Angewandte
Chemie
DOI: 10.1002/anie.200904069
Carbonyl Chemistry
a-Alkylation of Carbonyl Compounds by Direct Addition of Alcohols
to Enol Acetates**
Yoshihiro Nishimoto, Yoshiharu Onishi, Makoto Yasuda, and Akio Baba*
The catalytic a-alkylation of carbonyl compounds has con-
tributed remarkably to the development of organic synthesis,
and the reaction of enolate derivatives with alkyl electro-
philes is a powerful alkylation method.[1] Alcohols are
appealing electrophiles, as they are plentiful and readily
synthesized; however, the direct use of alcohols is effectively
prevented by the fact that the hydroxy group is a particularly
poor leaving group, and it often tends to decomposition of
catalysts and active intermediates.[2,3] The a-alkylation of
monocarbonyl compounds using an alcohol remains problem-
atic whereas many research groups have reported the direct
alkylation of 1,3-dicarbonyl compounds.[4] The transfer hydro-
genation method has achieved some direct a-alkylations of
ketones, although this is only applicable to primary alcohols
and requires a strong base to generate the enolate species.[5]
Hidai, Uemura et al. published a ruthenium-catalyzed system,
which was limited to the reactions of 1-arylpropargylic
alcohols, in the presence of an excess of ketone.[6] Methods
using metal enolates suffer from decomposition of the
enolates by the hydroxy group, critically narrowing the
scope of available alcohol substrates;[7] furthermore, the a-
alkylation of aldehydes has not been investigated to the
degree that ketones have.[8] Herein, we report a synthesis of a-
alkylated carbonyl compounds from enol acetates and
alcohols, catalyzed by InI3, GaBr3, or FeBr3, in which the a-
alkylation of not only ketones but also of aldehydes has been
successfully achieved. Furthermore, the exploitation of enol
acetates as readily available, stable, and easily-handled
enolate reagents enhances the practicality of this a-alkylation
method.[9] We employed Lewis acids to selectively activate
alcohols and thereby suppress side reactions, such as trans-
esterification.
nes;[3,4e] these results suggested that indium trihalide selec-
tively interacts with hydroxy groups in the presence of other
oxygen-containing moieties such as carbonyl groups.
As a model reaction, 1-phenylethanol (1a) and 2-propenyl
acetate (2a) were heated to reflux in 1,2-dichloroethane in the
presence of 5 mol% indium trihalide to afford the desired
product 3aa in satisfactory yields, of which InI3 gave the
highest (83%; Table 1, entries 1–3). By contrast, the more
Table 1: Effects of catalyst and solvent in the reaction of 1-phenylethanol
(1a) with isopropenyl acetate (2a).[a]
Entry
Catalyst
Yields [%]
3aa
4
5
1
2
3
4
5
6
7
8
InCl3
InBr3
InI3
In(OTf)3
GaCl3
GaBr3
FeBr3
FeCl3
FeBr2
60
70
83
25
62
73
77
48
38
0
0
0
0
25
0
0
0
0
0
0
0
0
0
31
17
46
10
34
0
6
0
0
0
0
0
0
0
0
0
0
0
31
66
43
27
0
0
35
0
0
0
0
6
9
10
11
12
13
14
15
16
17[b]
18[c]
19[d]
20[e]
FeCl2
BF3·OEt2
AlCl3
TiCl4
Sc(OTf)3
RuCl3
Cu(OTf)2
CH3COOH
InI3
We recently found that the moderate Lewis acidity of
indium trihalide effectively promoted the direct coupling of
alcohols with nucleophiles, such as allyl and alkenyl sila-
7
0
55
50
64
InI3
InI3
0
30
[*] Dr. Y. Nishimoto, Y. Onishi, Dr. M. Yasuda, Prof. Dr. A. Baba
Department of Applied Chemistry
[a] Reaction conditions: 1a (1 mmol), 2a (2 mmol), catalyst (5 mol%),
ClCH2CH2Cl (2 mL), 838C, 2 h. [b] 99% recovery of 1a. [c] CF3C6H5 used
instead of ClCH2CH2Cl. [d] Toluene used instead of ClCH2CH2Cl.
[e] CH2Cl2 used instead of ClCH2CH2Cl; 408C.
Center for Atomic and Molecular Technologies (CAMT)
Graduate School of Engineering, Osaka University
2-1, Yamada-oka, Suita, Osaka University (Japan)
Fax: (+81)6-6879-7387
E-mail: baba@chem.eng.osaka-u.ac.jp
[**] This work was supported by Grant-in-Aid for Scientific Research on
Priority Areas (No. 18065015, “Chemistry of Concerto Catalysis”
and No. 20036036, “Synergistic Effects for Creation of Functional
Molecules”) and for Scientific Research (No. 19550038) from
Ministry of Education, Culture, Sports, Science and Technology
(Japan).
Lewis acidic In(OTf)3 was less effective, giving only a 25%
yield of the a-alkylated product (Table 1, entry 4). Examina-
tion of various Lewis acids revealed that gallium and iron
halides also had high catalytic abilities (Table 1, entries 5–10);
however, representative strong Lewis acids such as BF3·OEt2,
AlCl3, and TiCl4 all promoted transesterification (4) and/or
dimerization (5) of the parent alcohol, with no formation of
Supporting information for this article is available on the WWW
Angew. Chem. Int. Ed. 2009, 48, 9131 –9134
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
9131