Ketone as electrophile

So at the moment, the scope of our skill at synthesis is rather limited. We can extend it by the use of a—p unsaturated ketones as electrophiles. Where would the compound we have just made (281b) be attacked by nucleophiles ... 

Reactions of phenylthiocyclopropyl lithium with alkyl halides and epoxides have also been reported to deliver products opened to a variety of carbonyl derivatives jS-(l-Phenylthio)cyclopropyl enones have been prepared by using lithium salts of a-hydroxymethylene ketones as electrophiles and dehydrating with acid (equation 110). Rearrangement to cyclobutanones occurs with trifluoroacetic acid, whereas thermal vinylcyclopropane-cyclopentene expansion sometimes gives mixtures of regioisomers . 

The behavior of polyunsaturated systems such as ot,p,y,8-unsaturated ketones as electrophiles in the Michael reaction under PTC conditions has been the subject of a thoughtful study (Scheme 5.13). The conjugate addition of p-ketoesters to this kind of particular conjugated systems has been found to occur with complete 1,6-selectivity, affording a final p,y-unsaturated adduct, which in some exceptional cases can isomerize to the more stable conjugated... 

The most challenging combination for this transformation is the use of an aldehyde as source of nucleophUe and a ketone as electrophile. This reaction has been successfully achieved by using several aldehydes 5 with high electrophilic ketones (38), such as diethyl ketomalonate or ethyl trifluoropyruvate, in the presence of... 

Whereas the intermolecular processes using ketones as source of nucleophile and aldehydes as electrophiles have been extensively stndied, other reactions, nsing either ketones or aldehydes as electrophiles, have been less studied, with reactions implying the use of aldehydes as source of nucleophile and ketones as electrophiles having scarcely investigated. Also the nse of poor reactive ketones such as a,p-unsaturated ketones or even alkyl aryl ketones is still elnsive. 

To extend the scope of the carbometallative aldol cycloreduction, the feasibility of Cu-catalyzed conjugate addition-aldol cyclization process was examined. Cu-catalyzed addition of organozinc compounds to o ,jS-unsaturated carbonyl compounds has been well established (169-171,187-189). Trapping of the Zn-enolates using aldehydes (169,188,190) and acetals/ketals (191) has been reported however, the use of ketones as electrophiles to trap Zn-enolates failed in the absence of strong Lewis acids (191). Rrische and co-workers reported the first successful example of Cu-catalyzed tandem conjugate addition-aldol cyclization with ketones, esters, and nitriles as electrophiles (Scheme 107) (192). In this cyclization process, enone-ketones 237 and 239 afforded products in good to excellent... 

Additionally, this methodology was applied to the reductive coupling of 1,3-enynes to glyoxalates [13, 14], a-ketoesters [15], and heterocyclic aromatic aldehydes [16] and ketones as electrophiles. The use of chiral phosphines as ligand to the rhodium catalyst allowed the enantioselective version of these reactions to take place. 

SCHEME 2.53 Michael-hemiketalization involving other a,P-unsaturated ketones as electrophiles. 

The use of oximes as nucleophiles can be quite perplexing in view of the fact that nitrogen or oxygen may react. Alkylation of hydroxylamines can therefore be a very complex process which is largely dependent on the steric factors associated with the educts. Reproducible and predictable results are obtained in intramolecular reactions between oximes and electrophilic carbon atoms. Amides, halides, nitriles, and ketones have been used as electrophiles, and various heterocycles such as quinazoline N-oxide, benzodiayepines, and isoxazoles have been obtained in excellent yields under appropriate reaction conditions. 

Thalllum(III) Compounds. Tb allium (ITT) derivatives have been used extensively as oxidants in organic synthesis. In particular, thaUic acetate and ttifluoroacetate are extremely effective as electrophiles in oxythaHation and thaHation reactions. For example, ketones can be prepared from terminal acetylenes by means of (OOCCH ) in acetic acid (oxythaHation) (30) ... 

Enol ethers are readily attacked in buffered medium by electrophilic reagents such as halogens, A -haloamides, perchloryl fluoride and organic peracids to give a-substituted ketones. Similarly, electrophilic attack on... 

Fluoroalkenolphosphates are not only stable but also sufficiently reactive to undergo olefinaaon reactions with yiides themselves. These enol phosphates are not only precursors to enolates or ketones but also can be used directly as electrophilic reagents [79] (equation 66) (Table 26). 

