Alkenyl Fluorosulfates – Expedient Partners for Palladium-Catalyzed Cross-Coupling Reactions

Alkenyl Fluorosulfates – Expedient Partners for Palladium-Catalyzed Cross-Coupling Reactions | 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 Research Article Alkenyl Fluorosulfates – Expedient Partners for Palladium-Catalyzed Cross-Coupling Reactions Vladyslav Hnativ, Serhii Aleksandrenko, Serhii Zhersh, Oleksandr Grygorenko This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8601840/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 Alkenyl fluorosulfates are evaluated as the partners of palladium-catalyzed cross-coupling reactions and alternative to more common triflates and halides. Efficient protocols for the multigram synthesis of title reactants using reaction of carbonyl compounds with SO 2 F 2 were documented. Reactivity of alkenyl fluorosulfates in Suzuki, Sonogashira, Heck, Stille, and Buchwald-Hartwig reactions, as well as Miyaura borylation under typical conditions was studied, and limitations of the methods were established. It was found that alkenyl flurosulfates have similar or even higher reactivity in the cross-coupling reactions as compared to alkenyl triflates. Organic Chemistry building blocks coupling reactions fluorosulfates palladium enolates Figures Figure 1 Introduction It is hard to imagine any other chemical transformation that changed the landscape of modern synthetic chemistry as much as palladium-catalyzed cross-coupling reactions did. Recognized with Nobel Prize in 2010, the advancements in this field made by Suzuki, Negishi, Heck, and others several decades ago now became everyday tools in the chemistry labs. [1] A major part of efforts was put into extending the scope of nucleophilic components of the cross-coupling reactions, with prominent examples of saturated boronates, [2] trifluoroborates, [3] MIDA boronates, [4,5] stannatranes, [6] heteroatom nucleophiles, [7,8] and many other outstanding developments. [9] The scope of electrophilic partners was typically considered self-explanatory. In the case of aromatic series, it typically included various (het)aryl halides, sometimes – triflates and other sulfonates (Fig. 1 ). [10] For aliphatic counterparts, alkenyl halides are also common but the corresponding triflates (easily obtained through enolization of carbonyl compounds) are used more often. While alkenyl triflates are reactive and versatile substrates for cross-coupling reactions, they have several drawbacks. Firstly, generation of alkenyl triflates involves the use of triflating agents like PhNTf 2 , Tf 2 O, or Comin’s reagent, [11] which complicates their isolation in pure form, and (typically) strong bases, which may limit functional group compatibility. Secondly, trifluoromethanesulfonate is produced as a by-product of the cross-coupling step, which reduces its atom economy and can raise environmental concerns. [12] In 1991, Roth and Fuller suggested aryl fluorosulfates as a possible alternative to aryl triflates in the cross-coupling reactions. [13] Since then, these compounds have been widely exploited for that purpose. [14–16] On the contrary, alkenyl fluorosulfates received virtually no attention in this regard. [17–20] Meanwhile, alkenyl fluorosulfates 1 can be easily prepared by the reaction of carbonyl compounds 2 and SO 2 F 2 in the presence of a relatively mild base (Scheme 1 ). [19–21] Due to that, this process can benefit from high functional group compatibility of the whole strategy, apart from consuming SO 2 F 2 which has been named among potent greenhouse gases. [22] In this work, we present our results on the multigram preparation of alkenyl fluorosulfates 1 and their thorough exploration as the electrophilic partners in the palladium-catalyzed cross-coupling reactions. The scope of the covered transformations includes Suzuki, Sonogashira, Heck, Stille, and Buchwald-Hartwig reactions, as well as Miyaura borylation. Results and Discussion We have started our work with the exploration of a wide range of carbonyl compounds 2a–t in the reaction with SO 2 F 2 (Scheme 1 ). Among the reported protocols for this transformation, we initially have turned our attention to the method of Leroux and co-authors using DBU as the base and CH 2 Cl 2 as the solvent; [19,21] other variations involving t BuOK, LDA, or LiHMDS [20,21] were less promising. The reaction was performed at rt (20 °C) using a two-fold excess of DBU (protocol A ). It was found that the method tolerated ketal ( 1b ), N -Boc-protected amine ( 1c and 1i ), ester ( 1d and 1e ), gem -CF 2 ( 1f ), and alkene ( 1g ) moieties, was compatible with α-tetralone (product 1h ) as the substrate. With aldehyde 2j and β-keto esters 2l and 2m a 1.1-fold excess of the base was used to decrease potential side reactions (protocol B ). In the case of β-diketone 2k and β-keto nitrile 2n , ethyl diisopropyl amine (1.1 eq) was used as the base instead of DBU (protocol C ), which diminished decomposition of the products significantly. Limitations of the method included aldehydes and ketones containing small rings ( 2o–q ) and acyclic ketones ( 2r ), which have complex mixtures of unidentified products under any of the above protocols. Imide 2s did not react with SO 2 F 2 in the presence of either DBU or i Pr 2 NEt. Piperidine derivative 2t did not work as well; no reaction occurred in the presence of i Pr 2 NEt (protocol C ), and complex mixtures of products were obtained following protocols A or B . Notably, all compounds 1a–n demonstrated considerable stability towards on-the-shelf storage: they remained unchanged at rt for at least six months. Next, a typical protocol for the Suzuki reaction of alkenyl triflates (Pd(PPh 3 ) 4 (0.1 eq), K 3 PO 4 (1.5 eq), 1,4-dioxane) originally published by Suzuki and co-authors [23] was applied to an equimolar mixture of fluorosulfate 1i and boronic acid 3a (Scheme 2 ). Variation of the reaction temperature in the range of 20–80 °C showed that the highest yield of product 4ia (according to 1 H NMR spectra) was observed at 40 °C. The applicability of the protocol was checked for a wider range of fluorosulfates 1a–i and (het)aryl boronic acids 4a–i . Corresponding products 4ac–ib were obtained in 50–85% yields. The method did not work with fluorosulfate 1n . A complex mixture was obtained in this case, likely due to polymerization at some step. Sonogashira reaction of alkenyl fluorosulfates 1a–n and various terminal alkynes 5 was another cross-coupling that worked well with wide range of substrates. Again, one of the common protocols was used in this case – alkyne 5 (1.05 eq), Pd(dppf)Cl 2 ⋅CH 2 Cl 2 (0.05 eq), CuI (0.1 eq), Et 3 N (5 eq), THF, rt. [24] Corresponding enynes 6ac – na′ were obtained in 75–87% yield (Scheme 3 ). Notably, the method was compatible with flurosulfate 1n . With trimethylsilyl acetylene ( 5a ), the products of C -desilylation ( 6ba′ , 6ca′ , and 6na′ ) were isolated in some cases after the HPLC purification. Limitation of the method included electron-poor alkynes such as ethyl propiolate ( 5f ), likely due to polymerization processes. Heck reaction of fluorosulfates 1a–n and monosubstituted alkenes 7 followed a protocol described by Stille and co-authors for alkenyl triflates (Pd(PPh 3 ) 2 Cl 2 (0.05 eq), Et 3 N (3 eq), DMF) (Scheme 4 ). [25] Variation of the reaction temperature for substrates showed that 60 °C were optimal to achieve good conversion of the starting materials and avoid excessive product polymerization. The method worked well with ethyl acrylate ( 7a ), so that products 8ba–da were isolated in 77–83% yield. Neither variation worked non-activated alkenes 7f–i . In the case of fluorosulfate 1n , product 8na was detected by 1 H NMR spectroscopy in 36% yield but could not be isolated in pure form. Stille coupling of alkenyl triflates 1a–i with heteroaromatic tris( n -butyl)stannanes 9 was performed in the presence of Pd(PPh 3 ) 2 Cl 2 (0.05 eq) – CuI (0.2 eq) as the catalytic system in refluxing THF as the solvent (Scheme 5 ). [26,27] Cross-coupling products 10ba–ia were obtained in 87–93% yield. This protocol was not compatible with aliphatic stannanes 9e–h ; in all cases, complex mixtures of unidentified products were obtained instead of target dienes. Miyaura borylation of alkenyl fluorosulfates 1a–i with B 2 Pin 2 involving the use of Pd(PPh 3 ) 2 Cl 2 ⋅2PPh 3 as a catalyst, PhOK as a base, and toluene as a solvent at 50°C [28,29] enabled full conversion of starting materials and gave target boropinacolates 11a–i in 70–95% yield (Scheme 6 ). Buchwald-Hartwig amination of alkenyl fluorosulfates 1a–n was most challenging, partially due to the limited stability of the corresponding products. After some preliminary experiments with substrate 1a and benzophenone imine ( 12a ) as the N -nucleophile, we have found that using a combination of Pd(OAc) 2 (3 mol%) and Pd 2 (dba) 3 (3 mol%), XantPhos (10 mol%) as a ligand, Cs 2 CO 3 (1.4 eq) as a base, and 1,4-dioxane as a solvent at 50°C was optimal. Both Pd(OAc) 2 and Pd 2 (dba) 3 were much less efficient when used individually. Other variations including BINAP as the ligand and t BuOK as the base were not fruitful either. An alternative protocol that gave comparable results involved the use of XantPhos Pd G3 (5 mol%) and Cs 2 CO 3 (1.4 eq) in toluene at 80°C. However, the process was complicated by partial product decomposition because of the higher reaction temperature. These optimized reaction conditions worked well for the amination of various alkenyl fluorosulfates 1a–n , so that corresponding imines 13aa – na could be isolated in 73–94% yield (Scheme 7 ). The reaction also worked well with pivaloyl amide ( 12c ) (91% yield of 13ac ). In the case of N -methylaniline ( 12b ), aniline ( 12e ), and 3-aminopyridine ( 12f ), corresponding enamine 13ib or imines 13ea and 13fa were formed in 67–70% yield according to 1 H NMR spectra, but we could not isolate them in pure form due to the hydrolytic lability. Further limitations of the method included aliphatic amines (likely due to side reactions at the sulfur atom) and heteroaromatic amines with low nucleophilicity (that did not react at all or gave complex mixtures upon elevated temperatures). Finally, fluorosulfate 1i and corresponding triflate 14 were evaluated in Suzuki, Sonogashira, and Stille reactions, as well as Miyaura borylation under the optimized conditions described above (Table 1 ). It was found that compound 1i demonstrated similar or higher product yields as compared to 14 according to 1 H NMR spectra. These data show that fluorosulfates can be indeed considered a very good alternative to triflates in terms of their reactivity towards the cross-coupling reactions. Conclusions Alkenyl fluorosulfates are readily accessible and convenient yet underexplored components for various palladium-catalyzed cross-coupling reactions that can become a valuable alternative to commonly used alkenyl triflates. The title compounds can be easily obtained by mild base-promoted reaction of carbonyl compounds and sulfuryl fluoride. They are stable towards storage and produce only inorganic by-products after the cross-coupling. The utility of alkenyl fluorosulfates was demonstrated for the typical protocols of Suzuki, Sonogashira, Heck, Stille, and Buchwald-Hartwig reactions, as well as Miyaura borylation. The limitations of the developed methods were related to the limited stability of the products or low reactivity of the second reaction partners. The reactivity of alkenyl fluorosulfates themselves was similar or superior to that of the corresponding alkenyl triflates in model experiments. Experimental Section The solvents were purified according to the standard procedures. [30] All starting materials were obtained from Enamine Ltd. Melting points were measured on MPA100 OptiMelt automated melting point system. Analytical TLC was performed using Polychrom SI F254 plates. Column chromatography was performed using Kieselgel Merck 60 (230–400 mesh) as the stationary phase. Reverse-phase HPLC purification was performed using XBridge C18 (100 × 19mm, 5 µm) or Chromatorex 18 SMB100-5T (100 × 19mm, 5 µm) columns with H 2 O/MeOH or H 2 O/CH 3 CN gradient elution. 1 H and 13 C NMR spectra were recorded on a Bruker 170 Avance 500 spectrometer (at 500 MHz for 1 H NMR, 126 MHz for 13 C NMR, and 470 MHz for 19 F NMR) and Varian Unity Plus 400 spectrometer (at 400 MHz for 1 H NMR, 101 MHz for 13 C NMR and 376 MHz for 19 F NMR). NMR chemical shifts are reported in pp (δ scale) downfield from TMS as an internal standard and are referenced using residual NMR solvent peaks at 7.26 and 77.16 ppm for 1 H and 13 C in CDCl 3 , Table 1 Cross-coupling reactions of substrates 1i and 14 . # Reaction Scheme [a] Coupling partner Product Yield (%), [b] starting from 1i 14 1 Suzuki 2 4-CF 3 C 6 H 4 B(OH) 2 ( 3a ) 4ia 80 40 2 Sonogashira 3 TMSC≡CH ( 5a ) 6ia 93 63 3 Stille 5 (2-py)SnBu 3 ( 9a ) 10ia 86 80 4 Miyaura 6 B 2 Pin 2 11i 77 81 [a] Reactions were performed under the conditions shown in Schemes 2 – 6 . [b] Yields according to 1 H NMR spectra; m -xylene was used as an internal standard for the integration. 2.50 and 39.52 ppm for 1 H and 13 C in DMSO-d 6 . Coupling constants ( J ) are given in Hz. Spectra are reported as follows: chemical shift (δ, ppm), multiplicity, integration, coupling constants (Hz). Elemental analyses were performed at the Laboratory of Organic Analysis, Department of Chemistry, Taras Shevchenko National University of Kyiv. Mass spectra were recorded on an Agilent 1100 LCMSD SL instrument (chemical ionization (CI)) and Agilent 5890 Series II 5972 MS instrument (electron impact ionization (EI)). High-resolution mass spectra (HRMS) were obtained on an Agilent 1260 Infinity UHPLC instrument coupled with an Agilent 6224 Accurate Mass TOF mass spectrometer. General procedure for the synthesis of alkenyl fluorosulfates 1. To a solution of carbonyl compound 2 (0.1 mol) in CH 2 Cl 2 (200 mL) DBU (29.9 mL, 0.2 mol, 2 eq) ( Method A ), or DBU (16.4 mL, 0.11 mol, 1.1 eq) ( Method B ), or i Pr 2 NEt (18.7 mL, 0.11 mol, 1.1 eq) ( Method C ) was added dropwise at rt, and the resulting mixture was stirred for 15 min. Then, the reactor was vacuumed, and a 5-L balloon filled with SO 2 F 2 was connected through a septum. The reaction mixture was stirred at rt for 12 h. Then, the balloon was disconnected, and the reaction mixture was poured into 1 M aq NaHSO 4 (200 mL). The organic phase was separated, washed with 1 M aq NaHSO 4 (70 mL), brine (70 mL), dried over Na 2 SO 4 . The residue was triturated in hexanes, hexanes – EtOAc (19:1), or hexanes – EtOAc (9:1) (100 mL). Activated charcoal (10 g) was added, and the mixture was stirred for 10 min, then filtered through a silica gel pad. The combined filtrates were evaporated in vacuo to give pure product 1 . General procedure for the Suzuki reaction of alkenyl fluorosulfates 1. To a solution of alkenyl fluorosulfate 1 (0.01 mol, 1 eq) in 1,4-dioxane (20 mL), boronic acid 3 (0.01 mol, 1 eq) and K 3 PO 4 (3.18 g, 0.015 mol, 1.5 eq) were added. Then, argon was passed through the reaction mixture upon stirring for 5 min. Pd(PPh 3 ) 4 (1.16 g, 1 mmol, 10 mol%) was added, and argon was passed through the reaction mixture upon stirring for additional 5 min. The resulting mixture