A four-component, one-pot synthesis of highly substituted 1,4-dihydro-1,8-naphthyridine-3-carboxamides

Article abstract of DOI:10.1016/j.tetlet.2009.08.104

A new, one-pot, four-component reaction for the synthesis of a novel class of highly substituted 1,4-dihydro-1,8-naphthyridine-3-carboxamide derivatives starting from readily available inputs including aliphatic or aromatic amines, diketene, aromatic alde

Full text of DOI:10.1016/j.tetlet.2009.08.104

Tetrahedron Letters 50 (2009) 6355–6357
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Tetrahedron Letters
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A four-component, one-pot synthesis of highly substituted
1,4-dihydro-1,8-naphthyridine-3-carboxamides
*
Ahmad Shaabani , Mozhdeh Seyyedhamzeh, Ali Maleki, Maryam Behnam
Department of Chemistry, Shahid Beheshti University, PO Box 19396-4716, Tehran, Iran
a r t i c l e i n f o
a b s t r a c t
Article history:
A new, one-pot, four-component reaction for the synthesis of a novel class of highly substituted 1,4-dihy-
dro-1,8-naphthyridine-3-carboxamide derivatives starting from readily available inputs including ali-
phatic or aromatic amines, diketene, aromatic aldehydes, and 2-aminopyridines in the presence of a
catalytic amount of p-toluenesulfonic acid under mild reaction conditions and in good yields at ambient
temperature is described.
Received 28 May 2009
Revised 8 August 2009
Accepted 28 August 2009
Available online 2 September 2009
Ó 2009 Published by Elsevier Ltd.
Keywords:
Multicomponent reaction
One-pot synthesis
1,4-Dihydro-1,8-naphthyridine-
3-carboxamide
2-Aminopyridine
Diketene
Naphthyridine derivatives have received significant attention
due to their exceptionally broad spectrum of biological activity.
Substituted 1,8-naphthyridine derivatives are used for diagnosis
and treatment of human diseases such as AIDS1 and allergies.2 Very
recently, substituted naphthyridines were reported as HIV-1
integrase inhibitors.3 The 1,8-naphthyridine core is incorporated
in numerous biologically active compounds and drugs which act
as antibacterials,4 anticonvulsants,5 antihypertensives6 as well as
inhibitors of platelet aggregation.7
1,8-Naphthyridine derivatives are used in cancer chemotherapy.
One such example is SNS-595, a cell cycle modulator, in second
phase clinical trials.8 1,8-Naphthyridines were found to display
moderate cytotoxic activity against murine P388 leukemia.8 They
also show promising cytotoxicity, anticancer, and anti-inflamma-
tory activities based on the molecular link between cancer and
inflammation.9
tives 5. The products were prepared via a one-pot process involv-
ing a four-component condensation reaction of an aliphatic or
aromatic amine 1, diketene 2, an aromatic aldehyde 3, and a 2-ami-
nopyridine 4 in the presence of a catalytic amount of p-toluenesul-
fonic acid (p-TsOHÁH2O) under mild reaction conditions and in
good yields at ambient temperature (Scheme 1).
In a pilot experiment, the reaction of N-alkyl-3-oxobutanamide
6, which was prepared by addition of benzylamine to diketene 2,
with 4-chlorobenzaldehyde and 2-aminopyridine in the presence
of catalytic p-TsOHÁH2O was performed in dry dichloromethane
at ambient temperature. The progress of the reaction was
monitored by TLC. After completion of the reaction, the product,
N-benzyl-4-(4-chlorophenyl)-2-methyl-1,4-dihydro-1,8-naphthyri-
dine-3-carboxamide 5a was obtained in 73% yield.12
Three substituents in the products can be varied independently
of each other. We have shown that the use of a wide range of
Multicomponent reactions (MCRs) are powerful synthetic tools
which have changed the landscape of organic and medicinal chem-
istry due to their environmental friendliness, atom economy, and
their ability to generate large libraries of compounds in one or
two synthetic steps.10
Due to the biological and pharmacological importance of naph-
thyridine-3-carboxamides, and in continuation of our interest in
MCRs,11 we describe herein the synthesis of a new class of highly
substituted 1,4-dihydro-1,8-naphthyridine-3-carboxamide deriva-
R2
O
CHO
O
R1
R3
R3
p-TsOH.H2O
N
R1 NH2
O
H
CH2Cl2, r.t.
