academy of Sciences,
ul. Arbuzova 8, Kazan, 420088 Tatarstan, Russia
e-mail: mamedov@iopc.kcn.ru
Received May 28, 2004
Abstract—A new and effective procedure was developed for the synthesis of 3-ethylquinoxalin-2(1H)-one
from o-phenylenediamine and ethyl 2-oxobutanoate. The latter was prepared by the Grignard reaction of
diethyl oxalate with ethylmagnesium bromide or iodide. The ethyl group in 3-ethylquinoxalin-2(1H)-one can
readily be converted into various functional groups: α-bromoethyl, α-thiocyanato, α-azidoethyl, α-phenyl-
aminoethyl, acetyl, and bromoacetyl. The reaction of 3-(bromoacetyl)quinoxalin-2(1H)-one with thiourea and
hydrazine-1,2-dicarbothioamide gives the corresponding 3-(2-amino-4-thiazolyl) derivatives.
We previously showed that 3-(α-chlorobenzyl)-
quinoxalin-2(1H)-one (I), which is readily available
via reaction of 3-chloro-3-phenyl-2-oxopropionates
with o-phenylenediamine, is a convenient polyfunc-
tional reagent for the synthesis of various fused quino-
xaline derivatives, such as thiazolo[3,4-a]-, imidazo-
building blocks in the design of macroheterocyclic
systems.
The only reported method for the synthesis of
3
-ethylquinoxalin-2(1H)-one (IIa) includes three steps:
(
1) reaction of ethyl α-(ethoxalyl)propionate [6] with
o-phenylenediamine, (2) alkaline hydrolysis of inter-
mediate ethyl α-(2-hydroxyquinoxalin-3yl)propionate,
and (3) decarboxylation of the acid thus formed [7].
The procedure based on oxidation of 3-alkyltetra-
hydroquinoxalin-2-ones formed by condensation of
o-phenylenediamine with α-halo carboxylic acids also
seems to be unreasonable: the yield of the target
[
[
1,5-a]-, pyrrolo[1,2-a]-, pyrazolo[3,4-b]-, pyrano-
5,6-b]-, and indolizino[2,3-b]quinoxalines [1–5]. The
key factor in the formation of all these compounds
is favorable arrangement of the α-chlorobenzyl group
with respect to the endocyclic imino and carbamoyl
moieties. Replacement of the chlorine atom by appro-
priate groups gives rise to structural fragments neces-
sary for the subsequent ring closure at the a or b side
of the pyrazine ring in the initial quinoxaline.
3
-alkylquinoxalin-2(1H)-ones ranges from 8 to 34%
[
8]. By analogy with the synthesis of 3-(α-chloro-
benzyl)quinoxalin-2(1H)-one (I), one of the simplest
procedures for the preparation of 3-(α-bromoethyl)-
quinoxalin-2(1H)-one (III) may be that based on reac-
tion of methyl 3-chloro-2-oxobutanoate with o-phen-
ylenediamine [9]. However, unlike 3-chloro-3-phenyl-
Replacement of the phenyl group in molecule I by
methyl could considerably extend the synthetic poten-
tial due to ready transformation of the α-chloroethyl
fragment into various functional groups. Therefore, the
goal of the present work was to develop procedures for
the preparation of 3-ethylquinoxalin-2(1H)-one (IIa)
as a convenient intermediate product for the synthesis
of various quinoxaline derivatives which are promising
2
-oxopropionates which are readily formed in high
yields by the Darzens reaction of dichloroacetates with
benzaldehyde [10], 3-chloro-2-oxobutanoates are very
difficult to obtain in such a way because of numerous
competing processes with participation of acetalde-
hyde used as electrophilic reagent.
Cl
Me
N
N
Retrosynthetic analysis [11] shows that molecule
IIa is built up from synthons A and B whose synthetic
equivalents are, respectively, o-phenylenediamine and
Ph
X
N
H
O
N
H
O
2
-oxobutanoic acid derivatives IV (Scheme 1). Among
I
IIa, III
various methods for the preparation of 2-oxobutanoic
IIa, X = H; III, X = Br.
acid derivatives IV, we selected the Grignard reaction
1
070-4280/05/4104-0599 © 2005 Pleiades Publishing, Inc.

6
00
MAMEDOV et al.
