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• The incorporation of fluoroalkyl group into organic molecules has been widely applied in pharmaceuticals and agrochemicals development [1-5]. In this context, the synthesis of bioactive molecules with C(sp³)–CF₃ scaffold is particularly sought after [6-15]. The amine or ether bearing α-CF₃ group is highly attractive for lead candidate study in medicinal chemistry. While, existing methods to give these compounds mainly focus on the nucleophilic addition of trifluoromethyl reagent or transformation of CF₃-substituted imines (ketones) [16-19]. These methods usually need multistep transformations or expensive reagents. An efficient and direct synthetic route is still highly desirable.

  In the last two decades, the gem-difluoroalkenes have been used as one type of ideal substrates for the synthesis of high-value-added organofluorine compounds [20-23]. However, these reports usually gave the monofluoroalkenes and derivatives via β-F elimination by transition-metal catalyst [20-30]. Recently, the fluorine retentive reaction to access functional α-fluoroalkyl containing products has been disclosed [31-43]. The nucleophilic addition of fluoride ion to gem-difluoroalkenes is a novel strategy to generate α-CF₃-containing products [35-39], which was applied in the palladium-catalyzed allylation and arylation [40-42]. In 2019, the Malcolmson group developed the synthesis of α-trifluoromethyl benzylic amines by using N-containing gem-difluoroalkenes through palladium catalyzed arylation (Scheme 1A) [43]. All of these reactions proceeded through C–C bond formation from α-CF₃ organopalladium intermediate, the C–N or C–O bond formation is still unexplored.

  Scheme 1

  

  Scheme 1.  The synthesis of α-fluoroalkyl containing amines with transition-metal catalyst.

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  On the other hand, the aminofluorination of simple olefins with transition metal catalysis is a powerful strategy for the synthesis of fluorine-containing amines [44-52]. Liu group developed pioneer and attractive palladium-catalyzed aminofluorination of simple styrenes [53]. The more steric hindrance trifluoromethyl products and the cleavage of C(sp³)–O bond by high valent Pd species has not been discovered. Later, Zhang group developed the radical aminofluorination by copper catalysis with regioselectivities opposite to that of palladium catalysis (Scheme 1B) [54]. Inspired by these remarkable works and our continuous interest in the synthesis of α-fluoroalkyl containing compounds, herein, we report the palladium catalyzed aminofluorination and multi components oxy-aminofluorination of gem-difluoroalkenes with N-fluorobenzenesulfonimide (NFSI), which was used as the nitrogen source as well as the oxidant, affording various functional α-CF₃ containing amines (Scheme 1C). Noteworthy, the three components oxy-aminofluorination reaction involved the cleavage of C(sp³)–O bonds in easily available alkyl ethers (such as THF, dioxane, DME), providing the α-CF₃ benzylic ethers bearing terminal amino groups with excellent regioselectivity. We also realized the succession C(sp³)–O bond cleavage, affording two ethers insertion products with excellent selectivity by addition of Lewis acids, which might be benefit for the coordination of ether to the Pd(Ⅳ) center. We suggested that the C(sp³)–O bond cleavage initiated by the coordination of ether to the Pd(Ⅳ) center would be one attractive strategy for the transformation of ethers [55-58]. Additionally, this reaction could access to α-CF₂H containing amines from monofluoroalkenes. The challenge of this catalytic system does not just include the steric hindrance of trifluoromethyl group and β-fluorine elimination, the one pot incorporation of a fluorine, an amino and an oxy substituent with high regioselectivity is also an important synthetic challenge.

  We began our studies by examining the reaction parameters of gem-difluoroalkene 1a and NFSI in the presence of Pd(OAc)₂ catalysis (Table 1). We found that the ligand L1 was efficient to give the oxy-aminofluorination product 2a in 47% yield with high chemoselectivity through C(sp³)–O cleavage in THF (entry 1). The yield of 2a could be increased to 75% when NaF was added (entry 2). Very interesting, the more challenged two THF insertion product 3a could be obtained in 60% yield when AgSbF₆ was used as an additive (entry 3, for more details see Table S1 in Supporting information). The addition of AgSbF₆ might be favored for the coordination of THF to Palladium center and accelerated the succession cleavage of C(sp³)–O bond [59-61]. Trace amount of three THF insertion products observed under the reaction conditions of entry 3 (3a: 3a' = 93:7). We next examined the solvent effect and found that the aminofluorination product 4a was obtained (entries 4–8, for more details see Table S2 in Supporting information). The product 4a could be obtained in 99% yield when MeO^tBu was used as solvent at 80 ℃ (entry 4). The DCE gave the comparative result, while DMF and ⁱPrOH gave no desired product (entries 5–8). The ligand structure plays an important role to deliver product 4a (entries 9–16). The PdCl₂ and Pd(dba)₂ exhibited similar reactivity to the Pd(OAc)₂ catalyst (entries 17 and 18). Low yield of 3a was observed when the reaction proceeded at 40 ℃ (entry 19). Furthermore, 4a could be obtained in 99% yield when the Pd catalysis loading decreased to 2 mol% (entry 20). The use of chiral ligands L1-L5 were found with low levels of enantiocontrol (for more details see Tables S4 and S5 in Supporting information).

