Energy-Transfer-Enabled Rearrangement Involving Pyridines

Open AccessCCS ChemistryRESEARCH ARTICLES9 Jan 2025Energy-Transfer-Enabled Rearrangement Involving Pyridines Shu-Ya Wen, Jun-Jie Chen, Yu Zheng and Huan-Ming Huang Shu-Ya Wen School of Physical Science and Technology, ShanghaiTech University, Shanghai 201210 , Jun-Jie Chen School of Physical Science and Technology, ShanghaiTech University, Shanghai 201210 , Yu Zheng School of Physical Science and Technology, ShanghaiTech University, Shanghai 201210 and Huan-Ming Huang *Corresponding author: E-mail Address: [email protected] School of Physical Science and Technology, ShanghaiTech University, Shanghai 201210 https://doi.org/10.31635/ccschem.024.202405071 SectionsSupplemental MaterialAboutAbstractPDF ToolsAdd to favoritesDownload CitationsTrack Citations ShareFacebookXLinked InEmail The exploration of novel synthetic methodologies centered on pyridine motifs continues to captivate researchers. Among these, radical transformations, particularly Minisci-type reactions and radical migrations within pyridines, predominantly revolve around electron-transfer mechanisms. Nevertheless, energy-transfer facilitated rearrangements involving pyridines, though scarce, are highly sought after. Herein we present two types of radical pyridine migrations, facilitated by energy-transfer catalysis under visible light irradiation. The first, a di-π-ethane rearrangement of pyridines, enables the construction of three-membered ring structures with broad functional group compatibility. This approach has been successfully employed in the postsynthetic modification of intricate drugs and in continuous-flow setups. Additionally, di-π-ethane rearrangement of pyridine functionalities showcases the precise skeletal remodeling of complex pyridine scaffolds with impeccable stereocontrol. Our discoveries underscore the potential of energy-transfer-catalysis-enabled pyridine functional group rearrangements to propel the field of di-π-ethane rearrangements and inspire a plethora of visible-light-mediated energy-transfer chemistry. Download figure Download PowerPoint Introduction Pyridine and its derivatives hold a prominent position across diverse fields such as synthetic chemistry, drug discovery, and material science, owing to their extensive applications and reactive nature. Notably, they are the second most frequently employed ring systems in small-molecule drugs approved by the Food and Drug Administration, further underscoring their significance and utility in the pharmaceutical industry. Additionally, they have garnered recognition as bioisosteric substitutes for benzene rings (Figure 1a).1,2 The Minisci-type reactions, which entail the addition of carbon-centered radicals to basic heteroarenes, followed by the subsequent loss of a hydrogen atom, have gained widespread recognition in the scientific community. Originally devised as a valuable synthetic method by Minisci in the late 1960s,3,4 this reaction type has been continuously leveraged by countless chemists over the past five decades to efficiently and directly functionalize heterocycles with improved reactivity and selectivity, thereby circumventing the need for complex de novo heterocycle synthesis.5–15 Alternatively, radical translocation has already become a powerful synthetic approach to migration different functional groups precisely.16–23 Remarkably, Zhu and coworkers24 pioneered an elegant protocol regarding distal heteroaryl ipso-migration and its application to the heteroarylation of unactivated alkenes successfully (Figure 1b, upper). Later on, they managed to achieve the remote C(sp3)–H bonds by sequential hydrogen atom and heteroaryl migrations19,25–27 and alkylheteroarylation of unactivated alkenes using bifunctional reagents.28–30 Hong and coworkers31,32 designed an innovative synthetic approach to the synthesis of trifluoromethylative pyridylation of unactivated alkenes