Self-promoted aldol reaction between aldehyde having lewis base moiety and trimethylsilyl enolate

Article abstract of DOI:10.1246/cl.2004.92

Self-promoted aldol reaction between aldehydes having Lewis base moieties and trimethylsilyl enolates proceeded smoothly to afford the corresponding aldols in good to high yields. It is noted that various functionalized aldols can be directly obtained wit

Full text of DOI:10.1246/cl.2004.92

92
Chemistry Letters Vol.33, No.2 (2004)
Self-promoted Aldol Reaction between Aldehyde Having Lewis Base Moiety
and Trimethylsilyl Enolate
Takashi Nakagawa,y;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 October 20, 2003; CL-030986)
Self-promoted aldol reaction between aldehydes having
self-promoted aldol reaction between aldehydes having Lewis
base moieties and TMS enolates.
Lewis base moieties and trimethylsilyl enolates proceeded
smoothly to afford the corresponding aldols in good to high
yields. It is noted that various functionalized aldols can be direct-
ly obtained without protection of functional groups in the above
reaction.
In the first place, aldehyde 2a was generated in situ3 and its
reaction with TMS enolate 1 was tried at ꢁ45 ꢂC in DMF. Ex-
pectedly, 2a did not effectively activate 1 at ꢁ45 ꢂC and the re-
action was very slow whereas the aldol adduct was obtained in
high yield at ꢁ20 ꢂC.4 On the other hand, the aldol reaction pro-
ceeded smoothly at ꢁ45 ꢂC to afford the corresponding aldol in
high yield when tetrabutylammonium salt 2b5 was used instead
of 2a (Scheme 1).
Recently, new Lewis base-catalyzed aldol reactions be-
tween trimethylsilyl (TMS) enolates and aldehydes in a N,N-di-
methylformamide (DMF) solvent were reported from our labora-
tory, which afforded the corresponding aldols in high yields by
using Lewis bases such as lithium diphenylamide, lithium pyrro-
lidone or lithium acetate (AcOLi).1 In addition, an effective aldol
reaction was established in water-containing DMF by using
AcOLi catalyst.2 One of the most characteristic points of this re-
action is that the aldehyde having acidic hydrogen such as car-
boxylic acid smoothly reacted to afford the desired aldol in mod-
erate yield (Eq 1).
OH
O
OSiMe3
OMe
H+
2a
or
2b
OMe
+
DMF, 1 h
CHO
HO2C
1
2a: −45 °C, 29%, −20 °C, 89%
2b: −45 °C, 86%
(1.4 equiv.)
LiO2C
Bu4NO2C
CHO
Lewis Base
Lewis Base
OSiMe3
OH
O
AcOLi (10 mol%)
2b
2a
(1)
RCHO
+
OMe
DMF−H2O
(Volume ratio 50:1)
R
OMe
Scheme 1. Self-promoted aldol reaction between silyl enolate 1 and
aldehydes having carboxylic acid salt moieties.
52%
1
rt, 24 h
−45 °C
(2 equiv.)
Next, the reactions of TMS enolate 1 with aldehydes having
various Lewis base moieties were tried (see Table 1).6 Similarly,
2-formylbenzoic acid salts 2c and 2d reacted smoothly to afford
