Intermolecular Michael Addition Research Articles

TfOH‐Catalyzed self‐Condensation of β‐Aminoketones for the Synthesis of Tetrahydropyridines

AbstractA novel self‐condensation of β‐aminoketones was described. Various multisubstituted 1, 2, 3, 6‐tetrahydropyridine derivatives were synthesized in medium to good yields in the presence of 20 mmol % of TfOH. This transformation probably processed a decomposition of β‐aminoketones (also named retro‐Michael addition), followed by intermolecular Michael addition and intramolecular ring closure. Furthermore, 1, 2, 5, 6‐tetrahydropyridines were obtained in a one‐pot manner through DBU‐promoted isomerization of the in‐situ generated 1, 2, 3, 6‐tetrahydropyridines. The present method exhibited good functional group tolerance, and convenient operation, making it a practical alternative for the construction of multisubstituted tetrahydropyridines.

Substituent-Oriented Synthesis of Substituted Pyridines/Pyrido[3,2-C]coumarins via Sequential Reactions of α-H and Me/Aryl Substituted Oxime Acetates and 3-Formylchromones.

A facile one pot sequential and highly chemoselective synthesis of substituted pyridines/pyrido[3,2-c]coumarins has been developed from oxime acetates and 3-formylchromones in the presence of FeCl2. This reaction was oriented by different substituents on the α-position (H, methyl/aryl) of oxime acetates. Mechanistic investigations suggested that substituted pyridines were formed via intramolecular aza-Michael addition followed by ring opening, while pyrido[3,2-c]coumarins were formed via intermolecular Michael addition. Besides, anti-TB activity was screened for some of the synthesized pyridines. Among the tested compounds, 3ga, 3ha, 3ja, 3ma, 3ac, 4pa, 4pb and 4sb were found to have good activity with an MIC of 12.5 μg/mL.

Access to 8-Aminoindolizine Fused with Quinone via Cu(OAc)2-Catalyzed Domino [4+2] Annulation

AbstractCu(OAc)2-catalyzed [4+2] annulation of N-substituted pyrrole-2-carbonitriles with quinones allowed access to a wide range of 8-aminoindolizines fused with quinones through a domino process involving a sequence of intermolecular Michael addition, Thorpe–Ziegler type cyclization, and aromatization. Biological evaluation of the resulting quinone-8-aminoindolizine hybrids revealed significant anticancer effects of these compounds in human hepatocellular cells (HepG2) and prostate adenocarcinoma cells (PC-3).

Enhancement of the Surface Hydrophilicity of Poly(Vinyl Chloride) Using Hyperbranched Polylysine with Polydopamine

In recent years, the application of polyvinyl chloride (PVC) material has significantly expanded within the realm of biomedical materials. However, the hydrophobicity of PVC has been found to cause many adverse reactions in patients within the biomedical field. It is imperative to urgently discover viable approaches for enhancing the hydrophilicity of PVC in order to ensure its safety in biomedical applications. In this study, the surface of PVC films was modified with a combination of hyperbranched polylysine (HBPL) and polydopamine (pDA) through either simultaneous deposition with polydopamine (PVC-pDA/HBPL) or successive deposition of pDA and HBPL (PVC-pDA-HBPL), aiming to investigate the influence of this modification method on surface hydrophilicity enhancement. The surface coatings were characterized using gravimetry, scanning electron microscopy (SEM), Fourier transform infrared spectroscopy (FTIR), Raman spectroscopy, and water contact angle measurements. The results demonstrated that the incorporation of HBPL led to a significant enhancement in both the deposition amount and stability of pDA, particularly when the mass ratio of DA/HBPL was approximately 1:1. Simultaneously, the morphology of the films exhibited an increase in roughness, while surface hydrophilicity was significantly enhanced upon incorporating pDA and HBPL, and the water contact angle was decreased to 43.2°. Moreover, the detachment of PVC-pDA/HBPL and PVC-pDA-HBPL after exposure to 1.0 M NaOH solutions was considerably lower compared to that of PVC-pDA alone, indicating improved stability under strongly basic conditions. Notably, these enhancements were more pronounced for PVC-pDA/HBPL than for PVC-pDA-HBPL, indicating that HBPL may act as a cross-linker during pDA deposition primarily through intermolecular Schiff base reactions, hydrogen bonding, or Michael addition. This work represents a pioneering effort in integrating HBPL and dopamine for hydrophilic modification of PVC materials, thereby expanding the potential applications of PVC materials. Additionally, we provide novel insights into constructing a hydrophilic surface based on bionic principles and expanding the potential applications of HBPL and pDA.

