A green one-pot three-component synthesis of tetrahydrobenzo[b]pyran and 3,4-dihydropyrano[c]chromene derivatives using a Fe3O4@SiO2-imid-PMAn magnetic nanocatalyst under ultrasonic irradiation or reflux conditi

Article abstract of DOI:10.1039/c5ra01021g

An efficient and environmentally benign procedure for the synthesis of tetrahydrobenzo[b]pyran and 3,4-dihydropyrano[c]chromene derivatives has been developed by a one-pot three-component reaction of various aldehydes, malononitrile, and dimedone or hydro

Full text of DOI:10.1039/c5ra01021g

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A green one‐pot three‐component synthesis of tetrahydrobenzo
b]pyran and 3,4‐dihydropyrano[c]chromene derivatives using
[
n
Fe O @SiO -imid-PMA magnetic nanocatalystunder ultrasonic
3
4
2
irradiationor reflux conditions
a
b,c
a
b
Mohsen Esmaeilpour,* JaberJavidi,* FarzanehDehghani and FatemehNowrooziDodeji
a
Chemistry Department, College of Science, Shiraz University, Shiraz, Iran
b
Department of Pharmaceutics, School of Pharmacy, ShahidBeheshti University of Medical Sciences,
Tehran, Iran
c
Students Research Committee, School of Pharmacy, ShahidBeheshti University of
Medical Sciences, Tehran, Iran
*Corresponding author. Tel.: +98 7116137738, fax: +98 7112286008.
Eꢀmail address:m1250m551085@yahoo.com (M. Esmaeilpour), JaberJavidi@ gmail.com (J. Javidi),
Abstract
An efficient and environmentally benign procedure for the synthesis of tetrahydrobenzo [b]pyran
and 3,4‐dihydropyrano[c]chromene derivatives has been developed by oneꢀpot threeꢀcomponent
reaction of various aldehydes, malononitrile, and dimedoneor hydroxycoumarinin the presence
n
of Fe O @SiO ꢀimidꢀPMA nanoparticles as magnetic catalysts under ultrasonic irradiation or
3
4
2
reflux conditions in water.This new procedure has the notable advantages such as operational
simplicity, excellent yields, short reaction time, and absence of any tedious workup or
purification. In addition, the excellent catalytic performance in water medium and the easy
preparation, thermal stability and separation of the catalyst make it a good heterogeneous system
and a useful alternative to other heterogeneous catalysts. Also, the catalyst can be easily
recovered by a magnetic field and reused for eight consecutive reaction cycles without
significant loss of activity.
Keywords
n
Fe O @SiO ꢀimidꢀPMA magnetic nanocatalyst; Multicomponent reactions; Green synthesis;
3
4
2
Tetrahydrobenzo[b]pyrans; 3,4ꢀDihydropyrano[c]chromenes; Oneꢀpot reactions;Ultrasonic
irradiation.
1
. Introduction
Today the efficiency of a chemical synthesis can be measured, not only by parameters
such as selectivity and overall yield but also by its raw material, time, human resources,
and energy requirements, as well as the toxicity and hazards of the chemicals and the
protocols involved[1].Multiꢀcomponent reactions (MCRs) have developed as efficient
and powerful tool in modern synthetic organic chemistry because the synthesis of
1

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complex organic molecules from simple and readily available substrates can be achieved
in a very fast and efficient manner without the isolation of any intermediate[2]. In
addition, the employment of several transformations in a single manipulation is highly
compatible with the goals of sustainable and “green” chemistry[3].Developing MCR
procedures in aqueous medium is an active area of research in this direction that have
many advantages, such as devoid of any carcinogenic effects, reduced pollution, lower
cost, and simplicity in processing, which are valuable to the industry as well as to the
environment[4].On the other hand, the use of ultrasound irradiation represents very
powerful green chemical protocols from both the economic and synthetic point of
view[5]. The use of ultrasonic irradiation accelerates an organic transformation at
ambient conditions which otherwise require harsh conditions of temperature and
pressure[6].The interaction between molecules and ultrasound isn't direct but the energy
of theses long wavelength can cause cavitation which makes the reaction faster[7].
Pyran derivatives have received significant attention due to their important biological and
pharmacological
properties[8].
Among
the
pyrans,
the
substituted
tetrahydrobenzo[b]pyranhave a special importance among the 6ꢀmembered oxygenꢀ
containing heterocycles as they have been utilized in synthesis of blood anticoagulant
warfarin[9], they have been also used as anticancer and antimicrobial agents[10], and
photoactive materials[11].
The conventional synthetic method for the preparation of tetrahydrobenzo[b]pyran
derivatives is a threeꢀcomponent reaction of cyclic 1,3ꢀdiketones, aryl aldehydes, and
activated methylene compounds under various reaction conditions, e.g., in the presence
of piperidine and triethylamine in acetic acid or DMF[12]. Other methods include use of
microwaves[13], ultrasonic radiation[14], and electrogenerated base[15] or usingsome
catalysts
such
as
triethylbenzylammonium
chloride
(TEBA)[16],perfluorooctanoate[17],(S)ꢀproline[18],silica bonded n-propylꢀ4ꢀazaꢀ1ꢀ
azoniabicyclo[2.2.2]octane
chloride
[19],nꢀ
TiO /H [NaP W O ][20],nanozeoliteclinoptilolite[21],SO Hꢀbearing
carbonaceous
2
14
5
30 110
3
solid catalyst (PEGꢀSAC)[22],Multiꢀwalled carbon nanotube supported Fe O4
3
nanoparticles[23],FreeꢀZnO nanoparticles[24],acetic acid functionalized imidazolium
salts[25],Nano
αꢀAl O supported
ammonium
dihydrogenphosphate
2
3
(
NH H PO /Al O )[26]and amino functionalized ionic liquids[27]. However, these
4
2
4
2
3
methods show varying degrees of success as well as limitations such as long reaction
times, low yields, and use of toxic solvents. Thus, the development of an alternate milder
and cleaner procedure, which surpasses those limitations, is very much relevant for the
synthesis oftetrahydrobenzo[b]pyran.
Also, Dihydropyrano[3,2ꢀc]chromeneand its derivatives are very useful compounds in
various fields of chemistry,biology and pharmacology[28]. Some of these compounds
exhibit spasmolytic, diuretic, anticoagulant, anticancer, andantianaphylactic
activity[28].Moreover they can be used as cognitive enhancers, for the handling of
neurodegenerative diseases, including amyotrophic lateral sclerosis, Alzheimer’s disease,
Parkinson’s disease, Huntington’s disease, AIDS associated dementia and Down’s
2

