Efficient one-pot four-component synthesis of fused thiazolopyridin-2-ones in ionic liquid

Article abstract of DOI:10.1007/s12039-013-0522-7

An efficient one-pot synthesis of fused thiazolopyridinone derivatives (5-amino-6,7-diphenyl-4,7- dihydro-3H-thiazolo[4,5-b]pyridin-2-ones) by four-component reaction of aldehyde, benzylcyanide, ammonium acetate and thiazolidine-2,4-dione in ionic liquid

Full text of DOI:10.1007/s12039-013-0522-7

c
J. Chem. Sci. Vol. 125, No. 6, November 2013, pp. 1471–1480. ꢀ Indian Academy of Sciences.
Efficient one-pot four-component synthesis of fused
thiazolopyridin-2-ones in ionic liquid
PRASHANT SINGHa,b,∗, KAMLESH KUMARIc, GAURAV KAITHWASd
and GOPAL K MEHROTRAc
aAtma Ram Sanatan Dharma College, University of Delhi, New Delhi 110 021, India
bDepartment of Applied Chemistry, Babasaheb Bhimrao Ambedkar University, Lucknow 226 025, India
cDepartment of Chemistry, Motilal Nehru National Institute of Technology, Allahabad 211 004, India
dDepartment of Pharmaceutical Sciences, Babasaheb Bhimrao Ambedkar University, Lucknow 226 025, India
e-mail: arsdchemistry@yahoo.in
MS received 22 March 2012; revised 16 July 2012; accepted 3 October 2012
Abstract. An efficient one-pot synthesis of fused thiazolopyridinone derivatives (5-amino-6,7-diphenyl-4,7-
dihydro-3H-thiazolo[4,5-b]pyridin-2-ones) by four-component reaction of aldehyde, benzylcyanide, ammo-
nium acetate and thiazolidine-2,4-dione in ionic liquid is reported. This protocol has the advantages of envi-
ronmental friendliness, higher yields, less reaction time, and convenient operation. Also, optimization of the
synthesized compounds has been done using Hyperchem 8.0.
Keywords. One-pot synthesis; thiazolopyridinone derivatives; multicomponent reactions; ionic liquid.
1. Introduction
solvents, and more attention has been currently drawn
on organic reactions promoted by ionic liquids.
They are non-volatile, recyclable, eco-friendly, non-
explosive, easily operable, and thermally robust.8–10 We
described here a simple and efficient synthesis of thi-
azolopyridinone derivatives (5-amino-6,7-diphenyl-4,
7-dihydro-3H-thiazolo[4,5-b]pyridin-2-ones) by four-
component reaction of aldehyde, benzonitrile, ammo-
nium acetate and thiazolidine-2,4-dione in ionic liq-
uid without any catalyst. Also, the optimization and
QSAR properties of the synthesized compounds have
been evaluated using Hyperchem 8.0.
Multi-component reactions (MCRs) in which several
reactions are combined into one synthetic operation has
been used extensively to form carbon–carbon bonds in
the synthetic chemistry. Such reactions offer a wide
range of possibilities for the efficient construction of
highly complex molecules in a single procedure step,
thus avoiding the complicated purification operations
and allowing savings of both solvents and reagents.
Thus, they are perfectly amenable to automation for
combinatorial synthesis. In the last few decades, there
have been tremendous development in three- as well as
four-component reactions and greater efforts are being
continued to develop new MCRs. Thiazoles and pyra-
zoles are gaining importance in medicinal and organic
chemistry. They have shown broad spectrum of pharma-
cological and biological activities, such as antibacterial,
antidepressant, antihyperglycemic, antiinflammatory,
and antitumour.1–6 Many of the methods reported for
the synthesis of organic compounds are associated with
the use of hazardous organic solvents, long reaction
time, and lack of general applicability.7
2. Experimental
2.1 General information
Unless indicated, reagents and solvents were purchased
from SRL and Merck, India Aldrich chemicals and
used without purification, with the following excep-
tions. Methanol and dimethyl formamide were distilled
from calcium hydride under nitrogen. Flash column
chromatography was performed using silica gel 60
(Merck) with indicated solvents. Thin-layer chromato-
graphy (TLC) was performed using Kieselgel F254
plates (Merck). Infrared spectra were recorded on a
Jasco FT/IR 430 spectrometer. 1H- and 13C-NMR
Room temperature ionic liquids (RTILs), have shown
as an attractive substitute to conventional organic
∗For correspondence
1471

