Synthesis of 5,7-dihydrodibenzo[b,f][1,7]naphthyridine-6,12-dione, an unexpected isolate from Isatis tintoria

Article abstract of DOI:10.1002/hlca.200800337

The dye plant Isatis tinctoria yields a number of heterocyclic compounds with interesting anti-inflammatory and cytotoxic properties, formed mainly in an unknown manner by post-harvest treatment. A synthesis of the incidently isolated 5,7-dihydrodibenzo[b

Full text of DOI:10.1002/hlca.200800337

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Helvetica Chimica Acta – Vol. 92 (2009)
Synthesis of 5,7-Dihydrodibenzo[b,f][1,7]naphthyridine-6,12-dione, an
Unexpected Isolate from Isatis tintoria
by Herbert M. Riepl* and Melanie Kellermann
Institute of Resource and Energy Technology, Technical University of Munich, Petersgasse 18,
DE-94315 Straubing
(phone: þ 49-9421-187120; fax: þ 49-9421-187111; e-mail: herbert.riepl@wzw.tum.de)
The dye plant Isatis tinctoria yields a number of heterocyclic compounds with interesting anti-
inflammatory and cytotoxic properties, formed mainly in an unknown manner by post-harvest treatment.
A synthesis of the incidently isolated 5,7-dihydrodibenzo[b,f][1,7]naphthyridine-6,12-dione (4a) is
presented. Starting from different 1,2-diarylhydrazines, adducts 11 with acetylenedicarboxylates (¼ but-
2-ynedioates) are thermally treated (Scheme). In a Fischer-type rearrangement, 3-(arylamino)quinoli-
necarboxylic acids 9 are obtained, which can be cyclized under Friedel – Crafts conditions to yield a
number of analoga 4 of the title compound.
1. Introduction. – Isatis tinctoria (Brassicaceae), a plant native to the temperate
climate of Europe and Asia, is one of the sources of the indigo dye since its discovery
more than four or five thousand years ago. The dye is formed from some indole
glycosides present in the cells [1][2]. Some other plants like Indigofera species
(Leguminosae), Wrightia tinctoria (Apocynaceae), Polygonum tinctorium (Polygona-
ceae), or Baphicacanthes cusia (Acanthaceae), all native to South East Asia, also
produce these precursors. Preparations from the plant as well as the dye itself have
been and are used as a phytopharmaceutical. Quing Dai [3], a preparation of the
Chinese Traditional Medicine from various indigo-yielding plants, is mentioned as a
cure against malaria, various inflammations, namely gingival, jaundice, and ꢀcancerꢁ.
With respect of the last topic, one of the dyes present, indirubin (1; Fig. 1) and much
more interesting, the nonnaturally occurring indirubinsulfonic acid, has been found as
an effective inhibitor of cyclin-dependent kinases [4] and thus establishes the tradition
to be right. In Europe, there are hints on a use against ꢀallergyꢁ in the folk medicine. As
Fig. 1. Major compounds of pharmaceutical value from Isatis tinctoria besides indigo: indirubin (1) and
tryptanthrin (2)
ꢂ 2009 Verlag Helvetica Chimica Acta AG, Zꢃrich

Helvetica Chimica Acta – Vol. 92 (2009)
669
early as 1951, De Landsheere observed a decreasing effect on the blood-cell count of
eosinophiles of experimental animals after administration of indirubin (1) [5].
Besides these dyes, various other heterocycles have been isolated, e.g., tryptanthrin
(2), with interesting anti-inflammatory properties, and some more complex derivatives
[6][7].
2. Results and Discussion. – Considering the interesting medical properties of I.
tinctoria, the properties and synthesis of a new heterocycle will be reported here.
During an attempt to obtain quingdaone from an European Isatis spp. – a molecule first
isolated by Li [8] from Chinese I. tinctoria – we have collected a fraction from which a
tiny amount of a highly insoluble material separated. Having the same relative
molecular mass as indigo or indirubin, i.e., corresponding to the formula C16H10O2N2,
but having different mass spectra and being a dull yellow substance with lmax (DMF;
log e) 389 (0.43), 369 (0.41), 352 (0.23), 333 (0.39), and 319 (0.25) nm, this unknown
compound is different from both dyes or even from isoindigo.
