Room-Temperature Direct C4-Hydroxyalkylation of Pyridines via Paired Electrolysis

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Dixneuf This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8259255/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted You are reading this latest preprint version Abstract Direct and selective functionalization of ubiquitous pyridine rings is of paramount importance across numerous fields, but it remains a challenge due to pyridine's inherent thermodynamic stability, kinetic inertness, and multiple competitive reaction sites. Herein, by using an undivided cell tolerant to ambient air and moisture, we report a room-temperature paired electrolysis strategy for C4-selective hydroxyalkylation of diverse inert pyridines with readily available carbonyl compounds. Employing a Zn cathode, graphite anode, and TEMPO mediator, this method features a broad substrate scope, operational simplicity, metal-free conditions, and high step/atom economy. It overcomes the limitations of conventional approaches requiring pre-functionalized substrates or stoichiometric activators, establishing a practical platform for direct access to C4-hydroxyalkyl pyridines. Mechanistic studies reveal that acetic acid activates both reactants, and the products are formed via cross-coupling of cathodic reduction-induced pyridyl radicals and hydroxy α -radicals followed by protonation and anodic oxidative aromatization. In this work, the concept merging electroreduction-induced dearomatization followed by radical transformations will open a door to further develop useful transformations with inert chemical systems. Physical sciences/Chemistry/Organic chemistry/Synthetic chemistry methodology Physical sciences/Chemistry/Electrochemistry/Electrocatalysis Pyridines Carbonyls Paired electrolysis radical cross-coupling regioselective hydroxyalkylation Figures Figure 1 Figure 2 Introduction Pyridine represents most prevalent N-heterocyclic scaffold in FDA-approved pharmaceuticals [ 1 ] and serves as a key structural motif in numerous agrochemicals, functional materials, ligands, and natural products. [ 2 – 6 ] Among its derivatives, 4-hydroxyalkylated pyridines constitute a significantly important subclass due to their distinctive properties and broad applications. [ 7 – 14 ] As illustrated in Scheme 1a , representative examples include pyridoxine ( 1 , a natural form of vitamin B6 ), [ 11 ] a CCR6 antagonist ( 2 ) for autoimmune diseases, [ 7 ] and LY2874455 ( 3 ), a commercially available second-generation FGFR inhibitor used in cancer therapy. [ 8 ] Additionally, compounds 4 and 5 function as a surface-grafting agent for MOF-based polymers and a precursor for polymer-supported catalysts, respectively. [ 12 , 13 ] Despite their significance, synthetic routes to 4-hydroxyalkyl pyridines remain notably scarce. Conventional syntheses typically rely on either initial preparation of C4-halopyridines followed by lithiation, nucleophilic addition, and protonation or Grignard addition to preinstalled 4-pyridyl ketones and subsequent hydrolysis (Scheme 1b ). [ 15 , 16 ] These methods often require harsh conditions, exhibit poor functional group tolerance, and suffer from low step and atom economy, and generate substantial metal wastes. Thus, the development of efficient and direct strategies for diverse synthesis of 4-hydroxyalkyl pyridines is highly demanded. Despite the challenges posed by pyridine's inherent thermodynamic stability, kinetic inertness, and multiple competitive reaction sites, several elegant strategies have been established for direct functionalization at the C2 [ 17 – 22 ] and C3 [ 23 – 32 ] positions. In contrast, functionalization at the C4 position typically relies on multistep sequences employing pre-activated substrates such as pyridinium salts, N-oxides, or pyridyl salts (Scheme 1c1–1c3). [ 33 – 47 ] Although Minisci-type radical addition enables direct functionalization of heteroarenes, [ 17 – 22 ] it generally yields C2-substituted products alongside minor amounts of C4 regioisomers (Scheme 1c4). In this context, cross-coupling between single-electron reduction (SER)-generated pyridyl radicals and polarity-matched radicals offers a promising strategy for achieving direct C4 functionalization. Nonetheless, this objective remains a yet unresolved challenge in synthetic chemistry. In recent years, electrochemistry has emerged as an appealing tool in synthetic chemistry owing to the facile tunability of key reaction parameters (e.g., electrolyte, electrode, current, and potential). [ 48 – 72 ] Capitalizing on these advantages, we previously reported a direct method for constructing N-heterocyclic vicinal amino alcohols via electroreductive cross-coupling of the quinolyl C2-site with carbonyl compounds. [ 73 ] Inspired by this work, we envisioned a new electrochemical cross-coupling strategy for direct C4-functionalization of inert pyridines ( A ) with carbonyls ( B ). As shown in Scheme 1d , our proposed strategy involves the simultaneous cathodic reduction of pyridine A and carbonyl agent B , generating radicals A-1 and B-1 . Subsequent radical-radical cross-coupling, followed by protonation and anodic oxidative aromatization of the resulting intermediate C-1 , affords the desired product C . Notably, being significantly different from the reactive quinoline reactions employing a sacrificial zinc anode, [ 73 ] the electrons released from the anodic oxidation of the coupling adduct ( C-1 ) in this approach are subsequently consumed in the cathodic reduction process. Such a paired electrolysis [ 74 – 76 ] substantially improves the synthetic efficiency while avoiding the need for sacrificial oxidants or reductants, thereby providing a greener and more environmentally benign route to functionalize inert pyridines. However, realizing the above synthetic purpose presents several critical challenges: (1) Rate matching issue: The high reduction potentials (E red < -2.2 V vs. SCE) of inert pyridines need to be lowered to match those of carbonyl compounds. This adjustment is essential for compatible reaction kinetics and to prevent overreduction of the more reactive carbonyl agents ( B ) into alcohols ( B'' ). (2) Selectivity control: Diverse radical intermediates generated during pyridine reduction require precise reaction modulation for high C4-regioselectivity ( C rather than C' ). Additionally, radicals derived from carbonyl reduction should exhibit sufficient persistence to timely trap the pyridyl radicals in situ . This persistence is crucial for achieving high chemoselectivity by suppressing homocoupling processes ( A' and B' ). (3) Requiring effective linear paired electrolysis: Coupling adduct ( C-1 ) must rapidly diffuse away from the cathode's electrical double layer to undergo efficient anodic oxidative aromatization, thereby preventing its decomposition and enabling linear paired electrolysis by avoiding efficiency losses. Here, by integrating acetic acid activation of both reactants with TEMPO-mediated oxidative aromatization, we report, for the first time, a room-temperature paired electrolysis strategy for direct C4-hydroxyalkylation of inert pyridines with readily available carbonyls. This newly developed method circumvents the limitations of conventional pyridyl functionalization that require pre-functionalized steps or stoichiometric activators. Furthermore, it achieves air/moisture tolerance, broad substrate scope, operational simplicity, metal-free conditions, high step and atom economy, and diverse synthesis. Results Investigation of reaction conditions. To evaluate the feasibility of the envisioned synthetic protocol, we chose the coupling reaction between 2-phenylpyridine ( A 1 ) and 4'-methoxyacetophenone ( B 1 ) as a model system for parameter screening. The reaction was conducted in an undivided cell equipped with a graphite anode and a zinc cathode, using N , N -dimethylformamide (DMF) as the solvent and tetra- n -butylammonium tetrafluoroborate ( n -Bu₄NBF₄, 0.1 M) as the electrolyte. The reaction was applied with constant current of 25 mA for 9 h in the presence of TEMPO (2,2,6,6-tetramethylpiperidin-1-oxyl) and acetic acid (AcOH). As shown in Table 1 , this reaction afforded the C4-hydroxyalkyl product C 1 with an optimal isolated yield of 81% (entry 1). Excellent regioselectivity was confirmed by GC-MS and HPLC analyses ( C 1 : C 1 ' >20:1). Control experiments confirmed that both electricity (entry 2) and AcOH (entry 3) were indispensable for the reaction. The absence of TEMPO significantly decreased the product yield, along with low conversion of B 1 (entry 4), indicating that TEMPO acts as a reaction mediator. Current variations proved critical: no reaction was occurred at 15 mA (entry 5) with substrates fully recovered, while increasing the current to 30 mA reduced the yield (entry 6). Moderate yields were obtained when adjusted