Cyclic Ketimines as Superior Electrophiles for NHC-Catalyzed Homoenolate Additions with Broad Scope and Low Catalyst Loadings

Abstract

Cyclic sulfonyl imines derived from ketones were identified as stable and readily prepared compounds that serve as superior electrophiles for N-heterocyclic carbene (NHC)-catalyzed annulations with α,β-unsaturated aldehydes to afford highly substituted γ-lactams. Their superior reactivity and properties are highlighted by the first example of NHC-catalyzed reactions of enals with low catalyst loadings (0.5 mol %) and broad substrate scope encompassing alkyl, aryl, and heteroaromatic substituents. These findings and supporting studies suggest an alternative, ene-like mechanism rather than the catalytic generation of a catalyst-bound homoenolate equivalent.

Organocatalytic Reactions Enabled by N-Heterocyclic Carbenes

“…156 Aryl and aliphatic enals are tolerated in the reaction, as well as a wide variety of saccharin-derived ketimines bearing both aryl and aliphatic groups; yields of 67 range from 55–95% with diastereoselectivity varying from 1:1 to >20:1 dr. Remarkably aryl-enals require just 0.5 mol% of catalyst for quantitative yield at room temperature (Scheme 78).…”

Late‐Stage Diversification of Chiral N‐Heterocyclic‐Carbene Precatalysts for Enantioselective Homoenolate Additions

“…[7d] Our preliminary studies showed that the catalyst structure had a profound effect on the stereochemical outcome. Interestingly, the azolium precatalysts that gave the highest enantioselectivities gave the poorest diastereoselectivity.…”

“…This mild and simple protocol catalytically generates homoenolates at ambient temperature without the need for stoichiometric additives or exclusion of water. Following our initial report on the use of this chemistry for the preparation of γ-lactones, NHC-catalyzed homoenolate formation has been extended to the synthesis of γ-lactams and related heterocycles, [7] spiro γ-butyrolactones, [8] and pyridazinones [9] (see Scheme 1). Similar conditions and catalysts can be used to prepare cyclopentenes and cyclopentane derivatives in good yield and with high enantioselectivity, but more-complex mechanisms, rather than a simple homoenolate equivalent, may be involved in those processes.…”

Exploiting Acyl and Enol Azolium Intermediates via N‐Hetero‐ cyclic Carbene‐Catalyzed Reactions of α‐Reducible Aldehydes

“…[64] NHC precursor 46 facilitates the reaction with aliphatic and aromatic enals 37 and saccharin-derived imines 172 to give cyclic sulfonamide derivatives 173 in 55-95 % and 1:1 to >20:1 d.r. (Scheme 50, a).…”