Controllable Chemodivergent Synthesis of α-Trifluoromethyl Boronates and gem-Difluoroalkenyl Boronates via Photoredox 1,2-Boron Migratory Carbonylation

Abstract

Fluorinated organoborons are highly valuable building blocks in drug discovery and materials science. However, the direct and step-economic synthesis of these complex structures remains a major challenge. Herein, we report a visible-light-driven, transition-metal-free chemodivergent borocarbonylation of α-trifluoromethyl styrenes. This multicomponent platform precisely controls the ultimate fate of the transient α-CF₃ benzylic radical. Under catalyst-free conditions, an electron donor-acceptor (EDA) complex with Hantzsch ester drives the radical cascade and a subsequent hydrogen atom transfer (HAT) to yield α-trifluoromethyl boronates. Alternatively, an Eosin Y/PMP photoredox system promotes a single-electron transfer (SET) and subsequent β-fluoride elimination to afford gem-difluoroalkenyl boronates. Overall, this strategy successfully manages the kinetic challenges of multi-step radical trapping, providing a practical and programmable platform to construct densely functionalized fluorinated organoborons.

Keywords

Carbonylation / 1,2-Boron migration / Chemodivergence / Photochemistry / Multicomponent / Cascade

References

[1] Han, J.; Kiss, L.; Mei, H.; Remete, A. M.; Ponikvar-Svet, M.; Sedgwick, D. M.; Roman, R.; Fustero, S.; Moriwaki, H.; Soloshonok, V. A. Chemical Aspects of Human and Environmental Overload with Fluorine. Chem. Rev. 2021, 121, 4678–4742.

[2] Ogawa, Y.; Tokunaga, E.; Kobayashi, O.; Hirai, K.; Shibata, N. Current Contributions of Organofluorine Compounds to the Agrochemical Industry. iScience 2020, 23, 101467.

[3] Gu, Y.-Q.; Long, H.-X.; Zhang, D.-D.; Ruan, M.-F.; Liu, G.-K. Difluoromethyl Phenoxathiinium Salt: A New General and Versatile Difluoromethylating Reagent with Divergent ·CF₂H, CF₂H⁺, and :CF₂ Reactivities. Sci. China Chem. 2024, 67, 953–962.

[4] Wang, X.-Y.; Xu, P.; Liu, W.-W.; Jiang, H.-Q.; Zhu, S.-L.; Guo, D.; Zhu, X. Divergent Defluorocarboxylation of α-CF₃ Alkenes with Formate via Photocatalyzed Selective Mono- or Triple C-F Bond Cleavage. Sci. China Chem. 2024, 67, 368–373.

[5] He, J.; Li, Z.; Dhawan, G.; Zhang, W.; Sorochinsky, A. E.; Butler, G.; Soloshonok, V. A.; Han, J. Fluorine-Containing Drugs Approved by the FDA in 2021. Chin. Chem. Lett. 2023, 34, 1001–8417.

[6] Yu, Y.; Liu, A.; Dhawan, G.; Mei, H.; Zhang, W.; Izawa, K.; Soloshonok, V. A.; Han, J. Fluorine-Containing Pharmaceuticals Approved by the FDA in 2020: Synthesis and Biological Activity. Chin. Chem. Lett. 2021, 32, 3342–3354.

[7] Liu, Y.; Wang, X.; Ni, C.; Hu, J. Nucleophilic Trifluoromethylation with CF₃H/LiHMDS: Probing the Nucleophilic Reactivity of LiCF₃ Species. Sci. China Chem. 2025, 68, 505–511.

[8] Suzuki, A. Cross-Coupling Reactions of Organoboranes: An Easy Way to Construct C-C Bonds (Nobel Lecture). Angew. Chem. Int. Ed. 2011, 50, 6722–6737.

[9] Ollivier, C.; Renaud, P. Organoboranes as a Source of Radicals. Chem. Rev. 2001, 101, 3415–3434.

[10] Miyaura, N.; Suzuki, A. Palladium-Catalyzed Cross-Coupling Reactions of Organoboron Compounds. Chem. Rev. 1995, 95, 2457–2483.

[11] Fyfe, J. W. B.; Watson, A. J. B. Recent Developments in Organoboron Chemistry: Old Dogs, New Tricks. Chem 2017, 3, 31–55.

[12] Leonori, D.; Aggarwal, V. K. Stereospecific Couplings of Secondary and Tertiary Boronic Esters. Angew. Chem. Int. Ed. 2015, 54, 1082–1096.

[13] Sandford, C.; Aggarwal, V. K. Stereospecific Functionalizations and Transformations of Secondary and Tertiary Boronic Esters. Chem. Commun. 2017, 53, 5481–5494.