the stoichiometric ratio of TEMPO/AcOH or replaced AcOH with HCOOH (entries 7–9). Neither ferrocene mediator nor n -Bu 4 NI electrolyte enabled the formation of C 1 (entries 10–11). Solvent screening demonstrated that DMF outperformed NMP and acetone (entry 12). Cathode substitution (graphite or nickel) diminished the yield (entry 13), while platinum or zinc anodes performed the reaction poorly (entry 14). Notably, identical yields were obtained under argon and air atmospheres (entry 15), whereas the addition of H 2 O (10 equiv.) led to a slight decrease in yield (entry 16). This indicates that the reaction exhibits excellent compatibility with water and oxygen. Moreover, both extended and shortened reaction times failed to improve the outcomes (Table S1 ). Substrate Scope. With the optimal conditions in hand, we set out to evaluate the substrate scope of the new synthetic protocol. As shown in Scheme 2 , diverse ketones and aldehydes ( B 1 –B 28 , B 40 ; see Scheme S1 for their structures) were employed to couple with pyridines. Ketones lacking redox-sensitive groups ( B 1 –B 23 ) gave C4-hydroxyalkyl pyridines ( C 1 –C 23 ) in moderate to good isolated yields. Electron-donating groups and halogens were well tolerated ( C 1 –C 9 ), 1-(4-chlorophenyl)ethan-1-one ( B 6 ) required shorter reaction time to prevent hydrodehalogenation of product C 6 . After stoichiometric adjustment, trifluoromethyl-containing aryl ketone B 11 was able to afford product C 11 in moderate yield. 3-Acetylthiophene provided product C 12 in acceptable yield. Cyclic and different alkyl-substituted ketones reacted smoothly ( C 13 –C 19 ). Trifluoromethyl ( B 20 –B 22 ) and vinyl ketones ( B 23 ) also generate the desired products in moderate yields. Noteworthy, 3-penten-2-one yielded C 23a along with the regioisomer C 23b , the latter suggests a 1,3-spin center shift (SCS) of the hydroxy α -radical. Gratifyingly, aryl aldehydes ( B 24 –B 28 ) also underwent efficient transformation, delivering products C 24 –C 28 in reasonable yields. However, cyclohexanone ( B 40 ) failed to react productively, and pyridine homocoupling product was obtained instead. Next, we investigated the reaction of diverse N -heteroarenes ( A 1 − A 28 , Scheme S1). Given the obvious variation in reduction potentials among these substrates, adjustments to the standard reaction conditions were necessary. A range of functionalities (e.g., −OMe, −Cl, − i -Pr, −CO 2 Et, −Me, −TMS, −F) proved compatible, affording the desired products ( C 29 − C 38 ) in moderate to good yields. Notably, electron-rich pyridines required either a graphitic cathode or extended reaction time to improve the yields. Thiophene-substituted pyridines yielded the desired products ( C 39 and C 40 ) within shorter times. Electron-withdrawing groups (− CO 2 Et, −CF 3 ) and unsaturated substituents (vinyl, alkynyl) were well tolerated ( C 41 − C 44 ). It is noteworthy that 2,2'-bipyridine underwent 4,4'-bisfunctionalization to afford compound C 45 , demonstrating the potential of the present chemistry in developing novel bidentate N -ligands. Pyridine ( A 19 ) also underwent hydroxyalkylation smoothly, producing the C4-functionalized products ( C 46 ) in 40% yield. Interestingly, when equimolar amounts of aldehyde and amine were added, the in-situ -generated imines ( B 35 − B 36 ) could also be used in the coupling reaction with A 1 , affording the C4-aminoalkyl pyridines ( C 47 , C 48 ) in reasonable yields. This result further demonstrates the broader potential of the present synthetic method. Further experiments revealed that extending the reaction time for the coupling of 4-phenylpyridine ( A 20 ) and B 1 from 4 h to 9 h shifted the product from the C2-hydroxyalkyl species ( C 49 ' , 41%) to the 2,6-dihydroxyalkyl product ( C 50 '). 3-phenylpyridine ( A 21 ) exclusively yielding the C2-functionalized product C 51 ', a selectivity dictated by the steric effects. In contrast, the disubstituted pyridines ( A 22 , A 23 ) afforded products C 52 and C 53 with exclusive C4-selectivity. Fused pyridines were also suitable substrates. For instance, thieno[3,2- b ]pyridine ( A 24 ) and furo[3,2- b ]pyridine ( A 25 ) afforded mixtures of major C4- and minor C2-regioisomers ( C 54 / C 54 ' , C 55 / C 55 ' ). Conversely, quinolines ( A 26 , A 27 ) and 4,7-phenanthroline ( A 28 ) selectively provided C2-functionalized products ( C 56 ' − C 58 ' ), a class of potential hemilabile bidentate ligands. These examples show that the present synthetic protocol is also applicable for direct functionalization of fused pyridines, and the regioselectivity differences are attributed to the combined effects of radical stability and the steric influence. To gain mechanistic insights into the newly established reaction, we initially conducted various control experiments. As shown in Fig. 1 A, separate treatment of 2-phenylpyridine A 1 and 4-methoxyacetophenone B 1 under the standard conditions yielded the homocoupling products D 1 and D 2 , respectively (Fig. 1 A-I and 1 A-II). Introducing the radical scavenger TEMPO (2.5 equiv.) into the model reaction completely suppressed the formation of product C 1 ; instead, a TEMPO-trapping pyridine adduct TEMPO- B 1 was observed (Fig. 1 A-III). These results indicate a radical-involved pathway. Subsequently, a radical clock experiment using cyclopropyl ketone B 30 and A 1 afforded a ring-opening product ( C 59 ), demonstrating that the ketone also acts as a radical precursor (Fig. 1 B). Finally, a kinetic isotope effect (KIE) experiment with equimolar A 1 and A 1 - d 6 afforded the desired product in 34% yield with a k H / k D value of 1.94 (Fig. 1 C), revealing that C–H bond cleavage at the pyridyl C4 position is the rate-determining step. Next, we performed cyclic voltammetry (CV) and open-circuit voltage (OCV) experiments to probe the electrochemical behavior of the model reaction (Fig. 1 D and Figure S8). The CV of 2-phenylpyridine ( A 1 ) displayed a reversible redox process with a reduction peak at − 2.42 V (vs. SCE in DMF), while 4′-methoxyacetophenone ( B 1 ) exhibited a reduction potential of − 2.28 V. Upon addition of AcOH, both A 1 and B 1 showed two reduction peaks ( A 1 : −2.26 V and − 2.79 V; B 1 : −2.13 V and − 2.55 V). The positive shift in reduction potentials and the enhanced catalytic current show that AcOH activates both reactants. Their similar onset potentials (− 1.68 V) and peak potentials provide compelling evidence for concurrent reduction. This conclusion was further supported by OCV experiments (Figure S8), which revealed a stable cathodic plateau at − 1.95 V (vs. SCE). Notably, the oxidation peak intensities of A 1 and B 1 decreased in the presence of AcOH, suggesting that AcOH stabilizes their radical intermediates generated by cathodic reduction. Based on the above findings and the transformations employing paired electrolysis, [ 77 , 78 ] we propose a plausible reaction pathway for the paired electrolysis of A 1 and B 1 to form product C 1 (Fig. 1 E). Initially, cathodic reduction of proton-activated 4'-methoxyacetophenone ( B 1 -H ) generates a persistent benzyl radical (or hydroxy α -radical B 1 ' ), while electroreduction of protonated 2-phenylpyridine ( A 1 -H ) yields the pyridyl radical INT-1 . Simultaneously, anodic single-electron oxidation of TEMPO ( I ) forms oxoammonium species II . Subsequent cross-coupling of radicals INT-1 and B 1 ' affords the coupling adduct INT-2 . Species II then mediates oxidative aromatization of INT-2 , delivering product C 1 along with release of TEMPOH ( III ). Finally, anodic oxidation of III regenerates TEMPO ( I ), completing the catalytic cycle. Further, DFT calculations were applied to analyze the proposed reaction pathway. All geometries were fully optimized, and the parameters are given in Table S3 in the SI. As shown in Fig. 2, A 1 -H is initially generated from the protonation of A 1 due to the presence of acetic acid in the reaction system. This protonation step will facilitate a subsequent single electron transfer process and generate radical INT-1 . Spin density analysis of INT-1 reveals that the electron spin predominantly located on the C4 and C6 positions, with little spin density at C2 position. Mulliken spin population calculation further supports that the electron population on C4 position (0.367) is significantly higher than on C2 position (0.0896). These results suggest that the C4 position will be more reactive towards radical coupling. To study the chemoselectivity of the radical coupling step, the reaction energy barrier between radical B 1 ' (Generated from cathodic reduction of ketone B 1 ) and INT-1 are calculated for C2 and C4 position. The radical combination energy barrier at C4 position is 9.7 kcal/mol, which is 2.3 kcal/mol lower than that at C2 position. Thus, the radical coupling process will preferentially undergo at C4 position and afford INT-2 