English

• Difluorocarbene (: CF₂) is a versatile intermediate widely used in synthetic chemistry to introduce mono-, di-, and tri-fluorine fragments. It plays a vital role in the total synthesis of natural products and drugs, and in the preparation of radiotracers for positron emission tomography (PET) [1-4]. Difluorides are usually prepared via difluorocarbene-derived difluoromethylation, gem-difluorocyclization and gem-difluoroolefination [5,6], while trifluoromethylation has been used to synthesize ¹⁸F-radiotracers for PET imaging and to optimize the physicochemical properties of drug leads [7-12]. However, the difluorocarbene-derived synthesis of trifluoromethyl triazoles and ¹⁸F-trifluoromethyl triazole radiotracers has not been adequately explored.

  Difluorocarbene as a singlet carbene with an empty p-orbital, has been used as an electrophile in difluoromethylation reactions involving diverse nucleophiles to generate multifunctional molecules bearing C-, N-, O-, S-, P- and Sn-CF₂H groups [13-18]. Difluorocarbene is also a useful intermediate in gem-difluoroolefination reactions involving carbonyl compounds [19,20], while it has been used as a bipolar unit for [2 + 1], [4 + 1] and [8 + 1] cycloadditions to construct mono- and di-fluorides such as fluoroindoles, gem-difluorocyclopropanes, gem-difluorocyclopropenes, gem-difluorinated azetidines and gem-difluorinated 2, 3-dihydrobenzofurans [14,21-24]. Very recently, the Gouverneur group developed [¹⁸F]difluorocarbene to construct ¹⁸F-labeled difluorides for PET [25].

  Difluorocarbene can also be trapped by the nucleophilic fluoride ion and converted into the trifluoromethyl anion (CF₃⁻), which serves as a nucleophilic intermediate in trifluoromethylation [13,26-33]. For instance, SCF₃⁻, OCF₃⁻ and SeCF₃⁻ have been used for the trifluoromethylthiolation, trifluoromethoxylation, and trifluoromethylselenolation of halides by the Xiao and the Liang group [26-30], while ¹⁸F-labeled trifluorides for PET imaging have been synthesized via difluorocarbene-derived ¹⁸F-trifluoromethylthiolation (SCF₂¹⁸F) of halides [27,28] and ¹⁸F-trifluoromethylation (CF₂¹⁸F) of (hetero)aryl iodides (Scheme 1a) [31-33].

  Scheme 1

  

  Scheme 1.  Difluorocarbene-derived trifluoromethylation and ¹⁸F-labeling of triazoles.

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  On the other hand, the Cu(I)-catalyzed azide–alkyne cycloaddition (CuAAC) reaction is considered a powerful tool for the preparation of 1, 2, 3-triazoles, which are widely used in pharmaceutical research, preparation of biocompatible materials, and late-stage modification of biomacromolecules [34-36]. Its size and geometry make the 1, 2, 3-triazole ring a frequently used bioisostere of native peptide-based trans-amide connectors [37], and it has become one of the most widespread heterocycles in medicinal scaffolds due to its wide range of bioactivities against bacteria, viruses, and cancer [34,37].

  In recent years, the synthesis of trifluoromethyl 1, 2, 3-triazoles has attracted attention due to the metabolic stability, high lipophilicity, and high bioavailability of the trifluoromethyl group [38-42]. ¹⁸F-Labeled triazoles have also been developed as PET imaging agents for disease diagnosis and in vivo monitoring of the metabolism and distribution of tagged drugs [43-45]. ¹⁸F-Labeled triazoles are usually prepared through the click reaction of alkynes with ¹⁸F-labeled azides in at least two steps (Scheme 1b) [43-45]. However, the difluorocarbene-derived synthesis of ¹⁹F/¹⁸F-trifluoromethyl 1, 2, 3-triazoles has not yet been reported.

