9
Procopio and co-workers have also reported the use of Ce(OTf)3
Indium(III) Trifluoromethanesulfonate as an
Efficient Catalyst for the Deprotection of Acetals
and Ketals
in polar solvents such as CH3NO2 or CH3CN saturated with
water as a viable deprotection procedure. Most relevant is the
work of Lipshutz10 where the use of PdCl2(CH3CN)2 and acetone
was found to be a mild catalytic system for the deprotection of
cyclic ketals and acetals. While this methodology has a wide
range of application, it suffers from the competitive deprotection
of TBS and THP functional groups under the ketal deprotection
conditions. In our laboratories the use of pyridinium p-toluen-
esulfonate and p-toluenesulfonic acid in the presence of ace-
tone11 has been shown to facilitate the transacetalization depro-
tection of acetals and ketals with limited application and versa-
tility. While many of these cited reagents do afford the desired
carbonyl compounds in reasonable yields, they tend to have li-
mitations such as (1) not being readily obtainable from commer-
cial sources, (2) resulting in unwanted side reactions, or (3) not
being easily applied to parallel or larger scale syntheses. It was
our intention to find a catalytic system that facilitated the
deprotection of a wide variety of acetals and ketals under mild,
neutral conditions with reagents that are commercially available,
easy to handle, cost-effective, and amenable to parallel synthetic
applications. We herein describe the deprotection of acetals and
ketals via transacetalization with acetone and indium(III)
trifluoromethanesulfonate as the Lewis acid catalyst.
Brian T. Gregg,* Kathryn C. Golden, and John F. Quinn
Department of Medicinal Chemistry, AMRI, Albany, New York
12203
ReceiVed April 5, 2007
Acetals and ketals are readily deprotected under neutral
conditions in the presence of acetone and catalytic amounts
of indium(III) trifluoromethanesulfonate (<0.8 mol %) at
room temperature or mild microwave heating conditions to
give the corresponding aldehydes and ketones in good to
excellent yields.
Our standard deprotection protocol involved preparing a
solution of acetal or ketal (2 mmol) in acetone (25 mL) to which
was added indium(III) trifluoromethanesulfonate (0.8 mol %).
For these reactions there was no deleterious effect on the
reactions due to moisture or air sensitivity of the catalyst and,
as a result, all reagents were standard laboratory grade and used
“as is” from commercial sources. Depending on the nature of
the substrate, the reactions were conducted either at room
temperature or with brief microwave heating. The selection of
acetals and ketals that were deprotected by using our standard
conditions are shown in Table 1. Commercially available
reagents 1a, 1b, 3, 5, 7, 9, 11, 17, 19, 21, 23, 25, 29, 31, 33,
35, and 37 were used “as is” from the vendor. Additional
reagents 13, 15, 27, 39, and 41 were prepared in-house and
were fully characterized by 1H, 13C, and HRES-MS.12 The
identity of commercially available reaction products 2, 4, 6, 8,
10, 18, 20, 22, 24, 26, 30, 32, 34, 36, 38, and 40 was verified
by comparison with published spectral data as well as comparing
to authentic material. Additional reaction products 14, 16, 28,
and 42 were prepared in-house and were fully characterized by
1H, 13C, and HRES-MS.12
The use of acetals and ketals for the protection of aldehydes
and ketones has been well established in the literature as an
important part of many multistep synthetic protocols. The sub-
sequent deprotection of these moieties is paramount to their suc-
cessful use in these syntheses.1 While a variety of methods are
available for the deprotection of acetals and ketals to give the
corresponding carbonyl compounds,2-5 many of these proce-
dures involve acidic conditions which have the potential to cause
unwanted side reactions such as aldol condensation or result in
the degradation of other protecting groups such as the N-tert-
butyl carbamate moiety. Venanzi and co-workers have reported
the ruthenium transitions metal complex [Ru(CH3CN)3(triphos)]-
(OTf)2 to be an effective catalyst for the nonacidic deprotection
of acetals and ketals with good yields for a limited number of
substrates.6 The use of Bi(OTf)3‚xH2O in water/THF7a has been
shown to facilitate the deprotection of a wide variety of acetals
and ketals; however, this system has been reported to be quite
acidic (pH 2) and may not be amenable to acid-sensitive protec-
ting groups.7b Additionally BiCl3 in methanol has been reported
to be an efficient Lewis acid for acetal and ketal deprotection.8
In general, all deprotections involving aromatic or aliphatic
acyclic acetals (entries 1, 2, 3, 7, and 8, Table 1) and ketals
(entries 4 and 5, Table 1) were readily deprotected within 20 to
(1) Greene, T. W.; Wuts, P. G. M. ProtectiVe Groups in Organic
Synthesis; 3rd ed.; John Wiley and Sons: New York, 1999. (b) Kocienski,
P. J. Protecting Groups; 1st ed.; Georg Thieme Verlag: Stuttgart, Germany,
1994.
(2) Kaur, G.; Trehan, A.; Trehan, S. J. Org. Chem. 1998, 63, 2365.
(3) Sun, J.; Dong, Y.; Cao, L.; Wang, X.; Wang, S.; Hu, Y. J. Org.
Chem. 2004, 69, 8932.
(4) Sen, S. E.; Roach, S. L.; Boggs, J. K.; Ewing, G. J.; Magrath, J. J.
Org. Chem. 1997, 62, 6684.
(5) Marcantoni, E.; Nobili, F. J. Org. Chem. 1997, 62, 4183.
(6) Ma, S.; Venanzi, L. M. Tetrahedron Lett. 1993, 34, 8071.
(7) (a) Carrigan, M. D.; Sarapa, D.; Smith, R. C.; Wieland, L. C.; Mohan,
R. S. J. Org. Chem. 2002, 67, 1027. (b) Procopio and co-workers have
reported that a suspension of Bi(OTf)3‚xH2O in water/THF is acidic and
that the aqueous layer from the workup was found to have a pH of 2.9
(8) Sabitha, G.; Babu, R. S.; Reddy, V.; Yadav, J. S. Chem. Lett. 2000,
1074.
(9) Dalpozzo, R.; De Nino, A.; Maiuolo, L.; Procopio, A.; Tagarelli,
A.; Sindona, G.; Bartoli, G. J. Org. Chem. 2002, 67, 9093.
(10) Lipshutz, B. H.; Pollart, D.; Monforte, J.; Kotsuki, H. Tetrahedron
Lett. 1985, 26, 705.
(11) Unpublished results; reaction times typically require from 10 to 20
h; conversion to the corresponding carbonyl compounds is sometimes
incomplete with additional byproducts being detected. Most common
protecting groups (TBS, TBDMS, TBDPS) undergo complete or partial
deprotection under the reaction conditions.
(12) In addition to many commercially available substrates several were
prepared in-house (13, 14, 15, 16, 27, 28, 39, 41, and 42) with each starting
material and product being fully characterized by 1H, 13C NMR, and mass
spectroscopyssee the Supporting Information for details.
10.1021/jo0707075 CCC: $37.00 © 2007 American Chemical Society
Published on Web 06/27/2007
5890
J. Org. Chem. 2007, 72, 5890-5893