Synthesis, properties, and reactions of 5-substituted derivatives of 2,3-diphenylquinoxaline

Article abstract of DOI:10.1007/s00706-003-0058-5

Catalytic hydrogenation of 5-nitro-2,3-diphenylquinoxaline led to the corresponding amine which, in turn, afforded products of nucleophilic substitution on reaction with alkoxymethylene derivatives. Thermal cyclization of selected alkoxymethylene derivatives yielded substituted pyridoquinoxalines. The conditions for successful hydrolysis of ester, decarboxylation of the acid, following chlorination of pyridone and reductive removal of the chlorine atom from it to produce parental heterocycle 2,3-diphenyl-pyrido[2,3-f]quinoxaline were found. All of the tested products of the nucleophilic substitution showed no antibacterial activity. Springer-Verlag 2003.

Full text of DOI:10.1007/s00706-003-0058-5

Monatshefte f€ur Chemie 135, 283–291 (2004)
DOI 10.1007/s00706-003-0058-5
Synthesis, Properties, and Reactions
of 5-Substituted Derivatives
of 2,3-Diphenylquinoxaline [1]
1;ꢀ
1
ˇ1
´
´
Jozef Salon , Viktor Milata , Miloslav Chudık ,
Nadezda Pronayova , Jan Lesko , Milan Seman ,
2
2;y
3
ˇ
´
3
´
ˇ
´
and Anna Belicova
1
Department of Organic Chemistry, Faculty of Chemical Technology,
Slovak Technical University, SK-812 37-Bratislava, Slovakia
2
Central laboratory of Chemical Technique, Faculty of Chemical Technology,
Slovak Technical University, SK-812 37-Bratislava, Slovakia
3
Institute of Cells Biology, Faculty of Natural Sciences of the Comenius University,
SK-811 07 Bratislava, Slovakia
Received March 27, 2003; accepted (revised) April 15, 2003
Published online December 30, 2003 # Springer-Verlag 2003
Summary. Catalytic hydrogenation of 5-nitro-2,3-diphenylquinoxaline led to the corresponding amine
which, in turn, afforded products of nucleophilic substitution on reaction with alkoxymethylene
derivatives. Thermal cyclization of selected alkoxymethylene derivatives yielded substituted pyrido-
quinoxalines. The conditions for successful hydrolysis of ester, decarboxylation of the acid, following
chlorination of pyridone and reductive removal of the chlorine atom from it to produce parental
heterocycle 2,3-diphenyl-pyrido[2,3-f]quinoxaline were found. All of the tested products of the nucleo-
philic substitution showed no antibacterial activity.
Keywords. Nucleophilic substitutions; Enols; Cyclizations; Pyridoquinoxalines; Antibacterial
activity.
Introduction
Numerous quinoxaline derivatives have attracted attention by their biological
importance and have been synthesized by many research groups [2]. For example,
quinoxaline-2-one has been shown to possess anti-inflammatory, tranquilizing, and
antidepressant properties. Imidazoquinoxalines have even been found to be strong
carcinogens in food [3]. Due to this and in continuation of our strategy aiming at
ꢀ
Corresponding author. E-mail: vmilata@cvt.stuba.sk
Dedicated to Prof. Dr. M. Uher on the occasion of his 65th birthday
y

ꢀ
J. Salon et al.
284
polyheterocyclic fused systems containing the quinoxaline moiety, we report the
synthesis and antibacterial activity of some new quinoxaline pyridoquinoxalines.
Results and Discussion
The starting material for the synthesis of 5-substituted derivatives 3 was
5-nitro-2,3-diphenylquinoxaline obtained by the reaction of benzil with 3-nitro-
1,2-phenylenediamine [4]. Catalytic hydrogenation of the nitro group of 5-nitro-
2,3-diphenylquinoxaline with palladium on charcoal in methanol yielded the
corresponding amine 1, which was immediately subjected to the subsequent reac-
tion with alkoxymethylene derivatives (Scheme 1).
The relative ratio of the individual geometric isomers could be estimated from
their NMR spectral data considering the integral intensities of signals. For instance,
the (E):(Z) ratio for 3g was found to be 1:10, whereas with other compounds the
energetically more favored (E) isomers prevailed. The (E):(Z) ratio of derivatives
with a cyano group (3h, 3i) was 3:1, that of derivatives with bulkier acetyl group (3e,
3f) was 4:1 and 6:1. This finding can most probably be explained by intramolecular
hydrogen bonding between the acetyl group and an imino hydrogen. This bonding,
Scheme 1

5-Substituted Derivatives of 2,3-Diphenylquinoxaline
285
however, does not exist in (E)-isomers of cyano derivatives, but for acetoacetate
derivatives the intramolecular hydrogen bond is stronger with the carbonyl of the
acetyl group than with that of the ester group. The presence of hydrogen bonding is
demonstrated by the value of the coupling constant 3JCH–NH between 12–14 Hz. In
addition, the carbonyl carbon resonates at higher field as compared with ‘‘free’’,
non-bonded carbonyls, and the wave numbers ꢀꢁ(C¼O) of ester and acetyl bands are
found at more than 1680 cmꢁ1 and 1620 cmꢁ1. The spectroscopic properties (IR,
UV, 1H and 13C NMR, MS) were in accord with the structures of compounds 3.
Thermal cyclocondensation of 3 at 250ꢂC in an inert solvent gave exclusively
the angularly fused pyrido[2,3-f ]quinoxalines 4 (Scheme 1). The determining fac-
tors for successful ring closure are a temperature above 250ꢂC, reaction time, high
purity of the starting material, the appropriate ratio of the starting material:solvent
(for diesters, 3-oxobutanoates, and Meldrum acid 1 g:15 cm3 or for 2-cyano-2-
propenoates 1 g:100 cm3), and performing the reaction with direct heating using
a heating jacket.
At the conditions of acid hydrolysis [5] the cyclization products 4j (concen-
trated hydrochloric acid) involve the acid 5 (Scheme 1); the latter can be consi-
dered a nonalkylated (at the pyridone nitrogen atom) analogue of nalidixic acid.
