English

• N-Aryl benzimidazoles, serving as a pivotal core, are prevalent in a multitude of biologically and pharmacologically active compounds [1, 2]. The distinct pharmacological activities are attributed to their atropisomerism, including RXR partial agonist [3] and PI3Kβ inhibitor [4, 5]. Additionally, they serve as functional materials in the field of organic synthesis and pharmaceutical chemistry, such as chiral ligand Biminap [6] and chiral derivatizing agent (Fig. 1) [7]. The enantioselective synthesis of N-aryl benzimidazole atropisomers remained undeveloped until 2019, when the first atroposelective synthesis of these compounds was achieved by the Miller group (Fig. 2a) [8]. Their approach involved the use of chiral phosphoric acids (CPAs) or peptide-based phosphoric acids to catalyze an enantioselective cyclodehydration process between the amide and amine derivatives, producing the axially chiral N-aryl benzimidazoles. Subsequently, several research groups have developed new approaches for the atroposelective construction of N-aryl benzimidazoles. The Fu group [9] redesigned and developed a CPA-catalyzed carbon-carbon bond cleavage approach (Fig. 2b), while the Liu group [10] reported the first Pd-catalyzed intramolecular cross-coupling strategy (Fig. 2c). Later, the Tan group [11] developed a novel CPA-catalyzed ring formation approach using nitrosobenzene (Fig. 2d).

  Figure 1

  

  Figure 1.  Representative biologically active compounds and functional materials.

  DownLoad: Full-Size Img PowerPoint

  Figure 2

  

  Figure 2.  Atroposelective construction of axially chiral N-aryl benzimidazoles.

  DownLoad: Full-Size Img PowerPoint

  As in earlier advancements, homogeneous CPAs occupy a leading position in the asymmetric synthesis of N-aryl benzimidazoles. However, the use of homogeneous catalyst protocols presents considerable challenges for future industrial applications due to their high costs, high catalyst loading (5–20 mol%), complex purification processes, and recyclability issue. To overcome these drawbacks, the immobilization of CPAs became a practical and advantageous alternative. In 2010, Rueping group demonstrated the first immobilization of CPAs by copolymerization [12]. Since then, the immobilization of CPAs has garnered extensive attention and has undergone significant development over the past decade [13-17]. Meanwhile, the application of immobilized CPAs in asymmetric synthesis has been well explored, including asymmetric hydrogenation [13], asymmetric allylation [18], asymmetric cyclization [19], asymmetric dearomatization [15] and desymmetrization [20]. However, to the best of our knowledge, atroposelective construction of N-aryl benzimidazoles using immobilized CPAs has not been developed. Styrene copolymerization is one of the most robust strategies to achieve catalyst immobilization, and our group has previously applied this approach to the immobilization of BINOL-derivative ligands [21]. Moreover, polystyrene support will provide a hydrophobic microenvironment for the catalytic sites [22-24], which may accelerate the reaction and avoid the use of additives like molecular sieves. Therefore, we decided to develop a polystyrene-supported CPA catalyst for the atroposelective construction of N-aryl benzimidazoles.

  In this communication, we report the synthesis of polystyrene-supported CPA 1 and the first atroposelective construction of axially chiral N-aryl benzimidazoles using an immobilized CPA catalyst (Fig. 2e). This immobilized catalyst 1, offers products in high yield and excellent enantioselectivity without the use of molecular sieves, representing a more straightforward reaction setup.

  The synthesis of catalyst 1 was based on a modified procedure from our previous report [21], which commenced with the bromination of a BINOL derivative bearing two tris-isopropyl benzene substituents. This was followed by Suzuki-coupling, copolymerization, phosphorylation, and hydrolysis to give the CPA catalyst 1 in 65% overall yield. The structural integrity and materials morphology of the catalyst 1 were characterized by solid-state nuclear magnetic resonance (NMR), X-ray photoelectron spectroscopy (XPS), inductively coupled plasma optical emission spectrometry (ICP-OES), transmission electron microscopy (TEM) and energy-dispersive X-ray spectrometer (EDS) in detail. The solid-state ¹³C NMR spectrum of 1 exhibited connected peaks ranging from 120 ppm to 160 ppm, which are assigned to the aromatic carbons, and from 10 ppm to 50 ppm, assigned to the isopropyl carbons, respectively (Fig. 3a). In the solid-state ³¹P NMR spectrum of 1, only one broad peak at 4.12 ppm was observed, which is similar to the characteristic signal of the chiral phosphoric acid monomer (TRIP) at 1.5 ppm (Fig. 3b). Furthermore, similar P 2p peak signals were observed for 1 and TRIP in the XPS spectra (132.8 vs. 133.5 eV, Fig. 3c). The ICP-OES analysis showed that the P content in 1 is 0.48% (see Supporting information for details), which revealed the TRIP loading to be 95% (theoretical P content is 0.50%). TEM images showed that 1 consisted of sphere particles with diameters of 100 nm (Fig. 3d). The location of TRIP at 1 was verified by TEM-EDS overlap map, which indicated that the elements C, O and P are uniformly distributed in the solid matrix (Fig. 3e). All these results suggest that the chemical structure and properties of the phosphoric acid were well retained after immobilization.

