Synthesis of 2-amino-5-alkylidenethiazol-4-ones from ketones, rhodanine, and amines with the aid of re-usable heterogeneous silica-pyridine based catalyst

Article abstract of DOI:10.1016/j.tet.2011.08.032

A new methodology has been developed towards the synthesis of novel 2-amino-5-alkylidenethiazol-4-ones from ketones, amines, and rhodanine. This is the first report of the use of ketones in contrast to aldehydes in all the earlier reported procedures. A n

Full text of DOI:10.1016/j.tet.2011.08.032

Tetrahedron 67 (2011) 7936e7945
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Synthesis of 2-amino-5-alkylidenethiazol-4-ones from ketones, rhodanine, and
amines with the aid of re-usable heterogeneous silica-pyridine based catalyst
*
Chhanda Mukhopadhyay , Suman Ray
Department of Chemistry, University of Calcutta, 92 APC Road, Kolkata 700009, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 8 April 2011
Received in revised form 11 August 2011
Accepted 12 August 2011
Available online 18 August 2011
A new methodology has been developed towards the synthesis of novel 2-amino-5-alkylidenethiazol-4-
ones from ketones, amines, and rhodanine. This is the first report of the use of ketones in contrast to
aldehydes in all the earlier reported procedures. A new heterogeneous dipolar catalyst is designed and
synthesized for this reaction. The unique properties of this catalyst facilitate the synthesis of such
compounds. These 5-alkylidene rhodanine precursors display wide range of biological activities to
possess antiviral, antimicrobial, cardiotonic and anti-inflammatory effects.
Keywords:
2-Amino-5-alkylidenethiazol-4-ones
Ketones
Ó 2011 Elsevier Ltd. All rights reserved.
Rhodanine
Amines
Dipolar catalyst
Silica based substituted pyridine
1. Introduction
mesilate5 (1) and PD-0167570 (2) [both in Fig. 1] are used as dual
inhibitors6 of cellular prostaglandin (PGF2a) and leukotriene pro-
The 2-amino-5-alkylidene-1,3-thiazol-4(5H)-ones and their 5-
arylidene rhodanine precursors represent privileged scaffolds in
drug discovery. A survey of recent papers dealing with the phar-
macological properties of such compounds reveals that they display
a wide range of activities. For example, compounds containing 2-
amino-5-arylidene-1,3-thiazol-4(5H)-one moiety are reported to
have antiviral,1 antimicrobial,2 cardiotonic,3 andanti-inflammatory4
effects. Among the anti-inflammatory agents, Darbufelone
duction (LTB4). Additionally, Darbufelone is orally active in animal
models of inflammation and arthritis7 and is nonulcerogenic at very
high doses.
Numerous synthetic routes8e14 have been developed in order to
obtain this heterocyclic core. However, all of them involve at least
two subsequent steps with lengthy reaction times and laborious
work-up. Thus, such methods are rather inconvenient. Pulici and
Quartieri tried to overcome this by a traceless two-step solid-phase
synthesis.15 It involves reaction of rhodanine with bromo-Wang
resin [4-(bromomethyl)phenoxymethyl polystyrene] in DMF un-
der basic condition. This is immediately followed by a base cata-
lyzed Knoevenagel condensation. Finally an exhaustive piperidine-
mediated cleavage in DMEeTFE (9:1) followed by silica-gel chro-
matography led to the recovery of the expected 2-amino-1-yl-
thiazol-4-one. Therefore, it still suffers from a rather expensive
solid support, lengthy reaction times and additional steps of load-
ing of rhodanine on solid support and cleavage. Moreover, this
protocol is not a very general one, working well for all aldehydes
but not at all effective for ketones. Bourahla et al. reported an ef-
ficient microwave assisted one-pot tandem reaction.16 They,
employed aldimine instead of aldehyde to avoid the use of base in
the Knoevenagel condensation step. However, it comprises a rather
complicated sequence of reaction steps of generation of aldimines,
addition of rhodanine followed by addition of secondary amines. In
recent years, Anderluh et al. reported an acid catalyzed microwave
O
O
N
N
S
S
NH
O
NH2
HO
HO
MeSO3H
PD-67570
Derbufelone
(2)
(1)
Fig. 1. Biologically active 2-amino-1,3-thiazol-4(5H)-one lead compounds.
* Corresponding author. Tel.: þ91 33 23371104; e-mail address: cmukhop@
yahoo.co.in (C. Mukhopadhyay).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.08.032

