Ketones phosphorus nucleophile-carbonyl

The first examples of diastereoselective additions of phosphorus nucleophiles to carbonyl compounds, applied to the synthesis of natural product analogs, involved carbohydrate-derived aldehydes and ketones. The achieved diastereoselectivity depended on the kind of sugar and protective groups used, and for the cyclic ketones usually higher diastereoselectivities were observed. In the aldose... 

The initial step of olefin formation is a nucleophilic addition of the negatively polarized ylide carbon center (see the resonance structure 1 above) to the carbonyl carbon center of an aldehyde or ketone. A betain 8 is thus formed, which can cyclize to give the oxaphosphetane 9 as an intermediate. The latter decomposes to yield a trisubstituted phosphine oxide 4—e.g. triphenylphosphine oxide (with R = Ph) and an alkene 3. The driving force for that reaction is the formation of the strong double bond between phosphorus and oxygen ... 

O The nucleophilic carbon atom of the phosphorus ylide adds to the carbonyl group of a ketone or aldehyde to give an alkoxide ion intermediate. 

This section deals with reactions that correspond to Pathway C, defined earlier (p. 64), that lead to formation of alkenes. The reactions discussed include those of phosphorus-stabilized nucleophiles (Wittig and related reactions), a a-silyl (Peterson reaction) and a-sulfonyl (Julia olefination) with aldehydes and ketones. These important rections can be used to convert a carbonyl group to an alkene by reaction with a carbon nucleophile. In each case, the addition step is followed by an elimination. 

Intermediates such as 224 resulting from the nudeophilic addition of C,H-acidic compounds to allenyl ketones such as 222 do not only yield simple addition products such as 225 by proton transfer (Scheme 7.34) [259]. If the C,H-acidic compound contains at least one carbonyl group, a ring dosure is also possible to give pyran derivatives such as 226. The reaction of a similar allenyl ketone with dimethyl mal-onate, methyl acetoacetate or methyl cyanoacetate leads to a-pyrones by an analogous route however, the yields are low (20-32%) [260], The formation of oxaphos-pholenes 229 from ketones 227 and trivalent phosphorus compounds 228 can similarly be explained by nucleophilic attack at the central carbon atom of the allene followed by a second attack of the oxygen atom of the ketone at the phosphorus atom [261, 262], Treatment of the allenic ester 230 with copper(I) chloride and tributyltin hydride in N-methylpyrrolidone (NMP) affords the cephalosporin derivative 232 [263], The authors postulated a Michael addition of copper(I) hydride to the electron-... 

The most useful methods for the formation of C-C bonds are based on the addition of C-nucleophiles to carbonyl compounds. Among the many variations of this basic scheme phosphorus ylides, capable of olefinating aldehydes or ketones in a single step, have proven to be exceedingly valuable reagents in organic synthesis. 

Nucleophilic Reactions of (Silylamino)phosphines. The reactions of (silylamino)phosphines with simple aldehydes and ketones proceed via nucleophilic attack by phosphorus followed by a [1,4] silyl migration from nitrogen to oxygen to yield new N-silylphosphinimines ( 3). With a,B-unsaturated carbonyl compounds, 1,4-addi-... 

Ylids can be isolated, but are usually used in reactions immediately they are formed. They are nucleophilic species that will attack the carbonyl groups of aldehydes or ketones, generating the four-membered ring oxaphosphetane intermediates. Oxaphosphetanes are unstable they undergo elimination to give an alkene (65% yield for this particular example) with a phosphine oxide as a byproduct. The phosphorus-oxygen double bond is extremely strong and it is this that drives the whole reaction forward. 

Addition of thiamine. The conversion of pyruvate to acetyl CoA begins by reaction of pyruvate with thiamine pyrophosphate, a derivative of vitamin B, The hydrogen on the heterocyclic thiamine pyrophosphate is weakly acidic and can be removed by reaction with base to yield a nucleophilic ylide much like the phosphorus ylides u.sed in Wittig reactions /Section 19.12>. This nucleophilic yJide adds to the ketone carbonyl group of pyruvate to yield a tetrahedral intermediate. 

The high nucleophilicity of a-selenoalkyllithiums towards carbonyl conqiounds, even those that are the most hindered or enolizable, such as 2,2,6-trimethyl- and 2,2,6,6-tetramethyl-cyclohexanone (Schemes 113 and 164), di-t-butyl ketone, pennethylcyclobutanone, peimethylcyclopenta-none (Schemes 113 and 187) °- and deoxybenzoin (Schemes 115, 116 and i65y 4 49 23 iqws the synthesis of related alkenes, epoxides and rearranged ketones which are not available from the same carbonyl compounds on reaction with phosphorus or sulfur ylides - or diazoalkanes. ... 

Phosphorus ylides are very important because of their use in the well-known Wittig reaction (1954) for the synthesis of alkenes. In the Wittig reaction, a phosphorus ylide (1) reacts with an aldehyde or ketone to yield the corresponding alkene (16) (Scheme 7). The reaction involves nucleophilic attack by the ylide (1) on the electrophilic carbonyl carbon atom to yield the betaine intermediate, which then collapses with elimination of the phosphine oxide and formation of the alkene (16). The driving force of the Wittig reaction is the production of the very strong phosphorus-oxygen double bond in the phosphine oxide (Scheme 7). 

As an alternative to the manner in which the stability of the intermediate species 277 is raised by increasing electron input to phosphorus, a reduction in nucleophilic character of the original carbonyl oxygen might be contemplated. In this respect, it may be noted that a reaction between the lithium salt of diisopropyl (fluoromethyl)phosphonate and the ketones R R CO affords both the alkene (s) predicted from the Wittig mechanism, but also the alcohols (Pr 0)2p(0)CHFC(0H)R R as mixtures of diastereoisomers, distinguishable spectroscopically but not separable ... 

Depending on their reactivity towards carbonyl components, the phosphorus ylides can be classified into three groups [3,5]. When R and/or R is an electron donor, e.g. an alkyl group, the nucleophilicity of the ylide, and thus its reactivity towards carbonyl groups, are increased. These ylides are termed reactive or non-stabilized . Strongly electron-withdrawing groups such as esters, nitriles, and ketones, on the other hand, stabilize the carbanion and thus reduce the nucleophilic reactivity of the ylide. These are so-called stable ylides . 

Reactive ylides must be produced in the absence of oxygen and moisture, whereas stable ylides can be isolated as solid substances which are relatively insensitive to hydrolysis. Ylides which are stabilized by a carbonyl group generally only react with aldehydes if need be, they can be made to react with ketones under relatively drastic conditions [3]. In these cases, the Horner-Emmons reaction is the method of choice because of the greater nucleophilicity of the phosphonate carbanions in comparison to phosphorus ylides [6] (see Section E). 

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