Palladium-Catalyzed, N-(2-Aminophenyl)acetamide-Assisted Ortho-Arylation of Substituted Benzamides: Application to the Synthesis of Urolithins B, M6, and M7

Abstract

Pd-catalyzed, selective, monoarylation of ortho-C-H bonds of various benzamides with aryl/heteroaryl iodides has been realized using N-(2-aminophenyl)acetamide (APA) as a new bidentate directing group for the first time. The reaction was tolerant of a wide range of functional groups, and a variety of biaryl amide derivatives were successfully prepared in good to moderate yield. The utilization of N-(2-aminophenyl)acetamide as a novel directing group, Mn(OAc) as a co-oxidant (silver free reaction conditions), and absolute ortho-monoaryl selectivity are notable features of this reaction. In addition, the obtained monoarylated products could be further transformed into the bioactive natural products and human microflora metabolites of dietary ellagic acid derivatives, urolithin B, urolithin M6, and urolithin M7.

A comprehensive overview of directing groups applied in metal-catalysed C–H functionalisation chemistry

“…Very recently, a new N , N -bidentate DG based on a 2-aminophenyl moiety was designed by Watkins ( Scheme 87D ). 527 It was successfully employed in a Pd-catalysed arylation of benzamide derivatives (>30 examples, up to 84% yield). Mono-arylated compounds were obtained and (hetero)aromatic iodides such as benzophenone, pyrimidines, and pyridine were suitable coupling partners.…”

C–H Functionalization of Aromatic Amides

“…In 2017, the Watkins group first described a procedure for the selective ortho ‐C–H monoarylation of aromatic amides with aryl iodides using N ‐(2‐aminophenyl)acetamide as a new bidentate directing group and transition metal Pd(II) as a catalyst (Scheme ) . With Mn(OAc) 2 as co‐oxidant, the reaction without silver was realized.…”

“…In 2017, the Watkins group first described ap rocedure for the selective ortho-C-H monoarylation of ar-omatic amides with aryl iodides using N-(2-aminophenyl)acetamide as an ew bidentated irecting group and transitionm etal Pd(II) as ac atalyst (Scheme40). [66] With Mn(OAc) 2 as co-oxidant, the reactionw ithout silver was realized. Ther eactionp rovides am oderate to good yield and exhibitse xcellent functional group tolerance.Apossible reactionm echanism is proposed:f irstly,a romatica mide substrates coordinate with Pd(OAc) 2 Recently,W angst eam reported aP d-catalyzed ortho-C-H activation/cross-coupling reactiono ft ertiary benzamides with a-oxocarboxylic acids to achieve the ortho-acylation of aromatica mides using tertiary amide as directing group (Scheme 42).…”

Step-Economical C–H Activation Reactions Directed by In Situ Amidation

“…Control experiments proved that the hydroxy group in OAP was indispensable for the reaction, serving as a chelating site for the Pd catalyst in the possible intermediates 3B-D. Although N-substituted o-phenylene diamines had previously been used as directing groups for the o-arylation of benzamides, 20 OAP demonstrates advantages in terms of its easy availability, flexible variability, application to different C-H activation reactions and other enriched transformations, 21 and above all, its ability to be used in one-pot transformations without the requirement of an additional amidation operation.…”