Alkaline hydrolysis does not lead to free acid. Probably, hydrolysis is prevented by
the low solubility of the starting ester in aqueous sodium hydroxide.
Aromatization of the pyridine ring was achieved by treatment with phosphorus
oxytrichloride and addition of DMF (necessary for the generation of the Vilsmeier
complex) at room temperature. Chlorination was performed also with 10H-py-
rido[2,3-f]quinoxalin-7-one 6 under the same conditions as above. Reductive
dechlorination of 7 was effected by the catalytic method using palladium on carbon
in the presence of sodium hydroxide. This produces the parent heterocycle 9,
unsubstituted on the pyridine ring.
The activity of 3a–3j against two Gram-positive (E. coli, S. enterica) and two
Gram-negative (S. aureus, B. subtilis) bacteria was tested. Unfortunately, the data
indicated that these compounds have much weaker antibacterial activities as com-
pared to nalidixic acid.
Experimental Section
Melting points were measured on a Kofler micro hot-stage, and their values were not corrected. IR
(0.5mg, 300 mg KBr) and UV spectra (methanol, c ¼ 1ꢃ10ꢁ3 molꢃdmꢁ3, cell width 2 mm) were
recorded with FTIR PU 9802 (Philips) and Specord (Zeiss, Jena) spectrophotometers. 1H and
1
13C NMR spectra were measured with a Varian VXR-300 apparatus (300MHz for H, 75MHz for
13C) with hexamethyldisiloxane as internal standard. EI mass spectra were taken with an MS 902S
(AEI-Kratos) instrument at 70 eV and 100 ꢁA current trap. The reactions were monitored using TLC
(Silufol 254 UV, CHCl3=MeOH ¼ 10=1, UV detection at 254 nm). Elemental analyses agreed satis-
factory with the calculated values.
5-Nitro-2,3-diphenylquinoxaline (1) was prepared according to Ref. [6]. The alkoxymethylene
derivatives dimethyl methoxymethylene malonate (2a), diethyl ethoxymethylene malonate (2b) and
ethoxymethylenepropane dinitrile (2c) are commercially available. Others were synthesized by con-
densation of alkyl orthoformate with an activated methylene component (derivatives of malonic and 3-
oxobutanoic acid, 2,4-pentadione) [7, 8]. Details of the preparation of 6, ethoxymethylene Meldrum’s
acid 2j, and a new procedure for preparing 2g are described in Ref. [9].

ꢀ
J. Salon et al.
286
Preparation of 3a–3j
5-Nitro-2,3-diphenylquinoxaline (10 mmol) was dissolved in 100cm3 of methanol, mixed with 350 mg
of 3% Pd=C catalyst, and hydrogenated (with magnetic stirring) under 120 kPa H2 until the H2
consumption stopped (about 670 cm3). The mixture was filtered into the methanolic solution of
corresponding alkoxymethylene derivative (10 mmol) and shortly boiled with magnetic stirring. After
cooling the reaction mixture is evaporated in vacuo to dryness and the residue is recrystallized from
indicated solvent.
2-[(2,3-Diphenylquinoxalin-5-ylamino)methylene]malonic acid dimethyl ester
(3a, C26H21N3O4)
Yield: 68%; mp 221–223ꢂC (methanol=benzene); IR: ꢀꢁ¼ 1720, 1624 (C¼O) cmꢁ1; UV: ꢂmax ¼ 262,
302, 368, 383 nm; MS(EI): m=z (%) ¼ 440 (Mþ þ 1, 17), 439 (Mþ, 60), 408 (7), 407 (16), 379 (6), 345
(12), 321 (25), 320 (100), 308 (7), 282 (11); 1H NMR (300 MHz, CDCl3): ꢃ ¼ 3.86 (s, OCH3), 3.93 (s,
OCH3), 7.33–7.64 (m, 2 ꢄ Ph), 7.67–7.82 (m, 6-H þ 7-H), 7.95 (d, J ¼ 8.1Hz, 8-H), 8.85 (d,
J ¼ 14.1Hz, 9-H), 11.33 (d, J ¼ 14.1Hz, NH) ppm; 13C NMR (75 MHz, CDCl3): ꢃ ¼ 51.2 (OCH3),
51.3 (OCH3), 95.0 (C10), 113.3 (C6), 121.8 (C8), 128.6, 128.8, 129.6, 129.8, 137.8, 138.7 (CHPh),
129.0, 129.1 (CPh), 130.1 (C7), 131.2 (C4a), 134.9 (C5), 140.9 (C8a), 153.6 (C9), 151.7, 154.0 (C2, C3),
165.0, 167.0 (CO) ppm.
2-[(2,3-Diphenylquinoxalin-5-ylamino)methylene]malonic acid diethyl ester
(3b, C28H25N3O4)
Yield: 72%; mp 170–172ꢂC (ethanol=benzene); IR: ꢀꢁ¼ 1725, 1652 (C¼O) cmꢁ1; UV: ꢂmax ¼ 265, 312,
323, 389 nm; MS(EI): m=z (%) ¼ 468 (Mþ þ 1, 29), 467 (Mþ, 89), 423 (33), 422 (100), 376 (13), 349
(27), 348 (30), 321 (12), 320 (19), 115 (13); 1H NMR (300MHz, CDCl3): ꢃ ¼ 1.37 (t, OCH2CH3), 1.42
(t, OCH2CH3), 4.29 (q, OCH2CH3), 4.37 (q, OCH2CH3), 7.30–7.54 (m, 2 ꢄ Ph), 7.54–7.62 (m, 6-H þ 7-
H), 8.05 (d, J ¼ 8.2Hz, 8-H), 8.71 (d, J ¼ 13.2Hz, 9-H), 11.28 (d, J ¼ 13.2 Hz, NH) ppm; 13C NMR
(75 MHz, CDCl3): ꢃ ¼ 14.3 (OCH2CH3), 14.5 (OCH2CH3), 60.3 (OCH2CH3), 60.7 (OCH2CH3), 95.9
(C10), 112.8 (C6), 121.8 (C8), 129.3, 129.5, 129.8, 131.3, 137.9, 138.9 (CHPh), 128.8, 129.0 (CPh), 130.1
(C7), 132.1 (C4a), 134.9 (C5), 140.4 (C8a), 150.6, 152.2 (C2, C3), 154.5 (C9), 165.1, 168.9 (CO) ppm.
