An efficient synthetic route for quinazolinyl 4-thiazolidinones

Article abstract of DOI:10.1016/j.tetlet.2009.06.086

An efficient solvent-free cyclocondensation route for condensing mercaptoacetic acid with quinazolinyl-substituted azomethines has been developed using silica chloride as a catalyst for obtaining heteryl-substituted 4-thiazolidinones. The route is found t

Full text of DOI:10.1016/j.tetlet.2009.06.086

Tetrahedron Letters 50 (2009) 5025–5027
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Tetrahedron Letters
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An efficient synthetic route for quinazolinyl 4-thiazolidinones
*
Jyotirling R. Mali, Umesh R. Pratap, Prashant D. Netankar, Ramrao A. Mane
Department of Chemistry, Dr. Babasaheb Ambedkar Marathwada University, Aurangabad 431 004, India
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient solvent-free cyclocondensation route for condensing mercaptoacetic acid with quinazoli-
nyl-substituted azomethines has been developed using silica chloride as a catalyst for obtaining
heteryl-substituted 4-thiazolidinones. The route is found to be rapid, relatively economical, and eco-
friendly. The precursors, quinazolinyl azomethines have been obtained in multisteps starting from
quinazolinone.
Received 19 May 2009
Revised 15 June 2009
Accepted 17 June 2009
Available online 21 June 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
4-Thiazolidinones
Quinazolin-4-(3H)-one
Silica chloride
Solvent-free condition
1. Introduction
media used are found to be carcinogenic and hazardous. The reac-
tion conditions require prolonged heating, tedious work-up, and
4-thiazolidinones and their derivatives are an important class of
compounds in organic and medicinal chemistry. The 4-thiazolidi-
none ring system is a core structure in various synthetic pharma-
costly dehydrating agents. Therefore it was thought worthwhile
to develop a new rapid method for the cyclocondensation.
Silica chloride is gaining importance as a heterogeneous cata-
lyst and is used in various organic transformations. It has also been
used as a dehydrating agent.19 Some cyclocondensations yielding
dihydropyrimidinone,20 2-amino thiazoles,21 6-methyl-3-propy-
nylthio-1,2,4-triazin-5(2H)-one,22 pyranoquinolines, or furano-
quinolines23 are catalyzed by silica chloride. The use of silica
chloride to expedite oxidation of alcohol,24 esterification and
transesterification,25 transdithioacetalization of acetals,26 depro-
tection of oximes/hydrazones/semicarbazones,27 synthesis of ni-
triles and amides,28 synthesis of sulfoxide,29 synthesis of bis-
indolylmethanes,30 etc. has been well explored.
Considering the significance of the silica chloride and in contin-
uation of our earlier interest in providing new and convenient syn-
thetic protocols for the construction of bioactive heterocycles31
herein, we report a rapid, efficient method for the cyclocondensa-
tion of quinazolinyl azomethines and mercaptoacetic acid to yield
4-thiazolidinones using silica chloride as a heterogeneous catalyst
under solvent-free condition (Scheme 1).
ceutical agents, displaying
a broad spectrum of biological
activities1 such as anti-tubercular,2 anti-convulsant,3 anti-cancer,4
anti-fungal,5 anti-inflammatory, and analgesic.6
Quinazolinones are gaining importance as medicinal agents.7
Quinazolinone and its derivatives have been found to possess a
wide spectrum of biological activities such as anti-tubercular,
anti-convulsant, anti-cancer, anti-diabetic, anti-hypertensive, and
anti-inflammatory.8 The combination of quinazolin-4-(3H)-ones
and 4-thiazolidinones in
a molecular framework has shown
remarkable anti-microbial and anti-inflammatory activities.9,10
Literature survey reveals that several synthetic protocols have
been developed for the synthesis of 4-thiazolidinones. The most
commonly employed method11 allows cyclocondensation of azo-
methines (Schiff’s base) with mercaptoacetic acid. The media used
are volatile organic solvents such as toluene, benzene, 1,4-dioxane,
and THF. Attempts have also been made to accelerate the cyclocon-
densation by simultaneous removal of reaction water azotropically
or by using dehydrating agents such as anhydrous ZnCl2,12 sodium
sulfate,13 and DCC.14 The use of Hunig’s base,15 ionic liquid,16 KSF
Montmorillonite,17 and DMF in ZnCl2,18 etc. has also been reported
to expedite the cyclocondensation of the azomethines and mercap-
toacetic acid. It is observed that the reported methods used for the
cyclocondensation are having one or other kind of drawbacks. The
2. Results and discussion
In the present work, the synthesis of 4-thiazolidinones (6)
bearing quinazolinone moiety has been carried using quinazolin-
4-(3H)-one (1). Quinazolin-4-(3H)-one on N-alkylation with ethyl-
bromoacetate in the presence of K2CO3 in N,N-dimethylacetamide
at room temperature gave ethyl-2-(4-oxoquinazolin-3-(4H)-yl)
acetate (2) in a quantitative yield (95%). There is a possibility of
* Corresponding author. Tel.: +91 240 2403311; fax: +91 240 2400291.
