Michael Cyclization Research Articles

Reagent-Controlled Regiodivergent Annulations of Achmatowicz Products with Vinylogous Nucleophiles: Synthesis of Bicyclic Cyclopenta[b]pyrans and 8-Oxabicyclo[3.2.1]octane Derivatives.

Two reagent-controlled regiodivergent annulation protocols for Achmatowicz products with vinylogous nucleophiles have been developed, which furnished a series of bicyclic cyclopenta[b]pyrans and 8-oxabicyclo[3.2.1]octane derivatives in 28-90% yields. Plausible mechanisms were proposed to involve either Pd-catalyzed Tsuji-Trost allyl-allyl coupling and concomitant Michael cyclization or quinine-promoted cascade stepwise [5 + 2] cycloaddition and intramolecular Michael cyclization.

Umpolung Chemo- and Regioselective Cascade Addition of Diethylzinc to α-Diketones Followed by Intramolecular Michael Reaction: Stereoselective Synthesis of Highly Substituted 1- Indanones.

Herein we report an efficient stereoselective umpolung 1,2-addition of Et2Zn onto α-diketones followed by intramolecular cascade Michael cyclization. This strategy effectively delivers a broad range of substituted 1-indanones in excellent yields in a chemo- and regioselective fashion. Additionally, we performed a variety of synthetic transformations on the 1-indanone products. Furthermore, a hitherto-unexplored asymmetric variant of this methodology that provides up to 94:6 er using an easily accessible cinchona alkaloid ligand has been addressed.

Cu(ii)-thiophene-2,5-bis(amino-alcohol) mediated asymmetric Aldol reaction and Domino Knoevenagel Michael cyclization: a new highly efficient Lewis acid catalyst.

The highly efficient Lewis acid-catalytic system Cu(ii)-thiophene-2,5-bis(amino-alcohol) has been developed for enantioselective Aldol reaction of isatin derivatives with ketones. The new catalytic system also proved to be highly enantioselective for the one pot three-component Domino Knoevenagel Michael cyclization reaction of substituted isatin with malononitrile and ethylacetoacetate. The chiral ligand (2S,2′S)-2,2′-((thiophene-2,5-diylbis(methylene))bis(azanediyl))bis(3-phenylpropan-1-ol) (L1) in combination with Cu(OAc)2·H2O employed as a new Lewis acid catalyst, furnished 3-substituted-3-hydroxyindolin-2-ones derivatives (3a–s) in good to excellent yields (81–99%) with high enantioselectivities (up to 96% ee) and spiro[4H-pyran-3,3-oxindole] derivatives (6a–l) in excellent yields (89–99%) with high ee (up to 95%). These aldol products and spiro-oxindoles constitute a core structural motif in a large number of pharmaceutically active molecules and natural products.

Synthesis of Chromeno[4,3-b]pyrrol-4(1H)-ones through a Multicomponent Reaction and Cyclization Strategy.

A novel three-component reaction of 2-oxo-2H-chromene-3-carbaldehydes with isocyanides and anilines was developed for one-pot assembly of biologically intriguing chromeno[4,3-b]pyrrol-4(1H)-ones, which can also be transferred into diverse polycyclic fused scaffolds through further synthetic manipulations. The described method tolerates a broad substrate scope and proceeds in moderate to good yield via a sequential multicomponent reaction and intramolecular Michael cyclization.

New 2-Oxopyridine/2-Thiopyridine Derivatives Tethered to a Benzotriazole with Cytotoxicity on MCF7 Cell Lines and with Antiviral Activities

Background:Perturbation of nucleic acids structures and confirmation by small molecules through intercalation binding is an intriguing application in anticancer therapy. The planar aromatic moiety of anticancer agents was inserted between DNA base pairs leading to change in the DNA structure and subsequent functional arrest.Objective:The final scaffold of the target compounds was annulated and linked to a benzotriazole ring. These new pharmacophoric features were examined as antiviral and anticancer agents against MCF7 and their effect on DNA damage was also assessed.Methods:A new series of fully substituted 2-oxopyridine/2-thioxopyridine derivatives tethered to a benzotriazole moiety (4a-h) was synthesized through Michael cyclization of synthesized α,β- unsaturated compounds (3a-e) with appropriate active methylene derivatives. The DNA damage study was assessed by comet assay. In silico DNA molecular docking was performed using Open Eye software to corroborate the experimental results and to understand molecule interaction at the atomic level.Results:The highest DNA damage was observed in Doxorubicin, followed by 4h, then, 4b, 4g, 4f, 4e, and 4d. The docking study showed that compound 4h formed Hydrogen Bonds (HBs) as a standard ligand with GSK-3. Compound 4h was the most active compound against rotavirus Wa, HAVHM175, and HSV strains with a reduction of 30%, 40%, and 70%, respectively.Conclusion:Compound 4h was the most active compound and could act as a prospective lead molecule for anticancer agent.

