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

   https://doi.org/10.1002/anie.202109271  

   Fricke, Patrick_J; Dolewski, Ryan_D; McNally, Andrew (August 2021, Angewandte Chemie International Edition)

   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. PyridineN‐activation is key to this strategy, andN‐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‐catalyzedsp²‐sp³cross‐coupling reactions and Minisci‐type processes. 

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2. A Pyridine–Pyridine Cross‐Coupling Reaction via Dearomatized Radical Intermediates

   https://doi.org/10.1002/anie.201906267  

   Koniarczyk, J. Luke; Greenwood, Jacob W.; Alegre‐Requena, Juan V.; Paton, Robert S.; McNally, Andrew (September 2019, Angewandte Chemie International Edition)

   Abstract A pyridine–pyridine coupling reaction has been developed between pyridyl phosphonium salts and cyanopyridines using B₂pin₂as an electron‐transfer reagent. Complete regio‐ and cross‐selectivity are observed when forming a range of valuable 2,4′‐bipyridines. Phosphonium salts were found to be the only viable radical precursors in this process, and mechanistic studies indicate that the process does not proceed through a Minisci‐type coupling involving a pyridyl radical. Instead, a radical–radical coupling process between a boryl phosphonium pyridyl radical and a boryl‐stabilized cyanopyridine radical explains the C−C bond‐forming step. 

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3. Radical surface chemistry: Augmentation of reactivity by radicals at aqueous interfaces

   https://doi.org/10.1016/j.surfrep.2025.100668  

   Kolasinski, Kurt W (November 2025, Surface Science Reports)

   Cooperativity and non-additive interactions play central roles in the unusual and surprising behavior of water. A host of reactive oxygen species (ROS) including the hydroxyl radical •OH, superoxide radical anion (O2–•), hydroperoxide radical (HO2•), singlet oxygen (1O2), and also the more recently discussed water radical cation/anion pair (H2O+•/H2O–•) all add to the more familiar acid/base chemical pathways tread by hydronium (H3O+) and hydroxide (OH–). This is amplified in surface science because interfacial water – whether found at the gas/liquid, gas/solid, or liquid/solid interface – poses yet more unique behavior. This review explores the unexpected chemistry associated with ambient temperature aqueous interfaces much of which is mediated not only by ions and neutrals as expected, but also radical species. Water microdroplets catalyze numerous reactions and can also support simultaneous oxidation and reduction reactions through the production of reactive intermediates that owe their existence to the unique influence of the air/water or oil/water interface. Interfacial water influences and is influenced by the ubiquitous phenomenon of contact electrification, a manifestation of spontaneous symmetry breaking. The mechanisms of chemistry not only on and in microdroplets but also at the gas/solid and liquid/solid interfaces rely on a broad set of chemical transformations mediated by radicals. Furthermore, because aqueous macro- and micro-interfaces are ubiquitous on Earth, we find that water radical-mediated chemistry has applications to atmospheric chemistry, geochemistry, mineral weathering, pre-biotic chemistry, enhanced enzyme performance, wastewater remediation, public health, mechanochemistry, and potentially novel routes to pharmaceuticals. 

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4. α-Branched amines through radical coupling with 2-azaallyl anions, redox active esters and alkenes

   https://doi.org/10.1039/D2SC00500J  

   Duan, Shengzu; Zi, Yujin; Wang, Lingling; Cong, Jielun; Chen, Wen; Li, Minyan; Zhang, Hongbin; Yang, Xiaodong; Walsh, Patrick J. (March 2022, Chemical Science)

   α-Branched amines are fundamental building blocks in a variety of natural products and pharmaceuticals. Herein is reported a unique cascade reaction that enables the preparation of α-branched amines bearing aryl or alkyl groups at the β- or γ-positions. The cascade is initiated by reduction of redox active esters to alkyl radicals. The resulting alkyl radicals are trapped by styrene derivatives, leading to benzylic radicals. The persistent 2-azaallyl radicals and benzylic radicals are proposed to undergo a radical–radical coupling leading to functionalized amine products. Evidence is provided that the role of the nickel catalyst is to promote formation of the alkyl radical from the redox active ester and not promote the C–C bond formation. The synthetic method introduced herein tolerates a variety of imines and redox active esters, allowing for efficient construction of amine building blocks. 

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5. A General Strategy for N-(Hetero)arylpiperidine Synthesis Using Zincke Imine Intermediates

   https://doi.org/10.1021/jacs.3c11504  

   Selingo, Jake D; Greenwood, Jacob W; Andrews, Mary Katherine; Patel, Chirag; Neel, Andrew J; Pio, Barbara; Shevlin, Michael; Phillips, Eric M; Maddess, Matthew L; McNally, Andrew (January 2024, Journal of the American Chemical Society)

   Lloyd-Jones, Guy (Ed.)

   Methods to synthesize diverse collections of sub- stituted piperidines are valuable due to the prevalence of this heterocycle in pharmaceutical compounds. Here, we present a general strategy to access N-(hetero)arylpiperidines using a pyridine ring-opening and ring-closing approach via Zincke imine inter- mediates. This process generates pyridinium salts from a wide variety of substituted pyridines and (heteroaryl)anilines; hydro- genation reactions and nucleophilic additions then access the N- (hetero)arylpiperidine derivatives. We successfully applied high- throughput experimentation (HTE) using pharmaceutically relevant pyridines and (heteroaryl)anilines as inputs and developed a one-pot process using anilines as nucleophiles in the pyridinium salt-forming processes. This strategy is viable for generating piperidine libraries and applications such as the convergent coupling of complex fragments. 

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