Metal chloride-promoted aldol reaction of α-dimethylsilylesters with aldehydes, ketones, and α-enones

Article abstract of DOI:10.1055/s-2005-871938

In the presence of a catalytic amount of LiCl, α-dimethylsilylesters (α-DMS-esters) 1 smoothly reacted with various aldehydes at 30°C to give aldols in good to high yields. On the other hand, the aldol reaction with ketones was effectively promoted by MgCl2 rather than by LiCl. α-Enones also underwent the metal chloride-promoted addition of 1 at the carbonyl carbon or β-carbon. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2005-871938

LETTER
1917
Metal Chloride-Promoted Aldol Reaction of a-Dimethylsilylesters with
Aldehydes, Ketones, and a-Enones
Aldol Reaction of
a
a
-Dimethyl
t
silyles
s
ters ukiyo Miura,*a,b Takahiro Nakagawa,a,b Akira Hosomi*a,b
a
Department of Chemistry, 21st Century COE, Graduate School of Pure and Applied Sciences, University of Tsukuba, Tsukuba,
Ibaraki 305-8571, Japan
b
CREST, Japan Science and Technology Corporation (JST), Tsukuba, Ibaraki 305-8571, Japan
Fax +81(29)8536503; E-mail: miura@chem.tsukuba.ac.jp; E-mail: hosomi@chem.tsukuba.ac.jp
Received 13 May 2005
1) MXn (0.25 equiv)
DMF, 30 °C, 5 h
Abstract: In the presence of a catalytic amount of LiCl, a-dimeth-
ylsilylesters (a-DMS-esters) 1 smoothly reacted with various alde-
hydes at 30 °C to give aldols in good to high yields. On the other
hand, the aldol reaction with ketones was effectively promoted by
MgCl2 rather than by LiCl. a-Enones also underwent the metal
chloride-promoted addition of 1 at the carbonyl carbon or b-carbon.
O
O
OH
+
PhCHO
SiHMe2
2) 2 M HCl
EtO
EtO
Ph
1a (1.2 equiv)
2a
3aa
MXn, yield (%): none, 61; LiCl, 95; MgCl2, 82; CaCl2, 81; Bu4NCl, 68;
LiBr, 70; LiOTf, 69.
Key words: aldehydes, aldol reactions, ketones, Michael additions,
a-silylesters
Scheme 1
Bu4NCl, LiBr, and LiOTf showed lower catalytic activity
than these metal chlorides.
The Mukaiyama-aldol reactions of silyl enolates provide
regio- and stereoselective methods for C–C bond forma-
tion and functionalization.1 Since the pioneering work by
Mukaiyama et al.,2 Lewis acid catalysts have frequently
been used for the synthetically valuable transformations.
It is also well known that fluoride ion sources work as
Lewis base catalysts to promote the aldol reaction via nu-
cleophilic activation of silyl enolates.3 In recent years,
however, much attention has been focused on the devel-
opment of other Lewis base-catalyzed systems.1,4,5 In this
context, we have reported that the aldol reaction of di-
methylsilyl enolates derived from ketones is accelerated
by chloride ion sources such as alkali and alkali earth
metal chlorides.6,7 The known Lewis base-catalyzed sys-
tems including the fluoride ion-catalyzed ones are useful
for the reaction with aldehydes, while there are few suc-
cessful examples of the use of ketones as electrophiles.8,9
We herein disclose that a-dimethylsilylesters (a-DMS-es-
ters) work as enolate equivalents under catalysis by metal
chlorides to achieve an efficient aldol reaction of simple
ketones and a-enones as well as aldehydes.10
Under catalysis by LiCl, a-DMS-ester 1a added smoothly
to aromatic and aliphatic aldehydes 2a–h to afford the
corresponding b-hydroxyesters 3aa–ah in good to high
yields (entries 1–8 in Table 1).12 The aldol reaction with
2c took place only at the aldehyde carbonyl (entry 3). In
the case of chiral aldehyde 2g, moderate syn (Cram-type)
selectivity was observed (entry 7). The stereochemical
outcome with b-alkoxyaldehyde 2h (dr = 57:43) indicates
that the present reaction system is not suitable for chela-
tion control (entry 8). The use of hydroxy-substituted
benzaldehydes 2i–j resulted in low yields of 3ai–aj even
when an increased amount of 1a was employed (entries 9,
10). The aldol reaction of 2i competed with the reduction
of 2i to 2-hydroxybenzyl alcohol (4). Such a side reaction
was not observed with 2j, and an increased amount of
LiCl improved the yield of 3aj. In these cases, the acidic
hydroxy groups of 2i,j would cause the protodesilylation
of 1a. The DMS ether thus formed from 2i would be
converted into 4 by intramolecular hydride transfer
(Scheme 2). a-DMS-esters 1b,c, substituted at the a-car-
bon, showed similar reactivities to aldehydes as did 1a
(entries 11–20). Unfortunately, the reaction of 1b
proceeded with low diastereoselectivity.
