Cu-Catalyzed Site-Selective Benzylic Chlorination Enabling Net C-H Coupling with Oxidatively Sensitive Nucleophiles

Abstract

Site-selective chlorination of benzylic C-H bonds is achieved using a Cu^ICl/bis(oxazoline) catalyst with N-fluorobenzenesulfonimide as the oxidant and KCl as a chloride source. This method exhibits higher benzylic selectivity, relative to established chlorination protocols, and is compatible with diverse alkyl arenes. Sequential benzylic C-H chlorination/nucleophilic substitution affords C-O, C-S, and C-N coupling products with oxidatively sensitive coupling partners.

Figure 1.

Chlorine radical as an unselective HAT agent (A), representative Cu/NFSI benzylic functionalization methods (B), and reaction sequence illustrating Cu/NFSI benzylic chlorination (C).

Figure 2.

Proposed mechanistic cycle for benzylic chlorination leveraging redox-buffering

Figure 3.

Applications of varied C─H chlorination methods on isobutylbenzene and isopentylbenzene. Yields determined by ¹H NMR spectroscopy (external std. = mesitylene).

Figure 4.

Scope of alkylarene benzylic chlorination. Reactions were run on a 0.2, 0.5, or 1.2 mmol scale. ^aReaction run at 35 °C. ^bReaction run at RT. ^cReaction run at 70 °C. ^c10 mol% TMSCl added. ^dYields determined by ¹H NMR spectroscopy (ext. std. = mesitylene). ^eIsolated as the alcohol.

Figure 5.

Benzylic chloride displacement. Reactions were run on a 0.2 mmol scale. ^aReaction run with DMF. ^bReaction run with MeCN.