A convenient method for the synthesis of 2,3-dioxo-1,2,3,4- tetrahydroquinoxalines

Article abstract of DOI:10.1007/s10593-006-0202-3

A method for the synthesis of substituted 2,3-dioxo-1,2,3,4- tetrahydroquinoxalines by the reduction of substituted (o-nitrophenyl)glycines with subsequent oxidation of the 2-oxo-1,2,3,4-tetrahydroquinoxaline products has been developed. When tin(II) chlo

Full text of DOI:10.1007/s10593-006-0202-3

Chemistry of Heterocyclic Compounds, Vol. 42, No. 8, 2006
A CONVENIENT METHOD FOR
THE SYNTHESIS OF 2,3-DIOXO-
1,2,3,4-TETRAHYDROQUINOXALINES
A. V. Vlaskina and V. P. Perevalov
A method for the synthesis of substituted 2,3-dioxo-1,2,3,4-tetrahydroquinoxalines by the reduction of
substituted (o-nitrophenyl)glycines with subsequent oxidation of the 2-oxo-1,2,3,4-tetrahydroquinoxaline
products has been developed. When tin(II) chloride was used as the reducing agent a chlorine atom was
introduced ortho to the NHC(O) fragment of the heterocycle.
Keywords: 2,3-dioxo-1,2,3,4-tetrahydroquinoxaline-5-carboxylic acid, 2,3-dioxo-1,2,3,4-tetrahydro-
quinoxaline-6-carboxylic acid, substituted (o-nitrophenyl)glycine, reductive cyclization.
With the objective of finding biologically active substances with structures similar to the known material
ACEA-1021 (1), Kornberg et al [1] synthesized a substituted 2,3-dioxo-1,2,3,4-tetrahydroquinoxaline in which a
carbamoyl group was present in place of the electron-withdrawing nitro group. One of the intermediate products
in this scheme is methyl 6-methyl-7-nitro-2,3-dioxo-1,2,3,4-tetrahydroquinoxaline-5-carboxylate (2).
CO2Me
NO2
H
H
Me
N
O
O
Cl
Cl
N
O
O
N
H
O2N
N
H
2
1
For the synthesis of this heterocycle a complex multistep route was proposed, the possibility of which
was limited by the presence of a methyl group in the 2-amino-6-methylbenzoic acid starting material. We have
developed a simpler and universal method for the synthesis of analogous compounds based on 2-chloro-3,5-
dinitrobenzoic acid. Methyl 8-chloro-7-nitro-2,3-dioxo- (3) and 7-nitro-2,3-dioxo-1,2,3,4-tetrahydroquinoxaline-
5-carboxylates (4) were synthesized as follows:
__________________________________________________________________________________________
D. I. Mendeleev Russian University of Chemical Technology, Moscow 125047, Russia; e-mail:
sark@muctr.edu.ru. Translated from Khimiya Geterotsikicheskikh Soedinenii, No. 8, 1206-1210, August, 2006.
Original article submitted November 19, 2003; revision submitted June 8, 2006.
1046
0009-3122/06/4208-1046©2006 Springer Science+Business Media, Inc.

Cl
Cl
O2N
CO2H
O2N
CO2Me
NO2
NO2
NHCH2CO2H
CO2Me
O2N
H2NCH2CO2H
NO2
5
CO2Me
CO2Me
H
H
N
N
SnCl2, HCl
H2S, Et3N
O2N
O2N
N
H
O
N
O
H
Cl
7
6
H2O2, AcOH
H2O2, AcOH
CO2Me
CO2Me
H
N
H
O
O
N
O
O
O2N
N
H
4
O2N
N
H
Cl
3
The reductive cyclization of N-(6-methoxycarbonyl-2,4-dinitrophenyl)glycine (5) deserves particular
attention. Previously [2] the synthesis of 3-methyl-7-nitro- (8), 7-nitro- (9) and 5-methoxy-7-nitro-2-oxo-1,2,3,4-
tetrahydroquinoxaline (10) by the reduction of the corresponding substituted (o-nitrophenyl)glycines was
reported..
OMe
H
N
H
N
H
N
Me
O
N
H
O
O2N
N
H
O
O2N
N
H
O2N
10
8
9
In the first case ammonium sulfide was used as the reducing agent and the reaction occurred readily and
unambiguously. In our work the best results were obtained in the reduction of compound 5 with hydrogen
sulfide in the presence of triethylamine. Our results were different from those reported in [2] when tin(II)
chloride was used as the reducing agent.
Horner et al [2] carried out the reduction of the corresponding substituted (o-nitrophenyl)glycine in
ethanol saturated with HCl and obtained satisfactorily high yields of compounds 9 and 10. Under the same
conditions we obtained the chlorine-containing compound 6. Introduction of a chlorine atom into an aromatic
ring is not a rare phenomenon in the reduction of a nitro compound with tin(II) chloride, which is facilitated by
1047

