A Facile Synthesis of 5-Phenyl-Dibenzo[b, g][1,8]Napthyridines

Article abstract of DOI:10.1002/jhet.2256

The Vilsmeier Haack heterocyclization of 2-aryl amino-4-phenyl quinolines quinoline yielded the hitherto unknown 5-phenyl-dibenzo[b,g][1,8]naphthyridines in quantitative yield. The synthesis of aryl amines was achieved by the action of anilines on 2-chloro-4-phenyl quinoline, which in turn was sourced through the combes reaction of benzoyl acetanilides.

Full text of DOI:10.1002/jhet.2256

924
A Facile Synthesis of 5-Phenyl-Dibenzo[b, g][1,8]Napthyridines
Natarajan Sampathkumar, Arumugam Murugesh, and Subramaniam Parameswaran Rajendran
School of Chemical Sciences, Bharathiar University, Coimbatore 641 046, Tamil Nadu, India
Vol 53
*
*
E-mail: rajendransp@yahoo.com
Additional Supporting Information may be found in the online version of this article.
Received January 28, 2014
DOI 10.1002/jhet.2256
Published online 29 September 2015 in Wiley Online Library (wileyonlinelibrary.com).
The Vilsmeier Haack heterocyclization of 2-aryl amino-4-phenyl quinolines quinoline yielded the hitherto
unknown 5-phenyl-dibenzo[b,g][1,8]naphthyridines in quantitative yield. The synthesis of aryl amines was
achieved by the action of anilines on 2-chloro-4-phenyl quinoline, which in turn was sourced through the
combes reaction of benzoyl acetanilides.
J. Heterocyclic Chem., 53, 924 (2015).
INTRODUCTION
electron-rich aliphatic aromatic and heteroaromatic sub-
strates [14]. Even though it is now used as a powerful tool
for the construction of various heterocycles [15], the in situ
or simultaneous formylation/cyclization process using the
same is little explored. As a continuation of this research,
we now report the new approaches toward the synthesis of
5-phenyl-dibenzo[b,g][1,8]naphthyridines (5) through the
heterocyclization of 2-aryl amino-4-phenyl quinolines (4)
using Vilsmeier reagent in a convenient and efficient process.
Naphthyridines represent a group of six isomeric hetero-
cyclic systems containing two fused pyridine rings with
different mutual arrangement of nitrogen atoms. Among
the isomers, [1,8]naphthyridines have received the most at-
tention in the last 15 years as their skeleton is present in a
large number of compounds isolated from natural sources.
Their importance is reflected in the many routes to these
compounds with more than 900 publications, which include
200 patents [1], in the last few years alone. They are the
basis for the design of highly efficient antibacterial drugs
such as enoxacin [2] and trovafloxacin [3–6]. A part from
these, they are used as antitumor and DNA intercalating
agents [7,8]. Phenyl-substituted [1,8]naphthyridines are
especially reported to possess antitubercular properties [9].
Few methods are reported for the synthesis of dibenzo[b,
g][1,8]naphthyridines [10,11]. Recently, our laboratory fo-
cused on the synthesis of dibenzo[b,g][1,8]naphthyridines
through a novel one-step reaction [12] of 2-chloro-3-formyl
quinolines with aryl amines as well as 1,2,3,4-tetrahydro-
dibenzo [b,g][1,8]naphthyridines [13] from 2-amino-3-
formyl quinolines through a Friedlander type condensation
reaction.
RESULTS AND DISCUSSION
The aryl amino quinolines (4), 2-chloro-4-Phenyl/(4′-
methoxyphenyl)quinolines (3) were prepared through ethyl
benzoyl acetate and ethyl 4′-methoxybenzoyl acetate, re-
spectively. While the former was used as such, the latter
was prepared form p-anisic acid using thionyl chloride.
The respective benzoyl acetanilides were prepared by
the Knorr reaction [16], where in the benzoyl acetates were
condensed with aniline at 140°C in xylene medium.
