Professor Wu Lei, Nanjing Agricultural University Research Group: free radical cleavage C (SP2 / SP3) - s bond and functional group transfer cyclization mediated by Di tert butyl peroxide

Benzothiazole and benzothiophene are the core skeletons of many drug molecules and functional materials, and also important intermediates in organic synthesis and drug synthesis In recent years, the efficient synthesis of these compounds has attracted the attention of chemical researchers It has been reported that the free radical cutting of aryl thioether (r = methyl, benzyl, phenyl) provides a variety of synthesis methods of benzothiazole and benzothiophene, but these studies sacrifice the atomic economy Recently, based on the previous research work of the research group (org Lett 2018, 20, 3144; org Lett 2016, 18, 452), Professor Wu Lei of Nanjing Agricultural University reported the substitution of phenylthioether isonitriles with various functional groups (alkanes, cycloalkanes, aromatics and heteroaromatics) Under the action of DTBP, the C (SP 2 / SP 3) - s bond was cut off, and the transfer cyclization of various functional groups (alkanes, cycloalkanes, aromatics and heteroaromatics) was realized Benzothiazole derivatives have very high atomic economy Relevant results were published online in organic letters (DOI: 10.1021/acs.orglett.9b02837) Brief introduction to Professor Wu Lei's research group in recent years, the research group has focused on the synthesis methods of functional organophosphorus compounds and heterocyclic compounds and nano catalytic materials, etc., in ACS catalyst., org Lett., chem Commun., org Chem Front., adv.synth Catalyst., catalyst SCI Technol., J org Chem, Chem EUR J and other international journal systems published many achievements At present, the research group has 1 associate professor, 1 lecturer, 4 doctoral students and 11 master students Profile of Professor Wu Lei, born on January 28, 1980, Professor, doctoral supervisor and vice president of School of science, Nanjing Agricultural University In 2007, he received a doctorate in science from the Chinese Academy of Sciences (Institute of chemistry, Chinese Academy of Sciences, tutor: researcher fan Qinghua) From 2007 to 2009, he respectively worked in Syracuse University and University of Notre Dame in the United States for postdoctoral research From 2010 to 2012, we introduced talents for the "hundred talents plan" of Harbin University of technology In August 2012, talents were introduced to the Department of chemistry, School of science, Nanjing Agricultural University He has been selected as the middle-aged and young academic leader of "333 high-level talent training project" of Jiangsu Province, "321 plan" of Nanjing City "and" blue and green project "of Jiangsu Province, and won the title of" excellent graduate teacher "of Nanjing Agricultural University in 2018 Frontier research achievements: the free radical cleavage of C (SP 2 / SP 3) - s bond and the transfer cyclization of functional group mediated by Di tert butyl peroxide based on the cleavage of C-S bond of S-R (r = me, et, BN, pH) to construct sulfur-containing five membered heterocycles have attracted extensive attention of scientists In 2012, K ö nig group reported the first case of photocatalytic C (SP 3) - s bond cracking of o-thiomethylarene diazonium salt and alkynes for intramolecular cyclization to build benzothiophene derivatives (org Lett 2012, 14, 5334) Subsequently, various researches focused on the cyclization of thioethers by C-S cleavage initiated by internal or external radicals However, these studies all sacrifice the atomic economy Only in 2019, Wu Jie's group used sodium bisulfite to capture the cleaved methyl radicals, while the yield of ethyl captured was only 30% (org Lett 2019, 21, 1156) This study is based on the basis of previous research of the research group (org Lett 2018, 20, 3144; org Lett 2016, 18, 452), a series of benzothiazole derivatives were designed and synthesized, which were substituted by various functional groups (alkanes, cycloalkanes, aromatics, heteroaromatics) The C (SP 2 / SP 3) - s bond was cut off under the action of DTBP, and a series of benzothiazole derivatives were constructed by in-situ transfer cyclization of various functional groups (alkanes, cycloalkanes, aromatics, heteroaromatics) , with a very high atomic economy (Figure 1) Fig 1 free radical series reaction of thioether derivatives (source: Organic letters) the author first used o-thiomethylphenyl isonitrile as raw material, optimized different free radical initiator and temperature, and obtained the target product 2-methylbenzothiazole in 93% yield under the optimal conditions Since it is well known that DTBP produces methyl when heated, the methyl source of 2-methylbenzothiazole may be confusing Therefore, the source of methyl should be clarified at this stage, which will provide the basis for the preliminary understanding of the reaction mechanism, and then provide the direction for the expansion of the substrate range Therefore, the author designed and synthesized the phenylisonitrile of deuterium substituted thiomethyl, and reacted with N, n-diallyl-4-methylbenzenesulfonamide under the optimal conditions Through the analysis of 1H-NMR and HR-MS of the reaction mixture, it is clear that the CD3 radical is dominant in the reaction pathway, which also supports that the CD3 group triggered group transfer cyclization takes precedence over the methyl radical transfer cyclization (Figure 2) In this sense, it is also possible to predict other thioethers with alkyl or aryl substituents Fig 2 capture of CD 3 and CH 3 radicals (source: Organic letters) In order to verify the feasibility of other thioethers with alkyl or aryl substituents and the application scope of the method's substrate, the author first investigated the electronic effect of thioether isonitrile aromatic ring, and these substrates can react smoothly Then, the author also investigated various alkyl substituted thioethers and found that they have good functional compatibility In addition, the author also investigated all kinds of aryl substituted thioethers, and found that the reaction can proceed smoothly It is worth mentioning that the smooth progress of thiophene substituted thioethers indicates the first case of free radical C-S bond cutoff of heterocyclic thioethers The experimental results show that aromatic rings or thioethers substituted by different functional groups have wide applicability The phenylisonitriles of various ortho ome, seme and NME were also tested, but only seme successfully obtained the product Fig 3 study on the application scope of substrate (source: Organic letters) Finally, in order to study the mechanism of the reaction, the author designed many kinds of experiments to verify (Fig 4) a Through the inhibition of tempo, it was verified that the reaction went through a free radical process; B methyl radical and cyclohexyl radical were captured by HR-MS; C H / D exchange experiment and free radical capture experiment excluded the possible participation of tbuo radical; D cross experiment verified that the reaction took place between molecules Fig 4 mechanism verification experiment (source: Organic letters) According to the literature reports and experimental results, the author speculates that the reaction mechanism is as follows (Fig 5): DTBP is pyrolyzed after heating to obtain tert butyl oxygen radicals, and then β - pyrolyzed to produce methyl radicals and release propanone At the same time, the intermediate was partially cyclized with - SR to produce 2-methylbenzothiazole (2a) and release r-radicals When the R group is not equal to the methyl group, the reaction proceeds smoothly with a small amount of byproduct 2A (usually the yield is less than 5%) It is worth noting that once r radical is produced, it will attack raw materials to obtain intermediates [C] and [D], and repeat similar reaction process to obtain the final product (2) Fig 5 possible reaction mechanism (source: organicletters) This achievement was recently published in organicletters (DOI: 10.1021 / ACS Orglett 9b02837) The authors of this paper are Kai Luo, Wen Chao Yang, Kai Wei, Yue Liu, Jun Ke Wang, and Lei Wu The above research work has been supported by Jiangsu Natural Science Foundation, basic scientific research business fees of central universities, Jiangsu University Blue project, and Jiangsu Province "333 high level talent training project" 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, CBG information wechat subscription number and other platforms jointly launch the column of "people and scientific research", approach the representative research groups in China, pay attention to their research, listen to their stories, record their demeanor, and explore their scientific research spirit.