Lithium acetate-catalyzed aldol reaction between aldehyde and trimethylsilyl enolate

Article abstract of DOI:10.1246/cl.2003.462

Lithium acetate-catalyzed aldol reaction between trimethylsilyl enolates and aldehydes proceeded smoothly in a DMF or pyridine solvent to afford the corresponding aldols in good to high yields under weakly basic conditions.

Full text of DOI:10.1246/cl.2003.462

462
Chemistry Letters Vol.32, No.5 (2003)
Lithium Acetate-Catalyzed Aldol Reaction between Aldehyde and Trimethylsilyl Enolate
Takashi Nakagaway;yy, Hidehiko Fujisawa,#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 February 18, 2003; CL-030136)
Lithium acetate-catalyzed aldol reaction between trimethyl-
sence of the catalyst, on the other hand, the aldol adduct was
obtained only in 14% yield even when the reaction was carried
out at 70 ꢂC in pyridine. These results indicated the capability of
AcOLi that behaved as an effective Lewis base catalyst in this
aldol reaction.
silyl enolates and aldehydes proceeded smoothly in a DMF or
pyridine solvent to afford the corresponding aldols in good to
high yields under weakly basic conditions.
Next, the reactions of TMS enolate 1 with various alde-
hydes were tried by using 10 mol% of AcOLi in DMF or pyri-
dine (see Table 1).5 Aromatic aldehydes having an electron-do-
nating group reacted smoothly to afford the desired aldols in
high yields (Entries 1–4). On the other hand, aromatic alde-
hydes having an electron-withdrawing group and aliphatic alde-
hyde as 3-Phenylpropionaldehyde gave the corresponding al-
dols in moderate yields in DMF while the aromatic aldehydes
gave the aldol adducts in high yields when the reactions were
carried out in pyridine at 70 ꢂC.
The present Lewis base catalyzed reaction has a remarkable
advantage of forming aldols especially when the aldehydes hav-
ing basic functions in the same molecules were used: that is, the
reactions proceeded smoothly at ꢁ45 ꢂC in DMF and the corre-
sponding aldols were afforded in high yields (Table 2, Entries
1–4).
The AcOLi-catalyzed aldol reaction was further examined
using several other silyl enolates (see Table 3). When the eno-
late generated from S-ethyl ethanethioate was employed, the al-
dol adduct was obtained in high yield (Entry 1) while no effec-
tive activation took place at ꢁ45 ꢂC when the enolate generated
from acetophenone was used. The above reaction proceeded
smoothly at 0 ꢂC to afford the aldol adduct in good yield (Entry
2). Next, it was observed that the corresponding aldol adduct
was obtained only in 4% yield when sterically hindered triethyl-
A new method for a catalytic aldol reaction between silyl
enolates and aldehydes was recently reported from our labora-
