A base-controlled switch of SO2 reincorporation in photocatalyzed radical difunctionalization of alkenes

•Switchable, base-controlled reincorporation/release of SO2•Highly chemoselective and scalable photoinduced protocol•Gaseous alkenes were well tolerated•Broad substrate scope application to functionalization high value-added molecules Control selectivity is a centrally important issue in radical chemistry. In this field, switching product the difunctionalization alkenes, stemming from same starting material, remains greatly challenging owing reactivity instability species their intrinsic patterns. Herein, switchable, SO2 photocatalyzed has been described, offering selective route toward series otherwise difficult-to-obtain ?-trifluoromethylated ketones trifluoromethylated sulfonyl ketones. With this, we could address key challenge chemistry not only understand but also utilize base-switchable chemoselectivity. We believe that method would have diverse applications across many fields chemistry, drug pharmaceutical research material pivotal species. strategy described. By chemodivergent strategy, variety valuable, difficult-to-access can be selectively furnished materials. This features chemoselectivity, broad scope, excellent functional group tolerance, facile scale-up was applied one-pot synthetic procedure. Evaluation reaction conditions mechanistic studies indicate choice base invert chemoselectivity reaction, demonstrating control over pattern. The tuning considered central often particularly areas medical materials science.1Liu J.-Q. Shatskiy A. Kärkäs M.D. Closing gap chemical synthesis.Science. 2020; 368: 1312-1313Google Scholar, 2Plesniak M.P. Huang H.-M. Procter D.J. Radical cascade reactions triggered by single electron transfer.Nat. Rev. Chem. 2017; 1Google 3Zhang B. Studer Recent advances synthesis nitrogen heterocycles via using isonitriles as acceptors.Chem. Soc. 2015; 44: 3505-3521Google 4Wang S. Tang Lei Tuning for radical/radical cross-coupling.Sci. Bull. 2018; 63: 1006-1009Google 5Wang L. Lear J.M. Rafferty S.M. Fosu S.C. Nagib D.A. Ketyl atom transfer catalysis.Science. 362: 225-229Google 6Liu Q. Jackstell R. Beller M. Oxidative catalytic coupling reactions: formation C–C C–X bonds processes.Angew. Int. Ed. 2013; 52: 13871-13873Google 7Zhu Y. Zhang Z. Jin Liu J. G. Han Jiao N. DMSO-enabled O–H activation 1,3(4)-diols.Angew. Engl. 59: 19851-19856Google 8Yang Wang Y.-H. Qiao Gau Carroll P.J. Walsh Schelter E.J. Photocatalytic C–H subtle role chlorine complexation reactivity.Science. 2021; 372: 847-852Google 9Constantin T. Zanini Regni Sheikh N.S. Juliá F. Leonori D. Aminoalkyl radicals halogen-atom agents alkyl aryl halides.Science. 367: 1021-1026Google 10Su Sun X. Wu Catalyst-controlled highly oxygenation olefins: direct approach alcohols, ketones, diketones.Angew. 9808-9812Google 11Jia P. Li Poh W.C. Jiang H. Deng Light-promoted bromine-radical-mediated alkylation amination unactivated C(sp3)–H Bonds.Chem. 6: 1766-1776Google Scholar Over past decade, conceptual photocatalysis electrosynthesis enabled more controllable applicable, which provides attractive tools preparative chemistry.12Prier C.K. Rankic MacMillan D.W.C. Visible light photoredox catalysis with transition metal complexes: organic synthesis.Chem. 113: 5322-5363Google 13Kärkäs Porco Jr., J.A. Stephenson C.R.J. Photochemical approaches complex chemotypes: natural 2016; 116: 9683-9747Google 14Zhou Q.-Q. Zou Y.-Q. Lu L.-Q. Xiao W.-J. Visible-light-induced photochemical through energy-transfer pathways.Angew. 