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syndrome as well as for the treatment of schizophrenia and myoclonus[29].Despite their
importance from pharmacological, industrial and synthetic point of views, comparatively
few methods for the preparation of dihydropyrano[3,2ꢀc]chromenederivatives have been
reported[30].Some of the reported procedures require long reaction times; afford products
with only modest yields and nonꢀreusability of the catalyst. Therefore, the development
of more effective methods for their preparation is still necessary.
In recent years, brønsted acids such as Kegginꢀtype heteropolyacids(HPAs) have been
used as efficient catalysts for a variety of organic reactions because of their redox
properties and superacidic, high thermal stability, ease of handling, high proton mobility,
stronger acids than homogeneous acid catalysts, low toxicity, development of clean
technologies and low cost [31].Although HPAs are versatile compounds intheir acidic
form, their main disadvantages are high solubility inpolar solvents and low surface area
2
(
<10 m /g). Therefore, in a homogeneous reaction the isolationof the products and the
reuse of the catalyst after reaction become difficult[32].Therefore, in order to overcome
this problem, these materials disperse on supports (such as active carbon, silica, acidic
ionꢀexchange resins and etc.,) which possess large surfacearea. The use of support allows
the heteropolyacids to be dispersed over a large surface area and increases their catalytic
activity [33].In previous work[34], we introduce a simple, repaid, inexpensiveand one
n
step method, solvothermal, for synthesis ofH PMo O nanoparticles (PMA ) from
3
12
4
b
H PMo O bulk particles (PMA ). Acidity of asꢀprepared nanoparticles was
3
12
4
investigatedby pyridine adsorption method. Results showed acidity of PMA rise by
declining particle size.
Magnetic nanoparticles (MNPs)such as magnetite (Fe O ) have attracted great interest
3
4
because ofmagnetic and electrical properties, high specific surface area, their unique
catalytic and their wide applications, including drug delivery systems, targeted gene
therapy, ion exchange separation, magnetic resonance imaging, biosensors, magnetic data
storage, and environmental remediation and catalysis[35].For many applications,
magnetic nanoparticles are suitable to be chemically stable and uniform in size. But the
magnetic nanoparticlestrendtoaggregateduetotheirnanoscale and
stronginteractionbetweeneachother.This problem can be solved by coating of magnetite
nanoparticles with a silica layer as the stabilizer, which prevents direct contact between
thenanoparticles. Furthermore, the abound hydroxyl groups on the surface of composite
particles provide the opportunity to conjugate various function molecules for many
special applications[36].Recently, a number of functionalized Fe O nanoparticles have
3
4
been employed in a range of organic transformations, and the studies on immobilization
of organo catalysts on silica coated ironoxide nanoparticles have been reported [37].
Therefore, as part of our continuing interest in developing newer methods for the
synthesis of useful compounds, we have recently successfully developedFe O @SiO ꢀ
3
4
2
n
imidꢀPMA as recyclable catalyst for the oneꢀpot synthesis of 1ꢀamidoalkylꢀ2ꢀnaphthols
38].Compared to other substrates (silica, acidic ionꢀexchange resins, active carbon and
nanotitania), Fe O @SiO ꢀimid nanoparticles have various advantagessuch as high
[
3
4
2
3

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loading capacity, low leaching and simpleand efficient recovery procedure. Fig. 1
n
presents the procedurefor the preparation of Fe O @SiO ꢀimidꢀPMA stepwise.
3
4
2
n
Fig. 1: Process for preparation of Fe O @SiO ꢀimidꢀPMA nanoparticles and characterization by
3
4
2
TEM,SEM and DLS technique.
4

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Encouraged by these efforts and aiming to show the efficiency and generality of
n
Fe O @SiO ꢀimidꢀPMA as catalysts for further, we have utilized this novel catalyst for
3
4
2
the synthesis of tetrahydrobenzo[b]pyrans and dihydropyrano[3,2ꢀc]chromenesfrom
simple and easily available starting materials under much milder reaction
conditions(Scheme.1).
n
Scheme.1: Fe O @SiO ꢀimidꢀPMA catalyzed synthesis of tetrahydrobenzo[b]pyran and
3
4
2
dihydropyrano[3,2ꢀc]chromene derivativesunder ultrasonic irradiation or reflux conditions.
2
. Results and discussion
In our previous work[38], the Fe O , Fe O @SiO and Fe O @SiO ꢀimidꢀ
3
4
3
4
2
3
4
2
n
PMA nanocatalysts were characterized by various methods such as transmission electron
microscopy (TEM), scanning electron microscopy (SEM), dynamic light scattering
(
DLS), Fourier transform infrared (FTꢀIR), vibrating sample magnetometer (VSM) and
n
etc. As shown in Fig. 1 Fe O @SiO ꢀimidꢀPMA nanoparticles have spherical shapes
3
4
2
with approximately 50 nm diameters. The size distribution of these is centered at a value
n
of 55 nm. The magnetic properties of Fe O , Fe O @SiO , Fe O @SiO ꢀimidꢀPMA
3
4
3
4
2
3
4
2
nanoparticles were measured by VSM at room temperature. All the samples show a
typical superparamagnetic behavior. Hysteresis phenomenon was not found and the
magnetization and demagnetization curves were coincident. The saturation magnetization
n
ꢀ1
of Fe O , Fe O @SiO and Fe O @SiO ꢀimidꢀPMA is 63.4, 39.7, 33.2 emu g ,
3
4
3
4
2
3
4
2
respectively.
n
Due to ability of Fe O @SiO ꢀimidꢀPMA as a mild and efficient acid catalyst, we
3
4
2
decided to apply this catalyst for synthesis oftetrahydrobenzo[b]pyrans. At the first stage,
5

