3-alkylidene Oxindoles Research Articles

A Tunable and Enantioselective Hetero‐Diels–Alder Reaction Provides Access to Distinct Piperidinoyl Spirooxindoles

AbstractThe active complexes of chiral N,N′‐dioxide ligands with dysprosium and magnesium salts catalyze the hetero‐Diels–Alder reaction between 2‐aza‐3‐silyloxy‐butadienes and alkylidene oxindoles to selectively form 3,3′‐ and 3,4′‐piperidinoyl spirooxindoles, respectively, in very high yields and with excellent enantioselectivities. The exo‐selective asymmetric cycloaddition successfully regaled the construction of sp3‐rich and highly substituted natural‐product‐based spirooxindoles supporting many chiral centers, including contiguous all‐carbon quaternary centers.

Enantioselective Vinylogous Michael-Michael Cascade Reactions of 3-Alkylidene Oxindoles and Nitroolefin Enoates.

A novel bifunctional squaramide catalyzed vinylogous Michael-Michael cascade reaction of 3-alkylidene oxindoles with nitroolefin enoates was developed. This convenient, one-pot cascade reaction serves as a powerful tool for the enantioselective construction of potential bioactive chiral chromans, which have three continuous tertiary stereocenters, in moderate to good yields (up to 85%) with excellent stereoselectivities (up to >19:1 dr and >99% ee).

Biocatalysed olefin reduction of 3-alkylidene oxindoles by baker's yeast

3-Substituted oxindoles are very interesting molecules both for their potential biological activity and for their role as starting materials toward more complex oxindole-based structures. These molecules can be prepared by the reduction of a 3-ylidene oxindole precursor by classical metal-catalysed chemical reductions of the olefin. In this work we present a biocatalytic approach for the reduction of oxindole-based olefins using baker's yeast. All the substrates were efficiently reduced in high yields. When an α,β-unsaturated ketone was used, the corresponding saturated alcohol was obtained in high yield and ee. To further investigate the enzyme-substrate interactions a molecular docking study was also performed.

Enantioselective Organocatalyzed Vinylogous Michael Reactions of 3-Alkylidene Oxindoles with Enals.

An efficient asymmetric vinylogous Michael addition of 3-alkylidene oxindoles and enals has been achieved using a chiral TBS-protected diphenylprolinol catalyst. The γ-substituted alkylidene oxindoles obtained bear a chiral tertiary center and are afforded in moderate to good yields and good to excellent enantioselectivities.

Solvent-free iodine-promoted synthesis of 3,2'-pyrrolinyl spirooxindoles from alkylidene oxindoles and enamino esters under ball-milling conditions.

A novel solvent-free iodine-promoted cyclization of alkylidene oxindoles with enamino esters via C-C/C-N bond formation has been demonstrated under ball-milling conditions. This protocol provides efficient and green access to a variety of 3,2'-pyrrolinyl spirooxindoles with remarkable functional group tolerance, good yields and excellent diastereoselectivities.

ChemInform Abstract: An Asymmetric Assembly of Spirooxindole Dihydropyranones Through a Direct Enantioselective Organocatalytic Vinylogous Aldol‐Cyclization Cascade Reaction of 3‐Alkylidene Oxindoles with Isatins.

A highly enantioselective organocatalytic vinylogous aldol-cyclization cascade reaction of 3-alkylidene oxindoles to isatins has been achieved by using bifunctional organocatalysts. The unexpected intramolecular lactonization which follows the initial aldol reaction, leading to the cleavage of the oxindole ring and generation of enantioenriched spirooxindole dihydropyranones in good to excellent yields with high enantioselectivities.

An asymmetric assembly of spirooxindole dihydropyranones through a direct enantioselective organocatalytic vinylogous aldol-cyclization cascade reaction of 3-alkylidene oxindoles with isatins.

A highly enantioselective organocatalytic vinylogous aldol-cyclization cascade reaction of 3-alkylidene oxindoles to isatins has been achieved by using bifunctional organocatalysts. The unexpected intramolecular lactonization which follows the initial aldol reaction, leading to the cleavage of the oxindole ring and generation of enantioenriched spirooxindole dihydropyranones in good to excellent yields with high enantioselectivities.

Scandium triflate-catalyzed selective ring opening and rearrangement reaction of spiro-epoxyoxindole and carbonyl compounds

Scandium triflate-catalyzed reactions between spiro-epoxyoxindole and carbonyl compounds have been disclosed. Furthermore, an unprecedented rearrangement takes place to yield alkylidene oxindoles when aromatic aldehydes are used as carbonyl components.

Stereochemical implications in the synthesis of 3,3′-spirocyclopropyl oxindoles from β-aryl/alkyl-substituted alkylidene oxindoles

3,3′-Spirocyclopropane oxindoles were synthesized in good to excellent yield and diastereoselectivity employing a Kukhtin–Ramirez reaction between readily accessible E-alkylidene oxindoles, commercially available P(NMe2)3, and α-keto esters. The stereoselectivity in the cyclopropanation event can be traced to the starting alkylidene geometry and the propensity of the exocyclic alkene to undergo isomerization in the presence of an electron rich phosphine.

ChemInform Abstract: Direct Asymmetric Vinylogous Michael Addition of 3‐Alkylidene Oxindoles to Chalcones Catalyzed by a Chiral N,N′‐Dioxide Ytterbium(III) Complex.

A chiral ytterbium(III)–N,N′-dioxide catalyst system has been developed for the catalytic direct asymmetric vinylogous Michael addition of 3-alkylidene oxindoles to chalcones, delivering the γ-substituted alkylideneoxindoles in high yields, enantioselectivities and good Z/E selectivities under mild reaction conditions.

