Zhao Yingsheng, Professor of Suzhou University: rhodium / iridium catalyzed C-H bond amidation of aromatic hydrocarbons

C-H bond amidation of lead aromatics has important application value in organic synthesis For example, amide compounds are widely found in bioactive compounds, natural products and approved drugs, so they are very important skeleton in organic synthesis chemistry Recently, Zhao Yingsheng group of Suzhou University used n-methoxybenzamide as a new type of amidation reagent to realize the amidation reaction of various arene substrates, and successfully used the reagent to realize the connection of two kinds of bioactive molecular skeleton, which may promote the development of new drug active molecules The results were published in org Lett (DOI: 10.1021/acs.orglett.9b02625 and doi: 10.1021/acs.orglett.9b03717) Brief introduction of Professor Zhao Yingsheng's research group at present, the main research directions of Professor Zhao Yingsheng's research group include: conversion of hydrocarbon bond functional group, activation of carbon oxygen bond; activation of small molecules (CO, CO2, no, O2, etc.); semi synthesis of natural products and bioactive molecules; expansion of the range of hydrocarbon bond activation substrate, and promotion of practical production and application of hydrocarbon bond activation Prof Zhao Yingsheng, Professor, School of chemistry, Suzhou University, supervisor of doctoral students From 1999 to 2003, he studied in Southwest University, from 2003 to 2008, he studied in the research group of Professor Lei Aiwen / Zhang Xumu of Wuhan University, from 2008 to 2010, he conducted postdoctoral research in the research group of Prof Ryoji Noyori (Nobel Prize winner of Chemistry) of Nagoya University in Japan, from 2010 to 2012, he conducted postdoctoral research in the research group of Prof Gong Chen of Pennsylvania State University in the United States, 2012- Professor of Suzhou University The related research work was published in NAT Commun., angew Chem Int ed., ACS catalyst and other international authoritative chemical academic journals as the first author or corresponding author Leading scientific research achievements: rhodium / iridium catalyzed C-H bond amidation of aromatic hydrocarbons amide bond is one of the important functional groups widely existing in various natural products, proteins, drugs and fine chemicals According to the results of the 2006 survey, about two-thirds of the drugs or candidate drugs have amide bonds in their structures In the past few decades, scientists have developed various methods for the construction of aromatic alkylamines, among which the most effective strategy is to directly generate C-H bond functionalization by using transition metal catalysis, the biggest advantage of which is to avoid the pre functionalization of the substrate Among them, Professor Zhi Zhiming of the University of Hong Kong used alkylamides as amidation reagents to realize amidation reaction of oxime ether substrates (j.am.chem.soc 2006, 128, 9048); next, Chang Group and Ackermann group used azides or 1,4, respectively, A series of amidation reactions of aromatic compounds have been realized with 2-dioxazole-5-one derivatives （ ACS Catal 2016 , 6 , 793; J Am.Chem Soc 2013 , 135 , 12861; Angew Chem Int Ed 2015 , 54 ,14103 ）。 Although these methods have greatly enriched the amidation reaction of aromatic substrate, it is more challenging and significant to develop and use an easily synthesized and cheap amidation reagent, and use the amidation reagent to couple a series of bioactive molecules A new amidation reagent n - methoxybenzamide was synthesized from carboxylic acid substrate A series of amidation reactions (Fig 1, c) of arene substrates have been carried out by using the reagent, and the two bioactive molecules have been successfully coupled (Fig 1, d) Figure 1: a new application of C-N bonding (source: org Lett Doi: 10.1021 / ACS Orglett 9b03717) the author first optimized the reaction conditions with 2-phenylpyridine (1a) and n-methoxybenzamide (2a) as raw materials, and obtained a single amidation product with 91% yield under the optimal conditions A series of 2-phenylpyridine substrates, acetophenone (formaldehyde) oxime ethers and a series of heterocyclic substrates containing different substituents were investigated Firstly, the electronic effects of aromatic rings and the substrates containing pyrimidine, pyrazole, benzothiazole, benzothiophene, benzoxazole and other aromatic heterocycles were investigated All of these substrates can react smoothly Then, various acetophenone (formaldehyde) oxime ethers were also investigated and found to have good functional compatibility It is worth mentioning that the active hydrogen in the benzaldehyde oxime ether type substrate is not affected, and the substrate also has good adaptability (Fig 2) Figure 2: the expansion of the substrate range (source: org Lett Doi: 10.1021 / ACS Orglett 9b02625) Then, the author conducted a series of studies on the substrate range of amidation reagents Firstly, n-methoxybenzamide substituted by various functional groups was used to react under standard reaction conditions It is well tolerated for a variety of functional groups, including ome, t-Bu, F, Cl, Br, I, CF 3 and no 2, which are substituted in their ortho, meso or para positions Using 2,6-difluoro-substituted n-methoxybenzamide and n-methoxyfuramide can also obtain good yield When n-methoxyalkylamide (5q-5y) is used, these amidation reagents can easily introduce aromatics (Fig 3) Figure 3: extension of substrate range (source: org Lett Doi: 10.1021 / ACS Orglett 9b02625) Next, the