An efficient synthesis of phenyl-substituted dibenzonaphthyridines

Article abstract of DOI:10.3184/030823409X466726

A one-pot synthesis of 9-chloro-6-methyl-7-phenyldibenzo[b,h][1,6] naphthyridines from 4-chloro-2-methylquinolines is reported. Since the yield of the dibenzonaphthyridine was low, in an alternative method the title compounds were prepared from the 4-chlo

Full text of DOI:10.3184/030823409X466726

JOURNAL OF CHEMICAL RESEARCH 2009
AUGUST, 485–488
RESEARCH PAPER 485
An efficient synthesis of phenyl-substituted dibenzonaphthyridines
Manickam Manoj and Karnam Jayaramapillai Rajendra Prasad*
Department of Chemistry, Bharathiar University, Coimbatore, Tamil Nadu, India
A one-pot synthesis of 9-chloro-6-methyl-7-phenyldibenzo[b,h][1,6]naphthyridines from 4-chloro-2-methylquinolines
is reported. Since the yield of the dibenzonaphthyridine was low, in an alternative method the title compounds were
prepared from the 4-chloro-2-methylquinolines via 2-methyl-4-[(4-chlorophenyl)amino]quinolines as intermediates,
which provided improved yields.
Keywords: quinolines, fused 1,6-naphthyridines
Quinoline alkaloids in general and phenylaminoquinolines
in particular have attracted considerable attention because of
their powerful antimalarial property.1 Since the discovery of
the cinchona alkaloids as antimalarial agents the quinoline
(π-electron deficient heterocycle) core has become a “privileged
structure” for the design and development of new drugs.
Interest in naphthyridine derivatives arises from their
exceptionally broad spectrum of biological activities. They
are used in the therapy of human disease including AIDS2,3
and cancer.4 In particular, some dibenzonaphthyridines, viz.
quinoline dimers, act as potent and selective 3-phosphoinositide-
dependent kinase-I inhibitors.5
A literature survey revealed that the reactions of chloro-
quinolines have been studied extensively, the objective
being to obtain substitution products possessing biological
activity.6,7
There are several references to the synthesis of simple
dibenzonaphthridines,8-11 but only very few accomplish their
construction through anilinoquinolines [(N-phenylamino)
quinolines].12,13 Here we report the synthesis of phenyl
substituted dibenzo[b,h][1,6]naphthyridines utilising 4-chloro-
2-methylquinolines in two different ways, one of the methods
involving (N-phenylamino)quinolines as intermediates.
2-amino-5-chlorobenzophenone (3) under acidic condition,
similar to our earlier report,14 was not successful (Scheme 1),
we considered an alternative approach in which 4-chloro-
2,6-dimethylquinoline (4a) was treated with the amino-
benzophenone (3) under neat conditions at 160°C for
half an hour in the hope of obtaining the ketone 5a which
may be a suitable intermediate to the target molecule 1a
(Scheme 2).
The structure of the product was established by spectral
means. The absence of a C=O group in the IR and 13C NMR
spectra revealed that the expected uncyclised compound 5a
was not formed. The absence of C3-H of a quinoline moiety
in its 1H NMR spectrum confirmed this view. Its mass
spectrum showed the molecular ion peak at m/z 368 (M+) as
the base peak and the isotopomeric satellite peak at m/z 370.
All the spectral and analytical data were in agreement with
the cyclised structure, namely 9-chloro-2,6-dimethyl-7-
phenyldibenzo[b,h][1,6]naphthyridine (1a). The preparations
were generalised with other substituted chloroquinolines
(4b–d) to afford the respective dibenzonaphthyridines (1b–d).
The mechanism for the formation of this product can be
interpreted as via the formation of the intermediate 6 by the
elimination of HCl, which further catalyses the cyclisation by
the protonation of the 2'-carbonyl group to form the oxonium
ion intermediate 6. Its reaction at the quinoline C3-position by
intramolecular electrophilic cyclisation gives the intermediate
7 which on aromatisation to 8 and subsequent loss of a water
molecule under the influence of acid yields the final product 1
(Scheme 3).
