1-Butyl-3-methylimidazolium p-toluenesulfinate: A novel reagent for synthesis of sulfones and β-ketosulfones in ionic liquid

Article abstract of DOI:10.1016/j.tetlet.2011.08.035

A novel task-specific ionic liquid, 1-butyl-3-methylimidazolium p-toluenesulfinate, [bmim][p-TolSO₂] has been synthesized and used as a nucleophile for the reaction with alkyl bromides and phenacyl bromides to prepare sulfones and β-ketosulfones in excellent yields (80-93%) in [bmim][BF₄] ionic liquid. The isolated yields of sulfones and β-ketosulfones were higher in [bmim][BF₄] than other organic solvents at room temperature.

Full text of DOI:10.1016/j.tetlet.2011.08.035

Tetrahedron Letters 52 (2011) 5368–5370
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
1-Butyl-3-methylimidazolium p-toluenesulfinate: a novel reagent
for synthesis of sulfones and b-ketosulfones in ionic liquid
⇑
Anil Kumar , Manoj Kumar Muthyala
Department of Chemistry, Birla Institute of Technology and Science, Pilani 333 031, Rajasthan, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel task-specific ionic liquid, 1-butyl-3-methylimidazolium p-toluenesulfinate, [bmim][p-TolSO2]
has been synthesized and used as a nucleophile for the reaction with alkyl bromides and phenacyl bro-
mides to prepare sulfones and b-ketosulfones in excellent yields (80–93%) in [bmim][BF4] ionic liquid.
The isolated yields of sulfones and b-ketosulfones were higher in [bmim][BF4] than other organic solvents
at room temperature.
Received 7 March 2011
Revised 5 August 2011
Accepted 7 August 2011
Available online 11 August 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Ionic liquid
Task-specific ionic liquid
b-Ketosulfones
Nucleophilic substitution
Phenacyl bromides
Sulfones and b-Ketosulfones are important synthetic intermedi-
years, ionic liquids have attracted increasing interest as recyclable
solvents, catalysts and reagents owing to their green credentials
and tunable properties.8 The task specific ionic liquids, which are
synthesized with properties for specific chemical tasks in mind
and have been used as reagents in synthesis, catalysis, purification
and as scavengers in parallel synthesis.9
Ionic liquids have been shown to enhance nucleophilicity and
the rate of a reaction for nucleophilic substitution reactions when
compared to organic solvents.10 Kamal et al. have synthesized
ates in organic synthesis. They have been utilized for the synthesis
of natural product such as lycopodine alkaloid,1
a
-halo b-ketosulf-
ones,
a-halo methylsulfones, a,a-dihalo methylsulfones, quino-
lines, allenes, vinyl sulfones, and polyfunctionalized 4H-pyrans.2
They are useful intermediate for the conversion of ketones to al-
kynes.3 b-Ketosulfones can also be transformed to corresponding
ketones by reductive desulfonylation.4 Certain b-ketosulfones ex-
hibit biological activities such as antibacterial, antifungal,5 and
inhibition of 11b-hydroxysteroid dehydrogenase type 1.6 Indolyl
aryl sulfones are known as potent nonnucleoside inhibitors for
the growth of wild-type and drug-resistant human immunodefi-
ciency virus type 1 (HIV-1).6b Because of their synthetic utility
and versatile reactivity several methods have been developed for
their preparation.7 The general method for synthesis of sulfones
and b-ketosulfones is by alkylation of sodium sulphinates with al-
kyl halide or phenacyl halide in organic solvents, respectively.
However, most of these methodologies often suffer from some or
other drawbacks such as long reaction times, tedious reaction con-
ditions involving high temperature or microwave heating, low
yields, use of expensive reagents and the difficulties associated
with isolation of sulfones and b-ketosulfones from solvents.
