Derivatives of 5-oxy-pyrido[2,3-b]quinoxaline-9-carboxylic acid: 1173 A tricyclic system useful for the synthesis of potential intercalators

Article abstract of DOI:10.1002/jhet.5570390610

The synthesis of a new series of 5-oxy-pyrido[2,3-b]quinoxaline-9-carboxamides 4a-i and N¹,N²-Bis(5-oxy-pyrido[2, 3-b]quinoxaline-9-benzoyl)ethylenediamine (5) is reported starting from 2-chloro-3-nitropyridine. Fundamental steps of the synthetic pathway are i) preparation of 2-(3-nitro-pyridin-2-ylamino)benzoic acid (1) via copper-catalyzed condensation of 2-chloro-3-nitropyridine with o-anthranilic acid, ii) intramolecular cyclization of the acid 1 to 5-oxy-pyrido[2,3-b]quinoxaline-9-carboxylic acid (2b) upon treatment with concentrated sulfuric acid and oleum and iii) conversion of the acid 2 to the desired amides 4a-i and 5. Compounds 4a-i and 5 are oxygenated azaanalogs of phenazines, a wellknown series of intercalators with cytotoxic activity.

Full text of DOI:10.1002/jhet.5570390610

Nov-Dec 2002
Derivatives of 5-Oxy-pyrido[2,3-b]quinoxaline-9-carboxylic Acid:
1173
A Tricyclic System Useful for the Synthesis of Potential Intercalators
Athanasia Varvaresou* and Kriton Iakovou
University of Athens, School of Pharmacy, Department of Pharmaceutical Chemistry, Panepistimiopolis-
Zografou, GR-157 71, Athens, Greece
Received June 18, 2002
The synthesis of a new series of 5-oxy-pyrido[2,3-b]quinoxaline-9-carboxamides 4a-i and N1,N2-Bis(5-
oxy-pyrido[2,3-b]quinoxaline-9-benzoyl)ethylenediamine (5) is reported starting from 2-chloro-3-nitropyri-
dine. Fundamental steps of the synthetic pathway are i) preparation of 2-(3-nitro-pyridin-2-ylamino)benzoic
acid (1) via copper-catalyzed condensation of 2-chloro-3-nitropyridine with o-anthranilic acid, ii) intramol-
ecular cyclization of the acid 1 to 5-oxy-pyrido[2,3-b]quinoxaline-9-carboxylic acid (2b) upon treatment
with concentrated sulfuric acid and oleum and iii) conversion of the acid 2 to the desired amides 4a-i and 5.
Compounds 4a-i and 5 are oxygenated azaanalogs of phenazines, a wellknown series of intercalators with
cytotoxic activity.
J. Heterocyclic Chem., 39, 1173(2002).
Introduction.
under alkaline conditions failed. When 2-(3-nitro-pyridin-
2-ylamino)benzoic acid (1) was heated with potassium
hydroxide powder at 130-190 °C [19,20], a mixture of the
uncyclized compound 1 and o-anthranilic acid was isolated,
Several classes of compounds including the anthracen-
diones [1], anthrapyrazoles [2], thioxanthenones [3],
(aza)acridine-4-carboxamides [4,5], (aza)dibenzodioxin-
1-carboxamides [6], phenazine-1-carboxamides [7] and
pyrido-, pyrazino-, imidazo-, pyrrolo-, pyrazolophenazine-
carboxamides [8] can be distinguished among the cur-
rently recognized synthetic antineoplastic compounds
designed as "DNA complexing agents".
These compounds are characterized by two common
features which seem to determine their antineoplastic
activity: a planar polycyclic nucleus, capable of binding to
DNA by intercalation [9] and one or two cationic side
chains, which have the function of additionally stabilizing
the drug-DNA complex [10].
Furthermore, some N-oxides of DNA intercalators are
bioreductive prodrugs that selectively kill hypoxic cells
[11]. Many human tumors differ from normal tissues in
that they contain a substantial number of hypoxic cells
[12]. It is known that these cells can contribute to radiation
resistance of tumors [13] and to neoplastic progression
within unirradiated tumors [14].
