Deconstrutive Difunctionalizations of Cyclic Ethers Enabled by Difluorocarbene to Access Difluoromethyl Ethers

Abstract

Open AccessCCS ChemistryRESEARCH ARTICLE7 Dec 2022Deconstrutive Difunctionalizations of Cyclic Ethers Enabled by Difluorocarbene to Access Difluoromethyl Ethers Heyun Sheng, Jianke Su, Xue Li and Qiuling Song Heyun Sheng Institute of Next Generation Matter Transformation, College of Materials Science and Engineering, Huaqiao University, Xiamen, Fujian 361021 , Jianke Su Institute of Next Generation Matter Transformation, College of Materials Science and Engineering, Huaqiao University, Xiamen, Fujian 361021 , Xue Li Institute of Next Generation Matter Transformation, College of Materials Science and Engineering, Huaqiao University, Xiamen, Fujian 361021 and Qiuling Song *Corresponding author: E-mail Address: [email protected] Institute of Next Generation Matter Transformation, College of Materials Science and Engineering, Huaqiao University, Xiamen, Fujian 361021 School of Chemistry and Chemical Engineering, Henan Normal University, Xinxiang, Henan 453007 https://doi.org/10.31635/ccschem.022.202101576 SectionsSupplemental MaterialAboutAbstractPDF ToolsAdd to favoritesDownload CitationsTrack Citations ShareFacebookTwitterLinked InEmail An unprecedented difluorocarbene-mediated C–O bond cleavage of cyclic ethers for the construction of difluoromethyl ethers is herein disclosed. This protocol is distinguished by its mild conditions, high efficiency, and wide substrate scope, which can tolerate both sensitive functional groups such as the hydroxyl group, olefin and C–C triple bonds, as well as complex molecules. It thus demonstrates excellent chemoselectivities and great potential for late-stage modification of pharmaceutical compounds and natural products. It is worth noting that this method not only introduces fluorine atoms into the final molecules, but it can also effectively form an ester or ether linkage. Download figure Download PowerPoint Introduction Difluoromethyl ethers containing difluoromethoxy moiety have gained significant attention in pharmaceuticals, agrochemicals, and medicinal chemistry1,2 (Figure 1a), since the introduction of the difluoromethoxy group can significantly improve metabolic stability, biological activity, and target specificity of the parent molecules. Thus, difluoromethyl ethers provide opportunities for the development of new drugs.3 Due to the practical applicability of difluoromethyl ethers, many synthetic methods have been developed to construct them.4–9 In 2017, Fu and co-workers10 reported a strategy that enabled preparation of aromatic difluoromethyl ethers under visible-light photocatalytic conditions. Subsequently, Ngai et al.11,12 reported a distinct radical approach for catalytic C–H difluoromethoxylation of (hetero)arenes using difluoromethoxylative reagents (Figure 1b, left). Of note, as an important and special fluorine-containing intermediate in organic synthesis,13–24 difluorocarbene has been combined with various alcohols and thiols to synthesize difluoromethyl ethers25–28 and thioethers29,30 (Figure 1b, right). Despite the progress achieved in recent years on the synthesis of difluoromethyl ethers, efficient methods for their synthesis are still rare, and the development of a general and practical strategy for their construction is very desirable, especially in terms of the complexity and versatility of difluoromethoxy compounds. Compared with alcohols and thiols, the C–O in ethers31–39 is also a prevalent structural motif in biomedicines, agrochemicals, and natural products. Moreover, it is often used as a protecting group or linker in chemical synthesis and has good tolerance to both acids and bases, oxidants and reductants.40–42 In contrast to C–O bond constructions, deconstructive functionalizations of Csp3–O bonds in cyclic ethers43–48 are difficult and relatively rare because of the strength and stability of these linkages. If an easy protocol for C–O bond editing could be developed by a prevailing fluorine-containing species, it would