Synthesis of novel substituted dibenzonaphthyridines

Article abstract of DOI:10.1515/znb-2009-0714

4-Chloro-2-methylquinolines 1a - d on reaction with p-toluidine afforded 2,4′-dimethyl-4-(Nphenylamino) quinolines 2a - d which on reaction with aliphatic and aromatic carboxylic acids yielded the respective 7-substituted dibenzonaphthyridines 3a - d and

Full text of DOI:10.1515/znb-2009-0714

Synthesis of Novel Substituted Dibenzonaphthyridines
Manickam Manoj and Karnam J. R. Prasad
Department of Chemistry, Bharathiar University, Coimbatore, Tamil Nadu, India
Reprint requests to Prof. Dr. K. J. R. Prasad. E-mail: prasad 125@yahoo.com
Z. Naturforsch. 2009, 64b, 851 – 857; received April 8, 2009
4-Chloro-2-methylquinolines 1a – d on reaction with p-toluidine afforded 2,4ꢀ-dimethyl-4-(N-
phenylamino)quinolines 2a – d which on reaction with aliphatic and aromatic carboxylic acids
yielded the respective 7-substituted dibenzonaphthyridines 3a – d and 4a – d whereas a heterocyclic
acid afforded 5a – c and 6a – c.
Key words: 4-Chloro-2-methylquinolines, 2,4ꢀ-Dimethyl-4-(N-phenylamino)quinolines,
Acetic Acid, Benzoic Acid, 2-Chloro-8-methylquinoline-3-carboxylic Acid
Introduction
moieties utilizing anilinoquinolines, namely 2,4ꢀ-di-
methyl-4-(N-phenylamino)quinolines 2a – d, as pre-
cursors.
Heterocyclic compounds are very widely distributed
in nature and are essential to life as they play a vi-
tal role in the metabolism of living cells. There are a
vast number of pharmacologically active heterocyclic
compounds of which many are in regular therapeu-
Results and Discussion
With the objective to derive 2,4ꢀ-dimethyl-4-(N-
tic usage. Among various heterocyclic compounds, phenylamino)quinolines 2a – d which could be used as
quinoline-based drugs such as quinine, chloroquine, potential precursors to achieve the target molecules,
4-chloro-2-methyl-quinolines 1a – d were reacted with
pamaquine and quinacrine are well known for their
antimalarial property. In this regard some of the anili-
◦
p-toluidine under neat condition at 160 C. Com-
noquinolines particularly attracted considerable atten- pounds 2a – d were found to be in equilibrium with
their imino forms (ratio of amino form : imino form is
1 : 1) from 1H NMR spectroscopy (Scheme 1).
After obtaining the potential intermediates 2 we fo-
tion [1]. The interest in naphthyridine derivatives is
due to the exceptionally broad spectrum of their bio-
logical activities. They are used for the diagnosis and
therapy of diseases of humans including AIDS [2, 3] cused our attention to react them with aliphatic, aro-
and cancer [4]. Some of the dibenzonaphthyridines, matic and heterocyclic acids thereby anticipating to
i. e. quinoline dimers, have been shown to possess var- get these moieties as substitutents of the respective di-
ious biological activities like antimicrobial [5] and an- benzonaphthyridines. Hence 2a – d were reacted with
ticancer [6] activity, and are potent and selective 3- acetic acid and benzoic acid in the presence of PPA as
◦
phosphoinostide-dependent kinase-I inhibitors [7]. A catalyst at 160 C each for 5 h to afford the respec-
detailed survey of the literature points out that many tive products, 6,7,9-trimethyldibenzo[b,h][1,6]naphth-
reactions of chloroquinolines aimed to get substitution yridines 3a – d and 6,9-dimethyl-7-phenyldibenzo[b,h]
products possessing biological activity [8, 9]. Since the [1,6]naphthyridines 4a – d.
discovery of the first naphthyridine by Reissert in the
year 1893 [10], many procedures have been evolved
for the synthesis of simple benzo- and dibenzonaphth-
yridines [11– 14], but only very few accomplished the
construction through anilinoquinolines, i. e. (N-phen-
ylamino)quinolines [15, 16].
Since, both the quinoline and naphthyridine chem-
istry are well known for their biological importance,
we wanted to combine the quinoline moiety with
the naphthyridine unit. Therefore quinolines 2 were
reacted with 2-chloro-8-methylquinoline-3-carboxyl-
ic acid [17] for 8 h to afford two products. The
Herein we opt to synthesize the various 3-substitu- less polar products (35 %) eluted with a petroleum
ted dibenzonaphthyridines holding a diversity of sub- ether : ethyl acetate (99: 1) mixture answered Las-
stituents such as aliphatic, aromatic and heterocyclic saigne’s test for chlorine, and finally their structure was
c
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M. Manoj – K. J. R. Prasad · Synthesis of Novel Substituted Dibenzonaphthyridines
1, 2a: R1 = CH3, R2 = H
b: R1 = H, R2 = CH3
c: R1 = Cl, R2 = H
d: R1 = H, R2 = H
Scheme 1.
2, 3, 4a: R1 = CH3, R2 = H
b: R1 = H, R2 = CH3
c: R1 = Cl, R2 = H
d: R1 = H, R2 = H
5, 6a: R1 = CH3, R2 = H
b: R1 = H, R2 = CH3
c: R1 = Cl, R2 = H
Scheme 2.
assigned as 6,9-dimethyl-7-(2-chloro-8-methylquin-
The conversion of 5 to 6 was also done with 6 N HCl
olin-3-yl)dibenzo[b,h][1,6]naphthyridines 5a – c. The to get the same result. The reverse conversion of 6 to 5
more polar products (15 %) eluted with a petroleum through the familiar chlorination reaction using POCl3
ether: ethyl acetate (95 : 5) mixture showed a broad was also confirmed in the present case (Scheme 4).
