Ketene t-Butyldimethylsilyl Methyl Acetal1

[91390-62-4]  · C9H20O2Si  · Ketene t-Butyldimethylsilyl Methyl Acetal  · (MW 188.34)

(silylation of a variety of substrates;3 promotion of Pummerer reaction of sulfoxides;4-8 Lewis acid mediated aldol-type8-22 and Michael additions,31-38 under either stoichiometric or catalytic conditions)

Physical Data: colorless liquid; bp 76-76.5 °C/24 mmHg.

Solubility: sol n-pentane, diethyl ether, dichloromethane, etc.

Analysis of Reagent Purity: (NMR) 1H 0.14 (s, 6H), 0.93 (s, 9H), 2.95 (d, 1H, J = 3.0 Hz), 3.10 (d, 1H, J = 3.0 Hz), 3.49 (s, 3H) ppm.

Preparative Method: obtained by reaction of methyl acetate with Lithium Diisopropylamide in THF/HMPA and subsequent trapping with t-Butyldimethylchlorosilane (72% yield).2

Handling, Storage, and Precautions: should be stored in the absence of moisture at -15 °C.

Silylation.

The reagent silylates a variety of substrates (alcohols, acids, thiols, phenols, imides) under mild conditions (a catalytic amount of p-Toluenesulfonic Acid is occasionally added) with excellent yields (91-100%).3

Pummerer Reaction.

The reagent transforms sulfoxides in the presence of catalytic amounts of Zinc Iodide into the corresponding a-silyloxy sulfides (eq 1).4 Vinyl sulfoxides undergo a Michael-Pummerer type reaction to give g-silyloxy-g-phenylthio esters (eq 2).5

As an extention of this reaction, the reagent promotes the intramolecular Pummerer-type rearrangement of o-carbamoyl sulfoxides to give a-thio lactams.6 The reaction proves particularly useful in the field of b-lactam synthesis (eq 3).7,8a

Addition to C=X Double Bonds (X = N, O).1b

The reagent undergoes Lewis acid catalyzed Mukaiyama-type additions1b to azetinones, or their corresponding iminium ions, to give trans-azetidin-2-one esters with good yields and excellent stereoselectivity (eq 4).7b,8,9

In the presence of a diphosphonium salt (7 mol %),10a Trimethylsilyl Trifluoromethanesulfonate (10 mol %),10b or Iron(III) Nitrate-K10 Montmorillonite Clay,10c the reagent adds to imines or N-tosyliminium ions to give the corresponding b-amino esters in good yield.

ZnI2-catalyzed additions of the reagent to chiral a,b-dialkoxy nitrones (eq 5; R1 = H) proceed with good yield (86-100%) and high diastereoselectivity (ca. 90:10) in favor of the syn isomer (R1 = H, R2 = CH2Ph, R3 = Me). The anti isomer is obtained (ca. 90:10) by increasing the steric hindrance of R2 and R3 (R2 = CHPh2, R3 = t-Bu).11a,b Addition to a different nitrone (eq 5; R1 = Me) gives the anti isomer (R1 = Me, R2 = CHMePh, R3 = Me) in quantitative yield and 100% diastereofacial selectivity. This material has been further elaborated to N-benzoyl-L-daunosamine.11c,d

New catalysts have been recently developed for promoting the aldol-type addition of acetate-derived silyl ketene acetals with high efficiency: 10-methylacridinium perchlorate (5 mol %),12a cationic mono- and dinuclear iron complexes (5 mol %),12b t-butyldimethylsilyl chloride-indium(III) chloride (10 mol %),12c [1,2-benzenediolato(2-)-O,O]oxotitanium (20 mol %),12d phosphonium salts (7 mol %),12e and trityl salts (5-20 mol %).12f-i The reagent undergoes Lewis acid promoted Mukaiyama-type additions1b to chiral aldehydes with moderate to good stereocontrol (eq 6).13 It is remarkable that high chelation control can be obtained by using a catalytic amount (3 mol %) of Lithium Perchlorate.13e,f

With other substrates and under different conditions (eqs 7 and 8), non-chelated products are obtained with excellent selectivity.13f,14

In the field of C-glycoside synthesis, selective b-glycosylation is realized via neighboring group participation of a 2a-acyl group.15a In the case of 2-deoxy sugars the neighboring participation of a group at the 3a-position is exploited for selective formation of the b-anomer (b:a = 91:9) (eq 9).15b

Enantioselective Aldol-Type Additions.

Highly enantioselective aldol-type reactions are successfully carried out by the combined use of a chiral diamine-coordinated tin(II) triflate and tributyltin fluoride (eq 10).16,17 A catalytic amount of chiral bis(sulfonamido)zinc(II), easily prepared from diethylzinc and chiral sulfonamides, promotes the aldol addition in high yield and good enantiomeric excess (72-93%) only with chloral and bromal (CX3CHO).18

Chiral borane complexes (20 mol %) catalyze the aldol-type addition to achiral aldehydes in good to excellent yield and enantiomeric excess (eq 11).19-21

A chiral boron reagent, derived from equimolar amounts of (R)- or (S)-binaphthol and triphenyl borate, promotes the condensation of chiral imines with t-butyl acetate silyl ketene acetal in high diastereomeric excess (eq 12).22

Addition to Various Electrophiles.

Various Lewis acids promote the addition of the reagent to an allylic acetate, following a carbon-Ferrier rearrangement pathway.23 Titanium(IV) Chloride promotes the addition of the reagent to 2,2-dialkoxycyclopropanecarboxylic esters to give 3-alkoxy-2-cyclopentenones (eq 13).24

1,3-Dioxolan-2-ylium cations, derived from aldehyde ethylene acetals and trityl cation, react with the reagent to give the corresponding b-keto esters.25 Montmorillonite K10 catalyzes the addition of the reagent to pyridine derivatives with electron withdrawing groups to give N-silyldihydropyridines.26 The ketene silyl acetal of ethyl acetate reacts with a chiral bromide to give the corresponding syn-lactone in 64% yield via a direct SN2-type displacement and inversion of stereochemistry (eq 14).27

Six-membered chiral acetals, derived from aliphatic aldehydes, undergo aldol-type coupling reactions with silyl ketene acetals in the presence of TiCl4 with high diastereoselectivity (eq 15).28 This procedure, in combination with oxidative destructive elimination of the chiral auxiliary, has been applied to the preparation of (R)-(+)-a-lipoic acid28a and mevinolin analogs.28b

Addition to chiral, bicyclic acetals has been exploited in an approach to the synthesis of the tetrahydropyran subunit of the polyether nigerin.29 The particular acetal generated by the Diisobutylaluminum Hydride reduction of aliphatic esters undergoes aldol addition in good yields (eq 16).30

Michael Addition.

The reagent undergoes Michael addition to a,b-enones in acetonitrile in the absence of a Lewis acid to afford the corresponding O-silylated Michael adducts in high yield. These silyl enol ethers undergo site-specific reaction with a variety of electrophiles (eq 17).31a,b Inability to repeat this procedure led to the discovery that the `noncatalyzed' Michael reaction is due to traces of phosphorus compounds introduced by drying acetonitrile with P4O10. The new catalyst system, formed from P4O10 in acetonitrile, was found to be highly effective with a variety of substrates.31c

In those instances where the thermal Michael reaction is sluggish due to sterically hindered substrates, the use of high pressure (15 kbar, 20 °C),32a or of LiClO4 (3 mol % in CH2Cl213f or 1.0-2.5 M in Et2O32b) prove extremely advantageous (eq 18). The lithium perchlorate-catalyzed Michael reaction can be carried out on a,b-unsaturated d-lactones and on sterically demanding b,b-disubstituted unsaturated carbonyl systems in high yield and under mild conditions.32b

Michael addition of the reagent to enoates and enones occurs at low temperature (-50 to -78 °C) in the presence of catalytic amounts of various Lewis acids.33 A catalytic amount of Triphenylmethyl Perchlorate (5 mol %) effectively catalyzes the tandem Michael reaction of ethyl acetate-derived silyl ketene acetal to a,b-unsaturated ketones and the sequential aldol addition to aldehydes with high stereoselectivity.34 HgI2 mediates the Michael addition to chiral enones, followed by Lewis acid-mediated addition to aldehydes. The Michael-aldol protocol has been used for the stereoselective synthesis of key intermediates on the way to prostaglandins, compactin, and ML-236A (eq 19).35

The mechanism of the TiCl4-mediated Michael addition of silyl ketene acetals has been investigated, and criteria for suppressing the electron transfer process have been devised.36 Chiral enones show good to excellent diastereofacial preference in TiCl4-mediated reactions with silyl ketene acetals (eq 20).37

ZnI2-mediated multiple Michael additions to bis-enoates proceed in good yield and with modest stereocontrol (eq 21).38

Related Reagents.

1-t-Butylthio-1-t-butyldimethylsilyloxypropene; 1-t-Butylthio-1-t-butyldimethylsilyloxyethylene.


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Cesare Gennari

Università di Milano, Italy



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