1
as it was indicated from the H nmr and mass spectra.
Moreover, the reactions of the acid 1 with sodium boro-
hydride either in refluxing sodium hydroxide solution [7]
or in refluxing ethanol in the presence of sodium ethoxide
[21,22] afforded 2-(3-amino-pyridin-2-ylamino)benzoic
acid (2a) or o-anthranilic acid, respectively.
Therefore, we decided to perform the cyclization in
acidic media by using the concentrated sulfuric acid-oleum
method, developed in the literature for the preparation of
phenazines N-oxides from o-nitrodiphenylamines [20,23].
In our case, the application of this method led to the
desired azaphenazine N-oxide 2b in 75% yield, only when
the quantity of oleum was 7-fold decreased, otherwise a
mixture of decomposition products was obtained.
To the best of our knowledge, compound 2b has not
been reported before and we believe that 2b is a useful
starting material for the synthesis of other 9-substituted
azaphenazines.
Attempts to couple the acid 2b with the appropriate
amines by using 1,1-carbonyldiimidazole were unsuccess-
ful. Finally, the acid 2b was transformed to the correspond-
ing methylester 3 upon heating in methanol in the presence
of concentrated sulfuric acid.
Reaction of the ester 3 with the appropriate amines in
the presence of sodium cyanide in methanol [24] afforded
the desired amides 4a-i and 5.
In conclusion, we have herein described an efficacious
procedure for obtaining derivatives of 2b, a novel tricyclic
ring system useful as lead structure for the design of new
potential DNA interactive agents.
The new compounds 4a-i and 5 and their deoxygenated
analogs (unpublished results) are currently being evaluated
for their cytotoxicity against a broad spectrum of tumour
cell lines.
On the basis of these considerations and in continuation
of our research on such polyheterocyclic DNA binding
agents with cytotoxic activity [15-18], we report in the pre-
sent study the synthesis of a new series of potential inter-
calators, hypoxia selective agents, the pyrido[2,3-b]-
quinoxaline-9-carboxamides 5-oxides 4a-i and N ,N -Bis-
(5-oxy-pyrido[2,3-b]quinoxaline-9-benzoyl)ethylene-
diamine (5) considered as azaanalogs of phenazine-1-car-
boxamides.
1
2
Results and Discussion.
The synthetic pathway followed for the preparation of
compounds 4a-i and 5 is delineated in Scheme 1. Thus,
commercially available 2-chloro-3-nitropyridine reacted
with o-anthranilic acid under Ullmann conditions to afford
the hitherto unknown acid 1. Attempts to cyclize the acid 1

1174
A. Varvaresou and K. Iakovou
Vol. 39
EXPERIMENTAL
at 180-190 °C, under stirring for 5 hours. The reaction mixture
was cooled to room temperature, water and ethyl acetate were
added and the precipitate formed was removed by filtration. The
organic layer was discarded from the filtrate and the aqueous
layer was extracted with ethyl acetate (2x50 ml). The aqueous
phase was carefully acidified with acetic acid (60 ml). The
deposited material was filtered, washed with hot water, dried and
recrystallized from benzene to give 1.25 g (44%) of 1, mp 185-
187 °C; Rf 0.37 (eluent ethyl acetate); ir (Nujol): 3265 (NH),
1705 (CO), 1490, 1310; 1H nmr (dimethylsulfoxide-d6, 400
MHz): d 8.56 (m, 4H), 7.96 (m, 1H), 7.57 (m, 1H), 7.15 (m, 2H).
Anal. Calcd for C12H9N3O4: C, 55.60; H, 3.50; N, 16.21.
Found: C, 55.93; H, 3.17; N, 16.56.
