LETTER
A One-Pot Method for the Synthesis of Naphthyridines
381
4-Ethyl-1,8-naphthyridine (3e)
SeO2
Procedure B was used. Yield 82%. Appearance: dark oil; Rf = 0.37
(MeCN). 1H NMR (500 MHz, CDCl3): d = 9.12 (dd, J = 4.2, 1.9 Hz,
1 H), 9.04 (d, J = 4.5 Hz, 1 H), 8.44 (dd, J = 8.4, 1.9 Hz, 1 H), 7.51
(dd, J = 8.4, 4.2 Hz, 1 H), 7.34 (d, J = 4.5 Hz, 1 H), 3.14 (q, J = 7.6
Hz, 2 H), 1.41 (t, J = 7.6 Hz, 3 H). MS (APCI+): m/z = 159 [M +
H]+.
pyridine, reflux
N
N
CO2H
N
N
CH3
12
86%
6
Cl
TMSCH2MgBr
Ni(acac)2, Et2O, 0 °C to r.t.
TMS
N
N
4-Chloro-1,8-naphthyridine (3f)14 – General Procedure C
A solution of compound 1f (4.56 g, 20.0 mmol) and TMEDA (7.0
mL, 46.5 mmol) in THF (60 mL) was cooled to –70 °C and n-BuLi
(2.5 M in hexane, 18 mL, 45.0 mmol) was added dropwise. The re-
action was stirred at –50 °C for 1 h. Compound 2 was then added
dropwise, and the reaction stirred at –70 °C for 1.5 h followed by
quenching with 3 N HCl (30 mL). After warming to r.t., the aqueous
layer (pH 8–9) was separated and the organic layer extracted with 3
N HCl (40 mL). The acidic aqueous extract was then heated to re-
flux for 3 h. After this time the reaction was cooled to r.t., treated
with solid K2CO3 (40 g) and the resulting mixture immediately ex-
tracted with EtOAc (4 × 100 mL), decanting the extracts. The re-
sulting crude material was purified by column chromatography to
afford 3f in 30% yield (0.97 g). Appearance: tan solid; mp 48–
N
N
3d
13
69%
Scheme 5
1,8-Naphthyridine (3a)4b – General Procedure A
A solution of compound 1a (3.65 g, 20.5 mmol) in THF (40 mL)
was cooled to –70 °C and n-BuLi (2.5 M in hexane, 18 mL, 45.0
mmol) was added dropwise. The reaction was warmed to 0 °C,
stirred at this temperature for 3 h, and then re-cooled to –70 °C.
Compound 2 was then added dropwise, the reaction stirred at
–70 °C for 1 h then slowly warmed to 0 °C over 2 h. The reaction
was then quenched with 4 N HCl (30 mL); the aqueous layer was
separated and heated to 80–90 °C, distilling off most of the organic
solvent. After a further 45 minutes, the reaction was cooled, treated
with solid K2CO3 (30 g) and the resulting solids extracted with
EtOAc (4 × 50 mL), decanting the extracts. After concentration, the
resulting crude material was purified by column chromatography to
afford 3a in 80% isolated yield (2.14 g). Appearance: brown solid;
1
50 °C; Rf = 0.30 (EtOAc). H NMR (300 MHz, CDCl3): d = 9.20
(dd, J = 4.2, 1.9 Hz, 1 H), 9.04 (d, J = 4.7 Hz, 1 H), 8.63 (dd,
J = 8.4, 1.9 Hz, 1 H), 7.62 (dd, J = 8.4, 4.2 Hz, 1 H), 7.60 (d, J = 4.8
Hz, 1 H). MS (ESI): m/z = 165 [M + H]+.
1,6-Naphthyridine (4)15
Procedure A was used but the reaction was heated at reflux for 3 h.
Yield 71%. Appearance: brown solid; mp 25–26 °C; Rf = 0.42 (6%
MeOH in CH2Cl2). 1H NMR (500 MHz, CDCl3): d = 9.30 (d, J = 1.0
Hz, 1 H), 9.12 (dd, J = 4.5, 2.0 Hz, 1 H), 8.78 (d, J = 6.0 Hz, 1 H),
8.31 (ddd J = 8.0, 2.0, 1.0 Hz, 1 H), 7.94 (d, J = 6.0 Hz, 1 H), 7.56
(dd, J = 8.0, 4.5 Hz, 1 H). MS (ESI): m/z = 131 [M + H]+.
1
mp 84–86 °C; Rf = 0.33 (6% MeOH in CH2Cl2). H NMR (300
MHz, CDCl3): d = 9.15 (dd, J = 4.2, 1.9 Hz, 2 H), 8.22 (dd, J = 8.2,
1.9 Hz, 2 H), 7.51 (dd, J = 8.2, 4.2 Hz, 2 H). MS (ESI): m/z = 131
[M + H]+.
2-Methyl-1,8-naphthyridine (6)4b
4-Methyl-1,8-naphthyridine (3b)4b – General Procedure B
The dianion of 1b was obtained as follows. A solution of compound
1b (9.60 g, 50.0 mmol) in Et2O (200 mL) was cooled to –70 °C and
t-BuLi (1.7 M in pentane, 65 mL, 111 mmol) was added dropwise.
