Cyanation of Aryl Halides

Mild cyanation methods.

The preparation of aryl cyanides is one of those reactions that med chemists do sooner rather than later. Many protocols are available, from the old diazocompounds Sandmeyer reaction to modern Cu and Pd mediated methods. However, though the Copper mediated methods are well developed there is still a need of improved Palladium cyanation methods. We present here two recent papers aimed to fill this gap.

In the first paper by Lilly chemists the chosen Pd source is Pd on carbon, which is unusual, and the cyanide source is Zn(CN)2. The protocol involves heating a mixture of the aryl halide (typically a bromide, though chlorides can be used also) with Zn(CN)2 (60 mol%), Pd/C (2 mol%), dppf (4 mol%) and Zn(CHO2)2·H2O (10 mol%) in DMAC. The mixture is heated to 100-120 °C for 12 h. For conditions that look really harsh, yields are surprisingly good, ranging from 77 to 96%. Many examples with heterocycles are included.

The second paper by Kwong et al. (The Hong Kong Polytechnic University, China) follows similar guidelines, but with a very different outcome. Their protocol involves heating a mixture of the aryl halide, specifically aryl chlorides with K4[Fe(CN)6]·3H2O, Pd(OAc)2 (2 mol%), CM-phos (4 mol%) and Na2CO3 (12 mol%) in acetonitrile/water at 70 °C for 18 h. They report 16 examples, including several heterocycles, with yields ranging from 74 to 97%.
I must add that it is a very nice paper. The authors have carried out a screening of ligands, they have studied the effect of base and solvent on the outcome of the reaction and they include even some data on how the water content of the solvent mixture affects the yield, all very useful if someone wants to scale up this reaction. In this case, an added bonus of this protocol is the low toxicity of K4[Fe(CN)6]·3H2O compared to the highly toxic Zn(CN)2.

Development of Pd/C-Catalyzed Cyanation of Aryl Halides J. Org. Chem., 2011, 76 (2), pp 665–668. See: 10.1021/jo102037y

A Mild and Efficient Palladium-Catalyzed Cyanation of Aryl Chlorides with K4[Fe(CN)6] Org. Lett., 2011, 13 (4), pp 648–651. See: 10.1021/ol1028892