Abstract: A simple, efficient and one-pot procedure has been described for the synthesis of 2-amino-4-phenyl-1,8-naphthyridine-3-carbonitrile derivatives. A mixture of 2-amino pyridine, malononitrile and aromatic aldehydes were reacted in presence of catalytic amount of 3-nitrophenylboronic acid as catalyst at room temperature to produce 2-amino-4-phenyl-1,8-naphthyridine-3-carbonitriles. The mild reaction condition, short reaction time, high yield and simple experimental operation are the salient future of this method

Bhimrao C Khade

Prashant B Thorat

Santosh V Goswami

Sudhakar R Bhusare

CiteSeerX

228 
ISSN: 2249 –4820 
Chemistry & Biology Interface, 2012, 2, 4, 28-233 
 
 
 
 
 
 
Chemistry & Biology Interface 
An official Journal of ISCB, Journal homepage; www.cbijournal.com 
 
Research Paper 
A Convenient One-Pot Synthesis of 2-Amino-4-Phenyl-1,8-Naphthyridine-3-Carbonitrile 
Derivatives  
 
Santosh V. Goswami, Prashant B. Thorat, Bhimrao C. Khade and Sudhakar R. Bhusare* 
 
Department of Chemistry, Dnyanopasak College, Parbhani-431 401, MS, India 
Received 21 May 2012; Accepted 14 June 2012 
                                     
Keywords: 2-Amino-4-phenyl-1,8-naphthyridine-3-carbonitriles; aromatic aldehydes; 2-aminopyridine; 
malononitrile; 3-nitrophenylboronic acid. 
 
Abstract: A simple, efficient and one-pot procedure has been described for the synthesis of 2-amino-4-
phenyl-1,8-naphthyridine-3-carbonitrile derivatives. A mixture of 2-amino pyridine, malononitrile and 
aromatic aldehydes were reacted in presence of catalytic mount of 3-nitrophenylboronic acid as catalyst 
at room temperature to produce 2-amino-4-phenyl-1,8-naphthyridine-3-carbonitriles. The mild reaction 
condition, short reaction time, high yield and simple experimental operation are the salient future of this 
method.  
 
 
Introduction 
 
Naphthyridine derivatives are of significant 
class of organic molecules that catch the 
attention of researcher from synthetic and 
medicinal chemistry [1].  The highly 
functionalized derivatives of naphthyridine 
find application in the medicinal area as 
antibacterial [2a], anti-inflammatory [2b], 
antihypertensive [2c] and anticancer 
activities [2d]. The naphthrydine derivatives 
are found to be potent against fungicides, 
bactericides, herbicides and insecticides as 
well as helpful synthetic blocks in the 
preparation of several natural products [3-5]. 
They have been used in the antibiotics for 
the diagnostics and chemotherapy of 
infectious diseases of humans including  
---------------------------------------------------------------- 
Corresponding Author* E-mail: bhusare71@yahoo.com 
AIDS [6]. Also 1,8-naphthyridine 
derivatives have attracted significant 
attention as a backbone isolated from natural 
substances with various biological activities 
[7]. 
 
The review of literature reveals the synthesis 
of 1,8-naphthyridine derivatives involving 
the condensation of 2-aminopyridine with 
carbonyl compounds containing an activated 
methylene group [8-10] or with β-ketoesters 
[11]. 1, 8-Naphthyridines are also prepared 
by the condensation of ethanolic 2-amino-3-
formylpyridines in the presence of strong 
base such as piperidine with active 
methylene compounds, aldehydes, acyclic 
and cyclic ketones or diketones [12]. Thus 
due to immense biological significance, 
various protocols was reported for synthesis 
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of naphthyridine derivatives utilizing 
different type of reagents [13-16].  
In recent years, Multi component reactions 
(MCRs) have gained significant attention 
from the organic area due to their 
advantages over conventional multistep 
synthesis. MCRs are more environmentally 
benign and atom economic as they avoid 
time-consuming and protection-deprotection 
steps. In this regard, the developments of 
new MCRs are most important in the fields 
of organic and medicinal chemistry.  
 
