Enantiospecific electrochemical rearrangement for the synthesis of hindered triazolopyridinone derivatives

Zenghui Ye,Yanqi Wu,Kai Zhu,Yong Li,Fengzhi Zhang,Mingruo Ding,Hong Zhang,Min Liu,Na Chen

doi:10.1038/s41467-020-17389-w

Zenghui Ye, Yanqi Wu + Show 7 more

Open Access

https://doi.org/10.1038/s41467-020-17389-w

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Journal: Nature Communications	Publication Date: Jul 20, 2020
Citations: 27	License type: open-access

Affiliation: Zhejiang University of Technology

Abstract

Triazolopyridinone derivatives are of high value in both medicinal and material chemistry. However, the chiral or hindered triazolopyridinone derivatives remain an underexplored area of chemical space because they are difficult to prepare via conventional methods. Here we report an electrochemical rearrangement for the efficient synthesis of otherwise inaccessible triazolopyridinones with diverse alkyl carboxylic acids as starting materials. This enables the efficient preparation of more than 60 functionalized triazolopyridinones under mild conditions in a sustainable manner. This method is evaluated for the late stage modification of bioactive natural products, amino acids and pharmaceuticals, and it is further applied to the decagram scale preparation of enantiopure triazolopyridinones. The control experiments support a mechanism involving an oxidative cyclization and 1,2-carbon migration. This facile and scalable rearrangement demonstrates the power of electrochemical synthesis to access otherwise-inaccessible triazolopyridinones and may find wide application in organic, material and medicinal chemistry.

Highlights

Triazolopyridinone derivatives are of high value in both medicinal and material chemistry
Triazolopyridinone derivatives are of high value for different applications in materials[1], pharmaceuticals[2,3,4], or agrochemicals[4] (Fig. 1a)
There are only scarce reports about the synthesis of secondary substituted triazolopyridinone derivatives due to the synthetic challenge associated with elimination side reactions or steric issues, and there are only two articles reported for the access of enantiomerically enriched triazolopyridinones using Mitsunobu (only three examples, no enantiomeric excess values reported)[5] or aza-Michael[6] conditions, respectively

Summary

Introduction

Triazolopyridinone derivatives are of high value in both medicinal and material chemistry. Alkyl carboxylic acids have been well explored for the Kolbe-type electrolysis[13] and decarboxylation via activated Barton or N-hydroxyphthalimide esters[14,15,16,17,18,19,20,21,22], which could generate alkyl radicals or carbocations for further coupling reactions (Fig. 1c).

Results

Conclusion