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Nitrene-mediated intermolecular N–N coupling for efficient synthesis of hydrazides

Nature Chemistry volume 13, pages 378–385 (2021)Cite this article

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Abstract

N–N linkages are found in many natural compounds and endow fascinating structural and functional properties. In comparison to the myriad methods for the construction of C–N bonds, chemistry for N–N coupling, especially in an intermolecular fashion, remains underdeveloped. Here, we report a nitrene-mediated intermolecular N–N coupling of dioxazolones and arylamines under iridium or iron catalysis. These reactions offer a simple and efficient method for the synthesis of various hydrazides from readily available carboxylic acid and amine precursors. Although the Ir-catalysed conditions usually give higher N–N coupling yield than the Fe-catalysed conditions, the reactions of sterically more demanding dioxazolones derived from α-substituted carboxylic acids work much better under the Fe-catalysed conditions. Mechanistic studies revealed that the nitrogen atom of Ir acyl nitrene intermediates has strong electrophilicity and can undergo nucleophilic attack with arylamines with the assistance of Cl···HN hydrogen bonding to form the N–N bond with high efficiency and chemoselectivity.

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Fig. 1: Occurrence and synthesis of N–N-containing compounds.
Fig. 2: Formation and selected transformation of hydrazide 24.
Fig. 3: Mechanistic studies with control experiments.
Fig. 4: Computational studies of the reaction mechanism.

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Data availability

The X-ray crystallographic data for compounds 10c and [Ir]-TolNH2 have been deposited in the Cambridge Crystallographic Data Centre with CCDC nos. 1952123 and 1956819, respectively, and can be obtained free of charge from the CCDC via www.ccdc.cam.ac.uk/getstructures. All other data supporting the findings of this study are available within the Article and its Supplementary Information.

References

  1. Hili, R. & Yudin, A. K. Making carbon–nitrogen bonds in biological and chemical synthesis. Nat. Chem. Biol. 2, 284–287 (2006).

    Article  CAS  PubMed  Google Scholar 

  2. Ricci, A. Amino Group Chemistry: from Synthesis to the Life Sciences (Wiley, 2008).

  3. Blair, L. M. & Sperry, J. Natural products containing a nitrogen–nitrogen bond. J. Nat. Prod. 76, 794–812 (2013).

    Article  CAS  PubMed  Google Scholar 

  4. Waldman, A. J., Ng, T. L., Wang, P. & Balskus, E. P. Heteroatom–heteroatom bond formation in natural product biosynthesis. Chem. Rev. 117, 5784–5863 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Ragnarsson, U. Synthetic methodology for alkyl substituted hydrazines. Chem. Soc. Rev. 30, 205–213 (2001).

    Article  CAS  Google Scholar 

  6. Guo, Q. H. & Lu, Z. Recent advances in nitrogen–nitrogen bond formation. Synthesis 49, 3835–3847 (2017).

    Article  CAS  Google Scholar 

  7. Wolter, M., Klapars, A. & Buchwald, S. L. Synthesis of N-aryl hydrazides by copper-catalyzed coupling of hydrazides with aryl iodides. Org. Lett. 3, 3803–3805 (2001).

    Article  CAS  PubMed  Google Scholar 

  8. Evans, D. A. & Johnson, D. S. Catalytic enantioselective amination of enolsilanes using C2-symmetric copper(ii) complexes as chiral Lewis acids. Org. Lett. 1, 595–598 (1999).

    Article  CAS  PubMed  Google Scholar 

  9. Vidal, J., Hannachi, J. C., Hourdin, G., Mulatier, J. C. & Collet, A. N-Boc-3-trichloromethyloxaziridine: a new, powerful reagent for electrophilic amination. Tetrahedron Lett. 39, 8845–8848 (1998).

    Article  CAS  Google Scholar 

  10. Rosen, B. R., Werner, E. W., O’Brien, A. G. & Baran, P. S. Total synthesis of dixiamycin B by electrochemical oxidation. J. Am. Chem. Soc. 136, 5571–5574 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Ryan, M. C., Martinelli, J. R. & Stahl, S. S. Cu-catalyzed aerobic oxidative N–N coupling of carbazoles and diarylamines including selective cross-coupling. J. Am. Chem. Soc. 140, 9074–9077 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Ryan, M. C. et al. Mechanistic insights into copper-catalyzed aerobic oxidative coupling of N–N bonds. Chem. Sci. 11, 1170–1175 (2020).

