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).     

New Routes to Oxindole Derivatives

A new, practical synthesis of the antirheumatic oxindole derivative, tenidap, has been elaborated. The new approach has initiated studies on the mechanism of the acylation reactions of oxindoles. Methods have been developed for the synthesis of 1-[alkoxy(or aryloxy)carbonyl]- and 1,3-di[alkoxy(or aryloxy)carbonyl]oxindoles starting from oxindoles. The route designed for tenidap has provided a facile access to several analogues, too.On another front, new reaction conditions are described, which turn Wenkerts synthesis of 3-alkyloxindoles (by Raney nickel induced alkylation of oxindoles with alcohols) into a highly efficient synthetic tool. The method has been extended to the synthesis of 3-alkyloxindoles from isatins and to the preparation of 3-(-hydroxyalkyl)oxindoles from oxindoles and isatins.     

New Routes to Oxindole Derivatives

Summary. A new, practical synthesis of the antirheumatic oxindole derivative, tenidap, has been elaborated. The new approach has initiated studies on the mechanism of the acylation reactions of oxindoles. Methods have been developed for the synthesis of 1-[alkoxy(or aryloxy)carbonyl]- and 1,3-di[alkoxy(or aryloxy)carbonyl]oxindoles starting from oxindoles. The route designed for tenidap has provided a facile access to several analogues, too.On another front, new reaction conditions are described, which turn Wenkerts synthesis of 3-alkyloxindoles (by Raney nickel induced alkylation of oxindoles with alcohols) into a highly efficient synthetic tool. The method has been extended to the synthesis of 3-alkyloxindoles from isatins and to the preparation of 3-(-hydroxyalkyl)oxindoles from oxindoles and isatins.     

A Metal‐free Approach to 3‐Aryl‐3‐hydroxy‐2‐oxindoles by Treatment of 3‐Acyloxy‐2‐oxindoles with Diaryliodonium Salts

A mild, metal‐free approach has been realized for the facile construction of highly valuable 3‐(hetero)aryl‐3‐hydroxy‐2‐oxindoles. Direct arylations of 3‐acyloxy‐2‐oxindoles with diaryliodonium salts as arylation reagents are implemented in the presence of K₂CO₃ at room temperature without using an organometallic promoter to deliver an array of 3‐(hetero)aryl‐3‐hydroxy‐2‐oxindoles in good yields.     

Transition‐metal‐free Chemoselective Oxidative C−C Coupling of the sp3 C−H Bond of Oxindoles with Arenes and Addition to Alkene: Synthesis of 3‐Aryl Oxindoles,and Benzofuro‐ and Indoloindoles

A transition‐metal (TM)‐free and halogen‐free NaOt Bu‐mediated oxidative cross‐coupling between the sp³ C−H bond of oxindoles and sp² C−H bond of nitroarenes has been developed to access 3‐aryl substituted and 3,3‐aryldisubstituted oxindoles in DMSO at room temperature in a short time. Interestingly, the sp³ C−H bond of oxindoles could also react with styrene under TM‐free conditions for the practical synthesis of quaternary 3,3‐disubstituted oxindoles. The synthesized 3‐oxindoles have also been further transformed into advanced heterocycles, that is, benzofuroindoles, indoloindoles, and substituted indoles. Mechanistic experiments of the reaction suggests the formation of an anion intermediate from the sp³ C−H bond of oxindole by tert ‐butoxide base in DMSO. The addition of nitrobenzene to the in‐situ generated carbanion leads to the 3‐(nitrophenyl)oxindolyl carbanion in DMSO which is subsequently oxidized to 3‐(nitro‐aryl) oxindole by DMSO.     

Reactions of Hydroxyazolidines with π-Donor Heterocycles. 3. Reaction of 1-Acetyl-5-hydroxypyrazolidines with Oxindoles

The reaction of oxindoles with 5-hydroxypyrazolidines on the surface of potassium fluoride-modified alumina leads to 3-(5-pyrazolidinyl)oxindoles. The structure of these products was studied.     

