Microwave-mediated reactions of 3-aminomethylpyridines with acetylenedicarboxylates. A novel synthetic route to dihydronaphthyridines and naphthyridine-1-ones

Article abstract of DOI:10.1016/j.tetlet.2005.04.053

Reaction of 3-(1-alkylamino)pyridines with electron deficient acetylenes in the presence of acids yields 1,2-dihydro[2,7]naphthyridine-3,4- dialkyldicarboxylates 4 in 35-72% yield. Compounds 4 unsubstituted in position 1 can be easily oxidized with potassium permanganate into the respective naphthyridine-1-ones derivatives 5 in good yields.

Full text of DOI:10.1016/j.tetlet.2005.04.053

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 3953–3956
Microwave-mediated reactions of 3-aminomethylpyridines
with acetylenedicarboxylates. A novel synthetic route
to dihydronaphthyridines and naphthyridine-1-ones
Vladimir Y. Vvedensky,* Yury V. Ivanov, Volodymyr Kysil, Caroline Williams,
Sergei Tkachenko, Alexander Kiselyov, Alexander V. Khvat and
Alexandre V. Ivachtchenko
ChemDiv Inc., 11558 Sorrento Valley Rd., San Diego, CA 92121, USA
Received 22 March 2005; revised 9 April 2005; accepted 12 April 2005
Abstract—Reaction of 3-(1-alkylamino)pyridines with electron deficient acetylenes in the presence of acids yields 1,2-dihydro-
[2,7]naphthyridine-3,4-dialkyldicarboxylates 4 in 35–72% yield. Compounds 4 unsubstituted in position 1 can be easily oxidized with
potassium permanganate into the respective naphthyridine-1-ones derivatives 5 in good yields.
ꢀ 2005 Elsevier Ltd. All rights reserved.
The 2,7-naphthyridine template is well represented both
in nature (e.g., Sceavodimerine C,1a see Fig. 1) as well as
in drug discovery programs of pharmaceutical compa-
nies (see characteristic compounds A,1b B,1c C,1d Fig.
1). Derivatives of [2,7]naphthyridine could be consid-
ered as rigidified analogs of nicotine.1e In the course of
our medicinal chemistry efforts, a robust and reliable
approach to this template was needed.
onto the reaction of substituted pyridines, including
l-anabasine 1a (Scheme 1), with activated acetylenes.
Reaction of acetylenes with amines has been studied in
great details. It has been suggested that the outcome is
dependent on (i) stoichiometry of reagents, (ii) nature
of reagents, and (iii) reaction conditions.2a–c For exam-
ple, it has been reported that the reaction of one equiv-
alent of acetylenecarboxylates with amines yields the
respective enamines.1a In our hands, slow addition of
the stoichiometric amount of diethyl acetylenedicarb-
oxylate to a solution of l-anabasine 1a in EtOH or
As part of our ongoing program of new Ôdrug-likeÕ
library templates development we decided to look closer
O
N
O
S
HN
O
N
O
Heterocyclyl
N
O
O
O
O
N
NH
O
O
N
N
O
O
NH
N
N
N
O
S
O
O
O
N
Cl
O
N
N
A
B
C
O
Sceavodimerine C
F
Figure 1.
Keywords: [2,7]Naphthyridines; Anabasine; Enamines.
*
Corresponding author. E-mail: vv@chemdiv.com
0040-4039/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.04.053

