A Continuous-Flow Protocol for Light-Induced Benzylic Fluorinations

Abstract

A continuous-flow protocol for the light-induced fluorination of benzylic compounds is presented. The procedure uses Selectfluor as the fluorine source and xanthone as an inexpensive and commercially available photoorganocatalyst. The flow photoreactor is based on transparent fluorinated ethylene propylene tubing and a household compact fluorescent lamp. The combination of xanthone with black-light irradiation results in very efficient fluorination. Good to excellent isolated yields were obtained for a variety of substrates bearing different functional groups applying residence times below 30 min.

Application of Benzylic C-H Fluorination for the Formal Synthesis of syn-α, β-Difluoro-γ-amino Acid

“…Because no corrosive and toxic nucleophilic fluorinating reagents are used and the overall yield is 18% (the previous approach is about 5%), the approach developed in this work could be viewed as more practical than the previous one. The key benzylic C-H reaction developed by Chen and co-workers [11,14] was scaled up to one gram without decreasing its original efficiency. A striking fluorine effect was observed: a carbon with one fluorine atom on the adjacent carbon is much less reactive than an ordinary carbon for the benzylic C-H fluorination.…”

“…Then the mixture of 14 and 3 was purified by flash column chromatography with silica gel [V(n-he-xane)∶V(dioxane) ＝15∶1] to afford 14 as a white solid (297 mg, 28%) and recovered starting material 3 (100 mg). [11,14] 2-((2R,3R)-2,3-Difluoro-3-phenylpropyl)isoindoline-1,3-dione (2): [21a] …”

“…In a parallel, the research groups of Chen, [11] Inoue [8] Lectka, [12,13] Kappe [14] group achieved benzylic C-H bonds fluorination with the aid of visible light in the presence of an organocatalyst such as diarylketones, N,N-dihydroxypyromellitimide and 1,2,4,5-tetracyanobenzene. Method without using transition-metal catalysts and organocatalysts has also been developed.…”

“…[30] To our delight, however, the modified conditions of Chen's method [11,14] (Entry 4, Table 2) showed a promise for overcoming this fluorine effect, as the yield of the reaction was increased to 38% when the reaction temperature was increased (Entry 7, Table 2). After extensive investigation (not shown), the products were obtained in 68% yield with 1.58∶1 of syn/anti ratio, when a large amount of photocatalyst and fluorinating reagent were used at 60 ℃ (Entries 8～9).…”

The past, present, and future of the Yang reaction

“…De Frutos and Kappe have further shown that the reaction efficiency could be significantly improved with flow chemistry and black-light irradiation. 46 …”