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A ring expansion strategy towards diverse azaheterocycles

Abstract

The development of innovative strategies for the synthesis of N-heterocyclic compounds is an important topic in organic synthesis. Ring expansion methods to form large N-heterocycles often involve the cycloaddition of strained aza rings with π bonds. However, in some cases such strategies suffer from some limitations owing to the difficulties in controlling the regioselectivity and the accessibility of specific π-bond synthons. Here, we report the development of a general ring expansion strategy that involves a formal cross-dimerization between three-membered aza heterocycles and three- and four-membered-ring ketones through synergistic bimetallic catalysis. These formal cross-dimerizations of two different strained rings are efficient and scalable, and provide a straightforward and broadly applicable means of assembling diverse N-heterocycles, such as 3-benzazepinones, dihydropyridinones and uracils, which are versatile units in numerous drugs and biologically active compounds. Preliminary mechanistic studies revealed that the C–C bond of strained ring ketones is first cleaved by the Pd0 species during the reaction.

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Fig. 1: Examples of important N-heterocycles and our reaction design.
Fig. 2: Synthetic applications.
Fig. 3: Mechanistic studies.
Fig. 4: DFT calculations.

Data availability

All the data generated or analysed during this study are included in this article and its Supplementary Information. Crystallographic data have been deposited at the Cambridge Crystallographic Data Centre (CCDC) as CCDC 2008377 (3aa), 2008376 (5sa), 2008375 (7a) and 2010994 ((R)-8a) and can be obtained free of charge from the CCDC via www.ccdc.cam.ac.uk/getstructures.

References

  1. 1.

    Vitaku, E., Smith, D. T. & Njardarson, J. T. Analysis of the structural diversity, substitution patterns, and frequency of nitrogen heterocycles among US FDA approved pharmaceuticals. J. Med. Chem. 57, 10257–10274 (2014).

    CAS  Article  Google Scholar 

  2. 2.

    Taylor, R. D., MacCoss, M. & Lawson, A. D. Rings in drugs. J. Med. Chem. 57, 5845–5859 (2014).

    CAS  PubMed  Article  Google Scholar 

  3. 3.

    Royer J. Asymmetric Synthesis of Nitrogen Heterocycles (Wiley-VCH, 2009).

  4. 4.

    Eicher, T., Hauptmann, S. & Speicher, A. The Chemistry of Heterocycles: Structures, Reactions, Synthesis, and Applications (Wiley-VCH, 2012).

  5. 5.

    Wu, X.-F. Transition Metal-Catalyzed Heterocycle Synthesis via C–H Activation (Wiley-VCH, 2015).

  6. 6.

    D’hooghe, M. & Ha, H.-J. Synthesis of 4- to 7-Membered Heterocycles by Ring Expansion (Springer, 2016).

  7. 7.

    Mack, D. J. & Njardarson, J. T. Recent advances in the metal-catalyzed ring expansions of three- and four-membered rings. ACS Catal. 3, 272–286 (2013).

    CAS  Article  Google Scholar 

  8. 8.

    Chen, P.-h, Billett, B. A., Tsukamoto, T. & Dong, G. ‘Cut and sew’ transformations via transition-metal-catalyzed carbon−carbon bond activation. ACS Catal. 7, 1340–1360 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  9. 9.

    Huang, C.-Y. & Doyle, A. G. The chemistry of transition metals with three-membered ring heterocycles. Chem. Rev. 114, 8153–8198 (2014).

    CAS  PubMed  Article  Google Scholar 

  10. 10.

    Fumagalli, G., Stanton, S. & Bower, J. F. Recent methodologies that exploit C−C single-bond cleavage of strained ring systems by transition metal complexes. Chem. Rev. 117, 9404–9432 (2017).

    CAS  PubMed  Article  Google Scholar 

  11. 11.

    Wang, F., Yu, S. & Li, X. Transition metal-catalysed couplings between arenes and strained or reactive rings: combination of C–H activation and ring scission. Chem. Soc. Rev. 45, 6462–6477 (2016).

    CAS  PubMed  Article  Google Scholar 

  12. 12.

    Garayalde, D. & Nevado, C. Synthetic applications of gold-catalyzed ring expansions. Beilstein J. Org. Chem. 7, 767–780 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  13. 13.

    Wu, X. & Zhu, C. Recent advances in ring-opening functionalization of cycloalkanols by C–C σ-bond cleavage. Chem. Rec. 18, 587–598 (2018).

    CAS  PubMed  Article  Google Scholar 

  14. 14.

    Murakami, M. & Ishida, N. Cleavage of carbon−carbon σ-bonds of four-membered rings. Chem. Rev. 121, 264–299 (2021).

