A highly efficient metal-free selective 1,4-addition of difluoroenoxysilanes to chromones

Abstract

A highly efficient metal-free selective 1,4-addition reaction of difluoroenoxysilanes to chromones was developed using the low-cost and readily available HOTf as the catalyst, which is a facile and straightforward method to access valuable C2-difluoroalkylated chroman-4-one derivatives. Interestingly, the products could be readily converted to the difluorinated bioisostere of the natural product (S)-2,6-dimethylchroman-4-one and a difluorinated benzo-seven-membered heterocycle via the Schmidt rearrangement reaction. In addition, the in vitro anti-proliferative activities of these synthesized derivatives against human colon carcinoma cells (HCT116) revealed that compound 3g exhibited potent inhibitory effect on HCT116 cancer cells with an IC₅₀ value of 6.37 μM, representing a novel lead compound for further structural optimization and biological evaluation.

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The selective introduction of fluorine at appropriate positions of organic and biologically active molecules has strong beneficial effects on their physical, chemical, and biological properties and has emerged as a widely used strategy for structural modification in drug research and development.¹ In particular, due to its unique physicochemical properties, for example its H-bond donor ability,² the introduction of a gem-difluoroalkyl (CF₂) moiety in therapeutic drugs and bioactive molecules was realized to enhance their metabolic stabilities, biological activities and drug properties,³ such as the selective type-2 chloride channel activator lubiprostone,⁴ the anti-hepatitis C drugs glecaprevir and voxilaprevir,⁵ the PDE-4 inhibitor roflumilast,⁶ and a range of natural analogues.⁷ Consequently, the development of new reagents and new synthetic methods toward structurally diverse difluoroalkyl-containing derivatives has become an appealing area of research.

On the other hand, the synthesis of natural product hybrid systems with varied biological and pharmacological properties has received increasing attention in the past decades.⁸ Chroman-4-ones, especially 2-substituted chroman-4-ones, are the core structural scaffolds of various natural compounds and bioactive molecules. For instance, the natural products sophoranone,⁹ pinostrobin,¹⁰ blennolide D,¹¹ (S)-2,6-dimethylchroman-4-one,¹² and LL-D253α,¹³ all contain such privileged units and have shown a wide variety of biological activities, including antioxidant, anti-inflammatory, antimicrobial, and antitumor activities (Fig. 1). Besides, the substituents at the 2-position of chroman-4-ones usually play a crucial role in their biological activities and pharmacokinetic properties, for example, the potent and selective SIRT2 inhibitors¹⁴ (Fig. 1). Therefore, the introduction of a difluoro substituent into a chroman-4-one structural motif to assemble the difluoroalkylated chroman-4-one skeleton can not only enrich the diversity of chroman-4-ones but also offer novel bioactivities for drug discovery campaigns.

Fig. 1 Representative examples of bioactive compounds containing the 2-substituted chroman-4-one moiety.

In this context, while some attention has been paid to develop methods to merge a gem-difluoroalkyl group into the chromone framework,¹⁵ until recently,^16,17 only three protocols, with limited success, have been reported for the preparation of C2-difluorinated chroman-4-ones, as shown in Scheme 1A. For example, during the examination of the generality of difluoroalkylation using zinc difluoromethanesulfinate (DFMS)^16a and heteroarylether bioisoster synthesis using sodium difluoroethylsulfinate (DFES-Na),^16b Baran and co-workers also tested both reagents for conjugate addition reactions with chromone. However, although 4 and 3 equivalents of DFMS and DFES-Na were used, as well as stoichiometric amounts of oxidants and acids, the desired difluoroalkylated chroman-4-ones were obtained in only 30% and 26% yields, respectively (eqn (1)).¹⁶ Very recently, Chen et al. accomplished a Ag-mediated decarboxylative C-2 difluoromethylation of chromone-3-carboxylic acids and arylthio-difluoroacetic acids in the presence of 3 equivalents of K₂S₂O₈ (eqn (2)).¹⁷ In their report, improved yields, 50–76%, were realized, but the use of the more active but expensive chromone-3-carboxylic acids was required; therefore, only seven examples were shown. Furthermore, the synthetic utility of the products was not shown. Therefore, the development of new and efficient synthetic methods for the selective incorporation of the gem-difluoroalkyl group at the C2 position of chroman-4-one scaffolds is highly desirable.