through visible-light-induced ortho-selective migration on pyridyl ring (Figure 1b, down). Dixon and coworkers33 developed a reductive photocatalytic dearomatization of quinoline derivatives using N-arylimines to build a variety of bridged 1,3-diazepane architectures. Sarlah and coworkers34 developed an elegant example regarding arenophile-mediated dearomatization of pyridines. In contrast to the abundant elegant exemplars showcasing pyridine migration through electron transfer, radical transformations involving pyridine motifs, facilitated by energy transfer, are scarce yet highly sought after. This stems from the novelty of the reaction model for creating radical species and the potential for diradical intermediates to uncover unprecedented reaction pathways, offering a complementary approach to the established electron transfer mechanisms. Figure 1 | Background and rational design. Download figure Download PowerPoint Alternatively, photochemical skeletal enlargement of pyridine derivatives for the synthesis of 1,2-diazepines under ultraviolet (UV)-light irradiation utilizing their singlet excited state was developed by Ghiazza and coworkers.35 Independently, Zheng and coworkers36 reported an efficient one-pot photochemical skeletal editing protocol for the transformation of pyridines into diverse bicyclic pyrazolines and pyrazoles under mild conditions. In recent years, energy-transfer catalysis has appeared as an attractive method in the generation of triplet diradical species, which triggered the following synthetic transformations.37–44 For instance, Glorius and coworkers45 developed an elegant example to achieve the direct dearomatization of pyridines via an energy-transfer-enabled intramolecular [4+2] reaction, employing a polymer-immobilized Ir-based photocatalyst (Figure 1c). König and Chatterjee46 showcased a photochemical hydrogenation process where i-Pr2NEt acted as the reducing agent and the Ir-based photocatalyst as a photosensitizer to trigger the generation of the triplet state of quinoline and the photoreductant that supplies an electron to an intermediate in its excited state. Ma and coworkers47 and Brown and coworkers48 independently demonstrated the photochemical reduction of quinolines. Very recently, Nagashima and coworkers49 developed an efficient approach to dearomatize quinoline via nucleophilic addition/borate-mediated photocycloaddition. Compared to cycloaddition and reduction, energy-transfer-enabled migration of pyridines remains unknown. Inspired by Zimmerman's seminal work on di-π-methane rearrangement,50–52 we recently discovered and demonstrated the di-π-ethane rearrangement for the first time.53,54 Considering the importance of the pyridine motif in medicinal chemistry1,2 and limited examples of energy-transfer-enabled synthetic transformations of pyridine,45–49 we would like to demonstrate unprecedented radical migration of pyridines enabled by energy-transfer catalysis. With this in mind, two types of substrates containing pyridine motifs were synthesized, and we aimed to develop two general synthetic approaches that could undergo pyridine migration and radical–radical combination with suitable energy-transfer catalysis under visible-light conditions to construct three-membered and bicyclic pyridine motifs (Figure 1d). Experimental Methods General procedure for the di-π-ethane rearrangement of pyridine to construct three-membered scaffolds An oven-dried 8 mL vial equipped with a magnetic stir bar was charged with the substrate 1 (0.2 mmol, 1.0 equiv) and the photocatalyst Ir-F (0.004 mmol, 2.0 mol %). The vial was pumped into a glovebox, and then MeCN (2.0 mL, 0.1 M) was added via a syringe. The vial was sealed and removed from the glovebox and irradiated with 30 W-450 nm light-emitting diodes (LEDs) (with a stream of air blowing over the vials in a water bath to keep the reaction at 25–30 °C). After being irradiated at 450 nm