Research group of Professor Huang you of Nankai University: efficient synthesis of six and seven membered nitrogen heterocyclic compounds by multiple domino cyclization of thioylide

Lead six and seven nitrogen heterocyclic compounds exist widely in medicine and bioactive molecules, so it is very important to synthesize these compounds through cheap raw materials In recent years, more and more attention has been paid to diversity oriented synthesis, which can efficiently construct a series of heterocyclic compounds with different skeletons Therefore, how to synthesize heterocyclic compounds by simple methods has become a challenging topic in organic synthesis Recently, the research group of Professor Huang you of Nankai University has realized the diversified domino cyclization reaction of thiofulide and azadiene, and realized the efficient and highly selective synthesis of benzofuran six membered and seven membered azacyclic compounds by simply changing the alkali strategy (Figure 1, DOI: 10.1021 / ACS Orglett 8b02810) Fig 1 diversity of domino cyclization reaction of thiophyllide and azadiene (source: org Lett.) brief introduction of Professor Huang You's research group there are 10 researchers in Professor Huang You's research group, including 1 Professor, 6 doctoral students and 3 postgraduate students At present, the main research fields of the research group include the domino cyclization reaction catalyzed by organic phosphine, the domino cyclization reaction participated by sulfur ylide, the design and synthesis of a new chiral phosphine catalyst and its asymmetric catalytic reaction At present, the research group has published more than 80 papers in the international chemical journals such as angew Chem Int ed., ACS catalyst., org Lett., chem Commun., chem EUR J Professor Huang You's cutting-edge scientific research achievements: thioyelide's Domino cyclization reaction diversity and efficient synthesis of six and seven membered nitrogen heterocyclic compounds, especially six and seven membered nitrogen heterocyclic compounds, widely exist in many natural products and drug molecules with biological activities Therefore, the development of efficient synthesis methods to synthesize six and seven membered nitrogen heterocyclic compounds has become the focus of chemists Diversity oriented synthesis can effectively synthesize heterocyclic organic compounds with different core skeletons A series of carbon and nitrogen-containing small ring compounds can be synthesized efficiently by the domino cyclization reaction involving thiogerate However, the application of thiolide's reaction model in diversity oriented domino cyclization is very limited Professor Huang You's research group has carried out a series of research work on the domino cyclization reaction of thioyelide, and developed the [4 + 1], [5 + 1], [3 + 3], [3 + 2] domino cyclization reaction participated by thioyelide to synthesize five and six membered ring compounds (J org Chem 2011, 76, 7699; adv synth Catalyst 2018, 360, 3044; adv synth Catalyst 2014, 356, 2422; Org Lett 2017, 19, 412), and a series of [3 + 3] / [1 + 2], [1 + 2] / [2 + 3], [1 + 4] / [2 + 3] continuous cyclization reactions to synthesize challenging 6 / 3, 3 / 5, 5 / 5 bicycles (org Lett 2016, 18, 2475; org Lett., 2017, 19, 4664; adv synth Catalyst 2018, 360, 438) Recently, on the basis of previous work, the research group of Professor Huang youyou of Nankai University developed the diversity oriented [4+2] and [4+3] Domino cyclization reaction of thioyelide, which can simply change the diversity of alkali, so as to efficiently synthesize 6 yuan and 7 yuan heterocyclic compounds This work was published in the Journal of organic chemistry, org Lett (DOI: 10.1021 / ACS Orglett 8b02810) Chen Junlong, Ph.D student, School of chemistry, Nankai University, was the first author, and Jia Penghao, Ph.D student, participated in the project Thioylide was discovered by organic chemists in 1960s Because of its mild reaction conditions and simple operation, it has been successfully used in the efficient synthesis of ternary ring compounds In 2010, Tang Yong's research group realized a cyclization reaction of thiogerate derived from crotonate and cycloimine, in which thiogerate was used as a C1 synth to construct a nitrogen heterocyclopropane compound containing vinyl group Subsequently, Huang You's research group reported a case of continuous cyclization of thiogerate and α, β - unsaturated cyclic imines derived from crotonate