  Since the half-life of ¹⁸F is 109.8 min, it should be preferably introduced into the triazole ring in the last synthesis step. Therefore, in the present study, we developed a novel strategy for difluorocarbene-derived late-stage trifluoromethylation of iodotriazoles with high functional group compatibility (Scheme 1c). A wide range of 5-trifluoromethyl-1, 2, 3-triazoles were generated in good yields, including rarely reported analogues. The usefulness of this approach for late-stage functionalization was demonstrated by producing trifluoromethylated derivatives of bioactive molecules. Late-stage ¹⁸F-trifluoromethylation of iodotriazoles generated triazole radiotracers for PET imaging.

  Based on a previous study [31], the trifluoromethylation of 1-benzyl-5-iodo-4-phenyl-1H-1, 2, 3-triazole (1a) was first performed in DMF using ClCF₂CO₂Me as difluorocarbene source, KF as fluoride source, CuI as metal source, and N, N, Nʹ, Nʹ-tetramethylethylenediamine (TMEDA) as ligand (Table S1 in Supporting information). However, the desired product did not form; the main product was a protonated analogue generated by reductive dehalogenation. Interestingly, the addition of a base can successfully obtain the target product 2a, while 1, 10-phenanthroline (Phen) proved to be the most effective ligand, probably due to the generation of the stable intermediate PhenCuCF₃ [46]. Various Cu(I) salts were also well tolerated, with the combination of CuI and Phen giving the highest yield of 61% in 25 min (Tables S1 and S2 in Supporting information).

  Next, we investigated the influence of different functional groups of 5-iodotriazoles on the efficiency of difluorocarbene-derived trifluoromethylation reaction (Scheme 2). Under the optimized conditions, all iodotriazoles were completely transformed in 25 min, confirmed by thin-layer chromatography (TLC), and iodotriazoles bearing electron-neutral/rich and electron-deficient aryl groups rapidly gave the corresponding 5-trifluoromethyl triazoles (2a–2l) in moderate to good yields up to 85%. Compared with para-substituted aryl iodotriazoles, the reaction was slightly less efficient for meta- and ortho-substituted aryl iodotriazoles (2m–2q). Nevertheless, various aryl substituents, including ether (2e, 2f), nitro (2g), bromine (2i, 2p), aldehyde (2j, 2q), amide (2k), ester (2l, 2o), and fluorine (2f, 2 h, 2m, 2n) groups, were well tolerated, providing opportunities for further conversion. Iodotriazoles bearing fused (2r) and heterocyclic (2s–2u) ring systems also reacted smoothly under these conditions, and acetyl- and benzoyl-substituted iodotriazoles were successfully trifluoromethylated, affording analogues not yet reported in previous trifluoromethylation (2v–2x). Moreover, alkyl-substituted iodotriazoles bearing protected amino and alcohol groups were well tolerated, giving analogues 2y and 2z, which are suitable for further modifications (Scheme 2).

  Scheme 2

  

  Scheme 2.  Difluorocarbene-derived trifluoromethylation of 5-iodotriazoles transformed from benzyl azide and various alkynes. Reactions conditions: 1 (0.1 mmol, 1.0 equiv.), ClCF₂CO₂Me (0.2 mmol, 2.0 equiv.), KF (0.2 mmol, 2.0 equiv.), Cs₂CO₃ (0.1 mmol, 1.0 equiv.), CuI (0.1 mmol, 1.0 equiv.), Phen (0.1 mmol, 1.0 equiv.), DMF (1.6 mL), 110 ℃, 25 min. Yield of isolated product.

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  The developed reaction proceeded well on a gram scale with bromoaryl iodotriazole 1i (4.16 mmol), giving analogue 2i in 83% isolated yield (1.31 g) (Scheme 2). This product could be used as an intermediate for additional transformations.