tory: that is, simple and commonly employed trimethylsilyl
(TMS) enolates reacted with aldehydes smoothly to afford the
corresponding aldols by using a catalytic amount of lithium di-
phenylamide or lithium pyrrolidone as Lewis base in a N,N-di-
methylformamide (DMF) or pyridine solvent.1 In order to ex-
tend the scope of this reaction, lithium acetate, a milder and
readily available Lewis base, was chosen in place of the above
mentioned lithium salts. In our previous paper, lithium succi-
mide was shown to have effectively been employed in a cataly-
tic Michael reaction between TMS enolates and ꢀ; ꢁ-unsatu-
rated carbonyl compounds.2 It is interesting to note that the
TMS enolate was activated by the nucleophilic attack of lithium
succimide on silicon atom though the pKa value of N–H bond
of succimide was much lower than that of diphenylamine or
pyrrolidone.3 In order to examine the possibility of using
lithium carboxylates in these types of reactions as catalysts, car-
boxylic acids such as acetic acid were tried considering the ad-
vantages of their availability, inexpensiveness and pKa values
of their O–H bonds which were relatively close to that of N–
H bond of succimide.3 In this communication, we would like
to report on the lithium acetate (AcOLi) catalyzed aldol reaction
between TMS enolates and aldehydes.
In the first place, reaction of benzaldehyde and TMS eno-
late (1) derived from methyl isobutyrate was tried in the pre-
sence of 10 mol% of AcOLi at ꢁ45 ꢂC in DMF, and the aldol
adduct was obtained in 83% yield.4 Since AcOLi is a weak nu-
cleophile, the reaction did not proceed at 0 ꢂC in pyridine
although the same reaction went on smoothly when lithium di-
phenylamide or lithium pyrrolidone was used.1 However, the
corresponding aldol was obtained in high yield when the reac-
tion was carried out at 70 ꢂC in pyridine (Scheme 1). In the ab-
Table 1.
1) AcOLi (10 mol%)
Solv., Temp, Time
OSiMe3
OMe
1
OH
O
O
+
2) 1N HClaq
THF, rt
R
OMe
R
H
Temp /oC Time /h
Yielda /%
94b
Entry
1
Aldehyde
Solv.
DMF
−45
1
4-MeOC6H4CHO
96b
84
98
63
rt
−45
70
−45
70
2
2
2
3
2
3
4
5
6
7
8
Pyridine
DMF
Pyridine
DMF
Pyridine
DMF
Pyridine
4-MeOC6H4CHO
4-MeC6H4CHO
4-MeC6H4CHO
4-ClC6H4CHO
4-ClC6H4CHO
4-NO2C6H4CHO
4-NO2C6H4CHO
OSiMe3
OMe
OH
O
O
AcOLi (10 mol%) 1N HClaq
DMF, −45 oC, 1.5 h THF, rt
+
Ph
OMe
Ph
Ph
H
H
1
83%
4.5
2 d
3
93
69
82
(1.4 equiv.)
rt
−45
70
−45
70
OSiMe3
OMe
OH
O
O
65b
AcOLi (10 mol%) 1N HClaq
Pyridine, 70 oC, 1.5 h THF, rt
DMF
Pyridine
9
10
2
4.5
CHO
Ph
+
54b
Ph
OMe
1
aYield was determined by H NMR analysis (270 MHz) using
1,1,2,2-tetrachloroethane as an internal standard. bIsolated
yields.
1
95%
(1.4 equiv.)
Scheme 1.
Copyright Ó 2003The Chemical Society of Japan

