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Sci Adv. 2017 Aug 9;3(8):e1700826. doi: 10.1126/sciadv.1700826. eCollection 2017 Aug.

In situ generation of N-unsubstituted imines from alkyl azides and their applications for imine transfer via copper catalysis.

Author information

1
School of Pharmaceutical Sciences, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology (Ministry of Education), Tsinghua University, Beijing 100084, China.
2
Medicinal Chemistry, Genomics Institute of the Novartis Research Foundation, San Diego, CA 92121, USA.

Abstract

Although azides have been widely used in nitrene transfer reactions, in situ generation of N-H imines from azides for downstream transformations has rarely been explored. We report copper-mediated formation of N-unsubstituted aliphatic imines from easily available aliphatic azides using a customized phenanthroline-based ligand (L1*). Through trapping in situ-generated N-H imines, multisubstituted pyridines or indoles were readily synthesized. 13C-labeled azide was used as part of an isotope labeling study, which suggests that the construction of pyridine derivatives involves a three-component dehydrogenative condensation. The construction of 2,3,5-triaryl pyridines using this method provided evidence supporting a proposed pathway involving both imine formation and abnormal Chichibabin pyridine synthesis. The generation of N-unsubstituted imine intermediates was also confirmed by formation of indole derivatives from alkyl azides.

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