The discovery of modern medicine relies on the sustainable development of synthetic methodologies to meet the needs associated with drug molecular design. Heterocycles containing difluoromethyl groups are an emerging but scarcely investigated class of organofluoro molecules with potential applications in pharmaceutical, agricultural and material science. Herein, we developed an organophotocatalytic direct difluoromethylation of heterocycles using O2 as a green oxidant. The C–H oxidative difluoromethylation obviates the need for pre-functionalization of the substrates, metals and additives. The operationally straightforward method enriches the efficient synthesis of many difluoromethylated heterocycles in moderate to excellent yields. The direct difluoromethylation of pharmaceutical moleculars demonstrates the practicability of this methodology to late-stage drug development. Moreover, 2′-deoxy-5-difluoromethyluridine (F2TDR) exhibits promising activity against some cancer cell lines, indicating that the difluoromethylation methodology might provide assistance for drug discovery.
Organofluoro compounds are widely used in the fields of pharmaceutical, agricultural, and material science1,2,3. The introduction of fluorine atoms or fluorine-containing groups into the framework of organic molecules often changes the physicochemical properties or biological activities of compounds4,5,6,7,8, and has become an essential topic for chemists. During the past few decades, much attention has been focused on the synthesis of fluorinated9,10,11,12 and trifluoromethylated molecules13,14,15,16,17,18,19. On the other hand, the difluoromethyl is also a critical fluorinated functional group due to its use as a lipophilic hydrogen bond donor. In addition, CF2H group can be considered as the isostere of a thiol, a hydroxyl, and an amide, which brings out its potential value in drug development with novel scaffold20,21. However, unlike well-developed synthesis of fluorinated and trifluoromethylated compounds, the construction of difluoromethylated substances22,23,24,25,26,27, especially for difluoromethylated heterocycles, which widely exist in bioactive molecules (Fig. 1a), has been less explored. The traditional strategies for the synthesis of difluoromethylated heterocycles include deoxyfluorination of aldehydes28, difluorination of benzylic C−H bonds29,30, decarbonylation/decarboxylation difluoromethylation31,32, cycloaddition reactions24,33,34, and conversion of CF2R containing heterocycles precursors35,36. However, these above-mentioned methods need expensive and toxic fluorinating agents, harsh reaction conditions, and are limited in functional group compatibility. Recently, difluoromethylation of heteroaromatic compounds catalyzed by transition metals37, such as copper, palladium, nickel, has been developed. However, most of these approaches depend on preactivation of substrates (i.e., aryl halides38,39,40,41,42, aryl boronic acids43,44,45, arylzincs46, arenediazonium salts47).
The radical-based difluoromethylation method has been developed as an advantageous synthetic strategy for the construction of difluoromethylated heterocycles. The pioneering work was reported by Baran and co-workers (Fig. 1b), in which they developed a new difluoromethylated reagent Zn(SO2CF2H)2 (DFMS) that can effectively release CF2H radical in the presence of tert-butyl hydroperoxide (TBHP) as a stoichiometric oxidant48. Sakamoto et al. presented a photolytic direct C–H difluoromethylation of heterocycles using hypervalent iodine(III) reagents that contain difluoroacetoxy ligands (Fig. 1c)49. Shortly afterward, Tung et al. developed direct difluoromethylation of heterocycles using difluoroacetic acid as CF2H radical precursors via transition metal catalysis (Fig. 1d)50. In 2018, Zhu et al. reported a new strategy through the copper-mediated C−H oxidative difluoromethylation of heterocycles with TMSCF2H (Fig. 1e)51. It should be noted that these protocols of direct difluoromethylation of heterocycles need either expensive/toxic metal catalysts or external oxidants and strictly inert conditions, which narrow the functional group tolerance and limit the substrate scope. During the submission of this manuscript, Duan and Xia reported an efficient photocatalytic strategy for C–H perfluoroalkylation of quinoxalinones under aerobic oxidation conditions, however, the corresponding difluoromethylation has not been reported52. Therefore, it is highly desirable to develop new approaches to achieve direct C–H difluoromethylation of heterocycles, which can overcome the above-mentioned defects and avoid the safety problems with stoichiometric oxidant at a larger scale.
