Intermolecular Radical Fluoroalkylative Olefination of Unactivated Alkenes

Open AccessCCS ChemistryCOMMUNICATION1 Apr 2022Intermolecular Radical Fluoroalkylative Olefination of Unactivated Alkenes Jiajia Yu†, Huihui Zhang†, Xinxin Wu and Chen Zhu Jiajia Yu† Key Laboratory of Organic Synthesis of Jiangsu Province, College of Chemistry, Chemical Engineering and Materials Science, Soochow University, Suzhou, Jiangsu 215123 †J. Yu and H. Zhang contributed equally to this work.Google Scholar More articles by this author , Huihui Zhang† Key Laboratory of Organic Synthesis of Jiangsu Province, College of Chemistry, Chemical Engineering and Materials Science, Soochow University, Suzhou, Jiangsu 215123 †J. Yu and H. Zhang contributed equally to this work.Google Scholar More articles by this author , Xinxin Wu Key Laboratory of Organic Synthesis of Jiangsu Province, College of Chemistry, Chemical Engineering and Materials Science, Soochow University, Suzhou, Jiangsu 215123 Google Scholar More articles by this author and Chen Zhu *Corresponding author: E-mail Address: [email protected] Key Laboratory of Organic Synthesis of Jiangsu Province, College of Chemistry, Chemical Engineering and Materials Science, Soochow University, Suzhou, Jiangsu 215123 Key Laboratory of Synthetic Chemistry of Natural Substances, Shanghai Institute of Organic Chemistry, Chinese Academy of Science, Shanghai 200032 Google Scholar More articles by this author https://doi.org/10.31635/ccschem.021.202100944 SectionsSupplemental MaterialAboutAbstractPDF ToolsAdd to favoritesDownload CitationsTrack Citations ShareFacebookTwitterLinked InEmail We have disclosed a novel, efficient radical-mediated intermolecular fluoroalkylative olefination of unactivated alkenes. The transformation proceeded through a radical docking-migration cascade, in which a portfolio of strategically designed dual-function alkenylating reagents was harnessed to afford vinylated products with exclusive E-configuration. The reaction featured mild conditions, broad functional group compatibility, and unique chemo-, regio-, and stereoselectivities. The protocol has also provided a useful approach for late-stage olefination of complex natural products and drug derivatives containing alkenyl moieties. Download figure Download PowerPoint Introduction Alkenes are ubiquitous in naturally occurring products and readily available as bulk chemicals widely used in synthetic chemistry. Radical-mediated difunctionalization of alkenes offers a robust tool for alkene utilization by installing two extra valuable functional groups and has received significant attention over the past few decades.1–7 Most of the current approaches rely highly on the properties of alkenes; activated alkenes are usually suitable substrates, for example, styrenes, enol ethers, enamines, acrylates, and so forth, owing to the presence of p–π conjugation that stabilizes nascent alkyl radicals arising from radical addition to alkenes. To surmount the obstacles in radical difunctionalization of unactivated alkenes, the strategy of remote functional group migration (FGM) was unveiled,8–12 and has been applied successfully to a set of elusive alkene transformations, including cyanation,13,14 (hetero)arylation,15–19 alkynylation,20,21 alkenylation,22–26 acylation,27,28 and oximination.28–30 Incorporation of a fluoroalkyl group (CF3, CF2R, or CFRR’) to bioactive molecules usually rendered a substantial change in lipophilicity, metabolic stability, and other bioactivities.31–35 Recently, Liu et al.22 and Studer23 reported elegant examples of fluoroalkylative olefination of unactivated alkenes utilizing FGM (Scheme 1a). Strategic placement of allylic alcohol moiety is a requisite for intramolecular alkenyl migration. Nonetheless, this specific structural feature restricts the practicality of the method to