CuFe2O4 nanoparticles as a highly efficient and magnetically recoverable catalyst for the synthesis of medicinally privileged spiropyrimidine scaffolds

Article abstract of DOI:10.1039/c2ra22477a

A highly efficient and green protocol for the synthesis of medicinally important fluorinated spiropyrimidine derivatives involving creation of six new covalent bonds has been developed using a magnetically separable and reusable heterogeneous copper ferri

Full text of DOI:10.1039/c2ra22477a

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CuFe2O4 nanoparticles as a highly efficient and
magnetically recoverable catalyst for the synthesis of
Cite this: RSC Advances, 2013, 3,
2924
medicinally privileged spiropyrimidine scaffolds3
Anshu Dandia,* Anuj K. Jain and Sonam Sharma
A
highly efficient and green protocol for the synthesis of medicinally important fluorinated
spiropyrimidine derivatives involving creation of six new covalent bonds has been developed using a
magnetically separable and reusable heterogeneous copper ferrite nanocatalyst under mild reaction
conditions. The synthesis of inverse spinel copper ferrite magnetic nanoparticles with average size of 38
nm has been achieved using combined sonochemical and co-precipitation techniques in aqueous medium
from readily available inexpensive starting materials without any surfactant or capping agent. The particle
size was determined by transmission electron microscopy (TEM), scanning electron microscopy (SEM) and
X-ray diffraction (XRD) analysis. The magnetic nature of catalyst facilitates its easy removal from the
reaction medium and can be reused five times without any significant loss of its catalytic activity.
Negligible leaching of Cu and Fe in consecutive cycles makes the catalyst economical and environmentally
benign. The structure of final products was established by single crystal X-ray analysis and spectroscopic
techniques.
Received 10th October 2012,
Accepted 17th December 2012
DOI: 10.1039/c2ra22477a
www.rsc.org/advances
recoverable, thereby eliminating the requirement for either
solvent swelling before or catalyst filtration after completion of
1. Introduction
In recent years, nanoscience is an emerging field in the search
to exploit diverse technological applications and magnetic
nanomaterials are envisaged to have a major impact in many
areas, including biotechnology, environmental remediation
and especially catalysis.1 Nanoparticles have materialized as
viable alternatives to conventional materials as robust, readily
available, large-surface-area, fewer coordination sites, and
reactive morphologies, which maximize the reaction rates
and minimize consumption of the catalyst. In view of their
nano-size, the contact between reactants and catalyst increases
dramatically thus mimicking the heterogeneous catalyst.
However, the recoverable problem must be addressed before
nanocatalytic processes can be scaled-up, due to the fact that
nanoparticles, which include nano-scaled metal catalysts and
supports, are difficult to separate from the reaction mixture,
which can lead to the blocking of filters and valves by the
nanoparticle catalyst. Currently, a method used to address this
problem is the use of magnetic nanoparticles (MNPs),2 a route
that has attracted wide research interest for its unique physical
properties. They possess advantage of being magnetically
the reaction. The strategy of magnetic separation, taking
advantage of MNPs, is typically more effective than filtration or
centrifugation as it prevents loss of the catalyst. The magnetic
separation of MNPs, is simple, economical and promising for
industrial applications.
The increased interest in organofluorine compounds has
led to the development of novel medicinal agents and new
strategies in drug discovery and development. The synthesis of
fluorine containing complexes or compounds and their
derivatives provide unlimited potential for creating novel
pharmacologically active lead compounds for use as thera-
peutics.3 The selective introduction of one or more fluorine
atoms or trifluormethyl group into specific positions in an
organic molecule changes the molecules’ physicochemical
properties, including its stability, bioavailability, and lipophi-
licity. The above behavior could be explained by the unique
physical, chemical, and biological properties of the fluorine
atom.4
The hexahydropyrimidine skeleton is present in a number
of alkaloids, eudistomidines
H
and I,5 tetraponerines,6
verbametrine7 and verbamethine.8 Hexetidine is a formalde-
hyde-releasing antimicrobial agent employed in mouthwashes
and numerous products of veterinary and human drugs.9
Different N-substituted hexahydropyrimidines are synthetic
intermediates for spermidine-nitroimidazole drugs for the
treatment of A549 lung carcinoma.10 They form structural
Center for Advance Studies, Department of Chemistry, University of Rajasthan,
Jaipur-302004, India. E-mail: dranshudandia@yahoo.co.in; Fax: +91 141 2609549;
Tel: +91 941 4073436
Electronic supplementary information (ESI) available. CCDC 897553. For ESI
3
and crystallographic data in CIF or other electronic format see DOI: 10.1039/
c2ra22477a
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units in trypanothione reductase inhibiting ligands for the
regulation of oxidative stress in parasite cells.11 N-(4-amino-
butyl) hexahydropyrimidine and N-(3-aminopropyl) hexahy-
dropyrimidine are shown to compete with spermidine for
uptake by L1210 cells.12 Due to their significant biologically
activity, hexahydropyrimidines have received a great deal of
attention in recent years.