    CAS  PubMed  Article  Google Scholar 

  15. 15.

    Takeda, Y., Sameera, W. M. C. & Minakata, S. Palladium-catalyzed regioselective and stereospecific ring-opening cross-coupling of aziridines: experimental and computational studies. Acc. Chem. Res. 53, 1686–1702 (2020).

    CAS  PubMed  Article  Google Scholar 

  16. 16.

    Singh, S. et al. Recent advances in anticancer chemotherapeutics based upon azepine scaffold. Anticancer Agents Med. Chem 16, 539–557 (2016).

    CAS  PubMed  Article  Google Scholar 

  17. 17.

    Smith, B. M. et al. Discovery and structure−activity relationship of (1R)-8-chloro-2,3,4,5-tetrahydro-1-methyl-1H-3-benzazepine (lorcaserin), a selective serotonin 5-HT2C receptor agonist for the treatment of obesity. J. Med. Chem. 51, 305–313 (2008).

    CAS  PubMed  Article  Google Scholar 

  18. 18.

    Ladd, D. L. et al. Synthesis and dopaminergic binding of 2-aryldopamine analogs: phenethylamines, 3-benzazepines, and 9-(aminomethyl)fluorenes. J. Med. Chem. 29, 1904–1912 (1986).

    CAS  PubMed  Article  Google Scholar 

  19. 19.

    Tewes, B. et al. Design, synthesis, and biological evaluation of 3-benzazepin-1-ols as NR2B-selective NMDA receptor antagonists. ChemMedChem 5, 687–695 (2010).

    CAS  PubMed  Article  Google Scholar 

  20. 20.

    Tewes, B. et al. Crystal structure of (1S*,2R*)-7-benz­yloxy-2-methyl-3-tosyl-2,3,4,5-tetra­hydro-1H-3-benz­azepin-1-ol: elucidation of the relative configuration of potent allosteric GluN2B selective NMDA receptor antagonists. Bioorg. Med. Chem. 18, 8005–8015 (2010).

    CAS  PubMed  Article  Google Scholar 

  21. 21.

    Ishida, N., Ikemoto, W. & Murakami, M. Cleavage of C–C and C–Si σ-bonds and their intramolecular exchange. J. Am. Chem. Soc. 136, 5912–5915 (2014).

    CAS  PubMed  Article  Google Scholar 

  22. 22.

    Okumura, S., Sun, F., Ishida, N. & Murakami, M. Palladium-catalyzed intermolecular exchange between C–C and C–Si σ-bonds. J. Am. Chem. Soc. 139, 12414–12417 (2017).

    CAS  PubMed  Article  Google Scholar 

  23. 23.

    Zhao, W.-T., Gao, F. & Zhao, D. Intermolecular σ-bond cross-exchange reaction between cyclopropenones and (benzo)silacyclobutanes: straightforward access towards sila(benzo)cycloheptenones. Angew. Chem. Int. Ed. 57, 6329–6332 (2018).

    CAS  Article  Google Scholar 

  24. 24.

    Yudin, A. K. Aziridines and Epoxides in Organic Synthesis (Wiley-VCH, 2006).

  25. 25.

    Sabir, S., Kumar, G., Verma, V. P. & Jat, J. L. Aziridine ring opening: an overview of sustainable. ChemistrySelect 3, 3702–3711 (2018).

    CAS  Article  Google Scholar 

  26. 26.

    Dauth, A. & Love, J. A. Synthesis and reactivity of 2-azametallacyclobutanes. Dalton Trans. 41, 7782–7791 (2012).

    CAS  PubMed  Article  Google Scholar 

  27. 27.

    Lin, B. L., Clough, C. R. & Hillhouse, G. L. Interactions of aziridines with nickel complexes: oxidative-addition and reductive-elimination reactions that break and make C–N bonds. J. Am. Chem. Soc. 124, 2890–2891 (2002).

    CAS  PubMed  Article  Google Scholar 

  28. 28.

    Ney, J. E. & Wolfe, J. P. Synthesis and reactivity of azapalladacyclobutanes. J. Am. Chem. Soc. 128, 15415–15422 (2006).

    CAS  PubMed  Article  Google Scholar 

  29. 29.

    Duda, M. L. & Michael, F. E. Palladium-catalyzed cross-coupling of N-sulfonylaziridines with boronic acids. J. Am. Chem. Soc. 135, 18347–18349 (2013).

    CAS  PubMed  Article  Google Scholar 

  30. 30.