was stirred at 40 °C for 16 h, then cooled. The precipitate was filtered off, the combined filtrates were evaporated in vacuo, and the residue was purified by preparative HPLC to give product 4 . General procedure for the Sonogashira reaction of alkenyl fluorosulfates 1. To a solution of alkenyl fluorosulfate 1 (0.01 mol, 1 eq) in THF (20 mL), alkyne 5 (0.0105 mol, 1.05 eq), Et 3 N (6.97 mL, 0.05 mol, 5 eq), and CuI (0.190 g, 1 mmol, 10 mol%) were added. Then, argon was passed through the reaction mixture upon stirring for 5 min. Pd(dppf)Cl 2 ⋅CH 2 Cl 2 (0.408 g, 0.5 mmol, 5 mol%) was added, and argon was passed through the reaction mixture upon stirring for additional 5 min. The resulting mixture was stirred at rt for 16 h. The precipitate was filtered off, the combined filtrates were evaporated in vacuo, and the residue was purified by preparative HPLC to give product 6 . General procedure for the Heck reaction of alkenyl fluorosulfates 1. To a solution of alkenyl fluorosulfate 1 (0.01 mol, 1 eq) in DMF (20 mL), alkene 7 (0.02 mol, 2 eq), and Et 3 N (4.18 mL, 0.03 mol, 3 eq) were added. Then, argon was passed through the reaction mixture upon stirring for 5 min. Pd(PPh 3 ) 2 Cl 2 (0.351 g, 0.5 mmol, 5 mol%) was added, and argon was passed through the reaction mixture upon stirring for additional 5 min. The resulting mixture was stirred at 70 °C for 16 h, then cooled. The precipitate was filtered off, the combined filtrates were evaporated in vacuo, and the residue was purified by preparative HPLC to give product 8 . General procedure for the Stille reaction of alkenyl fluorosulfates 1. To a solution of alkenyl fluorosulfate 1 (0.01 mol, 1 eq) in THF (20 mL), stannane 9 (0.012 mol, 1.2 eq) and CuI (0.952 g, 5 mmol, 0.2 eq) were added. Then, argon was passed through the reaction mixture upon stirring for 5 min. Pd(PPh 3 ) 2 Cl 2 (0.351 g, 0.5 mmol, 5 mol%) was added, and argon was passed through the reaction mixture upon stirring for additional 5 min. The resulting mixture was refluxed upon stirring for 16 h, then cooled. MeOH (2 mL) and CsF (3.04 g, 0.02 mol, 2 eq) were added, the resulting mixture was stirred at 40 °C for 3 h and then cooled. The precipitate was filtered off, the combined filtrates were evaporated in vacuo, and the residue was purified by preparative HPLC to give product 10 . General procedure for the Miyaura borylation of alkenyl fluorosulfates 1. To a solution of alkenyl fluorosulfate 1 (0.01 mol, 1 eq) in toluene (20 mL), B 2 Pin 2 (3.81 g, 0.015 mol, 1.5 eq), PhOK (1.98 g, 0.015 mol, 1.5 eq), and PPh 3 (1.31 g, 5 mmol, 0.2 eq) were added. Then, argon was passed through the reaction mixture upon stirring for 5 min. Pd(PPh 3 ) 2 Cl 2 (0.702 g, 1 mmol, 10 mol%) was added, and argon was passed through the reaction mixture upon stirring for additional 5 min. The resulting mixture was stirred at 50 °C for 16 h, then cooled. The precipitate was filtered off, the combined filtrates were evaporated in vacuo, and the residue was purified by preparative HPLC to give product 11 . General procedure for the Buchwald-Hartwig reaction of alkenyl fluorosulfates 1. To a solution of alkenyl fluorosulfate 1 (0.01 mol, 1 eq) in dioxane (20 mL), amine 12 (0.012 mol, 1.2 eq), XantPhos (0.58 g, 1 mmol, 0.1 eq) and Cs 2 CO 3 (3.59 g, 0.014 mol, 1.4 eq) were added. Then, argon was passed through the reaction mixture upon stirring for 5 min. Pd(OAc) 2 (0.067 g, 0.3 mmol, 3 mol%) and Pd 2 (dba) 3 (0.274 g, 0.3 mmol, 3 mol%) were added, and argon was passed through the reaction mixture upon stirring for additional 5 min. The resulting mixture was stirred at 50 °C for 16 h, then cooled. The precipitate was filtered off, the combined filtrates were evaporated in vacuo, and the residue was purified by preparative HPLC to give product 13 . Declarations Supporting Information The authors have provided compound characterization data and copies of NMR spectra in the Supporting Information File. Funding Information The work was funded by Enamine Ltd. O. O. G. received additional funding from Ministry of Education and Science of Ukraine, grant No. 25BF037-01 (0125U002249). Acknowledgements The authors thank Mr. Bohdan Sosunovych and Dr. Bohdan Vashchenko for their help with the Supporting Information preparation, Prof. Andrii A. Tolmachov for his encouragement and support, and all the brave people of Ukraine for making finalizing this publication possible. Conflict of Interests The authors are employees of Enamine Ltd. offering the building blocks and products described in this paper in the company’s catalog. References [1] Johansson Seechurn, C. C. C.; Kitching, M. O.; Colacot, T. J.; Snieckus, V. Palladium-Catalyzed Cross-Coupling: A Historical Contextual Perspective to the 2010 Nobel Prize. 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Schemes Schemes 1 to 7 are available in the Supplementary Files section Additional Declarations The authors declare potential competing interests as follows: The authors are employees of Enamine Ltd. offering the building blocks and products described in this paper in the company’s catalog. Supplementary Files HnativSI20260114.pdf Supplementary Information Alkenylfluorosulfatesaresuggestedasconvenientpartnersforpalladium.docx SC1.png Scheme 1. Synthesis of alkenyl fluorosulfates 1a–n. SC2.png Scheme 2. Suzuki reactions of alkenyl fluorosulfates 1a–n. SC3.png Scheme 3. Sonogashira reactions of alkenyl fluorosulfates 1a–n. SC4.png Scheme 4. Heck reactions of alkenyl fluorosulfates 1a–n. SC5.png Scheme 5. Stille reactions of alkenyl fluorosulfates 1a–i. SC6.png Scheme 6. Miyaura borylation of alkenyl fluorosulfates 1a–i. SC7.png Scheme 7. Buchwald-Hartwig reactions of alkenyl fluorosulfates 1a–n. 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. 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. 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Information\u003c/p\u003e","description":"","filename":"HnativSI20260114.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8601840/v1/f4fe4187d7809336ef503d14.pdf"},{"id":100408917,"identity":"4147e3b2-3a41-4fcc-9a86-16338224aa8a","added_by":"auto","created_at":"2026-01-16 13:06:39","extension":"docx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":31456,"visible":true,"origin":"","legend":"","description":"","filename":"Alkenylfluorosulfatesaresuggestedasconvenientpartnersforpalladium.docx","url":"https://assets-eu.researchsquare.com/files/rs-8601840/v1/c40ee96f34fc955433a459a1.docx"},{"id":100408318,"identity":"95102bbb-5401-4a6c-b31b-bbe7ecb954bc","added_by":"auto","created_at":"2026-01-16 13:05:58","extension":"png","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":98864,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eScheme 1.\u003c/strong\u003e Synthesis of alkenyl fluorosulfates \u003cstrong\u003e1a–n\u003c/strong\u003e.\u003c/p\u003e","description":"","filename":"SC1.png","url":"https://assets-eu.researchsquare.com/files/rs-8601840/v1/46cfb04cd53418e3dfebd058.png"},{"id":100421981,"identity":"2d636d62-acfd-45b4-84d0-8052e230b960","added_by":"auto","created_at":"2026-01-16 14:04:32","extension":"png","order_by":4,"title":"","display":"","copyAsset":false,"role":"supplement","size":52791,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eScheme 2.\u003c/strong\u003e Suzuki reactions of alkenyl fluorosulfates \u003cstrong\u003e1a–n\u003c/strong\u003e.\u003c/p\u003e","description":"","filename":"SC2.png","url":"https://assets-eu.researchsquare.com/files/rs-8601840/v1/e2b165c2d718ba8871b928ab.png"},{"id":100408404,"identity":"30f3ec4b-1820-48ce-8575-b1b0e49c0e2e","added_by":"auto","created_at":"2026-01-16 13:06:05","extension":"png","order_by":5,"title":"","display":"","copyAsset":false,"role":"supplement","size":42210,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eScheme 3.