Iron-oxide nanoparticles mediated cyclization of 3-(4-chlorophenyl)-1- hydrazinylisoquinoline to 1-(4,5-dihydropyrazol-1-yl)isoquinolines

Article abstract of DOI:10.1007/s11164-011-0372-1

Iron-oxide nanoparticles were obtained using chitosan templates and their crystalline character and particle size have been confirmed through powder x-ray diffraction and transmission electron microscopy measurements. The particle sizes were found to be 10-25 nm. The diversified chalcones 2 were reacted with 1-hydrazinylisoquinoline 1 in the presence of iron-oxide nanoparticles to the corresponding pyrazolines 3a-j in high yield and purity. The pyrazolines were characterized by spectroscopic techniques. Springer Science+Business Media B.V. 2011.

Full text of DOI:10.1007/s11164-011-0372-1

Res Chem Intermed (2012) 38:571–582
DOI 10.1007/s11164-011-0372-1
Iron-oxide nanoparticles mediated cyclization
of 3-(4-chlorophenyl)-1-hydrazinylisoquinoline
to 1-(4,5-dihydropyrazol-1-yl)isoquinolines
•
F. Nawaz Khan P. Manivel K. Prabakaran
•
•
•
•
•
Jong Sung Jin Euh Duck Jeong Hyun Gyu Kim
T. Maiyalagan
Received: 2 August 2011 / Accepted: 23 August 2011 / Published online: 13 September 2011
Ó Springer Science+Business Media B.V. 2011
Abstract Iron-oxide nanoparticles were obtained using chitosan templates and their
crystalline character and particle size have been confirmed through powder x-ray
diffraction and transmission electron microscopy measurements. The particle sizes were
found to be 10–25 nm. The diversified chalcones 2 were reacted with 1-hydrazinyliso-
quinoline 1 in the presence of iron-oxide nanoparticles to the corresponding pyrazolines
3a–j in high yield and purity. The pyrazolines were characterized by spectroscopic
techniques.
Keywords Chalcones Á Pyrazolines Á Heterocycles Á Nanoparticles Á Iron oxide
Introduction
Pyrazolines are considered as potential bacteriostatic, fungicidal, anti-cancer,
anti-inflammatory, anti-diabetic, anesthetic, and analgesic agents [1–3]. They are
extensively used in organic synthesis [4–6]. The synthesis of pyrazolines generally
Electronic supplementary material The online version of this article (doi:
10.1007/s11164-011-0372-1) contains supplementary material, which is available to authorized users.
F. Nawaz Khan (&) Á P. Manivel Á K. Prabakaran
Organic and Medicinal Chemistry Research Laboratory, Organic Chemistry Division,
School of Advance Sciences, VIT University, Vellore 632 014, Tamil Nadu, India
e-mail: nawaz_f@yahoo.co.in
F. Nawaz Khan Á J. S. Jin Á E. D. Jeong Á H. G. Kim
Division of High Technology Material Research, Busan Center, Korea Basic Science Institute,
Busan 618 230, Korea
e-mail: jsjin@kbsi.re.kr
T. Maiyalagan
School of Chemical and Biomedical Engineering, Nanyang Technological University,
50 Nanyang Drive, Singapore 639798, Singapore
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F. Nawaz Khan et al.
involves the condensation of chalcones and hydrazine or its derivatives [7, 8].
In recent years, significant research work has been devoted to pyrazolines
synthesis; however, pyrazolines carrying isoquinoline ring substituents has been
little attempted. The magnetic nanoparticles are produced through different
methodologies [9–12], however, all resulted in aggregated nanoparticles. In order
to overcome this, copolymer templates and their application has been reported
[13–19]. The current study envisioned the use of chitosan templates for the synthesis
Fe2O3 nanoparticles by controlled heat treatment. X-ray diffraction (XRD) and
transmission electron microscopy (TEM) have been used to characterize the
nanoparticles. In our continued interest on isoquinolines and related compounds
[20–40], in this paper we report some 3,5-disubstituted pyrazolines with the
mediation of iron-oxide nanoparticles obtained through a chitosan template-assisted
synthesis.
Results and discussion
The chitosan template provided binding sites for the Fe, which on subsequent
controlled heat treatment, generate smaller size and non-agglomerated iron-oxide
nanoparticles [41, 42], which are spatially well separated. The morphology and
microstructure of the as-prepared samples [41, 42] were detected on a TEM (Tecnai
F20 HR TEM) operated at 200 kV and equipped with an energy-dispersive x-ray
spectrometer and on a high-resolution TEM (FEI TECNAI F30) with HAADF
detector operated at 300 kV.
TEM of the iron-oxide nanoparticles were obtained by dispersing in ethanol and
the droplets of the dispersion were placed on copper grids coated with carbon film
and dried under natural conditions. The TEM images suggest that the use of
chitosan in the material synthesis limits the particle size. The iron-oxide–chitosan
mixture generates particles that are significantly smaller.
