Ammonium phenoxides-catalyzed syn-selective aldol reaction between an aldehyde and an trimethylsilyl enolate

Article abstract of DOI:10.1246/cl.2005.842

Aldol reactions between aldehydes and trimethylsilyl enolates generated from ketones or thioesters proceeded smoothly in the presence of a Lewis base catalyst such as tetrabutylammonium phenoxide or p-methoxyphenoxide in THF to afford the corresponding al

Full text of DOI:10.1246/cl.2005.842

842
Chemistry Letters Vol.34, No.6 (2005)
Ammonium Phenoxides-catalyzed syn-Selective Aldol Reaction
Between an Aldehyde and an Trimethylsilyl Enolate
Hidehiko Fujisawa,y;yy Yuzo Nagata, Yoshinori Sato,y;yy and Teruaki Mukaiyamaꢀy;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 February 28, 2005; CL-050256)
Aldol reactions between aldehydes and trimethylsilyl eno-
Table 1. Screening of the catalyst on aldol reaction of PhCHO
with TMS enolate 1
lates generated from ketones or thioesters proceeded smoothly
in the presence of a Lewis base catalyst such as tetrabutylam-
monium phenoxide or p-methoxyphenoxide in THF to afford
the corresponding aldols in high yields with high syn-selectivity.
OH
O
O
OSiMe3
Cat. (10 mol%)
H+
+
Ph
Ph
H
Ph
1(1.4 equiv)
Catalyst
Ph
2-syn
Solv. Temp. Time Yielda syn:antib
Entry
/°C
DMF 0 to rt
DMF −45
DMF −45
/h
/%
Aldol reaction is one of the most important and frequently
employed tools for carbon–carbon bond formation.1 In the
course of our investigation on the Lewis base-catalyzed aldol re-
actions between aldehydes and trimethylsilyl (TMS) enolates,
nitrogen- or oxygen-containing anions generated from amines,
amides, imides, or carboxylic acids were found to behave as ef-
fective Lewis base catalysts.2 It was also found that these Lewis
base are also useful catalysts in Michael,3 Mannich-type,4
Strecker-type reactions,5 and trifluoromethylation of aldehydes
or aldimines.6 Then, in order to extend further synthetic utilities
of these Lewis base-catalyzed reactions, diastereoselective aldol
reactions were examined. In this communication, we would like
to report on tetrabutyl ammonium phenoxides-mediated syn-se-
lective aldol reactions of aldehydes with TMS enolates generat-
ed from ketones or thioesters.
1
2
3
AcOLi
AcOLi
AcONBu4
O
6
6
87
63:37


n.d.c
n.d.c
6
3
4
5
NLi
DMF −45
25
50:50
DMF −45
DMF −45
PhONBu4 (3) THF −45
n.d.c
98
95
92
79
23
6
5
1
3
1
1
1

