Introduction

Fluorine-containing compounds have drawn increasing attention in pharmaceutical science1,2, organic synthesis3, and materials development4,5, due to their unique biological and physicochemical properties. Specifically, the CF2-containing alkenes, which typically serve as lipophilic isosteric and isopolar synthons to alcohols, amino, thiols, or carbonyl groups, play critical roles in pharmaceuticals and drug design and are thus one of the most attractive fluorine-containing structural motifs (Fig. 1A)6,7,8. Conventional approaches to access CF2-containing alkenes mainly involve the use of active pre-synthetic difluoromethylating reagents through electrophilic substitution9, nucleophilic substitution10, radical pathways11,12,13, or difluorocarbene insertion14,15. However, the modular synthesis of diverse CF2-containing alkenes from a single starting material remains underdeveloped. Only one known method has been identified for the synthesis of these valuable molecules with controllable selectivity: the rhodium-catalyzed regioselective nucleophilic addition of gem-difluoroallenes with thiols, enabling the formation of two types of CF2-containing olefins (Fig. 1B)16.

Fig. 1: Background and challenges in divergent defluoroborylation of trifluoromethylated alkynes.
figure 1

A Drug molecules with CF2/CF2H-containing alkenes. B Rhodium-catalyzed regioselective nucleophilic addition of gem-difluoroallenes with thiols. C Known structurally diverse gem-difluorovinyl organoboron. D Possible products from borylation of trifluoromethyl alkynes. E Defluoroborylation or hydrodefluorination of trifluoromethyl alkynes (this work).

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On the other hand, fluorine-containing organoboron compounds have emerged as novel synthons in organic synthesis due to the ease of converting C-B bond into various types of functional groups, which brings diversity and complexity to the target molecules17,18,19,20. Several methods for the construction of these valuable building blocks have been established in recent years21,22,23. For instance, selective monodefluoroborylation of trifluoromethyl olefin has been reported as an efficient and general approach for the formation of gem-difluorovinyl mono-organoboron compounds containing a C(sp3)-B bond24,25,26,27,28,29. More recently, a range of elegant and intriguing works on the preparation of gem-difluoroalkenes containing C(sp2)-B bonds, such as β/γ/δ/ε-substituted C-B bonds, have been reported by Hosoya30, Shibata31, Ito32, Fu33,34, Cho35, et al. (Fig. 1C). Furthermore, Song and co-workers disclosed a fascinating copper-catalyzed diborylation of 1-chloro-1-trifluoromethylalkenes, affording sp2/sp3 diborylated products bearing CF2 functionality36. Although great progresses have been made, exploiting a unified system for the selective construction of fluorinated organoboron skeletons with a controllable number of boronate moieties would present an appealing and highly adaptable strategy for synthesizing these valuable building blocks, potentially paving the way for novel approaches to the synthesis of fluorinated pharmaceutical candidates.

To commence the goal for divergent synthesis of CF2-containing alkenes and fluorinated organoboron reagents, we are particularly intrigued by trifluoromethylated alkynes. Firstly, these types of compounds are readily available through known methods37,38,39,40. Secondly, the defluorinative functionalization of fluorinated compounds is one of the most effective ways to synthesize fluorinated skeletons which are difficult to be prepared by conventional methods41,42,43,44. While recent progress has been made in the catalytic defluorination of gem-difluoroalkenes45,46,47 and trifluoromethyl alkenes48,49,50,51,52, the selective defluorinative functionalization of polyfluorinated alkynes has been rarely reported53. We speculate that the high reactivity and multiple addition sites of alkynes may result in an exceptionally complex reaction system during the repetitive addition/defluorination processes of B-M species with carbon-carbon triple bonds of polyfluorinated alkynes54,55,56. As a result, this complexity imparts intricacy and unpredictability into the selective synthesis of target molecules (Fig. 1D). Therefore, controlling the chem- and regioselectivity is a formidable challenge for the defluorinative functionalization of polyfluorinated alkynes. Furthermore, achieving divergent synthesis from the same starting materials to obtain structurally diverse building blocks by precisely regulating reaction conditions is always an intriguing topic21,57,58.

