Ruthenium(III) chloride-catalyzed chemoselective synthesis of acetals from aldehydes

Article abstract of DOI:10.1016/j.tetlet.2004.09.060

A mild and chemoselective acetalization procedure for the protection of various aldehydes in the presence of ketones is described.

Full text of DOI:10.1016/j.tetlet.2004.09.060

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 8141–8144
Ruthenium(III) chloride-catalyzed chemoselective synthesis of
acetals from aldehydes
Surya K. De* and Richard A. Gibbs
Department of Medicinal Chemistry and Molecular Pharmacology, School of Pharmacy, Purdue Cancer Center,
Purdue University, West Lafayette, IN 47907, USA
Received 26 May 2004; revised 7 September 2004; accepted 8 September 2004
Available online 22 September 2004
Abstract—A mild and chemoselective acetalization procedure for the protection of various aldehydes in the presence of ketones is
described.
Ó 2004 Elsevier Ltd. All rights reserved.
The protection of carbonyl compounds plays an impor-
tant role during multistep syntheses in organic, medici-
nal, carbohydrate, and drug design chemistry. Among
carbonyl protecting procedures, acetalization is one of
the most widely used methods for protecting aldehydes
and ketones.1 Generally, they are prepared by the con-
densation of carbonyl compounds with the alcohols
and/or the corresponding orthoformates in the presence
of a protic or Lewis acid catalyst. Some methods
employing dry HCl,2 DCC–SnCl4,3 PTSA,4 TMSOTf,5
TMSOFs,6 PhSO2NHOH,7 DDQ,8 ZrCl4,9 Sc(OTf)3,10
LaCl3,11 CeCl3,12 InCl3,13 have been reported. A large
number of these methods require long reaction times,
high temperatures, and stoichiometric amount of cata-
lyst and provide low yields in some cases. Interestingly,
only a few of these methods have demonstrated chemo-
selective protection of aldehydes in the presence of
ketones.9,14 Therefore, there is still a need to develop a
simple and efficient method for chemoselective protec-
tion of aldehydes in the presence of ketones.
desired acetal in 85% yield. Similarly, benzaldehyde was
treated with ethanol and 2-propanol in the presence of a
catalytic amount of RuCl3 yielding the corresponding
acetals in good yields (Table 1). Several activated and
deactivated aromatic aldehydes and aliphatic aldehydes
underwent the protection reactions to give the corre-
sponding carbonyl derivatives (Scheme 1). The use of
cationic Ru(II) for acetal deprotection has been
reported.16 It is well known that acetalization and deace-
talization reactions are reversible reactions. Therefore,
we can use a higher proportion of RuCl3 for accelera-
tion of reaction but it can cause serious setbacks as well.
Proper maintenance of the reaction time and conditions
is necessary for the success of the reaction. Otherwise, a
considerable amount of product can revert to the start-
ing aldehydes.
The results have been summarized in Table 1, which
clearly indicates the scope and generality of the reaction
with respect to different aromatic, aliphatic, and unsatu-
rated aldehydes. The experimental procedure17 is very
simple, convenient, and does not need any halogenated
solvent or additive. It should be mentioned that addition
of trimethylorthoformate accelerated the acetalization,
but was not required for complete conversion (entry 2,
Table 1). The method has the ability to tolerate a variety
of other protecting groups such as acetyl, benzyl, ben-
zoyl, allyl, and esters. Moreover, this procedure is highly
chemoselective, providing selective acetalization of an
aldehyde in the presence of a ketone. For instance, when
an equimolar mixture of benzaldehyde and acetophe-
none was allowed to react with methanol in the presence
of a catalytic amount of RuCl3, only the acetal of
In this letter we wish to report the chemoselective acetal-
ization of aldehydes, without affecting ketones, using a
catalytic amount of ruthenium chloride. Most recently,
we have reported that RuCl3 is a mild Lewis acid for
acylation of alcohols, phenols, amines, and thiols.15
The reaction of benzaldehyde with methanol in the pres-
ence of 5mol% RuCl3 at reflux temperature afforded the
*
Corresponding author. Tel.: +1 7657439702; fax: +1 7654941414;
e-mail: skd125@pharmacy.purdue.edu
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.09.060

