Homoenolates 3-protonation

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). 

In a related transformation, Bode and co-workers have demonstrated the utility of homoenolate protonation in an azadiene Diels-Alder reaction catalyzed by aminoin-danol derived A-mesityl pre-catalyst 214 [118,119], The cyclization products 213 are obtained as a single diastereomer in excellent enantiomeric excess (Table 16). Electron-deficient enals are used in order to increase the electrophihcity and reactivity of the compounds. After protonation of the homoeneolate moiety, an inverse electron demand Diels-Alder is proposed to provide the desired cychzed product. 

SCHEME 16.25. NHC-catalyzed homoenolate protonation/intramolecular aldol/acylation domino reaction. 

Allyltitanium complexes derived from a chiral acetal have been reacted with carbonyl compounds and imines [63], While the chiral induction proved to be low with carbonyl compounds, high induction was observed with imines. This complex represents the first chiral homoenolate equivalent that reacts efficiently with imines. Finally, the reactions with electrophiles other than carbonyl compounds and imines, namely a proton source, NCS, and I2, furnished the corresponding alkene, chloro, and iodo derivatives in good yields [64]. 

DePuy, as early as 1966 [14], reported that cw-1-methyl-2-phenylcyclopropanol gave exclusively deuterated 4-phenyl-2-butenone in 0.1 M NaOD/D20/dioxane. However, homoenolates derived from simple cyclopropanols by base-induced proton abstraction fail to react with electrophiles such as aldehydes and ketones, which would afford directly 1,4-D systems. Lack of a reasonably general preparative method was another factor which impeded the studies of homoenolate chemistry. For this reason, in the past twenty years more elaborated cyclopropanols, which might be suitable precursors of "homoenolates", have been prepared and studied. 

Bode and co-workers have shown that the outcome of internal redox reactions is uniquely dependent on the base [111]. When diisopropylethyl amine is used in the reaction of an enol and an alcohol, the initially generated homoenolate is protonated... 

The proposed catalytic cycle is shown in Scheme 35 and begins with the imida-zolylidene carbene adding to the enal. Proton transfer provides acyl anion equivalent XLVII, which may be drawn as its homoenolate resonance form XLVIII. Addition of the homoenolate to aldehyde followed by tautomerization affords L the precursor for lactonization and regeneration of the carbene. 

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. 

Methylcyclopropane 6 reacts selectively (> 98 %) with ZnCl2 at the less hindered site to give the homoenolate of 2-methylpropionate, whereas phenyl substituted analogue 7 is cleaved selectively (>98%) at the more substituted site [27], The latter homoenolate however suffers in situ protonation under the reaction conditions and could not be isolated. 

Recently, Bode et al. were able to demonstrate that the products formed after generation of the homoenolate equivalents 67 are determined by the catalytic base [64]. Strong bases such as KOt-Bu led to carbon-carbon bond-formation (y-butyrolactones), while weaker bases such as diisopropylethylamine (DIPEA) allowed for protonation of the homoenolate and the subsequent generation of activated carboxylates. The combination of triazolium catalyst 72 and DIPEA in THF as solvent required no additional additives and enabled milder reaction conditions (60 °C), accompanied by still high conversions in the formation of saturated esters out of unsaturated aldehydes (Scheme 9.21). Aliphatic and aromatic enals 62, as well as primary alcohols, secondary alcohols and phenols, are suitable substrates. a-Substituted unsaturated aldehydes did not yield the desired products 73. 

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 formation of the observed products can be explained by the following catalytic cycle (Scheme 8). Addition of the nucleophilic carbene leads to adduct I, followed by proton transfer to give conjugate enamine Ha. Homoenolate equivalent Ha (see also resonance structure lib) can add to the aldehyde reaction partner providing zwitterion III and after... 

The homoenolate dianion 129 rearranges to the more stable species 130 presumably through dilithiocyclopropane intermediate 131 (Scheme 50) . Other electrophilic species can take the place of a proton in this ring-cleavage reaction. Table 23 lists representative examples. 

Enolisation 1 involves the removal of the a-proton from a carbonyl compound to form an enolate ion 2. Homoenolisation involves the removal of a (i-proton 3 to form the homoenolate ion 4 or 5. Both the enolate and the homoenolate can be represented as carbanions, but whereas the enolate version 2b is merely a different way of representing a single delocalised structure, the homoenolate 5 is a different compound from the cyclopropane 4. No literal examples of homoenolates 5 are known so they have the status of synthons which may be represented in real life by reagents derived from cyclopropanols 4 among many other possibilities.1... 

Just as anions of allyl derivatives can be homoenolate equivalents (chapter 13) so anions of vinyl derivatives can be acyl anion equivalents. Vinyl (or enol) ethers can be lithiated reasonably easily, especially when there is no possibility of forming an allyl derivative, as with the simplest compound 81. The most acidic proton is the one marked and the vinyl-lithium derivative 82 reacts with electrophiles to give the enol ether of the product17 84. However, tertiary butyl lithium is needed and compounds with y-CHs usually end up as the chelated allyl-lithium 85. These vinyl-lithium compounds add directly to conjugated systems but the cuprates will do conjugate addition.18... 

Hoppe has extended this work to d3 reagents 159 (homoenolates - see chapter 13 for achiral versions) by the addition of a double bond.29 Lithiation occurs at C-l by removal of one of the enantiotopic protons at C-3. Aldol reaction with acetone occurs at C-3 of the complex 160 as expected for a homoenolate (chapter 13) giving a single enantiomer of the homoaldol product 161. All these reactions use an excess of sparteine. 

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). 

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). 

Addition of enals to enones to give cA-cyclopentenes is an example of a stereoselective annulation with homoenolates. Catalysed by NHCs and Lewis acids such as Ti(OPr-t)4, the cooperative nature of these species has been explored in a DFT study Another DFT study into the NHC-catalysed cycloannulation of the homoeno- 0 late derived from butenal with pentenone has examined pathways to cyclopentene and cyclopentanone derivatives and the effect of the presence of DABCO on proton transfer steps. ... 

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). 

Ready access to the allylic anion (26) is obtained as a result of the increased kinetic acidity of the proton a- to the carbamate group. The anions react with electrophiles at the y-position (R 5 H), and thus function as homoenolate equivalents. ... 

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