Synthesis of spiro heterobicyclic rings using cellulose sulfuric acid under solvent free conditions

Article abstract of DOI:10.14233/ajchem.2013.13774

Cellulose sulfuric acid is found to be a heterogenic recyclable catalyst for the rapid and efficient synthesis spiro heterobicyclic rings via a three component condensation reaction between aldehydes, barbituric acid and urea (or thiourea) under solvent-f

Full text of DOI:10.14233/ajchem.2013.13774

Asian Journal of Chemistry; Vol. 25, No. 6 (2013), 3373-3375
http://dx.doi.org/10.14233/ajchem.2013.13774
Synthesis of Spiro Heterobicyclic Rings Using Cellulose
Sulfuric Acid Under Solvent Free Conditions
*
NASER MONTAZERI , KHALIL POURSHAMSIAN, MASOUD BAYAZI and SOUDABEH KABIRI
Department of Chemistry, Tonekabon Branch, Islamic Azad University, Tonekabon, Iran
*Corresponding author: Fax: +98 192 4274409; Tel: +98 192 4274415; E-mail: montazer50@toniau.ac.ir, montazer1350@gmail.com
(Received: 21 March 2012; Accepted: 21 December 2012) AJC-12590
Cellulose sulfuric acid is found to be a heterogenic recyclable catalyst for the rapid and efficient synthesis spiro heterobicyclic rings via
a three component condensation reaction between aldehydes, barbituric acid and urea (or thiourea) under solvent-free conditions. The
method offers several advantages, including high yields, short reaction times, simple work-up procedure and reusability of the catalyst.
We believe that this applicability of cellulose sulfuric acid with mention advantages makes our method superior over all reported methods
to the synthesis of spiro heterobicyclic compounds.
Key Words: Cellulose sulfuric acid, Solvent-free, Spiro heterobicyclic rings, Barbituric acid.
of stable cellulose derivatives used in many areas of industry
and domestic life. Cellulose and its derivatives have some
unique properties such as biodegradable, inexpensive,
extremely inert and environmentally benign, which make them
attractive catalysts for organic or inorganic transformations16.
Recently, cellulose sulfuric acid has emerged as a promising
biopolymeric solid support acid catalyst for various acid-
catalyze reactions17-22. However, there are no reports on the
use of cellulose sulfuric acid for one-pot three-component
synthesis of tetra aza spiro [5.5] undecane. In continuation of
our previous works on the applications of reusable catalysts
in the synthesis of heterocyclic compounds23-28. We report
cellulose sulfuric acid as a highly efficient, reusable, clean
and economically valuable catalyst for the one-pot, three-
component synthesis of 2,4,8,10- tetra aza spiro [5.5] undecane
-1,3,5,9 tetraone derivatives (4a-h) from reaction of barbituric
acid (1), aryl aldehydes (2) and urea or thiourea (3) under
solvent-free conditions (Scheme-I).
INTRODUCTION
Multicomponent condensation reactions have recently
been discovered to be a powerful method for the synthesis of
organic compounds, since the products are formed in a single
step and diversity can be achieved by simply varying each
component1-3.
Spiro heterocyclic derivatives are important class of
heterocycles with a wide range of biological and pharmaco-
logical activities such as antiviral, antitumor, antihypertensive,
hypertensive, narcotic and analgesic4-8. In addition, spiro
heterocyclic units are present in several bioactive natural prod-
ucts9-12. 2,4,8,10-tetra aza spiro [5.5] undecane-1,3,5,9-tetraone
compounds are one type of spiro heterocycles that generally
synthesized from the reaction of aryl aldehydes, barbituric acid
and urea (or thiourea) in the presence of different catalysts
such as p-TSA13 and iodine14 or without any catalyst and under
microwave irradiation15. Despite the merits of these method-
ologies, harsh reaction conditions, long reaction times, toxicity
or difficulty in product separation remain concerns. Therefore,
the search for the new protocol for the synthesis of 2,4,8,10-
tetra aza spiro [5.5] undecane-1,3,5,9-tetraone is still being
actively pursued. Cellulose is a polymer raw material used for
two general purposes. For many centuries it has served mankind
as a construction material, mainly in the form of intact wood
and textile fibers such as cotton or flax, or in the form of paper
and board. On the other hand, cellulose is a versatile starting
material for chemical conversions, being used at the production
of artifact, cellulose-based thread and films as well as a variety
Scheme-I:Synthesis of spiro [2-oxo-4,6-bis(aryl) hexahydropyrimidine-5,5'-
barbituric acid]