  To further expand the scope of the reaction, we successfully synthesized 5-iodotriazoles from benzyl azide (2aa, 2ak, 2am), azidobenzene (2ab, 2aj), ethyl azidoacetate (2ac–2ai), and (1-azidoethyl)benzene (2al) moieties, and obtained the corresponding 5-trifluoromethylated triazoles in a short time with moderate yields (Scheme 3). These 5-trifluoromethyl triazoles are rarely available through previously reported strategies.

  Scheme 3

  

  Scheme 3.  Difluorocarbene-derived trifluoromethylation of 5-iodotriazoles and late-stage trifluoromethylation of bioactive molecules. Reactions conditions: 1 (0.1 mmol, 1.0 equiv.), ClCF₂CO₂Me (0.2 mmol, 2.0 equiv.), KF (0.2 mmol, 2.0 equiv.), Cs₂CO₃ (0.1 mmol, 1.0 equiv.), CuI (0.1 mmol, 1.0 equiv.), Phen (0.1 mmol, 1.0 equiv.), DMF (1.6 mL), 110 ℃, 25 min. Yield of isolated product.

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  The usefulness of the proposed method was demonstrated by the successful late-stage trifluoromethylation of bioactive triazoles (Scheme 3). For example, analogue 2ak was obtained in 67% yield from the benzothiazinone derivative 4, which is effective against the H37Ra strain of Mycobacterium tuberculosis [47]. Similarly, 2aj was synthesized in moderate yield from the isatin derivative 3, which is known for its activity against fungal, oxidative damage, and M. tuberculosis [48]. Analogue 2al was obtained in 60% yield from compound 5, which acts against acute myeloid leukemia [37]. Moreover, analogue 2am was obtained from the imidazopyridine-linked triazole 6, which shows antitumor activity [49].

  To expand the applicability of this strategy, we investigated the late-stage ¹⁸F-trifluoromethylation of 5-iodotriazoles for the preparation of PET imaging agents (Scheme 4). PET is a non-invasive molecular imaging technique that relies on radiolabeled probes and has become an invaluable tool for drug discovery and clinical diagnosis [50-52]. Among the positron-emission radionuclides used in PET, ¹⁸F is the most frequently applied due to its relatively short half-life of 109.8 min, low positron energy (635 keV), and clean decay profile with 97% positron emission [52-57]. The [¹⁸F]KF/K₂₂₂ complex is a commonly available fluorine source for ¹⁸F-labeling. Our late-stage trifluoromethylation approach can also be applied for ¹⁸F-labeling molecules of interesting by replacing KF with [¹⁸F]KF/K₂₂₂ without excessive condition screening as 25 min is suitable reaction time for ¹⁸F radiolabeling (Scheme 4, Tables S3–S12, Figs. S1–S10 in Supporting information). The reaction tolerated benzyl azide (3a–3e, 3j), ethyl azidoacetate (3f–3h), azidobenzene (3i), aryl groups (3a, 3f, 3g), alkyl groups (3b, 3h, 3i), and carbonyl groups (3c–3e, 3j) as substituents. The reaction also tolerated a broad range of functional groups, including esters (3a, 3f–3h) amides (3b), ketones (3c–3e, 3j), halides (3c, 3j), ethers (3d), nitro groups (3i), and fluorine groups (3c, 3g). In all cases, ¹⁸F labeling proceeded with moderate to good radiochemical conversion (RCC).

  Scheme 4

  

  Scheme 4.  Difluorocarbene-derived ¹⁸F-trifluoromethylation of iodotriazoles and late-stage ¹⁸F-radiolabelling of bioactive molecules. Reactions conditions: 1 (2.0 mg, 3.7–6.1 µmol), ClCF₂CO₂Me (2.3 µL, 22 µmol), [¹⁸F]KF/K₂₂₂ (5–20 mCi), Cs₂CO₃ (1.8 mg, 5.5 µmol), CuI (1.1 mg, 5.5 µmol), Phen (1.0 mg, 5.5 µmol), DMF (0.4 mL), 110 ℃, 20 min. Radiochemical conversion (RCC) and product identity were determined by radio-HPLC.