The x-ray diffraction pattern (Fig. 1a) of iron-oxide nanoparticles are in
agreement with the theoretical data and suggest that the crystalline character has
been improved in the presence of the template. The crystallite size was found to be
between 10 and 25 nm when iron oxide was synthesized using the chitosan
template. Figure 1b displays the TEM of the magnetic nanoparticles generated on a
chitosan template. The nanoparticles obtained have good uniform distribution of
particle morphology, with a size of 10–25 nm. The chemical composition of the
catalyst was determined by energy dispersive x-ray (EDX) analysis. The EDX of
such particles showed the presence of oxygen and iron atoms (Fig. 2).
In this paper, a series of 3,5-disubstitutedpyrazolines 3a–3j with different
substituents both on the isoquinoline and pyrazoline rings were attempted using
iron-oxide nanoparticles. These compounds were obtained by the action of
isoquinoline hydrazine, 1 on chalcones 2a–2j, which in turn generated aldol
condensation intermediates of the corresponding aldehydes and ketones in ethanolic
NaOH solution (Scheme 1). The chalcones 2a–2j were confirmed on the basis of
their characteristic IR absorption peak at due to the presence of a conjugated
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Iron-oxide nanoparticles mediated cyclization
573
Fig. 1 X-ray diffraction pattern and TEM image of iron-oxide nanoparticles
C
400
300
200
100
Cu
Fe
Fe
O
Cu
Cu
Fe
0
0
2
4
6
8
10
Energy(KeV)
Fig. 2 SAED and EDAX images of iron-oxide nanoparticles
R1
R1
NHNH2
N
O
N
R2
R2
N
2
N
Ironoxide nanoparticles
heating-30 min
Cl
3a-j
1
Cl
Scheme 1 Cyclization of hydrazine and chalcones in the presence of iron-oxide nanoparticles
123

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F. Nawaz Khan et al.
1
carbonyl group and their H-NMR spectra suggest the a, b- protons appear in the
downfield aromatic region.
The optimization of the reaction condition was carried using condensation of
1-hydrazino-3-(4-chlororpheny)isoquinoline 1 and chalcone 2a (Scheme 2) as a
model reaction. The development of optimized condition, screening of various
catalysts, solvents, and catalyst loading was explored as presented in Tables 1, 2,
and 3. As shown in Table 1, the reaction proceeds well in the presence of iron-oxide
nanoparticles (entry 7). However, other nano-material catalysts (Table 1, entries 2,
3, and 5) and bulk catalysts (Table 1, entries 1, 4, and 6) are less effective and
produced lower yields.
The influence of solvents was then explored, which indicated ethanol was as an
efficient solvent (Table 2, entry 2) and the methanol, a moderate solvent. Further, to
optimize the reaction condition, the amount of iron nanoparticles loading was
investigated, which clearly suggested that an optimized amount of 5 mol% catalyst
required for the effective conversion (Table 3, entry 5).
With the optimized result in hand, various pyrazolines were obtained (as shown
in Scheme 1; Table 4). The desired products 3a–j, were obtained in high yield
NHNH2
N
O
N
N
2a
N
Ironoxide nanoparticles
heating-30 min
Cl
3a
1
Cl
Scheme 2 3-(4-Chlorophenyl)-1-{5-(4-methylphenyl)-3-phenyl-4,5-dihydro-1H-pyrazol-1-yl}
isoquinoline
Table 1 Effect of catalyst in the condensation of 1 with chalcone 2a
Entry
Catalyst
Yielda (%)
1
2
3
4
5
6
7
ZnO (bulk)
30
40
42
46
48
48
60
ZnO (nanorod)
ZnO (nanoparticles)
SnO (bulk)
SnO (nanoparticles)
Iron oxide (bulk)
Iron oxide (nanoparticles)
Reaction conditions: 1 (0.1 mmol), 2 (0.11 mmol), catalyst (5 mol%), 1,4-dioxane (10 mL), reflux for
30 min
a
Isolated yield
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Iron-oxide nanoparticles mediated cyclization
575
Table 2 Effect of solvent in the reaction of 1 with, 2a
Entry
Base
Yielda (%)
1
2
3
4
5
1,4-dioxane
Ethanol
60
94
79
54
52
Methanol
Toluene
Benzene
Reaction conditions: 1 (0.1 mmol), 2a (0.11 mmol), iron-oxide nanoparticles (5 mol%), solvent (10 mL);
reflux for 30 min
a
Isolated yield
Table 3 Effect of iron-oxide nanoparticles loading in the condensation of 1 and 2a
Entry
Mol%
Yielda (%) 3a
1
2
3
4
5
6
7
8
9
10
1
2
20
56
4
68
4.5
5
70
94
5.5
6
96
96
8
97
10
Nil
97
Trace
Reaction conditions: 1 (0.1 mmol), 2a (0.11 mmol), ethanol (10 mL) reflux for 30 min
a
Isolated yield
(85–97%) and purity. The purified products were characterized by different spectral
1
techniques including H, 13C NMR, LC–MS, IR, and CHN analysis.
The proposed mechanism (as depicted in Scheme 3) of the condensation reaction
involved the initial nucleophilic addition of the carbonyl carbon of the chalcones.
The chalcones adsorbed on the iron-oxide nanoparticles surface were activated for
nucleophilic addition due to C=O polarization and increased electrophilicity,
towards more nucleophilic nitrogen atoms of the hydrazine with the formation of
hydroxyl derivative, which then undergo dehydration and subsequent cyclization to
form the pyrazolines product again with the facilitation of the iron-oxide
nanoparticles. The advantages of this catalyst include their non-toxicity compared
to conventional copper, cobalt, or nickel catalysts, and mild reaction condition
requirement; easy removal from the reaction mixture facilitated due to their
magnetic properties and further the elimination of auto-oxidation of the desired
pyrazolines to the corresponding pyrazoles.
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F. Nawaz Khan et al.
Table 4 Pyrazolinesa
R1
R1
NHNH2
O
N
R2
R2
N
2
N
N
Ironoxide nanoparticles
heating-30 min
Cl
3a-j
1
Cl
Entry
R1
R2
Yield (%)
Compound
a
b
c
d
e
f
C6H5
4-CH3C6H4
4-CH3C6H4
C6H5
94
90
84
91
89
86
83
90
94
85
3a
3b
3c
3d
3e
3f
3-CH3C6H4
4-ClC6H4
4- Pyridyl-
4-FC6H4
C6H5
4-FC6H4
4-CH3C6H4
C6H5
4-FC6H4
g
h
i
3-FC6H4
3g
3h
3i
3-OHC6H4
4-CH3C6H4
4-OHC6H4
C6H5
4-CH3C6H4
C6H5
j
3j
Reaction conditions: 1 (0.1 mmol), 2a (0.11 mmol), iron-oxide nanoparticles (5 mol%), ethanol (10 mL);
reflux for 30 min
a
Isolated yield
Experimental methods
The chemicals and reagents were purchased from Aldrich Chemicals (India) and
solvents were purchased from S.D. Fine Chemicals (India). Melting points were
taken on an Elchem microprocessor-based DT apparatus in open capillary tubes. IR
spectra were obtained on a Nucon infrared spectrophotometer, India (KBr disc).
NMR spectra were recorded on a Bruker 500 spectrometer, India, and chemical
shifts are reported in parts per million (d) relative to tetramethylsilane (TMS) as an
internal standard.
General procedure for the preparation of 3,5-disubstituted-pyrazolines (3a–3j)
The chalcones 2a–2j were prepared by stirring a mixture of the appropriate
aldehyde and ketones (0.1 mol of each) in ethanolic NaOH solution (80 mL) for
several hours at room temperature until a yellow to orange color had developed.
Then, the reaction mixture was filtered and the resulting precipitate was washed
with 3% aqueous HCl. The crude material was recrystallized from ethanol (96%) to
obtain a bright-yellow crystalline product. The structures of these chalcones were
established on the basis of their chemical properties and spectral data.
Method A: Chalcones 2a–2j (0.05 mol) were dissolved in dry acetic acid
(100 mL) was then reacted with an appropriate isoquinoline hydrazine 1 for several
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Iron-oxide nanoparticles mediated cyclization
577
R1
NHNH2
N
O
R2
2
R1
1
Cl
N
R2
N
R2
R1
OH
NHNH
N
N
Cl
3a-j
Cl
R2
R1
-H2O
NHN
N
Cl
Scheme 3 Mechanism of the reaction
hours at 90–100 °C until the cyclization was complete and a deep-orange color
developed. The reaction mixture was then evaporated in vacuo to separate the acetic
acid, and the residue was recrystallized from ethanol or acetonitrile to obtain the
pure crystalline pyrazolines 3a–j.
Method B: A solution of chalcones 2a–2j (0.05 mol), in ethanol (10 mL) was
refluxed with an appropriate isoquinoline hydrazine, 1 in the presence of 5 mol%
iron-oxide nanoparticles until the cyclization was complete and a deep-orange color
developed. The reaction mixture was then filtered to remove iron-oxide nanopar-
ticles and evaporated in vacuo, and the residue was re-crystallized from ethanol or
acetonitrile to obtain the pure crystalline pyrazolines 3a–j. The structures of these
compounds were established on the basis of their chemical properties and spectral
analysis.
The chalcones when reacted with isoquinolinylhydrazines 1, cyclizes through
a,b-unsaturated hydrazone to give a 2-pyrazoline ring 3a–3j in the presence of a
suitable cyclizing agent like dry acetic acid under prolonged refluxing condition or
with iron-oxide nanoparticles in 30 min. All the structures of products were
appropriately established by spectroscopic data and analytical methods. In general,
the pyrazolines exhibited C=N stretching vibrations in the m * 1,650–1,450 cm-1
range. In addition, 1H-NMR spectra of these compounds generally exhibit an AMX
pattern for the presence of two diastereotopic protons (CH2 protons of the
pyrazoline ring) at C-4 resonated as a pair of doublets of doublets at *d 3.30 ppm
(HA), *d 3.90 ppm (HB) and one single proton at the C-5 position appear as
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F. Nawaz Khan et al.
doublets of doublets, due to vicinal coupling with the two magnetically non-
equivalent protons of the methylene group at position 4 of the pyrazoline ring. The
13C NMR data of pyrazolines exhibited the chemical shift values of the carbon
atoms at *d 25–43 ppm (C-4), *d 64 ppm (C-5), and d * 150 ppm (C-3) of the
2-pyrazoline ring.
3-(4-Chlorophenyl)-1-{5-(4-methylphenyl)-3-phenyl-4,5-dihydro-1H-pyrazol-1-
yl} isoquinoline (3a)
Yellow solid, mp 151–152 °C, IR (cm-1) 3,051, 3,019, 2,910, 1,614, 1,592, 1,567,
1,513, 1,496, 1,410, 1,351, 1,204, 1,143, 1,053, 902, 828, 786, 756. 1H NMR
(DMSO-D6): d 9.33–9.30 (d, 1H, J = 7.71 Hz), 7.97–7.94 (d, 2H, J = 8.52 Hz),
7.88–7.82 (m, 4H), 7.73–7.61 (m, 4H), 7.51–7.44 (m, 4H), 7.35–7.32 (d, 2H,
J = 7.89 Hz),7.11–7.08 (d, 2H, J = 7.86 Hz), 6.16–6.098 (t, 1H, J = 8.46 Hz),
3.96–3.86 (t, 1H, J = 12.03 Hz), 3.25–3.08 (m, 1H), 2.15 (s, 3H). 13C NMR
(DMSO-D6): 152.0, 151.9, 145.8, 140.9, 139.5, 138.0, 136.4, 133.4, 132.4, 130.5,
129.9, 129.5, 129.2, 128.8, 128.4, 128.3, 127.8, 126.7, 126.5, 126.3, 119.5, 110.0,
64.1, 21.0. LC–MS: m/e 474.16, C31H24ClN3 requires Mol. wt.: 473.17. Elemental
analysis, calculated: C, 78.55; H, 5.10; Cl, 7.48; N, 8.87%. Found: C, 78.61; H,
5.06; N, 8.81%.
3-(4-Chlorophenyl)-1-{5-(4-methylphenyl)-3-(3-methyl phenyl)-4,5-dihydro-
1H-pyrazol-1-yl} isoquinoline (3b)
Yellow solid, mp 135–136.5 °C, IR (cm-1) 2,921, 2,865, 1,552, 1,493, 1,455, 1,409,
1,331, 1,089.4, 1,054, 1,033, 1,012, 879, 816, 780, 750, 717, 682, 545. H NMR
1
(DMSO-D6): d 9.32–9.29 (d, 1H, J = 8.31 Hz),7.96–7.93 (d, 2H, J = 8.61 Hz),
7.87–7.81 (m, 2H), 7.72–7.61 (m, 4H), 7.46–7.43 (d, 2H, J = 8.58 Hz), 7.39–7.23
(m, 4H), 7.10–7.07 (d, 2H, J = 7.86 Hz), 6.14–6.07 (t, 1H, J = 8.28 Hz),
3.92–3.82 (t, 1H, J = 11.88 Hz), 3.14–3.06 (dd, 1H, J = 8.22,17.52 Hz), 2.20
(s, 3H), 2.4 (s, 3H). 13C NMR (DMSO-D6): 152.1, 151.9, 145.8, 140.9, 139.5, 138.4,
138.0, 136.4, 133.4, 132.3, 130.6, 130.5, 129.5, 129.1, 128.8, 128.4, 127.8, 127.1,
126.7, 126.3, 123.7, 119.5, 110.0, 64.0, 21.5, 21.0. LC–MS: m/e 489.18.,
C32H26ClN3 requires Mol. wt.: 487.18. Elemental analysis, calculated: C, 78.76;
H, 5.37; N, 8.61%. Found: C, 78.69; H, 5.29; N, 8.54%.
3-(4-Chlorophenyl)-1-{5-phenyl-3-(4-chloro phenyl)-4,5-dihydro-1H-pyrazol-1-
yl} isoquinoline (3c)
Yellow solid, mp 221–222 °C, IR (cm-1) 3,058, 2,954, 2,921, 1,611, 1,588, 1,546,
1,494, 1,435, 1,400, 1,367, 1,331, 1,236, 1,141, 1,089, 1,057, 1,008, 961, 899, 873,
1
818, 749, 671, 646, 592. H NMR (DMSO-D6), 9.31–9.29 (d, 1H, J = 8.40 Hz),
7.92–7.85 (m, 6H), 7.74–7.71 (t, 1H, J = 6.8 Hz), 7.67–7.64 (t, 1H, J = 6.8 Hz),
7.58–7.55 (d, 2H, J = 8.4 Hz), 7.47–7.44 (m, 4H), 7.34–7.30 (t, 2H, J = 7.60 Hz),
7.21–7.18 (t, 1H, J = 7.6 Hz), 6.2–6.15 (t, 1H, J = 8.8 Hz), 3.98–3.91 (dd, 1H,
J = 12.00, 5.60 Hz), 3.21–3.14 (q, 1H). 13C NMR (DMSO-D6): 151.9 8, 149.5,
123

Iron-oxide nanoparticles mediated cyclization
579
146.6, 143.2, 139.4, 138.1, 135.0, 133.8, 131.0, 129.8, 128.9, 128.6, 128.3, 128.2,
127.9, 127.2, 127.1, 127.1, 126.0, 125.9, 119.7, 110.2, 64.7, 40.9. LC–MS: m/e
494.11, C30H21Cl2N3 requires Mol. Wt.: 493.11. Elemental analysis, calculated: C,
72.88; H, 4.28; N, 8.50%. Found: C, 72.81; H, 4.21; N, 8.45%.
3-(4-Chlorophenyl)-1-{5-phenyl-3-(4-Pyridyl)-4,5-dihydro-1H-pyrazol-1-yl}
isoquinoline (3d)
Yellow solid, mp 137–138.5 °C, IR (cm-1) 3,026, 2,955, 2,920, 2,851, 2,361, 2,336,
1,701, 1,588, 1,494, 1,429, 1,334, 1,260, 1,135, 1,089, 1,057, 1,009, 900, 872, 808,
749, 717, 672. 1H NMR (DMSO-D6), 9.29-9.26 (d, 1H, J = 8.22 Hz), 8.68–8.66 (d,
2H, J = 5.52 Hz), 7.78–7.65 (m, 3H), 7.62–7.60 (d, 4H, J = 6.18 Hz), 7.54–7.48
(m, 2H), 7.35–7.32 (d, 4H, J = 8.31 Hz), 7.13–7.11 (d, 2H, J = 7.83 Hz),
6.18–6.29 (t, 1H, J = 8.56 Hz), 3.89–3.65 (q, 1H), 3.21–3.14 (q, 1H). 13C NMR
(DMSO-D6): 151.5, 150.0, 147.8, 146.6, 139.8, 139.4, 137.9, 137.00, 134.0, 129.9,
129.5, 129.3, 129.1, 128.7, 128.4, 128.0, 127.9, 127.2, 126.2, 125.9, 119.9, 119.7,
110.9, 64.7, 40.3. LC–MS: 461.2, C29H21ClN4 requires Mol. wt.: 460.15. Elemental
analysis, calculated: C, 75.56; H, 4.59; N, 12.15%. Found: C, 75.61; H, 4.52; N,
12.18%.
3-(4-Chlorophenyl)-1-{5-(4-fluoro phenyl)-3-(4-fluoro phenyl)-4,5-dihydro-1H-
pyrazol-1-yl} isoquinoline (3e)
Yellow solid, mp 201–202 °C, IR (cm-1) 3,053, 2,922, 1,603, 1,554, 1,508, 1,491,
1,405, 1,330, 1,294, 1,216, 1,172, 1,153, 1,129, 1,092, 1,053, 1,010, 962, 899, 874,
816, 749, 716, 671, 645, 592. 1H NMR (DMSO-D6), 9.30–9.28 (d, 1H, J = 8.64 Hz),
7.93–7.85 (m, 6H), 7.74–7.70 (t, 1H, J = 8.00 Hz), 7.66–7.62 (t, 1H, J = 8.36 Hz),
7.52–7.45 (m, 4H), 7.36–7.32 (t, 2H, J = 8.88 Hz), 7.16–7.12 (t, 2H, J = 8.88 Hz),
6.19–6.14 (t, 1H, J = 8.56 Hz), 3.96–3.89 (q, 1H), 3.21–3.14 (q, 1H). 13C NMR
(DMSO-D6): 164.6, 163.0, 162.1, 160.6, 152.0, 149.6, 146.5, 139.4, 139.0, 139.0,
138.1, 133.9, 129.8, 128.6, 128.6, 128.4, 128.2, 127.9, 127.9, 127.8, 127.6, 127.5
127.2, 125.9, 119.7, 115.2, 115.0, 115.7, 115.5, 110.5, 63.2, 41.1. LC–MS: m/e
496.2, C30H20ClF2N3 requires Mol. wt.: 495.13. Elemental analysis, calculated: C,
72.65; H, 4.06; N, 8.47%. Found: C, 72.71; H, 4.01; N, 8.39%.
3-(4-chlorophenyl)-1-{5-(4-methylphenyl)-3-(4-fluoro phenyl)-4,5-dihydro-1H-
pyrazol-1-yl} isoquinoline (3f)
Yellow solid, mp 186–187 °C, IR (cm-1) 3,053, 2,956, 2,919, 1,596, 1,551, 1,512,
1,490, 1,436, 1,353, 1,330, 1,296, 1,229, 1,144, 1,087, 1,054, 1,010, 897, 873, 814,
748, 716, 677, 593. 1H NMR (DMSO-D6), 9.29–9.26 (d, 1H, J = 8.31 Hz),
7.95–7.92 (d, 2H, J = 8.55 Hz), 7.87–7.81 (m, 4H), 7.69–7.62 (m, 2H), 7.45–7.43
(d, 2H, J = 8.49 Hz), 7.34–7.28 (m, 4H), 7.09–7.07 (d, 2H, J = 7.8 Hz), 6.09–6.16
(t, 1H, J = 8.46 Hz), 3.96–3.86 (q, 1H), 3.25–3.08 (q, 1H), 2.18 (s, 3H). 13C NMR
(DMSO-D6): 164.8, 161.6 151.9, 151.2, 145.8, 140.8, 139.5, 138.0, 136.4, 133.4,
130.5, 129.5, 129.1, 129.0, 128.8, 128.7, 128.4, 128.3, 127.8, 126.7, 126.3, 119.5,
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F. Nawaz Khan et al.
116.4, 116.1, 110.1, 64.2, 21.0. LC–MS: m/e 492.2, C31H23ClFN3 requires Mol. wt.:
491.16. Elemental analysis, calculated: C, 75.68; H, 4.71; N, 8.54%. Found: C,
75.62; H, 4.65; N, 8.47%.
3-(4-Chlorophenyl)-1-{5-phenyl-3-(3-fluoro phenyl)-4,5-dihydro-1H-pyrazol-1-
yl} isoquinoline (3g)
Yellow solid, mp 175–176 °C, IR (cm-1) 3,029, 2,927, 2,361, 2,336, 1,595, 1,611,
1,572, 1,552, 1,491, 1,455, 1,418, 1,353, 1,371, 1,331, 1,278, 1,177, 1,155, 1,132,
1
1,083, 1,053, 1,028, 926, 885, 860, 814, 749, 697, 673. H NMR (DMSO-D6),
9.29–9.27 (d, 1H, J = 8.52 Hz), 7.91–7.88 (m, 4H), 7.74–7.52 (m, 6H), 7.50–7.42
(m, 4H), 7.33–7.18 (m, 4H), 6.18–6.17 (t, 1H, J = 8.46 Hz), 3.94–3.92 (q, 1H),
3.24–3.13 (q, 1H). 13C NMR (DMSO-D6): 164.8, 161.6, 151.1, 145.8, 140.8, 143.7,
139.5, 138.0, 136.4, 133.4, 130.6, 129.0, 129.0, 128.8, 128.7, 128.3, 128.2, 127.8,
127.4, 126.9, 126.4, 119.4, 113.2, 110.4, 64.7, 21.0. LC–MS: 478.2, C30H21ClFN3
requires Mol. wt.: 477.14. Elemental analysis, calculated: C, 75.39; H, 4.43; N,
8.79%. Found: C, 75.36; H, 4.37; N, 8.71%.
3-(4-Chlorophenyl)-1-{5-phenyl-3-(3-hydroxy phenyl)-4,5-dihydro-1H-pyrazol-
1-yl} isoquinoline (3h)
Yellow solid, mp 212.5–213.5 °C, IR (cm-1) 3,468, 3,411, 3,028, 2,927, 2,361,
2,336, 1,595, 1,551, 1,493, 1,455, 1,420, 1,371, 1,352, 1,337, 1,278, 1,187, 1,137,
1,087, 1,057, 1,027, 1,010, 960, 910, 878, 857, 821, 748, 701.2, 677.3, 648.5, 621.4,
588.3, 546.6. 1H NMR (DMSO-D6), 9.61–9.92 (bs, 1H), 9.32–9.30 (d, 1H,
J = 8.48 Hz), 7.88–7.84 (d, 3H, J = 8.60 Hz), 7.78 (s, 1H), 7.70–7.62 (m, 2H),
7.43–7.40 (d, 4H, J = 7.08 Hz), 7.31–7.25 (m, 4H), 7.22–7.16 (m, 2H), 6.87–6.84
(d, 1H, J = 7.88 Hz), 6.11–6.06 (t, 1H, J = 8.44 Hz), 3.91–3.81 (t, 1H,
J = 8.40 Hz), 3.11–3.04 (q, 1H). 13C NMR (DMSO-D6): 157.5, 151.6, 151.4,
145.3, 143.3, 139.0, 137.5, 133.0, 132.9, 130.0, 129.8, 128.5, 128.2, 127.8, 127.3,
126.8, 126.1, 125.8, 118.9, 117.2, 116.7, 112.3, 109.5, 64.0, 40.7. LC–MS: m/e
476.2, C30H22ClN3O requires Mol. wt.: 475.15. Elemental analysis, calculated: C,
75.70; H, 4.66;; N, 8.83%. Found: C, 75.64; H, 4.58; N, 8.76%.
