Amide/Ester Cross-Coupling via C-N/C-H Bond Cleavage: Synthesis of β‑Ketoesters Jiajia Chen, Devaneyan Joseph, Yuanzhi Xia, and Sunwoo Lee* Cite This: J. Org. Chem. 2021, 86, 5943-5953 Read Online ACCESS Metrics & More Article Recommendations * sı Supporting Information ABSTRACT: Activated primary, secondary, and tertiary amides were coupled with enolizable esters in the presence of LiHMDS to obtain good yields of β-ketoesters at room temperature. Notably, this protocol provides an efficient, mild, and high chemoselectivity method to synthesis of β-alkylketoesters using the cross-coupling between aliphatic amides and esters. Meanwhile, gram-scale secondary and primary amides reacted via in situ generated activated tertiary amides and exhibited good reactivity when coupled with esters. T he Claisen condensation reaction, which generates a β- ketoester from the reaction of two esters in the presence of a strong base, is a quintessential carbon-carbon bond- forming methodology utilized extensively in organic synthesis. 1 In addition, Claisen condensation between an ester and an amide bearing an α-proton is a classic and indispensible tool for the synthesis of β-ketoamides. 2 To the best of our knowledge, a Claisen-type coupling between an amide and an enolizable ester has not been reported, with the exception of Weinreb, acylbenzotriazole, and acylimidazole-type amides. 3 Furthermore, there has been no account of a coupling reaction between an amide and an ester, wherein they both contain α-protons, to yield β- ketoesters, since Claisen condensation was first reported in 1886. One of the reasons for this stems from a practical rationale, wherein the β-ketoester product can be readily obtained from classical Claisen condensation between two different esters. However, one of the drawbacks of Claisen condensation is the undesired cross-condensation product formed when both esters possess α-protons (Scheme 1a). Therefore, the combination of enolizable and nonenolizable esters has generally been employed to obtain various β- ketoesters. Another reason for avoiding the use of an amide as an electrophilic carbonyl species is that C-N bond activation in amides for further transformation has been a long-standing challenge. Transformations via C-N bond cleavage of amides have received much attention, resulting in the development of numerous synthetic methods over the past decade. 4 For example, reactions between amides and amine nucleophiles afford transamidated products via transition-metal catalysis, as well as under metal-free conditions. 5 The use of alcohols as nucleophiles generates esters. 6 Transition-metal-catalyzed Suzuki, Negishi, and Sonogashira-type reactions entail the reaction of a carbon nucleophile with amides to form corresponding ketones (Scheme 1b). 7 Recently, we reported Received: December 2, 2020 Published: March 1, 2021 Scheme 1. Claisen Condensation and C-N Bond Cleavage of Amides Note pubs.acs.org/joc © 2021 American Chemical Society 5943 https://dx.doi.org/10.1021/acs.joc.0c02868 J. Org. Chem. 2021, 86, 5943-5953 Downloaded via CHONNAM NATL UNIV on April 16, 2021 at 11:42:54 (UTC). See https://pubs.acs.org/sharingguidelines for options on how to legitimately share published articles.