In the past decade, visible-light catalysis has attracted extensive attention, by which highly active radical species generated under mild conditions can be involved in various chemical bond formation53,54,55,56,57,58,59. Notably, organic dyes are cheaper and more reliable than expensive metal photoredox catalysts in many valuable reactions55,56,59. In this study, we focus our attention on developing an straightforward and practical method for difluoromethylation reactions using the inexpensive, commercially available, and user friendly Hu’s reagent sodium difluoromethane sulfonate (CF2HSO2Na) as the difluoromethyl radical precursor60 under mild conditions. This protocol combines organic photocatalysis with green air oxidant for the difluoromethylation of many categories of heterocycles. Notably, the difluoromethylation product 2′-deoxy-5-difluoromethyluridine (F2TDR) commendably inhibits the proliferation of cancer cells, such as HCT116, HepG-2, and MCF-7 (Fig. 1f).
Investigation of the reaction conditions
We started our investigation by the model reaction of 1-methyl quinoxolin-2-one 1a with CF2HSO2Na 2 as a fluorine source and eosin Y as a photocatalyst in DMSO at room temperature under green LEDs irradiation. To our delight, the difluoromethylation product 3a was obtained in 64% yield (Table 1, entry 1). Then, different photocatalysts were examined (Table 1, entries 2–8), in which rose bengal (RB) was the best one, providing 3a in 72% yield in 12 h. After identifying the optimal photocatalyst, we found that DMSO was the best reaction media through solvent screening (Table 1, entries 2 and 9–16). The yield of product reduced obviously when the loading of the photocatalyst was further decreased to 1 mol% (Table 1, entry 17). Control experiments indicated that photocatalyst and green light source were both essential for the reaction efficiency (Table 1, entries 18 and 19).
Scope of quinoxalin-2(1H)-ones on the phenyl ring
With the optimal reaction conditions in hand, the substrate scope of various quinoxalin-2(1H)-ones was then investigated. As exhibited in Fig. 2, the reactions worked well with a range of substituted quinoxalin-2(1H)-ones bearing either electron-donating or -withdrawing substituents (methyl, fluoro, chloro, bromo, methoxy, nitro, and naphthyl), giving the desired difluoromethylation products 3a–3j in moderate to good yields. To highlight the utility of this transformation, a variety of N-substituted quinoxalin-2(1H)-ones (1k−1n) were also tested. As a result, all the N-substituted quinoxalin-2(1H)-ones are compatible with the reaction, furnishing the expected products 3k–3n in 34–73% yields. Notably, N-unsubstituted quinoxalin-2(1H)-one also proceeded smoothly, delivering the desired product 3o in 87% yield.
Scope of heteroaromatics
To further extend the scope of this methodology, some other heteroaromatic substrates were investigated (Fig. 3). A wide range of five- and six-membered difluoromethylated heteroarenes, such as pyrazines (5a and 5b), quinoxalines (5c and 5d), pyrrole (5e), imidazoles (5f and 5g), thiophene (5i), pyridines (5j), thiadiazole (5k), indoles (5l and 5m), RNA-based dimethyluracils (5n and 5o), quinoline (5p), purine derivatives (5q and 5r), and pyrimidine (5 s), provided final products with good yields. Several heteroarenes with potentially sensitive functional groups (OH, NH2, or CHO) (5a, 5k, and 6j) that are barely reported in the previous study48,49,50,51 are also compatible with this difluoromethylation strategy. Moreover, this direct C–H difluoromethylation method also suitable for some arenes (5t and 6j).
