Research group of song wangze, associate professor, Dalian University of Technology

Lead amide bond is one of the important functional groups widely existing in various natural products, proteins, drugs and fine chemicals According to the survey results in 2006, about two-thirds of drugs or candidate drugs contain amide bonds, such as paracetamol, melatonin, moclobemide, acetazolamide, etc (Figure 1) According to the statistical results in 2016, about 60% of the organic reactions frequently used in the pharmaceutical industry belong to the formation of amide bond Therefore, pharmaceutical chemists and organic chemists have been looking for more efficient and green amide bond formation methods Fig 1 The traditional synthesis method of amide bond of drugs containing amide bond (source: org Lett.) is mainly condensation reaction between carboxylic acid (or its derivatives) and amine (Fig 2a) However, this method usually needs high temperature and strict water free condition to facilitate the removal of water molecules to promote the reaction Amide coupling reagents, such as DCC or EDC, can promote the formation of amide bonds under mild conditions, but also produce stoichiometric waste, which does not meet the requirements of green chemistry Recently, boron catalyzed or metal catalyzed amide bond formation reactions have been developed in succession Although these problems can be partially solved, the development of new green chemical methods for amide bond formation is still very urgent and has a broad application prospect Photocatalysis, through the conversion of light energy into chemical energy, to achieve the conversion of various functional groups, is one of the hot areas of green chemistry research Recently, Tan group used the metal photosensitizer Ru (bpy) 3cl2 to obtain amides through the formation of disulfide intermediates Biswas group reported that CdS nanoparticles were used as metal photosensitizers to prepare amides through heterogeneous photocatalysis (Fig 2b) However, in most successful cases, expensive or toxic metal catalysts are used for light conversion In addition, a large number of organic bases or inorganic bases need to be used, which limits their further application in practice Especially for pharmaceutical industry, it is urgent to develop a new method of amide bond formation without metal, alkali and additives However, the synthesis of amides without metal, alkali or additives under mild conditions has not been reported Recently, song wangze group of Dalian University of technology has developed an environmentally friendly green synthesis method (Figure 2C) for the formation of amide bonds induced by visible light, and synthesized a series of amino acid compounds and small molecule drugs This method has the advantages of mild conditions, no need of additional alkali, metal and additives, wide range of substrates, good resistance to air and water, high yield and good functional group selectivity, and has potential application value in the field of pharmaceutical engineering The related research results were published in organic letters (org Lett 2019 Doi: 10.1021/acs.orglett 9b03905) Figure 2 Introduction to the research group of the method of forming amide bond (source: org Lett.) song wangze, associate professor The research group mainly focuses on "intelligent synthesis of functional fine chemicals such as pharmaceutical intermediates", and carries out research work in the fields of new methods of green pharmaceutical, development of sugar based chemicals and design of intelligent targeted drugs At present, there are two doctoral students and five master students in the research group Profile of associate professor Song wangze: Song wangze graduated from school of chemistry of Nankai University in 2008, master's degree from Department of chemistry of Zhejiang University in 2011, and doctor's degree from school of pharmacy of University of Wisconsin Madison in 2016 In 2016, he was employed as an associate professor by Dalian University of technology At present, he is a young member of fine chemical industry professional committee, editorial board member of several international journals and reviewer of more than ten international journals The research group mainly focused on "intelligent synthesis of functional fine chemicals such as pharmaceutical intermediates", and carried out research work in the fields of new methods of green pharmaceutical, development of sugar based chemicals and design of intelligent targeted drugs At present, there are two doctoral students and five master students in the research group Since 2017, the research results have been published in ACS Appl Mater Inter.; org Lett.; adv synth Catalyst.; J org Chem.; org Bio Chem And other well-known international journals Leading scientific research achievements: a new type of amido bond formation reaction without metal induced by visible light Under the condition that mes-acr-mebf 4 is used as photosensitizer, blue LED lamp as light source and acetonitrile as solvent, the author first investigated the substrate application scope of visible light induced amido bond formation (Fig 3) All kinds of thioacids and amines can be used as substrates to obtain corresponding amides, showing high yield (< 95%) and excellent functional group selectivity Both electron rich and electron deficient aniline can produce amide (3a - 3e) in good yield (73% - 95%) The yield of p-toluidine and p-methoxyaniline with electron donor was significantly higher than that of p-chloroaniline