Atom Recombination of Difluorocarbene Enables 3-Fluorinated Oxindoles from 2-Aminoarylketones

Open AccessCCS ChemistryRESEARCH ARTICLE1 May 2022Atom Recombination of Difluorocarbene Enables 3-Fluorinated Oxindoles from 2-Aminoarylketones Guan Zhang, Qianqian Shi, Mengyuan Hou, Kai Yang, Shihui Wang, Shuai Wang, Wangyang Li, Chaokun Li, Jian Qiu, Hetao Xu, Lu Zhou, Cece Wang, Shi-Jun Li, Yu Lan and Qiuling Song Guan Zhang Key Laboratory of Molecule Synthesis and Function Discovery, Fujian Province University, College of Chemistry at Fuzhou University, Fuzhou, Fujian 350108 , Qianqian Shi Green Catalysis Center, College of Chemistry, Zhengzhou University, Zhengzhou, Henan 450001 , Mengyuan Hou Key Laboratory of Molecule Synthesis and Function Discovery, Fujian Province University, College of Chemistry at Fuzhou University, Fuzhou, Fujian 350108 , Kai Yang Key Laboratory of Molecule Synthesis and Function Discovery, Fujian Province University, College of Chemistry at Fuzhou University, Fuzhou, Fujian 350108 , Shihui Wang Institute of Next Generation Matter Transformation, College of Materials Science Engineering at Huaqiao University, Xiamen, Fujian 361021 , Shuai Wang Institute of Next Generation Matter Transformation, College of Materials Science Engineering at Huaqiao University, Xiamen, Fujian 361021 , Wangyang Li Key Laboratory of Molecule Synthesis and Function Discovery, Fujian Province University, College of Chemistry at Fuzhou University, Fuzhou, Fujian 350108 , Chaokun Li Key Laboratory of Molecule Synthesis and Function Discovery, Fujian Province University, College of Chemistry at Fuzhou University, Fuzhou, Fujian 350108 , Jian Qiu Key Laboratory of Molecule Synthesis and Function Discovery, Fujian Province University, College of Chemistry at Fuzhou University, Fuzhou, Fujian 350108 , Hetao Xu Key Laboratory of Molecule Synthesis and Function Discovery, Fujian Province University, College of Chemistry at Fuzhou University, Fuzhou, Fujian 350108 , Lu Zhou Key Laboratory of Molecule Synthesis and Function Discovery, Fujian Province University, College of Chemistry at Fuzhou University, Fuzhou, Fujian 350108 , Cece Wang Key Laboratory of Molecule Synthesis and Function Discovery, Fujian Province University, College of Chemistry at Fuzhou University, Fuzhou, Fujian 350108 , Shi-Jun Li Green Catalysis Center, College of Chemistry, Zhengzhou University, Zhengzhou, Henan 450001 , Yu Lan *Corresponding authors: E-mail Address: [email protected] E-mail Address: [email protected] Green Catalysis Center, College of Chemistry, Zhengzhou University, Zhengzhou, Henan 450001 School of Chemistry and Chemical Engineering, Chongqing Key Laboratory of Theoretical and Computational Chemistry, Chongqing University, Chongqing 400030 and Qiuling Song *Corresponding authors: E-mail Address: [email protected] E-mail Address: [email protected] Key Laboratory of Molecule Synthesis and Function Discovery, Fujian Province University, College of Chemistry at Fuzhou University, Fuzhou, Fujian 350108 Institute of Next Generation Matter Transformation, College of Materials Science Engineering at Huaqiao University, Xiamen, Fujian 361021 https://doi.org/10.31635/ccschem.021.202100979 SectionsSupplemental MaterialAboutAbstractPDF ToolsAdd to favoritesDownload CitationsTrack Citations ShareFacebookTwitterLinked InEmail Contrary to the traditional implementation as a difluoromethyl group and recently disclosed role of C1 synthons in synthetic organic chemistry, difluorocarbene (:CF2) is reported herein to proceed in unprecedented atom recombination as both a C1 synthon and F1 reagent simultaneously to render valuable 3-fluorinated oxindoles from 2-aminoarylketones. The reaction does not require catalyst and features a broad range of substrates with good functional group compatibility and ease of execution. This transformation could be employed to the quick-constructions of certain bioactive molecule derivatives. The mechanistic