3-alkylidene Oxindoles Research Articles

Asymmetric (3 + 3) and (4 + 2) Annulation Reactions of 2,3-Dioxopyrrolidines with 3-Alkylidene Oxindoles to Construct Diverse Chiral Heterocyclic Frameworks.

Two substrate-controlled regiodivergent annulation protocols for 2,3-dioxopyrrolidines with 3-alkylidene oxindoles have been developed, which furnished a series of fused dihydropyrrolidone derivatives in high yields with excellent stereoselectivities. Plausible mechanistic pathways for both annulation reactions are proposed that [3 + 3] annulation reaction involves vinylogous Michael addition followed by intramolecular aldol cyclization, while [4 + 2] annulation reaction occurs through a vinylogous Michael addition and a subsequent intramolecular oxa-Michael cyclization.

Synthesis of Spiro[indoline-pyridine]-dicarboxylates and Substituted Alkylidene Oxindoles by Azomethine Ylides and MBH Carbonates of Isatins.

We have developed an efficient protocol for the synthesis of spiro[indoline-pyridine]dicarboxylates and substituted alkylidene oxindoles through [3 + 3] cycloaddition and Michael addition individually by azomethine ylides and various MBH carbonates of isatins. The selective generation of cyclic products and chain products was achieved by changing the substituents at the 3-position of the oxindoles. The features of this method include convenient catalysts, mild reaction conditions, and broad substrate scopes.

Light-Induced Generation and Cycloaddition Reactions of Benzyne: Synthesis of Naphthoxindoles E and Annulated Indolizines.

By virtue of their high electrophilic nature, benzynes serve as reactive dienophiles in numerous cycloaddition reactions. However, in situ generation of benzyne involves either base-mediated thermal reactions, low-temperature conditions, or metal-catalyzed reactions of substituted arenes. This limits the applicability of benzynes as suitable dipolarophiles in cycloaddition reactions. Herein, we have reported a UVA (365 nM)-induced in situ generation of benzynes (from triazenyl benzoic acid) and subsequently their [4 + 2] Diels-Alder and [3 + 2] cycloaddition reactions with appropriate reaction partners such as N-protected alkylidene oxindole carboxylates and pyridinium ylides to afford naphthoxindoles E and pyrido[2,1-a]isoindole, respectively, in moderate to excellent yield. The reactions occurred at room temperature and under reagent-free reaction conditions. Each of these building blocks is pharmaceutically relevant; hence, this highlights an interesting strategy to access these classes of compounds.

Organocatalytic Asymmetric Direct Vinylogous Michael Initiated Ring Closure Reaction of 4-Nitroisoxazole Derivatives to 3-Isopropylidene Oxindoles.

Herein, we present the first ever use of 3-isopropylidene oxindoles as electrophiles in vinylogous Michael initiated ring closure reaction (MIRC). Among the various alkylidene oxindoles used in enantioselective spirocyclization reactions, isopropylidene oxindoles are the least explored to date. The competing reactivity of isopropylidene oxindoles (electrophilicity vs nucleophilicity) in the presence of a chiral organocatalyst is controlled by the logical selection of a more reactive nucleophile. The methodology produces a library of densely substituted highly enantioenriched spirocyclopropyl oxindoles with excellent yield and stereoselectivities. Moreover, the first enantioselective synthesis of HIV-1 NNRT inhibitor indicates the importance of our synthesized spiro-cyclopropyl oxindole core.

Visible Light Promoted Metal‐Free Sustainable Reduction of α‐Alkylidene Oxindoles/Succinimides

AbstractVisible light promoted chemoselective metal free hydrogenation of activated double bond has been achieved via photoredox catalysis. Eosin Y has proved to be an efficient catalyst for the effective reduction of C−C double bonds of alkylidene oxindoles and succinimides under visible light. Commercially viable DIPEA has been employed as a sacrificial electron donor and it's in‐situ generated cationic radical acts as reductant in this transformation. The method proved to be practical as a broad range of substrates containing activated double bond were easily reduced. The method proved to be scalable on a gram quantity and the reduced product has been utilized successfully for the further synthetic application. The systematic and detailed mechanistic studies reveal the oxidative quenching of the photocatalyst by the activated double bond.

N-Iodosuccinimide-Promoted Selective Construction of Cyclopropyl and Dihydrofuranyl Spirooxindoles from Alkylidene Oxindoles and Annular β-Dicarbonyl Compounds

AbstractAn efficient N-iodosuccinimide-promoted cyclization of readily available alkylidene oxindoles with annular β-dicarbonyl compounds has been demonstrated. With five-membered cyclic β-dicarbonyl compounds as the starting materials, a series of cyclopropyl oxindoles can be obtained in good to excellent yields, whereas the method affords dihydrofuranyl spirooxindoles almost quantitatively when six- or seven-membered cyclic β-dicarbonyl compounds are employed. This protocol provides a new alternative to the practical synthesis of structurally diverse spirooxindoles.

