Al(H2PO4)3 as an efficient and recyclable catalyst for the one-pot synthesis of naphthopyranopyrimidines

Article abstract of DOI:10.1039/c5ra00679a

An efficient one-pot protocol has been developed for the synthesis of naphthopyranopyrimidine derivatives via a three-component reaction of aromatic aldehydes, β-naphthol and 6-amino-1,3-dimethyl uracil in the presence of Al(H₂PO₄)₃ as a catalyst under solvent-free conditions at 110°C. The presented methodology offers several advantages such as simplicity of operation, easy workup, good to high yields, short reaction times, inexpensive and readily available starting materials and catalyst. Furthermore, the catalyst can be reused several times without any significant loss of activity.

Full text of DOI:10.1039/c5ra00679a

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Al(H2PO4)3 as an efficient and recyclable catalyst
for the one-pot synthesis of
Cite this: RSC Adv., 2015, 5, 28038
naphthopyranopyrimidines
*
Seyed Sajad Sajadikhah
An efficient one-pot protocol has been developed for the synthesis of naphthopyranopyrimidine derivatives
via a three-component reaction of aromatic aldehydes, b-naphthol and 6-amino-1,3-dimethyl uracil in the
presence of Al(H2PO4)3 as a catalyst under solvent-free conditions at 110 ꢀC. The presented methodology
offers several advantages such as simplicity of operation, easy workup, good to high yields, short reaction
times, inexpensive and readily available starting materials and catalyst. Furthermore, the catalyst can be
reused several times without any significant loss of activity.
Received 12th January 2015
Accepted 12th March 2015
DOI: 10.1039/c5ra00679a
www.rsc.org/advances
derivatives and 1,3-dimethylbarbituric acid using catalyst such
as InCl3,14 I2,15 KAl(SO4)2$12H2O,16 cyanuric chloride,17 and
Zr(HSO4)4.18 Literature reveals only a few protocols to synthesis
of naphthopyranopyrimidines from the reaction of b-naphthol,
aldehydes and 6-amino-1,3-dimethyl uracil catalyzed by InCl3
and heteropolyacid.19,20 Owing to the wide applications and
signicance of naphthopyranopyrimidine derivatives, there is
still the need to develop an efficient and environmentally
benign methodology for the synthesis of these important
compounds.
Introduction
The development of novel methodologies that reduce pollution
during chemical synthesis has received considerable attention
due to increasing environmental concerns. In this context, one
active area is the utilization of eco-friendly recyclable heteroge-
neous catalysts instead of conventional, toxic and polluting
1
¨
Bronsted acid catalysts. The heterogeneous catalysts have many
other advantages such as operational simplicity, low cost, non-
toxicity, and ease of preparation, handling and isolation.
Aluminum tris(dihydrogen phosphate) (Al(H2PO4)3) is well
known as an efficient heterogeneous catalyst for organic
synthesis.2–5 On the other hand, multi-component reactions
(MCRs) are the most powerful tools to access diverse complex
molecular scaffolds. MCRs have merits over conventional
multistage syntheses in several aspects including exibility, time
and energy saving, high yields, no separation of intermediates
and so reducing solvents as well as waste.6,7 Therefore, the
development of new MCRs using recyclable heterogeneous
catalysts is highly valuable.
Results and discussion
As a part of our continued interest towards the development of
efficient methodologies for the synthesis of heterocycles,21–24
herein Al(H2PO4)3 was utilized as a heterogeneous catalyst for
the synthesis of naphthopyranopyrimidines 4 via one-pot three-
component reaction of b-naphthol, aromatic aldehydes and
6-amino-1,3-dimethyl uracil under solvent-free conditions at
ꢀ
110 C (Scheme 1).
Synthesis of six-membered heterocycles such as pyrimidine
and its derivatives are very important because of their phar-
macological and biological properties. In this context, pyr-
anopyrimidines exhibit diverse biological activity such as
analgesic and anticonvulsant,8 antimicrobial,9 fungicides,10 and
herbicides.11 Additionally, naphthopyranopyrimidines are bio-
logically interesting compounds with antibacterial and anti-
fungal activities,12 and recently reported as an potentially novel
drug for treatment of sleep and anxiety disorders (Fig. 1).13
Recently, some methods have been reported for the
synthesis of naphthopyranopyrimidines by means of one-pot
three-component reactions of aldehydes, naphthols or phenol
First, the reaction of b-naphthol, benzaldehyde and 6-amino-
1,3-dimethyl uracil was carried out in the presence of
Fig. 1 Biologically active compounds containing naphthopyranopyr-
imidine framework as a novel drug target for the treatment of sleep
and anxiety disorders.
Department of Chemistry, Payame Noor University (PNU), P. O. Box 19395-3697,
Tehran, Iran. E-mail: sssajadi@pnu.ac.ir
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Scheme 1 Synthesis of naphthopyranopyrimidines 4.