2-[(2,3-Diphenylquinoxalin-5-ylamino)methylene]malononitrile (3c, C24H15N5)
Yield: 65%; mp 253–256ꢂC (xylene); IR: ꢀꢁ¼ 2216 (CN) cmꢁ1; UV: ꢂmax ¼ 259, 298, 360 nm;
MS(EI): m=z (%) ¼ 374 (Mþ þ 1, 27), 373 (Mþ, 100), 372 (10), 309 (12), 308 (50), 269 (14), 167
(7), 140 (16), 115 (12), 77 (12); 1H NMR (300MHz, DMSO-d6): ꢃ ¼ 7.32–7.62 (m, 2 ꢄ Ph), 7.86 (d,
J ¼ 8.2 Hz, 6-H), 7.89 (d, J ¼ 8.2 Hz, 8-H), 8.04 (dd, J ¼ 8.2, 8.2Hz, 7-H), 9.02 (s, 9-H), 10.79 (s,
NH) ppm; 13C NMR (75 MHz, DMSO-d6): ꢃ ¼ 54.1 (C10), 113.9 (CN), 116.0 (CN), 114.4 (C6), 122.3
(C8), 128.0, 128.4, 129.6, 129.9, 137.7, 138.6 (CHPh), 128.7, 128.9 (CPh), 130.0 (C7), 131.0 (C4a),
134.1 (C5), 140.4 (C8a), 152.1, 153.7 (C2, C3), 155.9 (C9) ppm.
3-[(2,3-Diphenylquinoxalin-5-ylamino)methylene]pentane-2,4-dione (3d, C26H21N3O2)
Yield: 51%; mp 201-203ꢂC (ethanol=benzene); IR: ꢀꢁ¼ 1632 (C¼O) cmꢁ1; UV: ꢂmax ¼ 258, 301, 333,
370, 386 nm; MS(EI): m=z (%) ¼ 408 (Mþ þ 1, 31), 407 (Mþ, 96), 392 (21), 364 (26), 322 (34), 296
(13), 283 (23), 282 (100), 77 (12), 43 (24); 1H NMR (300MHz, CDCl3): ꢃ ¼ 3.86 (s, OCH3), 3.93 (s,
OCH3), 7.22–7.44 (m, 2 ꢄ Ph), 7.48–7.52 (m, 6-H þ 7-H), 7.96 (d, J ¼ 8.1Hz, 8-H), 8.58 (d,
J ¼ 12.6Hz, 9-H), 13.80 (d, J ¼ 12.6Hz, NH) ppm; 13C NMR (75 MHz, CDCl3): ꢃ ¼ 27.6 (OCH3),

5-Substituted Derivatives of 2,3-Diphenylquinoxaline
287
31.6 (OCH3), 113.7 (C10), 114.2 (C6), 123.3 (C8), 128.0, 128.3, 129.7, 129.9, 137.9, 138.7 (CHPh),
128.7, 128.9 (CPh), 130.1 (C7), 131.2 (C4a), 134.2 (C5), 137.9 (C8a), 151.9, 152.1 (C2, C3), 153.7 (C9),
195.8, 199.9 (CO) ppm.
2-[(2,3-Diphenylquinoxalin-5-ylamino)methylene]-3-oxobutanoic acid methylester
(3e, C26H21N3O3)
Yield: 73%; mp 206–208ꢂC (ethanol=benzene); IR: ꢀꢁ¼ 1696, 1672 (C¼O) cmꢁ1; UV: ꢂmax ¼ 238,
258, 355 nm; MS(EI): m=z (%) ¼ 424 (Mþ þ 1, 28), 423 (Mþ, 100), 391 (37), 380 (15), 363 (27), 362
(35), 348 (15), 322 (18), 320 (34), 282 (58); 1H NMR (300MHz, CDCl3): ꢃ ¼ (E) 2.61 (s, CH3), 3.83
(s, OCH3), 7.37–7.92 (m, 2 ꢄ Phþ 6-8 H), 8.77 (d, J ¼ 13.8Hz, 9-H), 13.85 (d, J ¼ 13.8Hz, NH), (Z)
2.55 (s, CH3), 3.89 (s, OCH3), 7.37–7.92 (m, 2 ꢄ Ph þ 6-8 H), 8.88 (d, J ¼ 14.7Hz, 9-H), 12.14 (d,
J ¼ 14.7Hz, NH) ppm; 13C NMR (75 MHz, CDCl3): ꢃ ¼ (E) 31.5 (CH3), 51.4 (OCH3), 104.1 (C10),
112.0 (C6), 124.4 (C8), 128.4, 128.5, 129.8, 130.3, 138.1, 138.9 (CHPh), 129.2, 129.4 (CPh), 129.9 (C7),
132.1 (C4a), 136.0 (C5), 141.2 (C8a), 149.4 (C9), 152.1, 154.5 (C2, C3), 167.4, 199.9 (CO), (Z) 30.9
(CH3), 51.3 (OCH3), 105.0 (C10), 111.3 (C6), 123.9 (C8), 128.4, 128.5, 129.8, 130.3, 138.1, 138.9
(CHPh), 129.2, 129.4 (CPh), 130.2 (C7), 131.8 (C4a), 135.7 (C5), 141.3 (C8a), 148.5 (C9), 151.8, 154.5
(C2, C3), 168.0, 196.3 (CO) ppm.
