Mild microwave-assisted hydrolysis of acetals under solvent-free conditions

Article abstract of DOI:10.1081/SCC-200036616

Acetals are efficiently hydrolyzed with silica gel-supported pyridinium tosylate moistened with water in solvent-free conditions under microwave irradiation. The method is efficient and mild, with acid-sensitive 3-hydroxyacetals and 3-methoxyacetals being hydrolyzed in minutes in good yields.

Full text of DOI:10.1081/SCC-200036616

This article was downloaded by: [Stanford University Libraries]
On: 29 May 2012, At: 04:03
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954
Registered office: Mortimer House, 37-41 Mortimer Street, London W1T
3JH, UK
Synthetic Communications:
An International Journal
for Rapid Communication of
Synthetic Organic Chemistry
Publication details, including instructions for
authors and subscription information:
http://www.tandfonline.com/loi/lsyc20
Mild Microwave‐Assisted
Hydrolysis of Acetals Under
Solvent‐Free Conditions
a
a
a
Yanhong He , Martin Johansson & Olov Sterner
a
Department of Organic and Bioorganic Chemistry,
Lund University, P.O. Box 124, Lund, 22100,
Sweden
Available online: 10 Jan 2011
To cite this article: Yanhong He, Martin Johansson & Olov Sterner (2004): Mild
Microwave‐Assisted Hydrolysis of Acetals Under Solvent‐Free Conditions, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic
Organic Chemistry, 34:22, 4153-4158
To link to this article: http://dx.doi.org/10.1081/SCC-200036616
PLEASE SCROLL DOWN FOR ARTICLE
Full terms and conditions of use: http://www.tandfonline.com/page/terms-
and-conditions
This article may be used for research, teaching, and private study
purposes. Any substantial or systematic reproduction, redistribution,
reselling, loan, sub-licensing, systematic supply, or distribution in any form
to anyone is expressly forbidden.

The publisher does not give any warranty express or implied or make any
representation that the contents will be complete or accurate or up to
date. The accuracy of any instructions, formulae, and drug doses should
be independently verified with primary sources. The publisher shall not
be liable for any loss, actions, claims, proceedings, demand, or costs or
damages whatsoever or howsoever caused arising directly or indirectly in
connection with or arising out of the use of this material.

w
SYNTHETIC COMMUNICATIONS
Vol. 34, No. 22, pp. 4153–4158, 2004
Mild Microwave-Assisted Hydrolysis of
Acetals Under Solvent-Free Conditions
*
Yanhong He, Martin Johansson, and Olov Sterner
Department of Organic and Bioorganic Chemistry,
Lund University, Lund, Sweden
ABSTRACT
Acetals are efficiently hydrolyzed with silica gel-supported pyridinium tosy-
late moistened with water in solvent-free conditions under microwave
irradiation. The method is efficient and mild, with acid-sensitive 3-hydro-
xyacetals and 3-methoxyacetals being hydrolyzed in minutes in good yields.
Key Words: Acetal; Deprotection; Microwave; Solvent-free.
INTRODUCTION
Aldehydes, ketones, and diols (1,2- or 1,3-) are frequently protected as
acetals in organic synthesis, and a number of methods for their hydrolysis
*
Correspondence: Olov Sterner, Department of Organic and Bioorganic Chemistry,
Lund University, P.O. Box 124, Lund 22100, Sweden; E-mail: olov.sterner@
bioorganic.lth.se.
4
153
DOI: 10.1081/SCC-200036616
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com
Copyright # 2004 by Marcel Dekker, Inc.

