One-pot three component cascade synthesis of fused ring quinazoline-2,4-dione derivatives employing heterocyclic ketene aminals as a versatile synthone

Article abstract of DOI:10.14233/ajchem.2015.18004

One-pot three component cascade protocol for the synthesis of quinazoline-2,4-dione derivatives was designed and a series of twenty fused ring quinazoline-2,4-dione derivatives 11a-11j and 12a-12j were synthesized by the reaction of heterocyclic ketene am

Full text of DOI:10.14233/ajchem.2015.18004

Asian Journal of Chemistry; Vol. 28, No. 1 (2016), 69-74
A
SIAN
J
OURNAL OF HEMISTRY
C
http://dx.doi.org/10.14233/ajchem.2016.19231
One-Pot Three Component Synthesis of Highly Functionalized Novel 1,8-Naphthyridine
Derivatives from Substituted 2-Aminopyridines, Aldehydes and Malononitrile
1
,*
1
1
MUHAMMAD YAQUB , MUHAMMAD KASHIF NAVEED , MUHAMMAD TARIQ RIAZ ,
1
1
1
2
RUQAYIA PERVEEN , JAVARIA BATOOL , NADIA ARIF and MUHAMMAD YASEEN
1
2
Institute of Chemical Sciences, Organic Chemistry Division, Bahauddin Zakariya University, Multan-60800, Pakistan
Mohi-ud-Din Islamic Institute of Pharmaceutical Sciences, Mohi-ud-Din Islamic University, Mirpur, Pakistan
*
Corresponding author: Fax: +92 61 9210083; Tel: +92 61 9239278; E-mail: mayaqub2@yahoo.com
Received: 7 April 2015; Accepted: 31 May 2015; Published online: 5 October 2015;
AJC-17549
Protocol for one-pot three component cascade synthesis was planned to achieve the highly functionalized novel 1,8-naphthyridine derivatives
from readily available starting material. Substituted aldehydes and malononitrile were refluxed in THF followed by the addition of
substituted 2-aminopyridine to obtain highly functionalized novel 1-8-naphthyridine (12a-12x), in good to excellent yields. The structures
1
of the newly synthesized 1,8-naphthyridine derivatives have been established on the basis of analytical (C, H, N) and spectroscopic ( H
13
NMR and C NMR) data. These fully functionalized heterocycles would be employed as versatile synthons for further chemical
transformation and eventually, screened for biological studies.
Keywords: Amino acid, Ultrasound, Aqueous media, Cavitation.
derivatives having close resemblance with above said medici-
nally important luxuries. As a part of our ongoing research
INTRODUCTION
The 1,8-naphthyridine derivatives posses a prominent
[
13-15], we wish to report a series of 1,8-naphthyridine deri-
place in the field of medicinal chemistry [1], as the presence
of two nitrogen atom in the aromatic ring make appropriate
linkage sites through hydrogen bonding with microbes.
Hydrogen bonding is very effective in the medicinal area as
antibacterial [2], anti-inflammatory [3], antihypertensive [4]
and anticancer activities [5].
Considerable attention have been attracted due to the
presence of its skeleton in number of naturally occurring organic
compounds like vosaroxin (1), having a range of biological
activities [6,7]. Nalidixic acid (2) used mainly for the treatment
of urinary area infections with Gram-negative pathogens
because of possessing strong antibacterial activity [8]. In addition,
antimicrobial activity [9] of gemifloxacin (3) have established
many year ago whereas 1,8-Naphthyridine series of (E)- and
vatives synthesized through three component one-pot reaction
of aldehydes, malononitrile and substituted 2-aminopyridines.
EXPERIMENTAL
All chemicals and solvents were purchased fromAldrich,
Fluka and Merck-Schuchatdt. Arylidine derivatives were
synthesized through the standard procedure. Melting points
were determined on cover slips by using a Fisher-Johns melting
point apparatus and are uncorrected. Elemental (C, H, N) analyses
were performed on a Leco CHNS-9320 (USA) elemental analyzer
and were in full agreement with the proposed structures within
± 0.4 ꢀ of the theoretical limits, except where noted other-
wise. Infrared (IR) spectra (KBr discs) were run on Shimadzu
(
Z)-O-(diethylamino)ethyl oximes (4) is known potential drugs
for local anaesthesia [10] and 1-(2-fluorobenzyl)-3-(2-tolyl)-
,8-naphthyridin-2(1H)-one (5) is used for the treatment of
Alzheimer’s disease [11].
-Amino-N-hydroxy-1,8-naphthyridine-3-carboxamidine
6, Fig. 1) possesses herbicidal properties and used for the
Prestige-21 FT-IR spectrometer. Proton nuclear magnetic
1
resonance ( H NMR) spectra were recorded in DMSO-d
6
on
1
Bruker (Rhenistetten-Forchheim, Germany)AM 300 spectro-
meter, operating at 300 MHz and using TMS as an internal
standard. The chemical shifts (δ) are reported in ppm and
2
13
(
coupling constants (Hz). C NMR spectra were recorded at
300 MHz with the same internal standard. The progress of the
reaction and purity of the products were checked on TLC plates
coated with Merck silica gel 60 GF254 and the spots were
discriminatory control of weeds in barley, wheat, maize, sorghum
and rice crops [12]. These naturally occurring compounds (1-
6
) provoked to investigate a new series of naphthyridine

7
0 Yaqub et al.
Asian J. Chem.