Scheme 1.
potassium hydroxide) to afford 1,3-diethylquinoxalin-
N2+
NH2
2(1H)-one (IIb) (no O-alkyl derivative V is formed;
Scheme 3). The structure of N-ethylquinoxalinone IIb
is confirmed by the presence in its IR spectrum of
absorption bands due to stretching vibrations of C=N
NH+
Me
O
NH2
A
N
–1
and C=O bonds at 1602 and 1655 cm , respectively;
+
these bands are displaced to higher frequencies by 5
and 15 cm , respectively, relative to the corresponding
–
1
N
H
O
2
bands in the spectrum of initial quinoxalinone IIa. The
IIa
1
H NMR spectrum of IIb contained signals from
O
RO
O
protons in the benzo fragment at δ 7.25–7.82 ppm and
protons of two nonequivalent methylene groups at
δ 2.95 (CCH ) and 4.29 ppm (NCH ).
B
2
2
of diethyl oxalate with ethylmagnesium bromide or
iodide [12]. Taking into account that this reaction
usually leads to formation of tertiary alcohols, it was
necessary to find out temperature conditions, reactant
ratio, and reaction time to force the process to be
terminated at the stage of formation of adduct C [13]
Scheme 3.
N
Et
O
N
KOH, EtBr
(
Scheme 2). The subsequent decomposition of unstable
adduct C should give highly reactive keto ester IV and
dioxane, 6 h
Et
IIa
IIb
halomagnesium alkoxide.
N
N
Et
Scheme 2.
OEt
O
Et
OMgHlg
OEt
V
OEt
+
EtMgHlg
EtO
EtO
Functionalization of quinoxalinone IIa was per-
formed via substitution of the bromine atom in
α-bromoethyl derivative III by the action of various
nucleophiles. Compound III is readily obtained by
bromination of IIa in acetic acid; however, this
reaction is accompanied by side bromination at the
aromatic ring. In order to avoid this process, we
carried out bromination of IIa under mild conditions,
by treatment of a suspension of IIa in dioxane with
bromine at 12–15°C; in this case, the brominating
agent is a complex of bromine with dioxane. As
a result, quinoxalinone III thus obtained contained no
impurity of dibromo derivative. The bromine atom in
III is readily replaced by such nucleophiles as KSCN,
NaN , and PhNH in DMSO to give the corresponding
O
O
C
O
OEt
Et
–
EtOMgHlg
O
IV
The resulting mixture containing diethyl oxalate
and keto ester IV (without additional purification or
separation) was brought into reaction with o-phen-
ylenediamine to obtain quinoxaline IIa; here, the
required amount of o-phenylenediamine was calculat-
ed from the H NMR spectrum of crude product IV.
Insofar as the reactivity of ethyl 2-oxobutanoate is
higher than that of diethyl oxalate, 3-ethylquinoxalin-
1
3
2
3-(α-X-ethyl)quinoxalines VI–VIII (Scheme 4).
2
(1H)-one (IIa) was smoothly obtained at room tem-
Compounds VI–VIII displayed in the IR spectra
perature, and it contained no quinoxaline-2,3-dione
impurity.
absorption bands typical of the quinoxalin-2-one
system and those corresponding to vibrations of the
–
1
The structure of compound IIa was confirmed by
elemental analysis and spectral methods, as well as by
comparing with published data [6, 7]. 3-Ethylquino-
xalin-2(1H)-one (IIa) can readily be alkylated at the
nitrogen atom with ethyl bromide under standard
conditions [14] (in boiling dioxane in the presence of
thiocyanato group (2160 cm , VI), azido group
–
1
–1
(2135 cm , VII), and amino group (3300 cm , VIII).
1
The H NMR spectra of α-substituted 3-ethylquino-
xalin-2-one derivatives VI–VIII contained signals
from the CH and CH
protons of the substituent in
3
position 3, which appeared as a quartet and doublet,
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 41 No. 4 2005

SYNTHESIS AND FUNCTIONALIZATION OF 3-ETHYLQUINOXALIN-2(1H)-ONE
601
Scheme 4.
Me
N
KSCN, DMSO
SCN
N
H
O
VI
Me
Br ·1,4-dioxane
dioxane
2
N
NaN
, DMSO
N3
3
IIa
III
N
H
O
VII
Me
N
PhNH , DMSO
NHPh
2
N
H
O
VIII
respectively, in a stronger field, as compared to the
corresponding signals of 3-(1-bromoethyl)quinoxalin-
acetic acid at 50–60°C (2 h) [15] gave the desired
ketones IXa and IXb (Scheme 6). Their IR spectra
contained absorption bands belonging to the ketone
2
(1H)-one (III).
