Scandium triflate as a recyclable catalyst for chemoselective thioacetalization

Article abstract of DOI:10.1016/S0040-4039(01)02378-4

Scandium triflate [Sc(OTf)₃] has been found to be an extremely efficient and recyclable catalyst for the addition of ethanethiol, 1,2-ethanedithiol and 1,3-propanedithiol to both aromatic and aliphatic aldehydes. In addition, by employing this catalyst, high chemoselective thioacetalization of carbonyl compounds has been achieved.

Full text of DOI:10.1016/S0040-4039(01)02378-4

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 1347–1350
Scandium triflate as a recyclable catalyst for chemoselective
thioacetalization
Ahmed Kamal* and Gagan Chouhan
Division of Organic Chemistry, Indian Institute of Chemical Technology, Hyderabad 500007, India
Received 10 October 2001; revised 5 December 2001; accepted 14 December 2001
Abstract—Scandium triflate [Sc(OTf)3] has been found to be an extremely efficient and recyclable catalyst for the addition of
ethanethiol, 1,2-ethanedithiol and 1,3-propanedithiol to both aromatic and aliphatic aldehydes. In addition, by employing this
catalyst, high chemoselective thioacetalization of carbonyl compounds has been achieved. © 2002 Elsevier Science Ltd. All rights
reserved.
Thioacetalization of carbonyl compounds plays an
important role in organic synthesis. Since the introduc-
tion of 1,3-dithianes as nucleophilic acylating reagents
by Corey and Seebach,1 dithioacetals have become
widely used tools for CꢀC bond formation. Further-
more, the stability exhibited by 1,3-dithiolanes under
acidic and basic conditions has led to their synthetic
utility as carbonyl protecting groups and as intermedi-
ates for the conversion of carbonyl compounds to their
parent hydrocarbons.2 In the literature there are numer-
ous methods reported for the preparation of thioacetals
from carbonyl compounds employing acid catalysts
Scandium triflate has several advantages over other
Lewis acids, it is stable in water and therefore does not
decompose under aqueous work-up conditions, unlike
other conventional Lewis acids. Thus, recyclization of
the scandium triflate is often possible and renders the
procedure relatively environmentally acceptable by uti-
lizing these properties; this catalyst has been success-
fully applied to several synthetic reactions.16
We here in report an efficient method for the thioac-
etalization of carbonyl compounds in good to high
yields, as well as the chemoselective protection of vari-
ous carbonyl compounds by employing scandium trifl-
ate. This methodology provides selective protection of
the aldehyde functionality of b- and g-ketoaldehydes.
Moreover, this catalyst has been recovered almost
quantitatively from the aqueous layers and has been
reused for second thioacetalization processes and the
yields of the second runs were comparable to those of
the first run (Table 1, products 2b, 2d, 3g).
such as Zn or Mg(OTf)2,3 BF3·Et2O,4 AlCl3,5 TiCl4
6
and LaCl3.7 A large number of these methods require
long reaction times and reflux temperatures and result
in unwanted side reactions whilst offering poor selectiv-
ity when applied to mixtures of aldehydes and ketones.
Although some recent methods employing LiBr,8 InCl3
9
10
and LiBF4 have been reported to show chemoselectiv-
ity, these Lewis acids are destroyed in the work-up
procedure and cannot be recovered and reused. How-
ever, the developments in this area demand further
searches for better catalysts that could be superior to
the existing ones with regard to toxicity, handling,
selectivity and recyclability. Recently, scandium triflate
has been identified as a mild and selective reagent for
various transformations in organic synthesis.11 In par-
ticular, scandium(III) trifluoromethanesulfonate (trifl-
ate) has been used extensively as a Lewis acid in aldol,12
Diels–Alder,13 Friedel–Crafts14 and Fries rearrange-
ment reactions.15
Interestingly, the experimental procedure for thioacetal-
ization is remarkably simple and does not require the
use of dry solvents or inert atmospheres. A catalytic
quantity of scandium triflate (4 mol%) was added to a
stirred solution of the carbonyl compound in
dichloromethane and to this was added the required
thiol (1.2 equiv.) and the mixture stirred at room tem-
perature. The generality of this process has been proved
with a wide range of aromatic, aliphatic and hetero-
cyclic aldehydes. Accordingly, dithioacetals, 1,3-dithi-
olanes and 1,3-dithianes have been obtained by the
reaction of ethanethiol, 1,2-ethanedithiol and 1,3-
propanedithiol, respectively, in the presence of catalytic
amounts of Sc(OTf)3 (Scheme 1); the results are illus-
trated in Table 1.17
* Corresponding author. Tel.: +91-40-7193157; fax: 91-40-7160757;
e-mail: ahmedkamal@iict.ap.nic.in
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)02378-4