3-(4-Chlorophenyl)-1-{5-(4-methylphenyl)-3-(4-methyl phenyl)-4,5-dihydro-
1H-pyrazol-1-yl} isoquinoline (3i)
Yellow solid, mp 206.5–207.5 °C, IR (cm-1) 3,727, 3,625, 3,021, 2,920, 2,854,
2,361, 2,336, 1,893, 1,734, 1,651, 1,608, 1,590, 1,551, 1,514, 1,491, 1,437, 1,371,
1,331, 1,298, 1,237, 1,183, 1,142, 1,087, 1,054, 1,027, 961, 898, 872, 808, 742, 711,
669, 640, 595, 542. 1H NMR (DMSO-D6), 9.43–9.41 (d, 1H, J = 8.36 Hz),
7.74–7.68 (m, 5H), 7.64–7.55 (m, 2H), 7.47 (s, 1H), 7.38–7.31 (m, 4H), 7.29–7.24
(m, 2H), 7.13–7.11 (d, 2H, J = 7.96 Hz), 6.15–6.10 (q, 1H), 3.78–3.70 (q, 1H),
3.19–3.13 (q, 1H), 2.41(s, 3H), 2.30 (s, 3H). 13C NMR (DMSO-D6): 152.1, 150.7,
146.5, 140.5, 139.4, 139.3, 138.2, 133.7, 129.6, 129.6, 129.3, 129.1, 128.5, 128.2,
127.89 126.9, 125.9, 125.6, 119.8, 109.7, 64.0, 41.1, 21.4, 21.0. LC–MS: m/e 488.2,
123

Iron-oxide nanoparticles mediated cyclization
581
C32H26ClN3 requires Mol. wt.: 487.18. Elemental analysis, calculated: C, 78.76; H,
5.37; N, 8.61%. Found: C, 78.68; H, 5.29; N, 8.55%.
3-(4-Chlorophenyl)-1-{5-phenyl-3-(4-hydroxy phenyl)-4,5-dihydro-1H-pyrazol-
1-yl} isoquinoline (3j)
Yellow solid, mp 75–76.5 °C, IR (cm-1) 3,561, 3,027, 2,921, 2,851, 2,361, 2,336,
1,701, 1,603, 1,552, 1,518, 1,494, 1,432, 1,353, 1,333, 1,245, 1,167, 1,140, 1,088,
1,053, 1,010, 820, 750, 695, 597. 1H NMR (DMSO-D6), 9.42–9.39 (d, 1H,
J = 8.22 Hz), 7.74–7.54 (m, 6H), 7.48–7.46 (d, 4H, J = 6.75 Hz), 7.37–7.19
(m, 6H), 6.93–6.90 (d, 2H, J = 8.55 Hz), 6.15–6.10 (q, 1H), 3.78–3.70 (q, 1H),
3.18–3.10 (q,1H). 13C NMR (DMSO-D6): 156.8, 150.5, 146.5, 143.5, 139.4, 138.2,
133.7, 129.6, 128.5, 128.2, 127.8, 127.7, 126.9, 126.9, 125.9, 125.5, 125.2, 119.7,
115.6, 109.7, 64.3, 41.1. LC–MS: m/e 477.0, C30H22ClN3O requires Mol. wt.:
475.15. Elemental analysis, calculated: C, 75.70; H, 4.66; N, 8.83%, Found: C,
75.68; H, 4.59; N, 8.77%.
Conclusions
An efficient, simple, and high-yielding method for the iron-oxide nanoparticles
mediated cyclization of 3-(4-chlorophenyl)-1-hydrazinylisoquinoline to 1-(4,5-
dihydropyrazol-1-yl)isoquinolines was established. The advantages of this catalyst
include their non-toxicity, mild reaction condition requirement, easy removal from
reaction mixture, and elimination of auto-oxidation of the desired pyrazolines to the
corresponding pyrazoles.
Acknowledgments The authors wish to express their gratitude to the management of VIT University,
India, for their support and facilities. The authors thank DST, India, for the Fast Track Young Scientist
Fellowship to Dr. F. N. Khan.
References
1. R.O. Clinton, A.J. Manson, F.W. Stonner, A.L. Beyler, G.O. Potts, J. Am. Chem. Soc. 81, 1513
(1995)
2. R. Krishna, B.R. Pande, S.P. Bharthwal, S.S. Parmar, Eur. J. Med. Chem. 15, 567 (1980)
3. M.I. Husain, S. Shukla, Ind. J. Chem. 25B, 983 (1986)
4. E.I. Klimova, M. Marcos, T.B. Klimova, A.T. Cecilio, A.T. Ruben, R.R. Lena, J. Organometallic
Chem. 585, 106 (1999)
