Palladium Difluorocarbene Involved Catalytic Coupling with Terminal Alkynes

Open AccessCCS ChemistryRESEARCH ARTICLE1 Oct 2020Palladium Difluorocarbene Involved Catalytic Coupling with Terminal Alkynes Xue-Ying Zhang, Xia-Ping Fu, Shu Zhang and Xingang Zhang Xue-Ying Zhang Key Laboratory of Organofluorine Chemistry, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200032 (China) Google Scholar More articles by this author , Xia-Ping Fu Key Laboratory of Organofluorine Chemistry, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200032 (China) Google Scholar More articles by this author , Shu Zhang School of Materials and Energy, University of Electronic Science and Technology of China, Chengdu, Sichuan 611731 (China) Google Scholar More articles by this author and Xingang Zhang *Corresponding author: E-mail Address: [email protected] Key Laboratory of Organofluorine Chemistry, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200032 (China) College of Chemistry, Henan Institute of Advanced Technology, Zhengzhou University, Zhengzhou 450001 (China) Google Scholar More articles by this author https://doi.org/10.31635/ccschem.020.202000146 SectionsSupplemental MaterialAboutAbstractPDF ToolsAdd to favoritesDownload CitationsTrack Citations ShareFacebookTwitterLinked InEmail Difluoromethylated alkynes are a versatile synthon for the diversity-oriented synthesis of difluoromethyl compounds that are of great interest in life and materials sciences. However, the catalytic cross-coupling for the synthesis of difluoromethylated alkynes remains challenging, despite impressive achievements made in the cross-coupling reactions for alkynes, including the Sonogashira reaction. Here, we report a palladium difluorocarbene involvement in catalytic coupling with terminal alkynes, representing a new mode of conjugation reaction, which circumvents the radical pathway usually encountered during the coupling of alkynes with fluoroalkyl electrophiles. The reaction uses inexpensive and abundant industrial raw material chlorodifluoromethane (ClCF2H) as the difluorocarbene precursor, and features cost-effectiveness, excellent functional group tolerance, and broad substrate scope, including synthesis of drug-like complex molecules. Our mechanistic studies showed a unique catalytic pathway of this process, in which additive hydroquinone plays a pivotal role in promoting the reaction. Download figure Download PowerPoint Introduction Organofluorinated compounds have paramount applications in pharmaceuticals, agrochemicals, and materials science because the incorporation of fluorine atom(s) into organic molecules often changes their physical, chemical, and biological properties.1–4 Notably, the site-selective introduction of a difluoromethyl group (CF2H) into the biologically active compounds could dramatically influence the metabolic stability, solubility, and bioactivity of the newly formed molecules. These fluorine effects are attributable to the unique properties of CF2H, which acts as a lipophilic hydrogen bond donor, showing lower lipophilicity than a trifluoromethyl group,5 and also, behaves as a metabolically stable bioisostere for hydroxyl and thiol groups.6 In an effort to fulfill the ever-increasing demand for discovering new bioactive molecules, there are increasing requirements to synthesize diversified difluoromethylated structures in an efficient, straightforward, and economical way. In this context, tremendous efforts have been made in the catalytic synthesis of difluoromethylated arenes over the past decade7–14; nonetheless, efficient and direct catalytic difluoromethylation processes of terminal alkynes remain elusive. Scheme 7 | Proposed reaction mechanism. (a) Proposed roles of hydroquinone in the reaction. (b) Outline of a possible pathway for palladium difluorocarbene involved coupling with terminal alkynes. Download figure Download PowerPoint We envisaged that since alkynes are a versatile building block in organic synthesis,15 the connection with a CF2H to terminal alkynes would lead to a series of synthetically useful synthons for the construction of a wide range of difluoromethylated structures that would be of great interest in medicinal chemistry, chemical biology, and advanced functional materials. The traditional preparation of difluoromethylated alkynes relies on the reaction of acetylide ions with fluorine sources,16–18 but the requirement of strong bases in this approach restricts its widespread synthetic applications due to the poor functional group tolerance. To circumvent this limitation, copper-mediated