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    Home > Team Xie Jin and Zhu Chengjian of Nanjing University: visible light and phosphine radicals synergize to catalyze direct deoxydeuterium reaction of carboxylic acid

    Team Xie Jin and Zhu Chengjian of Nanjing University: visible light and phosphine radicals synergize to catalyze direct deoxydeuterium reaction of carboxylic acid

    • Last Update: 2018-11-02
    • Source: Internet
    • Author: User
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    Author: Wang Dongping's deuterium labeling technology has long been considered as an important tool for drug metabolism analysis, reaction mechanism research, nuclear magnetic resonance spectroscopy and mass spectrometry analysis Deuterium can significantly enhance metabolism and pharmacokinetics of parent and candidate drugs In 2017, the FDA approved the first deuterium drug detetrabenazine to enter the market As a milestone event, this initiative significantly promoted the development of deuterium synthesis methodology, and also accelerated the discovery and development of deuterium labeled drugs Recently, Xie Jin and Zhu Chengjian of Nanjing University realized the direct deoxydeuterium reaction of carboxylic acid catalyzed by visible light and phosphine radicals This achievement was published on angelw Chem Int ed (DOI: 10.1002 / anie 201811522) under the title of "deoxygenated computerization of carbon acids with D 2O" The first author of the paper is Zhang Muliang, a 2016 level doctoral student, and associate professor Xie Jin is the corresponding author of the paper Aromatic aldehydes are very useful raw materials in organic synthesis Developing efficient synthesis methods to construct deuterium aromatic aldehydes can rapidly enrich deuterium molecular library At present, there are several methods to prepare deuterium aromatic aldehydes, but the reaction conditions are relatively harsh (Fig 1a), so it is difficult to satisfy the modification of complex molecules Fig 1 preparation method of deuterium aromatic aldehydes (source: angelw Chem Int ed.) in early 2018, Xie Jin and Zhu Chengjian research team realized the reverse polar borohydride reaction of imine with NHC borane for the first time through the cooperative catalysis of visible light and organic small molecules (angelw Chem Int ed 2018, 57, 3990) Subsequently, the research team successfully realized the specific and selective c-o-linked free radical trifluoromethylthiolation of tertiary ethers under mild conditions through the cooperative catalysis of visible light and organic small molecules (angel Chem Int ed 2018, 57, 10357) Recently, the team developed a new mechanism of direct deoxidization and activation of aromatic carboxylic acids by visible light catalyzed triphenylphosphine cation free radical coordination, breaking through the limitation of substrate dependent redox potential in the photocatalytic system, and providing a new method for rapid and efficient construction of aromatic ketone compounds (NAT Commun 2018, 9, 3517) Based on the interest and research of visible light cooperative catalysis, the team once again realized the deoxydeuterium reaction of D 2O to carboxylic acid by using cooperative catalysis, and proposed a new catalytic mode In this catalytic cycle, the excited photocatalyst, as a strong oxidant, can oxidize three phenylphosphine to produce three phenylphosphine radical cation 7, which reacts with carboxylate anion to form intermediate 8 Due to the strong affinity between phosphine and oxygen atoms, 8 can break through β - C to produce triphenylphosphine oxide and active nucleophilic acyl radical 9 DFT calculation shows that the BDE (94 kcal / mol) of C-H bond of aldehydes is much higher than that of S-H bond in mercaptan 2a-d (80-88 kcal / mol); in this case, under the control of polarity matching effect, 9 can easily form deuterium aldehyde 3 from mercaptan 4 through hat, and the electrophilic sulfur free radical 5 produced in this process is followed by IR II The species accepts an electron to complete the photo oxidation-reduction cycle and produce mercaptan anion 6 6 obtains a deuterium atom from D 2O to restart mercaptan catalyst regeneration (Fig 2) Fig 2 catalytic cycle process (source: angelw Chem Int ed.) Next, the author optimized the reaction conditions with 4-phenylbenzoic acid 1A as the reaction substrate, and finally took cheap D 2O as the ideal deuterium source The product was obtained in 86% yield and 96% deuterium efficiency (Table 1) Table 1 Optimization of conditions (source: angelw Chem Int ed.) then, the author examined the applicability of the reaction (Figure 3) All kinds of O -, M - and p-aromatic carboxylic acids can be used as suitable substrates, and high deuterium products can be obtained in a better yield The more sensitive functional groups, such as amino group, hydroxyl group, halogen, aldehyde group, carbonyl group, borate ester, terminal olefin and terminal alkyne, do not affect the normal process of the reaction The scale of the reaction was enlarged to gram, and the yield and deuterium efficiency were not affected Quinoline, indole and other heteroaromatic acids, as well as fatty acids, can also be successfully deoxidized in this system The excellent functional group tolerance of the reaction can provide a new and convenient method for the late functionalization of bioactive molecules, natural product molecules, drugs and agricultural chemicals Fig 3 applicability of the reaction (source: angelw Chem Int ed.) the deuterium products of the reaction can also be converted into other useful deuterium products For example, it can rapidly prepare β - deuterized α, β - unsaturated ester 10 and deuterium amine 11, and it can also provide a simple synthesis method for the preparation of deuterium heterocyclic compounds 12 and 13 (Fig 4) Fig 4 diversified transformation of products (source: angelw Chem Int ed.) reduction of carboxylic acid to aldehyde under mild conditions is one of the most important and challenging functional group transformation in organic synthesis Only H 2O is used instead of D 2O, the carboxylic acid can be selectively reduced to aldehyde under the same conditions, and the reaction has good selectivity and functional group compatibility (Fig 5) Figure 5 selective conversion of carboxylic acids to aldehydes (source: angelw Chem Int ed.) Summary: Xie Jin and Zhu Chengjian research team first realized the deoxidation deuterization of aromatic and aliphatic carboxylic acids with D 2O as a cheap deuterium source by using the synergistic effect of visible light catalysis and phosphono radicals The synthesis method has good universality and generality, further enriches and develops the deoxydeuterium reaction of carboxylic acid, and successfully constructs a series of deuterium aromatic aldehydes with various and complex structures The above research work was supported by the youth thousand talents program of the Central Organization Department, the talent support program of Nanjing University, the National Natural Science Foundation, and the basic scientific research business fees of the Central University Thanks for the great support provided by the school of chemistry and chemical engineering and the State Key Laboratory of coordination chemistry in the early stage of the construction of Xiejin research group At the same time, I would also like to thank Dr Zhang Muliang for his support from the innovative and creative research program of Nanjing University Review of previous reports: Xie Jin and Zhu Chengjian of Nanjing University have made important breakthroughs in the field of visible light catalysis
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