8142
S. K. De, R. A. Gibbs / Tetrahedron Letters 45 (2004) 8141–8144
Table 1. Ruthenium(III) chloride catalyzed protection of aldehydes as acetals
Entry
Substrate
Alcohols
Time (h)
Yielda (%)
1
Benzaldehyde
Benzaldehyde
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
EtOH
5
4
85
86b
84
80
71
80
81
82
72
82
72
85
81
76
70
73
70
83
76
74
81
65
71
68
62
2
3
4-Methoxybenzaldehyde
4-Chlorobenzaldehyde
4-Nitrobenzaldehyde
Furfural
5
4
5
5
9
6
4
7
4-Benzyloxybenzaldehyde
Cinnamaldehyde
2-Naphthaldehyde
Thiophene 2-carboxaldehyde
2-Nitrobenzaldehyde
4-Carbomethoxybenzaldehyde
4-Allyloxybenzaldehyde
Hexanal
5
8
3
9
12
6
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
7
8
6
8
Octanal
Butanal
Decanal
9
8
8
4-Acetyloxybenzaldehyde
4-Benzoyloxybenzaldehyde
Benzaldehyde
8
6
8
4-Methoxybenzaldehyde
Hexanal
EtOH
EtOH
8
14
12
12
16
4-Chlorobenzaldehyde
4-Methoxybenzaldehyde
Butanal
i-PrOH
i-PrOH
i-PrOH
a Yields refer to pure isolated products,27 characterized by IR, 1H NMR, and MS.
b Trimethylorthoformate used (2equiv).
O
is well known that ketones are less reactive than alde-
hydes due to the presence of alkyl groups that provide
more electron density through the sigma bond. More-
over, the transition state of an aldehyde after its reaction
has a lower energy than that of ketone due to steric
crowding, and thus a ketone has a lower reactivity than
aldehyde. The aldehyde functionality of a keto-alde-
hyde, was protected chemoselectively under identical
condition20 (Scheme 4). Interestingly, a highly reactive
b-keto-aldehyde was selectively acetalized without
affecting ketone functionality and in this case we did
not observe any b-elimination product21 (Scheme 5).
These results illustrate the chemoselectivity22 and mild-
ness of the present method.
RuCl3 (cat)
R'OH
R
CH(OR')2
R
H
1
'
R = aryl, alkyl; R = Me, Et, i-Pr
Scheme 1.
benzaldehyde was obtained,18 while the ketone was
completely recovered (Scheme 2). To explain this fact
the electron density at the carbonyl carbon has been cal-
culated using semi-empirical molecular orbital calcula-
tions by the AM1 method (Hyperchem, Inc,
Grainsville, FL). The electron densities for benzalde-
hyde and acetophenone are 0.223 and 0.267, respec-
tively. Due to the higher electron density of the
aromatic ketone, acetophenone did not form a dialkyl
ketal. Further, aliphatic aldehydes are selectively acetal-
ized in the presence of aliphatic ketones19 (Scheme 3). It
We propose the mechanism of ruthenium(III) chloride
catalyzed acetalization of aldehyde as shown in Scheme
6. Like other Lewis acids catalyzed acetalizations,23–25
ruthenium(III) first forms a reactive intermediate (A),
after that methanol addition to carbonyl carbon occurs
in concerted manner to form B. Finally, hemiacetal
CHO
OMe
(5 mol%)
RuCl3
OMe
CH(OMe)2
+
MeOH, reflux, 5 h
COCH3
85%
4%
2
3
Scheme 2.

S. K. De, R. A. Gibbs / Tetrahedron Letters 45 (2004) 8141–8144
8143
O
CH(OMe)2
RuCl
3 (5 mol%)
H
76%
O
4
MeOH, reflux, 8 h
+
OMe
OMe
5%
5
Scheme 3.
CHO
CH(OMe)2
+
RuCl
CHO
3 (5 mol%)
CH(OMe)2
H3COC
Me O
Me O
H3COC
MeOH
+
MeO
OMe
reflux, 7 h
72%
3%
6%
6
7
8
Scheme 4.
O
O
O
OMe
OMe
O
RuCl (cat)
H
3
OMe
+
MeOH, reflux, 2 h
10
0%
9
88%
O
MeO
OMe
H
+
3%
11
Scheme 5.
MeOH
L3
RCHO
H
Me
MeOH
O
H
Ru
O
Me
O
L3
Ru
H
O
Me
R
A
L= Cl
H
OMe
H
L3
Ru
O
O
R
Me
H
2 MeOH
RCH(OMe)2 + H2O
B
Scheme 6.

