Synthesis of 2,4,8-trisubstituted 1,7-naphthyridines by the reaction of 4-(1-aryl-2-methoxyethenyl)-3-isocyanopyridines with excess organolithiums

Article abstract of DOI:10.1002/hlca.201000214

A convenient method for the synthesis of 2,4,8-trisubstituted 1,7-naphthyridines 6 by the reaction of (E)-4-(1-aryl-2-methoxyethenyl)-3- isocyanopyridines 4, which could be easily prepared from commercially available 3-aminopyridine via aroylation of lithium (4-lithiopyridin-3-yl)pivalamide with N-methoxy-N-methylbenzamides, with excess organolithiums has been developed.

Full text of DOI:10.1002/hlca.201000214

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Synthesis of 2,4,8-Trisubstituted 1,7-Naphthyridines by the
Reaction of 4-(1-Aryl-2-methoxyethenyl)-3-isocyanopyridines with
Excess Organolithiums
by Kazuhiro Kobayashi*, Taketoshi Kozuki, Shuhei Fukamachi, and Hisatoshi Konishi
Division of Applied Chemistry, Department of Chemistry and Biotechnology, Graduate School
of Engineering, Tottori University, 4-101 Koyama-minami, Tottori 680-8552, Japan
(phone/fax: þ 81-857-315263; e-mail: kkoba@chem.tottori-u.ac.jp)
A convenient method for the synthesis of 2,4,8-trisubstituted 1,7-naphthyridines 6 by the reaction of
(E)-4-(1-aryl-2-methoxyethenyl)-3-isocyanopyridines 4, which could be easily prepared from commer-
cially available 3-aminopyridine via aroylation of lithium (4-lithiopyridin-3-yl)pivalamide with N-
methoxy-N-methylbenzamides, with excess organolithiums has been developed.
Introduction. – In previous papers, we reported an efficient synthesis of 2,4-
disubstituted quinolines by the reaction of 1-(1-aryl-2-methoxyethenyl)-2-isocyano-
benzenes with various organolithiums [1]. We anticipated that the use of 4-(1-aryl-2-
methoxyethenyl)-3-isocyanopyridines 4 in place of 1-(1-aryl-2-methoxyethenyl)-2-
isocyanobenzenes would give 2,4-disubstituted 1,7-naphthyridines. In this article, we
report the results of our study on reactions of 4 with organolithiums. We found that 2,4-
disubstituted naphthyridines could not be prepared satisfactorily, but that 2,4,8-
trisubstituted naphthyridines 6 were obtained instead in reasonable yields by reacting 4
with excess organolithiums. 1,7-Naphthyridine derivatives have attracted considerable
attention, mainly because some of these derivatives exhibit significant biological
activities [2]. Although several efficient methods for the preparation of this class of
heterocycles have been reported [3]1), to date, there are no examples of the synthesis
of 2,4,8-trisubstitued derivatives in the literature.
Results and Discussion. – 3-Aminopyridin-4-yl aryl ketones 1, which could be easily
prepared from commercially available 3-aminopyridine using the reaction of lithium
(4-lithiopyridin-3-yl)pivalamide [4] with N-methoxy-N-methylbenzamides as descri-
bed in the Exper. Part, were converted to (E)-4-(1-aryl-2-methoxyethenyl)-3-isocya-
nopyridines 4 via the route illustrated in Scheme 1. The first step was N-formylation of
amino ketones 1 with HCOOH in the presence of Ac2O at 08 to form N-(4-
aroylpyridin-3-yl)formamides 2. Dehydration of these formamides to form the
corresponding isocyano derivatives 3 was accomplished on treatment with POCl3 in
THF in the presence of Et3N as a base at 08. These isocyano ketones were allowed to
1
)
See also pertinent references cited in [2].
ꢀ 2010 Verlag Helvetica Chimica Acta AG, Zꢁrich

Helvetica Chimica Acta – Vol. 93 (2010)
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Scheme 1
react with (methoxymethyl)triphenylphosphonium chloride in THF at 08 to give 4; in
each case, the (E)-isomer was obtained exclusively.
First, the reaction of (E)-3-isocyano-4-(2-methoxy-1-phenylethenyl)pyridine (4a)
with PhLi was examined. Thus, 4a was treated with an equimolar amount of PhLi in 1,2-
dimethoxyethane (DME) at ꢀ 788 for 3 h, as shown in Scheme 2. After the usual
aqueous workup, only a trace amount of 2,4-diphenylnaphthyridine (5) was obtained,
and the starting material 4a was recovered almost quantitatively (Table 1, Entry 1). An
Scheme 2
Table 1. Results of Reactions of 4a with PhLi in DME at ꢀ 788
Entry
PhLi [equiv.]
