Synthesis of fused pyridines in the presence of thiamine hydrochloride as an efficient and reusable catalyst in aqueous conditions

Article abstract of DOI:10.1039/c3nj00711a

Efficient and straightforward synthesis of fused pyridine derivatives was achieved from electron-rich amino heterocycles and Knoevenagel products derived from aldehyde and malononitrile under aqueous media at 90 °C in the presence of thiamine hydrochlorid

Full text of DOI:10.1039/c3nj00711a

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Synthesis of fused pyridines in the presence of
thiamine hydrochloride as an efficient and reusable
catalyst in aqueous conditions
Cite this: DOI: 10.1039/c3nj00711a
I. R. Siddiqui,* Pragati Rai, Rahila, Anushree Srivastava, Arjita Srivastava and
Anjali Srivastava
Efficient and straightforward synthesis of fused pyridine derivatives was achieved from electron-rich
amino heterocycles and Knoevenagel products derived from aldehyde and malononitrile under aqueous
media at 90 1C in the presence of thiamine hydrochloride as a reusable, green catalyst. The strategy in
this protocol involves addition on an activated olefinic bond formed in situ by Knoevenagel
condensation between an aromatic aldehyde and an active methylene compound. The Michael product
on subsequent cyclo condensation yielded fused pyridine in high yield. It offers several advantages such
as inexpensive, easily available and recyclable catalyst, simple operational procedure, excellent yield and
use of aqueous medium that is considered to be relatively eco-friendly. Vitamin B1 was recovered and
reused thrice.
Received (in Montpellier, France)
2
9th June 2013,
Accepted 27th August 2013
DOI: 10.1039/c3nj00711a
www.rsc.org/njc
Many heterocycles containing pyrido[2,3-d]pyrimidines and
naphthyridines as a core unit reflect the large spectrum of
Introduction
Industrial and academic researchers during the last ten years biological, therapeutic and pharmaceutical activities such as
1
2
13
14
have developed and recognized the one pot multicomponent antifoliate, antitumour, antihypertensive, cyclin-dependent
1
5
16
17
reaction as an effective tool for combinatorial synthesis in drug kinase 4 inhibition, anti-inflammatory, and antibacterial,
discovery processes. Multicomponent reactions (MCRs) have which can be used in drug discovery. Naphthyridines are also
1
–3
1
8
been proven to be a powerful and efficient tool with unique used in the chemotherapy of infectious disease, as a growth
1
9
advantages of atom economy, low waste, quick assembly of regulator, inhibitor of HIV-1integrase in vitro and infected
2
0
molecules of complex structure and furnishing diverse molecules cell. Substituted 2-aminopyridine-3-carbonitriles are also used
for optimization processes for drug discovery research. It is a as cholinergic and neuroprotective drugs for the treatment of
challenge in the field of modern chemical research to develop Alzheimer’s and neuronal vascular diseases. A literature survey
efficient and non-hazardous methods to perform organic synthesis. reveals different types of modified methods for the synthesis of
Most solvents used in organic synthesis have hazardous effects pyrido[2,3-d]pyrimidine-6-carbonitrile and [1,8]-naphthyridine-3-
on the environment and human beings. In view of the above carbonitrile under different and improved conditions using
4
2
1
2
2
overwhelming challenges, water, being an ideal green solvent, is diammonium hydrogen phosphate, microwave, bismuth(III)-
commonly used as a reaction medium and is gaining more and nitrate pentahydrate, magnesium oxide and TEBAC.
2
3
24
25a,b
5
more importance in the field of modern organic synthesis.
However, so far most of these methods suffer from one or
As part of recent investigations in the field of biocatalysis, more problems such as the use of toxic organic solvents, use of
thiamine hydrochloride (VB1) and its analogues have been used expensive metals as catalysts, harsh reaction conditions, volatile
as versatile catalysts which has reflected their applications in solvents, non-recyclability of catalysts and lower yield.2
diverse organic reactions and transformations, for example
6–28
6–9
Knoevenagel condensation, Michael addition and cyclisation. In
creating carbon–carbon bonds and carbon–heteroatom bonds in
Result and discussion
various ongoing transformations, VB1 as a green catalyst has created In this manuscript we investigated the synthesis of pyrido[2,3-d]-
10
enormous interest in researchers because of its non-toxicity, pyrimidine-6-carbonitrile, [1,8]-naphthyridine-3-carbonitrile and
1
1
low cost, ease of handling and water and air compatibility.