Scheme 1 Synthetic strategies toward C2-difluoroalkylated chroman-4-ones.

As part of our continuous efforts toward selective difluoralkylation^18a using difluoroenoxysilanes 2 ,¹⁹ which have been identified as one among the powerful synthons for the introduction of the gem-difluoroalkyl ketone functionality in the past decades,^18,20–26 we recently conducted a program focusing on the synthesis of difluorinated heterocyclic systems based on natural product skeletons.²⁷ For instance, by using Fe(OTf)₃ as the catalyst, we established a highly efficient nucleophilic substitution of 3-hydroxyoxindoles with difluoroenoxysilanes 2^27a and a 1,6-conjugate addition of para-quinone methides with 2.^27b On the basis of these results, we envisioned the possibility of developing a selective 1,4-addition reaction of chromone using difluoroenoxysilanes, thus providing a facile method for constructing C2-difluoroalkylated chroman-4-ones with structural diversity. Herein, we utilized the cheap HOTf as an acid catalyst to realize the selective 1,4-addition reaction of difluoroenoxysilanes with chromones, which is a straightforward and practical protocol toward C2-difluoroalkylated chroman-4-ones that are inaccessible via other methods (Scheme 1B, eqn (3)).

Initially, we began this study by using difluoroenoxysilane 2a and chromone 1a as model substrates for the optimization of 1,4-addition reaction conditions (Table 1). Based on our previous experience of metal Lewis acid catalyzed difluoroalkylation with 2, we first examined the performance of metal triflates. We were pleased to find that the use of 10 mol% of Fe(OTf)₃, Al(OTf)₃, Bi(OTf)₃, Cu(OTf)₂, or trimethylsilyl trifluoromethanesulfonate (TMSOTf) allowed the model reaction to take place and afforded the desired 1,4-addition product 3a in moderate yields (entries 1–5), while almost no reaction occurred in the presence of Y(OTf)₃, Sc(OTf)₃, Ga(OTf)₃, and Zn(OTf)₂. Interestingly, when changing the Lewis acid catalyst to the Brønsted acid catalyst CF₃SO₃H (HOTf), the reaction yield of 3a could be greatly improved to 78% within 19 h (entry 10). Other Brønsted acids, such as p-TsOH, MeSO₃H or Tf₂NH, did not deliver better results (entries 11–13). Among all the tested catalysts, HOTf was identified to be the best.

Table 1 Optimization of the reaction conditions

Entry	Cat. (10 mol%)	Solvent	Time (h)	Yield^b (%)
a 2a (1.5 equiv.). b NMR yield. c Isolated yield.
1	Fe(OTf)3	CH2Cl2	27	67
2	Al(OTf)3	CH2Cl2	27	31
3	Bi(OTf)3	CH2Cl2	27	52
4	Cu(OTf)2	CH2Cl2	27	47
5	TMSOTf	CH2Cl2	19	72
6	Y(OTf)3	CH2Cl2	27	Trace
7	Sc(OTf)3	CH2Cl2	27	Trace
8	Ga(OTf)3	CH2Cl2	27	Trace
9	Zn(OTf)2	CH2Cl2	27	Trace
10	HOTf	CH2Cl2	19	78
11	p-TsOH	CH2Cl2	8	41
12	MeSO3H	CH2Cl2	19	42
13	Tf2NH	CH2Cl2	19	70
14	HOTf	Hexane	28	85
15	HOTf	Toluene	28	81
16	HOTf	THF	9	84
17	HOTf	CH3CN	28	63
18	HOTf	EtOAc	9	67
19	HOTf (5 mol%)	THF	9	76^c
20^a	HOTf (5 mol%)	THF	9	76^c