O
N
O
O
N
COOH
F
COOH
COOH
N
N
N
N
N
MeHN
MeO
H CON
3
H C
N
3
N
S
C H
2 5
H N
2
1
Vosaroxin
2
Nalidixic acid
3
gemifloxacin
H N
2
O
O
N
COOH
NOCH CH N(C H )
5 2
2
2
2
F
COOH
R1
R2
N
N
N
N
N
F
N
N
HN
C H
2 5
H
4
5
F
(
diethyl amino)ethyl oximes
Enoxacin
6
H N
CN
2
1
,8-naphthyridine-3-
carboxamidine
N
R1
R2
N
7
Targeted compound
Fig. 1. Some medicinal important naturally occurring 1,8-naphthyridine derivatives (1-6) and targeted compounds (7)
visualized under ultraviolet light at 254 and 366 nm and/or
spraying with iodine vapours.
4-Amino-2-(2-chloro-phenyl)-[1,8]naphthyridine-3-
carbonitrile (12b):Yield 78 ꢀ as yellow colour product m.p.:
-1
General procedure of the preparation of substituted
220-222 °C; IR (KBr, νmax, cm ): 3321, 3276 (NH stretching),
1
,8-naphthyridines (12a-12t): The solution of malononitrile
2905 (C-H stretching), 2854, 2231 (CN), 1691 (C=N), 1589
1
(
(
0.01 mol) and appropriate aldehyde (0.01 mol) in dry THF
20 mL) was refluxed for 0.5 h in presences of trace of pyridine
(C=C), 1527, 1491, 1505, 1235, 1057, 879, 746; H NMR
(300 MHz, DMSO-d
6
); δ, ppm, 4.72 (broad s, 2H, NH ), 6.94
2
as base. The appropriate 2-aminopyridine (0.01 mol) dissolved
in 5 mL of THF was added when TLC showed the complete
formation of arylidine intermediate and reaction mixture was
further refluxed for 3 h with continuous stirring. The reaction
was monitored by TLC during the course of the reaction. The
reaction mixture was cooled to room temperature and coloured
precipitates formed during refluxing were filtered, washed with
methanol and dried to furnish the desire 1,8-naphthyridines
derivatives pure enough for further characterization.
(dd, J = 8.2 & 1.3 Hz, 1H), 7.25 (m, 2H), 7.49 (t J = 6.5 Hz,
1H), 7.57 (d, J = 6.4 Hz, 1H), 7.79 (dd, J = 8.3 & 1.4 Hz, 1H),
13
9.01 (d, J = 6.4 Hz, 1H); C NMR (300 MHz, CDCl
3
-d ); δ,
6
ppm, 88.14, 111.24, 113.32, 122.54, 124.76, 127.48, 128.26,
128.97, 132.71, 133.51, 134.92, 146.23, 158.54, 159.34,
160.73. Anal. calcd. (ꢀ) for C15
H
9
N Cl: C, 64.18; H, 3.23; N,
4
19.96. Found (ꢀ): C, 64.14; H, 3.22; N, 19.95.
4-Amino-2-(3-chloro-phenyl)-[1,8]naphthyridine-3-
carbonitrile (12c): Yield 74 ꢀ as yellow colour product m.p.:
-1
4
-Amino-2-phenyl-1,8-naphthyridine-3-carbonitrile
205-207 °C; IR (KBr, νmax, cm ): 3371, 3245 (NH), 2954,
(
12a):Yield 85 ꢀ as yellow solid; m.p.: 192-194 °C; IR (KBr,
2823, 2215 (CN), 1698 (C=N), 1645 (C=C), 1573, 1467, 1465,
-
1
1
ν
max, cm ): 3311, 3285 (NH stretching), 2196 (CN), 1637
1315, 987; H NMR (300 MHz, DMSO-d
6
); δ, ppm, 4.87
), 7.10 (dd, J = 8.2 & 1.6 Hz, 1H), 7.28 (t, J
= 8.4 Hz, 1H), 7.54-7.69 (m, 3H), 7.74 (s, 1H), 7.82 (dd, J =
1
(
C=N), 1620 (C=C), 1514, 1475, 1272, 767, 752, 688; H NMR
300 MHz, DMSO-d ); δ, ppm, 4.78 (broad s, 2H, NH ), 7.39
m, 3H), 7.56 (t, J = 6.4 Hz, 1H), 7.66 (d, J = 6.3 Hz, 1H),
(broad s, 2H, NH
2
(
(
6
2
13
8.3 & 1.4Hz, 1H), 9.16 (dd, J = 6.5 & 1.1 Hz, 1H); C NMR
(300 MHz, CDCl -d ); δ, ppm, 86.47, 110.52, 115.31, 124.67,
13
7
.80 (d, J = 8.3 Hz, 2H), 9.26 (d, J = 6.4 Hz, 1H); C NMR
-d ); δ, ppm, 84.91, 107.12, 112.43, 122.65,
4.93, 125.43, 128.13, 130.27, 133.76, 135.51, 139.28, 148.43,
53.83, 156.46, 161.24. Anal. calcd. (ꢀ) for C15 : C,
3.16; H, 4.09; N, 22.75. Found (ꢀ): C, 73.11; H, 4.08; N, 22.73.
