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Difluorocarbene-derived rapid late-stage trifluoromethylation of 5-iodotriazoles for the synthesis of 18F-labeled radiotracers
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Fang Yuana, 1, Hongbao Suna, 1, Cheng Yanga, Haojie Yanga, Lili Panb, Xiaoyang Zhanga, Rong Tianb, Lingjun Lic, Wei Chenb, Xiaoai Wub, *, Haoxing Wua, *
Chinese Chemical Letters | 2023, 34(6) : 107960
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Chinese Chemical Letters | 2023, 34(6): 107960
• Communication •
Difluorocarbene-derived rapid late-stage trifluoromethylation of 5-iodotriazoles for the synthesis of 18F-labeled radiotracers
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Fang Yuana, 1, Hongbao Suna, 1, Cheng Yanga, Haojie Yanga, Lili Panb, Xiaoyang Zhanga, Rong Tianb, Lingjun Lic, Wei Chenb, Xiaoai Wub, *, Haoxing Wua, *
Affiliations
  • aHuaxi MR Research Center, Department of Radiology, Functional and Molecular Imaging Key Laboratory of Sichuan Province, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu 610041, China
  • bDepartment of Nuclear Medicine, Laboratory of Clinical Nuclear Medicine, West China Hospital, Sichuan University, Chengdu 610041, China
  • cSchool of Chemistry and Chemical Engineering, Collaborative Innovation Center of Henan Province for Green Manufacturing of Fine Chemicals, State Key Laboratory of Cell Differentiation Regulation and Target Drug, Henan Normal University, Xinxiang 453007, China
Published: 2023-06-15 doi: 10.1016/j.cclet.2022.107960
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Difluorocarbene has emerged as a valuable intermediate to synthesize fluorides. However, difluorocarbene-derived synthesis of 19F/18F-trifluoromethyl triazoles has not been explored. Herein, we reported the Cu(I)-promoted difluorocarbene-derived 19F/18F-trifluoromethylation of iodotriazoles using KF/K18F as the fluorine source. This approach rapidly generated a wide range of 5-trifluoromethyl-1, 2, 3-triazoles in good yields showing high functional group compatibility. The reaction was effective for late-stage functionalization of bioactive molecules and 18F-trifluoromethylation of iodotriazoles. This work provides a practical synthetic methodology for the development of triazole drugs and 18F-radiotracers for positron emission tomography.

Difluorocarbene  /  Trifluoromethylation  /  Triazole  /  Late-stage functionalization  /  18F-Labeled radiotracer
Fang Yuan, Hongbao Sun, Cheng Yang, Haojie Yang, Lili Pan, Xiaoyang Zhang, Rong Tian, Lingjun Li, Wei Chen, Xiaoai Wu, Haoxing Wu. Difluorocarbene-derived rapid late-stage trifluoromethylation of 5-iodotriazoles for the synthesis of 18F-labeled radiotracers[J]. Chinese Chemical Letters, 2023 , 34 (6) : 107960 - . DOI: 10.1016/j.cclet.2022.107960
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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].
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).
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.
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).
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
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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
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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
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Supplementary material associated with this article can be found, in the online version, at doi:10.1016/j.cclet.2022.107960.
References
Less
[1]
A.D. Dilman, V.V. Levin, Acc. Chem. Res. 51 (2018) 1272–1280.
[2]
Z. Feng, Y.L. Xiao, X. Zhang, Acc. Chem. Res. 51 (2018) 2264–2278.
[3]
J.H. Lin, J.C. Xiao, Acc. Chem. Res. 53 (2020) 1498–1510.
[4]
W. Zhou, W.J. Pan, J. Chen, et al., Chem. Commun. 57 (2021) 9316–9329.
[5]
X. Ma, Q. Song, Chem. Soc. Rev. 49 (2020) 9197–9219.
[6]
J.B.I. Sap, C.F. Meyer, N.J.W. Straathof, et al., Chem. Soc. Rev. 50 (2021) 8214–8247.
[7]
O.A. Tomashenko, V.V. Grushin, Chem. Rev. 111 (2011) 4475–4521.
