Catalytic Generation of Activated Carboxylates

Since these initial reports, the NHC-catalyzed generation of activated carboxylates from a-functionalized aldehydes has been extended to a remarkably wide range of substrate classes. Bode first reported the generation of activated carboxylates from a,p-unsaturated aldehydes as part of his work on the catalytic generation of homoenolates vide infra) These studies were further explored to develop improved catalysts and render this a general process. This work, which identified the uniquely high reactivity of A-mesityl substituted triazolium pre-catalysts as superior to all other catalyst classes for NHC-catalyzed redox reactions of a,p-unsaturated aldehydes, was crucial to the development of the remarkable annulation reactions described below. Zeitler reported analogous 

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The broad scope of the catalytic generation of activated carboxylates was demonstrated by Bode et al. in the diastereoselective synthesis of / -hydroxy esters 79 from a,/ -epoxy aldehydes 80 employing achiral thiazolium salts 81 as precatalysts (Scheme 9.24) [67]. The incorporation of a reducible functionality into the aldehyde substrate is the premise for a catalyst-induced intramolecular redox reaction generating the activated carboxylate 82. 

Chow KYK, Bode JW (2004) Catalytic generation of activated carboxylates direct, stereoselective synthesis of fi-hydroxyesters from. J Am Chem Soc 126 8126-8127... 

Sohn SS, Bode JW (2005) Catalytic generation of activated carboxylates from enals a product-determining role for the base. Org Lett 7 3873-3876... 

Scheme 14.5 Catalytic generation of activated carboxylates (DIPEA = A, Af-diisopropylethylamine).

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. 

Consideration of the reaction pathways shown in Scheme 14.12 for the NHC-catalyzed generation of activated carboxylates from enals reveals the intermediacy of an NHC-bound ester enol or enolate equivalent that could be trapped by a suitable electrophile. This was first achieved by Bode, who in 2006 reported highly enantioseleetive inverse electron-demand Diels-Alder reactions of the catalytically generated enolate equivalents and ot,p-unsaturated N-sul-fonyl imines (Scheme 14.19). At the time, this was the first report of a highly... 

The proposed catalytic cycle for this reaction begins with the initial attack of the in situ generated thiazolylidene carbene on the epoxyaldehyde followed by intramolecular proton transfer (Scheme 28, XXXII-XXXIII). Isomerization occurs to open the epoxide forming XXXIV which undergoes a second proton transfer forming XXXV. Diastereoselective protonation provides activated carboxylate intermediate XXXVI. Nucleophilic attack of the activated carboxylate regenerates the catalyst and provides the desired P-hydroxy ester. 

Another example of promising research is the efficient electrochemical dicarbo-xylations of aryl-acetylenes with C02, using an uncomplicated bimetallic redox couple as the catalytic system. In this case, metallic nickel was used as the cathode and aluminum as the anode, to generate in situ carboxylation-active nickel species (Scheme 5.20) [61]. 

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