\u003c/strong\u003e Sonogashira reactions of alkenyl fluorosulfates \u003cstrong\u003e1a–n\u003c/strong\u003e.\u003c/p\u003e","description":"","filename":"SC3.png","url":"https://assets-eu.researchsquare.com/files/rs-8601840/v1/7738f9cb601eadac1c72c55a.png"},{"id":100408346,"identity":"a525896c-200e-4967-9e06-9d3e7c62bafa","added_by":"auto","created_at":"2026-01-16 13:06:01","extension":"png","order_by":6,"title":"","display":"","copyAsset":false,"role":"supplement","size":49987,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eScheme 4.\u003c/strong\u003e Heck reactions of alkenyl fluorosulfates \u003cstrong\u003e1a–n\u003c/strong\u003e.\u003c/p\u003e","description":"","filename":"SC4.png","url":"https://assets-eu.researchsquare.com/files/rs-8601840/v1/fe19efd3b237b71a2a3e7fe7.png"},{"id":100409053,"identity":"8ec1fcff-7f88-4b6c-95cb-6937219a756c","added_by":"auto","created_at":"2026-01-16 13:06:43","extension":"png","order_by":7,"title":"","display":"","copyAsset":false,"role":"supplement","size":49965,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eScheme 5.\u003c/strong\u003e Stille reactions of alkenyl fluorosulfates \u003cstrong\u003e1a–i\u003c/strong\u003e.\u003c/p\u003e","description":"","filename":"SC5.png","url":"https://assets-eu.researchsquare.com/files/rs-8601840/v1/86db5afc42d802d4d81836f6.png"},{"id":100408819,"identity":"9aa37d0f-48c4-4b97-bce5-4ce611b78a7c","added_by":"auto","created_at":"2026-01-16 13:06:35","extension":"png","order_by":8,"title":"","display":"","copyAsset":false,"role":"supplement","size":35504,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eScheme 6.\u003c/strong\u003e Miyaura borylation of alkenyl fluorosulfates \u003cstrong\u003e1a–i\u003c/strong\u003e.\u003c/p\u003e","description":"","filename":"SC6.png","url":"https://assets-eu.researchsquare.com/files/rs-8601840/v1/1897c0dc5b826c9e92de9760.png"},{"id":100408395,"identity":"5b6feab7-70d5-413d-9e2e-82f54014c748","added_by":"auto","created_at":"2026-01-16 13:06:04","extension":"png","order_by":9,"title":"","display":"","copyAsset":false,"role":"supplement","size":110020,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eScheme 7.\u003c/strong\u003e Buchwald-Hartwig reactions of alkenyl fluorosulfates \u003cstrong\u003e1a–n\u003c/strong\u003e.\u003c/p\u003e","description":"","filename":"SC7.png","url":"https://assets-eu.researchsquare.com/files/rs-8601840/v1/37a7ad44696944ef7d7e62d1.png"}],"financialInterests":"The authors declare potential competing interests as follows: The authors are employees of Enamine Ltd. offering the building blocks and products described in this paper in the company’s catalog.","formattedTitle":"\u003cp\u003eAlkenyl Fluorosulfates – Expedient Partners for Palladium-Catalyzed Cross-Coupling Reactions\u003c/p\u003e","fulltext":[{"header":"Introduction","content":"\u003cp\u003eIt is hard to imagine any other chemical transformation that changed the landscape of modern synthetic chemistry as much as palladium-catalyzed cross-coupling reactions did. Recognized with Nobel Prize in 2010, the advancements in this field made by Suzuki, Negishi, Heck, and others several decades ago now became everyday tools in the chemistry labs.\u003csup\u003e[1]\u003c/sup\u003e A major part of efforts was put into extending the scope of nucleophilic components of the cross-coupling reactions, with prominent examples of saturated boronates,\u003csup\u003e[2]\u003c/sup\u003e trifluoroborates,\u003csup\u003e[3]\u003c/sup\u003e MIDA boronates,\u003csup\u003e[4,5]\u003c/sup\u003e stannatranes,\u003csup\u003e[6]\u003c/sup\u003e heteroatom nucleophiles,\u003csup\u003e[7,8]\u003c/sup\u003e and many other outstanding developments.\u003csup\u003e[9]\u003c/sup\u003e The scope of electrophilic partners was typically considered self-explanatory. In the case of aromatic series, it typically included various (het)aryl halides, sometimes \u0026ndash; triflates and other sulfonates (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003csup\u003e[10]\u003c/sup\u003e For aliphatic counterparts, alkenyl halides are also common but the corresponding triflates (easily obtained through enolization of carbonyl compounds) are used more often.\u003c/p\u003e \u003cp\u003eWhile alkenyl triflates are reactive and versatile substrates for cross-coupling reactions, they have several drawbacks. Firstly, generation of alkenyl triflates involves the use of triflating agents like PhNTf\u003csub\u003e2\u003c/sub\u003e, Tf\u003csub\u003e2\u003c/sub\u003eO, or Comin\u0026rsquo;s reagent,\u003csup\u003e[11]\u003c/sup\u003e which complicates their isolation in pure form, and (typically) strong bases, which may limit functional group compatibility. Secondly, trifluoromethanesulfonate is produced as a by-product of the cross-coupling step, which reduces its atom economy and can raise environmental concerns.\u003csup\u003e[12]\u003c/sup\u003e\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eIn 1991, Roth and Fuller suggested aryl fluorosulfates as a possible alternative to aryl triflates in the cross-coupling reactions.\u003csup\u003e[13]\u003c/sup\u003e Since then, these compounds have been widely exploited for that purpose.\u003csup\u003e[14\u0026ndash;16]\u003c/sup\u003e On the contrary, alkenyl fluorosulfates received virtually no attention in this regard.\u003csup\u003e[17\u0026ndash;20]\u003c/sup\u003e Meanwhile, alkenyl fluorosulfates \u003cb\u003e1\u003c/b\u003e can be easily prepared by the reaction of carbonyl compounds \u003cb\u003e2\u003c/b\u003e and SO\u003csub\u003e2\u003c/sub\u003eF\u003csub\u003e2\u003c/sub\u003e in the presence of a relatively mild base (Scheme \u003cspan refid=\"Sch1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003csup\u003e[19\u0026ndash;21]\u003c/sup\u003e Due to that, this process can benefit from high functional group compatibility of the whole strategy, apart from consuming SO\u003csub\u003e2\u003c/sub\u003eF\u003csub\u003e2\u003c/sub\u003e which has been named among potent greenhouse gases.\u003csup\u003e[22]\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eIn this work, we present our results on the multigram preparation of alkenyl fluorosulfates \u003cb\u003e1\u003c/b\u003e and their thorough exploration as the electrophilic partners in the palladium-catalyzed cross-coupling reactions. The scope of the covered transformations includes Suzuki, Sonogashira, Heck, Stille, and Buchwald-Hartwig reactions, as well as Miyaura borylation.