Lithium acetate-catalyzed Michael reaction between trimethylsilyl enolate and α,β-unsaturated carbonyl compound

Article abstract of DOI:10.1246/cl.2004.1016

Lithium acetate-catalyzed Michael reaction between trimethylsilyl enolates and α,β-unsaturated carbonyl compounds in DMF proceeded smoothly to afford the corresponding Michael-adducts in good to high yields. Hindered α,β-unsaturated ketones also behaved as an excellent Michael-acceptor in the above reaction at room temperature.

Full text of DOI:10.1246/cl.2004.1016

1016
Chemistry Letters Vol.33, No.8 (2004)
Lithium Acetate-catalyzed Michael Reaction between Trimethylsilyl Enolate
and ꢀ,ꢁ-Unsaturated Carbonyl Compound
Takashi Nakagawa,y;yy Hidehiko Fujisawa,y;yy Yuzo Nagata,y;yy and Teruaki Mukaiyamaꢀy;yy
yCenter for Basic Research, The Kitasato Institute, 6-15-5 (TCI) Toshima, Kita-ku, Tokyo 114-0003
yyKitasato Institute for Life Sciences, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641
(Received May 21, 2004; CL-040583)
Lithium acetate-catalyzed Michael reaction between trime-
thylsilyl enolates and ꢀ,ꢁ-unsaturated carbonyl compounds in
DMF proceeded smoothly to afford the corresponding Mi-
chael-adducts in good to high yields. Hindered ꢀ,ꢁ-unsaturated
ketones also behaved as an excellent Michael-acceptor in the
above reaction at room temperature.
O
Ph
O
O
1) Cat. (10 mol %)
DMF
O
1
+
Ph
OMe
OMe
Ph
Ph
2) 1 M HClaq
THF, rt
(1.4 equiv.)
4
5
+
Conditions
5
6
Cat.
Me3SiO Ph
−45 °C, 1.5 h
−45 °C, 1.0 h
0 °C, 0.5 h
93%
87%
99%
7%
13%
<1%
AcOLi
AcOK
AcOLi
Ph
Several effective Lewis base catalysts for the activation of
simple silyl enolates such as trimethylsilyl (TMS) enolate were
recently introduced from our laboratory, which were employed
successfully in aldol,1 Michael,2 and Mannich-type reactions3
via the formation of active hypervalent silicate (Eqs 1–3).
6
Scheme 1. AcOLi catalyzed Michael reaction between TMS
enolate 1 and chalcone.
used instead of AcOLi. Next, the reaction conditions were care-
fully screened using AcOLi so as to reduce the amount of 1,2-ad-
ducts and the desired 1,4-addition proceeded at 0 ꢂC to afford 5
exclusively in high yield (Scheme 1).4 In the absence of the cat-
alyst, on the other hand, 5 was not obtained at all, which indicat-
ed that AcOLi worked as an efficient Lewis base catalyst in this
Michael reaction.
Next, reactions of TMS enolate 1 with various Michael-ac-
ceptors were tried by using AcOLi as a catalyst (Table 1).5 Then,
the enolate 1 reacted smoothly with various Michael-acceptors
to give the corresponding Michael-adducts in high yields. In
the case when 3-nonene-2-one 9 was used, AcOLi worked more
effectively than the previously-reported 3 (Entry 3). One of the
1) AcOLi (10 mol%)
OSiMe3
OH
O
O
DMF, −45 °C
(1)
+
OMe
R
OMe
R
R
H
2) 1 M HClaq
1
THF, rt
1)Lewis base
(10 mol%)
DMF
OSiMe3
OMe
O
R'
O
O
+
(2)
R
OMe
R'
2)1 M HClaq
THF
1
Li
O
N
or
Li
Lewis base:
2
3
O
O
Ph
N
H
O
Ts
Ts
N K
2 or
OSiMe3
HN
O
N
Table 1. AcOLi catalyzed Michael reaction using various
Michael acceptors
O
(3)
(10 mol%)
DMF, rt
+
OMe
R
OMe
R
H
1
It is interesting to note that the TMS enolate was activated
1) AcOLi (10mol%)
DMF, Temp, Time
OSiMe3
OMe
Michael Acceptor
+
Product
either by lithium succimide 3 or by lithium acetate (AcOLi) that
is a weaker nucleophile toward silicon atom compared with lith-
ium benzamide 2. From the synthetic point of view, AcOLi has
such advantages as easy availability, low cost and could be used
under mild conditions because of its weak basicity. Also, the
acetate can be prepared from AcOH by using weak bases such
as lithium carbonate (Li2CO3) while preparation of 2 or 3 from
amide or imide require strong bases such as alkyl lithium. In ad-
dition, from the environmental points of view, they would be
very useful for its low toxicity and is disposable without any spe-
cial treatment. In this communication, we would like to report on
AcOLi-catalyzed Michael reaction between TMS enolates and
ꢀ,ꢁ-unsaturated carbonyl compounds in order to demonstrate
the usefulness of AcOLi as a Lewis base catalyst.
2) 1 M HClaq
THF, rt
1 (1.4 equiv.)
Entry
Michael Acceptor
Temp /°C Time /h Yielda /%
7
8
9
cyclopentenone
4-hexene-3-one
3-nonene-2-one
0
0
rt
0.5
0.5
0.5
98
98
99 (83b)
85 (34c)
83 (44c)
1
2
3
4
5
mesityl oxide
10
11
3
6
rt
rt
3-methyl-cyclohexenone
O
6
7
0
rt
0.5
6
91d
64e
12
13
4-NMe2-C6H4
methyl acrylate
Ph
Reactions were carried out using Michael acceptor (0.4 mmol) in
DMF (3 mL). aYield was determined by 1H NMR analysis
(270 MHz) using 1,1,2,2-tetrachloroethane or 2,4,6-trimethyl-
benzene (Entry 3) as an internal standard. bBy using 3 as a cata-
lyst at rt for 3 h (See Ref. 2). cBy using 3 as a catalyst under the
same reaction conditions. dIsolated yield. e2 equiv. of 1 was
used.
In the first place, reaction of chalcone 4 and TMS enolate 1
in DMF was tried by using 10 mol % of AcOLi at ꢁ45 ꢂC, and
the Michael-adduct 5 was obtained in 93% yield together with
1,2-addition product, silyl ether 6, in 7% yield. In the above re-
action, the amount of 1,2-adduct increased when AcOK was
Copyright Ó 2004 The Chemical Society of Japan