[8]
W. Zhu, J. Wang, S. Wang, et al., J. Fluorine Chem. 167 (2014) 37–54.
[9]
F. Francis, F. Wuest, Molecules 26 (2021) 6478.
[10]
R. Britton, V. Gouverneur, J.H. Lin, et al., Nat. Rev. Methods Prim. 1 (2021) 47.
[11]
H. Xiao, Z. Zhang, Y. Fang, L. Zhu, C. Li, Chem. Soc. Rev. 50 (2021) 6308–6319.
[12]
H. Wang, Y. Xie, Y. Zhou, N. Cen, W. Chen, Chin. Chem. Lett. 33 (2022) 221–224.
[13]
L. Li, F. Wang, C. Ni, J. Hu, Angew. Chem. Int. Ed. 52 (2013) 12390–12394.
[14]
C. Ni, J. Hu, Synthesis 46 (2014) 842–863.
[15]
Q. Xie, C. Ni, R. Zhang, et al., Angew. Chem. Int. Ed. 56 (2017) 3206–3210.
[16]
M. Zhang, J.H. Lin, J.C. Xiao, Angew. Chem. Int. Ed. 58 (2019) 6079–6083.
[17]
X.P. Fu, X.S. Xue, X.Y. Zhang, et al., Nat. Chem. 11 (2019) 948–956.
[18]
L. Peng, H. Wang, C. Guo, J. Am. Chem. Soc. 143 (2021) 6376–6381.
[19]
J. Zheng, J.H. Lin, J. Cai, J.C. Xiao, Chem. Eur. J. 19 (2013) 15261–15266.
[20]
J. Zheng, J. Cai, J.H. Lin, Y. Guo, J.C. Xiao, Chem. Commun. 49 (2013) 7513–7515.
[21]
A. García-Domínguez, T.H. West, J.J. Primozic, et al., J. Am. Chem. Soc. 142 (2020) 14649–14663.
[22]
Y. Jia, Y. Yuan, J. Huang, Z.X. Jiang, Z. Yang, Org. Lett. 23 (2021) 2670–2675.
[23]
J. Su, X. Hu, H. Huang, Y. Guo, Q. Song, Nat. Commun. 12 (2021) 4986.
[24]
Y. Wang, S. Mu, X. Li, Q. Song, Chin. Chem. Lett. 33 (2021) 1511–1514.
[25]
J.B.I. Sap, C.F. Meyer, J. Ford, et al., Nature 606 (2022) 102–108.
[26]
J. Zheng, J.H. Lin, X.Y. Deng, J.C. Xiao, Org. Lett. 17 (2015) 532–535.
[27]
J. Zheng, L. Wang, J.H. Lin, J.C. Xiao, S.H. Liang, Angew. Chem. Int. Ed. 54 (2015) 13236–13240.
[28]
J. Zheng, R. Cheng, J.H. Lin, et al., Angew. Chem. Int. Ed. 56 (2017) 3196–3200.
[29]
X.L. Chen, S.H. Zhou, J.H. Lin, Q.H. Deng, J.C. Xiao, Chem. Commun. 55 (2019) 1410–1413.
[30]
J. Yu, J.H. Lin, D. Yu, R. Du, J.C. Xiao, Nat. Commun. 10 (2019) 5362.
[31]
M. Huiban, M. Tredwell, S. Mizuta, et al., Nat. Chem. 5 (2013) 941–944.
[32]
H.Y. Kim, J.Y. Lee, Y.S. Lee, J.M. Jeong, J. Label. Compd. Radiopharm. 62 (2019) 566–579.
[33]
Z. Fu, Q. Lin, B. Hu, et al., J. Nucl. Med. 60 (2019) 930–936.
[34]
P. Thirumurugan, D. Matosiuk, K. Jozwiak, Chem. Rev. 113 (2013) 4905–4979.
[35]
H.C. Kolb, M.G. Finn, K.B. Sharpless, Angew. Chem. Int. Ed. 40 (2001) 2004–2021.
[36]
Y. Xie, S. Du, Z. Liu, et al., Angew. Chem. Int. Ed. 61 (2022) e202200303.
[37]
D. Dheer, V. Singh, R. Shankar, Bioorg. Chem. 71 (2017) 30–54.
[38]
D. Fu, J. Zhang, S. Cao, J. Fluorine Chem. 156 (2013) 170–176.
[39]
K.P.S. Cheung, G.C. Tsui, Org. Lett. 19 (2017) 2881–2884.
