Lewis base catalyzed aldol reaction of trimethylsilyl enolates with aldehydes

Article abstract of DOI:10.1002/hlca.200290025

A new Lewis base catalyzed aldol reaction of trimethylsilyl enolates with aldehydes is established in DMF or pyridine solvent by using a Lewis base such as lithium diphenylamide (Tables 4 and 5) or lithium 2-pyrrolidone (Tables 6-8). The effect of solvent

Full text of DOI:10.1002/hlca.200290025

4518
Helvetica Chimica Acta Vol. 85 (2002)
Lewis Base Catalyzed Aldol Reaction of Trimethylsilyl Enolates with
Aldehydes
by Teruaki Mukaiyama*, Hidehiko Fujisawa, and Takashi Nakagawa
The Kitasato Institute, Center for Basic Research, TCI, 6-15-5, Toshima, Kita-ku, Tokyo 114-0003, Japan
Dedicated to Professor Dr. Dieter Seebach on the occasion of his 65th birthday
A new Lewis base catalyzed aldol reaction of trimethylsilyl enolates with aldehydes is established in DMF
or pyridine solvent by using a Lewis base such as lithium diphenylamide (Tables 4 and 5) or lithium 2-
pyrrolidone (Tables 6 8). The effect of solvent suggests that this reaction proceeds via the pentacoordinated
hypervalent silicate generated by the coordination of the above Lewis base to a trimethylsilyl enolate.
Successive coordination of the solvent to the thus-formed pentacoordinated silicate leads to an active enolate
intermediate having hexacoordinated silicate, which, in turn, attacks carbonyl compounds to form the desired
aldols (Scheme 5).
1. Introduction. The aldol reaction is one of the most important tools for CÀC
bond-formation and is frequently employed in synthetic organic chemistry (for reviews,
see [1]). Reactions involving silyl enolates, aldol donors, have become very popular
since the crossed aldol reaction between silyl enolates and aldehydes promoted by
Lewis acids was reported from our laboratory [2], and they are frequently employed in
the construction of C-skeletons. There are also reaction patterns of silyl enolates with
aldehydes without using any Lewis acids. For example, reactions via metal enolates
formed by transmetallation of silyl enolates with various metal salts including its
original MeLi [3] to the recent transition metal catalysts [4], and also those via enolate
anions generated by nucleophilic cleavage of the OÀSi bond with a fluoride ion [5] or
phosphines [6]. Reactions of silyl enolates such as trichlorosilyl enolates [7],
dimethyl(trifloxy)silyl enolates [8], enoxysilacyclobutanes [9], and dimethylsilyl
enolates [10] that readily form hypervalent silicates with acceptor aldehydes were
shown to proceed even in the absence of catalysts. Moreover, reactions of silyl ketene
acetals with aldehydes were carried out in H2O [11], DMSO, DMF, and DME [12], and
under high pressure [13]. Recently, several methods to activate silyl enolate by using
Lewis bases were established: Denmark and Stavenger introduced a Lewis base-
catalyzed aldol reaction of trichlorosilyl enolates with aldehydes by using phosphor-
amides [7], and Hosomi and co-workers reported a reaction by using a combination of
dimethylsilyl enolate and CaCl2 in aqueous DMF [14]. In these Lewis base catalyzed
aldol reactions, several silyl enolates with an enhanced Lewis acidic Si-atom interacted
with Lewis bases more readily. Now, to activate simple and popular silyl enolates such
as trimethylsilyl enolates, exploration of newer Lewis base catalysts was planned. In
this paper, we would like to describe a new catalytic aldol reaction of trimethylsilyl
enolates with aldehydes by using the Lewis base catalysts lithium diphenylamide
(LiNPh2) [15] and lithium 2-pyrrolidone [16].

