Pyrazolo[4′,3′:5,6]pyrano[2,3-b]quinoxalin-4(1H)-one: Synthesis and characterization of a novel tetracyclic ring system

Article abstract of DOI:10.1002/jhet.5570440526

(Chemical Equation Presented) Derivatives of the hitherto unknown ring system, pyrazolo[4′,3′:5,6]pyrano[2,3-b]quinoxalin-4(1H)-one, are synthesized in one step from the corresponding 1-substuituted or 1,3-disubstituted 2-pyrazolin-5-ones and 3-chloroquinoxaline-2-carbonyl chloride using calcium hydroxide in boiling 1,4-dioxane. The parent system carrying no substituent in positions 1 and 3 is obtained upon treatment of the 1-PMB (p-methoxybenzyl) protected congener with trifluoroacetic acid. Detailed NMR spectroscopic investigations including unambiguous chemical shift assignments of all ¹H, ¹³C, and ¹⁵N resonances of the obtained tetracycles are reported.

Full text of DOI:10.1002/jhet.5570440526

Sep-Oct 2007
1139
Pyrazolo[4',3':5,6]pyrano[2,3-b]quinoxalin-4(1H)-one:
Synthesis and Characterization of a Novel Tetracyclic Ring System
Gernot A. Eller,* Barbara Datterl, and Wolfgang Holzer*
Department of Drug and Natural Product Synthesis,
Faculty of Life Sciences, University of Vienna, A-1090 Vienna, Austria
Fax +43(1)42779556; E-mail: gernot.eller@univie.ac.at; E-mail: wolfgang.holzer@univie.ac.at
Received January 18, 2007
O
R3
N
N
N
O
N
R1
R1 = Ph, R3 = H; R1 = Ph, R3 = Me; R1 = R3 = Ph;
R1 = p-methoxybenzyl, R3 = H; R1 = R3 = H
Derivatives of the hitherto unknown ring system, pyrazolo[4',3':5,6]pyrano[2,3-b]quinoxalin-4(1H)-one,
are synthesized in one step from the corresponding 1-substuituted or 1,3-disubstituted 2-pyrazolin-5-ones
and 3-chloroquinoxaline-2-carbonyl chloride using calcium hydroxide in boiling 1,4-dioxane. The parent
system carrying no substituent in positions 1 and 3 is obtained upon treatment of the 1-PMB (p-
methoxybenzyl) protected congener with trifluoroacetic acid. Detailed NMR spectroscopic investigations
1
including unambiguous chemical shift assignments of all H, 13C, and 15N resonances of the obtained
tetracycles are reported.
J. Heterocyclic Chem., 44, 1139 (2007).
Scheme 1
INTRODUCTION
Reported synthesis of pyrido-pyrano[2,3-c]pyrazol-4(1H)-ones
Recently, we reported the preparation of novel
heterocyclic ring systems containing a pyrano[2,3-c]-
pyrazol-4(1H)-one moiety [1–3] as building blocks for
biologically active compounds. Specifically, the reaction
of 2-pyrazolin-5-ones (tautomers to 5-hydroxypyrazoles
[4]) with different o-haloarenecarbonyl chlorides under
conditions of the Jensen reaction (calcium hydroxide,
refluxing 1,4-dioxane [5]) gave acylated pyrazole
intermediates, which were then cyclized with sodium
hydride in boiling dimethylformamide to polycyclic
compounds (Scheme 1). However, we found that with N-
heterocyclic acid chlorides carrying an 'activated' halogen
atom in ortho position to the ring nitrogen (derived from
2-chloronicotinic acid, 4-chloronicotinic acid, 3-fluoro-
picolinic acid, 4-chloropyridazine-3-carboxylic acid, and
*
O
X
N
R3
Ca(OH)2
