Synthesis of alkyl and aryl substituted benzo[ h[naphtho[1,2-b][1,6] naphthyridines

Article abstract of DOI:10.1080/00397911.2011.555649

The reaction of 4-chloro-2-methylquinolines and 1-naphthylamine under neat conditions yielded 2-methyl-N-(1-naphthyl)quinolin-4-amines. These potential intermediates on reaction with aliphatic and aromatic carboxylic acids yielded the respective 7-alkyl a

Full text of DOI:10.1080/00397911.2011.555649

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Synthesis of Alkyl and Aryl
Substituted Benzo[h]Naphtho[1,2-b]
[1,6]naphthyridines
K. Prabha a & K. J. Rajendra Prasad a
a Department of Chemistry , Bharathiar University , Coimbatore ,
Tamil Nadu , India
Accepted author version posted online: 17 Nov 2011.Published
online: 09 Apr 2012.
To cite this article: K. Prabha & K. J. Rajendra Prasad (2012) Synthesis of Alkyl and Aryl Substituted
Benzo[h]Naphtho[1,2-b][1,6]naphthyridines, Synthetic Communications: An International
Journal for Rapid Communication of Synthetic Organic Chemistry, 42:15, 2277-2289, DOI:
10.1080/00397911.2011.555649
To link to this article: http://dx.doi.org/10.1080/00397911.2011.555649
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Synthetic Communications1, 42: 2277–2289, 2012
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2011.555649
SYNTHESIS OF ALKYL AND ARYL SUBSTITUTED
BENZO[h]NAPHTHO[1,2-b][1,6]NAPHTHYRIDINES
K. Prabha and K. J. Rajendra Prasad
Department of Chemistry, Bharathiar University, Coimbatore,
Tamil Nadu, India
GRAPHICAL ABSTRACT
Abstract The reaction of 4-chloro-2-methylquinolines and 1-naphthylamine under neat
conditions yielded 2-methyl-N-(1-naphthyl)quinolin-4-amines. These potential intermedi-
ates on reaction with aliphatic and aromatic carboxylic acids yielded the respective 7-alkyl
and -aryl substituted benzo[h]naphtho[1,2-b][1,6]naphthyridines. The highly deshielded
protons in the final compounds were assigned on the basis of 2D NMR studies.
Keywords 4-Chloro-2-methylquinolines; 2-methyl-N-(1-naphthyl)quinolin-4-amines;
6-methyl-7-substituted-benzo[h]naphtho[1,2-b][1,6]naphthyridines; 1-naphthylamine
INTRODUCTION
Among various heterocyclic compounds, quinoline-based drugs such as
chloroquine and primaquine are well known for their antimalarial properties against
Plasmodium falciparum.[1] Moreover, the quinoline nucleus has found broad
application in drug development for the treatment of MCH (melanin-concentrating
hormone)–receptor–related disorders;[2] cell proliferative diseases;[3] transmissible
spongiform encephalopathies;[4] malignant tumors such as stomach cancer, brain
tumors, and large intestine cancer,[5] and bacterial infections in mammals.[6] Some
of the anilinoquinolines are also considered as synthetic antimalarials.[7,8] Literature
studies point out that the reaction of chloroquinolines was aimed to get substituted
quinolines possessing biological activity,[9,10] including the amination reaction to
derive the respective anilinoquinolines.
Received December 9, 2010.
Address correspondence to K. J. Rajendra Prasad, Department of Chemistry, Bharathiar
University, Coimbatore, Tamil Nadu, India. E-mail: prasad_125@yahoo.com
2277

2278
K. PRABHA AND K. J. RAJENDRA PRASAD
Naphthyridines have received considerable attention over the past years
because of their wide range of biological activities including anti-inflammatory,[11,12]
antifungal,[11,12] anti-arrhythmic,[13] anti-alalgesic,[14] anti-HIV,[15] and anticancer[16]
activities. Particularly some of the dibenzonaphthyridines (i.e., quinoline dimers),
act as potent and selective 3-phosphoinostide-dependent kinase-I inhibitors.[17] The
naphthonaphthyridine ring system is a rare heterocycle compared with simple[18,19]
as well as benzonaphthyridines,[20] and it is envisioned that naphtho[2,1-c][2,7]
naphthyridines, which contained both naphthalene rings and naphthyridine moieties,
may afford unique biological activities, like the spiro[naphto[2,1-c][2,7]
naphthyridine-5,40-piperidine] derivatives that inhibit lipid peroxidation.[21]
Naphthonaphthyridines were synthesized from 2-aminobenzo[f]-quinoline and
glycerol in the presence of H2SO4,[22] by the Skraup reaction of 3-aminobenzo[h]qui-
noline with ketone,[23] from a multicomponent reaction[24,25] of aromatic aldehydes,
2-naphtylamines, and piperidone derivatives, and by several other methods.[26,27]
Recently, dibenzonaphthyridines have been synthesized by a reaction in which
anilinoquinolines were exploited as potential intermediates.[28–30] In continuation,
herein we report a mild and efficient synthesis of alkyl and aryl substituted benzo-
naphthonaphthyridines utilizing 4-chloro-2-methylquinolines and involving
naphthylaminoquinolines as potential intermediates.
The present investigation was aimed to study the reaction of 4-chloro-2-
methylquinolines 1 and 1-naphthylamine 2 to get the 2-methyl-N-(1-naphthyl)quino-
lin-4-amine 3, which in turn can be utilized as potential intermediates to derive the
alkyl and aryl substituted benzonaphthonaphthyridines 4 and 5.
In view of these considerations, 4-chloro-2,8-dimethylquinoline (1b) was
reacted with 1-naphthylamine 2 under neat conditions at 190 ꢀC for half an hour to
obtain a single product. In its infrared (IR) spectrum, NH stretching vibration was
1
observed at 3437 cmꢁ1. Its H NMR spectrum showed the presence of two methyl
groups at d 2.50 and d 2.77 for C2-CH3 and C8-CH3 respectively. The peculiar
C3-H appeared as a singlet at d 6.12. All the 10 aromatic protons appeared at d
7.54–8.86 while two broad singlets (each for one proton) integrated at d 11.21 and
d 12.65 and were assigned C4-NH amino form and N1-H imino form. The ratio of
amino to imino form was found to be 1:1. 13C NMR spectra confirmed the presence
of 21 carbons. From the elemental analysis, the molecular formula was found to be
C21H18N2 and its mass spectrum showed the molecular ion peak at m=z 298. From
these details, the structure of the compound was confirmed as 2,8-dimethyl-N-
(1-naphthyl)quinolin-4-amine (3b). The reaction sequence was extended to other
quinoline derivatives (1a,c,d) to afford the corresponding 2-methyl-N-(1-naphthyl)
quinolin-4-amines (3a,c,d) (Scheme 1). The compounds 3a, 3b, and 3d were identical
with the compounds reported earlier,[31] but our procedure described here is
ecofriendly because it involves solvent-free conditions.
Having obtained the potential intermediates 3, the synthesis of alkyl and aryl
substituted benzonaphthonaphthyridines was intended, employing alkyl and aryl
carboxylic acids under acidic condition.
Hence 2,8-dimethyl-N-(1-naphthyl)quinolin-4-amine (3b) was reacted with ben-
zoic acid in the presence of polyphosphoric acid as catalyst (Scheme 2). The reaction
yielded a single product. Its IR spectrum did not show the presence of a NH group.
1
Its H NMR spectrum exhibited two singlets each at d 2.35 and d 2.86 for C4-CH3

BENZONAPHTHONAPHTHYRIDINES
2279
Scheme 1. Preparation of 2-methyl-N-(1-naphthyl)quinolin-4-amine 3.
and C6-CH3 respectively. All the aromatic protons resonated at d 7.27–7.81 except for
two proton doublets, which were very much deshielded at d 9.37 (J ¼ 7.50Hz) and d
9.68 (J ¼ 8.00Hz). With the help of advanced NMR studies such as correlation
spectroscopy [H,H-COSY, C,H-COSY heteronuclear single-quantum correlation
(HSQC)], and heteronuclear multiple-bond correlation (HMBC) correlations, the
deshielded proton at d 9.37 was assigned to C1-H while the proton at d 9.68 was
assigned C13-H. A one-proton doublet at d 9.37 (J ¼ 7.50Hz) and a six-proton multi-
plet at 7.51–7.61 have H,H-COSY connections. The proton at d 9.37 was characteristics
of C1-H while the multiplet was assigned to C2, C8, C9, C03, C40 , and C50 -H. A one-proton
doublet at d 9.68 (J ¼ 8.00Hz) and a one proton triplet at d 7.77 (J ¼ 7.50Hz) have
H,H-COSY connections, which are characteristic of C13-H and C12-H respectively.
The assignment of coupling protons for all the other aromatic protons using
H,H-COSY is mentioned in Table 1. From the C,H-COSY (HSQC) spectrum, the
values of C1 and C13 carbons were assigned as d 122.3 and d 125.9 respectively. The
values of all other carbons holding protons are denoted in Table 2. The peculiar
C1-H has HMBC connectivity with C2-H while the C13-H have connectivities with
Scheme 2. Preparation of 6-methyl-7-substituted-benzo[h]naphtho[1,2-b][1,6]naphthyridines 4, 5, and 6.

2280
K. PRABHA AND K. J. RAJENDRA PRASAD
Table 1. 1H NMR and their coupling protons of the compound 4b assigned by H,H-COSY
Entry
1H NMR (d)
Coupling protons (d)
1
2
3
4
5
2.35 (s, 3H, C4-CH3)
2.86 (s, 3H, C6-CH3)
—
—
7.27 (d, 1H, C3-H, J ¼ 9.50 Hz)
7.35 (d, 2H, C02 & C06-H, J ¼ 7.20 Hz)
7.51–7.61m, 6H which
includes C2, C03 & C50 -H)
7.51–7.61 (m, 6H which includes C2-H)
7.51–7.61 (m, 6H which includes C03 & C50 -H)
7.27 (d, 1H, C3-H, J ¼ 9.50 Hz)
7.35 (d, 2H, C02 & C06-H, J ¼ 7.20 Hz)
7.77 (t, 1H, C12-H, J ¼ 7.50 Hz)
7.81 (d, 1H, C10-H, J ¼ 7.50 Hz)
7.70 (t, 1H, C11-H, J ¼ 7.50 Hz)
9.68 (d, 1H, C13-H, J ¼ 8.00 Hz)
7.70 (t, 1H, C11-H, J ¼ 7.50 Hz)
7.51–7.61 (m, 6H which includes C2-H)
7.77 (t, 1H, C12-H, J ¼ 7.50 Hz)
6
7
7.70 (t, 1H, C11-H, J ¼ 7.50 Hz)
7.77 (t, 1H, C12-H, J ¼ 7.50 Hz)
8
9
7.81 (d, 1H, C10-H, J ¼ 7.50 Hz)
9.37 (d, 1H, C1-H, J ¼ 7.50 Hz)
9.68 (d, 1H, C13-H, J ¼ 8.00 Hz)
10
C11, C13a, and C13b carbons. The connectivity of all other protons with the carbons is
denoted in Table 3. The HMBC connectivity is diagrammatically shown in Fig. 1.
Its 13C NMR spectrum showed the appearance of 28 carbon signals, and the
mass spectrum identified the molecular ion peak at m=z 384. The molecular formula
was deduced as C28H20N2 from its elemental analysis data. All these spectral and
analytical details attest to the structure of the compound as 4,6-dimethyl-7-phenyl-
benzo[h]naphtho[1,2-b][1,6]naphthyridine (4b). The generality of the reaction was
tested against other 2-methyl-N-(1-naphthyl)quinolin-4-amines (3a,c,d) in order to
get the corresponding benzonaphthonaphthyridines (4a,c,d). A similar set of reac-
tions was also extended to other carboxylic acids (i.e., acetic acid and 1-naphthoic
acid) in which the 2-methyl-N-(1-naphthyl)quinolin-4-amines 3 was reacted with
acetic acid and 1-naphthoic acid in the presence of polyphosphoric acid (PPA) at
160 ꢀC to get 6,7-dimethylbenzo[h]naphtho[1,2-b] [1,6]naphthyridines 5 and 6-methyl-
7-(naphthalen-1-yl)benzo[h]naphtho[1,2-b][1,6]naphthyridines6respectively(Scheme2).
In the present case, also the C1-H and C13-H were deshielded around ꢂ9.25 and ꢂ9.79
respectively. The numbering of the core skeleton of the benzo[h]naphtho[1,2-b][1,6]
naphthyridine moiety is represented in Fig. 2.
Table 2. 1H NMR and their carbon of the compound 4b assigned by C,H-COSY (HSQC)
Entry
1H NMR (d)
13C NMR (d)
1
2
3
4
5
2.35 (s, 3H, C4-CH3)
2.86 (s, 3H, C6-CH3)
29.5 (C4)
17.8 (C6)
127.7 (C3)
7.27 (d, 1H, C3-H, J ¼ 9.50 Hz)
7.35 (d, 2H, C02 &C06-H, J ¼ 7.20 Hz)
7.51–7.61 (m, 6H, C2, C8, C9, C03, C40 , C50 -H)
130.0 (C02 & C06)
131.8 (C2), 125.1 (C8), 124.2 (C9),
128.5 (C03, C50 ), 128.4 (C04)
6
7
7.70 (t, 1H, C11-H, J ¼ 7.50 Hz)
7.77 (t, 1H, C12-H, J ¼ 7.50 Hz)
7.81 (d, 1H, C10-H, J ¼ 7.50 Hz)
9.37 (d, 1H, C1-H, J ¼ 7.50 Hz)
9.68 (d, 1H, C13-H, J ¼ 8.00 Hz)
129.5 (C11
127.3 (C12
127.6 (C10
122.3 (C1)
125.9 (C13
)
)
)
8
9
10
)