Chemistry Letters Vol.32, No.5 (2003)
463
Table 2.
the reactivity of E enolate was lower than that of Z enolate
when the previously mentioned Lewis bases such as lithium di-
phenylamide or lithium pyrrolidone were used.1 The syn-dia-
stereoselectivity of the AcOLi-catalyzed aldol reaction indi-
cated that the reaction proceeded mostly via acyclic transition
states.4b,6
OSiMe3
Me3SiO
R
O
O
AcOLi (10 mol%)
+
OMe
DMF, −45 °C, Time
OMe
R
H
1
Yielda /%
99
Entry
1b
Time /h
Aldehyde
This catalytic aldol reaction can also be performed
smoothly by using other lithium carboxylates that are prepared
easily in situ by treating carboxylic acids with lithium carbonate
(Li2CO3) while Lewis bases employed in the previous studies
needed strong bases such as alkyl lithium.1 For example, aldol
reaction of 4-methoxybenzaldehyde with silyl enolate 1 gave
the aldol adduct in 92% yield by using 10 mol% of lithium iso-
butyrate prepared from isobutyric acid and Li2CO3 in DMF.
Thus, lithium acetate-catalyzed aldol reaction between
TMS enolates and aldehydes under weakly basic conditions in
a DMF or pyridine solvent was established. This method is
practically applicable for the synthesis of various aldols because
it uses such a mild, readily-available, and inexpensive Lewis
base catalyst. Further extension of this reaction is now in pro-
gress.
N
CHO
1
N
1.5
2
3
84
CHO
91c
CHO
CHO
1.5
N
4
5
2.5
1
99
90
N
Boc
CHO
O
aYield was determined by H NMR analysis (270 MHz) using
1
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.
1,1,2,2-tetrachloroethane as an internal standard. b5 mol% of
AcOLi was used. Isolated yield after desilylation.
c
Table 3.
References and Notes
1) AcOLi (10 mol%)
Solv., Temp., Time
#
1
A doctor course student of Science University of Tokyo.
H. Fujisawa and T. Mukaiyama, Chem. Lett., 2002, 182; H.
Fujisawa and T. Mukaiyama, Chem. Lett., 2002, 858; T.
Mukaiyama, H. Fujisawa, and T. Nakagawa, Helv. Chim. Acta,
85, 4518 (2002).
O
Silyl enolates
+
Products
syn : anti
−
2) 1N HClaq, THF, rt
Temp /oC
Ph
H
Yielda /%
Entry Silyl enolates
Solv.
DMF
Time /h
OSiMe3
2
T. Mukaiyama, T. Nakagawa, and H. Fujisawa, Chem. Lett., 32,
56 (2003).
1
−45
2
91
SEt
3F. G. Bordwell, Acc. Chem. Res., 21, 456 (1988); F. G. Bordwell,
J. C. Branca, D. L. Hughes, and W. N. Olmstead, J. Org. Chem.,
45, 3305 (1980).
OSiMe3
−
−
DMF
DMF
2
0
2
85
4
Ph
4
Although a small amount of acetal 2 was co-produced, it was ea-
sily converted to normal aldol and starting aldehyde on treatment
with 1 N HCl.
OSiEt3
3
−45
1.5
OMe
Me SiO
3
OH
O
O
1N HCl
aq
R
O
O
+
OMe
R
THF, rt
R
H
OSiMe3
4
R
OMe
DMF
87
86
1.8 : 1
1.5 : 1
−45
3
2
2
OMe
5
Pyridine
70
See: a) E. Nakamura, M. Shimizu, I. Kuwajima, J. Sakata, K.
Yokoyama, and R. Noyori, J. Org. Chem., 48, 932 (1983). b) S.
Matsukawa, N. Okano, and T. Imamoto, Tetrahedron Lett., 41,
103(2000).
(E:Z =5:1)
6
7
DMF
79
94
2.7 : 1
1.9 : 1
OSiMe3
−45
3
2
5
Typical experimental procedure is as follows (Table 1, Entry 1):
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 4-meth-
oxybenzaldehyde (54.5 mg, 0.4 mmol) in DMF (1.5 mL) at
ꢁ45 ꢂC. The mixture was stirred for 1 h at the same temperature,
and quenched with saturated aqueous NH4Cl. The mixture was
extracted with Et2O and the residue was dissolved in a mixture
of HCl (1.0 N, 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 aldol (89.6 mg, 94%) as a white powder.
Pyridine
70
OMe
(E:Z =1:9)
aYield was determined by H NMR analysis (270 MHz) using
1,1,2,2-tetrachloroethane as an internal standard.
1
silyl enolate derived from methyl isobutyrate was employed in
place of the above TMS enolate 1 (Entry 3). This result showed
that the reaction proceeded via the activation of TMS enolate by
forming hypervalent silicate between AcOLi and silicon atom
of the enolate.1 Further, the aldol adducts were obtained in high
yields with moderate syn-diastereoselectivity irrespective of
geometry of the two isomeric silyl enolates derived from methyl
propionate (Entries 4–7). Both reactivities of E and Z enolates
were nearly the same when AcOLi was used as a catalyst while
´
Y. Genisson and L. Gorrichon, Tetrahedron Lett., 41, 4881
(2000).
6
Published on the web (Advance View) April 23, 2003; DOI 10.1246/cl.2003.462