Chemistry of halonitroethenes, 1: First synthesis of functionalized 3-chloroquinoxalin-2(1H)-one 4-oxides

Article abstract of DOI:10.1055/s-2008-1067207

A one-pot annulation reaction of aniline and its ring-substituted derivatives with 1,1,2-trichloro-2-nitroethene (TCNiE) was developed delivering 3-chloroquinoxalin-2(1H)-one 4-oxides, exclusively, in good yields. The structure was proved by X-ray analysis. The C-N cyclization, a competing reaction to the double S_NVin reaction of 1,1,2-trichloro-2- nitroethene with amines, can be controlled by the mode of addition. Some of the resulting quinoxalinones are promising candidates with respect to their prospective biological, especially pharmacological, activity. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2008-1067207

PAPER
2575
Chemistry of Halonitroethenes, 1: First Synthesis of Functionalized
3-Chloroquinoxalin-2(1H)-one 4-Oxides
S
ynthesis of Func
h
tionalized 3
r
-Chloroq
i
uinoxa
s
lin-2(1
H
)-
t
one 4-
i
O
xidesan Meyer,a Viktor A. Zapol’skii,a Arnold E. W. Adam,b Dieter E. Kaufmann*a
a
Institut für Organische Chemie, TU Clausthal, Leibnizstr. 6, 38678 Clausthal-Zellerfeld, Germany
Fax +49(5323)722834; E-mail: dieter.kaufmann@tu-clausthal.de
b
Institut für Anorganische und Analytische Chemie, TU Clausthal, Paul-Ernst-Str. 4, 38678 Clausthal-Zellerfeld, Germany
Received 29 February 2008; revised 11 April 2008
Exclusive formation of 1-chloro-1-nitro-2,2-bis(phenyl-
amino)ethene (3a) as a product of a twofold SNVin reac-
tion has already been reported by Declerqc et al.8 when a
solution of 2 was added to excess aniline (1a) in a solvent
Abstract: A one-pot annulation reaction of aniline and its ring-sub-
stituted derivatives with 1,1,2-trichloro-2-nitroethene (TCNiE) was
developed delivering 3-chloroquinoxalin-2(1H)-one 4-oxides, ex-
clusively, in good yields. The structure was proved by X-ray analy-
sis. The C–N cyclization, a competing reaction to the double SNVin such as diethyl ether at room temperature or below. This
reaction of 1,1,2-trichloro-2-nitroethene with amines, can be con-
twofold substitution reaction is not restricted to the parent
trolled by the mode of addition. Some of the resulting quinoxalin-
compound aniline itself, but also takes place with ring-
ones are promising candidates with respect to their prospective
substituted anilines such as 4-chloroaniline (1b). The
biological, especially pharmacological, activity.
mode of addition is crucial in determining the reaction
product that will be formed. Successive heating of 3a in a
polar solvent such as ethanol to at least 50 °C resulted in
Key words: annulation, C–N coupling, amines, halides, nitro com-
pounds, nitrones, quinoxalinones
isomerization to an amidine, generating a CH(Cl)NO2
group simultaneously, which then leads to a Friedel–
Crafts-type cyclization reaction forming 3-nitro-2-(phe-
Halonitroalkenes are valuable building blocks for the di-
rected synthesis of four-, five-, and six-membered hetero-
nylamino)-1H-indole (4a), as mentioned by Perekalin et
cycles with a unique substitution pattern.1 In particular, to
date an impressive number of different reactions of pen-
tachloro-2-nitrobuta-1,3-diene have been documented;2
further efforts are underway to explore the whole synthet-
ic potential of this class of compounds. The group of
known halonitroethenes is still rather small, consisting of
14 members, which have been prepared by four different
synthetic routes.3,4 Synthetic applications of halonitro-
ethenes are rare in the literature.5 In this context we be-
came interested in the availability and chemistry of 1,1,2-
trichloro-2-nitroethene (TCNiE, 2), a perchlorovinyl ana-
logue of nitryl chloride, representing the reactive key unit
of many polychloroalkenes. 1,1,2-Trichloro-2-nitroeth-
ene (2) is now easily accessible by electrophilic nitration
of the inexpensive industrial solvent trichloroethene with
nitric acid.3k,4 Nitration of a solution of trichloroethene in
cyclohexane in a liquid–liquid extractor with nitric acid at
comparatively low temperatures leads to lower amounts
of oxidative destruction and, thus, to a higher yield of 2.
Careful control of the reaction and distillation conditions
allows the synthesis of 2 on a 100 g scale and with high
purity.
al.7a (Scheme 1).
When the mode of addition is reversed, thus the aniline
solution (1 equiv) is slowly added by a syringe pump to a
solution of 2 (1 equiv) at temperatures between –10 and
50 °C under isothermal conditions, to our surprise a new
product precipitated, independent of the solvent used
(Scheme 2). Due to the 1:1 ratio of the starting materials
2 and 1a, an intermediate such as 5 or an equivalent is
formed. The low solubility of the product in combination
with its high melting point and the NMR, IR, and MS
spectra made formation of the 3-chloroquinoxalin-2(1H)-
NO2
R
PhHN
PhHN
NO2
Cl
b
a
N
H
NHPh
NH2
3a (53%)8
3b (59%)
4a
1a
1b
R = H
Cl
a: 2 (TCNiE), Et2O, 0 °C
b: EtOH, 78 °C
Scheme 1 Formation of 3-nitroindole 4a starting from 1a and 2 (4:1)
Most reactions of 2 known in the literature start with pri-
mary Michael addition, then lead to the product of a
SNVin reaction of 3;6 only one synthetic example has been
reported of subsequent cyclization with C–C coupling.7
Therefore, we started with a detailed investigation of the
reaction of 1,1,2-trichloro-2-nitroethene (2) with anilines.
O
N
Cl
O
Cl
Cl
NO2
Cl
PhHN
Cl
NO2
Cl
a
N
H
2
5
6
a: PhNH2, Et3N, MeOH, 1 h, 40 °C
73%
SYNTHESIS 2008, No. 16, pp 2575–2581
x
x.
x
x
.
