Ma Jun'an research group of Tianjin University: synthesis of difluoromethylpyrazoles with new difluoroalkyl diazo

Lead pyrazoles have been widely used in medicine and pesticide industry In order to improve the activity of these compounds, difluoromethyl, trifluoromethyl and other special pharmacophores are often introduced Therefore, how to efficiently construct pyrazoles containing difluoromethyl and trifluoromethyl has attracted the attention of chemists Recently, Ma Junan, Tianjin University, has developed a new type of difluoromethylation reagent, which has been used to synthesize difluoromethylpyrazoles (DOI: 10.1021 / ACS Orglett 8b01854) Brief introduction of Ma Jun'an research group Professor Ma Jun'an's research group was founded in July 2005 At present, there are 1 Professor, 5 associate professors, 8 doctors and 8 masters in the research group It relies on Tianjin Key Laboratory of molecular Optoelectronic Science and Tianjin collaborative innovation center of chemical industry The research group is mainly engaged in asymmetric synthesis and organic fluorine chemical engineering research, including: design and synthesis of new chiral catalysts; research on new catalytic asymmetric reactions and new synthesis methods; design and synthesis of chiral compounds with biological activity; design, synthesis and reaction research of fluorine-containing organic functional compounds; 18 f-pet Imaging probe and drug design and synthesis, mainly used for tumor diagnosis; natural products and drug fluorine engineering modification and activity screening Prof Ma Jun'an, Professor of Tianjin University, doctoral supervisor, now vice president of School of science of Tianjin University In 1999, he received a doctor's degree from Nankai University, and stayed in school as a teacher He worked as a research assistant in Professor Zhou Qilin's research group, engaged in chiral catalytic asymmetric synthesis and related drug research In 2001, he was employed as an associate professor In 2002, he was engaged in post doctoral research (co Professor: Dominique cahard) in Fine Chemistry Research Institute of CNRS, and carried out organic fluorine chemistry and related asymmetric synthesis; in 2004, he was transferred to Coal Chemistry Research Institute of MPI, Germany, and engaged in post doctoral research (co Professor: Manfred t reetz ）, engaged in asymmetric synthesis and bio organic chemistry research In July 2005, he was employed as a professor and doctoral supervisor by Tianjin University In 2005, he was selected as the excellent talents of the Ministry of education in the new century, and in 2006, he was selected as the first level candidate of Tianjin "131" innovative talents training project Supported by the National Science Fund for Distinguished Young Scholars in 2012, Professor Ma has been committed to the research of organic asymmetric chemistry and organic fluorine chemistry At present, he has published more than 130 academic papers and cited more than 3800 times He has applied for 15 patents (7 of which have been authorized), participated in the compilation of 5 books As the project leader, he has successively undertaken and completed more than 10 national, provincial and ministerial scientific research projects He participated in international and domestic academic conferences and was invited to make conferences and oral reports for nearly 40 times Cutting edge scientific research achievements: the new difluoroalkyl diazo is used in the synthesis of difluoromethylpyrazoles Professor Ma Junan's research group of Tianjin University has made a series of in-depth studies on the fluorodiazo compounds in recent years, and has made a number of innovative achievements In 2012, they realized the end-to-end trifluoroethylation of alkynes with trifluoroethylene Chem Int ed 2012, 51, 6227), and then a series of pyrazoles, triazoles, and tetraazoles containing trifluoromethyl were synthesized by cycloaddition reaction (angel Chem Int ed 2013, 52, 6255; org Lett 2014, 16, 1606; org Lett 2015, 17, 3442; org Lett 2014, 16, 3122; org Lett 2017, 19, 3406-3409; angel Chem Int ed