Pyridine-catalyzed ring-opening reaction of cyclopropenone with bromomethyl carbonyl compounds toward furan-2(5H)-ones.

We developed a pyridine-catalyzed annulation of diaryl cyclopropenone with bromomethyl carbonyl compounds leading to 5-carbonyl furan-2(5H)-ones. Pyridinium, derived from the reaction of bromomethyl carbonyl and pyridine, triggered the reaction by the inter-molecular Michael addition to cyclopropenone. This procedure was sensitive neither to air nor moisture and proceeded at room temperature with broad substrate scopes and good functional group tolerance in moderate-to-good yields. As such, it represents a facile and practical pathway leading to 5-carbonyl furan-2(5H)-one derivatives.

Bi(OTf)3-promoted cascade annulation of hydroxy-pyranones and unsaturated γ-ketoesters for the construction of polycyclic bridged pyrano-furopyranones.

An efficient protocol for constructing complex three dimensional polycyclic bridged chromano-furopyranones and pyrano-furopyranones (closely related to bioactive natural products) via bismuth(III)-catalyzed cascade annulation of hydroxy-pyranones and unsaturated γ-ketoesters is presented. This process involves intermolecular Michael addition, intramolecular hemiketalization, lactonization, formation of one C-C bond and two C-O bonds, rings, and contiguous stereocenters.

A Cascade Synthesis of Unsymmetrical Furanized Triarylmethanes via Gold Self-Relay Catalysis

In this paper, A new gold self-relay catalysis enabling intramolecular annulation and intermolecular Michael addition of 3-yne-1,2-diols with aurone-derived azadienes (or para-quinone methides) is reported, efficiently furnishing a range of unsymmetrical furanized triarylmethanes with substituent diversity in good yields. The overall process was governed by the π- and σ-Lewis acid capability of gold complexes, providing a catalytic strategy for constructing triarylmethane skeletons.

Total Synthesis of (+)-Pancratistatin and Its Potent Topo I Inhibition Activity Studies

As a preeminent anticancer natural product, (+)-pancratistatin has always been a privileged synthetic target. Herein, the total synthesis of (+)-pancratistatin is reported in 10 linear steps by utilizing a known aldehyde as chiral source. This synthetic route features a highly stereoselective intermolecular Michael addition and intramolecular Henry reaction to construct a cyclohexane ring bearing 6 successive stereocenters. Moreover, all of the synthetic steps are reliable and efficient and can be easily scaled up, which facilitated anticancer pharmacological tests of (+)-pancratistatin. Importantly, a new pharmacological mechanism of action was discovered for the first time where (+)-pancratistatin is able to inhibit the activity of topoisomerase I, which would pave the way for the development of new-type Topo I inhibitors.

Two independent and consecutive Michael addition of 1,3-dimethylbarbituric acid to (2,6-diarylidene)cyclohexanone: Flying-bird-shaped 2D-polymeric structure

Abstract Two independent and consecutive intermolecular Michael addition of 1,3-dimethylbarbituric acid to 2,6-diarylidenecyclohexanone as an α,β-unsaturated ketone leads to synthesis of a new type of meso form 5,5′-((2-oxocyclohexane-1,3-diyl)bis(arylmethylene))bis(1,3-dimethylpyrimidine-2,4,6(1H,3H,5H)-trione) in good yield. These compounds showed a 2D-polymeric structure via intermolecular H-bonds. Structure elucidation is carried out by 1H NMR, 13C NMR, FT-IR, and X-ray diffraction analyses. A plausible reaction mechanism is discussed.

Total Synthesis of (±)-Spiroaxillarone A via a Reversible Sulfa-Michael Addition.

A bioinspired strategy is described for the total synthesis of spiroaxillarone A, which exhibited significant antimalarial activity against resistant Plasmodium falciparum (IC50 = 2.32 μM). The key steps include an intermolecular ethanethiol Michael addition, o-quinone Michael addition, and subsequent β-ethanethiol elimination. This synthetic sequence provides a potential biosynthetic pathway of spiroaxillarone A.

