Late-stage conversion of carboxylic acids to nitriles with Mg and Pd cocatalysis

The direct synthetic approach from versatile and abundantly sourced carboxylic acids to nitriles has garnered considerable attention for a long time. However, the highly unfavourable thermodynamics of this process make it challenging to achieve under mild conditions and with broad functional-group tolerance. Here, inspired by biosynthetic pathways of nitrile synthesis and urea activation, we present a mild Mg- and Pd-cocatalysed nitrile synthesis from carboxylic acids with the simple, inexpensive and readily available urea as the nitrogen source. A pathway involving nucleophilic addition of carboxylic acid to urea is supported by both mechanistic studies and density functional theory calculations. This chemistry also demonstrates efficiency for the late-stage modification of complex drugs and natural products and offers substantial opportunities for the synthesis and optimization of valuable compounds. (Figure presented.)