Pd-Catalyzed (3 + 2) Heterocycloadditions between Alkylidenecyclopropanes and Carbonyls: Straightforward Assembly of Highly Substituted Tetrahydrofurans

Abstract

A Pd catalyst made from a Pd(0) source and a bulky biaryl phosphine ligand promotes highly efficient intramolecular (3 + 2) heterocycloadditions between alkylidenecyclopropanes (ACPs) and carbonyls. The annulations provide a straightforward access to fused polycyclic systems featuring β-methylene tetrahydrofuran moieties. DFT data support a pallada–ene process and shed light on the critical role of hemilabile interactions between the Pd center and the bulky biaryl phosphine. Significantly, these Pd(0) catalysts are also effective for promoting intermolecular formal cycloadditions between ACPs and trifluoromethyl ketones, thus providing for a direct entry to chiral tetrahydrofuran moieties (THFs) bearing trifluoromethyl–substituted carbons.

Palladium‐Catalyzed Tandem Cycloisomerization/Cross‐Coupling of Carbonyl‐ and Imine‐Tethered Alkylidenecyclopropanes

“…This contrasts with the experimental results obtained using bulky biaryl phosphines (e.g. RuPhos, t BuXPhos), [3a] which produce the (3+2) cycloadducts, regardless the presence of an excess (2 equiv) of boronic acid in the media (Table 1, entries 1–3 and Table S1). A DFT exploration of the reaction between model ACP 1 d′ and the boronic acid 3 a , using t BuXPhos as ligand confirms that the formation of σ‐allyl square planar species of type IIa (Scheme 1b), wherein the palladium center establishes a hemilabile interaction with the biaryl moiety, is favored over π‐allyl intermediates IIb (Figure S26).…”

“…When adding 2 equiv of boronic acid 3 a to the milieu, under standard cycloaddition conditions (i.e. using RuPhos or t BuXPhos as ligands), [3a] we did not observe any product other than the expected cycloadduct 2 a (Table 1, entries 1–3 and Table S1). We then tested simple monodentate ligands which, according to the relative energies indicated in Scheme 1b, may disfavor the cycloaddition path and facilitate the desired alternative pathway.…”

“…We couldn't identify alternative σ‐allyl Pd species (e.g. T‐shape tautomers like IIc , previously located in the context of the (3+2) cycloaddition using the biaryl phosphine ligand t BuXPhos) [3a] …”

“…DFT studies revealed that these ligands enable the hetero‐cycloadditions by favoring an energetically accessible pathway through key oxapalladacyclic species of type IIa . Notably, these σ‐allyl square‐planar Pd II species, which hold a secondary stabilizing interaction between the Pd center and the biaryl phosphine moiety, are significantly more stable than alternative π‐ or σ‐allyl T‐shape tautomers IIb – IIc , which lack such hemilabile interactions (Scheme 1b) [3a] …”

“…[1,2] While most of these reactions entail carbonbased unsaturated cycloaddition partners, [2] we have recently developed conditions to perform highly efficient (3+2) cycloadditions between ACPs and carbonyls, using Pd 0 catalysts that feature Buchwald type of biaryl phosphines, such as RuPhos or BrettPhos (Scheme 1a). [3] DFT studies revealed that these ligands enable the hetero-cycloadditions by favoring an energetically accessible pathway through key oxapalladacyclic species of type IIa. Notably, these σ-allyl square-planar Pd II species, which hold a secondary stabilizing interaction between the Pd center and the biaryl phosphine moiety, are significantly more stable than alternative π-or σ-allyl T-shape tautomers IIb-IIc, which lack such hemilabile interactions (Scheme 1b).…”