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  The same protocol also supported efficient late-stage ¹⁸F-trifluoromethylation of bioactive triazoles. For instance, the triazole-incorporated isatin derivative was labeled with [¹⁸F]CF₃ in 56% RCC (3i, Scheme 4). Analogue 3j was synthesized in 24% RCC from the iodide derivative of imidazopyridine-linked triazole 6 (Scheme 3). Analogue 6 is a known tubulin inhibitor that can effectively trigger apoptosis, making it quite toxic against A549 human lung cancer cells (IC₅₀ = 0.63 µmol/L) [49]. Thus, the ¹⁸F-labeled tracer 3j can be used in PET imaging to study the distribution and metabolism of imidazopyridine-linked triazole hybrids in vivo, promote drug discovery, and develop lung cancer detection reagents. To further evaluate the applicability of this protocol, we attempted to prepare ¹⁸F-labelled triazole 3j. The radiotracer 3j was successfully obtained with moderate isolated decay-corrected radiochemical yield (RCY) of 13%, as confirmed by spectroscopic analysis (Scheme 4, Fig. S11 and Table S13 in Supporting information).

  In summary, we have developed a rapid difluorocarbene-derived strategy for late-stage ¹⁹F/¹⁸F-trifluoromethylation of 5-iodotriazoles. This reaction tolerates a wide variety of functional groups, enabling the synthesis of rarely reported derivatives as well as the direct radiolabeling triazoles, demonstrating its potential as an effective tool for the development of novel triazole drugs and radiotracers. Further efforts are underway to explore the scope of substrates, including those with sterically hindered groups in meta- or ortho-positions, and to improve the method to make it compatible with more functional groups of medicinal molecules. In addition, studies on the production and use of ¹⁸F-labeled bioactive molecules in PET imaging are in progress.

  Declaration of competing interest

  The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

  Acknowledgments

  This study was financially supported by the National Natural Science Foundation of China (Nos. 21977075, 22271200, 21801178, 21907070, 81971653), 1.3.5 Project for Disciplines of Excellence, West China Hospital, Sichuan University, Central Plains Science and Technology Innovation Leader Project (No. 214200510008 to L. Li), and Scientific and Technological Innovation Team of Colleges and Universities in Henan Province (No. 21IRTSTHN001). We also acknowledge the help of Feijing Su and Qifeng Liu (core facilities of West China Hospital), and Xiaoyan Wang and Yuanming Zhai (Analytical & Testing Center of Sichuan University) for NMR analysis.

  Supplementary materials

  Supplementary material associated with this article can be found, in the online version, at doi:10.1016/j.cclet.2022.107960.

  
  
• 1. [1]

     A.D. Dilman, V.V. Levin, Acc. Chem. Res. 51 (2018) 1272–1280. doi: 10.1021/acs.accounts.8b00079

  2. [2]

     Z. Feng, Y.L. Xiao, X. Zhang, Acc. Chem. Res. 51 (2018) 2264–2278. doi: 10.1021/acs.accounts.8b00230

  3. [3]

     J.H. Lin, J.C. Xiao, Acc. Chem. Res. 53 (2020) 1498–1510. doi: 10.1021/acs.accounts.0c00244

  4. [4]

     W. Zhou, W.J. Pan, J. Chen, et al., Chem. Commun. 57 (2021) 9316–9329. doi: 10.1039/D1CC04029D

  5. [5]

     X. Ma, Q. Song, Chem. Soc. Rev. 49 (2020) 9197–9219. doi: 10.1039/D0CS00604A

  6. [6]

     J.B.I. Sap, C.F. Meyer, N.J.W. Straathof, et al., Chem. Soc. Rev. 50 (2021) 8214–8247. doi: 10.1039/D1CS00360G

  7. [7]

     O.A. Tomashenko, V.V. Grushin, Chem. Rev. 111 (2011) 4475–4521. doi: 10.1021/cr1004293

  8. [8]

