Efficient synthesis of new pyrano[3,2-b]pyran derivatives via Fe3O4@SiO2-IL-Fc catalyzed three-component reaction

Article abstract of DOI:10.1515/hc-2017-0140

Ferrocene-containing ionic liquid supported on silica-coated Fe₃O₄ magnetic nanoparticles (nano Fe₃O₄@SiO₂-IL-Fc), a novel heterogeneous nanocatalyst, was synthesized. The structure of the catalyst was characterized by Fourier-transform infrared spectroscopy (FT-IR), X-ray diffraction patterns (XRD), energy-dispersive X-ray spectroscopy (EDX) and field emission scanning electron microscopy (FE-SEM). The novel nanomagnetic catalyst was used in the one-pot synthesis of pyrano[3,2-b]pyran derivatives by the three-component reaction of various aldehydes, malononitrile and kojic acid or chlorokojic acid at room temperature under ultrasonic irradiation. This new method has many advantages such as simplicity, short reaction times, high yields, easy workup and easy purification. Also, the nanocatalyst can be separated on an external magnet and reused for at least six consecutive runs without any significant loss of its catalytic activity.

Full text of DOI:10.1515/hc-2017-0140

Heterocycl. Commun. 2017; aop
REefzfaiTceiimeurni-Mtosfrayd*n, StohmeaysehisEsmoafti,nMeaswoumpehyRraabieni aond[3Ma,h2d-i Gbh]oplamyhroassneini-Nazari
derivatives via Fe3O4@SiO2-IL-Fc catalyzed three-
component reaction
https://doi.org/10.1515/hc-2017-0140
can act as excellent supports for various homogeneous
catalysts, and diverse organic transformations catalyzed
by supported MNPs have been reported [7]. Besides, sup-
ported ionic liquids (SILs) are an important class of het-
erogeneous catalysts and have many advantages over free
ILs, including a higher number of accessible active sites
on the catalyst, reduction in the amount of required IL and
improved recyclability of catalysts [8]. Ferrocene contain-
ing SILs have been synthesized and used in some organic
reactions [9, 10], but the development andꢀexpansion of
these types of catalysts needs more attention.
Pyran derivatives are important structural units of
many natural products and synthetic compounds which
possess a wide range of pharmacological and biological
activities such as anti-HIV [11], anticancer [12, 13], antimi-
crobial [14], antifungal [15], antidiabetic [16], antiviral and
anti-inflammatory [17] and antioxidant [18] properties,
among others [19–22]. Pyrano[3,2-b]pyrans are of great
interest in organic synthesis, and various methods using
different homogeneous and heterogeneous catalysts have
Received July 6, 2017; accepted August 21, 2017
Abstract: Ferrocene-containing ionic liquid supported on
silica-coated Fe3O4 magnetic nanoparticles (nano Fe3O4@
SiO2-IL-Fc), a novel heterogeneous nanocatalyst, was
synthesized. The structure of the catalyst was character-
ized by Fourier-transform infrared spectroscopy (FT-IR),
X-ray diffraction patterns (XRD), energy-dispersive X-ray
spectroscopy (EDX) and field emission scanning electron
microscopy (FE-SEM). The novel nanomagnetic catalyst
was used in the one-pot synthesis of pyrano[3,2-b]pyran
derivatives by the three-component reaction of various
aldehydes, malononitrile and kojic acid or chlorokojic
acid at room temperature under ultrasonic irradiation.
This new method has many advantages such as simplicity,
short reaction times, high yields, easy workup and easy
purification. Also, the nanocatalyst can be separated on
an external magnet and reused for at least six consecutive
runs without any significant loss of its catalytic activity.
Keywords: ferrocene; heterogeneous catalysis; multicom- been reported for the preparation of these compounds
ponent reaction; nanostructures; pyrano[3,2-b]pyran; and analogues [23–29].
supported ionic liquids.
In continuation of our research on the synthesis and
applications of ferrocene derivatives [30, 31] and the devel-
opment of multicomponent reactions [32–35], herein we
report the design and synthesis of novel ferrocene labeled
ionic liquid supported on MNPs as an efficient catalyst for
the synthesis of a series of pyrano[3,2-b]pyran derivatives
under ultrasound irradiation.