C. Mukhopadhyay, S. Ray / Tetrahedron 67 (2011) 7936e7945
7937
assisted three component one-pot synthesis of 2-amino-5-
O
alkylidenethiazol-4-ones.17 This condition worked well for all al-
dehydes but again not for ketones. In one of the papers,18 Irvine
et al. reported that despite employing conditions previously
reported as suitable for condensing rhodanine with ketones,19 they
were unable to synthesize the compound from rhodanine and 3,4-
dimethoxyacetophenone, the reasons being both steric and elec-
tronic. Till date, no general methodology is reported for ketones
and only one or two isolated case of formation of 2-amino-5-
alkylidenethiazol-4-ones from ketones is known. We therefore
wish to disclose the development and implementation of a new
methodology for the synthesis of 2-amino-5-alkylidenethiazol-4-
ones with ketones. This is therefore the first report of describing
the synthesis of 2-amino-5-alkylidenethiazol-4-ones from ketones,
rhodanine and amines. It represents a very clean reaction condition,
minimization of undesired product formation, high yield of the
desired product and use of greener solvents.
Again the vast generality of the protocol makes it more ac-
ceptable than the previously reported methodologies, works well
with aliphatic ketones; activated, neutral, hetero-aromatic, elec-
tron donating aromatic kerones; cyclic and acyclic secondary
amines, as well as primary amines. Moreover employing our
methodology we could smoothly synthesize the product from
rhodanine, 3,4-dimethoxyacetophenone and amines, which was
not possible with the earlier methodologies.18
R1
R2
NH
O
S
N
S
(4)
N
R3
R4
The detrimental effect of excess amine to the yield is also
reported.17Under high temperature and in presence of excess base, it
is also expected for the ketones to undergo aldol type condensation
or polymerization reaction. Therefore, use of equivalent amount of
amine is an essential criterion for good yield and a clean reaction. In
that case an additional base catalyst must be used for Knoevenagel
condensation. This additional base catalyst must maximize the de-
sired yield; minimize the side products, since it would minimize the
reaction time and temperature. Therefore, it seems impossible for
ketones to undergo such one-pot three-component condensation
reaction affording 2-amino-5-alkylidenethiazol-4-ones in good
yield and also in short reaction time. This is why no general meth-
odology is still reported for ketones.
We were in search of a model catalyst that would simulta-
neously minimize the reaction temperature and time. It would
increase the electrophilicity of the carbonyl carbon of the ketone by
the coordination of oxygen lone pair with the Lewis acid site or
Bronsted acid present in the catalyst. It would also have a basic site,
and the basicity must be lower than amines to minimize waste
production. Thus both the reaction time and temperature would be
reduced.
2. Results and discussion
We were particularly interested in the synthesis of 2-amino-5-
alkylidenethiazol-4-ones from ketones, rhodanine and amines. It
involves the displacement of rhodanine thiocarbonyl sulfur with
the amine either directly or by activation via alkyl thioether, the
resulting aminothiazolone being condensed with carbonyl via
Knoevenagel condensation.6b,15,20 Alternatively, rhodanine is first
condensed with a carbonyl and the resulting alkylidene rhoda-
nine is reacted with an amine.14aec,16,20a,b The amine acts as the
catalyst in the Knoevenagel condensation and as a nucleophile in
the second step.17 We, therefore, tried the reaction with equi-
molar quantity of rhodanine, 2-acetylthiophene and morpholine
following the procedure for aldehyde reported by Anderluh et al.
However, we isolated the compound (3) and unreacted ketone.
Due to the low electrophilicity of the carbonyl carbon of ketones,
the Knoevenagel condensation did not proceed at al. Therefore,
use of a stronger base, prolonged reaction time and high tem-
perature were essential for reaction with ketones.
The one-pot synthesis was optimized on a model reaction in-
volving 2-acetylthiophene, rhodanine, and morpholine under
a variety of conditions and the results are summarized in Table 1
(detailed optimization table is given in Supplementary data). The
reaction was first tried with a slight excess (2 equiv) of morpholine
under reflux in aqueous ethanol for 120 min. The yield (isolated) of
the desired product was only 30%. As it is expected, the use of
a Lewis acid, FeCl3 as a co-catalyst reduced the reaction time to
60 min and yield also increased to 45%. Comparative yield was
obtained with other Lewis acids like copper iodide, indium chlo-
ride, zinc chloride, and silver triflate. However, maximum yield of
50% was attained within 50 min when silica is used as a Lewis acid.
This is due to the well documented fact that the silanol groups
present on the silica coordinate with the carbonyl oxygen to in-
crease its electrophilicity.22,23 Decreasing the amount of morpho-
line to 1.2 mmol in presence of silica catalyst increased the yield to
63%. Interestingly, when we used equivalent amounts of morpho-
line and silica, we isolated the compound (3) and unreacted 2-
acetylthiophene. Therefore, presence of a base is mandatory for
the Knoevenagel condensation between rhodanine and ketones,
particularly when equivalent quantity of amine is used. Therefore
reagent quantity is optimized as 1 equiv of each of the amine,
rhodanine, and ketone. In that case the use of a weak base catalyst
and silica co-catalyst represents the most powerful methodology
for preparation of 2-amino-5-alkylidenethiazol-4-ones with ke-
tones. The yield decreased substantially when NaOH was used as
a base catalyst. Decreasing the base strength increased the yield;
however the reaction time was slightly extended. This is probably
due to minimization of side product (4) with weaker base catalyst.
Pyridine as a base gave maximum yield. Further decrease in base
strength results in incomplete conversion. Some of the products
obtained after silica-gel column chromatography was contami-
nated with the organic bases used as catalyst proven by 1H NMR
O
S
N
N
(3)
However, long reaction times give rise to compounds (4) as side
products.21 The latter may arise from the nucleophilic displacement
of an alkylidene thiazolone group by means of the anion generated
on a second thiazolone moiety. Interestingly the amount of this
type of side product depended also on the temperature and on the
strength of the bases: in both cases, the greater the strength, the
higher the yield.