1
singlet around δ = 9.3 ppm in their H NMR spec-
tra. The appearance of a carbonyl stretching vibration
Experimental Section
around 1640 cm−1 in the IR spectra and the pres-
Melting points (m. p.) were determined on a Mettler
ence of a carbonyl carbon signal around δ = 170 ppm
in the 13C NMR spectra revealed that the prod-
FP 51 apparatus (Mettler Instruments, Switzerland) and
are uncorrected. IR spectra were recorded on a Schimadzu
ucts formed were 6,9-dimethyl-7-(8-methylquinolin-
FTIR-8201PC spectrophotometer (Schimadzu, Japan) using
2[1H]-on-3-yl)dibenzo[b,h][1,6]naphthyridines 6a – c
1
a KBr disc. H NMR and 13C NMR spectra were recorded
(Scheme 2).
on a Bruker AMX 400 [400 MHz (1H) and 100 MHz (13C)]
spectrometer using tetramethylsilane (TMS) as an internal
reference. The chemical shifts are expressed in parts per mil-
lion (ppm). Mass spectra (MS) were recorded on an Au-
We assumed that the minor compounds 6 were defi-
nitely formed from the major compounds 5. The mech-
anism for the conversion of 5 to 6 under PPA condition
(Scheme 3) might involve the protonation of the ring
toSpec EI+ Shimadzu QP 2010 PLUS GC-MS mass spec-
nitrogen of 5 to give the intermediate I followed by the
ipso attack of the −OP2O6HR2 ion at the C-2ꢀ carbon
of the quinoline nucleus to yield the intermediate II.
Subsequent elimination of HCl would afford 6.
trometer. Microanalyses were performed with a Vario EL III
model CHNS analyzer (Vario, Germany) at the Department
of Chemistry, Bharathiar University. The purity of the prod-
ucts was tested by TLC with plates coated with silica gel-G
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M. Manoj – K. J. R. Prasad · Synthesis of Novel Substituted Dibenzonaphthyridines
853
5, I, II, 6a: R1 = CH3, R2 = H
b: R1 = H, R2 = CH3
c: R1 = Cl, R2 = H
d: R1 = H, R2 = H
Scheme 3.
5, 6a: R1 = CH3, R2 = H
b: R1 = H, R2 = CH3
c: R1 = Cl, R2 = H
d: R1 = H, R2 = H
Scheme 4.
with petroleum ether, ethyl acetate and methanol as develop- 11.20 (s, 1 H, C4-NH, amino form), 13.08 (s, 1H, N-1-H,
ing solvents.
imino form; the ratio of amino form : imino form is 1 : 1). –
13C NMR (100 MHz, [D6]DMSO): δ = 17.12 (4ꢀ-CH3),
18.25 (6-CH3), 19.80 (2-CH3), 109.03 (C-3), 114.36 (C2ꢀ,
C6ꢀ), 121.32 (C3ꢀ, C5ꢀ), 122.18 (C-5), 125.55 (C4ꢀ), 126.89
(C-8), 127.42 (C-7), 132.21 (C-6), 132.49 (C-4a), 143.67
(C1ꢀ), 148.93 (C-4), 149.56 (C-8a), 153.34 (C-2). – MS (EI,
70 eV): m/z (%) = 262 (100) [M]+. – C18H18N2 (262.35):
calcd. C 82.44, H 6.87, N 10.69; found C 82.37, H 6.91,
N 10.72.
Preparation of 2,4ꢀ-dimethyl-4-(N-phenylamino)quinolines
2, general procedure
4-Chloro-2-methylquinoline (1, 0.002 mol) was reacted
with p-toluidine (0.002 mol) under neat condition at 160 ◦C
for half an hour. The product obtained was washed with wa-
ter, dried, and purified by column chromatography over silica
gel using an ethyl acetate : methanol (95 : 5) mixture to get 2
as a white solid. It was recrystallized using methanol.
2,8,4ꢀ-Trimethyl-4-(N-phenylamino)quinoline (2b)
◦
2,6,4ꢀ-Trimethyl-4-(N-phenylamino)quinoline (2a)
M. p. > 300 C. – Yield: 0.236 g (45 %). – IR (KBr):
ν = 3397 (NH), 1599, 1545 cm−1. – 1H NMR (400 MHz,
M. p. > 300 C. – Yield: 0.262 g (50 %). – IR (KBr): [D6]DMSO): δ = 2.38 (s, 3 H, 4ꢀ-CH3), 2.67 (s, 3 H, 8-CH3),
ν = 3405 (NH), 1601, 1541 cm−1. – 1H NMR (400 MHz, 2.70 (s, 3 H, 2-CH3), 6.63 (s, 1 H, 3-H), 7.30 – 7.37 (m,
[D6]DMSO): δ = 2.41 (s, 3 H, 4ꢀ-CH3), 2.51 (s, 3 H, 6-CH3), 4 H, 2ꢀ-H, 3ꢀ-H, 5ꢀ-H, 6ꢀ-H), 7.64 (m, 1 H, 6-H), 7.82 (d,
2.62 (s, 3 H, 2-CH3), 6.49 (s, 1 H, 3-H), 7.25 – 7.36 (m, J = 7.08 Hz, 1 H, 7-H), 8.62 (d, J = 7.89 Hz, 1 H, 5-H),
4 H, 2ꢀ-H, 3ꢀ-H, 5ꢀ-H, 6ꢀ-H), 7.43 (d, J = 8.20 Hz, 1 H, 10.81 (s, 1 H, C4-NH, amino form), 12.51 (s, 1 H, N-1-H,
7-H), 8.03 (d, J = 8.80 Hz, 1 H, 8-H), 8.49 (s, 1 H, 5-H), imino form; the ratio of amino form : imino form is 1 : 1). –
◦
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M. Manoj – K. J. R. Prasad · Synthesis of Novel Substituted Dibenzonaphthyridines
13C NMR (100 MHz, [D6]DMSO): δ = 17.12 (4ꢀ-CH3), into excess ice water, extracted with ethyl acetate and puri-
18.97 (8-CH3), 20.13 (2-CH3), 108.69 (C-3), 114.93 (C2ꢀ, fied using silica gel column chromatography, and the product
C6ꢀ), 121.31 (C3ꢀ, C5ꢀ), 123.05 (C-5), 125.55 (C4ꢀ), 127.16 eluted with a petroleum ether : ethyl acetate (98 : 2) mixture
(C-6), 127.85 (C-7), 132.99 (C-8), 133.64 (C-4a), 144.08 to get 3, which was recrystallized using ethanol.