Helvetica Chimica Acta Vol. 85 (2002)
4519
2. Results and Discussion. 2.1. Activation of Trimethylsilyl Enolate by Lithium
Amide. Lithium amides derived from the hindered amines, e.g., lithium diisopropyla-
mide (LDA), were known to behave as strong bases with low nucleophilicity and were
often employed in the formation of enolates from carbonyl compounds, or of lithiated
C-skeletons. Conventionally, such amides were employed only as Br˘nsted bases and
have never been used as the Lewis bases to generate an active trimethylsilyl enolate
having a hypervalent silicate.
Aldol reaction of a trimethylsilyl enolate derived from methyl isopropionate
with benzaldehyde (PhCHO) was tried in THF by using 1.4 equiv. of the lithium
amide as an activator. The reaction then proceeded to afford the aldol adduct in
24% yield, suggesting that the amides would be able to promote the above aldol
reaction (Table 1, Entry 2). Next, the effect of various lithium amides was screened
to establish an effective lithium amide mediated aldol reaction under the above
conditions by taking the reaction of trimethylsilyl enolate derived from methyl
isopropionate with PhCHO as a model reaction. Of all lithium amides screened
lithium diphenylamide (LiNPh2) turned out to be most effective, as shown in
Table 1.
Then, the following control experiments were tried to clarify the effect of LiNPh2 on
this reaction (Scheme 1). When lithium enolate generated from trimethylsilyl enolate
and MeLi were allowed to react under the above conditions, the aldol adduct was
obtained in low yield. Since the application of LiNPh2 alone did not generate the
lithium enolate, it was noted that the above lithium enolate was not the key
intermediate of this reaction. Also, the reaction did not take place when 1.5 equiv. of
weakly basic Ph2NH were used in place of the above LiNPh2; therefore, it is noted that
Ph2NH itself is not a promoter of the aldol reaction.
Thereafter, LiNPh2 was chosen as one of the catalysts of the present aldol reaction.
2.2. Catalytic Aldol Reaction with LiNPh2 as Lewis Base. Next, several catalytic
aldol reactions were tried by using LiNPh2 as the Lewis base. When the above reaction
was carried out in THF solvent with 20 mol-% of LiNPh2, aldol adduct was obtained
in 15% yield. This indicated that a stoichiometric amount of LiNPh2 was required
for the completion of the reaction. The aldol adducts thus formed after quenching
were a mixture of aldol (R ˆ H, 1) and O-silyl ether (R ˆ Me3Si (TMS), 2), which
suggested the existence of both lithium aldolate and O-silyl ether. In addition,
it was noted in all cases that the amount of O-silyl ether formed was less than that
of the aldol in THF irrespective of the kind of lithium amide employed (Table 1).
To establish a catalytic aldol reaction, the aldol adduct should be transformed
to its O-silyl ether rapidly. Lithium aldolate was formed along with silyl amide, and it
showed that a catalytic aldol reaction did not take place under the above conditions.
The silyl amide was regarded as a silylating reagent, and silylation of the lithium
aldolate by the thus-formed silyl amide was expected to afford O-silyl ether along with
the regeneration of lithium amide when suitable reaction conditions were chosen
(Scheme 2).
Since it was assumed that solvents influenced the silyl transfer of silyl amide to the
lithium aldolate [1a][17], various solvents were further screened to obtain higher yields
and higher O-silyl ether to aldol ratios (Table 1). It was found that DMF (H/TMS 1:35)
and pyridine (H/TMS 1:6) were excellent solvents to afford the aldol adducts in

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Helvetica Chimica Acta Vol. 85 (2002)
Table 1. Lithium Amide Mediated Aldol Reaction of Trimethylsilyl Enolate and Benzaldehydea)
Entry
Amine
Yieldb)/%
SMRc)/%
1/2
1
2
Et2NH
(i-Pr)2NH
35
24
6
3
3 : 1
2 : 1
3
4
35
67
8
2 : 1
4 : 1
18
5
6
7
8
9
(Me3Si)2NH
BnNH2
Ph2NH
(4-MeOC6H4)NH2
(4-MeOC6H4)2NH
trace
62
81
66
62
17
5
n.d.
trace
5
3 : 1
9 : 5
2 : 1
6 : 5
3 : 2
10
58
trace
8 : 5
11
12
58
70
18
10
3 : 2
7: 5
Me2N(CH2)2NHMe
a
)
b) Yields were determined by 1H-NMR analysis (270 MHz) with 1,1,2,2-tetrachloroethane as an internal
standard. c) Starting material recovered.
quantitative yields (Table 2). The possibility to establish a catalytic cycle was suggested
because the major product in these reactions was O-silyl ether.
¬
Recently, Genisson and Gorrichon reported that the aldol reaction of this
combination proceeded −spontaneously× in DMSO, DME, and DMF at room temper-
ature [12]. To examine the effect of LiNPh2 catalyst on the present reaction, the
conditions under which the reaction did not proceed in those solvents alone were
examined. As a result, the reaction proceeded neither in DMF at the temperatures
below À 458 nor in pyridine at 08 (Table 3).
Then, the same reaction was tried by adding 5 mol-% of LiNPh2 in DMF at À 458,
and the desired aldol was obtained in 80% yield along with 18% of the starting
material. Likewise, the aldol adduct was obtained in quantitative yield when the
reaction was carried out at 08 with 20 mol-% of LiNPh2 in pyridine (Scheme 3).

Helvetica Chimica Acta Vol. 85 (2002)
4521
Scheme 1
OSiMe3
OR
O
O
O
MeLi (1.4 equiv.)
+
+
OMe
Ph
Ph
OMe
THF, 0°, 3 h
Ph
Ph
H
H
(1.4 equiv.)
36%
1 : 2 = 2 : 1
OSiMe3
OR
O
Ph2NH (1.5 equiv.)
OMe
OMe
THF, 0°, 3 h
(1.4 equiv.)
n.d.
1 R = H, 2 R = SiMe3
Scheme 2
Me3Si
Li
O
O
O
O
Li NPh2
+
Me3Si NPh2
+
Ph
OMe
Ph
OMe
Solvent effect
regeneration of catalyst
Table 2. Effect of Solvent on the LiNPh2-Mediated Aldol Reaction of Trimethylsilyl Enolate and
Benzaldehydea)
Entry
Solvent
Yieldb)/%
1/2
1
2
3
4
5
6
7
8
THF
Et2O
81
n.d.
6
7
n.d.
47
2 : 1
CH2Cl2
Toluene
Hexane
MeCN
DMF
5 : 7
1 : 12
1 : 9
1 : 35
1 : 6
96
quant
Pyridine
a
)
OSiMe3
OMe
1)Ph2NH (1.5 equiv.)
2)MeLi (1.4 equiv.)
OR
O
O
+
Ph
OMe
Ph
H
THF, 0°, 3 h
(1.4 equiv.)
1 R = H
2 R = Me3Si
b) Yields were determined by 1H-NMR analysis (270 MHz) with 1,1,2,2-tetrachloroethane as an internal
standard.