2019; 58: 1586-1604Google 15Strieth-Kalthoff James M.J. Teders Pitzer Glorius Energy mediated visible light: principles, applications, directions.Chem. 47: 7190-7202Google 16Strieth-Kalthoff Triplet energy photocatalysis: unlocking next level.Chem. 1888-1903Google 17Yan Kawamata Baran P.S. Synthetic electrochemical methods since 2000: on verge renaissance.Chem. 117: 13230-13319Google 18Tang Electrochemical oxidative cross-coupling hydrogen evolution: green sustainable way bond formation.Chem. 4: 27-45Google Alkenes, thanks abundance nature man-made commodities, are sought-after substrates transformations, both academic industrial settings.19Huang Bellotti Ma Dalton Bifunctional reagents synthesis.Nat. 5: 301-321Google 20Tang K. C. Olefinic alkenylation.Chem. 1070-1082Google 21Jiang Intermolecular carboamination alkenes.Chem. 49: 1790-1811Google 22Koike Akita New horizons photocatalytic Fluoromethylative 409-437Google 23Jin S.F. Larionov O.V. A new look alkene carboboration.Chem. 1205-1207Google 24Li Cheng H.-G. Yin Difunctionalization involving migration.Angew. 7990-8003Google 25Liu Wei Toward acylation (hetero)arenes: palladium-catalyzed carbonylation olefins ketones.ACS Cent. Sci. 30-38Google 26Hu Jung Zheng Lee Ullah Xie Harms Baik M.-H. Meggers E. Catalytic asymmetric dearomatization visible-light-activated [2+2] photocycloaddition.Angew. 57: 6242-6246Google 27Zhu You S.-L. Synthesis cyclobutane-fused angular tetracyclic spiroindolines visible-light-promoted intramolecular indole derivatives.J. Am. 141: 2636-2644Google 28Pan Ping Guo Kong W. Ni-catalyzed ligand-controlled regiodivergent reductive Dicarbofunctionalization alkenes.J. 143: 10282-10291Google field utilization, three- two-component offers straightforward powerful platform construction molecules, addresses previously intractable challenges enabling novel pathways (Figure 1A).19Huang Nonetheless, difunctionalizations patterns.29Li Luo Cheo H.W. Lan Photoredox-catalysis-modulated, nickel-catalyzed divergent ethylene.Chem. 192-203Google Sulfonyl compounds precursors intermediates chemistry.30Frankel B.A. Bentley Kruger R.G. McCafferty D.G. Vinyl sulfones: inhibitors SrtA, transpeptidase required cell wall protein anchoring virulence Staphylococcus aureus.J. 2004; 126: 3404-3405Google 31Lu Zhao Qi Dioxygen-triggered reaction: aerobic terminal alkynes ?-keto sulfones.J. 135: 11481-11484Google 32Smith Dixon deGruyter J.N. Alkyl sulfinates: discovery.J. Med. 62: 2256-2264Google 33Wang Saidhareddy Construction sulfur-containing moieties total products.Nat. Prod. Rep. 37: 246-275Google 34Markovic Murray P.R.D. Rocke B.N. Shavnya Blakemore D.C. Willis M.C. Heterocyclic Allylsulfones latent heteroaryl nucleophiles reactions.J. 140: 15916-15923Google Sulfone-based participate according two distinct scenarios: retention release. To date, one-sided either or release established.35Yan Teo W.K. Shi Idres S.B. L.-W. smiles rearrangement promoted neutral eosin Y photocatalyst.J. 142: 11357-11362Google 36Li He Liao W.-W. CF3SO2Na bifunctional reagent: trifluoromethylation accompanied insertion access cyclic N-sulfonylimines.Angew. 7266-7270Google 37Monos T.M. McAtee R.C. Arylsulfonylacetamides aminoarylation.Science. 361: 1369-1373Google 38Yu Zhu Efficient docking–migration Difluoromethylation alkenes.Angew. 17156-17160Google 39Tanaka Nakayama Konishi Koike Fluoroalkanesulfinate salts dual fluoroalkyl sources: atom-economical fluoroalkyl-sulfonylation catalysis.Org. Lett. 22: 2801-2805Google For instance, described an SO2-retaining Smiles photocatalysis.35Yan Additionally, trifluoromethylation/SO2 insertion/cyclization developed group.36Li On other hand, Stephenson’s successful aminoarylation electron-rich sulfonylacetamides SO2.37Monos From perspective, switch between reincorporation simple modification conditions, constructing different identical feedstocks, elusive. potential switchable concept include: (1) SO2-reincorporation process, low concentration generated may insufficient react high-energy, short-lived intermediates, produced concentrations; (2) attacked species,40Sarver Bissonnette N.B. Decatungstate-catalyzed sulfinylation: rapid organosulfur functionality.J. 9737-9743Google interfering case desired leading valuable motifs medicinal agrochemical stands among most real-world faced chemists. regard, building blocks 1C).41Kisselev A.F. van der Linden W.A. Overkleeft H.S. Proteasome inhibitors: expanding army attacking unique target.Chem. Biol. 2012; 19: 99-115Google 42Bogen Arasappan Pan Ruan Padilla Saksena A.K. Girijavallabhan V. Njoroge F.G. Hepatitis C virus NS3-4A serine protease SAR P1 derivatives SCH 503034.Bioorg. 