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. 2020 Jul 1;142(26):11388-11393.
doi: 10.1021/jacs.0c05362. Epub 2020 Jun 23.

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

Sung-Eun Suh  1 , Si-Jie Chen  1 , Mukunda Mandal  2 , Ilia A Guzei  1 , Christopher J Cramer  2 , Shannon S Stahl  1
Affiliations

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

Sung-Eun Suh et al. J Am Chem Soc. .

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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Figures

Figure 1.
Figure 1.
Azides are important intermediates in organic syntheses (A) and medicinal chemistry (B) and are ideally prepared by direct azidation of sp3 C─H bonds (C). NFSI, N-fluorobenzenesulfonimide. Mes-Acr, 9-mesityl-10-alkylacridinium catalyst.
Figure 2.
Figure 2.
(A) Synthesis and crystal structure of [(BPhen)CuII(N3)(μ-N3)]2 (hydrogen atoms and chlorobenzene molecule omitted for clarity). (B) Reaction of [(BPhen)CuII(N3)(μ-N3)]2 with Gomberg’s dimer (6 mol% Cu(OAc)2/BPhen, 3.6 equiv. TMSN3, 2.5 equiv. NFSI).
Figure 3.
Figure 3.
Three proposed pathways for azidation of the benzyl radical (A), and simplified energy diagrams comparing the three pathways (B) (see text and Supporting Information for details).
Figure 4.
Figure 4.
Azidation site selectivity with different catalytic methods (see Section 5 in the Supporting Information for details). Standard condition for method I; substrate (0.4 mmol), Cu(OAc)2 (2.0 mol%), BiOx (4.0 mol%), TMSN3 (3.6 equiv.), NFSI (2.5 equiv.), 0.2 M MeNO2, 30 °C, 24 h for 3b, 48 h for 3c and 3d.
Figure 5.
Figure 5.
Derivatization of azides to access primary amine in (−)-dehydroabietylamine (A), pyrrole in Lipitor precursor (B), triazole in anti-tuberculosis agent (C), and tetrazoles in celestolide analogues (D).
See this image and copyright information in PMC

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