some extent. Thus, developing different intermolecular alkenylating approaches applicable to general unactivated alkenes is of high synthetic value yet remains unmet. Prompted by our achievements in the upgraded FGM protocol, namely docking-migration,36–39 aimed to fill the gap in the present confined alkene scope, we considered pursuing the intermolecular fluoroalkylative olefination of alkenes, which offers superior generality and practicality over the intramolecular pattern. Herein, we reveal the proof-of-principle studies (Scheme 1b), in which a portfolio of rationally designed sulfone-based dual-function reagents was synthesized and applied in the radical-mediated fluoroalkylative olefination of alkenes. The reaction manifested broad functional group compatibility; a vast array of unactivated alkenes bearing various substituents were converted stereospecifically to the vinylated products with uniformly E-configuration. This method was also suitable for activated alkenes and provides a convenient platform for late-stage modification of complex molecules containing alkenyl moieties. Scheme 1 | (a and b) Radical-mediated fluoroalkylative olefination of unactivated alkenes. Download figure Download PowerPoint Results and Discussion The rational design of alkenylating reagents is crucial to the transformation. The dual-function reagents by tethering a bromofluoroalkyl group and an alkenyl group to sulfone are counted to facilitate the docking-migration cascade. At the outset, the fluoroacetonitrile/fluoroacetate-decorated sulfones 2a and 4a were prepared within a few steps (for synthetic details, see Supporting Information) and subjected to the reaction with 1-phenylbutene 1a. After a brief survey of reaction parameters (see Supporting Information), the fluoroalkylative olefination readily occurred, leading to the desired products 3a and 5a in good yields under photochemical conditions.40–43 The addition of tetrabutylammonium bromide (TBAB) massively increased the reaction outcome (Scheme 2). Scheme 2 | Optimized conditions for docking-migration cascade. Download figure Download PowerPoint The optimized reaction conditions were applied to assess the universality of the protocol with the use of the fluoroacetonitrile-decorated reagent 2a. A plethora of unactivated alkenes bearing various functional groups was tested (Scheme 3). Linear alkenes, including low boiling-point alkanes such as isobutene, were transformed readily to the products ( 3b and 3c); a new quaternary all-carbon center was constructed despite the steric hindrance. Many susceptible groups (e.g., hydroxyl, formyl, etc.) remained intact in the reaction ( 3d and 3e). Both enamine and enol ether were also apt to afford the corresponding products ( 3j and 3k). The dual-function reagents could be varied easily on the alkenyl part. The transformation involving harnessing other alkenylating reagents 2b– 2g bearing extra functional groups also proceeded readily, regardless of the electronic properties of the substituents ( 3l– 3q). The presence of arylbromide in products provided a platform for product modification by cross-couplings ( 3p). Scheme 3 | Scope of unactivated alkenes with the use of fluoroacetonitrile-decorated reagents 2a–2g. Reaction conditions: 1 (0.2 mmol), 2a–2g (0.4 mmol), fac-Ir(ppy)3 (2 mol %), and Bu4NBr (0.6 mmol) in dry CH3CN (2.0 mL), irradiated with 14 W blue light-emitting diodes (LEDs) at rt. The yields of isolated products are given. a0.8 mmol Bu4NBr was used. Download figure Download PowerPoint Of particular note, the synthetic value of the protocol was explicitly illustrated in the late-stage olefination of intricate natural products and drug derivatives ( 3r– 3y). A set of complex alkene substrates based on diverse structural features, for example, sulphonamide ( 3r and 3v), steroid ( 3s and 3u), amino