Microwave assisted L‐proline catalyzed one‐pot three–component reaction for the synthesis of 4‐aminoaryl‐2‐phenyl‐2H‐3‐nitrochromene hybrid via Domino Michael‐Henry‐Michael addition reaction

AbstractA highly efficient oxidant free, microwave assisted L‐proline catalyzed one pot three‐component reaction has been developed for the synthesis of 4‐aminoaryl‐3‐nitro‐2H‐chromene using o‐hydroxy‐ω‐nitrostyrene, arylaldehyde and arylamine in DMSO solvent. This method involves the stepwise intermolecular Aza Michael addition, nitro‐enolate formation, Henry reaction and intramolecular Oxa‐Michael addition to produce the final product. Various controlled experiments were carried out and intermediates were characterized by ESI‐MS to support the possible reaction path for the formation of desired product. A wide range of substrates were well tolerated and the diverse range of 4‐(phenylamino)‐3‐nitro‐2‐phenyl‐2H‐chromenes have been synthesized in good‐to‐high yields at 80°C within 8–10 min.

Bifunctional Iminophosphorane-Catalyzed Enantioselective Sulfa-Michael Addition to Unactivated α,β-Unsaturated Amides

The first metal-free catalytic intermolecular enantioselective Michael addition to unactivated α,β-unsaturated amides is described. Consistently high enantiomeric excesses and yields were obtained over a wide range of alkyl thiol pronucleophiles and electrophiles under mild reaction conditions, enabled by a novel squaramide-based bifunctional iminophosphorane catalyst. Low catalyst loadings (2.0 mol %) were achieved on a decagram scale, demonstrating the scalability of the reaction. Computational analysis revealed the origin of the high enantiofacial selectivity via analysis of relevant transition structures and provided substantial support for specific noncovalent activation of the carbonyl group of the α,β-unsaturated amide by the catalyst.

Forrestiacids C and D, unprecedented triterpene-diterpene adducts from Pseudotsuga forrestii

Forrestiacids C (1) and D (2), a pair of C-25 epimeric triterpene–diterpene adducts were isolated from the needles and twigs of the vulnerable conifer Pseudotsuga forrestii. This unprecedented class of compounds might be generated via an intermolecular Michael addition reaction of a rearranged 6/6/5/5-fused spiro-lanostene with an abietene. Their structures were established by spectroscopic data and X-ray crystallography. The adducts showed inhibitory activities against the ATP-citrate lyase (ACL) and acetyl-CoA carboxylase 1 (ACC1), two rate-limiting enzymes in the de novo lipogenesis pathway.

Modular access to chiral cyclopentanes via formal [2+2+1] annulation enabled by palladium/chiral squaramide relay catalysis

An enantio- and diastereodivergent [2+2+1] annulation reaction of allyl ketones, acidic methylene compounds, and nitroalkenes to assemble highly functionalized cyclopentanes from readily available substances enabled by asymmetric relay catalysis of chiral bifunctional squaramide and palladium complex has been established. This method showcases that allyl ketones can serve as latent 1,2-dication synthons via a linear-selective allylic C–H functionalization and sequential 1,4-conjugated addition, enabling the rapid assembly of cyclopentane skeleton with a broad scope of methylene nucleophiles and nitroalkenes. Notably, chiral bifunctional squaramide catalyst engages in both the intermolecular and intramolecular Michael addition reactions accompanying with a kinetic resolution behavior to amplify the enantioselection. In addition, the stereodivergent synthesis of diastereomers from the resultant chiral cyclopentane derivatives is also accessible by a simple manipulation with base.