Chemistry Letters Vol.33, No.8 (2004)
1017
most characteristic points of the present reaction is that the hin-
dered ꢀ,ꢁ-unsaturated ketones also behaved as an excellent
Michael-acceptor to form the corresponding Michael-adduct in
high yields at room temperature (Entries 4, 5). This Lewis
base-catalyzed reaction is effective especially when Michael-
acceptors having basic functions within the same molecule are
used. Actually, the reaction proceeded smoothly and the corre-
sponding Michael-adduct was afforded in high yield, as expected
(Entry 6).
Several methods were recently reported concerning Lewis
base-catalyzed Michael reaction. However, each of them had
worked only with limited kinds of silyl enolates, i.e. one worked
only with dimethylsilyl enolates derived from ketones,6,7 and an-
other was performed only with keten silyl acetals.8 On the other
hand, AcOLi-catalyzed Michael reaction also proceeded
smoothly to afford the corresponding Michael-adducts in good
to high yields even when various TMS enolates derived from es-
ters, thioesters or ketones were employed (Table 2).
This catalytic Michael reaction was also carried out by using
other lithium carboxylates that were prepared easily in situ by
treating carboxylic acids with Li2CO3. For example, Michel re-
action of 4 with silyl enolate 1 gave the Michael-adduct 5 in high
yield when 10 mol % of lithium isobutyrate prepared from isobu-
tyric acid and Li2CO3 in DMF was used (Scheme 2).9
Thus, AcOLi-catalyzed Michael reaction between trime-
thylsilyl enolates and ꢀ,ꢁ-unsaturated carbonyl compounds
was established. This is a useful method for the synthesis of var-
ious 1,5-dicarbonyl compounds since the reactions proceed
Li2CO3 (1.0 equiv.)
DMF, rt
i-PrCOOH
i-PrCOOLi
(10 mol%)
(1.0 equiv.)
1 M HClaq
THF, rt
4
5
99%
1
+
DMF, 0 °C, 0.5 h
(1.4 equiv.)
Scheme 2. Michael Reaction by using i-PrCOOLi prepared
from i-PrCOOH and lithium carbonate.
smoothly by using such a mild and readily-available Lewis base
catalyst. Further expansion of this reaction is now in progress.
This study was supported in part by the Grant of the 21st
Century COE Program from Ministry of Education, Culture,
Sports, Science and Technology (MEXT), Japan.
References and Notes
1
a) H. Fujisawa and T. Mukaiyama, Chem. Lett., 2002, 182.
b) H. Fujisawa and T. Mukaiyama, Chem. Lett., 2002, 858.
c) T. Mukaiyama, H. Fujisawa, and T. Nakagawa, Helv. Chim.
Acta, 85, 4518 (2002). d) T. Nakagawa, H. Fujisawa, and T.
Mukaiyama, Chem. Lett., 32, 462 (2003). e) T. Nakagawa, H.
Fujisawa, and T. Mukaiyama, Chem. Lett., 32, 696 (2003).
f) T. Nakagawa, H. Fujisawa, and T. Mukaiyama, Chem. Lett.,
33, 92 (2004).
T. Mukaiyama, T. Nakagawa, and H. Fujisawa, Chem. Lett., 32,
56 (2003).
H. Fujisawa, E. Takahashi, T. Nakagawa, and T. Mukaiyama,
Chem. Lett., 32, 1036 (2003).
2
3
4
The Michael adduct 5 was not observed at all by treating silyl
ether 6 with the reaction conditions [AcOLi (10 mol %), DMF,
30 min].
