Copper-catalyzed defluorinative arylboration of vinylarenes with polyfluoroarenes

An unprecedented but challenging defluorinative arylboration has been achieved. Enabled by a copper catalyst, an interesting procedure on defluorinative arylboration of styrenes has been established. With polyfluoroarenes as the substrates, this methodology offers flexible and facile access to provide a diverse assortment of products under mild reaction conditions. In addition, by using a chiral phosphine ligand, an enantioselective defluorinative arylboration was also realized, affording a set of chiral products with unprecedented levels of enantioselectivity.

Polyuorinated aromatics are highly prized molecules in pharmaceutical chemistry 1 and materials science 2 due to their special properties such as metabolic stability and intermolecular p-p F -interactions (Scheme 1). 3 Two new polyuorinated aromatic-containing drugs were approved by the FDA in 2021. 4 During the past decades, the dominant uorination approaches were the introduction of a single uorine atom into an aromatic ring via C-H activation 5 or C-X substitution. 6 While these methods are more applicable for the preparation of mono-uorinated arenes, they are unsuitable for polyuoroarenes due to the requirement of the preinstallation of multiple functional groups or unique directing groups. Actually, polyuorinated aromatics were produced by the substitution of a uorine atom (deuorinative functionalization) of easily available simple polyuoroarenes, including nucleophilic aromatic substitution (S N Ar), reaction via a radical polyuoroaryl intermediate, and metal-catalyzed C-F bond functionalization (Scheme 2a). 7 For example, a simple and robust hydrodeuorination of polyuoroarenes (HDF) has been well established. 8 In addition, deuorinative borylation of polyuoroarenes has also been realized in recent years. 9 Among the synthetic transformations, carbon-carbon crosscoupling of simple polyuoroarenes is one of the most widespread applications of deuorinative functionalization, offering a general approach for synthesizing more complex polyuoroaryl-containing products. However, the reactions are usually limited to carbon nucleophiles and using stoichiometric amounts of organometallic reagents such as alkyl-or arylmetallic reagents (metal: lithium, magnesium, and zinc), which is a great challenge for complex molecules because of the poor compatibility with diverse functional groups. 10 To avoid the use of stoichiometric organometallic regents, Ritter's group reported a photocatalytic decarbonylative polyuoroarylation of aliphatic carboxylic acid via radical addition to polyuoroarenes and then elimination of a uoride. 11 Additionally, several examples of transition-metalcatalyzed carbon-carbon cross-coupling of polyuoroarenes have also been disclosed in the absence of organometallic reagents. 12 Radius and co-workers 13 described a nickel-catalyzed C-F bond arylation of polyuoroarenes with aryl boronic acid as the nucleophilic reagent in 2006. Subsequently, such reactions were extended to palladium based catalytic systems. 14 Recently, Xiong and co-workers reported a deuorinative hydroarylation of alkenes with polyuoroarenes by in situ catalyst formation. 15 Additionally, the metal-catalyzed arylboration of alkenes has recently emerged as a general method to access diverse alkyl boronic esters with good regioselectivity. 16 In 2014, Semba and Nakao 17 reported their results on arylboration of alkenes by cooperative Pd/Cu catalysis. The reaction was generally initiated by alkene migratory insertion into a Cu-Bpin species, which leads to  19 Yin, 20 and Liao. 21 However, most of the aryl electrophile leaving groups are restricted to I, Br, or OTf (Scheme 2b). The arylboration of aryl uorides with alkenes has not been realized because of the strength of the C-F bond. Inspired by their creative achievements and our continual interest in borylation of alkenes, 22 we attempted to develop a new catalyst system for the simultaneous borylation and deuorinative C-C cross coupling. We speculated that the b-boryl alkylcopper(I) complex, which is generated in situ, might attack the C-F bond of polyuoroarenes through the S N Ar mechanism, bypassing the metal oxidative addition step. In addition, stereospecic transformation of the chiral b-boryl alkylcopper(I) complex could be realized in the presence of a chiral ligand. 23 Herein, we report a copper-catalyzed deuorinative arylboration of vinylarene with polyuoroarenes to access b-polyuoroaryl boronates with excellent reactivity and regioselectivity. With slight modications of the reaction conditions, an enantioselective deuorinative arylboration of alkenes was developed as well, producing a set of chiral b-polyuoroaryl boronates with unprecedented levels of enantioselectivity (Scheme 2c).
To study this deuorinative arylboration transformation, styrene 1a, pentauorobenzonitrile 2a, and B 2 pin 2 were selected as the model substrates. As shown in Table 1, by using low valent CuCl as the catalyst, xantphos L1 as the ligand, and NaO t Bu as the base at 60°C for 16 h, para-deuorinative b-polyuoroaryl boronates 3a were successfully obtained in 35% yield and a small amount of ortho-deuorinative product was detected (Table 1, entry 1). In the testing of solvents, non-polar solvent n-heptane decreased the reaction efficiency and regioselectivity (Table 1, entry 2). When the reaction was performed in coordinative solvents such as 1,4-dioxane or THF, product 3a was obtained in moderate yield with excellent regioselectivity. Then bidentate phosphine ligands were examined, and smaller bite angle DPEphos L3 delivered the desired product 3a in 64% yield, while side product b-boryl styrene was detected ( With optimized reaction conditions in hand, we investigated various vinylarenes for this transformation. As shown in Scheme 3, styrenes bearing electron-donating groups can be utilized successfully and deliver the