Herein, we report the Cu-catalyzed highly switchable defluoroborylation and hydrodefluorination of trifluoromethylated alkynes (Fig. 1E). The reaction features readily accessible starting materials, high chem- and regioselectivity, and broad substrate scope with excellent functionality tolerance. The primary advantage of this strategy lies in its capability to establish a unified catalytic system that synthesize four types of highly adjustable fluorine-containing compounds from a single starting material, which can further be derivatized into various types of fluorinated molecules that are otherwise difficult to synthesize. Additionally, both experimental results and density functional theory (DFT) calculations provide comprehensive explanations for the chem- and regioselectivities of Cu-Bpin addition process as well as the crucial regulatory role of ligands in the selective defluoroborylation reaction.

Results

Optimization of the reaction conditions

We began our study by using 4-(3,3,3-trifluoroprop-1-yn-1-yl)−1,1’-biphenyl 1a and B2pin2 2 as the model substrates (Table 1). The sp2/sp3 diborylated product 3 was achieved in 82% yield under optimal conditions: CuSCN (10 mol%) and Phen (10 mol%), with 1.0 equiv. MeOLi as the base and 2.0 equiv. H2O as the additive, in THF at 60 °C for 4 hours (Table 1, entry 1, Condition A). Increasing the B2pin2 amount did not enhance the reaction yield (Table 1, entry 2). Subsequent investigation of various copper salts (Table 1, entries 3-4) showed no notable yield improvement among different copper(I) salts. Further exploration of phosphine and N, N-bidentate ligands with varying steric hindrance and electron richness led to substantially lower yields of 3 (Table 1, entries 5-8). Strong bases like t-BuOK or DBU promote the formation of additional deborylation products 4 and 5, complicating the control of the reaction to exclusively yield the diborylated product 3 (Table 1, entries 9, 10). Increasing MeOLi quantity showed a similar trend (Table 1, entry 11), highlighting the critical role of base strength and quantity in determining chemo-selectivity in product distribution. Considering that the ligand Phen can act as a weak Lewis base, augmenting its quantity could potentially enhance reaction selectivity. Based on this assumption, upon increasing the ligand amount to 1.0 equiv., the reaction predominantly favored product 4, while the formation of compound 5 was suppressed (Table 1, entry 12). However, when using acetonitrile as the solvent, the selectivity of the reaction underwent significant changes: the diborylated product 3 was completely converted, a portion of the mono-borylated product 4 underwent further protodeborylation to yield the gem-difluoroalkene 5 (Table 1, entry 13). Encouragingly, shortening the reaction time to 2 hours inhibited this protodeborylation, resulting in high selectivity for monoborylated product 4 (Table 1, entry 14, Condition B). These results confirm that the solvent and the basicity of the reaction system, along with precise control of the reaction time, are crucial for regulating the selectivity of the protodeborylation process. Furthermore, after carefully adjusting the reaction temperature, solvent types, and the content of components, the optimal conditions for further hydrodefluorination product 5 was also obtained (Table 1, entry 15, Condition C, see Supplementary Table 1 for the detailed optimization).

Table 1 Optimization of the reaction conditions
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Substrate scopes

Having established the optimal reaction conditions (Condition A, Condition B, Condition C) for the Cu-catalyzed defluoroborylation and hydrodefluorination of 1-(trifluoromethyl)alkynes, the sp2/sp3 diborylated products were initially assessed with Condition A. As showcased in Fig. 2, a variety of substituents, such as alkyl groups (Me, t-Bu), thioether (CH3S), chlorine (Cl) and phenyl groups on the benzene ring, were well-tolerated, yielding the corresponding products (3, 6-9) in moderate to good yields. Substrates bearing fused rings and heterocycles such as benzothiophene and 4,4-dimethyl-thiochroman also demonstrated good reactivity, affording the target derivates 10-12 in high yield. Additionally, an amide with an active N-H bond was also successfully tolerated under the standard condition, yielding product 13 in 55%. Gratifyingly, by simply changing the reaction conditions, this transformation was not limited to aromatic trifluoromethylated alkynes; the desired diborylated products (14-17) could also be obtained from unactivated aliphatic trifluoromethylated alkynes.

Fig. 2: Substrate scope of diborylated gem-difluoroalkenes.
figure 2

Condition A: the reaction was carried out with 1 (0.2 mmol), B2pin2 2 (2.0 equiv.), CuSCN (10 mol%), Phen (10 mol%), MeOLi (1.0 equiv.), and H2O (2.0 equiv.) in THF (2.0 mL) at 60 °C for 4 h under nitrogen atmosphere. a CuSCN (10 mol%), tris(4-methoxyphenyl)phosphine (10 mol%), B2pin2 2 (3.0 equiv.), MeOLi (3.0 equiv.) in toluene (2.0 mL), 120 °C, 12 h.