NaH
N
N
R1
O
H
DMF
1,4-dioxane
O
X
O
O
R3
R3
Cl
N
N
+
N
N
N
N
O
R1
R1
* not isolated with some o-halo derivatives of picolinic,
nicotinic, 3-pyridazinic, and 2-quinolic acid chlorides
3-chloroquinoxaline-2-carboxylic acid) a spontaneous
intramolecular cyclization to the target polycycles was
Scheme 2
N
CH3
O
N
CH3
Cl
N
H
N
N
COOH
Cl
N
COCl
Cl
NH2
NH2
4
5
N
N
8
2
N
COOEt
O
N
COOEt
Cl
N
H
N
6
7
Synthesis of the acid chloride 2

1140
G. A. Eller, B. Datterl, and W. Holzer
Vol 44
Scheme 3
O
O
R3
N
N
R3
N
N
R1
Ph
Ph
Ph
R3
H
Me
Ph
H
Ca(OH)2
1/3
a
b
c
d
Cl
H2C
+
N
N
PMB =
N
R1
O
Cl
N
R1
O
1,4-dioxane
O
PMB
CH3
1
2
3
Synthesis of the tetracyclic title compounds
observed under Jensen reaction condition (Scheme 1)
[1, 3]. In contrast, no such behavior was noticed in the
reactions of 3-chloroisonicotinic acid chloride and of 5-
chloro-2-(methylthio)pyrimidine-4-carbonyl chloride [3].
Due to the importance of the N-heterocycle quinoxaline
as a structural element in many biologically active
compounds [6], even in drugs like Brimonidine
(Alphagan™) [7, 8], we aimed at the enlargement of our
heterocyclic portfolio to include also the new quinoxalino
fused skeleton of type 3. The synthesis of compounds 3
was envisaged as outlined in Scheme 3 and we were
interested in whether the primary product in the reaction
of 1 with 2 would undergo spontaneous ring closure
during the acylation reaction.
aqueous KMnO4 did not yield the desired acid. Thus, we
changed our plan and introduced the desired carbonyl
group to the quinoxaline core in the first reaction step
(Scheme 2, lower line). Subsequent transformations
according to known procedures gave the acid chloride 2.
Four different pyrazolones (1a–d), either commercially
available or easily accessible according to known literature
procedures, were reacted with 3-chloroquinoxaline-2-
carbonyl chloride (2) using calcium hydroxide in boiling
Table 2
15N NMR shifts of compounds 3 (solvents as in Table 1)
Comp
N-1
N-2
N-5
N-10
–97.5
3a
3b
3c
3d
3e
–185.4
–85.4
–38.1
a
a
a
a
Scheme 4
–
–
–
–
–
–
–
–
a
a
a
a
O
O
O
O
–188.9
–83.0
–37.9
–37.9
–98.0
–98.6
N
N
N
N
TFA
–176.9b
N
N
H
N
N
a too badly soluble. b only one N-signal found.
PMB
3d
3e
1,4-dioxane (Scheme 3). NMR analysis of the products
proved that cyclization had already occurred under the
conditions of the acylation reaction – no intermediate
4-aroylpyrazol-5-ols were isolated.
Synthesis of the unsubstituted parent ring system
RESULTS AND DISCUSSION
Since the quinoxaline-2-carbonyl chloride 2 is not
commercially available, we planned its synthesis as
outlined in Scheme 2 (upper line) according to literature
methods. Unfortunately, methylquinoxaline 5 was not
oxidized to the corresponding acid 8, which has been
reported recently by Mahesh et al. [9] using Na2CrO7/
H2SO4 as the oxidation reagent. Even switching to
The synthesis of the N1- and C3-unsubstituted
compound 3e was achieved by treatment of the N1-PMB
(p-methoxybenzyl) protected congener 3d with trifluoro-
acetic acid (Scheme 4).
