C–C Bond Fluorination via Manganese Catalysis

Abstract

β- and γ-fluorinated ketones are desirable moieties in building blocks for bioactive molecules. Recent progress in installing this functionality has centered around ring-opening carbon–carbon bond cleavage/fluorination of strained cycloalkanols, either using precious silver catalysis or superstoichiometric ceric ammonium nitrate (CAN). Careful study of these methods has allowed us to design and develop a general Earth-abundant-element-catalyzed method for remotely fluorinated ketone synthesis via C–C bond cleavage. Critically, the use of manganese as a catalyst allows for the system to turnover with Selectfluor, permitting low catalyst loadings and high reaction efficiencies. This method allows the efficient synthesis of a wide variety of β- and γ-fluoroketones and is highly scalable, proceeding with no loss of efficiency on gram scale. Preliminary mechanistic experiments implicate a radical pathway. Together, we introduce a robust and simple approach to the remote fluorination of ketones using Earth-abundant-element catalysis with wide substrate tolerance and scalability.

Ring-Opening Selenation of Cyclopropanol for the Selective Synthesis of β-Hydroxy-Substituted Selenylated Ketones

“…1 H NMR (400 MHz, CDCl 3 ) δ 7.72 (d, J = 6.8 Hz, 2H), 7.58 (t, J = 7.5 Hz, 1H), 7.49 (d, J = 6.2 Hz, 2H), 7.41 (t, J = 7.7 Hz, 2H), 7.29−7.16 (m, 3H), 5.28 (td, J = 6.7, 3.6 Hz, 1H), 3.96 (d, J = 6.6 Hz, 1H), 3.40 (dd, J = 13.0, 3.7 Hz, 1H), 3.08 (dd, J = 13.0, 6.9 Hz, 1H). 13…”

“…1 4.08 (dt, J = 11.6, 5.7 Hz, 1H), 2.53 (t, J = 6.9 Hz, 1H). 13 General Procedure for the Synthesis of Cyclopropanols 4a− 4t. Under air atmosphere, cyclopropanol derivatives (1, 0.4 mmol, 1 equiv), diphenyl diselenide (2a, 62.4 mg, 0.2 mmol, 0.5 equiv), and I 2 (∼101.5 mg, 0.4 mmol, 1 equiv) in 1.8 mL of DMSO and 0.2 mL of H 2 O were mixed and heated at 80 °C in a heating block for 18 h. After that, the reaction mixture was quenched with water (10 mL) and extracted with ethyl acetate (3 × 10 mL).…”

“…1 H NMR (400 MHz, CDCl 3 ) δ 7.73 (s, 1H), 7.66 (d, J = 7.8 Hz, 1H), 7.46 (d, J = 8.0 Hz, 1H), 7.36 (d, J = 6.4 Hz, 2H), 7.29 (t, J = 8.0 Hz, 2H), 7.21 (t, J = 8.5 Hz, 2H), 4.53 (dd, J = 8.2, 5.4 Hz, 1H), 4.08 (dt, J = 14.3, 7.3 Hz, 1H), 3.99 (dt, J = 11.9, 5.9 Hz, 1H), 2.41 (t, J = 7.0 Hz, 1H). 13…”

“…1 H NMR (400 MHz, CDCl 3 ) δ 7.84 (td, J = 7.6, 1.9 Hz, 1H), 7.56−7.51 (m, 1H), 7.40−7.33 (m, 3H), 7.28−7.23 (m, 3H), 7.12−7.07 (m, 1H), 4.71 (dd, J = 8.0, 5.4 Hz, 1H), 4.13−4.06 (m, 1H), 4.01 (dt, J = 12.1, 5.6 Hz, 1H), 2.43 (t, J = 7.0 Hz, 1H). 13 19 F NMR (377 MHz, CDCl 3 ) δ −108.17. HRMS (ESI-TOF) m/z: [M + H] + calcd for C 15 H 14 FO 2 Se + , 325.0138; found, 325.0150.…”

Photoinduced Fe-catalyzed bromination and iodination of unstrained cyclic alcohols

“…In this context, the single electron oxidation of cyclic alcohols would generate the O-radical, which undergoes an efficient β-scission and carbon–halogen bond formation. 6 Pioneering works by the groups of Flowers, 7 Murakami, 8 Zhu, 9 Lectka, 10 Loh, 11 and West 12 have shown that the ring-strain release of cyclopropanols or cyclobutanols would provide a strong driving force to enable the ring-opening and halogenation. The transformation of unstrained cyclic alcohols is more challenging.…”