Introduction
Synthesis of efficient and recyclable catalysts has been
an increasingly important goal for chemists and material
scientists for both economic and environmental reasons
[1, 2]. In this regard, magnetic nanoparticles (MNPs) have
been widely used as catalysts due to their high surface
area, easy synthesis and functionalization, good stability,
low toxicity and facile separation by an external magnetic
force [3–6]. Recent investigations have revealed that MNPs
Results and discussion
The ferrocene functionalized ionic liquid supported
on magnetic nanoparticle (Fe3O4@SiO2-IL-Fc) as the
catalyst was prepared according to Scheme 1. A chemi-
cal co-precipitation method was used for the prepa-
ration of nanomagnetite (Fe3O4). Subsequently, Fe3O4
nanoparticles were covered with silica (Fe3O4@SiO2)
using the Stober method [36]. The silica-coated MNPs
were subsequently allowed to react with (3-chloro-
propyl)triethoxysilane to obtain the functionalized
*Corresponding author: Reza Teimuri-Mofrad, Department of
Organic and Biochemistry, Faculty of Chemistry, University of Tabriz,
Tabriz 5166614766, Iran, e-mail: teymouri@tabrizu.ac.ir
Somayeh Esmati, Masoumeh Rabiei and Mahdi Gholamhosseini-
Nazari: Department of Organic and Biochemistry, Faculty of
Chemistry, University of Tabriz, Tabriz 5166614766, Iran
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2ꢀ
ꢀR. Teimuri-Mofrad et al.: Synthesis of pyrano[3,2-b]pyrans
FeCl2 4H2O
FeCl3 6H2O
NH4OH
SiO2
Si(OEt)4
Fe3O4
Fe3O4
EtOH, 24 h
SiO2
MeO
N
NH
Si
Cl
Cl
Fe3O4
MeO
MeO
Fe
Toluene
∆, 24 h
NaH/THF
∆, 12 h
SiO2
Fe3O4
O
O
N
N
Si
Cl
Fe
OMe
Toluene
80°C, 72 h
SiO2
Fe3O4
O
Si
N
N
Fe
O
OMe
Cl
Scheme 1ꢀPreparation of Fe3O4@SiO2-IL-Fc nanocatalyst.
nanoparticles. Then, 1-(4-ferrocenylbutyl)-1H-imidazole nanocatalyst. The XRD pattern of Fe3O4@SiO2-IL-Fc is
was prepared by the reaction of imidazole with 4-chlo- the same as that of Fe3O4 and shows diffraction peaks at
robutylferrocene. Finally, ferrocene containing ionic 2θꢀ=ꢀ30.4°, 35.7°, 43.3°, 53.9°, 57.3° and 63.0°. These results
liquid supported on MNPs was synthesized by the reac- indicate that the functionalization process did not induce
tion of chloropropyl functionalized silica-coated MNPs any phase change of Fe3O4. The surface morphology of the
with 1-(4-ferrocenylbutyl)-1H-imidazole.
nanoparticles was investigated by field emission scan-
The nanomagnetic Fe3O4 particles show the IR absorp- ning electron microscopy (FE-SEM) analysis. The FE-SEM
tion peak at about 572 cm−1 which is related to Fe-O bond images show that the particles are uniformly distributed
vibrations. The Fe3O4@SiO2-propyl chloride core-shell and the sizes of MNPs are under 60 nm.
MNPs show the Fe-O and Si-O-Si bonds IR vibrations, and
For optimization of the catalyst and reaction condi-
the absorption peak at 2925 cm−1 is related to the asymmet- tions, the reaction of 4-methylbenzaldehyde (1 mmol),
ric stretching vibration of aliphatic C-H moieties. Finally, malononitrile (1.2 mmol) and kojic acid (1 mmol) was
in the infrared (IR) spectrum of the Fe3O4@SiO2-IL-Fc selected. Initially, the model reaction was examined with
MNPs, absorption peak above 3000 cm−1 is related to the some catalysts including typical ILs, ferrocene labeled
stretching vibration of aromatic C-H moieties of imidazole IL and newly synthesized Fe3O4@SiO2-IL-Fc nanocata-
and ferrocene groups. The absorption peak at 1644 and lyst under solvent-free conditions at 80°C. It was found
1385 cm−1 are linked to the stretching vibrations of C=N that Fe3O4@SiO2-IL-Fc shows the best catalytic activity.
and C=C bonds of aromatic rings.