E-mail address: manera@indiatimes.com (R.A. Mane).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.06.086

5026
J. R. Mali et al. / Tetrahedron Letters 50 (2009) 5025–5027
O
O
N
O
N
OEt
OEt
NHNH2
Br
N
NH2NH2 H2O
rt, 2 hr
NH
N
O
O
O
K2 CO3, DMAc
rt, 2.5 hr
N
2
3
1
EtOH
Reflux 3 hr
Ar-CHO
4
O
N
O
Ar
H
H
N
OH
N
HS
N
N
N
Ar
O
S
O
O
N
N
Silica Chloride
50oC 1-1.5 hr
O
6a-h
5a-h
Scheme 1. Synthesis of 3-quinazolinyl-substituted acetamido-4-thiazolidinones.
O-alkylation of enolic-OH. It was confirmed by 13C NMR that the N-
alkylation takes place at the ring nitrogen. Ethyl 2-(4-oxoquinazo-
lin-3-(4H)-yl) acetate (2) on further neat condensation with hydra-
zine hydrate at room temperature yielded 2-(4-oxoquinazolin-
3(4H) acetohydrazide) (3). The acetohydrazide (3) condensation
with the various aromatic aldehydes (4) gave the respective qui-
nazolinyl-substituted azomethines (5) in high yields.
and also may be working as a dehydrating agent to remove the
water formed in the reaction. Hence it is claimed that the devel-
oped route for the cyclocondensation is high yielding and needs
simple reaction parameters.
3. Experimental
Various attempts were made to cyclocondense the azomethines
(5) and mercaptoacetic acid using the literature procedures. It was
noticed that none of the approach was convenient to obtain the de-
sired 4-thiazolidinones (6) at least in moderate yields. Considering
the synthetic utilities of silica chloride as a condensing catalyst and
a dehydrating agent here it was therefore thought worthwhile to
incorporate silica chloride to carry out cyclocondensation of azo-
methines and mercaptoacetic acid for obtaining the 4-thiazolidi-
nones (6a–h) (Table 1).
3.1. Preparation of silica chloride
Silica chloride was prepared by following the literature proce-
dure.21 A suspension of silica gel (20 mL) in CH2Cl2 (50 mL) was
added dropwise to SOCl2 (20 mL) at room temperature. Evolution
of a copious amount of HCl and SO2 gas was observed. After stirring
the reaction mass for 1 h, the solvent was removed under reduced
pressure. The silica chloride obtained was dried and stored in a
desiccator.
To optimize the reaction conditions, several alternatives were
attempted. The condensation was carried by using equimolar
amount of the azomethines, mercaptoacetic acid, and 25 mmol %
of silica chloride in refluxed toluene/acetonitrile. The reaction
was monitored by thin layer chromatography (TLC) and was found
to reach completion in 4 h giving 75–80% yields of the 4-thiazolid-
inones. It was observed in another attempt that when the cyclo-
condensation was carried under neat condition using the same
mole proportions of the reactants and silica chloride the cyclocon-
densation was completed within an hour at 50 °C and gave 88–93%
yields of the 4-thiazolidinones. This was found to be the better
alternative for obtaining 4-thiazolidinones as the time required
for the completion of the reaction had been reduced and it does
not require an organic medium.
3.2. Synthesis of ethyl 2-(4-oxoquinozolin-3(4H)-yl) acetate
from quinazolin-4- (3H)–one (2)
Quinazolin-4-(3H)–one
1 (0.01 mol), potassium carbonate
(0.02 mol), and ethyl bromoacetate were dissolved in N,N-dimeth-
ylacetamide (DMAc) (20 mL) and the reaction solution was stirred
for 2.5 h. After completion of the reaction, the reaction mixture
was poured on crushed ice and acidified with hydrochloric acid.