3374 Montazeri et al.
Asian J. Chem.
RESULTS AND DISCUSSION
EXPERIMENTAL
All chemicals were available commercially and used with-
out additional purification. Melting points were recorded on
an electro-thermal type 9100 melting point apparatus. The IR
spectra were obtained using 4300 Shimadzu spectrophotometer
as KBr disks. The 1H NMR (400 MHz) spectra were recorded
with a Bruker DRX 400 spectrometers.
In the last decade, the development of environmentally
green and easily recyclable catalyst for the production of fine
chemicals has been an area of growing interest. In this context,
cellulose sulfuric acid as a solid acid catalyst, play prominent
role in the synthesis of organic heterocyclic compounds.
Cellulose sulfuric acid with high reactivity, high stability, low
toxicity, easy preparation and recyclability is one of the most
attractive catalysts for organic synthesis17-22. Prompted by these
findings, we decided to investigate the efficiency of cellulose
sulfuric acid as a catalyst in the synthesis of 2,4,8,10-tetra aza
spiro [5.5] undecane-1,3,5,9-tetraone derivatives under
solvent-free conditions. First, we investigated the synthesis of
4a as a model reaction to select suitable reaction condition.
The reaction was carried out under solvent-free conditions in
various amounts of cellulose sulfuric acid and also in different
temperatures (Table-1). The efficiency of the reaction is mainly
affected by different amounts of cellulose sulfuric acid and
temperature. In the absence of the catalyst at 110 ºC (entry 1)
or in the presence of the catalyst at room temperature (entry
2) low yield of product was obtained even after 1 h. These
observations indicate that both catalyst and temperature are
necessary for completing the reaction. Increasing in amount
of the catalyst until 0.05 g and reaction temperature until 110
ºC, increased the yield of the product 4a, whereas further
increase in both catalyst amount and temperature have an
inhibitory effect on formation of the product (entries 12-16).
The effects of solvents such as acetone, dichloromethane,
chloroform, acetonitrile, methanol and ethanol were also
studied. According to entries 14-16 the yield of the reaction
under solvent-free conditions was greater and the reaction time
was generally shorter than the conventional method.
Preparation of cellulose sulfuric acid: To a magnetically
stirred mixture of cellulose (5 g) and of n-hexane (20 mL),
chlorosulfonic acid (1.00 g, 9 mmol) was added dropwise at
0 ºC during 2 h. HCl gas was removed from the reaction. Vessel
immediately the reaction mixture was stirred for 2 h and
filtered. The residue was washed with acetonitrile (30 mL)
and dried at room temperature to afford 5.15 g of cellulose
sulfuric acid as a white powder22.
Synthesis of spiro[2-oxo-4,6-bis(aryl)hexahydro pyri-
midine-5,5'-barbituricAcids] (4a-h) catalyzed by cellulose
sulfuric acid: A mixture of burbituric acid 1 (1 mmol), aryl
aldehydes 2 (2 mmol), urea or thiourea 3 (1mmol ) and
cellulose sulfuric acid (0.05 g) as a catalyst was heated at
110 ºC with stirring for 4 min.After completion of the reaction
as indicated by TLC, the resulting solid product was cooled to
room temperature. The boiling ethanol was added and the
catalyst was filtrated. The filtrate was concentrated to give the
solid product that washed with water and recrystallized in the
ethanol to give pure products (4a-h). The structures of the
products were confirmed by 1H NMR and IR spectroscopies
and comparison with authentic samples prepared by reported
methods4,14
.
Recycling and reusing of the catalyst: At the end of the
reaction, the catalyst could be recovered by a simple filtration.
The recovered catalyst was washed with chloroform and dried
at 60 ºC under vacuum for 5 h. It was reused in another reaction
without appreciable reduction in the catalytic activity.
Spiro-(2-oxo-4,6-diphenylhexahydropyrimidine-5,5-
barbituric acid): 4a m.p. 240-241 ºC. IR (KBr, νmax, cm-1):
3360, 3150 (NH), 1735 and 1690 (CO). 1H NMR (DMSO-d6
400 MHz) δ (ppm); δH, 5.30 (s, 2H, 2CH), 7.10-7.50 (m,
10H, aromatic), 7.65 (s, 2H, NH), 11.02, 11.36 (2s, 2H, NH).
13C NMR (100 MHz, DMSO-d6) δ (ppm); δ 57.5 (Cspiro), 62.2
(2CH), 127.8, 129.0, 129.5, 137.1, 150.1, 156.1, 166.5 and
170.5 (4CO).
TABLE-1
EFFECT OF CATALYST, TEMPERATURE AND SOLVENT
ON THE SYNTHESIS OF SPIRO [2-OXO-4,6-BIS-(ARYL)
HEXAHYDROPYRIMIDINE-5, 5'-BARBITURIC
ACID ]a (MODEL REACTION)
Entry Catalyst (g) T (ºC) Solvent Time (min) Yield (%)b
1
2
None
0.05
0.03
0.03
0.03
0.04
0.04
0.04
0.05
0.05
0.06
0.06
0.05
0.05
0.05
0.05
110
r.t.
None
None
None
None
None
None
None
None
None
None
None
None
None
EtOH
60
60
10
7
65
67
86
89
91
88
90
92
89
91
95
94
95
54
64
70
3
90
4
100
110
90
5
6
Spiro-(2-oxo-4,6-bis(p-chlorophenylhexahydropyri-
6
7
midine-5,5-barbituric acid): 4b 290-291 ºC. IR (KBr, νmax
,
7
100
110
90
6
cm-1): 3205 and 3065 (NH), 1770, 1731 and 1687 (C=O). 1H
NMR (DMSO-d6 400 MHz) δ (ppm); δ 5.25 (2H, s, CH), 7.20
(4H, d, 4CH), 7.31 (2H, s, 2NH), 7.44 (4H, d, 4CH), 11.19-
11.56 (2H, 2s, NH). 13C NMR (100MHz DMSO-d6) δ (ppm);
δ 57.7 (Cspiro), 60.7 (2CH), 105.7, 155.1 (Ar), 159.6, 165.3
(CO).
8
6
9
5
10
11
12
13
14
15
16
100
110
100
110
Reflux
5
4
6
6
60
40
45
Spiro(2-thioxo-4,6-bis(p-methyl)hexahydropyri-
midine-5.5'-barbituric acid): 4f m.p. 275-277 ºC. IR (cm-1,
1
KBr): 3325-3213 (NH), 1766, 1716, 1685 (C=O). H NMR
Reflux CH2Cl2
Reflux CHCl3
a1 mmol barbituric acid, 2 mmol benzaldehyde and 1 mmol urea under
different conditions. bIsolated yields
(DMSO-d6 400 MHz) δ (ppm); δ 2.45 (6H, s, 2CH3), 5.36
(2H, s, 2CH), 7.31 (4H, d, 4CH), 8.10 (4H, d, 2NH), 11.23-
11.37 (2H, 2s, NH) 13C NMR(100 MHz, DMSO-d6) δ (ppm);
δ 21.8 (2CH3), 56.9 (CH), 57.06 (Cspiro), 129.3-150.5 (Ar),
155.4(C=S) 162.2-164.08(CO).
Based on the above results, this process was extended to
variety of aryl aldehydes and urea or thiourea in the optimized
system. The results are summarized in Table-2. In all cases,

