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).     

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.     

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 2 mol % 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).     

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.     

Azirine/Oxindole Ring Enlargement via Amidinium Intermediates

A novel general method for the synthesis of oxindoles, namely the ‘azirine/oxindole ring enlargement via amidinium‐intermediates’ has been established: the reaction of 2H‐azirin‐3‐amines 1 with BF₃?OEt₂ in THF solution at ?78° leads to 1,3,3‐trialkyl‐2‐amino‐3H‐indolium tetrafluoroborates 14 in good yields (Scheme 5). Treatment of aqueous solutions of 14 at 0° with aqueous NaOH (30%) and extraction with CH₂Cl₂ gives oily substances that are either hydrates of 1,3,3‐trialkyl‐2‐dihydroindol‐2‐imines 15 or the corresponding indolium hydroxides. These products are transformed to the corresponding 1,3,3‐trialkyl‐2,3‐dihydroindol‐2‐ones 17 in modest yields upon refluxing in H₂O/THF. Reaction of 14 with Ac₂O in pyridine at ca. 23° for 16 h followed by aqueous workup and chromatographic separation leads to mixtures of N‐(1,3,3‐trialkyl‐2,3‐dihydro‐indol‐2‐yliden)acetamides 16 and oxindoles 17 (Scheme 6). Hydrolysis of 16 with aqueous HCl under reflux for 1–2 h gives oxindoles 17 in a good yield. Several oxindoles, spiro‐oxindoles, and 5‐substituted oxindoles were synthesized by means of the reactions mentioned above.     

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.     

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.     

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.     

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.     

Autoxidation/Aldol Tandem Reaction of 2‐Oxindoles with Ketones: A Green Approach for the Synthesis of 3‐Hydroxy‐2‐Oxindoles

In the presence of tetrabutylammonium fluoride and molecular sieves (MS) 4 Å in DMF, an efficient autoxidation reaction of 2‐oxindoles with ketones under air at room temperature has been developed. This approach may provide a green, practical, and metal‐free protocol for a wide range of biologically important 3‐hydroxy‐3‐(2‐oxo‐alkyl)‐2‐oxindoles.     

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.     

Palladium-catalyzed C-H functionalization of N-arylpropiolamides with aryliodonium salts: selective synthesis of 3-(1-arylmethylene)oxindoles

A selective and efficient method for the synthesis of 3-(1-arylmethylene)oxindoles by palladium-catalyzed C-H functionalization of anilides with aryliodonium salts has been developed. In the presence of Pd(OAc)2 and Et3N, a variety of anilides underwent the reaction with aryliodonium salts to afford the corresponding 3-(1-arylmethylene)oxindoles in moderate to good yields. It is noteworthy that the reaction can be conducted providing moderate yields even without bases. The mechanism of the reaction was also discussed.     

Organocatalytic Tandem Reaction to Construct Six‐Membered Spirocyclic Oxindoles with Multiple Chiral Centres through a Formal [2+2+2] Annulation

An efficient tandem reaction for the asymmetric synthesis of six‐membered spirocyclic oxindoles has been successfully developed through a formal [2+2+2] annulation strategy. The amine‐catalysed stereoselective Michael addition of aliphatic aldehydes to electron‐deficient olefinic oxindole motifs gave chiral C3 components, which were further combined with diverse electrophiles (activated olefins or imines) to afford spirocyclic oxindoles with versatile molecular complexity (up to six contiguous stereogenic centres, high diastereo‐ and enantioselectivities).     

Synthesis of 3,3-disubstituted oxindoles through Pd-catalyzed intramolecular cyanoamidation

The cyanoamidation of olefins was achieved. When N-(2-vinylphenyl)cyanoformamides were treated with palladium catalyst, intramolecular cyanoamidation took place to give corresponding 3,3-disubstituted oxindoles. P(t-Bu)₃ showed a remarkable effect on this reaction. When it was used with Pd(dba)₂, the reaction was completed in 15 min at 100 °C for many substrates. Furthermore, the enantioselective cyanoamidation was accomplished with Pd(dba)₂ and an optically active phosphoramidite to provide optically active 3,3-disubstituted oxindoles. Manipulation of the resulting oxindoles has been studied.     

A Direct CH/ArH Coupling Approach to Oxindoles,Thio‐oxindoles, 3,4‐Dihydro‐1 H‐quinolin‐2‐ones,and 1,2,3,4‐Tetrahydroquinolines

A copper(II)‐catalysed approach to oxindoles, thio‐oxindoles, 3,4‐dihydro‐1H‐quinolin‐2‐ones, and 1,2,3,4‐tetrahydroquinolines via formal C?H, Ar?H coupling is described. In a new variant, copper(II) 2‐ethylhexanoate has been identified as an inexpensive and efficient catalyst for this transformation, which utilises atmospheric oxygen as the re‐oxidant.     

Stereoselective synthesis of 3-spiro-α-methylene-γ-butyrolactone oxindoles from Morita-Baylis-Hillman adducts of isatin

A concise stereoselective synthesis of 3-spiro-α-methylene-γ-butyrolactone oxindoles from Morita-Baylis-Hillman adducts of isatin in excellent yield has been achieved following a three-step reaction sequences viz. (1) Isomerisation of the Morita-Baylis-Hillman adducts of isatin with trimethyl orthoformate and montmorillonite K10 clay catalyst, (2) a second Morita-Baylis-Hillman reaction with formaldehyde, and (3) an acid catalysed lactonization. The structure and stereochemistry of the products were assigned by X-ray crystallographic and NMR spectroscopic studies. Formation and mechanism of the minor product spirofuran oxindoles and a one-pot base promoted second Morita-Baylis-Hillman adduct formation-lactonization reaction have also been achieved.     

Diastereoselective synthesis of 3,3-disubstituted oxindoles from atropisomeric N-aryl oxindole derivatives

Diastereoselective synthesis of 3,3-disubstituted oxindoles has been examined by transformations involving nucleophilic addition, alkylation, and cycloaddition using chiral racemic N-aryl oxindoles bearing C–N axial chirality. The most striking features of this approach are high diastereoselectivities (up to >95:<5) when using ortho-monosubstituted N-aryl oxindoles and easy removal of the p-(benzyloxy)aryl moiety in the axially twisted amides by a mild two-step sequence.     

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.     

靛红Morita-Baylis-Hillman碳酸酯与环状N-磺酰亚胺的不对称烯丙基烷基化反应研究

本课题组近年来发展的通过路易斯碱催化靛红Morita-Baylis-Hillman(MBH)碳酸酯的烯丙基烷基化反应是合成光学纯3,3-二取代2-氧化吲哚化合物的一种有效方法. 在此基础上, 本文研究了手性叔胺催化靛红MBH碳酸酯与环状N-磺酰亚胺的不对称烯丙基烷基化反应, 通过亲电反应途径以较高的立体选择性(达86% ee, dr＞95∶5)和高收率(达96%)合成C-3位含季碳手性中心的多官能团氧化吲哚产物. 通过简单的转化可以得到含多个手性中心的2-吲哚酮-3,4'-哌啶环类骨架, 这为进一步合成生理活性物质研究奠定了基础.