Diastereodivergent Synthesis of Multi-Substituted Cyclohexanes via Alkene Hydroamidation

Diastereodivergent Synthesis of Multi-Substituted Cyclohexanes via Alkene Hydroamidation | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Diastereodivergent Synthesis of Multi-Substituted Cyclohexanes via Alkene Hydroamidation Yao Fu, Zhen Li, Yi-Zhou Tong, Kai-Ran Duan, Boru Men, Qian-Qian Lu, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8313233/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract The construction of three-dimensional (3D) organic molecular structures is pivotal in modern organic chemistry. For disubstituted cyclohexanes, substituent orientation dictates thermodynamic stability, physicochemical properties, and biological activities, but precise stereocontrol of saturated cycloalkane substituents is challenging. Hydrogenation of substituted cyclohexanones/cyclic imines is a classic model for multi-substituted cyclohexane stereochemistry, in which stereoselectivity is governed by steric and electronic effects. In contrast, stereocontrol of exocyclic C=C bonds remains a major hurdle. Herein, we achieved diastereodivergent hydroamidation of methylenecyclohexanes: a nickel catalytic system efficiently synthesizes 1,4-cis/trans and 1,3-cis/trans isomers, while a cobalt system realizes 1,2-cis/trans stereodivergence. The core achievement lies in the differentiated active catalytic species strategy, which precisely regulates the spatial structure and electronic properties of metal-hydride or metal-functional group species. This work broadens the chemical space for multi-substituted cyclohexane synthesis, provides a powerful tool for the preparation of sp3-rich drug molecules, and offers an important case for research on substituted cyclohexane stereochemistry. Physical sciences/Chemistry/Organic chemistry/Stereochemistry Physical sciences/Chemistry/Organic chemistry/Synthetic chemistry methodology Physical sciences/Chemistry/Organic chemistry/Reaction mechanisms Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Introduction The construction of three-dimensional (3D) structures of organic molecules is pivotal in modern organic chemistry 1,2 . The tetrahedral carbon configuration theory established a stereochemical framework centered on sp 3 -hybridized carbon, advancing molecular spatial structure study from “planar cognition” to “3D exploration” 3 . For disubstituted cyclohexanes, which exist cis- and trans - two possible configurations, substituent orientation determines thermodynamic stability and induces significant differences in physicochemical properties and biological activities 4,5 . However, precise stereocontrol of saturated cycloalkane substituents remains challenging 6,7 (Fig. 1a). Hydrogenation of exocyclic unsaturations is a classic model for multi-substituted cyclohexane stereochemistry, with substituted cyclohexanone/cyclic imine hydrogenation widely studied 8-14 . Their polar C=O/C=N bonds readily react with metal hydrides, such as sodium borohydride or lithium aluminum hydride 15 , and stereoselectivity is governed by steric and electronic effects 16-19 . In contrast, exocyclic C=C bond stereocontrol is limited: poor polarity matching between hydrides and nonpolar C=C bonds hinders direct addition, and axial/equatorial attack differences are indistinct, complicating selectivity 20-24 (Fig. 1b). Transition-metal catalytic systems offer a potential solution to this challenge: by rationally tuning the metal or ligand, the spatial structure and electronic properties of metal-hydride species or metal-functional group species can be precisely regulated 25-31 . This enables highly selective addition of active species to carbon-carbon double bonds, thereby achieving diastereodivergent synthesis 32 . However, the introduction of transition-metals may be accompanied by side reactions such as alkene isomerization, alkene hydrogenation, and decomposition of functionalization reagents. On the other hand, the complexity of reaction mechanisms increases the uncertainty in selectivity control. Thus, transition-metal-catalyzed hydrofunctionalization of exocyclic C=C bonds presents both opportunities and challenges for the diastereodivergent synthesis of multi-substituted cycloalkanes 32,33 (Fig. 1c). Herein, we achieved the diastereodivergent hydroamidation of methylenecyclohexanes. Specifically, a nickel catalytic system enables efficient synthesis of 1,4- cis , 1,4- trans , 1,3- cis , 1,3- trans , and 1,2- cis disubstituted cyclohexanes, while a cobalt system realizes 1,2- cis and 1,2- trans stereodivergent synthesis. Mechanistically, the key to the successful control of reaction selectivity lies in the differentiated active catalytic species strategy, which precise regulate the spatial structure and electronic properties of metal-hydride or metal-functional group species. This study not only broadens the chemical space for the multi-substituted cyclohexane synthesis and provides a powerful tool for the synthesis of sp 3 -rich drug molecules, but also offers an important case for “substituted cyclohexane stereochemistry” in organic chemistry (Fig. 1d). Results and discussion Reaction development We initiated our investigation by employing 1-( tert -butyl)-4-methylenecyclohexane ( 1 ) and 3-phenyl-1,4,2-dioxazol-5-one ( 2 ) as model substrates to explore the diastereodivergent hydroamidation reaction (Fig. 2). Then, cis - N -((4-( tert -butyl)cyclohexyl)methyl)benzamide ( 3 ) and trans - N -((4-( tert -butyl)cyclohexyl)methyl)benzamide ( 4 ) emerged as our target products. It is worth noting that numerous catalytic systems based on both base metals and noble metals have been proven to exhibit excellent catalytic activity for hydroamidation reactions with dioxazolones 34,35 . For instance, copper-catalyzed and nickel-catalyzed systems are widely recognized for enabling hydroamidation between alkenes and dioxazolones 36-40 . More recently, the Chang group reported that Lewis acid/iron relay catalysis can facilitate the hydroamidation of α,β-unsaturated esters with dioxazolones 41 . Additionally, cobalt catalysis allows for enantioselective ipso - and migratory hydroamidation of heterocyclic alkenes 42 . Our objective, however, was to identify a suitable catalytic system for the stereodivergent synthesis of multi-substituted cycloalkanes via hydroamidation of methylenecyclohexanes. Thus, discovering an appropriate initial catalytic system from the extensive range of available systems presented both an opportunity and a challenge. Benefiting from high-throughput experiment technology, we were able to rapidly analyze the combinatorial arrangements of different metal catalysts and ligands. We visualized the results of combinations involving 4 catalysts [Fe(OAc) 2 , Co(SCN) 2 , NiCl 2 (DME), and Cu(OAc) 2 ] and 7 ligands ( L1 , L8 , L14 , L15 , L21 , PPh 3 , and BINAP) in the form of a heatmap. As observed, the iron and copper catalytic systems exhibited almost no catalytic activity toward our model reaction. Similar to our previous findings on hydroalkylation of methylenecyclohexanes, the cobalt-hydride catalytic system also displayed diastereodivergent behavior for the hydroamidation 32 . However, the cobalt-hydride system afforded low yields and unsatisfactory selectivity control (24% yield with 3.1:1 cis / trans selectivity for the synthesis of 3 and 6% yield with 7.2:1 trans / cis selectivity for the synthesis of 4 ). In contrast, the nickel catalytic system delivered promising initial results for the synthesis of the cis -isomer ( 3 ), achieving 60% yield and 24:1 cis / trans selectivity. Nevertheless, we were unable to obtain trans -selective product ( 4 ) using the nickel catalytic system under the initial conditions. To fulfill our research goal, we subsequently conducted extensive ligand screening and condition optimization targeting both the cobalt and nickel catalytic systems. For the cobalt-hydride system, the selectivity could be moderately improved through the modulation of ligands and other conditions (see Supplementary Information for details). However, the reaction efficiency remained low, never exceeding 30% yield. For the nickel catalytic system, we expanded the ligand screening scope to include 125 ligands across 11 categories (see Supplementary Information for details). Among these, the use of BiOX or PyOX -type ligands predominantly favored the formation of the cis -selective product. In contrast, the employment of BOX , BIM , and PHOX -type ligands failed to yield the