A novel and efficient method for the synthesis of 5-arylnaphtho[2,1-c][2,7] naphthyridine derivatives catalyzed by iodine

Article abstract of DOI:10.1002/jhet.212

(Chemical Equation Presented) A novel method for the synthesis of 1,2-dihydro-5-arylnaphtho[2,1-c][2,7]naphthyridine derivatives via a three-component reaction of aromatic aldehyde, naphthalen-2-amine, and N-substituted piperidin-4-one derivatives is desc

Full text of DOI:10.1002/jhet.212

November 2009
A Novel and Efficient Method for the Synthesis of
5-Arylnaphtho[2,1-c][2,7]naphthyridine Derivatives
Catalyzed by Iodine
1229
Xiang-Shan Wang,a,b* Qing Li,a Jian-Rong Wu,b Chang-Sheng Yao,a
and Shu-Jiang Tua,b
aSchool of Chemistry and Chemical Engineering, Xuzhou Normal University,
Xuzhou, Jiangsu 221116 China
bThe Key Laboratory of Biotechnology for Medical Plant of Jiangsu Province,
Xuzhou, Jiangsu 221116 China
*E-mail: xswang1974@yahoo.com
Received November 20, 2008
DOI 10.1002/jhet.212
Published online 5 November 2009 in Wiley InterScience (www.interscience.wiley.com).
A novel method for the synthesis of 1,2-dihydro-5-arylnaphtho[2,1-c][2,7]naphthyridine derivatives
via a three-component reaction of aromatic aldehyde, naphthalen-2-amine, and N-substituted piperidin-
4-one derivatives is described using 5 mol % iodine as catalyst. The features of this new procedure are
mild reaction condition, high yield, operational simplicity, and uses available reactants.
J. Heterocyclic Chem., 46, 1229 (2009).
INTRODUCTION
with ketone [10], or by any other methods [11]. How-
ever, despite their potential utility, many of these
reported methods suffer from drawbacks such as harsh
reaction conditions, unsatisfactory yields, prolonged
reaction time, multistep reactions, and cumbersome
product isolation procedure. This work is in connection
with our previous research on the MCRs to the intrigu-
ing heterocycles [12] and successfully realized a three-
component reaction of aromatic aldehyde, naphthalen-2-
amine, and N-substituted piperidin-4-one catalyzed by
iodine in THF without isolating and purifying the inter-
mediates to afford naphtho[2,1-c][2,7]naphthyridine
moiety.
Multicomponent reactions (MCRs) can be distin-
guished from classical, sequential two-component chem-
istry synthesis processes in that they use three or more
chemical starting materials as the input for product for-
mation. Up to seven starting components have been
used, and MCRs have often been shown to produce
higher product yields than classical chemistry [1]. They
provide a powerful tool toward the one-pot synthesis of
diverse and complex compounds, as well as small and
drug-like heterocycles [2].
The naphtho[2,1-c][2,7]naphthyridine 1 ring system
(Fig. 1) is a rare heterocycle compared with [1,8]naph-
thyridine 2 and [1,5]naphthyridine 3 substructures.
Naphthyridines, which encompass two pyridine rings,
are known to display a wide range of biological activ-
ities, including antibacterial activity [3], antimalarial ac-
tivity [4], antimicrobial activity [5], anticancer activity
[6], and antiinflammatory activity [7]. Moreover, it is
envisioned that naphtho[2,1-c][2,7]naphthyridines 1,
which contained both naphthalene ring and naphthyri-
dine moieties, may afford unique biological activities,
such as Barta-Szalai et al. [8] revealed in 2003 that spi-
ro[naphto[2,1-c][2,7]naphtiridine-5,4’-piperidine] deriva-
tives were potent inhibitors of lipid peroxidation.
RESULTS AND DISCUSSION
The treatment of aromatic aldehyde 4, naphthalen-2-
amine 5, and ethyl 4-piperidinone-1-carboxylate 6 in
THF in the presence of 5 mol % iodine at reflux
afforded the corresponding ethyl 1,2-dihydro-5-arylnaph-
tho[2,1-c][2,7]naphthyridine-3(4H)-carboxylate deriva-
tives 1 in high yields (Scheme 1).
In an initial endeavor, 3,4-dichlorobenzaldehyde 4a,
naphthalen-2-amine 5, and ethyl 4-piperidinone-1-car-
boxylate 6 were stirred in THF in the absence of I2. No
reaction occurred at room temperature and reflux condi-
tion (Table 1, entries 1 and 2). Similar reactions were
then attempted in the presence of 5, 10, and 20 mol %
of I2. The results from Table 1 (entries 5–7) showed
Previously, it has been demonstrated that naphtho-
naphthyridines can be obtained from 2-aminobenzo[f]-
quinoline with glycerol in the presence of H2SO4 [9], or
by the Skraup reaction of 3-aminobenzo[h]quinoline
C
V
2009 HeteroCorporation

1230
X.-S. Wang, Q. Li, J.-R. Wu, C.-S. Yao, and S.-J. Tu
Vol 46
Table 1
Synthesis of 1a in THF under different reaction conditions.a
Temperature
(ꢁC)
I2
(mol %)
Yieldsb
(%)
Entry
Solvent
1
2
3
RT
0
0
5
THF
THF
THF
THF
0
0
Reflux
RT
50
Trace
62
91
88
89
82
86
78
83
4
5
Figure 1.
5
6
Reflux
Reflux
Reflux
Reflux
Reflux
80
5
THF
THF
10
20
5
7
8
THF
that 5 mol % I2 at reflux in THF was sufficient to push
the reaction forward. Based on these observations, we
have also conducted the reaction with 5 mol % of I2 at
room temperature, and 50 mol % at reflux temperature,
resulting in the isolation of 1a in trace amount, 62 and
91% yields (Table 1, entries 3–5), respectively. In addi-
tion, CH3CN, benzene, DMF, and CHCl3 (Table 1,
entries 8–11) were also tested as the solvents. In these
cases, product 1a was formed in slightly lower yield
(Table 1, entries 8–11).
CH3CN
Benzene
DMF
CHCl3
9
10
11
5
5
Reflux
5
a Reagents and conditions: 4 (0.350 g, 2 mmol), 5 (0.286 g, 2 mmol),
6 (0.343 g, 2 mmol), solvent (10 mL).
b Isolated yields.
The 1-(3-chlorobenzoyl)-4-piperidinone was also chosen
as reactant to react with benzaldehyde, naphthalen-2-
amine (Scheme 2), and were found to generate the cor-
responding naphtho[2,1-c][2,7]naphthyridines (8a-8d,
Table 3). However, to our surprise, we failed to get the
expected products when 4-piperidinone, N-methyl-4-
piperidinone, and N-benzyl-4-piperidinone were used as
reactants. Perhaps the stabilities of these above-men-
tioned 4-piperidinones restrained their reactions.
To evaluate the efficiency of iodine as a catalyst, a
range of benzaldehydes 4b–p were subjected to react
with 5 and 6 in the presence of 5 mol % I2 to generate
1, and the results are summarized in Table 2. It can be
observed that the process tolerates both electron-donat-
ing and electron-withdrawing substituents in the benzal-
dehydes. In all cases, the reactions proceeded efficiently
at reflux under mild conditions to afford the correspond-
ing naphtho[2,1-c][2,7]naphthyridines in high yields (Ta-
ble 2).
It was interesting that the 1,4-di(1,2,3,4-tetrahydro-3-
ethoxycarbonyl-naphtho[2,1-c][2,7]naphthyridine-5-yl)
1
benzene
9
was obtained in 87% yield when
The structure of 1 was characterized by H NMR, IR,
and HRMS. The analyses were in agreement with their
1
structures. For example, in the H NMR of 1a, the pro-
Table 2
tons on the ethyl group appear at 1.31 (triplet, J ¼ 6.8
Hz) and 4.22 ppm (quartet, J ¼ 6.8 Hz), respectively.
The adjacent methylene groups exhibit two triplets at
3.66 (J ¼ 5.6 Hz) and 3.76 (J ¼ 5.6 Hz), respectively.
The singlet at 4.73 ppm is assigned as another methyl-
ene group in the pyridine moiety. Totally, nine corre-
sponding protons detected make further confirmation of
structure 1a. The IR spectra for 1a exhibit strong bands
at 1715 cmꢀ1 for the carboxyl group in the structure.
The HRMS of 1a is in good agreement with its structure
(Calcd for C25H20Cl2N2NaO2 (MþNaþ) 473.0800,
found 473.0791) with a deviation of 1.9 ppm.
I2 catalyzed reaction of benzaldehydes, naphthalen-2-amine, and ethyl
4-piperidinone-1-carboxylate in THF.a
Time
(h)
Yieldsb
(%)
Entry
Ar
Products
1
2
3,4-Cl2C6H3
3-NO2C6H4
2-Thiophenyl
2,4-Cl2C6H3
4-BrC6H4
1a
1b
1c
1d
1e
1f
1g
1h
1i
1j
1k
1l
1m
1n
1o
1p
14
12
16
14
12
12
10
10
14
10
16
18
10
16
12
16
91
92
81
83
86
88
90
87
87
90
83
82
84
83
88
86
3
4
5
6
7
4-ClC6H4
2,3-Cl2C6H3
4-NO2C6H4
4-FC6H4
8
9
As expected, the substrate of ethyl 4-piperidinone-1-
carboxylate could be extended to other 4-piperidinones.
10
11
12
13
14
15
16
2-NO2C6H4
3-ClC6H4
4-CH3OC6H4
4-Cl-2-NO2C6H3
C6H5
Scheme 1
2-FC6H4
3,5-(CH3O)2C6H3
a Reagents and conditions: 4 (2 mmol), 5 (2 mmol, 0.286 g), 6
(2 mmol, 0.342 g), I2 (0.1 mmol, 0.026 g), THF (10 mL).
b Isolated yields.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

November 2009
A Novel and Efficient Method for the Synthesis of
5-Arylnaphtho[2,1-c][2,7]naphthyridine Derivatives Catalyzed by Iodine
1231
Scheme 2
Scheme 3
reaction conditions, high yields, operational simplicity,
and environmentally friendly procedure.
terephthalaldehyde was chosen as aromatic aldehyde to
react with two equivalent of naphthalen-2-amine and
ethyl 4-piperidinone-1-carboxylate (Scheme 3).
EXPERIMENTAL
According to the literatures [13], we think that iodine
catalyzes the reaction as a mild Lewis acid. The mecha-
nism was proposed as shown in Scheme 4. In the pres-
ence of iodine, cyclophentone is in equilibrium with the
enol form I. The enol immediately attack iodine-acti-
vated Schiff base to form intermediate II, followed by
an intramolecular Friedel–Crafts cyclization to give III.
The subsequent dehydration of III results in tetrahydro-
naphtho[2,1-c][2,7]naphthyridine IV, which is further
oxidized by air to afford an aromatized naphtho[2,1-
c][2,7]naphthyridine 1.
To verify the mechanism, we individually performed
each separate step. The Schiff base, N-(3,4-dichlorophe-
nylidene) naphthalen-2-amine, was obtained in 92%
yield, when the 3,4-dichlorobenzaldehyde (1, Ar ¼ 3,4-
Cl2C6H3) was treated with naphthalen-2-amine in THF
at ambient temperature (Scheme 5). As expected, Schiff
base smoothly reacted with 6 to give the corresponding
ethyl 1,2-dihydro-5-(3,4-dichlorophenyl) naphtha [2,1-
c][2,7]naphthyridine-3(4H)-carboxylate 1a. This result
suggests that a formation of Schiff base took place dur-
ing the reaction. It should be noted that the overall yield
was low (76%) in the above separate reaction.
Melting points were determined in open capillaries and are
uncorrected. Infrared (IR) spectra were recorded on a TEN-
SOR 27 spectrometer in KBr pellet. 1H NMR spectra were
obtained from solution in DMSO-d6 with Me4Si as internal
standard using a Bruker-400 spectrometer. HRMS analyses
were carried out using a Bruker-micro-TOF-Q-MS analyzer.
General procedure for the syntheses of 1,2-dihydro-5-
arylnaphtho [2,1-c] [2,7]naphthyridine derivatives 1 and
8. A dry 50-mL flask was charged with aromatic aldehyde (2.0
mmol), naphthalen-2-amine (2.0 mmol, 0.286 g), ethyl 4-piper-
idinone-1-carboxylate or (3-chlorobenzoyl)-4-piperidinone (2.0
mmol), I2 (0.1 mmol, 0.026 g), and THF (10 mL). The reac-
tion mixture was stirred at reflux for 10–18 h. After comple-
tion of the reaction, as indicated by TLC, a little DMF was
added to the mixture until the all yellow solid was dissolved.
The generated crystals were collected by filtration to give 1 or
8 when the mixture was cooled to room temperature.
Ethyl 1,2-dihydro-5-(3,4-dichlorophenyl)naphtho[2,1-c][2,7]
naphthyridine-3(4H)-carboxylate (1a). This compound was
obtained as pale yellow crystals (0.819 g, 91%), mp 192–
194ꢁC. IR (KBr): mmax 3057, 2983, 2957, 2869, 1715, 1564,
1549, 1473, 1451, 1381, 1338, 1282, 1255, 1203, 1169, 1138,
1110, 1087, 1059, 1029, 966, 954, 894, 838, 808, 788, 779,
755 cmꢀ1
.
1H NMR (DMSO-d6): d 1.31 (t, J ¼ 6.8 Hz, 3H,
In conclusion, we found an efficient method for the
synthesis of naphtho[2,1-c][2,7]naphthyridine derivatives
by three-component reaction of aromatic aldehyde,
naphthalen-2-amine, and ethyl 4-piperidinone-1-carboxy-
late or (3-chlorobenzoyl)-4-piperidinone using 5 mol %
I2 as catalyst. The features of this procedure are mild
Scheme 4
Table 3
I2 catalyzed reaction of benzaldehyde, naphthalen-2-amine
and 1-(3-chlorobenzoyl)-4-piperidinone in THF.a
Entry
Ar
Products
Time (h)
Yieldsb (%)
1
2
3
4
4-ClC6H4
4-BrC6H4
2,4-Cl2C6H3
4-NO2C6H4
8a
8b
8c
8d
15
16
14
12
82
86
78
83
a Reagents and conditions: 4 (2 mmol), 5 (2 mmol, 0.286 g), 7 (2
mmol, 0.474 g), I2 (0.1 mmol, 0.026 g), THF (10 mL).
b Isolated yields.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

1232
X.-S. Wang, Q. Li, J.-R. Wu, C.-S. Yao, and S.-J. Tu
Vol 46
Scheme 5
CH2), 7.59 (d, J ¼ 8.4 Hz, 2H, ArH), 7.72–7.75 (m, 4H,
ArH), 7.86 (d, J ¼ 8.8 Hz, 1H, ArH), 8.07–8.11 (m, 2H,
ArH), 8.70–8.72 (m, 1H, ArH). HRMS (ESI, m/z): calcd for
C25H22BrN2O2 (MþHþ) 461.0865, found 461.0831.
Ethyl 1,2-dihydro-5-(4-chlorophenyl)naphtho[2,1-c][2,7]naph-
thyridine-3(4H)-carboxylate (1f). This compound was obtained
as pale yellow crystals (0.730 g, 88%), mp 210ꢀ212ꢁC. IR
(KBr): mmax 3055, 2979, 1695, 1595, 1559, 1481, 1460, 1432,
1382, 1362, 1337, 1321, 1302, 1284, 1246, 1203, 1169, 1138,
CH3), 3.66 (t, J ¼ 5.6 Hz, 2H, CH2), 3.76 (t, J ¼ 5.6 Hz, 2H,
CH2), 4.22 (q, J ¼ 6.8 Hz, 2H, CH2O), 4.73 (s, 2H, CH2),
7.42 (dd, J ¼ 8.0 Hz, J’ ¼ 2.0 Hz, 1H, ArH), 7.60 (d, J ¼ 8.0
Hz, 1H, ArH), 7.66–7.70 (m, 2H, ArH), 7.74 (d, J ¼ 2.0 Hz,
1H, ArH), 7.96–8.00 (m, 3H, ArH), 8.00–8.63 (m, 1H, ArH).
HRMS (ESI, m/z): calcd for C25H20Cl2N2NaO2 (MþNaþ)
473.0800, found 473.0791.
1114, 1087, 1046, 1014, 979, 945, 870, 837, 757 cmꢀ1 1H
.
NMR (DMSO-d6): d 1.20 (b, 3H, CH3), 3.58 (t, J ¼ 5.6 Hz,
2H, CH2), 3.75 (t, J ¼ 5.6 Hz, 2H, CH2), 4.09 (q, J ¼ 6.8 Hz,
2H, CH2O), 4.66 (s, 2H, CH2), 7.63–7.74 (m, 4H, ArH), 7.75–
7.76 (m, 2H, ArH), 7.87 (d, J ¼ 8.8 Hz, 1H, ArH), 8.09–8.13
(m, 2H, ArH), 8.73–8.75 (m, 1H, ArH). HRMS (ESI, m/z):
calcd for C25H22ClN2O2 (MþHþ) 417.1370, found 417.1387.
Ethyl 1,2-dihydro-5-(2,3-dichlorophenyl)naphtho[2,1-c][2,7]
naphthyri-dine-3(4H)-carboxylate (1g). This compound was
obtained as pale yellow crystals (0.810 g, 90%), mp
165ꢀ167ꢁC. IR (KBr): mmax 3057, 2979, 2905, 1694, 1604,
1561, 1482, 1430, 1379, 1362, 1343, 1253, 1207, 1170, 1142,
Ethyl 1,2-dihydro-5-(3-nitrophenyl)naphtho[2,1-c][2,7]naph-
thyridine-3(4H)-carboxylate (1b). This compound was obtained
as pale yellow crystals (0.785 g, 92%), mp 156ꢀ157ꢁC. IR
(KBr): mmax 3090, 2960, 1694, 1534, 1466, 1447, 1382, 1348,
1303, 1260, 1204, 1095, 1081, 1001, 832, 807, 771, 759, 738,
708 cmꢀ1 1H NMR (DMSO-d6): d 1.20 (b, 3H, CH3), 3.58–
.
3.60 (m, 2H, CH2), 3.74–3.76 (m, 2H, CH2), 4.08 (q, J ¼ 6.4
Hz, 2H, CH2), 4.69 (s, 2H, CH2), 7.75 (dd, J ¼ 6.0 Hz, J’ ¼ 3.2
Hz, 2H, ArH), 7.86–7.91 (m, 2H, ArH), 8.11–8.13 (m, 3H,
ArH), 8.40 (dd, J ¼ 8.0 Hz, J’ ¼ 1.6 Hz, 1H, ArH), 8.49 (s, 1H,
ArH), 8.74–8.76 (m, 1H, ArH). HRMS (ESI, m/z): calcd for
C25H22N3O4 (MþHþ) 428.1610, found 428.1611.
1
1117, 1048, 1028, 870, 833, 788, 770, 753, 717, 701 cmꢀ1. H
NMR (DMSO-d6): d 1.29 (b, 3H, CH3), 3.67–3.76 (m, 4H,
2CH2), 4.16–4.23 (m, 2H, CH2O), 4.57 (s, 2H, CH2), 7.33–
7.40 (m, 2H, ArH), 7.60 (d, J ¼ 8.8 Hz, 1H, ArH), 7.67–7.70
(m, 2H, ArH), 7.97–8.00 (m, 3H, ArH), 8.67–8.69 (m, 1H,
ArH). HRMS (ESI, m/z): calcd for C25H21Cl2N2O2 (MþHþ)
451.0980, found 451.0956.
Ethyl 1,2-dihydro-5-(2-thiophenyl)naphtho[2,1-c][2,7]naph-
thyridine-3(4H)-carboxylate
(1c). This
compound
was
Ethyl 1,2-dihydro-5-(4-nitrophenyl)naphtho[2,1-c][2,7]naph-
was
obtained as pale yellow crystals (0.629 g, 81%), mp
111ꢀ112ꢁC. IR (KBr): mmax 3057, 2981, 1697, 1606, 1551,
1478, 1436, 1379, 1359, 1332, 1304, 1258, 1227, 1199, 1169,
thyridine-3(4H)-carboxylate
(1h). This
compound
obtained as pale yellow crystals (0.743 g, 87%), mp
209ꢀ211ꢁC. IR (KBr): mmax 3063, 2999, 2982, 2960, 2941,
2902, 1684, 1600, 1581, 1515, 1468, 1451, 1385, 1347, 1261,
1228, 1170, 1140, 1098, 1083, 1017, 968, 952, 886, 858, 837,
1134, 1117, 1074, 1028, 969, 827, 817, 767, 749, 712 cmꢀ1
.
1H NMR (DMSO-d6): d 1.26 (t, J ¼ 7.2 Hz, 3H, CH3), 3.62–
3.63 (m, 2H, CH2), 3.73–3.74 (m, 2H, CH2), 4.16 (q, J ¼ 7.2
Hz, 2H, CH2), 5.01 (s, 2H, CH2), 7.29–7.31 (m, 1H, ArH),
7.62 (d, J ¼ 3.6 Hz, 1H, ArH), 7.72–7.74 (m, 2H, ArH), 7.81–
7.85 (m, 2H, ArH), 8.08–8.11 (m, 2H, ArH), 8.71–8.73 (m,
1H, ArH). HRMS (ESI, m/z): calcd for C23H20N2NaO2S
(MþNaþ) 411.1143, found 411.1130.
770, 751, 700 cmꢀ1 1H NMR (DMSO-d6): d 1.20 (b, 3H,
.
CH3), 3.58–3.59 (m, 2H, CH2), 3.74–3.75 (m, 2H, CH2), 4.07
(q, J ¼ 7.2 Hz, 2H, CH2), 4.65 (m, 2H, CH2), 7.76 (dd, J ¼
6.0 Hz, J’ ¼ 3.2 Hz, 2H, ArH), 7.87–7.92 (m, 3H, ArH),
8.11–8.13 (m, 2H, ArH), 8.41 (d, J ¼ 8.8 Hz, 2H, ArH), 8.73–
8.76 (m, 1H, ArH). HRMS (ESI, m/z): calcd for C25H22N3O4
(MþHþ) 428.1610, found 428.1605.
Ethyl 1,2-dihydro-5-(2,4-dichlorophenyl)naphtho[2,1-c][2,7]
naphthyridine-3(4H)-carboxylate (1d). This compound was
obtained as pale yellow crystals (0.729 g, 83%), mp
168ꢀ169ꢁC. IR (KBr): mmax 3083, 2975, 1708, 1587, 1557,
1474, 1426, 1379, 1360, 1341, 1303, 1281, 1247, 1201, 1170,
1139, 1116, 1098, 1064, 1051, 947, 863, 837, 800, 767, 746
Ethyl 1,2-dihydro-5-(4-fluorophenyl)naphtho[2,1-c][2,7]naph-
thyridine-3(4H)-carboxylate (1i). This compound was obtained
as pale yellow crystals (0.695 g, 87%), mp 207ꢀ209ꢁC. IR
(KBr): mmax 3060, 2982, 2943, 2906, 1697, 1602, 1561, 1509,
1482, 1461, 1433, 1384, 1361, 1337, 1321, 1285, 1248, 1159,
cmꢀ1 1H NMR (DMSO-d6): d 1.22 (b, 3H, CH3), 3.42–3.45
.
1113, 1046, 1030, 979, 944, 869, 837, 808, 758 cmꢀ1 1H
.
(m, 1H, CH), 3.68–3.70 (m, 1H, CH), 3.78–3.84 (m, 2H,
CH2), 4.08–4.13 (m, 2H, CH2), 4.34–4.38 (m, 1H, CH), 4.48–
4.51 (m, 1H, CH), 7.59 (d, J ¼ 8.4 Hz, 1H, ArH), 7.66 (dd,
J ¼ 8.4 Hz, J’ ¼ 2.0 Hz, 1H, ArH), 7.74–7.77 (m, 2H, ArH),
7.86–7.88 (m, 2H, ArH), 8.11–8.14 (m, 2H, ArH), 8.77–8.80
(m, 1H, ArH ). HRMS (ESI, m/z): calcd for C25H21Cl2N2O2
(MþHþ) 451.0980, found 451.0983.
NMR (DMSO-d6): d 1.20 (b, 3H, CH3), 3.54–3.57 (m, 2H,
CH2), 3.71–3.74 (m, 2H, CH2), 4.07 (q, J ¼ 6.8 Hz, 2H,
CH2O), 4.64 (s, 2H, CH2), 7.37–7.42 (m, 2H, ArH), 7.66–7.76
(m, 4H, ArH), 7.86 (d, J ¼ 9.2 Hz, 1H, ArH), 8.07–8.11 (m,
2H, ArH), 8.70–8.73 (m, 1H, ArH). HRMS (ESI, m/z): calcd
for C25H22FN2O2 (MþHþ) 401.1665, found 401.1661.
Ethyl 1,2-dihydro-5-(2-nitrophenyl)naphtho[2,1-c][2,7]naph-
thyridine-3(4H)-carboxylate (1j). This compound was obtained
as pale yellow crystals (0.769 g, 90%), mp 218ꢀ220ꢁC. IR
(KBr): mmax 3057, 2978, 2924, 2905, 2851, 2684, 1608, 1560,
1529, 1468, 1442, 1383, 1350, 1302, 1266, 1224, 1140, 1118,
1092, 1028, 979, 954, 895, 860, 840, 790, 758, 740, 705, 693
Ethyl 1,2-dihydro-5-(4-bromophenyl)naphtho[2,1-c][2,7]
naphthyridine-3(4H)-carboxylate (1e). This compound was
obtained as pale yellow crystals (0.790 g, 86%), mp
188ꢀ190ꢁC. IR (KBr): mmax 3050, 2980, 1687, 1590, 1564,
1516, 1429, 1380, 1321, 1300, 1248, 1204, 1169, 1136, 1115,
1
1084, 1010, 953, 911, 886, 832, 765 cmꢀ1. H NMR (DMSO-
.
cmꢀ1 1H NMR (DMSO-d6): d 1.13–1.22 (m, 3H, CH3), 3.64
(b, 2H, CH2), 3.75 (b, 2H, CH2), 4.08 (b, 2H, CH2), 4.51 (s,
d6): d 1.20 (b, 3H, CH3), 3.54–3.57 (m, 2H, CH2), 3.70–3.73
(m, 2H, CH2), 4.09 (q, J ¼ 7.2 Hz, 2H, CH2), 4.65 (s, 2H,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

November 2009
A Novel and Efficient Method for the Synthesis of
5-Arylnaphtho[2,1-c][2,7]naphthyridine Derivatives Catalyzed by Iodine
1233
2H, CH2), 7.74–7.85 (m, 5H, ArH), 7.92–7.96 (m, 1H, ArH),
8.08–8.12 (m, 2H, ArH), 8.27 (d, J ¼ 8.0 Hz, 1H, ArH), 8.78–
8.80 (m, 1H, ArH). HRMS (ESI, m/z): calcd for C25H22N3O4
(MþHþ) 428.1610, found 428.1610.
ArH), 7.57–7.65 (m, 2H, ArH), 7.74–7.76 (m, 2H, ArH), 7.88
(d, J ¼ 8.8 Hz, 1H, ArH), 8.10–8.13 (m, 2H, ArH), 8.75–8.77
(m, 1H, ArH). HRMS (ESI, m/z): calcd for C25H21FN2NaO2
(MþNaþ) 423.1485, found 423.1467.
Ethyl 1,2-dihydro-5-(3-chlorophenyl)naphtho[2,1-c][2,7]naph-
thyridine-3(4H)-carboxylate (1k). This compound was obtained
as pale yellow crystals (0.691 g, 83%), mp 131ꢀ132ꢁC. IR
(KBr): mmax 3053, 2969, 2869, 1700, 1568, 1479, 1466, 1417,
1363, 1346, 1280, 1255, 1202, 1170, 1137, 1111, 1060, 1027,
Ethyl 1,2-dihydro-5-(3,5-dimethoxyphenyl)naphtha [2,1-c][2,7]
naphthyridine-3(4H)-carboxylate (1p). This compound was
obtained as pale yellow crystals (0.760 g, 86%), mp
157ꢀ159ꢁC. IR (KBr): mmax 3052, 2985, 2936, 2843, 1694,
1599, 1454, 1423, 1372, 1321, 1301, 1247, 1204, 1193, 1112,
997, 957, 875, 837, 794, 768, 752, 722, 696 cmꢀ1
.
1H NMR
1088, 1058, 969, 897, 852, 836, 802, 770, 752, 729 cmꢀ1. H
1
(DMSO-d6): d 1.22 (b, 3H, CH3), 3.57–3.58 (m, 2H, CH2),
3.71–3.72 (m, 2H, CH2), 4.09 (q, J ¼ 6.4 Hz, 2H, CH2), 4.66
(s, 2H, CH2), 7.59–7.60 (m, 3H, ArH), 7.73–7.76 (m, 3H,
ArH), 7.87 (d, J ¼ 8.8 Hz, 1H, ArH), 8.09–8.13 (m, 2H,
ArH), 8.71–8.74 (m, 1H, ArH). HRMS (ESI, m/z): calcd for
C25H22ClN2O2 (MþHþ) 417.1370, found 417.1350.
NMR (DMSO-d6): d 1.30 (b, 3H, CH3), 3.66–3.69 (m, 2H,
CH2), 3.74–3.76 (m, 2H, CH2), 3.85 (s, 6H, 2CH3O), 4.21 (q,
J ¼ 6.8Hz, 2H, CH2O), 4.77 (s, 2H, CH2), 6.57 (s, 1H, ArH),
6.70 (d, J ¼ 2.0 Hz, 2H, ArH), 7.65–7.68 (m, 2H, ArH), 7.94–
8.01 (m, 3H, ArH), 8.61–8.64 (m, 1H, ArH). HRMS (ESI, m/
z): calcd for C27H27N2O4 (MþHþ) 443.1971, found 443.1948.
1,2,3,4-Tetrahydro-3-(3-chlorobenzoyl)-5-(4-chlorophenyl)-
naphtho[2,1-c][2,7]naphthyridine (8a). This compound was
obtained as pale yellow crystals (0.789 g, 82%), mp
184ꢀ185ꢁC. IR (KBr): mmax 3062, 3014, 2977, 2899, 2853,
1623, 1560, 1479, 1430, 1361, 1322, 1259, 1211, 1165, 1126,
1085, 1055, 1045, 1012, 965, 946, 900, 838, 805, 744, 699
Ethyl 1,2-dihydro-5-(4-methoxyphenyl)naphtho[2,1-c][2,7]
naphthyridine-3(4H)-carboxylate (1l). This compound was
obtained as pale yellow crystals (0.674 g, 82%), mp
193ꢀ194ꢁC. IR (KBr): mmax 3018, 2978, 2958, 2934, 2903,
2871, 2841, 1702, 1610, 1556, 1518, 1418, 1367, 1292, 1204,
1135, 1109, 1087, 1060, 964, 952, 858, 836, 795, 759 cmꢀ1
.
1H NMR (DMSO-d6): d 1.20 (b, 3H, CH3), 3.55 (t, J ¼ 5.2
Hz, 2H, CH2), 3.72 (s, 2H, CH2), 3.86 (s, 3H, CH3O), 4.08 (q,
J ¼ 7.2 Hz, 2H, CH2), 4.69 (s, 2H, CH2), 7.11 (d, J ¼ 8.4 Hz,
2H, ArH), 7.59 (d, J ¼ 8.4 Hz, 2H, ArH), 7.73 (t, J ¼ 4.4 Hz,
2H, ArH), 7.86 (d, J ¼ 8.8 Hz, 1H, ArH), 8.06–8.11 (m, 2H,
ArH), 8.69–8.71 (m, 1H, ArH). HRMS (ESI, m/z): calcd for
C26H25N2O2 (MþHþ) 413.1865, found 413.1865.
cmꢀ1 1H NMR (DMSO-d6): d 3.54–3.80 (m, 4H, 2CH2),
.
4.67–4.85 (m, 2H, CH2), 7.43–7.75 (m, 10H, ArH), 7.89 (d, J
¼ 8.8 Hz, 1H, ArH), 8.10–8.13 (m, 2H, ArH), 8.14 (s, 1H,
ArH). HRMS (ESI, m/z): calcd for C29H20Cl2N2NaO
(MþNaþ) 505.0850, found 505.0857.
