Science: solve the problems in copper catalytic oxidation addition reaction through free radicals

Coupling reaction is a direct and efficient bonding method The generalized coupling reaction refers to the process that two molecules form a new molecule through a certain reaction However, with the development of transition metal catalysts, when it comes to coupling reaction, the first thing that scholars think about must be the carbon carbon coupling reaction participated by transition metal SP 2 hybrid aryl carbon and alkenyl carbon play an irreplaceable role in organic synthesis, drug development and other fields, but most of SP 2 hybrid carbon are difficult to be coupled by simple nucleophilic substitution reaction, so scholars have realized efficient carbon carbon coupling reaction by introducing transition metal catalyst into the reaction Nowadays, most coupling reactions, such as Suzuki miyaara reaction and Heck reaction, use nickel and palladium as catalysts, while copper, which is the real catalyst to open the transition metal coupling reaction, has not been used similarly Compared with nickel and palladium, copper is not only cheap but also low toxic However, copper can not be oxidized and added efficiently to form the key intermediate product of copper (Ⅲ) - aromatics in coupling reaction, which is the main reason limiting the wide application of copper catalysts Although recently there has been a method to increase the oxidation rate of copper catalyst by designing different ligands, this strategy is not suitable for aryl iodide and aryl bromide Figure 1 Coupling reaction of aryl halides with copper catalyst (picture source: Science) Recently, David W C Macmillan, Professor of Merck Catalysis Research Center at Princeton University, bypassed the problem of low oxidation and addition efficiency of copper catalyst in catalytic coupling reaction through the capture mechanism of aromatic free radicals Many studies have shown that for some groups with high electronegativity, such as csp2-cf3, csp2-f and csp2-n, the reduction and elimination steps catalyzed by copper are more active and mild Based on this characteristic, the author realized the trifluoromethylation of aryl bromide with copper catalyst under mild conditions by introducing the strategy of free radicals (Fig 1) This achievement was published in Science (DOI: 10.1126 / science Aat4133) under the title of "a radial approach to the copious addition problem: trifluoromethylation of bromoorenes" Fig 2 A) the mechanism of trifluoromethylation of arylbromides; b) the generation mechanism of active methylsilane radicals; c) the optimization of reaction conditions; d) the structure of dmesscf 3 (picture source: Science) The inspiration of this strategy is not groundless In the previous research, the author successfully realized electrophilic cross coupling by using the photocatalysis / metal double catalysis reaction In this study, alkyl radicals can be produced by extracting halogen from silicon radicals Inspired by this method, the author speculates that silicon radicals can also be used to produce aryl radicals, and copper (II) is a good trapping agent for aryl radicals Therefore, it is possible to bypass the inefficient oxidation and addition process to obtain the intermediate product Cu (Ⅲ) - arene After the preliminary assumption, the author designed the reaction in detail (Fig 2) The first is the generation of aryl radicals: photocatalyst 1 produces excited ruthenium (Ⅲ) - complex (2) with strong oxidation by light irradiation; then 2 rapidly transfers one electron to trimethylsilyl siloxane (4) by single electron transfer (set), and at the same time of receiving electrons, 4 obtains silicon radical 5 through oxidation, deprotonation and silicon transfer At the same time, the electrophilic trifluoromethyl reagent 8 and the reduced 3 are set to form trifluoromethyl radical 9 The second is the formation of aryl copper (Ⅲ) - CF 3 intermediate: trifluoromethyl radical (9) and active copper (I) complex (10) form Cu (Ⅱ) - CF 3 complex (11); then 11 quickly captures the former aryl radical 7 and forms aryl copper (Ⅲ) - CF 3 intermediate 12 Finally, the coupling product 13 was obtained by reduction of the valence 12, and the copper (I) catalyst 10 was regenerated at the same time Fig 3 After the accurate experimental design of trifluoromethane reaction products and yields of different arylbromides (picture source: Science), the author first optimized the reaction conditions (Fig 2C), and found that the hydrogen atom on the aryl free radical initiator - silanol should have a great impact on the reaction The weak Si-H bond on silanol will react with aryl radicals and produce a large number of by-products Therefore, the author selected the completely methyl substituted silanol In addition, although different diaryl trifluoromethylsulfonium salts can produce trifluoromethyl radicals, dmesscf 3 (8) not only has the highest activity, but also is easy to be prepared in large quantities After that, the author studies the general applicability of this free radical mechanism in detail (Figure 3) The experimental results show that this strategy can effectively carry out trifluoromethylation reaction for bromobenzene (15-20) with different substituents, bromobenzene (21-22) with different substituents, bromobenzene (23-26) with heterocyclic consistency, heterocyclic aromatic bromide (27-50) and even bioactive molecule (51-54) Fig 4 Verification test of aryl radical mechanism (picture source: Science) Finally, the author proved that the reaction process did involve free radicals through isotope labeling, introduction of tempo and free radical clock, and the participation of free radicals largely determined the yield of the reaction Full text author: chip Le, Tiffany Q Chen, Tao Liang * Patricia Zhang, David W C Macmillan