3
6
(300 MHz, CDCl
3
6
127.31, 128.43, 130.37, 132.76, 133.58, 137.92, 148.63,
155.83, 158.66, 159.61, 161.76. Anal. calcd. (ꢀ) for
2
1
7
H
10
N
4
C
15
9 4
H N Cl: C, 64.18; H, 3.23; N, 19.96. Found (ꢀ): C, 64.15;
H, 3.22; N, 19.94.

Vol. 28, No. 1 (2016)
Synthesis of Highly Functionalized Novel 1,8-Naphthyridine Derivatives 71
141.92, 149.56, 152.83, 155.43, 160.53. Anal. calcd. (ꢀ) for
4
-Amino-2-(4-chlorophenyl)-1,8-naphthyridine-3-
carbonitrile (12d): Yield 76.4 ꢀ as yellow colour product
m.p.: 210-212 °C; IR (KBr, νmax, cm ): 3311, 3286 (NH), 2916,
C
15
H
9
N Cl: C, 64.18; H, 3.23; N, 19.96. Found (ꢀ): C, 64.12;
4
-1
H, 3.22; N, 19.95.
4-Amino-6-chloro-2-(2-chloro-phenyl)[1,8]naphthyri-
dine-3-carbonitrile (12i): Yield 79 ꢀ as pale yellow solid;
m.p.: 205-207 °C; IR (KBr, νmax, cm ): 3323, 3254 (NH
stretching), 2216 (CN), 1642 (C=N), 1623 (C=C), 1521, 1515,
2
844, 2204 (CN), 1651 (C=N), 1620 (C=C), 1517, 1494, 1265,
1
1
087, 920, 758; H NMR (300 MHz, DMSO-d
), 7.06 (d, J = 8.1 Hz, 2H), 7.31 (t, J = 6.2
Hz, 1H), 7.50 (d, J = 6.3 Hz, 1H), 7.78 (d, J = 8.3 Hz, 2H),
6
); δ, ppm, 4.71
-
1
(broad s, 2H, NH
2
13
1
9
.16 (d, J = 6.4 Hz, 1H); C NMR (300 MHz, CDCl
ppm, 87.39, 112.22, 116.34, 122.54, 126.33, 129.23, 130.37,
33.58, 134.92, 145.23, 155.83, 158.61, 160.76. Anal. calcd.
Cl: C, 64.18; H, 3.23; N, 19.96. Found (ꢀ):
C, 64.16; H, 3.23; N, 19.95.
-Amino-2-(3-nitro-phenyl)-[1,8]naphthyridine-3-
carbonitrile (12e): Yield 79 ꢀ as yellow colour product m.p.:
-d
3 6
); δ,
1254, 787, 762, 638; H NMR (300 MHz, DMSO-d
6
); δ, ppm,
), 6.84 (d, J = 7.8 Hz, 1H), 7.39 (t, J =
7.8 Hz, 1H), 7.56-7.72 (m, 2H), 7.89 (d, J = 7.9 Hz, 1H), 8.12
4.72 (broad s, 2H, NH
2
1
13
(
ꢀ) for C15
H N
9 4
(s, 1H); C NMR (300 MHz, CDCl
114.31, 123.24, 125.17, 126.09, 127.45, 129.77, 131.21,
133.76, 135.58, 137.65, 148.63, 156.87, 158.89. Anal. calcd.
(ꢀ) for C15
C, 57.14; H, 2.55; N, 17.75.
4-Amino-2-(3-bromophenyl)-6-chloro-[1,8]naph-
thyridine-3-carbonitrile (12j):Yield 72 ꢀ (0.04g) as reddish
solid m.p.: 75-77 °C; Solubility (soluble in chloroform,
3
-d ); δ, ppm, 89.37, 110.12,
6
4
H
8
N
4
Cl : C, 57.17; H, 2.56; N, 17.78. Found (ꢀ):
2
-1
1
2
1
4
8
96-199 °C; IR (KBr, νmax, cm ): 3385, 3223 (NH), 2914,
833, 2215 (CN), 1675 (C=N), 1643 (C=C), 1573 (N-O), 1465,
1
461, 1311, 977; H NMR (300 MHz, DMSO-d
6
); δ, ppm,
), 7.41 (t, J = 6.2 Hz, 1H), 7.52 (t, J =
.6 Hz, 1H), 7.90 (d, J = 6.4 Hz, 1H), 8.07 (dd, J = 8.5 & 1.9
.85 (broad s, 2H, NH
2
-1
DMSO); IR (KBr, ν 1m ax, cm ): 3461 (NH
2
), 3296 (NH), 2229
-d ); δ, ppm,
Hz, 1H), 8.23 (dd, J = 8.6 & 1.9 Hz, 1H), 9.19 (d, J = 6.6 Hz,
(CN), 1625 (C=N); H NMR (300 MHz, CDCl
3
6
1
3
1
1
1
H); C NMR (300 MHz, CDCl
3
-d
6
); δ, ppm, 87.52, 110.15,
4.55 (s, 2H, NH2), 6.49 (d, J = 8.7, 1H), 7.39-7.47 (m, 2H),
7.73-7.78 (m, 1H), 7.91 (d, J = 7.8, 1H), 7.98 (t, J = 1.5 Hz
15.13, 124.41, 124.73, 125.13, 128.35, 129.73, 132.54,
34.58, 138.86, 149.34, 157.31, 158.61, 160.76. Anal. calcd.