BnOLi
PhOLi
6
7
8
9
10
75:25
78:22
91:9
94:6
94:6
PhONBu4
2-MeOC6H4ONBu4
3-MeOC6H4ONBu4
THF −78
THF −78
THF
−78
4-MeOC6H4ONBu4 (4) THF −78
quant. 95:5
11
12
4-ClC6H4ONBu4
ONBu4
THF −78
3
15
96:4
Lewis base catalysts were shown to be effective in promot-
ing the reaction of ketene silyl acetals.2 However, higher temper-
ature was needed to complete the reaction since they were not
reactive toward silyl enolate such as 1 at low temperature
(Table 1, Entries 1–5).
13
(5) THF −78
1
91
94:6
aYield was determined by H NMR analysis (270 MHz) using
1
1,1,2,2-tetrachloroethane as an internal standard. bThe ratio
was determened by H NMR. n.d.; not detected.
1
c
Then, Lewis base catalyst was screened in order to increase
the reactivity and it was found that a lithium phenoxide (PhOLi)
catalyst was successfully employed to promote the aldol reac-
tion; that is, the reaction proceeded smoothly to afford the corre-
sponding aldol in quantitative yield with moderate syn-selectiv-
ity7 (syn:anti = 3:1) when the reaction was carried out by using
10 mol % of PhOLi in DMF at ꢁ45 ꢂC (Entry 6). Further, higher
yield and better syn-selectivities were attained when the reaction
was carried out by using tetrabutylammonium phenoxide
(PhONBu4 3) in THF at ꢁ78 ꢂC (Entry 8). Then, screening of
the phenoxide anions revealed that the efficiency of this reaction
was influenced by the catalysts employed, and 4 and 5 were also
found to be effective catalysts for the above aldol reaction.
Next, the scope of acceptor aldehydes in the ammonium
phenoxides-catalyzed aldol reaction was examined by using
TMS enolate 1 in the presence of 10 mol % of 3, 4, or 5 in
THF (Table 2). Various aldehydes smoothly reacted with TMS
enolate 1 to afford the corresponding aldols in good to high
yields with syn-selectivities. When aromatic aldehydes having
electron-donating or -withdrawing group were used, the reac-
tions proceeded smoothly to give the corresponding aldols in
high yields with good syn-selectivities while the selectivity
was moderate when 4-nitrobenzaldehyde was used. This reac-
tion is also applicable to an aldehyde having a basic function
(Entries 5 and 6). In the case when aliphatic aldehyde such as
3-phenylpropionaldehyde was used, the reaction proceeded to
afford the corresponding aldols with moderate syn-selectivity.
The yields were dependent on the nature of the catalysts
employed, and 3 was found to be a favorable catalyst. Improved
results were obtained when a more hindered aldehyde such as
cyclohexanecarbaldehyde was used in the presence of 3.
Silyl enolates generated from thioesters were further applied
to this reaction (Table 3). When TMS enolate 6 having S-t-butyl
substituent was used, the aldol adducts were obtained in good
yields with moderate selectivities. On the other hand, good
yields and high selectivities were attained by using TMS
enolates such as 7, 8, or 9. Especially, it was observed that the
TMS enolate 8 and 9 gave the aldols in good yield with high
syn-selectivity irrespective of the geometry of the enolates
(Entries 4 and 5). These results indicated that the reaction
proceeded via the acyclic transition states.2c
Thus, phenoxide anions are proved to be good Lewis
base catalysts to promote aldol reactions and syn-selective aldol
Copyright Ó 2005 The Chemical Society of Japan

Chemistry Letters Vol.34, No.6 (2005)
843
Table 2. Tetrabutylammonium phenoxides-catalyzed syn-se-
lective aldol reaction of various aldehydes with 1
reaction between TMS enolates and aldehydes was established
by using a catalytic amount of PhONBu4 or 4-MeOC6H4ONBu4
in THF. Further study on this reaction is now in progress.
OH
O
H+
O
OSiMe3
Cat. (10 mol%)
+
R
Ph
THF, −78 °C
R
H
Ph
This work was supported by Grant-in-aid for Scientific
Research from the Ministry of Education, Science, Sports, and
Culture, Japan.
1 (1.4 equiv)
syn
syn:antib
Entry
Aldehyde
Cat. Time /h Yielda /%
quant.c
95:5
91:9
1
2
4-MeC6H4CHO
4-MeC6H4CHO
3
4
2
2
References
quant.
1
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3
4
4-NO2C6H4CHO
4-NO2C6H4CHO
3
4
3
2
87c
93
74:26
76:24
N
CHO
3
4
5
2
84c
quant.
5
6
94:6
94:6
2
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O
7
8
CHO
CHO
3
4
4
2
82c
96:4
97:3
quant.c
9
10
11
3
4
5
4
3
5
56
44
52
77:23
74:26
81:19
Ph
3
4
5
2
3
5
69
51
34
91:9
93:7
73:27
12
13
14
CHO
aIsolated yield. The ratio was determined by H NMR. Yield
was determined by 1H NMR analysis (270 MHz) using
1,1,2,2-tetrachloroethane as an internal standard.
b
1
c
3
Table 3. PhONBu4-catalyzed aldol reaction of PhCHO with
TMS enolate genarated from thioesters
OSiMe3
OH
O
O
PhONBu4 (10 mol %) H+
+
SR
SR
Ph
H
THF, −78 °C,
Ph
4
Silyl enolates
OSiMe3
syn:antib
62:38
Entry
1
Equiv
1.4
Time /h Yielda /%
(6)
3
82
St-Bu
OSiMe3
SCy
2
3
2
3
2
2
70
84
92:8
93:7
(7)
5
6
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OSiMe3
SEt
4
(8)
(9)
2
1.5
78
93:7
OSiMe3
SEt
5
2
1
88
94:6
7
aYield was determined by H NMR analysis (270 MHz) using
1,1,2,2-tetrachloroethane as an internal standard. bThe ratio
was determined by 1H NMR.
1
Published on the web (Advance View) May 21, 2005; DOI 10.1246/cl.2005.842