Studies On The Palladium-catalyzed Decarbonylative Cyanation Of Carboxylic Acids

Nitriles are a class of important fine chemicals,which are widely used for preparing dyes,pesticidesthe,drugs and functionalized polymers.Thus,their synthesis attracts much attention of chemists.Nitriles are conventionally produced by treatment of diazonium salts or aryl halides with Cu CN.To facilitating diverse synthesis of nitriles,many other efficient methods have also been developed.Among them,transition metal–catalyzed introduction of CN into functional molecular frameworks via cyanation of(pseudo)halides with variety of organic and inorganic cyanide sources represents one of the most efficient approaches.Other new electrophiles have also been developed,and organometallic reagents,special arenes and phenol derivatives are successfully applied in synthesis of nitriles.Herein,we used the readily available carboxylic acids and safe TMSCN to prepare nitriles through decarbonylative coupling.The specific contents come as follows:(1)Optimization of reaction conditions: We chose 2-naphthoic acid and TMSCN as the model substrates.By screening the metal catalysts,ligands,bases,solvents,temperature and the in situ activators of carboxylic acids,we obtained the optimal reaction conditions to achieve the decarbonylative cyanation of 2-naphthoic acid,producing the expected2-naphthonitrile in high yields.(2)Investigation on substrate scope: Under the optimal reaction conditions,we investigated the substrate scope of carboxylic acids.It is found that both electron-rich and electron-deficient aromatic carboxylic acids worked well and were efficiently converted into the expected nitriles.Alpha-aryl cinnamonitrile was also synthesized from the corresponding acid.Notably,this reaction is applicable to the direct cyanating modification of bioactive moluecules such as probenecid,3-Methylflavone-8-carboxylic acid,adapalene,eudesmic acid,piperonylic acid and telmisartan.Those results well demonstrate the potential synthetic value in organic synthesis.(3)Mechanistic studies: Hammett analysis showed a good linear correlation and positive slop(ρ = +1.26),indicating a relatively strong substituent effect in this reaction.The large positive ρ value also implied that the rating step would be an electron-density increasing process.In the combination of previous DFT calculations,we deduce that decarbonylation would be the rate-determining step of this reaction.The intermolecular experiments showed that this reaction favored electron-deficient carboxylic acids,which is well consistent with Hammett analysis.Control experiments showed benzoyl cyanide and anhydrides could produce the corresponding nitriles under the reaction conditions,indicating that those compounds might be involved in the current reaction as ke intermediates.On the basis of those results and previous references,a plausible mechanism was proposed.