On the mechanism of N-heterocyclic carbene-catalyzed reactions involving acyl azoliums.

Catalytic reactions promoted by N-heterocyclic carbenes (NHCs) have exploded in popularity since 2004 when several reports described new fundamental reactions that extended beyond the long-studied generation of acyl anion equivalents. These new NHC-catalyzed reactions allow chemists to generate unique reactive species from otherwise inert starting materials, all under simple, mild reaction conditions and with exceptional selectivities. In analogy to transition metal catalysis, the use of NHCs has introduced a new set of elementary steps that operate via discrete reactive species, including acyl anion, homoenolate, and enolate equivalents, usually generated by oxidation state reorganization ("redox neutral" reactions).

Catalytic selective synthesis.

Complete control of the product of a catalytic reaction can be achieved on the basis of catalyst structure, even when the reaction conditions are nearly identical. Catalyst-controlled selectivity is well established for enantioselective catalysis but less formulated for catalytic regio-, chemo-, or product-selective reactions. This Review describes selective transformations of the same starting materials into two or more different products simply by the choice of catalyst.

Oxyanion steering and CH-Ï€ interactions as key elements in an N-heterocyclic carbene-catalyzed [4 + 2] cycloaddition.

The N-heterocyclic carbene catalyzed [4 + 2] cycloaddition has been shown to give γ,δ-unsaturated δ-lactones in excellent enantio- and diastereoselectivity. However, preliminary computational studies of the geometry of the intermediate enolate rendered ambiguous both the origins of selectivity and the reaction pathway. Here, we show that a concerted, but highly asynchronous, Diels-Alder reaction occurs rather than the stepwise Michael-type or Claisen-type pathways.

Chiral N-Heterocyclic Carbene Catalyzed Annulations of Enals and Ynals with Stable Enols: A Highly Enantioselective Coates-Claisen Rearrangement.

A combination of a chiral N-heterocyclic carbene catalyst and α,β-unsaturated aldehyde leads to a catalytically generated α,β-unsaturated acyl azolium, which participates in a highly enantioselective annulation to give dihydropyranone products. This full account of our investigations into the scope and mechanism of this reaction reveals the critical role of both the type and substitution pattern of the chiral triazolium precatalyst in inducing and controlling the stereochemistry. In an effort to explain why stable enols such as naphthol, kojic acid, and dicarbonyl are uniquely efficient, we have postulated that this annulation occurs via a Coates-Claisen rearrangement that invokes the formation of a hemiacetal prior to a sigmatropic rearrangement.

The effect of the -mesityl group in NHC-catalyzed reactions.

The majority of N-heterocyclic carbene catalyzed reactions of -functionalized aldehydes, including annulations, oxidations, and redox reactions, occur more rapidly with -mesityl substituted NHCs. In many cases, no reaction occurs with NHCs lacking ortho-substituted aromatics. By careful competition studies, catalyst analogue synthesis, mechanistic investigations, and consideration of the elementary steps in NHC-catalyzed reactions of enals, we have determined that the effect of the -mesityl group is to render the initial addition of the NHC to the aldehyde irreversible, thereby accelerating the formation of the Breslow intermediate.

Enantioselective synthesis of dihydropyridinones via NHC-catalyzed aza-Claisen reaction.

N-Heterocyclic carbene catalyzed aza-Claisen annulations of enals or their α'-hydroxyenone surrogates with vinylogous amides afford dihydropyridinones. The reaction proceeds with a broad range of substrates, and no nitrogen protecting group is required.

α,β-Unsaturated acyl azoliums from N-heterocyclic carbene catalyzed reactions: observation and mechanistic investigation.

Catalytically generated acyl azoliums and their α,β-unsaturated counterparts are thought to be key reactive intermediates in a rapidly growing number of transformations promoted by N-heterocyclic carbene (NHC) catalysts. Acyl azoliums are invoked in the postulated catalytic cycles of nearly all of the new NHC-catalyzed reactions of α-functionalized aldehydes reported since 2004, in which they are generally assumed to possess the reactivity of an activated carboxylic acid, that is, analogous to an activated ester. In NHC-catalyzed processes, they are most often obtained through internal redox reactions of functionalized aldehydes but have also been prepared by oxidations of the Breslow intermediates or additions to ketenes.

An enantioselective Claisen rearrangement catalyzed by N-heterocyclic carbenes.

In the presence of a chiral azolium salt (10 mol %), enols and ynals undergo a highly enantioselective annulation reaction to form enantiomerically enriched dihydropyranones via an N-heterocyclic carbene catalyzed variant of the Claisen rearrangement. Unlike other azolium-catalyzed reactions, this process requires no added base to generate the putative NHC-catalyst, and our investigations demonstrate that the counterion of the azolium salt plays a key role in the formation of the catalytically active species. Detailed kinetic studies eliminate a potential 1,4-addition as the mechanistic pathway; the observed rate law and activation parameters are consistent with a Claisen rearrangement as the rate-limiting step.