1472
Prashant Singh et al.
spectra were recorded on Toxi-Spin 300 MHz spec- complete the reaction and it was monitored by thin-
trometer as solutions in deuteriochloroform (CDCl3) layer chromatography. Then, 50 mL water was added.
or deuteriodimethyl sulphoxide ((CD3)2SO). Chemical The solid was filtered off and washed with water. The
shifts are expressed in parts per million (ppm, δ) down- crude product was purified by recrystallization from
field from an internal standard, tetramethylsilane. Opti- ethanol to afford the product and well characterized
mization of the synthesized compounds has been done by FTIR, proton and carbon NMR, which confirm the
using Hyperchem 8.0.
sturcture of the compound.
Similarly, other derivatives are being synthesized by
varying the reactants and characterized by FTIR, proton
and carbon NMR techniques.
2.2 General procedure for the synthesis
of thiazolopyridinone (compound 5aa)
A dry 100 mL flask was charged with thiazolidine-
2, 4-dione 1 (5 mmol), benzaldehyde 2a (5 mmol),
3. Result and discussion
benzylcyanide 3a (5 mmol) and ammonium acetate 4 To overcome the disadvantages such as volatility and
(5.2 mmol), and ionic liquid [bmim]Br (15 mL). The toxicity (many organic solvents inherently have), we
mixture was stirred at 90◦C for appropriate time to employed RTILs into the four-component reaction as
Scheme 1. One-pot synthesis of thiazolopyridin-2-ones.
Table 1. Optimization of reaction conditions (solvent, mol ratio and temperature of the reactants) for the catalyst-free
multicomponent reactions.a
Sl. No.
Solvent
Mol ratio (1:2a:3a:4)
Time (h)
Temp (◦C)
Yield (%)
1
2
3
4
5
6
7
8
Dioxane
Acetonitrile
DMF
Toluene
Water
DMSO
THF
[Net3][Ac]
[bmim][Cl]
[bmim][Br]
[bmim][Br]
[bmim][Br]
[bmim][Br]
[bmim][Br]
[bmim][Br]
[bmim][Br]
[bmim][Br]
[bmim][Br]
1:1:1:1
1:1:1:1
1:1:1:1
1:1:1:1
1:1:1:1
1:1:1:1
1:1:1:1
1:1:1:1
1:1:1:1
8
10
12
8
60
12
6
3
3
2
2
2
2
2
2
2
2
2
30
30
30
30
30
30
30
30
30
30
30
30
30
30
30
45
60
80
65
64
65
50
No reaction
55
70
80
78
80
82
84
79
72
65
82
90
94
9
10
11
12
13
14
15
16
17
18
1:1:1:1
1:1:1:1.1
1:1:1.1:1.1
1:1:1:1.2
1:1:1:0.9
1:1:1:0.8
1:1:1.1:1.1
1:1:1.1:1.1
1:1:1.1:1.1
aReactions were carried out amongst thiazolidine-2,4-dione (1), benzaldehyde (2a), benzylcyanide (3a) and ammonium
acetate (4) in a solvent (15 mL)

Catalyst-free one-pot synthesis of thiazolopyridin-2-ones
1473
Table 2. Catalyst-free one-pot synthesis of 9-phenyl-3,9-dihydro-chromeno [2,3-d] thiazol-2-one via MCRs in
thiazolidine-2,4-dione, aromatic aldehyde and urea derivative.
Sl. No. Reactant2
Reactant3
Product
Compound no. Time (h) Yield (%)
1
2
3
4
5
5aa
5ab
5ac
5ad
5ae
2.5
2.5
2.5
2.5
4.0
94
88
90
95
90
CHO
CHO
CHO
CHO
CHO
CN
S
O
N
H
H2N
N
H
CN
CN
S
O
N
H2N
N
H
H
MeO
S
O
OMe
CN
N
H
H2N
N
H
Cl
S
O
Cl
N
H
H2N
N
H
CN
Br
S
O
Br
N
H
H2N
N
H