First, the substance was suspected to be epindolidione1) (3; Fig. 2), known from the
industrial production of indigo as a minor component [9], or an isomeric ketenaminal
[10]. But the 1H- and 13C-NMR spectra (Table) revealed a structure with eight
recordable H-atoms, thus rendering impossible all symmetric structures. The compli-
cated C,H-COSY plot was consistent with a highly conjugated aromatic ring system,
1
featuring, e.g., three 13C-NMR signals connected with one H-NMR signal at d 7.41,
representing three H-atoms of two different rings (Table, cf. Footnotes b and c). Full
HBMC assignment of the NMR data was possible only for a corresponding quaternary
N-methyl salt, reported elsewhere.
Fig. 2. Possible dibenzonapthyridindione isomers from natural and synthetic sources: Epindolidione (3),
a minor impurity in the technical indigo synthesis, and dibenzo[b,h][1,6]naphthyridine-6,7-diol (5), and
11H-indolo[3,2-c]quinoline-6-carboxylic acid (6) from Tabernanthe iboga
The UV/VIS spectra of the unknown structure gave a hint to a six-membered-ring
system rather than to an indoxyl- or an indolone-like indigoid system, thus a structure
such as 4a, 4a’, 5, or 6 was proposed for this natural product (Figs. 2 and 3); however,
tautomeric forms could not be established up to now.
Unfortunately, the substance 4a or 4a’ was found only once by us in I. tinctoria plant
material. The lack of crystals suitable for X-ray analysis made necessary a synthetic
effort to reveal the correct structure of this substance by comparison. The possibility of
1
)
lmax (DMF; log e) 444 (0.22), 419 (0.185), 398 (0.033), 334 (0.072), and 274 (1.13) nm.

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Helvetica Chimica Acta – Vol. 92 (2009)
Table. 1H- and 13C-NMR Data (H,H- and C,H-COSY) of 5,7-Dihydrodibenzo[b,f][1,7]naphthyridine-
6,12-dione (4a/4a’; see Fig. 3). In (D6)DMSO; d in ppm.
13C-NMR
1H-NMR
HꢀC(1) to HꢀC(4) (ring A)
HꢀC(8) to HꢀC(11) (ring D)
177.86
157.28
138.85
134.63
133.09
127.72
126.18
126.16
125.78
125.16
123.92
123.27
119.48
118.04
115.65
114.96
(C(12)¼O)
(C(6)¼O)
(sa))
7.76
(sa))
7.41b)c)
(sa))
(sa))
9.73
8.33
8.11
7.41b)c)
7.35
(sa))
(sa))
7.41b)c)
c
a) Quaternary C-atoms. b) Tentative assignment to either ring A or D. ) Signal belonging to both rings A
and D (not resolved in (D6)DMSO.
Fig. 3. Dibenzo[b,f][1,7]naphthyridine-6,12-diol (4a) and 5,7-Dihydrodibenzo[b,f][1,7]naphthyridine-
6,12-dione (4a’) as possible tautomers
a whole set of isomeric structures for which very few data were available rendered
insecure a purely NMR-based approach. However, some isomeric systems could be
ruled out based on a HR-MS evidence, such as 5 [11] or 6. Moreover, the ethyl ester of
6 was synthesized as published [12]; the free acid 6 easily lost CO2 in the mass
spectrometer under various ionization conditions.
The alternative structure proposal 4a or 4a’ proved to be the correct ones. This class
of heterocycles is not very common in the chemical literature. Some related 6-
phenyldibenzonaphthyridine derivatives [13] are reported, as well as various chloro
derivatives or a 6-deoxy variant [14].
Retrosynthetic analysis suggests as starting material for the synthesis of 4a a
condensation product 7 from isatin (¼1H-indole-2,3-dione) with 2-nitrophenylpyruvic

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671
acid (¼ 3-(2-nitrophenyl)-2-oxopropanoic acid) (Fig. 4), which should be subjected to
reductive amidation of the nitro group. However, different attempts to synthesize 7 did
not yield any isolable product. Even by means of Pd-catalyzed CꢀC coupling of the N-
(2-bromophenyl)-substituted amide 8 of kynureninic acid (¼4-hydroxyquinoline-2-
carboxylic acid), no trace of 4a was obtained.
