Unified Approach to the Chemoselective α-Functionalization of Amides with Heteroatom Nucleophiles.

Carlos R Gonçalves,Nuno Maulide,Miran Lemmerer,Boris Maryasin,Pauline Adler,Christopher J Teskey,Daniel Kaiser,Leticia González

doi:10.1021/jacs.9b06956

Carlos R Gonçalves, Nuno Maulide + Show 6 more

Open Access

https://doi.org/10.1021/jacs.9b06956

Copy DOI

Abstract

Functionalization at the α-position of carbonyl compounds has classically relied on enolate chemistry. As a result, the generation of a new C–X bond, where X is more electronegative than carbon requires an oxidation event. Herein we show that, by rendering the α-position of amides electrophilic through a mild and chemoselective umpolung transformation, a broad range of widely available oxygen, nitrogen, sulfur, and halogen nucleophiles can be used to generate α-functionalized amides. More than 60 examples are presented to establish the generality of this process, and calculations of the mechanistic aspects underline a fragmentation pathway that accounts for the broadness of this methodology.

Highlights

The α-functionalization of carbonyl compounds has been classically dominated by enolate chemistry
More than 60 examples are presented to establish the generality of this process, and calculations of the mechanistic aspects underline a fragmentation pathway that accounts for the broadness of this methodology
Introducing such a species into the α-position of a carbonyl formally requires an oxidation event, either in the reaction itself[3,4] or in the generation of highly reactive electrophilic heteroatom reagents.[5−7] this can result in poor functional group tolerance under the reaction conditions, it more significantly means that a truly unified approach has failed to materialize, with specific reagents required for each element (Figure 1a)

Summary

■ INTRODUCTION

The α-functionalization of carbonyl compounds has been classically dominated by enolate chemistry. The recognition of the synthetic value of nucleophilic enolates, available by treatment of a carbonyl precursor with a strong base, has rendered them the reactants of choice for C−C, C−O, C−N, C−S, and C−halogen bond formation at the α-position of a carbonyl moiety for more than half a century.[1,2] Because of the inherent electronegativity of most heteroatoms listed in the preceding sentence (O, N, and halogens), their derivatives are typically nucleophilic in nature Introducing such a species into the α-position of a carbonyl formally requires an oxidation event, either in the reaction itself[3,4] or in the generation of highly reactive electrophilic heteroatom reagents.[5−7] this can result in poor functional group tolerance under the reaction conditions, it more significantly means that a truly unified approach has failed to materialize, with specific reagents required for each element (Figure 1a). This study results in a unified approach to the αfunctionalization of amides in a fully chemoselective fashion

■ RESULTS AND DISCUSSION

■ CONCLUSIONS

■ ACKNOWLEDGMENTS

■ REFERENCES