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A. Kamal, G. Chouhan / Tetrahedron Letters 43 (2002) 1347–1350
Table 1. Preparation of dithioacetals 1,3-dithiolanes and 1,3-dithianes using scandium triflate
Entry (1)
Products (2-4)a
Time (min)
20
Yield (%)b
94
N3
a
(2a)
(2b)
CH(SEt)2
93/88c
59
Cl
CH(SEt)2
20
b
c
HO
H3CO
H3CO
(2c)
360
CH(SEt)2
80/80c
57
(2d)
(2e)
d
e
CH(SEt)2
CH(SEt)2
35
360
(2f)
f
50
50
90
87
CH(SEt)2
CH(SEt)2
g
(2g)
N3
a
(3a)
20
92
S
S
S
S
88/85c
76
g
(3g)
(3h)
50
S
S
h
240
N
H
S
S
(4i)
i
50
30
80
90
S
S
S
(4b)
Cl
b
HO
c
(4c)
S
360
55
H3CO
S
1
b
aAll products were characterised by H NMR, IR and mass spectroscopy. Isolated yields after
c
column chromatography on silica gel. Isolated yields with reused catalyst (recovered catalyst
92%)
O
4 mol% Sc(OTf)3, EtSH or HS(CH2)nSH
CH2Cl2, 20-360 min
S
S
CH(SEt)2
R
( )n
R
or
H
R
1a-i
2a-g
3 and 4
n=2, 3
R=aryl, alkyl,
allyl, heterocyclic
Scheme 1.
It has been observed that both activated and weakly
activated aromatic aldehydes form thioacetals in near
quantitative yields, whereas in the cases of entries 1c
and 1e the yields are only moderate even after pro-
longed reaction times. Aliphatic aldehydes (entries 1f
and 1g) also react efficiently to produce the correspond-
ing thioacetals. Similarly, 1,3-dithiolanes (3a, 3g, 3h)
and 1,3-dithianes (4b, 4c, 4i) have been obtained by the

A. Kamal, G. Chouhan / Tetrahedron Letters 43 (2002) 1347–1350
1349
the presence of ketones. With this objective, as a rep-
resentative example we carried out some experiments
with equimolar mixtures of an aldehyde and a ketone
(Scheme 2, Table 2). It was observed that in this
mixture, the corresponding aldehyde formed the dithi-
olane whilst the ketone was almost completely recov-
ered.
reaction of 1,2-ethanedithiol and 1,3-propanedithiol,
respectively, in good yields.
It is interesting to note that ketones did not produce
the corresponding thioacetals under the same reaction
conditions. This reactivity of Sc(OTf)3 led us to
explore the chemoselective protection of aldehydes in
S
S
CHO
COCH3
COCH3
4 mol% Sc(OTf)3, HS(CH2)3SH
CH2Cl2, r.t.
+
+
x
5a-c
x
x
6a-c
x
7a-c
x=H, Br, F
90-94%
97%
Scheme 2.
Table 2. Chemoselective protection of aldehyde functionalities using scandium triflate
_______________________________________________________________________
Product a
Yield (%)b
Time (min)
Entry
Substrate
_______________________________________________________________________
CHO
5a
6a
5b
S
S
(7a)
(7b)
30
30
94
92
COCH3
Br
Br
CHO
S
S
Br
COCH3
6b
F
CHO
5c
6c
S
(7c)
(9a)
30
90
90
60
F
F
COCH3
S
O
O
O
O
S
S
8a
( )2
H
( )2
H3CO
H3CO
O
O
S
S
8b
(9b)
120
57
H
H
O
O
O
O
S
S
8c
(9c)
(9d)
80
90
63
60
S
S
O
O
S
8d
H
S
_____________________________________________________________________
aAll products were characterised by 1H NMR, IR and mass spectroscopy. bIsolated yields
after column chromatography on silica gel.