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Subsequently, the investigation of solvent effects using HOTf as the catalyst revealed that both polar and non-polar solvents could afford acceptable reaction yields, and tetrahydrofuran (THF) turned out to be the optimal one, affording the target product 3a in 84% yield within 9 h (entry 16). Additionally, decreasing the amount of HOTf from 10 to 5 mol% or that of 2a from 2.0 to 1.5 equiv. had no remarkable influence on the yield of 3a (entry 19 vs. 16, entry 20 vs. 16, respectively). Therefore, the optimal reaction conditions were identified as follows: 5 mol% of HOTf as the catalyst and THF as the solvent at room temperature (entry 20).

With the set of the optimized reaction conditions in hand, we investigated the scope and generality of this HOTf-catalyzed 1,4-addition reaction to access structurally diverse C2-difluoroalkylated chroman-4-ones. As shown in Table 2, chromone substrates bearing electron-donating groups at the C-6 position were first subjected to the reaction with 2a, and it turned out that all of them afforded the corresponding products 3b and 3c in good yields. Furthermore, substituted chromones with electron-deficient groups (F, Cl, Br, and NO₂) at the C-6 position also gave the corresponding products in 64–78% yields (3d–3g). Notably, the C7-substituted chromone substrates with electron-donating and electron-withdrawing substituents were also found to be suitable for this 1,4-addition. It was found that these chromones bearing electron-donating groups afforded the desired products (3h and 3i) in a higher yield than the substrates bearing electron-withdrawing groups (3j–3l). The efficient formation of 3a–3l illustrated that the substituents at different positions and with different electronegativities were well tolerated under the optimized conditions, indicating the potential for further synthetic elaboration. Subsequently, the scope of phenyl substituted difluoroenoxysilanes 2 was evaluated. It is noteworthy that substrates 2 featuring electron-donating or electron-deficient substituents at the phenyl ring converted well to generate the target products 3m–3o in relatively high yields (89–93% yields). In addition, the heterocyclic substituted substrate 2, for example the 2-thienyl-derived difluoroenoxysilane, could also undergo the selective 1,4-addition reaction with 1a, affording the desired product 3p in 79% yield.

Table 2 Scope of the 1,4-addition reaction^a

a Isolated yields are given.

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To demonstrate the synthetic utility of the current method, a gram-scale reaction between 1a (5.0 mmol) and 2a was conducted under the standard conditions. As shown in Scheme 2A, 1.292 g of adduct 3a could be obtained in 85% yield. In addition, the carbonyl moieties in product 3a could be readily reduced to give diol 4 in a high yield by using NaBH₄. Moreover, the subsequent Schmidt rearrangement reaction of 3a enabled the facile construction of benzo-seven-membered heterocycles, as exemplified by the synthesis of compound 5 in a good yield (Scheme 2B). Finally, to further explore the reaction, we also tried to extend this difluoroalkylation to pharmaceutical molecules or natural products. For instance, the difluorinated bioisostere (target compound 6) of the plant product (S)-2,6-dimethylchroman-4-one was obtained under basic conditions from product 3b (Scheme 2C), providing a simple, feasible, and reliable means for medicinal chemists to synthesize difluoroalkylated mimics of natural product scaffolds. Thus, this useful product elaboration not only leads to novel molecular diversity in heterocyclic frameworks, but also further highlights the practicality of this methodology.

Scheme 2 Gram-scale synthesis of 3a and further synthetic transformations.

