Lithium acetate-catalyzed crossed aldol reaction between aldehydes and trimethylsilyl enolates generated from other aldehydes

Article abstract of DOI:10.1246/cl.2005.614

Crossed aldol reaction between aromatic aldehydes having an electron-withdrawing group and trimethylsilyl enolates generated from several aldehydes proceeded smoothly in dry or water-containing DMF in the presence of a catalytic amount of a Lewis base such as lithium acetate or lithium benzoate. Successive reduction of the produced aldehydes with sodium borohydride (NaBH₄) afforded the corresponding 1,3-diols in good to high yields in one-pot. Copyright

Full text of DOI:10.1246/cl.2005.614

614
Chemistry Letters Vol.34, No.4 (2005)
Lithium Acetate-catalyzed Crossed Aldol Reaction between Aldehydes
and Trimethylsilyl Enolates Generated from Other Aldehydes
Yoshikazu Kawano,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 February 3, 2005; CL-050156)
Crossed aldol reaction between aromatic aldehydes having
tivities between starting aldehydes and the formed aliphatic al-
dehydes are differentiated since Lewis base catalyzed reaction
occasionally exhibits the higher reactivity toward aromatic alde-
hyde than that of aliphatic one. iii) Formation of ꢀ,ꢁ-unsaturated
carbonyl compounds by successive dehydration of the aldol
adducts is prevented when weak Lewis base catalysts such as
AcOLi are used. In this communication, we would like to report
on the crossed aldol reaction between aldehydes and TMS eno-
lates generated from other aldehydes in the presence of AcOLi.
an electron-withdrawing group and trimethylsilyl enolates gen-
erated from several aldehydes proceeded smoothly in dry or
water-containing DMF in the presence of a catalytic amount of
a Lewis base such as lithium acetate or lithium benzoate. Succes-
sive reduction of the produced aldehydes with sodium borohy-
dride (NaBH4) afforded the corresponding 1,3-diols in good to
high yields in one-pot.
OSiMe3
H
Me3SiO
Ar
O
Aldol reaction is one of most important and useful tools for
the carbon–carbon bond formation in synthetic organic chemis-
try. It is mostly carried out between carbonyl compounds and
enolates generated from a ketone, ester, or amide. However, only
a few examples have been reported on the crossed-aldol reaction
between an aldehyde and an enolate derived from various other
aldehydes.1 The crossed aldol reactions by using Lewis acidic-
metal enolates such as titanium enolates generated from
aldehydes were independently reported by Mahrwald2a–c and
Oshima.2d,e There are a few reports on the aldol reactions by us-
ing a catalytic amount of an activator; for example, MacMillan
et al. reported a direct catalytic crossed-aldol reaction of alde-
hydes by using L-proline as a catalyst.4 Denmark et al. described
the reaction using Lewis acidic-trichlorosilyl enolates of alde-
hydes in the presence of a phosphoramide as a Lewis base cata-
lyst.3 However, the catalytic aldol reaction of an aldehyde eno-
late by using a commonly employed silyl enolate such as TMS
enolate is not yet reported since the produced aldehyde is very
reactive to form an adduct faster than a starting aldehyde in
the presence of a Lewis acid (Scheme 1).
In our previous papers, it was reported that lithium 2-pyr-
rolidone or lithium acetate (AcOLi) was an effective Lewis base
catalyst for the activation of trimethylsilyl (TMS) enolate in al-
dol reaction.5 In order to extent the utilities of this reaction, aldol
reaction by using silyl enolates of aldehydes in the presence of a
catalytic amount of a Lewis base was attempted. The advantages
of a Lewis base catalyst for this reaction are considered as fol-
lows: i) silylation of the formed lithium aldolate takes place rap-
idly to form O-silyl ether that is not activated by a lithium cation.
ii) In the case when aromatic aldehyde was employed, the reac-
O
Cat. (10 mol%)
DMF, rt, 16 h
+
H
Ar
H
2
Ar = 4-NCC6H4
1 (1.4 equiv.)
HO
NaBH4
1N HClaq
Ar
OH
−45 °C
3
Yield of 3 : AcOLi (90), PhCO2Li (91), CF3CO2Li (29), CF3SO3Li (27),
AcONa (86), AcOK (85), AcONn-Bu4 (93), AcONn-Bu4 (81a)
aReaction was carried out in THF.
Scheme 2.
Table 1. AcOLi-catalyzed aldol reaction of various aldehydes
OSiMe3
AcOLi
HO
O
NaBH4
(10 mol%)
+
H
R
OH
DMF, rt, Time
R
H
1 (1.4 equiv.)
Time Yielda
Time Yielda
Entry
R
Entry
R
/h
/%
/h
/%
1
2
3
4
5
4-MeOC6H4 41 traceb
6
7
8
9
4-MeO2CC6H4 16
83
87
73
83
24c
C6H5
40
40
16
16
40b
76b
90
4-NO2C6H4
2-Furyl
16
16
17
41
4-ClC6H4
4-NCC6H4
4-CF3C6H4
2-Quinolyl
87
10 PhCH2CH2
aYield was determined by 1H NMR analysis (270 MHz) using Cl2HCCH-
Cl2 as an internal standard. b2.0 equiv. of 1 were used. cIsolated yield.
In the first place, the reaction of 4-cyanobenzaldehyde and
TMS enolate 1 derived from 2-methylpropionaldehyde was tried
in the presence of 10 mol % of AcOLi at room temperature in
DMF and the successive reduction of the formed aldehyde with
NaBH4 in situ gave the corresponding 1,3-diol in 90% yield.6
Next, the effects of various lithium carboxylates or sulfonates
were examined as shown in Scheme 2. The acetate and benzoate
anions turned out to be effective promoters for the acceleration
of this reaction. The acetates having such counter cations as so-
dium, potassium or ammonium ion also worked effectively and
the desired 1,3-diols were obtained in good yields. Also, the re-
action was performed smoothly in THF by using AcONn-Bu4 as
a catalyst. In all cases, the products were isolated and analyzed
Lewis acid
Lewis base
L.B.
M
Me3Si
O
Activated
by Lewis Acid
O
O
O
O
SiMe3
O
Ar
H
R
H
Me3SiO
R'
R'
H
R'
R'
R
H
O
High Reactivity toward
Aromatic Aldehyde
H
Ar
H
Scheme 1.
Copyright Ó 2005 The Chemical Society of Japan