dramatically increase the diversity and complexity of difluoromethoxy compounds and thus meet our goal of synthesizing dimethyl ethers. Figure 1 | Synthesis and application of difluoromethyl ether. (a) Representive bioactive molecules bearing difluoromethoxy moiety. (b) Typical synthesis of difluoromethyl ethers enabled by difluorocarbene or difluoromethoxy radical. (c) Difluorocarbene-mediated cyclic C–O cleavage to access difluoromethyl ethers (this work). Download figure Download PowerPoint Given the prevalence of alkyl ethers and our previous work on the deconstructive functionalization of tertiary amines by difluorocarbene,49–52 we envisaged that the electron-deficient53 difluorocarbene might interact with the lone pair electrons21,22,54,55 of the oxygen atom in alkyl ether. This interaction would form a zwitterionic intermediate that could undergo a nucleophilic attack by a third component of the carbon atom adjacent to the oxygen in cyclic ethers to procure difluoromethyl ethers via ether editing. If successful, we could significantly expand the substrate scope for difluoromethyl ethers by developing a three-component reaction with readily accessible starting materials. Meanwhile we could increase the diversity of difluoromethoxy compounds and provide a versatile pool for medicinal chemistry. Moreover, this might provide a new reference for the breaking of carbon-oxygen bonds in alkyl ethers.35–38,43–47 However, there are several challenges for our hypothesis: (1) Difluorocarbene is not a highly electron-deficient carbene species compared with well-known normal carbenes, because the lone pair electrons in a fluorine atom can conjugate with the carbene empty orbital to make it more stable and relatively "electron-rich." Thus, the interaction between difluorocarbene and the neutral O atom in alkyl ethers will not be very strong. (2) Because of the weak interaction, it will not significantly weaken the C–O bond and thus makes the cleavage of the C–O bond difficult. (3) There are competitions between the third component which serves as a nucleophile to break the C–O bond and the alkyl ether, and the reaction for the third nucleophilic component and difluorocarbene might be the dominant one.56–58 And (4) the choice of the third component will be critical for the success of this hypothesis. Herein, we report an unprecedented method for the construction of difluoromethyl ethers via deconstructive difunctionalizations of the C–O bond in alkyl ethers enabled by difluorocarbene and various carboxylic acids, with successive C–O bond cleavage of cyclic ethers and concomitant functionalization of both constituent atoms to lead to difluoromethyl ethers (Figure 1c). Compared with traditional methods, our strategy promotes the cleavage of the Csp3–O bond at room temperature under the action of base alone. Of note, not only can the fluorine atom be introduced into the eventual molecules, ester and ether linkages can also effectively be formed. This reaction features high efficiency, mild conditions, and great chemoselectivity with an additive- and transition-metal-free protocol. The reaction substrates are extremely broad and have great potential for late-stage modification of drug molecules, which means that this method is an alternative and complementary to the currently known strategies and dramatically increases the diversity and complexity of difluoromethoxy compounds. Experimental Methods In air, a 25 mL Schlenk tube was charged with acid (0.2 mmol, 1 equiv) and potassium phosphate (84.8 mg, 2 equiv). The tube was evacuated and filled with nitrogen three times. Then, tetrahydrofuran (THF) or cyclic ether (2 mL) and TMSCF2Br (93.6 μL, 3 equiv) were added to the tube at room temperature. The reaction was allowed to stir for 36 h. Upon completion with the removal of the solvent, the crude reaction mixture was purified on silica gel (petroleum ether:ethyl acetate = 10:1) to afford the desired product 3–100. Results and Discussion To verify our hypothesis, we chose 4-methylbenzoic acid ( 1) and TMSCF2Br ( 2a) and THF