Melting points were determined on a Büchi 530 apparatus and
are uncorrected. IR spectra were run on a Perkin Elmer 883 spec-
trophotometer. NMR spectra were taken in deuterochloroformor
dimethylsulfoxide-d6, or acetone-d6. 1H nmr spectra were
recorded either on a Brucker AC200 or a Brucker DRX400 MHz
spectrometer, and the spectra are reported in d. 13C nmr spectra
were taken at 50 MHz on a Brucker AC200 spectrometer and are
reported in d. Tetramethylsilane was used as internal standard.
Molecular weights were determined by ESI mass spectrometry
on a Finnigan AQA mass spectrometer. All the experiments were
carried out under atmosphere of Argon unless stated otherwise.
The solvents used were dried as follows: Methanol and octanol
2-(3-Amino-pyridin-2-ylamino)benzoic Acid (2a).
over calcium oxide. DC-Alufolien plates (Kieselgel 60 F254
,
To a mixture of 1 (0.05 g, 0.00019 mole) and sodium borohy-
dride (0.05 g, 0.0013 mole) an aqueous solution of sodium
hydroxide (4.6 ml, 2 N) was added. The resulting mixture was
refluxed for 1 hour, allowed to reach room temperature, cooled at
0 °C and acidified with acetic acid (10 ml). The mixture was
extracted with ethyl acetate, the organic layer dried (sodium sul-
fate) and concentrated in vacuo. After addition of benzene, the
mixture was stirred and filtered. The filtrate was evaporated to
dryness. Crystallization of the residue from cyclohexane afforded
0.026 g (59%) of 2-(3-amino-pyridin-2-ylamino)-benzoic acid
(2a), mp 142-144 °C; 1H nmr (deuterochloroform, 200 MHz): d
Schichtdicke 0.2 mm, Merck) were used for analytical TLC and
were visualized with ultraviolet light or developed with iodine or
phosphomolybdic acid. Microanalyses were carried out by the
Microanalytical Section of the Institute of Organic and
Pharmaceutical Chemistry, NHRF-Greece.
2-(3-Nitro-pyridin-2-ylamino)benzoic Acid (1).
A mixture of 2-chloro-3-nitropyridine (2 g, 0.013 mole),
anthranilic acid (1.48 g, 0.011 mole), potassium carbonate (9.28
g, 0.067 mole), a catalytic amount of potassium iodide and cop-
per powder (0.132 g, 0.002 mole) in octanol (20 ml) was heated

Nov-Dec 2002
Derivatives of 5-Oxy-pyrido[2,3-b]quinoxaline-9-carboxylic Acid
1175
8.40 (d, J=8.4 Hz, 1H), 8.34 (dd, J=6.9 Hz, J=1.5 Hz, 1H), 7.77
(m, 2H), 7.45 (m, 1H), 6.70 (d, J=6.9 Hz, 1H), 6.64 (dd, J=7.5
Hz, J=1.5 Hz, 1H), 5.30 (br s, 3H, D2O exch., NH+NH2);
(dimethylsulfoxide-d6, 400 MHz): d 8.25 (d, J=8.8 Hz, 1H), 8.13
(dd, J= 7.1 Hz, J=1.1 Hz, 1H), 7.84 (m, 1H), 7.74 (d, J=7.7, 1H),
7.46 (m, 1H), 6.88 (m, 1H), 6.70 (dd, J=7.7 Hz, J=1.1 Hz, 1H),
6.15 (br s, 3H, D2O exch., NH+NH2); 13C nmr (dimethylsulfox-
ide-d6, 50 MHz): d 159.0, 147.3, 140.4, 134.2, 133.7, 126.9,
124.6, 116.4, 115.8, 114.5, 113.4, 107.6.
nmr (deuterochloroform, 400 MHz): d 8.30 (d, J=7.7 Hz, 1H), 7.81
(m, 3H), 7.6 (t, J=6.9 Hz, 1H), 7.30 (br s, 1H), 7.25 (br s, 1H).
Anal. Calcd for C12H8N4O2: C, 60.00; H, 3.36; N, 23.32.
