Cu-Mediated Ullmann-Type Cross-Coupling and Industrial Applications in Route Design, Process Development, and Scale-up of Pharmaceutical and Agrochemical Processes

Abstract

Cu-mediated Ullmann-type cross-coupling has experienced significant advances over the last century since the seminal publication by Ullmann in 1901. These advances have significantly expanded the scope of the original classical Ullmann coupling of aryl halides for formation of diaryl compounds to include the formation of carbon−heteroatom and other carbon− carbon bonds. The introduction of bidentate ligands drastically improved the performance of this class of transformations to enable milder reaction conditions that can tolerate a wide range of sensitive functional groups. Recent development of more powerful second-generation bidentate ligands has further allowed the coupling of less reactive aryl chlorides to proceed smoothly and realized low catalyst and ligand loadings for a broad scope of Ullmann-type cross-coupling reactions. As a result of these breakthrough advances in the past decades, Cu-mediated Ullmann-type cross-coupling reactions have been frequently implemented in academic research and have found ubiquitous industrial applications including the preparation of pharmaceutical and agrochemical products. This review provides an overview of selected general Cu-mediated Ullmann-type transformations for the formation of carbon− carbon and carbon−heteroatom (C−N, C−O, C−S, and C−P) bonds and their applications in route design, process development, and scale-up of pharmaceutical and agrochemical processes.

Copper‐Catalyzed Carboxylation of Aryl Thianthrenium Salts with CO2

“…In the presence of ZnEt 2 , oxalic diamide L16 may be deprotonated to form an O,O‐ or N,O‐bidentate zinc complex. Such deprotonated ligands were reported to have good coordination effect with copper to form catalytic active species [15e] . Next, several reductants were tested and ZnEt 2 was found to be irreplaceable choice (Table 2, entries 1–6).…”

Pyridyl Glycosyl Triazole/CuI-Mediated Domino/Tandem Synthesis of Quinazolinones

“…Several synthetic approaches have been reported for the synthesis of quinazolinones using different types of starting substrates. − A classical method for the synthesis of quinazolinones involves a condensation reaction of anthranilic acid and its derivative with formamide synthons. − However, this approach suffers from low yields, multistep reaction, and harsh reaction conditions. In addition to the classical method, the ligand-assisted transition-metal-catalyzed Ullmann coupling reaction followed by cyclization is a well known and proficient method to assemble these derivatives. − Various conventional and new ligands have been reported, which stabilized the oxidation states of Cu during the coupling reaction. − A major breakthrough for the synthesis of quinazolinones was independently reported by the Ding and Fu Group via a domino reaction under mild Cu-catalyzed conditions starting from N -substituted o -halobenzamides and o -halobenzoic acids. , Furthermore, the Ma group developed a facile and efficient approach to assemble these derivatives via the Cu­(I)/-4-hydroxy- l -proline-catalyzed aryl amidation reactions . Here, we have explored the application of carbohydrate-derived ligands in our study, moreover, to establish 4-hydroxy- l -proline-mediated catalysis.…”

Ullmann homocoupling of arenediazonium salts in a deep eutectic solvent. Synthetic and mechanistic aspects

“…3 In fact, they are highly valuable synthetic tool used for the preparation of a wide variety of organic compounds, from natural and synthetic bioactive compounds to new organic materials, in all fields of chemistry. The oldest (1901) of these metal-catalyzed coupling reactions is certainly the Ullmann reaction, 4 an useful protocol for the formation of a new C–C bond between two aryls by the condensation of two molecules of an aromatic halide in the presence of copper. It must be stressed that biaryl compounds are one of the important scaffolds in the field of organic chemistry, and have been extensively applied to pharmaceuticals, functional materials, and agrochemicals.…”