as model substrates to optimize the conditions (Table 1). When K3PO4 was used as a base and exposed in THF (2 mL), the desired product 3 was obtained with 58% isolated yield (entry 1). Base screening of K2CO3, Na2CO3, Cs2CO3, and KF suggested that K3PO4 was the optimal choice (entries 2–5). Subsequently, when the temperature was lowered to 60 °C, the target product 3 was obtained in 68% yield (entry 6). When the reaction time was appropriately extended, the yield of the corresponding products was increased accordingly (entries 7 and 8). To our surprise and delight, when the reaction proceeded at room temperature for 36 h (entry 9), 83% yield of 3 was obtained. However, when the ratio of 1 to 2a was changed, the yield was not improved; rather, it dropped (entry 10). Addition of 10 equiv of THF in acetonitrile as solvent did not improve the yield at all (entry 11). Other difluoroalkylative reagents were subsequently examined, and the results suggested that among TMSCF2Br ( 2a), BrCF2COOEt ( 2b), BrCF2PO(OEt)2 ( 2c), ClCF2COONa ( 2d), and HCF2Cl ( 2e) (entries 12–15), the best reaction efficiency was endowed by 2a (entry 9). Table 1 | Explorations and Optimizations Entry :CF2 Base T (°C) t (h) 3 Yielda (%) 1 2a K3PO4 100 12 58 2 2a K2CO3 100 12 38 3 2a Na2CO3 100 12 50 4 2a Cs2CO3 100 12 48 5 2a KF 100 12 42 6 2a K3PO4 60 12 68 7 2a K3PO4 60 24 70 8 2a K3PO4 60 36 78 9 2a K3PO4 rt 36 83 10b 2a K3PO4 rt 36 52 11c 2a K3PO4 rt 36 nd 12 2b K3PO4 rt 36 nd 13 2c K3PO4 rt 36 nd 14 2d K3PO4 rt 36 nd 15 2e K3PO4 rt 36 nd Reaction conditions: 1 (0.2 mmol), 2 (0.6 mmol), base (0.4 mmol), THF (2 mL), N2. aIsolated yields. b 1 (0.3 mmol), 2 (0.2 mmol). cTHF (10 equiv), CH3CN (2 mL). Substrate scope With the optimal reaction conditions in hand (Table 1, entry 9), we investigated the substrate range of carboxylic acids, testing the compatibility of the reaction (Figure 2). Under the standard reaction conditions, model substrates and methyl-substituted benzoic acid at different positions of the aromatic ring obtained the target products ( 3–5) with good yields (69–83%). Both electron-donating and electron-withdrawing groups were compatible in our system, and para-substituted benzoic acid with methoxyl group led to the desired product 6 in 75% yield, while the unsubstituted benzoic acid afforded the corresponding product 7 in 82% yields. We also investigated the benzoic acid containing sensitive groups (alkenyl and alkynyl), and the results were surprising yet exciting. The corresponding target products ( 8–9) were obtained in moderate yields (68–72%) without interference of C–C double bonds and C–C triple bonds, since it is well-known that difluorocarbene reacts with carbon–carbon unsaturated bonds to form cyclopropanes or cyclopropenes. In our experiment, the reactions demonstrated excellent chemoselectivities. Both halogens and other strong electron-withdrawing substituents (acetyl, NO2, and CF3) were compatible in our system, and the desired products were obtained in good to excellent yields ( 10–13, 14–16), respectively. Meanwhile, heterocyclic aromatic carboxylic acids were also examined, and the target products could be procured in decent yields ( 17–19). Pentafluorobenzoic acid and terephthalic acid were also tolerable in our system to render the desired products 20 and 21 in 82% and 53% yields respectively under the standard conditions. Moreover, 2,4-disubstituted benzoic acid indicated good reactivity and the target product ( 22) was obtained with 95% yield. Figure 2 | Scope of aromatic and aliphatic carboxylic acids. Standard reaction conditions: acid (0.2 mmol), TMSCF2Br (0.6 mmol), THF (2 mL), K3PO4 (0.4 mmol), at room temperature for 36 h. Isolated yields are reported. aReaction performed with TMSCF2Br (1.2 mmol). bThe conversion rate is indicated in parentheses. cConversion rates were determined by 1H NMR, 1,3,5-trimethoxybenzene as an internal standard. Download figure Download PowerPoint We next explored the substrate range of benzylic carboxylic acids and aliphatic carboxylic acids under the same reaction