Table 2. AcOLi catalyzed Michael reaction using various silyl
enolates
5
Typical experimental procedure is as follows (Table 1, Entry 6):
to a stirred solution of AcOLi (2.6 mg, 0.04 mmol) in DMF
(0.5 mL) were added successively a solution of silyl enolate 1
(97.6 mg, 0.56 mmol) in DMF (1.0 mL) and a solution of 40-
(dimethylamino)chalcone10 (100.5 mg, 0.4 mmol) in DMF
(1.5 mL) at 0 ꢂC. The mixture was stirred for 0.5 h at the same
temperature, and quenched with saturated aqueous NH4Cl.
The mixture was extracted with Et2O and the residue was dis-
solved in a mixture of HCl (1.0 M, 0.5 mL) and THF (5 mL) after
evaporation of the solvent. The mixture was stirred for 30 min
and was extracted with Et2O. Organic layer was washed with
brine and dried over anhydrous sodium sulfate. After filtration
and evaporation of the solvent, the crude product was purified
by preparative TLC to give the corresponding Michael-adduct
(128.7 mg, 91%) as a yellow powder.
K. Miura, T. Nakagawa, and A. Hosomi, Synlett, 2003, 2068.
It is difficult to synthesize or isolate dimethylsilyl enolates de-
rived from esters selectively because C-silylation or both C-
and O-silylation of enolates take place when lithium enolates
derived from esters are silylated with chlorodimethylsilane. K.
Miura, H. Sato, K. Tamaki, H. Ito, and A. Hosomi, Tetrahedron
Lett., 39, 2585 (1998).
Y. Kita, J. Segawa, J.-i. Haruta, H. Yasuda, and Y. Tamura, J.
Chem. Soc., Perkin Trans. 1, 1982, 1099; T. V. RajanBabu, J.
Org. Chem., 49, 2083 (1984); Y. Genisson and L. Gorrichon,
Tetrahedron Lett., 41, 4881 (2000); R. Gnaneshwar, P. P. Wadg-
aonkar, and S. Sivaram, Tetrahedron Lett., 44, 6047 (2003).
When the above reaction was carried out without using the iso-
butyric acid, the corresponding Michael-adduct was obtained
only in 10% yield. This result clearly indicates that 1 was acti-
vated effectively by lithium isobutyrate prepared from isobuty-
ric acid and Li2CO3 in DMF.
1) AcOLi (10 mol %)
DMF, Temp, Time
Acceptor 4 or 7
Silyl enolate
(1.4 equiv.)
+
Product
2) 1 M HClaq, THF, rt
Yielda /% syn : antib
Acceptor Silyl enolates
Entry
1
Temp /°C Time /h
OSiMe3
7
0
0
rt
rt
3
3
64
74
55:45
54:56
OMe
2c
7
(E:Z = 6:1)
OSiMe3
3
2
59:41
60:40
7
0
0
89
84
OMe
(E:Z = 1:9)
4c
7
1.5
OSiMe3
6
7
−
0
0
rt
1
1
5
6
7
7
87
SEt
OSiMe3
59:41
26:74e
7
93
SEt
OSiMe3
83d
4
10
Ph
8
9
OSiMe3
´
30:70e,f
75d
8
4
8
70
Reactions were carried out using Michael acceptor (0.4 mmol) in
a
b
c
DMF (3 mL). Isolated yield. Determined by GC. Reactions
were carried out using Michael acceptor (0.8 mmol) in DMF
(3 mL). dYield was determined by 1H NMR analysis
(270 MHz) using 1,1,2,2-tetrachloroethane as an internal stand-
f
ard. eDetermined by 1H NMR analysis (270 MHz). Relative
10 M. Matsui, A. Oji, K. Hiramatsu, K. Shibata, and H. Muramatsu,
J. Chem. Soc., Perkin Trans. 2, 1992, 201.
configurations were not determined.
Published on the web (Advance View) July 12, 2004; DOI 10.1246/cl.2004.1016