–1
and lactam carbonyl groups at 1714 and 1710 cm ,
Having such derivatives as 3-(1-bromoethyl), 3-(1-
respectively, and the acetyl fragment in IXa and IXb
thiocyanatoethyl), and 3-(1-azidoethyl) (compounds
III, VI, and VII) at our disposal, it seemed reasonable
to obtain a more promising (from the synthetic view-
point) quinoxaline derivative, namely 3-acetylquino-
xalin-2(1H)-one (IXa) [5]. It can be prepared by
analogy with 3-(α-X-benzyl) derivatives, or from
bromo and thiocyanato derivatives III and VI by the
Kornblum reaction, or by acid hydrolysis of azido
derivative VII. However, we failed to obtain the
desired results by heating quinoxaline VI in DMSO
both in the presence and in the absence of base or by
heating azide VII in dilute hydrochloric acid or in
acetic acid. On the other hand, by treatment of azido-
ethylquinoxaline VII with 70% aqueous acetic acid we
succeeded in obtaining ketone IXa as the major prod-
uct (Scheme 5).
1
gave rise to a singlet at δ ~ 2.7 ppm in the H NMR
spectra.
Scheme 6.
Me
CrO , 95% AcOH
50–60°C, 2 h
3
N
O
IIa, IIb
N
R
O
IXa, IXb
R = H (a), Et (b).
Further functionalization of 3-acetylquinoxalin-
2
(1H)-ones IXa and IXb included synthesis of their
bromoacetyl analogs; the presence of an α-bromocar-
bonyl fragment in the latter opens new prospects in
the preparation of various heterocyclic systems. The
bromination of IXa and IXb to bromoacetylquino-
xalines Xa and Xb was effected with the use of
bromine–1,4-dioxane complex in THF (12–15°C,
Scheme 5.
Me
N
AcOH/H O
O
2
VII
3
0 min; Scheme 7). The structure of products Xa and
N
H
O
Xb is confirmed by a high-frequency shift of the
carbonyl absorption bands in the IR spectra (by 10–
IXa
–
1
1
5 cm ), as compared to initial ketones IXa and IXb.
1
We also made an attempt to directly oxidize the
ethyl group in quinoxalines IIa and IIb to acetyl
fragment. Reactions of IIa and IIb with CrO in 95%
The H NMR spectra of Xa and Xb lacked methyl
group singlet at δ 2.7 ppm, but a new singlet appeared
at δ 4.7 ppm due to protons of the bromomethyl group.
3
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 41 No. 4 2005

6
02
MAMEDOV et al.
Scheme 7.
monoclinic crystals containing one molecule in the
CH Br
asymmetric part of a unit cell. The quinoxaline frag-
ment is planar within 0.050(3) Å, and it forms a di-
2
N
Br ·C H O
2
O
2
4
8
hedral angle of 15.9(1)° with the thiazole ring plane
IXa, IXb
1
(
Fig. 1). The ethyl group on C strongly declines from
N
O
the quinoxaline plane. The crystalline structure is
characterized by an extended system of intra- and
intermolecular contacts, the main kinds of which are
N–H···N, C–H···N, and C–H···O. Thus, a couple of
identical intermolecular contacts between protons of
the amino group and thiazole nitrogen atoms in two
molecules related through a symmetry center give rise
to dimers shown in Fig. 2. The parameters of these
R
Xa, Xb
R = H (a), Et (b).
One of the most typical reactions of α-halo ketones
is the reaction with thioamides or thiourea, which
underlies the main procedure for the synthesis of thia-
zoles (Hantzsch reaction [16]). Moreover, this reaction
may be used to identify α-halo ketones. We performed
reactions of α-bromo ketones Xa and Xb with thiourea
under standard conditions, i.e., by heating the reactants
in boiling methanol, followed by treatment of the re-
action mixture with a solution of sodium hydrogen
carbonate [16] (Scheme 8).
3
22
33'
contacts are as follows: d(H · · · N ) = 2.35 Å,
32
322
33'
∠
(N –H ···N ) = 135°. The dimers are linked
together through contacts between protons of the thia-
zole rings and carbonyl oxygen atoms: d(H ···O ) =
3
5
2''
35
35
2''
2
.38 Å, ∠(C –H ···O ) = 129.3°; symmetry trans-
formation –1/2 – x, 1/2 – y, 1/2 – z. As a result, infinite
chains of H-bonded molecules are formed along the
crystallographic 0x axis (Fig. 2). Intermolecular con-
Scheme 8.
