The fast and highly stereoselective Mannich reaction of aldehydes and ketones with the N‐(p‐methoxyphenyl) ethyl glyoxylate imine catalyzed by polystyrene resins functionalized with ...(2S,4R)‐hydroxyproline is reported. The effect of the nature of the linker connecting proline with the polymeric backbone has been studied, and a 1,2,3‐triazole linker constructed from azidomethyl polystyrene and O‐propargyl hydroxyproline turns out to be optimal for catalytic activity and enantioselectivity. With aldehyde donors, fast reactions leading to complete conversion in 1–3 h are recorded in DMF. With ketone donors, the reactions tend to be slower, but can be efficiently accelerated (six‐membered ring cycloalkanones) by low‐power microwave irradiation. This approach, which greatly facilitates product isolation since the catalyst is removed by simple filtration, has allowed the implementation of the reactions of aldehyde substrates in a continuous‐flow, single‐pass system. In this manner, the continuous synthesis of the enantiomerically and diastereomerically pure adducts (syn/anti>97:3; ee>99 %) has been achieved at room temperature with residence times of 6.0 min. This methodology has allowed for the preparation of up to 7.8 mmol of the desired Mannich adduct through the use of 0.46 mmol of catalytic resin (5.9 mol %), in a greatly simplified experimental protocol that avoids purification steps.
Let it flow! Stereoselective Mannich reactions of aldehydes and ketones with the N‐(p‐methoxyphenyl) ethyl glyoxylate imine are efficiently catalyzed by a functionalized polystyrene resin. For aldehydes, the reactions have been implemented in a flow system (see figure); continuous synthesis of the enantiomerically and diastereomerically pure adducts was achieved in just minutes at room temperature.
α,α‐Diphenylprolinol methyl‐ and trimethylsilyl ethers anchored onto a polystyrene resin have been prepared by a copper‐catalyzed azide–alkyne cycloadditions (CuAAC). The catalytic activity and ...enantioselectivity displayed by the O‐trimethylsilyl derivative are comparable to those exhibited by the best known homogeneous catalysts for the addition of aldehydes to nitroolefins and of malonates or nitromethane to α,β‐unsaturated aldehydes. The combination of the catalytic unit, the triazole linker, and the polymeric matrix provides unprecedented substrate selectivity, in favor of linear, short‐chain aldehydes, when the organocatalyzed reaction proceeds by an enamine mechanism. High versatility is noted in reactions that proceed via an iminium ion intermediate. The catalytic behavior of polystyrene‐supported α,α‐diphenylprolinol methyl ether was also evaluated in asymmetric Michael addition reactions. As a general trend, the CuAAC immobilization of diarylprolinol ethers onto insoluble polystyrene resins offers important operational advantages, such as high catalytic activity, easy recovery from the reaction mixture by simple filtration, and the possibility of extended reuse.
Better than homogeneous! α,α‐Diphenylprolinol trimethylsilyl ether anchored onto a polystyrene resin by a copper‐catalyzed azide–alkyne cycloaddition displays catalytic activity and enantioselectivity comparable to the best homogeneous organocatalysts in the Michael addition of aldehydes to nitroolefins and of malonates or nitromethane to α,β‐unsaturated aldehydes (see scheme).
The development of a highly efficient, polymer-supported organocatalyst for the Michael addition of ketones to nitroolefins is described. A 1,2,3-triazole ring, constructed through a click ...1,3-cycloaddition, plays the double role of grafting the chiral pyrrolidine monomer onto the polystyrene backbone and of providing a structural element, complementary to pyrrolidine, key to high catalytic activity and enantioselectivity. Optimal operation in water and full recyclability make the triazole linker attractive for the immobilization of organocatalysts.
The application of polystyrene-immobilized proline-based catalysts in packed-bed reactors for the continuous-flow, direct, enantioselective α-aminoxylation of aldehydes is described. The system ...allows the easy preparation of a series of β-aminoxy alcohols (after a reductive workup) with excellent optical purity and with an effective catalyst loading of ca. 2.5% (four-fold reduction compared to the batch process) working at residence times of ca. 5 min.
Several strategies to synthesize desired 1,2,4‐triazolo1,5‐apyridine‐2‐carboxylate targets have been reported over the years. The most convenient way features the preparation of the precursor ...triazolopyridine‐N‐oxide through a condensation step between sulfilimines and a nitrile oxide species, followed by a deoxygenation step. This paper presents a detailed work on the synthesis of 1,2,4triazolo1,5‐apyridine‐2‐carboxylate‐N‐oxide, featuring a synergistic experimental‐theoretical approach. Herein, we report the development of an efficient and straightforward method to prepare ethyl 1,2,4triazolo1,5‐apyridine‐2‐carboxylate 3‐oxide in continuous flow. The transfer from batch to flow processing resulted in a significant boost in isolated yield (53 % vs. 31 %) and a decrease in the simultaneous presence of starting materials and product in the reaction media from 4 hours to 3.5 minutes. An in‐depth mechanistic study of the reaction using density functional theory provided a deeper understanding of the whole reaction manifold and key indications on how to further improve the process in flow.
