English

• The development of low-cost, earth-abundant and environmentally benign transition metal catalysts, which can catalyze multiple different types of asymmetric reactions, is an important objective in asymmetric catalysis. Transition-metal (TM)-catalyzed asymmetric allenylic substitution of racemic allenylic electrophiles of the type Ⅰ, which involves alkylene-π-allyl-metal intermediates, provides a platform to synthesize axially chiral allenes (Fig. 1a) [1-8]. However, TM-catalyzed asymmetric allenylic substitution reactions are still limited to the use of precious-metal-based catalysts, such as palladium complexes [9,10]. To our knowledge, non-precious and earth-abundant metal catalysts, such as nickel complexes, have not been used in the asymmetric allenylic substitution reactions. Meanwhile, allenylic substrates bearing good leaving groups, such as carboxylates (acetates), carbonates, and phosphates, have been successfully utilized to form alkylene-π-allyl-metal complexes. However, the direct use of allenic ethers Ⅱ in TM-catalyzed asymmetric allenylic substitution remains an elusive challenge, because of the high stability of the C—O bond of allenic ethers. To expand catalytic systems as well as the type and scope of substrates that are applicable to asymmetric allenylic substitution reactions, we became interested in developing chiral nickel complexes as the catalysts and accessible allenic ethers as the substrates for the asymmetric allenylic substitution reactions.

  Figure 1

  

  Figure 1.  Backgrounds and this work.

  DownLoad: Full-Size Img PowerPoint

  On the other hand, TM-catalyzed asymmetric 1,4-hydrofunctionzation of prochiral 1,3-enynes has emerged as an attractive complementary strategy to synthesize axially chiral allenes (Fig. 1b) [11-13]. In this regard, Malcolmson recently disclosed a Pd-catalyzed 1,4-hydroamination to deliver chiral allenes with pendant allylic amines [14]. Tsukamoto reported an elegant palladium(0)−lithium iodide cocatalyzed asymmetric hydroalkylation of 1,3-enynes [15]. He and Lin described a protocol for the synthesis of tertiary fluoride-tethered allenes bearing a stereogenic center and stereogenic axis via Pd/Cu synergistic catalysis [16]. In 2023, Luo and Mi developed an asymmetric α-allylic allenylation of β-ketocarbonyls and aldehydes with 1,3-enynes by synergistic Pd/chiral primary amine catalysis [17]. Despite these impressive advances, the application of chiral nickel catalysts in the asymmetric 1,4-hydrofunctionalization of 1,3-enynes with nucleophiles to synthesize axially chiral allenes remains elusive, although it can enable the development of unprecedented transformations that is not possible by use of precious-metal-based catalysts, and can potentially enable the assembly of structurally diverse axially chiral allene products that are not readily accessible otherwise. Several questions remained with regard to the reactivity, regio- and enantio-selectivity for the Ni-catalyzed process. (1) Could a nickel catalyst activate 1,3-enynes and enable the 1,4-hydrofunctionzation of 1,3-enynes? (2) How does a nickel catalyst control the regioselectivity (olefin insertion versus alkyne insertion)? It is noted that Buchwald group recently disclosed a copper hydride catalyzed asymmetric reaction of 1,3-enynes with electrophiles [18]. In this protocol, Cu—H insertion occurs at the olefin rather than at the alkyne, and 1,2-hydrofunctionzation products were obtained. Although Ni—H insertion could occur at the olefin, this cannot generate a stable alkylene-π-allyl-complex for nucleophilic addition. (3) Would a nickel catalyst, which is active and can control regio-selectivity, also provide a high level of enantioselectivity control?

