Enantioselective Catalysis by the Umpolung of Conjugate Acceptors Involving N-Heterocyclic Carbene or Organophosphine 1,4-Addition

Abstract

Conspectus Conjugate acceptors are one of the most common electrophilic functional groups in organic synthesis. While useful in a diverse range of transformations, their applications are largely dominated by the reactions from which their name is derived (i.e., as an acceptor of nucleophiles in the conjugate position). In 2014, we commenced studies focused on their ability to undergo polarity inversion through the conjugate addition of Lewis base catalysts. The first step in this process provides an enolate, from which the well-developed Rauhut–Currier (RC) and Morita–Baylis–Hillman (MBH) reactions can occur; however, tautomerization to provide a species in which the β-carbon of the conjugate acceptor can now act as a donor is also possible. When we commenced studies on this topic, reaction designs with this type of species, particularly when accessed using N-heterocyclic carbenes (NHCs), had been reported on only a handful of occasions. Despite a lack of development, conceptually it was felt that reactions taking advantage of polarity switching by Lewis base conjugate addition have a number of desirable features. Perhaps the most significant is the potential to reimagine a ubiquitous functional group as an entirely new synthon, namely, a donor to electrophiles from the conjugate position. Our work has focused on catalysis with both simple conjugate acceptors and also those embedded within more complicated substrates; the latter has allowed a series of cycloiso­merizations and annulation reactions to be achieved. In most cases, the reactions have been possible using enantioenriched chiral NHCs or organophosphines as the Lewis base catalysts thereby delivering enantioselective approaches to novel cyclic molecules. While related chemistry can be accessed with either family of catalyst, in all cases reactions have been designed to take advantage of one or the other. In addition, a fine balance exists between reactions that exploit the initially formed enolate and those that involve the polarity-inverted β-anion. In our studies, this balance is addressed through substrate design, although catalyst control may also be possible. We consider the chemistry discussed in this Account to be in its infancy. Significant challenges remain to be addressed before our broad aim of discovering a universal approach to the polarity inversion of all conjugate acceptors can be achieved. These challenges broadly relate to chemoselectivity with substrates bearing multiple electrophilic functionalities, reliance upon the use of conjugate acceptors, and catalyst efficiency. To address these challenges, advances in catalyst design and catalyst cooperativity are likely required.

N-Heterocyclic carbene catalyzed synthesis of benzotrifluorides from enals and β-trifluoromethylenones

“…In the past decades, N-heterocyclic carbenes (NHCs) have emerged as a powerful tool to construct various organic molecules 11 including multi-substituted benzenes. 12 For example, Lupton and coworkers developed the NHC-catalyzed synthesis of arenes via [4 + 2] annulation/decarboxylation/aromatization of silyl dienol ethers with α,β-unsaturated acyl fluorides, 13 and the following redox isomerization of esters.…”

A Facile Preparation of N‐Heterocyclic Olefins: Ring‐Opening Polymerization of β‐Butyrolactone and Frustrated Lewis Pair Reactivity**

“…[26][27][28][29][30][31] NHOs are finally important intermediates in catalytic transformations initiated by conjugate additions of N-heterocyclic carbenes (NHCs) leading to the umpolung of Michael acceptors. [32][33][34] Despite the above, the chemistry and applications of NHOs has not proceeded as rapidly as that of NHCs, in part because their difficult preparation and isolation has impeded their study. NHOs have been prepared by the deprotonation of the corresponding 2-alkylimidazoli(ni)um salts (Scheme 1a) [5] or 5alkyl-1,2,3-triazolium salts in the case of mesoionic NHOs (mNHOs, Scheme 1b).…”

“…Most notably, NHOs arose as polymerization initiators or catalysts, either on their own or as frustrated Lewis pairs (FLPs), that are suited for the ring‐opening polymerization (ROP) of sustainably sourced lactones to yield biodegradable polyhydroxyalkanoates (PHAs) [26–31] . NHOs are finally important intermediates in catalytic transformations initiated by conjugate additions of N‐heterocyclic carbenes (NHCs) leading to the umpolung of Michael acceptors [32–34] …”

Phosphine-Catalyzed (3 + 2) Annulation of γ-Substituted Cinnamic Aldehyde-Derived Morita–Baylis–Hillman Carbonates through Remote Activation

“…Organophosphine catalysis, which is commonly regarded as a powerful strategy for the synthesis of functional cyclic compounds nowadays, has witnessed great success in past decades . The widely used phosphine catalyst acceptors in phosphine-catalyzed annulations mainly consist of electron-deficient alkenes, alkynes, allenes, and Morita–Baylis–Hillman (MBH) carbonates, which represent the most reliable synthons in phosphine catalysis toward functionalized cyclic compounds …”