The thus-obtained solid was filtered, washed with water, and crys-
tallized from aqueous ethanol. Yield: 95%, mp: 67 °C.
3.3. Synthesis of 2-(4-oxoquinazolin-3(4H)-yl) acetohydrazide
from ethyl 2-(4-oxoquinozolin-3(4H)-yl) acetate (3)
The expedition rate can be accounted for the electrophilic
behavior of silica chloride which might be helping to enhance
the nucleophilic character of mercapto of mercaptoacetic acid
Ethyl 2-(4-oxoquinozolin-3(4H)-yl) acetate 2 (0.01 mol) and ex-
cess hydrazine hydrate were mixed thoroughly and stirred at room
temperature for 2 h under solvent-free condition. The reaction was
monitored by TLC. After completion of the reaction, the reaction
mass was poured on crushed ice and the solid formed was filtered,
washed with water, and crystallized from DMF.
Table 1
Physical data of the quinazolinyl 4-thiazolidinones
Entry
Ar
4-Thiazolidinones
Time (h)
Yielda (%)
Mp (°C)
Yield: 89%, mp: 225 °C.
1
2
3
4
5
6
7
8
H
6a
6b
6c
6d
6e
6f
1
1
1
1.15
1.25
1
1.50
1
91
93
89
90
89
88
89
89
185–187
140–143
245–247
213–215
233–235
220–223
155–157
218–220
4-OMe
4-Me
4-F
4-NO2
4-Cl
3.4. Synthesis of N0-(4-methoxybenzylidene)-2-(4-
oxoquinazolin-3(4H)-yl) acetohydrazide (5b)
2-(4-Oxoquinazolin-3(4H)-yl) acetohydrazide 3 (0.01 mol) and
4-methoxy benzaldehyde 4b (0.01 mol) were dissolved in ethanol
(10 mL) and the solution was refluxed for three and half hour. After
completion of the reaction ethanol was removed under reduced
2,3-Cl
3,4-OMe
6g
6h
a
Isolated yields.

J. R. Mali et al. / Tetrahedron Letters 50 (2009) 5025–5027
5027
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The solid that was obtained was filtered, washed with water, and
crystallized from ethanol–DMF.
Yield: 90%, mp: 230–231 °C.
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3.5. Synthesis of N-(2-(4-methoxyphenyl)-4-oxothiazolidin-3-
yl)-2-(4-oxoquinazolin-3-(4H)–yl) acetamide (6b quinazolinyl
4-thiazolidinone)
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A mixture of N0-(4-methoxybenzylidene)-2-(4-oxoquinazolin-
3-(4H)–yl) acetohydrazide 5b (0.1 mol), mercaptoacetic acid
(0.15 mol), and silica chloride (0.025 mol) was heated at 50 °C un-
der solvent-free condition for 1 h. The progress of the reaction was
monitored by TLC using hexane–ethyl acetate (7:3). After the com-
pletion of the reaction, the reaction mixture was extracted with
ethyl acetate and organic layer was washed with 5% sodium bicar-
bonate solution and brine. Organic layer was separated and dried
over anhydrous sodium sulfate. From the organic extract the sol-
vent was removed under reduced pressure and the residual crude
solid, thiazolidinone was crystallized from ethanol.
Yield: 93%, mp: 140–143 °C.
All the synthesized compounds were characterized by IR, 1H
NMR, and mass spectroscopic techniques.32
28. Srinivas, K. V. N. S.; Mahender, I.; Das, B. Chem. Lett. 2003, 32, 738.
29. Mohanazadeh, F.; Momeni, A. J. Sci. I.R. Iran 1996, 7, 261.
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Zare, A. R. M. Can. J. Chem. 2007, 85, 416.
31. (a) Pratap, U. R.; Mali, J. R.; Jawale, D. V.; Mane, R. A. Tetrahedron Lett. 2009, 50,
1352; (b) Mahalle, S. R.; Netankar, P. D.; Bondge, S. P.; Mane, R. A. Green Chem.
Lett. Rev. 2008, 2, 103.
4. Conclusion
The use of silica chloride to accelerate the rate of the cyclocon-
densation of azomethines and mercaptoacetic acid to obtain 4-
thiazolidinones under solvent-free condition has been reported
for the first time. The developed synthetic route is simple, eco-
friendly, and high yielding.