  As particularly attractive pro-nucleophiles we selected pyrazolidine-3,5-diones. Pyrazolidine-3,5-diones are a class of important nitrogen heterocyclic scaffolds, which are widely present in drugs and biologically active molecules such as antiphlogistics, antirheumatics, diuretics, analgesics, insecticides, acaricides, herbicides, and acetyl-CoA carboxylase inhibitors (Fig. 1c) [19-23]. Thus, the development of methods to prepare diverse pyrazolidine-3,5-dione derivatives is of great interest due to their versatile pharmacological activities. Although a variety of non-asymmetric reactions have been developed, general, catalytic and asymmetric variants to allow for the synthesis of chiral pyrazolidine-3,5-diones derivatives have been less developed [24,25]. Kang and co-workers reported a Rh-catalyzed enantioselective Michael addition reaction of pyrazolidine-3,5-diones with α, β-unsaturated 2-acyl imidazoles [24]. We recently reported a Pd-catalyzed asymmetric spirocyclization of pyrazolidine-3,5-diones with 1,3-enynes (Fig. 1d) [25]. Both reports target chiral pyrazolidine-3,5-diones with a central chirality. To our knowledge, chiral pyrazolidine-3,5-diones with a different type of chiral element such as axial chirality have not been synthesized, and their applications remain unknown. Chiral allenes represent an important type of axially chiral structural motif in natural products and bioactive molecules, and also are a versatile functional group in chemical transformations [26-29]. The development of efficient methods for catalytic asymmetric synthesis of allene-containing compounds have attracted much attention [30-34]. We envisioned that the enantioselective 2,3-allenylation of pyrazolidine-3,5-diones would not only be an attractive combination for medicinal chemistry due to the unique biological and chemical properties of the axially chiral allene unit and pyrazolone motif but also dramatically increase the diversity of pyrazolidine-3,5-diones derivatives.

  As part of our interest in the TM-catalyzed asymmetric 1,4-hydrofunctionzation of 1,3-enynes [12,25] and allenylic substitution reactions [7,8], we herein demonstrate that a chiral Ni/P-Phos catalyst to achieve both asymmetric 1,4-hydroalkylation of prochiral 1,3-enynes and asymmetric allenylic substitution of racemic allenic ethers with pyrazolidine-3,5-diones (Fig. 1e). Two methods do not require any additives, complement each other, and produce various axially chiral allene derivatives bearing a pyrazolidine-3,5-dione unit with high levels of regioselectivity and enantioselectivity. Moreover, we have designed a new class of multifunctional reagents, enynyl ethers, and developed an unprecedented Ni-catalyzed asymmetric double alkylation, providing a platform for the reaction development and the allene synthesis.

  On the basis of our previous work [25], we initially examined chiral palladium catalysts for the asymmetric 1,4-hydroalkylation of 1,3-enyne 1a with pyrazolidine-3,5-dione 2a in the presence of [Pd(allyl)Cl]₂ and chiral ligands (Table 1). The use of WingPhos L4 [35,36], which was effective in the Pd-catalyzed asymmetric spirocyclizations of pyrazolidine-3,5-diones with 1,3-enynes [25], led to the 1,4-hydroalkylation product 3a in 54% yield but with 28% enantioselectivity. Other several chiral ligands also furnished the 1,4-hydroalkylation product 3a, with (S)-P-Phos L6 offering the highest yield (90%) (entry 6). Unfortunately, no enantioselectivity can be obtained in all chiral ligands examined. Interestingly, when Ni(PPh₃)₂Cl₂ was used in combination of (S)-P-Phos L6, the desired axially allene 3a was obtained in 91% ee and 77% yield (entry 7). Screening other nickel salts (entries 8–17) and chiral ligands (see Supporting information for details), no better results were obtained. It is worth mentioning that despite P-Phos as a family of versatile and effective atropisomeric dipyridylphosphine ligands in asymmetric catalysis [37], this class of chiral ligands has not been successfully applied in the catalytic asymmetric 1,4-hydrofunctionzation reaction of 1,3-enynes.

  Table 1

  

  Table 1.  Reaction optimization.^a

  DownLoad: CSV

  With the optimized catalytic system in hand, we explored the substrate scope of nickel-catalyzed 1,4-hydroalkylation of 1,3-enynes (Scheme 1). A variety of 1,3-enynes bearing electron neutral, donating, and withdrawing groups on the (hetero)aryl group substituents reacted smoothly with various pyrazolidine-3,5-diones to furnish the products 3b-3q in good yields with high levels of regio- and enantioselectivity. The absolute configuration of the product 3r was determined by X-ray analysis.

  Scheme 1

  

  Scheme 1.  Ni-catalyzed asymmetric 1,4-hydroalkylation of 1,3-enynes 1 with pyrazolidine-3,5-diones. Reactions were performed with 1 (0.1 mmol), 2 (0.12 mmol), Ni(PPh₃)₂Cl₂ (5 mol%), (S)-P-Phos (6 mol%) and BnN(Me)₂ (8 equiv.) in 0.5 mL of solvent (CH₃OH/CH₃CN = 3:2).