cross-coupling of both alkynyl halides and terminal alkynes with difluoroalkylating reagents has been developed.19,20 However, problems still remained with these approaches, including the requirement of stoichiometric copper, prefunctionalization of alkynes, additional steps to prepare fluoroalkylating reagents, or using expensive fluoroalkylating reagents. Therefore, the development of a new model for the difluoromethylation of alkynes to overcome the limitations of previous methods is highly desirable. It has been anticipated that transition-metal-catalyzed cross-coupling of terminal alkynes with difluoromethylating reagents would be a promising strategy to access difluoroalkylated alkynes. However, it is of great challenge when applying the well-established Sonogashira reaction,21–23 a cross-coupling reaction between terminal alkynes and electrophiles, for the preparation of difluoroalkylated alkynes using fluoroalkyl halides. The observation made from this reaction was that most fluoroalkyl halides are prone to undergo a single-electron transfer (SET) pathway in the presence of low-valent transition metals to generate fluoroalkyl radicals, which, are easily trapped by alkynes to generate alkenes,24,25 thereby, suppressing the catalytic cycle (Scheme 1a). We envisaged that, in the context of the palladium catalytic coupling Pd(0) catalytic system, there is no formation of fluoroalkyl radical species; hence, the key facilitator of the catalytic cycle for the coupling reaction would be fluoroalkyls with alkynes. Recently, we developed a method for the generation of difluoromethyl palladium complex from a nucleophilic palladium(0) difluorocarbene [Pd0]=CF2, which reacted with a proton to generate difluoromethyl palladium complex [PdII]–CF2H (Scheme 1b).26 Based on the high reactivity of [Pd0]=CF2 we hypothesized that employing this species in a catalytic cycle involving coupling with alkynes would prevent the generation of fluoroalkyl radicals via the single-electron-transfer (SET) pathway. This assumption was made due to the protonation of [Pd0]=CF2 to generate [PdII]–CF2H complex in the overall catalytic cycle could bypass the reaction of [Pd0] with fluoroalkyl halides. As shown in Scheme 1c, once the nucleophilic [Pd0]=CF2 was formed between palladium(0) and difluorocarbene, protonation of this complex could occur in the presence of proton sources. Subsequently, the resulting difluoromethyl palladium complex [PdII]–CF2H reacted with a terminal alkyne to generate the key intermediate, difluoromethyl alkynyl palladium complex (alkynyl–[PdII]–CF2H). Finally, upon reductive elimination, difluoromethylated alkyne was generated with the release of [Pd0] to complete the catalytic cycle. This new mode of coupling reaction would overcome the limitations of previous methods with an efficient and straightforward preparation of difluoromethylated alkynes, not reported thus far, and also would expand the understanding of catalytic metal difluorocarbene chemistry. To date, only rare examples of catalytic metal difluorocarbene involved coupling (MeDIC) reactions have been documented,12,13,26 due to the inert reactivity of the known metal difluorocarbene complexes.27–31 Here, we report a palladium difluorocarbene involvement in the catalytic cross-coupling of terminal alkynes with chlorodifluoromethane (ClCF2H), an inexpensive and abundant industrial raw material used for the production of fluorinated polymers, such as Teflon. The reaction progressed under mild reaction conditions with broad substrate scope and excellent functional group tolerance, including complex and drug-like molecules. This palladium difluorocarbene involved catalytic coupling reaction provides a cost-efficient and straightforward access to difluoromethylated alkynes that is of great interest in the synthesis of diverse difluoromethylated compounds for medicinal chemistry and chemical biology. Scheme 1 | Palladium-catalyzed cross-coupling with terminal alkynes. Download figure Download PowerPoint Experimental Methods The Experimental Methods are available in the Supporting Information. Results and Discussion Optimization studies To investigate our hypothesis illustrated in Scheme 1c, we focused initially on choosing a suitable difluorocarbene precursor in the model reaction shown in Table 1. The strong C–Cl bond in ClCF2H ( 1), used as the difluorocarbene precursor,32 was unfavorable in generating difluoromethyl radical with [Pd0]. Additionally, ClCF2H is an inexpensive and abundant raw industrial material,33 which makes the approach