Yield of 5 [%]a)
Yield of 6a [%]a)
1
2
3
4
1
2
3
4
trace
14
7
0
4
25
47
0
a) Yields of isolated products.

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Helvetica Chimica Acta – Vol. 93 (2010)
extended reaction time and/or a higher reaction temperature (08) led to similar results.
Interestingly, use of 2 mol-equiv. of PhLi under similar conditions resulted in the
formation of 2,4,8-triphenyl-1,7-naphthyridine (6a) in 4% yield along with 14% of 5a
(Entry 2). We assumed that the formation of 6a was due to the preference of the
addition of the second molecule of PhLi to C(8) of 5a. For this reason, we focused our
efforts on obtaining 6a as the sole product in a reasonable yield. Compound 4a was
allowed to react with 3 mol-equiv. of PhLi to give 6a in 25% yield along with 7% of 5a
(Entry 3). Subsequently, we found that treatment of 4a with 4 mol-equiv. of PhLi gave
6a in 47% yield after column chromatography on silica gel (Entry 4); no trace of 5a was
detected.
To examine the generality of the present procedure, we conducted reactions using
four (E)-4-(1-aryl-2-methoxyethenyl)-3-isocyanopyridines 4 including 4a and six
organolithiums including PhLi under the conditions given in Table 1, Entry 4, as
shown in Scheme 3, and obtained ten 2,4,8-disubstituted 1,7-naphthyridines including
6a. The results are summarized in Table 2, which indicates that yields of the desired
products, 2,4,8-trisubstituted 1,7-naphthyridines 6, are generally modest. When
alkyllithiums, such as BuLi and MeLi (Entries 2 and 7, resp.), were used, the yields
of the corresponding products 6b and 6g are significantly lower than those with
aryllithiums. It should be noted that there is no significant difference in yields between
substrates 4 with an a-aryl substituent containing electron-donating or electron-
withdrawing groups.
Scheme 3
Table 2. Preparation of 1,7-Naphthyridines 6
Entry
4
R in RLi
Ar
6
Yielda) [%]
1
2
3
4
5
6
7
8
9
4a
4a
4b
4b
4b
4c
4c
4c
4d
4d
Ph
Bu
Ph
Ph
Ph
p-Tol
p-Tol
6a
6b
6c
6d
6e
6f
6g
6h
6i
47
25
45
43
47
48
25
47
43
46
4-ClꢀC6H4
4-MeOꢀC6H4
Ph
Me
p-Tol
p-Tol
3-ClꢀC6H4
3-ClꢀC6H4
3-ClꢀC6H4
4-MeOꢀC6H4
4-MeOꢀC6H4
Ph
10
4-ClꢀC6H4
6j
a) Yields of isolated products.

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A possible mechanism for the formation of 1,7-naphthyridines 6 from 4 and
organolithiums starts with the addition of 1 equiv. of organolithium compound to the
isocyano C-atom of 4, which generates the imidoyl anion intermediates 7 (Scheme 4).
Then, the 1,7-naphthyridine skeleton 8 is formed by the intramolecular attack of this
anion to the C(a)-atom of the methoxyethenyl moiety with loss of MeOLi.
Subsequently, 8 is attacked by a second equiv. of the organolithium compound at
C(8) to form the intermediate 9, from which elimination of LiH gives rise to 6.
Alternatively, formation of 6 may be accomplished by dehydrogenation of 7,8-dihydro-
1,7-naphthyridines, formed by protonation of 9, during workup and/or isolation
procedures.
Scheme 4
In conclusion, we have demonstrated that 2,4,8-trisubstituted 1,7-naphthyridines
could be prepared by the reaction of (E)-4-(1-aryl-2-methoxyethenyl)-3-isocyanopyr-
idines with excess amounts of organolithiums. Although the yields of the products are
not so high, in view of the ready availability of the starting materials as well as the ease
of operations, the present procedure offers a convenient synthetic method for this class
of heterocycles. Studies toward the synthesis of related heterocycles utilizing 3-
isocyanopyridin-4-yl ketones are currently under way in our laboratory.
Experimental Part
General. All of the org. solvents used in this study were dried over appropriate drying agents and
distilled prior to use. TLC: Merck silica gel 60 PF254. Column chromatography (CC): Wako Gel C-200E.