1474
Prashant Singh et al.
Table 2. (Continued).
Sl. No.
6
Reactant2
Reactant3
Product
Compound no.
Time (h)
5.0
Yield (%)
98
5af
CHO
CN
H2N
S
O
NH2
CN
N
H2N
N
H
H
7
5ag
6.0
90
CHO
Cl
Cl
S
O
O
O
N
H
H2N
N
H
8
5ah
7.5
4.0
9.5
8.5
85
85
84
90
CN
CN
CN
CN
Br
CHO
Br
S
N
H
H2N
N
H
9
5ai
F
CHO
F
S
N
H
H2N
N
H
10
5aj
CHO
OMe
OMe
CHO
S
O
O
N
H
H2N
N
H
11
5ak
NO2
NO2
S
N
H
H2N
N
H

Catalyst-free one-pot synthesis of thiazolopyridin-2-ones
1475
a green medium. Initially, the four-component reaction substrate was investigated to establish the feasibility of
of thiazolidine-2, 4-dione 1, benzaldehyde 2a, benzyl- the strategy and to optimize the reaction conditions to
cyanide 3a and ammonium acetate 4 as a simple model afford 5aa (scheme 1).
Table 2. (Continued).
Sl. No.
12
Reactant2
Reactant3
Product
Compound no.
Time (h)
8.5
Yield (%)
92
5al
CHO
CN
Cl
Cl
S
O
N
H
H2N
N
H
13
5am
3.0
95
CHO
Br
CN
CN
CN
Br
S
O
N
H
H2N
N
H
14
5an
4.0
89
F
CHO
F
S
O
N
H
H2N
N
H
15
5ao
7.0
90
NO2
CHO
NO2
S
O
N
H
H2N
N
H
16
5ap
4.5
80
CHO
Cl
Cl
CN
MeO
S
OMe
O
N
H
H2N
N
H

1476
Prashant Singh et al.
Screening of the reaction conditions was established (table 1). It was exciting that the chosen solvents such
by using suitable solvents, the mol ratio of reac- as dioxane, N,N–dimethylformamide (DMF), acetoni-
tants as well as temperature for the desired MCRs trile (CH3CN), dimethylsulphoxide (DMSO), toluene,
Table 2. (Continued).
Sl. No.
17
Reactant2
Reactant3
Product
Br
Compound no.
Time (h)
6.5
Yield (%)
86
5aq
CN
CHO
MeO
Br
S
OMe
CN
O
N
H
H2N
N
H
18
5ar
2.5
87
CHO
F
F
MeO
S
OMe
CN
O
N
H
H2N
N
H
CHO
OMe
19
5as
3.5
87
OMe
MeO
S
OMe
CN
O
N
H
H2N
N
H
20
NO2
5at
5.5
90
CHO
MeO
NO2
S
O
OMe
CN
N
H
H2N
N
H
CHO
Cl
21
5au
6.5
94
Cl
Cl
S
Cl
O
N
H2N
N
H
H

Catalyst-free one-pot synthesis of thiazolopyridin-2-ones
1477
etc. were suitable for the MCRs (table 1, entries 1–10). has been formed even after 60 h (table 1, entry 5). To
Ionic liquid ([bmim]Br) proved to be the best among modulate the ratio of reactants and improve the yield,
them (table 1, entry 10). While under water, no product we examined various ratios of thiazolidine-2, 4-dione
Table 2. (Continued).
Sl. No.
22
Reactant2
Reactant3
Product
Compound no.
Time (h)
8.0
Yield (%)
80
5av
Br
CHO
CN
Cl
Br
S
Cl
O
N
H
H2N
N
H
23
5aw
9.0
82
CHO
F
F
CN
Cl
S
Cl
O
N
H
H2N
N
H
24
5ax
2.0
87
OMe
CHO
OMe
CN
Cl
Cl
S
Cl
O
O
N
H
H2N
N
H
25
NO2
5ay
2.5
89
CHO
CN
NO2
S
Cl
N
H
H2N
N
H
26
5ap
3.0
92
Cl
CHO
Cl
CN
Br
S
Br
O
N
H
H2N
N
H