Next, to preliminarily demonstrate the potential anticancer effects of these difluorinated derivatives, we tested their in vitro anti-proliferative activity against human colon carcinoma cells (HCT116) by using the CCK-8 assay, and their inhibition rates at 20 μM are given in Table 3. The results demonstrated that compounds 3d, 3g, 3h, 3k, 3l, and 3o showed greater than 50% inhibition rate toward the HCT116 cell line, especially 3g, which potently inhibited the growth of HCT116 cancer cells with 99.5% inhibition rate. Furthermore, the IC₅₀ values were determined when the inhibition rate was higher than 70% using cisplatin as the positive control (Table 3). Compounds 3h, 3l, and 3o displayed weak antiproliferative effects toward the HCT116 cell line (IC₅₀ > 10 μM). As expected, 3g exhibited potent inhibitory activity with an IC₅₀ value of 6.37 μM, and even showed a better inhibition activity relative to the positive control drug, cisplatin. The results also indicated that the synthesized difluorinated new chemical entities (NCEs) may be useful as promising lead compounds for further structural optimization and biological screening.

Table 3 In vitro anti-proliferative activity against HCT116 human colon carcinoma cells^a

Entry	Inhibition rate (%)	IC50 (μM)	Entry	Inhibition rate (%)	IC50 (μM)
a The given values are mean values of three experiments. b Not determined.
3a	2.2	ND^b	3k	62.2	ND
3b	16.7	ND	3l	73.3	>10
3c	4.3	ND	3m	7.1	ND
3d	55.8	ND	3n	25.6	ND
3e	12.4	ND	3o	90.9	>10
3f	48.8	ND	4	0	ND
3g	99.5	6.37 ± 0.81	5	0	ND
3h	90.0	>10	6	0	ND
3i	0	ND	Cisplatin	ND	9.47 ± 0.68
3j	6.8	ND

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Conclusions

In summary, a highly efficient selective 1,4-addition of chromones and difluoroenoxysilanes catalyzed by HOTf has been developed, which is highlighted by the following salient features: metal-free conditions, low-cost, simple operation and broad substrate scope. This method provides a facile means for the synthesis of a wide range of structurally novel C-2 difluorinated chroman-4-ones from readily available chromones under mild conditions. Notably, this methodology can be used to prepare novel difluoroalkylated mimics of drug molecules and natural products, providing a powerful strategy for structural modification and drug discovery. Moreover, in vitro anticancer evaluations of the synthesized difluorinated derivatives were also conducted, and a potential lead compound was obtained for further development and research on new drugs. We believe that the HOTf-catalyzed synthetic strategy will bring new possibilities to efficiently prepare structurally diverse and bioactive fluorinated oxygen-containing heterocycles. Further studies on the asymmetric version as well as on the evaluation of the biological activities of these difluorinated chroman-4-ones are underway in our lab.

Author contributions

Conceptualization: Y. Z., J. Z., and Y. H.; investigation: X. W.; supervision: J. Z. and Y. H.; data curation: X. W., M. Y., and Y. H.; and writing: M. Y., Y. Z., J. Z., and Y. H.

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

The financial support from the National Natural Science Foundation of China (No. 81660576), Projects of Guizhou Province (Qian Ke He Ji Chu-ZK [2021] Yi Ban 561, Qian Jiao He KY Zi [2021]018), and the Projects of Guizhou University of Traditional Chinese Medicine (2018YFC170810207, 2018-27) is highly appreciated.