BENZONAPHTHONAPHTHYRIDINES
2281
Table 3. HMBC connectivity of the protons with the carbons of the compound 4b
Entry
1H NMR
HMBC 2J, 3J
1
2
2.35 (s, 3H, C4-CH3)
2.86 (s, 3H, C6-CH3)
C3, C4, C4a
C6, C6a
C4a
3
7.27 (d, 1H, C3-H, J ¼ 9.50 Hz)
7.35 (d, 2H, C02 & C06-H, J ¼ 7.20 Hz)
7.51–7.61 (m, 6H, C2, C8, C9, C03, C40 , C50 -H)
7.70 (t, 1H, C11-H, J ¼ 7.50 Hz)
7.77 (t, 1H, C12-H, J ¼ 7.50 Hz)
7.81 (d, 1H, C10-H, J ¼ 7.50 Hz)
9.37 (d, 1H, C1-H, J ¼ 7.50 Hz)
9.68 (d, 1H, C13-H, J ¼ 8.00 Hz)
4
C03, C04, C05
5
C1, C3, C4, C7, C7a, C9a, C10, C01, C30 , C40 , C50
6
C9a, C10, C12, C13
C10, C13a
C9a, C13a
7
8
9
10
C2
C11, C13a, C13b
The reason for the two protons being deshielded might be the interaction of
these protons with the nitrogen atom at the 14th position.
The plausible mechanism for the conversion of 1 to 4,5,6 might be as shown in
Scheme 3.
Amination of 4-chloro-2-methylquinolines 1 with 1-naphthylamine 2 under
neat conditions at 190 ꢀC afforded the 2-methyl-N-(1-naphthyl)quinoline-4-amines
Figure 1. Bold lines represent H,H-COSY and arrows represent HMBC connectivity of compound 4b.
Figure 2. Numbering of the benzo[h]naphtho[1,2-b][1,6]naphthyridine core.

2282
K. PRABHA AND K. J. RAJENDRA PRASAD
Scheme 3. Mechanism for the formation of the final benzonaphthonaphthyridines.
3. The 2-methyl-N-(1-naphthyl)quinolin-4-amines 3 on acylation with alkyl or aryl
carboxylic acids at the 3rd position of the quinoline moiety yielded the intermediate
I. The intermediate I on internal electrophilic cyclization at the C3-carbonyl carbon
through the b-position of the naphthylamino moiety gave the intermediate II, which
on aromatization and prototropic shift followed by the elimination of H2O molecule
through the intermediate III ended up in the formation of final products 4–6.
From the experimental work it is concluded that the reaction of 4-chloro-2-
methylquinolines 1 and 1-naphthylamine 2 yielded 2-methyl-N-(1-naphthyl)quino-
lin-4-amines 3, which were utilized as potential intermediates to prepare 7-substi-
tuted benzonaphthonaphthyridines 4–6 where the substituents hold alkyl and aryl
moieties.
EXPERIMENTAL
Melting points (mp) were determined on a Mettler FP 51 apparatus (Mettler
Instruments, Switzerland) and are uncorrected. They are expressed in degrees centi-
grade (ꢀC). IR spectra were recorded on Schimadzu FTIR-8201PC spectrophot-
1
ometer (Schimadzu, Japan) using KBr disc. H NMR and 13C NMR spectra were
recorded on Bruker AV 400 [400-MHz(1H) and 100-MHz(13C)] spectrometers, and
2D-NMR were recorded on Bruker AV 500 [500-MHz (1H) and 125-MHz (13C)]

BENZONAPHTHONAPHTHYRIDINES
2283
spectrometers using tetramethylsilane (TMS) as an internal reference. The chemical
shifts are expressed in parts per million (ppm). Mass spectra (MS) were recorded
on an AutoSpec EIþShimadzu QP 2010 Plus GC-MS mass spectrometer. Micro
analyses 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 thin-layer chromatography (TLC) with plates coated with silica gel G
using petroleum ether and ethyl acetate as developing solvents.
2-Methyl-N-(1-naphthyl)quinolin-4-amine (3)
General procedure. 4-Chloro-2-methylquinoline (1, 0.004 mol) was heated
with 1-naphthylamine (2, 0.004 mol) under neat conditions at 190 ꢀC for half an
hour. The product was washed with water, dried, adsorbed, and purified using silica-
gel column chromatography and eluted with ethylacetate–methanol (99:1) mixture to
get 3, which was then recrystallized using methanol.
Compound 3a. Brown solid; mp 295–297 ꢀC; yield: 0.870 g (73%). IR nmax
(cmꢁ1) : 3431 (NH), 1603, 1520, 1148; 1H NMR (DMSO-d6) d: 2.47 (s, 3H,
C2-CH3), 2.59 (s, 3H, C6-CH3), 6.15 (s, 1H, C3-H), 7.55–8.03 (m, 8H, C7-, C8-,
C02-, C03-, C04-, C50 -, C60 -, and C70 -H), 8.10 (dd, 1H, C08-H Jo ¼ 7.75 Hz and Jm ¼
3.50 Hz), 8.76 (s, 1H, C5-H), 10.94 (b s, 1H, C4-NH amino form), 14.47 (b s, 1H,
N1-H imino form). The ratio of amino and imino form was found to be 1:1. 13C
NMR (DMSO-d6) d: 20.1 (C6-CH3), 21.6 (C2-CH3), 100.5 (C3), 116.4 (C02), 120.3
(C5), 123.0 (C04), 123.1 (C4a), 125.8 (C80 ), 126.8 (C80 a), 127.4 (C70 ), 127.6 (C60 ), 129.0
(C03), 129.1 (C50 ), 129.8 (C8), 133.8 (C7), 134.6 (C6), 135.6 ðC04aÞ, 136.9 (C01), 137.6
(C8a), 154.2 (C4), 155.8 (C2); MS: m=z (%) 298 (Mþ, 85), 297 (100), 283 (20), 268
(15), 124 (10), 105 (18), 89 (15), 51 (30). Anal. calcd. for C21H18N2: C, 84.53; H,
6.08; N, 9.39. Found : C, 84.42; H, 6.13; N, 9.45%.
Compound 3b. Brown solid; mp 297–299 ꢀC; yield: 0.894 g (75%). IR nmax
1
(cmꢁ1): 3437 (NH), 1598, 1525, 1144; H NMR (DMSO-d6) d: 2.50 (s, 3H, C2-
CH3), 2.77 (s, 3H, C8-CH3), 6.12 (s, 1H, C3-H), 7.54–7.87 (m, 8H, C6-, C7-, C02-,
C03-, C40 -, C50 -, C06-, and C70 -H), 8.11 (d, 1H, C80 -H J ¼ 8.50 Hz), 8.86 (d, 1H, C5-H
J ¼ 8.50 Hz), 11. 21 (b s, 1H, C4-NH amino form), 12.65 (b s, 1H, N1-H imino form).
The ratio of amino and imino form was found to be 1:1; 13C NMR (DMSO-d6) d:
19.4 (C8-CH3), 21.5 (C2-CH3), 100.8 (C3), 116.4 (C0 ), 121.0 (C5), 123.0 (C0 ) 122.9
(C4a), 125.8 (C08), 126.8 (C0 ), 127.4 (C70 ), 127.6 (C0 2), 129.0 (C30 ), 129.1 (C054), 129.0
(C6), 133.5 (C7), 135.6 ðC40 8aaÞ, 136.3 (C8), 136.9 (C016), 140.2 (C8a), 154.8 (C4), 155.9
(C2). MS: m=z (%) 298 (Mþ, 80), 297 (100), 283 (15), 268 (12), 123 (15), 105 (20),
65 (18), 51 (35). Anal. calcd. for C21H18N2: C, 84.53; H, 6.08; N, 9.39. Found: C,
84.65; H, 5.99; N, 9.36%.
Compound 3c. Brown solid; mp 294–296 ꢀC; yield: 0.858 g (72%); IR nmax
1
(cmꢁ1) : 3430 (NH), 1596, 1540, 1131. H NMR (DMSO-d6) d: 2.47 (s, 3H, C2-
CH3), 6.17 (s, 1H, C3-H), 7.56–8.06 (m, 8H, C7-, C8-, C02-, C30 -, C04-, C50 -, C60 -, and
C07-H), 8.10 (dd, 1H, C08-H Jo ¼ 8.02 Hz and Jm ¼ 2.50 Hz), 9.05 (s, 1H, C5-H), 10.
94 (b s, 1H, C4-NH amino form), 14.63 (b s, 1H, N1- H imino form). The ratio
of amino and imino form was found to be 1:1. 13C NMR (DMSO-d6) d: 21.9

