Synthesis of Primary Aromatic Amides by Aminocarbonylation of Aryl Halides Using Formamide as an Ammonia Synthon

Abstract

Primary aromatic amides were prepared by a palladium-catalyzed aminocarbonylation reaction of aryl halides in high yields (70-90%) using formamide as the amine source. The reactions require a palladium catalyst in combination with a nucleophilic Lewis base such as imidazole or 4-(dimethylamino)pyridine (DMAP). Aryl, heteroaryl, and vinyl bromides and chlorides were converted to the primary amides under mild conditions (5 bar, 120 degrees C) using 1 mol % of a palladium-phosphine complex. Best results were obtained in dioxane using triphenylphosphine as the ligand and DMAP as the base. For activated aryl bromides, a phosphine-to-palladium ratio of 2:1 was sufficient, but less reactive aryl bromides or aryl chlorides required ligand-to-palladium ratios up to 8:1 in order to stabilize the catalyst and achieve full conversion. The influence of catalyst, base, solvent, pressure, and temperature was studied in detail. The mechanism of the reaction could be clarified by isolating and identifying the reaction intermediates. In addition, methylamides and dimethylamides were prepared by the same method using N-methylformamide and N,N-dimethylformamide as the amine source.

N,N‐Dimethylformamide: A Multipurpose Building Block

“…In 2001, the group of Indolese observed the formation of dimethylamide in the reductive carbonylation of 3-bromobenzotrifluoride (13) in DMF [Eq. (1) in Scheme 5].…”

“…(1) in Scheme 5]. [13] With the employment of imidazole, which is known as a powerful Lewis base and acylating catalyst, and the adjustment of the Pd/P ratio, an 89 % yield of the amide 14 was obtained . Since this reaction was conducted under CO (5 bar), DMF was considered to be the amine source.…”

Industrial R&D on Catalytic CC and CN Coupling Reactions: A Personal Account on Goals, Approaches and Results

“…Consequently, such transformations are usually developed by specialized groups, either inside a company or by a CRO such as Solvias. [26] The Pd-catalyzed aminocarbonylation is an important method for the selective and direct synthesis of aromatic amides starting from aryl halides. While reactions of primary and secondary amines to the corresponding amides work well, no convenient catalytic method for [14b] ).…”

A General Palladium‐Catalyzed Aminocarbonylation of Phenols to Primary Benzamides via In Situ Generation of Aryl Nonaflates

“…The standard ligand PPh 3 gave 17 % of the desired benzamide (Table 1, entry 1), while other tested monophosphines and bidentate ligands with small bite angles gave no product at all (Table 1, entries 2-5). However, other chelating ligands gave benzamide in 37-46 % yield (Table 1, entries [6][7][8][9][10][11]. Considering the price of the ligands, we decided to choose DPEphose for the further optimization.…”