Chemistry Letters Vol.34, No.4 (2005)
615
as 1,3-diols after the reduction of thus formed aldehydes with
NaBH4 because the 3-hydroxyaldehydes are unstable and de-
composed rapidly.3
(50:1) and the following by reduction afforded the corresponding
1,3-diols in high yields (Entries 1–3 and 6). The reaction pro-
ceeded to afford the adduct in a moderate yield even when the
reaction was carried out in DMF–H2O (2:1) (Entry 5).
Thus, it is noted that the AcOLi-catalyzed aldol reaction us-
ing TMS enolates derived from aldehydes proceeded smoothly
under weakly basic conditions in dry DMF or water-containing
DMF, and the subsequent reduction of the formed aldehydes
with NaBH4 afforded the corresponding 1,3-diols in good to high
yields. This method is practically applicable for the synthesis of
various 1,3-diols in a one-pot procedure. Further investigation
on this reaction is now in progress.
Next, the reaction of TMS enolate 1 with various aldehydes
was tried by using AcOLi in DMF (Table 1). Aromatic alde-
hydes having electron-donating groups or aliphatic aldehydes af-
forded the corresponding 1,3-diols in low yields (Entries 1, 2,
and 10). On the other hand, when the aromatic aldehydes having
electron-withdrawing groups were used as acceptors, the reac-
tions proceeded smoothly and the corresponding 1,3-diols were
afforded in good yields (Entries 3–9). It is noteworthy to point
out that the corresponding 1,3-diol was also obtained in good
yield when an aldehyde having a basic function in the same
molecule was used (Entry 9).
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.
Table 2. Aldol reaction using various silyl enolates
O
OSiMe3
OH
AcOLi
(10 mol%)
NaBH4
+
References and Notes
1
R
Ar
H
Ar
OH
H
Using Lewis acid: a) T. Mukaiyama, K. Banno, and K. Narasaka,
J. Am. Chem. Soc., 96, 7503 (1974). b) T. Mukaiyama and T.
Inoue, Chem. Lett., 1976, 559. Via metal enolate: c) C. H.
Heathcock, C. T. Buse, W. A. Kleschick, M. C. Pirrung, J. E. Sohn,
and J. Lampe, J. Org. Chem., 45, 1066 (1980). d) E. Nakamura,
S. Yamago, D. Machii, and I. Kuwajima, Tetrahedron Lett., 29,
2207 (1988). Via enamine: e) G. Wittig and A. Hesse, Org. Synth.,
Coll. Vol. VI, 526 (1988). f) C. F. Barbas, III, Y.-F. Wang, and
C.-H. Wong, J. Am. Chem. Soc., 112, 2013 (1990). g) H. J. M.
Gijsen and C.-H. Wong, J. Am. Chem. Soc., 116, 8422 (1994).
Via titanium enolate: a) R. Mahrwald, B. Costisella, and B.
DMF, Temp.
Time
R
Ar = 4-NCC6H4
(1.4 equiv.)
Entry
R
Temp./ꢁC Time/h Yielda/% syn:antib
1
2
3
4
5
Me (E:Z = 1:4)
Et (E:Z = 1:3)
Bn (E:Z = 1:2)
i-Pr (E:Z = 1:4)
H
0
0
16
17
17
16
16
84
82
87
72
79
57:43
51:49
50:50
33:67
—
0
0
ꢂ45
aYield was determined by 1H NMR analysis (270 MHz) using Cl2HC-
CHCl2 as an internal standard. bDetermined by 1H NMR analysis
(270 MHz).
2
Gundogan, Tetrahedron Lett., 38, 4543 (1997). b) R. Mahrwald,
¨
Mahrwald and B. Gundogan, Chem. Commun., 1998, 2273.
¨
B. Costisella, and B. Gundogan, Synthesis, 1998, 262. c) R.
¨
The lithium acetate-catalyzed aldol reaction was further ex-
