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    Home > JACS: aza rubottom oxidation opens up a new method of α - aminoketone synthesis

    JACS: aza rubottom oxidation opens up a new method of α - aminoketone synthesis

    • Last Update: 2019-02-19
    • Source: Internet
    • Author: User
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    α - aminoketones are widely found in bioactive molecules, natural product molecules and drug molecules At present, two-step synthesis is the most common strategy for the synthesis of α - aminoketone In this method, azido, nitro or hydroxyamino groups are introduced into the α position, and then catalytic hydrogenation is carried out (Figure 1a) However, the chemical selectivity of this method is poor, and the stability of azido or nitro intermediate is poor, which limits the application of this method Another synthesis strategy first uses the reaction of ketone with azodicarbonyl compound catalyzed by alkali or organic catalyst to prepare α - hydrazine compound (Figure 1b) Although the α - hydrazination reaction has the advantages of high yield and good enantioselectivity, it still needs multi-step reaction to cut N-N bond and get the required primary amino ketone Rubottom oxidation has a wide range of applicability, and even has been used in the synthesis of extremely complex natural products for many times (Figure 1c) However, similar aza rubottom oxidation has not been reported Recently, the research group of Professor L á SZL ó K ü RTI of Rice University in the United States has reported a new method of converting enol silicone ether to α - primary amino ketone: aza rubottom oxidation for the first time Hexafluoroisopropanol (HFIP) solvent is necessary for the success of the reaction This method is very suitable for nitrogen functionalization and derivatization of complex organic molecules Relevant research results were published in j.am Chem SOC (j.am Chem SOC 2019, 141, 2242) (source: J am Chem SOC.) in the study of enantioselective NH aziridination of olefins, the author found that when HFIP was used as the solvent, the four electron rich olefin substrate could be completely converted to the corresponding NH aziridine without transition metal catalyst, but the rate was slow The possibility of trace metal contamination of HFIP was eliminated by using the heavy distillation HFIP as a control experiment Furthermore, the more electron rich enol silyl ether (1) is considered to be used for aziridization to prepare the corresponding α - aminoketone In order to make the characterization and separation of the product more convenient, the free amine is converted into the hydrochloride 1b The results showed that when DPH (3) was used as aminating agent, ipr2net as base and HFIP as solvent, the target product 1B (Table 1) could be obtained in 85% yield (source: J am Chem SOC.) next, the author examined the substrate range (scheme 1) of the reaction The target product (7b - 9b) was obtained in good yields from phenyl and various alkyl substituted substrates When R 1 is phenyl, the yield of electron rich substrate is higher than that of electron deficient substrate (10b vs 12b) Thiophene, imidazole, benzofuran and other heterocycles can also be tolerated in the reaction (13b - 15b) In addition, the reaction can be successfully applied to amination of indomethacin derivative 19 These results show that the reaction has excellent functional group tolerance and has great potential for application in the late functionalization of drug intermediates However, when the substrate contains a strong electron withdrawing group (20 - 22), the reaction cannot proceed (source: J am Chem SOC.) for enol silicone ether with low activity, when Hosa is used as nitrogen source and transition metal RH or Cu is used as catalyst, the reaction can be carried out smoothly and α - primary amino ketone with electron withdrawing substituent (scheme 2) can be obtained in good to extremely good yield Similar to the uncatalyzed reactions, the transition metal catalyzed oxidation of AZA rubottom also requires HFIP as the solvent (source: J am Chem SOC.) through literature research, the author thinks that the acceleration of HFIP is probably caused by the hydrogen bond interaction The high-level solvent aggregates formed by multiple HFIP molecules activate the hydroxylamine derived amination reagent (scheme 3) through the coordinated hydrogen bond interaction This explains the adverse effects of cosolvent, which affects the concentration of active HFIP aggregates (source: J am Chem SOC.) conclusion: Professor L á SZL ó K ü RTI of Rice University in the United States has developed a new method for the synthesis of α - primary amino ketone from enol silicone ether The substrate with electron rich base can be α - aminated without transition metal catalyst, and the substrate with electron absorbing base can be α - aminated with RH or Cu catalyst.
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