Green oxidation and coupling reaction of furan and indole

Lead furan and indole are electron rich aromatic heterocyclic compounds, which are easy to oxidize and are important sources of other heterocyclic compounds, so they are widely used in organic synthesis Although there are many oxidation reagents and conditions that can be used for the selective oxidation of furan and indole, the problem of green chemistry is usually ignored Professor Tong Rongbiao's research group of Hong Kong University of science and technology took this opportunity to develop a green catalytic system: O xone-h alide, a complex salt of potassium Peroxysulfate, to realize green oxidation of furan (J org Chem 2016, 81, 4847) and indole (g reen chem., 2017, 19, 2952; NAT Commun 2019, 10, 4754) An important feature of this system is that it is easy to operate, not afraid of water and oxygen The equivalent by-product of the reaction is only potassium sulfate, but no other organic by-product For the utilization of oxidation rearrangement products of furan, the research group has recently made a new breakthrough: the direct coupling with arylboronic acid has been realized to construct 2-arylpiperidine pharmacophore efficiently (org Lett 2020, 22, 458) Fig 1 green oxidation of indole and furan and coupling reaction of furan oxidation products and aryl boric acid Tong Rongbiao, Professor Tong Rongbiao, associate professor, Department of chemistry, Hong Kong University Science & Technology, doctoral supervisor From 1996 to 2003, he studied in the school of chemistry and chemical engineering of Hunan University and obtained bachelor's degree and master's degree From 2003 to 2008, he studied for a Ph.D in Chemistry Department of Emory University in the United States He studied the biomimetic cyclization of polyepoxy compounds and applied them to the total synthesis of natural products (AB udinol) under the guidance of Professor Frank E McDonald In 2008, he obtained a Ph.D in Science (Chemistry) and won the C Harles Lester award In 2008-2011, he engaged in postdoctoral research in Amos B Smith, III professor's laboratory, University of Pennsylvania, and developed a series of key linkers suitable for three-component anion relay chemistry He has been an assistant professor in the Department of chemistry, Hong Kong University of science and technology since July 2011, and started to establish an independent laboratory for organic synthesis research; in July 2017, he was promoted to associate professor (long-term Professor) Introduction to Professor Tong Rongbiao's research group since its establishment in Hong Kong University of science and technology in 2011, the research group has been mainly engaged in the research of total synthesis of natural products, pharmaceutical chemistry and green chemistry with the goal of training talents - young synthetic chemists, the mission of education and personal interests In the field of total synthesis, each class of natural products is independently developed, explored and completed by one student based on the goal of cultivating people The selection of target molecules is based on the individual's preference for the molecular structure of natural products rather than the pursuit of popular complex molecules, and there is a intention to avoid the suspicion of popular molecules However, the concept of total synthesis of the research group is to develop characteristic, efficient and collective synthesis strategies For example, the research group has established new and unique synthesis strategies, such as furan oxidation rearrangement (a-chromowicz rearrangement), phenol oxidation and dearomatization, series reaction, three-component reaction, etc., and completed the total synthesis of more than 100 natural products On the one hand, these topics promote the development of organic synthesis, on the other hand, lay the foundation for new drug research and development The research interests of the research group in the field of pharmaceutical chemistry are mainly focused on the antibacterials, antibiotics, natural products of anti-cancer and antiviral and their analogues containing oxygen nitrogen heterocycles In the field of green chemistry, we mainly develop the green oxidation reaction with the participation of halogen ions, and simulate the reaction activity of halogenase Green chemistry is to reduce, replace or eliminate the use and production of hazardous and harmful chemicals from the source by using new technologies, new methods, new designs and other strategies, which is a huge driving force for chemists and chemical industry to constantly pursue and explore synthetic methods On the other hand, halogens exist widely in nature and organisms and participate in many chemical reactions, such as halogenation and oxidation In organic synthesis, n-halo-succinimide (NBS, NCS, NIS) and other organic halogenated reagents are usually used to achieve the corresponding halogenation and oxidation reactions However, this kind of halogenated reagent is toxic and expensive Behind the reaction results, there are also a large number of harmful or toxic stoichiometric organic by-products, which greatly increase the difficulty of separation and purification, increase the cost of chemical waste treatment, and cause a huge negative impact on the environment Therefore, it is of great significance to find and develop more efficient, cheap and low toxic green chemical methods to obtain the application of organic halogenated reagents in organic synthesis Leading scientific achievements (1): the green system of indole oxidation is a basic organic transformation, which can provide a variety of nitrogen-containing compounds, especially 2-oxindole These compounds have been widely used in organic synthesis and drug development The electron rich properties of indole make it oxidized under many oxidation conditions However, due to the competitive oxidation of nitrogen, C2 and C3, as well as potential rearrangement and over oxidation, mixtures of oxidation products are usually observed Challenging chemical and regioselectivity requires not only a position selective oxidant, but also a suitable substituent at C2 or C3 and a protective group on nitrogen Therefore, it is not surprising that a few oxidants have been developed for one or two