General Co-catalytic Hydrothiolation of gem-Difluoroalkenes

Abstract

Regioselective functionalization of gem-difluoroalkenes enables convergent late-stage access to fluorinated functional groups, though most functionalization reactions proceed through defluorinative functionalization processes that deliver monofluorovinyl products. In contrast, fewer reactions undergo net hydrofunctionalization to generate difluorinated products. Herein, we report a photocatalytic hydrothiolation of gem-difluoroalkenes that enables access to a broad spectrum of α,α-difluoroalkylthioethers. Notably, the reaction successfully couples nonactivated substrates, which expands the scope of accessible molecules relative to previously reported reactions involving organo-or photocatalytic strategies. Further, this reaction successfully couples biologically relevant molecules under aqueous conditions, highlighting potential applications in both late-stage and biorthogonal functionalizations.

Peroxide-Initiated Hydrophosphinylation of gem-Difluoroalkenes

“…16 In contrast, the addition of P-based radicals into gemdifluoroalkenes avoids the pitfalls of nucleophilic addition/ elimination sequences (Figure 2D). 17 This radical-based strategy has proved useful in hydrothiolation reactions of aliphatic gem-difluorinated alkenes to generate new C−S bonds 18 and hydrophosphinylation reactions of unactivated alkenes to generate new C−P bonds. 19 However, for gemdifluoroalkenes, only a single example exists of a corresponding hydrophosphinylation reaction of a dialkyl-substituted gemdifluoroalkene to generate an α,α-difluorodiphenylphosphine oxide, which uses an uncommon peroxide to initiate the radical chain process, and generates a mixture of regioisomers (Figure 2D).…”

Synthesis of Difluorocyclopropanes via Visible‐Light‐Mediated [1+2] Cycloaddition of Diazo Esters with gem‐Difluoroalkenes and Evaluation of their Antifungal Activity

“…[45][46][47][48][49][50][51][52][53][54] Meanwhile, gemdifluoroalkenes has been used in the synthesis of various mono-and difluorinated compounds. [54,55] Theoretically, photo-induced [1 + 2] cyclization of diazo esters with gem-difluoroalkenes could provide a valuable and clean pathway for the synthesis of more diversified difluorocyclopropanes. Based on previous work, [56][57][58][59] herein, we have achieved a [1 + 2] cyclization of gem-difluoroalkenes with carbene, leading to a series of unique difluorocyclopropanes, which exhibit high antifungal activity (Scheme 1d).…”

A diselenide additive enables photocatalytic hydroalkoxylation ofgem-difluoroalkenes

“…Initial reaction design was inspired by successful applications of photocatalytic hydrothiolation reactions of gem-difluoroalkenes that proceed through a thiyl radical intermediate. [29][30][31] Accordingly, initial screening focused on the identification of photocatalysts and bases that might promote a proton-coupled electron transfer (PCET) event to generate alkoxyl radicals, which would then add to gem-difluoroalkene substrates. While exploring this strategy, we failed to obtain 410% yields of the desired a,adifluorinated ethers, and instead regularly formed ArCH 2 -CF 3 and (Ar)(H)CQC(F)(OR) as side products.…”

“…Thioether 8 presumably formed through the addition of phenylthiyl radicals to the gemdifluoroalkene substrate, which can occur under similar photocatalytic conditions. [29][30][31] Thus, the use of a sterically hindered disulfide and several diselenides were evaluated with the goal of identifying additives that would facilitate the hydroalkoxylation reaction and also reduce the nonproductive hydrothiolation reaction (Table S1, ESI †). 32,40,41 Notably, the use of (PhSe) 2 and (BnSe) 2 provided high yields of desired a,a-difluorinated ether 7a and did not form selenoether side product 8 (entries 8, 9, Table 1).…”