Ferric Chloride-catalyzed Synthesis of 2-Oxo-1,2-dihydro-1,8-naphthyridine-3-carboxylate Derivatives and Their Biological Evaluation

Article abstract of DOI:10.1134/S1070363218060294

A new methodology has been developed for the synthesis of novel 2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxylates from 2-aminonicotinaldehyde, Meldrum’s acid, and the corresponding alcohols in the presence of anhydrous iron(III) chloride as a cheap and readily available catalyst. The structure of the synthesized compounds was established by IR, ¹H NMR, and mass spectral data and elemental analyses. All the synthesized compounds were evaluated for their in vitro antibacterial and antifungal activity, and the activity of some derivatives was comparable with the activity of Ciprofloxacin and Nystatin used as reference drugs.

Full text of DOI:10.1134/S1070363218060294

ISSN 1070-3632, Russian Journal of General Chemistry, 2018, Vol. 88, No. 6, pp. 1224–1227. © Pleiades Publishing, Ltd., 2018.
Ferric Chloride-catalyzed Synthesis
of 2-Oxo-1,2-dihydro-1,8-naphthyridine-3-carboxylate
Derivatives and Their Biological Evaluation1
B. Sakrama*, P. Madhua, B. Sonyanaika, S. Rambabua, D. Ravia, and A. Kurumannaa
a Department of Chemistry, Osmania University, Hyderabad, 500007 India
*e-mail: bschemou@gmail.com
Received February 22, 2018
Abstract—A new methodology has been developed for the synthesis of novel 2-oxo-1,2-dihydro-1,8-
naphthyridine-3-carboxylates from 2-aminonicotinaldehyde, Meldrum’s acid, and the corresponding alcohols
in the presence of anhydrous iron(III) chloride as a cheap and readily available catalyst. The structure of the
synthesized compounds was established by IR, 1H NMR, and mass spectral data and elemental analyses. All the
synthesized compounds were evaluated for their in vitro antibacterial and antifungal activity, and the activity of
some derivatives was comparable with the activity of Ciprofloxacin and Nystatin used as reference drugs.
Keywords: 2-aminonicotinaldehyde, Meldrum’s acid, anhydrous iron(III) chloride, antimicrobial activity.
DOI: 10.1134/S1070363218060294
1,8-Naphthyridine derivatives constitute an important
class of heterocyclic compounds possessing diverse
biological properties, in particular antibacterial [1],
antimycobacterial [2], antitumor [3], anti-inflammatory
[4], analgesic [5], antiplatelet [6], gastric antisecretory
[7], local anesthetic [8], anticonvulsant [9], and
antihypertensive activity [10, 11]. Some of biologically
potent 1,8-naphthyridines are shown in Scheme 1.
high atom economy, and high purity of products with
excellent yields [12–14]. In view of pharmacological
importance of 1,8-naphthyridines, we have developed
a novel methodology for the synthesis of these compounds
from 2-aminonicotinaldehyde (1), Meldrum’s acid (2),
and alcohol 3a–3k in the presence of anhydrous ferric
chloride and obtained the corresponding 2-oxo-1,2-
dihydro-1,8-naphthyridine-3-carboxylates 4a–4k with
good yields. To the best of our knowledge, there is no
method reported for the construction of these com-
pounds using anhydrous ferric chloride as a catalyst.
Multicomponent coupling reactions (MCRs) provide
an efficient synthetic tool for the construction of
chemically and biologically active compounds. Their
distinctive advantages include generation of highly
diverse and complex products from readily available
substrates in a single synthetic step without isolation of
intermediates, maximum selectivity in minimal time,
Scheme 2 illustrates the formation of 2-oxo-1,2-di-
hydro-1,8-naphthyridine-3-carboxylates 4a–4k catalyzed
by anhydrous ferric chloride. Initially, 2-aminonicotin-
aldehyde (1), Meldrum’s acid (2), and ethanol were
Scheme 1.
O
N
O
O
N
O
OH
F3C
F3C
F
OH
N
N
N
N
H
N
O
N
N
H2N
HN
O
NH2
N
S
N
O
NH
Potent anti-HCV agent
Antibacterial agent
Anticancer agent
1 The text was submitted by the authors in English.
1224

