General synthetic method for naphthyridines and their N-oxides containing isoquinolinic nitrogen

Article abstract of DOI:10.1055/s-1999-3379

Substituted naphthyridines containing isoquinolinic nitrogen were synthesized by the reaction of o-ethynylpyridinecarbaldehydes with ammonia. The synthesis of their N-oxides was also achieved by a basic cyclization reaction of the same pyridine derivatives via the corresponding oximes.

Full text of DOI:10.1055/s-1999-3379

306
PAPER
General Synthetic Method for Naphthyridines and Their N-Oxides Containing
Isoquinolinic Nitrogen
Atsushi Numata, Yoshinori Kondo, Takao Sakamoto*
Faculty of Pharmaceutical Sciences, Tohoku University, Aobayama, Aoba-ku, Sendai 980-8578, Japan
Fax +81(222)176864: E-mail: sakamoto@mail.pharm.tohoku.ac.jp
Received 3 June 1998; revised 29 June 1998
We have already reported a simple and general synthesis
Abstract: Substituted naphthyridines containing isoquinolinic ni-
of isoquinolines and their N-oxides from o-ethynylbenzal-
trogen were synthesized by the reaction of o-ethynylpyridinecarbal-
dehydes which were prepared by the palladium-catalyzed
dehydes with ammonia. The synthesis of their N-oxides was also
reaction of o-halobenzaldehydes with terminal acety-
lenes.7 Based on the background described above, we now
report the general synthesis of naphthyridines and their N-
oxides containing an isoquinolinic nitrogen by the appli-
cation of our isoquinoline synthesis.
achieved by a basic cyclization reaction of the same pyridine deriv-
atives via the corresponding oximes.
Key words: naphthyridines, N-oxides, cyclization, palladium-cata-
lyzed acetylene cross-coupling, lithiation
First, o-bromopyridinecarbaldehydes 4Ð6 were synthe-
sized via the lithiation of bromopyridines 1Ð3 followed by
electrophilic substitution with DMF. Compounds 4Ð6
were allowed to react with phenylacetylene, oct-1-yne,
and trimethylsilylacetylene under the conventional palla-
dium-catalyzed cross-coupling conditions to give the cor-
responding ethynyl derivatives 7Ð9.
Although preparations of naphthyridines (pyridopyridines)
have been developed using various types of cyclization re-
actions, there are few methods which have a wide scope
and generality.1 The construction of naphthyridine rings is
principally achieved by application of the quinoline or iso-
quinoline cyclization reaction to pyridine derivatives. Since
most quinoline or isoquinoline cyclization reactions pro-
ceed through electrophilic attack at the benzene ring, appli-
cation of the methods to pyridine rings have been limited,
because the pyridine ring is electron deficient.
One of the general synthetic methods for naphthyridines
having a quinolinic nitrogen is the Skraup-type reaction of
aminopyridines for which the reaction conditions have
been developed.2 However, it has limitations in that 1,7-
naphthyridines and the derivatives containing alkyl or aryl
substituents cannot be prepared by this method. The oth-
ers are the FriedlŠnder-type3 and GouldÐJacobs-type reac-
tions,4 but these methods have also some limitations; for
instance, in the latter case, the reaction of 2-aminopyri-
dine gave a pyridopyrimidine derivative instead of the ex-
pected 1,8-naphthyridines.4d
Scheme 1
Table 1 Synthesis of o-Bromopyridinecarbaldehydes 4–6 from Bro-
mopyridines 1–3
Bromopyridine Time 1 Time 2 Time 3 Product Yield (%)
On the other hand, general synthetic methods for four iso-
meric naphthyridines containing an isoquinolinic nitrogen
are scarcely known. The cyclization reaction of o-cyan-
opyridineacetonitriles or -acetaldehyde equivalent deriva-
tives with hydrogen bromide is one method that has
generality for the synthesis of naphthyridines containing
an isoquinolinic nitrogen.5
2-Br (1)
3-Br (2)
4-Br (3)
4 h
10 min
30 min 15 min 30 min
30 min
1 h
2 h
30 min
4
5
6
90
92
61
Table 2 Palladium-Catalyzed Synthesis of o-Ethynylpyridinecarbal-
dehydes 7–9 from o-Bromopyridinecarbaldehydes 4–6
Since naphthyridines contain two nitrogens, the synthesis
of the N-oxides has some problems. One of them is that the
selective synthesis of naphthyridine mono-N-oxides is dif-
ficult.6 In general, the N-oxidation reaction of naph-
thyridines gives a mixture of mono-N-oxides and di-N-
oxides even if limited N-oxidizing reagents were used.6b A
second problem is that the naphthyridines containing an
isoquinolinic nitrogen sometimes gave ring-oxidized prod-
ucts under N-oxidation conditions.6a,c Moreover, it has been
reported that the formation of naphthyridine N-oxides by
cyclization reaction affords the products in poor yields.6d
Bromopyridine-
carbaldehyde
Time Temp.
