Asymmetric Synthesis of β-Lactam via Palladium-Catalyzed Enantioselective Intramolecular C(sp³)–H Amidation

Abstract

β-Lactams are important scaffolds in drug design and frequently used as reactive intermediates in organic synthesis. Catalytic reactions featuring intramolecular C–H amidation of alkyl carboxamide substrates could provide a straightforward disconnection strategy for β-lactam synthesis. Herein, we report a streamlined method for asymmetric synthesis of β-aryl β-lactams from propanoic acid and aryl iodides via Pd-catalyzed sequential C­(sp3)–H functionalization. The lactam-forming reaction provides an example of PdII-catalyzed enantioselective intramolecular C­(sp3)–H amidation reaction and proceeds up to 94% ee. The use of a 2-methoxy-5-chlorophenyl iodide oxidant is critical to control the competing reductive elimination pathways of the PdIV intermediate to achieve the desired chemoselectivity. Mechanistic studies suggest that both steric and electronic effects of the unconventional aryl iodide oxidant are responsible for controlling the competing C–N versus C–C reductive elimination pathways of the PdIV intermediate.

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

“…The successful enantioselective amidation of benzylic C(sp 3 )–H bonds led us to test the compatibility with unbiased aliphatic secondary C(sp 3 )–H bonds, a kind of more challenging substrates [3c,15] . Gratifyingly, we found that a variety of unbiased aliphatic carboxamides reacted efficiently when using ( S )‐3,3’‐fluorinated‐H8‐BINOL ( L9 ) as chiral ligand (Table ).…”

“…The effect of 8‐aminoquinoline DG was also evaluated. Unfortunately, no amidation product was obtained under identical reaction conditions ( 2aa ), indicating the superior effect of PIP auxiliary in asymmetric functionalization of unbiased methylene C(sp 3 )−H bonds …”

“…Herein, we report the first synthesis of chiral β-lactams via a Pd(II)-catalyzed enantioselective intramolecular amidation of both benzylic and unbiased methylene C(sp 3 )−H bonds enabled by PIP auxiliary and BINOL-derived ligands using 2-fluoro-1-iodo-4-nitrobenzene as oxidant (Scheme 1d). [15]…”

“…Unfortunately, no amidation product was obtained under identical reaction conditions (2aa), indicating the superior effect of PIP auxiliary in asymmetric functionalization of unbiased methylene C(sp 3 )−H bonds. [14,15] To demonstrate the robustness of this transformation, the enantioselective amidation reaction was performed on a 3.0 mmol scale. To our delight, the desired product was gained in 76% yield and 90% ee when 15 mol% L6 was used (Scheme 3a).…”

An Efficient Metal-Free Oxidative Esterification and Amination of Benzyl C–H Bond

“…This strategy has also been successfully employed for the direct esterification and amination of C-H bonds including benzylic C-H bonds under oxidative reaction conditions. Various transition-metals efficiently catalyzed the direct esterification [7,8] and amination [9][10][11] of C-H bonds. Due to the toxicity and cost of transition-metal catalysts, increasing interest has been paid on metal-free esterifications of benzylic C-H bonds.…”