desired hydroamidation products altogether. Surprisingly, SadPhos -type ligands—rarely utilized in nickel-catalyzed reactions—not only exhibited moderate activity but also achieved a complete reversal of trans -selectivity 43-45 . Based on the BiOX and SadPhos ligand classes, we obtained the optimal reaction conditions through further meticulous condition screening, which were primarily categorized into two sets. Condition A employs a combination of NiCl 2 (DME) and BiOX ligand L1 as the precatalyst, (MeO) 3 SiH as the hydrogen source, KF as the base, DMAc as the solvent, and MeOH along with LiCl as additives, conducted at 25 °C. This condition afforded the 1,4- cis -isomer ( 3 ) with 77% GC yield, 71% isolated yield, and >20:1 cis / trans selectivity (entry 1). Condition B, on the other hand, uses NiCl 2 (DME) in combination with SadPhos ligand L30 as the precatalyst, (MeO) 3 SiH as the hydrogen source, KF as the base, and t BuOH as the solvent, performed at 0 °C. This setup produced the 1,4- trans -isomer ( 4 ) with 86% GC yield, 78% isolated yield, and 13:1 trans / cis selectivity (entry 8). Control experiments revealed that LiCl, as an additive, was beneficial for improving the reaction yield of condition A but significantly diminished the selectivity of condition B 46 . In addition, condition A was sensitive to reaction temperature, with both increases and decreases impairing reaction efficiency. In contrast, for condition B, a lower reaction temperature not only enhanced the reaction yield but also effectively improved the reaction selectivity. Substrate scope After establishing the optimal reaction conditions, we systematically evaluated the substrate scope of nickel-catalyzed hydroamidation of methylenecyclohexane (Fig. 3). Notably, the results demonstrate that the ligand exerts a significant and general regulatory effect on the product configuration. When condition A was employed, 4-substituted and 3-substituted methylenecyclohexanes predominantly afforded thermodynamically disfavored products, namely the 1,4- cis or 1,3- trans isomers ( 3 , 5 - 14 ). In contrast, condition B preferred the formation of thermodynamically favored products, enabling the highly selective synthesis of 1,4- trans and 1,3- cis isomers ( 4 , 15 - 24 ). This reaction system exhibited moderate to excellent yields and diastereoselectivity. Substrate scope investigations revealed that a broad range of substituents at the 4- or 3-position are compatible, including alkyl, aryl, heteroaryl, N or O-containing heterocyclic groups, and ester functionalities. Moreover, the electronic and steric effects of these substituents exerted minimal disruptions on reaction selectivity. To begin with, steric hindrance had no significant impact on diastereoselectivity. For instance, the transition from bulky tert -butyl groups ( 3 , 4 , 11 , 21 ) to moderately hindered isopropyl groups ( 8 , 18 ) and even small methyl groups ( 5 , 12 , 15 , 22 ) only resulted in a slight decrease in selectivity. Furthermore, regarding electronic effects, the introduction of different groups such as phenyl ( 7 , 13 , 16 , 23 ), indole ( 14 , 24 ), phthalimido ( 6 , 20 ), and dioxolane ( 10 , 19 ) did not perturb the reaction selectivity. However, the incorporation of ester groups ( 9 , 17 ) led to a certain degree of reduced selectivity. This catalytic system was successfully extended to 3,5-disubstituted methylenecyclohexane substrates, achieving diastereodivergent synthesis with access to both thermodynamically disfavored and favored products ( 25 , 26 ). In addition, we attempted to apply this nickel-catalyzed system to 2-substituted methylenecyclohexane. We successfully obtained the 1,2- cis configured products ( 27 , 28 ) using condition A; however, when using condition B, not only was the yield significantly reduced, but the selectivity also became uncontrollable. Finally, the configurations of 9 representative products ( 3 , 5 , 7 , 13 , 15 , 16 , 22 , 24 , and 28 ) were determined by single-crystal X-ray diffraction. The configuration of other products is inferred by analogy. To further advance the investigation, we examined the scope of the amidation reagent dioxazolone (Fig. 4). It was found that upon replacing the phenyl substituent in the model substrate 3-phenyl-1,4,2-dioxazol-5-one, a broad range of substrates—whether bearing electron-deficient aryl ( 29 , 35 ), electron-rich aryl ( 30 , 36 ), heteroaryl ( 32 , 38 ), or alkyl ( 34 , 39 , 40 ) groups—could be smoothly converted to the target products, with moderate to excellent yields and diastereoselectivity consistently retained. It is worth noting that, to extend the applicability to a broader range of dioxazolone derivatives, the ratio of dioxazolone derivatives to methylenecyclohexane was appropriately adjusted from 1:2 to 1:3. Mechanistic investigation To gain insights into the stereodivergent hydroamidation reaction, hydrogenation experiments were conducted using alkene 41 in the absence of dioxazolones under both condition A and condition B (Fig. 5a). Under both reaction conditions, the alkene hydrogenation products, 42 and 43 , were observed along with partial residual starting material 41 , while a substantial amount of alkene isomerization product ( 44 ) was detected under condition B. Notably, under condition A, the cis/trans selectivity of the hydrogenation products ( cis/trans = 4.0:1) was significantly reduced compared to that of hydroamidation products ( cis/trans = 16:1), whereas no substantial difference in trans/cis selectivity was observed between the hydrogenation and hydroamidation products under condition B ( trans/cis = 9.0:1 for hydrogenation products, trans/cis = 10:1 for hydroamidation products). These results suggest that distinct catalytically active species may be involved in the two hydroamidation catalytic systems. When using the ligand L1 , the significant steric effect of the Ni-N species in the presence of dioxazolones leads to excellent cis -selectivity of the reaction; whereas in the absence of dioxazolones, the Ni-H species exhibits no advantage in facial selectivity control. In contrast, the scenario differs when the ligand L30 is employed—the absence of significant selectivity differences between hydrogenation and hydroamidation is more consistent with the hypothesis that the stereochemical outcome of the reaction is directly dictated by the insertion of the alkene into the Ni-H species. In addition, to obtain experimental evidence for the generation of a putative nickel nitrenoid intermediate within the catalytic system, a trapping experiment was performed (see Supplementary Information for details). Consistent with expectations, iminophosphorane was formed in both condition A and B, whereas it was not generated in the absence of the nickel catalyst. Based on these experimental evidences, density functional theory (DFT) calculations were performed to elucidate the mechanistic origins of the stereodivergent hydroamidation reactions. Through comparing the hydronickelation and dioxazolone activation steps, L1-Ni II -NHCOPh and L30-Ni II -H were proposed as the active species for condition A and condition B, respectively (see Supplementary Information for details). In this context, we calculated the equatorial and axial transition states for alkene insertion. As shown in Fig. 5b, the equatorial transition state of alkene insertion L1-TS4- cis is 8.7 kcal/mol lower than the axial transition state L1-TS4- trans , indicating 1,4- cis hydroamidation product as the main product under condition A. In contrast, 1,4- trans hydroamidation product would be delivered in the condition B catalytic system due to the lower energy of L30-TS3- trans . Furthermore, independent gradient model-Hirshfeld (IGMH) visualizations 47,48 revealed that both L1-TS4- cis and L1-TS4- trans exhibit weak interactions such as C-H···O and C-H···Cl, without showing significant differences. In contrast, L30-TS3- trans involves more C-H···H-C interactions between ligand and alkene, indicating the crucial role of electronic interactions in directing the formation of the trans -selective product (Fig. 5c). In the distortion and interaction energy analysis (Fig. 5d), alkene distortion energy is consistently larger in the axial transition states of alkene insertion ( L1-TS4- trans and L30-TS3- trans ) in both condition A and condition B catalytic systems, highlighting the steric disfavorability of the axial reaction pathway 49 . Further analysis reveals that the distortion effect dominates in L1-TS4 , whereas the interaction effect prevails in L30-TS3 . Consistent with IGMH analysis, these results indicate that the selectivity of condition B is attributed to favorable C-H···H-C interactions that promote the formation of 1,4- trans products, while the preferred selectivity of condition A is driven by steric hindrance, leading to the formation of 1,4- cis products. Reaction expansion. Finally, we analyzed the differences between the nickel catalytic system developed in this work and the previously established cobalt catalytic system through the hydroamidation of 2-substituted methylenecyclohexanes (Fig. 6). In the context of stereodivergent hydrogenation of exocyclic unsaturations, substrates with bulky substituents at the 2-position—including not only methylenecyclohexanes but also 2-substituted cyclohexanones—pose significant challenges. The underlying reason is that axial attack is hindered by the bulky group at the 2-position. As expected, our nickel catalytic system exclusively afforded 1,2- cis isomers via equatorial attack. Moreover, the combination of sterically hindered SadPhos ligand and the mechanism involving alkene insertion into Ni-N active species resulted in a complete inability to obtain 1,2- trans selective products. In contrast, cobalt-catalyzed systems exhibit remarkable stereocontrol and achieve stereodivergent hydroamidation, which may involve alkene insertion into Co-H active species. Using a precatalyst composed of Co(SCN) 2 and the BOX ligand L14 , with DEMS as the hydrogen source, K 3 PO 4 as the base, THF as the solvent, and MeOH as an additive, the reaction at 0 °C yielded product 27 in 45% yield with >20:1 cis / trans selectivity. When the PHOX ligand L21 was used under otherwise identical conditions, product 47 was obtained in 26% yield with >20:1 trans / cis selectivity. These results demonstrate that ligand tuning in cobalt-catalyzed hydroamidation enables stereodivergent access to 1,2-isomeric products, even for sterically demanding substrates, thereby serving as a valuable complement to the nickel catalytic system. Conclusion We report a stereodivergent hydroamidation of methylenecyclohexanes, where stereodivergence is enabled by ligand switching to generate differentiated catalytically active species. Specifically, the nickel catalytic system enables efficient synthesis of 1,4- cis/trans , 1,3- cis/trans , and 1,2- cis disubstituted cyclohexanes, while cobalt systems complement this scope by accessing 1,2- cis/trans isomers. Mechanistic experiments and DFT calculations demonstrate that the Ni-H species participates in the competition between hydronickelation and dioxazolone activation steps, which dictates the divergence of reaction pathways. In the ligand L1 system, the steric effect associated with alkene insertion into the Ni-N species governs the formation of the thermodynamically disfavored configuration products. In contrast, in the ligand L30 system, the selectivity of alkene insertion into the Ni-H species is reversed under the influence of C-H···H-C interactions, affording the thermodynamically favored configuration products. The differentiated active species strategy and the ligand steric-electronic principles provide a key case for substituted cycloalkene stereochemistry, guiding future stereoselective catalyst design. Experimental Section General procedure for condition A. In air, a 10 mL Schlenk flask equipped with a magnetic stirrer was charged with L1 (0.024 mmol, 12 mol%), NiCl 2 (DME) (0.020 mmol, 10 mol%), LiCl (0.10 mmol, 50 mol%) and KF (0.60 mmol, 3.0 equiv.). If the alkene or the dioxazolones were solid, they were also added at this time. The Schlenk flask was evacuated and backfilled with argon three times. Then, 1.5 mL of DMAc was added, followed by 0.40 mmol of MeOH (2.0 equiv.), 0.40 mmol of alkene (2.0 equiv., if liquid) and 0.20 mmol of dioxazolones (1.0 equiv., if liquid). The resulting solution was stirred for 2 min at 0 °C. Then, (MeO) 3 SiH (0.60 mmol, 3.0 equiv.) was slowly added dropwise via a syringe. After that, the reaction mixture was stirred at 25 °C for 12 h. The reaction mixture was diluted with H 2 O, followed by extraction with ethyl acetate. The organic layer was dried with anhydrous Na 2 SO 4 , and concentrated in vacuo. The residue was purified by column chromatography on silica gel to deliver the desired products. General procedure for Condition B. In air, a 10 mL Schlenk flask equipped with a magnetic stirrer was charged with L30 (0.024 mmol, 12 mol%), NiCl 2 (DME) (0.020 mmol, 10 mol%), and KF (0.60 mmol, 3.0 equiv.). If the alkene or the dioxazolones were solid, they were also added at this time. The Schlenk flask was evacuated and backfilled with argon three times. Then, 1.5 mL of DMAc was added, followed by 0.40 mmol of t BuOH (2.0 equiv.), 0.40 mmol of alkene (2.0 equiv., if liquid) and 0.20 mmol of dioxazolones (1.0 equiv., if liquid). The resulting solution was stirred for 2 min at 0 °C. Then, (MeO) 3 SiH (0.60 mmol, 3.0 equiv.) was slowly added dropwise via a syringe. After that, the reaction mixture was stirred at 0 °C for 12 h. The reaction mixture was diluted with H 2 O, followed by extraction with ethyl acetate. The organic layer was dried with anhydrous Na 2 SO 4 , and concentrated in vacuo. The residue was purified by column chromatography on silica gel to deliver the desired products. Declarations Data availability Data supporting the findings of this study are available within the article and Supplementary Information. The general information, optimization of reaction conditions, experimental procedures, characterization of all new compounds and computational results are available in the Supplementary Information. Acknowledgment Financial support was received from the National Natural Science Foundation of China (22293011 for Y.F., 22371273 for X.L., 22522115 for X.L., and 22003026 for Q.Q.L.), and the Youth Innovation Promotion Association of the Chinese Academy of Sciences (2023476 for X.L.). The authors acknowledge the supports from the Instruments Center for Physical Science of University of Science and Technology of China and Supercomputing Center of the University of Science and Technology of China. Author contributions X.L. and Y.F. directed the project and conceived of the idea. Z.L. designed and performed the synthetic experiments, Y.Z.T., K.R.D. and B.R.M. helped to complete the experiments. Y.F. directed and Q.Q.L. conducted the DFT calculations. X.L. wrote the manuscript draft. 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Am. Chem. Soc. 147 , 13983-13992 (2025). Li, W. & Zhang, J. Sadphos as Adaptive Ligands in Asymmetric Palladium Catalysis. Acc. Chem. Res. 57 , 489-513 (2024). Pan, Q. et al. Ligand-Controlled, Nickel-Catalyzed Stereodivergent Construction of 1,3-Nonadjacent Stereocenters. J. Am. Chem. Soc. 146 , 15453-15463 (2024). Xu, X.-Y., Liu, L.-G., Xu, L.-C., Zhang, S.-Q. & Hong, X. Transfer Learning-Enabled Ligand Prediction for Ni-Catalyzed Atroposelective Suzuki-Miyaura Cross-Coupling Based on Mechanistic Similarity: Leveraging Pd Knowledge for Ni Discovery. J. Am. Chem. Soc. 147 , 15318-15328 (2025). Lyu, X., Jung, H., Kim, D. & Chang, S. Enantioselective Access to β-Amino Carbonyls via Ni-Catalyzed Formal Olefin Hydroamidation. J. Am. Chem. Soc. 146 , 14745-14753 (2024). Lu, T. & Chen, F. Multiwfn: A multifunctional wavefunction analyzer. J. Comput. Chem. 33 , 580-592 (2012). Lu, T. & Chen, Q. Independent gradient model based on Hirshfeld partition: A new method for visual study of interactions in chemical systems. J. Comput. Chem. 43 , 539-555 (2022). Liu, F., Paton, R. S., Kim, S., Liang, Y. & Houk, K. N. Diels-Alder Reactivities of Strained and Unstrained Cycloalkenes with Normal and Inverse-Electron-Demand Dienes: Activation Barriers and Distortion/Interaction Analysis. J. Am. Chem. Soc. 135 , 15642-15649 (2013). Additional Declarations There is NO Competing Interest. Supplementary Files SupportingInformation20251209.pdf Supporting Information-20251209 Cite Share Download PDF Status: Posted 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. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-8313233","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":571940211,"identity":"1640fad2-0fe9-4960-82f7-82f7b906eaed","order_by":0,"name":"Yao Fu","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAxElEQVRIiWNgGAWjYBAC9gYQWQHl8RCjhecAiDwDVU28FsY2krRI5Bh++DjvsL09+wHGB2/bGOTNidBiLDlz2+HEHp4EZsO5bQyGOxsIaLGXyDGQ5t12OIFHgoFNmreNIcHgABG2/Oadc9geqIX9N7FazKR5Gw4z9gBtYSZOC8+zMssZx9ITe84kNkvOOSdhuIGgFvbkzTc+1Fjbs7cfPvjhTZmNPEFbGBg4DKAMxgYgIUFQPRCwPyBG1SgYBaNgFIxkAABmbDgKLH1+ygAAAABJRU5ErkJggg==","orcid":"https://orcid.org/0000-0003-2282-4839","institution":"University of Science and Technology of China","correspondingAuthor":true,"prefix":"","firstName":"Yao","middleName":"","lastName":"Fu","suffix":""},{"id":571940212,"identity":"b02de845-7efa-4731-a9db-9173b45e181a","order_by":1,"name":"Zhen Li","email":"","orcid":"","institution":"University of Science and Technology of China","correspondingAuthor":false,"prefix":"","firstName":"Zhen","middleName":"","lastName":"Li","suffix":""},{"id":571940213,"identity":"12294201-12b1-4ee7-8045-af54cbe9b450","order_by":2,"name":"Yi-Zhou Tong","email":"","orcid":"","institution":"University of Science and Technology of China","correspondingAuthor":false,"prefix":"","firstName":"Yi-Zhou","middleName":"","lastName":"Tong","suffix":""},{"id":571940214,"identity":"3af82f03-1494-46e7-9ca1-a611b9273083","order_by":3,"name":"Kai-Ran Duan","email":"","orcid":"","institution":"University of Science and Technology of China","correspondingAuthor":false,"prefix":"","firstName":"Kai-Ran","middleName":"","lastName":"Duan","suffix":""},{"id":571940215,"identity":"b6ee16ef-0d5d-42d0-b5e1-f2b4a3663237","order_by":4,"name":"Boru Men","email":"","orcid":"","institution":"University of Science and Technology of China","correspondingAuthor":false,"prefix":"","firstName":"Boru","middleName":"","lastName":"Men","suffix":""},{"id":571940216,"identity":"a326949e-d30c-42e0-9bd7-cdab51586ded","order_by":5,"name":"Qian-Qian Lu","email":"","orcid":"","institution":"Nanjing Agricultural University","correspondingAuthor":false,"prefix":"","firstName":"Qian-Qian","middleName":"","lastName":"Lu","suffix":""},{"id":571940217,"identity":"62f7ed83-7829-4149-a64e-8c6e9d74e306","order_by":6,"name":"Xi Lu","email":"","orcid":"https://orcid.org/0000-0002-9338-0780","institution":"University of Science and Technology of China","correspondingAuthor":false,"prefix":"","firstName":"Xi","middleName":"","lastName":"Lu","suffix":""}],"badges":[],"createdAt":"2025-12-09 05:15:16","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-8313233/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8313233/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":100017782,"identity":"6df62c8f-7520-4d4f-ad5d-5f26c56b96aa","added_by":"auto","created_at":"2026-01-12 07:11:52","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":155524,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eSynthesis of multi-substituted cycloalkanes. a\u003c/strong\u003e, 3D structural characteristics of multi-substituted cyclohexanes and representative analogues. \u003cstrong\u003eb\u003c/strong\u003e, Hydrogenation of polar C=O/C=N bonds is a classic model in cycloalkane stereochemistry. \u003cstrong\u003ec\u003c/strong\u003e, Transition-metal-catalyzed hydrofunctionalization of exocyclic C=C bonds offers opportunities and challenges in diastereodivergent synthesis of multi-substituted cycloalkanes. \u003cstrong\u003ed\u003c/strong\u003e, This work: diastereodivergent hydroamidation of methylenecyclohexanes via differentiated active catalytic species strategy. M, metal; FG, functional group; [N], amido group or other nitrogen-containing functional groups.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-8313233/v1/1d8ca2d1261862a9c3d98f59.png"},{"id":100362727,"identity":"fc893549-5b51-4b77-bae7-d219632eeb4e","added_by":"auto","created_at":"2026-01-16 07:47:57","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":172674,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eReaction development. \u003c/strong\u003eReactions were carried out under an argon atmosphere. Conditions: \u003cstrong\u003e1\u003c/strong\u003e (0.20 mmol, 2.0 equiv), \u003cstrong\u003e2\u003c/strong\u003e(0.10 mmol, 1.0 equiv), metal catalyst (10 mol %), ligand (12 mol %), silane (3.0 equiv), base (3.0 equiv), alcohol (2.0 equiv) solvent (0.133 mol/L), 25 °C, 12 h, 0.1 mmol scales. \u003cem\u003ea\u003c/em\u003e, GC (gas chromatography) yield. Triphenylmethane was used as an internal standard.\u003cem\u003e b\u003c/em\u003e, The facial selectivity was determined by GC analysis. \u003cem\u003ec\u003c/em\u003e, DMAc:\u003cem\u003et\u003c/em\u003eBuOH (\u003cem\u003ev\u003c/em\u003e:\u003cem\u003ev\u003c/em\u003e = 4:1).\u003cem\u003e d\u003c/em\u003e, Isolated yields are given in parentheses. \u003cem\u003et\u003c/em\u003eBu, \u003cem\u003etert\u003c/em\u003e-butyl; Bz, benzoyl; OAc, acetoxy; SCN, thiocyanate; DME, 1,2-dimethoxyethane; BINAP, 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl; DMAc, \u003cem\u003eN\u003c/em\u003e,\u003cem\u003eN\u003c/em\u003e-dimethylacetamide; Bn, benzyl; \u003cem\u003ei\u003c/em\u003ePr, isopropyl; Cy, cyclohexyl; \u003cem\u003es\u003c/em\u003eBu, \u003cem\u003esec\u003c/em\u003e-butyl.\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-8313233/v1/aca94135d2b7f9bc2c0cb0b2.png"},{"id":100017783,"identity":"cba8ea18-ad80-4b7d-b28e-397cab6fed77","added_by":"auto","created_at":"2026-01-12 07:11:52","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":179281,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eSubstrate scope\u003c/strong\u003e\u003cem\u003e\u003cstrong\u003e \u003c/strong\u003e\u003c/em\u003e\u003cstrong\u003eof methylenecyclohexanes.\u003c/strong\u003e For both condition A and condition B, reactions were conducted on 0.20 mmol scales, isolated yield., the facial selectivity was determined by GC analysis. \u003cem\u003ea. \u003c/em\u003e3.0 equivalents alkene were used. \u003cem\u003eb\u003c/em\u003e. Facial selectivity was determined by \u003csup\u003e1\u003c/sup\u003eH NMR (nuclear magnetic resonance) spectroscopic analysis.\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-8313233/v1/1b564f89dea01a3a4ac0a126.png"},{"id":100017780,"identity":"a12cd8d5-53f5-4632-9342-a30d49004bcd","added_by":"auto","created_at":"2026-01-12 07:11:52","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":99678,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eSubstrate scope\u003c/strong\u003e\u003cem\u003e\u003cstrong\u003e \u003c/strong\u003e\u003c/em\u003e\u003cstrong\u003eof dioxazolones. \u003c/strong\u003eFor both condition A and condition B, reactions were conducted on 0.20 mmol scales, isolated yield., the facial selectivity was determined by GC analysis.\u003c/p\u003e","description":"","filename":"4.png","url":"https://assets-eu.researchsquare.com/files/rs-8313233/v1/46b271b33340d6c6fe6b20b9.png"},{"id":100017785,"identity":"ad488cfb-a903-44d8-9d74-7c85a9461b1e","added_by":"auto","created_at":"2026-01-12 07:11:52","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":229461,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eMechanistic investigation. a\u003c/strong\u003e, Hydrogenation of methylenecyclohexanes. \u003cstrong\u003eb\u003c/strong\u003e, Stereodetermining transition states. \u003cstrong\u003ec\u003c/strong\u003e, Independent gradient model based on Hirshfeld partition visualizations. \u003cstrong\u003ed\u003c/strong\u003e, Distortion and interaction analysis. Gibbs free energies were calculated at the M06/6-311+G(d,p)-SDD/SMD//B3LYP/D3(BJ)/6-31G(d)-SDD level of theory. Energies are given in kcal/mol.\u003c/p\u003e","description":"","filename":"5.png","url":"https://assets-eu.researchsquare.com/files/rs-8313233/v1/6fe8ba66ed71476eb618f93b.png"},{"id":100361790,"identity":"29487718-8673-40fa-8c63-24e47c8a83fc","added_by":"auto","created_at":"2026-01-16 07:45:43","extension":"png","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":90900,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eStereodivergent hydroamidation to access 1,2-isomers via cobalt catalysis. \u003c/strong\u003eReactions were conducted on 0.20 mmol scales, isolated yield., the facial selectivity was determined by GC analysis. N.R., no reaction; DEMS, 1,2-dimethoxyethane.\u003c/p\u003e","description":"","filename":"6.png","url":"https://assets-eu.researchsquare.com/files/rs-8313233/v1/36259304a4fb8aae433092aa.png"},{"id":100381336,"identity":"673fed1b-dff2-49c9-ac1f-1d509b65ac0a","added_by":"auto","created_at":"2026-01-16 10:38:18","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1506254,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8313233/v1/b43a2ffc-51b5-403d-a294-4d055395ef3d.pdf"},{"id":100017787,"identity":"1751b729-0a56-4a7c-b77f-b75c5e2177f6","added_by":"auto","created_at":"2026-01-12 07:11:52","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":7987423,"visible":true,"origin":"","legend":"\u003cp\u003eSupporting Information-20251209\u003c/p\u003e","description":"","filename":"SupportingInformation20251209.