M.p.: Laboratory Devices MEL-TEMP II melting-point apparatus; uncorrected. IR Spectra: Shimadzu
1
FT-IR-8300 spectrophotometer. H-NMR Spectra: in CDCl3 with TMS as an internal reference, with a
JEOL ECP500 FT NMR spectrometer, at 500 MHz. 13C-NMR Spectra: measured in CDCl3 with TMS as
an internal reference with a JEOL ECP500 FT NMR spectrometer, at 125 MHz. LR- and HR-MS (EI,
70 eV): JEOL JMS AX505 HA spectrometer.
(3-Aminopyridin-4-yl)(phenyl)methanone (1a) and (3-aminopyridin-4-yl)(4-methoxyphenyl)metha-
none (1d) were prepared according to the method described in [4]. All other chemicals used in this study
were commercially available.

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N-(4-Aroylpyridin-3-yl)-2,2-dimethylpropanamides. These compounds were prepared by a succes-
sive treatment of 2,2-dimethyl-N-(pyridin-3-yl)propanamide [4] with 2 mol-equiv. of BuLi and N-
methoxy-N-methylbenzamides under the conditions reported previously for the reaction of 2,2-
dimethyl-N-lithio-N-(4-lithiopyridin-3-yl)propanamide with benzaldehyde [4].
2,2-Dimethyl-N-[4-(4-methylbenzoyl)pyridin-3-yl]propanamide. Yield: 68%. Pale-yellow solid. M.p.
151 – 1538 (hexane/CH2Cl2). IR (KBr): 3318, 1678. 1H-NMR: 1.34 (s, 9 H); 2.47 (s, 3 H); 7.33 (d, J ¼ 7.8,
2 H); 7.37 (d, J ¼ 4.1, 1 H); 7.67 (d, J ¼ 7.8, 2 H); 8.45 (d, J ¼ 4.1, 1 H); 9.90 (s, 1 H); 10.35 (br. s, 1 H).
Anal. calc. for C18H20N2O2 (296.37): C 72.95, H 6.80, N 9.45; found: C 72.72, H 7.02, N 9.43.
N-[4-(3-Chlorobenzoyl)pyridin-3-yl]-2,2-dimethylpropanamide. Yield: 75%. Pale-yellow solid. M.p.
119 – 1208 (hexane/Et2O). IR (KBr): 3400, 1674. 1H-NMR: 1.35 (s, 9 H); 7.35 (d, J ¼ 4.6, 1 H); 7.48 (t, J ¼
7.8, 1 H); 7.61 (d, J ¼ 7.8, 1 H); 7.63 (d, J ¼ 7.8, 1 H); 7.76 (s, 1 H); 8.48 (d, J ¼ 4.6, 1 H); 9.92 (s, 1 H); 10.34
(br. s, 1 H). Anal. calc. for C17H17ClN2O2 (316.79): C 64.46, H 5.41, N 8.84; found: C 64.36, H 5.58, N 8.78.
(3-Aminopyridin-4-yl)(aryl)methanones 1. These compounds were prepared by acid hydrolysis
under the conditions reported previously for the conversion of N-(4-benzoylpyridin-3-yl)-2,2-dimethyl-
propanamide into (3-aminopyridin-4-yl)(phenyl)methanone [4].
(3-Aminopyridin-4-yl)(4-methylphenyl)methanone (1b). Yield: 81%. Pale-yellow solid. M.p. 115 –
1
1178 (hexane/CH2Cl2). IR (KBr): 3435, 3327, 1651, 1613. H-NMR: 2.45 (s, 3 H); 5.72 (br. s, 2 H); 7.24
(d, J ¼ 5.5, 1 H); 7.29 (d, J ¼ 7.8, 2 H); 7.62 (d, J ¼ 7.8, 2 H); 7.95 (d, J ¼ 5.5, 1 H); 8.28 (s, 1 H). Anal. calc.
for C13H12N2O (212.25): C 73.56, H 5.70, N 13.20; found: C 73.51, H 5.94, N 13.10.
(3-Aminopyridin-4-yl)(3-chlorophenyl)methanone (1c). Yield: 81%. Yellow solid. M.p. 165 – 1678
(hexane/THF). IR (KBr): 3445, 3306, 1634, 1607. 1H-NMR: 3.89 (br. s, 2 H); 7.20 (d, J ¼ 5.0, 1 H); 7.44 (t,
J ¼ 7.8, 1 H); 7.54 (dd, J ¼ 7.8, 1.8, 1 H); 7.56 (dd, J ¼ 7.8, 1.8, 1 H); 7.67 (t, J ¼ 1.8, 1 H); 7.95 (d, J ¼ 5.0,
1 H); 8.30 (s, 1 H). Anal. calc. for C12H9ClN2O (232.67): C 61.95, H 3.90, N 12.04; found: C 61.94, H 3.94,
N 11.82.