4522
Helvetica Chimica Acta Vol. 85 (2002)
Table 3. Effect of Solvent andTemperature on the Spontaneous Aldol Reaction of Trimethylsilyl Enolate and
Benzaldehydea)
Entry
Solvent
Temp./8
Time/h
Yieldb)/%
1
2
3
4
DMF
DMF
DMF
Pyridine
0
À 19
À 45
0
1
1
1
4
84
43
trace
n.d.
a
)
OSiMe3
OMe
OR
O
O
+
Ph
OMe
Solv., Temp., Time
Ph
H
(1.4 equiv.)
1 R = H
2 R = Me3Si
b) Yields were determined by 1H-NMR analysis (270 MHz) with 1,1,2,2-tetrachloroethane as an internal
standard.
Apparently, these results indicated that LiNPh2 did behave as an effective catalyst in
promoting the present aldol reaction in DMF or pyridine.
2.3. LiNPh2-Catalyzed Aldol Reaction between Trimethylsilyl Enolate and Alde-
hydes. Taking these results into consideration, reactions with other aldehydes were
tried, and the results are summarized in Table 4. Here, a trimethylsilyl enolate derived
from methyl isopropionate reacted smoothly with various aromatic aldehydes to afford
the corresponding aldols in high yields. Either aromatic aldehydes, which have an
electron-withdrawing group such as 4-nitrobenzaldehyde, or aliphatic aldehydes also
afforded the desired aldol adducts in moderate yields. When a conjugated aldehyde was
used, 1,2- and 1,4-addition reactions took place simultaneously in DMF, while the aldol
adduct was exclusively formed in high yield without accompanying 1,4-adduct in
pyridine.
Next, the LiNPh2-catalyzed aldol reaction with several silyl enolates was studied
(Table 5). In the first place, enolates generated either from S-ethyl ethanethioate or
Scheme 3
OSiMe3
OMe
OR
O
O
O
LiNPh2 (5 mol-%)
+
+
Ph
Ph
OMe
OMe
DMF, -45°, 3 h
Ph
Ph
H
H
(1.4 equiv.)
OSiMe3
80%
OR
O
LiNPh2 (20 mol-%)
OMe
Pyridine, 0°, 3 h
(1.4 equiv.)
quant
R : H, TMS

Helvetica Chimica Acta Vol. 85 (2002)
4523
Table 4. LiNPh2 Catalyzed Aldol Reaction of Trimethylsilyl Enolate and Aldehydesa)
Entry
Aldehyde
Solv.
Temp./8
Time/h
Product
Yieldb)/%
1
2
DMF
Pyridine
À 45
1
7
3
3
96
98
0
3
4
DMF
Pyridine
À 45
1
1
4
4
98
97
0
5
6
DMF
Pyridine
À 45
1
6
5
5
97
95
0
7
DMF
À 45
1
6
70c)
8
9
DMF
Pyridine
À 45
1
6
7, 8
7, 8
99 (12 : 1)c)d)
96 (100 : 0)c)d)
0
10
DMF
À 45
2
9
60
a
)
OSiMe3
OMe
OH
O
O
+
H
Ph2NLi (20 mol-%)
Solv., Temp., Time
1N HClaq
THF, r.t.
R
OMe
R
(1.4 equiv.)
3-9
OH
O
OH
O
OH
O
OMe
OMe
OMe
MeO
3
OH
4
5
8
O
OH
O
O
Ph
O
OMe
Ph
OMe
MeO
H
O2N
Ph
6
7
OH
O
OMe
9
c
b) Isolated yield. ) Yields were determined by H-NMR analysis (270 MHz) with 1,1,2,2-tetrachloroethane as
1
an internal standard. d) In parentheses, the ratio 7/8.

4524
Helvetica Chimica Acta Vol. 85 (2002)
Table 5. LiNPh2 Catalyzed Aldol Reaction of Trimethylsilyl Enolate and Benzaldehydea)
Entry
1
Silyl enolate
Temp./8
Time/h
Product
Yieldb)/%
syn/anti
À 45
2
10
95
2
3
À 45
5
5
11
11
93c )
8c )
0
4
5
À 45
À 45
5
5
12
12
41
79
1.9 : 1
2.7: 1
a
)
b) Yields were determined by 1H-NMR analysis (270 MHz) with 1,1,2,2-tetrachloroethane as an internal
standard. c) Isolated yield.
Scheme 4
OSiMe3
OMe
OH
O
Lithium 2-pyrrolidone
(5 mol-%)
O
1N HClaq
THF, r.t.
+
Ph
OMe
Ph
H
DMF, –45°, 2 h
(1.4 equiv.)
95%
acetophenone were allowed to react with PhCHO in the presence of a catalytic amount
of LiNPh2, and the corresponding aldol adducts were obtained in good yields (Entries 1
and 2). Further, it was observed that the silyl enolate derived from methyl propionate
gave aldols with moderate syn-diastereoselectivity irrespective of the geometry of the
two isomeric silyl enolates (Entries 4 and 5).
2.4. Lithium 2-Pyrrolidone-Catalyzed Aldol Reaction between Trimethylsilyl
Enolates and Aldehydes. It turned out that LiNPh2 is an effective Lewis base catalyst
for the aldol reaction of several trimethylsilyl enolates with various aldehydes in DMF

