Nickel-Catalyzed Reductive Cyanation of Aryl Halides and Epoxides with Cyanogen Bromide

Abstract

Nitriles are valuable compounds because they have widespread applications in organic chemistry. This report details the nickel-catalyzed reductive cyanation of aryl halides and epoxides with cyanogen bromide for the synthesis of nitriles. This robust protocol underscores the practicality of using a commercially available and cost-effective cyanation reagent. A variety of aryl halides and epoxides featuring diverse functional groups, such as -TMS, -Bpin, -OH, -NH₂, -CN, and -CHO, were successfully converted into nitriles in moderate-to-good yields. Moreover, the syntheses at gram-scale and application in late-stage cyanation of natural products and drugs reinforces its potentiality.

Keywords: cyanation; cyanogen bromide; nickel catalysis; nitriles; reductive coupling.

Scheme 1

Preparation of nitriles via cyanation.

Scheme 2

Substrate scope for aromatic nitriles. Reaction conditions: 1 (0.2 mmol), BrCN (0.4 mmol), NiCl₂·1,10-phen (10 mol%), Zn (3.0 equiv), and dioxane (0.5 mL) at 50 °C for 12 h. Isolated yields.

Scheme 3

Mechanistic studies for cyanation of aryl halides.

Scheme 4

Substrate scope of epoxides. Reaction conditions: 3 (0.2 mmol), BrCN (0.6 mmol), NiBr₂ (10 mol%), L1 (12 mol%), Mn (3.0 equiv), DBU (1.5 equiv), and dioxane (0.5 mL) at 50 °C for 12 h. Isolated yields.

Scheme 5

Reaction intermediate experiments.

Figure 1

Reaction kinetics. (a) Reaction profile of cyanation of aryl halide 1h; (b) reaction profile of cyanation of epoxide 3a; (c) order in [NiBr₂] of cyanation of epoxide 3a; (d) order in [3a] of cyanation of epoxide.

Scheme 6

Proposed reaction mechanism.