Electrochemical Synthesis of Fluorinated Orthoesters from 1,3‐Benzodioxoles

Abstract

A scalable, dehydrogenative, and electrochemical synthesis of novel highly fluorinated orthoesters is reported. This protocol provides easy and direct access to a wide variety of derivatives, using a very simple electrolysis setup. These compounds are surprisingly robust towards base and acid with an unusual high lipophilicity, making them interesting motifs for potentially active compounds in medicinal chemistry or agro applications. The use of electricity enables a safe and environmentally benign chemical transformation as only electrons serve as oxidants.

Electrosynthesis 2.0 in 1,1,1,3,3,3‐Hexafluoroisopropanol/Amine Mixtures

“…In contrast to benzylic anodic oxidation of phenols, anisoles and anilides, 1,3-benzodioxoles were found to exhibit unexpected reactivity at complete conversion. [36] Functionalization of 24 occurred at position 2 (26), even in the presence of benzylic methyl groups. This is in contrast to previous work, wherein the benzylic position was functionalized (25) (Scheme 7).…”

“…This can be explained by stabilization of the respective cations after twofold oxidation and deprotonation. Halo substituents (29,32,36), as well as a substitution pattern in position 2 and 5 were tolerated (33, 34, 35). The logP-values of 1,3-benzodioxoles and the corresponding orthoesters were calculated and compared, to determine the lipophilicity of the orthoesters in comparison to the respective 1,3-benzodioxoles (see SI of Ref.…”

“…The logP-values of 1,3-benzodioxoles and the corresponding orthoesters were calculated and compared, to determine the lipophilicity of the orthoesters in comparison to the respective 1,3-benzodioxoles (see SI of Ref. [36]). Remarkably, these values increased by a factor of 1.5 to 2 when fluorinated side chains were installed.…”

“…[35] Many more seminal applications of this powerful combination have been recently published and will be discussed within this review. [36][37][38][39][40]…”

About the selectivity and reactivity of active nickel electrodes in C–C coupling reactions

“…In all these cases, stirring was crucial for successful benzylic crosscoupling reactions, enabling enhanced convection. Sometimes, the formation of additional HFIP ethers was observed, [55][56][57] which could be isolated in lower yields of 12% (4a 0 ). Single crystals were successfully obtained for derivative 4d proving the formation of 2,2-biaryl acetonitrile compounds (CCDC: 1976461).…”