ACS catalyst: Heterocyclic C-N coupling reaction catalyzed by Ni optimized by ligand design

(hetero) aromatic amines and N-arylated heterocyclic compounds have great application space in bioactive molecules, functional materials and other fields For example, with the commercially available 5-aminoindole compounds as raw materials, many functional molecules can be obtained by C-N coupling Based on the great potential value of these compounds in practical applications, chemists have been committed to developing more convenient and efficient C-N bond construction methods When it comes to the construction of C-N bond, this problem has long been in the research of organic chemistry With the continuous efforts of chemists, a series of methods have been developed to solve this problem From snar reaction to metal catalyzed C-N coupling, such as Buchwald Hartwig coupling and Ullmann reaction (Figure 1a), there are more and more methods The most commonly used construction method in modern chemical industry is to use cheap and stable chloroheterocyclic compounds to carry out C-N bond coupling under the catalysis of PD, but this is often accompanied by another problem, that is, the recovery of precious metal catalyst, which will bring great loss if not handled properly Chemists have been trying to find cheaper and more efficient catalysts to replace the expensive PD metals Among them, using Cu and Ni as catalysts for C-N bond coupling has been proved to be a feasible strategy But so far, there is still a big problem in this field, that is, the reaction of C-N bond construction often needs to be carried out at a very high temperature, so it is an urgent problem to make the reaction under a more moderate condition It has been reported that photocatalytic or electrocatalytic strategies have been used to assist the realization of Ni catalyzed C-N coupling at room temperature, but these reactions are not suitable for heterocyclic substrates Recently, mark stradiotto's team from Dalhousie University in Canada reported their progress in ligand optimization for Ni catalyzed C-N bond coupling reaction on ACS catalyst (DOI: 10.1021 / acscalal 9b03715) (source: ACS Catalysis) the research team used the PaD2 dalphos ligands they reported earlier as the optimization template to replace the PCG group attached to p with other electron deficient π - receptor groups to optimize it Based on the above strategy, they obtained two new ligands: L1 (phen dalphos) and L2 (Figure 2a) The preliminary test results of these two ligands are shown in Figure 2B L1 ligands show very high reactivity in amination and amidation reactions (source: ACS Catalysis) later, they selected 5-aminoindole and 2-chloroquinoline as standard substrates to detect the specific performance of the ligand in catalyzing the C-N coupling of the heterocyclic substrate (Figure 2C) Through a series of experiments, they confirmed that the reaction can take place at room temperature At the same time, they found that when C1 catalyst (prepared from L1 and NiCl2) and C4 catalyst (prepared from PaD2 dalphos and NiCl2) were used, the reaction showed very high regioselectivity to two different amino sites of 5-aminoindole When C1 is used, 1a is the main product, while when C4 is used, 2a is the main product After that, the author carried out a series of substrate suitability test reactions to explore the applicability of L1 ligand (Figure 3) A series of coupling reactions between heterocyclic chlorides and heterocyclic amines were tested with C1 catalyst Most of the reactions can be carried out in high yield at room temperature At the same time, C1 catalyst can also efficiently catalyze the reaction of chlorides and ammonia at room temperature, which shows the high activity and universality of this kind of ligand (source: ACS Catalysis) finally, the author used the standard reaction as a template, and made a gram scale preparation experiment for the Ni assisted C-N coupling reaction (Figure 4) Through investigation, they found that the Ni catalyst with such ligands can catalyze the C-N bond coupling in high yield at room temperature; at the same time, when using different catalysts (C1 or C4), the reaction also showed very high selectivity Moreover, in the experiment of G-grade preparation, the catalyst loading can be reduced to 0.25 mol% without affecting the yield, which shows the application prospect of the catalyst in industry (source: ACS Catalysis) Summary: mark stradiotto's group reported a novel ligand structure The Ni catalyzed C-N coupling reaction can be carried out efficiently at room temperature At the same time, in the gram scale preparation experiment, the application of the ligand can greatly reduce the amount of catalyst loading, making the reaction have the prospect of large-scale use in industry.