Michael-benzoin reaction

Scheme 2.17 Domino Michael-benzoin reaction catalysed by a combination of chiral diphenylprolinol trimethylsilyl ether and a chiral N-hetero-cyclic carbene.

The thiazolium-catalyzed addition of an aldehyde-derived acyl anion with a receptor is a valuable synthetic tool leading to the synthesis of highly funtionalized products. Acyl anion receptors include Michael acceptor (Stetter reaction), aromatic aldehyde (benzoin reaction), ketone, nitroalkene, aziridine, activated imine. Recently, nucleophilic addition of acyl anions to unactivated imines has been explored <07CC852>. Treatment of aryl aldehydes with imines 146 in the presence of triazolium salt 147 (20 mol%) and triethylamine (20 mol%) provides the a-amino ketones 148 in good yields. However, this methodology does not work for 4-pyridylaldehyde and tert-buty laldehyde. 

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 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]. 

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). ... 

Very significant structures such as y-butyrolactones can be synthesised using NHCs that promote a tandem transesterifieation/intramoleeular Michael addition reaction with benzoins or benzaldebydes and metbyl acrylate. A recent advance in the synthesis of this manifold using imi-dazolium ionic liquids has been reported by Harper et al Also, a general process for methylation of carbo)ylic acids has been recently developed by Gorin et... 

Dicaibonyl derivatives from aldehydes and a,p-unsaturated ketones and esters. The thiazolium catalyst serves as a safe surrogate for "CN. Also known as the Michael-Stetter reaction. Cf. Benzoin condensation. 

As well as the traditional benzoin and Stetter reactions, some new synthetic transformations were disclosed via carbene catalysis. In 2007, the Scheldt group developed an intramolecular Michael-type reaction with unsaturated substrates 56 through catalysis with chiral triazolium salt 55. The intermediates 57 were generated via a domino Michael addition/lactonization sequence, and bicyclic products 58 were afforded in satisfactory yields and with excellent enantioselectivity after... 

With a similar strategy of combined diarylprolinol silyl ether and N-heterocyclic carbene catalysts, j0rgensen and coworkers [21] examined the cascade reaction of easily accessible i-keto heteroaryl-sulfones as nucleophiles with a,P-unsaturated aldehydes (Scheme 43.11). In this cascade reaction, following the initial iminium ion-catalyzed Michael reaction of nucleophiles to a,(i-unsaturated aldehydes, the subsequent step was then promoted by carbene catalyst 57 to afford 2,4-disubstituted cyclopentenones 55 via an intramolecular benzoin condensation initiated Smiles rearrangement. The superiority of combinational use of two catalysts in the similar Michael/benzoin cascade reaction was also independently demonstrated by Enders et al. (Scheme 43.12) [22]. 

An illustrative example of the Michael reaction is that of the thiirene dioxide 19b with either hydroxylamine or hydrazine to give desoxybenzoin oxime (87) and desoxybenzoin azine (88), respectively, in good yields6 (see equation 29). The results were interpreted in terms of an initial nucleophilic addition to the a, j8-unsaturated sulfone system, followed by loss of sulfur dioxide and tautomerization. Interestingly, the treatment of the corresponding thiirene oxide (18a) with hydroxylamine also afforded 86 (as well as the dioxime of benzoin), albeit in a lower yield, but apparently via the same mechanistic pathway6. 

The mechanism of the cyanide- and thioazolium ion-catalyzed conjugate addition reactions is considered to be analogous to the Lapworth mechanism for the cyanide-catalyzed benzoin condensation. Thus the cyano-stabilized carbanion resulting from deprotonation of the cyanohydrin of the aldehyde is presumed to be the actual Michael donor. After conjugate addition to the activated olefin, cyanide is eliminated to form the product and regenerate the catalyst. 

NHCs have also been shown to promote the reaction of benzoins and methyl acrylate to produce y-butyrolactones (Scheme 44) [143], In the absence of dimeth-ylimidazolium iodide, the reaction does not proceed. The mechanism is still under investigation, although the authors propose that the transformation may proceed via a tandem transesterification/intramolecular Michael addition LXVin or Michael... 

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 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 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... 

A Michael-type addition has been used to insert suitable Michael acceptors (47 R = CN, COMe, C02Me/Et) between the carbonyls of benzils (48), to give a range of 1,4-diketones (49). The reaction is catalysed by cyanide (typically as B114NCN), and the aryl rings can bear substituents such as chloro or methoxy. Reminiscent of the Benzoin condensation, the reaction proceeds through an O-aroylmandelonitrile anion (50). The reaction has also been extended to C—O rather than C—C insertion benzaldehyde inserts into benzil under the same conditions to give an a-aroyloxy-ketone (51). 

Numerous organic reactions have been studied in aqueous solutions. It was observed that water is able to induce dramatic rate accelerations in Diels-Alder cycloadditions [66], benzoin condensation [67], Claisen rearrangements [68], Mu-kaiyama aldol reactions [57], Michael reactions [69], Baylis-Hillman reactions [70], and 1,3-dipolar cycloadditions [71], All these reactions are characterized by negative volume changes and negative volumes of activation. It is expected that ground state destabilization in aqueous media associated with transition state stabilization is one of the determining kinetic factors. 

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