Unexpected regioselectivity in nitration of 3-aminoquinoxalin-2(1H)-ones a

Article abstract of DOI:10.1039/a910234p

Regioselective nitration takes place at position 8 of 6,7-disubstituted-3-aminoquinoxalin-2(1H)-ones 3a-d. The orientation is not disturbed by the electronic or steric effects of the substituents on the aromatic ring and on the amino group. The isomeric 5-nitro derivative 9 is formed only in a roundabout way from 3,6,7-trichloroquinoxalin-2(1H)-one 7. When position 8 is occupied, the 5-nitro derivatives appear only as a minor component. The isomers were identified by NMR techniques. Theoretical calculations (AMI, Hartree-Fock, B3LYP) and NMR investigations confirmed the presumed nitronium cation attack on the monoprotonated species 3ap. The Royal Society of Chemistry 2000.

Full text of DOI:10.1039/a910234p

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Unexpected regioselectivity in nitration of 3-aminoquinoxalin-
2(1H)-ones†
Csaba Gönczi, Éva Csikós, Benjamin Podányi, Tamás Nusser, Zsolt Böcskei and
István Hermecz
1
Chinoin Pharmaceutical and Chemical Works Ltd., Research Centre, PO Box 110,
H-1325 Budapest, Hungary
Received (in Cambridge, UK) 22nd December 1999, Accepted 8th March 2000
Regioselective nitration takes place at position 8 of 6,7-disubstituted-3-aminoquinoxalin-2(1H)-ones 3a–d. The
orientation is not disturbed by the electronic or steric effects of the substituents on the aromatic ring and on the
amino group. The isomeric 5-nitro derivative 9 is formed only in a roundabout way from 3,6,7-trichloroquinoxalin-
2(1H)-one 7. When position 8 is occupied, the 5-nitro derivatives appear only as a minor component. The isomers
were identified by NMR techniques. Theoretical calculations (AM1, Hartree–Fock, B3LYP) and NMR investigations
confirmed the presumed nitronium cation attack on the monoprotonated species 3ap.
4a. The direct nitration of 3a with potassium nitrate in concen-
trated sulfuric acid or with nitronium tetrafluoroborate in
sulfolane‡ gave exclusively 4a.
Introduction
An increasing number of publications have appeared in the field
of central nervous system (CNS) research, and, in particular,
the N-methyl--aspartate receptor glycine site antagonists have
Evidence concerning the structure of 4a was obtained by
NMR spectroscopy. We reported6 earlier that the 13C chemical
been investigated in detail. Of the quinoxaline derivatives, quin-
shifts of C-5 and C-8 in 3a are 124.6 and 115.6 ppm, respect-
oxaline-2,3(1H,4H)-diones proved to have excellent activity.1
ively. The chemical shift of the only aromatic CH carbon in 4a,
However enhanced activity was observed1b when a nitro group
easily identified from the DEPT7 spectrum, was 126.5 ppm,
was introduced into the quinoxaline molecule.
confirming the substitution at C-8 in the reaction. 15N NMR
Our research has suggested that a more favourable therapeu-
investigations provided further evidence: the signals at 88.7,
tic index can be expected in the series of 3-aminoquinoxalin-
144.0, 226.4 and 363.8 ppm were assigned to the amine,
the amide, the imine and the nitro moieties, respectively. The
2(1H)-one derivatives,2 so we decided to prepare its nitro
derivatives. A literature search indicated that the area of elec-
trophilic substitution concerned is little studied.
only aromatic hydrogen in the compound gave a crosspeak
1
with the imine nitrogen at 226.4 ppm in the H–15N HMBC
The orientation of aromatic electrophilic substitution has
spectrum.
been investigated for several heterocyclic compounds. The site
This regioselectivity of the nitration was unexpected and
preference was explained by the energy differences between the
further efforts were made to prepare the other nitro isomer
by another synthetic pathway. As we expected, 4a was again the
σ-complexes.3
Some preliminary information was also available concerning
sole product of the ring closure reaction with oxalomonoimidic
the substituent directing effects of substituted quinoxalines.
acid diethyl ester, as a consequence of the directing effects.6,8
Quinoxalin-2(1H)-one in mixed acid yields the 6-nitro deriv-
of the 4,5-dichloro-3-nitro-substituents of the 1,2-phenylene-
ative, presuming attack to be on the diprotonated species,4 and
diamine9 5 (Scheme 1).
2-aminoquinoxaline similarly gives the 6-nitro derivative.5
Since none of the direct syntheses of 3-amino-6,7-dichloro-5-
nitroquinoxalin-2(1H)-one 9 were fruitful, the only possibility
remaining was to introduce first the nitro group into the
quinoxaline molecule and then the amino group. The electron-
Therefore one can only guess the isomer ratio in the nitration
reaction of 3-aminoquinoxalin-2(1H)-one. We considered it a
challenge to find out not only the place of attack, but also the
reasons as well.
withdrawing effect of the nitro group resulted in a regiospecific
monochlorination at the more electron-deficient carbon in 6.1
The formation of 2,3,6,7-tetrachloroquinoxaline 8 accom-
Results and discussion
In the nitration of 6,7-dichloro-3-aminoquinoxalin-2(1H)-one
we expected to obtain the 5- and 8-nitro isomers in equal
amounts because, considering the substituent effects, there is
only a slight difference between the chemical environments of
C-5 and C-8. In contrast, nitration of the protected amino
derivative 3-acetylamino-6,7-dichloroquinoxalin-2(1H)-one 1
furnished the 8-nitro derivative 2 only, so that hydrolysis led to
panied that of 7, especially at higher temperatures. The struc-
ture of 7 was identified from the X-ray diffraction data. The 15
N
NMR data were also in agreement with this structure: the
aromatic hydrogen gave a crosspeak with the amide nitrogen
at 145.1 ppm in the HMBC spectrum. Nucleophilic attack by
ammonia on 7 led to the desired 5-nitro derivative 9 (Scheme
2). A crosspeak between the aromatic hydrogen and the
1
amide nitrogen was found at 146.0 ppm in its H–15N HMBC
spectrum.
