Lithium alkoxide-promoted michael reaction between silyl enolates and α,β-unsaturated carbonyl compounds

Article abstract of DOI:10.1246/cl.2004.1410

Michael reaction between silyl enolates and α,β-unsaturated carbonyl compounds by using a catalytic amount of Lewis base such as lithium alkoxide in DMF proceeds smoothly to afford the corresponding Michael-adducts in good yields with moderate to high diastereoselectivities. This reaction can be reasonably explained by considering an alkoxide anion-initiated autocatalytic process.

Full text of DOI:10.1246/cl.2004.1410

1410
Chemistry Letters Vol.33, No.11 (2004)
Lithium Alkoxide-promoted Michael Reaction between Silyl Enolates
and ꢀ,ꢁ-Unsaturated Carbonyl Compounds
Teruaki Mukaiyama,ꢀy;yy Takashi Tozawa,y;yy and Hidehiko Fujisaway;yy
yCenter for Basic Research, The Kitasato Institute (TCI), 6-15-5 Toshima, Kita-ku, Tokyo 114-0003
yyKitasato Institute for Life Sciences, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641
(Received August 2, 2004; CL-040905)
Michael reaction between silyl enolates and ꢀ,ꢁ-unsaturat-
ed carbonyl compounds by using a catalytic amount of Lewis
base such as lithium alkoxide in DMF proceeds smoothly to af-
ford the corresponding Michael-adducts in good yields with
moderate to high diastereoselectivities. This reaction can be rea-
sonably explained by considering an alkoxide anion-initiated au-
tocatalytic process.
Table 1. Michael reaction of chalcone 1 with TMS enolate 2 in
the presence of a catalytic amount of lithium alkoxides
O
OSiMe3
+
Ph
Ph
Ph
2 (1.5 equiv.)
1
O
Ph
O
H+
ROLi (10mol%)
DMF, −45 °C, Time
Ph
Ph
In our preceding paper, new possibilities of various Lewis
base catalysts in synthetic reactions were demonstrated.1 There,
nitrogen- or oxygen-containing organic anions generated from
amines, amides, imides, and carboxylic acids were found to
work effectively as Lewis base catalysts for the activation of
commonly used trimethylsilyl (TMS) enolates. For example,
Lewis bases such as lithium benzamide,1g lithium succimide,1g
or lithium acetate1j efficiently catalyzed the Michael reaction
of TMS enolates with ꢀ,ꢁ-unsaturated carbonyl compounds in
N,N-dimethylformamide (DMF).
Entry
ROLia
MeOLi
Time /h
10
Yieldb /%
anti:syn c
90:10
90:10
92:8
64
91
93
1
2
3
4
EtOLi
BnOLi
BnOLi
BnOLi
6
4
88d
quant.e
5
0.5
6
91:9
5
6
89:11
0f
BnOLi
60:40
60:40
7
8
i-PrOLi
t-BuOLi
6
4
65
90
Then, in the course of our continuous investigations on the
usefulness of oxygen-containing organic anions for Lewis bases
in organic reactions, the use of alkoxide anions was focused
upon. It was reported in the previous report that the catalytic al-
dol reaction between TMS ketene acetals and aldehydes by using
alkoxide anion proceeded smoothly to afford the corresponding
aldol in DMF.2 It was demonstrated there that the in situ formed
aldolate anion worked as a useful catalyst of the above reaction.
Now, we would like to describe on Michael reaction between sil-
yl enolates and ꢀ,ꢁ-unsaturated carbonyl compounds by using a
catalytic amount of alkoxide anion in DMF at low temperatures.
In the first place, various lithium alkoxides were screened by
taking the Michael reaction of chalcone 1 with TMS enolate 2 in
DMF at ꢁ45 ꢂC as a model (Table 1). In the case of lithium alk-
oxides generated from primary alcohols, the reactions proceeded
smoothly to afford the corresponding Michael-adducts in good
yields with high anti-diastereoselectivities even when 5 mol %
of lithium benzylate was used (Entries 1–4). When the reaction
was carried out at 0 ꢂC, the Michael-adduct was obtained in
quantitative yield, virtually without losing diastereoselectivity
(Entry 5). The desired Michael-adduct was not formed when
the reaction was tried in THF different from the cases attempted
in DMF (Entry 6). These results indicate that the alkoxide anions
promoted the catalytic Michael reaction as effective Lewis bases
and the solvent also played an important role on this reaction. On
the other hand, the use of lithium alkoxides generated from steri-
cally hindered secondary or tertiary alcohols was found to give
the products while the diasteroselectivities were lost (Entries 7
and 8). It was thought then that the sterically hindered alkoxide
anions would not only serve as Lewis bases to activate TMS eno-
aLithium alkoxides were prepared from alcohol and MeLi.
c
1
bIsolated yield. Determined by H NMR analysis (270 MHz).
d5 mol % of BnOLi was used. eReaction was carried out at
f
0 ꢂC. Reaction was carried out in THF.
lates by a nucleophilic attack, but also behave as Brꢀnsted bases
to promote the epimerization of the formed adducts.
Several examples of Michael reactions by using 10 mol % of
lithium benzylate in DMF are summarized in Table 2.3 This
Lewis base-promoted reaction was more effective than the pre-
viously reported lithium acetate-catalyzed reaction1j when
TMS enolates derived from ketones were used. Actually, it
was observed that TMS enolates derived from ketones smoothly
reacted with various Michael-acceptors to give the correspond-
ing products in good to high yields with moderate to high dia-
stereoselectivities at low temperatures. On the other hand, higher
reaction temperature was still required in the lithium acetate-cat-
alyzed Michael reaction. It is noteworthy to point out that the
Michael-adducts were also obtained in good yields when ꢀ,ꢁ-
unsaturated carbonyl compounds having active hydrogen atoms
at ꢀ-position of carbonyl moiety or having sterically hindered
group were applied to this catalytic system (Entries 3 and 4).
In addition, the desired product was obtained in good yield with-
out diminution of the diastereoselectivity when triethylsilyl
(TES) enolate derived from propiophenone was employed in
place of the above TMS enolate 2 (Entry 7).
The present catalytic Michael reaction is assumed to pro-
ceed by a pathway similar to the previously reported product-
Copyright Ó 2004 The Chemical Society of Japan