Ionic liquids are interesting materials for chemists as they offer
new robust chemical and physical properties, such as high thermal
stability, very low to negligible vapor pressure, good solvating
ability, non-coordinating nature and ease of recyclability. In recent
1-butyl-3-methylimidazolium thiocyante [bmim][SCN]
a task
specific ionic liquid and used for nucleophilic substitution reaction
to convert alkyl halides to alkyl thiocyantes.11 Yadav et al. have
also used this ionic liquid for the conjugate hydrothiocyanation
of chalcones.12 Recently, D’Anna et al. have synthesized 1-butyl-
3-methylimidazolium azide [bmim][N3] and used it as a nucleo-
phile for the nulceophilic substitution of some activated aryl or
heteroaryl halides.13 As most common method for the synthesis
of sulfones and b-ketosulfones involves nucleophilic substitution
of halide from phenacyl bromide by sulfinate anion, we envisaged
that incorporating sulfinate anion in ionic liquid might enhance the
nucleophilicity of this anion toward reaction with alkyl halides and
phenacyl halides. Thus, in view of the prominent merits of ionic
liquids in organic synthesis and in continuation of our efforts on
development of novel organic transformations in ionic liquids,14
herein, we report synthesis of a novel task-specific ionic liquid,
1-butyl-3-methylimidazolium p-toluenesulfinate, [bmim][p-Tol-
SO2] (Scheme 1) and its application in synthesis of b-ketosulfones
from phenacyl bromides in [bmim][BF4] ionic liquid (Scheme 2). To
the best of our knowledge this is the first report on synthesis and
application of [bmim][p-TolSO2].
⇑
Corresponding author. Tel.: +91 1596 515514.
E-mail address: anilkumar@bits-pilani.ac.in (A. Kumar).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.08.035

A. Kumar, M. K. Muthyala / Tetrahedron Letters 52 (2011) 5368–5370
5369
Table 1
N
N
1
p-TolSO2Na
Optimization of reaction condition
Br
Reflux
4
N
N
N
N
+
O
O
S
-
O
Acetone
p-TolSO2
Br
5
Br
3
5
2
O
[bmim][BF4]
CH3
Cl
Cl
Scheme 1. Synthesis of [bmim][p-TolSO2].
6a
7a
Entry
Solvent
Reagent
Temp (°C)
Time (h)
Yield (%)a
1
2
3
4
5
6
7
8
—
5
5
60
30
30
30
30
80
30
30
30
30
30
30
12
4
4
4
4
10
10
4
4
4
60
87
40
O
[bmim][BF4]
[bmim][BF4]
[bmim][Br]
Ethanol
Ethanol
Ethanol
DMSO
Acetonitrile
DCM
THF
5
pTolSO2Na
5
5
S
b
R
Br
-
R
[bmim][BF4]
O
62
67
64
79
pTolSO2Na
CH3
5
5
5
5
5
5
6a-m
7a-m
b
9
—
O
O
O
10
11
12
39
58
38
O
O
4
4
b
e
a
c
f
MeOH
Cl
a
Isolated yield.
No product isolated.
b
O
O
O2N
d
g
H3C
O
O
O
Table 2
Synthesis of sulfones using 517
N
Br
h
H3CO
i
l
Entry
Substrate
Producta
Time (h)
Yield (%)b
OH
O
O
1
2
3
4
5
6
6a
6b
6c
6d
6e
6f
7a
7b
7c
7d
7e
7f
7g
7h
7i
4
4
4
5
5
5
6
5
5
5
5
5
5
87
90
92
90
91
85
87
92
90
93
89
83
80
k
n
j
S
S
OH
Br
m
7
8
9
6g
6h
6i
Scheme 2. Synthesis of sulfones using 5.
10
11
12
13
6j
6k
6l
7j
7k
7l
6m
7m
Synthesis of [bmim][p-TolSO2] (5) was achieved following the
reaction sequences shown in Scheme 1. Initially, the reaction of
1-methylimidazole (1) with 1-bromobutane (2) at room tempera-
ture afforded 1-butyl-3-methylimidazolium bromide (3). Subse-
quent reaction of 3 with sodium p-toluenesulfinate (4) in acetone
at room temperature for 6 h gave 5. The structure of 5 was con-
firmed by 1H NMR and high-resolution mass spectrometry.15 1H
NMR spectrum showed two doublet at 7.38 and 7.12 ppm for aro-
matic protons of toluenesulfinate ring and a singlet at 2.15 ppm for
the methyl protons along with other protons of imidazolium cat-
ion. In HRMS peaks appeared at 294.1463 [M]+ and 139.1246
[MÀp-TolSO2]+ which confirmed the structure of 5.
All the compounds showed satisfactory 1H NMR, 13C NMR and mass data.
Isolated yield.
a
b
of the phenacyl bromide by the acidic nature of the proton H–C(2)
of the imidazolium cation (pKa = 22.7 in DMSO).16 The ionic liquid
probably activates the phenacyl bromide through hydrogen bond
formation with the carbonyl group.
