Synthesis of α,β-unsaturated ketones through nickel-catalysed aldehyde-free hydroacylation of alkynes

Synthesis of α,β-unsaturated ketones through nickel-catalysed aldehyde-free hydroacylation of alkynes | 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 Synthesis of α,β-unsaturated ketones through nickel-catalysed aldehyde-free hydroacylation of alkynes Joon Ho Rhlee, Saikat Maiti, Ho Seung Lee, Soochan Lee, Jaehyun Park, and 6 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-108963/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 03 Feb, 2022 Read the published version in Communications Chemistry → Version 1 posted You are reading this latest preprint version Abstract α,β-Unsaturated ketones are common feedstocks in functional materials, pharmaceuticals and natural compounds. Transition metal-catalysed hydroacylation reactions of alkynes using aldehydes have been widely applied for the atom-economical synthesis of α,β-unsaturated ketones through chemoselective aldehydic C–H activation. However, previous hydroacylation reactions using rhodium, cobalt, or ruthenium catalysts require chelating moiety-bearing aldehydes to prevent undesired decarbonylative product via an unstable acyl-metal-H complex. Herein, we report a nickel-catalysed reductive and anti-Markovnikov selective coupling process to afford non-tethered E-enones from terminal alkynes through an acyl-nickel-thiopyridine complex in the presence of zinc metal as a reducing agent. Utilization of a thioester as an acylating agent and water as a hydrogen donor enables this mechanistically distinctive and aldehyde-free hydroacylation of terminal alkynes under mild reaction conditions at room temperature, with a broad substrate scope including versatile functional groups and even simple aryl and alkyl moieties. Organic Chemistry Catalysis Feedstocks Atom-economical Synthesis Anti-Markovnikov Selective Coupling Mechanistic Distinction Figures Figure 1 Figure 2 Figure 3 Introduction α,β-Unsaturated ketones have been extensively applied as versatile compounds in synthetic organic chemistry, for example, as key substrates for conjugate addition 1–4 , Morita–Baylis–Hillman 5,6 , Diels–Alder 7,8 , and epoxidation 9–11 reactions. They have been conventionally prepared through aldol condensation 12 , Horner–Wadsworth–Emmons olefination 13 , the dehydrogenation of ketones 14,15 , or palladium-catalysed carbonylation 16,17 reactions. However, these methods often require pre-functionalized substrates or operate through multi-step sequences. Alkynes have widely applied as readily available synthetic platforms for catalytic transformations to directly access functionalized cyclic or acyclic products 18 –22 . The catalytic hydroacylation of alkynes using aldehydes inherently provides an atom-economical process leading to the formation of enones. Organocatalytic intramolecular hydroacylation reactions of alkynes using organophosphines or N -heterocyclic carbenes have been demonstrated (Fig. 1a) 23 –25 . Metal-catalysed intermolecular hydroacylation has emerged as a prominent method for rapidly accessing E -enones through alkyne–aldehyde coupling 26 –31 . This atom-economical method involves the chemoselective activation of an aldehydic C( sp 2 )–H, and chelating moiety-bearing aldehydes have been applied to prevent decarbonylative side pathways (Fig. 1b). Stabilization of an acyl-metal complex assisted by heteroatom chelation is a powerful strategy for obtaining E -enones. However, the installation and removal of the coordinating moieties entailed extra synthetic steps while reducing the step economy of the hydrofunctionalization. Though nondirected hydroacylation methods have been developed for alkenes or dienes 32–36 , to our knowledge, there is no general hydroacylation method for unactivated terminal alkynes that lead to chelating moiety-free E -enones. Recently, the Weix group reported that 2-thiopyridyl esters act as potential acyl donors for cross-electrophile coupling reactions 37 . We surmised that a thioester may act as both a transient thiopyridyl (SPy) ligand and an acyl component under nickel-catalysed reductive coupling conditions to lead to acyl-Ni-SPy complex. A consecutive alkyne insertion and subsequent protodemetalation process may lead to hydroacylation product formation (Fig. 1c). However, the challenges of this anticipated reaction process to attain traceless alkyne hydroacylation are fourfold: (i) competition with non-conjunctive cross-electrophile (proton and thioester) coupling, (ii) reduction of substrates, (iii) iterative alkyne additions, and (vi) regio- and stereoselectivity issues. Therefore, precise reactivity and selectivity control is crucial for a general approach to the hydroacylation of unactivated terminal alkynes. Results Optimisation studies. To optimize the reaction conditions, S -(pyridin-2-yl) 4-methoxybenzothioate ( 1 ) and 3,3-dimethyl-1-butyne ( 2 ) were chosen as model substrates, and a thorough screening of catalysts, reducing agents, additives, and solvents was conducted (Table 1, see also the Supplementary Information, Section III). The standard conditions were