The phenylboronic acid particularly those 
with electron-withdrawing substituent on 
aromatic ring work as an efficient Lewis 
acid catalyst. Recently phenylboronic acid 
has been effectively used as a catalyst in 
organic transformation as mild Lewis acid 
for several synthetic protocol such as 
amidation of carboxylic acids, asymmetric 
Diels-Alder cycloadditions and 
enantioselective allylation reactions [17], 
synthesis of 3,4-dihydropyrimidinones [18] 
and synthesis of 1,4-dihydropyridines [19]. 
 
As a continuation of our interest in the 
development of MCRs using organoboron 
compounds as a catalyst [20], herein we 
describe a mild and efficient one-pot 
synthesis of 2-amino-4-phenyl-1,8-
naphthyridine-3-carbonitrile derivatives 
starting from 2-aminopyridine, malononitrile 
and aromatic aldehydes using 3-
nitrophenylboronic acid as a catalyst at 
ambient temperature condition (Scheme 1). 
 
Materials and Methods 
 
Experimental  
 
All solvents were used as commercial 
anhydrous grade without further 
purification. Aluminium sheets 20 x 20cm, 
Silica gel 60 F254, Merck grade was used for 
thin layer chromatography to determine 
progress of reaction. The column 
chromatography was carried out over silica 
gel (80–120 mesh). Melting points were 
determined in open capillary tube and are 
uncorrected. 1H and 13C NMR spectra were 
recorded on a Bruker 300 MHz spectrometer 
in CDCl3 solvent.  
 
General procedure for the synthesis of 2-
amino-4-phenyl-1,8-naphthyridine-3-
carbonitrile derivatives (4a-j):  
 
2-Aminopyridine (10 mmol), aromatic 
aldehyde (15 mmol) and malononitrile (10 
mmol) were mixed in methanol (15 ml). 
Catalytic amount of 3-nitrophenylboronic 
acid (20 mole %) was added. Reaction 
mixture was stirred at room temperature for 
appropriate time (Table 2). The progress of 
reaction was monitored by thin layer 
chromatography (pet ether: ethyl acetate 
9:1). After the completion of reaction, 
reaction mixture was poured in crushed ice. 
Obtained precipitate was filtered and 
washed with hot water to obtain crude 
product. The crude product was further 
purified by column chromatography on 
silica gel (60–120 mesh size) using 20 % 
ethyl acetate in petroleum ether as eluent to 
get pure product.  
 
Synthesis of 2-Amino-4-(4-chlorophenyl)-
1,8-naphthyridine-3-carbonitrile (4a): 1H 
NMR (300 MHz, CDCl3): δ = 5.40 (s, 2H), 
7.40-7.62 (m,4H), 8.15-8.35 (m, 3H);  13C 
NMR (300 MHz, CDCl3): δ 92.1, 114.2, 
116.8, 125.6, 133.2, 136.1, 139.3, 142.8, 
151.5, 156.1, 164.1; Mass GC-MS (m/z): 
281.56 [M+], Elem. Anal for C15H9ClN4: C, 
64.18; H, 3.23; Cl, 12.63; N, 19.96 Found C, 
64.25; H, 3.32; Cl, 12.56; N, 19.84. 
 
Synthesis of 2-Amino-4-(2-chlorophenyl)-
1,8-naphthyridine-3-carbonitrile (4b): 1H 
NMR (300 MHz, CDCl3): δ = 5.36 (s, 2H), 
7.25-7.42 (m,4H), 8.10-8.28 (m, 3H);  13C 
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Chemistry & Biology Interface, 2012, 2, 4, 28-233 
 
 
 
NMR (300 MHz, CDCl3): δ 91.2, 112.1, 
118.4, 124.2, 130.6, 136.1, 138.4, 140.2, 
151.1, 157.6, 165.2; Mass GC-MS (m/z): 
280.71 [M+], Elem. Anal for C15H9ClN4: C, 
64.18; H, 3.23; Cl, 12.63; N, 19.96 Found C, 
64.21; H, 3.25; Cl, 12.58; N, 19.88. 
 