Eco‐friendly Polyethylene Glycol‐400 as a Rapid and Efficient Recyclable Reaction Medium for the Synthesis of Anticancer Isatin‐linked Chalcones and Their 3‐Hydroxy Precursor

Isatin chalcones and their 3‐hydroxy precursors are shown to possess potential anticancer activity and are also versatile substrates and key intermediates for the synthesis of a large variety of bioactive spiro‐oxindoles. An environmental friendly tandem synthesis, using PEG 400 as green solvent cum phase transfer catalyst, for a series of 3‐hydroxy‐2‐oxindoles and 3‐methylene‐2‐oxindoles has been developed. Reported one‐pot sustainable synthetic strategy was compared with the conventional method and was found to be superior to existing two‐step syntheses in terms of simplicity, product yield, and reaction time and have a large substrate scope.     

A [3+2] dipolar cycloaddition route to 3-hydroxy-3-alkyl oxindoles: an approach to pyrrolidinoindoline alkaloids

A [3 + 2] cycloaddition approach to the 3-hydroxy-3-alkyl oxindole scaffold is described. Isoxazolines obtained by cycloaddition of nitrile oxide 3 with 3-methylene oxindoles were elaborated to 3-hydroxy-3-cyanomethyl oxindoles employing a one-pot protocol en route to the pyrrolidinoindoline moiety which is found in many natural products. The total syntheses of alkaloids (±)-alline and (±)-CPC-1 were achieved using this methodology.     

Enantioselective Michael addition of 3-aryl-substituted oxindoles to methyl vinyl ketone catalyzed by a binaphthyl-modified bifunctional organocatalyst

The enantioselective conjugate addition reaction of 3-aryl-substituted oxindoles with methyl vinyl ketone promoted by binaphthyl-modified bifunctional organocatalysts was investigated. The corresponding Michael adducts, containing a quaternary center at the C3-position of the oxindoles, were generally obtained in high yields with excellent enantioselectivities (up to 91% ee).     

FeIII‐Catalyzed Cross‐Dehydrogenative Arylation (CDA) between Oxindoles and Arenes under an Air Atmosphere

An efficient Fe^III‐catalyzed cross‐dehydrogenative arylation (CDA) of 3‐substituted oxindoles with activated arenes under an air atmosphere was developed to provide 3,3′‐disubstituted oxindoles in good yields.     

Stereoselective oxidative rearrangement of 2-aryl tryptamine derivatives

The oxidation of 2-aryl tryptamines followed by a stereoselective rearrangement provides a versatile strategy for the synthesis of C3-quaternary oxindoles bearing a C3-aryl group. Treatment of optically active 2-aryl hydroxyindolenines with scandium trifluoromethanesulfonate in toluene at 110 degrees C leads to complete and stereoselective isomerization to the corresponding C3-aryl oxindoles which represent versatile intermediates for the synthesis of C3a-aryl hexahydropyrroloindoles.     

Vinylogous N,N-dimethylaminomethylenation of 3-[(1-substituted)ethylidene]-oxindoles with N,N-dimethylformamide dimethylacetal

An efficient stereoselective synthesis of various 3-(3-dimethylaminoprop-2-enylidene)oxindoles has been disclosed. The compounds were synthesized via a vinylogous N,N-dimethylaminomethylenation at the γ-position of 3-[(1-substituted)ethylidene]oxindoles with DMF-DMA.     

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).     

Two new stereochemically complementary oxindole synthesis

Two routes have been developed for the conversion of ketones to oxindoles in the general sense (3 → 4); with norbornanone, the two routes gave different oxindoles (22 and 4).     