13
1H), 8.02 (d, J = 2.4 Hz, 1H); C NMR (300 MHz, CDCl
); δ, ppm, 84.62, 109.87, 112.04, 113.21, 120.93, 123.66,
128.65, 131.11, 132.53, 133.49, 137.30, 138.00, 145.89,
156.73, 158.16. Anal. calcd. (ꢀ) for C15 BrCl: C, 50.10;
3
-
(
ꢀ) for C15
H
9
N
5
O
2
: C, 61.85; H, 3.11; N, 24.04. Found (ꢀ):
C, 61.82; H, 3.10; N, 24.02.
-Amino-2-(4-nitro-phenyl)-[1,8]naphthyridine-3-
carbonitrile (12f): Yield 75 ꢀ as yellow colour product m.p.:
d
6
4
H N
8 4
H, 2.24; N, 15.58. Found (ꢀ): C, 50.06, H, 2.23; N, 15.53.
4-Amino-2-(4-chlorophenyl)-6-chloro-[1,8]naphthyri-
dine-3-carbonitrile (12k): Yield 74 ꢀ (0.03g) as brown colour
precipitates m.p.: 120-122 °C; Solubility (soluble in
-1
1
2
78-182 °C; IR (KBr, νmax, cm ): 3382, 3289 (NH), 2936,
824, 2212 (CN), 1672 (C=N), 1631 (C=C), 1517, 1454, 1395
1
(NO
2
), 1215, 987; H NMR (300 MHz, DMSO-d
.29 (broad s, 2H, NH
6
); δ, ppm,
), 7.40 (t, J = 6.3 Hz, 1H), 7.58 (d, J =
.2 Hz, 1H), 7.94 (d, J = 8.4 Hz, 2H), 8.23 (d, J = 8.4 Hz, 2H),
-1
4
6
9
2
chloroform, DMSO); IR (KBr, ν 1m ax, cm ): 3461 (NH
(NH), 2229 (CN), 1625 (C=N) ; H NMR (300 MHz, CDCl
); δ, ppm, 4.59 (s, 2H, NH ), 6.47 (d, J = 8.7 Hz, 1H), 7.39
(d, J = 7.2, 1H), 7.52 (d, J = 8.1, 1H), 7.75 (s, 1H), 7.85 (d, J
2
), 3303
3
-
13
.27 (d, J = 6.3 Hz, 2H); C NMR (300 MHz, CDCl
-d
3 6
); δ,
d
6
2
ppm, 87.95, 111.62, 115.31, 123.74, 127.31, 128.43, 129.37,
33.58, 146.92, 155.83, 158.65, 160.61, 163.12. Anal. calcd.
: C, 61.85; H, 3.11; N, 24.04. Found (ꢀ):
C, 61.81; H, 3.11; N, 24.01.
-Amino-2-(4-hydroxy-3-methoxyphenyl)-1,8-naph-
thyridine-3-carbonitrile (12g): Yield 79.8 ꢀ as dark yellow
13
1
= 8.1, 1H), 8.01 (s, 1H); C NMR (300 MHz, CDCl
ppm, 83.26, 109.58, 112.38, 113.49, 120.90, 129.25, 130.09,
131.87, 137.68, 141.18, 146.22, 156.79, 158.38. Anal. calcd.
(ꢀ) for C15
C, 57.15; H, 2.56; N, 17.76.
