A new molecular iodine-catalyzed thioketalization of carbonyl compounds: Selectivity and scope

Article abstract of DOI:10.1016/S0040-4039(01)00752-3

A new molecular iodine-catalyzed thioketalization of carbonyl compounds has been developed.

Full text of DOI:10.1016/S0040-4039(01)00752-3

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 4425–4427
A new molecular iodine-catalyzed thioketalization of carbonyl
compounds: selectivity and scope
Susanta Samajdar, Manas K. Basu, Frederick F. Becker and Bimal K. Banik*
The University of Texas, M. D. Anderson Cancer Center, Department of Molecular Pathology, Box 89, 1515 Holcombe Bovd,
Houston, TX 7703, USA
Received 20 March 2001; revised 4 May 2001; accepted 5 May 2001
Abstract—A new molecular iodine-catalyzed thioketalization of carbonyl compounds has been developed. © 2001 Elsevier Science
Ltd. All rights reserved.
The protection of aldehydes and ketones as thioketals is
a widely used method and in general, the reaction is
usually performed in the presence of acids.1 However,
there are shortcomings to using acid in the thioketaliza-
tion reaction of carbonyl compounds, namely long
reaction time, reflux temperature, unwanted side reac-
tions and non-selectivity. Many other methods are
reported in the literature, such as titanium tetra-
chloride,2 magnesium or zinc triflates,3 lanthanum chlo-
ride,4 and Nafion-H.5 But, the chemoselectivity between
these groups has only been reported with silica-gel–
thionyl chloride,6 Amberlyst-15 catalyst,7 ceric ammo-
nium nitrate8 and indium trichloride.9 Selective
protection of a ketone in the presence of another in a
complex molecule has never been addressed by the
reported methods (Scheme 1).
a mixture, and reduction chemistry targeting the non-
protected group can then be accomplished with the
simultaneous regeneration of the protected one in a
single step. Moreover, we report here an excellent
intramolecular chemoselectivity between two ketone
functionalities.
At the inception of this work, we reacted several aro-
matic aldehydes with ethane thiol (1) and 1,3-propane
thiol (2) in the presence of iodine (10 mol%) in dry
THF as the solvent at room temperature. The protected
thioketal was obtained in excellent yield within a few
minutes (Table 1).
Application of this method was then extended for the
protection of ketones of different structures. The
thioketals were formed, although time required for the
completion of the reaction was found to be longer
(Table 1).
We now report a facile and convenient iodine-catalyzed
thioketalization for various carbonyl compounds in
high yield. We believe that our method is very general,
simple, mild, rapid and new to the literature. In addi-
tion, by using this method, a particular carbonyl group
can be selectively blocked in the presence of another in
The differences of reactivities of the aldehydes and
ketones suggest that this method can be used for the
selective protection of these groups, and resulted in the
successful protection of an aldehyde in the presence of
a ketone. This has been shown by a reduction experi-
ment with sodium borohydride (Scheme 2).
HS(CH2)nSH/I2(cat)
THF, 87-99%
R1
R2
S
S
R1
R2
O
n
We were also able to achieve a selective protection of
an aliphatic ketone (2-methyl cyclopentanone) in the
presence of an aromatic ketone (acetophenone) by this
method and this has been demonstrated by a subse-
quent reduction reaction (Scheme 3).
R1 = alkyl, R2 = H
R1 = R2 = alkyl
R1 = alkyl, R2 = aryl
R1 = aryl, R2 = aryl
n = 2, 3
Scheme 1.
* Corresponding author. E-mail: banik@mdanderson.org
This method was then used for selective protection of a
six-membered ketone as
a
thioketal present in
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00752-3

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S. Samajdar et al. / Tetrahedron Letters 42 (2001) 4425–4427
Table 1. Thioketalization of aldehydes and ketones
OH
S
S
CHO
COCH3
Entry
Carbonyl compounds Thiol
Time
(h)
Yield
(%)
(i) HS(CH2)3SH/I2/THF
(ii) NaBH4
+
+
1
2
Propionaldehyde
trans-Cinnamalde-
hyde
1, 2
2
0.5
0.5
98
94
98%
95%
3
4
Benzaldehyde
2-Bromobenzalde-
hyde
1, 2
2
0.5
0.5
99
91
Scheme 2.
5
6
7
1-Naphthaldehyde
2-Furaldehyde
3-Methoxy-2-
nitrobenzaldehyde
Ferrocenecarbox-
aldehyde
2
2
2
0.5
0.5
0.5
97
96
89
8
2
0.5
87
9
10
11
Hexane-2,5-dionea
Cyclohexanone
2-Methylcyclo-
pentanone
2
2
1, 2
3
4
3
94
97
98
OH
COCH3
O
S
S
(i) HS(CH2)3SH/I2/THF
(ii) NaBH4
+
+
12
13
14
Acetophenone
1-Tetralone
9-Fluorenone
1, 2
2
2
7
5
6
92
90
91
99%
96%
a Use of 1 equiv. of thiol gave monothio ketal and 2 equiv. gave
dithio ketal.
Scheme 3.
O
O
OH
(i) NaBH4
(ii) CAN, 91%
HS(CH2)3SH
I2/THF, 96%
S
O
O
S
3
4
5
Scheme 4.
androstane 3. Sodium borohydride reduction of the
protected androstane 4 and removal of the protective
group by oxidation afforded the keto-alcohol 5 in a
single step (Scheme 4).
Acknowledgements
This work was supported in part by a grant received
from the Robert J. Kleberg, Jr. and Helen C. Kleberg
Foundation and NIH Cancer Center Support Grant,
5-P30-CA16672-25, in particular the shared resources
of the Pharmacology and Analytic Center Facility.
The present iodine-catalyzed thioketalization deserves
some special comments. For a successful reaction of
this type, one would expect the use of a stoichiometric
amount of iodine. But, in the present investigation, we
used catalytic amounts of iodine (10 mol%). Moreover,
in a large-scale reaction, even a smaller amount of
iodine (5 mol%) can be used with success. We suspect
that hydroiodic acid is the actual catalyst involved in
the reaction.
References
1. (a) Loewenthal, H. J. E. In Protective Groups in Organic
Chemistry; McOmie, J. F. W., Ed.; Plenum Press: New
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Groups in Organic Synthesis; John Wiley: New York,
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2. Kumar, V.; Dev, S. Tetrahedron Lett. 1983, 24, 1289.
3. Corey, E. J.; Shimoji, K. Tetrahedron Lett. 1983, 24, 169.
4. Garlaschelli, L.; Vidari, G. Tetrahedron Lett. 1990, 31,
5815.
In summary, our presently reported iodine-catalyzed
thioketalization method of carbonyl groups is a novel,
generally applicable, chemoselective and convenient one
for practical application. The selectivities described
herein are not only remarkable, but also they can be
applied to a wide range of carbonyl compounds. This
method10 with its mild conditions, sharp selectivity
differences between functional groups, should have
broad applicability.
5. Olah, G. A.; Narang, S. C.; Meider, D.; Salem, G. F.
Synthesis 1981, 282.

S. Samajdar et al. / Tetrahedron Letters 42 (2001) 4425–4427
4427
6. Kamitori, T.; Hojo, K.; Masuda, R.; Kimura, T.;
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Tetrahedron Lett. 2001, 42, 359.
10. A representative procedure is as follows: To a stirred
solution of carbonyl compound (1 mmol) and thiol (1
mmol) in THF (2 mL) was added iodine (0.1 mmol).
After a period specified in Table 1 the solvent was
removed under reduced pressure. The crude product was
then passed through a short silica-gel column to afford
pure thioketal (87–99%).
.