     W. Zhu, J. Wang, S. Wang, et al., J. Fluorine Chem. 167 (2014) 37–54. doi: 10.1016/j.jfluchem.2014.06.026

  9. [9]

     F. Francis, F. Wuest, Molecules 26 (2021) 6478. doi: 10.3390/molecules26216478

  10. [10]

      R. Britton, V. Gouverneur, J.H. Lin, et al., Nat. Rev. Methods Prim. 1 (2021) 47. doi: 10.1038/s43586-021-00042-1

  11. [11]

      H. Xiao, Z. Zhang, Y. Fang, L. Zhu, C. Li, Chem. Soc. Rev. 50 (2021) 6308–6319. doi: 10.1039/D1CS00200G

  12. [12]

      H. Wang, Y. Xie, Y. Zhou, N. Cen, W. Chen, Chin. Chem. Lett. 33 (2022) 221–224. doi: 10.1016/j.cclet.2021.06.008

  13. [13]

      L. Li, F. Wang, C. Ni, J. Hu, Angew. Chem. Int. Ed. 52 (2013) 12390–12394. doi: 10.1002/anie.201306703

  14. [14]

      C. Ni, J. Hu, Synthesis 46 (2014) 842–863. doi: 10.1055/s-0033-1340856

  15. [15]

      Q. Xie, C. Ni, R. Zhang, et al., Angew. Chem. Int. Ed. 56 (2017) 3206–3210. doi: 10.1002/anie.201611823

  16. [16]

      M. Zhang, J.H. Lin, J.C. Xiao, Angew. Chem. Int. Ed. 58 (2019) 6079–6083. doi: 10.1002/anie.201900466

  17. [17]

      X.P. Fu, X.S. Xue, X.Y. Zhang, et al., Nat. Chem. 11 (2019) 948–956. doi: 10.1038/s41557-019-0331-9

  18. [18]

      L. Peng, H. Wang, C. Guo, J. Am. Chem. Soc. 143 (2021) 6376–6381. doi: 10.1021/jacs.1c02697

  19. [19]

      J. Zheng, J.H. Lin, J. Cai, J.C. Xiao, Chem. Eur. J. 19 (2013) 15261–15266. doi: 10.1002/chem.201303248

  20. [20]

      J. Zheng, J. Cai, J.H. Lin, Y. Guo, J.C. Xiao, Chem. Commun. 49 (2013) 7513–7515. doi: 10.1039/c3cc44271c

  21. [21]

      A. García-Domínguez, T.H. West, J.J. Primozic, et al., J. Am. Chem. Soc. 142 (2020) 14649–14663. doi: 10.1021/jacs.0c06751

  22. [22]

      Y. Jia, Y. Yuan, J. Huang, Z.X. Jiang, Z. Yang, Org. Lett. 23 (2021) 2670–2675. doi: 10.1021/acs.orglett.1c00577

  23. [23]

      J. Su, X. Hu, H. Huang, Y. Guo, Q. Song, Nat. Commun. 12 (2021) 4986. doi: 10.1038/s41467-021-25313-z

  24. [24]

      Y. Wang, S. Mu, X. Li, Q. Song, Chin. Chem. Lett. 33 (2021) 1511–1514. doi: 10.1016/j.cclet.2021.08.089

  25. [25]

      J.B.I. Sap, C.F. Meyer, J. Ford, et al., Nature 606 (2022) 102–108. doi: 10.1038/s41586-022-04669-2

  26. [26]

      J. Zheng, J.H. Lin, X.Y. Deng, J.C. Xiao, Org. Lett. 17 (2015) 532–535. doi: 10.1021/ol503548s

  27. [27]

      J. Zheng, L. Wang, J.H. Lin, J.C. Xiao, S.H. Liang, Angew. Chem. Int. Ed. 54 (2015) 13236–13240. doi: 10.1002/anie.201505446

  28. [28]

