Facile Synthesis of N-Aryl Pyrroles via Cu(II)-Mediated Cross Coupling of Electron Deficient Pyrroles and Arylboronic Acids

Abstract

N-Arylation of electron-deficient pyrroles has been achieved by cross-coupling with arylboronic acids at room temperature in the presence of stoichiometric amounts of copper(II) acetate. The generality of this reaction has been established with variously substituted pyrroles as well as boronic acids. A key intermediate in the synthesis of a matrix metalloprotease inhibitor has been achieved using this methodology.

Modern Synthetic Methods for Copper‐Mediated C(aryl)O, C(aryl)N, and C(aryl)S Bond Formation

“…[38] In general these molecular motifs appear to be excellent substrates for N-arylation reactions, and in nearly all cases high yields of the products 90-95 were obtained (Scheme 16). However, the reaction times ranged from 2-13 days, but generally were in the 2-day range (Scheme 16).…”

Five‐Membered Heterocycles: Pyrrole and Related Systems

“…Pyrrole has also been N-arylated with an aryl iodide using CuI/trans-1,2-cyclohexanediamine in the presence of K 3 PO 4 as the catalytic system [576]. 2-Acetylpyrrole, as well as pyrrole-2-carboxaldehydes possessing an additional electron-withdrawing substituent at C4, undergoes efficient N-arylation with arylboronic acids at ambient temperature using stoichiometric amounts of Cu(OAc) 2 [577]. Treatment of pyrroles with vinyl triflates in the presence of the system Pd 2 (dba) 3 /Xphos/K 3 PO 4 constitutes a new route to 1-vinylpyrroles [578].…”

Recent Advances in Copper‐Promoted C–Heteroatom Bond Cross‐Coupling Reactions with Boronic Acids and Derivatives

“…However, Mederski [31], and Srirangam and co-workers [32] showed that N-arylation proceeded in good yields when there is a chelating aldehyde, ketone or ester alpha to the NH group. In contrast, for phenylalanine, which has an α-carboxylate group, no N-arylation was observed indicating that the α-carboxylate has a deleterious effect, probably due to tight binding to the copper center [23a, b].…”