2008; 18: 4219-4223Google 43Zhu Gu Aceña J.L. Izawa Soloshonok V.A. methodology CF3-containing drugs.J. Fluor. 2014; 167: 37-54Google 44Dai S.-Y. Yang near-infrared activatable diazocoumarin probe fluorogenic labeling living cells.J. 17156-17166Google 45Lansbergen Meister C.S. McLeod Unexpected rearrangements 1,1-dichloro-1-alkenones 1,1,1-trifluoroalkanones aluminium trichloride.Beilstein Org. 17: 404-409Google 46Kawamoto Sasaki Kamimura ?-trifluoromethylated vinyl triflates absence external trifluoromethyl sources.Angew. 56: 1342-1345Google 47Zheng An Metal-free Aminosulfonylation aryldiazonium tetrafluoroborates DABCO?(SO2)2 hydrazines.Angew. 53: 2451-2454Google types seldomly reported. within gateway 1B). transformation, enol used trifunctional commercially available bases. one K2CO3 enable situ ketones; alternatively, achieved replacement KOH, successfully obtained selectivity. Due dissociation O–S bond, undergo desulfurization-fragmentation, followed formal addition multiple generate manifold.46Kawamoto Scholar,48Su Yuan desulfur-fragmentation reconstruction triflates: ?-trifluoromethyl ketones.Angew. 1338-1341Google Scholar,49Liu Jie Yu induced migration: easy triflates.Adv. Synth. Catal. 360: 267-271Google principle, divided into three components, namely group, SO2, ketone moiety. evaluate hypothesized use triflate products phenyl (1a) reagent 1-hexene (2a) served acceptor 2). While no observed when PhCO2Na NEt3 additives (entries 1 4), 2 3) allowed 3a 4a simultaneously obtained. Interestingly, satisfactory yields good additive (entry 5). stark contrast, upon detected, while 66% 6). Further screening showed [Ir(ppy)2(dtbbpy)][PF6] slightly increase yield 7). Noteworthy, plays essential 4a, none 8 9). Similarly, neither nor without irradiation 10 11). examined solvent effect (see Table S3 details).50Hu X.-Q. Chen J.-R. N-radical hydrazones deprotonation TEMPO mediation.Nat. Commun. 7: 11188Google applying condition-based sensitivity-screening 3),51Pitzer Schäfers Rapid assessment reaction-condition-based sensitivity transformations.Angew. 8572-8576Google discovered compound sensitive oxygen concentration, being generally tolerant temperatures intensities 3; see S1 Figure S2 details). Subsequently, regard optimal condition. As shown 2, such (3a), decene (3b), 4-methylpent-1-ene (3c), allylcyclohexane (3d), amenable protocol. Moreover, groups including ester (3e 3l), ether (3f), (3g), succinimide (3i), phosphate (3j), polyfluoroalkyl (3k) tolerated affording long chain featuring biaryl (3m), (3n), (3o) reacted smoothly 1a, corresponding moderate (49%–65%). 1,2-disubstituted longer times provided 2-pentene 3-hexene substrates, respectively (3p-3r). Pleasingly, ?-methyl substituted (3s-3u) acceptors 3), contain quaternary carbon centers yields. Disubstituted larger steric hindrance converted (3v-3x). Importantly, trisubstituted alkene, 2-methylbut-2-ene, 1a form 60% (3y). Despite prohibitive hinderance, tetrasubstituted 2,3-dimethylbut-2-ene transformed containing 31% after 36 h (3z). utility protocol, examined. monosubstituted commonly nonsteroidal anti-inflammatory drugs (NSAIDs) ibuprofen indometacin proved compatible protocol (3aa 3af). analogs, chloroxylenol (3ab), 2,4-D (3ac), diprogulic acid (3ae) ciprofibrate (3ag), achieved. amino-acid tolerated, 3ad 3ah-3aj These results demonstrate pharmaceutically relevant motifs. Furthermore, disubstituted segments amino tested, providing (3ak-3ao). transformation gaseous high-added-value target attractive, yet target.29Li Scholar,52Tang Zeng Cobalt-catalyzed electrooxidative C-H/N-H [4+2] annulation ethylene ethyne.Nat. 9: 798Google Hence, further benchmark propene ethylene, various 4). aromatic propene, electron-withdrawing groups, halogens (3aq 3ar), nitrile (3as), sulfone (3at), (3au), (3av 3ay), electron-donating reacting 67% (3aw) 62% (3ax), respectively. feasible ?