\u003c/p\u003e"},{"header":"Results and Discussion","content":"\u003cp\u003eWe have started our work with the exploration of a wide range of carbonyl compounds \u003cstrong\u003e2a\u0026ndash;t\u003c/strong\u003e in the reaction with SO\u003csub\u003e2\u003c/sub\u003eF\u003csub\u003e2\u003c/sub\u003e (Scheme \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e). Among the reported protocols for this transformation, we initially have turned our attention to the method of Leroux and co-authors using DBU as the base and CH\u003csub\u003e2\u003c/sub\u003eCl\u003csub\u003e2\u003c/sub\u003e as the solvent;\u003csup\u003e[19,21]\u003c/sup\u003e other variations involving \u003cem\u003et\u003c/em\u003eBuOK, LDA, or LiHMDS\u003csup\u003e[20,21]\u003c/sup\u003e were less promising. The reaction was performed at rt (20 \u0026deg;C) using a two-fold excess of DBU (protocol \u003cem\u003eA\u003c/em\u003e). It was found that the method tolerated ketal (\u003cstrong\u003e1b\u003c/strong\u003e), \u003cem\u003eN\u003c/em\u003e-Boc-protected amine (\u003cstrong\u003e1c\u003c/strong\u003e and \u003cstrong\u003e1i\u003c/strong\u003e), ester (\u003cstrong\u003e1d\u003c/strong\u003e and \u003cstrong\u003e1e\u003c/strong\u003e), \u003cem\u003egem\u003c/em\u003e-CF\u003csub\u003e2\u003c/sub\u003e (\u003cstrong\u003e1f\u003c/strong\u003e), and alkene (\u003cstrong\u003e1g\u003c/strong\u003e) moieties, was compatible with \u0026alpha;-tetralone (product \u003cstrong\u003e1h\u003c/strong\u003e) as the substrate. With aldehyde \u003cstrong\u003e2j\u003c/strong\u003e and \u0026beta;-keto esters \u003cstrong\u003e2l\u003c/strong\u003e and \u003cstrong\u003e2m\u003c/strong\u003e a 1.1-fold excess of the base was used to decrease potential side reactions (protocol \u003cem\u003eB\u003c/em\u003e). In the case of \u0026beta;-diketone \u003cstrong\u003e2k\u003c/strong\u003e and \u0026beta;-keto nitrile \u003cstrong\u003e2n\u003c/strong\u003e, ethyl diisopropyl amine (1.1 eq) was used as the base instead of DBU (protocol \u003cem\u003eC\u003c/em\u003e), which diminished decomposition of the products significantly.\u003c/p\u003e\n\u003cp\u003eLimitations of the method included aldehydes and ketones containing small rings (\u003cstrong\u003e2o\u0026ndash;q\u003c/strong\u003e) and acyclic ketones (\u003cstrong\u003e2r\u003c/strong\u003e), which have complex mixtures of unidentified products under any of the above protocols. Imide \u003cstrong\u003e2s\u003c/strong\u003e did not react with SO\u003csub\u003e2\u003c/sub\u003eF\u003csub\u003e2\u003c/sub\u003e in the presence of either DBU or \u003cem\u003ei\u003c/em\u003ePr\u003csub\u003e2\u003c/sub\u003eNEt. Piperidine derivative \u003cstrong\u003e2t\u003c/strong\u003e did not work as well; no reaction occurred in the presence of \u003cem\u003ei\u003c/em\u003ePr\u003csub\u003e2\u003c/sub\u003eNEt (protocol \u003cem\u003eC\u003c/em\u003e), and complex mixtures of products were obtained following protocols \u003cem\u003eA\u003c/em\u003e or \u003cem\u003eB\u003c/em\u003e.\u003c/p\u003e\n\u003cp\u003eNotably, all compounds \u003cstrong\u003e1a\u0026ndash;n\u003c/strong\u003e demonstrated considerable stability towards on-the-shelf storage: they remained unchanged at rt for at least six months.\u003c/p\u003e\n\u003cp\u003eNext, a typical protocol for the Suzuki reaction of alkenyl triflates (Pd(PPh\u003csub\u003e3\u003c/sub\u003e)\u003csub\u003e4\u003c/sub\u003e (0.1 eq), K\u003csub\u003e3\u003c/sub\u003ePO\u003csub\u003e4\u003c/sub\u003e (1.5 eq), 1,4-dioxane) originally published by Suzuki and co-authors\u003csup\u003e[23]\u003c/sup\u003e was applied to an equimolar mixture of fluorosulfate \u003cstrong\u003e1i\u003c/strong\u003e and boronic acid \u003cstrong\u003e3a\u003c/strong\u003e (Scheme \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e). Variation of the reaction temperature in the range of 20\u0026ndash;80 \u0026deg;C showed that the highest yield of product \u003cstrong\u003e4ia\u003c/strong\u003e (according to \u003csup\u003e1\u003c/sup\u003eH NMR spectra) was observed at 40 \u0026deg;C. The applicability of the protocol was checked for a wider range of fluorosulfates \u003cstrong\u003e1a\u0026ndash;i\u003c/strong\u003e and (het)aryl boronic acids \u003cstrong\u003e4a\u0026ndash;i\u003c/strong\u003e. Corresponding products \u003cstrong\u003e4ac\u0026ndash;ib\u003c/strong\u003e were obtained in 50\u0026ndash;85% yields. The method did not work with fluorosulfate \u003cstrong\u003e1n\u003c/strong\u003e. A complex mixture was obtained in this case, likely due to polymerization at some step.\u003c/p\u003e\n\u003cp\u003eSonogashira reaction of alkenyl fluorosulfates \u003cstrong\u003e1a\u0026ndash;n\u003c/strong\u003e and various terminal alkynes \u003cstrong\u003e5\u003c/strong\u003e was another cross-coupling that worked well with wide range of substrates. Again, one of the common protocols was used in this case \u0026ndash; alkyne \u003cstrong\u003e5\u003c/strong\u003e (1.05 eq), Pd(dppf)Cl\u003csub\u003e2\u003c/sub\u003e\u0026sdot;CH\u003csub\u003e2\u003c/sub\u003eCl\u003csub\u003e2\u003c/sub\u003e (0.05 eq), CuI (0.1 eq), Et\u003csub\u003e3\u003c/sub\u003eN (5 eq), THF, rt.\u003csup\u003e[24]\u003c/sup\u003e Corresponding enynes \u003cstrong\u003e6ac\u003c/strong\u003e\u0026ndash;\u003cstrong\u003ena\u0026prime;\u003c/strong\u003e were obtained in 75\u0026ndash;87% yield (Scheme \u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e). Notably, the method was compatible with flurosulfate \u003cstrong\u003e1n\u003c/strong\u003e. With trimethylsilyl acetylene (\u003cstrong\u003e5a\u003c/strong\u003e), the products of \u003cem\u003eC\u003c/em\u003e-desilylation (\u003cstrong\u003e6ba\u0026prime;\u003c/strong\u003e, \u003cstrong\u003e6ca\u0026prime;\u003c/strong\u003e, and \u003cstrong\u003e6na\u0026prime;\u003c/strong\u003e) were isolated in some cases after the HPLC purification. Limitation of the method included electron-poor alkynes such as ethyl propiolate (\u003cstrong\u003e5f\u003c/strong\u003e), likely due to polymerization processes.\u003c/p\u003e\n\u003cp\u003eHeck reaction of fluorosulfates \u003cstrong\u003e1a\u0026ndash;n\u003c/strong\u003e and monosubstituted alkenes \u003cstrong\u003e7\u003c/strong\u003e followed a protocol described by Stille and co-authors for alkenyl triflates (Pd(PPh\u003csub\u003e3\u003c/sub\u003e)\u003csub\u003e2\u003c/sub\u003eCl\u003csub\u003e2\u003c/sub\u003e (0.05 eq), Et\u003csub\u003e3\u003c/sub\u003eN (3 eq), DMF) (Scheme \u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003e).\u003csup\u003e[25]\u003c/sup\u003e Variation of the reaction temperature for substrates showed that 60 \u0026deg;C were optimal to achieve good conversion of the starting materials and avoid excessive product polymerization. The method worked well with ethyl acrylate (\u003cstrong\u003e7a\u003c/strong\u003e), so that products \u003cstrong\u003e8ba\u0026ndash;da\u003c/strong\u003e were isolated in 77\u0026ndash;83% yield. Neither variation worked non-activated alkenes \u003cstrong\u003e7f\u0026ndash;i\u003c/strong\u003e. In the case of fluorosulfate \u003cstrong\u003e1n\u003c/strong\u003e, product \u003cstrong\u003e8na\u003c/strong\u003e was detected by \u003csup\u003e1\u003c/sup\u003eH NMR spectroscopy in 36% yield but could not be isolated in pure form.\u003c/p\u003e\n\u003cp\u003eStille coupling of alkenyl triflates \u003cstrong\u003e1a\u0026ndash;i\u003c/strong\u003e with heteroaromatic tris(\u003cem\u003en\u003c/em\u003e-butyl)stannanes \u003cstrong\u003e9\u003c/strong\u003e was performed in the presence of Pd(PPh\u003csub\u003e3\u003c/sub\u003e)\u003csub\u003e2\u003c/sub\u003eCl\u003csub\u003e2\u003c/sub\u003e (0.05 eq) \u0026ndash; CuI (0.2 eq) as the catalytic system in refluxing THF as the solvent (Scheme \u003cspan class=\"InternalRef\"\u003e5\u003c/span\u003e).\u003csup\u003e[26,27]\u003c/sup\u003e Cross-coupling products \u003cstrong\u003e10ba\u0026ndash;ia\u003c/strong\u003e were obtained in 87\u0026ndash;93% yield. This protocol was not compatible with aliphatic stannanes \u003cstrong\u003e9e\u0026ndash;h\u003c/strong\u003e; in all cases, complex mixtures of unidentified products were obtained instead of target dienes.\u003c/p\u003e\n\u003cp\u003eMiyaura borylation of alkenyl fluorosulfates \u003cstrong\u003e1a\u0026ndash;i\u003c/strong\u003e with B\u003csub\u003e2\u003c/sub\u003ePin\u003csub\u003e2\u003c/sub\u003e involving the use of Pd(PPh\u003csub\u003e3\u003c/sub\u003e)\u003csub\u003e2\u003c/sub\u003eCl\u003csub\u003e2\u003c/sub\u003e\u0026sdot;2PPh\u003csub\u003e3\u003c/sub\u003e as a catalyst, PhOK as a base, and toluene as a solvent at 50\u0026deg;C\u003csup\u003e[28,29]\u003c/sup\u003e enabled full conversion of starting materials and gave target boropinacolates \u003cstrong\u003e11a\u0026ndash;i\u003c/strong\u003e in 70\u0026ndash;95% yield (Scheme \u003cspan class=\"InternalRef\"\u003e6\u003c/span\u003e).