Molecular iodine in [bmim][BF4]: A highly efficient green catalytic system for one-pot synthesis of 1,3-oxathiolan-5-one

Article abstract of DOI:10.1016/j.tetlet.2010.09.052

Aldehydes and mercaptoacetic acid are coupled in the presence of a catalytic amount of economical and non-toxic molecular iodine in [bmim][BF ₄] ionic liquid under mild conditions to afford the corresponding 1,3-oxathiolan-5-one in excellent yields. Molecular iodine acts faster in ionic liquids when compared to conventional solvents such as DMSO, DMF, ethyl acetate, and acetonitrile. The recovered ionic liquids can be recycled in subsequent reactions with consistent activity.

Full text of DOI:10.1016/j.tetlet.2010.09.052

Tetrahedron Letters 51 (2010) 6108–6110
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Molecular iodine in [bmim][BF4]: a highly efficient green catalytic system
for one-pot synthesis of 1,3-oxathiolan-5-one
Manika Dewan a, Ajeet Kumar a, Amit Saxena a, Arnab De b, Subho Mozumdar a,
⇑
a Department of Chemistry, University of Delhi, Delhi 110 007, India
b Department of Microbiology and Immunology, Columbia University Medical Centre, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 11 May 2010
Revised 8 September 2010
Accepted 11 September 2010
Available online 17 September 2010
Aldehydes and mercaptoacetic acid are coupled in the presence of a catalytic amount of economical and
non-toxic molecular iodine in [bmim][BF4] ionic liquid under mild conditions to afford the corresponding
1,3-oxathiolan-5-one in excellent yields. Molecular iodine acts faster in ionic liquids when compared to
conventional solvents such as DMSO, DMF, ethyl acetate, and acetonitrile. The recovered ionic liquids can
be recycled in subsequent reactions with consistent activity.
Ó 2010 Elsevier Ltd. All rights reserved.
Ionic liquids are rapidly becoming green alternatives to the con-
ventional and environmentally detrimental volatile organic sol-
vents.1 Recently, they have attracted a great deal of attention due
to their high thermal stability, good conductivity, non-volatility,
non-flammability, suitable polarity, wide electrochemical window,
and recyclability.2–8 The ionic liquids based on imidazolium cations
are especially favorable for green industrial applications.9 These
classes of ionic liquidshave especially low volatility at room temper-
ature, one reason that ionic liquids are often considered than tradi-
tional organic solvents.10 Moreover, when an ionic liquid is used as
a reaction media, the solute is solvated homogeneously by ions only.
Thus, the reaction can proceed in an environment totally different
from that when water or ordinary organic solvents are used and as
a result high selectivity is possible.11 Oxathiolan-5-one derivatives
are of great interest because they exhibit a broad spectrum of biolog-
ical activities and are important heterocycles occurring in natural
and medicinal molecules. They are intermediates in the synthesis
of many bioactive compounds.12 To exemplify, derivatives of
2-(hydroxy-methyl)-1,3-oxathiolan-5-ones can be used as building
blocks for the preparation of the oxathiolanyl-nucleoside Covira-
cil.13–15 Yadav and Rai have used 2-methyl-2-phenyl-1,3-oxathio-
lan-5-one for high yield synthesis of polyfunctionalised bicyclic
pyrimidines, which are of industrial as well as biological impor-
tance.16 2-Amino-1,3-thiazinesandtheirderivativeswithantibacte-
rial, antitumour, insecticidal, and fungicidal activities have also been
prepared using 2-methyl-2-phenyl-1,3-oxathiolan-5-one in a green
synthesis approach.17 1,3-Oxathiolan-5-ones and their derivatives
have been synthesised conventionally from disconnection approach
using synthetic equivalents; a derivative of a ketone and mercapto-
acetic acid employing vigorous heating with PTSA.18 Yadav et.al.