After 1 h at –78 °C, the mixture was warmed to –10 °C over 30 min
then re-cooled to –70 °C. Then procedure A was followed. Yield
77%. Appearance: brown solid; mp 25–27 °C; Rf = 0.32 (6%
Compounds 1a and 5 were reacted using procedure A but the reac-
tion was heated at reflux for 4 h. 2-Methyl-1,8-naphthyridine (6)
was separated from regioisomer 3a using flash chromatography on
silica gel and eluting with a gradient from 100% EtOAc to 90:10
EtOAc–MeOH. Compound 6 eluted first. Yield 58%. Appearance:
tan solid; mp 95–96 °C; Rf = 0.34 (6% MeOH in CH2Cl2). 1H NMR
(500 MHz, CDCl3): d = 9.07 (dd, J = 4.5, 2.0 Hz, 1 H), 8.14 (dd,
J = 8.0, 2.0 Hz, 1 H), 8.07 (d, J = 8.5 Hz, 1 H), 7.43 (dd, J = 8.0, 4.0
Hz, 1 H), 7.38 (d, J = 8.0 Hz, 1 H), 2.82 (s, 3 H). MS (ESI): m/z =
145 [M + H]+.
1
MeOH in CH2Cl2). H NMR (500 MHz, CDCl3): d = 9.12 (dd,
J = 4.2, 1.9 Hz, 1 H), 8.98 (d, J = 4.4 Hz, 1 H), 8.40 (dd, J = 8.3, 2.0
Hz, 1 H), 7.51 (dd, J = 8.4, 4.2 Hz, 1 H), 7.33 (d, J = 4.4 Hz, 1 H),
2.73 (s, 3 H). MS (APCI+): m/z = 146 [M + H]+.
3-Methyl-1,8-naphthyridine (3c)13
1,8-Naphthyridin-4-one Hydrochloride Hydrate (9)
Acrylate 8 (7.0 mL, 48.4 mmol) was added dropwise at –70 °C to
the dianion obtained from 3.56 g (20.0 mol) of 1a (see procedure
A). The mixture was stirred at –50 °C to –40 °C for 5.5 h and
quenched with AcOH (3.0 mL, 50 mmol) followed by H2O (30 mL).
The organic layer was separated, washed with sat. NaHCO3 and the
components were isolated by flash chromatography. Yield of 10
Procedure A was used but the acid-mediated condensation reaction
was heated at reflux overnight. Yield 60%. Appearance: tan solid;
mp 109–110 °C; Rf = 0.46 (6% MeOH in CH2Cl2). H NMR (300
MHz, CDCl3): d = 9.07 (dd, J = 4.2, 1.8 Hz, 1 H), 9.00 (d, J = 2.4
Hz, 1 H), 8.13 (dd, J = 8.1, 1.8 Hz, 1 H), 7.95 (d, J = 0.9 Hz, 1 H),
7.47 (dd, J = 8.1, 4.2 Hz, 1 H), 2.57 (s, 3 H). MS (ESI): m/z = 145
[M + H]+.
1
1
42% (2.71 g). Appearance: yellow solid; Rf = 0.40 (EtOAc). H
NMR (500 MHz, DMSO-d6): d = 10.46 (s, 1 H), 8.51 (dd, J = 4.8,
1.8 Hz, 1 H), 8.05 (dd, J = 7.7, 1.8 Hz, 1 H), 7.30 (dd, J = 7.7, 4.8
Hz, 1 H), 4.84 (t, J = 5.5 Hz, 1 H), 3.55 (m, 2 H), 3.42 (m, 2 H), 3.08
(d, J = 5.6 Hz, 2 H), 1.21 (s, 9 H), 1.03 (t, J = 7.1 Hz, 6 H). MS
(ESI): m/z = 323 [M + H]+.
3-Chloro-1,8-naphthyridine (3d)14
Modified procedure A was used. The dianion of 1d was obtained as
follows. A solution of compound 1d (4.40 g, 20.5 mmol) in THF (40
mL) was cooled to –70 °C. Then, t-BuLi (1.7 M in pentane, 27 mL,
45.1 mmol) was added dropwise and the mixture was stirred for 3 h
at –78 °C. Then procedure A was followed. Yield 77%. Appear-
ance: tan solid; mp 147–149 °C; Rf = 0.36 (EtOAc). 1H NMR (500
MHz, CDCl3): d = 9.14 (dd, J = 4.0, 2.0 Hz, 1 H), 9.06 (d, J = 2.5
Hz, 1 H), 8.19 (d, J = 2.5 Hz, 1 H), 8.16 (dd, J = 8.5, 2.0 Hz, 1 H),
7.55 (dd, J = 8.0, 4.0 Hz, 1 H). MS (ESI): m/z = 165 [M + H]+.
Compound 10 (2.71 g, 9.78 mmol) was heated with 3 N HCl in H2O
for 2 h. Upon cooling to 10 °C, 9 precipitated and was filtered off
and dried. Yield 51% (1.00 g). Appearance: light yellow solid; mp
243–245 °C; Rf = 0.21 (6% MeOH in CH2Cl2). 1H NMR (500 MHz,
DMSO-d6): d = 15.00–11.70 (br s, 1 H), 9.00 (dd, J = 4.4, 1.9 Hz,
1 H, H-7), 8.65 (dd, J = 8.2, 1.9 Hz, 1 H, H-5), 8.49 (d, J = 7.2 Hz,
1 H, H-2), 7.66 (dd, J = 8.2, 4.4 Hz, 1 H, H-6), 6.85 (d, J = 7.2 Hz,
Synlett 2006, No. 3, 379–382 © Thieme Stuttgart · New York