Professor Bao Ming group of Dalian University of Technology: decarboxylation and halogenation of 2-picolinic acid compounds without transition metal catalysis

The decarboxylation and halogenation of lead aromatic carboxylic acids is one of the most important methods for the construction of C-X bonds, which has aroused widespread interest However, the reported decarboxylation and halogenation reaction has some disadvantages, such as harsh reaction conditions, narrow substrate range, and the use of expensive transition metal catalysts, which seriously limits its wide application Recently, Bao Ming group of Dalian University of Technology reported the decarboxylation and halogenation of 2-picolinic acid compounds without transition metal catalysis The dihalomethane used is both a solvent and a source of halogens The new decarboxylation halogenation reaction has the advantages of mild reaction conditions and good functional group compatibility It is speculated that the reported decarboxylation and halogenation may have experienced n - chlorocarbene intermediate Professor Feng Xiujuan and Professor Bao Ming are the corresponding authors of the article, and Zhang Xitao, a doctoral student, is the first author of the article Relevant research results are published on green chem (DOI: 10.1039 / c9gc02407g) Baoming research group was founded in 2005, which belongs to the University of chemical engineering and the State Key Laboratory of fine chemical industry The main research directions are: (1) the selective conversion of molecules; (2) the resource utilization of carbon dioxide; (3) the synthesis and device research of functional materials of light conversion At present, the team has 3 professors, 3 associate professors, 1 lecturer and 1 engineer; there are 20 doctoral students and 33 postgraduate students The research group undertakes a number of national, Liaoning Province and enterprise cooperation projects The research group has long been committed to the development of new methods of clean organic synthesis in order to achieve green manufacturing of fine chemicals A series of research achievements have been made in benzyl palladium chemistry, nano porous metal catalysis, and carbon dioxide catalytic conversion (angel Chem Int ed., 2019, 58, 2495; ACS catalyst, 2017, 7, 8296; J am Chem SOC., 2016, 138, 10356; J am Chem SOC., 2012, 134, 5492; J am Chem SOC., 2012, 134, 17536) About Professor Bao Ming Bao Ming, Professor, National Key Laboratory of fine chemical industry, Dalian University of technology, head of research group; leader of science and technology innovation of Liaoning Province "Xingliao talent plan" (Liaoning distinguished professor); deputy director of homogeneous catalysis Professional Committee of Catalysis Society of China Chemical Society; science and technology expert of Fushun Institute of fine chemical application technology, national fine chemical industry base; Dalian University of Technology- Chinese director, joint research center for catalysis science, Northeastern University, Japan In 2001, he received his doctorate from Northeastern University of Japan, and in 2001-2004, he worked as a special researcher of the Institute and a special researcher of the Japan Society for the promotion of science and technology In 2005, he returned to China and mainly engaged in the research of organometallic chemistry, focusing on the development of new organic synthesis methods that are resource-saving, energy-saving and environment-friendly The research fields involve the development of selective construction methods of chemical bonds such as C-C and C-N, the catalytic conversion and resource utilization of carbon dioxide, the creation of functional materials for light conversion and the development of new synthesis methods Prof Feng Xiujuan, Professor of Fine Chemical State Key Laboratory of Dalian University of technology, Chinese member of catalytic science joint research center of Dalian University of technology and Northeastern University of Japan In 2004, he graduated from Dalian University of technology and stayed in the University From 2014 to 2015, he worked as a visiting scholar in the Department of chemistry, University of Minnesota It is mainly engaged in the research of high efficiency catalytic conversion of carbon dioxide, chemical synthesis and molecular catalytic reaction in environmentally friendly media such as supercritical fluid, development and application of new nano catalyst The research field involves the catalytic conversion and resource utilization of carbon dioxide, the creation of new nano porous metal catalysts and the development of new synthesis methods Catalytic reactions include molecular catalysis, atomic cluster catalysis and nano porous metal catalysis Frontier research achievements: the decarboxylation and halogenation of 2-picolinic acid compounds without transition metal catalysis 2-picolinic acid skeleton structure widely exists in natural products and bioactive molecules, and is an important structural unit In addition, 2-halopyridine derivatives are also important intermediates for the synthesis of drug molecules and functional materials, which are widely used in the synthesis of pharmaceuticals, pesticides, dyes, etc The transition metal catalyzed decarboxylation and halogenation is one of the important methods to construct C ‒ x bond However, the use of expensive transition metals and harsh reaction conditions seriously limit the application of this method Recently, Larrosa group reported the decarboxylation and halogenation of benzoic acid compounds with tetra-n-butyl-tribromide [n (n Bu 4) Br 3] or iodine as halogen source in the presence of no transition metal (chem SCI., 2018, 9, 3860; J am Chem SOC., 2017, 139, 11527) However, neither of these two methods can be used to synthesize 2-halopyridine, because 2-picolinic acid is prone to decarboxylation In the long-term research on the synthesis method of aromatic halides, the author found that 2-halopyridine can be synthesized