Found: C, 59.81; H, 3.68; N, 22.90
General Procedure for the Preparation of Amides 4b-i.
The appropriate amine (0.018 mole) was added to a mixture of
ester 3 (0.18 g, 0.0007 mole) and sodium cyanide (0.05 g, 0.001
mole for compound 4b and 0.01 g, 0.0002 mole for compounds
4c-i) in methanol (6 ml). The reaction mixture was heated at 45
°C, under continuous stirring, for 30 minutes. The solvent was
removed under reduced pressure, the oily residue was diluted
with water and extracted with ethyl acetate. The organic phase
was dried (sodium sulfate) and evaporated to dryness.
Crystallization from cyclohexane gave the desired products in
14-53 % yield.
Anal. Calcd for C12H11N3O2: C, 62.87; H, 4.84; N, 18.33.
Found: C, 62.61; H, 5.13; N, 17.91.
5-Oxy-pyrido[2,3-b]quinoxaline-9-carboxylic Acid (2b).
Concentrated sulfuric acid (8.4 ml) was added at 0 °C to (3 g,
0.012 mole) of 1. To the stirred and cooled (0 °C) solution, oleum
30% (1.5 ml) was added dropwise for five minutes. After being
warmed to room temperature, the mixture was stirred for 1 hour.
The reaction mixture was then basified by ammonium hydroxide
25% (31 ml) at 0 °C. The resulted solid was collected, treated with
hot benzene and filtered. The filtrate was evaporated in vacuo.
Crystallization of the residue from cyclohexane afforded 2.1 g
(75%) of 5-oxy-pyrido[2,3-b]quinoxaline-9-carboxylic acid (2b),
mp 202-205 °C; Rf 0.93 (eluent ethyl acetate); ir (Nujol): 1705
(CO), 1510, 1414; 1H nmr (deuterochloroform, 200 MHz): d 8.97
(dd, J=7.3 Hz, J=1.5 Hz, 1H), 8.44 (dd, J=8.4 Hz, J=1.1 Hz, 1H),
7.90 (m, 2H), 7.56 (m, 1H), 6.82 (t, J=7.1 Hz, 1H); 1H nmr
(dimethylsulfoxide-d6, 200 MHz):d 8.93 (dd, J=7.7 Hz, J=1.5 Hz,
1H), 8. 36 (m, 1H), 7.97 (m, 1H), 7.74 (dd, J=8.4 Hz, J=0.7 Hz,
1H), 7.61 (m, 1H), 7.11 (t, J=7.3 Hz, 1H); 13C nmr (dimethylsul-
foxide-d6, 50 MHz): d 158.6, 147.8, 145.5, 141.1, 136.7, 131.2,
131.1, 129.3, 128.0, 127.3, 117.5, 111.2; ms: m/z 241 (M+)
Anal. Calcd for C12H7N3O3: C, 59.75; H, 2.93; N, 17.42.
Found: C, 59.60; H, 3.10; N, 17.71.
5-Oxy-pyrido[2,3-b]quinoxaline-9-carboxylic Acid (2-Amino-
ethyl)amide (4b).
This compound was obtained in 14% yield (0.028 g), mp 147-
150 °C; 1H nmr (deuterochloroform, 400 MHz): d 8.32 (d, J=7.2
Hz, 1H), 7.79 (m, 4H), 7.55 (m, 1H), 3.67 (m, 2H, CONHCH2),
2.79 (m, 2H, CH2NH2).
Anal. Calcd for C14H13N5O2: C, 59.36; H, 4.63; N, 24.72.
Found: C, 59.75; H, 4.26; N, 24.86.
5-Oxy-pyrido[2,3-b]quinoxaline-9-carboxylic Acid (2-Dimethyl-
aminoethyl)amide (4c).