Helvetica Chimica Acta Vol. 85 (2002)
4525
Table 6. Lithium 2-Pyrrolidone Catalyzed Aldol Reaction of Trimethylsilyl Enolate and Aldehydesa)
Entry
Aldehyde
Solv.
Temp./8
Time/h
Product
Yieldb)/%
1
2
DMF
Pyridine
À 45
1.5
3
3
3
95
93
0
3
4
DMF
Pyridine
À 45
2
3
4
4
92
95
0
5
6
DMF
Pyridine
À 45
4
5
5
5
91c)
83c )
0
7
DMF
À 45 ! r.t.
3 d
6
57
8
9
DMF
Pyridine
À 45
3
5
13
13
78
89
0
10
11
DMF
Pyridine
À 45
2
30
14
14
87
82
0
12
13
DMF
Pyridine
À 45
3
30
15
15
92
88
0
14
DMF
À 45
4
9
55c )
a
)
b) Yields were determined by 1H-NMR analysis (270 MHz) with 1,1,2,2-tetrachloroethane as an internal
standard. c) Isolated yields.

4526
Helvetica Chimica Acta Vol. 85 (2002)
Table 7. Lithium 2-Pyrrolidone Catalyzed Aldol Reaction of Trimethylsilyl Enolate and Aldehydes with Basic
Parta)
Entry
Aldehyde
Time/h
Product
Yieldb)/%
1
1
16
97
2
3
2
3
17
18
91
97c )
a
)
b) Yields were determined by 1H-NMR analysis (270 MHz) with 1,1,2,2-tetrachloroethane as an internal
standard. c) Isolated yield.
or pyridine. The above catalyst, however, has some problems in separating it from the
resulting reaction mixture. Having as a goal the activation of a simple and popular silyl
enolate such as trimethylsilyl enolate, another Lewis base catalyst that could be easily
removed from an organic layer by simple extraction with H2O was considered. Then,
our attention was focused on a lactam such as 2-pyrrolidone as a precursor of the
catalyst. It is not only easy to dissolve in H2O, it is readily available, inexpensive, and
the pKa value of the NÀH bond is relatively close to that of Ph2NH measured in DMSO
[18]. Thus, a catalytic aldol reaction of trimethylsilyl enolates with aldehydes was tried
in the presence of a catalytic amount of lithium 2-pyrrolidone.
When trimethylsilyl enolate derived from methyl isopropionate and PhCHO was
allowed to react in the presence of a stoichiometric amount of lithium 2-pyrrolidone in
THF at 08, the aldol adduct was obtained in only 39% yield. On the other hand, the
above reaction proceeded smoothly by using a catalytic amount of lithium 2-
pyrrolidone in DMF or pyridine. That is, the reaction was carried out by adding
5 mol-% of lithium 2-pyrrolidone either at À 458 in DMF or at 08 in pyridine, and the
desired aldol was obtained in 95% yield in DMF (Scheme 4) or 78% yield in pyridine.

Helvetica Chimica Acta Vol. 85 (2002)
4527
Table 8. Lithium 2-Pyrrolidone Catalyzed Aldol Reaction of Silyl Enolates and Benzaldehydea)
Entry
1
Silyl enolates
Solv.
Temp./8
Time/h
Product
Yieldb)/%
syn/anti
DMF
À 45
2
10
95
2
DMF
À 45
3
11
77
3
4
DMF
DMF
À 45
À 45
2
3
1
1
95c)
trace
5
6
7
DMF
DMF
Pyridine
À 45
0
À 19 ! 0
3
3
18
12
12
12
42
50
4
63 : 37
62 : 38
62 : 38
8
9
10
DMF
DMF
Pyridine
À 45
0
À 19 ! 0
3
3
18
12
12
12
88
95
70
73 : 27
71 : 29
71 : 29
a
)
b) Yields were determined by 1H-NMR analysis (270 MHz) with 1,1,2,2-tetrachloroethane as an internal
standard. c) 5 mol-% of lithium 2-pyrrolidone was used.
These results indicated that the lithium 2-pyrrolidone as the Lewis base did catalyze the
aldol reaction of trimethylsilyl enolates with aldehydes in DMF or pyridine.
The scope of acceptor aldehydes was further examined by using 10 mol-% of
lithium 2-pyrrolidone in DMF or pyridine (Table 6). Trimethylsilyl enolate derived
from methyl isopropionate smoothly reacted with various aromatic aldehydes to afford
the corresponding aldols in high yields. Either aromatic aldehydes, which have an
electron-withdrawing group such as 4-nitrobenzaldehyde, or aliphatic aldehydes also
afforded the aldol adducts in moderate yields. Thus, the lithium 2-pyrrolidone, like
LiNPh2, behaved as an effective catalyst in aldol reaction.
Lewis base catalyzed reaction exhibits its full power in aldol reaction especially
when aldehydes having basic functions are used. To show the utility of this Lewis base
catalyzed aldol reaction, trimethylsilyl enolates generated from methyl isopropionate
and aldehydes having basic functions were allowed to react in DMF at À 458

