N-Functionalized Pyridinium Salts: A New Chapter for Site-Selective Pyridine C–H Functionalization via Radical-Based Processes under Visible Light Irradiation

Abstract

Conspectus The radical-mediated C–H functionalization of pyridines has attracted considerable attention as a powerful tool in synthetic chemistry for the direct functionalization of the C–H bonds of the pyridine scaffold. Classically, the synthetic methods for functionalized pyridines often involve radical-mediated Minisci-type reactions under strongly acidic conditions. However, the site-selective functionalization of pyridines in unbiased systems has been a long-standing challenge because the pyridine scaffold contains multiple competing reaction sites (C2 vs C4) to intercept free radicals. Therefore, prefunctionalization of the pyridine is required to avoid issues observed with the formation of a mixture of regioisomers and overalkylated side products. Recently, N-functionalized pyridinium salts have been attracting considerable attention in organic chemistry as promising radical precursors and pyridine surrogates. The notable advantage of N-functionalized pyridinium salts lies in their ability to enhance the reactivity and selectivity for synthetically useful reactions under acid-free conditions. This approach enables exquisite regiocontrol for nonclassical Minisci-type reactions at the C2 and C4 positions under mild reaction conditions, which are suitable for the late-stage functionalization of bioactive molecules with greater complexity and diversity. Over the past five years, a variety of fascinating synthetic applications have been developed using various types of pyridinium salts under visible light conditions. In addition, a new platform for alkene difunctionalization using appropriately designed N-substituted pyridinium salts as bifunctional reagents has been reported, offering an innovative assembly process for complex organic architectures. Intriguingly, strategies involving light-absorbing electron donor–acceptor (EDA) complexes between pyridinium salts and suitable electron-rich donors further open up new reactivity under photocatalyst-free conditions. Furthermore, we developed enantioselective reactions using pyridinium salts to afford enantioenriched molecules bearing pyridines through single-electron N-heterocyclic carbene (NHC) catalysis. Herein, we provide a broad overview of our recent contributions to the development of N-functionalized pyridinium salts and summarize the cornerstones of organic reactions that successfully employ these pyridinium salts under visible light conditions. The major advances in the field are systematically categorized on the basis of the pyridines’ N-substituent, N–X (X = O, N, C, and SO2CF3), and its reactivity patterns. Furthermore, the identification of new activation modes and their mechanistic aspects are discussed by providing representative contributions to each paradigm. We hope that this Account will inspire broad interest in the continued innovation of N-functionalized pyridinium salts in the exploration of new transformations.

Photocatalytic Late-Stage C–H Functionalization

“…Additionally, photocatalytic strategies that employ in situ-generated intermediates via nonphotochemical LSFs are introduced. The latter examples offer a sound perspective on sulfonium and pyridinium salts 25 as LSF synthons. The Review covers the peer-reviewed scientific literature and ChemRxiv literature up to November 2022.…”

Recent Advances in Catalytic and Technology-Driven Radical Addition to N,N-Disubstituted Iminium Species

“…Following a similar activation model ( Figure 2 ), several addition sequences of radical species to N- alkoxy and N -amine azaarenium platform molecules (R 1 = OR, NR 2 ) emerged in the literature as powerful functionalization strategies showing that the regioselectivity issue highly depends on the architecture and substitution pattern of the heterocycles. This field of research was covered by very instructive recent reviews [ 17 , 18 , 19 , 20 , 21 ].…”

Photocatalytic Decarboxylative Pyridylation of Carboxylic Acids Using In Situ-Generated Amidyl Radicals as Oxidants

“…N -Functionalized pyridinium salts have been used as versatile pyridine surrogates for diverse visible-light-promoted reactions. , We investigated the suitability of the carboxylic acid moiety for visible-light-mediated decarboxylative pyridyl couplings using N -functionalized pyridinium salts as coupling partners to develop a mild and efficient synthetic method of functionalizing pyridines with diverse groups at precise sites. N -Amidopyridinium salts were chosen to avoid the issues associated with the classic Minisci-type chemistry and because of the following intriguing merits: (i) they react readily in Minisci-type radical addition under H + -free conditions and perform well when subjected to photocatalysis in photochemical applications; (ii) the released amidyl radical may serve as an effective SET oxidant (this feature might enable the regeneration of a photocatalyst, thus circumventing the need for external oxidants); (iii) they exhibit excellent reactivity, C4 regiochemical outcomes, and broad functional group tolerance with various substitution patterns at the C2 and C3 positions.…”

“…The alkylated product 3a was obtained in 74% yield with exclusive C4 selectivity under mild conditions when [( t Bu) 2 Mes-PhAcr]­BF 4 was employed as a photocatalyst (entry 1). We reasoned that the acridinium-based photocatalyst outperformed the other photocatalysts because of its efficient regeneration by the amidyl radical and the minimal decomposition of the N -aminopyridinium salt ( E red = −0.6 to −0.8 V vs SCE) . Among the screened bases, dibasic potassium phosphate was most suitable for this reaction (entries 3 and 4).…”

“…The solubility of salt 1a in solvent played an important role in the reactivity (entries 5 and 6, and Table S2 in the Supporting Information). For example, the low product yield and a large quantity of pyridine in dimethyl sulfoxide (DMSO) indicated that the formation of the electron donor–acceptor (EDA) complex between the pyridinium salt and carboxylate led to the decomposition of the salt under blue LED irradiation . Indeed, mixing 1a and pivalate in DMSO resulted in a large bathochromic shift in the UV/vis absorption peak (Figure S2 in the SI).…”