2
0
0
8
Advanced online publication: 30.07.2008
DOI: 10.1055/s-2008-1067207; Art ID: T03508SS
© Georg Thieme Verlag Stuttgart · New York
Scheme 2 Formation of quinoxalinone 4-oxide 6 starting from 2
and 1a (1:1)

2576
C. Meyer et al.
PAPER
O
O
N
O
O
HO
N
N
Cl
O
N
S
C12H25SH
~ H+
O
1
C12H25
Cl
Cl
Cl
2
NaOEt, MeOH
10 h, 45 °C
N
N
MeO
N
H
MeO
N
H
O
Cl
Cl
H
H2
Cl
7
8
9
10
– H2O
89%
Scheme 3 Transformation of 7 to a soluble derivative 8
O
N
O
N
Cl
Cl
Cl
+ H2O, 2 Et3N
– 2 HNEt3Cl
one 4-oxide (6) appear likely. An unambiguous spectro-
scopic analysis of the product proved difficult.
N
H
O
N
H
Cl
Additionally, single crystals could not be obtained by re-
crystallization. Fortunately, the C–Cl group of the C-chlo-
6
11
ronitrone unit of
7
allowed SN reactions. By
Scheme 4 Postulated mechanism for the formation of 6
transformation of the 7-methoxy derivative 7 into 8 using
the strong nucleophile dodecane-1-thiol, the long alkyl
chain improved the solubility and we were able to isolate
single crystals of 3-(dodecylsulfanyl)-7-methoxyquinoxa-
lin-2(1H)-one 4-oxide (8) (Scheme 3). X-ray analysis
confirmed the structure (Figure 1).9
tuted derivatives by means of SN reactions. A small num-
ber of syntheses for 3-alkyl- and 3-arylquinoxalin-2(1H)-
ones 4-oxides are known.12
Various bioactivities of quinoxalinones and their corre-
sponding N-oxides have been reported, some examples
are noteworthy: antibacterial, antiviral, anticancer, anti-
fungal, antihelmintic, and insecticidal activities are
documented13a–13e as well as their potential as antiallergic
agents.13f Additionally, the variety of pharmacological
agents can be illustrated by antimalarial activity.13g There-
fore, the new heterocyclic compounds present interesting
entities for biological screening.
To evaluate the synthetic scope and limitation of this an-
nulation reaction, all reaction conditions were modified in
a stepwise process. If one equivalent of aniline or a deriv-
ative and two equivalents of a tertiary amine such as tri-
ethylamine or 1,4-diazabicyclo[2.2.2]octane were added
to a solution of 2 in a solvent such as methanol, tetrahy-
drofuran, or toluene, the new quinoxalin-2(1H)one 4-ox-
ide 6 precipitated completely (Scheme 2). The product
yield always depended on the reaction temperature, the
addition rate of the aniline to the reaction mixture, the sol-
vent, and the substitution pattern of the aniline.
Figure 1 X-ray crystal structure of the quinoxalin-2-one derivative
89
The detailed mechanism of formation of the parent hetero-
cycle 6 remains unclear. Apparently, the reaction starts
with Michael addition of the aromatic amine at the C2 po-
sition of 1,1,2-trichloro-2-nitroethene (2) forming an in-
termediate such as 9. N-Alkylanilines do not form
quinoxalinones. Then a proton shift occurs: the ammoni-
um proton migrates to the nitro group thus forming a ni-
tronic acid 10. In the following steps an intramolecular SE
process appears feasible under C–N cyclization and elim-
ination of water generating 2,2,3-trichloro-1,2-dihydro-
quinoxaline 4-oxide (11). Hydrolysis of the gem-C2
dichloride unit in 11 by water in the reaction leads to for-
mation of the final product 6, even in dry solvents
(Scheme 4).
The annulation reaction was exothermic. Under isother-
mal conditions the product yield increased with higher re-
action temperatures. Reaction rate and yield were also
dependent on the ring substituents of the aniline deriva-
tives (Figure 2). In a number of cases the reaction was al-
most complete within 1–3 hours. Not all reactions were
optimized with respect to time.
The product yield of 7 was not strongly dependent on the
nature of the reaction solvent (Table 1); methanol and tet-
rahydrofuran were especially well suited. Only in the case
of acetonitrile did the yield decreased.
Syntheses of such 3-haloquinoxalin-2(1H)-ones 4-oxides
are completely unknown. Additionally, this type of ring-
closure reaction has not previously been reported under
comparable conditions. Only the cyclization of nitro-
enamines containing a heteroaromatic or oxido-substituted
aromatic base is known, but the reaction proceeds under
strong acidic conditions and in low yields.11 Additionally,
6 represents a key compound for the synthesis of 3-substi-
The broad range of applicability of this annulation reac-
tion is documented in Table 2, many different substituents
are tolerated.
In the case of m-anisidine the reaction was highly regiose-
lective. Only the 3-chloro-7-methoxyquinoxalin-2(1H)-
Synthesis 2008, No. 16, 2575–2581 © Thieme Stuttgart · New York

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Synthesis of Functionalized 3-Chloroquinoxalin-2(1H)-one 4-Oxides
2577
Table 1 Yields of Quinoxalinone 7 in Various Solventsa
Table 3 Yields of Various Quinoxalinones under Identical Reaction
Conditionsa
Solvent
MeOH
THF
Yield (%)
Product
Yield (%)
66
74
62
39
6
7
63
65
51
16
42
9
toluene
MeCN
12
17
18
19
a Reaction conditions: Et3N (2 equiv), r.t., 12 h.
Table 2 Range of Newly Synthesized 3-Chloroquinoxalin-2(1H)-
one 4-Oxidesa
a Reaction conditions: Et3N (2 equiv), MeOH, 30 °C, 1 h.
R4
O
N
R3
R2
Cl
O
N
H
R1
R1
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Cl
Cl
H
R2
R3
H
R4
H
H
H
H
H
OH
H
H
H
H
H
H
H
H
H
H
H
Product
6
Yield (%)
73
H
OMe
H
H
7
73
OMe
OMe
H
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
54
OMe
OH
H
40
59b
6b
H
Figure 2 Correlation between yield of 6 and 12 and the reaction
temperature [Et3N (2 equiv), MeOH, 1 h]
F
H
30
H
F
48
such as the halogens F and Cl, had a negative effect on the
reaction rate (Table 3) as did electron-donating methoxy
groups at C6 or C7 (Figure 2).
