Palladium-Catalyzed Inter- and Intramolecular α-Arylation of Amides. Application of Intramolecular Amide Arylation to the Synthesis of Oxindoles

Abstract

2A palladium-catalyzed α-arylation of amides is reported. Intermolecular arylation of N,N-dimethylamides and lactams occurs using aryl halides, silylamide base, and a palladium catalyst. Intramolecular arylation of N-(2-halophenyl)amides occurs using alkoxide base and a palladium catalyst. The palladium catalyst was formed in situ from Pd(dba)2 (dba = trans,trans-dibenzylidene acetone) and BINAP (2,2‘-bis(diphenylphosphino)-1,1‘-binaphthalene). Although the intermolecular arylation of amides is less general than that reported previously for ketones, unfunctionalized and electron-rich aryl halides gave α-arylamides in 48−75% yield and N-methyl-α-phenylpyrrolidinone in 49% yield. These reactions provided the highest yields yet reported for regioselective amide arylations. Intramolecular amide arylation of 2-bromoanilides gave oxindoles in 52−82% yield. Mono- and disubstituted acetanilides gave 1,3-di- and 1,3,3-trisubstituted oxindoles. The use of dioxane, rather than THF, solvent was important for some of the amide arylations.

Mild and Efficient CuI Catalyzed Coupling Reactions of Amides with Bromides

“…2,141.3,138.2,133.4,131.1,129.8,129.4,128.2,126.5,120.2,24.3,20.4;IR (KBr) NO: C 79.97,H 6.71,N 6.22;found C 79.77,H 6.58,N 6.08. …”

“…1 So far significant improvements have been achieved in Pd-catalyzed amide arylation reactions, 2 but it remains hard to apply these reactions to large and industrial scale syntheses due to the high cost of Pd and the difficulty in removing Pd residues from polar reaction products.…”

“…amino acids. Any coupling reactions that can use amino acids as ligand would be very interesting because of the following reasons: (1) the amino acid ligand is inexpensive, conveniently available, and environmentally benign, (2) there are a large number of different amino acids that can be tried, and (3) amino acid related reactions might have biological implications. Herein, we report novel, mild condition for the CuI-catalyzed coupling reactions of aryl iodides or bromides with amide using amino acids as the ligand.…”

Transition‐Metal‐Mediated Routes to 3,3‐Disubstituted Oxindoles through Anilide Cyclisation

“…[71] In 1998, Hartwig and co-workers reported the first example of intramolecular enolate arylation for the preparation of oxindoles. [72] The procedure used a strong base (typically NaOtBu), catalytic Pd(dba) 2 and a range of bidentate phosphane ligands, of which dppf and BINAP performed the best (Scheme 27). This protocol was also applied to the synthesis of 3-spirocyclic indolin-2-ones, [73,74] as well as to that of 1,1Ј-H-spiro[indoline-3,3Ј-piperidine] via an oxindole intermediate.…”

“…First example of intramolecular enolate arylation for the preparation of oxindoles. [72] The original procedure was later improved [76] by use of monodentate ligands such as PCy 3 or the Arduengo-type NHC ligands SIPr·Cl or SIPr·BF 4 , [77] which enabled the reaction temperature to be reduced to 50°C and allowed aryl chlorides to be used in the reaction. With these improvements, attention was focused on the development of asymmetric variants of the intramolecular enolate arylation reaction.…”