Professor Feng Chao Group of Nanjing University of Technology: alkylation of C − H bond via indole migration with α, α - difluoroethylene p-toluenesulfonate as alkylating agent

In recent years, the transition metal catalyzed functionalization of C-H bonds has become an efficient and widely used synthesis strategy This reaction has attracted the attention of synthetic chemists due to its high step and atomic economy Among them, C-H bond alkylation as an efficient method to introduce alkyl functional groups into molecules has also made great progress However, the commonly used alkylation reagents, such as haloalkanes, alkylmetal organic reagents, diazo compounds, olefins and so on, have some shortcomings, such as harsh reaction conditions, limited application scope, limited functional group compatibility and so on Therefore, the development of new alkylation reagents still has important theoretical and application value Recently, Professor Feng Chao, research group of advanced chemical manufacturing Institute of Nanjing University of technology and School of chemistry and molecular engineering, reported on the utilization of α, The alkylation of indole 2-position C − H bond with α - difluoroethylene p-toluenesulfonate under the action of trivalent rhodium catalyst not only provides a new method for the synthesis of related compounds, but also provides a new idea for the study of C − H bond alkylation reaction The related results are published on Chemical Communications (DOI: 10.1039 / c8cc02183j) Brief introduction of Professor Feng Chao's research group members of the research group include 1 Professor, 1 associate professor, 5 doctoral students, 9 master's students and 4 undergraduate students The main research fields of Professor Feng Chao's research group are: (1) organic fluorine chemistry; (2) transition metal catalyzed C-H bond functionalization; (3) free radical chemistry At present, the research group has sufficient funds and is in a period of rapid development Every year, there are postdoctoral, doctoral and master's candidates We welcome students who are interested in organic chemistry to join the research group Prof Feng Chao, Professor of Nanjing University of technology In 2012, he graduated from Nanyang University of technology, Singapore, and obtained a doctor's degree in organic chemistry He studied with the academicians of Singapore and Malaysia Academy of Sciences, and Professor rodping, the winner of the "Thousand Talents Program" Later, he continued to carry out postdoctoral research in Nanyang University of Technology During his doctoral degree and postdoctoral work, Professor Feng Chao, as the first author and corresponding author, published 15 academic papers in international famous journals such as nat.common., j.am Chem SOC., angel Chem Int ed., chem SCI., org Lett., chem Commun., org BIOMOL Chem In February 2016, Professor Feng Chao joined Nanjing University of technology through the talent introduction plan of "young thousand talents" of the Central Organization Department, and was employed as "Jiangsu distinguished professor" in 2017 After working independently, he worked in j.am Chem SOC., angel Chem Int ed., ACS catalyst., chem Commun., org Lett., chemsuschem, adv syn Catalyst, Asian J.Org Chem And other journals published 15 high-level research papers as corresponding authors, and was invited to write a review on tetrahedron letters In 2018, Professor Feng Chao won Thieme chemistryjournal Award for his outstanding performance after working independently The latest research results of the research group: with α, Study on a new synthesis method of fluorinated block by C-H bond alkylation of α - difluoroethylene p-toluenesulfonate via indole migration Due to the high electronegativity and small atomic radius of fluorine atom, the introduction of fluorine atom in organic compounds can often make it show a significant difference from its non fluorinated analogues in the reaction activity, so the development of new synthesis methods using fluorine-containing organic compounds has become one of the hot spots in organic chemistry research Professor Feng Chao's research group has long been devoted to the research of new synthesis methods based on fluorine-containing blocks, and has prepared a variety of novel fluorine-containing compounds and heterocyclic compounds In 2017, Professor Feng Chao's research group reported for the first time that α, α - difluoromethyl alkynes participated in the rhodium catalyzed hydroformylation and aryl transfer reaction of alkynes, which provided a new method for the synthesis of 2-alkenylaniline derivatives containing bifluoromethyl segments The mechanism study showed that the reaction may go through