R
Product Yield
(%)
(h)
(°C)
2-Bromopyridine-
3-carbaldehyde (4)
2
15
1.5
15
15
2
2
15
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
50
r.t.
r.t.
Ph
7a
7b
7c
8a
8b
8c
9a
9b
9c
73
79
57
67
41
42
67
87
49
C6H13
SiMe3
Ph
C6H13
SiMe3
Ph
3-Bromopyridine-
4-carbaldehyde (5)
4-Bromopyridine-
3-carbaldehyde (6)
C6H13
SiMe3
0.5
Synthesis 1999, No. 2, 306–311 ISSN 0039-7881 © Thieme Stuttgart á New York

PAPER
General Synthetic Method for Naphthyridines
307
Table 3 Synthesis of Naphthyridines 14–17 from o-Ethynylpyridine-
carbaldehydes 7–9, 13
By employing the above method, 3-bromopyridine-2-
carbaldehyde can not be prepared. We then developed an
alternative way to prepare 3-ethynylpyridine-2-carbalde-
hydes 12. Namely, 2-bromopyridin-3-ol (10) was trans-
formed into 2-bromopyridinyl trifluoromethanesulfonate
(11) by the reaction with trifluoromethanesulfonic anhy-
dride. The palladium-catalyzed alkynylation of 11 selec-
tively occurred at the 3-position to give 2-bromo-3-
ethynylpyridines 12 which were lithiated with butyllithi-
um through the halogen-lithium exchange reaction fol-
lowed by electrophilic substitution to give 3-
ethynylpyridine-2-carbaldehydes 13.
Ethynylpyridine-
carbaldehyde
R
Product
R'
Yield
(%)
7a
7b
7c
8a
8b
8c
9a
9b
9c
Ph
14a
14b
14c
15a
15b
15c
16a
16b
16c
17a
17b
17c
Ph
C6H13
H
Ph
C6H13
H
Ph
C6H13
H
Ph
C6H13
H
20
31
62
83
99
92
23
73
54
31
59
58
C6H13
SiMe3
Ph
C6H13
SiMe3
Ph
C6H13
SiMe3
Ph
C6H13
SiMe3
13a
13b
13c
Table 4 Synthesis of o-Ethynylpyridinecarbaldehyde Oximes 18–21
from o-Ethynylpyridinecarbaldehydes 7–9, 13
Ethynylpyridine-
carbaldehyde
R
Time
(h)
Product
Yield
(%)
7a
7b
7c
8a
8b
8c
9a
9b
9c
13a
13b
Ph
15
15
1
15
15
2
15
15
2
15
15
18a
18b
18c
19a
19b
19c
20a
20b
20c
21a
21b
97
68
93
97
96
94
96
98
52
73
99
Scheme 2
C6H13
SiMe3
Ph
C6H13
SiMe3
Ph
C6H13
SiMe3
Ph
o-Ethynylpyridinecarbaldehydes 7Ð9, 13 prepared by the
above two methods were allowed to react with ammonia
in ethanol in a sealed tube at 80¡C for 2 hours to give the
corresponding naphthyridines 14Ð17 in the yields shown
in Table 3.
C6H13
Table 5 Synthesis of Naphthyridine N-Oxides 22–25 from o-Ethy-
nylpyridinecarbaldehyde Oximes 18–21
Ethynylpyri-
dinecarbalde-
hyde Oxime
R
Conditions
Product R'
Yield
(%)
Temp Time
(°C) (h)
18a
18b
18c
19a
19b
19c
20a
20b
20c
21a
21b
21c
Ph
80
80
80
80
r.t.
80
80
80
r.t.
r.t.
80
–
15
15
1
15
15
2
15
15
1
22a
22b
22c
23a
23b
23c
24a
24b
24c
25a
25b
25c
Ph
C6H13 55
H
Ph
C6H13 73
H
Ph
C6H13 85
H
Ph
C6H13 87
H
67
C6H13
SiMe3
Ph
C6H13
SiMe3
Ph
C6H13
SiMe3
Ph
C6H13
SiMe3
53
80
50
77
Scheme 3
66
75
3
15
–
23a
Next, o-ethynylpyridinecarbaldehydes 7Ð9, 13 were con-
verted to the corresponding oximes 18Ð21 by a conven-
tional procedure, and then cyclized under basic conditions
to give the corresponding naphthyridine N-oxides 22Ð25
as shown in Tables 4 and 5.
a 1,7-Naphthyridine 7-oxide (25c) was directly obtained from 3-[(tri-
methylsilyl)ethynyl]-2-pyridinecarbaldehyde (13c) by reaction with
NH2OH · HCl.
