An efficient solvent-free synthesis of naphthopyranopyrimidines using heteropolyacid as an ecofriendly catalyst

Article abstract of DOI:10.1080/15533174.2013.783858

An efficient, one-pot, three-component synthesis of naphthopyranopyrimidines using β-naphthol, aldehydes, and 6-amino-1,3-dimethyl uracil catalyzed by heteropolyacid has been achieved within a short period of time. The present methodology offers several advantages such as ecofriendly catalyst, low catalyst loading, short reaction time, simple purification procedure, and excellent yields.

Full text of DOI:10.1080/15533174.2013.783858

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An Efficient Solvent-Free Synthesis of
Naphthopyranopyrimidines Using Heteropolyacid as an
Ecofriendly Catalyst
Shivkumar S. Jalde a , Hemant V. Chavan b , Laxman K. Adsul a , Valmik D. Dhakane a
Babasaheb P. Bandgar a
&
a Medicinal Chemistry Research Laboratory, School of Chemical Sciences , Solapur
University , Solapur , Maharashtra , India
b Department of Organic Chemistry , University of Mumbai, Ratnagiri sub-center , Ratnagiri ,
Maharashtra , India
Accepted author version posted online: 05 Nov 2013.Published online: 21 Nov 2013.
To cite this article: Shivkumar S. Jalde , Hemant V. Chavan , Laxman K. Adsul , Valmik D. Dhakane & Babasaheb P.
Bandgar (2014) An Efficient Solvent-Free Synthesis of Naphthopyranopyrimidines Using Heteropolyacid as an Ecofriendly
Catalyst, Synthesis and Reactivity in Inorganic, Metal-Organic, and Nano-Metal Chemistry, 44:4, 623-626, DOI:
10.1080/15533174.2013.783858
To link to this article: http://dx.doi.org/10.1080/15533174.2013.783858
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Synthesis and Reactivity in Inorganic, Metal-Organic, and Nano-Metal Chemistry, 44:623–626, 2014
Copyright ꢀ Taylor & Francis Group, LLC
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ISSN: 1553-3174 print / 1553-3182 online
DOI: 10.1080/15533174.2013.783858
An Efficient Solvent-Free Synthesis
of Naphthopyranopyrimidines Using Heteropolyacid
as an Ecofriendly Catalyst
Shivkumar S. Jalde,1 Hemant V. Chavan,2 Laxman K. Adsul,1
Valmik D. Dhakane,1 and Babasaheb P. Bandgar1
1Medicinal Chemistry Research Laboratory, School of Chemical Sciences, Solapur University, Solapur,
Maharashtra, India
2Department of Organic Chemistry, University of Mumbai, Ratnagiri sub-center, Ratnagiri,
Maharashtra, India
super acid region, Brønsted acidity; on the other hand, they are
efficient oxidants, exhibiting fast reversible multielectron redox
transformations under mild conditions. HPAs have a very high
solubility in polar solvents and fairly high thermal stability in the
solid state. These properties render HPA as potentially promis-
ing acid, redox, and bifunctional catalyst in homogenous as well
as in heterogenous systems.[6] They have been found to exhibit
excellent catalytic properties in the isomerization of styrene ox-
ide to phenylacetaldehyde,[7] synthesis of dihydroquinoline,[8]
synthesis of arylbenzimidazoles,[9] Friedel-Craft alkylation,[10]
tetrahydropyranylation of alcohols,[11] Prince reaction,[12] and
Dakin-West reaction.[13]
An efficient, one-pot, three-component synthesis of naphthopy-
ranopyrimidines using β-naphthol, aldehydes, and 6-amino-1,3-
dimethyl uracil catalyzed by heteropolyacid has been achieved
within a short period of time. The present methodology offers sev-
eral advantages such as ecofriendly catalyst, low catalyst loading,
short reaction time, simple purification procedure, and excellent
yields.
Keywords heteropolyacid, multicomponent reaction, naphthopyra-
nopyrimidines
Pyrimidine entity is one of the most prominent structures
found in nucleic acid chemistry. Vitamin B1 (thiamine) is well
known example of naturally occurring pyrimidine that is en-
countered in our daily lives. There is continuous wide spread
interest in pyranopyrimidines because of diverse biological ac-
tivities such as antitumor,[14] antimicrobial,[15] and antihyperten-
sive.[16] Pyranopyrimidines fused with coumarin ring are used
as fungicides[17] and herbicides.[18] Naphthopyranopyrimidines
are biologically important compounds with antimicrobial activ-
ity.[19] Neuropeptide S receptor, previously known as GPR-154,
is highly expressed in brain areas that have been implicated in
modulation of arousal, stress and anxiety. Therefore, Neuropep-
tide S receptor represents a novel drug target for the treatment
of sleep and anxiety disorders.[20] Naphthopyranopyrimidines
are selective antagonists of Neuropeptide S receptor (Figure 1).
Though there is great importance of naphthopyranopyrimidines,
only one report for the synthesis of naphthopyranopyrimidines
by multicomponent condensation of β-napthol, aldehyde, and
6-amino-1,3-dimethyluracil using InCl3 as an expensive cata-
lyst is available in the literature.[21] More recently, Pravin Ku-
mar et al. reported iodine catalyzed one-pot three-component
synthesis of naphthopyranopyrimidines under solvent-free con-
dition, long reaction time, and moderate yields are the notable
drawbacks of this method.[22] Therefore, the development of
INTRODUCTION
Multicomponent reactions (MCRs) play an important role
in modern synthetic organic chemistry because they generally
occur in a single pot and exhibit a high atom-economy and selec-
tivity. Multicomponent reaction reduces time and saves energy
and raw material.[1] Over the past decade, various advanced
sequential MCRs have been developed where 1,3-dicarbonyl
derivatives are important synthetic intermediates due to its mul-
tiple functionalities that can be involved either as nucleophilic
or electrophilic species in a large variety of synthetic transfor-
mation.[2] Their versatility and effectiveness as potential multi-
component substrates has been used in various MCRs such as
Hantzsch 1,4-dihydropyridine synthesis,[3] Biginelli reaction,[4]
and Michael addition reaction.[5]
Heteropolyacids (HPAs) have several advantages as a cata-
lyst that make them economically and environmentally attrac-
tive. On one hand, HPAs have a very strong, approaching the
Received 1 February 2013; accepted 5 March 2013.
Address correspondence to Babasaheb P. Bandgar, Medicinal
Chemistry Research Laboratory, School of Chemical Sciences, Solapur
University, Solapur 413 255, Maharashtra, India. E-mail: bandgar bp@
yahoo.com
623