2-[(2,3-Diphenylquinoxalin-5-ylamino)methylene]-3-oxobutanoic acid ethylester
(3f, C27H23N3O3)
Yield: 70%; mp 183–184ꢂC (ethanol=benzene); IR: ꢀꢁ¼ 1696, 1648 (C¼O) cmꢁ1; UV: ꢂmax ¼ 242,
259, 353 nm; MS(EI): m=z (%) ¼ 438 (Mþ þ 1, 29), 437 (Mþ, 100), 393 (25), 392 (56), 364 (45), 363
(47), 349 (28), 322 (32), 320 (43), 282 (70); 1H NMR (300 MHz, CDCl3): ꢃ ¼ (E) 1.39 (t, OCH2CH3),
2.61 (s, CH3), 4.31 (q, OCH2CH3), 7.37–7.92 (m, 2 ꢄ Ph þ 6-8 H), 8.77 (d, J ¼ 13.5 Hz, 9-H), 13.83 (d,
J ¼ 13.5Hz, NH) ppm; 13C NMR (75 MHz, CDCl3): ꢃ ¼ (E) 14.5 (OCH2CH3), 31.5 (CH3), 60.1
(OCH2CH3), 104.3 (C10), 111.8 (C6), 124.4 (C8), 128.3, 128.4, 129.8, 130.3, 138.1, 139.0 (CHPh),
129.2, 129.4 (CPh), 129.9 (C7), 132.0 (C4a), 136.1 (C5), 141.3 (C8a), 149.2 (C9), 152.0, 154.5 (C2, C3),
167.1, 199.9 (CO) ppm.
2-[(2,3-Diphenylquinoxalin-5-ylamino)methylene]-3-oxobutanenitrile (3g, C25H18N4O)
Yield: 79%; mp 242ꢂC (decomp) (xylene); IR: ꢀꢁ¼ 2207 (CN), 1655 (C¼O) cmꢁ1; UV: ꢂmax ¼ 237,
257, 350 nm; MS(EI): m=z (%) ¼ 391 (Mþ þ 1, 28), 390 (Mþ, 100), 375 (15), 348 (12), 347 (48), 308
1
(22), 283 (15), 282 (73), 77 (12), 43 (18); H NMR (300MHz, CDCl3): ꢃ ¼ (Z) 2.49 (s, CH3), 7.38–
7.78 (m, 2 ꢄ Ph þ 6, 7-H), 7.96 (d, J ¼ 8.4 Hz, 8-H), 8.11 (d, J ¼ 13.5Hz, 9-H), 13.54 (d, J ¼ 13.5Hz,
NH); 1H NMR (300 MHz, DMSO-d6): ꢃ ¼ (Z) 2.34 (s, CH3), 7.35–7.85 (m, 2 ꢄ Phþ 6, 7-H), 8.10 (d,
J ¼ 8.2 Hz, 8-H), 8.82 (d, J ¼ 13.8Hz, 9-H), 13.40 (d, J ¼ 13.8 Hz, NH) ppm; 13C NMR (75 MHz,
CDCl3): ꢃ ¼ (Z) 28.8 (CH3); 86.5 (C10), 111.7 (C6), 119.9 (CN), 125.3 (C8), 128.4, 128.5, 129.8, 130.2,
137.9, 138.7 (CHPh), 129.3, 129.6 (CPh), 129.8 (C7), 131.6 (C4a), 134.8 (C5), 141.2 (C8a), 148.9 (C9),
152.4, 154.8 (C2, C3), 196.6 (CO) ppm; 13C NMR (75 MHz, DMSO-d6): ꢃ ¼ (Z) 28.4 (CH3); 85.6
(C10), 113.2 (C6), 119.9 (CN), 124.2 (C8), 128.2, 128.2, 129.7, 129.9, 137.9, 138.5 (CHPh), 129.1,
129.3 (CPh), 130.5 (C4a), 130.6 (C7), 134.4 (C5), 140.4 (C8a), 150.9 (C9), 151.6, 154.1 (C2, C3), 196.2
(CO) ppm.
2-Cyano-3-(2,3-diphenylquinoxalin-5-ylamino)propenoic acid methyl ester
(3h, C25H18N4O2)
Yield: 69%; mp 243–245ꢂC (xylene); IR: ꢀꢁ¼ 2216 (CN), 1696 (C¼O) cmꢁ1; UV: ꢂmax ¼ 261, 302,
369 nm; MS(EI): m=z (%) ¼ 407 (Mþ þ 1, 28), 406 (Mþ, 100), 347 (22), 346 (24), 345 (31), 309 (14),

ꢀ
J. Salon et al.
288
308 (62), 282 (13), 114 (11), 77 (12); 1H NMR (300MHz, DMSO-d6): ꢃ ¼ (E) 3.81 (s, OCH3), 7.38–
8.07 (m, 2 ꢄ Ph þ 6, 7, 8-H), 8.91 (d, J ¼ 13.8Hz, 9-H), 14.25 (d, J ¼ 13.8 Hz, NH), (Z) 3.78 (s, OCH3),
7.38–8.07 (m, 2 ꢄ Phþ 6, 7, 8-H), 9.08 (d, J ¼ 14.7 Hz, 9-H), 12.20 (d, J ¼ 14.7Hz, NH) ppm; 13C NMR
(75 MHz, DMSO-d6): ꢃ ¼ (E) 51.8 (OCH3), 76.9 (C10); 114.3 (C6); 115.3 (CN); 122.5 (C8), 128.0,
128.2, 129.6, 129.9, 138.0, 138.5 (CHPh), 128.7, 128.9 (CPh), 130.5 (C4a), 130.7 (C7), 134.4 (C5), 140.5
(C8a), 152.0, 154.2 (C2, C3), 153.7 (C9), 164.6 (CO) ppm, (Z) 52.0 (OCH3), 75.8 (C10), 112.6 (C6),
117.8 (CN), 123.6 (C8), 128.0, 128.2, 129.6, 129.9, 138.1, 138.3 (CHPh), 128.7, 128.9 (CPh), 130.5
(C4a), 130.7 (C7), 134.4 (C5), 140.6 (C8a), 151.7 (C9), 151.5, 154.4 (C2, C3), 166.6 (CO) ppm.