    Article  CAS  Google Scholar 

  13. Stokes, B. J., Vogel, C. V., Urnezis, L. K., Pan, M. & Driver, T. G. Intramolecular Fe(ii)-catalyzed N–O or N–N bond formation from aryl azides. Org. Lett. 12, 2884–2887 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Neumann, J. J., Suri, M. & Glorius, F. Efficient synthesis of pyrazoles: oxidative C–C/N–N bond-formation cascade. Angew. Chem. Int. Ed. 49, 7790–7794 (2010).

    Article  CAS  Google Scholar 

  15. Zhang, Y. et al. Fe(iii)-catalyzed aerobic intramolecular N–N coupling of aliphatic azides with amines. Org. Lett. 21, 4960–4965 (2019).

    Article  CAS  PubMed  Google Scholar 

  16. Diccianni, J. B., Hu, C. H. & Diao, T. N. N–N bond forming reductive elimination via a mixed-valent nickel(ii)–nickel(iii) intermediate. Angew. Chem. Int. Ed. 55, 7534–7538 (2016).

    Article  CAS  Google Scholar 

  17. Maestre, L. et al. Functional-group-tolerant, silver-catalyzed N–N bond formation by nitrene transfer to amines. J. Am. Chem. Soc. 139, 2216–2223 (2017).

    Article  CAS  PubMed  Google Scholar 

  18. Li, J. et al. Erratum: Simultaneous structure–activity studies and arming of natural products by C–H amination reveal cellular targets of eupalmerin acetate. Nat. Chem. 5, 634–634 (2013).

    Article  Google Scholar 

  19. Kono, M., Harada, S. & Nemoto, T. Chemoselective intramolecular formal insertion reaction of Rh-nitrenes into an amide bond over C–H insertion. Chem. Eur. J. 25, 3119–3124 (2019).

    CAS  PubMed  Google Scholar 

  20. Dehghany, M., Eshon, J., Roberts, J. M. & Schomaker, J. M. in Silver Catalysis in Organic Synthesis (eds Li, C. J. & Bi, X. H.) Ch. 8, 439–532 (Wiley, 2019).

  21. Lang, K., Torker, S., Wojtas, L. & Zhang, X. P. Asymmetric induction and enantiodivergence in catalytic radical C–H amination via enantiodifferentiative H-atom abstraction and stereoretentive radical substitution. J. Am. Chem. Soc. 141, 12388–12396 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Ju, M. et al. Tunable catalyst-controlled syntheses of β- and γ-amino alcohols enabled by silver-catalysed nitrene transfer. Nat. Catal. 2, 899–908 (2019).

    Article  CAS  Google Scholar 

  23. Davies, H. M. L. & Manning, J. R. Catalytic C–H functionalization by metal carbenoid and nitrenoid insertion. Nature 451, 417–424 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Park, Y., Heo, J., Baik, M.-H. & Chang, S. Why is the Ir(iii)-mediated amido transfer much faster than the Rh(iii)-mediated reaction? A combined experimental and computational study. J. Am. Chem. Soc. 138, 14020–14029 (2016).

    Article  CAS  PubMed  Google Scholar 

  25. Park, Y., Kim, Y. & Chang, S. Transition metal-catalyzed C–H amination: scope, mechanism and applications. Chem. Rev. 117, 9247–9301 (2017).

    Article  CAS  PubMed  Google Scholar 

  26. Hong, S. Y. et al. Selective formation of γ-lactams via C–H amidation enabled by tailored iridium catalysts. Science 359, 1016–1021 (2018).

    Article  CAS  PubMed  Google Scholar 

  27. Park, Y., Park, K. T., Kim, J. G. & Chang, S. Mechanistic studies on the Rh(iii)-mediated amido transfer process leading to robust C–H amination with a new type of amidating reagent. J. Am. Chem. Soc. 137, 4534–4542 (2015).

    Article  CAS  PubMed  Google Scholar 

  28. Dequirez, G., Pons, V. & Dauban, P. Nitrene chemistry in organic synthesis: still in its infancy? Angew. Chem. Int. Ed. 51, 7384–7395 (2012).