H
Cl
66
Cl
H
H
59
In conclusion, we have found a novel one-pot synthesis of
a broad range of substituted 3-chloroquinoxalin-2(1H)-
ones starting from easily accessible 1,1,2-trichloro-2-ni-
troethene (2) and subsequent addition of substituted
anilines. This addition mode is crucial. The structure of a
long-chain derivative was proven by X-ray. The products
should offer interesting biological, in particular pharma-
cological, properties. Therefore, corresponding tests of
these promising compounds are presently underway.
Br
I
74
H
79
H
CO2H
CN
Cl
77
H
65
H
43
Cl
H
H
35
Me
16
All chemicals were obtained from commercial suppliers and used
without further purification. MeOH was purchased as reagent
grade. Melting points were determined with a Büchi apparatus 520
a Reaction conditions: Et3N (2 equiv), MeOH, r.t. to 30 °C, 1–62 h.
b Parallel formation of 14/15 from 2 and 3-aminophenol.
1
1
and are uncorrected. H and H-decoupled 13C NMR spectra were
measured on a Bruker Avance 400 (400 MHz) or Bruker DPX 200
(200 MHz) in CDCl3 or DMSO-d6. All NMR data are reported
downfield from TMS as the internal standard. The 14N NMR spec-
trum was externally referenced: MeNO2, d = 0.0. IR spectral data
were obtained for liquids as film and for solids as KBr discs on a
Bruker Vector 22 FT-IR. Mass spectra were recorded on a Hewlett
Packard MS 5989B (EI, 70 eV). In the case of chlorinated com-
pounds, all peak values of molecular ions as well as fragments m/z
refer to the isotope 35Cl. HRMS were measured with a Finnigan
MAT 95 sector field instrument (EI) or with a Bruker APEX IV 7
one 4-oxide (7) could be isolated from the reaction mix-
ture. For 3-aminophenol, we obtained 3-chloro-5-hy-
droxyquinoxalin-2(1H)-one 4-oxide (15) in only 6% yield
and the 7-hydroxy derivative 14 in 59% yield.
Under identical reaction conditions the yields of the 3-
chloroquinoxalin-2(1H)-ones 4-oxides depend strongly
on the substituents of the introduced anilines, ranging
from 9 to 65%. Electron-withdrawing substituents at C6,
Synthesis 2008, No. 16, 2575–2581 © Thieme Stuttgart · New York

2578
C. Meyer et al.
PAPER
Tesla FT ion cyclotron resonance mass spectrometer (ESI). TLC
was performed on Merck TLC plates (aluminum-backed) silica gel
60 F 254. Flash chromatography was carried out on silica gel 60
(Merck).
7.40 (dd, J = 8.3, 0.5 Hz, 1 H, H7), 7.36 (ddd, J = 8.6, 7.4, 1.0 Hz,
1 H, H8).
13C NMR (100 MHz, DMSO-d6): d = 153.4 (C2), 133.9, 132.5,
131.0 (C3), 130.4, 123.9, 119.4, 116.6.
MS (EI): m/z (%) = 196 (M+) (100), 180 (M+ – O) (5), 166 (M+ –
NO) (58).
HRMS (ESI): m/z [M + H]+ calcd for C8H6ClN2O2: 197.01122;
found: 197.01123.
1,1,2-Trichloro-2-nitroethene (2)
A mixture of concd HNO3 (900 mL, 65%) and cyclohexane (200
mL) in the extractor vessel of a rotating Normag liquid–liquid ex-
tractor for solvents lighter than H2O was heated in an oil bath to 55
°C. Trichloroethene (250 mL, 2.81 mol) and cyclohexane (100 mL)
was added to the evaporator vessel. After continuous reaction and
extraction for 9 h the organic layers were separated and washed with
H2O and brine. Redistillation on a Fischer Spaltrohr column HMC
500 C gave pure 2; yield: 96.9 g (32%) related to reisolated trichlo-
roethene (139 g, 1.06 mol); bp 56–57 °C/25 mbar.
3-Chloro-7-methoxyquinoxalin-2(1H)-one 4-Oxide (7); Typical
Procedure II
Under N2 at r.t. a soln of m-anisidine (1.11 mL, 10 mmol) and Et3N
(2.88 mL, 20 mmol) in anhyd MeOH (20 mL) was added via syringe
pump over 12 h with stirring to a soln of 2 (1.76 g, 10 mmol) in an-
hyd MeOH (10 mL). The product precipitated from the mixture and
was isolated by filtration with suction. The solid was washed with
MeOH, dil aq HCl, H2O, and Et2O and subsequently dried in vacuo
to give 7 as a pale green solid; yield: 1.67 g (73%); mp 246–247 °C
(dec).
IR (NaCl): 2868, 2623, 2361, 2342, 1548, 1324, 1052, 933, 871,
777, 750, 707 cm–1.
13C NMR (100 MHz, CDCl3): d = 136.5 (CClNO2); 128.1 (CCl2).
14N NMR (28.9 MHz, CDCl3): d = –18.6.
MS (EI): m/z (%) = 177 (M+) (44), 129 (M+ – O) (100), 94 (M+ –
ClNO2) (44).
HRMS (EI): m/z [M]+ calcd for C2Cl3NO2: 174.8995; found:
174.8996.
IR (KBr): 3122, 3085, 3029, 2948, 2914, 1679 (C=O), 1613, 1534,
1494, 1439, 1385, 1341, 1307, 1233, 1217, 1171, 1110, 1024, 838,
587 cm–1.
1H NMR (200 MHz, DMSO-d6): d = 12.65 (br s, 1 H, NH), 8.05 (d,
J = 9.3 Hz, 1 H, H5), 6.98 (dd, J = 9.3, 2.5 Hz, 1 H, H6), 6.82 (d,
J = 2.5 Hz, 1 H, H8), 3.85 (s, 3 H, OCH3).