rather than INT-3 . Subsequently, given the nucleophilic positions in INT-2 and potential hydrogen donor characteristics, the subsequent reaction between TEMPO + (Generated from the anodic oxidation of TEMPO) may have multiple pathways. When the C3 carbon attack the nitrogen in the N = O double bond of TEMPO + , the reaction energy barrier is 21.1 kcal/mol, which is relatively high. In addition, this step is also thermodynamically unfavorable (ΔG = 17.7 kcal/mol). Thus, the following cope elimination from INT-5 to aromatization and forming INT-4 is unlikely to occur. Attempts to locate a stable intermediate via nucleophilic attack from the nitrogen atom of INT-2 were unsuccessful, possibly due to the steric hinderance between the tera-methyl groups in TEMPO + and the phenyl group in INT-2 . Alternatively, a both kinetically and thermodynamically favorable hydride transfer mechanism was identified, [ 79 – 81 ] as 1,4-dihyropyridines are well-documented hydrogen donors. [ 82 – 84 ] The hydrogen transfer between INT-2 and TEMPO + has a low energy barrier (15.9 kcal/mol) and favored thermodynamics (ΔG = -37.1 kcal/mol), which will lead to the formation of protonated product INT-4 and TEMPOH. Final deprotonation mediated by acetate affords the desired product C 1 . This deprotonation step may also be assisted by substrate A 1 . Finally, we explored the synthetic utility of the developed methodology. Even with reduced loadings of TEMPO/AcOH (Scheme 4 A), the reaction of A 1 (3 mmol) with B 1 (9 mmol) afforded the product C 1 in good yield (62%, 0.57 g). This yield represents a significant improvement over the multistep procedure reported previously [ 14 ] and demonstrates the scalability potential of the protocol. Treating C 1 to HCl in toluene (12 h) followed by neutralization afforded the 1,1-diarylethylene D 3 in 85% yield. Hydroboration-oxidation of D 3 gave the secondary alcohol D 4 in 88% yield, while epoxidation with m -CPBA followed by ring-opening yielded the vicinal diol D 5 in 50% yield. Enabled by the pyridyl directing group, palladium-catalyzed ortho -C–H acylation of the phenyl moiety in C 1 provided D 6 in 39% yield. Direct esterification of C 1 with ibuprofen furnished D 7 in 51% yield. We next applied the synthetic method to the functionalization of bioactive substrates. Reaction of Isophorone ( B 31 ) with A 1 gave the desired product C 60a in merely 16% yield, while the 1,3-rearrangement product C 60b predominated with a 56% yield. Tonalide ( B 32 ), Epoxyprogesterone ( B 33 ) and L-menthol-derived ketone ( B 34 ) reacted efficiently with A 1 to exclusively afford C4-functionalized pyridines ( C 61 –C 63 ). Furthermore, the reactions of Myrtenol-derived pyridine A 29 and Abametapir A 30 with B 1 proceeded smoothly, affording C 64 and C 65 in moderate to good yields. Conclusion In conclusion, we have developed a room-temperature direct C4-hydroxyalkylation of inert pyridines with readily available carbonyl compounds via paired electrolysis. Using a zinc cathode, graphite anode, and TEMPO mediator, this strategy achieves broad substrate scope, operational simplicity, metal-free conditions, and high step and atom economy. It overcomes the limitations of conventional pyridyl functionalization that require pre-functionalized substrates or stoichiometric activators, establishing a practical platform for direct access to C4-hydroxyalkyl pyridines. In addition, preliminary studies indicate that fused pyridines and imines are also amenable to this transformation, demonstrating broad potentials of the present chemistry. Mechanistic studies reveal that acetic acid activates both reactants, while cathodic reduction generates key pyridyl and hydroxy α -radicals. Product formation proceeds via electroreduction-induced radical-radical cross-coupling, followed by anodic oxidative aromatization. This work demonstrates how merging reductive dearomatization with further radical transformations unlocks new reactivity paradigms for inert chemical systems. Furthermore, it paves the way for constructing novel functional ligands and for functionalizing bioactive molecules to promising derivatives. Declarations Competing interest The authors declare no conflict of interest. Additional information Supplementary information The online version contains supplementary material available at http://www.nature.com/naturechemistry . Reprints and permission information is available online at http://nature.com/reprints Author contributions M. Z. conceived the idea, analyzed the data, directed the project, and wrote the manuscript. C. -Q. Z. and M.-R. W. carried out all the catalytic experiments. C.-Q. Z. drew the structures of all the obtained compounds, analyzed the single crystal structures, synthesized the raw materials and carried out NMR tests. M.-R. W. performed the DFT calculations. H.-F. J. and P. H. D. discussed the mechanistic aspects and revised the manuscript. All the authors have read the manuscript and agree with its content. Acknowledgements The authors are grateful for the financial support of the National Natural Science Foundation of China (22471080), Natural Science Foundation of Guangdong Province (2025A1515012079), Guangdong Basic and Applied Basic Research Foundation (2024B1515040027), and the Postdoctoral Fellowship Program of CPSF (GZB20250265). References Marshall CM, Federice JG, Bell CN, Cox PB, Njardarson JT (2024) An Update on the Nitrogen Heterocycle Compositions and Properties of U.S. FDA-Approved Pharmaceuticals (2013–2023). 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Org Biomol Chem 13:6255–6268 Table 1 Table 1 is available in the Supplementary Files section. Schemes Schemes 1 to 4 are available in the Supplementary Files section. Additional Declarations There is NO Competing Interest. Supplementary Files 2025123SI.docx Room-Temperature Direct C4-Hydroxyalkylation of Pyridines via Paired Electrolysis Table1.docx schemes.docx Cite Share Download PDF Status: Under Review Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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05:49:07","extension":"html","order_by":19,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":172152,"visible":true,"origin":"","legend":"","description":"","filename":"earlyproof.html","url":"https://assets-eu.researchsquare.com/files/rs-8259255/v1/bcc917430fcdc4aea1bfba90.html"},{"id":97674128,"identity":"5426b4cc-ad9c-4e40-9118-bc4b791f897e","added_by":"auto","created_at":"2025-12-08 09:42:28","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":152706,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eMechanism research.\u003c/strong\u003e (A) Control experiments. (B) Radical clock experiment. (C) Kinetic isotope effect experiment. (D) Cyclic voltammetry experiments. (E) Plausible mechanism.\u003c/p\u003e","description":"","filename":"1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-8259255/v1/ee0fa0849686452d95b323e6.jpg"},{"id":97649188,"identity":"963f5360-b9fe-43d1-bd63-5b85b196a429","added_by":"auto","created_at":"2025-12-08 05:49:07","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":81305,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eDFT calculations for the reaction pathways.\u003c/strong\u003e All energies are calculated at M06-2X-D3/def2-TZVPP/SMD(DMF)/M06-2x-dd3/def2-SVP/PCM(DMF) level of theory. Spin density and spin population of \u003cstrong\u003eINT-1\u003c/strong\u003e are shown.\u003c/p\u003e","description":"","filename":"2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-8259255/v1/9bd63467c186d9fc5eb240d4.jpg"},{"id":97678759,"identity":"bc04b5c5-c58c-4b30-b9dd-1f027d5d5734","added_by":"auto","created_at":"2025-12-08 09:56:01","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1022887,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8259255/v1/5f4d3a6e-299c-4bfa-a526-bd9670481e39.pdf"},{"id":97673987,"identity":"981df1d2-7b4b-4662-aab4-0fa27ed0ecb5","added_by":"auto","created_at":"2025-12-08 09:42:04","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":24422497,"visible":true,"origin":"","legend":"Room-Temperature Direct C4-Hydroxyalkylation of Pyridines via Paired Electrolysis","description":"","filename":"2025123SI.docx","url":"https://assets-eu.researchsquare.com/files/rs-8259255/v1/015a522e26213b80263eb838.docx"},{"id":97649191,"identity":"5a2396cd-bd11-463b-b080-5c9d3d0bff60","added_by":"auto","created_at":"2025-12-08 05:49:07","extension":"docx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":44172,"visible":true,"origin":"","legend":"","description":"","filename":"Table1.docx","url":"https://assets-eu.researchsquare.com/files/rs-8259255/v1/9e355c6c3f8a3645ca61f11f.docx"},{"id":97674739,"identity":"76ca50b6-b252-432c-ad12-dc07b2af349a","added_by":"auto","created_at":"2025-12-08 09:44:05","extension":"docx","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":6046871,"visible":true,"origin":"","legend":"","description":"","filename":"schemes.docx","url":"https://assets-eu.researchsquare.com/files/rs-8259255/v1/fb372039b67ac18bb890d9dd.docx"}],"financialInterests":"There is \u003cb\u003eNO\u003c/b\u003e Competing Interest.","formattedTitle":"Room-Temperature Direct C4-Hydroxyalkylation of Pyridines via Paired Electrolysis","fulltext":[{"header":"Introduction","content":"\u003cp\u003ePyridine represents most prevalent N-heterocyclic scaffold in FDA-approved pharmaceuticals \u003csup\u003e[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]\u003c/sup\u003e and serves as a key structural motif in numerous agrochemicals, functional materials, ligands, and natural products.