In order to study the scope and limitations of observed
regioselectivity we nitrated further 3-aminoquinoxalin-2(1H)-
† Optimized geometries of the σ-complexes 3a1, 3a2, 3ap1 and 3ap2 with
the AM1, HF and B3LYP methods together with the X-ray crystal
structure of 7, are available as supplementary data from BLDSC
(SUPPL. NO. 57698, 5 pp.) or the RSC Library. See Instructions for
Authors available via the RSC web page (http://www.rsc.org/authors).
‡ IUPAC name for sulfolane is 2,3,4,5-tetrahydrothiophene 1,1-dioxide.
DOI: 10.1039/a910234p
J. Chem. Soc., Perkin Trans. 1, 2000, 1417–1421
This journal is © The Royal Society of Chemistry 2000
1417

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Table 1 Calculated energies (Eh) of optimized σ-complexes
Energy/Eh
σ-complex
AM1
RHF
B3LYP
3a1
0.3347354
0.3228892
0.17181325
0.7255667
Ϫ1666.46566
Ϫ1666.48085
Ϫ1666.67657
Ϫ1666.66864
Ϫ1672.36746
Ϫ1672.37693
Ϫ1672.58383
Ϫ1672.57781
3a2
3ap1
3ap2
Table 2 Energy differences between 8-nitro- and 5-nitro-σ-complexes
obtained by different methods
E(3a1) Ϫ E(3a2)/
E(3ap1) Ϫ E(3ap2)/
Method
kcal molϪ1
kcal molϪ1
AM1
RHF
B3LYP
7.43
9.53
5.94
Ϫ4.67
Ϫ4.98
Ϫ3.78
Scheme
1
Synthesis of 3-amino-6,7-dichloro-8-nitroquinoxalin-
2(1H)-one 4a. Reagents: (a) KNO3, conc. H2SO4; (b) Ac2O; (c) ethanol,
5 M NaOH; (d) BF4NO2, sulfolane; (e) oxalomonoimidic acid diethyl
ester, ethanol.
R1
R2
R3
R1
R2
R3
R4
3b
3c
Br
F
CH3
Cl
Br
F
CH3
Cl
H
H
H
H
4b
4c
Br
F
CH2
Cl
Cl
Cl
Br
F
NO2
NO2
NO2
NO2
Cl
Cl
Cl
Cl
H
H
H
H
H
H
H
H
NO2
H
NO2
H
H
3d
4d
11a
13
14
CH3
Cl
NO3
NO2
NO2
H
Cl
NO2
H
10a
12
Cl
H
Cl
16aa Cl
15a
Cl
H
Cl
16ba Cl
17a
17b
H
Cl
Cl
H
H
H
18a
18b
20
NO2
Cl
NO2
NO2
H
H
19
H
H
H
21
H
NO2
a R5 = CH3.
Scheme 3 Preparation of 3-aminoquinoxalin-2(1H)-ones. Reagents:
(a) KNO3, conc. H2SO4.
Scheme
2
Synthesis of 3-amino-6,7-dichloro-5-nitroquinoxalin-
2(1H)-one 9. Reagents and conditions: (a) POCl3, DMF, rt; (b) POCl3,
ture of 18a and 18b with an unchanged isomer ratio of 82:18,
as indicated by the two aromatic singlets of each set of signals
in the 1H NMR spectrum.
DMF, 50 ЊC; (c) NH3, ethanol.
ones (Scheme 3). The 3-amino-6,7-dihalogenoquinoxalin-
2(1H)-ones 3b,c behaved in a similar manner to 3a, giving
The nitration of 3-aminoquinoxalin-2(1H)-one 19 regio-
specifically afforded the 6-nitro derivative 20, which is identical
to the derivative obtained by ring closure.8 Under the forcing
reaction conditions, a small amount (13%) of 6,8-dinitro-3-
aminoquinoxalin-2(1H)-one 21 was identified.
3-amino-6,7-dihalogeno-8-nitroquinoxalin-2(1H)-ones
4b,c.
The directing effect was not even perturbed by the methyl
groups in 3d: only 4d was obtained.
We also investigated other substituent patterns for further
characterization of the title compound. The methyl group on
the 3-amino moiety in 10 did not disturb the regioselectivity of
the reaction: only the 8-nitro derivative 11 was formed.
The question then arose as to whether it is possible to intro-
duce a nitro group at position 5 at all. When position 8 was
occupied, as in 3-amino-6,8-dichloroquinoxalin-2(1H)-one 12,
the nitration started at position 7 rather than at position 5,
giving 13 and a trace (5%) of 3-amino-6,8-dichloro-5,7-dinitro-
quinoxalin-2(1H)-one 14, formed as a consequence of the
forced nitration (Scheme 3). In contrast with the situation for
10, we observed a slight effect of the methyl group during the
nitration of 15, which gave a mixture of 16a and 16b, in an
isomer ratio of 88:12 according to 1H NMR.
