Highly Site-Selective Metal-Free C–H Acyloxylation of Stable

Letter Cite This: Org. Lett. 2018, 20, 1256−1260

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Highly Site-Selective Metal-Free C−H Acyloxylation of Stable Enamines Fei Wang,† Wangbing Sun,† Yixin Wang,† Yaojia Jiang,*,† and Teck-Peng Loh*,†,‡,§ †

Institute of Advanced Synthesis, Institute of Advanced Materials, School of Chemistry and Molecular Engineering, Jiangsu National Synergetic Innovation Center for Advanced Materials, Nanjing Tech University, Nanjing 211816, China ‡ Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological University, Singapore 637616, Singapore § Department of Chemistry, University of Science and Technology of China, Hefei, Anhui 230026, China S Supporting Information *

ABSTRACT: A highly site-selective acyloxylation of stable enamines with PhI(OAc)2 under metal-free conditions to afford (E)-vinyl acetate derivatives in good to excellent yields is described. Depending on the judicious choice of the solvent system, either the α- or β-site-selective product could be obtained with high selectivity. For the α-site-selective product, the rearranged amide compound is obtained as the major product. This reaction proceeds under mild reaction conditions (room temperature, metal-free, and open-flask) and features a broad substrate scope.

E

Our studies commenced with acyloxylation of enaminone 1a with phenyliodine(III) diacetate (PIDA, 2a) under various conditions. We were delighted to find that the acyloxylation product 3a could be obtained, albeit in low yield, using aprotic solvents (Table 1, entries 1 and 2), together with another minor product, (Z)-3-(dimethylamino)-3-oxo-1-phenylprop-1en-1-yl acetate (4a), the structure of which was confirmed by single-crystal X-ray diffraction analysis (Figure 1; CCDC no. 1519780). Attempts to improve the selectivity by carrying out the reaction using different solvents revealed that alcohols led to a positive effect (Table 1, entries 4−6), while acetic acid gave the product in only 15% yield, probably because of the stability problem of 1a under acidic conditions (Table 1, entry 3). Further screening of the reaction conditions showed that fluorinated solvents such as hexafluoroisopropanol (HFIP) and 2,2,2-trifluoroethanol (TFE) afforded 3a as the sole product in 59% and 65% yield, respectively. Gratifyingly, the yield of 3a could be improved to 88% when 1.3 equiv of PIDA was used in the reaction (Table 1, entry 9). Further reduction of the amount of PIDA resulted in a decreased yield (Table 1, entry 10). Interestingly, when the solvent system was changed to acetonitrile, the α-site-selective product could be obtained as the major product in 34% yield. Furthermore, it was found that a trace amount of water increased the regioselectivity dramatically (Table 1, entries 12−15). Finally, the optimized reaction conditions for the α-acyloxylation of enamines 1a involve carrying out the reaction with PIDA in the presence of 2.0 equiv of H2O at room temperature.

namines and their derivatives are useful synthetic building blocks1 since they can function as stable enolates to react with a wide variety of electrophiles under neutral conditions. Furthermore, they can also function as latent amino groups since they can easily be obtained via reduction of the unsaturated double bond.2 Accordingly, their syntheses have attracted tremendous attention from synthetic chemists.3 In recent years, our group4 and other groups5 have developed efficient methods for the construction of functionalized enamides via direct sp2 C−H bond functionalization of simple enamides. Enaminones are another class of enamine derivative that have attracted the attention of synthetic chemists since they contain additional functional groups that can be easily manipulated.6 They are also easy to handle, as they can be purified by silica gel chromatography. Cabri’s group7 and others8 reported palladium-catalyzed C−H bond arylation of αsite enamides (Scheme 1A). Georg’s group9 has elegantly demonstrated the possibilities of carrying out β-site C−H bond functionalization of cyclic enamides using transition-metal catalysts. Acyclic enamides have also been studied in β-site C−H bond functionalition by Loh,10 Zhao,11 and other groups12 (Scheme 1B). Dong’s group developed a novel method for the synthesis of spiro-fused dihydrofuran-3(2H)ones that resulted in β-acyloxylation of enaminones as side products.13 In this paper, we report a metal-free method to carry out highly site-selective sp2 alkenyl C−H bond acyloxylation of enaminones. Both α- and β-site-selective products can be obtained selectively by the judicious choice of the solvent employed in the reaction. In the case of the αsite-selective product, the rearranged amide compound is obtained as the major product. This offers an efficient method to construct amide bonds. © 2018 American Chemical Society

