Highly efficient chemoselective deprotection of O,O-acetals and O,O-ketals catalyzed by molecular iodine in acetone

Article abstract of DOI:10.1021/jo0486239

An extremely convenient method for deprotection of acetals and ketals catalyzed by molecular iodine (10 mol %) in acetone is reported. The protocol achieved the deprotection of acyclic or cyclic O,O-acetals and O,O-ketals in excellent yields within a few minutes under neutral conditions. The double bond, hydroxyl group, and acetate group remained unchanged, and the highly acid-sensitive furyl, tert-butyl ethers, and ketone-oxime stayed intact under these conditions.

Full text of DOI:10.1021/jo0486239

SCHEME 1
Highly Efficient Chemoselective
Deprotection of O,O-Acetals and O,O-Ketals
Catalyzed by Molecular Iodine in Acetone
Jianwei Sun, Yanmei Dong, Liya Cao, Xinyan Wang,
Shaozhong Wang, and Yuefei Hu*
Department of Chemistry, Tsinghua University,
Beijing 100084, P. R. China
yfh@mail.tsinghua.edu.cn
Received August 9, 2004
SCHEME 2
Abstract: An extremely convenient method for deprotection
of acetals and ketals catalyzed by molecular iodine (10 mol
%) in acetone is reported. The protocol achieved the depro-
tection of acyclic or cyclic O,O-acetals and O,O-ketals in
excellent yields within a few minutes under neutral condi-
tions. The double bond, hydroxyl group, and acetate group
remained unchanged, and the highly acid-sensitive furyl,
tert-butyl ethers, and ketone-oxime stayed intact under these
conditions.
Iodine-containing reagents, such as PI3,11 P2I4,11 Me3-
SiI,12 Me3SiCl-NaI,13 and BF3-NaI,14 have been em-
ployed for the deprotection of acetals and ketals for
decades. They have lost their appeal, to a great extent,
due to low chemoselectivity, unsatisfactory yields, or the
need for anhydrous conditions. Recently, the molecular
iodine-catalyzed acetalization,15 thioacetalization16 of car-
bonyl groups, and transthioacetalization of O,O-acetals
have been reported in excellent yields under neutral
conditions. However, no molecular iodine-catalyzed depro-
tection of acetals and ketals has been reported to date.
Realizing iodine-catalyzed transthioacetalization of O,O-
acetals16a results essentially from the exchange between
strongly and weakly nucleophilic protective groups, we
reasoned that the deprotection of acetals and ketals can
be achieved by exchange between substrates in a similar
way (Scheme 1).
Thus, acetone was chosen as both the substrate and
reaction solvent. Then, (3aR,7aS)-5,5-dimethoxy-7a-meth-
yloctahydroinden-1-one (1a) and (3aR,7aS)-hexahydro-
7a-methylspiro[1,3-dioxolane-2,5′(3H)inden]-1′(2H)-one (1j)
were treated with 10 mol % of iodine in acetone at room
temperature. To our great surprise, 1a and 1j gave the
corresponding deprotected ketone (3aR,7aS)-octahydro-
7a-methylinden-1,5-dione (2a) in almost quantitative
yields within 5 and 45 min, respectively (Scheme 2). The
control experiments revealed that no deprotections oc-
Carbonyl groups are protected frequently as O,O-
