Recent Developments in Transition-Metal-Free Functionalization and Derivatization Reactions of Pyridines

Abstract

Pyridine is an important structural motif that is prevalent in natural products, drugs, and materials. Methods that functionalize and derivatize pyridines have gained significant attention. Recently, a large number of transition-metal-free reactions have been developed. In this review, we provide a brief summary of recent advances in transition-metal-free functionalization and derivatization reactions of pyridines, categorized according to their reaction modes.1 Introduction2 Metalated Pyridines as Nucleophiles2.1 Deprotonation2.2 Halogen–Metal exchange3 Activated Pyridines as Electrophiles3.1 Asymmetric 2-Allylation by Chiral Phosphite Catalysis3.2 Activation of Pyridines by a Bifunctional Activating Group3.3 Alkylation of Pyridines by 1,2-Migration3.4 Alkylation of Pyridines by [3+2] Addition3.5 Pyridine Derivatization by Catalytic In Situ Activation Strategies3.6 Reactions via Heterocyclic Phosphonium Salts4 Radical Reactions for Pyridine Functionalization4.1 Pyridine Functionalization through Radical Addition Reactions4.2 Pyridine Functionalization through Radical–Radical Coupling Reactions5 Derivatization of Pyridines through the Formation of Meisenheimer-Type Pyridyl Anions6 Conclusion

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 ].…”

“…In this review, we intend to cover the recent evolution of the catalytic and technology-driven addition of radical species to iminium and azaarenium compounds having a trisubstituted nitrogen atom ( Figure 2 , R 1 ≠ H). In a complementary point of view of what has been covered in the literature, we will hereby focus on both dipole derivatives (N-R 1 with R 1 = Y − ) and N -alkyl azaarenium salt, which has never been covered in a unified fashion despite some sporadic examples being found in previous reviews on pyridine derivatives [ 17 , 18 , 19 , 20 , 21 , 22 , 23 ]. We essentially cover the literature from 2015, since the Opatz’s review has already discussed this field of research before [ 14 ].…”

Multicomponent Dearomative Difluoroalkylation of Isoquinolines with Difluorinated Silyl Enol Ethers: Divergent Synthesis of gem-Difluorinated Heterocycles

“…Transformative functionalization of electron-deficient N -heteroarenes represents a unique strategy in the organic synthesis arsenal due to the abundance of readily available N -heteroaromatic systems and the rapid access to valuable molecules both with core N -heterocyclic substructure and with various featured functionalities that are in high demand in medicinal chemistry and drug discovery . Despite significant advances, such as directed metalations, Minisci-type radical reactions, and photoredox transformations, dearomatization strategies especially with a multicomponent fashion through a nucleophilic addition process on N -activation mode have attracted extensive interest owing to the easy achievement of structurally complex and functionally diverse sets of dihydroazaarenes with high atom and step economy (Scheme a).…”

Electron-Transfer-Enabled Concerted Nucleophilic Fluorination of Azaarenes: Selective C–H Fluorination of Quinolines

“…5−11 Fluorination of sixmembered azaarenes is even more challenging, and there is currently no method for a C4-selective fluorination at all. 12,13 The sp 2 -hybridized nitrogen atom on electron-deficient azaarenes renders electrophilic aromatic substitution (S E Ar) difficult due to a highly unstable potential Wheland intermediate (Figure 1a). 6,13 Radical aromatic substitution of azaarenes such as Minisci-type reactions can afford C−C, C−B and C−Si bonds 14−18 but not C−F bonds.…”

“…12,13 The sp 2 -hybridized nitrogen atom on electron-deficient azaarenes renders electrophilic aromatic substitution (S E Ar) difficult due to a highly unstable potential Wheland intermediate (Figure 1a). 6,13 Radical aromatic substitution of azaarenes such as Minisci-type reactions can afford C−C, C−B and C−Si bonds 14−18 but not C−F bonds. 19 Nucleophilic fluorination is challenging because, after fluoride addition to form a Meisenheimer intermediate, a hydride must be removed for rearomatization.…”