Breslow mechanism, Stetter reaction

Since mechanistic studies modeling the Stetter reaction have not yet been reported, the proposed mechanism is based on that elucidated by Breslow for the thiazolium catalyzed benzoin reaction (Scheme 9). The carbene, formed in situ by deprotonation... 

In the thiazolium cation the proton in the 2-position is acidic and its removal gives rise to the ylide/carbene 227. This nucleophilic carbene 227 can add, e.g., to an aldehyde to produce the cationic primary addition product 228. The latter, again via C-deprotonation, affords the enamine-like structure 229. Nucleophilic addition of 229 to either an aldehyde or a Michael-acceptor affords compound(s) 230. The catalytic cycle is completed by deprotonation and elimination of the carbene 227. Strictly speaking, the thiazolium salts (and the 1,2,4-triazolium salts discussed below) are thus not the actual catalysts but pre-catalysts that provide the catalytically active nucleophilic carbenes under the reaction conditions used. This mechanism of action of thiamine was first formulated by Breslow [234] and applies to the benzoin and Stetter-reactions catalyzed by thiazolium salts [235-237] and to those... 

The mechanism of this reaction was hrst described by Breslow as early as 1958 [4], Subsequently, the natural enzyme thiamine, found in yeast, was replaced by related nucleophiles like thiazole [5,6], triazole [7] and imidazole [8], Reactions that follow this mechanism include the very important Stetter reaction (the benzoin condensation of aliphatic aldehydes), the Michael-Stetter reaction (a variant of the Stetter reaction where the aldehyde reacts with an a,P-unsaturated ketone) [1], transesteriflcations [9] or the acylation of alcohols [9,10], All four reactions are carbene catalysed nucleophilic acylation processes. 

Unfettered by the bounds of common Michael acceptors with electron-withdrawing groups, the Glorius group have impressively demonstrated the Stetter reaction of aldehydes with tethered unactivated 1,1-disubstituted alkenes. The cyclization reaction generally proceeds smoothly to afford cyclic ketones with quaternary stereocenters in excellent yields with high enantioselectivity. Based on detailed DFT calculations, they proposed a concerted mechanism for this reaction the proton migration and C—C bond formation between the Breslow enolate and the alkene occur simultaneously (Scheme 7.23). 

A prominent example of this catalytic methodology is the Stetter reaction. Although numerous NHC-organocatalysed versions of this reaction have been developed, it is only very recently that a mechanistic investigation has been detailed in the literature. The intramolecular asymmetric Stetter reaction of substrates (102) catalysed by triazolinylidene-based NHC (103) has been employed as the model reaction and the experimental results obtained have evidenced that the [l,2]-proton shift giving precisely Breslow intermediate (101) is not only slow but above all, the first irreversible step of the transformation. Also noteworthy is that (102) precursors are prone to cyclize not only to the expected six-membered Stetter products (104) but also to benzofurans (105), the latter resulting from a base-mediated mechanism related to the basic feature of the catalyst. 

The widely accepted Breslow mechanism" for carbene-catalyzed acylanion chemistry is illustrated for the Stetter reaction. The thiazolium precatlyst is deprotonated by base to give the active thiazolylidine carbene, and the reaction is initiated by nucleophilic addition of the catalyst to aldehyde 1, giving intermediate 4. The thiazolium substituent is sufficiently electron-... 

More than forty years ago, Stetter reported for the first time a different reactivity of the Breslow intermediate that involved a nucleophilic attack to an electron-deficient alkene, a Michael acceptor, giving access to 1,4-dicarbonyl compounds.This reaction can happen under conditions where the benzoin condensation is reversible and allows the use of a,p-unsaturated esters, ketones, nitriles, sulfones or phosphonates. " Regarding the mechanism, studies have yet to be conducted, and the current proposal is based on the one disclosed by Breslow for the benzoin reaction (Scheme 2.20). ... 

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