1478
Prashant Singh et al.
Hyperchem 8.0 is a powerful computational soft-
1, benzaldehyde 2a, benzylcyanide 3a and ammonium
acetate 4 by using acetonitrile as a solvent (table 1, ware developed by Hypercube Inc, Gainsville USA
entries 11–15). The best result obtained when the ratio for molecular and quantum mechanics calculations. To
of thiazolidine-2, 4-dione 1, benzaldehyde 2a, benzyl- understand the properties of a designated molecule, we
cyanide 3a and ammonium acetate 4 is 1:1:1.1:1.1 to need to generate a well-defined structure that represents
afford the product 4a i.e., entry 12. Further, optimiza- a minimum on a potential energy surface. Hyperchem
tion of temperature was done (table 1, entries 16–18) provides parameters to enable geometry optimization
and we found the best yield at 90◦C (entry 17). With the so as to deduce a structure with minimum energy. The
optimized conditions in hand, we examined the scope QSAR approach has proved extremely useful to iden-
of the multicomponent reaction (table 2, entries 1–30). tify and quantify the physico-chemical properties of
We found that the reaction proceeded smoothly, and the an organic molecule. The geometry of thiazolidine-2,
desired products in excellent yields. The ionic liquid 4-dione and its derivatives has been optimized based
used for the transformation was recovered and used for on semi-empirical calculations, using the molecular
further reaction and to obtain good yields (table 3).
modelling program Hyperchem 8.0. Various parameters
Table 2. (Continued).
Sl. No.
27
Reactant2
Reactant3
Product
Compound no.
Time (h)
3.0
Yield (%)
90
5ba
Br
CHO
CN
Br
Br
S
Br
O
N
H
H2N
N
H
28
29
30
5bb
5bc
5bd
2.5
5.5
6.5
86
86
85
F
CHO
CN
Br
F
S
Br
O
N
H
H2N
N
H
CHO
OMe
CN
Br
Br
OMe
CHO
S
Br
O
O
N
H
H2N
N
H
NO2
CN
NO2
S
Br
N
H
H2N
N
H