established on the basis of inexpensive nickel(II) perchlorate hexahydrate, Zn, and ZnCl 2 in 1,2-DME to exclusively afford E -enone 3 in 81% isolated yield at room temperature (entry 1). The use of THF resulted in a similar yield (entry 2). Interestingly, coordinated water molecules were also found to be a suitable proton source (entries 3–5). The use of 17 mol% of Ni catalyst was appropriate for providing a stoichiometric 1 equiv of protons to the reaction. No desired product formation was observed in the absence of the nickel catalyst, Zn, or ZnCl 2 (entries 6–8). Mn as the reducing agent instead of Zn also appeared successful; however, this resulted in a diminished yield (entry 9). ZnCl 2 was found to be superior to MgCl 2 (entry 10). Using 1.5 equiv of terminal alkyne 2 was required for better conversion of the thioester (entry 11). The standard optimized reaction conditions were developed under an inert argon atmosphere; however, a significant amount of product formation was observed even under open atmosphere conditions (entry 12). Reduced reaction time or a decreased amount of Ni catalyst led to diminished yields (entries 13, 14). In addition, the employment of acyl chloride or aldehyde as an acyl donor instead of thioester appeared to be completely unproductive (entries 15, 16). Additional ligands in the hydroacylation resulted in slightly diminished yields (entries 17, 18). Scope of the reaction. With the optimized conditions in hand, we set out to explore the generality of this alkyne hydroacylation by determining the thioester scope (Table 2). Various alkyl substituents worked well to afford E -enone products ( 5 – 8 ) in moderate to good yields. Hydrogen and phenyl groups, however, led to slightly lower yields ( 4 , 9 ). Generally, electron donating groups gave the products in moderate to good yields ( 10 – 13 ). Although yields were low, halide groups were tolerated in the reaction ( 14 – 16 ). Electron withdrawing groups such as CO 2 Me and CF 3 led to products ( 17 , 18 ) with low yields. Meta - and ortho -substitution patterns also provided the products in moderate yields ( 19 – 24 ). A 2-naphthyl substituent afforded the product in a slightly higher yield (44%) than a 1-naphthyl substituent (32%) ( 25 , 26 ). An electron-rich indole substituent led to product 27 with 82% yield. Both acyclic- and cyclic aliphatic substituents could access the products with moderate yields ( 28 – 32 ). We then examined the scope of a wide range of alkynes. Acyclic- as well as cyclic aliphatic terminal alkynes underwent the reaction to afford the corresponding vinyl ketones ( 33 – 3 8 ) in moderate yields, although cyclopropyl- and cyclopentyl-derived alkynes gave the diminished yields. Aromatic alkynes bearing alkyl, phenyl, and phenoxy substituents worked well to give the desired products ( 39 – 45 ) with moderate to good yields. Ortho -, meta -, and para -substituted methoxy groups were also tolerated to obtain the products ( 46 – 48 ). Product 49 was isolated in 55% yield by using a disubstituted arylalkyne. Fluoro- and chloro- groups were examined and gave 50 and 51 in 69% and 56% yields, respectively. The strongly electron withdrawing trifluoromethyl group led to product formation ( 52 , 53 ) with diminished yields. 2-Ethylnyl-6-methoxy-naphthalene efficiently produced 54 in 76% yield. 2-Ethynylthiophene and 3-ethynylthiophene underwent the reaction smoothly to obtain the corresponding products ( 55 , 56 ) in 39% and 58% yields, respectively. A free hydroxyl group was compatible affording 57 in 62% yield. We were delighted to find that the reaction was feasible with ethisterone, an agent for gynecological disease treatment, to afford 58 in 56% yield. The chemistry was also operative on a 1 mmol scale to give a similar yield. Interestingly, symmetrical as well as unsymmetrical internal alkynes gave hydroacylation products ( 59 – 61 ), albeit in low yields. Activated alkenes also underwent the reaction very smoothly to afford 62 – 64 in good yields. Mechanistic investigations and deuterium labeling experiments. Control experiments were conducted to gain the insight into the reaction pathway. When TEMPO was added under the standard reaction conditions, the desired hydroacylation completely shut down and an acyl-TEMPO adduct ( 65 ) was isolated in 70% yield. This study corroborates the involvement of an acyl radical intermediate during the course of the reaction (Fig. 2a). Remarkably, formation of the acyl-TEMPO adduct was also observed by employing Zn and ZnCl 2 in the absence of any nickel catalyst, indicating its role in acyl radical generation from the thioester through single-electron transfer (SET). The formation of hydroacylation product 60 suggests the protodemetalation of nucleophilic vinyl nickel complex I 38 . Interestingly, formation of 66 was also observed verifying an iterative double alkyne insertion (Fig. 2b). In addition to this, cyclic product 67 was isolated illustrating the intermediacy of vinyl nickel species II 39,40 . To identify the proton source of the hydroacylation, deuterium labeling tests were performed (Fig. 2c). First, a reaction