their derivatives by using VB1 as a catalyst in the presence of
water for the first time. It is also known to all that this biocatalyst
is a stable and storable reagent which contains a pyrimidine ring
Laboratory of Green synthesis, Department of Chemistry, University of Allahabad,
Allahabad – 211002, India. E-mail: dr.irsiddiqui@gmail.com
2
9
and a thiazole ring linked by a methylene bridge. To the best of
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our knowledge there are no reports on the three-component Table 1 Influence of various catalysts on synthesis of compounds 6c and 9c
one-pot synthesis of pyrido[2,3-d]pyrimidine-6-carbonitriles and
1,8]-naphthyridine-3-carbonitriles using thiamine hydrochloride
c
Yield (%)
[
a
b
Entry
Solvent
Catalyst (10 mol%)
—
Time (h)
6c
9c
as catalyst in the presence of water. In continuation of our work
on the multicomponent synthesis of heterocyclic scaffolds by
1
2
3
4
5
6
7
H
2
H
2
H
2
H
2
H
2
H
2
H
2
O
O
O
O
O
O
O
12
12
12
12
12
12
2.5
—
19
22
—
—
—
94
—
30
ZnCl
MgCl
SiO
Al
2
17
25
—
—
—
95
environmentally benign methods, herein we report a highly
efficient one-pot protocol for the synthesis of pyrido[2,3-d]pyrimi-
dine-6-carbonitriles and [1,8]-naphthyridine-3-carbonitriles via the
three component condensation of aldehydes, malononitrile and
electron-rich amino heterocycles like 6-amino-1-methyluracil and
2
2
O
2
3
Alum
VB1
a
Reaction conditions: 4-methoxybenzaldehyde (1 mmol), malononitrile
1 mmol) and 6-amino-1-methyluracil (1 mmol) were stirred in 4 mL water
in the presence of catalyst (10 mol%) at 90 1C. Reaction conditions:
2-aminopyridine catalyzed by VB1 in water at 90 1C. At first, the
(
reaction was performed in two steps. In the first step, benzylidene
b
malononitrile 3 was obtained in 89% yield by the VB1-promoted 4-methoxybenzaldehyde (1 mmol), malononitrile (1 mmol) and 2-amino
pyridine (1 mmol) were stirred in 4 mL water in the presence of catalyst
Knoevenagel condensation of 4-methoxybenzaldehyde with
c
(10 mol%) at 90 1C. Isolated yield of product.
malononitrile in water at 90 1C. In the second step, the isolated
benzylidene malononitrile 3 was treated with 6-amino-1-methyl-
uracil (Scheme 1) and 2-aminopyridine (Scheme 2) separately in
the presence of VB1 under similar conditions to afford the
desired products (6 and 9) with excellent yield. In order to make
the synthesis more convenient, we preferred to perform the
above two steps in a one-pot procedure.
Table 2 Optimization of mol% of catalyst for the synthesis of compounds 6c
and 9c
c
Yield (%)
a
b
Entry
Catalyst (mol%)
Time (h)
6c
9c
In our initial endeavour to synthesize pyrido[2,3-d]pyrimidine-
-carbonitriles, the reaction of 6-amino-1-methyluracil, 4-methoxy-
1
2
3
0
5
10
15
14
10
2.5
2.5
—
40
94,91,91
94
—
47
95,93,89
95
6
d
benzaldehyde and malononitrile were carried out in the absence
of any catalyst at 90 1C. The reaction did not occur even after 12 h.
To investigate the suitable conditions, the model reaction was
performed in the presence of various catalysts such as SiO , ZnCl ,
4
a
Reaction conditions: 4-methoxybenzaldehyde (1 mmol), malononitrile
(
1 mmol) and 6-amino-1-methyluracil (1 mmol) were stirred in 4 mL water
b
2
2
in the presence of catalyst at 90 1C. Reaction conditions: 4-methoxy-
MgCl , Al O and alum in the presence of water at 90 1C. The benzaldehyde (1 mmol), malononitrile (1 mmol) and 2-amino pyridine
2
2 3
(
1 mmol) were stirred in 4 mL water in the presence of catalyst at 90 1C.
results summarized in Table 1 revealed that the reaction did not
occur in the presence of SiO , Al or alum and in the presence of
MgCl and ZnCl the yield was very low.
Then we conducted the above reaction in the presence of
c
d
Isolated yield of product. Catalyst was reused three times.
2
2 3
O
2
2
With the hope of increasing the yield, the reactions were
VB1 in water at 90 1C. It was observed that reactivity was much performed in other solvents such as non-polar (DCM, toluene,
improved and the reaction was completed within 2.0–2.5 h, dioxan), polar aprotic (CH CN, THF, DMF) and polar protic
3
affording the solid product in excellent yield. Now we focused our (H O, MeOH) (Table 3); however, water was found to be the
2
attention to optimize the amount of catalyst. For this, a model best solvent for carrying out this VB1-promoted conversion.
reaction was carried out under different amounts of catalyst
(
1
Table 2). After some experiments, we observed that the use of
0 mol% VB1 instead of 5 mol% dramatically increased the yield
Table 3 Optimization of reaction conditions with respect to solvent and
temperature for the synthesis of compounds 6c and 9c
of product (Table 2, entries 2 and 3). However the use of 15 mol%
of catalyst showed the same yield and the same time was required
for the synthesis of the products (Table 2, entry 4).
a
Yield (%)
b
c
Entry
Catalyst (10 mol%)
Solvent
Temp.
6c
9c
1
2
3
4
5
6
7
8
9
VB1
VB1
VB1
VB1
VB1
VB1
VB1
VB1
VB1
VB1
VB1
H
H
H
DCM
THF
CH
Dioxan
H O
2
DMF
MeOH
Toluene
2
2
2
O
O
O
90 1C
50 1C
r.t.
94
30
—
63
45
61
14
94
29
54
23
95
18
—
59
47
55
15
95
25
51
19
Reflux
Reflux
Reflux
Reflux
90 1C
Reflux
Reflux
Reflux
3
CN
Scheme 1 VB1-catalyzed synthesis of pyrido[2,3-d]pyrimidine-6-carbonitriles.
1
1
0
1
a
b
Isolated yield of product. 4-Methoxybenzaldehyde (1 mmol), malono-
nitrile (1 mmol) and 6-amino-1-methyluracil (1 mmol) were stirred in
c
4
mL water in the presence of catalyst (10 mol%) at 90 1C. 4-Methoxy-
benzaldehyde (1 mmol), malononitrile (1 mmol) and 2-aminopyridine
1 mmol) were stirred in 4 mL water in the presence of catalyst (10 mol%)
at 90 1C.