of the four main types of indole oxidation: (I) tetrahydro - β - carboline oxidation rearrangement into spirocyclic indole, (II) C3 substituted indole conversion into oxidized indole, (III) C2, C3 substituted indole oxidation cracking into 2-ketoacetylaniline (Witkop oxidation), (IV) halocyclized tryptamine And its derivatives Although these oxidants can solve chemical and regional selectivity with high yield under the optimized conditions, their environmental and health effects have not been solved Recently, Professor Tong Rongbiao's research group of Hong Kong University of science and technology re studied indole oxidation from the perspective of green chemistry, and developed a universal green chemistry system (oxone halide) to realize these four important indole oxidation reactions (figure-2) (green chem., 2017, 19, 2952, NAT Comm., 2019, 10:4754) This method can not only eliminate the use of harmful oxidants (such as Pb (OAC) 4, CrO 3, oso 4, t-buocl, NBS and m-CPBA), but also eliminate the production of organic by-products or toxic substances Potassium persulfate complex salt (oxone) is widely used as a green, cheap and safe oxidant, because the by-product of its reduction is non-toxic inorganic salt: potassium sulfate Although potassium persulfate complex salt is not as stable as hydrogen peroxide from the perspective of atomic economy, it not only has very good stability in storage and transportation, but also has unique selectivity for the oxidation of halides (such as bromide and chloride) under weak acid / alkaline or even neutral conditions without direct oxidation of indole By using the green indole oxidation method, we can realize the simple synthesis of natural products, such as coercecine, horsfiline, deoxyyeroline, physicol methyl ether, esermethole and protobiones A / b According to the relevant literature, the author proposed the mechanism of indole oxidation in which halogen ions participate (Fig 2) The most important feature is that halide positive ions produced by oxidation of oxone and C2-C3 double bonds of indole rich electrons form ternary Halon ions (intermediate I), and then ring opening produces electrophilic active imines Different products can be obtained by intramolecular or intermolecular nucleophilic attack Figure 2 Green oxidation of indole and its possible mechanism This achievement was recently published in green chemistry (g reen chem., 2017, 19, 2952) and nature communications (NAT Comm., 2019, 10, 4754) The main participants of this work are Dr Xu Jun and Liang Lixin postgraduates, and the corresponding author is Professor Tong Rongbiao The above research work was supported by the National Natural Science Foundation of China and the Hong Kong Research Grants Council Frontier research achievements (2): aza achmatowicz green chemistry and palladium catalyzed coupling with arylboric acid achmatowicz rearrangement reaction is based on renewable furfurfuryl alcohol as raw material, which is converted into dihydropyranone acetal through oxidation rearrangement Dihydropyranone acetals can be further converted into various synthesis intermediates and blocks, such as tetrahydropyran, dihydropyranone, oxidized pyran and pyranose, which are widely used in the synthesis of natural products In the past, the most commonly used oxidants in achmatowicz rearrangement reactions were m-CPBA and NBS, but both of the above two oxidants would produce equivalent organic by-products (succinimide and m-CHLOROBENZOIC acid) In order to overcome the drawback of appeal, Professor Tong Rongbiao's research group of Hong Kong University of science and technology has developed a green catalytic system (J org Chem., 2016, 81, 4847) with potassium bromide as catalyst and oxone as the only oxidant The only by-product of the reaction is only inorganic potassium sulfate In order to further reduce the separation and purification of the product and facilitate the subsequent conversion reaction, the research group further optimized the green catalytic system, using a small amount of water treated silica gel chromatography as the reaction carrier to realize the achmatowicz rearrangement reaction in a variety of anhydrous organic solvents (TE trahedron, 2019, 75, 1669), which can directly transform the products of achmatowicz rearrangement reaction by one pot method, thus reducing the time cost of separation and environmental damage However, the use of organic solvents does not conform to the concept of green chemistry, so the further green improvement of achmatowicz rearrangement reaction is to realize the solvent-free green catalytic reaction system (green chem 2019, 21, 64), and achieve better substrate tolerance and yield Some series of improvements and optimizations not only achieve green and efficient reaction, but also reduce the reaction cost, avoiding the tedious operation of extraction and column chromatography purification with a large number of organic solvents On the other hand, Professor Tong Rongbiao's research group has extended the green system of oxone KBr to aza achmatowicz rearrangement reaction, and completed the construction of carbon carbon bond with phenylboronic acid in one pot under the catalysis of PD (OAC) 2 after the product acetylation By using this strategy, two NK1 inhibitors ((+) - cp-99994 and (+) - l-733060) were synthesized asymmetrically （ Org Lett., 20 20 , 22 , 458-463） 。 Fig 3 The coupling reaction between aza achmatowicz rearrangement product and arylboric acid Nitrogen-containing heterocyclic system is widely existed in organic small molecule drugs, among which 2-arylpiperidine ring system is the antagonist of many targets (such as NK1, TRPM8 and PARP), and widely exists in natural products Therefore, the efficient synthesis of the pharmacophore has always been a hot topic for organic and pharmaceutical chemists At present, the synthesis strategy of 2-arylpiperidine ring system can be divided into two types: one is to introduce aryl side chain in advance, and then construct piperidine ring through chain amine cyclization reaction; the other is to directly arylate piperidine ring with strong base or lithium metal reagent (Fig 4) However, the above two strategies are based on non renewable raw materials, and need to be introduced into the substituent through lengthy steps