4
154
He, Johansson, and Sterner
[
1]
[1,2]
are known. Most of these involve either treatment with aqueous acid,
[
acid-catalyzed exchange with acetone, or nonaqueous media acidified
3]
[
4]
with organic acids. However, these conditions are normally incompatible
with the presence of other acid-sensitive functional groups. Hence, milder
[
techniques that use less acidic conditions or even neutral conditions have
5]
[
6,7]
been developed for the deprotection of acetals,
and, in addition, a few
[8]
examples of solvent-free cleavage of acetals have been reported. During
an ongoing synthesis of some terpene analogues, we required a milder
and more selective way to deprotect 3-hydroxyacetals to yield 3-hydroxycy-
clohexanones (entry 1, Table 1). With conventional aqueous acid hydrolysis,
such acetals only yield the corresponding a,b-unsaturated ketone. A pro-
cedure for the hydrolysis of acetals with silica gel supported pyridinium
tosylate moistened with water in solvent-free conditions under microwave
irradiation was, therefore, developed and described here.
RESULTS AND DISCUSSION
Pyridinium tosylate [pyridinium p-toluenesulfonate (PPTS)], an inexpen-
sive and safe reagent, has been found to be an excellent catalyst for the clea-
[5]
vage of dioxolane-type of acetals by transacetalization with acetone. PPTS
is a weaker acid (pH 3.0 in 1.0 M aqueous solution) than acetic acid (pH 2.4 in
[
.0 M aqueous solution), suggesting that it should be useful as a catalyst in
9]
1
deprotection of acid-sensitive compounds, although the deprotection of
acetals with PPTS in the absence of acetone and under solvent-free conditions
has not been reported. In addition, organic reactions on solid support assisted
[10,11]
[12]
by microwaves
especially under solvent-free conditions,
have
recently attracted attention because of the enhanced selectivity obtained
under the mild reaction conditions. Therefore, we report the deprotection of
a number of cyclic and acyclic acetals, shown in Table 1, with silica gel sup-
ported PPTS moistened with water under microwave irradiation.
In general, the hydrolysis of the acetals was rapid, and the products were
obtained in high yields; in several cases, the pure product was obtained after
only aqueous workup. The 1,3-dioxolanes and dialkylacetals of cyclohexa-
none underwent smooth deprotection, and typically the hydrolysis was
finished after a few minutes. Acetals of aromatic aldehydes (entries 8–10)
required longer reaction times at lower microwave power to be completely
hydrolyzed, but the free aldehydes were also obtained in excellent yields.
The acid-labile 3-hydroxyketone (entry 1) was obtained in 90% yield after
only 3 min without any trace of cyclohex-2-enone, whereas the acetal group
of 1,1,3-trimethoxycyclohexan (entry 6) selectively was hydrolyzed 3-methoxy-
cyclohexanonoe in 84% yield without elimination of methanol. The benzyli-
dene acetal group (entry 11) was selectively cleaved without affecting the

Hydrolysis of Acetals Under Solvent-Free Conditions
4155
Table 1. Microwave-assisted deprotection of acetals/ketals under solvent-free conditions.
PPTS
(mol%)
Microwave
power
Time/
min
Yield
a
(%)
Entry
1
Substrate
Product
10
10
10
50% of (1300w,
2
3
3
3
90
81
89
20v, 50 Hz)
2
3
50%
50%
4
5
10
10
50%
50%
1
3
88
82
6
7
10
10
50%
50%
1
3
84
97
8
9
10
10
10%
30%
20
3
88
90
1
1
0
1
10
20
10%
50%
15
8
90
91
1
9
0
2
2
1
100
50%
10
73
a
Refers to yield of isolated product after chromatography (when required).