a high temperature and a high concentration of HCl. This is explained by the intermediate formation of an
arylhydroxylamine and its subsequent rearrangement [3, 4]. We turn our attention to the fact that during the
synthesis of compound 6 the chlorine atom does not enter the para position, as is normally observed [3], but into
the position ortho to the amino group formed. The same was observed in the reduction of
N-(4-isopropylcarboxyl-2,6-dinitrophenyl)glycine (11) with tin(II) chloride in isopropanol saturated with HCl
which gave isopropyl 5-chloro-8-nitro-3-oxo-1,2,3,4-tetrahydroquinoxaline-6-carboxylate (12).
NHCH2CO2H
NO2
NO2
H
N
O2N
N
H
O
i-PrO2C
Cl
i-PrO2C
12
11
It is most likely that this orientation is connected to the electron–withdrawing nitro- and alkoxycarboxyl
groups, but a steric factor is not excluded. We propose the following scheme for the cyclization:
MeO2C
NHCH2CO2H
NO2
NHCH2CO2H
NH2
H
N
MeO2C
MeO2C
Cl
O
O2N
N
H
NO2
NO2
Cl
In the first step reduction of a nitro group is accompanied by chlorination while in the second step
intramolecular acylation occurs which leads to the closing of the 1,2,3,4-tetrahydroquinoxalin-2-one ring. The
position of the chlorine in compounds 6 and 12 was determined by two-dimensional correlation NOESY spectra.
The signal corresponding to the interaction of the proton of the NHC(O) unit with the neighboring proton of the
aromatic ring, which is observed, for example in the spectrum of compound 7, is absent from the spectra of
compounds 6 and 12. This is explained by the presence of a chlorine atom in the corresponding position of the
aromatic ring. We used hydrogen peroxide in glacial acetic acid for the oxidation of compounds 6 and 7 into 3
and 4 respectively.
EXPERIMENTAL
1H NMR spectra of DMSO-d6 solutions with TMS as internal standard were recorded with a Bruker WP-
200 (200 MHz) machine. Chromato mass spectroscopic investigations of isolated compounds were carried out
with Hewlett Packard 6890 gas chromato-mass spectrometer with a 5973 mass spectromer detector, an HP-5MS
column (30 m × 0.25 µm) with a 0.25 µm thich liquid phase, helium carrier gas (40 cm/s), a flow split of 20:1,
source temperature 150°C, injector temperature 230°C, temperature gradient from 40 to 320°C (25°C/min), and
EI ionization. Two-dimensional NOESY spectra were recorded with a Bruker DAX-500 at 30°C using a Bruker
standard method.
Methyl 2-chloro-3,5-dinitrobenzoate and isopropyl 4-chloro-3,5-dinitrobenzoate were made by a
standard method [5].
1048

