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Free carbenes from complementarily paired alkynes


Carbenes (R1R2C:) like radicals, arynes and nitrenes constitute an important family of neutral, high-energy, reactive intermediates—fleeting chemical entities that undergo rapid reactions. An alkyne (R3C≡CR4) is a fundamental functional group that houses a high degree of potential energy; however, the substantial kinetic stability of alkynes renders them conveniently handleable as shelf-stable chemical commodities. The ability to generate metal-free carbenes directly from alkynes, fuelled by the high potential (that is, thermodynamic) energy of the latter, would constitute a considerable advance. We report here that this can be achieved simply by warming a mixture of a 2-alkynyl iminoheterocycle (a cyclic compound containing a nucleophilic nitrogen atom) with an electrophilic alkyne. We demonstrate considerable generality for the process: many shelf-stable alkyne electrophiles engage many classes of (2-alkynyl)heterocyclic nucleophiles to produce carbene intermediates that immediately undergo many types of transformations to provide facile and practical access to a diverse array of heterocyclic products. Key mechanistic aspects of the reactions are delineated.

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Fig. 1: The high potential energy (thermodynamic instability) of alkynes can drive the formation of reactive intermediates.
Fig. 2: Two early reactions suggest the formation of carbene intermediates (further supported by DFT computations) en route to indolizine-containing products.
Fig. 3: Insertion (a–d) and 1,3-dipolar cycloaddition (e–g) reactions of the carbene intermediates.
Fig. 4: Scope of electrophilic alkynes.
Fig. 5: Examples in which various arrays of a carbene-capture process, of an electron-deficient alkyne and of an alkynyl iminoheterocycle are melded.
Fig. 6: A series of unusual transformations.

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Preparation procedures and characterization data for all new compounds, computational methodology and data, and copies of all NMR spectra are provided in the PDF of Supplementary Information.


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Support for this research came from a grant from the National Science Foundation (NSF, CHE-2155042). A portion of the NMR spectra were obtained with the help of the Shared Instrumentation Grant programme (S10 OD011952) of the National Institutes of Health (NIH). Electrospray ionization high-resolution mass spectrometry data were taken in the Analytical Biochemistry Shared Resource laboratory at the University of Minnesota; a portion of the instrumentation in this Masonic Cancer Center was obtained with the support of the NIH National Cancer Institute (P30 CA077598). DFT computations were carried out using resources provided by the University of Minnesota Supercomputing Institute (MSI).

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Q.X. discovered the first example and performed all of the experimental and computational studies; Q.X. and T.R.H. designed the experiments, interpreted the data and wrote the paper together.

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Correspondence to Thomas R. Hoye.

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Supplementary Figs. 1–5, experimental protocols for preparation of all new compounds and full characterization data for their assigned structures, computational results and copies of NMR spectra.

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Xu, Q., Hoye, T.R. Free carbenes from complementarily paired alkynes. Nat. Chem. 16, 1083–1092 (2024).

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