\u003csup\u003e[\u003cspan additionalcitationids=\"CR3 CR4 CR5\" citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]\u003c/sup\u003e Among its derivatives, 4-hydroxyalkylated pyridines constitute a significantly important subclass due to their distinctive properties and broad applications.\u003csup\u003e[\u003cspan additionalcitationids=\"CR8 CR9 CR10 CR11 CR12 CR13\" citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]\u003c/sup\u003e As illustrated in Scheme \u003cspan refid=\"Sch1\" class=\"InternalRef\"\u003e1a\u003c/span\u003e, representative examples include pyridoxine (\u003cb\u003e1\u003c/b\u003e, a natural form of vitamin \u003cb\u003eB6\u003c/b\u003e),\u003csup\u003e[\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]\u003c/sup\u003e a CCR6 antagonist (\u003cb\u003e2\u003c/b\u003e) for autoimmune diseases,\u003csup\u003e[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]\u003c/sup\u003e and LY2874455 (\u003cb\u003e3\u003c/b\u003e), a commercially available second-generation FGFR inhibitor used in cancer therapy.\u003csup\u003e[\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]\u003c/sup\u003e Additionally, compounds \u003cb\u003e4\u003c/b\u003e and \u003cb\u003e5\u003c/b\u003e function as a surface-grafting agent for MOF-based polymers and a precursor for polymer-supported catalysts, respectively.\u003csup\u003e[\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]\u003c/sup\u003e Despite their significance, synthetic routes to 4-hydroxyalkyl pyridines remain notably scarce. Conventional syntheses typically rely on either initial preparation of C4-halopyridines followed by lithiation, nucleophilic addition, and protonation or Grignard addition to preinstalled 4-pyridyl ketones and subsequent hydrolysis (Scheme \u003cspan refid=\"Sch1\" class=\"InternalRef\"\u003e1b\u003c/span\u003e).\u003csup\u003e[\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]\u003c/sup\u003e These methods often require harsh conditions, exhibit poor functional group tolerance, and suffer from low step and atom economy, and generate substantial metal wastes. Thus, the development of efficient and direct strategies for diverse synthesis of 4-hydroxyalkyl pyridines is highly demanded.\u003c/p\u003e\u003cp\u003eDespite the challenges posed by pyridine's inherent thermodynamic stability, kinetic inertness, and multiple competitive reaction sites, several elegant strategies have been established for direct functionalization at the C2\u003csup\u003e[\u003cspan additionalcitationids=\"CR18 CR19 CR20 CR21\" citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]\u003c/sup\u003e and C3\u003csup\u003e[\u003cspan additionalcitationids=\"CR24 CR25 CR26 CR27 CR28 CR29 CR30 CR31\" citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e]\u003c/sup\u003e positions. In contrast, functionalization at the C4 position typically relies on multistep sequences employing pre-activated substrates such as pyridinium salts, N-oxides, or pyridyl salts (Scheme 1c1\u0026ndash;1c3).\u003csup\u003e[\u003cspan additionalcitationids=\"CR34 CR35 CR36 CR37 CR38 CR39 CR40 CR41 CR42 CR43 CR44 CR45 CR46\" citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e47\u003c/span\u003e]\u003c/sup\u003e Although Minisci-type radical addition enables direct functionalization of heteroarenes,\u003csup\u003e[\u003cspan additionalcitationids=\"CR18 CR19 CR20 CR21\" citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]\u003c/sup\u003e it generally yields C2-substituted products alongside minor amounts of C4 regioisomers (Scheme 1c4). In this context, cross-coupling between single-electron reduction (SER)-generated pyridyl radicals and polarity-matched radicals offers a promising strategy for achieving direct C4 functionalization. Nonetheless, this objective remains a yet unresolved challenge in synthetic chemistry.\u003c/p\u003e\u003cp\u003eIn recent years, electrochemistry has emerged as an appealing tool in synthetic chemistry owing to the facile tunability of key reaction parameters (e.g., electrolyte, electrode, current, and potential).\u003csup\u003e[\u003cspan additionalcitationids=\"CR49 CR50 CR51 CR52 CR53 CR54 CR55 CR56 CR57 CR58 CR59 CR60 CR61 CR62 CR63 CR64 CR65 CR66 CR67 CR68 CR69 CR70 CR71\" citationid=\"CR48\" class=\"CitationRef\"\u003e48\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR72\" class=\"CitationRef\"\u003e72\u003c/span\u003e]\u003c/sup\u003e Capitalizing on these advantages, we previously reported a direct method for constructing N-heterocyclic vicinal amino alcohols via electroreductive cross-coupling of the quinolyl C2-site with carbonyl compounds.\u003csup\u003e[\u003cspan citationid=\"CR73\" class=\"CitationRef\"\u003e73\u003c/span\u003e]\u003c/sup\u003e Inspired by this work, we envisioned a new electrochemical cross-coupling strategy for direct C4-functionalization of inert pyridines (\u003cb\u003eA\u003c/b\u003e) with carbonyls (\u003cb\u003eB\u003c/b\u003e). As shown in Scheme \u003cspan refid=\"Sch1\" class=\"InternalRef\"\u003e1d\u003c/span\u003e, our proposed strategy involves the simultaneous cathodic reduction of pyridine \u003cb\u003eA\u003c/b\u003e and carbonyl agent \u003cb\u003eB\u003c/b\u003e, generating radicals \u003cb\u003eA-1\u003c/b\u003e and \u003cb\u003eB-1\u003c/b\u003e. Subsequent radical-radical cross-coupling, followed by protonation and anodic oxidative aromatization of the resulting intermediate \u003cb\u003eC-1\u003c/b\u003e, affords the desired product \u003cb\u003eC\u003c/b\u003e. Notably, being significantly different from the reactive quinoline reactions employing a sacrificial zinc anode,\u003csup\u003e[\u003cspan citationid=\"CR73\" class=\"CitationRef\"\u003e73\u003c/span\u003e]\u003c/sup\u003e the electrons released from the anodic oxidation of the coupling adduct (\u003cb\u003eC-1\u003c/b\u003e) in this approach are subsequently consumed in the cathodic reduction process. Such a paired electrolysis\u003csup\u003e[\u003cspan additionalcitationids=\"CR75\" citationid=\"CR74\" class=\"CitationRef\"\u003e74\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR76\" class=\"CitationRef\"\u003e76\u003c/span\u003e]\u003c/sup\u003e substantially improves the synthetic efficiency while avoiding the need for sacrificial oxidants or reductants, thereby providing a greener and more environmentally benign route to functionalize inert pyridines.\u003c/p\u003e\u003cp\u003eHowever, realizing the above synthetic purpose presents several critical challenges: (1) Rate matching issue: The high reduction potentials (E\u003csub\u003ered\u003c/sub\u003e \u0026lt; -2.2 V vs. SCE) of inert pyridines need to be lowered to match those of carbonyl compounds. This adjustment is essential for compatible reaction kinetics and to prevent overreduction of the more reactive carbonyl agents (\u003cb\u003eB\u003c/b\u003e) into alcohols (\u003cb\u003eB''\u003c/b\u003e). (2) Selectivity control: Diverse radical intermediates generated during pyridine reduction require precise reaction modulation for high C4-regioselectivity (\u003cb\u003eC\u003c/b\u003e rather than \u003cb\u003eC'\u003c/b\u003e).\u003c/p\u003e\u003cp\u003eAdditionally, radicals derived from carbonyl reduction should exhibit sufficient persistence to timely trap the pyridyl radicals \u003cem\u003ein situ\u003c/em\u003e. This persistence is crucial for achieving high chemoselectivity by suppressing homocoupling processes (\u003cb\u003eA'\u003c/b\u003e and \u003cb\u003eB'\u003c/b\u003e). (3) Requiring effective linear paired electrolysis: Coupling adduct (\u003cb\u003eC-1\u003c/b\u003e) must rapidly diffuse away from the cathode's electrical double layer to undergo efficient anodic oxidative aromatization, thereby preventing its decomposition and enabling linear paired electrolysis by avoiding efficiency losses.\u003c/p\u003e\u003cp\u003eHere, by integrating acetic acid activation of both reactants with TEMPO-mediated oxidative aromatization, we report, for the first time, a room-temperature paired electrolysis strategy for direct C4-hydroxyalkylation of inert pyridines with readily available carbonyls. This newly developed method circumvents the limitations of conventional pyridyl functionalization that require pre-functionalized steps or stoichiometric activators. Furthermore, it achieves air/moisture tolerance, broad substrate scope, operational simplicity, metal-free conditions, high step and atom economy, and diverse synthesis.