Results and discussion
Since the approach to the preparation of the 9-chloro-2,6-
dimethyl-7-phenyldibenzo[b,h][1,6]naphthyridine (1a) from
the reaction of 2,6-dimethylquinolin-4(1H)-one (2) and
H3C
O
Cl
N
H3C
(i, ii)
Cl
H2N
+
CH3
N
H
PhCO
Ph
N
CH3
2
3
1a
Scheme 1 Reagents: (i) H2SO4/AcOH, (ii) HCl/EtOH
Cl
R1
Cl
N
Cl
N
R1
3
+
3
HN
N
+
R1
COPh
CH3
D 160oC
D 160oC
CH3
R2
Ph
N
R2
CH3
4
1
1,4,5 a: R1 = CH3, R2 = H
b: R1 = H, R2 =CH3
c: R1 = Cl, R2 = H
d: R1 = R2 = H
R2
5
Scheme 2
* Correspondent. E-mail: prasad_125@yahoo.com

486 JOURNAL OF CHEMICAL RESEARCH 2009
Cl
R1
H
Cl
+
N
+
- HCl
+ H
HN
OH
5
4
3
+
R1
H
Ph
H
O
R2
N
Ph
CH3
N
6
CH3
R2
7
R1
R1
H
1,4-8 a: R1 = CH3, R2 = H
b: R1 = H, R2 =CH3
c: R1 = Cl, R2 = H
d: R1 = R2 = H
N
N
Cl
Cl
- H2O
+
+
H
- H
OH
R2
R2
Ph
N
N
Ph
CH3
CH3
8
1
Scheme 3
The yields of the one pot synthesis of the dibenzonaphthyridine
(1a–d) as outlined in Scheme 2 were only moderate (ca
24%), so we devised an alternative route in which 4-chloro-
2-methylquinoline (4a) was heated with p-chloroaniline (9)
under neat conditions at 160°C for half an hour (Scheme 4).
The product obtained was assigned as 4'-chloro-2,6-dimethyl-
4-(N-phenylamino)quinoline (10a) which was found to be
in tautomeric equilibrium with its imino form (11a) on the
basis of two broad NH signals in its H NMR spectrum. The
reaction was extended to other chloroquinolines (4b–d) to
obtain the respective anilinoquinolines (10b–d).
The anilinoquinoline 10a was heated with benzoic acid in
the presence of polyphosphoric acid to 160°C for five hours
to give the product. From the TLC, mixed melting point and
superimposable IR spectra, the compound was identified
as the same (1a) as that obtained earlier from 4-chloro-2-
methylquinoline (1) and 2-amino-5-chlorobenzophenone in
the one pot synthesis under neat conditions. A plausible route
to the product, through the intermediate 12 via benzoylation of
10 at the quinoline 3-position, and acid-catalysed cyclisation
to the aniline ring through the intermediate 8 as proposed
above, is shown in Scheme 4.
Even though the synthesis involves two steps to the product,
the overall yield was somewhat better (ca 31%) than the one
pot synthesis. The yields of the products obtained from the
above two methods are compared in Table 1.
1
In conclusion: alternative routes are described for the
preparation of four substituted dibenzo[b,h][1,6]naphthyridines.
Table 1 Comparison of yields: Method 1 (Scheme 2) and Method 2 (Scheme 4)
Yields/%
Method 1
Method 2
Products
R1
R2
One-pot 4 → 1
4 → 10
10 → 1
overall
1a
1b
1c
1d
CH3
H
H
CH3
H
23
25
22
25
70
75
65
72
43
45
40
45
30
34
26
33
Cl
H
H
Cl
Cl
Cl
HN
N
N
4 +
R1
R1
H2N
9
CH3
N
CH3
a-d: R1, R2 as in Scheme 3
H
R2
R2
10
11
PhCO2H
PPA
160oC
Cl
R1
R1
H
HN
N
N
Cl
Cl
R1
COPh
OH
R2
R2
CH3
Ph
N
N
N
Ph
R2
CH3
CH3
8
1
12
Scheme 4

JOURNAL OF CHEMICAL RESEARCH 2009 487
Preparation of 4'-chloro-2-methyl-4-(N-phenylamino)quinolines (10)
from 4-chloro-2-methyl quinolines (4), general procedure
The compounds synthesised were tested for antimicrobial
activity against the species Bacillus subtilis, Escherichia coli,
Pseudomonas aeruginosa, Staphylococcus aureus, Klebsiella
pneumoniae and Vibrio cholerae.
