Synthesis of novel phenyl substituted dibenzonaphthyridines

Article abstract of DOI:10.3184/030823409X12572441140695

The reaction of 2,4-dichloroquinolines with 2-amino-5-chlorobenzophenone yielded 2-[(2-benzoyl-4-chlorophenyl) amino]-4-chloroquinolines which with sodium methoxide afforded 2-[(2-benzoyl-4-chlorophenyl)amino]-4- methoxyquinolines. These on PPA-catalysed

Full text of DOI:10.3184/030823409X12572441140695

720 RESEARCH PAPER
DECEMBER, 720–725
JOURNAL OF CHEMICAL RESEARCH 2009
Synthesis of novel phenyl substituted dibenzonaphthyridines
Manickam Manoj and Karnam Jayaramapillai Rajendra Prasad*
Department of Chemistry, Bharathiar University, Coimbatore 641 046, Tamil Nadu, India
The reaction of 2,4-dichloroquinolines with 2-amino-5-chlorobenzophenone yielded 2-[(2-benzoyl-4-chlorophenyl)
amino]-4-chloroquinolines which with sodium methoxide afforded 2-[(2-benzoyl-4-chlorophenyl)amino]-4-
methoxyquinolines. These on PPA-catalysed cyclisation gave 2-chloro-12-phenyldibenzo[b,g][1,8]naphthyridin-
11(6H)-ones. Temperature differences for the formation of the final products were due to the in situ formation
of the 2-[(2-benzoyl-4-chlorophenyl)amino]quinolin-4-ones from the chloro and methoxy intermediates.
The dibenzonaphthyridin-11-ones were N-methylated at N(6); a methyl group at C(7) was found to hinder the
methylation reaction sterically, when a considerably longer reaction time was needed.
Keywords: fused 1,8-naphthyridines, cyclisation, quinolines, methylation, steric effects
Small and structurally interesting compounds that have a
readily reactive functional group are new targets of synthetic
organic chemists due to the importance of these compounds
in the combinatorial approach to drug discovery. In this
respect, amino-substituted quinolines have generated from
the π-electron deficient quinoline core chemical entities
for the synthesis of anti-malarial drugs, e.g., chloroquine,
primaquine, active against Plasmodium falciparum,1
Some of the phenylaminoquinolines are also considered
as synthetic anti-malarials2 and have attracted chemists by
their utility in deriving various heterocyclic systems such
as dibenzonaphthyridines, indoloquinolines, etc. A detailed
survey of the literature points out the wide utility of chloro-
quinolines in the preparation of substituted quinolines
possessing biological activity,3,4 in particular, their amino-
dechlorination reaction involving aromatic amines, thereby
furnishing anilinoquinolines. Research on the chemistry of
naphthyridines has expanded considerably in recent years
owing to the fact that biologically active compounds have
been detected among their derivatives. Numerous reports have
claimed that these heterocycles may act as anti-arrhythmic,5
analgesic,6 anti-HIV,7 and anti-cancer agents.8 In particular,
some dibenzonaphthyridines, i.e. quinolinoquinolines, act as
potent and selective 3-phosphoinositide-dependent kinase-I
inhibitors.9 Many reports present the synthesis of simple
dibenzonaphthyridines,10-15 but only a few accomplish their
construction through anilinoquinolines.14,15
obtained, irrespective of the mole ratio of 2-amino-5-chloro-
benzophenone taken for the reaction, were assigned as the
2-substituted products, 2-[(2-benzoyl-4-chlorophenyl)amino]-
4-chloroquinolines (2) on the basis of the reactivity of the 2-
and 4-chloro groups of the 2,4-dichloroquinoline16 (Scheme 1).
In the 1H NMR spectrum the C2-NH appeared as a
broad singlet around d 11.00 ppm. All the aromatic protons
appeared between the region around d 7.00–8.00 ppm except
for a one proton doublet which was shifted abnormally
downfield around d 9.40 ppm. With the help of DEPT-
135, H,H-COSY and HMBC correlations the deshielded
proton in 2-[(2-benzoyl-4-chlorophenyl)amino]-4-chloro-8-
methylquinoline (2b) was identified as C6'-H. A one proton
doublet at d 9.39 (J = 8.31 Hz) and a one proton doublet at
d 7.58 (J = 8.31 Hz) have H, H-COSY connection, which
are characteristic of C6'- and C5'- protons. The assignment
of coupling protons for all the other aromatic protons using
H, H-COSY is given in Table.1. The DEPT-135 spectrum
displayed 12 CH signals besides the methyl and the carbonyl
carbons, the remaining being quaternary carbons. The isolated
C6' proton has HMBC connectivity with C1' and C5' carbons.
The connectivities of all other protons with the carbons are
shown in Fig. 1.
It could be speculated that the reason for the abnormal
deshielding of C6'-H is on account of hydrogen bonding
between the C2-NH and 2'-carbonyl group fixing the
2-substituent in a particular plane, whereby the C6'-H
We report here the synthesis of phenyl substituted dibenzo-
naphthyridines utilising 2,4-dichloroquinolines (1) involving
theanilinoquinolinesi.e.2-[(2-benzoyl-4-chlorophenyl)amino]
-4-chloroquinolines (2) and 2-[(2-benzoyl-4-chlorophenyl)
amino]-4-methoxyquinolines (5) as probable intermediates
in the synthesis of phenyl-substituted linear and angular
dibenzonaphthyridines.
H
Cl
H
H
H
H
H
Cl
N
N
H
H
CH3
H
C
O
H
H
Results and discussion
H
H
In consideration of the above, the 2,4-dichloroquinolines (1)
were reacted with 2-amino-5-chlorobenzophenone under
neat conditions at 160°C for 30 min. The only products
Fig. 1 HMBC connectivity of 2b.
