Benzoin condensation Stetter reaction

In the second part, we want to report some significant procedures of electrosynthesis, carried out in RTILs as well as in VOC-supporting electrolyte systems, including a comparison between the results obtained according to the two different procedures. The synthesis of P-lactams, the utilization of CO as renewable carbon source and the carbon-carbon bond formation via umpolung of aldehydes (benzoin condensation, Stetter reaction) and via Hemy reaction have been selected as typical procedures. 

Recently, the reactivity (base, nucleophile, catalyst) and the role in modem organic synthesis of N-heterocyclic carbenes (cychc carbenes bearing at least one amino substituent) has been set-up by Ender et al. [60,61]. The possible utilization of NHCs as ligands for transition-metal catalyst [62,63] and as organocatalyst has been emphasized [61]. The inversion of the normal reactivity (umpolung) induced via NHCs has been extensively discussed. Classical carbon-carbon-bond-forming reactions (benzoin condensation, Stetter reaction, etc.) have been re-examined using ionic liquids as pre-catalysts in the presence of bases. 

NHC-catalyzed reactions are unique in organic synthesis, and very useful for the construction of carbon-carbon bonds. Great success has been made for the NHC-catalyzed benzoin condensation, Stetter reactions, and a -d Umpolung reactions in the past decades. NHC catalysis has also hnd application in many other reactions, such as umpolung of Michael acceptors, Morita-Baylis-Hilman reaction, Michael additions, redox reaction, and reactions of ketenes. With the rapid development of NHC catalysis, more reactions will surely be found, and the wide applications in organic synthesis could be expected. 

It is worth noting, however, that the rise of enantioselective benzoin and Stetter reactions were one of the forerunners of the new generation of NHC-catalyzed processes that have been reported since 2004. These studies, particularly the work of Knight and keeper on chiral triazolium salts for benzoin and Stetter reactions, formed the basis for the design and synthesis of the now widely used chiral NHCs (Scheme 14.2). These designs were elegantly extended by Enders and by Rovis for the development of catalytic enantioselective benzoin condensations, intramolecular Stetter reactions, and the wide variety of enantioselective NHC-catalyzed transformations detailed below. 

Cyanide-catalyzed condensation of aryl aldehyde to benzoin. Now cyanide is mostly replaced by a thiazolium salt. Cf. Stetter reaction. 

Dicarbonyl derivatives from aldehydes and a,P-unsaturated ketones. The thi-azolium catalyst serves as a safe surrogate for CN. Also known as the Mi-chael-Stetter reaction. Cf. Benzoin condensation. 

The general reaction patterns of the benzoin condensation and the related Stetter reaction are depicted in Scheme 6.104. Both reactions are nucleophilic acylations,... 

The Stetter Reaction is a 1,4-addition (conjugate addition) of an aldehyde to an a,p-unsaturated compound, catalyzed by cyanide or a thiazolium salt. This reaction competes with the corresponding 1,2-addition, which is the Benzoin Condensation. However, the Benzoin-Condensation is reversible, and since the Stetter Reaction leads to more stable products, the main product will be derived from 1,4-addition. 

In the intermolecular Stetter reaction, self-condensation of the donor aldehyde usually dominates over the conjugate addition, leading to benzoins as the major... 

The reactions discussed above have focused on an a1 to d1 umpolung, as exemplified by the reaction of the resulting d1 nucleophile with aldehydes (benzoin condensation [9]) or with Michael acceptors (Stetter reaction [38]) [3]. In contrast, a,/ -unsaturated aldehydes can react as d3 nucleophiles by utilizing a conjugated umpolung that involves a homoenolate reactivity. 

The Benzoin Condensation 331 The Stetter Reaction 338 Further Applications 344 a3 to d3 Umpolung 344 Transesterifications and Polymerizations 349 References 353... 

The triazolium salt 2 has also been used as a purely organic catalyst [17]. It is an active catalyst for asymmetric benzoin-type condensation reactions yielding the reaction products with enantiomeric excesses of 20-80%, which at the time marked a major advance with respect to the previously established catalysts (Scheme 5, Eq. 1) [18]. It was also found to catalyze the asymmetric intramolecular Stetter reaction with moderate to good enantioselectivities (41-74% ee) (Scheme 5, Eq. 2) [19]. 

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). 

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. 

Note The Stetter reaction is a benzoin condensation using aliphatic aldehydes. 

Note The Michael-Stetter reaction is a benzoin condensation between an aliphatic aldehyde and an a, jd-unsaturated ketone. 

It is only a small step from the asymmetric benzoin condensation to the asymmetric Stetter reaction, the aliphatic variant of the benzoin condensation. The literatnre refers to the Stetter reaction when at least one of the two reactants is an aliphatic aldehyde. Normally, the reaction is performed as a cross-coupling reaction with two different reactants, one of which is not an aldehyde, bnt an a, 3-unsaturated ketone. Strictly speaking, most thiazole catalysed reactions referred to as Stetter reactions are in fact Michael-Stetter reactions [21,22] (see Fignre 6.4). The reaction received the name because Stetter used a Michael reagent, an acceptor with an activated double bond, as the second component of a cross-coupled Stetter reaction [11]. 

The thiazolium-catal)fzed addition reactions of an aldehyde-derived acyl anion with a Michael acceptor (Stetter reaction) and the benzoin condensation (most often between two aldehydes) are well-known synthetic tools leading to the synthesis of highly funtionalized... 

In the laboratory of A. Millar, the convergent enantloselective synthesis of CI-981, a potent and tissue-selective Inhibitor of HMG-CoA reductase was achieved. The central tetrasubstituted pyrrole ring was prepared via the Paal-Knorr pyrrole synthesis. The required 1,4-diketone precursor was efficiently prepared by the Stetter reaction between p-fluorobenzaldehyde and an unsaturated amide. Interestingly, the A/-benzyl thiazolium chloride catalyst afforded only the benzoin condensation product and none of the desired diketone. However, when the A/-ethyl thiazolium bromide catalyst was employed, under anhydrous and concentrated reaction conditions, the 1,4-diketone was formed in good yield. The authors also noted that the simple dilution of the reaction mixture resulted in a dramatic increase in the formation of the undesired benzoin condensation product. 

Variants of the Michael addition include the allylation of cyclopropenone acetals and the intramolecular Stetter reaction. So far, only moderate enantioselectivity for the latter reaction has been achieved. (Note that the same chiral catalyst is useful for benzoin condensation. )... 

This reaction is very closely related to the Baylis-Hillman Reaction, and is also related to Stetter Reaction and Benzoin Condensation in mechanism. 

The diamino enol formed after reaction of a NHC with simple aldehydes (Breslow intermediate) can react with other aldehydes or imines to aehieve the benzoin or azabenzoin condensation, and the Stetter reaction when reacting with electron-poor alkenes. 

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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