conditions (Figure 2, bottom). First, we investigated 4-chlorophenylacetic acid, 4-phenylphenylacetic acid, 4′-methoxy-biphenyl-4-acetic acid, 2-naphthylacetic acid, and 2-methyl-2-(p-tolyl) propanoic acid, and the corresponding products ( 23–27) were obtained in good yields. After that, 2-(3,5-dichlorophenoxy) acetic acid, 2,3-dihydrobenzo[b] [1,4] dioxine-2-carboxylic acid, 2-phenylcyclopropane-1-carboxylic acid, and 2-oxo-2-phenylacetic acid were examined as well under the standard conditions, and the corresponding target products ( 28–31) were rendered in moderate to good yields (46–73%). Our system was also compatible with pure aliphatic carboxylic acids, which had been well demonstrated by the products 32–37. Most remarkably, atropic acid, sorbic acid, and cinnamic acid, which have carbon–carbon double bonds in their structures, were also good candidates in our system. The corresponding targeted products 38– 41 were obtained in moderate to good yields (54–80%) without the interference of the C=C bond, although it is well known that difluorocarbene readily reacts with the carbon–carbon unsaturated bond. Gratifyingly, our reaction system also tolerated the free hydroxyl group; for instance, α-hydroxy carboxylic acid was a good substrate to lead to the final product 42 in a moderate yield while leaving free OH intact. The above results clearly demonstrate that our method has excellent chemoselectivity, a broad substrate scope, and wide functional group compatibility, which further prompted our efforts to extrapolate this strategy to late-stage modifications of bioactive molecules and therapeutic agents (Figure 3). Amino acid is one of the most common active molecules, and considering its importance in people's lives, we tried to modify it under our optimal conditions. Gratifyingly, a series of protected amino acids (Boc-isoleucine, Boc-d-Phenylalanine, Fmoc-Met-OH, Boc-d-Phenylglycine, Boc-O-benzyl-l-tyrosine, Boc-l-Proline, N-Phthaloylglycine, Boc-l-Leucine monohydrate, N-Boc-glycine, and N-Boc-l-tert-Leucine) were introduced into the corresponding product ( 43– 47, 49– 53) with moderate to good yields. It is worth noting that the hydroxyl-containing amino acid (Boc-d-Serine) can also obtain the target product ( 48) with a yield of 43% and a conversion of 65%. Moreover, drug compounds, such as bezafibrate, gemfibrozil, isoxepac, ketoprofen, (S)-ibuprofen, artesunate, stearic acid, sulbactam, aspirin, indomethacin, fenbufen, naproxen, and dehydrocholic acid, were also successfully introduced into the corresponding product ( 54– 66) without loss of efficiency. The isolated yields were moderate to excellent (49–95%). Of note, when there are complex molecules (oleanic acid, lithocholic acid, ursolic acid, and glycyrrhetinic acid) with sensitive groups, the reaction can still proceed smoothly to lead to the corresponding desired products ( 67–70). The above results show that our strategy has great potential for late-stage modification which might help to find new drug candidates. Figure 3 | Late-stage modifications of complex molecules. Standard reaction conditions: acid (0.2 mmol), TMSCF2Br (0.6 mmol), THF (2 mL), K3PO4 (0.4 mmol), at room temperature for 36 h. Isolated yields are reported. aThe conversion rate is indicated in parentheses. bConversion rates were determined by 1H NMR, 1,3,5-trimethoxybenzene as an internal standard. Download figure Download PowerPoint We next focused on the commonly used cyclic ether solvents. Without significant changes in the conditions, the expected products were obtained with excellent functional group tolerance (Figure 4). For example, with tetrahydropyran as the solvent, the reaction demonstrated similar substrate compatibility. Regardless of the electron-neutral group (Me), electron-withdrawing group (NO2, acetyl, CF3, sulfone), or halogen (Br), the corresponding products were all obtained in good to excellent yields ( 71– 76). When the substrates contained conjugated olefins, the corresponding products were procured with medium yield ( 77– 79). Aliphatic carboxylic acids