Cl
Cl
R1
Cl
R1
PhOC
PhOC
H2N
Cl
160 oC
1
2
1,2 a: R =CH , R =H
3
1
2
b: R =H, R =CH
N
N
H
N
Cl
3
1
2
R2
R2
c: R =Cl, R =H
1
2
d: R =H, R =H
1
2
Scheme 1
* Correspondent. E-mail: prasad_125@yahoo.com
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JOURNAL OF CHEMICAL RESEARCH 2009 721
Table 1 1H NMR and their coupling protons of the compound 2b assigned by H,H-COSY
1H NMR (d)
Coupling protons (d)
1
2
7.11 (s, 1H, C3-H)
7.34 (t, 1H, C6-H, J = 8.18 Hz)
7.53 (m, 1H, C4''-H)
7.54 (m, 2H, C3'', C5''-H)
7.58 (s, 1H, C3'-H)
7.58 (d, 1H, C5'-H, J = 8.31 Hz)
7.59 (d, 1H, C7-H, J = 7.92 Hz)
7.72 (d, 2H, C2'', C6''-H, J = 7.14 Hz)
7.95 (d, 1H, C5-H, J = 8.24 Hz)
9.39 (d, 1H, C6'-H, J = 8.31 Hz)
–
7.59 (d, 1H, C7-H, J = 7.92 Hz), 7.95 (d, 1H, C5-H, J = 8.24 Hz)
7.54 (m, 2H, C3'', C5''-H)
3
4
7.53 (m, 1H, C4''-H), 7.72 (d, 2H C2'', C6''-H, J = 7.14 Hz)
–
9.39 (d, 1H, C6'-H, J = 8.31 Hz)
7.34 (t, 1H, C6-H, J = 8.18 Hz)
7.54 (m, 2H, C3'', C5''-H)
7.34 (t, 1H, C6-H, J = 8.18 Hz)
7.58 (d, 1H, C5'-H, J = 8.31 Hz)
5
6
7
8
9
10
Cl
R1
Cl
H
N
N
H
R2
C
O
Fig. 2 Preferred orientation of the amines 2.
(ringed in Fig. 2) becomes situated in the deshielding zone
of the quinoline ring current, thus experiencing a reinforced
anisotropic effect which shifts the proton to around d 9.40
ppm. The orientation of the molecule 2 could be assigned as
represented. (Fig. 2)
In order to produce the linear dibenzonaphthyridine
system by acid-catalysed cyclisation, the 2-[(2-benzoyl-4-
chlorophenyl)amino]-4-chloroquinolines (2) were heated with
PPA. The reaction started only at a temperature of 205–210°C
and was completed in 5 h. Spectral analysis of the product
revealed a broad singlet for NH group and the formed
products were assigned as 2-chloro-12-phenyldibenzo[b,g]
[1,8]naphthyridin-11(6H)-ones (3) and not the expected
dichloro compounds 4 (Scheme 2). Further, the structure of
one of the product, 2-chloro-7-methyl-12-phenyldibenzo[b,g]
[1,8]naphthyridin-11(6H)-one (3b) was confirmed by a single
crystal XRD study, and its ORTEP diagram is shown in Fig. 3.
Here the mechanism for the conversion of 2 to 3 under
PPA conditions (Scheme 3) might be the protonation of the
ring nitrogen of 2 to give the intermediate I followed by
Fig.
3
ORTEP diagram of 2-chloro-7-methyl-12-phenyl-
dibenzo[b,g][1,8]naphthyridin-11(6H)-one (3b).
internal electrophilic substitution at the quinoline C3-position,
and the same effect might also explain the rather low yields
of the dibenzonaphthyridines 3. We therefore converted the
4-chloro group in the intermediate 2 into a methoxy group
in order to facilitate the reaction. The 2-[(2-benzoyl-4-
chlorophenyl)amino]-4-chloroquinolines (2) on treatment
with sodium methoxide for 10 h afforded the expected
4-methoxyquinolines (5) (Scheme 4). In this case also the
C6'-H was abnormally deshielded at around d 9.50 ppm in the
1H NMR, presumably for the same reason as proposed above
for compounds 2.
The 2-[(2-benzoyl-4-chlorophenyl)amino]-4-methoxyquino-
lines (5) was then subjected to PPA and monitored for
the initiation of the reaction by gradually increasing the
temperature. At a temperature of 130–135°C, the reaction
was found to proceed and was completed in 4 h. Surprisingly,
the products proved to be identical with the earlier-formed
products 3 from the reaction of 2 in PPA, and not the expected
methoxy-products 7 (Scheme 4). A probable explanation
for the formation of 3 is that it arises by acid-catalysed
ether cleavage17 of the OCH3 group of 2-[(2-benzoyl-
–
ipso attack of the OP2O6HR2 ion to the C4-carbon yielding
the intermediate II which subsequently on intramolecular
elimination of a molecule of HCl affords the intermediate
III. Then III on internal electrophilic attack on the positively
induced 2'-carbonyl carbon gives the intermediate IV which
on loss of water yields the product 3.
It was assumed that the reluctance of the reaction of
2-[(2-benzoyl-4-chlorophenyl)amino]-4-chloroquinolines
(2) to proceed at lower temperature might be due to the
deactivating nature of the chloro group which inhibits the
Cl
N
O
Cl
R1
Cl
R1
Cl
R1
PhOC
Cl
PPA
205-210 oC
N
N
H
N
N
N
H
R2
R2
R2
4
2
3
(not formed)
Scheme 2 (a–d: R1, R2 as in Scheme 1).
