The counterattack of amine organic base: the use of soluble organic weak base in C-N coupling reaction by electron deficient palladium catalyst

Palladium catalyzed C-N bond formation has become a powerful tool for complex molecular synthesis In the past 20 years, researchers have established a large number of palladium catalyzed C-N cross coupling reactions of aryl halides and pseudo halophiles with different kinds of amine nucleophiles, and made a lot of progress in the development of ligands and pre catalysts However, there is no general method for this kind of reaction using amine organic bases Because most of the existing catalytic systems use inorganic bases, amination methods are limited by functional group compatibility and alkali solubility (Figure 1) For example, metal alkoxides and amino lithium are sensitive to humidity and have poor functional group compatibility, so the reaction tends to take place nucleophilic attack; other inorganic bases, such as CS 2CO3, K 3PO 4, K 2CO 3, are usually insoluble in organic solvents, and the reaction often requires phase transfer reagents or higher catalyst loading and temperature In addition, because the deprotonation process of heterogeneous system often occurs on the surface of alkali particles, when the stirring mode or particle size is different, the use of these bases in large-scale reactions will have repeatability problems Moreover, the insolubility of inorganic bases challenges the application of coupling reactions in continuous flow chemistry and machine miniaturization, and hinders the development of industrial technology It can be seen that the development of a catalytic system involving amine organic weak bases and suitable for a variety of amine substrates will provide an important solution to this long-term synthesis challenge Figure 1 palladium catalyzed coupling reaction of aryl halides with amines (source: J am Chem SOC.) recently, Stephen L Buchwald team from MIT reported the first general solution to the above problems, and pointed out the key factors for the success of the catalytic system in the paper, which provided guidance for the discovery of more effective catalytic system in the future Relevant papers were published on J am Chem SOC (DOI: 10.1021 / JACS 8b01696) Because of its wide range of pkbh +, organic bases are suitable for continuous flow chemistry and have good compatibility with electrophilic functional groups, so they are widely used in synthesis However, in the C-N coupling method, the use of organic bases is rare (Fig 2) One of them is the use of organophosphoronitrile P 2-et in nanomolar high-throughput screening (org Lett 2015, 17, 3370-3373; science 2015, 347, 49-53) Although the effect is good, it is expensive and needs to be stored in inert environment Under microwave irradiation, amines with weak alkalinity, such as 1,8-diazabicyclo [5.4.0] undedecarbon-7-ene (DBU) and 7-methyl-1,5,7-diazabicyclo [4.4.0] decyl-5-ene (mtbu), can be used for C-N coupling of arylperfluorobutylene sulfonate (NF) (J org Chem 2006, 71, 430-433) In this kind of reaction, DBU can only act on simple aniline, while heterocyclic amines need humidity sensitive and expensive mtbd C-N coupling can also be realized by 1,4-diazabicyclo [2.2.2] octane (DABCO) using photo oxidation-reduction Catalysis (Science 2016, 353, 279-283) This method has mild conditions, but the substrate is mainly aliphatic amine nucleophile In addition, the electrochemical mediated nickel catalyst system can also be used to realize the amidation and amination of aryl bromide (angelw Chem Int ed 2017, 56, 13088) In order to overcome the limitations of the existing methods, Buchwald group developed a catalytic system for the coupling of various amines using commercial ligands and organic weak bases Fig 2 the activity of various ligands in the coupling reaction of p-benzyltrifluoromethylsulfonic acid and different amines was explored by using oxidation addition complex as catalyst in the initial study of metal catalyzed C-N coupling method (source: J am Chem SOC.) participated by soluble amine organic bases (Fig 3) The results show that the pre catalyst P5 and P6 have the highest activity in the coupling reaction of aniline Considering the different catalytic species activities of P5 ligands and different aromatic (pseudo) halogenated compounds, the author chose the commercial pre catalyst cod (L6 PD) 2, which is stable in air, for the next study Further study shows that the coupling reaction of benzamide and benzylamine can also achieve high yield by increasing reaction temperature and time Fig 3 Comparison Experiment of ligand activity (source: J am Chem SOC.) after obtaining the best catalytic system, the author expanded the reaction substrate It can be seen from Fig 4 that amination / amidation products can be obtained in good yields from different aryl halides and aryl otfs Nucleophiles are also widely used A series of five and six membered heterocyclic amines, amines containing acid functional groups, various fats and aromatic amides can all be compatible with such reaction conditions Amine substrates which are easy to be eliminated and replaced under strong alkali conditions are also suitable for such reactions Figure 4 substrate expansion experiment (source: J am Chem SOC.) in the stoichiometric and catalytic experiments, the author observed that the ligands containing large alkyl groups performed better Inspired by Tyler's work (inorg Chem 2016, 55, 3079-3090), the author hypothesized that the size of the linked alkyl group on the phosphorus atom might affect the electrophilicity of palladium through geometric deformation Single crystal X-ray diffraction, NMR analysis, DFT calculation and other studies show that the size of the substituent of phosphorus atom can adjust the charge on the palladium atom, and the ligand L6 can generate the amine palladium complex with the most cations and the highest activity Conclusion: Buchwald group developed a catalytic system using amine organic weak base, and realized the coupling reaction of aryl (pseudo) halides with various amines and amides with wide substrate applicability Corresponding author: Professor Stephen L Buchwald