Detailed NMR spectroscopic analyses for all prepared
compounds are reported. Full and unambiguous
assignment for all proton, carbon, and nitrogen resonances
Table 1
1H NMR data of compounds 3
Comp
Solvent
H-6
H-7
H-8
H-9
H of R1
R3-H or H-3
3a
3b
3c
3d
DMSO-d6
DMSO-d6
CDCl3
8.40a
8.41a
8.53
8.01a
8.00a
7.94
8.10a
8.09a
8.01b
8.07a
8.18a
8.17a
8.17b
8.14a
Ph: 7.55 (4), 7.71 (3,5), 7.95 (2,6)
Ph: 7.52 (4), 7.68 (3,5), 7.92 (2,6)
Ph: 7.49 (4), 7.64 (3,5), 8.08 (2,6) Ph: 7.49 (4), 7.54 (3,5), 8.51 (2,6)
3.71 (OMe), 5.48 (CH2); Ph:
6.93 (3,5), 7.36 (2,6)
13.96 (NH)
8.52
2.62
DMSO-d6
8.36a
7.98a
8.25
8.75
3e
DMSO-d6
8.32
7.92
8.02
8.09
a 3J(H-6,H-7) = 8.4 Hz, 4J(H-6,H-8) = 1.4 Hz, 5J(H-6,H-9) = 0.6 Hz, 3J(H-7,H-8) = 6.8 Hz, 4J(H-7,H-9) = 1.4 Hz, 3J(H-8,H-9) = 8.4 Hz.
b 3J(H-8,H-9) = 8.4 Hz.

Sep-Oct 2007
Pyrazolo[4',3':5,6]pyrano[2,3-b]quinoxalin-4(1H)-ones
1141
anhydrous 1,4-dioxane (5 mL). The reaction mixture was
refluxed for 3 h under stirring. After cooling to room
temperature, the mixture was treated with 2 M HCl (15–20 mL),
stirred for 15 min, and poured into H2O (20 mL). After 30 min,
the solid product was collected by filtration, washed with H2O,
and recrystallized. NMR data are presented in Tables 1–3.
1-Phenylpyrazolo[4',3':5,6]pyrano[2,3-b]quinoxalin-
4(1H)-one (3a). This compound was obtained in 47% yield as
beige crystals (1-propanol), mp 298–299 °C; IR: CO 1698 cmꢀ1;
MS: m/z 315 (M+ + 1, 19), 314 (M+, 100), 186 (28), 91 (35), 77
(30). Anal. Calcd. for C18H10N4O2: C, 68.79; H, 3.21; N, 17.83.
Found: C, 68.49; H, 3.22; N, 17.62.
of tetracycles 3 was achieved by combined application of
standard NMR spectral techniques [10] such as NOE-
difference experiments, fully 1H-coupled 13C NMR
spectra, APT, HMQC and HMBC spectra as well as
experiments with selective excitation such as 1D-TOCSY
[11], 1D-HETCOR [12] and selective long-range INEPT
[13, 14]. The 15N NMR spectra were mainly recorded
using the gradient selected, sensitivity enhanced HMBC
sequence [15]. The obtained data show a high degree of
consistency and are summarized in Table 1 (1H NMR), in
Table 2 (15N NMR), and in Table 3 (13C NMR).