N-(4-Aroylpyridin-3-yl)formamides 2. These compounds were prepared by treating 1 with HCO2H/
Ac2O under the previously reported conditions [5].
N-(4-Benzoylpyridin-3-yl)formamide (2a). Pale-yellow, viscous oil. Rf (THF/hexane 1:1) 0.35. IR
1
(neat): 3308, 1699, 1668. H-NMR: 7.39 (d, J ¼ 5.0, 1 H); 7.54 (dd, J ¼ 7.8, 7.3, 2 H); 7.68 (tt, J ¼ 7.3, 1.4,
1 H); 7.77 (d, J ¼ 7.8, 2 H); 8.48 (s, 1 H), 8.53 (d, J ¼ 5.0, 1 H); 9.90 (br. s, 1 H); 9.91 (s, 1 H). Anal. calc.
for C13H10N2O2 (226.23): C 69.02, H 4.46, N 12.38; found: C 68.97, H 4.50, N 12.27.
N-[4-(4-Methylbenzoyl)pyridin-3-yl]formamide (2b). Pale-yellow, viscous oil. Rf (AcOEt/hexane
1:2) 0.35. IR (neat): 3308, 1697, 1661, 1605. 1H-NMR: 2.47 (s, 3 H); 7.33 (d, J ¼ 7.8, 2 H); 7.38 (d, J ¼ 5.0,
1 H); 7.69 (d, J ¼ 7.8, 2 H); 8.46 (s, 1 H); 8.52 (d, J ¼ 5.0, 1 H); 9.79 (br. s, 1 H); 9.88 (s, 1 H). Anal. calc.
for C14H12N2O2 (240.26): C 69.99, H 5.03, N 11.66; found: C 69.72, H 5.23, N 11.47.
N-[4-(3-Chlorobenzoyl)pyridin-3-yl]formamide (2c). Beige solid. M.p. 115 – 1178 (hexane/THF). IR
1
(KBr): 3277, 1699, 1670. H-NMR: 7.37 (d, J ¼ 4.6, 1 H); 7.48 (t, J ¼ 7.8, 1 H); 7.62 (d, J ¼ 7.8, 1 H); 7.65
(dd, J ¼ 7.8, 1.4, 1 H); 7.77 (t, J ¼ 1.4, 1 H); 8.48 (s, 1 H); 8.55 (d, J ¼ 4.6, 1 H); 9.84 (br. s, 1 H); 9.90 (s,
1 H). Anal. calc. for C13H9ClN2O2 (260.68): C 59.90, H 3.48, N 10.75; found: C 59.82, H 3.72, N 10.73.
N-[4-(4-Methoxybenzoyl)pyridin-3-yl]formamide (2d). Beige solid. M.p. 140 – 1438 (hexane/
CH2Cl2). IR (KBr): 3349, 1701, 1640. 1H-NMR: 3.92 (s, 3 H); 7.00 (d, J ¼ 8.7, 2 H); 7.39 (d, J ¼ 5.0,
1 H); 7.80 (d, J ¼ 8.7, 2 H); 8.44 (s, 1 H); 8.53 (d, J ¼ 5.0, 1 H); 9.62 (br. s, 1 H); 9.84 (br. s, 1 H). Anal.
calc. for C14H12N2O3 (256.26): C 65.62, H 4.72, N 10.93; found: C 65.52, H 4.72, N 10.70.
(Aryl)(3-isocyanopyridin-4-yl)methanones 3. These compounds were prepared by dehydration of 2
with POCl3/Et3N under the conditions reported in [6].
(3-Isocyanopyridin-4-yl)(phenyl)methanone (3a). Yellow solid. M.p. 72 – 758 (dec.; hexane). IR
1
(KBr): 2124, 1672. H-NMR: 7.43 (dd, J ¼ 5.0, 0.9, 1 H); 7.54 (dd, J ¼ 8.2, 7.3, 2 H); 7.69 (tt, J ¼ 7.3, 1.4,
1 H); 7.81 (dd, J ¼ 8.2, 1.4, 2 H); 8.78 (d, J ¼ 5.0, 1 H); 8.83 (s, 1 H). Anal. calc. for C13H8N2O (208.22): C
74.99, H 3.87, N 13.45; found: C 75.01, H 4.05, N 13.21.