Reaction mechanism aspects
The unambiguous direction of nitration was presumed to be
due to the presence of a strong directing group in the quin-
oxaline ring, i.e. an ammonium type structure. We investigated
the protonation of 3a by NMR spectroscopy. There were two
NH signals at 8.15 and 7.77 ppm, each with 1H intensity, in the
1H NMR spectrum recorded in concentrated H2SO4. This sug-
gested that protonation took place on N(4). This was confirmed
by 15N NMR investigations. We reported earlier6 that the chem-
ical shifts of N(1), N(4) and the amino nitrogens in DMSO are
144.4, 227.2 and 85.0 ppm, respectively. The chemical shifts of
these nitrogens in concentrated D2SO4 were 147.1, 134.7 and
98.5 ppm. The first two displayed long-range couplings with the
In order to acquire a more complete picture, we investi-
gated derivatives with one substituent on the benzenoid ring.
Nitration of a mixture of isomers 17a and 17b yielded a mix-
1
aromatic hydrogens in the H–15N HMBC spectrum, and they
were therefore assigned to N(1) and N(4), respectively. The
1418
J. Chem. Soc., Perkin Trans. 1, 2000, 1417–1421

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maximized. Elemental analyses for C, H, N were performed on
a Carlo Erba Mod 1106 instrument; halogen was determined by
titration after Schöniger oxidation. The NMR spectra were
recorded on a Bruker DRX-400 instrument at 400.13 (1H),
1
100.6 (13C) and 40.5 (15N) MHz. The H–15N HMBC spectra
were measured on a Bruker DRX-500 instrument, using gradi-
ent coherence12 selection. 1H and 13C chemical shifts are referred
to internal tetramethylsilane; 15N chemical shifts are referred to
external liquid NH3. In DMSO, the 15N chemical shifts refer-
encing was solved by means of the XWINNMR program, util-
izing the frequency of the lock signal. In D2SO4, a coaxial tube
containing Na15NO3 in D2O was used (376.6 ppm). All J values
are quoted in Hz. The ratio of isomers was determined by
NMR. MS spectra were measured on a VG-TS 250 instrument.
Flash chromatography was carried out on silica gel 60H (5–40
µm, Merck, for thin-layer chromatography).
3-Acetylamino-6,7-dichloroquinoxalin-2(1H)-one (1)
A mixture of 3-amino-6,7-dichloroquinoxalin-2(1H)-one8 (3a,
1.15 g, 5 mmol) and acetic anhydride (5 mL) was heated at
reflux for 20 min and was then cooled down to 25 ЊC. Methanol
(10 mL) was added and the mixture was refluxed for 30 min. It
was then cooled down to 25 ЊC and the precipitated crystals
were filtered off and washed with methanol. White crystals
Scheme 4 The 8-nitro- and 5-nitro-σ-complexes of 3a and the mono-
protonated 3ap.
1
(1.03 g, 76%), mp 306 ЊC, H NMR (400 MHz, DMSO-d6)
δ 2.34 (s, 3H, CH3), 7.38 (s, 1H, 8-H), 7.78 (s, 1H, 5-H), 9.83 (br
s, 1H, 3-NH), 12.77 (br s, 1H, N(1)-H); 13C NMR (100 MHz,
DMSO-d6) δ 25.2 (q, CH3), 116.4 (d, C-8), 127.9 (d, C-5), 125.4,
129.3, 130.0, 131.1 (each s, C-8a, C-7, C-6, C-4a), 147.0 (s, C-3),
150.8 (s, C-2), 169.4 (s, CO). Anal. calcd for C10H7Cl2N3O2: C,
44.13; H, 2.59; N, 15.44. Found: C, 43.94; H, 2.78; N, 15.35%.
large chemical shift decrease of N(4) is in agreement with the
protonated structure 3ap (Scheme 4). Similar chemical shift
decreases for N(3) in 2-aminothiazole,10 and for N(1) in adenine
and adenosine derivatives,11 were reported upon protonation of
the ring nitrogens of amidine moieties.
The calculated energy difference between the two σ-com-
plexes 3a1 and 3a2 (Tables 1 and 2) suggested that nitronium
cation attack on the neutral 6,7-dichloroquinoxaline would give
the 5-nitro derivative. On the other hand, the calculated energy
of 3ap1 is lower than that of 3ap2, in agreement with the
experimental findings, e.g. formation of the 8-nitro derivative.
These σ-complexes are formed from the monoprotonated spe-
cies, indicating nitronium cation attack on this, rather than on a
neutral or on a diprotonated species as described in the
literature.4
3-Amino-6,7-dichloro-8-nitroquinoxalin-2(1H)-one (4a)
By hydrolysis from 2. 3-Acetylamino-6,7-dichloro-8-nitro-
quinoxalin-2(1H)-one (2, 1.54 g, 4.9 mmol) was dissolved in
ethanol (96%, 16 mL) and sodium hydroxide solution (5 M, 2.5
mL) at pH 9, and the solution was heated to 80 ЊC. It was then
treated with charcoal, which was subsequently filtered off. The
solution was acidified with hydrochloric acid (5 M, 2 mL) to pH
4.5–5 and crystals of 4a were obtained. Yellow crystals (1.13 g,
85%), mp 295 ЊC, 1H NMR (400 MHz, DMSO-d6) δ 7.64 (s, 1H,
5-H), 7.61, 7.98 (each br s, each 1H, 3-NH2), 12.67 (br s, 1H,
N(1)-H); 13C NMR (100 MHz, DMSO-d6) δ 116.4 (d,
Conclusions
JC8a,5H = 9.4, C-8a), 121.4 (d, JC7,5H = 9.7, C-7), 126.0 (d, JC6,5H
=
The nitration of 6,7-disubstituted-3-aminoquinoxalin-2(1H)-
ones takes place at position 8 rather than at position 5. The
reaction is selective in the presence of electron-withdrawing
halogeno groups. The electron-donating methyl group does not
decrease the regioselectivity, either when it is present at posi-
tions 6 and 7 or when it is on the amino moiety. An electron-
withdrawing group, such as acetyl in 1, does not influence the
selectivity of the electrophilic substitution reaction. The electro-
philic nitronium ion seems to be unable to attack at position 5.