[14] Qiao, J. X.; Lam, P. Y. S. Copper-Promoted Carbon-Heteroatom Bond Cross-Coupling with Boronic Acids and Derivatives. Synthesis 2010, 2011, 829–856.

[15] Suzuki, A. Cross-Coupling Reactions Of Organoboranes: An Easy Way to Construct C–C Bonds (Nobel Lecture). Angew. Chem. Int. Ed. 2011, 50, 6722–6737.

[16] Yin, C.; Tang, S.; Mei, J.; Hu, X.; Zhang, H. Electrochemical Synthesis and Transformation of Organoboron Compounds. Org. Chem. Front. 2023, 10, 3361–3377.

[17] Bull, S. D.; Davidson, M. G.; van den Elsen, J. M. H.; Fossey, J. S.; Jenkins, A. T. A.; Jiang, Y.-B.; Kubo, Y.; Marken, F.; Sakurai, K.; Zhao, J.; James, T. D. Exploiting the Reversible Covalent Bonding of Boronic Acids: Recognition, Sensing, and Assembly. Acc. Chem. Res. 2013, 46, 312–326.

[18] Jiang, N.; Chen, D.; Liu, C. Recent Advances in the Chemistry of α-Oxylboronate Reagents. Org. Chem. Front. 2023, 10, 3684–3700.

[19] Li, X.; Zhang, G.; Song, Q. Recent Advances in the Construction of Tetracoordinate Boron Compounds. Chem. Commun. 2023, 59, 3812–3820.

[20] Zhang, L.; Lovinger, G. J.; Edelstein, E. K.; Szymaniak, A. A.; Chierchia, M. P.; Morken, J. P. Catalytic Conjunctive Cross-Coupling Enabled by Metal-Induced Metallate Rearrangement. Science 2016, 351, 70–74.

[21] Sang, R.; Noble, A.; Aggarwal, V. K. Chiral Benzothiophene Synthesis via Enantiospecific Coupling of Benzothiophene S-Oxides with Boronic Esters. Angew. Chem. Int. Ed. 2021, 60, 25313–25317.

[22] Suzuki, A. Cross-Coupling Reactions Of Organoboranes: An Easy Way to Construct C–C Bonds. Angew. Chem. Int. Ed. 2011, 50, 6722–6737.

[23] Bennett, S. H.; Fawcett, A.; Denton, E. H.; Biberger, T.; Fasano, V.; Winter, N.; Aggarwal, V. K. Difunctionalization of C–C σ-Bonds Enabled by the Reaction of Bicyclo[1.1.0]Butyl Boronate Complexes with Electrophiles: Reaction Development, Scope, and Stereochemical Origins. J. Am. Chem. Soc. 2020, 142, 16766–16775.

[24] Bonet, A.; Odachowski, M.; Leonori, D.; Essafi, S.; Aggarwal, V. K. Enantiospecific Sp²–Sp³ Coupling of Secondary and Tertiary Boronic Esters. Nat. Chem. 2014, 6, 584–589.

[25] Shen, H.-C.; Popescu, M. V.; Wang, Z.-S.; De Lescure, L.; Noble, A.; Paton, R. S.; Aggarwal, V. K. Iridium-Catalyzed Asymmetric Difunctionalization of C–C σ-Bonds Enabled by Ring-Strained Boronate Complexes. J. Am. Chem. Soc. 2023, 145, 16508–16516.

[26] Matteson, D. S.; Mah, R. W. H. Neighboring Boron in Nucleophilic Displacement. J. Am. Chem. Soc. 1963, 85, 2599–2603.

[27] Bigler, R.; Aggarwal, V. K. ortho-Directing Chromium Arene Complexes as Efficient Mediators for Enantiospecific C(Sp²)–C(Sp³) Cross-Coupling Reactions. Angew. Chem. Int. Ed. 2018, 57, 1082–1086.

[28] Xu, J.-X.; Kuai, C.-S.; Chen, B.; Wu, X.-F. Transition-metal-catalyzed carbonylative cross-coupling with alkyl carbon nucleophiles. Chem Catal. 2022, 2, 477–498.

[29] Zhang, W.; Mao, S.; Peng, M.; Xi, Y. Positional Editing of Diverse Functional Groups through Radical 1,2-Boron Shifts. Nat. Synth 2026, https://doi.org/10.1038/s44160-026-01018-3.