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8313233/v1/e526c0137de27b4c79fad3d9.pdf"}],"financialInterests":"There is \u003cb\u003eNO\u003c/b\u003e Competing Interest.","formattedTitle":"Diastereodivergent Synthesis of Multi-Substituted Cyclohexanes via Alkene Hydroamidation","fulltext":[{"header":"Introduction","content":"\u003cp\u003eThe construction of three-dimensional (3D) structures of organic molecules is pivotal in modern organic chemistry\u003csup\u003e1,2\u003c/sup\u003e. The tetrahedral carbon configuration theory established a stereochemical framework centered on \u003cem\u003esp\u003c/em\u003e\u003csup\u003e3\u003c/sup\u003e-hybridized carbon, advancing molecular spatial structure study from \u0026ldquo;planar cognition\u0026rdquo; to \u0026ldquo;3D exploration\u0026rdquo;\u003csup\u003e3\u003c/sup\u003e. For disubstituted cyclohexanes, which exist \u003cem\u003ecis-\u003c/em\u003e and \u003cem\u003etrans\u003c/em\u003e- two possible configurations, substituent orientation determines thermodynamic stability and induces significant differences in physicochemical properties and biological activities\u003csup\u003e4,5\u003c/sup\u003e. However, precise stereocontrol of saturated cycloalkane substituents remains challenging\u003csup\u003e6,7\u003c/sup\u003e (Fig. 1a).\u003c/p\u003e\n\u003cp\u003eHydrogenation of exocyclic unsaturations is a classic model for multi-substituted cyclohexane stereochemistry, with substituted cyclohexanone/cyclic imine hydrogenation widely studied\u003csup\u003e8-14\u003c/sup\u003e. Their polar C=O/C=N bonds readily react with metal hydrides, such as sodium borohydride or lithium aluminum hydride\u003csup\u003e15\u003c/sup\u003e, and stereoselectivity is governed by steric and electronic effects\u003csup\u003e16-19\u003c/sup\u003e. In contrast, exocyclic C=C bond stereocontrol is limited: poor polarity matching between hydrides and nonpolar C=C bonds hinders direct addition, and axial/equatorial attack differences are indistinct, complicating selectivity\u003csup\u003e20-24\u003c/sup\u003e (Fig. 1b).\u003c/p\u003e\n\u003cp\u003eTransition-metal catalytic systems offer a potential solution to this challenge: by rationally tuning the metal or ligand, the spatial structure and electronic properties of metal-hydride species or metal-functional group species can be precisely regulated\u003csup\u003e25-31\u003c/sup\u003e. This enables highly selective addition of active species to carbon-carbon double bonds, thereby achieving diastereodivergent synthesis\u003csup\u003e32\u003c/sup\u003e. However, the introduction of transition-metals may be accompanied by side reactions such as alkene isomerization, alkene hydrogenation, and decomposition of functionalization reagents. On the other hand, the complexity of reaction mechanisms increases the uncertainty in selectivity control. Thus, transition-metal-catalyzed hydrofunctionalization of exocyclic C=C bonds presents both opportunities and challenges for the diastereodivergent synthesis of multi-substituted cycloalkanes\u003csup\u003e32,33\u003c/sup\u003e (Fig. 1c).\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;Herein, we achieved the diastereodivergent hydroamidation of methylenecyclohexanes. Specifically, a nickel catalytic system enables efficient synthesis of 1,4-\u003cem\u003ecis\u003c/em\u003e, 1,4-\u003cem\u003etrans\u003c/em\u003e, 1,3-\u003cem\u003ecis\u003c/em\u003e, 1,3-\u003cem\u003etrans\u003c/em\u003e, and 1,2-\u003cem\u003ecis\u003c/em\u003e disubstituted cyclohexanes, while a cobalt system realizes 1,2-\u003cem\u003ecis\u003c/em\u003e and 1,2-\u003cem\u003etrans\u003c/em\u003e stereodivergent synthesis. Mechanistically, the key to the successful control of reaction selectivity lies in the differentiated active catalytic species strategy, which precise regulate the spatial structure and electronic properties of metal-hydride or metal-functional group species. This study not only broadens the chemical space for the multi-substituted cyclohexane synthesis and provides a powerful tool for the synthesis of \u003cem\u003esp\u003c/em\u003e\u003csup\u003e3\u003c/sup\u003e-rich drug molecules, but also offers an important case for \u0026ldquo;substituted cyclohexane stereochemistry\u0026rdquo; in organic chemistry (Fig. 1d).\u003c/p\u003e"},{"header":"Results and discussion","content":"\u003cp\u003e\u003cstrong\u003eReaction development\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe initiated our investigation by employing 1-(\u003cem\u003etert\u003c/em\u003e-butyl)-4-methylenecyclohexane (\u003cstrong\u003e1\u003c/strong\u003e) and 3-phenyl-1,4,2-dioxazol-5-one (\u003cstrong\u003e2\u003c/strong\u003e) as model substrates to explore the diastereodivergent hydroamidation reaction (Fig. 2). Then, \u003cem\u003ecis\u003c/em\u003e-\u003cem\u003eN\u003c/em\u003e-((4-(\u003cem\u003etert\u003c/em\u003e-butyl)cyclohexyl)methyl)benzamide (\u003cstrong\u003e3\u003c/strong\u003e) and \u003cem\u003etrans\u003c/em\u003e-\u003cem\u003eN\u003c/em\u003e-((4-(\u003cem\u003etert\u003c/em\u003e-butyl)cyclohexyl)methyl)benzamide (\u003cstrong\u003e4\u003c/strong\u003e) emerged as our target products. It is worth noting that numerous catalytic systems based on both base metals and noble metals have been proven to exhibit excellent catalytic activity for hydroamidation reactions with dioxazolones\u003csup\u003e34,35\u003c/sup\u003e. For instance, copper-catalyzed and nickel-catalyzed systems are widely recognized for enabling hydroamidation between alkenes and dioxazolones\u003csup\u003e36-40\u003c/sup\u003e. More recently, the Chang group reported that Lewis acid/iron relay catalysis can facilitate the hydroamidation of \u0026alpha;,\u0026beta;-unsaturated esters with dioxazolones\u003csup\u003e41\u003c/sup\u003e. Additionally, cobalt catalysis allows for enantioselective \u003cem\u003eipso\u003c/em\u003e- and migratory hydroamidation of heterocyclic alkenes\u003csup\u003e42\u003c/sup\u003e. Our objective, however, was to identify a suitable catalytic system for the stereodivergent synthesis of multi-substituted cycloalkanes via hydroamidation of methylenecyclohexanes. Thus, discovering an appropriate initial catalytic system from the extensive range of available systems presented both an opportunity and a challenge.\u003c/p\u003e\n\u003cp\u003eBenefiting from high-throughput experiment technology, we were able to rapidly analyze the combinatorial arrangements of different metal catalysts and ligands. We visualized the results of combinations involving 4 catalysts [Fe(OAc)\u003csub\u003e2\u003c/sub\u003e, Co(SCN)\u003csub\u003e2\u003c/sub\u003e, NiCl\u003csub\u003e2\u003c/sub\u003e(DME), and Cu(OAc)\u003csub\u003e2\u003c/sub\u003e] and 7 ligands (\u003cstrong\u003eL1\u003c/strong\u003e, \u003cstrong\u003eL8\u003c/strong\u003e, \u003cstrong\u003eL14\u003c/strong\u003e, \u003cstrong\u003eL15\u003c/strong\u003e, \u003cstrong\u003eL21\u003c/strong\u003e, PPh\u003csub\u003e3\u003c/sub\u003e, and BINAP) in the form of a heatmap. As observed, the iron and copper catalytic systems exhibited almost no catalytic activity toward our model reaction. Similar to our previous findings on hydroalkylation of methylenecyclohexanes, the cobalt-hydride catalytic system also displayed diastereodivergent behavior for the hydroamidation\u003csup\u003e32\u003c/sup\u003e. However, the cobalt-hydride system afforded low yields and unsatisfactory selectivity control (24% yield with 3.1:1 \u003cem\u003ecis\u003c/em\u003e/\u003cem\u003etrans\u003c/em\u003e selectivity for the synthesis of \u003cstrong\u003e3\u003c/strong\u003e and 6% yield with 7.2:1 \u003cem\u003etrans\u003c/em\u003e/\u003cem\u003ecis\u003c/em\u003e selectivity for the synthesis of \u003cstrong\u003e4\u003c/strong\u003e). In contrast, the nickel catalytic system delivered promising initial results for the synthesis of the \u003cem\u003ecis\u003c/em\u003e-isomer (\u003cstrong\u003e3\u003c/strong\u003e), achieving 60% yield and 24:1 \u003cem\u003ecis\u003c/em\u003e/\u003cem\u003etrans\u003c/em\u003e selectivity. Nevertheless, we were unable to obtain \u003cem\u003etrans\u003c/em\u003e-selective product (\u003cstrong\u003e4\u003c/strong\u003e) using the nickel catalytic system under the initial conditions.