experiments and density functional theory (DFT) calculations indicate that this atom recombination reaction of :CF2 for the synthesis of 3-fluorinated oxindoles may involve a rearrangement process of epoxide intermediates. Download figure Download PowerPoint Introduction The transformation of difluorocarbene (:CF2) has emerged as a powerful difluorination platform, which can be widely used to introduce fluorine into organic molecules.1–4 Typical conversion of :CF2, including attachment with a nucleophile and an electrophile,5–16 Wittig reaction with carbonyls,17–20 [2+1] cycloaddition with alkenes or alkynes21, metal-:CF2 involved catalytic coupling,22–24 and combining with other carbenes,25–29 can quickly construct different organofluorine compounds, such as gem-difluoroalkenes and gem-difluorocyclopropanes and other gem-difluorinated compounds (Figure 1a). Despite these many transformations, :CF2 is limited to the introduction of a difluoromethyl group. Recently, we have found that :CF2 can be captured by amines and served as a C1 synthon to synthesize isocyanides,30 formamides,31,32 and various nitrogen-containing heterocycles33–39 (Figure 1b). However, fluorine atoms from :CF2 are discarded in these reactions and cannot be reused, and it is a significant drawback for such transformations. The atomic recombination of :CF2, which can be used as both a C1 synthon and fluorination reagent separately, has not been reported yet, which is also one of our long-term goals for the transformation of :CF2 species. Grounded in this knowledge inspired by our previous work, we surmise that a cascade reaction can occur with a substrate which contains dual reaction sites: nucleophilic and electrophilic ones on one molecule. It is well known that :CF2 is an electron-deficient species, so the nucleophilic site of the substrate captures :CF2 first, then the newly formed difluorocarbanion intramolecularly reacts with the electrophilic site followed by a possible rearrangement process, which perhaps accomplishes the atomic rearrangement of :CF2 (Figure 1c). Figure 1 | Transformations of difluorocarbene. Download figure Download PowerPoint On the other hand, in view of potential therapeutic values,40–43 the synthesis of 3-fluorooxindoles has attracted considerable attention, including fluorination of existing oxindoles,44–49 fluoroarylation of diazoacetamides,50 arylation of fluoracetamides51,52 as well as the derivatization of 3-fluorooxindoles.53,54 Based on the above conjecture, we envision 3-fluorinated oxindoles from 2-aminoarylketones, which bear both an amino group as a nucleophilic site and carbonyl group as an electrophilic site, could be accessible via an atom recombination of :CF2 as both a C1 synthon and F1 reagent (Figure 1d). However, there are several unprecedented challenges in this hypothesis: (1) the difluorocarbanion intermediate A might undergo undesired formylation of amine instead of intramolecular attack on the carbonyl group; (2) the intermediate B would be hydrolyzed and the corresponding alcohol will be resulted. Herein, we report an atomic recombination of :CF2 with 2-aminoarylketones toward 3-fluorinated oxindoles. This reaction proceeds under mild conditions featuring a catalyst-free, novel reaction pathway, ease of execution, valuable products, broad substrate scope, high efficiency, and good functional group tolerance. Experimental Methods General procedure for atom recombination of :CF2 with tertiary amines In air, a 25 mL Schlenk tube was charged with potassium carbonate (41.5 mg, 1.5 equiv). The tube was evacuated and filled with argon three times. Then, tertiary amines (0.2 mmol, 1 equiv) previously dissolved in acetonitrile (1.5 mL) and ethyl bromodifluoroacetate (64 μL, 2.5 equiv) were added to the tube at room temperature. The reaction was allowed to stir at 90 °C for 12 h. Upon completion, the reaction was cooled to room temperature and a proper amount of silica gel was