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. 2024 Dec 17;9(52):51690-51700.
doi: 10.1021/acsomega.4c09973. eCollection 2024 Dec 31.

Mechanistic Studies on the Gold-Catalyzed Intramolecular Hydroalkylation of Ynamides to Indenes

Julien Annibaletto  1 , Clément Jacob  1   2 , Pierre Thilmany  1 , Anaïs Loison  1 , Jorge Escorihuela  3 , Gwilherm Evano  1   4
Affiliations

Mechanistic Studies on the Gold-Catalyzed Intramolecular Hydroalkylation of Ynamides to Indenes

Julien Annibaletto et al. ACS Omega. .

Abstract

An in-depth experimental and computational study to rationalize the mechanism underlying the gold-catalyzed intramolecular hydroalkylation of ynamides to indenes is reported. Evaluating the reactivity of a set of deuterated ynamides and gold complexes allowed to get valuable insights into the mechanism of this reaction, while DFT calculations allowed to determine a plausible reaction pathway for this unprecedented transformation. This pathway involves the activation of the ynamide followed by a [1,5]-hydride shift from the highly reactive, in situ generated keteniminium ion, and a subsequent cyclization before deprotonation followed by a final protodeauration. According to DFT calculations, the initial [1,5]-hydride shift was identified as the rate-determining step of the reaction mechanism. Additionally, computational studies allowed to rationalize the differences in reactivity of various ynamides and the pivotal role of gold complexes in the catalysis of this reaction.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Scheme 1
Scheme 1. Potential Mechanism Involved in the Synthesis of Indenes via a Gold-Catalyzed Intramolecular Hydroalkylation of Ynamides
Scheme 2
Scheme 2. Synthesis of Deuterium-Labelled Ynamide 1aD
Scheme 3
Scheme 3. Deuterium Migration, Kinetic Isotopic Effect and Crossover Experiments
Figure 1
Figure 1
Relative Gibbs free energies (in kcal/mol) of the intermediates for the gold-catalyzed (blue and green pathways) and noncatalyzed (red pathway) cyclization of ynamides to indenes. Bond distances given in Å.
Figure 2
Figure 2
Optimized calculated geometries for the transition states involved in the gold-catalyzed cyclization process. Relative Gibbs free energies given in kcal/mol.
Scheme 4
Scheme 4. Influence of the Ynamide Substitution on the Observed Reactivity; Relative Gibbs Free Energies Given in kcal/mol,,
Isolated yields. Determined by 1H NMR analysis using 1,1,2,2-tetrachloroethane as internal reference. Reaction performed in 1,2-dichloroethane at 80 °C.
Figure 3
Figure 3
NCI isosurfaces (isovalue at 0.6) associated with TS1 for compounds 1a, 1c, 1d and 1e. NCI interactions are shown in green, steric effects in red.
Figure 4
Figure 4
Analysis of distortion, interaction, and activation (blue: distortion energy of ynamides, green: distortion energy of Au-catalyst, red: interaction energy, black: activation energy). Energies are given in kcal/mol.
Figure 5
Figure 5
Activation strain diagrams for TS1 of compounds 1a, 1c, 1d and 1e along the reaction coordinate projected onto the C···H bond stretch.
See this image and copyright information in PMC

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