7938
C. Mukhopadhyay, S. Ray / Tetrahedron 67 (2011) 7936e7945
Table 1
Optimization of reaction conditionsa
Entry
Amount of morpholine (mmol)
Base catalysts (mmol)
Lewis acid catalysts
Solvent (mL)
Time (min)
Isolated yields (%)
1
2
3
4
5
6
7
8
9
2.0
2.0
1.5
1.2
1.0
1.0
1.0
1.0
1.0
1.0
d
d
EtOHþH2O (2þ2)
EtOHþH2O (2þ2)
EtOHþH2O (2þ2)
EtOHþH2O (2þ2)
EtOHþH2O (2þ2)
EtOHþH2O (2þ2)
EtOHþH2O (2þ2)
EtOHþH2O (2þ2)
EtOHþH2O (2þ2)
EtOHþH2O (2þ2)
120
50
55
60
120
40
55
56
70
240
15
50
61
63
0
15
45
50
65
10
d
Silica (40 mg)
Silica (40 mg)
Silica (40 mg)
Silica (40 mg)
Silica (40 mg)
Silica (40 mg)
Silica (40 mg)
Silica (40 mg)
Silica (40 mg)
d
d
d
NaOH (0.2)
Ammonia (0.2)
DABCO (0.2)
Pyridine (0.2)
Urea (0.2)
10
a
Reaction conditions: Rhodanine (1 mmol), 2-acetylthiophene (1 mmol), different amounts of morpholine, different base catalysts, under refluxing condition.
spectra. Particularly when N-methylpiperazine and dimethylamine
are used in 2-amino-5-alkylidenethiazol-4-ones preparation, the
compounds resulted became highly polar and were eluted from the
column along with weak organic bases that were used. Therefore,
additional crystallization became necessary.
ion is assisted by the aromatic ring in 3-chloromethylpyridine
(mechanism shown in Supplementary data). The canonical struc-
tures contain positive charge only on carbon atom. However, for 2-
or 4-chloromethyl pyridine one of the canonical forms contains
positive charge on nitrogen atom.
Replacement of homogeneous organic base by a heterogeneous
base of similar basic strength would overcome this problem.
Therefore, we have designed and synthesized the following bi-
functional silica based substituted pyridine catalyst (7) according to
Scheme 1.
Using this catalyst we were able to synthesize a variety of 2-
amino-5-alkylidenethiazol-4-ones from rhodanine (1 mmol),
amines (1 mmol), and a variety of ketones (1 mmol) according to
Scheme 2. Except for two cases the desired products (Table 2) were
obtained in excellent yields.
Here, 2-chloromethylpyridine moiety may provide straightfor-
ward possibilities for catalyst design, together with a simple im-
mobilization procedure compared to other less- functionalized
organocatalysts. Significant enhancement in product yield and
a clean reaction condition was the outcome when the catalyst (7)
was used. The products obtained after column chromatography
were highly pure as proven from 1H NMR spectra.
MeO
MeO Si
MeO
SH
6(N)HCl
H2O
OH
OH
OH
SiO2
O
OH
SiO2
Reflux for
24h.
Dry toluene
Reflux, 18h.
f
d
e
2.1. Product characterization
g
Cl
h
i
N
(6)
The products were characterized by IR, 1H NMR, 13NMR, HRMS,
CHN analysis, and X-ray single crystal analysis. As only Z-isomers
were produced with aldehydes in all previous reports,15e17 for ke-
tones also only the Z-isomers were produced as conformed from X-
ray single crystal analysis of 2-dimethylamino-5-(1-thiophen-2-
ylethylidene)-thiazol-4-one (8n) (Table 2, entry 14) (CCDC 812620).
a
c
O
SiO2
Si
O
SH
b
O
Dry toluene
Et3N (excess)
Reflux, 18h.
(5)
c'
d'
f'
a'
e'
g'
h'
O
SiO2
Si
b'
S
O
+
Et3N.HCl
2.2. Mechanism
O
i'
N
(7)
Here, condensation of rhodanine with amine preceded the
Knoevenagel condensation as confirmed from the 1H NMR spectra
of the isolated product obtained by quenching the reaction of
rhodanine, morpholine and 2-acetylfluorene after few minutes.
This is in contrast to the aldehydes, where Knoevenagel conden-
sation is the first step.17 The quenching was done by simply
Scheme 1. Preparation of silica based substituted pyridine catalyst.
Thus we could avoid the harmful effect of pyridine and also
combined the cooperative effect of silica and the organic base.
Here, we have chosen only 3-chloromethylpyridine and not the
2- or 4-substituted pyridine, because the displacement of chloride
O
O
O
SiO2
Si
S
R1
(7)
O
N
R2
O
O
H
N
40 mg
S
N
+
R2
R1
+
S
NH
N
H2O (2 ml) + EtOH (2 ml)
Reflux
S
1 mmol
1 mmol
1 mmol
(8)
R1 = alkyl, aryl.
R2 = alkyl, aryl.
Z-isomer
Scheme 2. Preparation of 2-amino-5-alkylidenethiazol-4-ones.