NH2
N
N
N
R2
H
1
3
4
2
5
R1 = Bn, 4-MeC6H4CH2, nPr
R2 = 4-Cl, 4-Br, 4-F, 4-CH3, 3-NO2
R3 = H, Br, CH3
* Corresponding author. Tel.: +98 21 29902800; fax: +98 21 22431663.
E-mail address: a-shaabani@cc.sbu.ac.ir (A. Shaabani).
Scheme 1.
0040-4039/$ - see front matter Ó 2009 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2009.08.104

6356
A. Shaabani et al. / Tetrahedron Letters 50 (2009) 6355–6357
Cl
Cl
Cl
O
O
O
O
Br
N
N
N
N
H
H
H
H
N
N
H
N
N
H
N
N
H
N
N
H
5c
5d
5b
5a
F
Br
O2N
O
O
O
Br
Br
N
N
N
H
H
H
N
N
N
N
N
N
H
H
H
5f
5e
5g
Figure 1.
R2
O
O
R1
O
NH2
N
N
R3
R1
H
-H2O
4
NH
5
(1)
N
N
R1
HN
R2
R3
8A
R2
10
O
O
O
R1
3
1
R2
2
N
H
O
R2
(2)
7
O
6
O
R1
R3
R3
-H2O
R1
4
NH
NH
5
N
N
N
N
8B
9
Scheme 2. Possible mechanisms for the formation of compounds 5a–g.
amines 1, aromatic aldehydes 3 and 2-aminopyridines 4 in this
four-component reaction make possible the syntheses of libraries
of compounds. The results are shown in Table 1. As anticipated
from our initial results, these reactions proceeded very cleanly un-
der mild conditions at room temperature and no undesirable side
reactions were observed. All the compounds described in this Let-
ter are new (Fig. 1).
It is noteworthy that aromatic aldehydes possessing both
electron-withdrawing and electron-releasing substituents were
converted into the corresponding 1,4-dihydro-1,8-naphthyridine-
3-carboxamide derivatives in good yields. We also reacted
aliphatic propylamine to assess the scope and generality of this
reaction (Table 1).
7 results from the initial condensation of the aldehyde 3 with
N-alkylated-3-oxobutanamide 6, itself derived from the addition
of amine 1 to diketene 2. Next, a Michael-type addition of 2-amino-
pyridine 4 to 7 would produce intermediate 8A. Alternatively,
condensation of 4 with 7 gives imine 8B. Intramolecular condensa-
tion of 8A or cyclization of 8B would give 10 or 9. Finally, aroma-
tization of 9 or imine-enamine tautomerization of 10 yields
product 5 (Scheme 2).
In summary, we have described an efficient four-component,
one-pot approach for the synthesis of highly substituted 1,4-dihy-
dro-1,8-naphthyridine-3-carboxamide derivatives via cyclocon-
densation of a primary aliphatic or aromatic amine, diketene,
aromatic aldehydes, and 2-aminopyridines in CH2Cl2 using
p-TsOHÁH2O as the catalyst at ambient temperature. All the prod-
ucts were obtained in high purity and in good yields. We hope that
this novel class of compounds will meet with success as biologi-
cally active substances.
Compounds 5a–g are stable solids whose structures were deter-
mined by IR, 1H and 13C NMR spectroscopy, mass spectrometry,
and elemental analysis. The mass spectra of products 5a–g dis-
played molecular ion peaks at values consistent with the proposed
structures.
Possible mechanisms for the formation of products 5a–g are
illustrated in Scheme 2. It is rational to assume that intermediate
Acknowledgment
We gratefully acknowledge financial support from the Research
Council of Shahid Beheshti University.
Table 1
Synthesis of 1,4-dihydro-1,8-naphthyridine-3-carboxamides 5a–g
R1
R2
R3
Product
Time (h)
Yielda (%)
References and notes
PhCH2
PhCH2
PhCH2
4-MeC6H4CH2
4-MeC6H4CH2
4-MeC6H4CH2
n-C3H7
4-Cl
4-Cl
4-Cl
4-CH3
4-F
H
5a
5b
5c
5d
5e
5f
8
6
8
6
7
73
69
71
67
71
77
76
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H
Br
H
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1807–1810.
3-NO2
4-Br
9
10
Br
5g
a
Isolated yield.