Table 3
13C NMR data of compounds 3 (solvents as in Table 1)
Comp C-3 C-3a C-4 C-4a C-5a C-6
C-7
C-8
C-9 C-9a C-10a C-11a
C of R1
C of R3
–
3a 137.4 108.2 171.0 136.3 140.55 130.1 130.6 133.8 127.6 140.58 152.7 152.5 Ph: 121.9 (2,6), 128.4
(4), 129.8 (3,5), 136.2 (1)
3b 147.7 106.4 171.7 136.7 140.6 130.1 130.6 133.8 127.6 140.6 152.9a 152.6a Ph: 121.7 (2,6), 128.0
(4), 129.7 (3,5), 136.2 (1)
13.8 (Me)
3c 150.6 105.5 171.0 135.5 142.1 131.1 130.7 134.0 127.9 141.7 153.0a 151.9a Ph: 122.2 (2,6), 128.4
Ph: 128.4 (3,5), 128.6
(4), 129.7 (3,5), 136.6 (1) (2,6), 129.9 (4), 130.8 (1)
3d 136.1b 106.9c 170.8 136.5 140.42 130.0 130.4 133.6 127.5 140.43 152.7 152.7d
50.4e (CH2), 55.1f
(OMe); Ph: 114.1 (3,5),
127.3 (1), 129.4 (2,6),
159.1 (4)
–
3e 130.3g 107.3 172.8 136.1 140.0 130.1 129.8 133.5 127.5 141.0 154.0 160.3g
–
–
a not unambiguously assigned. b 1J = 194.5 Hz. c 2J(C-3a,H-3) = 10.5 Hz. d 3J(C-11a,CH2) = 2.6 Hz. e 1J = 142.5 Hz. f 1J = 144.4 Hz. g broad signal.
3-Methyl-1-phenylpyrazolo[4',3':5,6]pyrano[2,3-b]quin-
oxalin-4(1H)-one (3b). This compound was obtained in75%
yield as a beige powder, mp 295–297 °C; IR: CO 1678 cmꢀ1;
MS: m/z 329 (M+ + 1, 17), 328 (M+, 100), 91 (83), 77 (47). Anal.
Calcd. for C19H12N4O2: C, 69.51; H, 3.68; N, 17.06. Found: C,
69.25; H, 3.63; N, 16.81.
EXPERIMENTAL
Materials and Methods: Melting points were determined on
a Reichert–Kofler hot-stage microscope and are uncorrected.
Mass spectra were obtained on a Shimadzu QP 1000 instrument
(EI, 70 eV) and on a Finnigan MAT 8230 instrument (EI, 70 eV,
HRMS). IR spectra were recorded on a Perkin-Elmer FTIR
spectrum 1000 spectrophotometer. Elemental analyses were
performed at the Microanalytical Laboratory, University of
Vienna, using a Perkin-Elmer 2400 CHN Elemental Analyzer.
1H- and 13C-NMR spectra were recorded on a Varian UnityPlus
1,3-Diphenylpyrazolo[4',3':5,6]pyrano[2,3-b]quinoxalin-
4(1H)-one (3c). This compound was obtained in 45% yield as a
yellowish powder (toluene–hexanes), mp 301–303 °C; IR: CO
1676 cmꢀ1; MS: m/z 391 (M+ + 1, 20), 390 (M+, 100), 361 (31),
91 (35), 77 (48), 51 (20). Anal. Calcd. for C24H14N4O2·0.3 H2O:
C, 72.83; H, 3.72; N, 14.16. Found: C, 72.81; H, 3.90; N, 14.11.
1-(4-Methoxybenzyl)pyrazolo[4',3':5,6]pyrano[2,3-b]-
quinoxalin-4(1H)-one (3d). This compound was obtained in
25% yield as brownish crystals (toluene), mp 225–227 °C; IR:
CO 1687 cmꢀ1; MS: m/z 358 (M+, 16), 121 (100). Anal. Calcd.
for C20H14N4O3: C, 67.03; H, 3.94; N, 15.63. Found: C, 67.13; H,
4.03; N, 15.38.
Pyrazolo[4',3':5,6]pyrano[2,3-b]quinoxalin-4(1H)-one
(3e). Under anhydrous conditions, a solution of 3d and excess
TFA (5 mL) was stirred overnight at 70 °C. After removal of
TFA under reduced pressure, the residue was dried over solid
KOH for 1 h. Then ice-cold Et2O–acetone (2:1, 5 mL) was
added and the resulting suspension was filtered and the solid
was washed with cold Et2O to give the unsubstituted parent
compound 3e in 81% yield as a brownish powder, mp > 320 °C;
IR: CO 1674 cmꢀ1; MS: m/z 238 (M+, 100), 110 (80), 53 (28).