cost-effective for practical applications. We found that the combination of palladium catalyst Pd(CF3CO2)2 (2.5 mol %) with phosphine ligand (Xantphos; 7.5 mol %), in the presence of additive hydroquinone and a Bronsted base (K2CO3), dissolved in dioxane, and allowing to heat at 80°C, generated difluoromethylated alkyne 3 in 33% yield, when 10 equiv of ClCF2H in dimethylacetamide (DMA) and the model substrate, 1-(tert-butyl)-4-ethynylbenzene 2a (see the Supporting Information Table S1), were used in the reaction. Other readily available difluorocarbene precursors, such as BrCF2CO2Et and BrCF2PO(OEt)2, provided the desired product in much lower yields [6% for BrCF2CO2Et; 2% for BrCF2PO(OEt)2; see the Supporting Information Table S2] due to enigma side reactions, which provided major forms of products. By optimizing the reaction conditions further (see Supporting Information Tables S3–S9), we found that Xantphos and hydroquinone played critical roles in the reaction (Table 1, entries 3–7). Decreasing the loading amount of Xantphos from 7.5 to 2.5 mol % improved the yield of 3 to 53%. Further reduction of the loading amount of DMA from 34 equiv to 18 equiv dramatically improved the yield in 3 to 82% upon isolation (Table 1, entry 1), while the absence of DMA led to only an 18% yield of 3 (Table 1, entry 7). We speculated that DMA probably stabilized the cationic palladium species generated in situ, but excessive DMA likely passivated the palladium catalyst. The coupling reaction failed when palladium salt, ligand, or hydroquinone were omitted from the setup (Table 1, entries 2–4), ruling out a direct reaction of alkyne with difluorocarbene. Table 1 | Optimization of Reaction Conditionsa Entry Reaction Conditions 3, Yield (%)b 1 Standard conditions 85 (82) 2 Without palladium nd 3 Without Xantphos nd 4 Without hydroquinone nd 5 Using resorcinol instead of hydroquinone 32 6 Using phenol instead of hydroquinone 15 7 Without DMA 18 aReaction conditions (unless otherwise specified): 2a (0.3 mmol, 1.0 equiv); 1 (1.5 M in dioxane, 3.0 mmol, 10 equiv); dioxane (1 mL); DMA (0.5 mL, 18 equiv); 12 h. bDetermined by 19F NMR using fluorobenzene as an internal standard; the number given in parentheses is the isolated yield. Scope of the reaction With the optimized conditions of the reaction in hand, we examined the reaction of alkynes 2 with ClCF2H 1 (Scheme 2). Generally, moderate to high yields were obtainable. In the case of the aromatic alkyne bearing electron-withdrawing substituents, the use of PdCl2(CH3CN)2 as a catalyst without DMA produced the corresponding difluoromethylated alkynes with even higher yields ( 14– 20). A variety of useful synthetic handles showed good tolerance with the reaction, including strong base and nucleophile-sensitive moieties, such as esters, enolizable ketones, formyl, and cyano, and other groups, such as aryl chloride, ferrocenyl, and thioether ( 11– 19, 23, 24). Remarkably, alcohol- and carbamate-containing substrates with free protons were also competent coupling partners ( 21, 22), thus providing straightforward access to difluoromethylated alkyne without tedious protection–deprotection procedures. Steric substrates, such as 1-ethynylpyrene ( 6) and the aromatic alkyne bearing an ortho substituent ( 8), did not interfere with the reaction efficiency. Moreover, a series of heteroaromatic alkynes, such as thiophene-, quinoline-, and pyridine-containing substrates, could be applied to the reaction ( 25– 28). Furthermore, the reaction is readily scalable, as demonstrated by the gram-scale synthesis of 15 with even a higher yield (95%). In addition to the aromatic alkynes, an enyne also underwent the coupling reaction smoothly without the formation of [2+1] cyclization products34 between difluorocarbene and alkene ( 29); thus, this protocol demonstrated good chemoselectivity, except that we obtained a low yield when an aliphatic terminal alkyne was used ( 30). Scheme 2 | Reaction scope of the palladium difluorocarbene involved coupling with terminal alkynes. aReaction conditions (unless otherwise specified): 2 (0.3 mmol, 1.0 equiv), 1 (1.5 M in dioxane, 3 mmol, 10 equiv), DMA (0.5 mL), dioxane (1 mL), 12 h. All reported yields are isolated yields. The values provided in parentheses were determined by 19F NMR using fluorobenzene as an internal standard. bReaction run for 20–24 h. cPdCl2(CH3CN)2 (2.5 mol %), Xantphos (7.5 mol %), dioxane (1 mL), 24 h. dReaction run was 36 h. eReaction run for 72 h. Download figure Download PowerPoint The promising functional group tolerance of this method