LEDs for 96 h, the reaction mixture was concentrated under reduced pressure and then purified by flash column chromatography to provide the product. More experimental details and characterization are available in the Supporting Information. General procedure for the di-π-ethane rearrangement of pyridine to construct bicyclic scaffolds An oven-dried 8 mL vial equipped with a magnetic stir bar was charged with the substrate 41 (0.2 mmol, 1.0 equiv), Gd(OTf)3 (0.6 mmol, 3.0 equiv), and a photocatalyst Ir-F (0.006 mmol, 3.0 mol %). The vial was pumped into a glovebox, and then MeCN (4.0 mL, 0.05 M) was added via a syringe. The vial was sealed and removed from the glovebox and irradiated with 30 W-450 nm LEDs (with a stream of air blowing over the vials in a water bath to keep the reaction at 25∼30 °C). After being irradiated at 450 nm LEDs for 24 h, the reaction mixture was quenched with NaHCO3 (aq), then extracted with dichloromethane (3 × 5.0 mL), dried over Na2SO4, filtered, and then concentrated. The residue was purified by silica gel column chromatography to provide the product. More experimental details and characterization are available in the Supporting Information. Results and Discussion Reaction design and optimization Guided by this concept, we investigated substrate 1a, enabling the efficient synthesis of the targeted three-membered ring product 2 (80% isolated yield) using a simple Ir-F photocatalyst and acetonitrile as the reaction mediums under 450 nm LED illumination for 96 h (Table 1, entry 1). Control experiments, devoid of photocatalysis or light, conclusively showed that product 2 could not be produced (entries 2–3). Substituting Ir-F with other common organic dyes yielded only trace amounts of product 2, underscoring the efficacy of the Ir-F photocatalyst (entries 4–6). Further optimization revealed that the reaction time and acetonitrile were crucial factors (entries 7–9). However, attempts to activate pyridine motifs by adding Gd(OTf)3 or trifluoro acid to the optimized conditions failed to yield the desired product 2, the starting material 1a was decomposed (entries 11&12). With the optimal conditions established, we explored the substituent effects on the rationally designed starting material 1 (see Supporting Information for detailed information). Substituting one ester group with a methyl group yielded product 3 in 98% isolated yield with a 3:1 diastereomeric ratio. However, attempts to replace two ester groups with methyl groups failed to yield the desired product 4, and similarly substituting two ester groups with one ester group and one hydrogen did not result in the formation of the corresponding product 6. Shifting the nitrogen atom to the para position on the pyridine ring also prevented the generation of product 5. Moreover, tetra- and trisubstituted alkenes 1f and 1h failed to produce the intended products 7 and 9. Lastly, our attempt to synthesize a five-membered product 8 from substrate 1g was also unsuccessful. Table 1 | Reaction Design and Optimization Table Entry Variations from Standard Conditions Yield (%) Entry Variations from Standard Conditions Yield (%) 1 None 87 (80)a 7 24 h, 48 h, 72 h stead of 96 h 38, 56, 71 2 No photocatalysis or no light N.D. 8 DCE instead of MeCN 80 3 40 °C instead of light N.D. 9 EtOAc instead of MeCN 68 4 4CzIPN (10 mol %) instead of Ir-F N.D. 10 0.1 equiv TFA was added Trace 5b Thioxanthone (10 mol %) instead of Ir-F Trace 11 2 equiv Gd(OTf)3 was added N.D. 6c Benzophenone (10 mol %) instead of Ir-F Trace 12 2 equiv TFA was added N.D. Reaction conditions: 1a (0.2 mmol), Ir-F (2 mol %), and MeCN (2 mL, 0.1 M) at room temperature under 30 W 450 nm LEDs with a cooling fan for 96 h under N2. aIsolated yield. b390 nm instead of 450 nm. c365 nm instead of 450 nm. Substrate scope Having secured the initial outcomes, we embarked on a comprehensive exploration of the substrate's versatility (depicted in Figure 