    Article  CAS  Google Scholar 

  29. Shimbayashi, T., Sasakura, K., Eguchi, A., Okamoto, K. & Ohe, K. Recent progress on cyclic nitrenoid precursors in transition-metal-catalyzed nitrene-transfer reactions. Chem. Eur. J. 25, 3156–3180 (2019).

    CAS  PubMed  Google Scholar 

  30. van Vliet, K. M. & de Bruin, B. Dioxazolones: stable substrates for the catalytic transfer of acyl nitrenes. ACS Catal. 10, 4751–4769 (2020).

    Article  Google Scholar 

  31. Sauer, J. & Mayer, K. K. Thermolyse und photolyse von 3-subtituierten Δ2-1.4.2-dioxazolinonen-(5), Δ2-1.4.2-dioxazolin-thionen-(5) und 4-substituierten Δ3-1.2.5.3-thiadioxazolin-s-oxiden. Tetrahedron Lett. 9, 319–324 (1968).

    Article  Google Scholar 

  32. Bizet, V., Buglioni, L. & Bolm, C. Light-induced ruthenium-catalyzed nitrene transfer reactions: a photochemical approach towards N-acyl sulfimides and sulfoximines. Angew. Chem. Int. Ed. 53, 5639–5642 (2014).

    Article  CAS  Google Scholar 

  33. Lebel, H., Piras, H. & Bartholomeus, J. Rhodium-catalyzed stereoselective amination of thioethers with N-mesyloxycarbamates: DMAP and bis(DMAP)CH2Cl2 as key additives. Angew. Chem. Int. Ed. 53, 7300–7304 (2014).

    Article  CAS  Google Scholar 

  34. van Vliet, K. M. et al. Efficient copper-catalyzed multicomponent synthesis of N-acyl amidines via acyl nitrenes. J. Am. Chem. Soc. 141, 15240–15249 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  35. Park, Y. & Chang, S. Asymmetric formation of γ-lactams via C–H amidation enabled by chiral hydrogen-bond-donor catalysts. Nat. Catal. 2, 219–227 (2019).

    Article  CAS  Google Scholar 

  36. Wang, H. et al. Iridium-catalyzed enantioselective C(sp3)–H amidation controlled by attractive noncovalent interactions. J. Am. Chem. Soc. 141, 7194–7201 (2019).

    Article  CAS  PubMed  Google Scholar 

  37. Xing, Q., Chan, C. M., Yeung, Y. W. & Yu, W. Y. Ruthenium(ii)-catalyzed enantioselective γ-lactams formation by intramolecular C–H amidation of 1,4,2-dioxazol-5-ones. J. Am. Chem. Soc. 141, 3849–3853 (2019).

    Article  CAS  PubMed  Google Scholar 

  38. Roizen, J. L., Harvey, M. E. & Du Bois, J. Metal-catalyzed nitrogen-atom transfer methods for the oxidation of aliphatic C–H bonds. Acc. Chem. Res. 45, 911–922 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Wang, H., Tang, G. & Li, X. Rhodium(iii)-catalyzed amidation of unactivated C(sp3)–H bonds. Angew. Chem. Int. Ed. 54, 13049–13052 (2015).

    Article  CAS  Google Scholar 

  40. Mei, R., Loup, J. & Ackermann, L. Oxazolinyl-assisted C–H amidation by cobalt(iii) catalysis. ACS Catal. 6, 793–797 (2016).

    Article  CAS  Google Scholar 

  41. Lei, H. & Rovis, T. Ir-catalyzed intermolecular branch-selective allylic C–H amidation of unactivated terminal olefins. J. Am. Chem. Soc. 141, 2268–2273 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Knecht, T., Mondal, S., Ye, J. H., Das, M. & Glorius, F. Intermolecular, branch-selective, and redox-neutral Cp*Ir(iii)-catalyzed allylic C–H amidation. Angew. Chem. Int. Ed. 58, 7117–7121 (2019).

    Article  CAS  Google Scholar 

  43. Scamp, R. J., deRamon, E., Paulson, E. K., Miller, S. J. & Ellman, J. A. Co(iii)-catalyzed C–H amidation of dehydroalanine for the site-selective structural diversification of thiostrepton. Angew. Chem. Int. Ed. 59, 890–895 (2020).