C. Mukhopadhyay, S. Ray / Tetrahedron 67 (2011) 7936e7945
7939
Table 2
Preparation of 2-amino-5-alkylidenethiazol-4-onesa
Entry
Compound numbering
Structureb
Time (min)
Melting Point (ꢀC)
Isolated Yields (%)
1
5
O
4
S
N
1
8a
68
178e180
91
91
82
93
3
1
2
N
O
O
2
3
4
8b
8c
8d
66
67
65
172e174
78e80
d
S
N
N
2
CH3
O
4
1
5
S
N
3
1
2
N
O
CH3
O
S
N
N
CH3
S
O
79
N
5
8e
71
192e194
N
(continued on next page)
O

7940
C. Mukhopadhyay, S. Ray / Tetrahedron 67 (2011) 7936e7945
Table 2 (continued )
Entry
Compound numbering
Structureb
Time (min)
Melting Point (ꢀC)
Isolated Yields (%)
CH3
O
S
N
6
8f
65
82e84
70
N
N
Me
2
CH3
2'
3'
1'
O
4
4'
1
5
Cl
7
8g
71
d
62
6'
S
N
3
5'
1
2
N
Me
Me
CH3
O
N
Cl
S
8
8h
71
228e230
89
N
O
CH3
O
N
Cl
S
9
8i
78
224e226
86
NH
O
83
10
8j
73
224e226
S
N
N
O