(
Scheme 2 VB1-catalyzed synthesis of [1,8]-naphthyridine-3-carbonitriles.
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Table 4 Substrate scope for the formation of compound 6
Table 5 Substrate scope for formation of product 9
a
b
a
b
Entry
1
Aldehyde 1(a–h)
Product (9a–h)
Time (h)
Yield (%)
Entry
Aldehyde 1(a–h)
Product 6(a–h)
Time (h)
2.5
Yield (%)
2.5
95
1
94
2
3
2.5
2.5
95
95
2
3
2.5
2.0
94
92
4
5
6
2.5
2.0
2.0
94
95
95
4
5
6
2.5
2.0
2.0
93
93
93
7
2.0
2.5
94
94
7
2.5
94
94
8
8
2.5
a
1
13
All products were characterized by IR, H NMR, C NMR and mass
a
1
13
b
All products were characterized by IR, H NMR, C NMR and mass spectroscopy. Isolated yield of pure product.
b
spectroscopy. Isolated yield of pure product.
Thus water shows superiority over other solvents in terms of
To explore the scope and generality of the one-pot Knoevenagel
yield and reaction time. The reaction temperature was also condensation, Michael addition and cyclisation reaction, a range
examined and for this we carried out the same experiment in of pyrido[2,3-d]pyrimidine-6-carbonitrile derivatives were synthe-
water under different temperature.
sized under optimized conditions (6a–h) using 6-aminouracil,
The reaction did not occur at room temperature (Table 3, malononitrile and different aldehydes. To extend the scope of
entry 3) and gives a lower yield at low temperature (Table 3, this protocol, 6-aminouracil was replaced by 2-aminopyridine and
entry 2). The best catalytic activity of VB1 was found at 90 1C.
the reaction was carried out under optimized conditions using
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low cost and easily available starting materials. In this strategy,
purification is not essential, avoiding the waste generated from
column chromatography. More than this, we can say that herein we
are giving details of a highly efficient, convenient, novel, rapid and
very promising method with a diversity-oriented system for the
synthesis of pyrido[2,3-d]pyrimidine, [1,8]-naphthyridine and their
derivatives by using VB1 as a reusable catalyst in aqueous medium
which has promising potential in the fields of chemical research
and drug discovery.
Experimental
Materials and method
All chemical were reagent grade, purchased from Aldrich and
Alfa Aesar and were used without purification. IR spectra were
recorded on a Perkin Elmer – Spectrum RX-IFTIR spectrometer.
NMR spectra were recorded on a BRUKER AVANCE II-400FT
1
13
spectrometer (400 for H NMR, 100 MHz for C) using DMSO
as solvent and TMS as an internal reference. Mass spectra were
recorded on a JEOL SX-102 (FAB) mass spectrometer at 70 eV.
Elemental analyses were carried out in a Coleman automatic
carbon, hydrogen and nitrogen analyzer. All the reactions were
monitored by TLC using precoated sheets of silica gel G/UV-254 of
Scheme 3 Plausible mechanism of VB1-catalyzed synthesis of compounds 6
and 9.
0
.25 mm thickness (Merck 60F254). Melting points were determined
malononitrile and a variety of aldehydes, and the yields were found by open glass capillary method and were uncorrected.
to be consistently good (9a–h) 92–94%. It was observed that the
General procedure for the synthesis of 7-amino-2,4-dioxo-5-aryl-
electronic nature of the substituent on the aromatic ring of 1,2,3,4-tetrahydro-pyrido[2,3-d]pyrimidine-6-carbonitrile derivatives
aldehyde did not show any influence on the yield of product in (6a–h). To a well-stirred solution of aromatic aldehyde 1 (1 equiv.)
both the cases, demonstrating the wide scope of this methodology. and malononitrile 2 (1 equiv.) in the presence of thiamine hydro-
All the results are summarized in Tables 4 and 5.
chloride (10 mol%) in water (4 mL), 6-amino-1-methyluracil
On the basis of our observation, together with the literature (1 equiv.) was added and the reaction mixture was heated at
7
,9a
survey,
the formation of products 6 and 9 in this protocol 90 1C for the stipulated time period. After completion of the
may be rationalized by the initial formation of an intermediate reaction as monitored by TLC, the solid product was formed. The
cyanolefin 3 from the Knoevenagel condensation of aldehyde and reaction mixture was cooled and the product was isolated by simple
malononitrile and subsequent Michael addition of 6-amino-1- filtration.
methyluracil or 2-aminopyridine generates an intermediate 4 which
General procedure for the synthesis of 2-amino-4-phenyl-1,8-
was not isolable. This intermediate 4 undergoes intramolecular naphthyridine-3-carbonitrile derivatives (9a–h). To a well-stirred
cyclization to give another intermediate 5 which converts into final solution of aromatic aldehyde 1 (1 equiv.) and malononitrile 2
6,31,32
product 6 or 9 via air oxidation
(Scheme 3).