acid ( 3t), carbohydrate ( 3w), ester ( 3x), and indole ( 3y), were smoothly converted to the corresponding alkenylated products in good yields. To further examine the practicality of our approach, the method was then used to functionalize activated alkenes (Scheme 4). Electronic characters of styrenes had little impact on the reaction outcome; the existence of either electron-withdrawing (e.g., halides, trifluoromethyl, nitro, and cyano) or -donating (e.g., tert-butyl and acetoxy) substitution resulted in the comparable yields ( 3aa– 3ah). The organoboron Bpin was tolerated, which could serve as the precursor for Suzuki coupling ( 3ai). Positional change (meta- or ortho-) of substituent did not impede the transformation ( 3al, 3ao, and 3ap). The reaction occurred selectively at the terminal alkenyl part in the presence of an alkynyl moiety, also reactive to radical conditions ( 3ak). In addition to styrenes, naphthylalkenes were also suitable substrates for the reaction ( 3am and 3an). Scheme 4 | Fluoroalkylative olefination of aryl alkenes. Reaction conditions: 1 (0.2 mmol), 2a (0.4 mmol), fac-Ir(ppy)3 (2 mol %), and Bu4NBr (0.6 mmol) in dry CH3CN (2.0 mL), irradiated with 14 W blue LEDs at rt. The yields of isolated products are given. a0.8 mmol Bu4NBr was used. Download figure Download PowerPoint Afterward, we turned our attention to evaluating the performance of the fluoroacetate-decorated reagents 4a. A more extensive investigation of substrate scope and functional group tolerance was carried out with a broad range of functionalized unactivated alkenes (Scheme 5). Both linear and cyclic alkenes were suitable substrates ( 5b– 5f). Remarkably, the conversion of cyclohexene gave rise to the unusual cis-product 5e with good diastereoselectivity. Mechanistically, it was attributed to the formation of a five-membered cyclic intermediate, leading to the cis-kinetic product rather than a common trans-thermodynamic product. A diversity of groups such as ester ( 5f and 5k), alkynyl ( 5g), the carboxylic acid ( 5h), unprotected alcohol ( 5j), silyl ( 5l), phosphonate ( 5m), cyano ( 5n), nitro ( 5o), alkylbromide ( 5p), and several heteroarenes ( 5q– 5u), including coumarin were tolerated in the photochemical conditions. Electron-deficient acrylate was apt to afford the desired product, albeit in a low yield ( 5v). Notably, the reaction proceeded readily by variation of the dual-function reagents ( 4b– 4f), leading to the products ( 5w– 5aa). Scheme 5 | Scope of unactivated alkenes with the use of fluoroacetate-decorated reagents 4a–4f. Reaction conditions: 1 (0.2 mmol), 4a–4f (0.4 mmol), fac-Ir(ppy)3 (2 mol %), and Bu4NBr (0.6 mmol) in dry CH3CN (2.0 mL), irradiated with 14 W blue LEDs at rt. The yields of isolated products are given. Download figure Download PowerPoint A series of experiments were conducted to gain deeper insight into the mechanistic pathways (for details, see Supporting Information). The reduction potential of 2a [(Ep/2 = −0.58 V vs saturated calomel electrode (SCE)] determined by cyclic voltammetry indicated that the C–Br bond of 2a could be reduced readily by the excited IrIII* species (E1/2III*/IV = −1.73 V vs SCE). The Stern–Volmer study also verified that the photoexcited fac-Ir(ppy)3 was oxidatively quenched by 2a but could not be reductively quenched by TBAB. The quantum yield of the reaction (Φ = 0.32) along with the light on/off experiment suggested that the reaction mainly went through a photoredox catalytic pathway. However, an appreciable increase in the isolated yield was observed by continuously stirring the reaction in the dark for 36 h after initiating the reaction with visible-light irradiation for 2 h, implying that a subsidiary radical-chain process might also be involved. The proposed mechanism for the intermolecular radical fluoroalkylative olefination is