There is a slight departure from this rule when positions 6 and 8
are occupied, so that a small amount of the 5,7-dinitro deriv-
ative 14 is produced. The 5-nitro derivative 16b is formed as a
minor component from 15. The reactivity sequence is C6 >
C7 > C8 ӷ C5 when ortho, para directing substituents are
present on the benzenoid ring. In the case of meta directing
substituents the meta directing prevails.
4.4, C-6), 126.5 (d, JC5,5H = 69.8, C-5), 135.3, 137.3 (each s,
C-8,4a), 151.6, 153.1 (each s, C-2,3); 15N NMR (40.5 MHz,
DMSO-d6) δ 88.7 (3-NH2), 144.0 (N(1), 226.4 (N(4), 363.8
(8-NO2); MS (EI): m/z 274 (Mϩ); νmax (KBr)/cmϪ1 3535, 3433,
3321, 1708. Anal. calcd for C8H4Cl2N4O3: C, 34.93; H, 1.47; N,
20.37. Found: C, 34.70; H, 1.55; N, 20.33%.
Compound 4a by ring closure from 5. 4,5-Dichloro-3-nitro-
1,2-diaminobenzene9 (5, 0.51 g, 2.3 mmol) was dissolved in
absolute EtOH (15 mL), and oxalomonoimidic acid diethyl
ester (0.36 g, 2.5 mmol) was added. The reaction mixture was
kept at 25 ЊC for 24 h. The precipitate was then filtered off,
washed with EtOH (3 × 5 mL) and dried. The crude material
was analysed, and proved to be identical to the hydrolysis
product of 2. Yellow crystals (0.61 g, 96%), mp 295 ЊC.
Our results show that the main mechanism of the nitration
involves nitronium cation attack on a monoprotonated species.
The protonated amidine moiety plays the key role in the
orientation of the aromatic electrophilic substitution.
Compound 4a from by nitronium tetrafluoroborate with 3a.
3-Amino-6,7-dichloroquinoxalin-2(1H)-one (3a, 0.46 g,
2
mmol) was suspended in sulfolane (1.5 mL), NO2BF4 (0.53 g, 4
mmol) was added, and the mixture was stirred at 10 ЊC for 1 h,
followed by ageing at room temperature for 4 h. It was next
quenched into ice (5 g), and the precipitate was filtered off and
washed with water. Yellow crystals (0.16 g, 29%), mp 295 ЊC.
The material was identical to the hydrolysis product of 2.
Experimental
Melting points were determined in open capillary tubes on a
Büchi 535 apparatus and are uncorrected. The yields were not
J. Chem. Soc., Perkin Trans. 1, 2000, 1417–1421
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Nitration of 3-aminoquinoxalin-2(1H)-ones (1, 3a–d, 10, 12, 15,
17ab, 19). General procedure
6,8-Dichloro-3-methylamino-7-nitroquinoxalin-2(1H)-one
(16a) and 6,8-dichloro-3-methylamino-5-nitroquinoxalin-2(1H)-
one (16b). Yellow crystals (from 0.5 mmol of 15: 0.14 g, 97%),
3-Aminoquinoxalin-2(1H)-one (5 mmol) was dissolved in conc.
H2SO4 (10 mL), and the solution was cooled down to 10 ЊC.
KNO3 (1.01 g, 10 mmol) was added slowly to the solution,
which was then stirred at 10 ЊC for 1 h and aged at room tem-
perature for 4 h. It was next quenched into ice (25 g), and the
precipitate was filtered off and washed with water.
1
1
isomer ratio: 16a:16b = 88:12 by H NMR; H NMR (400
MHz, DMSO-d6) δ 16a: 2.92 (d, 3H, JNH,CH = 4.8, CH3), 7.51
(s, 1H, 5-H), 8.44 (br d, 1H, NH), 12.22 (br s,31H, N(1)-H); 16b:
2.83 (d, 3H, JNH,CH3 = 5.2, CH3), 7.55 (s, 1H, 7-H), 8.56 (br d,
1H, NH), 12.20 (br s, 1H, N(1)-H); 13C NMR (100 MHz,
DMSO-d6) δ 16a: 28.1 (q, NCH3), 111.2 (s, C-8), 118.2 (d,
JC6,5H = 3.8, C-6), 123.7 (d, JC5,5H = 171.2, C-5), 125.6 (d,
JC8a,5H = 7.1, C-8a), 136.9 (s, C-4a), 142.2 (d, JC7,5H = 8.5, C-7),
152.2, 152.4 (each s, C-2,3); 16b: 27.9 (q, NCH3), 117.1 (d,
JC6,7H = 3.9, C-6), 120.4 (d, JC8,7H = 3.9, C-8), 122.3 (d,
JC7,7H = 176.4, C-7), 126.3 (d, JC8a,7H = 7.8, C-8a), 128.8 (s,
C-4a), 142.4 (d, JC5,7H = 7.8, C-5), 151.9, 152.3 (each s, C-2,3);
MS (EI): m/z 288 (Mϩ). Anal. calcd for C9H6Cl2N4O3: C, 37.39;
H, 2.09; N, 19.38. Found: C, 37.45; H, 2.27; N, 19.24%.
