7-Alkylseleno-1,4-dihydro-1,6-naphthyridines
Russ.Chem.Bull., Int.Ed., Vol. 50, No. 1, January, 2001
123
drugs, as well as those that prevent arrhythmia and
inhibit the activity of acetylcholine.57
Hence, 7-alkylseleno-1,4-dihydro-1,6-naphthyridines
were found to be convenient reagents in the regiospecific
synthesis of not easily available, including annelated,
heterocycles with potential biological activity.
The literature data on the oxidation of 1,4-dihydro-
1,6-naphthyridines are lacking, while successful diazoti-
zation of 1,6-naphthyridine derivatives was described in
the only paper.8 For this reason, we found it interesting
to examine the conditions under which the functional
groups of naphthyridine 1 containing labile furan and
dihydropyridine fragments can be oxidized. It turned out
that, when treated with a solution of NaNO2 in conc.
H2SO4 at 1822 °C, naphthyridine 1 in AcOH under-
goes aromatization with elimination of the furyl residue
to give 4-unsubstituted naphthyridine 3 (method A, see
Scheme 1). Aromatization is also effective when
naphthyridine 1 is refluxed in glacial AcOH (method B).
At the same time, an excess of NaNO2 causes nitrosation
of the amino group in the oxidized naphthyridine 3 with
a NaNO2H2SO4AcOH system (method A) and the
formation of hydroxy derivative 4. Refluxing of
naphthyridine 1 in glacial AcOH in the presence of
NaNO2 brings about simultaneous acid aromatization
and diazotization, yielding hydroxynaphthyridine 5.
Thus, substituted 5-amino-1,4-dihydro-1,6-naphthy-
ridine 1 can be oxidized selectively to a desired state by
choosing an appropriate oxidative medium.
Experimental
Melting points were determined on a Kofler stage. IR
spectra were recorded on an IKS-29 instrument (Vaseline oil).
1H NMR spectra were recorded on a Bruker AM-300 instru-
ment (300.13 MHz) in DMSO-d6 with Me4Si as the internal
standard. Pyridine was dried according to a standard pro-
cedure.11
The course of the reactions was monitored and the purity of
the products was checked by TLC on Silufol UV-254 plates in
an acetoneheptane system (3 : 5); visualization with iodine
vapors.
1-Acetyl-5-acetylamino-7-benzylseleno-8-cyano-3-ethoxy-
carbonyl-4-(2-furyl)-2-methyl-1,4-dihydro-1,6-naphthyridine
(2). Anhydrous pyridine (1 mL) was added to a suspension of
2
naphthyridine 1 (0.60 g, 1.2 mmol) in 7 mL of Ac2O. The
reaction mixture was refluxed for 1.5 h and then cooled. The
precipitate that formed was filtered off and washed with 95%
EtOH. Yield 0.64 g (92%), m.p. 210212 °C. Found (%):
C, 58.40; H, 4.43; N, 9.59; Se, 13.61. C28H26N4O5Se. Calcu-
1
lated (%): C, 58.23; H, 4.54; N, 9.70; Se, 13.67. IR, ν/cm
:
3255, 3308 (NH); 2200 (C≡N); 1673, 1702, 1736 (C=O).
1H NMR, δ: 1.21 (t, 3 H, CH3CH2O, J = 8.0 Hz); 1.30 (s, 3 H,
C(2)Me); 2.45, 2.50 (both s, each 3 H, 2 Ac); 4.07 (q, 2 H,
CH3CH2O, J = 8.0 Hz); 4.38, 4.41 (both d, each 1 H, SeCH2,
J = 12.4 Hz); 4.84 (s, 1 H, C(4)H); 6.02 (d, 1 H, furyl C(3)H,
J = 3.0 Hz); 6.27 (dd, 1 H, furyl C(4)H, J = 3.0 Hz,
J = 2.2 Hz); 7.137.38 (m, 6 H, furyl C(5)H, Ph); 9.57 (br.s,
1 H, NHCO).
5-Amino-7-benzylseleno-8-cyano-3-ethoxycarbonyl-2-me-
thyl-1,6-naphthyridine (3). Method A. A solution of NaNO2
(0.10 g, 1.5 mmol) in 1 mL of conc. H2SO4 was slowly added to
a suspension of naphthyridine 1 (0.50 g, 1.0 mmol) in 5 mL of
glacial AcOH, the reaction temperature being maintained within
1822 °C. The reaction mixture was stirred for 5 min, and then
pH was adjusted to pH 7 by slow addition of a saturated
aqueous solution of AcONa. The precipitate that formed was
filtered off and washed with water and with 95% EtOH. Yield
0.28 g (65%).
Heating of substituted allylselenonaphthyridine 6 with
iodine in chloroform causes its iodocyclization into
tetrahydroselenazolo[3,2-g][1,6]naphthyridinium triiodide
7 (Scheme 2). This reaction can be regarded as an
synchronous, regio- and stereoselective, intramolecular
electrophilic heterocyclization.9,10
The structures of the products synthesized were con-
firmed by elemental analysis and 1H NMR and IR
spectroscopy (see Experimental).
Scheme 2
O
O
NH2
N
Method B. A suspension of naphthyridine 1 (0.50 g,
1.0 mmol) in 15 mL of glacial AcOH was refluxed for 1 h. After
24 h, the precipitate that formed was filtered off and washed
with 95% EtOH. Yield 0.31 g (72%), m.p. 259260 °C (from
BuOH). Found (%): C, 56.35; H, 4.39; N, 13.26; Se, 18.72.
C20H18N4O2Se. Calculated (%): C, 56.48; H, 4.27; N, 13.17;
Se, 18.56. IR, ν/cm1: 3249, 3338, 3392 (NH2); 2190 (C≡N);
1695 (C=O); 1607 (δ N H2). 1H NMR, δ: 1.40 (t, 3 H,
CH3CH2O, J = 7.7 Hz); 2.86 (s, 3 H, C(2)Me); 4.37 (q, 2 H,
CH3CH2O, J = 7.7 Hz); 4.58 (s, 2 H, SeCH2); 7.137.49 (m,
5 H, Ph); 8.38 (br.s, 2 H, NH2); 9.13 (s, 1 H, C(4)H).
7-Benzylseleno-8-cyano-3-ethoxycarbonyl-5-hydroxy-2-me-
thyl-1,6-naphthyridine (4) was obtained as described in method
A for compound 3 from naphthyridine 3 (0.70 g, 1.65 mmol)
and NaNO2 (0.17 g, 2.47 mmol). Yield 0.41 g (59%),
m.p. 207209 °C (from EtOH). Found (%): C, 56.14; H, 4.20;
N, 9.71; Se, 18.63. C20H17N3O3Se. Calculated (%): C, 56.35;
H, 4.02; N, 9.86; Se, 18.52. IR, ν/cm1: 3342 (OH); 2215
EtO
Me
N
Se
H
CN
6
CHCl3 2 I2
O
O
NH2
+
N
CH2I
I3
EtO
Me
N
H
Se
1
CN
(C≡N); 1713 (C=O). H NMR, δ: 1.36 (t, 3 H, CH3CH2O,
7
J = 7.7 Hz); 2.84 (s, 3 H, C(2)Me); 4.35 (q, 2 H, CH3CH2O,