HRMS Calcd. for C12H6N4O2: 238.0491. Found: 238.0487.
NMR data are presented in Tables 1–3.
1
300 spectrometer at 28 °C (299.95 MHz for H, 75.43 MHz for
13C) or on a Bruker Avance 500 spectrometer at 293 K (500.13
MHz for H, 125.77 MHz for 13C). The centre of the solvent
1
signal was used as an internal standard which was related to
TMS with ꢀ = 7.26 ppm (1H in CDCl3), ꢀ = 2.49 ppm (1H in
DMSO-d6), ꢀ = 77.0 ppm (13C in CDCl3), and ꢀ = 39.5 ppm (13C
in DMSO-d6). 15N-NMR spectra were obtained on a Bruker
Avance 500 instrument with a ‘directly’ detecting broadband
observe probe and were referenced against external
nitromethane (coaxial capillary). Systematic names according to
IUPAC recommendations were generated with ACD/Name [16]
and subsequently proved manually to ensure correct
nomenclature within this publication [17]. Starting materials 1
were commercially available or prepared according to literature
procedures: 1a [18], 1c [19], 1d [20]. Product yields were not
optimized.
General Procedure for the Synthesis of Tetracycles 3.
Under anhydrous conditions, to a suspension of pyrazolone 1a–d
(3 mmol) and Ca(OH)2 (6 mmol) in anhydrous 1,4-dioxane
(5 mL) was added a suspension of acid chloride 2 (3 mmol) in
3-Methylquinoxalin-2(1H)-one (4). o-Phenylenediamine (21.63
g, 200 mmol), pyruvic acid (17.61 g, 200 mmol), and ethanol (96%,

1142
G. A. Eller, B. Datterl, and W. Holzer
Vol 44
700 mL) were refluxed for 90 min. The reaction mixture was
allowed to gain room temperature. Upon staying in the refrigerator
overnight, the product separated as orange crystals, which were
filtered off and washed with cold ethanol to yield 19.90 g (62%) of
differentiation between H-5/8 and H-6/7 was not unambiguously
possible; 13C NMR (75 MHz, CDCl3): ꢀ 14.1 (CH3, 1J = 127.5 Hz,
2J(CH3,CH2) = 2.7 Hz), 62.9 (CH2, 1J = 148.9 Hz, 2J(CH2,CH3) = 4.5
Hz), 128.3* (C-5), 129.6* (C-8), 130.9* (C-7), 132.5* (C-6), 139.6*
(C-8a), 142.1* (C-4a), 143.8* (C-2), 144.7* (C-3), 163.8 (CO); *
the differentiation between C-2/3, C-4a/8a, C-5/8, and C-6/7 was not
unambiguously possible; 15N NMR (50 MHz, CDCl3): ꢀ –61.2 (N-
4), –47.7 (N-1); MS: 238 (M+, 3), 236 (M+, 8), 192 (23), 166
(33), 165 (21), 164 (100), 163 (40), 129 (42), 102 (50), 75 (21).
3-Chloroquinoxaline-2-carboxylic Acid (8). To ester 7 (9.94
g, 42 mmol), dissolved in aqueous methanol (80%, 200 mL),
was added Na2CO3 (2.50 g, 24 mmol) and the reaction mixture
was refluxed for 4 h. Then the solution was acidified with 2 M
HCl and the solvent was removed under reduced pressure to
yield the crude acid 8, which was used 'as is' in the next reaction,
mp 142–145 °C (lit. [23] 146–147 °C); MS: m/z 210 (M+, 13),
208 (M+, 39), 166 (34), 164 (100), 129 (80), 102 (95), 76 (32),
75 (40), 50 (27).