The attempted cyclization of the benzoyl acetanilides (1)
to the 2-hydroxy 4-phenyl quinolines (2) in acid medium
by the Combes process [17,18] gave average yields in sul-
furic acid, while maximum yields was obtained through in
situ prepared and activated polyphosphoric acid. Literature
The Vilsmeier Haack reaction is one of the useful gen-
eral methods employed for the formylation of various
© 2015 HeteroCorporation

May 2016
A Facile Synthesis of 5-Phenyl-Dibenzo[b, g][1,8]Napthyridines
925
reveals that K. Hino and co-workers [19] have prepared the
2-hydroxyl-4-(4′-methoxy)phenyl quinoline (2g) by the
Camps quinoline syntheses route and found them to be
antiulcer agents. Their reported yields were 67%. We got
a yield of 96% of the same through the benzoyl acetanilide
route by the Combes reaction [17,18].
In our case, it was felt that DMF/POCl3 would be a very
good formylating/cyclizing agent, where by both the process
could be done simultaneously in a single step in achieving the
titled compounds 5 from 4. Here, the 2-aryl amino 4-phenyl/
(4′-methoxyphenyl)quinoline (4) and the Vilsmeier adduct
prepared in the ratio of [1:1:5 (1-reactant, 1-DMF and 5-
POCl3)] gave good results. Here, the POCl3 was added to
the reactant in DMF and not the usual way of reactant to
the Vilsmeier adduct. A clear change in TLC was observed
after heating on a water bath for 4.5–5 h. Further heating
resulted in a decrease in the concentration of the observed
new compound observed. After the usual work up, the com-
pound was confirmed as the 5-phenyl-dibenzo[b,g][1,8]
naphthyridine (5) by the spectral and the analytical technique.
Here, the formylation was expected to take place on the or-
tho position of the N-phenyl ring rather than on the C3-carbon
of the quinoline ring, followed by cyclization with the C3-
proton on the quinoline ring. This could be rather explained
on the basis of steric factor, where in the formylation on the
quinoline ring is impeded by the 4-phenyl ring, while it is
not so on the N-aryl side. This conclusion was drawn on
the basis of our failed attempts to formylate the 2-hydroxy-
4-phenyl quinoline (2) as well as the 2-hydroxy-3-dihydro-
4-phenyl quinoline on the C3-position by the Vilsmeier route.
We always ended up with the 2-cloro-4-phenyl quinoline in
both the attempts. In the reaction we were unable to isolate
the aldehyde intermediate confirming that after formylation,
the cyclization was simultaneous and immediate under the
acidic Vilsmeier Haack reaction condition itself. The reaction
was very well generalized and was extended to the other
derivatives with moderate to very good yields (Scheme 1).
The 2-hydroxy-4-phenyl/(4′-methoxyphenyl)quinoline
(2) were converted to the precursor 2-chloro-4-phenyl/(4′-
methoxyphenyl)quinolines by the action of POCl3 in the
presence of N,N-dimethylaniline. To achieve the 2-aryl
amino 4-phenyl/(4′-methoxyphenyl)quinoline, we attempted
the condensation of (3) with aniline in ethanol medium in the
presence of triethyl amine. It did not show any result even
after several hours of reflux. On expectation that high
temperature would initiate the reaction, keeping the
reactants as such, the solvent was changed to t-butanol, and
the mixture was heated on an oil bath for several hours. Here,
some change was observed, but it was not very significant
and well pronounced. A pinch of aniline hydrochloride was
added to the reaction mixture, and here, after 12 h, the
change was well defined and clear; moreover, the starting
compound completely disappeared in thin-layer chromatog-
raphy (TLC) showing that the addition of aniline hydrochlo-
ride accelerated the reaction, probably aniline hydrochloride
helps in the removal of chlorine during its nucleophilic
displacement by the aromatic amine.
Literature cites that 3-formyl-4-(N-phenylamino) pyri-
dines [20,21] underwent cyclization easily in the presence
of POCl3 to give [1,6] naphthyridines; here, the formyl
group was located at the ortho position to the aryl amino
group on the pyridine ring.
Scheme 1
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

926
N. Sampathkumar, A. Murugesh, and S. P. Rajendran
Vol 53
Mechanism.
The whole of the reaction can be
summarized in the probable mechanism.
EXPERIMENTAL
4-Methoxy-benzoyl chloride.
p-Anisic acid (25 g,
0.03289 mole) and thionyl chloride (24 mL, 0.03289 mole) were
heated on a water bath for about 2 h. Excess thionyl chloride
was striped under reduced pressure, and the residue was taken
in dry benzene for the next step as such.