321
tacts involving the H atom (amino group) and 5-H
S
atom of the fused benzene ring link the above chains to
a three-dimensional supramolecular structure in crystal
(
(
1) H NC(S)NH2
2
MeOH, 1 h, ∆
NH
2
N
2) 5% aq. NaHCO3
N
(
Fig. 3). These interactions are characterized by the
Xa, Xb
321
4''
following parameters: d(H ···N )(–1/2 + x, –y, z) =
3
(
N
R
O
3
2
321
4''
5
32'''
.12(1) Å, ∠(N –H ···N ) = 148°; d(H ···N
)
5
5
32'''
1/2 + x, –y, z) = 3.40(1) Å, ∠(C –H ···N ) = 144°.
Likewise, α-bromo ketones Xa and Xb reacted with
XIa, XIb
R = H (a), Et (b).
hydrazine-1,2-dicarbothioamide to afford the corre-
sponding bis-thiazolyl-substituted hydrazines which
were not isolated due to their ready oxidation with
atmospheric oxygen; furthermore, these products are
poorly soluble in common organic solvents, except for
dimethyl sulfoxide which also acts as oxidant. There-
Closure of thiazole ring follows from the presence
of a singlet at δ 8.27±1 ppm from the 5-H proton and
of a broadened singlet at δ 6.5 ppm from the amino
1
group in the H NMR spectra of the products. The
1
structure of compound XIb was proved by the X-ray
diffraction data. Compound XIb crystallizes to form
fore, we failed to obtain their satisfactory H NMR
spectra, and the isolated products were azo compounds
XII, which were readily formed by heating in DMSO
for 1 h at ~100°C (Scheme 9).
6
C
5
C
7
C
4
A
Thus we have developed a simple and convenient
procedure for the synthesis of 3-ethylquinoxalin-
2(1H)-one and shown that the ethyl group therein is
readily transformed into various functional groups
which can be successfully used in further syntheses.
C
8
8A
4
C
C
N
3
2
32
3
3
N
C
3
4
N
3
C
C
1
C
9
C
31
2
S
C
3
5
C
2
O
1
0
EXPERIMENTAL
C
The IR spectra were recorded in mineral oil on
1
a Bruker Vector-22 Fourier spectrometer. The H NMR
spectra were measured on a Bruker MCL-250 instru-
ment (250.13 MHz) using signals from residual
Fig. 1. Structure of the molecule of 3-(2-aminothiazol-4-yl)-
quinoxalin-2(1H)-one (XIb) according to the X-ray diffrac-
tion data.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 41 No. 4 2005

SYNTHESIS AND FUNCTIONALIZATION OF 3-ETHYLQUINOXALIN-2(1H)-ONE
603
Scheme 9.
R
O
N
(
(
(
1) H NC(S)NHNHC(S)NH , MeOH, 1 h
2) 5% aq. NaHCO3
3) DMSO, 100°C, 1 h
2
2
N
S
N
N
Xa, Xb
N
N
S
N
N
R
O
XIIa, XIIb
R = H (a), Et (b).
–
1
protons in the solvent as reference. The melting points
were determined on a Boetius melting point apparatus.
(from acetone). IR spectrum, ν, cm : 1605 (C=N),
1
1660 (C=O), 2380–3220 (NH). H NMR spectrum
(
(
8
CDCl ), δ, ppm: 1.33 t (3H, CH , J = 7.40 Hz), 2.91 q
3
3
X-Ray analysis of a single crystal of compound
XIb was performed on an Enraf–Nonius CAD-4 auto-
2H, CH , J = 7.40 Hz), 7.30–7.58 m (3H, 6-H, 7-H,
2
-H), 7.80 d (1H, 5-H, J = 7.85 Hz), 11.21 br.s (1H,
matic four-circle diffractometer (λCuK irradiation,
α
NH). Found, %: C 68.75; H 5.97; N 16.35. C H N O.
Calculated, %: C 68.95; H 5.79; N 16.08.
10
10
2
graphite monochromator, ω/2θ scanning, θ ≥ 74.2°).