2017 , 56 , 4569 ）。 In 2018, the research group obtained a series of α - aminophosphonylide through the series reaction of trifluoroenzene, triphenylphosphine and diene, and pyrazolone compounds can be synthesized through conversion (chem EUR J 2018, 24, 7749) On the basis of the previous work, the research team used thiophene and ethyl bromodifluoroacetate as starting materials to prepare a new difluoromethylation reagent, phenylsulfonyldifluoro diazoethane, through five steps reaction, and realized the efficient synthesis of difluoromethylpyrazoles First of all, phenylsulfonyl difluoro diazoethane (PS DFA) was prepared from phenylthiophenol and ethyl bromodifluoroacetate by five steps of thioetherification, ester reduction, sulfur oxidation, ammoniation and diazotization The reagent is stable at room temperature and easy to store and use Figure 1 Synthesis route of phenylsulfonyldifluorodenzene (source: org Lett.) later, the author studied the reaction between phenylsulfonyldifluorodenzene and electron deficient alkynes, and determined the optimal reaction conditions after simple optimization of reaction substrate ratio, solvent and temperature The molar ratio of alkyne to phenylsulfonyldifluoro diazoethane is 1:1, toluene is used as solvent, the relative concentration is 0.1 mmol / ml, and the reaction time is 18 hours at 40 ℃ The reaction has good substrate compatibility In this reaction, the stability of phenylsulfonyldifluoro diazoethane is high, and the target product can be obtained in high yield only under the condition of one equivalent feed, which shows the important application value of the reagent in the synthesis Fig 2 The reaction of difluoro diazoethane with electron deficient alkynes (source: org Lett.) the author then tried to remove the phenylsulfone protecting group from the product to synthesize difluoromethylpyrazoles Under the catalysis of magnesium, the protection group of phenylsulfone can be easily removed at room temperature, so difluoromethylpyrazoles can be successfully obtained For the compounds containing keto carbonyl group, the reduction of keto carbonyl group to alcohol can also occur during the reaction, but the corresponding difluoromethylpyrazoles (4D and 4e) can still be obtained Figure 3 Synthesis of difluoromethylpyrazoles (source: org Lett.) The synthesis of difluoromethylpyrazoles from phenylsulfone difluoromethane and alkynes needs two steps The author thinks that the synthesis of difluoromethylpyrazoles can be realized by one pot multi-step reaction with alkene as the substrate, and acrylate as the initial substrate The reaction conditions are optimized The results show that the final product can be obtained by using 1,4-dioxane as solvent and DBU as base Figure 4 One pot multi-step synthesis of difluoromethylpyrazoles (source: org Lett.) then, the author examined the substrate application scope of the reaction All kinds of electron deficient alkenes can be well compatible in this reaction It is worth mentioning that mono substituted vinyl sulfones can be converted into mono substituted difluoroalkylpyrazoles by this reaction Figure 5 Examination of the application scope of the substrate (source: org Lett.) in order to further demonstrate the application potential of this reaction, the author has carried out a study on the amplification synthesis of 4P, and successfully constructed 4-bromo-3-difluoromethyl-1-methylpyrazol, an important intermediate for agricultural drug synthesis, through methylation, desulfonation and bromination Figure 6 Construction of 4-bromo-3-difluoromethyl-1-methylpyrazole (source: org Lett.) the author first speculated on the reaction mechanism as follows: firstly, olefin and phenylsulfonyldifluorodenzene were [3 + 2] cycloaddition to form intermediate I-1, then organic base DBU seized ammonia hydrogen in the substrate to form intermediate I-2, and then isomerized to form intermediate I-3 Secondly, difluoromethylpyrazoles were produced under the synergism of protonated DBU Then, 5b was used as the substrate to verify the reaction mechanism Through the first step [3 + 2] cycloaddition reaction, the intermediate i-1a was obtained, and its structure was determined by analysis Then i-1a was used as the substrate, and 7 was obtained by adding DBU and heating The author has determined that 7 is DBU phenylsulfite by single crystal, which is easy to be oxidized to phenylsulfonate in the air Figure 7 One pot multi-step synthesis mechanism (source: org Lett.) Summary: Professor Ma Junan's research group has formed a new difluoromethylation reagent - phenylsulfonyl difluorodiazoethane, which has been used to realize the efficient synthesis of difluoromethylpyrazoles This method has mild conditions, simple operation and good amplification effect The corresponding authors of the research results are Professor Ma Jun'an and Associate Professor Zhang Hui, and the first author is Zeng Junliang, a doctoral student 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.