  DownLoad: Full-Size Img PowerPoint

  It is worth noting that in the above asymmetric 1,4-hydroalkylation of 1,3-enynes, although alkyl-substituted enynes have good reactivity, the enantioselectivity of the corresponding products is low (3s and 3t). Fortunately, we found that when allenic ethers 4a and 4b were used as alternative allenylation reagents, the target products 3s (87% yield, 89% ee) and 3t (80% yield, 90% ee) could be obtained in good yield and good enantioselectivity in the presence of Ni/P-Phos catalytic system (Scheme 2). Other alkyl-substituted allenic ether substrates were also suitable (3u-3z) for the asymmetric allenylic substitution. Moreover, aryl-substituted allenic ethers also provided the corresponding product 3a in 88% yield with 90% ee (Eq. 1) and 3ab in 76% yield with 92% ee (Eq. 2). It is important to synthesize allenylic substituted product 3a on a gram-scale with 74% yield and 92% ee (Eq. 1). Other heterocyclic 1,3-dicarbonyl compounds such as barbituric acid 5 can also be compatible with Ni/P-Phos catalyst, providing the product 6 in 80% yield with 89% ee (Eq. 3). In addition, we also investigated the leaving groups of allelic ethers, and found that (4-bromobenzyl)oxy was a good leaving group rather than phenoxy and benzyloxy (see Supporting information for details).

  Scheme 2

  

  Scheme 2.  Ni-catalyzed asymmetric allenylic substitution of allenic ethers with pyrazolidine-3,5-diones. Reactions were performed with 1a (0.1 mmol) or 5 (0.1 mmol), 4 (0.12 mmol), Ni(PPh₃)₂Cl₂ (5 mol%), (S)-P-Phos (6 mol%) and BnN(Me)₂ (12 equiv.) in 0.5 mL of CH₃CN at 30 ℃.

  DownLoad: Full-Size Img PowerPoint

  In order to further test the generality of Ni/P-Phos catalytic system and develop new chemistry, we designed a new class of bifunctional reagents, enynyl ethers 7, and investigated the Ni/P-Phos catalyzed asymmetric reaction of such substrates with pyrazolidine-3,5-diones (Scheme 3). To our delight, the double alkylation products 8 with novel structures were obtained in good yields and good enantioselectivity.

  Scheme 3

  

  Scheme 3.  Ni-catalyzed asymmetric double alkylation of enynyl ethers with pyrazolidine-3,5-diones. Reactions were performed with 1 (0.12 mmol), 7 (0.1 mmol), Ni(PPh₃)₂Cl₂ (5 mol%), (S)-P-Phos (6 mol%) and BnN(Me)₂ (12 equiv.) in 0.5 mL of CH₃CN at 60 ℃.

  DownLoad: Full-Size Img PowerPoint

  To understand the mechanism of Ni-catalyzed symmetric reaction of enynyl ethers 7, we attempted to synthesize a possible intermediate 4aa (Eq. 4). When 4aa reacted with pyrazolidine-3,5-dione 1a in the Ni/P-Phos catalytic system, the product 8a was obtained with 77% yield and 90% ee (Eq. 5). The results indicate that Ni/P-Phos catalyzed asymmetric reaction of enynyl ethers proceeds through a new one-pot sequence involving intermolecular 1,4-hydroalkylation and intermolecular allenylic alkylation where intermolecular allenylic alkylation was the enantio-determining step.

  A possible mechanism for the Ni-catalyzed asymmetric reaction of enynyl ethers 7 was proposed in Fig. 2. The intermediate A was formed by regioselective Ni—H insertion occurs at the olefin group in enynyl ethers 7. A was captured by 1a, forming the intermediate 4aa. Next, 4aa underwent a nickel(0)-catalyzed oxidation addition to form the intermediate B. Then the intermediate B reacted with 1a to provide the double alkylation product 8a and regenerate nickel(0).

  Figure 2

  

  Figure 2.  Proposed mechanism for Ni-catalyzed asymmetric reaction of enynyl ethers.

  DownLoad: Full-Size Img PowerPoint

  In conclusion, we have developed chiral Ni-catalyzed asymmetric 1,4-hydroalkylation of prochiral 1,3-enynes and asymmetric allenylic substitution of racemic allenic ethers with pyrazolidine-3,5-diones, and synthesized a class of important nitrogen heterocyclic compounds which are key motifs widely present in drugs and biologically active molecules. Two methods do not require any additives, complement each other and furnish a variety of axially chiral allene derivatives bearing a pyrazolidine-3,5-dione unit with high levels of regio- and enantioselectivity. These studies provide not only an elusive example of asymmetric 1,4-hydrofunctionalization of 1,3-enynes using low-cost chiral nickel catalyst, enriching the catalytic systems and providing a new opportunity for the activation of 1,3-enynes for reaction development, but also offer an elusive asymmetric allenylic substitution using a chiral nickel catalyst, expanding the substrate type/scope and enabling stable allenic ethers bearing a challenging leaving group as the substrates in TM-asymmetric allenylic substitution reaction that has not previously been reported. Moreover, we have designed a new class of multifunctional reagents, enynyl ethers, and developed an unprecedented Ni-catalyzed asymmetric double alkylation, providing a platform for the reaction development and the allene synthesis.