and p-fluoroaniline without electron donor For the p-aminobenzyl alcohol and p-aminophenol containing hydroxyl group, the amide product (3f-3g) can also be generated in good yield (78-79%) No ester by-product can be observed, which has excellent functional group selectivity It is worth mentioning that paracetamol (3G) is a widely used non anti-inflammatory antipyretic and analgesic drug In addition to p-toluidine, m-methyl and o-toluidine can also achieve this transformation The corresponding products 3H and 3I were generated in 88% and 84% yields respectively, which may be due to the low yield of 3I due to the steric hindrance For other aromatic amines, N - (naphthalene-2-yl) acetamide (3j) can be obtained in 86% yield and 3K in 71% yield When 4.0 equivalent thioic acid is used to react with p-phenylenediamine, only 3L can be separated as the main product with a yield of 75% Next, we used other thioacids instead of thioacetic acid to expand the substrate (3m - 3W) For alkylthioic acids, such as cyclohexyl, isobutyl and n-hexyl bases, amides (3m - 3O) can be obtained in similar yields The thioic acid substrates of benzyl and phenylethyl can also produce corresponding amides (3P - 3R) in good yield When arylthioic acid is used as the substrate, the reaction has a very obvious electronic effect (3T - 3W) The electron deficient substrate (3V and 3W) can provide a higher yield than the electron rich substrate (3T and 3U) Fig 3 The substrate range of photocatalytic amide bond formation reaction (source: org Lett.), then, a series of amino acid derivatives are further prepared by this method (Fig 4) When Fmoc Gly sh was used as the substrate, the corresponding amidation product 4A was obtained in 84% yield Besides Fmoc protecting group, CBZ and BOC Group also have good applicability (4B - 4D, 79% - 87%) Other amino acids (such as pro, met and THR) can participate in the reaction, and the corresponding amide product 4E - 4G is obtained in good yield (77% - 85%), which shows that the method has good functional group selectivity again The yield (4h) of Phe is 84%, and the BOC protecting group can be easily removed by one pot method (4I, 75%) Figure 4 The substrate range of photocatalytic amino acid modification reaction (source: org Lett.) later, the author demonstrated the potential application value of this method in the field of pharmaceutical engineering by preparing a series of important drug molecules (Figure 5) Moclobemide (3x) was synthesized by reaction of 4-chlorobenzoic acid (1V) and alkylamine (2x) in 89% yield Moclobemide, a selective reversible monoamine oxidase inhibitor (MAOI) for Rima, is used in the treatment of depression and social anxiety Melatonin (3Y) can be obtained by N-acetylation of indoleamine 2Y in 92% yield The amide bond is selectively formed in the alkylamine part rather than the NH part of indole Melatonin is a hormone secreted by the pineal gland It can regulate the sleep wake cycle through chemical reactions, and is related to autism spectrum disorder (ASD) and many other diseases 5-amino-1,3,4-thiadiazole-2-sulfonamide (2Z) can be used as a substrate to prepare acetazolamide (3Z) in 76% yield and has good functional group selectivity Acetazolamide, as an inhibitor of carbonic anhydrase, is used in the treatment of glaucoma, as well as in the treatment of tonic, clonic, myoclonic and asthenic epilepsy Fig 5 Preparation of drug molecules by photocatalytic amide bond formation (source: org Lett.) according to the experimental results of mechanism research and relevant literature reports, a possible mechanism of photocatalytic amide bond formation is shown in Fig 6 Under the irradiation of visible light, intermediate a forms free radical intermediate B through single electron transfer (set), and then two free radical intermediates are coupled to form the key intermediate disulfide compound C the disulfide compound reacts with amine substrate 2 to obtain amide product 3 Figure 6 Reaction mechanism of photocatalytic amide bond formation (source: org Lett.) in summary, the author reported a new environmentally friendly method of visible light induced amide bond formation without additional alkali, metal and additives This green method has mild conditions, excellent functional group selectivity, good tolerance to water and air, a wide range of substrates, and can be used for amino acid modification Through the synthesis of important drug molecules, such as paracetamol, melatonin, moclobemide and acetazolamide, the potential application value of this method in the field of pharmaceutical engineering is proved The above research work has been supported by the "star sea backbone" cultivation plan of Dalian University of technology, the National Natural Science Foundation and Dalian Science and technology innovation fund Nowadays, people and scientific research have been paid more and more attention in the economic life China has ushered in the "node of science and technology explosion" Behind the progress of science and technology is the work of countless scientists In the field of chemistry, in the context of the pursuit of innovation driven, international cooperation has been strengthened, the influence of Returned Scholars in the field of R & D has become increasingly prominent, and many excellent research groups have emerged in China For this reason, CBG information adopts the 1 + X reporting mechanism CBG information website, chembeangoapp, chembeango official micro blog, 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