Amino Acid-Promoted Ullmann-Type Coupling Reactions and Their Applications in Organic Synthesis (Report‪)‬

Since their discovery in the early 1990s, Ullmann-type coupling reactions have become a typical method for preparing aryl amines, biaryl ethers, and N-aryl heterocycles that are important in the pharmaceutical and materials world. However, a significant drawback of these reactions is the requirement of a high reaction temperature, which greatly limits its scope of application. This problem has been solved in recent years, mainly by using some N,N- or N,O-bidentate compounds as the reaction promoters [1]. These achievements not only provide mild conditions for known transformations, but also open a new avenue to heterocycle preparation and asymmetric synthesis. Herein, we wish to summarize our results on using amino acids as the promoters. In 1998, we first revealed that there exists an accelerating effect induced by the structure of [alpha]-amino acid in Cu-catalyzed Ullmann reaction, leading to completion of the coupling reactions of aryl halides 1 and [alpha]-amino acids 2 at 80-90[degrees]C (Scheme 1) [2]. This discovery offers a facile method for assembly of enantiopure N-aryl amino acids that are potential building blocks for assembling bioactive molecules [2]. Soon after that, several groups reported that some bidentate compounds like 1,10-phenanthroline, 1,2-diamines, and 1,2-diols could serve as ligands to facilitate Ullmann-type aryl amination at relatively low temperatures [3]. These results prompted us to explore if amino acids have the similar function. We were pleased to find that when L-proline was used as a ligand, coupling of aryl halides with primary amines, cyclic secondary amines, and N-containing heterocycles proceeded at 40-90[degrees]C to give the corresponding anilines 4 and N-aryl heterocycles 5 in good yields (Scheme 2) [4].