The 4-chloro-2-methylquinoline (1, 2 mmol) was heated with p-
chloroaniline (0.255 g. 2 mmol) under neat conditions at 160°C
for half an hour. The product was washed with water, adsorbed and
purified by chromatography on silica gel, eluting with ethyl acetate:
methanol (95: 5) mixture to get the anilinoquinoline 3 which was
then recrystallised from methanol.
Experimental
Melting points were determined on a Mettler FP 51apparatus (Mettler
Instruments, Switzerland). IR spectra were recorded on a Shimadzu
FTIR-8201PC spectrophotometer (Shimadzu, Japan) using KBr discs.
1H NMR and 13C NMR spectra were recorded on Bruker AMX 400
spectrometer; the chemical shifts are expressed in parts per million
(ppm) from tetramethylsilane (TMS) as internal reference. Mass
spectra (MS) were recorded on AutoSpec EI + Shimadzu QP 2010
PLUS GC-MS mass spectrometer. Microanalyses were performed
on a Vario EL III model CHNS analyser (Vario, Germany) at the
Department of Chemistry, Bharathiar University. The purity of the
products was tested by TLC with plates coated with silica gel-G with
petroleum ether, ethyl acetate and methanol as developing solvents.
4'-Chloro-2,6-dimethyl-4-(N-phenylamino)quinoline
(10a):
Colourless needles (0.399 g, 70%), m.p. >300°C. IR: nmax 3467 cm-1
(NH). NMR: dH 2.54 (s, 3H, C2-CH3), 2.59 (s, 3H, C6-CH3), 6.75 (s,
1H, C3-H), 7.48–7.94 (m, 6H, C7-, C8-, C2'-, C3'-, C5', C6'-H), 8.51
(s, 1H, C5-H), 10.58 (b s, 1H, C4-NH amino form), 14.31 (b s, 1H,
N1-H imino form. The ratio of amino form: imino form 1: 1); dC 19.7
(C2-CH3), 21.1 (C6-CH3), 100.1 (C3), 116.3 (C4a), 119.5 (C2', C6'),
122.5 (C3', C5'), 127.0 (C5), 129.8 (C4'), 131.0 (C8), 135.1 (C7),
136.4 (C6), 136.5 (C1'), 136.8 (C8a), 153.4 (C4), 154.0 (C2). MS:
m/z (%) 284–282 (M+, 32/100), 267 (40), 266 (20), 252 (15), 247
(10), 130 (18), 123 (25), 77 (12). Anal. Calcd for. C17H15ClN2: C,
72.34; H, 5.32; N, 9.93. Found: C, 71.72; H, 5.11; N, 9.41%.
Preparation of 9-chloro-6-methyl-7-phenyldibenzo[b,h][1,6]naph-
thyridines (1) from 4-chloro-2-methylquinolines (4), general procedure
The appropriate 4-chloro-2-methylquinoline (4, 1 mmol) was heated
with 2-amino-5-chlorobenzophenone (3, 0.23 g, 1 mmol) under neat
conditions at 160°C for half an hour. The product was washed with
water, adsorbed and purified by chromatography on silica gel, eluting
with petroleum ether:ethyl acetate (98:2) to get 1 which was then
recrystallised from methanol.
