Aldehydes reaction with nucleophilic carbenes

The triazole 76, which is more accurately portrayed as the nucleophilic carbene structure 76a, acts as a formyl anion equivalent by reaction with alkyl halides and subsequent reductive cleavage to give aldehydes as shown (75TL1889). The benzoin reaction may be considered as resulting in the net addition of a benzoyl anion to a benzaldehyde, and the chiral triazolium salt 77 has been reported to be an efficient asymmetric catalyst for this, giving the products (/ )-ArCH(OH)COAr, in up to 86% e.e. (96HCA1217). In the closely related intramolecular Stetter reaction e.e.s of up to 74% were obtained (96HCA1899). 

The preparative value of this compound lies in the surprising fact that bis(l,3-diphenylimidazolidinylidenc-2) behaves in many reactions ie.g., with aromatic aldehydes,2,7 and with carbon acids 2 7-fJ) as if it dissociated to form a nucleophilic carbene. The hydrolytic cleavage of these derived imidazolidine derivatives makes possible the preparation of formyl compounds, so that the amino olefin can be considered as a potential carbonyla-tion reagent. In many reactions it is not necessary to isolate... 

Abstract The photoinduced reactions of metal carbene complexes, particularly Group 6 Fischer carbenes, are comprehensively presented in this chapter with a complete listing of published examples. A majority of these processes involve CO insertion to produce species that have ketene-like reactivity. Cyclo addition reactions presented include reaction with imines to form /1-lactams, with alkenes to form cyclobutanones, with aldehydes to form /1-lactones, and with azoarenes to form diazetidinones. Photoinduced benzannulation processes are included. Reactions involving nucleophilic attack to form esters, amino acids, peptides, allenes, acylated arenes, and aza-Cope rearrangement products are detailed. A number of photoinduced reactions of carbenes do not involve CO insertion. These include reactions with sulfur ylides and sulfilimines, cyclopropanation, 1,3-dipolar cycloadditions, and acyl migrations. 

Isonitrile complexes, having a similar electronic structure to carbonyl complexes, can also react with nucleophiles. Amino-substituted carbene complexes can be prepared in this way (Figure 2.6) [109-112]. Complexes of acceptor-substituted isonitriles can undergo 1,3-dipolar cycloaddition reactions with aldehydes, electron-poor olefins [113], isocyanates [114,115], carbon disulfide [115], etc., to yield heterocycloalkylidene complexes (Figure 2.6). 

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. 

The reaction has to be carried out in the absence of oxygen and water, otherwise the intermediately formed nucleophilic carbene is oxidized to the tria-zolinone or suffers hydrolysis with subsequent aminal-type ring opening. Attempts to apply catalyst 7 to the synthesis of aliphatic acyloins gave very low yields and low enantioselectivities. Optimization of the catalyst structure with regard to activity and enantioselectivity yielded triazolium salt 8 as the best-suited system for the condensation of aliphatic aldehydes (Scheme 5) [37]. However, the enantiomeric excesses obtained, only up to 26%, and the rather low total turnover numbers, ranging from 4 to 8, are modest and a search for new, more active catalyst systems is highly desirable. 

Gaunt and coworkers discovered that heteroaromatic aldehydes could be converted to the corresponding ketones by arylation under metal-free conditions using a conunercially available V-heterocyclic carbene catalyst (Scheme 22b) [52], The reaction was proposed to proceed by formation of a Breslow intermediate from the aldehyde and the carbene, acting as a nucleophile in the subsequent arylation. Reactions with unsynunetric salts were rather unselective with conunon dununy groups, but salts with a uracil dunuiay substituent proved to be highly selective (see Sect. 2). 

It is proposed that primarily a nucleophilic carbene 24 (cf. p. 221) is generated by deprotonation of 22, which adds to the a,f -unsaturated aldehyde to give a homoenolate equivalent 25 as umpoled R-CH=CH-CH=0 synthon. Protonation of 25 in P-position leads to the 2-substituted imidazohum ion 26 on reaction with 26, the sahcylalde-hyde is O-acylated 27), the imidazohum ion 22 is regenerated, and (base-induced) intramolecular Claisen condensation of 27 provides the coumarin (23). 

Reactions with Carbonyl Compounds and Utilization of 2-Diazo-2-(trimethyIsiIyI)ethanoIs. Diazo(trimethylsilyl)-methyllithium (TMSC(Li)N2) reacts with aldehydes and ketones to give lithium 2-diazo-2-(trimethylsilyl)ethoxides by nucleophilic addition, which produce alkylidene carbenes by expulsion of TMSOLi and nitrogen (eq 12). 

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]. 

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]. 

When 2,2-dichloro-3-phenylpropanal 203 is subjected to standard reaction conditions with chiral triazolium salt 75c, the desired amide is produced in 80% ee and 62% yield Eq. 20. This experiment suggests that the catalyst is involved in an enantioselec-tive protonation event. With this evidence in hand, the proposed mechanism begins with carbene addition to the a-reducible aldehyde followed by formation of activated car-boxylate XLII (Scheme 32). Acyl transfer occurs with HOAt, presumably due to its higher kinetic nucleophilicity under these conditions, thus regenerating the carbene. In turn, intermediate XLin then undergoes nucleophilic attack by the amine and releases the co-catalyst back into the catalytic cycle. 

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