Fig. 5.

Benchmarking Mn(CF₃-PDP) 1 oxidation to known chemoselective methylene C–H oxidations via experimental and chemoinformatic analysis. (A) Large-scale (1 to 1.5 g) oxidation of 69 and 71 with Mn(CF₃-PDP) 1 at low catalyst loadings (2.5 to 5 mol%) affords known penconazole metabolite 70 and buspirone/tiospirone metabolite precursor 72 in preparative quantities (0.41 to 1.1 g). This compares favorably to previously reported electrochemical oxidations. (B) Mn(CF₃-PDP) 1 oxidation enables streamlining synthesis of 74 en route to linrodostat (BMS-986205). (C) Chemoinformatic investigation of Mn(CF₃-PDP) 1 and all other methods reporting methylene oxidation in N-heterocyclic compounds relative to pharmaceutical chemical space. All examples with ≥15% yield of mono-oxidized compounds were included. Pyrrolidine, piperidine, and azepane from NaDT (sodium decatungstate) were filtered out due to low molecular weight (<100 g/mol). ^aNitrogen was HBF₄•OEt₂ protected followed by modified method D at 0 °C. ^bNitrogen was HBF₄•OEt₂ protected followed by method A at 0 °C. ^cFrom ref. 38. ^dMethod D. ^eMethod B. ^fQuinoline (1.05 equiv.), Fe(acac)₃ (3.75 mol%) and cyclohexyl Grignard (1.0 equiv.) in THF/NMP at rt for 75 min as described in ref. 66. ^gNitrogen was HBF₄•OEt₂ protected followed by method A. ^hRatios are statistically corrected. ⁱThese catalysts can be found in refs. 26, 29, 36–42.