NMR spectra were recorded on Varian Gemini 2000 (300 MHz)
and Hitachi R-300 (300 MHz) spectrometers. Chemical shifts are
expressed in d (ppm) values with TMS as an internal reference, and
coupling constants are expressed in Hz. MS and HRMS were re-
corded on JMS-DX303 and JMS-AX500 instruments.
THF and Et2O were distilled from sodium/benzophenone ketyl be-
fore use. BuLi was titrated using 2,5-dimethoxybenzyl alcohol be-
fore use. All melting points and boiling points are uncorrected. IR
1
spectra were taken on a JASCO IR-810 spectrophotometer. H
Synthesis 1999, No. 2, 306–311 ISSN 0039-7881 © Thieme Stuttgart · New York

308
A. Numata et al.
PAPER
2-Bromopyridine-3-carbaldehyde (4)8 and 3-bromopyridine-4-
carbaldehyde (5)9 were prepared according to a modification of the
methods reported in literature.
4-Bromopyridine-3-carbaldehyde (6): yield: 61%; mp 49Ð50¡C.
IR (KBr): n = 1710 cmÐ1.
1H NMR (CDCl3): d = 7.63 (1 H, d, J = 5.4 Hz), 8.57 (1 H, d, J =
5.4 Hz), 9.00 (1 H, s), 10.39 (1 H, s).
MS: m/z = 185, 187 (M+).
HRMS: calc. for C6H479BrNO: 184.9477. Found: 184.9462.
o-Bromopyridinecarbaldehydes 4Ð6; General Procedure
To a LDA solution prepared from BuLi (hexane solution, 3.3 mmol)
and i-Pr2NH (4 mmol) in THF (10 mL) at Ð78¡C for 1 h under an
Ar atmosphere, was added freshly distilled bromopyridine 1Ð3
(3 mmol) slowly and the mixture was stirred at Ð78¡C for the time
1 shown in Table 1. After addition of DMF (1 mL, 13 mmol), the
mixture was stirred for the time 2 shown in Table 1. The mixture
was allowed to warm to r.t. and stirred for the time 3 shown in Table
1. Sat. aq NH4Cl solution was added and the mixture was extracted
with Et2O. The Et2O extract was washed with brine and dried
(MgSO4). The residue was purified by silica gel column chromatog-
raphy using EtOAc/hexane (1:10) as eluent to give the product.
o-Ethynylpyridinecarbaldehydes 7Ð9; General Procedure
A mixture of o-bromopyridinecarbaldehyde 4Ð6 (2.0 mmol), the
appropriate alkyne (2.5Ð4 mmol), Pd(PPh3)2Cl2 (60 mg), CuI
(30 mg), Et3N (300 mg), and DMF (10 mL) was stirred under the
conditions shown in Table 2. The mixture was diluted with H2O and
extracted with Et2O. The residue obtained from the Et2O extract was
purified by silica gel column chromatography using EtOAc/hexane
(1:10) as eluent. The product was purified by distillation or recrys-
tallization (Table 6).
2-Bromopyridine-3-carbaldehyde (4): yield: 90%; mp 64Ð65¡C
(Lit.8 mp 65¡C).
IR (KBr): n = 1690 cmÐ1.
1H NMR (CDCl3): d = 7.44 (1 H, dd, J = 4.5, 8.0 Hz), 8.18 (1 H, dd,
J = 2.0, 8.0 Hz), 8.60 (1 H, dd, J = 2.0, 4.5 Hz), 10.35 (1 H, s).
3-(2-Bromopyridinyl) Trifluoromethanesulfonate (11)
To a solution of 2-bromo-3-hydroxpyridine (870 mg, 5 mmol) in
anhyd Et2O (15 mL) was added a mixture of Et3N (0.78 mL,
5.5 mmol) and trifluoromethanesulfonic anhydride (1.552 g,
5.5 mmol) slowly at 0¡C under an Ar atmosphere with stirring. The
mixture was allowed to warm to r.t. over 3 h, and extracted with
Et2O. The Et2O extract was washed with brine and dried (MgSO4).
The residue was purified by silica gel column chromatography us-
ing EtOAc/hexane (1:10) as eluent to give a colorless liquid; yield:
1.125 g (73%); bp 70¡C/3 Torr.
MS: m/z = 185, 187 (M+).
3-Bromopyridine-4-carbaldehyde (5): yield: 92%; mp 77Ð78¡C.
IR (KBr): n = 1710 cmÐ1.
1H NMR (CDCl3): d = 7.70 (1 H, d, J = 4.8 Hz), 8.71 (1 H, d, J =
4.8 Hz), 8.91 (1 H, s), 10.37 (1 H, s).
IR (film): n = 1410, 1220 cmÐ1.
MS: m/z = 185 (M+).