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722 JOURNAL OF CHEMICAL RESEARCH 2009
O
O
(-O P
O
RO
O
R =
RO P O
OR
O
)
n
P
O
OR
O
P
OH
OH
P
O
H
Cl
O
Cl
Cl
N
R1
Cl
R1
R1
Cl
Cl
H
N
N
N
H
N
H
N
H
H
H
R2
COPh
R2
COPh
R2
COPh
2
I
II
-HCl
+ H
-2RPO3
O
H
HO
HO
C
O
Ph
O
Ph
R1
Cl
R1
Cl
R1
C
Cl
-H2O
H
..
..
N
N
H
N
H
N
N
H
N
H
R2
H
R2
R2
IV
III
3
Scheme 3 (a–d: R1, R2 as in Scheme 1).
4-chlorophenyl)amino]-4-methoxyquinolines (5) to the
intermediate 2-[(2-benzoyl-4-chlorophenyl)amino]quinolin-
4-ones which further gets cyclised to the final products 3 by
the route shown in Scheme 3.
is readily explained by steric hindrance by the C7-methyl
group of the approach of methyl iodide to the N atom at
position 6. (Scheme 4)
In summary: (1) the reaction of 2,4-dichloroquinolines (1)
with 2-amino-5-chloro-benzophenone, whether in excess
or not, provided only the monosubstituted products, the
2-[(2-benzoyl-4-chlorophenyl)amino]-4-chloroquinolines (2).
(2) Acid-catalysed cyclisation of the compounds 2 using
PPA at 205–210°C yielded the 2-chloro-12-phenyldibenzo
[b,g][1,8]naphthyridin-11(6H)-ones (3), probably via the
quinolinone intermediate III.
(3) Treatment of compounds 2 with methanolic sodium
methoxide yielded 2-[(2-benzoyl-4-chlorophenyl)amino]-
4-methoxyquinolines (5) which with PPA at 130–135°C
formed 3, again via the proposed intermediate III.
(4) The temperature difference for the formation of 3 from
2 and 5 reflects the relative readiness of the conversion of the
Cl and OCH3 into an OH group (intermediate III) under the
same acidic conditions. The difference in the yields of the
final products 3 from 2 (ca 21%) and 5 (ca 31%) may have the
same explanation.
Not only were the temperatures milder, for the formation
of the dibenzonaphthyridinones
3 from the methoxy-
intermediates 5 (Scheme 4) than from the chloro-compounds
2 (Scheme 2), but the yields were better, on average some
50% improved on the direct method. However, the yields of
the methoxy from the chloro compounds were only in the
region of 40–50%, so the two-step route cannot be pronounced
advantageous over the direct route, in terms of yield.
Finally, 2-chloro-12-phenyldibenzo[b,g][1,8]naphthyridin-
11(6H)-one (3d) was refluxed with methyl iodide in acetone
in the presence of ignited potassium carbonate. The product
was formed over 1 h, and was identified as the N-methylated
product, namely 2-chloro-6-methyl-12-phenyldibenzo[b,g]
[1,8]naphthyridin-11(6H)-one (6d). The reaction was
generalised for the other naphthyridine derivatives, when it
was found that the 7-methyl compound (3b) took considerably
longer (5 h) for the formation of 2-chloro-6,7-dimethyl-12-
phenyldibenzo[b,g][1,8]naphthyridin-11(6H)-one (6b). This
Cl
N
OCH3
O
R1
R1
Cl
R1
Cl
Cl
NaOCH3
PPA
PPA
130-135 oC
N
H
N
N
N
H
N
H
H
R2
R2
R2
COPh
COPh
COPh
2
5
O
N
O
OCH3
MeI
R1
R1
Cl
R1
Cl
Cl
K2CO3
acetone
N
N
N
N
H
N
R2
R2
R2
Me
7
6
3
Scheme 4 (a–d: R1, R2 as in Scheme 1).
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JOURNAL OF CHEMICAL RESEARCH 2009 723
145.6 (C4), 149.9 (C8a), 151.8 (C2), 168.8 (C=O). MS: m/z (%)
396/394/392 (M+, 15/32/47), 364 (65), 357 (26), 340 (21), 301 (22),
105 (68), 77 (88), 44 (100). Anal. Calcd for C22H14Cl2N2O: C, 67.35;
H, 3.57; N, 7.14. Found: C, 67.26; H, 3.63; N, 7.28%.
(5) N-Methylation of compounds 3 gave the N(6)-
methylated products 6. The reaction was subject to steric
deceleration when a methyl group was present at C7.
Experimental
2-Chloro-12-phenyldibenzo[b,g][1,8]naphthyridin-11(6H)-ones (3a–
d) from 2-[(2-benzoyl-4-chlorophenyl)amino]-4-chloroquinolines (2)
2-[(2-Benzoyl-4-chlorophenyl)amino]-4-chloroquinoline (2a–d, 2 mmol)
was added to polyphosphoric acid (6 g of P2O5 in 3 mL of H3PO4)
and heated at 205–210°C for 5 h. The reaction was monitored by
using TLC. After the completion of the reaction, the reaction mixture
was poured into ice-water and extracted with ethyl acetate, then
purified by column chromatography using silica gel, the product
eluted with petroleum ether:ethyl acetate (96:4) mixture to get 3
which was recrystallised from methanol.
2-Chloro-9-methyl-12-phenyldibenzo[b,g][1,8]naphthyridin-
11(6H)-one (3a): Colourless needles (0.170 g, 23%), m.p. 208–
210°C. IR: nmax 3428 (NH), 1647 (C=O), 1608, 1560 and 1471 cm-1.