General.
Ethyl-4-methoxy benzoyl acetate was sourced
from Aldrich. Other reagents were obtained from local
commercial sources. Melting points (mps) were determined on a
Boetius microheating table and are uncorrected. TLC were
performed on glass plates coated with silica gel-G incorporating
13% CaSO4 as binder. Purification of the crude samples was
carried out using chromatographic columns packed with silica gel
(60–120 mesh) and neutral alumina. Infrared spectra were
recorded on a Perkin-Elmer-597 Infrared Spectrophotometer as
KBr pellets. 1H-NMR spectra were recorded on an AMX-
400 MHz NMR spectrophotometer using CDCl3 as the solvent
and Me4Si as internal standard, and the chemical shifts are
quoted in δ ppm. Mass spectra were recorded on an EI
Autospec mass Spectrophotometer. Elemental analyses were
performed on Cario-Elmer 1106 and Perkin-Elmer Analyzer.
Microanalyses were obtained (C,H,N 0.4%).
Ethyl-4-methoxybenzoyl acetate.
Freshly
distilled
ethylacetoacetate (20mL, 0.1580mole) and toluene (30.4mL)
were added and cooled to 5°C in an ice bath. Out of 40mL of
33% NaOH, 8 mL was added, and pH was raised to 11, and the
mixture was stirred. To it, p-methoxybenzoylchloride (28 mL,
0.1642mole) in benzene was added in drops, further the
remaining NaOH solution (32mL) were added, and the reaction
mixture was stirred well at 35°C. After half an hour, the
aqueous layer was separated, and to it, NaCl (11 g) and NH4Cl
(9.7g) were added. The aqueous layer was collected and taken
in a separating funnel, and to it, 40mL of benzene was added.
The organic layer was separated and dried using anhydrous
sodium sulfate. The benzene was distilled under reduced
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

May 2016
A Facile Synthesis of 5-Phenyl-Dibenzo[b, g][1,8]Napthyridines
927
pressure. The yield of ethyl-4-methoxybenzoyl acetate was
(24 mL, 70%).
7-Methyl-2-(N-phenylamino)-4-phenylquinoline (4c). The
compound was obtained as white needles from petroleum ether:
chloroform (8:2)(430 mg, 70.3%); mp 115°C; IR: 3225(ÀNH),
Benzoyl acetanilide/4-methoxy-benzoyl acetanilide (1a–o). To
ethylbenzoyl acetate (3.9 mL, 0.0225 mole)/ethyl 4′-methoxybenzoyl
acetate (6 mL, 0.0225 mole) in a round bottom flask, aniline (2.1 mL,
0.0225 mole) was added. To this reaction mixture, xylene (6 mL)
was added, and the whole of the reaction mixture was heated at
140°C on an oil bath for 4 h. After the completion of the reaction,
the reaction mixture was cooled to allow crystallization to take
place. To rinse out the xylene in the flask, 10 mL of petroleum
ether was added twice. The product was washed with 30mL of
1:1 petroleum ether and benzene. The washing was repeated three
times. The benzoyl acetanilide/4′-methoxybenzoyl acetanilide was
obtained as shining crystals.
1
1615 (ÀC═N); H-NMR δ: 2.52 (s, 3H, C7-CH3), 6.52 (bs, 1H,
ÀNH), 6.9 (s, 1H, C3-H), 7.3-7.79 (m, 13H, C5-H, C6-H, C8-H,
C4-ArH, 2-N-ArH). Anal. Calcd for C22H18N2: C, 85.13; H,
5.84; N, 9.03. Found: C, 85.09; H, 5.82; N, 8.95.
8-Methyl 2-(N-phenylamino)-4-phenylquinoline (4d).
The
compound was obtained as white needles from petroleum ether:
chloroform (8:2)(430mg, 70.5%); mp 157–58°C; IR: 3145
1
(ÀNH), 1608 (ÀCN); H-NMR δ: 2.77(s, 3H, C8-CH3), 6.73(bs,
1H, ÀNH), 6.79(s,1H, C3-H), 7.02–7.75 (m, 13H, C5-H, C6-H,
C7-H, C4-ArH, 2-N-ArH). Anal. Calcd for C22H18N2: C, 85.13;
H, 5.84; N, 9.03. Found: C, 85.11; H, 5.81; N, 8.99; MS (EI) m/z
(%): 311(30(M + 1), 310(100) M+, 233(45).
