N-heterocyclic carbene-catalyzed atroposelective synthesis of N-Aryl phthalimides and maleimides via activation of carboxylic acids.

Traditionally, N-aryl phthalimides are synthesized by the condensation of phthalic anhydride and aniline derivatives, usually proceeding under harsh conditions. The alternative mild and organocatalytic strategies for their synthesis are underdeveloped. Herein, we demonstrate the organocatalytic atroposelective synthesis of N-aryl phthalimides via the traditional N-CC=O disconnection under mild conditions. The in-situ acid activation of phthalamic acid and subsequent N-heterocyclic carbene (NHC)-catalyzed atroposelective amidation allowed the synthesis of well-decorated N-aryl phthalimides in excellent yields and enantioselectivities. Mechanistic studies reveal the addition of NHC to the in situ generated isoimides, thus introducing a unique mode of generating acylazoliums. Interestingly, both enantiomers of the product can be accessed from the same phthalic anhydride and aniline using the same NHC pre-catalyst. Moreover, this strategy has been extended to the atroposelective synthesis of N-aryl maleimides.

Nucleophilic Acylation-Annulation Cascade of 2-Chlorobenzonitriles Using Aldehydes Triggered by N-Heterocyclic Carbenes.

A general and practical route to the synthesis of functionalized isoindolin-2-ones from commercially available aldehydes and 2-chlorobenzonitriles under mild conditions initiated by N-heterocyclic carbenes is presented. The catalytically generated Breslow intermediates from aldehydes and carbenes underwent smooth SNAr with 2-chlorobenzonitriles followed by annulation triggered by adventitious water present in DMF to furnish the functionalized isoindolin-2-ones in good to excellent yields.

Dynamic kinetic resolution of γ,γ-disubstituted indole 2-carboxaldehydes via NHC-Lewis acid cooperative catalysis for the synthesis of tetracyclic ε-lactones.

The ubiquity of ε-lactones in various biologically active compounds inspired the development of efficient and enantioselective routes to these target compounds. Described herein is the enantioselective synthesis of indole-fused ε-lactones by the N-heterocyclic carbene (NHC)-Lewis acid cooperative catalyzed dynamic kinetic resolution (DKR) of in situ generated γ,γ-disubstituted indole 2-carboxaldehydes. The Bi(OTf)3-catalyzed Friedel-Crafts reaction of indole-2-carboxaldehyde with 2-hydroxy phenyl p-quinone methides generates γ,γ-disubstituted indole 2-carboxaldehydes, which in the presence of NHC and Bi(OTf)3 afforded the desired tetracyclic ε-lactones in up to 93% yield and >99 : 1 er. Moreover, preliminary studies on the mechanism of this formal [4 + 3] annulation are also provided.

Kinetic Resolution Approach to the Synthesis of C-N Axially Chiral N-Aryl Aminomaleimides via NHC-Catalyzed [3 + 3] Annulation.

Chiral NHC-catalyzed kinetic resolution of N-aryl aminomaleimides allowing the synthesis of C-N axially chiral N-aryl aminomaleimides via remote chirality control is presented. The catalytically generated α,ß-unsaturated acylazoliums from 2-bromoenals underwent selective [3 + 3] annulation with one of the enantiomers of maleimide to furnish fused-dihydropyridinone (bearing axial/central chirality, up to 6:1 dr, >99:1 er) leaving the enantioenriched opposite enantiomer (up to >99:1 er). Studies on C-N bond rotation barrier and dependence on temperature are also provided.

Synthesis of Functionalized Dihydrocoumarins by NHC-Catalyzed [3 + 3] Annulation of Enals with 2-Substituted Naphthoquinones.

The [3 + 3] annulation of α,ß-unsaturated aldehydes with 2-substituted 1,4-naphthoquinones allowing the facile synthesis of functionalized dihydrocoumarins catalyzed by N-heterocyclic carbene (NHC) is reported. The initially formed NHC-homoenolates underwent an efficient Michael-isomerization-lactonization cascade to furnish the products. Preliminary studies on mechanism shed light on the homoenolate pathway over the intermediacy of the α,ß-unsaturated acylazolium intermediates. Moreover, using chiral NHCs, the desired products were formed in up to 49% yield and 99:1 er.

NHC-Catalyzed Desymmetrization of N-Aryl Maleimides Leading to the Atroposelective Synthesis of N-Aryl Succinimides.

Although the construction of axially chiral C-C bonds leading to the atroposelective synthesis of biaryls and allied compounds are well-known, the related synthesis of compounds bearing axially chiral C-N bonds are relatively rare. Described herein is the N-heterocyclic carbene-catalyzed atroposelective synthesis of N-aryl succinimides having an axially chiral C-N bond via the desymmetrization of N-aryl maleimides. The NHC involved intermolecular Stetter-aldol cascade of dialdehydes with prochiral N-aryl maleimides followed by oxidation afforded N-aryl succinimides in good yields and ee values. Preliminary studies on rotation barrier for the C-N bond, the temperature dependence, and detailed DFT studies on mechanism are also provided.

NHC-Catalyzed [3 + 3] Annulation of Thioamides and Modified Enals for the Enantioselective Synthesis of Functionalized Thiazinones.

N-Heterocyclic carbene (NHC)-catalyzed [3 + 3] annulation of thioamides with modified enals allowing the enantioselective synthesis of functionalized 1,3-thiazin-4-ones is reported. The NHC generated from the chiral triazolium salt was optimal and the reaction is initiated by the thia-Michael addition to catalytically generated α,ß-unsaturated acylazolium intermediates derived from 2-bromoenals, followed by intramolecular cyclization. This operationally simple procedure offers a straightforward and rapid access to target compounds in moderate to good yields and enantiomeric ratio values.