Silyl ketone enolates

A useful catalyst for asymmetric aldol additions is prepared in situ from mono-0> 2,6-diisopropoxybenzoyl)tartaric acid and BH3 -THF complex in propionitrile solution at 0 C. Aldol reactions of ketone enol silyl ethers with aldehydes were promoted by 20 mol % of this catalyst solution. The relative stereochemistry of the major adducts was assigned as Fischer- /ir o, and predominant /i -face attack of enol ethers at the aldehyde carbonyl carbon atom was found with the (/ ,/ ) nantiomer of the tartaric acid catalyst (K. Furuta, 1991). 

Palladium-catalyzed bis-silylation of methyl vinyl ketone proceeds in a 1,4-fashion, leading to the formation of a silyl enol ether (Equation (47)).121 1,4-Bis-silylation of a wide variety of enones bearing /3-substituents has become possible by the use of unsymmetrical disilanes, such as 1,1-dichloro-l-phenyltrimethyldisilane and 1,1,1-trichloro-trimethyldisilane (Scheme 28).129 The trimethylsilyl enol ethers obtained by the 1,4-bis-silylation are treated with methyllithium, generating lithium enolates, which in turn are reacted with electrophiles. The a-substituted-/3-silyl ketones, thus obtained, are subjected to Tamao oxidation conditions, leading to the formation of /3-hydroxy ketones. This 1,4-bis-silylation reaction has been extended to the asymmetric synthesis of optically active /3-hydroxy ketones (Scheme 29).130 The key to the success of the asymmetric bis-silylation is to use BINAP as the chiral ligand on palladium. Enantiomeric excesses ranging from 74% to 92% have been attained in the 1,4-bis-silylation. 

E)-Enol silyl ethers.1 A new highly stereoselective route to (E)-enol silyl ethers involves addition of CH,Li to silyl ketones substituted at the a -position by a SC6H5 group such as 1. The adduct (a) undergoes a Brook rearrangement and... 

Silyl enol ethers have also been used as a trap for electrophilic radicals derived from a-haloesters [36] or perfluoroalkyl iodides [32]. They afford the a-alkylated ketones after acidic treatment of the intermediate silyl enol ethers (Scheme 19, Eq. 19a). Similarly, silyl ketene acetals are converted into o -pcriluoroalkyl esters upon treatment with per fluoro alkyl iodides [32, 47]. The Et3B/02-mediated diastereoselective trifluoromethylation [48,49] (Eq. 19b) and (ethoxycarbonyl)difluoromethylation [50,51] of lithium eno-lates derived from N-acyloxazolidinones have also been achieved. More recently, Mikami [52] succeeded in the trifluoromethylation of ketone enolates... 

This method can also be applied to silyl enol ethers of homologous unsaturated ketones as well as of unsaturated aldehydes or esters [85-87]. While unmodified unsaturated esters give only the corresponding aldehydes without cyclization under tandem hydroformylation/aldol reaction conditions, the corresponding silylated ester enolates smoothly cyclize in a tandem hy-droformylation/ Mukaiyama aldol reaction (Scheme 32) [85-87]. 

Ketone Enolates Derived from Silyl Enol Ethers as Nucleophiles... 

Scheme 9.15 Alkylations with ketone enolates derived from silyl enol ethers as nucleophiles.

Retro-Brook rearrangement of the [l,3]-variant will readily take place in sp and sp carbanion systems. Kuwajima and Takeda and Corey and Rticker have developed the [l,3]-retro-Brook rearrangement of silyl enol ether anions which provide a-silyl ketones (equation 100 and 101). 

ElectrophiHc substitutions with carbon and hetero electrophiles a to the carbonyl group of aldehydes and ketones are among the most important synthetic operations. Such regio-, diastereo-, and enantioselective substitutions can be carried out efficiently with the SAMP/RAMP hydrazone methodology [3]. For cases where virtually complete asymmetric inductions could not be attained, an alternative approach based on a-silylated ketones 2 was developed [4]. They can be prepared easily from ketones 1 in high enantiomeric purity (ee > 98%) by asymmetric carbon silylation employing the SAMP/RAMP hydrazone method (Fig. 1.1.1). After the introduction of various electrophiles via classical enolate chemistry with excellent asymmetric inductions, the desired product ketones 3... 

As depicted in Scheme 1.1.2, the silyl ketones (S)-ll of high enantiomeric purity were converted into the Z-configured silyl enol ethers (S) -12, which were used in the aminomethylation step by treatment with dibenzyl(methoxymethyl)amine in the presence of a Lewis acid. The silylated Mannich bases S,R)-13 were obtained in excellent yields and diastereomeric excesses (de = 92-96%). Finally,... 

Analogues of (751) react with derivatives of phosphorus-containing acids to form 1-phosphoryl-imidazoles (90CHE599). The same compound also silylates ketones to give enol silyl ethers and/or siloxyalkylimidazoles (Scheme 107) (87JC271). 

Enantioselective condensation of aldehydes and enol silyl ethers is promoted by addition of chiral Lewis acids. Through coordination of aldehyde oxygen to the Lewis acids containing an Al, Eu, or Rh atom (286), the prochiral substrates are endowed with high electrophilicity and chiral environments. Although the optical yields in the early works remained poor to moderate, the use of a chiral (acyloxy)borane complex as catalyst allowed the erythro-selective condensation with high enan-tioselectivity (Scheme 119) (287). This aldol-type reaction may proceed via an extended acyclic transition state rather than a six-membered pericyclic structure (288). Not only ketone enolates but ester enolates... 

Silyl enol ethers Trimethylsilyl enol ethers can be obtained from a-silyl ketones by thermal rearrangement or by catalysis with HRh(CO)[P(C6H5)3]3, (CH3)3SiOTf, or ISi(CH3)3. The first two methods are (E)-selective in the case of unsymmetrical ketones, whereas the latter two are (Z)-selective. 

Ketoacids126,127 form the same intermediates as the allyl 3-ketoesters by nucleophilic addition of the carboxylate to a n-allylpalladium complex. Decarboxylation generates the allylpalladium enolate, which again yields Pd° and allylated ketone. Enol silyl ethers have also been employed with allyl arsenites93 to provide allylated ketones. 

Figure 12.24 depicts the oxidation of a silyl enol ether A to give an a,/3-unsaturated ketone B. Mechanistically, three reactions must be distinguished. The first justifies why this reaction is introduced here. The silyl enol ether A is electrophilically substituted by palladium(II) chloride. The a-palladated cyclohexanone E is formed via the intermediary O-silylated oxocarbenium ion C and its parent compound D. The enol content of cyclohexanone, which is the origin of the silyl enol ether A, would have been too low to allow for a reaction with palladium(II) chloride. Once more, the synthetic equivalence of a silyl enol ether and a ketonic enol is the basis for success (Figure 12.24). 

Tsai and coworkers89,91,246,247 reported the synthesis of cyclic silyl enol ethers and silyl ethers by using a radical cyclization followed by the radical Brook rearrangement (equation 111). The cyclization of 4-bromo-4-stannylbutyl silyl ketones 188 in benzene with a catalytic amount of tributyltin hydride and AIBN gave cyclic silyl enol ethers 18989 91 247. The whole catalytic cycle proposed is shown in equation 112. 

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. 

Simpkins and coworkers reported the use of chiral bases in the enantioselective generation of bridgehead enolates (Scheme 36)76. Initial studies revealed that external quench protocols were ineffective in trapping the carbanion. Addition of a mixture containing chiral base (R,R) 3 and LiCl to a solution of ketone 55 and TMSC1 at —105 °C gave mono (—)-a-silylated ketone 56 in 76% yield and >96% ee. 

Among common carbon-carbon bond formation reactions involving carbanionic species, the nucleophilic substitution of alkyl halides with active methylene compounds in the presence of a base, e. g., malonic and acetoacetic ester syntheses, is one of the most well documented important methods in organic synthesis. Ketone enolates and protected ones such as vinyl silyl ethers are also versatile nucleophiles for the reaction with various electrophiles including alkyl halides. On the other hand, for the reaction of aryl halides with such nucleophiles to proceed, photostimulation or addition of transition metal catalysts or promoters is usually required, unless the halides are activated by strong electron-withdrawing substituents [7]. Of the metal species, palladium has proved to be especially useful, while copper may also be used in some reactions [81. Thus, aryl halides can react with a variety of substrates having acidic C-H bonds under palladium catalysis. 

Relatively less acidic ketones compared to 1,3-dicarbonyl compounds are also suitable substrates for the palladium catalyzed coupling. a-Aryl ketones are obtained as products. In the early examples, masked ketone enolates such as silyl enol ethers [42] and enol acetates [43-45] were used in the presence of a tin source. These reactions involve tin enolates or acylmethyltins as intermediates and thus proceed by transmetalation (mechanism B in Scheme 1). 

OL-Iodo aldehydes and ketones. Enol silyl ethers are converted by this system into a-iodo carbonyl compounds in yields of >80%. 1 he method fails with enamines, and is only marginally useful with enol ethers. This system converts cyclohexene into trans- -chloro-2-iodocyclohexane (66% yield). 

OL-Silyl ketones,l Silyl enol ethers with sterically hindered silyl groups rearrange to a-silyl ketones in the presence of /i-BuLi (2 equiv.) and KO-f-Bu (2.5 equiv.). Tri-methylsilyl ethers do not undergo this rearrangement, but triisopropylsilyl (TIPS) and diisopropylmethylsilyl (DIMS) ethers do if they contain an allylic a-proton. The silyl group rearranges preferentially to the less hindered terminus of the intermediate allyl anion. The rearrangement is less useful with acyclic substrates because of side reactions. 

Aldol coupling of chiral acetals.6 The acetals (2) prepared from an aldehyde and (2R,4R)-pentanediol react with a-silyl ketones or enol silyl ethers in the presence of TiCl4 to form aldol ethers 3 and 4 with high diastereoselectivity (>95 5). Removal of the chiral auxiliary usually results in decomposition of the aldol, but can be effected after reduction... 

The sulfenylation of metalloimines is equally applicable to ketones, although using more reactive sulfur electrophiles it is possible to bring about reaction on the unmetallated enamine. ° Sulfenylation of ketone enol silyl ethers also proceeds well with the more reactive sulfur species. Sulfenamides and their derivatives e.g. 11) are particularly suited to the direct sulfenylation of ketones and active methylene compounds such as -diketones, -keto esters and malonates, which undergo facile reaction at room temperature (equation 5). This procedure, however, does not appear to have been exploited for the dehydrogenation of active methylene compounds icf. Section 2.2.4.1). By preparing the dianion (13)... 

The use of Moriarty s hypervalent iodine system vide supra) has been extended to reaction with silyl enol ethers. In this case a more activated electrophile is required and the reactions are carried out with iodosylbenzene in the pres ice of boron trifluoiide etherate. However, yields are only moderate and the process seems less useful than the corresponding ketone/enol application. 

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). 

---