NMR (CDCl3): dH 2.38 (s, 3H, C9-CH3), 7.16-7.87 (m, 10H, C1-,
C3-, C4-, C7-, C8-, C2'-, C3'-, C4'-, C5'- and C6'-H), 8.02 (s, 1H,
C10-H), 8.66 (b s, 1H, N6-H; dC 18.6 (C9-CH3), 121.5 (C2), 122.9
(C1), 125.8 (C2', C6'), 126.2 (C3', C4', C5'), 126.8 (C4), 127.8 (C3),
128.0 (C7), 128.1 (C10), 128.3 (C8), 130.0 (C9), 133.4 (C1'), 137.3
(C12), 138.8 (C12a), 147.8 (C10a), 148.3 (C11a), 149.7 (C4a), 150.9
(C6a), 153.4 (C5a), 179.6 (C=O). MS: m/z (%) 372/370 (M+, 26/80),
369 (100), 355 (15), 354 (10), 335 (15), 334 (10), 184 (10), 77 (42).
Anal. Calcd for C23H15ClN2O: C, 74.60; H, 4.05; N, 7.57. Found:C,
74.49; H, 3.95; N, 7.68%.
Melting points were determined on a Mettler FP51 apparatus
(Mettler Instruments, Switzerland). IR spectra were recorded on
Shimadzu FTIR-8201PC spectrophotometer (Shimadzu, Japan)
using KBr discs. H NMR and 13C NMR spectra were recorded on
1
a Bruker AMX 400 spectrometer at 400 MHz (1H) and 100 MHz
(13C) using tetramethylsilane (TMS) as an internal reference;
2D-NMR were recorded on a Bruker AV 300 MHz. The chemical
shifts (d) are expressed in parts per million (ppm). Mass spectra (MS)
were recorded on an 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 and ethyl
acetate as developing solvents.
2-[(2-Benzoyl-4-chlorophenyl)amino]-4-chloroquinolines
general procedure
(2a–d):
The 2,4-dichloroquinoline (1, 4 mmol) was heated with 2-amino-
5-chlorobenzophenone (4 mmol or excess) under neat conditions
at 160°C for 30 min. The product was washed with water, dried,
and purified using silica gel column chromatography eluting with
petroleum ether:ethyl acetate mixture (98:2) to obtain 2 which was
recrystallised from methanol.
2-Chloro-7-methyl-12-phenyldibenzo[b,g][1,8]naphthyridin-
11(6H)-one (3b): Colourless prisms (0.155 g, 21%), m.p. 206–
208°C. IR: nmax 3430 (NH), 1644 (C=O), 1601, 1561 and 1480 cm-1.
NMR (CDCl3): dH 2.58 (s, 3H, C7-CH3), 7.08–7.88 (m, 10H, C1-,
C3-, C4-, C8-, C9-, C2'-, C3'-, C4'-, C5'- and C6'-H), 8.11 (d, 1H,
C10-H, J = 8.10 Hz), 8.51 (b s, 1H, N6-H; dC 16.8 (C7-CH3), 121.5
(C2), 122.9 (C1), 125.8 (C2', C6'), 126.2 (C3', C4', C5'), 126.8 (C4),
127.8 (C3), 127.8 (C9), 128.0 (C10), 128.2 (C8), 130.8 (C7), 133.4
(C1'), 137.3 (C12), 138.8 (C12a), 147.6 (C10a), 148.3 (C11a), 149.7
(C4a), 151.3 (C6a), 153.5 (C5a), 179.6 (C=O). MS: m/z (%) 372/370
(M+, 22/75), 369 (100), 355 (16), 354 (13), 335 (10), 334 (17), 184
(22), 77 (36). Anal. Calcd for C23H15ClN2O: C, 74.60; H, 4.05; N,
7.57. Found:C, 74.71; H, 4.11; N, 7.45%.
2,9-Dichloro-12-phenyldibenzo[b,g][1,8]naphthyridin-11(6H)-
one (3c): White solid (0.140 g, 18%), m.p. 212–214°C. IR nmax 3431
(NH), 1642 (C=O), 1605, 1557 and 1473 cm-1. NMR (CDCl3): dH
7.19–7.87 (m, 10H, C1-, C3-, C4-,C7-, C8-, C2'-, C3'-, C4'-, C5'- and
C6'-H), 8.18 (d, 1H, C10-H, J = 2.40 Hz), 8.96 (b s, 1H, N6-H; dC
121.5 (C2), 122.9 (C1), 125.8 (C2', C6'), 126.2 (C3', C4', C5'), 126.8
(C4), 127.8 (C3), 127.9 (C7), 128.0 (C10), 128.1 (C8), 129.4 (C9),
133.4 (C1'), 137.3 (C12), 138.8 (C12a), 147.6 (C10a), 148.3 (C11a),
149.7 (C4a), 150.8 (C6a), 153.4 (C5a), 179.6 (C=O). MS: m/z (%)
394/392/390 (M+, 32/61/100), 389 (82), 375 (18), 355 (16), 354 (10),
328 (25), 184 (27), 75 (15). Anal. Calcd for C22H12Cl2N2O: C, 67.69;
H, 3.08; N, 7.18. Found:C, 67.80; H, 2.99; N, 7.25%.
