Synthesis of β‐Lactams by Palladium(0)‐Catalyzed C(sp³)−H Carbamoylation

Abstract

Ageneral and user-friendly synthesis of b-lactams is reported that makes use of Pd 0 -catalyzed carbamoylation of C(sp 3 )ÀHb onds,a nd operates under stoichiometric carbon monoxide in at wo-chamber reactor.T his reaction is compatible with ar ange of primary,s econdary and activated tertiary C À Hbonds,incontrast to previous methods based on C(sp 3 ) À Ha ctivation. In addition, the feasibility of an enantioselective version using ac hiral phosphonite ligand is demonstrated. Finally,t his method can be employed to synthesize valuable enantiopure free b-lactams and b-amino acids.

Synthesis of Chiral β‐Lactams by Pd‐Catalyzed Enantioselective Amidation of Methylene C(sp3)–H Bonds

“…Cramer and co‐workers reported the Pd(0)‐catalyzed desymmetrization of enantiotopic methylene C(sp 3 )–H bonds of α‐chloroamides using TADDOL‐derived phosphoramidite as chiral ligand (Scheme 1b, inner sphere) . An uncommon disconnection of C(O)–C α bond was achieved by the Baudoin group through desymmetrization of unactivated methyl groups by Pd(0)/TADDOL‐derived phophonite catalyzed C—H carbamoylation (Scheme 1c, inner sphere) …”

“…In particular, transition metal‐ catalyzed asymmetric C(sp 3 )–H functionalization could offer highly efficient and new retrosynthetic disconnections to access these chiral skeletons . Several innovative disconnection strategies have been developed based on asymmetric C—H activation either in outer‐sphere or inner‐sphere pathway (Scheme ) . Retrosynthetic disconnection of C α —C β bond has been first realized.…”

sp3C–H activationvia exo-type directing groups

“…Two other types of sp 3 C–H activation via the formation of exo -metallacycles are also worth mentioning, although the DGs or the directing motifs applied in these reactions may not strictly qualify as typical exo -DGs ( Scheme 24 ). In the first case, a carbamoyl-metal species is generated from either (i) oxidative addition of acyl chlorides 32 or (ii) carbonylation of free amines. 27c , 33 Upon cyclometalation at the β-C–H bond, an exo -metallacycle is formed, which further transforms to a β-lactam through reductive elimination 32 , 33 ( Scheme 24a ).…”

“…In the first case, a carbamoyl-metal species is generated from either (i) oxidative addition of acyl chlorides 32 or (ii) carbonylation of free amines. 27c , 33 Upon cyclometalation at the β-C–H bond, an exo -metallacycle is formed, which further transforms to a β-lactam through reductive elimination 32 , 33 ( Scheme 24a ). A similar reaction mode was also reported with vinyl bromides through sequential oxidative addition/C–H metalation to induce intramolecular C(sp 3 )–H activation and the subsequent formation of C–C bonds.…”

Palladium(II)‐Catalyzed Enantioselective Arylation of Unbiased Methylene C(sp3)−H Bonds Enabled by a 2‐Pyridinylisopropyl Auxiliary and Chiral Phosphoric Acids

“…[1,3] Recent efforts have led to significant progress in palladium-catalyzed enantioselective C(sp 3 )-H functionalizations through the desymmetrization of prochiral methyl groups. [4][5][6][7][8][9] Fore xample,the groups of Kagan, Kündig, Baudoin, and Cramer have developed highly enantioselective Pd 0 -catalyzed intramolec-ular cyclizations by using chiral N-heterocyclic carbene or phosphine ligands. [4][5][6][7] By combining monodentate directing groups with bidentate chiral ligands,Y ua nd co-workers achieved the Pd-catalyzed enantioselective desymmetrization of prochiral methyl groups by C(sp 3 ) À Ha ctivation.…”