One‐pot and green synthesis 1H-pyrazolo[1,2-b]phthalazine-5,10-dione and dihydropyrano[3,2-c]chromene derivatives by Fe3O4@SiO2-imine/phenoxy-Cu(II) as an efficient and reusable catalyst

Article abstract of DOI:10.1007/s11164-021-04498-4

In the current study, magnetite-silica core–shell nanoparticles modified with Cu-salen complex (Fe₃O₄@SiO₂-imine/phenoxy-Cu(II)) was utilized as a heterogeneous catalyst for the one-pot multicomponent synthesis of 1H-pyraz

Full text of DOI:10.1007/s11164-021-04498-4

Research on Chemical Intermediates
https://doi.org/10.1007/s11164-021-04498-4
One‐pot and green synthesis 1H‑pyrazolo[1,2‑b]
phthalazine‑5,10‑dione and dihydropyrano[3,2‑c]
chromene derivatives by Fe3O4@SiO2‑imine/
phenoxy‑Cu(II) as an efcient and reusable catalyst
Milad Nesarvand1 · Davood Azarifar1 · Hakimeh Ebrahimiasl1
Received: 6 February 2021 / Accepted: 18 May 2021
© The Author(s), under exclusive licence to Springer Nature B.V. 2021
Abstract
In the current study, magnetite-silica core–shell nanoparticles modifed with Cu-
salen complex (Fe3O4@SiO2-imine/phenoxy-Cu(II)) was utilized as a heterogeneous
catalyst for the one-pot multicomponent synthesis of 1H-pyrazolo[1,2-b]phthala-
zine-5,10-dione and dihydropyrano[3,2-c]chromene derivatives under solvent-free
conditions, without using any harmful organic reagents/solvent. The current syn-
thetic protocol demonstrates that the reactions proceeds to completing step, leading
to the successful synthesis of high purity compounds. Advantages of this method
include easy purifcation, reusability of the catalyst, green and mild procedure and
synthesis of new derivatives in high yields within short reaction time.
Keywords Green chemistry · Magnetic nanoparticles · 1H-pyrazolo[1,2-b]
phthalazine-5,10-dione · dihydropyrano[3,2-c]chromene
Introduction
The synthesis of new heterocyclic compounds is of paramount importance,
because of their abundance, pharmaceutical and industrial applications [1]. So
far, many methods have been proposed to synthesize these compounds. In the
last two decades, multi-component reactions (MCRs) have become a powerful,
rapid and efcient approach for the synthesis of heterocyclic compounds [2–7].
The utilization of MCRs ofers several advantages such as increased reaction rate,
* Hakimeh Ebrahimiasl
h_ebrahimiasl64@yahoo.com
Davood Azarifar
azarifar@basu.ac.ir
1
Department of Organic Chemistry, Faculty of Chemistry, Bu-Ali Sina University,
6517838683 Hamedan, Iran
Vol.:(0123456789)
1 3