2-Hydroxy-4-phenyl) quinoline/2-hydroxy-4-(4′-methoxy-
6,8-Dimethyl-2-(N-phenylamino)-4-phenylquinoline (4e). The
compound was obtained was white needles from petroleum
ether: chloroform (8:2)(420 mg, 77.6%); mp 137°C; IR: 3345
(ÀNH), 1608.18 (ÀC═N); 1H-NMR δ: 2.45 (s, 3H, C6-CH3),
2.72(s, 3H, C8-CH3), 6.60 (bs, 1H, ÀNH), 6.79 (s,1H, C3-H),
7.25–8.12 (m, 12H, C5-H, C7-H, C4-ArH, 2-N-ArH). Anal.
Calcd for C22H20N2: C, 85.15; H, 6.21; N, 8.64. Found: C,
85.10; H, 6.19; N, 8.61. See Supporting Information File 1 for
full experimental data.
phenyl)quinoline (2a–o).
Benzoyl acetanilide (1.5 g, 0.0063
mole)/4′-methoxybenzoylacetanilide (1.50 g, 0.0056mole) was
added to in situ prepared and activated polyphosphoric acid
24mL (15 g P2O5 + 4 mL H3PO4) taken in a round bottom flask.
The reaction mixture was heated on a water bath for about 6 h.
After the completion of the reaction, the reaction mixture was
poured into crushed ice and stirred well. The precipitated 2-
hydroxy-4-methoxy-phenylquinolines were filtered, washed well
with water, and dried.
General procedure for the synthesis of 5-phenyl-dibenzo[b,
2-Chloro-4-phenylquinolines/2-chloro-4-(4′-methoxphenyl)
quinolines (3a–o). 2-Hydroxy-4-phenylquinoline (1 g, 0.0045
mole)/2-hydroxy-4-(4′-methoxyphenyl)quinolines (1 g, 0.0037 mole),
phosphorous oxychloride (6.28 mL, 0.08549 mole), and 2 drops of
N,N-dimethyl aniline were taken in a round bottom flask and
heated on a water bath for 4.5 h. After the completion of the
reaction, the reaction mixture was poured into crushed ice and
stirred well. The precipitated 2-chloro-4-phenyl quinolines/2-
chloro-4-(4′-methoxyphenyl)quinolines were filtered, washed
well with water, and dried. Pure chloro compound was obtained
by column chromatography over silica gel using petroleum ether
and ethyl acetate (98:2) as eluant.
g][1,8]naphthyridines/5-(4′-methoxyphenyl) dibenzo[b,g] [1,8]
naphthyridines (5a–o).
2-(N-phenylamino)-4-phenylquinoline
(0.282g, 0.00092 mole)/2-(N-phenylamino)-4-(4′-ethoxyphenyl)
quinoline (300 g, 0.00092 mole) and dimethyl-formamide
(≈0.1 mL, 0.00092mole) were taken in a round bottom flask and
was added to it phosphorous oxychloride (0.43mL, 0.0046 mole),
drop wise. The reaction mixture was heated on a water bath for
5 h. After the completion of reaction, the whole of the reaction
mixture was poured into crushed ice, the precipitated solid was
filtered. Neutralization of the mother liquor using sodium
bicarbonate yielded a further crop of the precipitate, which
together was dried. The mixture was chromatographed over
neutral alumina using petroleum ether: ethylacetate (95:5) as
eluant, which furnished the pure compound.
General procedure for the synthesis of 2-(N-phenylamino)-
4-phenyl)quinolines/2-(N-phenylamino)-4-(4′-methoxyphenyl)
quinolines (4a–o).