Scope of bioactive molecules
The methodology can also be applied to late-stage functionalization of complex nitrogen-containing bioactive molecules (Fig. 4). For example, the modification of caffeine and its derivatives delivers the desired difluoromethylated products 6a–6c in 38–74% yields. In addition, deoxyuridine, uridine, and 2′-fluoro-2′-deoxyuridine, which have free OH group as well as amide group, could tolerate this difluoromethylation reaction, leading to 6d–6f in 57–81% yields. Furthermore, melatonin, allopurinol, and uracil, which bear free secondary N–H groups, furnished the difluoromethylation reaction with moderate to good yields (6g, 6h, and 6l). Moreover, some other bioactive heteroarene substrates, such as voriconazole, flavorant, metyrapone, and sulfonylureas, can also proceed well with the reaction, giving the difluoromethylated products 6i, 6j, 6k, and 6m in acceptable yields.
The substrate scope results of Figs. 2–4 show that most of the difluoromethylation occurs on the C2–H bond adjacent to the heteroatom. Some heterocycle substrates bearing more than one radical attacked carbon center were also examined (Fig. 5). As a result, the unsubstituted indole substrate 7 gave the major product at the C2 position in 54% yield with 10:1 regioselectivity. The 5-nitro-substituted indole substrate 9 can obtain a single regioselective difluoromethylation product 10 with 71% yield. When 4-chloro-7H-pyrrolo[2,3-d] pyrimidine was used as substrate, the reaction furnish the mixture of product 12 (C2/C6 = 5:1) in 46% yield. Notably, other electron-rich heteroarenes (benzofuran 13 and thianaphthene 15), which have not been investigated as substrates in previous reported radical difluoromethylation reactions48,49,50, also exhibited good reaction efficiency, producing the difluoromethylation products 14 and 16 in 92% and 65% yield, respectively. Unfortunately, other types of heteroarenes, including phenanthroline, 1,3,5-triazine, and thiazone, are not ideal substrates in this difluoromethylation reaction (Supplementary Fig. 2).
To evaluate the synthetic potential of this methodology, sunlight-driven experiment was performed. When the reaction was conducted under sunlight irradiation, the desired product 3a was obtained in 68% yield (Fig. 6a). Furthermore, a slight reduction of yields with large scale preparation of 6d and 6g also prove the practicability of this difluoromethylation strategy (Fig. 4, yields in parentheses for 6d and 6g). We further explored the potential application of the synthesized difluoromethylated product in medicinal chemistry. The F2TDR 6d has a similar structure to the trifluridine, which has been approved by FDA for the treatment of adult patients with metastatic colorectal cancer (for details, see https://www.drugbank.ca/drugs/DB00432). Therefore, we selected four tumor cell lines to evaluate the inhibitory activities of 6d, and made the comparison of the result with trifluridine. As shown in Fig. 6b, 6d higher tumor cell inhibitory capability than the trifluridine with relatively low IC50 values. Notably, the IC50 values of 6d against HCT116 and HepG-2 cells reach low micromolar level, which are about 57- and 6-fold lower than that of trifluridine, respectively. The improvement of antitumor activity indicates the practicality of this difluoromethylation methodology and the potential in the field of discovery of active drug molecules.
To gain insights into the current studied reaction, control experiments were conducted. When a radical scavenger, 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO) or 1,1-diphenylethylene (Fig. 7a, b) was existing in the mixture containing 1a and CF2HSO2Na, the reaction was completely suppressed, while the radical intermediate was detected by ESI-HRMS (Supplementary Fig. 5), indicating the existence of CF2H radical. When the reaction was carried out under inert atmosphere (Fig. 7c), the formation of 3a was completely inhibited, revealing that oxygen is crucial for the reaction. In situ 1H NMR experiment demonstrated that hydrogen peroxide (H2O2) does not form after irradiation of the reaction mixture in DMSO-d6 for 12 h under the optimized reaction condition. In addition, the observed water peak (H2O) growth indicating that the oxygen was eventually converted to H2O rather than H2O2 (Supplementary Figs. 6 and 7). The generated H2O2 could participate in the catalytic cycle and ultimately converted to H2O as the byproduct61. These experimental results illustrated an available radical pathway. Moreover, we also conducted the light/dark experiment. As shown in Fig. 7, the desired product 3a formed only under continuous irradiation, which ruled out the possibility of a radical chain propagation. On the basis of our experimental observations and previous studies59, a possible mechanism was proposed (Fig. 7e). Upon absorption of visible light, the photocatalyst RB is excited into RB* (Ered = 0.99 V vs SCE) and a single electron is transferred from CF2HSO2Na62 (E = 0.59 V vs SCE) to RB*, which affords CF2H radical and generates an RB•− radical anion. The photoredox cycle is completed by the molecular oxygen oxidation of RB•−, giving RB and O2•−. After that, addition of CF2H radical to 1a occurs, leading to intermediate A, which undergoes a 1,2-H shift to generate carbon radical intermediate B. The intermediate B loses a hydrogen atom to O2•− to furnish the desired product 3a.
