Deng Guojun group, Xiangtan University: selective synthesis of pyrimidine and pyridine compounds by multicomponent reactions of aromatic ketones, aldehydes and ammonium salts without transition metals

Introduction multicomponent reaction is a kind of important organic chemical reaction with the characteristics of simple operation, good atomic economy and high resource utilization However, because there are many active sites in multicomponent reactions, the selective control of reactions is a challenging research topic Transition metal catalysts are widely used to control the selectivity of multicomponent reactions because of their high activity and selectivity However, there are still some problems such as high cost of catalysts and heavy metal residues Therefore, the selective control of multicomponent reactions without transition metals is of great significance Recently, Deng Guojun, Professor of the school of chemistry, Xiangtan University, selected pyrimidine and pyridine compounds from aromatic aldehydes and ketones, aldehydes and ammonium salts without transition metals The results were published on green chem (DOI: 10.1039 / c9gc02077b) Brief introduction of Professor Deng Guojun's research group Professor Deng Guojun's research group was founded in March 2009 At present, there are 1 Professor, 2 associate professors, 1 lecturer, 2 postdoctoral students, 8 doctoral students and 30 master's students in the research group The research group is mainly engaged in the research of green organic synthesis and catalytic reaction, and has undertaken more than 10 projects at the provincial and ministerial level including 7 National Natural Science Funds Abundant research achievements have been made in nitro hydrogen reduction, cyclohexanone dehydroaromatization, sulfite selective conversion, oxime ester conversion, indole direct functionalization and heterocycle formation involving inorganic sulfur More than 190 SCI papers have been published, 12 of which have been selected as the most cited papers in ESI At present, 7 doctoral students and more than 30 master's degree students have been trained, and 5 papers have been awarded Excellent Doctoral and master's degree papers in Hunan Province Prof Deng Guojun: Prof Deng Guojun, Dean of the school of chemistry, Xiangtan University, second level Professor, doctoral supervisor In 1999, he graduated from the school of chemistry and chemical engineering of Xiangtan University; in 2004, he obtained a doctor of Science degree from the Institute of chemistry of Chinese Academy of Sciences, under the guidance of researcher fan Qinghua and academician Huang Zhitang; from 2004 to 2009, he successively engaged in postdoctoral research in Germany, the United States and Canada; in 2009, he passed the "academic leader" of Xiangtan University As a professor and doctoral supervisor of the school of chemistry, he is mainly engaged in the research on the methodology of environmentally friendly carbon carbon bond and carbon heterobond formation reaction In 2010, he was selected into the hundred talents plan of Hunan Province, and in 2011, he was selected into the "new century excellent talents support plan of the Ministry of education" So far, more than 140 SCI papers have been published in science, angelw Chem Int ed., j.am Chem SOC., org Lett., chem Commun., green chem And other journals, with more than 4500 citations (up to 600 citations); 7 Chinese invention patents have been authorized, 14 patents have been applied for; 1 Chinese monograph has been written, 3 English monographs have been written The leading green organic synthesis and catalysis team was approved by Hunan Provincial Key Laboratory (green organic synthesis and application) in 2017 "Green chemistry oriented dehydrogenation and transformation of alcohol and ketone" won the second prize of Hunan Natural Science in 2015, the 10th Hunan Youth Science and Technology Award in 2016, and the "Baosteel excellent teacher award" in 2017 Frontier research achievements: under the condition of no transition metal, aromatic ketones, aldehydes and ammonium salts react selectively to synthesize pyrimidine and pyridine compounds Nitrogen-containing heterocyclic compounds such as pyrimidine and pyridine are widely found in natural products, bioactive molecules and functional materials, which are of great significance Therefore, they are widely concerned by organic chemists Since brugnatelli and Kolbe synthesized pyrimidine (ANN Chim Phys 1818, 8, 201; Justus liebigs Ann Chem 1848, 65, 269), many synthesis methods of pyrimidine have been reported in succession In these methods, nitriles and amidines are usually used to construct pyrimidines as nitrogen-containing structures Nitrile and ketone (org Lett 2018, 20, 3399; tetrahedron 2002, 58, 10053; tetrahedron 2002, 58, 3755) or N-vinyl / arylamide (J org Chem 2009, 74, 8460; NAT Protoc 2007, 2, 2018; J am Chem SOC 2006, 148, The condensation reaction of 14254) and the intermolecular cycloaddition reaction of nitriles and alkynes (J am Chem SOC 2018, 140, 11906; org Lett 2017, 19, 5569; NAT Commun 2016, 7, 10914; angel Chem., int ed 2014, 53, 9072) are important methods for the construction of pyrimidines (scheme 1a) However, transition metal catalysts or a large number of strong protonic acids are usually used in this reaction As a nitrogen-containing structure, amidines are usually associated with ketones (org Chem Front 2017, 4, 1107; J org Chem 2017, 82, 1145), propargylic alcohols (synlett 2011, 8, 1179), 1,2,3-triazines (org Lett 2015, 17, 4002; org Lett 2014, 16, 5084; J am Chem SOC 2014, 136, 2119; J am Chem SOC 2011, 133, 12285), allyl compounds (J org Chem 2016, 81, 5538) to construct pyrimidines In addition, the multicomponent reaction involving amidine is also an effective strategy for the formation of pyrimidine In 2015, Kempe research group first reported the multicomponent reaction of amidine and alcohol