amined by using various silyl enolates (Table 2). The reactions
proceeded smoothly at 0 ꢁC in DMF to afford the corresponding
1,3-diols in good yields while the diastereoselectivities were low
(Entries 1–4). Interestingly, when vinyloxytrimethylsilane giv-
ing highly reactive primary aldehyde was employed, the reaction
proceeded smoothly at ꢂ45 ꢁC without accompanying any by-
products (Entry 5).
It was reported that the acetate anion worked as an effective
catalyst of aldol reaction in water-containing organic solvent.
However, the reaction by using silyl enolate derived from an al-
dehyde has not been tried in aqueous media yet. Then, reaction
in water-containing DMF was tried and it was found that the
yield of 1,3-diols increased a little more than that in dry DMF
(Table 3). When the reactions were carried out in DMF–H2O
d) K. Yachi, H. Shinokubo, and K. Oshima, J. Am. Chem. Soc.,
121, 9465 (1999). e) Z. Han, H. Yorimitsu, H. Shinokubo, and
K. Oshima, Tetrahedron Lett., 41, 4415 (2000).
3
4
5
Catalytic enantioselective crossed aldol reaction: S. E. Denmark
and S. K. Ghosh, Angew. Chem., Int. Ed., 40, 4759 (2001).
Direct enantioselective crossed aldol reaction: A. B. Northrup and
D. W. C. MacMillan, J. Am. Chem. Soc., 124, 6798 (2002).
Aldol reaction: 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. Nakagawa, H. Fujisawa, Y. Nagata, and T.
Mukaiyama, Bull. Chem. Soc. Jpn., 77, 1555 (2004). h) H.
Fujisawa, T. Nakagawa, and T. Mukaiyama, Adv. Synth. Catal.,
346, 1241 (2004).
A typical experimental procedure is as follows (Table 1, Entry 1);
to a stirred solution of AcOLi (2.6 mg, 0.04 mmol) in DMF (0.4
mL) were added successively a solution of TMS enolate 1 (80.8
mg, 0.56 mmol) in DMF (0.6 mL) and a solution of 4-cyano-
benzaldehyde (52.5 mg, 0.4 mmol) in DMF (1.5 mL) at room
temperature. The mixture was stirred for 16 h at room temperature
and quenched with aqueous HCl (1.0 M, 0.3 mL) at ꢂ45 ꢁC and
stirred an additional 1 h. Then saturated aqueous NaHCO3 (0.6
mL), MeOH (2.0 mL) and NaBH4 were added. The reaction mix-
ture was warmed slowly to room temperature and after stirring for
16 h at the same temperature, and it was quenched with saturated
aq NH4Cl. The mixture was extracted with EtOAc and organic
layer was washed with brine and dried over anhydrous Na2SO4.
After filtration and evaporation of the solvent, the crude product
was purified by preparative TLC to afford the corresponding
1,3-diol (74.0 mg, 90%) as an colorless oil.
Table 3. Aldol reaction using AcOLi in DMF–H2O
6
OSiMe3
HO
O
AcOLi (10 mol%) NaBH4
+
H
1 ( 1.4 equiv. )
R
R
OH
Temp., Time
R
H
DMF−H2O
Entry
DMF:H2Oa Temp./ꢁC Time/h Yieldb/%
1
2
3
4
5
6
4-NCCC6H4
50:1
50:1
50:1
5:1
rt
0
16
16
16
16
16
17
91
4-MeO2CC6H4
4-NO2C6H4
4-NO2C6H4
4-NO2C6H4
2-Quinolyl
90
rt
rt
rt
0
94
95c
58c
87
2:1
50:1
aVolume ratio. bYield was determined by 1H NMR analysis (270 MHz)
using Cl2HCCHCl2 as an internal standard. c2.0 equiv. of 1 were used.
Published on the web (Advance View) March 25, 2005; DOI 10.1246/cl.2005.614