\u003c/p\u003e\n\u003cp\u003eBuchwald-Hartwig amination of alkenyl fluorosulfates \u003cstrong\u003e1a\u0026ndash;n\u003c/strong\u003e was most challenging, partially due to the limited stability of the corresponding products. After some preliminary experiments with substrate \u003cstrong\u003e1a\u003c/strong\u003e and benzophenone imine (\u003cstrong\u003e12a\u003c/strong\u003e) as the \u003cem\u003eN\u003c/em\u003e-nucleophile, we have found that using a combination of Pd(OAc)\u003csub\u003e2\u003c/sub\u003e (3 mol%) and Pd\u003csub\u003e2\u003c/sub\u003e(dba)\u003csub\u003e3\u003c/sub\u003e (3 mol%), XantPhos (10 mol%) as a ligand, Cs\u003csub\u003e2\u003c/sub\u003eCO\u003csub\u003e3\u003c/sub\u003e (1.4 eq) as a base, and 1,4-dioxane as a solvent at 50\u0026deg;C was optimal. Both Pd(OAc)\u003csub\u003e2\u003c/sub\u003e and Pd\u003csub\u003e2\u003c/sub\u003e(dba)\u003csub\u003e3\u003c/sub\u003e were much less efficient when used individually. Other variations including BINAP as the ligand and \u003cem\u003et\u003c/em\u003eBuOK as the base were not fruitful either. An alternative protocol that gave comparable results involved the use of XantPhos Pd G3 (5 mol%) and Cs\u003csub\u003e2\u003c/sub\u003eCO\u003csub\u003e3\u003c/sub\u003e (1.4 eq) in toluene at 80\u0026deg;C. However, the process was complicated by partial product decomposition because of the higher reaction temperature.\u003c/p\u003e\n\u003cp\u003eThese optimized reaction conditions worked well for the amination of various alkenyl fluorosulfates \u003cstrong\u003e1a\u0026ndash;n\u003c/strong\u003e, so that corresponding imines \u003cstrong\u003e13aa\u003c/strong\u003e\u0026ndash;\u003cstrong\u003ena\u003c/strong\u003e could be isolated in 73\u0026ndash;94% yield (Scheme \u003cspan class=\"InternalRef\"\u003e7\u003c/span\u003e). The reaction also worked well with pivaloyl amide (\u003cstrong\u003e12c\u003c/strong\u003e) (91% yield of \u003cstrong\u003e13ac\u003c/strong\u003e). In the case of \u003cem\u003eN\u003c/em\u003e-methylaniline (\u003cstrong\u003e12b\u003c/strong\u003e), aniline (\u003cstrong\u003e12e\u003c/strong\u003e), and 3-aminopyridine (\u003cstrong\u003e12f\u003c/strong\u003e), corresponding enamine \u003cstrong\u003e13ib\u003c/strong\u003e or imines \u003cstrong\u003e13ea\u003c/strong\u003e and \u003cstrong\u003e13fa\u003c/strong\u003e were formed in 67\u0026ndash;70% yield according to \u003csup\u003e1\u003c/sup\u003eH NMR spectra, but we could not isolate them in pure form due to the hydrolytic lability. Further limitations of the method included aliphatic amines (likely due to side reactions at the sulfur atom) and heteroaromatic amines with low nucleophilicity (that did not react at all or gave complex mixtures upon elevated temperatures).\u003c/p\u003e\n\u003cp\u003eFinally, fluorosulfate \u003cstrong\u003e1i\u003c/strong\u003e and corresponding triflate \u003cstrong\u003e14\u003c/strong\u003e were evaluated in Suzuki, Sonogashira, and Stille reactions, as well as Miyaura borylation under the optimized conditions described above (Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e). It was found that compound \u003cstrong\u003e1i\u003c/strong\u003e demonstrated similar or higher product yields as compared to \u003cstrong\u003e14\u003c/strong\u003e according to \u003csup\u003e1\u003c/sup\u003eH NMR spectra. These data show that fluorosulfates can be indeed considered a very good alternative to triflates in terms of their reactivity towards the cross-coupling reactions.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eAlkenyl fluorosulfates are readily accessible and convenient yet underexplored components for various palladium-catalyzed cross-coupling reactions that can become a valuable alternative to commonly used alkenyl triflates. The title compounds can be easily obtained by mild base-promoted reaction of carbonyl compounds and sulfuryl fluoride. They are stable towards storage and produce only inorganic by-products after the cross-coupling. The utility of alkenyl fluorosulfates was demonstrated for the typical protocols of Suzuki, Sonogashira, Heck, Stille, and Buchwald-Hartwig reactions, as well as Miyaura borylation. The limitations of the developed methods were related to the limited stability of the products or low reactivity of the second reaction partners. The reactivity of alkenyl fluorosulfates themselves was similar or superior to that of the corresponding alkenyl triflates in model experiments.\u003c/p\u003e"},{"header":"Experimental Section","content":"\u003cp\u003eThe solvents were purified according to the standard procedures.\u003csup\u003e[30]\u003c/sup\u003e All starting materials were obtained from Enamine Ltd. Melting points were measured on MPA100 OptiMelt automated melting point system. Analytical TLC was performed using Polychrom SI F254 plates. Column chromatography was performed using Kieselgel Merck 60 (230\u0026ndash;400 mesh) as the stationary phase. Reverse-phase HPLC purification was performed using XBridge C18 (100 \u0026times; 19mm, 5 \u0026micro;m) or Chromatorex 18 SMB100-5T (100 \u0026times; 19mm, 5 \u0026micro;m) columns with H\u003csub\u003e2\u003c/sub\u003eO/MeOH or H\u003csub\u003e2\u003c/sub\u003eO/CH\u003csub\u003e3\u003c/sub\u003eCN gradient elution. \u003csup\u003e1\u003c/sup\u003eH and \u003csup\u003e13\u003c/sup\u003eC NMR spectra were recorded on a Bruker 170 Avance 500 spectrometer (at 500 MHz for \u003csup\u003e1\u003c/sup\u003eH NMR, 126 MHz for \u003csup\u003e13\u003c/sup\u003eC NMR, and 470 MHz for \u003csup\u003e19\u003c/sup\u003eF NMR) and Varian Unity Plus 400 spectrometer (at 400 MHz for \u003csup\u003e1\u003c/sup\u003eH NMR, 101 MHz for \u003csup\u003e13\u003c/sup\u003eC NMR and 376 MHz for \u003csup\u003e19\u003c/sup\u003eF NMR). NMR chemical shifts are reported in pp (\u0026delta; scale) downfield from TMS as an internal standard and are referenced using residual NMR solvent peaks at 7.26 and 77.16 ppm for \u003csup\u003e1\u003c/sup\u003eH and \u003csup\u003e13\u003c/sup\u003eC in CDCl\u003csub\u003e3\u003c/sub\u003e,\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n \u003ctable id=\"Tab1\" border=\"1\"\u003e\n \u003ccaption\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eCross-coupling reactions of substrates \u003cstrong\u003e1i\u003c/strong\u003e and \u003cstrong\u003e14\u003c/strong\u003e.\u003c/p\u003e\n \u003cp\u003e\u003cimg width=\"307\" height=\"99\" 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\" 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align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e14\u003c/strong\u003e\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cem\u003eSuzuki\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4-CF\u003csub\u003e3\u003c/sub\u003eC\u003csub\u003e6\u003c/sub\u003eH\u003csub\u003e4\u003c/sub\u003eB(OH)\u003csub\u003e2\u003c/sub\u003e (\u003cstrong\u003e3a\u003c/strong\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e4ia\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e80\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e40\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cem\u003eSonogashira\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eTMSC\u0026equiv;CH (\u003cstrong\u003e5a\u003c/strong\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e6ia\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e93\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e63\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cem\u003eStille\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e(2-py)SnBu\u003csub\u003e3\u003c/sub\u003e (\u003cstrong\u003e9a\u003c/strong\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e10ia\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e86\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e80\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cem\u003eMiyaura\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eB\u003csub\u003e2\u003c/sub\u003ePin\u003csub\u003e2\u003c/sub\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e11i\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e77\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e81\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e[a] Reactions were performed under the conditions shown in Schemes \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e\u0026ndash;\u003cspan class=\"InternalRef\"\u003e6\u003c/span\u003e.