Skip to content
DraconiticResearch
Search Sources API
203,234 studies31 sourcesUpdated 9 min ago
PreprintCC BY-NCChemRxiv

Direct C(sp3)–H/C(sp2)–F Cross-Coupling of Methylpyridines with Aryl Fluorides

  • Seishu Ochiai1,2
  • Zhengyu Zhao3,2
  • Norio Shibata3,2
  1. 1Department of Nanopharmaceutical Sciences
  2. 2Nagoya Institute of Technology
  3. 3Department of Engineering
Open at sourcePDFDOICite

Abstract

Direct C(sp3)–H functionalization of methylpyridines is intrinsically challenging. Herein, we report a transition-metal-free, silylboronate-mediated heterobenzylation of methylpyridines with aryl fluorides. The combination of a silylboronate and KOtBu enables direct C(sp3)–H/C(sp2)–F coupling under mild conditions, providing efficient access to structurally diverse azaarylmethanes. The reaction accommodates π-extended aryl fluorides, polyfluoroarenes, and various 4-alkylpyridines, including substrates bearing multiple potentially reactive C–H or C–F bonds, with useful levels of chemo- and regioselectivity. The method is also applicable to the late-stage functionalization of structurally complex molecules. Alkyl fluorides are also compatible via the C(sp3)–H/C(sp3)–F coupling reaction. Mechanistic studies, including aryl-halide comparison, radical-trapping, investigation of pronucleophile, Hammett plot, competition experiments, and DFT calculation support an ionic pathway involving generation of a heterobenzylic nucleophile followed by nucleophilic substitution of the C–F bond. For electronically neutral and electron-rich aryl fluorides, the observed reactivity is consistent with a concerted SNAr pathway. This strategy provides a complementary approach to conventional transition-metal-catalyzed heterobenzylic arylation and expands the synthetic utility of organofluorine compounds as coupling partners for C–C bond formation.

Related

  1. Structure – Stability Relationships in Aryl- and Heteroarylmethanesulfonyl Chlorides and Fluorides
    Oleksandr I. Shevchuk, Oleksandra V. Shvek, Bohdan V. Vashchenko +5
    ChemRxivPreprintLicence not statedGeneral chemistryChemRxiv
  2. In situ Activation of Ni(II) with Boronic Acids and Application of a Phosphasilinane Ligand enable the Suzuki-Miyaura Cross-Coupling of Deactivated (Hetero)Aryl Chlorides
    Christoph Kremser, Dino Berthold, Alexander F. Siegle +1
    ChemRxivPreprintCC BYFull textOrganic chemistryChemRxiv
  3. Stereoselective β‐C‐aryl Glycosylation Through Ni‐Catalyzed Reductive Cross‐Coupling
    Victor Crespin, Abir Jertila, Eric Daiann Sosa Carrizo +5
    ChemistryEuropePeer-reviewedCC BY 4.0Full textCatalysisOrganic chemistryHAL
  4. Direct Access to α-Aryl-β-Amino Aldehydes via Hypervalent Iodine-Mediated Oxidative Rearrangement of Cinnamyl Amines
    Ali Mubarik, Jin Hang Tang, Hongyu Zhong
    ChemRxivPreprintLicence not statedGeneral chemistryChemRxiv
  5. (iso-bpy)Ni: Isomeric Bipyridine Ligands in Nickel-Catalyzed Coupling of Aryl Chlorides and Alcohols Under Thermal Conditions.
    Maedeh Bagheri, Tanvi Kadaba, Bailey S. Bouley +1
    ChemRxivPreprintLicence not statedGeneral chemistryChemRxiv

Cite

BibTeXRIS
BibTeX
@misc{ochiai2026direct,
  title = {{Direct C(sp3)–H/C(sp2)–F Cross-Coupling of Methylpyridines with Aryl Fluorides}},
  author = {Seishu Ochiai and Zhengyu Zhao and Norio Shibata},
  howpublished = {ChemRxiv},
  year = {2026},
  month = oct,
  doi = {10.26434/chemrxiv.15010838/v1},
  url = {https://chemrxiv.org/doi/full/10.26434/chemrxiv.15010838/v1},
  note = {CC BY-NC},
}
RIS
TY  - UNPB
TI  - Direct C(sp3)–H/C(sp2)–F Cross-Coupling of Methylpyridines with Aryl Fluorides
AU  - Seishu Ochiai
AU  - Zhengyu Zhao
AU  - Norio Shibata
PY  - 2026
DA  - 2026/10/22
PB  - ChemRxiv
DO  - 10.26434/chemrxiv.15010838/v1
UR  - https://chemrxiv.org/doi/full/10.26434/chemrxiv.15010838/v1
AB  - Direct C(sp3)–H functionalization of methylpyridines is intrinsically challenging. Herein, we report a transition-metal-free, silylboronate-mediated heterobenzylation of methylpyridines with aryl fluorides. The combination of a silylboronate and KOtBu enables direct C(sp3)–H/C(sp2)–F coupling under mild conditions, providing efficient access to structurally diverse azaarylmethanes. The reaction accommodates π-extended aryl fluorides, polyfluoroarenes, and various 4-alkylpyridines, including substrates bearing multiple potentially reactive C–H or C–F bonds, with useful levels of chemo- and regioselectivity. The method is also applicable to the late-stage functionalization of structurally complex molecules. Alkyl fluorides are also compatible via the C(sp3)–H/C(sp3)–F coupling reaction. Mechanistic studies, including aryl-halide comparison, radical-trapping, investigation of pronucleophile, Hammett plot, competition experiments, and DFT calculation support an ionic pathway involving generation of a heterobenzylic nucleophile followed by nucleophilic substitution of the C–F bond. For electronically neutral and electron-rich aryl fluorides, the observed reactivity is consistent with a concerted SNAr pathway. This strategy provides a complementary approach to conventional transition-metal-catalyzed heterobenzylic arylation and expands the synthetic utility of organofluorine compounds as coupling partners for C–C bond formation.
ER  -