624
S. S. JALDE ET AL.
O
O
O
O
TABLE 2
Synthesis of naphthopyranopyrimidines
O
O
NH
O
NH
O
NH
O
N
N
N
N
N
N
Entry
Aldehyde
Product Time (min) Yield (%)a
O
N
N
N
MLS000558527
NCGC00183145
NCGC00183146
1
4a
4b
4c
4d
20
20
29
26
90
90
88
89
FIG. 1. Selective antagonists of neuropeptide S receptor.
simple, efficient and high yielding protocol for the synthesis of
naphthopyranopyrimidines is still desirable.
2
3
4
As a part of our research interest directed toward the develop-
ment of highly expedient methods,[23] herein we report simple,
efficient and environmentally benign synthesis of naphthopyra-
nopyrimidines using silicotungstic acid (H4[SiW12O40]) as an
inexpensive catalyst under solvent-free condition (Scheme 1).
5
6
7
4e
4f
24
20
27
90
92
88
O
O
N
OH
CHO
HPA
100 oC, neat
N
N
+
+
H2N
N
O
O
O
4a
1
2
3
SCH. 1. Synthesis of naphthopyranopyrimidines.
4g
8
9
4h
4i
26
23
90
91
EXPERIMENTAL
General Procedure for the Synthesis
of Naphthopyranopyrimidines (4a–n)
Silicotungstic acid (5 mol%) was added to a mixture of 2-
naphthol (1.0 mmol), aldehyde (1.0 mmol), and 6-amino-1,3-
dimethyl uracil (1.2 mmol) in a round-bottom flask, heated
at 100◦C under solvent-free condition. After completion of
10
11
12
13
14
4j
4k
4l
19
27
24
23
02
86
89
85
90
88
TABLE 1
The optimization of catalyst loading for the synthesis of
naphthopyranopyrimidines
Catalyst
(mol%) Solvent
Temp
Yield
Entry
Catalyst
(◦C) Time (%)a
4m
4n
1
2
3
4
5
6
7
8
—
—
5
5
5
5
—
100 12 h NRb
H4[SiW12O40]
H4[SiW12O40]
H4[SiW12O40]
H4[SiW12O40]
H4[SiW12O40]
Acetonitrile Reflux 12 h 55
Methanol Reflux 12 h 58
Toluene Reflux 12 h 46
aIsolated yield.
—
—
—
—
100 20 min 90
100 20 min 70
100 20 min 88
100 20 min 85
2
H4[SiW12O40] 10
H4[SiW12O40] 15
reaction (TLC), flask was cooled to room temperature, methanol
(5 mL) was added and stirred for 10 min, poured over crushed
ice, and the precipitated product was filtered, washed with wa-
ter, dried, and recrystallized from methanol to obtain the desired
product in pure form.
Reaction condition: β-naphthol (1.0 mmol), anisaldehyde
(1.0 mmol), and 6-amino-1,3-dimethyluracil (1.2 mmol). aIsolated
yield; bNo reaction.