2-Cyano-3-(2,3-diphenylquinoxalin-5-ylamino)propenoic acid ethyl ester
(3i, C26H20N4O2)
Yield: 68%; mp 238–239ꢂC (xylene); IR: ꢀꢁ¼ 2216 (CN), 1688 (C¼O) cmꢁ1; UV: ꢂmax ¼ 240, 259,
352 nm; MS(EI): m=z (%) ¼ 421 (Mþ þ 1, 28), 420 (Mþ, 100), 375 (8), 347 (20), 346 (19), 345 (26), 309
(12), 308 (47), 282 (12), 77 (15); 1H NMR (300 MHz, DMSO-d6): ꢃ ¼ (E) 1.38 (t, OCH2CH3), 4.37 (q,
OCH2CH3), 7.33–8.05 (m, 2 ꢄ Phþ 6, 7, 8-H), 8.43 (d, J ¼ 13.8Hz, 9-H), 14.12 (d, J ¼ 13.8 Hz, NH),
(Z) 1.32 (t, OCH2CH3), 4.27 (q, OCH2CH3), 7.33–8.05 (m, 2 ꢄ Phþ 6, 7, 8-H), 8.89 (d, J ¼ 14.5Hz,
9-H), 12.19 (d, J ¼ 14.5Hz, NH) ppm; 13C NMR (75 MHz, DMSO-d6): ꢃ ¼ (E) 14.2 (OCH2CH3), 60.8
(OCH2CH3), 76.8 (C10), 114.3 (C6), 115.4 (CN), 122.7 (C8), 128.1, 128.1, 129.6, 130.0, 138.0, 138.3
(CHPh), 129.1, 129.3 (CPh), 130.5 (C7), 130.6 (C4a), 134.4 (C5), 140.5 (C8a), 151.8, 154.1 (C2, C3),
153.5 (C9), 164.4 (CO), (Z) 14.2 (OCH2CH3), 60.8 (OCH2CH3), 76.0 (C10), 112.5 (C6), 117.8 (CN),
123.5 (C8), 128.1, 128.1, 129.6, 130.0, 138.1, 138.5 (CHPh), 129.1, 129.3 (CPh), 130.5 (C4a), 130.6
(C7), 134.4 (C5), 140.5 (C8a), 151.6 (C9), 151.4, 153.9 (C2, C3), 166.2 (CO) ppm.
5-[(2,3-Diphenylquinoxalin-5-ylamino)methylene]-2,2-dimethyl-[1,3]-dioxane-4,6-dione
(3j, C27H21N3O4)
Yield: 62%; mp 258–260ꢂC (xylene); IR: ꢀꢁ¼ 1722, 1688 (C¼O) cmꢁ1; UV: ꢂmax ¼ 257, 298,
377 nm; MS(EI): m=z (%) ¼ 451 (Mþ, 18), 393 (30), 350 (22), 349 (82), 348 (52), 321 (50), 320
(100), 143 (14), 115 (18); 1H NMR (300MHz, CDCl3): ꢃ ¼ 1.78 (s, C(CH3)2), 7.35–7.81 (m,
2 ꢄ Ph þ 6, 7-H), 8.00 (d, J ¼ 8.1 Hz, 8-H), 8.95 (d, J ¼ 14.7 Hz, 9-H), 14.11 (d, J ¼ 14.7 Hz, NH)
ppm; 13C NMR (75 MHz, CDCl3): ꢃ ¼ 27.2 (C(CH3)2), 88.9 (C10), 105.2 (C(CH3)2), 112.2 (C6), 125.8
(C8), 128.4, 128.5, 129.8, 130.2, 137.7, 138.7 (CHPh), 129.4, 129.6 (CPh), 129.8 (C7), 131.7 (C4a),
134.3 (C5), 141.1 (C8a), 150.1 (C9), 152.4, 154.9 (C2, C3), 163.7, 164.9 (CO) ppm.
Thermal Cyclization of Selected Aminoethylene Derivatives
A mixture of 3a, 3b, 3f, 3i, or 3j (1g; 2.3, 2.1, 2.3, 2.4, or 2.2 mmol) and 15cm3 of Dowtherm
(100 cm3 for 3i) was refluxed at 250ꢂC for 20, 20, 20, 360, or 10min. The precipitate formed after
cooling was collected by suction on a B€uchner funnel and washed several times with n-heptane. The
reaction was monitored by TLC (Silufol 254 UV, CHCl3) until the starting material disappeared. The
crude product was recrystallized from DMF.
7-Oxo-2,3-diphenyl-7,10-dihydropyrido[2,3-f]quinoxaline-8-carboxylic acid methyl ester
(4a, C25H17N3O3)
Yield: 82%; mp 320–325ꢂC; IR: ꢀꢁ¼ 1721, 1628 (C¼O) cmꢁ1; UV: ꢂmax ¼ 245, 318, 366, 382nm;
MS(EI): m=z (%) ¼ 408 (Mþ þ 1, 12), 407 (Mþ, 41), 376 (17), 375 (12), 374 (17), 364 (5), 363 (18), 350
(26), 349 (100), 348 (22), 347 (9), 320 (9), 319 (15), 318 (5), 304 (13), 273 (6), 272 (32), 216 (5), 188
(7), 187.5 (15), 174.5 (5), 173.5 (6), 169 (7), 143 (17), 141 (11), 115 (9), 114 (8), 113 (9), 77 (13), 73

5-Substituted Derivatives of 2,3-Diphenylquinoxaline
289
(42), 53 (10), 51 (5); 1H NMR (300 MHz, CF3COOD): ꢃ ¼ 3.91 (s, OCH3), 7.13–7.43 (m, 2 ꢄ Ph), 8.35
(d, J ¼ 9.0Hz, 5-H), 8.71 (d, J ¼ 9.0 Hz, 6-H), 9.30 (s, 9-H) ppm; 13C NMR (75 MHz, CF3COOD):
ꢃ ¼ 56.6 (OCH3), 111.9 (C8), 123.7 (C6a), 124.1 (C5), 130.9 (C6), 131.4 (C4a), 131.4, 132.1, 132.3,
132.5, 135.9, 136.9 (CHPh), 134.7, 137.1 (CPh), 136.1 (C10b), 139.7 (C10a), 149.2 (C9), 156.7, 162.4
(C2, C3), 169.7 (CO), 175.6 (C7) ppm.