Monoclinic crystals, C H N OS, with the following
1
3
11
4
unit cell parameters (at 20°C): a = 8.977(7), b =
1
2
8.698(1), c = 14.923(1) Å; β = 93.26(2)°; V =
3
3
500(1) Å ; Z = 8, d = 1.44 g/cm ; space group I2/a.
calc
5
H
Total of 5424 reflections were measured, 2602 of
which were with I ≥ 4σ(I). No drop in the intensity of
three control reflections was observed during data
acquisition. The structure was solved by the direct
method using SIR program [17] and was refined first
in isotropic and then in anisotropic approximation. The
positions of hydrogen atoms were determined from the
difference electron density series; their contributions
to structural amplitudes were taken into account with
fixed temperature and positional parameters. The final
1
N
4
N
2
O
33
N
3
22
H
3
2
N
3
21
H
divergence factors were R = 0.084 and R = 0.111
w
2
(
from 2602 reflections with F ≥ 4σ). All calculations
were performed on an AlphaStation 200 computer
using MolEN software package [18]. The coordinates
of atoms are available from the authors. The molecular
structure and crystal packing were plotted, and intra-
and intermolecular interactions were calculated, using
PLATON software [19].
Fig. 2. Formation of H-bonded chains of molecules XIb in
crystal (hydrogen bonds are shown as dashed lines).
c
3
-Ethylquinoxalin-2(1H)-one (IIa). Isopropyl
alcohol, 300 ml, and o-phenylenediamine, 17 g
157.41 mmol), were added to 41 g of a mixture of
(
compound IV and diethyl oxalate. The mixture was
stirred for 6 h (a solid began to separate in 5 min) and
was left to stand overnight. The precipitate was filtered
off and washed with isopropyl alcohol. The filtrate was
poured into water and was left overnight, and the
precipitate was filtered off. Yield 93%, mp 192–194°C
0
b
Fig. 3. Packing of molecules XIb in crystal (projection along
the 0a crystallographic axis).
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 41 No. 4 2005

6
04
MAMEDOV et al.
1
,3-Diethylquinoxalin-2(1H)-one (IIb). A mixture
of 2.32 g (13.3 mmol) of 3-ethylquinoxalin-2(1H)-one
IIa) and 1.12 g (20.0 mmol) of potassium hydroxide
250 ml). The extracts were washed with water (2×
150 ml), dried over sodium sulfate, filtered, and evap-
orated to obtain 41 g of a mixture of compound IV
and diethyl oxalate at a ratio of 1:1 (according to the
(
in 70 ml of dioxane was heated to the boiling point.
A solution of 1.67 g (15.3 mmol) of ethyl bromide was
added, and the mixture was heated for 5 h under reflux.
The solvent was removed under reduced pressure
1
H NMR data).
3
-(1-Thiocyanatoethyl)quinoxalin-2(1H)-one
(
VI). Potassium thiocyanate, 0.24 g (2.53 mmol), was
(
water-jet pump), the residue was treated with water,
added to a solution of 0.4 g (1.58 mmol) of compound
III in 10 ml of DMSO. The mixture was stirred for 6 h,
left to stand overnight, and poured into water, and the
precipitate was filtered off and washed with water.
Yield 78%, mp 186–188°C (from isopropyl alcohol).
the mixture was left to stand for 0.5 h, and the pre-
cipitate was filtered off and washed with a solution of
potassium hydroxide and water. Yield 66%, mp <70°C
–
1
(
1
from hexane). IR spectrum, ν, cm : 1602 (C=N),
1
655 (C=O). H NMR spectrum (CDCl ), δ, ppm: 1.33 t
–1
3
IR spectrum, ν, cm : 1603 (C=N), 2160 (SCN), 1670
(
3H, CH CH C, J = 7.25 Hz), 1.37 t (3H, CH CH N,
1
3
2
3
2
(
(
(
C=O), 2500–3220 (NH). H NMR spectrum
J = 7.85 Hz), 2.95 q (2H, CH CH C, J = 7.25 Hz),
.29 q (2H, CH CH N, J = 7.25 Hz), 7.26 d (1H, 8-H,
J = 8.13 Hz), 7.28 d.d (1H, 7-H, J = 8.13, 6.38 Hz),
.46 d.d.d (1H, 6-H, J = 7.28, 7.26, 1.28 Hz), 7.82 d.d
1H, 5-H, J = 8.55, 1.73 Hz). Found, %: C 71.32;
H 6.71; N 13.57. C H N O. Calculated, %: C 71.26;
3
2
CD OD), δ, ppm: 1.91 d (3H, CH , J = 6.80 Hz), 4.98 d
3
3
4
3 2
1H, CHSCN, J = 6.80 Hz), 7.30–7.42 m (2H, 6-H or
7
1
-H, 8-H), 7.57 d.d.d (1H, 7-H or 6-H, J = 7.43, 7.43,
.2 Hz), 7.85 d.d (1H, 5-H, J = 8.03 Hz). Found, %:
7
(
C 57.23; H 3.65; N 18.15; S 14.02. C H N OS.