FERRIC CHLORIDE-CATALYZED SYNTHESIS
1225
Scheme 2.
O
O
Me
O
Me
O
R
CHO
NH2
Anhydrous FeCl3
O
+
+
R−OH
Reflux, 6−8 h
O
O
N
N
H
4a–4k
N
1
2
3a–3k
3, 4, R = Et (a), Me (b), i-Pr (c), t-Bu (d), Pr (e), Bu (f), C5H11 (g), i-Bu (h), CH≡CCH2 (i), furan-2-ylmethyl (j), PhCH2 (k).
chosen as starting materials for the model reaction
where the alcohol acted as both reactant and solvent.
The reaction in the absence of a catalyst failed to
provide the desired product. When iron(III) chloride
was used as catalyst, the yield of 4a was 60–80%.
Under these conditions (0.05 mmol of FeCl3, 0.01 mmol
of 2-aminonicotinaldehyde, 0.01 mmol of Meldrum’s
acid, and 3 mL of alcohol 3a–3k; reflux), we have
successfully synthesized a series of 2-oxo-1,2-dihydro-
1,8-naphthyridine-3-carboxylates 4a–4k (Table 1).
tions were distilled prior to use. Column chromato-
graphy was performed using 100–200 mesh silica gel
according to standard techniques. The melting points
were determined in open capillary tubes with a Büchi
1
melting point apparatus and are uncorrected. The H
NMR spectra were recorded on a Bruker 400 MHz
spectrometer using DMSO-d6 as solvent. The mass
spectra (electrospray ionization) were obtained with an
Agilent 6120 single quadrapole time-of-flight mass
spectrometer. The IR spectra were recorded in KBr
with a Bruker Tensor 27 spectrometer. The elemental
analyses were obtained using a Carlo Erba EA 1108
analyzer.
All newly synthesized compounds were screened
for their in vitro antibacterial activity against Streptococcus
pyogenes (Gram positive) and Escherichia coli (Gram
positive) using Ciprofloxacin as reference drug. The
activity was evaluated by the agar well diffusion
technique according to [15]. The results are collected
in Table 2. Compounds 4b, 4i, and 4j showed a good
activity comparable with the activity of Ciprofloxacin.
Compounds 4a–4k were also screened for antifungal
activity against Saccharomyces cerevisiae and
Aspergillus terreus by the agar well diffusion
technique according to [16] using Nystain as reference
drug. All these compounds showed inhibitory activity
against the tested pathogenic fungal strains; among
them, compounds 4i, 4b, and 4j showed the highest
antifungal activity (Table 2).
General procedure for the synthesis of 2-oxo-1,2-
dihydro-1,8-naphthyridine-3-carboxylates 4a–4k.
Anhydrous FeCl3 (0.05 mmol) was added to a stirred
solution of 2-aminonicotinaldehyde (1, 0.01 mmol)
and Meldrum’s acid (2, 0.01 mmol) in alcohol 3a–3k
(3 mL). The mixture was heated on an oil bath at
Table 1. Synthesis of 2-oxo-1,2-dihydro-1,8-naphthyridine-
3-carboxylates 4a–4k in the presence of anhydrous FeCl3
Compound
no.
Reaction
time, h
Yield,a %
mp, °C
4a
4b
4c
4d
4e
4f
7.0
8.0
6.0
6.5
7.0
7.0
7.5
7.5
8.0
6.0
7.5
76
65
80
73
67
71
56
72
65
59
64
107
99
In summary, we have synthesized a series of novel
2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxylates in
good yields by the conventional method using an-
hydrous ferric chloride as catalyst. Some of the syn-
thesized compounds showed high antibacterial and
antifungal activity in vitro, which was comparable to
the activity of Ciprofloxacin and Nystatin used as
reference drugs.
121
138
118
133
141
134
128
139
148
4g
4h
4i
EXPERIMENTAL
All the starting materials were purchased from
commercial sources and used as received; the solvents
were purified and dried by standard procedures.
Technical grade solvents for chromatographic separa-
4j
4k
a
After isolation and purification.
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 88 No. 6 2018