3-Acetylamino-6,7-dichloro-8-nitroquinoxalin-2(1H)-one (2).
1
White crystals (0.95 g, 60%), mp 237–241 ЊC, H NMR (400
MHz, DMSO-d6) δ 2.34 (s, 3H, CH3), 8.03 (s, 1H, 5-H), 10.07 (s,
1H, 3-NH), 13.3 (br s, 1H, N(1)-H); 13C NMR (100 MHz,
DMSO-d6) δ 25.3 (CH3), 120.8 (C-8a), 123.7, 125.9 (C-6,7),
129.3 (C-5), 132.6, 137.6 (C-8,4a), 147.3, 151.5 (C-2,3), 169.5
(CO); νmax (KBr)/cmϪ1 3481, 3262, 1694. Anal. calcd for
C10H6Cl2N4O4ؒH2O: C, 35.83; H, 2.40; N, 16.72. Found: C,
35.98; H, 2.56; N, 16.88%.
7-Chloro-3-amino-6-nitroquinoxalin-2(1H)-one (18a) and
6-chloro-3-amino-7-nitroquinoxalin-2(1H)-one (18b). Yellow
crystals (from 0.5 mmol of 17a and 17b6: 0.11 g, 88%), isomer
ratio: 18a:18b = 82:18 by 1H NMR; 1H NMR (400 MHz,
DMSO-d6) δ 18a: 7.23 (s, 1H, 8-H), 7.57, 7.94 (each br s, each
1H, NH), 7.87 (s, 1H, 5-H), 12.55 (br s, 1H, N(1)-H); 18b: 7.39
(s, 1H, 5-H), 7.80 (s, 1H, 8-H), 7.9, 8.22 (each br s, 1H, NH),
12.44 (br s, 1H, N(1)-H); 13C NMR (100 MHz, DMSO-d6)
δ 18a: 116.7 (d, C-8), 119.2 (C-7), 120.8 (d, C-5), 132.2, 133.0
(C-4a,8a), 142.1 (C-6), 151.6, 153.3 (C-2,3); 18b: 113.0 (d, C-8),
120.3 (C-6), 125.3 (d, C-5), 127.5 (C-8a), 138.6 (C-4a), 140.5
(C-7), 151.3, 154.6 (C-2,3). Anal. calcd for C8H5ClN4O3ؒ¹H2O:
3-Amino-6,7-dichloro-8-nitroquinoxalin-2(1H)-one (4a). Yel-
low crystals (1.18 g, 86%), mp 295 ЊC. The material was identi-
cal to the hydrolysis product of 2, to the ring-closure product of
5, and to the product obtained by nitration with nitronium
fluoroborate.
3-Amino-6,7-dibromo-8-nitroquinoxalin-2(1H)-one (4b). Yel-
low crystals (1.24 g, 68%), mp 301–303 ЊC, 1H NMR (400 MHz,
DMSO-d6) δ 7.74 (s, 5-H), 7.64, 8.00 (each br s, each 1H,
3-NH2), 12.6 (br s, 1H, NH); 13C NMR (100 MHz, DMSO-d6)
δ 108.1 (C-7), 117.4 (C-6), 121.3 (C-8a), 128.5 (C-5), 135.5
(C-4a), 139.0 (C-8), 151.3, 152.6 (C-2,3); MS (EI): m/z 362
(Mϩ); νmax (KBr)/cmϪ1 3429, 3323, 1705. Anal. calcd for C8H4-
Br2N4O3ؒH2O: C, 25.14; H, 1.58; N, 14.66; Br, 41.84. Found: C,
25.09; H, 1.62; N, 14.48; Br, 42.02%.
¯
²
C, 38.49; H, 2.42; N, 22.45. Found: C, 38.72; H, 2.13; N,
22.53%.
Nitration of 3-amino-6,8-dichloroquinoxalin-2(1H)-one.6
From 12 (1.00 g, 4.3 mmol); the crude yellow crystals (1.00 g,
83%) were purified by flash chromatography, giving 13 and 14.
3-Amino-6,7-difluoro-8-nitroquinoxalin-2(1H)-one (4c). Yel-
low crystals (0.29 g, 24%), mp 288–290 ЊC, 1H NMR (400 MHz,
DMSO-d6) δ 7.55 (dd, 1H, J5H,6F = 11.4, J5H,7F = 7.9, 5-H), 7.45,
7.78 (each br s, each 1H, NH2), 12.06 (br s, 1H, NH); 13C NMR
(100 MHz, DMSO-d6) δ 115.0 (d, JC5,6F = 18.6, C-5), 119.3 (s,
C-8a), 126.9 (d, JC8,7F = 12.1, C-8), 131.2 (d, JC4a,6F = 8.6, C-4a),
3-amino-6,8-dichloro-7-nitroquinoxalin-2(1H)-one (13). Yel-
1
low crystals (0.72 g, 72%), mp >300 ЊC, H NMR (400 MHz,
DMSO-d6) δ 7.46 (s, 1H, 5-H), 7.77, 8.12 (each br s, each 1H,
3-NH2), 12.24 (br s, 1H, N(1)-H); 13C NMR (100 MHz,
DMSO-d6) δ 111.3 (C-8), 118.3 (C-6), 123.6 (C-5), 126.1 (C-8a)
136.7 (C-4a), 142.6 (C-7), 152.1, 154.2 (C-2,3); MS (EI): m/z
274 (Mϩ); νmax (KBr)/cmϪ1 3499, 3382, 1701. Anal. calcd for
C8H4Cl2N4O3: C, 34.93; H, 1.57; N, 20.37. Found: C 34.77; H,
1.62; N, 20.29%.