9-Chloro-2,6-dimethyl-7-phenyldibenzo[b,h][1,6]naphthyridine
(1a): Colourless prisms (0.083 g, 23%), m.p. 250–252°C. IR: nmax
1625 and 1609 cm-1 (C=N). NMR: dH 2.27 (s, 3H, C6-CH3), 2.67 (s,
3H, C2-CH3), 7.39–7.64 (m, 7H, C8, C3, C2'-6'H), 7.77 (dd, 1H, C10-
H, Jm = 2.28, Jo = 9.08 Hz), 7.90 (d, 1H, C4-H, J = 8.16 Hz), 8.31(d,
1H, C11-H, J = 9.08 Hz), 9.10 (s, 1H, C1-H); dC 19.7 (C6-CH3),
20.9 (C2-CH3), 118.0 (C8), 122.8 (C9), 125.1 (C1), 126.3 (C2', C6'),
127.9 (C3'-5'), 128.1 (C1'), 129.5 (C7), 129.8 (C7a), 131.9 (C10),
132.2 (C11), 132.9 (C4), 135.8 (C3), 137.9 (C2), 144.2 (C12b), 146.8
(C6a), 147.2 (C11a), 148.5 (C12a), 149.9 (C4a), 159.1 (C6). MS:
m/z (%) 370–368 (M+, 35/100), 367 (25), 353 (12), 333 (15), 332 (8),
166 (15), 77 (32), 41 (35). Anal. Calcd for C24H17ClN2: C, 78.26; H,
4.62; N, 7.61. Found: C, 77.95; H, 4.34; N, 7.38%.
4'-Chloro-2,8-dimethyl-4-(N-phenylamino)quinoline (10b): White
solid (0.423 g, 75%), m.p. >300°C. IR: nmax 3378 cm-1 (NH). NMR:
dH 2.84 (s, 3H, C2-CH3), 2.91(s, 3H, C8-CH3), 6.51 (s, 1H, C3-H),
7.35-7.60 (m, 6H, C6-, C7-, C2'-, C3'-, C5'-, C6'-H), 8.71 (d, 1H, C5-
H, J = 7.12 Hz), 10.64 (b s, 1H, C4-NH amino form), 12.94 (b s, 1H,
N1-H imino form. The ratio of amino form: imino form 1: 1); dC 18.3
(C2-CH3), 24.8 (C8-CH3), 100.3 (C3), 117.4 (C4a), 118.8 (C2', C6'),
123.5 (C3', C5'), 127.2 (C5), 130.0 (C4'), 131.5 (C6), 135.9 (C7),
137.2 (C8), 137.3 (C1'), 137.9 (C8a), 151.4 (C4), 152.6 (C2). MS:
m/z (%) 284–282 (M+, 37/100), 267 (10), 266 (5), 251 (10), 247 (28),
123 (35), 89 (15), 51 (10). Anal. Calcd for C17H15ClN2: C, 72.34; H,
5.32; N, 9.93. Found: C, 72.05; H, 5.20; N, 9.22%.
4',6-Dichloro-2-methyl-4-(N-phenylamino)quinoline (10c): White
solid (0.416 g, 65%), m.p. >300°C. IR: nmax 3468 cm-1 (NH). NMR:
dH 2.61 (s, 3H, C2-CH3), 6.81 (s, 1H, C3-H), 7.48–8.13 (m, 6H, C7-,
C8-, C2'-, C3'-, C5'- and C6'-H), 8.89 (s, 1H, C5-H) 10.74 (br s, 1H, C4-
NH amino form), 14.71 (br s 1H, N1-H imino form. The ratio of amino
form: imino form 1: 1); dC 20.1 (C2-CH3), 99.8 (C3), 115.2 (C4a), 117.9
(C2', C6'), 124.0 (C3', C5'), 128.5 (C5), 131.0 (C4'), 132.1 (C6), 136.1
(C8), 138.1 (C7), 138.8 (C1'), 139.1 (C8a), 152.9 (C4), 154.3 (C2). MS:
m/z (%) 306–304/302 (M+, 39/66/100), 301 (95), 287 (50), 286 (10), 267
(35), 232 (12), 122 (28), 52 (8). Anal. Calcd for C16H12Cl2N2: C, 63.58;
H, 3.99; N, 9.27. Found: C, 63.35; H, 3.88; N, 8.99%.
