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    Home > Research group of Professor Shu Xingzhong of Lanzhou University: reduction cross coupling reaction of benzyl oxalate and alkyl bromide catalyzed by nickel

    Research group of Professor Shu Xingzhong of Lanzhou University: reduction cross coupling reaction of benzyl oxalate and alkyl bromide catalyzed by nickel

    • Last Update: 2018-05-16
    • Source: Internet
    • Author: User
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    The author: yanxiaobiao oxygenated organic compounds widely exist in nature Therefore, it is very important to realize the transformation and modification of organic compounds by C-O bond activation In recent years, based on the advantages of low toxicity and low cost, more and more researchers pay attention to the construction of C-C bond with non sulfonate C-O electrophilic reagent Up to now, the cross coupling reaction between C-O electrophilic reagent and organometallic reagent (Grignard reagent, zinc reagent, etc.) is the main reaction, among which arylation reaction involving aryl metallic reagent is the most prominent In contrast, there are only a few successful cases of CSP3 – CSP3 coupling reaction (Figure 1a) Compared with alkyl metal reagents, alkyl halogenated hydrocarbons have the advantages of simple and easy to obtain, convenient use and storage, and good functional group compatibility If alkyl halides can be used instead of alkyl metal reagents to realize the cross coupling reaction with C-O electrophilic reagents, it will be beneficial to broaden the substrate applicability and functional compatibility of the reaction and enhance the practicability of the reaction However, the research is very challenging Recently, Professor Shu Xingzhong, National Key Laboratory of functional organic molecular chemistry, Lanzhou University, found that the reduction cross coupling reaction of benzyl oxalate and alkyl bromide can be realized by using oxalate as the leaving group (Fig 1b) The reaction is suitable for primary and secondary alkyl bromides, and has a wide range of substrate applicability and good functional group compatibility This achievement was published online in the Journal of Chemical Science (DOI: 10.1039 / c8sc00609a), Royal Society of chemistry, under the title of "reducing coupling of benzyl oxides with highly functional alkyl bromides by nickel catalyst" Figure 1 The reduction cross coupling reaction of benzyloxalate and alkyl bromide catalyzed by nickel (source: Chemical Science) Through the selection of a series of reaction conditions, the author determined that NIBR 2 was used as catalyst, P (4-cf 3 PH) 3 as ligand, Mn powder as reducing agent, DMSO / DMF (1:1), 0.4 m) is the optimal solvent, and the cross coupling of C-O bond activation of benzyl group and reduction of alkyl bromide is realized at room temperature Under the optimal reaction conditions, the author first investigated the influence of various leaving groups on the reaction (Fig 2) When benzyl ether and carbonate are used as the leaving group, the activation of C-O bond is difficult to achieve (1-6) When trifluoroacetate with stronger leaving ability is used as the leaving group, the target product (7) can be obtained in 19% yield 3-picolinate (8) can not be activated, while 2-picolinate (9) can obtain the target product in 22% yield The results show that the double coordination leaving group can promote the reaction Then the author tried several commonly used double coordination leaving groups, and finally found that oxalate ester can get the target product (11-13a) with 75% separation yield Fig 2 The effect of leaving group on the reaction a (source: Chemical Science) then, the author examined the applicability of alkyl bromide in detail (Fig 3) Due to the difficulty of oxidation and addition of non active alkyl halogenated hydrocarbons, the elimination of β - H and isomerization of metal intermediates, the alkylation of non active alkyl halogenated hydrocarbons has always been a difficulty in the field of coupling reactions In this study, the reaction developed by the authors is not only suitable for the benzylation of ordinary long-chain halogenated hydrocarbons, but also for the benzylation of various high-level group halogenated hydrocarbons The reaction shows good chemical selectivity and functional group compatibility It is compatible with Fluoroalkane (15F), chloroalkane (15g), ether (15h, 15q), ester (15I, 15m), amide (15J, 15N, 15O), amine (15K), phosphonate (15L), alcohol (15p), silica ether (15R), acetal (15s), aldehyde (15t), borate (15u), etc In addition, the target product (15v-15x) can also be obtained in medium yield for the second-order brominated hydrocarbons Figure 3 Applicability of alkyl bromide a (source: Chemical Science) then, the author further investigated the substrate applicability of benzyloxalate (Figure 4) The reaction occurred selectively in the position of benzyl ester, while the aryl ester remained (15y - 15ac) The reaction has good functional compatibility for tension ring, amino acid, α - hydroxy acid derivative and acid amide The chirality of amino acids and α - hydroxy acid derivatives can be completely preserved (15ab, 15ac) Heterocyclic aromatic hydrocarbons (quinoline, indole, pyrrole, thiophene, etc.) containing nitrogen and sulfur can obtain the target product (15af - 15aj) in medium yield At present, most of the C-O bond activation at the benzyl position depends on the use of large π - conjugated aromatic ring substrates; however, in the reaction developed by the authors, pyrrole, thiophene, phenyl and other common aromatic ring substrates can also obtain alkylation products (15ai - 15ak) in medium yield Figure 4 Substrate applicability of benzyl oxalate a (source: Chemical Science) post modification of natural products is an important way to obtain highly active biomolecules In the subsequent experiments, the method developed by the authors can be applied to the benzylation of a variety of complex active molecules, and the corresponding target product can be obtained in medium yield (Fig 5) Fig 5 The mechanism of the later modification of bioactive molecules (source: Chemical Science) has been preliminarily studied by the authors (Fig 6) The results show that the alkyl bromide in the reaction is likely to be activated by free radicals, but it may not be through the free radical chain reaction process The detailed mechanism of this reaction needs further study Figure 6 Mechanism study (source: Chemical Science) Summary: the author uses oxalate, a new leaving group, to realize the activation of C-O bond at benzyl position and alkylation reaction with halohydrocarbon catalyzed by nickel The reaction not only has a wide range of substrate applicability, but also shows good compatibility for hydroxyl, borate ester, amide, aldehyde group, heterocycle and other functional groups The above research work has been supported by the National Natural Science Foundation of China, the special fund of the Central University and the project of the young thousand talents program.
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