13C NMR (50 MHz, DMSO-d6): d = 162.1 (C2), 153.7 (C7), 132.9
(C9), 131.4 (C3), 125.0 (C10), 121.1(C5), 112.3 (C6), 98.8 (C8),
56.1 (OCH3).
1-Chloro-2,2-bis(4-chlorophenylamino)-1-nitroethene (3b)
To a mixture of 4-chloroaniline (1b, 5.19 g, 41.9 mmol) in anhyd
MeOH (10 mL) at 10 °C was added dropwise over 1 h a soln of 2
(1.76 g, 10 mmol) in anhyd MeOH (10 mL). The resulting brown
soln was stirred for an additional 2 h. Subsequently, an N2 stream
was passed through the mixture to remove the solvent. The precip-
itate was isolated and washed with H2O (50 mL), aq 4 M HCl (20
mL), and H2O (30 mL), and finally dried in vacuo to give a green
solid; yield: 2.13 g (59%); mp 129–130 °C (dec).
MS (EI): m/z (%) = 226 (M+) (95), 210 (M+ – O) (7), 196 (M+ – NO)
(100).
Anal. Calcd for C9H7ClN2O3 (226.62): C, 47.70; H, 3.11; Cl, 15.64;
N, 12.36. Found: C, 47.71; H, 3.12; Cl, 15.78; N, 12.33.
IR (KBr): 3060, 3014, 2878, 1679, 1590, 1571, 1471, 1442, 1415,
1319, 1271, 1203, 1130, 1071, 1035, 1004, 941, 867, 819, 798, 749
cm–1.
1H NMR (200 MHz, DMSO-d6): d = 10.43 (br s, 2 H, NH), 7.29 (d,
J = 8.8 Hz, 4 H, H3Ph, H3¢Ph, H5Ph, H5¢Ph), 7.11 (d, J = 8.8 Hz, 4 H,
H2Ph, H2¢Ph, H6Ph, H6¢Ph).
13C NMR (50 MHz, DMSO-d6): d = 149.3 (1 C, NCN), 137.4 (2 C,
C1Ph, C1¢Ph), 129.0 [4 C, C3Ph, C3¢Ph, C5Ph, C5¢Ph), 128.7 (2 C, C4Ph,
C4¢Ph), 123.0 (4 C, C2Ph, C2¢Ph, C6Ph, C6¢Ph), 106.4 (1 C, ClCNO2).
3-Chloro-6-methoxyquinoxalin-2(1H)-one 4-Oxide (12); Typi-
cal Procedure III
Under N2 at r.t. a soln of p-anisidine (1.23 g, 10 mmol) and DABCO
(1.12 g, 10 mmol) in anhyd MeOH (20 mL) was added via syringe
pump over 12 h with stirring to a soln of 2 (1.76 g, 10 mmol) in an-
hyd MeOH (10 mL). The product precipitated from the mixture and
was isolated by filtration with suction. The solid was washed with
MeOH, dil aq HCl, H2O, and Et2O and subsequently dried in vacuo
to give 12 as a green solid; yield: 1.23 g (54%); mp 234–235 °C
(dec).
MS (EI): m/z (%) = 356 (M+) (13), 312 (M+ – NO2) (22), 127
(C6H6NCl+) (100).
IR (KBr): 2979, 2943, 2902, 2824, 1665 (C=O), 1603, 1530, 1489,
1440, 1407, 1373, 1353, 1273, 1222, 1132, 1026, 847, 772, 677,
549 cm–1.
1H NMR (200 MHz, DMSO-d6): d = 12.70 (br s, 1 H, NH), 7.49 (d,
J = 1.4 Hz, 1 H, H5), 7.28–7.38 (m, 2 H, H7, H8), 3.83 (s, 3 H,
OCH3).
HRMS (EI): m/z [M]+ calcd for C14H10Cl3N3O2: 356.9839; found:
356.9839.
3-Chloroquinoxalin-2(1H)-one 4-Oxide (6); Typical Procedure
I
Under N2 at 40 °C a soln of aniline (1a, 0.46 mL, 5 mmol) and Et3N
(1.44 mL, 10 mmol) in anhyd MeOH (15 mL) was added via syringe
pump over 1 h with stirring to a soln of 2 (0.88 g, 5 mmol) in anhyd
MeOH (5 mL). The product precipitated from the mixture and was
isolated by filtration with suction. The solid was washed with
MeOH, diluted aq HCl, H2O, and MeOH and subsequently dried in
vacuo to give 6 as a pale beige solid; yield: 0.72 g (73%); mp 225–
226 °C (dec).
13C NMR (100 MHz, DMSO-d6): d = 155.9 (C2), 152.8 (C6), 134.2
(C3), 130.9 (C9 or C10), 125.1 (C9 or C10), 121.7, 118.0, 101.0,
56.0 (OCH3).
MS (EI): m/z (%) = 226 (M+) (100), 210 (M+ – O) (7), 196 (M+ –
NO) (18).
Anal. Calcd for C9H7ClN2O3 (226.62): C, 47.70; H, 3.11; Cl, 15.64;
N, 12.36. Found: C, 47.60; H, 3.10; Cl, 15.36; N, 12.26.
IR (KBr): 2979, 2943, 2902, 2824, 1665 (C=O), 1603, 1530, 1489,
1440, 1407, 1373, 1353, 1273, 1222, 1132, 1026, 847, 772, 677,
549 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 12.77 (br s, 1 H, NH), 8.12 (dd,
J = 8.5,1.3 Hz, 1 H, H5), 7.88 (ddd, J = 8.3, 7.2, 1.3 Hz, 1 H, H6),
3-Chloro-6,7-dimethoxyquinoxalin-2(1H)-one 4-Oxide (13)
Following typical procedure I gave 13 as a pale green solid; yield:
40%; mp 268–269 °C (dec).
IR (KBr): 3138, 3083, 3038, 2942, 1672 (C=O), 1630, 1604, 1527,
1511, 1460, 1442, 1426, 1411, 1379, 1333, 1307, 1256, 1213, 1187,
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Synthesis of Functionalized 3-Chloroquinoxalin-2(1H)-one 4-Oxides
2579
1119, 1030, 1003, 927, 855, 830, 792, 769, 723, 688, 664, 624, 575,
541, 527 cm–1.
