Silica supported tungstic acid (STA): An efficient catalyst for the synthesis of bis-spiro piperidine derivatives under milder condition

Article abstract of DOI:10.1016/j.tetlet.2012.12.105

A mild, efficient, and expeditious method has been developed for the synthesis of 3,5-dispirosubstituted piperidines via a three component, one-pot cyclocondensation reaction of aromatic amines, formaldehyde, and dimedone using Silica supported tungstic acid as heterogeneous catalyst for the first time. The reaction involving formation of six new covalent bonds was conveniently promoted by Silica supported tungstic acid and the catalyst could be recovered easily after the reaction and reused without any loss of its catalytic activity. The advantageous features of this methodology are high atom-economy, operational simplicity, shorter reaction time, convergence, and facile automation.

Full text of DOI:10.1016/j.tetlet.2012.12.105

Tetrahedron Letters 54 (2013) 1302–1306
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Silica supported tungstic acid (STA): an efficient catalyst for the synthesis of
bis-spiro piperidine derivatives under milder condition
⇑
Amol B. Atar, Yeon Tae Jeong
Department of Image Science and Engineering, Pukyong National University, Busan 608-737, Republic of Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
A mild, efficient, and expeditious method has been developed for the synthesis of 3,5-dispirosubstituted
piperidines via a three component, one-pot cyclocondensation reaction of aromatic amines, formalde-
hyde, and dimedone using Silica supported tungstic acid as heterogeneous catalyst for the first time.
The reaction involving formation of six new covalent bonds was conveniently promoted by Silica sup-
ported tungstic acid and the catalyst could be recovered easily after the reaction and reused without
any loss of its catalytic activity. The advantageous features of this methodology are high atom-economy,
operational simplicity, shorter reaction time, convergence, and facile automation.
Received 22 November 2012
Revised 24 December 2012
Accepted 26 December 2012
Available online 3 January 2013
Keywords:
Silica supported tungstic acid
Heterogeneous catalyst
3,5-Dispirosubstituted piperidines
Multicomponent reaction
Ó 2012 Elsevier Ltd. All rights reserved.
The condensation reaction of carbonyl compounds with active
methylene compounds in the presence of amines, known as the
Knoevenagel condensation,1 represents one of the most significant
bond-forming reactions in organic chemistry.2 Especially, due to
to the formation of 3,5-dispirosubstituted piperidines. The synthe-
sis of highly functionalized piperidines is an important synthetic
transformation9 as these compounds find extensive applications
in the synthesis of a number of organic fine and bioactive com-
pounds.10 Also the piperidine ring is present in many natural prod-
ucts11 such as alkaloids, which are responsible for a number of
unique activities including anti-hypertensive,12 anticonvulsant,
and anti-inflammatory activities. Spiropiperidinyl compounds
have attracted an increasing interest as the synthetic targets
due to their important activity as pharmacophores in several
biologically active compounds, mainly alkaloids.13 The synthetic
compounds with a 4-spiropiperidine motif (types A–D) possess
interesting activities as well14 (Fig. 1). In addition, spirofused
piperidines have attracted particular attention due to their miscel-
laneous interesting physiological activities.15
the fact that the resulting
a,b-unsaturated dicarbonyl or related
compounds are useful intermediates, combination of this reaction
with other reactions in a domino fashion3 has been increasingly
employed, thereby making the formation of multiple bonds possi-
ble.4 For example, Knoevenagel condensation has been successfully
combined with hetero Diels–Alder reactions, Michael addition
reactions, ene reactions, and/or sigmatropic rearrangements for
the synthesis of highly functionalized molecules.5 The combined
achievement of making multiple bonds in a one-pot synthesis is
well known as multicomponent coupling reaction promotes a sus-
tainable synthetic approach to new molecule discovery.
Multicomponent reactions (MCRs), defined as one-pot reactions
in which at least three different substrates join through covalent
bonds, have steadily gained importance in synthetic organic chem-
istry. MCRs allow the creation of several bonds in a single opera-
tion and offer remarkable advantages like convergence,
operational simplicity, facile automation, and reduction in the
number of work-up, extraction, and purification processes, and
hence minimize waste generation, rendering the transformations
green.6–8
O
NH
S
N
N
H
B
N
R
A
O
O
O
One of the important reactions in the field of multicomponent
synthesis is a three-component condensation of anilines with
dimedone and formaldehyde in the presence of catalyst leading
R
N
N
H
D
NH
C
⇑
Corresponding author. Tel.: +82 51 629 6411; fax: +82 51 629 6408.
E-mail address: ytjeong@pknu.ac.kr (Y.T. Jeong).
Figure 1. Compounds with 4-spiro piperidine skeleton as pharmaceuticals.
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.12.105