  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 work was supported by the National Natural Science Foundation of China (No. 22171240), and Yunling Scholars of Yunnan Province. We thank the Advanced Analysis and Measurement Center of Yunnan University for the sample testing service.

  Supplementary materials

  Supplementary material associated with this article can be found, in the online version, at doi:10.1016/j.cclet.2024.109518.

  
  
• 1. [1]

     Y. Imada, K. Ueno, K. Kutsuwa, S.I. Murahashi, Chem. Lett. 31 (2002) 140–141. doi: 10.1246/cl.2002.140

  2. [2]

     B.M. Trost, D.R. Fandrick, D.C. Dinh, J. Am. Chem. Soc. 127 (2005) 14186–14187. doi: 10.1021/ja0543705

  3. [3]

     S. Song, J. Zhou, C. Fu, S. Ma, Nat. Commun. 10 (2019) 507. doi: 10.1038/s41467-018-07908-1

  4. [4]

     B.M. Trost, J.E. Schultz, T. Chang, M.R. Maduabum, J. Am. Chem. Soc. 141 (2019) 9521–9526. doi: 10.1021/jacs.9b04658

  5. [5]

     S. Song, S. Ma, Chin. J. Chem. 38 (2020) 1233–1238. doi: 10.1002/cjoc.202000300

  6. [6]

     J. Zhang, X. Huo, J. Xiao, et al., J. Am. Chem. Soc. 143 (2021) 12622–12632. doi: 10.1021/jacs.1c05087

  7. [7]

     J. Dai, L. Li, R. Ye, et al., Angew. Chem. Int. Ed. 62 (2023) e202300756. doi: 10.1002/anie.202300756

  8. [8]

     T. Zha, J. Rui, Z. Zhang, et al., Angew. Chem. Int. Ed. 62 (2023) e2023008.

  9. [9]

     D.A. Petrone, M. Isomura, I. Franzoni, S.L. Rössler, E.M. Carreira, J. Am. Chem. Soc. 140 (2018) 4697–4704. doi: 10.1021/jacs.8b01416

  10. [10]

      F. Glatz, D.A. Petrone, E.M. Carreira, Angew. Chem. Int. Ed. 59 (2020) 16404–16408. doi: 10.1002/anie.202005599

  11. [11]

      L. Fu, S. Greßies, P. Chen, G.S. Liu, Chin. J. Chem. 38 (2020) 91–100. doi: 10.1002/cjoc.201900277

  12. [12]

      L. Li, S. Wang, A. Jakhar, Z. Shao, Green Synth. Catal. 4 (2023) 124–134. doi: 10.1117/12.2660370

  13. [13]

      C. Ma, Y.W. Chen, Z.T. He, Sci. Sin. Chim. 53 (2023) 474–484. doi: 10.1360/ssc-2022-0196

  14. [14]

      N.J. Adamson, H. Jeddi, S.J. Malcolmson, J. Am. Chem. Soc. 141 (2019) 8574–8583. doi: 10.1021/jacs.9b02637

  15. [15]

      H. Tsukamoto, T. Konno, K. Ito, T. Doi, Org. Lett. 21 (2019) 6811–6814. doi: 10.1021/acs.orglett.9b02439

  16. [16]

      S.Q. Yang, Y.F. Wang, W.C. Zhao, G.Q. Lin, Z.T. He, J. Am. Chem. Soc. 143 (2021) 7285–7291. doi: 10.1021/jacs.1c03157

  17. [17]

      C. You, M. Shi, X. Mi, S. Luo, Nat. Commun. 14 (2023) 2911. doi: 10.1038/s41467-023-38488-4

  18. [18]

      Y. Yang, I.B. Perry, G. Lu, P. Liu, S.L. Buchwald, Science 353 (2016) 144. doi: 10.1126/science.aaf7720

  19. [19]

      H. Fabre, B. Mandrou, J. Pharm. Sci. 70 (1981) 460. doi: 10.1002/jps.2600700432

  20. [20]

      Siegfried, FR Pat., 1440629, 1966.

  21. [21]

      Amerivan Home Products Corporation, US Pat, 4288602, 1981.