For comparison, 7a was also prepared by the reaction of sodium
p-toluenesulfinate (pTolSO2Na) in [bmim][BF4] ionic liquid (Table
1, entry 3). The yield of 7a was 40% at room temperature after
4 h. It is noteworthy to mention that reactivity of sulfinate anion
After synthesizing, we studied reaction of 5 with 2-bromo-1-(4-
chlorophenyl)ethanone (6a) as model reaction under different con-
ditions. In our initial studies, we tested effect of different solvents
such as THF, DMSO, EtOH, MeOH, [bmim][Br] and [bmim][BF4]. As
shown in Table 1, among all the screened solvents, [bmim][BF4]
was found to be the best solvent in terms of yield and reaction
time.
(p-TolSOÀ) in 5 is higher as compared to pTolSO2Na under these
2
conditions. Moreover, traditional method for the synthesis of b-
ketosulfones by alkylation of pTolSO2Na with phenacyl bromide
(6a) in refluxing ethanol required 10 h and resulted 7a in only
67% yield (Table 1, entry 6).
The exact reason for higher reactivity in [bmim][BF4] is not
clear, however based on literature reports the increased rate of
reaction in [bmim][BF4] may be attributed to the non-coordinating
nature of [bmim][BF4] which increases effective nucleophilicity of
the anion (p-TolSO2-). Similar effect in nuleophilicity has also been
observed for the synthesis of sulfones from alkyl halides using sulf-
inates in aprotic solvents in presence of tetrabutylammonium
salt.7d,e Apart from enhancing nucleophilicity, the effect of ionic li-
quid may well be due primarily to solubility of 5 in [bmim][BF4].
Further, the increased rate of reaction may also be due to activation
After establishing the higher reactivity of 5 over sodium
sulfinate and optimum reaction condition, we investigated nucleo-
philic substitution of a variety of alkyl bromides to give corres-
ponding sulfones to validate the general scope of the reaction.
Excellent yield of sulfones and b-ketosulfones 7a–m (80–93%)
were obtained from different alkyl bromides and phenacyl
bromides in short reaction time and the results are summarized
in Table 2. The product was extracted from the reaction mixture
with hexane/ethyl acetate mixture (1:1, v/v) leaving behind
[bmim][Br] dissolved in [bmim][BF4]. Structure of all the

5370
A. Kumar, M. K. Muthyala / Tetrahedron Letters 52 (2011) 5368–5370
compounds (7a–m) was confirmed by 1H NMR, 13CNMR and mass
spectroscopic data (Supplementary data).
Artico, M.; Martino, C. D.; Regina, G. L.; Crespan, E.; Zanoli, S.; Hübscher, U.;
Spadari, S.; Maga1, G. Antimicrob. Agents Chemother. 2005, 49, 4546.
7. (a) Kaiser, E. M.; Solter, L. E.; Schwartz, R. A.; Beard, R. D.; Hauser, C. R. J. Am.
Chem. Soc. 1971, 93, 4237; (b) Kondo, K.; Tunemoto, D. Tetrahedron Lett. 1975,
1397; (c) Suryakiran, N.; Reddy, T. S.; Ashalatha, K.; Lakshman, M.;
Venkateswarlu, Y. Tetrahedron Lett. 2006, 47, 3853; (d) Veenstra, G. E.;
Zwanenburg, B. Synthesis 1975, 519; (e) Wildeman, J.; van Leusen, A. M.
Synthesis 1979, 733; (f) Ju, Y.; Kumar, D.; Varma, R. S. J. Org. Chem. 2006, 71,
6697; (g) Murakami, T.; Furusawa, K. Synthesis 2002, 479; (h) Truce, W. E.;
Milionis, J. P. J. Org. Chem. 1952, 17, 1529.
8. For reviews see: (a) Jain, N.; Kumar, A.; Chauhan, S.; Chauhan, S. M. S.
Tetrahedron 2005, 61, 1015; (b) Plechkova, N. V.; Seddon, K. R. Chem. Soc. Rev.
2008, 37, 123; (c) Welton, T. Chem. Rev. 1999, 99, 2071; (d) Zhang, Z. C. Adv.
Catal. 2006, 49, 153; (e) Van Rantwijk, F.; Sheldon, R. A. Chem. Rev. 2007, 107,
2757.
In summary, we have described synthesis of novel 1-butyl-3-
methylimidazolium p-toluenesulfinate ionic liquid [bmim][p-Tol-
SO2] and its ability to act as a nucleophile toward alkyl bromides
and phenacyl bromides in ionic liquid [bmim][BF4]. The
[bmim][p-TolSO2] afforded corresponding sulfones and b-ketosulf-
ones in excellent yield (80–93%) at room temperature. This meth-
odology could be an alternative to the existing methods for the
synthesis of sulfones and b-ketosulfones. Further studies on the
properties of [bmim][p-TolSO2] and its application in organic syn-
thesis are in progress in our laboratory.
