Ligand Enabled Pd(II)-Catalyzed γ-C(sp³)–H Lactamization of Native Amides

Abstract

γ-Lactams form important structural cores of a range of medicinally relevant natural products and clinical drugs, principal examples being the new generation of immunomodulatory imide drugs (IMiDs) and the brivaracetam family. Compared to conventional multistep synthesis, an intramolecular γ-C−H amination of aliphatic amides would allow for the direct construction of valuable γ-lactam motifs from abundant amino acid precursors. Herein we report a novel 2-pyridone ligand enabled Pd(II)-catalyzed γ-C(sp 3 )−H lactamization of amino acid derived native amides, providing the convenient synthesis of γlactams, isoindolinones, and 2-imidazolidinones. C6-Substitution of the 2-pyridone ligand is crucial for the lactam formation. This protocol features the use of N-acyl amino acids, which serve as both the directing group and cyclization partner, practical and environmentally benign tert-butyl hydrogen peroxide (TBHP) as the sole bystanding oxidant, and a broad substrate scope. The utility of this protocol was demonstrated through the two-step syntheses of a lenalidomide analog and brivaracetam from readily available carboxylic acids and amino acids.

Dual ligand approach increases functional group tolerance in the Pd-catalysed C–H arylation of N-heterocyclic pharmaceuticals

“…A wide range of ligands were evaluated that were previously found to be effective in literature for various state-of-the-art (hetero)aromatic direct C–H arylations, as well as oxidative couplings and C–H alkenylations. The screening included N -protected amino acids, 40–45 2-pyridones, 46–51 thioether 52–57 and carboxylate 58,59 ligands (Scheme 2). The carboxylate ligands were tested via in situ formation of catalytic quantities of the corresponding carboxylic acid ( L2–L4 ) with the stoichiometric KOH base.…”

Ligand‐Enabled β‐C(sp3)−H Lactamization of Tosyl‐Protected Aliphatic Amides Using a Practical Oxidant

“…While β‐lactam product 2 a was observed with 2‐pyridone ligands L4 and L5 that previously promoted γ‐lactamization of native amides, [9] yields were unsatisfactory (20 % and 21 %, respectively). In our previous publication, we employed a bidentate amino acid directing group with 2‐pyridone ligand to achieve γ‐C−H lactamization [8b] . Under the current reaction conditions, the γ‐C(sp 3 )−H bonds are not activated as six‐membered cyclopalladation is much less favored.…”

“…However, despite their potential utility as targeted covalent inhibitors, β‐lactones are less stable both in solution at pH 7 and in serum, compared with their homologous β‐lactams [10] . Although we have recently developed a ligand enabled γ‐C(sp 3 )−H lactamization of amino acid derived native amides using TBHP as the terminal oxidant, [8b] this ligand was not reactive for β‐C−H lactamization. Thus, we embarked on the development of a ligand to β‐lactamization from abundant aliphatic carboxylic acid derived amides using a practical oxidant [11]…”

Recent Progress in Benzylic C(sp3)—H Functionalization of Toluene and Its Derivatives

“…2021 年, 余金权课题组 [86] 也报道了一种有效的 Pd(II)催化的分子内 γ-C(sp [87] . 2014 年, 雷爱文 课题组 [88] 以甲基烷烃和硫醇为亲核试剂, 过氧化二叔 丁基(DTBP)为氧化剂, 实现了 I 2 催化氧化的 C(sp 3 )-H/S-H 偶联(Scheme 49).…”