Xie Jin and Zhu Chengjian research team of Nanjing University: synergistic catalysis of TERT ether polar inversion trifluoromethylthiolation

Lead organic fluoride is widely used in medicine, material science and other fields Among them, the SF3 functional group has strong electricity absorption and high fat solubility, which can significantly improve the membrane permeability and metabolic stability of parent drug molecules Therefore, the introduction of trifluoromethylthiol to organic molecules, especially complex drug molecules, has become a new research hotspot in the field of fluorine chemistry Recently, Xie Jin and Zhu Chengjian of Nanjing University have successfully realized the selective C-O radical trifluoromethylthiolation of tertiary ethers under mild conditions through further study on the synergistic catalytic system of visible light and organic small molecules Relevant research results were published in angelw Chem Int ed (DOI: 10.1002 / anie 201805927) Xie Jin, associate professor of Nanjing University, doctoral director In 2008, he received his bachelor's degree from Northeast Forestry University; in 2013, he received his doctor's degree from Nanjing University; in 2014-2017, he was engaged in postdoctoral research in the research group of Professor A Stephen K Hashmi from Heidelberg University of Germany; in July 2017, he was selected into the "peak talent support plan" of Nanjing University, joined the school of chemical engineering, and was selected into the fourteenth batch of national "thousand talents plan" The main research directions are binuclear metal catalysis and double system synergistic catalysis Prof Zhu Chengjian, Prof Zhu Chengjian, doctoral director of Nanjing University, vice president of School of chemical engineering In 1996, he received his doctorate from Shanghai Institute of organic science, Chinese Academy of Sciences, under the guidance of Professor Qian changtao From 1997 to 2000, postdoctoral research was carried out in the group led by Dr Baudry, University de Bourgogne, France, the group led by Professor Halterman, University of Houston, and the laboratory led by Professor Kochi He was employed as an associate professor of Chemistry Department of Nanjing University in 2000, promoted to Professor in 2003, and served as the director of teaching and research section of organic chemistry from 2001 to the first half of 2011 The main research fields are organometallic chemistry and organic synthesis chemistry Design and synthesize new chiral ligands, synthesize chiral catalysts with these ligands and main group or transition metal elements, and study the asymmetric reactions induced by them; explore new asymmetric organic reactions, expand the research of asymmetric synthesis methodology; apply highly selective asymmetric reactions to the total synthesis of chiral drug intermediates and chiral drugs, and expand the asymmetric synthesis method Application of the method Recent years, organic synthetic chemists have successfully developed the direct nucleophilic trifluoromethylthiolation of haloalkanes, the electrophilic trifluoromethylthiolation of alkyl metal reagents and alkenes, and the selective trifluoromethylthiolation of inert SP 3 C-H bonds However, most of these ionic strategies can only achieve the construction of first-order and second-order alkyltrifluoromethyl sulfide, and the construction of third-order alkyltrifluoromethyl sulfide with significant steric hindrance effect is still very difficult In early 2018, Xie Jin and Zhu Chengjian team realized the reverse borohydride reaction of imine with NHC borane for the first time through the cooperative catalysis of visible light catalysis and organic catalysis (angelw Chem Int ed 2018, 57, 3990) Based on the interest in and further research on synergistic catalysis, the team once again successfully solved the important problems in the research field of trifluoromethane sulfonation, and realized the specific and selective C-O bond free radical trifluoromethane sulfonation (scheme 1) of tertiary ether under mild conditions Scheme 1 C-O bond free radical trifluoromethylthiolation strategy (source: angelw Chem Int ed.) based on the previous study of the double catalytic system, the author proposed the mechanism of synergistic catalytic ether trifluoromethylthiolation Firstly, the excited state photocatalyst PC * and thiol anion undergo single electron transfer to obtain sulfur radical 4 Strong electrophilic sulfur radical 4 and substrate 1 undergo hydrogen atom transfer to produce alkoxy radical 5, and C-O bond is split to form TERT alkyl radical 6 Tert alkyl radical 6 can not only cross couple with phth-scf 3 radical anion 7, but also directly react with phth-scf 3 to form the target product 3 (scheme 2) Scheme 2 Possible reaction mechanism (source: angelw Chem Int ed.) the key to the successful realization of fixed-point trifluoromethane sulfurization is that the sulfur free radical produced can efficiently capture the hydrogen atom of methylene on the mom ether, and then generate the third-order alkyl free radical to participate in the subsequent reaction Based on the above hypothesis and conjecture, the author selected different conditions such as scheme 3b, photocatalyst, mercaptan and so on It was found that when methoxymethyl ether was used as the reactant for 1 D, 4czipn as the photocatalyst and 2 g as the organic catalyst, the target product could be obtained in 74% yield In addition, the calculated results of the organic catalyst mercaptan are also in accordance with the experimental results (scheme3a) Among the selected mercaptan, the sulfur free radical of binaphthol phosphate 2G Has the highest electrophilic activity, which is consistent with the best catalytic effect in the experiment Scheme 3 screening of reaction conditions (source: Angew.Chem Int Ed.) subsequently, the author investigated the substrate applicability of the reaction and found that the reaction has a wide range of substrate applicability Even when the substrate has benzyl C-H bond, the site specific C-O bond three fluoromethylthiolation of TERT alkylether can be realized The reaction has good compatibility with ketone, ester, amide, heteroaromatic ether and halogen Most of the C-H trifluoromethylthiolation reactions controlled by hydrogen atom transfer usually take place on the methylene C-H bond, but the methylene C-H bond is not affected in this reaction (scheme 4) Scheme 4 Investigation on the applicability of substrates (source: angel Chem Int ed.) difluoromethylthiol is widely used in medicine and agricultural chemicals Therefore, the introduction of difluoromethylthiol into organic molecules has attracted great attention of researchers Under the same conditions, the reaction is also suitable for scheme 5 Scheme 5 Difluoromethylthiolation of tertiary ethers (source: angel Chem Int ed.) in order to further prove the practicability of the scheme, the author successfully realized the trifluoromethylthiolation with complex tertiary alcohols (scheme 6), but the known nucleophilic method can not realize the trifluoromethylthiolation of tertiary alcohols Scheme 6 Trifluoromethylthiolation of tertiary alcohols (source: angelw Chem Int ed.) conclusion: this method has mild reaction conditions, very good functional group tolerance and regional selectivity, and is also very compatible with benzyl C-H bond with lower BDE This work provides a new idea for the construction of three-stage alkyltrifluoromethyl sulfide with steric hindrance Relevant research work has applied for Chinese patent (Xie Jin, a method for preparing three-stage alkyltrifluoromethyl sulfide, patent application No.: 201810431033 X) 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, chembeangoapp, chembeango official microblog, CBG wechat subscription number and other platforms jointly launch the column of "people and scientific research", approach the domestic representative research group, pay attention to their research, listen to their stories, record their demeanor, and explore their scientific research spirit.