Different solvents including CH2Cl2, CH3CN, EtOH and
The energy-dispersive X-ray spectrum of the Fe3O4@ H2O were examined in the presence of Fe3O4@SiO2-IL-
SiO2-IL-Fc nanocatalyst is consistent with the presence of Fc as catalyst. For the reaction conducted in ethanol or
the expected elements (Fe, Cl, Si, O, N and C) in the struc- aqueous ethanol the product 4a is obtained rapidly and
ture. The X-ray diffraction (XRD) analyses illustrate the in high yield. However, the best yield of 95% is obtained
degree of crystallinity of the synthesized Fe3O4@SiO2-IL-Fc in aqueous ethanol containing 30% of water under
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ꢁꢀꢀꢀ
R. Teimuri-Mofrad et al.: Synthesis of pyrano[3,2-b]pyransꢂ ꢂ3
ultrasonic irradiation. The amount of the catalyst under
A possible mechanism for the Fe3O4@SiO2-IL-Fc cata-
optimized conditions is 6 mg per 1 mmol of the aldehyde. lyzed condensation reaction is proposed in Scheme 4. The
Different aromatic aldehydes were allowed to react under first step is the Knoevenagel condensation of aromatic
this optimal procedure with ultrasonic irradiation. The aldehyde and malononitrile to generate the intermedi-
results are summarized in Scheme 2. The reactions of aro- ate product (A). Then, the Michael addition of (chloro)
matic aldehydes with both electron-releasing and elec- kojic acid enolate (B) with (A) furnishes an intermedi-
tron-withdrawing substituents furnish the corresponding ate product (C), which undergoes cyclization to (D). The
2-aminopyrano[3,2-b]pyrans 4 in good to high yields intermediate product (D) is a direct precursor to the final
under the optimized conditions. Aldehydes with electron- pyrano[3,2-b]pyran product.
withdrawing substituents react more rapidly, while elec-
tron donating substituents decrease the reactivity and the investigated using the model reaction leading to 4a. After
reactions are completed at longer reaction times. completion of the reaction, the catalyst was separated
The reusability of the magnetic nanocatalyst was
Chlorokojic acid (5) was also subjected to this reaction with an external magnet. The collected nanocatalyst was
under optimized conditions and the target compounds 6a–f repeatedly washed with EtOH prior to use in the next
were synthesized in high yields (Scheme 3). All products 4 round of catalysis. The catalyst exhibited a consistent
1
and 6 were characterized by melting points, IR, H nuclear activity up to the sixth consecutive cycle. Specifically, the
magnetic resonance (NMR), 13C NMR and elemental analysis. yield of 4a of 95% after the first cycle was only lowered
O
HO
O
NC
NC
H2N
NC
O
Fe3O4@SiO2-IL-Fc
OH
O
3
OH
2
EtOH/H2O (70:30), )))
O
O
H
Ar
4a–l
1a–l
Ar
4a: Ar = p-tolyl (95%, 10 min); mp 204–206 [37]
4b: Ar = phenyl (91%, 10 min); mp 220–222 [25]
4g: Ar = 4-bromophenyl (90%, 10 min); mp 224–226 [37]
4h: Ar = 4-methoxyphenyl (81%, 15 min); mp 220–223 [37]
4c: Ar = 4-fluorophenyl (93%, 10 min); mp 248–250 [25] 4i: Ar = 3-nitrophenyl (96%, 10 min); mp 215–217 [37]
4d: Ar = 2-chloropheny (87%, 15 min); mp 201–203 [37] 4j: Ar = pyridin-4-yl (85%, 15 min); mp 233–235 [25]
4e: Ar = 4-chlorophenyl (95%, 10 min); mp 198–200 [37] 4k: Ar = thiophen-2-yl (83%, 15 min); mp 235–237 [25]
4f: Ar = 3-bromophenyl (89%, 10 min); mp 242–244 [25] 4l: Ar = furan-2-yl (82%, 15 min); mp 223–225 [25]
Scheme 2ꢀFe3O4@SiO2-IL-Fc catalyzed three-component synthesis of pyrano[3,2-b]pyran derivatives in EtOH/H2O (70:30) at room tempera-
ture under ultrasonic irradiation.
O
HO
NC
NC
O
6a: Ar = 4-isopropylphenyl (90%, 10 min)
6b: Ar =p-tolyl (90%, 10 min)
H2N
NC
O
Cl
Fe3O4@SiO2-IL-Fc
O
6c: Ar = 4-nitrophenyl (95%, 5 min)
6d: Ar = 3-nitrophenyl (92%, 5 min)
6e: Ar = 4-chlorophenyl (95%, 8 min)
6f: Ar = thiophen-2-yl (88%, 10 min)
3
5
Cl
EtOH/H2O (70:30), )))
O
O
H
Ar
6a–f
1a–f
Ar
Scheme 3ꢀSynthesis of pyrano[3,2-b]pyran derivatives 6a–f.
CH2(CN)2
Ar
H
Ar
H
Knoevenagel
condensation
O
NC
CN
A
Michael addition
O
O
O
O
O
O
O
O
OH
O
O
N
O
NH2
CN
O
NH
CN
+H
C
Cl
Cl
Cl
Cl
Cl
CN
O
–H
O
H
H
H
Ar H
Ar
Ar
6
B
C
D
H
H
Scheme 4ꢀProposed mechanism for the Fe3O4@SiO2-IL-Fc catalyzed three-component reaction.
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4ꢀ ꢀR. Teimuri-Mofrad et al.: Synthesis of pyrano[3,2-b]pyrans
filtered, washed with toluene (3ꢀ×ꢀ20 mL), MeOH (3ꢀ×ꢀ20 mL), CH2Cl2
(3ꢀ×ꢀ20 mL) and dried under reduced pressure at 50°C for 48 h to
afford Fe3O4@SiO2-IL-Fc.
to 90% after the sixth cycle and the initial reaction time
of 10 min had to be increased to 12 min to complete the
reaction.
General procedure for the synthesis of pyrano[3,2-b]
pyrans 4a–l and 6a–f
Conclusion
A simple, rapid and efficient method for the three-com-
ponent synthesis of pyrano[3,2-b]pyran derivatives using
a novel Fe3O4 supported ionic liquid phase catalyst with a
ferrocenyl group under ultrasonic irradiation was devel-
oped. The protocol provides a practical benefit of facile
removal of the catalyst that can subsequently be reused.
A 50-mL flask was charged with aldehyde (1 mmol), malononitrile
(1.2 mmol), kojic acid or chlorokojic acid (1 mmol) and Fe3O4@SiO2-
IL-Fc nanocatalyst (6 mg) in 3 mL EtOH/H2O (70:30). The mixture was
sonicated at 25°C. When the reaction was completed [monitored by
thin layer chromatography (TLC), using n-hexane/ethyl acetate (3:1)
as eluent], the catalyst was separated using an external magnet and
the reaction mixture was cooled and the precipitate was filtered,
washed and dried. The crude product was crystallized from ethanol.
The structures of new compounds 6a–f were characterized by IR, 1H
NMR, 13C NMR and CHN analysis. The spectra for 4a–l were virtually
identical with those reported (Scheme 2).
Experimental
Melting points were measured with a MEL-TEMP model 1202D. Fourier
transform infrared (FT-R) spectra were recorded on a Bruker Tensor
27 spectrometer using KBr disks. The 1H NMR spectra (400 MHz) were
determined with a Bruker Spectrospin Avance 400 spectrometer with
DMSO-d6 as a solvent and tetramethylsilane (TMS) as an internal
standard. 13C NMR spectra were recorded on the same instrument at
100 MHz. Elemental analyses were performed on a Vario EL III ana-
lyzer. Sonication was performed using a Hielscher (UP400s) ultra-
sonic probe system at a frequency of 24 KHz. XRD patterns of samples
were taken on a Siemens D500 X-ray powder diffraction diffractome-
ter (CuK radiation, λꢀ=ꢀ1.5406 Å). FE-SEM images of the products were
visualized with a TESCAN MIRA3 FE-SEM.
2-Amino-6-(chloromethyl)-4-(4-isopropylphenyl)-8-oxo-4,8-di-
hydropyrano[3,2-b]pyran-3-carbonitrile (6a)ꢁWhite powder; mp
207–209°C; IR: 3379, 3290, 3027, 2960, 2199, 1647, 1598 cm−1; 1H NMR:
δ 1.18 (d, 6H, Jꢀ=ꢀ6.47 Hz, 2CH3), 2.84–2.90 (m, 1H, CH), 4.52–4.60 (m,
2H, CH2), 4.78 (s, 1H, methin-H), 6.59 (s, 1H, Ar-H), 7.18–7.27 (m, 6H,
NH2, Ar-H); 13C NMR: δ 23.8, 33.1, 40.8, 41.2, 55.7, 114.9, 119.4, 126.9,
127.6, 136.5, 138.3, 148.0, 150.0, 159.2, 161.9, 169.6. Anal. Calcd for
C19H17ClN2O3: C, 63.96; H, 4.80; N, 7.85. Found: C, 63.71; H, 4.84; N, 7.89.
2-Amino-6-(chloromethyl)-8-oxo-4-(p-tolyl)-4,8-dihydropyrano
[3,2-b]pyran-3-carbonitrile (6b)ꢁWhite powder; mp 236–238°C; IR:
1
3376, 3322, 3017, 2953, 2200, 1647, 1599 cm−1; H NMR: δ 2.28 (s, 3H,
CH3), 4.51–4.59 (m, 2H, CH2), 4.78 (s, 1H, methin-H), 6.59 (s, 1H, Ar-H),
7.16 -7.21 (m, 4H, Ar-H), 7.25 (s, 2H, NH2); 13C NMR: δ 20.6, 39.6, 40.8,
55.7, 114.9, 119.2, 127.6, 129.5, 136.5, 137.1, 137.6, 149.9, 159.1, 161.8,169.4.
Anal. Calcd for C17H13ClN2O3: C, 62.11; H, 3.99; N, 8.52. Found: C, 61.88;
H, 4.03; N, 8.57.
Synthesis of 1-(4-ferrocenylbutyl)-1H-imidazole
To a suspension of NaH (60%, 0.80 g, 20 mmol) in dry THF (100 mL),
imidazole (1.36 g, 20 mmol) was added and the mixture was stirred at
0°C for 1 h. Then, 4-chlorobutylferrocene (1.38 g, 5 mmol) was added
and the mixture was heated under reflux for 12 h. After cooling, the
excess amount of NaH was quenched by the addition of water. After
extraction with dichloromethane, the extract was concentrated and
the residue was subjected to silica column chromatography eluting
with n-hexane/ethyl acetate, 9:1, to give 1-(4-ferrocenylbutyl)-1H-im-
idazole as brown viscous oil; IR: 3394, 2859, 1506, 1453, 1105, 1228,
1000, 650, 486 cm−1; 1H NMR: δ 1.42–1.49 (m, 2H, -CH2-), 1.75–1.78 (m,
2H, -CH2-), 2.34 (t, Jꢀ=ꢀ7.5 Hz, 2H, -CH2-), 3.90 (t, Jꢀ=ꢀ6.6 Hz, 2H, -CH2-),
4.00–4.03 (m, 4H, Cp-H), 4.06 (s, 5H, Cp-H), 6.98–7.26 (m, 2H,
imid-H), 7. 49 (s, 1H, imid-H); 13C NMR: δ 27.0, 28.0, 29.7, 45.9, 66.1,
66.9, 67.3, 87.0, 118.2, 128.7, 136.6 ppm.
