Acyclic Ketone Enolates

The addition of sulphinyl chlorides to trimethylsilyl enol ether 138 affording a-ketosulphoxides 139 (equation 76) represents an extension of the reaction of sulphinyl chlorides with ketones. This reaction has attracted attention only recently. Sergeev and coworkers192 reported that treatment of sulphinyl chlorides with acyclic enol ethers afforded a-ketosulphoxides 139 in good to excellent yields. Meanwell and Johnson193 observed that in the case of cyclic enol ethers the corresponding sulphoxides were formed only in very low yields. They found, however, that the introduction of an equivalent amount of a Lewis acid into the reaction mixture markedly promotes the desired reaction, whereas the use of catalytic amounts of a Lewis acid led to a substantial reduction in the yield. This is most probably due to the formation of a complex, between the a-ketosulphoxide and the Lewis acid. 

The enone system itself is usually part of a five- or six membered ring, although acyclic a,(3-unsaturated ketones and enols of P-diketones are also found to undergo cycloadditions under certain conditions. For seven- and higher membered rings the primary photochemical event is Z—E isomerization around the C—C double bond, the E-isomer then eventually undergoing further thermal reactions. 

Aldol Condensations of Acyclic Ketone Boryl Enolates (6)... 

Moreover, fermentation of various a-substituted cycloalkanone enol esters results in optically active six-, eight-, ten-, and twelve-membered ring ketones with 70-96% ee (84). Isolated enzymes catalyze similar transformations. Bacillus coagubns and Candida cyBndmceahpase OF (Meito Sangyo) hydrolyze a number of cyclic and acyclic enol esters, giving ketones in 40—80% yield and 14—85% ee (85,86). 

Triethylgallium has been used as a non-nucleophilic base to generate enolates from ketones, both cyclic and acyclic, without forming carbonyl addition products.290 The gallium enolates can then be C-benzoylated, and can participate in aldol reactions. Unsymmetrical ketones preferentially enolized at the methylene, under kinetic control. 

If the metal enolate contains a center of chirality, diastereoselection may be exhibited in the C—C bond formation process. Evans has identified three classes of metal enolates in which chirality transfer may occur (i) endo- and exo-cyclic enolates such as (27) or (28), which contain a chiral center ( ) in a ring bonded to the enolate at two points (ii) acyclic enolates such as (29) or (30), in which the moiety containing the chiral center ( ) is bonded to the enolate at only one point and (iii) chelated enolates such as (31) or (32), in which the chiral center is a part of the chelate ring. (Z)-Endocyclic enolates are also possible for large ring cyclic ketones. 

The utility of BF3-OEt2, a monodentate Lewis acid, for acyclic stereocontrol in the Mukaiyama aldol reaction has been demonstrated by Evans et al. (Scheme 10.3) [27, 28]. The BF3-OEt2-mediated reaction of silyl enol ethers (SEE, ketone silyl enolates) with a-unsubstituted, /falkoxy aldehydes affords good 1,3-anti induction in the absence of internal aldehyde chelation. The 1,3-asymmetric induction can be reasonably explained by consideration of energetically favorable conformation 5 minimizing internal electrostatic and steric repulsion between the aldehyde carbonyl moiety and the /i-substituents. In the reaction with anti-substituted a-methyl-/ -alkoxy aldehydes, the additional stereocontrol (Felkin control) imparted by the a-substituent achieves uniformly high levels of 1,3-anti-diastereofacial selectivity. 

As described in the sections above, it is well established that reactions of Lewis acid-activated aldehydes and ketones with silyl enolates afford -hydroxy or /7-sil-oxy carbonyl compounds (Mukaiyama aldol reactions). Occasionally, however, ene-type adducts, that is /-siloxy homoallyl alcohols, are the main products. The first example of the carbonyl-ene reaction of silyl enolates was reported by Snider et al. in 1983 [176]. They found that the formaldehyde-MesAl complex reacted smoothly with ketone TMS enolates to give y-trimethylsiloxy homoallyl alcohols in good yield. Yamamoto et al. reported a similar reaction of formaldehyde complexed with methylaluminum bis(2,6-diphenylphenoxide) [177]. After these early reports, Kuwajima et al. have demonstrated that the aluminum Lewis acid-promoted system is valuable for the ene reactions of several aldehydes [178] and for-maldimine [179] with silyl enolates bearing a bulky silyl group. A stepwise mechanism including nucleophihc addition via an acyclic transition structure has been proposed for the Lewis acid-promoted ene reactions. 

Open-chain ketones are not well suited for this procedure, because acyclic enol esters are usually obtained as a mixture of stereoisomers from which different enantiomers are produced. This difficulty can be overcome by employing enol esters of sulfur-containing cyclanones, as demonstrated by the following sequence179, l8°. 

