An efficient method for chemoselective thioacetalization of aldehydes in the presence of a catalytic amount of acidic ionic liquid under solvent-free conditions

Article abstract of DOI:10.1055/s-0029-1217550

A water-stable Br?nsted acidic ionic liquid with an alkane sulfonic acid group was synthesized. This ionic liquid catalyzed the thioacetalization reaction smoothly to afford 1,3-dithianes in excellent yield and less time. In this article we describe a mil

Full text of DOI:10.1055/s-0029-1217550

1974
LETTER
An Efficient Method for Chemoselective Thioacetalization of Aldehydes in the
Presence of a Catalytic Amount of Acidic Ionic Liquid under Solvent-Free
Conditions
C
hemoselective
T
h
b
ioacetalizati
d
on of
A
ldehy
o
des l Reza Hajipour,*a,b Ghobad Azizi,a Arnold E. Ruohoa
a
Department of Pharmacology, University of Wisconsin Med. Sch., 1300 University Avenue, Madison, WI 53706-1532, USA
Fax +1(608)2621257; E-mail: arhajipour@wisc.edu
Pharmaceutical Research Laboratory, Department of Chemistry, Isfahan University of Technology, Isfahan 84156, Iran
b
Received 18 February 2009
–
+
Abstract: A water-stable Brønsted acidic ionic liquid with an al-
kane sulfonic acid group was synthesized. This ionic liquid cata-
lyzed the thioacetalization reaction smoothly to afford 1,3-dithianes
in excellent yield and less time. In this article we describe a mild and
chemoselective thioacetalization procedure for the protection of
various aldehydes in the presence of catalytic amount of ionic liquid
(2 mol%).
SO3
O
OH
S
Et3N
O
Figure 1 Triethyl(butyl-4-sulfonyl) ammonium toluene sulfonate
The protection of carbonyl group as a dithioacetal is a
common practice in organic chemistry, as they are quite
stable under basic or mildly acidic conditions.15 The
dithioacetals are also utilized as masked acyl anions16 or
masked methylene functions.17 Generally, they are pre-
pared by condensation of carbonyl compounds with thiols
or dithiols using strong acid catalysts such as HCl,18 PT-
SA,19 BF3·OEt2,20 AlCl3,21 TiCl4,22 Mg(OTf)3,23 and
LaCl3.24 A large number of these methods require long re-
action times, reflux temperature, and stoichiometric
amount of catalyst and provide low yields. A further lim-
itation is the use of the highly volatile solvent as reaction
medium.
Most recently, some methods employing LiBr,25 LiBF4,26
InCl3,27 Sc(OTf)3,28 and I229 have been reported. Interest-
ingly, only a few of these methods have demonstrated the
chemoselective protection of aldehydes in the presence of
ketones. Some methods fail to protect deactivated aromat-
ic substrates.28 Therefore, there is still a need to develop a
simple and efficient method for chemoselective protec-
tion of aldehydes.
Key words: acid catalysis, thioacetalization, Brønsted acidic ionic
liquid
Ionic liquids (IL), when used in place of classical organic
solvents, offer a new and environmentally benign ap-
proach to modern chemical process.1–4 The use of task-
specific IL further enhances the versatility of IL for the
cases in which the reagent and medium are coupled.5–8
One of the increasing interests in specific IL focuses on
designing acidic IL to replace traditional liquid acids,
such as sulfuric acid and hydrochloric acid, in chemical
processes. Such acidic IL have potential as dual solvent/
catalyst in organic reactions. It is well known that IL with
metal halide anions manifest Lewis acidity, especially
those based on chloroaluminate anions. However, these
IL are sensitive to moisture and unstable in water,1,2,9 so
the preparation and application of such types of IL often
necessitate extreme operating conditions. Recently, some
greener IL that involve phosphate or octyl sulfate anions
have been synthesized.10–12 These IL are halogen-free and
relatively stable against hydrolysis.10,13 Furthermore,
Cole14 first synthesized Brønsted acidic IL that bear an al-
kane sulfonic acid group in a imidazole or triphenylphos-
phine cation. However, Brønsted acidic IL with
triphenylphosphine as the cation have a high melting tem-
perature (ca. 80 °C), which limits their application. Fur-
thermore, IL with imidazole as the cation are relatively
expensive, which hinders their industrial applications.
