Rationally Designing Regiodivergent Dipolar Cycloadditions: Frontier Orbitals Show How To Switch between [5 + 3] and [4 + 2] Cycloadditions

Abstract

A pyridinium zwitterion substrate is employed with two different types of transition metal catalysts to develop a regiodivergent cycloaddition. The pyridinium zwitterion is a highly reactive dipolar substrate that can undergo a dipolar cycloaddition with various reactants. It has multiple reaction sites, and the chemoselectivity is determined by the electronic demand of the catalyst−substrate complex. The reaction with nucleophilic Pd reagents affords fused N-heterocyclic compounds via regioselective [4 + 2] cycloaddition. The origin of the site selectivity and the mechanism of this reaction are investigated in this combined experimental and computational study. We found that the pyridinium zwitterion plays a completely different role in the palladium(0)-catalyzed [4 + 2] cycloaddition reaction and in the rhodium(II)-catalyzed [5 + 3] cycloaddition, which was examined experimentally in a previous study. The frontier molecular orbitals of the pyridinium substrate and activated catalyst complex reveal that the pyridinium zwitterion can act as both a nucleophile and an electrophile depending on the reaction partner in a manner much more defined than that of conventional substrates, leading to the observed regiodivergent chemical reactivity.

Advances in Palladium‐Catalyzed Decarboxylative Cycloadditions of Cyclic Carbonates, Carbamates and Lactones

“…In 2018, Yoo and Baik et al reported a palladium-catalyzed DCs of γ-methylidene-δ-valerolactones 155 a with pyridinium zwitterion 181, constructing a number of fused N-heterocyclic compounds 182 in high yields (Scheme 86). [62] The carbanion of zwitterionic species 4.1A selectively attacked the C4 position of pyridinium rather than the usual C6 position to form the species 4.1G. Then the C5 position of dihydropyridine moiety attacked the terminal carbon atom of π-allyl palladium moiety to produce 4.1H.…”

“…Palladium-catalyzed DCs of γ-methylidene-δ-valerolactones with pyridinium zwitterion. [62] Scheme 87. Comparison between VECs and vinyl methylene cyclic carbonates.…”

Transition-Metal-Catalyzed Nucleophilic Dearomatization of Electron-Deficient Heteroarenes

“…In 2018, the Yoo group reported a palladium-catalyzed [4+2] cycloaddition of pyridinium zwitterions 88 and -methylidene--valerolactones 89, providing an efficient access to fused N-heterocyclic compounds 90 (Scheme 23, a). 49 Mechanistically, Pd(II)-1,4-zwitterionic complex 91 is formed via oxidative addition with 89 at the beginning. Next, the C4 position of the pyridinium zwitterion is attacked by the nucleophilic part of the Pd(II)-1,4-zwitterionic complex to give intermediate 92.…”

Nucleophilic Dearomatization of Activated Pyridines

“…Then, the intermediate immediately cyclized with another molecule of benzyne, leading to the formation of polycyclic 1,4-benzodiazepines (Scheme 41). Very recently, Yoo and co-authors [119] realized that the intrinsic and permanent charge polarization in the pyridinium zwitterion could lead to dipole-controlled divergent cycloadditions in a rational and predictable manner. They reported the first example of divergent cycloadditions of pyridinium zwitterions controlled by the electronic properties of the metal-bound reaction partners (Scheme 42).…”