1H NMR (CDCl3): d = 7.29 (1 H, dd, J = 4.3, 8.1 Hz), 7.55 (1 H,
dd, J = 1.5, 8.1 Hz), 8.29 (1 H, dd, J = 1.3, 4.5 Hz).
HRMS: calc. for C6H479BrNO: 184.9477. Found: 184.9462.
Table 6 o-Ethynylpyridinecarbaldehydes 7–9, 13 Prepared
Prod-
uct
mp (°C) or
bp (°C)/Torr
IR (KBr)
1H-NMR (CDCl3/TMS); d, J (Hz)
n (cm–1)
7a
7b
7c
8a
8b
96–97
2110, 1690
2220, 1695
2170, 1690
2220, 1710
2210, 1710
7.34–7.47 (4 H, m), 7.64–7.68 (2 H, m), 8.22 (1 H, dd, J = 1.8, 7.8), 8.83 (1 H, dd, J = 1.8, 6.6), 10.68
(1 H, s)
77/3
0.92 (3 H, br s), 1.30–1.37 (4 H, m), 1.47–1.50 (2 H, m), 1.63–1.71 (2 H, m), 2.54 (2 H, t, J = 7.2),
7.36 (1 H, dd, J = 4.9, 8.0), 8.16 (1 H, dd, J = 1.8, 8.0), 8.76 (1 H, dd, J = 1.8, 4.9), 10.55 (1 H, s)
50–51
120/3
90/32
0.29 (9 H, s), 7.37 (1 H, dd, J = 4.5, 7.8), 8.15 (1 H, dd, J = 2.0, 7.8), 8.75 (1 H, dd, J = 2.0, 4.5),
10.53 (1 H, s)
7.28–7.43 (3 H, m), 7.54–7.60 (2 H, m), 7.72 (1 H, d, J = 4.8), 8.74 (1 H, s), 8.97 (1 H, d, J = 4.8),
10.63 (1 H, s)
0.91 (3 H, br s), 1.25–1.35 (3 H, m), 1.43–1.49 (2 H, m), 1.61–1.74 (3 H, m), 2.51 (2 H, t, J = 6.9),
7.64 (1 H, d, J = 5.2), 8.65 (1 H, d, J = 5.2), 8.82 (1 H, s), 10.51 (1 H, s)
8c
9a
46–47
51–53
2190, 1710
2220, 1700
0.29 (9 H, s), 7.70 (1 H, s), 8.73 (1 H, br), 8.91 (1 H, br), 10.53 (1 H, s)
7.42–7.45 (3 H, m), 7.50 (1 H, dd, J = 1.0, 5.1), 7.59–7.62 (2 H, m), 8.77 (1 H, d, J = 5.1), 9.11 (1 H,
d, J = 1.0), 10.63 (1 H, s)
9b
9c
85/57
2240, 1700
2170, 1710
2210, 1710
2220, 1720
2170, 1718
0.85 (3 H, br s), 1.11–1.44 (6 H, m), 1.54–1.64 (2 H, m), 2.46 (2 H, t, J = 6.9), 7.30 (1 H, d, J = 5.0),
8.62 (1 H, d, J = 5.0), 8.98 (1 H, s), 10.46 (1 H, s)
viscous
liquid
0.17 (9 H, br s), 7.29 (1 H, d, J = 5.0), 8.61 (1 H, d, J = 5.0), 8.94 (1 H, s), 10.40 (1 H, s)
13a
13b
13c
115/3
7.38–7.43 (3 H, m), 7.50 (1 H, dd, J = 4.5, 8.0), 7.61–7.65 (2 H, m), 7.99 (1 H, dd, J = 1.6, 8.0), 8.75
(1 H, dd, J = 1.6, 4.5), 10.43 (1 H, s)
85/57
0.91 (3 H, br s), 1.31–2.49 (8 H, m), 2.16 (2 H, t, J = 7.2), 7.42 (1 H, dd, J = 4.6, 7.8), 7.85 (1 H, dd,
J = 1.5, 7.8), 8.90 (1 H, dd, J = 1.5, 4.6), 10.40 (1 H, s)
viscous
liquid
0.28 (9 H, s), 7.46 (1 H, dd, J = 4.6, 7.9), 7.93 (1 H, dd, J = 1.5, 7.9), 8.74 (1 H, dd, J = 1.5, 4.6),
10.43 (1 H, s)
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PAPER
General Synthetic Method for Naphthyridines
309
MS: m/z = 305, 307 (M+).
2-Bromo-3-[(trimethylsilyl)ethynyl]pyridine (12c)
From 11 (612 mg, 2.0 mmol) and trimethylsilylacetylene (392 mg,
4.0 mmol) for 2 h; colorless liquid; yield: 195 mg (38%); bp 55¡C/
3 Torr.
IR (film): n = 2170 cmÐ1.