2-[(2-Benzoyl-4-chlorophenyl)amino]-4-chloro-6-methylquinoline
(2a): Colourless prisms (1.186 g, 73%), m.p. 172–174°C. IR: nmax
3432 (NH), 1636 (C=O), 1581, 1521, 1148 cm-1. NMR (CDCl3): dH
2.54 (s, 3H, C6-CH3), 7.09 (s, 1H, C3-H), 7.30–7.80 (m, 9H, C7-,
C8-, C3'-, C5'-, C2''-, C3''-, C4''-, C5''- and C6''-H), 7.86 (s, 1H, C5-
H), 9.22 (d, 1H, C6'-H, J = 8.21 Hz), 10.86 (b s, 1H, NH); dC 21.5
(C6-CH3), 114.3 (C3), 121.4 (C4'), 122.5 (C4a), 124.3 (C2') 127.2
(C6') 128.3 (C5) 129.4 (C2'', C6''), 129.7 (C3'', C5''), 130.1 (C4''),
130.9 (C3'), 131.3 (C8), 133.2 (C7), 133.9 (C6), 137.1 (C5'), 138.6
(C1''), 142.6 (C1'), 146.0 (C4), 150.3 (C8a), 151.9 (C2), 168.8
(C=O). MS: m/z (%) 410/408/406 (M+, 8/20/35), 391 (15), 378
(47), 377 (65), 343 (27), 105 (38), 77 (79), 44 (100). Anal. Calcd for
C23H16Cl2N2O: C, 67.98; H, 3.94; N, 6.90. Found:C, 67.82; H, 4.14;
N, 7.02%.
2-[(2-Benzoyl-4-chlorophenyl)amino]-4-chloro-8-methyl-
quinoline (2b): Colourless needles (1.218 g, 75%), m.p. 168–170°C.
IR: nmax 3435 (NH), 1632 (C=O), 1591, 1521, 1152 cm-1. NMR
(CDCl3): dH 2.75 (s, 3H, C8-CH3), 7.11 (s, 1H, C3-H), 7.32–7.97 (m,
9H, C6-, C7-, C3'-, C5'-, C2''-, C3''-, C4''-, C5''- and C6''-H), 7.95
(d, 1H, C5-H, J = 8.24 Hz), 9.39 (d, 1H, C6'-H, J = 8.31 Hz), 11.04
(b s, 1H, NH); dC 19.8 (C8-CH3), 114.3 (C3), 121.4 (C4'), 122.5
(C4a), 124.3 (C2') 127.2 (C6') 128.1 (C5) 129.4 (C2'', C6''), 129.7
(C3'', C5''), 130.1 (C4''), 130.9 (C3'), 131.5 (C6), 132.8 (C7), 133.1
(C8), 137.1 (C5'), 138.6 (C1''), 142.6 (C1'), 146.1 (C4), 150.1 (C8a),
151.8 (C2), 168.8 (C=O). MS: m/z (%) 410/408/406 (M+, 10/23/39),
391 (10), 378 (55), 377 (60), 343 (42), 105 (38), 77 (85), 44 (100).
Anal. Calcd for C23H16Cl2N2O: C, 67.98; H, 3.94; N, 6.90. Found:C,
68.10; H, 4.07; N, 6.88%.
2-Chloro-12-phenyldibenzo[b,g][1,8]naphthyridin-11(6H)-one
(3d): Colourless prisms (0.142 g, 20%), m.p. 205–207°C. IR: nmax
3430 (NH), 1645 (C=O), 1607, 1559 and 1477 cm-1. NMR (CDCl3):
2-[(2-Benzoyl-4-chlorophenyl)amino]-4,6-dichloroquinoline (2c):
White solid (1.227 g, 72%), m.p. 174–176°C. IR: nmax 3432 (NH),
1636 (C=O), 1581, 1521, 1148 cm-1. NMR (CDCl3): dH 7.13 (s, 1H,
C3-H), 7.52–7.82 (m, 9H, C7-, C8-, C3'-, C5'-, C2''-, C3''-, C4''-, C5''-
and C6''-H), 8.06 (s, 1H, C5-H), 9.27 (d, 1H, C6'-H, J = 8.19 Hz),
10.89 (b s, 1H, NH); dC 114.3 (C3), 121.4 (C4'), 122.3 (C4a), 124.3
(C2') 127.2 (C6') 127.8 (C5) 129.4 (C2'', C6''), 129.7 (C3'', C5''),
130.1 (C4''), 130.9 (C3'), 130.9 (C8), 131.8 (C6), 133.0 (C7), 137.1
(C5'), 138.6 (C1''), 142.6 (C1'), 145.8 (C4), 150.0 (C8a), 151.7 (C2),
168.8 (C=O). MS: m/z (%) 432/430/428/426 (M+, 1/11/34/35), 398
(35), 397 (55), 391 (21), 321 (30), 105 (55), 77 (71), 44 (100). Anal.
Calcd for C22H13Cl3N2O: C, 61.97; H, 3.05; N, 6.57. Found:C, 62.13;
H, 3.12; N, 6.39%.
d
H 7.57–7.87 (m, 11H, C1-, C3-, C4-, C7-, C8-, C9-, C2'-, C3'-, C4'-,
C5'- and C6'-H), 8.21 (dd, 1H, C10-H, J = 1.30 Hz, 8.08 Hz), 8.86
(b s, 1H, N6-H; dC 121.5 (C2), 122.9 (C1), 125.8 (C2', C6'), 126.2 (C3',
C4', C5'), 126.8 (C4), 127.8 (C3), 127.9 (C7), 128.2 (C10), 128.9 (C9),
129.4 (C8), 133.4 (C1'), 137.1 (C12), 138.8 (C12a), 147.6 (C10a),
148.3 (C11a), 149.7 (C4a), 151.0 (C6a), 153.4 (C5a), 179.6 (C=O).
MS: m/z (%) 358/356 (M+, 30/85), 355 (100), 321 (31), 320 (15), 298
(18), 183 (21), 77 (27), 75 (32). Anal. Calcd for C22H13ClN2O: C,
74.16; H, 3.65; N, 7.87. Found:C, 74.05; H, 3.59; N, 7.94%.