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Subsequently, we extensively explored the applicability and compatibility of the assembly process for the mono-borylated products under Condition B, as depicted in Fig. 3. Due to the inherent instability of mono-borylated gem-difluoroalkenes during column chromatography30, a two-step reaction involving organobromides was employed to yield a range of compounds featuring the gem-difluorovinyl motif, effectively showcasing their synthetic diversity. First, we explored the scope of the aryl-substituted trifluoromethyl alkynes (Fig. 3, top). Various substituents such as carbonyls (18-19), naphthalene (20), amide (21), benzothiophene (22), halogen (23), ester (24-25), ether (26) and thioether (27), as well as a naphthyl group (28), were all well-tolerated under Condition B, yielding the corresponding products in moderate to good yields. Next, we turned our attention to the scope of organohalides (Fig. 3, bottom). The electronic effects of the substituents on the aryl bromides had minimal influence on this cross-coupling reaction. Aryl bromides bearing electron-deficient, electron-neutral and electron-rich substrates were all compatible in this transformation, enabling the generation of the corresponding gem-difluoroalkenes products in 31%-63% yields (29-45). Notably, aryl bromides with active aldehyde (43) or amine (45) groups reacted smoothly, achieving moderate yields. Heteroaryl bromides, including quinolines, thiophenes, furans, pyridines etc., also proved to be suitable coupling partners (46-51). Additionally, benzyl chloride, alkenyl bromide, and allyl bromide were found to be compatible in these reactions, affording the corresponding products (52-54) with moderate yields. Additionally, it was observed that predominantly hydroboration by-product formed when alkyl-substituted trifluoromethyl alkyne was used as a substrate under conditions B. After careful adjustment of reaction conditions, the mono-borylated products (15b, 16b) of alkyl-substituted trifluoromethyl alkynes can also be obtained in good yield. Notably, the location of the Bpin group in these mono-borylated products differ from that in aromatic compounds, as the reactivity of the C(sp3)-Bpin bond at the allyl site is lower than that of the C(sp2)-Bpin bond in alkyl-substituted products (see Supplementary Table 4 and Supplementary Section 4.3 for more details).

Fig. 3: Substrate scope of the monoborylated gem-difluoroalkenes and coressponding Suzuki-Miyaura coupling reaction with organohalides.
figure 3

Condition B: the reaction was carried out with 1 (0.2 mmol), B2pin2 2 (2.0 equiv.), CuSCN (10 mol%), Phen (1.0 equiv.), H2O (2.0 equiv.), and MeOLi (2.0 equiv.) in CH3CN (2.0 mL) at 60 °C for 2 h under nitrogen atmosphere. aUsing CuI (10 mol%), CsF (1.5 equiv.), and the reaction was carried out at 80 °C. bCuSCN (10 mol%), tris(4-methoxyphenyl)phosphine (10 mol%), B2pin2 (4.0 equiv.), H2O (2.0 equiv.) and MeOLi (4.0 equiv.) in THF (2.0 mL) at 120 °C for 24 h. cUsing benzyl chloride instead of benzyl bromide.

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With the optimized conditions for further protodeboronation in hand (Condition C), the substrate scope of trifluoromethylated alkynes were also investigated, the results were shown in Fig. 4, top. In general, the established conditions exhibited remarkable tolerance for a wide array of functional groups on the benzene rings, such as Ph (5), ether (56) and thioether (58), carbonyl (57), ester (59), amide (60), thiophene (64), and naphthalene (65), and the corresponding products were obtained with commendable yields. Notably, substrates containing sensitive functional groups, such as Br (good leaving group, 55), were amenable with high regio- and chemo-selectivity as well, allowing the compound for further transformations by cross-coupling reaction. Molecules bearing fused rings (61, 62) and heterocycles such as benzothiophene (63) and quinolines (66, 67) also reacted successfully to afford the corresponding gem-difluoroalkenes in high yields.