encouraged us to evaluate the palladium difluorocarbene involvement in the catalytic coupling with complex molecules. Febuxostat, a drug used for the treatment of hyperuricemia, derived alkyne was compatibly utilized in the reaction ( 31). Also, terminal alkyne bearing an amino acid underwent the difluoromethylation smoothly ( 32). Even a carbohydrate-containing substrate was viable in the cross-coupling with high efficiency ( 33). Further, nortropine-derived alkyne furnished the corresponding product 34 efficiently. Thus, these transformations provided a straightforward route for applications in the synthesis of interesting new biologically active molecules. Synthetic utility We demonstrated the utility of this cross-coupling further by using the resultant difluoromethylated alkyne for diversified transformations (Scheme 3). The treatment of compound 15 with a gold catalyst in the presence of MeOH, followed by hydrolysis, provided ketone 35 in 91% yield (Scheme 3a).35 The construction of indole 36 through Larock’s approach36 by a reaction of the alkyne 15 with 2-iodoaniline proceeded smoothly (Scheme 3a). Besides, the alkyne could be employed to generate difluoromethylated isoxazole 37 through [3+2] cyclization (Scheme 3b).37 The structures of compounds 36 and 37 were confirmed further by single-crystal X-ray diffraction studies (see the Supporting Information Figures S1 and S2). Since both heteroarenes and CF2H have essential applications in the synthesis of bioactive molecules, these transformations provide opportunities for applications in medicinal chemistry. Additionally, the alkyne 15 underwent click chemistry with bioactive molecule derivative 40 efficiently (Scheme 3c),38 thereby, demonstrating further the utility of the resulting difluoromethylated alkynes. Scheme 3 | Synthetic applications of the difluoroalkylated alkynes. Download figure Download PowerPoint Mechanistic studies To gain mechanistic insight into the current cross-coupling approach, we carried out the following studies: First, we investigated the possibility that the formation of the difluoromethyl palladium complex originated from the oxidative addition of the Cl–CF2H bond to [Pd0] by conducting a stoichiometric reaction of Pd2(dba)3/Xantphos (dba, dibenzylideneacetone) with ClCF2H (Scheme 4a). There was no formation of apparent difluoromethyl palladium complex, and the addition of α-cyclopropylstyrene 41, a radical clock probe,39,40 to the reaction 2b with ClCF2H did not affect the reaction efficiency (Scheme 4b), suggesting that the existence of a free difluoromethyl radical via a SET pathway between [Pd0] and ClCF2H was less likely to have been involved in the reaction. These results demonstrated that ClCF2H exhibited inert reactivity to the current palladium catalyst, thus ruling out the possibilities mentioned above. Scheme 4 | A stoichiometric reaction of Pd2(dba)3/Xantphos with ClCF2H and radical clock experiment. Download figure Download PowerPoint Secondly, we examined the dependence of the initial reaction rate on the concentration of alkyne, hydroquinone, and Pd(CF3CO2)2/Xantphos separately. A zero-order relationship of the initial rate with the concentration of alkyne 2b was observed (Figure 1a), whereas both hydroquinone and Pd(CF3CO2)2/Xantphos showed first-order relationships (Figure 1b–c). These observations suggested that hydroquinone and the active palladium species were involved in the turnover-limiting step. We determined how hydroquinone was involved in the reaction by conducting a reaction between the alkyne 2b with ClCF2H in the presence of D2O (Scheme 5a). We found that the formation of deuterated 4 was increased proportionally with increased loading amount of D2O (Figure 1d). Based on our previous understanding of the chemistry of palladium difluorocarbene complex,26 our current results suggested that: (1) a difluorocarbene was involved in the reaction. Otherwise, the direct hydrogen/deuterium (H/D) exchange of D2O with ClCF2H could not occur under the current reaction conditions to produce deuterated 441; (2) H/D exchange between D2O and hydroquinone occurred during the reaction, and hydroquinone provided proton for the formation of difluoromethyl group. Given hydroquinone showed a first-order relationship in the reaction, the increase in the deuterated hydroquinone would likely result in a proportional increase in the ratio of deuterated 4. We confirmed this deduction further by performing a reaction between hydroquinone and D2O, in which the deuterated hydroxyl/hydroxyl (OD/OH) ratio in deuterated