4
156
He, Johansson, and Sterner
galactosidic linkage. The isopropylidene group attached to secondary
hydroxyls of a sugar (entry 12) was more resistant to hydrolysis, requiring
longer reaction times, but the diol was still obtained in acceptable yields.
In conclusion, the simple protocol for the deprotection of acetals pre-
sented here is both selective and efficient. The reaction is performed with
an inexpensive and safe reagent under solvent-free conditions; the reaction
is carried out in minutes and the product does often not even have to be puri-
fied by chromatography.
EXPERIMENTAL
The NMR spectra (in CDCl ) were recorded with a Bruker DRX300
3
1
spectrometer at 300 MHz ( H) and at 75 MHz ( C), a Bruker DRX400
13
spectrometer (at 400/100 MHz) and a Bruker DRX500 spectrometer
(
˚
at 500/125 MHz). All flash chromatography was performed on 60 A
3
5–70 mm Matrex silica gel (Grace Amicon), and with mixtures between
ethyl acetate and heptane as eluent. TLC analyses were made on Silica Gel
0 F254 (Merck) plates and visualized with anisaldehyde/sulphuric acid and
6
heating. The inorganic and organic reagents were all of commercial guaran-
teed grade and used without further purification. Acetals (entry 1–5, 7,
[
13–20]
9
hyde diethyl acetal (entry 8, Table 1) was purchased from Janssen Chimica
–12) were prepared according to the literature procedures.
2-Furalde-
(
investigation is given below. PPTS was prepared according to Ref.
Belgium). A typical procedure for the acetal hydrolysis performed in this
[9]
Deprotection of acetals with silica gel supported PPTS moistened with
water under microwave irradiation, exemplified with entry 5, Table 1.
A solution of PPTS (50 mg, 0.20 mmol) in H O (1 mL) was added to
2
8
-methyl-1,4-dioxaspiro[4,5]decane (312 mg, 2.0 mmol) absorbed on silica
gel 60 (1 g). The mixture was transferred into a sealed tube and exposed to
microwave heating (placed in a household microwave oven operating at
5
5
1
0% of 1300 W) (650 W, 220 V, 50 Hz) for 3 min. After cooling to r.t.,
mL of water was added, and the mixture was extracted with three times
0 mL diethyl ether. The combined organic phases were washed with brine
and dried (MgSO ). The solvents were removed, and the residue was purified
4
by column chromatography (silica gel, hexane/EtOAc, 5 : 1) to yield 184 mg
(
82%) of 4-methylcyclohexanone.
1
tion of 2-cyclohexen-1-one (1.50 g, 15.6 mmol) and TsOH H O (296 mg,
,1,3-trimethoxycyclohexane (entry 6) was prepared by refluxing a solu-
.
2
1
.56 mmol) in CH OH (30 mL) for 4 hr. After cooling to r.t., NaHCO (Sat.
3 3
8 mL) was added, and the mixture was extracted with three times 15 mL
diethyl ether. The combined organic phases were washed with water and

Hydrolysis of Acetals Under Solvent-Free Conditions
4157
then brine and dried (MgSO ). The solvents were removed, and the residue
4
was purified by column chromatography (silica gel, petroleum ether/
EtOAc, 4 : 1) to yield 1.67 g (62%) of 1,1,3-trimethoxycyclohexane, identical
[
21]
to that previously reported.
ACKNOWLEDGMENTS
Financial support from the Swedish Research Council is gratefully
acknowledged. The authors thank Dr. Ulf Ellervik and Dr. Andr e´ as Meijer
for the generous gift of protected sugars.
REFERENCES
1
2
3
. Greene, T.W.; Wuts, P.G.M. Protection for the carbonyl group. In Protec-
tive Groups in Organic Synthesis, 2nd Ed.; John Wiley and Sons:
New York, 1991, 178.
. Grieco, P.A.; Nishizawa, M.; Orguri, T.; Burke, S.D.; Marinovic, N.
Sesquiterpene lactones: total synthesis of (. þ -.)-vernolepin and (. þ -.)-
vernomenin. J. Am. Chem. Soc. 1977, 99 (17), 5773.
. Bauduin, G.; Bondon, D.; Pietrasanta, Y.; Pucci, B. Reactions de transce-
talisation. II. Influence des facteurs steriques et electroniques sur les ener-
gies de cetalisation. Tetrahedron 1978, 34 (23), 3269.
4
5
6
. Ichihara, A.; Ubukata, M.; Sakamura, S. Stereoselective synthesis of
(+)-palitantin. Tetrahedron Lett. 1977, 18 (39), 3473.
. Sterzycki, R. Pyridinium tosylate, a mild catalyst for formation and clea-
vage of dioxolane-type acetals. Synthesis 1979 (9), 724.
. Mark o´ , I.E.; Ates, A.; Gautier, A.; Leroy, B.; Plancher, J.-M.; Quesnel, Y.;
Vanherck, J.-C. Cerium(IV)-catalyzed deprotection of acetals and ketals
under mildly basic conditions. Angewandte Chemie. Int. Ed. 1999,
3
8 (21), 3207.
7
. Carrigan, M.D.; Sarapa, D.; Smith, R.C.; Wieland, L.C.; Mohan, R.S. A
simple and efficient chemoselective method for the catalytic deprotection
of acetals and ketals using bismuth triflate. J. Org. Chem. 2002, 67 (3),
1
027.
8
. Subhas, B.D.; Jayalakshmi, B.; Venkat, N.A. Efficient method for selec-
tive cleavage of acetals and ketals using peroxymonosulfate on alumina
under solvent-free conditions. Synthesis 2000 (1), 67.
9
. Miyashita, M.; Yoshikoshi, A.; Grieco, P.A. Pyridinium p-toluenesulfonate.
A mild and efficient catalyst for the tetrahydropyranylation of alcohols.
J. Org. Chem. 1977, 42 (23), 3772.