2-[(2-Benzoyl-4-chlorophenyl)amino]-4-methoxyquinolines (5a–d):
general procedure
2-[(2-Benzoyl-4-chlorophenyl)amino]-4-chloroquinoline (2a–d, 2 mmol)
was added to methanolic sodium methoxide (2 g sodium in 15 mL
methanol) and heated on a water bath for 10 h. The reaction was
monitored by TLC. After the completion of the reaction, excess of
methanol was evaporated, the reaction mixture was poured into ice-
water and neutralised with dilute HCl. The resulting precipitate was
filtered, dried and purified by column chromatography over silica
gel using petroleum ether:ethyl acetate (95:5) to give 5, which was
recrystallised from methanol.
2-[(2-Benzoyl-4-chlorophenyl)amino]-4-chloroquinoline
(2d):
Colourless prisms (1.16 g, 74%), m.p. 169–171°C. IR: nmax 3428
(NH), 1632 (C=O), 1589, 1522, 1117 cm-1. NMR (CDCl3): dH 7.11
(s, 1H, C3-H), 7.42–7.90 (m, 10H, C6-, C7-, C8-, C3'-, C5'-, C2''-,
C3''-, C4''-, C5''- and C6''-H), 8.09 (dd, 1H, C5-H, J = 1.10, 8.28
Hz), 9.23 (d, 1H, C6'-H, J = 8.24 Hz), 10.89 (b s, 1H, NH); dC 114.3
(C3), 121.4 (C4'), 123.1 (C4a), 124.3 (C2') 127.2 (C6') 128.5 (C5)
129.4 (C2'', C6''), 129.7 (C3'', C5''), 130.1 (C4''), 130.9 (C3'), 131.1
(C6), 131.4 (C8), 132.9 (C7), 137.1 (C5'), 138.6 (C1''), 142.6 (C1'),
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724 JOURNAL OF CHEMICAL RESEARCH 2009
2-[(2-Benzoyl-4-chlorophenyl)amino]-4-methoxy-6-methyl-
quinoline (5a): Colourless prisms (0.346 g, 43%), m.p. 183–185°C
IR: nmax 3430 (NH), 1626 (C=O), and 1593, 1522 and 1237 cm-1
(OCH3). NMR (CDCl3): dH 2.51 (s, 3H, C6-CH3), 4.06 (s, 3H,
OCH3), 6.31(s, 1H, C3-H), 7.25–7.81 (m, 9H, C7-, C8-, C3'-, C5'-,
C2''-, C3''-, C4''-, C5''- and C6''-H), 7.90 (s, 1H, C5-H), 9.56 (d, 1H,
C6'-H, J = 8.53 Hz), 10.91 (b s, 1H, NH); dc: 21.1 (C6-CH3), 55.8
(O-CH3), 92.3 (C3), 118.5 (C4'), 119.4 (C4a), 121.5 (C2') 122.0 (C6')
122.8 (C5) 128.4 (C2'', C6''), 129.6 (C3'', C5''), 130.4 (C4''), 131.6
(C3'), 132.3 (C8), 133.2 (C7), 134.3 (C6), 134.6 (C5'), 138.9 (C1''),
143.1 (C1'), 146.9 (C8a), 152.9 (C4), 163.4 (C2), 199.2 (C=O). MS:
m/z (%) 404/402 (M+, 20/55), 401 (14), 387 (18), 386 (27), 374
(44), 371 (32), 105 (50), 77 (100). Anal. Calcd for C24H19ClN2O2:
C, 71.64; H, 4.73; N, 6.97. Found: C, 71.81; H, 4.66; N, 7.03%.
2-[(2-Benzoyl-4-chlorophenyl)amino]-4-methoxy-8-methyl-
quinoline (5b): Colourless needles (0.370 g, 46%), m.p. 179–181°C.
IR nmax 3435 (NH), 1632 (C=O), 1587, 1519, 1231 cm-1 (OCH3).
NMR (CDCl3): dH 2.74 (s, 3H, C8-CH3), 4.03 (s, 3H, OCH3), 6.29 (s,
1H, C3-H), 7.21–7.75 (m, 9H, C6-, C7-, C3'-, C5'-, C2''-, C3''-, C4''-,
C5''- and C6''-H), 7.92 (d, 1H, C5-H, J = 8.40 Hz), 9.53 (d, 1H, C6'-H,
J = 8.55 Hz), 11.05 (br s, 1H, NH); dC 18.7 (C6-CH3), 55.7 (OCH3),
92.2 (C3), 118.5 (C4'), 119.4 (C4a), 121.5 (C2') 122.0 (C6') 123.0
(C5) 128.4 (C2'', C6''), 129.6 (C3'', C5''), 130.4 (C4''), 131.6 (C3'),
131.8 (C6), 133.6 (C7), 134.0 (C8), 134.6 (C5'), 138.9 (C1''), 143.1
(C1'), 146.7 (C8a), 153.1 (C4), 163.4 (C2), 199.2 (C=O). MS: m/z (%)
