康 · 学术 | Reaction of the Day No. 1503

转自：康龙化成

Bridging the Pyridine-pyridazine Synthesis Gap by Skeletal Editing

Mikus Puriņš, Hikaru Nakahara, Mark D. Levin*

Department of Chemistry, University of Chicago, Chicago, IL, USA.

—Science, 2025, 10.1126/science.adx4762

Recommended by Rui Jin _ MC5

KEY WORDS:photo chemistry, skeletal editing, C to N swap (反应类型), C(sp2)-N, N=N(成键类型), 2-halo pyridines (原料), pyridazines (产物), aminating reagent, PPTS, NaN3, benzophenone (其他)

ABSTRACT:Pairs of heterocycles differing by a single constitutive ring atom can exhibit stark differences in the retrosynthetic disconnections available for their preparation. Such a synthesis gap is exemplified by pyridine and pyridazine. Pyridine (a six-membered C5N ring) has risen to prominence in discovery chemistry, its ease of assembly spurring further synthetic development. Despite a host of favorable properties, pyridazine (an analogous C4N2ring) has comparatively lagged behind—a discrepancy attributable to its often-challenging preparation, which arises from an electronically dissonant heteroatom arrangement. In this work, Mark D. Levin et al. achieve a single-atom skeletal edit that produces pyridazines from pyridines by direct carbon-to-nitrogen atom replacement: Azideintroduction at the ortho position enables a photoinitiated rearrangement of N-amino-2-azidopyridinium cations. This transformation links the two heterocycles such that the richness of pyridine retrosynthesis becomes available to pyridazines.

Background and this work: (A) Synthesis gap between pyridine and pyridazine. (B) Examples of recently approved pyridazine pharmaceuticals. (C)Pyridine C(2)-to-N atom replacement reported in this work. (D) Relevant precedents of thermal and photochemical rearrangements of 2-azidopyridine N-oxides.

Substrate scope: (A)Functional group and substitution pattern tolerance. (B)Examples of pyridine syntheses mapping onto pyridazines; shaded bo below the precursors represents the disconnection pattern used in ring synthesis. PPTS= pyridinium p-toluenesulfonate

Applications: (A)A 1-mmol scale reaction and net formal C(2) deletion.(B)Nitrogen scan family tree.(C) Capitalizing on selectivity; chlorination conditions: (i) meta-chloroperoxybenzoic acid and (ii) POCl3. Minisci conditions: isobutyric acid, AgNO3, Selectfluor. (D)Selective 15N monolabeling.

Computational and experimental mechanistic analysis

Editor’s summary (by Jake S. Yeston)

Six-membered rings with five carbons and one nitrogen are very common motifs in pharmaceuticals. By contrast, analogs with two adjacent nitrogens and four carbons are seen much less often in drug research, notwithstanding their appealing properties. The discrepancy likely stems from the comparative synthetic challenge of incorporating the extra nitrogen. Two groups now report complementary approaches to conveniently access these compounds. Puriņš et al.used photochemistry to slice into six-membered pyridine, add in a nitrogen, and expel the carbon. Li et al. started with five-membered pyrrolidine and introduced the nitrogen through ring expansion.

在药物化学中，含五个碳和一个氮的六元环结构（如吡啶）是极为常见的药效团，而具有两个相邻氮原子和四个碳的类似结构（如哒嗪）尽管具备诱人的理化性质，却在药物研发中较为罕见。这种差异主要源于引入额外氮原子所面临的合成挑战。近期两个研究团队分别报道了互补性的解决方案：Puriņš等人（芝加哥大学Mark D. Levin课题组，本文）利用光化学反应对吡啶六元环进行切割，通过氮原子插入/碳原子挤出策略实现转化；李京昊等人（南京大学陆红健课题组，Science