hydroquinone showed a linear relationship with the loading amount of D2O (see the Supporting Information Figure S3). Additionally, we conducted a kinetic isotope effect (KIE) experiment for hydroquinone, which showed a primary KIE of 2.68 (Scheme 5b). Since a previous calculation revealed that the protonation of [Pd0]=CF2 required higher energy than the formation of [Pd0]=CF2 between difluorocarbene and [Pd0],26 our present results implied that the protonation of [Pd0]=CF2 with hydroquinone was the turnover-limiting step in the catalytic cycle. Figure 1 | Kinetic studies of the formation of 4 and reaction of 2b with ClCF2H in the presence of D2O. Plot of δ[4]/δt × 103 versus initial concentration of (a) alkyne 2b, (b) [Pd(CF3CO2)2/Xantphos], and (c) hydroquinone. (d) Relation of D/H ratio of 4 with loading amount of D2O in the reaction of 2b with ClCF2H. Download figure Download PowerPoint Thirdly, we conducted deuterium-labeling experiments (Scheme 6a) to investigate the difluoromethyl palladium formation from the palladium difluorocarbene of the reaction. We noted that in the presence of a single deuterated reagent, the reaction of alkyne 2b with ClCF2H proceeded smoothly under standard reaction conditions when deuterated hydroquinone (d- I) was used, providing the corresponding product in 72% yield with an H/D of 6.5∶1. Meanwhile, 61% yield was obtained with H/D ratio of 19∶1 when deuterated alkyne 2b (d- 2b) was used. These observations demonstrated that the original hydroquinone and alkyne could provide proton to form difluoromethyl, but they were not the primary proton sources in the reaction. The higher hydrogen ratios in the labeled difluoromethyl suggested that ClCF2H was the primary proton source in the reaction. We proposed that the corresponding hydrogen-transfer process follows the pathway shown in Scheme 7a: (1) Before d- I reacted with CF2 = Pd(0) species, the reaction between d- I and K2CO3 formed potassium phenolate ( II). (2) The resulting phenolate ( II), which was more soluble in the organic solvent than the inorganic base K2CO3, served as a base and abstracted proton from ClCF2H to produce hydroquinone ( III) plus chlorodifluoromethyl anion (ClCF2−). (3) The α-elimination of ClCF2− delivered difluorocarbene. In reference to our hypothesis, the hydroquinone assisted difluorocarbene formation was supported by the carbene trapping experiments, as shown in Scheme 6b and c. The reaction of K2CO3 with ClCF2H in the presence of difluorocarbene trapping reagent, tetramethylethylene, did not lead to gem-difluorocyclopropane 43. In contrast, the addition of hydroquinone to the reaction resulted in 6% yield of 43, thus demonstrating the essential role of hydroquinone in the generation of difluorocarbene. Scheme 6 | Mechanistic studies of the palladium difluorocarbene involved coupling with terminal alkynes. Download figure Download PowerPoint In the case of protonation of [Pd0]=CF2 during the process, the newly generated hydroquinone ( III) became the primary proton source to react with [Pd0]=CF2 and to generate difluoromethyl palladium complex (HCF2)[PdII]X as the main product; as a result, a high ratio of H/D was observed (Scheme 7a). Additionally, we found that hydroquinone might serve as a reductant to reduce [PdII] into [Pd0] at the initial stage of the reaction. The GC-MS analysis of the reaction of 2b with ClCF2H under standard reaction conditions showed that a small amount of benzoquinone was generated during the reaction process (Scheme 6d). The reductive role of hydroquinone was confirmed further by the reaction of Pd(CF3CO2)2 with hydroquinone in the presence of Xantphos, in which a palladium(0) complex [(Xantphos)Pd0(benzoquinone)] ( D) was generated (Scheme 6e). However, complex D was not an active species in the reaction. Scheme 5 | Reaction of 2b with ClCF2H in the presence of D2O and KIE experiment of hydroquinone. Download figure Download PowerPoint Further investigation revealed that the combination of a catalytic amount of benzoquinone (10 mol%) with phenol could facilitate the catalytic cycle to provide the difluoromethylated alkyne 3 in a comparable yield (79%) with the sole use of hydroquinone (Scheme 6f). In contrast, the absence of benzoquinone only led to a poor yield (15%). These results suggested that benzoquinone might be critical in promoting the reaction. However, its exact role remains elusive at this stage. Collectively, hydroquinone in the reaction played the following three roles: (1) assisted the generation of difluorocarbene; (2) functioned as the proton