References

1. (a) J. Wang and H. Liu, Chin. J. Org. Chem., 2011, 31, 1785; (b) J. Wang, M. Sánchez-Roselló, J. L. Aceña, C. del Pozo, A. E. Sorochinsky, S. Fustero, V. A. Soloshonok and H. Liu, Chem. Rev., 2014, 114, 2432; (c) E. P. Gillis, K. J. Eastman, M. D. Hill, D. J. Donnelly and N. A. Meanwell, J. Med. Chem., 2015, 58, 8315.
2. (a) N. A. Meanwell, J. Med. Chem., 2011, 54, 2529; (b) M. D. Martíne, L. Luna, A. Y. Tesio, G. E. Feresin, F. J. Durán and G. Burton, J. Pharm. Pharmacol., 2016, 68, 233.
3. (a) K. Ando, F. Koike, F. Kondo and H. Takayama, Chem. Pharm. Bull., 1995, 43, 189; (b) Y. Zhou, J. Wang, Z. Gu, S. Wang, W. Zhu, J. L. Aceña, V. A. Soloshonok, K. Izawa and H. Liu, Chem. Rev., 2016, 116, 422; (c) Y. Zafrani, D. Yeffet, G. Sod-Moriah, A. Berliner, D. Amir, D. Marciano, E. Gershonov and S. Saphier, J. Med. Chem., 2017, 60, 797; (d) Y. Zafrani, G. Sod-Moriah, D. Yeffet, A. Berliner, D. Amir, D. Marciano, S. Elias, S. Katalan, N. Ashkenazi, M. Madmon, E. Gershonov and S. Saphier, J. Med. Chem., 2019, 62, 5628.
4. K. McKeage, G. L. Plosker and M. A. A. Siddiqui, Drugs, 2006, 66, 873.
5. Y. Zhang, Acta Pharm. Sin. B, 2021, 56, 2182.
6. D. P. Tashkin, Expert Opin. Pharmacother., 2014, 15, 85.
7. (a) K. Uoto, S. Ohsuki, H. Takenoshita, T. Ishiyama, S. Iimura, Y. Hirota, I. Mitsui, H. Terasawa and T. Soga, Chem. Pharm. Bull., 1997, 45, 1793; (b) K. Nakayama, H. C. Kawato, H. Inagaki, R. Nakajima, A. Kitamura, K. Someya and T. Ohta, Org. Lett., 2000, 2, 977.
8. (a) K. C. Nicolaou, J. A. Pfefferkorn, A. J. Roecker, G.-Q. Cao, S. Barluenga and H. J. Mitchell, J. Am. Chem. Soc., 2000, 122, 9939; (b) H.-B. Zhang, Synlett, 2014, 1953; (c) E. N. Hancock, J. M. Wahl and M. K. Brown, Nat. Prod. Rep., 2019, 36, 1383; (d) S.-M. Fu and B. Liu, Org. Chem. Front., 2020, 7, 1903.
9. W. Zhang, X. Wei, L. Zhang, X. Hu, Y.-Q. Zhou and Y. Zhou, Chem. Nat. Compd., 2020, 56, 1140.
10. H. Häberlein and K. P. Tschiersch, Biochem. Syst. Ecol., 1998, 26, 97.
11. I. N. Siddiqui, A. Zahoor, H. Hussain, I. Ahmed, V. U. Ahmad, D. Padula, S. Draeger, B. Schulz, K. Meier, M. Steinert, T. Kurtán, U. Flörke, G. Pescitelli and K. Krohn, J. Nat. Prod., 2011, 74, 365.
12. N. Comey, I. Hook, H. Sheridan and J. Walsh, J. Nat. Prod., 1997, 60, 148.
13. I. M. Chandler, C. R. Mclntyre and T. J. Simpson, J. Chem. Soc., Perkin Trans. 1, 1992, 2271.
14. T. Seifert, M. Malo, T. Kokkola, K. Engen, M. Fridén-Saxin, E. A. A. Wallén, M. Lahtela-Kakkonen, E. M. Jarho and K. Luthman, J. Med. Chem., 2014, 57, 9870.
15. (a) K. Li, J. Chen, C. Yang, K. Zhang, C. Pan and B. Fan, Org. Lett., 2020, 22, 4261; (b) C. Li, Y.-X. Cao, R. Wang, Y.-N. Wang, Q. Lan and X.-S. Wang, Nat. Commun., 2018, 9, 4951.