Al(H2PO4)3 (0.05 g) under solvent-free conditions at 100 ꢀC. The acid monohydrate (p-TsOH$H2O) as a potential catalyst gener-
corresponding naphthopyranopyrimidine 4a was obtained in ates a mixture of 12-phenyl-8,12-dihydro-8,10-dimethyl-9H-
58% yield aer 90 min. In order to optimize the reaction naphtho[10,20:5,6]pyrano[2,3-d]pyrimidine-9,11-(10H)-dione 4a
conditions, this reaction was considered as the model and and phenyl-14H-dibenzo[a,j]xanthene 5 (Scheme 2). The 1H
performed using different catalyst amounts at 100 ꢀC (Table 1). NMR spectra of the crude products clearly indicated the
The best result was achieved in the presence of 0.1 g of formation of undesired product
5 in the presence of
Al(H2PO4)3. Next, to optimize the reaction temperature, the p-TsOH$H2O (Fig. 2).
model reaction was carried out using 0.1 g of the catalyst at
To further explore scope and limitation of this protocol, a
various temperatures under solvent-free conditions. It was variety of mono and disubstituted benzaldehydes were reacted
ꢀ
found that 110 C is an effective temperature in terms of reac- with b-naphthol and 6-amino-1,3-dimethyl uracil under opti-
tion time and yield obtained (Table 1, entry 8). Additionally, the mized reaction conditions. The results are summarized in Table
effect of solvents such as methanol and acetonitrile was exam- 2. The reaction was found to be compatible with both electron-
ined on the model reaction, but the low yields were obtained withdrawing and electron-donating substituents such as Me,
under reux conditions (Table 1, entries 11 and 12). To illus- OMe, OH, F, Cl, Br and NO2. In general, the one-pot three-
trate the real effectiveness of Al(H2PO4)3 in these reactions, the component reaction proceeded smoothly to produce the corre-
model reaction was also studied in the absence of the catalyst sponding naphthopyranopyrimidines 4a–n in good to high
under solvent-free conditions, where no product was obtained yields. Some aliphatic aldehydes such as propionaldehyde and
ꢀ
at 110 C even aer 12 h (Table 1, entry 13).
cinnamaldehyde were used in this protocol under optimized
It is noteworthy that the reaction of b-naphthol, benzalde- conditions, but unfortunately the desired product could not be
hyde and 6-amino-1,3-dimethyl uracil using p-toluenesulfonic obtained.
Table 1 Optimization of the reaction conditions for the synthesis of naphthopyranopyrimidine 4aa
Entry
Catalyst (g)
Solvent
Temperature (ꢀC)
Time (min)
Yieldb (%)
1
2
3
4
5
6
7
8
Al(H2PO4)3 (0.05)
Al(H2PO4)3 (0.03)
Al(H2PO4)3 (0.07)
Al(H2PO4)3 (0.1)
Al(H2PO4)3 (0.15)
Al(H2PO4)3 (0.2)
Al(H2PO4)3 (0.1)
Al(H2PO4)3 (0.1)
Al(H2PO4)3 (0.1)
Al(H2PO4)3 (0.1)
Al(H2PO4)3 (0.1)
Al(H2PO4)3 (0.1)
No catalyst
—
—
—
—
—
—
—
—
—
—
MeOH
MeCN
—
100
100
100
100
100
100
90
110
120
130
Reux
Reux
110
90
120
65
50
50
45
120
40
40
35
58
46
73
80
81
78
64
85
84
79
43
38
—
9
10
11
12
13
6 h
6 h
12 h
a
Reaction conditions: b-naphthol (1 mmol), benzaldehyde (1 mmol) and 6-amino-1,3-dimethyl uracil (1 mmol). b Isolated yield.
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Scheme 2 Reaction of b-naphthol, benzaldehyde and 6-amino-1,3-dimethyl uracil using Al(H2PO4)3 and p-TsOH$H2O.
A possible reaction mechanism for the synthesis of naph-
thopyranopyrimidines is suggested on the basis of reported
literature19,20 (Scheme 3). At rst, the nucleophilic addition of
Experimental
Preparation of the catalyst Al(H2PO4)3
b-naphthol 1 to aldehyde 2 in the presence of Al(H2PO4)3 leads
to the intermediate of ortho-quinone methide A. Next,
6-amino-1,3-dimethyl uracil 3 reacted with Lewis-acid acti-
vated intermediate A through a [4 + 2] cycloaddition reaction to
produce intermediate B.25 Eventually, deamination of inter-
mediate C leads to the corresponding naphthopyranopyr-
imidine 4.
The reusability of the catalyst is an important factor from an
economical and environmental point of views and has attracted
much attention in recent years. Thus, the reusability of
Al(H2PO4)3 was examined in the synthesis of naphthopyr-
anopyrimidine 4a as an example. Since Al(H2PO4)3 is a hetero-
geneous catalyst, it was separated and reused aer being
washed with methanol and dried at 100 ꢀC for 60 min. The
results show that the catalyst can be used up to ve times
without signicant loss of its activity (Fig. 3).