conducted using deuterium oxide (3.0 equiv) resulted in formation of the product with 64% and 33% [D] incorporation at the b- and α-positions, respectively, of unsaturated ketone [D]- 3 . Employing deuterated nickel(II) perchlorate hexahydrate resulted in the similar ratio of ~1.9:1 (i.e. 38%:20%, see also the Supplementary Information, Section V). To confirm the non-involvement of solvent molecules, we performed the hydroacylation reaction using deuterated THF, and no D-incorporation was detected in the final product. The employment of terminally deuterated alkyne [D]- 2 for the Ni-catalysed reductive coupling reaction also demonstrated H–D exchange resulting from the weak acidity of the terminal alkyne 41,42 . Proposed mechanism. Based on the above mechanistic studies and findings from previous reports 38 –40,43,44 , we proposed a reaction pathway for this reductive hydroacylation as illustrated in Fig. 3. The reaction is initiated by the generation of an acyl radical and a thiopyridyl anion through the single-electron reduction of a redox-active thioester promoted by Zn and ZnCl 2 . The SPy anion can undergo a consecutive ligand exchange reaction with the nickel(I)X A , which is generated in-situ from the reduction of the Ni(II)X 2 pre-catalyst by Zn/ZnCl 2 . Engagement of the acyl radical with intermediate A directs the formation of acyl-Ni(II)-X complex B . Migratory insertion of terminal alkynes gives rise to vinyl nickel complex D . Then, protodemetalation of nucleophilic vinyl Ni(II) species D with the help of water affords the desired E -enone 38 . The reduction of Ni(II)(OH)X species E by zinc regenerates the active Ni(I) species A . Conclusions In summary, we have demonstrated a nickel-catalysed hydroacylation approach using terminal alkynes to exclusively afford non-tethered E -enones. This nondirected and aldehyde-free process proceeds by the single-electron reduction of a redox-active 2-pyridyl thioester to give an acyl radical that is promoted by Zn/ZnCl 2 . It requires neither additional steps for removal of the coordinating group, nor use of a nucleophilic hydride source, further enhancing the efficacy of the method. We anticipate that these Ni-catalysed reductive hydroacylation reactions will have an impact on synthesizing important synthetic intermediates, functional materials and pharmaceuticals. Methods General experimental procedure for E -enones. A 1-dram screw-cap vial equipped with a magnetic stir bar was charged with thioester (0.2 mmol, 1.0 equiv), Zn (33 mg, 0.5 mmol, 2.5 equiv), ZnCl 2 (27 mg, 0.2 mmol, 1.0 equiv), and Ni(ClO 4 ) 2 ·6H 2 O (12 mg, 0.034 mmol, 17 mol%) inside a glove box. The mixture was dissolved in 1,2-DME (1 mL). Then, alkyne (0.3 mmol, 1.5 equiv) was added. The reaction mixture was stirred for 24 h at room temperature. After completion of the reaction, the mixture was purified by flash column chromatography to afford the desired product. Data availability Detailed experimental procedures, HRMS-ESI data and NMR spectra (PDF) for all compounds were provided in the Supplementary Information. Single crystal X-ray data for 27 and 67 (CIF) are available free of charge from the Cambridge Crystallographic Database Centre (CCDC) under reference numbers 2039192 and 2036543. References Wu, H., Garcia, J. M., Haeffner, F., Radomkit, S., Zhugralin, A. R. & Hoveyda, A. H. 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W.C. acknowledges Pohang Accelerator Laboratory for 2D beamline use (2020-3rd-2D-012). S.M. is grateful for the financial support from the Institute of Basic Science (IBS-R022-D1) Korea. Author contributions J.H.R., S.M., K.M., and S.Y.H. conceived the project. J.H.R., S.M., and H.S.L. prepared substrates, and examined the catalytic reactions. S.L. and W.C. solved single crystal X-ray structures of compounds 27 and 67 . J.H.R., J.P., S.J.K., Y.S.K., and J.K.S. worked on analytical sections for the mechanistic and deuterium labeling experiments. J.H.R., S.M., and S.Y.H. wrote the manuscript. All authors discussed results and provided input on the manuscript. Competing interests The authors declare no competing interests. Tables Tables 1 and 2 are available in the Supplementary Files. Additional Declarations There is NO Competing Interest. Supplementary Files CommunChemSIfinal.docx Supplementary Information Tables.docx Tables 1 and 2 compound67checkcif.pdf compound 67 checkcif compound27checkcif.pdf compound 27 checkcif Cite Share Download PDF Status: Published Journal Publication published 03 Feb, 2022 Read the published version in Communications Chemistry → 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. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. 