(1 equiv.) in the presence of thiamine hydrochloride (10 mol%)
Further we experimented with the reusability of VB1 because it in water (4 mL), 2-aminopyridine (1 equiv.) was added and the
is soluble in water and the product is insoluble. At the end of the reaction mixture was heated at 90 1C for the stipulated time
reaction (as monitored by TLC) we isolated our desired product by period. After completion of the reaction as monitored by TLC,
simple filtration of the precipitate formed. The filtrate containing the solid product was formed. The reaction mixture was cooled
VB1 was again used in the reaction with model reactant giving 94, and the product was isolated by simple filtration.
91, 91% and 95, 93, 89% yields of products 6c and 9c, respectively,
6a: 7-amino-1-methyl-5-(4-nitro-phenyl)-2,4-dioxo-1,2,3,4-tetra-
after 1–3 cycles. Thus the result of the study demonstrated that VB1 hydro-pyrido[2,3-d]pyrimidine-6-carbonitrile. Red solid, Mp. 4
À1
could be efficiently used as a recyclable catalyst for our three 300 1C; IR (KBr, cm ): 3607, 3534, 3297, 2222, 1703, 1590;
1
component reaction and it proves to be an ideal catalyst for MCR
H NMR (400 MHz, DMSO): d 3.87 (s, 3H) 7.58 (d, 2H, HAr,
in organic synthesis with strong future potential. One clear advan- J = 8.6 Hz), 7.75 (brs, 2H, NH ), 8.27 (d, 2H, HAr, J = 8.6 Hz), 11.55
2
1
3
tage of the VB1–water system is that it yields very pure isolated (s, 1H, NH); C NMR (100 MHz, DMSO): d 87.9, 98.2, 115.1,
products by simple filtration.
122.9, 129.2, 144.0, 147.3, 150.2, 155.5, 156.6, 160.1, 160.8, 166.4;
+
EIMS: (m/z): 338 (M ), Anal. calcd for C H N O : C; 53.26, H;
1
5
10 6 4
2
.98, N; 24.84; found C; 53.23, H; 2.97, N; 24.86.
Conclusion
6b: 7-amino-1-methyl-5-(2-chloro-phenyl)-2,4-dioxo-1,2,3,4-
This described approach has many advantages like efficient and tetrahydro-pyrido[2,3-d]pyrimidine-6-carbonitrile. White solid,
À1
simple operation, better yield, non-hazardous reaction conditions, Mp. 4 300 1C; IR (KBr, cm ): 3390, 3311, 3188, 2228, 1699,
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648; H NMR (400 MHz, DMSO): d 3.9 (s, 3H), 7.28 (dd, 1H,
Paper
1
1
6h: 7-amino-1-methyl-5-(2,4-dichloro-phenyl)-2,4-dioxo-1,2,3,4-
HAr, J = 7.4, 1.5 Hz), 7.38 (t, 1H, HAr, J = 7.9 Hz), 7.43 (dt, 1H, tetrahydro-pyrido[2,3-d]pyrimidine-6-carbonitrile. White solid,
À1
HAr, J = 7.4, 1.5 Hz), 7.51 (d, 1H, HAr, J = 7.9 Hz), 7.75 (brs, 2H, Mp. 4 300 1C; IR (KBr, cm ): 3377, 3318, 3143, 2206, 1699,
1
3
1
NH ), 11.55 (s, 1H, NH); C NMR (100 MHz, DMSO): d 88.3, 1648; H NMR (400 MHz, DMSO): d 3.79 (s, 3H), 7.34 (d, 1H, HAr,
2
9
1
C
8.5, 114.8, 126.9, 128.8, 129.0, 129.9, 130.5, 135.9, 150.1, 155.4, J = 8.2 Hz), 7.50 (d, 1H, HAr, J = 8.2 Hz), 7.72 (brs, 1H, HAr), 7.81 (brs,
+
13
55.8, 159.7, 160.9; EIMS: (m/z): 327 (M ), Anal. calcd for 2H, NH2), 11.58 (s, 1H, NH); C NMR (100 MHz, DMSO): d 88.1, 98.4,
10ClN : C; 54.97, H; 3.08, N; 21.37; found C; 54.99, H; 114.7, 127.2, 128.4, 130.3, 131.7, 133.7, 135.0, 150.1, 154.6, 155.4,
.11, N; 21.39.
c: 7-amino-1-methyl-5-(4-methoxy-phenyl)-2,4-dioxo-1,2,3,4-tetra- 49.74, H; 2.50, N; 19.34; found C; 49.72, H; 2.53, N; 19.38.
hydro-pyrido[2,3-d]pyrimidine-6-carbonitrile. Red solid, Mp. 4 9a: 2-amino-4-(4-nitrophenyl)-1,8-naphthyridine-3-carbo-
00 1C; (KBr, cm ): 3404, 3328, 3188, 2219, 1700, 1645; H NMR nitrile. White solid, Mp. 159–162 1C; (KBr, cm ): 3265, 3326,
15
H
5 2
O
+
3
9 2 5 2
159.8, 160.9; EIMS: (m/z): 361 (M ), Anal. calcd for C15H Cl N O : C;
6
À1
1
À1
3
1
(400 MHz, DMSO): d 3.88 (s, 3H), 3.80 (s, 3H, OCH ), 6.94 (m, 2H, 2226; H NMR (400 Hz, DMSO): d 7.16 (s, 2H, NH ), 7.19
3
2
H Ar), 7.19 (m, 2H, HAr), 7.57 (brs, 2H, NH ), 10.73 (s, 1H, NH); (m, 2HAr), 7.27 (m, 2HAr), 7.32 (m, 1HAr), 7.33 (m, 1HAr),
2
1
3
13
C NMR (100 MHz, DMSO): d 55.0, 88.8, 98.3, 112.9, 115.7, 128.6, 7.37 (m, 1HAr); C NMR (100 MHz, DMSO): d 111.1, 114.3,
29.23, 150.1, 155.5, 158.8, 169.3, 160.0, 160.8; EIMS: (m/z): 323 (M ), 116.8, 118.8, 122.3, 125.7, 128.5, 133.1, 136.5, 139.3, 142.5,
+
1
+
Anal. calcd for C16
9.47, H; 4.03, N; 21.69.
d: 7-amino-1-methyl-5-(3-hydroxy-phenyl)-2,4-dioxo-1,2,3,4- Found: C; 61.82, H; 3.13, N; 24.07, O; 10.98.