in 2016 Thiogerate, as a C3 synth, constructed 2-alkenylazacyclopropanes On the basis of the previous work (org Lett 2017, 19, 5609), the author realized the diversified domino cyclization reaction of thiophyllide and azadiene by simply changing the base It should be noted that in this reaction, thioylide, as a new C2 synthon, synthesized six membered nitrogen heterocyclic compounds for the first time, in addition, it also synthesized seven membered nitrogen heterocyclic compounds which are difficult to be constructed by general methods as C3 synthon for the first time (Fig 2) Fig 2 previous research work and the work of this study (source: org Lett.) the author has carried out a series of screening on the solvent and temperature, and found that when the reaction temperature is 15 ℃ and the solvent is CHCl3, the best yield can be obtained Among them, when DABCO is used as base, the product 3a of [4 + 2] cyclization can be obtained in 80% yield; when K2CO3 is used as base, the product 4a of [4 + 3] cyclization can be obtained in 85% yield Under the optimal reaction conditions, the substrate suitability of DABCO promoted [4 + 2] cyclization was investigated (Fig 3) When R 1 is used as electron acceptor or electron acceptor, a good yield of 3A - 3G can be obtained In addition, with the increase of steric hindrance, the yield of 3I - 3K can also be obtained After investigating the R 2 group, the author found that the yield of BR decreased obviously at 5 position The product 3O - 3P can still be obtained in good yield when thioylidene has different ester groups Fig 3 the substrate range of [4 + 2] reaction promoted by DABCO (source: org Lett.), followed by the applicability of [4 + 3] cyclization promoted by K 2CO 3 (Fig 4) For the R 1 group, the author found that when the benzene ring was attached to the electron group, the yield of 4A - 4G was moderate to good With the increase of steric hindrance, the product 4H - 4L can still be obtained with medium to excellent yield It is worth noting that when R1 has a 1-naphthyl group with large steric hindrance, the product 4K can be obtained in 95% yield The yield of 4O - 4P can still be obtained by the reaction when thioylidene has different ester groups Fig 4 the substrate range of K 2CO 3-promoted [4 + 3] cyclization (source: org Lett.) is further studied by the author through deuterium experiment on the mechanism of alkali promoted diversified domino cyclization (Fig 5) The deuterium experiment results show that the reaction process may involve carbon anion The author thinks that the structure of DABCO bridge ring induces the formation of [4 + 2] product, while K 2CO 3, as an alkali, only produces allylthioylide, which has no suitable steric hindrance, so only the formation of [4 + 3] product Fig 5 deuterium experiment (source: org Lett.) based on the above experimental results and previous reports, the author proposed the possible reaction mechanism (Fig 6) Sulfonium salt 2A produces allylthioylide I and II under the action of alkali (DABCO or K2CO3), and then conjugates with 1a to obtain intermediate a [4 + 2] reaction has two paths: path I, intermediate a is obtained by intramolecular nucleophilic addition, intermediate B is obtained by proton transfer, intermediate C is obtained by BR attack me 2S +, product 3a is obtained by path I ', intermediate a is obtained by proton transfer, intermediate e is further obtained by intramolecular Michael addition, proton transfer and Br attack me 2S + 3A [4 + 3] reaction through path II, nitrogen anion attack intermediate e to get product 4a Fig 6 possible reaction mechanism (source: org Lett.) Summary: Professor Huang You's research group successfully realized the diversity [4 + 2] and [4 + 3] domino cyclization of thioylide, and synthesized benzofuran six and seven membered nitrogen heterocyclic compounds with high yield and regional selectivity The reaction conditions are mild, the raw materials are easy to obtain, the operation is simple, and it has a wide range of substrate applicability By simply changing the base, thiofulide can be selected as a novel C2 or C3 synthon, which extends the application of thiofulide The research was supported by NSFC (2147209721672109, 21871148) and Nankai University Review of previous reports: Professor Huang you, Nankai University Research Group: DBU catalyzed desymmetric cyclization of Cyclohexanedione Today, science and technology elements are increasingly valued in 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.