Research group of Associate Professor Li Jian of Changzhou University: Lewis acid mediated series reaction of 3-hydroxyisoindoline-1-one with alkyne

Lead isoindolinone derivatives have become the focus of scientific research because of their good physiological activity Because of the disadvantages of the traditional synthesis methods, such as harsh reaction conditions, low yield, poor selectivity and so on, they do not meet the needs of current green chemistry Therefore, it is difficult to find a simple, effective and economic synthesis method Recently, the research group of Associate Professor Li Jian of Changzhou University has made new breakthroughs in this field (J org Chem Doi: 10.1021 / ACS JOC 8b00283) Brief introduction of Associate Professor Li Jian, doctor, associate professor of Changzhou University In 2010, he obtained a doctor's degree from Nanjing University, and his main research direction is chiral organic small molecule catalysis He joined the school of pharmacy and life sciences of Changzhou University in 2010, and conducted postdoctoral research in a.s.k Hashmi research group of Heidelberg University in Germany from August 2014 to August 2015 Li Jian, associate professor, presided over and participated in a number of research projects such as the National Natural Science Foundation of China and the youth fund of Jiangsu Natural Science Foundation In the past few years, he has conducted in-depth research on the high valent iodine reagent and gold catalytic reaction, including org Lett., adv.synth Catalyst, J Org Chem And other international SCI journals published nearly 20 research papers, and was invited to serve as reviewers of multiple journals Frontier research achievements: the series reaction of 3-hydroxy-isoindoline-1-one and alkyne mediated by Lewis acid, the derivatives of isoindoline-1-one are widely found in natural products and drug molecules because of their physiological activities such as anti ulcer, anti hypertension and antiviral Therefore, the development of synthesis methods of isoindolinone has been a hot topic in the chemical field In recent two years, Li Jian group of Changzhou University has made some achievements in the exploration of new methods for the synthesis of isoindolinone (adv.synth Catalyst., 2018, DOI: 10.1002/adsc.201701580; adv.synth Catalyst., 2017, 359, 1283; J org Chem., 2017, 82, 11084) Recently, Li Jian's team has used BF 3 · et 2O to mediate the series reaction of 3-hydroxyisoindoline-1-one and phenylacetylene Through the process of C (SP 3) - Oh fracture, C-C bond construction and hydrolysis, a series of 3 - (2-oxopropyl) - isoindolinone derivatives have been successfully synthesized The reaction avoids the process of adding protonic acid and metal catalyst, increasing protective group, high temperature and multi-step reaction Figure 1 Synthesis of 3 - (2-oxopropyl) - isoindolinone (source: J org Chem) under the action of BF 3 · et 2O Through a lot of conditions screening and optimization, the author realized the coupling reaction of 3-hydroxyisoindoline-1-one and phenylacetylene under the action of BF 3 · et 2O at room temperature for two hours, and expanded the reaction substrate under this condition According to the data in the table, we can see that All kinds of substrates have good tolerance to the reaction system Table 1 The product 3 - (2-oxopropyl) - isoindolinone 3 obtained from the reaction substrate expansion of 3-hydroxyisoindoline-1-one and phenylacetylene (source: J org Chem.) in series can be used as a key intermediate for the synthesis of various physiologically active compounds For example, compound 3 is oxidized by Baeyer Villiger to produce compound 4 in high yield, and further, a biologically active molecule pd172938 can be obtained; if the ortho substituent R2 is a halogen, isoindole [2] can be obtained by intramolecular cyclization via PD catalysis, 1-A] quinoline; N-arylation product 5 can be obtained by the arylation of compound 3, and the sedative jm1232 can be further synthesized In addition, the biologically active dihydroisoindole [2,1-a] quinoline-11 (5H) - one skeleton can be constructed by two steps of compound 5 Fig 2 Synthesis of isoindolinone ketones (source: J org Chem.) in order to understand the reaction mechanism in depth, the author conducted a control experiment, and determined that the oxygen atom in the product came from water with the 18 O-labeled h 218 O on this basis, the author proposed the possible reaction mechanism (Fig 3) Firstly, 3-hydroxyisoindoline-1-one 1a is dehydrated under the action of BF 3 · et 2O to form n-acylimide a; then, the nitrogen ion intermediate a is attacked by the nucleophile phenylacetylene 2a, and the alkynyl group is also attacked by water to produce intermediate B, and then the onium ion C is formed Finally, 3 - (2-oxopropyl) - isoindolinone 3A was obtained by removing BF 3 · et 2O Figure 3 Possible reaction mechanism (source: J org Chem.) research work was recently published in J org Chem This work has been greatly supported by the National Natural Science Foundation youth program (2140223) and Jiangsu Natural Science Foundation youth program (bk2014, 0259), mainly completed by Liu Li, assistant researcher, Master Li, etc 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, chembeango app, 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.