Received: January 22, 2018 Published: February 8, 2018 1256

DOI: 10.1021/acs.orglett.8b00222 Org. Lett. 2018, 20, 1256−1260

Letter

Organic Letters Scheme 1. Site-Selective sp2 C−H Bond Functionalization

Figure 1. X-ray structure of 4a.

Scheme 2. Substrate Scope of β-Acyloxylationa,b

Table 1. Optimization of the Reaction Conditionsa

yields (%)b c

entry

solvent

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15

toluene DCE AcOH MeOH EtOH IPA HFIP TFE TFE TFE ACN ACN ACN ACN ACN

equiv of H2O

1a:2a

3a

4a

− − − − − − − − − − − 1.0 2.0 3.0 5.0

1:1.5 1:1.5 1:1.5 1:1.5 1:1.5 1:1.5 1:1.5 1:1.5 1:1.3 1:0.6 1:2.0 1:2.0 1:2.0 1:2.0 1:2.0

48 45 15 31 45 41 59 65 83 42 19 − − − 8

18 20 − 27 45 41 − − − − 34 71 73 70 61

a

Unless otherwise noted, the reactions were carried out using 1 (0.20 mmol) and PIDA (0.30 mmol) in TFE (0.1 M, 2 mL) at room temperature for 0.5−2.0 h in an open flask. bIsolated yields are shown. c The reaction was carried out in EtOH.

delivering good to excellent yields. To examine the electronic effect, enaminones with aryl groups bearing electron-donating and -withdrawing groups were subjected to the optimized reaction conditions. Substrates with electron-rich and electrondeficient aryl groups provided the desired products in good yields (3b−d). A range of halogen substituents (F, Cl, Br, and I) at the para position of the phenyl groups were also welltolerated (3e−h). It is important to note that the bromo and iodo functionalities could be further employed in many useful coupling reactions.14 Heterocycles including furan, thiophene, and pyridine remained intact during the reaction (3i−k). It was

a Unless otherwise noted, the reactions were performed using 1a (0.1 mmol) and 2a in the solvent (0.1 M, 1 mL) at room temperature in an open flask. bYields determined by isolation. cIPA = isopropyl alcohol; HFIP = hexafluoroisopropanol; TFE = 2,2,2-trifluoroethanol.

Encouraged by the above results, we continued to investigate the substrate scope of β-acyloxylation of enamines (Scheme 2). In general, the reaction tolerated a broad range of substitutions, 1257

DOI: 10.1021/acs.orglett.8b00222 Org. Lett. 2018, 20, 1256−1260

Letter

Organic Letters found that the acyloxylation occurred at the β-site of the enamine with excellent regioselectivity rather than other reactive C(sp2)−H bonds in the heterocycles. This is consistent with selectivity based on Mayer’s nucleophilicity constants.15 Naphthalenyl (3l) and alkyl-substituted substrates (3m−o) could also provide the products as single regioisomers in moderate to good yields. When the N-substituent was changed to alkyl and aryl groups, the desired acyloxylation products were obtained in promising yields of 56% and 70%, respectively (3p and 3q). On the other hand, dibenzyl substitution (3r) has a slightly negative influence on the transformation, as the desired product was obtained in 46% yield. Furthermore, cyclic amino functional groups were also well-tolerated (3s−v). Besides enaminones, enaminolates were explored to extend the potential application of this methodology. Delightfully, the reactions proceeded smoothly and gave the desired products in moderate to good yields with both acyclic and cyclic enamines (3w−y). The reactio ngave the β-acyloxylation product in 68% yield when the N,N-unsubstituted enamine 1z was examined in TFE (3z). Next, we explored the α-acyloxylation of enamines to afford the rearranged products (Scheme 3). Substrates with both electron-rich and electron-deficient aryl groups provided the desired products in promising yields (4a−g). Neither the electronic properties of the substituents nor their position on the phenyl group had a significant effect on the reaction.