AN EFFICIENT SOLVENT-FREE SYNTHESIS
625
O
+
OH
N
N
R
OH
H
O
R
O
NH2
H
R
OH
-H2O
+
OH
O
N
O
O
H
N
O
N
R
O
O
R
N
R
H
+
N
NH2
OH
-NH3
NH2
O
N
O
SCH. 2. Proposed mechanism for the formation of naphthopyranopyrimidines.
12-(4-methoxyphenyl)-8,12-dihydro-8,10-dimethyl-9H-
naphtho[1’,2’:5,6]pyrano[2,3-d]pyrimidine-9,11-(10H)-
dione (4b)
12-(3-Chlorophenyl)-8,12-dihydro-8,10-dimethyl-9H-
naphtho[1’,2’:5,6]pyrano[2,3-d]pyrimidine-9,11-(10H)-
dione (4i)
Solid; mp 257–259◦C; IR (KBr, cm−1): 3054, 2958, 1700,
Solid; mp 250–252◦C; IR (KBr, cm−1): 3054, 2958, 1700,
1695, 1650, 1580, 1480; 1H NMR (DMSO-d6, 400 MHz): δ = 1695, 1650, 1580, 1480; H NMR (DMSO-d6, 400 MHz):
7.95 (d, 1H, J = 8.4 Hz), 7.84 (m, 2H), 7.50–7.31 (m, 3H), 7.28 δ = 5.71 (s, 3H), 3.56 (s, 3H), 3.19 (s, 3H); 8.10 (m, 2H),
(d, 2H, J = 8.0 Hz), 6.75 (d, 2H, J = 8.0 Hz), 5.76 (s, 1H), 7.95 (d, 2H, J = 8.0 Hz), 7.69 (d, 1H, J = 8.0 Hz), 7.54 (m,
3.85 (s, 3H), 3.62 (s, 3H), 3.32 (s, 3H); 13C NMR (100 MHz, 2H), 7.42 (s, 1H), 7.29 (m, 2H), 7.24 (d, 1H, J = 8.2 Hz), 5.71
CDCl3): 161.4, 160.5, 158.5, 153.4, 153.1, 153.1, 135.2, 133.0, (s, 1H), 3.56 (s, 3H), 3.19 (s, 3H); 13C NMR (100 MHz, CDCl3):
129.4, 128.5, 128.0, 125.4, 122.8, 122.1, 118.2, 115.4, 114.6, 161.4, 159.5, 153.7, 153.5, 144.4, 134.3, 133.4, 130.4, 128.8,
1
81.3, 56.0, 29.1, 28.9, 28.2; Mass: m/z = 401 [M+1].
128.7, 128.0, 126.5, 126.4, 125.9, 122.8, 122.2, 118.2, 115.4,
81.3, 29.1, 28.7, 27.5; Mass: m/z = 404 [M+1].
12-(3-Nitrophenyl)-8,12-dihydro-8,10-dimethyl-9H-
naphtho[1’,2’:5,6]pyrano[2,3-d]pyrimidine-9,11-(10H)-
dione (4f)
RESULTS AND DISCUSSION
Solid; mp 310–312◦C; IR (KBr, cm−1): 3054, 2958, 1700,
1695, 1650, 1580, 1553, 1480,1340; 1H NMR (DMSO-d6,
400 MHz): δ = 8.12 (s, 1H), 8.05 (d, 1H, J = 8.2 Hz), 7.96–7.81
(m, 4H), 7.56–7.40 (m, 4H), 5.96 (s, 1H), 3.72 (s, 3H), 3.39 (s,
3H); 13C NMR (100 MHz, CDCl3): 161.9, 159.8, 153.5, 152.8,
148.7, 143.6, 134.4, 133.4, 129.9, 128.7, 128.0, 125.9, 123.5,
122.8, 122.2, 121.1, 118.2, 115.4, 81.3, 29.1, 28.9, 27.5; Mass:
m/z = 416 [M+1].
In order to evaluate the catalytic efficiency of H4[SiW12O40]
and to determine the most appropriate reaction conditions; a
