Catalytic Desymmetrization of 1,3‐Difluoropropan‐2‐ols via C−F Bond Activation Using a Phosphazene Base Affords Monofluoromethyl‐Substituted Epoxides

Abstract

A facile synthetic route to monofluoromethyl substituted epoxides via the desymmetrization of 1,3‐difluoropropan‐2‐ols is reported. A silicon‐containing additive activates the inert C(sp3)−F bond in aliphatic fluorides to promote the intramolecular epoxidation under metal‐free reaction conditions. A phosphazene base, which acts as a catalyst, is indispensable for this silicon‐induced defluorinative cyclization.

C-F bond activation under transition-metal-free conditions

“…Activation of the allylic C-F bond could be accomplished through treatment with a Lewis acid (Scheme 35), which was demonstrated by Ichikawa's group [97]. In the presence of stoichiometric EtAlCl 2 , the (trifluoromethyl)alkenes readily eliminated F − and underwent cationic substitution with arenes to produce 3,3-difluoroallylated arenes (197)(198)(199)(200)(201)(202) in good yields. The silyl ether 202 was isolated after the quenching procedure.…”

“…Based on the previous work (Scheme 70), Shibata's group [202] reported a phosphazene base-catalyzed C−O bond formation to synthesize monofluoromethyl-substituted epoxides (Scheme 79). The proposed mechanism shows that the sterically demanding base P 4 -t Bu first reacts with the alcohol 446 to afford reactive alkoxide ion pair A.…”

Synthesis of Fluoro‐, Monofluoromethyl‐, Difluoromethyl‐, and Trifluoromethyl‐Substituted Three‐Membered Rings

“…Shortly after Pace's report, Luisi, Nagaki, and co‐workers [83] reported the formation of the fluoroiodomethyl lithium and fluoroiodostanylmethyl lithium under continuous‐flow conditions to tackle the high instability of these species in batch. The authors applied their methodology to the trapping of various electrophiles including ketones, which afforded the corresponding fluoroepoxides (Scheme 59).…”

“…In 2019, Shibata′s group [83] reported the synthesis of α‐substituted monofluoromethylated epoxides 180 . Starting from 1,3‐difluoropropan‐2‐ol derivatives, the corresponding epoxides 180 a – h were obtained according to a defluorinative cyclization catalyzed by the P 4 ‐ t Bu phosphazene base in the presence of N(TMS) 3 (Scheme 60).…”

Role of donor‐acceptor functional groups in N3P3 cyclic‐triphosphazene backbone. Unraveling bonding characteristics from natural orbitals within an extended transition state‐natural orbital for the chemical valence scheme

“…Phosphazene compounds depict an important class of compounds because they exhibit outstanding properties that can be involved in the development of new applications, such as liquid crystals, and in the obtaining of photosensitive materials . Such systems give rise to potential applications including drug delivery systems, biological activity, and catalysis . Such systems have also been used as base support for the formation of nanomaterials, as well as heterocyclic‐triphosphazenes that can form interacting host‐guest systems.…”