\u003c/p\u003e\n\u003cp\u003eTo fulfill our research goal, we subsequently conducted extensive ligand screening and condition optimization targeting both the cobalt and nickel catalytic systems. For the cobalt-hydride system, the selectivity could be moderately improved through the modulation of ligands and other conditions (see\u0026nbsp;Supplementary Information\u0026nbsp;for details). However, the reaction efficiency remained low, never exceeding 30% yield. For the nickel catalytic system, we expanded the ligand screening scope to include 125 ligands across 11 categories (see\u0026nbsp;Supplementary Information\u0026nbsp;for details). Among these, the use of \u003cstrong\u003eBiOX\u003c/strong\u003e or \u003cstrong\u003ePyOX\u003c/strong\u003e-type ligands predominantly favored the formation of the \u003cem\u003ecis\u003c/em\u003e-selective product. In contrast, the employment of \u003cstrong\u003eBOX\u003c/strong\u003e, \u003cstrong\u003eBIM\u003c/strong\u003e, and \u003cstrong\u003ePHOX\u003c/strong\u003e-type ligands failed to yield the desired hydroamidation products altogether. Surprisingly, \u003cstrong\u003eSadPhos\u003c/strong\u003e-type ligands\u0026mdash;rarely utilized in nickel-catalyzed reactions\u0026mdash;not only exhibited moderate activity but also achieved a complete reversal of \u003cem\u003etrans\u003c/em\u003e-selectivity\u003csup\u003e43-45\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003eBased on the \u003cstrong\u003eBiOX\u003c/strong\u003e and \u003cstrong\u003eSadPhos\u003c/strong\u003e ligand classes, we obtained the optimal reaction conditions through further meticulous condition screening, which were primarily categorized into two sets. Condition A employs a combination of NiCl\u003csub\u003e2\u003c/sub\u003e(DME) and \u003cstrong\u003eBiOX\u003c/strong\u003e ligand \u003cstrong\u003eL1\u003c/strong\u003e as the precatalyst, (MeO)\u003csub\u003e3\u003c/sub\u003eSiH as the hydrogen source, KF as the base, DMAc as the solvent, and MeOH along with LiCl as additives, conducted at 25 \u0026deg;C. This condition afforded the 1,4-\u003cem\u003ecis\u003c/em\u003e-isomer (\u003cstrong\u003e3\u003c/strong\u003e) with 77% GC yield, 71% isolated yield, and \u0026gt;20:1 \u003cem\u003ecis\u003c/em\u003e/\u003cem\u003etrans\u003c/em\u003e selectivity (entry 1). Condition B, on the other hand, uses NiCl\u003csub\u003e2\u003c/sub\u003e(DME) in combination with \u003cstrong\u003eSadPhos\u003c/strong\u003e ligand \u003cstrong\u003eL30\u003c/strong\u003e as the precatalyst, (MeO)\u003csub\u003e3\u003c/sub\u003eSiH as the hydrogen source, KF as the base, and \u003cem\u003et\u003c/em\u003eBuOH as the solvent, performed at 0 \u0026deg;C. This setup produced the 1,4-\u003cem\u003etrans\u003c/em\u003e-isomer (\u003cstrong\u003e4\u003c/strong\u003e) with 86% GC yield, 78% isolated yield, and 13:1 \u003cem\u003etrans\u003c/em\u003e/\u003cem\u003ecis\u003c/em\u003e selectivity (entry 8). Control experiments revealed that LiCl, as an additive, was beneficial for improving the reaction yield of condition A but significantly diminished the selectivity of condition B\u003csup\u003e46\u003c/sup\u003e. In addition, condition A was sensitive to reaction temperature, with both increases and decreases impairing reaction efficiency. In contrast, for condition B, a lower reaction temperature not only enhanced the reaction yield but also effectively improved the reaction selectivity.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSubstrate scope\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAfter establishing the optimal reaction conditions, we systematically evaluated the substrate scope of nickel-catalyzed hydroamidation of methylenecyclohexane (Fig. 3). Notably, the results demonstrate that the ligand exerts a significant and general regulatory effect on the product configuration. When condition A was employed, 4-substituted and 3-substituted methylenecyclohexanes predominantly afforded thermodynamically disfavored products, namely the 1,4-\u003cem\u003ecis\u003c/em\u003e or 1,3-\u003cem\u003etrans\u003c/em\u003e isomers (\u003cstrong\u003e3\u003c/strong\u003e, \u003cstrong\u003e5\u003c/strong\u003e-\u003cstrong\u003e14\u003c/strong\u003e). In contrast, condition B preferred the formation of thermodynamically favored products, enabling the highly selective synthesis of 1,4-\u003cem\u003etrans\u003c/em\u003e and 1,3-\u003cem\u003ecis\u003c/em\u003e isomers (\u003cstrong\u003e4\u003c/strong\u003e, \u003cstrong\u003e15\u003c/strong\u003e-\u003cstrong\u003e24\u003c/strong\u003e). This reaction system exhibited moderate to excellent yields and diastereoselectivity. Substrate scope investigations revealed that a broad range of substituents at the 4- or 3-position are compatible, including alkyl, aryl, heteroaryl, N or O-containing heterocyclic groups, and ester functionalities. Moreover, the electronic and steric effects of these substituents exerted minimal disruptions on reaction selectivity. To begin with, steric hindrance had no significant impact on diastereoselectivity. For instance, the transition from bulky \u003cem\u003etert\u003c/em\u003e-butyl groups (\u003cstrong\u003e3\u003c/strong\u003e, \u003cstrong\u003e4\u003c/strong\u003e, \u003cstrong\u003e11\u003c/strong\u003e, \u003cstrong\u003e21\u003c/strong\u003e) to moderately hindered isopropyl groups (\u003cstrong\u003e8\u003c/strong\u003e, \u003cstrong\u003e18\u003c/strong\u003e) and even small methyl groups (\u003cstrong\u003e5\u003c/strong\u003e, \u003cstrong\u003e12\u003c/strong\u003e, \u003cstrong\u003e15\u003c/strong\u003e, \u003cstrong\u003e22\u003c/strong\u003e) only resulted in a slight decrease in selectivity. Furthermore, regarding electronic effects, the introduction of different groups such as phenyl (\u003cstrong\u003e7\u003c/strong\u003e, \u003cstrong\u003e13\u003c/strong\u003e, \u003cstrong\u003e16\u003c/strong\u003e, \u003cstrong\u003e23\u003c/strong\u003e), indole (\u003cstrong\u003e14\u003c/strong\u003e, \u003cstrong\u003e24\u003c/strong\u003e), phthalimido (\u003cstrong\u003e6\u003c/strong\u003e, \u003cstrong\u003e20\u003c/strong\u003e), and dioxolane (\u003cstrong\u003e10\u003c/strong\u003e, \u003cstrong\u003e19\u003c/strong\u003e) did not perturb the reaction selectivity. However, the incorporation of ester groups (\u003cstrong\u003e9\u003c/strong\u003e, \u003cstrong\u003e17\u003c/strong\u003e) led to a certain degree of reduced selectivity. This catalytic system was successfully extended to 3,5-disubstituted methylenecyclohexane substrates, achieving diastereodivergent synthesis with access to both thermodynamically disfavored and favored products (\u003cstrong\u003e25\u003c/strong\u003e, \u003cstrong\u003e26\u003c/strong\u003e). In addition, we attempted to apply this nickel-catalyzed system to 2-substituted methylenecyclohexane. We successfully obtained the 1,2-\u003cem\u003ecis\u003c/em\u003e configured products (\u003cstrong\u003e27\u003c/strong\u003e, \u003cstrong\u003e28\u003c/strong\u003e) using condition A; however, when using condition B, not only was the yield significantly reduced, but the selectivity also became uncontrollable. Finally, the configurations of 9 representative products (\u003cstrong\u003e3\u003c/strong\u003e, \u003cstrong\u003e5\u003c/strong\u003e, \u003cstrong\u003e7\u003c/strong\u003e, \u003cstrong\u003e13\u003c/strong\u003e, \u003cstrong\u003e15\u003c/strong\u003e, \u003cstrong\u003e16\u003c/strong\u003e, \u003cstrong\u003e22\u003c/strong\u003e, \u003cstrong\u003e24\u003c/strong\u003e, and \u003cstrong\u003e28\u003c/strong\u003e) were determined by single-crystal X-ray diffraction. The configuration of other products is inferred by analogy.\u003c/p\u003e\n\u003cp\u003eTo further advance the investigation, we examined the scope of the amidation reagent dioxazolone (Fig. 4). It was found that upon replacing the phenyl substituent in the model substrate 3-phenyl-1,4,2-dioxazol-5-one, a broad range of substrates\u0026mdash;whether bearing electron-deficient aryl (\u003cstrong\u003e29\u003c/strong\u003e, \u003cstrong\u003e35\u003c/strong\u003e), electron-rich aryl (\u003cstrong\u003e30\u003c/strong\u003e, \u003cstrong\u003e36\u003c/strong\u003e), heteroaryl (\u003cstrong\u003e32\u003c/strong\u003e, \u003cstrong\u003e38\u003c/strong\u003e), or alkyl (\u003cstrong\u003e34\u003c/strong\u003e, \u003cstrong\u003e39\u003c/strong\u003e, \u003cstrong\u003e40\u003c/strong\u003e) groups\u0026mdash;could be smoothly converted to the target products, with moderate to excellent yields and diastereoselectivity consistently retained. It is worth noting that, to extend the applicability to a broader range of dioxazolone derivatives, the ratio of dioxazolone derivatives to methylenecyclohexane was appropriately adjusted from 1:2 to 1:3.