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to obtain the best reaction conditions, the reaction ofdimedone, benzaldehyde and
malononitrile, as a model reaction was chosen. The model reaction was refluxed in the
n
presence of 0.02 g of Fe O @SiO ꢀimidꢀPMA and a variety of solvents such as H O,
3
4
2
2
EtOH, MeOH, EtOAc, CHCl and CH CN. The represented data in Table 1, showed the
3
3
reaction proceeded efficiently in refluxing H O and resulted in high yields of the desired
2
product (Table 1, entry 6). This three‐component condensation wasalso accomplished in
protic solvents such asEtOH and MeOH under reflux and the corresponding products
were obtained in 87% and 79% yield, respectively (Table 1, entries 1 and 3). Aprotic
solvents such as CHCl , EtOAc and CH CN afforded the desired product in lower yields
3
3
and longer reaction times (Table 1, entries 2, 4 and 5).Moreover, the model reaction was
examined under solvent‐free conditions at 100 °C and gave the corresponding product in
71% yield after 70 min (Table 1, entry 7).
Table.1: Optimization of the amount of catalyst, solvent and temperature in a oneꢀpot synthesis
a
of the model reaction.
b
Entry Catalyst amount (g)
Solvent
EtOH
EtOAc
MeOH
CHCl3
Condition
reflux
Time (min) Yield (%)
1
2
3
4
5
6
7
8
9
0.02
0.02
0.02
0.02
0.02
0.02
0.02
None
0.005
0.01
20
80
30
100
60
20
70
360
60
60
30
20
120
90
40
20
15
10
7
87
43
79
Trace
28
94
71
ꢀ
33
67
87
92
46
77
85
ꢀ
reflux
reflux
reflux
reflux
CH CN
3
H O
reflux
2
o
Solventꢀfree
100 C
H O
reflux
reflux
reflux
reflux
reflux
r.t
2
H O
2
1
0
1
2
3
4
5
6
7
8
9
0
H O
2
1
1
1
1
1
1
1
1
1
2
0.015
0.025
0.02
0.02
0.02
None
0.005
0.01
0.015
0.02
H O
2
H O
2
H O
2
o
H O
60 C
2
o
H O
80 C
2
H O
Sonication (40 kHz)/r.t
Sonication (40 kHz)/r.t
Sonication (40 kHz)/r.t
Sonication (40 kHz)/r.t
Sonication (40 kHz)/r.t
2
H O
54
88
96
93
2
H O
2
H O
2
H O
2
7
a
Reaction conditions: benzaldehyde (1 mmol), malonitrile (1.2mmol), dimedone (1 mmol), Fe O @SiO ꢀimidꢀ
3
4
2
n
PMA catalyst and solvent (5 mL).
b
Isolated yield.
After that we checked the model reaction in presence of H O as a green solvent under
2
reflux conditions and various amount of catalyst. As it was shown in Table 1 the best
result was obtained when we carried out the model reaction in the presence of 0.02 g of
catalyst. This condensation was carried out with low amounts of Fe O @SiO ꢀimidꢀ
3
4
2
n
PMA of 0.005, 0.01 and 0.015 g and the corresponding products were obtained in 33%,
6

