Copper-Catalyzed Regioselective and Enantioselective Hydropyridylation of Dienes for the Synthesis of Chiral Diaryl Compounds via Concerted Nucleophilic Aromatic Substitution
Minjeong Seo
Department of Chemistry, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, 34141 Republic of Korea
These authors contributd equally to this work. The authors declare no competing financial interest.
Search for more papers by this authorSanghyup Seo
Department of Chemistry, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, 34141 Republic of Korea
These authors contributd equally to this work. The authors declare no competing financial interest.
Search for more papers by this authorJoonho Jung
Department of Chemistry, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, 34141 Republic of Korea
Search for more papers by this authorCorresponding Author
Prof. Dr. Hyunwoo Kim
Department of Chemistry, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, 34141 Republic of Korea
Search for more papers by this authorMinjeong Seo
Department of Chemistry, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, 34141 Republic of Korea
These authors contributd equally to this work. The authors declare no competing financial interest.
Search for more papers by this authorSanghyup Seo
Department of Chemistry, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, 34141 Republic of Korea
These authors contributd equally to this work. The authors declare no competing financial interest.
Search for more papers by this authorJoonho Jung
Department of Chemistry, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, 34141 Republic of Korea
Search for more papers by this authorCorresponding Author
Prof. Dr. Hyunwoo Kim
Department of Chemistry, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, 34141 Republic of Korea
Search for more papers by this authorAbstract
The synthesis of chiral 1,1-diaryl compounds, particularly those containing a pyridine moiety, is of significant interest due to their pharmaceutical applications. Here, we report the development of a copper-catalyzed enantioselective 1,4-hydropyridylation of conjugated dienes. Utilizing 2-fluoropyridine as the electrophile, CuOAc, and the chiral ligand Tol-BINAP, we optimized reaction conditions to achieve the desired chiral 1,1-diaryl products containing both a pyridine and a cis-crotyl group. Mechanistic studies and DFT calculations revealed that the 1,2-hydrocupration step is enantio-determining, and the concerted nucleophilic aromatic substitution proceeds via six-membered cyclic transition states.
Conflict of Interests
The authors declare no conflict of interest.
Open Research
Data Availability Statement
The data that support the findings of this study are available from the corresponding author upon reasonable request.
Supporting Information
As a service to our authors and readers, this journal provides supporting information supplied by the authors. Such materials are peer reviewed and may be re-organized for online delivery, but are not copy-edited or typeset. Technical support issues arising from supporting information (other than missing files) should be addressed to the authors.
| Filename | Description |
|---|---|
| ange202420918-sup-0001-misc_information.pdf13 MB | Supporting Information |
Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
References
- 1For relevant reviews:
- 1aE. Vitaku, D. T. Smith, J. T. Njardarson, J. Med. Chem. 2014, 57, 10257–10274;
- 1bD. Amen, T. J. Snape, MedChemComm 2013, 4, 893–907.
- 2For selected examples:
- 2aD. B. Horne, K. Biswas, J. Brown, M. D. Bartberger, J. Clarine, C. D. Davis, V. K. Gore, S. Harried, M. Horner, M. R. Kaller, S. G. Lehto, Q. Liu, V. V. Ma, H. Monenschein, T. T. Nguyen, C. Yuan, B. D. Youngblood, M. Zhang, W. Zhong, J. R. Allen, J. J. Chen, N. R. Gavva, J. Med. Chem. 2018, 61, 8186–8201;
- 2bW. J. Moree, B. F. Li, F. Jovic, T. Coon, J. Yu, R. S. Gross, F. Tucci, D. Marinkovic, S. Zamani-Kord, S. Malany, M. J. Bradbury, L. M. Hernandez, Z. O'Brien, J. Wen, H. Wang, S. R. Hoare, R. E. Petroski, A. Sacaan, A. Madan, P. D. Crowe, G. Beaton, J. Med. Chem. 2009, 52, 5307–5310.
- 3For selected examples of functionalization π-unsaturated compound with pyridine:
- 3aZ. Liu, Z.-J. Shi, L. Liu, M. Zhang, M.-C. Zhang, H.-Y. Guo, X.-C. Wang, J. Am. Chem. Soc. 2023, 145, 11789–11797;
- 3bW. Ding, M. Li, J. Fan, X. Cheng, Nat. Commun. 2022, 13, 5642;
- 3cH. Choi, G. R. Mathi, S. Hong, S. Hong, Nat. Commun. 2022, 13, 1776;
- 3dJ.-B. Ma, X. Zhao, D. Zhang, S.-L. Shi, J. Am. Chem. Soc. 2022, 144, 13643–13651;
- 3eM. W. Gribble, R. Y. Liu, S. L. Buchwald, J. Am. Chem. Soc. 2020, 142, 11252–11269;
- 3fD. Zhang, S. Dong, Q. He, Y. Luo, Y. Liu, X. Liu, X. Feng, Chem. Commun. 2020, 56, 12757;
- 3gA. Kundu, M. Inoue, H. Nagae, H. Tsurugi, K. Mashima, J. Am. Chem. Soc. 2018, 140, 7332–7342;
- 3hG. Song, W. W. N. O., Z. Hou, J. Am. Chem. Soc. 2014, 136, 12209–12212.