A. B. Atar, Y. T. Jeong / Tetrahedron Letters 54 (2013) 1302–1306
1303
In continuation of our ongoing effort to development of new
environmentally benign methodology for the synthesis of an useful
precursor in the field of biology, industry, and key intermediate for
the multistep synthesis,20 we decided to investigate the efficiency
of supported silica tungstic acid catalyst for the synthesis of 3,5-
dispirosubstituted piperidines. So herein we wish to report the
multicomponent reaction for the synthesis of 3,5-dispirosubstitut-
ed piperidines from Dimedone, formaldehyde, and various aro-
matic amines using silica tungstic acid as a reusable catalyst at
room temperature in quantitative yield (Scheme 1). The reaction
is easy to perform and allows synthesizing various multi function-
alized derivatives. These reaction work-up procedures were simple
and we can isolate products with high purity and yields.
Initially, in search of best catalytic system for this one-pot syn-
thesis, optimization of various reaction parameters like different
metal Lewis acid catalysts, temperature, and solvent was carried
out (Table 1) with the standard reaction of aniline, dimedone,
and formaldehyde. In order to establish the real effectiveness of
the catalyst for the synthesis of 3,5-dispirosubstituted piperidines,
a test reaction was performed without catalyst using aniline, form-
aldehyde, and dimedone at room temperature. It was found that
only a trace amount of product was obtained in the absence of cat-
alyst even after 10 h (Table 1, entry 1).
R
O
N
O
NH2
1
O
O
3
O
O
Silica tugstic acid
H
DCM, rt.
H
R
O
2
4
Scheme 1.
Recently, only two reports16 on the synthesis of various
3,5-dispirosubstituted piperidines have used FeCl3 and In(OTf)3
for spirohexahydropyrimidine, but unfortunately, both reports
use homogenous catalysts. The use of homogenous catalysts has re-
ceived little attention as alternatives in alleviating some of the lim-
itations. Thus, the search for an inexpensive, readily available, and
convenient catalyst is desirable. The usage of heterogeneous metal
Lewis catalyst instead of traditional homogeneous metal Lewis and
Brønsted acid catalysts, could possess a more environmentally
friendly alternative. The development of environmentally friendly
solid catalysts for the synthesis of fine chemicals and pharmaceuti-
cals is becoming an area of growing interest because the use of het-
erogeneous catalytic processes allows easier separation, recovery,
and recycling of the catalysts from the reaction mixtures.17 Solid
catalysts provide numerous opportunities for recovering and recy-
cling catalysts from reaction environments. Among the various het-
erogeneous catalysts, particularly, silica gel-supported tungstic
acid (STA) has advantages of low cost, ease of preparation, environ-
ment friendly, highly efficient, and catalyst recycling. Karami et al.
reported that silica tungstic acid is an efficient catalyst for the syn-
thesis of benzimidazoles18 and benzopyrazines.19
Even though we increased the temperature up to 100 °C for this
catalyst free reaction, there was no appreciable improvement in
yield (Table 1, entry 2). In search of effective, eco-friendly, and effi-
cient reusable catalytic system for this reaction, same test reaction
was performed with different supported metal Lewis acid catalysts
such as Cu–Sn (200 mesh, 100 mg), Cu(OTf)2ÁSiO2, Zn(OTf)2ÁSiO2,
TiO2ÁSiO2, BF3ÁSiO2, and ZnCl2ÁSiO2 (Table 1). To study the role of
SiO2, the reaction was tested with SiO2 (100 mg) only, and we
Table 1
Screening of various types of catalysts and solvents for the synthesis of compound 4aa
O
N
O
NH2
O
O
O
O
Silica tugstic acid
H
DCM, rt.
H
O
3
2
4a
1
Entry
Catalyst (10 mol %)
Solvent
Condition
Time (h)
Yieldb (%)
1
2
3
4
5
6
7
8
—
—
SiO2
DCM
Neat
rt
100 °C
rt
Reflux
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
10
5
10
10
6
6
4
6
4
4
5.5
8
8
6
6
8
8
6
Trace
610
58
52
58
40
78
50
80
93
85
85
82
74
52
65
72
88
85
93
82
90
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
Ethanol
DCM
Ethanol
Water
THF
Toluene
ACN
DCE
DCM
DCM
DCM
DCM
CuSn (200 mesh, 100 mg)
ZnCl2ÁSiO2
BF3ÁSiO2
Cu(OTf)2ÁSiO2
TiO2ÁSiO2
Zn (OTf)2ÁSiO2
STA
9
10
11
12
13
14
15
16
17
18
19
20
21
22
STA
FeCl3ÁSiO2
FeCl3ÁSiO2
STA
STA
STA
STA
STA
STA
STA
rt
rt
Reflux
100 °C
rt
2
4
4
4
STA (05 mol %)
STA (20 mol %)
rt
a
Reactions and conditions: aniline (1 mmol), Dimedone (2 mmol), formaldehyde (3 mmol).
Isolated yields.
b