4528
Helvetica Chimica Acta Vol. 85 (2002)
in the presence of 10 mol-% of lithium 2-pyrrolidone. The reaction proceeded
smoothly, and the corresponding aldol adducts were obtained in high yields (Table 7).
Several silyl enolates were further employed in this lithium 2-pyrrolildone-
catalyzed aldol reaction (Table 8). In the first place, enolates prepared from S-ethyl
ethanethioate or acetophenone were employed, and the corresponding aldol adducts
were obtained in good yields (Entries 1 and 2). On the other hand, only a trace amount
of the desired aldol was detected when a bulkier silyl derivative such as triethylsilyl
enolate derived from methyl isopropionate was employed (Entry 4) in place of the
above-mentioned trimethylsilyl enolate (Entry 3). Since the reactivity of this aldol was
strongly influenced by the bulkiness of the silyl group of the enolate, the reaction was
assumed to proceed via activation of trimethylsilyl enolates by coordination of the
lithium 2-pyrrolidone catalyst to the Si-atom of the enolate [12]. In addition, the
reaction would proceed mostly via acyclic transition states, since the silyl enolate
derived from methyl propionate was observed to give aldols with moderate syn-
diastereoselectivity irrespective of the geometry of the two isomeric silyl enolates
(Entries 4 9). Thus, the reaction was shown to proceed mostly via acyclic transition
states [10].
It should be noted that the solvent also plays an important role in this aldol reaction.
Nucleophilicity of the amide anion was amplified by coordination of a Lewis basic
solvent such as DMF or pyridine to the lithium ion and resulted in both acceleration of
the aldol reaction and the silylation of the aldolate. To supplement the solvent effect,
the aldol reaction of trimethylsilyl enolate of methyl isopropionate with PhCHO and
5 mol-% of lithium 2-pyrrolidone was performed in pyridine or substituted pyridines
such as 4-picoline, 2-picoline, and 2,6-lutidine, to give yields of 54%, 18%, and trace,
respectively. These results show that the reactivity diminished remarkably when bulky
substituents were present around the N-atom of the solvent; therefore, it is noted that
the coordination of the solvent to the Si-atom plays an important role in this reaction.
Since this reaction in pyridine at 08 did not take place in the absence of catalyst, the
mechanism of the reaction can be explained as follows: in the first place, lithium 2-
pyrrolidone coordinates to the Si-atom of trimethylsilyl enolates to form a pentacoor-
dinated hypervalent silicate; the solvent further coordinates to the Si-atom of thus-
formed pentacoordinated silicate to produce a hexacoordinated hypervalent silicate.
The reactivity of the enolate, therefore, increased enough for it to attack the aldehyde,
forming the desired aldol via acyclic transition states. Subsequent silylation of lithium
aldolate by the thus-formed silyl amide afforded O-silyl ether along with the
regeneration of lithium amide to establish a catalytic cycle (Scheme 5).
3. Conclusions.
In summary, a new Lewis base catalyzed aldol reaction of
trimethylsilyl enolates with aldehydes was established by using Lewis bases such as
LiNPh2 or lithium 2-pyrrolidone in DMF or pyridine solvent.
This work was supported by Grant-in-aidfor Scientific Research from the Ministry of Education, Science,
Sports andCulture , Japan. We thank Mr. H. Kitagawa and Miss S. Miki, Meiji Seika Kaisha, Ltd. for mass-
spectrometry analysis.