H
13
N
5
O
3
: C; 59.44, H; 4.05, N; 21.66; found C; 147.5, 148.4, 151.0 156.3, 164.3; EMIS: (m/z): 291.32 (M ) Anal.
5
calcd for C15 : C; 61.85, H; 3.11, N; 24.04, O; 10.99.
9 5 2
H N O
6
tetrahydro-pyrido[2,3-d]pyrimidine-6-carbonitrile. Red solid,
9b: 2-amino-4-(2-chloro-phenyl)-1,8-naphthyridine-3-carbo-
À1
À1
Mp. 4 300 1C; IR (KBr, cm ): 3391, 3322, 3164, 2237, 1686, nitrile. White solid Mp. 168–171 1C; IR (KBr, cm ): 3257,
1
1
1
649; H NMR (400 MHz, DMSO): d 3.75 (s, 1H), 6.59 (s, 1H, 3324, 2231. H NMR (400 Hz, DMSO): d 7.13 (s, 2H, NH2),
HAr), 6.62 (d, 1H, HAr, J = 7.4 Hz), 6.78 (dd, 1H, HAr, J = 8.0, 7.17 (m, 1HAr), 7.21 (m, 1HAr), 7.33 (m, 1HAr), 7.36 (m, 1HAr),
1
3
1
(
.9 Hz), 7.18 (t, 1H, HAr, J = 8.0 Hz), 7.58 (br s, 2H, NH
2
), 9.46 7.38 (m, 1HAr), 7.41 (m, 1HAr), 7.44 (m, 1HAr); C NMR
1
3
s, 1H, OH), 11.06 (s, 2H, 2NH); C NMR (100 MHz, DMSO): d (100 MHz, DMSO): d 116.1, 119.3, 122.2, 123.1, 126.4, 129.3,
8
1
8.5, 98.3, 114.3, 115.2, 115.4, 118.1, 128.8, 137.9, 150.2, 155.4, 133.7, 136.1, 138.2, 142.0, 147.2, 149.4, 153.3, 157.1, 166.2,
56.6, 159.0, 159.8, 160.8; EIMS: (m/z): 309 (M ), Anal. calcd for 169.4; EMIS: (m/z): 280 (M ). Anal. calcd for C16H N ; C;
12 4
+
+
C H N O : C 58.25, H 3.58, N 22.64; found C; 58.29, H; 3.55, 64.18, H; 3.23, N; 12.63. Found: C; 64.15, H; 3.22, N; 12.60.
1
5
11 5 3
N; 22.67.
9c: 2-amino-4(4-methoxy-phenyl)-1,8-naphthyridine-3-carbo-
À1
6e: 7-amino-1-methyl-5-(3-nitro-phenyl)-2,4-dioxo-1,2,3,4-tetra- nitrile. White solid Mp. 156–158 1C; IR (KBr cm ): 3245, 3289,
1
hydro-pyrido[2,3-d]pyrimidine-6-carbonitrile. Pale yellow solid 2235. H NMR (400 MHz, DMSO): d 3.84 (s, 3H), 6.89 (m, 2H,
À1
Mp. 4 300 1C; IR (KBr, cm ): 3384, 3321, 3172, 2216, 1718, HAr), 7.27 (m, 1HAr), 7.33 (m, 1HAr), 7.35 (s, 2H, NH
2
), 7.39
1
13
1
662; H NMR (400 MHz, DMSO): d 3.81 (s, 3H), 7.75 (m, 2H, (m, 2H, HAr), 7.43 (m, 1HAr); C NMR (400 MHz, DMSO): d
HAr), 7.77 (brs, 2H, NH ), 8.19 (1H, HAr, J = 1.7 Hz), 8.29 112.3, 117.6, 122.1, 124.0, 125.3, 128.4, 130.5, 134.7, 136.2,
2
1
3
(
(
qd, 1H, HAr, J = 7.0, 1.1 Hz), 11.54 (s, 1H, NH); C NMR 142.0, 146.3, 147.4, 150.9, 152.2, 158.5, 168.3; EIMS: (m/z):
100 MHz, DMSO): d 88.3, 98.3, 115.2, 122.8, 123.1, 129.4, 134.4, 260 (M ). Anal. calcd for C H N : C; 73.83, H; 4.65, N; 21.52.
16 12 4
+
1
38.4, 147.1, 150.1, 155.5, 156.1, 160.2, 160.8; EIMS: (m/z): 338 Found: C; 73.81, H; 4.66, N; 21.50.
