Umpolung acyl anion equivalents

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... 

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... 

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. 

These are only three of many ways that have been reported for the formation of acyl anion equivalents, which are among the most common umpolung synthons to be found in the literature. All are prepared by a similar strategy in that they contain functional groups which can sustain a negative charge on an adjacent carbon and can be converted back to a carbonyl group. 

In both reactions cyanide has usually been employed as catalyst [231, 232], Under these conditions, the acyl anion equivalent is represented by the tautomeric form XIX of the cyanohydrin anion which results from addition of cyanide to an aldehyde (Scheme 6.104). In nature, this type of Umpolung is performed enzymatically, with the aid of the cofactor thiamine pyrophosphate 226 (vitamin Bl, Scheme 6.105) [232, 233]. 

Umpolung. Show how each of the following compounds can be prepared from the given starting material using either a formyl or an acyl anion equivalent in the synthetic scheme. 

Three approaches leading to 8 were considered (Figure 3.6.9) Following the biosynthetic pathway directly, polymer-supported thiamine 9 was constructed (path A) and could lead via crossed acyloin couplings to the target structure. Polymer-supported hydrazones 10 were reported to add directly to aldehydes in a non-catalyzed Umpolung reaction (path B) with results reported in due course. Finally, phosphine ylides 11 were investigated as polymer-supported acyl anion equivalents (path C). 

In the case of vinyl radical cyclizations of 49E , the intermediate silacycle could be oxidized under Tamao conditions to afford ketone 51 (2) [124], The consequence is an umpolung installation of an acetyl group, with the vinyl radical serving as an acyl anion equivalent, further expanding the synthetic potential of the Si-tethered radical additions. 

The most utilized Umpolung strategy is based on formyl and acyl anion equivalents derived from 2-lithio-l,3-dithiane species. These are readily generated from 1,3-dithianes (thioacetals) because the hydrogens at C(2) are relatively acidic (p f 31). In this connection it should be noted that thiols (EtSH, pi 11) are stronger acids compared to alcohols (EtOH, 16). Also, the lower ionization potential and the greater polarizability of the valence electrons of sulfur compared to oxygen make the divalent sulfur compounds more nucleophilic in Sj,2 reactions. The polarizability factor may also be responsible for the stabilization of carbanions a to sulfur. ... 

Specific enol equivalents (e. g. (3-keto esters) and umpolung (e. g., with cyanide or acetylide ions as acyl anion equivalents) have of course been used in synthesis for many years. What is new is the recognition of their role, as a result of the disconnec-... 

The mechanistic model, proposed by Breslow, has been extensively discussed [149]. The core of the benzoin reaction is the polarity reversal (umpolung) of the carbonyl, initiated by nucleophihc attack of NHC to the aldehyde yielding an acyl anion equivalent that triggers the carbon-carbon bond formation. The a-hydroxy ketone results from the addition of the acyl anion equivalent to another aldehyde (Scheme 16.21). 

A novel entry into these important intermediates is the anionic addition of the trimethylsilyl group, generated from 8, to acyl cyanides28. The final product is the result of an umpolung effect of the addition when the adduct, an a,/ -unsaturated acyl anion equivalent, adds to another molecule of acyl cyanide (equation 21). 

B.ii. Acyl Anion Equivalents. The most common umpolung equivalent is that for acyl anion 339, and dithianes 344 are the most common reagent used for this purpose. Dithiane 344 is prepared from an aldehyde, but ketones are also precursors (sec. 7.3.B.ii). Removal of the hydrogen adjacent to the sulfur requires a base such as n-butyllithium and the product is a-lithiodithiane (345). The acidity of this hydrogen is largely... 

Carbonyl Umpolung. When deprotonated with a strong base, O-(trimethylsilyl) cyanohydrins can function as effective acyl anion equivalents that can be used to convert aldehydes to ketones, and in the synthesis of 1,4-diketones, tricyclic ketones, and the highly sensitive a, -epoxy ketone functionality (eq 18). ... 

Methods involving Umpolung.—Exploration of the chemistry of enamidines has revealed their potential for homologation of carbonyl compounds via inter-mediate acyl anion equivalents. A variety of methods for the release of the product from its enamidine were discussed (Scheme 4). t-Butyl ketones may be... 

The a-ethylthiosulfoxides can be converted to the corresponding carbonyl compounds by hydrolysis catalyzed by mercuric ion. In both the dithiane and alkylthiomethylsulfoxide systems, an umpolung is achieved on the basis of the carbanion-stabilizing ability of the sulfur substituents. Scheme 13.2 summarizes some examples of synthetic sequences which employ acyl anion equivalents. 

FIGURE 20.7 Use of dithianes as acyl anion equivalents (umpolung). 

Since formyl and acyl anions are not accessible, one has to use synthetic equivalents of these anions. Several reagents are synthetically equivalent to formyl or acyl anions, permitting the Umpolung of carbonyl reactivity. 

The acyl cation 2a or acylium ion 2b is a familiar intermediate in the Friedel-Crafts reaction. It is easy to make (acid chloride + Lewis acid 1) and it can be observed by NMR as it expresses the natural reactivity pattern of the acyl group. The acyl anion by contrast has umpolung or reverse polarity.1 One might imagine making it from an aldehyde by deprotonation 3 and that it would be trigonal 4a or possibly an oxy-carbene 4b. Such species are (probably) unknown and their rarity as well as their potential in synthesis has led to many synthetic equivalents for this elusive synthon. The acyl anion, the d1 synthon, is the parent of all synthons with umpolung2 and should perhaps have been treated before the homoenolates dealt with in the previous chapter. 

Review. Seebach and Corey have published a general paper on the preparation and metalation of 1,3-dithianes and examples of the reaction of 2-lithio-l,3-dithianes with electrophilic reagents (alkyl halides, carbonyl compounds, acids, and oxides). The value of these sulfur-stabilized anionic reagents is that they are equivalent to acyl anions (a), in which the normal polarity of the carbonyl group is reversed (reversible umpolung). 

Aminoalkenylation, Enamines of this type can be metallated at Ci with replacement of Cl, and the resulting compounds behave as equivalents of acyl anions (Umpolung). ... 

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