The catalyst was prepared by taking a mixture of alumina
(neutral) and concentrated phosphoric acid (88%) in a silica
boat, maintaining the molar ratio of alumina : H3PO4 as 1 : 3
and heating at 200–220 ꢀC in a hot sand bath. The mixture was
stirred at the stipulated temperature until the swampy mass
solidied, and then the temperature was lowered to around
100 ꢀC. The whole solidied product was then placed in a
vacuum desiccator and cooled to ambient temperature. The
catalyst thus prepared was nally transferred and stored in an
air tight sample vial.2,3
General procedure for the synthesis of
naphthopyranopyrimidine 4
To a mixture of b-naphthol 1 (1.0 mmol), aldehyde 2 (1 mmol)
and 6-amino-1,3-dimethyl uracil 3 (1.0 mmol), Al(H2PO4)3 (0.1 g)
was added and the mixture was heated on an oil bath at 110 ꢀC
Fig. 2 1H NMR spectra of crude products in the presence of (I) Al(H2PO4)3 and (II) p-TsOH$H2O.
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Table 2 Synthesis of naphthopyranopyrimidines 4a–n
Entry
Aldehyde
Product
Time (min)
Yielda (%)
M.p. (ꢀC)
Lit. m.p. (ꢀC) (Ref.)
1
2
3
4
5
6
7
8
Ph
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
—
—
40
40
45
60
40
50
40
40
35
45
45
40
40
75
6 h
6 h
85
88
86
77
86
85
88
89
81
87
84
85
80
68
223–225
198–200
254–256
288–290
301–303
271–273
241–243
270–272
219–221
246–248
283–285
304–306
287–289
210–212
—
226–228 (ref. 14)
196–198 (ref. 14)
257–258 (ref. 19)
293–294 (ref. 19)
305–307 (ref. 15)
270–272 (ref. 14)
250–252 (ref. 20)
274–276 (ref. 15)
222–224 (ref. 14)
243–245 (ref. 15)
288–290 (ref. 14)
310–312 (ref. 20)
291–293 (ref. 15)
215–217 (ref. 19)
—
4-Me–C6H4
4-OMe–C6H4
3-OH–C6H4
4-F–C6H4
2-Cl–C6H4
3-Cl–C6H4
4-Cl–C6H4
2,4-Di-Cl–C6H3
4-Br–C6H4
2-NO2–C6H4
3-NO2–C6H4
4-NO2–C6H4
2-OH-5-NO2C6H3
n-Propyl
9
10
11
12
13
14
15
16
No reaction
No reaction
PhCH]CH
—
—
a
Isolated yield.
for the appropriate time (see Table 2). The reaction progress was Next, the resulting mixture was cooled to room temperature and
monitored by TLC. Aer completion of the reaction, methanol poured over crushed ice. The precipitated product was ltered
(5 mL) was added and the heterogeneous catalyst was ltered. off and washed with water, dried, and recrystallized from
Scheme 3 Proposed mechanism for the synthesis naphthopyranopyrimidines 4.
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J ¼ 8.2 Hz, 2H, ArH); 7.83–7.95 (m, 3H, ArH), 8.04 (d, J ¼ 8.4 Hz,
2H, ArH); 13C NMR (100 MHz, CDCl3): d ¼ 28.4, 29.3, 35.7, 91.2,
117.4, 118.3, 124.2, 125.6, 126.7, 128.9, 129.7, 129.9, 131.8,
132.0, 134.1, 143.6, 147.8, 150.8, 151.5, 161.6.
Conclusions
In summary, we have developed an efficient and eco-friendly
approach for the synthesis of naphthopyranopyrimidine deriv-
atives via one-pot three-component reaction of aromatic alde-
hydes, b-naphthol and 6-amino-1,3-dimethyl uracil in the
presence of Al(H2PO4)3 as a catalyst under solvent-free condi-
tions. The important aspects of this protocol are simple
procedure, cleaner reaction and easy workup, use of inexpensive
and reusable catalyst, short reaction times and good to high
yields.
Fig. 3 Recyclability of the catalyst in the synthesis of 4a over 5 runs.
methanol to give the pure product 4. All products are known
and their structures were conrmed by comparison of their
melting points and spectral data (1H and 13C NMR) with liter-
ature.14,15,19,20 Spectral data for selected compounds are pre-
sented below.
Acknowledgements
I gratefully acknowledge nancial support from the Research
Council of the Payame Noor Universitry (PNU).
12-Phenyl-8,12-dihydro-8,10-dimethyl-9H-naphtho[10,20:5,6]
1
pyrano[2,3-d]pyrimidine-9,11-(10H)-dione (4a). White solid; H
NMR (400 MHz, CDCl3): d ¼ 3.37 (s, 3H, CH3), 3.63 (s, 3H, CH3),
5.83 (s, 1H, CH), 7.12–7.50 (m, 8H, ArH), 7.85 (t, J ¼ 8.4 Hz, 2H,
ArH), 7.98 (d, J ¼ 8.0 Hz, 1H, ArH); 13C NMR (100 MHz, CDCl3):
d ¼ 28.3, 29.1, 35.6, 91.8, 116.9, 118.0, 124.3, 125.5, 126.4, 127.9,
128.5, 128.8, 129.1, 130.0, 131.1, 131.8, 143.7, 148.6, 151.1,
152.3, 161.8.
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