7-Oxo-2,3-diphenyl-7,10-dihydropyrido[2,3-f]quinoxaline-8-carboxylic acid ethyl ester
(4b, C26H19N3O3)
Yield: 91%; mp 306–308ꢂC; IR: ꢀꢁ¼ 1712, 1628 (C¼O) cmꢁ1; UV: ꢂmax ¼ 243, 312, 365, 380nm;
MS(EI): m=z (%) ¼ 422 (Mþ þ 1, 13), 421 (Mþ, 42), 420 (6), 377 (6), 376 (12), 375 (14), 374 (17), 350
(26), 349 (100), 348 (20), 347 (10), 320 (9), 319 (18), 318 (21), 273 (6), 272 (34), 216 (6), 190 (5), 188
(5), 187.5 (14), 173.5 (5), 169 (8), 143 (14), 141 (13), 115 (9), 114 (8), 113 (8), 77 (12), 73 (6), 53 (8);
1H NMR (300MHz, CF3COOD): ꢃ ¼ 1.21 (t, OCH2CH3), 4.41 (q, OCH2CH3), 7.10–7.42 (m, 2 ꢄ Ph),
8.34 (d, J ¼ 9.0 Hz, 5-H), 8.70 (d, J ¼ 9.0Hz, 6-H), 9.31 (s, 9-H) ppm; 13C NMR (75 MHz,
CF3COOD): ꢃ ¼ 14.6 (OCH2CH3), 68.0 (OCH2CH3), 112.1 (C8), 123.7 (C6a), 124.0 (C5), 130.9
(C6), 131.4 (C4a), 131.4, 132.1, 132.2, 132.5, 135.8, 136.9 (CHPh), 134.7, 137.1 (CPh), 136.1 (C10b),
139.7 (C10a), 149.0 (C9), 156.6, 162.4 (C2, C3), 169.3 (CO), 175.8 (C7) ppm.
8-Acetyl-2,3-diphenyl-10H-pyrido[2,3-f]quinoxalin-7-one (4f, C25H17N3O2)
Yield: 94%; mp 287–289ꢂC; IR: ꢀꢁ¼ 1676, 1624 (C¼O) cmꢁ1; UV: ꢂmax ¼ 247, 283, 311, 368,
382 nm; MS(EI): m=z (%) ¼ 392 (Mþ þ 1, 14), 391 (Mþ, 80), 390 (9), 377 (27), 376 (100), 363
(15), 349 (12), 348 (10), 288 (10), 270 (8), 190 (5), 187.5 (7), 170 (8), 143 (7), 115 (5), 114 (7),
87 (6), 77 (9), 53 (6); 1H NMR (300MHz, DMSO-d6): ꢃ ¼ 2.89 (s, CH3), 7.37–7.62 (m, 2 ꢄ Ph), 7.90
(d, J ¼ 9.0 Hz, 5-H), 8.44 (d, J ¼ 9.0 Hz, 6-H), 8.65 (s, 9-H) ppm; 13C NMR (75 MHz, DMSO-d6):
ꢃ ¼ 30.4 (CH3), 118.2 (C5), 120.7 (C8), 123.0, 123.7 (CPh), 126.4 (C6a), 127.7, 128.7, 129.3, 129.6,
137.7, 138.0 (CHPh), 129.5 (C6), 131.3 (C4a), 135.7 (C10b), 141.6 (C10a), 143.1 (C9), 151.9, 154.7 (C2,
C3), 174.2 (C7), 196.0 (CO) ppm.
7-Oxo-2,3-diphenyl-7,10-dihydropyrido[2,3-f]quinoxaline-8-carbonitrile
(4i, C24H14N4O)
Yield: 79%; mp >350ꢂC; MS(EI): m=z (%) ¼ 375 (Mþ þ 1, 25), 374 (Mþ, 100), 373 (85), 169 (5), 168
1
(42), 140 (24), 117 (6), 113 (9), 77 (9), 51 (5); H NMR (300MHz, CF3COOD): ꢃ ¼ 7.29–7.60 (m,
2 ꢄ Ph), 8.23 (d, J ¼ 9.3 Hz, 5-H), 8.71 (s, 9-H), 8.82 (d, J ¼ 9.3 Hz, 6-H) ppm; 13C NMR (75 MHz,
CF3COOD): ꢃ ¼ 101.9 (C8), 119.8 (C5), 127.9 (C6a), 131.2 (C4a), 131.5, 132.3, 132.5, 136.3 (CHPh),
134.1 (CN), 134.3 (C6), 134.6, 137.2 (CPh), 138.0 (C10b), 139.0 (C10a), 149.9 (C9), 154.5, 161.0 (C2,
C3), 178.7 (C7) ppm.