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-108963","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":7991597,"identity":"559696ee-cd48-42ad-885e-e8460fb3187a","order_by":0,"name":"Joon Ho Rhlee","email":"","orcid":"","institution":"Ulsan National Institute of Science and Technology","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Joon","middleName":"Ho","lastName":"Rhlee","suffix":""},{"id":7991598,"identity":"d4a1d8cf-4b1e-4e60-a782-d00b39617027","order_by":1,"name":"Saikat Maiti","email":"","orcid":"","institution":"Ulsan National Institute of 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Hong","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA10lEQVRIiWNgGAWjYFACHhBhw8DADOVLEKklDaSFsYEULYdBBJFa5GfkHnxc8Ot84nZ29ucPGGrsGCRnH8CvxeBGXrLxzL7biTubeQwbGI4lM0jzJRDQIpFjJs3bcztxw2EeoMPYDjDI8RB0GFjLOaAW9ocNDP+I0MJwA6iF58cBoBYGwwbGtgMM0oS0GJx5Y2zM25BsDHSY4YzEvmQeyR5CDmvPMXzM88dOdsP54w8+fPhmJydxhpDDBBKAEdIG5SRAowk/4D8AJP4QVjcKRsEoGAUjGAAAvqk/1AkU4l0AAAAASUVORK5CYII=","orcid":"https://orcid.org/0000-0002-5785-4475","institution":"Ulsan National Institute of Science and Technology","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Sung","middleName":"You","lastName":"Hong","suffix":""}],"badges":[],"createdAt":"2020-11-16 09:40:37","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-108963/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-108963/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1038/s42004-022-00633-3","type":"published","date":"2022-02-03T13:26:07+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":4931565,"identity":"e8cadbad-b337-4813-a89d-8dc8e9b4d4e8","added_by":"auto","created_at":"2021-01-13 17:47:19","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":44634,"visible":true,"origin":"","legend":"Hydroacylation of alkynes. Previous works: aldehyde-alkyne coupling. a, Intramolecular organocatalytic approach. b, C–H activation approach. c, this work: non-directed and aldehyde-free approach.","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-108963/v1/9353a3c042154623932ee0ec.png"},{"id":4931902,"identity":"6e82bd28-75ad-4dc8-bc6d-0e9770bfe2cc","added_by":"auto","created_at":"2021-01-13 17:53:19","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":103087,"visible":true,"origin":"","legend":"Mechanistic and deuterium labeling studies. a, Trapping of acyl radical. b, Iterative alkyne insertion. c, Deuterium labeling.","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-108963/v1/356b60e4e3d999fd5ee8648a.png"},{"id":4931693,"identity":"9f8f78f6-e997-4cd0-960b-47b71165ba8e","added_by":"auto","created_at":"2021-01-13 17:50:19","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":29829,"visible":true,"origin":"","legend":" Proposed mechanism of Ni-catalysed aldehyde-free alkyne hydroacylation","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-108963/v1/a79d1060f2e89173a28febb1.png"},{"id":18161204,"identity":"59870bf6-2fc7-4fc4-b27b-6b036d7d43e2","added_by":"auto","created_at":"2022-02-12 13:27:26","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":630673,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-108963/v1/17dac39e-5bc3-4462-a7a5-55e257e886d0.pdf"},{"id":4931570,"identity":"aac8afc9-fac8-4af7-80b3-bc96b658a8c8","added_by":"auto","created_at":"2021-01-13 17:47:20","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":7249566,"visible":true,"origin":"","legend":"Supplementary Information","description":"","filename":"CommunChemSIfinal.docx","url":"https://assets-eu.researchsquare.com/files/rs-108963/v1/5ed7ae5e970ea259c1718a7d.docx"},{"id":4931696,"identity":"ba5a9e25-405b-47d8-aa3d-088b29561fff","added_by":"auto","created_at":"2021-01-13 17:50:19","extension":"docx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":184330,"visible":true,"origin":"","legend":"Tables 1 and 2","description":"","filename":"Tables.docx","url":"https://assets-eu.researchsquare.com/files/rs-108963/v1/5ea2c6920047af205367861b.docx"},{"id":4931694,"identity":"bdeab8c4-b57e-4f73-837b-827d26f50436","added_by":"auto","created_at":"2021-01-13 17:50:19","extension":"pdf","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":126360,"visible":true,"origin":"","legend":"compound 67 checkcif","description":"","filename":"compound67checkcif.pdf","url":"https://assets-eu.researchsquare.com/files/rs-108963/v1/3d039567b06a2328058891de.pdf"},{"id":4931567,"identity":"d484b730-9eec-4de0-8e07-d2a28aff2177","added_by":"auto","created_at":"2021-01-13 17:47:19","extension":"pdf","order_by":4,"title":"","display":"","copyAsset":false,"role":"supplement","size":123886,"visible":true,"origin":"","legend":"compound 27 checkcif","description":"","filename":"compound27checkcif.pdf","url":"https://assets-eu.researchsquare.com/files/rs-108963/v1/0e0a274c085d773e1ed4333d.pdf"}],"financialInterests":"There is \u003cb\u003eNO\u003c/b\u003e Competing Interest.","formattedTitle":"Synthesis of α,β-unsaturated ketones through nickel-catalysed aldehyde-free hydroacylation of alkynes","fulltext":[{"header":"Introduction","content":"\u003cp\u003e\u0026alpha;,\u0026beta;-Unsaturated ketones have been extensively applied as versatile compounds in synthetic organic chemistry, for example, as key substrates for conjugate addition\u003csup\u003e1\u0026ndash;4\u003c/sup\u003e, Morita\u0026ndash;Baylis\u0026ndash;Hillman\u003csup\u003e5,6\u003c/sup\u003e, Diels\u0026ndash;Alder\u003csup\u003e7,8\u003c/sup\u003e, and epoxidation\u003csup\u003e9\u0026ndash;11\u003c/sup\u003e reactions. They have been conventionally prepared through aldol