Regiochemistry in Cobalt-Mediated Intermolecular Pauson–Khand Reactions of Unsymmetrical Internal Heteroaromatic Alkynes with Norbornene

Abstract

The intermolecular Pauson-Khand (PK) reactions of sterically comparable (2-phenylethynyl)heteroaromatic compounds with norbornene, mediated by Co(2)(CO)(8) to give cyclopentenone products, were examined in this study. A synthetic protocol utilizing focused-microwave dielectric heating proved indispensable in the efficient synthesis of the PK cyclopentenone products. "π-Deficient" heteroaromatic substrates, e.g., 2-pyrones, and some "π-excessive" heteroaromatics such as 2- and 3-thiophene and 2-furan favor the β-position in the newly formed cyclopentenone ring. Other π-excessive heteroaromatics such as 2-pyrrole or 2-indole favor the α-position. A π-excessive 3-indole derivative gave a nearly equal mixture of regioisomers. The position of the nitrogen in pyridyl-containing alkyne substrates also affects the regiochemical outcome of the PK reaction. A 2-pyridyl alkyne, possessing a proximal nitrogen, influences the regioselectivity relative to a 4-pyridyl variant quite dramatically, favoring the β-position in the newly formed cyclopentenone ring. A 2-pyrimidylalkyne exhibits similar behavior to the 2-pyridylalkyne. Compounds that do not participate in PK reactions with norbornene include (2-phenylethynyl)imidazoles and the related benzimidazoles, which promote rapid decomposition of the in situ generated (μ(2)-alkyne)Co(2)(CO)(6) complexes. This stands in contrast with other nitrogen-containing heteroaromatics, e.g., pyrrole-, indole-, and pyrimidine-derived compounds, which effectively undergo PK reactions. Overall, the type of heteroaromatic group dramatically influences PK regioselectivity, which can in part be explained by rationalization of the current reaction mechanism, but not fully.

Pauson-Khand Reaction of Internal Dissymmetric Trifluoromethyl Alkynes. Influence of the Alkene on the Regioselectivity

“…The intermolecular reaction with terminal alkynes is completely regioselective affording adducts with the substituent always in α-position of the enone. In the case of internal dissymmetric alkynes, the regioselectivity of the PK adducts depends on a combination of steric and electronic effects [2,3,4,5,6,7]. In the absence of steric effects, electron-donating groups (EDGs) show preference for the α-position whereas electron-withdrawing groups (EWGs) tend to place at the β-position [3,4,5].…”

“…In the absence of steric effects, electron-donating groups (EDGs) show preference for the α-position whereas electron-withdrawing groups (EWGs) tend to place at the β-position [3,4,5]. However, recent studies have shown that the electronic effects are less significant than previously described [3,4,5] and can, therefore, be overcome by steric effects [6,7]. In this context, we became interested in exploring the reactivity of dissymmetric fluorinated alkynes in the intermolecular PKR in order to uncover how the particular electronic and steric properties of these substrates affect the regiochemical outcome of the intermolecular PKR [8,9].…”

Mild Pd/Cu-Catalyzed Sila-Sonogashira Coupling of (Hetero)aryl Bromides with (Hetero)arylethynylsilanes under PTC Conditions

“…Having successfully demonstrated the feasibility of the Pd/Cu-catalyzed sila-Sonogashira cross-coupling under PTC conditions of 1a with 2a, we then tested the scope and limitations of this coupling by applying the reaction conditions of entry 8 (Table 1) to the synthesis of compounds 3 starting from (hetero)arylethynyltrimethylsilanes 1 and commercially available (hetero)aryl bromides 2 (Scheme 2). [22][23][24] Scheme 2…”

Recent Advances in the Pauson–Khand Reaction

“…Fairlamb and coworkers [30] used various (2-phenylethynyl)-aromatic heterocycles to investigate how the regioselectivity in the intermolecular PKR changes based on the relative electron richness of the heterocycles (Scheme 18). An exact correlation with the electronic nature of the heterocycle was not observed within the substrates used, however several general trends were observed.…”