-CF3 3az 26% yield. speculated stability carbon-centered formed accounted 4, 3az). investigate 5),51Pitzer found water content, increased temperature, concentrations 5; Then, SO2. First, offer incorporation final (4b-4f). extended (4g), showing applicability. When submitted standard (4h-4j). Alkenyl halides, 10-chloronon-1-decene (4k), 6-iodo-1-hexene (4l) 5-bromo-1-pentene (4m) fused rings thus functional-group tolerance strategy. thiophene (4q), pyridine (4r), quinoline (4s), amide (4t), naphthalene (4u), benzothiazole (4v), etc., tolerated. It worth mentioning cyclohexene (4w) trans-2-pentene (4x 4y), delivered Unfortunately, trace amounts 2-methylbut-2-ene substrates. investigated (4z-4ab): leucine (4z) valine (4aa) furnish 61% 64% yields, dipeptide (4ab). tested compliance molecule (4ac-4ae). Notably, these base. order streamline present carbotrifluoromethylation carbononafluorobutylation (3ba-3be) synthesized telescoped sulfonic anhydride Analogously, trifluoromethylated/nafluorobutylated (4a, 4af, 4ag). highlight strategic avoiding requirement isolating reactive 6A). scalability carried out scale 6B). 1.37 g (66% yield) 7 mmol presence KOH. scaled up base, allowing 1.48 (63% yield). gain insight mechanism, experiments performed significantly inhibited scavenger, butylated hydroxytoluene (BHT) 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO), suggesting process (for details, supplemental information). evidence 7A). 2aa acceptor, 3bf, resulted ?-fragmentation cyclobutylmethyl radical, afforded ring-opening 30% 2ab acceptor. Stern-Volmer fluorescence-quenching revealed excited state ?IrIII effectively quenched rather than 2a 7B). K2S2O5 added any 7C). result suggested K2S2O5, K2CO3, might intermediate process.53Meng Multicomponent inorganic sulfur dioxide surrogate: diversely functionalized sulfones.Angew. 1346-1353Google Scholar,54For information. Chemical equation KOH + 2KOH ? K2SO3 H2O 2SO2 CO2 consumed excessive K2SO3, source and, thus, offered information).54For voltammetry (CV) study redox (1a 2a), 7D. No obvious oxidation peak before 1.5 V versus SCE (saturated calomel electrode). reduction 2a) detected ?1.8 7D). According literature CV,12Prier Scholar,15Strieth-Kalthoff Scholar,55Teders Henkel Anhäuser Strieth-Kalthoff Gómez-Suárez Kleinmans Kahnt Rentmeister Guldi energy-transfer-enabled biocompatible disulfide–ene reaction.Nat. 10: 981-988Google oxidized reduced ?[Ir(ppy)2(dtbbpy)][PF6] (E1/2(M?/M?) = 0.66 SCE; E1/2(M+/M?) ?0.96 SCE) ?fac-Ir(ppy)3 0.31 ?1.73 SCE), excludes possibility transfer. interaction photosensitizers, photosensitizers properties tested. Figures 7E 7F, (3a 4a) correlate triplet potentials. quenchers, sharp decrease Tables S4 S5 Therefore, abovementioned support plausible mechanism underlying alkenes. Finally, quantum determined 2.1, involve information Based studies, propose 8). Trifluoromethyl catalysis, attack (I). take place pathway A, I II, fragmentation product, along re-formation CF3 initiates again generation scenario, excess acid-base therefore preventing III K2S2O5. Then sulfur-centered add Simultaneously, triflate, trapped newly summary, (88 examples), Trifluoromethylated Various ranging (propene ethylene) mono-, di-, tri-, ones functionalized. played controlling selectivity, manifold. beyond anticipate