condensation\u003csup\u003e12\u003c/sup\u003e, Horner\u0026ndash;Wadsworth\u0026ndash;Emmons olefination\u003csup\u003e13\u003c/sup\u003e, the dehydrogenation of ketones\u003csup\u003e14,15\u003c/sup\u003e, or palladium-catalysed carbonylation\u003csup\u003e16,17\u003c/sup\u003e reactions. However, these methods often require pre-functionalized substrates or operate through multi-step sequences. Alkynes have widely applied as readily available synthetic platforms for catalytic transformations to directly access functionalized cyclic or acyclic products\u003csup\u003e18\u003c/sup\u003e\u003csup\u003e\u0026ndash;22\u003c/sup\u003e. The catalytic hydroacylation of alkynes using aldehydes inherently provides an atom-economical process leading to the formation of enones. Organocatalytic intramolecular hydroacylation reactions of alkynes using organophosphines or \u003cem\u003eN\u003c/em\u003e-heterocyclic carbenes have been demonstrated (Fig. 1a)\u003csup\u003e23\u003c/sup\u003e\u003csup\u003e\u0026ndash;25\u003c/sup\u003e. Metal-catalysed intermolecular hydroacylation has emerged as a prominent method for rapidly accessing \u003cem\u003eE\u003c/em\u003e-enones through alkyne\u0026ndash;aldehyde coupling\u003csup\u003e26\u003c/sup\u003e\u003csup\u003e\u0026ndash;31\u003c/sup\u003e. This atom-economical method involves the chemoselective activation of an aldehydic C(\u003cem\u003esp\u003csup\u003e2\u003c/sup\u003e\u003c/em\u003e)\u0026ndash;H, and chelating moiety-bearing aldehydes have been applied to prevent decarbonylative side pathways (Fig. 1b).\u003c/p\u003e\n\u003cp\u003eStabilization of an acyl-metal complex assisted by heteroatom chelation is a powerful strategy for obtaining \u003cem\u003eE\u003c/em\u003e-enones. However, the installation and removal of the coordinating moieties entailed extra synthetic steps while reducing the step economy of the hydrofunctionalization. Though nondirected hydroacylation methods have been developed for alkenes or dienes\u003csup\u003e32\u0026ndash;36\u003c/sup\u003e, to our knowledge, there is no general hydroacylation method for unactivated terminal alkynes that lead to chelating moiety-free \u003cem\u003eE\u003c/em\u003e-enones. Recently, the Weix group reported that 2-thiopyridyl esters act as potential acyl donors for cross-electrophile coupling reactions\u003csup\u003e37\u003c/sup\u003e. We surmised that a thioester may act as both a transient thiopyridyl (SPy) ligand and an acyl component under nickel-catalysed reductive coupling conditions to lead to acyl-Ni-SPy complex. A consecutive alkyne insertion and subsequent protodemetalation process may lead to hydroacylation product formation (Fig. 1c). However, the challenges of this anticipated reaction process to attain traceless alkyne hydroacylation are fourfold: (i) competition with non-conjunctive cross-electrophile (proton and thioester) coupling, (ii) reduction of substrates, (iii) iterative alkyne additions, and (vi) regio- and stereoselectivity issues. Therefore, precise reactivity and selectivity control is crucial for a general approach to the hydroacylation of unactivated terminal alkynes.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cstrong\u003eOptimisation studies. \u003c/strong\u003eTo optimize the reaction conditions, \u003cem\u003eS\u003c/em\u003e-(pyridin-2-yl) 4-methoxybenzothioate (\u003cstrong\u003e1\u003c/strong\u003e) and 3,3-dimethyl-1-butyne (\u003cstrong\u003e2\u003c/strong\u003e) were chosen as model substrates, and a thorough screening of catalysts, reducing agents, additives, and solvents was conducted (Table 1, see also the Supplementary Information, Section III). The standard conditions were established on the basis of inexpensive nickel(II) perchlorate hexahydrate, Zn, and ZnCl\u003csub\u003e2\u003c/sub\u003e in 1,2-DME to exclusively afford \u003cem\u003eE\u003c/em\u003e-enone \u003cstrong\u003e3\u003c/strong\u003e in 81% isolated yield at room temperature (entry 1). The use of THF resulted in a similar yield (entry 2). Interestingly, coordinated water molecules were also found to be a suitable proton source (entries 3\u0026ndash;5). The use of 17 mol% of Ni catalyst was appropriate for providing a stoichiometric 1 equiv of protons to the reaction. No desired product formation was observed in the absence of the nickel catalyst, Zn, or ZnCl\u003csub\u003e2\u003c/sub\u003e (entries 6\u0026ndash;8). Mn as the reducing agent instead of Zn also appeared successful; however, this resulted in a diminished yield (entry 9). ZnCl\u003csub\u003e2\u003c/sub\u003e was found to be superior to MgCl\u003csub\u003e2\u003c/sub\u003e (entry 10). Using 1.5 equiv of terminal alkyne \u003cstrong\u003e2\u003c/strong\u003e was required for better conversion of the thioester (entry 11). The standard optimized reaction conditions were developed under an inert argon atmosphere; however, a significant amount of product formation was observed even under open atmosphere conditions (entry 12). Reduced reaction time or a decreased amount of Ni catalyst led to diminished yields (entries 13, 14). In addition, the employment of acyl chloride or aldehyde as an acyl donor instead of thioester appeared to be completely unproductive (entries 15, 16). Additional ligands in the hydroacylation resulted in slightly diminished yields (entries 17, 18).