  Table 1

  

  Table 1.  Investigation of reaction conditions.^a

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  With the optimized reaction conditions, we first explored the generality of the three components oxy-aminofluorination reaction. To our delight, the substrate scope was found to be very broad, and gave corresponding α-trifluoromethyl benzylic ethers with terminal amino groups in moderate to high yield. As shown in Scheme 2, the reaction was tolerated with an array of substituents at the para-, meta- or ortho-position and produced the corresponding products 2b-2j in 34%−93% yield. The (hetero)aryl-substituted alkenes and biaryl gem-difluoroalkenes were also briefly investigated and yielded the oxy-aminofluorination products 2k-2o in 52%−88% yield. The structure of 2k was confirmed by X-ray crystallography (CCDC: 2215518). Subsequently, we examined C(sp³)–O cleavage process of other cyclic ethers. Delightedly, when dioxane was used instead of THF, the corresponding α-trifluoromethyl benzylic ether could be obtained in moderate yield through C(sp³)–O cleavage in dioxane (2p, 66% yield and 2q, 60% yield). The six number ring pyran was also successfully applied in this oxy-aminofluorination reaction, giving the corresponding product 2r in 68% yield. Low efficiency for the seven number cyclic ether and gave the corresponding product 2s in 12% yield. The α-trifluoromethyl benzylic ether without terminal amino group 2t was obtained in 52% yield when linear ether DME was used instead of cyclic ether. The monofluoroalkene delivered the α-CF₂H benzylic amine 2u in 50% yield with THF. Other ethers such as 2-phenyloxirane and phenyl methyl ether failed to give desired products.

  Scheme 2

  

  Scheme 2.  Substrate scope of oxy-aminofluorination reaction with one ether insertion. Reaction conditions: 1 (0.20 mmol), NFSI (0.40 mmol), Pd(OAc)₂ (10 mol%), L1 (10 mol%), ether (2.0 mL), 80 ℃, 36 h, isolated yields.

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  Then, we investigated the generality of the much more challenged four components oxy-aminofluorination reaction, giving two THF insertion products (Scheme 3). A series of functional gem-difluoroalkenes with electron-donating groups were well tolerated to give two THF insertion products with high selectivity through the succession double C(sp³)–O cleavage (3a, 60% yield, 3f, 45% yield, 3g, 54% yield and 3h, 59% yield). Trace amount of desired product observed for the Cl-substituted alkene. The substituents at meta- or ortho-position and the (hetero)aryl-substituted alkenes were compatible (3i-3k, 34%−42% yield). Some biaryl gem-difluoroalkenes were briefly investigated (3m-3p, 41%−54% yield). Other cyclic ether such as pyran was successfully to deliver the desired two ether insertion product (3r, 26% yield). No desired products obtained when dioxane or seven number ether were used. The conjugated gem-difluoroalkene only gave the aminofluorination product 4y in 35% yield.

  Scheme 3

  

  Scheme 3.  Substrate scope of oxy-aminofluorination reaction with two ether insertion. Reaction conditions: 1 (0.20 mmol), NFSI (0.40 mmol), Pd(OAc)₂ (10 mol%), L1 (10 mol%), AgSbF₆ (0.02 mmol), hexane (1.5 mL), ether (0.5 mL), 80 ℃, 15 h, isolated yields. ^a PdCl₂ (10 mol%) was used instead of Pd(OAc)₂.