In summary, we have achieved a visible-light triggered direct C–H difluoromethylation of heterocycles by using commercially available and inexpensive sodium difluoromethane sulfonate as CF2H radical source. The process is under mild conditions using O2 as a green oxidant and without using metal additive. Furthermore, we also use this highly efficient methodology for direct difluoromethylation of some nitrogen-containing biological and pharmaceutical active molecules. In addition, the bioactivity evaluation of a representative difluoromethylation product 2′-deoxy-5-difluoromethyluridine (6d) exhibited promising activity against cancer cell lines. We expect this simple protocol to be of broad utility for the development of new drugs. Further synthetic applications and bioactivity tests are ongoing.
Procedure for difluoromethylation of quinoxalin-2(1H)-ones
To a 10 mL Schlenk tube equipped with a magnetic stir bar added quinoxalin-2(1H)-ones 1 (0.2 mmol), CF2HSO2Na 2 (0.4 mmol), and RB (0.004 mmol, 2 mol.%) in DMSO (1.0 mL). Then the mixture was stirred and irradiated by two 3 W green LEDs at room temperature for 12 h. The residue was added water (10 mL) and extracted with ethyl acetate (5 mL × 3). The combined organic phase was dried over Na2SO4. The resulting crude residue was purified via column chromatography on silica gel to afford desired products.
Procedure for difluoromethylation of other heterocycles
To a 10 mL Schlenk tube equipped with a magnetic stir bar added heteroarenes 4 (0.1 mmol), CF2HSO2Na 2 (0.4 mmol), and RB (0.002–0.005 mmol, 2–5 mol.%) in DMSO (1.0 mL). Then the mixture was stirred and irradiated by two 3 W green LEDs at room temperature for 24 h. The residue was added water (10 mL) and extracted with ethyl acetate (5 mL × 3). The combined organic phase was dried over Na2SO4. The resulting crude residue was purified via column chromatography on silica gel to afford desired products.
The authors declare that the data supporting the findings of this study are available within the article and its Supplementary Information files. Extra data are available from the author upon reasonable request. The X-ray crystallographic coordinates for structures of 3a reported in this article have been deposited at the Cambridge Crystallographic Data Center as CCDC 1920406. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via http://www.ccdc.cam.ac.uk/data_request/cif.
Kirsch, P. Modern Fluoroorganic Chemistry: Synthesis Reactivity, Applications 2nd edn (Wiley-VCH, Weinheim, 2013).
Hagmann, W. K. The many roles for fluorine in medicinal chemistry. J. Med. Chem. 51, 4359–4369 (2008).
Shimizu, M. & Hiyama, T. Modern synthetic methods for fluorine-substituted target molecules. Angew. Chem. Int. Ed. 44, 214–231 (2005).
Chambers, R. D. Fluorine in Organic Chemistry (Blackwell, Oxford, 2004).
Filler, R., Kobayashi, Y. & Yagupolskii, L. M. Organofluorine Compounds in Medicinal Chemistry and Biomedical Applications. (Elsevier, New York, 1993).
Mgller, K., Faeh, C. & Diederich, F. Fluorine in pharmaceuticals: looking beyond intuition. Science 317, 1881–1886 (2007).
Purser, S., Moore, P. R., Swallow, S. & Gouverneur, V. Fluorine in medicinal chemistry. Chem. Soc. Rev. 37, 320–330 (2008).
