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Arenes participate in 1,3-dipolar cycloaddition with in situ-generated diazoalkenes

Nature Chemistry volume 15, pages 764–772 (2023)Cite this article

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Abstract

The venerable 1,3-dipolar cycloaddition has been widely used in organic synthesis for the construction of various heterocycles. However, in its century-long history, the simple and omnipresent aromatic phenyl ring has remained a stubbornly unreactive dipolarophile. Here we report 1,3-dipolar cycloaddition between aromatic groups and diazoalkenes, generated in situ from lithium acetylides and N-sulfonyl azides. The reaction results in densely functionalized annulated cyclic sulfonamide-indazoles that can be further converted into stable organic molecules that are important in organic synthesis. The involvement of aromatic groups in the 1,3-dipolar cycloadditions broadens the synthetic utility of diazoalkenes, a family of dipoles that have been little explored so far and are otherwise difficult to access. The process described here provides a route for the synthesis of medicinally relevant heterocycles and can be extended to other arene-containing starting materials. Computational examination of the proposed reaction pathway revealed a series of finely orchestrated bond-breaking and bond-forming events that ultimately lead to the annulated products.

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Fig. 1: In situ-generated diazoalkenes engage aromatic rings in 1,3-dipolar cycloaddition.
Fig. 2: Reaction mechanism investigation.
Fig. 3: DFT calculations support the proposed mechanism.

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Data availability

Crystallographic data for the structures reported in this Article have been deposited at the Cambridge Crystallographic Data Centre, under deposition numbers CCDC 2166171 (1f) and CCDC 2166170 (11b). Copies of the data can be obtained free of charge via https://www.ccdc.cam.ac.uk/structures/. Relevant data for this study are available within the Article and its Supplementary Information.

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Acknowledgements

We acknowledge the Center for Advanced Research Computing (CARC) at the University of Southern California for providing HPC resources that have contributed to the research results reported within this paper (https://carc.usc.edu). Mass spectra (MS) were acquired at the Agilent Center for Excellence in Biomolecular Characterization at USC. S.A. gratefully acknowledges support from the Dornsife College of Letters, Arts and Sciences through the Chemistry-Biology Interface T32 fellowship. A.V. acknowledges the USC Bridge Institute for their support through the BUGS program. D.B.E gratefully acknowledges Agilent Technologies for support through an Agilent Fellowship.

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Authors and Affiliations

  1. The Bridge@USC, Loker Hydrocarbon Research Institute and Department of Chemistry, University of Southern California, Los Angeles, CA, USA

    Shubhangi Aggarwal, Alexander Vu, Dmitry B. Eremin, Rudra Persaud & Valery V. Fokin

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Contributions

S.A.: conceptualization, investigation, condition optimization, NMR, IR and MS analysis, synthesis, manuscript writing. A.V.: computational study, manuscript writing. D.B.E.: computational study, IR study, MS processing, manuscript writing. R.P.: synthesis of azides. V.V.F.: conceptualization, project administration, resources, supervision, manuscript writing.

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Correspondence to Valery V. Fokin.

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Nature Chemistry thanks De-Cai Fang and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Supplementary information

Supplementary Information

Experimental details and protocols, detailed reaction optimization data, characterization data (including NMR and MS) of synthesized compounds, supplementary PES figures, visuals of reactions, MS spectra, FTIR data, X-ray crystallographic data, NMR spectra.

Supplementary Data 1

Crystallographic data for compound 1f; CCDC reference 2166171.

Supplementary Data 2

Crystallographic data for compound 11b; CCDC reference 2166170.

Supplementary Data 3

Cartesian coordinates of computational data.

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Aggarwal, S., Vu, A., Eremin, D.B. et al. Arenes participate in 1,3-dipolar cycloaddition with in situ-generated diazoalkenes. Nat. Chem. 15, 764–772 (2023). https://doi.org/10.1038/s41557-023-01188-z

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