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A. Kamal, G. Chouhan / Tetrahedron Letters 43 (2002) 1347–1350
Acknowledgements
4 mol% Sc(OTf)3, HS(CH2)3SH
O
O
O
S
S
( )n
( )n
H
R
H
R
CH2Cl2, r.t.
n=1,2
One of the authors (G.C.) would like to thank the
8a-d
9a-d
IICT, Hyderabad for the award of
Fellowship.
a Research
R=p-OCH3Ph, Ph,
CH3, 2-thiophene
Scheme 3.
References
1. (a) Corey, E. J.; Seebach, D. J. Org. Chem. 1966, 31,
4097; (b) Seebach, D. Synthesis 1969, 17; (c) Groebel,
B.-T.; Seebach, D. Synthesis 1977, 357; (d) Seebach, D.
Angew. Chem., Int. Ed. Engl. 1979, 18, 239; (e) Bulman
Page, P. C.; van Niel, M. B.; Prodger, J. Tetrahedron
1989, 45, 7643.
2. Greene, T. W. Protective Groups in Organic Synthesis;
John Wiley: New York, 1981; pp. 129–133.
3. Corey, E. J.; Shimoji, K. Tetrahedron Lett. 1983, 24, 169.
4. Fieser, L. F. J. Am. Chem. Soc. 1954, 76, 1945.
5. Ong, B. S. Tetrahedron Lett. 1980, 21, 4225.
6. Kumar, V.; Dev, S. Tetrahedron Lett. 1983, 24, 1289.
7. Garlaschelli, L.; Vidari, G. Tetrahedron Lett. 1990, 31,
5815.
4 mol% Sc(OTf)3, HS(CH2)3SH
CH2Cl2, r.t., 8 h
O
O
O
S
S
OC2H5
R
OC2H5
R
R=Ph, CH3,
2-thiophene
0%
Scheme 4.
COCH3
+
O
COCH3
S
S
4 mol% Sc(OTf)3, HS(CH2)3SH,
CH2Cl2, r.t., 5 h
+
8. Firouzabadi, H.; Iranpoor, N.; Karimi, B. Synthesis
1999, 58.
9. Muthusamy, S.; Arulananda Babu, S.; Gunanathan, C.
97%
90%
Tetrahedron Lett. 2001, 42, 359.
10. Yadav, J. S.; Reddy, B. V. S.; Pandey, S. K. Synlett 2001,
238.
Scheme 5.
11. For a review, see: Kobayashi, S. Eur. J. Org. Chem. 1999,
1, 15.
12. Crotti, P.; Bussol, V. D.; Favero, L.; Psero, M. J. Org.
Chem. 1996, 61, 9548.
13. Kobayshi, S.; Hachiya, I.; Araki, M.; Ishitani, H. Tetra-
hedron Lett. 1993, 34, 3755.
14. Kawada, A.; Mitamura, S.; Kobayashi, S. Synlett 1994,
545.
This method has also been extended for the intramolec-
ular chemoselectivity between keto and aldehyde func-
tionalities (Scheme 3). However, enolizable ketones
under the same conditions with scandium triflate did
not produce the corresponding dithioacetals, even after
prolonged reaction times (Scheme 4).
15. Kobayashi, S.; Moriwaki, M.; Hachiya, I. J. Chem. Soc.,
Chem. Commun. 1995, 1527.
16. Kobayashi, S. Synlett 1994, 689.
Furthermore, it was also observed that the aliphatic
ketone, cyclohexanone, could be selectively protected in
the presence of the aromatic ketone, acetophenone, by
employing the present methodology (Scheme 5).
17. Typical experimental procedure: To a stirred solution of
scandium triflate (4 mol%) and p-chlorobenzaldehyde (4
mmol) in dichloromethane (50 ml) at room temperature
was added ethanethiol (4.8 mmol). The mixture was
stirred at room temperature for 20 min. After completion
of the reaction, as indicated by TLC, water (25 ml) was
added to the reaction mixture, which was then extracted
with dichloromethane. The crude product was purified by
silica gel column chromatography to furnish the thioac-
etal in 93% yield. The aqueous layer containing the
catalyst could be evaporated under reduced pressure to
give a white solid. The FT-IR spectrum of the recovered
material was identical to that of the commercially avail-
able salt, which could be reused for the next thioacetal-
ization reaction (Table 1, product 2b).
In conclusion, we have demonstrated the use of scan-
dium triflate for the thioacetalization of aromatic,
aliphatic and heterocyclic aldehydes under extremely
mild conditions where the catalyst could be readily
recovered and reused thus making this procedure envi-
ronmentally acceptable. Moreover, the demonstration
of the high chemoselectivity between the two keto
functionalities as well as the keto and aldehyde groups,
in good to high yields and in short reaction times
makes the present method a practical protocol for
thioacetalization.