have used LiBr to catalyze the reaction between acetophenone and
mercaptoacetic acid to produce 2-methyl-2-phenyl-1,3-oxathio-
lan-5-ones in substantial yields.19 2-Trifluoromethyl-1,3-oxathio-
lan-5-ones, which are potential synthetic equivalents for obtaining
fluorinated analogs of biologically active compounds have also been
synthesized by Tolmachev and co-workers by a two-step process
employing zinc chloride.20 However many of these methods seem
to have technical limitations, such as, long reaction times, difficult
workup, and formation of over-oxidation products leading to lower
yields,requirementsofstrongoxidizingagents, strongacidicorbasic
media, use of expensive, toxic, and explosive (LiBr) reagents. As the
aforesaid conditions are not compatible with heat or acid sensitive
substrates, there is a compelling need to develop an effective syn-
thetic procedure for synthesizing 1,3-oxathiolan-5-one derivatives
under more eco-friendly conditions. Our reaction is more environ-
mentally benign as compared to the reactions described above. As
part of our ongoing interest in exploring various green methods for
organic transformations, we disclose herein our results for the syn-
thesis of 1,3-oxathiolan-5-one derivatives using catalytic amounts
of molecular iodine in ionic liquid as an inexpensive, versatile,
non-toxic, and a readily available catalyst that can serve as a green
alternative method for this important reaction. Iodine in ionic liquid
was already reported21–24 but we report here, for the first time, the
use of iodine in ionic liquids as a novel and recyclable polar reaction
media for the synthesis of 1,3-oxathiolan-5-one derivatives using
aldehydes and mercaptoacetic acid (Table 1). In a general reaction,
treatment of benzaldehyde with mercaptoacetic acid in hydrophilic
ionic liquid, [bmim][BF4] afforded 1,3-oxathiolan-5-one in 95% yield
(Table 1, entry 1).
The reaction was very clean and took only 3 h at room temper-
ature. Various aldehyde derivatives with different electron donat-
ing/withdrawing groups) reacted with mercaptoacetic acid in the
presence of catalytic amounts of molecular iodine (in ionic liquid)
to give the corresponding 1,3-oxatiolan-5-one derivative in high
⇑
Corresponding author. Tel.: +91 9810728438.
E-mail address: subhoscom@yahoo.co.in (S. Mozumdar).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.09.052

M. Dewan et al. / Tetrahedron Letters 51 (2010) 6108–6110
6109
Table 1
Synthesis of 1,3-oxathiolan-5-one derivativesa,b
S. No
1
Aldehydes
CHO
Product
Time (h)
3
Yield (%)
95
Mpc (°C)
S
O
87
O
CHO
S
O
O
2
3
3
3
92
98
67
130
Cl
Cl
CHO
S
O
O
4
132
—
H3CO
H3CO
CHO
NO2
CHO
S
O
O
3.5
NO2
S
O
O
4
3
58
—
NO2
NO2
CHO
S
O
O
5
6
4
4
68
90
—
O2N
O2N
H3CO
CHO
OCH3
CHO
S
O
O
H
3CO
O
150
OCH3
S
H3CO
HO
H3CO
O
7
8
3
87
—
244
—
HO
—
—
O
a
b
c
Reaction condition: 10 mmol of aldehyde and 10 mmol of mercaptoacetic acid catalyzed by1 mmol of molecular iodine in 5 ml ionic liquid at room temperature.
Confirmed by (FT-IR, TLC, 1H NMR and 13C NMR).
Isolated pure.
yields (Table 1).25 In all cases, the reactions proceeded readily at
room temperature with high efficiency. Therefore, the prime focus
of this letter is on the synthesis of biologically active 1,3-oxatiolan-
5-one derivatives using molecular iodine as an inexpensive and
versatile catalyst, in ionic liquid as a reaction media. The results
obtained are hereby incorporated in Table 1 and the proposed reac-
tion mechanism is shown in Scheme 1.
In order to elucidate the role of molecular iodine, a controlled
reaction was carried out using mercaptoacetic acid and benzalde-
hyde in ionic liquid without using molecular iodine. The reaction
did not proceed even after 48 h and no products were formed. It
is to be noted that the reaction proceeded to give ꢀ50% yields
(and took 12 h) when iodine was used alone in the absence of an
ionic liquid. It is important to note that electronic factors played
an important role in this iodine mediated condensation reaction
in ionic liquid as a reaction media. In order to elucidate the role
of the solvents, various solvents were screened to evaluate the
scope and limitation of this reaction. The result substantiates our
hypothesis that the iodine catalyzed synthesis of 1,3-oxathiolan-
5-one derivatives would not only be faster but would also result
in higher yields in ionic liquids as compared to other conventional
solvents. It is interesting to note that the yield of the products is
rather low in the case of polar aprotic solvents such as DMF and
DMSO (Table 2). In solvent free conditions the conversion rate
was found to be negligible. Clearly, ionic liquid stands out as the
solvent of choice, with its fast conversion and quantitative yield.
Scheme 1. Proposed mechanism of the one-pot synthesis of 1,3-oxathiolan-5-one
derivatives using molecular iodine as catalyst in ionic liquid.