16. (a) Y. Fujiwara, J. A. Dixon, R. A. Rodriguez, R. D. Baxter, D. D. Dixon, M. R. Collins, D. G. Blackmond and P. S. Baran, J. Am. Chem. Soc., 2012, 134, 1494; (b) Q.-H. Zhou, A. Ruffoni, R. Gianatassio, Y. Fujiwara, E. Sella, D. Shabat and P. S. Baran, Angew. Chem., Int. Ed., 2013, 52, 3949.
17. Z. Chen, J. Sun, Z. Ke, X. Huang and Z. Li, Org. Chem. Front., 2022, 9, 757.
18. For reviews, see: (a) X.-S. Hu, J.-S. Yu and J. Zhou, Chem. Commun., 2019, 55, 13638; (b) M. Decostanzi, J. M. Campagne and E. Leclerc, Org. Biomol. Chem., 2015, 13, 7351; (c) Y. Gong, J.-S. Yu, Y.-J. Hao, Y. Zhou and J. Zhou, Asian J. Org. Chem., 2019, 8, 610; (d) Y.-J. Hao, J.-S. Yu, Y. Zhou, X. Wang and J. Zhou, Acta Chim. Sin., 2018, 76, 925.
19. For the synthesis of difluoroenoxysilanes 2, see: (a) H. Amii, T. Kobayashi, Y. Hatamoto and K. Uneyama, Chem. Commun., 1999, 1323; (b) G. K. S. Prakash, J. Hu and G. A. Olah, J. Fluorine Chem., 2001, 112, 355.
20. For aldol-type reactions using 2, see: (a) S. Sasaki, T. Suzuki, T. Uchiya, S. Toyota, A. Hirano, M. Tanemura, H. Teramoto, T. Yamauchi and K. Higashiyama, J. Fluorine Chem., 2016, 192, 78; (b) J. Yang, S. Liu, P. Hong, J. Li, Z. Wang and J. Ren, J. Org. Chem., 2022, 87, 1144. For our contributions, see: (c) Y.-L. Liu, X.-P. Zeng and J. Zhou, Acta Chim. Sin., 2012, 70, 1451; (d) Y.-L. Liu and J. Zhou, Chem. Commun., 2012, 48, 1919; (e) J.-S. Yu, Y.-L. Liu, J. Tang, X. Wang and J. Zhou, Angew. Chem., Int. Ed., 2014, 53, 9512; (f) F.-M. Liao, Y.-L. Liu, J.-S. Yu, F. Zhou and J. Zhou, Org. Biomol. Chem., 2015, 13, 8906; (g) F.-M. Liao, X.-T. Gao, X.-S. Hu, S.-L. Xie and J. Zhou, Sci. Bull., 2017, 62, 1504; (h) Y.-P. Tian, Y. Gong, X.-S. Hu, J.-S. Yu, Y. Zhou and J. Zhou, Org. Biomol. Chem., 2019, 17, 9430; (i) J.-X. He, Z.-H. Zhang, B.-S. Mu, X.-Y. Cui, J. Zhou and J.-S. Yu, J. Org. Chem., 2021, 86, 9206.
21. For selected examples, see: (a) L. Chu, X. Zhang and F.-L. Qing, Org. Lett., 2009, 11, 2197; (b) Z. Yuan, Y. Wei and M. Shi, Chin. J. Chem., 2010, 28, 1709; (c) Z. Yuan, L. Mei, Y. Wei, M. Shi, P. V. Kattamuri, P. McDowell and G. Li, Org. Biomol. Chem., 2012, 10, 2509; (d) J.-S. Yu and J. Zhou, Org. Biomol. Chem., 2015, 13, 10968; (e) J.-S. Yu and J. Zhou, Org. Chem. Front., 2016, 3, 298; (f) J.-S. Li, Y.-J. Liu, G.-W. Zhang and J.-A. Ma, Org. Lett., 2017, 19, 6364; (g) X.-S. Hu, Y. Du, J.-S. Yu, F.-M. Liao, P.-G. Ding and J. Zhou, Synlett, 2017, 2194; (h) Y.-B. Wu, L. Wan, G.-P. Lu and C. Cai, Eur. J. Org. Chem., 2017, 3438; (i) X.-S. Hu, J.-S. Yu, Y. Gong and J. Zhou, J. Fluorine Chem., 2019, 219, 106; (j) X.-S. Hu, P.-G. Ding, J.-S. Yu and J. Zhou, Org. Chem. Front., 2019, 6, 2500; (k) M.-Y. Rong, J.-S. Li, Y. Zhou, F.-G. Zhang and J.-A. Ma, Org. Lett., 2020, 22, 9010; (l) L. Wang, J. Zhang and X. Lin, Synlett, 2021, 417.