the corresponding ꢀ-lactones (Entries 1 and 2). When the nucle-
ophilic abilities of anions in aldehydes were higher than that of
carboxylate anion, lithium or sodium salts such as 2e–2h activat-
ed 1 effectively at ꢁ45 ꢂC and the reactions proceeded smoothly
to afford the aldol adducts in high yields (Entries 3–6). The most
characteristic point of the present reaction is that various func-
tionalized aldols having acetamide, sulfonamide and indole moi-
eties were obtained in high yields by one pot reaction without
protecting their functional groups (Entries 4–6).
This aldol reaction can be performed smoothly by using oth-
er TMS enolates. For example, TMS enolates derived from S-
tert-butyl isobutanethioate and acetophenone afforded the corre-
sponding aldols in good to high yields. Moreover, the present re-
action can also be applied to that in water-containing DMF by
using 2b and the desired aldol was obtained in good yield
(Scheme 2).
CO H
2
R=
In order to improve the yield, this reaction was examined
under non-aqueous condition at ꢁ45 ꢂC for 3 h. However, the al-
dol adduct was obtained only in 23 and 35% yields, when 10 and
140 mol % of AcOLi were used, respectively. It was then as-
sumed that the proton transfer from 4-formylbenzoic acid to
AcOLi took place rapidly to let aldehyde 2a behave as Lewis
base (Eq 2). The aldehyde 2a did not effectively activate TMS
enolate 1, which was derived from methyl isobutylate at
ꢁ45 ꢂC because of its low nucleophilic ability compared to that
of AcOLi. The enolate 1 was decomposed by free carboxylic
acids before the aldol reaction and thus the yield of this reaction
lowered under non-aqueous condition at ꢁ45 ꢂC.
AcOLi
(2)
+ AcOH
CHO
HO2C
LiO2C
CHO
2a
Next, the aldol reaction between TMS enolate 1 and an
equivalent molar amount of 2a was planned. It was considered
that the aldehyde 2a having metallated lithium carboxylate
would behave as a Lewis base catalyst and decomposition of 1
would be prevented by using an equivalent molar amount of
2a. From a synthetic point of view, this aldol reaction excels
in affording the corresponding aldol without protecting function-
al groups of various substrates when the metallation is carried
out in situ. In this communication, we would like to report on
The reaction mechanism of the present self-promoted aldol
reaction using aldehydes having Lewis base moiety is assumed
to proceed by a pathway similar to that of previously-reported
Lewis baes-catalyzed aldol reactions.1c Namely, Lewis base
moieties of the substrates and DMF coordinated to silyl enolates
to proceed the reaction via a hexacoodinated hypervalent silicate
to afford lithium aldolate. Subsequent silylation of lithium aldo-
Copyright Ó 2004 The Chemical Society of Japan