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  Finally, we turned our attention to study the substrate scope of aminofluorination reaction (Scheme 4). The reaction also tolerated with various functional groups at the para-position of the benzene ring of gem-difluoroalkenes (4b-4g, 72%−99% yield). The reaction showed high efficiency for the electron rich substrates. While the electron-withdrawing substituted alkene (CF₃ group at para-position) could not give the desired product (4h), only with starting materials recovered. Low reactivity might be due to the coordination of electron-deficient alkene to low-valent palladium, which would stabilize the low oxidation state and not benefit for the generation of high-valent Pd(Ⅳ) species [62,63]. The alkenes with substituents at the meta-position were also tolerated to yield the α-trifluoromethyl benzylic amines 4i-4l in 48%−95% yield. The ortho-substituted alkenes with methyl group needed higher temperature to produce the amine product 4m, possibly due to steric effect. While, the electron-rich alkene with MeO- group at the ortho-position delivered the product 4n in 80% yield even with 2 mol% Pd catalysis loading. The structure of 4m was confirmed by X-ray crystallography (CCDC: 2212514). (Hetero)aryl-substituted alkene gave the corresponding products 4o in 68% yield. Furthermore, the biaryl gem-difluoroalkenes with electron-donating groups, electron-withdrawing groups or halo-groups at the benzene ring worked smoothly to deliver the products 4p-4x in 53%−99% yield. The conjugated gem-difluoroalkene was also compatible to afford the trifluoromethylated allylic amine 4y in 60% yield with excellent regioselectivity. However, the reaction of (1, 1-difluoroprop-1-en-2-yl)benzene or (4, 4-difluorobut-3-en-1-yl)benzene all failed to give the desired products, only with starting materials recovered.

  Scheme 4

  

  Scheme 4.  Substrate scope of aminofluorination reaction. Reaction conditions: 1 (0.20 mmol), NFSI (0.40 mmol), Pd(OAc)₂ (10 mol%), L1 (10 mol%), MeO^tBu (2.0 mL), 80 ℃, 24 h, isolated yields. ^a Pd(OAc)₂ (2 mol%), L1 (2 mol%). ^b Pd(OAc)₂ (10 mol%), L1 (10 mol%), 48 h, 120 ℃.

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  The CF₃-containing amine products could undergo several transformations (Scheme 5). These reactions were successfully scaled up to 2.0 mmol without the erosion of yield, giving product 2a in 74% yield and 4a in 99% yield (Scheme 5A). The α-trifluoromethyl ether 2a could be reduced to product 5 in 84% yield. The α-trifluoromethyl benzylic amine 4a also could be reduced to product 6 in 85% yield. Furthermore, the primary amine 7 was obtained in 65% yield and could be combined with aldehyde via reductive amination to obtain the product 8 in 53% yield (Scheme 5B).

  Scheme 5

  

  Scheme 5.  Scale-up reaction and derivatization.

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  We then performed several experiments to investigate the influence of substituent in the alkene and ether (Scheme 6). When the simple styrene was used, only starting materials were recovered with Pd/L1 catalysis. The reaction worked smoothly for the monofluoroalkene (, affording the α-difluoromethyl benzylic amine products 10 in 90% yield. The monofluoroalkene ( was also successfully converted to 10 in 87% yield. These results indicated the importance of fluorine atom at the alkenes, but irrelevant with the alkene configuration. When methyl n-butyl ether was used instead of cyclic ether, α-trifluoromethyl benzylic ether 11 was obtained in 24% yield and 12 was obtained in 8% yield. This result suggested that the C(sp³)–O cleavage prior occurred at the position with small steric hindrance substituent. When different amount of THF was added in MeO^tBu solvent, the THF insertion product was the major product after 50 equiv. THF was added (for more details see Table S3 in Supporting information). Several kinetic studies of the reaction of gem-difluoroalkene 1a, NFSI, [Pd] catalysis and ligand effect by the method of initial rates were performed (Scheme 6C). This reaction exhibited a first-order dependence on the concentration of gem-difluoroalkene 1a, [Pd] catalysis and NFSI (for more details in Supporting information). Notably, these kinetic data are consistent with gem-difluoroalkene into Pd(Ⅱ)–F, but are inconsistent with the Pd(Ⅳ)–F insertion [53,64-66].

  Scheme 6

  

  Scheme 6.  Mechanistic studies. (a) Influence of substituents at the alkenes. (b) Influence of substituents at the ether. (c) Kinetic studies.