    Takeda, Y., Ikeda, Y., Kuroda, A., Tanaka, S. & Minakata, S. Pd/NHC-catalyzed enantiospecific and regioselective Suzuki−Miyaura arylation of 2-arylaziridines: synthesis of enantioenriched 2- arylphenethylamine derivatives. J. Am. Chem. Soc. 136, 8544–8547 (2014).

    CAS  PubMed  Article  Google Scholar 

  31. 31.

    Jensen, K. L., Standley, E. A. & Jamison, T. F. Highly regioselective nickel-catalyzed cross-coupling of N-tosylaziridines and alkylzinc reagents. J. Am. Chem. Soc. 136, 11145–11152 (2014).

    CAS  PubMed  Article  Google Scholar 

  32. 32.

    Nielsen, D. K., Huang, C.-Y. & Doyle, A. G. Directed nickel catalyzed Negishi cross-coupling of alkyl aziridines. J. Am. Chem. Soc. 135, 13605–13609 (2013).

    CAS  PubMed  Article  Google Scholar 

  33. 33.

    Takeda, Y., Kuroda, A., Sameera, W., Morokuma, K. & Minakata, S. Palladium-catalyzed regioselective and stereo-invertive ring-opening borylation of 2-arylaziridines with bis(pinacolato)diboron: experimental and computational studies. Chem. Sci. 7, 6141–6152 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  34. 34.

    Woods, B. P., Orlandi, M., Huang, C.-Y., Sigman, M. S. & Doyle, A. G. Nickel-catalyzed enantioselective reductive cross-coupling of styrenyl aziridines. J. Am. Chem. Soc. 139, 5688–5691 (2017).

    CAS  PubMed  Article  Google Scholar 

  35. 35.

    Cardoso, A. L. & Pinho e Melo, M. V. D. Aziridines in formal [3+2] cycloadditions: synthesis of five-membered heterocycles. Eur. J. Org. Chem. 2012, 6479–6501 (2012).

    CAS  Article  Google Scholar 

  36. 36.

    Singh, G. S., D’hooghe, M. & De Kimpe, N. Synthesis and reactivity of C-heteroatom-substituted aziridines. Chem. Rev. 107, 2080–2135 (2007).

    CAS  PubMed  Article  Google Scholar 

  37. 37.

    Murakami, M. & Matsuda, T. Metal-catalysed cleavage of carbon–carbon bonds. Chem. Commun. 47, 1100–1105 (2011).

    CAS  Article  Google Scholar 

  38. 38.

    Flores-Gaspar, A. & Martin, R. Recent advances in the synthesis and application of benzocyclobutenones and related compounds. Synthesis 45, 0563–0580 (2013).

    CAS  Article  Google Scholar 

  39. 39.

    Murakami, M. & Chatani, N. Cleavage of Carbon–Carbon Single Bonds by Transition Metals (Wiley-VCH, 2015).

  40. 40.

    Murakami, M., Amii, H. & Ito, Y. Selective activation of carbon–carbon bonds next to a carbonyl. Nature 370, 540–541 (1994).

    CAS  Article  Google Scholar 

  41. 41.

    Bender, M., Turnbull, B. W. H., Ambler, B. R. & Krische, M. J. Ruthenium-catalyzed insertion of adjacent diol carbon atoms into C–C bonds: entry to type II polyketides. Science 357, 779–781 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  42. 42.

    Deng, L., Chen, M. & Dong, G. Concise synthesis of (−)-cycloclavine and (−)-5-epi-cycloclavine via asymmetric C−C activation. J. Am. Chem. Soc. 140, 9652–9658 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  43. 43.

    Deng, L. & Dong, G. Carbon‒carbon bond activation of ketones. Trends Chem. 2, 183–198 (2020).

    CAS  Article  Google Scholar 

  44. 44.

    Bai, D., Yu, Y., Guo, H., Chang, J. & Li, X. Nickel(0)-catalyzed enantioselective [3+2] annulation of cyclopropenones and α,β-unsaturated ketones/imines. Angew. Chem. Int. Ed. 59, 2740–2744 (2020).

    CAS  Article  Google Scholar 

  45. 45.

    Busacca, C. A. & Johnson, R. E. Synthesis of novel tetrahydrobenzazepinones. Tetrahedron Lett. 33, 165–168 (1992).

    CAS  Article  Google Scholar 

  46. 46.

    Griebenow, N. et al. Identification and optimization of tetrahydro-2H-3-benzazepin-2-ones as squalene synthase inhibitors. Bioorg. Med. Chem. Lett. 21, 2554–2558 (2011).

    CAS  PubMed  Article  Google Scholar 

  47. 47.

