Nucleophilic/electrophilic umpolung

C2 is electrophilic, and C4 is. .. electrophilic To make a bond between them, C2 must be turned into a nucleophile (umpolung). This must be the purpose of the -CN. Aldehydes are not acidic at the carbonyl C, so the CN cannot simply deprotonate C2. Instead, it must add to C2. Now C2 is a to a nitrile, it is much more acidic, and it can be deprotonated by excess CN to give an enolate, which can add to C4. Finally, deprotonation of 01 and elimination of CN gives the observed product. 

TABLE 8.1 Electrophilic and Nucleophilic Umpolung Reagents and Their Equivalents... 

Allylic metal compounds useful for further transformations can be prepared by Pd-catalyzed reactions of allylic compounds with bimetallic reagents. By this transformation, umpolung of nucleophilic 7r-allylpalladium complexes to electrophilic allylmetal species can be accomplished. Transfer of an allyl moiety from Pd to Sn is a typical umpolung. 

In the oxidative Eschenmoser sulfide contraction (Scheme 11), thioamide 59 is oxidized by benzoyl peroxide to give either a symmetrical disulfide or the O-benzoate of the thiolactam-S-oxide. In any event, the once-nucleophilic thioamide sulfur atom is now forced to adopt the role of electrophile a reactivity umpolung has, in effect, been achieved.13 The nucleophilic enamide 65 attacks the sulfur atom leading to the formation of sulfur-bridged intermediate 66. The action of a phosphine or a phosphite thiophile on the putative episulfide then gives vinylogous amidine 67. 

The attack of the nucleophile on the acceptor-substituted allene usually happens at the central sp-hybridized carbon atom. This holds true also if no nucleophilic addition but a nucleophilic substitution in terms of an SN2 reaction such as 181 — 182 occurs (Scheme 7.30) [245]. The addition of ethanol to the allene 183 is an exception [157]. In this case, the allene not only bears an acceptor but shows also the substructure of a vinyl ether. A change in the regioselectivity of the addition of nucleophilic compounds NuH to allenic esters can be effected by temporary introduction of a triphenylphosphonium group [246]. For instance, the ester 185 yields the phos-phonium salt 186, which may be converted further to the ether 187. Evidently, the triphenylphosphonium group induces an electrophilic character at the terminal carbon atom of 186 and this is used to produce 187, which is formally an abnormal product of the addition of methanol to the allene 185. This method of umpolung is also applicable to nucleophilic addition reactions to allenyl ketones in a modified procedure [246, 247]. 

The benzoin reaction dates back to 1832 when Wohler and Liebig reported that cyanide catalyzes the formation of benzoin 6 from benzaldehyde 5, a seminal example in which the normal mode of polarity of a functional group was reversed (Eq. 1) [26], This reversal of polarity, subsequently termed Umpolung [27], effectively changes an electrophilic aldehyde into a nucleophilic acyl anion equivalent. 

Stetter expanded Umpolung reactivity to include the addition of acyl anion equivalents to a,P-unsaturated acceptors to afford 1,4-dicarbonyls Eq. 5a [57-60]. Utilizing cyanide or thiazolylidene carbenes as catalysts, Stetter showed that a variety of aromatic and aliphatic aldehydes act as competent nucleophilic coupling partners with a wide range of a,p-unsaturated ketones, esters, and nitriles [61]. The ability to bring two different electrophilic partners... 

Amines are generally prepared by nucleophilic amination, which is a coupling of carbon electrophiles with a nucleophilic amination reagent, NR2, and Ni and Pd catalyzed reaction of aryl halides with arylamines (Hartwig-Buchwald amination) . Thus, the direct C—N bond formation between carbon nucleophiles and electrophilic nitrogen functionality R2N+ constitutes an example of the umpolung methodology. 

Umpolung The reversal of polarity of the carbonyl carbon atom is termed umpolung (German for polarity reversal). Normally the carbonyl carbon atom of an aldehyde (or a ketone) is partially positive i.e., electrophilic and therefore it reacts with nucleophiles. When the aldehyde is converted to a dithiane by reaction with 1,3-propanedithiol and reacted with butyl lithium the same carbon now becomes negatively charged to react with electrophiles. This reversed polarity of the carbonyl carbon is termed umpolung which increases the versatility of the carbonyl group in synthesis. The sulphur atoms stabilize... 

