Alkylidenation of ketones with

First studies in relation to the conjugate addition of ketones with alkylidene malonates were performed by Barbas group initially using L-proline [107] and proline-derived diamines such as 31 [49, 138] (Fig. 2.4) as organocatalysts, showing that acetone, cyclohexanones, and cyclopentanone could add to various aryl- and alkylidene malonates with moderate yields and enantioselectivities. Very recently. 

Phosphinothioic amides are highly effective reagents for the alkylidenation of ketones, and the method has been developed as a means of methylenation coupled with optical resolution. The reaction of the anion of the phosphinothioic amide (21) gives the diastereoisomeric mixture (22), which, after separation, can be converted into the optically active olefins (23). The method has been applied to the synthesis of the (+)- and ( —)-iridoid monoterpene hop ether (24), and can be extended to alkylidenation with resolution. 

Conjugate dcLiicii of nkro ilkdnes to illyl Baylis-Hillman acetates in the pesence of NaOH (0.6 N in THF ves 2-alkylidene-4-nitro ketones with high sieteoselecdvity these are convened via the Nef teacdon into the conesponding 1,4-diketones fEq. 4.1... 

The synthetic method leading to Nb-alkylidenes and Nb-alkylidynes was particularly successful, due to a quite remarkable difference in the reaction rate of 29 with ketones or aldehydes, vs the subsequent reaction of the alkylidene with ketones and aldehydes (see Scheme 37). The former reaction takes a few minutes at -40°C, while the latter one occurs in hours at room temperature.88 The reaction between 178 and benzaldehyde led to triphenylethylene and the niobyl derivative 184. Due to the difference in reaction rates between a and b in Scheme 37, it was found that the sequential addition of two different ketones or aldehydes to a THF solution of 29 produced a nonsymmetric olefin in a stepwise McMurry-type reaction.84 This is exemplified in the coupling shown in reaction c (Scheme 37). The proposed reaction pathway does not involve the intermediacy of a pinacolato ligand and therefore differs from the mechanism of the McMurry reaction and related reductive couplings at activated metal sites.89... 

Conjugate addition of nitroalkanes to ailyl Baylis-Hillman acetates in the presence of NaOH (0.6 N) in THF gives 2-alkylidene-4-nitro ketones with high stereoselectivity these are converted via the Nef reaction into the corresponding 1,4-diketones (Eq. 4.119).164... 

Scheme 4. Ketone olefination reaction of a ketone with a metal alkylidene, which results in the destruction of the catalytic species...

Alkylidenes (alkylidene carbenes) are valence isomers of alkynes. They have been prepared by alkyne pyrolysis, by homologation of ketones, and by generation of alkenyl anions bearing oc-leaving groups. Generated by any of these means, an alkylidene will insert intramolecularly into a remote C- H bond to form a new C—C bond and thus a cyclopentene. A concerted two-electron process, this reaction proceeds with retention of absolute configuration at the C - H site. 

The required oxaspiropentanes are obtained by epoxidation of alkylidenecyelopropanes (A Section 3.2.2.1.), by reacting aldehydes and/or ketones with diphenylsulfonium cyclopropanide (B Section 3.2.2.2.), and by reacting ketones with 1-bromo-l-lithiocyclopropanes (C Section 3.2.2.3.) or diazocyclopropane (D Section 3.2.2.4.). Most widely used is diphenylsulfoni-um cyclopropanide, but for higher than 2,2-disubstituted cyclobutanones the use of alkylidene-cyclopropanes or 1-bromo-l-lithiocyclopropanes may be advantageous. Once formed, oxaspiropentanes rearrange with extreme ease. 

Oxaspiropentanes have been generated and rearranged in a large variety of different environments. A series of alkylidene- and allylidenecyclopropanes, present in the structures of bicy-clo[3.1.0]hexanes or bicyclo[4.1.0]heptanes, were epoxidized and rearranged in situ to bicyclic ketones with the alkyl or allyl group preferentially to exclusively in the exo position (Table 4).51 This corresponds to a preferential to exclusive epoxidation of the corresponding alkenes from the sterically less demanding exo face. 

We have just seen in a preceding scheme (see Section 4.2.1.5) an example of alkylation of a silylated enolate with phenylthiomethyl chloride. The Lewis acid-promoted phenylthioalkylation of O-silylated enolates of ketones, aldehydes, esters and lactones has been used by Paterson and Fleming as a convenient synthetic route to a-alkylated or alkylidenated carbonyl compounds [323-325] according to the accompanying scheme. 

However, certain phosphonium ylides, such as those with an electron-withdrawing substituent in the alkylidene moiety, are relatively unreac-tive toward certain substrates such as ketones (22, 77, 95). This led us to consider whether arsonium ylides might be preferable to phosphonium ylides in certain reactions (48, 94). The overlap of the p orbitals of carbon with d orbitals of arsenic is less effective than with d orbitals of phosphorus. Therefore the covalent canonical form (la) should make a smaller contribution to the overall structure of arsonium ylides than to that of the corresponding phosphonium ylides. 

