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Dr. Chao Li’s laboratory developed a new method for acylation of aryl and alkyl bromides with acylimidazoles

Publication Date:2020/03/12

On Mar 10, 2020, Dr. Chao Li’s laboratory (www.lichaolab.com) published a research article entitled “Nickel-Catalyzed Direct Acylation of Aryl and Alkyl Bromides with Acylimidazoles” in ACS Catalysis (doi: 10.1021/acscatal.0c00246). This study revealed that acylimidazole, an underexplored and easy-to-prepared species, can serve as a viable coupling partner for nickel catalyzed acylation of alkyl and aryl bromides. Detailed mechanism studies disclosed an unprecedented catalytic mode that amide C–N bond could be activated via a single-electron reductive approach. The practicality and scalability of this method was demonstrated with syntheses of drug molecules and structurally complex natural products.

Ketones have been at the center-stage of synthetic organic chemistry since the inception of the discipline. Traditionally, ketone C−C bonds can be formed from the reaction between carboxylic acid derivatives and organometallic reagents (e.g., RLi or RMgX). However, the use of highly basic organometallic reagents leads to a restricted window of chemoselectivity. Recently, transition-metal-catalyzed cross-coupling between highly engineered amides and boronic acids, organozinc species, or Grignard reagents has emerged as an attractive choice for the ketone synthesis due to their relatively mild reaction conditions. This newly developed synthetic reaction between easily accessible acylimidazoles and organobromides features a broad substrate scope bearing a wide gamut of functionalities: acylimidazoles derived from primary, secondary, tertiary, and aromatic carboxylic acids were demonstrated as viable coupling partners; Alkyl bromides and aryl bromides including a series of medicinally relevant heterocycles were shown to be competent coupling partners as well. Moreover, a series of functional groups including esters, carbonyl groups, sily ethers, and carbamates were found to be tolerated in the reaction conditions. In addition, researchers have successfully applied this method to the modification and synthesis of complex natural products and drugs, such as the modification of several complex steroids, the synthesis of an anti-Parkinson drug molecule Tolcapone, and the synthesis of a complex furan diterpenoid natural product. Detailed mechanistic study revealed that the sterically less-hindered acylimidazoles underwent C–N bond cleavage by a single-electron transfer (one-electron process), whereas sterically encumbered acylimidazoles went through amide C–N bond cleavage via an oxidative addition (two-electron process).

In summary, Dr. Chao Li’s laboratory developed a novel nickel-catalyzed reductive cross-coupling reaction that enabled the efficient construction of ketone C−C bonds from readily available acylimidazoles and alkyl/aryl bromides. Mechanistically, they revealed an unprecedented approach to achieve amide C−N bond activation via single-electron reduction. Of note, the systematically mechanistic studies also highlight how steric effects can regulate the adoption of a preferentially favorable catalytic pathway.

Junming Zhuo (2017, Graduate School of Peking Union Medical College and Chinese Academy of Medical Sciences) and Yong Zhang (2020, PTN project) from Dr. Chao Li’s laboratory are the co-first authors of this paper. Zijian Li from Dr. Chao Li’s laboratory is a co-author. Dr. Chao Li is the corresponding author. The study was supported by Beijing Municipal Science & Technology Commission, Tsinghua University, and MOST of China. The research work was carried out at National Institute of Biological Sciences, Beijing.