This compound was obtained in 29% yield (0.063 g), mp 151-
153 °C; ir (Nujol): 1645 (CO), 1518, 1420;1H nmr (deuterochlo-
roform, 200 MHz): d 8.23 (m, 2H), 7.73 (m, 3H), 7.47 (m, 1H),
3.26 (m, 2H, NHCH2), 2.72 (m, 2H, NHCH2CH2), 2.21 (s, 6H,
N(CH3)2); ms: m/z 311 (M+), 280 [M+-(CH3+O)], 207 [M+-
(O+NH(CH2)2N(CH3)2)], 129, 75.
5-Oxy-pyrido[2,3-b]quinoxaline-9-carboxylic Acid Methyl
Ester (3).
Anal. Calcd for C16H17N5O2: C, 61.72; H, 5.50; N, 22.49.
Found: C, 61.65; H, 5.26; N, 22.86.
To a solution of 5-oxy-pyrido[2,3-b]quinoxaline-9-carboxylic
acid (2) (2 g, 0.008 mole) in dry methanol (140 ml) concentrated
sulfuric acid (1 ml) was added and the mixture was heated at 55
°C for 3 hours. The solvent was evaporated in vacuo and then the
residue was made alkaline with a solution of sodium hydrogen
carbonate (280 ml, 0.08 M). The mixture was extracted with ethyl
acetate, the organic layer dried (sodium sulfate) and concentrated
in vacuo. Crystallization from cyclohexane afforded 2 g (95%) of
5-Oxy-pyrido[2,3-b]quinoxaline-9-carboxylic Acid (2-Diethyl-
aminoethyl)amide (4d).
This compound was obtained in 30% yield (0.072 g), mp
152-156 °C; 1H nmr (acetone-d6, 400 MHz): d 9.06 (br s, 1H),
8.15 (d, 1H, J=7.5 Hz), 7.79 (t, 1H, J=7.2 Hz), 7.74 (br s, 1H),
7.44 (t, 1H, J=7.5), 3.87 (t, 2H, NHCH2CH2, J= 5.4 Hz), 2.81
(t, 2H, NHCH2CH2, J= 5.4 Hz), 2.66 (q, 4H, N(CH2CH3)2, J=
7.1 Hz), 1.05 (t, 6H, N(CH2CH3)2, J= 7.1 Hz); 1H nmr
(deuterochloroform, 400 MHz): d 8.95 (m, 1H), 8.26 (d,
J=7.84, 1H), 7.71 (m, 1H), 7.56 (d, J=8.16 Hz, 1H), 7.41 (m,
1H); ms: m/z 339 (M+).
1
3, mp 177-180 °C; Rf 0.61 (eluent chloroform); H nmr (deute-
rochloroform, 400 MHz): d 8.52 (m, 2H), 8.05 (m, 1H), 7.52 (m,
1H), 7.11 (m, 1H), 6.88 (m, 1H), 3.96 (s, 3H, CH3).
Anal. Calcd for C13H9N3O3: C, 61.18; H, 3.55; N, 16.46.
Found: C, 61. 40; H, 3.23; N, 16.67.
Anal. Calcd for C18H21N5O2: C, 63.70; H, 6.24; N, 20.64.
Found: C, 63.62; H, 6.26; N, 20.86.
5-Oxy-pyrido[2,3-b]quinoxaline-9-carboxylic Acid Amide (4a).
5-Oxy-pyrido[2,3-b]quinoxaline-9-carboxylic Acid (3-Dimethyl-
aminopropyl)amide (4e).