Hetero-substituted allyl compounds obtained by electrophilic attack in the 1-position can be reduced to give the heteroalkyl compounds carrying the new substituent on the a-carbon atom ( ). In this case, the double bond was used as an activating substituent only, to achieve easier deprotonation and higher nucleophilicity. In both cases the synthetically important umpolung of reactivity was achieved20. 

This is another example of umpolung (see 0-95) 1478 the normally electrophilic carbon of the aldehyde is made to behave as a nucleophile. The reaction can be applied to the unsubstituted dithiane (R = H) and one or two alkyl groups can be introduced, so a wide variety of aldehydes and ketones can be made starting with formaldehyde.1504 R may be primary or secondary alkyl or benzylic. Iodides give the best results. The reaction has been used to close rings.1505 A similar synthesis of aldehydes can be performed starting with ethyl ethyl-thiomethyl sulfoxide EtSOCH2SEt.1506... 

The synthesis of C-glycosyl compounds, commonly known as C-glycosides, in ionic reactions relies on the electrophilicity of the anomeric center and, therefore, involves the attack of an appropriate C-nucleophile. An umpolung method has been developed, and is described in the previous chapter. But instead of going from a carbocation to a carbanion, one can also consider homolytic or radical reactions to reverse the philicity (Scheme 1). 

From the retrosynthetic point of view, electrochemical redox reactions are an easy way to accomplish the principle of redox-umpolung (polarity reversal) [2]. As can be seen in Scheme 22.1, oxidation of an electron-rich neutral compound will lead to an electrophilic cation radical, or starting with a nucleophilic anion, anodic oxidation may lead to an electrophilic cation. In the mirror image reductions, an electron-poor neutral compound is transformed to a nucleophilic anion radical, or an electrophilic cation will end up as a nucleophilic anion. 

The realization of the principle of umpolung , in which reactivity at a normally electrophilic site is inverted to that of a nucleophilic species,161 has resulted in the development of numerous masked acyl anion equivalents for carbon-carbon bond formation.162 The use of masked acyl anion equivalents for conjugate additions was made possible by several observations. First, Stork reported that protected cyanohydrins afforded preferential kinetic 1,4-addition with ot, 3-enonesl6b and second, Brown reported that preferential kinetic 1,4-addition of 1,3-dithianes was effected by the use of HMPA.163... 

Both of these methods could be included as examples of umpolung of ir-allyl species, as the electrophilic allylpalladium has now been transformed into a nucleophilic allyl moiety. Finally, Bn can also be added to ir-allylpalladium complexes (equation 134).342... 

In the same way, disconnection of a 1,4-diketone requires either an acyl anion equivalent reacting with a normal /3-carbonyl electrophile or a normal o -carbonyl nucleophile reacting with an abnormal cr-carbonyl electrophile. These abnormal or reversed-polarity reagents are said to have umpolung reactivity. 

Another common umpolung synthon is a homoenolate. Normally the ft position of a carbonyl compound is an electrophilic center (by Michael addition to an 0, /3-unsaturated carbonyl derivative). To make it a nucleophilic center, an organometallic is needed since it is unactivated and nonconjugated. A common way to do this is to use a /3-bromo acetal. 

A three-component reaction based on the umpolung of re-allylpalladium (II) complexes indium metal was reported by Grigg and co-workers (Scheme 8.31) [74]. In this reaction, the electrophilic nature of the n-allyl palladium species generated from aryl halides and allenes is reversed by transmetallation with indium metal. The resultant nucleophilic allylindium reagent subsequently adds to the third component - aldehyde [75] or imine [76] - to give the corresponding homo-allylic alcohol 64 or amine 65 respectively. 

Allylstannane 176 is formed by the reaction of allyl acetate with distannanes [97,98], In this reaction, umpolung of the electrophilic 7r-ally] palladium to the nucleophilic allylstannane occurs. Allylation of bromoindole 198 to give allylindole 199 involves the oxidative addition of 198 to Pd, transmetallation with the allylstannane 176, and final reductive elimination [99],... 

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