\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eScope of the reaction.\u003c/strong\u003e With the optimized conditions in hand, we set out to explore the generality of this alkyne hydroacylation by determining the thioester scope (Table 2). Various alkyl substituents worked well to afford \u003cem\u003eE\u003c/em\u003e-enone products (\u003cstrong\u003e5\u003c/strong\u003e\u0026ndash;\u003cstrong\u003e8\u003c/strong\u003e) in moderate to good yields. Hydrogen and phenyl groups, however, led to slightly lower yields (\u003cstrong\u003e4\u003c/strong\u003e, \u003cstrong\u003e9\u003c/strong\u003e). Generally, electron donating groups gave the products in moderate to good yields (\u003cstrong\u003e10\u003c/strong\u003e\u0026ndash;\u003cstrong\u003e13\u003c/strong\u003e). Although yields were low, halide groups were tolerated in the reaction (\u003cstrong\u003e14\u003c/strong\u003e\u0026ndash;\u003cstrong\u003e16\u003c/strong\u003e). Electron withdrawing groups such as CO\u003csub\u003e2\u003c/sub\u003eMe and CF\u003csub\u003e3\u003c/sub\u003e led to products (\u003cstrong\u003e17\u003c/strong\u003e, \u003cstrong\u003e18\u003c/strong\u003e) with low yields. \u003cem\u003eMeta\u003c/em\u003e- and \u003cem\u003eortho\u003c/em\u003e-substitution patterns also provided the products in moderate yields (\u003cstrong\u003e19\u003c/strong\u003e\u0026ndash;\u003cstrong\u003e24\u003c/strong\u003e). A 2-naphthyl substituent afforded the product in a slightly higher yield (44%) than a 1-naphthyl substituent (32%) (\u003cstrong\u003e25\u003c/strong\u003e, \u003cstrong\u003e26\u003c/strong\u003e). An electron-rich indole substituent led to product \u003cstrong\u003e27 \u003c/strong\u003ewith 82% yield. Both acyclic- and cyclic aliphatic substituents could access the products with moderate yields (\u003cstrong\u003e28\u003c/strong\u003e\u0026ndash;\u003cstrong\u003e32\u003c/strong\u003e).\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eWe then examined the scope of a wide range of alkynes. Acyclic- as well as cyclic aliphatic terminal alkynes underwent the reaction to afford the corresponding vinyl ketones (\u003cstrong\u003e33\u003c/strong\u003e\u0026ndash;\u003cstrong\u003e3\u003c/strong\u003e\u003cstrong\u003e8\u003c/strong\u003e) in moderate yields, although cyclopropyl- and cyclopentyl-derived alkynes gave the diminished yields. Aromatic alkynes bearing alkyl, phenyl, and phenoxy substituents worked well to give the desired products (\u003cstrong\u003e39\u003c/strong\u003e\u0026ndash;\u003cstrong\u003e45\u003c/strong\u003e) with moderate to good yields. \u003cem\u003eOrtho\u003c/em\u003e-,\u003cem\u003e meta\u003c/em\u003e-, and \u003cem\u003epara\u003c/em\u003e-substituted methoxy groups were also tolerated to obtain the products (\u003cstrong\u003e46\u003c/strong\u003e\u0026ndash;\u003cstrong\u003e48\u003c/strong\u003e). Product \u003cstrong\u003e49\u003c/strong\u003e was isolated in 55% yield by using a disubstituted arylalkyne. Fluoro- and chloro- groups were examined and gave \u003cstrong\u003e50 \u003c/strong\u003eand\u003cstrong\u003e 51\u003c/strong\u003e in 69% and 56% yields, respectively. The strongly electron withdrawing trifluoromethyl group led to product formation (\u003cstrong\u003e52\u003c/strong\u003e, \u003cstrong\u003e53\u003c/strong\u003e) with diminished yields. 2-Ethylnyl-6-methoxy-naphthalene efficiently produced \u003cstrong\u003e54\u003c/strong\u003e in 76% yield. 2-Ethynylthiophene and 3-ethynylthiophene underwent the reaction smoothly to obtain the corresponding products (\u003cstrong\u003e55\u003c/strong\u003e, \u003cstrong\u003e56\u003c/strong\u003e) in 39% and 58% yields, respectively. A free hydroxyl group was compatible affording \u003cstrong\u003e57\u003c/strong\u003e in 62% yield. We were delighted to find that the reaction was feasible with ethisterone, an agent for gynecological disease treatment, to afford \u003cstrong\u003e58\u003c/strong\u003e in 56% yield. The chemistry was also operative on a 1 mmol scale to give a similar yield. Interestingly, symmetrical as well as unsymmetrical internal alkynes gave hydroacylation products (\u003cstrong\u003e59\u003c/strong\u003e\u0026ndash;\u003cstrong\u003e61\u003c/strong\u003e), albeit in low yields. Activated alkenes also underwent the reaction very smoothly to afford \u003cstrong\u003e62\u003c/strong\u003e\u0026ndash;\u003cstrong\u003e64\u003c/strong\u003e in good yields.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMechanistic investigations and deuterium labeling experiments.