    Ishibashi, H. et al. A convenient synthesis of 1,3,4,5-tetrahydro-2H-3-benzazepin-2-ones by acid-catalyzed cyclization of N-(2-arylethyl)-N-methyl-2-sulfinylacetamides. Chem. Pharm. Bull. 37, 939–943 (1989).

    CAS  Article  Google Scholar 

  48. 48.

    Cobb, J. E., Nanthakumar, S. S., Rutkowske, R. & Uehling, D. E. Functionalized 2,5-disubstituted benzazepines: stereoselective synthesis of 3-methyl-5-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine-2-carbonitrile and related derivatives. Synlett 2004, 1394–1398 (2004).

    Google Scholar 

  49. 49.

    Krull, O. & Wunsch, B. Synthesis and structure/NMDA receptor affinity relationships of 1-substituted tetrahydro-3-benzazepines. Bioorg. Med. Chem. 12, 1439–1451 (2004).

    CAS  PubMed  Article  Google Scholar 

  50. 50.

    Crecente-Campo, J., Vázquez-Tato, M. P. & Seijas, J. A. Direct syntheses of 4-aryl-1,2,3,4-tetrahydroisoquinolines and 1-aryl-2,3,4,5-tetrahydro-3-benzazepines via hydroamination of enol carbamates. Tetrahedron 65, 2655–2659 (2009).

    CAS  Article  Google Scholar 

  51. 51.

    Donets, P. A. & Van der Eycken, E. V. Efficient synthesis of the 3-benzazepine framework via intramolecular Heck reductive cyclization. Org. Lett. 9, 3017–3020 (2007).

    CAS  PubMed  Article  Google Scholar 

  52. 52.

    Becica, J. & Dobereiner, G. E. The roles of Lewis acidic additives in organotransition metal catalysis. Org. Biomol. Chem. 17, 2055–2069 (2019).

    CAS  PubMed  Article  Google Scholar 

  53. 53.

    Allen, A. E. & MacMillan, D. W. C. Synergistic catalysis: a powerful synthetic strategy for new reaction development. Chem. Sci. 3, 633–658 (2012).

    CAS  Article  Google Scholar 

  54. 54.

    Wang, C. & Xi, Z. Co-operative effect of Lewis acids with transition metals for organic synthesis. Chem. Soc. Rev. 36, 1395–1406 (2007).

    CAS  PubMed  Article  Google Scholar 

  55. 55.

    Lohr, T. L. & Marks, T. J. Orthogonal tandem catalysis. Nat. Chem. 7, 477–482 (2015).

    CAS  PubMed  Article  Google Scholar 

  56. 56.

    Guan, W., Zeng, G., Kameo, H., Nakao, Y. & Sakaki, S. Cooperative catalysis of combined systems of transition-metal complexes with Lewis acids: theoretical understanding. Chem. Rec. 16, 2405–2425 (2016).

    CAS  PubMed  Article  Google Scholar 

  57. 57.

    Komatsu, K. & Kitagawa, T. Cyclopropenylium cations, cyclopropenones, and heteroanalogues—recent advances. Chem. Rev. 103, 1371–1428 (2003).

    CAS  PubMed  Article  Google Scholar 

  58. 58.

    Nakamura, M., Isobe, H. & Nakamura, E. Cyclopropenone acetals—synthesis and reactions. Chem. Rev. 103, 1295–1326 (2003).

    CAS  PubMed  Article  Google Scholar 

  59. 59.

    Potts, K. T. & Baum, J. S. Chemistry of cyclopropenones. Chem. Rev. 74, 189–213 (1974).

    CAS  Article  Google Scholar 

  60. 60.

    Wender, P. A., Paxton, T. J. & Williams, T. J. Cyclopentadienone synthesis by rhodium(i)-catalyzed [3 + 2] cycloaddition reactions of cyclopropenones and alkynes. J. Am. Chem. Soc. 128, 14814–14815 (2006).

    CAS  PubMed  Article  Google Scholar 

  61. 61.

    Wang, X., Seidel, F. W. & Nozaki, K. Synthesis of polyethylene with in-chain α,β-unsaturated ketone and isolated ketone units: Pd-catalyzed ring-opening copolymerization of cyclopropenone with ethylene. Angew. Chem. Int. Ed. 58, 12955–12959 (2019).

    CAS  Article  Google Scholar 

  62. 62.

    Xie, F., Yu, S., Qi, Z. & Li, X. Nitrone directing groups in rhodium(iii)-catalyzed C−H activation of arenes: 1,3-dipoles versus traceless directing groups. Angew. Chem. Int. Ed. 55, 15351–15355 (2016).

    CAS  Article  Google Scholar 

  63. 63.