1226
SAKRAM et al.
Table 2. Antibacterial and antifungal activities (inhibition zone diameter, mm) of compounds 4a–4k at 100 μg/disk at three
different concentrations (10, 20, and 30 μg/mL)a
Bacterial strains
Streptococcus pyogenes Escherichia coli
Fungal strains
Saccharomyces cerevisiae Aspergillus terreus
Compound no.
10
6
20
13
17
11
14
10
11
10
14
18
16
13
18
–
30
24
27
21
23
19
21
19
23
28
26
19
30
–
10
5
20
11
18
10
13
9
30
19
26
19
21
17
18
21
22
27
25
17
29
–
10
7
8
7
6
5
6
6
5
8
7
6
–
9
20
12
17
12
11
13
12
11
14
18
17
15
–
30
19
26
21
22
20
19
20
22
27
25
19
–
10
5
20
11
16
13
15
13
10
12
11
17
16
9
30
21
26
22
21
19
16
19
15
27
25
17
–
4a
4b
8
7
8
4c
6
5
6
4d
6
7
7
4e
5
4
7
4f
4
5
10
11
13
19
17
11
19
–
6
4g
5
4
5
4h
7
6
4
4i
9
8
9
4j
8
7
8
4k
7
5
5
Ciprofloxacin
10
–
10
–
–
–
Nystatin
19
30
10
19
29
a The bold values indicate the compounds of the highest antimicrobial activity.
60–80°C for 6-8 h. The mixture was then cooled down
to room temperature, and excess alcohol was removed
under reduced pressure. The residue was purified by
column chromatography on silica gel with ethyl
acetate and petroleum ether (1 : 6, v/v) as eluent. The
yields and melting points of compounds 4a–4k are
given in Table 1.
δ, ppm: 1.17 d (6H, J = 7.3 Hz), 4.17 m (1H), 7.49 m
(1H), 8.53 d (1H, J = 6.5 Hz), 8.86 s (1H), 9.10 d (1H,
J = 7.3 Hz), 13.62 s (1H). Mass spectrum: m/z 233.0
[M + H]+. Found, %: C 62.06; H 5.21; N 12.06.
C12H12N2O3. Calculated, %: C 62.43; H 5.29; N 12.14.
t-Butyl 2-oxo-1,2-dihydro-1,8-naphthyridine-3-
carboxylate (4d). Yellow solid. IR spectrum, ν, cm–1:
1
Ethyl
2-oxo-1,2-dihydro-1,8-naphthyridine-3-
3320, 1751, 1681, 1651, 1210. H NMR spectrum, δ,
carboxylate (4a). Light brown solid. IR spectrum, ν,
ppm: 1.08 s (9H), 7.50 m (1H), 8.51 d (1H, J =
6.9 Hz), 8.79 s (1H), 8.99 d (1H, J = 7.5 Hz), 13.56 s
(1H). Mass spectrum, m/z 247.00 [M + H]+. Found, %:
C 63.54; H 5.56; N 11.23. C13H14N2O3. Calculated, %:
C 63.86; H 5.73; N 11.46.
1
cm–1: 3396, 1741, 1647, 1616, 1224. H NMR spec-
trum, δ, ppm: 1.20 m (3H), 4.11 m (2H), 7.51 m (1H),
8.53 d (1H, J = 8.5 Hz), 8.79 s (1H), 9.0 d (1H, J =
6.9 Hz), 13.57 s (1H). Mass spectrum: m/z 219.1 [M +
H]+. Found, %: C 60.55; H 4.62; N 12.84. C11H10N2O3.
Calculated, %: C 60.59; H 4.73; N 12.89.
Propyl 2-oxo-1,2-dihydro-1,8-naphthyridine-3-
carboxylate (4e). Yellow solid. IR spectrum, ν, cm–1:
1
Methyl 2-oxo-1,2-dihydro-1,8-naphthyridine-3-
3400, 1739, 1649, 1616, 1224. H NMR spectrum, δ,
carboxylate (4b). Yellow solid. IR spectrum, ν, cm–1:
ppm: 1.24 m (3H), 1.82 m (2H), 3.34 m (2H), 7.49 m
(1H), 8.50 d (1H, J = 6.6 Hz), 8.79 s (1H), 8.99 d (1H,
J = 6.9 Hz), 13.55 s (1H). Mass spectrum: m/z 233.10
[M + H]+. Found, %: C 62.36; H 5.27; N 11.06.
C12H12N2O3. Calculated, %: C 62.12; H 5.39; N 11.87.
1
3332, 1720, 1651, 1618, 1217. H NMR spectrum, δ,
ppm: 4.07 s (3H), 7.56 m (1H), 8.42 d (1H, J =
6.5 Hz), 8.61 s (1H), 8.99 d (1H, J = 6.9 Hz), 13.49 s
(1H). Mass spectrum: m/z 205.07 [M + H]+. Found, %:
C 58.82; H 3.95; N 13.72. C10H8N2O3. Calculated, %:
C 58.93; H 3.97; N 13.95.
Butyl
2-oxo-1,2-dihydro-1,8-naphthyridine-3-
carboxylate (4f). Yellow solid. IR spectrum, ν, cm–1:
1
Ppropan-2-yl 2-oxo-1,2-dihydro-1,8-naphthyridine-
3-carboxylate (4c). Light brown solid. IR spectrum, ν,
cm–1: 3400, 1720, 1649, 1602, 1224. 1H NMR spectrum,
3402, 1735, 1681, 1647, 1080. H NMR spectrum, δ,
ppm: 0.87 m (3H), 1.33 m (2H), 1.53 m (2H), 4.07 m
(2H), 7.48 m (1H), 8.50 d (1H, J = 6.4 Hz), 8.78 s
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 88 No. 6 2018