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  Based on these above results and previous studies in palladium-catalyzed aminofluorination of alkenes [44-52,64-72], we proposed a plausible mechanism in Scheme 7. The reaction was initiated by the generation of Pd(Ⅱ) intermediate A. After the coordination of gem-difluoroalkene 1a to the Pd(Ⅱ)–F species (TS1), Pd(Ⅱ)–F inserted or F⁻nucleophilic addition to the 1a and formed the intermediate B, which would undergo oxidative addition of intermediate B to NFSI and gave the Pd(Ⅳ) species C. The oxidation of intermediate B to give the Pd(Ⅳ) intermediate C is consistent with our kinetic studies in Scheme 6C. The reductive elimination from the intermediate C delivered the α-trifluoromethyl benzylic amine product 4a. When the cyclic ether was used, the cyclic ether (THF) coordinated to the Pd(Ⅳ) center and the C(sp³)–O bond cleavage occurred to form the Pd(Ⅳ)–O species from Pd(Ⅳ)–N species intermediate C (TS2) and gave the intermediate D, which would undergo reductive elimination to give the α-trifluoromethyl benzylic ether product 2a. Alternatively, another THF would coordinated to the Pd(Ⅳ) center (TS3) and C(sp³)–O bond cleavage from the Pd(Ⅳ)–O species to give the intermediate E, which undergo reductive elimination to deliver the two THF insertion product 3a.

  Scheme 7

  

  Scheme 7.  Proposed mechanism.

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  In summary, we have developed a novel palladium-catalyzed aminofluorination and three/four components oxy-aminofluorination of gem-difluoroalkenes, in which the NFSI was served not only as the fluorine and nitrogen source but also the oxidant. The reaction proceeded with excellent regioselectivity and atom economy, affording a variety of functionalized α-trifluoromethyl benzylic amines and ethers. Particularly, the intermolecular oxy-aminofluorination simultaneously introduced a fluorine, an amino and an oxy substituent in one pot through C(sp³)–O bonds cleavage of the easily available ethers. We not only realized one ether insertion process, but also two ether insertion process through succession C(sp³)–O bonds cleavage. This study contributed to the rapid and divergent synthesis of α-fluoroalkyl containing compounds, and provided insight for further development of functionalization of olefins.

  Acknowledgments

  This work is supported by the National Natural Science Foundation of China (Nos. 82130103, U1804283, 21801067), the Central Plains Scholars and Scientists Studio Fund (No. 2018002), and the Project funded by the Natural Science Foundation of Henan Province (Nos. 202300410225, 222102310562) and Henan Postdoctoral Science Foundation (No. 202103087). We also thank the financial support from Henan Key Laboratory of Organic Functional Molecules and Drug Innovation.

  Supplementary materials

  Supplementary material associated with this article can be found, in the online version, at doi:10.1016/j.cclet.2023.109155.

  
  
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  Scheme 1  The synthesis of α-fluoroalkyl containing amines with transition-metal catalyst.

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  Scheme 2  Substrate scope of oxy-aminofluorination reaction with one ether insertion. Reaction conditions: 1 (0.20 mmol), NFSI (0.40 mmol), Pd(OAc)₂ (10 mol%), L1 (10 mol%), ether (2.0 mL), 80 ℃, 36 h, isolated yields.

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  Scheme 3  Substrate scope of oxy-aminofluorination reaction with two ether insertion. Reaction conditions: 1 (0.20 mmol), NFSI (0.40 mmol), Pd(OAc)₂ (10 mol%), L1 (10 mol%), AgSbF₆ (0.02 mmol), hexane (1.5 mL), ether (0.5 mL), 80 ℃, 15 h, isolated yields. ^a PdCl₂ (10 mol%) was used instead of Pd(OAc)₂.

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  Scheme 4  Substrate scope of aminofluorination reaction. Reaction conditions: 1 (0.20 mmol), NFSI (0.40 mmol), Pd(OAc)₂ (10 mol%), L1 (10 mol%), MeO^tBu (2.0 mL), 80 ℃, 24 h, isolated yields. ^a Pd(OAc)₂ (2 mol%), L1 (2 mol%). ^b Pd(OAc)₂ (10 mol%), L1 (10 mol%), 48 h, 120 ℃.

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  Scheme 5  Scale-up reaction and derivatization.

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  Scheme 6  Mechanistic studies. (a) Influence of substituents at the alkenes. (b) Influence of substituents at the ether. (c) Kinetic studies.

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  Scheme 7  Proposed mechanism.

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  Table 1.  Investigation of reaction conditions.^a

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