3954
V. Y. Vvedensky et al. / Tetrahedron Letters 46 (2005) 3953–3956
Z
Z
2
Z
Z
N
N
N
N
H
+
N
O
Z
Z
N
Z
N
2a
9
Z
4a
Z
1a
Z
Z= COOEt
Scheme 1.
DMF at RT led to the exclusive formation of enamine
2a (isolated yield 87%), as expected (Scheme 1). How-
ever, rapid addition of two equivalents of acetylenecarb-
oxylate to a vigorously stirred mixture of anabasine 1a,
and K2CO3 in dry DMF at RT afforded complex mix-
ture of products and ca. 50% of unreacted anabasine.
Preparative TLC separation of this mixture (silica
gel, 5% MeOH in CHCl3) allowed us to identify two
unexpected products: 1,2-dihydro[2,7]naphthyridine
4a3 (yield 10%) and acroleine derivative 9 (yield
4.5%)4 (Scheme 1).
170 ꢁC) of enamines 2 did not result in formation of
naphthyridines 4 (Scheme 2). Mechanistically, the for-
mation of compounds 4 is explained as intramolecular
electrophilic attack of sp2 carbon at b-position of dien-
amine 3 at the position 4 of its pyridine ring. Formally,
this process should be accompanied with diethyl malei-
nate or fumarate formation. However, appropriate
molecular ions were not detected on LC–MS spectra.
During the course of this study, we found that com-
pounds 4a–d substituted at position 1 of naphthyridine
cycle are stable upon storage. In contrast, 1-unsubsti-
tuted compounds (R1 = H, 4e–h) are prone to a gradual
oxidation by air into the respective naphthyridine-1-
ones 5e–h. This conversion is facilitated by KMnO4 in
CH2Cl2 (cat. 18-crown-6, Scheme 2)7 to yield 5e–h in
good yields (61–92%). Attempts to synthesize 5e–h
directly from N-benzylnicotinamides and diethyl acetyl-
enedicarboxylate under a variety of experimental condi-
tions described in the literature8 were unsuccessful.
In order to further investigate this conversion, we varied
the reaction conditions as well as the amine input. In
this paper, we report an optimized general route to
1,2- and 2-substituted 1,2-dihydro[2,7]naphthyridine
dialkyl-3,4-dicarboxylates 4 and their derivatives.
Slow addition of dialkyl acetylene dicarboxylate
(2 equiv, 30 min) to the EtOH solution of amine 1a–h
in the presence of TFA or HCl at 0 ꢁC led to the forma-
tion of the respective enamine 2a–h (LCMS analysis).
These species gradually reacted with the second equiva-
lent of the acetylene to yield dienes 3a–h (Scheme 2,
LCMS detection).2a–c Attempted isolations of interme-
diates 3a–h by flash chromatography were not success-
ful, probably due to their instability on silica gel.
Microwave irradiation of dienes 3a–h without isolation
(150 ꢁC, 20 min) followed by flash chromatography or
HPLC purification yielded naphthyridines 4a–h in 35–
76% isolated yields.5 In contrast, the conventional
heating of the mixtures at 150 ꢁC in stainless steel auto-
clave required 3–5 h for complete conversion of dienes 3,
and the yields of 4a–h were ca. 10–15% lower. In
addition, under conventional heating we observed de-
carboxylated products 6a–h (yield 10–12% vs 1–2% at
microwave heating).6 Microwave heating (up to
We further investigated the reaction of compound 4a
with aqueous methylamine (Scheme 3). Under the reac-
tion conditions (0.2 M solution of 4a in 40% aq MeNH2,
microwave heating, 30 min, 150 ꢁC) the isolated prod-
ucts of the reaction were acid 10 (major component,
85% isolated yield) along with 4-substituted mono-meth-
ylamide 11 (minor component, yield 10%). Thus, the
MeNH2
N
N
4a
N
N
+
HOOC
11
10
CONHMe
COOEt
Scheme 3.
R1
R1
R1
Z
Z
R2
R2
Z
R2
Z
Z
N
Z
Z
N
N
H
Z
N
Z
N
N
Z
2a-h
1a-h
3a-h
R1
R1
O
Z
R2
R1 = H
[O]
R2
Z
R2
Z
N
N
N
N
N
N
∆
6a-h
Z
4a-h
5e-h
Z
Scheme 2.