+
(M ), Anal. calcd for C H N O : C; 53.26, H; 2.98, N; 24.84;
9d: 2-amino-4-(3-hydroxyphenyl)-1,8-naphthyridine-3-carbo-
1
5
10 6 4
À1
found C; 53.23, H; 2.99, N; 24.81.
nitrile. White solid, Mp. 162–164 1C; IR (KBr, cm ): 3251, 3312,
1
6
f: 7-amino-1-methyl-5-(phenyl)-2,4-dioxo-1,2,3,4-tetrahydro- 2225. H NMR (400 MHz, DMSO): d 7.17 (s, 2H, NH
2
), 7.16
pyrido[2,3-d]pyrimidine-6-carbonitrile. White solid, Mp. 4 300 1C; (s, 1HAr), 7.19 (m, 1HAr), 7.22 (m, 1HAr), 7.26 (m, 1HAr), 7.27
À1
1
13
IR (KBr, cm ): 3403, 3331, 3174, 2224, 1707, 1643; H NMR (m, 1HAr), 7.31 (m, 1HAr), 7.35 (m, 1HAr); C NMR (100 MHz,
(
(
400 MHz, DMSO): d 3.79 (s, 3H), 7.24 (m, 2H, HAr), 7.40 DMSO): d 105.6, 112.6, 116.2, 117.0, 118.9, 120.2, 121.4, 130.8,
m, 3H, HAr), 7.59 (brs, 2H, NH ), 11.44 (s, 1H, NH); 139.4, 148.1, 152.1, 153.1, 160.1, 160.9, 161.7; EIMS: (m/z): 262
2
1
3
+
C NMR (100 MHz, DMSO): d 88.7, 98.3, 115.5, 127.5, 127.7, (M ). Anal. calcd for C H N O: C; 68.69, H; 3.84, N; 21.36,
1
5
10 4
1
28.3, 136.8, 150.3, 155.6, 159.0, 160.1, 160.9; EIMS: (m/z): 293 found: C; 68.71, H; 3.83, N; 21.35.
+
(
M ), Anal. calcd for C15
found C; 61.45, H; 3.75, N; 23.92.
g: 7-amino-1-methyl-5-(4-methyl-phenyl)-2,4-dioxo-1,2,3,4-
H
11
N
5
O
2
: C; 61.43, H; 3.78, N; 23.88;
9e: 2-amino-4-(3-nitrophenyl)-1,8-naphthyridine-3-carbonitrile.
À1
White solid, Mp. 160–162 1C; IR (KBr, cm ): 3249, 3311, 2234.
1
6
2
H NMR (400 MHz, DMSO): d 7.19 (s, 2H, NH ), 7.23 (s, 1HAr),
tetrahydro-pyrido[2,3-d]pyrimidine-6-carbonitrile. White solid, 7.24 (m, 1HAr), 7.26 (m, 1HAr), 7.28 (m, 1HAr), 7.32 (m, 1HAr),
À1
13
Mp. 4 300 1C; IR (KBr, cm ): 3394, 3281, 3167, 2222, 1699, 7.35 (m, 1HAr), 7.39 (m, 1HAr); C NMR (100 MHz, DMSO): d
1
1
7
6 459; H NMR (400 MHz, DMSO): d 3.81 (s, 3H), 2.36 (s, 3H, CH ), 111.5, 112.2, 113.9, 118.2, 122.4, 124.8, 129.2, 134.3, 136.5, 139.3,
3
+
.12 (d, 2H, HAr, J = 8.0 Hz), 7.20 (d, 2H, HAr, J = 8.0 Hz), 7.60 (br s, 142.3, 147.0, 149.2, 151.5, 155.2, 165.4; EIMS: (m/z): 291.41 (M ).
13
2
H, NH2), 11.43 (s, 1H, NH); C NMR (100 MHz, DMSO) d 20.9, Anal. calcd for C H N O : C; 61.85, H; 3.11, N; 24.04, O; 10.99.
15 9 5 2
8
8.7, 98.3, 115.5, 127.5, 128.1, 133.7, 137.4, 150.1, 155.5, 159.1, Found: C; 69.85, H; 3.13, N; 24.03, O; 11.00.
+
159.9, 160.8; EIMS: (m/z): 307 (M ), Anal. calcd for C16
H
13
N
5
O
2
: C;
9f: 2-amino-4-phenyl-1,8-naphthyridine-3-carbonitrile. White
À1
1
62.53, H; 4.26, N; 22.79; found C; 62.56, H; 4.23, N; 22.81.
solid Mp. 152–155 1C; IR (KBr cm ): 3251, 3319, 2229. H NMR
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NJC
(
(
(
1
1
7
400 Hz, DMSO): d 7.10 (s, 2H, NH
2
), 7.12 (m, 1HAr), 7.15
69, 2896; (d) R. K. Sharma and J. L. Fry, J. Org. Chem., 1983,
48, 2113.
7 K. Pradhan, P. Bhattacharyya, S. Paul and A. R. Das, Tetra-
hedron Lett., 2012, 53, 5840.
8 (a) J. Liu, M. Lie and L. Hu, Green Chem., 2012, 14, 840;
(b) Y. Chen, W. Shan, M. Lei and L. Hu, Tetrahedron Lett.,
2012, 53, 5923; (c) H. Sun and S. G. Di Magno, J. Am. Chem.
Soc., 2005, 127, 2050.