Cametti, M., Crousse, B., Metrangolo, P., Milani, R. & Resnati, G. The fluorous effect in biomolecular applications. Chem. Soc. Rev. 41, 31–42 (2012).
Champagne, P. A., Desroches, J., Hamel, J.-D., Vandamme, M. & Paquin, J. F. Monofluorination of organic compounds: 10 years of innovation. Chem. Rev. 115, 9073–9174 (2015).
Campbell, M. G. & Ritter, T. Modern carbon–fluorine bond forming reactions for aryl fluoride synthesis. Chem. Rev. 115, 612–633 (2015).
Furuya, T., Kamlet, A. S. & Ritter, T. Catalysis for fluorination and trifluoromethylation. Nature 473, 470–477 (2011).
Liang, T., Neumann, C. N. & Ritter, T. Introduction of fluorine and fluorine-containing functional groups. Angew. Chem. Int. Ed. 52, 8214–8264 (2013).
Charpentier, J., Frîh, N. & Togni, A. Electrophilic trifluoromethylation by use of hypervalent iodine reagents. Chem. Rev. 115, 650–682 (2015).
Merino, E. & Nevado, C. Addition of CF3 across unsaturated moieties: a powerful functionalization tool. Chem. Soc. Rev. 43, 6598–6608 (2014).
Egami, H. & Sodeoka, M. Trifluoromethylation of alkenes with concomitant introduction of additional functional groups. Angew. Chem. Int. Ed. 53, 8294–8308 (2014).
Chu, L. & Qing, F. L. Oxidative trifluoromethylation and trifluoromethylthiolation reactions using (trifluoromethyl) trimethylsilane as a nucleophilic CF3 source. Acc. Chem. Res. 47, 1513–1522 (2014).
Yang, X., Wu, T., Phipps, R. J. & Toste, F. D. Advances in catalytic enantioselective fluorination, mono-, di-, and trifluoromethylation, and trifluoromethylthiolation reactions. Chem. Rev. 115, 826–870 (2015).
Alonso, C., Mart.nez de Marigorta, E., Rubiales, G. & Palacios, F. Carbon trifluoromethylation reactions of hydrocarbon derivatives and heteroarenes. Chem. Rev. 115, 1847–1935 (2015).
Ni, C., Hu, M. & Hu, J. Good partnership between sulfur and fluorine: sulfur-based fluorination and fluoroalkylation reagents for organic synthesis. Chem. Rev. 115, 765–825 (2015).
Studer, A. A. “Renaissance” in radical trifluoromethylation. Angew. Chem. Int. Ed. 51, 8950–8958 (2012).
Sessler, C. D. et al. CF2H, a hydrogen bond donor. J. Am. Chem. Soc. 139, 9325–9332 (2017).
Tang, X.-J. & Dolbier, W. R. Efficient Cu-catalyzed atom transfer radical addition reactions of fluoroalkylsulfonyl chlorides with electron-deficient alkenes induced by visible light. Angew. Chem. Int. Ed. 54, 4246–4249 (2015).
Lin, Q.-Y., Xu, X.-H., Zhang, K. & Qing, F.-L. Visible-light-induced hydrodifluoromethylation of alkenes with a bromodifluoromethylphosphonium bromide. Angew. Chem. Int. Ed. 55, 1479–1483 (2016).
Rong, J. et al. Radical fluoroalkylation of isocyanides with fluorinated sulfones by visible-light photoredox catalysis. Angew. Chem. Int. Ed. 55, 2743–2747 (2016).
Noto, N., Koike, T. & Akita, M. Metal-free di- and tri-fluoromethylation of alkenes realized by visible-light-induced perylene photoredox catalysis. Chem. Sci. 8, 6375–6379 (2017).
Xiong, P., Xu, H.-H., Song, J. & Xu, H.-C. Electrochemical difluoromethylarylation of alkynes. J. Am. Chem. Soc. 140, 2460–2464 (2018).
Meyer, C. F., Hell, S. M., Misale, A., Trabanco, A. A. & Gouverneur, V. Hydrodifluoromethylation of alkenes with difluoroacetic acid. Angew. Chem. Int. Ed. 58, 8829–8833 (2019).
