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    Home > Asymmetric allyl alkylation of β, γ - Unsaturated - α - aminonitrile catalyzed by angelw: RH

    Asymmetric allyl alkylation of β, γ - Unsaturated - α - aminonitrile catalyzed by angelw: RH

    • Last Update: 2019-05-03
    • Source: Internet
    • Author: User
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    Heteroatom stable allylic anions can be used as high enol equivalents for the synthesis of β - substituted carbonyl compounds, but there is a problem of poor regioselectivity in this reaction (scheme 1a) Although the asymmetric functionalization of allylamine, carbamate and α - aminonitrile has been successfully reported, these reactions must be promoted by the use of chiral adjuvants or chemically equivalent chiral bases (scheme 1b) Therefore, the P Andrew Evans group of Chemistry Department of Queen's University of Canada envisages that the strategy of obtaining β - substituted carbonyl derivatives through asymmetric addition of heteroatom stable allylic anion and allylic electrophilic reagent catalyzed by transition metal seems to be a better way to solve these problems Although the asymmetric transition metal catalyzed allyl cross coupling of non chiral allylics has made good progress (scheme 1c), so far, there is no report about the transition metal catalyzed heteroatom stable allylic anions In addition, the process of forming high enol equivalents requires three different selection modes: coordination of region, enantioselectivity and geometric control, which increases the difficulty of the author's work On the basis of the above study, the first case of asymmetric allylic alkylation of β, γ - Unsaturated - α - aminonitrile catalyzed by RH is reported, in which β, γ - Unsaturated - α - aminonitrile is used as the high enol equivalent for the synthesis of β - substituted carboxylic acid derivatives (scheme 1D) Relevant research results were published in angelw Chem Int ed (DOI: 10.1002 / anie 201900442) (picture source: angel Chem Int ed.) firstly, the author optimized the reaction conditions with allyl substituted α - aminonitrile 1A '(prepared by one pot Strecker reaction of cinnamaldehyde, N-methylaniline and trimethylsilylcyanide) and allyl acetate 2 as template substrate (Table 1) After screening the substrate, catalyst, solvent and temperature, the author found that the reaction energy was 81% and 93% with ethyl substituted α - aminonitrile 1a and allyl acetate 2 as the substrate, 10 mol% RhCl (PPh3) 3 and 40 mol% (R) - BINOL pome as the catalyst, 1.6 equiv LiHMDS as the additive and DME / THF (4:1) as the solvent at 0 ° C for 16 h The target product of e configuration was obtained (image source: angelw Chem Int ed.) then, under the optimal reaction conditions, the author examined the substrate range of allylic substituted α - aminonitriles (Table 2) All kinds of aryl substitution, heterocyclic substitution with N, s, O, vinyl substitution and allylic substitution with ε can adapt to the reaction conditions well, and the target compounds can be obtained with good yield and excellent enantioselectivity (image source: angelw Chem Int ed.) in order to prove the potential value of the synthesis method, the author further carried out the gram reaction and derivative reaction Although the amount of catalyst used in the gram level reaction is reduced, the target product 3A (Scheme 2A) can still be obtained by the reaction with good yield and excellent enantioselectivity 3A can be hydrolyzed to β - substituted carboxylic acid 5A (scheme 2b) in situ under the action of HCl 5A can be converted into methyl ketone 6A under the action of methyl lithium, methyl hydrocinnate 7a in acid methanol solution, and benzylamide 8A (scheme 2C) under the condition of standard amide bond formation (picture source: angelw Chem Int ed.) in order to explore the determinants of the E / Z configuration in RH catalyzed allyl alkylation, the author conducted a control experiment (scheme 3) Under the optimal reaction conditions, the author added the aqueous solution of ammonium chloride or methyl iodine to the protonation of 1a, and found that the geometric selectivity was significantly reduced and the main product was the Z-configuration product (scheme 3a) This shows that the E / Z configuration of allylic anion is dependent on electrophilic reagent and independent of catalyst Two kinds of allylic anions will be formed in deprotonated 1a Then, under the catalysis of RH, the intermediate of e-configuration will preferentially react with allyl acetate to obtain e-configuration products Moreover, the two geometries of allyl anions play a decisive role in enantioselectivity (scheme 3b) (photo source: angelw Chem Int ed.) Summary: P Andrew Evans research group, Department of chemistry, Queen's University of Canada, reported the first case of RH catalyzed asymmetric allylation of β, γ - Unsaturated - α - aminonitrile, in which β, γ - Unsaturated - α - aminonitrile is used as the homoenol equivalent in the synthesis of β - substituted carbonyl compounds, and β - substituted esters and amide derivatives are obtained by simple derivative reactions.
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