to synthesize pyrimidine with iridium as catalyst (angew Chem., int ed 2017, 56, 1663) Kempe and Kirchner then used manganese catalysts to achieve this type of reaction (J am Chem SOC 2015, 137, 12804; J am Chem SOC 2016, 138, 15543) (scheme 1b) Although the synthesis of pyrimidine has made great progress, the synthesis of pyrimidine compounds by multi-component reactions under simple conditions using simple and easy to get raw materials is still worthy of further study Ammonium salt is an ideal nitrogen source for the construction of nitrogen-containing heterocyclic compounds, because they are cheap, easy to obtain and easy to operate However, there are few effective methods to construct pyrimidine from ammonium salt and simple organic compounds Recently, the research group has realized the synthesis of thiazole (green chem 2019, 21, 986), quinazoline (green chem 2018, 20, 5459) and pyridine (org BIOMOL Chem 2015, 13, 4404) by using ammonium salt as nitrogen source Based on the recent work of the research group on the synthesis of nitrogen-containing heterocycles by simple substrate reactions (J org Chem 2019, 84, 568; chem Commun 2019, 55, 4079; J org Chem 2019, 84, 1238; org Chem Front 2019, 6, In this paper, we report an effective scheme 1C for the selective generation of pyrimidine and pyridine from aromatic ketones, aldehydes and ammonium salts Scheme 1 Synthesis of pyrimidine from different nitrogen sources (source: Green chem.) the author first used p-methyl acetophenone, benzaldehyde and ammonium salt as raw materials to optimize the reaction conditions (Table 1) When 40 mol% NaIO 4 was used as additive and NH 4oac as nitrogen source, pyrimidine compounds were obtained; when NH 4I was used as nitrogen source, pyridine compounds were obtained Table 1 Optimization of reaction conditions (source: Green chem.) in order to explore the universality of the multicomponent reaction to aromatic aldehyde substrate, the author investigated the aromatic aldehydes substituted by different functional groups (Table 2) The target product (3AB - 3aD) can be obtained in good yield when benzaldehyde has alkyl substituent in its para position The substrates with halogen groups (such as F, Cl, CF 3 and OCF 3) can also be well compatible, and the target product (3aE - 3ah) can be obtained in 42-76% yield When the substituent is in the intermediate position, it has little effect on the yield (3AI - 3AK), but when the methyl is in the adjacent position, the yield is low 2-naphthylaldehyde with high steric hindrance can also be successfully reacted with a yield of 68% (3an), which proves that the reaction has good functional group tolerance Unfortunately, fatty aldehydes are not suitable for this reaction system Table 2 After the development of aromatic aldehyde substrate (source: Green chem.), the author also studied the universality of different aromatic ketones (Table 3) In general, when acetophenone has different electron donating groups, the corresponding products (3ba - 3EA) can be obtained in medium to good yields, and halogen and strong electron absorbing groups can also exist stably The author also investigated the meso -, ortho - and polysubstituted acetophenone, and found that they can all get pyrimidine products in good yields Aromatic heteroketone and fused ring ketone can also react smoothly, with medium yield (3ta - 3VA) Table 3 Aromatic ketone substrate extension (source: Green chem.) the author also investigated the substrate range (Table 4) for the synthesis of pyridine compounds by the multi-component reaction Aromatic ketones and aromatic aldehydes with different substituents can be successfully reacted, and 2,4,6-trisubstituted pyridine compounds can be generated in good to excellent yields Table 4 Substrate extension of pyridine synthesis (source: Green chem.) in order to study the practicability of this method, the author has carried out a series of structural transformation (scheme 2) on pyrimidine compound 3HA through Suzuki miyaara coupling aromatization, Pd / Cu catalyzed Sonogashira coupling acetylation, and Buchwald Hartwig amination Scheme 2 Structural transformation of pyrimidine products (source: Green chem.) based on experimental results and related literature, the author proposed a possible reaction mechanism (scheme 3) Firstly, p-methyl acetophenone (1a) and benzaldehyde (2a) were dehydrated and condensed to form chalcone a, which reacted with ammonium acetate to form intermediate B the existence of intermediate B was detected by GC-MS Then, the imine intermediate formed by the reaction of benzaldehyde with ammonium acetate is cyclized with intermediate B to obtain intermediate C Finally, the target product was obtained by oxidative dehydrogenation of intermediate C Scheme 3 Possible reaction mechanism (source: Green chem.) Summary: Professor Deng Guojun's research group of Xiangtan University has developed an effective strategy for the synthesis of pyrimidine and pyridine from aromatic ketones, aromatic aldehydes and ammonium salts under the condition of no transition metal In this reaction, two aldehydes participate in the reaction, ammonium salt is the nitrogen source, and the catalytic amount of NaIO4 plays an important role in the selective control of the reaction This reaction has the advantages of no transition metal catalyst, high selectivity, simple raw materials and ammonium salt as nitrogen source It provides a simple and effective method for the synthesis of pyrimidine and pyridine compounds This achievement was recently published in green chem The first author of this article is Chen Jinjin, a doctoral student in the school of chemistry, Xiangtan University The above research work has been supported by the National Natural Science Foundation of China, China Postdoctoral Science Foundation and Hunan graduate innovation fund 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, the pursuit of innovation driven