Synthesis of small nitrogen heterocycles by photooxidation reduction imidization of olefins

Small nitrogen heterocycles constitute the core structure of many drugs and pesticides, and they are also the main epitopes in biological screening Therefore, the synthesis methods of these molecules have been studied The main goal of method design is how to transform simple raw materials into products containing various functional groups and available chemical space Nitrogen radicals are a kind of widely used synthesis intermediates Their activities can achieve a series of strong bonding reactions, such as intramolecular cyclization and hydrogen abstraction In recent years, thanks to the application of visible light redox catalysis in the single electron transfer (set) process, the development of nitrogen free radicals ushered in a recovery Daniele, Iain and Nadeem (Sheffield 2014) source: TheLeonori Research Group recently, Jacob Davies and Dr Jacob from University of Manchester, and Feisal, from the University of king of Saudi Arabia In this paper, it is reported that the imine radicals produced by the visible light activated redox catalyst can be used for the synthesis of a series of multifunctional nitrogen heterocycles In the early work of the team, the electron deficient o-aryloxime and aryloxyamide were used as the reaction substrate, and through reductive set, imine free radicals and amide free radicals were obtained, thus realizing the free radical hydrogen amination reaction (Fig 1a) When the team tried to use this reaction mode to synthesize nitrogen heterocycles with more substituents, it failed They realized that there was a chemical reactivity problem in the envisaged catalytic cycle Fig 1 Synthesis and mechanism analysis of nitrogen heterocycle source: imine free radical a generated by angelw Chem Int ed o-aryloxime is electrophilic, and nucleophilic carbon free radical B is obtained by exo trig cyclization Under the action of polarity effect, B reacts with somophile X-Y to form imine functionalized product C and free radical y (Fig 1c) Although y · does not participate in any bonding reaction, it controls the fate of the photoreduction process In order to react with B effectively, X-Y needs to be polarized in a specific way, which makes the Y generated must be electrophilic The team concluded that imine free radical a needs to be generated by the oxidative set of Photocatalyst (PC), and the set of Y · - and PC · - is easy to occur, so as to ensure the smooth completion of the catalytic cycle (Figure 1D, right) In the early stage of the team, the photoreduction cycle [PC • + + y •→ PC + y +] did not match the results of mechanism analysis, so the reaction was difficult to succeed (Figure 1D, left) After the mechanism of photo redox cycle is analyzed clearly, the next challenge is to find suitable reaction substrate and SOMO reagent Inspired by previous work, the author speculates that imine compound I can get II through deprotonation, and then generate free radical III through set oxidation, after releasing CO2 and hcoh, it can be converted into imine free radical IV (Fig 2a) Thus, the author carried out an electrochemical analysis of the substrate with similar structure (Fig 2b) The results show that the oxidation potential of 2a is beyond the range of photo redox reaction (E 1 / 2 ox = 2.10 V vs SCE) The electron density of carboxylates increased with the increase of substituents in the methylene position of 2a, and the E 1 / 2ox of the compounds decreased Finally, the compound 2D (E 1 / 2 ox = 1.65 V vs SCE) which can be oxidized by organic redox catalyst was selected Figure 2 Substrate design and electrochemical research source: angelw Chem Int ed next, the author selected 3A as the reaction substrate and 4 (E * 1 / 2 = + 2.06 V vs SCE) as the photoreduction catalyst Under the blue LEDs irradiation, a series of solvents and bases were screened and different types of imidization reactions were studied As shown in Figure 3, the author has realized 14 different imidization reactions, including hydroamination, imine halogenation, imine azide, imine amination, imine thioetherification, imine selenidation, imine Michael, imine cyanation, imine Olefination, imine alkyne For different types of reactions, alkali and solvent need to be adjusted to achieve the maximum reaction efficiency In general, inorganic bases CS 2CO 3 and K 2CO 3, as well as solvents dichloromethane and toluene, can give the best results In addition, the comparison shows that the photocatalyst 4 is indispensable Figure 3 Research source of reaction conditions: angelw Chem Int ed finally, the author expanded the reaction substrate It can be seen from Figure 4 that different olefin substrates, such as terminal olefin, disubstituted olefin and cycloolefin, can be imidized to obtain five membered nitrogen heterocyclic products with different functional groups In addition, this method was used to functionalize imines of bioactive molecules Figure 4 Expanded source of reaction substrate: angelw Chem Int ed conclusion: the team developed a method for rapid synthesis of multifunctional nitrogen heterocycles In the presence of visible light and photo redox catalysts, imine radicals were generated by oxidative set, and then cyclized functionalized with a variety of SOMO reagents This method can be used to construct valuable molecular modules in one step, and it has wide application space in the late functionalization of bioactive molecules Paper link: http://onlinelibrary.wiley.com/doi/10.1002/anie.201708497/abstract