including the substrate which contains hydroxy group were compatible in our system to render the targeted molecules in decent yields ( 80– 82). When 2-methyltetrahydrofuran took the place of tetrahydrofuran to participate in the reaction, just as it did with tetrahydrofuran and tetrahydropyran, the reaction proceeded smoothly to generate the corresponding desired products with moderate regioselectivity and could not be separated ( 83– 90). Of note, in the presence of methoxy and dioxole groups on the benzene ring of benzoic acids, the desired products were obtained with MeO and dioxole untouched ( 87, 90) under the standard conditions, albeit with a lower yield with 90. With 1,4-dioxane, 1,3-dioxolane, and 1,3-dioxane acting as solvents, the corresponding products ( 91– 97) could be obtained in medium to good yields (35–69%). A myriad of nucleophiles, such as hydroxylamine ( 98), phosphoric acid ( 99), and saccharin ( 100) were also investigated, and they performed well under the standard conditions to render the targeted products in good yields (32–75%). Figure 4 | Scope of cycloethers and nucleophiles. Standard reaction conditions: acid (0.2 mmol), TMSCF2Br (0.6 mmol), THF (2 mL), K3PO4 (0.4 mmol), at room temperature for 36 h. Isolated yields are reported: aReaction carried out at 50 °C, Na2CO3 instead of K3PO4. bRatio is calculated by fluorine spectrum. cReaction carried out at 60 °C, Na2CO3 instead of K3PO4. dNa2CO3 instead of K3PO4. eThe conversion rate is indicated in parentheses. fConversion rates were determined by 1H NMR, 1,3,5-trimethoxybenzene as an internal standard. Download figure Download PowerPoint In order to further verify the good functional group compatibility of our reactions, the substrates which contain both free hydroxyl groups and free carboxylic acids (lithocholic acid, glycyrrhetinic acid, and tropine acid) were subjected to reaction with TMSCF2Br under our standard conditions and previously reported conditions9 (Figure 5). To our delight, the corresponding difluoromethylative products were rendered in stepwise fashion ( 68′, 70′, 101′). The smooth transformations of these complex drug molecules were sufficient to verify the superiority of our reaction. Figure 5 | Synthesis and transformation. Standard conditions: acid (0.3 mmol), TMSCF2Br (3 equiv), K3PO4 (2 equiv), THF (3 mL), at room temperature for 36 h. Download figure Download PowerPoint Intrigued by the features of the methodology presented here, we conducted several control experiments to shed light on the reaction mechanism (Figure 6). When water was replaced by deuterium oxide, a deuterium atom was introduced into the difluoromethyl group of the final product 3-D, and the deuteration rate was 67% (Figure 6a). We tried to react with deuterated benzoic acid in anhydrous THF, and 10% deuterated products were formed (Figure 6b; see Supporting Information), possibly resulting from the fast exchange of D/H between D-acid and the trace amount of water in the solvent. In order to explore the intermediates of the reaction, we used 3′ as the starting material. Under the standard conditions, the formation of the target product was not detected (Figure 6c). This suggests that 3′ should not be an intermediate. When the difluorocarbene capture reagent benzimidazole ( 1a) and pyridine-2-thiol ( 1b) were added to the reaction system, 1-(difluoromethyl)-1H-benzo[d]imidazole ( 1a′) and 2-((difluoromethyl)thio) pyridine ( 1b′) were isolated in good yields, while product 3 was not detected (Figures 6d and 6e), which suggests that difluorocarbene was generated in our transformations. Figure 6 | Control experiments. Download figure Download PowerPoint On the basis of the above results, a plausible mechanism is proposed as depicted in Figure 7. Cyclic ether A reacts with difluorocarbene, which is in situ generated from compound 2 to lead to intermediate B or E. In the case of intermediate B, the nucleophilic attack on the adjacent carbon breaks the C–O bond to form intermediate C, and then protonation under the action of water renders the target