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67% and 87% yield, respectively (Table 1, entries 9ꢀ11).The effect of temperature was
also studied by carrying out the model reaction in the presence of water as a solvent and
o
o
0
.02 g of catalyst at room temperature, 60 C and 80 C.It was observed that the yield
wasincreased when the reaction temperature was increased (Table 1, entries 13ꢀ15).
The reaction was also checked without the catalyst in which the reaction did not proceed
even after 6 h(Table 1, entry 8). These observations established the crucial rule of
n
Fe O @SiO ꢀimidꢀPMA for the expedition of the reaction time and the product yield.
3
4
2
For investigation of the ability of ultrasonic irradiation for the acceleration of organic
reactions, we examined the model reaction under ultrasonic irradiation at room
temperaturein presence of H O as a green solvent and various amount of catalyst.As it is
2
reveal from Table 1, the best results were obtained in the presence of 0.015 g of catalyst
(
Table 1, entry 19). However, synthesis of organic compounds under ultrasound
irradiation has been limited by the need for a specialized apparatus that may not be
available in many laboratories. Because of this limitation, herein we report both
ultrasonic irradiation in H O in presence of 0.015 g of catalyst at room temperature and
2
also refluxing water in presence of0.02 g of catalyst (Table 1, entries 6 and 19) for the
synthesis oftetrahydrobenzo[b]pyrans.
After optimizing the reaction conditions, the generality of this catalytic system was
confirmed by the employment of a series of aldehydes, dimedone and malononitrile to
obtain desired products under the optimized conditions. The results are summarized in
Table 2.
Table.2: Synthesis of derivatives of 2ꢀaminoꢀ5ꢀoxoꢀ5,6,7,8ꢀtetrahydroꢀ4Hꢀbenzo[b]pyran in the
n
presence of Fe O @SiO ꢀimidꢀPMA .
3
4
2
O
O
Ar
CN
n
Fe O @SiO ꢀImidꢀPMA Catalyst
ArCHO + CH (CN)2
+
3
4
2
2
H O/Reflux or Ultrasonic/H O/r.t
2
2
(1)
(2)
O
O
NH2
(3)
4(a-x)
H O/Reflux
Ultrasonic/H O/r.t
o
2
2
Entry
Ar
Product
M.p. C (Lit.)
b
b
Time (min) Yield (%)
Time (min) Yield (%)
[
[
[
[
[
[
39]
39]
26]
21]
26]
21]
1
2
3
4
5
6
7
8
9
C H5
4ꢀMeꢀC H
2ꢀMeꢀC H
4ꢀMeOꢀC H4
3ꢀMeOꢀC H4
4ꢀMe NꢀC H
3,4ꢀ(MeO) ꢀC H
2,3ꢀ(MeO) ꢀC H
4a
4b
4c
4d
4e
4f
4g
4h
4i
20
30
40
25
30
25
30
50
30
94
85
82
87
88
90
84
85
92
7
96
91
92
94
92
95
93
90
96
238ꢀ240 (227ꢀ239)
212ꢀ214 (214ꢀ216)
210ꢀ211 (210ꢀ212)
201ꢀ203 (198ꢀ202)
195ꢀ197 (196ꢀ198)
212ꢀ214 (210ꢀ213)
6
10
12
10
10
8
12
12
9
6
4
6
4
6
6
2
6
4
[
24]
229ꢀ 231 (227ꢀ229)
2
6
3
[
21]
12]
216ꢀ218 (216ꢀ217)
225ꢀ227 (224ꢀ226)
2
4
6
3
[
4ꢀOHꢀC H
6
7

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[
[
[
[
24]
21]
21]
26]
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
4ꢀOHꢀ3ꢀMeOꢀC H3
4j
4k
4l
4m
4n
4o
4p
4q
4r
4s
40
10
18
10
15
10
5
10
12
10
30
25
40
35
30
88
95
90
96
93
93
97
94
96
95
89
92
90
92
90
12
5
7
4
7
5
5
5
5
4
12
8
14
10
10
91
97
93
97
95
92
96
97
95
97
90
93
91
94
89
230ꢀ231 (227ꢀ229)
212ꢀ213 (213ꢀ214)
213ꢀ214 (212ꢀ213)
179ꢀ181 (180ꢀ182)
6
4ꢀClꢀC H4
6
2ꢀClꢀC H4
6
4ꢀNO ꢀC H
2
6
4
4
4
[
4]
3ꢀNO ꢀC H
209ꢀ211 (210)
2
6
[24]
[24]
[26]
2ꢀNO ꢀC H
237ꢀ238 (238ꢀ239)
214ꢀ216 (216ꢀ217)
227ꢀ228 (225ꢀ228)
2
6
4ꢀClꢀ3ꢀNO ꢀC H
2
6
3
4ꢀCNꢀC H4
6
[26]
4ꢀFꢀC H4
188ꢀ 189 (190ꢀ191)
6
[
26]
19]
8]
2,4ꢀ(Cl) ꢀC H
192ꢀ194 (190ꢀ192)
191ꢀ193 (193ꢀ194)
232ꢀ233 (232ꢀ234)
190ꢀ191 (187ꢀ189)
221ꢀ222 (223ꢀ225)
219ꢀ221 (220ꢀ223)
2
6
4
[
3ꢀOPhꢀC H4
4t
6
[
2ꢀNaphthalene
4ꢀC H ꢀC H
4u
4v
4w
4x
[8]
3
7
6
4
[
21]
21]
2ꢀThionyl
2ꢀFuryl
[
a
Reaction conditions: aldehyde (1 mmol), dimedone (1 mmol), malononitrile (1.2mmol), water (5 mL, reflux),
Fe O @SiO ꢀimidꢀPMA (0.02 g) or water (5 mL, ultrasonic irradiation (40 kHz), r.t), Fe O @SiO ꢀimidꢀPMA (0.015
n
n
3
4
2
3
4
2
g).
b
The yields refer to isolated products.
As shown in Table 2, we investigated the reaction with a wide range of aromatic
aldehydes with electron donating and electron withdrawing groups. Both electronꢀrich
and electronꢀdeficient aldehydes worked well and give high yields of productsunder both
refluxing H O and ultrasonic irradiation.
2
Electronꢀdeficient aldehydes furnished excellent yields of the corresponding products in
the shorter reaction times (Table 2, entries 11ꢀ19), but the aromatic aldehydes with
electronꢀdonating substituents carried out the reaction at longer reaction times in lower
yields of the corresponding tetrahydrobenzo[b]pyrans(Table 2, entries 2ꢀ10). Moreover, it
is clear that, under the same reaction conditions, reactions under ultrasonic irradiation led
to shorter reaction times.
Also both of our methodologies have been successfully used for heteroaromatic
aldehydes that are acidsensitive species such as thiopheneꢀ2ꢀcarbaldehyde and furanꢀ2ꢀ
carbaldehyde and the corresponding tetrahydrobenzo[b]pyranswere obtained in excellent
yields without the formation of any byproduct (Table 2, entries 23 and 24).
Encouraged by these results, we replaced the dimedone with 4ꢀhydroxycoumarinto
explore its further applications toward the synthesis of dihydropyrano[3,2ꢀ
c]chromenederivatives. Initially, we optimized the reaction coditions. For this purpose,
the reaction of 4ꢀhydroxycoumarin, benzaldehyde and malononitrile was chosen as a
model reaction then the model reaction was refluxed in the presence of 0.025 g of
n
Fe O @SiO ꢀimidꢀPMA and a variety of solvents such as H O, EtOH, MeOH, EtOAc,
3
4
2
2
CHCl , CH Cl , THF and CH CN. As shown in Table 3, the best result in terms of the
3
2
2
3
reaction time (15 min) and yield (96%) was obtained when the reaction was carried out in
refluxing H O (Table 3, entry 8). This condensation was also accomplished efficiently in
2
refluxing EtOH and MeOH and resulted in high yields of the desired products (Table 3,
entries 1, 2). The model reaction was also examined under solvent‐free conditions at 100
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°
C and gave the corresponding product in 81% yield after 60 min (Table 3, entry 9). Due
to green nature and cost effective of the reactions in H O, we decided to choose H O as a
2
2
solvent in this condensation and checked the model reaction in presence of H O as a
2
solvent under reflux and various amount of catalyst. As shown in Table 3 the best result
was obtained when the model reaction carried out in the presence of 0.025 g of catalyst.
The resultsshow clearly that the catalyst is effective for this transformationand in its
absence; the reaction did not take place evenafter higher reaction time (Table 3, entry 13).
Use of a higheramount of catalysts did not improve the yield (Table 1, entry 17)while a
decrease in the amount of catalysts decreases the yield(Table 3, entry 13).
We also checked the model reaction in presence of water as a solvent and 0.025 g of
o
o
catalyst at room temperature, 60 C and 80 C and observed that the corresponding product
was formed in longer reaction time and lower yield (Table 3, entries 10ꢀ12).
Because of the ability of ultrasonic irradiation for the synthesis
oftetrahydrobenzo[b]pyrans, we examined the model reaction under ultrasonic irradiation
at room temperature in presence of H O as a green solvent and various amount of catalyst
2
at room temprature.As shown in Table3, the best results were obtained in the presence of
0.025 g of catalyst (Table 3, entry 22).
Table.3: Effect of solvent, temperature and catalyst amount on the condensation of benzaldehyde,
a
malononitrile, and 4ꢀhydroxycoumarin.
b
Entry Catalyst amount (g)
Solvent
EtOH
Condition
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
Time (min) Yield (%)
1
2
3
4
5
6
7
8
9
0.025
0.025
0.025
0.025
0.025
0.025
0.025
0.025
0.025
0.025
0.025
0.025
None
0.01
15
25
90
90
60
90
60
15
60
100
60
30
300
60
40
15
15
20
15
10
8
92
87
22
Trace
48
35
52
96
81
56
75
88
ꢀ
22
44
81
94
ꢀ
44
77
94
97
96
MeOH
CHCl3
CH Cl
2
2
CH CN
3
THF
EtOAc
H O
2
o
Solventꢀfree
100 C
1
0
1
2
3
4
5
6
7
8
9
0
1
2
3
H O
r.t
2
o
1
1
1
1
1
1
1
1
1
2
2
2
2
H O
60 C
2
o
H O
80 C
2
H O
reflux
reflux
reflux
reflux
2
H O
2
0.015
0.02
0.03
H O
2
H O
2
H O
reflux
2
None
0.01
0.015
0.02
H O
Sonication (40 kHz)/r.t
Sonication (40 kHz)/r.t
Sonication (40 kHz)/r.t
Sonication (40 kHz)/r.t
Sonication (40 kHz)/r.t
Sonication (40 kHz)/r.t
2
H O
2
H O
2
H O
2
0.025
0.03
H O
6
8
2
H O
2
9