Therefore, it is necessary to synthesize less expensive
Brønsted acidic IL with low melting point. Therefore, we
synthesized the acidic IL from triethylamine, butane sul-
tone and PTSA (Figure 1).
In this context we report synthesis of acidic IL
[Et3N(CH2)4SO3H][OTs]. This IL has already been syn-
–
thesized with other anions such as HSO4 and other cation
such as phosphonium cation.14 The acid must possess a
pKa sufficiently low to convert the pendant sulfonate
group into an alkane sulfonic acid, the pKa of the latter be-
ing expected to be ca. –2. The result is the transformation
of the zwitterion into an IL cation bearing an appended
sulfonic acid group, with the conjugate base of the exoge-
nous acid becoming the IL anion.
For the IL synthesis reported here, the donor acids were
PTSA·H2O. This acid was chosen largely because of the
resistance of its anion toward hydrolytic decomposition, a
common problem with some strong acid anions (e.g., PF6–).
Washing IL with toluene or diethyl ether results in no ex-
traction of free PTSA (soluble in either liquid). This be-
havior was consistent with the donor acid being fully
SYNLETT 2009, No. 12, pp 1974–1978
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x
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Advanced online publication: 03.07.2009
DOI: 10.1055/s-0029-1217550; Art ID: S02209ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Chemoselective Thioacetalization of Aldehydes
1975
Table 1 Conversion of Aldehydes to the Corresponding Thioacetalsa
incorporated into its respective IL structure rather than re-
maining simply mixture of added strong acid with dis-
solved zwitterion. This IL was screened as solvent/
catalysts for thioacetalization of aldehydes.
Entry Substrate
Productb
Time Yield
(min) (%)c
In our ongoing research program to develop new synthetic
methodologies for protection of carbonyl compounds, we
have found that this IL, which acts as a mild Brønsted
acid, can be used for thioacetalization of carbonyl com-
pounds. In this Letter, we wish to report a simple, effi-
cient, and fast method for chemoselective protection of
various aldehydes as 1,3-dithiolanes using a catalytic
amount of acidic IL (2 mol%) in good to excellent yields
(Scheme 1, Scheme 2).
S
CHO
1
3
90
S
S
H
OMe
OMe
S
CHO
2
3
4
5
2
2
95
92
H
S
H
S
CHO
CHO
MeO
MeO
S
O
O
O
O
S
S
O–
CH2Cl2, reflux, 24 h
86%
O
Et3N
+
+
H
NEt3
1.5 95
S
O
O
PTSA, 40 °C
12 h, nitrogen atmosphere
MeO
MeO
MeO
S
MeO
MeO
MeO
OH
OTs–
NEt3
S
CHO
+
1
3
2
95
88
93
S
H
Scheme 1
S
CHO
HSCH2CH2SH (1.1 mmol)
IL (0.02 mmol)
6
7
8
R
R
S
S
O
H
NC
Br
grinding (r.t.)
88–96%
NC
Br
H
S
H
R = alkyl, aryl, allyl
S
CHO
S
Scheme 2
H
Initially, we studied the conversion of 3,4-dimethoxy-
benzaldehyde into 2-(3,4-dimethoxyphenyl)-1,3-dithio-
lane under solvent-free conditions (grinding) with IL.
Treatment of 3,4-dimethoxybenzaldehyde with 1,2-
ethanedithiol in the presence of IL (2 mol%) at room tem-
perature afforded the desired 2-(3,4-dimethoxyphenyl)-
1,3-dithiane in short reaction time (1 min). Similarly, sev-
eral activated and deactivated aromatic aldehydes and al-
iphatic aldehydes underwent the protection reactions to
give the corresponding thioacetal derivatives in the time
range between 1–5 minutes (Table 1). However in the ab-
sence of catalyst the reaction of 3,4-dimethoxybenzalde-
hyde with 1,2-ethanedithiol did not occur at all, even after
3 hours grinding.
S
CHO
5
90
S
H
S
O2N
O2N
O2N
O2N
CHO
9
5
2
88
92
S
H
S
H
CHO
10
S
S
MeO
MeO
CHO
MeO
MeO
S
11
12
1
2
96
91
The reusability of the catalyst was also checked. After
each run, water and hexane were added to the reaction
mixture, the organic layer was washed with water (3×);
then the water was evaporated under reduced pressure,
and the catalyst was dried at 65 °C under reduced pressure
in a vacuum oven for two hours and reused in the reaction
for the thioacetalization of 3-nitro benzaldehyde. The re-
sults show that the catalyst can be employed four times,
although the activity of the catalyst was gradually de-
creased. However, the result shows that this catalyst can
be employed as a green and reusable IL for thioacetaliza-
tion of aldehydes under solvent-free conditions.