N-(6-Methoxycarbonyl-2,4-dinitrophenyl)glycine (5). A solution of Na2CO3 (4.6 g, 45.0 mmol) and
glycine (2.2 g, 30.0 mmol) in water (20 ml) was added to a boiling solution of methyl 2-chloro-3,5-dinitro-
benzoate (7.8 g, 30.0 mmol) in methanol (20 ml), the mixture was boiled for 20 min, cooled, acidified with 10%
HCl, and the yellow precipitate was filtered off and recrystallized from methanol to give compound 5, 4.4 g,
(64%); mp 153-155°C.
N-(4-Isopropoxycarbonyl-2,6-dinitrophenyl)glycine (11) was obtained analogously from isopropyl
4-chloro-3,5-dinitrobenzoate in 2-propanol. Yield 93%; mp 177-179°C.
Methyl 8-Chloro-7-nitro-2-oxo-1,2,3,4-tetrahydroquinoxaline-5-carboxylate (6). A solution of
SnCl2·2H2O (9.0 g, 40.0 mmol) in methanol (40 ml) saturated with HCl was added dropwise to a boiling solution
of compound 5 (3.0 g, 10.0 mmol) in methanol (50 ml) saturated with HCl for 9 h. After cooling, the precipitate
was filtered off and recrystallized from dilute acetic acid to give compound 6 (1.7 g, 60%) as yellow needles; mp
269-271°C. 1H NMR spectrum, δ, ppm: 9.44 (1H, br. s, NH); 8.42 (1H, br. s, NH); 8.27 (1H, s, Harom); 4.13 (2H,
s, CH2); 3.86 (3H, s, CH3). Mass spectrum, m/z: 285, 287 [M+]. Found, %: 45.25; H 2.98; N 15.80.
C10H8ClN3O5. Calculated, %: C 45.20; H 3.01; N 15.82.
Methyl 7-Nitro-2-oxo-1,2,3,4-tetrahydroquinoxaline-5-carboxylate (7). Hydrogen sulfide (made by
adding dilute HCl solution Na2S·9H2O (8.0 g, 33.3 mmol) was passed through a solution of compound 5 (1.0 g,
3.3 mmol) and Et3N (2.4 ml, 17.3 mmol) in water (20 ml) heated to 50°C. At the end of the reaction, the mixture
was cooled, acidified with HCl solution, the yellow precipitate was filtered off, dissolved in glacial acetic acid,
filtered from sulfur, diluted with water, and the precipitate filtered off. Recrystallization from dilute acetic acid
gave compound 7 (0.2 g, 24%); mp <300°C. 1H NMR spectrum, δ, ppm (J, Hz): 10.82 (1H, s, NH); 8.47 (1H, s,
NH). 8.29 (1H, d, J = 2.76, Harom); 7.66 (1H, d, J = 2.76, Harom); 4.15 (2H, s, CH2); 3.87 (3H, s, CH3). Mass
spectrum, m/z: 251 [M+]. Found, %: C 45.25; H 2.98; N 15.80. C10H9N3O5. Calculated, %: C 45.40; H 3.01;
N15.82.
Methyl 8-Chloro-7-nitro-2,3-dioxo-1,2,3,4-tetrahydroquinoxaline-5-carboxylate (3). A hot solution
of compound 6 (0.8 g, 2.8 mmol) in glacial acetic acid (30 ml) was added to a mixture of glacial acetic acid
(30 ml) and 50% H2O2 (2 ml) heated to 60°C, the mixture was heated to boiling and kept at that temperature for
30 min, the solvent was evaporated to 20 ml and diluted with water. The yellow-orange precipitate was filtered
1
off and recrystallized from dilute acetic acid to give compound 3 (0.6 g, 76%); mp 284-286°C. H NMR
spectrum, δ, ppm: 11.52 (2H, br. s, NH); 8.32 (1H, s, Harom); 3.97 (3H, s, CH3). Mass spectrum, m/z: 299, 301
[M+] . Found, %: C 40.05; H 2.00; N 14.04. C10H6ClN3O6. Calculated, %: C 40.07; H 2.00; N 14.02.
Methyl
7-Nitro-2,3-dioxo-1,2,3,4-tetrahydroquinoxaline-5-carboxylate
(4)
was
prepared
1
analogously. Yield 47%; mp 267-268°C. H NMR spectrum, δ, ppm (J, Hz): 12.37 (1H, s, NH); 11.39 (1H, s,
NH); 8.39 (1H, d, J = 2.30, Harom); 8.14 (1H, d, J = 2.30, Harom); 3.99 (3H, s, CH3). Mass spectrum, m/z: 265
[M+], Found, %: C 45.27; H 2.66; N 15.85. C10H7N3O6. Calculated, %: C 45.28; H 2.64; N 15.85.
Isopropyl 5-Chloro-8-nitro-3-oxo-1,2,3,4-tetrahydroquinoxaline-6-carboxylate (12). A boiling
solution of compound 11 (0.5 g, 1.5 mmol) in 2-propanol (10 ml) was saturated with gaseous HCl for 35 min, a
solution of SnCl2⋅2H2O (1.2 g, 4.7 mmol) in 2-propanol (10 ml) saturated with HCl was added dropwise while
boiling, the mixture was cooled poured onto ice, acidified with 35% HCl solution, the orange precipitate was
filtered off and recrystallized from dilute acetic acid to give compound 12, (0.3 g, 63%); mp 193-195°C.
1H NMR spectrum, δ, ppm (J, Hz): 9.10 (1H, s, NH); 8.45 (1H, s, NH); 8.29 (1H, s, Harom); 5.20 (1H, t, J = 7.70,
CH); 4.15 (2H, s, CH2); 1.45 (6H, d, J = 7.70, 2 CH3). Mass spectrum, m/z: 313, 315 [M+]. Found, %: C 45.90; H
3.85; N 13.40. C12H12ClN3O5. Calculated, %: C 45.93; H 3.83; N 13.40.
1049

REFERENCES
1.
2.
3.
4.
B. E. Kornberg, S. S. Nikam, and M. F. Rafferty, J. Heterocycl. Chem., 36, 1271 (1999).
L. Horner, U. Schwank, and E. Junghanns, Liebigs Ann. Chem., 579, 212 (1953).
D. Scröter, in: Houben-Weyl, Metoden der Organischen Chemie, Stuttgart, 1976, Vol. XI/1, p. 423.
A. V. Vlaskina and V. P. Perevalov, Khim. Geterotsikl. Soedinen., 620 (2004). [Chem. Heterocycl.
Comp., 40, 523 (2004)].
5.
F. Ullman, Liebigs Ann. Chem., 366, 82 (1909).
1050