Utilizing Carbonyl Coordination of Native Amides for Palladium-Catalyzed C(sp3 )-H Olefination

Abstract

Pd^II -catalyzed C(sp³ )-H olefination of weakly coordinating native amides is reported. Three major drawbacks of previous C(sp³ )-H olefination protocols, 1) in situ cyclization of products, 2) incompatibility with α-H-containing substrates, and 3) installation of exogenous directing groups, are addressed by harnessing the carbonyl coordination ability of amides to direct C(sp³ )-H activation. The method enables direct C(sp³ )-H functionalization of a wide range of native amide substrates, including secondary, tertiary, and cyclic amides, for the first time. The utility of this process is demonstrated by diverse transformations of the olefination products.

Keywords: C−H activation; Mizoroki-Heck reaction; amides; ligand design; palladium.

Scheme 1.

Pd-catalyzed C(sp³)–H Olefination.

Scheme 2.

Diversification of Olefination Products. (a) 2j (0.1 mmol), dimethyl malonate (2 equiv.), Cs₂CO₃ (1 equiv.), CH₃CN (0.1 M), 70 °C, 32 h. (b) 2j (0.1 mmol), DBU (1.5 equiv.), CH₃NO₂ (0.5 M), 0 °C, 3 h. (c) 2j (0.1 mmol), PhSH (2 equiv.), K₂CO₃ (2.2 equiv.), THF (0.1 M), 70 °C, 32 h. (d) 2j (0.96 mmol), 10% Pd/C (0.07 mmol), EtOAc (0.1 M), H₂ balloon (1 atm), r.t., 24 h. (e) 5g (0.38 mmol), 10% Pd/C (0.03 mmol), EtOAc (0.1 M), H₂ balloon (1 atm), r.t., 48 h. (f) 5g (0.1 mmol), n-amylamine (4 equiv.), CH₃CN (0.1 M), r.t., 30 min. (g) 2u (0.49 mmol), DBU (1 equiv.), EtOH (0.25 M), reflux, 1 h. (h) 6d (0.053 mmol), Ar–OTBS (1.05 equiv.), DBU (10 mol%), CH₃CN (0.1 M), r.t., 16 h.