C. Mukhopadhyay, S. Ray / Tetrahedron 67 (2011) 7936e7945
7941
Table 2 (continued )
Entry Compound numbering
Structureb
Time (min)
Melting Point (ꢀC)
Isolated Yields (%)
O
11
8k
68
168e170
93
S
N
N
O
12
8l
67
190e192
73
S
N
N
CH3
O
S
N
13
8m
75
184e186
79
N
O
CH3
S
O
S
14
8n
72
158e160
68
N
N
Me
Me
CH3
S
O
N
S
15
8o
74
214e216
75
N
(continued on next page)
O

7942
C. Mukhopadhyay, S. Ray / Tetrahedron 67 (2011) 7936e7945
Table 2 (continued )
Entry
Compound numbering
Structureb
Time (min)
Melting Point (ꢀC)
Isolated Yields (%)
CH3
O
S
S
N
16
8p
8q
8r
8s
67
140e142
92
N
CH3
S
O
S
N
17
65
86
50
82e84
65
73
82
N
N
Me
CH3
O
MeO
S
N
18
234e236
MeO
N
CH3
S
O
H3C
N
19
172e174
N
a
Reaction conditions: Rhodanine (1 mmol), ketones (1 mmol), amines (1 mmol), 40 mg silica based substituted pyridine catalyst (7), aqueous ethanol (1:1), reflux.
The Z-diastereoselectivity is conformed from X-ray single crystal analysis of a compound (Table 2, entry 14).
b
removing the catalyst from the reaction mixture through filtra-
coordinates with the silanol22,23 groups on silica surface in-
creasing the electrophilicity of the carbonyl carbon and thereby
making it possible to carry out the reaction at a moderate tem-
perature and in short time (Fig. 2). The formation of the Z-isomer
may be explained by the plausible mechanism given below
(Fig. 2). In the compound (9) generated by attack of rhodanine on
ketone, the large group remains as far apart as possible as we have
shown in Fig. 2. A subsequent cis-elimination explains the Z-dia-
stereoselectivity in the final product. The cis-elimination is justi-
fied as the pyridine unit of the catalyst (7) approaches from the
side in which the hydroxyl oxygen coordinates with the silanol
group of the catalyst.
tion. Here, again lies the advantage of heterogeneous catalyst over
homogeneous catalyst of similar basicity. The starting organic
compounds remain in the homogeneous phase of aqueous etha-
nol. Since, the catalyst is heterogeneous, it is outside the homo-
geneous phase.23 Water forms several hydrogen bonds between
the nitrogen atom of catalyst (7) and the organic molecules,
thereby acting as a bridge between the homogeneous and het-
erogeneous phases.23 Here, water brings the active methylene
groups to the lone pair of electrons of pyridine nitrogen of the
catalyst through hydrogen-bonding (Fig. 2) and thereby favoring
the ionization into carbanion donor.23,24 The carbonyl oxygen

C. Mukhopadhyay, S. Ray / Tetrahedron 67 (2011) 7936e7945
7943
O
H
H
O
_
O
O Si
O
NR3R4
O Si
O
B
H
B
S
H NR3R4
H
S
HN
O
O
H
OH
OH
Water brings the amines towards the
lone pair of electron of nitrogen.
NR3R4
S
S
H
N
O
O
O Si
O
O
O Si
O
H
B
H
HS
+
O
B
H
N
S
H
NR3R4
OH
O
OH
+
+
- H2S
O
- H / + H
O
C
H
H
O
H
R1
R2
R2
R1
O
O Si
O
O
O Si
O
H
B
H
O
B
>
R2
H
O
O
H
OH
C
N
O
R1
N
S
S
NR3R4
Oxygen lonepairs coordinates with
the silanol group on silica surface.
NR3R4
O
O Si
O
B
Small group
H
O
H
C-C bond rotation followed
by cis-elimination
O
R2
HO
C
O
H
R1
N
R1
C
S
N
S
HO
R2
NR3R4
NR3R4
Large group
- H2O
(9)
R2
R1
>
Large groups avoid each other
O
R1
R2
N
S
pure covalent bonds
H-bond or other weak interactions.
NR3R4
Z-isomer
Fig. 2. Mechanism of preparation of 2-amino-5-alkylidenethiazol-4-ones.