22. (a) T. Chen and C. Cai, New J. Chem., 2017, 41, 2519; (b) J. Li, S. Liu, R. Zhong, Y. Yang, J. Xu, J. Yang, H. Ding and Z. Wang, Org. Lett., 2021, 23, 9526; (c) J. Li, W. Xi, S. Liu, Y. Yang, J. Yang, H. Ding and Z. Wang, Chin. Chem. Lett., 2022, 33, 3007; (d) S. Liu, Y. Li, F. Wang, C. Ma, G. Yang, J. Yang and J. Ren, Synthesis, 2022, 161; (e) H. Wu, P. Hong, W. Xi and J. Li, Org. Lett., 2022, 24, 2488.
23. (a) J.-S. Yu, F.-M. Liao, W.-M. Gao, K. Liao, R.-L. Zuo and J. Zhou, Angew. Chem., Int. Ed., 2015, 54, 7381; (b) M. Mamone, E. Morvan, T. Milcent, S. Ongeri and B. Crousse, J. Org. Chem., 2015, 80, 1964; (c) X.-S. Hu, J.-X. He, S.-Z. Dong, Q.-H. Zhao, J.-S. Yu and J. Zhou, Nat. Commun., 2020, 11, 5500; (d) Y. Shi, B.-W. Pan, J.-X. He, Y. Zhou, J. Zhou and J.-S. Yu, J. Org. Chem., 2021, 86, 7797; (e) J. Li, S. Liu, R. Zhong, Y. Yang, Y. He, J. Yang, Y. Ma and Z. Wang, Org. Lett., 2021, 23, 5859; (f) G. Chen and Y. Liu, Chin. J. Org. Chem., 2021, 41, 869.
24. (a) F.-M. Liao, Z.-Y. Cao, J.-S. Yu and J. Zhou, Angew. Chem., Int. Ed., 2017, 56, 2459; (b) J. Li, W. Xi, S. Liu, C. Ruan, X. Zheng, J. Yang, L. Wang and Z. Wang, Org. Lett., 2021, 23, 7264.
25. X. Gao, R. Cheng, Y.-L. Xiao, X.-L. Wan and X.-G. Zhang, Chem, 2019, 5, 2987.
26. (a) J. Li, Y. Chen, R. Zhong, Y. Zhang, J. Yang, H. Ding and Z. Wang, Org. Lett., 2020, 22, 1164; (b) H. Song, R. Chen, Q.-Q. Min and X. Zhang, Org. Lett., 2020, 22, 7747; (c) F.-S. He, Y. Yao, W. Xie and J. Wu, Chem. Commun., 2020, 56, 9469; (d) B.-W. Pan, Y. Shi, Y.-P. Tian, Y. Zhou, J. Zhou and J.-S. Yu, Chem. – Asian J., 2020, 15, 4028; (e) J. Li, W. Xi, R. Zhong, J. Yang, L. Wang, H. Ding and Z. Wang, Chem. Commun., 2021, 57, 1050; (f) J.-Y. Zou, Y.-Z. Wang, W.-H. Sun, W.-J. Lin and X.-Y. Liu, Org. Biomol. Chem., 2021, 19, 8696; (g) Q.-P. Huang, Y. Huang, A.-J. Wang, L. Zhao, J. Jia, Y.-B. Yu, J. Tong, J.-W. Gu and C.-Y. He, Org. Chem. Front., 2021, 8, 4438.
27. (a) Y.-J. Hao, Y. Gong, Y. Zhou, J. Zhou and J.-S. Yu, Org. Lett., 2020, 22, 8516; (b) Y.-J. Hao, X.-S. Hu, J.-S. Yu, F. Zhou, Y. Zhou and J. Zhou, Tetrahedron, 2018, 74, 7395.

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Footnote

† Electronic supplementary information (ESI) available. See DOI: https://doi.org/10.1039/d2ob02152h

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