[30] Chambers, K. J.; Sanghong, P.; Carter Martos, D.; Casoni, G.; Mykura, R. C.; Prasad Hari, D.; Noble, A.; Aggarwal, V. K. Stereospecific Conversion of Boronic Esters into Enones Using Methoxyallene: Application in the Total Synthesis of 10-Deoxymethynolide. Angew. Chem. Int. Ed. 2023, 62, e202312054.

[31] Llaveria, J.; Leonori, D.; Aggarwal, V. K. Stereospecific Coupling of Boronic Esters with N-Heteroaromatic Compounds. J. Am. Chem. Soc. 2015, 137, 10958–10961.

[32] Aparece, M. D.; Gao, C.; Lovinger, G. J.; Morken, J. P. Vinylidenation of Organoboronic Esters Enabled by a Pd-Catalyzed Metallate Shift. Angew. Chem. Int. Ed. 2019, 58, 592–595.

[33] Xiang, P.; Sun, K.; Shi, A.; An, J.; Chen, X.; Qu, L.; Yu, B. Visible-Light-Induced 1,3-Difunctionalization of Allylboronic Esters Enabled by a 1,2-Boron Shift. Green Chem. 2025, 27, 1820–1827.

[34] Lin, Y.; Guo, Y.; Mu, S.; Lin, G.; Kong, W.; Lei, X.; Xu, J.; Song, Q. Radical 1,2-Boron Shift-Enabled Synthesis of β-Thioalkylboronic Esters from β-Boryl NHPI Esters. Org. Lett. 2025, 27, 9825–9830.

[35] Tan, G.; Paulus, F.; Petti, A.; Wiethoff, M.-A.; Lauer, A.; Daniliuc, C.; Glorius, F. Metal-Free Photosensitized Radical Relay 1,4-Carboimination across Two Distinct Olefins. Chem. Sci. 2023, 14, 2447–2454.

[36] Kaiser, D.; Noble, A.; Fasano, V.; Aggarwal, V. K. 1,2-Boron Shifts of β-Boryl Radicals Generated from Bis-Boronic Esters Using Photoredox Catalysis. J. Am. Chem. Soc. 2019, 141, 14104–14109.

[37] Mahato, S.; Ghorai, D.; Das, K. K.; Roy, L.; Panda, S. Alkoxide-Assisted Stereoselective Functionalization of 1,2-Bis-Boronic Esters Under Photoredox Catalysis. Org. Lett. 2024, 26, 6760–6765.

[38] Jana, K.; Studer, A. Allylboronic Esters as Acceptors in Radical Addition, Boron 1,2-Migration, and Trapping Cascades. Org. Lett. 2022, 24, 1100–1104.

[39] Guo, Y.; Wang, X.; Li, C.; Su, J.; Xu, J.; Song, Q. Decarboxylation of β-Boryl NHPI Esters Enables Radical 1,2-Boron Shift for the Assembly of Versatile Organoborons. Nat. Commun. 2023, 14, 5693.

[40] Wang, H.; Han, W.; Noble, A.; Aggarwal, V. K. Dual Nickel/Photoredox-Catalyzed Site-Selective Cross-Coupling of 1,2-Bis-Boronic Esters Enabled by 1,2-Boron Shifts. Angew. Chem. Int. Ed. 2022, 61, e202207988.

[41] Wang, D.; Mück-Lichtenfeld, C.; Studer, A. Hydrogen Atom Transfer Induced Boron Retaining Coupling of Organoboronic Esters and Organolithium Reagents. J. Am. Chem. Soc. 2019, 141, 14126–14130.

[42] Zhang, F.; Liao, S.; Zhou, L.; Yang, K.; Wang, C.; Lou, Y.; Wang, C.; Song, Q. An Olefinic 1,2-α-Boryl Migration Enables 1,2-Bis(Boronic Esters) via Radical-Polar Crossover Reaction. Chin. J. Chem. 2021, 40, 582–588.

[43] Silvi, M.; Sandford, C.; Aggarwal, V. K. Merging Photoredox with 1,2-Metallate Rearrangements: The Photochemical Alkylation of Vinyl Boronate Complexes. J. Am. Chem. Soc. 2017, 139, 5736-5739

[44] Silvi, M.; Aggarwal, V. K. Radical Addition to Strained σ-Bonds Enables the Stereocontrolled Synthesis of Cyclobutyl Boronic Esters. J. Am. Chem. Soc. 2019, 141, 9511–9515

[45] Guo, Y.; Wang, X.; Li, C.; Su, J.; Xu, J.; Song, Q. Decarboxylation of β-Boryl NHPI Esters Enables Radical 1,2-Boron Shift for the Assembly of Versatile Organoborons. Nat. Commun. 2023, 14, 5693.