Chemistry Letters Vol.33, No.2 (2004)
93
Table 1. Aldol reactions using aldehydes having various Lewis Base
moietyies.a
NaH
(0.9 equiv.)
OSiMe3
OMe
Ac
HN
2f
+
CHO
OSiMe3
OMe
1
OH
O
DMF, 0 °C
0.5 h
DMF
−45 °C, 0.5 h
O
1) DMF, −45 °C, Time
+
1
2) 1N HCl aq
THF, rt
R'
OMe
R
H
(1.4 equiv.)
Me3SiO
O
Yieldb /%
99d
BnBr
(1.4 equiv.)
Aldehyde
Entry
1c
Time /h
1
R'
OMe
CHO
DMF
−45 °C, 0.5 h
Ac
2c
2d
N
Na
CO2Li
CHO
OH
O
CO2H
91d
2
1
1N HClaq
THF, rt
OMe
CO2NBu4
Ac
3
4
94e
99
N
LiO
Ac
CHO 2e
CHO 2f
1
HO
Bn
96% (based on NaH)
Scheme 3. Three component coupling reaction.
Ac
0.5
N
HN
Na
CHO
the reaction by TLC, alkylation was found to proceed smoothly
at acetamide moiety and the three-component-coupling product
was obtained in high yield, as expected (Scheme 3).
Thus, self-promoted aldol reaction between aldehydes hav-
ing Lewis base moieties and TMS enolates was established. This
method is quite practical to the syntheses of various funtional-
ized aldols as it proceeded conveniently without protecting their
functional groups and can be applied to one-pot three-compo-
nent-coupling reactions. Further development of this reaction
is now in progress.
96e,f
2g
5
6
0.5
N
H
N
Na
CHO
PhO2S
2h 0.5 PhO2S
93e
N
N
H
Na
aAll reactions were carried out with molar ratio of aldehyde:metallat-
ing reagent:1 = 1:0.9:1.4. See refs. 3,5 and 6 for preparetions of Lewis
base moieties. bYield was determined by 1H-NMR analysis
(270 MHz) using 1,1,2,2-tetrachloroethane as an internal standard.
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.
cReaction was carried out at ꢁ20 ꢂC. Product was obtained as a ꢀ-
d
lactone. eIsolated yield. fProduct was obtained as a silyl ether without
carring out a desilylation step.
References and Notes
OH
O
OSiMe3
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).
H+
2e
St-Bu
+
St-Bu
DMF
−20 °C, 1 h
HO
2
3
T. Nakagawa, H. Fujisawa, and T. Mukaiyama, Chem. Lett., 32, 696 (2003).
Lithium salt was prepared from carboxylic acid (0.4 mmol) and lithium
ethoxide (freshly prepared from dry EtOH and n-BuLi) (0.36 mmol) in THF.
After solvent was removed under reduced pressure, the residue was used
without further purification.
96%
O
(1.4 equiv.)
O
O
H+
OSiMe3
Ph
2c
+
4
5
6
In the case of aldol reaction between silyl enolate 1 and benzaldehyde in DMF
at ꢁ19 ꢂC for 1 h, 1 was activated by DMF and the corresponding aldol was
obtained in 43% yield without adding any catalyst (See Ref. 1a). The result
of present reaction clearly indicates that 1 was activated effectively by 2a in
DMF at ꢁ20 ꢂC.
DMF
rt, 2 h
Ph
(1.4 equiv.)
79%
OH
O
OSiMe3
OMe
Tetrabutylammonium salt was prepared by treating carboxylic acid (0.4 mmol)
with methanol solution of tetrabutylammonium hydroxide (0.36 mmol) in
THF. After solvent was removed under reduced pressure, the residue was
azeotroped with toluene (1.0 mL, twice) and was used without further
purification.
OMe
2b+
DMF−H2O
(Volume ratio 50:1)
HO2C
1
72%
(2 equiv.)
−45 °C, 2 h
Typical experimental procedure is as follows (Table 1, Entry 6): to a stirred
suspension of NaH (55% in oil, 15.7 mg, 0.36 mmol) in DMF (0.2 mL) was
Scheme 2. Self-promoted aldol reaction using various silyl enolates.
added
a
solution of N-(4-formylphenyl)benzenesulfonamide7 (104.5 mg,
0.4 mmol) in DMF (0.6 mL) at 0 ꢂC and the mixture was stirred for 0.5 h. After
the mixture was cooled to ꢁ45 ꢂC, a solution of silyl enolate 1 (97.6 mg,
0.56 mmol) in DMF (1.0 mL) was added and the mixture was stirred for
0.5 h at the same temperature. The mixture was quenched with saturated aque-
ous NH4Cl, 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 mix-
ture 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 (134.8 mg, 93%) as a white powder.
A. Tanaka, T. Terasawa, H. Hagihara, Y. Sakuma, N. Ishibe, M. Sawada, H.
Takasugi, and H. Tanaka, Bioorg. Med. Chem., 6, 15 (1998).
late by thus-formed silylated Lewis base afforded O-silyl ether
along the regeneration of Lewis base. In the present aldol reac-
tion, a product is formed as an O-silyl ether that has metallated
Lewis base moiety. So, further bond formation at Lewis base
moiety is possible by quenching the reaction with electrophiles
other than water. Actually, the aldehyde having Lewis base moi-
ety 2f was generated in situ and the subsequent reaction between
silyl enolate 1 and 2f was tried in a usual manner. By adding ben-
zyl bromide to the reaction mixture after checking completion of
7
Published on the web (Advance View) December 27, 2003; DOI 10.1246/cl.2004.92