(3-Isocyanopyridin-4-yl)(4-methylphenyl)methanone (3b). Pale-yellow solid. M.p. 72 – 738 (dec.;
hexane/CH2Cl2). IR (KBr): 2126, 1669, 1604. 1H-NMR: 2.46 (s, 3 H); 7.33 (d, J ¼ 8.2, 2 H); 7.41 (d, J ¼
5.0, 1 H); 7.70 (d, J ¼ 8.2, 2 H); 8.77 (d, J ¼ 5.0, 1 H); 8.81 (s, 1 H). Anal. calc. for C14H10N2O (222.24): C
75.66, H 4.54, N 12.60; found: C 75.40, H 4.61, N 12.39.

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(3-Chlorophenyl)(3-isocyanopyridin-4-yl)methanone (3c). Brown solid. M.p. 74 – 768 (dec.; pen-
tane). IR (KBr): 2133, 1668. 1H-NMR: 7.42 (d, J ¼ 5.0, 1 H); 7.49 (t, J ¼ 7.8, 1 H); 7.65 – 7.68 (m, 2 H); 7.80
(t, J ¼ 1.8, 1 H); 8.81 (d, J ¼ 5.0, 1 H); 8.85 (s, 1 H). Anal. calc. for C13H7ClN2O (242.66): C 64.34, H 2.91,
N 11.54; found: C 64.17, H 2.98, N 11.51.
(3-Isocyanopyridin-4-yl)(4-methoxyphenyl)methanone (3d). Brown solid. M.p. 50 – 528 (pentane).
IR (KBr): 2124, 1661. 1H-NMR: 3.91 (s, 3 H); 6.99 (d, J ¼ 8.7, 2 H); 7.40 (d, J ¼ 5.0, 1 H); 7.78 (d, J ¼ 8.7,
2 H); 8.76 (d, J ¼ 5.0, 1 H); 8.80 (s, 1 H). Anal. calc. for C14H10N2O2 (238.24): C 70.58, H 4.23, N 11.76;
found: C 70.40, H 4.39, N 11.68.
4-[(E)-1-Aryl-2-methoxyethenyl]-3-isocyanopyridines 4. These compounds were prepared by
reacting 3 with (methoxymethyl)(triphenyl)phosphonium chloride under the conditions reported for
the conversion of (2-isocyanophenyl)(phenyl)methanone to 1-isocyano-2-(2-methoxy-1-phenylethenyl)-
benzene [1b].
3-Isocyano-4-[(E)-2-methoxy-1-phenylethenyl]pyridine (4a). Pale-yellow oil. Rf 0.28 (THF/hexane
1:5). IR (neat): 2124, 1645, 1634. 1H-NMR: 3.86 (s, 3 H); 6.73 (s, 1 H); 7.10 (dd, J ¼ 8.2, 1.4, 2 H); 7.20 (d,
J ¼ 5.0, 1 H); 7.26 (tt, J ¼ 7.3, 1.4, 1 H); 7.30 (dd, J ¼ 8.2, 7.3, 2 H); 8.54 (d, J ¼ 5.0, 1 H); 8.69 (s, 1 H). HR-
MS: 236.0937 (C15H12N2Oþ; calc. 236.0950).
3-Isocyano-4-[(E)-2-methoxy-1-(4-methylphenyl)ethenyl]pyridine (4b). Yellow oil. Rf (THF/hexane
1:5) 0.28. IR (neat): 2126, 1636. 1H-NMR: 2.33 (s, 3 H); 3.84 (s, 3 H); 6.69 (s, 1 H); 6.99 (d, J ¼ 7.8, 2 H);
7.11 (d, J ¼ 7.8, 2 H); 7.19 (d, J ¼ 5.0, 1 H); 8.53 (d, J ¼ 5.0, 1 H); 8.68 (s, 1 H). HR-MS: 250.1086
(C16H14N2Oþ; calc. 250.1106).
4-[(E)-1-(3-Chlorophenyl)-2-methoxyethenyl]-3-isocyanopyridine (4c). Yellow oil. Rf (THF/hexane
1:5) 0.29. IR (neat): 2123, 1636. 1H-NMR: 3.87 (s, 3 H); 6.77 (s, 1 H); 6.94 – 6.98 (m, 1 H); 7.08 – 7.09 (m,
1 H); 7.19 (d, J ¼ 5.0, 1 H); 7.22 – 7.24 (m, 2 H); 8.22 (d, J ¼ 5.0, 1 H); 8.71 (s, 1 H). HR-MS: 270.0553
(C15H11ClN2Oþ; calc. 270.0560).
3-Isocyano-4-[(E)-2-methoxy-1-(4-methoxyphenyl)ethenyl]pyridine (4d). Colorless needles. M.p.
