Ketene silyl acetals, nucleophilic substitution

Unfortunately, attempts to perform this substitution reaction on cyclohexenol and geraniol led to the exclusive formation of the corresponding silyl ethers. It thus would seem that one requirement for effective carbon-carbon bond formation is that allylic alcohols be secondary and have possess y,y-disubstitution. Pearson, however, discovered a method with less restriction on the natiue of the substrate he used allylic acetates with y-mono-substitution or primary alcohols [96]. Not only ketene silyl acetals but also a diverse set of nucleophiles including aUyl silane, indoles, MOM vinyl ether, trimethylsilyl azide, trimethylsilyl cyanide, and propargyl silane participate in the substitution of y-aryl allylic alcohol 90 to give allylated 91 (Sch. 45). Further experimental evidence suggests that these reactions proceed via ionization to allylic carboca-tions—alcohols 90 and 92 both afforded the identical product 93. 

It is important to emphasize that three different types of reactions, i.e., electron transfer from (TPP)Co to Q (Eq. 13), Diels-Alder reaction of anthracenes with Q (Scheme 12) and hydride transfer from BNAH to Q (Scheme 14), have the common rate-determining step of Mg +-catalyzed electron transfer from these electron donors to Q. In each case, the relative catalytic dependence of A obs on [Mg ] is the same as indicated by Eq. 14, irrespective of different electron donors. The nucleophilic addition of a / ,/ -dimethyl-substituted ketene silyl acetal such as Me2C= C(OMe)OSiMe3 is also catalyzed by Mg + in MeCN [227, 228]. No reaction takes... 

Narasaka found that optically enriched oxabicydic substrate 277 bearing a vinyl sulfide moiety reacts with a silyl enol ether or ketene silyl acetal in the presence of a Lewis acid to afford the protected cyclohexenols 278a and 278b, Eq. 175 [18]. The reaction was proposed to occur via a ring-opening and alkylation sequence which is equivalent to overall nucleophilic substitution with retention of configuration. Presumably, the nucleophile attacked the carbocationic intermediate from the exo face, because the methylene-OTIPS substituent was blocking the endo side. 

In addition to allylation by the usual nucleophihc attack at the terminal carbon of allylic systems, substituted cyclopropanes are formed by the attack of a nucleophile at the central sp carbon of the allylic systems via palladacyclobutane under certain conditions. " Cyclopropanation can be understood by the attack of the enolate ion at the central carbon of TT-allylpalladiuin to form palladacyclobutane, followed by reductive elimination (Scheme 17). 2-Cyclohexenyl acetate reacts with the ketene silyl acetal of methyl acetate using the Pd catalyst coordinated by dppp, to afford cyclopropane and the expected methyl 2-cyclohexenylacetate. Cyclopropanation becomes the main path when TMEDA as a ligand and thallium acetate are added. 

Cyclopropane formation was also observed as a side reaction (1 9 up to 1 1) in the palladium-catalyzed coupling of ketene alkyl silyl acetals with open-chain and cyclic allyl acetates. The reaction is interpreted as proceeding via nucleophilic central attack of a jr-allyl intermediate. Although cyclopropane formation proceeds only with low yields, a highly stereospecific pathway was observed with substituted 3-cyclohexenyl acetates. ... 

Pearson et al. [21] described that allyl alcohols and their acetic acid esters (21) are subject to a nucleophilic substitution by silyl ketene acetals and other C- and N-nucleophi-les (Scheme 7). This process offers an advantageous alternative to transition metal catalysed processes. 