Fig. 4: Substrate scope of gem-difluoroalkenes and difluoromethylated alkenes.
figure 4

Condition C: the reaction was carried out with 1 (0.2 mmol), B2pin2 2 (2.0 equiv.), CuI (20 mol%), Phen (1.0 equiv.), H2O (4.0 equiv.), and t-BuOK (1.5 equiv.) in DCM (2.0 mL) at 110 °C for 2 h under nitrogen atmosphere. Condition D: Step 1, the reaction was carried out with 1 (0.2 mmol), B2pin2 2 (2.0 equiv.), CuI (20 mol%), Phen (1.0 equiv.), H2O (4.0 equiv.), and t-BuOK (1.5 equiv.) in DCM (2.0 mL) at 110 °C for 2 h under nitrogen atmosphere, then concentrated under vacuum. Step 2, without additional purify, t-BuOK (5.0 equiv.), DMF (2.0 mL) was added into the reaction mixture at 60 °C for additional 2 h.

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Taking inspiration from the aforementioned outcomes and recognizing the significance of difluoromethyl group (-CF2H) in pharmaceutical sciences, we envisioned that the difluoromethylated alkenes should also be formed through meticulous adjustment of reaction conditions. To our delight, after fine-tuning reaction conditions (see Supplementary Table 2), the addition of an additional 5 equiv. t-BuOK to the model reaction of 1a under condition C through the one-pot two-step approach led to the efficient formation of the difluoromethylated product 68 in 65% yield (Condition D). In view of this, a series of difluoromethylated alkenes were also successfully obtained under Condition D, which served as crucial synthetic intermediates due to their potential to function as lipophilic hydrogen bond donors and to act as bioisosteres for thiol and alcohol functional groups (Fig. 4, bottom). In general, the reaction demonstrates good compatibility with electron-neutral, electron-deficient, and electron-rich groups in moderate to good yields (68-84).

Synthetic applications

To highlight its amenability to the late-stage functionalization of bioactive compounds or drug molecules, the estrone was evaluated under our standard conditions. Encouragingly, we successfully obtained the corresponding estrone derivatives in good yield under four standard conditions (85-89). These outcomes underscore the outstanding functional group tolerance of our highly switchable defluoroborylation and hydrodefluorination methods, thus reinforcing their potential application in the rapid and efficient synthesis of fluorine/boron analogs of bioactive molecules. This capability holds promise for facilitating the discovery of promising drug candidates (Fig. 5A). To further demonstrate the practical utility of these transformations, a series of conversions involving the four types of products were conducted, which enabled the generation of a diverse range of fluorinated molecules with more complex structures (Fig. 5B). The borylated products exhibit exceptional versatility as synthetic intermediates, allowing for their facile transformation into various valuable active compounds through selective derivatization. For instance, the C(sp2)-B bond of product 4 was easily transformed to the C-halogen bonds, and 91-93 can be obtained in high yield. Via the oxidation of 4 with H2O2, ketone 90, containing difluoromethyl group, was achieved in 62% yield. Starting from compound 3, versatile transformations on both C(sp2)-B and C(sp3)-B bonds were successfully performed. For example, dideuterated gem-difluoroalkene 94 could be easily obtained with D2O, and the 1,4-dihydroxylated product containing gem-difluoroalkene 95, which is difficult to be obtained by known strategies, was synthesized via homologation of diboronates with ClCH2Li followed by oxidation with H2O2. Moreover, by subjecting compound 68 to dihydroxylation and epoxidation processes, the HCF2- containing dihydroxyl compound 96 and epoxide compound 97 can be successfully obtained with the yields of 64% and 61% respectively. Additionally, the gem-difluoroalkene product 5 could undergo a complete hydrogenation with Pd/C catalyst to yield a terminal difluoromethylated alkanes 98. The Z- and E-fluoroalkene (99 and 100) could also be easily accessed by further hydrodefluorination of gem-difluoroalkene product 5 under the identified conditions. Furthermore, treatment of compound 5 with TMSCF3 and sodium iodide led to the formation of tetrafluorocyclopropane 101.

Fig. 5: Synthetic applications.
figure 5

A late-stage functionalization of bioactive compounds; B Synthetic transformations of the CF2-containing products. a CuCl2, MeOH, 80 °C; b CuBr2, MeOH, 80 °C; c CuI, KI, Phen, MeOH, 80 °C; d H2O2, NaOH, THF, 0 °C to r.t.; e D2O, K2CO3, 110 °C; f CH2ICl, n-BuLi, THF, −78 °C to r.t., N2, then H2O2, NaOH, MeOH, 0 °C to r.t.; g tert-butyl alcohol, H2O, AD-mix-a, CH3SO2NH2, r.t.; h m-CPBA, CHCl3, 0 °C to r.t.; i Pd/C, H2, THF, r.t.; j CuTC, Xantphos, B2pin2, t-BuOLi, H2O, DMAc, 40 °C, N2; k red-Al, toluene, 0 °C to 80 °C; l TMSCF3, NaI, THF, 80 °C.