139.4 (dd, JC7,7F = 254.4, JC7,6F = 17.6, C-7), 145.0 (dd, JC6,6F
=
242.0, JC6,7F = 12.4, C-6), 151.4, 152.4 (each s, C-2,3); MS (EI):
m/z 242 (Mϩ); νmax (KBr)/cmϪ1 3435, 3313, 1683. Anal. calcd for
C8H4F2N4O3: C, 39.68; H, 1.67; N, 23.14. Found: C, 39.60; H,
1.56; N, 22.97%.
3-Amino-6,8-dichloro-5,7-dinitroquinoxalin-2(1H)-one (14).
Yellow crystals (50 mg, 5%), mp >300 ЊC, 1H NMR (400
MHz, DMSO-d6) δ 8.34, 8.71 (each br s, each 1H, 3-NH2),
12.65 (br s, 1H, N(1)-H); 13C NMR (100 MHz, DMSO-d6)
δ 109.7 (C-6), 112.4 (C-8), 128.2 (C-8a), 130.2 (C-4a),
140.7, 140.9 (C-5,7), 151.9, 154.9 (C-2,3); MS (EI): m/z
319 (Mϩ); νmax (KBr)/cmϪ1 3491, 3379, 1691. Anal. calcd for
C8H3Cl2N5O5: C, 30.02; H, 0.94; N, 21.88. Found: C 30.12;
H, 1.13; N, 21.64%.
3-Amino-6,7-dimethyl-8-nitroquinoxalin-2(1H)-one (4d). Yel-
low crystals (0.59 g, 50%), mp 283 ЊC, H NMR (400 MHz,
1
DMSO-d6) δ 2.13 (s, 3H, CH3), 2.29 (s, 3H, CH3), 7.2 (br s, 2H,
NH2), 7.29 (s, 1H, 5-H), 11.98 (br s, 1H, NH); 13C NMR (100
MHz, DMSO-d6) δ 14.2 (q, CH3), 19.6 (q, CH3), 122.9 (s, C-8a),
125.6 (s, C-7), 126.9 (d, C-5), 131.9, 132.7 (each s, C-4a, C-6),
139.2 (s, C-8), 151.9, 152.1 (each s, C-2,3); MS (EI): m/z 234
(Mϩ). Anal. calcd for C10H10N4O3: C, 51.28; H, 4.30; N, 23.92.
Found: C, 51.18; H, 4.43; N, 23.77%.
Nitration of 3-aminoquinoxalin-2(1H)-one:8 from 19 (240 mg, 1.5
mmol)
6,7-Dichloro-3-methylamino-8-nitroquinoxalin-2(1H)-one
(11). Yellow crystals (from 0.5 mmol of 10: 0.13 g, 90%), mp
1
276–279 ЊC, H NMR (400 MHz, DMSO-d6) δ 2.90 (d, 3H,
3-Amino-6-nitroquinoxalin-2(1H)-one (20). Yellow crystals
1
JNH,CH = 4.8, CH3), 7.68 (s, 1H, 5-H), 8.25 (br d, 1H, NH),
(180 mg, 59%), mp 293–296 ЊC, H NMR (400 MHz, DMSO-
3
12.62 (br s, 1H, N(1)-H); 13C NMR (100 MHz, DMSO-d6)
δ 27.7 (q, NCH3), 115.6 (d, JC8a, 5H = 9.5, C-8a), 121.0 (d,
JC7,5H = 8, C-7), 125.5 (s, C-6), 126.3 (d, JC5,5H = 169.9, C-5),
135.3 (s, C-8), 137.2 (s, C-4a), 151.3, 151.6 (each s, C-2,3); MS
(EI): m/z 288 (Mϩ); νmax (KBr)/cmϪ1 3360, 3316, 1722. Anal.
calcd for C9H6Cl2N4O3: C, 37.39; H, 2.09; N, 19.38. Found: C,
37.28; H, 2.15; N, 19.17%.
d6) δ 7.29 (d, J8H,7H = 8.9, 1H, 8-H), 8.00 (dd, J7H,5H = 2.5, 1H,
7-H), 8.05 (d, 1H, 5-H), 8.2, 8.4 (each br, each 1H, NH), 12.76
(br s, 1H, N(1)-H); 13C NMR (100 MHz, DMSO-d6) δ 116.0
(C-8), 117.1 (C-5), 119.3 (C-7), 130.3, (C-8a), 133.7 (C-4a),
143.0 (C-6), 151.8, 152.6 (C-2,3); MS (EI): m/z 206 (Mϩ). Anal.
calcd for C8H6N4O3: C, 46.61; H, 2.93; N, 27.18. Found: C
46.42; H, 3.12; N, 27.29%.
1420
J. Chem. Soc., Perkin Trans. 1, 2000, 1417–1421

View Article Online
3-Amino-6,8-dinitroquinoxalin-2(1H)-one (21). The mother
liquor was extracted with ethyl acetate, and was then purified by
flash chromatography, giving yellow crystals (50 mg, 13%), mp
247–250 ЊC, 1H NMR (400 MHz, DMSO-d6) δ 7.79, 8.11 (each
br s, each 1H, NH), 8.22 (d, J5H,7H = 2.6, 1H, 7-H), 8.56 (d, 1H,
5-H), 11.80 (br s, 1H, N(1)-H); 13C NMR (100 MHz, DMSO-
d6) δ 114.3 (C-7), 123.0 (C-5), 128.8 (C-8a), 134.2, 136.2
(C-8,4a), 141.2 (C-6), 151.4, 153.0 (C-2,3); MS (EI): m/z 251
(Mϩ). Anal. calcd for C8H5N5O5: C, 38.26; H, 2.01; N, 27.88.
