182
Chemistry Letters 2002
A Catalytic Aldol Reaction between Ketene Silyl Acetals and Aldehydes
Promoted by Lithium Amide under Non-acidic Conditions
Hidehiko Fujisawa and Teruaki Mukaiyamaꢀ
Department of Applied Chemistry, Faculty of Science, Science University of Tokyo, Kagurazaka, Shinjuku-ku, Tokyo 162-8601
(Received October 25, 2001;CL-011053)
A catalytic aldol reaction between trimethylsilyl enol ethers
and aldehydes by using lithium diphenylamide, a Lewis base
catalyst, in DMF or pyridine solvent proceeded smoothly to afford
the corresponding aldols under mild conditions.
Table 1.
a)amine (1.5 equiv)
b)MeLi (1.4 equiv)
OTMS
OMe
OR
O
O
+
Ph
OMe
R : H, TMS
THF, 3 h, 0
Ph
H
(1.4 equiv)
SMRb /%
Yielda /%
Entry
Amine
-
Et2NH
iPro2NH
Piperidine
H : TMS
2 : 1
3 : 1
Aldol reaction is one of the most important and frequently
employed tools for carbon–carbon bond formation in synthetic
organic chemistry. Ever since a crossed aldol reaction between
aldehydes and silyl enol ethers promoted by Lewis acids was
reported from our laboratory,1 the aldol reaction of this type has
become very popular. Then, the above combination of carbonyl
compounds and silyl enol ethers was effectively employed: for
example, the reactions via the metal enolates formed by
transmetallation of silyl enol ethers with metal salts from original
use of MeLi to recent catalytic use of transition metals2 and also via
the enolate anion generated by nucleophilic cleavage of the O–Si
bond using a fluoride ion3 or phosphines.4 Further, respective
reactions of silyl enol ethers such as trichlorosilyl enol ethers,5
dimethyl(trifloxy)silyl enol ethers,6 enoxysilacyclobutane7 and
dimethylsilyl enolates8 derived from ketones with carbonyl
compounds and of a combination of trichlorosilyl enol ethers and
Lewis bases5 withaldehydes were reported. Moreover, the reactions
of silyl ketene acetals with aldehydes were carried out in water,9
DMSO, DMF, and DME10 or under high-pressure.11
Thus, it was considered important to explore a new and
catalytic aldol reaction of the above combination which is to be
carried out smoothly under non-acidic conditions. In this regard,
Denmark et al. established a Lewis bases catalyzed aldol reaction
using trichlorosilyl enol ethers and phosphoramides.5 However,
trichlorosilyl enol ethers were not prepared so conveniently, and
thus to exprone a possibility of using simple enol ethers such as
trimethylsilyl ether and a catalytic amount of Lewis bases was
planned. In this communication, we would like to describe a new
catalytic aldol reaction between trimethylsilyl enol ethers and
aldehydes by using Lewis bases such as lithium amides.
1
2
3
4
5
36
35
24
n.d.
6
3
2 : 1
4 : 1
2 : 1
67
18
8
2,2,6,6,-Tetramethylpiperidine
35
trace
81
1,1,1,3,3,3-Hexamethyldisilazane
Ph2NH
-
6
7
8
17
n.d.
5
2 : 1
3 : 2
(p-MeOC6H4)2NH
62
aYield was determined by 1H NMR analysis (270 MHz) using 1,1,2,2-tetrachloroethane
as an internal standard. bStarting material recovered.
When the reaction was carried out in THF, stoichiometric
amount of lithium diphenylamide was required to complete the
reaction. In order to establish a catalytic aldol reaction, it was
needed that the aldol adducts were to be afforded selectively as O-
silyl ether (R ¼ TMS). But the adducts thus formed in THF were a
mixture of aldol (R ¼ H) and O-silyl ether. In addition, the amount
of O-silyl ether was less than that of aldol, irrespective of the kind of
lithium amides employed (Table 1). Then, in order to obtain better
yields and higher ratios of O-silyl ether, the effect of solvents was
examined by using lithium diphenylamide under the same
conditions as shown in Table 1. Then, it was found that the aldol
adduct was obtained in almost quantitative yields when DMF
(H : TMS ¼ 1 : 35) and pyridine (H : TMS ¼ 1 : 6) were used. In
these reactions, the major product was O-silyl ether which indicated
the possibility to perform a catalytic cycle.
´
Recently, Genisson et al. reported that the aldol reaction of this
combination proceeded ‘‘spontaneously’’ in DMSO, DME and
DMF at room temperature.10 Then, in order to examine the effect of
Lithium amides which are derived from hindered amines such
as lithium diisopropylamide (LDA) were known to behave as strong
bases with low nucleophilicity, and were frequently employed in
organic synthesis, e.g., in the formation of enolates from carbonyl
compounds or of lithiated carbon skeleton. To the best of our
knowledge, such amides were used only as brꢀnsted bases and never
have they used as Lewis bases to activate silyl enol ethers by
forming its hypervalent silicate.
Then effects of various lithium amides were examined by
taking the reaction of benzaldehyde and trimethylsilyl enol ether
derived from methyl isopropionate in THF as a model. Of the
amides screened, lithium diphenylamide turned out to be the most
effective promoter for the acceleration of the reaction as shown in
Table 1.
Table 2.
OTMS
OMe
OR
O
O
+
Ph
OMe
Solv., Time, Temp.
Ph
H
(1.4 equiv)
R : H, TMS
Yielda /
Entry
Temp. /
Solvent
Time /h
1
2
3
4
1
0
84
43
trace
DMF
DMF
DMF
DMF
Pyridine
1
1
1
-19
-45
-78
trace
n.d.
5
0
4
aYield was determined by 1H NMR analysis (270 MHz) using
1,1,2,2-tetrachloroethane as an internal standard.
Copyright Ó 2002 The Chemical Society of Japan