Synthesis of novel alkyl and aryl substituted dibenzo[b,h][1,6] naphthyridines

Article abstract of DOI:10.1080/00397911.2010.525336

A one-pot synthesis of 7-alkyl and aryl substituted dibenzo[b,h][1,6] naphthyridines is reported from the reaction of 4-chloro-2-methylquinolines and alkyl/aryl substituted aminoketones. Because the yield of the dibenzonaphthyridines was poor, in an alter

Full text of DOI:10.1080/00397911.2010.525336

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Synthesis of Novel Alkyl and
Aryl Substituted Dibenzo[b,h]
[1,6]naphthyridines
M. Manoj a & K. J. Rajendra Prasad a
a Department of Chemistry , Bharathiar University , Coimbatore ,
Tamil Nadu , India
Accepted author version posted online: 29 Jul 2011.Published
online: 06 Oct 2011.
To cite this article: M. Manoj & K. J. Rajendra Prasad (2012) Synthesis of Novel Alkyl and Aryl
Substituted Dibenzo[b,h][1,6]naphthyridines, Synthetic Communications: An International
Journal for Rapid Communication of Synthetic Organic Chemistry, 42:3, 434-446, DOI:
10.1080/00397911.2010.525336
To link to this article: http://dx.doi.org/10.1080/00397911.2010.525336
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Synthetic Communications1, 42: 434–446, 2012
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2010.525336
SYNTHESIS OF NOVEL ALKYL AND ARYL
SUBSTITUTED DIBENZO[b,h][1,6]NAPHTHYRIDINES
M. Manoj and K. J. Rajendra Prasad
Department of Chemistry, Bharathiar University, Coimbatore,
Tamil Nadu, India
GRAPHICAL ABSTRACT
Abstract A one-pot synthesis of 7-alkyl and aryl substituted dibenzo[b,h][1,6]naphthyri-
dines is reported from the reaction of 4-chloro-2-methylquinolines and alkyl/aryl substi-
tuted aminoketones. Because the yield of the dibenzonaphthyridines was poor, in an
alternative method the title compounds were prepared from the 4-chloro-2-methylquinolines
via anilinoquinolines as intermediates employing alkyl and aryl carboxylic acids, which
improved yields.
Keywords Aminoketones; anilinoquinolines; 4-chloro-2-methylquinolines; substituted
dibenzo[b,h][1,6]naphthyridines
INTRODUCTION
There are a vast number of pharmacologically active heterocyclic compounds,
of which many are in regular therapeutic usage. The heterocyclic system containing a
quinoline nucleus has found broad application in drug development for the treat-
ment of MCH (melanin concentrating hormone) receptor-related disorders,[1] cell
proliferative diseases,[2] transmissible spongiform encephalopathies,[3] malignant
tumors (such as stomach cancer, brain tumor, and large intestine cancer),[4] and
bacterial infections in mammals.[5] Since the discovery of cinchona alkaloids as
Received August 16, 2010.
Address correspondence to K. J. Rajendra Prasad, Department of Chemistry, Bharathiar
University, Coimbatore, Tamil Nadu, India. E-mail: prasad_125@yahoo.com
434

SUBSTITUTED DIBENZONAPHTHYRIDINES
435
antimalarial agents, quinoline alkaloids in general and amino substituted quinolines
in particular, research has focused on turning the quinoline (p-electron deficient het-
erocycle) core into active chemical entities for the synthesis of antimalarial drugs
active against Plasmodium falciparum[6] (e.g., chloroquine, primaquine, etc.). Some
of the phenylaminoquinolines are also considered as synthetic, antimalarials,[7]
and chemists have utilized them in deriving various heterocycles such as dibenzo-
naphthyridines and indoloquinolines. A detailed survey of the literature shows that
the reaction of chloroquinolines has been aimed at getting substituted quinolines
that possessed biological activity.[8,9] One among them is the amination reaction
involving aromatic amines, which derives the respective anilinoquinolines [i.e.,
(N-phenylamino)quinolines].
Research on the chemistry of naphthyridines has expanded considerably in
recent years because biologically active compounds have been detected among the
derivatives of these heterocycles. Numerous reports have pertained to these hetero-
cycles as anti-arrhythmic,[10] anti-alalgesic,[11] anti-HIV,[12] and anticancer agents.[13]
Particularly, some of the dibenzonaphthyridines (i.e., quinoline dimers) act as potent
and selective 3-phosphoinostide-dependent kinase-I inhibitors.[14] Since the dis-
covery of first naphthyridine by Reissert in 1893,[15] many procedures have evolved
for the synthesis of simple benzo and dibenzonaphthridines,[16–19] and only very few
accomplish their construction through anilinoquinolines.[20,21]
Recently in our laboratory dibenzonaphthyridines have been synthesized
via anilinoquinolines as potential intermediates.[22–24] In continuation, herein we
report the synthesis of alkyl and aryl substituted dibenzo[b,h][1,6]naphthyridines
utilizing 4-chloro-2-methylquinolines in two different ways. One of the methods
employs one-pot synthesis while the other exploits (N-phenylamino)quinolines as
intermediates.
RESULTS AND DISCUSSION
Because the approach to 7-alkyl and aryl-substituted-2,6-dimethyl diben-
zo[b,h][1,6]naphthyridines (4a, 5a) from the reaction of 2,6-dimethylquinolin-4(1H)-
one (1) and o-aminoacetophenone (2)=o-aminobenzophenone (3) under acidic
condition was not successful (Scheme 1), similar to our earlier report,[25] we con-
sidered an alternative approach[22] in which 4-chloro-2,8-dimethylquinoline (6b)
Scheme 1. Attempted synthesis of dibenzonaphthyridines.

436
M. MANOJ AND K. J. RAJENDRA PRASAD
Scheme 2. One-pot synthesis of dibenzonaphthyridines.
was treated with o-aminoacetophenone 2 under neat conditions at 160 ꢀC for half an
hour in the hope of obtaining the respective ketones 7, 8, which may be suitable
intermediates to the target molecule 4, 5 (Scheme 2). The reaction yielded a single
product.
Its infrared (IR) spectrum showed stretching vibrations at 1627 cmꢁ1 and
1
1596 cmꢁ1 due to the presence of C N groups. Its H NMR spectrum showed the
=
presence of three methyl protons at d 2.83, 3.23, and 3.31 due to C4-CH3, C7-CH3,
and C6-CH3 respectively. All the aromatic protons appeared between d 7.51 and
8.19, while C1-H appeared at d 9.10 as a doublet (J ¼ 7.59 Hz). The absence of a
C O group in the IR and 13C NMR spectra revealed that the expected uncyclized
=
compound 7b was not formed. Further, 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 272 and elemental analysis supported the molecular
formula as C19H16N2. All the spectral and analytical data were in agreement with
the cyclized structure, namely 4,6,7-trimethyldibenzo[b,h][1,6]naphthyridine (4b).
The reaction was generalized for other quinoline derivatives 6a, c, d to yield the
respective dibenzonaphthyridines 4a, c, d.
A similar set of reactions was extended to o-aminobenzophenone to afford
6-methyl-7-phenyldibenzo[b,h][1,6]naphthyridines 5 and not the uncyclized product
8. The structure of the obtained product 5 was confirmed by spectral and analytical
data. The structure of one of the compounds [namely, 2-chloro-6-methyl-7-phenyl-
dibenzo[b,h][1,6]naphthyridine (5c)] has been solved through single-crystal x-ray
diffraction (XRD) studies and its ORTEP diagram is shown in Fig. 1.
The mechanism for the formation of the products 4 and 5 from 6 and amino-
ketones 2 and 3 can be interpreted via the formation of the intermediate I by the
elimination of HCl from 6, which further catalyzes the cyclization by the protona-
tion of the 20-carbonyl group to form the oxonium ion intermediate II. Its reaction
at the quinoline C3-position by intramolecular electrophilic cyclisation gives the

SUBSTITUTED DIBENZONAPHTHYRIDINES
437
Figure 1. ORTEP diagram of 2-chloro-6-methyl-7-phenyldibenzo[b,h][1,6]naphthyridine (5c). (Figure is
provided in color online.)
Scheme 3. Mechanism for the formation of 6-methyl-7-substituted dibenzo[b,h][1,6]naphthyridines from
4-chloro-2-methylquinolines.

438
M. MANOJ AND K. J. RAJENDRA PRASAD
Scheme 4. Preparation of anilinoquinolines.
intermediate III, which on aromatization to IV and subsequent loss of a water mol-
ecule under the influence of acid yields the final products (4 and 5) (Scheme 3).
The yield of the one-pot synthesis of 6-methyl-7-substituted dibenzo[b,h][1,6]
naphthyridine (4, 5) as outlined in Scheme 2 was only moderate (ꢂ27%), so we
devised an alternative route in which 4-chloro-2,8-dimethylquinoline (6b) was heated
with aniline (9) under neat conditions at 160 ꢀC for half an hour (Scheme 4). Its IR
spectrum showed stretching at 3378 cmꢁ1 due to the presence of the NH group. In its
1H NMR spectrum, the two methyl protons appeared at d 2.76 and d 2.95 due to C8-
CH3 and C2-CH3 respectively. The peculiar C3-H emerged as a singlet at d 6.71. The
rest of the aromatic protons were found between d 7.31 and d 8.80. Two one-proton-
broad singlets at d 10.50 and d 12.41 were due to C4-NH of amino form and N1-H of
imino form respectively. The ratio of amino and imino forms was 1:1. Its 13C NMR
spectrum showed the presence of 17 carbons. Hence, the structure of the product
obtained was assigned as 2,8-dimethyl-4-(N-phenylamino)quinoline (10b), which
was found to be in tautomeric equilibrium with its imino form. The generality of
Scheme 5. Cyclization of anilinoquinolines to dibenzonaphthyridines.

SUBSTITUTED DIBENZONAPHTHYRIDINES
439
Scheme 6. Mechanism for the formation of 6-methyl-7-substituted dibenzo[b,h][1,6]naphthyridines from
anilinoquinolines.
the reaction was tested with other quinoline derivatives 6a, c, d to accomplish the
respective anilinoquinolines 10a, c, d.
Next, the anilinoquinoline 10b was heated with acetic acid in the presence of
polyphosphoric acid to 160 ꢀC for 5 h to give the product (Scheme 5). From
thin-layer chromatography (TLC), mixed melting point, and superimposible IR
spectra, the compound was identified as the same one (4b) obtained earlier from
4-chloro-2,8-dimethylquinoline (6b) and o-aminoacetophenone (2) in the one-pot
synthesis under neat condition. Similarly 10a, c, d afforded the respective 4a, c, d.
In another set of experiments, 10 was reacted with benzoic acid in the presence of
PPA to furnish the respective dibenzonaphthyridines 5.
Table 1. Comparison of yield: Method 1 and Method 2
Yield (%)
Final compounds
Method 1
Method 2
Compound
R1
R2
R3
One pot 6!4 or 6!5
6!10
10!4 or 10!5
Overall
4a
4b
4c
4d
5a
5b
5c
5d
CH3
H
H
CH3
H
CH3
CH3
CH3
CH3
Ph
30
30
29
30
23
25
22
25
70
75
65
72
70
75
65
72
52
45
52
50
43
40
43
40
36
36
34
38
32
28
30
30
Cl
H
H
CH3
H
H
CH3
H
Ph
Ph
Cl
H
H
Ph

440
M. MANOJ AND K. J. RAJENDRA PRASAD
A plausible mechanism to the product, through the intermediate V via acyla-
tion of 10 at the quinoline 3 position and acid-catalyzed cyclization to the aniline
ring through the intermediates VI and IV, is shown in Scheme 6.
Even though the synthesis involves two steps to the product, the overall yield
was somewhat better (ꢂ33%) than that of the one-pot synthesis. The yield of the
products obtained from the two methods are compared in Table 1.
CONCLUSION
The one-pot synthesis (method 1) of the final products from the reaction
of 4-chloro-2-methylquinolines and aminoketones under neat conditions takes the
least time but gives poor yield. Even though the alternate method (Method 2)
involves two steps, the overall yield is comparatively better, but the time consump-
tion is large.
EXPERIMENTAL
Melting points (mp) were determined on Mettler FP 51 apparatus (Mettler
Instruments, Switzerland) and are uncorrected. They are expressed in degree centi-
grade (ꢀC). IR spectra were recorded on Schimadzu FTIR-8201PC spectrophoto-
1
meter (Schimadzu, Japan) using KBr disc. H NMR and 13C NMR spectra were
recorded on Bruker AMX 400 [400 MHz (1H) and 100 MHz (13C)] spectrometer,
and 2D-NMR were recorded on Bruker AV (30-MHz) instrument using tetramethyl-
silane (TMS) as an internal reference. The chemical shifts are expressed in parts per
million (ppm). Mass spectra (MS) were recorded on AutoSpec EIþ Shimadzu QP
2010 Plus gas chromatography–mass spectrometry (GC-MS) instrument. Micro-
analyses were performed on a Vario EL III model CHNS analyzer (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.
6,7-Dimethyldibenzo[b,h][1,6]naphthyridines (4) from 4-Chloro-
2-methyl-quinolines (6)
General procedure. The appropriate 4-chloro-2-methylquinoline (6,
0.001 mol) was heated with o-aminoacetophenone (2, 0.13 mL, 0.001 mol) under neat
conditions at 160 ꢀC for half an hour. The crude product was washed with water,
adsorbed, and purified by column chromatography over silica gel, eluting with a pet-
roleum ether=Ethyl acetate (97:3) mixture to get 4, which was then recrystallized
from methanol.
Compound 4a. Colorless needles; mp 200–202 ꢀC; yield: 0.092 g (30%); IR
1
nmax (cmꢁ1): 1621 and 1590 (C N), 1532, 1450; H NMR (CDCl3) d: 2.71 (s, 3H,
=
C2-CH3), 3.04 (s, 3H, C7-CH3), 3.14 (s, 3H, C6-CH3), 7.59–8.12 (m, 5H, C3-, C4-,
C8-, C9-, C10-H), 8.16 (d, 1H, C11-H, J ¼ 8.22 Hz), 9.09 (s, 1H, C1-H); 13C NMR
(CDCl3) d: 20.14 (C2-CH3), 25.51 (C7-CH3), 28.92 (C6-CH3), 117.11 (C7a), 122.04
(C6a), 122.90 (C8), 126.18 (C1), 126.51 (C9), 126.79 (C7), 127.89 (C4), 128.86 (C3),

SUBSTITUTED DIBENZONAPHTHYRIDINES
441
129.56 (C10), 130.13 (C11), 132.66 (C2), 134.91 (C12b), 136.60 (C11a), 145.75 (C4a),
147.50 (C12a), 158.90 (C6); MS: m=z (%) 272 (100, Mþ), 271 (11), 257 (12), 242
(7), 230 (8), 136 (14), 128 (6), 115 (8), 89 (12). 77 (10). Anal. calcd. for C19H16N2:
C, 83.83; H, 5.88; N, 10.29. Found: C, 83.70; H, 6.11; N, 10.19%.
Compound 4b. Colorless needles; mp 203–205 ꢀC; yield: 0.086 g (30%); IR
1
nmax (cmꢁ1) 1627, 1596 (C N), 1533, 1455; H NMR (CDCl3) d: 2.83 (s, 3 H,
=
C4-CH3), 3.23 (s, 3H, C7-CH3), 3.31 (s, 3H, C6-CH3), 7.51–8.02 (m, 5H, C2-, C3-,
C8-, C9-, C10-H), 8.19 (d, 1H, C11-H, J ¼ 8.52 Hz), 9.10 (d, 1H, C1-H, J ¼ 7.59 Hz);
13C NMR (CDCl3) d: 22.66 (C4-CH3), 25.51 (C7-CH3), 28.92 (C6-CH3), 117.11
(C7a), 122.04 (C6a), 122.90 (C8), 126.16 (C1), 126.51 (C9), 126.79 (C7), 127.15 (C2),
128.14 (C3), 129.56 (C10), 130.13 (C11), 132.66 (C4), 134.91 (C12b), 136.60 (C11a),
147.09 (C4a), 147.50 (C12a), 158.90 (C6). MS: m=z (%) 272 (100, Mþ), 271 (12), 257
(8), 242 (6), 230 (5), 136 (10), 128 (7), 115 (12), 89 (14). 77 (10). Anal. calcd. for
C19H16N2: C, 83.83; H, 5.88; N, 10.29. Found: C, 83.92; H 6.01; N, 10.07%.
Compound 4c. White solid; mp 207–209 ꢀC; yield : 0.089 g (29%); IR nmax
(cmꢁ1) : 1632, 1601 (C N), 1537, 1452; 1H NMR (CDCl3) d: 3.12 (s, 3H,
=
C7-CH3), 3.18 (s, 3H, C6-CH3) 7.51–8.13 (m, 5H, C3-, C4-, C8-, C9-, C10-H), 8.15
(d, 1H, C11-H, J ¼ 8.50 Hz), 9.14 (s, 1H, C1-H); 13C NMR (CDCl3) d: 25.51
(C7-CH3), 28.92 (C6-CH3), 117.11 (C7a), 122.04 (C6a), 122.90 (C8), 126.01 (C1),
126.51 (C9), 126.79 (C7), 127.76 (C4), 128.80 (C3), 129.56 (C10), 130.13 (C11),
131.45 (C2), 134.91 (C12b), 136.60 (C11a), 145.09 (C4a), 147.50 (C12a), 158.90 (C6);
MS: m=z (%) 294=292 (30=95) (M þ 2=Mþ), 277 (8), 262 (12), 257 (7), 256 (15),
136 (12), 128 (10), 115 (6), 77(18). Anal. calcd. for C18H13N2Cl: C, 73.97; H, 4.45;
N, 9.58. Found: C, 74.35; H, 4.79; N, 9.20%.
Compound 4d. Colorless prisms; mp 198–200 ꢀC; yield : 0.082 g (30%); IR
1
nmax (cmꢁ1): 1625, 1596 (C N), 1524, 1451; H NMR (CDCl3) d: 3.10 (s, 3 H,
=
C7-CH3), 3.18 (s, 3H, C6-CH3) 7.49–8.07 (m, 6H, C2-, C3-, C4-, C8-, C9-, C10-H),
8.13 (d, 1H, C11-H, J ¼ 8.49 Hz), 9.07 (d, 1H, C1-H, J ¼ 7.99 Hz); 13C NMR (CDCl3)
d: 25.51 (C7-CH3), 28.92 (C6-CH3), 117.11 (C7a), 122.04 (C6a), 122.90 (C8), 126.16
(C1), 126.51 (C9), 126.79 (C7), 127.15 (C2), 127.66 (C4), 128.14 (C3), 129.56 (C10),
130.13 (C11), 134.91 (C12b), 136.60 (C11a), 147.09 (C4a), 147.50 (C12a), 158.90 (C6).;
MS: m=z (%) 258 (93, Mþ), 257 (14), 243 (8), 232 (6), 228 (10), 141 (8), 126 (6),
115 (12), 77 (15). Anal. calcd. for C18H14N2: C, 83.72; H, 5. 43; N, 10.85. Found:
C, 83.70; H, 5.81; N, 10.49%.
6-Methyl-7-phenyldibenzo[b,h][1,6]naphthyridines (5) from
4-Chloro-2-methylquinolines (6)
General procedure. The appropriate 4-chloro-2-methylquinoline (6,
0.001 mol) was heated with o-aminobenzophenone (3, 0.20 g, 0.001 mol) 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) mixture to get 5, which was then recrystallized from methanol.
Compound 5a. Colorless prisms; mp 250–252 ꢀC; yield: 0.083 g (23%); IR
nmax (cmꢁ1): 1625 and 1609 cmꢁ1 (C N); 1H NMR (CDCl3) d: 2.33 (s, 3H,
=

442
M. MANOJ AND K. J. RAJENDRA PRASAD
C6-CH3), 2.70 (s, 3H, C2-CH3), 7.41–7.92 (m, 10H, C3-, C4-, C8-, C9-, C10-, C02-, C30 -,
C04-, C50 -, C60 -H), 8.30 (d, 1H, C11ꢁH, J ¼ 8.51 Hz), 9.06 (s, 1H, C1-H); 13C NMR
(100 MHz, CDCl3) d (ppm): 19.7 (C2-CH3), 28.4 (C6-CH3), 117.6 (C8), 124.1 (C1),
125.0 (C9), 125.9 (C20 , C60 ), 126.5 (C30 , C40 , C50 ), 127.5 (C01), 128.5 (C7), 128.7 (C4),
128.9 (C7a), 129.0 (C10), 131.2 (C11), 131.3 (C3), 135.0 (C2), 138.3 (C12b), 143.1
(C6a), 146.9 (C11a), 147.7 (C12a), 148.1 (C4a), 157.2 (C6); MS: m=z (%) 334 (Mþ
100), 333 (25), 319 (10), 293 (15), 257 (32), 166 (23), 77 (32), 43 (48). Anal. calcd.
for C24H18N2: C, 86.23; H, 5.39; N, 8.38. Found: C, 85.97; H, 5.59; N, 8.44%.
Compound 5b. Colorless needles; mp 245–247 ꢀC; yield: 0.092 g (25%); IR
1
nmax (cmꢁ1): 1635 and 1605 (C N); H NMR (CDCl3) d: 2.35 (s, 3H, C6-CH3)
=
2.85 (s, 3H, C4-CH3), 7.39–7.84 (m, 10H, C2-, C3-, C8-, C9-, C10-, C02-, C30 -, C40 -,
C05-, C06-H), 8.33 (d, 1H, C11-H, J ¼ 8.53 Hz), 9.10 (d, 1H, C1-H, J ¼ 7.92 Hz); 13C
NMR (CDCl3) d: 20.2 (C4-CH3), 28.6 (C6-CH3), 117.6 (C8), 124.4 (C1), 125.0 (C9),
125.9 (C02, C06), 126.5 (C30 , C40 , C50 ), 127.5 (C10 ), 128.5 (C7), 128.7 (C2), 128.9 (C7a),
129.0 (C10), 131.2 (C11), 131.7 (C3), 136.2 (C4), 138.3 (C12b), 143.1 (C6a), 146.9
(C11a), 147.7 (C12a), 148.8 (C4a), 157.2 (C6); MS: m=z (%) 334 (Mþ 100), 333 (35),
319 (15), 293 (10), 257 (10), 166 (42), 77 (55), 43 (55). Anal. calcd. for C24H18N2:
C, 86.23; H, 5.39; N, 8.38. Found: C, 86.01; H, 5.50; N, 8.49%.
Compound 5c. White solid; mp 255–257 ꢀC; Yield: 0.081 g (22%); IR nmax
(cmꢁ1): 1633 and 1610 (C N); 1H NMR (CDCl3) d: 2.36 (s, 3H, C6-CH3),
=
7.37–7.96 (m, 10H, C3-, C4-, C8-, C9-, C10-, C02-, C30 -, C40 -, C05-, C60 -H), 8.34 (d, 1H,
C11-H, J ¼ 8.41 Hz), 9.19 (s, 1H, C1-H); 13C NMR (CDCl3) d: 28.8 (C6-CH3),
117.6 (C8), 123.8 (C1), 125.0 (C9), 125.9 (C02, C60 ), 126.5 (C30 , C04, C50 ), 127.5 (C10 ),
128.5 (C7), 128.5 (C4), 128.9 (C7a), 129.0 (C10), 131.2 (C11), 131.2 (C3), 134.5 (C2),
138.3 (C12b), 143.1 (C6a), 146.9 (C11a), 147.7 (C12a), 148.1 (C4a), 157.2 (C6); MS:
m=z (%) 356=354 (Mþ, 31=100), 341 (55) 339 (19), 319 (350), 292 (25), 177 (18),
165 (23), 77 (12), 43 (22). Anal. calcd. for C23H15ClN2: C, 77. 97; H, 4.24; N,
7.91. Found: C, 77.89; H, 4.33; N, 7.87%.
Compound 5d. Colorless prisms; mp 242–244 ꢀC; yield: 0.088 g (25%); IR
1
nmax (cmꢁ1): 1623 and 1607 (C N); H NMR (CDCl3) d 2.34 (s, 3H, C6-CH3),
=
7.40–7.99 (m, 11H, C2-, C3-, C4-, C8-, C9-, C10-, C02-, C30 -, C40 -, C05-, C60 -H), 8.41 (d,
1H, C11-H, J ¼ 8.96 Hz), 9.14 (d, 1H, C1-H, J ¼ 8.10 Hz); 13C NMR (CDCl3) d:
28.6 (C6-CH3), 117.6 (C8), 124.1 (C1), 125.0 (C9), 125.9 (C02, C60 ), 126.5 (C30 , C40 ,
C05), 127.5 (C10 ), 128.5 (C7), 128.5 (C2), 128.9 (C7a), 129.0 (C10), 131.2 (C11), 131.3
(C3), 133.0 (C4), 138.3 (C12b), 143.1 (C6a), 146.9 (C11a), 147.7 (C12a), 148.0 (C4a),
157.2 (C6); MS: m=z (%) 320 (Mþ, 100), 319 (75), 315 (20), 168 (23), 121 (43), 68
(54), 44 (42). Anal. calcd. for C23H16N2: C, 86.25; H, 5.00; N, 8.75. Found: C,
86.49; H, 5.20; N, 8.31%.
6-Methyldibenzo[b,h][1,6]naphthyridines (4 and 5) from 2-Methyl-4-
(N-phenylamino)quinolines (10)
Preparation of 2-methyl-4-(N-phenylamino)quinolines (10) from
4-chloro-2-methyl quinolines (6): General procedure. 4-Chloro-2-methylqui-
noline (6, 0.002 mol) was heated with aniline (9, 0.002 g, 0.002 mol) under neat

SUBSTITUTED DIBENZONAPHTHYRIDINES
443
condition at 160 ꢀC for half an hour. The product was washed with water, adsorbed
and purified by chromatography on silica gel, and eluted with an ethyl acetate=
Methanol (95:5) mixture to get the anilinoquinoline 10, which was then recrystallized
from methanol.
Compound 10a. Colorless needles; mp > 300 ꢀC; yield: 0.399 g (70%); IR nmax
1
(cmꢁ1): 3367 (NH); H NMR (DMSO-d6) d: 2.54 (s, 3H, C2-CH3), 2.59 (s, 3H, C6-
CH3), 6.75 (s, 1H, C3-H), 7.48–7.94 (m, 7H, C7-, C8-, C02-, C03-, C40 , C05-, C60 -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 to imino form is 1:1. 13C NMR (DMSO-d6) d:
18.9 (C2-CH3), 24.8 (C6-CH3), 100.5 (C3), 117.4 (C4a), 118.9 (C02, C60 ), 123.5 (C30 ,
C05), 125.2 (C5), 125.6 (C04), 132.6 (C7), 135.1 (C8), 136.9 (C6), 137.8 (C01), 137.8
(C8a), 151.9 (C4), 153.7 (C2); MS: m=z (%) 248 (Mþ 100), 247 (40), 232 (20), 218
(15), 191 (35), 130 (19), 123 (15), 77 (42). Anal. calcd. for C17H16N2: C, 82.25; H,
6.46; N, 11.29. Found: C, 82.05; H, 6.60; N, 11.35%.
Compound 10b. White solid; mp > 300 ꢀC; yield: 0.423 g (75%); IR (KBr)
1
nmax (cmꢁ1): 3378 (NH); H NMR (DMSO-d6) d: 2.76 (s, 3H, C8-CH3), 2.95 (s,
3H, C2-CH3), 6.71 (s, 1H, C3-H), 7.31–7.65 (m, 7H, C6-, C7-, C02-, C30 -, C40 -, C50 -,
C06-H), 8.80 (d, 1H, C5-H, J ¼ 7.12 Hz), 10.50 (b s, 1H, C4-NH amino form), 12.41
(b s, 1H, N1-H imino form). The ratio of amino form to imino form is 1:1). 13C
NMR (DMSO-d6) d; 19.2 (C2-CH3), 25.1 (C8-CH3), 100.8 (C3), 117.4 (C4a), 118.9
(C20 , C60 ), 123.5 (C30 , C05), 124.8 (C5), 125.6 (C40 ), 131.5 (C6), 136.1 (C7), 137.4 (C8),
137.8 (C01), 138.2 (C8a), 151.9 (C4), 153.7 (C2); MS: m=z (%) 248 (Mþ 100), 247
(25), 232 (15), 218 (20), 191 (31), 130 (18), 77 (42), 44(35). Anal. calcd. for
C17H16N2: C, 82.25; H, 6.46; N, 11.29. Found: C, 82.15; H, 6.30; N, 11.55%.
Compound 10c. White solid; mp> 300 ꢀC; yield: 0.416 g (65%); IR nmax (cmꢁ1):
1
3368 (NH); H NMR (DMSO-d6) d: 2.61 (s, 3H, C2-CH3), 6.81 (s, 1H, C3-H),
7.48–8.13 (m, 7H, C7 , C8 , C20 -, C30 -, C40 -, C50 , C60 -H), 8.89 (s, 1H, C5-H), 10.74 (b
-
-
s, 1H, C4-NH amino form), 14.71 (b s 1H, N1-H imino form). The ratio of amino
form to imino form is 1:1). 13C NMR (DMSO-d6) d: 19.4 (C2-CH3), 100.4 (C3),
117.2 (C4a), 118.9 (C20 , C60 ), 123.5 (C30 , C05), 125.0 (C5), 125.6 (C40 ), 132.5 (C7),
134.8 (C8), 136.2 (C6), 137.8 (C10 ), 137.8 (C8a), 151.9 (C4), 153.7 (C2); MS: m=z
(%) 268 (Mþ 100), 267 (50), 253 (15) 232 (18), 122 (28), 77 (52), 65 (36), 44
(60). Anal. calcd. for C16H13ClN2: C, 71.64; H, 4.85; N, 10.44. Found: C, 71.25;
H, 4.68; N, 10.65%.
Compound 10d. White solid; mp > 300 ꢀC; yield: 0.386 g (72%); IR nmax (cmꢁ1):
1
3365 (NH); H NMR (DMSO-d6) d: 2.60 (3H, s, C2-CH3), 6.69 (s, 1H, C3-H),
7.46–8.08 (m, 8H, C6-, C7-, C8-, C02-, C03-, C40 -, C50 -, C60 -H), 8.51 (d, 1H, C5-H,
J ¼ 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 to imino form is 1:1). 13C NMR (DMSO-d6) d:
19.0 (C2-CH3), 100.6 (C3), 117.3 (C4a), 118.9 (C02, C60 ), 123.5 (C03, C50 ), 124.7
(C5), 125.6 (C04), 131.4 (C6), 136.1 (C8), 136.4 (C7), 137.8 (C01), 138.2 (C8a), 151.9
(C4), 153.7 (C2); MS: m=z (%) 234 (Mþ 100), 233 (20), 191 (25), 124 (10), 90(8),
77 (52) 76 (30), 44 (25). Anal. calcd. for C16H14N2: C, 82.06; H, 5.98; N, 11.96.
Found: C, 82.52; H, 6.05; N, 11.43%.

444
M. MANOJ AND K. J. RAJENDRA PRASAD
Cyclization of 2-methyl-4-(N-phenylamino)quinoline (10) with acetic
acid. A mixture of 2-methyl-4-(N-phenylamino)quinoline (10, 0.001 mol) and acetic
acid (0.122 mg, 0.0011 mmol) was added to polyphosphoric acid (P2O5, 1 g, and
H3PO4, 0.5 mL) and heated at 160 ꢀC for 5 h. The reaction mixture was poured into
ice water and extracted with ethyl acetate. The crude product obtained was purified
by column chromatography over silica gel using a petroleum ether=ethyl acetate
(97:3) mixture to get a pale yellow solid. The product 6,7-dimethyldibenzo[b,h][1,6]-
naphthyridine (4) was recrystallized using methanol as prisms. From the TLC and
superimposible IR spectra, the compound was identified as the same one obtained
from the earlier one-pot synthesis of 4-chloro-2-methylquinoline (6) with o-amino-
acetophenone under neat conditions. Further, the mixed melting points of this
compound and the compound obtained earlier from the one-pot synthesis were
undepressed. The yields of the products obtained by the two methods are compared
in Table 1.
Cyclization of 2-methyl-4-(N-phenylamino)quinoline (10) with benzoic
acid. A mixture of 2-methyl-4-(N-phenylamino)quinoline (10, 0.001 mmol) and
benzoic acid (0.122 mg, 0.0011 mmol) was added to polyphosphoric acid (P2O5,
1 g, and H3PO4, 0.5 mL) and heated at 160 ꢀC for 5 h. The reaction mixture was
poured into ice water, neutralized with saturated sodium bicarbonate solution,
and extracted with ethyl acetate. The crude product obtained was purified by column
chromatography over silica gel using a petroleum ether=ethyl acetate (98:2) mixture
to get a pale yellow solid. The product 6-methyl-7-phenyldibenzo[b,h][1,6]naphthyr-
idines (5) was recrystallized using methanol as prisms. From the TLC and superim-
posible IR spectra, the compound was identified as the same one obtained from the
earlier one-pot synthesis of 4-chloro-2-methylquinoline (6) with o-aminobenzophe-
none under neat conditions. Further, the mixed melting points of this compound
and the compound obtained earlier from the one-pot synthesis were undepressed.
The yield of the products obtained by the two methods are compared in Table 1.
X-Ray Crystallographic Data
Crystallographic data of the structure 5c (obtained from method 2) in this arti-
cle have been deposited with the Cambridge Crystallographic Data Centre as sup-
plementary publication CCDC No. 750053. Copies of the data can be obtained,
free of charge, on application to CCDC, 12 Union Road, Cambridge CB2 1EZ,
UK, or via e-mail to deposit@ccdc.cam.ac.uk.
ACKNOWLEDGMENTS
The authors thank IISc, Bangalore, and MKU, Madurai for NMR spectra; the
Indian Institute for Chemical Technology, Hyderabad, for mass spectral data; and
IIT, Madras, Chennai, for single-crystal XRD data.
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