Hexahydropyrimidines are classically prepared by conden-
sation between substituted propane-1,3-diamines and alde-
hydes or ketones.13a–f This method, however, limits the range
of substitution at 5-position of the hexahydropyrimidines,
being restrained by the availability of appropriately functio-
nalized 1,3-diamines. There are also a few reports in the
literature describing the synthesis of substituted hexahydro-
pyrimidine derivatives by using a,b-unsaturated nitriles, by the
reaction of substituted alanine and carbamide14a,b or by the
reaction of 1,3-dicarbonyl compounds or cyclic ketones,
aromatic amines and formaldehyde.15a,b Thus each of the
known procedure has its own merits; however, further studies
are still necessary for the versatile, simple, ecofriendly and
economical multicomponent methodology.
Multicomponent reactions allow the creation of several
bonds in a single operation and are attracting increasing
attention as one of the most powerful emerging synthetic tools
for the creation of molecular diversity and complexity.16
Considering the above points and in continuation of our
ongoing program in the development of greener and sustain-
able processes for heterocyclic synthesis17 and nano-cataly-
sis,18,19 we were, thus, intrigued by the possibility of applying
nanotechnology to the design of highly efficient, recyclable
and magnetically recoverable CuFe2O4 nanoparticles as a
heterogeneous catalyst for the synthesis of highly substituted
spiropyrimidines incorporating pharmacophoric fluorine or
trifluoromethyl group under mild reaction conditions for the
first time.
2. Results and discussion
The first step entails the synthesis of highly stable copper
ferrite nanoparticles. The catalyst was prepared by combined
sonochemical and co-precipitation technique in aqueous
medium without using any surfactant or capping agent. The
nanostructure of CuFe2O4 nanoparticles has been well
characterized by using X-ray diffraction (XRD), scanning
electron microscopy (SEM) and transmission electron micro-
scopy (TEM) technique. The crystallinity and phase purity of
CuFe2O4 nanoparticles were examined by XRD measurements.
As shown in Fig. 1, the strong and sharp reflection peaks in
XRD patterns of dried precipitate which is mainly composed of
tetragonal CuFe2O4 with a good crystallinity (JCPDS card N
034-0425).20 The average particle size was calculated to be 38
nm using Scherrer formula,
D = 0.94 l/b cosh
where D is the average size of the particles, l is the wavelength of
the incident X-ray, h is the Bragg angle (in degrees), b is the full-
width (in radians) subtended by the half-maximum intensity width
of the powder peak, expressed in units of 2h.
The structural composition and crystallinity of CuFe2O4
nanoparticles was further ascertained by SEM and TEM (Fig. 2
and 3). The EDX analysis showed that the distribution of the
elements in the product was Cu = 14.28%, Fe = 28.95% and O =
56.77%. Thus the iron\copper ratio in the nanocrystals by EDX
was found to be 2.02 which is very much close to the atomic
ratio in the formula CuFe2O4. The particle size were also
measured in SEM micrograph and were found to be in the
range of 35–50 nm which is consistent with the particle size
obtained from XRD analysis.
The FTIR spectra (Fig. S4, ESI ) of the CuFe O nanopar-
3
2
4
ticles indicate the presence of two absorption bands at 562
cm21 and 480 cm21. These intense absorption bands are
attributed to the stretching vibration of Fe3+–O22 in the
Fig. 1 (a) XRD spectrum of native CuFe2O4 catalyst. (b) XRD spectrum of reused CuFe2O4 catalyst after 4th cycle.
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Fig. 2 (a) SEM image of native CuFe2O4 catalyst. (b) SEM image of reused CuFe2O4 catalyst after 4th cycle.
tetrahedral complexes and Cu2+–O22 in the octahedral com-
plexes respectively. The positions of these bands confirm the
existence of Cu2+ ions entirely in the octahedral sites and the
Fe3+ ions in tetrahedral ones.21
separation of nanoparticle catalysts, by reducing the viscosity
of the reaction mixture and facilitating the congregation of
magnetic catalyst, when the reaction was complete. Slightly
lower yields were obtained when acetonitrile, dimethyl
sulfoxide (DMSO), and DMF were used as the solvent
(Table 1, entries 3, 4 and 5). Dichloromethane, tetrahydrofur-
ane and dioxane afforded the products in only low to moderate
yields (Table 1, entries 6–8). The corresponding product was
also obtained in good yield under neat conditions (Table 1,
entry 9). However, the mixture was viscous in the absence of a
solvent and made the separation of catalyst from products
difficult magnetically unless an extraction solvent such as
ether was added. Performing the reaction with a higher
catalyst loading (20 mol%) had no significant effect on yield.
However, if the amount of the catalyst was reduced to 5 and 1
mol%, the product yield was reduced to 62% and 26%
respectively.
The choice of an appropriate reaction medium is of crucial
importance for successful synthesis. Initially, the three-
component condensation reaction of cyclohexanone 1a,
formaldehyde 2 and 4-fluoroaniline 3a in the presence of 10
mol% CuFe2O4 as a simple model substrate was investigated
to establish the feasibility of the strategy and to optimize the
reaction conditions (Scheme 1). Different solvents such as
ethanol, acetonitrile, dimethyl sulfoxide (DMSO), DMF,
dichloromethane, tetrahydrofuran and dioxane, were explored.
After optimization, we observed that ethanol was the most
effective solvent for this three-component condensation
reaction. The use of ethanol effected not only the condensa-
tion reaction of ketone, formaldehyde and aromatic amine in
good yield, but also performed well in the process of magnetic
Fig. 3 (a) TEM image of native CuFe2O4 catalyst. (b) The EDX spectrum of native CuFe2O4 catalyst.
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Scheme 1 Synthesis of spirohexahydropyrimidine 4a.
The CuFe2O4 nanoparticle catalyst plays a crucial role in the
success of the reaction. In the absence of CuFe2O4 nanopar-
ticle catalyst, the model reaction (Scheme 1) could be carried
out, but the product was obtained in very low yield after
prolonged reaction time (Table 1, entry 1).
With these encouraging results in hand, we turned to
explore the scope of the reaction using different aromatic
amines as substrates under the optimized reaction conditions
(Table 2). It was observed that the aromatic amines having
electron donating as well as electron withdrawing group
reacted successfully to furnish spiropyrimidine derivatives
with good yields. In addition, we have also explored the
reactivity of cyclic ketones for this transformation. From the
results, it is clear that cyclohexanone showed better reactivity
than 4-methylcyclohexanone and slightly higher yields were
obtained, while, 1,4-dioxaspiro[4.5]decan-8-one is found to be
less active than cyclohexanone (Table 2).
Further, the leaching of the metal from the CuFe2O4
nanoparticles was investigated. After completion of the
reaction, the supernatant was collected and tested for Fe and
Cu by inductively coupled plasma-atomic emission spectro-
scopy (ICP-AES). The leaching of Fe and Cu in three
consecutive cycles was found to be ¡0.5 ppm, which is well
below the permissible level concerning the toxicity in
humans.22 This study clearly demonstrated that there was no
significant amount of leaching. It is also observed from
spectral studies that there is no change in the nature of the
catalyst even after four cycles. The powder X-ray diffraction
analysis exhibited identical peaks for both fresh and recovered
CuFe2O4 nanoparticles, which were compared with those
reported in the literature (Fig. 1).20 In addition, the SEM
analysis of CuFe2O4 nanoparticles before and after the
reaction showed identical shape and size (Fig. 2). These
experimental results clearly suggest that there was no
significant change in the catalytic activity of nano-CuFe2O4
before and after the reaction.
The proposed mechanism for the formation of spirohex-
ahydropyrimidine derivatives is shown in Scheme 2. Initially
an imine is formed due to nucleophilic addition of aromatic
amine to formaldehyde and subsequent loss of water
molecule. After the imine formation, in situ generated enolate
attacks imine to afford b-amino carbonyl derivative A.
Intermediate A reacts further in the same manner to form
substituted propane-1,3-diamine B. Finally the condensation
of the resulting substituted propane-1,3-diamine B with
formaldehyde furnishes the desired spirohexahydropyrimi-
dines.
Here, oxide (O22) of the metal oxide framework acting as a
Lewis base and Fe3+ as Lewis acid coordinate with the carbonyl
oxygen, thus increasing the electrophilicity of the carbonyl
carbon and thereby making it possible to carry out the reaction
at room temperature in short reaction time.
The reusability of the nano-CuFe2O4 catalyst was examined
and the results are summarized in Table 3. The catalyst was
magnetically separated from the reaction mixture after
completion of the reaction, washed with ethanol, air dried
and used directly for further catalytic reactions. No significant
loss of catalyst (CuFe2O4) activity was observed up to four
cycles.
Table 1 Optimization for the synthesis of 4a
Entry Solvents
CuFe2O4 (mol%) Time (h) Yield (%)a
a
Isolated yield.
1
2
3
4
5
6
7
8
9
Ethanol
Ethanol
Acetonitrile
DMSO
—
10
10
10
10
24
3
4
4
4
5
5
4
3
3
3
4
14
82
70
76
75
67
58
39
82
83
62
26
DMF
Dichloromethane 10
All the products were well characterized by IR, 1H, 13C NMR,
mass spectra and elemental analysis. The final structure was
confirmed by single crystal X-ray analysis of 9,11-bis-(4-
fluorophenyl)-1,4-dioxa-9,11-diazadispiro [4.1.5.3]pentadecan-
13-one (4k) (Fig. 4).23
Tetrahydrofuran
Dioxane
Neat
Ethanol
Ethanol
10
10
10
20
5
10
11
12
Ethanol
1
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Table 2 Synthesis of spirohexahydropyrimidines
Entry
1
Ketone
Amine
Product
Time (h)
3
Yield(%)a
82
MP (uC)
122–124
2
4
73
178–180
3
3
79
160–162
4
4
74
124–126
5
4
75
248–250
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Table 2 (Continued)
Entry
6
Ketone
Amine
Product
Time (h)
4
Yield(%)a
76
MP (uC)
130–132
7
4.5
70
204–206
8
4
75
166–168
9
4
72
104–106
10
4
64
236–238
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Table 2 (Continued)
Entry
11
Ketone
Amine
Product
Time (h)
4
Yield(%)a
58
MP (uC)
130–132
12
4.5
54
144–146
13
4
61
132–134
14
4.5
52
126–128
15
5
55
206–208
a
Isolated yield.
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Scheme 2 Plausible mechanism for the reaction of 4-fluoroaniline and formaldehyde with cyclohexanone.
(3.34 g, 8.2 mmol) and Cu(NO3)2?3H2O (1 g, 4.1 mmol) in 75
mL of distilled water, 3 g (75 mmol) of NaOH dissolved in 15
mL of water was added at room temperature over a period of
10 min during which a reddish-black precipitate was formed.
Then the reaction mixture was warmed to 90 uC and stirred
under ultrasonic irradiation for two hours. After 2 h, it was
cooled to room temperature and the magnetic particles so
formed were separated by a magnetic separator. It was then
washed with water (3 6 30 mL) and catalyst was kept in an air
oven for overnight at 80 uC. Then the catalyst was ground in a
mortar-pestle and kept in a furnace at 700 uC for 5 h (step up
temperature 20 uC min21) and then cooled to room tempera-
3. Experimental
3.1 General
All the chemicals used were of research grade and were used
without further purification. The melting points of all
compounds were determined on a Toshniwal apparatus. The
purity of compounds was checked on thin layers of silica Gel–
G coated glass plates and n-hexane : ethyl acetate (8 : 2) as
eluent. IR spectra were recorded on a Shimadzu FT IR–8400S
spectrophotometer using KBr pellets. 1H and 13C NMR spectra
were recorded in CDCl3 using TMS as an internal standard on
a Bruker spectrophotometer at 300 and 75 MHz respectively.
Mass spectra of representative compounds were recorded on
JEOL-SX-102 mass spectrometer at 70 eV. Elemental micro-
analyses were carried out on a Carlo-Erba 1108 CHN analyzer.
Single crystal X-ray diffraction was performed on a Bruker
Kappa Apex II instrument.
3.2 Preparation CuFe2O4 nanoparticles
CuFe2O4 nanoparticles were prepared by thermal decomposi-
tion of Cu(NO3)2 and Fe(NO3)3 in water in the presence of
sodium hydroxide. Briefly, to a solution of Fe(NO3)3?9H2O
Table 3 Reusability of the nano-CuFe2O4 catalyst for the synthesis of 4a
No. of cycles
Yield (%)a
1
2
3
4
5
82
81
80
79
79
Fig. 4 Single crystal X-ray structure of 9,11-bis-(4-fluorophenyl)-1,4-dioxa-9,11-
diazadispiro[4.1.5.3]pentadecan-13-one (4k).
a
Isolated yields.
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ture. 930 mg of magnetic CuFe2O4 particles of size 35–50 nm
were obtained.
(300 MHz, CDCl3): d 1.71–1.67 (m, 2H), 1.90–1.86 (m, 4H), 2.37
(t, J = 6.3 Hz, 2H), 3.51 (l, 4H), 4.22 (d, J = 11.4 Hz, 1H), 4.74 (d,
J = 11.4 Hz, 1H), 6.98 (d, J = 7.2 Hz, 4H), 7.24 (d, J = 10.2 Hz,
4H), 13C NMR (75 MHz, CDCl3): 20.8, 27.6, 34.7, 39.1, 49.9,
55.2, 67.9, 118.2, 125.2, 129.1, 148.3, 212.5; MS (ESI) m/z: 389
[M]+. Anal. Calcd for C21H22Cl2N2O: C, 64.79; H, 5.70; N, 7.20.
Found: C, 64.88; H, 5.77; N, 7.08.
(4d) 2,4-Di-p-tolyl-2,4-diazaspiro[5.5]undecan-7-one. White
solid; (Yield: 74%); mp 124–126 uC; IR (KBr): 2932, 1708,
1546, 1460, 1234, 1210, 816 cm21; 1H NMR (300 MHz, CDCl3):
d 1.68–1.66 (m, 2H), 1.88–1.86 (m, 4H), 2.29 (s, 6H), 2.39 (t, J =
6.0 Hz, 2H), 3.40 (d, J = 12.3 Hz, 2H), 3.52 (d, J = 12.6 Hz, 2H),
4.10 (d, J = 11.4 Hz, 1H), 4.79 (d, J = 11.1 Hz, 1H), 6.96 (d, J = 8.1
Hz, 4H), 7.10 (d, J = 8.1 Hz, 4H), 13C NMR (75 MHz, CDCl3):
20.4, 20.8, 27.7, 29.6, 34.6, 39.1, 50.0, 55.4, 69.4, 117.4, 129.7,
147.8, 213.3; MS (ESI) m/z: 348 [M]+. Anal. Calcd for
3.3 Catalyst characterization
The wide angle X-ray diffraction pattern of the sample was
obtained using Bragg–Brentanno geometry on PANalytical
X9pert pro diffractometer in 2h range of 20–70u with Cu-Ka
radiation source (l = 1.5406 Å). The X-ray tube was operated at
45 kV and 40 mA. TEM measurements of the sample were
carried out using a JEOL transmission electron microscope.
Sample for the TEM was prepared by making a clear
dispersion of nanoparticles in dimethyl formaldehyde and
putting a drop of it on a carbon-coated copper grid. Formation
of copper ferrite nanoparticles was first ascertained by electron
dispersive X-ray (EDX) analysis combined with scanning
electron microscopy (SEM). SEM was done on a ‘JEOL JSM-
6610LV’ Scanning Electron Microscope combined with EDX
system (INCA Analyzer). For SEM analysis, the sample was
dispersed on the aluminium stub used for sample mounting.
The sample was scanned at an accelerating voltage of 20 kV at
a working distance of 15 mm. The particle size was measured
at a magnification of 10 kX.
C
23H28N2O: C, 79.27; H, 8.10; N, 8.04. Found: C, 79.41; H,
8.21; N, 7.95.
(4e) 2,4-Bis-(3-chloro-4-fluorophenyl)-2,4-diazaspiro[5.5]un-
decan-7-one. White solid; (Yield: 75%); mp 248–250 uC; IR
1
(KBr): 2948, 2782, 1708, 1592, 1488, 1232, 1216, 828 cm21; H
NMR (300 MHz, CDCl3): d 1.72–1.69 (m, 2H), 1.99–1.81 (m,
4H), 2.46 (t, J = 6.9 Hz, 2H), 3.35 (d, J = 12.6 Hz, 2H), 3.59 (d, J =
12.6 Hz, 2H), 4.28 (d, J = 11.4 Hz, 1H), 4.71 (d, J = 11.4 Hz, 1H),
6.87 (d, J = 8.4 Hz, 2H), 6.92 (s, 2H), 7.24 (d, J = 8.7 Hz, 2H), 13C
NMR (75 MHz, CDCl3): 20.3, 27.9, 34.8, 39.2, 50.8, 55.4, 69.3,
114.4, 119.9, 129.2, 131.6, 135.5, 148.7, 213.3; MS (ESI) m/z: 425
[M]+. Anal. Calcd for C21H20Cl2F2N2O: C, 59.31; H, 4.74; N,
6.59. Found: C, 59.19; H, 4.82; N, 6.69.
(4f) 2,4-Bis-(4-fluorophenyl)-10-methyl-2,4-diazaspiro[5.5]un-
decan-7-one. White solid, (Yield: 76%); mp 130–132 uC; IR
(KBr): 2978, 2922, 2863, 1712, 1609, 1498, 1474, 1256, 1126,
1026, 912, 806, 744 cm21; 1H NMR (300 MHz, CDCl3): d 0.83 (d,
J = 6.0 Hz, 3H), 1.06 (t, J = 12.6 Hz, 1H), 1.41–1.31 (m, 1H), 2.00
(br s, 2H), 2.37–2.22 (m, 2H), 2.57–2.45 (m, 1H), 3.03 (d, J =
12.3 Hz, 1H), 3.30 (d, J = 12.6 Hz, 1H), 3.61 (d, J = 12.6 Hz, 1H),
3.75 (d, J = 12.6 Hz, 1H), 4.14 (d, J = 11.4 Hz, 1H), 4.62 (d, J =
11.1 Hz, 1H), 7.00–6.98 (m, 8H), 13C NMR (75 MHz, CDCl3):
21.2, 27.3, 35.7, 38.6, 43.1, 49.3, 56.0, 57.1, 70.2, 115.6, 115.9,
118.9, 119.0, 119.6, 146.2, 156.1, 159.1, 213.0; MS (ESI) m/z: 370
[M]+. Anal. Calcd for C22H24F2N2O: C, 71.33; H, 6.53; N, 7.56.
Found: C, 71.60; H, 6.58; N, 7.35.
3.4 General procedure for the synthesis of spiropyrimidine
derivatives 4(a–o)
To a solution of cyclic ketones (1 mmol), aromatic amines (2
mmol), formaldehyde (3.3 mmol, 36% aqueous solution), and
a catalytic amount of CuFe2O4 (10 mol%) in ethanol (5 mL)
was stirred at room temperature for the stipulated times. After
completion of the reaction monitored by TLC, 10 mL ethanol
was added to the reaction mixture and the catalyst CuFe2O4
was separated magnetically. The reaction mixture was allowed
to stand overnight. The solid material was filtered off, washed
with water (2 6 10 mL), dried and recrystallized from ethanol
to furnish pure spiropyrimidine derivatives.
Spectral data of compounds 4(a–o). (4a) 2,4-Bis-(4-fluoro-
phenyl)-2,4-diazaspiro[5.5]undecan-7-one. White solid; (Yield:
82%); mp 122–124 uC; IR (KBr): 2944, 2785, 1712, 1576, 1486,
1233, 1208, 827 cm21; 1H NMR (300 MHz, CDCl3): d 1.70–1.64
(m, 2H), 1.87–1.84 (m, 4H), 2.36 (t, J = 6.3 Hz, 2H), 3.50–3.37 (q,
J = 12.6 Hz, 4H), 4.15 (d, J = 11.4 Hz, 1H), 4.61 (d, J = 11.1 Hz,
1H), 7.00–6.97 (m, 8H, ArH), 13C NMR (75 MHz, CDCl3): 20.8,
27.8, 35.0, 39.1, 49.9, 56.2, 70.1, 115.6, 115.9, 119.2, 146.2,
156.0, 159.2, 212.8; MS (ESI) m/z: 356 [M]+. Anal. Calcd for
C21H22F2N2O: C, 70.77; H, 6.22; N, 7.86. Found: C, 70.65; H,
6.17; N, 8.05.
(4g) 2,4-bis-(4-trifluoromethylphenyl)-10-methyl-2,4-diazas-
piro[5.5]undecan-7-one. White solid, (Yield: 70%); mp 204–
206 uC; IR (KBr): 2972, 2934, 2855, 1710, 1617, 1532, 1463,
1222, 1138, 1018, 922, 806, 738 cm21 1H NMR (300 MHz,
;
(4b) 2,4-Bis-(4-trifluoromethylphenyl)-2,4-diazaspiro[5.5]un-
decan-7-one. White solid; (Yield: 73%); mp 178–180 uC; IR
CDCl3): d 0.92 (d, J = 6.6 Hz, 3H), 1.05 (t, J = 12.0 Hz, 1H), 1.63–
1.58 (m, 1H), 2.13–2.01 (m, 2H), 2.58–2.52 (m, 3H), 3.24 (d, J =
12.3 Hz, 1H), 3.48 (d, J = 12.9 Hz, 1H), 3.68 (d, J = 11.7 Hz, 1H),
3.82 (d, J = 12.3 Hz, 1H), 4.21 (d, J = 11.7 Hz, 1H), 4.69 (d, J =
11.7 Hz, 1H), 7.11 (d, J = 8.1 Hz, 4H), 7.29 (d, J = 8.4 Hz, 4H),
13C NMR (75 MHz, CDCl3): 21.8, 27.1, 37.7, 39.4, 42.1, 50.5,
55.9, 57.6, 69.4, 115.3, 118.1, 123.5, 127.1, 130.2, 135.6, 142.4,
150.9, 212.5; MS (ESI) m/z: 470 [M]+. Anal. Calcd for
1
(KBr): 2958, 2802, 1716, 1562, 1498, 1236, 1222, 816 cm21; H
NMR (300 MHz, CDCl3): d 1.76–1.69 (m, 2H), 1.93–1.88 (m,
4H), 2.42 (t, J = 6.6 Hz, 2H), 3.63 (m, 4H), 4.19 (d, J = 11.1 Hz,
1H), 4.60 (d, J = 11.7 Hz, 1H), 7.32–6.95 (m, 8H, ArH), 13C NMR
(75 MHz, CDCl3): 21.2, 27.5, 34.3, 41.8, 49.5, 55.4, 69.9, 112.7,
113.2, 117.6, 145.9, 153.5, 159.8, 211.3; MS (ESI) m/z: 456 [M]+.
Anal. Calcd for C23H22F6N2O: C, 60.52; H, 4.86; N, 6.14. Found:
C, 60.58; H, 4.72; N, 6.04.
C
24H24F6N2O: C, 61.27; H, 5.14; N, 5.95. Found: C, 61.50; H,
5.18; N, 5.78.
(4c) 2,4-Bis-(4-chlorophenyl)-2,4-diazaspiro[5.5]undecan-7-
one. White solid; (Yield: 79%); mp 160–162 uC; IR (KBr):
(4h) 2,4-bis-(4-chlorophenyl)-10-methyl-2,4-diazaspiro[5.5]
undecan-7-one. White solid, (Yield: 75%); mp 166–168 uC; IR
(KBr): 2960, 2928, 2860, 1704, 1618, 1502, 1462, 1240, 1126,
1
2948, 2782, 1708, 1592, 1488, 1232, 1216, 828 cm21; H NMR
2932 | RSC Adv., 2013, 3, 2924–2934
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1014, 910, 814, 736 cm21; 1H NMR (300 MHz, CDCl3): d 0.85 (d,
J = 6.3 Hz, 3H), 1.09 (t, J = 12.6 Hz, 1H), 2.04–1.98 (m, 3H),
2.35–2.28 (m, 2H), 2.51–2.49 (m, 1H), 3.14 (d, J = 12.9 Hz, 1H),
3.39 (d, J = 12.6 Hz, 1H), 3.71 (d, J = 12.6 Hz, 1H), 3.84 (d, J =
12.9 Hz, 1H), 4.25 (d, J = 11.4 Hz, 1H), 4.75 (d, J = 11.7 Hz, 1H),
7.06–6.98 (m, 4H), 7.27–7.23 (m, 4H), 13C NMR (75 MHz,
CDCl3): 21.2, 27.4, 35.6, 38.6, 42.9, 49.4, 55.0, 56.1, 68.1, 118.0,
118.6, 125.0, 125.6, 129.1, 129.2, 148.3, 212.6; MS (ESI) m/z: 403
[M]+. Anal. Calcd for C22H24Cl2N2O: C, 65.51; H, 6.00; N, 6.95.
Found: C, 65.42; H, 6.07; N, 6.82.
(4m) 2,4-Bis(4-chlorophenyl)-10-(1,1-dioxa-2,2-dimethylene)-
2,4-diazaspiro[5.5]undecan-7-one. White solid, (Yield: 61%);
mp 132–134 uC; IR (KBr): 2954, 1708, 1512, 1456, 1244, 1042,
918, 826, 726 cm21; 1H NMR (300 MHz, CDCl3): d 2.02 (t, J = 6.9
Hz, 2H), 2.11 (s, 2H), 2.58 (t, J = 6.9 Hz, 2H), 3.37 (d, J = 12.6 Hz,
2H), 3.85–3.74 (m, 4H), 3.93–3.88 (m, 2H), 4.08 (d, J = 11.1 Hz,
1H), 4.84 (d, J = 11.4 Hz, 1H), 6.98 (d, J = 9.0 Hz, 4H), 7.23 (d, J =
9.0 Hz, 4H), 13C NMR (75 MHz, CDCl3): 34.9, 36.3, 40.4, 48.7,
56.0, 64.4, 67.7, 106.9, 118.3, 125.2, 129.1, 148.4, 211.2; MS
(ESI) m/z: 447 [M]+. Anal. Calcd for C23H24Cl2N2O3: C, 61.75; H,
5.41; N, 6.26. Found: C, 61.84; H, 5.47; N, 6.18.
(4i)
10-Methyl-2,4-di-p-tolyl-2,4-diazaspiro[5.5]undecan-7-
(4n) 10-(1,1-Dioxa-2,2-dimethylene)-2,4-di-p-tolyl-2,4-diazas-
piro[5.5]undecan-7-one. White Solid, (Yield: 52%); mp 126–
one. White solid, (Yield: 72%); mp 104–106 uC; IR (KBr):
2962, 2926, 1710, 1614, 1520, 1456, 1388, 1224, 1136, 918, 816,
732, 524 cm21; 1H NMR (300 MHz, CDCl3): d 0.79 (d, J = 5.6 Hz,
3H), 1.03 (t, J = 12.8 Hz, 1H), 1.42–1.25 (m, 1H), 1.99–1.94 (m,
2H), 2.28–2.22 (l, 7H), 2.42–2.38 (m, 1H), 2.60–2.49 (m, 1H),
3.16 (d, J = 12.6 Hz, 1H), 3.21 (d, J = 12.6 Hz, 1H), 3.56 (d, J =
12.6 Hz, 1H), 3.82 (d, J = 12.6 Hz, 1H), 4.10 (d, J = 11.4 Hz, 1H),
4.78 (d, J = 11.4 Hz, 1H), 6.88–6.83 (m, 4H), 7.11 (d, J = 9.2 Hz,
4H), 13C NMR (75 MHz, CDCl3): 20.5, 21.0, 27.3, 35.4, 37.1,
43.1, 49.8, 55.0, 56.9, 70.3, 116.7, 117.6, 129.5, 130.3, 147.9,
212.8; MS (ESI) m/z: 362 [M]+. Anal. Calcd for C24H30N2O: C,
79.52; H, 8.34; N, 7.73. Found: C, 79.63; H, 8.26; N, 7.62.
(4j) 2,4-Bis-(3-chloro-4-fluorophenyl)-10-methyl-2,4-diazas-
piro[5.5]undecan-7-one. White solid, (Yield: 64%); mp 236–
238 uC; IR (KBr): 2960, 2928, 2860, 1704, 1618, 1502, 1462,
128 uC; IR (KBr): 2928, 1710, 1522, 1108, 914, 734, 652 cm21
;
1H NMR (300 MHz, CDCl3): d 2.02 (t, J = 7.6 Hz, 2H), 2.16 (s,
2H), 2.27 (s, 6H), 2.62 (t, J = 6.6 Hz, 2H), 3.24 (d, J = 12.8 Hz,
2H), 3.79–3.72 (l, 4H), 3.88–3.82 (m, 2H), 3.93 (d, J = 11.1 Hz,
1H), 4.92 (d, J = 10.8 Hz, 1H), 6.98 (d, J = 8.6 Hz, 4H), 7.08 (d, J =
8.6 Hz, 4H), 13C NMR (75 MHz, CDCl3): 20.7, 35.3, 36.4, 40.1,
49.6, 56.4, 64.3, 69.7, 107.2, 117.4, 129.3, 149.7, 212.4; MS (ESI)
m/z: 406 [M]+. Anal. Calcd for C25H30N2O3: C, 73.86; H, 7.44; N,
6.89. Found: C, 73.75; H, 7.54; N, 6.74.
(4o)
2,4-Bis(3-chloro-4-fluorophenyl)-10-(1,1-dioxa-2,2-
dimethylene)-2,4-diazaspiro[5.5] undecan-7-one. White solid,
(Yield: 55%); mp 206–208 uC; IR (KBr): 2954, 1708, 1512, 1456,
1
1244, 1042, 918, 826, 726 cm21; H NMR (300 MHz, CDCl3): d
2.09 (t, J = 7.5 Hz, 2H), 2.23 (s, 2H), 2.64 (t, J = 6.9 Hz, 2H), 3.38
(d, J = 12.3 Hz, 2H), 3.84–3.72 (m, 4H), 3.92–3.88 (m, 2H), 4.21
(d, J = 11.7 Hz, 1H), 4.85 (d, J = 11.7 Hz, 1H), 6.91 (s, 2H), 6.99
(d, J = 9.0 Hz, 2H), 7.29 (d, J = 9.0 Hz, 2H), 13C NMR (75 MHz,
CDCl3): 24.6, 30.1, 37.1, 45.7, 54.1, 62.9, 64.8, 105.9, 118.2,
122.5, 128.1, 134.5, 138.5, 148.3, 211.3; MS (ESI) m/z: 483 [M]+.