depicted in Scheme 6. First, the excited state of IrIII* arose from visible-light irradiation of IrIII complex is oxidatively quenched by the dual-function reagent 2a, leading to the intermediate a and IrIV species. Radical addition of a to alkene 1 generates the alkyl radical b. Intramolecular interception of the alkyl radical by alkenyl to form the cyclic intermediate c, followed by a sequence of ring-opening homolysis and SO2 extrusion, gives rise to the intermediate e. Simultaneously, single-electron transfer from TBAB (E1/2ox = +0.76 V vs SCE) to IrIV (E1/2IV/III = +0.77 V vs SCE) affords Br radical or bromine,44,45 which reacts with the intermediate e to furnish the final product and regenerates IrIII species (path a). Alternatively, the alkyl radical e might abstract the Br atom from 2a to form the product. Meanwhile, intermediate a is regenerated to perpetuate the radical-chain process (path b). Scheme 6 | Proposed reaction mechanism for the intermolecular radical fluoroalkylative olefination. Download figure Download PowerPoint The multifunctionalized products were transformed into other valuable molecules to demonstrate the product utility (Schemes 7a–7c). The cyano and ester in products were readily hydrolyzed to the corresponding amide ( 6) and carboxylic acid ( 7). The nickel-catalyzed Suzuki coupling of 3a with arylboronic acid converted the C(sp3)–Br bond to a new C–C bond ( 8). Reduction of 5a by lithium aluminum hydride (LAH) afforded the resultant alcohol 9, which could be further transformed into α-methoxy ketone 10 through successive debromination and defluorination under basic reaction conditions. Scheme 7 | (a–c) Product transformations during the intermolecular radical fluoroalkylative olefination process. Download figure Download PowerPoint Conclusion We have uncovered an efficient radical-mediated approach for an intermolecular fluoroalkylative olefination of unactivated alkenes for the first time. The transformation was achieved through a radical docking-migration cascade. Portfolios of rationally designed fluoroalkylative alkenylating reagents were prepared to react with various alkenes, leading to the alkene products with exclusive E-configuration. The reaction featured an extremely broad scope of alkenes. A diversity of substituents, including many susceptible functional groups, were compatible with mild conditions. This protocol also offers a practical tool for late-stage elaboration of alkene into complex molecules. Mechanistic studies revealed that the reaction mainly goes through a photoredox catalytic pathway, but a synergistic radical-chain process might be involved. Supporting Information Supporting Information is available and includes general comments, general procedures, analytic data, and NMR spectra. Conflicts of Interest The authors declare no competing interests. Acknowledgments C.Z. is grateful for the financial support from the National Natural Science Foundation of China (grant no. 21971173), the Project of Scientific and Technologic Infrastructure of Suzhou (grant no. SZS201905), and the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD). References 1. Pintauer T.; Matyjaszewski K.Atom Transfer Radical Addition and Polymerization Reactions Catalyzed by ppm Amounts of Copper Complexes.Chem. Soc. Rev.2008, 37, 1087–1097. Google Scholar 2. Minisci F.Free-Radical Additions to Olefins in the Presence of Redox Systems.Acc. Chem. Res.1975, 8, 165–171. Google Scholar 3. Giese B.Formation of CC Bonds by Addition of Free Radicals to Alkenes.Angew. Chem. Int. Ed.1983, 22, 753–764. Google Scholar 4. Cao M.-Y.; Ren X.; Lu Z.Olefin Difunctionalizations via Visible Light Photocatalysis.Tetrahedron Lett.2015, 56, 3732–3742. Google Scholar 5. Clark A. J.Copper Catalyzed Atom Transfer Radical Cyclization Reactions.Eur. J. Org. Chem.2016, 2016, 2231–2243. Google Scholar 6. Kindt S.; Heinrich M. R.Recent Advances in Meerwein Arylation Chemistry.Synthesis2016, 48, 1597–1606. Google Scholar 7. Song R.