Functional groups including heterocycle, triple bond, and double bond were all well-tolerated and led to the corresponding products in 53%−78% yield (4h−n). It is worth noting that diene compounds play a pivotal role in organic synthesis. Therefore, various conjugated alkenyl groups were explored, and the corresponding conjugated vinyl acyloxylated amides were obtained under the established conditions. When different aminol groups were installed on the enamine, the reaction proceeded smoothly to give the desired products in good to excellent yields (4q−u). Importantly, when enamines with different amino acids as the N-substituents were explored under the reaction conditions, amides with an amino acid residue were formed in promising yields (4t, 4u). According to the obtained results, we proposed the possible reaction pathway shown in Scheme 4. Initially, enaminone 1 Scheme 4. Proposed Pathway for Acyloxylation of Enaminones

Scheme 3. Substrate Scope of α-Acyloxylationa,b

may react with PIDA to generate iodonium intermediate A. There are two possible pathways by which the −OAc anion may attack A. First, A may be attacked by the OAc anion at the βsite of the enamine to give intermediate B (path a)11c with release of iodobenzene and acetate anion. Cation intermediate B then is pronated to afford the β-acyloxylation product 3. On the other hand, if −OAc attacks the α-site of the enamine, intermediate C is probably obtained (path b) and consequently undergoes elimination to give D. Finally, the amide product 4 can be obtained by rearrangement of α-acyloxylation intermediate D through protonation intermediate E.16 To better understand the mechanism, several control and isotopic labeling experiments were investigated (Scheme 5). First, we carried out the reaction using 18O-labeled water (Scheme 5a). The result showed that 18O was not incorporated into the product, supporting the possible intramolecular acyl transfer pathway. A D2O exchange experiment was then performed under standard reaction conditions, and the Dlabeled product was detected (Scheme 5b). Considering that the role of water may be to liberate small amounts of AcOH to protonate intermediate D, we also employed a small amount of AcOD to test the reaction (Scheme 5c). As expected, the Dlabeled product 4a″ was observed. In the meantime, the deuterium-free product 4a was examined with 2.0 equiv of D2O, and there was no H/D exchange product (Scheme 5d). These obtained results provide evidence that the possible protonation step is involved to generate intermediate E. When isolated product 3a was used as the substrate under the standard reaction conditions, there was no rearranged product 4a, but the known amide 6a was obtained in 36% yield.17 This ruled out the possibility of the conversion of product 3a into 4a (Scheme 4).

a

Unless otherwise noted, the reactions were carried out using 1 (0.20 mmol) and PIDA (0.40 mmol) in CH3CN (0.1 M, 2 mL) at room temperature for 0.5−2.0 h in an open flask. bIsolated yields are shown. 1258

DOI: 10.1021/acs.orglett.8b00222 Org. Lett. 2018, 20, 1256−1260

Organic Letters Scheme 5. Mechanism Study

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ACKNOWLEDGMENTS

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REFERENCES

The authors gratefully acknowledge funding from the National Natural Science Foundation of China (21502089), the Jiangsu Province Funds Surface Project (BK 20161541), and the Starting Funding of Research (39837107) from Nanjing Tech University. We also thank the Jiangsu National Synergetic Innovation Center for Advanced Materials for financial support through a SICAM Fellowship. Dr. Li Yongxing (NTU) is thanked for single-crystal X-ray diffraction analysis.