11
9
3
1
2
14
2
Calculated, %: C 57.13; H 3.92; N 18.17; S 13.86.
H 6.98; N 13.85.
3
-(1-Azidoethyl)quinoxalin-2(1H)-one (VII).
3
-(1-Bromoethyl)quinoxalin-2(1H)-one (III).
Sodium azide, 0.16 g (2.5 mmol), was added to a solu-
tion of 0.40 g (1.58 mmol) of compound III in 12 ml
of DMSO. The mixture was stirred for 6 h, left to stand
overnight, and poured into water, and the precipitate
was filtered off and washed with water. Yield 84%,
mp 199–200°C (from isopropyl alcohol). IR spectrum,
A mixture of 0.16 ml (3.88 mmol) of bromine and 5 ml
of dioxane was added under stirring at 12–15°C to
a suspension of 0.62 g (3.56 mmol) of quinoxaline IIa
in 30 ml of dioxane. The mixture was stirred for 4 h,
and the precipitate was filtered off and washed with
isopropyl alcohol, a solution of sodium carbonate, and
water. Yield 99%, mp 206–210°C (from acetone). IR
–
1
ν, cm : 1605 (C=N), 1673 (C–O), 2091, 2134 (N ),
3
1
–
1
2
1
6
390–3240 (NH). H NMR spectrum (CDCl ), δ, ppm:
spectrum, ν, cm : 1605 (C=N), 1665 (C=O), 2380–
3
1
.72 d (3H, CH , J = 6.78 Hz), 4.92 q (1H, CHN , J =
3
2
6
180 (NH). H NMR spectrum (CDCl ), δ, ppm:
3
3
3
7.8 Hz), 7.29–7.62 m (3H, 6-H, 7-H, 8-H), 7.92 d
.14 d (3H, CH , J = 6.58 Hz), 5.76 q (1H, CHBr, J =
.58 Hz), 7.30–7.62 m (3H, 6-H, 7-H, 8-H), 7.90 d
3
(
1H, 5-H, J = 7.75 Hz), 12.62 br.s (1H, NH). Found,
%
: C 55.61; H 4.46; N 32.41. C H N O. Calculated,
(
%
1H, 5-H, J = 7.90 Hz), 11.83 br.s (1H, NH). Found,
: C 47.62; H 3.50; Br 31.73; N 11.32. C H BrN O.
10 9 5
%
: C 55.81; H 4.22; N 32.54.
-(1-Phenylaminoethyl)quinoxalin-2(1H)-one
1
0
9
2
Calculated, %: C 47.46; H 3.58; Br 31.60; N 11.07.
3
Ethyl 2-oxobutanoate (IV). A solution of 39.4 g
361.54 mmol) of ethyl bromide in 100 ml of THF was
added dropwise under stirring to a mixture of 8.8 g
361.96 mmol) of magnesium turnings and 200 ml of
THF. The mixture became turbid and warmed up to the
boiling point. When the addition was complete, the
mixture was heated for 0.5 h under reflux and cooled
to –60°C, and a solution of 52.78 g (361.51 mmol) of
diethyl oxalate in 100 ml of THF was added, main-
taining the temperature below –20°C. The mixture was
stirred for 2 h at –20°C, and dilute hydrochloric acid
was added dropwise to a weakly acidic reaction. The
organic phase was separated, washed with water
(VIII). Aniline, 0.15 g (1.6 mmol), was added to a so-
lution of 0.20 g (0.8 mmol) of compound III in 12 ml
of DMSO. The mixture was stirred for 6 h, left to stand
overnight, and poured into water, and the precipitate
was filtered off and washed with water. Yield 71%,
mp 163–166°C (from isopropyl alcohol). IR spectrum,
(
(
–
1
ν, cm : 1605 (C=N), 1673 (C–O), 2390–3450 (NH).