acetals or O,O-ketals in the process of multistep organic
synthesis. Therefore, deprotection of O,O-acetals or O,O-
ketals is an essential functional group transformation.1
This transformation is usually accomplished by aqueous
acid hydrolysis, which suffers from incompatibility of
many other functional groups. Although some weak acidic
or nonacidic reagents have been developed and each
showed some advantages,1-10 such as CeCl3‚7H2O,2 FeCl3,3
TMSN(SO2F)2,4 Magtrieve,5 CAN,6 Bi(NO3)3‚5H2O,7 Ce-
(OTf)3,8 Bi(OTf)3,9 and hydrothermal conditions,10 there
remains a great need for a mild, neutral, and chemo-
selective protocol. Herein, we report a highly chemo-
selective deprotection procedure of acetals and ketals
catalyzed by molecular iodine in acetone, which depro-
tects acyclic or cyclic acetals and ketals in excellent yields
within a few minutes under neutral conditions.
* To whom correspondence should be addressed. Phone: +86-10-
62795380. Fax: +86-10-62771149.
(1) Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic
Synthesis, 3rd ed.; John Wiley & Sons: New York, 1999.
(2) Marcantoni, E.; Nobili, F. J. Org. Chem. 1997, 62, 4183.
(3) Sen, S. E.; Roach, S. L.; Boggs, J. K.; Ewing, G. J.; Magrath, J.
J. Org. Chem. 1997, 62, 6684.
(4) Kaur, G.; Trehan, A.; Trehan, S. J. Org. Chem. 1998, 63, 2365.
(5) Ko, K.-Y.; Park, S.-T. Tetrahedron Lett. 1999, 40, 6025.
(6) (a) Marko, I. E.; Ates, A.; Gautier, A.; Leroy, B.; Plancher, J.-
M.; Quesnel, Y.; Vanherck, J.-C. Angew. Chem., Int. Ed. 1999, 38, 3207.
(b) Ates, A.; Gautier, A.; Leroy, B.; Plancher, J.-M.; Quesnel, Y.; Marko,
I. E. Tetrahedron Lett. 1999, 40, 1799. (c) Ates, A.; Gautier, A.; Leroy,
B.; Plancher, J.-M.; Quesnel, Y.; Vanherck, J.-C.; Marko, I. E.
Tetrahedron 2003, 59, 8989;
(11) Denis, J. N.; Krief, A. Angew. Chem., Int. Ed. Engl. 1980, 19,
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(12) Jung, M. E.; Andew, W. A.; Ornstein, P. L. Tetrahedron Lett.
1977, 48, 4175.
(13) Olah, G. A.; Hussain, A.; Singh, B. P.; Malhotra, A. K. J. Org.
Chem. 1983, 48, 3667.
(7) Eash, K. J.; Pulia, M. S.; Wieland, L. C.; Mohan, R. S. J. Org.
Chem. 2000, 65, 8399.
(14) Mandal, A. K.; Shrotri, P. Y.; Ghogare, A. D. Synthesis 1986,
221.
(8) Dalpozzo, R.; De Nino, A.; Maiuolo, L.; Procopio, A.; Tagarelli,
A.; Sindona, G.; Bartoli, G. J. J. Org. Chem. 2002, 67, 9093.
(9) Carrigan, M. D.; Sarapa, D.; Dusan, S.; Russell, C.; Wieland, L.
C.; Mohan, R. S. J. Org. Chem. 2002, 67, 1027.
(10) Sato, K.; Kishimoto, T.; Morimoto, M.; Saimoto, H.; Shigemasa,
Y. Tetrahedron Lett. 2003, 44, 8623.
(15) (a) Karimi, B.; Golshani, B. Synthesis 2002, 784. (b) Basu, M.
K.; Samajda, S.; Becker, F. F.; Banik, B. K. Synlett 2002, 319.
(16) (a) Firouzabadi, H.; Iranpoor, N.; Hazarkhani, H. J. Org. Chem.
2001, 66, 7527. (b) Samajdar, S.; Basu, M. K.; Becker, F. F.; Banik, B.
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10.1021/jo0486239 CCC: $27.50 © 2004 American Chemical Society
Published on Web 11/12/2004
8932
J. Org. Chem. 2004, 69, 8932-8934

