DOI: 10.1002/anie.201104140
Synthetic Methods
Indium Tribromide Catalyzed Cross-Claisen Condensation between
Carboxylic Acids and Ketene Silyl Acetals Using Alkoxyhydrosilanes**
Yoshihiro Nishimoto, Aya Okita, Makoto Yasuda, and Akio Baba*
Table 1: Cross-Claisen condensation between benzoic acid (1a) with
Carbon acylations play an important role in the construction
of carbon frameworks having a carbonyl group. Among them,
dimethylketene silyl acetal 2a.[a]
the Claisen condensation is one of the most useful methods, as
it furnishes various b-ketoesters.[1] A classical example is the
homocondensation of esters promoted by a strong base.[2]
Recent successful developments in the cross-condensation
Entry InX3
Additive
Conversion of
Yield of
between metal enolates and active acylating reagents, such as
acid anhydrides or acid chlorides, have resulted in a reduction
in side reactions.[3–5] Carboxylic acids are promising candi-
dates as acylating reagents, but their direct use remains a
challenging problem because the acidic proton often causes
decomposition of the catalyst and undesired side reactions.
Most of the reported reactions require the use of harsh
1a [%][b]
3aa [%][b]
1
2
3
4
5
6
7
8
InBr3
InBr3
InBr3
InBr3
InBr3
InBr3
InBr3
–
–
7
9
62
100
85
3
2
Me3SiCl
Me2ClSiH
(MeO)3SiH
(EtO)3SiH
(EtO)Me2SiH 80
Et3SiH
(MeO)3SiH
(MeO)3SiH
(MeO)3SiH
39
90
85
80
7
[6]
reagents such as SOCl2 or N,N’-carbonyldiimidazole to
14
7
86
30
18
prepare active intermediates from carboxylic acids,[7] and
these reactions result in troublesome by-products being
generated. Recently, Tanabe and co-workers reported the
cross-condensation of titanium and silyl enolates under mild
reaction conditions, but the system also required an extra step
to prepare active intermediates.[3c,4c] Herein, we describe a
convenient indium-catalyzed cross-Claisen condensation, in
which the simple and sequential addition of a carboxylic acid,
an alkoxyhydrosilane, and a ketene silyl acetal in the presence
of InBr3 gives the desired product.
0
9
InI3
72
10
0
10
11
InCl3
In(OTf)3 (MeO)3SiH
[a] 1a (1 mmol), 2a (2 mmol), InX3 (0.1 mmol), additive (1.05 mmol),
CH2Cl2 (1 mL), RT, 3 h. [b] Values were determined by 1H NMR
spectroscopy using 1,1,2,2-tetrachloroethane as an internal standard.
Tf =trifluoromethanesulfonyl.
reaction conversion (Table 1, entry 3).[9] These results indi-
cated that the combination of an indium halide and a silyl
halide, which often acts as a strong Lewis acid,[8d,e,10] is not
applicable for this reaction. Gratifyingly, the employment of
alkoxyhydrosilanes, instead of Me2ClSiH, accelerated the
cross-Claisen condensation, which was accompanied by the
vigorous generation of hydrogen gas; (MeO)3SiH gave the
best result (Table 1, entries 4–6).[11] This method has a clear
advantage that the successive addition of all the reagents in
the order of InBr3, 1a, hydrosilane, and 2a gave high yields of
3aa, and a specific step for the generation of an active
acylating reagent was not required. When Et3SiH was used a
rapid evolution of hydrogen gas occurred, but the desired
product was obtained in only 7% yield (Table 1, entry 7). The
use of (MeO)3SiH in the absence of indium trihalide
furnished no product (Table 1, entry 8). The combination of
(MeO)3SiH with InI3 gave a satisfying result (Table 1,
entry 9), while InCl3 and In(OTf)3 showed low activity
(Table 1, entries 10 and 11).
Direct acylations using a variety of carboxylic acids were
examined under the optimized reaction conditions, which
included InBr3 catalyst, and (MeO)3SiH (Table 2). Aromatic
carboxylic acids bearing either electron-donating and elec-
tron-withdrawing groups reacted with ketene silyl acetals 2a
to give the desired b-ketoesters 3 (Table 2, entries 1–3).
Aliphatic carboxylic acids were also applicable except for the
bulky pivalic acid (1g; Table 2, entries 4–6). A notable
Owing to its moderate Lewis acidity, high tolerance to an
acidic proton, and compatibility with various functional
groups, we recently focused on using indium trihalides to
achieve a direct coupling reaction of alcohols with various
nucleophiles and the Friedel–Crafts acylation using carbox-
ylic acids.[8,9] These results prompted us to attempt the
condensation reaction between benzoic acid 1a and dime-
thylketene methyltrimethylsilyl acetal (2a) in the presence of
an indium trihalide. The use of a catalytic amount of InBr3
gave hardly any condensation product (Table 1, entry 1) and
the addition of Me3SiCl was ineffective (Table 1, entry 2).
Next, the use of Me2ClSiH, which was effective in the Friedel–
Crafts acylation using carboxylic acids, furnished the desired
product 3aa, but the yield was only 39% despite a high
[*] Dr. Y. Nishimoto, A. Okita, Dr. M. Yasuda, Prof. Dr. A. Baba
Department of Applied Chemistry, Graduate School of Engineering
Osaka University, 2-1, Yamada-oka, Suita (Japan)
E-mail: baba@chem.eng.osaka-u.ac.jp
[**] This work was supported by a Grant-in-Aid for Scientific Research on
Innovative Areas (No. 22106527, “Organic Synthesis Based on
Reaction Integration. Development of New Methods and Creation
of New Substances”) and Scientific Research (No. 21350074) from
the Ministry of Education, Culture, Sports, Science and Technology
(Japan).
Supporting information for this article is available on the WWW
Angew. Chem. Int. Ed. 2011, 50, 8623 –8625
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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