3-Chloro-5-hydroxyquinoxalin-2(1H)-one 4-Oxide (15)
Orange solid; yield: 6%; mp 274–275 °C (dec).
1H NMR (400 MHz, DMSO-d6): d = 12.64 (br s, 1 H, NH), 7.52 (s,
1 H, H5), 6.82 (s, 1 H, H8), 3.84 (s, 3 H, OCH3). 3.83 (s, 3 H,
OCH3).
IR (KBr): 3423, 3121, 3019, 2929, 2862, 1665 (C=O), 1625, 1608,
1513, 1450, 1374, 1338, 1306, 1238, 1174, 1144, 1130, 1088, 866,
810, 758, 596 cm–1.
13C NMR (100 MHz, DMSO-d6): d = 153.2 (C6), 153.0 (C7) 146.5
(C2), 131.6 (C3), 126.1, 124.2, 100.3, 98.0, 56.3 (OCH3), 56.2
(OCH3).
1H NMR (400 MHz, DMSO-d6): d = 13.02 (s, 1 H, OH), 12.82 (br
s, 1 H, NH), 7.47 (dd, J = 8.3, 8.3 Hz, 1 H, H7), 6.79 (dd, J = 8.3,
1.2 Hz, 1 H, H6 or H8) 6.72 (dd, J = 8.3, 1.2 Hz, 1 H, H6 or H8).
MS (EI): m/z (%) = 256 (M+) (100), 24 (M+ – O) (10), 226 (M+ –
NO) (60), 150 (30).
13C NMR (100 MHz, DMSO-d6): d = 152.8 (C2), 152.4 (C5), 133.7
(C3), 133.4 (C7), 132.4 (C10), 117.6 (C9), 110.6 (C8), 106.2 (C6).
HRMS (ESI): m/z [M + H]+ calcd for C10H10ClN2O4: 257.03236;
MS (EI): m/z (%) = 212 (M+) (72), 196 (M+ – O) (22), 182 (M+ –
found: 257.03236.
NO) (100).
Anal. Calcd for C8H5ClN2O3 (212.59): C, 45.20; H, 2.37; Cl, 16.68;
N, 13.18. Found: C, 45.15; H, 2.37; Cl, 16.52; N, 12.78.
3-(Dodecylsulfanyl)-7-methoxyquinoxalin-2(1H)-one 4-Oxide
(8)
Under N2 at r.t. a suspension of 3-chloro-7-methoxyquinoxalin-
2(1H)-one 4-oxide (7, 1.00 g, 4.41 mmol), NaOEt (0.721 g, 10.59
mmol), and dodecane-1-thiol (1.95 g, 9.71 mmol) in anhyd MeOH
(10 mL) was stirred for 1 h. Subsequently, the mixture was heated
to 50 °C for 10 h. After cooling to r.t., dil aq HCl was added. The
product precipitated from the mixture and was isolated by filtration
with suction. The solid was washed with dil aq HCl, H2O, and
MeOH and then dried in vacuo to obtain 8 as a yellow solid; yield:
1.56 g (89%); mp 138–140 °C.
3-Chloro-7-fluoroquinoxalin-2(1H)-one 4-Oxide (16)
Following typical procedure I gave 16 as a white solid; yield: 30%;
mp 218–219 °C (dec).
IR (KBr): 3072, 2987, 2908, 2863, 2819, 2706, 1667 (C=O), 1627,
1611, 1535, 1492, 1439, 1367, 1317, 1267, 1128, 1103, 1090, 974,
876, 861, 823, 798, 733, 656, 592, 483 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 12.83 (br s, 1 H, NH), 8.16 (dd,
J = 9.4 Hz, JHF = 5.5 Hz, 1 H, H5), 7.19–7.25 (m, 1 H, H6), 7.11
(dd, J = 2.7 Hz, JHF = 9.2 Hz, 1 H, C8).
13C NMR (100 MHz, DMSO-d6): d = 163.5 (d, J = 249.4 Hz, C7),
153.6 (C2), 133.4 (C3), 132.7 (d, J = 13.2 Hz, C9), 127.5 (d, J = 1.5
Hz, C10), 122.4 (d, J = 11.0 Hz, C5), 111.8 (d, J = 24.2 Hz, C6),
102.6 (d, J = 27.1 Hz, C8).
IR (KBr): 3129, 3078, 3038, 2954, 2920, 2851, 1666 (C=O), 1657,
1616, 1530, 1467, 1378, 1333, 1308, 1264, 1251, 1220, 1182, 1158,
1033, 961, 868, 843, 816, 768, 735, 721, 694, 647, 530 cm–1.
1H NMR (200 MHz, CDCl3): d = 12.38 (br s, 1 H, NH), 8.20 (d,
J = 9.3 Hz, 1 H, H5), 6.92 (dd, J = 9.3, 2.5 Hz, 1 H, H6), 6.83 (d,
J = 2.5 Hz, 1 H, H8), 3.92 (s, 3 H, OCH3), 3.48 (t, J = 7.4 Hz, 2 H,
SCH2), 1.60–1.74 (m, 2 H, SCH2CH2), 1.36–1.50 (m, 2 H,
SCH2CH2CH2), 1.16–1.28 (m, 16 H, HAlkyl), 0.87 (t, J = 6.8 Hz, 3 H,
CH2CH3).
MS (EI): m/z (%) = 214 (M+) (100), 198 (M+ – O) (45), 184 (M+ –
NO) (70), 108 (M+ – C2NO2Cl) (48).
HRMS (EI): m/z [M]+ calcd for C8H4ClFN2O2: 213.9945; found:
213.9945.
13C NMR (50 MHz, CDCl3): d = 162.0, 158.4, 138.0, 131.5, 125.9,
121.0, 113.2, 98.6, 55.9 (OCH3), 31.9, 31.8, 30.5, 29.6, 29.6, 29.5,
29.4, 29.3, 29.1, 28.8, 22.6, 14.1.
3-Chloro-6-fluoroquinoxalin-2(1H)-one 4-Oxide (17)
Following typical procedure I gave 17 as a green solid; yield: 48%;
mp 214–215 °C (dec).