Fig. 4. Potential starting materials 7 – 9 from retrosynthetic designs for substance 4. The synthesis of 7
seems not to be feasible; 8 was obtained in 90% yield but did not react further; derivatives of 9 could be
cyclized (see Scheme).
Finally, it was shown that under certain circumstances, 3-(arylamino)-2-hydroxy-
quinoline-4-carboxylic acids 9a – 9e could be cyclized in a Friedel – Crafts-like manner
to give 4a – 4e (Scheme). Provided the reaction was performed in suspension, yields
were good, otherwise decarboxylation occurred quickly; this was ascertained by use of
PCl3 as a medium which has the additional advantage of a low boiling point. The use of
POCl3 also promoted cyclization but yielded the chloro derivatives 10a – 10c (Scheme),
as expected. Access to the 3-(arylamino)-2-hydroxyquinoline-4-carboxylic acids 9a – 9d
was easy; they are the products of a Fischer-type rearrangement of diesters 11, which
are adducts of symmetric 1,2-diarylhydrazines with acetylenedicarboxylic acid dimethyl
ester (¼dimethyl but-2-ynedioate) [15]. With nonsymmetric 1,2-diarylhydrazines, this
reaction gave mixtures whose purification was difficult. Generally, even for the
reported case, the success of this reaction depended very much on the quality of the 1,2-
diarylhydrazines. In our hands, all commercially available diarylhydrazines failed to
give the products 11 completely. The addition worked best with 1,2-diarylhydrazines
obtained by reduction from the corresponding azobenzenes with Zn powder in AcOH
under moderate conditions in the absence of air [16].
For the time being, the synthesis of additional analogues 4 according to the protocol
described above is confined since further 3-(arylamino)-2-hydroxyquinoline-4-carbox-
ylic acids 9 could not be synthesized by use of this reaction.
For instance, 1,2-(4-bromophenyl)hydrazine did not give useful products. A small
yield of 3-[(3,4-dimethylphenyl)amino]-1,2-dihydro-6,7-dimethyl-2-oxoquinoline-4-
carboxylic acid (9e) was obtained from 1,2-bis(3,4-dimethylphenyl)hydrazine with
dimethyl acetylenedicarboxylate; its low yield was due to a 18% admixture of the
regioisomeric 3-[(3,4-dimethylphenyl)amino]-1,2-dihydro-5,6-dimethyl-2-oxoquino-
line-4-carboxylic acid, which had to be removed by fractional crystallization. The
major crystallizate was pure and characterized by its 1H-NMR spectrum to be 9e (four
clear s for the Me groups) Acid 9e was cyclized according to the general protocol to

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Scheme. Successful Protocol for the Synthesis of Compounds of Type 4
a) Addition in MeOH, reflux. b) 1. Fischer-type rearrangement in pyridine or picoline (¼2-
methylpyridine), reflux; 2. 15% aq. NaOH soln. c) Friedel – Crafts cyclization with AlCl3/PCl3 or d)
POCl3/reflux.
yield two regioisomers 4e and 4e’ of a tetramethyl derivative in a nearly 1:1 ratio. In
case of shorter reaction times, the isomer ratio 4e/4e’ was 3 :1 or better whereby the
isomers could be distinguished by their 1H-NMR signals in (D6)DMSO (minor isomer
4e’ with two d/s systems for the aromatic H-atoms clearly separated from 4e with four s
where one s coincides with a s of 4e’). The regioisomers 4e and 4e’ could not be
separated sufficiently by crystallization.

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The above described synthesis supplied us with a useful number of analogues 4 for
an ongoing clarification of their possible cytotoxic activities and of the speculations
about the bioformation of 4a, an isolate which must be considered as an interesting
artefact until another isolation is successfully achieved. Indigo is a product of the
hydrolysis at basic pH in the dyeing broth and enzyme-free oxidative dimerization of
indoxyl (¼1H-indol-3-ol, mainly from isatan B or indican which is the b-d-glucoside of
1H-indol-3-ol). It occurs in very small concentrations in the fresh, intact plant. The
formation of indirubin (1) or other substances may be as well a nonenzymatic
condensation of indoxyl with isatin (¼1H-indole-2,3-dione), which is present in Isatis
species [17]. The marked influence of post-harvest treatment on the synthesis of
tryptanthrin (2) in the extracts of Isatis – it is formally condensed in this manner from
isatine and anthranilic acid (¼2-aminobenzoic acid) under less known circumstances –
was already a matter of concern [18].