9. (a) Davis, H., Jr. Chem. Lett. 2004, 33, 1072; (b) Lee, S.-G. Chem. Commun. 2006,
1049; (c) Ranu, B. C.; Banerjee, S. Org. Lett. 2005, 7, 3049; (d) Ranu, B. C.; Jana, R.
Eur. J. Org. Chem. 2006, 3767; (e) Chakraborti, A. K.; Roy, S. R.; Kumar, D.;
Chopra, P. Green Chem. 2008, 10, 1111.
Acknowledgments
10. (a) Lourenço, N. M. T.; Afonso, C. A. M. Tetrahedron 2003, 59, 789; (b) Betti, C.;
Landini, D.; Maia, A. Tetrahedron 2008, 64, 1689; (c) Jorapur, Y. R.; Chi, D. Y. Bull.
Korean Chem. Soc. 2006, 27, 345.
11. Kamal, A.; Chouhan, G. Tetrahedron Lett. 2005, 46, 1489.
12. Yadav, L. D. S.; Patel, R.; Rai, V. K.; Srivastava, V. P. Tetrahedron Lett. 2007, 48,
7793.
This work was financially supported by the Council of Scientific
and Industrial Research (CSIR), New Delhi (Project No. 01(2214)/
08/EMR-II). MMK thanks CSIR, New Delhi for junior research fel-
lowship (JRF).
13. D’Anna, F.; Marullo, S.; Noto, R. J. Org. Chem. 2008, 73, 6224.
14. (a) Kumar, A.; Rao, M. S.; Rao, V. K. Aust. J. Chem. 2010, 63, 1538; (b) Kumar, A.;
Rao, M. S.; Rao, V. K. Aust. J. Chem. 2010, 63, 135; (c) Chhikara, B. S.; Tehlan, S.;
Kumar, A. Synlett 2005, 63; (d) Kumar, A.; Jain, N.; Chauhan, S. M. S. Synlett
2007, 411.
15. Synthesis of 1-butyl-3-methylimidazolium p-toluenesulfinate (5): To the solution
of [bmim][Br] (5.0 g, 22.8 mmol) in acetone (20 mL) sodium toluenesulfinate
(6.11 g 34.2 mmol) was added and reaction mixture was stirred vigorously at
room temperature for 48 h. After completion of reaction, reaction mixture was
filtered and acetone was evaporated. The crude product was dissolved in
minimum amount of DCM and filtered to remove NaBr. Finally, residual
obtained on evaporation of DCM was passed through silica bed (60–120 mesh)
to get pure product 5. Yield: 3.48 g (92%); viscous liquid; 1HNMR (300 MHz,
DMSO-d6) d 9.28 (s, 1H), 7.79 (s, 1H), 7.71 (s, 1H), 7.38 (d, J = 7.2 Hz, 2H), 7.12
(d, J = 7.8, 2H), 4.15 (t, J = 7.2, 2H), 3.83 (s, 3H), 2.15 (s, 3H), 1.25–1.13 (m, 2H),
0.85–0.80 (t, J = 7.6 Hz, 3H).
16. Kim, Y.-J.; Streitwieser, A. J. Am. Chem. Soc. 2002, 124, 5757.
17. General procedure for synthesis of sulfones and b-ketosulfones: Ionic liquid 5
(1.2 mmol) was added to the solution of alkyl bromide or phenacyl bromide
(1 mmol) in [bmim][BF4] (2 mL) and the reaction mixture was stirred
vigorously at 30 °C for 4–6 h. The progress of reaction was monitored by TLC.
After completion of reaction, the product was extracted from ionic liquid by
hexane/ethyl acetate mixture (4 Â 10 mL, 1:1 v/v) leaving both ionic liquids in
the round bottom flask. The organic layers were combined and concentrated to
give crude product which was passed through a bed of silica gel (100–120
mesh) to give pure sulfones or b-ketosulfone. Physical data of representative b-
ketosulfone (7a): Colorless solid, mp 139–140 °C (Lit.2g 138–130 °C).
Supplementary data
Supplementary data (1H NMR and 13C NMR of compound 7a–m)
associated with this article can be found, in the online version, at
doi:10.1016/j.tetlet.2011.08.035.
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