1118 (hexane/Et2O). IR (KBr): 2126, 1636. 1H-NMR: 3.80 (s, 3 H); 3.84 (s, 3 H); 6.63 (s, 1 H); 6.84 (d,
J ¼ 9.2, 2 H); 7.02 (d, J ¼ 9.2, 2 H); 7.18 (d, J ¼ 5.0, 1 H); 8.52 (d, J ¼ 5.0, 1 H); 8.68 (s, 1 H). Anal. calc. for
C16H14N2O2 (266.29): C 72.16, H 5.30, N 10.52; found: C 72.07, H 5.37, N 10.26.
2,4,8-Triphenyl-1,7-naphthyridine (6a) (Representative Procedure). To a stirred soln. of 4a (0.14 g,
0.59 mmol) in 1,2-dimethoxyethane (DME; 3 ml) at ꢀ 788 was added PhLi (1.08m in cyclohexane/Et2O;
2.4 mmol); the mixture was stirred for 3 h at the same temp. before addition of sat. aq. NH4Cl (10 ml).
The warmed mixture was extracted with Et2O (3 ꢁ 10 ml), and the combined extracts were washed with
brine and dried (anh. Na2SO4). Evaporation of the solvent gave a residue, which was purified by CC
(silica gel; THF/hexane 1:10) to give 6a (0.10 g, 47%). Pale-yellow needles. M.p. 150 – 1538 (hexane/
1
CH2Cl2). IR (KBr): 1593. H-NMR: 7.45 – 7.60 (m, 11 H); 7.70 (d, J ¼ 5.5, 1 H); 8.07 (s, 1 H); 8.21 (dd,
J ¼ 8.2, 1.4, 2 H); 8.26 (dd, J ¼ 8.2, 1.4, 2 H); 8.64 (d, J ¼ 5.5, 1 H). 13C-NMR: 117.31; 121.55; 127.48;
127.66; 128.71; 128.83; 128.85; 128.88; 129.46; 129.86; 129.92; 131.59; 137.35; 138.65; 138.94; 141.72;
142.97; 148.49; 156.73; 160.51. MS: 358 (100, Mþ). Anal. calc. for C26H18N2 (358.44): C 87.12, H 5.06, N
7.82; found: C 87.22, H 5.14, N 7.66.
2,4-Diphenyl-1,7-naphthyridine (5). This compound was obtained by using less than 4 mol-equiv. of
PhLi. Pale-yellow solid. M.p. 123 – 1258 (hexane/Et2O). IR (KBr): 1593. 1H-NMR: 7.50 – 7.61 (m, 8 H);
7.75 (dd, J ¼ 5.5, 0.9, 1 H); 8.03 (s, 1 H); 8.23 (dd, J ¼ 7.8, 1.4, 2 H); 8.57 (d, J ¼ 5.5, 1 H); 9.63 (d, J ¼ 0.9,
1 H). 13C-NMR: 117.77; 122.65; 127.59; 128.87; 128.91; 128.98 (2 C); 129.39; 129.98; 136.78; 138.74;
143.63; 148.83; 148.16; 154.74; 158.44. MS: 282 (100, Mþ). Anal. calc. for C20H14N2 (282.34): C 85.08, H
5.00, N 9.92; found: C 84.95, H 5.16, N 9.72.
2,8-Dibutyl-4-phenyl-1,7-naphthyridine (6b). Pale-yellow oil. Rf (THF/hexane 1:10) 0.42. IR (neat):
1597. 1H-NMR: 0.99 (t, J ¼ 7.3, 3 H); 1.00 (t, J ¼ 7.3, 3 H); 1.43 – 1.55 (m, 4 H); 1.86 – 1.93 (m, 4 H); 3.03 (t,
J ¼ 7.3, 2 H); 3.56 (t, J ¼ 7.8, 2 H); 7.38 (s, 1 H); 7.47 – 7.54 (m, 6 H); 8.39 (d, J ¼ 6.0, 1 H). 13C-NMR:
13.98; 14.07; 22.43; 22.98; 31.19; 31.88; 33.84; 38.69; 116.11; 124.82; 128.55; 128.66 (2 C); 129.41; 137.36;
141.92; 141.95; 147.34; 162.47; 165.17. MS: 318 (100, Mþ). Anal. calc. for C22H26N2 (318.46): C 82.97, H
8.23, N 8.80; found: C 82.88, H 8.35, N 8.77.