The mechanism of 1,3-oxathiolan-5-one formation suggests
that, iodine plays a key role in the reaction by polarizing the

6110
M. Dewan et al. / Tetrahedron Letters 51 (2010) 6108–6110
Table 2
References and notes
Effect of various solventsa,b
1. Joseph, T.; Sahoo, S.; Halligudi, S. B. J. Mol. Catal. A: Chem. 2005, 234, 107.
Entry
Solvent
Reaction time (h)
Yield (%)
2. Consorti, C. S.; Suarez, P. A. Z.; de Souza, R. F.; Burrow, R. A.; Farrar, D. H.; Lough,
A. J.; Loh, W.; da Silva, L. H. M.; Dupont, J. J. Phys. Chem. B 2005, 109, 4341.
3. Li, W. J.; Zhang, Z. F.; Zhang, J. L.; Han, B. X.; Wang, B.; Hou, M. Q.; Xie, Y. Fluid
Phase Equilib. 2006, 248, 211.
4. Gao, Y.; Zhao, X.; Dong, B.; Zheng, L.; Li, N.; Zhang, S. J. Phys. Chem. B 2006, 110,
8576.
1
2
3
4
5
DMF
Ethylacetate
DMSO
[bmim][BF4]
Acetonitrile
14
10
15
3
45
75
49
95
87
9
5. Wang, S. F.; Chen, T.; Zhang, Z. L.; Pang, D. W.; Wong, K. Y. Electrochem.
Commun. 2007, 9, 1709.
a
Reaction condition: 10 mmol of benzaldehyde and 10 mmol of mercaptoacetic
6. Charkrabarty, D.; Seth, D.; Chakraborty, A.; Sarkar, N. J. Phys. Chem. B 2005, 109,
5753.
7. Bomparola, R.; Caporali, S.; Lavacchi, A. Surf. Coat. Technol. 2007, 201, 9485.
8. Anderson, J. L.; Ding, J.; Welton, T.; Armstrong, D. W. J. Am. Chem. Soc. 2002, 124,
14247.
acid catalyzed by 1 mmol of molecular iodine in 5 ml ionic liquid at room
temperature.
b
Confirmed by (FT-IR, TLC, 1H NMR and 13C NMR).
9. Earle, M. J.; Seddon, K. R. Pure Appl. Chem. 2000, 72, 1391.
10. Zhou, Y. Curr. Nanosci. 2005, 1, 35.
Table 3
11. Li, W.; Bin, Z.; Yong, Y. Z.; Jun, Z. X.; Duan, W. Q.; Xian, C. L.; Jun, Z. W. Sci. China,
Ser. B: Chem. 2007, 50.
12. Popp, A.; Gilch, A.; Mersier, A. L.; Petersen, H.; Mechlem, J. R.; Stohrer, J. Adv.
Synth. Catal. 2004, 346, 682.
13. Choi, W. B.; Wilson, L. J.; Yeola, S.; Lotta, D. C.; Schinazi, R. F. J. Am. Chem. Soc.
1991, 113, 9377.
Recyclability of ionic liquid
Table 1
entry 1
Run 1
Run 2
95
Run 3
94
Run 4
92
Run 5
90
Yield (%)
95
14. Lotta, D. C.; Schinazi, R. F.; Choi, W. B. Emory University, USA, WO 9214743 A2,
1992; Chem. Abstr. 1993, 118, 22551.
15. Liotta, D. C.; Choi, W. B.; Emory University, USA, WO 9111186 A1, 1991; Chem.
Abstr. 1991, 115, 208463.
16. Yadav, L. D. S.; Rai, A. Carbohydr. Res. 2009, 344, 2329.
17. Yadav, L. D. S.; Rai, V. K.; Yadav, B. S. Tetrahedron 2009, 65, 1306.
18. Uang, B. J.; Po, S. Y.; Hung, S. C.; Liu, H. H.; Hsu, C. Y.; Lin, Y. S.; Chang, J. W. Pure
Appl. Chem. 1997, 69, 615.
19. Yadav, L. D. S.; Yadav, S.; Rai, V. K. Tetrahedron 2005, 61, 10013.
20. Pustovit, Y. M.; Alekseenko, A. N.; Subota, A. I.; Tolmachev, A. A. Chem.
Heterocycl. Compd. 2006, 42.
carbonyl group of the substrate, thereby enhancing the
electrophilicity of the carbonyl carbon. This facilitates the nucleo-
philic reaction of the sulfohydro group of the mercaptoacetic acid.
It also illustrates the enhanced reactivity of the carbonyl substrate
in case of electronic withdrawing groups in the first step and elec-
tron donating groups in the second step. However the results show,
that the reactivity of the substrate is effectively increased in the
cases when we employ electron donating groups, for example, in
the attack of mercaptoacetic acid on anisaldehyde (Table 1, entry
3) and is drastically reduced in cases when electron withdrawing
groups are present, for example, in ortho-, meta-, and para-nitro-
substituted benzaldehydes (Table 1, entry 4–6). The results indi-
cate that the first step, that is, the attack of nucleophilic thiol
group on electrophilic carbon of the carbonyl compound is the rate
determining step in the synthesis of 1,3-oxathiolan-5-one.