1
H NMR spectrum (DMSO-d
CH , J = 6.43 Hz), 4.93–5.15 m (1H, CHN), 5.82 d
), δ, ppm: 1.49 d (3H,
6
3
(1H, NHPh, J = 8.58 Hz), 6.52 d.d (1H, p-H, J = 7.30,
6.88 Hz), 6.65 d.d (2H, o-H, J = 7.75 Hz), 6.95–7.55 m
(5H, 6-H, 7-H, 8-H, m-H), 7.75 d (1H, 5-H, J =
7.75 Hz), 12.36 br.s (1H, NH). Found, %: C 72.20;
(
2×150 ml), and dried over sodium sulfate, and the
H 6.04; N 15.76. C16
H N O. Calculated, %: C 72.44;
15 3
aqueous phase was extracted with chloroform (3×
H 5.70; N 15.84.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 41 No. 4 2005

SYNTHESIS AND FUNCTIONALIZATION OF 3-ETHYLQUINOXALIN-2(1H)-ONE
605
–
1
3
-Acetylquinoxalin-2(1H)-one (IXa). A solution
DMSO–CH CN, 1:1). IR spectrum, ν, cm : 1606,
3
of 5.17 g (52 mmol) of chromium(VI) oxide in 3 ml of
water and 5 ml of acetic acid was added under stirring
to a solution of 6.00 g (34 mmol) of compound IIa in
0 ml of acetic acid. The mixture was stirred for 2 h at
5–60°C, poured into water, and extracted with chloro-
1619 (C=C, C=N); 1664 (C=O); 2500–3650 (NH,
1
NH ). H NMR spectrum (DMSO-d ), δ, ppm: 7.38 d
2
6
(1H, 8-H, J = 7.75 Hz), 7.39 d.d (1H, 6-H or 7-H, J =
7.75, 6.88 Hz), 7.59 d.d (1H, 7-H or 6-H, J = 7.30,
5
5
6
.88 Hz), 7.90 d (1H, 5-H, J = 7.73 Hz), 8.26 s (1H,
form (3×25 ml). The extract was dried over sodium
sulfate and passed through a column (300×15 mm)
charged with 10 g of silica gel, and the column was
washed with 200 ml of chloroform. The solvent was
removed under reduced pressure (water-jet pump) to
isolate analytically pure compound IXa. Yield 40%,
5
'-H), 12.50 s (1H, NH). Found, %: C 61.23; H 3.49;
N 25.99; S 13.03. C H N OS. Calculated, %: C 61.09;
H 3.73; N 25.91; S 13.12.
11
8
4
3-(2-Aminothiazol-4-yl)-3-ethylquinoxalin-2(1H)-
one (XIb) was synthesized in a similar way from com-
pound Xb. Yield 84%, mp 159–161°C (from DMSO–
CH
–
1
mp 173–175°C. IR spectrum, ν, cm : 1610 (C=N),
–
1
1
3
CN, 1:1). IR spectrum, ν, cm : 1600, 1603 (C=C,
1
659 (C=O), 1712 (C=O), 2500–3220 (NH). H NMR
1
C=N); 1665 (C=O); 2750–3470 (NH ). H NMR spec-
2
spectrum (CD OD), δ, ppm: 2.66 s (3H, CH ), 7.33 d
3
3
trum (CD OD), δ, ppm: 1.38 t (3H, CH , J = 6.93 Hz),
3
3
(
1H, 8-H, J = 8.33 Hz), 7.39 d.d.d (1H, 6-H or 7-H,
4.43 q (3H, CH , J = 6.93 Hz), 7.41 d.d.d (1H, 6-H
2
J = 7.74, 7.73, 1.13 Hz), 7.64 d.d.d (1H, 7-H or 6-H,
J = 7.77, 7.76, 1.13 Hz), 7.87 d.d (1H, 5-H, J = 8.14,
or 7-H, J = 7.16, 7.16, 1.4 Hz), 7.55–7.65 m (2H, 7-H
or 6-H, 8-H), 7.96 d (1H, 5-H, J = 7.40 Hz), 8.28 s
1
.15 Hz). Found, %: C 63.98; H 4.58; N 14.61.
(
1H, 5'-H). Found, %: C 63.69; H 4.95; N 22.87;
C H N O . Calculated, %: C 63.83; H 4.22; N 14.89.
10
8
2
2
S 11.93. C H N OS. Calculated, %: C 63.91; H 4.95;
1
3
12
4
3
-Acetyl-1-ethylquinoxalin-2(1H)-one (IXb) was
N 22.93; S 11.77.