Chemistry Letters Vol.33, No.11 (2004)
1411
catalyzed aldol reaction2 (Scheme 1), that is; an alkoxide anion
and a solvent coordinated to the silicon atom of TMS enolate to
form a highly nucleophilic hexacoordinated hypervalent silicate
A. Thus, the enolate became more reactive and attacked smooth-
ly the ꢀ,ꢁ-unsaturated carbonyl compounds to form lithium eno-
late B and TMS ether of alcohol. The alkoxide anion just served
as an initiator of the reaction and was not involved in the catalyt-
ic cycle. In the next step, lithium enolate B similarly activated
TMS enolate to form a silylated Michael-adduct via a hexacoor-
dinated hypervalent silicate C and then regenerated the lithium
enolate (enolate anion) B that behaved as a key species in the
above catalytic cycle.
Table 2. Lithium alkoxide-promoted Michael reaction using
various Michael acceptors and silyl enolates
1) BnOLi
(10mol%)
O
R2
O
O
OSiMe3
R4
DMF
3
R1
R4
+
R
R1
R2
2) HClaq, THF
or TFA, CH2Cl2
R3
(1.5 equiv.)
anti:synb
Yielda /%
93
Entry
1
Acceptor
O
Enolate
Conditions
−45 °C, 4 h
2
92:8
Ph
Ph
1
O
Thus, Michael reaction between silyl enolates and ꢀ,ꢁ-
unsaturated carbonyl compounds by using a catalytic amount
of Lewis base such as lithium alkoxide in DMF at low temper-
atures proceeded smoothly to afford the corresponding
Michael-adducts. This reaction is induced by a readily available
alkoxide anion and then is further catalyzed by the in situ formed
enolate anion. It is noted that these two oxygen-containing
anions work effectively as Lewis base for the promotion of silyl
enolates. Further investigation on this reaction is now in
progress.
2
3
2
2
−20 °C, 4 h
−20 °C, 6 h
75:25
96:4
88
92
Ph
O
Ph
O
−20 °C, 8 h
4
5
70
2
2
96:4
ndd
Ph
O
60c
−10 °C, 10 h
OSiMe3
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.
75:25 e
90:10
0 °C, 10 h
0 °C, 10 h
6
7
1
1
86
72
OSiEt3
Ph
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). g) T. Mukaiyama, T. Nakagawa, and H. Fujisawa,
Chem. Lett., 32, 56 (2003). h) H. Fujisawa, E. Takahashi, T.
Nakagawa, and T. Mukaiyama, Chem. Lett., 32, 1036 (2003).
i) E. Takahashi, H. Fujisawa, and T. Mukaiyama, Chem. Lett.,
33, 936 (2004). j) T. Nakagawa, H. Fujisawa, Y. Nagata, and
T. Mukaiyama, Chem. Lett., 33, 1016 (2004).
aIsolated yield. bDetermined by 1H NMR analysis (270 MHz). c2
equivalents of 2 were used. dnd = not determined. eThe relative
configuration was not determined.
OR
ROLi
Si
O
OSiMe3 (cat.)
DMF
R1
R2
Li
R1
DMF
R2
2
3
H. Fujisawa, T. Nakagawa, and T. Mukaiyama, Adv. Synth.
Catal., (2004), in press.
O
A
Typical experimental procedure is as follows (Table 2, Entry 1):
a) Preparation of lithium benzylate; To a solution of benzyl alco-
hol (227 mg, 2.1 mmol) in Et2O (18 mL) was added methyllithi-
um in Et2O (0.98 M, 2.0 mL, 2.0 mmol) at 0 ꢂC and the mixture
was stirred for 30 min. b) General procedure of lithium alkox-
ide-promoted Michael reaction; An etheral solution containing
lithium benzylate (0.6 mL, 0.06 mmol) was concentrated under
reduced pressure and residual lithium reagent was dissolved in
DMF (1.2 mL). The resulting solution was cooled to ꢁ45 ꢂC
and then solutions of silyl enolate 2 (186 mg, 0.9 mmol) in
DMF (0.6 mL) and chalcone (125 mg, 0.6 mmol) in DMF (1.2
mL) were added. The mixture was stirred for 4 h at the same tem-
perature, and quenched with saturated aqueous NH4Cl. The mix-
ture was extracted with EtOAc and the residue was dissolved in a
mixture of HCl (1.0 M, 2 mL) and THF (8 mL) after evaporation
of the solvent. The mixture was stirred for 30 min and was ex-
tracted with EtOAc. Organic layer was washed with brine and
dried over anhydrous Na2SO4. After filtration and evaporation
of the solvent, the crude product was purified by silica gel
column chromatography to give the corresponding Michael-
adduct (190 mg, 93%).
R3
R4
ROSiMe3
Li
OSiMe3
R2
O
R4
O
R1
Me3SiO
R3
R4
O
R3
R1
DMF
R1
R2
B
R2
R2
R1
R3
O
Li
O
R4
O
R3
R4
Si
O
DMF
R1
R2
C
Scheme 1.
Published on the web (Advance View) September 29, 2004; DOI 10.1246/cl.2004.1410