TABLE 1. Molecular Iodine-Catalyzed Deprotection of Acetals and Ketals in Acetone
a Isolated yields. b Low temperature (0-5 °C) was used.
SCHEME 3
curred for either 1a or 1j without iodine or when acetone
was replaced with another solvent such as THF, MeCN,
or CH2Cl2. Although deprotection of acyclic ketal 1a still
occurred with prolonged reaction times (3-5 h) in those
nonacetone solvents in the presence of equimolar H2O,
no reaction took place with the cyclic ketal 1j even in
the presence of 20 mol % of iodine.
It was interesting to find that the deprotection of cyclic
ketal 1j was slowed as the concentration of water in
acetone increased. By using anhydrous acetone or com-
mercial acetone (reagent ACS, e0.5% H2O), the depro-
tection finished in 45 min at room temperature. However,
it took 4.5 h in the presence of equimolar H2O. Only a
10% yield of deprotected product was detected when the
deprotection was carried out in aqueous acetone (1.0%
H2O) in 4.5 h. These phenomena (including the results
from the replacements of solvents studies) are in full
agreement with our hypothesis that the molecular iodine-
catalyzed deprotection of acetals and ketals goes through
a substrate exchange mechanism, rather than a hydroly-
sis mechanism. We presume that the deprotection ini-
tially involves a polarization of carbonyl group in acetone
by molecular iodine, and a possible mechanism is pro-
posed as shown in Scheme 3.
fast. Ketal 1j was deprotected in 91% yield in the first 5
min, and an extra 40 min was required to convert the
last 9% of 1j to 2a. However, this equilibrium can be
shifted easily by elevating the reaction temperature.
Thus, compound 1j was deprotected completely in 30 min
at 35 °C or in just 5 min at acetone refluxing temperature
(56 °C).
To determine the scope and chemoselectivity of the
reaction, different acetals and ketals (1a-p) were tested.
As shown in Table 1, all substrates (entries 1a-q) were
deprotected in excellent yields under the mild conditions.
The deprotection of dialkyl acetals and ketals (1a-i) was
so fast that no reactivity differences were observed among
those structurally diverse aldehydes and ketones. The
double bond (1c), hydroxyl group (1k), and acetate group
(1m) were tolerated under these conditions. Furthermore,
the highly acid-sensitive furyl moiety (1i), tert-butyl
ethers (1f, 1g, 1o), and ketone-oxime (1l) stayed intact.
At 0-5 °C, the 3-ketal group in diketal 1p was depro-
We also found that a primary equilibrium of substrate
exchange between 1j and acetone was established very
J. Org. Chem, Vol. 69, No. 25, 2004 8933

SCHEME 4
Experimental Section
General Procedure for the Molecular Iodine Catalyzed
Deprotection of Acetals and Ketals in Acetone. A mixture
of acetal or ketal (1, 5 mmol) and iodine (125 mg, 0.5 mmol) in
acetone (20 mL, reagent ACS, e0.5% H2O) was stirred at room
temperature for 5 min [for dialkoxyl moieties (1a-i)] or at
refluxing temperature (56 °C) for 5 min [for 1,3-dioxolane
moieties (1j-p)]. Most of the acetone was then removed under
vacuum, and the residue was diluted with dichloromethane (50
mL). The mixture was washed successively with 5% aqueous
Na2S2O3 (10 mL), H2O (20 mL), and brine (20 mL). The organic
layer was separated, dried over Na2SO4, and filtered. The solvent
was removed to give product 2, which was purified by short
column chromatography (Table 1).
tected regioselectively to give 2p in 94% yield. It is
noteworthy that this protocol achieved excellent chemose-
lectivity and gave extremely clean products at different
temperatures (Scheme 4).
In conclusion, a substrate exchange based molec-
ular iodine-catalyzed deprotection of acetals and ketals
was developed. The reaction featured convenience,
mild and neutral conditions, high chemoselectivity, and
excellent yields. It is likely to find use in the manipula-
tion of carbonyl groups in complex natural product
synthesis.
Acknowledgment. We are grateful to the National
Natural Science Foundation of China for financial
support.
Supporting Information Available: 1H NMR and 13C
NMR spectra of all substrates and products in Table 1. This
material is available free of charge via the Internet at
http://pubs.acs.org.
JO0486239
8934 J. Org. Chem., Vol. 69, No. 25, 2004