2-Chloro-4-phenylquinoline (0.5 g, 0.00209
5-Phenyl-dibenzo[b,g][1,8]naphthyridine (5a). The compound
was obtained as pale yellow crystals in petroleum ether:
chloroform (9:1)(210 mg, 74.67%); mp 123°C; IR: 1610 (ÀC═N);
1H-NMR δ: 7.15–7.95(m, 13H, C1-H, C2-H, C3-H, C4-H, C7-H,
C8-H, C9-H, C10-H, C5-ArH), 9.01(s, 1H, C6-H). Anal. Calcd for
C22H14N2: C, 86.25; H, 4.61; N, 9.14. Found: C, 86.18; H, 4.59;
N, 9.15.
3-Methyl-5-phenyl-dibenzo[b,g][1,8]naphthyridin (5b). The
compound was obtained as pale yellow crystals in petroleum
ether: chloroform (9:1)(240 mg, 77.5%); mp 148°C; IR: 1615
(ÀC═N); 1H-NMR δ: 2.5(s, 3H, C3-CH3), 7.2–7.95 (m, 12H, C1-
H, C2-H, C4-H, C7-H, C8-H, C9-H, C10-H, C5-ArH), 8.95(s, 1H,
C6-H). Anal. Calcd for C23H16N2: C, 86.22; H, 5.03; N, 8.75.
Found: C, 86.18; H, 4.98; N, 8.72.
mole)/2-Chloro-4-(4′-methoxyphenyl)quinoline (0.5 mg 0.001855 mole),
aniline (0.168 mL, 0.0018 mole), t-butanol(5 mL), Et3N (0.00185
mole), and a pinch of aniline hydrochloride were taken in a
round bottom flask fitted with a condenser. The mixture was
refluxed on an oil bath for about 12 h at 120°C. After the
appropriate time, the excess butanol was removed under reduced
pressure. The product was recrystallised from petroleum ether
and chloroform (8:2) mixture.
2-(N-phenylamino)-4-phenylquinoline (4a). The compound was
obtained as white needles from petroleum ether: chloroform (8:2)
(290 mg, 47%); mp 110°C; IR: 3210 (ÀNH), 1610 (ÀCN); 1H-
NMR δ: (7.95–7.21) (m, 14H, C5-H, C6-H, C7-H, C8-H and N-Ph
H, C4-PhH), 6.84(s, 1H, C3-H), 6.65 (bs, 1H, ÀNH). Anal. Calcd
for C21H16N2: C, 85.11; H, 5.44; N, 9.45. Found: C, 85.05; H, 5.36;
N, 9.43.
2-Methyl-5-phenyl-dibenzo[b,g][1,8]napthyridine (5c).
The
compound was obtained as pale yellow crystals in petroleum
ether: chloroform (9:1) (210 mg, 67.8%); mp 181°C; IR: 1605.2
(ÀC═N). Anal. Calcd for C23H16N2: C, 86.22; H, 5.03; N, 8.75.
Found: C, 86.17; H, 4.97; N, 8.71.
6-Methyl-2-(N-phenyl amino)-4-phenylquinoline (4b). The
compound was obtained as white flakes from petroleum ether:
chloroform (8:2) (400mg, 65.39%); mp163°C; IR: 3290 (ÀNH),
1
1620 (ÀC═N); H-NMR δ: 2.35 (s, 3H, C6-CH3), 6.62 (bs, 1H,
1-Methyl-5-phenyl-dibenzo[b,g][1,8]naphthyridine (5d).
The
ÀNH), 6.75 (s, 1H, C3-H), 7.1–8.01 (m, 13H, C5-H, C7-H, C8-H,
C4-ArH, 2-N-ArH). Anal. Calcd for C22H18N2: C, 85.13; H, 5.84;
N, 9.03. Found: C, 85.07, H, 5.76, N, 9.04.
compound was obtained as pale yellow crystals in petroleum ether:
chloroform (9:1)(250 mg, 80.7%); mp 118°C; IR: 1612.6 (ÀC═N);
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

928
N. Sampathkumar, A. Murugesh, and S. P. Rajendran
Vol 53
1H-NMR δ: 2.81(s, 3H, C1-CH3), 7.27–7.72(m, 12H, C2-H, C3-H,
C4-H, C7-H, C8-H, C9-H, C10-H, C5-ArH), 8.97 (s, 1H, C6-H).
Anal. Calcd for C23H16N2: C, 86.22; H, 5.03; N, 8.75. Found: C,
86.15; H, 4.96; N, 8.69.