9 (a) M. Lei, L. Ma and L. Hu, Synth. Commun., 2011, 41, 3424;
(b) P. D u¨ nkelmann, D. K. Jung, A. Nitsche, A. S. Demir,
P. Siegert, B. Lingen, M. Baumann, M. Pohl and M. M u¨ ller,
J. Am. Chem. Soc., 2002, 124, 12084.
m, 2HAr), 7.18 (m, 2HAr), 7.23 (m, 1HAr), 7.24 (m, 1HAr), 7.27
1
3
m, 1HAr); C NMR (100 MHz, DMSO): d 118.2, 120.3, 124.1,
26.4, 127.2, 128.3, 129.1, 132.5, 136.0, 139.3, 143.4, 154.7, 158.5,
+
70.3, 171.2; EIMS: (m/z): 242 (M ), Anal. calcd for C H N : C;
1
5
10 4
3.16, H; 4.09, N; 22.75. Found: C; 73.14, H; 4.07, N; 22.72.
9g: 2-amino-4-(4-methyl-phenyl)-1,8-naphthyridine-3-carbo-
À1
nitrile. White solid, Mp. 156–158 1C; IR (KBr, cm ): 3250,
3
1
289, 2239. H NMR (400 MHz, DMSO): d 2.01 (s, 3H), 7.01
(s, 2H, NH ), 7.11 (m, 2HAr), 7.14 (m, 2HAr), 7.17 (m, 1HAr),
2
1
3
7
1
1
2
.20 (m, 1HAr), 7.24 (m, 1HAr); C NMR (100 MHz, DMSO): d
12.1, 117.0, 122.2, 124.3, 125.6, 128.4, 130.5, 134.3, 136.2,
42.3, 146.4, 147.7, 150.5, 152.3, 158.1, 168.0; EIMS: (m/z): 10 (a) M. Lei, L. Ma and L. Hu, Monatsh. Chem., 2010,
+
60 (M ). Anal. calcd for C16
H
12
N
4
: C; 73.83, H; 4.65, N; 21.52.
141, 1005; (b) M. Lei, L. Ma and L. Hu, Synth. Commun.,
2011, 41, 1969; (c) M. Lei, L. Ma and L. Hu, Tetrahedron Lett.,
2010, 51, 4186.
Found: C; 73.81, H; 4.66, N; 21.50.
9h: 2-amino-4-(2,4-dichlorophenyl)-1,8-naphthyridine-3-carbo-
À1
nitrile. White solid, Mp. 164–166 1C; IR (KBr, cm ): 3245, 3293, 11 (a) C. Noonan, L. Baragwanath and S. J. Connon, Tetrahe-
1
2
6
6
1
1
227. H NMR (400 MHz, DMSO): d 6.41 (s, 2H, NH
2
), 6.86 (s, 1H),
dron Lett., 2008, 49, 4003; (b) J. C. Sheehan and T. Hara,
J. Org. Chem., 1974, 39, 1196; (c) J. C. Sheehan and
D. H. Hunneman, J. Am. Chem. Soc., 1966, 88, 3666.
.79 (d, 1H, J = 8.4), 6.73 (d, 1H, J = 8.4), 6.75 (m, 1H), 6.82 (s, 1H),
13
.77 (s, 1H, J = 8.2); C NMR (100 MHz, DMSO): d 109.8, 117.2,
18.9, 122.1, 127.5, 129.8, 130.9, 133.8, 134.2, 136.1, 136.8, 151.1, 12 A. Gangjee, A. Vasudevan, S. F. Queener and L. K. Roy,
+
61.8; EIMS: (m/z): 314 (M ). Anal. calcd for C15
8 l2 4
H C N : C; 57.17,
J. Med. Chem., 1996, 39, 1438.
H; 2.56, N; 17.78, found: C; 57.15, H; 2.55, N; 17.80.
13 (a) B. Insuasty, D. Becerra, J. Quiroga, R. Abonia,
M. Nogueras and J. Cobo, Eur. J. Med. Chem., 2013, 60, 1;
(
1
b) J. W. Ellingboe and N. J. Princeton, Chem. Abstr., 1996,
24, 176.
Acknowledgements
1
4 A. B. Deyanov, R. K. Niyazov, F. Y. Nazmetdivov,
B. Y. Syropyatov, V. E. Kolla and M. E. Konshin, Pharm.
Chem. J., 1991, 25, 248.
5 S. N. Vander Wel, J. P. Harvey, D. J. McNamara, T. J. Repine,
R. K. Paul, J. Quin III, R. J. Booth, L. W. Elliott,
M. E. Dobrusin, W. D. Fry and L. P. Toogood, J. Med. Chem.,
We gratefully acknowledge the financial support from the
Council of Scientific and Industrial Research and University
Grant Commission. Authors gratefully acknowledge the SAIF,
Punjab University, Chandigarh, for providing all the spectro-
scopic and analytical data.
1
2005, 48, 2371.
1
6 G. Grossi, D. M. Braccio, G. Roma, M. Tognolini and
E. Barocelli, Eur. J. Med. Chem., 2005, 40, 155.
Notes and references
1
2
3
4
5
(a) A. Domling, Chem. Rev., 2006, 106, 17; (b) A. V. R. Orru 17 A. M. Seefeld, H. W. Miller, A. K. Newlander, J. W. Burgess,
and M. Degreef, Synthesis, 2003, 1471; (c) C. Hulme and
V. Gore, Curr. Med. Chem., 2003, 10, 51.
(a) H. Bienayme, C. Hulme, G. Oddon and P. Schmitt,
Chem.–Eur. J., 2000, 6, 3321; (b) M. Shen and T. G. Driver,
Org. Lett., 2008, 10, 3367.