H
OMe
MeO
S
CHO
S
H
Cl
Cl
a Reaction conditions: Substrate (1 mmol), 1,2-ethanedithiol (1.1
mmol), IL (2 mol%) under solvent-free conditions.
b All products were characterized by 1H NMR and IR spectroscopy.
c Isolated yield after purification by column chromatography on silica
gel.
Synlett 2009, No. 12, 1974–1978 © Thieme Stuttgart · New York

1976
A. R. Hajipour et al.
LETTER
Table 2 Reaction Time for Thioacetalization of some Aldehyde Compared with our Reaction Time30–34
Aldehydes
Time (min)
This work
Ref. 30
Ref. 31
Ref. 32
60
Ref. 33
Ref. 34
Ref. 27
benzaldehyde
3
8
8
–
10
–
20
–
–
4-methyl benzaldehyde
4-nitro benzaldehyde
4-methoxy benzaldehyde
2
–
60
–
5
35
6
30
5
240
30
28
10
45
20
20
15
1.5
To show the efficiency of this method with reported meth- It is noteworthy that ketones did not produce the corre-
ods in Table 2 we compared the reaction time for thioace- sponding thioacetals under the same reaction conditions.
talization of some aldehydes. As demonstrated in Table 2, This result prompted us to explore the chemoselective
our reaction times are shorter than that of the reported protection of aldehydes in the presence of ketones. For ex-
methods.
ample, when an equimolar mixture of 4-methoxy benzal-
dehyde and 4-methoxy acetophenone was allowed to react
with 1,2-ethanedithiol with a catalytic amount of IL, only
the 1,3-ditholane derivative of the 4-methoxy benzalde-
hyde was obtained (Scheme 3). Also this method is selec-
tive for activated aldehydes toward deactivated
aldehydes. For this reason, an experiment was performed
on a mixture of 4-ethoxybenzaldehyde and 4-nitrobenzal-
dehyde. The predominant product was 2-(4-methoxyphe-
nyl)-1,3-dithiolane (Scheme 4). In another experiment we
treated the 4-formyl acetophenone with 1,2-dithioethane
in the presence of catalyst, we observed the formyl was
protected and the ketone was intact (Scheme 5).
In order to show the thioacetalization of aldehydes under
solvent-free conditions and in solvents, several solvents
were examined under the mentioned conditions. Cyclo-
hexane, dichloromethane, and ethyl acetate were used as
solvents. As demonstrated in Table 3 under solvent-free
conditions, the reaction time is shorter, and the yields are
higher than in solvents.
Table 3 Conversion of 3,4-Dimethoxy Benzaldehyde 2-(3,4-
Dimethoxyphenyl)-1,3-dithiane under Different Conditionsa
Reaction conditions
cyclohexane
Reaction time (min) Yield (%)b
35
45
30
1
80
88
85
95
The possible mechanism is shown in Scheme 5; initially
IL protonated the carbonyl oxygen to generate a more
electrophile carbonyl group. This activated group reacts
CH2Cl2
EtOAc
solvent-free (grinding)
O
S
S
H
a Reaction conditions: IL (2 mol%) and 1,2-ethanedithiol (1.1 mmol).
H
b Isolated yield after purification by column chromatography on silica
gel.
92%
MeO
MeO
HSCH2CH2SH
IL (2 mmol%)
1.5 min
O
S
S
In order to optimize the amount of IL, we used different
amounts of IL. Figure 2 demonstrates the correlation be-
tween time, yield, and amount of IL in the reaction be-
0%
MeO
tween
3,4-dimethoxy
benzaldehyde
and
1,2-
Scheme 3
ethanedithiol. The higher yield associated to a short reac-
tion time was obtained in the presence of 0.02 mmol (2
mmol%) of IL. Higher amount of IL decrease yield.