1H NMR (CDCl3): δ = 0.24 (9 H, br s), 7.22 (1 H, dd, J = 4.8, 7.6 Hz),
7.74 (1 H, dd, J = 2.1, 7.6 Hz), 8.29 (1 H, dd, J = 2.1, 4.8 Hz).
MS: m/z = 254 (M+).
HRMS: calc. for C6H379BrF3NO3S, 304.8969. Found: 304.8961.
2-Bromo-3-ethynylpyridines 12; General Procedure
A mixture of 11 (2Ð4 mmol), the appropriate acetylene (2.2Ð
4 mmol), Pd(PPh3)2Cl2 (60 mg), LiCl (200 mg), Et3N (300 mg), and
DMF (10 mL) was stirred at 55¡C for the time given individually
below for each product 12. The mixture was diluted with H2O, and
extracted with Et2O. The residue obtained from the Et2O exact was
purified by silica gel column chromatography using EtOAc/hexane
(1:10) as eluent. The product was purified by distillation or recrys-
tallization.
HRMS: calc. for C10H1279BrNSi, 252.9922. Found: 252.9930.
3-Ethynylpyridine-2-carbaldehydes 13; General Procedure
To a solution of 12 (1.0 mmol) in anhyd Et2O (5 mL), was added
BuLi in hexane (1.1 mmol) under an Ar atmosphere at Ð78¡C, and
the mixture was stirred for 1 h at the same temperature. After addi-
tion of DMF (1 mL, 13 mmol), the mixture was stirred for 30 min.
The mixture was allowed to warm to r.t. over 10 min. Sat. aq NH4Cl
solution was added, and the mixture was extracted with Et2O. The
Et2O extract was washed with brine and dried (MgSO4). The residue
was purified by silica gel column chromatography using EtOAc/
hexane (1:10) as eluent (Table 6).
2-Bromo-3-phenylethynylpyridine (12a)
From 11 (1.08 g, 3.5 mmol) and phenylacetylene (393 mg,
3.9 mmol) for 15 h; yellow needles; yield: 608 mg (69%); mp 73Ð74¡C.
IR (KBr): n = 2220 cmÐ1.
1H NMR (CDCl3): d = 7.28 (1 H, dd, J = 4.5, 7.5 Hz), 7.38Ð7.41 (3
H, m), 7.58Ð7.61 (2 H, m), 7.81 (1 H, dd, J = 2.1, 7.8 Hz), 8.31 (1
H, dd, J = 1.8, 4.8 Hz).
MS: m/z = 257 (M+).
o-Ethynylpyridinecarbaldehyde Oximes 18Ð21; General Proce-
dure
Analysis: calc. for C13H18BrN: C, 60.49; H, 3.12; N, 5.42. Found:
C, 60.45; H, 3.30; N, 5.67.
A mixture of o-ethynylpyridinecarbaldehyde 7Ð9, 13 (1 mmol),
NH2OHáHCl (1.5 mmol), and NaOAc (1.5 mmol) in EtOH (5 mL)
was stirred at r.t. for the time shown in Table 4. After removal of the
solvent in vacuo, sat. aq K2CO3 solution was added to the residue,
and the mixture was extracted with CHCl3. The CHCl3 extract was
washed with brine and dried (MgSO4). The residue was purified by
silica gel column chromatography using CHCl3/EtOH (100:1) as
eluent (Table 7).
2-Bromo-3-(1-octynyl)pyridine (12b)
From 11 (918 mg, 3.0 mmol) and oct-1-yne (441 mg, 4 mmol) for
15 h, colorless liquid; yield: 567 mg (71%); bp 94¡C/3 Torr.
IR (film): n = 2220 cmÐ1.
1H NMR (CDCl3) : d = 0.91(3 H, br s), 1.26Ð1.67 (8 H, m), 2.48 (2
H, t, J = 6.6 Hz), 7.19 (1 H, dd, J = 4.8, 7.5 Hz), 7.67 (1 H, dd, J =
2.0, 7.8 Hz), 8.24 ( 1 H, dd, J = 2.0, 4.8 Hz).
Naphthyridines 14Ð17; General Procedure
A solution of an o-ethynylpyridinecarbaldehyde 7Ð9, 13 (1 mmol)
in EtOH (5 mL) which was saturated with NH3 was heated at 80¡C
MS: m/z = 265 (M+).
HRMS: calc. for C13H1679BrN, 265.0466. Found: 265.0505.