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cb\u003eInvestigation of reaction conditions.\u003c/b\u003e To evaluate the feasibility of the envisioned synthetic protocol, we chose the coupling reaction between 2-phenylpyridine (\u003cb\u003eA\u003c/b\u003e\u003csub\u003e\u003cb\u003e1\u003c/b\u003e\u003c/sub\u003e) and 4'-methoxyacetophenone (\u003cb\u003eB\u003c/b\u003e\u003csub\u003e\u003cb\u003e1\u003c/b\u003e\u003c/sub\u003e) as a model system for parameter screening. The reaction was conducted in an undivided cell equipped with a graphite anode and a zinc cathode, using \u003cem\u003eN\u003c/em\u003e,\u003cem\u003eN\u003c/em\u003e-dimethylformamide (DMF) as the solvent and tetra-\u003cem\u003en\u003c/em\u003e-butylammonium tetrafluoroborate (\u003cem\u003en\u003c/em\u003e-Bu₄NBF₄, 0.1 M) as the electrolyte. The reaction was applied with constant current of 25 mA for 9 h in the presence of TEMPO (2,2,6,6-tetramethylpiperidin-1-oxyl) and acetic acid (AcOH). As shown in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e, this reaction afforded the C4-hydroxyalkyl product \u003cb\u003eC\u003c/b\u003e\u003csub\u003e\u003cb\u003e1\u003c/b\u003e\u003c/sub\u003e with an optimal isolated yield of 81% (entry 1). Excellent regioselectivity was confirmed by GC-MS and HPLC analyses (\u003cb\u003eC\u003c/b\u003e\u003csub\u003e\u003cb\u003e1\u003c/b\u003e\u003c/sub\u003e:\u003cb\u003eC\u003c/b\u003e\u003csub\u003e\u003cb\u003e1\u003c/b\u003e\u003c/sub\u003e\u003cb\u003e'\u003c/b\u003e \u0026gt;20:1). Control experiments confirmed that both electricity (entry 2) and AcOH (entry 3) were indispensable for the reaction. The absence of TEMPO significantly decreased the product yield, along with low conversion of \u003cb\u003eB\u003c/b\u003e\u003csub\u003e\u003cb\u003e1\u003c/b\u003e\u003c/sub\u003e (entry 4), indicating that TEMPO acts as a reaction mediator. Current variations proved critical: no reaction was occurred at 15 mA (entry 5) with substrates fully recovered, while increasing the current to 30 mA reduced the yield (entry 6). Moderate yields were obtained when adjusted the stoichiometric ratio of TEMPO/AcOH or replaced AcOH with HCOOH (entries 7\u0026ndash;9). Neither ferrocene mediator nor \u003cem\u003en\u003c/em\u003e-Bu\u003csub\u003e4\u003c/sub\u003eNI electrolyte enabled the formation of \u003cb\u003eC\u003c/b\u003e\u003csub\u003e\u003cb\u003e1\u003c/b\u003e\u003c/sub\u003e (entries 10\u0026ndash;11). Solvent screening demonstrated that DMF outperformed NMP and acetone (entry 12). Cathode substitution (graphite or nickel) diminished the yield (entry 13), while platinum or zinc anodes performed the reaction poorly (entry 14). Notably, identical yields were obtained under argon and air atmospheres (entry 15), whereas the addition of H\u003csub\u003e2\u003c/sub\u003eO (10 equiv.) led to a slight decrease in yield (entry 16). This indicates that the reaction exhibits excellent compatibility with water and oxygen. Moreover, both extended and shortened reaction times failed to improve the outcomes (Table \u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003eS1\u003c/span\u003e).\u003c/p\u003e\u003cp\u003e\u003cb\u003eSubstrate Scope.\u003c/b\u003e With the optimal conditions in hand, we set out to evaluate the substrate scope of the new synthetic protocol. As shown in Scheme \u003cspan refid=\"Sch2\" class=\"InternalRef\"\u003e2\u003c/span\u003e, diverse ketones and aldehydes (\u003cb\u003eB\u003c/b\u003e\u003csub\u003e\u003cb\u003e1\u003c/b\u003e\u003c/sub\u003e\u003cb\u003e\u0026ndash;B\u003c/b\u003e\u003csub\u003e\u003cb\u003e28\u003c/b\u003e\u003c/sub\u003e, \u003cb\u003eB\u003c/b\u003e\u003csub\u003e\u003cb\u003e40\u003c/b\u003e\u003c/sub\u003e; see Scheme S1 for their structures) were employed to couple with pyridines. Ketones lacking redox-sensitive groups (\u003cb\u003eB\u003c/b\u003e\u003csub\u003e\u003cb\u003e1\u003c/b\u003e\u003c/sub\u003e\u003cb\u003e\u0026ndash;B\u003c/b\u003e\u003csub\u003e\u003cb\u003e23\u003c/b\u003e\u003c/sub\u003e) gave C4-hydroxyalkyl pyridines (\u003cb\u003eC\u003c/b\u003e\u003csub\u003e\u003cb\u003e1\u003c/b\u003e\u003c/sub\u003e\u003cb\u003e\u0026ndash;C\u003c/b\u003e\u003csub\u003e\u003cb\u003e23\u003c/b\u003e\u003c/sub\u003e) in moderate to good isolated yields. Electron-donating groups and halogens were well tolerated (\u003cb\u003eC\u003c/b\u003e\u003csub\u003e\u003cb\u003e1\u003c/b\u003e\u003c/sub\u003e\u003cb\u003e\u0026ndash;C\u003c/b\u003e\u003csub\u003e\u003cb\u003e9\u003c/b\u003e\u003c/sub\u003e), 1-(4-chlorophenyl)ethan-1-one (\u003cb\u003eB\u003c/b\u003e\u003csub\u003e\u003cb\u003e6\u003c/b\u003e\u003c/sub\u003e) required shorter reaction time to prevent hydrodehalogenation of product \u003cb\u003eC\u003c/b\u003e\u003csub\u003e\u003cb\u003e6\u003c/b\u003e\u003c/sub\u003e. After stoichiometric adjustment, trifluoromethyl-containing aryl ketone \u003cb\u003eB\u003c/b\u003e\u003csub\u003e\u003cb\u003e11\u003c/b\u003e\u003c/sub\u003e was able to afford product \u003cb\u003eC\u003c/b\u003e\u003csub\u003e\u003cb\u003e11\u003c/b\u003e\u003c/sub\u003e in moderate yield. 3-Acetylthiophene provided product \u003cb\u003eC\u003c/b\u003e\u003csub\u003e\u003cb\u003e12\u003c/b\u003e\u003c/sub\u003e in acceptable yield. Cyclic and different alkyl-substituted ketones reacted smoothly (\u003cb\u003eC\u003c/b\u003e\u003csub\u003e\u003cb\u003e13\u003c/b\u003e\u003c/sub\u003e\u003cb\u003e\u0026ndash;C\u003c/b\u003e\u003csub\u003e\u003cb\u003e19\u003c/b\u003e\u003c/sub\u003e). Trifluoromethyl (\u003cb\u003eB\u003c/b\u003e\u003csub\u003e\u003cb\u003e20\u003c/b\u003e\u003c/sub\u003e\u003cb\u003e\u0026ndash;B\u003c/b\u003e\u003csub\u003e\u003cb\u003e22\u003c/b\u003e\u003c/sub\u003e) and vinyl ketones (\u003cb\u003eB\u003c/b\u003e\u003csub\u003e\u003cb\u003e23\u003c/b\u003e\u003c/sub\u003e) also generate the desired products in moderate yields. Noteworthy, 3-penten-2-one yielded \u003cb\u003eC\u003c/b\u003e\u003csub\u003e\u003cb\u003e23a\u003c/b\u003e\u003c/sub\u003e along with the regioisomer \u003cb\u003eC\u003c/b\u003e\u003csub\u003e\u003cb\u003e23b\u003c/b\u003e\u003c/sub\u003e, the latter suggests a 1,3-spin center shift (SCS) of the hydroxy \u003cem\u003eα\u003c/em\u003e-radical. Gratifyingly, aryl aldehydes (\u003cb\u003eB\u003c/b\u003e\u003csub\u003e\u003cb\u003e24\u003c/b\u003e\u003c/sub\u003e\u003cb\u003e\u0026ndash;B\u003c/b\u003e\u003csub\u003e\u003cb\u003e28\u003c/b\u003e\u003c/sub\u003e) also underwent efficient transformation, delivering products \u003cb\u003eC\u003c/b\u003e\u003csub\u003e\u003cb\u003e24\u003c/b\u003e\u003c/sub\u003e\u003cb\u003e\u0026ndash;C\u003c/b\u003e\u003csub\u003e\u003cb\u003e28\u003c/b\u003e\u003c/sub\u003e in reasonable yields. However, cyclohexanone (\u003cb\u003eB\u003c/b\u003e\u003csub\u003e\u003cb\u003e40\u003c/b\u003e\u003c/sub\u003e) failed to react productively, and pyridine homocoupling product was obtained instead.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eNext, we investigated the reaction of diverse \u003cem\u003eN\u003c/em\u003e-heteroarenes (\u003cb\u003eA\u003c/b\u003e\u003csub\u003e\u003cb\u003e1\u003c/b\u003e\u003c/sub\u003e\u0026thinsp;\u0026minus;\u0026thinsp;\u003cb\u003eA\u003c/b\u003e\u003csub\u003e\u003cb\u003e28\u003c/b\u003e\u003c/sub\u003e, Scheme S1). Given the obvious variation in reduction potentials among these substrates, adjustments to the standard reaction conditions were necessary. A range of functionalities (e.g., \u0026minus;OMe, \u0026minus;Cl, \u0026minus;\u003cem\u003ei\u003c/em\u003e-Pr, \u0026minus;CO\u003csub\u003e2\u003c/sub\u003eEt, \u0026minus;Me, \u0026minus;TMS, \u0026minus;F) proved compatible, affording the desired products (\u003cb\u003eC\u003c/b\u003e\u003csub\u003e\u003cb\u003e29\u003c/b\u003e\u003c/sub\u003e\u0026thinsp;\u0026minus;\u0026thinsp;\u003cb\u003eC\u003c/b\u003e\u003csub\u003e\u003cb\u003e38\u003c/b\u003e\u003c/sub\u003e) in moderate to good yields. Notably, electron-rich pyridines required either a graphitic cathode or extended reaction time to improve the yields. Thiophene-substituted pyridines yielded the desired products (\u003cb\u003eC\u003c/b\u003e\u003csub\u003e\u003cb\u003e39\u003c/b\u003e\u003c/sub\u003e and \u003cb\u003eC\u003c/b\u003e\u003csub\u003e\u003cb\u003e40\u003c/b\u003e\u003c/sub\u003e) within shorter times. Electron-withdrawing groups (\u0026minus;\u0026thinsp;CO\u003csub\u003e2\u003c/sub\u003eEt, \u0026minus;CF\u003csub\u003e3\u003c/sub\u003e) and unsaturated substituents (vinyl, alkynyl) were well tolerated (\u003cb\u003eC\u003c/b\u003e\u003csub\u003e\u003cb\u003e41\u003c/b\u003e\u003c/sub\u003e\u0026thinsp;\u0026minus;\u0026thinsp;\u003cb\u003eC\u003c/b\u003e\u003csub\u003e\u003cb\u003e44\u003c/b\u003e\u003c/sub\u003e). It