4-(4-Methylphenyl)-2,8-diphenyl-1,7-naphthyridine (6c). Pale-yellow solid. M.p. 144 – 1468 (hexane/
Et2O). IR (KBr): 1591. 1H-NMR: 2.50 (s, 3 H); 7.39 (d, J ¼ 8.2, 2 H); 7.44 – 7.52 (m, 6 H); 7.57 (t, J ¼ 7.3,

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2 H); 7.72 (d, J ¼ 5.5, 1 H); 8.04 (s, 1 H); 8.20 (d, J ¼ 7.3, 2 H); 8.26 (d, J ¼ 7.3, 2 H); 8.63 (d, J ¼ 5.5, 1 H).
13C-NMR: 21.32; 117.41; 121.49; 127.48; 127.65; 128.68; 128.88; 129.39; 129.54; 129.82; 130.05; 131.60;
134.44; 138.74; 138.91; 138.99; 141.77; 142.89; 148.55; 156.73; 160.51. MS: 372 (100, Mþ). Anal. calc. for
C27H20N2 (372.46): C 87.07, H 5.41, N 7.52; found: C 87.05, H 5.52, N 7.32.
2,8-Bis(4-chlorophenyl)-4-(4-methylphenyl)-1,7-naphthyridine (6d). Pale-yellow crystals. M.p. 195 –
1978 (hexane/Et2O). IR (KBr): 1593. 1H-NMR: 2.51 (s, 3 H); 7.40 (d, J ¼ 7.8, 2 H); 7.47 (d, J ¼ 7.8, 2 H);
7.49 (d, J ¼ 8.7, 2 H); 7.54 (d, J ¼ 8.7, 2 H); 7.74 (d, J ¼ 6.0, 1 H); 8.01 (s, 1 H); 8.12 (d, J ¼ 8.7, 2 H); 8.20 (d,
J ¼ 8.7, 2 H); 8.63 (d, J ¼ 6.0, 1 H). 13C-NMR: 21.34; 117.76; 121.27; 127.90; 128.69; 129.19; 129.35; 129.62;
130.13; 132.86; 134.12; 135.00; 136.24; 137.03; 137.32; 139.15; 141.57; 143.06; 148.97; 155.67; 159.15. MS:
440 (100, Mþ). Anal. calc. for C27H18Cl2N2 (441.35): C 73.48, H 4.11, N 6.35; found: C 73.30, H 4.10, N
6.22.
2,8-Bis(4-methoxyphenyl)-4-(4-methylphenyl)-1,7-naphthyridine (6e). Pale-yellow solid. M.p. 102 –
1
1048 (hexane/Et2O). IR (KBr): 1603. H-NMR: 2.49 (s, 3 H); 3.88 (s, 3 H); 3.94 (s, 3 H); 7.02 (d, J ¼
8.7, 2 H); 7.10 (d, J ¼ 8.7, 2 H); 7.38 (d, J ¼ 7.8, 2 H); 7.47 (d, J ¼ 7.8, 2 H); 7.63 (d, J ¼ 6.0, 1 H); 7.97 (s,
1 H); 8.17 (d, J ¼ 8.7, 2 H); 8.28 (d, J ¼ 8.7, 2 H); 8.56 (d, J ¼ 6.0, 1 H). 13C-NMR: 21.31; 55.36; 55.38;
113.13; 114.27; 116.83; 120.95; 128.89; 129.38; 129.49; 129.78; 131.51; 131.75; 133.06; 134.65; 138.77;
141.74; 142.52; 148.32; 156.16; 159.63; 160.22; 161.14. MS: 432 (100, Mþ). Anal. calc. for C29H24N2O2
(432.51): C 80.53, H 5.59, N 6.48; found: C 80.39, H 5.50, N 6.40.
4-(3-Chlorophenyl)-2,8-diphenyl-1,7-naphthyridine (6f). Pale-yellow solid. M.p. 148 – 1508 (hexane/
Et2O). IR (KBr): 1601, 1589. 1H-NMR: 7.46 – 7.59 (m, 10 H); 7.65 (d, J ¼ 5.5, 1 H); 8.05 (s, 1 H); 8.21 (dd,
J ¼ 8.2, 1.4, 2 H); 8.25 (dd, J ¼ 8.2, 1.4, 2 H); 8.67 (d, J ¼ 5.5, 1 H). 13C-NMR: 116.87; 121.51; 127.47;
127.66; 127.68; 128.80; 128.93; 129.00; 129.44; 129.54; 129.99; 130.11; 131.59; 134.89; 138.40; 138.77;
139.05; 141.63; 143.21; 146.92; 156.73; 160.59. MS: 392 (100, Mþ). Anal. calc. for C26H17ClN2 (392.88): C
79.48, H 4.36, N 7.13; found: C 79.48, H 4.57, N 7.08.