the aryl transfer process of spiro intermediate Among them, the strong pull electron effect of α, α - difluoromethylene inhibits the conventional [4 + 2] cycloaddition reaction via alkenyl migration, which makes the aryl migration possible Recently, based on the strategy of aryl transfer, Professor Feng Chao's research group has successfully developed a c-h-bond alkylation of indole 2 via indole transfer using α, α - difluoroethylene-p-toluenesulfonate as alkylation reagent The reaction substrate is simple and easy to obtain, easy to operate, mild condition, without additional additives, high yield, good functional group compatibility (halogen atom, methyl, methoxy, ester, nitro, amide and other functional groups can be well compatible) It is worth pointing out that fluorine atoms play an important role in selective migration and insertion of olefins and indole group migration In addition, the fluorine atom as an auxiliary group will be dissociated by alcohol in the conversion process, and the alkylation product will be obtained in high yield (1) Rhodium catalyzed hydroformylation and aryl transfer of alkynes involving α, α - difluoromethylene (2) rhodium catalyzed α, The c-h-alkylation of α - difluoroethylene-p-toluenesulfonate (source: chem Commin.) was amplified to 4 mmol and the target product was still obtained in 75% yield Meanwhile, the removal of pyrimidine guided group and hydrolysis of ester group could be realized by the treatment of sodium alcohol, and 2-indoleacetic acid was obtained in 65% yield These results fully show the practicability of this method a) In order to clarify the reaction mechanism, the author carried out a series of mechanism research experiments as shown in the following figure When deuterium substituted α, α - difluoroethylene p-toluenesulfonate (D1-2) was used as raw material and reacted under standard conditions for 0.5 hours, a product with 98% deuterium substituted α hydrogen was obtained The results showed that the carbon in the product directly linked to indole C2 came from the carbon atom in the substrate α, α - difluoroethylene p-toluenesulfonate (2) connected to the sulfonate In the past, when α, α - difluoroethylene reacts with aryl Rh (III), the aryl is usually added to the more electronegative fluorinated carbon atom due to the pull electron induced effect of fluorine atom (see the original reference for details) Therefore, the author speculates that when the intermediate of indolyl Rh (III) reacts with α, α - difluorenyl p-toluenesulfonate, the indolyl group is added to the fluorocarbon atom first, and then the product is obtained by migration (equation 1) The KIE = 1 (equation 2) obtained from the parallel isotopic competition experiment indicates that the cutting off of the hydrocarbon bond in the reaction may not be a critical step In addition, the author further synthesized a possible intermediate compound 6, which can also be converted into product 3A (equation 3) under standard conditions, but the yield is only 8%, which indicates that the reaction route through compound 6 may not be the main route Mechanism research experiment (source: chem Commun.) based on the previous reports and experimental results, the author proposed the possible reaction mechanism: first, with the help of pyrimidine guiding group, cation Rh (III) catalyst cut off the C − H bond on indole 2, forming a five membered ring rhodium intermediate I, followed by intermediate I The intermediate II was formed by regionally specific addition to the difluoroethylene, followed by the departure of the OTS group at the α position to form the rhodium carbene intermediate III Then, the indole group is transferred to form trivalent rhodium intermediate V through difluorocyclopropane intermediate under the nucleophilic attack of methanol After alcoholysis of intermediate V, the target product can be obtained and the active rhodium catalyst can be regenerated (path a) Although path a is the most likely reaction process, according to the existing experimental results, the possibility of completing the reaction through path B can not be completely ruled out Possible reaction mechanism (source: chem Commin.) the research results were published on chemical communication (DOI: 10.1039 / c8cc02183j), and Zhou Lu, a postgraduate, was the first author of the paper The work was supported by the national young Thousand Talents Program (51237007), Jiangsu distinguished professors program (54937004), Jiangsu Natural Science Foundation (bk20170984 and bk20170992), Nanjing University of technology start-up funding and Jiangsu advanced biological and chemical manufacturing collaborative innovation center (sICAM) 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.