2). Initially, we scrutinized a broad spectrum of substituted functional groups adorned on the aromatic rings, encompassing methyl ( 10), methoxyl ( 11), fluoro ( 12, 15–17), chloro ( 18), ester ( 14), and even heterocyclic motifs like pyrrole ( 19) and furan ( 20 and 21). Encouragingly, these diverse substituents enabled the formation of the targeted three-membered rings ( 10–21) with yields ranging from good to exceptional. Figure 2 | Scope of substrates containing the pyridine motifs and synthesis of complex architectures. Reaction conditions: 1 (0.2 mmol), Ir-F (2 mol %), and MeCN (2 mL, 0.1 M) at room temperature under 30 W 450 nm blue LEDs with a cooling fan for 96 h under N2. a144 h. Download figure Download PowerPoint Subsequently, we shifted our focus to examining various functional groups appended to pyridine motifs. Our investigations revealed that a wide array of functionalities, including chloride ( 22), alcohol ( 23), fluoro ( 24–27), methoxyl ( 28–30), trifluoromethyl ( 31-32), and methyl ( 33–36), positioned at different sites, were compatible under the product optimized conditions. This compatibility translated into the successful synthesis of the desired products ( 22–36) in satisfactory yields. Notably, a 93% isolated yield was achieved for ( 37) when the nitrogen atom was shifted from the ortho to the meta position. Lastly, we ventured into the challenging territory of applying our standard conditions to more intricate structures, specifically, the drug motifs of ketoprofen ( 38), fenofibric acid ( 39), and ibuprofen ( 40). Even these complex three-membered architectures could be synthesized under our conditions, yielding products in the range of 57%–70% isolated yields. We synthesized the cyclic pyridine motif 41a and subjected it to the predefined reaction conditions outlined in Table 2, entry 1. However, our efforts failed to yield the desired product 42. Surprisingly, upon the addition of three equivalents of Gd(OTf)3, we observed the formation of the cyclic product 42 with complete stereocontrol and a yield of 77%. In an attempt to optimize this reaction, we explored various activators such as trifluoroacetic acid (TFA), Zn(OTf)2, Lu(OTf)2, and varying amount of Gd(OTf)3, but only moderate yields of 42 were achieved (entries 2–4). Notably, increasing the acetonitrile concentration or employing different photocatalysts resulted in decreased yields of 42 (entries 5–7). Encouragingly, when the quantity of Ir-F photocatalyst was elevated to 3 mol%, the isolated yield of the desired product 42 improved to 81% (entry 8). Our control experiments undeniably underscored the pivotal roles of light and the photocatalyst in facilitating this intricate skeletal reorganization via di-π-ethane rearrangement. Table 2 | Reaction Design and Optimization Table Entry Variations from Standard Conditions Yield (%) 1 Without Gd(OTf)3 N.D. 2 TFA, Zn(OTf)2 or Lu(OTf)3 instead of Gd(OTf)3 45, 46, 54 3 Using 0.2 equiv Gd(OTf)3 Trace 4 Using 2.0 equiv or 4.0 equiv Gd(OTf)3 45, 55 5 Using 0.1 M MeCN 63 6 Ir-Me (2 mol %) instead of Ir-F 60 7a Thioxanthone (5 mol %) instead of Ir-F Trace 8 3 mol % Ir-F 81 9 No photocatalyst under 450 nm or 365 nm N.D. 10 40 °C instead of light N.D. Reaction conditions: 41a (0.2 mmol, 1 equiv), Ir-F (3 mol %), Gd(OTf)3 (3.0 equiv), MeCN (4 mL, 0.05 M) at room temperature under 30 W 450 nm LEDs with a cooling fan for 24 h under N2. aUsing 390 nm instead of 450 nm. We further investigated the substrate scope regarding cyclic pyridine motifs (Figure 3). We found that under the optimized conditions, a diverse array of bicyclic pyridine motifs could be efficiently synthesized, incorporating various functional groups such as fluoro ( 44 & 52), chloride ( 45), bromo ( 46), nitrile ( 47), methyl ( 48), ester ( 49), trifluoromethyl ( 50), and trifluoromethoxyl ( 51). Notably, the desired cyclic pyridine 54 was obtained in a 64% isolated yield as a