-J.; Liu Y.; Xie Y.-X.; Li J.-H.Difunctionalization of Acrylamides Through C-H Oxidative Radical Coupling: New Approaches to Oxindoles.Synthesis2015, 47, 1195–1209. Google Scholar 8. Studer A.; Bossart M.Radical Aryl Migration Reactions.Tetrahedron2001, 57, 9649–9667. Google Scholar 9. Chen Z.; Zhang X.; Tu Y.Radical Aryl Migration Reactions and Synthetic Applications.Chem. Soc. Rev.2015, 44, 5220–5245. Google Scholar 10. Wu X.; Wu S.; Zhu C.Radical-Mediated Difunctionalization of Unactivated Alkenes through Distal Migration of Functional Groups.Tetrahedron Lett.2018, 59, 1328–1336. Google Scholar 11. Li W.; Xu W.; Xie J.; Yu S.; Zhu C.Distal Radical Migration Strategy: An Emerging Synthetic Means.Chem. Soc. Rev.2018, 47, 654–667. Google Scholar 12. Wu X.; Zhu C.Radical-Mediated Remote Functional Group Migration.Acc. Chem. Res.2020, 53, 1620–1636. Google Scholar 13. Wu Z.; Ren R.; Zhu C.Combination of a Cyano Migration Strategy and Alkene Difunctionalization: The Elusive Selective Azidocyanation of Unactivated Olefins.Angew. Chem. Int. Ed.2016, 55, 10821–10824. Google Scholar 14. Wang N.; Li L.; Li Z.-L.; Yang N.-Y.; Guo Z.; Zhang H.-X.; Liu X.-Y.Catalytic Diverse Radical-Mediated 1,2-Cyanofunctionalization of Unactivated Alkenes via Synergistic Remote Cyano Migration and Protected Strategies.Org. Lett.2016, 18, 6026–6029. Google Scholar 15. Wu Z.; Wang D.; Liu Y.; Huan L.; Zhu C.Chemo- and Regioselective Distal Heteroaryl IPSO-Migration: A General Protocol for Heteroarylation of Unactivated Alkenes.J. Am. Chem. Soc.2017, 139, 1388–1391. Google Scholar 16. Wu X.; Wang M.; Huan L.; Wang D.; Wang J.; Zhu C.Tertiary-Alcohol-Directed Functionalization of Remote C(sp3)-H Bonds by Sequential Hydrogen Atom and Heteroaryl Migrations.Angew. Chem. Int. Ed.2018, 57, 1640–1644. Google Scholar 17. Monos T. M.; McAtee R. C.; Stephenson C. R. J.Arylsulfonylacetamides as Bifunctional Reagents for Alkene Aminoarylation.Science2018, 361, 1369–1373. Google Scholar 18. Douglas J. J.; Albright H.; Sevrin M. J.; Cole K. P.; Stephenson C. R. J.A Visible-Light-Mediated Radical Smiles Rearrangement and Its Application to the Synthesis of a Difluoro-Substituted Spirocyclic ORL-1 Antagonist.Angew. Chem. Int. Ed.2015, 54, 14898–14902. Google Scholar 19. Studer A.; Bossart M.Stereoselective Radical Aryl Migrations from Sulfur to Carbon.Chem. Commun.1998, 2127–2128. Google Scholar 20. Xu Y.; Wu Z.; Jiang J.; Ke Z.; Zhu C.Merging Distal Alkynyl Migration and Photoredox Catalysis for Radical Trifluoromethylative Alkynylation of Unactivated Olefins.Angew. Chem. Int. Ed.2017, 56, 4545–4548. Google Scholar 21. Tang X.; Studer A.α-Perfluoroalkyl-β-Alkynylation of Alkenes via Radical Alkynyl Migration.Chem. Sci.2017, 8, 6888–6892. Google Scholar 22. Li L.; Li Z. L.; Gu Q. S.; Wang N.; Liu X.A Remote C-C Bond Cleavage-Enabled Skeletal Reorganization: Access to Medium-/Large-Sized Cyclic Alkenes.Sci. Adv.2017, 3, e1701487. Google Scholar 23. Tang X.; Studer A.Alkene 1,2-Difunctionalization by Radical Alkenyl Migration.Angew. Chem. Int. Ed.2018, 57, 814–817. Google Scholar 24. Wu S.; Wu X.; Wang D.; Zhu C.Regioselective Vinylation of Remote Unactivated C(sp3)-H Bonds: Access to Complex Fluoroalkylated Alkenes.Angew. Chem. Int. Ed.2019, 58, 1499–1503. Google Scholar 25. Yang S.; Wu X.; Wu S.; Zhu C.Regioselective Sulfonylvinylation of the Unactivated C(sp3)-H Bond via a C-Centered Radical-Mediated Hydrogen Atom Transfer (HAT) Process.Org. Lett.2019, 21, 4837–4841. Google Scholar 26. Wu S.; Wu X.; Wu Z.; Zhu C.Regioselective Introduction of Vinyl Trifluoromethylthioether to Remote Unactivated C (sp3)-H Bonds via Radical Translocation Cascade.Sci. China Chem.2019, 62, 1507–1511. Google Scholar 27. Li Z.