A. Shaabani et al. / Tetrahedron Letters 50 (2009) 6355–6357
6357
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Roma, G.; Fantozzi, R. J. Inflamm. 2006, 3, 4.
13C NMR (75.47 MHz, DMSO-d6) d 17.4, 21.2 (CH3), 42.2 (CH2), 90.1 (CH),
114.6, 122.7, 125.9, 126.7, 127.3, 128.3, 129.2, 129.9, 130.7, 134.0, 136.8,
138.4, 138.9, 144.5, 145.6 (C-Ar and C@C), 148.9, 166.8 (CO). MS m/z: 297 (M+-
106, 6), 271 (10), 229 (14), 172 (15), 106 (100), 91 (80), 65 (42). Anal. Calcd for
C24H22ClN3O: C, 71.37; H, 5.49; N, 10.40. Found: C, 71.25; H, 5.43; N, 10.35.
N-Benzyl-6-bromo-4-(4-chlorophenyl)-2-methyl-1,4-dihydro-1,8-naphthyridine-
3-carboxamide 5c: White powder (0.33 g, 71%): mp 170–171 °C. IR (KBr) cmÀ1
:
3342, 3177, 3108, 2924, 1675, 1652, 1566, 1490, 1374. 1H NMR (300.13 MHz,
DMSO-d6) d 2.28 (3H, s, CH3), 4.34–4.39 (2H, m, CH2), 6.41 (1H, s, CH), 7.08–
8.20 (11H, m, H-Ar), 9.01 (1H, br s, NH), 9.97 (1H, br s, NH). 13C NMR
(75.47 MHz, DMSO-d6) d 21.2 (CH3), 42.8 (CH2), 103.2 (CH), 111.2, 115.3,
125.9, 128.6, 128.9, 129.1, 129.8, 131.9, 132.8, 134.4, 135.2, 138.4, 138.8,
145.7, 146.0 (C-Ar and C@C), 156.0, 167.0 (CO). MS m/z: 361 (M+-106, 6), 333
(12), 295 (35), 202 (8), 174 (30), 157 (50), 106 (100), 91 (84), 65 (34). Anal.
Calcd for C23H19BrClN3O: C, 58.93; H, 4.09; N, 8.96. Found: C, 58.97; H, 4.16; N,
8.89.
2-Methyl-N-(4-methylbenzyl)-4-p-tolyl-1,4-dihydro-1,8-naphthyridine-3-carbox-
amide 5d: White powder (0.26 g, 67%): mp 159–161 °C. IR (KBr) cmÀ1: 3416,
3328, 3113, 2916, 1678, 1653, 1574, 1439, 1379. 1H NMR (300.13 MHz, DMSO-
d6) d 2.23 (3H, s, CH3), 2.28 (3H, s, CH3), 2.37 (3H, s, CH3), 4.22–4.34 (2H, m,
3
CH2), 5.01 (1H, br s, CH), 6.57 (2H, d, JHH = 7.7 Hz, H-Ar), 6.90 (2H, d,
3JHH = 7.6 Hz, H-Ar), 6.96–7.48 (5H, m, H-Ar), 7.83–7.91 (1H, m, H-Ar), 8.26–
8.36 (2H, m, H-Ar and NH), 8.43 (1H, br s, NH). 13C NMR (75.47 MHz, DMSO-d6)
d 21.1 (CH3), 21.3 (CH3), 25.0 (CH3), 53.2 (CH2), 90.3 (CH), 113.3, 114.9, 125.9,
126.9, 128.6, 128.9, 129.8, 132.2, 135.9, 138.3, 138.8, 145.9 (C-Ar and C@C),
150.4, 166.8 (CO). MS m/z: 263 (M+-120, 14), 223 (6), 195 (30), 172 (18), 145
(16), 120 (100), 105 (32), 91 (60), 79 (82), 65 (30). Anal. Calcd for C25H25N3O: C,
78.30; H, 6.57; N, 10.96. Found: C, 78.38; H, 6.53; N, 10.91.
10. (a) Zhu, J.; Bienayme, H. Multicomponent Reactions; Wiley-VCH: Weinheim,
2005; (b) Dömling, A.; Ugi, I. Angew. Chem., Int. Ed. 2000, 39, 3168–3210; (c)
Ganem, B. Acc. Chem. Res. 2009, 42, 463–472.
