Activation of diverse carbon–heteroatom and carbon–carbon bonds via palladium(ii)-catalysed β-X elimination

Abstract

Chemists' ability to synthesize structurally complex, high-value organic molecules from simple starting materials is limited by methods to selectively activate and functionalize strong alkyl C(sp) covalent bonds. Recent activity has focused on the activation of abundant C-O, C-N and C-C bonds via a mechanistic paradigm of oxidative addition of a low-valent, electron-rich transition metal. This approach typically employs nickel(0), rhodium(I), ruthenium(0) and iron catalysts under conditions finely tuned for specific, electronically activated substrates, sometimes assisted by chelating functional groups or ring strain. By adopting a redox-neutral strategy involving palladium(II)-catalysed C-H activation followed by β-heteroatom/carbon elimination, we describe here a catalytic method to activate alkyl C(sp)-oxygen, nitrogen, carbon, fluorine and sulfur bonds with high regioselectivity. Directed hydrofunctionalization of the resultant palladium(II)-bound alkene leads to formal functional group metathesis. The method is applied to amino acid upgrading with complete regioselectivity and moderate to high retention of enantiomeric excess. Low-strain heterocycles undergo strong-bond activation and substitution, giving ring-opened products.

Catalytic, Enantioselective α‐Alkylation of Azlactones with Nonconjugated Alkenes by Directed Nucleopalladation

“…For nucleopalladation, the activation free‐energy barrier for the ( S )‐nucleopalladation pathway ( TS1_S , 10.3 kcal mol −1 ) is lower than that of the ( R )‐pathway ( TS1_R , 11.2 kcal mol −1 ). However, the subsequent protodepalladation step has a higher activation energy, indicating that the nucleopalladation step is reversible and therefore that the reaction is under Curtin–Hammett control. The CPA‐assisted protodepalladation step to form the S enantiomer ( TS2_S ) has a lower activation free energy (13.5 kcal mol −1 ) than the protodepalladation to form the R enantiomer ( TS2_R , 14.9 kcal mol −1 ).…”

Protodepalladation as a Strategic Elementary Step in Catalysis

“…83 Engle and co-workers further developed an elegant formal C-X bond activation (where X = O, N, C, F, S) based on this transformation, by accessing alkene substrates in situ via β -X elimination (Scheme 33). 84…”

Anti-Selective [3+2] (Hetero)annulation of Non-Conjugated Alkenes via Directed Nucleopalladation

“…Under the standard conditions, no reaction was observed. However, in the presence of 1-Ada-CO2H, which presumably facilitates C(sp 3 )-H activation via a concerted metalation/deprotonation (CMD) mechanism, [24] we were able to obtain the [3+2] product 3ab. The result suggests that C(sp 3 )-O bond formation is reversible from the alkylpalladium(II) species-at least when accessed through this alternative C(sp 3 )-H activation pathway.…”