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMechanistic investigation\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTo gain insights into the stereodivergent hydroamidation reaction, hydrogenation experiments were conducted using alkene \u003cstrong\u003e41\u003c/strong\u003e in the absence of dioxazolones under both condition A and condition B (Fig. 5a). Under both reaction conditions, the alkene hydrogenation products, \u003cstrong\u003e42\u003c/strong\u003e and \u003cstrong\u003e43\u003c/strong\u003e, were observed along with partial residual starting material \u003cstrong\u003e41\u003c/strong\u003e, while a substantial amount of alkene isomerization product (\u003cstrong\u003e44\u003c/strong\u003e) was detected under condition B. Notably, under condition A, the \u003cem\u003ecis/trans\u003c/em\u003e selectivity of the hydrogenation products (\u003cem\u003ecis/trans\u003c/em\u003e = 4.0:1) was significantly reduced compared to that of hydroamidation products (\u003cem\u003ecis/trans\u003c/em\u003e = 16:1), whereas no substantial difference in \u003cem\u003etrans/cis\u003c/em\u003e selectivity was observed between the hydrogenation and hydroamidation products under condition B (\u003cem\u003etrans/cis\u003c/em\u003e = 9.0:1 for hydrogenation products, \u003cem\u003etrans/cis\u003c/em\u003e = 10:1 for hydroamidation products). These results suggest that distinct catalytically active species may be involved in the two hydroamidation catalytic systems. When using the ligand \u003cstrong\u003eL1\u003c/strong\u003e, the significant steric effect of the Ni-N species in the presence of dioxazolones leads to excellent \u003cem\u003ecis\u003c/em\u003e-selectivity of the reaction; whereas in the absence of dioxazolones, the Ni-H species exhibits no advantage in facial selectivity control. In contrast, the scenario differs when the ligand \u003cstrong\u003eL30\u003c/strong\u003e is employed\u0026mdash;the absence of significant selectivity differences between hydrogenation and hydroamidation is more consistent with the hypothesis that the stereochemical outcome of the reaction is directly dictated by the insertion of the alkene into the Ni-H species. In addition, to obtain experimental evidence for the generation of a putative nickel nitrenoid intermediate within the catalytic system, a trapping experiment was performed (see\u0026nbsp;Supplementary Information\u0026nbsp;for details). Consistent with expectations, iminophosphorane was formed in both condition A and B, whereas it was not generated in the absence of the nickel catalyst.\u003c/p\u003e\n\u003cp\u003eBased on these\u0026nbsp;experimental evidences, density functional theory (DFT) calculations were performed to elucidate the mechanistic origins of the stereodivergent hydroamidation reactions. Through comparing the hydronickelation and dioxazolone activation steps, \u003cstrong\u003eL1-Ni\u003csup\u003eII\u003c/sup\u003e-NHCOPh\u003c/strong\u003e and \u003cstrong\u003eL30-Ni\u003csup\u003eII\u003c/sup\u003e-H\u003c/strong\u003e were proposed as the active species for condition A and condition B, respectively (see\u0026nbsp;Supplementary Information\u0026nbsp;for details). In this context, we calculated the equatorial and axial transition states for alkene insertion. As shown in Fig. 5b, the equatorial transition state of alkene insertion \u003cstrong\u003eL1-TS4-\u003cem\u003ecis\u003c/em\u003e\u003c/strong\u003e is 8.7 kcal/mol lower than the axial transition state \u003cstrong\u003eL1-TS4-\u003cem\u003etrans\u003c/em\u003e\u003c/strong\u003e, indicating 1,4-\u003cem\u003ecis\u003c/em\u003e hydroamidation product as the main product under condition A. In contrast, 1,4-\u003cem\u003etrans\u003c/em\u003e hydroamidation product would be delivered in the condition B catalytic system due to the lower energy of \u003cstrong\u003eL30-TS3-\u003cem\u003etrans\u003c/em\u003e\u003c/strong\u003e.\u003c/p\u003e\n\u003cp\u003eFurthermore, independent gradient model-Hirshfeld (IGMH) visualizations\u003csup\u003e47,48\u003c/sup\u003e revealed that both \u003cstrong\u003eL1-TS4-\u003cem\u003ecis\u003c/em\u003e\u003c/strong\u003e and \u003cstrong\u003eL1-TS4-\u003cem\u003etrans\u003c/em\u003e\u003c/strong\u003e exhibit weak interactions such as C-H\u0026middot;\u0026middot;\u0026middot;O and C-H\u0026middot;\u0026middot;\u0026middot;Cl, without showing significant differences. In contrast, \u003cstrong\u003eL30-TS3-\u003cem\u003etrans\u003c/em\u003e\u003c/strong\u003e involves more C-H\u0026middot;\u0026middot;\u0026middot;H-C interactions between ligand and alkene, indicating the crucial role of electronic interactions in directing the formation of the \u003cem\u003etrans\u003c/em\u003e-selective product (Fig. 5c).\u0026nbsp;In the distortion and interaction energy analysis (Fig. 5d), alkene distortion energy is consistently larger in the axial transition states of alkene insertion (\u003cstrong\u003eL1-TS4-\u003cem\u003etrans\u003c/em\u003e\u003c/strong\u003e and \u003cstrong\u003eL30-TS3-\u003cem\u003etrans\u003c/em\u003e\u003c/strong\u003e) in both condition A and condition B catalytic systems, highlighting the steric disfavorability of the axial reaction pathway\u003csup\u003e49\u003c/sup\u003e. Further analysis reveals that the distortion effect dominates in \u003cstrong\u003eL1-TS4\u003c/strong\u003e, whereas the interaction effect prevails in \u003cstrong\u003eL30-TS3\u003c/strong\u003e. Consistent with IGMH analysis, these results indicate that the selectivity of condition B is attributed to favorable\u0026nbsp;C-H\u0026middot;\u0026middot;\u0026middot;H-C\u0026nbsp;interactions that promote the formation of 1,4-\u003cem\u003etrans\u003c/em\u003e products, while the preferred selectivity of condition A is driven by steric hindrance, leading to the formation of 1,4-\u003cem\u003ecis\u003c/em\u003e products.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eReaction expansion.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFinally, we analyzed the differences between the nickel catalytic system developed in this work and the previously established cobalt catalytic system through the hydroamidation of 2-substituted methylenecyclohexanes (Fig. 6). In the context of stereodivergent hydrogenation of exocyclic unsaturations, substrates with bulky substituents at the 2-position\u0026mdash;including not only methylenecyclohexanes but also 2-substituted cyclohexanones\u0026mdash;pose significant challenges. The underlying reason is that axial attack is hindered by the bulky group at the 2-position. As expected, our nickel catalytic system exclusively afforded 1,2-\u003cem\u003ecis\u003c/em\u003e isomers via equatorial attack. Moreover, the combination of sterically hindered \u003cstrong\u003eSadPhos\u003c/strong\u003e ligand and the mechanism involving alkene insertion into Ni-N active species resulted in a complete inability to obtain 1,2-\u003cem\u003etrans\u003c/em\u003e selective products. In contrast, cobalt-catalyzed systems exhibit remarkable stereocontrol and achieve stereodivergent hydroamidation, which may involve alkene insertion into Co-H active species. Using a precatalyst composed of Co(SCN)\u003csub\u003e2\u003c/sub\u003e and the \u003cstrong\u003eBOX\u003c/strong\u003e ligand \u003cstrong\u003eL14\u003c/strong\u003e, with DEMS as the hydrogen source, K\u003csub\u003e3\u003c/sub\u003ePO\u003csub\u003e4\u003c/sub\u003e as the base, THF as the solvent, and MeOH as an additive, the reaction at 0 \u0026deg;C yielded product \u003cstrong\u003e27\u003c/strong\u003e in 45% yield with \u0026gt;20:1 \u003cem\u003ecis\u003c/em\u003e/\u003cem\u003etrans\u003c/em\u003e selectivity. When the \u003cstrong\u003ePHOX\u003c/strong\u003e ligand \u003cstrong\u003eL21\u003c/strong\u003e was used under otherwise identical conditions, product \u003cstrong\u003e47\u003c/strong\u003e was obtained in 26% yield with \u0026gt;20:1 \u003cem\u003etrans\u003c/em\u003e/\u003cem\u003ecis\u003c/em\u003e selectivity. These results demonstrate that ligand tuning in cobalt-catalyzed hydroamidation enables stereodivergent access to 1,2-isomeric products, even for sterically demanding substrates, thereby serving as a valuable complement to the nickel catalytic system.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eWe report a stereodivergent hydroamidation of methylenecyclohexanes, where stereodivergence is enabled by ligand switching to generate differentiated catalytically active species.