Helvetica Chimica Acta Vol. 85 (2002)
4529
Scheme 5
Me3SiO
R
O
OSiMe3
OR'
OR'
Li LB
LB
Si
OLi
O
Li
+
Me3Si LB
O
R
OR'
OR'
LB
Si
Li
Solv
Solvent
O
O
R
H
OR'
LB: diphenylamide or pyrrolidone
Experimental Part
General. All reactions were carried out under an Ar atmosphere in dried glassware. DMF was dried with
P2O5 and then distilled from CaH2 under reduced pressure and dried (molecular sieves (4 ä)). Pyridine was
distilled from P2O5 and dried (KOH). All reagents were purchased from Tokyo Kasei Kogyo, Kanto Chemical,
or Aldrich Chemical. Column chromatography (CC): silica gel 60 (Merck) or Wakogel B5F. M.p.: Yanaco MP-
S3 micro melting-point apparatus. IR Spectra: Horiba FT300 infrared spectrometer; in cmÀ1. NMR Spectra:
JEOL JNM-EX270L spectrometer; CDCl3 solns., with SiMe4 and CHCl3 as internal standard; d in ppm, J in Hz.
High-resolution (HR) MS: JEOL JMS-700 mass spectrometer with 4-nitrobenzyl alcohol and glycerol as
matrix. Elemental analysis: Yanaco MT-6 CHN CORDER.
General Procedure for the LiNPh2 CatalyzedAldol Reaction . To a soln. of Ph2NH (71.6 mg, 0.42 mmol) in
THF (1.5 ml) was added MeLi in Et2O (1.14m, 0.29 ml, 0.30 mmol) at 08 and was stirred for 30 min. After
evaporation of the solvent, DMF (2.0 ml) was added. To the soln. were successively added a soln. of a silyl
enolate (2.4 mmol) in DMF (1.0 ml) and a soln. of aldehyde (1.6 mmol) in DMF (1.2 ml) at À 458. The mixture
was stirred for an appropriate time at À 458, and then sat. aq. NH4Cl was added. The mixture was extracted with
Et2O. After evaporation of the solvent, the residue was dissolved in a mixture of HCl (1.0m, 1.5 ml) and THF
(6 ml). The mixture was stirred for 30 min, extracted with Et2O, and the org. layer was washed with brine and
dried (Na2SO4). After filtration of the mixture and evaporation of the solvent, the crude product was purified by
CC to afford corresponding aldol. Products and yields were as reported in the text.
Methyl 3-Hydroxy-2,2-dimethyl-3-phenylpropionate (1) [19]. White powder. M.p. 67.18. IR (neat): 3394,
2985, 1704, 1450, 1281, 1149, 1049. 1H-NMR (270 MHz, CDCl3): 1.11 (s, 3 H); 1.14 (s, 3 H); 3.12 (d, J ˆ 4.1, 1 H);
3.72 (s, 3 H); 4.90 (d, J ˆ 4.0, 1 H); 7.22 7.47 (m, 5 H). 13C-NMR (67.8 MHz, CDCl3): 19.0; 23.0; 47.7; 52.1; 78.6;
127.6; 127.7; 139.9; 178.2.
Methyl 2,2-Dimethyl-3-phenyl-3-(trimethylsiloxy)-3-phenylpropionate (2) [20]. Colorless oil. IR (neat):
2947, 1736, 1458, 1257, 1134, 1095. 1H-NMR (270 MHz, CDCl3): À 0.05 (s, 9 H); 0.99 (s, 3 H); 1.12 (s, 3 H); 3.67