Anal. Calcd for C21H32N2O3S (392.56): C, 64.25; H, 8.22; N, 7.14;
S, 8.17. Found: C, 64.37; H, 8.17; N, 7.04; S 8.44.
IR (KBr): 2990, 2947, 2902, 1653 (C=O), 1524, 1483, 1441, 1404,
1349, 1295, 1256, 1203, 1124, 1075, 880, 830, 781, 672, 640, 535
cm–1.
1H NMR (400 MHz, DMSO-d6): d = 12.83 (br s, 1 H, NH), 7.89 (dd,
JHF = 9.2 Hz, J = 2.9 Hz, 1 H, H5), 7.63–7.57 (m, 1 H, H7), 7.43
(dd, J = 9.1 Hz, JHF = 4.8 Hz, 1 H, H8).
13C NMR (100 MHz, DMSO-d6): d = 158.1 (d, J = 242.1 Hz, C6),
153.2 (C2), 135.0 (C3), 130.8 (d, J = 10.2 Hz, C10), 128.0 (d,
J = 1.5 Hz, C9), 120.7 (d, J = 24.2 Hz, C7), 118.7 (d, J = 8.8 Hz,
C8), 105.7 (d, J = 28.6 Hz, C5).
3-Chloro-7-hydroxyquinoxalin-2(1H)-one 4-Oxide (14) and
3-Chloro-5-hydroxyquinoxalin-2(1H)-one 4-Oxide (15)
Following typical procedure II, addition time 62 h. The precipitated
solid was a mixture of 2 regioisomers. The 7-hydroxyquinoxalinone
14 was separated by washing the solid with CHCl3 (50 mL) and
acetone (50 mL). Subsequently, the second isomer 15 was isolated
by evaporating the solvents.
3-Chloro-7-hydroxyquinoxalin-2(1H)-one 4-Oxide (14)
Red-brown solid; yield: 59%; mp 276–277 °C.
MS (EI): m/z (%) = 214 (M+) (100), 198 (M+ – O) (45), 184 (M+ –
NO) (70), 108 (M+ – C2NO2Cl) (48).
IR (KBr): 3343, 3094, 3010, 2941, 2843, 1661 (C=O), 1630, 1608,
1543, 1489, 1432, 1347, 1324, 1291, 1239, 1182, 1107, 850, 602,
498 cm–1.
1H NMR (200 MHz, DMSO-d6): d = 12.56 (br s, 1 H, NH), 10.66
(s, 1 H, OH), 7.97 (d, J = 9.1 Hz, 1 H, H5), 6.73–6.82 (m, 2 H, H6,
H8).
13C NMR (100 MHz, DMSO-d6): d = 161.1 (C2), 153.7 (C7), 132.7
(C10), 130.7 (C3), 124.2 (C9), 121.2 (C5), 113.3 (C6), 100.5 (C8).
MS (EI): m/z (%) = 212 (M+) (100), 196 (M+ – O) (5), 182 (M+ –
NO) (100).
HRMS (EI): m/z [M]+ calcd for C8H4ClFN2O2: 213.9945; found:
213.9945.
3,6-Dichloroquinoxalin-2(1H)-one 4-Oxide (18)
Following typical procedure I gave 18 as a green solid; yield: 66%;
mp 242–243 °C (dec).
IR (KBr): 2995, 2926, 2892, 2854, 2697, 1651 (C=O), 1620, 1517,
1473, 1441, 1395, 1351, 1299, 1261, 1135, 1113, 885, 820, 670,
518 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 12.86 (br s, 1 H, NH), 8.06 (s,
1 H, H5), 7.71 (dd, J = 8.8, 2.1 Hz, 1 H, H7), 7.38 (d, J = 8.8 Hz, 1
H, H8).
Anal. Calcd for C8H5ClN2O3 (212.59): C, 45.20; H, 2.37; Cl, 16.68;
N, 13.18. Found: C, 44.92; H, 2.41; Cl, 16.66; N, 12.81.
Synthesis 2008, No. 16, 2575–2581 © Thieme Stuttgart · New York

2580
C. Meyer et al.
PAPER
3-Chloro-2-oxo-1,2-dihydroquinoxaline-6-carboxylic Acid
13C NMR (100 MHz, DMSO-d6): d = 153.2 (C2), 134.9 (C3), 132.5
(C5), 130.9, 130.1, 127.7, 118.7 (C7 or C8), 118.6 (C7 or C8).
4-Oxide (22)
Following typical procedure I gave 22 as a yellow solid; yield: 77%;
mp 234 °C (dec).
MS (EI): m/z (%) = 230 (M+) (100), 214 (M+ – O) (12), 200 (M+ –
NO) (63).
IR (KBr): 3454 (O–H), 3165, 3105, 2960, 2702, 2627, 2551, 1904,
1699 (C=O), 1627, 1536, 1491, 1432, 1402, 1346, 1288, 1259,
1234, 1170, 1143, 1109, 1077, 1003, 954, 920, 849, 788, 768, 740,
685, 672, 633, 571, 444 cm–1.
1H NMR (200 MHz, DMSO-d6): d = 13.30 (br s, 1 H, NH), 13.00
(br s, 1 H, COOH), 8.60 (d, J = 1.9 Hz, 1 H, H5), 8.15 (dd, J = 8.6,
1.9 Hz, 1 H, H7) 7.44 (d, J = 8.6 Hz, 1 H, H8).
Anal. Calcd for C8H4Cl2N2O2 (229.96): C, 41.59; H, 1.75; Cl,
30.69; N, 12.13. Found: C, 41.43; H, 1.71; Cl, 30.54; N, 12.02.
3,7-Dichloroquinoxalin-2(1H)-one 4-Oxide (19)
Following typical procedure I gave 19 as a green solid; yield: 59%;
mp 242–243 °C (dec).
IR (KBr): 3442, 3141, 3084, 2604, 1677 (C=O), 1619, 1480, 1429,
1360, 1236, 1134, 1081, 1036, 933, 871, 808, 732, 686, 634, 558,
472 cm–1.
