96
Chemistry Letters Vol.38, No.1 (2009)
A Facile Procedure for Acetalization of Aldehydes
and Ketones Catalyzed by Cerium(III) Trifluoromethanesulfonate
Fumiaki Ono, Yoshiko Inatomi, Yuusuke Tada, Masaki Mori, and Tsuneo SatoÃ
Department of Life Science, Kurashiki University of Science and the Arts, Kurashiki 712-8505
(Received October 2, 2008; CL-080952; E-mail: sato@chem.kusa.ac.jp)
Aldehydes and ketones are readily protected in the presence
Table 1. Ce(OTf)3-catalyzed dimethyl acetalization of alde-
a
of trialkyl orthoformate and a catalytic amount of cerium(III) tri-
fluoromethanesulfonate under mild conditions to give the corre-
sponding acetals in good to excellent yields. Due to the mild re-
action conditions, this method is compatible with acid-sensitive
substrates.
hydes and ketones using HC(OMe)3
Yield
/%b
Time
/min
R1R2C=O
Entry
99 (90)
96 (80)
97 (70)
1
2
3
PhCHO
1
1
1
p-BrC6H4CHO
p-MeOC6H4CHO
The protection of carbonyl groups as acetals is now com-
monly used as an important synthetic technique in the course
of preparation of many organic compounds.1 The introduction
of new methods and modification of existing methodology for
making acetals is thus an important challenge. Among acetaliza-
tion methods,2 Luche’s procedure3 with trimethyl orthoformate
and cerium(III) chloride hexahydrate as Lewis acid is useful
for the synthesis of acetals under almost neutral conditions and
has been widely used during the synthesis of many biologically
important compounds.4 However, a stoichiometric amount of
99 (90)
4
2
1
CHO
O
92 (60)
99 (75)
90
5
CHO
S
CHO
6
1
5
Ph
CHO
7c
n-C3H7
99d (95)
CHOd
CHO
8
5
.
CeCl3 6H2O and excessive amounts of HC(OMe)3 (7 equiv)
are required to accomplish the reaction completely and this
method is applied only to aldehydes.3 Recently, Okano et al. re-
ported the dimethyl acetalization of carbonyl compounds with
trimethyl orthoformate in methanol catalyzed by ytterbium(III)
trifluoromethanesulfonate.5 Cerium(III) trifluoromethanesulfo-
nate has been often used as a mild and efficient Lewis acid to cat-
alyze acylation,6 cyclization,7 or deprotection8 of organic com-
pounds. In this paper, we wish to report a facile procedure for
the synthesis of acetals from the parent ketones and aldehydes
using a slight excess of trialkyl orthoformates and a catalytic
amount of Ce(OTf)3 under mild conditions (Scheme 1).
9c
5
1
99
Et
n-C7H15CHO
95 (100)
10
cyclo-C6H11CHO
(CH2)4C=O
98 (95)
90
11
12
1
45
(CH2)5C=O
13
14
15
20
30
93
99
98
98
-C H13(Me)C=O
6
n
Ph(Me)C=O
Ph2C=O
30
16e
300
First, we undertook examination of the conversion of a se-
ries of aldehydes and ketones to the corresponding dimethyl ace-
tals. The reaction was carried out by stirring the carbonyl com-
pounds and trimethyl orthoformate (1.1–2.0 equiv) in methanol
with 1–5 mol % of Ce(OTf)3. The results that we have obtained
are summarized in Table 1.9 Both activated and deactivated
aldehydes including acid-sensitive furfural and 2-thiophene-
carboxaldehyde (Entries 1–5) and ꢀ,ꢁ-unsaturated aldehydes
(Entries 6–9) underwent smooth acetalization without any trace
of by-products to give the corresponding acetals in excellent
yields and in very short reaction times. Aliphatic aldehydes
worked equally well (Entries 10 and 11). Application of this
method was then extended to the protection of different types
of cyclic (Entries 12 and 13) and acyclic (Entry 14) ketones.
aConditions: R1R2C=O (3.0 mmol), HC(OMe)3 (3.3 mmol),
Ce(OTf)3 (0.03 mmol), MeOH (3 mL), rt, unless otherwise noted.
bIsolated yield. The yield reported by Luche and Gemal3a is given
in parenthesis to compare with our result. cAt 0 ꢀC. dE/Z = 55/45.
eCe(OTf)3 (0.15 mmol) and HC(OMe)3 (6.0 mmol) were used.
The corresponding acetals were formed in high yields. Simi-
larly, acetophenone gave the desired acetal in 98% yield (Entry
15). Diaryl ketones such as benzophenone are quite resistant to
standard conditions for acetalization.10 However, with the pres-
ent method, benzophenone could easily be converted to its
dimethyl acetal in 98% yield (Entry 16).11 The most valuable
result was found in the acetalization of 4-hydroxy-4-methyl-
2-pentanone, a typical tertiary aldol, utilizing our protocol
(Scheme 2). When the aldol was allowed to react with
HC(OMe)3/Ce(OTf)3 under usual conditions, only the desired
acetal was obtained in 77% yield. 1H NMR analysis of the crude
product showed that neither substitution by-product nor dehy-
dration by-product was produced at all under the reaction condi-
tions. In contrast to this result, when acetalization was carried
R1
R2
R1 OR
R2 OR
Ce(OTf)3 (1-5 mol%)
ROH, 0 oC-rt
HC(OR)3
+
O
R = Me, Et
1.1-2.0 equiv
Scheme 1.
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