Found: C 38.15; H, 2.12; N, 27.73%.
matrix least squares method on F2 using SHELXL97.18 Hydro-
gen atoms were included in calculated positions and refined in
riding mode. Refinement converged at R = 0.137 (wR = 0.3673
for 2892 data and 193 parameters).
X-ray data for 7.§ C10H8Cl3N3O4S; M = 372.60, triclinic, a =
9.170(17), b = 9.477(7), c = 8.883(6) Å, α = 91.52(6), β =
104.20(12), γ = 101.15(14)Њ, V = 732.0(15) Å3, Z = 2, Dc = 1.691
Ϫ3
¯
g cm , space group P1, Cu-Kα radiation (λ = 1.5418 Å), µ
(Cu-Kα) = 7.194 mmϪ1, F(000) = 376.
Crystals grown in an NMR tube from DMSO were mounted
in a capillary and X-ray data were collected at room tempera-
ture on a Rigaku AFC6S diffractometer (out of 3085 collected
reflections 2899 were independent, Rint = 0.1588, wR2 =
0.4196). The crystals available were of inferior quality, therefore
the collected data are also of low quality, but do give
unambiguous proof of the structure of 7.
3,6,7-Trichloro-5-nitroquinoxalin-2(1H)-one (7)
Phosphoryl chloride (0.58 g, 0.35 mL, 3.8 mmol) was added
slowly to a suspension of 61 (1.00 g, 3.6 mmol) in DMF (2 mL).
The mixture was aged at room temperature for 24 h and was
then quenched into water (20 mL). The precipitate was filtered
off and the crude material (1.1 g) was purified by flash chrom-
1
atography. Pale yellow crystals (0.80 g, 75%), mp >300 ЊC, H
§ CCDC reference number 207/410. See http://www.rsc.org/suppdata/
p1/a9/a910234p/ for crystallographic files in .cif format.
NMR (400 MHz, DMSO-d6) δ 7.63 (s, 1H, 8-H), 13.33 (br s,
1H, N(1)-H); 13C NMR (100 MHz, DMSO-d6) δ 116.5 (C-4a),
118.1 (C-8), 122.3 (C-6), 133.3 (C-8a), 133.6 (C-7), 145.6 (C-5),
151.0, 154.3 (C-2,3); MS (EI): m/z 293 (Mϩ). Anal. calcd for
C8H2Cl3N3O3: C, 32.62; H, 0.68; N, 14.27. Found: C, 32.65; H,
0.78; N, 14.06%.
References
1 (a) S. M. Kher, S. X. Cai, E. Weber and J. F. W. Keana, J. Org.
Chem., 1995, 60, 5838 and references therein; (b) S. X. Cai, S. M.
Kher, Z. L. Zhou, V. Ilyn, S. A. Espitia, M. Tran, J. E. Hawkinson,
R. M. Woodward, E. Weber and J. F. W. Keana, J. Med. Chem.,
1997, 40, 730.
2,3,6,7-Tetrachloro-5-nitroquinoxaline (8)
2 Cs. Gönczi, É. Csikós, S. Erdö, J. Bencze, V. Lakics, P. Molnár,
A. Szappanos, B. Podányi, I. Hermecz, G. Héja, S. Báthori, I. Bata,
A. Csutor, I. Szvoboda, Zs. Böcskei and I. Ritz, WO9719934, 1997;
Chem. Abstr., 1997, 127, 95295c.
3 (a) K. J. Szabó, G. Timári and S. Gronowitz, Chem. Scr., 1989, 29,
313; (b) K. J. Szabó, A. B. Hörnfeldt and S. Gronowitz, J. Org.
Chem., 1991, 56, 1590.
4 A. E. A. Porter, in Comprehensive Heterocyclic Chemistry, eds. A. R.
Katritzky, C. W. Rees, A. J. Boulton and E. McKillop, Pergamon
Press, Oxford, 1984, vol. 3, p. 163.
5 H. Poradowska, Zesz. Nauk. Uniw. Jagiellon. Pr. Chem., 1987, 30,
97; Chem. Abstr., 1988, 109, 92044n.
6 É. Csikós, Cs. Gönczi, B. Podányi, G. Tóth and I. Hermecz,
J. Chem. Soc., Perkin Trans. 1., 1999, 1789.
7 D. M. Doddrell, D. T. Pegg and M. R. Bendall, J. Magn. Reson.,
1982, 48, 323.
8 (a) A. McKillop, A. Henderson, P. S. D. Ray, Tetrahedron Lett.,
1982, 23, 3357; (b) A. McKillop, S. K. Chattopadhyay, A.
Henderson and C. Avendano, Synthesis, 1997, 301.
9 W. Tian, S. Grivas and K. Olsson, J. Chem. Soc., Perkin Trans. 1.,
1993, 257.
10 G. Tóth and B. Podányi, J. Chem. Soc., Perkin Trans. 2, 1984, 91.
11 (a) V. Markowski, G. R. Sullivan and J. D. Roberts, J. Am. Chem.