M. Nesarvand et al.
reduction of time, high atom economy and avoidance of complicated purifcation
processes. These benefts make MCRs a considerable method for the synthesis of
complex heterocyclic compounds [8]. One the key driving forces of the MCRs is
the utilization of heterogeneous recyclable catalysts, that very recently, the eforts
have been directed to surface and structural modifcation of the heterogeneous
catalysts by using the recent trends in the nanoarchitecture [9–16].
1H-pyrazolo[1,2-b]phthalazine-5,10-dione and dihydropyrano[3,2-c]chromene
derivatives are two crucial classes of heterocycles for which several synthetic
methods have been developed for the synthesis of their derivatives. Their bio-
logical and pharmacological properties and thus, their clinical applications
are the notable reasons for the interest in these compounds [17–23]. Anti-con-
vulsant, vasorelaxant, cardiotonic, antipyretic, anti-infammatory, anticancer,
antifungal and antibacterial activities are some examples of biological proper-
ties of 1H-pyrazolo[1,2-b]phthalazine-5,10-dione derivatives [24–27]. Also,
dihydropyrano[3,2-c]chromenes are well known for anti-anaphylactic, antitumor,
antimicrobial, anti-tuberculosis agents, analgesic, anti-cancer and anticoagulant
activities [28–31]. Owing to all the above-mentioned importance and applica-
tions of these compounds, it is of primary importance to fnd the superior synthe-
sis approaches for them by scientists. So far, innumerable approaches have been
proposed by researchers for the manufacture of these compounds, among which
there is a commonly employed strategy which consists of one-pot three-compo-
nent reaction. This reaction has been studied with diferent catalysts and condi-
tions. As an illustration, in 2019, 1H-pyrazolo[1,2-b]phthalazine-5,10-dione was
synthesized by Pati et al. using CuO nanoparticles as a reusable catalyst under
solvent-free conditions [32]. Piltan et al. in 2017, synthesized 1H-pyrazolo[1,2-b]
phthalazine-5,10-dione using the ZrO2 nanoparticles as a catalyst, at 100 °C and
under solvent-free conditions [2–7]. In 2019, dihydropyrano[3,2-c]chromenes
derivatives were synthesized by Hallaoui et al. using Co3(PO4)2 as a catalyst at
80 °C. This reaction was performed in a mixture of water/ethanol (4:1) [33]. In
another research work, Sharma et al. in 2018, reported the new derivatives of
dihydropyrano[3,2-c]chromenes at 80 °C in the presence of [Bmim] Sac as a
non-toxic and green ionic liquid in aqueous media [34]. In the last few decades,
magnetic nanoparticles (MNPs) have attracted a lot of attention as sustainable
and efcient catalysts for multi-component reactions (MCRs) due to their features
such as large surface to volume ratio, high thermal stability, chemical stability,
easy magnetic separation and high potential of recyclability.
Given the fact that we have recently introduced Copper‐based Schif Base
Complex Immobilized on Core‐shell Fe3O4@SiO2 as a magnetically recyclable
and highly efcient nanocatalyst for green synthesis of 2‐amino‐4H‐chromene
derivatives [35], in this article, we have presented another important applica-
tion of Fe3O4@SiO2-Imine/Phenoxy-Cu(II) catalyst as an efcient, low price,
safe, catalytic performance and magnetic powerful solid acid catalyst for one-pot
synthesis of 1H-pyrazolo[1,2-b]phthalazine-5,10-dione and dihydropyrano[3,2-
c]chromenes. The schematic illustration of the synthesis route is exhibited in
Scheme 1.
1 3

One‐pot and green synthesis…
Scheme 1 One-pot synthesis of 1H-pyrazolo[1,2-b]phthalazine-5,10-dione and dihydropyrano[3,2-c]
chromenes
Experimental
Chemicals and instruments
All chemicals were purchased from Merck and Fluka Companies. 1H NMR and 13
C
NMR spectra were measured on a spectrometer at 250, 400, 300, 90 MHz and 62.5,
100, 75 MHz, respectively, in DMSO-d6. Fourier transform infrared (FT-IR) spec-
tra were obtained using the Shimadzu 435-U-04 FT spectrophotometer from KBr
pellets. Melting points were recorded on a BUCHI 510 apparatus in open capillary
tubes.
Preparation of Fe3O4–SiO2–(CH2)3–1,3‑Phenylenediamine‑Schif base Complex
of Cu(II)
Magnetic Fe3O4 nanoparticles were synthesized via co-precipitation of solu-
tions containing Fe3+ and Fe2+ ions [36]. FeCl3·6H2O (11.3 g, 0.0418 mol) and
FeCl2·4H2O (5.648 g, 0.0209 mol) were dissolved in 100 ml of deionized water. The
mixture was stirred at 85 °C for 30 min, and then 25 ml of ammonia (28% aque-
ous solution) was added rapidly to the reaction mixture. The reaction was stirred for
another 30 min at 85 °C. Then, the black Fe3O4 nanoparticles were separated with an
external magnet. They were washed with distilled water followed by EtOH and dried
1 3