added. After removal of the solvent, the crude reaction mixture was purified on silica gel (petroleum ether: ethyl acetate = 10:1) to afford the desired product ( 3a– 3aj, 3ao– 3at, 4a– 4i). General procedure for atom recombination of :CF2 with secondary amines In air, a 25 mL Schlenk tube was charged with potassium carbonate (27.6 mg, 1.0 equiv). The tube was evacuated and filled with argon three times. Then, secondary amines (0.2 mmol, 1 equiv) previously dissolved in acetonitrile (1.5 mL) and ethyl bromodifluoroacetate (38 μL, 1.5 equiv) were added to the tube at room temperature. The reaction was allowed to stir at 90 °C for 3 h, and then potassium carbonate (27.6 mg, 1.0 equiv) and ethyl bromodifluoroacetate (38 μL, 1.5 equiv) were added every 3 h (twice). Upon completion, the reaction was cooled to room temperature and a proper amount of silica gel was added. After solvent removal, the crude reaction mixture was purified on silica gel (petroleum ether: ethyl acetate = 10∶1) to afford the desired product ( 3ak– 3an). Results and Discussion Exploratory investigations toward our envisioned atom recombination reaction of :CF2 were conducted with 2-aminoarylketone 1a and ethyl bromodifluoroacetate ( 2a) as test substrates. Bases play a vital role in the formation of :CF2, so NaHCO3 could promote the formation of the desired 3-fluorooxindole 3a in 22% isolated yield (entry 1, Table 1). After solvent screening on trichoromethane (DCM), CHCl3, tetrahydrofuran (THF), 1,4-dioxane, CH3CN, and MeOH, it was found that the target product 3a could be obtained in CH3CN with superior yield (entries 1−6). Screening different bases revealed that the best reaction efficiency was endowed by K2CO3 (entries 7−13). Increased base loading could slightly improve the isolated yield to 56% (entry 14). Increasing temperature could increase the yield of the target product, and the yield of 3a was increased to 90% when the temperature was increased from 70 to 90°C (entries 15 and 16). This atom recombination reaction of :CF2 could occur with other :CF2 precursor reagents, including HCF2Cl ( 2b), TMSCF2Br ( 2c), and ethyl iododifluoroacetate ( 2d), but the yields were lower than that of ethyl bromodifluoroacetate ( 2a) (entries 17–19). Table 1 | Optimization of Reaction Conditionsa Entry Base Solvent Temperature (°C) Yield (%)b 1 NaHCO3 DCM 70 22 2 NaHCO3 CHCl3 70 18 3 NaHCO3 THF 70 Trace 4 NaHCO3 1,4-Dioxane 70 Trace 5 NaHCO3 CH3CN 70 31 6 NaHCO3 MeOH 70 Trace 7 Cs2CO3 MeCN 70 15 8 K2CO3 MeCN 70 55 9 K3PO4 MeCN 70 Trace 10 Na3PO4 MeCN 70 10 11 KF MeCN 70 Trace 12 CsF MeCN 70 40 13 Na2CO3 MeCN 70 50 14 K2CO3c MeCN 70 56 15 K2CO3c MeCN 80 71 16 K2CO3c MeCN 90 90 17d K2CO3c MeCN 90 Trace 18e K2CO3c MeCN 90 52 19f K2CO3c MeCN 90 13 aReaction conditions: Unless otherwise specified, 1a (0.2 mmol, 1 equiv), 2a (0.5 mmol, 2.5 equiv), base (1.2 equiv), and solvent (1.5 mL) under an argon atmosphere for 12 h. bIsolated yield. cBase (1.5 equiv). d 2b (0.5 mmol, 2.5 equiv). e 2c (0.5 mmol, 2.5 equiv). f 2d (0.5 mmol, 2.5 equiv). With optimized conditions in hand, we first examined the scope of this atom recombination reaction of :CF2 for tertiary amines (Scheme 1). Various substituents (R1) on the aromatic ring of 2-aminoarylketone were tested ( 3b– 3j). Halogens ( 3b– 3f), which could be readily modified in further structural elaborations, were all tolerated well to obtain the desired 3-fluorooxindole products in high yields, and the substitution positions ( 3d– 3f) had little effect on the efficiency. Similarly, both electron-deficient ( 3g and 3h) and electron-neutral ( 3i and 3j) 2-aminoarylketones were found to be compatible with this reaction, and the corresponding products were obtained with good to excellent yields (76–96%). Next, the scope of R2 was also investigated. Aryl bearing halogens ( 3k– 3n and 3t) and alkyl ( 3o– 3r) and methoxy ( 3s and 3t) groups smoothly provided the corresponding 3-fluorooxindole products in 