      J. Zheng, R. Cheng, J.H. Lin, et al., Angew. Chem. Int. Ed. 56 (2017) 3196–3200. doi: 10.1002/anie.201611761

  29. [29]

      X.L. Chen, S.H. Zhou, J.H. Lin, Q.H. Deng, J.C. Xiao, Chem. Commun. 55 (2019) 1410–1413. doi: 10.1039/C8CC09719D

  30. [30]

      J. Yu, J.H. Lin, D. Yu, R. Du, J.C. Xiao, Nat. Commun. 10 (2019) 5362. doi: 10.1038/s41467-019-13359-z

  31. [31]

      M. Huiban, M. Tredwell, S. Mizuta, et al., Nat. Chem. 5 (2013) 941–944. doi: 10.1038/nchem.1756

  32. [32]

      H.Y. Kim, J.Y. Lee, Y.S. Lee, J.M. Jeong, J. Label. Compd. Radiopharm. 62 (2019) 566–579. doi: 10.1002/jlcr.3772

  33. [33]

      Z. Fu, Q. Lin, B. Hu, et al., J. Nucl. Med. 60 (2019) 930–936. doi: 10.2967/jnumed.118.222547

  34. [34]

      P. Thirumurugan, D. Matosiuk, K. Jozwiak, Chem. Rev. 113 (2013) 4905–4979. doi: 10.1021/cr200409f

  35. [35]

      H.C. Kolb, M.G. Finn, K.B. Sharpless, Angew. Chem. Int. Ed. 40 (2001) 2004–2021. doi: 10.1002/1521-3773(20010601)40:11<2004::AID-ANIE2004>3.0.CO;2-5

  36. [36]

      Y. Xie, S. Du, Z. Liu, et al., Angew. Chem. Int. Ed. 61 (2022) e202200303.

  37. [37]

      D. Dheer, V. Singh, R. Shankar, Bioorg. Chem. 71 (2017) 30–54. doi: 10.1016/j.bioorg.2017.01.010

  38. [38]

      D. Fu, J. Zhang, S. Cao, J. Fluorine Chem. 156 (2013) 170–176. doi: 10.1016/j.jfluchem.2013.10.006

  39. [39]

      K.P.S. Cheung, G.C. Tsui, Org. Lett. 19 (2017) 2881–2884. doi: 10.1021/acs.orglett.7b01116

  40. [40]

      F. Wei, T. Zhou, Y. Ma, C.H. Tung, Z. Xu, Org. Lett. 19 (2017) 2098–2101. doi: 10.1021/acs.orglett.7b00701

  41. [41]

      A. Zhu, X. Xing, S. Wang, et al., Green Chem. 21 (2019) 3407–3412. doi: 10.1039/C9GC00647H

  42. [42]

      H. Yang, T.H. Xu, S.N. Lu, Z. Chen, X.F. Wu, Org. Chem. Front. 8 (2021) 3440–3445. doi: 10.1039/D1QO00445J

  43. [43]

      T.H. Witney, L. Carroll, I.S. Alam, et al., Cancer Res. 74 (2014) 1319–1328. doi: 10.1158/0008-5472.CAN-13-2768

  44. [44]

      S.P. McCluskey, A. Haslop, C. Coello, et al., J. Nucl. Med. 60 (2019) 1750–1756. doi: 10.2967/jnumed.119.226787

  45. [45]

      B.S. Lee, S.Y. Chu, W.J. Jung, et al., Prostate 80 (2020) 1383–1393. doi: 10.1002/pros.24062

  46. [46]

      H. Morimoto, T. Tsubogo, N.D. Litvinas, et al., Angew. Chem. Int. Ed. 50 (2011) 3793–3798. doi: 10.1002/anie.201100633

  47. [47]

      M.H. Shaikh, D.D. Subhedar, M. Arkile, et al., Bioorg. Med. Chem. Lett. 26 (2016) 561–569. doi: 10.1016/j.bmcl.2015.11.071

  48. [48]

