Nickel-catalyzed C-3 direct arylation of pyridinium ions for the synthesis of 1-azafluorenes

Abstract

The direct arylation of pyridine substrates using non-precious catalysts is underdeveloped but highly desirable due to its efficiency to access important motifs while being extremely cost-effective. The first nickel-catalyzed C-3 direct arylation of pyridine derivatives to provide a new approach to valuable 1-azafluorene pharmacophore frameworks was developed. This transformation is accomplished using air-stable nickel catalyst precursors combined with phenanthroline ligands and tolerates a variety of substituents. Computational studies suggest facile oxidative addition via the pyridinium form, deprotonation, and a subsequent carbo-nickelation cyclization. Nickel homolysis/recombination permits isomerization to the stereochemical array needed for the final elimination.

Heterocyclic group transfer reactions with I(iii) N-HVI reagents: access to N-alkyl(heteroaryl)onium salts via olefin aminolactonization

“…In organic chemistry, they serve as ionic liquids 5 (2) and phase transfer catalysts, 6 exhibit a diverse range of biological activities (3, 4), and have a long history as synthetic intermediates, an area that has seen a recent surge of new advancements. Representative of their versatile reactivity, pyridinium and related salts can undergo full or partial reductions, [7][8][9] cycloadditions, 10,11 photochemical isomerizations, 12 cross couplings, 13 addition of one-or two-electron heteroatom or carbon nucleophiles, 8,14 and facile C-H metalations, 15 and many of these include asymmetric variants [16][17][18] (Fig. 1).…”

Domino Reaction Sequence for the Synthesis of [2.2.2]Diazabicycloalkenes and Base-Promoted Cycloreversion to 2-Pyridone Alkaloids

“…Additionally, only a limited number of methods have been exploited for the synthesis of 1-azafluorene structures. 14,15 …”

Sequential C–H Arylation and Enantioselective Hydrogenation Enables Ideal Asymmetric Entry to the Indenopiperidine Core of an 11β-HSD-1 Inhibitor

“…Moreover, this work further serves as the basis for development of a nickel catalyzed intramolecular arylation as a general method for the synthesis of 1-azafluorenes. 17,18 …”

“…17 Although significant amounts of both aryl palladium species are expected based on the computed equilibrium for the acid–base interchange, the subsequent migratory insertion onto a double bond of the charged species is untenable (48.1 kcal/mol) due to the aromatic stabilization of the pyridinium. However, the energetic barrier (29.6 kcal/mol) for migratory insertion of the neutral species is readily accessible under the reaction conditions of this process.…”