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Mechanism experiments

To gain mechanistic insights into these switchable defluoroborylation and hydrodefluorination process, several control experiments were carried out (Fig. 6). First, when we performed the reaction of 1a with B2pin2 (1.0 equiv.) under standard conditions A at room temperature, the mono-borylated compounds 102 and 103 were obtained in 75% and 13% yield, along with a small amount (11%) of alkene 104 (Fig. 6A, a). To evaluate the potential reactive intermediates for these reactions, we used compounds 102–104 as the starting materials under standard conditions A-C, respectively. Surprisingly, only compound 102 could successfully afforded diborylated product 3, monoborylated compound 4, and gem-difluoroalkene 5 in excellent yield (Fig. 6A, b–f); the result of these experiments inferred that compounds 103 and 104 are not the intermediates in these transformations. We subsequently monitored the yield changes of intermediate 102 and product 3, 4 over time under standard condition B, and observed that the yield of 4 gradually increased as the reaction progressed; meanwhile, the yields of compound 102 and 3 initially showed an increase within the first 10 minutes, but gradually decreased thereafter (Fig. 6B). These results further confirmed that compound 102 acts as an intermediate in the initial transformation, and that compound 3 undergoes further chemoselective hydrodeborylation to produce product 4. Additionally, a series of control experiments were carried out to confirm the importance of stoichiometric Phen in further chemoselective hydrodeborylation of compound 3 to produce the monoborylated product 4 (Fig. 6C, a). When compound 3 was used as the starting material under conditions where only the base MeOLi was present, it underwent further hydrodeborylation, albeit without selectivity. However, when only stoichiometric Phen or CuSCN (10 mol%) + Phen (1 equiv.) was introduced into the system, the diborylated product 3 selectively underwent deborylation of the benzyl boronate group, yielding the mono-borylated product 4, albeit with a relatively lower yield. Remarkably, simultaneous addition of MeOLi (2 equiv.) and Phen (1 equiv.) significantly enhanced the efficiency and selectivity of the hydrodeborylation of 3, even in the absence of CuSCN. All the results above clearly demonstrate the critical importance of stoichiometric amounts of Phen in enhancing the selectivity of the hydrodeborylation process. Additionally, the involvement of the base MeOLi significantly boosts the efficiency of hydrodeborylation. Moreover, when compound 4 or 5 was used as the starting material under conditions where the base t-BuOK was present, the corresponding hydrodeborylation product 5 or isomerization product 68 could be selectively formed within 2 hours (Fig. 6C, b, c). To confirm the role of trace water, deuterium-labeling experiments (Fig. 6D) were conducted. When 1a and B2pin2 2 were reacted in the presence of D2O (10 equiv.) under conditions A-D, the corresponding deuterated products 105-108 were obtained with 80-95% deuterium incorporation. This confirms that H2O acts as the essential proton source for defluoroborylation and hydrodefluorination processes.

Fig. 6: Mechanistic experiments.
figure 6

A Control experiments I; B Monitoring the intermediates of defluoroborylation of trifluoromethylated alkyne 1a under condition B; C, Control experiments II; D Deuterium-labeling experiments.

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Based on our experimental findings and prior studies21,36,57, we propose a mechanism for the switchable defluoroborylation and hydrodefluorination of trifluoromethylated alkyne 1 under Conditions A-D, as depicted in Fig. 7. All of these reactions initiate with the regioselective insertion of carbon-carbon triple bond of 1 into the cuprous boryl species B, yielding the alkenyl cuprous intermediate C, followed by protonation with H2O to form intermediate 102. In Condition A, this intermediate then undergoes secondary borylation and subsequent β-F elimination to yield product 3. Augmenting the quantity of the ligand Phen and the base in Condition B induces selective deborylation of product 3 at the benzyl site, yielding product 4. Further elevating the basicity and reaction temperature in Condition C facilitates deborylation of product 4, resulting in the formation of product 5. In Condition D, the addition of 5 equiv. of t-BuOK via the one-pot two-step approach allows the formation of the difluoromethylated product 68. This work demonstrates precise control over the chemical and regioselectivity of the reaction by adjusting the amount and intensity of ligand and base, which allows the reaction to be stopped at the desired steps, leading to the formation of specific products.