1
4, mp 237–239 °C (lit. [21] 241–243 °C); H NMR (300 MHz,
DMSO-d6): ꢀ 2.37 (3H, s, Me), 7.22 (1H, m, H-6), 7.24 (1H, m, H-
8), 7.42 (1H, m, H-7), 7.65 (1H, m, H-5), 12.25 (1H, s, NH); 13C
NMR (75 MHz, DMSO-d6): ꢀ 20.4 (Me, 1J = 128.4 Hz), 115.2 (C-8,
3
1
1J = 163.3 Hz, J(C-8,H-6) = 7.9 Hz), 122.9 (C-6, J = 163.1 Hz,
3J(C-6,H-8) = 8.5 Hz), 127.8 (C-5, 1J = 161.6 Hz, 3J(C-5,H-7) = 7.7
Hz), 129.2 (C-7, 1J = 163.3 Hz, 3J(C-7,H-5) = 8.5 Hz), 131.6 (C-4a),
3
2
131.9 (C-8a), 154.9 (C-2, J(C-2,Me) = 2.7 Hz), 159.1 (C-3, J(C-
3,Me) = 7.1 Hz); 15N NMR (50 MHz, DMSO-d6): ꢀ –233.0 (N-1), –
53.5 (N-4); MS: m/z 160 (M+, 82), 132 (97), 131 (100).
2-Chloro-3-methylquinoxaline (5). Quinoxalinone 4 (11.69
g, 73 mmol) and excess POCl3 (150 mL) were refluxed for 90 min.
Under reduced pressure, POCl3 was distilled off and the residue was
poured onto ice-water (~ 300 mL). Upon treatment of the solution
with concd. NH3 (pH was brought to 3–4) and standing for 3 h, the
red–brownish product 5 separated (6.17 g, 47%), mp 91–93 °C (lit.
3-Chloroquinoxaline-2-carbonyl Chloride (2). A suspen-
sion of the crude acid 8 in toluene (30 mL) was treated with
DMF (1 drop) and with excess SOCl2 (30 mL) and the mixture
was refluxed for 3 h. The solution was filtered, and the SOCl2
was removed under reduced pressure. Upon further concen-
tration under reduced pressure, the acid chloride 2 separated as
yellow crystals (3.46 g, 36%), mp 106–110 °C (lit. [25] 117–119
1
[22] 90–92 °C); H NMR (300 MHz, CDCl3): ꢀ 2.81 (3H, s, Me),
7.68* (1H, m, H-7), 7.71* (1H, m, H-6), 7.94* (1H, m, H-8), 7.98*
(1H, m, H-5); * the differenttiation between H-5/8 and H-6/7 was
not unambiguously possible; 13C NMR (75 MHz, CDCl3): ꢀ 23.2
1
(Me, J = 129.2 Hz), 128.1* (C-8), 128.4* (C-5), 129.9* (C-7),
1
°C, lit. [26] 127 °C); IR: CO 1778 cmꢀ1; H NMR (500 MHz,
130.0* (C-6), 140.8* (C-8a), 140.9* (C-4a), 147.7 (C-2, 3J(C-2,Me)
2
CDCl3): ꢀ 7.92* (1H, m, H-7), 7.98* (1H, m, H-6), 8.10* (1H, m,
H-5), 8.24* (1H, m, H-8); * the differentiation between H-5/8 and
H-6/7 was not unambiguously possible; 13C NMR (125 MHz,
CDCl3): ꢀ 128.3* (C-5), 130.1* (C-8), 131.7* (C-7), 134.3* (C-6),
139.4* (C-8a), 142.8* (C-4a), 142.9* (C-2), 143.0* (C-3), 166.0
(CO); * the differentiation between C-2/3, C-4a/8a, C-5/8, and C-6/7
was not unambiguously possible; 15N NMR (50 MHz, CDCl3): ꢀ –
57.8 (N-4), –40.6 (N-1); MS: m/z 230 (M+, 2), 228 (M+, 10), 226
(M+, 15), 193 (17), 191 (47), 165 (31), 163 (100), 102 (49), 75
(19). Anal. Calcd. for C9H4Cl2N2O: C, 47.61; H, 1.78; N, 12.34.