Dishington, A. et al. Synthesis of functionalized cyanopyrazoles via magnesium bases. Org. Lett. 16, 6120–6123 (2014).
Xia, J. B., Zhu, C. & Chen, C. Visible light-promoted metal-free C–H activation: diarylketone-catalyzed selective benzylic mono- and difluorination. J. Am. Chem. Soc. 135, 17494–17500 (2013).
Xu, P., Guo, S., Wang, L. & Tang, P. Silver-catalyzed oxidative activation of benzylic C-H bonds for the synthesis of difluoromethylated arenes. Angew. Chem. Int. Ed. 53, 5955–5958 (2014).
Pan, F., Boursalian & G. B. Ritter, T. Palladium-catalyzed decarbonylative difluoromethylation of acid chlorides at room temperature. Angew. Chem. Int. Ed. 57, 16871–16876 (2018).
Zeng, X. J. et al. Copper-catalyzed decarboxylative difluoromethylation. J. Am. Chem. Soc. 141, 11398–11403 (2019).
Mykhailiuk, P. K. In situ generation of difluoromethyl diazomethane for [3+2] cycloadditions with alkynes. Angew. Chem. Int. Ed. 54, 6558–6561 (2015).
Wu, J., Xu, W., Yu, Z. X. & Wang, J. Ruthenium-catalyzed formal dehydrative [4 + 2] cycloaddition of enamides and alkynes for the synthesis of highly substituted pyridines: reaction development and mechanistic study. J. Am. Chem. Soc. 137, 9489–9496 (2015).
Gui, J. H. et al. C–H methylation of heteroarenes inspired by radical SAM methyl transferase. J. Am. Chem. Soc. 136, 4853–4856 (2014).
Shi, H. et al. Synthesis of 18F-difluoromethylarenes from aryl (pseudo) halides. Angew. Chem. Int. Ed. 55, 10786–10790 (2016).
Rong, J., Ni, C. & Hu, J. Metal-catalyzed direct difluoromethylation reactions. Asian J. Org. Chem. 6, 139–152 (2017).
Fier, P. S. & Hartwig, J. F. Copper-mediated difluoromethylation of aryl and vinyl iodides. J. Am. Chem. Soc. 134, 5524–5527 (2012).
Gu, Y., Leng, X. B. & Shen, Q. Cooperative dual palladium/silver catalyst for direct difluoromethylation of aryl bromides and iodides. Nat. Commun. 5, 5405–5412 (2014).
Xu, L. D. & Vicic, A. Direct difluoromethylation of aryl halides via base metal catalysis at room temperature. J. Am. Chem. Soc. 138, 2536–2539 (2016).
Xu, C. et al. Difluoromethylation of (hetero) aryl chlorides with chlorodifluoromethane catalyzed by nickel. Nat. Commun. 9, 1170–1180 (2018).
Bacauanu, V. et al. Metallaphotoredox difluoromethylation of aryl bromides. Angew. Chem. Int. Ed. 57, 12543–12548 (2018).
Feng, Z., Min, Q. Q. & Zhang, X. Access to difluoromethylated arenes by Pd-catalyzed reaction of arylboronic acids with bromodifluoroacetate. Org. Lett. 18, 44–47 (2016).
Feng, Z., Min, Q.-Q., Fu, X. P., An, L. & Zhang, X. Chlorodifluoromethane-triggered formation of difluoromethylated arenes catalysed by palladium. Nat. Chem. 9, 918–923 (2017).
Hori, K., Motohashi, H., Saito, D. & Mikami, K. Precatalyst effects on Pd-catalyzed cross-coupling difluoromethylation of aryl boronic acids. ACS Catal. 9, 417–421 (2019).
Miao, W. et al. Iron-catalyzed difluoromethylation of arylzincs with difluoromethyl 2-pyridyl sulfone. J. Am. Chem. Soc. 140, 880–883 (2018).
