Phosphine catalyzed aldol reaction between ketene silyl acetals and aldehydes: Nucleophilic O-Si and C-Si bond cleavage by phosphines

Article abstract of DOI:10.1016/S0040-4039(99)02014-6

A highly nucleophilic phosphine, tris(2,4,6-trimethoxyphenyl)phosphine (TTMPP), catalyzes the aldol reaction between ketene silyl acetals and aldehydes to give the corresponding aldol products in good to high yields. This reaction is considered to proceed through naked enolates produced by nucleophilic O-Si and C-Si bond cleavage.

Full text of DOI:10.1016/S0040-4039(99)02014-6

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 103–107
Phosphine catalyzed aldol reaction between ketene silyl acetals
and aldehydes: nucleophilic O–Si and C–Si bond cleavage by
phosphines
Satoru Matsukawa, Naoko Okano and Tsuneo Imamoto ∗
Department of Chemistry, Faculty of Science, Chiba University, Inage-ku, Chiba 263-8522, Japan
Received 20 September 1999; accepted 7 October 1999
Abstract
A highly nucleophilic phosphine, tris(2,4,6-trimethoxyphenyl)phosphine (TTMPP), catalyzes the aldol reaction
between ketene silyl acetals and aldehydes to give the corresponding aldol products in good to high yields. This
reaction is considered to proceed through naked enolates produced by nucleophilic O–Si and C–Si bond cleavage.
© 1999 Elsevier Science Ltd. All rights reserved.
Keywords: phosphines; aldol reactions; naked enolates.
The aldol reaction has become a fundamental method of carbon–carbon bond forming reactions in
modern organic synthesis.1 One of the most commonly used and best understood is the Mukaiyama
aldol reaction (Lewis acid-promoted carbonyl addition of silyl enol ethers).2 On the other hand, it is well
known that the reaction between carbonyl compounds and silyl enol ethers could proceed under various
conditions. For example, several efficient activators such as a fluoride ion,3 trityl salts,4 water,5 transition
metal salts,6 HMPA derivatives,7 high pressure8 and elevated temperature9 etc., have been developed to
realize high yields and selectivities of this reaction. In this paper, we report the use of phosphines as
catalysts10 in the aldol reaction of ketene silyl acetals through nucleophilic cleavage of the O–Si bond
(Scheme 1).
Scheme 1.
∗
Corresponding author.
0040-4039/00/$ - see front matter © 1999 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(99)02014-6
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First, we examined the catalytic activity of various phosphines in the reaction of benzaldehyde with
a trimethylsilyl enol ether derived from methyl isobutylate. The reaction was carried out by adding
the trimethylsilyl enol ether and benzaldehyde to THF containing 20 mol% of phosphine at room
temperature. The reaction was monitored by TLC. Careful hydrolytic work-up with 1 M HCl, followed
by column chromatography, afforded the desired aldol product. The results are summarized in Table 1.
Moderate to good product yields were obtained in the presence of a catalytic amount of the phosphine.
Especially, tris(2,4,6-trimethoxyphenyl)phosphine (TTMPP)11 was found to be quite effective (Table 1,
Table 1
Table 2

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entry 5). TTMPP is a highly nucleophilic and basic phosphine and, thus, it is likely to have played
an important role in this reaction. A bidentate phosphine, 1,2-bis(diphenylphosphino)ethane, did not
catalyze this reaction (Table 1, entry 6). Phosphine oxides, phosphate, HMPA and amines were also used
as catalysts. Although this reaction proceeded under these conditions, chemical yields were low (Table
1, entries 7–12). Thus, only phosphine among these activators effectively catalyzed this aldol reaction.
In order to clarify the scope of this phosphine catalyzed reaction, several aldehydes were examined in
the presence of 20 mol% of TTMPP (Table 2). Good results were obtained for both aromatic and aliphatic
aldehydes. In some cases, the addition of a small amount of water increased the chemical yield (entries 1
versus 2), but the role of water is not clear. Small amounts of acetal products were produced in all cases,
particularly when aliphatic aldehydes were used. These acetal products were easily converted to normal
aldol product by treatment with 1 M HCl. Furthermore, moderate syn-diastereoselectivity was observed
irrespective of the geometry of the silyl enol ether derived from methyl propionate.
The observed diastereoselectivity can be reasonably explained by considering an extended transition
state A12 rather than a cyclic transition state B,13 because it is well recognized that, via the cyclic
transition state, (E)-enolate affords anti-diastereomer and (Z)-enolate leads to syn-diastereomer. On the
other hand, syn-diastereomer is formed via transition state A irrespective of the geometry of silyl enol
ether. In addition, acetal products are produced in this reaction. It is well known that acetal products
are obtained in the fluoride ion-catalyzed aldol reaction.3d These facts suggest that naked enolates
are generated through a nucleophilic O–Si cleavage by phosphines, similar to a fluoride ion-catalyzed
reaction.
The reaction of α-silyl ester with benzaldehyde in the presence of TTMPP (20 mol%) was also
examined. The reaction proceeded to give the corresponding product in 60% yield. Reaction of phenyl-
trimethylsilyl acetylene with benzaldehyde also took place under similar conditions. These reactions are
considered to proceed through a pathway in which TTMPP attacks the silyl atom and the generated
carbanion14 reacts with aldehyde (Scheme 2).
In summary, phosphines catalyze the aldol reaction through a nucleophilic O–Si and C–Si bond
cleavage. Further studies along these lines, including asymmetric reactions are now underway in our
laboratory.

106
Scheme 2.
Acknowledgements
This work was supported by a Grant-in-Aid for Encouragement of Young Scientists No. 11740381
from the Japanese Ministry of Education, Science, Sports and Culture.
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