\u0026nbsp;Specifically, the nickel catalytic system enables efficient synthesis of 1,4-\u003cem\u003ecis/trans\u003c/em\u003e, 1,3-\u003cem\u003ecis/trans\u003c/em\u003e, and 1,2-\u003cem\u003ecis\u003c/em\u003e disubstituted cyclohexanes, while cobalt systems complement this scope by accessing 1,2-\u003cem\u003ecis/trans\u003c/em\u003e isomers. Mechanistic experiments and DFT calculations demonstrate that the Ni-H species participates in the competition between hydronickelation and dioxazolone activation steps, which dictates the divergence of reaction pathways. In the ligand \u003cstrong\u003eL1\u003c/strong\u003e system, the steric effect associated with alkene insertion into the Ni-N species governs the formation of the thermodynamically disfavored configuration products. In contrast, in the ligand \u003cstrong\u003eL30\u003c/strong\u003e system, the selectivity of alkene insertion into the Ni-H species is reversed under the influence of C-H\u0026middot;\u0026middot;\u0026middot;H-C interactions, affording the thermodynamically favored configuration products. The differentiated active species strategy and the ligand steric-electronic principles provide a key case for substituted cycloalkene stereochemistry, guiding future stereoselective catalyst design.\u003c/p\u003e"},{"header":"Experimental Section","content":"\u003cp\u003e\u003cstrong\u003eGeneral procedure for condition A.\u0026nbsp;\u003c/strong\u003eIn air, a 10 mL Schlenk flask equipped with a magnetic stirrer was charged with \u003cstrong\u003eL1\u003c/strong\u003e (0.024 mmol, 12 mol%), NiCl\u003csub\u003e2\u003c/sub\u003e(DME) (0.020 mmol, 10 mol%), LiCl (0.10 mmol, 50 mol%) and KF (0.60 mmol, 3.0 equiv.).\u0026nbsp;If the alkene or the dioxazolones were solid, they were also added at this time. The Schlenk flask was evacuated and backfilled with argon three times. Then, 1.5 mL of DMAc was added, followed by 0.40 mmol of MeOH (2.0 equiv.), 0.40 mmol of alkene (2.0 equiv., if liquid) and 0.20 mmol of dioxazolones (1.0 equiv., if liquid). The resulting solution was stirred for 2 min at 0 \u0026deg;C. Then, (MeO)\u003csub\u003e3\u003c/sub\u003eSiH (0.60 mmol, 3.0 equiv.) was slowly added dropwise via a syringe. After that, the reaction mixture was stirred at 25 \u0026deg;C for 12 h. The reaction mixture was diluted with H\u003csub\u003e2\u003c/sub\u003eO, followed by extraction with ethyl acetate. The organic layer was dried with anhydrous Na\u003csub\u003e2\u003c/sub\u003eSO\u003csub\u003e4\u003c/sub\u003e, and concentrated in vacuo. The residue was purified by column chromatography on silica gel to deliver the desired products.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eGeneral procedure for Condition B.\u0026nbsp;\u003c/strong\u003eIn air, a 10 mL Schlenk flask equipped with a magnetic stirrer was charged with \u003cstrong\u003eL30\u003c/strong\u003e (0.024 mmol, 12 mol%), NiCl\u003csub\u003e2\u003c/sub\u003e(DME) (0.020 mmol, 10 mol%), and KF (0.60 mmol, 3.0 equiv.).\u0026nbsp;If the alkene or the dioxazolones were solid, they were also added at this time. The Schlenk flask was evacuated and backfilled with argon three times. Then, 1.5 mL of DMAc was added, followed by 0.40 mmol of \u003cem\u003et\u003c/em\u003eBuOH (2.0 equiv.), 0.40 mmol of alkene (2.0 equiv., if liquid) and 0.20 mmol of dioxazolones (1.0 equiv., if liquid). The resulting solution was stirred for 2 min at 0 \u0026deg;C. Then, (MeO)\u003csub\u003e3\u003c/sub\u003eSiH (0.60 mmol, 3.0 equiv.) was slowly added dropwise via a syringe. After that, the reaction mixture was stirred at 0 \u0026deg;C for 12 h. The reaction mixture was diluted with H\u003csub\u003e2\u003c/sub\u003eO, followed by extraction with ethyl acetate. The organic layer was dried with anhydrous Na\u003csub\u003e2\u003c/sub\u003eSO\u003csub\u003e4\u003c/sub\u003e, and concentrated in vacuo. The residue was purified by column chromatography on silica gel to deliver the desired products.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eData availability\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eData supporting the findings of this study are available within the article and Supplementary Information. The general information, optimization of reaction conditions, experimental procedures, characterization of all new compounds and computational results are available in the Supplementary Information.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgment\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFinancial support was received from the National Natural Science Foundation of China (22293011 for Y.F., 22371273 for X.L., 22522115 for X.L., and 22003026 for Q.Q.L.), and the Youth Innovation Promotion Association of the Chinese Academy of Sciences (2023476 for X.L.). The authors acknowledge the supports from the Instruments Center for Physical Science of University of Science and Technology of China and Supercomputing Center of the University of Science and Technology of China.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eX.L. and Y.F. directed the project and conceived of the idea. Z.L. designed and performed the synthetic experiments, Y.Z.T., K.R.D. and B.R.M. helped to complete the experiments. Y.F. directed and Q.Q.L. conducted the DFT calculations. X.L. wrote the manuscript draft. All the authors participated in the discussion and preparation of the paper.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare no competing interests.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eKellogg, R. M. Practical Stereochemistry. \u003cem\u003eAcc. Chem. Res.\u003c/em\u003e \u003cstrong\u003e50\u003c/strong\u003e, 905-914 (2017).\u003c/li\u003e\n\u003cli\u003eMitra, A. K. Journey through the ages: historical milestones in organic stereochemistry. \u003cem\u003eChemTexts\u003c/em\u003e \u003cstrong\u003e11\u003c/strong\u003e, 10 (2025).\u003c/li\u003e\n\u003cli\u003eMeijer, E. W. 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Soc.\u003c/em\u003e \u003cstrong\u003e135\u003c/strong\u003e, 15642-15649 (2013).\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-8313233/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8313233/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"The construction of three-dimensional (3D) organic molecular structures is pivotal in modern organic chemistry. For disubstituted cyclohexanes, substituent orientation dictates thermodynamic stability, physicochemical properties, and biological activities, but precise stereocontrol of saturated cycloalkane substituents is challenging. Hydrogenation of substituted cyclohexanones/cyclic imines is a classic model for multi-substituted cyclohexane stereochemistry, in which stereoselectivity is governed by steric and electronic effects. In contrast, stereocontrol of exocyclic C=C bonds remains a major hurdle. Herein, we achieved diastereodivergent hydroamidation of methylenecyclohexanes: a nickel catalytic system efficiently synthesizes 1,4-cis/trans and 1,3-cis/trans isomers, while a cobalt system realizes 1,2-cis/trans stereodivergence. The core achievement lies in the differentiated active catalytic species strategy, which precisely regulates the spatial structure and electronic properties of metal-hydride or metal-functional group species. This work broadens the chemical space for multi-substituted cyclohexane synthesis, provides a powerful tool for the preparation of sp3-rich drug molecules, and offers an important case for research on substituted cyclohexane stereochemistry.","manuscriptTitle":"Diastereodivergent Synthesis of Multi-Substituted Cyclohexanes via Alkene Hydroamidation","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-01-12 07:11:41","doi":"10.21203/rs.3.rs-8313233/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"e7826361-b6e4-4645-a894-a4457fca0f9a","owner":[],"postedDate":"January 12th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":60865455,"name":"Physical sciences/Chemistry/Organic chemistry/Stereochemistry"},{"id":60865456,"name":"Physical sciences/Chemistry/Organic chemistry/Synthetic chemistry methodology"},{"id":60865457,"name":"Physical sciences/Chemistry/Organic chemistry/Reaction mechanisms"}],"tags":[],"updatedAt":"2026-01-12T07:11:50+00:00","versionOfRecord":[],"versionCreatedAt":"2026-01-12 07:11:41","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8313233","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8313233","identity":"rs-8313233","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}