The Room-Temperature Palladium-Catalyzed Cyanation of Aryl Bromides and Iodides with Tri-t-butylphosphine as Ligand

Abstract

The palladium-catalyzed cyanation of aryl bromides and iodides to the corresponding nitriles occurs at room temperature when tri-t-butylphosphine is used as ligand, Zn(CN) 2 as the cyanide source and Zn dust as a co-catalyst in DMF as solvent. A variety of aromatic halides, including electron-withdrawing and electrondonating, can be efficiently cyanated under these conditions. The reactions are completed in less than 1 hour and products are produced in good to excellent yield.Aryl nitriles are important synthetic intermediates in the pharmaceutical industry because they serve as building blocks for a number of different functionalities with interesting biological properties. 1 The most direct method for the synthesis of aryl nitriles is the transition metal-catalyzed cyanation of aryl halides. 2 Although a number of elegant methods have been developed, the general procedure calls for elevated temperatures and in many cases long reaction times. In the course of our work, we needed a mild method for the preparation of aryl cyanide from an aryl bromide and thus explored other reaction conditions. We focused on the possibility of using a palladium(0) catalyzed process since palladium catalysts can be fine-tuned to perform a number of reactions at lower temperature. For example, during the past few years, the use of tri-t-butylphosphine as ligand in a variety of palladium-catalyzed processes, including Suzuki, 3 Heck, 4 Negishi, 5 Sonogashira, 6 amination of aryl halides 7 and Stille 8 couplings have been reported to occur under very mild conditions. Encouraged by these reports, we explored conditions for the cyanation of aryl halides using a Pd-P(t-Bu) 3 catalyst system.The use of Zn(CN) 2 as the cyanide source in the palladium-catalyzed cyanation of aryl halides in DMF has been shown to be general and reliable, albeit at elevated temperatures. 2a,2c-e Using this protocol, with 4¢-bromoacetophenone as a model substrate, we explored a number of room temperature reaction conditions (Table 1). To our delight, with 2.5 mol% Pd 2 (dba) 3 , 5 mol% tri-t-butylphosphine and zinc as a co-catalyst, the reaction was complete in 1 hour and we obtained an excellent isolated yield of 4¢-cyanoacetophenone (Scheme 1) ( Table 1, entry 1). A lower catalyst loading greatly affected the yield. When 1.25 mol% Pd 2 (dba) 3 , and 2.5 mol% tri-t-butylphosphine were used, an isolated yield of 60% was obtained after one hour (Table 1, entry 2). Increasing the reaction time to two hours gave an improved yield of 75%. However when 0.62 mol% Pd 2 (dba) 3 and 1.25 mol% tri-t-butylphosphine were used no product was obtained (Table 1, entry 3). Scheme 1The reaction was also highly dependent on the ligand. A number of ligands which have been reported to be effective at higher temperatures for palladium-catalyzed cyanation reactions, were used in place of tri-t-butylphosphine. Replacement of tri-t-butylphosphine with PPh 3 , Dppf, Xantphos, or 2¢-dicyclohexylphosphinobiphenyl in the general procedure yielded no product after 1 hour at room temperatur...

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“…To accomplish two-fold cyanation of 2, we had to change the cyanation conditions from those used for cyanating 1. By replacing the triphenylphosphine ligands with bulky and electron rich tris(tert-butyl)phosphine ligands (inspired by conditions reported by Maddaford and co-workers [36] ) and adding zinc powder to avoid cyanide-induced catalyst deactivation, [37,38] we were able to obtain dcIF-TTF in a yield of 60 % using Zn(CN) 2 as the cyanation agent.…”