\n\u003c/div\u003e\n\u003cdiv class=\"gridtable\"\u003e[b] Yields according to \u003csup\u003e1\u003c/sup\u003eH NMR spectra; \u003cem\u003em\u003c/em\u003e-xylene was used as an internal standard for the integration.\u003c/div\u003e\n\u003cp class=\"gridtable\"\u003e2.50 and 39.52 ppm for \u003csup\u003e1\u003c/sup\u003eH and \u003csup\u003e13\u003c/sup\u003eC in DMSO-d\u003csub\u003e6\u003c/sub\u003e. Coupling constants (\u003cem\u003eJ\u003c/em\u003e) are given in Hz. Spectra are reported as follows: chemical shift (\u0026delta;, ppm), multiplicity, integration, coupling constants (Hz). Elemental analyses were performed at the Laboratory of Organic Analysis, Department of Chemistry, Taras Shevchenko National University of Kyiv. Mass spectra were recorded on an Agilent 1100 LCMSD SL instrument (chemical ionization (CI)) and Agilent 5890 Series II 5972 MS instrument (electron impact ionization (EI)). High-resolution mass spectra (HRMS) were obtained on an Agilent 1260 Infinity UHPLC instrument coupled with an Agilent 6224 Accurate Mass TOF mass spectrometer.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eGeneral procedure for the synthesis of alkenyl fluorosulfates 1.\u003c/strong\u003e To a solution of carbonyl compound \u003cstrong\u003e2\u003c/strong\u003e (0.1 mol) in CH\u003csub\u003e2\u003c/sub\u003eCl\u003csub\u003e2\u003c/sub\u003e (200 mL) DBU (29.9 mL, 0.2 mol, 2 eq) (\u003cem\u003eMethod\u003c/em\u003e \u003cstrong\u003eA\u003c/strong\u003e), or DBU (16.4 mL, 0.11 mol, 1.1 eq) (\u003cem\u003eMethod\u003c/em\u003e \u003cstrong\u003eB\u003c/strong\u003e), or \u003cem\u003ei\u003c/em\u003ePr\u003csub\u003e2\u003c/sub\u003eNEt (18.7 mL, 0.11 mol, 1.1 eq) (\u003cem\u003eMethod\u003c/em\u003e \u003cstrong\u003eC\u003c/strong\u003e) was added dropwise at rt, and the resulting mixture was stirred for 15 min. Then, the reactor was vacuumed, and a 5-L balloon filled with SO\u003csub\u003e2\u003c/sub\u003eF\u003csub\u003e2\u003c/sub\u003e was connected through a septum. The reaction mixture was stirred at rt for 12 h. Then, the balloon was disconnected, and the reaction mixture was poured into 1 M aq NaHSO\u003csub\u003e4\u003c/sub\u003e (200 mL). The organic phase was separated, washed with 1 M aq NaHSO\u003csub\u003e4\u003c/sub\u003e (70 mL), brine (70 mL), dried over Na\u003csub\u003e2\u003c/sub\u003eSO\u003csub\u003e4\u003c/sub\u003e. The residue was triturated in hexanes, hexanes \u0026ndash; EtOAc (19:1), or hexanes \u0026ndash; EtOAc (9:1) (100 mL). Activated charcoal (10 g) was added, and the mixture was stirred for 10 min, then filtered through a silica gel pad. The combined filtrates were evaporated in vacuo to give pure product \u003cstrong\u003e1\u003c/strong\u003e.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eGeneral procedure for the Suzuki reaction of alkenyl fluorosulfates 1.\u003c/strong\u003e To a solution of alkenyl fluorosulfate \u003cstrong\u003e1\u003c/strong\u003e (0.01 mol, 1 eq) in 1,4-dioxane (20 mL), boronic acid \u003cstrong\u003e3\u003c/strong\u003e (0.01 mol, 1 eq) and K\u003csub\u003e3\u003c/sub\u003ePO\u003csub\u003e4\u003c/sub\u003e (3.18 g, 0.015 mol, 1.5 eq) were added. Then, argon was passed through the reaction mixture upon stirring for 5 min. Pd(PPh\u003csub\u003e3\u003c/sub\u003e)\u003csub\u003e4\u003c/sub\u003e (1.16 g, 1 mmol, 10 mol%) was added, and argon was passed through the reaction mixture upon stirring for additional 5 min. The resulting mixture was stirred at 40 \u0026deg;C for 16 h, then cooled. The precipitate was filtered off, the combined filtrates were evaporated in vacuo, and the residue was purified by preparative HPLC to give product \u003cstrong\u003e4\u003c/strong\u003e.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eGeneral procedure for the Sonogashira reaction of alkenyl fluorosulfates 1.\u003c/strong\u003e To a solution of alkenyl fluorosulfate \u003cstrong\u003e1\u003c/strong\u003e (0.01 mol, 1 eq) in THF (20 mL), alkyne \u003cstrong\u003e5\u003c/strong\u003e (0.0105 mol, 1.05 eq), Et\u003csub\u003e3\u003c/sub\u003eN (6.97 mL, 0.05 mol, 5 eq), and CuI (0.190 g, 1 mmol, 10 mol%) were added. Then, argon was passed through the reaction mixture upon stirring for 5 min. Pd(dppf)Cl\u003csub\u003e2\u003c/sub\u003e\u0026sdot;CH\u003csub\u003e2\u003c/sub\u003eCl\u003csub\u003e2\u003c/sub\u003e (0.408 g, 0.5 mmol, 5 mol%) was added, and argon was passed through the reaction mixture upon stirring for additional 5 min. The resulting mixture was stirred at rt for 16 h. The precipitate was filtered off, the combined filtrates were evaporated in vacuo, and the residue was purified by preparative HPLC to give product \u003cstrong\u003e6\u003c/strong\u003e.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eGeneral procedure for the Heck reaction of alkenyl fluorosulfates 1.\u003c/strong\u003e To a solution of alkenyl fluorosulfate \u003cstrong\u003e1\u003c/strong\u003e (0.01 mol, 1 eq) in DMF (20 mL), alkene \u003cstrong\u003e7\u003c/strong\u003e (0.02 mol, 2 eq), and Et\u003csub\u003e3\u003c/sub\u003eN (4.18 mL, 0.03 mol, 3 eq) were added. Then, argon was passed through the reaction mixture upon stirring for 5 min. Pd(PPh\u003csub\u003e3\u003c/sub\u003e)\u003csub\u003e2\u003c/sub\u003eCl\u003csub\u003e2\u003c/sub\u003e (0.351 g, 0.5 mmol, 5 mol%) was added, and argon was passed through the reaction mixture upon stirring for additional 5 min. The resulting mixture was stirred at 70 \u0026deg;C for 16 h, then cooled. The precipitate was filtered off, the combined filtrates were evaporated in vacuo, and the residue was purified by preparative HPLC to give product \u003cstrong\u003e8\u003c/strong\u003e.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eGeneral procedure for the Stille reaction of alkenyl fluorosulfates 1.\u003c/strong\u003e To a solution of alkenyl fluorosulfate \u003cstrong\u003e1\u003c/strong\u003e (0.01 mol, 1 eq) in THF (20 mL), stannane \u003cstrong\u003e9\u003c/strong\u003e (0.012 mol, 1.2 eq) and CuI (0.952 g, 5 mmol, 0.2 eq) were added. Then, argon was passed through the reaction mixture upon stirring for 5 min. Pd(PPh\u003csub\u003e3\u003c/sub\u003e)\u003csub\u003e2\u003c/sub\u003eCl\u003csub\u003e2\u003c/sub\u003e (0.351 g, 0.5 mmol, 5 mol%) was added, and argon was passed through the reaction mixture upon stirring for additional 5 min. The resulting mixture was refluxed upon stirring for 16 h, then cooled. MeOH (2 mL) and CsF (3.04 g, 0.02 mol, 2 eq) were added, the resulting mixture was stirred at 40 \u0026deg;C for 3 h and then cooled. The precipitate was filtered off, the combined filtrates were evaporated in vacuo, and the residue was purified by preparative HPLC to give product \u003cstrong\u003e10\u003c/strong\u003e.