Chemistry Letters Vol.32, No.8 (2003)
697
Next, the reactions of TMS enolate 1 with various alde-
hydes were tried (see Table 1).8 In every case, the aldol adducts
were obtained in high yields. It is remarkable that both aromatic
aldehydes having electron-withdrawing groups and an aliphatic
aldehyde, 3-phenypropionaldehyde, reacted smoothly to afford
the desired aldols in high yields while the corresponding aldols
were obtained in moderate yields in non-aqueous solvent (En-
tries 1–2 and 7).2b 2-Pyridinecarboxaldehyde afforded the aldol
adduct in high yield, on the other hand, the reaction did not gen-
erally proceed by using Lewis acids (Entry 8). One of the most
characteristic points of the present reaction carried out in a wa-
ter-containing DMF solvent is that the aldehydes having free
amide, hydroxy, or even carboxylic functions reacted smoothly
to afford the desired aldols in moderate to high yields although
such functions were incompatible with metal enolates or Lewis
acids (Entries 9–11).
OSiMe3
OMe
O
Li
H2O
O
DMF
O
O
Si
O
Li
O
+ LiOH
H
DMF
O
OMe
O
SiMe3
O
Me3SiOH
+
+
Assumed catalytic cycle of the present reaction was illus-
trated in Scheme 1. The same reaction pattern may be consid-
ered until lithium aldolate is formed via a hexacoodinated hy-
pervalent silicate under non-aqueous conditions.2 In case of
the reaction carried out in a water-containing DMF solvent,
the initially formed lithium aldolate and silyl acetate are rapidly
hydrolyzed to produce lithium hydroxide and acetic acid. Sub-
sequent neutralization should afford lithium acetate to establish
a catalytic cycle.
Under non-aqueous conditions, the initially formed lithium
aldolate was converted into its TMS ether with trimethylsilyl
acetate and the catalyst was regenerated.2 Aromatic aldehydes
having electron-withdrawing groups and 3-phenypropionalde-
hyde afforded silyl acetals as co-products via the reaction with
lithium aldolates because they were more electrophilic than
benzaldehyde.9 Thereby, yields of the desired aldols were mod-
erate under non-aqueous conditions. In the presence of water,
on the other hand, lithium aldolates were rapidly hydrolyzed
and formations of the above-mentioned silyl acetals were re-
strained;therefore, the desired aldols were obtained in high
yields.
OLi
O
OH
O
2H2O
O
R
R
OMe
R
OMe
H
Scheme 1.
sive Lewis base catalyst. Further development 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
2
T. Mukaiyama, K. Banno, and K. Narasaka, J. Am. Chem. Soc., 96, 7503 (1974).
a) T. Mukaiyama, H. Fujisawa, and T. Nakagawa, Helv. Chim. Acta, 85, 4518
(2002). b) T. Nakagawa, H. Fujisawa, and T. Mukaiyama, Chem. Lett., 32, 462
(2003).
By using Lewis acids: S. Kobayashi and K. Manabe, Acc. Chem. Res., 35, 209
(2002) and references cited therein.
Via transmetallation: a) M. Sodeoka, K. Ohrai, and M. Shibasaki, J. Org.
Chem., 60, 2648 (1995). b) M. Sodeoka, R. Tokunoh, F. Miyazaki, E. Hagiwara,
and M. Shibasaki, Synlett, 1997, 463. c) A. Fujii and M. Sodeoka, Tetrahedron
Lett., 40, 8011 (1999). d) Y. Mori, J. Kobayashi, K. Manabe, and S. Kobayashi,
Tetrahedron, 58, 8263 (2002).
3
4
5
6
7
Via nucleophillic cleavage of O–Si bond: S. Matsukawa, N. Okano, and T.
Imamoto, Tetrahedron Lett., 41, 103 (2000).
By using Lewis bases: K. Miura, T. Nakagawa, and A. Hosomi, J. Am. Chem.
Soc., 124, 536 (2002).
This catalytic aldol reaction can also be performed smooth-
ly by using other TMS enolates. For example, TMS enolates de-
rived from S-tert-butyl isobutanethioate and acetophenone af-
forded the corresponding aldols in good yields (Eqs 2 and 3).
Other systems: a) A. Lubineau, J. Org. Chem., 51, 2142 (1986). b) T.-P. Loh,
L.-C. Feng, and L.-L. Wei, Tetrahedron, 56, 7309 (2000). c) M. Ohkouchi,
M. Yamaguchi, and T. Yamagishi, Enantiomer, 5, 71 (2000). d) M. Ohkouchi,
D. Masui, M. Yamaguchi, and T. Yamagishi, J. Mol. Catal. A: Chem., 170, 1
(2001). e) M. Ohkouchi, D. Masui, M. Yamaguchi, and T. Yamagishi, Nippon
Kagaku Kaishi, 2002, 223.
Typical experimental procedure is as follows (Table 1, Entry 1): to a stirred sol-
ution of AcOLi (2.6 mg, 0.04 mmol) in DMF (0.5 mL) and H2O (0.06 mL) were
added successively a solution of 4-nitrobenzaldehyde (60.4 mg, 0.4 mmol) in
DMF (1.5 mL) and a solution of silyl enolate 1 (139.5 mg, 0.8 mmol) in DMF
(1.0 mL) at ꢁ45 ꢂC. The mixture was stirred for 3 h at the same temperature,
and quenched with 1.0 N HCl. The mixture was extracted with Et2O and organic
layer was washed with brine and dried over anhydrous sodium sulfate. After fil-
tration and evaporation of the solvent, the crude product was purified by prep-
arative TLC to give the corresponding aldol (98.3 mg, 97%) as a white powder.
Although a small amount of acetal 2, a co-product, was obtained under the non-
aqueous condition, it was easily converted to normal aldol and starting aldehyde
on treatment with 1 N HCl.
OSiMe3
OH
O
AcOLi (10 mol%)
O
(2)
+
St-Bu
Ph
St-Bu
DMF−H2O
(Volume ratio 50:1)
0 oC, 5 h
Ph
H
8
83%
OH
(2 equiv.)
AcOLi (10 mol%)
OSiMe3
O
O
(3)
+
DMF−H2O
R
H
Ph
(2 equiv.)
R
Ph
(Volume ratio 50:1)
86%
R=p-NO2C6H4
0 oC, 5 h
−45oC
Thus, lithium acetate catalyzed aldol reaction between
9
TMS enolates and aldehydes in a water-containing DMF sol-
vent was established. This is the first example of Lewis base-
caralyzed aldol reaction which afforded aldol adducts even
when silyl enolates derived from carboxylic esters were used
in a water-containing organic solvent. This method is quite
practical and is applicable to the synthesis of various aldols
since the reaction is carried out under the conditions not strictly
anhydrous and uses such a mild, readily-available and inexpen-
Me SiO
3
OH
O
O
1N HCl
aq
R
O
O
+
OMe
R
THF, rt
R
H
R
OMe
2
See: E. Nakamura, M. Shimizu, I. Kuwajima, J. Sakata, K. Yokoyama, and
R. Noyori, J. Org. Chem., 48, 932 (1983), Ref 2b and Ref 5.
Published on the web (Advance View) July 7, 2003;DOI 10.1246/cl.2003.696