1,3-Dimethyl-5-phenyl-dibenzo[b,g][1,8]napthyridine (5e). The
compound was obtained as pale yellow crystals in petroleum ether:
chloroform (9:1)(230 mg, 74.3%); mp 212°C; IR: 1620 (ÀC═N);
1H-NMR δ: 2.42 (s, 3H, C3-CH3), 2.78 (s, 3H, C1-CH3), 6.9–8.23
(m, 12H, C2-H, C4-H, C6-H, C7-H, C8-H, C9-H, C10-H and C5-ArH).
Anal. Calcd for C24H18N2: C, 86.20; H, 5.42; N, 8.38. Found: C,
86.12; H, 5.37; N, 8.31. See Supporting Information File 2 for full
experimental data.
[3] (a) Urbaskova, P.; Trupl, J.; Hupkova, H.; Appelbaum, P. C.;
Jacobs, M. R. Eur J Clin Microbial Infect Dis 1996, 15, 686; (b) Chem
Abstr 1997, 126, 16683.
[4] Kaatz, G. W.; Seo, S. M.; Aeschlimann, J. R.; Houlihan, H. H.;
Mercier R. C.; Rybak, M. J. Antimicrob Agents Chemother 1998, 42, 254.
[5] Vilsmeier, E.; Goerz, T. Synthesis 1998, 739.
[6] (a) Garey, K. W.; Amdsen, G. W. Pharmacotheraphy 1999, 19,
21; (b) Chem Abstr 1999, 130, 290 888.
[7] L. Dalla Via; O. Gia; S. Marciani Magno; A. Da Settimo; G.
Primofiore; F. Da Settimo; F. Simorini; Marini, A. M. Eur J Med Chem
2002, 37, 475.
[8] Lerman, L. S. J Mol Biol 1961, 3, 18.
[9] Ferrarini, P. L.; Manera, C.; Mori, C.; Badawneh, M.;
Saccomanni, G. Il Farmaco 1998, 53, 741.
[10] Shi, S.; Wudl, F. J Org Chem 1998, 53, 5379.
[11] Tominaga, Y.; Michioka, T.; Moriyama, K.; Hosomi, A.
J Heterocyclic Chem 1990, 27, 1217.
Acknowledgments. We thank the services rendered by the
“Sophisticated Instrumentation Facility” at Indian Institute of
Science, Bangalore, and “Indian Institute of Chemical
Technology”, Hyderabad in recording the 1H-NMR and mass
spectra, respectively. Authors also gratefully acknowledge
University Grants Commission, Bahadurshah Zafer Marg, New
Delhi for the financial assistance.
[12] Sampathkumar, N.; Venkatesh Kumar, N.; Rajendran, S. P.
Syn Commun 2004, 34, 2019.
[13] Prakash, G. A.; Rajendran, S. P. Heterocyclic Commun 2000, 6, 63.
[14] Marson, C. M. Tetrahedron, 1992, 48, 3659.
[15] Meth-Cohn, O. Heterocycles, 1993, 35, 539.
[16] Jones, G. Heterocycl. Compd. 1977, 32, 137, John Wiley and
Sons Inc.: New York.
[17] Manske, R. H. Chem Rev 1942, 30, 113.
[18] Elderfield, R. C. Heterocycl Compd 1952, 4, 31, John Wiley
and Sons Inc.: New York.
[19] Hino, K.; Kwashima, K.; Oka, M.; Nagai, Y.; Uno, H. Matsui J
Chem Pharm Bull 1989, 37, 110.
REFERENCES AND NOTES
[20] Yalysheva, N. Z.; Solov’eva, N. P.; Chistyakov, V. V.; Y. N.,
SHeinker; Granik, V. G. Khim Geterotsikl Soedin 1986, 1118.
[21] Tugusheva, N. Z.; Ershov, L. V.; Granik, V. G.; Ya Shvarts,
G.; Syubaev, R. D.; Mashkovskii, M. D. Khim Farm Zh 1986, 20, 830.
[1] Litvinov, V. P. Russ Chem Rev, 2004, 73(7), 637.
[2] Miyamoto, T.; Egawa, H.; Matsumoto, J. Chem Pharm Bull
1987, 35, 2280.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet