ZnCl2-promoted intramolecular hetero-diels-alder reaction of o-alkynylphenylcarbodiimides for synthesis of dihydrodibenzo[b,g][1,8]-naphthyridines

Article abstract of DOI:10.1248/cpb.c16-00363

The ZnCl₂-promoted intramolecular hetero-Diels-Alder reaction of N-(ortho-propargylphenyl)-N'- arylcarbodiimides, in which the aryl-NC moiety functioned as a 2-azabuta-1,3-diene, 4π component, has been achieved. By this method, very rare 5,12-d

Full text of DOI:10.1248/cpb.c16-00363

1364
Chem. Pharm. Bull. 64, 1364–1369 (2016)
Vol. 64, No. 9
Regular Article
ZnCl2-Promoted Intramolecular Hetero-Diels–Alder Reaction of
o-Alkynylphenylcarbodiimides for Synthesis of Dihydrodibenzo[b,g][1,8]-
naphthyridines
,a,b
Noriki Kutsumura,* Yasuaki Koyama,b Kotaro Tateno,b Naoshi Yamamoto,a
,b
Hiroshi Nagase,a and Takao Saito*
a International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba; 1–1–1 Tennodai, Tsukuba,
b
Ibaraki 305–8575, Japan: and Department of Chemistry, Faculty of Science, Tokyo University of Science;
Kagurazaka, Shinjuku-ku, Tokyo 162–8601, Japan.
Received April 29, 2016; accepted May 31, 2016; advance publication released online June 16, 2016
The ZnCl2-promoted intramolecular hetero-Diels–Alder reaction of N-(ortho-propargylphenyl)-Nꢀ-
arylcarbodiimides, in which the aryl-N=C moiety functioned as a 2-azabuta-1,3-diene, 4π component, has
been achieved. By this method, very rare 5,12-dihydrodibenzo[b,g][1,8]naphthyridines and fully aromatized
dibenzo[b,g][1,8]naphthyridines were successfully synthesized.
Key words hetero-Diels–Alder; carbodiimide; naphthyridine; zinc chloride; heterocycle; one-pot
Indoloquinoline alkaloids are biologically attractive com- by-products 2-aminoquinolines 2 via 6π-electrocyclization.19)
pounds because they have potential uses as antifungal,1,2) anti- Therefore, the Lewis acid-promoted reaction under mild
bacterial,3) antimalarial,4,5) anticancer,6–8) anti-inflammatory,9) conditions offers a more effective method for the synthesis
and DNA intercalating agents,10–15) as well as inhibitors of of the intramolecular HDA products30) than obtained with
topoisomerase II.16,17) The intramolecular hetero-Diels–Alder thermal reactions. Based on this background of research, we
(HDA) reaction is a powerful synthetic method for such het- envisioned that the Lewis acid-promoted reaction of N-(ortho-
erocyclic compounds. For example, the intramolecular aza-DA propargylphenyl)-N′-arylcarbodiimides 331–34) would enable a
reactions of the carbon–carbon double or triple bond-conju- facile synthetic approach to the 5,12-dihydrodibenzo[b,g][1,8]-
gated diarylcarbodiimides under thermal conditions have been naphthyridine derivatives 435–39) (Chart 1, Eq. 2). Herein, we
reported for the synthesis of indolo[2,3-b]quinoline derivatives describe the results in detail.
1 by the Saito and Motoki,18,19) Molina and Alajarín,20–22)
We initially screened various Lewis and Brønsted acids
Wang,23–26) Pieters,27) and Schmittel28,29) groups (Chart 1, Eq. using 3a and d as model substrates. The selected data are
1). Furthermore, Saito et al. previously reported the Lewis shown in Table 1. As a result, the reactions of 3a and d in the
acid-controlled, highly periselective intramolecular aza-DA presence of 1.0eq of zinc chloride (1.0M in diethyl ether) at
reactions of the N-arylcarbodiimides with an inner carbon– room temperature gave the best results; 11-phenyl- and 11-pro-
carbon double bond dienophile, depressing the formation of pyl-5,12-dihydrodibenzo[b,g][1,8]naphthyridine 4a and m were
Chart 1. Intramolecular Ring-Forming Reactions of the Carbon–Carbon Double or Triple Bond Bearing Diarylcarbodiimides under Thermal or
Lewis Acid Conditions
*To whom correspondence should be addressed. e-mail: kutsumura.noriki.gn@u.tsukuba.ac.jp; tsaito@rs.kagu.tus.ac.jp
© 2016 The Pharmaceutical Society of Japan

Vol. 64, No. 9 (2016)
Chem. Pharm. Bull.
Table 2. Evaluation of Stoichiometry of ZnCl2 Used
1365
Table 1. Screening of Acids
Entry
R1 (S.M.)
Acids
AlCl3
Time (h) Product Yield (%)a)
Entry
X (eq)
Yield (%)a)
1
2
Ph (3a)
Ph (3a)
Ph (3a)
Ph (3a)
nPr (3d)
Ph (3a)
nPr (3d)
Ph (3a)
nPr (3d)
Ph (3a)
2.0
1.0
6.0
1.0
3.0
2.5
3.0
2.5
48.0
4.0
4a
4a
4a
4a
4m
4a
4m
4a
4m
4a
30
35
55
66
8
TiCl4
1b)
2
0.2
1.0
2.0
3.0
5.0
48
73
86
72
58
3
AgOTf
TfOH
4
3
5
TfOH
4
6
BF3·OEt2
BF3·OEt2
ZnCl2
71
40
73
67
65
5
7
a) Yields of isolated 4a. b) The reaction time was 24h and 3a was recovered
(25%).
8
9
ZnCl2
Δb)
10
generality of this one-pot reaction to give 4 using substrates
5 bearing a variety of substituents in R1 and para-R2-substit-
uents on phenyl isocyanates (R2=H, NO2, OMe, Me) (Table
3). In all cases, the initial aza-Wittig reactions of the imino-
phosphoranes 5 with the isocyanates proceeded smoothly at
room temperature for 1.0–4.0h to afford the corresponding
functionalized carbodiimides 3. Subsequent intramolecular
HDA reactions in one pot gave the desired 11-phenyl-5,12-
dihydrodibenzo[b,g][1,8]naphthyridine derivatives 4a–l in
good-to-excellent yields (61–99%) from 5a–d, when the sub-
stituted group R1 was an aromatic ring (Entries 1–12). On the
a) Yields of isolated 4. b) Reflux in toluene.
n
other hand, when R1 was the Pr group, the second intramo-
lecular HDA reaction notably required slightly longer reac-
tion times (Entries 13–16), resulting in lower yields of 4n–p
(Entries 14–16).
In addition, the aza-Wittig reaction of the iminophosphorane
5a with 2-thienyl isocyanate or trans-styryl isocyanate and the
following intramolecular HDA reaction in one pot also gave
4-phenyl-5,10-dihydrobenzo[b]thieno[3,2-g][1,8]naphthyridine
Fig. 1. X-Ray Structure of 11-Phenyl-5,12-dihydrodibenzo[b,g][1,8]-
naphthyridine 4a
satisfactorily obtained in 73 and 67% yields (Table 1, Entries 7 in 33% yield and 3,4-diphenyl-5,10-dihydrobenzo[b][1,8]-
8, 9). The both reaction systems were relatively clear, though naphthyridine 9 in 90% yield, respectively (Chart 2). It is
there was a difference in their reaction times. The thermal noteworthy that Saito et al.18) and Molina et al.21) separately
reaction was also performed for comparisons. However, the reported that the HDA reaction of N-(ortho-alkynylphenyl)-N′-
yield did not exceed 73% (Entry 8 vs. Entry 10). The chemi- 2-thienyl- and N′-trans-styryl-carbodiimides also proceeded
1
cal structures of 4a and m were determined by using H- and under thermal reaction conditions to produce indolo[2,3-b]-
13C-NMR spectroscopic analysis and X-ray crystallographic pyridine derivatives.
analysis of 4a40) (Fig. 1).
Moreover, since it was found that the dihydropyridine
Next, we examined appropriate amounts of zinc chloride in rings of products 4 were slowly aromatized in chloroform, we
this HDA reaction of 3a as shown in Table 2. When 0.2eq of therefore carried out oxidation of 4a with manganese dioxide
zinc chloride were used, the reaction proceeded very slowly in dichloromethane at an ambient temperature. Gratifyingly,
at room temperature and 25% of the starting material 3a 11-phenyl-dibenzo[b,g][1,8]naphthyridine 1036) was readily
remained even after 24h (Table 2, Entry 1). Treatment of 3a obtained in excellent yield (Chart 3). Such ring-fused aromatic
with 2.0eq of zinc chloride gave the desired 4a in higher yield N-containing molecules have the potential to intercalate into
(86%) than when only 1.0eq zinc chloride was used (Entries the DNA base stack as intercalator reagents by forming the
2, 3), whereas the use of 3.0 or 5.0eq of zinc chloride had ad- corresponding complexes.12,47)
verse effects on the yields of 4a (Entries 4, 5).
In addition, we incorporated our one-pot methodology41–43) ZnCl2-promoted intramolecular HDA reaction of N-(ortho-
into a series of these reactions to establish more efficient syn- propargylphenyl)-N′-arylcarbodiimides for unique and
In conclusion, we developed a one-pot aza-Wittig–
3
thetic method of 4. Specifically, we performed the aza-Wittig effective syntheses of the novel 5,12-dihydrodibenzo[b,g][1,8]-
reaction44–46) of iminophosphoranes 5 with aryl isocyanates naphthyridines 4 and the analogues 7 and 9.
and the following intramolecular HDA cyclization caused by
subsequent addition of zinc chloride in one pot under the same
Experimental
reaction conditions. After confirming that the one-pot reac-
General All melting points were determined on a Yanaco
tion proceeded without any difficulty, we next examined the MP melting point (mp) apparatus and are uncorrected. Infra-

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Chem. Pharm. Bull.
Vol. 64, No. 9 (2016)
Table 3. Synthesis of 5,12-Dihydrodibenzo[b,g][1,8]naphthyridines 4 via the One-Pot Aza-Wittig/ZnCl2-Promoted Intramolecular HDA Reaction
Entry
R1
R2
Time 1 (h)
Time 2 (h)
Product
Yield (%)a)
1
2
Ph (5a)
H
1.0
2.0
4.0
2.5
1.5
2.0
1.0
1.5
1.5
2.0
1.5
2.5
3.5
3.0
3.0
2.0
4.0
3.5
4a
4b
4c
4d
4e
4f
99
91
81
77
79
61
85
75
74
70
70
74
73
52
37
47
Ph (5a)
NO2
OMe
Me
3
Ph (5a)
5.0
4
Ph (5a)
2.5
5
p-CF3C6H4 (5b)
p-CF3C6H4 (5b)
p-CF3C6H4 (5b)
p-CF3C6H4 (5b)
p-Tolyl (5c)
p-Tolyl (5c)
p-Tolyl (5c)
p-Tolyl (5c)
nPr (5d)
H
17.0
22.0
11.0
44.0
2.0
6
NO2
OMe
Me
7
4g
4h
4i
8
9
H
10
11
12
13
14
15
16
NO2
OMe
Me
2.0
4j
2.0
4k
4l
2.5
H
48.0
48.0
48.0
48.0
4m
4n
4o
4p
nPr (5d)
NO2
OMe
Me
nPr (5d)
nPr (5d)
a) Yields of isolated 4 from 5 in a one-pot reaction.
Chart 3. Oxidation of 4a to the Aromatized Naphthyridine Derivative
10
are quoted in ppm using tetramethylsilane (δ=0ppm) as the
1
reference for H-NMR spectroscopy, and CDCl3 (δ=77.0ppm)
for 13C-NMR spectroscopy. Mass spectra were measured with
a Bruker Daltonics micrOTOF, a Hitachi double focusing
M-80B, or a JEOL JMS-T100LP spectrometer. Column chro-
matography was carried out on silica gel (spherical, neutral,
40–60µm, Kanto Chemical Co., Japan or Merck Co., Ltd.,
U.S.A.) or Aluminum oxide 90 active neutral (70–230 mesh
ASTM, Merck). All reactions were performed under an argon
atmosphere.
Typical Procedure for the ZnCl2-Promoted HDA Reac-
tion (the Diarylcarbodiimide 3a to the Dihydrodibenzo[b,g]-
[1,8]naphthyridine 4a, Table 2, Entry 3) A mixture of
3a (27.0mg, 0.088mmol) and zinc chloride (1.0M in Et2O,
0.18mL, 0.18mmol) in dichloromethane (2.0mL) was stirred
at room temperature for 2.5h. The reaction was quenched with
Chart 2. Synthesis of 5,10-Dihydrobenzonaphthyridines 7 and 9 via the
One-Pot Aza-Wittig/ZnCl2-Promoted Intramolecular HDA Reaction
red spectra were recorded with a Horiba FT-710 or a JASCO sat. aq NaHCO3 (15mL), and then mixture was extracted with
FT/IR 4100 spectrophotometer. 1H- and 13C-NMR spectral chloroform (20mL×3). The combined organic extracts were
data were obtained with JEOL JNM-ECS 400, JEOL JNM- washed with brine (30mL), dried (MgSO4), and concentrated
LA 500, or JEOL JNM-AL 300 instruments. Chemical shifts in vacuo. The residue was purified by silica gel column chro-

Vol. 64, No. 9 (2016)
Chem. Pharm. Bull.
1367
matography (hexane–ethyl acetate=10:1) to afford 4a as yel- 3.4Hz), 8.07 (1H, brs) ppm; 13C-NMR (100MHz, CDCl3) δ:
low crystals (23.1mg, 86%). 21.4, 30.1, 114.0, 115.4, 119.5, 121.1, 125.1, 125.4, 125.9, 127.3,
Typical Procedure for aza-Wittig Reaction/the ZnCl2- 128.0, 128.4, 128.8 (×2), 129.0 (×2), 131.2, 132.5, 136.6, 138.7,
Promoted HDA Reaction in One Pot (the Iminophospho- 144.6, 146.6, 151.2ppm; IR (KBr) ν 3449, 1585, 751cm−1;
rane 5a to the Dihydrodibenzo[b,g][1,8]naphthyridine 4a, HR-MS (ESI m/z) Calcd for C23H19N2 (M+H+) 323.1548.
Table 3, Entry 1) A mixture of 5a (56.7mg, 0.121mmol) and Found 323.1553.
phenyl isocyanate (13.2µL, 0.121mmol) in dichloromethane
11-[4-(Trifluoromethyl)phenyl]-5,12-dihydrodibenzo-
(1.2mL) was stirred at room temperature for 1.0h. After con- [b,g][1,8]naphthyridine (4e) Yellow crystals; mp 216.2–
firming the consumption of 5a by TLC, zinc chloride (1.0M in 217.3°C; 1H-NMR (300MHz, CDCl3) δ: 3.91 (2H, s), 6.73
Et2O, 0.24mL, 0.24mmol) was added to the reaction mixture (1H, d, J=8.2Hz), 6.86 (1H, dd, J=7.6, 7.2Hz), 6.99 (1H, d,
at room temperature, and the mixture was stirred for 4h. The J=7.2Hz), 7.08–7.20 (3H, m), 7.45 (2H, d, J=7.9Hz), 7.55 (1H,
reaction was quenched with sat. aq NaOH (1.0M, 4.0mL), and ddd, J=8.2, 7.9, 2.5Hz), 7.73 (1H, brs), 7.75 (1H, d, J=8.5Hz),
then mixture was extracted with chloroform (10mL×3). The 7.86 (2H, d, J=7.9Hz) ppm; 13C-NMR (75MHz, CDCl3) δ:
combined organic extracts were washed with brine (10mL), 30.1, 114.1, 115.4, 119.1, 121.5, 123.1 (q, J=271.3Hz), 123.3,
dried (MgSO4), and concentrated in vacuo. The residue was 125.0, 125.6, 125.9 (×2, q, J=3.6Hz), 126.3, 127.6, 128.4,
purified by silica gel column chromatography (hexane–ethyl 129.5 (×2), 130.5 (q, J=32.5Hz), 137.7, 138.2, 140.3, 145.5,
acetate=10:1) to afford 4a as yellow crystals (37.3mg, 99%).
146.3, 151.5ppm; IR (KBr) ν 3419, 1425, 1331, 1068, 756cm−1;
11-Phenyl-5,12-dihydrodibenzo[b,g][1,8]naphthyridine HR-MS (ESI m/z) Calcd for C23H16F3N2 (M+H+) 377.1260.
1
(4a) Yellow crystals; mp 196.4–196.9°C; H-NMR (500MHz, Found 377.1258.
CDCl3) δ: 3.95 (2H, s), 6.70 (1H, d, J=7.7Hz), 6.81 (1H, dd,
9 -Nit ro -11-[4 - (t r i f luoromethyl)phenyl]- 5,12 -
J=7.4, 7.4Hz), 6.96 (1H, d, J=7.4Hz), 7.04 (1H, dd, J=7.7, dihydrodibenzo[b,g][1,8]naphthyridine (4f) Red crystals;
1
7.4Hz), 7.14 (1H, dd, J=8.0, 7.4Hz), 7.24 (1H, d, J=8.0Hz), mp 203.0–203.4°C; H-NMR (300MHz, CDCl3) δ: 3.95 (2H,
7.30 (2H, d, J=8.0Hz), 7.51 (2H, dd, J=7.8, 7.4Hz), 7.59 (2H, s), 6.79 (1H, d, J=8.2Hz), 6.93 (1H, dd, J=7.3, 6.8Hz), 7.01
dd, J=7.8, 7.4Hz), 7.77 (1H, d, J=7.7Hz), 8.47 (1H, brs) ppm; (1H, d, J=6.8Hz), 7.16 (1H, dd, J=8.2, 7.3Hz), 7.46 (2H, d,
13C-NMR (125MHz, CDCl3) δ: 30.1, 114.1, 115.5, 119.5, 121.2, J=8.0Hz), 7.67 (1H, brs), 7.75 (1H, d, J=9.0Hz), 7.92 (2H,
122.9, 125.5, 126.0, 126.1, 127.3, 128.0, 128.4, 128.8 (×2), d, J=8.0Hz), 8.07 (1H, d, J=2.3Hz), 8.32 (1H, dd, J=9.0,
129.0 (×2), 129.1, 136.5, 138.5, 146.2, 147.2, 151.94ppm; IR 2.3Hz) ppm; 13C-NMR (75MHz, CDCl3) δ: 30.0, 114.6, 117.8,
(KBr) ν 3294, 1574, 756cm−1; high resolution (HR)-MS (elec- 118.9, 122.5, 122.7, 123.6, 123.8, 126.5 (×2, q, J=3.8Hz),
trospray ionization (ESI) m/z) Calcd for C22H17N2 (M+H+) 126.9 (q, J=270.1Hz), 127.2, 127.9, 128.6, 129.3 (×2), 130.9
309.1386. Found 309.1382.
(q, J=32.2Hz), 136.8, 138.6, 142.9, 146.9, 150.0, 153.6ppm; IR
9-Nitro-11-phenyl-5,12-dihydrodibenzo[b,g][1,8]naph- (KBr) ν 3433, 1581, 1419, 1327, 748cm−1; HR-MS (ESI m/z)
thyridine (4b) Red crystals; mp 228.1–229.0°C; 1H-NMR Calcd for C23H15F3N2O2 (M+H+) 422.1111. Found 422.1112.
(500MHz, CDCl3) δ: 3.99 (2H, s), 6.74 (1H, d, J=8.2Hz), 6.91
9-Methoxy-11-[4-(trif luoromethyl)phenyl]-5,12-
(1H, dd, J=7.7, 7.2Hz), 7.00 (1H, d, J=7.7Hz), 7.12 (1H, dd, dihydrodibenzo[b,g][1,8]naphthyridine (4g) Brown crys-
1
J=8.2, 7.2Hz), 7.30 (2H, d, J=6.7Hz), 7.58–7.65 (3H, m), 7.73 tals; mp 218.5–219.7°C; H-NMR (300MHz, CDCl3) δ: 3.68
(1H, d, J=9.0Hz), 8.11 (1H, brs), 8.17 (1H, d, J=2.3Hz), 8.29 (3H, s), 3.88 (2H, s), 6.47 (1H, d, J=2.7Hz), 6.72 (1H, d,
(1H, dd, J=9.0, 2.3Hz) ppm; 13C-NMR (125MHz, CDCl3) J=7.7Hz), 6.85 (1H, dd, J=7.4, 7.1Hz), 6.98 (1H, d, J=7.4Hz),
δ: 30.2, 114.7, 118.0, 119.7, 122.7, 123.3, 123.6, 124.7, 127.3, 7.10 (1H, dd, J=7.7, 7.1Hz), 7.24 (1H, dd, J=9.2, 2.7Hz), 7.46
128.0, 128.9, 128.9 (×2), 129.2, 129.6 (×2), 135.0, 137.3, (2H, d, J=8.0Hz), 7.56 (1H, brs), 7.69 (1H, d, J=9.2Hz),
149.1, 148.9, 150.0, 154.1ppm; IR (KBr) ν 3390, 3026, 1581, 7.86 (2H, d, J=8.0Hz) ppm; 13C-NMR (75MHz, CDCl3) δ:
1419 cm−1; HR-MS (ESI m/z) Calcd for C22H16N3O2 (M+H+) 30.2, 55.4, 105.1, 113.9, 115.7, 119.0, 120.1, 121.2, 125.4, 126.0
354.1237. Found 354.1246.
(×2, q, J=3.8Hz), 127.5, 127.8, 128.4, 129.5 (×2), 130.4 (q,
9-Methoxy-11-phenyl-5,12-dihydrodibenzo[b,g][1,8]naph- J=30.7Hz), 130.3 (q, J=267.7Hz), 138.6, 140.5, 141.8, 144.5,
1
thyridine (4c) Brown crystals; mp 179.7–180.3°C; H-NMR 150.1, 155.6ppm; IR (KBr) ν 3433, 3286, 1489, 1327cm−1;
(500MHz, CDCl3) δ: 3.66 (3H, s), 3.92 (2H, s), 6.58 (1H, d, HR-MS (ESI m/z) Calcd for C24H18F3N2O (M+H+) 407.1366.
J=2.3Hz), 6.70 (1H, d, J=7.6Hz), 6.81 (1H, dd, J=7.7, 7.4Hz), Found 407.1366.
6.95 (1H, d, J=7.7Hz), 7.06 (1H, dd, J=7.6, 7.4Hz), 7.21 (1H,
9-Methyl-11-[4 -(trif luoromethyl)phenyl]-5,12-
dd, J=9.2, 2.3Hz), 7.30 (2H, d, J=7.3Hz), 7.51 (1H, dd, J=7.3, dihydrodibenzo[b,g][1,8]naphthyridine (4h) Yellow crys-
1
7.3Hz), 7.57 (2H, dd, J=7.3, 7.3Hz), 7.68 (1H, d, J=9.2Hz), tals; mp 212.2–214.0°C; H-NMR (400MHz, CDCl3) δ: 2.34
7.98 (1H, brs) ppm; 13C-NMR (125MHz, CDCl3) δ: 30.2, 55.3, (3H, s), 3.88 (2H, s), 6.71 (1H, d, J=7.8Hz), 6.84 (1H, dd,
105.6, 113.9, 115.7, 119.4, 120.3, 121.0, 126.0, 127.3, 127.5, J=7.4, 7.3Hz), 6.88 (1H, s), 6.98 (1H, d, J=7.3Hz), 7.08
128.1, 128.4, 128.9 (×2), 128.9 (×2), 136.6, 138.8, 141.7, 146.2, (1H, dd, J=7.8, 7.4Hz), 7.38 (1H, d, J=8.2Hz), 7.44 (2H, d,
150.4, 155.3ppm; IR (KBr) ν 3440, 1489, 1412, 748cm−1; J=7.8Hz), 7.66 (1H, d, J=8.7Hz), 7.86 (2H, d, J=7.8Hz),
HR-MS (ESI m/z) Calcd for C23H19N2O (M+H+) 339.1492. 7.90 (1H, brs) ppm; 13C-NMR (100MHz, CDCl3) δ: 21.4,
Found 339.1492.
30.1, 114.0, 115.4, 119.1, 121.3, 124.1 (q, J=272.2Hz), 124.6,
9-Methyl-11-phenyl-5,12-dihydrodibenzo[b,g][1,8]naph- 124.8, 125.9 (×2, q, J=2.9Hz), 126.1, 127.5, 128.4, 129.5 (×2),
thyridine (4d) Yellow amorphous; 1H-NMR (400MHz, 130.3 (q, J=32.6Hz), 131.5, 133.0, 138.4, 140.5, 144.6, 145.0,
CDCl3) δ: 2.32 (3H, s), 3.92 (2H, s), 6.70 (1H, d, J=7.8Hz), 151.1ppm; IR (KBr) ν 3434, 2925, 1587, 749cm−1; HR-MS
6.82 (1H, dd, J=7.5, 7.3Hz), 6.95 (1H, d, J=7.3Hz), 6.99 (1H, (ESI m/z) Calcd for C24H18F3N2 (M+H+) 391.1422. Found
s), 7.06 (1H, dd, J=7.8, 7.5Hz), 7.29 (2H, d, J=6.9Hz), 7.36 391.1418.
(1H, d, J=8.7Hz), 7.50–7.60 (3H, m), 7.66 (1H, dd, J=8.7,
11-(p-Tolyl)-5,12-dihydrodibenzo[b,g][1,8]naphthyridine

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Vol. 64, No. 9 (2016)
1
(4i) Yellow amorphous; H-NMR (400MHz, CDCl3) δ: 2.50
9-Nitro-11-propyl-5,12-dihydrodibenzo[b,g][1,8]naphthy-
(3H, s), 3.96 (2H, s), 6.71 (1H, d, J=7.8Hz), 6.83 (1H, dd, ridine (4n) Yellow crystals; mp 269.9–271.2°C; 1H-NMR
J=7.8, 7.5Hz), 6.97 (1H, d, J=7.8Hz), 7.07 (1H, dd, J=7.8, (300MHz, CDCl3) δ: 1.19 (3H, t, J=7.3Hz), 1.71 (2H, qt,
7.3Hz), 7.15 (1H, dd, J=8.2, 7.5Hz), 7.19 (2H, d, J=7.8Hz), J=8.2, 7.3Hz), 3.06 (2H, t, J=8.2Hz), 4.34 (2H, s), 6.77 (1H,
7.27 (1H, d, J=8.2Hz), 7.38 (2H, d, J=7.8Hz), 7.51 (1H, dd, d, J=7.7Hz), 7.00 (1H, dd, J=7.8, 7.1Hz), 7.19 (1H, dd, J=7.7,
J=8.2, 6.9Hz), 7.74 (1H, d, J=8.2Hz), 8.00 (1H, brs) ppm; 7.1Hz), 7.23 (1H, d, J=7.8Hz), 7.47 (1H, brs), 7.69 (1H, d,
13C-NMR (100MHz, CDCl3) δ: 21.4, 30.1, 114.0, 115.5, 119.6, J=9.4Hz), 8.32 (1H, dd, J=9.4, 2.5Hz), 8.80 (1H, d, J=2.5Hz)
121.3, 122.9, 125.7, 126.09, 126.11, 127.3, 128.4, 128.8 (×2), ppm; 13C-NMR (75MHz, CDCl3) δ: 14.6, 22.9, 28.9, 29.9,
129.1, 129.5 (×2), 133.3, 137.8, 138.5, 146.3, 147.3, 151.8ppm; 114.4, 117.1, 119.2, 120.8, 122.4, 123.0, 123.6, 127.7, 127.9,
IR (NaCl) ν 2922, 1585, 751cm−1; HR-MS (ESI m/z) Calcd for 128.7, 137.1, 142.8, 148.0, 150.2, 153.4ppm; IR (KBr) ν 3439,
C23H19N2 (M+H+) 323.1548. Found 323.1544.
9-Nitro-11-(p-tolyl)-5,12-dihydrodibenzo[b,g][1,8]naph- (M+H+) 320.1394. Found 320.1398.
thyridine (4j) Yellow amorphous; 1H-NMR (400MHz,
9-Methoxy-11-propyl-5,12-dihydrodibenzo[b,g][1,8]naph-
1652, 1332, 468cm−1; HR-MS (ESI m/z) Calcd for C19H18N2O2
1
CDCl3) δ: 2.53 (3H, s), 4.01 (2H, s), 6.74 (1H, d, J=7.8Hz), thyridine (4o) Yellow crystals; mp 174.2–175.3°C; H-NMR
6.91 (1H, dd, J=7.3, 7.2Hz), 7.00 (1H, d, J=7.2Hz), 7.12 (300MHz, CDCl3) δ: 1.13 (3H, t, J=7.3Hz), 1.71 (2H, qt,
(1H, dd, J=7.8, 7.3Hz), 7.18 (2H, d, J=7.8Hz), 7.43 (2H, d, J=7.8, 7.3Hz), 2.97 (2H, t, J=7.8Hz), 3.91 (3H, s), 4.26 (2H,
J=7.8Hz), 7.74 (1H, d, J=9.2Hz), 8.11 (1H, brs), 8.20 (1H, s), 6.67 (1H, d, J=8.0Hz), 6.87 (1H, dd, J=7.5, 7.2Hz), 7.09
d, J=2.8Hz), 8.29 (1H, dd, J=9.2, 2.8Hz) ppm; 13C-NMR (1H, dd, J=8.0, 7.2Hz), 7.16 (1H, d, J=7.5Hz), 7.17 (1H, d,
(100MHz, CDCl3) δ: 21.4, 30.0, 114.4, 117.8, 119.5, 122.5, J=2.6Hz), 7.21 (1H, dd, J=8.6, 2.6Hz), 7.63 (1H, d, J=8.6Hz),
123.20, 123.24, 124.6, 126.9, 127.7, 128.56 (×2), 128.60, 130.0 7.70 (1H, brs) ppm; 13C-NMR (75MHz, CDCl3) δ: 14.4, 22.0,
(×2), 131.6, 137.1, 138.8, 142.8, 148.9, 149.7, 153.8ppm; IR 28.8, 29.7, 55.2, 103.4, 113.6, 115.1, 118.9, 119.5, 120.6, 125.0,
(KBr) ν 3422, 2923, 1580, 748cm−1; HR-MS (ESI m/z) Calcd 127.2, 127.8, 128.2, 138.5, 141.4, 144.8, 149.8, 155.1ppm; IR
for C23H18N3O2 (M+H+) 368.1399. Found 368.1394.
9-Methoxy-11-(p-tolyl)-5,12-dihydrodibenzo[b,g][1,8]- Calcd for C20H21N2O (M+H+) 305.1648. Found 305.1651.
naphthyridine (4k) Yellow crystals; mp 201.2–203.1°C; 9-Methyl-11-propyl-5,12-dihydrodibenzo[b,g][1,8]naph-
(KBr) ν 3432, 2954, 1589, 1496, 748cm−1; HR-MS (ESI m/z)
1
1H-NMR (400MHz, CDCl3) δ: 2.50 (3H, s), 3.68 (3H, s), 3.92 thyridine (4p) Yellow crystals; mp 226.6–228.0°C; H-NMR
(2H, s), 6.61 (1H, d, J=2.8Hz), 6.69 (1H, d, J=7.6Hz), 6.82 (400MHz, CDCl3) δ: 1.14 (3H, t, J=7.3Hz), 1.64–1.74 (2H, m),
(1H, dd, J=7.4, 7.3Hz), 6.97 (1H, d, J=7.3Hz), 7.07 (1H, dd, 2.49 (3H, s), 2.98 (2H, t, J=8.2Hz), 4.25 (2H, s), 6.67 (1H, d,
J=7.6, 7.4Hz), 7.18 (2H, d, J=7.9Hz), 7.19 (1H, dd, J=8.9, J=7.8Hz), 6.88 (1H, dd, J=7.4, 7.3Hz), 7.09 (1H, dd, J=7.8,
3.2Hz), 7.37 (2H, d, J=7.9Hz), 7.50 (1H, brs), 7.64 (1H, d, 7.4Hz), 7.16 (1H, d, J=7.3Hz), 7.35 (1H, dd, J=8.5, 1.4Hz),
J=8.9Hz) ppm; 13C-NMR (100MHz, CDCl3) δ: 21.4, 30.2, 7.590 (1H, s), 7.592 (1H, d, J=8.5Hz), 7.69 (1H, brs) ppm;
55.4, 105.6, 113.8, 115.7, 119.5, 120.3, 121.0, 126.2, 127.3, 13C-NMR (100MHz, CDCl3) δ: 14.6, 21.7, 22.6, 29.0, 29.7,
127.4, 128.4, 128.8 (×2), 129.6 (×2), 133.4, 137.8, 138.8, 113.8, 114.9, 119.3, 120.9, 122.7, 124.6, 126.5, 127.4, 128.5,
141.7, 146.3, 150.2, 155.3ppm; IR (KBr) ν 3423, 2922, 1585, 130.8, 132.3, 138.7, 144.6, 145.6, 150.9ppm; IR (KBr) ν 3448,
752 cm−1; HR-MS (ESI m/z) Calcd for C24H21N2O (M+H+) 2958, 1591, 745cm−1; HR-MS (ESI m/z) Calcd for C20H21N2
353.1654. Found 353.1652.
9-Methyl-11-(p-tolyl)-5,12-dihydrodibenzo[b,g][1,8]naph-
(M+H+) 289.1705. Found 289.1700.
4-Phenyl-5,10-dihydrobenzo[b]thieno[3,2-g][1,8]naphthy-
thyridine (4l) Yellow amorphous; 1H-NMR (400MHz, ridine (7) Brown amorphous; H-NMR (400MHz, CDCl3)
CDCl3) δ: 2.33 (3H, s), 2.51 (3H, s), 3.92 (2H, s), 6.70 (1H, d, δ: 3.99 (2H, s), 6.74 (1H, d, J=8.0Hz), 6.78 (1H, d, J=6.0Hz),
J=8.0Hz), 6.82 (1H, dd, J=7.4, 7.3Hz), 6.96 (1H, d, J=7.3Hz), 6.85 (1H, dd, J=7.4, 7.3Hz), 6.98 (1H, d, J=7.3Hz), 7.06 (1H,
7.02 (1H, s), 7.06 (1H, dd, J=8.0, 7.4Hz), 7.18 (2H, d, d, J=6.0Hz), 7.09 (1H, brs), 7.10 (1H, dd, J=8.0, 7.4Hz),
J=7.8Hz), 7.34 (1H, dd, J=8.2, 1.8Hz), 7.38 (2H, d, J=7.8Hz), 7.36 (2H, ddd, J=6.4, 2.3, 1.4Hz), 7.41–7.57 (3H, m) ppm;
7.65 (1H, d, J=8.2Hz), 7.86 (1H, brs) ppm; 13C-NMR 13C-NMR (100MHz, CDCl3) δ: 29.4, 110.3, 113.9, 119.5,
(100MHz, CDCl3) δ: 21.4 (×2), 30.1, 113.9, 115.4, 119.6, 121.1, 120.9, 121.36, 121.40, 127.3, 127.7, 128.2, 128.4, 128.6 (×2),
125.1, 125.6, 125.9, 127.3, 128.4, 128.8 (×2), 129.5 (×2), 131.1, 128.7 (×2), 136.8, 138.8, 144.5, 151.0, 158.4ppm; IR (NaCl) ν
132.5, 133.5, 137.7, 138.7, 144.6, 146.7, 151.2ppm; IR (KBr) 3247, 2926, 1564cm−1; HR-MS (ESI m/z) Calcd for C20H15N2S
ν 3423, 2919, 1586, 747cm−1; HR-MS (ESI m/z) Calcd for (M+H+) 315.0956. Found 315.0944.
1
C24H21N2 (M+H+) 337.1705. Found 337.1712.
3,4-Diphenyl-5,10-dihydrobenzo[b][1,8]naphthyridine (9)
11-Propyl-5,12-dihydrodibenzo[b,g][1,8]naphthyri- Yellow crystals; mp 230.4–231.0°C; 1H-NMR (500MHz,
dine (4m) Yellow crystals; mp 156.3–157.0°C; 1H-NMR CDCl3) δ: 3.89 (2H, s), 6.74 (1H, d, J=7.8Hz), 6.83 (1H, dd,
(500MHz, CDCl3) δ: 1.14 (3H, t, J=7.4Hz), 1.70 (2H, qt, J=7.5, 7.4Hz), 6.94 (1H, d, J=7.4Hz), 7.02 (2H, dd, J=7.3,
J=8.0, 7.4Hz), 3.00 (2H, t, J=8.0Hz), 4.28 (2H, s), 6.70 (1H, 1.7Hz), 7.07–7.11 (3H, m), 7.13–7.17 (3H, m), 7.25 (1H, brs),
d, J=7.8Hz), 6.90 (1H, dd, J=7.5, 7.2Hz), 7.11 (1H, dd, J=7.8, 7.28–7.33 (3H, m), 8.10 (1H, s) ppm; 13C-NMR (125MHz,
7.2Hz), 7.18 (1H, d, J=7.5Hz), 7.29 (1H, dd, J=8.2, 7.5Hz), CDCl3) δ: 29.8, 112.6, 113.8, 119.4, 121.3, 126.3, 127.3, 127.4,
7.52 (1H, dd, J=8.1, 7.5Hz), 7.52 (1H, brs), 7.68 (1H, d, 127.8 (×2), 128.2 (×2), 128.5, 129.3 (×2), 129.7 (×2), 130.5,
J=8.1, Hz), 7.84 (1H, d, J=8.2Hz) ppm; 13C-NMR (125MHz, 137.2, 138.3, 138.9, 146.4, 148.2, 152.1ppm; IR (KBr) ν 3410,
CDCl3) δ: 14.6, 22.7, 28.9, 29.8, 113.9, 115.0, 119.3, 121.2, 3248, 3024, 1412, 748cm−1; HR-MS (ESI m/z) Calcd for
122.9, 123.6, 124.8, 126.8, 127.5, 128.5, 128.9, 138.4, 146.2, C24H19N2 (M+H+) 335.1548. Found 335.1540.
146.4, 151.3ppm; IR (KBr) ν 3448, 2954, 1589, 1427, 748cm−1;
HR-MS (ESI m/z) Calcd for C19H19N2 (M+H+) 275.1543. and manganese dioxide (90% active, 71.0mg, 0.735mmol) in
Found 275.1545. dichloromethane (0.7mL) was stirred at room temperature for
Synthesis of 10 A mixture of 4a (22.7mg, 0.0736mmol)

Vol. 64, No. 9 (2016)
Chem. Pharm. Bull.
1369
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1h, and filtered through a Celite pad. The filtrate was evapo-
rated and purified by aluminum oxide column chromatogra-
phy (hexane–ethyl acetate=2:1) to afford 10 (21.0mg, 93%) as
a red amorphous.
11-Phenyldibenzo[b,g][1,8]naphthyridine
(10)36) Red
1
amorphous; H-NMR (300MHz, CDCl3) δ: 7.38–7.47 (2H, m),
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Conflict of Interest The authors declare no conflict of
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