Synthesis of 3-alkylquinoxalin-2(1H)-ones via Grignard reaction

Article abstract of DOI:10.1134/S1070428009070185

A two-step procedure has been developed for the synthesis of 3-alkylquinoxalin-2(1H)-ones from o-phenylenediamine and ethyl 2-oxoalkanoates prepared by the Grignard reaction of diethyl oxalate with alkyl bromides. Analogous reaction with α,ω-dibromoalkanes instead of alkyl bromides leads to the formation of 3,3'-(alkane-α,ω-diyl)di[quinoxalin-2(1H) -ones].

Full text of DOI:10.1134/S1070428009070185

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2009, Vol. 45, No. 7, pp. 1098–1101. © Pleiades Publishing, Ltd., 2009.
Original Russian Text © A.A. Kalinin, V.A. Mamedov, 2009, published in Zhurnal Organicheskoi Khimii, 2009, Vol. 45, No. 7, pp. 1109–1112.
Synthesis of 3-Alkylquinoxalin-2(1H)-ones via Grignard Reaction
A. A. Kalinin and V. A. Mamedov
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.knc.ru
Received August 3, 2008
Abstract—A two-step procedure has been developed for the synthesis of 3-alkylquinoxalin-2(1H)-ones from
o-phenylenediamine and ethyl 2-oxoalkanoates prepared by the Grignard reaction of diethyl oxalate with alkyl
bromides. Analogous reaction with α,ω-dibromoalkanes instead of alkyl bromides leads to the formation of
3,3′-(alkane-α,ω-diyl)di[quinoxalin-2(1H)-ones].
DOI: 10.1134/S1070428009070185
Quinoxaline derivatives are used as starting com-
pounds in the synthesis of various more complex
heterocyclic systems. On the other hand, quinoxaline
core constitutes a structural fragment of many impor-
tant pharmaceuticals and biologically active substances
so that compounds containing a quinoxaline fragment
attract strong interest of synthetic chemists and bio-
chemists. Quinoxaline derivatives were found to ex-
hibit antimicrobial [1–3], antitumor [4], and antituber-
culous activity [5].
condensation of o-phenylenediamine with α-dicarbon-
yl compounds [6], despite mild reaction conditions and
high yields, has not found wide application in the syn-
thesis of 3-alkylquinoxalin-2(1H)-ones [15] because of
difficult accessibility of α-keto acids and their esters
(except for pyruvic acid derivatives). The fourth gen-
eral procedure is four-step [14].
Taking the above stated into account, the present
study was aimed at developing a simple general proce-
dure for the synthesis of 3-alkylquinoxalin-2(1H)-ones,
as well as of α,ω-bis(2-oxo-1,2-dihydroquinoxalin-3-
yl)alkanes, from accessible starting compounds. Bis-
quinoxaline derivatives attracted specific interest, for
such compounds were shown to possess stronger bio-
logical activity as compared to those containing only
one quinoxaline fragment [16].
Conventional methods for the synthesis of quinoxa-
line derivatives are based on reactions of o-phenylene-
diamines with two-carbon synthons such as α-dicar-
bonyl [6] and α-halocarbonyl compounds [7, 8]. Some
o-nitroanilines [9] and benzofuroxans [5] can also be
used instead of o-phenylenediamines. Among known
methods for the preparation of 2-hydroxyquinoxalines
or quinoxalin-2(1H)-ones, the following four general
procedures may be noted: (1) condensation of o-phen-
ylenediamine with α-halocarboxylic acids [10, 11] and
subsequent oxidation of dihydroquinoxalines thus
formed, (2) reaction of o-phenylenediamine with
2-ethoxalylpropionates followed by alkaline hydrolysis
[12], (3) reaction of 3-methylquinoxalin-2(1H)-one
with alkyl halides in the presence of butyllithium [13],
and (4) reaction of α-hydroxyiminocarboxylic acid
esters with o-phenylenediamine [14]. The first three
procedures include three steps. The first procedure en-
sures only 8–34% yield of the target products [10], the
scope of the second procedure is restricted due to
inaccessibility of initial ethoxalylalkanoates [12], and
the third procedure involves experimental difficulties
[13]. On the other hand, the procedure based on the
We synthesized 3-alkylquinoxalin-2(1H)-ones by
condensation of o-phenylenediamine with α-oxo esters
which were prepared by the Grignard reaction from
Scheme 1.
O
R
OMgBr
OEt
RMgBr
OEt
EtO
EtO
O
O
I
II
O
OEt
R
–EtOMgBr
O
IIIa–IIId
R = Et (a), Bu (b), C8H16 (c), C9H18 (d).
1098