Matheis, C., Jouvin, K. & Goossen, L. Sandmeyer difluoromethylation of (hetero-) arenediazonium salts. Org. Lett. 16, 5984–5987 (2014).
Fujiwara, Y. et al. A new reagent for direct difluoromethylation. J. Am. Chem. Soc. 134, 1494–1497 (2012).
Sakamoto, R., Kashiwagi, H. & Maruoka, K. The direct C–H difluoromethylation of heteroarenes based on the photolysis of hypervalent iodine(III) reagents that contain difluoroacetoxy ligands. Org. Lett. 19, 5126–5129 (2017).
Tung, T. T., Christensen, S. B. & Nielsen, J. Difluoroacetic acid as a new reagent for direct C-H difluoromethylation of heteroaromatic compounds. Chemistry 23, 18125–18128 (2017).
Zhu, S., Liu, Y., Li, H., Xu, X. & Qing, F. Direct and regioselective C-H oxidative difluoromethylation of heteroarenes. J. Am. Chem. Soc. 140, 11613–11617 (2018).
Wei, Z. et al. Visible light-induced photocatalytic C-H perfluoroalkylation of quinoxalinones under aerobic oxidation condition. Adv. Synth. Catal. 361, 5490–5498 (2019).
Narayanam, J. M. R. & Stephenson, C. R. J. Visible light photoredox catalysis: applications in organic synthesis. Chem. Soc. Rev. 40, 102–113 (2011).
Prier, C. K., Rankic, D. A. & MacMillan, D. W. C. Visible light photoredox catalysis with transition metal complexes: applications in organic synthesis. Chem. Rev. 113, 5322–5363 (2013).
Hari, D. P. & König, B. Synthetic applications of eosin Y in photoredox catalysis. Chem. Commun. 50, 6688–6699 (2014).
König, N. A. & Nicewicz, D. A. Organic photoredox catalysis. Chem. Rev. 116, 10075–10166 (2016).
Skubi, K. L., Blum, T. R. & Yoon, T. P. Dual catalysis strategies in photochemical synthesis. Chem. Rev. 116, 10035–10074 (2016).
Shaw, M. H., Twilton, J. & MacMillan, D. W. C. Photoredox catalysis in organic chemistry. J. Org. Chem. 81, 6898–6926 (2016).
Sharma, S. & Sharma, A. Recent advances in photocatalytic manipulations of Rose Bengal in organic synthesis. Org. Biomol. Chem. 17, 4384–4405 (2019).
He, Z., Tan, P., Ni, C. & Hu, J. Fluoroalkylative aryl migration of conjugated N-arylsulfonylated amides using easily accessible sodium Di- and monofluoroalkanesulfinates. Org. Lett. 17, 1838–1841 (2015).
Liu, W. Q. et al. Visible light promoted synthesis of indoles by single photosensitizer under aerobic conditions. Org. Lett. 19, 3251–3254 (2017).
Zou, Z. L. et al. Electrochemically promoted fluoroalkylation-distal functionalization of unactivated alkenes. Org. Lett. 21, 1857–1862 (2019).
The project was supported by NSFC (21971120, 21933008, and 81573354). We thanks Prof. Bin Chen and Dr Xu-Zhe Wang at the Technical Institute of Physics and Chemistry, Chinese Academy of Sciences, for helpful discussions.
The authors declare no competing interests.
Peer review information Nature Communications thanks the anonymous reviewers for their contribution to the peer review of this work.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
This work is dedicated to the 100th anniversary of Nankai University.
About this article
Cite this article
Zhang, W., Xiang, XX., Chen, J. et al. Direct C–H difluoromethylation of heterocycles via organic photoredox catalysis. Nat Commun 11, 638 (2020). https://doi.org/10.1038/s41467-020-14494-8
This article is cited by
Molecular Diversity (2023)
Photocatalysed Synthesis and Structure Activity Evaluation of Cyclohexyloxyphenethylpyridinones as Potent HIV-1 Inhibitor
Catalysis Letters (2023)
Radical hydrodifluoromethylation of unsaturated C−C bonds via an electroreductively triggered two-pronged approach
Communications Chemistry (2022)