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

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 Cu II -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.

Anionic Bisoxazoline Ligands Enable Copper‐Catalyzed Asymmetric Radical Azidation of Acrylamides

“…The remarkably different enantioselectivities between the neutral Box L1 and the anionic CN‐Box L4 triggered us to investigate the insight of these ligands. Considering the versatile bridging modes of azide in copper complexes, neutral Box (e.g., L1 ) coordinated monomeric (L1)Cu II azide species could simultaneously dimerize to give an azide bridged (L1)Cu II dimer, which was supported by our DFT calculation at the ω B97X‐D level of theory (Δ G =−13.6 kcal mol −1 , see Figure S2) [3g, 12] …”

“…Radical azidation represents a powerful tool for the synthesis of alkylazides [3d–g, 6] . However, nearly all the present protocols lead to the racemic targets, [7] which results from notorious difficulty as the following reasons: (1) the ready generation of the azidyl radical could result in the undesired side reactions, which would depletes the desired radical coupling with carbon‐centered radicals; [8] (2) transition metal‐catalyzed radical azidation reactions were demonstrated as efficient tools for the alkylazide synthesis, [3g, 6, 7, 9] where the C‐N 3 bonds are generated from an outer sphere pathway with carbon radical attacking at terminal N 3 atom (Scheme 1 A). Thus, the relatively far away of reaction site to catalyst chiral center make enantioselective radical azido‐transfer even more challenging.…”

“…More importantly, Stahl and co‐workers recently reported a radical azidation of benzylic C−H bond, in which a copper‐azide dimer having neutral bisoxazoline (Box) ligands was involved, and both bridging and terminal azides can be attacked by the carbon centered radical to lead to two opposite azidation enantiomers, which compromise the enantioselectivity and result in poor er values (Scheme 1 B, for details, see the supporting information of ref. [3g]).…”

Benzylic Methylene Functionalizations of Diarylmethanes

“…Stahl and group came up with another such important transformation involving site-selective copper-catalyzed azidation of benzylic CÀ H bonds. [38] Although the authors have demonstrated a wide substrate scope for benzylic CÀ H azidation, most of the examples are demonstrated employing alkylarenes. Only a few substrates exemplify benzylic CÀ H azidation of diarylmethanes (Scheme 22).…”

“…For this reason, several efforts have been demonstrated for specific sp 3 C−H azidation (one such example is included above; Scheme ). Stahl and group came up with another such important transformation involving site‐selective copper‐catalyzed azidation of benzylic C−H bonds . Although the authors have demonstrated a wide substrate scope for benzylic C−H azidation, most of the examples are demonstrated employing alkylarenes.…”