    Article  CAS  Google Scholar 

  44. Zhou, Z. et al. Non-C2-symmetric chiral-at-ruthenium catalyst for highly efficient enantioselective intramolecular C(sp3)–H amidation. J. Am. Chem. Soc. 141, 19048–19057 (2019).

    Article  CAS  PubMed  Google Scholar 

  45. Burman, J. S., Harris, R. J., B. Farr, C. M., Bacsa, J. & Blakey, S. B. Rh(iii) and Ir(iii)Cp* complexes provide complementary regioselectivity profiles in intermolecular allylic C–H amidation reactions. ACS Catal. 9, 5474–5479 (2019).

    Article  CAS  Google Scholar 

  46. Tan, P. W., Mak, A. M., Sullivan, M. B., Dixon, D. J. & Seayad, J. Thioamide-directed cobalt(iii)-catalyzed selective amidation of C(sp3)−H bonds. Angew. Chem. Int. Ed. 56, 16550–16554 (2017).

    Article  CAS  Google Scholar 

  47. Fukagawa, S., Kojima, M., Yoshino, T. & Matsunaga, S. Catalytic enantioselective methylene C(sp3)–H amidation of 8-alkylquinolines using a Cp*Rhiii/chiral carboxylic acid system. Angew. Chem. Int. Ed. 58, 18154–18158 (2019).

    Article  CAS  Google Scholar 

  48. Dube, P. et al. Carbonyldiimidazole-mediated Lossen rearrangement. Org. Lett. 11, 5622–5625 (2009).

    Article  CAS  PubMed  Google Scholar 

  49. Legnani, L. & Morandi, B. Direct catalytic synthesis of unprotected 2-amino-1-phenylethanols from alkenes by using iron(ii) phthalocyanine. Angew. Chem. Int. Ed. 55, 2248–2251 (2016).

    Article  CAS  Google Scholar 

  50. Liu, G.-S., Zhang, Y.-Q., Yuan, Y.-A. & Xu, H. Iron(ii)-catalyzed intramolecular aminohydroxylation of olefins with functionalized hydroxylamines. J. Am. Chem. Soc. 135, 3343–3346 (2013).

    Article  CAS  PubMed  Google Scholar 

  51. Zhang, Y.-Q., Yuan, Y.-A., Liu, G.-S. & Xu, H. Iron(ii)-catalyzed asymmetric intramolecular aminohydroxylation of indoles. Org. Lett. 15, 3910–3913 (2013).

    Article  CAS  PubMed  Google Scholar 

  52. Zhang, Y. et al. Fe(iii)-catalyzed aerobic intramolecular N−N coupling of aliphatic azides with amines. Org. Lett. 21, 4960–4965 (2019).

    Article  CAS  PubMed  Google Scholar 

  53. Yu, H., Li, Z. & Bolm, C. Three-dimensional heterocycles by iron-catalyzed ring-closing sulfoxide imidation. Angew. Chem. Int. Ed. 57, 12053–12056 (2018).

    Article  CAS  Google Scholar 

  54. Yao, J., Feng, R., Lin, C., Liu, Z. & Zhang, Y. Synthesis of 2,3-dihydro-1H-indazoles by Rh(iii)-catalyzed C–H cleavage of arylhydrazines. Org. Biomol. Chem. 12, 5469–5476 (2014).

    Article  CAS  PubMed  Google Scholar 

  55. Han, S. et al. Rh(iii)-catalyzed oxidative coupling of 1,2-disubstituted arylhydrazines and olefins: a new strategy for 2,3-dihydro-1H-indazoles. Org. Lett. 16, 2494–2497 (2014).

    Article  CAS  PubMed  Google Scholar 

  56. Zhan, F. & Liang, G. Formation of enehydrazine intermediates through coupling of phenylhydrazines with vinyl halides: entry into the Fischer indole synthesis. Angew. Chem. Int. Ed. 52, 1266–1269 (2013).

    Article  CAS  Google Scholar 

  57. Patureau, F. W. & Glorius, F. Oxidizing directing groups enable efficient and innovative C–H activation reactions. Angew. Chem. Int. Ed. 50, 1977–1979 (2011).