1,2,4‐triazolo1,5‐apyridine‐2‐carboxylates are conveniently prepared from triazolopyridine‐N‐oxide precursors, by reacting sulfilimine and a nitrile oxide species. Herein, an efficient and straightforward procedure to prepare 1,2,4triazolo1,5‐apyridine‐2‐carboxylate‐N‐oxide in continuous flow is reported. A mechanistic study performed using density functional theory (DFT) provided deep insights on the whole reaction manifold and indication on how to reduce the generation of by‐product.
Several strategies to synthesize desired 1,2,4‐triazolo1,5‐apyridine‐2‐carboxylate targets have been reported over the years. The most convenient way features the preparation of the precursor ...triazolopyridine‐N‐oxide through a condensation step between sulfilimines and a nitrile oxide species, followed by a deoxygenation step. This paper presents a detailed work on the synthesis of 1,2,4triazolo1,5‐apyridine‐2‐carboxylate‐N‐oxide, featuring a synergistic experimental‐theoretical approach. Herein, we report the development of an efficient and straightforward method to prepare ethyl 1,2,4triazolo1,5‐apyridine‐2‐carboxylate 3‐oxide in continuous flow. The transfer from batch to flow processing resulted in a significant boost in isolated yield (53 % vs. 31 %) and a decrease in the simultaneous presence of starting materials and product in the reaction media from 4 hours to 3.5 minutes. An in‐depth mechanistic study of the reaction using density functional theory provided a deeper understanding of the whole reaction manifold and key indications on how to further improve the process in flow.
A polystyrene-supported 1,5,7-triazabicyclodec-5-ene (TBD) was used as a highly recyclable and stable catalyst for the conversion of epoxy amines into various 2-oxazolidone scaffolds. This approach ...combines the use of CO
2
as an attractive, cheap and abundant C
1
source with a halide-free, organocatalytic continuous flow approach to promote the efficient synthesis of a small library of pharmaceutically relevant 2-substituted oxazolidinones, including the known drug Toloxatone. A packed bed reactor containing the same batch of immobilized catalyst could be applied for the continuous synthesis of a series of heterocyclic products over a two week period without significant changes in catalytic activity.
A catalytic continuous flow approach towards pharmaceutically relevant oxazolidinones has been developed using epoxy alcohols and CO
2
as reagents, taking advantage of a stable, scalable and metal- and halide-free protocol.
A polymer‐supported α,α‐diarylprolinol silyl ether displays catalytic activity and enantioselectivity comparable to the best homogeneous catalysts in the Michael addition of aldehydes to ...nitroolefins. Above all, the combination of polymer backbone, triazole linker, and catalytic unit confers to it an unprecedented substrate selectivity in favor of linear, short‐chain aldehydes.
Glycerol carbonate is a useful compound of value for a variety of cosmetic, material, and synthetic applications. Its synthesis relies either on the carbonation of glycerol or the conversion of ...glycidol by reacting it with carbon dioxide under appropriate catalytic conditions. Here, we report the first continuous flow preparation of glycerol carbonate using an immobilized organocatalyst (TBD@Merrifield) that mediates the coupling of glycidol and CO2 under comparative mild reaction and halide-free conditions. Under optimized conditions, glycerol carbonate could be produced throughout a period of 48 h (17.3 g (147 mmol); TON, 99; productivity, 2.04 mmol h–1 mmolcat –1) without any noticeable loss of catalytic performance in this time frame.
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•Capsid Assembly Modulators are promising agents for curing chronic HBV infection.•Target-based in silico screening study leads to the discovery of novel HBV CAMs.•Lead compounds show ...in vitro potency in the sub-micromolar range.•A novel series of pyrazines is classified as non-HAP like HBV CAMs.
Small-molecule capsid assembly modulators (CAMs) have been recently recognized as promising antiviral agents for curing chronic hepatitis B virus (HBV) infection. A target-based in silico screening study is described, aimed towards the discovery of novel HBV CAMs. Initial optimization of four weakly active screening hits was performed via focused library synthesis. Lead compound 42 and close analogues 56 and 57 exhibited in vitro potency in the sub- and micromolar range along with good physico-chemical properties and were further evaluated in molecular docking and mechanism of action studies.
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