Alkylation acyclic ketone enolates

Extraannular chirality transfer has been observed for alkylations of acyclic ketone enolates having chiral (3-carbon atoms (Scheme 24). In these reactions, methylation occurs anti to the (3-dimethylphe-nylsilyl and (3-isopropyl groups with good to excellent diastereoselectivity. Variation in the size of the... 

With these substrates, achiral 1-24 is strongly favoured with Pd catalysts (for other metals, the situation is different) except in special cases. Diazaphos-pholidine-oxazoline 20 shows moderate performance in the alkylation of butenyl acetate compared to the exceptionally good results with SiocPhox phosphonamidate ligands for alkyl- and aryl-substituted substrates. The same type of ligands have also been applied to the alkylation of other challenging substrates such as polyenyl esters and acyclic ketone enolates. ... 

A study of the alkylation of the trimethylsilyl enol ether of octahydro-1 (2//)-naphthalenone reveals that the diastereoselectivity of the reaction is similar to that of the methylation of the corresponding lithium enolate (see Section 1.1.1.3.1.1.2 1.)89. Lewis acid cataly2ed phenyl-thioalkylations of the type indicated (i.e., 3 -> 4) have been used for a-alkylations of several cyclic and acyclic ketones, as well as aldehydes89. The easy removal of the phenylthio group by catalytic hydrogenation completes this convenient procedure for a-alkylation of carbonyl compounds89. 

The /3-oxido carbenoid rearrangement then took place to give one-carbon expanded magnesium enolate having a chlorine atom (217), which was treated with water to afford a-chloroketone (218) in moderate yield. Unfortunately, this method could not be applied to larger cycloalkanones and acyclic ketones. Application of this method to aldehydes gave chloromethyl aryl ketones and chloromethyl alkyl ketones in moderate yields. ... 

Palladium-catalysed asymmetric a-allyl alkylation of acyclic ketones has been reported allyl enol carbonates of a wide range of ketones undergo allyl transfer in high yields and ees at room temperature.197... 

For satisfactory diemo- and stereoselectivity, most catalytic, direct cross-aldol methods are limited to the use of non enolizable (aromatic, a-tert-alkyl) or kineti-cally non enolizable (highly branched, ,/funsaturated) aldehydes as acceptor carbonyls. With aromatic aldehydes, however, enantioselectivity is sometimes moderate, and the dehydration side-product may be important. With regard to the donor counterpart, the best suited pronucleophile substrates for these reactions are symmetric ketones (acetone) and ketones with only one site amenable for enolization (acetophenones). With symmetric cyclic or acyclic ketones superior to acetone, syn/anti mixtures of variable composition are obtained [8b, 11, 19a]. Of particularly broad scope is the reaction of N-propionylthiazolidinethiones with aldehydes, which regularly gives high enantioselectivity of the syn aldol adduct of aromatic, a,fi-unsaturated, branched, and unbranched aldehydes [13]. 

The reaction of these lithium enolates with alkyl halides is one of the most important C-C bondforming reactions in chemistry. Alkylation of lithium enolates Works with both acyclic and cyclic ketones as well as with acyclic and cyclic esters (lactones). The general mechanism is shown below, alkylation of an ester enolate alkylation of a ketone enolate... 

Ethyl a-(bromomethyl)acrylate has proved to be an excellent reagent for conversion of aldehydes and ketones, both acyclic and cyclic, into the corresponding a-methylene-y-butyrolactone derivatives4"9 in a Re-formatsky type reaction. The yield was excellent in the case of several spiro a-methylene-y-butyrolactones.10 Synthetic a-methylene-y-butyrolactone derivatives have been shown to possess antitumor activity.5 6,7 1112 Ethyl a-(bromomethyl)acrylate has also proven of value in the synthesis of alkylated products of enol ethers of cyclohexane-1,3-dione.13... 

Conversely, Hosomi and Sakurai have shown that deprotonation with alkyllithium reagents occurs predominantly at the more substituted side of the cyclohexylimine of 2-methylcyclohexanone (equation 41). However, the low yield in this sequence (as compared with, for example, equations 39 and 40) places this route to 2,2-disubstituted systems only equal with other techniques such as those that employ the more stable enolate-derived 2-alkyl cyclic ketones. Further, in no case did deprotonation of an unsymmetrical, acyclic ketone imine with an alkyllithium result in synthetically usable selectivity for the more substituted carbon. 