7944
C. Mukhopadhyay, S. Ray / Tetrahedron 67 (2011) 7936e7945
2.3. Characterization of the catalyst
2.7. TGA analysis
The catalyst (7) was characterized by solid state carbon 13 CP
MAS NMR spectra, IR, elemental analysis, TGA studies, and pH
experiment.
For silica-gel SiO2 in the room temperature to 150 ꢀC interval,
a first loss of 2.4% is attributed to physisorbed water molecules
released and a second loss of 2.9% from 150 to 600 ꢀC is attributed
to the condensation of silanol groups bonded to the surface and the
remaining water molecules.31 Different from silica gel, the silica
based substituted piperidine catalyst (7) presents an additional
11.10% weight loss, mainly attributed to the organic arm. From this
loss mass of organic arm a loading23 of 0.67 mmol/g is obtained,
which is very close to that obtained from elemental analysis.
2.4. Carbon 13 CP MAS NMR spectra
The structure of mercaptopropylsilica22,23,25e29 (5) has been
characterized from our laboratory earlier by solid state carbon-13
CP MAS NMR spectrum. The solid state carbon-13 CP MAS NMR
spectrum of (5) showed peaks at
d 26.9 corresponding to (b, c)
2.8. pH analysis
and at 10.7 for (a). The prepared silica based substituted pyri-
d
dine catalyst (7) was characterized by comparing the solid state
carbon-13 CP MAS NMR spectrum of the prepared catalyst (7)
with that of (5) and the normal solution phase carbon-13 NMR
spectrum of 3-chloromethylpyridine (6). The normal solution
phase carbon-13 NMR spectrum of 3-chloromethylpyridine
To check the basic property of the prepared catalyst (7), the
nitrogen atom of pyridine unit in the catalyst (7) was protonated
with dilute HCl (details in the Supplementary data) and when 1 g of
the protonated species was placed in 100 ml saturated NaCl solu-
tion, the pH of the resultant solution dropped to 3.50 since ion-
exchange occurred between sodium ions and protons. From this
ion-exchange pH analysis the same catalyst loading was obtained
as that from elemental analysis.
showed peaks corresponding to
141.6(f), 145.7, and 145.8 (for h and i). When the catalyst was
prepared, the peak at 41.4 corresponding to (d) of 3-
d 41.4(d), 127.4(g), 137.7(e),
d
chloromethylpyridine vanished and appeared at
d
33.0 as (d0)
along with (c0). This indicates that bond formation has taken
place through carbon (d) and atom S. The remaining peaks for
2.9. Study on optimization of catalyst loading and choice of
solvent
carbons showed slight deviations and appeared at
22.7 for (b0). The0aromatic carbons appeared with little deviations
at
130.4 (e0, g ), 146.8 and 148.4 (f0, h0, i0). This confirms the
d
12.0 for (a0),
To study the effect of catalyst loading the reaction of rhodanine
with 2-acetylthiophene and piperidine was chosen as model re-
action. The results show clearly that silica based substituted pyri-
dine (7) is an effective catalyst for this transformation and 40 mg of
the catalyst was the optimum usage under this condition and the
yields did not increase largely with higher amount of catalyst. It
should be noted that, the yield was best32 with EtOHewater [(2þ2)
mL]. The yield decreased substantially when the reaction was
conducted in the presence of other solvents, such as CH2Cl2, ACN,
and THF etc.
d
structure of the prepared silica based substituted pyridine cata-
lyst (7).
2.5. IR spectra
When the samples are prepared using the well-known method
of KBr pellet, infrared data are useful only to confirm the existence
of the bonded species. Due to the low concentration of the organic
part of modifier on the surface, the intensity of the new bands
attesting the presence of organic groups is weak.30 Hardly we
observe any differences in the 2800e3000 cmꢁ1 range, where
2.10. Recycling experiment
(CeH) vibrations of the eCH2e groups are evidenced.30 The
The possibility of recycling the catalyst was examined using the
reaction of 40-chloroacetophenone with rhodanine and morpho-
line under optimized conditions. The recycled catalyst could be
used at least eight times without any further treatment. Detailed
characterization of the catalyst after first run showed that it was
unaffected under the condition of the reaction. Elemental analysis
of the recovered catalyst after first run showed carbon and ni-
trogen content to be 6.8% and 0.88%, respectively, and a catalyst
site loading of 0.63 mmol/g was obtained which was almost same
with the original catalyst (0.65 mmol/g). The TGA diagram of the
recovered catalyst showed same pattern with the original catalyst.
From TGA also almost same catalyst loading was obtained as that
of original catalyst. In IR also no additional peak appeared and
only the original peaks retained. This may be due to the fact that
since the amino group of the catalyst is tertiary in nature, it does
not interact with the starting materials. A negligible loss in the
catalytic activity of silica based substituted pyridine catalyst was
observed (Table 3). The slightly extended time for the recycles is
probably due to loss of some amount of catalyst in the time of
filtration.
n
strong and broad band in the range 3500e3400 cmꢁ1 corresponds
to the hydrogen bonded SieOH groups and adsorbed water.29,31
The signal at 3080 cmꢁ1 is due to aromatic CeH stretching. The
thio-propyl groups, which is attached to the silicon framework are
identified by the methylene CeH stretching bands29 at roughly
2940e2875 cmꢁ1 and another broad at 1645 cmꢁ1 is also due to O-
H vibration of adsorbed water.31 The weak signal between 1580
and 1450 is due to ]CH2] bending and C]C and C]N ring
stretching.31 The band at 1222 cmꢁ1 corresponds to the vibration
of SieC bond29 and the sharp features around 1092 cmꢁ1 indicated
SieOeSi stretching vibrations.31 These results showed that the
silica surface has been immobilized by covalent bonded organic
molecules.
In addition to structural confirmation, quantitative de-
termination of covalently anchored substituted pyridine group onto
the surface of catalyst (7) was performed by elemental analysis,
TGA analysis and ion-exchange pH analysis.
2.6. Elemental analysis
3. Conclusion
The elemental analysis of MPS (5) showed the carbon content to
be 2.49%.25 In the catalyst (7) the carbon and nitrogen content was
found to be 7.00% and 0.91%, respectively, which ensured a total
conversion of the mercapto group to the S-substituted pyridine
unit. From this a loading of catalyst of 0.65 mmol/g was obtained.
In conclusion, we have developed a rather novel protocol using
a new silica-based heterogeneous catalyst for the one-pot three-
component synthesis of 2-amino-5-alkylidenethiazol-4-ones from
rhodanine, amines, and ketones in contrast to the aldehydes in all