[46] Huang, H.; Yu, Z.-Y.; Han, L.-Y.; Wu, Y.-Q.; Jiang, L.; Li, Q.-Z.; Huang, W.; Han, B.; Li, J.-L. N-Heterocyclic Carbene Catalytic 1,2-Boron Migrative Acylation Accelerated by Photocatalysis. Sci. Adv. 2024, 10, eadn84011.

[47] Cui, X.-F.; Wang, L.-C.; Wu, X.-F. Photoredox Borocarbonylation through 1,2-Boron Migration. Catal. Sci. Technol. 2026, 16, 293–301

[48] Zi, Y.; Yang, B.; Ye, Z.; Lin, Y.-M.; Zhao, Q.; Wang, B.; Gong, L. Copper- Catalyzed Phosphorus Radical Transformations for the Assembly of P-Stereogenic Architectures. Angew. Chem. Int. Ed. 2026, 65, e21100.

[49] Xia, G.-D.; He, Y.-Y.; Zhang, J.; Liu, Z.-K.; Gao, Y.; Hu, X.-Q. Deoxygenative gem-Difluorovinylation of Aliphatic Alcohols. Chem. Commun. 2022, 58, 6733–6736.

[50] Wang, M.; Pu, X.; Zhao, Y.; Wang, P.; Li, Z.; Zhu, C.; Shi, Z. Enantioselective Copper-Catalyzed Defluoroalkylation Using Arylboronate-Activated Alkyl Grignard Reagents. J. Am. Chem. Soc. 2018, 140, 9061–9065.

[51] Ichitsuka, T.; Fujita, T.; Ichikawa, J. Nickel-Catalyzed Allylic C(Sp³)–F Bond Activation of Trifluoromethyl Groups via β-Fluorine Elimination: Synthesis of Difluoro-1,4-Dienes. ACS Catal. 2015, 5, 5947–5950.

[52] Lang, S. B.; Wiles, R. J.; Kelly, C. B.; Molander, G. A. Photoredox Generation of Carbon-Centered Radicals Enables the Construction of 1,1-Difluoroalkene Carbonyl Mimics. Angew. Chem. Int. Ed. 2017, 56, 15073–15077.

[53] Fuchibe, K.; Takahashi, M.; Ichikawa, J. Substitution of Two Fluorine Atoms in a Trifluoromethyl Group: Regioselective Synthesis of 3-Fluoropyrazoles. Angew. Chem. Int. Ed. 2012, 51, 12059–12062.

[54] Liu, Y.; Zhou, Y.; Zhao, Y.; Qu, J. Synthesis of Gem-Difluoroallylboronates via FeCl₂-Catalyzed Boration/β-Fluorine Elimination of Trifluoromethyl Alkenes. Org. Lett. 2017, 19, 946–949.

[55] Yamauchi, D.; Nakamura, I.; Nishimura, T. Iridium-Catalyzed Enantioselective Addition of an N-Methyl C–H Bond to α-Trifluoromethylstyrenes via C–H Activation. Chem. Commun. 2021, 57, 11787–11790.

[56] Vayer, M.; Mayer, R. J.; Moran, J.; Lebœuf, D. Leveraging the Hydroarylation of α-(Trifluoromethyl)Styrenes to Access Trifluoromethylated All-Carbon Quaternary Centers. ACS Catal. 2022, 12, 10995–11001.

[57] Guo, Y.; Pei, C.; Jana, S.; Koenigs, R. M. Synthesis of Trifluoromethylated Aziridines Via Photocatalytic Amination Reaction. ACS Catal. 2021, 11, 337–342.

[58] Zeng, H.; Zhu, C.; Liu, C.; Cai, Y.; Chen, F.; Jiang, H. Three Component Hydroxyletherification and Hydroxylazidation of (Trifluoromethyl)alkenes: Access to α-Trifluoromethyl β-Heteroatom Substituted Tertiary Alcohols. Chem. Commun. 2020, 56, 6241–6244.

[59] Martínez-Balart, P.; Velasco-Rubio, Á.; Barbeira-Arán, S.; Jiménez-Cristóbal, H.; Fañanás-Mastral, M. Chemodivergent Alkylation of Trifluoromethyl Alkenes via Photocatalytic Coupling with Alkanes. Green Chem. 2024, 26, 11196–11205.

[60] Zhu, T.; Xie, X.; Zhang, Y.; Liu, H.-W.; Zhang, J.-J.; Tang, L.; Fang, W.; Chen, Z. Chemodivergent Defluorinative Alkylation and Hydroalkylation of α-Trifluoromethyl Alkenes via Eosin Y Catalysis and EDA Photochemistry. Sci. China Chem. 2025, 69, 863–870.