Direct asymmetric vinylogous Michael addition of 3-alkylidene oxindoles to chalcones catalyzed by a chiral N,N'-dioxide ytterbium(III) complex.

A chiral ytterbium(III)-N,N'-dioxide catalyst system has been developed for the catalytic direct asymmetric vinylogous Michael addition of 3-alkylidene oxindoles to chalcones, delivering the γ-substituted alkylideneoxindoles in high yields, enantioselectivities and good Z/E selectivities under mild reaction conditions.

An asymmetric allylic alkylation reaction of 3-alkylidene oxindoles.

An efficient asymmetric allylic alkylation reaction with respect to 3-alkylidene oxindoles and racemic Morita-Baylis-Hillman carbonate has been achieved by using a chiral biscinchona alkaloid catalyst, which delivers the γ-substituted alkylideneoxindoles with a chiral tertiary center in moderate to good yields (up to 92%) and very good enantioselectivities (up to >99% ee).

Titanium(IV)-catalyzed stereoselective synthesis of spirooxindole-1-pyrrolines.

A stereoselective cyclization between alkylidene oxindoles and 5-methoxyoxazoles has been developed using catalytic titanium(IV) chloride (as low as 5 mol %) to afford spiro[3,3′-oxindole-1-pyrrolines] in excellent yield (up to 99%) and diastereoselectivity (up to 99:1). Using a chiral scandium(III)–indapybox/BArF complex affords enantioenriched spirooxindole-1-pyrrolines where a ligand-induced reversal of diastereoselectivity is observed. This methodology is further demonstrated for the synthesis of pyrrolines from malonate alkylidene and coumarin derivatives.

Organocatalytic asymmetric vinylogous Michael addition of 3-alkylidene oxindoles to α-substituted β-nitroacrylates: facile construction of a chiral all-carbon quaternary center

A highly enantioselective vinylogous Michael addition reaction of 3-alkylidene oxindoles to α-substituted β-nitroacrylates has been developed by using a cinchona alkaloid-squaramide bifunctional organocatalyst, which provides a series of chiral products bearing all-carbon quaternary stereocenters in excellent yields with high enantioselectives (up to 97%).

ChemInform Abstract: Catalytic Asymmetric Tamura Cycloadditions.

AbstractThe novel designed squaramide‐based catalyst (I) promotes the highly enantioselective Tamura cycloaddition of enolizable anhydrides with alkylidene oxindoles.

Catalytic enantioselective carboannulation with allylsilanes.

The first catalytic asymmetric carboannulation with allylsilanes is presented. The enantioselective [3+2] annulation is catalyzed using a scandium(III)/indapybox complex with tetrakis-[3,5-bis(trifluoromethyl)phenyl]-borate (BArF) to enhance catalytic activity and control stereoselectivity. Functionalized cyclopentanes containing a quaternary carbon center are derived from alkylidene oxindole, coumarin, and malonate substrates with high stereoselectivity. The enantioselective 1,4-conjugate addition and enantioselective lactone formation (by trapping of the β-silyl carbocation) is also described.

Catalytic Asymmetric Tamura Cycloadditions

In the presence of a novel, tert-butyl-substituted squaramide-based catalyst, enolizable anhydrides react with alkylidene oxindoles to generate spirooxindole products of significant synthetic interest with excellent enantio- and diastereocontrol. The methodology is of wide scope and encompasses both homophthalic and glutaconic anhydride derivatives, which lead to structurally diverse products. Glutaconic acid-derived anhydrides undergo a clean post-cyclization decarboxylation process which is not a feature of reactions involving homophthalic acid-derived anhydrides. The unusual influence of reaction temperature on diastereocontrol has been probed, with reactions occurring at 30 °C and -30 °C delivering products epimeric at one stereocenter only, in near optical purity.

Catalytic Asymmetric Tamura Cycloadditions

AbstractIn the presence of a novel, tert‐butyl‐substituted squaramide‐based catalyst, enolizable anhydrides react with alkylidene oxindoles to generate spirooxindole products of significant synthetic interest with excellent enantio‐ and diastereocontrol. The methodology is of wide scope and encompasses both homophthalic and glutaconic anhydride derivatives, which lead to structurally diverse products. Glutaconic acid‐derived anhydrides undergo a clean post‐cyclization decarboxylation process which is not a feature of reactions involving homophthalic acid‐derived anhydrides. The unusual influence of reaction temperature on diastereocontrol has been probed, with reactions occurring at 30 °C and −30 °C delivering products epimeric at one stereocenter only, in near optical purity.

ChemInform Abstract: Asymmetric Organocatalytic Synthesis of Spiro‐cyclopropaneoxindoles.

AbstractA wide range of spiro‐cyclopropaneoxindoles is prepared via organocatalytic cyclopropanation of alkylidene oxindoles or α,β‐unsaturated aldehydes.

Asymmetric Synthesis of Congested Spiro-cyclopentaneoxindoles via an Organocatalytic Cascade Reaction

Starting from simple alkylidene oxindoles and nitroketones, a highly stereoselective methodology was developed for the synthesis of spiro-cyclopentaneoxindoles with four consecutive stereogenic centers. Using an organocatalytic cascade of Michael and aldol reactions in the presence of a chiral thiourea catalyst products were obtained in moderate to high yields and excellent enantioselectivities. Nitro, ester, and hydroxyl groups were introduced to the spiro ring, which could be used to facilitate further functionalization of the products.