Nickel(II) Catalyzed Synthesis of Arylboron and Arylstannane [¹⁸F]Fluorination Precursors from Aryl Fluoride Reference Standards

Objectives: Several published methods enable the conversion of fluoroarenes to their complementary boronic esters (Bpins), which are substrates for copper-catalyzed nucleophilic [¹⁸F]fluorination of electron-neutral and electron-rich arenas [1]. Standard-to-substrate synthetic routes enable the conversion of fluoroarene-appended pharmaceutical agents to their [¹⁸F]radiofluorination substrates without the need to carry out a lengthy multi-step synthesis of precursor. Herein, we report the optimization of a previously reported nickel-catalyzed defluoroboronation reaction, where replacement of an air-sensitive Ni(0) catalyst with Ni(II)trifluoromethanesulfonate (Ni(OTf)₂) enables the preparation of Bpin precursors without the need for specialized equipment, such as a glovebox. In addition, this method can also be used to produce analogous arylstannanes, which are an alternate [¹⁸F]fluorination precursor species [2].

Methods: All reagents were used as received from commercial suppliers. Defluoroborylation conditions reported by Martin et al. were the starting point for further optimization, albeit with Ni(OTf)₂ instead of Ni(COD)₂ as catalyst and the reportedly inactive bis(pinacolato)diboron (Bpin₂) as the boron source instead of bis(neopentyl)diboron. Hexabutylditin (Sn₂Bu₆) was used as the tin source in defluorostannylation reactions. Optimization of reaction parameters was carried out in 4 mL sealed borosilicate vials at a 0.05 mmol scale (w.r.t 4-fluoroanisole substrate). No attempts were made to reduce air/moisture exposure during reaction preparation beyond typical chemical handling procedures. Vials were sealed with a PTFE cap and held at 110 ⁰C without stirring for 18 hours. Thin layer chromatography and analytical HPLC (Luna C18, 5µ, 4.6x150mm; MeCN/H₂O (0.1% TFA) gradient) were then used to determine % yield of 4Bpin-anisole product.

Results: The following reactant loading conditions provided the best %yield: 4-fluoroanisole (0.05 mmol, 1 eq), Ni(OTf)₂ (0.2 eq), tricyclohexylphosphine (0.2 eq), sodium phenoxide (3 eq), Bpin₂ (3 eq), in 1 mL solvent. Other phosphorous- and nitrogen-based ligands were tested but were found to be inferior to PCy­₃. Addition of a chloride ion source (LiCl or TBACl) did not affect yield. MTBE solvent led to the greatest yield (18.3%; HPLC yield), although product formation was also observed with THF, 1,4-dioxane, and toluene as solvents. An isolated yield of 17% was obtained following work-up and column chromatographic purification, and ¹H-NMR was used to confirm identity via comparison with the spectrum of commercially available 4-Bpin-anisole. Formation of 4-SnBu₃-anisole was qualitatively observed with TLC when Bpin₂ was replaced with Sn₂Bu₆.

Conclusion: This work demonstrates proof-of-principle for an operationally simple method to synthesize boron and tin [¹⁸F]fluorination precursors from an electron-rich fluoroarenes in one step and in low but reasonable yield. Effort is currently underway to further optimize this process and increase % yield of the boron and tin products and to determine the overall scope of this method. References [1] Mossine, A. V. et. al. Org. Lett., 2015, 17, 5780-5783; [2] Makaravage, K. J. Org. Lett. 2016, 18, 5440-5443. Research Support: We acknowledge the NIH (R01EB021155 to M.S.S. and P.J.H.S.), US DOE/NIBIB (DE-SC0012484 to P.J.H.S.), and Merck (M.S.S. and P.J.H.S.) for financial support.

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