Reductive cyanation catalyzed by JACS: Ni

Ni catalyzed reductive coupling reaction is a powerful tool for the construction of C-C bond Two electrophilic reagents can be coupled together by this method Compared with the coupling reaction of traditional Grignard reagent, the coupling reaction of organic halides with alkenes, CO2 and carbonyl compounds has the advantages of less reaction steps and high selectivity Therefore, the development of new coupling reagents is of great significance to promote the development of reactions Benzonitrile structure widely exists in medicine It is a convenient method to prepare these compounds directly through aryl halides and electrophilic cyanogen reagents This process is equivalent to the catalytic version of traditional multi-step electrophilic cyanogenation reaction The addition reaction of aryl nickel to cyano compounds has been reported before, but the products are usually ketones, but the benzonitrile products produced by similar processes have not been reported Recently, Sophie A L rousseaux group of the University of Toronto, Canada, first synthesized benzonitrile by one-step reduction coupling reaction The reaction uses 2-methyl-2-phenylmalondinitrile (MPMN), a nontoxic reagent, as the cyanogen source, without the participation of cyanide anion, and the reaction is safe The reaction is mainly carried out through the migration and insertion of cyano group and β - carbon elimination by Ni (I) - aryl intermediate It is worth mentioning that NaBr can increase the reaction activity as an additive (source: J am Chem SOC.) firstly, the author used 3-Bromoanisole (1a) as template substrate to optimize the conditions (Table 1) By optimizing the reaction conditions of ligands, reducers and cyanogens, the author determined that the optimal reaction conditions were as follows: Ni (bpy), H 2O as metal salt, zinc powder as reducing agent, DMA as solvent, MPMN as cyanogen source, substrate reacted at 80 ℃ for 16 h, and the final yield was 90% It is worth noting that aryl iodide can only be obtained in 53% yield (source: J am Chem SOC.) determined the optimal reaction conditions, the author inspected the universality of the reaction (Table 2) Among them, electric effect and potential resistance effect have no effect on the reaction The ortho substituted substrate can also obtain the corresponding products, and both the rich and the lack of electricity substrates can participate in the reaction Many functional groups are also compatible with reaction conditions, including olefins, halogens, OTS, acetals, alcohols, ester groups and amides Subsequently, the heterocyclic aryl bromine substrates were investigated, and the heterocycles of indole, carbazole, dibenzofuran, pyrrole, quinoline, pyridine and so on did not affect the reaction At last, the target product can be obtained in medium yield by cyanation of the active molecules (source: J am Chem SOC.) finally, the author studied the mechanism of oxidation addition intermediate, and proposed a catalytic cycle (scheme 2): firstly, Ni (0) oxidizes and adds aryl bromine to form nickel intermediate 6, which is then reduced to Ni aryl intermediate 7 by zinc powder, and then 7 MPMN In the process of migration and insertion, 8 was produced, and the final product and 9 were produced by β - carbon elimination Then 9 was exchanged with zinc bromide to produce Ni (I) - Br intermediate 10, and finally 10 regenerated Ni (0) catalyst under the action of zinc powder (source: J am Chem SOC.) because NaBr can promote the reaction, the author then used NaBr as an additive to realize the cyanation reaction of aryl chlorine and aryl OTS, aryl OMS, aryl OTF and other substrates (Table 4) It is speculated that NaBr may promote the oxidation addition step (source: J am Chem SOC.) Summary: Sophie A L rousseaux group developed the reductive cyanation of aryl halides and aryl pseudo halides, and synthesized a series of cyano compounds In the reaction, the nontoxic MPMN was used as the source of cyanogen, and the migration and insertion of cyanogen and the elimination of β - carbon by Ni (I) - aryl intermediate were carried out It is found that NaBr may promote the oxidation addition step of the reaction and improve the catalytic activity of the reaction.