single isomer, further validated by X-ray analysis ( CCDC 2382481). Even with the exploration of a larger ring structure motif 41n, the targeted cyclic compound 55 was successfully synthesized in an 84% isolated yield. Furthermore, we tested seven intricate architectures incorporating biologically relevant moieties like l-(-)-borneol ( 56), l-menthol ( 57), gemfibrozil ( 58), flurbiprofen ( 59), ibuprofen ( 60), citronellol ( 61), and cholesterol ( 62). Encouragingly, all the desired products 56–62 were formed in good to excellent isolated yields, demonstrating complete stereocontrol throughout the synthesis. This comprehensive study underscores the versatility and robustness of our method in constructing complex cyclic pyridine motifs. Figure 3 | Scope of cyclic substrates containing the pyridine motifs to produce complex architectures. Reaction conditions: 41 (0.2 mmol, 1 equiv), Ir-F (3 mol %), Gd(OTf)3 (3.0 equiv), and MeCN (0.05 M) at room temperature under 30 W 450 nm LEDs with a cooling fan for 24 h under N2. The desired products 42–62 was obtained as a single isomer; a48 h and busing 1,2-dichloroethane (DCE) instead of MeCN. Download figure Download PowerPoint To further elucidate the efficacy and practical applications of these two energy-transfer-mediated rearrangements of pyridine structures, we successfully demonstrated the di-π-ethane transformation of pyridine motifs in a continuous-flow reactor, achieving a 75% isolated yield on a 5 mmol scale, as depicted in Figure 4a. Furthermore, we scaled up the synthesis of bicyclic pyridine motifs 42 through a large-flask reaction, attaining a high yield of 78% and isolating 1.2 grams of the product, which could then be efficiently converted into alcohol 63, verified by X-ray crystallography ( CCDC 2382482, Figure 4b). To gain insights into the underlying mechanisms, we conducted preliminary mechanistic investigations. Notably, the targeted products 2 and 42 failed to form under conditions that inhibited radical formation (using 2,2,6,6-Tetramethylpiperidine-1-oxyl) or quenched triplet energy (employing 2,5-dimethylhexa-2,4-diene) or classical radical initiation conditions (2,2′-azobis(2-methylpropionitrile) or benzoyl peroxide), indicating a likely energy-transfer pathway (Figure 4c). Our UV–vis absorption (Figure 4d), fluorescence quenching (Figure 4e), and Stern-Volmer quenching (Figure 4f) experiments collectively revealed that only the photocatalyst absorbed visible light and was subsequently deactivated by the substrates 1a or 41a. Figure 4 | Synthetic applications and mechanistic studies. Download figure Download PowerPoint Based on these findings, we propose the following mechanisms: In the type I rearrangement, efficient energy-transfer catalysis fosters the generation of diradical species I, which undergoes 5-exo-trig cyclization with the pyridine moiety to form diradical intermediate II. Subsequent rearomatization transforms II into 1,3-diradical intermediate III, which undergoes intersystem crossing to form IV upon radical recombination and efficiently yields the desired three-membered product 2. In parallel, substrate 41a is activated to produce diradical intermediate V, which adds to the pyridine framework via a Minisci-type reaction with the activation of Gd(OTf)3, yielding tricyclic intermediate VI. Sequential rearomatization, intersystem crossing, and 1,3-diradical recombination ultimately lead to the efficient formation of bicyclic pyridine 42 (Figure 4g). These discoveries underscore the potential of energy-transfer catalysis in facilitating complex molecular rearrangements and opening avenues for the synthesis of novel pyridine derivatives. Conclusion In summary, we have successfully introduced two novel, unprecedented forms of di-π-ethane rearrangement, facilitated by a simple photocatalyst under visible light conditions. This method efficiently relocates pyridine functional groups through an