Soc., 1977, 99, 714; (b) N. C. Gonella, H. Nakanishi, J. B. Holtwick,
D. S. Horowitz, K. Kanamori, N. J. Leonard and J. D. Roberts,
J. Am. Chem. Soc., 1983, 105, 2050.
12 W. Wieker, D. Leibfritz, R. Kerssebaum and W. Bermel, Magn.
Reson. Chem., 1993, 31, 287.
13 Gaussian 98 (Revision A.1), M. J. Frisch, G. W. Trucks, H. B.
Schlegel, G. E. Scuseria, M. A. Robb, J. R. Cheeseman, V. G.
Zakrzewski, J. A. Montgomery, R. E. Stratmann, J. C. Burant,
S. Dapprich, J. M. Millam, A. D. Daniels, K. N. Kudin, M. C.
Strain, Ö. Farkas, J. Tomasi, V. Barone, M. Cossi, R. Cammi,
B. Mennucci, C. Pomelli, C. Adamo, S. Clifford, J. Ochterski,
G. A. Petersson, P. Y. Ayala, Q. Cui, K. Morokuma, D. K. Malick,
A. D. Rabuck, K. Raghavachari, J. B. Foresman, J. Cioslowski,
J. V. Ortiz, B. B. Stefanov, G. Liu, A. Liashenko, P. Piskorz,
I. Komaromi, R. Gomperts, R. L. Martin, D. J. Fox, T. Keith, M. A.
Al-Laham, C. Y. Peng, A. Nanayakkara, C. Gonzalez, M.
Challacombe, P. M. W. Gill, B. G. Johnson, W. Chen, M. W. Wong,
J. L. Andres, M. Head-Gordon, E. S. Replogle and J. A. Pople,
Gaussian, Inc., Pittsburgh PA, 1998.
Phosphoryl chloride (1.34 g, 0.81 mL, 8.6 mmol) was added
slowly to a suspension of 6 (1.00 g, 3.6 mmol) in DMF (2 mL).
The mixture was heated at 50 ЊC for 4 h, aged at room temper-
ature for 24 h, and then quenched into water (20 mL). The
precipitate was filtered off and the crude material (0.98 g) was
purified by flash chromatography. Off-white crystals (0.62 g,
1
55%), mp 118–120 ЊC, H NMR (400 MHz, DMSO-d6) δ 8.83
(s, 1H, 8-H); 13C NMR (100 MHz, DMSO-d6) δ 125.9 (C-6),
130.9 (C-8), 131.2 (C-7), 134.5 (C-4a), 138.8 (C-8a), 145.0
(C-5), 148.8, 149.0 (C-2,3); MS (EI): m/z 311 (Mϩ). Anal. calcd
for C8HCl4N3O2: C, 30.71; H, 0.32; N, 13.43. Found: C, 30.70;
H, 0.45; N, 13.25%.
3-Amino-6,7-dichloro-5-nitroquinoxalin-2(1H)-one (9)
3,6,7-Trichloro-5-nitroquinoxalin-2(1H)-one (7, 0.30 g,
1
mmol) was dissolved in ethanol (20 mL) saturated with ammo-
nia. The solution was heated at 70 ЊC for 8 h in a sealed tube.
The solvent was then removed, and the residue was washed with
chloroform, ethyl acetate and ethanol. Yellow crystals (0.20 g,
1
71%), mp > 300 ЊC, H NMR (400 MHz, DMSO-d6) δ 7.37 (s,
1H, 8-H), 7.77, 8.25 (each br s, each 1H, 3-NH2), 12.58 (br s,
1H, N(1)-H); 13C NMR (100 MHz, DMSO-d6) δ 115.4 (d,
JC4a,8H = 9.4, C-4a), 116.4 (d, JC8,8H = 169.3, C-8), 124.2
(d, JC7,8H = 4.6, C-7), 126.9 (d, JC6,8H = 7.3, C-6), 129.8 (d,
JC8a,8H = 2.6, C-8a), 143.4 (d, JC5,8H = 1.5, C-5), 151.1, 154.0
(each s, C-2,3); MS (EI): m/z 274 (Mϩ); νmax (KBr)/cmϪ1 3483,
3367, 1693. Anal. calcd for C8H4Cl2N4O3: C, 34.93; H, 1.47; N,
20.37. Found: C 35.25; H, 1.57; N, 20.13%.
Computational methods
All calculations were carried out with the Gaussian 98W
program.13 The geometries of the σ-complexes 3a1, 3ap1,
3a2 and 3ap2 were optimized at the semi-empirical AM1,14
ab initio Hartree–Fock15 and B3LYP16 level. For the ab initio
and the density functional methods, Dunning–Huzinaga full
double zeta basis sets17 were used. The energies of optimized
σ-complexes are given in Table 2. The energy differences
between 8-nitro- and 5-nitro-σ-complexes are listed in Table 3.
14 M. Dewar and W. Thiel, J. Am. Chem. Soc., 1977, 99, 4499.
15 C. C. J. Roothan, Rev. Mod. Phys., 1951, 23, 69.
16 A. D. Becke, J. Chem. Phys., 1993, 98, 5648.
17 T. H. Dunning Jr. and P. J. Hay, Modern Theoretical Chemistry III,
ed. H. F. Schaefer, Plenum, New York, 1976, vol. 3, p. 1.
18 G. M. Sheldrick, SHELXL97, Program for the Refinement of
Crystal Structures, University of Göttingen, Göttingen, Germany,
1997.
X-ray crystallographic study
The structure was solved by direct methods and refined by full
J. Chem. Soc., Perkin Trans. 1, 2000, 1417–1421
1421