Synthesis of 2-Amino-4-(4-methylphenyl)-
1,8-naphthyridine-3-carbonitrile (4c): 1H 
NMR (300 MHz, CDCl3): δ = 6.10 (s, 2H), 
6.85 (d, 2H), 7.01-7.20 (m, 3H), 7.64 
(d,1H), 8.12 (d, 1H), 13C-NMR (CDCl3): δ 
110.2, 114.4, 120.1, 124.4, 126.1, 128.2, 
131.1, 133.9, 136.2, 141.2, 144.8, 146.5, 
150.2, 153.1, 159.4, 166.8; Mass GC-MS 
(m/z): 260.51 [M+];  Elem. Anal for 
C16H12N4: C; 73.83, H; 4.65, N; 21.52. 
Found: C; 73.81, H; 4.66, N; 21.50.  
 
Synthesis of 2-Amino-4-(4-
methoxyphenyl)-1,8-naphthyridine-3-
carbonitrile (4d): 1H NMR (300 MHz, 
CDCl3): δ = 3.60 (s, 3H), 5.69 (s, 2H), 6.79-
7.10 (m, 3H), 7.55-8.10 (m, 5H); 13C NMR 
(300 MHz, CDCl3): δ 58.1, 91.8, 116.3, 
118.2, 119.8, 123.1, 129.9, 135.4, 149.5, 
156.1, 164.3; Mass GC-MS (m/z): 277.21 
[M+]; Elem. Anal for C16H12N4O: C, 69.55; 
H, 4.38; N, 20.28; O, 5.79 Found: C, 69.81; 
H, 4.32; N, 20.38; O, 5.56. 
 
Synthesis of 2-amino-4-(4-hydroxy-3-
methoxyphenyl)-1,8-naphthyridine-3-
carbonitrile (4e): 1H NMR (300 MHz, 
CDCl3): δ = 3.60 (s, 3H), 5.69 (s, 2H), 6.21 
(s, 1H), 6.74 (d, 1H), 6.76 (d, 1H), 7.21 (d, 
1H), 8.02-8.10 (m, 3H),13C NMR (300 
MHz, CDCl3): δ 57.6, 91.2, 116.2, 118.2, 
119.4, 122.2, 125.8, 129.1, 133.2, 135.5, 
139.4, 141.8, 147.1, 149.7, 155.8, 165.1 
Mass GC-MS (m/z): 293.16 [M+]; Elem. 
Anal for C16H12N4O2: C, 65.75; H, 4.14; N, 
19.17; O, 10.95 Found: C, 65.78; H, 4.12; 
N, 19.18; O, 10.97. 
 
Synthesis of 2-amino-4-(3,4-
dimethoxyphenyl)-1,8-naphthyridine-3-
carbonitrile (4f): 1H NMR (300 MHz, 
CDCl3): δ = 3.81 (s, 6H), 5.68 (s, 2H), 6.72 
(d, 1H), 6.74 (d, 1H) 7.21-7.50 (m, 4H), 13C 
NMR (300 MHz, CDCl3): δ 57.2, 90.6, 
116.1, 118.6, 119.1, 123.1, 126.3, 129.9, 
133.1, 135.8, 139.2, 142.1, 147.4, 149.5, 
156.1, 164.3; Mass GC-MS (m/z): 306.34 
[M+];  Elem. Anal for C17H14N4O2: C, 66.66; 
H, 4.61; N, 18.29; O, 10.45. Found: C, 
66.68; H, 4.64; N, 18.27; O, 10.48. 
 
Synthesis of 2-Amino-4-phenyl-1,8-
naphthyridine-3-carbonitrile (4g):  1H 
NMR (300 MHz, CDCl3): δ = 6.05 (s, 2H), 
6.55 (d, 1H), 6.72 (d, 1H), 7.25-7.54 (m, 
4H), 8.12 (d, 1H); 13C-NMR (CDCl3): δ 
118.2, 120.4, 124.6, 126.2, 127.4, 128.5, 
129.1, 132.0, 136.4, 139.8, 143.1, 154.2, 
158.2, 170.1, 171.4; Mass GC-MS (m/z): 
247.66 [M+]; Elem. Anal for C15H10N4: C, 
73.16, H; 4.09, N; 22.75. Found: C; 73.13, 
H; 4.08, N; 22.73. 
 