Found: C, 47.79; H, 2.01; N, 12.39.
= 3.8 Hz), 152.7 (C-3, J(C-3,Me) = 7.0 Hz); * the differentiation
between C-4a/8a, C-5/8, and C-6/7 was not unambiguously
possible; 15N NMR (50 MHz, CDCl3): ꢀ –67.3 (N-1), –50.6 (N-4);
MS: m/z 180 (M+, 12), 178 (M+, 39), 143 (100), 102 (29).
Ethyl 3-Oxo-3,4-dihydroquinoxaline-2-carboxylate (6). To a
suspension of diethyl oxomalonate (26.56 g, 150 mmol) in ethanol
(96%, 250 mL) was added o-phenylenediamine (16.44 g, 150
mmol). The mixture was refluxed for 2 h and the hot solution was
filtered. After addition of water (400 mL) the mixture was
refluxed again until the solution became clear. This solution was
filtered again, and upon standing at room temperature overnight,
product 6 crystallized as yellowish needles (24.51 g, 75%), mp
176–178 °C (lit. [23] 175.5–176.5 °C); 1H NMR (300 MHz,
Acknowledgement. We are grateful to Dr. L. Jirovetz
for recording the mass spectra.
3
CDCl3): ꢀ 1.46 (3H, t, J(CH3,CH2) = 7.1 Hz, CH3), 4.54 (2H, q,
3J(CH2,CH3) = 7.1 Hz, CH2), 7.39 (1H, m, H-7), 7.47 (1H, m, H-
5), 7.61 (1H, m, H-6), 7.93 (1H, m, H-8), 12.95 (1H, s, NH); 13C
NMR (75 MHz, CDCl3): ꢀ 14.2 (CH3, 1J = 127.4 Hz, 2J(CH3,CH2)
= 2.6 Hz), 62.5 (CH2, 1J = 148.7 Hz, 2J(CH2,CH3) = 4.5 Hz), 116.4
(C-5), 124.9 (C-7), 130.1 (C-8), 132.0 (C-8a), 132.2 (C-4a), 132.7
(C-6), 148.5 (C-2), 154.6 (C-3), 163.4 (CO); 15N NMR (50 MHz,
CDCl3): ꢀ –225.0 (N-4), –40.3 (N-1); MS: m/z 218 (M+, 56), 174
(31), 146 (100), 145 (34), 144 (35), 118 (68), 90 (58).
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Basic NMR Experiments: A Practical Course, 2nd ed., Wiley-VCH,
Weinheim, 1998, pp. 596; Chem. Abstr. 1999, 131, 184497.
Ethyl 3-Chloroquinoxaline-2-carboxylate (7). A mixture of
quinoxalinone 6 (18.95 g, 85 mmol) and excess POCl3 (100 mL)
was refluxed for 30 min. Under reduced pressure, POCl3 was
distilled off and the residue was poured onto ice-water (~ 300
mL). Upon neutralization with concentrated NH3, product 7
separated and was then collected by filtration. To increase the
yield, the filtrate was extracted with CH2Cl2 (3 x 50 mL) and the
combined organic layers were washed once with water (10 mL),
dried over anhydrous Na2SO4, and concentrated to dryness under
reduced pressure. Compound 7 was obtained as a beige solid in
1
a total yield of 95% (19.11 g), mp 40 °C (lit. [24] 40 °C); H
3
NMR (300 MHz, CDCl3): ꢀ 1.46 (3H, t, J(CH3,CH2) = 7.2 Hz,
CH3), 4.55 (2H, q, 3J(CH2,CH3) = 7.2 Hz, CH2), 7.80* (1H, m, H-7),
7.85* (1H, m, H-6), 8.03* (1H, m, H-5), 8.15* (1H, m, H-8); * the

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