Catalyst-free one-pot synthesis of thiazolopyridin-2-ones
1479
Supplementary information
Table 3. Optimization of the activity of ionic liquid after
reuse.
Table S1 and analytical data can be seen in www.ias.
Sl. No.
No. of cycle
Yield (%)
ac.in/chemsci website.
1
3
3
4
5
I
II
III
IV
V
94
94
92
92
90
Acknowledgements
Authors thank the University Grant Commission
(UGC) and the Department of Science and Technology
(DST), New Delhi, India.
References
were applied to calculate molecular properties of
synthesized compounds like surface area, volume,
refractivity, polarizability, hydrophobicity (Log P), and
hydration energy. The structure of thiazolidine-2,4-
dione was taken from invoke database using single
point calculation parameter, the molecular energy and
gradient for a given fixed geometry was set. Further
geometry optimization calculations were employed for
energy minimization algorithms to find the most sta-
ble conformation. Geometry optimization was taken
as criteria to determine the most stable conformer for
compounds as in table S1. Hydrophobicities of com-
pounds can be readily determined by measuring
partition coefficients designated as P. Partition coeffi-
cients dealing with neutral species. By convention, P
is defined as the ratio of concentration of the drugs in
octanol to its concentration in water. More the value
of log P, more will be the hydrophobicity. The values
for log P and other parameters for the following pairs
{(5aa and 5ab), (5ap, 5aq and 5as), (5au and 5av) and
(5aw and 5ax)} are of same values for the compounds
as in table S1. Log P value for the synthesized com-
pounds varies from −0.58 to −2.36 which indicates
that lesser the value of log P, more will be hydrophilic.
Therefore, compound 5ar is the most hydrophilic in
nature.
1. (a) Cantello B C C, Cawthorne M A, Cottam G P, Duff
P T, Haigh D, Hindley R M, Lister C A, Smith S A and
Thurlby P L 1994 J. Med. Chem. 37 3977; (b) Reaven
G M 1988 Diabetes 37 1595
2. (a) Chen C, Xu S, Wang W X, Ding Y M, Yu K H,
Wang B and Chen X Y 2009 Arch. Med. Res. 40 79; (b)
Cruz P D L, Diez-Barra E, Loupy A and Langa F 1996
Tetrahedron Lett. 37 1113; (c) Aronoff S, Rosenblatt S,
Braithwaite S, Egan J W, Mathisen A L and Schneider
R L 2000 Diabetes Care 23 1605
3. (a) Barnett D, Craig J G, Robinson D S and Rogers
M P 1977 Br. J. Clin. Pharmacol. 4 455; (b) Berger
J and Moller D E 2002 Annu. Rev. Med. 53 409;
(c) Cantello B C, Cawthorne M A, Cottam G P, Duff
P T, Haigh D, Hindley R M, Lister C A, Smith S A
and Thurlby P L 1994 J. Med. Chem. 37 3977; (d) Cox
S L 2006 Drugs Today (Barc) 42 139, Desvergne B and
Wahli W 1999 Endocrinol. Rev. 20 649; (e) Devasthale
P V, Chen S, Jeon Y, Qu F, Shao C, Wang W, Zhang H,
Cap M, Farrelly D and Golla R 2005 J. Med. Chem. 48
2248; (f) Ibrahimi A, Teboul L, Gaillard D, Amri E Z,
Ailhaud G, Young P, Cawthorne M A and Grimaldi P A
1994 Mol. Pharmacol. 46 1070
4. (a) Kersten J R, Toller W G, Gross E R, Pagel
P S and Warltier D C 2000 Am. J. Physiol. Heart
Circ. Physiol. 278 H1218; (b) Kletzien R F, Clarke
S D and Ulrich R G 1992 Mol. Pharmacol. 41 393;
(c) Lehmann J M, Moore L B, Smith-Oliver T A,
Wilkison W O, Willson T M and Kliewer S A 1995
J. Biol. Chem. 270 12953; (d) Ljung B, Bamberg
K, Dahllof B, Kjellstedt A, Oakes N D, Ostling J,
Svensson L and Camejo G 2002 J. Lipid Res. 43 1855;
(e) Sohda T, Momose Y, Meguro K, Kawamatsu Y,
Sugiyama Y and Ikeda H 1990 Arzneimittelforschung
40 37; (f) Yajima K, Hirose H, Fujita H, Seto Y, Fujita
H, Ukeda K, Miyashita K, Kawai T, Yamamoto Y,
Ogawa T, Yamada T and Saruta T 2003 Am. J. Physiol.
Endocrinol. Metabol. 284 E966; (g) Yoshioka T, Fujita
T, Kanai T, Aizawa Y, Kurumada T, Hasegawa K and
Horikoshi H 1989 J. Med. Chem. 32 421
4. Conclusion
We have described an efficient one-pot, four-component
reaction of thiazolidine-2, 4-dione, benzaldehyde, ben-
zonitrile and ammonium acetate, for the synthesis
of 5-amino-6,7-diphenyl-4,7-dihydro-3H-thiazolo[4,5-
b]pyridin-2-one derivatives in ionic liquid {[bmim]Br}.
This method has the advantages of high yields, mild
reaction conditions, short reaction time, convenient pro-
cedure, and environmental friendliness. Given the large
number of commercially available building blocks, the
present method should be applicable to synthesis of
libraries with high diversity.
5. (a) Bienayme H, Hulme C, Oddon G and Schmitt P 2000
Chem. Eur. J. 6 3321; (b) Tietze L F and Modi A 2000
Med. Res. Rev. 20 304; (c) Deomling A and Ugi I 2000
Angew. Chem. Int. Ed. 39 3168; (d) Zhu J 2003 Eur. J.
Org. Chem. 1133; (e) Orru R V A and de Greef M 2003
Synthesis 1471; (f) Nair V, Rajesh C, Vinod A U, Bindu
S, Sreekanth A R, Mathen J S and Balagopal L 2003