Table 7 o-Ethynylpyridinecarbaldehyde Oximes 18–21 Prepared
Prod-
uct
mp (°C) or
bp (°C)/Torr
IR (KBr)
1H-NMR (CDCl3/TMS); d, J (Hz)
n (cm–1)
18a
18b
18c
19a
19b
175–178
2220
2220
2170
2210
2210
7.28 (1 H, dd, J = 5.0, 7.8), 7.38–7.39 (3 H, m), 7.62–7.65 (2 H, m), 8.11 (1 H, s), 8.19 (1 H, d, J =
7.8), 8.63 (1 H, d, J = 5.0), 8.70 (1 H, s)
95–97
0.91 (3 H, br s), 1.30–1.69 (8 H, m), 2.50 (2 H, t, J = 7.5), 7.24 (1 H, dd, J = 4.8, 8.1), 7.84 (1 H, s),
8.12 (1 H, d, J = 8.1), 8.55 (1 H, d, J = 4.8), 8.59 (1 H, s)
137–139
174–177
73–74
0.30 (9 H, s), 7.26 (1 H, d, J = 8.1), 7.31 (1 H, b), 8.16 (1 H, dd, J = 1.8, 8.1), 8.57 (1 H, d, J =1.8),
8.59 (1 H, s)
7.26 (1 H, s), 7.39–7.40 (3 H, m), 7.56–7.59 (2 H, m), 7.76 (1 H, d, J = 5.2), 8.53 (1 H, d, J = 5.2),
8.63 (1 H, s), 8.81 (1 H, s)
0.91 (3 H, br s), 1.26–1.67 (8 H, m), 2.48 (2 H, t, J = 6.6), 7.26 (1 H, s), 7.67 (1 H, d, J = 4.9), 8.45
(1 H, d, J = 4.9), 8.53 (1 H, s), 8.66 (1 H, s)
19c
20a
148–150
170–173
2170
2220
0.29 (9 H, s), 7.72 (1 H, d, J = 5.5), 8.50 (1 H, d, J = 5.5), 8.52 (1 H, s), 8.72 (1 H, s), 8.76 (1 H, br)
7.41 (1 H, d, J = 5.1), 7.41–7.42 (3 H, m), 7.57–7.60 (2 H, m), 8.33 (1 H, s), 8.56 (1 H, d, J = 5.1),
8.64 (1 H, s), 9.15 (1 H, s)
20b
viscous liquid
2220
0.91 (3 H, br s), 1.19–1.64 (6 H, m), 2.48 (2 H, t, J = 6.9), 7.28 (1 H, d, J = 5.2), 8.46 (1 h, d, J = 5.2),
8.55 (1 H, s), 9.16 (1 H, s), 10.28 (1 H, br)
20c
21a
133–137
165–167
2170
2210
0.29 (9 H, s), 7.35 (1 H, d, J = 5.1), 8.50 (1 H, d, J = 5.1), 8.55 (1 H, s), 9.21 (1 H, s), 10.45 (1 H, br)
7.31 (1 H, dd, J = 4.6, 8.0), 7.38–7.40 (3 H, m), 7.55–7.58 (2 H, m), 7.87 (1 H, dd, J = 1.5, 8.0), 8.63
(1 H, dd, J = 1.5, 4.6), 8.80 (1 H, s), 9.15 (1 H, s)
21b
121–123
2220
0.91 (3 H, br s), 1.19–2.25 (8 H, m), 2.47 (2 H, t, J = 6.9), 7.22 (1 H, dd, J = 4.8, 7.8), 7.72 (1 H, dd,
J = 1.8, 7.8), 8.56 (1 H, dd, J = 1.8, 4.8), 8.72 (1 H, s), 9.71 (1 H, s)
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310
A. Numata et al.
PAPER
Table 8 Naphthyridines (14–17) Prepared
Prod-
uct
mp (°C) or
bp (°C)/Torr
1H NMR (CDCl3/TMS); d, J (Hz)
14a
14b
14c
138–139
7.46–7.56 (4 H, m), 8.18 (2 H, d, J = 8.4), 8.32 (1 H, d, J = 8.4), 8.36 (1 H, s), 9.11 (1 H, dd, J = 1.5, 4.5), 9.36 (1
H, s)
85/3
0.88 (3 H, br s), 1.30–1.41 (6 H, m), 1.84 (2 H, m), 3.00 (2 H, t, J = 7.5), 7.47 (1 H, dd, J = 4.0, 8.2), 7.74 (1 H, s),
8.26 (1 H, d, J = 8.2), 9.05 (1 H, d, J = 4.0), 9.22 (1 H, s)
35–36a
7.53 (1 H, dd, J = 4.3, 8.2), 7.91 (1 H, d, J = 6.1), 8.28 (1 H, dd, J =1.6, 8.2), 8.75 (1 H, d, J = 6.1), 9.09 (1 H, dd,
J =1.6, 4.3), 9.26 (1 H, s)
15a
15b
76–80
79/3
7.57–7.46 (3 H, m), 7.80 (1 H, d, J = 5.8), 8.13–8.18 (3 H, m), 8.70 (1 H, d, J = 5.8), 9.39 (1 H, s), 9.42 (1 H, s)
0.89 (3 H, br s), 1.29–1.41 (6 H, m), 1.83 (2 H, m), 2.99 (2 H, t, J = 7.5), 7.59 (1 H, s), 7.74 (1 H, d, J = 5.8), 8.64
(1 H, d, J = 5.8), 9.27 (1 H, s), 9.28 (1 H, s)
15c
16a
118–119b
127–128c