author explored the challenging amidation reagents synthesized from cinnamic acid derivatives and obtained the corresponding amidation products The amidation reagents of sorbic acid and undecylic acid also have good tolerance and yield Amino acids are a kind of very important compounds, which are rarely involved in the previous intramolecular studies Good yield (6e - 6h) can also be obtained by introducing amino acid amidation reagents into the system Several drugs, such as pregabalin, gabapentin and probenecid, are easily converted into corresponding amidation reagents Under standard reaction conditions, they are successfully coupled with 2-phenylpyridine by intermolecular C-H amidation (6i-6l) This method can also introduce the key intermediates of vimodeggi (6m) and rofluorostat (6N) into 2-phenylpyridine, providing a new way for the development of new drugs (Figure 4) Figure 4: expansion of the range of substrates (source: org Lett Doi: 10.1021 / ACS Orglett 9b02625) n-methoxyamides are stable compounds that can be easily synthesized from carboxylic acid derivatives At the same time, carboxyl is a very important functional group, which is the key intermediate of bioactive compounds and well-known drugs It is possible to connect the bioactive compounds with N-heterocycles and the drugs containing carboxylic acid by C-N bond Finally, the reaction was carried out by using [Cp * IR (III) Cl 2] 2 and agsbf 6 as solvent at 140 ℃ The key intermediates of various famous drugs and bioactive compounds, such as adapalin, ataluren (PTC124), probenecid, vitamin E succinate, pregabalin, gabapentin, undecanonic acid, stearic acid and rofluorostat, were transformed into amidation agents Because 6-arylpurine nucleosides usually show effective anti Mycobacterium, anti HCV and cell growth inhibition activities, when known drugs introduce 6-arylpurine nucleosides through C-N bond, new biological characteristics may be obtained The authors studied whether these bioactive compounds can directly introduce 6-arylpurine nucleoside through iridium catalyzed intermolecular amination All these drugs can be directly coupled with 6-arylpurine nucleoside, and the corresponding products can be obtained in medium to good yields (Fig 5) Figure 5: extension of substrate range (source: org Lett Doi: 10.1021 / ACS Orglett 9b03717) The author further linked the two bioactive molecules together through intermolecular C-H amination For example, the benzyl protected celecoxib has the effect of treating pain and inflammation related to osteoarthritis, rheumatoid arthritis and ankylosing spondylitis The author used it to couple with various amidation reagents with bioactive compounds, such as gabapentin (6b), alanine (6c) and butynine (6D), and obtained good to medium yield Amino acids are a kind of very important bioactive compounds, which are often used as key intermediates of various drugs, such as pantothenic acid, remifentanil and so on The amino acids were converted into aminating reagents and introduced into ataluren (6e) in high yield through intermolecular amination Edaravone is a kind of medicine which can be used for rehabilitation and treatment of ALS after stroke However, when some amidation reagents are used to react with edaravone directly, the required intermolecular amidation products cannot be obtained, but CBZ protected edaravone can react effectively For example, amidation reagents from probenecid and ataluren are successfully coupled with edaravone protected by CBZ under standard reaction conditions, so as to obtain intermolecular amination products (6G and 6h) in high yield Amination reagents from key intermediates of rofluorostat can be introduced into edaravone protected by CBZ in good yields (6F and 6I) It is important that the method is easy to achieve gram level reaction, and the product can be obtained in 58% yield for 6h Next, the author proved that CBZ protecting group can be easily removed, thus producing coupling bioactive molecule 7 with excellent yield It is worth noting that under mild conditions, the acetyl group in 3B can be easily removed, resulting in an excellent yield of 3B 'product (Fig 6) Figure 6: expansion of substrate range and further transformation (source: org Lett Doi: 10.1021 / ACS Orglett 9b03717) The author then made control experiments to prepare the amidation reagent 8, and further reacted under the standard reaction conditions The yield of the product 9 was 63%, and the yield of 4-biphenylmethanol 10 was 60% % The results show that when n-methoxyamide is used as aminating agent, the by-product is methanol Although the catalytic amount of sodium acetate promoted the conversion, the yield of 9 decreased sharply when the amount of sodium acetate increased more than 50 mol% These results show that the reaction is more likely to take place under acidic conditions Although the exact reason is not clear, it may be that protonic acid plays an important role in activating C-O bond during the catalytic cycle (Fig 7) Figure 7: control experiment (source: org Lett Doi: 10.1021/acs.orglett.9b03717) Finally, the author proposed a possible reaction mechanism First, five membered ring intermediate I was formed by iridium (III) - induced C-H bond activation Amination reagent is coordinated with intermediate I to form complex II The active protons in complex II can be removed with the help of acetate anion to form complex III Protonic acid can activate methoxy group to produce iridium (V) complex, which is then reduced and eliminated to obtain complex IV, and finally protonated to produce product 9 (Fig 8) Figure 8: catalytic cycle (source: org Lett Doi: 10.1021/acs.orglett.9b037