is noteworthy that 2,2'-bipyridine underwent 4,4'-bisfunctionalization to afford compound \u003cb\u003eC\u003c/b\u003e\u003csub\u003e\u003cb\u003e45\u003c/b\u003e\u003c/sub\u003e, demonstrating the potential of the present chemistry in developing novel bidentate \u003cem\u003eN\u003c/em\u003e-ligands. Pyridine (\u003cb\u003eA\u003c/b\u003e\u003csub\u003e\u003cb\u003e19\u003c/b\u003e\u003c/sub\u003e) also underwent hydroxyalkylation smoothly, producing the C4-functionalized products (\u003cb\u003eC\u003c/b\u003e\u003csub\u003e\u003cb\u003e46\u003c/b\u003e\u003c/sub\u003e) in 40% yield. Interestingly, when equimolar amounts of aldehyde and amine were added, the \u003cem\u003ein-situ\u003c/em\u003e-generated imines (\u003cb\u003eB\u003c/b\u003e\u003csub\u003e\u003cb\u003e35\u003c/b\u003e\u003c/sub\u003e\u0026thinsp;\u0026minus;\u0026thinsp;\u003cb\u003eB\u003c/b\u003e\u003csub\u003e\u003cb\u003e36\u003c/b\u003e\u003c/sub\u003e) could also be used in the coupling reaction with \u003cb\u003eA\u003c/b\u003e\u003csub\u003e\u003cb\u003e1\u003c/b\u003e\u003c/sub\u003e, affording the C4-aminoalkyl pyridines (\u003cb\u003eC\u003c/b\u003e\u003csub\u003e\u003cb\u003e47\u003c/b\u003e\u003c/sub\u003e, \u003cb\u003eC\u003c/b\u003e\u003csub\u003e\u003cb\u003e48\u003c/b\u003e\u003c/sub\u003e) in reasonable yields. This result further demonstrates the broader potential of the present synthetic method. Further experiments revealed that extending the reaction time for the coupling of 4-phenylpyridine (\u003cb\u003eA\u003c/b\u003e\u003csub\u003e\u003cb\u003e20\u003c/b\u003e\u003c/sub\u003e) and \u003cb\u003eB\u003c/b\u003e\u003csub\u003e\u003cb\u003e1\u003c/b\u003e\u003c/sub\u003e from 4 h to 9 h shifted the product from the C2-hydroxyalkyl species (\u003cb\u003eC\u003c/b\u003e\u003csub\u003e\u003cb\u003e49\u003c/b\u003e\u003c/sub\u003e\u003cb\u003e'\u003c/b\u003e, 41%) to the 2,6-dihydroxyalkyl product (\u003cb\u003eC\u003c/b\u003e\u003csub\u003e\u003cb\u003e50\u003c/b\u003e\u003c/sub\u003e'). 3-phenylpyridine (\u003cb\u003eA\u003c/b\u003e\u003csub\u003e\u003cb\u003e21\u003c/b\u003e\u003c/sub\u003e) exclusively yielding the C2-functionalized product \u003cb\u003eC\u003c/b\u003e\u003csub\u003e\u003cb\u003e51\u003c/b\u003e\u003c/sub\u003e', a selectivity dictated by the steric effects. In contrast, the disubstituted pyridines (\u003cb\u003eA\u003c/b\u003e\u003csub\u003e\u003cb\u003e22\u003c/b\u003e\u003c/sub\u003e, \u003cb\u003eA\u003c/b\u003e\u003csub\u003e\u003cb\u003e23\u003c/b\u003e\u003c/sub\u003e) afforded products \u003cb\u003eC\u003c/b\u003e\u003csub\u003e\u003cb\u003e52\u003c/b\u003e\u003c/sub\u003e and \u003cb\u003eC\u003c/b\u003e\u003csub\u003e\u003cb\u003e53\u003c/b\u003e\u003c/sub\u003e with exclusive C4-selectivity. Fused pyridines were also suitable substrates. For instance, thieno[3,2-\u003cem\u003eb\u003c/em\u003e]pyridine (\u003cb\u003eA\u003c/b\u003e\u003csub\u003e\u003cb\u003e24\u003c/b\u003e\u003c/sub\u003e) and furo[3,2-\u003cem\u003eb\u003c/em\u003e]pyridine (\u003cb\u003eA\u003c/b\u003e\u003csub\u003e\u003cb\u003e25\u003c/b\u003e\u003c/sub\u003e) afforded mixtures of major C4- and minor C2-regioisomers (\u003cb\u003eC\u003c/b\u003e\u003csub\u003e\u003cb\u003e54\u003c/b\u003e\u003c/sub\u003e/\u003cb\u003eC\u003c/b\u003e\u003csub\u003e\u003cb\u003e54\u003c/b\u003e\u003c/sub\u003e\u003cb\u003e'\u003c/b\u003e, \u003cb\u003eC\u003c/b\u003e\u003csub\u003e\u003cb\u003e55\u003c/b\u003e\u003c/sub\u003e/\u003cb\u003eC\u003c/b\u003e\u003csub\u003e\u003cb\u003e55\u003c/b\u003e\u003c/sub\u003e\u003cb\u003e'\u003c/b\u003e). Conversely, quinolines (\u003cb\u003eA\u003c/b\u003e\u003csub\u003e\u003cb\u003e26\u003c/b\u003e\u003c/sub\u003e, \u003cb\u003eA\u003c/b\u003e\u003csub\u003e\u003cb\u003e27\u003c/b\u003e\u003c/sub\u003e) and 4,7-phenanthroline (\u003cb\u003eA\u003c/b\u003e\u003csub\u003e\u003cb\u003e28\u003c/b\u003e\u003c/sub\u003e) selectively provided C2-functionalized products (\u003cb\u003eC\u003c/b\u003e\u003csub\u003e\u003cb\u003e56\u003c/b\u003e\u003c/sub\u003e\u003cb\u003e'\u003c/b\u003e\u0026minus;\u003cb\u003eC\u003c/b\u003e\u003csub\u003e\u003cb\u003e58\u003c/b\u003e\u003c/sub\u003e\u003cb\u003e'\u003c/b\u003e), a class of potential hemilabile bidentate ligands. These examples show that the present synthetic protocol is also applicable for direct functionalization of fused pyridines, and the regioselectivity differences are attributed to the combined effects of radical stability and the steric influence.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eTo gain mechanistic insights into the newly established reaction, we initially conducted various control experiments. As shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eA, separate treatment of 2-phenylpyridine \u003cb\u003eA\u003c/b\u003e\u003csub\u003e\u003cb\u003e1\u003c/b\u003e\u003c/sub\u003e and 4-methoxyacetophenone \u003cb\u003eB\u003c/b\u003e\u003csub\u003e\u003cb\u003e1\u003c/b\u003e\u003c/sub\u003e under the standard conditions yielded the homocoupling products \u003cb\u003eD\u003c/b\u003e\u003csub\u003e\u003cb\u003e1\u003c/b\u003e\u003c/sub\u003e and \u003cb\u003eD\u003c/b\u003e\u003csub\u003e\u003cb\u003e2\u003c/b\u003e\u003c/sub\u003e, respectively (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eA-I and \u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eA-II). Introducing the radical scavenger TEMPO (2.5 equiv.) into the model reaction completely suppressed the formation of product \u003cb\u003eC\u003c/b\u003e\u003csub\u003e\u003cb\u003e1\u003c/b\u003e\u003c/sub\u003e; instead, a TEMPO-trapping pyridine adduct TEMPO-\u003cb\u003eB\u003c/b\u003e\u003csub\u003e\u003cb\u003e1\u003c/b\u003e\u003c/sub\u003e was observed (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eA-III). These results indicate a radical-involved pathway. Subsequently, a radical clock experiment using cyclopropyl ketone \u003cb\u003eB\u003c/b\u003e\u003csub\u003e\u003cb\u003e30\u003c/b\u003e\u003c/sub\u003e and \u003cb\u003eA\u003c/b\u003e\u003csub\u003e\u003cb\u003e1\u003c/b\u003e\u003c/sub\u003e afforded a ring-opening product (\u003cb\u003eC\u003c/b\u003e\u003csub\u003e\u003cb\u003e59\u003c/b\u003e\u003c/sub\u003e), demonstrating that the ketone also acts as a radical precursor (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eB). Finally, a kinetic isotope effect (KIE) experiment with equimolar \u003cb\u003eA\u003c/b\u003e\u003csub\u003e\u003cb\u003e1\u003c/b\u003e\u003c/sub\u003e and \u003cb\u003eA\u003c/b\u003e\u003csub\u003e\u003cb\u003e1\u003c/b\u003e\u003c/sub\u003e\u003cb\u003e-\u003c/b\u003e\u003cb\u003ed\u003c/b\u003e\u003csub\u003e\u003cb\u003e6\u003c/b\u003e\u003c/sub\u003e afforded the desired product in 34% yield with a \u003cem\u003ek\u003c/em\u003e\u003csub\u003eH\u003c/sub\u003e/\u003cem\u003ek\u003c/em\u003e\u003csub\u003eD\u003c/sub\u003e value of 1.94 (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eC), revealing that C\u0026ndash;H bond cleavage at the pyridyl C4 position is the rate-determining step.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eNext, we performed cyclic voltammetry (CV) and open-circuit voltage (OCV) experiments to probe the electrochemical behavior of the model reaction (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eD and Figure S8). The CV of 2-phenylpyridine (\u003cb\u003eA\u003c/b\u003e\u003csub\u003e\u003cb\u003e1\u003c/b\u003e\u003c/sub\u003e) displayed a reversible redox process with a reduction peak at \u0026minus;\u0026thinsp;2.42 V (vs. SCE in DMF), while 4\u0026prime;-methoxyacetophenone (\u003cb\u003eB\u003c/b\u003e\u003csub\u003e\u003cb\u003e1\u003c/b\u003e\u003c/sub\u003e) exhibited a reduction potential of \u0026minus;\u0026thinsp;2.28 V. Upon addition of AcOH, both \u003cb\u003eA\u003c/b\u003e\u003csub\u003e\u003cb\u003e1\u003c/b\u003e\u003c/sub\u003e and \u003cb\u003eB\u003c/b\u003e\u003csub\u003e\u003cb\u003e1\u003c/b\u003e\u003c/sub\u003e showed two reduction peaks (\u003cb\u003eA\u003c/b\u003e\u003csub\u003e\u003cb\u003e1\u003c/b\u003e\u003c/sub\u003e: \u0026minus;2.26 V and \u0026minus;\u0026thinsp;2.79 V; \u003cb\u003eB\u003c/b\u003e\u003csub\u003e\u003cb\u003e1\u003c/b\u003e\u003c/sub\u003e: \u0026minus;2.13 V and \u0026minus;\u0026thinsp;2.55 V). The positive shift in reduction potentials and the enhanced catalytic current show that AcOH activates both reactants. Their similar onset potentials (\u0026minus;\u0026thinsp;1.68 V) and peak potentials provide compelling evidence for concurrent reduction. This conclusion was further supported by OCV experiments (Figure S8), which revealed a stable cathodic plateau at \u0026minus;\u0026thinsp;1.95 V (vs. SCE). Notably, the oxidation peak intensities of \u003cb\u003eA\u003c/b\u003e\u003csub\u003e\u003cb\u003e1\u003c/b\u003e\u003c/sub\u003e and \u003cb\u003eB\u003c/b\u003e\u003csub\u003e\u003cb\u003e1\u003c/b\u003e\u003c/sub\u003e decreased in the presence of AcOH, suggesting that AcOH stabilizes their radical intermediates generated by cathodic reduction.