Fig. 7
figure 7

Possible processes for obtaining different products under four experimental conditions.

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We have also conducted detailed theoretical calculations on the reaction process under Conditions A and B, and the comparison between these two conditions can well reflect the ligand and base-regulated chemo- and regio-selectivities. The key steps determining the selectivity have been identified as the regio-selective Cu-Bpin insertion into alkyne 1, then insertion into intermediate 102, and selective diborylation of 3. The detailed free energy profiles have been collated in Supplementary Fig. 57–63. The structural information, charge information, and energy data of the related key transition states are shown in Fig. 8. Under Condition A, the Cu-Bpin insertion into the C ≡ C bond of 1 exhibits a lower energy barrier for Bpin addition to C1 atom adjacent to CF3 (20.5 kcal/mol for A-TS1 in light blue, Fig. 8A), compared to Bpin addition to C2 atom adjacent to the aryl group (21.7 kcal/mol for A-TS1ʹ in pink, Fig. 8A). The natural population analysis (NPA) charges of A-TS1 and A-TS1ʹ indicate that the more negative charge on C1 favors the attack by the more positively charged B atom of Bpin, therefore the Bpin-C1 bonding is favored. Next, the Cu-Bpin insertion into the C = C bond of 102 shows a lower energy barrier for Bpin addition to C2 atom (24.9 kcal/mol for A-TS5 in light blue, Fig. 8B), compared to Bpin addition to C1 atom (40.0 kcal/mol for A-TS5ʹ in pink, Fig. 8B). Structural analysis of A-TS5 and A-TS5ʹ indicates the former avoids the significant steric hindrance of two bulky Bpin groups. Note that, Condition B shows the similar regio-selective Bpin-C1 bonding in alkyne 1 insertion, and Bpin-C2 bonding in alkene 102 insertion, as shown in Fig. 8A and B with dark blue and red color (see Supplementary Fig. 62 for details).

Fig. 8: The regioselectivity and chemical selectivity control mechanism.
figure 8

A Regioselective insertion of C≡C triple bond of 1 in Condition A and B; B Regioselective insertion of C=C double bond of 102 in Condition A and B; C Deborylation of 3 in Condition A; D Deborylation of 3 and 4 in Condition B.

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The dissimilarity between conditions A and B lies in the selective diborylation of 3. Under Condition A, the deborylation of 3 is prevented due to the high energy barrier of 32.9 kcal/mol (A-Int4 → A-TS9, Fig. 8C). Specifically, the deborylation is initiated by A-Int4, which is attained through the combination of F-CuL species with LiOH-THF formed after protonation. The intermediate strips off LiF-THF to give the HO-CuL species to participate in deborylation of 3 via A-TS9, which is kinetically difficult. In contrast to Condition A, the deborylation of 3 is promoted to yield 4 in Condition B (Fig. 8D). This is due to the participation of the MeO-LiL species, formed by increased 1.0 equiv. L (Phen) and 2.0 equiv. LiOMe. Specifically, the deborylation of 3 shows a lower energy barrier at the benzyl site (21.4 kcal/mol for B-TS6) than that at the vinyl site (23.5 kcal/mol for B-TS6ʹ), which is due to the favorable η3-coordination of Li with the benzyl group. Compared to 3, the further deborylation of 4 is challenging due to the higher energy barrier (24.5 kcal/mol, B-TS6ʹʹ, Fig. 8D) than that of B-TS6 and B-TS6ʹ. Thus, the reaction chemically selectively stops at 4 under condition B. Accordingly, the ligand and base regulated selective production of 3 and 4 under Condition A and B has been clarified.

Discussion

In summary, we have developed a Cu-catalyzed, highly switchable defluoroborylation and hydrodefluorination of trifluoromethylated alkynes, marking a rare instance of selectively generating four types of CF2-containing compounds from a single substrate. The chemo- and regio-selectivity were achieved by simply varying the solvent, base, and ligand quantity. The method’s substrate versatility, compatibility with complex molecules, and potential for diverse downstream transformations make it a valuable approach for constructing versatile fluorinated compound skeletons, unattainable by existing methods. Both experimental results and DFT calculations confirmed the key intermediate and elucidated the chemo- and regioselectivity of these transformations.

