Copper-Catalyzed Cyanation of Heteroaryl Bromides: A Novel and Versatile Catalyst System Inspired by Nature

Abstract

An improved copper catalyst system for the cyanation of heteroaryl halides leading to substituted heteroaryl nitriles is described. The catalyst system consists of simple CuI and N-alkyl­imidazoles, and mimics known Cu-containing metalloproteins. It is stable, commercially available, cheap and easily tunable. By using inexpensive and non-toxic K₄[Fe(CN)₆] and the novel Cu catalysts we were able to cyanate both activated and non-activated heteroarenes with high yield and selectivity. The generality of the procedure is demonstrated by a variety of different examples, some of which did not react under other known methods.

Key words

copper - coupling - cyanation - heterocycles - nitriles

References and Notes

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21

Initial amination reactions of bromobenzenes in the presence of Cu/1-butylimidazole showed that these catalysts are also active for other coupling reactions.

22

All chemicals are commercially available and were used without further purification. Products were fully characterized after isolation (NMR, IR, MS, EA) or in the case of commercially available products by comparison of GCMS data.
General Procedure: First, K₄[Fe(CN)₆]·3H₂O is ground to a fine powder and dried in vacuum (ca. 2 mbar) at 80 °C overnight. Then, 0.4 mmol dry K₄[Fe(CN)₆], 0.2 mmol copper precursor, the additive, and 2 mmol aryl halide are placed in a pressure tube under argon. Afterwards, 200 µL tetradecane (internal standard for GC) and 2 mL solvent are added. The pressure tube is sealed and heated for 16 h at the temperature specified in Table [1] and Table [2] . After cooling to r.t., 3 mL CH₂Cl₂ are added and the mixture is analyzed by GC. Conversion and yield are calculated as an average of two parallel runs. For isolation of the products the reaction mixture is washed with H₂O and the organic phase is dried over Na₂SO₄. After evaporation of the solvents the residue is subjected to column chromatography (silica, hexane-EtOAc). All prepared nitriles are known compounds and identified by comparison with commercially available materials.
Analytical data of 5-cyanopyrimidine: ¹H NMR (300 MHz, CDCl₃, 300 K): δ = 9.42 (s, 1 H), 9.04 (s, 2 H). ¹³C NMR (75 MHz, CDCl₃, 300 K): δ = 160.5, 159.5, 114.0, 110.2.