4
158
He, Johansson, and Sterner
1
0. Perreux, L.; Loupy, A. A tentative rationalization of microwave effects
in organic synthesis according to the reaction medium, and mechanistic
considerations. Tetrahedron 2001, 57 (45), 9199.
1
1
1
1. Lidstr o¨ m, P.; Tierney, J.; Wathey, B.; Westman, J. Microwave assisted
organic synthesis—a review. Tetrahedron 2001, 57 (45), 9225.
2. Tanaka, K.; Toda, F. Solvent-free organic synthesis. Chem. Rev 2000,
1
00 (3), 1025.
3. Rodriguez, J.-G.; Temprano, F.; Esteban-Calderon, C.; Martinez-Ripoll, M.
Synthesis of 4-(N,N-dimethylaminoethyl)-1,2,3,4-tetrahydrocarbazole:
molecular structure and reactivity of the 1,2-dihydrocarbazol-4(3H)-one
and derivatives. J. Chem. Soc. Perkin Trans. 1 1989 (11), 2117.
1
1
4. Becker, D.; Kalo, J.; Brodsky, N.C. New approach to the synthesis of
4,4-disubstituted cycloalkenones. J. Org. Chem. 1978, 43 (13), 2562.
5. Chen, Y.-S.; Kampf, J.W.; Lawton, R.G. Aromatic stacking in folded
architectures through hydrogen bonding. Tetrahedron Lett. 1997,
3
6. Kawakami, Y.; Asai, T.; Umeyama, K.; Yamashita, Y. Selectively
8 (33), 5781.
1
deuterated and optically active cyclic ethers. J. Organ. Chem. 1982,
4
7 (18), 3581.
1
7. Lu, T.-J.; Yang, J.-F.; Sheu, L.-J. An efficient method for the acetalization
of a,b-unsaturated aldehydes. J. Organ. Chem. 1995, 60 (9), 2931.
8. Gopinath, R.; Haque, S.J.; Patel, B.K. Tetrabutylammonium tribromide
1
(
TBATB) as an efficient generator of HBr for an efficient chemoselective
reagent for acetalization of carbonyl compounds. J. Organ. Chem. 2002,
7 (16), 5842.
6
1
2
2
9. Ellervik, U.; Magnusson, G. A high yielding chemical synthesis of sialyl
Lewis ꢀ tetrasaccharide and lewis ꢀ trisaccharide: examples of regio-
and stereo differentiated glycosylations. Journal of Organic Chemistry
1
998, 63 (25), 9314.
0. Ziegler, T.; Herold, G. Preparation of diastereomeric 3,4-O-pyruvate
acetal-containing D-galactopyranose derivatives, structural assignment
and use for oligosaccharide synthesis. Liebigs Annalen der Chemie
1
994 (9), 859.
1. Lambert, J.B.; Marko, D.E.; Chelius, E.C. A comparison of the through-
space, dipolar repulsion of alkenic and allenic groups. J. Organ. Chem.
1
988, 53 (11), 2642.
Received in the UK June 10, 2004