4-Amino-6-chloro-2-(3-nitro-phenyl)-[1,8]naphthyri-
dine-3-carbonitrile (12l): Yield 75 ꢀ as reddish solid; m.p.:
223-225 °C; IR (KBr, νmax, cm ): 3392, 3284 (NH stretching),
2243 (CN), 1645 (C=N), 1617 (C=C), 1531, 1552, 1211, 756,
3
6
-d ); δ,
(
ꢀ) for C15
H N O
9 5 2
4
H
8
N
4
Cl : C, 57.17; H, 2.56; N, 17.78. Found (ꢀ):
2
-1
precipitates m.p.: 116-118 °C; IR (KBr, νmax, cm ): 3550(OH),
3
1
315, 3209 (NH stretching), 2214 (CN), 1566 (C=C), 1506,
456, 1294, 1242, 1128, 1024, 767, 622, 594; H NMR (300
1
-1
MHz, DMSO-d
6
); δ, ppm, 3.60 (s, 3H, CH
), 6.08 (broad s, 1H, OH), 6.59 (d, J = 8.4 Hz, 1H),
.25 (s, 1H), 7.41 (t, J = 6.4 Hz, 1H), 7.59 (d, J = 6.5 Hz, 1H),
3
), 4.68 (broad s,
1
2
7
7
H, NH
2
742, 658; H NMR (300 MHz, DMSO-d
6
); δ, ppm, 4.74 (broad
), 7.42 (t, J = 8.3 Hz 1H), 7.89 (dd, J = 8.4 & 1.6
Hz, 1H), 7.96 (s, 1H), 8.13 (s, 1H), 8.37 (dd, J = 8.4 & 1.4 Hz,
s, 2H, NH
2
13
.80 (d, J = 8.4 Hz, 1H), 8.97 (d, J = 6.4 Hz, 1H),; C NMR
-d ); δ, ppm, 87.34, 112.89, 115.37, 121.74,
13
(300 MHz, CDCl
3
6
1H), 8.63 (s, 1H); C NMR (300 MHz, CDCl
3
6
-d ); δ, ppm,
1
1
24.67, 127.31, 128.43, 130.37, 133.76, 136.98, 137.92,
48.63, 154.66, 159.61, 160.16. Anal. calcd. (ꢀ) for
85.69, 113.42, 119.21, 121.34, 124.17, 128.13, 129.35, 131.56,
132.58, 134.92, 148.73, 151.83, 156.66, 158.61, 162.76. Anal.
C
16
H
12
N O
4 2
: C, 65.75; H, 4.14; N, 19.17. Found (ꢀ): C, 65.70;
calcd. (ꢀ) for C15
H
8
N
5
ClO : C, 55.31; H, 2.48; N, 21.50. Found
2
H, 4.13; N, 19.13.
(ꢀ): C, 55.26; H, 2.47; N, 21.47.
4
-Amino-6-chloro-2-phenyl-[1,8]naphthyridine-3-
4-Amino-6-chloro-2-(4-nitro-phenyl)-[1,8]naphthyri-
dine-3-carbonitrile (12m): Yield 76 ꢀ as reddish solid; m.p.:
carbonitrile (12h): Yield 83 ꢀ as yellow solid; m.p.: 198-
-1
-1
2
(
6
2
2
8
01 °C; IR (KBr, νmax, cm ): 3341, 3278 (NH stretching), 2176
245-247 °C; IR (KBr, νmax, cm ): 3413, 3344 (NH stretching),
CN), 1654 (C=N), 1629 (C=C), 1514, 1475, 1272, 767, 752,
2256 (CN), 1667 (C=N), 1626 (C=C), 1532, 1561, 1253, 776,
1
1
88; H NMR (300 MHz, DMSO-d
H, NH ), 7.20-7.36 (m, 3H), 7.53 (s, 1H), 7.79 (d, J = 7.6Hz,
H), 8.27 (s, 1H); C NMR (300 MHz, CDCl
6.57, 109.23, 113.78, 122.14, 125.67, 127.72, 133.76, 134.54,
6
); δ, ppm, 4.92 (broad s,
767, 691; H NMR (300 MHz, DMSO-d
6
); δ, ppm, 4.64 (broad
2
s, 2H, NH
1H), 8.39 (d, J = 7.6 Hz, 2H), ; C NMR (300 MHz, CDCl
); δ, ppm, 86.27, 118.21, 121.14, 122.67, 127.13, 129.35,
2
), 7.52 (s, 1H), 7.68 (d, J = 7.6 Hz, 2H), 8.03 (s,
1
3
13
3
-d
6
); δ, ppm,
3
-
d
6

7
2 Yaqub et al.
Asian J. Chem.
1
31.58, 135.92, 148.63, 150.83, 157.66, 158.61, 161.76. Anal.
calcd. (ꢀ) for C15 ClO : C, 55.30; H, 2.46; N, 21.51;.
-Amino-5-methyl-2-phenyl-[1,8]naphthyridine-3-
carbonitrile (12n): Yield 79.2 ꢀ as light yellow solid m.p.:
CDCl
3
-d
6
); δ, ppm, 22.31, 85.51, 115.14, 119.32, 127.81,
H N
8 5
2
128.91, 131.32, 133.38, 153.92, 138.63, 149.65, 152.86,
155.69, 161.16. Anal. calcd. (ꢀ) for C16
3.76; N, 19.01. Found (ꢀ): C, 65.18; H, 3.76; N, 18.99.