  Figure 3

  

  Figure 3.  Characterizations of the solid catalyst. (a) Solid-state ¹³C NMR spectrum of 1. (b) Solid-state ³¹P NMR spectrum of 1. (c) XPS spectra of TRIP and 1. (d) TEM and (e) EDS mapping images of 1.

  DownLoad: Full-Size Img PowerPoint

  Having synthesized the polystyrene-supported CPA, we then proceeded to investigate the reactivity and atroposelectivity of the catalyst by using N¹-(naphthalen-1-yl)benzene-1, 2-diamine (2a) and acetylacetone (3a) as the model substrates. Our investigation began with reaction optimization (Table 1). In comparison to homogeneous TRIP catalyst (entry 1, 88% yield with 92% ee [9]), the reaction using 1 exhibited greater efficiency, yielding the target compound 4aa in 91% isolated yield with 96% ee (entry 2). Given that the swelling ability of the supported catalyst in different solvents significantly impacts its performance [25], we next investigated the solvent effect. The employment of polar protic solvent MeOH was harmful, giving the product in 12% yield with 20% ee (entry 3). Subsequently, three different types of polar aprotic solvents were evaluated but only unsatisfactory results were obtained (entries 4–6). Performing the reaction in a less swelling nonpolar solvent hexane produced compound 4aa with a 91% ee, albeit with a diminished yield (entry 7). Leveraging the high efficiency of 1, we successfully reduced the catalyst loading to 2 mol% without compromising on catalytic performance (entries 8 and 9). Further lowering the catalyst loading (0.5 or 1 mol%) provoked a decrease in yield but left the enantioselectivity undamaged (entries 10 and 12). Attempt to improve yield by extending the reaction time proved unsuccessful (entry 11). As expected, the heterogenous catalyst 1 could work smoothly without the molecular sieves (90% yield and 96% ee, entry 15). This can be attributed to the hydrophobicity of the polystyrene support, which encourages the formation of the imine intermediate by facilitating the removal of water molecules. In contrast, the homogeneous TRIP catalyst suffered a roughly 10% loss in both yield and ee (entry 16). Therefore, these optimal conditions (2 mol% of 1 in toluene at 60 ℃ without molecular sieves) were used in further studies.

  Table 1

  

  Table 1.  Reaction optimization of the atroposelective construction with 2a and 3a using immobilized catalyst 1.^a

  DownLoad: CSV

  Next, we explored the versatility of this immobilized catalyst 1 by varying substituents on the benzene ring of the substrate 2 (Scheme 1), including 4-methyl, 4-fluoro, 4‑chloro, 4‑bromo, 6‑chloro, and 5‑methoxy substituents (2d-2g). Additionally, we also examined the substrate bearing a N-heterocyclic group instead of a naphthalene (2h). Regarding the scope of the multicarbonyl compounds 3, we chose three β-dicarbonyl compounds (3a, 3b, 3c), dimethyl 1, 3-acetonedicarboxylate (3d), and three cyclic β-dicarbonyl compounds (3e, 3f, 3g). Comparison of yield and ee between our immobilized CPA catalyst and homogeneous TRIP [9] catalyst was also included (Fig. 4).

  Scheme 1

  

  Scheme 1.  Scope of N¹-(aryl)benzene-1, 2-diamines 2 and multicarbonyl compounds 3 in the atroposelective construction of axially chiral N-aryl benzimidazoles.

  DownLoad: Full-Size Img PowerPoint

  Figure 4

  

  Figure 4.  Comparison of the catalytical efficiency between TRIP and 1, the data of TRIP are from the literature [9].