Initially, the reaction of ethyl DMS-acetate (1a) with
benzaldehyde (2a) was selected to examine the catalytic
activity of metal salts and Bu4NCl.11 As previously report-
ed by us,11a 1a reacted spontaneously with 2a in DMF
(30 °C, 5 h). An acidic, desilylative work-up followed by
purification by silica gel column chromatography gave b-
hydroxyester 3aa in 61% yield. A catalytic amount of
MgCl2, LiCl, or CaCl2 effectively promoted the aldol re-
action under the same conditions. Particularly, the use of
LiCl achieved a quantitative yield of 3aa. In contrast,
Unlike benzaldehyde, cyclohexanone (5a) never under-
went the addition of 1a in the absence of a promoter
(30 °C, 24 h, Scheme 3). An equimolar amount of LiCl or
CaCl2 induced the aldol reaction; however, the rate-accel-
erating ability was not high enough to realize a successful
aldol reaction. In contrast, MgCl2 was found to be an ef-
fective promoter. The use of a catalytic amount of MgCl2
resulted in a lower yield of the desired product 6aa. The
rate-accelerating abilities of Bu4NCl and Mg(OTf)2 were
rather low.
SYNLETT 2005, No. 12, pp 1917–1921
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Advanced online publication: 07.07.2005
DOI: 10.1055/s-2005-871938; Art ID: U14605ST
© Georg Thieme Verlag Stuttgart · New York

1918
K. Miura et al.
LETTER
Table 1 LiCl-Catalyzed Addition of a-DMS Esters to Aldehydesa
O
OH
CHO
1a
HCl
1) LiCl (0.25 equiv)
DMF, 30 °C
+
O
O
OH
1a 2i
EtO
OSiHMe2
R3CHO
SiHMe2
+
EtO
EtO
R3
HO
2) 2 M HCl
2
R1 R2
R1 R2
3ai
1a: R1 = R2 = H
3
HCl
1b: R1 = Me, R2 = H
1c: R1 = R2 = Me
OH
OH
Entry
1
Aldehyde 2
3
Yield (%)b
R3
(syn:anti)
4
1
2
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1b
1b
1b
1b
1b
1c
1c
1c
1c
1c
2a
2b
2c
2d
2e
2f
Ph
3aa
3ab
3ac
3ad
3ae
3af
3ag
3ah
3ai
95
Scheme 2
4-MeO-C6H4
96
O
1) MXn (1.0 equiv)
DMF, 30 °C, 24 h
3
4-MeC(O)-C6H4
(E)-PhCH=CH
Ph(CH2)2
i-Pr
77
O
OH
+
1a
4
95
EtO
2) 2 M HCl
(1.5 equiv)
5
79
5a
6aa
6
89
MXn, yield (%): none, 0; LiCl, 35; MgCl2, 88; MgCl2*, 59; CaCl2, 35;
Bu4NCl, <5; MgBr2, 29; Mg(OTf)2, 13.
7
2g
2h
2i
MeCH(Ph)
MeCH(OBn)CH2
2-HO-C6H4
4-HO-C6H4
Ph
68 (74:26)
76 (57:43)c
51,d,e 66e,f
40,e 83e,f
97 (69:31)
98 (56:44)
75 (54:46)
92 (53:47)
75e,f (63:31)
97
*0.25 equiv of MgCl2 was used.
8
Scheme 3
9
methylsilyl enolates.10 The presence of a hydroxy group
in the substrate lowered the reaction efficiency (entry 6).
The aldol reaction with 1,3-dicarbonyl compounds such
as 2,4-pentanedione and ethyl 3-oxobutanoate did not
occur at all. These results are probably due to the deproto-
nation of the activated methylene by 1a, which not only
consumes 1a but also reduces the electrophilicity of the
carbonyl carbon.