energy-transfer mechanism, enabling the synthesis of both three-membered ring and bicyclic pyridine structures with excellent yields, a wide range of compatible substrates, and under gentle conditions. Our novel energy-transfer rearrangement represents a promising tool for manipulating pyridine functional groups and intricately editing complex pyridine architectures, which holds significant potential for both industrial and academic applications. Our laboratory is actively pursuing further investigations to unlock the full potential of this di-π-ethane rearrangement strategy. Supporting Information Supporting Information is available and includes experimental procedures, characterization data for all new compounds, and nuclear magnetic resonance spectra. Conflict of Interest There is no conflict of interest to report. Acknowledgments We are grateful for financial support from the National Natural Science Foundation of China (grant no. 22201179 to H.-M. H.), the startup funding from ShanghaiTech University (H.-M. H.), the China Postdoctoral Science Foundation (grant no. 2023M742366 to Y. Z.), the Shanghai Postdoctoral Excellence Program (grant no. 223525 to Y. Z.), and the Double First-Class Initiative Fund of ShanghaiTech University (Y. Z.). We sincerely thank Prof. Jiajun Yan, Prof. Chaodan Pu, and Zhuo Zhao for help with the continuous-flow experiment and mechanistic studies. References 1. Taylor R. D.; Maccoss M.; Lawson A. D. G.Rings in Drugs.J. Med. Chem.2014, 57, 5845–5859. Google Scholar 2. Shearer J.; Castro J. L.; Lawson A. D. G.; MacCoss M.; Taylor R. D.Rings in Clinical Trials and Drugs: Present and Future.J. Med. Chem.2022, 65, 8699–8712. Google Scholar 3. Minisci F.; Galli R.; Cecere M.; Malatesta V.; Caronna T.Nucleophilic Character of Alkyl Radicals: New Syntheses by Alkyl Radicals Generated in Redox Processes.Tetrahedron Lett.1968, 9, 5609–5612. Google Scholar 4. Minisci F.; Bernardi R.; Bertini F.; Galli R.; Perchinummo M.Nucleophilic Character of Alkyl Radicals—VI.Tetrahedron1971, 27, 3575–3579. Google Scholar 5. Josephitis C. M.; Nguyen H. M. H.; McNally A.Late-Stage C–H Functionalization of Azines.Chem. Rev.2023, 123, 7655–7691. Google Scholar 6. Proctor R. S. J.; Phipps R. J.Recent Advances in Minisci-Type Reactions.Angew. Chem. Int. Ed.2019, 58, 13666–13699. Google Scholar 7. Ma X.; Herzon S. B.Intermolecular Hydropyridylation of Unactivated Alkenes.J. Am. Chem. Soc.2016, 138, 8718–8721. Google Scholar 8. Bacoş P. D.; Lahdenperä A. S. K.; Phipps R. J.Discovery and Development of the Enantioselective Minisci Reaction.Acc. Chem. Res.2023, 56, 2037–2049. Google Scholar 9. O'Hara F.; Blackmond D. G.; Baran P. S.Radical-Based Regioselective C–H Functionalization of Electron-Deficient Heteroarenes: Scope, Tunability, and Predictability.J. Am. Chem. Soc.2013, 135, 12122–12134. Google Scholar 10. Kim I.; Kang G.; Lee K.; Park B.; Kang D.; Jung H.; He Y. T.; Baik M. H.; Hong S.Site-Selective Functionalization of Pyridinium Derivatives via Visible-Light-Driven Photocatalysis with Quinolinone.J. Am. Chem. Soc.2019, 141, 9239–9248. Google Scholar 11. Proctor R. S. J.; Davis H. J.; Phipps R. J.Catalytic Enantioselective Minisci-Type Addition to Heteroarenes.Science2018, 360, 419–422. Google Scholar 12. Kim J. H.; Constantin T.; Simonetti M.; Llaveria J.; Sheikh N. S.; Leonori D.A Radical Approach for the Selective C–H Borylation of Azines.Nature2021, 595, 677–683. Google Scholar 13. Jin J.; MacMillan D. W. C.Alcohols as Alkylating Agents in Heteroarene C–H Functionalization.Nature2015, 525, 87–90. Google Scholar 14. Cao H.; Cheng Q.; Studer A.Radical and Ionic Meta -C–H Functionalization of Pyridines, Quinolines, and Isoquinolines.Science2022, 378, 779–785. Google Scholar 15. Boyle B. T.; Levy J. N.; de Lescure L.; Paton R. S.; McNally A.Halogenation of the 3-Position of Pyridines Through Zincke Imine Intermediates.Science2022, 378, 773–779. Google Scholar 