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Synthesis of azetidines via visible-light-mediated intermolecular [2+2] photocycloadditions

Nature Chemistry volume 12, pages 898–905 (2020)Cite this article

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Abstract

Intermolecular [2+2] photocycloadditions represent a powerful method for the synthesis of highly strained, four-membered rings. Although this approach is commonly employed for the synthesis of oxetanes and cyclobutanes, the synthesis of azetidines via intermolecular aza Paternò–Büchi reactions remains highly underdeveloped. Here we report a visible-light-mediated intermolecular aza Paternò–Büchi reaction that utilizes the unique triplet state reactivity of oximes, specifically 2-isoxazoline-3-carboxylates. The reactivity of this class of oximes can be harnessed via the triplet energy transfer from a commercially available iridium photocatalyst and allows for [2+2] cycloaddition with a wide range of alkenes. This approach is characterized by its operational simplicity, mild conditions and broad scope, and allows for the synthesis of highly functionalized azetidines from readily available precursors. Importantly, the accessible azetidine products can be readily converted into free, unprotected azetidines, which represents a new approach to access these highly desirable synthetic targets.

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Fig. 1: Synthesis of azetidines via intermolecular [2+2] photocycloadditions.
Fig. 2: Development of an intermolecular aza Paternò–Büchi reaction.
Fig. 3: Synthetic modification of the azetidine products.
Fig. 4: Mechanistic investigation of the title reaction.

Data availability

Experimental data as well as characterization data for all new compounds prepared in the course of these studies are provided in the Supplementary Information of this manuscript. The X-ray crystallographic coordinates for compounds 44, 46 and 59 have been deposited at the Cambridge Crystallographic Data Center (CCDC) with accession codes 1980947 (44), 1980951 (46) and 1980952 (59). These data can be obtained free of charge from the Cambridge Crystallographic Data Center via www.ccdc.cam.ac.uk/structures/.

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Acknowledgements

We thank J. W. Kampf for X-ray crystallographic studies. C.S.S. thanks the Alfred P. Sloan Foundation, the David and Lucile Packard Foundation and the Camille and Henry Dreyfus Foundation for fellowships. M.R.B. is thankful for a Peter A. S. Smith Endowment Award for research and a Rackham Predoctoral Fellowship. E.R.W. thanks the National Science Foundation for a predoctoral fellowship. We thank C. R. J. Stephenson for helpful discussions.

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  1. Willard Henry Dow Laboratory, Department of Chemistry, University of Michigan, Ann Arbor, MI, USA

    Marc R. Becker, Emily R. Wearing & Corinna S. Schindler

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Contributions

M.R.B., E.R.W. and C.S.S. designed the experiments. M.R.B. and E.R.W. conducted and analysed the experiments described in this report. M.R.B., E.R.W. and C.S.S. prepared this manuscript for publication.

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Correspondence to Corinna S. Schindler.

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Supplementary information

Supplementary Information

Supplementary Figs. 1–20, Tables 1–11, experimental procedures, new compound characterization data, X-ray crystallographic information and mechanistic experiments.

Supplementary Data 1

Crystallographic data for compound 59. CCDC reference 1980952.

Supplementary Data 2

Crystallographic data for compound 44. CCDC reference 1980947.

Supplementary Data 3

Crystallographic data for compound 46. CCDC reference 1980951.

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Becker, M.R., Wearing, E.R. & Schindler, C.S. Synthesis of azetidines via visible-light-mediated intermolecular [2+2] photocycloadditions. Nat. Chem. 12, 898–905 (2020). https://doi.org/10.1038/s41557-020-0541-1

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