11. (a) Shaabani, A.; Maleki, A.; Moghimi-Rad, J. J. Org. Chem. 2007, 72, 6309–6311;
(b) Shaabani, A.; Maleki, A.; Mofakham, H.; Moghimi-Rad, J. J. Org. Chem. 2008,
73, 3925–3927; (c) Shaabani, A.; Seyyedhamzeh, M.; Maleki, A.; Rezazadeh, F.;
Behnam, M. J. Comb. Chem. 2009, 11, 375–377; (d) Shaabani, A.; Seyyedhamzeh,
M.; Maleki, A.; Behnam, M.; Rezazadeh, F. Tetrahedron Lett. 2009, 50, 2911–
2913.
6-Bromo-4-(4-fluorophenyl)-2-methyl-N-(4-methylbenzyl)-1,4-dihydro-1,8-naph-
thyridine-3-carboxamide 5e: White powder (0.33 g, 71%): mp 157–159 °C. IR
(KBr) cmÀ1: 3344, 3178, 3008, 2925, 1675, 1569, 1508, 1437, 1375. 1H NMR
(300.13 MHz, DMSO-d6) d 2.23 (3H, s, CH3), 2.29 (3H, s, CH3), 4.20–4.34 (2H, m,
CH2), 5.07 (1H, br s, CH), 6.55 (2H, d, 3JHH = 7.5 Hz, H-Ar), 6.90–7.64 (8H, m, H-
Ar), 8.38 (1H, br s, NH), 9.95 (1H, br s, NH). 13C NMR (75.47 MHz, DMSO-d6) d
21.2 (CH3), 21.6 (CH3), 42.6 (CH2), 92.8 (CH), 111.5, 117.4, 123.9, 126.9, 127.4,
128.9, 129.7, 129.9, 133.2, 134.8, 136.3, 137.5, 138.8, 143.4, 146.5 (C-Ar and
C@C), 152.7, 168.7 (CO). MS m/z: 345 (M+-120, 4), 317 (14), 280 (6), 238 (8),
212 (12), 172 (48), 120 (100), 105 (30), 91 (55), 65 (28). Anal. Calcd for
C24H21BrFN3O: C, 61.81; H, 4.54; N, 9.01. Found: C, 61.86; H, 4.59; N, 9.08.
2-Methyl-N-(4-methylbenzyl)-4-(3-nitrophenyl)-1,4-dihydro-1,8-naphthyridine-
12. Typical procedure for the synthesis of N-benzyl-4-(4-chlorophenyl)-2-methyl-1,4-
dihydro-1,8-naphthyridine-3-carboxamide (5a):
A solution of benzylamine
(0.107 g, 1.0 mmol) and diketene (0.084 g, 1.0 mmol) was magnetically
stirred in 5 mL of dry CH2Cl2 for 2 h. Then, 4-chlorobenzaldehyde (0.140 g,
1.0 mmol), 2-aminopyridine (0.094 g, 1.0 mmol), and p-TsOHÁH2O (0.019 g,
0.1 mmol) were added simultaneously. The reaction mixture was allowed to
stir for 8 h until a precipitate appeared. After completion of the reaction, as
indicated by TLC (EtOAc:n-hexane, 1:2), the reaction mixture was filtered and
the residue was washed with water and then with ethanol and dried in vacuo
to give 5a.
3-carboxamide 5f: White powder (0.32 g, 77%): mp 147–149 °C. IR (KBr) cmÀ1
:
3391, 3267, 3083, 2924, 1715, 1642, 1603, 1554, 1519, 1480, 1419. 1H NMR
(300.13 MHz, DMSO-d6) d 2.21 (3H, s, CH3), 2.23 (3H, s, CH3), 4.07–4.29 (2H, m,
CH2), 5.81–5.90 (1H, m, CH), 6.43–8.09 (11H, m, H-Ar), 8.29 (1H, br s, NH), 8.73
(1H, br s, NH). 13C NMR (75.47 MHz, DMSO-d6) d 21.1 (CH3), 28.7 (CH3), 42.5
(CH2), 109.3 (CH), 113.1, 122.2, 122.5, 122.6, 127.0, 127.3, 128.0, 128.9, 129.2,
129.9, 135.4, 136.1, 144.6, 148.0 (C-Ar and C@C), 157.9, 165.6 (CO). MS m/z:
323 (M+-91,10), 226 (6), 202 (12), 176 (20), 160 (12), 120 (100), 105 (18), 91
(12), 79 (22), 65 (25). Anal. Calcd for C24H22N4O3: C, 69.55; H, 5.35; N, 13.52.