Excellent support from the instrumental analytics by G. Krutsch, R. Dumitrescu, and U. Ammari is
given special attention here. We are indebted for financial support of the project by G. Klinge, the Klinge
Pharma Holding GmbH & Co. KG.
Experimental Part
General. UV/VIS Spectra: Analytik Jena-Specord 210; lmax (log e) in nm. IR Spectra: Perkin-Elmer
481; in KBr pellets, n˜ in cmꢀ1. NMR Spectra: Bruker AMX-400; d in ppm, J in Hz. MS: Finnigan MAT 70,
EI at 70 eV, CI in isobutane; in m/z (rel. %). Elemental analyses were obtained from the
Mikroanalytisches Labor, Institut fꢃr Anorganische Chemie, Technische Universitꢄt Mꢃnchen.
Synthesis of 11 and 9. Dimethyl acetylenedicarboxylate (¼dimethyl but-2-ynedioate) was purchased
from Sigma Aldrich. A limited number of 3-(arylamino)-1,2-dihydro-2-oxoquinoline-4-carboxylic acid
methyl esters could be prepared according to a known procedure [15] with freshly prepared 1,2-
diarylhydrazines. Shortly, the hydrazine and dimethyl (or diethyl) acetylenedicarboxylate were used in
equimolar amounts and boiled in MeOH. After crystallization, the adduct 11 was heated in a base,
pyridine or picoline. The 3-(arylamino)-1,2-dihydro-2-oxoquinoline-4-carboxylic acid 9 was obtained by
alkaline treatment of the respective methyl ester (ca. 2 g) by refluxing in 15% aq. NaOH soln (50 ml)
mixed with MeOH (3 – 4 ml) for 45 min. Insoluble materials were removed by filtration, and the filtrate
was then acidified with dil. aq. HCl soln. The solid acid was isolated by suction and dried in the air.
Friedel – Crafts Cyclization 9 ! 4: General Procedure. Exemplified by 6-chloro-3-[(4-chlorophenyl)-
amino]-1,2-dihydro-2-oxoquinoline-4-carboxylic acid (9b): A suspension of dry 9b (0.340 g, 0.001 mol) in
PCl3 (10 ml) was stirred for 30 min. Then PCl5 (0.2 g) was added, and the mixture was heated to reflux.
After 1 h, coarse-grained anh. AlCl3 (0.36 g; Fluka) was added while continuing the reflux for additional
4 to 5 h. The fine suspension turned redish, and an oil separated which was scratched from the walls from
time to time to ensure complete mixture with the rest of the soln. Finally, the solvent mixture was
decanted from the red oil, and ice (20 g) was added. By continued stirring, the oil turned into a yellow
powder: 0.276 g (83%) of 4b. Recrystallization was achieved from boiling DMF (or dimethylacetamide
or DMSO).
1,2-Dihydro-2-oxo-3-(phenylamino)quinoline-4-carboxylic Acid (9a). Yield 59%. Yellow needles
(MeOH). M.p. 2538. IR: 3379m (br.), 2985w, 2957w, 2887w, 2853w, 1689m, 1655vs, 1560s, 1519s, 1427m,
1375m, 1313w, 905w, 755m, 704m. 1H-NMR ((D6)DMSO): 12.25 (s, 1 H); 7.89 (s, 1 H); 7.63 (d, J ¼ 7.82,
1 H); 7.37 – 7.32 (m, 2 H); 7.19 – 7.15 (m, 3 H); 6.96 (d, J ¼ 7.82, 2 H); 6.87 (t, J ¼ 7.82, 1 H). 13C-NMR
((D6)DMSO): 167.0 (COOH); 158.8 (CONH); 142.7; 133.7; 130.7; 128.5; 127.1; 123.6; 122.5; 121.2; 120.7;
118.6; 117.4; 115.3. HR-CI-MS: 282 (18), 281 (100), 280 (38, [M þ 1]þ), 263 (7), 237 (17), 236 (10). Anal.
calc. for C16H12N2O3 (280.29): C 68.57, H 4.32, N 9.99; found: C 68.43, H 4.17, N 9.95.
