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Generation and reactivity of unsymmetrical strained heterocyclic allenes

Nature Synthesis volume 3, pages 329–336 (2024)Cite this article

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Abstract

Strained cyclic allenes are short-lived intermediates that confine a functional group with a preferred linear geometry, an allene, into a small ring, inducing strain-driven reactivity. Nitrogen-containing variants, or azacyclic allenes, have proved valuable for the assembly of complex nitrogen-containing compounds. Whereas 3,4-azacyclic allenes, which bear a symmetrical core, have been the focus of multiple studies, their unsymmetrical 2,3-azacyclic counterparts have remained underexplored. In the present study, we report density functional theory studies investigating the structure of such unsymmetrical azacyclic allenes and experimental efforts to access and engage them in strain-promoted cycloadditions under mild conditions. Control experiments support either concerted or stepwise diradical mechanisms for these reactions, depending on the type of cycloaddition examined. Moreover, we generate the corresponding 2,3-oxacyclic allene and demonstrate its reactivity in cycloadditions and a metal-catalysed process. Given the scaffolds accessed, coupled with the observed selectivity trends, these results are expected to encourage the application of unsymmetrical heterocyclic allenes for the synthesis of heterocycles that bear a high fraction of sp3-hybridized atoms.

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Fig. 1: Application and overview of in situ-generated, strained azacyclic intermediates.
Fig. 2: Resonance structure of cyclic allene (7) and structural analysis of 3,4-azacyclic allene (8) and 2,3-azacyclic allene (9).
Fig. 3: Synthesis of silyl triflate allene precursor 12.
Fig. 4: Empirically observed selectivity trends.
Fig. 5: Selectivity considerations in cycloaddition reactions of 9.
Fig. 6: Reactions of oxacyclic allene 62.

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Data availability

The data supporting the findings of the present study are available within the article and its Supplementary Information. Crystallographic data for 51 have been deposited at the Cambridge Crystallographic Data Centre under deposition no. CCDC 2247612. Copies of the data can be obtained free of charge via https://www.ccdc.cam.ac.uk/structures.

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Acknowledgements

We thank the National Institutes of Health (NIH)–National Institute of General Medical Sciences (grant no. R35 GM139593 to N.K.G. and supplement to A.T.M.), the National Science Foundation (NSF; grant no. DGE-2034835 to A.V.K.), the Foote family (A.V.K. and A.T.M.) and the Trueblood family (N.K.G.). These studies were supported by shared instrumentation grants from the NSF (grant no. CHE-1048804), the NIH National Center for Research Resources (grant no. S10RR025631) and the NIH Office of Research Infrastructure Programs (grant no. S10OD028644). Calculations were performed on the Hoffman2 cluster and the University of California, Los Angeles (UCLA) Institute of Digital Research and Education and the Extreme Science and Engineering Discovery Environment, which is supported by the NSF (OCI-1053575). We thank K. N. Houk (UCLA) for computational resources and helpful discussions and S. Khan (UCLA) for X-ray analysis.

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  1. Department of Chemistry and Biochemistry, University of California, Los Angeles, Los Angeles, CA, USA

    Andrew V. Kelleghan, Arismel Tena Meza & Neil K. Garg

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Contributions

A.V.K. and A.T.M. designed and performed experiments and analysed experimental data. A.V.K. designed, performed and analysed computational studies. N.K.G. directed the investigations and prepared the manuscript with contributions from all authors. All authors contributed to discussions.

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Correspondence to Neil K. Garg.

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Nature Synthesis thanks the anonymous reviewers for their contribution to the peer review of this work. Primary Handling Editor: Peter Seavill, in collaboration with the Nature Synthesis team.

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Supplementary information

Supplementary Information

Experimental details Parts I (A–F) and II (A–F), Supplementary Figs. 1–7 and Tables 1–3.

Supplementary Data 1

Crystallographic data for compound 51 (CCDC 2247612).

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Kelleghan, A.V., Tena Meza, A. & Garg, N.K. Generation and reactivity of unsymmetrical strained heterocyclic allenes. Nat. Synth 3, 329–336 (2024). https://doi.org/10.1038/s44160-023-00432-1

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