(1) (a) Matsubara, R.; Kobayashi, S. Acc. Chem. Res. 2008, 41, 292− 301. (b) Gopalaiah, K.; Kagan, H. B. Chem. Rev. 2011, 111, 4599− 4657. (c) Carbery, D. R. Org. Biomol. Chem. 2008, 6, 3455−3460. (d) Dake, G. R. Synlett 2012, 23, 814−824. (e) Gu, Z.-Y.; Zhu, T.-H.; Cao, J.-J.; Xu, X.-P.; Wang, S.-Y.; Ji, S.-J. ACS Catal. 2014, 4, 49−52. (f) Guan, Z.-H.; Li, L.; Ren, Z.-H.; Li, J.; Zhao, M.-N. Green Chem. 2011, 13, 1664−1668. (g) Suryavanshi, P. A.; Sridharan, V.; Menendez, J. C. Chem. - Eur. J. 2013, 19, 13207−13215. (h) Xiang, D.; Xin, X.; Liu, X.; Zhang, R.; Yang, J.; Dong, D. Org. Lett. 2012, 14, 644−647. (i) Yang, Z.; Jiang, B.; Hao, W.-J.; Zhou, P.; Tu, S.-J.; Li, G. Chem. Commun. 2015, 51, 1267−1270. (j) Chen, G.; Wang, Z.; Zhang, X.; Fan, X. J. Org. Chem. 2017, 82, 11230−11237. (2) (a) Hsiao, Y.; Rivera, N. R.; Rosner, T.; Krska, S. W.; Njolito, E.; Wang, F.; Sun, Y.; Armstrong, J. D., III; Grabowski, E. J. J.; Tillyer, R. D.; Spindler, F.; Malan, C. J. Am. Chem. Soc. 2004, 126, 9918−9919. (b) Huang, K.; Zhang, X.; Geng, H.; Li, S.-K.; Zhang, X. ACS Catal. 2012, 2, 1343−1345. (c) Imamoto, T.; Tamura, K.; Zhang, Z.; Horiuchi, Y.; Sugiya, M.; Yoshida, K.; Yanagisawa, A.; Gridnev, I. D. J. Am. Chem. Soc. 2012, 134, 1754−1769. (d) Zhou, M.; Xue, Z.; Cao, M.; Dong, X.-Q.; Zhang, X. Org. Biomol. Chem. 2016, 14, 4582−4584. (e) Kraft, S.; Ryan, K.; Kargbo, R. B. J. Am. Chem. Soc. 2017, 139, 11630−11641. (3) (a) Volkov, A.; Tinnis, F.; Slagbrand, T.; Trillo, P.; Adolfsson, H. Chem. Soc. Rev. 2016, 45, 6685−6697. (b) Patel, M.; Saunthwal, R. K.; Verma, A. K. Acc. Chem. Res. 2017, 50, 240−254. (c) Rabet, P. T. G.; Boyd, S.; Greaney, M. F. Angew. Chem., Int. Ed. 2017, 56, 4183−4186. (d) Ning, Y.; Zhao, X.-F.; Wu, Y.-B.; Bi, X. Org. Lett. 2017, 19, 6240− 6243. (e) Liu, G.; Shen, Y.; Zhou, Z.; Lu, X. Angew. Chem., Int. Ed. 2013, 52, 6033−6037. (f) Sun, J.; Zheng, G.; Xiong, T.; Zhang, Q.; Zhao, J.; Li, Y.; Zhang, Q. ACS Catal. 2016, 6, 3674−3678. (g) DavisGilbert, Z. W.; Yao, L. J.; Tonks, I. A. J. Am. Chem. Soc. 2016, 138, 14570−14573. (4) (a) Xu, Y.-H.; Chok, Y.-K.; Loh, T.-P. Chem. Sci. 2011, 2, 1822− 1825. (b) Pankajakshan, S.; Xu, Y.-H.; Cheng, J.-K.; Low, M.-T.; Loh, T.-P. Angew. Chem., Int. Ed. 2012, 51, 5701−5705. (c) Feng, C.; Loh, T.-P. Chem. Sci. 2012, 3, 3458−3462. (d) Xu, Y.-H.; He, T.; Zhang, Q.-C.; Loh, T.-P. Chem. Commun. 2014, 50, 2784−2786. (e) Ding, R.; Zhang, Q.-C.; Xu, Y.-H.; Loh, T.-P. Chem. Commun. 2014, 50, 11661− 11664. (f) Xu, Y.-H.; Zhang, Q.-C.; He, T.; Meng, F.-F.; Loh, T.-P. Adv. Synth. Catal. 2014, 356, 1539−1543. (5) (a) Wu, J.; Lang, M.; Wang, J. Org. Lett. 2017, 19, 5653−5656. (b) Xing, D.; Dong, G. J. Am. Chem. Soc. 2017, 139, 13664−13667. (c) Gigant, N.; Chausset-Boissarie, L.; Gillaizeau, I. Chem. - Eur. J. 2014, 20, 7548−7564. (d) Le Bras, J.; Muzart, J. Chem. Rev. 2011, 111, 1170−1214. (e) Ackermann, L. Chem. Rev. 2011, 111, 1315−1345. (f) Gigant, N.; Bäckvall, J.-E. Chem. - Eur. J. 2013, 19, 10799−10803. (g) Gu, X.; Georg, G. Tetrahedron Lett. 2015, 56, 5874−5877. (h) Yu, Y.-Y.; Ranade, A. R.; Georg, G. Adv. Synth. Catal. 2014, 356, 3510− 3518. (6) (a) Ni, M.; Zhang, J.; Liang, X.; Jiang, Y.; Loh, T.-P. Chem. Commun. 2017, 53, 12286−12289. (b) Jiang, Y.; Liang, G.; Zhang, C.; Loh, T.-P. Eur. J. Org. Chem. 2016, 2016, 3326−3330. (c) Lourdusamy, E.; Yao, L.; Park, C.-M. Angew. Chem., Int. Ed. 2010, 49, 7963−7967. (d) Jiang, Y.; Khong, V. Z. Y.; Lourdusamy, E.; Park, C.-M. Chem. Commun. 2012, 48, 3133−3135. (e) Thomas, J.; Goyvaerts, V.; Liekens, S.; Dehaen, W. Chem. - Eur. J. 2016, 22, 9966−9970. (f) Yu,