- 4
- 4aS. D. Friis, M. T. Pirnot, L. N. Dupuis, S. L. Buchwald, Angew. Chem. Int. Ed. 2017, 56, 7242–7246;
- 4bS. D. Friis, M. T. Pirnot, S. L. Buchwald, J. Am. Chem. Soc. 2016, 138, 8372–8375.
- 5S. Yu, H. L. Sang, S. Ge, Angew. Chem. Int. Ed. 2017, 56, 15896–15900.
- 6For selected reviews and examples:
- 6aA. M. Canfield, D. Rodina, S. M. Paradine, Angew. Chem. Int. Ed. 2024, 63, e202401550;
- 6bG. J. P. Perry, T. Jia, D. J. Procter, ACS Catal. 2020, 10, 1485–1499;
- 6cW.-S. Zhang, D.-W. Ji, Y. Li, X.-X. Zhang, Y.-K. Mei, B.-Z. Chen, Q.-A. Chen, Nat. Commun. 2023, 14, 651;
- 6dL. Cheng, M.-M. Li, M.-L. Li, L.-J. Xiao, J.-H. Xie, Q.-L. Zhou, CCS Chem. 2022, 4, 2612–2619;
- 6eA. Y. Jiu, H. S. Slocumb, C. S. Yeung, X.-H. Yang, V. M. Dong, Angew. Chem. Int. Ed. 2021, 60, 19660–19664;
- 6fS. R. Sardini, M. K. Brown, J. Am. Chem. Soc. 2017, 139, 9823–9826;
- 6gJ. S. Marcum, C. C. Roberts, R. S. Manan, T. N. Cervarich, S. J. Meek, J. Am. Chem. Soc. 2017, 139, 15580–15583.
- 7K. B. Smith, Y. Huang, M. K. Brown, Angew. Chem. Int. Ed. 2018, 57, 6146–6149.
- 8J.-F. Li, H.-R. Wang, T. Zhang, Y. Li, G. Huang, M. Ye, J. Am. Chem. Soc. 2022, 144, 18810–18816.
- 9Buchwald and co-workers have reported the Cu-catalyzed 1,4-hydroarylation of benzimidazoles to 1,3-dienes (ref 9b). However, the ligands Ph-BPE and DTBM-Segphos employed in this study exhibited poor diastereoselectivity and enantioselectivity in the hydropyridylation process; J. L. Knippel, Y. Ye, S. L. Buchwald, Org. Lett. 2021, 23, 2153–2157.
- 10
- 10aJ. Lu, I. Paci, D. C. Leitch, Chem. Sci. 2022, 13, 12681;
- 10bK. Watanabe, M. Takeda, K. Nagao, H. Ohmiya, Eur. J. Org. Chem. 2022, 8, e202200005;
- 10cC. Liao, J. Li, X. Chen, J. Lu, Q. Liu, L. Chen, Y. Huang, Y. Li, Org. Biomol. Chem. 2020, 18, 1185;
- 10dE. E. Kwan, Y. Zeng, H. A. Besser, E. N. Jacobsen, Nat. Chem. 2018, 10, 917–923.
- 11Deposition Numbers 2354869 (for 4 o) contains the supplementary crystallographic data for this paper. These data are provided free of charge by the joint Cambridge Crystallographic Data Centre and Fachinformationszentrum Karlsruhe Access Structures service.
- 12
- 12aC. Li, R. Y. Liu, L. T. Jesikiewicz, Y. Yang, P. Liu, S. L. Buchwald, J. Am. Chem. Soc. 2019, 141, 5062–5070;
- 12bC. Li, K. Shing, R. Y. Liu, S. L. Buchwald, Angew. Chem. Int. Ed. 2019, 58, 17074–17080;
- 12cX.-W. Chen, L. Zhu, Y.-Y. Gui, K. Jing, Y.-X. Jiang, Z.-Y. Bo, Y. Lan, D.-G. Yu, J. Am. Chem. Soc. 2019, 141, 18825–18835.
- 13
- 13aY. Wang, J. Yin, Y. Li, X. Yuan, T. Xiong, Q. Zhang, ACS Catal. 2022, 12, 9611–9620;
- 13bJ. S. Bandar, M. T. Pirnot, S. L. Buchwald, J. Am. Chem. Soc. 2015, 137, 14812–14818;
- 13cS. Tobisch, Chem. Eur. J. 2016, 22, 8290–8300.
- 14
- 14aQ. Li, X. Jiao, M. Xing, P. Zhang, Q. Zhao, C. Zhang, Chem. Commun. 2019, 55, 8651;
- 14bK. Semba, T. Fujihara, T. Xu, J. Terao, Y. Tsuji, Adv. Synth. Catal. 2012, 345, 1542–1550.
- 15Y. Xi, J. F. Hartwig, J. Am. Chem. Soc. 2017, 139, 12758–12772.
This is the
German version
of Angewandte Chemie.
Note for articles published since 1962:
Do not cite this version alone.
Take me to the International Edition version with citable page numbers, DOI, and citation export.
We apologize for the inconvenience.
