Asymmetric decarboxylation and allyl alkylation of α - arylnitroester catalyzed by angelw: PD

Nitroalkanes are widely found in natural products and bioactive compounds, and they are also common intermediates in organic synthesis They can be converted into amines and alkanes by simple reduction or oxidation reactions (Figure 1) Therefore, nitroalkanes are widely used in asymmetric Michael reaction, aldol reaction and Mannich reaction However, the selectivity of C - and O-alkylation of nitroalkanes has always been a problem With the development of the times, the free radical reaction of nitroalkanes catalyzed by transition metals (such as Cu and Ni) can successfully solve this selective problem, but the reaction substrate catalyzed by transition metals is only limited to primary nitroalkanes and α - bromoamides, and so far there is no alkylation reaction of primary benzyl or secondary benzyl nitroalkanes catalyzed by transition metals Transition metal Pd can successfully realize the c-alkylation of primary and secondary nitroalkanes (scheme 1a), but secondary benzyl nitroalkanes are prone to O-alkylation (scheme 1b) Therefore, the c-alkylation of SEC benzyl nitroalkanes is still facing great challenges On the basis of the above research background, Barry M Trost group of Stanford University in the United States has developed PD and diphenylphosphine benzamide ligands (Figure 2) to catalyze the asymmetric c-alkylation of SEC benzyl nitroalkanes and synthesize a series of tetrasubstituted chiral tertiary nitroalkanes (scheme 1c) Relevant research results were published in angelw Chem Int ed (DOI: 10.1002 / anie 201904034) (image source: angelw Chem Int ed.) (image source: angelw Chem Int ed.) (image source: angelw Chem Int ed.) used benzylnitroalkane 1 and allylmethylcarbonate 2 as template substrate The author found that the C- Allyl alkylation can proceed smoothly, but scheme 2 can only be obtained with moderate enantioselectivity Moreover, the reaction of 2-substituted carbonate can not produce the corresponding products Therefore, the author wants to enhance the kinetic process of asymmetric decarboxyallyl alkylation, so as to improve the enantioselectivity of the reaction (scheme 3) (picture source: angelw Chem Int ed.) (picture source: angelw Chem Int ed.) with 4 as template substrate, through the repeated screening of reaction conditions such as substrate, ligand and solvent, the author determined that the optimal reaction conditions were (Table 1 & 2): 2-substituted nitroester 4C as substrate, 2.5 mol% PD 2 DBA 3 · CHCl 3 and 7.5 mol% chiral complex L1 was used as catalyst and ethyl acetate as solvent After reaction at - 78 ℃ for a period of time, the reaction was moved to 4 ℃, and the corresponding products were obtained with 87% yield and 87% enantioselectivity (picture source: angelw Chem Int ed.) (picture source: angelw Chem Int ed.) wherein, the preparation step of α - arylnitroester is (scheme 4): under the condition of gradually rising temperature, lithium nitrate 6 and allylimidazole 7 can react rapidly to form nitroester 8 Then, PD daaa substrate 4 can be formed by α - arylation of 8 with aryliodide (picture source: angelw Chem Int ed.) under the optimal reaction conditions, the author investigated the substrate range of the reaction (Table 3) The nitro ester substituted by α - ethyl and larger β - methylsilyl silyl silyl ester can adapt to the reaction conditions, and the corresponding products can be obtained with excellent yield and enantioselectivity All kinds of aryl substituted, pyridine substituted and 2-naphthyl substituted Nitroesters also have good tolerance, and the corresponding products can be obtained with good to excellent yield and enantioselectivity Among them, the yield of the nitroester substituted by electronic aryl group will decrease slightly, mainly because the O-alkylation by-products of the reaction will increase In addition, the corresponding products can only be obtained with good yield and enantioselectivity for the unsubstituted allyl ester, while the corresponding products can only be obtained with low yield for the 2-bromoaryl-substituted allyl ester (picture source: angelw Chem Int ed.) in order to prove the application potential of the reaction, the author carried out gram level reaction and derivative reaction (scheme 5) Under the standard conditions, the catalyst dosage is reduced by half, and the product 3Q can be obtained with 86% yield and 97% enantioselectivity Then, the derivative reaction was carried out with 3Q template substrate In the presence of O 3, 3Q alkenyl can be selectively reduced to carbonyl to form compound 10 In the presence of Lindlar catalyst, 3Q alkynyl group can be selectively reduced to alkenyl group to form compound 11 In the acetic acid solution of Zn, 3Q nitro group can be selectively reduced to amino group to form compound 12 (picture source: angelw Chem Int ed.) the influence of solvent and ligand effect on PD daaa reaction shows that the catalyst is activated in the form of monomer, and c-alkylation is closely related to the ligand framework, which fully explains the reason why no O-alkylation reaction occurs in α - arylnitroester In addition, the effect of reaction concentration on enantioselectivity is consistent with that of oligomeric catalyst Therefore, the author uses the model in Figure 3 to explain the reaction mechanism Summary: Barry M Trost group of Stanford University has successfully developed PD catalyzed asymmetric decarboxyallyl alkylation of α - arylnitroester, which can obtain a series of tetrasubstituted TERT nitroalkanes with good yield and enantioselectivity At the same time, this strategy provides a new and simple method for the synthesis of chiral α - tertiary amines.