In summary, we have developed an efficient method for the synthesis of (E)-vinyl acetate derivatives through acyloxylation of stable enamines with PIDA under metal-free conditions. Both α- and β-site-selective products could be obtained selectively by the judicious choice of the solvent employed in the reaction. For the α-site-selective products, the rearranged amide compounds were obtained as the major products. This offers an efficient method to synthesize peptides. The reactions feature a broad substrate scope with wide functional group tolerance.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.8b00222. Experimental procedures and characterization data for new compounds (PDF) Accession Codes

CCDC 1519780 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by e-mailing [email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, U.K.; fax: +44 1223 336033.

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AUTHOR INFORMATION

Corresponding Authors

*[email protected] *[email protected] ORCID

Teck-Peng Loh: 0000-0002-2936-337X Notes

The authors declare no competing financial interest. 1259

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Organic Letters Y.-Y.; Niphakis, M. J.; Georg, G. I. Org. Lett. 2011, 13, 5932−5935. (g) Zhou, S.; Wang, J.; Wang, L.; Song, C.; Chen, K.; Zhu, J. Angew. Chem., Int. Ed. 2016, 55, 9384−9388. (h) Narasaka, K.; Okauchi, T.; Tanaka, K.; Murakami, M. Chem. Lett. 1992, 21, 2099−2102. (i) Chang, L.; Guo, T.; Wang, Z.; Wang, S.; Yao, Z.-J. J. Org. Chem. 2017, 82, 1567−1574. (j) Wan, J.-P.; Zhong, S.; Xie, L.; Cao, X.; Liu, Y.; Wei, L. Org. Lett. 2016, 18, 584−587. (k) Wan, J.-P.; Cao, S.; Liu, Y. Org. Lett. 2016, 18, 6034−6037. (l) Toh, K. K.; Wang, Y.-F.; Ng, E. P. J.; Chiba, S. J. Am. Chem. Soc. 2011, 133, 13942−13945. (m) Toh, K. K.; Biswas, A.; Wang, Y.-F.; Tan, Y. Y.; Chiba, S. J. Am. Chem. Soc. 2014, 136, 6011−6020. (n) Wan, J.-P.; Zhou, Y.; Jiang, K.; Ye, H. Synthesis 2014, 46, 3256−3262. (o) Wan, J.-P.; Lin, Y.; Huang, Q.; Liu, Y. J. Org. Chem. 2014, 79, 7232−7238. (7) Cabri, W.; Candiani, I.; Bedeschi, A.; Santi, R. J. Org. Chem. 1992, 57, 3558−3563. (8) (a) Mo, J.; Xu, L.; Xiao, J. J. Am. Chem. Soc. 2005, 127, 751−760. (b) Mo, J.; Xiao, J. Angew. Chem., Int. Ed. 2006, 45, 4152−4157. (c) Liu, Y.; Li, D.; Park, C.