More complex products are obtained from cyclizations in which the oxidizable functionality and the alkene are present in the same molecule. y9-Keto esters have been used extensively for Mn(III)-based oxidative cyclizations and react with Mn(OAc)3 at room temperature or slightly above [4, 10, 11, 15], They may be cyclic or acyclic and may be a-unsubstituted or may contain an a-alkyl or chloro substituent. Cycloalkanones are formed if the unsaturated chain is attached to the ketone. y-Lactones are formed from allylic acetoacetates [10, 11]. Less acidic /3-keto amides have recently been used for the formation of lactams or cycloalkanones [37]. Malonic esters have also been widely used and form radicals at 60-80 °C. Cycloalkanes are formed if an unsaturated chain is attached to the a-position. y-Lactones are formed from allylic malonates [10, 11]. yff-Diketones have been used with some success for cyclizations to both alkenes and aromatic rings [10, 11]. Other acidic carbonyl compounds such as fi-keto acids, /3-keto sulfoxides, j8-keto sulfones, and P-nitro ketones have seen limited use [10, 11]. We have recently found that oxidative cyclizations of unsaturated ketones can be carried out in high yield in acetic acid at 80 °C if the ketone selectively enolizes to one side and the product cannot enolize... 

Trost was importantly able to extend this catalyst system to DAAA of acyclic enolate precursors to form a number of a-tertiary ketones using the same catalytic conditions [40]. More significant was the observation that the geometry of the enolate precursor affected both the rate of the reaction and the absolute configuration of the product suggesting that there is no significant geometric isomerisation of the enol carbonate or the Pd-enolate complex. 

In acyclic ketones, the enol or enolate formed can be E) or (Z). Protonation on one face of the E) isomer and protonation on the same face of the (Z) isomer produces enantiomers. 

Shibasaki and co-workers used a ring-closing metathesis approach to prepare a number of five-, six-, and seven-membered rings from electron-deficient olefins. Treatment of acyclic enol ether 18 with 7 mol % of 3 in refluxing benzene provided the corresponding cyclic enol ether 19 in 94% yield. Deprotection of the silyl ether 19 (not shown) resulted in the corresponding cyclic ketone, a valuable synthetic intermediate in natural products synthesis and a number of industrial processes. The authors reported additional examples of the synthesis of five-membered ring carbocycles as part of this study. 

Kobayashi et al. disclosed the effectiveness of lanthanides triflates as Lewis acid fear Mukaiyama-Michael reactions of a,p-unsaturated ketones and enol silyl ethers [llj. Virtually all of the lanthanide triflates except for Ce(OTf)3 and Tb(OTf)3 worked well and could be reused. By using 10mol% of Yb(OTf)3, the reaction proceeded smoothly with both cyclic and acyclic a,p-unsaturated ketones to afford 1,5-dicarbonyl compounds in high yield (Scheme 13.3). Remarkably, the recovered catalyst exhibited comparable catalytic performance in the second runs. 

Intramolecular hydrogen-atom abstraction is also an important process for acyclic a,/ -unsaturated ketones. The intermediate diradical then cyclizes to give the enol of a cyclobutyl ketone. Among the by-products of such photolyses are cyclobutanols resulting from alternative modes of cyclization of the diradical intermediate ... 

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. 

Cyclic and acyclic silyl enol ethers can be nitrated with tetranitromethane to give ct-nitro ketones in 64-96% yield fEqs. 2.42 and 2.43. " The mechanism involves the electron transfer from the silyl enol ether to tetranitromethane. A fast homolydc conphng of the resultant cadon radical of silyl enol ether with NO leads tn ct-nitro ketones. Tetranitromethane is a neutral reagent it is commercially available or readdy prepared. " ... 

In contrast, the tin(Il) enolates of cyclohexanone undergo addition to (2f)-(2-nitroethenyl)ben-zene to give 2-(2-nitro-l-phenylethyl)cyclohexanones with high anti diastereoselection5. The analogous reactions with cyclopentanone and 4-tert-butylcyclohexanone were less diastereose-lective with anti/syn ratios of 70 30 and 62 38. respectively. Modest to excellent diastereoselec-tivity was observed with acyclic ketones (d.r. 75 25 to 90 10) however the precise stereochemical details were not provided. 

Direct treatment of TIPS enol ethers of a variety of cyclic and acyclic ketones with the strong-base combination of n-BuLi/KO-t-Bu leads to /3-ketosilanes (2) after aqueous work-up. In contrast with the earlier method, this rearrangement appears to proceed through allylic, rather than vinylic, metallation, since enol ethers lacking an allylic a-proton are unreactive. 

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]. 

Organo copper and lithium enolates of cyclic ketones, lactones, and lactams or acyclic ketones are converted with acylimidazoles or imidazole-N-carboxylates into the corresponding / -diketones or / -ketoesters ... 

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