3-substituted Oxindoles Research Articles

Assembly of Spirooxindole Derivatives via Organocatalytic Iminium-Enamine Cascade Reactions

The assembly of complex spirocyclopentaneoxindoles via a novel organocatalytic iminium-enamine cascade process is reported. Reactions between 3-substituted oxindoles and α,β-unsaturated aldehydes catalyzed by second generation prolinol ethers provided the desired products in high yield with excellent levels of enantioselectivity in a single step.

Organocatalytic Asymmetric Conjugate Addition of 3-Alkyl-Substituted Oxindoles to Vinyl Ketones

phosphate. 5 Although there have been reports for the catalytic enantioselective conjugate addition reaction of 3-aryl-substituted oxindoles to vinyl ketones, 5 a few examples for the catalytic enantioselective conjugate addition reaction of 3alkyl-substituted oxindoles to cyclic enones were reported using chiral primary or secondary amine catalysts. 6 Therefore, the development of alternative catalysts for the catalytic enantioselective conjugate addition reaction of 3-alkyl-substituted oxindoles to vinyl ketones would be highly desirable. As part of the research program toward the development of synthetic methods for the catalytic carbon-carbon bond formations, 7 we recently reported the organocatalytic conjugate addition reaction to α,β-unsaturated carbonyl compounds 8 and the other Michael acceptors. 9 In this communications, we wish to describe the enantioselective conjugate addition reaction of prochiral 3-alkyl-substituted oxindoles with vinyl ketones catalyzed by binaphthyl-modified bifunctional organocatalysts bearing both central and axial chiral elements. In an attempt to validate the feasibility of the organocatalytic enantioselective conjugate addition reaction of 3substituted oxindoles, we first investigated the reaction system with 3-benzyl oxindole 1a with methyl vinyl ketone (2a) in the presence of 10 mol % of catalyst in toluene at room temperature. We examined the impact of the structure of catalysts I-IV on enantioselectivities (Table 1, entries 1-4). Quinine-derived thiourea catalyst I was ineffective (Table 1, entriry 1). While binaphthyl-modified chiral bifunctional organocatalysts II-III bearing both central and axial chiral

Highly Enantioselective Fluorination of Unprotected 3-Substituted Oxindoles: One-Step Synthesis of BMS 204352 (MaxiPost)

The catalytic enantioselective fluorination of N-H-free 3-substituted oxindoles was accomplished by a Sc(III)/N,N'-dioxide complex. Under mild reaction conditions, a series of 3-aryl- and 3-alkyl-3-fluoro-2-oxindoles were obtained in excellent yields (up to 98%) and enantioselectivities (up to 99% ee) by using N-fluorobisbenzenesulfonimide (NFSI) as the fluorination agent. MaxiPost was synthesized efficiently in 81% yield with 96% ee.

Organocatalytic asymmetric Michael addition of unprotected 3-substituted oxindoles to 1,4-naphthoquinone

We reported the first example of organocatalytic Michael addition of unprotected 3-prochiral oxindoles 1 to 1,4-naphthoquinone. Quinidine derivative (DHQD)2PYR was found to be able to catalyze this reaction in up to 83% ee, with moderate to excellent yields. This method could be used for the synthesis of enantioenriched 3,3-diaryloxindoles, and the catalytic synthesis of which was unprecedented.

Enantioselective Organocatalyzed Sulfenylation of 3-Substituted Oxindoles

A highly enantioselective sulfenylation reaction with respect to 3-substituted oxindoles and electrophilic sulfur reagents by a quinidine catalyst was investigated.

ChemInform Abstract: Assembly of Spirooxindole Derivatives Containing Four Consecutive Stereocenters via Organocatalytic Michael—Henry Cascade Reactions.

A novel organocatalytic strategy for the synthesis of highly substituted spirocyclopentaneoxindoles was developed employing simple nitrostyrenes and 3-substituted oxindoles as starting materials. Michael-Henry cascade reactions, enabled through cinchona alkaloid organocatalysis, provided products in high yield and excellent enantioselectivity in a single step.

Squaramide-catalyzed diastereo- and enantioselective Michael addition of 3-substituted oxindoles to nitroalkenes

An efficient diastereo- and enantioselective Michael addition of 3-substituted oxindoles onto nitroalkenes catalyzed by a bifunctional chiral squaramide catalyst has been developed. This organocatalytic reaction with 2mol% of catalyst proceeded smoothly to afford 3,3-disubstituted oxindoles in high yields with good diastereoselectivities and enantioselectivities (up to 98:2 dr, 88% ee).

Organocatalytic Enantioselective Stereoablative Hydroxylation of 3‐Halooxindoles: An Effective Method for the Construction of Enantioenriched 3‐Substituted 3‐Hydroxy‐2‐Oxindoles

3-Substituted oxindoles as electrophilic partners: An unprecedented method for the construction of hydroxylated 3-substituted oxindoles in high yields and excellent enantioselectivities through stereoablative hydroxylation of 3-halooxindoles with an organocatalyst has been developed. This process not only differs from the common convention of using 3-substituted oxindoles as nucleophiles, but also provides a viable entry to optically active 3-substituted 3-hydroxy-2-oxindoles (see scheme).

Catalytic Asymmetric Sulfenylation of Unprotected 3-Substituted Oxindoles

Catalytic asymmetric sulfenylation of unprotected 3-substituted oxindoles has been developed via cooperative catalysis of a chiral N,N'-dioxide-Sc(OTf)(3) complex and a Brønsted base. Utilizing readily available N-(phenylthio)phthalimide as the sulfur source, a wide range of optically active 3-phenylthiooxindoles were obtained in excellent yields with excellent enantioselectivities under mild reaction conditions.