Enolate equilibration and di- and poly-alkylation are the major side reactions, which lead to reduced yields of desired products in ketone alkylations. These processes occur as a result of equilibration of the starting enolate (or enolate mixture) with the neutral monoalkylation product(s) via proton transfer reactions. Polyalkylation may also occur when bases, in addition to the starting enolate, which are capable of deprotonating the monoalkylated ketone are present in the medium. With symmetrical ketones, e.g. cyclopentanone and cyclohexanone, the problem of regioselectivity does not arise. However, except under special conditions, polyalkylation occurs to a significant extent during enolate alkylations of more kinetically acidic ketones such as cyclobutanone, cyclopentanone and acyclic ketones, particularly methyl ketones. Polyalkylation is also a troublesome side reaction with less acidic ketones such as cyclohexanone. 

As shown in Scheme 38, several primary alkyl-substituted cyclohexanones have been prepared by Lewis acid catalyzed phenylthioalkylation of the TMS enol ether of cyclohexanone followed by reductive removal of a phenylsulfenyl group. The two-step neopentylation sequence is particularly noteworthy. This methodology has been used to prepare numerous a-alkylated cyclic and acyclic ketones. a-Alkylated aldehydes can be produced in a like manner. a-Alkylidenation can also be accomplished by oxidative removal of sulfur. Lee and coworkers have found that TMS triflate-catalyzed reactions of silyl enol ethers of cyclic ketones and aldehydes with saturated and unsaturated l,l-dimethoxy-(i>-tri-methylstannanes, followed by addition of titanium tetrachloride, provide novel routes to fused and spiro-cyclic ring systems. Phenylthiomethylstannylations of silyl enol ethers have also been reported. ... 

Enolates with Chiral Auxiliaries. Enantioselective alkylation of carbonyl derivatives encompassing chiral auxiliaries constitutes an important synthetic process. The anions derived from aldehydes, acyclic ketones, and cyclic ketones with (S)-l-Amino-2-methoxymethylpyrrolidine (SAMP) are used to obtain alkylated products in good to excellent yields and high enan-tioselectivity (e.g. eq 21). ... 

Scheme 16 Enol carbonates derived from acyclic ketones in asymmetric allylic alkylation...

Kinetically controlled deprotonation also leads to the lower substituted alkali enolates of acyclic ketones, as illustrated by selected examples in Scheme 2.5 2-heptanone [27], 3-methyl-2-butanone [26a], and 2-methyl-3-pentanone [23]. Under the conditions of kinetic deprotonation with LDA, a-alkoxy-substituted ketones behave similar to their alkyl-substituted counterparts giving predominantly the less substituted enolate, as illustrated for 2-methoxycyclohexanone [28] in Scheme 2.5. a-Dialkylamino ketones also follow this tendency. In M-carbamato-substituted ketones, however, regioselectivity is reversed, and enolization predominantly occurs toward the nitrogen atom - a result that might be caused by the electron-withdrawing nature of the urethane moiety this effect becomes even more dominant when the enolate is formed under thermodynamic control (LiHMDS, equilibrating conditions) [29]. 

Scheme 5.10 Regioselective, diastereoselective, and enantioselective palladium

Thus the reactions of cyclic or acyclic enamines with acrylic esters or acrylonitrile can be directed to the exclusive formation of monoalkylated ketones (3,294-301). The corresponding enolate anion alkylations lead preferentially to di- or higher-alkylation products. However, by proper choice of reaction conditions, enamines can also be used for the preferential formation of higher alkylation products, if these are desired. Such reactions are valuable in the a substitution of aldehydes, which undergo self-condensation in base-catalyzed reactions (117,118). Monoalkylation products are favored in nonhydroxylic solvents such as benzene or dioxane, whereas dialkylation products can be obtained in hydroxylic solvents such as methanol. The difference in products can be ascribed to the differing fates of an initially formed zwitterionic intermediate. Collapse to a cyclobutane takes place in a nonprotonic solvent, whereas protonation on the newly introduced substitutent and deprotonation of the imonium salt, in alcohol, leads to a new enamine available for further substitution. 

NHC-promoted enolate formation from an enal, followed by a desymmetrising aldol event to generate P-lactones and loss of CO, has been exploited by Scheidt and co-workers to generate functionalised cyclopentenes 240 in high ee from enal substrates 238 (Scheme 12.52) [94]. Interestingly, the use of alkyl ketones in this reaction manifold allows the isolation of the p-lactone intermediates with acyclic diketones, P-lactones 239 are formed with the R group anti- to the tertiary alkox-ide, while with cyclic diketones the P-lactone products have the R group with a syn relationship to the alkoxide [95]. 

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