hetero-Michael Addition Reaction Research Articles

Tandem Allylic Amination/oxa-Michael Addition of Vinyl Methylene Cyclic Carbonates via Palladium-Organo Relay Catalysis.

A tandem allylic amination/oxa-Michael addition of vinyl methylene cyclic carbonates (VMCCs) has been developed to construct heterocycles by single palladium catalysis or palladium-organo relay catalysis. In this process, the bisnucleophiles first underwent regioselective allylic amination, and then the second nucleophilic group further completed the hetero-Michael addition reaction to form a series of heterocycles. Among them, the chiral 3,4-dihydro-2H-benzo[b][1,4]oxazines could be produced in medium to high yield with good enantioselectivity under a palladium-organo relay catalysis.

Inhibition of XPO-1 Mediated Nuclear Export through the Michael-Acceptor Character of Chalcones.

The nuclear export receptor exportin-1 (XPO1, CRM1) mediates the nuclear export of proteins that contain a leucine-rich nuclear export signal (NES) towards the cytoplasm. XPO1 is considered a relevant target in different human diseases, particularly in hematological malignancies, tumor resistance, inflammation, neurodegeneration and viral infections. Thus, its pharmacological inhibition is of significant therapeutic interest. The best inhibitors described so far (leptomycin B and SINE compounds) interact with XPO1 through a covalent interaction with Cys528 located in the NES-binding cleft of XPO1. Based on the well-established feature of chalcone derivatives to react with thiol groups via hetero-Michael addition reactions, we have synthesized two series of chalcones. Their capacity to react with thiol groups was tested by incubation with GSH to afford the hetero-Michael adducts that evolved backwards to the initial chalcone through a retro-Michael reaction, supporting that the covalent interaction with thiols could be reversible. The chalcone derivatives were evaluated in antiproliferative assays against a panel of cancer cell lines and as XPO1 inhibitors, and a good correlation was observed with the results obtained in both assays. Moreover, no inhibition of the cargo export was observed when the two prototype chalcones 9 and 10 were tested against a XPO1-mutated Jurkat cell line (XPO1C528S), highlighting the importance of the Cys at the NES-binding cleft for inhibition. Finally, their interaction at the molecular level at the NES-binding cleft was studied by applying the computational tool CovDock.

Diversity-Oriented Approach to N-Heterocyclic Compounds from α-Phenyl-β-enamino Ester via a Mitsunobu-Michael Reaction Sequence.

Herein we delineate a novel route for the diastereoselective construction of diversely substituted N-heterocyclic ring systems as valuable scaffolds for natural products and pharmaceuticals, starting from an easily accessible prochiral α-phenyl-β-enamino ester. The reaction sequence relies on the unexplored reactivity of α-phenyl-β-enamino ester as a nucleophilic partner in the Mitsunobu reaction to forge the N-tethered alkene-alcohol/thiol/amine intermediate, which was subjected to an intramolecular hetero-Michael addition reaction under mild conditions to furnish the respective N-heterocyclic compounds embedded with an exocyclic chiral center in high yields and excellent diastereoselectivities. The methodology is amenable for a broad range of substrates based on a metal-free approach.

Diastereoselective Synthesis of Morphan Derivatives by Michael and Hetero-Michael Addition of 1,1-Enediamines to Quinone Monoketals

A general and concise method was developed for the synthesis of highly functionalized morphans 3–4 by the Michael and hetero-Michael addition reaction of different types of quinone monoketals 1 and 1,1-enediamines 2 in ethanol or 1,4-dioxane at reflux. This method is suitable for the efficient parallel syntheses of N-containing heterocycles. A library of highly functional morphan derivatives was easily constructed using the Michael/hetero-Michael reaction.

Covalent Modifiers: A Chemical Perspective on the Reactivity of α,β-Unsaturated Carbonyls with Thiols via Hetero-Michael Addition Reactions.

Although Michael acceptors display a potent and broad spectrum of bioactivity, they have largely been ignored in drug discovery because of their presumed indiscriminate reactivity. As such, a dearth of information exists relevant to the thiol reactivity of natural products and their analogues possessing this moiety. In the midst of recently approved acrylamide-containing drugs, it is clear that a good understanding of the hetero-Michael addition reaction and the relative reactivities of biological thiols with Michael acceptors under physiological conditions is needed for the design and use of these compounds as biological tools and potential therapeutics. This Perspective provides information that will contribute to this understanding, such as kinetics of thiol addition reactions, bioactivities, as well as steric and electronic factors that influence the electrophilicity and reversibility of Michael acceptors. This Perspective is focused on α,β-unsaturated carbonyls given their preponderance in bioactive natural products.

Ecofriendly and efficient procedure for hetero-Michael addition reactions with an acidic ionic liquid as catalyst and reaction medium

Methylimidazolium trifluoroacetate ((Hmim)- TFA) is reported as a cost-effective catalyst for a simple and environmentally benign hetero-Michael reaction. (Hmim)TFA works both as reaction medium and catalyst. The reaction is applicable to various aromatic sulfur and nitrogen nucleophiles. This method has advantages such as high yields, short reaction time, and simple workup. The catalyst could be recycled several times without any loss of activity.

