Spontaneous aldol and Michael additions of simple enoxytrimethylsilanes in DMSO

Article abstract of DOI:10.1016/S0040-4039(00)00725-5

Activation of simple trimethylsilyl ketene acetals by dipolar aprotic solvents has been evidenced, allowing efficient solvent assisted aldol and Michael additions under extremely simple, mild and metal free conditions. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00725-5

Tetrahedron Letters 41 (2000) 4881±4884
Spontaneous aldol and Michael additions of simple
enoxytrimethylsilanes in DMSO
Yves Genisson* and Liliane Gorrichon
Á Â Â Ã
Synthese et Physicochimie de Molecules d'Interet Biologique, CNRS et Universite Paul Sabatier, 118 route de Narbonne,
F-31062 Toulouse cedex 04, France
Â
Received 16 March 2000; accepted 14 April 2000
Abstract
Activation of simple trimethylsilyl ketene acetals by dipolar aprotic solvents has been evidenced, allow-
ing ecient solvent assisted aldol and Michael additions under extremely simple, mild and metal free
conditions. # 2000 Elsevier Science Ltd. All rights reserved.
Keywords: Mukaiyama reaction; aldol addition; Michael additions; enoxysilanes; solvent e€ect.
Since the initial report of Mukaiyama, the use of enoxysilanes as latent enolates in aldol
additions attained an impressive level of sophistication. Ecient catalytic processes are now
available that a€ord high control of both diastereo- and enantioselectivity.1
The Mukaiyama reaction is classically promoted by a Lewis acid (or a trityl salt2) which
initiates the enoxysilane addition through the electrophilic activation of the aldehyde. Facial
discrimination of the carbonyl group also depends on this chelation in the asymmetric version of
the reaction. The exact mechanistic pathway has been shown to be complex.3
Alternatively, the latent enolate can also be subject to activation, either through nucleophilic
cleavage of the O±Si bond (upon action of a ¯uoride salt4 or a phosphine5), or via Lewis base
coordination to the silicon atom. In the later strategy developed by Denmark,6 the presence of
highly electronegative chlorides on the silicon atom of the enoxysilane ensures a strong chelation
(essential for a signi®cant level of asymmetric induction with a chiral promoter), while giving rise
in some cases to a concurrent uncatalysed reaction pathway.7
Strictly unpromoted enoxysilane additions have also been described. All the reported examples
are based on an unusual substitution pattern that renders the enolsilane appropriately electrophilic.8
The rate acceleration resulting from incorporation of the silicon atom within a four-membered
ring have been studied by Myers9 and Denmark.10 Highly ecient and diastereoselective
uncatalysed additions of such silacyclobutyl ketene acetals rely on the coordination of the
* Corresponding author. Tel: 33-(0)5 61 55 62 99; fax: 33-(0)5 61 55 82 45; e-mail: genisson@ramses.ups-tlse.fr
0040-4039/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00725-5

4882
aldehyde oxygen to the silicon atom. For this, the strong Lewis acidity due to the angle strain
introduced by the four-membered ring is necessary. Smooth addition of dimethyl(tri¯oxy)silyl enol
ethers generated in situ to various nucleophiles have been shown to occur diastereoselectively in
the absence of any external promoter.11 The thermal aldolisation of dimethylsilyl enol ethers and
a-dimethylsilyl esters was also reported to proceed slowly upon gentle heating in DMF, albeit
without appreciable stereoselectivity.12
We wish to report here that trivial trimethylsilyl ketene acetals can also readily participate in
spontaneous addition reactions. While screening for new catalysts we incidentally found that
highly dipolar aprotic media have a profound rate accelerating e€ect on aldolisation with enoxy-
trimethylsilanes.13 Thus, enoxysilane 1 adds to benzaldehyde at room temperature to furnish the
trimethylsilyl ether of the expected aldol product in 70±80% yield after one day, when solvents
such as DMA, DMF or DMSO are employed. Interested by this ®nding we further optimised the
reaction conditions. DMSO was chosen for its stronger ability to promote the reaction.14
Concentration of the reaction medium to 1 M increased the reaction rate. Strict exclusion of
moisture was critical for optimum eciency, though the reaction tolerates traces of water (70%
yield after one day in DMSO containing water in 0.5% volume). Thus, treatment of benzaldehyde
with a slight excess of trimethylsilyl ketene acetal 1 during one day at room temperature in freshly
distilled DMSO, and in the presence of activated 4 A molecular sieves, gives silyl ether of the
desired adduct nearly quantitatively. Desilylation followed by ®ltration over silica gel a€ords
pure aldol in 95% yield. It is worth noting that the same reaction has been reported to require
heating at 150ꢀC (neat) for 18 h to furnish 81% yield in the expected aldolisation product.15
The mildness of our reaction conditions clearly originates from the strong coordinating
capacity of DMSO, and is likely to proceed through an activation of the enoxysilane by chelation
of the silicon atom. This interpretation is supported by the fact that the more hindered t-butyl-
dimethylsilyl ketene acetal 4 failed to react with benzaldehyde under similar conditions.
We then generalised our study to other electrophiles. Silyl ketene acetal 1 smoothly reacts with
various aromatic and conjugated aldehydes (Table 1, entries 1±4). Addition to aliphatic
derivatives occurs less eciently but still furnishes the aldol compound in a synthetically useful
fashion (Table 1, entries 5 and 6). Michael additions also readily operate in DMSO with di€erent
enones to a€ord high yields of 1,4-adducts (Table 2, entries 1±3).
These reaction conditions are also applicable to other silyl ketene acetals such as 2.16 While
addition to various aldehydes occurs in a comparable fashion (Table 1, entries 7±10), a slight
drop in reactivity towards enones was noticed (Table 2, entries 4 and 5).17
Use of monosubstituted enoxysilanes allowed us to address the stereochemical outcome of
these spontaneous aldolisations (Table 1, entries 7 and 11). Addition of this E silyl ketene acetal to
benzaldehyde proceeds with a slight diastereoselectivity in favour of the syn adduct (d.r. 60/40),
similarly to what was reported for the original TiCl4 catalysed Mukaiyama reaction.18 The Z
isomer 3 gives a 66/43 d.r. in favour of the same syn adduct. These observations suggest the
intervention of an acyclic transition state as generally admitted for the Lewis acid mediated
reaction.19

4883
Table 1
Table 2
In conclusion, we have found new conditions for aldolisations and Michael additions of
trimethylsilyl enoxysilanes. These ecient solvent assisted reactions can simply be carried out at
low cost and without the necessity of any metallic derivatives.
References
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4884
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scavenger (Galvinoxyl) giving the aldol product in only 60% yield (instead of 95%).
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