1,2,3,4-Tetrahydro-3-(3-chlorobenzoyl)-5-(4-bromophenyl)-
naphtho[2,1-c][2,7]naphthyridine (8b). This compound was
obtained as pale yellow crystals (0.902 g, 86%), mp
171ꢀ172ꢁC. IR (KBr): mmax 3060, 3016, 2980, 2946, 2898,
2852, 1634, 1563, 1518, 1479, 1430, 1362, 1321, 1259, 1227,
1211, 1165, 1125, 1083, 1068, 1009, 966, 900, 833, 805, 745,
Ethyl 1,2-dihydro-5-(4-chloro-2-nitrophenyl)naphtha [2,1-
c][2,7] naphthyridine-3(4H)-carboxylate (1m). This compound
was obtained as pale yellow crystals (0.774 g, 84%), mp
185ꢀ186ꢁC. IR (KBr): mmax 3061, 2986, 2906, 1698, 1683,
1605, 1567, 1537, 1484, 1470, 1435, 1383, 1339, 1297, 1246,
1224, 1204, 1144, 1117, 1026, 980, 960, 894, 868, 834, 756
703, 683 cmꢀ1 1H NMR (DMSO-d6): d 3.79–3.85 (m, 4H,
.
2CH2), 4.67–4.85 (m, 2H, CH2), 7.32–7.80 (m, 10H, ArH),
7.89 (d, J ¼ 8.8 Hz, 1H, ArH), 8.09–8.12 (m, 2H, ArH), 8.74
(s, 1H, ArH). HRMS (ESI, m/z): calcd for C29H21BrClN2O
(MþHþ) 527.0526, found 527.0525.
1
cmꢀ1. H NMR (DMSO-d6): d 1.31 (b, 3H, CH3), 3.75 (b, 4H,
2CH2), 4.20 (b, 2H, CH2), 4.54 (b, 2H, CH2), 7.51 (s, 1H,
ArH), 7.62–7.69 (m, 3H, ArH), 7.86 (d, J ¼ 9.2 Hz, 1H,
ArH), 7.94–8.01 (m, 2H, ArH), 8.22 (d, J ¼ 8.8 Hz, 1H,
ArH), 8.65–8.67 (m, 1H, ArH). HRMS (ESI, m/z): calcd for
C25H21ClN3O4 (MþHþ) 462.1221, found 462.1201.
1,2,3,4-Tetrahydro-3-(3-chlorobenzoyl)-5-(2,4-dichlorophe-
nyl)naphtho[2,1-c][2,7]naphthyridine (8c). This compound
was obtained as pale yellow crystals (0.805 g, 78%), mp
217ꢀ218ꢁC. IR (KBr): mmax 3058, 3022, 2944, 1641, 1588,
1562, 1518, 1477, 1460, 1439, 1380, 1360, 1343, 1321, 1263,
1228, 1170, 1131, 1099, 1049, 971, 906, 870, 834, 798, 781,
Ethyl
1,2-dihydro-5-phenylnaphtho[2,1-c][2,7]naphthyri-
dine-3(4H)-carboxylate (1n). This compound was obtained as
pale yellow crystals (0.634 g, 83%), mp 175ꢀ177ꢁC. IR
(KBr): mmax 3056, 2975, 2931, 2869, 1703, 1565, 1478, 1446,
1419, 1376, 1364, 1344, 1278, 1261, 1231, 1200, 1169, 1135,
1110, 1088, 1060, 1029, 954, 880, 853, 838, 782, 757, 737,
759, 745, 698 cmꢀ1 1H NMR (DMSO-d6): d 3.49–3.95 (m,
.
4H, 2CH2), 4.44–4.74 (m, 2H, CH2), 7.43–7.78 (m, 9H, ArH),
7.89 (d, J ¼ 8.8 Hz, 1H, ArH), 8.12–8.14 (m, 2H, ArH), 8.80
(s, 1H, ArH). HRMS (ESI, m/z): calcd for C29H19Cl3N2NaO
(MþNaþ) 539.0461, found 539.0456.
700 cmꢀ1 1H NMR (DMSO-d6): d 1.29 (b, 3H, CH3), 3.65–
.
3.66 (m, 2H, CH2), 3.73–3.75 (m, 2H, CH2), 4.20 (q, J ¼ 6.8
Hz, 2H, CH2), 4.74 (s, 2H, CH2), 7.47–7.60 (m, 5H, ArH),
7.64–7.68 (m, 2H, ArH), 7.93–8.00 (m, 3H, ArH), 8.60–8.63
(m, 1H, ArH). HRMS (ESI, m/z): calcd for C25H22N2NaO2
(MþNaþ) 405.1579, found 405.1579.
1,2,3,4-Tetrahydro-3-(3-chlorobenzoyl)-5-(4-nitrophenyl)-
naphtho[2,1-c][2,7]naphthyridine (8d). This compound was
obtained as pale yellow crystals (0.818 g, 83%), mp
133ꢀ134ꢁC. IR (KBr): mmax 3055, 2944, 2887, 2855, 1658,
1629, 1564, 1515, 1478, 1430, 1349, 1322, 1258, 1211, 1098,
Ethyl 1,2-dihydro-5-(2-fluorophenyl)naphtho[2,1-c][2,7]naph-
thyridine-3(4H)-carboxylate (1o). This compound was obtained
as pale yellow crystals (0.704 g, 88%), mp 95ꢀ97ꢁC. IR
(KBr): mmax 3059, 2990, 2964, 2902, 2851, 1701, 1616, 1579,
1561, 1528, 1489, 1438, 1385, 1365, 1247, 1216, 1141, 1046,
1045, 859, 837, 807, 757, 737, 701 cmꢀ1 1H NMR (DMSO-
.
d6): d 3.57–3.87 (m, 4H, 2CH2), 4.67–4.86 (m, 2H, CH2),
7.36–7.58 (m, 4H, ArH), 7.76–7.78(m, 2H, ArH), 7.91 (d, J ¼
8.8 Hz, 1H, ArH), 7.96–7.99 (m, 2H, ArH), 8.13 (d, J ¼ 9.2
Hz, 2H, ArH), 8.26–8.45 (m, 2H, ArH), 8.76–8.78 (m, 1H,
ArH). HRMS (ESI, m/z): calcd for C29H20ClN3NaO3
(MþNaþ) 516.1091, found 516.1099.
1024, 978, 951, 896, 858, 842, 814, 755 cmꢀ1 1H NMR
.
(DMSO-d6): d 1.22 (b, 3H, CH3), 3.60–3.74 (m, 4H, 2CH2),
4.08 (b, 2H, CH2O), 4.52 (b, 2H, CH2), 7.41–7.45 (m, 2H,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

1234
X.-S. Wang, Q. Li, J.-R. Wu, C.-S. Yao, and S.-J. Tu
Vol 46
werlen, C.; Surivet, J-P.; Zumbrunn, A. C. Chem Abstr 2007, 147,
386019; (b) Daines, R. A.; Price, A. T. WO2007016610 A2 (2007);
Daines, R. A.; Price, A. T. Chem Abstr 2007, 146, 229364.
[4] (a) Goerlitzer, K.; Bode, M.; Jones, P. G.; Jomaa, H.; Wies-
ner, J. Pharmazie 2007, 62, 15; (b) Auparakkitanon, S.; Chapoomram,
S.; Kuaha, K.; Chirachariyavej, T.; Wilairat, P. Antimicrob Agents
Chemother 2006, 50, 2197.
General procedure for the syntheses of binaphtho[2,1-c]
[2,7]naphthyridine 9. A dry 50-mL flask was charged with
terephthalaldehyde (1.0 mmol, 0.134 g), naphthalen-2-amine
(2.0 mmol, 0.286 g), ethyl 4-piperidinone-1-carboxylate (2.0
mmol, 0.342 g), I2 (0.05 mmol, 0.013 g), and THF (10 mL).
The reaction mixture was stirred at reflux for 10 h. After com-
pletion of the reaction, as indicated by TLC, a little DMF was
added to the mixture until the all yellow solid was dissolved.
The generated crystals were collected by filtration to give 9
when the mixture was cooled to room temperature.
[5] Daines, R. A.; Price, A. T. WO2007016610 A2
(2007);Daines, R. A.; Price, A. T. Chem Abstr 2007, 146, 229364.
[6] Atanasova, M.; Ilieva, S.; Galabov, B. Eur J Med Chem
2007, 42, 1184.
1,4-di(1,2,3,4-tetrahydro-3-ethoxycarbonyl-naphtho[2,1-c][2,7]
naphthyri-dine-5-yl)benzene (9). This compound was obtained
as pale yellow crystals (0.597 g, 87%), mp 249ꢀ250ꢁC. IR
(KBr): mmax 3054, 2987, 2872, 1708, 1564, 1479, 1449, 1419,
[7] Brehm, C.; Klein, T.; Buhr, W.; Chiesa, M. V.; Palmer, A.;
Zimmermann, P. J.; Simon, W-A.; Postius, S.; Kromer, W.; Grundler,
G. WO2006117316 A1 (2006);Brehm, C.; Klein, T.; Buhr, W.; Chiesa,
M. V.; Palmer, A.; Zimmermann, P. J.; Simon, W-A.; Postius, S.;
Kromer, W.; Grundler, G. Chem Abstr 2006, 145, 489254.
[8] Barta-Szalai, G.; Gere, A.; Takacs-Novak, K.; Domany, G.
Arzneimittelforschung 2003, 53, 722;Barta-Szalai, G.; Gere, A.;
Takacs-Novak, K.; Domany, G. Chem Abstr 2003, 140, 321254.
[9] Takeuchi, I.; Hamada, Y.; Okamura, K. Heterocycles 1989,
29, 2109.
1379, 1362, 1259, 1205, 1137, 1112, 1086, 853, 837, 752cmꢀ1
.
1H NMR (DMSO-d6): d 1.21–1.23 (b, 6H, 2CH3), 3.61–3.64
(m, 4H, 2CH2), 3.78–3.80 (m, 4H, 2CH2), 4.12 (q, J ¼ 6.8 Hz,
4H, 2CH2O), 4.80 (s, 4H, 2CH2), 7.75–7.77 (m, 4H, ArH), 7.83
(s, 4H, ArH), 7.95 (d, J ¼ 9.2 Hz, 2H, ArH), 8.12–8.15 (m, 4H,
ArH), 8.76–8.78 (m, 2H, ArH). HRMS (ESI, m/z): calcd for
C44H39N4O4 (MþHþ) 687.2971, found 687.2936.
[10] Takeuchi, I.; Hamada, Y.; Hirota, M. Chem Pharm Bull
1993, 41, 747.
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hara, Y.; Onikura, H.; Shibano, Y.; Watanabe, S.; Mikami, Y.; Kubo,
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ada, Y.; Hatano, K. Chem Pharm Bull 2000, 48, 755; (e) Takeuchi, I.;
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cycl Chem 1997, 34, 1233; (g) Vales, M.; Lokshin, V.; Pepe, G.;
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Acknowledgments. We thank the National Natural Science
foundation of China (20802061), the Natural Science foundation
(08KJD150019), and Qing Lan Project (08QLT001) of Jiangsu
Education Committee for financial support.
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet