Synthesis of bis-spiropiperidines using nano-CuFe2O4@chitosan as a robust and retrievable heterogeneous catalyst

Article abstract of DOI:10.3184/174751917X14967701767067

An efficient pseudo six-component synthesis of bis-spiropiperidines is described by one-pot condensation of formaldehyde, aromatic amine and dimedone or N,N-dimethyl-barbituric acid using nano-CuFe₂O₄@chitosan at room temperature. This method provides several advantages including mild reaction conditions, applicability to wide range of substrates, reusability of the catalyst and little catalyst loading.

Full text of DOI:10.3184/174751917X14967701767067

416 RESEARCH PAPER
VOL. 41 JULY, 416–419
JOURNAL OF CHEMICAL RESEARCH 2017
Synthesis of bis-spiropiperidines using nano-CuFe2O4@chitosan as a robust
and retrievable heterogeneous catalyst
Javad Safaei-Ghomi*a, Mohammad Rasool Lashkaria and Hossein Shahbazi-Alavia,b
aDepartment of Organic Chemistry, Faculty of Chemistry, University of Kashan, Kashan, PO Box 87317-51167, Iran
bYoung Researchers and Elite Club, Kashan Branch, Islamic Azad University, Kashan, Iran
An efficient pseudo six-component synthesis of bis-spiropiperidines is described by one-pot condensation of formaldehyde, aromatic
amine and dimedone or N,N-dimethyl-barbituric acid using nano-CuFe O4@chitosan at room temperature. This method provides several
advantages including mild reaction conditions, applicability to wide r2ange of substrates, reusability of the catalyst and little catalyst
loading.
Keywords: six-component synthesis, CuFe2O4@chitosan, bis-spiropiperidines, nanocatalyst, one-pot synthesis
Piperidines and its derivatives are important heterocyclic
compounds with wide pharmacological properties, such as
antibacterial,1 antihistaminic,2 anticonvulsants,3 anti-HIV,4
antitumor,5 acetyl-CoA carboxylase inhibitors,6 and treatment
of influenza virus infection.7 These activities make piperidines
attractive targets in organic synthesis. A number of procedures
have been improved for the synthesis of piperidines in the
presence of catalysts such as FeCl3,8 tartaric acid,9 ZrCl4,10
acetic acid,11,12 silica supported tungstic acid (STA),13 iron(III)
trifluoroacetate,14 cerium supported on chitosan,15 Dy/
chitosan,16 and silica-supported copper.17 Despite the availability
of these ways, there remains enough choice for a capable and
reusable catalyst with high catalytic activity for the preparation
of piperidines. The combination of multicomponent reactions
with a suitable catalyst could expand their effectiveness from
operating cost and conservation points of view. Chitosan
is a biopolymer that can be used as a green catalyst in many
reactions.18–20 Presence of both hydroxyl and amino groups in
chitosan make it useful as an efficient catalyst. The chitosan
can be utilised as a support for the preparation of heterogeneous
catalysts.21–23 Ideally, utilising environmental and green
catalysts which can be simply recycled at the end of reactions
has obtained significant attention in recent years. Magnetic
materials have emerged as a suitable group of heterogeneous
catalysts owing to their numerous applications in synthesis and
catalysis. To overcome the separation problems of the nano-
catalysts, magnetic materials have emerged as recoverable
catalysts. The surface of MNPs can be functionalised easily
through appropriate surface modifications to enable the loading
of a diversity of required functionalities.24–27 Nano-CuFe2O4@
chitosan was prepared easily by crosslinking method. The
CuFe2O4@chitosan nanoparticles were obtained by crosslinking
the amino groups on the chitosan using glutaraldehyde. Herein
we report the use of CuFe2O4@chitosan nanoparticles as an
efficient catalyst for the preparation of bis-spiropiperidines by
one-pot condensation of formaldehyde, aromatic amine and
dimedone or N,N-dimethyl-barbituric acid (Scheme 1).
Results and discussion
Initially, we had explored and optimised different reaction
parameters for the synthesis of bis-spiropiperidines by the
MCR of formaldehyde, 4-chloroaniline and dimedone as a
model reaction (Table 1). These reactions were carried out in
the presence of various catalysts, such as (NH4)2Ce(NO3)6,
BF3·SiO2, FeCl3, chitosan, nano-Fe3O4, nano-Fe3O4@chitosan,
nano-CuFe2O4 and nano-CuFe2O4@chitosan. The best results
R
O
O
N
O
2
O
2a
NH2
O
O
4a i
or
−
nano-CuFe2O4@Chitosan
EtOH
3 HCHO
+
+
or
R
3
O
R
1
N
2
N
O
O
O
N
N
O
N
N
2b
O
N
O
O
O
5a e
−
Scheme 1 Synthesis of bis-spiropiperidines.
* Correspondent. E-mail: safaei@kashanu.ac.ir

JOURNAL OF CHEMICAL RESEARCH 2017 417
were obtained in ethanol and found that the reaction gave
satisfying results in the presence of nano-CuFe2O4–chitosan.
Nano-CuFe2O4 structure contains Fe3+–O2– in the tetrahedral
sites and Cu2+–O2– in the octahedral sites.24 Therefore, copper
plays an important role in the catalytic activity. In order to
optimise the reaction conditions, we have performed the
reaction using varied quantities of the catalyst. There was no
difference in yield and reaction time when catalyst loading was
enhanced to 30 mg.
To investigate the scope and limitation of this catalytic
process, formaldehyde, aromatic amines and dimedone or
N,N-dimethyl-barbituric acid were chosen as substrates (Table
2). Investigations of the reaction scope revealed that various
aromatic amines (bearing electron-withdrawing and electron-
donating groups) can be utilised in this protocol.
examined and it was found that product yields decreased to a
small extent on each reuse (run 1, 88%; run 2, 88%; run 3, 87%;
run 4, 87%; run 5, 86%, run 6, 85%).
Conclusion
In conclusion, we have developed a straightforward method for
the synthesis of bis-spiropiperidines by one-pot condensation of
formaldehyde, aromatic amine and dimedone or N,N-dimethyl-
barbituric acid using nano-CuFe2O4@chitosan at room
temperature. The procedure offers several advantages including
cleaner reaction profiles, use of easily available, cheap, high
yields, shorter reaction time and simple method, reusability of
the catalyst and little catalyst loading.
Experimental
Reusability of the catalysts is one of the significant properties
of every catalyst used in large scale production. Therefore, the
reusability of the heterogeneous catalyst was explored using
the model reaction system under the optimised conditions.
After completion of the reaction, the magnetic nanocatalyst is
easily and efficiently separated from the product by an external
magnetic field. The nano-CuFe2O4–chitosan was washed three
to four times with ethanol and dried at room temperature for
5 h. The reusability of the nano-CuFe2O4–chitosan catalyst was
The products were isolated and characterised by physical and spectral
data. 1H NMR and 13C NMR spectra were recorded on Bruker
Avance-400 MHz spectrometers in the presence of tetramethylsilane
as internal standard. The IR spectra were recorded on FTIR Magna
550 apparatus using with KBr plates. Melting points were determined
on Electro thermal 9200, and are not corrected. The elemental
analyses (C, H, N) were obtained from a Carlo ERBA Model EA
1108 analyser. Powder X-ray diffraction (XRD) was carried out on a
Philips diffractometer of X’pert Company with monochromatised Cu
Kα radiation (λ= 1.5406 Å). Microscopic morphology of products was
visualised by SEM (QBSD). The thermogravimetric analysis (TGA)
curves are recorded using a V5.1A DUPONT 2000. The magnetic
property of magnetite nanoparticle has been measured with a vibrating
sample magnetometer (VSM) (Meghnatis Daghigh Kavir Co.; Kashan
Kavir; Iran) at room temperature.
Table 1 Optimisation of reaction conditions using different catalystsa
Time Yield
Entry Solvent
Catalyst
(h)
20
12
12
7
(%)b
trace
30
37
1
—
—
2
3
4
5
CH3CN
CHCl3
EtOH
EtOH
EtOH
(NH4)2Ce(NO3)6 (5 mol%)
BF3·SiO2 (0.04 g)
FeCl3 (5 mol%)
chitosan (0.03 g)
nano-CuFe2O4 (0.04 g)
Preparation of nano-CuFe2O4@chitosan
Nano-CuFe2O4@chitosan was prepared according to the procedure
reported in the literature with some modification.25 For the preparation
of nano-CuFe2O4@chitosan, chitosan (0.5 g) in 100 mL of 2.0 wt%
acetic acid solution, 1.5 g oleic acid modified CuFe2O4 NPs were added
into a three-necked flask. The mixture was subjected to ultrasonic
wavea for 10 min and stirred for 20 min. Then 2 mL of glutaraldehyde
solution (25 wt%) was added into the mixture at 40 ºC and crosslinking
reaction was kept for 180 min. After the reaction the composites were
gathered through magnetic separation and were washed with deionised
water and ethanol several times. The products were dried under
vacuum conditions.
56
5
60
6
3
67
7
H2O/EtOH (5:5) nano-CuFe2O4@chitosan (0.02 g)
2
74
8
9
CHCl3
CH3CN
EtOH
EtOH
EtOH
EtOH
EtOH
nano-CuFe2O4@chitosan (0.02 g)
nano-CuFe2O4@chitosan (0.02 g)
nano-CuFe2O4@chitosan (0.01 g)
nano-CuFe2O4@chitosan (0.02 g)
nano-CuFe2O4@chitosan (0.03 g)
nano-Fe3O4@chitosan (0.02 g)
nano-Fe3O4
2
2
2
2
2
2
3
52
78
82
88
88
80
61
10
11
12
13
14
Synthesis of bis-spiropiperidines; general procedure
A mixture of formaldehyde (3 mmol), dimedone or N,N-dimethyl-
barbituric (2 mmol), aniline derivatives (1 mmol) and CuFe2O4@
chitosan nanoparticles (0.02 g) in ethanol (15 mL) was stirred at room
b
aFormaldehyde (3 mmol), 4-chloroaniline (1 mmol) and dimedone (2 mmol); Isolated
yield
a
Table 2 Synthesis of bis-spiropiperidines using nano-CuFe2O4@chitosan
Entry
1
2
3
4
5
6
7
8
R
4-Cl
4-Br
Dicarbonyl compound
Dimedone
Dimedone
Dimedone
Dimedone
Dimedone
Dimedone
Dimedone
Dimedone
Product
4a
4b
4c
4d
4e
4f
4g
4h
4i
5a
5b
5c
5d
5e
Time (min)
120
120
120
120
120
120
120
120
120
140
140
145
140
140
Yield (%)a
88
88
84
86
85
90
88
92
85
80
82
81
83
85
m.p. °C (Found)
216–218
200–202
224–226
187–189
250–252
198–200
144–146
190–192
240–242
270–272
230–232
261–263
215–217
247–249
Lit. m.p. °Cref
216–21812
200–20214
220–22214
187–18912
—
199–20115
142–14412
186–18817
238–24012
—
4-NO2
3-NO2
2,3-Cl
4-CH3
4-F
3,4-Me
3,4-Cl
4-NO2
4-Cl
9
Dimedone
10
11
12
13
14
N,N-Dimethyl-barbituric acid
N,N-Dimethyl-barbituric acid
N,N-Dimethyl-barbituric acid
N,N-Dimethyl-barbituric acid
N,N-Dimethyl-barbituric acid
—
—
—
—
2-NO2
4-Br
4-CH3
aIsolated yield

418 JOURNAL OF CHEMICAL RESEARCH 2017
1
temperature. The reaction was monitored by TLC. After completion of
the reaction, the nanocatalyst was easily separated using an external
magnet. The solid product was recrystallised with n-hexane/ethyl
acetate to get pure product.
1687, 1582, 1373, 1255, 1220, 996, 763, 662; H NMR (400 MHz,
CDCl3) δ 2.60 (s, 2H, CH2), 2.75 (s, 12H, NCH3), 3.44 (s, 4H, NCH2),
7.05 (d, J = 8.2 Hz, 2H, ArH), 8.12 (d, J = 8.2 Hz, 2H, ArH); 13C NMR
(100 MHz, CDCl3) δ 28.4, 31.1, 38.2, 52.2, 117.4, 124.6, 139.2, 151.7,
157.4, 168.3; Anal. calcd for C21H22N6O8: C, 51.85; H, 4.56; N, 17.28;
found: C, 51.73; H, 4.47; N, 17.14%.
15-(4-Chlorophenyl)-3,3,11,11-tetramethyl-15-azadispiro [5.1.5.3]
hexadecane-1,5,9,13-tetrone (4a): White solid; yield 88%; m.p.
216–218 °C; IR (νmax/cm–1) KBr: 2964, 2926, 2865, 2834, 2795, 1725,
1735, 1706, 1694, 1598, 1496, 1432, 1340, 1249, 825, 674, 516; 1H NMR
(400 MHz, CDCl3) δ 1.03 (s, 12H, CH3), 2.51 (s, 2H, CH2), 2.65 (d,
J = 12.0 Hz, 4H, COCH2), 2.84 (d, J = 12.0 Hz, 4H, COCH2), 3.43
(s, 4H, NCH2), 7.04 (d, J = 8.4 Hz, 2H, ArH), 7.25 (d, J = 8.4 Hz, 2H,
ArH); 13C NMR (100 MHz, CDCl3) δ 28.4, 28.6, 30.7, 32.3, 51.3, 54.7,
65.6, 120.2, 126.5, 129.1, 150.2, 205.8; Anal. calcd for C25H30ClNO4: C,
67.63; H, 6.81; N, 3.15; found: C, 67.71; H, 6.86; N, 3.23%.
15-(4-Chlorophenyl)-2,4,10,12-tetra-N-methyl-15-azadispiro
[5.1.5.3] hexadecane-1,3,5,9,11,13-hexaone (5b): White solid; yield
82%; m.p. 230–232 ºC; IR (νmax/cm–1) KBr: 3025, 2982, 2935, 1690,
1
1675, 1585, 1473, 1255, 1220, 996, 763, 662; H NMR (400 MHz,
CDCl3): δ 2.63 (s, 2H, CH2), 2.74 (s, 12H, NCH3), 3.42 (s, 4H, NCH2),
6.72 (d, J = 7.8 Hz, 2H, ArH), 7.12 (d, J = 7.8 Hz, 2H, ArH); 13C NMR
(100 MHz, CDCl3): δ 28.4, 31.1, 38.5, 52.6, 116.2, 124.1, 128.6, 147.6,
151.7, 169.5; Anal. calcd for C21H22ClN5O6: C, 53.00; H, 4.66; N, 14.72;
found: C, 52.92; H, 4.57; N, 14.64%.
15-(2-Nitrophenyl)-2,4,10,12-tetra-N-methyl-15-azadispiro [5.1.5.3]
hexadecane-1,3,5,9,11,13-hexaone (5c): Yellow solid; yield 81%; m.p.
261–263 ºC; IR (νmax/cm–1) KBr: 3009, 2971, 2933, 292, 1693, 1685,
1583, 1379, 1252, 1222, 994, 653; 1H NMR (400 MHz, CDCl3) δ 2.59 (s,
2H, CH2), 2.72 (s, 12H, NCH3), 3.40 (s, 4H, NCH2), 6.96 (m, 2H, ArH),
7.35 (t, J = 8.2 Hz, 1H, ArH), 8.03 (d, J = 8.2 Hz, 1H, ArH); 13C NMR
(100 MHz, CDCl3) δ 27.8, 30.6, 37.7, 52.1, 117.2, 120.3, 122.3, 132.4,
136.9, 139.2, 150.8, 168.1; Anal. calcd for C21H22N6O8: C, 51.85; H, 4.56;
N, 17.28; found: C, 51.61; H, 4.38; N, 17.19%.
15-(4-Bromophenyl)-3,3,11,11-tetramethyl-15-azadispiro [5.1.5.3]
hexadecane-1,5,9,13-tetrone (4b): Yellow solid; yield 88%; m.p.
200–202 ºC; IR (νmax/cm–1) KBr: 2956, 1730, 1720, 1705, 1690, 1586,
1
1492, 1247, 1223, 1149, 1075, 823, 661, 515; H NMR (400 MHz,
CDCl3) δ 1.03 (s, 6H, CH3), 1.04 (s, 6H, CH3), 2.52 (s, 2H, CH2), 2.67
(d, J = 13.6 Hz, 4H, COCH2), 2.86 (d, J = 13.6 Hz, 4H, COCH2), 3.45
(s, 4H, NCH2), 7.00 (d, J = 7.2 Hz, 2H, ArH), 7.35 (d, J = 7.2 Hz, 2H,
ArH); 13C NMR (100 MHz, CDCl3) δ 28.3, 28.5, 30.6, 32.2, 51.4, 54.6,
65.5, 120.5, 127.3, 128.2, 151.6, 205.6; Anal. calcd for C25H30BrNO4: C,
61.48; H, 6.19; N, 2.87; found: C, 61.37; H, 6.11; N, 2.75%.
15-(4-Nitrophenyl)-3,3,11,11-tetramethyl-15-azadispiro [5.1.5.3]
hexadecane-1,5,9,13-tetrone (4c): Yellow solid; yield 84%; m.p.
224–226 °C; IR (νmax/cm–1) KBr: 2955, 2932, 2872, 1728, 1703, 1593,
1495, 1325, 1225, 664, 502; 1H NMR (400 MHz, DMSO-d6) δ 0.99 (s,
6H, CH3), 1.01 (s, 6H, CH3), 2.62 (s, 2H, CH2), 2.76 (d, J = 12.0 Hz, 4H,
COCH2), 2.89 (d, J = 12.0 Hz, 4H, COCH2), 3.86 (s, 4H, NCH2), 7.24
(d, J = 8.6 Hz, 2H, ArH), 8.06 (d, J = 8.6 Hz, 2H, ArH); 13C NMR (100
MHz, DMSO-d6) δ 27.9, 28.1, 31.2, 32.4, 49.3, 50.7, 64.8, 117.5, 125.8,
135.0, 153.8, 206.7; Anal. calcd for C25H30N2O6: C, 66.06; H, 6.65; N,
6.16; found: C, 66.14; H, 6.75; N, 6.23%.
15-(3-Nitrophenyl)-3,3,11,11-tetramethyl-15 azadispiro [5.1.5.3]
hexadecane-1,5,9,13-tetrone (4d): Yellow solid; yield 86%; m.p.
187–189 ºC; IR (νmax/cm–1) KBr: 2955, 2929, 1723, 1703, 1534, 1342,
1202, 873, 785, 675; 1H NMR (400 MHz, CDCl3) δ 1.01 (s, 6H, CH3),
1.03 (s, 6H, CH3), 2.56 (s, 2H, CH2), 2.68 (d, J = 12.0 Hz, 4H, COCH2),
2.87 (d, J = 12.0 Hz, 4H, COCH2), 3.59 (s, 4H, NCH2), 7.42–7.75 (m,
4H, ArH); 13C NMR (100 MHz, CDCl3): δ 28.3, 28.5, 30.7, 32.4, 51.3,
53.5, 65.4, 112.8, 115.6, 124.7, 129.6, 149.2, 151.6, 205.7; Anal. calcd
for C25H30N2O6: C, 66.06; H, 6.65; N, 6.16; found: C, 66.12; H, 6.73; N,
6.23%.
15-(4-Bromophenyl)-2,4,10,12-tetra-N-methyl-15-azadispiro
[5.1.5.3] hexadecane-1,3,5,9,11,13-hexaone (5d): White solid; yield
83%; m.p. 215–217 ºC; IR (νmax/cm–1) KBr: 3012, 2984, 2935, 2933,
1696, 1679, 1583, 1471, 1253, 1222, 997, 766, 632, 553; 1H NMR (400
MHz, CDCl3): δ 2.65 (s, 2H, CH2), 2.76 (s, 12H, NCH3), 3.49 (s, 4H,
NCH2), 6.75 (d, J = 7.6 Hz, 2H, ArH), 7.26 (d, J = 7.6 Hz, 2H, ArH);
13C NMR (100 MHz, CDCl3): δ 28.8, 30.6, 38.6, 53.1, 112.5, 117.8,
132.4, 148.3, 151.8, 168.8; Anal. calcd for C21H22BrN5O6: C, 48.47; H,
4.26; N, 13.46; found: C, 48.33; H, 4.18; N, 13.38%.
15-(4-Methylphenyl)-2,4,10,12-tetra-N-methyl-15-azadispiro
[5.1.5.3] hexadecane-1,3,5,9,11,13-hexaone (5e): White solid; yield
85%; m.p. 247–249 ºC; IR (νmax/cm–1) KBr: 3022, 2980, 2935, 1696,
1680, 1583, 1471, 1253, 1222, 997, 766, 632, 553; 1H NMR (400 MHz,
CDCl3) δ 2.25 (s, CH3), 2.68 (s, 2H, CH2), 2.79 (s, 12H, NCH3), 3.51
(s, 4H, NCH2), 6.55 (d, J = 8.2 Hz, 2H, ArH), 7.01 (d, J = 8.2 Hz, 2H,
ArH); 13C NMR (100 MHz, CDCl3) δ 23.8, 28.1, 31.2, 39.4, 53.5, 115.2,
127.5, 130.2, 147.8, 151.5, 168.2; Anal. calcd for C22H25N5O6: C, 58.01;
H, 5.53; N, 15.38; found: C, 58.08; H, 5.61; N, 15.41%.
Electronic Supplementary Information
15-(2,3-Dichlorophenyl)-3,3,11,11-tetramethyl-15-azadispiro
[5.1.5.3]hexadecane-1,5,9,13-tetrone (4e): White solid; yield 85%;
m.p. 250–252 ºC; IR (νmax/cm–1) KBr: 2964, 2939, 2931, 1725, 1706,
Some characteristics of the catalyst are described in the ESI
available through:
stl.publisher.ingentaconnect.com/content/stl/jcr/supp-data/
content-jcr1704765_esi
1
1692, 1584, 1475, 1256, 1223, 998, 768, 669; H NMR (400 MHz,
CDCl3) δ 1.03 (s, 12H, CH3), 2.51 (s, 2H, CH2), 2.66 (d, J = 14.0 Hz,
4H, COCH2), 2.85 (d, J = 14.0 Hz, 4H, COCH2), 3.44 (s, 4H, NCH2),
7.02 (d, J = 8.2 Hz, 1H, ArH), 7.15 (t, J = 8.0 Hz, 1H, ArH), 7.38 (d,
J = 8.8 Hz, 1H, ArH); 13C NMR (100 MHz, CDCl3) δ 28.3, 28.5, 30.7,
32.2, 51.3, 54.4, 65.5, 118.6, 119.8, 124.5, 130.5, 132.8, 150.7, 205.8;
Anal. calcd for C25H29Cl2NO4: C, 62.76; H, 6.11; N, 2.93; found: C,
62.65; H, 6.21; N, 2.85%.
Received 12 May 2017; accepted 4 June 2017
Paper 1704765
https://doi.org/10.3184/174751917X14967701767067
Published online: 2 July 2017
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hexadecane-1,5,9,13-tetrone (4f): White solid; yield 90%; m.p.
198–200 ºC; IR (νmax/cm–1) KBr: 2953, 2931, 1720, 1706, 1535, 1343,
1
2
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CH3), 2.43 (2H, s, CH2), 2.68 (4H, d, J = 13.8 Hz, COCH2), 2.87 (4H,
d, J = 13.8 Hz, COCH2), 3.51 (4H, s, NCH2), 7.26 (2H, d, J = 8.0 Hz,
ArH), 7.48 (2H, d, J = 8.0 Hz, ArH); 13C NMR (100 MHz, CDCl3) δ
20.3, 28.5, 28.6, 30.8, 32.3, 51.6, 55.7, 66.2, 119.5, 129.2, 131.8, 149.4,
206.7; Anal. calcd for C26H33NO4: C, 73.73; H, 7.85; N, 3.31; found: C,
73.78; H, 7.93; N, 3.23%.
15- (4-Nitrophenyl)-2,4,10,12-tetra-N-methyl-15-azadispiro
[5.1.5.3] hexadecane-1,3,5,9,11,13-hexaone (5a): Yellow solid; yield
80%; m.p. 270–272 ºC; IR (νmax/cm–1) KBr: 3021, 2974, 2936, 1691,
3
4
5
6
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