Synthesis of 2-amino-4-(3-nitrophenyl)-
1,8-naphthyridine-3-carbonitrile (4h): 1H 
NMR (300 MHz, CDCl3): δ = 5.48 (s, 2H), 
7.44-7.68 (m,4H), 8.14-8.31 (m, 3H); 13C 
NMR (300 MHz, CDCl3): δ 90.3, 113.9, 
115.9, 118.2, 122.4, 124.8, 129.1, 134.2, 
136.1, 139.5, 142.3, 147.2, 149.1, 151.7, 
156.1, 165.3; Mass GC-MS (m/z): 291.41 
[M+]; Elem. Anal for C15H9N5O2: C, 61.85; 
H, 3.11; N, 24.04; O, 10.99. Found: C, 
69.86; H, 3.14; N, 24.03; O, 10.97. 
 
Synthesis of 2-amino-4-(4-nitrophenyl)-
1,8-naphthyridine-3-carbonitrile (4i): 1H 
NMR (300 MHz, CDCl3): δ = 5.46 (s, 2H), 
7.42-7.65 (m,4H), 8.11-8.30 (m, 3H); 13C 
NMR (300 MHz, CDCl3): δ 90.1, 114.2, 
116.8, 118.6, 122.2, 125.6, 128.5, 133.2, 
136.1, 139.3, 142.8, 147.4, 148.2, 151.5, 
156.1, 164.1; Mass GC-MS (m/z): 291.32 
[M+];  Elem. Anal for C15H9N5O2: C, 61.85; 
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H, 3.11; N, 24.04; O, 10.99. Found: C, 
61.82; H, 3.13; N, 24.07; O, 10.96. 
Synthesis of 2-amino-4-(4-cyanophenyl)-
1,8-naphthyridine-3-carbonitrile (4j):  1H 
NMR (300 MHz, CDCl3): δ = 5.82 (s, 2H), 
6.84 (d, 2H), 7.04-7.18 (m, 3H), 7.62 
(d,1H), 8.10 (d, 1H),; 13C NMR (300 MHz, 
CDCl3): δ 91.5, 112.6, 114.2, 116.3, 118.2, 
119.8, 123.1, 126.2, 127.6, 129.9, 135.4, 
149.5, 153.2, 156.1, 159.4 164.3; Mass GC-
MS (m/z): 271.25 [M+]; Elem. Anal for 
C16H9N5: C, 70.84; H, 3.34; N, 25.82 Found: 
C, 70.86; H, 3.31; N, 25.83.  
 
Result and Discussion 
 
In general experimental procedure, a 
mixture of 2-aminopyridine (1), aromatic 
aldehyde (2a-j) and malononitrile (3) was 
stirred in methanol in the presence of 
catalytic amount of 3-nitrophenylboronic 
acid at room temperature to obtain desired 
products (4a-j) with good to moderate yield. 
To the best of our knowledge, this is the first 
approach in which organoboron compound 
is used as catalyst for the synthesis of 2-
amino-4-phenyl-1,8-naphthyridine-3-
carbonitrile derivatives.   
 
In initial investigation, a model reaction of 
2-aminopyridine, 4-chlorobenzaldehyde and 
malononitrile was carried out in different 
solvent using 10 mole % of 3-
nitrophenylboronic acid at room temperature 
and reflux condition. In the solvent 
dichloromethane, only trace amount of 
product was obtained after 8 hours of 
stirring (entry 1, Table 1). We observed in 
our course of investigation, phenylboronic 
acid as catalyst worked well in polar 
solvents [20], so we performed same 
reaction in the solvent acetonitrile at room 
temperature. We were glad to note that 
reaction completed in 1.2 hours, but yield 
was not so impressive (entry 2, Table 1). We 
subjected reaction to reflux, however there 
was not significant increase in the yield of 
the product and taking more time for 
completion of reaction (entry 3, Table 1). 
Then, we used solvent ethanol and 
continued same reaction at room 
temperature which gave 71 % yield and 
under reflux condition gave almost similar 
yield 72 % (entry 4 and 5 respectively, 
Table 1). Reaction shown much better 
performance in solvent methanol, reaction 
completed in just 1 hour to obtain yield of 
79 % (entry 6, Table 1). However under 
reflux condition reaction showed adverse 
effect on the time for completion and 
obtained yield 74 % (entry 7, Table 1).    
 
