Alkylation of silyl enol ether

On the other hand, methylaluminum bis(4-bromo-2,6-di-fert-butylphenoxide) can effect the a-alkylation of enol silyl ethers of a variety of ketones, esters and some aldehydes108. Use of the (Z-Bu)Me2Si group is recommended in the ketene silyl acetal substrates. Use of a less bulky Me3Si or Et3Si group leads to a mixture of monoalkylation products and rearranged a-silyl esters. 

The active intermediates of these reactions are believed to be titanium enolates formed by the transmetallation with titanium(IV) chloride. Alkylation of enol silyl ethers is also elTected by use of benzyltrimethyl ammonium fluoride, in which quaternary ammonium enolates are produced as intermediates (eq (27)) [24]. 

The notion of enol silyl ethers (ESE) as electron donors was first provided by Gassman and Bottorff,34 who showed that selective (carbonyl) deprotection can be readily achieved in the presence of an alkyl silyl ether group via an electron-transfer activation (e.g., equation 9). 

Cross-coupling of enol silyl ethers with primary alkyl Grignard reagents is also catalyzed by Ni complexes, as exemplified by the conversion of an enol silyl ether into an allylsilane (equation 54) and by stereoselective alkylation (equation 55). ... 

The titanium(IV) chloride-promoted reactions of enol silyl ethers with aldehydes, ketones, and acetals, known as Mukaiyama reaction, are useful as aldol type reactions which proceed under acidic conditions (eq (23)) [20], Enol silyl ethers also undergo the Michael type reactions with enones or p.y-unsaturated acetals (eq (24)) [21]. Under similar reaction conditions, enol silyl ethers are alkylated with reactive alkyl halides such as tertiary halides or chloromethyl sulfides (eq (25)) [22], and acylated with acid halides to give 1,3-diketones (eq (26)) [23]. 

Enol silyl ether is one of the most useful organosilicon reagents, and various methods for the preparation from a variety of precursors have been investigated. The most widely used method is silation of enols or enolates of ketones or aldehydes with trialkylchlorosilanes. The reaction of ketones with triethylamine and chlorotrimethyl-silane in DMF alTords the thermodynamic equilibrium mixtures of enol silyl ethers (eq (48)) [44]. The use of silyl trifiates instead of chlorosilanes generally shortens the reaction time and permits the preparation of some enol silyl ethers which are difficult with halosilanes (eq (49)) [45]. Trialkylsilyl trifiates are also employed for the syntheses of enol silyl ethers of esters and S-alkyl thiol esters (eq (50)) [46]. 

SCHEME 3.35 Synthesis of enol silyl ethers by Ni-catalyzed reductive coupling of aryl/alkyl halides, enones, and trialkyIchlorosilane. 

A catalytic and enantioselective alkylation of Af,0-acetals, protected by the SES group, is an interesting method to prepare various chiral a-amino esters from a common precursor, the SES hydroxyglycine (21), which is easier to form and more resistant to hydrolysis than the corresponding imine (eq 21). A first equivalent of enol silyl ether reacts with iV,0-acetal (21) to form the imine intermediate in situ. Eventually, a second equivalent of enol silyl ether is necessary to perform the alkylation of the Cu(I) SES imine complex. 

In the prostaglandin synthesis shown, silyl enol ether 216, after transmetaJ-lation with Pd(II), undergoes tandem intramolecular and intermolecular alkene insertions to yield 217[205], It should be noted that a different mechanism (palladation of the alkene, rather than palladium enolate formation) has been proposed for this reaction, because the corresponding alkyl enol ethers, instead of the silyl ethers, undergo a similar cyclization[20I],... 

Titanium(IV) is a powerful but selective Lewis acid which can promote the coupling of allylsilanes with carbonyl compounds and derivatives In the presence of titanium tetrachlonde, benzalacetone reacts with allyltnmethylsilane by 1,4-addition to give 4-PHENYL-6-HEPTEN-2-ONE. Similarly, the enol silyl ether of cyclopentanone is coupled with f-pentyl chloride using titanium tetrachlonde to give 2-(tert-PENTYL)CYCLOPENTANONE, an example of a-tert-alkylation of ketones. 

Williams and Rastetter also accomplished an elegant synthesis of ( )-hyalodendrin (83) in 1980 [39]. Beginning with the sarcosine anhydride-derived enolic aldehyde 78, silyl protection of the enal enabled alkylation of the glycine center with benzyl bromide and thiolation using LDA and monoclinic sulfur a la Schmidt. After protection of the thiol with methylsulfenyl chloride and deprotection of the silyl ether, the enol was sulfenylated with triphenylmethyl chlorodisulfide to afford bis(disulfide) 82 as a 2 1 mixture of diastereomers favoring the anti isomer. Reduction of the disulfides with sodium borohydride and oxidation with KI3 in pyridine afforded ( )-hyalodendrin (83) in 29 % yield (Scheme 9.4). 

Acetals of benzaldehydes may undergo EGA-catalyzed aldol reactions also with alkyl enol ethers, (22) (R = alkyl), as nucleophiles [31] but in contrast to the reaction with enol silyl ethers the threo isomer is favored in this case. 

In the aliphatic series, the C-alkylation of enolates 17 is achieved through their O-silylated derivatives 66. In the presence of a catalytic amount of ZnBr2, the silyl enol ether 66 reacted with CICH2OCH3 to give only the C-alkylated a-ketoester 67. The alkylation is regiospecific but the ketoesters (67a, c) are obtained with modest yields (about 50% yield). 

Similarly, siloxycyclopropanes (e.g., 3) react smoothly with mercuric acetate in methanol at 20 °C to give 3-mercurio ketones (e.g., 4) [8]. The attack of the metal occurs in such a way that the less alkyl-substituted bond is cleaved. Thus, starting from the enol silyl ether, the overall sequence represents a-mercurio-methylation of the parent ketone. The reaction is likely to proceed via an ionic intermediate Eq. (10). 

Co2(CO)8-catalyzed reactions of benzylic acetates with trimethylsilane and CO proceed under mild reaction conditions to give trimethylsilylethers of /3-phenethylalcohol in 43-76% yield. The highest yields are observed for benzyl acetates with electron-donating substituents.111 Secondary alkyl acetates are also good substrates in the reaction system, yielding enol silyl ethers.112 In addition, the cobalt complex is an effective catalyst for siloxymethylation of five-membered cyclic ortho esters, as shown in Eq. (41).113... 

Unsaturated 1,5-dicarbonyl compounds. The phenylthioalkylation of silyl enol ethers of carbonyl compounds (9, 521-522) can be extended to the synthesis of unsaturated 1,5-dicarbonyl compounds. In a typical reaction the enol silyl ether of a ketone is alkylated with the unsaturated chloride 1 under ZnBr2 catalysis to give a homoallyl sulfide. Ozonolysis of the methylene group is accompanied by oxidation of the phenylthio group sulfoxide elimination results in an unsaturated 1,5-aldehydo ketone (equation I). Alkylation with 2 results in a methyl ketone (equation II). 

Rearrangement of (a-methyldiphenylsilyl)alkyl ketones.1 These a-silyl ketones rearrange thermally to a mixture of (Z)- and (E)-enol silyl ethers. However, rearrangement in acetonitrile results in only the (Z)-enol silyl ethers (>99 1). These enol silyl ethers are useful precursors to (Z)-lithium enolates. 

Alkylations of enolates, enamines, and silyl enol ethers of cyclohexanone usually show substantial preference for axial attack. The enamine of 4-f-butylcyclohexanone, which has a fixed conformation because of the i-butyl group, gives 90% axial alkylation and only 10% equatorial alkylation with n-Prl. 

The sulfide (SR) can be removed from the product with Raney nickel to give a simple ketone. This ketone has apparently been made by the alkylation of a silyl enol ether with a primary alkyl group (R2CH2). This would be impossible without stabilization of the cation by the sulfur atom. 

In this case, alkene insertion into the h-H bond is likely to occur first, producing a linear alkyl species. CO insertion would produce an acyl species, which would then be followed by reductive elimination of the acylsilane product. Enohzation, followed by rapid reaction of HSiR3 with the OH group, traps out the enol silyl ether. The Hy produced Irom this sUylation step is used to hydrogenate some of the starting alkene. Thus, the maximum yield will generally be only 66% of the enol silyl ether product. The enol silyl ethers can be readily converted into silyl ketones (equation 10). 

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