    Article  CAS  Google Scholar 

  58. Lu, T. & Chen, F. Multiwfn: a multifunctional wavefunction analyzer. J. Comput. Chem. 33, 580–592 (2012).

    Article  PubMed  Google Scholar 

  59. Rummelt, S. M., Radkowski, K., Rosca, D. A. & Furstner, A. Interligand interactions dictate the regioselectivity of trans-hydrometalations and related reactions catalyzed by [Cp*RuCl]. hydrogen bonding to a chloride ligand as a steering principle in catalysis. J. Am. Chem. Soc. 137, 5506–5519 (2015).

    Article  CAS  PubMed  Google Scholar 

  60. Kuijpers, P. F., van der Vlugt, J. I., Schneider, S. & de Bruin, B. Nitrene radical intermediates in catalytic synthesis. Chem. Eur. J. 23, 13819–13829 (2017).

    Article  CAS  PubMed  Google Scholar 

  61. Hennessy, E. T. & Betley, T. A. Complex N-heterocycle synthesis via iron-catalyzed, direct C–H bond amination. Science 340, 591–595 (2013).

    Article  CAS  PubMed  Google Scholar 

  62. Shing, K.-P. et al. N-heterocyclic carbene iron(iii) porphyrin-catalyzed intramolecular C(sp3)–H amination of alkyl azides. Angew. Chem. Int. Ed. 57, 11947–11951 (2018).

    Article  CAS  Google Scholar 

  63. Wang, P. & Deng, L. Recent advances in iron-catalyzed C–H bond amination via iron imido intermediate. Chin. J. Chem. 36, 1222–1240 (2018).

    Article  CAS  Google Scholar 

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Acknowledgements

G.C. acknowledges financial support from grants NSFC-21725204, NSFC-21672105, NSFC-21421062, NSFC-21901127 and NCC2020FH02, the China Postdoctoral Science Foundation (2018M640225, 2019T120179) and Laviana Pharma for the experimental part of this work. S.C. thanks the Institute for Basic Science (IBS-R010-D1) in the Republic of Korea for financial support.

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Authors and Affiliations

  1. State Key Laboratory and Institute of Elemento-Organic Chemistry, College of Chemistry, Nankai University, Tianjin, China

    Hao Wang, Fangfang Song, Shiyang Zhu, Ziqian Bai, Danye Chen, Gang He & Gong Chen

  2. Department of Chemistry, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea

    Hoimin Jung & Sukbok Chang

  3. Center for Catalytic Hydrocarbon Functionalizations, Institute for Basic Science (IBS), Daejeon, Republic of Korea

    Hoimin Jung & Sukbok Chang

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Contributions

H.W. formulated the initial ideas for this work, carried out most of the reaction optimization and structural determination of products studies, and prepared the Supplementary Information. F.S. helped with the development of reaction conditions and expansion of substrate scope. S.Z., Z.B. and D.C. helped with expanding the substrate scope. H.J. and H.W. conducted the computational studies and prepared part of the manuscript and Supplementary Information. S.C. supervised the computational studies and edited the manuscript. G.H. supervised experimental studies. G.C. supervised the project, coordinated with S.C. on computational studies, and prepared most of the manuscript.

Corresponding authors

Correspondence to Sukbok Chang or Gong Chen.

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The authors declare no competing interests.

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Peer review information Nature Chemistry thanks the anonymous reviewers for their contribution to the peer review of this work.

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Supplementary information

Supplementary Information

Supplementary Figs. 1–25 and Tables 1–19. Detailed synthetic procedures, compound characterization, NMR spectra, X-ray crystallographic data and computational details.

Supplementary Data 1

The single point energy output files.

Supplementary Data 1

Crystallographic data for compound 10c. CCDC reference 1952123.

Supplementary Data 2

Crystallographic data for compound [Ir]-TolNH2. CCDC reference 1956819.

Supplementary Data 1

Structure factors file for compound [Ir]-TolNH2. CCDC reference 1956819.

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Wang, H., Jung, H., Song, F. et al. Nitrene-mediated intermolecular N–N coupling for efficient synthesis of hydrazides. Nat. Chem. 13, 378–385 (2021). https://doi.org/10.1038/s41557-021-00650-0

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