13C NMR (50 MHz, DMSO-d6): d = 166.2 (COOH), 153.6 (C2),
134.6 (C3), 134.3, 132.7, 130.2, 125.9, 121.0, 117.1.
1H NMR (200 MHz, DMSO-d6): d = 12.95 (br s, 1 H, NH), 8.11–
8.15 (s, 1 H, H5), 7.39–7.45 (m, 2 H, H6 and H8).
MS (EI): m/z (%) = 240 (M+) (45), 210 (M+ – NO) (31), 204 (M+ –
HCl).
13C NMR (50 MHz, DMSO-d6): d = 153.2, 136.3, 133.9, 131.8,
129.1, 123.6, 121.2, 115.5.
HRMS (EI): m/z [M]+ calcd for C9H5ClN2O4: 239.9938; found:
239.9938.
MS (EI): m/z (%) = 230 (M+) (50), 214 (M+ – O) (10), 200 (M+ –
NO) (70), 77 (C6H5 ) (100).
HRMS (ESI): m/z [M + H]+ calcd for C8H5Cl2N2O2: 230.97229;
found: 230.97226.
3-Chloro-2-oxo-1,2-dihydroquinoxaline-6-carbonitrile 4-Oxide
(23)
Following typical procedure I gave 23 as a yellow solid; yield: 65%;
mp 243 °C (dec).
+
IR (KBr): 3163, 3075, 2933, 2230 (C≡N), 1665 (C=O), 1621, 1526,
1473, 1441, 1403, 1352, 1299, 1262, 1202, 1153, 1124, 1091, 953,
920, 890, 848, 809, 741, 677, 642, 598, 588, 556, 517 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 13.12 (br s, 1 H, NH), 8.54 (d,
J = 1.9 Hz, 1 H, H5), 8.05 (dd, J = 8.6, 1.9 Hz, 1 H, H7) 7.50 (d,
J = 8.6 Hz, 1 H, H8).
6-Bromo-3-chloroquinoxalin-2(1H)-one 4-Oxide (20)
Following typical procedure I gave 20 as a yellow solid; yield: 74%;
mp 245 °C (dec).
IR (KBr): 3110, 3035, 2993, 2851, 2808, 2697, 1904, 1759, 1655
(C=O), 1615, 1515, 1471, 1440, 1389, 1349, 1304, 1279, 1262,
1229, 1176, 1157, 1134, 1109, 954, 902, 883, 859, 817, 733, 699,
505 cm–1.
1H NMR (200 MHz, DMSO-d6): d = 13.11 (br s, 1 H, NH), 8.52 (d,
J = 1.8 Hz, 1 H, H5), 8.05 (dd, J = 8.6, 1.8 Hz, 1 H, H7), 7.49 (d,
J = 8.6 Hz, 1 H, H8).
13C NMR (100 MHz, DMSO-d6): d = 153.6 (C2), 135.2, 134.6,
130.4, 124.5, 118.1 (CN), 117.9, 105.8. C3 was not detected.
MS (EI): m/z (%) = 221 (M+) (85), 205 (M+ – O)(100), 191 (M+ –
NO) (42), 185 (M+ – HCl), 177 (M+ – N2O) (95).
13C NMR (50 MHz, DMSO-d6): d = 153.5 (C2), 135.2 (C5), 134.6
(C3), 130.3, 124.5 (C7), 118.0, 117.9 (C8), 105.8.
HRMS (EI): m/z [M]+ calcd for C9H4ClN3O2: 220.9992; found:
220.9992.
MS (EI): m/z (%) = 276 (M+) (100), 260 (M+ – O) (21), 246 (M+ –
NO) (55).
3,6,8-Trichloroquinoxalin-2(1H)-one 4-Oxide (24)
Following typical procedure I gave 24 as a yellow solid; yield: 43%;
mp 235 °C (dec).
Anal. Calcd for C8H4ClBrN2O2 (275.49): C, 34.88; H, 1.46; Cl,
12.87; Br, 29.00; N, 12.87. Found: C, 34.88; H, 1.48; Cl, 12.75; Br,
29.14; N, 12.75.
IR (KBr): 3085, 3036, 2908, 2814, 1866, 1808, 1782, 1752, 1656
(C=O), 1611, 1511, 1438, 1420, 1395, 1344, 1312, 1294, 1250,
1198, 1177, 1122, 944, 909, 894, 878, 827, 735, 708, 659, 607, 570,
523, 499, 474 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 12.56 (br s, 1 H, NH), 8.14 (d,
J = 2.4 Hz, 1 H, H5), 8.06 (d, J = 2.4 Hz, 1 H, H7).
13C NMR (100 MHz, DMSO-d6): d = 153.6 (C2), 135.2 (C3), 132.0
(C7), 129.1, 128.5, 127.6, 121.3, 118.3 (C5).
MS (EI): m/z (%) = 264 (M+) (78), 248 (M+ – O) (100), 234 (M+ –
NO) (57).
3-Chloro-6-iodoquinoxalin-2(1H)-one 4-Oxide (21)
Following typical procedure I gave 21 as a green solid; yield: 79%;
mp 243 °C (dec).
IR (KBr): 3186, 3056, 3005, 2896, 2816, 2700, 1674 (C=O), 1615,
1513, 1469, 1437, 1386, 1352, 1262, 1227, 1162, 1137, 1110, 955,
909, 899, 823, 782, 738, 691, 667, 636, 559, 545, 499, 441, 426
cm–1.
1H NMR (200 MHz, DMSO-d6): d = 12.85 (br s, 1 H, NH), 8.32 (d,
J = 1.8 Hz, 1 H, H5), 7.93 (dd, J = 8.6, 1.8 Hz, 1 H, H7), 7.18 (d,
J = 8.6 Hz, 1 H, H8).
13C NMR (50 MHz, DMSO-d6): d = 153.2 (C2), 140.7 (C8), 134.4
(C3), 131.2 (C9 or C10), 130.7 (C9 or C10), 127.2 (C7), 118.7 (C5),
86.8 (C6).
Anal. Calcd for C8H3Cl3N2O2 (263.93): C, 36.19; H, 1.14; Cl,
40.06; N, 10.55. Found: C, 36.37; H, 1.13; Cl, 39.96; N, 10.58.