32. Spectral data for selected compounds: compound 2: IR (KBr, cmꢀ1): 1736,
1611. 1H NMR (400 MHz, DMSO-d6): dppm 3.02 (t, 3H), 4.22 (q, 2H), 4.74 (s, 2H),
7.58 (d, 1H, J = 8 HZ), 7.77 (m, 2H), 7.80 (s, 1H), 8.29 (d, 1H, J = 8 HZ). 13C NMR
(400 MHz, DMSO-d6): 14.68, 47.92, 62.00, 121.94, 126.69, 128.01, 135.36,
148.61, 160.81, 168.62. Mass: m/z 233 (M+). Compound 3: IR (KBr, cmꢀ1): 3153,
3051, 1683, 1607. 1H NMR (400 MHz, DMSO-d6): dppm 4.27 (s, 2H), 4.58 (s, 2H),
7.52 (t, 1H, J = 8 Hz), 7.67 (d, 1H, J = 8 Hz), 7.80 (t, 1H, J = 8 Hz), 8.10 (d, 1H,
J = 8 Hz), 8.21 (s, 1H), 9.40 (s, 1H). Mass: m/z 219 (M+). Compound 5b: IR (KBr,
cmꢀ1): 3294, 1682, 1607. 1H NMR (400 MHz, DMSO-d6): dppm 3.80 (s, 3H), 5.21
(s, 2H), 7.04 (d, 2H, J = 8 Hz), 7.5–7.8 (m, 4H), 8.1 (s, 1H), 8.2 (d, 2H, J = 8 Hz), 8.
40 (s, 1H), 11.68 (s, 1H). Mass: m/z 337 (M+). Compound 6a: IR (KBr, cmꢀ1):
Acknowledgment
The authors are thankful to Professor D. B. Ingle for his invalu-
able discussions and guidance.
3423, 1573 cmꢀ1 1H NMR (400 MHz, DMSO-d6): dppm 3.68 (s, 2H), 4.70 (s, 2H),
.
5.73 (s, 1H), 7.37–7.44 (m, 5H, Ar), 7.53 (t, 1H, J = 8 Hz), 7.67 (d, 1H, J = 8 Hz),
7.81 (t, 1H, J = 8 Hz), 8.25 (s, 1H), 8.11 (d, 1H, J = 8 Hz), 10.65 (s, 1H). Mass: m/z
381 (M+). Compound 6b: IR (KBr, cmꢀ1): 3188, 1678, 1608, 1519. 1H NMR
(400 MHz, DMSO-d6): dppm 3.70 (s, 2H), 4.68 (s, 2H), 5.69 (s, 1H), 6.94 (d, 2H,
J = 8 Hz), 7.31 (d, 2H, J = 8 Hz), 7.55 (t, 1H, J = 8 Hz), 7.67 (d, 1H, J = 8 Hz), 7.82
(t, 1H, J = 8 Hz), 8.11 (d, 1H, J = 8 Hz), 8.25 (s, 1H), 10.58 (s, 1H). Mass: m/z 411
(M+). Compound 6c: IR (KBr, cmꢀ1): 3344, 1735, 1676, 1611. 1H NMR
(400 MHz, DMSO-d6): dppm 2.28 (s, 3H), 3.70 (s, 2H), 4.57 (s, 2H), 5.85 (s,
1H), 7.15 (d, 2H, J = 8 Hz), 7.25 (d, 2H, J = 8 Hz), 7.52 (t, 1H, J = 8 Hz), 7.65 (d, 1H,
J = 8 Hz), 7.81 (t, 1H, J = 8 Hz), 8.09 (d, 1H, J = 8 Hz), 8.20 (s, 1H). Mass: m/z 395
(M+). Compound 6d: IR (KBr, cmꢀ1): 3221, 1681, 1611, 1511. 1H NMR
(400 MHz, DMSO-d6): dppm 3.71 (s, 2H), 4.69 (s, 2H), 5.77 (s, 1H), 7. 27 (t, 1H,
J = 8 Hz), 7.56 (d, 1H, J = 8 Hz), 7.71 (d, 1H, J = 8 Hz), 7.82 (d, 2H, J = 8 Hz), 7.86
(t, 1H, J = 8 Hz), 8.15 (d, 2H, J = 8 Hz), 8.27 (s, 1H), 10.67 (s, 1H). Mass: m/z 399
(M+).
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