2,3-Diphenyl-10H-pyrido[2,3-f]quinoxalin-7-one (4j, C24H15N3O3)
Yield: 80%; mp 350–352ꢂC; IR: ꢀꢁ¼ 1622 (C¼O) cmꢁ1; UV: ꢂmax ¼ 242, 266, 313, 365 nm; MS(EI):
m=z (%) ¼ 350 (Mþ þ 1, 25), 349 (Mþ, 100), 348 (65), 321 (8), 320 (17), 174.5 (5), 143 (37), 115 (31),
1
114 (7), 88 (8), 77 (6), 51 (5); H NMR (300MHz, CDCl3 þ MeOD): ꢃ ¼ 6.69 (d, J ¼ 6.5 Hz, 8-H),
7.36–7.58 (m, 2 ꢄ Ph), 7.99 (d, J ¼ 9.0 Hz, 5-H), 8.06 (d, J ¼ 6.5 Hz, 9-H), 8.55 (d, J ¼ 9.0 Hz, 6-H)
ppm; 13C NMR (75 MHz, CF3COOD): ꢃ ¼ 113.5 (C8), 122.2 (C5), 123.7 (C6a), 131.3 (C4a), 132.2 (C6),
131.6, 131.7, 132.5, 135.0, 137.4 (CHPh), 134.6, 136.2 (CPh), 137.7 (C10b), 139.1 (C10a), 148.5 (C9),
155.4, 162.1 (C2, C3), 173.4 (C7) ppm.

ꢀ
J. Salon et al.
290
7-Oxo-2,3-diphenyl-7,10-dihydropyrido[2,3-f]quinoxaline-8-carboxylic acid
(5, C24H15N3O3)
A mixture of 1.0 g of 4b (2.4mmol) and 20cm3 of 36% HCl was refluxed with stirring for 30 min. The
solid which precipitated on cooling was collected by suction, washed with 3ꢄ 50cm3 of H2O, and
dried. For analyses the sample was recrystallized from a mixture of DMSO and water (10:1) to give a
colourless solid 5 (750mg, 79%). Mp 279–281ꢂC; IR: ꢀꢁ¼ 1700, 1622 (C¼O) cmꢁ1; UV: ꢂmax ¼ 243,
1
311, 365 nm; H NMR (300MHz, CF3COOD): ꢃ ¼ 7.30–7.59 (m, 2 ꢄ Ph), 8.50 (d, J ¼ 9.0 Hz, 5-H),
8.85 (d, J ¼ 9.0Hz, 6-H), 9.51 (s, 9-H) ppm; 13C NMR (75 MHz, CF3COOD): ꢃ ¼ 112.0 (C8), 124.0
(C5), 124.2 (C6a), 131.2 (C6), 131.6 (C4a), 131.6, 132.3, 132.4, 132.7, 134.9, 137.3 (CHPh), 136.0,
136.2 (CPh), 137.1 (C10b), 140.0 (C10a), 149.9 (C9), 156.8, 162.5 (C2, C3), 171.5 (CO), 176.7 (C7) ppm.
Decarboxylation of Acid 5
A mixture of 75 mg of 5 (0.19 mmol) and 5 cm3 of quinoline was refluxed for 3 h under Ar. After
cooling, 50cm3 of n-heptane were added with stirring. The precipitate was collected by suction, washed
several times with diethylether, dried, and purified as described for 4, yielding 38mg of 4j (58%).
7-Chloro-2,3-diphenyl-pyrido[2,3-f]quinoxaline (7, C23H14ClN3)
To a stirred mixture of 500 mg of pyridone 4j (1.4mmol) in 5 cm3 of freshly distilled POCl3 10cm3 of
dry DMF were added drop by drop. After stirring for 1 day at rt, the viscous liquid was added dropwise
into 100 cm3 of cold H2O. The precipitated solid was collected by suction, washed with H2O, and dried.
Crystallisation from DMF gave 980 mg of 7 as colourless solid (93%). Mp 273–274ꢂC; IR: ꢀꢁ¼ 1372,
702 cmꢁ1; UV: ꢂmax ¼ 248, 262, 304, 356, 369 nm; MS(EI): m=z (%) ¼ 370 (Mþ þ 3, 25), 369
(Mþ þ 2, 33), 368 (Mþ þ 1, 45), 367 (Mþ, 100), 366 (67), 266 (28), 265 (26), 264 (82), 263 (33),
184.5 (6), 184 (7), 183.5 (20), 183 (7), 182.5 (7), 161 (13), 127 (8), 126 (69), 100 (7), 99 (22), 77 (16),
1
76 (8), 75 (6), 51 (11), 50 (5); H NMR (300MHz, CDCl3): ꢃ ¼ 7.35–7.70 (m, 2 ꢄ Ph), 7.79 (d,
J ¼ 4.2 Hz, 8-H), 8.28 (d, J ¼ 9.3 Hz, 5-H), 8.51 (d, J ¼ 9.3 Hz, 6-H), 9.15 (d, J ¼ 4.2 Hz, 9-H) ppm;
13C NMR (75 MHz, CDCl3): ꢃ ¼ 123.7 (C5), 125.6 (C8), 126.8 (C6a), 128.3, 128.4, 130.0, 130.3, 128.9,
129.2 (CHPh), 129.1 (C6), 138.7 (C4a), 138.6, 138.8 (CPh), 142.4 (C10b), 143.1 (C7), 146.8 (C10a), 150.5
(C9), 153.8, 154.7 (C2, C3) ppm.
7-Chloropyrido[2,3-f]quinoxaline (8, C11H6ClN3)
To a stirred mixture of 500 mg of 6 (1.4mmol) in 4 cm3 of freshly distilled POCl3 5 cm3 of dry DMF
were added drop by drop. After stirring for 1 day at rt, the viscous liquid was added dropwise to 50cm3
of cold H2O, stirred with charcoal, and filtered. Then the reaction mixture was neutralized with 17%
aqueous NH4OH. The precipitated solid was collected by suction, washed with H2O, and dried.
Crystallisation from DMF gave 300 mg of 8 as colourless solid (55%). Mp 292–293ꢂC; IR:
ꢀꢁ¼ 2800, 1130, 831 cmꢁ1
;
1H NMR (300 MHz, CDCl3): ꢃ ¼ 7.79 (d, J ¼ 4.7Hz, 8-H), 8.20 (d,
J ¼ 9.0 Hz, 5-H), 8.51 (d, J ¼ 9.0Hz, 6-H), 9.10 (d, J ¼ 4.7 Hz, 9-H), 9.34 (d, J ¼ 1.9 Hz, 2-H), 9.39
(d, J ¼ 1.9Hz, 3-H) ppm; 13C NMR (75 MHz, CDCl3): ꢃ ¼ 145.1, 146.4 (C2, C3), 141.1, 144.4 (C4a,
C10b), 125.9, 129.1 (C5, C6), 126.7 (C6a), 143.0 (C7), 124.0 (C8), 150.5 (C9), 146.9 (C10a) ppm.