  DownLoad: Full-Size Img PowerPoint

  The Δyield and Δee mean the difference between employing 1 and TRIP as catalyst. The results suggest that the yield is generally higher (average value of Δyield = 5.8%) and the ee (average value of Δee = −2.1%) is comparable by using 1 as the catalyst. Most reactions proceeded efficiently with excellent yields and enantioselectivities (up to 95% yield, 98% ee). There were only a few special cases, where the yield or ee value conspicuous decreased (4ac, 4ad, 4db, and 4fe). The recycling stability of the catalyst 1 was also investigated. After the completion of the reaction, the heterogeneous catalyst 1 could be separated from the reaction mixture via simple filtration, followed by washing with dichloromethane until no signal was detected in the TLC analysis. It is noteworthy that before the next run, the recovered catalyst 1 needs to be dried in a vacuum oven at 60 ℃ for 24 h. With this approach, we have achieved consistent yields and ee even after 12 cycles, enabling the production of compound 4aa with a cumulative TON of 540 (Fig. 5).

  Figure 5

  

  Figure 5.  Recycling of 1 for the atroposelective construction of axially chiral N-aryl benzimidazole 4aa.

  DownLoad: Full-Size Img PowerPoint

  In conclusion, polystyrene-supported CPA 1 has been successfully synthesized and thoroughly characterized, spanning from chemical structure to materials morphology. This catalyst demonstrated efficient catalytic ability in the atroposelective construction of axially chiral N-aryl benzimidazoles for the first time. A diverse library of atropisomers has been synthesized, achieving yields ranging from 30% to 96% with ee values between 58% and 98%. In addition, the catalyst maintained its reactivity and selectivity even after 12 cycles (TON > 540).

  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.

  CRediT authorship contribution statement

  Chengyao Zhao: Writing – review & editing, Investigation. Jingyuan Liao: Writing – review & editing, Writing – original draft, Investigation, Conceptualization. Yuxiang Zhu: Writing – review & editing, Writing – original draft. Yiying Zhang: Writing – review & editing. Lianjie Zhai: Writing – review & editing, Supervision, Conceptualization. Junrong Huang: Writing – review & editing, Writing – original draft, Supervision, Project administration, Funding acquisition, Conceptualization. Hengzhi You: Writing – review & editing, Writing – original draft, Supervision, Project administration, Funding acquisition, Conceptualization.

  Acknowledgments

  This work was supported by Shenzhen Science and Technology Research (Nos. JSGG20201103153807021, GXWD20220811173736002, KCXFZ20230731094904009). We are also grateful to the Fundamental Research Funds for the Central Universities, Sun Yat-sen University (No. 24qnpy060), Natural Science Foundation of Guangdong Province (No. 2021A1515110366), National Natural Science Foundation of China (Nos. 22302048, 82204231, 22275146) and Shenzhen Key Laboratory of Advanced Functional Carbon Materials Research and Comprehensive Application.

  Supplementary materials

  Supplementary material associated with this article can be found, in the online version, at doi:10.1016/j.cclet.2024.110337.

  
  
• 1. [1]

     Y. Bansal, O. Silakari, Bioorg. Med. Chem. 20 (2012) 6208–6236.

  2. [2]

     Salahuddin, M. Shaharyar, A. Mazumder, Arab. J. Chem. 10 (2017) S157–S173. doi: 10.1016/j.arabjc.2012.07.017

  3. [3]

     F. Ohsawa, S. Yamada, N. Yakushiji, et al., J. Med. Chem. 56 (2013) 1865–1877. doi: 10.1021/jm400033f

  4. [4]

     S. Perreault, F. Arjmand, J. Chandrasekhar, et al., ACS Med. Chem. Lett. 11 (2020) 1236–1243. doi: 10.1021/acsmedchemlett.0c00095

  5. [5]

     J. Chandrasekhar, R. Dick, J. Van Veldhuizen, et al., J. Med. Chem. 61 (2018) 6858–6868. doi: 10.1021/acs.jmedchem.8b00797

  6. [6]

     I. Abdellah, N. Debono, Y. Canac, L. Vendier, R. Chauvin, Chem. Asian J. 5 (2010) 1225–1231. doi: 10.1002/asia.200900663

  7. [7]

     M. Kriegelstein, D. Profous, A. Lyčka, et al., J. Org. Chem. 84 (2019) 11911–11921. doi: 10.1021/acs.joc.9b01770

  8. [8]

     Y. Kwon, J. Li, J.P. Reid, et al., J. Am. Chem. Soc. 141 (2019) 6698–6705. doi: 10.1021/jacs.9b01911

  9. [9]

     N. Man, Z. Lou, Y. Li, et al., Org. Lett. 22 (2020) 6382–6387. doi: 10.1021/acs.orglett.0c02214

  10. [10]