3D Heterocycles from Sulfonimidamides by Sequential C−H Bond Alkenylation/Aza‐Michael Cyclization

Starting from NH-sulfonimidamides, rhodium-catalyzed C-H bond alkenylation followed by aza-Michael cyclization leads to unprecedented benzoisothiazole 1-oxides. The applicability and robustness of the method is demonstrated in 25 examples with yields up to 95 %. The resulting scaffolds are partly saturated, 3D heterocycles with potential significance for medicinal and agricultural chemistry.

One‐Pot Knoevenagel–Michael–Cyclization Cascade Reaction for the Synthesis of Functionalized Novel 4H‐pyrans by Using ZnCl2 as a Catalyst

An expedient and cost‐effective protocol has been developed for the synthesis of novel 2‐methyl‐6‐(methylamino)‐5‐nitro‐4‐(4‐aryl)‐4H‐pyran‐3‐carboxylate derivatives. This domino, one‐pot, three‐component reaction was carried out between β‐ketoesters, aromatic aldehydes, and (E)‐N‐methyl‐1‐(methylthio)‐2‐nitroethenamine (NMSM) in the presence of 30 mol% anhydrous ZnCl2 under the neat condition at 120°C. The synthesized 4H‐pyran derivatives were characterized by spectroscopic techniques such as IR, 1H NMR, 13C NMR, CHNS, and HRMS. The molecular structure of compound methyl‐2‐methyl‐6‐(methylamino)‐5‐nitro‐4‐(4‐nitrophenyl)‐4H‐pyran‐3‐carboxylate 4a was confirmed by the single crystal X‐ray analysis. This solvent‐free protocol has several advantages such as shorter reaction time, an inexpensive catalyst, good yields, simple workup, and column‐free purification.

Nanomagnetically modified thioglycolic acid (γ‐Fe2O3@SiO2‐SCH2CO2H): Efficient and reusable green catalyst for the one‐pot domino synthesis of spiro[benzo[a]benzo[6,7]chromeno[2,3‐c]phenazine] and benzo[a]benzo[6,7]chromeno[2,3‐c]phenazines

Superparamagnetic nanoparticles of modified thioglycolic acid (γ‐Fe2O3@SiO2‐SCH2CO2H) represent a new, efficient and green catalyst for the one‐pot synthesis of novel spiro[benzo[a]benzo[6,7]chromeno[2,3‐c]phenazine] derivatives via domino Knoevenagel–Michael–cyclization reaction of 2‐hydroxynaphthalene‐1,4‐dione, benzene‐1,2‐diamines, ninhydrin and isatin. This novel magnetic organocatalyst was easily isolated from the reaction mixture by magnetic decantation using an external magnet and reused at least six times without significant loss in its activity. The catalyst was fully characterized using various techniques. This procedure was also applied successfully for the synthesis of benzo[a]benzo[6,7]chromeno[2,3‐c]phenazines.

Synthesis of spiropyran derivatives over 1-(carboxymethyl) pyridinium iodide as nanostructured pyridinium salt under aqueous media

In this work, acetic acid functionalized pyridinium salt, namely 1-(carboxymethyl)pyridinium iodide {[cmpy]I}, has been applied as reusable nanostructured catalyst for green, simple and efficient preparation of spiropyrans by the one-pot domino Knoevenagel–Michael–cyclization reaction of isatin derivatives or acenaphthenquinone, with malononitrile, and 1,3-dicarbonyl compounds under aqueous media. Moreover, 1H and 13C NMR, mass, CHN analysis, Fourier transform infrared spectroscopy (FTIR), scanning electron microscope (SEM), thermal gravimetric analysis (TGA), differential thermal gravimetric (DTG), X-ray diffraction analysis (XRD), and calculation of crystallite size and interplaner distance of the catalyst have been studied.

Michael Cyclization of Polarized Systems: Synthesis and in vitro Anti-Diabetic Evaluation of Some Novel Pyrimidine, Pyridine, Pyrazole and Pyrazolo[3,4-b ]pyridine Derivatives

Michael Cyclization of Polarized Systems: Synthesis and in vitro Anti-Diabetic Evaluation of Some Novel Pyrimidine, Pyridine, Pyrazole and Pyrazolo[3,4-b ]pyridine Derivatives

ChemInform Abstract: Organocatalytic Tandem Enantioselective Michael—Cyclization of Isatin‐Derived β,γ‐Unsaturated α‐Ketoesters with 3‐Hydroxy‐4H‐chromen‐4‐one or 2‐Hydroxy‐1,4‐naphthoquinone Derivatives.

