Abstract
Pyrrole and 2-pyrrolone derivatives are valuable heterocyclic compounds and while classical condensation methods for their synthesis have a long history, many of the recent developments for their preparation involve the use of transition metal catalysis. Here we report a complementary, metal-free strategy for constructing structurally diverse derivatives of these heterocycles. The key feature of the approach is the in situ creation of a reactive intermediate by an initial facile event that simultaneously generates a pyrrole ring bearing a free carbene. This is straightforwardly accessed via a spontaneous, net [3 + 2] cyclization reaction of a linear alkynyl O-silylimidate or alkynyl aldimine with an electrophilic alkyne. The carbene then undergoes either 1,4-silyl migration (to produce 2-pyrrolone derivatives) or C–H insertion, cycloaddition, cyclopropanation or macrocyclization reactions (leading to pyrrole derivatives).
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Data availability
The Supplementary Information includes preparation procedures and characterization data for all new compounds, computational methodology and results, and static copies of NMR spectra of all new compounds. The X-ray diffraction structure of 44a can be found at the Cambridge Crystallographic Data Centre under Deposition Number 2431543. These data, available free of charge, can be accessed at https://www.ccdc.cam.ac.uk/structures/. A master.mnova file containing the raw data files of NMR spectra for all new compounds is available from figshare via https://doi.org/10.6084/m9.figshare.29649548 (ref. 34).
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Acknowledgements
This research was enabled by a grant from the United States National Science Foundation (CHE-2155042) (T.R.H.). High-resolution mass spectrometry data (electrospray ionization) were obtained in the Analytical Biochemistry Shared Resource Laboratory of the University of Minnesota (UMN). DFT computations were performed utilizing resources provided by the UMN Supercomputing Institute (MSI). The X-ray diffraction analysis of 44a was performed by A. Lovstedt in the X-Ray Crystallographic Laboratory in the Department of Chemistry, UMN.
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Supplementary information
Supplementary Information
Experimental details, Supplementary sections I–VII.
Supplementary Data 1
Excel data sheets for NMR spectroscopy computations.
Supplementary Data 2
Computed geometries for conformers for NMR spectroscopy calculations.
Supplementary Data 3
X-ray crystallographic data for compound 44a cif (.cif) and checkcif (as PDF) files, CCDC 2431543.
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Xu, Q., Shi, J. & Hoye, T.R. Pyrrole-stabilized free carbenes generated from alkynyl imidates or aldimines and electrophilic alkynes give pyrrolone- or pyrrole-containing products. Nat. Synth (2025). https://doi.org/10.1038/s44160-025-00899-0
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DOI: https://doi.org/10.1038/s44160-025-00899-0