FERRIC CHLORIDE-CATALYZED SYNTHESIS
ACKNOWLEDGMENTS
1227
(1H), 8.99 d (1H, J = 8.1 Hz), 13.56 s (1H). Mass
spectrum: m/z 247.0 [M + H]+. Found, %: C 62.96; H
5.73; N 11.28. C13H14N2O3. Calculated, %: C 63.10; H
5.77; N 11.44.
The authors thank the Head, Department of Chemistry,
Osmania University, for providing research facilities.
P. Madhu thanks the University Grant Commission
(UGC), New-Delhi, India, for the award of Junior
Research Fellowship.
Pentyl 2-oxo-1,2-dihydro-1,8-naphthyridine-3-
carboxylate (4g). Light yellow solid. IR spectrum, ν,
cm–1: 3377, 1739, 1649, 1616, 1224. 1H NMR
spectrum, δ, ppm: 0.93 m (3H), 1.37 m (2H), 1.37 m
(2H), 1.53 m (2H), 4.07 m (2H), 7.48 m (1H), 8.50 d
(1H, J = 7.3 Hz), 8.72 s (1H), 8.99 d (1H, J = 7.2 Hz),
13.45 s (1H). Mass spectrum: m/z 261 [M + H]+.
Found, %: C 64.56; H 6.13; N 10.94. C14H16N2O3.
Calculated, %: C 64.80; H 6.21; N 10.78.
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2-Methylpropyl
2-oxo-1,2-dihydro-1,8-napht-
hyridine-3-carboxylate (4h). Yellow solid. IR spectrum,
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4.12 d (2H, J = 9.6 Hz), 7.35 m (1H), 8.56 d (1H, J =
7.9 Hz), 8.82 s (1H), 9.00 d (1H, J = 6.4 Hz), 13.53 s
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C 63.66; H 5.85; N 11.73.
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Prop-2-yn-1-yl 2-oxo-1,2-dihydro-1,8-naphthy-
ridine-3-carboxylate (4i). Light brown solid. IR
1
spectrum, ν, cm–1: 3232, 1739, 1651, 1616. H NMR
spectrum, δ, ppm: 3.13 s (1H), 4.23 s (2H), 6.99 m
(1H), 8.34 d (1H, J = 7.5 Hz), 8.58 s (1H), 9.10 d (1H,
J = 7.5 Hz), 12.94 s (1H). Mass spectrum: m/z 229.1
[M + H]+. Found, %: C 63.16; H 3.53; N 12.28.
C12H8N2O3. Calculated, %: C 63.42; H 3.87; N 12.52.
Furan-2-ylmethyl 2-oxo-1,2-dihydro-1,8-napht-
hyridine-3-carboxylate (4j). Black solid. IR spec-
1
trum, ν, cm–1: 3224, 1740, 1680, 1135. H NMR
spectrum, δ, ppm: 4.37 s (2H), 6.29 m (1H), 6.37 d
(1H, J =3.4 Hz), 7.13 m (1H), 7.82 d (1H, J = 6.9 Hz),
7.86 d (1H, J = 3.6 Hz), 8.48 s (1H), 8.79 d (1H, J =
6.4 Hz), 13.46 s (1H). Mass spectrum: m/z 271.06
[M + H]+. Found, %: C 62.32; H 3.69; N 10.43.
C14H10N2O4. Calculated, %: C 62.74; H 3.69; N 10.33.
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Benzyl 2-oxo-1,2-dihydro-1,8-naphthyridine-3-
carboxylate (4k). Brown solid. IR spectrum, ν, cm–1:
1
3342, 1739, 1651, 1616, 1095. H NMR spectrum, δ,
ppm: 3.87 s (2H), 7.61–7.27 m (5H), 7.34 m (1H),
8.52 d (1H, J = 7.3 Hz), 8.78 s (1H), 9.17 d (1H, J =
6.1 Hz), 13.43 s (1H). Mass spectrum: m/z 280.04
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C16H12N2O3. Calculated, %: C 68.29; H 4.75; N 10.42.
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 88 No. 6 2018