Professor Zhong Fangrui, Huazhong University of science and technology research group: Lewis acid activated disulfide initiated selective thiamine synthesis of thionitrogen heterocycle

Lead organic sulfides are widely found in natural products, drugs and bioactive molecules Heterocyclic compounds containing sulfur and nitrogen have been developed and utilized for their unique molecular structure, and their synthesis has attracted the attention of many chemists At present, the synthesis of sulfur-containing nitrogen heterocyclic compounds is mainly carried out through Ritter type reaction under the action of acid or oxidant Recently, Professor Zhong Fangrui, School of chemistry and chemical engineering, Huazhong University of science and technology, developed a selective thiamine reaction initiated by disulfide activated by Lewis acid under aerobic conditions, which realized the efficient synthesis of thionitrogen heterocyclic derivatives (DOI: 10.1021/acs.orglett.8b01803) Brief introduction of Professor Zhong Fangrui's research group Professor Zhong Fangrui's research group was established at the beginning of 2016 The main research directions of the research group are: 1) sustainable synthesis methodology, mainly including aqueous organic reaction, mechanical synthesis chemistry and green oxidation reaction; 2 ）The development of biocompatible organic reactions, including artificial enzyme catalysis, biomacromolecule modification methodology; 3) asymmetric catalysis and synthesis, including new chiral catalysts, rapid construction of complex bioactive molecules, etc At present, the research group has 4 doctors, 6 masters and 2 undergraduates Welcome interested students to join us Introduction to Professor Zhong Fangrui, professor and doctoral supervisor of School of chemistry and chemical engineering, Huazhong University of science and technology Graduated from Zhejiang University in 2008 In 2012, he received his doctorate from the National University of Singapore under the guidance of Professor Lu Yixin From 2013 to 2015, he was engaged in the postdoctoral research of Humboldt scholars at the Technical University of Munich, Germany, under the guidance of Professor Thorsten Bach Since December 2015, he has been a professor and doctoral supervisor of the school of chemistry and chemical engineering of Huazhong University of science and technology In 2016, it was selected into the seventh batch of "hundred talents plan" of Hubei Province So far, more than 30 papers have been published in top-ranking international journals such as J am Chem SOC., angelw Chem Int ed., chem SCI., org Lett., among which 24 papers with an impact factor greater than 5 have been reviewed by synfacts The paper was cited more than 1900 times, and the highest citation of a single article was more than 250 times, and the H factor was 23 In recent years, the electrophilic activation of olefins for the construction of sulfurized ring skeleton has been reported The team reported the addition reaction of arylthiophthalimide and olefin, and the sulfonium ion generated was attacked by side chain amino nucleophilic to construct the thionitrogen heterocycle product In addition, Professor Li Wei's team reported the intramolecular and stereoselective sulfonation of thioimidazole with olefins to synthesize heterocyclic compounds However, these methods need to add additional oxidants and the substrate has limitations, which limits their further application Figure 1 The research highlights of this work (source: Organic letters) disulfide is widely used as curing agent because of its stability, easy access and good biocompatibility The polarization of disulfide bond makes it easy to be broken by strong nucleophiles However, the polarity of the functional group is not enough for direct electrophilic addition reaction of olefins, and it needs to be activated by equivalent oxidants (such as Pb (OAC) 4 and Mn (OAC) 3) The coordination of Lewis acid with sulfur can enhance the polarization of disulfide bond and promote its thiamination with nucleophiles However, this strategy is hindered by the competitive disulfide process and the inhibition of sulfur on the metal catalyst circulation Based on the study of Lewis acid catalytic synthesis of 2,2-disubstituted indoline, the authors conclude that the metal catalyst with weak coordination and nucleophilic reagents can minimize the inhibition of Lewis acid In order to verify the above assumption, the reaction between 1a and 2a was studied Fig 2 Optimization of reaction conditions (source: Organic letters) Firstly, the author optimized the reaction conditions (Fig 2) Common Lewis acids such as Zn (OTF) 2, SC (OTF) 3, AlCl 3, InCl 3, agotf and CuBr 2 can catalyze the reaction, and CuBr 2 has the best catalytic activity, which may be related to the sulfur affinity of copper catalyst Then, the solvent was screened The results showed that when DMSO was used as solvent, the yield was as high as 89% Fig 3 The substrate range (source: Organic letters) of the reaction of enamine with disulfide shows the superiority of the reaction (Fig 3) All kinds of substituted disulfides and enamines can well tolerate and obtain excellent yield This is the first report of "one pot" synthesis of alkyl thioindoline In addition, thiotetrahydroquinoline, thiopyrrole and thiopiperidine can also be synthesized by this method Fig 4 Synthesis of seleno heterocyclic compounds (source: Organic letters) Then, the author synthesized a series of seleno heterocyclic compounds by this method, with good yield (Fig 4) Fig 5 Control experiments (source: Organic letters) in order to study the reaction mechanism, the author has done a series of control experiments (Fig 5) Firstly, the oxidation of DMSO and O2 was studied by changing the reaction solvent and reaction gas atmosphere The results showed that DMSO and O2 coexisted in the system The excessive use of disulfide is due to the by-product sulfonic acid in the reaction process In addition, the addition of BHT in different dosage excluded the possibility that the reaction was a free radical process Fig 6 possible reaction mechanism (source: Organic Letters) Subsequently, the author proposed a possible reaction mechanism (Fig 6): first, the complexation of copper salt with two thioether polarized the two sulfur bond of 2a and triggered the reaction of 1B The sulfonium ion is formed by the electrophilic addition of the olefin part, and then the nucleophilic attack of the amino group makes the sulfonium ion region selectively ring open to obtain the product 3b and phenylthiophenol The latter part is oxidized to disulfide and re enters the catalytic cycle, while the other part is oxidized to the by-product sulfonic acid Fig 7 Product expansion (source: Organic letters) Finally, the author further expanded the product (Fig 7) 3B can successfully remove the protective group under the action of red aluminum, and can selectively oxidize to sulfoxide 7 and sulfone 8 under different oxidation conditions In addition, 1-indole-2-formaldehyde (9) can be obtained by the desulfurization aromatization of 3B under photocatalysis, which is an effective method to convert the alkenylaniline derivatives into indole-2-formaldehyde The research results were published on organizational letters, with Ni Yang, a master of Huazhong University of science and technology, as the first author This achievement was supported by the National Natural Science Foundation of China and the start-up fund of Huazhong University of science and technology 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 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