The advantage of using ionic liquid is that the products of the
reaction can be extracted into the organic solvent, ethyl acetate
leaving the ionic liquid behind which can be successfully recycled.
These are quite contrary to dipolar aprotic solvents which are dif-
ficult to remove from the product.
21. Ren, Y.; Cai, C. Synth. Commun. 2010, 40, 1670.
22. Liu, C. F.; Zhang, A. P.; Li, W. Y.; Yue, F. X.; Sun, R. C. Ind. Crops Prod. 2010, 31, 363.
23. Hajipour, A. R.; Mostafavi, M.; Ruoho, A. E. Org. Prep. Proced. Int. 2009, 41, 87.
24. Ren, Y.-M.; Cai, C. Tetrahedron Lett. 2008, 49, 7110.
25. General procedure for synthesis of 1,3-oxathiolan-5-ones derivatives. A mixture of
aromatic aldehyde (10 mmol), mercaptoacetic acid (0.7 ml, 10 mmol) and
catalytic amount of iodine (1 mmol) in ionic liquid, 1-butyl-3-
methylimidazolium tetrafluoroborate (5 ml) was stirred for 3 h at room
temperature. The mixture was then extracted thrice with 10 ml of ethyl
acetate and the combined organic extracts were treated with an aqueous
solution of Na2S2O3 (1 M) and washed with saturated solution of NaHCO3.
Drying of the organic layer in vacuum afforded a crude product, which was
then recrystallised with water to yield pure crystalline 1,3-oxathiolane-5-ones.
The ionic liquid residue was washed with hexane and dried in vacuum
resulting in recycled ionic liquid, [bmim][BF4] (Table 3).
Characterization data of some important compounds. 2-Phenyl-1,3-oxathiolan-5-
one (Table 1, entry 1). IR (KBr) m
max: 2974, 2930, 1726, 1474, 1027 cmÀ1.1H
NMR (DMSO-d6/TMS) d: 3.43 (d, 1H, J = 16.4 Hz, CH2), 3.43 (d, 1H, J = 16.4 Hz,
CH2), 5.4 (s, 1H, CH), 7.3–7.7 (m, 5Harom). 13C NMR (DMSO-d6/TMS) d: 38.2,
91.2, 126.9, 128.4, 128.9, 138.3, 171.0.
We have developed a relatively quicker and greener method for
synthesizing 1,3-oxathiolane-5-one under solvent free conditions
using molecular iodine as a catalyst. The efficacy of the reaction
lies in its high yield, ambient conditions of temperature, and recy-
clability of the reaction media, that is, the ionic liquid (Table 3).
2-(4-Chlorophenyl)-1,3-oxathiolan-5-one (Table 1, entry 2). IR (KBr) mmax: 2976,
1718, 1388, 1156 cmÀ1 1H NMR (DMSO-d6/TMS) d: 3.40 (d, 1H, J = 16.4 Hz,
.
CH2), 3.25 (d, 1H, J = 16.4 Hz, CH2), 5.31 (s, 1H, CH), 7.4–7.9 (m, 5Harom). 13C
NMR (DMSO-d6/TMS) d: 38.2, 91.2, 128.8, 130.3, 132.2, 136.4, 175.0.
2-(4-Methoxyphenyl)-1,3-oxathiolan-5-one (Table 1, entry 3). IR (KBr)
mmax: 2960,
1726, 1510, 1340 cmÀ1 1H NMR (DMSO-d6/TMS) d: 3.74 (s, 3H, CH3), 3.41 (d, 1H,
.
16.4 Hz, CH2), 3.28 (d, 1H, 16.4 Hz, CH2), 6.28 (s, 1H, CH), 6.77–7.46 (m, 5Harom).
13C NMR (DMSO-d6/TMS) d: 40.1, 56.0, 91.2, 115.4, 131.1, 133.1, 167.2, 178.0.
Acknowledgments
2-(2,5-Dimethoxyphenyl)-1,3-oxathiolan-5-one (Table 1, entry 6). IR (KBr) mmax
:
2928, 2836, 1701, 1497, 1279 cmÀ1 1H NMR (DMSO-d6/TMS) d: 3.76 (s, 3H, CH3),
.
S.M. and A.K. gratefully acknowledge financial support from the
Department of Biotechnology, Govt. of India (BT/PR8918/NNT/28/
05/2007).
3.88 (s, 3H, CH3), 3.43 (d, 1H, J = 16.4 Hz, CH2), 3.26 (d, 1H, J = 16.4 Hz, CH2), 5.58
(s, 1H, CH), 6.78–7.45 (m, 5Harom). 13C NMR (DMSO-d6/TMS) d: 38.4, 56.3, 81.6,
113.5, 115.5, 124.9, 154.1, 154.8, 174.5.