4-Amino-5-methyl-2-(3-nitro-phenyl)-[1,8]naphthyri-
dine-3-carbonitrile (12r): Yield 78 ꢀ as brown solid m.p.:
243-245 °C; Solubility (soluble in chloroform, DMSO); IR
4
H
11
4
N Cl: C, 65.20; H,
9
ν
1
2
7
7
1-94 °C; Solubility (soluble in chloroform, DMSO); IR (KBr,
-1
max, cm ): 3367 (NH ), 3219 (NH), 2251 (CN), 1636 (C=N),
2
1
539, 1274, 975, 786; H NMR (300 MHz, CDCl
.53 (s, 3H, CH ), 7.26 (t, J = 7.7 Hz, 2H), 7.39 (s, 2H, NH
.51 (t, J = 7.8 Hz, 1H), 7.90 (d, J = 7.9Hz, 2H), 8.09 (d, J =
.5 Hz, 1H), 9.26 (d, J = 7.2 Hz, 1H); C NMR (300 MHz,
-d ); δ, ppm, 23.42, 87.52, 112.21, 120.14, 122.75,
26.01, 128.13, 129.37, 130.46, 139.63, 151.94, 152.66,
53.61, 161.71; Anal. calcd. (ꢀ) for C16 : C, 73.83; H,
.65; N, 21.52. Found (ꢀ): C, 73.80; H, 4.64; N, 21.50.
-Amino-2-(2-chloro-phenyl)-5-methyl-[1,8]naph-
3
-d
6
); δ, ppm,
-1
3
2
),
(KBr, ν m1 ax, cm ): 3432 (NH
(C=N); H NMR (300 MHz, CDCl
CH ), 7.39 (m, 2H, NH ), 7. 52 (d, J = 7.2 Hz, 1H), 7.73 (t, J
= 7.9 Hz, 1H), 7.96 (dd, J = 7.8 & 1.2 Hz, 1H), 8.19 (dd, J =
2
), 3289 (NH), 2196 (CN), 1643
3
-d ); δ, ppm, 2.42 (s, 3H,
6
13
3
2
CDCl
3
6
13
1
1
4
7.8 & 1.2 Hz, 1H), 8.73 (s, 1H), 9.24 (d, J = 7.2 Hz, 1H); C
NMR (300 MHz, CDCl -d ); δ, ppm, 23.71, 89.98, 127.29,
129.56, 133.47, 135.81, 137.13, 139.35, 140.34, 141.58,
145.92, 148.63, 151.91, 154.56, 156.41, 162.36. Anal. calcd.
H
12
N
4
3
6
4
thyridine-3-carbonitrile (12o): Yield 83 ꢀ as reddish brown
(ꢀ) for C16
H
11
N
5
O : C, 62.95; H, 3.63; N, 22.94. Found (ꢀ):
2
solid m.p.: 85-87 °C; Solubility (soluble in chloroform, DMSO);
C, 62.92; H, 3.62; N, 22.93.
-1
IR (KBr, νmax, cm ): 3325 (NH
2
), 3291 (NH stretching), 2219
CN), 1643 (C=N); H NMR (300 MHz, CDCl -d ); δ, ppm,
.31 (s, 3H, CH ), 7.16 (d, J = 7.2 Hz, 1H), 7.29-7.35 (m, 3H,
NH ), 7.52 (t, J = 7.8 Hz, 1H), 7.74 (d, J = 7.90Hz, 1H), 8.01
d, J = 7.4 Hz, 1H), 9.26 (d, J = 7.0 Hz, 1H); C NMR (300
MHz, CDCl -d ); δ, ppm, 21.39, 82.56, 114.14, 119.32, 122.77,
25.21, 127.59, 128.35, 130.36, 132.58, 133.92, 138.63,
51.65, 152.86, 153.64, 160.16. Anal. calcd. (ꢀ) for
Cl: C, 65.20; H, 3.76; N, 19.01. Found (ꢀ): C, 65.16;
H, 3.75; N, 19.00.
4-Amino-5-methyl-2-(4-nitro-phenyl)-[1,8]naphthyri-
dine-3-carbonitrile (12s): Yield 76 ꢀ as reddish brown solid
m.p.: 213-215 °C; Solubility (soluble in chloroform, DMSO);
1
(
3
6
2
3
-1
2
IR (KBr, νmax, cm ): 3435 (NH
2
), 3354 (NH stretching), 2256
(CN), 1676 (C=N); H NMR (300 MHz, CDCl -d ); δ, ppm,
2.61 (s, 3H, CH ), 7.54 (d, J = 7.2 Hz, 2H), 7.63 (s, 2H, NH ),
7.89 (d, J = 7.8 Hz, 2H), 8.12 (d, J = 7.5 Hz, 1H), 9.29 (d, J =
13
1
(
3
6
3
6
3
2
1
1
13
7.4 Hz, 1H); C NMR (300 MHz, CDCl
3
-d ); δ, ppm, 25.12,
6
C
16
H
11
N
4
83.52, 116.14, 125.85, 127.87, 129.97, 132.32, 135.38, 136.92,
138.63, 149.78, 153.86, 155.08, 161.66. Anal. calcd. (ꢀ) for
4
-Amino-2-(3-chloro-phenyl)-5-methyl-[1,8]naph-
C
16
H
11
N
5
O : C, 62.95; H, 3.63; N, 22.94. Found (ꢀ): C, 62.93;
2
thyridine-3-carbonitrile (12p): Yield 80.5 ꢀ as brown solid
m.p.: 112-115 °C; Solubility (soluble in chloroform, DMSO);
H, 3.63; N, 22.92.