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Page 10 of 18
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a
Reaction conditions: benzaldehyde (1 mmol), malonitrile (1.2mmol), 4ꢀhydroxycoumarin (1 mmol), Fe O @SiO ꢀ
3
4
2
n
imidꢀPMA catalyst and solvent (5 mL).
b
Isolated yield.
So, the best results were obtained when the reaction was carried out under ultrasonic
irradiation in H O at room temperature and also refluxing water in presence of0.025 g of
2
catalyst (Table 3, entries 8 and 22).
In order to develop the scope of these reactions, we conducted the reaction with a series
of aromatic aldehydesbearing different substituent groups, heteroaromatic and aliphatic
aldehydes under the determined optimized conditions. The results are summarized in
Table 4.
n
Table.4: Synthesis of dihydropyrano[3,2ꢀc]chromenederivatives using Fe O @SiO ꢀimidꢀPMA
3
4
2
a
as catalyst.
NH2
CN
Ar
OH
O
O
n
Fe O @SiO ꢀImidꢀPMA Catalyst
ArCHO + CH (CN)2
+
3
4
2
2
H O/Reflux or Ultrasonic/H O/r.t
2
2
(1)
(2)
O
O
O
(
5)
6
(a-w)
o
Entry
Ar
Product
M.p. C (Lit.)
H O/Reflux
2
Ultrasonic/H O/r.t
2
b
b
Time (min) Yield (%)
Time (min) Yield (%)
[
[
[
[
[
[
[
[
[
[
[
[
[
40]
19]
19]
41]
42]
41]
19]
43]
42]
40]
22]
44]
40]
1
2
3
4
5
6
7
8
9
C H5
4ꢀMeOꢀC H4
4ꢀMeꢀC H5
4ꢀOHꢀC H5
3ꢀOHꢀC H5
4ꢀOHꢀ3ꢀMeOꢀC H5
4ꢀMe NꢀC H
3,4ꢀ(MeO) ꢀC H
3
3,4,5ꢀ(MeO) ꢀC H
4ꢀBrꢀC H4
4ꢀClꢀC H
2ꢀClꢀC H
2,4ꢀ(Cl) ꢀC H
4ꢀFꢀC H4
4ꢀCNꢀC H4
4ꢀNO ꢀC H
6a
6b
6c
6d
6e
6f
6g
6h
6i
6j
6k
6l
6m
6n
6o
6p
6q
6r
6s
15
25
25
25
30
30
20
30
40
15
12
15
8
10
12
5
10
10
30
30
40
35
96
88
90
93
95
86
91
86
89
92
95
88
93
93
96
96
91
89
87
92
90
86
6
8
8
10
7
12
10
10
12
6
5
8
5
6
6
5
6
5
97
93
95
96
95
92
94
90
88
95
96
90
97
91
95
97
93
96
92
90
93
89
260ꢀ261 (256ꢀ258)
244ꢀ246 (247ꢀ249)
253ꢀ255 (254ꢀ255)
261ꢀ263 (258ꢀ260)
268ꢀ270 (269ꢀ270)
254ꢀ256 (256ꢀ257)
224ꢀ226 (224ꢀ225)
225ꢀ227 (228ꢀ230)
234ꢀ236 (236ꢀ238)
250ꢀ251 (252ꢀ254)
265ꢀ267 (264ꢀ266)
267ꢀ269 (266ꢀ268)
260ꢀ261 (258ꢀ259)
6
6
6
6
6
6
2
6
4
2
6
3
6
2
1
1
1
1
1
1
1
1
1
1
2
2
2
0
1
2
3
4
5
6
7
8
9
0
1
2
6
6
5
6
5
2
6
4
[19]
260 (259ꢀ261)
281ꢀ283 (284ꢀ286)
6
[
30]
6
[
41]
252ꢀ 254 (250ꢀ252)
2
6
5
5
5
[
41]
42]
41]
17]
40]
19]
3ꢀNO ꢀC H
2ꢀNO ꢀC H
2ꢀFuryl
266ꢀ267 (263ꢀ265)
257ꢀ259 (258ꢀ260)
255ꢀ256 (253ꢀ255)
225ꢀ227 (228ꢀ229)
240ꢀ242 (243ꢀ245)
251ꢀ253 (250ꢀ252)
2
6
[
2
6
[
12
10
12
12
[
2ꢀThionyl
CH (CH )
6t
6u
6v
[
3
2 2
[
(CH ) CH
3
2
1
0