Intermolecular domino Michael/aldol reactions of α,β-unsaturated esters, aromatic aldehydes, and various nucleophiles promoted with a catalytic amount of a guanidine base in DMSO

In DMSO, a catalytic amount of Barton's base (2-t-butyl-1,1,3,3-tetramethylguanidine, BTMG) effectively catalyzed intermolecular three-component reactions of α,β-unsaturated esters, aldehydes, and carbon-, sulfur-, or nitrogen-pronucleophiles to give three-component addition products with the formation of two new σ-bonds: pronucleophiles and aldehydes reacted with α,β-unsaturated esters at their β-positions and α-positions, respectively. Mechanism studies suggested that these reactions proceeded by the first intermolecular Michael addition of anionic nucleophiles that were formed from pronucleophiles with a catalytic amount of BTMG, followed by intermolecular aldol reactions of transient ester enolates even in the presence of more than stoichiometric amounts of acidic pronucleophiles. High nucleophilicity over Brønsted basicity of transient enolates in polar solvents was observed for transient ester enolates rather than ketone enolates.

Bi(OTf)3 -catalyed One-pot Synthesis of α-Halo-β-amino Ketones and Acyl Aziridines from 3-Aryl Propargyl Alcohols.

A Bi(OTf)3 -catalyed reaction of 3-aryl propargyl alcohols with sulfonamide and halogen source was firstly investigated, which provided a facile route for the synthesis of a large variety of α-halo-β-amino ketones. The key intermediates, β-amino ketones, were obtained through tandem Meyer-Schuster rearrangement reaction of propargyl alcohols and intermolecular Michael addition of α, β-unsaturated ketones and sulfonamide. Then the in situ generated α-halo-β-amino ketones underwent the base-promoted intramolecular cyclization to give diverse acyl aziridines in a one-pot fashion. These transformations are reliable on a large scale. The high yields and convenient experimental operations make it a valuable method for the construction of α-halo-β-amino ketones and acyl aziridine derivatives.

Brønsted Base‐Catalyzed Formal Reductive [3+2] Annulation of 4,4,4‐Trifluorocrotonate and α‐Iminoketones

A formal reductive [3+2] annulation of 4,4,4-trifluorocrotonate and α-iminoketones was developed under Brønsted base catalysis. A single phosphazene base efficiently catalyzes the one-pot tandem reaction involving two mechanistically different elementary processes, namely the chemoselective reduction of an imine moiety of α-iminoketones with thiols as the reductant and the subsequent intermolecular Michael addition of an enolate of α-aminoketones concomitant with lactam formation. This operationally simple method provides β-trifluoromethyl-substituted γ-lactams with a tetrasubstituted carbon as a single diastereomer.

Lewis acid-promoted synthesis of highly substituted pyrrole-fused benzoxazinones and quinoxalinones

A synthesis of a series of novel fused tricyclic heterocyclic compounds has been achieved in one-pot reaction set up starting from (E)-3-(2-oxo-2-phenylethylidene)indolin-2-one and 1,4-benzoxazinone/quinoxalinone derivatives promoted by tin(IV) chloride. The reaction is supposed to occur via a sequential intermolecular Michael addition of the 1,4-benzoxazinone derivatives to the oxindoles, intramolecular cyclization, and aromatization with the elimination of water. Apart from spectroscopic characterization, the structure of one of the pyrrolo[1,4]benzoxazinone derivative is confirmed by single-crystal X-ray diffraction. Thus, the developed domino protocol provides easy access to multifunctional pyrrolo[1,4]benzoxazines in one-pot with high efficiency.

Protecting‐Group‐Directed Diastereoselective Synthesis of Substituted Tetrahydropyrroloquinolines

An efficient and protecting‐group‐directed highly diastereoselective (≥ 99:1) synthesis of tetrahydro‐3H‐pyrrolo[2,3‐c]quinolines bearing four contiguous chiral centers was achieved by using intermolecular Michael addition followed by intramolecular Mannich cyclization strategy. The domino reaction proceeded well with a broad scope of substrates under mild conditions and afforded the corresponding products in good to excellent yields. The synthetic protocol provided a straightforward synthetic route to tetrahydropyrroloquinolines as single diastereomers, which are difficult to synthesize by other methodologies.

A Silver‐Catalyzed Modular Intermolecular Access to 6,6‐Spiroketals

AbstractA modular synthesis of 6,6‐spiroketals via silver catalysis is reported. By combining an intermolecular Michael addition and a 6‐endo‐dig cyclization, this cascade reaction allows the modular preparation of highly substituted 6,6‐spiroketals by combining two substrate molecules. Established methods accessing this interesting substructure are complemented by this new transformation. The protocol tolerates diverse substitution patterns and functional groups.magnified image