1480
Prashant Singh et al.
Acc. Chem. Res. 36 899; (g) Simon C, Constantieux T
Kumari K, Dubey M, Vishwakarma V K, Pandey N D,
Chandra R and Mehrotro G K 2012 Competes rendus-
Chimie 15, 504; (e) Kumari K, Singh P, Dubey M,
Pandey N D, Chandra R and Mehrotro G K 2012 Com-
petes rendus-Chimie 15 267; (f) Singh P, Kumar P,
Kumari K, Sharma P, Mozumdar S and Chandra R 2011
Spect. Acta A: Mol. Biomol. Spect. 78 909; (g) Singh
P, Kumari K, Katyal A, Kalra R and Chandra R 2009
Cat. Lett. 127, 119; (h) Singh P, Kumari K, Katyal
A, Kalra R and Chandra R 2009 Cat. Lett. 130, 648;
(i) Singh P, Kumar S, Katyal A, Kalra R and Chan-
dra R 2008 Mat. Lett. 62, 4164; (j) Singh P, Katyal
A, Kalra R and Chandra R 2008 Cat. Commun. 9,
1618
and Rodriguez J 2004 Eur. J. Org. Chem. 4957
6. (a) Yuan Y, Li X and Ding K 2002 Org. Lett. 4 3309;
(b) Cheng J F, Chen M, Arrhenius T and Nadzen A 2002
Tetrahedron Lett. 43 6293; (c) Huma H Z S, Halder R,
Kalra S S, Das J and Iqbal J 2002 Tetrahedron Lett. 43
6485; (d) Bora U, Saikia A and Boruah R C 2003 Org.
Lett. 5 435; (e) Dallinger D, Gorobets N Y and Kappe
C O 2003 Org. Lett. 5 1205
7. (a) Hardy C R 1984 Adv. Heterocycl. Chem. 36 343;
(b) Orth R E 1968 J. Pharm. Sci. 57 537; (c) Elnagdi
M H, Elmoghayar M R H and Elgemeie G E H 1987 Adv.
Heterocycl. Chem. 41 319; (d) Elnagdi M H, Elmoghayar
M R H and Sadek K U 1990 Adv. Heterocycl. Chem. 48
223; (e) Liu X H, Cui P, Song B A, Bhadury P S, Zhu
H L and Wang S F 2008 Bioorg. Med. Chem. 16 4075;
(f) Palaska E, Aytemir M, Uzbay T and Erol D 2001
Eur. J. Med. Chem. 36 539; (g) Kees K L, Fitzgerald J J,
Steiner K E Jr, Mattes J F, Mihan B, Tosi T, Mondoro D
and McCaleb M L J 1996 Med. Chem. 39 3920
9. (a) Dzyuba S V and Bartsch R 2003 Angew. Chem. Int.
Ed. 42 148; (b) Wilker J S 2002 Green Chem. 4 73 (10)
(c) Welton T 1999 Chem. Rev. 99 2071; (d) Dupont J,
de Souza R F and Suarez P A Z 2002 Chem. Rev. 102
3667
10. (a) Fischer T, Sethi A, Welton T and Woolf J 1999 Tetra-
hedron Lett. 40 793; (b) Lee C W 1999 Tetrahedron Lett.
40 2461; (c) Ludley P and Karodia N 2001 Tetrahedron
Lett. 42 2011; (d) Carmichael A J, Earle M J, Holbrey
J D, McCormac P B and Seddon K R 1999 Org. Lett.
1, 997; (e) Calo V, Nacci A, Lopez L and Mannarini N
2000 Tetrahedron Lett. 41 8973
8. (a) Singh P, Katyal A, Kalra R and Chandra R 2008
Tet. Lett. 42, 727; (b) Singh P, Katyal A, Kalra R and
Chandra R 2009 Spectro. Chim. Acta A 73, 218;
(c) Kumari K, Singh P, Srivastava R C, Kumar P,
Mehrotra G K, Samim M, Chandra R and Mordhwaj
2011 CPHEE Perspectives 69, 329; (d) Singh P,