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A. B. Atar, Y. T. Jeong / Tetrahedron Letters 54 (2013) 1302–1306
Table 2
Table 2 (continued)
Synthesis of diversified 3,5-dispirosubstituted piperidine derivatives via Scheme 1a
Entry
Anilines
Products
Time (h)
Yieldsb (%)
Entry
Anilines
Products
Time (h)
Yieldsb (%)
NH2
NH2
O
N
O
O
4k
6
82
O
N
O
4a
4
93
O
O
O
O
NH2
NH2
F
4l
4
92
O
N
O
4b
5
4
88
90
O
N
O
O
F
O
NH2
MeO
O
OMe
NH2
OMe
OMe
O
O
N
O
4m
4n
4o
6
84
70
nr
MeO
4c
O
O
O
N
O
O
OMe
NH2
O
NH2
N
O
O
O
N
O
O
N
O
O
O
6
N
O
O
O
4d
4e
5
4
88
91
O
NH2
NH2
N
O
10
N
O
O
NH2
OEt
NH2
4p
4q
4r
4s
4
85
82
84
nr
O
O
O
O
N
O
O
O
OEt
4f
4
6
92
85
O
O
N
O
O
O
O
OPh
NH2
O
NH2
OMe
OMe
O
N
5
4g
N
OPh
O
O
O
O
Ph
NH2
Cl
NH2
4h
5.5
87
O
N
O
O
4.5
Cl
N
Ph
O
O
O
COOH
NH2
NH2
4i
4j
6
5
85
86
O
O
N
O
O
O
6
N
O
O
COOH
O
NH2
O
a
Reactions and conditions: aniline (1 mmol), Dimedone (2 mmol), formaldehyde
(3 mmol).
N
b
Isolated yields, nr = no reaction.
O
O
observed comparable good yield as compared to catalyst free reac-
tion (Table 1, entry 3). Among all screened catalysts STA gave the