2,3-Diphenylpyrido[2,3-f]quinoxaline (9, C23H15N3)
A mixture of 500 mg of 8 (1.4mmol), 54 mg of solid NaOH, 30 cm3 of ethanol, and 150 mg of 10%
Pd=C catalyst was hydrogenated with magnetic stirring under 120 kPa H2 overnight. The product 9 was
insoluble in the reaction mixture. It was crystallized together with catalyst from ethanol to give 290 mg
of yellow flakes (62%). It was not proved to be identical with the compound prepared disorderly from

5-Substituted Derivatives of 2,3-Diphenylquinoxaline
291
its tetrahydroderivative in Ref. [10] as judged from their data (mp 250ꢂC and UV: ꢂmax ¼ 297, 356,
367, 414). Mp 237–238ꢂC; IR: ꢀꢁ¼ 1362, 702cmꢁ1; UV: ꢂmax ¼ 242, 259, 299, 304, 354, 367nm;
MS(EI): m=z (%) ¼ 334 (Mþ þ 1, 27), 333 (Mþ, 100), 332 (75), 231 (14), 230 (86), 229 (55), 166.5 (17),
166 (9), 155.5 (7), 128 (5), 127 (44), 101 (6), 100 (21), 77 (10), 76 (10), 51 (9), 50 (6), 39 (5); 1H NMR
(300 MHz, CDCl3): ꢃ ¼ 7.31–7.68 (m, 2 ꢄ Ph), 7.69 (d, J ¼ 4.2 Hz, 8-H), 8.02 (d, J ¼ 9.0 Hz, 6-H),
8.16 (d, J ¼ 9.0 Hz, 5-H), 8.31 (dd, J ¼ 8.1, 1.7 Hz, 7-H), 9.25 (dd, J ¼ 4.2, 1.7 Hz, 9-H) ppm; 13C
NMR (75 MHz, CDCl3): ꢃ ¼ 123.4 (C5), 128.2 (C8), 128.2, 128.3, 130.0, 130.4, 128.8, 129.0 (CHPh),
128.8 (C6a), 130.0 (C6), 136.4 (C7), 138.9 (C4a), 139.0, 139.1 (CPh), 142.5 (C10b), 145.5 (C10a), 150.8
(C9), 153.3, 154.1 (C2, C3) ppm.
We were also interested in the potential antimicrobial activity of the synthetised compounds. The
basic antimicrobial screening was realised on the standard set of the Gram-negative (Escherichia coli
CNCTC 326=71, Salmonella enterica CCM 4420) and Gram-positive bacterial strains (Bacillus sub-
tilis CCM 2216, Staphylococcus aureus CNCTC 78=71). The bacterial strains were from the collec-
tions of the microorganisms CNCTC (Czechoslovak National Collection of Type Cultures, Prague) and
CCM (Czechoslovak Collection of Microorganisms, Brno).
Antimicrobial activity was characterised by value of MIC (minimal inhibitory concentration). The
MIC was defined as the lowest concentration of compound that completely inhibited growth of
bacteria after 24h incubation at 37ꢂC. The MIC was determined by serial tenfold dilutions in tubes
containing Mueller-Hinton broth as the assay medium. The final inoculum ranged from 5ꢄ 105 to
1 ꢄ 106 CFU=cm3. For the experiments the compounds were dissolved in DMSO. Concentrations of
tested substances ranged from 1 to 100 ꢁg=cm3. Nalidixic acid was used for control (E. coli
MIC=ꢁg=cm3 ¼ 4, S. enterica MIC=ꢁg=cm3 ¼ 16, S. aureus MIC=ꢁg=cm3 ¼ 128, B. subtilis
MIC=ꢁg=cm3 ¼ 64). For the tested compounds MIC was found to be >100 ꢁg=cm3.
Acknowledgments
ˇ ´
The authors thank the Slovak Grant Agency for financial support, Mrs. O. Lakatosova for measurement
ˇ ´
of the IR and UV spectra, and Mrs. M. Ondrejkovicova for elemental analyses.
References
ꢀ
ꢂ
´
ꢀ
[1] Salon J, Milata V, Pronayova N, Lesko J (2001) Utilisation of 6-Amino-2,3-dimethylquinoxaline
for the Synthesis of Tricyclic Pyridoquinoxalines via Gould-Jacobs reaction. In: Quinoxalines
Series Title with running series number 3., 2. – Part 2. Collect Czechoslov Chem Commun 66:
1691
[2] Ohmori J, Sakamoto S, Kupota H, Shimizu-Sasamata M, Okada M, Kawasaki S, Hidaka K,
Togami J, Furuya T and Murase K (1994) J Med Chem 37: 467
[3] Wakabayashi K, Nagao M, Esumi H and Sugimura T (1992) Cancer Res (Suppl). 52: 2092s
ꢀ
[4] Milata V, Salon J (1999) Org Prep Proc Int 31 (3): 347
[5] Milata V, Ilavsky D, Chudık M, Zalibera L’, Lesko J, Seman M, Belicova A (1995) Monatsh
´
ꢀ
´
ꢂ
Chem 126: 1349
[6] Borsche W, Rantscheff D (1911) Liebigs Ann 379: 162
[7] Claisen L (1893) Chem Ber 26: 2729
[8] De Bollemont EG (1901) Bull Soc Chim Fr 25: 18
´
[9] Salon J, Milata V, Pronayova N, Lesko J (2000) Monatsh Chem 131: 293
ꢀ
[10] Iljina IG, Kazennova NB, Yurasova EV, Potapov VM (1973) Khim Geterotsikl Soedin 4:
ꢂ
ꢀ
525