      P. Zhang, X.M. Wang, Q. Xu, et al., Angew. Chem. Int. Ed. 60 (2021) 21718–21722. doi: 10.1002/anie.202108747

  11. [11]

      Q.J. An, W. Xia, W.Y. Ding, et al., Angew. Chem. Int. Ed. 60 (2021) 24888–24893. doi: 10.1002/anie.202111251

  12. [12]

      M. Rueping, E. Sugiono, A. Steck, T. Theissmann, Adv. Synth. Catal. 352 (2010) 281–287. doi: 10.1002/adsc.200900746

  13. [13]

      D.S. Kundu, J. Schmidt, C. Bleschke, A. Thomas, S. Blechert, Angew. Chem. Int. Ed. 51 (2012) 5456–5459. doi: 10.1002/anie.201109072

  14. [14]

      W. Gong, X. Chen, H. Jiang, et al., J. Am. Chem. Soc. 141 (2019) 7498–7508. doi: 10.1021/jacs.9b02294

  15. [15]

      X.Y. Huang, Q. Zheng, L.M. Zou, et al., ACS Catal. 12 (2022) 4545–4553. doi: 10.1021/acscatal.2c00397

  16. [16]

      S. Li, J. Zhang, S. Chen, X. Ma, J. Catal. 416 (2022) 139–148. doi: 10.1016/j.jcat.2022.10.021

  17. [17]

      M.B. Chaudhari, P. Gupta, P. Llanes, M.A. Pericàs, Adv. Synth. Catal. 365 (2023) 527–534. doi: 10.1002/adsc.202201275

  18. [18]

      L. Clot-Almenara, C. Rodriguez-Escrich, L. Osorio-Planes, M.A. Pericas, ACS Catal. 6 (2016) 7647–7651. doi: 10.1021/acscatal.6b02621

  19. [19]

      B. Zhang, L. Shi, R. Guo, Catal. Lett. 145 (2015) 1718–1723. doi: 10.1007/s10562-015-1573-9

  20. [20]

      J. Lai, M. Fianchini, M.A. Pericàs, ACS Catal. 10 (2020) 14971–14983. doi: 10.1021/acscatal.0c04497

  21. [21]

      J. Wang, J. Li, Y. Wang, et al., ACS Catal. 12 (2022) 9629–9637. doi: 10.1021/acscatal.2c02056

  22. [22]

      Y. Huang, L. Yang, M. Huang, et al., Particuology 22 (2015) 128–133. doi: 10.1089/dia.2014.0203

  23. [23]

      B. Altava, M.I. Burguete, E. García-Verdugo, S.V. Luis, Chem. Soc. Rev. 47 (2018) 2722–2771. doi: 10.1039/c7cs00734e

  24. [24]

      T. Kitanosono, F. Lu, K. Masuda, Y. Yamashita, S. Kobayashi, Angew. Chem. Int. Ed. 61 (2022) e202202335. doi: 10.1002/anie.202202335

  25. [25]

      M. Heitbaum, F. Glorius, I. Escher, Angew. Chem. Int. Ed. 45 (2006) 4732–4762. doi: 10.1002/anie.200504212

• 

  Figure 1  Representative biologically active compounds and functional materials.

  下载: 全尺寸图片 幻灯片
  

  Figure 2  Atroposelective construction of axially chiral N-aryl benzimidazoles.

  下载: 全尺寸图片 幻灯片
  

  Figure 3  Characterizations of the solid catalyst. (a) Solid-state ¹³C NMR spectrum of 1. (b) Solid-state ³¹P NMR spectrum of 1. (c) XPS spectra of TRIP and 1. (d) TEM and (e) EDS mapping images of 1.

  下载: 全尺寸图片 幻灯片
  

  Scheme 1  Scope of N¹-(aryl)benzene-1, 2-diamines 2 and multicarbonyl compounds 3 in the atroposelective construction of axially chiral N-aryl benzimidazoles.

  下载: 全尺寸图片 幻灯片
  

  Figure 4  Comparison of the catalytical efficiency between TRIP and 1, the data of TRIP are from the literature [9].

  下载: 全尺寸图片 幻灯片
  

  Figure 5  Recycling of 1 for the atroposelective construction of axially chiral N-aryl benzimidazole 4aa.

  下载: 全尺寸图片 幻灯片

  Table 1.  Reaction optimization of the atroposelective construction with 2a and 3a using immobilized catalyst 1.^a

  下载: 导出CSV
•