4-(3-Chlorophenyl)-2,8-dimethyl-1,7-naphthyridine (6g). Pale-yellow solid. M.p. 124 – 1268 (hexane/
1
Et2O). IR (KBr): 1605, 1591. H-NMR: 2.82 (s, 3 H); 3.11 (s, 3 H); 7.36 (d, J ¼ 6.0, 1 H); 7.39 (s, 1 H);
7.45 – 7.50 (m, 4 H); 8.39 (d, J ¼ 6.0, 1 H). 13C-NMR: 21.36; 25.62; 115.89; 125.36; 127.52; 127.59; 128.81;
129.38; 129.97; 134.76; 138.85; 142.17; 142.36; 145.96; 158.91; 161.54. MS: 268 (100, Mþ). Anal. calc. for
C16H13ClN2 (268.74): C 71.51, H 4.88, N 10.42; found: C 71.41, H 5.02, N 10.21.
4-(3-Chlorophenyl)-2,8-bis(4-methylphenyl)-1,7-naphthyridine (6h). Pale-yellow crystals. M.p. 124 –
1
1268 (hexane/Et2O). IR (KBr): 1611, 1587. H-NMR: 2.43 (s, 3 H); 2.49 (s, 3 H); 7.33 (d, J ¼ 8.2, 2 H);
7.38 (d, J ¼ 8.2, 2 H); 7.45 – 7.47 (m, 1 H); 7.52 – 7.53 (m, 2 H); 7.58 (t, J ¼ 0.9, 1 H); 7.59 (d, J ¼ 5.5, 1 H);
8.00 (s, 1 H); 8.11 (d, J ¼ 8.2, 2 H); 8.18 (d, J ¼ 8.2, 2 H); 8.63 (d, J ¼ 5.5, 1 H). 13C-NMR: 21.35; 21.43;
116.57; 121.31; 126.49; 127.40; 127.68; 128.45; 128.92; 129.45; 129.67; 130.07; 131.58; 134.86; 135.78;
135.96; 138.72; 139.23; 140.19; 141.69; 143.01; 146.74; 156.63; 160.38. MS: 420 (100, Mþ). Anal. calc. for
C28H21ClN2 (420.93): C 79.89, H 5.03, N 6.66; found: C 79.62, H 5.11, N 6.42.
4-(4-Methoxyphenyl)-2,8-diphenyl-1,7-naphthyridine (6i). Pale-yellow solid. M.p. 157 – 1608
1
(CHCl3). IR (KBr): 1608, 1593. H-NMR: 3.94 (s, 3 H); 7.12 (d, J ¼ 8.7, 2 H); 7.46 – 7.59 (m, 8 H); 7.75
(d, J ¼ 5.5, 1 H); 8.04 (s, 1 H); 8.21 (d, J ¼ 8.2, 1.4, 2 H); 8.26 (d, J ¼ 8.2, 1.4, 2 H); 8.64 (d, J ¼ 5.5, 1 H).
13C-NMR: 55.44; 114.32; 117.40; 121.41; 127.47; 127.64; 128.67; 128.87; 129.60; 129.80; 130.11; 130.77;
131.58; 138.74; 138.99; 141.81; 142.85; 148.19; 156.71; 160.21; 160.49. MS: 388 (100, Mþ). Anal. calc. for
C27H20N2O (388.46): C 83.48, H 5.19, N 7.21; found: C 83.39, H 5.21, N 6.93.
2,8-Bis(4-chlorophenyl)-4-(4-methoxyphenyl)-1,7-naphthyridine (6j). Pale-yellow solid. M.p. 255 –
1
2578 (hexane/AcOEt). IR (KBr): 1611, 1595. H-NMR: 3.94 (s, 3 H); 7.17 (d, J ¼ 8.7, 2 H); 7.48 – 7.55
(m, 6 H); 7.75 (d, J ¼ 5.5, 1 H); 7.99 (s, 1 H); 8.12 (d, J ¼ 8.7, 2 H); 8.20 (d, J ¼ 8.7, 2 H); 8.63 (d, J ¼ 5.5,
1 H). 13C-NMR: 55.50; 114.44; 117.76; 121.23; 127.90; 128.71; 129.20; 129.32; 130.24; 130.77; 132.87;
135.01; 136.24; 137.08; 137.34; 141.66; 143.04; 148.65; 155.71; 159.20; 160.39. MS: 456 (100, Mþ). Anal.
calc. for C27H18Cl2N2O (457.35): C 70.91, H 3.97, N 6.13; found: C 70.85, H 4.03, N 6.36.
The authors wish to thank Mrs. Miyuki Tanmatsu of this university for recording mass spectra and
performing combustion analyses.

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Received May 31, 2010