(C1ꢀ), 149.44 (C-4), 150.31 (C-8a), 152.96 (C-2). – MS (EI,
70 eV): m/z (%) = 262 (100) [M]+. – C18H18N2 (262.35):
calcd. C 82.44, H 6.87, N 10.69; found C 82.56, H 6.99,
N 10.45.
2,6,7,9-Tetramethyldibenzo[b,h][1,6]naphthyridine (3a)
◦
M. p. 222 – 224 C. – Yield: 0.092 g (32 %). – IR (KBr):
ν = 1624 and 1594 (C=N), 1535, 1450 cm−1. – 1H NMR
(400 MHz, CDCl3): δ = 2.54 (s, 3 H, 9-CH3), 2.77 (s, 3 H,
2-CH3), 3.11 (s, 3 H, 7-CH3), 3.19 (s, 3 H, 6-CH3) 7.55 –
8.10 (m, 4 H, 3-H, 4-H, 8-H, 10-H), 8.18 (d, J = 8.53 Hz, 1 H,
11-H), 9.13 (s, 1 H, 1-H). – 13C NMR (100 MHz, CDCl3):
δ = 17.47 (9-CH3), 21.85 (2-CH3), 25.43 (7-CH3), 29.67
(6-CH3), 117.14 (C-7a), 122.04 (C-6a), 122.82 (C-8), 125.85
(C-1), 126.79 (C-7), 128.26 (C-9), 128.42 (C-3), 128.92
(C-4), 130.95 (C-10), 131.51 (C-11), 132.33 (C-2), 134.51
(C-12b), 136.67 (C-11a), 146.72 (C-4a), 147.32 (C-12a),
158.66 (C-6). – MS (EI, 70 eV): m/z (%) = 286 (100) [M]+. –
C20H18N2 (286.37): calcd. C 83.92, H 6.29, N 9.79; found
C 83.82, H 6.09, N 10.09.
6-Chloro-2,4ꢀ-dimethyl-4-(N-phenylamino)quinoline (2c)
M. p. > 300 ◦C. – Yield: 0.226 g (40 %). – IR (KBr):
ν = 3409 (NH), 1597, 1543 cm−1. – 1H NMR (400 MHz,
[D6]DMSO): δ = 2.36 (s, 3 H, 4ꢀ-CH3), 2.65 (s, 3 H,
2-CH3), 6.55 (s, 1 H, 3-H), 7.24 – 7.34 (m, 4 H, 2ꢀ-H, 3ꢀ-
H, 5ꢀ-H, 6ꢀ-H), 7.64 (d, J = 8.40 Hz, 1 H, 7-H), 8.02 (d,
J = 8.68 Hz, 1 H, 8-H), 8.69 (s, 1 H, 5-H), 10.94 (s,
1 H, C4-NH, amino form), 13.23 (s, 1 H, N-1-H, imino
form; the ratio of amino form : imino form is 1 : 1). –
13C NMR (100 MHz, [D6]DMSO): δ = 17.12 (4ꢀ-CH3),
20.14 (2-CH3), 109.27 (C-3), 114.41 (C2ꢀ, C6ꢀ), 121.38 (C3ꢀ,
C5ꢀ), 122.62 (C-5), 125.55 (C4ꢀ), 127.92 (C-8), 128.54 (C-7),
130.98 (C-6), 132.81 (C-4a), 143.70 (C1ꢀ), 148.64 (C-4),
149.05 (C-8a), 153.16 (C-2). – MS (EI, 70 eV): m/z (%) =
284/282 (34/100) [M+2]/[M]+. – C17H15N2Cl (282.77):
calcd. C 72.34, H 5.32, N 9.93; found C 72.45, H 5.23,
N 9.85.
4,6,7,9-Tetramethyldibenzo[b,h][1,6]naphthyridine (3b)
M. p. 220 – 222 ◦C. – Yield: 0.086 g (30 %). – IR
(KBr): ν = 1628 and 1599 (C=N), 1531, 1460 cm−1. –
1H NMR (400 MHz, CDCl3): δ = 2.58 (s, 3 H, 9-CH3),
2.81 (s, 3 H, 4-CH3), 3.16 (s, 3 H, 7-CH3), 3.24 (s, 3 H,
6-CH3) 7.53 – 8.07 (m, 4 H, 2-H, 3-H, 8-H, 10-H)), 8.21
(d, J = 8.60 Hz, 1 H, 11-H), 9.11 (d, J = 7.64 Hz,
1 H, 1-H). – 13C NMR (100 MHz, CDCl3): δ = 17.47
(9-CH3), 22.68 (4-CH3), 25.45 (7-CH3), 29.75 (6-CH3),
117.14 (C-7a), 122.04 (C-6a), 122.82 (C-8), 126.16 (C-1),
126.79 (C-7), 128.26 (C-9), 127.33 (C-2), 128.64 (C-3),
130.95 (C-10), 131.51 (C-11), 132.83 (C-4), 134.82 (C-12b),
136.67 (C-11a), 147.09 (C-4a), 147.50 (C-12a), 158.87
(C-6). – MS (EI, 70 eV): m/z (%) = 286 (100) [M]+. –
C20H18N2 (286.37): calcd. C 83.92, H 6.29, N 9.79; found
C 83.86, H 6.12, N 10.02.
2,4ꢀ-Dimethyl-4-(N-phenylamino)quinoline (2d)
◦
M. p. > 300 C. – Yield: 0.213 g (43 %). – IR (KBr):
ν = 3406 (NH), 1590, 1536 cm−1. – 1H NMR (400 MHz,
[D6]DMSO): δ = 2.35 (s, 3 H, 4ꢀ-CH3), 2.68 (s, 3 H, 2-CH3),
6.41 (s, 1 H, 3-H), 7.27 – 7.38 (m, 4 H, 2ꢀ-H, 3ꢀ-H, 5ꢀ-H, 6ꢀ-
H), 7.52 – 7.84 (m, 2 H, 6-H, 7-H), 8.06 (d, J = 8.26 Hz, 1 H,
8-H), 8.56 (d, J =7.95 Hz, 1 H, 5-H), 10.97 (s, 1H, C4-NH,
amino form), 12.81 (s, 1H, N-1-H, imino form; the ratio of
amino form : imino form is 1 : 1). – 13C NMR (100 MHz,
[D6]DMSO): δ = 17.12 (4ꢀ-CH3), 19.93 (2-CH3), 108.85
(C-3), 114.24 (C2ꢀ, C6ꢀ), 121.32 (C3ꢀ, C5ꢀ), 123.10 (C-5),
125.86 (C4ꢀ), 126.86 (C-6), 127.25 (C-7), 128.43 (C-8),
134.07 (C-4a), 144.82 (C1ꢀ), 148.83 (C-4), 150.12 (C-8a),
153.20 (C-2). – MS (EI, 70 eV): m/z (%) = 248 (100) [M]+. –
C17H16N2 (248.32): calcd. C 82.26, H 6.45, N 11.29; found
C 82.35, H 6.38, N 11.27.
2-Chloro-6,7,9-trimethyldibenzo[b,h][1,6]naphthyridine (3c)
◦
M. p. 228 – 230 C. – Yield: 0.089 g (29 %). – IR (KBr):
ν = 1630 and 1601 (C=N), 1537, 1455 cm−1. – 1H NMR
(400 MHz, CDCl3): δ = 2.55 (s, 3 H, 9-CH3), 3.15 (s,
3 H, 7-CH3), 3.20 (s, 3 H, 6-CH3) 7.50 – 8.15 (m, 4 H,
3-H, 4-H, 8-H, 10-H), 8.16 (d, J = 8.48 Hz, 1 H, 11-H),
9.16 (s, 1 H, 1-H). – 13C NMR (100 MHz, CDCl3):
δ = 17.47 (9-CH3), 25.42 (7-CH3), 29.65 (6-CH3), 117.14
(C-7a), 122.04 (C-6a), 122.82 (C-8), 125.62 (C-1), 126.79
(C-7), 128.26 (C-9), 128.05 (C-3), 128.78 (C-4), 130.95
(C-10), 131.51 (C-11), 132.83 (C-2), 134.26 (C-12b), 136.67
Reaction of 2 with acetic acid
Preparation of 6,7,9-trimethyldibenzo[b,h][1,6]naphthyrid-
ine (3), general procedure
A mixture of 2,4ꢀ-dimethyl-4-(N-phenylamino)quinoline (C-11a), 146.01 (C-4a), 146.98 (C-12a), 158.18 (C-6). – MS
(2, 0.001 mol) and acetic acid (0.0011 mol) was added to (EI, 70 eV): m/z (%) = 308/306 (30/95) [M+2]/[M]+. –
polyphosphoric acid (1 g of P2O5 and 0.5 mL H3PO4) and C19H15N2Cl (306.79): calcd. C 74.51, H 4.90, N 9.15; found
◦
heated at 160 C for 5 h. The reaction mixture was poured C 74.35, H 4.79, N 9.20.
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M. Manoj – K. J. R. Prasad · Synthesis of Novel Substituted Dibenzonaphthyridines
855
6,7,9-Trimethyldibenzo[b,h][1,6]naphthyridine (3d)
8-H, 10-H, 2ꢀ-H, 3ꢀ-H, 4ꢀ-H, 5ꢀ-H, 6ꢀ-H), 8.21 (d, J = 8.51 Hz,
1 H, 11-H), 9.20 (d, 1 H, J = 7.44 Hz,1-H). – 13C NMR
(100 MHz, CDCl3): δ = 17.75 (9-CH3), 23.01 (4-CH3),
30.04 (6-CH3), 117.81 (C-7a), 121.23 (C-6a), 122.45 (C-8),
124.92 (C-2ꢀ, C-6ꢀ), 125.98 (C-3ꢀ, C-4ꢀ, C-5ꢀ), 126.13 (C-1),
127.12 (C-7), 128.41 (C-9), 128.16 (C-2), 128.83 (C-3),
130.08 (C-1ꢀ), 131.34 (C-10), 133.74 (C-11), 134.80 (C-4),
136.14 (C-12b), 139.24 (C-11a), 147.92 (C-4a), 148.39
(C-12a), 158.77 (C-6). – MS (EI, 70 eV): m/z (%) = 348 (100)
[M]+. – C25H20N2 (348.44): calcd. C 86.21, H 5.75, N 8.40;
found C 86.35, H 5.61, N 8.04.
◦
M. p. 217 – 219 C. – Yield: 0.082 g (30 %). – IR (KBr):
ν = 1623 and 1596 (C=N), 1524, 1452 cm−1. – 1H NMR
(400 MHz, CDCl3): δ = 2.52 (s, 3 H, 9-CH3), 3.12 (s, 3 H,
7-CH3), 3.19 (s, 3 H, 6-CH3) 7.48 – 8.09 (m, 5 H, 2-H, 3-H,
4-H, 8-H, 10-H), 8.15 (d, J = 8.42 Hz, 1 H, 11-H), 9.09 (d,
J = 7.86 Hz, 1 H, 1-H). – 13C NMR (100 MHz, CDCl3):
δ = 17.47 (9-CH3), 25.40 (7-CH3), 29.62 (6-CH3), 117.14
(C-7a), 122.04 (C-6a), 122.82 (C-8), 125.04 (C-1), 126.75
(C-7), 126.94 (C-2), 127.26 (C-3), 128.06 (C-4), 128.26
(C-9), 130.95 (C-10), 131.51 (C-11), 134.13 (C-12b), 136.67
(C-11a), 146.34 (C-4a), 147.32 (C-12a), 158.54 (C-6). – MS
(EI, 70 eV): m/z (%) = 272 (93) [M]+. – C19H16N2 (272.34):
calcd. C 83.82, H 5.88, N 10.30; found C 83.74, H 5.77,
N 10.49.
2-Chloro-6,9-dimethyl-7-phenyldibenzo[b,h][1,6]naphthyr-
idine (4c)
M. p. 228 – 230 ◦C. – Yield: 0.118 g (32 %). – IR
(KBr): ν = 1632 and 1598 (C=N), 1537, 1454 cm−1. –
1H NMR (400 MHz, CDCl3): δ = 2.45 (s, 3 H, 9-CH3),
3.17 (s, 3 H, 6-CH3), 7.22 – 8.22 (m, 9 H, 3-H, 4-H, 8-H,
10-H, 2ꢀ-H, 3ꢀ-H, 4ꢀ-H, 5ꢀ-H, 6ꢀ-H), 8.19 (d, J = 8.38 Hz,
1 H, 11-H), 9.25 (s, 1 H, 1-H). – 13C NMR (100 MHz,
CDCl3): δ = 17.75 (9-CH3), 29.85 (6-CH3), 117.81 (C-7a),
121.23 (C-6a), 122.45 (C-8), 124.92 (C-2ꢀ, C-6ꢀ), 125.98
(C-3ꢀ, C-4ꢀ, C-5ꢀ), 126.31 (C-1), 127.12 (C-7), 128.41
(C-9), 128.22 (C-3), 129.27 (C-4), 130.08 (C-1ꢀ), 131.34
(C-10), 133.74 (C-11), 133.96 (C-2), 136.10 (C-12b), 139.24
(C-11a), 147.72 (C-4a), 148.56 (C-12a), 158.98 (C-6). – MS
(EI, 70 eV): m/z (%) = 370/368 (35/100) [M+2]/[M]+. –
C24H17N2Cl (368.87): calcd. C 78.26, H 4.62, N 7.61; found
C 78.35, H 4.73, N 7.50.
Reaction of 2 with benzoic acid
Preparation of 6,9-dimethyl-7-phenyldibenzo[b,h][1,6]
naphthyridines 4, general procedure
A mixture of 2,4ꢀ-dimethyl-4-(N-phenylamino)quinoline
(2, 0.001 mol) and benzoic acid (0.0011 mol) was added to
polyphosphoric acid (1 g of P2O5 and 0.5 mL H3PO4) and
◦
heated at 160 C for 5 h. The reaction mixture was poured
into ice water, neutralized with saturated sodium bicarbonate
solution to remove the excess of benzoic acid, extracted with
ethyl acetate and purified using silica gel column chromatog-
raphy. The product was eluted with a petroleum ether : ethyl
acetate (99 : 1) mixture to get 4, which was recrystallized us-
ing ethanol.
2,6,9-Trimethyl-7-phenyldibenzo[b,h][1,6]naphthyridine (4a)
6,9-Dimethyl-7-phenyldibenzo[b,h][1,6]naphthyridine (4d)
◦
M. p. 222 – 224 C. – Yield: 0.122 g (35 %). – IR (KBr):
◦
ν = 1630 and 1591 (C=N), 1552, 1448 cm−1. – 1H NMR
(400 MHz, CDCl3): δ = 2.46 (s, 3 H, 9-CH3), 2.69 (s, 3 H,
2-CH3), 3.16 (s, 3 H, 6-CH3) 7.25 – 8.27 (m, 9 H, 3-H, 4-H,
8-H, 10-H, 2ꢀ-H, 3ꢀ-H, 4ꢀ-H, 5ꢀ-H, 6ꢀ-H), 8.18 (d, J = 8.53 Hz,
1 H, 11-H), 9.18 (s, 1 H, 1-H). – 13C NMR (100 MHz,
CDCl3): δ = 17.75 (9-CH3), 22.08 (2-CH3), 29.78 (6-CH3),
117.81 (C-7a), 121.23 (C-6a), 122.45 (C-8), 124.92 (C-2ꢀ,
C-6ꢀ), 125.98 (C-3ꢀ, C-4ꢀ, C-5ꢀ), 126.46 (C-1), 127.12 (C-7),
128.41 (C-9), 128.56 (C-3), 129.45 (C-4), 130.08 (C-1ꢀ),
131.34 (C-10), 133.74 (C-11), 134.26 (C-2), 136.12 (C-12b),
139.24 (C-11a), 147.65 (C-4a), 148.31 (C-12a), 158.75
(C-6). – MS (EI, 70 eV): m/z (%) = 348 (100) [M]+. –
C25H20N2 (348.44): calcd. C 86.21, H 5.75, N 8.40; found
C 86.03, H 6.01, N 7.96.
M. p. 217 – 219 C. – Yield: 0.117 g (35 %). – IR (KBr):
ν = 1626 and 1600 (C=N), 1528, 1453 cm−1. – 1H NMR
(400 MHz, CDCl3): δ = 2.48 (s, 3 H, 9-CH3), 3.14 (s, 3 H,
6-CH3) 7.28 – 8.19 (m, 10 H, 2-H, 3-H, 4-H, 8-H, 10-H, 2ꢀ-H,
3ꢀ-H, 4ꢀ-H, 5ꢀ-H, 6ꢀ-H), 8.20 (d, J = 8.34 Hz, 1 H, 11-H), 9.19
(d, J = 7.86 Hz, 1 H, 1-H). – 13C NMR (100 MHz, CDCl3):
δ = 17.75 (9-CH3), 29.84 (6-CH3), 117.81 (C-7a), 121.23
(C-6a), 122.45 (C-8), 124.92 (C-2ꢀ, C-6ꢀ), 125.98 (C-3ꢀ, C-4ꢀ,
C-5ꢀ), 126.07 (C-1), 127.12 (C-7), 128.41 (C-9), 128.37
(C-2), 129.04 (C-3), 129.95 (C-4), 130.08 (C-1ꢀ), 131.34
(C-10), 133.74 (C-11), 136.10 (C-12b), 139.24 (C-11a),
147.72 (C-4a), 148.56 (C-12a), 158.98 (C-6). – MS (EI,
70 eV): m/z (%) = 334 (100) [M]+. – C24H18N2 (334.41):
calcd. C 86.23, H 5.39, N 8.38; found C 86.09, H 5.50,
N 8.41.
4,6,9-Trimethyl-7-phenyldibenzo[b,h][1,6]naphthyridine (4b)
Reaction of 2 with 2-chloro-8-methylquinoline-3-carboxylic
acid
◦
M. p. 220 – 222 C. – Yield: 0.132 g (38 %). – IR (KBr):
ν = 1627 and 1597 (C=N), 1530, 1457 cm−1. – 1H NMR
(400 MHz, CDCl3): δ = 2.49 (s, 3 H, 9-CH3), 2.73 (s, 3 H, Preparation of 6,9-dimethyl-7-(2-chloro-8-methylquinol-
4-CH3), 3.18 (s, 3 H, 6-CH3) 7.24 – 8.29 (m, 9 H, 2-H, 3-H, in-3-yl)dibenzo[b,h][1,6]naphthyridines 5 and 6,9-dimeth-
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856
M. Manoj – K. J. R. Prasad · Synthesis of Novel Substituted Dibenzonaphthyridines
yl-7-(8-methylquinolin-2[1H]-on-3-yl)dibenzo[b,h][1,6]
naphthyridines 6, general procedure
128.11 (C-5ꢀ), 128.52 (C-9), 128.84 (C-6ꢀ), 129.07 (C-7ꢀ),
129.18 (C-3), 129.93 (C-4), 130.52 (C-3ꢀ), 131.35 (C-10),
133.74 (C-11), 134.21 (C-2), 134.36 (C-8ꢀ), 135.03 (C-4ꢀ),
139.25 (C-12b), 142.33 (C-11a), 146.44 (C-4ꢀa), 147.40
(C-8ꢀa), 147.66 (C-4a), 148.37 (C-12a), 158.71 (C-6), 170.02
(2ꢀ-C=O). – MS (EI, 70 eV): m/z (%) = 429 (89) [M]+. –
C29H23N3O (429.51): calcd. C 81.12, H 5.36, N 9.79; found
C 81.08, H 5.12, N 9.69.
A mixture of 2,4ꢀ-dimethyl-4-(N-phenylamino)quinoline
(2, 0.001 mol) and 2-chloro-8-methylquinoline-3-carboxyl-
ic acid (0.0011 mol) was added to polyphosphori◦c acid (1 g
of P2O5 and 0.5 mL H3PO4) and heated at 160 C for 8 h.
The reaction mixture showed two spots on TLC, and after the
completion of the reaction the reaction mixture was poured
into ice water, neutralized with saturated sodium bicarbonate
solution to remove the excess of 2-chloro-8-methylquinol-
ine-3-carboxylic acid, and extracted with ethyl acetate. The
two products were separated using silica gel column chro-
matography. The first product 5 and the second product 6
were eluted with a petroleum ether : ethyl acetate (99 : 1) and
a petroleum ether : ethyl acetate (95 : 5) mixture, respectively.
Compounds 5 and 6 were recrystallized using ethanol and
methanol, respectively.
4,6,9-Trimethyl-7-(2-chloro-8-methylquinolin-3-yl)dibenzo
[b,h][1,6]naphthyridine (5b)
◦
M. p. 206 – 208 C. – Yield: 0.125 g (28 %). – IR (KBr):
ν = 1627 and 1608 (C=N), 1592, 1570 cm−1. – 1H NMR
(400 MHz, CDCl3): δ = 2.58 (s, 3 H, 9-CH3), 2.74 (s, 3 H,
4-CH3), 2.84 (s, 3 H, 8ꢀ-CH3), 3.12 (s, 3 H, 6-CH3) 7.51 –
7.73 (m, 7 H, 2-H, 3-H, 8-H, 10-H, 5ꢀ-H, 6ꢀ-H, 7ꢀ-H), 8.03 (s,
1 H, 4ꢀ-H), 8.19 (d, 1 H, J = 8.70 Hz, 11-H), 9.10 (d, 1 H, J =
7.82 Hz, 1-H). – 13C NMR (100 MHz, CDCl3): δ = 17.77
(9-CH3), 22.41 (4-CH3), 22.83 (8ꢀ-CH3), 30.16 (6-CH3),
118.13 (C-7a), 121.31 (C-6a), 122.48 (C-8), 127.15 (C-7),
127.48 (C-1), 128.07 (C-5ꢀ), 128.52 (C-9), 128.82 (C-6ꢀ),
129.06 (C-7ꢀ), 129.10 (C-2), 129.33 (C-3), 130.40 (C-3ꢀ),
131.35 (C-10), 133.74 (C-11), 134.32 (C-4), 134.41 (C-8ꢀ),
134.88 (C-4ꢀ), 139.28 (C-12b), 142.33 (C-11a), 146.42
(C-4ꢀa), 147.36 (C-8ꢀa), 147.73 (C-4a), 148.40 (C-12a),
152.45 (C-2ꢀ), 158.71 (C-6). – MS (EI, 70 eV): m/z (%) =
449/447 (34/100) [M+2]/[M]+. – C29H22N3Cl (447.96):
calcd. C 77.85, H 4.92, N 9.39; found C 77.71, H 4.69,
N 9.21.
2,6,9-Trimethyl-7-(2-chloro-8-methylquinolin-3-yl)dibenzo
[b,h][1,6]naphthyridine (5a)
◦
M. p. 210 – 212 C. – Yield: 0.118 g (35 %). – IR (KBr):
ν = 1628 and 1611 (C=N), 1590, 1561 cm−1. – 1H NMR
(400 MHz, CDCl3): δ = 2.56 (s, 3 H, 9-CH3), 2.70 (s,
3 H, 2-CH3), 2.81 (s, 3 H, 8ꢀ-CH3), 3.14 (s, 3 H, 6-CH3)
7.46 – 7.78 (m, 7 H, 3-H, 4-H, 8-H, 10-H, 5ꢀ-H, 6ꢀ-H, 7ꢀ-H),
8.08 (s, 1 H, 4ꢀ-H), 8.21 (d, J = 8.54 Hz, 1 H, 11-H), 9.17
(s, 1 H, 1-H). – 13C NMR (100 MHz, CDCl3): δ = 17.77
(9-CH3), 22.30 (2-CH3), 22.83 (8ꢀ-CH3), 30.14 (6-CH3),
118.13 (C-7a), 121.31 (C-6a), 122.48 (C-8), 127.15 (C-7),
127.55 (C-1), 128.07 (C-5ꢀ), 128.52 (C-9), 128.82 (C-6ꢀ),
129.06 (C-7ꢀ), 129.18 (C-3), 129.93 (C-4), 130.40 (C-3ꢀ),
131.35 (C-10), 133.74 (C-11), 134.20 (C-2), 134.32 (C-8ꢀ),
134.88 (C-4ꢀ), 139.25 (C-12b), 142.33 (C-11a), 146.42
(C-4ꢀa), 147.36 (C-8ꢀa), 147.66 (C-4a), 148.37 (C-12a),
152.45 (C-2ꢀ), 158.69 (C-6). – MS (EI, 70 eV): m/z (%) =
449/447 (28/91) [M+2]/[M]+. – C29H22N3Cl (447.96):
calcd. C 77.85, H 4.92, N 9.39; found C 78.02, H 4.64,
N 9.17.
4,6,9-Trimethyl-7-(8-methylquinolin-2[1H]-on-3-yl)dibenzo
[b,h][1,6]naphthyridine (6b)
◦
M. p. 260 – 262 C. – Yield: 0.064 g (15 %). – IR (KBr):
ν = 1642 (C=O), 1626 and 1598 (C=N), 1580 cm−1. –
1H NMR (400 MHz, CDCl3): δ = 2.48 (s, 3 H, 9-CH3),
2.71 (s, 3 H, 4-CH3), 2.82 (s, 3 H, 8ꢀ-CH3), 3.11 (s, 3 H,
6-CH3) 7.47 – 7.72 (m, 7 H, 2-H, 3-H, 8-H, 10-H, 5ꢀ-H,
6ꢀ-H, 7ꢀ-H), 7.97 (s, 1H, 4ꢀ-H), 8.29 (d, J = 8.70 Hz,
1 H, 11-H), 9.21 (dd, J = 7.90, 1.18 Hz, 1H, 1-H), 9.36
(b s, 1H, N-1-H of quinoline). – 13C NMR (100 MHz,
CDCl3): δ = 17.77 (9-CH3), 22.30 (4-CH3), 22.85 (8ꢀ-
2,6,9-Trimethyl-7-(8-methylquinolin-2[1H]-on-3-yl)dibenzo
[b,h][1,6]naphthyridine (6a)
◦
M. p. 265 – 267 C. – Yield: 0.073 g (17 %). – IR (KBr): CH3), 30.18 (6-CH3), 118.16 (C-7a), 121.34 (C-6a), 122.49
ν = 1649 (C=O), 1623 and 1602 (C=N), 1592 cm−1. – (C-8), 127.19 (C-7), 127.49 (C-1), 128.07 (C-5ꢀ), 128.52
1H NMR (400 MHz, CDCl3): δ = 2.50 (s, 3 H, 9-CH3), 2.69 (C-9), 128.82 (C-6ꢀ), 129.06 (C-7ꢀ), 129.10 (C-2), 129.33
(s, 3 H, 2-CH3), 2.80 (s, 3 H, 8ꢀ-CH3), 3.09 (s, 3 H, 6-CH3) (C-3), 130.52 (C-3ꢀ), 131.35 (C-10), 133.74 (C-11), 134.32
7.44 – 7.70 (m, 7 H, 3-H, 4-H, 8-H, 10-H, 5ꢀ-H, 6ꢀ-H, 7ꢀ- (C-4), 134.41 (C-8ꢀ), 135.03 (C-4ꢀ), 139.28 (C-12b), 142.33
H), 7.94 (s, 1 H, 4ꢀ-H), 8.28 (d, 1 H, J = 8.54 Hz, 11-H), (C-11a), 146.44 (C-4ꢀa), 147.40 (C-8ꢀa), 147.73 (C-4a),
9.23 (s, 1 H, 1-H) 9.29 (b s, 1H, N-1-H of quinoline). – 148.40 (C-12a), 158.72 (C-6), 169.88 (2ꢀ-C=O). – MS (EI,
13C NMR (100 MHz, CDCl3): δ = 17.77 (9-CH3), 22.30 70 eV): m/z (%) = 429 (98) [M]+. – C29H23N3O (429.51):
(2-CH3), 22.85 (8ꢀ-CH3), 30.17 (6-CH3), 118.16 (C-7a), calcd. C 81.12, H 5.36, N 9.79; found C 81.18, H 5.31,
121.34 (C-6a), 122.49 (C-8), 127.19 (C-7), 127.56 (C-1), N 10.01.