[61] Huang, M.-Z.; Xiao, L.-X.; Zhang, X.-G.; Song, X.-F.; Tu, H.-Y. Chemodivergent Sulfenylation of Trifluoromethylalkenes: Controlled Synthesis of Fluorinated 1,3-Dithioethers and β-Trifluoromethyl Thioethers. Org. Lett. 2025, 27, 7137–7142.

[62] Zhang, J.; Yang, J.-D.; Cheng, J.-P. Chemoselective Catalytic Hydrodefluorination of Trifluoromethylalkenes towards Mono-/gem-Di-Fluoroalkenes under Metal-Free Conditions. Nat. Commun. 2021, 12, 2835.

[63] Wang, J.-X.; Fu, M.-C.; Yan, L.-Y.; Lu, X.; Fu, Y. Photoinduced Triphenylphosphine and Iodide Salt Promoted Reductive Decarboxylative Coupling. Adv. Sci. 2024, 11, 2307241.

[64] Lai, Z.-M.; Xie, Y.; Huang, L.-L.; Guo, J.; Lu, G. Catalytic Enantioselective Synthesis of α-C Chiral Sulfones Enabled by Merging Photoactive Electron Donor–Acceptor Complexes with Nickel Catalysis. Chem. Sci. 2025, 16, 4352–4359.

[65] Guo, J.; Xie, Y.; Lai, Z.-M.; Weng, J.; Chan, A. S. C.; Lu, G. Enantioselective Hydroalkylation of Alkenylpyridines Enabled by Merging Photoactive Electron Donor–Acceptor Complexes with Chiral Bifunctional Organocatalysis. ACS Catal. 2022, 12, 13065–13074.

[66] Xu, M.; Zhao, C.; Huang, Y.; Hu, S.; Cheng, D.; Xu, X. Photoinduced Alkenylation of Alkenyl Sulfones with EDA Complexes between NHPI Esters and HE. Asian J. Org. Chem. 2024, 13, e202400122.

[67] Franceschi, P.; Rossin, E.; Goti, G.; Scopano, A.; Vega-Peñaloza, A.; Natali, M.; Singh, D.; Sartorel, A.; Dell’Amico, L. A Proton-Coupled Electron Transfer Strategy to the Redox-Neutral Photocatalytic CO₂ Fixation. J. Org. Chem. 2023, 88, 6454–6464.

[68] Liang, L.; Wang, Y.-H.; Cui, C.-X.; Deng, X.-S.; Wang, S.-L.; Guo, H.-M.; Li, Y.; Niu, H.-Y.; Mao, R. NADH Analogues Enable Metal- and Light-Free Decarboxylative Functionalization. Angew. Chem. Int. Ed. 2025, 64, e202415131.

[69] Shen, G.-B.; Fu, Y.-H.; Zhu, X.-Q. Thermodynamic Network Cards of Hantzsch Ester, Benzothiazoline, and Dihydrophenanthridine Releasing Two Hydrogen Atoms or Ions on 20 Elementary Steps. J. Org. Chem. 2020, 85, 12535–12543.

[70] Capaldo, L.; Ravelli, D.; Fagnoni, M. Direct Photocatalyzed Hydrogen Atom Transfer (HAT) for Aliphatic C–H Bonds Elaboration. Chem. Rev. 2022, 122, 1875–1924.

[71] Capaldo, L.; Ravelli, D. Hydrogen Atom Transfer (HAT): A Versatile Strategy for Substrate Activation in Photocatalyzed Organic Synthesis. Eur. J. Org. Chem. 2017, 2017, 2056–2071.

[72] Zhang, J.; Rueping, M. Metallaphotoredox Catalysis for Sp³ C–H Functionalizations through Hydrogen Atom Transfer (HAT). Chem. Soc. Rev. 2023, 52, 4099–4120.

[73] Jiang, Y.; Liu, D.; Rotella, M. E.; Deng, G.; Liu, Z.; Chen, W.; Zhang, H.; Kozlowski, M. C.; Walsh, P. J.; Yang, X. Net-1,2-Hydrogen Atom Transfer of Amidyl Radicals: Toward the Synthesis of 1,2-Diamine Derivatives. J. Am. Chem. Soc. 2023, 145, 16045–16057.

[74] Ma, W.-Y.; Leone, M.; Derat, E.; Retailleau, P.; Reddy, C. R.; Neuville, L.; Masson, G. Photocatalytic Asymmetric Acyl Radical Truce–Smiles Rearrangement for the Synthesis of Enantioenriched α-Aryl Amides. Angew. Chem. Int. Ed. 2024, 63, e202408154.

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