Catalytic enantioselective reductive domino alkyl arylation of acrylates via nickel/photoredox catalysis

• Published in: Nature communications Vol. 12; no. 1; pp. 6613 - 9
• Main Authors: Qian, Pengcheng, Guan, Haixing, Wang, Yan-En, Lu, Qianqian, Zhang, Fan, Xiong, Dan, Walsh, Patrick J., Mao, Jianyou
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 16.11.2021; Nature Publishing Group; Nature Portfolio
• Subjects: 140/131; 140/58; 639/638/549/972; 639/638/77/883; Acrylates; Anti-inflammatory agents; Carbonyl compounds; Carbonyls; Catalysis; Catalysts; Enantiomers; Functional groups; Humanities and Social Sciences; Inflammation; multidisciplinary; Nickel; Nonsteroidal anti-inflammatory drugs; Photoredox catalysis; Propionic acid; Reaction mechanisms; Reagents; Reducing agents; Science; Science (multidisciplinary)
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-021-26794-8

Nonsteroidal anti-inflammatory drug derivatives (NSAIDs) are an important class of medications. Here we show a visible-light-promoted photoredox/nickel catalyzed approach to construct enantioenriched NSAIDs via a three-component alkyl arylation of acrylates. This reductive cross-electrophile coupling avoids preformed organometallic reagents and replaces stoichiometric metal reductants by an organic reductant (Hantzsch ester). A broad range of functional groups are well-tolerated under mild conditions with high enantioselectivities (up to 93% ee) and good yields (up to 90%). A study of the reaction mechanism, as well as literature precedence, enabled a working reaction mechanism to be presented. Key steps include a reduction of the alkyl bromide to the radical, Giese addition of the alkyl radical to the acrylate and capture of the α-carbonyl radical by the enantioenriched nickel catalyst. Reductive elimination from the proposed Ni(III) intermediate generates the product and forms Ni(I). Enantioenriched α-aryl propionic acids are an important class of nonsteroidal anti-inflammatory medications. Here the authors use a visible-light-promoted photoredox/nickel catalyzed method to form such compunds via a three-component alkyl arylation of acrylates.