model study was carried out using β-naphthol 1 (1 mmol),
benzaldehyde 2 (1 mmol) and 6-amino-1,3-dimethyluracil 3
(1.2 mmol) to afford naphthopyranopyrimidine (4a) in differ-
ent sets of reaction conditions. Initially, when the reaction was
carried out in the absence of catalyst, no product formation
was observed even after prolonged heating (Table 1, entry 1).
Then the above model reaction was performed using catalytic
amount of H4[SiW12O40] under solvent free condition, for-
tunately excellent yield (90%) of expected naphthopyranopy-
rimidine was observed in a very short reaction time (Table 1,
entry 5).
Moreover, to evaluate the most appropriate catalyst loading,
an identical reaction was performed using 2 mol%, 10 mol%,
and 15 mol% of H4[SiW12O40] catalyst at 100◦C under solvent-
free condition, the yields were 70%, 88%, and 85% respectively
(Table 1, entries 6–8). Therefore, 5 mol% of silicotungstic acid
was sufficient to push the reaction forward, and, further, increas-
ing the amount of silicotungstic acid did not increase the yields.
12-(4-Bromophenyl)-8,12-dihydro-8,10-dimethyl-9H-
naphtho[1’,2’:5,6]pyrano[2,3-d]pyrimidine-9,11-(10H)-
dione (4k)
Solid; mp 250–252◦C; IR (KBr, cm−1): 3054, 2958, 1700,
1695, 1650, 1580, 1480; 1H NMR (DMSO-d6, 400 MHz): δ =
8.05 (m, 3H), 7.63 (d, 1H, J = 7.8 Hz), 7.52 (m, 2H), 7.38 (d,
2H, J = 8.2 Hz), 7.30 (d, 2H, J = 8.2 Hz), 5.68 (s, 1H), 3.55 (s,
3H), 3.15 (s, 3H); 13C NMR (100 MHz, CDCl3): 161.9, 159.8,
153.7, 153.2, 142.0, 133.4, 132.3, 130.6, 128.7, 128.0, 125.9,
122.8, 122.2, 120.6, 118.2, 115.4, 81.3, 29.1, 28.9, 27.7; Mass:
m/z = 450 [M+2].

626
S. S. JALDE ET AL.
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CONCLUSIONS
In conclusion, we have developed an efficient, solvent-free
and environmentally benign process for the synthesis of naph-
thopyranopyrimidines by one-pot, three-component reaction
of β-naphthol, aldehyde, and 6-amino-1,3-dimethyluracil cat-
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cal, and environmentally safe catalyst. Mild reaction condition,
low catalyst loading, excellent yields, simple purification, and
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