Benzoin condensation electrophiles

Thiazolium and triazolium salt-derived NHC, in particular, are well known catalysts for benzoin- and Stetter-type umpolung reactions. In the course of these reactions, the NHC catalyst adds to the electrophilic aldehyde, resulting in the formation of a nucleophilic enamine species. Subsequently, this enamine can react with a series of different electrophiles such as aldehydes (benzoin condensation) or a, )-unsaturalcd substrates (Stetter reaction) (Scheme 4). 

In the benzoin condensation, one molecule of aldehyde serves as an electrophile. If a carbanion is generated from protected cyanohydrins, a-aminonitriles or dithioacetals, it can react with electrophiles such as alkyl halides, strongly activated aryl halides or alkyl tosylates to form ketones. Amongst other electrophiles which are attacked by the above carbanions are heterocyclic A -oxides, carbonyl compounds, a,p-unsaturated carbonyl compounds, a,3-unsaturated nitriles, acyl halides, Mannich bases, epoxides and chlorotiimethyl derivatives of silicon, germanium and tin. 

The benzoin condensation has recently been recognized as belonging to the general class of reactions that involve masked acyl anions as intermediates. For example, an aldehyde is converted into an addition product RCH(OX)Y, which renders the C—H acidic. Then under basic conditions, a masked acyl anion (see 1) can be formed and may react with an electrophilic component E. Decomposition of the product RCE(OX)Y should regenerate the carbonyl group with formation of RC(0)E. Intermediates such as (1) are us in the conversion of aldehydes into a-hydroxy ketones, a-diketones and 1,4-dicarbonyl compounds, proving to be a powerful strategy in the development of new synthetic methods. ... 

The chiral NHC-catalyzed benzoin condensation has been studied theoretically by Honk and co-workers [3,120]. These authors found that the stereochemistry of the major product could be explained by assuming that the electrophilic attack on the Breslow intermediate takes place on the less hindered Re face of the Breslow intermediate, and with an approach of the aldehyde from the Re face, that minimizes the interaction of the aldehyde substituent with the N-Ph moiety of the NHC catalyst (Figure 2.26). Subsequently, Rovis, Houk, and co-workers have also performed theoretical DFT calculations on NHC-catalyzed asymmetric Stetter reactions [121],... 

However, cyanide ion is not suitable for inducing a benzoin-type condensation between two aliphatic aldehydes, since the basic character of this ion induces an aldol condensation between them. In Nature, nevertheless, condensations of this type take place easily. As Breslow proposed in 1958 [8], such condensations are catalysed by thiamine pyrophosphate 6 (or cocarboxylase), the active part of which is the conjugate base of the "thiazolium cation present in it. According to Breslow [8a], the mechanism is, in fact, identical to that described for the cyanide ion (see Scheme 5.7) that is to say, the conjugate base of thiamine (TPP ) reacts with an "aldehyde equivalent -such as an a-ketoacid 2- to generate the corresponding "active aldehyde" 8 with umpoled reactivity, which then reacts with the electrophile to give finally, after elimination of "thiamine anion", a 1,2-D system (9). 

---