Abstract
The hexadehydro-Diels-Alder (HDDA) reaction converts a 1,3-diyne bearing a tethered alkyne (the diynophile) into bicyclic benzyne intermediates upon thermal activation. With only a few exceptions, this unimolecular cycloisomerization requires, depending on the nature of the atoms connecting the diyne and diynophile, reaction temperatures of ca. 80-130 °C to achieve a convenient half-life (e.g., 1-10 h) for the reaction. In this report, we divulge a new variant of the HDDA process in which the tether contains a central, quaternized nitrogen atom. This construct significantly lowers the activation barrier for the HDDA cycloisomerization to the benzyne. Moreover, many of the ammonium ion-based, alkyne-containing substrates can be spontaneously assembled, cyclized to benzyne, and trapped in a single-vessel, ambient-temperature operation. DFT calculations provide insights into the origin of the enhanced rate of benzyne formation.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 7750-7757 |
| Number of pages | 8 |
| Journal | Journal of the American Chemical Society |
| Volume | 144 |
| Issue number | 17 |
| DOIs | |
| State | Published - May 4 2022 |
Bibliographical note
Funding Information:This study was made possible by a research grant from the National Institutes of General Medical Sciences (R35 GM127097), part of the U.S. Department of Health and Human Services. A portion of the NMR spectral data was collected using an instrument partially funded by the Shared Instrumentation Grant program (S10OD011952) of the National Institutes of Health. ESI HRMS data were obtained at the Masonic Cancer Center (Analytical Biochemistry Shared Resource laboratory) at the University of Minnesota; the instrumentation there was partially funded by the National Cancer Institute (Cancer Center Support Grant CA-77598). The X-ray diffraction data were collected using an instrument purchased with the support of the National Science Foundation (NSF/MRI 1229400). The DFT computational studies were performed using the facilities of the University of Minnesota Supercomputing Institute (MSI). Dr. Victor G. Young, Jr. (Department of Chemistry, University of Minnesota) is thanked for performing the X-ray diffraction analysis.
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