We found methanol to be the suitable 
solvent for reaction to synthesis of 2-amino-
4-phenyl-1,8-naphthyridine-3-carbonitrile 
derivatives but reaction yield was not 
meeting our expectations. Further, to 
optimize reaction condition, we increased 
catalyst concentration to 15 mole % which 
gave 82 % yield as per our anticipation 
(entry 8, Table 1). With this delightful result 
catalyst concentration was increased to 20 
mole %, reaction completed in 40 minutes 
and we obtained excellent yield 91 % (entry 
9, Table 1). Further increasing catalyst 
concentration was not showing improved 
performance.  
 
Optimized protocol was extended to other 
aromatic aldehydes having different 
substituents.  Effect of substituent showed 
very little difference in yield, but time 
required for completion of reaction was 
more in case of electron withdrawing 
substituent. Aromatic aldehyde having 
electron donating group were found to be 
more reactive (entry 1-10, Table 2). 
 
Conclusion 
 
Our results demonstrate that 3-
nitrophenylboronic acid play significant role 
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in success of the reaction in terms of 
reaction rate and yield of 2-amino-4-phenyl-
1,8-naphthyridine-3-carbonitrile derivatives. 
This method suggests several advantages 
such as mild reaction conditions, short 
reaction time, high yield and simple 
experimental operation. The products 
obtained were isolated in satisfactory yields 
by conventional work up.  
 
Acknowledgement 
 
We acknowledge Dr. P. L. More and Dr. W. 
N. Jadhav, Dnyanopasak College, Parbhani 
for providing necessary facilities, Indian 
Institute Chemical Technology, Hyderabad 
for providing spectral information and 
Financial support for this work by DST-
SERC, New Delhi (SR/FT/CS-023/2008) is 
highly appreciated. 
 
 
Scheme 1 
 
Table 1: Effect of catalyst concentration, solvent and temprature on synthesis of 2-amino-4-(4-
chlorophenyl)-1,8-naphthyridine-3-carbonitrile  
Entry  3-Nitrophenylboronic acid 
(mole %) 
Solvent Temperature Time (h) Yield (%) a 
1 10 DCM RT 8 - 
2 10 CH3CN RT 1.2 52 
3 10 CH3CN Reflux 2.0 58 
4 10 EtOH RT 1.2 71 
5 10 EtOH Reflux 1.2 72 
6 10 MeOH RT 1.0 79 
7 10 MeOH Reflux 1.2 74 
8 15 MeOH RT 1.0 82 
9 20 MeOH RT 0.40 91 
10 25 MeOH RT 1.0 68 
aIsolated yield. 
Table 2: Synthesis of 2-Amino-4-phenyl-1,8-naphthyridine-3-carbonitrile derivatives 
Entry  R Product Time (h) Mp (°C) Yield (%) a 
1 4-Cl 4a 0.40 165-1668 91 
2 2-Cl 4b 0.45 168-170 88 
3 4-CH3 4c 0.50 168-170
8 85 
4 4-OCH3 4d 0.40 162-164
8 90 
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5 3-OCH3,4-OH 4e 0.50 170-172 88 
6 3,4-(OCH3)2 4f 0.45 182-184 89 
7 H 4g 1.0 155-156
8 82 
8 3-NO2 4h 1.0 172-176 86 
9 4-NO2 4i 0.55 175-178 83 
10 4-CN 4j 1.0 140-141 87 
aIsolated yield. 
 
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Research Paper A Convenient One-Pot Synthesis of 2-Amino-4-Phenyl-1,8-Naphthyridine-3-Carbonitrile Derivatives

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Research Paper A Convenient One-Pot Synthesis of 2-Amino-4-Phenyl-1,8-Naphthyridine-3-Carbonitrile Derivatives

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