404/402 (M+, 23/61), 387 (22), 373 (52), 371 (18), 105 (42), 105 (50),
77 (100), 44 (75). Anal. Calcd for C24H19ClN2O2: C, 71.64; H, 4.73; N,
6.97. Found: C, 71.56; H, 4.80; N, 6.89%.
2-[(2-Benzoyl-4-chlorophenyl)amino]-6-chloro-4-methoxy-
quinoline (5c): White solid (0.355 g, 42%), m.p. 188–190°C. IR:
nmax 3433 (NH), 1634 (C=O), 1587, 1525, 1239 cm-1 (OCH3). NMR
(CDCl3): dH 4.11 (s, 3H, OCH3), 6.33 (s, 1H, C3-H), 7.48–7.88 (m,
9H, C7-, C8-, C3'-, C5'-, C2''-, C3''-, C4''-, C5''- and C6''-H), 8.11 (s,
1H, C5-H), 9.49 (d, 1H, C6'-H, J = 8.48 Hz), 10.89 (b s, 1H, NH);
dC 55.8 (OCH3), 92.3 (C3), 118.5 (C4'), 119.1 (C4a), 121.5 (C2') 122.0
(C6') 122.1 (C5) 128.4 (C2'', C6''), 129.6 (C3'', C5''), 130.4 (C4''),
131.6 (C3'), 131.9 (C8), 132.6 (C6), 133.1 (C7), 134.6 (C5'), 138.9
(C1''), 143.1 (C1'), 146.1 (C8a), 152.5 (C4), 163.3 (C2), 199.2 (C=O).
MS: m/z (%) 426/424/422 (M+, 8/24/73), 391 (25), 389 (10), 387 (32),
317 (15), 105 (26), 77 (100), 44 (41). Anal. Calcd for C23H16Cl2N2O2:
C, 65.40; H, 3.79; N, 6.64. Found: C, 65.32; H, 3.86; N, 6.71%
the excess of acetone and methyl iodide was evaporated off and the
residue treated with ice-water and neutralised with dilute HCl, then
extracted with ethyl acetate and purified by column chromatography
over silica gel using petroleum ether:ethyl acetate (99:1) as eluant to
get 6. This was recrystallised from ethanol.
2-Chloro-6,9-dimethyl-12-phenyldibenzo[b,g][1,8]naphthyridin-
11(6H)-one (6a): Pale yellow needles (0.173 g, 45%), m.p. 182–
184°C. IR: nmax 1648 (C=O), 1602, 1566, 1482 and 1178 cm-1. NMR
(CDCl3): dH 2.41 (s, 3H, C9-CH3), 4.04 (s, 3H, N6-CH3), 7.21–7.89
(m, 10H, C1-, C3-, C4-, C7-, C8-, C2'-, C3'-, C4'-, C5'- and C6'-H),
7.98 (s, 1H, C10-H); dC 18.5 (C9-CH3), 43.5 (N6-CH3), 121.5 (C2),
122.9 (C1), 125.8 (C2', C6'), 126.2 (C3', C4', C5'), 126.6 (C7), 126.8
(C4), 127.8 (C3), 127.9 (C10), 128.1 (C8), 129.7 (C9), 133.4 (C1'),
137.3 (C12), 138.8 (C12a), 147.6 (C10a), 148.3 (C11a), 149.7 (C4a),
150.1 (C6a), 151.7 (C5a), 179.6 (C=O). MS: m/z (%) 386/384 (M+,
35/100), 369 (25), 367 (10), 354 (12), 333 (15), 332 (8), 166 (15),
77 (32). Anal. Calcd for C24H17ClN2O: C, 75.00; H, 4.43; N, 7.29.
Found:C, 74.88; H, 4.34; N, 7.39%.
2-Chloro-6,7-dimethyl-12-phenyldibenzo[b,g][1,8]naphthyridin-
11(6H)-one (6b): Pale yellow needles (0.181 g, 47%), m.p. 180–
182°C. IR: nmax 1645 (C=O), 1607, 1568, 1484 and 1169 cm-1. NMR
(CDCl3): dH 2.52 (s, 3H, C7-CH3), 4.09 (s, 3H, N6-CH3), 7.17–7.92
(m, 10H, C1-, C3-, C4-, C8-, C9-, C2'-, C3'-, C4'-, C5'- and C6'-H),
8.20 (d, 1H, C10-H, J = 8.21 Hz); dC 17.8 (C7-CH3), 42.7 (N6-CH3),
121.5 (C2), 122.9 (C1), 125.8 (C2', C6'), 126.2 (C3', C4', C5'), 126.8
(C4), 127.8 (C3), 127.9 (C9), 128.0 (C10), 128.1 (C8), 129.8 (C7),
133.4 (C1'), 137.3 (C12), 138.8 (C12a), 147.4 (C10a), 148.3 (C11a),
149.7 (C4a), 152.0 (C6a), 152.3 (C5a), 179.6 (C=O). MS: m/z (%)
386/384 (M+, 33/100), 369 (38), 367 (15), 354 (23), 333 (10), 332
(19), 166 (36), 77 (54). Anal. Calcd for C24H17ClN2O: C, 75.00; H,
4.43; N, 7.29. Found:C, 75.11; H, 4.38; N, 7.34%.
2,9-Dichloro-6-methyl-12-phenyldibenzo[b,g][1,8]naphthyridin-
11(6H)-one (6c): Pale yellow solid, m.p. 186–188°C. Yield:(0.170 g,
42%). IR nmax (cm-1):1642 (C=O), 1612, 1560, 1481 and 1175 cm-1.
NMR (CDCl3): dH 4.23 (s, 3H, N6-CH3), 7.25–7.98 (m, 10H, C1-,
C3-, C4-, C7-, C8-, C2'-, C3'-, C4'-, C5'- and C6'-H), 8.27 (d, 1H,
C10-H, J = 2.56 Hz); dC 42.9 (N6-CH3), 121.5 (C2), 122.9 (C1),
125.8 (C2', C6'), 126.2 (C3', C4', C5'), 126.5 (C7), 126.6 (C4), 126.8
(C3), 127.8 (C10), 128.0 (C8), 128.1 (C9), 133.4 (C1'), 137.3 (C12),
138.8 (C12a), 147.5 (C10a), 148.3 (C11a), 149.7 (C4a), 150.3 (C6a),
151.2 (C5a), 179.6 (C=O). MS: m/z (%) 408/406/404 (M+, 19/55/82),
403 (100), 367 (24), 352 (18), 338 (10), 166 (12), 77 (52), 41 (44).