\u003c/strong\u003e Control experiments were conducted to gain the insight into the reaction pathway. When TEMPO was added under the standard reaction conditions, the desired hydroacylation completely shut down and an acyl-TEMPO adduct (\u003cstrong\u003e65\u003c/strong\u003e) was isolated in 70% yield. This study corroborates the involvement of an acyl radical intermediate during the course of the reaction (Fig. 2a). Remarkably, formation of the acyl-TEMPO adduct was also observed by employing Zn and ZnCl\u003csub\u003e2\u003c/sub\u003e in the absence of any nickel catalyst, indicating its role in acyl radical generation from the thioester through single-electron transfer (SET). The formation of hydroacylation product \u003cstrong\u003e60 \u003c/strong\u003esuggests the protodemetalation of nucleophilic vinyl nickel complex \u003cstrong\u003eI\u003c/strong\u003e\u003csup\u003e38\u003c/sup\u003e. Interestingly, formation of \u003cstrong\u003e66\u003c/strong\u003e was also observed verifying an iterative double alkyne insertion (Fig. 2b). In addition to this, cyclic product \u003cstrong\u003e67\u003c/strong\u003e was isolated illustrating the intermediacy of vinyl nickel species \u003cstrong\u003eII\u003c/strong\u003e\u003csup\u003e39,40\u003c/sup\u003e. To identify the proton source of the hydroacylation, deuterium labeling tests were performed (Fig. 2c). First, a reaction conducted using deuterium oxide (3.0 equiv) resulted in formation of the product with 64% and 33% [D] incorporation at the b- and \u0026alpha;-positions, respectively, of unsaturated ketone [D]-\u003cstrong\u003e3\u003c/strong\u003e. Employing deuterated nickel(II) perchlorate hexahydrate resulted in the similar ratio of ~1.9:1 (i.e. 38%:20%, see also the Supplementary Information, Section V). To confirm the non-involvement of solvent molecules, we performed the hydroacylation reaction using deuterated THF, and no D-incorporation was detected in the final product. The employment of terminally deuterated alkyne [D]-\u003cstrong\u003e2\u003c/strong\u003e for the Ni-catalysed reductive coupling reaction also demonstrated H\u0026ndash;D exchange resulting from the weak acidity of the terminal alkyne\u003csup\u003e41,42\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eProposed mechanism.\u003c/strong\u003e Based on the above mechanistic studies and findings from previous reports\u003csup\u003e38\u003c/sup\u003e\u003csup\u003e\u0026ndash;40,43,44\u003c/sup\u003e, we proposed a reaction pathway for this reductive hydroacylation as illustrated in Fig. 3. The reaction is initiated by the generation of an acyl radical and a thiopyridyl anion through the single-electron reduction of a redox-active thioester promoted by Zn and ZnCl\u003csub\u003e2\u003c/sub\u003e. The SPy anion can undergo a consecutive ligand exchange reaction with the nickel(I)X \u003cstrong\u003eA\u003c/strong\u003e, which is generated \u003cem\u003ein-situ\u003c/em\u003e from the reduction of the Ni(II)X\u003csub\u003e2\u003c/sub\u003e pre-catalyst by Zn/ZnCl\u003csub\u003e2\u003c/sub\u003e. Engagement of the acyl radical with intermediate \u003cstrong\u003eA\u003c/strong\u003e directs the formation of acyl-Ni(II)-X complex \u003cstrong\u003eB\u003c/strong\u003e. Migratory insertion of terminal alkynes gives rise to vinyl nickel complex \u003cstrong\u003eD\u003c/strong\u003e. Then, protodemetalation of nucleophilic vinyl Ni(II) species \u003cstrong\u003eD\u003c/strong\u003e with the help of water affords the desired \u003cem\u003eE\u003c/em\u003e-enone\u003csup\u003e38\u003c/sup\u003e. The reduction of Ni(II)(OH)X species \u003cstrong\u003eE\u003c/strong\u003e by zinc regenerates the active Ni(I) species \u003cstrong\u003eA\u003c/strong\u003e.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eIn summary, we have demonstrated a nickel-catalysed hydroacylation approach using terminal alkynes to exclusively afford non-tethered \u003cem\u003eE\u003c/em\u003e-enones. This nondirected and aldehyde-free process proceeds by the single-electron reduction of a redox-active 2-pyridyl thioester to give an acyl radical that is promoted by Zn/ZnCl\u003csub\u003e2\u003c/sub\u003e. It requires neither additional steps for removal of the coordinating group, nor use of a nucleophilic hydride source, further enhancing the efficacy of the method. We anticipate that these Ni-catalysed reductive hydroacylation reactions will have an impact on synthesizing important synthetic intermediates, functional materials and pharmaceuticals.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003e\u003cstrong\u003eGeneral experimental procedure for \u003cem\u003eE\u003c/em\u003e-enones.\u003c/strong\u003e A 1-dram screw-cap vial equipped with a magnetic stir bar was charged with thioester (0.2 mmol, 1.0 equiv), Zn (33 mg, 0.5 mmol, 2.5 equiv), ZnCl\u003csub\u003e2\u003c/sub\u003e (27 mg, 0.2 mmol, 1.0 equiv), and Ni(ClO\u003csub\u003e4\u003c/sub\u003e)\u003csub\u003e2\u003c/sub\u003e\u0026middot;6H\u003csub\u003e2\u003c/sub\u003eO (12 mg, 0.034 mmol, 17 mol%) inside a glove box. The mixture was dissolved in 1,2-DME (1 mL). Then, alkyne (0.3 mmol, 1.5 equiv) was added. The reaction mixture was stirred for 24 h at room temperature. After completion of the reaction, the mixture was purified by flash column chromatography to afford the desired product.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDetailed experimental procedures, HRMS-ESI data and NMR spectra (PDF) for all compounds were provided in the Supplementary Information. Single crystal X-ray data for \u003cstrong\u003e27\u003c/strong\u003e and \u003cstrong\u003e67 \u003c/strong\u003e(CIF) are available free of charge from the Cambridge Crystallographic Database Centre (CCDC) under reference numbers 2039192 and 2036543.