Anal. Calcd for C23H22Cl2F2N2O3: C, 57.15; H, 4.59; N, 5.80.
Found: C, 57.26; H, 4.70; N, 5.63.
1240, 1126, 1014, 910, 814, 736 cm21 1H NMR (300 MHz,
;
CDCl3): d 0.91 (d, J = 6.9 Hz, 3H), 1.03 (t, J = 12.6 Hz, 1H), 1.68–
1.61 (m, 1H), 2.04–1.98 (m, 2H), 2.51–2.45 (m, 3H), 3.29 (d, J =
12.3 Hz, 2H), 3.54 (d, J = 12.3 Hz, 1H), 3.83 (d, J = 12.3 Hz, 1H),
4.21 (d, J = 11.1 Hz, 1H), 4.73 (d, J = 11.1 Hz, 1H), 6.81–6.74 (m,
2H), 6.91(s, 2H), 7.19 (d, J = 8.4 Hz, 2H), 13C NMR (75 MHz,
CDCl3): 21.9, 27.8, 36.2, 39.7, 42.9, 50.3, 55.1, 56.8, 67.4, 115.3,
118.8, 120.5, 124.1, 130.5, 136.7, 151.3, 212.6; MS (ESI) m/z: 439
[M]+. Anal. Calcd for C22H22Cl2F2N2O: C, 60.15; H, 5.05; N,
6.38. Found: C, 60.03; H, 5.14; N, 6.27.
(4k) 2,4-Bis(4-fluorophenyl)-10-(1,1-dioxa-2,2-dimethylene)-
2,4-diazaspiro[5.5]undecan-7-one. White solid, (Yield: 58%);
mp 130–132 uC; IR (KBr): 2988, 1704, 1528, 1445, 1256, 1047,
932, 830, 718 cm21; 1H NMR (300 MHz, CDCl3): d 2.02 (t, J = 6.9
Hz, 2H), 2.14 (s, 2H), 2.57 (t, J = 6.6 Hz, 2H), 3.30 (d, J = 12.3 Hz,
2H), 3.92–3.66 (m, 6H), 4.00 (d, J = 10.8 Hz, 1H), 4.72 (d, J =
11.1 Hz, 1H), 6.99–6.97 (m, 8H), 13C NMR (75 MHz, CDCl3):
35.0, 36.3, 40.5, 48.7, 57.0, 64.4, 69.8, 107.1, 115.5, 115.8,
119.2, 146.4, 155.9, 159.1, 211.4; MS (ESI) m/z: 414 [M]+. Anal.
Calcd for C23H24F2N2O3: C, 66.65; H, 5.84; N, 6.76. Found: C,
66.82; H, 5.77; N, 6.48.
3.5 Reusability of the catalyst
After completion of the reaction, 10 mL ethanol was added to
the reaction mixture and the catalyst CuFe2O4 was separated
magnetically, washed with ethanol and then air dried. The
recovered catalyst was used directly in the next runs and no
substantial loss of activity was observed up to four cycles.
4. Conclusion
In conclusion, we have developed a novel, green and highly
efficient protocol for the synthesis of fluorine containing
spirohexahydropyrimidine derivatives using magnetically
separable and easily recyclable heterogeneous CuFe2O4 nano-
catalyst in ethanol at room temperature. The magnetic nature
of this heterogeneous nanocatalyst allows for its easy separa-
tion from the reaction mixture by using a simple bar magnet,
which is an additional greener attribute of this reaction.
Moreover, this method can be considered as an ideal tool for
green synthesis because (1) rapid assembly of medicinally
(4l)
2,4-Bis(4-trifluoromethylphenyl)-10-(1,1-dioxa-2,2-
dimethylene)-2,4-diazaspiro[5.5]undecan-7-one. White solid,
(Yield: 54%); mp 144–146 uC; IR (KBr): 2954, 1708, 1512,
1456, 1244, 1042, 918, 826, 726 cm21 1H NMR (300 MHz,
;
CDCl3): d 2.13–2.01 (m, 4H), 2.43–2.37 (m, 1H), 2.97–2.65 (m,
4H), 3.22–3.16 (m, 1H) 3.44–3.37 (m, 2H), 4.05–4.02 (m, 4H),
6.57 (d, J = 8.7 Hz, 4H), 7.37 (d, J = 8.7 Hz, 4H), 13C NMR (75
MHz, CDCl3): 34.4, 38.3, 38.7, 43.0, 46.0, 48.9, 64.7, 64.8, 107.0,
111.9, 126.6, 150.2, 211.5; MS (ESI) m/z: 514 [M]+. Anal. Calcd
for C25H24F6N2O3: C, 58.37; H, 4.70; N, 5.45. Found: C, 58.48;
H, 4.47; N, 5.52.
privileged heterocyclic molecules by
a three-component
process minimizes the generation of waste; (2) the process
has high atom economy and environmentally benign, since
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Acknowledgements
Financial assistance from the Council for scientific and
Industrial Research New Delhi is gratefully acknowledged.
We are thankful to the Bhabha Atomic Research Centre
(BARC), Mumbai and Central Drug Research Institute (CDRI),
Lucknow, for the spectral and elemental analyses. We are also
thankful to STIC Cochin for single crystal X-ray analysis.
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