Methods

General procedure for Cu-catalyzed highly switchable defluoroborylation and hydrodefluorination of trifluoromethylated alkynes

Condition A

In a nitrogen -filled glovebox, a 25.0 mL Schlenk tube with a stirring bar was added with B2pin2 (152.4 mg, 0.6 mmol, 2.0 equiv.), CuSCN (3.7 mg, 0.03 mmol, 10 mol%), Phen (5.4 mg, 0.03 mmol, 10 mol%), trifluoromethyl alkynes (0.3 mmol, 1.0 equiv.), and MeOLi (11.4 mg, 0.3 mmol, 1.0 equiv.). The tube with the mixture was then taken out of the glovebox and added with THF (3.0 mL), H2O (11.0 μL, 0.6 mmol, 2.0 equiv.) under N2 atmosphere. The reaction was allowed to stir at 60 °C for 4 h. The reaction mixture was then cooled to room temperature, dried over Na2SO4, filtered through a pad of celite, and concentrated in vacuo. The residue was subjected to Preparative HPLC to afford the corresponding products.

Condition B

In a nitrogen -filled glovebox, a 25.0 mL Schlenk tube with a stirring bar was added with CuSCN (3.7 mg, 0.03 mmol, 10 mol%), Phen (54 mg, 0.3 mmol, 1.0 equiv.), B2pin2 (152.4 mg, 0.6 mmol, 2.0 equiv.), trifluoromethyl alkynes (0.3 mmol, 1.0 equiv.), and MeOLi (22.8 mg, 0.6 mmol, 2.0 equiv.). The tube was then taken out of the glovebox and added with CH3CN (3.0 mL), H2O (11.0 μL, 0.6 mmol, 2.0 equiv.) under N2 atmosphere. The reaction was allowed to stir at 60 °C for 2 h. The reaction mixture was then cooled to room temperature, dried over Na2SO4, filtered through a pad of celite, and concentrated in vacuo. The residue purified by column chromatography on silica gel with petroleum ether/ethyl acetate to afford the corresponding products.

Condition C

In a nitrogen -filled glovebox, a 25.0 mL Schlenk tube with a stirring bar was added with CuI (11.4 mg, 0.06 mmol, 20 mol%), Phen (54 mg, 0.3 mmol, 1.0 equiv.), B2pin2 (152.4 mg, 0.6 mmol, 2.0 equiv.), trifluoromethyl alkynes (0.3 mmol, 1.0 equiv.), and t-BuOK (50.5 mg, 0.45 mmol, 1.5 equiv.). The tube with the mixture was taken out of the glovebox and added with DCM (3.0 mL), H2O (22.0 μL, 1.2 mmol, 4.0 equiv.) under N2 atmosphere. The reaction was allowed to stir at 110 °C for 2 h. The reaction mixture was then cooled to room temperature, dried over Na2SO4, filtered through a pad of celite, and concentrated in vacuo. The residue purified by column chromatography on silica gel with petroleum ether/ethyl acetate to afford the corresponding products.

Condition D

In a nitrogen -filled glovebox, a 25.0 mL Schlenk tube with a stirring bar was added with CuI (11.4 mg, 0.06 mmol, 20 mol%), Phen (54 mg, 0.3 mmol, 1.0 equiv.), B2pin2 (152.4 mg, 0.6 mmol, 2.0 equiv.), trifluoromethyl alkynes (0.3 mmol, 1.0 equiv.), and t-BuOK (50.5 mg, 0.45 mmol, 1.5 equiv.). The tube with the mixture was taken out of the glovebox and added with DCM (3.0 mL), H2O (22.0 μL, 1.2 mmol, 4.0 equiv.) under N2 atmosphere. The reaction was allowed to stir at 110 °C for 2 h and was monitored by TLC. The reaction mixture was concentrated to afford the yellow oily mixture, and then dissolved in the DMF (3.0 mL). t-BuOK (168.3 mg, 1.5 mmol, 5.0 equiv.) was added to the reaction mixture. The reaction was allowed to stir at 60 °C for another 2 h. After finished, the reaction mixture was then cooled to room temperature, dried over Na2SO4, filtered through a pad of celite and concentrated in vacuo. The residue purified by column chromatography on silica gel with petroleum ether/ethyl acetate to afford the corresponding products.