4-Amino-2-(3-bromophenyl)-5-methyl-[1,8]naphthy-
ridine-3-carbonitrile (12t): Yield 82 ꢀ (0.54 g) as yellow
solid m.p.: 97-99 °C; Solubility (soluble in chloroform,
-1
IR (KBr, νmax, cm ): 3332 (NH
2
), 3189 (NH), 2216 (CN), 1643
C=N); H NMR (300 MHz, CDCl -d ); δ, ppm, 2.45 (s, 3H,
), 7.26 (d, J = 7.2 Hz, 1H), 7.29-7.35 (m, 3H, NH ), 7.67
1
(
3
6
-1
CH
3
2
DMSO); IR (KBr, ν 1m ax, cm ): 3311 (NH
(CN), 1652 (C=N); H NMR (300 MHz, CDCl
2.53 (s, 3H, CH ), 7.06 (d, J = 7.2 Hz, 1H), 7.29-7.42 (m, 3H,
NH ), 7.65 (d, J = 7.8 Hz, 1H), 7.92 (d, J = 7.4 Hz, 1H), 8.09
(s, 1H), 9.26 (d, J = 7.2 Hz, 1H); C NMR (300 MHz, CDCl
); δ, ppm, 21.72, 85.52, 117.21, 119.14, 122.77, 125.01,
127.13, 128.35, 130.06, 131.58, 133.92, 138.63, 150.93, 152.66,
153.61, 161.76. Anal. calcd. (ꢀ) for C16 Br: C, 56.66; H,
2
), 3089 (NH), 2196
(
(
2
1
1
1
d, J = 7.9 Hz, 1H), 8.12 (s, 1H), 8.06 (d, J = 7.2 Hz, 1H), 9.10
3
-d ); δ, ppm,
6
13
d, J = 7.1 Hz, 1H); C NMR (300 MHz, CDCl
3
-d
3.71, 89.98, 117.21, 119.56, 123.47, 125.31, 127.13, 129.35,
30.34, 131.58, 135.92, 138.63, 151.91, 152.56, 153.41,
61.36. Anal. calcd. (ꢀ) for C16 Cl: C, 65.20; H, 3.76; N,
9.01. Found (ꢀ): C, 65.15; H, 3.75; N, 18.98
-Amino-2-(4-chloro-phenyl)-5-methyl-[1,8]naph-
6
); δ, ppm,
3
2
13
3
-
H
11
N
4
d
6
4
H
11
N
4
thyridine-3-carbonitrile (12q): Yield 82 ꢀ as reddish brown
3.27; N, 16.52. Found (ꢀ): C, 56.61; H, 3.26; N, 16.50.
solid m.p.: 89-92 °C; Solubility (soluble in chloroform,
-
1
RESULTS AND DISCUSSION
DMSO); IR (KBr, νmax, cm ): 3375 (NH
2
), 3254 (NH
stretching), 2232 (CN), 1612 (C=N); H NMR (300 MHz,
CDCl -d ); δ, ppm, 2.46 (s, 3H, CH ), 7.34 (d, J = 7.2 Hz,
H), 7.39 (s, 2H, NH ), 7.57 (d, J = 7.8 Hz, 2H), 8.01 (d, J =
.2 Hz, 1H), 9.16 (d, J = 7.2 Hz, 1H); C NMR (300 MHz,
1
To synthesize the novel 1,8-naphthyridine derivatives, 2-
aminopyridine (8), aromatic aldehyde (9) and malanonitriles
(10) were first chosen to examine the scope of reaction
(Scheme-I) in various polar and non-polar solvents to obtain
3
6
3
2
7
2
13
H N
2
CN
O
NC
CN
H
R2
NC
NC
N
NH2
H
8
R
1
N
R1
R2
N
R1
1
0
9
11
12a-12t
R = H, 2-Chloro, 3-Chloro, 4-Chloro, 3-bromo, 3-Nitro, 4-Nitro
1
R = H, 5-Chloro, 4-Methyl
2
Scheme-I: Cascade synthesis of fused ring heterocycles

Vol. 28, No. 1 (2016)
Synthesis of Highly Functionalized Novel 1,8-Naphthyridine Derivatives 73
the targeted compounds (12a) and THF was found to be the
best choice with respect to the product yield (Table-1, entry
2-aminopyridines (8) were examined under our optimized
reaction conditions using THF as solvent and catalytic quantity
of pyridine. The reaction resulted in the formation of fused ring
heterocycles (12a-12t) in good to excellent yields and results
are summarized in Table-2.
3). Different acids and bases were also used as catalyst to check
their effect on product yield and pyridine was found to be the
most suitable catalyst for the said synthesis (Table-1, entry 6).
Arylidines formation as an intermediate (11) act as bis-electro-
philic which reacted further with 2-aminopyridine, a bis-
nucleophile, through condensation followed by cyclization to
form desired 1,8-naphthyridine derivatives (12a-12t).
