Four‐Selective Pyridine Alkylation via Wittig Olefination of Dearomatized Pyridylphosphonium Ylides

Abstract

Methods to synthesize alkylated pyridines are valuable because these structures are prevalent in pharmaceuticals and agrochemicals. We have developed a distinct approach to construct 4‐alkylpyridines using dearomatized pyridylphosphonium ylide intermediates in a Wittig olefination‐rearomatization sequence. Pyridine N‐activation is key to this strategy, and N‐triazinylpyridinium salts enable coupling between a wide variety of substituted pyridines and aldehydes. The alkylation protocol is viable for late‐stage functionalization, including methylation of pyridine‐containing drugs. This approach represents an alternative to metal‐catalyzed sp2‐sp3 cross‐coupling reactions and Minisci‐type processes.

Late-Stage C–H Functionalization of Azines

“…McNally’s group applied Wittig olefination chemistry in a nonconventional method for pyridine 4-alkylation (Scheme A) . After forming N -triazinylpyridinium salts, they added tributylphosphine (PBu 3 ) to form dearomatized phosphonium ion 225 and, then, MeLi at low temperature to obtain the key ylide Int 15 (Scheme B).…”

“…McNally's group applied Wittig olefination chemistry in a nonconventional method for pyridine 4-alkylation (Scheme 47A). 135 48A). 137 The mechanism begins with reversible coordination of the silver reagent to the azine N atom Int 16, and the Ag−F bond subsequently adds across the pyridinium π-system to form the amidosilver(II)-fluoride Int 17 (Scheme 48B).…”

Synthesis of Bench-Stable N-Quaternized Ketene N,O-Acetals and Preliminary Evaluation as Reagents in Organic Synthesis

“…For example, Dudley’s reagent is a bench-stable pyridinium salt for O - and N -benzylation under neutral conditions N -acyl, N -fluoro, N -oxo, N- amino, and other N -activated pyridinium salts promote a broad range of valuable transformations or act as building blocks for cycloadditions, rearrangements, reductions, oxidations, transition-metal couplings, and nucleophilic additions . Protonated pyridinium salts such as pyridinium p -toluenesulfonate (PPTS), a mild organic soluble acid, and pyridinium chlorochromate (PCC), a mild organic soluble oxidant, represent two mainstay reagents in organic synthesis.…”

C3-Selective Trifluoromethylthiolation and Difluoromethylthiolation of Pyridines and Pyridine Drugs via Dihydropyridine Intermediates

“…As a result, pyridine is a high-value substrate for C–H functionalization reactions . Despite the development of radical C–H fluoroalkylation reactions of pyridines and the recent emergence of a method for phosphorus-mediated ligand-coupling reactions for C–H fluoroalkylation of azines, there are no broadly applicable methods for C–H trifluoromethylthiolation and difluoromethylthiolation of pyridines, and most existing methods for the synthesis of SCF 3 - or SCF 2 H-substituted pyridines have been based on transformations of other functional groups already present on the pyridine ring . The establishment of such methods would surely facilitate drug discovery (Figure b).…”