5,7-Dihydrodibenzo[b,f][1,7]naphthyridine-6,12-dione (4a). Yield 89%. Orange powder (dimethyl-
acetamide). M.p. > 4008. UV/VIS (DMF): 414 (0.05), 389 (0.43), 369 (0.41), 352 (0.23), 333 (0.39), 319

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Helvetica Chimica Acta – Vol. 92 (2009)
(0.25). IR: 3034s (br.), 1626m, 1603vs, 1542vs, 1499w, 1482m, 1442w, 1421m, 1396m, 1324w, 1295m,
1151w, 1117w, 1043w, 1020w, 956w, 888w, 854w, 777w, 753s, 721w, 701w, 677w, 628w, 599m, 572w, 538w,
515w, 470w. 1H-NMR (CDCl3): 12.53 (s, 1 H); 12.24 (s, 1 H); 9.73 (d, J ¼ 7.8, 1 H); 8.30 (d, J ¼ 7.8, 1 H);
8.12 (d, J ¼ 8.8, 1 H); 7.76 (t, J ¼ 7.8, 1 H); 7.46 – 7.39 (m, J ¼ 7.1, 3 H); 7.31 (t, J ¼ 7.3, 1 H). 13C-NMR
((D6)DMSO): 177.9; 157.3; 138.9; 134.6; 133.1; 127.7; 126.2; 126.2; 125.8; 125.2; 123.9; 123.3; 119.5; 118.0;
115.7; 115.0. HR-CI-MS: 263 (52), 262 (100), 244 (3). Anal. calc. for C16H10N2O2 (262.27): C 73.27, H
3.84, N 10.68; found: C 73.8, H 3.76, N 10.64.
6,12-Dichlorodibenzo[b,f][1,7]naphthyridine (10a). Yield 90%. Tan solid (dimethylacetamide).
M.p. > 3508. IR: 1674w, 1614w, 1581w, 1541w, 1479m, 1459m, 1398m, 1332w, 1291s, 1254w, 1199w, 1136w,
1054m, 1032m, 1011w, 903w, 860w, 822s, 752vs, 650w. 1H-NMR ((D6)DMSO): 9.77 (d, J ¼ 7.83, 1 H); 8.69
(d, J ¼ 8.8, 1 H); 8.41 (d, J ¼ 7.83, 1 H); 8.12 – 8.10 (m, 2 H); 8.04 (t, J ¼ 7.82, 1 H); 7.94 – 7.88 (m, 2 H).
HR-CI-MS: 302 (17), 301 (47), 300 (74), 299 (73), 298 (100), 263 (19), 228 (18).
6-Chloro-3-[(4-chlorophenyl)amino]-1,2-dihydro-2-oxoquinoline-4-carboxylic Acid (9b). Yield
82%. Bright yellow needles (MeOH). M.p. 3158. IR: 3024s (br.) 1663vs, 1637vs, 1538s, 1544vs, 1490s,
1421s, 1383s, 1321s, 1286s, 1235vs, 1086m, 1009w, 903s, 886s, 847m, 820s, 807m, 777w, 746w, 729s, 720w,
697m. 1H-NMR ((D6)DMSO): 12.38 (s, 1 H); 8.28 (s, 1 H); 7.63 (s, 1 H); 7.36 (d, J ¼ 9.8, 1 H); 7.30 (d, J ¼
9.8, 1 H); 7.22 (d, J ¼ 7.3, 2 H); 6.98 (d, J ¼ 7.3, 2 H). 13C-NMR ((D6)DMSO): 167.13 (CO); 158.68
(CONH); 141.3; 132.8; 132.3; 128.7 (Cp); 127.0; 126.8; 125.9; 122.6; 121.5 (C(6)); 119.2; 117.5; 116.9. HR-
CI-MS (methyl ester): 364 (67), 362 (100), 332 (17), 330 (25), 304 (31), 302 (49), 295 (23), 267 (24), 239
(19), 170 (34). Anal. calc. for C16H10Cl2N2O3 (349.18): C 55.04, H 2.89, Cl 20.31, N 8.02; found: C 55.11, H
2.95, Cl 20.46, N 8.01.
