P-Protonation of Homoenolates

Bode and Mahatthananchai have performed thorough studies on the effect of the N-Mes group [10]. The observed behavior of catalysts bearing this substituent is mainly the result of their increased steric bulk and electron-donating ability in homoenolate intermediates, particularly with respect to their N-CsFs counterparts. 

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Homoenolate Protonation The p-protonation of homoenolates has been observed by Scheidt and co-workers, resulting in a redox transformation of enals to afford saturated esters 48. This process is catalysed by the NHC derived from imidazolium salt 46 and utilises phenol as a proton source [14]. A range of primary and secondary alcohols, and phenol itself, are competent nucleophiles with which to trap the acylazolium intermediate 47 generated by protonation (Scheme 12.8). 

We decided to evaluate our new strategy with azomethine imines [111-116] as a possible reacting partner with homoenolates [117], Contrary to our findings with the p-protonation of homoenolates, the AfW-dimethyl substituted benzimidazole 4 was observed by NMR spectroscopy to interact irreversibly with the secondary electrophile, the starting azomethine imine [118], The more bulky A -mesityl-Ai-methylbenzimidazolium salt 5 was employed in order to sequester this nonproductive pathway (Scheme 11). The use of 20 mol% of this precatalyst in combination with DBU at 40°C catalyzed the reaction between enals and azomethine imines to afford tetrahydropyridazinones as a single diastereoisomer (all cis). A variety of substituents are tolerated on the azomethine imine. It was found that phenyl... 

Maki BE, Patterson EV, Cramer CE, Scheldt KA. Impact of solvent polarity on A-heterocyclic carbene-catalyzed P-protonations of homoenolate equivalents. Org. Lett. 2009 11 3942-3945. 

Scheme 3.46 Chiral iV-heterocyclic carbene-catalyzed enantioselective P-protonation of homoenolate equivalents...

In 2007, Scheldt and co-workers reported the intramolecular desynunetrization of 1,3-diketones utilizing triazolinm pre-catalyst 249 (Scheme 39) [129], Generation of a homoenolate is followed by P-protonation and aldol reaction. In accordance with the proposed mechanism by Nair (Scheme 37), acylation occurs followed by loss of carbon dioxide. Cyclopentenes are formed in enantioselectivities up to 94% ee. The scope of this reaction is limited to aryl substitution of the diketone and alkyl substitution of R. 

In 2013, the Chi group disclosed a substrate-independent selective generation of enolates over homoenolate equivalents in NHC-catalyzed reactions of enals and chalcones. Acid co-catalysts play vital roles in control of the reaction pathways, as the acid might promote the enal p-protonation by increasing the proton concentration. Also, the competing enolate/homoeno-late pathways were found to be sensitive to the steric bulkiness of the enal and enone substrates (Scheme 7.74). 

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). 

A-heterocyclic carbenes (NHC) are also efficient organocatalytic tools for generating homoenolate equivalents from a,P-unsaturated aldehydes. These reactive intermediates display a versatile reactivity in a number of catalytic transformations attesting to an important synthetic potential [38]. Recently, Scheldt et al. [39a] accomplished the first enantioselective protonation of a homoenolate species generated by a chiral NHC precursor 93 in the presence of DIE A and an excess of ethanol as the achiral proton source (Scheme 3.46). The suggested mechanism involves an initial addition of NHC 93 to the enal 89 followed by a formal 1,2-proton shift resulting in the formation of the chiral homoenolate equivalent 91. A diastereose-lective P-protonation/tautomerization sequence leads to the acyl triazolinium inter-... 

Stothers has published a more complete account of the homoenolization of fenchone (203 X = O) with t-butyl [2H]alcohol and potassium t-butoxide at 185 °C (Vol. 4, p. 48) and shown that proton exchange occurs at the five /3-positions kinetics for the five exchange processes are reported.289... 

The Bode group have documented an NHC-catalyzed enantioselective synthesis of ester enolate equivalents with a,p-unsaturated aldehydes as starting materials and their application in inverse electron demand Diels-Alder reactions with enones. Remarkably, the use of weak amine bases was crucial DMAP (conjugate acid = 9.2) andN-methyl morpholine (NMM, conjugate acid pAa = 7.4) gave the best results. A change in the co-catalytic amine base employed in these reactions could completely shift the reaction pathway to the hetero-Diels-Alder reaction, which proceeded via a catalytically generated enolate. An alternative pathway that occurred via a formal homoenolate equivalent was therefore excluded. It is demonstrated that electron-rich imidazolium-derived catalysts favor the homoenolate pathways, whereas tri-azolium-derived structures enhance protonation and lead to the enolate and activated carboxylates (Scheme 7.71). 

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