A. B. Atar, Y. T. Jeong / Tetrahedron Letters 54 (2013) 1302–1306
1305
O
O
H+
O
O
O
O
O
Knoevenagel
Condensation
H
H
Michael addition
H+
H
H+
H
O
O
H
O
O
O
H
O
NH O
Product 4a
NH2
Mannich Reaction
Mannich Reaction
O
O
O
Scheme 2. Probable mechanism of 3,5-dispirosubstituted piperidine ring formation.
Table 3
best result in view of yield and reaction time (Table 1, entry 10). In
contrast TiO2ÁSiO2, BF3ÁSiO2, and ZnCl2ÁSiO2 did not afford the de-
sired product in good yields (Table 1, entries 5, 6, and 8). The sup-
ported Lewis acid catalyst FeCl3ÁSiO2 shows effective, but required
time for the completion of the reaction which is more as compared
with STA catalyst with slight lower yield (Table 1, entry 10, 12, 13).
Careful analysis of screened supported Lewis acid catalyst, shows
that silica supported metal triflates such as Cu(OTf)2ÁSiO2,
Zn(OTf)2ÁSiO2 were effective, but promising results were obtained
with silica supported tugstic acid catalyst in lesser time with better
yield (Table 1, entry 7,9,10).
The reusability of STA in the synthesis of compound 4a
Entry
Reaction cycle
Yielda
1
2
3
4
5
6
Ist (Fresh run)
IInd cycle
93
90
88
88
86
86
IIIrd cycle
IVth cycle
Vth cycle
VIth cycle
a
Isolated yield.
Once we found STA as best catalyst for this reaction, tempera-
ture and solvent optimization was done. We screened various sol-
vents, such as toluene, EtOH, acetonitrile, DCM, DCE, Water, and
THF at room temperature. Among tested different organic solvents,
EtOH, DCM, and DCE found to give good yields. It is worthy of note,
that when we performed the reaction in dichloromethane, reaction
was completed with good yield as compared to dichloroethane and
ethanol in shorter time (Table 1, entries 10, 11, and 18). Once found
best catalyst and solvent condition, we studied the effect of varying
amounts of STA catalyst for this one-pot multicomponent system.
In order to evaluate the appropriate catalyst loading, a model reac-
tion was carried out using 5 and 20 mol % of STA at room temper-
ature (Table 1, entries 21 and 22). It was found that 10 mol % of
catalyst shows maximum yield in minimum time. A larger loading
amount of the catalyst (20 mol %) neither increases the yield nor
shortens the conversion time. So, 10 mol % of catalyst was found
to be the optimal quantity and sufficient to push the reaction
forward.
3,5-dispirosubstituted piperidine ring formation is outlined in
Scheme 2. The spirocyclization looks to proceed as a domino se-
quence of Knoevenagel, Michael, and double Mannich reactions.
The well known reaction of dimedone with formaldehyde leads
to the formation of the standard dimedone–formaldehyde adducts.
In cycle, this undergoes two consecutive Mannich reactions with
aniline to produce the spiro-piperidine.
The reusability of the STA catalyst was also examined. The cat-
alyst was reused six times and the results show that silica sup-
ported tungstic acid (STA) can be reused as such without a
significant loss in yield (Table 3). The reusability of the catalyst re-
duces the cost of the production. Accordingly, after the first fresh
run with 93% yield, the catalyst was removed by filtration. The
recovered catalyst was dried under vacuum at 120 °C for 12 h
and tested up to five more reaction cycles. Recycling and reuse of
the catalyst showed minimal decreases in yields. The product 4a
was obtained in 93%, 90%, 88%, 88%, 86%, and 86% yields after suc-
cessive cycles. (Table 3, entries 1–6), thus proving the catalyst’s
reusability. Careful analysis of Table 3 shows that there no signifi-
cant loss of catalytic activity of this supported catalyst.
After optimizing the conditions, the generality of this method21
was examined by the reaction of several substituted aryl/hetero-
aryl/aliphatic amines, dimedone, and formaldehyde using STA in
dichloromethane at room temperature, the results are shown in
Table 2. In all cases, aromatic amines substituted with either elec-
tron-donating or electron-withdrawing groups underwent the
reaction smoothly and gave the products in good yields. Unfortu-
nately, anilines bearing strong electron-withdrawing groups, for
example, COOH at para position did not give any spiro-products
(Table 2, entry 4s). It could also be concluded that the amines bear-
ing electron-donating groups required shorter time than electron-
withdrawing groups and gave higher yields (Table 2, entries 4b and
4c). On the basis of the above results, this process was then ex-
tended to heterocyclic and aliphatic amines. The 2-amino pyridine
afforded the corresponding product in 70% yield (Table 2, entry
4n), but unfortunately the chemistry not worked well with cyclo-
hexylamine (Table 2, entry 4o). Compared with aromatic amines,
heterocyclic amine afforded relatively lower yields of the corre-
sponding 3,5-dispirosubstituted piperidine.
The reported as well as synthesized novel compounds were fur-
ther characterized by their spectral properties (1H, 13C NMR, and
HRMS).
In summary, a mild, efficient, and expeditious method has been
developed for the synthesis of 3,5-dispirosubstituted piperidines
via a three component; one-pot cyclocondensation reaction of aro-
matic amines, formaldehyde, and dimedone using Silica supported
tungstic acid as heterogeneous catalyst. The main advantage of this
present methodology is the simple work-up, easy recovery of cat-
alyst, no need for anhydrous condition, no base or any additional
activator required, and the residue was crystallized from ethanol
to give the pure product without further purification.
Acknowledgment
This research work was supported by the Second Phase of Brain
Korea (BK21) Program.
A possible mechanism of this one pot reaction is expected on
the basis of reported literature. A possible mechanism for the

1306
A. B. Atar, Y. T. Jeong / Tetrahedron Letters 54 (2013) 1302–1306
Medicinal Natural Products: A Biosynthetic Approach, 2nd ed.; Wiley: New York,
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a
dichloromethane (5 mL) was stirred at room temperature for the stipulated
time mentioned in Table 2. The progress of the reaction was monitored by TLC.
After the completion of the reaction STA was removed from the reaction
mixture by filtration. The solvent was removed under reduced pressure. The
crude product was then purified directly by crystallization from ethanol. The
spectral and analytical data of one of the representative compounds is given
here: 3,3,11,11-Tetramethyl-15-(phenyl)-15 azadispiro [5.1.5.3]hexadecane-
1,5,9,13-tetrone (4a) (Table 2, entry 1) mp: 190–192 °C 1H NMR (400 MHz,
CDCl3): d 1.00 (s, 6H), 1.01 (s, 6H), 2.50 (s, 2H), 2.68-2.64 (d, J = 16 Hz, 4H),
2.86–2.82 (d, J = 16 Hz, 4H), 3.45 (s, 4H), 6.96–6.92 (t, J = 16 Hz, 1H), 7.12 7.10
(d, J = 8 Hz, 2H), 7.29–7.25(m, 2H). 13C NMR (100 MHz, CDCl3): d 28.35, 28.65,
30.78, 32.24, 51.23, 65.70, 118.89,121.66,129.11,151.64,205.95. HRMS (ESI, m/
z): Calcd for C25H31NO4 (m/z) 409.2253. Found: 409.2251.