8144
S. K. De, R. A. Gibbs / Tetrahedron Letters 45 (2004) 8141–8144
17. General acetalization procedure: A mixture of aldehyde
(1mmol) and RuCl3 (5mol%, anhydrous available from
Aldrich) in dry alcohol (10mL) was refluxed for the
specified time (Table 1). After completion of reaction
(TLC monitoring), the reaction mixture was concentrated
in vacuo. The residue was chromatographed over silica gel
(10% ethyl acetate in hexane) to afford the pure product in
good to excellent yields.
complex B probably converts to acetal via prior forma-
tion of an oxocarbenium ion26 and subsequent addition
of methanol.
In conclusion, a very simple, efficient, and eco-friendly
method has been developed for the protection of alde-
hydes as acetals in the presence of a number of protect-
ing groups using
a catalytic amount of RuCl3.
18. Experimental procedure: A mixture of benzaldehyde
(1mmol), acetophenone (1mmol), and RuCl3 (5mol%)
in methanol (10mL) was refluxed for 5h. After usual
work-up, the crude mixture showed primarily the acetal of
benzaldehyde. In the same reaction after 12h, the ratio of
Moreover, the high chemoselectivity, good to high
yields, and non-aqueous work-up are the main advan-
tages of this new method and will make a useful and
important addition to the present methodologies.
1
2 and 3 was 91:13, was determined by H NMR of crude
mixture.
Acknowledgements
19. Reaction condition: A mixture of hexaldehyde (1mmol),
2-hexanone (1mmol), and RuCl3 (5mol%) in methanol
was refluxed for 8h. The ratio of 4 and 5 after 12h was 82:
8.
We thank the reviewers for their valuable suggestions
and comments.
20. Experimental condition: A mixture of 4-acetylbenzalde-
hyde (1mmol) and RuCl3 (5mol%) in methanol (10mL)
was refluxed. After 12h, the ratio of 6 and 7 was 78: 9.
21. Reaction condition: A mixture of keto-aldehyde (1mol)
and RuCl3 (5mol%) in methanol (10mL) was refluxed for
2h.
References and notes
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22. All yields for the competition study were determined by
1H NMR analysis of crude mixture.
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27. Selected spectral data: 4-Nitrobenzaldehyde dimethyl acetal
(entry 4) 1H NMR (300MHz, CDCl3) d 3.35 (s, 6H),
5.46 (s, 1H), 7.64 (d, J = 8.2Hz, 2H), 8.21 (d, J = 8.2Hz, 2H);
13
C NMR (75MHz, CDCl3) d 52.8, 101.7, 123.4, 127.8,
145.1, 148.1; MS m/z 197 (M+); 2-Thiophenecarboxalde-
hyde dimethyl acetal (entry 9) 1H NMR (300MHz. CDCl3)
d 3.35 (s, 6H), 5.64 (s, 1H), 7.01 (dd, J = 3.9, 4.9Hz, 1H),
7.09 (d, J = 3.9Hz, 1H), 7.32 (d, J = 4.9Hz, 1H); 13C
NMR (75MHz, CDCl3) d 52.5, 100.1, 125.5, 125.7, 126.8,
141.6; 1-[4-(Dimethoxymethyl)phenyl]ethanone (com-
1
pound 6, Scheme 4) H NMR (300MHz, CDCl3) d 2.62
(s, 3H), 3.34 (s, 6H), 5.45 (s, 1H), 7.55 (d, J = 8.2Hz, 2H),
7.98 (d, J = 8.2Hz, 2H); 13C NMR (75MHz, CDCl3) d
26.8, 52.7, 102.4, 127.1, 128.4, 137.1, 143.2, 197.8; MS m/z
194 (M+), 163, 75, 43; 3,3-Dimethoxy-1-phenylpropan-1-
one (compound 9, Scheme 5) 1H NMR (300MHz, CDCl3)
d 3.31 (d, J = 5.2Hz, 2H), 3.46 (s, 6H), 5.03 (t, J = 5.2Hz,
1H), 7.40–7.62 (m, 3H), 7.92–8.01 (m, 2H); MS m/z 194
(M+), 163, 136, 105, 85, 77, 51.
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