desired products in moderate to good yields with excellent regioselectivity (3b-3g). meta-, ortho-Substituted or disubstituted styrenes underwent this transformation smoothly to give the target products (3i-3n). Electron-withdrawing groups such as F, acetyl, and highly lipophilic OCF 3 groups (3o-3q) on the styrenes were suitable as well. Furthermore, functional groups including borates, indole, pyrrole, morpholine, methylthio, amino, and furan groups (3r-3y) are well compatible, offering the corresponding products in moderate to good yields with excellent regioselectivity. In addition, the substrate containing terminal alkene (3z) was tolerated and selectively transformed. It is noteworthy that when 1,2-dihydronaphthalene was used, the corresponding anti-addition product (3aa) can be produced with good regioselectivity and diastereoselectivity which could benet from the benzo fused system. ortho-Deuorinative products were obtained when styrenes contain sterically bulky groups or strong electron-withdrawing groups (3bb-3dd). More complex vinylarenes were successfully transformed under our deuorinative arylboration conditions, delivering the corresponding products in moderate to good yields. However, no reaction occurred with aliphatic alkenes (both internal and terminal).
To further explore the substrate scope of this deuorinative arylboration reaction, we further evaluated a series of poly-uoroarenes (Scheme 4). Tetrauoro-substituted benzonitriles were competent coupling partners, providing the arylboration product 5a in moderate yield with poor regioselectivity and 5b with excellent regioselectivity. 3,4,5-Triuorobenzonitrile was also assessed, and meta-deuorinative arylboration product 5c was obtained in moderate yield. Moreover, p-uorobenzonitrile was tested as well, and a 15% yield of the corresponding product was detected by 1 H NMR. CF 3 -substituted polyuoroarenes and poly-uoropyridine were tested as well and corresponding products (5e and 5f) were obtained in moderate to good yields. However, this transformation is unsuitable with electron-rich polyuoroarenes. The results obtained here are due to the joint effects from electronic and steric inuences. Additionally, besides as the activating group, the nitrile group could also coordinate with the copper catalyst to facilitate C-F bond activation.
In order to further demonstrate the synthetic value of these deuorinative arylboration reactions, synthetic transformation of product 3a was carried out (Scheme 5). A gram-scale reaction was performed, and 3a was obtained in 60% yield. The C-B bond can be easily converted into a hydroxyl group by NaBO 3 oxidation, providing the corresponding b-hydroxy poly-uoroarene (6a). Furthermore, high-value potassium borate salt (6b) was obtained in a simple step with KHF 2 . Subsequently, functional groups including bromo and vinyl were produced through bromination (6c) and vinylation (6d). Additionally, the product 3a and also the potassium borate salt (6b) are suitable for palladium-catalyzed C-C bond formation reactions based on reported procedures. 24 We subsequently set out to develop an enantioselective variant of the copper-catalyzed deuorinative arylboration of vinylarenes (Scheme 6). Styrene 1a and pentauorobenzonitrile 2a were selected as model coupling partners. Copper complexes supported by chiral bidentate phosphine ligands were evaluated. In the presence of the chiral (S,S)-Ph-BPE L6*, the chiral 3a ′ was afforded in 48% yield with 73% ee. Low conversions and enantioselectivity were measured with other commercially available chiral phosphine ligands L7*-L11*. Although, (R,S p )-Josiphos ligand L12* effectively improves the yield of 3a ′ , enantioselectivity was very poor. Thus, with the L6* as the best Scheme 3 Reaction conditions: styrene (0.2 mmol), polyfluoroarenes (1.5 equiv.), B 2 pin 2 (1.5 equiv.), CuCl (10 mol%), DPEphos (10 mol%), NaO t Bu (2.0 equiv.), THF (0.2 M), stirred at room temperature (23°C) for 16 h, isolated yields. Site selectivity and ratio were determined by 1 H NMR, 19 F NMR and GC analysis. ligand, we further evaluated other parameters. The temperature has little effect on enantioselectivity, but an increase in the chemical yield was achieved. To our surprise, the transformation was processed with LiO t Bu as the base and delivered the 3a ′ in moderate yield with excellent enantioselectivity. However, other bases, mixed bases, and solvents all failed to improve the yields since the formation of the side hydroboration products and vinyl boronate products could not be avoided (see ESI †).
Aer obtaining the optimized asymmetric reaction conditions, we investigated the substrate scope of the reaction (Scheme 7). Overall, various styrene derivatives worked well under the catalytic system, leading to the corresponding chiral products in moderate yields with excellent enantioselectivities. Functional groups including boron, sulfur, and terminal alkene were all compatible to deliver the desired products with excellent enantioselectivities. The absolute conguration of 3c ′ was clearly conrmed by X-ray crystallography.
In summary, starting from readily available vinylarenes and polyuorenes, a copper-catalyzed deuorinative arylboration has been described in this study. The transformation provides a direct approach for the synthesis of b-polyuoroaryl boronates and displays a broad functional group tolerance. Synthetic transformations of the b-polyuoroaryl boronates demonstrate their utility. Notably, by using (S,S)-Ph-BPE as the ligand, an enantioselective deuorinative arylboration was also achieved.
[e] 5e and 5f were oxidized to the corresponding alcohols before isolation.
Scheme 5 Large-scale reaction and transformations of organoboranes.
Author contributions XFW directed this project and revised the manuscript. FPW, XWG and HQG performed all the experiments and prepared the manuscript and ESI. †

Conflicts of interest
There are no conicts to declare.