\u003c/p\u003e\u003cp\u003eBased on the above findings and the transformations employing paired electrolysis,\u003csup\u003e[\u003cspan citationid=\"CR77\" class=\"CitationRef\"\u003e77\u003c/span\u003e, \u003cspan citationid=\"CR78\" class=\"CitationRef\"\u003e78\u003c/span\u003e]\u003c/sup\u003e we propose a plausible reaction pathway for the paired electrolysis of \u003cb\u003eA\u003c/b\u003e\u003csub\u003e\u003cb\u003e1\u003c/b\u003e\u003c/sub\u003e and \u003cb\u003eB\u003c/b\u003e\u003csub\u003e\u003cb\u003e1\u003c/b\u003e\u003c/sub\u003e to form product \u003cb\u003eC\u003c/b\u003e\u003csub\u003e\u003cb\u003e1\u003c/b\u003e\u003c/sub\u003e (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eE). Initially, cathodic reduction of proton-activated 4'-methoxyacetophenone (\u003cb\u003eB\u003c/b\u003e\u003csub\u003e\u003cb\u003e1\u003c/b\u003e\u003c/sub\u003e\u003cb\u003e-H\u003c/b\u003e) generates a persistent benzyl radical (or hydroxy \u003cem\u003eα\u003c/em\u003e-radical \u003cb\u003eB\u003c/b\u003e\u003csub\u003e\u003cb\u003e1\u003c/b\u003e\u003c/sub\u003e\u003cb\u003e'\u003c/b\u003e), while electroreduction of protonated 2-phenylpyridine (\u003cb\u003eA\u003c/b\u003e\u003csub\u003e\u003cb\u003e1\u003c/b\u003e\u003c/sub\u003e\u003cb\u003e-H\u003c/b\u003e) yields the pyridyl radical \u003cb\u003eINT-1\u003c/b\u003e. Simultaneously, anodic single-electron oxidation of TEMPO (\u003cb\u003eI\u003c/b\u003e) forms oxoammonium species \u003cb\u003eII\u003c/b\u003e. Subsequent cross-coupling of radicals \u003cb\u003eINT-1\u003c/b\u003e and \u003cb\u003eB\u003c/b\u003e\u003csub\u003e\u003cb\u003e1\u003c/b\u003e\u003c/sub\u003e\u003cb\u003e'\u003c/b\u003e affords the coupling adduct \u003cb\u003eINT-2\u003c/b\u003e. Species \u003cb\u003eII\u003c/b\u003e then mediates oxidative aromatization of \u003cb\u003eINT-2\u003c/b\u003e, delivering product \u003cb\u003eC\u003c/b\u003e\u003csub\u003e\u003cb\u003e1\u003c/b\u003e\u003c/sub\u003e along with release of TEMPOH (\u003cb\u003eIII\u003c/b\u003e). Finally, anodic oxidation of \u003cb\u003eIII\u003c/b\u003e regenerates TEMPO (\u003cb\u003eI\u003c/b\u003e), completing the catalytic cycle.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eFurther, DFT calculations were applied to analyze the proposed reaction pathway. All geometries were fully optimized, and the parameters are given in Table S3 in the SI. As shown in Fig.\u0026nbsp;2, \u003cb\u003eA\u003c/b\u003e\u003csub\u003e\u003cb\u003e1\u003c/b\u003e\u003c/sub\u003e\u003cb\u003e-H\u003c/b\u003e is initially generated from the protonation of \u003cb\u003eA\u003c/b\u003e\u003csub\u003e\u003cb\u003e1\u003c/b\u003e\u003c/sub\u003e due to the presence of acetic acid in the reaction system. This protonation step will facilitate a subsequent single electron transfer process and generate radical \u003cb\u003eINT-1\u003c/b\u003e. Spin density analysis of \u003cb\u003eINT-1\u003c/b\u003e reveals that the electron spin predominantly located on the C4 and C6 positions, with little spin density at C2 position. Mulliken spin population calculation further supports that the electron population on C4 position (0.367) is significantly higher than on C2 position (0.0896). These results suggest that the C4 position will be more reactive towards radical coupling. To study the chemoselectivity of the radical coupling step, the reaction energy barrier between radical \u003cb\u003eB\u003c/b\u003e\u003csub\u003e\u003cb\u003e1\u003c/b\u003e\u003c/sub\u003e\u003cb\u003e'\u003c/b\u003e (Generated from cathodic reduction of ketone \u003cb\u003eB\u003c/b\u003e\u003csub\u003e\u003cb\u003e1\u003c/b\u003e\u003c/sub\u003e) and \u003cb\u003eINT-1\u003c/b\u003e are calculated for C2 and C4 position. The radical combination energy barrier at C4 position is 9.7 kcal/mol, which is 2.3 kcal/mol lower than that at C2 position. Thus, the radical coupling process will preferentially undergo at C4 position and afford \u003cb\u003eINT-2\u003c/b\u003e rather than \u003cb\u003eINT-3\u003c/b\u003e. Subsequently, given the nucleophilic positions in \u003cb\u003eINT-2\u003c/b\u003e and potential hydrogen donor characteristics, the subsequent reaction between TEMPO\u003csup\u003e+\u003c/sup\u003e (Generated from the anodic oxidation of TEMPO) may have multiple pathways. When the C3 carbon attack the nitrogen in the N\u0026thinsp;=\u0026thinsp;O double bond of TEMPO\u003csup\u003e+\u003c/sup\u003e, the reaction energy barrier is 21.1 kcal/mol, which is relatively high. In addition, this step is also thermodynamically unfavorable (ΔG\u0026thinsp;=\u0026thinsp;17.7 kcal/mol). Thus, the following cope elimination from \u003cb\u003eINT-5\u003c/b\u003e to aromatization and forming \u003cb\u003eINT-4\u003c/b\u003e is unlikely to occur. Attempts to locate a stable intermediate via nucleophilic attack from the nitrogen atom of \u003cb\u003eINT-2\u003c/b\u003e were unsuccessful, possibly due to the steric hinderance between the tera-methyl groups in TEMPO\u003csup\u003e+\u003c/sup\u003e and the phenyl group in \u003cb\u003eINT-2\u003c/b\u003e. Alternatively, a both kinetically and thermodynamically favorable hydride transfer mechanism was identified,\u003csup\u003e[\u003cspan additionalcitationids=\"CR80\" citationid=\"CR79\" class=\"CitationRef\"\u003e79\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR81\" class=\"CitationRef\"\u003e81\u003c/span\u003e]\u003c/sup\u003e as 1,4-dihyropyridines are well-documented hydrogen donors.\u003csup\u003e[\u003cspan additionalcitationids=\"CR83\" citationid=\"CR82\" class=\"CitationRef\"\u003e82\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR84\" class=\"CitationRef\"\u003e84\u003c/span\u003e]\u003c/sup\u003e The hydrogen transfer between \u003cb\u003eINT-2\u003c/b\u003e and TEMPO\u003csup\u003e+\u003c/sup\u003e has a low energy barrier (15.9 kcal/mol) and favored thermodynamics (ΔG = -37.1 kcal/mol), which will lead to the formation of protonated product \u003cb\u003eINT-4\u003c/b\u003e and TEMPOH. Final deprotonation mediated by acetate affords the desired product \u003cb\u003eC\u003c/b\u003e\u003csub\u003e\u003cb\u003e1\u003c/b\u003e\u003c/sub\u003e. This deprotonation step may also be assisted by substrate \u003cb\u003eA\u003c/b\u003e\u003csub\u003e\u003cb\u003e1\u003c/b\u003e\u003c/sub\u003e.\u003c/p\u003e\u003cp\u003eFinally, we explored the synthetic utility of the developed methodology. Even with reduced loadings of TEMPO/AcOH (Scheme \u003cspan refid=\"Sch4\" class=\"InternalRef\"\u003e4\u003c/span\u003eA), the reaction of \u003cb\u003eA\u003c/b\u003e\u003csub\u003e\u003cb\u003e1\u003c/b\u003e\u003c/sub\u003e (3 mmol) with \u003cb\u003eB\u003c/b\u003e\u003csub\u003e\u003cb\u003e1\u003c/b\u003e\u003c/sub\u003e (9 mmol) afforded the product \u003cb\u003eC\u003c/b\u003e\u003csub\u003e\u003cb\u003e1\u003c/b\u003e\u003c/sub\u003e in good yield (62%, 0.57 g). This yield represents a significant improvement over the multistep procedure reported previously\u003csup\u003e[\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]\u003c/sup\u003e and demonstrates the scalability potential of the protocol. Treating \u003cb\u003eC\u003c/b\u003e\u003csub\u003e\u003cb\u003e1\u003c/b\u003e\u003c/sub\u003e to HCl in toluene (12 h) followed by neutralization afforded the 1,1-diarylethylene \u003cb\u003eD\u003c/b\u003e\u003csub\u003e\u003cb\u003e3\u003c/b\u003e\u003c/sub\u003e in 85% yield. Hydroboration-oxidation of \u003cb\u003eD\u003c/b\u003e\u003csub\u003e\u003cb\u003e3\u003c/b\u003e\u003c/sub\u003e gave the secondary alcohol \u003cb\u003eD\u003c/b\u003e\u003csub\u003e\u003cb\u003e4\u003c/b\u003e\u003c/sub\u003e in 88% yield, while epoxidation with \u003cem\u003em\u003c/em\u003e-CPBA followed by ring-opening yielded the vicinal diol \u003cb\u003eD\u003c/b\u003e\u003csub\u003e\u003cb\u003e5\u003c/b\u003e\u003c/sub\u003e in 50% yield. Enabled by the pyridyl directing group, palladium-catalyzed \u003cem\u003eortho\u003c/em\u003e-C\u0026ndash;H acylation of the phenyl moiety in \u003cb\u003eC\u003c/b\u003e\u003csub\u003e\u003cb\u003e1\u003c/b\u003e\u003c/sub\u003e provided \u003cb\u003eD\u003c/b\u003e\u003csub\u003e\u003cb\u003e6\u003c/b\u003e\u003c/sub\u003e in 39% yield. Direct esterification of \u003cb\u003eC\u003c/b\u003e\u003csub\u003e\u003cb\u003e1\u003c/b\u003e\u003c/sub\u003e with ibuprofen furnished \u003cb\u003eD\u003c/b\u003e\u003csub\u003e\u003cb\u003e7\u003c/b\u003e\u003c/sub\u003e in 51% yield. We next applied the synthetic method to the functionalization of bioactive substrates. Reaction of Isophorone (\u003cb\u003eB\u003c/b\u003e\u003csub\u003e\u003cb\u003e31\u003c/b\u003e\u003c/sub\u003e) with \u003cb\u003eA\u003c/b\u003e\u003csub\u003e\u003cb\u003e1\u003c/b\u003e\u003c/sub\u003e gave the desired product \u003cb\u003eC\u003c/b\u003e\u003csub\u003e\u003cb\u003e60a\u003c/b\u003e\u003c/sub\u003e