Ullmann‐Ma Reaction: Development, Scope and Applications in Organic Synthesis^†

Abstract

SummaryCopper‐catalyzed cross‐couplings of aryl halides and nucleophiles, traditionally called Ullmann‐type coupling reactions, were initially reported by Ullmann et al. from 1901—1929. A seminal report in 1998 by Ma et al. from Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences revealed an accelerating effect caused by amino acids, which brought Ullmann‐type coupling reactions into a ligand‐accelerating era. From 1999 to the first 10 years of 2000s, the first‐generation ligands were developed by many researchers and promoted Ullmann‐type coupling reactions of aryl iodides and bromides under relatively mild conditions. Amino acid ligands, developed by Ma and coworkers, are one class of the most important first‐generation ligands. In the second 10 years of 2000s, Ma et al. led the discovery of second‐generation ligands for copper‐catalyzed cross‐coupling reactions. Two great breakthroughs have been realized by using second‐generation oxalic diamide and related amide ligands, with aryl chlorides as general coupling partner and with low catalyst loadings. Now copper‐catalyzed cross coupling reactions of aryl halides and nucleophiles with amino acids or oxalic diamides and related amides as ligands are recognized as Ullmann‐Ma reactions and have found extensive applications in organic synthesis.

An Expeditious Modular Hybrid Strategy for the Diversity-Oriented Synthesis of Lamellarins/Azalamellarins with Anticancer Cytotoxicity

“…In this case, the C1- H in the nonfully substituted pyrrole 15 may have different reactivity, which may or may not be compatible with the chemistry required for the lactone/lactam formation. To our delight, saponification of the ester could be affected by using NaNH 2 in “non-dried” 1,4-dioxane to afford the corresponding carboxylate, which was not isolated but directly subjected to the copper­(I)-thiophene carboxylate (CuTC)-catalyzed Ullmann-type C–O bond formation using Cs 2 CO 3 as a base with microwave irradiation to furnish the lactone 16 in 80% yield over two steps (Scheme ). Alternatively, also by a two-step process, the ester group of 15 could be converted directly using Me 3 Al, in 86% yield, to the corresponding PMB amide, which underwent the CuTC-catalyzed microwave-assisted Ullmann-type C–N bond formation to furnish the lactam 17 in 90% yield following some optimization (Table ).…”

Nickel-Catalyzed Paired Electrochemical Cross-Coupling of Aryl Halides with Nucleophiles

“…Given the ubiquitous nature of the aniline motif in drugs and natural products, there is a constant need for the development of new methods for mild and selective C (sp 2 )-N bond formation. Despite significant advances in palladium and copper catalytic systems (e.g., Buchwald-Hartwig reaction 40 and Ullmann reaction 41 ), the construction of the C-N bond is still a major challenge for organic chemists. In many cases, the involvement of harsh reaction conditions (use of strong base and elevated temperature) or the use of expensive catalysts is inevitable.…”

Tartramide Ligands for Copper‐Catalyzed N‐Arylation at Room Temperature

“…[7] Over the last two decades, a large number of oxygen and nitrogen based ligands have been found to effectively promote copper-catalyzed CÀ N bond formation, with recent advances demonstrating much improved increases in catalyst turnover number and frequency, [8] and the ability to activate more challenging substrates such as aryl chlorides. [9] Despite this, room-temperature copper-catalyzed amination remains challenging with elevated temperatures (80-120 °C) required in the majority of cases. [10] In addition, copper catalyzed processes can suffer from reproducibility issues as well as exhibiting high sensitivity to air and moisture.…”

“…However, copper catalyzed amination (Ullmann coupling) has recently been the subject of growing interest due to the low cost and low toxicity of copper (and its commonly employed ligands), as well as its good functional group tolerance [7] . Over the last two decades, a large number of oxygen and nitrogen based ligands have been found to effectively promote copper‐catalyzed C−N bond formation, with recent advances demonstrating much improved increases in catalyst turnover number and frequency, [8] and the ability to activate more challenging substrates such as aryl chlorides [9] . Despite this, room‐temperature copper‐catalyzed amination remains challenging with elevated temperatures (80–120 °C) required in the majority of cases [10] .…”