by 2-picolinic acid and dihalomethane under the condition of no transition metal, and speculated that the decarboxylation halogenation reaction may experience n-chlorocarbene intermediate (Fig 1) Fig 1 decarboxylation and halogenation of aromatic acids (source: Green chem.) firstly, the author took decarboxylation and chlorination of 2-quinolinoic acid as model reaction, and dichloromethane as solvent and chlorine source to optimize the reaction conditions (Table 1) In the absence of alkali, 2-chloroquinoline was obtained in 32% yield Subsequently, t-buocl was used as accelerant to screen different kinds of alkali in air The results show that NaHCO3 is the best one among all organic bases and inorganic bases, and the yield of the target product is 88% When the reaction is in nitrogen atmosphere, the yield of the target product is only 20%, which shows that the presence of oxygen is conducive to the occurrence of the target decarboxylation and chlorination reaction Other oxidants, such as K2S2O8, TBHP and p-chlorobenzoquinone, did not promote the reaction When the reaction was carried out in pure oxygen atmosphere, the yield did not increase significantly Whether reducing the reaction temperature or shortening the reaction time, the yield of the target product will decrease Therefore, the best reaction conditions are: 2-quinoline formic acid (0.3 mmol), dichloromethane (3 ml), t-buocl (1.5 equivalent), NaHCO 3 (1.0 equivalent), reacting at 60 ℃ for 20 hours Table 1 reaction condition screening a (source: Green chem.) under the optimal conditions, the author investigated the substrate range of decarboxylation and chlorination reaction, as shown in Figure 2 When 2-picolinic acid was used as the starting material, the target product (2a) with a yield of 73% was obtained When 2-picolinic acid has methyl, phenyl, chlorine and bromine, the yield of 2c-2f is between 80% and 91%, which shows that the steric hindrance of 3-substituent of 2-picolinic acid has no effect on the activity of the reaction substrate When the 3-position of 2-picolinic acid has strong electron absorbing nitro group, although the reaction is carried out in pure oxygen atmosphere and 3 equivalent tert butyl hypochlorite, the yield of the target product 2G is only 47% This may be due to the strong electron absorption of nitro group When there are substituents (methyl, chlorine, bromine) in the 4-position of 2-picolinic acid, decarboxylation and chlorination can also occur smoothly The yield of the target product (2h-2j) is between 52% - 74% The yield of 2k-2m of the corresponding decarboxylation and chlorination product is between 56% and 72% when the electron donor methyl, phenyl or electron acceptor methoxycarbonyl are attached to the 5-position of picolinic acid When 6-methyl-2-pyridinecarboxylic acid is used as the substrate, the target product 2n can also be obtained in high yield, which shows that the position of methyl has no effect on the activity of the substrate Disubstituted 2-picolinic acid, such as 3,5-dichloro-2-picolinic acid, is also suitable for this reaction system The target product 2O is obtained in 42% yield When 1-isoquinolinoic acid was used as the reactant, the reaction could be carried out smoothly, and the target product 2p was obtained in 92% yield In addition, when Dibromomethane is used as bromine source, decarboxylation and bromination can also be realized in this reaction system, and 2-bromopyridines can be obtained in medium or high yield (Fig 3) Fig 2 decarboxylation and chlorination substrate extension a, B (source: Green chem.) Fig 3 decarboxylation and bromination substrate extension a, B (source: Green chem.) in order to further study the mechanism of this decarboxylation and halogenation reaction, the author made some control experiments (Fig 4) When 2 equivalent free radical inhibitor tempo was added to the reaction system, the reaction was completely inhibited, which indicated that the reaction might involve a free radical process When t-buocl is removed from the reaction system, the reaction cannot proceed, indicating that t-buocl must exist for this reaction In order to study which is easier to carry out decarboxylation chlorination reaction or decarboxylation bromination reaction, the author added dichloromethane and Dibromomethane of the same mass to the reaction system, and found that the amount of chlorination products is obviously more than that of bromination products, which may be because it is more conducive to the formation of C ‒ CL bond in thermodynamics Fig 4 control experiment (source: Green chem.) based on preliminary results and previous studies, the author proposed a possible reaction mechanism (Fig 5) First, t-buocl can produce Cl and t-butoxy radicals under the condition of heating Then, under the action of oxygen, both of them generate Cl + and t-buo - The chloride ion (Cl -) then reacts with sodium picolinate B to form the intermediate C of sodium n-chloropyridine formate Through decarboxylation, intermediate C releases carbon dioxide and sodium TERT butanol to form n-chloropyridine salt intermediate D, which is then converted into n-chloropyridine intermediate E The intermediate e reacts with dihalomethane to form the target product 2B or 3B It is gratifying that 1-chloro-1-bromomethane (ch2clbr) was detected by GC-MS in the decarboxylation reaction Fig 5 possible mechanism of decarboxylation and aromatization of 2-picolinic acid (source: Green chem.) Summary: Baoming group has developed a simple and efficient method to synthesize 2-halopyridine The method is not only simple in raw materials, good in functional group compatibility, but also mild in conditions and does not need transition metals The reaction may go through N - chlorocarbene intermediate, which provides a new strategy for decarboxylation coupling reaction 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 Therefore, CBG information adopts 1 + X reporting mechanism, CBG information website, chembeangoapp, chembeango official microblog, C