7.80 (2 H, d, J = 6.0), 8.74 (2 H, d, J = 6.0), 9.36 (2 H, s)
7.45–7.57 (3 H, m), 7.70 (1 H, d, J = 5.5), 8.05 (1 H, s), 8.14–8.17 (2 H, m), 8.73 (1 H, d, J = 5.5), 9.43 (1 H, s),
9.50 (1 H, s)
16b
90/3
0.89 (3 H, br s), 1.33–1.39 (6 H, m), 1.79 (2 H, t, J = 7.4), 2.97 (2 H, t, J = 7.4), 7.45 (1 H, s), 7.57 (1 H, d, J = 5.9),
8.66 (1 H, d, J = 5.9), 9.35 (2 H, s)
16c
17a
92–94d
7.66 (2 H, d, J = 6.0), 8.75 (2 H, d, J = 6.0), 9.45 (2 H, s)
116–117
7.45–7.55 (3 H, m), 7.61 (1 H, d, J = 4.0, 8.4), 8.06 (1 H, s), 8.15 (2 H, m), 8.21 (1 H, d, J = 8.4), 9.01 (1 H, dd,
J = 1.5, 4.0), 9.61 (1 H, s)
17b
78/3
0.89 (3 H, br s), 1.29–1.43 (6 H, m), 1.81–1.86 (2 H, m), 2.98 (2 H, t, J = 7.8), 7.47 (1 H, s), 7.57 (1 H, dd, J = 4.0,
8.4), 8.10 (1 H, d, J = 8.4), 8.97 (1 H, d, J = 4.0), 9.48 (1 H, s)
17c
64–65e
7.29–7.67 (2 H, m), 8.18 (1 H, d, J = 8.4), 8.64 (1 H, d, J = 6.0), 9.05 (1 H, dd, J = 1.5, 3.9), 9.54 (1 H, s)
a Lit.1c mp 35–36°C.
b Lit.10 mp 114–115°C.
c Lit.11 mp 126–127°C.
d Lit.12 mp 92–94°C.
e Lit.13 mp 60–62°C.
Table 9 Naphthyridine N-Oxides 22–25 Prepared
Prod-
uct
mp (°C)
1H NMR (CDCl3/TMS); d, J (Hz)
22a
22b
196–199
97–98
7.48–7.53 (4 H, m), 7.83–7.86 (2 H, m), 8.03 (1 H, d, J = 8.1), 8.06 (1 H, s), 8.80 (1 H, s), 8.93 (1 H, d, J = 4.5)
0.90 (3 H, br s), 1.20–1.53 (6 H, m), 1.83 (2 H, t, J = 7.0), 3.06 (2 H, t, J = 7.0), 7.45 (1 H, dd, J = 5.0, 10.0), 7.87 (1 H,
s), 8.00 (1 H, d, J = 10.0), 8.81 (1 H, s), 8.91 (1 H, d, J = 5.0)
22c
150–151a
7.55 (1 H, dd, J = 3.6, 8.2), 7.94 (1 H, d, J = 7.3), 8.05 (1 H, d, J = 8.2), 8.33 (1 H, dd, J = 1.8, 7.3), 8.74 (1 H, s), 8.95
(1 H, s)
23a
23b
199–203
84–85
7.51–7.53 (4 H, m), 7.78–7.80 (2 H, m) , 7.91 (1 H, s), 8.64 (1 H, d, J = 5.7), 8.86 (1 H, s), 9.22 (1 H, s)
0.91 (3 H, br s), 1.31–1.50 (6 H, m), 1.84 (2 H, t, J = 8.0), 3.03 (2 H, t, J = 8.0), 7.48 (1 H, d, J = 5.0), 7.71 (1 H, s),
8.59 (1 H, d, J = 5.0), 8.79 (1 H, s), 9.18 (1 H, s)
23c
24a
24b
198–201
203–205
74–75
7.52 (1 H, d, J = 5.7), 7.80 (1 H, d, J = 7.2), 8.21 (1 H, d, J = 7.2), 8.67 (1 H, d, J = 5.7), 8.72 (1 H, s), 9.21 (1 H, s)
7.51–7.54 (3 H, m), 7.61 (1 H, d, J = 5.4), 7.79–7.82 (3 H, m), 8.64 (1 H, d, J = 5.4), 9.00 (1 H, s), 9.18 (1 H, s)
0.91 (3 H, br s), 1.33–1.48 (8 H, m), 1.81 (2 H, t, J = 7.8), 7.56 (1 H, d, J = 5.5), 7.60 (1 H, s), 8.60 (1 H, d, J = 5.5),
8.92 (1 H, s), 9.13 (1 H, s)
24c
25a
25b
213–215
212–214
86–88
7.63 (1 H, d, J = 5.7), 7.69 (1 H, d, J = 7.5), 8.29 (1 H, d, J = 7.5), 8.67 (1 H, d, J = 5.7), 8.48 (1 H, s), 9.18 (1 H, s)
7.44–7.54 (4 H, m), 7.76 (1 H, s), 7.79–7.82 (2 H, m), 8.10 (1 H, d, J = 8.4), 8.97 (1 H, d, J = 4.5), 9.14 (1 H, s)
0.91 (3 H, br s), 1.31–1.50 (8 H, m), 1.81 (2 H, t, J = 7.5), 7.47 (1 H, dd, J = 4.2, 8.1), 7.55 (1 H, s), 8.05 (1 H, d, J =
8.1), 8.91 (1 H, d, J = 4.2), 9.07 (1 H, s)
25c
142–145
7.51 (1 H, dd, J = 4.3, 8.2), 7.68 (1 H, d, J = 7.0), 8.14 (1 H, d, J = 8.2), 8.22 (1 H, d, J = 7.0), 8.99 (1 H, d, J = 4.3),
9.00 (1 H, s)
a Lit.6d mp 150°C.