Ammonium hydroxide 25 % (26 ml) was added to a mixture of
ester 3 (0.18 g, 0.0007 mole) and sodium cyanide (0.05 g, 0.001
mole) in methanol (25 ml) and the mixture was stirred at room
temperature for 3 hours. The solvent was removed under reduced
pressure, the residue suspended in water and extracted with ethyl
acetate. The organic phase was dried (sodium sulfate) and evapo-
rated in vacuo. Crystallization from cyclohexane gave 0.09 g (53
%) of 4a, mp 142-143 °C;1H nmr (acetone-d6, 400 MHz): d 8.20
(d, J= 8.2 Hz, 1H), 7.85 (m, 2H), 7.77 (brs, 1H, D2O exch., NH),
This compound was obtained in 16% yield (0.036 g), mp 145-
148 °C; Rf 0.15 (eluent methanol);1H nmr (deuterochloroform,
400 MHz): d 8.89 (m, 1H), 8.22 (d, J=7.7 Hz, 1H), 7.69 (m, 1H),
7.51 (d, J=8.1 Hz, 1H), 7.39 (m, 1H), 3.71 (br s, 2H, NHCH2-
CH2CH2), 2.43 (br s, 2H, NHCH2CH2CH2), 2.23 (s, 6H,
N(CH3)2), 1.91 (m, 2H, NHCH2CH2CH2).
Anal. Calcd for C17H19N5O2: C, 62.75; H, 5.89; N, 21.52.
Found: C, 63.10; H, 6.16; N, 21.81.
1
7.72 (brs, 1H, D2O exch., NH), 7.58 (m, 1H), 7.35 (m, 1H); H

1176
A. Varvaresou and K. Iakovou
Vol. 39
REFERENCES AND NOTES
New Address correspondence to Dr Athanasia Varvaresou,
General Hospital "SPILIOPOULIO AG. ELENI", Department of
Pharmacy, D. Soutsou 21, Abelokipi, GR-115 21, Athens, Greece;
e-mail: varvaresou@pharm.uoa.gr or varvaresou@hotmail.com; Tel:
003-0106810354; Fax: 003-0106447064.
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Radiat. Oncol. 6, 37, (1996).
5-Oxy-pyrido[2,3-b]quinoxaline-9-carboxylic Acid (3-Diethyl-
aminopropyl)amide (4f).
*
This compound was obtained in 19% yield (0.048 g), mp 153-
1
155 °C; H nmr (deuterochloroform, 400 MHz): d 8.91 (m, 1H),
8.26 (d, J=7.2 Hz, 1H), 7.71 (m, 1H), 7.50 (m, 1H), 7.41 (m, 1H),
3.73 (br s, 2H, NHCH2CH2CH2), 2.56 (br s, 6H,
CH2N(CH2CH3)2), 1.91 (m, 2H, NHCH2CH2CH2), 1.03 (br s,
6H, N(CH2CH3)2)
Anal. Calcd for C19H23N5O2: C, 64.57; H, 6.56; N, 19.82.
Found: C, 64.18; H, 6.19; N, 20.01.
5-Oxy-pyrido[2,3-b]quinoxaline-9-carboxylic Acid (2-Morpholin-
4-yl-ethyl)amide(4g).
This compound was obtained in 27% yield (0.068 g), mp 164-
1
165 °C; H nmr (deuterochloroform, 400 MHz): d 8.94 (m, 1H),
8.27 (dd, J=7.8 Hz, J=1.0 Hz, 1H), 7.72 (m, 1H), 7.60 (d, J=8.2
Hz, 1H), 7.40 (m, 1H), 3.84 (t, 4H, 2,6-morpholinyl, J= 5.1 Hz),
3.75 (q, 2H, NHCH2, J= 6.2 Hz), 2.73 (t, 2H, NHCH CH2, J= 6.2
2
Hz), 2.65 (t, 4H, 3,5- morpholinyl, J= 5.3 Hz).
Anal. Calcd for C18H19N5O3: C, 61.18; H, 5.42; N, 19.82.
Found: C, 61.27; H, 5.19; N, 20.07.
5-Oxy-pyrido[2,3-b]quinoxaline-9-carboxylic Acid (2-Piperidin-
1-yl-ethyl)amide (4h).