Asymmetric organocatalytic Michael addition of cyclopentane-1,2-dione to alkylidene oxindole.

An asymmetric Michael reaction between cyclopentane-1,2-dione and alkylidene oxindole was studied in the presence of a multifunctional squaramide catalyst. Michael adducts were obtained in high enantioselectivities and in moderate diastereoselectivities.

Hydrogen-Bond-Donor-Directed Switching of Enantioselectivity in the Vinylogous Aldol-Cyclization Cascade Reaction of Prostereogenic 3-Alkylidene Oxindoles with Isatins and o-Quinones.

In this study, we reported a hydrogen-bond-donor-directed enantiodivergent vinylogous aldol-cyclization cascade reaction of 3-alkylidene oxindoles with isatins and o-quinones. Both enantiomers can be prepared by thiourea or squaramide cinchona alkaloid bifunctional organocatalysts with the same quinine scaffold. Kinetic study data provided the possible reaction mechanism for the vinylogous aldol-cyclization cascade reaction. The DFT calculation data showed the geometry of the generated dienolates from pronucleophiles dominated the observed switch of enantioselectivity.

Enantioselective Organocatalytic Three-Component Vinylogous Michael/Aldol Tandem Reaction among 3-Alkylidene oxindoles, Methyleneindolinones, and Aldehydes.

We reported a one-pot enantioselective three-component vinylogous Michael/aldol tandem reaction of prochiral 3-alkylidene oxindoles with methyleneindolinones and aldehydes using bifunctional organocatalysts. A variety of enantioenriched 3,3-disubstituted oxindoles 3 and spirolactones 4 were generated in moderate yields (up to 78%) with high stereoselectivities (up to >20:1 dr, >99% ee). Intriguingly, we observed that the aldol reaction with paraformaldehyde generates 3,3-disubstituted oxindoles 3 bearing a hydroxymethyl group, while the reaction with aliphatic aldehydes generates spirolactones 4.

Diastereoselective trans Cyclopropanation of 3-Alkylidene Oxindoles with In Situ Generated α-Diazo Carbonyls or α,β-Unsaturated Diazo Compounds

AbstractAn efficient diastereoselective trans cyclopropanation of 3-alkylidene oxindoles with in situ generated α-diazo carbonyl compounds or α,β-unsaturated diazo compounds under metal-free conditions has been developed to synthesize 3-spirocyclopropyl-2-oxindole derivatives. The procedure is based on the 1,3-dipolar character of the corresponding diazo compounds under base-catalyzed conditions. The method has a wide substrate scope and uses easily available starting materials.

Enantioselective vinylogous aldol reaction of acylphosphonates with 3-alkylidene oxindoles.

A simple strategy for yielding chiral tertiary α-hydroxy phosphonates that integrates two highly biologically relevant scaffolds namely 3-alkylidene-2-oxindoles and phosphonates has been described. The hydrogen bonding ability of the bifunctional thiourea catalyst allows simultaneous dual activation of a vinylogous oxindole nucleophile and an acylphosphonate electrophile, affording hydroxyphosphonato-3-alkylidene-2-oxindoles as aldol adducts in high yields (up to 92%) with excellent stereocontrol (up to 99% ee).

Predicting the origin of selectivity in NHC-catalyzed ring opening of formylcyclopropane: a theoretical investigation

Using density functional theory, we investigated the origin of selectivity in the N-heterocyclic carbene (NHC)-catalyzed transformation of formylcyclopropane with an alkylidene oxindole.

Enantioselective organocatalytic vinylogous aldol-cyclization cascade reaction of 3-alkylidene oxindoles with o-quinones.

Spirocyclic o-quinone analogues show a broad spectrum of applications as biologically active compounds. We herein report the chiral bifunctional squaramide catalysed asymmetric vinylogous aldol-cyclization cascade reaction between 3-alkylidene oxindoles and o-quinones. A wide range of enantioenriched spirocyclic o-quinone analogues with a quaternary stereocenter could be smoothly synthesized in good to excellent yields (up to 99%) with high enantioselectivities (up to 99%).