2,10-Dichloro-5,7-dihydrodibenzo[b,f][1,7]naphthyridine-6,12-dione (4b). Yield 83%. Dull yellow
powder (dimethylacetamide). M.p. > 4008. IR: 3162m, 3032m, 1670vs, 1594vs, 1560vs, 1534vs, 1481m,
1457m, 1417m, 1391w, 1378w, 1338w, 1276w, 1231w, 1177w, 1143w, 1078w, 899w, 862w, 831m, 799w, 766w,
727s, 588m, 571m. 1H-NMR ((D6)DMSO): 12.57 (s, 1 H); 12.43 (s, 1 H); 9.63 (s, 1 H); 8.12 (s, 1 H); 8.08
1
(d, J ¼ 8.8,1 H); 7.74 (d, J ¼ 7.85, 1 H); 7.43 (d, J ¼ 7.85, 1 H); 7.34 (d, J ¼ 8.8, 1 H). H-NMR (CDCl3):
9.27 (d, J ¼ 2.25, 1 H); 7.8 (d, J ¼ 2.27, 1 H); 7.58 (d, J ¼ 8.8, 1 H); 7.11 (dd, J ¼ 2.25, 8.8, 1 H); 6.98 (d, J ¼
8.8, 1 H); 6.84 (dd, J ¼ 2.27, 8.8, 1 H). HR-CI-MS: 332 (12), 331 (4), 330 (19), 308 (11), 307 (15), 306
(70), 305 (40), 304 (100), 303 (29).
2,6,10,12-Tetrachlorodibenzo[b,f][1,7]naphthyridine (10b). Yield 83%. Yellow powder (dimethyl-
acetamide). M.p. > 4008. IR: 1603m, 1579m, 1543m, 1458m, 1393m, 1314s, 1235w, 1173w, 1139w, 1100m,
1085m, 1045s, 939m, 868m, 828vs, 787w, 731w, 688m, 665w, 589w, 561m. 1H-NMR (CDCl3): 9.75 (s, 1 H);
8.63 (s, 1 H); 8.39 (d, J ¼ 9.8, 1 H); 8.075 (d, J ¼ 8.6, 1 H); 7.9 (d, J ¼ 9.8, 1 H); 7.78 (d, J ¼ 8.6, 1 H). HR-
CI-MS: 372 (10), 371 (8), 370 (48), 369 (21), 368 (100), 367 (15), 366 (72), 333 (11), 332 (4), 331 (12), 298
(17), 297 (6), 296 (27), 262 (2), 261 (7).
1,2-Dihydro-6-methyl-3-[(4-methylphenyl)amino]-2-oxoquinoline-4-carboxylic Acid (9c). Yield
79%. Citron-yellow needles (MeOH). M.p. 2298. IR: 3385s (br.), 2875m, 1687s, 1658vs, 1565s, 1523s,
1472w, 1405w, 1368w, 1313w, 1258m, 1236w, 1187w, 945w, 898w, 859w, 809s, 774w, 684w, 614w, 530w.
1H-NMR ((D6)DMSO): 12.15 (s, 1 H); 7.4 (s, 1 H); 7.21 (d, J ¼ 8.8, 1 H); 7.15 (d, J ¼ 8.8, 1 H); 7.0 (d, J ¼
7.8, 2 H); 6.88 (d, J ¼ 7.8, 2 H); 2.3 (s, 3 H); 2.21 (s, 3 H). 1H-NMR (ethyl ester, CDCl3): 7.52 (s, 1 H); 7.4
(s, 1 H); 7.28 (d, J ¼ 8.05, 1 H); 7.11 – 7.09 (m, 3 H); 7.03 (d, J ¼ 8.05, 2 H); 3.46 (q, J ¼ 7.02, 2 H); 2.36 (s,
3 H); 2.31 (s, 3 H); 1.05 (t, J ¼ 7.03, 3 H). 13C-NMR (ethyl ester, CDCl3): 166.4 (COO); 160.0 (CON);
138.3; 133.6; 133.2; 132.8; 129.7; 127.7; 123.0; 121.5; 118.7; 115.9; 112.9; 61.0 (MeCH2); 21.3 (MeAr); 20.8
(MeAr); 13.8 (MeCH2). HR-CI-MS: 337 (25), 336 (100), 290 (15), 275 (11), 263 (11), 262 (43), 261 (10).