Anal. Calcd for C23H14Cl2N2O: C, 68.32; H, 3.47; N, 6.93. Found:C,
68.40; H, 3.53; N, 6.81%.
2-Chloro-6-methyl-12-phenyldibenzo[b,g][1,8]naphthyridin-
11(6H)-one (6d): Pale yellow prisms (0.167 g, 45%), m.p. 179–
181°C. IR: nmax 1646 (C=O), 1607, 1559, 1477 and 1170 cm-1.
NMR (CDCl3): dH 4.18 (s, 3H, N6-CH3), 7.54–7.90 (m, 11H, C1-,
C2-, C4-, C7-, C8-, C9-, C2'-, C3'-, C4'-, C5'- and C6'-H), 8.25 (d,
1H, C10-H, J = 8.39 Hz); dC 43.3 (N6-CH3), 121.5 (C2), 122.9 (C1),
125.8 (C2', C6'), 126.2 (C3', C4', C5'), 126.5 (C7), 126.8 (C4), 127.8
(C3), 127.9 (C10), 128.2 (C9), 129.4 (C8), 133.4 (C1'), 137.1 (C12),
138.8 (C12a), 147.4 (C10a), 148.3 (C11a), 149.7 (C4a), 149.9 (C6a),
151.2 (C5a), 179.6 (C=O). MS: m/z (%) 372/370 (M+, 36/100), 355
(35), 353 (12), 335 (15), 333 (8), 166 (16), 77 (52), 41 (42). Anal.
Calcd for C23H15ClN2O: C, 74.60; H, 4.05; N, 7.57. Found:C, 74.65;
H, 4.00; N, 7.63%.
2-[(2-Benzoyl-4-chlorophenyl)amino]-4-methoxyquinoline
(5d):
Colourless prisms (0.349 g 45%), m.p. 177–179°C. IR: nmax 3428
(NH), 1635 (C=O), 1589, 1522, 1233 (OCH3). 1H NMR (CDCl3)
d: 4.08 (s, 3H, OCH3), 6.30 (s, 1H, C3-H), 7.45–7.94 (m, 10H, C6-,
C7-, C8-, C3'-, C5'-, C2''-, C3''-, C4''-, C5''- and C6''-H), 8.10 (dd, 1H,
C5-H, J = 1.81 Hz, 8.36 Hz), 9.55 (d, 1H, C6'-H, J = 8.62 Hz), 10.99
(b s, 1H, NH); dC 55.8 (O-CH3), 92.3 (C3), 118.5 (C4'), 119.3 (C4a),
121.5 (C2') 122.0 (C6') 122.5 (C5) 128.4 (C2'', C6''), 129.6 (C3'',
C5''), 130.4 (C4''), 131.6 (C3'), 131.6 (C6), 133.4 (C8), 133.7 (C7),
134.6 (C5'), 138.9 (C1''), 143.1 (C1'), 145.9 (C8a), 152.3 (C4), 163.3
(C2), 199.2 (C=O). MS: m/z (%) 390/388 (M+, 25/68), 362 (18), 360
(36), 357 (42), 353 (22), 105 (42), 77 (100), 44 (55). Anal. Calcd for
C23H17ClN2O2: C, 71.13; H, 4.38; N, 7.22. Found:C, 71.01; H, 4.51;
N, 7.29%.
2-Chloro-12-phenyldibenzo[b,g][1,8]naphthyridin-11(6H)-ones (3a–
d) from 2-[(2-benzoyl-4-chlorophenyl)amino]-4-methoxy-quinolines
(5), general procedure
Supplementary data
2-[(2-Benzoyl-4-chlorophenyl)amino]-4-methoxyquinoline (5a–d,
0.002 mol) was added to polyphosphoric acid (6 g of P2O5 in
3 mL of H3PO4) and heated at 130–135°C for 4 h. The reaction was
monitored by TLC. After the completion of the reaction, the reaction
mixture was poured into ice water and extracted with ethyl acetate,
purified by column chromatography using silica gel and product
eluted with petroleum ether:ethyl acetate (96:4) to provide a white
solid. The product was recrystallised from methanol. From the TLC,
mixed melting point and superimposible IR spectra, the products
were identified as 3. The yield of the products 3 in this reaction were
as follows: 3a, 31%; 3b, 33%; 3c, 29%, 3d, 30%.
The cif file can be obtained as CCDC Deposit no. 751115.
These data may be obtained free of charge by emailing: www.
ccdc.cam.ac.uk/data_request/cif.
The authors thank IISc, Bangalore, and MKU, Madurai,
for NMR, and IICT, Hyderabad, for mass spectral data.
The authors acknowledge the financial assistance of UGC,
New Delhi, India, under Grant no. F31-122/2005.
Received 13 May 2009; accepted 27 October 2009
Paper 09/0585 doi: 10.3184/030823409X12572441140695
Published online: 8 December 2009
N-Methylation of 3a–d; preparation of 2-chloro-6-methyl-12-
phenyldibenzo[b,g][1,8]naphthyridin-11(6H)-ones (6a–d), general
procedure
2-Chloro-12-phenyldibenzo[b,g][1,8]naphthyridin-11(6H)-one
(3a–d, 1 mmol) was refluxed with methyl iodide (1 mL) in acetone
(10 mL) and in presence of ignited potassium carbonate (2 g) for
1 h (exceptionally, 5 h was required for the conversion of 3b). The
reaction was monitored by TLC. After completion of the reaction
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