Regioselectivity of Intermolecular Pauson–Khand Reaction of Aliphatic Alkynes: Experimental and Theoretical Study of the Effect of Alkyne Polarization

Abstract

Generally judged poor electronic regioselectivity of alkyne insertion in intermolecular Pauson-Khand reaction (PKR) has severely restricted its synthetic applications. In our previous rational study concerning diarylalkynes (Fager-Jokela, E.; Muuronen, M.; Patzschke, M.; Helaja, J. J. Org. Chem. 2012, 77, 9134-9147), both experimental and theoretical results indicated that purely electronic factors, i.e., alkyne polarization via resonance effect, induced the observed modest regioselectivity. In the present work, we substantiate that the alkyne polarization via inductive effect can result notable, synthetically valuable regioselectivity. Computational study at DFT level was performed to disclose the electronic origin of the selectivity. Overall, the NBO charges of alkynes correlated qualitatively with regioisomer outcome. In a detailed computational PKR case study, the obtained Boltzmann distributions of the transition state (TS) populations correlate closely with experimental regioselectivity. Analysis of the TS-structures revealed that weak interactions, e.g., hydrogen bonding and steric repulsion, affect the regioselectivity and can easily override the electronic guidance.

Pauson–Khand reaction of fluorinated compounds

“…This is dictated by the migratory insertion of the olefin into the most accessible Co-C bond (Scheme 3). This trend is strictly followed by terminal alkynes, for which exclusive formation of the α-substituted enone is observed, while mixtures are usually obtained with internal dissymmetric alkynes, although the major product follows the aforementioned trend [41]. On the other hand, for alkynes bearing groups of comparable steric demand at both ends of the alkyne, electronic effects come into play.…”

Regioselectivity of the Pauson–Khand reaction in single-walled carbon nanotubes

“…34,35 In fact, based on a study regarding diarylalkynes, it can be demonstrated that the alkyne polarization via inductive effect has a significant impact on the regioselectivity of the PKR. 36,37 The scope of the PKR and variations thereof encompasses several functional groups. 38 Two approaches can be distinguished: intramolecular and intermolecular PKR.…”

Recent Advances in the Pauson–Khand Reaction

“…[32] The authors also explored this reaction computationally. Alkynes with propargylic oxygens, and to a lesser extent nitrogen, selectively form mainly the β-exo isomer.…”