10
11
12
13
14
15
16
17
18
19
20
2j
3aj
3ba
3bd
3be
3bf
3bj
3ca
3cd
3ce
3cf
2a
2d
2e
2f
(E)-PhCH=CH
Ph(CH2)2
i-Pr
2j
4-HO-C6H4
Ph
a-DMS-ester 1b as well as 1a reacted smoothly with
ketones 5a,b to give the corresponding aldols in high
yields (entries 7, 8). The reaction with 5b resulted in low
diastereoselectivity. Sterically demanding DMS-ester 1c
was less reactive to ketones (entries 9, 10). The products
derived from 1c were easily decomposed by the acidic
work up. A neutral aqueous work up provided silyl ethers
7c in moderate yields.
2a
2d
2e
2f
(E)-PhCH=CH
Ph(CH2)2
i-Pr
95
77
86
2j
4-HO-C6H4
3cj
77e,f
a Unless otherwise noted, all reactions were performed with 1 (0.60
mmol), 2 (0.50 mmol), and LiCl (0.13 mmol) in DMF (1 mL) at 30 °C
for 5 h. For general procedure, see ref. 12.
b Isolated yield.
1)
2)
MgCl2 (1.0 equiv)
DMF, 30 °C, 24 h
O
+
1a
t-Bu
2 M HCl
5g
c The relative configuration was not determined.
d Alcohol 4 was obtained in 44% yield.
e With 2.0 equiv of 1a.
O
O
OH
EtO
+
f With 1.0 equiv of LiCl.
t-Bu
t-Bu
EtO
HO
cis-6ag, 57%
trans-6ag, 16%
The MgCl2-promoted aldol reaction of 1a was applicable
to both aromatic and aliphatic ketones (entries 1–5 in
Table 2). The reaction with ketone 5e required slightly
higher temperature for its complete conversion (entry 5).
4-tert-Butylcyclohexanone (5g) underwent equatorial at-
tack of 1a preferentially (Scheme 4).13 The present reac-
tion stands in sharp contrast with the TBAF-catalyzed
reaction of ethyl trimethylsilylacetate with simple ke-
tones, which causes deprotonative silylation to ketone tri-
Scheme 4
We further examined the reaction of 1a with a-enones 8
(Table 3). The MgCl2-promoed reaction of 1a with chal-
cone (8a) gave aldol 9aa in high yield (entry 1). The cor-
responding Michael adduct was not formed at all. The use
of CaCl2 instead of MgCl2 led to a slightly higher yield of
Synlett 2005, No. 12, 1917–1921 © Thieme Stuttgart · New York

LETTER
Aldol Reaction of a-Dimethylsilylesters
1919
Table 3 Addition of a-DMS Ester 1a with a-Enonesa
Table 2 MgCl2-Promoted Addition of a-DMS Esters to Ketonesa
1)
1) MgCl2 (1.0 equiv)
DMF, 30 °C
MCln, DMF
30 °C, 24 h
R4 OH
O
O
O
+
+
1a
1
R3
R4
EtO
R3
R3
R4
2)
2) 2 M HCl or H2O
2 M HCl
9a
8
5
O
OH
O
OSiHMe2
R4
R3
R4
R3
Entry MCln
a-Enone 8
9a
Yield (%)b
or
EtO
EtO
R3
Ph
Ph
Ph
Ph
H
R4
R1 R2
R1 R2
6
7
1
2
3
4
5
6
7
MgCl2
8a
Ph
9aa
9aa
9aa
9ab
9ac
9ad
9ae
89
92
77c
55c
60
78
0c
Entry
1
Ketone 5
6
Yield (%)b
CaCl2
LiCl
8a
8a
8b
8c
8d
8e
Ph
R3
R4
Ph
1
2
1a
5a
5b
5c
5d
5e
5f
(CH2)5
Ph
6aa
88
CaCl2
CaCl2
CaCl2
CaCl2
Me
Me
Ph
1a
1a
1a
1a
1a
Me
Et
6ab
6ac
6ad
6ae
6af
90
3
Ph
93
Me
Me
4
4-MeO-C6H4 Me
96
t-Bu
5
n-C11H23
HO(CH2)3
(CH2)5
Ph
Me
Me
59, 95c
25
a Unless otherwise noted, all reactions were carried out with 1 (0.75
mmol), 5 (0.50 mmol), and MgCl2 (0.50 mmol) in DMF (1.0 mL) at
30 °C for 24 h. The reaction mixture was treated with 2 M HCl (1 mL
in entries 1–8) or H2O (1 mL in entries 9 and 10) for 5 min.
b Isolated yield.
6
7
1b
1b
1c
1c
5a
5b
5a
5b
6ba
6bb
7ca
7cb
91
c Yields of the recovered 8: 20% (entry 3), 39% (entry 4), and >90%
(entry 7).
8
Me
88d
50
9
(CH2)5
Ph
1) 1b (1.5 equiv)
CaCl2 (1.0 equiv)
10
Me
57
O
a Unless otherwise noted, all reactions were carried out with 1 (0.75
mmol), 5 (0.50 mmol), and MgCl2 (0.50 mmol) in DMF (1.0 mL) at
30 °C for 24 h. The reaction mixture was treated with 2 M HCl (1 mL
in entries 1–8) or H2O (1 mL in entries 9 and 10) for 5 min.
b Isolated yield.
DMF, 30 °C, 24 h
2) 2 M HCl, 30 °C, 5 min
Ph
Ph
8a
O
O
Ph
O
Ph OH
+
c At 50 °C.
EtO
Ph
EtO
Ph
d Diastereomeric ratio = 45:55.
9ba, 27%, dr = 64:36
10ba, 64%, dr = 84:16
9aa, while LiCl was less effective than MgCl2 and CaCl2
(entries 2 and 3). Other a-enones 8b–d also underwent the
CaCl2-promoted aldol reaction to give 9ab–9ad in moder-
ate to good yields (entries 4–6). With the aid of Lewis
acids and bases, silyl enolates and a-silylesters react with
a-enones generally at the b-carbon in a conjugate
manner.14–16 The present reaction of 1a provided a novel
example of the aldol reaction with a-enones.9,17 Unfortu-
nately, a-enone 8e, bearing a tert-butyl group on the
carbonyl carbon, was unreactive to 1a (entry 7).
O
OH
O
as above
EtO
9bb, 91%, dr = 60:40
Ph
Ph
8b
O
O
O
as above
EtO
R4
R4
8d: R = Ph
8e: R = t-Bu
10bd, 73%, dr = 90:10
10be, 67%, dr = >95:5
The chemoselectivity of the CaCl2-promoted reaction of
1b heavily depended on the a-enone used (Scheme 5).
The reaction with 8a gave a mixture of aldol 9ba and the
Michael adduct 10ba in high yield. a-Enone 8b under-
went only the aldol reaction leading to 9bb. In contrast,
the use of 8d,e afforded only 10bd,be with high anti-se-
lectivity. These results indicate that a bulky group on the
carbonyl carbon of 8 and a small group on the b-carbon in-
duce the Michael reaction rather than the aldol reaction.
Scheme 5
sult, these a-silylesters bearing a sterically more crowded
silicon center were found to be much less reactive than 1a.
The difference in reactivity suggests that the present reac-
tion should include nucleophilic activation of a-DMS-es-
ters as the key step. The less catalytic activities of metal
bromides and triflates also lead to the same mechanistic
aspect because a chloride ion (a hard base) has higher si-
laphilicity than bromide and triflate ions (softer bases).18
We attempted to observe the active species generated
To gain mechanistic insight, we carried out the metal
chloride-catalyzed reactions of ethyl trimethylsilylacetate
and ethyl diisopropylsilylacetate with 2a and 5a. As a re-
from LiCl and 1a by H NMR and 13C NMR analyses.
1
Synlett 2005, No. 12, 1917–1921 © Thieme Stuttgart · New York

1920
K. Miura et al.
LETTER
(8) Denmark, S. E.; Fan, Y. J. Am. Chem. Soc. 2002, 124, 4233.
(9) Oisaki, K.; Suto, Y.; Kanai, M.; Shibasaki, M. J. Am. Chem.
Soc. 2003, 125, 5644.
(10) For the fluoride ion-catalyzed aldol reaction of ethyl
trimethylsilylacetate, see: (a) Nakamura, E.; Shimizu, M.;
Kuwajima, I. Tetrahedron Lett. 1976, 1699. (b) Nakamura,
E.; Hashimoto, K.; Kuwajima, I. Tetrahedron Lett. 1978,
2079.
(11) a-DMS-esters 1 can be easily prepared from the
corresponding esters by deprotonation with LiNi-Pr2
followed by silylation with Me2SiHCl. See: (a) Miura, K.;
Sato, H.; Tamaki, K.; Ito, H.; Hosomi, A. Tetrahedron Lett.