This topological rule readily explained the reaction product 211 (>90% stereoselectivity) of open-chain nitroolefins 209 with open-chain enamines 210. Seebach and Golinski have further pointed out that several condensation reactions can also be rationalized by using this approach (a) cyclopropane formation from olefin and carbene, (b) Wittig reaction with aldehydes yielding cis olefins, (c) trans-dialkyl oxirane from alkylidene triphenylarsane and aldehydes, (d) ketenes and cyclopentadiene 2+2-addition, le) (E)-silyl-nitronate and aldehydes, (f) syn and anti-Li and B-enolates of ketones, esters, amides and aldehydes, (g) Z-allylboranes and aldehydes, (h) E-alkyl-borane or E-allylchromium derivatives and aldehydes, (i) enamine from cyclohexanone and cinnamic aldehyde, (j) E-enamines and E-nitroolefins and finally, (k) enamines from cycloalkanones and styryl sulfone. 

CH2,CH2,C02Et. From the latter the three-carbon unit of diethyl succinate may be recognised, and the Stobbe condensation is a suitable illustration of this process. Thus the reaction of aldehydes or ketones with succinic esters in the presence of potassium t-butoxide (or with sodium hydride) gives alkylidene-succinic acid esters (25). The reaction is somewhat slower in the case of the less basic sodium ethoxide. 

The alkylidene- or benzylidene-1,3-dicarbonyl compounds formed in the Knoevena-gel condensation of aldehydes or ketones with 1,3-dicarbonyls, can act not only as a... 

In the study by Alexakis, unsymmetrical ketones (e.g. 2-butanone) yielded mixtures consisting of regioisomers and syn/anti diastereomers with ee of the predominant syn isomers not exceeding 51%. For 3-pentanone and cyclohexanone (Scheme 4.24) Barbas et al. also used the related (S)-l-(pyrrolidinylmethyl)-pyrrolidine 54 to catalyze the addition of ketones to alkylidene malonates (Scheme 4.25) [43],... 

Pyrrolidine-amine-based catalysts such as 18 and 19 can also mediate the addition of ketones to alkylidene malonates (Scheme 2.40) [14]. Aldehydes (e.g., isova-leraldehyde) do not react with vinylidenemalonate 16 under these conditions. 

C-Alkylpyrazines undergo extranuclear alkylidenation by aldehydes (or ketones,) with or without isolation of the intermediate (hydroxyalkyl)pyrazines. Several procedures are illustrated in the following examples ... 

Good yields of 2-alkylidene or 2-benzylidene ketones are readily achieved by condensation of enamines of cyclic ketones with aldehydes146-148. Except for the reaction with chloral149,150, where the intermediate carbinolamine (65) was isolated and hydrolysed to the /Miydroxyketone (66), the corresponding aldol intermediates formed in these reactions could not be isolated (Scheme 54). However, it has recently been shown that in the presence of a slight excess of Lewis acid the reaction can be carried out under very mild conditions and high yields of the crossed aldol products can be obtained from... 

Vinyl triflates are important intermediates, since they can be used as synthetic precursors for vinyl cations and alkylidene carbenes. and as substrates for regiospecific coupling reactions.2 3 Vinyl triflates are also valuable intermediates in a mild, two-step procedure for the deoxygenation of ketones.4 5 These new triflating reagents are highly reactive and easy to prepare and handle. When compared with... 

Reaction of alkylidene cycloalkanes (399) with cyanogen azide (400) (64JA4506), followed by hydrolysis, affords ring-expanded cyclic ketones (401), a reaction applicable to a wide variety of ring sizes and to both saturated and a,/S- unsaturated ketones (69JA3676,73joc282i). 

A series of molybdenum alkylidene complexes react with aldehydes, and in some cases ketones, to give the product of methylenation (equation 33). Some of the examples appear to involve an alkylidene, while others may follow an addition-elimination route typical of the Peterson alkenations. Probably the most interesting aspect of this work is the observation that some of the methylenation reactions can be carried out in aqueous or ethanolic media (equation 33). ... 

This very useful reaction resulted from a failed attempt to introduce a new protected methyl vinyl ketone equivalent for the all important Robinson annul-lation reaction. This failure turned out to be quite rewarding, for it allowed for a fast, simple, mild, and high yielding construction of a-alkylidene ketones, esters, and nitriles, as well as /3-methylenebutyrolactones, a family of compounds with several representatives among the tumor growth inhibitors. The method, unfortunately, has its own limitations, which will be discussed after exposing probable mechanisms. 

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