A dinickel-catalyzed three-component cycloaddition of vinylidenes

Abstract

A dinickel catalyst promotes the [2 + 2 + 1]-cycloaddition of two aldehyde equivalents and a vinylidene. The resulting methylenedioxolane products can be deprotected in one pot under acidic conditions to reveal α-hydroxy ketones. This method provides convenient access to unsymmetrical alkyl-substituted α-hydroxy ketones, which are challenging to synthesize selectively using cross-benzoin reactions. Mechanistic studies are consistent with an initial migratory insertion of the aldehyde into a dinickel bridging vinylidene. Insertion of the second aldehyde followed by C-O reductive elimination furnishes the cycloadduct. Under dilute conditions, an enone side product is generated due to a competing β-hydride elimination from the proposed metallacyclic intermediate. A DFT model consistent with the concentration-dependent formation of the methylenedioxolane and enone is presented.

Fig. 1. (a) A mechanism of the Pauson–Khand reaction initiated by a dinuclear oxidative coupling of the alkene and the alkyne. (b) A proposed vinylidene [2 + 2 + 1]-cycloaddition process involving a metallacycle derived from the migratory insertion of a 2π-component into a Ni₂(vinylidene).

Fig. 2. Substrate scope studies. Isolated yields were determined following purification and were averaged over two runs. Standard reaction conditions: dichloroalkene (0.2 mmol, 1.0 equiv.), aldehyde (2.0 equiv.), (^i-PrNDI)Ni₂Cl₂ (7) (10 mol%), Zn (4.0 equiv.), DMA (0.2 mL), Et₂O (0.8 mL), rt, 24 h; then TFA, 0 °C to rt, 2 h. ^aSynthesized using 2-(4-((trimethylsilyl)oxy)phenyl)acetaldehyde.

Fig. 3. Mechanistic studies. (a) Competing β-hydride elimination and aldehyde migratory pathways. Concentration dependence of β-hydride elimination vs. aldehyde migratory insertion under (b) catalytic and (c) stoichiometric conditions. (d) Deuterium labelling experiment tracking the hydrogen undergoing β-hydride elimination. (e) Experiment assessing the intermediacy of enone 42 in the cycloaddition.

Fig. 4. DFT modeling studies. All stationary points are fully optimized at the BP86/6-311g(d,p) level of theory and verified by frequency analysis. i-Pr groups on the catalyst were truncated to Me groups. Relative ΔG values at 298 K are shown in kcal mol⁻¹ and include a dispersion correction (GD3BJ) and an SMD solvent model. The major pathway leading to the [2 + 2 + 1]-cycloaddition product is shown in blue. Competing pathways to form the E-isomer of the product and the enone product are shown in green.