V. Y. Vvedensky et al. / Tetrahedron Letters 46 (2005) 3953–3956
3955
Boeck, B. D.; Jiang, S.; Janousek, Z.; Viehe, H. G.
Tetrahedron 1994, 7075–7092.
Z
Z
Z
Z
H
H
3. This reported reactivity of 3-aminomethylpyridines 1a–h
towards activated acetylenes appears to be unique. Similar
conversions of secondary amines and pyridines yield
pyrrolizines 7a,b2a or a mixture of 9aH-quinolizine 8 and
its 4H isomer 9, respectively9a,b (Scheme 4).
i)
Z
+
Z
Z
N
N
ii)
Z
Z
N
H
[1c]
7b
7a
4. Similar pyridine ring openings were described, e.g. (a)
Ferguson, G.; Fisher, K. J.; Ibrahim, B. E.; Ishag, C. Y.;
Iskander, G. M.; Katritzky, A. R.; Parvez, M. J. Chem.
Soc., Chem. Comm. 1983, 1216–1217; (b) Ishag, C. Y.;
Fisher, K. J.; Ibrahim, B. E.; Iskander, G. M.; Katritzky,
Z
Z
2
Z
Z
Z
Z
N
N
+
[9]
N
Z
Z
Z
Z
9
Z= COOMe
Scheme 4.
8
A. R. J. Chem. Soc., Perkin Trans.
920.
1 1988, 917–
5. General procedure for the synthesis of compounds 4a–h: A
solution of diethyl acetylenedicarboxylate (1 mmol) in 1 ml
EtOH was added dropwise over 30 min at 0 ꢁC to a mixture
of amine 1 (0.5 mmol), 4 ml EtOH and TFA (0.5 mmol).
The mixture was kept at 0 ꢁC for 30 min and for additional
12 h at room temperature. After 12 h, the solution was
heated for 20 min at 150 ꢁC in microwave reactor (Personal
Chemistry TMOptimizer, 300 W). The solvent were removed
under reduced pressure and obtained crude mixtures were
purified by preparative HPLC (Phenomenex Luna C18
column, mobile phase: water/acetonitrile with 0.05% TFA),
or by flash chromatography on silica (CHCl3/MeOH/
Et3N = 100:6:1). Yields: 34–76% (Table 1).
Table 1. Yields of naphthyridines 4a–h and naphthyridine-2-ones 5e–h
Compound
Z
R2
R1
Yield (%)
4a
COOEt
(CH2)4
34a
49
70
35
43
45
67
75
73
76
62b
92
89
61
4a0
4b
4c
4d
4e
4f
COOMe
COOEt
COOEt
COOEt
COOEt
COOEt
COOEt
COOEt
COOEt
COOEt
COOEt
COOEt
(CH2)4
(CH2)3
(CH2)3OMe
(CH2)2NMe2
PhCH2
Me
Me
H
2-F-PhCH2
3-F-PhCH2
4-F-PhCH2
PhCH2
H
Diethyl 2-(4-fluorobenzyl)-1,2-dihydro[2,7]naphthyridine-
3,4-dicarboxylate (4h). HRMS (ESI-TOF): m/z [M+H+]
calculated for C21H21N2O4F: 385.1558. Found: 385.1557.
1H NMR(DMSO, TMS, ppm): d 8.51 (1H, J = 6.5 Hz), s
8.41 (1H), d 8.33 (1H, J = 6.5 Hz), m 7.43 (2H), m 7.27
(2H), s 4.66 (2H), s 4.62 (2H), q 4.36 (2H, J = 7.2 Hz), q
4.22 (2H, J = 7.2 Hz) t 1.26 (3H, J = 7.2 Hz), t 1.24 (3H
J = 7.2 Hz). 13C NMR(DMSO, TMS, ppm) 164.0, 162.6,
162.1 d (J = 250.2 Hz), 155.9, 150.4, 146.7, 140.2, 137.1,
132.4 d (J = 8.4 Hz), 130.3 d (J = 8.4 Hz), 117.5, 115.7 d
(J = 21.4 Hz), 95.5 ppm.
4g
4h
5e
5f
H
H
H
2-F-PhCH2
3-F-PhCH2
4-F-PhCH2
H
5g
5h
H
H
a Conventional heating in stainless steel autoclave.
b Spontaneous oxidation by air.
6. Structure of compound 6b was confirmed by NOESY
experiment which showed cross-pick of N–CH@ proton at
position 3 (7.82 ppm) and equatorial proton of CH2CH2–N
group at 3.59 ppm.
reported protocol could be used for desymmetrization
of COOEt moieties in 4.
In a conclusion, we found a facile one-pot approach to
1,2-dihydro[2,7]naphthyridine-4-alkoxycarboxylates
7. The corresponding naphthyridine 4 (0.2 mmol) was added
into suspension of KMnO4 (158 mg, 1 mmol) in 20 ml of