E. W. DeWolf, A. P. Elkins, S. M. Head, R. D. Jakas,
A. C. Janson, M. P. Keller, J. P. Manley, D. T. Moore,
J. D. Payne, S. Pearson, J. B. Polizzi, X. Qiu,
F. S. Rittenhouse, I. N. Uzinskas, G. N. Wallis and
F. W. Huffman, J. Med. Chem., 2003, 46, 1627.
(a) G. Guillena, D. J. Ramon and M. Yus, Tetrahedron: 18 T. R. R. Naik, B. S. H. Naik, M. Raghavendra and K. G. S.
Asymmetry, 2007, 18, 693; (b) D. M. D’Souza and T. J. J.
Muller, Chem. Soc. Rev., 2007, 36, 1095.
(a) J. D. Ramon and M. Yus, Angew. Chem., Int. Ed., 2005,
Naik, ARKIVOC, 2006, 15, 84.
19 V. P. Litvinov, S. V. Roman and V. D. Dyachenko, Russ.
Chem. Rev., 2000, 69, 201.
4
4, 1602; (b) D. J. Sunderhaus, C. Dockendorff and 20 L. Zhuang, J. S. Wai, M. W. Embrey, T. E. Fisher,
F. S. Martin, Org. Lett., 2007, 9, 4223.
(a) M. U. Lindstrom, Organic Reactions in Water, Blackwell,
Oxford, 2007; (b) J. C. Li, Chem. Rev., 1993, 93, 2023;
M. S. Egbertson, L. S. Payne, J. P. Guare Jr., J. P. Vacca,
D. J. Hazuda, P. J. Felock, A. L. Wolfe, K. A. Stillmock,
M. V. Witmer, G. Moyer, W. A. Schleif, L. J. Gabryelski,
Y. M. Leonard, J. J. Lynch Jr., S. R. Michelson and
S. D. Young, J. Med. Chem., 2003, 46, 453.
(c) J. C. Li, Chem. Rev., 2005, 105, 3095; (d) A. Chanda and
V. V. Fokin, Chem. Rev., 2009, 109, 725; (e) C. H. Hailes, Org.
Process Res. Dev., 2007, 11, 114.
(a) M. Lei, L. Ma and L. Hu, Synth. Commun., 2012, 42, 2981;
21 A. Samadi, C. Valderas, C. de los R ´ı os, A. Bastida,
M. Chioua, L. G. Lafuente, I. Colmena, L. Gand ´ı a,
A. Romero, L. de Barrio, M. D. Mart ´ı n-de-Saavedra,
M. G. L o´ pez, M. Villarroya and J. Marco-Contelles, Bioorg.
Med. Chem., 2011, 19, 122.
6
(b) A. Yasuhara, N. Suzuki and T. Sakamoto, Chem. Pharm.
Bull., 2002, 50, 143; (c) D. Amantini, R. Beleggia,
F. Fringuelli, F. Pizzo and L. Vaccaro, J. Org. Chem., 2004,
New J. Chem.
This journal is c The Royal Society of Chemistry and the Centre National de la Recherche Scientifique 2013

View Article Online
NJC
Paper
22 S. Abdolmohammadi and S. Balalaie, Int. J. Org. Chem., 28 V. S. Goswami, B. P. Thorat, C. B. Khade and R. S. Bhusare,
2012, 2, 7. Chem. Biol. Interface, 2012, 2, 228–233.
2
2
3 R. R. T. Naik and B. S. H. Naik, Mol. Diversity, 2008, 12, 139. 29 F. Chen, M. Lei and L. Hu, Tetrahedron, 2013, 69, 2954.
4 (a) M. Seifi and H. Sheibani, Catal. Lett., 2008, 126, 275; 30 (a) I. R. Siddiqui, Shireen, S. Shamim, A. A. H. Abumhdi,
(
2
b) H. Sheibani, M. Seif and A. Bazigar, Synth. Commun.,
009, 39, 1055.
M. A. Waseem, A. Srivastava, Rahila and A. Srivastava, New J.
Chem., 2013, 37, 1258; (b) I. R. Siddiqui, S. Shamim,
D. Kumar, Shireen and M. A. Waseem, New J. Chem., 2012,
36, 2209; (c) I. R. Siddiqui, A. Singh, S. Shamim,
V. Srivastava, S. Yadav and R. K. P. Singh, Synthesis, 2010,
1613–1616.
2
5 (a) D. Shi, L. Niu, J. Shi, X. Wang and S. Ji, J. Heterocycl.
Chem., 2007, 44, 1083; (b) T. Yang, H. He, W. Ang, Y.-H. Yang,
J.-Z. Yang, Y.-N. Lin, H.-C. Yang, W.-Y. Pi, Z.-C. Li, Y.-L. Zhao,
Y.-F. Luo and Y. Wei, Molecules, 2012, 17, 2351.
2
6 J. Quiroga, M. Alvarado, B. Insuasty, M. Nogueras, 31 B. C. Ranu, R. Jana and S. Sowmiah, J. Org. Chem., 2007,
A. Sanchez and J. Cobo, J. Heterocycl. Chem., 1998, 35, 1309. 72, 3152.
7 S. X. Wang, S. Z. Zeng, Q. D. Shi, J. S. Tu, Y. X. Wei and 32 P. Prasanna, K. Balamurugan, S. Perumal and J. C. Me n´ endez,
M. Z. Zong, Synth. Commun., 2005, 35, 1921. Green Chem., 2011, 13, 2123.
2
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