Synthesis and Characterization of Silica@Copper Core–Shell Nanoparticles: Application for Conjugate Addition Reactions

Silica@copper (SiO2@Cu) core-shell nanoparticles were synthesized and well characterized by XRD, TEM, AFM, XPS, UV/Vis, TGA-MS, and ICP-AES techniques. The synthesized SiO2@Cu core-shell nanoparticles were employed as catalysts for the conjugate addition of amines to alpha,beta-unsaturated compounds in water to obtain beta-amino carbonyl compounds in excellent yields in shorter reaction times. Furthermore, the catalyst works well for hetero-Michael addition reactions of heteroatom nucleophiles such as thiols to alpha,beta-unsaturated compounds. As the reaction is performed in water, it allows for easy recycling of the catalyst with consistent activity.

A practical and green approach toward synthesis of N3-substituted dihydropyrimidinones: Using Aza-Michael addition reaction catalyzed by KF/Al 2O 3

A simple and efficient method for the synthesis of N3-substituted 3,4-dihydropyrimidinones by aza-Michael addition reactions of 3,4-dihydropyrimidinones to α,β-ethylenic compounds catalyzed by KF/Al 2O 3 is described. The advantage of this method is high regioselectivity, high purity, and the use of a cheaper, milder, and efficient catalyst for the hetero-Michael addition reaction.

Highly Efficient KF/Al2O3‐Catalyzed Versatile Hetero‐Michael Addition of Nitrogen, Oxygen, and Sulfur Nucleophiles to α,β‐Ethylenic Compounds.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Highly efficient KF/Al 2O 3-catalyzed versatile hetero-Michael addition of nitrogen, oxygen, and sulfur nucleophiles to α,β-ethylenic compounds

The first example of KF/Al 2O 3-catalyzed versatile hetero-Michael addition reaction of nitrogen, oxygen, and sulfur nucleophiles was developed for facile preparation of organic compounds of widely different structures. In contrast with the existing methods using many acidic catalysts, this method is very general, simple, high-yielding, environmentally friendly, and oxygen and moisture tolerant.

Synthesis and hetero-Michael addition reactions of 2-alkynyl oxazoles and oxazolines

Stereoselective conjugate additions of alcohols, amines, thiols, and halides to C(2)-alkynyl oxazoles and oxazolines provide a versatile entry to heterocyclic building blocks.

Evidence that Protons Can Be the Active Catalysts in Lewis Acid Mediated Hetero‐Michael Addition Reactions.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Evidence that protons can be the active catalysts in Lewis acid mediated hetero-Michael addition reactions.

The mechanism of Lewis acid catalysed hetero-Michael addition reactions of weakly basic nucleophiles to alpha,beta-unsaturated ketones was investigated. Protons, rather than metal ions, were identified as the active catalysts. Other mechanisms have been ruled out by analyses of side products and of stoichiometric enone-catalyst mixtures and by the use of radical inhibitors. No evidence for the involvement of pi-olefin-metal complexes or for carbonyl-metal-ion interactions was obtained. The reactions did not proceed in the presence of the non-coordinating base 2,6-di-tert-butylpyridine. An excellent correlation of catalytic activities with cation hydrolysis constants was obtained. Different reactivities of mono- and dicarbonyl substrates have been rationalised. A (1)H NMR probe for the assessment of proton generation was established and Lewis acids have been classified according to their propensity to hydrolyse in organic solvents. Brønsted acid-catalysed conjugate addition reactions of nitrogen, oxygen, sulfur and carbon nucleophiles are developed and implications for asymmetric Lewis acid catalysis are discussed.

Low melting N-4-functionalized-1-alkyl or polyfluoroalkyl-1,2,4-triazolium salts.

Butane sulfobetaines 2a,b, zwitterionic oxo perfluorocarboxylates 3a,b, and functionalized triazolium bromides 4b,c and 5a-c have been synthesized and subsequently reacted to give a series of hydrophilic and hydrophobic fluorinated and nonfluorinated N-1-alkyl-N-4-functionalized-triazolium compounds (6a-11b). With the exception of 11b (mp 41 degrees C), all are liquids at room temperature. Metathesis of the fluorinated quaternary triazolium halides with other anions led to the formation of a new class of compounds, namely, [(R)(R(funct))-Taz](+)Y(-), Y = PF(6), (CF(3)SO(2))( 2)N, and CF(3)SO(3), in good isolated yields. All of the new compounds were characterized by (1)H, (19)F, and (13)C NMR, and MS spectral and elemental analyses. Thermal analyses indicate that high temperatures are attainable prior to decomposition. DSC studies show glass transitions for several samples, and all functionalized compounds, 5-11, have T(g)s or T(m)s <100 degrees C. Densities range between 1.4 and 1.61 g cm(-)(3). 1-Heptyl-4-(butyl-4-sulfonic acid) triazolium trifluoromethanesulfonate, 6b, in its role as a Brønsted acid, is an effective solvent/catalyst for high yield esterification and hetero-Michael addition reactions and may be recycled for repetitive use.