16. Robertson J.; Pillai J.; Lush R. K.Radical Translocation Reactions in Synthesis.Chem. Soc. Rev.2001, 30, 94–103. Google Scholar 17. Li W.; Xu W.; Xie J.; Yu S.; Zhu C.Distal Radical Migration Strategy: An Emerging Synthetic Means.Chem. Soc. Rev.2018, 47, 654–667. Google Scholar 18. Wu X.; Ma Z.; Feng T.; Zhu C.Radical-Mediated Rearrangements: Past, Present, and Future.Chem. Soc. Rev.2021, 50, 11577–11613. Crossref, Google Scholar 19. Wu X.; Zhu C.Radical-Mediated Remote Functional Group Migration.Acc. Chem. Res.2020, 53, 1620–1636. Google Scholar 20. Studer A.; Bossart M.Radical Aryl Migration Reactions.Tetrahedron2001, 57, 9649–9667. Google Scholar 21. Holden C. M.; Greaney M. F.Modern Aspects of the Smiles Rearrangement.Chem. – A Eur. J.2017, 23, 8992–9008. Google Scholar 22. Chen Z. M.; Zhang X. M.; Tu Y. Q.Radical Aryl Migration Reactions and Synthetic Applications.Chem. Soc. Rev.2015, 44, 5220–5245. Google Scholar 23. Sivaguru P.; Wang Z.; Zanoni G.; Bi X.Cleavage of Carbon–Carbon Bonds by Radical Reactions.Chem. Soc. Rev.2019, 48, 2615–2656. Google Scholar 24. Wu Z.; Wang D.; Liu Y.; Huan L.; Zhu C.Chemo- and Regioselective Distal Heteroaryl Ipso-Migration: A General Protocol for Heteroarylation of Unactivated Alkenes.J. Am. Chem. Soc.2017, 139, 1388–1391. Google Scholar 25. Wu X.; Wang M.; Huan L.; Wang D.; Wang J.; Zhu C.Tertiary-Alcohol-Directed Functionalization of Remote C(Sp3)−H Bonds by Sequential Hydrogen Atom and Heteroaryl Migrations.Angew. Chem. Int. Ed.2018, 57, 1640–1644. Google Scholar 26. Wu X.; Zhang H.; Tang N.; Wu Z.; Wang D.; Ji M.; Xu Y.; Wang M.; Zhu C.Metal-Free Alcohol-Directed Regioselective Heteroarylation of Remote Unactivated C(Sp3)–H Bonds.Nat. Commun.2018, 9, 3343. Google Scholar 27. Wu X.; Zhu C.Radical Functionalization of Remote C(Sp3)–H Bonds Mediated by Unprotected Alcohols and Amides.CCS Chem.2020, 2, 813–828. Link, Google Scholar 28. Liu J.; Wu S.; Yu J.; Lu C.; Wu Z.; Wu X.; Xue X.; Zhu C.Polarity Umpolung Strategy for the Radical Alkylation of Alkenes.Angew. Chem. Int. Ed.2020, 59, 8195–8202. Google Scholar 29. Yu J.; Zhang X.; Wu X.; Liu T.; Zhang Z.-Q.; Wu J.; Zhu C.Metal-Free Radical Difunctionalization of Ethylene.Chem2023, 9, 472–482. Google Scholar 30. Niu T.; Liu J.; Wu X.; Zhu C.Radical Heteroarylalkylation of Alkenes via Three-Component Docking-Migration Thioetherification Cascade.Chin. J. Chem.2020, 38, 803–806. Google Scholar 31. Kim M.; Koo Y.; Hong S.N-Functionalized Pyridinium Salts: A New Chapter for Site-Selective Pyridine C–H Functionalization via Radical-Based Processes Under Visible Light Irradiation.Acc. Chem. Res.2022, 55, 3043–3056. Google Scholar 32. Jeon J.; He Y.; Shin S.; Hong S.Visible-Light-Induced Ortho-Selective Migration on Pyridyl Ring: Trifluoromethylative Pyridylation of Unactivated Alkenes.Angew. Chem. Int. Ed.2020, 59, 281–285. Google Scholar 33. Leitch J. A.; Rogova T.; Duarte F.; Dixon D. J.Dearomative Photocatalytic Construction of Bridged 1,3-Diazepanes.Angew. Chem. Int. Ed.2020, 59, 4121–4130. Google Scholar 34. Siddiqi Z.; Bingham T. W.; Shimakawa T.; Hesp K. D.; Shavnya A.; Sarlah D.Oxidative Dearomatization of Pyridines.J. Am. Chem. Soc.2024, 146, 2358–2363. Google Scholar 35. Boudry E.; Bourdreux F.; Marrot J.; Moreau X.; Ghiazza C.Dearomatization of Pyridines: Photochemical Skeletal Enlargement for the Synthesis of 1,2-Diazepines.J. Am. Chem. Soc.2024, 146, 2845–2854. Google Scholar 36. Luo J.; Zhou Q.; Xu Z.; Houk K. N.; Zheng K.Photochemical Skeletal Editing of Pyridines to Bicyclic Pyrazolines and Pyrazoles.J. Am. Chem. Soc.2024, 146, 21389–21400. Google Scholar 37. Dutta S.; Erchinger J. E.; Strieth-Kalthoff F.; Kleinmans R.; Glorius F.Energy Transfer Photocatalysis: Exciting Modes of Reactivity.Chem. Soc. Rev.2024, 53, 1068–1089. Google Scholar 38. Zhou Q.; Zou Y.; Lu L.; Xiao W.Visible-Light-Induced Organic Photochemical Reactions Through Energy-Transfer Pathways.Angew. Chem. Int. Ed.2019, 58, 1586–1604. Google Scholar 39. Großkopf J.; Kratz T.; Rigotti T.; Bach T.Enantioselective Photochemical Reactions Enabled by Triplet Energy Transfer.Chem. Rev.2022, 122, 1626–1653. Google Scholar 40. Neveselý T.; Wienhold M.; Molloy J. J.; Gilmour R.Advances in the E → Z Isomerization of Alkenes Using Small Molecule Photocatalysts.Chem. Rev.2022, 122, 2650–2694. Google Scholar 41. Zhu M.; Zhang X.; Zheng C.; You S.