      M.H. Shaikh, D.D. Subhedar, F.A.K. Khan, et al., J. Heterocycl. Chem. 54 (2017) 413–421. doi: 10.1002/jhet.2598

  49. [49]

      I.B. Sayeed, M. Vishnuvardhan, A. Nagarajan, S. Kantevari, A. Kamal, Bioorg. Chem. 80 (2018) 714–720. doi: 10.1016/j.bioorg.2018.07.026

  50. [50]

      X. Deng, J. Rong, L. Wang, et al., Angew. Chem. Int. Ed. 58 (2019) 2580–2605. doi: 10.1002/anie.201805501

  51. [51]

      W. Wei, Z.T. Rosenkrans, J. Liu, et al., Chem. Rev. 120 (2020) 3787–3851. doi: 10.1021/acs.chemrev.9b00738

  52. [52]

      T. Wang, Y. Zhang, X. Zhang, et al., Chin. Chem. Lett. 33 (2022) 3543–3548. doi: 10.1016/j.cclet.2022.03.099

  53. [53]

      C.N. Neumann, J.M. Hooker, T. Ritter, Nature 534 (2016) 369–373. doi: 10.1038/nature17667

  54. [54]

      S. Verhoog, C.W. Kee, Y. Wang, et al., J. Am. Chem. Soc. 140 (2018) 1572–1575. doi: 10.1021/jacs.7b10227

  55. [55]

      W. Chen, Z. Huang, N.E.S. Tay, et al., Science 364 (2019) 1170–1174. doi: 10.1126/science.aav7019

  56. [56]

      N.E.S. Tay, W. Chen, A. Levens, et al., Nat. Catal. 3 (2020) 734–742. doi: 10.1038/s41929-020-0495-0

  57. [57]

      R. Halder, T. Ritter, J. Org. Chem. 86 (2021) 13873–13884. doi: 10.1021/acs.joc.1c01474

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  Scheme 1  Difluorocarbene-derived trifluoromethylation and ¹⁸F-labeling of triazoles.

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  Scheme 2  Difluorocarbene-derived trifluoromethylation of 5-iodotriazoles transformed from benzyl azide and various alkynes. Reactions conditions: 1 (0.1 mmol, 1.0 equiv.), ClCF₂CO₂Me (0.2 mmol, 2.0 equiv.), KF (0.2 mmol, 2.0 equiv.), Cs₂CO₃ (0.1 mmol, 1.0 equiv.), CuI (0.1 mmol, 1.0 equiv.), Phen (0.1 mmol, 1.0 equiv.), DMF (1.6 mL), 110 ℃, 25 min. Yield of isolated product.

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  Scheme 3  Difluorocarbene-derived trifluoromethylation of 5-iodotriazoles and late-stage trifluoromethylation of bioactive molecules. Reactions conditions: 1 (0.1 mmol, 1.0 equiv.), ClCF₂CO₂Me (0.2 mmol, 2.0 equiv.), KF (0.2 mmol, 2.0 equiv.), Cs₂CO₃ (0.1 mmol, 1.0 equiv.), CuI (0.1 mmol, 1.0 equiv.), Phen (0.1 mmol, 1.0 equiv.), DMF (1.6 mL), 110 ℃, 25 min. Yield of isolated product.

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  Scheme 4  Difluorocarbene-derived ¹⁸F-trifluoromethylation of iodotriazoles and late-stage ¹⁸F-radiolabelling of bioactive molecules. Reactions conditions: 1 (2.0 mg, 3.7–6.1 µmol), ClCF₂CO₂Me (2.3 µL, 22 µmol), [¹⁸F]KF/K₂₂₂ (5–20 mCi), Cs₂CO₃ (1.8 mg, 5.5 µmol), CuI (1.1 mg, 5.5 µmol), Phen (1.0 mg, 5.5 µmol), DMF (0.4 mL), 110 ℃, 20 min. Radiochemical conversion (RCC) and product identity were determined by radio-HPLC.

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