SYNTHESIS OF 3-ALKYLQUINOXALIN-2(1H)-ONES VIA GRIGNARD REACTION
1099
Scheme 3.
diethyl oxalate (I) and alkyl bromides. Taking into
account that carboxylic acid esters react with Grignard
compounds to give tertiary alcohols, the main problem
was to find conditions (temperature, reactant ratio,
reaction time) ensuring formation of adduct II (hemi-
acetal salt) [17] which is unstable (it readily undergoes
decomposition to give highly reactive oxo ester III and
the corresponding alkoxide; Scheme 1).
O
O
( )n
BrMg
BrMg
I
( )n
EtO
OEt
O
O
Va–Vc
NH2
1
N
N
In the H NMR spectra of Grignard reaction prod-
( )n
NH2
ucts IIIa–IIId we observed signals from the ester
ethoxy group (a triplet at δ 1.1 ppm and a quartet at
δ 4.1 ppm), while signal from protons in the CH2CO
group appeared separately from the other signals as
a quartet (IIIa) or triplet (IIIb–IIId). Therefore, we
were able to determine the yield of α-oxo esters IIIa–
IIId, which ranged from 70 to 80% (20–30% of unre-
acted diethyl oxalate was present). Taking into account
different reactivities of diethyl oxalate (I) and α-oxo
esters III, the latter were brought into reaction with
o-phenylenediamine without isolation from the reac-
tion mixtures. We thus succeeded in simplifying the
experimental technique and raising the yield of 3-al-
kylquinoxalin-2(1H)-ones. Reactions of ethyl 2-oxo-
alkanoates IIIa–IIId with o-phenylenediamine in
ethanol at room temperature gave the corresponding
3-alkylquinoxalin-2(1H)-ones IVa–IVd in almost
quantitative yield (Scheme 2). Using α,ω-dibromo-
alkanes instead of alkyl bromides we obtained diesters
Va–Vc which reacted with 2 equiv of o-phenylenedi-
amine to give 3,3′-(alkane-α,ω-diyl)bis[quinoxalin-
2(1H)-ones] VIa–VIc (Scheme 3).
N
H
O
O
N
H
VIa–VIc
n = 2 (a), 3 (b), 4 (c).
distilled tetrahydrofuran was added dropwise over
a period of 1 h under stirring to 8.8 g (0.37 mol) of
magnesium turnings and 300 ml of THF. During the
addition, the mixture became turbid and warmed up to
the boiling point, so that the rate of addition of ethyl
bromide was controlled to maintain the mixture
slightly boiling. When the addition was complete, the
mixture was stirred for 30 min at 60°C, cooled, and
added dropwise under stirring to a solution of 53.0 g
(0.36 mol) of diethyl oxalate (I) in 100 ml of THF,
preliminarily cooled to –60°C. The mixture spontane-
ously warmed up, and its temperature was maintained
below –15°C. The mixture was stirred for 2 h at
–15°C, cooled to –30°C, and neutralized by quickly
adding a solution of 65 ml of 6 N hydrochloric acid in
200 ml of water. The organic phase was separated,
washed with water (2×100 ml), and dried over Na2SO4
or MgSO4, and the aqueous phase was extracted with
methylene chloride (3 × 50 ml). The extract was
washed with water, combined with the THF solution,
filtered, and evaporated. The residue was 47 g of
a mixture of ethyl 2-oxobutanoate (IIIa) and diethyl
oxalate (I), containing 80% of the former (according to
Scheme 2.
NH2
N
R
O
IIIa–IIId
+
NH2
N
H
IVa–IVd
1
R = Et (a), Bu (b), C8H16 (c), C9H18 (d).
the H NMR data). It was dissolved in 400 ml of
ethanol, 31 g (0.29 mol) of o-phenylenediamine was
added to the solution, and the mixture was stirred for
6 h and left overnight (a solid separated in 5 min). The
crystals were filtered off and washed with ethanol, the
filtrate was poured into water and left overnight, and
the precipitate was filtered off. Yield 93%, mp 192–
194°C (from acetone); published data: mp 192°C [14],
198°C [12]). IR spectrum, ν, cm–1: 2380–3220, 1660,
1605, 1570, 1500, 1490, 1430, 1160, 900, 720. 1H NMR
spectrum (CDCl3), δ, ppm: 1.33 t (3H, CH2CH3, J =
7.4 Hz), 2.91 q (2H, CH2CH3, J = 7.4 Hz), 7.30–
7.58 m (3H, 6-H, 7-H, 8-H), 7.80 d (1H, 5-H, J =
EXPERIMENTAL
The melting points were determined on a Boetius
melting point apparatus. The IR spectra were recorded
on a Bruker Vector-22 spectrometer with Fourier
transform from samples dispersed in mineral oil. The
1H NMR spectra were measured on a Bruker Avance-
600 instrument at 600 MHz using the residual proton
signal of the solvent as reference.
3-Ethylquinoxalin-2(1H)-one (IVa). A solution of
40.0 g (0.37 mol) of ethyl bromide in 100 ml of freshly
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 45 No. 7 2009

KALININ, MAMEDOV
1100
7.9 Hz), 11.21 br.s (1H, NH). Found, %: C 68.75;
H 5.97; N 16.25. C10H10N2. Calculated, %: C 68.95;
H 5.79; N 16.08.
(DMSO-d6), δ, ppm: 0.86 t (3H, CH3, J = 6.80 Hz),
1.26–1.37 m (12H, CH2), 1.65–1.76 m (2H, 3-CH2-
CH2), 2.79 t (2H, 3-CH2, J = 7.6 Hz), 7.28 d.d.d (1H,
6-H, J = 7.8, 7.7, 1.0 Hz), 7.29 d (1H, 8-H, J =
7.8 Hz), 7.48 d.d.d (1H, 7-H, J = 7.8, 7.7, 1.1 Hz),
7.71 d (1H, 5-H, J = 7.8 Hz). Found, %: C 74.46;
H 8.88; N 10.28. C17H24N2O. Calculated, %: C 74.33;
H 8.81; N 10.33.
3-Butylquinoxalin-2(1H)-one (IVb) was synthe-
sized in a similar way. From 9.00 g (0.37 mol) of
magnesium turnings, 50.7 g (0.37 mol) of 1-bromo-
butane, and 54.7 g (0.37 mol) of diethyl oxalate we
obtained 49.0 g of a mixture of diethyl oxalate and
compound IIIb (74% of the latter, according to the
1H NMR data). Yield of IVb 88%, mp 158–160°C
(from i-PrOH); published data: mp 156°C [14], 154–
155°C [10, 15], 153–154°C [11]. IR spectrum, ν, cm–1:
2500–3300, 1666, 1608, 1565, 1287, 1150, 624,
3,3′-(Butane-1,4-diyl)bis[quinoxalin-2(1H)-one]
(VIa) was synthesized in a similar way. From 4.4 g
(0.18 mol) of magnesium turnings, 20 g (0.09 mol) of
1,4-dibromobutane, and 27 g (0.18 mol) of diethyl
oxalate (I) we obtained 16 g of a mixture containing
initial diethyl oxalate and diethyl 2,7-dioxooctanedi-
oate (Va) (12% of the latter, according to the 1H NMR
data). Yield of VIa 74%, mp >300°C (decomp., from
DMSO). IR spectrum, ν, cm–1: 2500–3200, 1662,
1610, 1562, 1486, 1502, 1433, 1345, 1139, 1107, 896,
1
943, 893, 751, 706, 590, 469. H NMR spectrum
(DMSO-d6), δ, ppm: 0.93 t (3H, CH3, J = 7.3 Hz),
1.33–1.45 m (2H, CH2CH3), 1.63–1.77 m (2H, CH2-
CH2CH3), 2.80 t (2H, 3-CH2, J = 7.8 Hz), 7.33 d (1H,
8-H, J = 7.8 Hz), 7.36 d.d (1H, 6-H, J = 8.3, 7.3 Hz),
7.50 d.d (1H, 7-H, J = 7.8, 7.3 Hz), 7.91 d (1H, 5-H,
J = 8.3 Hz), 12.08 br.s (1H, NH). Found, %: C 71.34;
H 7.09; N 14.04. C12H14N2O. Calculated, %: C 71.26;
H 6.98; N 13.85.
1
705, 589. H NMR spectrum (DMSO-d6), δ, ppm:
1.80–1.85 m (4H, 3-CH2CH2), 2.87 t (4H, 3-CH2, J =
6.66 Hz), 7.22–7.32 m (2H, 6-H, 8-H), 7.48 d.d.d (2H,
7-H, J = 8.4, 7.2, 1.4 Hz), 7.70 d.d (2H, 5-H, J = 8.2,
1.4 Hz), 12.28 s (2H, NH). Found, %: C 70.26; H 5.38;
N 16.03. C20H18N4O2. Calculated, %: C 69.35; H 5.24;
N 16.17.
3-Octylquinoxalin-2(1H)-one (IVc) was synthe-
sized in a similar way. From 1.1 g (0.04 mol) of
magnesium turnings, 8.2 g (0.04 mol) of 1-bromo-
octane, and 6.2 g (0.04 mol) of diethyl oxalate (I) we
obtained 5.5 g of a mixture of initial diethyl oxalate
and ethyl 2-oxodecanoate (IIIc), containing 70% of the
3,3′-(Pentane-1,5-diyl)bis[quinoxalin-2(1H)-one]
(VIb) was synthesized in a similar way. From 3.0 g
(0.12 mol) of magnesium turnings, 14.1 g (0.06 mol)
of 1,5-dibromopentane, and 18.2 g (0.12 mol) of di-
ethyl oxalate (I) we obtained 16.8 g of a mixture of
initial diethyl oxalate and diethyl 2,8-dioxononanedi-
oate (Vb) (54% of the latter, according to the 1H NMR