C. Mukhopadhyay, S. Ray / Tetrahedron 67 (2011) 7936e7945
5. Johnson, A. R.; Marletta, M. A.; Dyer, R. D. Biochemistry 2001, 40, 7736.
7945
Table 3
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M.; Connor, D. T.; Dyer, R. D.; Jordan, J. H.; Imre, K. M.; Lesch, M. F.; Mullicam,
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Recycling of silica based substituted pyridine catalyst (7) for the reaction of
40-chloroacetophenone with rhodanine and morpholinea
Cyclesb
Time (min)
Yieldc (%)
1
2
3
4
5
6
7
8
71
71
75
77
76
83
90
95
89
84
84
81
83
79
81
75
a
Reaction conditions: Rhodanine (1 mmol), 40-chloroacetophenone (1 mmol),
morpholine (1 mmol), 40 mg silica based substituted pyridine catalyst (7), aqueous
ethanol (1:1), reflux.
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b
Rection was carried with recovered catalyst.
Isolated yield.
c
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ꢀ
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One of the authors (S.R.) thanks the Council of Scientific and
Industrial Research, New Delhi for his fellowship (JRF). We thank
the CAS Instrumentation Facility, Department of Chemistry, Uni-
versity of Calcutta for spectral data. We also acknowledge grant
received from UGC funded Major project, F. No. 37-398/2009 (S.R.)
dated 11-01-2010. Moreover, NMR Research Centre, IISc, Bangalore-
560012 is gratefully acknowledged for the solid state carbon-13 CP
MAS NMR spectrum.
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Supplementary data
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