M. Nesarvand et al.
at 80 °C in an oven. Then, 1.0 g of the MNPs was dispersed in a mixture of 80 ml of
deionized water, 20 ml of EtOH and 2.0 ml of ammonia (28 wt%), and then 2.0 mL
of tetraethyl orthosilicate (TEOS) was added to the mixture and stirred at 50 °C for
2 h. The core–shell MNPs (Fe3O4@SiO2 MNPs) were separated using a magnet and
washed with deionized water, EtOH, and then dried in an oven [37]. In the follow-
ing, Fe3O4@SiO2–functionalized Cl was synthesized via surface reaction of Fe3O4@
SiO2 using (3‐chloropropyl) triethoxysilane as the silylation agent. 1.0 g of Fe3O4@
SiO2 and 50.0 ml of toluene were mixed into a 250 ml round fask. Then, (3 Chloro-
propyl)triethoxysilane (2.0 ml) was added to the mixture and refuxed at 110 °C with
stirring for 12 h. In the end, Fe3O4@SiO2@Cl MNPs were separated by a magnet
and washed with toluene and EtOH several times. Finally, the product was dried in
an oven. Then, for Synthesis of Fe3O4@SiO2–(CH2)3–NH–(3-NH2C6H4) MNPs,1,
3-phenylenediamine (1.3 g, 0.012 mol) and a few drops of triethylamine as a base
were dissolved in ethanol (70 ml). Then Fe3O4@SiO2–(CH2)3–Cl (1 g) was added
to the mixture and dispersed (15 min). The resulting mixture was refuxed in N2 for
24 h. After refuxing, the fnal precipitate was separated with a magnet, washed sev-
eral times with ethanol and dried at room temperature. For the synthesis of Fe3O4@
SiO2- iminomethyl/phenol,at First, Fe3O4@SiO2–(CH2)3–NH–(3-NH2C6H4) nano-
particles (1 g) was dispersed in 50 ml of methanol (15 min) and refuxed. Then,
salicylaldehyde (2.93 g, 24 mmol) was dissolved in ethanol (30 ml) and added drop-
wise to the nanoparticles using a decanter funnel. The reaction mixture was refuxed
for 24 h and the product was separated using a magnet, washed several times with
ethanol, and dried in an oven. Finally, 1 g from the previously synthesized nanopar-
ticles was dispersed in 50 ml ethanol (15 min). Then 5% (w/v) solution of Cu(OAc)2
in ethanol (5 ml) was added dropwise to the previous mixture and the resulting mix-
ture was refuxed for 48 h. After the reaction completed, the product was separated
using the magnet, washed with 50 ml ethanol and water to remove the remaining
unreacted materials and dried in an oven. The resulted Fe3O4@SiO2‐imine/phenoxy‐
Cu(II) magnetic nanoparticles (MNPs) were characterized by various techniques
including SEM, TEM, XRD, XPS, EDX, VSM, FT‐IR and ICP [35].
General procedure for the synthesis of 1H‑pyrazolo[1,2‑b]phthalazine‑5,10‑dione
derivatives
Under the optimum reaction conditions, phthalhydrazide (1 mmol), malononi-
trile (1 mmol), aldehyde (1 mmol) and the catalyst (0.02 g) were added to a test
tube. The mixture was stirred magnetically and heated at 80 °C under solvent-
free conditions. After completion of the reaction (judged by the TLC (n-hexane/
ethyl acetate 10:3)), 10 ml of hot ethanol was added to the reaction mixture and
the catalyst was separated using an external magnet. Then, 20 ml of distilled
water was added to the reaction mixture and precipitated product isolated by
fltration. The product was washed with NaOH (0.5 mol) to produce a pure prod-
uct. The product was characterized using physical and spectroscopic data (FTIR,
NMR and MS).
1 3

One‐pot and green synthesis…
General procedure for the synthesis of dihydropyrano[3,2‑c]chromene derivatives
Under the optimum reaction conditions, 4-hydroxycoumarin (1 mmol), malononi-
trile (1 mmol), aldehyde (1 mmol) and 0.03 g catalyst were added to a test tube. The
mixture was stirred magnetically and heated at 90 °C under solvent-free conditions.
After completion of the reaction (by the TLC (n-hexane/ethyl acetate 7:4)), 10 ml
of hot ethanol was added to the reaction mixture and the catalyst separated using
an external magnet. Then, 20 ml distilled water was added to the reaction mixture
and precipitated product isolated by fltration. The product was washed with NaOH
(0.5 mol) to produce a pure product. The product was characterized using physical
and spectroscopic data (FT-IR, NMR and MS).
Analytical data of selected products
3-amino-5,10-dioxo-1-phenyl-5,10-dihydro-1H-pyrazolo[1,2-b]phthalazine-
2-carbonitrile (4a) Yellow solid; mp 249–251 °C. FT-IR (KBr, cm−1): 3361,
1
3260, 2197, 1682, 1660. H NMR (90 MHz, DMSO-d6, δ ppm): 6.12 (s, 1H, CH),
7.31–7.87 (m, 9H, Ar–H), 8.29 (t, 2H, NH2). 13C NMR (75 MHz, DMSO-d6, δ
ppm): 61.4, 62.9, 116.2, 126.5, 126.6, 127.3, 128.1, 128.5, 128.6, 128.7, 133.6,
134.7, 138.4, 150.6, 153.7, 156.5 ppm.
3-amino-1-(naphthalen-1-yl)-5,10-dioxo-5,10-dihydro-1H-pyrazolo[1,2-b]
phthalazine-2-carbonitrile (4b) Yellow solid; mp 275–276 °C. FT-IR (KBr, cm−1):
3365, 3260, 2192, 1682, 1655. 1H NMR (300 MHz, DMSO-d6, δ ppm): 6.27 (s, 1H,
CH), 7.50–8.28 (m, 11H, Ar–H), 8.29 (t, 2H, NH2). 13C NMR (75 MHz, DMSO-
d6, δ ppm): 61.3, 63.2, 116.0, 124.2, 125.0, 125.1, 126.3, 126.6, 126.9, 127.5,
127.7, 127.9, 128.4, 128.7, 128.9, 132.8, 132.9, 133.6, 134.5, 135.8, 150.7, 153.8,
156.7 ppm.
3-amino-1-(naphthalen-2-yl)-5,10-dioxo-5,10-dihydro-1H-pyrazolo[1,2-b]
phthalazine-2-carbonitrile (4c) Yellow solid; mp 265–269 °C. FT-IR (KBr, cm−1):
3367, 3258, 2192, 1682, 1655. 1H NMR (250 MHz, DMSO-d6, δ ppm): 6.27 (s, 1H,
CH), 7.51–8.13 (m, 11H, Ar–H), 8.25 (t, 2H, NH2).
3-amino-1-(2,4-dichlorophenyl)-5,10-dioxo-5,10-dihydro-1H-pyrazolo[1,2-b]
phthalazine-2-carbonitrile (4d) Yellow solid; mp 230–234 °C. FT-IR (KBr, cm−1):
3370, 3260, 2204, 1676, 1632, 698. 1H NMR (90 MHz, DMSO-d6, δ ppm): 6.35 (s,
1H, CH), 7.43–7.90 (m, 7H, Ar–H), 8.45 (t, 2H, NH2). 13C NMR (75 MHz, DMSO-
d6, δ ppm): 59.7, 60.6, 116.1, 125.5, 127.2, 127.9, 128.7, 128.7, 128.8, 129.3, 129.7,
132.7, 133.0, 134.0, 134.3, 135.0, 151.3, 154.1, 157.2 ppm.
3-amino-1-(4-chloro-3-nitrophenyl)-5,10-dioxo-5,10-dihydro-1H-
pyrazolo[1,2-b]phthalazine-2-carbonitrile (4e) Yellow solid; mp 262–264 °C.
1
FT-IR (KBr, cm−1): 3364, 3299, 2190, 1682, 1662, 1567, 1383, 693. H NMR
(250 MHz, DMSO-d6, δ ppm): 6.24 (s, 1H, CH), 7.78–8.18 (m, 7H, Ar–H), 8.29 (t,
2H, NH2). 13C NMR (62 MHz, DMSO-d6, δ ppm): 60.5, 62.0, 116.2, 124.1, 124.8,
127.1, 127.6, 128.8, 129.5, 132.0, 132.7, 134.2, 135.0, 140.3, 148.4, 151.5, 154.2,
157.2. MS: m/z: 395, 239, 217, 187, 162, 130, 104, 76, 50 [M+H]+.
1 3

M. Nesarvand et al.
3-amino-5,10-dioxo-1-(3,4,5-trimethoxyphenyl)-5,10-dihydro-1H-
pyrazolo[1,2-b]phthalazine-2-carbonitrile (4f) Yellow solid; mp 253–256 °C.
1
FT-IR (KBr, cm−1): 3372, 3295, 2841, 2185, 1681, 1658. H NMR (300 MHz,
DMSO-d6, δ ppm): 3.32–3.75 ( s, 9H, OCH3), 6.11 (s, 1H, CH), 6.73–8.26 (m, 6H,
Ar–H), 8.27 (t, 2H, NH2). 13C NMR (75 MHz, DMSO-d6, δ ppm): 56.0, 59.8, 61.2,
63.3, 104.1, 116.2, 126.7, 127.2, 128.7, 128.8, 133.7, 134.1, 134.5, 137.3, 150.6,
152.8, 153.9, 156.6 ppm.
3-amino-1-(4-methoxyphenyl)-5,10-dioxo-5,10-dihydro-1H-pyrazolo[1,2-
b]phthalazine-2-carbonitrile (4 g) Yellow solid; mp 239–241 °C. FT-IR (KBr,
cm−1): 3376, 3266, 2197, 1677, 1661. 1H NMR (300 MHz, DMSO-d6, δ ppm): 3.73
( s, 3H, OCH3), 6.07 (s, 1H, CH), 6.89–8.24 (m, 8H, Ar–H), 8.36 (t, 2H, NH2). 13
C
NMR (75 MHz, DMSO-d6, δ ppm): 55.1, 61.3, 62.6, 113.9, 116.2, 126.5, 127.1,
128.5, 128.6, 130.2, 133.1, 134.6, 150.6, 153.4, 156.6, 159.1 ppm.
3-amino-5,10-dioxo-1-(p-tolyl)-5,10-dihydro-1H-pyrazolo[1,2-b]phthalazine-
2-carbonitrile (4 h) Yellow solid; mp 253–255 °C. FT-IR (KBr, cm−1): 3366, 3263,
3036, 2197, 1682, 1658. 1H NMR (90 MHz, DMSO-d6, δ ppm): 2.31 ( s, 3H, CH3),
6.11 (s, 1H, CH), 7.09–7.83 (m, 8H, Ar–H), 8.32 (t, 2H, NH2). 13C NMR (75 MHz,
DMSO-d6, δ ppm): 61.5, 62.8, 116.0, 126.6, 126.7, 127.3, 128.5, 129.2, 133.6,
134.6, 135.3, 137.5, 150.4, 153.6, 156.6 ppm.
2-amino-4-(4-chloro-3-nitrophenyl)-5-oxo-4,5-dihydropyrano[3,2-c]
chromene-3-carbonitrile (5b) Cream solid; mp 252–258 °C. FT-IR (KBr, cm−1):
3392, 3319, 2198, 1694, 1530, 1380, 1255. 1H NMR (250 MHz, DMSO-d6, δ ppm):
4.65 (s, 1H, CH), 7.45–7.85 (m, 7H, Ar–H), 8.02 (t, 2H, NH2). 13C NMR (62 MHz,
DMSO-d6, δ ppm): 36.4, 57.0, 102.7, 113.4, 116.9, 119.3, 123.0, 123.7, 125.0,
131.8, 133.5, 133.7, 144.8, 148.2, 152.7, 154.5, 158.5, 160.0. MS: m/z: 395, 378,
348, 295, 282, 239, 120, 92, 66 [M+H]+.
2-amino-4-(naphthalen-1-yl)-5-oxo-4,5-dihydropyrano[3,2-c]chromene-
3-carbonitrile (5c) Cream solid; mp 259–264 °C. FT-IR (KBr, cm−1): 3311, 2188,
1
1696, 1255. H NMR (250 MHz, DMSO-d6, δ ppm): 5.45 (s, 1H, CH), 7.36–7.95
(m, 11H, Ar–H), 8.42 (t, 2H, NH2). 13C NMR (62 MHz, DMSO-d6, δ ppm): 31.9,
59.0, 105.0, 113.3, 117.0, 119.6, 122.9, 123.8, 125.1, 126.3, 126.5, 127.9, 128.9,
131.4, 133.3, 133.7, 141.1, 152.5, 154.2, 158.3, 160.0.
2-amino-4-(4-hydroxyphenyl)-5-oxo-4,5-dihydropyrano[3,2-c]chromene-
3-carbonitrile (5e) Cream solid; mp 264–266 °C. FT-IR (KBr, cm−1): 3407, 3286,
3218, 2196, 1696, 1215. 1H NMR (300 MHz, DMSO-d6, δ ppm): 4.31 (s, 1H, CH),
6.66–7.86 (m, 8H, Ar–H), 7.88 (t, 2H, NH2), 9.34 (s, 1H, OH).
2-amino-4-(2,4-dichlorophenyl)-5-oxo-4,5-dihydropyrano[3,2-c]chromene-
3-carbonitrile (5f) Cream solid; mp 254–256 °C. FT-IR (KBr, cm−1): 3296, 3160,
1
2200, 1716, 1258. H NMR (400 MHz, DMSO-d6, δ ppm): 4.98 (s, 1H, CH),
7.35–7.90 (m, 7H, Ar–H), 7.92 (t, 2H, NH2). 13C NMR (100 MHz, DMSO-d6, δ
ppm): 39.9, 56.4, 102.9, 113.3, 117.1, 119.1, 123.0, 125.2, 128.3, 129.3, 132.5,
132.8, 133.6, 139.9, 152.7, 154.6, 156.5, 158.6, 159.9.
2-amino-4-(2-chlorophenyl)-5-oxo-4,5-dihydropyrano[3,2-c]chromene-3-car-
bonitrile (5 g) Cream solid; mp 265–268 °C. FT-IR (KBr, cm−1): 3284, 3179, 2200,
1
1709, 1259. H NMR (400 MHz, DMSO-d6, δ ppm): 4.99 (s, 1H, CH), 6.81–7.90
(m, 8H, Ar–H), 7.92 (t, 2H, NH2). 13C NMR (100 MHz, DMSO-d6, δ ppm): 36.4,
1 3

One‐pot and green synthesis…
56.6, 103.1, 112.8, 116.5, 118.6, 122.5, 122.8, 124.6, 128.2, 129.0, 130.6, 132.7,
133.0, 152.1, 153.9, 158.0, 159.3.
2-amino-4-(3-bromophenyl)-5-oxo-4,5-dihydropyrano[3,2-c]chromene-3-car-
bonitrile (5 h) Cream solid; mp 272–276 °C. FT-IR (KBr, cm−1): 3380, 3292, 2195,
1
1716, 1258. H NMR (400 MHz, DMSO-d6, δ ppm): 5.00 (s, 1H, CH), 7.17–7.91
(m, 8H, Ar–H),7.93 (t, 2H, NH2). 13C NMR (100 MHz, DMSO-d6, δ ppm): 36.9,
57.1, 103.6, 113.3, 117.0, 119.2, 123.0,123.4, 125.1, 128.8, 129.3, 131.1, 133.2,
133.8, 142.4, 152.6, 154.4, 158.4, 159.5, 159.8.
Result and discussion
In this work, Fe3O4@SiO2-imine/phenoxy-Cu(II) was synthesized as an efcient and
recyclable catalyst for the synthesis of 1H-pyrazolo[1,2-b]phthalazine-5,10-dione
and dihydropyrano[3,2-c]chromenes derivatives. For synthesis of the catalyst, the
Fe3O4 nanoparticles were frst prepared via the co-precipitation method, in which
the silica was utilized as a protecting shell to coat the Fe3O4 nanoparticles and form
a core–shell structure (Fe3O4@SiO2), the nanoparticles of which were coated by
(3-chloropropyl)triethoxysilane, yielding the Fe3O4@SiO2–(CH2)3-Cl MNPs. In
the next step, the Fe3O4@SiO2–(CH2)3-Cl nanoparticles were reacted with 1,3-phe-
nylenediamine to yield the Fe3O4@SiO2–(CH2)3–NH–(3-NH2C6H4) nanoparti-
cles. Conversion of the Fe3O4@SiO2–(CH2)3–NH–(3-NH2C6H4) nanoparticles into
Fe3O4@SiO2-Iminomethyl/phenol was accomplished via the reaction of Fe3O4@
SiO2–(CH2)3–NH–(3-NH2C6H4) nanoparticles with salicylaldehyde. Ultimately,
Fe3O4@SiO2-imine/phenoxy-Cu (II) was synthesized by dispersing the material in
Cu(OAc)2 solution [35].
To check the catalytic activity of Fe3O4@SiO2-imine/phenoxy-Cu(II) in the one-
pot synthesis of 1H-pyrazolo[1,2-b]phthalazine-5,10-dione the reaction of phthal-
hydrazide, malononitrile and aldehyde was selected as a model reaction. The reac-
tion conditions, including solvent, temperature and diferent amount of catalyst,
were optimized and listed in Table 1. Based on these data, no reaction progress was
observed in the absence of a catalyst and 25 mg of the catalyst was a suitable amount
for this reaction. Then, a variety of temperatures were monitored in the model reac-
tion, by which the highest yield of product was achieved at 80 °C. Additionally, vari-
ous solvents were also employed to study the reaction. Therefore, The best result
for the synthesis of 1H-pyrazolo[1,2-b]phthalazine-5,10-dione derivatives can be
obtained by using 20 mg of catalyst, solvent-free conditions and a temperature of
80 °C.
This reaction was studied under the optimum condition for diferent aromatic
aldehydes with diferent electron‐withdrawing and electron‐donating groups and the
results were presented in Table 2. In this work, it was concluded that the reaction
could proceed much better when utilizing an aldehyde of the electron‐withdrawing
group.
A schematic illustration of a feasible mechanism for the synthesis of
1H-pyrazolo[1,2-b]phthalazine-5,10-dione derivatives by using Fe3O4@SiO2-
imine/phenoxy-Cu(II) catalyst, is presented in Scheme 2. Initially, the activation
1 3

M. Nesarvand et al.
Table 1 Efect of conditions in the synthesis of H1-pyrazolo[1,2-b]phthalazine-5,10-dione derivatives in
the presence of Fe3O4@SiO2-Imine/Phenoxy-Cu(II)[a]
CHO
O
O
O
NH
NH
N
N
+
NC
CN
2
+
CN
NH2
O
1a
3a
4a
Entry
Catalyst (mg)
Solvent
Temperature (°C)
Time (min)[b]
Yield (%)[c]
1
2
3
4
5
6
7
8
No catalyst
Solvent-free
Solvent-free
Solvent-free
Solvent-free
Water
Acetonitrile
Ethanol
Ethanol: water
Water
r.t
80
80
80
r.t
r.t
Refux
Refux
Refux
Refux
Refux
50
60
70
80
80
90
50
20
35
100
80
60
60
70
95
80
40
34
25
30
120
50
Trace
66
92
88
28
Trace
55
66
40
40
50
50
68
79
35
28
68
10
20
30
20
20
20
20
20
20
20
20
20
20
20
20
20
9
10
11
12
13
14
15[d]
16[e]
17[f]
Acetone
Toluene
Solvent-free
Solvent-free
Solvent-free
Solvent-free
Solvent-free
Solvent-free
80
[a]Reaction conditions: phthalhydrazide (1 mmol), malononitrile (1 mmol), benzaldehyde (1 mmol), sol-
vent (5 mL)
[b] Reaction progress monitored by TLC
[c] Isolated pure yield
[d] Fe3O4 nanoparticles were used as the catalyst
[e] Fe3O4@SiO2 nanoparticles were used as the catalyst
[f]Fe3O4@SiO2-Iminomethyl/Phenol nanoparticles were used as the catalyst
of C–H bond in malononitrile by the catalyst (as a Lewis acid catalyst) leads to
the attack of malononitrile on the activated carbonyl group of aldehyde. Knoeve-
nagel condensation reaction between malononitrile and aldehyde was followed by
dehydration to provide the intermediate (b). Then, the michael addition between
Intermediate b and phthalhydrazide, forms intermediate (c). Then intramolecular
cyclization and tautomerization in presence of the catalyst give 1H-pyrazolo[1,2-
b]phthalazine-5,10-dione.
1 3

One‐pot and green synthesis…
Table 2 Fe3O4@SiO2-Imine/Phenoxy-Cu(II) catalyzed synthesis of H1-pyrazolo[1,2-b]phthalazine-
5,10-diones under solvent-free conditions
Entry
Substrate
Products
Time (min.)
Yield (%)a M.p (°C)
Found
Reported[Ref]
4a
20
92
249–251 249–251[1]
4b
4c
15
16
95
91
275–276 275–277[2]
265–269 267–269[1]
4d
4e
15
14
92
96
230–234 231–232[1]
262–264
–
4f
23
22
20
88
89
90
253–256 253–255[8]
239–241 240–242[17–21]
253–255 253–255[1]
4 g
4 h
[a]Isolated yields
After the successful synthesis of 1H-pyrazolo[1,2-b]phthalazine-5,10-diones,
we evaluated the catalytic activity of Fe3O4@SiO2-imine/phenoxy-Cu(II) for the
synthesis of dihydropyrano[3,2-c]chromene derivatives. For this purpose, the
reaction of aldehyde (1 mmol), malononitrile (1 mmol) and 4-hydroxycoumarin
(1 mmol) were applied as a model, and diverse solvents, temperature and cata-
lyst content were used to optimize the reaction (Table 3). The best result for this
1 3

M. Nesarvand et al.
Scheme 2 Proposed mechanism for synthesis of 1H- pyrazolo[1,2-b]phthalazine-5,10-diones
reaction can be obtained by using 30 mg of catalyst, solvent-free conditions and a
temperature of 90 °C.
After optimizing the reaction parameters, the catalyst was investigated on
diferent aromatic aldehydes with diferent electron‐withdrawing and electron‐
donating groups and the results are presented in Table 4. In this work, it was
concluded that the reaction could proceed more efciently when utilizing an alde-
hyde possessing an electron‐withdrawing group.
Scheme 3 shows the probable mechanism for one-pot synthesis of
dihydropyrano[3,2-c]chromene derivatives by using Fe3O4@SiO2-imine/phe-
noxy-Cu(II) as a Lewis acid catalyst. Based on this mechanism, the activation
of C–H bond in malononitrile by the catalyst leads to the attack of malononitrile
on an activated carbonyl group of aldehyde. Knoevenagel condensation reaction
between malononitrile and aldehyde followed by dehydration to provide the inter-
mediate (b). Michael addition between Intermediate b and 4-hydroxycoumarin
further forms the intermediate (d). Then, the intramolecular cyclization and tau-
tomerization in presence of the catalyst results in dihydropyrano[3,2-c]chromene.
The model reaction was also used to assess the reusability of the catalyst. For
this purpose, after which the reaction was completed, the separated catalyst was
washed several times with water and hot ethanol, dried and reused in the next
cycle. Figure 1 exhibits the results (FT-IR,TEM,XRD of reused catalyst in the
1 3