    Li, X., Han, C., Yao, H. & Lin, A. Organocatalyzed [3 + 2] annulation of cyclopropenones and β-ketoesters: an approach to substituted butenolides with a quaternary center. Org. Lett. 19, 778–781 (2017).

    CAS  PubMed  Article  Google Scholar 

  64. 64.

    Ren, J. et al. Ag(i)-catalyzed [3 + 2]-annulation of cyclopropenones and formamides via C–C bond cleavage. Org. Lett. 20, 6636–6639 (2018).

    CAS  PubMed  Article  Google Scholar 

  65. 65.

    Wallbaum, J., Jones, P. G. & Werz, D. B. Reacting cyclopropenones with arynes: access to spirocyclic xanthene−cyclopropene motifs. J. Org. Chem. 80, 3730–3734 (2015).

    CAS  PubMed  Article  Google Scholar 

  66. 66.

    Schuster-Haberhauer, A. et al. CpCo-mediated reactions of cyclopropenones: access to CpCo-capped benzoquinone complexes. Organometallics 27, 1361–1366 (2008).

    CAS  Article  Google Scholar 

  67. 67.

    Zhu, Y., Cornwall, R. G., Du, H., Zhao, B. & Shi, Y. Catalytic diamination of olefins via N−N bond activation. Acc. Chem. Res. 47, 3665–3678 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  68. 68.

    Chagarovskiy, A. O. et al. (3+3)-Annulation of donor–acceptor cyclopropanes with diaziridines. Angew. Chem. Int. Ed. 57, 10338–10342 (2018).

    CAS  Article  Google Scholar 

  69. 69.

    Kaiser, C. et al. Absolute stereochemistry and dopaminergic activity of enantiomers of 2,3,4,5-tetrahydro-7,8-dihydroxy-l-phenyl-l/f-3-benzazepine. J. Med. Chem. 25, 697–703 (1982).

    CAS  PubMed  Article  Google Scholar 

  70. 70.

    Huang, K.-C. et al. Rhodium-catalyzed asymmetric addition of arylboronic acids to β-nitroolefins: Formal synthesis of (S)-SKF 38393. Org. Lett. 15, 5730–5733 (2013).

    CAS  PubMed  Article  Google Scholar 

  71. 71.

    Dwivedi, S. D., Kumar, R., Patel, S. T. & Shah, A. P. C. Process for preparation of ivabradine hydrochloride. WO patent 2008065681 (2008).

  72. 72.

    Dwivedi, S. D. & Sharma, P. R. An improved process for the preparation of ivabradine hydrochloride and intermediates thereof. IN patent 2009MU01825 (2009).

  73. 73.

    Wang, M. et al. A new facile synthetic route to [11C]GSK189254, a selective PET radioligand for imaging of CNS histamine H3 receptor. Bioorg. Med. Chem. Lett. 22, 4713–4718 (2012).

    CAS  PubMed  Article  Google Scholar 

  74. 74.

    Fuwa, H. & Sasaki, M. An efficient method for the synthesis of enol ethers and enecarbamates. Total syntheses of isoindolobenzazepine alkaloids, lennoxamine and chilenine. Org. Biomol. Chem. 5, 1849–1853 (2007).

    CAS  PubMed  Article  Google Scholar 

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Acknowledgements

We are grateful for the financial support from the National Natural Science Foundation of China (22022103, 21871146 and 22071114), the National Key Research and Development Program of China (2019YFA0210500), the 1000-Talent Youth Program (020/BF180181), the Natural Science Foundation of Tianjin (18JCYBJC20400) and the Fundamental Research Funds for the Central Universities and Nankai University.

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Contributions

R.L., H.Z., C.-W.J. and Y.Q. performed the experiments. B.L. and X.-S.X. conducted the DFT calculations. D.Z. developed the concept, directed the project and wrote the paper. All the authors approved the final version of the manuscript.

Corresponding author

Correspondence to Dongbing Zhao.

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Peer review information Nature Chemistry thanks Matthew Grayson, Masahiro Murakami and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Supplementary information

Supplementary Information

Supplementary Tables 1–17, Figs. 1–14, methods, text, experiments, NMR, HPLC spectra and references.

1

Crystallographic data for compound 3aa. CCDC reference 2008377.

2

Crystallographic data for compound 5sa. CCDC reference 2008376.

3

Crystallographic data for compound 7a. CCDC reference 2008375.

4

Crystallographic data for compound (R)-8a. CCDC reference 2010994.

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Li, R., Li, B., Zhang, H. et al. A ring expansion strategy towards diverse azaheterocycles. Nat. Chem. (2021). https://doi.org/10.1038/s41557-021-00746-7

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