Breslow intermediates

The simplest and most direct manner to generate acyl anion equivalents is through reaction of an NHC with an aldehyde, generating an enamine species 8, commonly referred to as a Breslow intermediate . Subsequent reaction with an electrophile, classically using aldehydes or enones, generates the benzoin and Stetter products 10 and 11 respectively (Scheme 12.1). 

Alternative methods to access the same Breslow intermediate using NHCs utilising acyl silanes [3] or a-keto-acids have been developed [4], although these processes have not been utilised in asymmetric transformations to date. 

Hydroxyenones have also been used in catalytic amide formation, although 1,2,4-triazole is required as a co-catalyst. Assumed protonation of the Breslow intermediate and tautomerisation generates an acylazolium intermediate, which is trapped by triazole, releasing the NHC and generating the acyltriazole 60 that is the active acylating agent for the amine (Scheme 12.11) [16]. 

In 1976, Stetter extended the synthetic utility of the Breslow intermediate (1) as an acyl anion equivalent by showing that aldehydes could be coupled with Michael acceptors to generate 1,4-dicarbonyl compounds [55]. 

Breslow and co-workers elucidated the currently accepted mechanism of the benzoin reaction in 1958 using thiamin 8. The mechanism is closely related to Lapworth s mechanism for cyanide anion catalyzed benzoin reaction (Scheme 2) [28, 29], The carbene, formed in situ by deprotonation of the corresponding thiazolium salt, undergoes nucleophilic addition to the aldehyde. A subsequent proton transfer generates a nucleophilic acyl anion equivalent known as the Breslow intermediate IX. Subsequent attack of the acyl anion equivalent into another molecule of aldehyde generates a new carbon - carbon bond XI. A proton transfer forms tetrahedral intermediate XII, allowing for collapse to produce the a-hydroxy ketone accompanied by liberation of the active catalyst. As with the cyanide catalyzed benzoin reaction, the thiazolylidene catalyzed benzoin reaction is reversible [30]. 

In the rationale of Scheidt et al., a carbene catalyst (48) adds to the acylsilane 49 to produce - after 1,2-silyl migration - the intermediate 50 (Scheme 9.13). The alcohol is believed to induce a desilylation, leading to the Breslow-intermediate 26. Due to the reduced electrophilicity of the acylsilane (in comparison with an aldehyde), the conjugate addition predominates. 

An alternative to generate esters 73 was reported by Rovis et al., who converted a-haloaldehydes into the corresponding dehalogenated esters (Scheme 9.22) [65]. In the proposed mechanism, the Breslow intermediate 74 (X1 = Br, X2 = H) contains a / -leaving group which allows the formation of the enol 75 that gives rise to the ester 73. 

However, the (/i/X)-geometry of the Breslow intermediate has not yet been determined, but is of relevance for the pre-orientation of the second aldehyde molecule. As shown in transition state 103, the corresponding ( )-isomer would probably favor a Si-Si-attack and therefore a (R)-configuration in the product. An unfavorable sterical interaction between the phenyl substituent of the enol moiety and the phenyl sub-... 

This versatile method has found a broad application in the synthesis of organic key intermediates and diverse natural products. In the catalytic cycle, the aldehyde 6 is presumably activated by the carbene under generation of the Breslow intermediate 83 and subsequent nucle-... 

In general, all extended umpolung reactions deal with aldehyde substrates that bear somehow reducible side chains prone to subsequent interaction at the stage of the common so-called Breslow intermediate (Zeitler 2005). Their subsequent participation leads—depending on the... 

A -Alkylated thiazolium and benzothiazolium salts also experience base-promoted deprotonation at the 2-position to form ylides. Such compounds, often referred to as TV-heterocyclic carbene (NHC), are nucleophilic catalysts in benzoin condensation. In 1943, Ugai and co-workers reported that thiazolium salts catalyze self-condensation of benzaldehyde to generate benzoin via an umpoulong process. Breslow at Columbia University in 1958 proposed thiazolium ylide as the actual catalyst for this transformation. In this mechanism, the catalytically active species was represented as a thiazolium zwitterion, the resonance structure of an NHC, and the reaction was postulated to ensue via the enaminol or the Breslow intermediate. ... 

The mechanism operating in A-heterocyclic carbene-mediated reactions was proposed initially by Breslow in 1958 for the thiazolium salt-catalyzed benzoin condensation (Scheme 6.1). This proposal involves the formation of a carbene as the catalytically active species by deprotonation of the thiazolium cation, which subsequently adds to one molecule of the aldehyde, generating a nucleophilic intermediate known as the Breslow intermediate. Next, this... 

The ability of A -heterocyclic carbenes to activate a,p-unsaturated carbonyl compounds via the formation of the corresponding Breslow intermediate, which plays the role of a homoenolate nucleophile, has also been applied to a cascade process involving a formal intramolecular Michael reaction/oxidation/ lactonization, leading to the formation of complex tricyclic carbon frameworks starting from a bifunctional substrate containing an enone and an a,p-unsa-turated aldehyde side chain linked to each other via a benzene tether (Scheme 7.82). The reaction involved a complex multistep mechanism which started with the activation of the enal by the catalyst, forming the Breslow intermediate, which subsequently underwent intramolecular Michael reaction and next the generated enol-type intermediate reacted intramolecularly with the... 

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. 

After the reaction of the Breslow intermediate with the carbonyl group of a second aldehyde, a proton transfer occurs and the elimination of the benzoin product regenerates the carbene catalyst (Scheme 2.19). 

Recently, there has heen some work dealing with the cross-henzoin condensation to afford nonsymmetrical products chemoselectively. In this case, the Breslow intermediate has to he formed predominantly with only one of the aldehydes and react selectively with the other one. Kuhl and Glorius have succeeded in this area developing a selective hydro gmiethylation of aldehydes.With a different approach, it is also possible to use hindered ortho-substituted aldehydes to inhibit the retro-benzoin reaction and the attack of the As an extension, the cross-benzoin reaction has been... 

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). ... 

Oxidation of the Breslow intermediate formed in the reaction of an ynal with an NHC reaction of an enal with an NHC... 

The nucleophilicity of the Breslow intermediate can be transferred to the p-position of an ot,p-unsaturated aldehyde when this reacts with a NHC, generating a homoenolate that can act as a d -synthon (Scheme 2.22). 

N-Heterocyclic carbenes (NHCs) have been well known for their unique reactivity to cleave the acyl C—H bond of aldehydes. In 2012, DiRocco and Rovis reported elegant asymmetric a-acylation reactions of tertiary amines 17 with various aldehydes 16 by employing a combination of an NHC catalyst and photoredox catalyst. Since the Breslow intermediate or NHC itself is sensitive to oxidative conditions, a judicious choice of oxidant and photoredox catalyst is crucial. After careful evaluation of the reaction conditions, Ru(bpy)3Cl2 was proved to be the optimal photoredox catalyst and m-dinitrobenzene (m-DNB) as the co-oxidant under irradiation with blue light. The aminoinda-nol-derived NHC C2 (generated in situ from the corresponding triazolium salt using NaH) exhibited the best asymmetric induction. An array of the desired products 18 was obtained in up to 94% yield and 92% ee (Scheme 2.7). 

In 1958, Breslow proposed the meehanism that the active catalytie speeies is a nucleophilic carbene derived from a thiazolium salt to generate the earban-ion known as the Breslow intermediate The study of asymmetrieally eatalytie acyl carbanion processes has been an area of immense interest e.g. benzoin reaction and Stetter reaction) since then (Scheme 7.2). 

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