5. D. Bhaskarreddy, A. Padmaja, P.V. Ramanareddy, B. Seenaiah, Sulfur Lett. 16, 227 (1993)
6. D. Bhaskarreddy, B. N. Chandrasekhar, V. Padmavathi, R. P. Sumathi, Synthesis. 491 (1998)
7. L. Knorr, Ber. Dt. Chem. Ges. 26, 100 (1893)
8. V.G. Thakare, K.N. Wadodkar, Ind. J. Chem. B 25, 610 (1986)
9. M.M. Sagrario, L.A. Gracia-Cerda, T.J.R. Lubian, Mater. Lett. 59, 1056 (2005)
10. B.R. Galindo, A.O. Valenzuela, L.A. Gracia-Cerda, R.O. Fernandez, M.J. Aquino, G. Ramos, Y.H.
Madeira, J. Magnet. Magn. Mater. 294, e33 (2005)
11. Z.L. Liu, X. Wang, K.L. Yao, G.H. Du, Q.H. Lu, Z.H. Ding, J. Tao, Q. Ning, X.P. Luo, D.Y. Tian, D.
Xi, J. Mater. Sci. 39, 2633 (2004)
123

582
F. Nawaz Khan et al.
12. J. Yu, X. Yu, B. Huang, X. Zhang, Y. Dai, Cryst. Growth Des. 9, 1474 (2009)
13. K. Sunderland, P. Brunetti, L. Spinu, J. Fang, Z. Wang, W. Lu, Mater. Lett. 58, 3136 (2004)
14. L.A. Gracia-Cerda, R. Chapa-Rodriguez, J. Bonilla-Rios, Polymer Bull. 58, 989 (2007)
15. H. Lin, Y. Watanabe, M. Kumura, K. Hanabusa, H. Shirai, J. Appl. Polymer Sci. 87, 1239 (2003)
16. P.S. Chowdhury, P.R. Arya, K. Raha, Synth. React. Inorg. Met. 37, 447 (2007)
17. D.M. Kim, M. Mikhaylova, F.H. Wang, J. Kehr, B. Bjelke, Y. Zhang, T. Tsakalakos, M. Muhammed,
Chem. Mater. 15, 4343 (2003)
18. Y.-Y. Liang, L.-M. Zhang, W. Li, Colloid Polym. Sci. 285, 1193 (2007)
19. X. Yu, S. Liu, J. Yu, Appl. Catal. B Environ 104, 12 (2011)
20. P. Manivel, F. Nawaz Khan, J. Chil. Chem. Soc. 54, 180 (2009)
21. P. Manivel, S. Mohana Roopan, R. Sathish kumar, F. Nawaz Khan, J. Chil. Chem. Soc. 54, 183
(2009)
22. P. Manivel, F. Nawaz Khan, Indian J. Chem. 48B, 825 (2009)
23. F.N. Khan, P. Manivel, K. Prabakaran, V.R. Hathwar, M. Akkurt, Acta Cryst. E66, o1081 (2010)
24. F.N. Khan, P. Manivel, K. Prabakaran, V.R. Hathwar, M. Akkurt, Acta Cryst. E66, o1094 (2010)
25. K. Prabakaran, P. Manivel, F.N. Khan, Tetrahedron Lett. 51, 4340 (2010)
26. F.N. Khan, P. Manivel, K. Prabakaran, V.R. Hathwar, S.W. Ng, Acta Cryst. E66, o370 (2010)
27. P. Manivel, F. Nawaz Khan, V.R. Hathwar, Phosphorus, Sulphur, Silicon Relat. Elem. 185, 1932
(2010)
28. F.N. Khan, P. Manivel, K. Prabakaran, V.R. Hathwar, S.W. Ng, Acta Cryst. E65, o2732 (2009)
29. V.R. Hathwar, P. Manivel, F. Nawaz Khan, T.N.G. Row, Acta Cryst. E 63, o3708 (2007)
30. S.M. Roopan, F.R.N. Khan, Arkivoc 13, 161 (2009)
31. P. Manivel, S. Mohana Roopan, F. Nawaz Khan, J. Chil. Chem. Soc. 53, 1609 (2008)
32. V.R. Hathwar, P. Manivel, F. Nawaz Khan, T.N. Guru Row, Cryst. Eng. Comm. 11, 284 (2009)
33. F.N. Khan, P. Manivel, K. Prabakaran, V.R. Hathwar, S.W. Ng, Acta Cryst. E66, o488 (2010)
34. N.T. Patil, F.N. Khan, Y. Yamamoto, Tetrahedron Lett. 45, 8497 (2004)
35. P. Manivel, S. Mohana Roopan, F. Nawaz Khan, Indian J. Heterocycl Chem. 18, 21 (2008)
36. P. Manivel, F. Nawaz Khan, Phosphorus, Sulphur, Silicon Relat. Elem. 184, 2910 (2009)
37. S. Mohana Roopan, T.R. Sakthi Sri, B. Ramakrishna Reddy, F. Nawaz Khan, Indian J. Heterocycl.
Chem. 19, 77 (2009)
38. S.S. Tajudeen, F.N. Khan, Synth. Commun. 37, 3649 (2007)
39. S.M. Roopan, T. Maiyalagan, F.N. Khan, Can. J. Chem. 86, 1019 (2008)
40. V.R. Hathwar, P. Manivel, F. Nawaz Khan, T.N.G. Row, Acta Cryst. E 63, o3707 (2007)
41. S.K. Janardhanan, I. Ramasamy, B.U. Nair, Transition Met. Chem. 33, 127 (2008)
42. G.P. Petrovaa, G.N. Vayssilova, B. Galabov, J. Mol. Catal. A Chem. 342–343, 67 (2011)
123