3,7,8-Trichloroquinoxalin-2(1H)-one 4-Oxide (25)
Following typical procedure I gave 25 as a beige solid; yield: 35%;
mp 236 °C (dec).
MS (EI): m/z (%) = 321 (M+) (100), 305 (M+ – O) (30), 291 (M+ –
NO) (35).
IR (KBr): 3188, 3130, 3078, 3022, 1924, 1666 (C=O), 1601, 1589,
1502, 1456, 1439, 1350, 1293, 1252, 1165, 1119, 954, 899, 827,
813, 784, 739, 729, 654, 577, 526, 472 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 12.53 (br s, 1 H, NH), 8.12 (d,
J = 9.2 Hz, 1 H, H5), 7.61 (d, J = 9.2 Hz, 1 H, H6).
Anal. Calcd for C8H4ClIN2O2 (321.90): C, 29.80; H, 1.25; Cl,
10.99; N, 8.69. Found: C, 29.76; H, 1.22; Cl, 11.06; N, 8.67.
Synthesis 2008, No. 16, 2575–2581 © Thieme Stuttgart · New York

PAPER
Synthesis of Functionalized 3-Chloroquinoxalin-2(1H)-one 4-Oxides
2581
13C NMR (100 MHz, DMSO-d6): d = 153.8 (C2), 135.4 (C3), 134.3,
130.6, 130.5, 124.3, 119.4, 118.5 (C5).
(5) Barrett, A. G. Chem. Soc. Rev. 1991, 20, 95.
(6) (a) Buevich, V. A.; Rudchenko, V. V.; Grineva, V. S.;
Perekalin, V. V. J. Org. Chem. USSR (Engl. Transl.) 1978,
2031. (b) Tiemann, C. H.; Kollmeyer, W. D.; Roman, S. A.
US 3,971,774, 1976; Chem. Abstr. 1976, 86, 5460.
(c) Buevich, V. A.; Nakova, N. Z.; Kempter, G.; Perekalin,
V. V. J. Org. Chem. USSR (Engl. Transl.) 1977, 2430.
(7) (a) Buevich, V. A.; Rudchenko, V. V.; Perekalin, V. V.
Chem. Heterocycl. Compd. (Engl. Transl.) 1976, 1185;
Chem. Abstr. 1977, 86, 72357. (b) Buevich, V. A.; Deiko, L.
I.; Volynskii, V. E. J. Org. Chem. USSR (Engl. Transl.)
1980, 2055.
(8) Francotte, E.; Verbruggen, R.; Viehe, H. G.; van Meerssche,
M.; Germain, G.; Declercq, J. P. Bull. Soc. Chim. Belg. 1978,
693.
(9) X-ray crystallographic analysis of C21H32N2O3S was
performed at 223(2) K by using a STOE IPDS II
MS (EI): m/z (%) = 264 (M+) (91), 248 (M+ – O) (12), 234 (M+ –
NO) (100).
Anal. Calcd for C8H3Cl3N2O2 (263.93): C, 36.19; H, 1.14; Cl,
40.06; N, 10.55. Found: C, 36.28; H, 1.14; Cl, 39.74; N, 10.49.
3-Chloro-6-methylquinoxalin-2(1H)-one 4-Oxide (26)
Following typical procedure I gave 26 as a beige solid; yield: 16%;
mp 230 °C (dec).
IR (KBr): 3113, 2992, 2951, 2907, 2863, 1673 (C=O), 1601, 1532,
1484, 1439, 1398, 1355, 1268, 1250, 1148, 1130, 1093,1037, 945,
819, 739, 676, 644, 552, 536, 457 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 12.71 (br s, 1 H, NH), 7.94 (s,
Hz, 1 H, H5), 7.50 (dd, J = 8.3, 1.5 Hz, 1 H, H7), 7.30 (d, J = 8.3
Hz, 1 H, H8), 2.39 (s, 3 H, CH3).
diffractometer with MoKa radiation (l = 0.71073 Å) and a
graphite monochromator. Crystal system: triclinic, P1 (No.
2), Z = 1, a = 632.32(13) pm, b = 900.7(2) pm,
13C NMR (100 MHz, DMSO-d6): d = 153.2 (C2), 133.8 (C3), 133.7,
133.6, 130.2, 128.8, 118.8, 116.5 (C5), 20.7 (CH3).
c = 1935.2(4) pm, a = 84.236(19), b = 83.827(17),
g = 77.126(18), VEZ = 1064.9(4) 106 pm3. The structure
was solved by direct methods (SHELXS-97)10a using 3704
independent reflections. Structure refinement: full matrix
least-squares methods on F2 using SHELXL-9710b all
nonhydrogen atoms with anisotropic displacement
parameters. All hydrogen atoms were taken from a
difference Fourier synthesis and were isotropically refined.
The refinement converged to a final wR2 = 0.1223 for 3704
unique reflections and R1 = 0.0540 for 2420 observed
reflections [I0 > 2s(I0)] and 373 refined parameters with a
goodness-of-fit of 1.053. Crystallographic data have been
deposited with the Cambridge Crystallographic Data Centre
as supplementary publication no. CCDC-679570. Copies of
the data can be obtained free of charge on application to
CCDC, 12 Union Road, Cambridge CB2 1EZ, UK [fax:
+44(1223)336033, e-mail: deposit@ccdc.cam.ac.uk].
(10) (a) Sheldrick, G. M. SHELXS-97; University of Göttingen:
Germany, 1997. (b) Sheldrick, G. M. SHELXL-97;
University of Göttingen: Germany, 1997.
MS (EI): m/z (%) = 210 (M+) (100), 194 (M+ – O) (32), 180 (M+ –
NO) (70).
Anal. Calcd for C9H7ClN2O2 (210.02): C, 51.32; H, 3.35; Cl, 16.83;
N, 13.30;. Found: C, 51.32; H, 3.33; Cl, 16.82; N, 12.51.
Acknowledgment
Financial support of this work by Bayer AG, Leverkusen, is grate-
fully acknowledged. We thank Dr. H. Frauendorf, University of
Göttingen, for high resolution mass spectra.
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