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[17]
2
3
Cyclohexyl
6w
40
91
12
94
283ꢀ285 (281ꢀ283)
a
Reaction conditions: aldehyde (1 mmol), 4ꢀhydroxycoumarin (1 mmol), malononitrile (1.2mmol), water (5 mL, reflux), or water
n
(
5 mL, ultrasonic irradiation (40 kHz), r.t), Fe O @SiO ꢀimidꢀPMA (0.025 g).
3 4 2
b
The yields refer to isolated products.
According to Table 4, aromatic aldehydes bearing electronꢀwithdrawing groups (Table 4,
entries 10ꢀ18) generally exhibit higher reactivity in this reaction compared to those
bearing electronꢀreleasing groups (Table 4, entries 2ꢀ9). In contrast, as seen in Table 4,
the present method is not only suitable for aromatic aldehydes but can also successfully
be applied to aliphatic and heteroaromatic aldehydes.
Heteroaromatic aldehydes such as thiopheneꢀ2ꢀcarbaldehyde and furanꢀ2ꢀcarbaldehyde
were also converted to the corresponding products in excellent yields under both of our
methodologies (Table 4, entries 19 and 20).
Moreover, it is clear that, about all of above results, reactions under ultrasonic irradiation
led to shorter reaction times.The generality of this catalytic system was also checked for
aliphatic aldehydes and a high yield of desired product was obtained(Table 4, entry 21ꢀ
23).
A proposed mechanism for the synthesis of tetrahydrobenzo[b]pyransiswas outlined in
Supplementary information. Based on this mechanism, as shown in S1, theintermediate
(
I)is produced upon initial condensationof aldehyde with malononitrile under the
n
catalytic activity of Fe O @SiO ꢀimidꢀPMA .
3
4
2
Subsequent nucleophilic addition of dimedoneto the intermediate (I)followed
successively by intramolecular cyclization to the intermediate (II),and rearrangement to
furnish the corresponding product. A similar mechanism mayoccur for the formation of
dihydropyrano [3,2ꢀc]chromenederivatives.
n
To compare the reactivity of the Fe O @SiO ꢀimidꢀPMA with previouslyreported
3
4
2
catalysts/reagents a comparative chart is presented in S2. Although, all the catalysts listed
in S2 were able to produce good yields of corresponding products, however some of
these reactions were carried out under harsh reaction conditions such as toxic solvents.
Moreover, some of the catalysts listed in S2 are not reusable and thus, our reusable
catalyst and green methodologies in water havebeen established as a better alternative
compared to the reported methods for the fabrication of corresponding products.
n
We also compared the catalytic activity of Fe O @SiO ꢀimidꢀPMA with H PMo O
3
4
2
3
12 40
b
n
(
PMA ) and nano H PMo O (PMA ) in these condensations and we observedthe best
3 12 40
results in terms of the reaction times and yields were obtained when the reaction was
n
carried outinthe presence of Fe O @SiO ꢀimidꢀPMA as a catalyst (S2, entries 17ꢀ19 and
3
4
2
35ꢀ37).
n
Fe O @SiO ꢀimidꢀPMA magnetic catalyst dispersed in H O can be easily separated by
3
4
2
2
external magnetic field within several minutes without the need for a centrifugation or
filtration step or a tedious workup of the final reaction mixture. However, magnetic
1
1