S
MeO
CHO
CHO
MeO
O2N
S
S
HSCH2CH2SH
90%
20%
H
S
IL (2 mmol%)
1 min
O2N
H
Scheme 4
O
O
S
H
HSCH2CH2SH
CHO
S
IL (2 mmol%)
1 min
90%
Figure 2 Correlation between time, yield, and amount of IL
Scheme 5
Synlett 2009, No. 12, 1974–1978 © Thieme Stuttgart · New York

LETTER
Chemoselective Thioacetalization of Aldehydes
1977
zwitterion and PTSA·H2O were liquefied, resulting in the formation
of [Et3N(CH2)4SO3H][OTS]. Then, the resulting liquid was washed
repeatedly with Et2O or toluene to remove the possible unreacted
materials and dried in vacuum oven to give the IL as viscous liquid
at r.t.
with dithiol to form a hemithioacetal-type intermediate,
which after elimination of water afforded the correspond-
ing dithioacetal derivative and IL (Scheme 6).
IL–
IR (KBr): 3400, 2990, 2952, 1685, 1488, 1455, 1398, 1231, 1190,
1121, 1030, 1000, 819, 682, 566 cm–1. 1H NMR (300 MHz, CDCl3):
d = 7.0–8.0 (4 H, d, arom. H), 6.45 (2 H, t), 4.6 (1 H, SO3H), 3.5 (2
H, t), 3.1 (6 H, m), 2.3 (3 H, s, CH3), 1.7 (4 H, m, CH2), 1.2 (9 H, t,
CH3) ppm. 13C NMR (500 MHz, D2O): d = 142.0, 141.0, 129.0,
125.0 (arom. C), 56.0 (CH2), 53.0 (CH2), 44.8 (CH2), 28.8 (CH3),
18.9 and 20.9 (CH2), 7.16 (CH3) ppm.
O
S
S
H
HIL
R
H
– H+
R
H
O+
+
S
S
Typical Procedure for Thioacetalization of Aldehydes
R
H
R
H
To a mixture of aldehydes (1 mmol) and 1,2-ethanedithiol (1.1
mmol) in a mortar was added IL (2 mol%, 0.01 g). The reaction
mixture was grinding at r.t., and the reaction progress was moni-
tored by TLC (EtOAc–cyclohexane, 1:4) until the disappearance of
aldehydes. Then the reaction mixture was diluted with hexane (5
mL) and washed with H2O (3 × 10 mL) to get rid of IL. The organic
phase was dried with CaCl2, and the solvent was evaporated under
reduced pressure to afford the crude product, which was purified by
column chromatography on silica gel (0.2–0.5 mm, 10 g) with
EtOAc–cyclohexane (1:4) as eluent.
HSCH2CH2SH
– H2O
H
H
H
+
O
O
S+
H
S
H
R
R
SH
SH
Acknowledgment
We gratefully acknowledge the funding support received for this
project from the Isfahan University of Technology (IUT), IR Iran
(A.R.H.), and Grant GM 33138 (A.E.R.) from the National Insti-
tutes of Health, USA. Further financial support from Center of
Excellency in Sensor and Green Chemistry Research (IUT) is gra-
tefully acknowledged.
HIL = protonated ionic liquid
IL–
= deprotonated ionic liquid
Scheme 6
In conclusion, we have developed a simple and efficient
method for the chemoselective dithioacetalization of var-
ious aldehydes using a catalytic amount of IL. Moreover,
highly deactivated aromatic aldehydes can be converted
into their corresponding thioacetals without any difficul-
ty. The advantages of this method compared to reported
methods are the use of a catalytic amount of acid catalyst,
short reaction times, high yields, reusability of the cata-
lyst, chemoselectivity of the reaction, and green chemis-
try.
References
(1) Welton, T. Chem. Rev. 1999, 99, 2071.
(2) Wassercheid, P.; Keim, W. Angew. Chem. Int. 2000, 39,
3772.
(3) Davis, J. H. Jr.; Fox, P. Chem. Commun. 2003, 1209.
(4) Sheldon, R. Chem. Commun. 2001, 2399.
(5) Bates, E. D.; Mayton, R. D.; Ntai, I.; Davis, J. H. Jr. J. Am.
Chem. Soc. 2002, 124, 926.
(6) Visser, A. E.; Swatloski, R. P.; Reichert, W. M.; Mayton, R.;
Sheff, S.; Wierzbicki, A.; Davis, J. H. Jr.; Rogers, R. D.
Chem. Commun. 2001, 135.
(7) Fraga-Dubreuil, J.; Bazureau, J. P. Tetrahedron Lett. 2001,
42, 6097.
(8) Wasserscheid, P.; Drießen-Hoelscher, B.; van Hal, R.;
Steffens, H. C.; Zimmermann, J. Chem. Commun. 2003,
2038.