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eWu, H., Garcia, J. M., Haeffner, F., Radomkit, S., Zhugralin, A. R. \u0026amp; Hoveyda, A. H. Mechanism of NHC-catalyzed conjugate additions of diboron and borosilane reagents to \u0026alpha;,\u0026beta;-unsaturated carbonyl compounds. \u003cem\u003eJ. Am. 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Decarboxylative cross-electrophile coupling of \u003cem\u003eN\u003c/em\u003e-hydroxyphthalimide esters with aryl iodides. \u003cem\u003eJ. Am. Chem. Soc.\u003c/em\u003e \u003cstrong\u003e138\u003c/strong\u003e, 5016\u0026ndash;5019 (2016).\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors are grateful for financial support provided by Electronics and Telecommunications Research Institute (ETRI) grant funded by the Korea government (20ZB1200, development of ICT materials, components and equipment technologies). W.C. acknowledges Pohang Accelerator Laboratory for 2D beamline use (2020-3rd-2D-012). S.M. is grateful for the financial support from the Institute of Basic Science (IBS-R022-D1) Korea.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eJ.H.R., S.M., K.M., and S.Y.H. conceived the project. J.H.R., S.M., and H.S.L. prepared substrates, and examined the catalytic reactions. S.L. and W.C. solved single crystal X-ray structures of compounds \u003cstrong\u003e27\u003c/strong\u003e and \u003cstrong\u003e67\u003c/strong\u003e. J.H.R., J.P., S.J.K., Y.S.K., and J.K.S. worked on analytical sections for the mechanistic and deuterium labeling experiments. J.H.R., S.M., and S.Y.H. wrote the manuscript. All authors discussed results and provided input on the manuscript.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\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":"Tables","content":"\u003cp\u003eTables 1 and 2 are available in the Supplementary Files.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"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":"Feedstocks, Atom-economical Synthesis, Anti-Markovnikov Selective Coupling, Mechanistic Distinction","lastPublishedDoi":"10.21203/rs.3.rs-108963/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-108963/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"α,β-Unsaturated ketones are common feedstocks in functional materials, pharmaceuticals and natural compounds. Transition metal-catalysed hydroacylation reactions of alkynes using aldehydes have been widely applied for the atom-economical synthesis of α,β-unsaturated ketones through chemoselective aldehydic C–H activation. However, previous hydroacylation reactions using rhodium, cobalt, or ruthenium catalysts require chelating moiety-bearing aldehydes to prevent undesired decarbonylative product via an unstable acyl-metal-H complex. Herein, we report a nickel-catalysed reductive and anti-Markovnikov selective coupling process to afford non-tethered E-enones from terminal alkynes through an acyl-nickel-thiopyridine complex in the presence of zinc metal as a reducing agent. Utilization of a thioester as an acylating agent and water as a hydrogen donor enables this mechanistically distinctive and aldehyde-free hydroacylation of terminal alkynes under mild reaction conditions at room temperature, with a broad substrate scope including versatile functional groups and even simple aryl and alkyl moieties.","manuscriptTitle":"Synthesis of α,β-unsaturated ketones through nickel-catalysed aldehyde-free hydroacylation of alkynes","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2021-01-13 17:47:17","doi":"10.21203/rs.3.rs-108963/v1","editorialEvents":[],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"communications-chemistry","isNatureJournal":true,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"commschem","sideBox":"Learn more about [Communications Chemistry](http://www.nature.com/commschem/)","snPcode":"","submissionUrl":"","title":"Communications Chemistry","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Communications Series","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"ac5a3f3c-52f2-4b21-a3b4-f91fc68d6d17","owner":[],"postedDate":"January 13th, 2021","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":1871825,"name":"Organic Chemistry"},{"id":1871826,"name":"Catalysis"}],"tags":[],"updatedAt":"2022-02-12T13:26:07+00:00","versionOfRecord":{"articleIdentity":"rs-108963","link":"https://doi.org/10.1038/s42004-022-00633-3","journal":{"identity":"communications-chemistry","isVorOnly":false,"title":"Communications Chemistry"},"publishedOn":"2022-02-03 13:26:07","publishedOnDateReadable":"February 3rd, 2022"},"versionCreatedAt":"2021-01-13 17:47:17","video":"","vorDoi":"10.1038/s42004-022-00633-3","vorDoiUrl":"https://doi.org/10.1038/s42004-022-00633-3","workflowStages":[]},"version":"v1","identity":"rs-108963","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-108963","identity":"rs-108963","version":["v1"]},"buildId":"7rjqhiLT3MXkJMwkYKINL","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}