5,7-Dihydro-2,10-dimethyldibenzo[b,f][1,7]naphthyridine-6,12-dione (4c). Yield 70%. Yellow pow-
der (dimethylacetamide). M.p. > 4008. UV/VIS: 325 (0.33), 339 (0.51), 358 (0.3), 375 (0.53), 396 (0.55),
415 (sh, 0.06). IR: 3160 (br.), 3024m, 2924m, 1670vs, 1602vs, 1558s, 1537s, 1504s, 1453w, 1421m, 1386m,
1342w, 1322w, 1291m, 1259w, 1209w, 1195w, 1160w, 1039w, 993w, 903w, 874w, 822m, 770m, 710m, 670w,
622w, 603m, 576w, 551w, 484w, 472w. 1H-NMR ((D6)DMSO): 12.42 (s, 1 H); 12.15 (s, 1 H); 9.58 (s, 1 H);
8.07 (s, 1 H); 8.01 (d, J ¼ 7.8, 1 H); 7.58 (d, J ¼ 8.8, 1 H); 7.3 – 7.24 (m, 2 H); 2.45 (s, 3 H); 2.41 (s, 3 H).
HR-CI-MS: 292 (8), 291 (50), 290 (100). Anal. calc. for C18H14N2O2 (290.31): C 74.47, H 4.86, N 9.65;
found: C 74.36, H 4.71, N 9.59.

Helvetica Chimica Acta – Vol. 92 (2009)
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2,10-Dimethyl-6,12-dichlorodibenzo[b,f][1,7]naphthyridine (10c). Yield 70%. White needles (dime-
thylacetamide). M.p. > 4008. UV/VIS (DMF): 325 (0.22), 339 (0.35), 357 (0.2), 375 (0.31), 395 (0.32).
IR: 1692s, 1614s, 1581m, 1547w, 1477s, 1397m, 1324w, 1311s, 1181w, 1165w, 1140w, 1115w, 1061w, 979w,
873w, 831s, 812s, 729m, 679w, 626w, 588m, 528w, 464w. 1H-NMR ((D6)DMSO): 9.5 (s, 1 H); 8.44 (s, 1 H);
8.3 (d, J ¼ 8.57, 1 H); 7.99 (d, J ¼ 8.57, 1 H); 7.95 (d, J ¼ 8.6, 1 H); 7.74 (d, J ¼ 8.6, 1 H); 2.69 (s, 3 H); 2.64
(s, 3 H).
1,2-Dihydro-6-methoxy-3-[(4-methoxyphenyl)amino]-2-oxoquinoline-4-carboxylic Acid (9d). Yield
64%. Citron-yellow needles (MeOH). M.p. 1408 (dec.). IR: 3341s, 2932m, 2833m, 1675s, 1660 (sh),
1615s, 1588m, 1555w, 1512vs, 1454w, 1411w, 1366m, 1321m, 1295s, 1245s, 1219s, 1190m, 1169m, 1129w,
1035m, 904w, 842m, 826w, 808w, 781w, 729w, 710w, 678w, 610m, 544w. 1H-NMR ((D6)DMSO): 12.12 (s,
1 H); 7.81 (s, 1 H); 7.23 (d, J ¼ 8.8, 1 H); 7.1 (s, 1 H); 6.99 – 6.94 (m, 3 H); 6.79 (d, J ¼ 8.8, 2 H); 3.7 (s,
6 H). 13C-NMR ((D6)DMSO): 167.38; 158.06; 156.0; 155.13; 154.8; 134.7; 133.0; 126.8; 122.6; 118.9;
116.4; 113.8; 105.7; 55.23. HR-CI-MS (methyl ester): 355 (1), 354 (1), 353 (7), 338 (4), 189 (11), 188
(100), 150 (12), 109 (15). Anal. calc. for C18H16N2O5 (340.34): C 63.53, H 4.74, N 8.23; found: C 63.41, H
4.56, N 8.18.
5,7-Dihydro-2,10-dimethoxydibenzo[b,f][1,7]naphthyridine-6,12-dione (4d). Yield 63%. Tan solid.
