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Skeletal editing of pyrrolidines by nitrogen-atom insertion

06 August 2025

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Single-atom skeletal editing has emerged as a transformative strategy for modifying molecular frameworks—particularly cyclic scaffolds—by enabling precise, atom-level modifications without requiring de novo synthesis.

N-heterocycles are privileged scaffolds in medicinal chemistry, playing critical roles in molecular recognition, pharmacokinetics, and physicochemical properties. Notably, 82% of FDA-approved small-molecule drugs (2013–2023) incorporate N-heterocycles, with pyridine, piperidine, pyrrolidine, and piperazine among the most prevalent (Figure 1A). Recent efforts have demonstrated the feasibility of N- atom insertion into N-heteroaromatic systems, such as nitrene intermediates for indole- to- quinoline conversions or photocatalytic strategies for pyridine- to- diazepine editing through aminopyridinium salts (Figure 1B). Despite their importance, methods for direct skeletal editing of saturated N-heterocycles (e.g., pyrrolidines) lag behind those for aromatic systems, due to challenges in cleaving and reforming inert C–N/C–C σ bonds without π-system activation.

Figure 1 N-atom insertion strategies in N-heterocycles.

Recently, professor Honglian Lu's research team at Nanjing University developed a skeletal editing method that enables direct nitrogen-atom insertion into pyrrolidine rings, converting them into tetrahydropyridazine scaffolds under mild, operationally simple conditions with readily available O-diphenylphosphinyl hydroxylamine (DPPH) (Figure 1C). The obtained tetrahydropyridazine features two critical functional groups—a nucleophilic amino group (NH) and a reactive carbon-nitrogen double bond (C=N)—which can be selectively oxidized or reduced to yield either saturated 1,2-diazinane or aromatic pyridazine scaffolds, respectively. Notably, these structural motifs have seen substantially increased utilization in recently approved pharmaceutical agents (Figure 1D).

Through systematic optimization, two sets of conditions were established: Condition I (DPPH/K₂CO₃/THF-H₂O at 65°C) for cis-hexahydroisoindole hydrochloride (1a) (68% yield) and Condition II (DPPH/NaOAc/DCM-MeOH at 45°C) for proline derivatives 2a (50% yield). Mechanistic investigations revealed the formation of key triazenium and isodiazene intermediates, with also fully consistent with the exclusive incorporation of the DPPH- derived nitrogen atom into the C=N bond, as demonstrated by the 15N-labeling experiment. (Figure 2).

Figure 2 Optimization of reaction conditions and mechanistic studies

• Innovative Transformation: Direct insertion of a nitrogen atom into pyrrolidines converts them into tetrahydropyridazines under mild conditions using commercially available O-diphenylphosphinyl hydroxylamine (DPPH, A184173).

· Product Information:

DPPH, A184173

Broad substrate scope, including monocyclic, fused, spirocyclic, and bridged architectures, with excellent functional group tolerance (Figure 3).

Figure 3 Editing pyrrolidine skeleton and transformations of tetrahydropyridazines.

• Mechanistic Insights: The reaction proceeds via a triazenium intermediate, confirmed by high-resolution mass spectrometry and isotopic labeling (¹⁵N-DPPH) (Figure 2D). Selective redox manipulation of products yields saturated piperidazines or aromatic pyridazines—valuable but synthetically challenging scaffolds.

• Late-Stage Applications: Successful editing of complex drug fragments (e.g., gliclazide, seltorexant) and natural products (e.g., nicotine metabolites). Gram-scale synthesis demonstrated practicality for industrial applications (Figure 4).

Figure 4 Editing and labeling bioactive compounds.

• Medicinal Relevance: Addresses the underrepresentation of diazacycles (e.g., pyridazines) in drug pipelines due to synthetic hurdles. Enables rapid access to ¹⁵N-labeled bioactive compounds for pharmaceutical research.

Related Products:

At AmBeed, we offer a diverse catalog of high-purity reagents to support your research in this field:

Pyrrolidines (15,000+) - are saturated five-membered heterocyclic compounds containing one nitrogen atom, that serves as an important building block and pharmacophore, widely found in alkaloids and pharmaceutical molecules, participating in reactions such as alkylation, acylation, and ring-opening transformations.

Synthetic Reagents (25,000+) - are indispensable in medicinal chemistry for oxidation, reduction, protection/deprotection, and selective functionalization.

Pyridazines (2700+) - are nitrogen-containing heterocyclic compounds with a six-membered ring containing two adjacent nitrogen atoms, widely used in medicinal chemistry and materials science.

References

[1]Lu H. J. et al. Skeletal editing of pyrrolidines by nitrogen-atom insertion. Science, 2025, 389, 275-281.

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