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separationperformance makes the nanoparticles more effective and convenient in
applications.
The reusability and recovery of the catalyst are important issues, especially when the
reactions use solid catalysts. Thus, the recovery and reusability of catalyst were
investigated for the preparationof2ꢀAminoꢀ3ꢀcyanoꢀ4ꢀ(4ꢀchlorophenyl)ꢀ7,7ꢀdimethylꢀ5ꢀ
oxoꢀ4Hꢀ5,6,7,8ꢀtetrahydrobenzo[b]pyran(4k) and 2ꢀaminoꢀ4ꢀ(4ꢀchlorophenyl)ꢀ5ꢀoxoꢀ4H,
5Hꢀpyrano[3,2ꢀc]chromeneꢀ3ꢀcarbonitrile (6k)at reflux conditions or ultrasonic
irradiation under optimized conditions in water (Table 5).The catalyst was recovered by a
magnetic field and the remainingsolid was washed with hot ethanol (2×10 mL). Then, the
o
recovered catalyst was dried under vacuum at 60 C. The performance of the recycled
catalyst in reaction up to eight successive runs was shown in Table 5.These bar diagrams
clearly suggest that the desired products were obtained in high yields without distinct
deterioration in catalytic activity.
n
To determine the exact PMA species responsible for the observed reactions and
tomeasure the extent of molybdenum (Mo) leaching after the reactions, we have used the
hot filtration test [63].For thisaim, we have studied the model reaction between 4ꢀ
chlorobenzaldehyde, malononitrile and dimedoneunder reflux conditions in water. The
hot reactionmixture was filtered after 27% conversion (GC) to remove the catalyst.
Continuation of the reaction upon the resulting filtrate under the same conditions showed
32% conversion (GC) after 6h. This result shows that the amount of leaching of the
catalyst into the reaction mixture should be lowand confirms that the catalyst acts
heterogeneously in the reaction.
Todetermine the degree of leaching of the metal from the heterogeneouscatalyst, the
catalyst was removed byusing a magneticfieldand the molybdenum amount in reaction
medium after each reaction cycle was measured through Inductively Coupled Plasma
(ICP) analyzer. The analysis of the reaction mixture by the ICP technique showed that the
leaching of H PMo O wasnegligible (Table 5).
3
12 40
SEM and DLS images of the catalyst after the first recycle have been represented in Fig.
n
1
7
.As shownin Fig. 1, Fe O @SiO ꢀimidꢀPMA nanoparticles hadanaveragediameterof
3 4 2
0nm, wereofuniformsize,andshowedgooddispersity. Additionally, the hydrodynamic
diameter of catalyst was investigated by DLStechnique. This size distribution is centered
at a value of 70 nm. Generally, leaching of H PMo O and increasing of catalyst size
3
12 40
lead to decreases the yieldafter each cycle.
1
2

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n
Table 5 Recyclability of Fe O @SiO ꢀimidꢀPMA in the synthesis of 4k and 6k under the
3
4
2
n
optimized conditions and PMA leaching (%) in each reaction cycle.
Run
1
2
3
4
5
6
7
8
Yield (%)
a
b
c
95
97
95
96
95
97
95
96
94
96
95
95
94
95
93
94
94
95
93
94
92
95
92
93
92
92
92
93
92
92
92
93
d
Leaching (%)
a
b
c
0.43 0.61
0.27 0.43
0.63 1.17
0.51 0.77
0.85 1.47 1.92 2.42 3.16 3.71
0.78 1.15 1.89 2.12 2.57 2.91
1.57 1.88 2.70 2.98 3.63 4.11
1.07 1.20 1.50 1.62 1.96 2.33
d
(
(
(
(
a) Reaction conditions: 4ꢀchlorobenzaldehyde (1 mmol), dimedone (1 mmol), malononitrile (1.2mmol), water (5
n
mL), reflux, Fe O @SiO ꢀimidꢀPMA (0.02 g), 10 min.
3
4
2
b) Reaction conditions: 4ꢀchlorobenzaldehyde (1 mmol), dimedone (1 mmol), malononitrile (1.2mmol), water (5
n
mL), ultrasonic irradiation (40 kHz), Fe O @SiO ꢀimidꢀPMA (0.015 g), r.t, 5 min.
3
4
2
c) Reaction condition: 4ꢀchlorobenzaldehyde (1 mmol), 4ꢀhydroxycoumarin (1 mmol), malononitrile (1.2mmol),
n
water (5 mL), reflux, Fe O @SiO ꢀimidꢀPMA (0.025 g), 15 min.
3
4
2
d) Reaction condition: 4ꢀchlorobenzaldehyde (1 mmol), 4ꢀhydroxycoumarin (1 mmol), malononitrile (1.2mmol),
n
water (5 mL),ultrasonic irradiation (40 kHz), Fe O @SiO ꢀimidꢀPMA (0.025g), 5 min.
3
4
2
3
. Conclusion
In conclusion, we have developed an easy, highly efficient and green methodology for
the synthesis of tetrahydrobenzo[b]pyran and dihydropyrano[3,2ꢀc]chromene derivatives
n
via oneꢀpot threeꢀcomponent reaction in the presence of Fe O @SiO ꢀimidꢀPMA
3
4
2
nanoparticles as efficient and magnetic catalyst under ultrasonic irradiation or reflux
conditions in water.
This method gives notable advantages such as easy preparation, heterogeneous nature,
thermal stability and easy separation of the catalyst, clean and simple procedure,
excellent yields, short reaction time, easy product separation and purification, lower
loading of catalyst compared with the other methods, and avoidance of using hazardous
organic solvents that makes this method an instrumental alternative to the previous
methodologies for the scale up of these oneꢀpot threeꢀcomponent reactions.Furthermore,
the catalyst is magneticallyseparable and eliminates the requirement of catalyst filtration
aftercompletion of the reaction, which represents a major advantage for reactions from an
economic and environmental point of view.In addition, the catalyst used is easily
1
3