data). Yield of VIb 85%, mp 268–270°C (decomp.,
from DMSO). IR spectrum, ν, cm–1: 2500–3500, 1663,
1612, 1563, 1500, 1431, 1348, 1290, 1152, 1114, 911,
1
latter (according to the H NMR data). Yield of IVc
91%, mp 126–128°C (from EtOH); published data
[14]: mp 126°C. IR spectrum, ν, cm–1: 2715–3165,
1667, 1608, 1564, 1433, 1377, 1151, 941, 892, 750,
708, 590, 469. 1H NMR spectrum (DMSO-d6), δ, ppm:
0.85 t (3H, CH3, J = 6.9 Hz), 1.26–1.37 m (10H, CH2),
1.64–1.75 m (2H, 3-CH2CH2), 2.77 t (2H, 3-CH2, J =
7.55 Hz), 7.26 d.d.d (1H, 6-H, J = 7.6, 7.6, 1.3 Hz),
7.27 d (1H, 8-H, J = 7.3 Hz), 7.47 d.d.d (1H, 7-H, J =
7.6, 7.3, 0.8 Hz), 7.71 d (1H, 5-H, J = 7.8 Hz), 12.28 br.s
(1H, NH). Found, %: C 74.18; H 8.18; N 10.84.
C16H22N2O. Calculated, %: C 74.05; H 8.13; N 10.98.
1
868, 751, 707, 591. H NMR spectrum (DMSO-d6), δ,
ppm: 1.76–1.88 m (6H, CH2), 2.82 t (4H, 3-CH2, J =
7.6 Hz), 7.25–7.32 m (4H, 6-H, 8-H), 7.48 d.d.d (2H,
7-H, J = 8.4, 7.1, 1.4 Hz), 7.70 d (2H, 5-H, J =
7.9 Hz), 12.28 s (2H, NH). Found, %: C 69.76; H 5.68;
N 15.71. C22H22N4O2. Calculated, %: C 69.98; H 5.59;
N 15.55.
3-Nonylquinoxalin-2(1H)-one (IVd) was synthe-
sized in a similar way. From 1.0 g (0.04 mol) of
magnesium turnings, 8.3 g (0.04 mol) of 1-bromo-
nonane, and 5.9 g (0.04 mol) of diethyl oxalate (I) we
obtained 5.1 g of a mixture of initial diethyl oxalate
and ethyl 2-oxoundecanoate (IIId), containing 74% of
3,3′-(Hexane-1,6-diyl)bis[quinoxalin-2(1H)-one]
(VIc) was synthesized in a similar way. From 3.0 g
(0.12 mol) of magnesium turnings, 15.3 g (0.06 mol)
of 1,6-dibromohexane, and 18.2 g (0.12 mol) of diethyl
oxalate we obtained 16 g of a mixture containing ini-
tial diethyl oxalate (I) and diethyl 2,9-dioxodecanedi-
oate (Vc) (60% of the latter, according to the 1H NMR
data). Yield of VIc 92%, mp 249–251°C (from DMSO).
IR spectrum, ν, cm–1: 2500–3500, 1658, 1557, 1498,
1
the latter (according to the H NMR data). Yield of
IVd 96%, mp 132–133°C (from EtOH); published data
[14]: mp 127°C. IR spectrum, ν, cm–1: 2718–3310,
1667, 1609, 1600, 1561, 1470, 1432, 1152, 894,
1
757, 750, 710, 702, 589, 469. H NMR spectrum
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 45 No. 7 2009

SYNTHESIS OF 3-ALKYLQUINOXALIN-2(1H)-ONES VIA GRIGNARD REACTION
1101
7. Puebla, P., Honores, Z., Medarde, M., Caballero, E., San
Feliciano, A., and Moran, L., J. Heterocycl. Chem.,
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1429, 1347, 1286, 1148, 1109, 946, 878, 756, 704,
589. H NMR spectrum (DMSO-d6), δ, ppm: 1.35–
1
1.50 m (4H, 3′-H, 4′-H), 1.70–1.80 m (4H, 2′-H, 5′-H),
2.80 t (4H, 1′-H, 6′-H, J = 7.6 Hz), 7.27 d.d (2H, 6-H,
J = 8.0, 7.6 Hz), 7.29 d (2H, 8-H, J = 8.3 Hz), 7.48 d.d
(2H, 7-H, J = 7.6, 7.6 Hz), 7.72 d (2H, 5-H, J =
7.8 Hz), 12.28 s (2H, NH). Found, %: C 70.76; H 5.88;
N 14.83. C22H22N4O2. Calculated, %: C 70.57; H 5.92;
N 14.96.
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