1998, 39, 2585. (b) Kaimakliotis, C.; Fry, A. J. J. Org.
Chem. 2003, 68, 9893. (c) Typical Procedure for the
Preparation of a-DMS-esters 1
However, the signals of 1a did not shift in the presence of
LiCl. The present reaction may involve reversible forma-
tion of a transient active species such as a chloride ion
bound silicate.
The low rate-accelerating ability of Bu4NCl (Scheme 1
and Scheme 3) suggests that the metal ion of a metal chlo-
ride also plays an important role for the present reaction.
In addition, the fact that MgCl2 promotes the aldol reac-
tion with 5a more effectively than LiCl and CaCl2 seems
to signify the role of the magnesium ion as Lewis acid.
When simple ketones are used as electrophiles, simulta-
neous activation of both 1 and ketones may be required for
a successful aldol reaction to compensate their low elec-
trophilicity.19
Under N2 atmosphere, n-BuLi (1.61 M in hexane, 62 mL,
100 mmol) was added to a solution of i-Pr2NH (14 mL, 100
mmol) in THF (100 mL) over 5 min at 0 °C. After 10 min,
the mixture was cooled to –78 °C. Then, EtOAc (9.3 mL, 95
mmol) was added to the solution of LDA over 5 min. After
2 h, the reaction mixture was treated with chlorodimethyl-
silane (12.2 mL, 110 mmol) and gradually warmed to r.t.
over 12 h. The resultant mixture was diluted with dry
pentane (50 mL) and filtered through Celite®. After
evaporation of the filtrate, the residual oil was diluted with
dry pentane (50 mL) again, filtered through Celite®, and
evaporated. Purification of the crude product by distillation
gave 1a (9.2 g, 63 mmol) in 66% yield.
In conclusion, we have demonstrated that a-DMS-esters 1
work as stable enolate equivalents in the presence of inex-
pensive, disposable metal chlorides such as LiCl, MgCl2,
and CaCl2. The aldol reaction of 1 proceeds efficiently un-
der very mild conditions and it is applicable to a variety of
aldehydes and ketones. The reaction mechanism would
involve nucleophilic activation of 1 by a chloride ion al-
though the participation of metal ions in promoting the
present reaction is also important.
Compound 1a: bp 58–60 °C (180 Torr). IR (neat): 1669
(C=O), 1253, 1205 cm–1. 1H NMR (CDCl3): d = 0.20 (d,
J = 3.6 Hz, 6 H), 1.23 (t, J = 6.9 Hz, 3 H), 1.96 (d, J = 3.3
Hz, 2 H), 4.06 (sept, d, J = 3.6, 3.3 Hz, 1 H), 4.10 (q, J = 6.9
Hz, 2 H). 13C NMR (CDCl3): d = –4.36 (CH3 × 2), 14.09
(CH3), 24.08 (CH2), 59.91 (CH2), 172.54 (C). Anal. Calcd
for C6H14O2Si (%): C, 49.53; H, 9.69. Found: C, 49.27; H,
9.65.
Acknowledgment
This work was partly supported by Grants-in-Aid for Scientific
Research from the Ministry of Education, Culture, Sports, Science,
and Technology, Government of Japan.
References
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Aldehydes 2
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added to a two-necked, round-bottomed flask (10 mL),
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mixture. After being stirred for 5 h, the reaction mixture was
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column chromatography.
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Synlett 2005, No. 12, 1917–1921 © Thieme Stuttgart · New York

LETTER
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(18) The bond dissociation energy of Si–Cl in Me3SiCl (472 kJ/
mol) is larger than that of Si–Br in Me3SiBr (402 kJ/mol).
See: Walsh, R. In The Chemistry of Organic Silicon
Compounds, Vol. 1; Patai, S.; Rappoport, Z., Eds.; Wiley:
Chichester UK, 1989, Chap. 5, 371.
(19) As shown in Table 3, the reaction of 1a with 8a proceeded
efficiently irrespective of the metal chloride used. This
observation may be due to higher coordinating ability
(Lewis basicity) of a-enones, which allows carbonyl
activation even with less Lewis acidic metal ions. For the
coordinating ability of a-enones, see ref. 17a.
Synlett 2005, No. 12, 1917–1921 © Thieme Stuttgart · New York