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recovered by using a permanent magnet and reused without any noticeable loss of
activity after at least eight times.
4
. Experimental
Chemicals were purchased from Merck and Aldrich Chemical Companies. All the
solvents were distilled, dried and purified by standard procedures. Determination of the
purity of the substrate andmonitoring of the reaction were accomplished by thinꢀlayer
chromatography(TLC) on a silicaꢀgel polygram SILG/UV 254 plates. The NMR spectra
were recorded on a BrukerAvance DPX 250 MHz spectrometer (using DMSOꢀd or
6
CDCl with TMS as the standard). Fourier transform infrared spectroscopy (FTꢀIR)
3
analysis of the samples was taken on a Shimadzu FTꢀIR 8300 spectrophotometer and the
sample and KBr were pressed to form a tablet. Magnetic characterization was carried out
on a vibrating sample magnetometer (MeghnatisDaghighKavir Co., Iran) at room
temperature. Dynamic light scatterings (DLS) were recorded on a HORIBAꢀLB550.
Scanning electron microscopy (SEM) image was obtained on Philips XLꢀ
30ESEM.Sonication was performed using an ultrasound cleaning bath (KQꢀ250B, China)
with a frequency of 40 Hz and voltage of 220 V. The C, H, N and S elemental analyses
were carried out by the using a Thermofinigan Flash EAꢀ1112 CHNSO rapid elemental
analyzer. Melting points were determined by open capillary method and were
1
uncorrected. Therefore, all of the products were characterized by FTꢀIR, H NMR and
1
3
C NMR, and also by comparison with authentic samples.
4.1. General procedure
4
.1.1. Preparation of Fe O @SiO core-shell
3
4
2
The coreꢀshell Fe O @SiO nanospheres were prepared by a modified Stober method in
3
4
2
our previous work(Fig. 1) [64].
4
.1.2. Preparation of Fe O @SiO -imid
3 4 2
Fe O @SiO (1 g) was added to the solution of 3ꢀchlorotrieꢀ thoxypropylsilane (1 mmol,
3
4
2
0.241 g) and imidazole (1 mmol, 0.0680 g) in pꢀxylene (20 mL) and the resultant mixture
was under reflux for 24 h under nitrogen atmosphere. After refluxing for about 24 h, the
mixture was cooled to room temperature, filtered by an external magnet and the product
o
was washed with pꢀxylene to remove any reacted species and dried at 70 C for 6 h[38].
n
4
.1.3. Preparation of H PMo O nanoparticles (PMA )
3
12 40
1
4

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n
PMA nanoparticles were prepared in our previous work[34]. In a typicalprocedure, 5
b
mmol of bulk H PMo O (PMA ) was dispersedin 50 mL nꢀoctane and the resulting
3
12 40
dispersion was stirredvigorously for 30 min at room temperature to form a
homogeneousdispersion. This dispersion was transferred into a Teflonꢀlinedstainless
autoclave filling 80% of the total volume. Theautoclave was sealed and maintained at 150
o
C for 12 h. Theautoclave was then cooled to room temperature. Finally, theresulted
powder was filtered and washed for several times by octane, and dried in a vacuum at 80
o
C for 12 h(Fig. 1).
n
4
.1.4. Preparation of Fe O @SiO -imid-PMA
3 4 2
n
Fig. 1 represents the anchoring of PMA onto Fe O @SiO ꢀimid. Fe O @SiO ꢀimid (1.0
3
n
4
2
3
4
2
g) was added to an acetonitrile solution of PMA (1.0 mmol) in 20 mL was taken in a
roundꢀbottom flask. The mixture was refluxed for 24 h under nitrogen atmosphere. After
2
4 h, the mixture was filtered by an external magnet, washed with acetonitrile and
o
dichloromethane, and dried at 70 C for 6 h[38].
4.1.5. General procedure for the synthesis of tetrahydrobenzo[b]pyrans
A mixture of aromatic aldehyde (1 mmol), malononitrile (1.2 mmol), 5,5ꢀdimethylꢀ1,3ꢀ
n
cyclohexanedione (1 mmol) and Fe O @SiO ꢀimidꢀPMA catalyst (0.02 or 0.015 g) in
3
4
2
water (5 mL) was refluxed in an oil bath or sonicated at room temperature for an
appropriate period of time as indicated in Table 2. During the procedure, the reactionwas
monitored by TLC. Upon completion, the catalyst was removed by using a magneticfield.
Then, the resulting solid product was recrystallized from ethanol to give pure products in
high yields.
4.1.6. General procedure for the synthesis of 3,4-dihydropyrano[c]chromene derivatives
Amixture of malononitrile (1.2 mmol), aromatic aldehyde (1 mmol),4ꢀhydroxycoumarin
n
(
1 mmol) and Fe O @SiO ꢀimidꢀPMA catalyst(0.025 g) in water (5 mL)was refluxed in
3 4 2
an oil bath or sonicated at room temperature for an appropriate time as mentioned in
Table 4. The progress of the reactionwas monitored by TLC, for disappearance of
aldehyde. After completion of the reaction, the catalyst was removed by using a
magneticfield. Then, for the purification of the product, the precipitates were washed
with cold aqueous ethanol and recrystallized from ethanol to give the pure product.
Acknowledgements
1
5

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Authors are grateful to the council of Iran National ScienceFoundation and University of Shiraz
for their unending effort toprovide financial support to undertake this work.
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