The enantioselective formal [3 + 3] annulation reaction of isatin-derived β,γ-unsaturated α-ketoesters with 3-hydroxy-4H-chromen-4-ones or 2-hydroxy-1,4-naphthoquinone was successfully implemented under catalysis of quinine-derived bifunctional tertiary amine-thiourea catalysts. The efficient tandem Michael-cyclization has provided facile access to optically active spiro[oxindole-pyrano[3,2-b]chromenone] and spiro[oxindole-benzo[g]chromene-dione] derivatives in high yields with excellent diastereo- and enantioselectivities.

ChemInform Abstract: Organocatalytic Asymmetric Synthesis of trans‐Configured Trispirooxindoles Through a Cascade Michael‐Cyclization Reaction.

AbstractA novel stereoselective Michael cyclization reaction of cyclic methyleneindolinones and 3‐isothiocyanatooxindoles is presented furnishing chiral trispirooxindoles in good yield and enantioselectivities.

Regioselective synthesis of functionalized [1,6]-naphthyridines by KF/basic alumina as a recyclable catalyst and a brief study of their photophysical properties

ABSTRACTAn efficient, one-pot, solvent-free, regioselective synthesis of functionalized [1,6]-naphthyridines was explored by a heterogeneous catalyst via a three-component multicomponent reaction (MCR). KF/basic alumina–catalyzed double heteroannulation of aryl alkyl ketones, malononitrile, and alkyl amines generates the compounds with high appendage diversity combinatorially via Knoevenagel condensation followed by Michael addition and cyclization pathway. Short reaction time, high yield, simple reaction technique, and recoverability and reusability of the catalyst without compromising the yield and purity of the compounds are the salient features of this methodology. Additionally, these compounds exhibit promising photophysical properties.

ChemInform Abstract: Three‐Step Synthesis of Substituted Isochromenes.

AbstractA novel three‐step approach to substituted isochromenes consisting of Henry reaction, aerobic Wacker‐type oxidation, and intramolecular Michael cyclization is developed.

Three-step synthesis of substituted isochromenes

A synthetic route toward isochromenes 6, starting with aldehydes 3, in good to excellent yield is described herein. This novel approach was carried out by the Henry reaction of 3 with NH4OAc and nitroalkanes (MeNO2 or EtNO2), aerobic Wacker-type oxidation of the resulting nitroalkenes 4, followed by K2CO3-promoted intramolecular Michael cyclization in modest to good yields.

ChemInform Abstract: Enantioselective Synthesis of Bicyclo[3.n.1]alkanes by Chiral Phosphoric Acid‐Catalyzed Desymmetrizing Michael Cyclizations.

Abstractof 2,2‐disubstituted cyclic 1,3‐diketones containing a tethered electron‐deficient alkene

ChemInform Abstract: A Route to Benzo‐Annelated δ‐Sultams Through Michael Cyclization.

A new approach to benzo-annelated δ-sultams containing an aryl–nitrogen bond is described. The method, which involves the intramolecular Michael cyclization of tert-butyl ortho-[N-(methoxycarbonylmethyl)sulfonylamino]cinnamates, allows the synthesis of secondary sultams as well as their tertiary analogues and bridged tricyclic derivatives efficiently and diastereoselectively.

A Route to Benzo‐Annelated δ‐Sultams through Michael Cyclization

AbstractA new approach to benzo‐annelated δ‐sultams containing an aryl–nitrogen bond is described. The method, which involves the intramolecular Michael cyclization of tert‐butyl ortho‐[N‐(methoxycarbonylmethyl)sulfonylamino]cinnamates, allows the synthesis of secondary sultams as well as their tertiary analogues and bridged tricyclic derivatives efficiently and diastereoselectively.

Enantioselective synthesis of bicyclo[3.n.1]alkanes by chiral phosphoric acid-catalyzed desymmetrizing Michael cyclizations.

2,2-Disubstituted cyclic 1,3-diketones containing a tethered electron-deficient alkene undergo chiral phosphoric acid-catalyzed desymmetrizing Michael cyclizations to give bridged bicyclic products in high enantioselectivities. Both bicyclo[3.2.1]octanes and bicyclo[3.3.1]nonanes are accessible using this methodology.

Enantiodivergent strategy for the synthesis of polyhydroxylated pyrrolizidines and evaluation of their inhibitory activities against glycosidases

The enantiodivergent synthesis of polyhydroxylated pyrrolizidines has been achieved, starting from common intermediate 1. The synthesis involved the stereoselective construction of the pyrrolizidine core unit by using intramolecular Michael cyclization reaction as the key reaction. The synthesized eight isomers were evaluated for various glycosidase inhibition effects. Compound 15 showed a moderate inhibitory activity against α-l-fucosidase and a high selectivity compared from the other glycosidases.