dichloromethane with catalytic amount of 18-crown-6 (3–4
drops of 10% solution in dichloromethane). The reaction
mixture was stirred at room temperature until no starting
naphthyridine was detected (ꢀ2 h, control by LC–MS). The
final suspension was filtered through Celite and washed
with concentrated solution of sodium metabisulfite in water
(1 · 20 ml). The organic layer was separated and filtered
through Celite to remove inorganic residue. The solvent
was removed under reduced pressure and the oily residue
was purified by flash chromatography (silica gel, hex-
ane:ethyl acetate = 1:2). The corresponding naphthyridines
5e–h were isolated as slightly yellow powders and the yields
were 60–92%.
4
from 3-alkylaminopyridines and electron deficient
acetylenes. The reaction was mediated by a microwave
irradiation. Upon oxidation of compounds 4e–h with
KMnO4, respective naphthyridine-1-ones 5 were iso-
lated in good yields (61–92%). The protocol for dysym-
metrization of carboxylic moieties in 4 was developed
and respective monosubstituted derivatives 6 and 10
were obtained.
References and notes
1. (a) Skaltsounis, A.-L.; Tillequin, F.; Koch, M.; Pusset, J.;
Chauviere, G. Heterocycles 1987, 599; (b) Failli, A. A. US
Pat. 216922, 1988; (c) Omori, K.; Kikkawa, K.; Ukita, T.
Pat. Japan 139701, 1999; 338301, 1998; 240838, 1998; (d)
Patchett, A. A.; Ye, Z.; Palucki, B. L.; Van der Ploeg,
L. H. T.; Nargund, R. P.; Bakshi, R. K. US Pat. 123260,
1999; (e) Sarkar, T. K.; Basak, S.; Wainer, I.; Moaddel, R.;
Yamaguchi, R.; Jozwiak, K.; Chen, H. T.; Lin, C. C.
J. Med. Chem. 2004, 47(27), 6691–6701.
Diethyl 2-(4-fluorobenzyl)-1-oxo-1,2-dihydro[2,7]naphthyr-
idine-3,4-dicarboxylate (5h). HRMS (ESI-TOF): m/z
[M+H+] calculated for C21H19FN2O5: 399.1351. Found:
399.1366. 1H NMR(CDCl 3, TMS): d 9.65 (1H, J = 0.8 Hz),
d
8.84 (1H, J = 5.8 Hz), dd 8.16 (1H, J = 5.8 Hz,
J = 0.8 Hz), m 7.22–7.29 (1H), m 6.97–7.03 (3H), s 5.34
(2H), q 4.40 (2H, J = 7.0 Hz), q 4.24 (2H, J = 7.0 Hz), t 1.41
(3H, J = 7.0 Hz), t 1.74 (3H J = 7.0 Hz). 13C NMR(CDCl 3,
TMS): 164.1, 163.6, 162.4 d (J = 247 Hz), 161.0, 152.3,
151.9, 144.2, 138.9, 131.2 d (J = 3.4 Hz), 129.3 d (J =
8.4 Hz), 119.7, 118.4, 115.6 d (J = 21.4 Hz), 106.8, 63.1,
62.2, 48.4, 14.1, 13.5 ppm.
2. (a) Ancos, B.; Maestro, M. C.; Martin, M. R.; Mateo, A. I.
Tetrahedron 1994, 50, 13857; (b) Jiang, S.; Janousek, Z.;
Viehe, H. G. Tetrahedron Lett. 1994, 35(8), 1185–1188; (c)

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V. Y. Vvedensky et al. / Tetrahedron Letters 46 (2005) 3953–3956
8. Known examples of reaction of amides with substituted
acetylenes: (a) Hayashi, Y.; Shoji, M.; Yamaguchi, S.;
Mukaiyama, T.; Yamaguchi, J.; Kakeya, H.; Osada, H.
Org. Lett. 2003, 5(13), 2287–2290; (b) Koseki, Y.; Kusano,
S.; Ichi, D.; Yoshida, K.; Nagasaka, T. Tetrahedron 2000,
56(45), 8855–8865; (c) Noritaka, A.; Tarozaemon, N. Bull.
Soc. Chem. Jpn. 1981, 54(4), 1277–1278.
9. (a) Acheson, R. M.; Foxton, M. W.; Hands, A. R. J. Chem.
Soc. C 1968, 387; (b) Acheson, R. M.; Feinberg, R. S.;
Gagan, J. M. F. J. Chem. Soc. 1965, 948.