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Helvetica Chimica Acta Vol. 85 (2002)
(s, 3 H); 4.97 (s, 1 H); 7.49 7.64 (m, 5 H). 13C-NMR (67.8 MHz, CDCl3): À 0.08; 19.1; 23.0; 49.0; 51.6; 79.2;
127.6; 127.7; 140.8; 177.3.
Methyl 3-Hydroxy-2,2-dimethyl-3-(4-methylphenyl)propionate (3). White powder. M.p. 70.08. IR (neat):
3502, 2950, 1730. 1H-NMR (270 MHz, CDCl3): 1.08 (s, 3 H); 1.12 (s, 3 H); 2.32 (s, 1 H); 3.05 (s, 1 H); 3.69
(s, 3 H); 4.83 (s, 1 H); 7.09 7.18 (m, 4 H). 13C-NMR (68.7 MHz, CDCl3): 19.0; 21.0; 22.8; 47.7; 51.9; 78.4; 127.4;
128.3; 137.0; 137.2; 178.1. Anal. calc. for C13H18O3: C 70.24, H 8.16; found: C 70.05, H 8.17.
Methyl 3-Hydroxy-3-(4-methoxyphenyl)-2,2-dimethylpropionate (4) [19][20]. White powder. M.p. 81.28. IR
(neat): 3502, 2985, 1720. 1H-NMR (270 MHz, CDCl3): 1.07 (s, 3 H); 1.12 (s, 3 H); 3.05 (s, 1 H); 3.70 (s, 3 H); 3.78
(s, 3 H); 4.83 (s, 1 H); 6.83 (m, 2 H); 7.20 (m, 2 H). 13C-NMR (68.7 MHz, CDCl3): 18.9; 22.8; 47.7; 51.9; 55.1;
78.1; 113.0; 128.6; 132.1; 159.0; 178.1.
Methyl 3-Hydroxy-2,2-dimethyl-3-(naphthalen-1-yl)propionate (5). Colorless oil. IR (neat): 3471, 2946,
1
1720. H-NMR (270 MHz, CDCl3): 1.07 (s, 3 H); 1.24 (s, 3 H); 3.72 (s, 3 H); 5.92 (s, 1 H); 7.42 7.51 (m, 3 H);
7.65 7.68 (m, 1 H); 7.77 7.86 (m, 2 H); 8.13 8.16 (m, 1 H). 13C-NMR (68.7 MHz, CDCl3): 18.9; 23.7; 48.7;
‡
52.1; 73.0; 123.7; 124.9; 125.2; 125.7; 125.7; 128.2; 128.7; 131.7; 133.4; 136.2; 178.4. HR-MS: 258.1259 (C16H18O3 ,
‡
M ; calc. 258.1256).
Methyl 3-Hydroxy-2,2-dimethyl-3-(4-nitrophenyl)propionate (6). White crystals. M.p. 114.58. IR (neat):
3517, 2985, 1712, 1519. 1H-NMR (270 MHz, CDCl3): 1.13 (s, 3 H); 1.15 (s, 3 H); 3.74 (s, 3 H); 5.01 (s, 1 H);
7.41 7.62 (m, 2 H); 8.09 8.32 (m, 2 H). 13C-NMR (68.7 MHz, CDCl3): 19.2; 22.7; 47.6; 52.3; 77.7; 122.9; 128.6;
‡
‡
147.3; 147.6; 177.7. HR-MS: 254.1029 (C12H16NO5 , [M ‡ H] ; calc. 254.1028).
Methyl (E)-3-Hydroxy-2,2-dimethyl-5-phenylpent-4-enoate (7) [4c]. Colorless oil. IR (neat): 3409, 2970,
1720, 1458, 1265, 1134, 971, 748, 702. H-NMR (270 MHz, CDCl3): 1.23 (s, 3 H); 1.24 (s, 3 H); 2.75 2.89 (br.
1
s, 1 H); 3.72 (s, 3 H); 4.29 4.44 (m, 1 H); 6.21 (dd, J ˆ 7.1, 15.8, 1 H); 6.64 (d, J ˆ 15.8, 1 H); 7.23 7.40 (m, 5 H).
13C-NMR (68.7 MHz, CDCl3): 20.0; 22.8; 47.2; 52.1; 77.8; 126.5; 127.4; 127.8; 128.5; 132.9; 136.5; 177.9.
Methyl 2,2-Dimethyl-3-phenyl-5-oxopentanoate (8). Colorless oil. IR (neat): 3464, 1712. 1H-NMR
(270 MHz, CDCl3): 1.10 (s, 3 H); 1.16 (s, 3 H); 2.69 (ddd, J ˆ 1.3, 4.3, 16.8, 1 H); 2.98 (ddd, J ˆ 2.6, 10.9, 16.8,
1 H); 3.62 (dd, J ˆ 4.3, 10.9, 1 H); 3.66 (s, 3 H); 7.16 7.32 (m, 5 H); 9.53 (dd, J ˆ 1.3, 2.6, 1 H). 13C-NMR
(68.7 MHz, CDCl3): 21.3; 24.3; 44.8; 46.1; 46.7; 51.9; 127.3; 128.2; 129.4; 139.0; 177.3; 201.3. HR-MS: 235.1335
‡
‡
(C14H19O3 , [M ‡ H] ; calc. 235.1334).
Methyl 3-Hydroxy-2,2-dimethyl-5-phenylpentanoate (9) [4c]. Colorless oil. IR (neat): 3465, 2939, 1720.
1H-NMR (270 MHz, CDCl3): 1.16 (s, 3 H); 1.18 (s, 3 H); 1.53 1.81 (m, 2 H); 2.51 (s, 1 H); 2.59 2.70 (m, 1 H);
2.90 3.00 (m, 1 H); 3.60 3.67 (m, 1 H); 3.68 (s, 3 H); 7.15 7.31 (m, 5 H). 13C-NMR (68.7 MHz, CDCl3): 20.3;
22.4; 32.8; 33.6; 47.1; 51.9; 76.0; 125.8; 128.4; 128.5; 142.1; 178.2.
S-Ethyl 3-Hydroxy-3-phenylpropanethioate (10) [21]. Colorless oil. IR (neat): 3502, 3425, 2970, 2924, 1682.
1H-NMR (270 MHz, CDCl3): 1.25 (t, J ˆ 7, 3 H); 2.84 3.04 (m, 4 H); 3.11 3.17 (br. s, 1 H); 5.12 5.21
(m, 1 H); 7.23 7.40 (m, 1 H). 13C-NMR (68.7 MHz, CDCl3):14.6; 23.5; 52.5; 70.8; 125.5; 127.7; 128.4; 142.2;
198.7.
3-Hydroxy-1,3-diphenylpropan-1-one (11) [19]. Colorless oil. IR (neat): 3548, 3425, 1673. 1H-NMR
(270 MHz, CDCl3): 3.37 (d, J ˆ 6, 2 H); 5.34 (t, J ˆ 6, 1 H); 7.29 7.58 (m, 8 H); 7.81 8.12 (m, 2 H). 13C-NMR
(68.7 MHz, CDCl3): 47.4; 70.0; 125.7; 127.7; 128.1; 128.6; 128.7; 133.6; 136.5; 142.9; 200.2.
Methyl 3-Hydroxy-2-methyl-3-phenylpropionate (12) [19]. syn-Isomer: Colorless oil. IR (neat): 3518,
3425,2978, 1728, 1443, 1188, 1049. 1H-NMR (270 MHz, CDCl3): 1.12 (d, J ˆ 7, 3 H); 2.62 3.09 (br s, 1 H); 2.79
(dq, J ˆ 4, 7, 1 H); 3.66 (s, 3 H); 5.09 (d, J ˆ 4, 1 H); 7.21 7.43 (m, 5 H). 13C-NMR (68.7 MHz, CDCl3): 10.7;
46.4; 51.8; 73.6; 125.9; 127.5; 128.2; 141.4; 176.1. anti-Isomer: White powder. M.p. 48.08. IR (neat): 3502, 2970,
1728, 1450, 1180, 1041. 1H-NMR (270 MHz, CDCl3): 1.00 (d, J ˆ 7, 3 H); 2.63 3.20 (br. s, 1 H); 2.82 (dq, J ˆ 7, 8,
1 H); 3.72 (s, 3 H); 4.74 (d, J ˆ 8, 1 H); 7.25 7.43 (m, 5 H). 13C-NMR (68.7 MHz, CDCl3): 14.4; 47.1; 51.9; 76.4;
126.6; 128.1; 128.5; 141.5; 176.2.
Methyl 3-(4-Cyanophenyl)-3-hydroxy-2,2-dimethylpropionate (13) [20]. White powder. M.p. 96.08. IR
(neat): 3479, 2985, 2229, 1728. 1H-NMR (270 MHz, CDCl3): 1.09 (s, 3 H); 1.13 (s, 3 H); 3.59 3.68 (m, 1 H); 3.71
(s, 3 H); 4.95 (d, J ˆ 4.3, 1 H); 7.38 7.48 (m, 2 H); 7.55 7.66 (m, 2 H). 13C-NMR (68.7 MHz, CDCl3): 19.1; 22.3;
47.6; 52.1; 77.5; 111.2; 118.6; 128.3; 131.3; 145.5; 177.5.
Methyl 3-(4-Chlorophenyl)-3-hydroxy-2,2-dimethylpropionate (14). White powder. M.p. 63.28. IR (neat):
3471, 2978, 1720. 1H-NMR (270 MHz, CDCl3): 1.08 (s, 3 H); 1.12 (s, 3 H); 3.21 (s, 1 H); 3.71 (s, 3 H); 4.85
(s, 1 H); 7.18 7.36 (m, 4 H). 13C-NMR (68.7 MHz, CDCl3): 19.0; 22.8; 47.6; 52.1; 77.9; 127.9; 129.0; 133.5; 138.4;
178.0. Anal. calc. for C12H15ClO3: C 59.39, H 6.23; found: C 59.29, H 6.22.
Methyl 3-(4-Bromophenyl)-3-hydroxy-2,2-dimethylpropionate (15). White powder. M.p. 70.88. IR (neat):
3471, 3410, 2978, 1705. 1H-NMR (270 MHz, CDCl3): 1.07 (s, 3 H); 1.11 (s, 3 H); 3.24 3.44 (br. s, 1 H); 3.70

