Wang Qingmin, Professor of Nankai University: direct alkylation of hydrocarbon bonds of azaaromatic rings by deoxidation of aldehydes or ketones

Lead azaaromatic rings are widely found in natural products, drug molecules, organic materials and ligands It is of great significance to modify azaaromatic ring by selective hydrocarbon bond functionalization Under the condition of acidity and oxidation, the addition reaction of free radicals to azaaromatic ring, i.e Minisci reaction, provides a very efficient method to synthesize alkyl substituted azaaromatic ring However, Minisci reaction often requires excessive oxidants, acids and high temperature, which greatly limits the application of substrates Up to now, the main precursor compounds used in Minisci reaction to produce free radicals include carboxylic acid, active and inactive alkane, boric acid, sulfite, halohydrocarbon, alcohol and amine However, Minisci reactions, which are widely used in nature and rich in aldehydes and ketones as the source of alkyl radicals, have not been reported yet The challenge is that the reactions need to break the carbon oxygen double bonds and the polarity of carbonyl compounds does not match the azaaromatic ring Recently, Professor Wang Qingmin's research group of Nankai University has made a great breakthrough in this field They combined the process of proton transfer electron coupling (PCET) under the condition of photocatalysis with the process of spin center transfer (SCS) in the organism, and realized the Minisci hydrocarbon bond alkylation reaction with aldehyde or ketone as the alkylation autoradical equivalent This method can be used for the functional modification of medicine, pesticide, natural products and organic materials in the later stage, which provides an efficient and practical method for the research and development of new drugs and materials Relevant research results are applied for invention patents and published in SCI Adv (SCI Adv 2019, 5, eaax9955) Wang Qingmin research group of Nankai University is affiliated to the State Key Laboratory of elemental organic chemistry and the school of chemistry of Nankai University and Tianjin collaborative innovation center of chemical industry At present, the research group has more than 20 teachers and graduate students The current research work of the research group includes: separation, identification, total synthesis and structural transformation of natural pesticides; molecular design, synthesis, biological activity and structure-activity relationship of new and efficient green chemical pesticides; total synthesis of natural products and efficient construction of heterocyclic molecular framework; and construction of heterocyclic molecules by free radical reaction under photocatalysis He has published more than 200 papers in J agric Food chem.; pest manag SCI.; SCI adv.; angel Chem Int ed.; chem SCI.; org Lett., etc Prof Wang Qingmin, Ph.D., Professor, doctoral supervisor Born in March 1970, graduated from the Department of modern physics, Lanzhou University with a bachelor's degree in radiochemistry in 1994, and obtained master's degree in organic chemistry and doctor's degree in agricultural pharmacy from Nankai University in 1997 and 2000 respectively In June 2000, he received a doctorate degree and stayed in school He was promoted to associate professor in December 2000, professor in December 2004 and doctoral supervisor in 2005 In 2004, it was selected into the "new century excellent talents support plan" of the Ministry of education, and in 2017, it was selected into the leading talents of Shandong Taishan industry (high-efficiency ecological agriculture innovation) Mainly engaged in the research and development of natural pesticide, green chemical pesticide and drug Since the work was carried out independently, I have worked in the international authoritative journal J agric Food chem., pest manag SCI., SCI adv., angel Chem Int ed., chem SCI., Arts & Rheumatism, j.med Chem., org Lett., chem Commun., adv synth Catalyst, Chem.eur J et al Published more than 200 papers included in SCI; applied for more than 90 invention patents in China, the United States and Europe with the first inventor, authorized more than 50 invention patents in China, the United States and Europe; published 3 works (chapters) A new clean production method of biomimetic pesticide pyrethroid series products, major pesticide varieties and high-end fine chemicals has been invented, which has been successfully applied to industrial production and has produced huge economic benefits A number of super efficient fungicides for plant virus disease control, green insecticides and acaricides as well as national class I new drugs have been created, which are in different stages of industrial development It has undertaken more than 30 scientific research projects, such as the national special fund for outstanding doctoral dissertation authors, the National Natural Science Foundation, the national science and technology support plan, 973 project, the national key R & D plan, the key project of the Ministry of education, the key project of Tianjin applied basic and cutting-edge technology research plan, and the special scientific research fund for the doctoral discipline point of colleges and universities He won the National Excellent Doctoral Dissertation in 2002, the 2003 Youth Chemistry Award of China Chemical Society, the 2005 invention patent award of Tianjin, the 2007 Life Chemistry Research Award of Wuxi apptec, the 2010 10th Tianjin Youth Science and technology award, the 2010 13th China Association for science and technology, the 2015 outstanding youth achievement transformation award In 1997, the 9th Dabei agricultural science and technology award, the 5th Nankai University "dedicated" award, the first prize of teaching gold, and four times won the title of "excellent doctoral dissertation instructor of Nankai University" 21 doctoral students and 41 master's students have been trained and graduated, and they have won the National Excellent Doctoral Dissertation nomination award, Tianjin excellent doctoral dissertation, Nankai University Excellent Doctoral Dissertation, Nankai University