(9) Abbott, A. P.; Capper, G.; Davies, D. L.; Munro, H. L.;
Rasheed, K.; Tambyrajah, V. Chem. Commun. 2001, 2010.
(10) Wasserscheid, P.; van Hal, R.; Bösmann, R. Green Chem.
2002, 4, 400.
(11) Fraga-Dubreuil, J.; Bourahla, K.; Rahmouni, M.; Bazureau,
J. P.; Hamelin, J. J. Catal. Commun. 2002, 3, 185.
(12) Wasserscheid, P.; Sesing, M.; Korth, W. Green Chem. 2002,
4, 134.
(13) Garcia, M. T.; Gathergood, N.; Scammells, P. J. Green
Chem. 2005, 7, 9.
(14) Cole, A. C.; Jensen, J. L.; Ntai, I.; Tran, K. L. T.; Weaver,
K. J.; Forbes, D. C.; Davis, J. H. Jr. J. Am. Chem. Soc. 2002,
124, 5962.
(15) Surya, K. D. Tetrahedron Lett. 2004, 45, 1035.
(16) Seebach, D. Angew. Chem., Int. Ed. Engl. 1969, 8, 639.
General
IR spectra were recorded on a Perkin-Elmer FT-IR spectrometer.
1H NMR spectra were recorded on a 300 MHz spectrometer and ref-
erenced to TMS. Thin-layer chromatography was performed on sil-
ica/alumina plates, and components were visualized by observation
under UV irradiation or iodine. Column chromatography was per-
formed on neutral silica gel. All yields refer to isolated products. All
reagents and solvents were purchased as the highest grade available
and used without further purification.
Preparation of Ionic Liquid
The syntheses of this IL consist of two steps (Scheme 3). The first
step is the preparation of zwitterion. In this case, equimolar quanti-
ties of Et3N and 1,4-butane sultone were mixed and refluxed in
CH2Cl2 for 24 h. The resulting white zwitterion was washed with
Et2O, and the solvent was evaporated under reduced pressure using
rotary evaporator to give the product in 86% yield. The zwitterion
was treated with equimolar amount of PTSA·H2O, and the mixture
was heated at 40 °C for 12 h under nitrogen atmosphere; the solid
Synlett 2009, No. 12, 1974–1978 © Thieme Stuttgart · New York

1978
A. R. Hajipour et al.
LETTER
(17) Pettit, G. R.; Van Tamelen, E. E. Org. React. 1962, 12, 356.
(18) Ralls, J. W.; Dobson, R. M.; Reigel, B. J. Am. Chem. Soc.
1949, 71, 3320.
(19) Djerassi, C.; Gorman, M. J. Am. Chem. Soc. 1953, 75, 3704.
(20) Fieser, L. F. J. Am. Chem. Soc. 1954, 76, 1945.
(21) Ong, B. S. Tetrahedron Lett. 1980, 21, 4225.
(22) Kumar, V.; Dev, S. Tetrahedron Lett. 1983, 24, 1289.
(23) Corey, E. J.; Shimoji, K. Tetrahedron Lett. 1983, 24, 169.
(24) Garlaschelli, L.; Vidari, G. Tetrahedron Lett. 1990, 31,
5815.
(27) Madhuswamy, S.; Arulananda Babu, S.; Gunanatham, C.
Tetrahedron Lett. 2001, 42, 359.
(28) Kamal, A.; Chouhan, G. Tetrahedron Lett. 2002, 43, 1347.
(29) Samajdar, S.; Basu, M. K.; Becker, F. F.; Banik, B. K.
Tetrahedron Lett. 2001, 42, 4425.
(30) Muthusamy, S.; Arulananda-Babu, S.; Gunanatan, C.
Tetrahedron Lett. 2002, 58, 7897.
(31) Firouzabadi, H.; Iranpoor, N.; Hazarkhani, H. J. Org. Chem.
2001, 66, 7527.
(32) De, S. K. Tetrahedron Lett. 2004, 45, 1035.
(33) De, S. K. Adv. Synth. Catal. 2005, 347, 673.
(34) De, S. K. J. Mol. Catal. A: Chem. 2005, 226, 77.
(25) Tandon, M.; Begley, T. P. Synth. Commun. 1997, 27, 2953.
(26) Yadav, J. S.; Reddy, B. V. S.; Pandey, S. K. Synlett 2001,
238.
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