One‐pot and green synthesis…
Table 3 Efect of conditions in the synthesis of dihydropyrano[3,2-c]chromene derivatives in the pres-
ence of Fe3O4@SiO2-Imine/Phenoxy-Cu(II)[a
NH2
CN
OH
O
CHO
+
CN
+
NC
O
O
O
O
1a
2
3b
5a
Entry
Catalyst (mg)
Solvent
Temperature (°C)
Time (min)[b]
Yield (%)[c]
1
2
3
4
5
6
7
No catalyst
10
20
30
50
30
30
30
30
30
30
30
30
30
30
30
30
Solvent-free
Solvent-free
Solvent-free
Solvent-free
Solvent-free
Solvent-free
Solvent-free
Solvent-free
Chloroform
Ethyl acetate
Toluene
Water
Ethanol
Dichloromethane
Water
Water
90
90
90
90
90
70
80
100
Refux
Refux
Refux
r.t
r.t
r.t
50
80
40
35
17
20
30
25
20
70
70
80
100
110
80
90
60
70
50
80
35
15
68
80
95
89
75
86
85
38
16
24
24
34
20
35
48
55
40
20
65
8
9
10
11
12
13
14
15
16
17
18[d]
19[e]
20[f]
Refux
Refux
90
90
90
Ethanol
30
30
30
Solvent-free
Solvent-free
Solvent-free
[a]Reaction conditions: 4-hydroxycoumarin (1 mmol), malononitrile (1 mmol), benzaldehyde (1 mmol),
solvent (5 mL)
[b]Reaction progress monitored by TLC
[c]Isolated pure yield
[d]Fe3O4 nanoparticles were used as the catalyst
[e]Fe3O4@SiO2 nanoparticles were used as the catalyst
[f]Fe3O4@SiO2-Iminomethyl/Phenol nanoparticles were used as the catalyst
ffth run), confrming the recyclability of the catalyst. Hot-fltration test also indi-
cated that the catalyst has no leaching in each cycle.
1 3

M. Nesarvand et al.
Table 4 Fe3O4@SiO2-Imine/Phenoxy-Cu(II) catalyzed synthesis of dihydropyrano[3,2-c]chromene
under solvent-free conditions
Entry
Substrate
Products
Time (min.)
Yield (%)a M.p (°C)
]
Found
Reported[Ref
256–258[22]
5a
17
95
96
93
88
89
255–258
252–258
259–264
255–258
264–266
5b
5c
5d
5e
15
17
21
24
–
–
255–257[23]
263–265[22]
5f
17
18
92
92
254–256
265–268
253–255[22]
261–263[22]
5 g
5 h
18
90
272–276
276–278[24, 25]
[a] Isolated yields
Our method is advantageous to other methods from viewpoint of the shorter
reaction time and higher yield of production with an insignifcant fraction of the
side products. This method compared with other methods shown in Table 5.
Conclusion
The application of Fe3O4@SiO2-imine/phenoxy-Cu(II) as a catalyst shows a highly
efcient catalytic activity for the synthesis of 1H-pyrazolo[1,2-b]phthalazine-
5,10-dione and dihydropyrano[3,2-c]chromene derivatives due to the presence of Cu
species in the catalyst which act as Lewis acid. The newly synthesized derivatives
1 3

One‐pot and green synthesis…
Scheme 3. Proposed mechanism for synthesis of dihydropyrano[3,2-c]chromene
Fig. 1 image of the FT-IR (a),XRD (b), TEM(c) of reused catalyst and, recyclability of the Fe3O4@
SiO2-imine/phenoxy-Cu(II) (d)
1 3

M. Nesarvand et al.
1 3

One‐pot and green synthesis…
were analyzed and their structure was corroborated. The main advantages of this
work are facile reaction workup, recyclability and reusability of the catalyst, low
catalyst loading, short reaction times and considerable yield of the product. Briefy,
our method is advantageous to other methods from viewpoint of the shorter reac-
tion time and higher yield of production with an insignifcant fraction of the side
products.
Acknowledgements We gratefully acknowledge the Research Council of Bu‐Ali Sina University for pro-
viding facilities and fnancial support of this research work.
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