ChemInform Abstract: Recent Progress in Enantioselective Synthesis of C3‐Functionalized Oxindoles: Rare Earth Metals Take Action.

AbstractReview: 99 refs.

Assembly of Spirooxindole Derivatives Containing Four Consecutive Stereocenters via Organocatalytic Michael–Henry Cascade Reactions

A novel organocatalytic strategy for the synthesis of highly substituted spirocyclopentaneoxindoles was developed employing simple nitrostyrenes and 3-substituted oxindoles as starting materials. Michael-Henry cascade reactions, enabled through cinchona alkaloid organocatalysis, provided products in high yield and excellent enantioselectivity in a single step.

Chiral phosphine-catalyzed asymmetric allylic alkylation of 3-substituted benzofuran-2(3H)-ones or oxindoles with Morita–Baylis–Hillman carbonates

An efficient chiral phosphine-catalyzed asymmetric substitution reaction of MBH carbonates with 3-substituted benzofuran-2(3H)-ones or 3-substituted oxindoles has been described in this context, giving the corresponding allylic alkylation products bearing adjacent quaternary and tertiary stereogenic centers in high yields, moderate diastereoselectivities and high enantioselectivities under mild conditions.

Recent progress in enantioselective synthesis of C3-functionalized oxindoles: rare earth metals take action

The enantioselective synthesis of 3-functionalized oxindole derivatives has experienced an explosive development. This minireview introduces the recent application of rare earth (RE) metal complex catalysts in the synthesis of targeted frameworks. The direct addition reactions of 3-substituted oxindoles or isatins are described, together with a discussion of the catalytic mechanism and related transformations to pharmaceuticals.

Enantioselective organocatalytic oxyamination of unprotected 3-substituted oxindoles

An enantioselective α-oxyamination of unprotected 3-substituted oxindoles with nitrosobenzene catalyzed by tertiary amine-thiourea bifunctional organocatalysts has been developed and affords the corresponding 3-amino-2-oxindole derivatives in good yields and with moderate to excellent enantioselectivities (up to > 99.9 : 0.1 er when the product is isolated by direct filtration from the reaction mixture). The absolute configuration of the major enantiomers of the products has been established both by chemical correlation and by comparison between the theoretically calculated and the experimental ECD.

Iridium-catalyzed asymmetric hydrogenation of 3-substituted unsaturated oxindoles to prepare C3-mono substituted oxindoles

An efficient and enantioselective hydrogenation of 3-substituted unsaturated oxindoles has been developed by an iridium complex of tropos phosphine–oxazoline ligands. It is the first example to prepare chiral C3-mono substituted oxindoles via asymmetric catalysis. And the reaction provides instant access to this kind of compounds with excellent conversion and enantioselectivities (up to 93% ee).

Diastereo- and Enantioselective Conjugate Addition of 3-Substituted Oxindoles to Nitroolefins Catalyzed by a Chiral Ni(OAc)2-Diamine Complex under Mild Conditions

A simple catalyst system assembled from an enantiomerically pure diamine ligand and Ni(OAc)(2) efficiently generates chiral metal enolates derived from 3-substituted oxindoles bearing an N-1 carbonyl group. The enolates smoothly undergo diastereo- and enantioselective conjugate addition to a wide range of nitroolefins under mild reaction conditions, furnishing 3,3-disubstituted oxindole products bearing two vicinal quaternary/tertiary stereocenters in 74-95% yields and 60:40 to 99:1 dr, 71-97% ee.

ChemInform Abstract: Facile Synthesis of Enantioenriched Cγ‐Tetrasubstituted α‐Amino Acid Derivatives via an Asymmetric Nucleophilic Addition/Protonation Cascade.

AbstractBoth enantiomers of the target compounds [cf.

ChemInform Abstract: Chiral 1,2,3‐Triazoliums as New Cationic Organic Catalysts with Anion‐Recognition Ability: Application to Asymmetric Alkylation of Oxindoles.

Chiral 1,2,3-triazoliums have been designed, and the rational structural modification based on their unique anion-binding abilities has led to the establishment of the highly enantioselective alkylation of 3-substituted oxindoles.

Highly Enantioselective Conjugate Addition of 3-Substituted Oxindoles to Vinyl Sulfone Catalyzed by Binaphthyl-Modified Tertiary Amines

The enantioselective conjugate addition reaction of 3-substituted oxindoles with 1,1-bis(benzenesulfonyl)ethylene by binaphthyl-modified bifunctional organocatalysts was investigated. The corresponding Michael adducts, containing a quaternary center at C3 position of the oxindoles, were generally obtained in high yields with excellent enantioselectivities (up to 99% ee).

Construction of bispirooxindoles containing three quaternary stereocentres in a cascade using a single multifunctional organocatalyst

Single-step constructions of molecules with multiple quaternary carbon stereocentres are rare. The spirooxindole structural motif is common to a range of bioactive compounds; however, asymmetric synthesis of this motif is complicated due to the presence of multiple chiral centres. The development of organocatalytic cascade reactions has proven to be valuable for the construction of several chiral centres in one step. Here, we describe a newly designed organocatalytic asymmetric domino Michael-aldol reaction between 3-substituted oxindoles and methyleneindolinones that affords complex bispirooxindoles. This reaction was catalysed by a novel multifunctional organocatalyst that contains tertiary and primary amines and thiourea moieties to activate substrates simultaneously, providing extraordinary levels of stereocontrol over four stereocentres, three of which are quaternary carbon stereocentres. This new methodology provides facile access to a range of multisubstituted bispirocyclooxindole derivatives, and should be useful in medicinal chemistry and diversity-oriented syntheses of this intriguing class of compounds.