TABLE-2
REACTIONS OF AMINOPYRIDINES WITH
ARYLIDINES AND MALONONITRILE
a
S. No.
R1
H
R2
Product
12a
12b
12c
12d
12e
12f
Yield ꢀ
85.0
78.0
74.0
76.4
79.0
75.0
79.8
83.0
79.0
72.0
74.0
75.0
76.0
79.0
83.0
80.5
82.0
78.0
76.4
82.0
1
2
3
4
5
6
7
8
9
H
H
H
H
H
H
TABLE-1
2-Chloro
3-Chloro
4-Chloro
3-Nitro
OPTIMIZATION OF REACTION CONDITIONS AND
EFFECT OF DIFFERENT CATALYSTS TO GET
FUSED RING HETEROCYCLES (12a-12t)
Reaction
solvents
Reaction
conditions
Entry
Catalysts
Yield (ꢀ)
4-Nitro
4-Hydroxy-3-methoxy
H
H
12g
12h
12i
12j
12k
12l
12m
12n
12o
12p
12q
12r
12s
1
2
3
4
5
6
7
8
9
Ethanol
Methanol
THF
Chloroform
DMSO
THF
–
–
–
–
–
Reflux, 3 h
Reflux, 3 h
Reflux, 3 h
Reflux, 3 h
Reflux, 3 h
Reflux, 6 h
Reflux, 3 h
Reflux, 3 h
Reflux, 3 h
Reflux, 3 h
Reflux, 3 h
Reflux, 3 h
52
48
76
63
40
85
35
42
40
32
80
22
5-Chloro
5-Chloro
5-Chloro
5-Chloro
5-Chloro
5-Chloro
4-Methyl
4-Methyl
4-Methyl
4-Methyl
4-Methyl
4-Methyl
4-Methyl
2-Chloro
3-Bromo
4-Chloro
3-Nitro
4-Nitro
H
2-Chloro
3-Chloro
4-Chloro
3-Nitro
4-Nitro
3-Bromo
10
11
12
13
14
15
16
17
18
19
20
Pyridine
AcOH
ZnCl2
AlCl3
THF
THF
THF
THF
THF
THF
10
11
12
Lead acetate
NEt
HCl
3
12t
In order to expand the scope of reaction, the reaction of
malononitrile (10), substituted benzaldehyde (9) and substituted
a
Isolated yield.
Cl
N
C
N
Cl
Cl
NC
CN
NC
+
C
–
– H
N
C N
N
NH2
NH
N
N
Ph
Ph
H
H
Ph
N
(
A)
H
(B)
+H
N
NH
H
C
Cl
Cl
Cl
CN
Ph
Cl
CN
H
CN
Ph
N
N
H
Ph
N
N
H
N
N
H
NH2
NH2
N
CN
Ph
Cl
CN
Ph
Air Oxidation
N
N
H
N
(
C)
Scheme-II: Plausible mechanism of the reaction

7
4 Yaqub et al.
Asian J. Chem.
The structure of the synthesized 1,8-naphthyridine deri-
vatives (12a-12t) was established on the bases of spectroscopic
ACKNOWLEDGEMENTS
1
13
This work was supported by the Bahauddin Zakariya
University, Multan, Pakistan.
(IR, H NMR and C NMR) and analytical (CHN-analysis)
data. The IR data of 1,8-naphthyridine derivatives (12a-12t)
showed three prominent absorption at about 3300, 2200 and
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(
2
M.A. Seefeld, W.H. Miller, K.A. Newlander, W.J. Burgess, W.E. DeWolf,
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2
indicated the difference of substitution at position-6 and
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1
13
The other H NMR absorptions and C NMR signals were
exactly according to the purposed structure of the said substi-
tuted 1,8-naphthyridines.
3
.
G. Grossi, M. Di Braccio, G. Roma, V. Ballabeni, M. Tognolini and E.
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nent domino reaction to form fused ring heterocyclic 1,8-
naphthyridine derivatives is depicted in Scheme-II. Reaction
is initiated with the Knoevenagel condensation of malononitrile
and aldehyde in presence of pyridine as base to form respective
arylidine intermediate with the loss of water molecule. The 2-
aminopyridine would act as bis-nucleophile and arylidine
intermediate would undergo aza-Michael addition reaction
followed by intramolecular cyclization to construct six member
ring of naphthyridine nucleus (c). The air-oxidation of naphthy-
ridine nucleus offered the highly substituted 1,8-naphthyridine
derivatives.
5
.
S.K. Srivastava, M. Jaggi, A.T. Singh, A. Madan, N. Rani, M. Vishnoi,
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.
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1
1
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Conclusion
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Lafuente, I. Colmena, L. Gandía, A. Romero, L. Barrio, M.D. Martín-
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Asian J. Chem., 27, 1013 (2015).
One-pot three component synthetic method has been deve-
loped for the preparation of highly substituted 1,8-naphthy-
ridine derivatives 12a-12t employing 2-aminopyridines as bis-
nucleophile, malononitrile and substituted aldehydes. The
newly synthesized 1,8-naphthyridine derivatives 12a-12t
resembles closely with the naturally occurring molecules (Fig. 1,
compounds 1-6) and contain a number of tunable functional
groups for further manipulation to develop valuable precursors
for the medicinally active compounds.
1
1
1
1