-L.Energy-Transfer-Enabled Dearomative Cycloaddition Reactions of Indoles/Pyrroles via Excited-State Aromatics.Acc. Chem. Res.2022, 55, 2510–2525. Crossref, Google Scholar 42. Ji P.; Duan K.; Li M.; Wang Z.; Meng X.; Zhang Y.; Wang W.Photochemical Dearomative Skeletal Modifications of Heteroaromatics.Chem. Soc. Rev.2024, 53, 6600–6624. Google Scholar 43. Palai A.; Rai P.; Maji B.Rejuvenation of Dearomative Cycloaddition Reactions via Visible Light Energy Transfer Catalysis.Chem. Sci.2023, 14, 12004–12025. Crossref, Google Scholar 44. Wang H.; Tian Y.-M.; König B.Energy- and Atom-Efficient Chemical Synthesis with Endergonic Photocatalysis.Nat. Rev. Chem.2022, 6, 745–755. Google Scholar 45. Ma J.; Strieth-Kalthoff F.; Dalton T.; Freitag M.; Schwarz J. L.; Bergander K.; Daniliuc C.; Glorius F.Direct Dearomatization of Pyridines via an Energy-Transfer-Catalyzed Intramolecular [4+2] Cycloaddition.Chem2019, 5, 2854–2864. Google Scholar 46. Chatterjee A.; König B.Birch-Type Photoreduction of Arenes and Heteroarenes by Sensitized Electron Transfer.Angew. Chem. Int. Ed.2019, 58, 14289–14294. Google Scholar 47. Liu D.; Nagashima K.; Liang H.; Yue X.; Chu Y.; Chen S.; Ma J.Chemoselective Quinoline and Isoquinoline Reduction by Energy Transfer Catalysis Enabled Hydrogen Atom Transfer.Angew. Chem. Int. Ed.2023, 62, e202312203. Google Scholar 48. Adak S.; Braley S. E.; Brown M. K.Photochemical Reduction of Quinolines with γ-Terpinene.Org. Lett.2024, 26, 401–405. Google Scholar 49. Shimose A.; Ishigaki S.; Sato Y.; Nogami J.; Toriumi N.; Uchiyama M.; Tanaka K.; Nagashima Y.Dearomative Construction of 2D/3D Frameworks from Quinolines via Nucleophilic Addition/Borate-Mediated Photocycloaddition.Angew. Chem.2024, 63, e202403461. Google Scholar 50. Hixson S. S.; Mariano P. S.; Zimmerman H. E.Di-π-Methane and Oxa-Di-π-Methane Rearrangements.Chem. Rev.1973, 73, 531–551. Google Scholar 51. Zimmerman H. E.; Armesto D.Synthetic Aspects of the Di-π-Methane Rearrangement.Chem. Rev.1996, 96, 3065–3112. Google Scholar 52. Riguet E.; Hoffmann N.Di-π-Methane, Oxa-di-π-Methane, and Aza-di-π-Methane Photoisomerization. In Comprehensive Organic Synthesis II, Vol. 5; Knochel P.; Molander G. A., Eds.; Elsevier: Amsterdam, 2014. Google Scholar 53. Zheng Y.; Dong Q.-X.; Wen S.-Y.; Ran H.; Huang H.-M.Di-π-Ethane Rearrangement of Cyano Groups via Energy-Transfer Catalysis.J. Am. Chem. Soc.2024, 146, 18210–18217. Google Scholar 54. Wen S.-Y.; Chen J.-J.; Zheng Y.; Han J.-X.; Huang H.-M.Energy-Transfer Enabled 1,4-Aryl Migration.Angew. Chem. Int. Ed.2024, DOI: https://doi.org/10.1002/anie.202415495 Crossref, Google Scholar Previous articleNext article FiguresReferencesRelatedDetails Issue AssignmentNot Yet AssignedSupporting Information Copyright & Permissions© 2025 Chinese Chemical SocietyKeywordsradicalsenergy transferphotorearrangementpyridinevisible lightskeletal rearrangementAcknowledgmentsWe are grateful for financial support from the National Natural Science Foundation of China (grant no. 22201179 to H.-M. H.), the startup funding from ShanghaiTech University (H.-M. H.), the China Postdoctoral Science Foundation (grant no. 2023M742366 to Y. Z.), the Shanghai Postdoctoral Excellence Program (grant no. 223525 to Y. Z.), and the Double First-Class Initiative Fund of ShanghaiTech University (Y. Z.). We sincerely thank Prof. Jiajun Yan, Prof. Chaodan Pu, and Zhuo Zhao for help with the continuous-flow experiment and mechanistic studies. Downloaded 0 times PDF downloadLoading ...