Extending NHC-Catalysis: Coupling Aldehydes with Unconventional Reaction Partners

Transition metal catalysis is a powerful means of effecting organic reactions, but it has some inherent drawbacks, such as the cost of the catalyst and the toxicity of the metals. Organocatalysis represents an attractive alternative and, in some cases, offers transformations unparalleled in metal catalysis. Unique transformations are a particular hallmark of N-heterocyclic carbene (NHC) organocatalysis, a versatile method for which a number of modes of action are known. The NHC-catalyzed umpolung (that is, the inversion of polarity) of electrophilic aldehydes, through formation of the nucleophilic Breslow intermediate, is probably the most important mode of action. In this Account, we discuss the reaction of Breslow intermediates with unconventional reaction partners. In two traditional umpolung reactions, the benzoin condensation and the Stetter reaction, some selectivity issues represent significant challenges, especially in intermolecular variants of these reactions. In intermolecular cross-benzoin reactions, high levels of selectivity were recently obtained, even in the hydroxymethylation of aldehydes with formaldehyde. The key to success was careful choice of the NHC catalyst and reaction conditions. Among asymmetric Stetter reactions, intermolecular versions have posed a long-standing challenge. Recently, the groups of Enders and Rovis reported the first selective and efficient systems. We have contributed to this field by developing an efficient intermolecular Stetter reaction for the formation of α-amino acid derivatives, with broad aldehyde scope and high enantiomeric excess. Moreover, tailor-made thiazolylidene catalysts allowed the unprecedented use of nonactivated olefins and alkynes as aldehyde coupling partners. The basis for this reactivity is a unique mode of NHC organocatalysis: dual activation. In a concerted but asynchronous transition state, the positively polarized proton of the Breslow intermediate activates the coupling partner (for example, an olefin), while the nucleophilic enamine moiety starts to attack the activated coupling partner. As a consequence of the concerted nature of this mechanism, excellent values for enantiomeric excess were obtained for many substrates in the intramolecular hydroacylation of alkenes. In addition, thiazolylidene catalysts have enabled the coupling of aldehydes with reactive species, for example, with arynes and with activated alkyl bromides. NHC catalysis should continue to flourish and lead to surprising developments. One remaining challenge is the asymmetric intermolecular hydroacylation of unactivated olefins. In this area, metal-based catalysts have shown promising early results, but they are far from being either general or practical. It will be interesting to see which class of catalyst, whether metal-based or NHC-based, eventually develops into the method of choice.