Regioselective Synthesis of Pyridine-SF₄-Methyl Ketones via Hydration of Pyridine-SF₄-Alkynes

Abstract

Herein, we report the metal-free hydration of pyridine-SF 4 -alkynes, under acidic conditions and with reaction durations ranging from 5 min to 10 h at room temperature, to synthesize pyridine-SF 4 -methyl ketones in yields of 59−93%. Further, we demonstrate the synthetic applications of the synthesized pyridine-SF 4 -methyl ketones, such as chlorination, NaBH 4 reduction, Baeyer− Villiger oxidation, and the generation of enol-triflates. These compounds hold promise as useful building blocks in the syntheses of a wide range of SF 4 -containing drug candidates.

De‐Risking S‐F Bond Formation: A Gas Cylinder‐Free Strategy to Access S(IV) and S(VI) Fluorinated Compounds**

“…Hydrotetrafluorosulfanylation was carried out by reacting ArSF 4 Cl with the corresponding α‐diazo ketone under basic conditions, and compounds 8 a – b were isolated in good yields. Up to date, α‐SF 4 R compounds could be accessed only via multiple step synthesis [27] . Finally, we dedicated our attention to the conversion of R‐SF 4 Cl into R‐SF 5 (Scheme 4‐E).…”

“…Up to date, α-SF 4 R compounds could be accessed only via multiple step synthesis. [27] Finally, we dedicated our attention to the conversion of R-SF 4 Cl into R-SF 5 (Scheme 4-E). As a proof of concept, four aromatic-SF 4 Cl precursors were converted into Ar-SF 5 either in presence of KHF 2 or AgBF 4 as a fluorinating agent.…”

Chemistry of Pentafluorosulfanyl Derivatives and Related Analogs: From Synthesis to Applications

“…[95] Furthermore, metal-free regioselective hydration of the C�C bond to give previously inaccessible α-pyridine-SF 4 -methyl ketones 146 was reported by the group of Shibata (Scheme 45, B). [96] However, this has not been the only strategy to acquire R-SF 4 -methyl ketones. The team of Welch prepared the targeted structures 146 under either acidic or basic conditions, starting from chloroacetates (Scheme 45, C and D).…”

“…Furthermore, metal‐free regioselective hydration of the C≡C bond to give previously inaccessible α ‐pyridine‐SF 4 ‐methyl ketones 146 was reported by the group of Shibata (Scheme 45, B) [96] . However, this has not been the only strategy to acquire R‐SF 4 ‐methyl ketones.…”

Hydration of Unsymmetrical Internal Alkynes: Factors Governing the Regioselectivity

“…Very recently, Shibata reported the synthesis of pyridine-SF 4 -methyl ketones 94 via a regioselective β-hydration of pyridine-SF 4 -alkynes 93 (Scheme 58). 104 DFT calculations and 13 C NMR spectroscopy experiments were used to determine the density charge on Cα (negative) and Cβ (positive) during the hydration reaction. The protonation of the pyridine nitrogen results in the addition of a second proton to Cα, forming a vinyl cation.…”