Enantioselective Construction of Spirooxindole‐Fused Cyclopenta[c]chromen‐4‐ones Bearing Five Contiguous Stereocenters via a Stepwise (3+2) Cycloaddition

AbstractThe bifunctional quinine‐catalyzed stepwise (3+2) cycloaddition for the enantioselective construction of spirooxindole‐fused cyclopenta[c]chromen‐4‐ones is developed. The reactions of 3‐homoacylcoumarins and alkylidene oxindole electrophiles generate aforementioned spirooxindole‐chromenone adducts bearing five contiguous stereocenters, of which one is the spiro all‐carbon quaternary stereocenter in high yields (up to 99%) with excellent stereoselectivities (up to >20:1 dr and 99% ee). This methodology was investigated for three different alkylidene oxindole electrophiles and could also be practically demonstrated on a gram scale. Mechanistic investigations revealed that the (3+2) cycloaddition for the enantioselective synthesis of spirooxindole‐fused cyclopenta[c]chromen‐4‐ones is proceeding via a stepwise reaction pathway.magnified image

Enantioselective Synthesis of Trifluoromethyl α,β-Unsaturated δ-Lactones via Vinylogous Aldol-Lactonization Cascade.

The novel vinylogous aldol-lactonization cascade of alkylidene oxindole with trifluoromethyl ketones is presented. The reaction, catalyzed by a bifunctional tertiary amine, provides an efficient application of the vinylogous reactivity of alkylidene oxindoles for the preparation of enantioenriched trifluoromethylated α,β-unsaturated δ-lactones.

Synthesis of 2-Mercapto-(2-Oxoindolin-3-Ylidene)Acetonitriles from 3-(4-Chloro-5H-1,2,3-Dithiazol-5-Ylidene)Indolin-2-ones.

Alkylidene oxindoles are important functional moieties and building blocks in pharmaceutical and synthetic chemistry. Our interest in biologically active compounds focused our studies on the synthesis of novel oxindoles, bearing on the exocyclic double bond at the C8, CN, and S groups. Extending the potential applications of Appel’s salt, we developed a new synthetic approach by investigating the reactions of C5-substituted 2-oxindoles with 4,5-dichloro-1,2,3-dithiazolium chloride (Appel’s salt) to give original (Z)-3-(4-chloro-5H-1,2,3-dithiazol-5-ylidene)indolin-2-one derivatives, and new 2-mercapto-(2-oxoindolin-3-ylidene)acetonitriles via a dithiazole ring-opening reaction. The work described in this article represents further applications of Appel’s salt in the conception of novel heterocyclic rings, in an effort to access original bioactive compounds. Fifteen new compounds were prepared and fully characterized.

Asymmetric vinylogous aldol addition of alkylidene oxindoles on trifluoromethyl-α,β-unsaturated ketones.

A novel vinylogous aldol addition of alkylidene oxindole with 1-trifluoromethyl-3-alkylidene-propan-2-ones is presented. The reaction, catalyzed by a bifunctional tertiary amine, provides an efficient application of the vinylogous reactivity of oxindoles for the preparation of enantioenriched trifluoromethylated allylic alcohols.

Part I: Diastereoselective Reactions Involving β‐Mono‐ and β,β′‐Disubstituted Alkylidene Oxindoles: Pondering Alkene Geometry

AbstractDiastereoselective reactions supported by metals and nonmetals offer a multifaceted path for the synthesis of robust intermediates of value to academia and industry. The reactions that involve mono‐ and disubstituted electron‐rich and electron‐deficient olefins offer facile construction of stereogenic carbon centers. Recent advances in the development of methods and an understanding of the chemistry of oxindoles has led to approaches that provide high levels of facial control, regiocontrol and diastereoselectivity. Part I of this focus review is devoted to the chemistry of β‐monosubstituted alkylidene oxindoles. Herein, we discuss reports made over the last decade of diastereoselective reactions that involve oxindole‐containing trisubstituted alkenes, which lead to the generation of stereogenic centers and the formation carbocyclic and heterocyclic skeletons.

Part II: Diastereoselective Reactions Involving β‐Mono‐ and β,β′‐Disubstituted Alkylidene Oxindoles: Pondering Alkene Geometry

AbstractPart II encompasses synthetic efforts towards the construction of acyclic and cyclic structures that contain carbon and heteroatoms by employing diastereoselective reactions of β,β′‐disubstituted alkylidene oxindole as the primary substrate. In addition to the construction of acyclic structures, carbocyclic and heterocyclic rings that contain three‐, five‐, six‐, and seven‐membered spirocycles or fused‐rings are also described. A few examples of the arylative cyclization of dienes have also been presented.

A Tunable and Enantioselective Hetero-Diels-Alder Reaction Provides Access to Distinct Piperidinoyl Spirooxindoles.

The 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.