Construction of Quaternary Stereocenters by Nickel‐Catalyzed Heck Cyclization Reactions

Abstract

A nickel-catalyzed Heck cyclization for the construction of quaternary stereocenters is reported. This transformation is demonstrated in the synthesis of 3,3-disubstituted oxindoles, which are prevalent motifs seen in numerous biologically active molecules. The method shows broad scope, proceeds in synthetically useful yields, and provides a rare means to construct stereochemically complex frameworks by nonprecious-metal catalysis.Supporting information and the ORCID identification number(s) for the author(s) of this article can be found under http://dx.

Breaking Amides using Nickel Catalysis

“…3j The esterification of amides has remained a challenging transformation for many decades, which rendered it an exciting starting point for our studies. Notable methods for the esterification of amides include classical alcoholysis under basic or acid conditions (often with heat and a large excess of nucleophile), 16a the nitrosation of N -methyl amides, 26 reactions of acyl aziridines, 27 and Keck’s methylation/hydrolysis protocol.…”

“…Following this paradigm, our laboratory has recently developed several C–C and C–heteroatom bond forming reactions of amides to give ketones, esters, and amide products. 3j–m,o This Perspective highlights such efforts. Although not our focus herein, many other related advances deserve high praise, such as the nickel-catalyzed decarbonylative borylation by Shi, 15a Szostak’s nickel-catalyzed Negishi coupling of amides to access biaryls, 15c Szostak’s decarbonylative and nondecarbonylative Pd-catalyzed reactions of twisted amides, 15e,23 Zou’s Pd-catalyzed Suzuki–Miyaura coupling of amide derivatives, 24 and Murakami’s insertion of alkenes into the C–N bonds of β-lactams.…”

“…1 Despite the longstanding prevalence of palladium catalysis in this field, much interest has recently been devoted to the use of base-metal catalysis to enable coupling reactions (Figure 1). 2 Our laboratory 3 and others have focused on the use of nickel catalysis due to (a) nickel’s natural abundance and consequential low cost ($720/oz. for Pd vs $0.47/oz for Ni), 2d–h (b) favorable toxicological profiles for orally administered drugs (permissible daily exposure: 100 μg/day for Pd vs 500 μg/day for Ni), 4 (c) opportunities in green chemistry, 3g–i,5 and (d) the potential to develop new chemical transformations on the basis of alternate reactivity profiles.…”

“…For example, intermolecular C–C bond forming reactions using unconventional substrates such as carbonates, carbamates, esters, and ethers have been reported for both aryl 2e,3a–i,7 and benzylic 8 electrophiles. Nickel has also been strategically employed in Heck reactions, 9 aminations, 10 and reductive couplings.…”

“…11 Other notable examples involving nickel catalysis include its synergistic use in photoredox catalysis, 12 in addition to efforts in C–H 13 and C–F bond activation. 14 Finally, the activation of amide C–N bonds 3j–o,15 using nickel catalysis, which is the topic of this Perspective, has recently emerged as a powerful synthetic tool.…”