Synthesis 1999, No. 2, 306–311 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
General Synthetic Method for Naphthyridines
311
(3) (a) Oakes, V.; Rydon, H. N. J. Chem. Soc. 1958, 204.
(b) Hawes, E. M.; Gorecki, D. K. J. J. Heterocycl. Chem.
1972, 9, 703; 1974, 11, 151.
for 2 h in a sealed tube. After removal of the EtOH, sat. aq K2CO3
solution was added to the residue, and the mixture was extracted
with CHCl3. The CHCl3 extract was washed with brine and dried
(MgSO4). The residue was purified by silica gel column chromatog-
raphy using CHCl3/EtOH (100:1) as eluent (Table 8).
(c) Baumgarten, H. E.; Cook, K. C. J. Org. Chem. 1957, 22,
138.
(d) Decormeille, A.; Guignant, F.; Queguiner, G.; Pastour, P.
J. Heterocycl. Chem. 1976, 13, 387.
(e) Hawes, E. M.; Wibberley, D. G. J. Chem. Soc. (C) 1966,
315; 1967, 1564.
Naphthyridine N-Oxides 22Ð25; General Procedure
A mixture of an o-ethynylpyridinecarbaldehyde oxime 18Ð21
(1 mmol) and K2CO3 (1.5 mmol) in EtOH (10 mL) was heated at the
temperature for the time shown in Table 5. After removal of the
EtOH in vacuo, the residue was made alkaline with sat. aq K2CO3
solution and extracted with CHCl3. The CHCl3 extract was washed
with brine and dried (MgSO4). The residue was purified by silica
gel column chromatography using CHCl3/EtOH (100:1) as eluent
(Table 9).
(4) (a) Adams, J. T.; Bradsher, C. K.; Breslow, D. S.; Amore, S.
T.; Hauser, C. R. J. Am. Chem. Soc. 1946, 68, 1317.
(b) Lappin, G. R. J. Am. Chem. Soc. 1948, 70, 3348.
(c) Hause, C. R.; Reynolds, G. A. J. Org. Chem. 1950, 15,
1224.
(d) Adams, R; Pachter, I. J. J. Am. Chem. Soc. 1952, 74, 5491.
(5) (a) Baldwin, J. J.; Mensler, K.; Ponticello, G. S. J. Org. Chem.
1978, 43, 4878.
(b) Tan, R.; Taurins, A. Tetrahedron Lett. 1966, 1233; 1965,
2737.
Acknowledgement
The authors express their appreciation to Mr. Kazuhiko Hayashi
and Miss Saori Yasuda for their helpful assistance of this work.
This work was supported in part by a Grant-in-Aid for ScientiÞc
Research (No. 09672135) from the Ministry of Education, Science,
Sports, and Culture, Japan.
(c) van den Haak, H. J. W.; van der Plas, H. C.; van Veldhui-
zen, B. J. Heterocycl. Chem. 1981, 18, 1349.
(6) (a) Takahashi, T.; Hamada, Y.; Takeuchi, I.; Uchiyama, H.
Yakugaku Zasshi 1969, 89, 1260; Chem. Abstr. 1970, 72,
12615.
(b) Pokorny, D. J.; Paudler, W. W. J. Org. Chem. 1972, 37,
310.
(c) Kobayashi, Y.; Kumadaki, I.; Sato, H. Chem. Pharm. Bull.
1969, 17, 1045.
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Synthesis 1999, No. 2, 306–311 ISSN 0039-7881 © Thieme Stuttgart · New York