1-Methoxy-1-(trimethylsilyloxy)propene1

(1; R1 = Me, R2 = Me)

[34880-70-1]  · C7H16O2Si  · 1-Methoxy-1-(trimethylsilyloxy)propene  · (MW 160.32) (E)-(1)

[72658-09-4] (Z)-(1)

[72658-03-8] (2; R1 = t-Bu, R2 = Et)

[83165-77-9]  · C11H24O2Si  · 1-Ethoxy-1-(t-butyldimethylsilyloxy)propene  · (MW 216.44) (E)-(2)

[89043-55-0] (Z)-(2)

[73967-98-3]

(reactive nucleophile in Mukaiyama-type aldol reactions2,3 with aldehydes,15-29 imines,30 acetals,36 dialkoxycarbenium ions,40 and orthoesters;41 Michael-type additions to a,b-unsaturated carbonyl compounds;42-46 substitution reactions with allylic alcohols and esters;56 acylations;53 aminations;54 hydroxylations;55 and pericyclic reactions;59 silylating agent67)

Alternate Name: methylketene methyl trimethylsilyl acetal.

Physical Data: (Z)-(1): bp 57 °C/18 mmHg; 1H NMR data have been reported.11 (Z)- and (E)-(2): 1H and 13C NMR data have been reported.8b

Solubility: highly sol organic solvents.

Preparative Methods: since the first preparation of a ketene trialkylsilyl acetal by Petrov in 1959 by the reaction of triethylsilane and methyl acrylate,4 several alternative pathways have been explored.5 Ainsworth and co-workers prepared 1-methoxy-1-(trimethylsilyloxy)propene in 90% yield by deprotonation of methyl propionate with Lithium Diisopropylamide at -78 °C followed by addition of Chlorotrimethylsilane.6 Reaction of the lithium enolate of methyl acetate with TMS-Cl provides 65% O-silylated and 35% C-silylated products (eq 1).7 Substitution on the alcohol portion of the ester favors C-silylation while substitution on the a-carbon favors O-silylation. An increase in the steric bulk of the silylating agent (e.g. use of t-Butyldimethylchlorosilane) results in significantly more O-silylation.

Silyl ketene acetal geometry is controlled by the selective formation of the (E)- and (Z)-ester enolate. Deprotonation of methyl propionate with LDA in THF at -78 °C gives, upon silylation, a 6:94 ratio of the thermodynamic (Z) and kinetic (E) silyl ketene acetals (eq 2).8 As noted by Ireland and co-workers, a change in the reaction solvent results in a reversal in selectivity. In a THF-23% HMPA mixture, the silyl ketene acetals are isolated in a 84:16 ratio. In THF-45% DMPU ratios of up to 98:2 are obtained. With bulkier amide bases and in the absence of dipolar additives, a (Z):(E) ratio of 5:95 is observed.9,10

Treatment of alkyl carboxylates with trialkylsilyl triflates in the presence of Triethylamine yields the thermodynamically more stable (Z)-ketene acetals at rt; however, a mixture of O- and C-silylated products is generally obtained.11 The (Z)-isomers are also prepared by the reaction of triethylsilyl perchlorates with aliphatic esters.12 The action of zinc powder on a-bromo esters in the presence of TMS-Cl and TMEDA-Et3N leads mainly to (E)-ketene acetals, while the reaction of trialkylsilanes on alkyl acrylates catalyzed by Wilkinson's reagent (Chlorotris(triphenylphosphine)rhodium(I)) gives the corresponding (Z)-isomers (Z:E >98:2).13

Handling, Storage, and Precautions: easily hydrolyzed and oxidized by exposure to air. Storage is possible in sealed tubes at rt. Use in a fume hood.

Alkylation.

The a-t-alkylation of silyl ketene acetals was reported by Reetz and Schwellnus.14

Additions to Aldehydes, Imines, and Oximes.

Silyl ketene acetals add to aldehydes2,3,19 in the presence of a Lewis acid (TiCl4, BF3, SnCl4, TrClO4, cationic iron complexes,15 HgI2,16 lanthanides,17 and clay montmorillonite).18 High diastereofacial selectivity in Lewis acid-mediated additions of methylketene acetals to aldehydes was reported by Heathcock and Flippin.20 -24 The scope of this reaction was further extended by the introduction of camphor and N-methylephedrine derived chiral silyl ketene acetals.25-28 The asymmetric variant of the Mukaiyama reaction also provides an efficient anti-selective chiral propionate equivalent (eqs 3 and 4). Reetz and Fox used a catalytic amount of Lithium Perchlorate suspended in CH2Cl2 for Mukaiyama aldol reactions of aldehydes with a silyl ketene acetal.29

High diastereoselectivities have been achieved in the Lewis acid-mediated addition of silyl ketene acetals to imines (eq 5).30,31 In related applications, additions of O-silylated ketene acetals to b-lactams were used in the synthesis of carbapenem antibiotics.32-34 Sekiya and co-workers have demonstrated that silyl ketene acetals add to O-benzyl oxime ethers in the presence of catalytic amounts of Trimethylsilyl Trifluoromethanesulfonate to afford b-benzyloxy amino esters.35

Additions to Acetals, Dialkoxycarbenium Ions, and Orthoesters.

Much attention has focused on the use of methylketene derivatives for the opening of chiral acetals.36 Trimethylsilyl triflate-catalyzed addition of (E)-methylketene methyl trimethylsilyl acetal to benzaldehyde dimethyl acetal gives syn- and anti-esters in a 50:50 ratio, whereas the (Z)-silyl ketene acetal results in a 55:45 ratio (eq 6).37

A chain-extended trimethylsilyl ketene acetal was used by Johnson et al. in combination with Titanium(IV) Chloride for a stereoselective acetal opening in the preparation of enantiomerically pure mevinolin analogs (eq 7).38,39

1,3-Dioxolan-2-ylium cations react with silyl ketene acetals to give b-keto esters, selectively monoprotected at the ketone carbonyl (eq 8).40

The reaction of an enolic orthoester with silyl ketene acetals results in the regiospecific formation of diketo ester monoacetals.41

Additions to a,b-Unsaturated Carbonyl Compounds.

The TiCl4-catalyzed addition of silyl ketene acetals to a,b-unsaturated enones is often superior to enolate addition protocols, especially for the preparation of b-quarternary centers.42,43 Danishefsky and co-workers reported an interesting tandem Michael-aldol sequence (eq 9).44 Acetonitrile or high pressure are often sufficient to promote additions in the absence of a Lewis acid.45,46 In a related process, aromatic heterocycles can be prepared by addition of silyl ketene acetals to nitrobenzenes.47

Alkylations with Allylic Alcohols and Esters.

Pearson and Schkeryantz48 used a lithium perchlorate-promoted substitution of a tertiary alcohol with ketene silyl acetals for the preparation of a key intermediate in the synthesis of (±)-g-lycorane.49,50 Grieco and co-workers have also used cyclopropyl alcohols in substitution reactions of this type.51 Pd0-catalyzed coupling of allyl acetates and ketene silyl acetals leads to cyclopropane derivatives via alkylation of the central carbon (C-2) of the allyl group.52

Acylation, Amination, and Hydroxylation.

Acylation of silyl ketene acetals with acid chlorides occurs regioselectively and results in b-keto esters after acid hydrolysis.53 a-Amino acid esters are prepared by amination of silyl ketene acetals with 3-acetoxyaminoquinazolin-4(3H)-ones followed by N-N bond cleavage.54 Silyl ketene acetals may be epoxidized by peroxyacids and subsequently cleaved with fluoride ion to reveal the a-hydroxy esters.55 Related sequences involve 1O2,56 and Lead(IV) Acetate,57 as well as camphor-derived auxiliaries.58

Claisen Rearrangements.

Silyl ketene acetals of allyl esters undergo rapid Claisen rearrangements,8b,59 at or above rt to give g,d-unsaturated carboxylic acid derivatives (eq 10).60

Reactions with Sulfur-Containing Electrophiles.

Paterson has developed an alkylation of geminal phenylthio chlorides with silyl enol ethers as a general method to prepare 1,5 dicarbonyl compounds (eq 11).61 Alkylation of the silyl enol ether gives a homoallylic sulfide. Ozonolysis of the alkene with concomitant sulfur oxidation produces an unstable sulfoxide which is thermally extruded to give a mixture of alkene isomers.

The ketene acetal has also been reported to react with dithianyl cations. Treatment of 1,3-dithian-2-ylium tetrafluoroborate with the silyl enol ether results in a b-dithio ester which can subsequently be hydrolyzed to a b-keto ester (eq 12).62

Cycloadditions and Photochemistry.

Silyl ketene acetals undergo inverse electron demand hetero-Diels-Alder reactions with enones.63 Photochemically induced Diels-Alder and [2 + 2] cycloadditions of silyl ketene acetals with dienes have been reported by Schuster and co-workers.64 Cyclopropanes with vicinal donor and acceptor ligands will heterolytically cleave to form zwitterionic intermediates. In the presence of the ketene silyl acetal, a [3 + 2] cycloaddition reaction can occur with the zwitterionic intermediate to form highly substituted cyclopentenones (eq 13).65

Reactions with Nitrenes.

N-Protected a-amino esters are produced by the reaction of (ethoxycarbonyl)nitrene with methylketene ethyl trimethylsilyl acetal.66

Use as a Silylating Agent.

1-Methoxy-1-(trimethylsilyloxy)propene has been used as a mild silylating agent for phenols, alcohols, carboxylic acids, thiols, and amides.67

Related Reagents.

Ketene Bis(trimethylsilyl) Acetal; Ketene t-Butyldimethylsilyl Methyl Acetal; Ketene Diethyl Acetal; 1-Methoxy-3-methyl-1-trimethylsilyloxy-1,3-butadiene; 1-Methoxy-2-trimethylsilyl-1-(trimethylsilyloxy)ethylene; Methylketene Bis(trimethylsilyl) Acetal; Methylketene Dimethyl Acetal; Tris(trimethylsilyloxy)ethylene.


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Peter Wipf

University of Pittsburgh, PA, USA

Dennis Wright & Mark C. McMills

Ohio University, Athens, OH, USA



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