Found: C, 69.51; H, 5.33; N, 13.57.
N-Benzyl-4-(4-chlorophenyl)-2-methyl-1,4-dihydro-1,8-naphthyridine-3-carbox-
amide 5a: White powder (0.28 g, 73%): mp 167–169 °C. IR (KBr) cmÀ1: 3463,
3335, 3069, 2916, 1654, 1565, 1491, 1448, 1388. 1H NMR (300.13 MHz,
DMSO-d6) d 2.28 (3H, s, CH3), 4.32–4.42 (2H, m, CH2), 5.44 (1H, s, CH), 6.60–
6.65 (2H, m, H-Ar), 7.00–7.16 (3H, m, H-Ar), 7.41–7.48 (3H, m, H-Ar), 7.84–
7.93 (2H, m, H-Ar), 8.26–8.51 (3H, m, H-Ar and NH), 9.74 (1H, br s, NH). 13C
NMR (75.47 MHz, DMSO-d6) d 21.3 (CH3), 42.2 (CH2), 90.3 (CH), 113.5, 114.9,
125.9, 126.7, 128.4, 128.7, 129.2, 129.9, 132.2, 134.0, 136.6, 138.5, 138.9,
142.4, 145.5 (C-Ar and C@C), 150.4, 166.7 (CO). MS m/z: 389 (M+, 2), 302 (15),
283 (25), 255 (45), 218 (30), 172 (32), 107 (50), 91 (100), 65 (46). Anal. Calcd
for C23H20ClN3O: C, 70.85; H, 5.17; N, 10.78. Found: C, 70.73; H, 5.23; N, 10.75.
N-Benzyl-4-(4-chlorophenyl)-2,6-dimethyl-1,4-dihydro-1,8-naphthyridine-3-car-
6-Bromo-4-(4-bromophenyl)-2-methyl-N-propyl-1,4-dihydro-1,8-naphthyridine-
3-carboxamide 5g: White powder (0.35 g, 76%): mp 164–166 °C. IR (KBr) cmÀ1
:
3374, 3335, 3066, 2963, 1711, 1659, 1592, 1548, 1479, 1408, 1366. 1H NMR
(300.13 MHz, DMSO-d6) d 0.48–0.74 (3H, m, CH3), 1.23–1.33 (2H, m, CH2), 2.09
(3H, s, CH3), 2.90–3.01 (2H, m, CH2), 5.60 (1H, br s, CH), 6.43–6.57 (1H, m, H-
Ar), 7.25–7.52 (5H, m, H-Ar), 7.92–8.00 (1H, m, NH), 8.06–8.14 (1H, m, NH). 13C
NMR (75.47 MHz, DMSO-d6) d 11.6, 22.2, 22.5, 28.3, 29.2 (CH3, CH2), 106.4
(CH), 111.2, 120.4, 120.6, 129.9, 130.2, 131.4, 132.1, 139.6, 141.2, 141.4, 148.1
(C-Ar and C@C), 156.7, 167.2 (CO). MS m/z: 377 (M+-86, 14), 339 (18), 157
(100), 102 (10), 78 (32), 57 (25). Anal. Calcd for C19H19Br2N3O: C, 49.06; H,
4.12; N, 9.03. Found: C, 49.01; H, 4.19; N, 9.09.
boxamide 5b: White powder (0.28 g, 69%): mp 178–179 °C. IR (KBr) cmÀ1
:
3332, 3117, 2928, 1678, 1588, 1565, 1491, 1450, 1379. 1H NMR (300.13 MHz,
DMSO-d6) d 2.23 (3H, s, CH3), 2.28 (3H, s, CH3), 4.33–4.45 (2H, m, CH2), 5.06
(1H, br s, CH), 6.63 (2H, d, 3JHH = 6.2 Hz, H-Ar), 6.98 (1H, d, 3JHH = 8.9 Hz, H-Ar),
7.07–7.16 (2H, m, H-Ar), 7.41–7.51 (3H, m, H-Ar), 7.76 (1H, d, 3JHH = 8.8 Hz, H-
Ar), 8.13 (1H, br s, H-Ar), 8.40–8.46 (2H, m, H-Ar and NH), 9.58 (1H, br s, NH).