Site-Selective Copper-Catalyzed Azidation of Benzylic C-H Bonds

Sung Eun Suh; Si Jie Chen; Mukunda Mandal; Ilia A. Guzei; Christopher J. Cramer; Shannon S. Stahl

doi:10.1021/jacs.0c05362

Site-Selective Copper-Catalyzed Azidation of Benzylic C-H Bonds

Sung Eun Suh, Si Jie Chen, Mukunda Mandal, Ilia A. Guzei, Christopher J. Cramer, Shannon S. Stahl

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104 Scopus citations

Abstract

Site selectivity represents a key challenge for non-directed C-H functionalization, even when the C-H bond is intrinsically reactive. Here, we report a copper-catalyzed method for benzylic C-H azidation of diverse molecules. Experimental and density functional theory studies suggest the benzyl radical reacts with a CuII-azide species via a radical-polar crossover pathway. Comparison of this method with other C-H azidation methods highlights its unique site selectivity, and conversions of the benzyl azide products into amine, triazole, tetrazole, and pyrrole functional groups highlight the broad utility of this method for target molecule synthesis and medicinal chemistry.

Original language	English (US)
Pages (from-to)	11388-11393
Number of pages	6
Journal	Journal of the American Chemical Society
Volume	142
Issue number	26
DOIs	https://doi.org/10.1021/jacs.0c05362
State	Published - Jul 1 2020

Bibliographical note

Funding Information:
This work was supported by funding from the NIH (R01 GM126832 and R35 GM134929). Spectroscopic instrumentation was supported by a gift from Paul J. Bender, the NSF (CHE-1048642), and the NIH (1S10 OD020022-1). M.M. acknowledges a doctoral dissertation fellowship from the University of Minnesota. The authors thank Dr. Joshua A. Buss for providing a sample of Gomberg’s dimer and Amelia M. Wheaton for assistance with X-ray crystallography.

Publisher Copyright:
© 2020 American Chemical Society.

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abstract = "Site selectivity represents a key challenge for non-directed C-H functionalization, even when the C-H bond is intrinsically reactive. Here, we report a copper-catalyzed method for benzylic C-H azidation of diverse molecules. Experimental and density functional theory studies suggest the benzyl radical reacts with a CuII-azide species via a radical-polar crossover pathway. Comparison of this method with other C-H azidation methods highlights its unique site selectivity, and conversions of the benzyl azide products into amine, triazole, tetrazole, and pyrrole functional groups highlight the broad utility of this method for target molecule synthesis and medicinal chemistry.",

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note = "Funding Information: This work was supported by funding from the NIH (R01 GM126832 and R35 GM134929). Spectroscopic instrumentation was supported by a gift from Paul J. Bender, the NSF (CHE-1048642), and the NIH (1S10 OD020022-1). M.M. acknowledges a doctoral dissertation fellowship from the University of Minnesota. The authors thank Dr. Joshua A. Buss for providing a sample of Gomberg{\textquoteright}s dimer and Amelia M. Wheaton for assistance with X-ray crystallography. Publisher Copyright: {\textcopyright} 2020 American Chemical Society.",

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AU - Suh, Sung Eun

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AU - Mandal, Mukunda

AU - Guzei, Ilia A.

AU - Cramer, Christopher J.

AU - Stahl, Shannon S.

N1 - Funding Information: This work was supported by funding from the NIH (R01 GM126832 and R35 GM134929). Spectroscopic instrumentation was supported by a gift from Paul J. Bender, the NSF (CHE-1048642), and the NIH (1S10 OD020022-1). M.M. acknowledges a doctoral dissertation fellowship from the University of Minnesota. The authors thank Dr. Joshua A. Buss for providing a sample of Gomberg’s dimer and Amelia M. Wheaton for assistance with X-ray crystallography. Publisher Copyright: © 2020 American Chemical Society.

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N2 - Site selectivity represents a key challenge for non-directed C-H functionalization, even when the C-H bond is intrinsically reactive. Here, we report a copper-catalyzed method for benzylic C-H azidation of diverse molecules. Experimental and density functional theory studies suggest the benzyl radical reacts with a CuII-azide species via a radical-polar crossover pathway. Comparison of this method with other C-H azidation methods highlights its unique site selectivity, and conversions of the benzyl azide products into amine, triazole, tetrazole, and pyrrole functional groups highlight the broad utility of this method for target molecule synthesis and medicinal chemistry.

AB - Site selectivity represents a key challenge for non-directed C-H functionalization, even when the C-H bond is intrinsically reactive. Here, we report a copper-catalyzed method for benzylic C-H azidation of diverse molecules. Experimental and density functional theory studies suggest the benzyl radical reacts with a CuII-azide species via a radical-polar crossover pathway. Comparison of this method with other C-H azidation methods highlights its unique site selectivity, and conversions of the benzyl azide products into amine, triazole, tetrazole, and pyrrole functional groups highlight the broad utility of this method for target molecule synthesis and medicinal chemistry.

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Site-Selective Copper-Catalyzed Azidation of Benzylic C-H Bonds

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