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M. Manoj – K. J. R. Prasad · Synthesis of Novel Substituted Dibenzonaphthyridines
857
2-Chloro-6,9-dimethyl-7-(2-chloro-8-methylquinolin-3-yl)
dibenzo[b,h][1,6]naphthyridine (5c)
1H NMR (400 MHz, CDCl3): δ = 2.51 (s, 3 H, 9-CH3), 2.72
(s, 3 H, 8ꢀ-CH3), 3.14 (s, 3 H, 6-CH3) 7.46 – 7.81 (m, 7 H
3-H, 4-H, 8-H, 10-H, 5ꢀ-H, 6ꢀ-H, 7ꢀ-H), 7.93 (s, 1 H, 4ꢀ-
H), 8.25 (d, J = 8.61 Hz, 1 H, 11-H), 9.24 (s, 1 H, 1-H),
9.33 (b s, 1H, N-1-H of quinoline). – 13C NMR (100 MHz,
CDCl3): δ = 17.77 (9-CH3), 22.85 (8ꢀ-CH3), 30.17 (6-CH3),
118.16 (C-7a), 121.34 (C-6a), 122.49 (C-8), 127.19 (C-7),
127.56 (C-1), 128.11 (C-5ꢀ), 128.52 (C-9), 128.84 (C-6ꢀ),
129.07 (C-7ꢀ), 129.18 (C-3), 129.93 (C-4), 130.52 (C-3ꢀ),
131.35 (C-10), 133.74 (C-11), 134.21 (C-2), 134.36 (C-8ꢀ),
135.03 (C-4ꢀ), 139.25 (C-12b), 142.33 (C-11a), 146.44
(C-4ꢀa), 147.40 (C-8ꢀa), 147.66 (C-4a), 148.37 (C-12a),
158.71 (C-6), 169.94 (2ꢀ-C=O). – MS (EI, 70 eV): m/z (%) =
451/449 (32/100) [M+2]/[M]+. – C28H20N3ClO (449.50):
calcd. C 74.83, H 4.45, N 9.35; found C 74.91, H 4.04,
N 9.19.
M. p. 215 – 217 ◦C. – Yield: 0.112 g (24 %). – IR
(KBr): ν = 1628 and 1606 (C=N), 1590, 1538 cm−1. –
1H NMR (400 MHz, CDCl3): δ = 2.59 (s, 3 H, 9-CH3),
2.73 (s, 3 H, 8ꢀ-CH3), 2.80 (s, 3 H, 6-CH3) 7.42 – 7.71
(m, 7 H, 3-H, 4-H, 8-H, 10-H, 5ꢀ-H, 6ꢀ-H, 7ꢀ-H), 8.06 (s,
1 H, 4ꢀ-H), 8.17 (d,, J = 8.61 Hz, 1 H 11-H), 9.22 (s,
1 H, 1-H). – 13C NMR (100 MHz, CDCl3): δ = 17.77
(9-CH3), 22.83 (8ꢀ-CH3), 30.14 (6-CH3), 118.13 (C-7a),
121.31 (C-6a), 122.48 (C-8), 127.15 (C-7), 127.53 (C-1),
128.07 (C-5ꢀ), 128.52 (C-9), 128.82 (C-6ꢀ), 129.06 (C-7ꢀ),
129.20 (C-3), 129.94 (C-4), 130.40 (C-3ꢀ), 131.35 (C-10),
133.74 (C-11), 134.17 (C-2), 134.32 (C-8ꢀ), 134.88 (C-4ꢀ),
139.25 (C-12b), 142.33 (C-11a), 146.42 (C-4ꢀa), 147.36
(C-8ꢀa), 147.66 (C-4a), 148.37 (C-12a), 152.45 (C-2ꢀ),
158.68 (C-6). – MS (EI, 70 eV): m/z (%) = 471/469/467
(32/59/98) [M+4]/[M+2]/[M]+. – C28H19N3Cl2 (468.38):
calcd. C 71.95, H 4.07, N 8.99; found C 71.78, H 3.88,
N 8.54.
Acknowledgements
The authors thank IISc, Bangalore, and IICT, Hyderabad,
for NMR and mass spectral data. The authors acknowledge
UGC, New Delhi, India, for the financial assistance under
Grant No. (F31-122/2005).
2-Chloro-6,9-dimethyl-7-(8-methylquinolin-2[1H]-on-3-yl)
dibenzo[b,h][1,6]naphthyridine (6c)
◦
M. p. 215 – 217 C. – Yield: 0.054 g (12 %). – IR (KBr):
ν = 1644 (C=O), 1624 and 1601 (C=N), 1588, 1540 cm−1. –
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