Synthesis and Physicochemical Properties of 2-SF₅-(Aza)Indoles, a New Family of SF₅ Heterocycles

Abstract

Structural diversity in heterocyclic chemistry is key to unlocking new properties and modes of action. In this regard, heterocycles embedding emerging fluorinated substituents hold great promise. Herein is described a strategy to access 2-SF5-(aza)­indoles for the first time. The sequence relies on the radical addition of SF5Cl to the alkynyl π-system of 2-ethynyl anilines followed by a cyclization reaction. A telescoped sequence is proposed, making this strategy very appealing and reproducible on a gram scale. Downstream functionalizations are also demonstrated, allowing an easy diversification of N- and C3-positions. Ames test, pK a, log P, and differential scanning calorimetry measurements of several fluorinated 2-Rf-indoles are also disclosed. These studies highlight the strategic advantages that a C2-pentafluorosulfanylated motif impart to a privileged scaffold such as an indole.

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

“…By applying the above-mentioned reaction conditions, they added SF 5 Cl to the triple bonds in a regio-and stereoselective fashion (Scheme 10, A). [46] In 2019, Paquin and co-workers synthesized SF 5 -alkynes 30 a-b in a one-pot fashion from the parent alkynes. Dolbier's Et 3 B-initiated method was used, [17] followed by a base-promoted elimination of the chloropentafluorosulfanylated adducts using LiOH (Scheme 10, B).…”

Recent Advances in the Synthesis and Medicinal Chemistry of SF5 and SF4Cl Compounds

“…Scheme 24 Synthesis of SF 5 -N-Ts-indoles 26 2-Oxazolines represent an important class of heterocyclic compounds with applications in many areas, such as medicinal chemistry, catalysis, and materials science. In this context, Paquin and co-workers successfully applied a silver-promoted intramolecular cyclization to a series of N-[2-chloro-3-(SF 5 )-propyl]amides to afford a library of 5-[(SF 5 )-methyl]-2-oxazolines (Scheme 25).…”

Oxidative Fluorination of Heteroatoms Enabled by Trichloroisocyanuric Acid and Potassium Fluoride

“…Moreover, several transformations have been developed in the past few years with SF 5 Cl that may become even more accessible with this ability to synthesize the reagent easily in house. [67][68][69][70][71]…”

“…Between our discovery of a gas‐reagent‐free SF 5 Cl synthesis and Qing's optimization of the extraction procedure, exploring new applications in SF 5 radical chemistry and even designing/synthesizing new possible SF 5 transfer reagents now seem within reach. Moreover, several transformations have been developed in the past few years with SF 5 Cl that may become even more accessible with this ability to synthesize the reagent easily in house [67–71] …”