2284
K. PRABHA AND K. J. RAJENDRA PRASAD
(C2-CH3), 101.0 (C3), 116.4 (C20 ), 120.0 (C5), 123.0 (C04), 123.2 (C4a), 125.8 (C08), 126.8
(C08a), 127.4 (C07), 127.6 (C06), 129.0 (C30 ), 129.1 (C05), 130.1 (C8), 133.2 (C7), 133.8 (C6),
135.6 ðC04aÞ, 136.9 (C10 ), 137.8 (C8a), 154.0 (C4), 155.8 (C2). MS: m=z (%) 320 (M þ 2,
26), 318 (Mþ, 80), 317 (100), 302 (20), 287 (25), 247 (15), 123 (10), 88 (40), 51 (65).
Anal. calcd. for C20H15ClN2: C, 75.35; H, 4.74; N, 8.79. Found : C, 75.38; H, 4.82;
N, 8.71%.
Compound 3d. Brown solid; mp 296–298 ꢀC; yield : 0.840 g (74%); IR nmax
1
(cmꢁ1) : 3423 (NH), 1587, 1520, 1115; H NMR (DMSO-d6) d: 2. 48 (s, 3H, C2-
CH3), 6.10 (s, 1H, C3-H), 7.56–8.12 (m, 9H, C6-, C7-, C8-, C02-, C03-, C40 -, C05-, C60 -,
and C07-H), 8.14 (d, 1H, C80 -H, J ¼ 8.00 Hz), 8.96 (s, 1H, C5-H J ¼ 7.50 Hz), 11.10
(b s, 1H, C4-NH amino form), 14.60 (b s, 1H, N1-H imino form). The ratio of amino
and imino form was found to be 1:1. 13C NMR (DMSO-d6) d 21.5 (C2-CH3) 101.1
(C3), 116.4 (C02), 121.3 (C5), 123.0 (C40 ), 122.6 (C4a), 125.8 (C08), 126.8 (C80 a), 127.4
(C07), 127.6 (C60 ), 129.0 (C03), 129.1 (C50 ), 129.1 (C6), 130.5 (C8), 133.3 (C7), 135.6
ðC04aÞ, 136.9 (C01), 139.7 (C8a), 154.6 (C4), 155.6 (C2). MS: m=z (%) 284 (Mþ, 95),
283 (100), 269 (25), 268 (15), 253 (10), 124 (20), 89 (22), 44 (35). Anal. calcd. for
C20H16N2: C, 84.48; H, 5.67; N, 9.85. Found : C, 84.56; H, 5.70; N, 9.74%.
Preparation of 6-Methyl-7-phenylbenzo[h]naphtho[1,2-b][1,6]
naphthyridine (4)
General procedure. 2-Methyl-N-(1-naphthyl)quinolin-4-amine (3, 0.002 mol)
and benzoic acid (0.0025 mol) were added to polyphosphoric acid (6 g of P2O5 in
3 mL of H3PO4) and heated at 160 ꢀC for 3 h. The reaction was monitored using
TLC. After the completion of the reaction, it was poured into ice water, neutralized
with saturated sodium bicarbonate solution to remove excess benzoic acid, extracted
with ethyl acetate, and purified by column chromatography using silica gel. The
product eluted with petroleum ether–ethyl acetate (99:1) mixture to get 4, which
was recrystallised using methanol.
Compound 4a. Colorless needles; mp 205–207 ꢀC; yield : 0.330 g (43%). IR
1
nmax (cmꢁ1) : 1616 (C N), 1608, 1560, 1471; H NMR (CDCl3) d: 2.26 (s, 3H, C2-
=
CH3), 2.90 (s, 3H C6-CH3), 7.27–7.94 (m, 12H, C3-, C4-, C8-, C9-, C10-, C11-, C12-,
C02-, C30 -, C40 -, C05-, and C06-H), 9.45 (d, 1H, C1-H, J ¼ 2.40 Hz), 9.68 (d, 1H, C13-H
J ¼ 8.00 Hz). 13C NMR (CDCl3) d: 17.8 (C6-CH3), 29.9 (C2-CH3), 117.9 (C6a),
122.5 (C1), 124.1 (C9), 125.0 (C8), 125.2 (C7a), 125.9 (C13), 126.4 (C14b), 127.3 (C12),
127.6 (C10), 128.0 (C4), 128.4 (C04), 128.5 (C30 & C05), 128.6 (C3), 129.5 (C11), 130.0
(C02 & C06), 131.1 (C2), 131.3 (C9a), 133.9 (C13a), 139.3 (C01), 143.4 (C7), 144.4 (C4a),
147.4 (C13b), 147.6 (C14a), 158.6 (C6); MS: m=z (%) 384 (Mþ, 100), 383 (20), 369
(10), 354 (12), 221 (10), 123 (5), 65 (10), 51 (10). Anal. calcd. for C28H20N2: C,
87.47; H, 5.24; N, 7.29. Found: C, 87.41; H, 5.28; N, 7.31%.
Compound 4b. Colorless prisms; mp 202–205 ꢀC; yield: 0.338 g (41%); IR
1
nmax (cmꢁ1) : 1621 (C N), 1601, 1561, 1480. H NMR (CDCl3) d: 2.35 (s, 3H, C4-
=
CH3), 2.86 (s, 3H, C6-CH3), 7.27 (d, 1H, C3-H, J ¼ 9.50 Hz), 7.35 (d, 2H, C02 & C60 -
H, J ¼ 7.20 Hz) 7.51–7.61 (m, 6H, C2, C8, C9, C03, C40 , C50 -H), 7.70 (t, 1H, C11-H,
J ¼ 7.50 Hz), 7.77 (t, 1H, C12-H, J ¼ 7.50 Hz), 7.81 (d, 1H, C10-H, J ¼ 7.50 Hz), 9.37

BENZONAPHTHONAPHTHYRIDINES
2285
(d, 1H, C1-H J ¼ 7.50 Hz), 9.68 (d, 1H, C13-H, J ¼ 8.00 Hz). 13C NMR (CDCl3) d:
17.8 (C6-CH3), 29.5 (C4-CH3), 117.9 (C6a), 122.3 (C1), 124.1 (C9), 124.5 (C2), 125.0
(C8), 125.2 (C7a), 125.9 (C13), 126.2 (C14b), 127.3 (C12), 127.6 (C10), 127.7 (C3),
128.4 (C04), 128.51 (C30 & C50 ), 129.5 (C11), 130.0 (C02 & C60 ), 131.3 (C9a), 133.9
(C13a), 136.1 (C4) 139.3 (C10 ), 143.4 (C7), 147.4 (C13b), 147.6 (C14a), 147.7 (C4a),
158.6 (C6). MS: m=z (%) 384 (Mþ, 100), 383 (28), 369 (5), 354 (5), 222 (10), 123
(15), 65 (6), 51 (5). Anal. calcd. for C28H20N2: C, 87.47; H, 5.24; N, 7.29. Found:
C, 87.58; H, 5.18; N, 7.24%.
Compound 4c. Colorless needles; mp 206–208 ꢀC; yield: 0.323 g (40%); IR
1
nmax (cmꢁ1): 1622 (C N), 1605, 1547, 1463; H NMR (CDCl3) d: 2.90 (s, 3H C6-
=
CH3), 7.25–7.94 (m, 12H, C3-, C4-, C8-, C9-, C10-, C11-, C12-, C02-, C30 -, C40 -, C50 -,
and C06-H), 9.29 (d, 1H, C1-H, J ¼ 2.40 Hz), 9.63 (d, 1H, C13-H, J ¼ 8.00 Hz); 13C
NMR (CDCl3) d: 17.8 (C6-CH3), 117.9 (C6a), 122.2 (C1), 124.1 (C9), 125.0 (C8),
125.2 (C7a), 125.9 (C13), 126.4 (C14b), 127.3 (C12), 127.6 (C10), 128.2 (C4), 128.4
(C04), 128.51 (C30 & C50 ), 128.8 (C3), 129.5 (C11), 130.0 (C02 & C60 ), 130.3 (C2), 131.3
(C9a), 133.9 (C13a), 139.3 (C10 ), 143.4 (C7), 144.4 (C4a), 147.4 (C13b), 147.6 (C14a),
158.6 (C6). MS: m=z (%) 406 (M þ 2, 35), 404 (Mþ, 100), 389 (18), 375 (12), 369
(5), 222 (18), 123 (10), 65 (12), 51 (15). Anal. calcd. for C27H17ClN2: C, 80.09; H,
4.23; N, 6.91. Found: C, 80.12; H, 4.29; N, 6.97%.
Compound 4d. Colorless prisms; mp 201–203 ꢀC; yield: 0.310 g (42%); IR
1
nmax (cmꢁ1) : 1618 (C N), 1607, 1549, 1467; H NMR (CDCl3) d: 2.88 (s, 3H, C6-
=
CH3), 7.37–8.13 (m, 13H, C2-, C3-, C4-, C8-, C9-, C10-, C11-, C12-, C02-, C30 -, C40 -, C50 -,
and C06-H), 9.61 (d, 1H, C1-H, J ¼ 7.40 Hz), 9.79 (d, 1H, C13-H, J ¼ 9.00 Hz); 13C
NMR (CDCl3) d: 17.8 (C6-CH3), 117.9 (C6a), 122.5 (C1), 124.1 (C9), 124.3 (C2),
125.0 (C8), 125.2 (C7a), 125.9 (C13), 126.2 (C14b), 126.6 (C4), 127.3 (C12), 127.6
(C10), 127.7 (C3), 128.4 (C40 ), 128.51 (C30 & C50 ), 129.5 (C11), 130.0 (C20 & C06), 131.3
(C9a), 133.9 (C13a), 139.3 (C10 ), 143.4 (C7), 147.4 (C13b), 147.6 (C14a), 147.7 (C4a)
158.6 (C6). MS: m=z (%) 370 (Mþ, 100), 369 (85), 341 (32), 293 (10), 263 (15), 124
(10), 64 (10), 44 (25). Anal. calcd. for C27H18N2: C, 87.54; H, 4.90; N, 7.56. Found:
C, 87.66; H, 4.81; N, 7.53%.
6,7-Dimethylbenzo[h]naphtho[1,2-b][1,6]naphthyridine (5)
General procedure. An appropriate mixture of 2-methyl-N-(1-naphthyl)
quinolin-4-amine (3, 0.002 mol) and acetic acid (0.0025 mol) was added to polypho-
sphoric acid (6 g of P2O5 in 3 mL of H3PO4) and heated at 160 ꢀC for 3 h. The reac-
tion was monitored using TLC. After the completion of the reaction, it was poured
into ice water, extracted with ethyl acetate, and purified by column chromatography
using silica gel. The product was eluted with petroleum ether–ethyl acetate (99:1)
mixture to get 5, which was recrystallized using methanol.
Compound 5a. Colorless prisms; mp 184–186 ꢀC; yield: 0.218 g (34%); IR nmax
1
(cmꢁ1) : 1623 (C N), 1591, 1522, 1437; H NMR (CDCl3) d: 2.53 (s, 3H, C2-CH3), 2.71
=
(s, 3H, C6-CH3), 3.12 (s, 3H, C7-CH3), 7.61–7.99 (m, 7H, C3-, C4-, C8-, C9-, C10-, C11-,
and C12-H), 9.25 (d, 1H, C1-H, J ¼ 2.00 Hz), 9.51 (d, 1H, C13-H, J ¼ 8.00 Hz). 13C
NMR (CDCl3) d: 16.9 (C6-CH3), 24.4 (C7-CH3), 29.1 (C2-CH3), 118.1 (C6a), 122.5

2286
K. PRABHA AND K. J. RAJENDRA PRASAD
(C1), 124.1 (C9), 125.2 (C8), 125.4 (C7a), 125.9 (C13), 126.4 (C14b), 127.3 (C12), 127.6
(C10), 128.0 (C4), 128.8 (C3), 129.5 (C11), 131.1 (C2), 131.1 (C9a), 133.9 (C13a), 139.1
(C7), 144.4 (C4a), 147.4 (C13b), 147.6 (C14a), 158.6 (C6). MS: m=z (%) 322 (Mþ, 100),
307 (80), 291 (15), 278 (15), 277 (42), 124 (10), 105 (20), 65 (28). Anal. calcd. for
C23H18N2: C, 85.69; H, 5.62; N, 8.69. Found: C, 85.79; H, 5.68; N, 8.54%.
Compound 5b. Colorless needles; mp 183–185 ꢀC; Yield: 0.231 g (36%); IR
1
nmax (cmꢁ1) : 1626 (C N), 1587, 1520, 1439; H NMR (CDCl3) d: 2.38 (s, 3H,
=
C2-CH3), 2.92 (s, 3H, C6-CH3), 3.34 (s, 3H, C7-CH3), 7.64–8.15 (m, 7H, C2-, C3-,
C8-, C9-, C10-, C11-, and C12-H), 9.25 (dd, 1H, C1-H Jo ¼ 8.00 Hz and Jm ¼ 1.50 Hz),
), 9.71 (d, 1H, C13-H, J ¼ 8.00 Hz); 13C NMR (CDCl3) dC: 16.9 (C6-CH3), 24.4 (C7-
CH3), 29.8 (C4-CH3), 118.1 (C6a), 122.3 (C1), 124.1 (C9), 125.2 (C8), 125.4 (C7a),
125.9 (C13), 126.4 (C14b), 127.3 (C12), 127.4 (C2), 127.6 (C10), 128.6 (C3), 129.5
(C11), 131.1 (C9a), 133.9 (C13a), 134.2 (C4), 139.1 (C7), 147.4 (C13b), 147.6 (C14a),
147.8 (C4a), 158.6 (C6). MS: m=z (%) 322 (Mþ, 100), 321 (55), 307 (38), 290 (10),
278 (8), 277 (28), 124 (15), 105 (18), 65 (25). Anal. calcd. for C23H18N2: C, 85.69;
H, 5.62; N, 8.69. Found: C, 85.66; H, 5.56; N, 8.78%.
Compound 5c. White solid; mp 186–188 ꢀC; Yield: 0.205 g (30%); IR nmax
1
(cmꢁ1) : 1627 (C N), 1585, 1518, 1442; NMR (CDCl3) dH: H NMR (500 MHz
=
CDCl3) d: 2.66 (s, 3H, C6-CH3), 3.09 (s, 3H, C7-CH3), 7.59–8.00 (m, 7H, C3-, C4-,
C8-, C9-, C10-, C11-, and C12-H), 9.21 (d, 1H, C1-H, J ¼ 2.00 Hz), 9.49 (d, 1H, C13-
H, J ¼ 8.00 Hz). 13C NMR (CDCl3) d: 16.9 (C6-CH3), 24.4 (C7-CH3), 118.1 (C6a),
122.2 (C1), 124.1 (C9), 125.2 (C8), 125.4 (C7a), 125.9 (C13), 126.4 (C14b), 127.3
(C12), 127.6 (C10), 128.0 (C4), 128.6 (C3), 129.5 (C11), 131.0 (C2), 131.1 (C9a),
133.9 (C13a), 139.1 (C7), 144.4 (C4a), 147.4 (C13b), 147.6 (C14a), 158.6 (C6). MS: m=
z (%) 344 (M þ 2, 30), 342 (Mþ, 100), 341 (60), 327 (10), 307 (12), 291 (10), 126
(15), 106 (12), 65 (25). Anal. calcd. for C22H15ClN2: C, 77.19; H, 4.39; N, 8.19.
Found: C, 77.10; H, 4.45; N, 8.24%.
Compound 5d. Colorless prisms; mp 182–184 ꢀC; yield: 0.203 g (23%); IR
1
nmax (cmꢁ1) : 1622 (C N), 1592, 1525, 1444; H NMR (CDCl3) d: 2.75 (s, 3H, C6-
=
CH3), 3.11 (s, 3H, C7-CH3), 7.64–8.16 (m, 8H, C2-, C3-, C4-, C8-, C9-, C10-, C11-,
and C12-H), 9.27 (d, 1H, C1-H Jo ¼ 8.00 Hz and Jm ¼ 1.50 Hz), 9.75 (d, 1H, C13-H,
J ¼ 8.00 Hz). 13C NMR (CDCl3) d: 16.9 (C6-CH3), 24.4 (C7-CH3), 118.1 (C6a),
122.5 (C1), 124.3 (C9), 124.5 (C2), 125.2 (C8), 125.4 (C7a), 125.9 (C13), 126.4 (C14b),
127.3 (C12), 127.6 (C10), 128.2 (C4), 128.6 (C3), 129.5 (C11), 131.1 (C9a), 133.9
(C13a), 139.1 (C7), 147.4 (C13b), 147.6 (C14a), 147.8 (C4a), 158.6 (C6). MS: m=z (%)
308 (Mþ, 100), 307 (85), 293 (20), 279 (15), 202 (18), 124 (10), 106 (20), 44 (35). Anal.
calcd. for C22H16N2: C, 85.69; H, 5.23; N, 9.08. Found: C, 85.79; H, 5.06; N, 9.15%.
6-Methyl-7-(naphthalen-1-yl)benzo[h]naphtho[1,2-b][1,6]
naphthyridine (6)
General procedure. 2-Methyl-N-(1-naphthyl)quinolin-4-amine (3, 0.002 mol)
and 1-naphthoic acid (0.0025 mol) were added to polyphosphoric acid (6 g of P2O5 in
3 mL of H3PO4) and heated at 160 ꢀC for 3 h. The reaction was monitored using
TLC. After the completion of the reaction, it was poured into ice water, neutralized

BENZONAPHTHONAPHTHYRIDINES
2287
with saturated sodium bicarbonate solution to remove excess of 1-naphthoic acid,
extracted with ethyl acetate, and purified by column chromatography using silica
gel. The product was eluted with petroleum ether–ethyl acetate (99:1) mixture to
get 6, which was recrystallized using methanol.
Compound 6a. Colorless needles; mp 222–224 ꢀC; yield: 0.346 g (40%); IR
1
nmax (cmꢁ1) : 1620 (C N), 1606, 1565, 1476; H NMR (CDCl3) d: 2.21 (s, 3H,
=
C2-CH3), 2.91 (s, 3H C6-CH3), 7.43–8.30 (m, 14H, C3-, C4-, C8-, C9-, C10-, C11-,
C12-, C20 -, C30 -, C40 -, C50 -, C60 -, C70 -, and C80 - H), 9.43 (d, 1H, C1-H, J ¼ 2.40 Hz),
9.74 (d, 1H, C13-H, J ¼ 8.00 Hz). 13C NMR (CDCl3) d: 18.0 (C6-CH3), 29.9 (C2-
CH3), 117.9 (C6a), 119.4 (C02), 122.5 (C1), 124.1 (C9), 125.0 (C8), 125.2 (C7a), 125.9
(C13), 126.4 (C14b), 127.3 (C12), 127.6 (C10), 127.8 (C08), 127.9 (C30 ) 128.0 (C4),
128.1 (C04), 128.3 (C50 ), 128.4 (C06), 128.5 (C70 ), 128.6 (C3), 129.5 (C11), 131.1 (C2),
131.3 (C9a), 132.6 (C80 a), 133.9 (C13a), 134.1 ðC04aÞ, 137.1 (C10 ), 143.4 (C7), 144.4
(C4a), 147.4 (C13b), 147.6 (C14a), 158.6 (C6). MS: m=z (%) 434 (Mþ, 100), 419 (15),
404 (14), 378 (12), 307 (18), 221 (10), 123 (5), 65 (10). Anal. calcd. for C32H22N2:
C, 88.45; H, 5.10; N, 6.45. Found: C, 88.38; H, 5.15; N, 6.47%.
Compound 6b. Colorless prisms; mp 225–227 ꢀC; yield: 0.356 g (41%); IR
1
nmax (cmꢁ1) : 1625 (C N), 1600, 1567, 1481; H NMR (CDCl3) d: 2.30 (s, 3H,
=
C4-CH3), 2.89 (s, 3H, C6-CH3), 7.44–8.32 (m, 14H, C2-, C3-, C8-, C9-, C10-, C11-,
C12-, C20 -, C30 -, C40 -, C50 -, C60 -, C70 -, and C80 - H), 9.39 (d, 1H, C1-H, J ¼ 7.50 Hz),
9.74 (d, 1H, C13-H, J ¼ 8.00 Hz). 13C NMR (CDCl3) d: 17.8 (C6-CH3), 29.5 (C4-
CH3), 117.9 (C6a), 119.4 (C02), 122.3 (C1), 124.1 (C9), 124.5 (C2), 125.0 (C8), 125.2
(C7a), 125.9 (C13), 126.2 (C14b), 127.3 (C12), 127.6 (C10), 127.7 (C3), 127.8 (C08),
127.9 (C03), 128.1(C40 ), 128.3 (C05), 128.4 (C60 ), 128.5 (C07), 129.5 (C11), 131.3 (C9a),
132.6 (C08a), 133.9 (C13a), 134.1 ðC40 aÞ, 136.1 (C4), 137.1 (C10 ), 143.4 (C7), 147.4
(C13b), 147.6 (C14a), 147.7 (C4a) 158.6 (C6). MS: m=z (%) 434 (Mþ, 100), 433 (28),
418 (5), 404 (20), 307 (10), 123 (15), 65 (6), 51 (5). Anal. calcd. for C32H22N2: C,
88.45; H, 5.10; N, 6.45. Found: C, 88.49; H, 5.08; N, 6.43%.
Compound 6c. Colorless needles; mp 228–230 ꢀC; yield: 0.318 g (35%). IR
1
nmax (cmꢁ1) : 1623 (C N), 1600, 1549, 1462. H NMR (CDCl3) d: 2.91 (s, 3H C6-
=
CH3), 7.40–8.33 (m, 14H, C3-, C4-, C8-, C9-, C10-, C11-, C12-, C02-, C30 -, C40 -, C50 -,
C06-, C07-, and C80 - H), 9.36 (d, 1H, C1-H, J ¼ 2.40 Hz), 9.71 (d, 1H, C13-H,
13
J ¼ 8.00 Hz). C NMR (CDCl3) d: 17.8 (C6-CH3), 117.9 (C6a), 119.4 (C02), 122.2
(C1), 124.1 (C9), 125.0 (C8), 125.2 (C7a), 125.9 (C13), 126.4 (C14b), 127.3 (C12),
127.6 (C10), 127.8 (C80 ), 127.9 (C30 ), 128.1 (C40 ), 128.2 (C4), 128.3 (C50 ), 128.4 (C06),
128.5 (C07), 128.8 (C3), 129.5 (C11), 130.3 (C2), 131.3 (C9a), 132.6 (C80 a), 133.9
(C13a), 134.1 ðC04aÞ, 139.3 (C10 ), 143.4 (C7), 144.4 (C4a), 147.4 (C13b), 147.6 (C14a),
158.6 (C6). MS: m=z (%) 456 (M þ 2, 35), 454 (Mþ, 100), 419 (18), 405 (12), 342
(5), 280 (18), 123 (10), 65 (12), 51 (15). Anal. calcd. for C31H19ClN2: C, 81.84; H,
4.20; N, 6.15. Found: C, 81.79; H, 4.24; N, 6.11%.
Compound 6d. Colorless prisms; mp 218–220 ꢀC; yield: 0.308 g (37%). IR
1
nmax (cmꢁ1): 1619 (C N), 1609, 1550, 1470. H NMR (CDCl3) d: 2.88 (s, 3H, C6-
=
CH3), 7.41–8.34 (m, 15H, C2-, C3-, C4-, C8-, C9-, C10-, C11-, C12-, C02-, C30 -, C40 -,
C05-, C60 -, C07-, and C80 - H), 9.47 (d, 1H, C1-H, J ¼ 7.40 Hz), 9.79 (d, 1H, C13-H,
13
J ¼ 9.00 Hz). C NMR (CDCl3) d: 17.8 (C6-CH3), 117.9 (C6a), 119.4 (C02), 122.5

2288
K. PRABHA AND K. J. RAJENDRA PRASAD
(C1), 124.1 (C9), 124.3 (C2), 125.0 (C8), 125.2 (C7a), 125.9 (C13), 126.2 (C14b), 126.6
(C4), 127.3 (C12), 127.6 (C10), 127.7 (C3), 127.8 (C08), 127.9 (C30 ), 128.1 (C40 ), 128.3
(C05), 128.4 (C60 ), 128.5 (C70 ), 129.5 (C11), 131.3 (C9a), 132.6 (C08a), 133.9 (C13a),
134.1 ðC04aÞ, 139.3 (C10 ), 143.4 (C7), 147.4 (C13b), 147.6 (C14a), 147.7 (C4a), 158.6
(C6). MS: m=z (%) 420 (Mþ, 100), 419 (85), 405 (32), 343 (10), 273 (15), 174 (10),
64 (10), 44 (25). Anal. calcd. for C31H20N2: C, 88.54; H, 4.80; N, 6.66. Found: C,
88.60; H, 4.76; N, 6.62%.
ACKNOWLEDGMENTS
The authors thank the Indian Institute of Science, Bangalore, and the Indian
Institute of Technology Madras, Chennai, for NMR and the Indian Institute of
Chemical Technology, Hyderabad, for mass spectral data.
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