-M. Angew. Chem., Int. Ed. 2011, 50, 7333− 7336. (d) Gigant, N.; Chausset-Boissarie, L.; Gillaizeau, I. Org. Lett. 2013, 15, 816−819. (9) Ge, H.; Niphakis, M. J.; Georg, G. I. J. Am. Chem. Soc. 2008, 130, 3708−3709. (10) (a) Zhou, H.; Xu, Y.-H.; Chung, W.-J.; Loh, T.-P. Angew. Chem., Int. Ed. 2009, 48, 5355−5357. (b) Zhou, H.; Chung, W.-J.; Xu, Y.-H.; Loh, T.-P. Chem. Commun. 2009, 3472−3474. (11) (a) Liu, X.; Cheng, R.; Zhao, F.; Zhang-Negrerie, D.; Du, Y.; Zhao, K. Org. Lett. 2012, 14, 5480−5483. (b) Chen, Y.; Ju, T.; Wang, J.; Yu, W.; Du, Y.; Zhao, K. Synlett 2010, 2010, 231−234. (c) Zhao, F.; Liu, X.; Qi, R.; Zhang-Negrerie, D.; Huang, J.; Du, Y.; Zhao, K. J. Org. Chem. 2011, 76, 10338−10344. (d) Dohi, T.; Kita, Y. Chem. Commun. 2009, 2073−2085. (e) Ochiai, M.; Takeuchi, Y.; Katayama, T.; Sueda, T.; Miyamoto, K. J. Am. Chem. Soc. 2005, 127, 12244−12245. (12) (a) Gigant, N.; Chausset-Boissarie, L.; Belhomme, M.-C.; Poisson, T.; Pannecoucke, X.; Gillaizeau, I. Org. Lett. 2013, 15, 278− 281. (b) Le Bras, J.; Muzart, J. Chem. Rev. 2011, 111, 1170−1214. (c) Wang, H.; Guo, L.-N.; Duan, X.-H. Org. Lett. 2012, 14, 4358− 4361. (d) Besset, T.; Kuhl, N.; Patureau, F. W.; Glorius, F. Chem. - Eur. J. 2011, 17, 7167−7171. (e) Yu, W.; Chen, J.; Gao, K.; Liu, Z.; Zhang, Y. Org. Lett. 2014, 16, 4870−4873. (13) Yuan, J.; Zhang, Q.; Yu, M.; Huang, P.; Zhang, R.; Dong, D. Org. Lett. 2015, 17, 5012−5015. (14) (a) Powers, L. J.; Fogt, S. W.; Ariyan, Z. S.; Rippin, D. J.; Heilman, R. D.; Matthews, R. J. J. Med. Chem. 1981, 24, 604−609. (b) Suryakiran, N.; Prabhakar, P.; Reddy, T. S.; Mahesh, K. C.; Rajesh, K.; Venkateswarlu, Y. Tetrahedron Lett. 2007, 48, 877−881. (15) (a) Kempf, B.; Hampel, N.; Ofial, A. R.; Mayr, H. Chem. - Eur. J. 2003, 9, 2209−2218. (b) Mayr, H.; Kempf, B.; Ofial, A. R. Acc. Chem. Res. 2003, 36, 66−77. (c) Ammer, J.; Nolte, C.; Mayr, H. J. Am. Chem. Soc. 2012, 134, 13902−13911. (16) Neuenschwander, M.; Lienhard, U.; Fahrni, H.-P.; Hurni, B. Helv. Chim. Acta 1978, 61, 2428−2436. (17) Wan, J.-P.; Lin, Y.; Cao, X.; Liu, Y.; Wei, L. Chem. Commun. 2016, 52, 1270−1273.

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