Fluorinated esters may also act as electrophiles in reactions with nonfluori-nated ketones [28] (equation 23) or malononitrile [29] (equation 24). Unfortunately, the yields of -diketones may be modest, but those of p-keto nitnles are excellent (Table 9)... 

Because of Us high polarity and low nucleophilicity, a trifluoroacetic acid medium is usually used for the investigation of such carbocationic processes as solvolysis, protonation of alkenes, skeletal rearrangements, and hydride shifts [22-24] It also has been used for several synthetically useful reachons, such as electrophilic aromatic substitution [25], reductions [26, 27], and oxidations [28] Trifluoroacetic acid is a good medium for the nitration of aromatic compounds Nitration of benzene or toluene with sodium nitrate in trifluoroacetic acid is almost quantitative after 4 h at room temperature [25] Under these conditions, toluene gives the usual mixture of mononitrotoluenes in an o m p ratio of 61 6 2 6 35 8 A trifluoroacetic acid medium can be used for the reduction of acids, ketones, and alcohols with sodium borohydnde [26] or triethylsilane [27] Diary Iketones are smoothly reduced by sodium borohydnde in trifluoroacetic acid to diarylmethanes (equation 13)... 

The Baylis-Hillman reaction is usually carried out under mild conditions (0°C or room temperature). The reaction time varies from a few minutes to even days. With the proper catalyst, good yields are possible. In the absence of an aldehyde or ketone as the electrophilic component, a dimerization of the activated alkene can take place under the influence of the catalyst, as also observed as a side reaction under the usual reaction conditions ... 

Whereas bromine radicals (133) and succinimidyl radicals (134) react by the Sh2 mechanism at the tin center in tetraalkyltins, but not in alkyltin halides, alkoxyl radicals (135) and ketone triplets (136) react with alkyltin halides, but not tetraalkyltins this may reflect the conflicting, electronic demands of the radical reagents which, as electrophilic species, should be more reactive towards tetraalkyltins than alkyltin halides, but which would also tend to make use of a 5d orbital... 

Entry 9 of Scheme 2.1 is an example of application of these conditions. Tin(II) enolates prepared in this way also show good reactivity toward ketones as the electrophilic component. 

Friedel-Crafts acylation reactions of aromatics are promoted by Tilv complexes.104 In some cases, a catalytic amount of the titanium compound works well (Scheme 28). In addition to acyl halides or acid anhydrides, aldehydes, ketones, and acetals can serve as electrophile equivalents for this reaction.105 The formylation of aromatic substrates in the presence of TiCl4 is known as the Rieche-Gross formylation metalated aromatics or olefins are also formylated under these conditions.106... 

Typical electrophiles that attack olefins like Br+ (Eq. 64)105) and (OH)+ (Eq. 65) 105) do lead to electrophilic addition with ring enlargement101 a). Most interesting is the ability for electrophiles that normally do not attack olefins to also react. Thus, an oxycarbonium ion generated from an acetal smoothly alkylates the double bond of this composite functional group in an overall highly stereocontrolled 1,1,2-trialkylation of a simple ketone as illustrated in Eq. 66 106). The chemo- and... 

Interestingly, deprotonation of the 3-oxo-pyrrolo[l,2-f]oxazole 277 with r-BuLi at —78°C took place at the C-5 position. Addition of an electrophile provided the substituted products 278 in good yields. Stannyl and silyl chlorides, dimethyl sulfate, ketones, and benzaldehyde were successfully used as electrophiles. A significant feature of this lithiation-substitution reaction is the generally high Ar-diastereoselectivity only single diastereomers of products were isolated (Scheme 41) <2001JA315>. 

The present procedure is a general method for the preparation of monoalkylated ketones from enamines of aldehydes and ketones with electrophilic olefins. There are many advantages in this method of alkylation. Only monoalkylation occurs, even when such reactive species as acrylonitrile are used and, when a cyclic ketone like 2-methylcyclohexanone is used, reaction occurs only at the lesser substituted center. In a general base-catalyzed reaction, substitution occurs on the more substituted center. 

Dondoni pioneered the use of 2-(trimethylsilyl)thiazole (71) as a formyl anion equivalent for the homologation of aldehydes. Extension of this reaction to ketones would be very useful, but has thus far been restricted to tritluoromethyl cases. However, it has now been widened to include several a, a -alkoxy ketones, as demonstrated in a new route to branched-chain monosaccharides. Aldehydes catalyse the reaction, although the scope is still limited electrophilic aldehydes, such as 2-fluorobenzaldehyde, promote the addition of (71) to electrophilic ketones. 

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