transfer shuttle to facilitate the formation of difluoromethylated alkynes; (3) served as a reductant to generate benzoquinone that might facilitate the catalytic cycle. Finally, we found that the palladium(0) difluorocarbene complex [4,7-di-t-Bu(t-Bu-Xantphos)]Pd0 = CF2 ( A1)26 indeed reacted with phenol to produce difluoromethyl palladium complex [4,7-di-t-Bu(t-Bu-Xantphos)]PdII(CF2H)(C6H5O) ( B2) with full conversion (Scheme 6g), thus demonstrating the nucleophilicity property of [Pd0]=CF2. Also, we performed the reaction of difluoromethyl palladium complex B1 with alkyne 2a in the presence of K2CO3, generating difluoromethylated alkyne 3 in 85% yield (Scheme 6h), suggesting that the formation of difluoromethylated alkyne through the reductive elimination of alkynyl–[PdII]–CF2H was reasonable. Since our kinetic studies revealed a zero-order relationship with an alkyne, this process might have proceeded at a relatively fast rate. Based on our results above, a conceivable reaction mechanism was proposed in Scheme 7b, as follows: The reaction began with the formation of the main palladium(0) complex [Pd0(Ln)]=CF2 ( A) formed between difluorocarbene and [Pd0(Ln)], in which difluorocarbene was generated by the reaction of ClCF2H with a base, as illustrated in Scheme 7a. Subsequently, the protonation of A with hydroquinone led to difluoromethyl palladium complex B, which was a rate-determining step of the reaction. The coordination of alkyne with complex B, followed by deprotonation of alkyne with a base, led to transmetalation, which afforded the key intermediate alkynyl difluoromethyl palladium complex C. Subsequently, via a reductive elimination, the corresponding difluoromethylated alkyne was produced with the release of [Pd0(Ln)]. Conclusion We have developed a palladium difluorocarbene involved catalytic cross-coupling with alkynes. The reaction proceeded under mild conditions, generating difluoromethylated alkynes with high efficiency. This new protocol overcame the limitation suffered by the Sonogashira reaction and featured a broad substrate scope, including the utilization of complex molecules and high functional group tolerance. Moreover, the reaction utilized an inexpensive raw industrial material, ClCF2H, as a difluorocarbene precursor, making it highly cost-efficient. Further, the resultant difluoromethylated alkyne could serve as a versatile building block for diversity-oriented synthesis, providing a straightforward and efficient route for applications in organic synthesis. Our preliminary mechanistic studies revealed that the protonation of [Pd0]=CF2 was the turn-over-limiting step. Hydroquinone played a crucial role in promoting the reaction; it did not only assist the generation of difluorocarbene but also functioned as a proton transfer shuttle to facilitate the formation of difluoromethylated alkynes. Finally, hydroquinone served as a reductant to generate benzoquinone that might play a critical role in facilitating the catalytic cycle. This catalytic MeDIC reaction paved a novel approach for harnessing the metal difluorocarbene, thus, applicable in medicinal and synthetic chemistry, and would prompt more research in this area. Supporting Information Supporting Information is available. Conflict of Interest There is no conflict of interest to report. Funding Information This research was made possible as a result of a generous grant from the National Natural Science Foundation of China (nos. 21931013, 21991122, 21672238, and 21421002) and the Strategic Priority Research Program of the Chinese Academy of Sciences (no. XDB20000000). 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Google Scholar Previous article FiguresReferencesRelatedDetailsCited ByZhang G, Shi Q, Hou M, Yang K, Wang S, Wang S, Li W, Li C, Qiu J, Xu H, Zhou L, Wang C, Li S, Lan Y and Song Q (2021) Atom Recombination of Difluorocarbene Enables 3-Fluorinated Oxindoles from 2-Aminoarylketones, CCS Chemistry, , (1613-1621)Sheng H, Su J, Li X and Song Q (2022) Deconstrutive Difunctionalizations of Cyclic Ethers Enabled by Difluorocarbene to Access Difluoromethyl Ethers, CCS Chemistry, , (1-12) Issue AssignmentVolume 2Issue 5Page: 293-304Supporting Information Copyright & Permissions© 2020 Chinese Chemical SocietyKeywordsdifluoromethylpalladiumdifluorocarbeneAlkynescross-couplingAcknowledgmentsThe authors wish to acknowledge Ming-Kuan Wang for repeating the preparation of some compounds and Dr. Xuebing Leng for the single-crystal X-ray diffraction analysis of palladium complex D. Downloaded 3,248 times PDF DownloadLoading ...