,4'-Bis(2-oxo-1,2-dihydroquinoxalin-3-yl)-2,2'-
azothiazole (XIIa). Hydrazine-1,2-dicarbothioamide,
.06 g (0.37 mmol), was added to a solution of 0.20 g
0.75 mmol) of compound Xa in 10 ml of methanol,
synthesized as described above for IXa from com-
pound IIb. Yield 45%, mp 84–85°C. IR spectrum, ν,
4
–1
1
sm : 1604 (C=N), 1670 (C=O), 1714 (C=O). H NMR
0
(
spectrum (CDCl ), δ, ppm: 1.40 t (3H, CH CH , J =
3
3
2
6
.83 = Hz), 2.68 s (3H, CH CO), 4.32 q (2H, CH CH ,
3 3 2
and the mixture was heated for 1.5 h under reflux.
The precipitate was filtered off, washed with aqueous
sodium hydrogen carbonate and water, dried, and dis-
persed in DMSO. The suspension was heated for 1 h
at 100°C and cooled, and the precipitate was filtered
off and washed with isopropyl alcohol. Yield 60%,
J = 6.83 Hz), 7.34 d (1H, 8-H, J = 7.70 Hz), 7.35 d.d
1H, 7-H, J = 7.70, 7.67 Hz), 7.63 d.d.d (1H, 6-H,
J = 8.38, 7.46, 1.30 Hz), 7.92 d.d (1H, 5-H, J = 8.53,
.70 Hz). Found, %: C 66.45; H 5.45; N 12.73.
C H N O . Calculated, %: C 66.66; H 5.59; N 12.95.
(
1
12
12
2
2
3
-Bromoacetylquinoxalin-2(1H)-one (Xa). A mix-
–1
mp >360°C (from DMSO). IR spectrum, ν, cm : 1607
C=N), 1664 (C=O). Found, %: C 54.38; H 2.67;
N 23.32; S 13.07. C H N O S Calculated, %:
ture of 0.30 ml (5.8 mmol) of bromine and 2 ml of
dioxane was added under stirring at 12–15°C to a solu-
tion of 1.00 g (5.3 mmol) of compound IXa in 30 ml
of THF. The mixture was stirred for 1 h, poured into
water, and extracted with chloroform (3×15 ml). The
extract was dried over sodium sulfate, filtered, and
evaporated under reduced pressure (water-jet pump).
The product was used in further syntheses without
additional purification.
(
2
2
12
8
2
2.
C 54.55; H 2.50; N 23.12; S 13.23.
4,4'-Bis(1-ethyl-2-oxo-1,2-dihydroquinoxalin-3-
yl)-2,2'-azothiazole (XIIb) was synthesized in a si-
milar way from compound Xb. Yield 63%, mp >360°C
–
1
(from DMSO). IR spectrum, ν, cm : 1601 (C=N),
1
1646 (C=O). H NMR spectrum (DMSO-d ), δ, ppm:
6
1
.37 t (3H, CH , J = 7.18 Hz), 4.45 q (3H, CH , J =
3 2
3
-Bromoacetyl-1-ethylquinoxalin-2(1H)-one (Xb)
was synthesized in a similar way from compound IXb.
-(2-Aminothiazol-4-yl)quinoxalin-2(1H)-one
XIa). Thiourea, 0.06 g (0.79 mmol), was added to
a solution of 0.20 g (0.75 mmol) of compound Xa in
8.08 Hz), 7.46–7.55 m (1H, 6-H or 7-H), 7.71–7.78 m
(
2H, 7-H or 6-H, 8-H), 8.04 d (1H, 5-H, J = 7.63 Hz),
.30 s (5'-H). Found, %: C 57.49; H 3.89; N 20.54;
S 12.05. C H N O S . Calculated, %: C 57.76;
3
9
(
2
6
20
8
2 2
H 3.73; N 20.72; S 11.86.
1
1
0 ml of methanol, and the mixture was heated for
.5 h under reflux. The precipitate was filtered off and
This study was performed under financial support
by the Russian Foundation for Basic Research (project
nos. 03-03-32865 and 02-03-32280).
washed with an aqueous solution of sodium hydrogen
carbonate and water. Yield 86%, mp > 360°C (from
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 41 No. 4 2005

6
06
MAMEDOV et al.
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RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 41 No. 4 2005