9-Chloro-4,6-dimethyl-7-phenyldibenzo[b,h][1,6]naphthyridine
(1b): Colourless needles (0.092 g, 25%), m.p. 245–247°C. IR nmax
:
1630 and 1608 cm-1 (C=N). NMR: dH 2.29 (s, 3H, C6-CH3) 2.82
(s, 3H, C4-CH3), 7.38–7.67 (8H, m, C2-H, C3-H, C8-H, C2'-6'-H),
7.77 (dd, 1H, C10-H, Jm = 2.24, Jo = 9.08 Hz), 8.30 (d, 1H, C11-H,
J = 9.08 Hz), 9.17 (d, 1H, C1-H, J = 7.92 Hz); dC 17.7 (C6-CH3),
29.6 (C4-CH3), 117.8 (C8), 122.4 (C9), 124.4 (C1), 125.9 (C2', C6'),
126.5 (C3'-C5'), 127.5 (C1'), 128.5 (C7), 128.9 (C7a), 129.8 (C10),
131.2 (C11), 131.7 (C4), 132.0 (C3), 136.2 (C2), 138.3 (C12b), 143.1
(C6a), 146.9 (C11a), 147.7 (C12a), 149.1 (C4a), 158.0 (C6). MS:
m/z (%) 370/368 (M+, 33/100), 367 (12), 353 (5), 333 (8), 332 (20),
317 (5), 166 (10), 51 (20). Anal. Calcd for C24H17ClN2: C, 78.26; H,
4.62; N, 7.61. Found: C, 78.10; H, 4.52; N, 7.49%.
4'-Chloro-2-methyl-4-(N-phenylamino)quinoline (10d): White
solid (0.386 g, 72%), m.p. >300°C. IR: nmax 3475 cm-1 (NH). NMR:
d
H 2.60 (3H, s, C2-CH3), 6.69 (s, 1H, C3-H), 7.46–8.08 (m, 7H, C6-,
C7-, C8-, C2'-, C3'-, C5'-, C6'-H), 8.51 (d, 1H, C5-H, J = 7.20 Hz),
10.61 (b s, 1H, C4-NH amino form), 13.91 (b s, 1H, N1-H imino
form. The ratio of amino form: imino form 1: 1); dC 19.5 (C2-CH3),
100.6 (C3), 117.0, (C4a), 118.1 (C2', C6'), 124.0 (C3', C5'), 127.1
(C5), 130.7 (C4'), 131.9 (C6), 137.0 (C8), 137.5 (C7), 138.2 (C1'),
138.4 (C8a), 152.4 (C4), 153.0 (C2). MS: m/z (%) 270–268 (M+,
34/100), 267 (85), 253 (55), 233 (25), 232 (18), 124 (10), 90 (8),
76 (10). Anal. Calcd for. C16H13ClN2: C, 71.64; H, 4.85; N, 10.45.
Found: C, 71.52; H, 5.05; N, 10.38%.
2,9-Dichloro-6-methyl-7-phenyldibenzo[b,h][1,6]naphthyridine
(1c): White solid (0.081 g, 22%), m.p. 255–257°C. IR: nmax 1635
and 1617 cm-1 (C=N). NMR: dH 2.28 (s, 3H, C6-CH3), 7.38–7.74
(m, 7H, C8-H, C3-H, C2'-6'-H), 7.80 (dd, 1H, C10-H, Jm = 2.32,
Jo = 9.08 Hz), 7.93 (d, 1H, C4-H, J = 8.60 Hz), 8.30 (d, 1H, C11-H,
J = 9.08 Hz), 9.28 (d, 1H, C1-H, J = 2.32 Hz); dC 18.1 (C6-CH3),
117.9 (C8), 121.8 (C9), 126.0 (C1), 127.0 (C2', C6'), 128.1 (C3'-
C5'), 128.5 (C1'), 128.9 (C7), 129.7 (C7a), 132.5 (C10), 132.8 (C11),
133.2 (C4), 136.1 (C3), 138.0 (C2), 144.0 (C12b), 147.1 (C6a), 147.2
(C11a), 149.4 (C12a), 150.1 (C4a), 160.0 (C6). MS: m/z (%) 392–
390/388 (M+, 11/64/100), 387 (70), 373 (20), 353 (30), 318 (10), 165
(15), 77 (8), 51 (12). Anal. Calcd for C23H14Cl2N2: C, 71.19; H, 3.61;
N, 7.21. Found: C, 70.93; H, 3.48; N, 7.11%.