1
M.p. 1408 (dec.). H-NMR ((D6)DMSO): 12.38 (s, 1 H); 12.29 (s, 1 H); 9.45 (s, 1 H); 8.08 (d, J ¼ 9.78,
1 H); 7.7 (s, 1 H); 7.42 (d, J ¼ 8.8, 1 H); 7.32 (d, J ¼ 8.8, 1 H); 7.07 (d, J ¼ 9.78, 1 H); 3.88 (s, 3 H); 3.83 (s,
3 H). 13C-NMR ((D6)DMSO): 176.7; 156.5; 155.9; 155.0; 133.8; 133.4; 127.0; 126.05; 123.7; 121.2; 118.8;
116.3; 115.2; 113.3; 108.8; 104.3; 55.4; 55.2.
3-[(3,4-Dimethylphenyl)amino]-1,2-dihydro-6,7-dimethyl-2-oxoquinoline-4-carboxylic Acid (9e).
Following the procedure reported in [15], a bright yellow powder was obtained in 78% yield, consisting
of 3-[(3,4-dimethylphenyl)amino]-1,2-dihydro-6,7-dimethyl-2-oxoquinoline-4-carboxylic acid methyl
ester and ca. 18% of 3-[(3,4-dimethylphenyl)amino]-2-hydroxy-5,6-dimethylquinoline-4-carboxylic acid
methyl ester. This ester mixture was saponified with base and the resulting acid mixture precipitated by
acid. Part of the acid mixture (5 g) was recrystallized with MeOH (30 ml) by heating and cooling to r.t.
The crystals from three such recrystallizations were pooled and recrystallized again in MeOH to yield
pure 9e in 33% yield. Bright yellow solid. M.p. 2788. IR: 3379s, 2919m, 1682s, 1642s, 1609w, 1583w, 1547s,
1514s, 1447m, 1405m, 1359w, 1320m, 1263w, 1241m, 1216m, 1193m, 1118w, 969w, 864w, 820w, 788w, 752w,
1
733m. H-NMR ((D6)DMSO): 12.07 (s, 1 H); 7.56 (s, 1 H); 7.36 (s, 1 H); 7.08 (s, 1 H); 6.91 (d, J ¼ 7.2,
1 H); 6.75 (s, 1 H); 6.7 (d, J ¼ 7.2, 1 H); 2.24 (s, 3 H); 2.21 (s, 3 H); 2.1 (s, 3 H); 2.09 (s, 3 H). 13C-NMR
((D6)DMSO): 167.35; 158.85; 140.3; 135.98; 135.76; 131.73; 130.79; 130.24; 129.54; 128.94; 123.64;
120.07; 119.14; 116.5; 115.74; 115.62; 19.57; 19.54; 19.35; 18.68. HR-CI-MS: 338 (19.5), 337 (100), 319
(19), 293 (21), 150.0 (19). Anal. calc. for C20H20N2O3 (336.4): C 71.41, H 5.99, N 8.33; found: C 70.36, H
5.99, N 8.21.
5,7-Dihydro-2,3,9,10-tetramethyldibenzo[b,f][1,7]naphthyridine-6,12-dione/5,7-Dihydro-2,3,10,11-
tetramethyldibenzo[b,f][1,7]naphthyridine-6,12-dione (4e/4e’). According to the general protocol, a
suspension of pure 9e (1.0 g, 0.001 mol) was stirred in PCl3/PCl5/AlCl3 and worked up after 1.5 h refluxing
time as indicated. Yellow solid (68%). After recrystallization from DMF, a powder was obtained
1
consisting of 4e/4e’ 3 :1 (two sets of H-NMR signals). 1H-NMR ((D6)DMSO): 4e: 12.29 (s, 1 H); 11.71
(s, 1 H); 9.35 (s, 1 H); 8.01 (s, 1 H); 7.83 (s, 1 H); 7.13 (s, 1 H); 2.5 – 2.3 (m, 12 H); 4e’: 12.32 (s, 1 H); 11.93
(s, 1 H); 9.5 (s, 1 H); 7.72 (d, J ¼ 7.28, 1 H); 7.44 (d, J ¼ 7.28, 1 H); 7.13 (s, 1 H); 2.5 – 2.3 (m, 12 H).
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Received August 29, 2008