Helvetica Chimica Acta Vol. 85 (2002)
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(s, 3 H); 4.82 (s, 1 H); 7.14 7.17 (m, 2 H); 7.42 7.45 (m, 2 H). 13C-NMR (68.7 MHz, CDCl3): 19.0; 22.7; 47.5;
52.1; 77.8; 121.5; 129.3; 130.8; 138.9; 177.9. Anal. calc. for C12H15BrO3: C 50.19, H 5.27; found: C 50.15, H 5.27.
Methyl 3-[4-(Dimethylamino)phenyl]-2,2-dimethyl-3-(trimethylsilyloxy)propionate (16) [19]. White pow-
der. M.p. 80.18. IR (neat): 2978, 1728, 1612, 1519, 1458, 1349, 1250, 1073. 1H-NMR (270 MHz, CDCl3): À 0.07
(s, 9 H); 1.00 (s, 3 H); 1.09 (s, 3 H); 2.91 (s, 6 H); 3.65 (s, 3 H); 4.87 (s, 1 H); 6.59 (d, J ˆ 8.7, 2 H); 7.31 (d, J ˆ 8.7,
2 H). 13C-NMR (68.7 MHz, CDCl3): À 0.1; 18.8; 21.9; 40.5; 49.2; 51.5; 79.0; 111.3; 128.4; 128.5; 149.8; 177.6.
Methyl 2,2-Dimethyl-3-(pyridin-2-yl)-3-(trimethylsilyloxy)propionate (17). Colorless oil. IR (neat): 3626,
3186, 2993, 1728. 1H-NMR (270 MHz, CDCl3): À 0.04 (s, 9 H); 0.98 (s, 3 H); 1.12 (s, 3 H); 3.65 (s, 3 H); 5.06
(s, 1 H); 7.07 7.17 (m, 1 H); 7.34 7.44 (m, 1 H); 7.56 7.70 (m, 1 H); 8.40 8.49 (m, 1 H). 13C-NMR (68.7 MHz,
CDCl3): 0.0; 20.2; 21.0; 48.7; 51.7; 79.8; 122.1; 135.6; 147.8; 161.1; 176.6. Anal. calc. for C14H23NO3Si: C 59.75, H
8.24, N 4.96; found: C 59.64, H 8.25, N 4.97.
Methyl 3-{1-[(tert-Butoxy)carbonyl]-1H-indol-3-yl}-2,2-dimethyl-3-(trimethylsiloxy)propionate (18). Col-
orless oil. IR (neat): 2978, 1736, 1458, 1373, 1257, 1149, 1280, 856, 756. 1H-NMR (270 MHz, CDCl3): À 0.04
(s, 9 H); 1.09 (s, 3 H); 1.25 (s, 3 H); 1.68 (s, 9 H); 3.67 (s, 3 H), 5.26 (s, 1 H); 7.12 7.37 (m, 2 H); 7.43 (s, 1 H);
7.68 7.84 (m, 1 H); 7.99 8.22 (m, 1 H). 13C-NMR (68.7 MHz, CDCl3): À 0.2; 19.9; 21.9; 28.2; 49.7; 51.7; 74.1;
‡
‡
83.7; 114.9; 120.8; 121.5; 122.3; 124.0; 129.9; 135.2; 149.7; 168.1; 177.2. HR-MS: 419.2120 (C22H33O5NSi , M ;
calc. 419.2128).
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ReceivedAugust 8, 2002