excellent master's dissertation and national scholarship Frontier research achievements: in the field of organic chemistry, carbonyl compounds are often used as the key synthon to synthesize molecules with complex structure The reaction types of carbonyl compounds, such as Grignard reaction, Wittig reaction and reductive amination reaction, are all reactions in which carbonyl compounds are regarded as carbon positive ion equivalents The reaction of carbonyl compounds as carbon anion equivalents can also be realized by polarity reversal However, the reaction of carbonyl compound deoxidation as an alkyl radical equivalent has never been realized (Fig 1a) Therefore, taking carbonyl compounds as nucleophilic alkyl radicals to participate in organic chemical reactions will undoubtedly enrich the reactivity of carbonyl compounds and make their application in synthesis more extensive There are many kinds of free radical reactions in organisms, among which proton transfer electron coupling (PCET) is a very important process to activate aldehydes and ketones Recently, the Knowles team reported a series of photocatalytic PCET processes to convert aldehydes and ketones to carbonyl groups (Fig 1b) As the synthesis unit of DNA, deoxyribose is synthesized by the process of free radical deoxygenation The key step of this process is the spin center transfer (SCS) of carbonyl group to remove one molecule of water to get the product of dehydrogenation (Fig 1c) Professor Wang Qingmin's research group of Nankai University has done a series of pioneering work in Minisci reaction (SCI Adv 2019, 5, eaax9955; chem SCI 2019, 10, 976; org Lett 2019, 21, 5728; org Lett 2018, 20, 5661; org Chem Front 2019, 6, 2902; J org Chem 2019, 84, 7532) Considering the high efficiency of PCET process and SCS process, Wang Qingmin group of Nankai University combined the PCET process and SCS process, activated carbonyl by PCET process to obtain carbonyl group, which added azaaromatic ring to carbonyl group and then broken C-O by SCS process The bond is used to realize Minisci reaction of carbonyl compound deoxidization (Fig 1D) Fig 1 Minisci reaction of carbonyl compound deoxidization (source: SCI Adv.) the author selected a variety of photocatalysts and reducers with 4-hydroxyquinoxaline and acetone (solvent) as reaction substrate When IR [DF (CF 3) PPy] 2 (dtbbpy) pf 6 (1 mol%) is used as photocatalyst, tri - (trimethylsilyl) silane (ttms, 2.0 equivalent) is used as reducing agent and TFA is used as Proton source, the target product 12 can be obtained with a nuclear magnetic yield of 96% Then the author selected the reaction solvent with cyclohexanone as alkylating agent, and obtained that acetonitrile was the best reaction solvent The control experiments were carried out further The reaction could not take place without light, photocatalyst, acid and reductant It is worth noting that ttms is very important for the reaction as reducing agent, because the commonly used amine reducing agent will form salt with TFA, and heh reducing agent will reduce the nitrogen heterocycle to get the hydrogenated product (Table 1) Table 1: after the optimal reaction conditions are obtained by the screening of reaction conditions (source: SCI Adv.), the author first investigated the substrate range of ketone and aldehyde, and found that the reaction has a wide application range for ketone and aldehyde, and the target product can be obtained in a medium to good yield (Table 2) Both ring and chain ketones can get the target product (12 - 23) in medium to good yield, but for chain ketones, with the increase of carbon chain length, the yield of the reaction decreases gradually It is speculated that with the increase of the length of the carbon chain, the steric resistance of the carbonyl group increases gradually, which makes the nucleophilic addition ability of the carbonyl group to azaaromatic ring decrease gradually The reaction is also suitable for a variety of aldehydes (24-37), and the yield of the chain aldehydes is higher than that of the chain ketones, because the position resistance of the carbonyl group (secondary carbon) formed by aldehydes is smaller than that of the carbonyl group (tertiary carbon) formed by ketones Subsequently, the author investigated the substrate application range of AZA aromatic ring The reaction has a wide application range for aza aromatic ring and the target product is obtained in a medium to good yield The reaction takes place at the position where the most electron is missing on the aza aromatic ring (Table 2) Firstly, the substrate of 4-hydroxyquinozoline was investigated The target product (38-43) can be obtained in a good yield by either electron withdrawing or electron supplying substitution of 4-hydroxyquinozoline Some common azaaromatic rings, such as benzothiazole, pyridazine and 4-methoxyquinoline, can also obtain the target product (44-49) in medium yield Pyridine type substrates can also be used in this reaction 4-phenyl and tert butyl pyridine can obtain the product (50,51) of C2 site monoalkylation in medium yield This is because it is difficult to carry out the Dialkylation of the products 50 and 51 due to their low electrophilicity 2,6-dimethylpyridine can obtain the target product (52) of C4 alkylation in good yield The introduction of small functional groups (methyl, ethyl, isopropyl, tert butyl, etc.) into drug molecules is of great significance to the study of the properties of these drugs by pharmaceutical chemists In order to demonstrate the practicability of this method, the author used this method to carry out late functional studies on some common drugs and natural products (Table 2) For example, the lipid regulating drug etobate can obtain pyridine cycloalkylation product 53 in medium yield Methylpyranone is an inhibitor of cortisol biosynthesis, which can selectively obtain monoalkylated product 54 in 35% yield Milrinone is an inhibitor and vasodilator of phosphodiesterase 3 Alkylation product 55 can be obtained in 41% yield Loratadine, an antihistamine, can be alkylated selectively at the C2 position of pyridine ring to obtain 56 Table 2 reaction substrate range study (source: SCI Adv.) explored the reaction