Vol. 25, No. 6 (2013)
Synthesis of Spiro Heterobicyclic Rings Using Cellulose Sulfuric Acid 3375
TABLE-2
CSA CATALYZED SYNTHESIS OF SPIRO [2-OXO-4,6-BIS-(ARYL) HEXAHYDROPY-
RIMIDINE-5,5'-BARBITURIC ACID ] (MODEL REACTION)a
m.p. (ºC)
Entry
Ar
X
Productb
Time (min)
Yieldc (%)
Found
Reported
1
2
3
4
5
6
7
8
C6H5
O
O
O
O
O
S
4
7
5
6
6
6
7
5
95
93
94
94
92
87
89
90
240-241
290-291
221-223
243-245
237-239
275-277
250-251
246-244
240-241[14]
289-291[14]
220-222[4]
246-248[14]
238-239[4]
-
4a
4b
4c
4d
4e
4f
4-ClC6H4
3-NO2 C6H4
4-MeC6H4
3-CH3OC6H4
4-CH3C6H4
3-ClC6H4
C6H5
O
S
252-253[4]
247[14]-245
4g
4h
aReaction condition: barbituric acid (1mmol), aromatic aldehyde (2 mmol), urea or thiourea (1 mmol) and CSA (0.05 g) at 110 ºC under solvent-
free conditions. bAll products were characterized by use of IR and 1H NMR spectral data and comparision their melting points with those of
outhentic samples. cIsolated yields based on barbituric acid their melting points with those of authentic samples
6. M.I. Al-Ashmawi, K.M. Ghoneim and M. Khalifa, Pharmaze, 35, 591
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in excellent yields. The type of aldehyde and urea or thiourea
had no significant effect on the reaction.
7. W.O. Foye, Principle of Medicinal Chemistry (Lea and Febiger, London)
159 (1989).
Reusability of the catalyst was also investigated for this
purpose, the reaction of barbitric acid, benzaldehyde urea and
cellulose sulfuric acid was again studied under the optimized
conditions. After completion of the reaction, the catalyst was
recovered according to the procedure mentioned in experi-
mental section and reused for a similar reaction. The catalyst
could be used at least three times with only slight reduction in
the catalytic activity (94 % for 1st use; 87 % for 2nd use; 84 %
for 3rd use).
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In conclusion, cellulose sulfuric acid has shown to be an
excellent catalyst for one pot three-component synthesis of
spiro heterocyle derivatives under solvent-free conditions. The
availability and stability of the catalyst, the simple work-up
procedure, excellent yields and recyclability of the catalyst,
make this method a valid contribution to the existing method-
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ACKNOWLEDGEMENTS
21. B.S. Kuarm, J.V. Madhav, B. Rajitha,Y.T. Reddy, P.N. Reddy and P.A.
Crooks, Syn. Commun., 41, 662 (2011).
The authors gratefully acknowledged the financial
support of this research by IslamicAzad University, Tonekabon
Branch.
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