Intermolecular addition of carbon nucleophiles to the ri2-pyrrolium complexes has shown limited success because of the decreased reactivity of the iminium moiety coupled with the acidity (pKa 18-20) of the ammine ligands on the osmium, the latter of which prohibits the use of robust nucleophiles. Addition of cyanide ion to the l-methyl-2//-pyr-rolium complex 32 occurs to give the 2-cyano-substituted 3-pyrroline complex 75 as one diastereomer (Figure 15). In contrast, the 1-methyl-3//-pyrrolium species 28, which possesses an acidic C-3-proton in an anti orientation, results in a significant (-30%) amount of deprotonation in addition to the 2-pyrroline complex 78 under the same reaction conditions. Uncharacteristically, 78 is isolated as a 3 2 ratio of isomers, presumably via epimerization at C-2.17 Other potential nucleophiles such as the conjugate base of malononitrile, potassium acetoacetate, and the silyl ketene acetal 2-methoxy-l-methyl-2-(trimethylsiloxy)-l-propene either do not react or result in deprotonation under ambient conditions. 

The transition metal-catalyzed allylation of carbon nucleophiles was a widely used method until Grieco and Pearson discovered LPDE-mediated allylic substitutions in 1992. Grieco investigated substitution reactions of cyclic allyl alcohols with silyl ketene acetals such as Si-1 by use of LPDE solution [95]. The concentration of LPDE seems to be important. For example, the use of 2.0 M LPDE resulted in formation of silyl ether 88 with 86 and 87 in the ratio 2 6.4 1. In contrast, 3.0 m LPDE afforded an excellent yield (90 %) of 86 and 87 (5.8 1), and the less hindered side of the allylic unit is alkylated regioselectively. It is of interest to note that this chemistry is also applicable to cyclopropyl carbinol 89 (Sch. 44). 

By analogy with previous results with enol silyl ethers of ketones, non-substituted silyl ketene acetals result in less stereoregulation. Propionate-derived silyl ketene acetals, on the other hand, result in a high level of asymmetric induction. Reactions with aliphatic aldehydes, however, result in slightly reduced optical yield. With phenyl ester-derived silyl ketene acetals, erythro adducts predominate, but selectivities are usually moderate compared with the reactions of ketone silyl enol ethers. Exceptions are a, 8-unsaturated aldehydes, for which diastereo- and enantioselectivity are excellent. The observed erythro selectivity and re-face attack of nucleophiles on the carbonyl carbon of aldehydes are consistent with the aforementioned aldol reactions of ketone enol silyl ethers [47]. 

The second method involves end-quenching of living polymers with appropriate nucleophiles. Although this approach appears to be more attractive than the first one, in situ end funaionali-zation of the living ends is limited to nucleophiles that do not react with the Lewis add coinitiator. Because the ionization equilibrium is shifted to the covalent spedes, the concentration of the ionic active species is very low. Quantitative functionalization can only be accomplished when ionization takes place continuously in the presence of nudeophile. Quenching the vinyl ether polymerization with the malonate anion,certain silyl enol ethers " and silyl ketene acetals have been successfully used to synthesize end-functionalized poly(vinyl ethers). Alkyl amines, " ring-substituted anilines, " " alcohols, " and water " have also been used to quench the vinyl... 

The stereoselectivity in TiCU-promoted reaction of silyl ketene acetals with aldehydes may be improved by addition of Triph-enylphosphine (eq 12). Enol ethers, as well as enol acetates, can be the nucleophile (eqs 13 and 14). 2-Acetoxyfuran, in analogy to vinyl acetates, reacts with aldehydes to furnish 4-substituted butenolides under the influence of TiCU (eq IS). ... 

Activation of C-X Bonds. Even more important than carbonyl activation, ZnBr promotes substitution reactions with suitably active organic halides with a variety of nucleophiles. Alkylation of silyl enol ethers and silyl ketene acetals using benzyl and allyl halides proceeds smoothly (eq 13). Especially useful electrophiles are a-thio halides which afford products that may be desulfurized or oxidatively eliminated to result in a,p-unsaturated ketones, esters, and lactones (eq 14). Other electrophiles that have been used with these alkenic nucleophiles include Chloromethyl Methyl Ether, HC(OMe)3, and Acetyl Chloride... 

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