73–98% yields. The substituents on the ortho position of the aryl groups ( 3q and 3t) did not affect the progress of the reaction. It is worth mentioning that strong electron-deficient groups, including cyano ( 3u and 3v), nitro ( 3w), acylamino ( 3x), and acetyl ( 3y) could be tolerated well, leading to the corresponding 3-fluorooxindole products in 84–94% yields. Substrates containing vinyl ( 3z), naphthalene ( 3aa), and benzothiophene ( 3ab) were also good substrates for this transformation. In addition to 2-aminodiarylketones, 2-aminoaryalkyllketones (R2 = alkyl) could also successfully obtain the corresponding desired 3-fluorinated oxindole products 3ac– 3ah. Notably, 2-aminoarylketones containing pyridine or quinoline were found to be compatible with this atom recombination reaction, and the desired products 3ai and 3aj were isolated in moderate yields. Scheme 1 | Substrate scope.a,b Reaction conditions: aUnless otherwise specified, 1 (0.2 mmol, 1 equiv), 2a (0.5 mmol, 2.5 equiv), K2CO3 (1.5 equiv), and solvent (1.5 mL) under an argon atmosphere for 12 h. bIsolated yield. c1 (0.2 mmol, 1 equiv), 2a (0.3 mmol, 1.5 equiv * 3), K2CO3 (0.2 mmol, 1 equiv * 3). Download figure Download PowerPoint We next evaluated the generality of secondary amines in current transformation, the reaction of the secondary amines and :CF2 gave the targetted products 3ak– 3ao in moderate yields. Compared with tertiary amines, secondary amines have lower nucleophilicity, resulting in lower yields than the former ones, yet providing more diversity to this transformation. Finally, 2-aminoarylketones bearing cyclic tertiary amines were tested as substrates for this atom recombination reaction, of note, such a method provided a convenient way to synthesize 3-fluorinated oxindole with bromide branches which could be further elaborated. Besides four-membered aza-rings providing the corresponding products in excellent yields ( 3ap– 3ar), five-membered aza-rings could also be used to obtain the desired product 3as in high yield. In terms of a six-membered aza-ring, the yield of the corresponding product 3at was reduced, probably due to less ring strain. The potential applicability of this method was studied further using complex 2-aminoarylketone substrates derived from drugs, bioactive molecules, or herbicides. 2-Aminoarylketones derived from ibuprofen, indometacin, oleic acid, flurbiprofen, naproxen, felbinac, probenecid, 2-Methyl-4-chlorophenoxyacetic acid (MCPA), and dichlorprop were smoothly converted into the desired 3-fluorooxindole products 4a– 4i in moderate to good yields (Scheme 2a). A noteworthy example is compound 4b, which lost the 4-chlorobenzoyl group of indomethacin during the preparation of the substrate, while the unprotected NH did not hinder the reaction. In addition, compound 6 with a bioactive molecular skeleton could be prepared under standard conditions with excellent yield, and it could further combine with drugs or active molecules to form new complex molecules 7 and 8 (Scheme 2b). Scheme 2 | Synthetic applications. Download figure Download PowerPoint Isotope labeling experiments were designed to indicate the mechanism of this transformation (Scheme 3). The 2-aminoarylketone 1a-O 18 labeled with O 18 obtained the labeled product 3a-O 18 under standard conditions, and the labeling rate of the product 3a-O 18 was consistent with that of the substrate 1a-O 18 [detected by gas chromatography–mass spectrometry (GC-MS)]. Further, no O 18 labeled product was detected in the reaction with added H2O18. These results implied that the oxygen in the 3-fluorooxindole products comes from the carbonyl of 2-aminoarylketones and water is not the source of oxygen in the final products. Treatment of 2-substituted indoles with oxone/acetone could afford an epoxide intermediate, which could further undergo a rearrangement to provide oxindoles. In addition, we found that 2-fluoroindole 9 could be converted to 3-fluorinated oxindole 