Highly Efficient and Mild Copper‐Catalyzed N‐ and C‐Arylations with Aryl Bromides and Iodides

Abstract

Mild, efficient, copper-catalyzed N-arylation procedures for nitrogen heterocycles, amides, carbamates, and C-arylation procedures for malonic acid derivatives have been developed that afford high yields of arylated products with excellent selectivity. The N-arylation of imidazole with aryl bromides or iodides was found to be greatly accelerated by inexpensive, air-stable catalyst systems, combining catalytic copper salts or oxides with a set of structurally simple chelating ligands. The reaction was shown to be compatible with a broad range of aryl halides, encompassing sterically hindered, electron-poor, and electron-rich ones, providing the arylated products under particularly mild conditions (50-82 degrees C). The lower limit in ligand and catalyst loading and the scope of Ullmann-type condensations catalyzed by complexes bearing those ligands with respect to the nucleophile class have also been investigated. Chelating Schiff base Chxn-Py-Al (1c) generates a remarkably general copper catalyst for N-arylation of pyrrole, indole, 1,2,4-triazole, amides, and carbamates; and C-arylation of diethyl malonate, ethyl cyanoacetate, and malononitrile with aryl iodides under mild conditions (50-82 degrees C). The new method reported here is the most successful to date with regard to Ullmann-type arylation of some of these nucleophiles.

Green alternative solvents for the copper-catalysed arylation of phenols and amides

“…The reaction of benzamide, 4-methoxy benzamide and 3-(trifluoromethyl)benzamide with electron-donating to electronwithdrawing aryl iodides occurred with good yields (25-32, 56% to 91% yields). Arylation of cyclohexanecarboxamide gave products 33-35 with yields between 71% and 78%, while cyclic amides such as 2-pyrrolidinone and 2-hydroxypyridine gave excellent results, with yields of 87-98% (36)(37)(38)(39)(40) [52][53][54] Benzylation also proved effective under these conditions: from the reaction of benzamide with 2-iodobenzyl bromide, a doubly substituted product was obtained in 30% yield (48, Scheme 5), while the coupling with benzyl bromide and benzyl chloride occurred with 52% and 33% yields respectively (49). It is worth noting that product 49 was not observed in reactions without CuI/ligand, either with benzyl bromide or benzyl chloride.…”

Theoretical Investigations on Deactivation of Copper Catalytic Species in Ullmann Cross Coupling Reactions

“…Modern Ullmann coupling reactions [1][2][3][4] (Scheme-I) are widely used in organic synthesis and C-hetero atom bond formation [5]. These reactions are essential tool in modern laboratories and industries for the synthesis of bio-active drugs, agro-chemicals and polymers [5,[6][7][8].…”

Ortho‐carboxylate Effects in Copper‐mediated Nucleophilic Substitution of Halothiophenecarboxylic Acids and Halobenzoic Acids with Sodium Bisulphite

“…The intervention of oxidative addition-reductive elimination mechanism in Ullmann condensation was first proposed by Cohen 23 in 1974 and substantiated by follow-up studies from others, 19,20,24 indicating Cu(I) and Cu(III) are intermediates in this type of reactions. The exceptionally high catalytic activity of copper(I) thiophene-2-carboxylate in Ullmann type nucleophilic substitution reactions has been ascribed to the stabilization of the Cu(III) complex formed in the oxidative addition step thereby driving the equilibrium to the forward direction.…”