This compound was obtained in 44% yield (0. 108 g), mp 157-
1
160 °C; H nmr (deuterochloroform, 400 MHz): d 12.26 (s, 1H),
8.94 (m, 1H), 8.23 (d, J=7.84 Hz, 1H), 7.70 (m, 1H), 7.64 (d,
J=8.2 Hz, 1H), 7.41 (m, 1H), 3.69 (brs, 2H, NHCH2), 2.65 (t,
2H, NHCH2CH2, J= 6.2 Hz), 2.51 (brs, 4H, 2,6-piperidyl), 1.67
(brs, 4H, 3,5- piperidyl), 1.52 (brs, 2H, 4- piperidyl)
Anal. Calcd for C19H21N5O2: C, 64.94; H, 6.02; N, 19.93.
Found: C, 64.77; H, 6.18; N, 20.27.
5-Oxy-pyrido[2,3-b]quinoxaline-9-carboxylic Acid (2-Pyrrolidin-
1-yl-ethyl)amide (4i).
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Bioorg. Med. Chem. Lett. 6, 865, (1996).
This compound was obtained in 29% yield (0.070 g), mp 150-
152 °C; 1H nmr (deuterochloroform, 400 MHz):d 8.94 (m, 1H),
8.26 (dd, J=8.2 Hz, J= 1.36 Hz, 1H), 7.70 (m, 1H), 7.53 (d, J=8.2
Hz, 1H), 7.41 (m, 1H), 3.73 (q, 2H, NHCH2, J= 6.2 Hz), 2.86 (t,
2H, NHCH2CH2, J= 6.2 Hz), 2.68 (brs, 4H, 2,5-pyrolidyl), 1.92
(brs, 4H, 3,4-pyrolidyl); ms: m/z 337 (M+).
Anal. Calcd for C18H19N5O2: C, 64.08; H, 5.68; N, 20.76.
Found: C, 64.36; H, 5.51; N, 20.39.
[17] A. Varvaresou, A. Tsotinis, Th. Siatra-Papastaikoudi and T.
Calogeropoulou, J. Heterocyclic Chem. 33, 831, (1996).
[18] A. Varvaresou, A. Tsotinis, A. Papadaki-Valiraki and Th.
Siatra-Papastaikoudi, J. Heterocyclic Chem. 33, 917, (1996).
[19] L. Birkofer and A. Widmann, Chem. Ber., 10, 1295 (1953).
[20] B. Cross, P. J. Williams and R. E. Woodall, J. Chem. Soc.
(C) 2085 (1971).
[21] P. K. Brooke, S. R. Challand, M. E. Flood, R. B. Herbert, F.
G. Holliman and P. N. Ibberson, J. Chem. Soc. Perkin I, 2248 (1976).
[22] G. W. Rewcastle and W. A. Denny, Synth. Comm., 17,
1171 (1987).
N1,N2- Bis(5-oxy-pyrido[2,3-b]quinoxaline-9-benzoyl)ethylene-
diamine (5).
Ethylenediamine (0.21 g, 0.0035 mole) was added to a mixture of
ester3 (1.8 g, 0.007 mole) and sodium cyanide (0.5 g, 0.01 mole) in
methanol (60 ml). The reaction mixture was refluxed for 1 hour and
then cooled at room temperature. Water was added and the resulting
precipitate 5 was collected by filtration. Crystallization from ben-
zene gave 0.45 g (13 %) of 5, mp 160-163 °C; 1H nmr (acetone-d6,
400 MHz): d 8.40 (d, 2H, J=8.4 Hz), 8.02 (d, 2H, J=7.7 Hz), 7.97
(m, 2H), 7.88 (d, 2H, J=8.4 Hz), 7.67 (m, 2H), 7.40 (s, 2H, NH),
6.94 (d, 2H, J=7.7 Hz), 3.34 (br s, 4H, NH(CH2)2NH).
[23] B. Cross, C. L. Dunn, D. H. Payne and J. D. Tipton, J. Sci.
Fd. Agric. 20, 8 (1969).
Anal. Calcd for C26H18N8O4: C, 61.66; H, 3.58; N, 22.12.
Found: C, 61.94; H, 3.40; N, 22.37.
[24] T. Högberg, P. Ström, M. Ebner and S. Rämsby, J. Org.
Chem., 52, 2033 (1987).