3ac under similar conditions, which suggests that our atom recombination reaction of :CF2 for the synthesis of 3-fluorinated oxindoles may also involve a rearrangement process of epoxide intermediates.55–57 Scheme 3 | Mechanistic experiments. Download figure Download PowerPoint According to the experimental results, we considered a possible pathway that involves the atomic recombination of :CF2 for the synthesis of 3-fluorinated oxindoles (Scheme 4). BrCF2COOEt first decomposes to render :CF2 under basic conditions, and then the in situ generated active species reacts with the amino moiety of 2-aminoarylketones to obtain the intermediate A. Nucleophile (Br−) attacks the α carbon of ammonium salt A to produce indole intermediate B, which further undergoes intramolecular cyclization and one of the C–F bonds is cleaved to render ethylene oxide epoxide intermediate C. The next 1,2-fluorine migration (path a)58,59 or fluorine ion attack (path b) may undergo intermediate D or E to generate the targetted 3-fluorinated oxindole products. Scheme 4 | Possible reaction mechanism. Download figure Download PowerPoint Computational Methods Based on the experimental observation and proposed mechanism for the annulation of :CF2 and 2-aminoarylketone, a theoretical study has been performed utilizing the density functional theory (DFT) method. The calculated free energy profiles for the generation of 3-fluorinated oxindoles using the M06 functional in the MeCN solvent are given in Figure 2. :CF2 generated in situ from the elimination of bromodifluoroacetate in the presence of base could be electrophilically attacked by the amino group of reactant 1a via transition state TS-A with a free energy barrier of 1.7 kcal/mol. Meanwhile, C–C bond formation with the intramolecular carbonyl group without an energy barrier results in a zwitterionic indoliniumolate intermediate A sequentially. The methyl group on the indolinum moiety of this intermediate provides electrophilicity. Therefore, a nucleophilic substitution by extra bromide takes place via a linear transition state TS-B with an energy barrier of 20.9 kcal/mol. Leaving of bromomethane gives indolinolate intermediate B. Driven by the strong nucleophilicity of oxygen anions in the intermediate B, an intramolecular substitution with a neighboring C–F bond could take place via transition state TS-C. The calculated free-energy barrier of this step is 23.5 kcal/mol, which could be considered to be the rate-limit for the whole transformation. After releasing an anionic fluoride, indole epoxide intermediate C is formed with exergonic 8.9 kcal/mol. The ring strain of the three-membered epoxide ring leads to heterolytic cleavage of the C–O bond with the generation of a more stable zwitterionic intermediate D. Then a rapid 1,2-fluorine shift via transition state TS-F yields final product indolinone 3a. Moreover, a fluoride-assisted C–O bond cleavage of intermediate C was also considered; however, the calculated energy barrier for this pathway via transition state TS-D is much higher than that of the stepwise process via transition states TS-E and TS-F. Figure 2 | The DFT calculated free energy profiles for the annulation of :CF2 and 2-aminoarylketone at M06/6-311++G(2d,2p) (SDD for Br)/SMD(MeCN)//M06/6-31G(d,p) (SDD for Br)/SMD(MeCN) level of theory. Values are the relative free energies given in kcal/mol. Download figure Download PowerPoint Conclusions We have disclosed a new atom recombination reaction of :CF2 as both a C1 synthon and F1 reagent in a single-vessel transformation, through which a series of valuable 3-fluorinated oxindoles were rapidly constructed. The reaction features no catalyst, ease of execution, broad substrate scope and good functional group compatibility. Further investigations on the mechanism of this transformation and expansion of the application range of the reaction are currently in progress. 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