9-Chloro-6-methyl-7-phenyldibenzo[b,h][1,6]naphthyridine (1d):
Colourless prisms (0.088 g 25%), m.p. 242–244°C. IR: nmax 1627
and 1611 cm-1 (C=N). NMR: dH 2.26 (s, 3H, C6-CH3), 7.39–7.70 (m,
8H, C2-H, C3-H, C8-H, C2'-6'-H), 7.75 (dd, 1H, C10-H, Jm = 2.26,
Jo = 9.08 Hz), 7.91 (d, 1H, C4-H, J = 8.49 Hz), 8.29 (d, 1H, C11-H,
J = 9.08 Hz), 9.18 (d, 1H, C1-H, J = 8.01 Hz); dC 17.9 (C6-CH3),
118.1 (C8), 121.1 (C9), 125.8 (C1), 127.3 (C2', C6'), 128.8 (C3'-
C5'), 129.0 (C1'), 129.2 (C7), 130.1 (C7a), 132.3 (C10), 132.9 (C11),
134.1 (C4), 136.6 (C3), 138.3 (C2), 143.8 (C12b), 147.3 (C6a), 147.6
(C11a), 149.9 (C12a), 150.2 (C4a), 158.9 (C6). MS: m/z (%) 356–
354 (M+, 28/90), 353 (100), 339 (15), 319 (25), 304 (35), 77 (20), 65
(12), 51 (10). Anal. Calcd for C23H15ClN2: C, 77.97; H, 4.24; N, 7.91.
Found: C, 77.88; H, 4.30; N, 7.82%.
Preparation of 9-chloro-6-methyl-7-phenyldibenzo[b,h][1,6]naph-
thyridine (1) from 4'-chloro-2-methyl-4-(N-phenylamino)quinoline
(10), general procedure
A
mixture of 4'-chloro-2-methyl-4-(N-phenylamino)quinoline
(10, 1 mmol) and benzoic acid (0.122 mg, 1.1 mol) was added to
polyphosphoric acid (P2O5, 1 g and H3PO4, 0.5 mL) and heated
at 160°C for five hours. The reaction mixture was poured into ice
water and neutralised with saturated sodium bicarbonate solution to
remove the excess of benzoic acid. The crude product obtained was
purified by column chromatography over silica gel using petroleum
ether:ethyl acetate mixture (98:2) to get a pale yellow solid. The
product was recrystallised using methanol as prisms. From the TLC
and superimposable IR spectra, the compound was identified as the
same one obtained from the earlier one-pot synthesis of 4-chloro-
2-methylquinoline (4) with 2-amino-5-chlorobenzophenone under
neat conditions. Further, the mixed melting point of this compound
and the compound obtained earlier from the one-pot synthesis was
undepressed. The yields of the products obtained by the two methods
are compared in Table 1.

488 JOURNAL OF CHEMICAL RESEARCH 2009
K.A. Stillmock, M.V. Witmer, G. Moyer, W.A. Schleif, L.J. Gabryelski,
Y.M. Leonard, J.J. Lynch, S.R. Michelson and S.D. Young, J. Med.
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M. Atanasova, S. Ilieva and B. Galabov, Eur. J. Med. Chem., 2007,
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The authors thank IISc, Bangalore and IICT, Hyderabad for
NMR and mass spectral data. The authors acknowledge UGC,
New Delhi, India for financial assistance under Grant No.
F31-122/2005.
4
5
Received 28 January 2009; accepted 30 May 2009
Paper 09/0414 doi: 10.3184/030823409X466726
Published online: 10 August 2009
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L.S. Payne, J.P. Guare, J.P. Vacca, D.J. Hazuda, P.J. Felock, A.L. Wolfe,