2-Amino-6-(chloromethyl)-4-(4-nitrophenyl)-8-oxo-4,8-dihy-
dropyrano[3,2-b]pyran-3-carbonitrile (6c)ꢁWhite powder; mp
193–195°C ; IR: 3400, 3300, 3084, 2924, 2197, 1642, 1591 cm−1; 1H NMR:
δ 4.51–4.59 (m, 2H, CH2), 5.14 (s, 1H, methin-H), 6.62 (s, 1H, Ar-H), 7.42
(s, 2H, NH2), 7.64 (d, 2H, Jꢀ=ꢀ8.23 Hz, Ar-H), 8.26 (d, 2H, Jꢀ=ꢀ8.23 Hz,
Ar-H); 13C NMR: δ 39.6, 40.8, 55.2, 114.9, 119.0, 128.9, 129.8, 132.6, 136.6,
139.5, 149.2, 159.1, 161.8, 169.4. Anal. Calcd for C16H10ClN3O5: C, 53.42; H,
2.80; N, 11.68. Found: C, 53.18; H, 2.83; N, 11.72.
2-Amino-6-(chloromethyl)-4-(3-nitrophenyl)-8-oxo-4,8-dihy-
dropyrano[3,2-b]pyran-3-carbonitrile (6d)ꢁWhite powder; mp
1
208–210°C ; IR: 3395, 3325, 3080, 2957, 2191, 1638, 1597 cm−1; H NMR:
δ 4.51–4.60 (m, 2H, CH2), 5.19 (s, 1H, methin-H), 6.62 (s, 1H, Ar-H), 7.43
(s, 2H, NH2), 7.71 (t, 1H, Jꢀ=ꢀ5.5 Hz, Ar-H), 7.83 (d, 1H, Jꢀ=ꢀ7.67 Hz, Ar-H),
8.21 (m, 2H, Ar-H); 13C NMR: δ 39.6, 40.8, 54.5, 115.0, 119.0, 122.7, 123.1,
130.7, 134.8, 136.8, 142.6, 148.0, 148.5, 159.4, 161.9, 169.5. Anal. Calcd for
C16H10ClN3O5: C, 53.42; H, 2.80; N, 11.68. Found: C, 53.15; H, 2.84; N, 11.73.
Synthesis of Fe3O4@SiO2-IL-Fc
Fe3O4@SiO2-propyl chloride nanoparticales were prepared as previ-
ously reported [38, 39]. Then, a mixture of Fe3O4@SiO2-(CH2)3Cl (1.0 g)
and 1-(4-ferrocenylbutyl)-1H-imidazole (0.92 g, 3 mmol) in 10 mL of
toluene was heated at 80°C in an oil bath. After 72 h, the residue was
2-Amino-6-(chloromethyl)-4-(4-chlorophenyl)-8-oxo-4,8-dihy-
dropyrano[3,2-b]pyran-3-carbonitrile (6e)ꢁWhite powder; mp
217–219°C; IR: 3374, 3312, 3028, 2958, 2198, 1641, 1594 cm−1; 1H NMR: δ
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4.52–4.59 (m, 2H, CH2), 4.91 (s, 1H, methin-H), 6.60 (s, 1H, Ar-H), 7.32– [11] He, M.; Yang, N.; Sun, C.; Yao, X.; Yang, M. Modification and
7.36 (m, 4H, Ar-H and NH2), 7.46 (d, 2H, Jꢀ=ꢀ8.34 Hz, Ar-H); 13C NMR: δ
39.6, 40.7, 55.2, 114.9, 119.0, 128.9, 129.8, 132.6, 136.6, 139.5, 149.2, 159.1,
161.8, 169.4. Anal. Calcd for C16H10Cl2N2O3: C, 55.04; H, 2.89; N, 8.02.
Found: C, 54.85; H, 2.92; N, 8.10.
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dropyrano[3,2-b]pyran-3-carbonitrile (6f)ꢁWhite powder; mp
190–192°C ; IR: 3381, 3312, 3028, 2925, 2200, 1640, 1598 cm−1; 1H NMR:
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126.1, 126.4, 127.3, 135.9, 144.6, 149.1, 159.3, 161.9, 169.4. Anal. Calcd for
C14H9ClN2O3S: C, 52.43; H, 2.83; N, 8.73. Found: C, 52.19; H, 2.87; N,
8.80.
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