[40]
F. Wei, T. Zhou, Y. Ma, C.H. Tung, Z. Xu, Org. Lett. 19 (2017) 2098–2101.
[41]
A. Zhu, X. Xing, S. Wang, et al., Green Chem. 21 (2019) 3407–3412.
[42]
H. Yang, T.H. Xu, S.N. Lu, Z. Chen, X.F. Wu, Org. Chem. Front. 8 (2021) 3440–3445.
[43]
T.H. Witney, L. Carroll, I.S. Alam, et al., Cancer Res. 74 (2014) 1319–1328.
[44]
S.P. McCluskey, A. Haslop, C. Coello, et al., J. Nucl. Med. 60 (2019) 1750–1756.
[45]
B.S. Lee, S.Y. Chu, W.J. Jung, et al., Prostate 80 (2020) 1383–1393.
[46]
H. Morimoto, T. Tsubogo, N.D. Litvinas, et al., Angew. Chem. Int. Ed. 50 (2011) 3793–3798.
[47]
M.H. Shaikh, D.D. Subhedar, M. Arkile, et al., Bioorg. Med. Chem. Lett. 26 (2016) 561–569.
[48]
M.H. Shaikh, D.D. Subhedar, F.A.K. Khan, et al., J. Heterocycl. Chem. 54 (2017) 413–421.
[49]
I.B. Sayeed, M. Vishnuvardhan, A. Nagarajan, S. Kantevari, A. Kamal, Bioorg. Chem. 80 (2018) 714–720.
[50]
X. Deng, J. Rong, L. Wang, et al., Angew. Chem. Int. Ed. 58 (2019) 2580–2605.
[51]
W. Wei, Z.T. Rosenkrans, J. Liu, et al., Chem. Rev. 120 (2020) 3787–3851.
[52]
T. Wang, Y. Zhang, X. Zhang, et al., Chin. Chem. Lett. 33 (2022) 3543–3548.
[53]
C.N. Neumann, J.M. Hooker, T. Ritter, Nature 534 (2016) 369–373.
[54]
S. Verhoog, C.W. Kee, Y. Wang, et al., J. Am. Chem. Soc. 140 (2018) 1572–1575.
[55]
W. Chen, Z. Huang, N.E.S. Tay, et al., Science 364 (2019) 1170–1174.
[56]
N.E.S. Tay, W. Chen, A. Levens, et al., Nat. Catal. 3 (2020) 734–742.
[57]
R. Halder, T. Ritter, J. Org. Chem. 86 (2021) 13873–13884.
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Year 2023 volume 34 Issue 6
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doi: 10.1016/j.cclet.2022.107960
  • Receive Date：2022-09-07
  • Online Date：2025-11-21
  • Published：2023-06-15
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  • Received：2022-09-07
  • Revised：2022-10-22
  • Accepted：2022-10-26
Affiliations
    aHuaxi MR Research Center, Department of Radiology, Functional and Molecular Imaging Key Laboratory of Sichuan Province, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu 610041, China
    bDepartment of Nuclear Medicine, Laboratory of Clinical Nuclear Medicine, West China Hospital, Sichuan University, Chengdu 610041, China
    cSchool of Chemistry and Chemical Engineering, Collaborative Innovation Center of Henan Province for Green Manufacturing of Fine Chemicals, State Key Laboratory of Cell Differentiation Regulation and Target Drug, Henan Normal University, Xinxiang 453007, China
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表12种不同金属材料的力学参数
科
Family		 属数
Number of
genus		 种数
Number of
species		 占总种数比例
Percentage of
total species (%)		 属
Genus		 种数
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species		 占总种数比例
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鹅膏菌科Amanitaceae 2 11 5.26 鹅膏菌属 Amanita 10 4.78
小菇科 Mycenaceae 2 12 5.74 丝盖伞属 Inocybe 5 2.39
多孔菌科 Polyporaceae 8 14 6.70 蜡蘑属 Laccaria 5 2.39
红菇科 Russulaceae 3 23 11.00 小皮伞属 Marasmius 6 2.87
小菇属 Mycena 11 5.26
光柄菇属 Pluteus 5 2.39
红菇属 Russula 17 8.13
栓菌属 Trametes 5 2.39
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