in merely 16% yield, while the 1,3-rearrangement product \u003cb\u003eC\u003c/b\u003e\u003csub\u003e\u003cb\u003e60b\u003c/b\u003e\u003c/sub\u003e predominated with a 56% yield. Tonalide (\u003cb\u003eB\u003c/b\u003e\u003csub\u003e\u003cb\u003e32\u003c/b\u003e\u003c/sub\u003e), Epoxyprogesterone (\u003cb\u003eB\u003c/b\u003e\u003csub\u003e\u003cb\u003e33\u003c/b\u003e\u003c/sub\u003e) and L-menthol-derived ketone (\u003cb\u003eB\u003c/b\u003e\u003csub\u003e\u003cb\u003e34\u003c/b\u003e\u003c/sub\u003e) reacted efficiently with \u003cb\u003eA\u003c/b\u003e\u003csub\u003e\u003cb\u003e1\u003c/b\u003e\u003c/sub\u003e to exclusively afford C4-functionalized pyridines (\u003cb\u003eC\u003c/b\u003e\u003csub\u003e\u003cb\u003e61\u003c/b\u003e\u003c/sub\u003e\u003cb\u003e\u0026ndash;C\u003c/b\u003e\u003csub\u003e\u003cb\u003e63\u003c/b\u003e\u003c/sub\u003e). Furthermore, the reactions of Myrtenol-derived pyridine \u003cb\u003eA\u003c/b\u003e\u003csub\u003e\u003cb\u003e29\u003c/b\u003e\u003c/sub\u003e and Abametapir \u003cb\u003eA\u003c/b\u003e\u003csub\u003e\u003cb\u003e30\u003c/b\u003e\u003c/sub\u003e with \u003cb\u003eB\u003c/b\u003e\u003csub\u003e\u003cb\u003e1\u003c/b\u003e\u003c/sub\u003e proceeded smoothly, affording \u003cb\u003eC\u003c/b\u003e\u003csub\u003e\u003cb\u003e64\u003c/b\u003e\u003c/sub\u003e and \u003cb\u003eC\u003c/b\u003e\u003csub\u003e\u003cb\u003e65\u003c/b\u003e\u003c/sub\u003e in moderate to good yields.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eIn conclusion, we have developed a room-temperature direct C4-hydroxyalkylation of inert pyridines with readily available carbonyl compounds via paired electrolysis. Using a zinc cathode, graphite anode, and TEMPO mediator, this strategy achieves broad substrate scope, operational simplicity, metal-free conditions, and high step and atom economy. It overcomes the limitations of conventional pyridyl functionalization that require pre-functionalized substrates or stoichiometric activators, establishing a practical platform for direct access to C4-hydroxyalkyl pyridines. In addition, preliminary studies indicate that fused pyridines and imines are also amenable to this transformation, demonstrating broad potentials of the present chemistry. Mechanistic studies reveal that acetic acid activates both reactants, while cathodic reduction generates key pyridyl and hydroxy \u003cem\u003eα\u003c/em\u003e-radicals. Product formation proceeds \u003cem\u003evia\u003c/em\u003e electroreduction-induced radical-radical cross-coupling, followed by anodic oxidative aromatization. This work demonstrates how merging reductive dearomatization with further radical transformations unlocks new reactivity paradigms for inert chemical systems. Furthermore, it paves the way for constructing novel functional ligands and for functionalizing bioactive molecules to promising derivatives.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003ch2\u003eCompeting interest\u003c/h2\u003e\u003cp\u003eThe authors declare no conflict of interest.\u003c/p\u003e\u003c/p\u003e\u003ch2\u003e\u003cb\u003eAdditional information\u003c/b\u003e\u003c/h2\u003e\u003cp\u003e\u003cstrong\u003eSupplementary information\u003c/strong\u003e\u003cp\u003eThe online version contains supplementary material available at \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://www.nature.com/naturechemistry\u003c/span\u003e\u003cspan address=\"http://www.nature.com/naturechemistry\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/p\u003e\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eReprints and permission information\u003c/strong\u003e\u003cp\u003e is available online at \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://nature.com/reprints\u003c/span\u003e\u003cspan address=\"http://nature.com/reprints\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\u003c/p\u003e\u003ch2\u003eAuthor contributions\u003c/h2\u003e\u003cp\u003eM. Z. conceived the idea, analyzed the data, directed the project, and wrote the manuscript. C. -Q. Z. and M.-R. W. carried out all the catalytic experiments. C.-Q. Z. drew the structures of all the obtained compounds, analyzed the single crystal structures, synthesized the raw materials and carried out NMR tests. M.-R. W. performed the DFT calculations. H.-F. J. and P. H. D. discussed the mechanistic aspects and revised the manuscript. All the authors have read the manuscript and agree with its content.\u003c/p\u003e\u003ch2\u003eAcknowledgements\u003c/h2\u003e\u003cp\u003eThe authors are grateful for the financial support of the National Natural Science Foundation of China (22471080), Natural Science Foundation of Guangdong Province (2025A1515012079), Guangdong Basic and Applied Basic Research Foundation (2024B1515040027), and the Postdoctoral Fellowship Program of CPSF (GZB20250265).\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eMarshall CM, Federice JG, Bell CN, Cox PB, Njardarson JT (2024) An Update on the Nitrogen Heterocycle Compositions and Properties of U.S. FDA-Approved Pharmaceuticals (2013\u0026ndash;2023). J Med Chem 67:11622\u0026ndash;11655\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eFeng J, Geng WC, Jiang H, Wu B (2022) Recent Advances in Biocatalysis of Nitrogen-containing Heterocycles. 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Org Biomol Chem 13:6255\u0026ndash;6268\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Table 1","content":"\u003cp\u003eTable 1 is available in the Supplementary Files section.\u003c/p\u003e"},{"header":"Schemes","content":"\u003cp\u003eSchemes 1 to 4 are available in the Supplementary Files section.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"nature-portfolio","isNatureJournal":true,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"","title":"Nature Portfolio","twitterHandle":"","acdcEnabled":false,"dfaEnabled":false,"editorialSystem":"ejp","reportingPortfolio":"","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Pyridines, Carbonyls, Paired electrolysis, radical cross-coupling, regioselective hydroxyalkylation","lastPublishedDoi":"10.21203/rs.3.rs-8259255/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8259255/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eDirect and selective functionalization of ubiquitous pyridine rings is of paramount importance across numerous fields, but it remains a challenge due to pyridine's inherent thermodynamic stability, kinetic inertness, and multiple competitive reaction sites. Herein, by using an undivided cell tolerant to ambient air and moisture, we report a room-temperature paired electrolysis strategy for C4-selective hydroxyalkylation of diverse inert pyridines with readily available carbonyl compounds. Employing a Zn cathode, graphite anode, and TEMPO mediator, this method features a broad substrate scope, operational simplicity, metal-free conditions, and high step/atom economy. It overcomes the limitations of conventional approaches requiring pre-functionalized substrates or stoichiometric activators, establishing a practical platform for direct access to C4-hydroxyalkyl pyridines. Mechanistic studies reveal that acetic acid activates both reactants, and the products are formed via cross-coupling of cathodic reduction-induced pyridyl radicals and hydroxy \u003cem\u003eα\u003c/em\u003e-radicals followed by protonation and anodic oxidative aromatization. In this work, the concept merging electroreduction-induced dearomatization followed by radical transformations will open a door to further develop useful transformations with inert chemical systems.\u003c/p\u003e","manuscriptTitle":"Room-Temperature Direct C4-Hydroxyalkylation of Pyridines via Paired Electrolysis","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-12-08 05:49:02","doi":"10.21203/rs.3.rs-8259255/v1","editorialEvents":[],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"nature-communications","isNatureJournal":true,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"NCOMMS","sideBox":"Learn more about [Nature Communications](http://www.nature.com/ncomms/)","snPcode":"","submissionUrl":"https://mts-ncomms.nature.com/","title":"Nature Communications","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature Communications","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"48927f56-4dff-454f-bc70-2e6f461e0fcb","owner":[],"postedDate":"December 8th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[{"id":59127030,"name":"Physical sciences/Chemistry/Organic chemistry/Synthetic chemistry methodology"},{"id":59127031,"name":"Physical sciences/Chemistry/Electrochemistry/Electrocatalysis"}],"tags":[],"updatedAt":"2026-03-30T12:15:31+00:00","versionOfRecord":[],"versionCreatedAt":"2025-12-08 05:49:02","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8259255","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8259255","identity":"rs-8259255","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}