Synthesis of 2-Fluorobenzofuran by Photocatalytic Defluorinative Coupling and 5-endo-trig Cyclization

Abstract

An alkyl radical-triggered dual C−F bond cleavage of α-CF 3 -ortho-hydroxystyrenes for the synthesis of 2-fluorobenzofurans was developed. The visible-light-induced defluorinative cross-coupling reactions of α-CF 3 -ortho-hydroxystyrenes with a variety of carboxylic acids produced gem-difluoroalkenes, which underwent S N V-type 5-endo-trig cyclization to give 2-fluorobenzofurans. Mechanistic studies indicated that the electron transfer between phenoxyl radicals and carboxylates was the major pathway for the generation of alkyl radicals.

Radical-mediated [3 + 2 + 1] annulation of α-polyfluoromethyl alkenes with arylisocyanates enabled by C(sp3)–F activation

“…The plausible mechanism for this [3 + 2 + 1] annulation protocol was proposed on the basis of the present results, reported precedent literature studies 4–8 and DFT calculations (Fig. 2 and Scheme 3).…”

“…In contrast to the impressive progress in C(sp 3 )–F functionalization of aryl-CF 3 and carbonyl-CF 3 made using transition-metal catalysis and the radical strategy in recent years, 3 direct C(sp 3 )–F functionalization of alkenyl-CF 3 has been comparatively far less developed (Scheme 1a-ii), 4 due to the challenge of a highly reactive alkene moiety in alkenyl-CF 3 that renders it predisposed to the competing γ-selective functionalization and fluoride elimination cascades for the synthesis of gem -difluoroalkenes (Scheme 1a-i). 5,6 To date, two available strategies for the direct C(sp 3 )–F functionalization of α-trifluoromethyl alkenes have been developed (Scheme 1a-ii): 4 the first one pioneeringly reported by Zhu, Jiang and co-workers 4 a is base-mediated direct anionic S N 2-type substitution of C(sp 3 )–F bonds with nucleophiles (such as oximes) (Scheme 1a-ii, top), 4 a – d and the other first established by Feng and co-workers 4 e involves the use of a transient activating reagent (an amine traceless mediator) to generate the highly active gem -difluoroallyl intermediate and indirectly accomplish C(sp 3 )–F functionalization through S N 2′-amination, ammonium formation and Pd-catalyzed regioselective allylic arylation cascades (Scheme 1a-ii, bottom). 4 e , f While efficient and highly selective, the methods for direct C(sp 3 )–F functionalization of α-trifluoromethyl alkenes remain extremely scarce so far, probably due to the limited availability of nucleophiles and transient activating reagents 6 besides the aforementioned competing γ-selective functionalization issue.…”

“…5,6 To date, two available strategies for the direct C(sp 3 )–F functionalization of α-trifluoromethyl alkenes have been developed (Scheme 1a-ii): 4 the first one pioneeringly reported by Zhu, Jiang and co-workers 4 a is base-mediated direct anionic S N 2-type substitution of C(sp 3 )–F bonds with nucleophiles (such as oximes) (Scheme 1a-ii, top), 4 a – d and the other first established by Feng and co-workers 4 e involves the use of a transient activating reagent (an amine traceless mediator) to generate the highly active gem -difluoroallyl intermediate and indirectly accomplish C(sp 3 )–F functionalization through S N 2′-amination, ammonium formation and Pd-catalyzed regioselective allylic arylation cascades (Scheme 1a-ii, bottom). 4 e , f While efficient and highly selective, the methods for direct C(sp 3 )–F functionalization of α-trifluoromethyl alkenes remain extremely scarce so far, probably due to the limited availability of nucleophiles and transient activating reagents 6 besides the aforementioned competing γ-selective functionalization issue. 5,6…”

“…4 e , f While efficient and highly selective, the methods for direct C(sp 3 )–F functionalization of α-trifluoromethyl alkenes remain extremely scarce so far, probably due to the limited availability of nucleophiles and transient activating reagents 6 besides the aforementioned competing γ-selective functionalization issue. 5,6…”

Picking Two out of Three: Defluorinative Annulation of Trifluoromethyl Alkenes for the Synthesis of Monofluorinated Carbo‐ and Heterocycles

“…Zhou et al switched the nucleophilic site from radical precursors to the trifluoromethyl alkenes, as exemplified by the defluorinative reaction of α-CF 3 -ortho-hydroxystyrenes with carboxylic acids for the synthesis of 2-fluorobenzofurans (Scheme 23). [55] α-CF 3 -ortho-hydroxystyrenes usually are exclusive substrates for the defluorinative reactions of trifluoromethyl alkenes. The o-OH group decreases the electron-deficient nature of α-trifluoromethylstyrenes, thus decreasing the reactivity of the CÀ C double bond toward nucleophilic radical species.…”