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eGeneral procedure for the Miyaura borylation of alkenyl fluorosulfates 1.\u003c/strong\u003e To a solution of alkenyl fluorosulfate \u003cstrong\u003e1\u003c/strong\u003e (0.01 mol, 1 eq) in toluene (20 mL), B\u003csub\u003e2\u003c/sub\u003ePin\u003csub\u003e2\u003c/sub\u003e (3.81 g, 0.015 mol, 1.5 eq), PhOK (1.98 g, 0.015 mol, 1.5 eq), and PPh\u003csub\u003e3\u003c/sub\u003e (1.31 g, 5 mmol, 0.2 eq) were added. Then, argon was passed through the reaction mixture upon stirring for 5 min. Pd(PPh\u003csub\u003e3\u003c/sub\u003e)\u003csub\u003e2\u003c/sub\u003eCl\u003csub\u003e2\u003c/sub\u003e (0.702 g, 1 mmol, 10 mol%) was added, and argon was passed through the reaction mixture upon stirring for additional 5 min. The resulting mixture was stirred at 50 \u0026deg;C for 16 h, then cooled. The precipitate was filtered off, the combined filtrates were evaporated in vacuo, and the residue was purified by preparative HPLC to give product \u003cstrong\u003e11\u003c/strong\u003e.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eGeneral procedure for the Buchwald-Hartwig reaction of alkenyl fluorosulfates 1.\u003c/strong\u003e To a solution of alkenyl fluorosulfate \u003cstrong\u003e1\u003c/strong\u003e (0.01 mol, 1 eq) in dioxane (20 mL), amine \u003cstrong\u003e12\u003c/strong\u003e (0.012 mol, 1.2 eq), XantPhos (0.58 g, 1 mmol, 0.1 eq) and Cs\u003csub\u003e2\u003c/sub\u003eCO\u003csub\u003e3\u003c/sub\u003e (3.59 g, 0.014 mol, 1.4 eq) were added. Then, argon was passed through the reaction mixture upon stirring for 5 min. Pd(OAc)\u003csub\u003e2\u003c/sub\u003e (0.067 g, 0.3 mmol, 3 mol%) and Pd\u003csub\u003e2\u003c/sub\u003e(dba)\u003csub\u003e3\u003c/sub\u003e (0.274 g, 0.3 mmol, 3 mol%) were added, and argon was passed through the reaction mixture upon stirring for additional 5 min. The resulting mixture was stirred at 50 \u0026deg;C for 16 h, then cooled. The precipitate was filtered off, the combined filtrates were evaporated in vacuo, and the residue was purified by preparative HPLC to give product \u003cstrong\u003e13\u003c/strong\u003e.\u003c/p\u003e\n\u003ch3\u003e\u0026nbsp;\u003c/h3\u003e"},{"header":"Declarations","content":"\u003cp\u003eSupporting Information\u003c/p\u003e\n\u003cp\u003eThe authors have provided compound characterization data and copies of NMR spectra in the Supporting Information File.\u003c/p\u003e\n\u003cp\u003eFunding Information\u003c/p\u003e\n\u003cp\u003eThe work was funded by Enamine Ltd. O.\u0026nbsp;O.\u0026nbsp;G. received additional funding from Ministry of Education and Science of Ukraine, grant No. 25BF037-01 (0125U002249).\u003c/p\u003e\n\u003cp\u003eAcknowledgements\u003c/p\u003e\n\u003cp\u003eThe authors thank Mr. Bohdan Sosunovych and Dr. Bohdan Vashchenko for their help with the Supporting Information preparation, Prof.\u0026nbsp;Andrii A. Tolmachov for his encouragement and support, and all the brave people of Ukraine for making finalizing this publication possible.\u003c/p\u003e\n\u003cp\u003eConflict of Interests\u003c/p\u003e\n\u003cp\u003eThe authors are employees of Enamine Ltd. offering the building blocks and products described in this paper in the company’s catalog.\u003c/p\u003e"},{"header":"References","content":"\u003cp\u003e[1] Johansson Seechurn, C. C. C.; Kitching, M. O.; Colacot, T. J.; Snieckus, V. Palladium-Catalyzed Cross-Coupling: A Historical Contextual Perspective to the 2010 Nobel Prize. \u003cem\u003eAngewandte Chemie - International Edition\u003c/em\u003e. John Wiley \u0026amp; Sons, Ltd May 21, 2012, pp 5062\u0026ndash;5085. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1002/anie.201107017\u003c/span\u003e\u003c/span\u003e.\u003c/p\u003e\n\u003cp\u003e[2] Volochnyuk, D. M.; Gorlova, A. O.; Grygorenko, O. O. Saturated Boronic Acids, Boronates, and Trifluoroborates: An Update on Their Synthetic and Medicinal Chemistry. \u003cem\u003eChem. \u0026ndash; A Eur. J.\u003c/em\u003e 27 no. 62 (2021): 15277\u0026ndash;15326. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1002/chem.202102108\u003c/span\u003e\u003c/span\u003e.\u003c/p\u003e\n\u003cp\u003e[3] Molander, G. A.; Sandrock, D. L. 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Vinyl MIDA Boronate: A Readily Accessible and Highly Versatile Building Block for Small Molecule Synthesis. \u003cem\u003eTetrahedron\u003c/em\u003e 65 no. 16 (2009): 3130\u0026ndash;3138. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1016/j.tet.2008.11.010\u003c/span\u003e\u003c/span\u003e.\u003c/p\u003e\n\u003cp\u003e[6] Li, L.; Wang, C. Y.; Huang, R.; Biscoe, M. R. Stereoretentive Pd-Catalysed Stille Cross-Coupling Reactions of Secondary Alkyl Azastannatranes and Aryl Halides. \u003cem\u003eNat. Chem.\u003c/em\u003e 5 no. 7 (2013): 607\u0026ndash;612. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1038/NCHEM.1652;SUBJMETA\u003c/span\u003e\u003c/span\u003e.\u003c/p\u003e\n\u003cp\u003e[7] Ruiz-Castillo, P.; Buchwald, S. L. Applications of Palladium-Catalyzed C\u0026ndash;N Cross-Coupling Reactions. \u003cem\u003eChem. 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F.; Chai, C. \u003cem\u003ePurification of Laboratory Chemicals\u003c/em\u003e, 5th ed.; Elsevier: Oxford, (2003).\u003c/p\u003e"},{"header":"Schemes","content":"\u003cp\u003eSchemes 1 to 7 are available in the Supplementary Files section\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[{"identity":"0093b090-099b-4b26-afbe-73339492dabd","identifier":"10.13039/501100019003","name":"Enamine","awardNumber":"N/A","order_by":0},{"identity":"857af275-3f96-4804-831a-e496dd675f7a","identifier":"10.13039/501100007684","name":"Ministry of Education and Science of Ukraine","awardNumber":"25BF037-01 (0125U002249)","order_by":1}],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"Enamine (Ukraine)","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":"building blocks, coupling reactions, fluorosulfates, palladium, enolates","lastPublishedDoi":"10.21203/rs.3.rs-8601840/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8601840/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eAlkenyl fluorosulfates are evaluated as the partners of palladium-catalyzed cross-coupling reactions and alternative to more common triflates and halides. Efficient protocols for the multigram synthesis of title reactants using reaction of carbonyl compounds with SO\u003csub\u003e2\u003c/sub\u003eF\u003csub\u003e2\u003c/sub\u003e were documented. Reactivity of alkenyl fluorosulfates in Suzuki, Sonogashira, Heck, Stille, and Buchwald-Hartwig reactions, as well as Miyaura borylation under typical conditions was studied, and limitations of the methods were established. It was found that alkenyl flurosulfates have similar or even higher reactivity in the cross-coupling reactions as compared to alkenyl triflates.\u003c/p\u003e","manuscriptTitle":"Alkenyl Fluorosulfates – Expedient Partners for Palladium-Catalyzed Cross-Coupling Reactions","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-01-16 11:04:28","doi":"10.21203/rs.3.rs-8601840/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":"68f413b5-412c-4cbe-ac8a-2d90efd06279","owner":[],"postedDate":"January 16th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":61135431,"name":"Organic Chemistry"}],"tags":[],"updatedAt":"2026-01-16T11:04:29+00:00","versionOfRecord":[],"versionCreatedAt":"2026-01-16 11:04:28","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8601840","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8601840","identity":"rs-8601840","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}