Pyrrolidine synthesis via ring contraction of pyridines

Article https://doi.org/10.1038/s41467-025-57527-w Pyrrolidine synthesis via ring contraction of pyridines Received: 9 October 2024 Ryoga Ueno1, Shohei Hirano1 & Jun Takaya 2 Accepted: 24 February 2025 1234567890():,; 1234567890():,; Check for updates A ring contraction of easily available cyclic compounds to smaller cycles that are valuable but difficult to synthetically access is one of important skeletal editing strategies. Pyrrolidine synthesis via a ring contraction of pyridines, which are abundant, cheap, and readily available bulk chemicals in chemical industry, is highly promising to accelerate drug discovery and development research due to the great demand of pyrrolidine skeletons in medicinal molecules. Herein we report a photo-promoted ring contraction of pyridines with silylborane to afford pyrrolidine derivatives bearing a 2-azabicyclo[3.1.0] hex-3-ene skeleton. The reaction demonstrates broad substrate scope with high functional group compatibility, realizing facile access to 6-silyl-2-azabicyclo[3.1.0]hex-3-ene derivatives that work as powerful synthons for the synthesis of functionalized pyrrolidines and nitrogen-containing compounds. The reaction mechanism is clarified to proceed via 2-silyl-1,2-dihydropyridine and vinylazomethine ylide as intermediates, which are connected via photochemical or thermal silyl migration. Pyrrolidine is one of prevalent core structures found in biologically active natural products and medicinal molecules1–3. Development of synthetic methods to access pyrrolidine skeletons with broad scope and high functional group compatibility is of great importance not only to accelerate drug discovery research but also to explore chemical spaces of nitrogen-containing compounds. [3 + 2] cycloaddition reactions of azomethine ylides with alkenes and alkynes have been widely investigated, affording pyrrolidine derivatives with a wide range of substitution patterns and excellent stereoselectivity (Fig. 1a)4,5. Intramolecular cyclization approaches utilizing such as amination of unsaturated carbon-carbon bonds6–9 and insertion of nitrene species into sp3C–H bonds10–12 have also been recognized as powerful methods for efficient construction of pyrrolidine rings (Fig. 1b). However, preparation of the appropriate starting materials is necessary in most case of these reactions, thus limiting their versatility. Meanwhile, a ring contraction of cyclic compounds to smaller cycles that are valuable but difficult to synthetically access is a useful strategy in synthetic organic chemistry. This is regarded as skeletal editing, which has rapidly emerged as a powerful concept to expand molecular diversity13,14. Considering the synthesis of pyrrolidine derivatives via ring contractions, it is highly desirable to use pyridines as starting materials, which are abundant, cheap, and readily available bulk chemicals in chemical industry. However, such ring contraction reactions have scarcely been achieved to date. There are several examples of pyrrole synthesis from N-alkylpyridinium salts or pyridines via sequential ring-cleavage and ring-closure under oxidative conditions15–19. Photoreactions are promising to realize skeletal editing although direct excitation of pyridine itself requires ultraviolet irradiation20–23, which often causes side reactions and is not suitable for practical synthetic reactions. As an early example of a photo-promoted ring contraction of pyridines, in 1969, Kellogg reported that irradiation of 254 nm light to pyridine diester afforded dihydropyridine along with a small amount of pyrrole (Fig. 1c)24. In 1972, Kaplan and Wilzbach reported a photoreaction of an N-methylpyridinium salt in water to yield an aziridine derivative, 6-azabicyclo[3.1.0]hex-3-ene-2-ol, via 4π electrocyclization followed by hydration25. This reaction was further extended by Mariano into practical synthesis of aminocyclopentene derivatives by combining it with a subsequent nucleophilic ringopening reaction of the aziridine moiety (Fig. 1d)26,27. The photolysis of pyridine N-oxides was reported to give 2-acylpyrroles in low yields28. Recently, optimizing this reaction, Levin realized skeletal editing of quinoline N-oxides to N-acylindoles via net one carbon deletion, in 1 Department of Chemistry, School of Science, Tokyo Institute of Technology, Tokyo, Japan. 2Division of Chemistry, Department of Material Engineering e-mail: Science, Graduate School of Engineering Science, Osaka University, Osaka, Japan. Nature Communications | (2025)16:2426 1 Article https://doi.org/10.1038/s41467-025-57527-w Representative methods for constraction of pyrrolidine skeletons a Photo-promoted ring contraction reactions of pyridine derivatives c [3+2]-Cycloaddition of azomethine ylides Formation of pyrrole from pyridine diester upon UV irradiation Me N hQ 254 nm Me N + N – H N Me EtOOC cycloaddition Intramolecular cyclization reactions d COOEt N N + ClO4– hydroamination of C=C bonds EtOOC COOEt Me hQ 254 nm MeOH e [M] Me 30% COOEt 16% R R N H OMe Nu–H NH Nu OMe H Synthesis of N-acylindoles from quinoline N-oxides via benzoxazepines H H N hQ 390 nm N sp3C–H amination +N R O H+ N N R O– f Me Photo-promoted ring contractions of N-alkylpyridinium salts to aminocyclopentenes R NH H N Me + EtOH Me b Me R O This work –Pyrrolidine synthesis from pyridines via a photo-promoted ring contraction– Bpin hQ 365 nm N R1 R3 PhMe2SiBpin R2 N H SiMe2Ph A useful building block bearing • an enamine moiety • a cyclopropane ring • a silyl group N-protection & derivatization N R3 R1 R2 pyrrolidine derivatives bearing a 2-azabicyclo[3.1.0]hex-3-ene skeleton Fig. 1 | Synthetic approaches to pyrrolidines and ring contraction reactions of pyridines. a [3 + 2]-Cycloaddition of azomethine ylides with alkenes and alkynes as a representative synthetic approach to pyrrolidine derivatives. b Examples for intramolecular cyclization reactions to access pyrrolidine skeletons via hydroamination and sp3C–H amination. c An early example of a photo-promoted direct ring contraction of pyridine to pyrrole upon UV light irradiation. d A ring contraction of pyridinium salts to cyclopentene derivatives under UV irradiation. e Synthesis of N-acylindoles via photo-promoted skeletal rearrangement of quinoline N-oxides to benzoxazepines followed by acidolysis. f This work: A photopromoted ring contraction of pyridines to pyrrolidine derivatives bearing a 2-azabicyclo[3.1.0]hex-3-ene skeleton. which quinoline N-oxides were photochemically converted to benzoxazepines upon 390 nm irradiation followed by ring-opening and closure under acidic conditions (Fig. 1e)29. These precedents evidenced high feasibility of the ring contraction strategy using pyridines as starting materials leading to 5-membered ring scaffolds, although most cases necessitate the preparation of N-alkylpyridinium salts or Noxides as pre-activation steps. Several related st (...truncated)