product D. In the case of intermediate E, there are two ways for the nucleophile to attack: one is to attack from the place with less steric hindrance to procure intermediate F (path a), and the another is to attack from the side with larger steric hindrance to render intermediates G (path b). Then both of the two intermediates undergo protonation, and the final products H and I are obtained. Figure 7 | Plausible mechanism. Download figure Download PowerPoint Conclusion We report a difluorocarbene-mediated method that promotes the cleavage of the C–O bond of cyclic alkyl ethers under the action of a cheap and easily available nucleophile to synthesize difluoromethyl ether. Compared to previous reports, this strategy is very general, mild, and efficient and does not use any transition metals or additives. It provides a convenient and alternative way to synthesize difluoromethyl ethers. Moreover, it has a wide range of substrates and good compatibility, showing great advantages in the modification of drug molecules and natural products. Further investigations to extend the reaction scope and applications of this process are currently in progress. Supporting Information Supporting Information is available and includes experimental procedures, analytical and spectroscopic data for new compounds, and copies of NMR spectra. Conflict of Interest The authors declare no competing interests. Acknowledgments Financial support by the National Natural Science Foundation of China (grant no. 21931013) and the Open Research Fund of the School of Chemistry and Chemical Engineering, Henan Normal University is gratefully acknowledged. The authors also thank the Instrumental Analysis Center of Huaqiao University for analysis support. References 1. Peter J.; Eckhard B.; Frederic R. L.α-Fluorinated Ethers as "Exotic" Entity in Medicinal Chemistry.Mini-Rev. Med. Chem.2007, 7, 1027–1034. Google E. J.; D. J.; of in Medicinal Med. Google from A Med. Google for Difluoromethyl Google for the of and Aliphatic Difluoromethyl Ethers from and a Google J.; of with an Google 7. and from and Google Li J.; of TMSCF2Br as a and Difluorocarbene under Google to the of In and Google J.; Fu of and with Google Ngai of and Google Ngai of and by Google to by Reaction of with Google of Google Fu An of by Google Song and of Google Fu Xue Difluorocarbene Access to Google Su J.; Song of with under Google of Enabled by 1, Google Fu Difluorocarbene with 2, Google E. as for Difluorocarbene Google of Difluorocarbene by Google Fu Fu for the Synthesis of an Google of Amino via Google J.; A Difluorocarbene and in the of Google of Difluoromethyl Ethers with Google and Google Li of Google J.; and with Difluorocarbene by Google of Difluoromethyl and Difluoromethyl from Aliphatic Google R. of Google of Ethers a Google Li Li J.; of with under Reaction 47, Google Li via of Google D. Google of Google Su B.; of and as in Chemical Google E. of with Cyclic Ethers and to or 7, Google via Google Synthesis of a of the of Google and in the Synthesis of a 1, Google Synthesis of Google Synthesis of Google J.; and of Scope and Google J.; and of Google R. B.; of from and Cyclic Ethers or under and Google of Cyclic and under Google Li Li Synthesis of with under Google Su J.; Song of Enabled by Google Li Li J.; Li Song of Difluorocarbene from Google Su J.; Song to Access from Google Sheng Su J.; Li Li Song of Difluorocarbene by the of Google for the Synthesis of via a Reaction of an Google J.; of Cyclic Enabled by Difluorocarbene Google via Difluorocarbene Google R. Difluoromethyl and 2, Google and Synthesis of Difluoromethyl as a Difluorocarbene Google Base of with Access to Difluoromethyl Google Information Chemical bond support by the National Natural Science Foundation of China (grant no. 21931013) and the Open Research Fund of the School of Chemistry and Chemical Engineering, Henan Normal University is gratefully acknowledged. The authors also thank the Instrumental Analysis Center of Huaqiao University for analysis support.

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