A pyridine reaction that moves the nitrogen instead of the substituents

A group led by Hong Sungwoo, associate director of the Institute for Basic Science's Center for Catalytic Hydrocarbon Functionalizations and a professor at KAIST, has reported a reaction that converts a pyridine directly into its positional isomers by relocating the ring nitrogen rather than shifting the groups attached to the ring ^[1][2]. The work, published in Nature by Choi, Ju, Park and co-authors, matters because the isomers medicinal chemists compare during structure-activity work have until now each required their own starting material and their own route ^[3][6][7].

The logic is a change of reference point. A pyridine is a six-membered aromatic ring with five carbons and one nitrogen, and it is one of the most common motifs in drug molecules ^[4]. Positions on that ring are defined relative to the nitrogen, so moving the nitrogen changes the positional relationship of every substituent even though each substituent stays bonded to the same carbon ^[8]. That relationship is not cosmetic: with identical substituents, changing where they sit relative to the nitrogen can substantially alter solubility, metabolic stability and interactions with biological targets ^[5]. Trying to move the substituents themselves has been hard to generalise, because different functional groups want different conditions ^[9].

Mechanically, the team inserts a new nitrogen into the pyridine framework to make an expanded intermediate, then deletes the original nitrogen, leaving the externally supplied one in the rebuilt ring ^[10]. The original nitrogen departs as N2, which supplies a strong thermodynamic driving force ^[11]. Because the intermediates are too short-lived to isolate, the mechanism rests on labelling: nitrogen-15 reagents showed the nitrogen in the new position came from the external reagent ^[12][13], the original ring nitrogen was confirmed to leave as part of N2 ^[14], and carbon-13 labelling showed the ring carbons kept their original positions ^[15]. That combination is what distinguishes genuine transposition from a wholesale skeletal rearrangement ^[16].

Two practical details stand out. Solvent choice steers the outcome: toluene strongly favoured one positional arrangement, while more polar solvents gave different isomer mixtures, so the same substrate can be pushed toward different products ^[17]. And because the substituents do not have to participate in the reaction, several can change their positional relationship at once while keeping their identities and relative arrangement ^[18]. The reported scope covers mono-, di- and multisubstituted pyridines with a range of functional groups common in medicinal chemistry ^[19][20], demonstrated on complex substrates derived from menthol, sulindac, paracetamol, flurbiprofen, indomethacin and tedizolid, among others ^[21][22].

What the publicly visible material does not give is numbers. Neither the Nature abstract nor the release reports yields or isomer ratios ^[23], and the supplementary information includes a section on positional isomers and unsuccessful substrates alongside the mechanistic studies, DFT-computed mechanism and an X-ray structure for one compound ^[24][25]. The authors' own framing is that substitution pattern becomes a mutable variable in retrosynthetic design ^[26]; whether that holds depends on how narrow the unsuccessful set turns out to be.

Watch the substrate table and the regioselectivity section when the supplementary data is read in detail: the questions for a planning chemist are which isomer ratios are achievable in toluene versus polar solvent, what the nitrogen source costs at scale, and whether basic nitrogens elsewhere in a drug-like molecule survive the insertion step.