Enol ethers, silyl addition

Silylated cyanohydrins have also been prepared via silylation of cyanohydrins themselves and by the addition of hydrogen cyanide to silyl enol ethers. Silylated cyanohydrins have proved to be quite useful in a variety of synthetic transformations, including the regiospecific protection of p-quinones, as intermediates in an efficient synthesis of a-aminomethyl alcohols, and for the preparation of ketone cyanohydrins themselves.The silylated cyanohydrins of heteroaromatic aldehydes have found extensive use as... 

The Mukaiyama aldol reaction refers to Lewis acid-catalyzed aldol addition reactions of silyl enol ethers, silyl ketene acetals, and similar enolate equivalents,48 Silyl enol ethers are not sufficiently nucleophilic to react directly with aldehydes or ketones. However, Lewis acids cause reaction to occur by coordination at the carbonyl oxygen, activating the carbonyl group to nucleophilic attack. 

A number of other chiral catalysts can promote enantioselective conjugate additions of silyl enol ethers, silyl ketene acetals, and related compounds. For example, an oxazaborolidinone derived from allothreonine achieves high enantioselectivity in additions of silyl thioketene acetals.323 The optimal conditions for this reaction also include a hindered phenol and an ether additive. 

The use of oxygen-containing dienophiles such as enol ethers, silyl enol ethers, or ketene acetals has received considerable attention. Yoshikoshi and coworkers have developed the simple addition of silyl enol ethers to nitroalkenes. Many Lewis acids are effective in promoting the reaction, and the products are converted into 1,4-dicarbonyl compounds after hydrolysis of the adducts (see Section 4.1.3 Michael addition).156 The trimethylsilyl enol ether of cyclohexanone reacts with nitrostyrenes in the presence of titanium dichloride diisopropoxide [Ti(Oi-Pr)2Cl2], as shown in Eq. 8.99.157 Endo approach (with respect to the carbocyclic ring) is favored in the presence of Ti(Oi-Pr)2Cl2. Titanium tetrachloride affords the nitronates nonselectively. 

Use of trimethylsilyl triflate to bring about Piunmeier rearrangement requires the presence of a base such as a tertiary amine (vide supra equations 15 and 26). In some instances, involving attempts to alkylate Pummerer intermediates with silyl enol ethers under such conditions, the base has been found to compete as a nucleophile. In the absence of the silyl enol ether, amine addition can be very efficient. For example, treatment of methallyl phenyl sulfoxide with diisopropylethylamine and trimethylsilyl inflate in dichloromethane (equation 29) at 0 C yields the ammonium triflate indicated in 91% yield. Other tertiary amines which undergo this reaction include niethylamine and Af,Af-diethyltrimethylsiI-amine. In the latter case with allyl phenyl sulfoxide as the substrate and a mildly acidic wotk-up, the Mannich derivative shown in equation (30) can be obtained in 90% yield. ... 

Coupling reaction. Photoinduced three-component coupling combines an alkene (enol ether, silyl enol ether, 1,3-diene, etc.) and ethyl propiolate to form a carbon chain in which the two PhSe groups from PhSeSePh are separately located. The reaction starts from p-addition of PhSe radical to the ester. 

In another example, addition of phenyl vinyl selenoxide into a mixture of an indanedione, hexamethyldisilazane, and TMSCl in dichloromethane affords the a-trimethylsiloxyselenide in 70% yield (eq 67). The reaction proceeds through a sequence of in situ formation of TMS silyl enol ether, Michael addition onto the phenyl vinyl selenoxide, and seleno Pummerer rearrangement of the resulting selenoxide. Trifluoroacetic anhydride and various other trialkylchlorosilanes give the same product for this reaction, but in much lower yields. 

This reaction was first reported by Mukaiyama et al. in 1974. It is a Lewis acid-catalyzed Michael conjugate addition of silyl enol ether to o ,/3-unsaturated compounds. Therefore, it is generally referred to as the Mukaiyama-Michael reaction. Because this reaction is essentially a conjugate addition, it is also known as the Mukaiyama-Michael addition or Mukaiyama-Michael conjugate addition. This reaction is a mechanistic complement for the base-catalyzed Michael addition, j and often occurs at much milder conditions and affords superior regioselectivity. s Besides silyl enol ether, silyl ketene acetals are also suitable nucleophiles in this reaction.For the hindered ketene silyl acetals, the Lewis acid actually mediates the electron transfer from the nucleophiles to o ,/3-unsaturated carbonyl molecules.On the other hand, the Q ,j8-unsaturated compounds, such as 3-crotonoyl-2-oxazolidinone, alkylidene malonates, and a-acyl-a,/3-unsaturated phosphonates are often applied as the Michael acceptors. It has been found that the enantioselectivity is very sensitive to the reactant structures —for example, Q -acyl-Q ,j8-unsaturated phosphonates especially prefers the unique syn- vs anft-diastereoselectivity in this reaction. In addition,... 

The four most common methods for the synthesis of late transition metal enolates are oxidative addition to halocarbonyl compoxmds, ligand metathesis with main group enolates or silyl enol ethers, nucleophilic addition of anionic metal complexes to halocarbonyl electrophiles, and insertion of an a,3-imsaturated carbonyl compoimd into a metal hydride. Examples of these synthetic routes are shown in Equation 3.47-Equation 3.50. Equation 3.47 shows the synthesis of a palladium enolate complex by oxidative addition of ClCHjC(0)CHj to Pd(PPh3), Equation 3.48 shows the synthesis of a palladium enolate complex by the addition of a potassium enolate to an aryl Pd(II) halide complex, and Equation 3.49 shows the synthesis of the C-bound W(II) enolate complex in Figure 3.7 by the addition of Na[( n -C5R5)(CO)jW] to the a-halocarbonyl compound. Finally, Equation 3.50 shows the synthesis of a rhodium enolate complex by insertion of but-l-en-3-one into a rhodium hydride. This last route has also been used to prepare enolates as intermediates in reductive aldol processes. - ... 

Radical Reactions. The a-p-tolylsulfonylmethyl radical, generated using either tributyltin hydride, azobisisobutyro-nitrile, or hexabutyldistannane with UV irradiation, adds to enol ethers, enatnines, and silyl enol ethers. The addition to enam-mes shows considerable syn diastereoselectivity which can be explained on the basis of an allylic 1,3-strain model (eq 11). When an alkenic or alkynic moiety is present in the a-substituent of the a-p-tolylsulfonylmethyl radical, cyclization can occur to give five-membered ring compounds (eqs 12 and IS). ... 

Formation of Trimethylsilyl Enol Ethers from Enolizable Aldehydes and Ketones. The most common methods for preparing silyl enol ethers use silyl chlorides or silyl triflate/base combinations and need careful attention during workup of the reaction and isolation of the enol ether. Silylations with BS A are generally mild and nearly neutral and do not require the addition of a supplementary base. Ionic liquids have been used for the preparation of silyl enol ethers 31 from aldehydes and ketones 30 with BS A in good yields (eq 38). These new reaction conditions open an important alternative to the use of highly toxic HMPA as solvent. ... 

Cyclopropyl ketones can be synthesized directly from silyl enol ethers by addition of acid chlorides to a reaction mixture of Simmons-Smith reagent and the enol ether (Scheme 3). In this reaction, the Znl by-product of the cyclopropanation sequence acts as a Friedel-Crafts type catalyst to activate the acid chloride. In related studies, Grignon-Dubois and co-workers have shown that the Friedel-Crafts acylation of cyclopropyltrimethylsilanes also provides an expeditious route to cyclopropyl ketones. 

The two reaction channels described represent the most important steps following the generation of the initial radical cation and can be directly incorporated into synthetic applications involving silyl enol ether radical cations. Deprotonation of the radical cation is a way to conduct a ketone-enone transformation via the silyl enol ether. Other synthetic applications utilizing the radical cation or the a-carbonyl radical are coupling reactions of silyl enol ethers, intramolecular addition to double bonds, or introduction of substituents other than carbon at the a-carbonyl position, respectively. Examples for these synthetic transformations will be presented in the following sections. 

Carbon-carbon bonds can be similarly formed at the anomeric centerof carbohydrates. Oxonium ions, formed by the treatment of l-(2 -thiopyridyl)glycosides v/ith Silver(I) Trifluoromethanesul-fonate, can be trapped with silyl enol ethers, silyl ketene acetals, and reactive aromatic compounds, where the stereoselectivity of the addition is determined by solvent and nucleophile choice. The intramolecular version of this process has also been examined (eq 5). Similarly, bicyclic piperazinediones are available by the intramolecular trapping of iminium ions, generated from the appropriate thiopyridyl derivatives with PhHgC104 (eq 6). ... 

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). 

Although ethereal solutions of methyl lithium may be prepared by the reaction of lithium wire with either methyl iodide or methyl bromide in ether solution, the molar equivalent of lithium iodide or lithium bromide formed in these reactions remains in solution and forms, in part, a complex with the methyllithium. Certain of the ethereal solutions of methyl 1ithium currently marketed by several suppliers including Alfa Products, Morton/Thiokol, Inc., Aldrich Chemical Company, and Lithium Corporation of America, Inc., have been prepared from methyl bromide and contain a full molar equivalent of lithium bromide. In several applications such as the use of methyllithium to prepare lithium dimethyl cuprate or the use of methyllithium in 1,2-dimethyoxyethane to prepare lithium enolates from enol acetates or triraethyl silyl enol ethers, the presence of this lithium salt interferes with the titration and use of methyllithium. There is also evidence which indicates that the stereochemistry observed during addition of methyllithium to carbonyl compounds may be influenced significantly by the presence of a lithium salt in the reaction solution. For these reasons it is often desirable to have ethereal solutions... 

The in situ cyanosilylation of p-an1saldehyde is only one example of the reaction which can be applied to aldehydes and ketones in general. - The simplicity of this one-pot procedure coupled with the use of inexpensive reagents are important advantages over previous methods. The silylated cyanohydrins shown in the Table were prepared under conditions similar to those described here. Enolizable ketones and aldehydes have a tendency to produce silyl enol ethers as by-products in addition to the desired cyanohydrins. The... 

Selective fluonnation in polar solvents has proved commercially successful in the synthesis of 5 fluorouracil and its pyrimidine relatives, an extensive subject that will be discussed in another section Selective fluonnation of enolates [47], enols [48], and silyl enol ethers [49] resulted in preparation of a/phn-fluoro ketones, fieto-diketones, heta-ketoesters, and aldehydes The reactions of fluorine with these functionalities is most probably an addition to the ene followed by elimination of fluonde ion or hydrogen fluoride rather than a simple substitution In a similar vein, selective fluonnation of pyridmes to give 2-fluoropyridines was shown to proceed through pyridine difluondes [50]... 

The synthetic problem is now reduced to cyclopentanone 16. This substance possesses two stereocenters, one of which is quaternary, and its constitution permits a productive retrosynthetic maneuver. Retrosynthetic disassembly of 16 by cleavage of the indicated bond furnishes compounds 17 and 18 as potential precursors. In the synthetic direction, a diastereoselective alkylation of the thermodynamic (more substituted) enolate derived from 18 with alkyl iodide 17 could afford intermediate 16. While trimethylsilyl enol ether 18 could arise through silylation of the enolate oxygen produced by a Michael addition of a divinyl cuprate reagent to 2-methylcyclopentenone (19), iodide 17 can be traced to the simple and readily available building blocks 7 and 20. The application of this basic plan to a synthesis of racemic estrone [( >1] is described below. 

The Lewis acid mediated addition of silyl enol ethers or silylketcne acetals to oc-alkoxyaldehydcs is the most versatile and reliable method of providing chelation control in aldol-type additions3. The stereochemical outcome is as predicted by Cram s cyclic model11 ... 

A combination of diethylzinc with sulfonamides 18 or 19 offers another possibility for the enantioselective acetate aldol reaction39,41. The addition of silyl enol ethers to glyoxylates can be directed in a highly enantioselective manner when mediated by the binaphthol derived titanium complex 2040. 

An interesting example from carbohydrate chemistry is the boron trifluoride-diethyl ether complex catalyzed nucleophilic addition of silyl enol ethers to chiral imines (from n-glyceralde-hyde or D-serinal)22. This reaction yields unsaturated y-butyrolactones with predominantly the D-arabino configuration (and almost complete Cram-type erythro selectivity). 

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