Organocatalytic Asymmetric Conjugate Addition of 3‐Monosubstituted Oxindoles to (E)‐1,4‐Diaryl‐2‐buten‐1,4‐diones: A Strategy for the Indirect Enantioselective Furanylation and Pyrrolylation of 3‐Alkyloxindoles

An asymmetric conjugate addition of 3‐monosubstituted oxindoles to a range of (E)‐1,4‐diaryl‐2‐buten‐1,4‐diones, catalyzed by commercially available cinchonine, is described. This organocatalytic asymmetric reaction affords a broad range of 3,3′‐disubstituted oxindoles that contain a 1,4‐dicarbonyl moiety and vicinal quaternary and tertiary stereogenic centers in high‐to‐excellent yields (up to 98 %), with excellent diastereomeric and moderate‐to‐high enantiomeric ratios (up to 99:1 and 95:5, respectively). Subsequently, cyclization of the 1,4‐dicarbonyl moiety in the resultant Michael adducts under different Paal–Knorr conditions results in two new kinds of 3,3′‐disubstituted oxindoles—3‐furanyl‐ and 3‐pyrrolyl‐3‐alkyl‐oxindoles—in high yields and good enantioselectivities. Notably, the studies presented here sufficiently confirm that this two‐step strategy of sequential conjugate addition/Paal–Knorr cyclization is not only an attractive method for the indirect enantioselective heteroarylation of 3‐alkyloxindoles, but also opens up new avenues toward asymmetric synthesis of structurally diverse 3,3′‐disubstituted oxindole derivatives.     

Synthesis of oxindoles via visible light photoredox catalysis

2-Electron-withdrawing-group-substituted 2-bromoanilides can be converted to the corresponding 3,3-disubstituted oxindoles with high efficiency under visible light irradiation by using fac-Ir(ppy)(3) as the photoredox catalyst. This protocol is suitable for the synthesis of oxindoles with chloro and bromo atoms attached to the phenyl ring.     

Organocatalytic enantioselective tandem Michael addition-oxidation of 3-substituted oxindoles with 1,4-benzoquinone

By employing a chiral bifunctional thiourea-tertiary amine as catalyst, enantioselective tandem Michael addition-oxidation of 3-monosubstituted oxindoles with 1,4-benzoquinones were realized. The reactions afforded a wide range of 3,3-disubstituted oxindoles with moderate to good yields (up to 87%) in moderate to good enantioselectivities (up to 96%).     

Iron-catalyzed carbonylation–arylation of N-arylacrylamides for synthesis of oxindole derivatives

An efficient method for oxindole synthesis is established by iron-catalyzed carbonylation–arylation of N-arylacrylamides with aldehydes. 3-Functionalized oxindoles are synthesized smoothly using FeCl₃ as catalyst and TBHP as oxidant. The obtained oxindoles can be used for further transformations to give diverse indole alkaloid structure motifs.     

Palladium‐Catalyzed Carbonylative α‐Arylation of 2‐Oxindoles with (Hetero)aryl Bromides: Efficient and Complementary Approach to 3‐Acyl‐2‐oxindoles

An efficient Pd‐catalyzed carbonylative α‐arylation of 2‐oxindoles with aryl and heteroaryl bromides for the one‐step synthesis of 3‐acyl‐2‐oxindoles has been developed. This reaction proceeds efficiently under mild conditions and is complementary to the more common oxindole forming reactions. The transformation only requires a mild base and provides good to excellent yields even with heteroaromatic substrates. Employing a near stoichiometric amount of ¹³COgen, the methodology was easily extended to [¹³C] acyl labeling. The general applicability of the reaction conditions was demonstrated in the synthesis of a structure related to the pharmaceutically active 3‐acyl‐2‐oxindoles, tenidap.     

CU2O-Catalyzed C(SP3)-H/C(SP3)-H Cross-Coupling Using TEMPO: Synthesis of 3-(2-Oxoalkyl)-3-hydroxyoxindoles

A simple, convenient, and efficient oxidative cross-coupling reaction of oxindoles with ketones toward a variety of 3-(2-oxoalkyl)-3-hydroxyoxindoles in moderate to excellent yields has been developed. This transformation proceeds via a tandem oxidative cross-coupling by using 2,2,6,6-tetramethylpiperidine N-oxyl (TEMPO) in air as an environmentally benign oxidant. This methodology provides an alternative approach for the direct generation of all-carbon quaternary centers at the C3 position of oxindoles.