  22. [22]

      M. Muehlebach, F. Cederbaum, D. Cornes, et al., Pest. Manag. Sci. 67 (2011) 1499. doi: 10.1002/ps.2204

  23. [23]

      M. Kamata, T. Yamashita, A. Kina, et al., Med. Chem. Lett. 22 (2012) 4769. doi: 10.1016/j.bmcl.2012.05.062

  24. [24]

      S.W. Li, Q. Kang, Chem. Commun. 54 (2018) 10479. doi: 10.1039/c8cc06426a

  25. [25]

      L. Li, S. Wang, P. Luo, et al., Nat. Commun. 12 (2021) 5667. doi: 10.1038/s41467-021-25981-x

  26. [26]

      A. Hoffmann-Röder, N. Krause, Angew. Chem. Int. Ed. 43 (2004) 1196–1216. doi: 10.1002/anie.200300628

  27. [27]

      S. Yu, S. Ma, Angew. Chem. Int. Ed. 51 (2012) 3074–3112. doi: 10.1002/anie.201101460

  28. [28]

      S. Ma, Chem. Rev. 105 (2005) 2829–2872. doi: 10.1021/cr020024j

  29. [29]

      N.A. Krause, S. Hashmi, Modern Allene Chemistry, Wiley-VCH, Weinheim, 2004.

  30. [30]

      M. Ogasawara, Tetrahedron 20 (2009) 259–271. doi: 10.1016/j.tetasy.2008.11.039

  31. [31]

      J. Ye, S. Ma, Org. Chem. Front. 1 (2014) 1210–1224. doi: 10.1039/C4QO00208C

  32. [32]

      W.D. Chu, Y. Zhang, J. Wang, Catal. Sci. Technol. 7 (2017) 4570–4579. doi: 10.1039/C7CY01319A

  33. [33]

      R.K. Neff, D.E. Frantz, ACS Catal. 4 (2014) 519–528. doi: 10.1021/cs401007m

  34. [34]

      X. Wang, X. Chen, W. Lin, P. Li, W. Li, Adv. Synth. Catal. 364 (2022) 1212– 1222. doi: 10.1002/adsc.202200085

  35. [35]

      G. Xu, C.H. Senanayake, W. Tang, Acc. Chem. Res. 52 (2019) 1101–1112. doi: 10.1021/acs.accounts.9b00029

  36. [36]

      X. Kang, C. Qian, H. Yang, et al., Green Synth. Catal. 3 (2022) 185–189. doi: 10.1016/j.gresc.2022.01.002

  37. [37]

      J. Wu, A.S.C. Chan, Acc. Chem. Res. 39 (2006) 711–720. doi: 10.1021/ar0680015

• 

  Figure 1  Backgrounds and this work.

  下载: 全尺寸图片 幻灯片
  

  Scheme 1  Ni-catalyzed asymmetric 1,4-hydroalkylation of 1,3-enynes 1 with pyrazolidine-3,5-diones. Reactions were performed with 1 (0.1 mmol), 2 (0.12 mmol), Ni(PPh₃)₂Cl₂ (5 mol%), (S)-P-Phos (6 mol%) and BnN(Me)₂ (8 equiv.) in 0.5 mL of solvent (CH₃OH/CH₃CN = 3:2).

  下载: 全尺寸图片 幻灯片
  

  Scheme 2  Ni-catalyzed asymmetric allenylic substitution of allenic ethers with pyrazolidine-3,5-diones. Reactions were performed with 1a (0.1 mmol) or 5 (0.1 mmol), 4 (0.12 mmol), Ni(PPh₃)₂Cl₂ (5 mol%), (S)-P-Phos (6 mol%) and BnN(Me)₂ (12 equiv.) in 0.5 mL of CH₃CN at 30 ℃.

  下载: 全尺寸图片 幻灯片
  

  Scheme 3  Ni-catalyzed asymmetric double alkylation of enynyl ethers with pyrazolidine-3,5-diones. Reactions were performed with 1 (0.12 mmol), 7 (0.1 mmol), Ni(PPh₃)₂Cl₂ (5 mol%), (S)-P-Phos (6 mol%) and BnN(Me)₂ (12 equiv.) in 0.5 mL of CH₃CN at 60 ℃.

  下载: 全尺寸图片 幻灯片
  

  Figure 2  Proposed mechanism for Ni-catalyzed asymmetric reaction of enynyl ethers.

  下载: 全尺寸图片 幻灯片

  Table 1.  Reaction optimization.^a

  下载: 导出CSV
•