Bioisosteres provide valuable design elements that medicinal chemists can use to adjust the structural and pharmacokinetic characteristics of bioactive compounds towards viable drug candidates. Aryl oxetane amines offer exciting potential as bioisosteres for benzamides—extremely common pharmacophores—but are rarely examined due to the lack of available synthetic methods. Here we describe a class of reactions for sulfonyl fluorides to form amino-oxetanes by an alternative pathway to the established SuFEx (sulfonyl–fluoride exchange) click reactivity. A defluorosulfonylation forms planar oxetane carbocations simply on warming. This disconnection, comparable to a typical amidation, will allow the application of vast existing amine libraries. The reaction is tolerant to a wide range of polar functionalities and is suitable for array formats. Ten oxetane analogues of bioactive benzamides and marketed drugs are prepared. Kinetic and computational studies support the formation of an oxetane carbocation as the rate-determining step, followed by a chemoselective nucleophile coupling step.
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The data supporting the findings of this work are provided in the Supplementary Information. Metrical parameters for the structure of amino-oxetanes 30 and 38, oxetane sulfonate esters 49, 89 and 93, oxetane ether 50 and sulfonyl fluorides 1, 54, 56 and 92 are available free of charge from the Cambridge Crystallographic Data Centre (https://www.ccdc.cam.ac.uk/data_request/cif) under reference nos. CCDC 2094791 (1), CCDC 2049639 (30), CCDC 2049640 (38), CCDC 2094792 (49), CCDC 2094793 (50), CCDC 2049754 (54), CCDC 2094794 (56), CCDC 2094795 (89), CCDC 2094871 (92) and CCDC 2094796 (93). Raw and processed characterization data for all novel compounds as well as compiled computational data are available at the Imperial College London Research Data Repository72.
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Rojas, J. J. et al. Amino-oxetanes as amide isosteres by an alternative defluorosulfonylative coupling of sulfonyl fluorides (Imperial College London Research Data Repository, 2021); https://doi.org/10.14469/hpc/8380
We acknowledge support from The Royal Society (University Research Fellowship UF140161 and URF\R\201019 to J.A.B., URF appointed grant no. RG150444 and URF enhancement grant no. RGF\EA\180031), the EPSRC (CAF to J.A.B. (EP/J001538/1) and a DTP studentship to E.L.B), Imperial College London for a Presidents scholarship (to R.A.C.) and Pfizer and Imperial College London for studentship funding (to J.J.R.). A.J.S. thanks the EPSRC Synthesis for Biology and Medicine CDT and the Oxford-Radcliffe Scholarship for support (EP/L015838/1).
The authors declare no competing interests.
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Extended scope, supplementary discussion, experimental, computational and procedural details, synthesis and characterization data, HPLC and LCMS traces, X-ray crystallographic data, NMR spectra, Supplementary Schemes 1–11, Figs. 1–63 and Tables 1–32.
Crystallographic data for compound 1; CCDC reference 2094791.
Crystallographic data for compound 30; CCDC reference 2049639.
Crystallographic data for compound 38; CCDC reference 2049640.
Crystallographic data for compound 49; CCDC reference 2094792.
Crystallographic data for compound 50; CCDC reference 2094793.
Crystallographic data for compound 54; CCDC reference 2049754.
Crystallographic data for compound 56; CCDC reference 2094794.
Crystallographic data for compound 89; CCDC reference 2094795.
Crystallographic data for compound 92; CCDC reference 2094871.
Crystallographic data for compound 93; CCDC reference 2094796.
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Rojas, J.J., Croft, R.A., Sterling, A.J. et al. Amino-oxetanes as amide isosteres by an alternative defluorosulfonylative coupling of sulfonyl fluorides. Nat. Chem. 14, 160–169 (2022). https://doi.org/10.1038/s41557-021-00856-2