-L.; Li X.-H.; Wang N.; Yang N.-Y.; Liu X.-Y.Radical-Mediated 1,2-Formyl/Carbonyl Functionalization of Alkenes and Application to the Construction of Medium-Sized Rings.Angew. Chem. Int. Ed.2016, 55, 15100–15104. Google Scholar 28. Yu J.; Wang D.; Xu Y.; Wu Z.; Zhu C.Distal Functional Group Migration for Visible-Light Induced Carbo-Difluoroalkylation/Monofluoroalkylation of Unactivated Alkenes.Adv. Synth. Catal.2018, 360, 744–750. Google Scholar 29. Chen D.; Ji M.; Yao Y.; Zhu C.Difunctionalization of Unactivated Alkenes Through SCF3 Radical-Triggered Distal Functional Group Migration.Acta Chim. Sinica2018, 76, 951–955. Google Scholar 30. Tang N.; Yang S.; Wu X.; Zhu C.Visible-Light-Induced Carbosulfonylation of Unactivated Alkenes via Remote Heteroaryl and Oximino Migration.Tetrahedron2019, 75, 1639–1646. Google Scholar 31. Fluorine in the Life Sciences.ChemBioChem.2004, 5, 557–726 (special issue). Google Scholar 32. Müller K.; Faeh C.; Diederich F.Fluorine in Pharmaceuticals: Looking Beyond Intuition.Science2007, 317, 1881–1886. Google Scholar 33. Purser S.; Moore P. R.; Swallow S.; Gouverneur V.Fluorine in Medicinal Chemistry.Chem. Soc. Rev.2008, 37, 320–330. Google Scholar 34. Hagmann W. K.The Many Roles for Fluorine in Medicinal Chemistry.J. Med. Chem.2008, 51, 4359–4369. Google Scholar 35. Cametti M.; Crousse B.; Metrangolo P.; Milani R.; Resnati G.The Fluorous Effect in Biomolecular Applications.Chem. Soc. Rev.2012, 41, 31–42. Google Scholar 36. Yu J.; Wu Z.; Zhu C.Efficient Docking–Migration Strategy for Selective Radical Difluoromethylation of Alkenes.Angew. Chem. Int. Ed.2018, 57, 17156–17160. Google Scholar 37. Wang M.; Zhang H.; Liu J.; Wu X.; Zhu C.Radical Monofluoroalkylative Alkynylation of Olefins by a Docking-Migration Strategy.Angew. Chem. Int. Ed.2019, 58, 17646–17650. Google Scholar 38. Liu J.; Wu S.; Yu J.; Lu C.; Wu Z.; Wu X.; Xue X.; Zhu C.Polarity Umpolung Strategy for the Radical Alkylation of Alkenes.Angew. Chem. Int. Ed.2020, 59, 8195–8202. Google Scholar 39. Zhang H.; Wang M.; Wu X.; Zhu C.Designed Heterocyclizing Reagents for Rapid Assembly of N-Fused Heteroarenes from Alkenes.Angew. Chem. Int. Ed.2021, 60, 3714–3719. Google Scholar 40. Yoon T. P.; Ischay M. A.; Du J.Visible Light Photocatalysis as a Greener Approach to Photochemical Synthesis.Nat. Chem.2010, 2, 527–532. Google Scholar 41. Narayanam J. M. R.; Stephenson C. R. J.Visible Light Photoredox Catalysis: Applications in Organic Synthesis.Chem. Soc. Rev.2011, 40, 102–113. Google Scholar 42. Prier C. K.; Rankic D. A.; MacMillan D. W. C.Visible Light Photoredox Catalysis with Transition Metal Complexes: Applications in Organic Synthesis.Chem. Rev.2013, 113, 5322–5363. Google Scholar 43. Xuan J.; Xiao W. J.Visible-Light Photoredox Catalysis.Angew. Chem. Int. Ed.2012, 51, 6828–6838. Google Scholar 44. Jia P.; Li Q.; Poh W. C.; Jiang H.; Liu H.; Deng H.; Wu J.Light-Promoted Bromine-Radical-Mediated Selective Alkylation and Amination of Unactivated C (sp3)-H Bonds.Chem.2020, 6, 1766–1776. Google Scholar 45. Jiang Y.-Y.; Dou G.-Y.; Xu K.; Zeng C.-C.Bromide-Catalyzed Electrochemical Trifluoromethylation/Cyclization of N-Arylacrylamides with Low Catalyst Loading.Org. Chem. Front.2018, 5, 2573–2577. Google Scholar Previous articleNext article FiguresReferencesRelatedDetails Issue AssignmentVolume 4Issue 4Page: 1190-1198Supporting Information Copyright & Permissions© 2021 Chinese Chemical SocietyKeywordsradical reactionsalkene difunctionalizationfluoroalkylmigrationolefinationAcknowledgmentsC.Z. is grateful for the financial support from the National Natural Science Foundation of China (grant no. 21971173), the Project of Scientific and Technologic Infrastructure of Suzhou (grant no. SZS201905), and the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD). Downloaded 1,464 times PDF DownloadLoading ...